PMID- 26632117 TI - Museum of Failed HIV Research. PMID- 26632118 TI - Diving bradycardia of elderly Korean women divers, haenyeo, in cold seawater: a field report. AB - The purpose of the present field study was to explore diving patterns and heart rate of elderly Korean women divers (haenyeo) while breath-hold diving in cold seawater. We hypothesized that the decreasing rate in heart rate of elderly haenyeos during breath-hold diving was greater and total diving time was shorter than those of young haenyeos from previous studies. Nine haenyeos participated in a field study [68 +/- 10 yr in age, ranged from 56 to 83 yr] at a seawater temperature of 10 to 13 degrees C. Average total diving time including surface swimming time between dives was 253 +/- 73 min (155-341 min). Total frequency of dives was 97 +/- 28 times and they dived 23 +/- 8 times per hour. All haenyeos showed diving bradycardia with a decreased rate of 20 +/- 8% at the bottom time (101 +/- 20 bpm) when compared to surface swimming time (125 +/- 16 bpm) in the sea. Older haenyeos among the nine elderly haenyeos had shorter diving time, less diving frequencies, and lower heart rate at work (p<0.05). These reductions imply that haenyeos voluntarily adjust their workload along with advancing age and diminished cardiovascular functions. PMID- 26632119 TI - Sharp injuries in Japanese operating theaters of HIV/AIDS referral hospitals 2009 2011. AB - The aim of this study was to identify how doctors and nurses experienced sharps injuries in operating rooms and the risks for these injuries by analyzing data from 78 Japanese hospitals participating in the nationwide EPINet surveillance system. The years of professional experience of the cases were classified into tertiles separately for doctors and nurses. Suture needles accounted for 54.9% of injuries in doctors and 48.3% of injuries in nurses. Among doctors, injuries occurred most frequently during the use of an item (range: 58.1-64.3%), while among nurses, injuries occurred most frequently (range: 24.7-29.0%) between steps of a multi-step procedure. The frequency of injury by a suture needle held by someone else was 41.1-47.3% (range) among doctors, and 27.0-48.1% (range) among nurses. In conclusion, sharps injuries in the operating room need to address the circumstances of injury and holder of devices based on the specific risk for doctors and nurses to decrease the number of injuries. PMID- 26632120 TI - Moderating effects of salivary testosterone levels on associations between job demand and psychological stress response in Japanese medical workers. AB - Levels of job stress have been shown to be inversely associated with testosterone levels, but some inconsistent results have been documented. We investigated the moderating effects of testosterone levels on associations between job stress factors and psychological stress responses in Japanese medical workers. The participants were 63 medical staff (20 males and 43 women; mean age: 30.6 years; SD=7.3) in Okayama, Japan. Their job-stress levels and psychological stress responses were evaluated using self-administered questionnaires, and their salivary testosterone collected. Multiple regression analyses showed that job demand was positively associated with stress responses in men and women. An interaction between testosterone and support from colleagues had a significant effect on depression and anxiety for women. In women with lower testosterone levels, a reducing effect of support from colleagues on depression and anxiety was intensified. In women with higher testosterone levels, depression and anxiety levels were identical regardless of support from colleagues. Testosterone may function as a moderator between perceived work environment and psychological stress responses for female medical workers. PMID- 26632121 TI - Hazard of ultraviolet radiation emitted in gas tungsten arc welding of aluminum alloys. AB - Ultraviolet radiation (UVR) emitted during arc welding frequently causes keratoconjunctivitis and erythema. The extent of the hazard of UVR varies depending on the welding method and conditions. Therefore, it is important to identify the levels of UVR that are present under various conditions. In this study, we experimentally evaluated the hazard of UVR emitted in gas tungsten arc welding (GTAW) of aluminum alloys. The degree of hazard of UVR is measured by the effective irradiance defined in the American Conference of Governmental Industrial Hygienists guidelines. The effective irradiances measured in this study are in the range 0.10-0.91 mW/cm(2) at a distance of 500 mm from the welding arc. The maximum allowable exposure times corresponding to these levels are only 3.3-33 s/day. This demonstrates that unprotected exposure to UVR emitted by GTAW of aluminum alloys is quite hazardous in practice. In addition, we found the following properties of the hazard of UVR. (1) It is more hazardous at higher welding currents than at lower welding currents. (2) It is more hazardous when magnesium is included in the welding materials than when it is not. (3) The hazard depends on the direction of emission from the arc. PMID- 26632122 TI - Letter writing: Reviving the lost art. PMID- 26632123 TI - Sympathetic ophthalmitis following vitreoretinal surgery: Does antecedent trauma make a difference? AB - BACKGROUND: Sympathetic ophthalmitis (SO) has been reported following vitrectomy; however, there is a lack of data on the role of antecedent penetrating ocular trauma impacting the disease manifestation in eyes developing SO following vitrectomy. AIM: To report differences in the presentation and outcomes of SO in eyes with or without a history of antecedent penetrating trauma; SO being diagnosed after vitreoretinal (VR) surgery. DESIGN: Comparative case series. METHODS: Seventeen consecutive patients presenting with SO following VR surgery, diagnosed between 1995 and 2011 were included. Eyes with and without prior penetrating injury were included in Group I (n = 7) and Group II (n = 10), respectively. All Group I patients had received systemic steroids prior to presentation. Demographic and clinical parameters were evaluated. RESULTS: Differences were observed between Group I and Group II mainly with regards to time interval between VR surgery and diagnosis of SO (1.5 months vs. 8 months, P = 0.10), presence of neurosensory detachments (100% vs. 30%, P = 0.01), and the inciting eye vision at presentation (nil light perception in 28.5% vs. 80%, P = 0.049). Other differences observed though not statistically significant were optic disc and retinal vessel involvement (42% vs. 70%, P = 0.28), Dalen-Fuchs nodules (localized vs. diffuse) and leaks on fundus fluorescein angiography (pin head vs. pin-point leak). CONCLUSION: SO in patients with antecedent penetrating ocular trauma present early with the central serous chorioretinopathy-like picture. Prior use of systemic steroids might have a bearing on the differences in presentation and the visual acuities between the two groups. PMID- 26632124 TI - Clinical outcomes of pars plicata anterior vitrectomy: 2-year results. AB - PURPOSE: To demonstrate the safety and outcome of a surgical approach that uses pars plicata site for anterior vitrectomy during phacoemulsification procedure complicated by posterior capsule rupture and residual cortical matter. DESIGN: Single center, retrospective, interventional, noncomparative study. MATERIALS AND METHODS: Medical records of a consecutive series of 35 eyes of 35 patients who underwent pars plicata anterior vitrectomy (PPAV) were reviewed. The main outcome measures were corrected and uncorrected distance visual acuity (CDVA, UDVA), early and late postoperative complications and intraocular pressure (IOP). Ultrasound biomicroscopic (UBM) evaluation of sclerotomy site and spectral domain optical coherence tomography analysis for central macular thickness (CMT) was performed. The final visual outcome at 2 years was evaluated. RESULTS: At 2 years follow-up, the mean postoperative UDVA (logarithm of the minimum angle of resolution [logMAR]) and CDVA (logMAR) was 0.49 +/- 0.26 and 0.19 +/- 0.14, respectively. There was no significant change in the IOP (P = 0.061) and the mean CMT at 2 years was 192.5 +/- 5.54 mm. The postoperative UBM image of the sclerotomy site at 8 weeks demonstrated a clear wound without any vitreous adhesion or incarceration. Intraoperative hyphema was seen in 1 (2.8%) case and postoperative uveitis was seen in 2 (5.7%) cases, which resolved with medications. No case of an iatrogenic retinal break or retinal detachment was reported. CONCLUSIONS: PPAV enables a closed chamber approach, allows thorough cleanup of vitreous in the pupillary plane and anterior chamber and affords better access to the subincisional and retropupillary cortical remnant with a significant visual outcome and an acceptable complication rate. PMID- 26632125 TI - Effects of dexmedetomidine for retrobulbar anesthesia in orbital ball implants after enucleation surgery. AB - BACKGROUND: Dexmedetomidine (DEX) can prolong the duration of local anesthetics, but the use of retrobulbar DEX has not been fully elucidated. This study was designed to determine the effects of adding DEX to lidocaine-bupivacaine for retrobulbar block in orbital ball implants after enucleation surgery. MATERIALS AND METHODS: A total of 200 patients of both sexes aged 30-60 years of American Society of Anesthesiologists I and II, scheduled for orbital ball implants after enucleation surgery, were enrolled for the study. Patients were randomly assigned into one of the two groups: Control (n = 100) received lidocaine-bupivacaine retrobulbar block, DEX (n = 100) received lidocaine-bupivacaine plus 1 ug/kg DEX retrobulbar block. Hemodynamic data, duration of motor and sensory blocks, pain by visual analog scale, bispectral index (BIS), side effects, consumption of dezocine as a rescue analgesic, patient and surgeon satisfaction were recorded. RESULTS: Duration of analgesia was prolonged in the DEX, compared with the control group ([258.35 +/- 66.82 min] as [130.75 +/- 29.52 min], [P < 0.05]). The median number of postoperative analgesic requests per patient during the first 24 h was decreased in the DEX group (P < 0.05). In the first 24 postoperative hours, DEX group consumed significantly less dezocine (P < 0.05). BIS values and mean arterial pressure remained lower in the DEX group, but within the safe range (P < 0.05). The side effect profile was similar between the two groups. Patients and surgeon satisfaction were higher in the DEX group (P < 0.05). Demographic characteristics were comparable in both groups (P > 0.05). CONCLUSION: Retrobulbar DEX reduces consumption of rescue analgesic, prolonged the duration of retrobulbar block, improved postoperative pain, provided better sedation effects, and increased patient and surgeon satisfaction after orbital ball implants after enucleation surgery. PMID- 26632126 TI - Ocular abnormalities in multi-transfused beta-thalassemia patients. AB - AIMS: The aim of this study was to assess ocular changes in thalassemia patients who have received multiple transfusions and chelate binding therapy in order to avoid iron accumulation. SETTINGS AND DESIGN: A cross-sectional study. SUBJECTS AND METHODS: A total of 54 thalassemia major patients were selected as case group, and 54 age- and sex-matched healthy subjects were regarded as a control group. Ocular examination included visual acuity, refraction testing, slit lamp examination, funduscopy, tonometry, perimetry, tear break-up time test, and color vision testing were performed for all the participants. We computed the frequency and duration of blood transfusion, the mean serum ferritin level, pretransfusion hemoglobin concentration, and type, duration, and daily dose of chelation therapy for thalassemia patients based on their records. STATISTICAL ANALYSIS USED: All data analysis was performed using SPSS, version 19. RESULTS: All the thalassemic patients were asymptomatic, but abnormal ocular findings (dry eye (33.3%), cataract (10.2%), retinal pigment epithelium degeneration (16.7%), color vision deficiency (3.7%), and visual field defects (33.7%)) were seen in 68.5% of thalassemic group. The prevalence of ocular abnormalities in normal group was 19.4%, which was significantly lower than that in thalassemia patients (P = 0.000). No significant correlation was found between ocular abnormalities and mean serum ferritin level (P = 0.627) and mean hemoglobin concentration (P = 0.143). Correlation of number of blood transfusion with the presence of ocular abnormalities was found to be statistically significant (P = 0.005). CONCLUSIONS: As life expectancy for beta-thalassemia patients extends, regular ophthalmological evaluation to detect early changes in their ocular system is recommended. PMID- 26632127 TI - Comparing sports vision among three groups of soft tennis adolescent athletes: Normal vision, refractive errors with and without correction. AB - BACKGROUND: The effect of correcting static vision on sports vision is still not clear. AIM: To examine whether sports vision (depth perception [DP], dynamic visual acuity [DVA], eye movement [EM], peripheral vision [PV], and momentary vision [MV],) were different among soft tennis adolescent athletes with normal vision (Group A), with refractive error and corrected with (Group B) and without eyeglasses (Group C). SETTING AND DESIGN: A cross-section study was conducted. Soft tennis athletes aged 10-13 who played softball tennis for 2-5 years, and who were without any ocular diseases and without visual training for the past 3 months were recruited. MATERIALS AND METHODS: DPs were measured in an absolute deviation (mm) between a moving rod and fixing rod (approaching at 25 mm/s, receding at 25 mm/s, approaching at 50 mm/s, receding at 50 mm/s) using electric DP tester. A smaller deviation represented better DP. DVA, EM, PV, and MV were measured on a scale from 1 (worse) to 10 (best) using ATHLEVISION software. STATISTICAL ANALYSIS: Chi-square test and Kruskal-Wallis test was used to compare the data among the three study groups. RESULTS: A total of 73 athletes (37 in Group A, 8 in Group B, 28 in Group C) were enrolled in this study. All four items of DP showed significant difference among the three study groups (P = 0.0051, 0.0004, 0.0095, 0.0021). PV displayed significant difference among the three study groups (P = 0.0044). There was no significant difference in DVA, EM, and MV among the three study groups. CONCLUSIONS: Significant better DP and PV were seen among soft tennis adolescent athletes with normal vision than those with refractive error regardless whether they had eyeglasses corrected. On the other hand, DVA, EM, and MV were similar among the three study groups. PMID- 26632128 TI - Comparability and repeatability of pachymetry in keratoconus using four noncontact techniques. AB - PURPOSE: To compare and determine the repeatability of central corneal thickness (CCT) measurements using four noncontact pachymetry instruments in eyes with keratoconus. MATERIALS AND METHODS: The CCT of consecutive patients with keratoconus was measured during a single visit using the swept source optical coherence tomography (SS-OCT, Casia SS-1000 degrees CT, Tomey, Nagoya, Japan), a rotating Scheimpflug camera system (Pentacam, Oculus Optikgerate GmbH, Wetzlar, Germany), scanning slit topographer (Orbscan IIz topography, Baush and Lomb Surgical Inc., San Dimas, CA, USA), and a hand-held spectral domain OCT (HHSD OCT, Bioptigen Inc., Durham, North Carolina, USA). Test-retest variability, correlation between measurements and interdevice agreement were analyzed. RESULTS: Fifty eyes of 25 participants were analyzed in this study. All measurement methods correlated well with each other (r > 0.9, P < 0.001). Mean +/ standard deviation CCT measured by HHSD-OCT, Orbscan IIz, SS-OCT, and Pentacam was 462 +/- 41 mm, 458 +/- 41 mm, 454 +/- 40 mm, and 447 +/- 42 mm, respectively. While the HHSD-OCT over-estimated the CCT (P < 0.001), there was a good correlation between the measurements obtained from the other three devices. However, the numerical difference was high and this trend was seen in all the paired comparisons. CONCLUSIONS: Though the measurements by different devices correlated well, the numerical agreement may be inadequate for their interchangeable use in clinical practice. PMID- 26632129 TI - Successful delayed treatment of the traumatic orbital apex syndrome by nasal endoscopic decompression surgery. AB - To report a patient with traumatic orbital apex syndrome, who fully recovered visual and extraocular function following surgery. A 34-year-old male presented with visual and extraocular function disorders in his right eye following traffic accident, who was referred to our hospital 5 weeks after accident. The patient underwent endoscopic optic nerve and orbital apex decompression with topical and systemic application of nerve growth factor and steroids after a failed trial of mega-dose intravenous corticosteroids. Visual acuity improved to 20/20 at 3 weeks after surgery, and the right eye globe moved in most directions at 1 year, which remained stable at 3 years. Surgical decompression should be considered even when symptoms have been present for over a month. PMID- 26632130 TI - Comparing two acromegalic patients with respect to central corneal thickness, intraocular pressure, and tear insulin-like growth factor levels before and after treatment. AB - The aim of the study was to compare the central corneal thickness (CCT), intraocular pressure (IOP), and tear insulin-like growth factor-1 (IGF-1) levels of 2 patients with acromegaly before and after the surgical treatment of the disease. CCTs, IOP levels, and tear IGF-1 values showed a decrease after the treatment in 2 patients. As we found higher CCT, IOP, and tear IGF-1 levels in the active phase of the disease in two acromegaly patients, detailed information about the activity of the disease may be important before the examination of these patients. PMID- 26632131 TI - Herpes zoster ophthalmicus presenting as orbital abscess along with superior orbital fissure syndrome: A case report. AB - Orbital abscess and superior orbital fissure syndrome (SOFS) are rare manifestations of herpes zoster ophthalmicus. Herein, we report a case of orbital abscess along with SOFS in a 2.5-year-old-male child secondary to herpes zoster infection. He presented with a 5-day history of proptosis and ptosis of the right eye that had been preceded by vesicular eruptions on the right forehead and scalp. Computed tomography scan of the head and orbit showed orbital abscess and right cavernous sinus thrombosis. A diagnosis of orbital abscess with SOFS secondary to herpes infection was made. The condition subsequently improved following antiviral therapy, intravenous vancomycin and amikacin, and oral corticosteroids. PMID- 26632132 TI - The changing patterns of uveitis in a tertiary institute of Northeast India. AB - Uveitis incorporates innumerable conditions, all of which are characterized by inflammation of the uveal tract. Study of etiological factors in uveitis in the population often give important disease-specific indications and changing pattern in subsequent studies are important to know further newer occurrences of various disease prevalence. Awareness of regional variation in disease configuration is essential to develop a region specific list of differential diagnoses and also for comparison with different sub-population of the country and the world. We report the changing pattern of uveitis in a tertiary institute in the Northeast India and found that tubercular uveitis had increased in hospital-based study. PMID- 26632133 TI - Unusual presentation of ocular trauma in sickle cell trait. AB - Sickle cell trait is usually considered as a benign condition. However under certain adverse circumstances, it can give rise to vaso-occlusive features as in sickle cell disease. We present here two cases, both involving healthy young males, who developed retinal vaso-occlusive features following blunt ocular trauma. There was a rapid progression of the retinopathy with the development of proliferative changes in both patients and also vitreous hemorrhage in one patient, within 2 months of the trauma. The development of retinopathy was independent of raised intraocular pressure. Both patients were found to have sickle cell trait. PMID- 26632134 TI - Prenatal genetic diagnosis of retinoblastoma--clinical correlates on follow-up. AB - Retinoblastoma is the most common malignant intraocular tumor in pediatric age group if undetected leads to ocular mortality. Prenatal diagnosis is an emerging technology to detect fatal diseases in utero such that subsequent management is planned to reduce the ocular morbidity. We describe a case demonstrating the importance of prenatal diagnosis in a child with a strong family history of retinoblastoma and importance of a long-term clinical follow-up in these cases. PMID- 26632135 TI - The effect of phacoemulsification surgery on intraocular pressure and anterior segment anatomy of the patients with cataract and ocular hypertension. AB - We evaluated the effect of phacoemulsification surgery on intraocular pressure (IOP), anterior chamber depth (ACD), iridocorneal angle (ICA), and central corneal thickness (CCT) of the patients with cataract and ocular hypertension. The decrease in IO P values of the 1 st week, 1 st month, 3 rd month, 6 th month, and 1 st year was statistically significant, but that of the 2 nd year was not significant. The increase in ACD and ICA values of the 1 st week, 1 st month, 3 rd month, 6 th month, and 1 st year was statistically significant, but that of the 2 nd year was not significant. The increase in CCT values of 1 st week and 1 st month was statistically significant, but those of 3 rd month, 6 th month, 1 st year, and 2 nd year were not significant. In conclusion, phacoemulsification surgery decreases IOP and increases ACD and ICA in the short-term. However, in the long-term it does not cause any significant changes. PMID- 26632136 TI - Orbital apex osteodural fistula--An unusual surgical access. AB - Dural arteriovenous fistulas (DAVFs) are fistulas connecting the branches of dural arteries to dural veins or a venous sinus. Osteodural fistulas are a rare subset of this group of diseases. We wish to report a rare case of an osteodural arteriovenous fistula at the foot of the superior ophthalmic vein (SOV), treatment of which required an unusual surgical approach via the orbit and SOV. Though access for endovascular treatment via the SOV for treatment of caroticocavernous fistulas is reported, the external approach is relatively infrequently performed, outside Europe and the Americas, with this being the first reported procedure from the Indian subcontinent. We wish to explain the steps of this unusual surgical access and highlight the salient precautions and pitfalls in the technique. PMID- 26632137 TI - Could Crocus sativus (saffron) be combined with conventional therapies for ocular diseases? PMID- 26632138 TI - Comment on: Intravitreal ziv-aflibercept for recurrent macular edema secondary to central retinal venous occlusion. PMID- 26632139 TI - Tests for color vision deficiency: Is it time to revise the standards? PMID- 26632140 TI - The question of causation and adequacy-iron as an example of intrinsic toxicity and other effects. PMID- 26632141 TI - Treatment of a Neglected Syndesmotic Injury Using a Unique Method of Reduction. AB - Syndesmotic injuries are challenging in diagnosis and management as delays in treating the injury lead to poorer functional outcomes. In this case report, we discuss management of an untreated Maisonneuve fracture. To our knowledge, our technique of using a composite braided suture with internal buttons fixed from the talus to the medial malleolus to supplement our syndesmotic repair has not previously been described. PMID- 26632142 TI - Determination of trace levels of triazines in corn matrices by bar adsorptive microextraction with a molecularly imprinted polymer. AB - This manuscript addresses the determination of triazines (ametryn, atrazine, simazine, and terbutryn) in corn matrices using bar adsorptive microextraction coated with a selective molecularly imprinted polymer phase following microliquid desorption and high-performance liquid chromatography with diode array detection. The molecularly imprinted polymer was synthesized using atrazine as a template and methacrylic acid as a functional monomer. Assays performed in 25 mL of ultrapure water samples spiked at 8.0 MUg/L yielded 80-120 % recoveries under the evaluated experimental conditions. The method showed an accuracy (0.2 < bias < 17.9%), precision (relative standard deviation <17.4%), convenient detection (0.2 MUg/L), and quantification (0.7 MUg/L) limits, as well as linear dynamic ranges (0.8-24.0 MUg/L) with remarkable determination coefficients (R(2) > 0.9926). The proposed analytical method was applied to monitor triazines in three types of corn matrices using the standard addition methodology. Experiments performed in corn samples spiked with triazines at the trace level (8.0 MUg/kg of each analyte) gave rise to recoveries (81.0-119.4%) with good reproducibility and robustness. The proposed methodology is also easy to implement and showed to be a good analytical alternative to monitor triazines in complex matrices, when compared with other sorption-based microextraction techniques. PMID- 26632143 TI - Biochemical properties of Bacillus Calmette Guerin ribonuclease III. AB - Double-stranded RNA (dsRNA) is discovered to participate in the regulation of gene expression in both bacterial and eukaryotic cells. Members of ribonuclease III (RNase III) family recognize RNA motifs and cleave substrates at specific sites in a divalent-metal-ion-dependent manner. In this study, we find the RNase III from Bacillus Calmette Guerin (BCG-RNase III) cleaves small hairpin RNA based on the conserved stem structure associated with Mycobacterium 16S ribosomal RNA precursor at specific sites which are not determined. To evaluate the influence of remnant endogenous ribonucleases from expression host on RNA cleavage assays for RNase III, we use E44A and D48A mutant of the enzyme to perform RNA cleavage assays and find that remnant ribonucleases have no effect on cleavage assays. The RNA cleavage activity of the enzyme can be supported by Mg(2+), Mn(2+), and Co(2+) and enhanced with the increasing salt concentration. The catalytic activity of the enzyme is exhibited when the temperature of the reaction buffer ranges from 30 to 55 degrees C and the pH of the buffer from 7.0 to 10.0. Two major cleavage sites in RNA substrate are identified using RNA Ligase Mediated Rapid Amplification of cDNA Ends (RLM-RACE). PMID- 26632144 TI - Exercise for Men with Prostate Cancer: A Systematic Review and Meta-analysis. AB - CONTEXT: Exercise could be beneficial for prostate cancer survivors. However, no systematic review across cancer stages and treatment types addressing potential benefits and harms exists to date. OBJECTIVE: To assess the effects of exercise on cancer-specific quality of life and adverse events in prostate cancer trials. EVIDENCE ACQUISITION: We searched the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, AMED, CINAHL, PsycINFO, SPORTDiscus, and PEDro. We also searched grey literature databases, including trial registers. Searches were from database inception to March 2015. Standardised mean differences (SMDs) were calculated for meta-analysis. EVIDENCE SYNTHESIS: We included 16 randomised controlled trials (RCTs) involving 1574 men with prostate cancer. Follow-up varied from 8 wk to 12 mo. RCTs involved men with stage I-IV cancers. A high risk of bias was frequently due to problematic intervention adherence. Seven trials involving 912 men measured cancer-specific quality of life. Pooling of the data from these seven trials revealed no significant effect on this outcome (SMD 0.13, 95% confidence interval [CI] -0.08 to 0.34, median follow-up 12 wk). Sensitivity analysis of studies that were judged to be of high quality indicated a moderate positive effect estimate (SMD 0.33, 95% CI 0.08-0.58; median follow-up 12 wk). Similar beneficial effects were seen for cancer-specific fatigue, submaximal fitness, and lower body strength. We found no evidence of benefit for disease progression, cardiovascular health, or sexual function. There were no deaths attributable to exercise interventions. Other serious adverse events (eg, myocardial infarction) were equivalent to those seen in controls. CONCLUSIONS: These results support the hypothesis that exercise interventions improve cancer specific quality of life, cancer-specific fatigue, submaximal fitness, and lower body strength. PATIENT SUMMARY: This review shows that exercise/physical activity interventions can improve quality of life, fatigue, fitness, and function for men with prostate cancer. PMID- 26632145 TI - Excellent Erectile Function Recovery after Focal Therapy: Is This Enough? PMID- 26632146 TI - Opioids and COPD. PMID- 26632147 TI - [Treatment of Cancer Pain and Medical Narcotics]. AB - The World Health Organization has reported that when morphine is used to control pain in cancer patients, psychological dependence is not a major concern. Our studies were undertaken to ascertain the modulation of psychological dependence on morphine under a chronic pain-like state in rats. Morphine induced a dose dependent place preference. We found that inflammatory and neuropathic pain-like states significantly suppressed the morphine-induced rewarding effect. In an inflammatory pain-like state, the suppressive effect was significantly recovered by treatment with a kappa-opioid receptor antagonist. In addition, in vivo microdialysis studies clearly showed that the morphine-induced increase in the extracellular levels of dopamine (DA) in the nucleus accumbens (N.Acc.) was significantly decreased in rats pretreated with formalin. This effect was in turn reversed by the microinjection of a specific dynorphin A antibody into the N.Acc. These findings suggest that the inflammatory pain-like state may have caused the sustained activation of the kappa-opioidergic system within the N.Acc., resulting in suppression of the morphine-induced rewarding effect in rats. On the other hand, we found that attenuation of the morphine-induced place preference under neuropathic pain may result from a decrease in the morphine-induced DA release in the N.Acc with a reduction in the MU-opioid receptor-mediated G-protein activation in the ventral tegmental area (VTA). Moreover, nerve injury results in the continuous release of endogenous beta-endorphin to cause the dysfunction of MU-opioid receptors in the VTA. This paper also provides a review to clarify misunderstandings of opioid analgesic use to control pain in cancer patients. PMID- 26632148 TI - [Hetero-oligomerization and Functional Interaction between Purinergic Receptors Expressed in Platelets to Regulate Platelet Shape Change]. AB - Adenosine and its precursors, ATP and ADP, exert various physiological effects via binding to purinergic receptors. We previously used co-immunoprecipitation, bioluminescence resonance energy transfer (BRET) and immunoelectron microscopy to demonstrate the hetero-oligomerization of purinergic receptor subtypes. Furthermore, pharmacological studies found significant changes in receptor mediated signaling in human embryonic kidney (HEK) 293T cells co-transfected with these receptors. These findings suggest that heterodimers of purinergic receptors may have distinct pharmacological profiles, possibly due to dimerization-induced conformational changes, further suggesting that hetero-dimerization may be employed to "fine-tune" purinergic receptor signaling. Adenosine A(2A) receptor (A(2A)R), P2Y1 receptor (P2Y1R) and P2Y12 receptor (P2Y12R) are predominantly expressed on human platelets. ADP activates human platelets by stimulating both P2Y1R and P2Y12R, which act sequentially and in concert to achieve complete platelet aggregation. In contrast, adenosine stimulates Gs-coupled A(2A)R, followed by activativation of adenylate cyclase, leading to an increase in intracellular cAMP levels, which potently inhibits platelet activation. We examined the hetero-oligomerization and functional interactions of A(2A)R, P2Y1R, and P2Y12R. In HEK293T cells triply expressing all three receptors, hetero oligomerization was observed among the three receptors. Additionally, P2Y1R agonist-evoked Ca(2+) signaling was significantly inhibited by co-treatment with an A(2A)R antagonist in HEK293T cells. In human platelets, we identified endogenous A(2A)R/P2Y1R and A(2A)R/P2Y12R heterodimers. We also observed functional Ca(2+)-signaling-related cross-talk similar to those found in HEK293T cells, and found that they appeared to affect platelet shape. These results collectively suggest that intermolecular signal transduction and specific conformational changes occur among components of the hetero-oligomers formed by these three receptors. PMID- 26632149 TI - [Multidimensional Analysis of Hippocampal Excitatory Neurotransmission and Development of Analytical Tools for Glycans]. AB - Sialidase removes sialic acid residues from sialoglycoconjugates such as glycoproteins and glycolipids. Since sialic acid plays crucial roles in synaptic plasticity and memory in the hippocampus, the regulation of sialyl signaling by sialidase is also necessary for neural functions. However, since mammalian sialidase activity is remarkably weak, it has been difficult to detect sialidase activity in mammalian tissues. Determination of the distribution of sialidase activity in living mammalian tissues would provide much valuable information for understanding the roles of sialidase in physiological functions. Therefore, we synthesized a novel benzothiazolylphenol-based sialic acid derivative (BTP Neu5Ac) as a fluorescent sialidase substrate. After cleavage of BTP-Neu5Ac, which is water soluble and shows little fluorescence, with sialidase, the water insoluble fluorophore benzothiazolylphenol (BTP) released from BTP-Neu5Ac stains tissue and shows bright fluorescence. BTP-Neu5Ac can visualize sialidase activity in brain tissue with high levels of sensitivity and specificity. The sialidase expression level is markedly high in various human cancers such as colon, renal, prostate, and ovarian cancers. BTP-Neu5Ac can detect human colon cancers sensitively. Thus, BTP-Neu5Ac is useful not only for physiological research but also as a cancer probe. BTP-Neu5Ac is now being used in virology research. In this review, methods for histochemical imaging of sialidase activity and the role of sialidase in hippocampal memory are described based on the author's study of multidimensional analysis of hippocampal excitatory neurotransmission and development of analytical tools for glycans, which was awarded a prize by the Tokai branch of the Pharmaceutical Society of Japan. PMID- 26632150 TI - [Development and Characterization of a Novel Adenovirus Vector Exhibiting MicroRNA-mediated Suppression of the Leaky Expression of Adenovirus Genes]. AB - Replication-incompetent adenovirus (Ad) vectors have gained attention as gene delivery vehicles. Theoretically, no Ad genes should be expressed following transduction; however, Ad genes are expressed from the vector genome, leading to induction of cellular immunity against Ad proteins and Ad protein-induced toxicity. To suppress the leaky expression of Ad genes, a microRNA (miRNA) regulated gene expression system was utilized. We developed novel Ad vectors by incorporating targeted sequences of miR-122a or miR-142-3p, which exhibit liver- or spleen-specific expression, respectively, in the 3'-untranslated region (UTR) of the E2A, E4, or pIX genes. These Ad vectors easily grew to high titers comparable to those of a conventional Ad vector in conventional human embryonic kidney 293 cells. The leaky expression of these Ad genes in mouse organs was significantly suppressed by 2- to 100-fold in an miRNA-dependent manner, compared with a conventional Ad vector, by the insertion of the miRNA-targeted sequences. Notably, the Ad vector carrying the miR-122a-targeted sequences into the 3'-UTR of the E4 gene (Ad-E4-122aT) expressed 1.5- to 34-fold higher and longer-term transgene expression and more than 20-fold lower levels of all the Ad early and late genes examined in the liver compared with a conventional Ad vector. miR-122a mediated suppression of E4 gene expression in the liver significantly reduced the hepatotoxicity that an Ad vector causes via both adaptive and non-adaptive immune responses. Ad-E4-122aT would be a promising framework for efficient gene delivery due to its ability to mediate higher and longer-term transgene expression and lower hepatotoxicity than a conventional Ad vector. PMID- 26632151 TI - [A Method for Protein Photo-cross-linking in Living Cells Facilitating Analysis of Physiological Interactions of Proteins]. AB - In living cells, most proteins form complexes with other proteins to exert their functions. Since protein functions are regulated in response to changes in the cellular environment, the components of the complexes can vary; therefore, proteins often interact in a weak and transient manner. To capture such labile protein interactions, we have developed a method for photo-cross-linking of proteins directly interacting in mammalian cells; this method involves expansion of the genetic code and site-specific incorporation of photoreactive amino acids into proteins. Upon cross-linking, protein complexes are stabilized by a covalent bond and can be readily isolated from cell extracts without the problems usually associated with simple affinity purification methods such as co immunoprecipitation. Photo-cross-linkers have another benefit: they react exclusively with molecules within a range defined by the linker length. This property becomes useful for determining the binding interface of two proteins because the linkers can be introduced in a site-directed manner with our method. In this review, we first describe the expansion of the genetic code of mammalian cells for the incorporation of non-natural amino acids into proteins. Then, we introduce our recent applications and developments of the cross-linking method: identification of intracellular binding partners of the signaling protein growth factor receptor binding protein 2; analysis of the binding between membrane proteins on the cell surface; and a novel photoreactive amino acid that enables wide-ranging photo-cross-linking. PMID- 26632152 TI - [Practical Use Evaluation of Aluminum Packaging for Medicinal Products Based on Universal Design]. AB - Many pharmacists have requested optimization of aluminum packaging of medicinal products in terms of usability. To improve operational efficiency of aluminum packaging, we used Universal Design (UD)-based approach, which enables products to be used properly and consistently regardless of users. The UD-pack used in this research is composed of a film that can be easily opened and torn linear. Here, we compared the UD-pack to conventional aluminum packaging by evaluating the practical use of each under the cooperation of 24 pharmacists. Following opening and removal of contents of one sample for both types of packaging, monitors were asked which type was easier to use in each case. Also, monitors were to repeat the opening and removal of contents of five samples in a row, and were asked the same question. Monitors were recorded by digital camera to measure the time required to finish the procedure for five samples in a row. After opening one sample, approximately 83% of monitors preferred the UD-pack, and after opening five samples, all (100%) preferred the UD-pack. Regarding the time required for opening five samples and removing the contents measured by analyzing the recorded video, the UD-pack significantly reduced the time required for all monitors. The average time ratio of the UD-pack to conventional aluminum packaging was approximately 59%, and no significant difference was observed between male and female pharmacists. Our results indicate the UD-pack improves ease of opening and removal of contents and increases efficiency of dispensing in a clinical setting compared with conventional aluminum packaging. PMID- 26632153 TI - [Improvement of the Convenience of White Petrolatum]. AB - White petrolatum is frequently used as an oleaginous base, but has a drawback of poor usability. In this trial, white petrolatum was prepared at a lower melting point to improve its usability. Characteristic pharmaceutical values such as melting point, yield, and consistency were compared between a conventional product and ophthalmic white petrolatum. Usability was compared by administering a survey questionnaire and evaluating the comparable moisturizing effect by conductivity in humans. The melting point and yield value of the improved product were significantly lower compared with other white petrolatum products. In the survey, the improved product was rated excellent in five criteria. On a scale of 1 to 5, the average values for the five criteria for the improved product were 4.7, while the conventional product and ophthalmic white petrolatum were rated 3.0 and 3.5, respectively. No difference in moisturizing effect was observed among all petrolatums after application, from day 1 to day 14. In conclusion, the improved white petrolatum demonstrated better usability, and the moisturizing effect was equivalent to conventional product, suggesting that the use of this improved product may lead to improved adherence. PMID- 26632154 TI - [Necessity of Disaster Medical Instructions in Pharmaceutical Education, and a Discussion of the Details of These Instructions]. AB - Since the Great East Japan Earthquake, the Ministry of Health, Labour, and Welfare, municipalities, and medical organizations have made various revisions to medical systems employed at the time of a disaster. To educate pharmacists who can contribute to medical teams conducting healthcare activities at the time of disasters, there is a need to develop disaster medical instructions in pharmaceutical education. However, the "Model Core Curriculum for Pharmaceutical Education", a new curriculum, contains little disaster medical care education. In the present study, in cooperation with the Ehime Society of Hospital Pharmacists and Ehime Pharmaceutical Association, we surveyed pharmacists living in Ehime Prefecture in order to investigate their views regarding the necessity of disaster medical instructions in pharmaceutical education, and what they considered essential to be taught. Our subjects considered that there is a strong need for teaching disaster medical instruction in college. In addition, they regarded all of the 16 investigated items concerning disaster medical instruction as highly necessary. Factor analysis led to the classification of these items into "disaster medical activities performed by pharmacists" and "responses to secondary issues in affected areas". On the basis of this classification, we established specific goals. Disaster medical instructions should be taught as a part of pharmaceutical education in college. However, to develop these instructions, it is important for universities to cooperate with local pharmaceutical and hospital pharmacist associations, as it is difficult for universities to teach such instructions independently. PMID- 26632155 TI - [Qualitative Research to Investigate the Needs of Pharmacists and Drug Therapy of Cancer Patients]. AB - We performed a survey of cancer patients' needs for drug treatment and support from pharmacists during treatment and evaluated the support that cancer patients can expect from community pharmacists in the future. The patients consisted of 16 members of the Cancer Patient Association in Aichi prefecture who underwent chemotherapy. The results of a semistructured group interview were qualitatively analyzed using the grounded theory method. Patients undergoing chemotherapy had high hopes for its effectiveness but were worried about side effects and medical costs. To overcome these problems, they hoped for a decrease in the economic burden, compassionate-use system, and development of novel drugs. The patients had anxiety because the side effects of chemotherapy often caused physical and psychological damage. Despite patients' confusion, pharmacists sometimes did not give adequate explanations to them. The patients expected more from pharmacists regarding medication support and hoped for a system allowing continuous side effect monitoring and consultation without hesitation. For patients undergoing cancer chemotherapy who are confused regarding side effects, pharmacists should understand the patient explanatory model and become more involved with patients as partners in treatment. PMID- 26632156 TI - [Basic Studies on the Stability of Flavored Oral Solutions of Rebamipide]. AB - Stomatitis frequently occurs during chemotherapy and radiotherapy for cancer. Because of its pharmacological properties including anti-inflammatory activity and stimulatory effects on endogenous prostaglandin synthesis, rebamipide has been suggested as a potentially effective treatment against stomatitis. In the present study we tested the stability of oral rebamipide solutions prepared in our hospital pharmacy using sodium alginate as a thickener to increase retention of this agent in the oral cavity, and the addition of different flavoring mixtures intended for use in enteral diets to reduce the bitterness of rebamipide and sodium alginate. Samples of oral rebamipide solution prepared with 13 kinds of flavoring and sodium alginate were evaluated in terms of their appearance, redispersibility, pH, viscosity, and rebamipide content immediately after preparation and 1, 3, 7, and 10 days after storage at room temperature under ambient light or in a cool, dark place. After 10 days of storage, favorable stability was observed in four sample solutions supplemented with green apple, pineapple, yogurt, and tomato flavoring mixtures intended for use in Elental((r)) diets. These oral solutions may have potential clinical application. PMID- 26632157 TI - [Analysis of Factors Influencing the Development of Hypomagnesemia in Patients Receiving Cetuximab Therapy for Head and Neck Cancer]. AB - Cetuximab was approved in Japan as the only clinically available molecular targeted drug for the treatment of head and neck cancer. Hypomagnesemia associated with cetuximab is considered one of the most serious adverse events. However, the factors influencing the development of hypomagnesemia are not clear, although the drug was previously approved for the treatment of patients with colorectal cancer. Thus, we studied the factors involved in the development of hypomagnesemia in patients receiving cetuximab therapy for head and neck cancer. Patients' background data and laboratory values before starting cetuximab therapy did not affect the development of hypomagnesemia. Among patients who had never been treated with cisplatin (NT group), 36.4% developed hypomagnesemia. In contrast, all patients who had previously been treated with cisplatin (T group) developed hypomagnesemia (p=0.034). Magnesium is reabsorbed by transient receptor potential subfamily melastatin 6 (TRPM6) in the distal convoluted tubule. The expression level of TRPM6 is controlled by the epidermal growth factor (EGF) pathway. Cetuximab is an EGF receptor inhibitor and reduces the expression of TRPM6. Additionally, recent studies have shown that the expression of TRPM6 is reduced by cisplatin. Therefore, we considered that the serum magnesium level was cumulatively reduced by cetuximab and cisplatin. In conclusion, the T group was more likely to develop hypomagnesemia than the NT group, and therefore the serum magnesium level in the T group requires careful monitoring so that magnesium supplementation can be provided to patients when the level decreases. PMID- 26632158 TI - Loss of Periostin Results in Impaired Regeneration and Pancreatic Atrophy after Cerulein-Induced Pancreatitis. AB - The extracellular matrix molecule periostin (POSTN, encoded by POSTN), which is secreted by activated pancreatic stellate cells, has important functions in chronic pancreatitis and pancreatic cancer. However, the role of POSTN in acute pancreatitis and subsequent regeneration processes has not been addressed so far. We analyzed the function of POSTN in pancreatic exocrine regeneration after the induction of a severe acute pancreatitis. Postn-deficient mice and wild-type control animals received repetitive cerulein injections, and a detailed histologic analysis of pancreatic tissues was performed. Although there was no difference in pancreatitis severity in the acute inflammatory phase, the recovery of the exocrine pancreas was massively impaired in Postn-deficient mice. Loss of Postn expression was accompanied by strong pancreatic atrophy and acinar-to adipocyte differentiation, which was also reflected in gene expression patterns. Our data suggest that POSTN is a crucial factor for proper exocrine lineage specific regeneration after severe acute pancreatitis. PMID- 26632160 TI - The effects of ciprofloxacin on early life stages of common carp (Cyprinus carpio). AB - The authors performed a toxicity test with ciprofloxacin in fertilized eggs of common carp according to guideline 210 of the Organisation for Economic Co operation and Development. The tested concentrations were 1 MUg L(-1) , 100 MUg L(-1) , 500 MUg L(-1) , 1000 MUg L(-1) , and 3000 MUg L(-1) . Accelerated hatching was found in all groups exposed to ciprofloxacin, but significant growth reduction was found only in the group exposed to the highest concentration (3000 MUg L(-1) ). Increased numbers of macroscopic morphological anomalies were observed on day 6 of the test (after hatching). The highest numbers of macroscopic morphological anomalies were observed in the groups of free embryos and larvae exposed to ciprofloxacin concentrations of 100 MUg L(-1) , 500 MUg L( 1) , 1000 MUg L(-1) , and 3000 MUg L(-1) (20-23% of tested samples). A gradual decrease in glutathione S-transferase activity was detected in all experimental groups exposed to ciprofloxacin, but significant differences (p < 0.01) were found only in groups treated with 500 MUg L(-1) and 3000 MUg L(-1) . Glutathione peroxidase and catalase exhibited increased activity in most of the tested concentrations (p < 0.01 and <0.05, respectively), whereas decreased glutathione reductase activity was found in the groups exposed to ciprofloxacin concentrations of 500 MUg L(-1) and 3000 MUg L(-1) (p < 0.05). The concentration of thiobarbituric acid-reactive substances was significantly lower (p < 0.01) in all experimental groups exposed to ciprofloxacin. The lowest-observed-effect concentration of ciprofloxacin was 1 MUg L(-1) . These results suggest that hatching, early ontogeny, occurrence of morphological anomalies, antioxidant and biotransformation enzyme activity, and lipid peroxidation in fish can be affected by ciprofloxacin. Environ Toxicol Chem 2016;35:1733-1740. (c) 2015 SETAC. PMID- 26632161 TI - Comparison between the Outcomes of Intracoronary and Intravenous Administration of Eptifibatide during Primary Percutaneous Coronary Intervention in Patients with Acute ST-Elevation Myocardial Infarction. AB - AIM: To compare the outcomes of intracoronary (IC) and intravenous (IV) administration of eptifibatide during primary percutaneous coronary intervention (PPCI) in patients with ST-elevation myocardial infarction (STEMI). METHODS: In this prospective double-blind randomized clinical trial, 76 patients with STEMI selected for PPCI were randomly assigned in two groups to receive either IC or IV bolus of eptifibatide. The primary end point was coronary perfusion assessment by thrombolysis in myocardial infarction (TIMI) flow grade (TFG), TIMI perfusion grade (TPG), and corrected TIMI frame count (cTFC). Secondary end points were left ventricular ejection fraction (LVEF) restoration, ST-segment elevation resolution, and in-hospital major cardiovascular adverse events (MACEs) (including recurrent MI, need for target vessel revascularization (TVR), stroke, and death resulting from any cause) until discharge. RESULTS: Assessment revealed significantly better TFG (95% CI: 1.01-10.26, OR=3.224, P=0.042), more TFG 3 (65.79% vs. 86.11% in IV and IC groups, respectively), better TPG (P=0.024), more achieved TPG 3 and TPG 2+3 (TPG 3: 44.74% vs. 72.22% and TPG 2+3: 78.95% vs. 94.44% in the IV and IC groups, respectively) with better cTFC in the IC group (37.33+/-15.84 vs. 32.53+/- 20.71 in the IV and IC groups, respectively; P=0.034). LVEF was better restored in the IC group (6.21+/-8.61% vs. 14.72+/ 5.34% in the IV and IC groups, respectively; P<0.001) and the ST-segment elevation resolution was better achieved in the IC administration (95% CI: -22.55 to -6.23, P=0.001). There were no recurrent MI, stroke, or need for TVR among patients during the in-hospital stay. CONCLUSIONS: IC administration of eptifibatide during PPCI in patients with STEMI in comparison with IV administration of eptifibatide is associated with significantly better coronary reperfusion and improved clinical outcomes (IRCT2012090510751N1). PMID- 26632162 TI - Body Mass Index Modifies an Association between Self-Reported Regular Exercise and Proteinuria. AB - AIM: Regular exercise habits are well-known to exert a favorable effect on the metabolic syndrome, which may cause proteinuria and chronic kidney disease (CKD). However, it remains unknown if exercise exerts a favorable effect on proteinuria and kidney dysfunction. The aim of this study was to reveal the association between exercise and the prevalence of proteinuria and kidney dysfunction and the attenuation by obesity. METHODS: This study was a cross-sectional cohort study that included 292,013 participants who underwent the Specific Health Check and Guidance in Japan. The exercise score (range 0-3) was based on the number of positive answers to three questions regarding exercise habits. The outcome was defined as urinary protein detected by a dipstick test and kidney dysfunction [estimated glomerular filtration rate (GFR) less than 45 ml/min/1.73 m(2)]. RESULTS: The exercise score was significantly associated with the prevalence of proteinuria in both males [vs. exercise score 0; exercise score 1, multivariate adjusted odds ratio 0.86 (95% confidence interval 0.81-0.92), P<0.001; exercise score 2, 0.84 (0.79-0.90), P<0.001; exercise score 3, 0.77 (0.72-0.82), P<0.001] and females (same as in males). After the male subjects were divided into quintiles according to body mass index (BMI) in more than three groups (22.9=18 years who had been prescribed LLDs for at least 3 months without dose changes for at least 6 weeks. A single visit was scheduled for data collection, including fasting plasma lipid and glucose levels. Cardiovascular risk profile and LDL-C goal attainment were assessed according to the 2004 updated US National Cholesterol Education Program Adult Treatment Panel III guidelines. RESULTS: In total, 35 121 patients (mean age: 60.4 years) were included, and 90.3% had been prescribed statin monotherapy. Overall, only 49.4% of patients reached their recommended LDL-C level. LDL-C goals were attained in 54.8% (5084/9273) and 22.8% (3287/14 429) of patients were at high and very high cardiovascular risk, respectively. Factors associated with an increased likelihood of LDL-C goal attainment were lower baseline cardiovascular risk; presence of diabetes mellitus, hypertension, or history of cardiovascular disease; and treatment with simvastatin, atorvastatin, or rosuvastatin (vs. all other LLDs). CONCLUSION: LDL-C goal attainment in patients taking LLDs is suboptimal worldwide, particularly in patients at high and very high cardiovascular risk. PMID- 26632164 TI - Cardio-Ankle Vascular Index is Independently Associated with Future Cardiovascular Events in Outpatients with Metabolic Disorders. AB - AIM: We investigated whether cardio-ankle vascular index (CAVI), an arterial stiffness marker, independently predicts future cardiovascular events in subjects with metabolic disorders. METHODS: 1562 outpatients underwent CAVI between April 2004 and March 2006 at Toho University, Sakura Medical Center in Chiba, Japan. Patients who already had cardiovascular events at baseline, patients with low ankle brachial index (<0.9), and patients with atrial fibrillation were excluded. After exclusion, 1080 subjects with metabolic disorders including diabetes mellitus, hypertension and dyslipidemia were screened and followed prospectively. RESULTS: Eventually, 1003 subjects (92.9% of 1,080 subjects) followed until March 2012 (follow-up duration 6.7+/-1.6 years) were analyzed. During the observation period, 90 subjects had new-onset myocardial infarction or angina pectoris confirmed by angiography. All subjects were stratified into quartiles by baseline CAVI (Q1: CAVI <=8.27, Q2: CAVI 8.28-9.19, Q3: CAVI 9.20-10.08, Q4: CAVI >=10.09). Age, male ratio and future cardiovascular events increased as CAVI quartile became higher. In Cox proportional hazards regression analysis, the factors independently associated with higher risk of future cardiovascular events were every 1.0 increment of CAVI [hazard ratio (HR) 1.126, p= 0.039], male gender (HR 2.276, p=0.001), smoking (HR 1.846, p=0.007), diabetes mellitus (HR 1.702,p=0.020), and hypertension (HR 1.682, p=0.023). CONCLUSION: In individuals with metabolic disorders, CAVI was a predictor of future cardiovascular events, independent of traditional coronary risk factors. CAVI is a potentially valuable tool to identify persons likely to benefit from more intensive therapeutic approaches. PMID- 26632165 TI - Myocardial Production of Plasminogen Activator Inhibitor-1 is Associated with Coronary Endothelial and Ventricular Dysfunction after Acute Myocardial Infarction. AB - AIM: Although plasminogen activator inhibitor-1 (PAI-1) is abundantly expressed in infarcted myocardium, the pathogenic role of myocardial PAI-1 remains unknown. This study examined whether PAI-1 in the infarcted lesion contributes to coronary endothelial dysfunction and left ventricular (LV) dysfunction in patients with acute myocardial infarction (AMI). METHODS: Plasma levels of PAI-1 activity and tissue-plasminogen activator (tPA) antigen were measured 2 weeks and 6 months after MI by ELISA in plasma obtained from the aortic root (AO) and anterior interventricular vein (AIV) in 28 patients with a first AMI due to occlusion of the left anterior descending coronary artery (LAD). Coronary blood flow responses in LAD to intracoronary infusion of acetylcholine (ACh) and left ventriculography were measured at the same time points: 2 weeks and 6 months after MI. RESULTS: The trans-myocardial gradient of PAI-1 from AO to AIV, reflecting production/release of PAI-1 in the infarcted lesion, was inversely correlated with the coronary blood flow response to ACh 6 months after MI (r=-0.43, p=0.02) and with the percentage change in LV regional motion in the LAD territory from 2 weeks to 6 months after MI (r=-0.38, p=0.04). The trans-myocardial gradient of tPA level showed no significant correlations. CONCLUSIONS: PAI-1 produced in the infarcted myocardium and released into the coronary circulation is associated with endothelial dysfunction in resistance vessels of the infarct-related coronary arteries and with progressive dysfunction of the infarcted region of the left ventricle in AMI survivors. PMID- 26632166 TI - Emerging Novel Biomarkers for Arteriosclerosis Obliterans. PMID- 26632167 TI - Utility of Carotid Wall Shear Stress as a Predictor of Coronary Atherosclerosis. PMID- 26632168 TI - Insights and clinical questions about the active surveillance of low-risk papillary thyroid microcarcinomas [Review]. AB - Over 20 years ago, two Japanese institutions initiated an active surveillance policy for papillary microcarcinomas (PMCs) without high-risk features (such as clinical lymph node and distant metastases) and suspected trachea or recurrent laryngeal nerve invasion. Since the most recent American Thyroid Association (ATA) guidelines adopt active surveillance as a therapy option for low-risk PMCs, the number of institutions worldwide carrying out this policy can be expected to increase. However, before adopting an active surveillance strategy, some important clinical questions must be considered. In this review, conceivable clinical questions with our answers based on the present accumulation of low-risk PMC surveillance data are presented. PMID- 26632169 TI - Issues with using only regression models for ecotoxicity studies. PMID- 26632170 TI - Analyses of fugu hoxa2 genes provide evidence for subfunctionalization of neural crest cell and rhombomere cis-regulatory modules during vertebrate evolution. AB - Hoxa2 gene is a primary player in regulation of craniofacial programs of head development in vertebrates. Here we investigate the evolution of a Hoxa2 neural crest enhancer identified originally in mouse by comparing and contrasting the fugu hoxa2a and hoxa2b genes with their orthologous teleost and mammalian sequences. Using sequence analyses in combination with transgenic regulatory assays in zebrafish and mouse embryos we demonstrate subfunctionalization of regulatory activity for expression in hindbrain segments and neural crest cells between these two fugu co-orthologs. hoxa2a regulatory sequences have retained the ability to mediate expression in neural crest cells while those of hoxa2b include cis-elements that direct expression in rhombomeres. Functional dissection of the neural crest regulatory potential of the fugu hoxa2a and hoxa2b genes identify the previously unknown cis-element NC5, which is implicated in generating the differential activity of the enhancers from these genes. The NC5 region plays a similar role in the ability of this enhancer to mediate reporter expression in mice, suggesting it is a conserved component involved in control of neural crest expression of Hoxa2 in vertebrate craniofacial development. PMID- 26632171 TI - Efficacy and safety of switching from insulin glargine to insulin degludec in young people with type 1 diabetes. AB - We evaluated the efficacy and safety of switching to insulin degludec (IDeg) from insulin glargine (IGlar) as basal-bolus therapy in young people with type 1 diabetes. The subjects were 36 patients, 21.3+/-1.0 years of age, with type 1 diabetes. IGlar had previously been injected once daily in 25 patients and twice daily in 11. They were then switched from IGlar to once-daily injection of IDeg. Both fasting plasma glucose (FPG) and HbA1c levels decreased significantly from 134+/-3.9 mg/dL and 7.9+/-0.2% at baseline to 116+/-2.2 mg/dL and 7.4+/-0.2% at 12 months after starting IDeg (P<0.0001 and P<=0.001, respectively). Overall and nocturnal hypoglycemia (PG<70 mg/dL) frequencies also decreased significantly from 4.9+/-0.7 and 2.0+/-0.3 times/month to 2.4+/-0.3 and 0.4+/-0.1 times/month at 12 months after starting IDeg (P<=0.005 and P<0.0005, respectively). The daily basal insulin dose was significantly reduced from 0.48+/-0.04 units/kg/day at baseline to 0.38+/-0.03 units/kg/day at the end of the study period (P<0.0001), which corresponded to 79.2% of the baseline value. Trends were similar in patients receiving the once-daily injection and those given twice-daily injections, but basal-insulin value reductions from baseline were more marked in patients receiving twice-daily injections of basal insulin (76.0% vs. 82.6% of the baseline value). These results suggest that switching from IGlar to an appropriate dose of IDeg may effectively control hyperglycemia while reducing the frequency of hypoglycemia episodes in young Japanese people with type 1 diabetes. PMID- 26632172 TI - Kinetic analyses of changes in serum TSH receptor antibody values after total thyroidectomy in patients with Graves' disease. AB - We often recommend total thyroidectomy for patients with Graves' disease who wish to have a child in the near future in order to prevent fetal or neonatal hyperthyroidism, especially if the patients' serum thyrotropin receptor antibody (TRAb) values are high. The aim of this study was to analyze changes in serum TRAb values using a quantitative third-generation assay after total thyroidectomy and the half-lives of serum TRAb values to estimate the postoperative time needed to achieve the safe TRAb value for mothers. We retrospectively examined the records of 45 Graves' disease patients who underwent a total thyroidectomy and had high serum TRAb values. We also evaluated factors that prolonged the postoperative reduction of serum TRAb values. The serum TRAb values decreased rapidly in most of the patients, especially within the early postoperative (3 month) period. The presence of Graves' ophthalmopathy (GO) (p=0.001), smoking (p=0.004), and serum thyroglobulin values > 0.5 ng/mL at postoperative 12 months (p=0.039) were significantly associated with prolonged half-lives of the serum TRAb values. The median TRAb value half-life was 93.5 days in the patients without GO or smoking, 162.5 days in the patients with GO or smoking, and 357.4 days in the patients with both GO and smoking. Our findings indicate that using the half-life of patients' serum TRAb values determined by this third-generation assay would be effective to evaluate the reduction of serum TRAb values after total thyroidectomy and to estimate the postoperative time needed to achieve the maternal safe value. PMID- 26632173 TI - Serum free thyroxine levels are associated with the efficacy of weight reduction therapy in obese female patients. AB - Thyroid function is strongly associated with obesity. The aim of this study is to investigate whether serum free thyroxine (FT4) and/or thyrotropin (TSH) levels are associated with the efficacy of weight reduction therapy in obese patients. We enrolled a total of 283 obese patients and cross-sectionally investigated the association of serum FT4 and/or TSH levels with metabolic features. Furthermore, in 97 obese patients who received 6-month weight reduction therapy, we assessed the relationship of serum FT4 and/or TSH levels to the efficacy of weight reduction therapy. Neither baseline serum FT4 nor TSH levels showed any correlations with body weight (BW) and body mass index (BMI) in these obese patients. However, in 57 obese female patients who underwent weight reduction therapy for six months, serum FT4 levels prior to the therapy was negatively correlated with the degrees of reduction of BW (r = -0.354, p = 0.007) and BMI (r = -0.373, p = 0.004). The correlation between baseline serum FT4 levels with the efficacy of weight reduction therapy was not observed in obese male or postmenopausal female patients. This study demonstrates that baseline serum FT4 levels are associated with weight reduction in obese female premenopausal patients. Therefore, baseline FT4 levels can be used as a clinical, noninvasive, hormonal predictor of weight reduction efficacy in obese patients. PMID- 26632174 TI - What constitutes a model organism in ecotoxicology? PMID- 26632175 TI - Antioxidant and Anti-inflammatory Activities of N-((3,4-Dihydro-2H benzo[h]chromene-2-yl)methyl)-4-methoxyaniline in LPS-Induced BV2 Microglial Cells. AB - Microglial activation is known to cause inflammation resulting in neurotoxicity in several neurological diseases. N-((3,4-Dihydro-2H-benzo[h]chromene-2 yl)methyl)-4-methoxyaniline (BL-M), a chromene derivative, was originally synthesized with the perspective of inhibiting nuclear factor-kappa B (NF kappaB), a key regulator of inflammation. The present study evaluated the antioxidant and anti-inflammatory potential of BL-M in lipopolysaccharide (LPS) stimulated BV2 microglial cells. Our results demonstrated that BL-M significantly inhibited the formation of 1,1-diphenyl-2-picrylhydrazyl radicals, as well as lipid peroxidation in rat brain homogenate in a concentration-dependent manner. In addition, it suppressed the generation of intracellular reactive oxygen species, and the levels of pro-inflammatory mediators including nitric oxide, tumor necrosis factor-alpha, and interleukin-6 in LPS-induced BV2 cells. Western blotting analyses revealed the inhibition of inhibitor of kappa B alpha (IkappaBalpha) phosphorylation and NF-kappaB translocation by BL-M in LPS activated cells. Therefore, our study highlights marked antioxidant and anti inflammatory activities of BL-M, and suggests that this compound may have a beneficial impact on various neurodegenerative diseases associated with inflammation. PMID- 26632176 TI - Incidence and Risk Factors of Osteonecrosis of the Jaw in Advanced Cancer Patients after Treatment with Zoledronic Acid or Denosumab: A Retrospective Cohort Study. AB - Zoledronic acid and denosumab are two antiresorptive drugs currently in use for treating osteoporosis. They have different mechanisms of action, but both have been shown to delay the onset of skeletal-related events in patients with advanced cancer. However, medication-related osteonecrosis of the jaw (MRONJ) has been reported in cancer patients treated with zoledronic acid or denosumab. We studied 155 patients with several types of advanced cancer who were treated with zoledronic acid or denosumab in our hospital during the period from April 2010 through March 2013. Thirteen of these 155 patients (8.4%) developed MRONJ. MRONJ development was significantly associated with the number of zoledronic acid or denosumab infusions (p<0.001) and the duration of zoledronic acid or denosumab therapy (p<0.001). Logistic regression analysis showed that diabetes [odds ratio (OR)=6.699, 95% confidence interval (CI), 1.435-31.277, p=0.016], anemia [OR=14.559, 95% CI, 2.161-98.069, p=0.006], and pus discharge [OR=6.491, 95% CI, 1.514-27.835, p=0.012] significantly increased the risk of developing MRONJ. However, the risk of MRONJ was significantly lower [OR=0.137, 95% CI, 0.020 0.944, p=0.043] when patients received periodical dentistry maintenance. Diabetes, anemia, and pus discharge may also play roles in its development. These findings suggest that the active inclusion of dentistry maintenance in bisphosphonate or denosumab treatment of cancer patients can reduce MRONJ development. PMID- 26632177 TI - Safety and Efficacy of Rice Bran Supercritical CO2 Extract for Hair Growth in Androgenic Alopecia: A 16-Week Double-Blind Randomized Controlled Trial. AB - We conducted a 16-week double-blind randomized controlled single-center trial to evaluate the safety and efficacy of dermal rice bran supercritical CO2 extract (RB-SCE) in the treatment of androgenic alopecia. Fifty alopecia patients were randomly assigned to the experimental and placebo groups. The experimental group received a dermal application of 0.5% RB-SCE (8 mL/d) to the head skin for 16 weeks while the control group received a dermal application of placebo. Changes in hair count, diameter, and density were evaluated with a Folliscope((r)). Patient satisfaction was evaluated via questionnaire and clinical photographs were rated by dermatologists. The results showed that RB-SCE significantly increased hair density and hair diameter in male subjects. Patient satisfaction and the evaluation of photographs by dermatologists also confirmed the effectiveness of RB-SCE in the treatment of alopecia. No adverse reactions related to RB-SCE were reported. Therefore, RB-SCE shows promise for use in functional cosmetics and pharmaceuticals. PMID- 26632178 TI - Resveratrol Ameliorates Clonidine-Induced Endothelium-Dependent Relaxation Involving Akt and Endothelial Nitric Oxide Synthase Regulation in Type 2 Diabetic Mice. AB - Diabetic vascular complication is one of the manifestations of endothelial dysfunction. Resveratrol (RV) is considered to be beneficial in protecting endothelial function. However, the exact protective effect and mechanisms involved have not been fully clarified. In this study, we investigated the relationship between Akt/endothelial nitric oxide synthase (eNOS) activation and RV in diabetes-induced endothelial dysfunction. Aortas were dissected and placed in organ chambers, and nitric oxide (NO) production in response to acetylcholine (ACh) and RV was measured. ACh-induced endothelium-dependent relaxation was markedly increased in controls by RV pretreatment. Furthermore, RV caused NO dependent relaxation via the Akt signaling pathway, which was weaker in the aortas of diabetic mice than age-matched controls. To further examine the underlying mechanisms, we measured the phosphorylation of Akt and eNOS by Western blotting. RV caused the phosphorylation of Akt and eNOS in aortas, which was decreased in diabetic mice. However, RV augmented the impaired clonidine-induced relaxation in diabetic mice. Interestingly, the phosphorylation of Akt and eNOS was increased under stimulation with RV and clonidine only in diabetic mice. Thus, either RV or clonidine causes Akt-dependent NO-mediated relaxation, which is weaker in diabetic mice than controls. However, additional exposure to RV and clonidine has an augmenting effect on the Akt/eNOS signaling pathway under diabetic conditions. RV-induced Akt/eNOS activity may be a common link involved in the clonidine-induced Akt/eNOS activity, so RV and clonidine may have a synergistic effect. PMID- 26632179 TI - Vasodilatory Effect of Wogonin on the Rat Aorta and Its Mechanism Study. AB - Wogonin, a natural flavonoid, is one of the bioactive compounds of the medicinal herb Eucommia ulmoides OLIV. widely used in southeastern Asia for treating hypertension. However, the molecular mechanisms for the therapeutic benefits remain largely unclear. The present study investigated the vasodilatory effect of wogonin and its possible mechanisms. The flavonoid (0.1-100 uM) caused concentration-dependent relaxations in endothelium-intact aortic rings precontracted with norepinephrine (NE, 1 uM) or potassium chloride (KCl, 60 mM). Preincubation with wogonin (10, 100 uM) for 20 min significantly inhibited the contractile responses to NE (0.1, 1, 10 uM) or KCl (7.5, 15, 30, 60 mM). Relaxant responses to wogonin were not inhibited by N(G)-nitro-L-arginine methylester (100 uM) or endothelial denudation. In a Ca(2+)-free Krebs' solution, wogonin not only blocked Ca(2+) influx-dependent vasoconstriction by either NE (1 uM) or KCl (100 mM), but also inhibited NE (1 uM)-induced tonic contraction, which is dependent on intracellular Ca(2+) release. Wogonin also suppressed the elevation of [Ca(2+)]i induced by KCl (60 mM) after exhausting the calcium store in sarcoplasmic and endoplasmic reticula with thapsigargin (1 uM) or by ATP (100 uM) in primary vascular smooth muscle cells. These findings suggest that wogonin induced responses are mainly due to the inhibition of both intracellular Ca(2+) release and extracellular Ca(2+) influx. PMID- 26632180 TI - Lower Squalene Epoxidase and Higher Scavenger Receptor Class B Type 1 Protein Levels Are Involved in Reduced Serum Cholesterol Levels in Stroke-Prone Spontaneously Hypertensive Rats. AB - A lower serum cholesterol level was recently shown to be one of the causes of stroke in an epidemiological study. Spontaneously hypertensive rats stroke-prone (SHRSP) have lower serum cholesterol levels than normotensive Wistar-Kyoto rats (WKY). To elucidate the mechanisms responsible for the lower serum cholesterol levels in SHRSP, we determined whether the amounts of cholesterol biosynthetic enzymes or the receptor and transporter involved in cholesterol uptake and efflux in the liver were altered in SHRSP. When the mRNA levels of seven cholesterol biosynthetic enzymes were measured using real-time polymerase chain reaction (PCR), farnesyl pyrophosphate synthase and squalene epoxidase (SQE) levels in the liver of SHRSP were significantly lower than those in WKY. SQE protein levels were significantly reduced in tissues other than the brain of SHRSP. No significant differences were observed in low-density lipoprotein (LDL) receptor (uptake of serum LDL-cholesterol) or ATP-binding cassette transporter A1 (efflux of cholesterol from the liver/formation of high-density lipoprotein (HDL)) protein levels in the liver and testis between SHRSP and WKY, whereas scavenger receptor class B type 1 (SRB1: uptake of serum HDL-cholesterol) protein levels were higher in the livers of SHRSP. These results indicated that the lower protein levels of SQE and higher protein levels of SRB1 in the liver were involved in the reduced serum cholesterol levels in SHRSP. PMID- 26632181 TI - Characterization and Mutational Analysis of a Two-Polypeptide Bacteriocin Produced by Citrus Iyo-Derived Lactobacillus brevis 174A. AB - In the present study, we isolated a lactic acid bacterium (LAB) from a citrus iyo fruit and identified it as Lactobacillus brevis. This plant-derived LAB strain, designated 174A, produces bacteriocin consisting of two polypeptides designated brevicin 174A-beta and 174A-gamma. Although each polypeptide itself displays antibacterial activity, the ability is enhanced 100 fold by mixing both polypeptides at a 1 : 1 ratio. Significantly, brevicin 174A inhibits even the growth of several pathogenic bacteria that are more resistant to a lantibiotic bacteriocin, nisin A, which is commonly utilized as a preservative added to foodstuffs. Structural analysis of the 174A bacteriocin using a program that predicts secondary structure suggests that both component polypeptides have a positively charged N-terminal region, as well as two cysteine residues in both the N- and C-terminals. Judging from a mutational analysis of the antibacterial polypeptides, these unique amino acid sequences of 174A-beta might be important for the expression of the synergistic activity that occurs in the presence of the two polypeptides combined. PMID- 26632182 TI - Estimating the Differences of UGT1A1 Activity in Recombinant UGT1A1 Enzyme, Human Liver Microsomes and Rat Liver Microsome Incubation Systems in Vitro. AB - Estimating the extent to which drugs inhibit uridine 5'-diphosphate glucuronosyltransferases1A1 (UGT1A1) enzyme activity is important for predicting hepatotoxicity and neurotoxicity. UGT1A1 enzyme activity is commonly evaluated by detecting the elimination of bilirubin substrate or the generation of bilirubin glucuronides. However, the present methods are inadequate for accurately assessing bilirubin metabolism, selecting incubation conditions, and comparing different systems. Therefore, in our study, we first established a ultra performance liquid chromatography (UPLC)-MS/MS method to identify bilirubin and bilirubin glucuronides. To ensure the reaction was linear, we performed assays to optimize the protein concentration and incubation time. Finally, we measured UGT1A1 activity using three different systems. Data revealed the optimum incubation conditions were 10 min with 0.5 mg/mL human liver microsomes (HLM), recombinant human UGT1A1 (rUGT1A1), and rat liver microsomes (RLM). Bilirubin glucuronidation obeyed Michaelis-Menten kinetics in all three systems. The diversity in bilirubin metabolism among species was revealed. rUGT1A1 had the strongest binding affinity for bilirubin, but the lowest metabolism velocity. Compared with the other systems, RLM exhibited a significant difference. It has the lowest CLint and the highest Km. The difference in parameters between three systems may be attributable to the species differences. In conclusion, these in vitro studies provide useful information regarding drug interactions and the prediction of toxicity for future studies. PMID- 26632183 TI - Pharmacokinetics and Antiinflammatory Effect of a Novel Gel System Containing Ketoprofen Solid Nanoparticles. AB - We previously reported that dermal application using nanoparticles improves skin penetration. In this study, we prepared novel topical formulations containing ketoprofen (KET) solid nanoparticles (KETnano gel ointment) and investigated the antiinflammatory effect of the KET nanoparticle formulations on rheumatoid arthritis using adjuvant-induced arthritis (AA) rats. The KETnano gel ointment was prepared using a bead mill method and additives including methylcellulose and Carbopol 934; the mean particle size of the KET nanoparticles was 83 nm. In the in vitro skin penetration experiment, the penetration rate (Jc) and penetration coefficient through the skin (Kp) values of the KETnano gel ointment were significantly higher than those of gel ointment containing KET microparticles (KETmicro gel ointment; mean particle size 7.7 um). On the other hand, in the in vivo percutaneous absorption experiment, the apparent absorption rate constant (ka) and the areas under the KET concentration-time curve values in the skin of rats receiving the KETnano gel ointment were significantly higher than those of rats receiving the KETmicro gel ointment, and the amounts of KET in the skin tissues of rats receiving the KETnano gel ointment were also significantly higher than those of rats receiving the KETmicro gel ointment. In addition, the application of the KETnano gel ointment attenuated the enhancement of paw edema of the hind feet of AA rats more than the application of the KETmicro gel ointment. Our findings suggest that a topical drug delivery system using nanoparticles could lead to expansion in the therapeutic use of KET. PMID- 26632184 TI - Age-Dependent Onset of Insulin Resistance in Insulin-Resistant Mice. AB - We have previously isolated spontaneous insulin-resistant mice (ddY-H) and non insulin-resistant mice (ddY-L) from ddY mice. In the present study, age-dependent onset of insulin resistance in obese ddY-H mice was investigated by comparing with lean ddY-L mice. In ddY-H mice fed a standard diet, an increase in elevation of glucose-stimulated plasma insulin level, glucose intolerance in an intraperitoneal glucose tolerance test, and a reduction of hypoglycemic action of insulin were found at 9 weeks of age, but not at 6 weeks of age. When ddY-H mice were administered nateglinide, a greater elevation of plasma insulin level and a less decrease of serum glucose level were observed at 9 weeks of age. These changes developed progressively with age. These findings suggest that insulin resistance is induced at 9 weeks of age. The age-related change in insulin resistance was correlated with reductions in mRNA expression and protein content of the insulin receptor (InsR), and insulin receptor substrate (IRS)-1 and IRS-2 in the epididymal adipose tissue. On the other hand, in the liver, mRNA expression of InsR and IRS-1 did not change at any age, although that of the IRS 2 was reduced. Thus, in ddY-H mice, insulin resistance and glucose-stimulated hyper-secretion of insulin are induced at 9 weeks of age and are reciprocally affected, resulting in progression to a more severe state at an older age. Insulin resistance may be attributed, at least in part, to the decreases in the mRNA expressions and proteins of InsR, IRS-1 and IRS-2 in adipose tissue. PMID- 26632185 TI - Effects of 2-Octynyladenosine (YT-146) on Mitochondrial Function in Ischemic/Reperfused Rat Hearts. AB - This study investigated the effects of an adenosine receptor agonist, 2 octynyladenosine (YT-146), on mitochondrial function in ischemic and ischemic/reperfused hearts. Isolated rat hearts were perfused in the Langendorff manner with a constant flow rate, and exposed to 30 min of ischemia followed by 60 min of reperfusion. Preischemic treatment with YT-146 significantly improved postischemic recovery of left ventricular developed pressure. The high-energy phosphate content in reperfused hearts treated with YT-146 was also more greatly restored than in untreated hearts. YT-146 treatment attenuated the Na(+) content of a mitochondria-enriched fraction, but not the myocardial Na(+) content, at the end of ischemia. These results suggest that preischemic YT-146 treatment preserves the energy-producing ability of mitochondria during ischemia in the Na(+)-accumulated myocardium. YT-146 also attenuated both the sodium lactate induced decrease in mitochondrial energy-producing ability and the increase in mitochondrial Na(+) concentration in the myocardial skinned fibers. YT-146 may attenuate Na(+) influx to myocardial mitochondria in ischemic cardiac cells, resulting in both preservation of the ability of mitochondria to produce energy and enhancement of the contractile recovery in reperfused hearts. Our findings suggest that the cardioprotective effects of YT-146 against ischemia/reperfusion injury are at least partially due to the preservation of mitochondrial function in the ischemic myocardium. PMID- 26632186 TI - Compound 48/80, a Mast Cell Stimulator, Enhances Synthesis of IgE and IgG Induced by Intranasal Application of Ovalbumin in Mice. AB - Mast cells are well established effector cells of type I hypersensitivity reactions such as allergic rhinitis. However, recent studies have suggested that activated mast cells enhance local immunoglobulin E (IgE) synthesis in the nasal mucosa of allergic rhinitis patients. Therefore, we hypothesized that non immunological mast cell activators may have the potential to enhance local IgE synthesis. Here, we examined the effect of compound 48/80 (C48/80), a mast cell activator, on IgE and immunoglobulin G (IgG) synthesis. Female Balb/c mice were intranasally administered a mixture of ovalbumin (OVA) (1-10 ug/nose) and C48/80 (1-100 ug/nose) on days 0, 7, 14 and 21 and on consecutive days from day 28 to day 42. Intranasal administration of C48/80 with OVA increased serum OVA-specific IgE and IgG. Double staining with fluorescent-labeled OVA and fluorescent-labeled IgE- or IgG-specific antibody demonstrated the presence of OVA-specific IgE- or IgG-producing cells in the nasal mucosa of sensitized mice. Moreover, intranasal administration of C48/80 with OVA increased the nasal mucosal interleukin (IL)-4 level and enhanced the OVA-induced symptom of sneezing. These results suggested that simultaneous activation of mast cells with antigen exposure enhances local IgE and IgG synthesis. PMID- 26632187 TI - Recommended Daily Dose of Sesame Lignans Has No Influence on Oral Absorption of P Glycoprotein Substrates in Rats. AB - Sesamin (SM) and episesamin (ESM) are constituents of sesame seeds, which are used in health foods and considered to have various beneficial effects in the prevention of lifestyle-related diseases. P-Glycoprotein (P-gp) is an ATP-binding cassette transporter involved in drug absorption in the human gastrointestinal tract. A recent report indicated that SM influences P-gp-mediated drug transport. In the present study, we investigated whether SM and ESM inhibit P-gp in vitro, using Caco-2 cells and the typical P-gp substrates rhodamine123 (Rho123) and fexofenadine. SM and ESM showed no effect on accumulation of these compounds, indicating that SM and ESM do not influence P-gp function. In addition, an in vivo study using Rho123 indicated that SM and ESM do not affect absorption of P gp substrates. Overall, these results suggest that health foods containing SM and ESM are unlikely to interact with P-gp substrates. PMID- 26632188 TI - Characterization of Motor Neuron Prostaglandin E2 EP3 Receptor Isoform in a Mouse Model of Amyotrophic Lateral Sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a motor neuron disease with adult onset, characterized by progressive loss of motor neurons. Prostaglandin E2 (PGE2), a lipid mediator, exerts its biological functions by binding to four subtypes of E prostanoid (EP1-4). Among them, EP3 has been shown to have multiple isoforms, EP3alpha, EP3beta, and EP3gamma, produced by alternative splicing. Since PGE2 has been shown to have important pathophysiological roles in ALS, experiments were performed to identify EP3 receptor isoform(s) in spinal motor neurons of wild type (WT) and ALS model (G93A) mice. Reverse transcription-polymerase chain reaction (RT-PCR) analysis of adult mice demonstrated expression of EP3alpha and EP3gamma mRNAs in the lumbar spinal cord, whereas EP3beta mRNA was barely detectable. Laser capture microdissection was used to dissect out motor neurons from frozen samples of lumbar spinal cord in these mice for analysis by real-time PCR. We found that expression of EP3gamma mRNA was predominant in these neurons, whereas EP3alpha and EP3beta mRNAs were undetectable. At the early symptomatic stage, the mRNA expression profiles of these splice isoforms in G93A motor neurons were comparable to those in neurons from WT mice. These results suggest that the PGE2-to-EP3 signaling pathway is mediated mainly by the EP3gamma isoform in the motor neurons of mice, and that modulation of the EP3gamma isoform in motor neurons may be a promising new therapeutic approach for ALS. PMID- 26632189 TI - Identification of a Novel Protein Kinase A Inhibitor by Bioluminescence-Based Screening. AB - We screened inhibitors in the adenylyl cyclase/protein kinase A/cAMP response element binding protein pathway (AC/PKA/CREB pathway) from a 2400 chemical library by a cell-based assay method using bioluminescence probes. We found a compound that inhibited forskolin-induced cAMP response element (CRE)-dependent transcription, the interaction between the kinase-inducible domain (KID) and the interacting domain (KIX), and endogenous CREB phosphorylation. Furthermore, this compound suppressed the activity of the PKA catalytic subunit dose-dependently. On the other hand, this compound did not inhibit forskolin-induced cAMP up regulation. Taken together, we conclude that we have identified a new PKA inhibitor that binds to the catalytic subunit directly. We also succeeded in shortening the screening protocol by excluding a screening step which was used in a previous method. PMID- 26632190 TI - Effects of Angiotensin II Receptor Blockers on Metabolism of Arachidonic Acid via CYP2C8. AB - Arachidonic acid (AA) is metabolized to epoxyeicosatrienoic acids (EETs) via cytochrome enzymes such as CYP 2C9, 2C8 and 2J2. EETs play a role in cardioprotection and regulation of blood pressure. Recently, adverse reactions such as sudden heart attack and fatal myocardial infarction were reported among patients taking angiotensin II receptor blockers (ARBs). As some ARBs have affinity for these CYP enzymes, metabolic inhibition of AA by ARBs is a possible cause for the increase in cardiovascular events. In this study, we quantitatively investigated the inhibitory effects of ARBs on the formation of EETs and further metabolites, dihydroxyeicosatrienoic acids (DHETs), from AA via CYP2C8. In incubations with recombinant CYP2C8 in vitro, the inhibitory effects were compared by measuring EETs and DHETs by HPLC-MS/MS. Inhibition of AA metabolism by ARBs was detected in a concentration-dependent manner with IC50 values of losartan (42.7 uM), telmisartan (49.5 uM), irbesartan (55.6 uM), olmesartan (66.2 uM), candesartan (108 uM), and valsartan (279 uM). Losartan, telmisartan and irbesartan, which reportedly accumulate in the liver and kidneys, have stronger inhibitory effects than other ARBs. The lower concentration of EETs leads to less protective action on the cardiovascular system and a higher incidence of adverse effects such as sudden heart attack and myocardial infarction in patients taking ARBs. PMID- 26632191 TI - CLINICAL APPLICATION OF L-MENTHOL IN THE UPPER GASTROINTESTINAL ENDOSCOPIC PROCEDURE. AB - AIM: Peppermint oil, which suppresses gastric peristalsis during esophagogastroduodenoscopy (EGD), is effective for determining the margin of a gastric tumor. This study was conducted to evaluate the utility of an L-menthol preparation for suppressing gastric peristalsis and for diagnosing gastric tumors. METHODS: The study examined 124 patients who underwent EGD between January and April 2012. After 20 mL of 0.8% L-menthol was sprayed directly onto the mucosal surface of the gastric antrum, the degree of peristalsis suppression in the antrum was evaluated. The effectiveness of L-menthol for identifying new gastric tumors and determining tumor margins was also evaluated. RESULTS: Gastric peristalsis was suppressed in 88.5% (69/78) of patients, with complete suppression of peristalsis achieved in 78.2%. L-menthol exerted a higher peristalsis-suppressive effect in patients with endoscopic gastric mucosal atrophy (93.3%, 56/60) than in patients without atrophy (72.2%, 13/18) (p = .014). L-menthol application caused the detection of new gastric tumors in 1.6% (2/124) of patients and clarification of the margin of three lesions (in 3 patients) identified as having an unclear margin before L-menthol application. CONCLUSION: These results suggest that L-menthol is effective for suppressing gastric peristalsis during EGD and suggest that it is useful for identifying gastric tumors and for determining tumor margins. PMID- 26632192 TI - DOWN'S SYNDROME WITH NEONATAL ALLOIMMUNE THROMBOCYTOPENIA DUE TO HLA-A2 ANTIBODY. AB - Anti-HLA antibodies reportedly exist in the one third of pregnant women. But few occurrences of neonatal alloimmune thrombocytopenia (NAIT) caused by anti-HLA antibodies have been reported. Here a male baby, who was admitted for low birth weight with Down syndrome (DS), was suffered from thrombocytopenia without transient myeloproliferative disorder (TMD). Positive reactions of HLA-specific antibodies were detected in maternal serum. Cross-matching tests between maternal serum and paternal platelets and lymphocytes were strongly positive. It is most conceivable that the previous pregnancy of the mother induced the production of anti-HLA-A2 antibody, which crossed the placenta and subsequently caused an NAIT in the case presented. This is the first case of DS with NAIT due to anti-HLA antibodies. PMID- 26632193 TI - INVESTIGATIVE RESEARCH PROJECTS RELATED TO THE TOHOKU EARTHQUAKE (THE GREAT EAST JAPAN EARTHQUAKE) CONDUCTED IN FUKUSHIMA. AB - BACKGROUNDS: On March 11(th) 2011, the Tohoku region of Japan was struck by catastrophic disasters. Thousands of people were killed due to a magnitude 9.0 earthquake and its subsequent tsunami. Furthermore, a serious nuclear crisis occurred in Fukushima Prefecture as a result of the disasters, and an emergency evacuation was ordered to people living near the nuclear power plants. There was a lot of anxiety regarding lost families as well as the influences of radioactivity on the health of people and their children. Based on these urgent and uncertain situations, a number of research projects were developed at many institutes both inside and outside Fukushima. METHODS: We herein report the investigative research projects related to the Tohoku Earthquake (The Great East Japan Earthquake) conducted after the disasters. The research projects were reviewed by the Institutional Review Board in Fukushima Medical University during the two years following the disasters. The research projects conducted in universities other than Fukushima Medical University were also examined using questionnaire analysis. RESULTS: Among the research projects conducted in Fukushima Medical University (n=424), 7% (n=32) were disaster-related investigative research. The mean duration planned to pursue the projects was 25.5 months. Among these projects, those focusing on the health of Fukushima citizens were most common (n=9), followed by the influence of chronic exposure of radiation on chronic inflammatory disorders (n=6), and the mental health of Fukushima citizens (n=5). They were carefully reviewed for the purpose, suitability, and necessity from ethical as well as scientific viewpoints. The majority of the research projects focused on the effects of the Tohoku Earthquake and/or chronic exposure to low-dose radioactivity on the health of children and pregnant women, as well as on various disorders, such as mental health and chronic inflammatory diseases. On the other hand, among 58 projects we collected from 22 institutes in prefectures other than Fukushima, mental health-related projects were the most common (n=18), followed by radiation exposure-related projects (n=10). CONCLUSIONS: Many of these projects are ongoing, and in particular, long term follow-up regarding the health of the residents of Fukushima Prefecture, especially children and pregnant women, is necessary. PMID- 26632194 TI - Validation of the Ten-Item Internet Gaming Disorder Test (IGDT-10) and evaluation of the nine DSM-5 Internet Gaming Disorder criteria. AB - INTRODUCTION: The inclusion of Internet Gaming Disorder (IGD) in the DSM-5 (Section 3) has given rise to much scholarly debate regarding the proposed criteria and their operationalization. The present study's aim was threefold: to (i) develop and validate a brief psychometric instrument (Ten-Item Internet Gaming Disorder Test; IGDT-10) to assess IGD using definitions suggested in DSM 5, (ii) contribute to ongoing debate regards the usefulness and validity of each of the nine IGD criteria (using Item Response Theory [IRT]), and (iii) investigate the cut-off threshold suggested in the DSM-5. METHODS: An online gamer sample of 4887 gamers (age range 14-64years, mean age 22.2years [SD=6.4], 92.5% male) was collected through Facebook and a gaming-related website with the cooperation of a popular Hungarian gaming magazine. A shopping voucher of approx. 300 Euros was drawn between participants to boost participation (i.e., lottery incentive). Confirmatory factor analysis and a structural regression model were used to test the psychometric properties of the IGDT-10 and IRT analysis was conducted to test the measurement performance of the nine IGD criteria. Finally, Latent Class Analysis along with sensitivity and specificity analysis were used to investigate the cut-off threshold proposed in the DSM-5. RESULTS: Analysis supported IGDT-10's validity, reliability, and suitability to be used in future research. Findings of the IRT analysis suggest IGD is manifested through a different set of symptoms depending on the level of severity of the disorder. More specifically, "continuation", "preoccupation", "negative consequences" and "escape" were associated with lower severity of IGD, while "tolerance", "loss of control", "giving up other activities" and "deception" criteria were associated with more severe levels. "Preoccupation" and "escape" provided very little information to the estimation IGD severity. Finally, the DSM-5 suggested threshold appeared to be supported by our statistical analyses. CONCLUSIONS: IGDT 10 is a valid and reliable instrument to assess IGD as proposed in the DSM-5. Apparently the nine criteria do not explain IGD in the same way, suggesting that additional studies are needed to assess the characteristics and intricacies of each criterion and how they account to explain IGD. PMID- 26632195 TI - Brain stimulation to treat Internet addiction: A commentary. AB - In February, 2015, French television screened a report on Internet addiction (IA) in which an individual, identifying himself as cyberdependent, was offered treatment with repetitive Transcranial Magnetic Stimulation (rTMS), a Non Invasive Brain Stimulation (NIBS) technique. Two issues deserve to be emphasized. Firstly, the concept of IA is not unanimously recognized by scientists and has raised a number of questions. Secondly, although the first results suggest that brain stimulation techniques could be a potential therapy for Substance Use Disorders (SUDs), no data are available on the therapeutic effects of rTMS on IA or even excessive Internet use. Currently, we cannot promote the use of rTMS for Internet detoxification because there is no evidence to prove its efficacy. Nevertheless, the similarities between SUDs and IA, and the results of NIBS on SUDs suggest that research can be done to examine the efficacy of NIBS techniques to treat Internet gaming disorder and other forms of IA. PMID- 26632196 TI - A certain shade of green: Can algal pigments reveal shading effects of nanoparticles? PMID- 26632197 TI - Gait alterations can reduce the risk of edge loading. AB - Following metal-on-metal hip arthroplasty, edge loading (i.e., loading near the edge of a prosthesis cup) can increase wear and lead to early revision. The position and coverage angle of the prosthesis cup influence the risk of edge loading. This study investigates the effect of altered gait patterns, more specific hip, and pelvis kinematics, on the orientation of hip contact force and the consequent risk of antero-superior edge loading using muscle driven simulations of gait. With a cup orientation of 25 degrees anteversion and 50 degrees inclination and a coverage angle of 168 degrees , many gait patterns presented risk of edge loading. Specifically at terminal double support, 189 out of 405 gait patterns indicated a risk of edge loading. At this time instant, the high hip contact forces and the proximity of the hip contact force to the edge of the cup indicated the likelihood of the occurrence of edge loading. Although the cup position contributed most to edge loading, altering kinematics considerably influenced the risk of edge loading. Increased hip abduction, resulting in decreasing hip contact force magnitude, and decreased hip extension, resulting in decreased risk on edge loading, are gait strategies that could prevent edge loading. (c) 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1069-1076, 2016. PMID- 26632198 TI - EZH2 phosphorylation regulates Tat-induced HIV-1 transactivation via ROS/Akt signaling pathway. AB - EZH2 plays a major role in HIV-1 latency, however, the molecular linkage between Tat-induced HIV-1 transactivation and EZH2 activity is not fully understood. It was shown Tat induced HIV-1 transactivation through inhibiting EZH2 activity. Tat decreased the levels of H3K27me3 and EZH2 occupy at the long terminal repeat (LTR) of HIV-1. We further showed for the first time that transfected with Tat construct resulted in an increase in phosphorylated EZH2 (p-EZH2), mediated by active Akt. ROS/Akt-dependent p-EZH2 was correlated with Tat-induced transactivation. Our study reveals that novel mechanisms allow Tat-induced HIV-1 transactivation by ROS/Akt-dependent downregulating the EZH2 epigenetic silencing machinery. PMID- 26632199 TI - Protective Effects of Manassantin A against Ethanol-Induced Gastric Injury in Rats. AB - Manassantin A, a neolignan isolated from Saururus chinensis, is a major phytochemical compound that has various biological activities, including anti inflammatory, neuroleptic, and human acyl-CoA : cholesterol acyltransferase (ACAT) inhibitory activities. In this study, we investigated the protective effects of manassantin A against ethanol-induced acute gastric injury in rats. Gastric injury was induced by intragastric administration of 5 mL/kg body weight of absolute ethanol to each rat. The positive control group and the manassantin A group were given oral doses of omeprazole (20 mg/kg) or manassantin A (15 mg/kg), respectively, 1 h prior to the administration of absolute ethanol. Our examinations revealed that manassantin A pretreatment reduced ethanol-induced hemorrhage, hyperemia, and epithelial cell loss in the gastric mucosa. Manassantin A pretreatment also attenuated the increased lipid peroxidation associated with ethanol-induced acute gastric lesions, increased the mucosal glutathione (GSH) content, and enhanced the activities of antioxidant enzymes. The levels of pro-inflammatory cytokines, tumor necrosis factor-alpha (TNF alpha), interleukin (IL)-6, and IL-1beta were clearly decreased in the manassantin A-pretreated group. In addition, manassantin A pretreatment enhanced the levels of cyclooxygenase (COX)-1, COX-2, and prostaglandin E2 (PGE2) and reduced the inducible nitric oxide synthase (iNOS) overproduction and nuclear factor kappa B (NF-kappaB) phosphorylation. Collectively, these results indicate that manassantin A protects the gastric mucosa from ethanol-induced acute gastric injury, and suggest that these protective effects might be associated with COX/PGE2 stimulation, inhibition of iNOS production and NF-kappaB activation, and improvements in the antioxidant and anti-inflammatory status. PMID- 26632200 TI - Dibutyl Maleate and Dibutyl Fumarate Enhance Contact Sensitization to Fluorescein Isothiocyanate in Mice. AB - Di-n-butyl phthalate (DBP), a phthalate ester, has been shown to have an adjuvant effect on fluorescein isothiocyanate (FITC)-induced contact hypersensitivity (CHS) mouse models. Di-n-butyl maleate (DBM), widely used as a plasticizer for industrial application, has been reported to cause dermatitis in humans. DBM is a butyl alcohol ester of di-carboxylic acid that represents a part of the DBP structure, while di-n-butyl fumarate (DBF) is a trans isomer of DBM. We examined whether DBM or DBF exhibits an adjuvant effect like DBP does. When BALB/c mice were epicutaneously sensitized with FITC in the presence of DBM or DBF, the FITC specific CHS response was enhanced, as we have observed for DBP. As to underlying mechanisms, DBM and DBF facilitated the trafficking of FITC-presenting CD11c(+) dendritic cells (DCs) from skin to draining lymph nodes and increased the cytokine production by draining lymph nodes. In conclusion, DBM and DBF may have an effect that aggravates contact dermatitis through a skin sensitization process. PMID- 26632201 TI - Possible effects of repeated exposure to ibuprofen and acetaminophen on the intestinal immune response in young infants. AB - There has been an exponential increase in the frequency of immune deviations in young children. Consequently, research investigating environmental causes for this increase has become a Public Health priority. We have summarized the experimental observations and epidemiological data that could link repeated acetaminophen and ibuprofen exposure in early infancy to this increase. Recent observations on the maturational immunity of the intestinal sub-mucosal lamina propria underscore indeed the importance of prostaglandins (PGE2s). PGE2 appearing at this sub-mucosal level is a product of arachidonic acid metabolism mediated by type-2 cyclooxygenase (COX-2) situated on the membrane of many immune cells. Moreover, it seems that acetaminophen - like ibuprofen - also carries a non-selective inhibitory action on peripheral COXs, besides its central action. This inhibitory action of acetaminophen on COX2 only relates to physiological, low arachidonic acid concentrations. This explains the difference in anti inflammatory effects. The impact of repeated inhibition of mucosal PGE2 synthesis due to COX-inhibitor exposure on maturational immunity has been demonstrated in animal experiments. Repeatedly exposed young animals do not develop tolerance to food antigens and exhibit autoimmune deviations. Several recent epidemiological studies have also reported on the magnitude of acetaminophen and ibuprofen exposure in children and the increase in immune deviations, it is important to better understand the potential negative impact of repeated inhibitions of prostaglandin synthesis by COX2s during infancy. Since acetaminophen and ibuprofen are commonly administered analgesics and antipyretics, a well-designed prospective strategy for pharmacovigilance and -epidemiology of COX-inhibitor exposure in infancy is urgently needed. PMID- 26632202 TI - Potential benefit of lamotrigine in managing ketamine use disorder. AB - Ketamine is an anesthetic derivative of phencyclidine (PCP; 'Angel dust') with dissociative, analgesic and psychedelic properties. Ketamine has become a popular recreational drug of abuse in many parts of the world in recent years. The preclinical studies demonstrate the reinforcing effects of ketamine and long-term ketamine abuse induces a delayed and persistent upregulation of dopamine system. In humans, there have been concerns about its liability to development of addiction. The dilemma of mental professionals in managing the treatment-seeking ketamine abusers comes from a lack of effective pharmacotherapy. Limiting evidence showed that lamotrigine, which inhibits glutamate release, is effective to reduce cocaine craving. We propose that lamotrigine might be beneficial for managing ketamine use disorder clinically. We also reported one case of ketamine use disorder who experienced a great reduction in craving and ketamine use after taking lamotrigine. Although the mechanisms underlying neuroadaptation and reward related to ketamine are not entirely clear, future clinical trials are needed to advance our understanding of the benefit yielded by lamotrigine to treat ketamine use disorder. PMID- 26632203 TI - Human gastric cancer, Helicobacter pylori and bracken carcinogens: A connecting hypothesis. AB - Long term infection of Helicobacter pylori (Hp) virulent strains is a key factor in the genesis of human gastric cancer, and so are certain dietary proinflammatory and genotoxic compounds. Carcinogenic bracken fern (Pteridium spp.) is one of these. Toxins from this plant are consumed as bracken culinary preparations, through milk and meat of bracken-exposed livestock, and drain waters from bracken swards. Bracken toxin ptaquiloside (PtQ), a suspected human carcinogen, elicits complex responses in animals leading to death. PtQ and Hp might cooperate in gastric pathologies. This paper presents an hypothesis on PtQ Hp association leading to the enhancement of carcinogenesis in the human gastric environment that might explain the high gastric cancer incidence and death rates among Hp-infected people living in bracken zones at two levels: (1) The macroscopic scale comprising the flow of PtQ in the human diet. (2) the microscopic scale encompassing (A) gastric luminal medium; (B) gastric mucus structure and mucin degradation elicited by Hp; (C) bacterial pH gradient modification of the gastric mucosa that favors PtQ survival and its penetration into epithelial tissue; (D) combined PtQ/Hp effects on gastric immune and inflammatory responses; (E) PtQ-Hp complementary activity at selected cell signaling cascades and genome disturbance. PMID- 26632204 TI - Pseudoreplication, one-tailed tests, neofisherianism, multiple comparisons, and pseudofactorialism. PMID- 26632205 TI - Retraction: Deficits of learning and memory in Hemojuvelin knockout mice. AB - This article has been retracted at the request of the authors. PMID- 26632206 TI - Comparison of natural crosslinking agents for the stabilization of xenogenic articular cartilage. AB - Osteochondral xenografts are potentially inexpensive, widely available alternatives to fresh allografts. However, antigen removal from xenogenic cartilage may damage the extracellular matrix and reduce compressive stiffness. Non-crosslinked xenogenic cartilage may also undergo rapid enzymatic degradation in vivo. We hypothesized that natural crosslinking agents could be used in place of glutaraldehyde to improve the mechanical properties and enzymatic resistance of decellularized cartilage. This study compared the effects of genipin (GNP), proanthocyanidin (PA), and epigallocatechin gallate (EGCG), on the physical and mechanical properties of decellularized porcine cartilage. Glutaraldehyde (GA) served as a positive control. Porcine articular cartilage discs were decellularized in 2% sodium dodecyl sulfate and DNase I followed by fixation in 0.25% GNP, 0.25% PA, 0.25% EGCG, or 2.5% GA. Decellularization decreased DNA by 15% and GAG by 35%. For natural crosslinkers, the average degree of crosslinking ranged from approximately 50% (EGCG) to 78% (GNP), as compared to 83% for the GA control. Among the natural crosslinkers, only GNP significantly affected the disc diameter, and shrinkage was under 2%. GA fixation had no significant effect on disc diameter. Decellularization decreased aggregate modulus; GA and GNP, but not EGCG and PA, were able to restore it to its original level. GNP, PA, and GA conferred a similar, almost complete resistance to collagenase degradation. EGCG also conferred substantial resistance but to a lesser degree. Overall, the data support our hypothesis and suggest that natural crosslinkers may be suitable alternatives to glutaraldehyde for stabilization of decellularized cartilage. (c) 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1037-1046, 2016. PMID- 26632207 TI - Effect of two assisted oocyte activation protocols used to overcome fertilization failure on the activation potential and calcium releasing pattern. AB - OBJECTIVE: To assess the effect of two assisted oocyte activation (AOA) protocols with the use of two calcium (Ca(2+)) ionophores, ionomycin and A23187 (calcimycin), on the intracellular Ca(2+) level in mouse and human oocytes and the fertilization rates. DESIGN: Comparison of two Ca(2+) ionophores, ionomycin and A23187, regarding their capacity to increase the intracellular Ca(2+) level and to support subsequent oocyte activation and development. SETTING: University hospital research laboratory. PATIENT(S)/ANIMAL(S): Patients undergoing intracytoplasmic sperm injection (ICSI) treatment and B6D2F1 mice. INTERVENTION(S): Assisted oocyte activation and microinjection of mouse and human oocytes with sperm. MAIN OUTCOME MEASURE(S): Measurement of the fertilizing and Ca(2+)-releasing ability of human sperm. RESULT(S): Ionomycin was more potent than A23187 in provoking Ca(2+) increases in both mouse and human oocytes with significantly higher amplitude and area under the receiver operating characteristic curve. The oocyte activation rate was significantly higher when mouse oocytes were activated with the use of the ionomycin- rather than the A23187-based AOA protocol. Furthermore, oocyte activation rate was higher when human in vitro matured oocytes were activated with the ionomycin-based AOA protocol, but the difference did not reach statistical significance. CONCLUSION(S): In both mouse and human oocytes, the AOA protocol that used ionomycin was more efficient than the one that used A23187. Bearing in mind that mammalian fertilization is successful when the total dose of Ca(2+) released reaches a minimal threshold, the use of ionomycin for human AOA might be justified instead of the use of A23187. PMID- 26632208 TI - Diversion neovaginitis after sigmoid vaginoplasty: endoscopic and clinical characteristics. AB - OBJECTIVE: To assess the endoscopic characteristics of the sigmoid-derived neovagina, which have been scarcely described. DESIGN: Prospective observational study. SETTING: University tertiary medical center. PATIENT(S): Patients that underwent sigmoid vaginoplasty. INTERVENTION(S): Patients were invited yearly to undergo neovaginoscopy and sigmoidoscopy, preceded by taking a medical history and physical examination, as routine follow-up. MAIN OUTCOME MEASURE(S): Endoscopic signs of neovaginal inflammation. RESULT(S): Thirty-four patients with a sigmoid neovagina underwent a total of 43 combined neovaginoscopies and sigmoidoscopies. After a mean postoperative time of 23 months, the most notable endoscopic features of the sigmoid-derived neovagina comprised a diminished vascular pattern, edema, granularity, friability, decreased resilience, and erythema. In the control rectosigmoidoscopy images, no concurrent abnormalities were observed. When applying the MAYO score to the neovaginal images, 12 (35%) patients scored MAYO 0, 19 (56%) MAYO I, 3 (9%) MAYO II, and none MAYO III. The presence of neovaginal discharge and malodor correlated with inflammatory endoscopic alterations. CONCLUSION(S): The endoscopic appearance of a sigmoid segment after use in neovaginoplasty differs significantly from that of the remaining rectosigmoid. Inflammatory changes of the sigmoid-derived neovagina were observed in most patients. Clinically, the inflammatory changes appear similar to those encountered in diversion colitis. PMID- 26632209 TI - Optimal polar bodies angle for higher subsequent embryo viability: a pilot study. AB - OBJECTIVE: To determine the optimal polar bodies (PB) angle for higher subsequent embryo implantation potential. DESIGN: Prospective study. SETTING: Academic fertility center. PATIENT(S): From January to July 2015, 116 patients were recruited in their first IVF-ET cycles. INTERVENTION(S): At the pronuclear stage, PB angle was measured with the use of E-ruler 1.1. MAIN OUTCOME MEASURE(S): The primary outcome measure was good-quality embryo rate. Secondary measures were clinical pregnancy rate (CPR) and embryo implantation rate (IR). RESULT(S): A total of 1,103 oocytes were retrieved. PB angle was measured in 454 zygotes, and 164 of their subsequent embryos were transferred into the uterus. All-or-none implantation took place in 129 embryos, and 89 patients accepted fresh embryo(s) transfer with known PB angle. By means of receiver operating characteristic analysis, the optimal PB angle for subsequent embryo implantation was 24.25 degrees . Based on this cutoff value, 454 zygotes were divided into two groups: small-angle and large-angle. A higher percentage of small-angle zygotes developed into good-quality embryos (70.97% vs. 58.58%). CPR and IR both decreased progressively from purely small-angle embryos to mixed embryos to purely large angle embryos (CPR: 72.41% vs. 38.46% vs. 26.47%, respectively; IR: 63.27% vs. 26.92% vs. 16.67%, respectively). CONCLUSION(S): Noninvasive assessment of PB angle is a viable technique for zygote selection and should be included in embryo selection parameters. CLINICAL TRIAL REGISTRATION NUMBER: CLINICAL TRIAL REGISTRATION NUMBER: ChiCTR-OOC-15005882. PMID- 26632210 TI - A Highly Selective Inhibitor of Glycine Transporter-1 Elevates the Threshold for Maximal Electroshock-Induced Tonic Seizure in Mice. AB - Many anti-epileptic drugs (AEDs) that mainly target ion channels or post-synaptic receptors are in clinical use, but a proportion of patients are resistant to these traditional AEDs and experience repeated severe break-out seizures. Given its involvement in the etiology of epilepsy, the neurotransmitter glycine may serve as a novel target for epilepsy treatment. Increasing evidence suggests that inhibitors of glycine transporter 1 (GlyT1) exhibit anti-seizure properties in mouse models and show potential as anti-convulsions drugs. In the present study, we investigated the effect of a highly selective GlyT1 inhibitor (named M22) on glycine transport kinetics using a radioactive substrate uptake assay and investigated the anti-seizure effects of M22 on the maximal electroshock seizure threshold (MEST) test and the timed intravenous (i.v.) pentylenetetrazole (PTZ) intravenous test. Our results demonstrate that M22 was capable of elevating the seizure threshold in the MEST test but did not alter the seizure threshold in the PTZ i.v. test. Strychnine, an inhibitor of glycine receptor activity, reversed the threshold elevation at a subconvulsive dosage (0.1 mg/kg subcutaneously) in the MEST test and did not affect M22 plasma levels in mice, suggesting that the anti-seizure effect in this model may be mediated by increased glycine receptor activity. Moreover, M22 administration did not influence motor function and coordination in mice. In combination with the previously reported excellent pharmacokinetic features of M22, our present results suggested that M22 has the potential to serve as a new anti-convulsive drug or as a lead compound for the development of AEDs. PMID- 26632211 TI - Calix[8]arene Sulfonic Acid Catalyzed Three-Component Reaction for Convenient Synthesis of 3,4-Dihydropyrimidin-2(1H)-ones/thiones under Ultrasonic Irradiation. AB - In this work, the catalytic activity of calix[8]arene sulfonic acid was successfully investigated for the famous Biginelli reaction. Under ultrasonic irradiation, calix[8]arene sulfonic acid could efficiently catalyzed the three component reaction of aldehydes with ethyl acetoacetate and urea or thiourea in ethanol to afford the corresponding 3,4-dihydropyrimidin-2(1H)-ones/thiones in 46 93%. The advantages of this method are the easy isolated procedure, short reaction time and low cost of the catalyst. PMID- 26632212 TI - Superbunching and Nonclassicality as new Hallmarks of Superradiance. AB - Superradiance, i.e., spontaneous emission of coherent radiation by an ensemble of two-level atoms in collective states introduced by Dicke in 1954, is one of the enigmatic problems of quantum optics. The startling gist is that even though the atoms have no dipole moment they radiate with increased intensity in particular directions. Following the advances in our understanding of superradiant emission by atoms in entangled W-states we examine the quantum statistical properties of superradiance. Such investigations require the system to have at least two excitations in order to explore the photon-photon correlations of the radiation emitted by such states. We present specifically results for the spatially resolved photon-photon correlations of systems prepared in doubly excited W states and give conditions when the atomic system emits nonclassial light. Equally, we derive the conditions for the occurrence of bunching and even of superbunching, a rare phenomenon otherwise known only from nonclassical states of light like the squeezed vacuum. We finally investigate the photon-photon cross correlations of the spontaneously scattered light and highlight the nonclassicalty of such correlations. The theoretical findings can be implemented with current technology, e.g., using ions in a linear rf-trap, atoms in an optical lattice or quantum dots in a cavity. PMID- 26632213 TI - Trends in incidence versus case fatality rates of pulmonary embolism: Good news or bad news? PMID- 26632214 TI - Imaging Features of Sinonasal Inverted Papilloma: A Pictorial Review. AB - Computed tomography and magnetic resonance imaging are widely used for evaluation of patients with nasal masses, playing an integral role in their diagnosis and treatment. Inverted papilloma is a rare tumor of the sinonasal region that demonstrates characteristic imaging appearances. Preoperative diagnosis and precise tumor extent are essential for surgical planning as this tumor grows centrifugally and has high potential to recur following incomplete surgery. This pictorial review aims to illustrate the spectrum of imaging features of inverted papilloma and highlight the key features that are useful for making an accurate diagnosis of this condition. Common differential diagnoses are also discussed. PMID- 26632215 TI - [In memoriam of Dr. Yoshiro Terawaki]. PMID- 26632216 TI - [Pathogenic factors of mycoplasma]. AB - Mycoplasmas are smallest organisms capable of self-replication and cause various diseases in human. Especially, Mycoplasma pneumoniae is known as an etiological agent of pneumonia. From 2010 to 2012, epidemics of M. pneumoniae infections were reported worldwide (e.g., in France, Israel, and Japan). In the diseases caused by mycoplasmas, strong inflammatory responses induced by mycoplasmas have been thought to be important. However, mycoplasmas lack of cell wall and do not possess inflammation-inducing endotoxin such as lipopolysaccharide (LPS). We purified inflammation-inducing factors from pathogenic mycoplasmas and identified that they were lipoproteins. Lipoproteins derived from mycoplasmas induced inflammatory responses through Toll-like receptor (TLR) 2. In addition, we demonstrated that cytadherent property of M. pneumoniae played an important role in induction of inflammatory responses. Cytadherent property of M. pneumoniae induced inflammatory responses through TLR2 independent pathway. TLR4, inflammasomes, and autophagy were involved in this TLR2 independent induction of inflammatory responses. PMID- 26632217 TI - [Mechanism of bacterial gliding motility]. AB - Bacteria have various way to move over solid surfaces, such as glass, agar, and host cell. These movements involve surface appendages including flagella, type IV pili and other "mysterious" nano-machineries. Gliding motility was a term used various surface movements by several mechanisms that have not been well understood in past few decades. However, development of visualization techniques allowed us to make much progress on their dynamics of machineries. It also provided us better understanding how bacteria move over surfaces and why bacteria move in natural environments. In this review, I will introduce recent studies on the gliding motility of Flavobacteium and Mycoplasma based on the detail observation of single cell and its motility machinery with micro-nano scales. PMID- 26632218 TI - [Diversity in genome and epigenome of Helicobacter pylori]. AB - Helicobacter pylori infects human stomach and cause various gastric diseases including gastric cancer. The species is also known for rapid evolution and wide geographical diversity of genome sequence. Our team sequenced whole genome sequences of H. pylori strains isolated from Japanese patients and compared with whole genome sequences of H. pylori strains with other geographic origin and found that not only the gene repertoire but also genome structures and epigenetic modifications such as DNA methylations had large diversity with various mechanisms. Genome inversion events were geography specific and some of them were found to occur with gene duplication at their termini. DNA methylation states of H. pylori genomes suggested that they are diversified by both existence/absence repertoire of methyltransferase genes and by the movement of target recognition domain in the methyltransferase genes. Omics analysis revealed that methylation target sequence and transcriptome status are actually diversified by the domain sequence movement. We suggested that H. pylori utilizes these genome structure and methylome diversity for its adaptive evolution. PMID- 26632219 TI - [Evaluation of resistance mechanism against antimicrobial factors in gram positive bacteria]. AB - It is known that various antibacterial agents are observed in human for preventing bacterial infection. In this study, in order to elucidate the resistance mechanism against antimicrobial agents derived of human and bacteriocins derived of commensal bacteria, we systematically evaluated the roles of the bacteria-specific two-component systems of Staphylococcus aureus and Streptococcus mutans which colonize to different sites. Two-component systems (TCSs) are specific regulatory systems in bacteria that play an important role in sensing and adapting to the environment. As the result, four TCSs of S. aureus and three TCSs of S. mutans were associated with resistance against defensin and LL37 as antimaicrobial peptides and nisin A and nukacin ISK-1 as bacteriocins. Two TCSs that are individually associated with resistance against the bacteriocins nisin A (class I type A[I]) and nukacin ISK-1 (class I type A[II]) were identified in S. mutans, whereas one TCS is associated with main resistance against the both of nisin A and nukacin ISK-1. This result suggested that TCSs play important roles on acquisition of human- and bacteria-derived antibacterial agents. However, the resistance mechanism via TCS in S. aureus is quite different from that of in S. mutans. Additional evidence suggests that these TCSs are required for co-existence with other bacteria producing to nisin A or nukacin ISK 1, meaning that the roles of bacteriocins in the interactions between different species of commensal bacteria and the importance of TCSs in this process. Our results will highlight the roles of bacterial colonization in human being are constituted on the adaptation against antibacterial agents derived from human and commensal bacteria via TCSs. PMID- 26632220 TI - Novel functions of platelets in the liver. AB - Platelets contain not only proteins needed for hemostasis but also many growth factors that are required for organ development, tissue regeneration, and repair. Thrombocytopenia, which is frequently observed in patients with chronic liver disease (CLD) and cirrhosis, is due to various causes, such as decreased thrombopoietin production and accelerated platelet destruction caused by hypersplenism; however, the relationship between thrombocytopenia and hepatic pathogenesis and the role of platelets in CLD are poorly understood. Thus, in this paper, the experimental evidence for platelets improving liver fibrosis and accelerating liver regeneration is summarized and addressed based on studies conducted in our laboratory and current progress reports from other investigators. Platelets improve liver fibrosis by inactivating hepatic stellate cells to decrease collagen production. The level of intracellular cAMP is increased by adenosine through its receptors on hepatic stellate cells, thereby resulting in inactivation of these cells. Adenosine is produced by degradation of adenine nucleotides, which are stored in abundance within the dense granules of platelets. The regenerative effect of platelets in the liver consists of three mechanisms: a direct effect on hepatocytes, a cooperative effect with liver sinusoidal endothelial cells, and a collaborative effect with Kupffer cells. Based on these experiments, a clinical trial suggested that the increase in platelets induced by platelet transfusion improved liver function in patients with CLD in a clinical setting.We highlight the current knowledge concerning the role of platelets in CLD and expect to open a novel avenue for application of these clinical therapies to treat liver disease. PMID- 26632221 TI - Biochemical surface modifications to titanium implants using the tresyl chlorideactivated method. AB - Tresyl chloride (2,2,2-trifluoroethanesulfonyl chloride)-activated method is an easy and simple method for immobilizing biological molecules onto a titanium surface. Tresyl chloride was directly dropped onto a titanium surface without any solvent. Tresylated titanium disks were immersed in a protein or peptide solution to give protein- or peptide-immobilized titanium. Frontier molecular orbital calculations suggested that tresylation of the OH compound improved its reactivity towards the amine groups of protein compounds. Quartz-crystal microbalance-dissipation measurements suggested that ionic interaction between the oxygen of the terminal hydroxyl groups of titanium and the nitrogen of fibronectin was important for fibronectin immobilization. Initial cell attachment was enhanced by fibronectin or collagen immobilization. Fibronectin and fibronectin-derived peptide immobilization improved the expression of specific genes related to bone formation. The immobilization of cytokine onto titanium enhanced bone formation following its implantation into rat femur defects. The tresyl chloride-activated method is useful for immobilizing biological molecules onto titanium surfaces. PMID- 26632222 TI - Effect on the bond strengths of glass fiber posts functionalized with polydopamine after etching with hydrogen peroxide. AB - This paper evaluated the push-out bond strengths of glass fiber posts with poly dopamine (poly-dopa) functionalized after etching with H2O2. Forty extracted human, single-rooted teeth were endodontically treated and a 9-mm post space was prepared in each tooth with post drills provided by the manufacturer. Specimens were randomly assigned into four groups (n=10 per group), depending on post surface treatment used: group C (control); group D (poly-dopa); group H (H2O2); and group HD (H2O2+poly-dopa). The push-out test was performed using a universal testing machine. RESULTS: Bond strengths (MPa) were as follows: 4.678+/-0.911 (group C); 7.909+/-1.987 (group D); 6.519+/-0.893 (group H); and 9.043+/-1.596 (group HD). The bond strength of the resin cement to posts functionalized with poly-dopa was not affected by H2O2 pre-treatment, while conditioning using H2O2+poly-dopa resulted in higher bond strengths than H2O2 treatment only. Compared to H2O2 treatment, the bond strength of poly-dopa conditioning was superior. PMID- 26632223 TI - Fracture behavior of pontics of fiber-reinforced composite fixed dental prostheses. AB - To evaluate the load-bearing capacities and failure mechanisms of FRC FDPs using shell-shaped acrylic denture teeth as pontics with different composite resins as filling materials. Eighty-four inlay-retained FDPs with FRC frameworks were made using shell-shaped posterior artificial teeth as pontics. Different composite resins were used as filling materials to complete the shape of the pontics. Four groups (n=21/group) were formed based on the filling material. Each group was subdivided into three subgroups and tested at 90o and 30 degrees . Each FDP was statically loaded from the pontic until the final fracture. ANOVA revealed statistically significant differences in the load-bearing capacities according to filling material, angle and storage (p<0.01). The fracture propagated from the fiber-rich part of the pontic towards the occlusal surface of the FDP. The filling material influenced the load-bearing capacities of FRC FDPs with shell shaped denture teeth used as pontics. PMID- 26632224 TI - Fluorescence of composite resins: A comparison among properties of commercial shades. AB - The aim of this study was to determine singular fluorescence qualities of different, commercially available resin composites shades. A total of 234 brand name colors including enamel, dentin and special shades were examined using a monochromator-based spectrophotometer. From the examined composites, Filtek Z250 (867+/-279) RFU and Supreme XT (dentin shades: (1,585+/-507) RFU; enamel shades: (4,473+/-330) RFU) are the only brands with a mean fluorescence maximum that resembles the fluorescence of natural samples. The shade types of the other brands showed a three to fifteen times higher mean maximum fluorescence (dentin shades: (10,331-47,774) RFU; enamel shades: (19,283-38,264) RFU; special shades: (35,934-60,001) RFU). The results of the present study supply for the first time individual fluorescence qualities of a vast sample of different composite shades, data needed not only for the development of new materials, but for diagnostic reasons in routine (re-)treatment, forensic and epidemiological endeavors. PMID- 26632225 TI - Tissue reactions after subcutaneous and intraosseous implantation of iRoot SP, MTA and AH Plus. AB - The purpose of this study was to evaluate the reactions of rat subcutaneous connective tissue and bone tissue to iRoot SP, ProRoot MTA, and AH Plus. Specimens were implanted in the dorsal subcutaneous connective tissue and tibias of 36 Wistar rats. Tissue specimens were collected after rats were sacrificed at 7, 30, and 60 days after implantation. Histologic evaluations comprising inflammation severity and new bone formation were blindly made on hematoxylin and eosin-stained sections. In subcutaneous implant test, AH Plus group showed more infiltration of inflammatory cells than the other three groups at 30 days (p<0.05). In intraosseous implant test, number of inflammatory cells decreased in all groups at 7, 30, and 60 days after implantation with no statistically significant differences. Given the similar inflammatory reactions to iRoot SP and MTA, it was concluded that iRoot SP and MTA were biocompatible with the subcutaneous and intraosseous tissues of rats. PMID- 26632226 TI - Application of noble metal cluster to PMMA resin and influence on mechanical properties and color. AB - To improve the mechanical strength of denture base resin, several types of noble metal cluster were introduced into PMMA, and the mechanical properties and color changes were evaluated. Complex salts of gold, silver, platinum, and palladium were used as the raw materials of noble metal clusters, and after adding each cluster to MMA, polymerization and thermal treatment were performed to produce PMMA-noble metal cluster complexes. Bending deflection, bending strength, and Vickers hardness were measured, and the formation conditions of metal clusters were investigated using EPMA, SEM, and TEM. Furthermore, color changes between before and after metal cluster creation were measured. The bending deflection increased with the addition of silver and platinum, and decreased with the addition of palladium. The bending strength was lowest with the addition of gold, highest with the addition of palladium. Vickers hardness increased with the addition of palladium. Color differences increased with increasing thermal treatment temperature. PMID- 26632227 TI - Experimental study of influence of direct bisphosphonate administration on bone substitute. AB - Articular cartilage has a low self-repair ability and natural healing cannot be expected. Treatment using various bone substitutes has been performed, but these have various disadvantages. Compared to autologous bone substitutes, the osteochondral repair ability of allogeneic bone substitutes is low, but the effective and safe utilization of these as a bone substitute may be possible by improving their osteochondral repair ability. We prepared a full-thickness osteochondral defect in the patellar fossa of rabbits, added a bisphosphonate preparation to bovine tooth-derived Demineralized Dentin Matrix (DDM), which has its own osteochondral repair ability, and investigated osteochondral repair ability in the defects. As a result, we suggest that the addition of high-dose BPs inhibits the osteochondral repair ability of DDM. PMID- 26632228 TI - Effects of various chair-side surface treatment methods on dental restorative materials with respect to contact angles and surface roughness. AB - Available chair-side surface treatment methods may adversely affect prosthetic materials and promote plaque accumulation. This study investigated the effects of treatment procedures on three resin restorative materials, zirconium-dioxide and polyetheretherketone in terms of surface roughness and hydrophobicity. Treatments were grinding with silicon carbide paper or white Arkansas stone, blasting with prophylaxis powder and polishing with diamond paste. Surface roughness was assessed using confocal laser scanning. Hydrophobicity as measured by water contact angle was determined by computerized image analysis using the sessile drop technique. All of the specific surface treatments performed led to significant changes in contact angle values and surface roughness (Ra) values. Median contact angle values ranged from 51.6 degrees to 114 degrees . Ra values ranged from 0.008 um to 2.917 um. Air-polishing as well as other polishing procedures increased surface roughness values in all materials except zirconium dioxide. Polyetheretherketone displayed greatest change in contact angle values after air-polishing treatment. PMID- 26632229 TI - Infiltration of trace metal ions in the oral mucosa of a rat analyzed using SRXRF, XAFS, and ICP-MS. AB - Although the accumulation and distribution of metals from metallic orthodontic appliances in the oral mucosa have been studied extensively, they remain unclear because their concentration is quite low. In this study, metal specimens (Ni, Ni Ti, and Co-Cr) were sutured in the unilateral oral mucosa of rats, and the distribution of the eluted elements in the mucosal tissue was estimated using inductively coupled plasma mass spectrometry (ICP-MS) and synchrotron radiation X ray fluorescence analysis (SR-XRF). While the infiltrations of Ni, Co, and Cr into the oral mucosal connective tissue were observed with SR-XRF, significant increases were only found in Ni from the pure Ni group and Cr from the Co-Cr group. Furthermore, Ni and Co were estimated as hydrated ions while Cr was estimated in oxide form through X-ray absorption fine structure (XAFS) analysis. PMID- 26632230 TI - Influence of resin coating on bond strength of self-adhesive resin cements to dentin. AB - This study evaluated the effect of resin coating (COA) on dentin bond strength (BS) of five resin cements (RC). Ten groups were tested, according to RC and COA combinations. RCs were applied onto prepolymerized resin discs, which were bonded to dentin surfaces. Teeth were stored in water for 24 h, subjected to 5,000 thermocycles and sectioned to obtain beams, which were tested in tension. The COA increased the BS for Panavia F2.0, RelyX Unicem, and RelyX Unicem 2, whereas no changes in BS were observed for two other RCs; Clearfil SA Cement, which showed the lowest BS among groups with COA and G-Cem, which showed the highest BS among RCs without COA. COA can increase the BS of RC depending on the type of RC. PMID- 26632231 TI - Enamel cracks evaluation - A method to predict tooth surface damage during the debonding. AB - The objective of this in vitro study was to evaluate the effect of the enamel cracks on the tooth damage during the debonding. Measurements of the cracks characteristics (visibility, direction, length, and location) were performed utilizing a scanning electron microscopy (SEM) technique and mathematically derived formulas (x=h/30, l=n*x) before and following the removal of mechanically retained metal and ceramic brackets. The likelihood of having greater extent enamel defects was higher for the teeth with pronounced cracks (odds vatios, OR=3.728), increased when the crack was located in more than one zone of the tooth (OR=1.998), and the inclination did not exceed 30-45 degrees (OR=0.505). Using ceramic brackets the risk of greater amount tooth structure defects raised 1.45 times (OR=1.450). Enamel crack showing all these characteristics at the beginning of the orthodontic treatment and the use of ceramic brackets might predispose to higher risk of greater extent tooth surface damage after the debonding by 20.4%. PMID- 26632232 TI - Digitization of dental alginate impression: Three-dimensional evaluation of point cloud. AB - The purpose of this study was to evaluate the digitization of alginate impressions by analyzing differences between the scan data of two types of impressions (alginate and rubber) taken from the master die and the scan data for the master die. The master die and impressions were digitized using a dental laser scanner (7 series, Dental Wings, Montreal, Canada). The crown portion of the abutment teeth in the digital data of 20 impressions was divided into three regions: cervical surface, middle surface, and occlusal surface. An independent t test showed a significant difference (p<0.05) in the mean difference for each experimental group (alginate and rubber). One-way ANOVA and Tukey's honest significant difference test revealed a significant difference (p<0.05) among the three regions in the rubber impression. The results of this study also carefully suggest the possibility of digitization of alginate impressions in the future. PMID- 26632233 TI - The effect of multi-ion releasing filler contents on the dentin bond strength of an adhesive resin developed for direct pulp-capping. AB - We aimed to evaluate the microtensile bond strength (uTBS) of experimentally developed all-in-one adhesives containing surface reaction-type pre-reacted glass ionomer (S-PRG) filler as a direct pulp-capping agent. Flattened dentin surfaces of extracted human molars were treated with four experimental adhesives of different S-PRG filler content (group 1: 0 wt%, group 2: 13 wt%, group 3: 27 wt% and group 4: 40 wt%) and Fluorobond Shakeone as the control. The beam samples were made and attached to the testing device, placed onto the tabletop-material tester, and subjected to uTBS test. The data were statistically analyzed using one-way ANOVA. The results demonstrated that the uTBS value of group 2 was significantly lower than that of the control. No other significant differences among the uTBS values of groups and control were observed. It was concluded that the uTBS values of the experimental adhesives were not affected by the S-PRG filler contents except in group 2. PMID- 26632234 TI - Pilot study of gingival connective tissue responses to 3-dimensional collagen nanofiber-coated dental implants. AB - The aim of the present study was to evaluate the gingival connective tissue response to screw-type titanium implants coated with Type I collagen nanofibers, which were prepared using the electrospray deposition method. Implants were immediately inserted into the socket of maxillary first molars after the extraction. Undecalcified sections after 4 weeks implantation were histologically observed. Better contact of the gingival connective tissue was generally observed around the collagen nanofiber-coated implants than titanium and non-fibrous collagen-immobilized implants. Gingival connective tissue to implant contact was significantly greater with the collagen nanofiber-coated implants than with the titanium and collagen-immobilized implants at the distal side, but not at the mesial side. Polarized light microscopy revealed that some birefringent collagen fiber bundles are oriented perpendicularly to the implant surfaces in the gingival connective tissue adjacent to the collagen nanofiber-coated implants. Collagen nanofiber-coating may have a possibility for improving gingival connective tissue response to titanium implants. PMID- 26632235 TI - Influence of surface treatment of contaminated lithium disilicate and leucite glass ceramics on surface free energy and bond strength of universal adhesives. AB - This study investigates the influence of surface treatment of contaminated lithium disilicate and leucite glass ceramic restorations on the bonding efficacy of universal adhesives. Lithium disilicate and leucite glass ceramics were contaminated with saliva, and then cleaned using distilled water (SC), or 37% phosphoric acid (TE), or hydrofluoric acid (CE). Specimens without contamination served as controls. The surface free energy was determined by measuring the contact angles formed when the three test liquids were placed on the specimens. Bond strengths of the universal adhesives were also measured. Saliva contamination and surface treatment of ceramic surfaces significantly influenced the surface free energy. The bond strengths of universal adhesives were also affected by surface treatment and the choice of adhesive materials. Our data suggest that saliva contamination of lithum disilicate and leucite glass ceramics significantly impaired the bonding of the universal adhesives, and reduced the surface free energy of the ceramics. PMID- 26632236 TI - Bond strength of composite resin to enamel and dentin prepared with Er,Cr:YSGG laser. AB - We aimed to examine the effect of various adhesive systems on the bond strength of composite resin to enamel or dentin prepared with erbium, chromium: yttrium scandium gallium garnet (Er,Cr:YSGG) laser. Each laser-cut enamel or dentin surface was treated with a bonding agent (SBB, Group 1); self-etching primer (SBP) and SBB (Group 2 and control); phosphoric-acid (KET), SBP and SBB (Group 3); KET, sodium-hypochlorite (ADG), SBP and SBB (Group 4); all-in-one adhesive (TSB, Group 5); or KET, ADG and TSB (Group 6). The control group was only polished with wet silicon carbide papers. The enamel shear bond strength of Group 5 was significantly lower than that of other groups (p<0.01). The control group showed higher bond strength compared to Groups 1-6 (p<0.05). Preconditioning using phosphoric acid or phosphoric acid followed by sodium hypochlorite increased the bond strength of composite resin to enamel and dentin prepared using an Er,Cr:YSGG laser. PMID- 26632237 TI - Proliferation and osteogenic differentiation of human mesenchymal stem cells on zirconia and titanium with different surface topography. AB - The purpose of this study was to elucidate behavior of human mesenchymal stem cells (hMSCs) on yttria stabilized tetragonal zirconia polycrystals (TZP) and commercial pure titanium (CpTi) with different surface topography. Mirror polished (MS), sandblasted with 150-MUm alumina (SB150) and SB150 acid-etched (SB150E) were prepared on TZP and CpTi. Proliferation, osteogenic differentiation of hMSCs was evaluated. The scanning electron microscopy showed that micro- and nano-topographies were created on both TZP and CpTi SB150E surfaces. The proliferation ability, ALP activity, expression of Runx2 on the both SB150E specimens was significantly higher than those on the other specimens. These results suggested that creation of micro- and nano-topographies on TZP and CpTi by blast and acid-etching may offer a promising method for enhancing the proliferation and differentiation of hMSCs in clinical application. PMID- 26632238 TI - Surface roughness and gloss of current CAD/CAM resin composites before and after toothbrush abrasion. AB - The purpose of this study was to evaluate the gloss and surface roughness behaviors of newly developed CAD/CAM composite blocks with different filler contents and characteristics. The gloss and surface roughness were quantified before and after a toothbrush dentifrice abrasion test; the results were compared to the gloss and surface roughness of a ceramic CAD/CAM block. Knoop hardness was determined before abrasion test. The results were analyzed by ANOVA, Tukey HSD, and Dunnett t test (p<0.05). The rank order of Knoop hardness was as follows: Vita Mark II>Vita Enamic>Gradia block>Shofu Block HC, Lava Ultimate>=Katana Avencia block>=Cerasmart. After toothbrush abrasion, a significant difference in the gloss unit was detected between the Shofu Block HC material and the ceramic block. The Ra and Rz of the Cerasmart and Shofu Block HC materials were significantly larger than those of the ceramic block after toothbrush abrasion. PMID- 26632239 TI - Reduction in static friction by deposition of a homogeneous diamond-like carbon (DLC) coating on orthodontic brackets. AB - In orthodontics, a reduction in static friction between the brackets and wire is important to enable easy tooth movement. The aim of this study was to examine the effects of a homogeneous diamond-like carbon (DLC) coating on the whole surfaces of slots in stainless steel orthodontic brackets on reducing the static friction between the brackets and the wire. The DLC coating was characterized using Raman spectroscopy, surface roughness and contact angle measurements, and SEM observations. Rectangular stainless steel and titanium-molybdenum alloy wires with two different sizes were employed, and the static friction between the brackets and wire was measured under dry and wet conditions. The DLC coating had a thickness of approximately 1.0 MUm and an amorphous structure was identified. The results indicated that the DLC coating always led to a reduction in static friction. PMID- 26632240 TI - Abutment screw loosening of endosseous dental implant body/abutment joint by cyclic torsional loading test at the initial stage. AB - Cyclic torsional loading tests were carried out in the laboratory using various implant systems, in order to clarify differences between the systems in loosening of abutment screws. Six samples from six commercially available abutment systems were used, giving a total of 36 samples. Four of the systems used internal connections, and two used external connections. The abutment screw for each system was tightened to a torque value specified by the manufacturer, and after 5 min, the loosening torque was measured using a digital torque meter. Measurements were taken twice, and a second measurement was taken as a reference value. A cyclic torsional loading test with 100,000 cycles was performed on the sample, and the loosening torque was again measured after the test. In conclusion, loosening of the abutment screw occurred as a result of cyclic torsional loading, and the degree of loosening varied with each implant system. PMID- 26632241 TI - Comparison of dentinal and apical crack formation caused by four different nickel titanium rotary and reciprocating systems in large and small canals. AB - This study compared dentinal and apical crack formation after instrumentation with different nickel-titanium systems at two different working lengths (WL) in large and small canals. Two hundred and eighty human teeth were randomly distributed into two control and 12 experimental groups (n=20 each). Large and small canals were instrumented by the WaveOne, Protaper Universal System (PTU), Twisted File (TF), or Twisted File Adaptive (TFA) at 1 mm shorter than canal length (CL-1 mm) or 1 mm beyond apical foreman (CL+1 mm). Horizontal sections were microscopically observed to evaluate the dentinal cracks (only large canals). Scanning electron microscopy images were taken before and after instrumentation to assess apical cracks. All file types caused more apical cracks in small canals than in large canals regardless of the WL. During over instrumentation (WL=CL+1 mm), the WaveOne and PTU groups developed significantly more dentinal cracks at the 6 and 9 mm sections than the TF and TFA groups. PMID- 26632242 TI - Translucency and flexural strength of monolithic translucent zirconia and porcelain-layered zirconia. AB - This study aims to investigate the effectiveness of monolithic translucent TZP with different colors and porcelain-layered TZP by evaluating their colors and strengths. Different mixing ratios of Zpex to Zpex-Yellow as translucent TZP, conventional opaque TZP (TZ-3YB-E) (Tosoh, Tokyo) as a control, and veneering porcelain (CERABIEN ZR, body porcelain, Noritake, Tokyo) with shade A3 as a typical shade. Disk-shaped specimens of 13 mm diameter and 1.5 mm thickness were prepared. These specimens were observed under reflected and transmitted light, and the translucency parameter (TP) values were measured. Strength was also evaluated with flexural strength in a biaxial bending test. The TP values of the monolithic TZP, Zpex100>Zpex70>Zpex50>TZ3YB, were larger in this order. The flexural strength of all the monolithic TZP showed approximately 1,000 MPa. It is suggested that colored translucent TZP is clinically useful when used as monolithic restorations. PMID- 26632243 TI - The influence of colored zirconia on the optical properties of all-ceramic restorations. AB - This study investigated the effects of different colored tetragonal zirconia polycrystal (TZP) core on the optical properties of TZP framework restorations. Three various colors of TZP discs (Katana Zirconia) 14 mm in diameter and 0.5 mm thickness were layered with 2 shades of veneering ceramics (shade A1 and A4: Cerabian ZR). These specimens were polished to approximately 1.5 mm. CIE L*a*b* coordinates, translucency (TP), and opalescence (OP) on the TZP restorations were evaluated. Consequently, TZP core color affected CIE L*a*b* values of TZP restorations however TP and OP did not significantly differ among the 3 core colors. Translucency and opalescence for colored TZP framework restorations were not influenced by the underlying TZP core color when veneering ceramics were layered to thicknesses of 1.0+/-0.1 mm. PMID- 26632244 TI - Systematic unravelling of the biosynthesis of poly (L-diaminopropionic acid) in Streptomyces albulus PD-1. AB - Poly(L-diaminopropionic acid) (PDAP) is one of the four homopoly(amino acid)s that have been discovered in nature. However, the molecular mechanism of PDAP biosynthesis has yet to be described. In this work, the general layout of the PDAP biosynthetic pathway is characterised in Streptomyces albulus PD-1 by genome mining, gene disruption, heterologous expression and in vitro feeding experiments. As a result, L-diaminopropionic acid (L-DAP), which is the monomer of PDAP, is shown to be jointly synthesised by two protein homologues of cysteine synthetase and ornithine cyclodeaminase. Then, L-DAP is assembled into PDAP by a novel nonribosomal peptide synthetase (NRPS) with classical adenylation and peptidyl carrier protein domains. However, instead of the traditional condensation or thioesterase domain of NRPSs, this NRPS has seven transmembrane domains surrounding three tandem soluble domains at the C-terminus. As far as we know, this novel single-module NRPS structure has only been reported in poly(epsilon-L-lysine) synthetase. The similar NRPS structure of PDAP synthetase and poly(epsilon-L-lysine) synthetase may be a common characteristic of homopoly(amino acid)s synthetases. In this case, we may discover and/or design more homopoly(amino acid)s by mining this kind of novel NRPS structure in the future. PMID- 26632246 TI - Rare Complication of Takotsubo Cardiomyopathy: Ventricular Septal Perforation with Septal Dissection. AB - We describe a rare case of takotsubo cardiomyopathy complicated by acute ventricular septal perforation with ventricular septal dissection. The ventricular perforation was successfully closed by repairing the dissecting site with a bovine pericardial patch. PMID- 26632245 TI - The temporal association between energy drink and alcohol use among adolescents: A short communication. AB - PURPOSE: To investigate the temporal relation between energy drink and alcohol use among adolescents. METHODS: Data were collected from adolescents attending public high schools in two waves (n=894). RESULTS: Path analysis indicated that energy drink use at baseline was positively associated with the number of drinking days but not binge drinking or average drinks per drinking day over the past 30 days at follow-up. This relation remained while controlling for race, age, gender, previous alcohol use, and impulsivity. CONCLUSIONS: Alcohol use prevention efforts should consider energy drink use as risk factors for adolescent alcohol use. PMID- 26632247 TI - Nutritional evaluation of children with chronic cholestatic disease. AB - OBJECTIVE: To evaluate the nutritional status of children with persistent cholestasis and to compare the anthropometric indices between children with and without liver cirrhosis and children with and without jaundice. METHODS: Children with persistent cholestasis, i.e. increased direct bilirrubin or changes in the canalicular enzyme gamma-glutamyl transferase (GGT), were included. The anthropometric measures were weight (W), height or length (H), arm circumference (AC), triceps skinfold thickness (TST), arm muscle circumference (AMC), and body mass index (BMI). RESULTS: Ninety-one children with cholestasis, with current median age of 12 months, were evaluated. W/age (A) and H/A indices below -2 Z scores were observed in 33% and 30.8% of patients, respectively. Concerning the W/H index and BMI, only 12% and 16% of patients, respectively, were below -2 Z scores. Regarding AC, 43.8% of 89 evaluated patients had some depletion. Observing the TST, 64% of patients had depletion, and 71.1% of the 45 evaluated patients had some degree of depletion regarding the ACM index. CONCLUSION: Evaluation using weight in patients with chronic liver diseases may overestimate the nutritional status due to visceromegaly, subclinical edema, or ascites. Indices that correlate weight and height, such as W/H and BMI, may also not show depletion because of the chronic condition in which there are depletion of both weight and height. TST, AC, and ACM are parameters that better estimate nutritional status and should be part of the management of patients with liver diseases and cholestasis. PMID- 26632248 TI - The mediator role of psychological morbidity on sleep and health behaviors in adolescents. AB - OBJECTIVE: This study examined the mediation role of psychological morbidity, defined in this study as depression/anxiety, in the relationship between excessive daytime sleepiness and sleep quality, and between sleep habits and health behaviors, in adolescents. METHODS: A total of 272 students, between 12 and 18 years old, underwent a psychological protocol assessing excessive daytime sleepiness, sleep quality, sleep habits, health behavior, and psychological morbidity. RESULTS: Psychological morbidity was not associated with the relationship between excessive daytime sleepiness and sleep quality, but was associated, with statistical significance, in the relationship between sleep habits and health behaviors. These results emphasize the role of psychological morbidity in adolescent health behaviors. CONCLUSION: Analyzing the symptoms of depression and anxiety in pediatric patients may help in a more accurate diagnosis, especially in relation to sleep problems and health behaviors. PMID- 26632249 TI - Flower-like PEGylated MoS2 nanoflakes for near-infrared photothermal cancer therapy. AB - Photothermal cancer therapy has attracted considerable interest for cancer treatment in recent years, but the effective photothermal agents remain to be explored before this strategy can be applied clinically. In this study, we therefore develop flower-like molybdenum disulfide (MoS2) nanoflakes and investigate their potential for photothermal ablation of cancer cells. MoS2 nanoflakes are synthesized via a facile hydrothermal method and then modified with lipoic acid-terminated polyethylene glycol (LA-PEG), endowing the obtained nanoflakes with high colloidal stability and very low cytotoxicity. Upon irradiation with near infrared (NIR) laser at 808 nm, the nanoflakes showed powerful ability of inducing higher temperature, good photothermal stability and high photothermal conversion efficiency. The in vitro photothermal effects of MoS2-PEG nanoflakes with different concentrations were also evaluated under various power densities of NIR 808-nm laser irradiation, and the results indicated that an effective photothermal killing of cancer cells could be achieved by a low concentration of nanoflakes under a low power NIR 808-nm laser irradiation. Furthermore, cancer cell in vivo could be efficiently destroyed via the photothermal effect of MoS2-PEG nanoflakes under the irradiation. These results thus suggest that the MoS2-PEG nanoflakes would be as promising photothermal agents for future photothermal cancer therapy. PMID- 26632250 TI - A spatially explicit estimate of the prewhaling abundance of the endangered North Atlantic right whale. AB - The North Atlantic right whale (NARW) (Eubalaena glacialis) is one of the world's most threatened whales. It came close to extinction after nearly a millennium of exploitation and currently persists as a population of only approximately 500 individuals. Setting appropriate conservation targets for this species requires an understanding of its historical population size, as a baseline for measuring levels of depletion and progress toward recovery. This is made difficult by the scarcity of records over this species' long whaling history. We sought to estimate the preexploitation population size of the North Atlantic right whale and understand how this species was distributed across its range. We used a spatially explicit data set on historical catches of North Pacific right whales (NPRWs) (Eubalaena japonica) to model the relationship between right whale relative density and the environment during the summer feeding season. Assuming the 2 right whale species select similar environments, we projected this model to the North Atlantic to predict how the relative abundance of NARWs varied across their range. We calibrated these relative abundances with estimates of the NPRW total prewhaling population size to obtain high and low estimates for the overall NARW population size prior to exploitation. The model predicted 9,075-21,328 right whales in the North Atlantic. The current NARW population is thus <6% of the historical North Atlantic carrying capacity and has enormous potential for recovery. According to the model, in June-September NARWs concentrated in 2 main feeding areas: east of the Grand Banks of Newfoundland and in the Norwegian Sea. These 2 areas may become important in the future as feeding grounds and may already be used more regularly by this endangered species than is thought. PMID- 26632251 TI - Cooperation in group-structured populations with two layers of interactions. AB - Recently there has been a growing interest in studying multiplex networks where individuals are structured in multiple network layers. Previous agent-based simulations of games on multiplex networks reveal rich dynamics arising from interdependency of interactions along each network layer, yet there is little known about analytical conditions for cooperation to evolve thereof. Here we aim to tackle this issue by calculating the evolutionary dynamics of cooperation in group-structured populations with two layers of interactions. In our model, an individual is engaged in two layers of group interactions simultaneously and uses unrelated strategies across layers. Evolutionary competition of individuals is determined by the total payoffs accrued from two layers of interactions. We also consider migration which allows individuals to move to a new group within each layer. An approach combining the coalescence theory with the theory of random walks is established to overcome the analytical difficulty upon local migration. We obtain the exact results for all "isotropic" migration patterns, particularly for migration tuned with varying ranges. When the two layers use one game, the optimal migration ranges are proved identical across layers and become smaller as the migration probability grows. PMID- 26632252 TI - MicroRNA-195 inhibits proliferation, invasion and metastasis in breast cancer cells by targeting FASN, HMGCR, ACACA and CYP27B1. AB - De novo lipogenesis, a hallmark for cancers is required for cellular transformation. Further it is believed that resistance to apoptosis and epithelial-to-mesenchymal-transition(EMT) facilitates metastasis via over expression of anti-apoptotic Bcl-2. Previously we demonstrated that hsa-miR-195 targets BCL2, induces apoptosis and augmented the effect of etoposide in breast cancer cells. However, the mechanism behind its function remains elusive. Herein gene expression profiling was done in presence/absence of hsa-miR-195 in Breast cancer cells. IPA revealed mitochondrial dysfunction, fatty acid metabolism and xenobiotic metabolism signalling among the top processes being affected. For the first time we herein identified ACACA, FASN (the key enzymes of de novo fatty acid synthesis), HMGCR (the key enzyme of de novo cholesterol synthesis) and CYP27B1 as direct targets of hsa-miR-195. We further showed that ectopic expression of hsa-miR-195 in MCF-7 and MDA-MB-231 cells not only altered cellular cholesterol and triglyceride levels significantly but also resulted in reduced proliferation, invasion and migration. We further demonstrated that over expression of hsa-miR-195 decreased the Mesenchymal markers expression and enhanced Epithelial markers. In conclusion we say that hsa-miR-195 targets the genes of de novo lipogenesis, inhibits cell proliferation, migration, and invasion which potentially opens new avenues for the treatment of breast cancer. PMID- 26632253 TI - Comparative study between unilateral and bilateral cochlear implantation in children of 1 and 2 years of age. AB - INTRODUCTION: The studies that have evaluated the effectiveness of bilateral cochlear implantation in children suggest an improvement in hearing about sound localization and speech discrimination. In this paper we show the differences in audio-linguistic achievements with early bilateral cochlear implantation versus unilateral, and differences between simultaneous and sequential bilateral implantation. MATERIAL AND METHODS: We present 88 children with bilateral profound sensorineural hearing loss, treated with bilateral cochlear implantation in 32 cases and unilateral in 56 cases, during the first 12 months (27 children) of life and between 12 and 24 months (61 children). We conducted a statistical comparison of both groups in the audiometry, IT-Mais, Nottingham, LittlEars scales and verbal tests. RESULTS: No significant differences in hearing thresholds and questionnaires between unilateral and bilateral implantation were detected in either the first or second year. Verbal tests do show statistically significant differences: children with bilateral cochlear implant obtain 100% recognition of disyllabic and phrases within 2-3 years after implantation whilst children with one implant do not obtain those results at 5 years after surgery. No differences between simultaneous and sequential bilateral implantation were detected. CONCLUSION: We emphasize the importance of ensuring good early audiological screening, to carry out an early and bilateral cochlear implantation with the consequent development of audio-language skills similar to normal hearing children. PMID- 26632254 TI - The efficacy of individual treatment of subjective tinnitus with cognitive behavioural therapy. AB - INTRODUCTION: It has been a long time since subjective tinnitus cases were described for the first time but they still lack a treatment with proven effectiveness. The main goal of this study was to evaluate the effectiveness of cognitive behavioural therapy in these patients. PATIENTS AND METHOD: Between 2012 and 2013, 310 patients that suffered from subjective tinnitus were studied. Of these, 267 were included in treatment based on cognitive behavioural therapy. The monitoring period lasted 18 months for most cases, while it lasted 21 months for 11 patients. RESULTS: Considering patients that interrupted their treatment as failures, the percentage of recovery was 95.7%. CONCLUSION: Cognitive behavioural therapy should always be included in the treatment of people suffering from tinnitus. PMID- 26632255 TI - Acetaminophen cytotoxicity is ameliorated in a human liver organotypic co-culture model. AB - Organotypic liver culture models for hepatotoxicity studies that mimic in vivo hepatic functionality could help facilitate improved strategies for early safety risk assessment during drug development. Interspecies differences in drug sensitivity and mechanistic profiles, low predictive capacity, and limitations of conventional monocultures of human hepatocytes, with high attrition rates remain major challenges. Herein, we show stable, cell-type specific phenotype/cellular polarity with differentiated functionality in human hepatocyte-like C3A cells (enhanced CYP3A4 activity/albumin synthesis) when in co-culture with human vascular endothelial cells (HUVECs), thus demonstrating biocompatibility and relevance for evaluating drug metabolism and toxicity. In agreement with in vivo studies, acetaminophen (APAP) toxicity was most profound in HUVEC mono-cultures; whilst in C3A:HUVEC co-culture, cells were less susceptible to the toxic effects of APAP, including parameters of oxidative stress and ATP depletion, altered redox homeostasis, and impaired respiration. This resistance to APAP is also observed in a primary human hepatocyte (PHH) based co-culture model, suggesting bidirectional communication/stabilization between different cell types. This simple and easy-to-implement human co-culture model may represent a sustainable and physiologically-relevant alternative cell system to PHHs, complementary to animal testing, for initial hepatotoxicity screening or mechanistic studies of candidate compounds differentially targeting hepatocytes and endothelial cells. PMID- 26632256 TI - Alopecic Plaques in a Cook. PMID- 26632257 TI - Identification of novel PKD1 and PKD2 mutations in a Chinese population with autosomal dominant polycystic kidney disease. AB - Autosomal dominant polycystic kidney disease (ADPKD) is one of the most frequently inherited renal diseases caused by mutations in PKD1 and PKD2. We performed mutational analyses of PKD genes in 49 unrelated patients using direct PCR-sequencing and multiplex ligation-dependent probe amplification (MLPA) for PKD1 and PKD2. RT-PCR analysis was also performed in a family with a novel PKD2 splicing mutation. Disease-causing mutations were identified in 44 (89.8%) of the patients: 42 (95.5%) of the patients showed mutations in PKD1, and 2 (4.5%) showed mutations in PKD2. Ten nonsense, 17 frameshift, 4 splicing and one in frame mutation were found in 32 of the patients. Large rearrangements were found in 3 patients, and missense mutations were found in 9 patients. Approximately 61.4% (27/44) of the mutations are first reported with a known mutation rate of 38.6%. RNA analysis of a novel PKD2 mutation (c.595_595 + 14delGGTAAGAGCGCGCGA) suggested monoallelic expression of the wild-type allele. Furthermore, patients with PKD1-truncating mutations reached end-stage renal disease (ESRD) earlier than patients with non-truncating mutations (47 +/- 3.522 years vs. 59 +/- 11.687 years, P = 0.016). The mutation screening of PKD genes in Chinese ADPKD patients will enrich our mutation database and significantly contribute to improve genetic counselling for ADPKD patients. PMID- 26632258 TI - Three-Dimensional Strains in Human Posterior Sclera Using Ultrasound Speckle Tracking. AB - Intraocular pressure (IOP) induced strains in the peripapillary sclera may play a role in glaucoma progression. Using inflation testing and ultrasound speckle tracking, the 3D strains in the peripapillary sclera were measured in nine human donor globes. Our results showed that the peripapillary sclera experienced through-thickness compression and meridional stretch during inflation, while minimal circumferential dilation was observed when IOP was increased from 10 to 19 mmHg. The maximum shear was primarily oriented in the through-thickness, meridional cross sections and had a magnitude slightly larger than the first principal strain. The tissue volume had minimal overall change, confirming near incompressibility of the sclera. Substantial strain heterogeneity was present in the peripapillary region, with local high strain areas likely corresponding to structural heterogeneity caused by traversing blood vessels. These 3D strain characteristics provide new insights into the biomechanical responses of the peripapillary sclera during physiological increases of IOP. Future studies are needed to confirm these findings and investigate the role of these biomechanical characteristics in ocular diseases. PMID- 26632259 TI - The RNA-binding proteomes from yeast to man harbour conserved enigmRBPs. AB - RNA-binding proteins (RBPs) exert a broad range of biological functions. To explore the scope of RBPs across eukaryotic evolution, we determined the in vivo RBP repertoire of the yeast Saccharomyces cerevisiae and identified 678 RBPs from yeast and additionally 729 RBPs from human hepatocytic HuH-7 cells. Combined analyses of these and recently published data sets define the core RBP repertoire conserved from yeast to man. Conserved RBPs harbour defined repetitive motifs within disordered regions, which display striking evolutionary expansion. Only 60% of yeast and 73% of the human RBPs have functions assigned to RNA biology or structural motifs known to convey RNA binding, and many intensively studied proteins surprisingly emerge as RBPs (termed 'enigmRBPs'), including almost all glycolytic enzymes, pointing to emerging connections between gene regulation and metabolism. Analyses of the mitochondrial hydroxysteroid dehydrogenase (HSD17B10) uncover the RNA-binding specificity of an enigmRBP. PMID- 26632260 TI - Finite Element Modeling of Mitral Valve Repair. AB - The mitral valve is a complex structure regulating forward flow of blood between the left atrium and left ventricle (LV). Multiple disease processes can affect its proper function, and when these diseases cause severe mitral regurgitation (MR), optimal treatment is repair of the native valve. The mitral valve (MV) is a dynamic structure with multiple components that have complex interactions. Computational modeling through finite element (FE) analysis is a valuable tool to delineate the biomechanical properties of the mitral valve and understand its diseases and their repairs. In this review, we present an overview of relevant mitral valve diseases, and describe the evolution of FE models of surgical valve repair techniques. PMID- 26632261 TI - Self-expanding metallic stent improves histopathologic edema compared with transanal drainage tube for malignant colorectal obstruction. AB - AIMS: To compare the usefulness of the self-expanding metallic stent (SEMS) with that of the transanal drainage tube (TDT) and emergency surgery after failure of decompression (ESFD) in patients with malignant colonic obstruction (MCO), and to evaluate post-decompression histopathologic changes. METHODS: From January 2010 to June 2015, 39 patients with MCO received SEMS, TDT, and ESFD. We evaluated the outcomes including success rates of placement, clinical outcomes after decompression, and histopathologic findings of the resected specimens. RESULTS: Technical success rates were 100% for SEMS and 78.9% for TDT. Clinical success rates were 100% for SEMS and 80.0% for TDT. Postoperative ileus was significantly less frequent after SEMS than after TDT (p = 0.014). Histopathologic edema grade was significantly lower for SEMS than for TDT and ESFD (p < 0.0001). There was no significant difference between edema grade and duration of decompression in the TDT group (p = 0.629), while all patients with SEMS were classified in a low edema grade (grade 0-2). The rate of stoma creation was significantly higher in patients with a high edema grade (grade 3) than in those with a low edema grade (grade 0-2) (p = 0.003). There was no microscopic perforation in any group. CONCLUSION: Significantly greater resolution of histopathologic edema was achieved after placement of SEMS than after placement of TDT. These findings provide an indication of favorable clinical outcomes of SEMS in comparison with TDT and ESFD. This article is protected by copyright. All rights reserved. PMID- 26632262 TI - Asymmetric ring structure of Vps4 required for ESCRT-III disassembly. AB - The vacuolar protein sorting 4 AAA-ATPase (Vps4) recycles endosomal sorting complexes required for transport (ESCRT-III) polymers from cellular membranes. Here we present a 3.6-A X-ray structure of ring-shaped Vps4 from Metallosphera sedula (MsVps4), seen as an asymmetric pseudohexamer. Conserved key interface residues are shown to be important for MsVps4 assembly, ATPase activity in vitro, ESCRT-III disassembly in vitro and HIV-1 budding. ADP binding leads to conformational changes within the protomer, which might propagate within the ring structure. All ATP-binding sites are accessible and the pseudohexamer binds six ATP with micromolar affinity in vitro. In contrast, ADP occupies one high affinity and five low-affinity binding sites in vitro, consistent with conformational asymmetry induced on ATP hydrolysis. The structure represents a snapshot of an assembled Vps4 conformation and provides insight into the molecular motions the ring structure undergoes in a concerted action to couple ATP hydrolysis to ESCRT-III substrate disassembly. PMID- 26632263 TI - Cryotherapy-Induced Persistent Vasoconstriction After Cutaneous Cooling: Hysteresis Between Skin Temperature and Blood Perfusion. AB - The goal of this study was to investigate the persistence of cold-induced vasoconstriction following cessation of active skin-surface cooling. This study demonstrates a hysteresis effect that develops between skin temperature and blood perfusion during the cooling and subsequent rewarming period. An Arctic Ice cryotherapy unit (CTU) was applied to the knee region of six healthy subjects for 60 min of active cooling followed by 120 min of passive rewarming. Multiple laser Doppler flowmetry perfusion probes were used to measure skin blood flow (expressed as cutaneous vascular conductance (CVC)). Skin surface cooling produced a significant reduction in CVC (P < 0.001) that persisted throughout the duration of the rewarming period. In addition, there was a hysteresis effect between CVC and skin temperature during the cooling and subsequent rewarming cycle (P < 0.01). Mixed model regression (MMR) showed a significant difference in the slopes of the CVC-skin temperature curves during cooling and rewarming (P < 0.001). Piecewise regression was used to investigate the temperature thresholds for acceleration of CVC during the cooling and rewarming periods. The two thresholds were shown to be significantly different (P = 0.003). The results show that localized cooling causes significant vasoconstriction that continues beyond the active cooling period despite skin temperatures returning toward baseline values. The significant and persistent reduction in skin perfusion may contribute to nonfreezing cold injury (NFCI) associated with cryotherapy. PMID- 26632264 TI - High-Performance Pseudocapacitive Microsupercapacitors from Laser-Induced Graphene. AB - All-solid-state, flexible, symmetric, and asymmetric microsupercapacitors are fabricated by a simple method in a scalable fashion from laser-induced graphene on commercial polyimide films, followed by electrodeposition of pseudocapacitive materials on the interdigitated in-plane architectures. These microsupercapacitors demonstrate comparable energy density to commercial lithium thin-film batteries, yet exhibit more than two orders of magnitude higher power density with good mechanical flexibility. PMID- 26632265 TI - Optogenetic mutagenesis in Caenorhabditis elegans. AB - Reactive oxygen species (ROS) can modify and damage DNA. Here we report an optogenetic mutagenesis approach that is free of toxic chemicals and easy to perform by taking advantage of a genetically encoded ROS generator. This method relies on the potency of ROS generation by His-mSOG, the mini singlet oxygen generator, miniSOG, fused to a histone. Caenorhabditis elegans expressing His mSOG in the germline behave and reproduce normally, without photoinduction. Following exposure to blue light, the His-mSOG animals produce progeny with a wide range of heritable phenotypes. We show that optogenetic mutagenesis by His mSOG induces a broad spectrum of mutations including single-nucleotide variants (SNVs), chromosomal deletions, as well as integration of extrachromosomal transgenes, which complements those derived from traditional chemical or radiation mutagenesis. The optogenetic mutagenesis expands the toolbox for forward genetic screening and also provides direct evidence that nuclear ROS can induce heritable and specific genetic mutations. PMID- 26632266 TI - Influence of the Level of Muscular Redundancy on the Validity of a Musculoskeletal Model. AB - While recent literature has clearly demonstrated that an extensive personalization of the musculoskeletal models was necessary to reach high accuracy, several components of the generic models may be further investigated before defining subject-specific parameters. Among others, the choice in muscular geometry and thus the level of muscular redundancy in the model may have a noticeable influence on the predicted musculotendon and joint contact forces. In this context, the aim of this study was to investigate if the level of muscular redundancy can contribute or not to reduce inaccuracies in tibiofemoral contact forces predictions. For that, the dataset disseminated through the Sixth Grand Challenge Competition to Predict In Vivo Knee Loads was applied to a versatile 3D lower limb musculoskeletal model in which two muscular geometries (i.e., two different levels of muscular redundancy) were implemented. This dataset provides tibiofemoral implant measurements for both medial and lateral compartments and thus allows evaluation of the validity of the model predictions. The results suggest that an increase of the level of muscular redundancy corresponds to a better accuracy of total tibiofemoral contact force whatever the gait pattern investigated. However, the medial and lateral contact forces ratio and accuracy were not necessarily improved when increasing the level of muscular redundancy and may thus be attributed to other parameters such as the location of contact points. To conclude, the muscular geometry, among other components of the generic model, has a noticeable impact on joint contact forces predictions and may thus be correctly chosen even before trying to personalize the model. PMID- 26632267 TI - Exome sequencing of osteosarcoma reveals mutation signatures reminiscent of BRCA deficiency. AB - Osteosarcomas are aggressive bone tumours with a high degree of genetic heterogeneity, which has historically complicated driver gene discovery. Here we sequence exomes of 31 tumours and decipher their evolutionary landscape by inferring clonality of the individual mutation events. Exome findings are interpreted in the context of mutation and SNP array data from a replication set of 92 tumours. We identify 14 genes as the main drivers, of which some were formerly unknown in the context of osteosarcoma. None of the drivers is clearly responsible for the majority of tumours and even TP53 mutations are frequently mapped into subclones. However, >80% of osteosarcomas exhibit a specific combination of single-base substitutions, LOH, or large-scale genome instability signatures characteristic of BRCA1/2-deficient tumours. Our findings imply that multiple oncogenic pathways drive chromosomal instability during osteosarcoma evolution and result in the acquisition of BRCA-like traits, which could be therapeutically exploited. PMID- 26632268 TI - On Buckling Morphogenesis. AB - Cell-generated mechanical forces drive many of the tissue movements and rearrangements that are required to transform simple populations of cells into the complex three-dimensional geometries of mature organs. However, mechanical forces do not need to arise from active cellular movements. Recent studies have illuminated the roles of passive forces that result from mechanical instabilities between epithelial tissues and their surroundings. These mechanical instabilities cause essentially one-dimensional epithelial tubes and two-dimensional epithelial sheets to buckle or wrinkle into complex topologies containing loops, folds, and undulations in organs as diverse as the brain, the intestine, and the lung. Here, I highlight examples of buckling and wrinkling morphogenesis, and suggest that this morphogenetic mechanism may be broadly responsible for sculpting organ form. PMID- 26632269 TI - Associated Microscale Spine Density and Macroscale Connectivity Disruptions in Schizophrenia. AB - BACKGROUND: Schizophrenia is often described as a disorder of dysconnectivity, with disruptions in neural connectivity reported on the cellular microscale as well as the global macroscale level of brain organization. How these effects on these two scales are related is poorly understood. METHODS: First (part I of this study), we collated data on layer 3 pyramidal spine density of the healthy brain from the literature and cross-analyzed these data with new data on macroscale connectivity as derived from diffusion imaging. Second (part II of this study), we examined how alterations in regional spine density in schizophrenia are related to changes in white matter connectivity. Data on group differences in spine density were collated from histology reports in the literature and examined in a meta-regression analysis in context of alterations in macroscale white matter connectivity as derived from diffusion imaging data of a (separately acquired) group of 61 patients and 55 matched control subjects. RESULTS: Densely connected areas of the healthy human cortex were shown to overlap with areas that display high pyramidal complexity, with pyramidal neurons that are more spinous (p = .0027) compared with pyramidal neurons in areas of low macroscale connectivity. Cross-scale meta-regression analysis showed a significant association between regional variation in level of disease-related spine density reduction in schizophrenia and regional level of decrease in macroscale connectivity (two data sets examined, p = .0028 and p = .0011). CONCLUSIONS: Our study presents evidence that regional disruptions in microscale neuronal connectivity in schizophrenia go hand in hand with changes in macroscale brain connectivity. PMID- 26632271 TI - Solution-Grown Silver Nanowire Ordered Arrays as Transparent Electrodes. AB - A transparent conducting film composed of regular networks of silver nanowires is obtained by combining a soft solution process (Tollens' reaction) and nanoimprint lithography. The solution-grown nanowire networks show a threefold higher conductivity than grids obtained by metal evaporation. This is due to the larger grain size in the solution-grown nanowires, which results in a strong reduction of electron scattering by grain boundaries. PMID- 26632270 TI - CX3CR1 deficiency promotes muscle repair and regeneration by enhancing macrophage ApoE production. AB - Muscle injury triggers inflammation in which infiltrating mononuclear phagocytes are crucial for tissue regeneration. The interaction of the CCL2/CCR2 and CX3CL1/CX3CR1 chemokine axis that guides phagocyte infiltration is incompletely understood. Here, we show that CX3CR1 deficiency promotes muscle repair and rescues Ccl2(-/-) mice from impaired muscle regeneration as a result of altered macrophage function, not infiltration. Transcriptomic analysis of muscle mononuclear phagocytes reveals that Apolipoprotein E (ApoE) is upregulated in mice with efficient regeneration. ApoE treatment enhances phagocytosis by mononuclear phagocytes in vitro, and restores phagocytic activity and muscle regeneration in Ccl2(-/-) mice. Because CX3CR1 deficiency may compensate for defective CCL2-dependant monocyte recruitment by modulating ApoE-dependent macrophage phagocytic activity, targeting CX3CR1 expressed by macrophages might be a powerful therapeutic approach to improve muscle regeneration. PMID- 26632272 TI - Myeloperoxidase in human peripheral blood lymphocytes: Production and subcellular localization. AB - Myeloperoxidase (MPO) is an important enzyme in the front-line protection against microorganisms. In peripheral blood, it is accepted that MPO is only produced by myeloid-lineage cells. Thus, MPO presence is unexpected in lymphocytes. We showed recently that B1-lymphocytes from mice have MPO. Here, we showed that subsets of human peripheral B, CD4(+) and CD8(+) T lymphocytes express MPO. The content of MPO in lymphocytes was very low compared to neutrophils/monocytes with a preferential distribution in the nucleus and perinuclear region. Also, we performed a MPO mRNA expression analysis from human blood cells derived from microarray raw data publicly available, showing that MPO is modulated in infectious disease. MPO was increased in CD4(+) T lymphocytes from HIV chronic infection and in CD8(+) T lymphocytes from HCV-positive patients. Our study points out MPO as a multifunctional protein due to its subcellular localization and expression modulation in lymphocytes indicating alternative unknown functions for MPO in lymphocytes. PMID- 26632273 TI - A Single-Material Logical Junction Based on 2D Crystal PdS2. AB - A single-material logical junction with negligible contact resistance is designed by exploiting quantum-confinement effects in 1T PdS2 . The metallic bilayer serves as electrodes for the semiconducting channel monolayer, avoiding contact resistance. Heat dissipation is then governed by tunnel loss, which becomes negligible at channel lengths larger than 2.45 nm. This value marks the integration limit for a conventional 2D transistor. PMID- 26632275 TI - Catalytic Polymer Multilayer Shell Motors for Separation of Organics. AB - A catalytic polymer multilayer shell motor has been developed, which effects fast motion-based separation of charged organics in water. The shell motors are fabricated by sputtering platinum onto the exposed surface of silica templates embedded in Parafilm, followed by layer-by-layer assembly of polyelectrolyte multilayers to the templates. The catalytic shell motors display high bubble propulsion with speeds of up to 260 MUm s(-1) (13 body lengths per second). Moreover, the polyelectrolyte multilayers assembled at high pH (pH>9.0) adsorb approximately 89% of dye molecules from water, owing to the electrostatic interaction between the positively charged polymers and the anionic dye molecules, and subsequently release them at neutral pH in a microfluidic device. The efficient propulsion coupled with the effective adsorption behavior of the catalytic shell motors in a microfluidic device results in accelerated separation of organics in water and thus holds considerable promise for water analysis. PMID- 26632274 TI - Osteoclasts control reactivation of dormant myeloma cells by remodelling the endosteal niche. AB - Multiple myeloma is largely incurable, despite development of therapies that target myeloma cell-intrinsic pathways. Disease relapse is thought to originate from dormant myeloma cells, localized in specialized niches, which resist therapy and repopulate the tumour. However, little is known about the niche, and how it exerts cell-extrinsic control over myeloma cell dormancy and reactivation. In this study, we track individual myeloma cells by intravital imaging as they colonize the endosteal niche, enter a dormant state and subsequently become activated to form colonies. We demonstrate that dormancy is a reversible state that is switched 'on' by engagement with bone-lining cells or osteoblasts, and switched 'off' by osteoclasts remodelling the endosteal niche. Dormant myeloma cells are resistant to chemotherapy that targets dividing cells. The demonstration that the endosteal niche is pivotal in controlling myeloma cell dormancy highlights the potential for targeting cell-extrinsic mechanisms to overcome cell-intrinsic drug resistance and prevent disease relapse. PMID- 26632277 TI - No more walls. PMID- 26632276 TI - When the dots are joined. PMID- 26632278 TI - Opportunities and challenges for quantum dot photovoltaics. PMID- 26632279 TI - Prospects for thermoelectricity in quantum dot hybrid arrays. PMID- 26632280 TI - What future for quantum dot-based light emitters? PMID- 26632281 TI - Navigating the fourth industrial revolution. PMID- 26632283 TI - Graphic design for scientists. PMID- 26632285 TI - Panels, Mini-Panels and Study GroupsMonday, December 7, 2015. PMID- 26632284 TI - Medicinal Plants Traditionally Used for Treatment of Obesity and Diabetes Mellitus - Screening for Pancreatic Lipase and alpha-Amylase Inhibition. AB - In order to find new pancreatic lipase (PL) and alpha-amylase inhibitors from natural sources for the treatment of obesity and related diseases as diabetes mellitus II, 23 medicinal plants with weight-reducing, serum glucose-reducing or related potential were investigated. Methanolic and water extracts of the plants were evaluated by using two in vitro test systems. Our findings have shown that the methanolic extract of Hibiscus sabdariffa L. (Malvaceae) showed high inhibitory activities to PL (IC50 : 35.8 +/- 0.8 ug/mL) and alpha-amylase (IC50 : 29.3 +/- 0.5 ug/mL). Furthermore, the methanolic extract of Tamarindus indica L. (Leguminosae) showed a high anti-lipase (IC50 : 152.0 +/- 7.0 ug/mL) and the aqueous extract a high anti-amylase (IC50 : 139.4 +/- 9.0 ug/mL) activity. This work provides a priority list of interesting plants for further study with respect to the treatment of obesity and associated diseases. PMID- 26632286 TI - Poster Session IMonday, December 7, 2015. PMID- 26632287 TI - Poster Session IITuesday, December 8, 2015. PMID- 26632288 TI - Poster Session IIIWednesday, December 9, 2015. PMID- 26632291 TI - Can New Collaborations Decrease Costs and Increase the Value of Clinical Education in Dentistry? PMID- 26632292 TI - Improving the Fiscal Sustainability of Teaching Clinics at Dental Schools. AB - Educational patient care clinics are becoming an increasingly important source of revenue for dental schools. Revenue from clinics can help offset the rising cost of dental education. In addition, those clinics represent a source of income over which the schools have reasonably direct control. Recently, a group of nine U.S. dental schools conducted a detailed financial survey of their clinics and shared the confidential results with each other. The purpose of their analysis was to develop benchmarks for key factors related to clinical financial productivity and expenses and to define best practices to guide improvements at each school. The survey found significant variations among the nine schools in revenue produced by predoctoral students and by postdoctoral residents. There were similar variations for levels of clinical staffing. By sharing the results of the survey with each other, the individual schools gained a strong understanding of the business strengths or weakness of their own clinical programs. That information gave each school's leaders the opportunity to investigate how they might improve their clinical fiscal sustainability. PMID- 26632293 TI - Helping Dental Students Make Informed Decisions About Private Practice Employment Options in a Changing Landscape. AB - According to the 2014 American Dental Education Association (ADEA) Survey of Dental School Seniors, 45.3% of new graduates planned to enter private practice immediately after graduation; of those, while 65% planned to become an associate dentist in a private practice, 28.3% intended to enter a corporate group practice the only category that saw an increase over the previous year. Current trends indicate that the number of new graduates choosing to enter some form of private practice without further education will continue to remain high, due in large part to the need to repay educational debt. In light of these trends, the question that must be asked is whether dental schools are optimally preparing students to make informed decisions regarding future employment options in the changing dental practice landscape. This article argues that dental schools should review their curricula to ensure graduates are being prepared for this changing environment and the increased business pressures associated with dental practice. Important considerations in preparing dental students to be successful in the process of selecting a practice model are identified. PMID- 26632294 TI - Noncognitive Indicators as Critical Predictors of Students' Performance in Dental School. AB - Dental educators have traditionally prioritized cognitive indicators (especially undergraduate grade point average and Dental Admission Test scores) in choosing students for admission to dental school. These indicators' role in predicting academic outcomes, including coursework and examination success, is well documented. However, noncognitive predictors including conscientiousness, self discipline, achievement-striving, task orientation, deliberation, resilience, and situational judgment have also been identified. This study's aims were to assess the significance of noncognitive indicators measured by the version of the Neuroticism-Extraversion-Openness Personality Inventory (NEO PI) known as the NEO PI-3, determine the place in the curriculum when these indicators' impact was most influential, and compare their influence with that of the cognitive indicators. Analysis was performed on stored data for three classes of dental students from admission through clinical exams at one U.S. dental school. Significant associations were found between NEO-PI-3 domains and facets (especially Conscientiousness) and the outcomes of coursework grades, standardized exam scores, and clinical behavior scores. Multiple regression analyses identified that the noncognitive indicators enhanced the prediction of students' academic and clinical performance early in the curriculum and then equaled or surpassed the predictive impact of cognitive indicators as they progressed through the curriculum sequence. The implications of noncognitive predictors for dental education are discussed including the challenge to identify and then weight the indicators, whether to include them as admissions criteria, how to assess their impact as compared with cognitive measures, the necessity of standardization of assessment, and if and when to evaluate their relevance to professional practice. PMID- 26632295 TI - Evaluation of a Local Anesthesia Simulation Model with Dental Students as Novice Clinicians. AB - The aim of this study was to evaluate the use of a local anesthesia (LA) simulation model in a facilitated small group setting before dental students administered an inferior alveolar nerve block (IANB) for the first time. For this pilot study, 60 dental students transitioning from preclinical to clinical education were randomly assigned to either an experimental group (N=30) that participated in a small group session using the simulation model or a control group (N=30). After administering local anesthesia for the first time, students in both groups were given questionnaires regarding levels of preparedness and confidence when administering an IANB and level of anesthesia effectiveness and pain when receiving an IANB. Students in the experimental group exhibited a positive difference on all six questions regarding preparedness and confidence when administering LA to another student. One of these six questions ("I was prepared in administering local anesthesia for the first time") showed a statistically significant difference (p<0.05). Students who received LA from students who practiced on the simulation model also experienced fewer post injection complications one day after receiving the IANB, including a statistically significant reduction in trismus. No statistically significant difference was found in level of effectiveness of the IANB or perceived levels of pain between the two groups. The results of this pilot study suggest that using a local anesthesia simulation model may be beneficial in increasing a dental student's level of comfort prior to administering local anesthesia for the first time. PMID- 26632296 TI - Measuring Curricular Impact on Dental Hygiene Students' Transformative Learning. AB - Previous research has suggested that transformative learning can be fostered in higher education by creating active learning experiences that are directly related to content taught, are personally engaging, and can stimulate reflection. The aim of this qualitative study was to assess changes experienced by students in an e-learning dental hygiene degree completion program beyond attainment of competence-changes that may be described as transformative learning. The data used were transcripts of focus groups that had been conducted with each of the first five cohorts of students to graduate from the program; a total of 30 of the 42 students in the five cohorts (71%) participated. Using their previously developed Transformation Rubric for Engaged Learning, the authors categorized focus group data to identify changes in students' confidence, pride, skills, perceptions of the world, and personal identity at the transformative and nontransformative levels. Every participant reported at least one change; overall, the students averaged 8.3 changes. The vast majority (84%) of these changes were transformative. Middle-performing students showed a disproportionately higher rate of transformational changes in the areas of confidence and pride. The e-learning program appeared to have had a significant transformative impact on students, but additional research on the effect on middle-performing students is warranted. PMID- 26632297 TI - Use of an Analytical Grading Rubric for Self-Assessment: A Pilot Study for a Periodontal Oral Competency Examination in Predoctoral Dental Education. AB - While educators agree that using self-assessment in education is valuable, a major challenge is the poor agreement often found between faculty assessment and student self-assessment. The aim of this study was to determine if use of a predefined grading rubric would improve reliability between faculty and dental student assessment on a periodontal oral competency examination. Faculty members used the grading rubric to assess students' performance on the exam. Immediately after taking the exam, students used the same rubric to self-assess their performance on it. Data were collected from all third- and/or fourth-year students in four classes at one U.S. dental school from 2011 to 2014. Since two of the four classes took the exam in both the third and fourth years, those data were compared to determine if those students' self-assessment skills improved over time. Statistical analyses were performed to determine agreement between the two faculty graders and between the students' and faculty assessments on each criterion in the rubric and the overall grade. Data from the upper and lower performing quartiles of students were sub-analyzed. The results showed that faculty reliability for the overall grades was high (K=0.829) and less so for individual criteria, while student-faculty reliability was weak to moderate for both overall grades (Spearman's rho=0.312) and individual criteria. Students in the upper quartile self-evaluated themselves more harshly than the faculty (p<0.0001), while the lower quartile students overestimated their performance (p=0.0445) compared to faculty evaluation. No significant improvement was found in assessment over time in the students who took the exam in the third and fourth years. This study found only limited support for the hypothesis that a grading rubric used by both faculty and students would increase correspondence between faculty and student assessment and points to a need to reexamine the rubric and instructional strategies to help students improve their ability to self-assess their work. PMID- 26632298 TI - Comparison of Dental Students' Self-Directed, Faculty, and Software-Based Assessments of Dental Anatomy Wax-Ups: A Retrospective Study. AB - Little is known about self-directed and self-reflective assessment in preclinical dental curricula. The aim of this study was to evaluate a visual dental anatomy teaching tool to train dental students to self-assess their dental anatomy wax carving practical examinations. The students self-assessed two waxing practical examinations (tooth #8 and tooth #19) using high-quality digital images in an assessment tool incorporated into a digital testing program. Student self assessments were compared to the faculty evaluations and the results of a software-based evaluation tool (E4D Compare). Out of a total 130 first-year dental students at one U.S. dental school, wax-ups from 57 participants were available for this study. The assessment data were submitted to statistical analyses (p<0.05). For tooth #8, the student self-assessments were significantly different from the faculty and software assessments at a 400 micrometer level of tolerance (p=0.036), whereas the faculty assessment was not significantly different from the software assessment at a 300 micrometer level of tolerance (p=0.69). The evaluation of tooth #19 resulted in no significant differences between faculty members (p=0.94) or students (p=0.21) and the software at a level of tolerance of 400 micrometers. This study indicates that students can learn to self-assess their work using self-reflection in conjunction with faculty guidance and that it may be possible to use software-based evaluation tools to assist in faculty calibration and as objective grading tools. PMID- 26632299 TI - The Validity of Using E4D Compare's "% Comparison" to Assess Crown Preparations in Preclinical Dental Education. AB - When a dental school is deciding which technology to introduce into a curriculum, it is important to identify the educational goals for the system. The authors' primary goal for the use of a computer-aided resource was to offer students another way to assess their performance, to enhance their learning, and to potentially decrease their learning curve in the preclinical environment prior to using the technique in clinical patient care. The aim of this study was to examine the validity of the "% Comparison" numbers derived from the E4D Compare software program. Three practical examinations were administered to a class of 82 students at one U.S. dental school over a six-week period. The grading of the practical examinations was performed with individual faculty members being responsible for evaluating specific aspects of each preparation. A digital image of each student's practical examination tooth was then obtained and compared to the digital image of an ideal preparation. The preparations were compared, and the "% Comparison" was recorded at five tolerance levels. Spearman's correlation coefficient (SCC) was used to measure the agreement in rankings between the faculty scores on practical exams 1-3 and the scores obtained using E4D Compare at the different tolerance levels. The SCC values for practical exams 2 and 3 were all between 0.2 and 0.4; for practical exam 1, the SCC values ranged from 0.47 to 0.56. There was no correlation between the faculty scores and the numbers given by the "% Comparison" of the software. PMID- 26632300 TI - Can Clinical Scenario Videos Improve Dental Students' Perceptions of the Basic Sciences and Ability to Apply Content Knowledge? AB - Dental students often have difficulty understanding the importance of basic science classes, such as physiology, for their future careers. To help alleviate this problem, the aim of this study was to create and evaluate a series of video modules using simulated patients and custom-designed animations that showcase medical emergencies in the dental practice. First-year students in a dental physiology course formatively assessed their knowledge using embedded questions in each of the three videos; 108 to 114 of the total 120 first-year students answered the questions, for a 90-95% response rate. These responses indicated that while the students could initially recognize the cause of the medical emergency, they had difficulty in applying their knowledge of physiology to the scenario. In two of the three videos, students drastically improved their ability to answer high-level clinical questions at the conclusion of the video. Additionally, when compared to the previous year of the course, there was a significant improvement in unit exam scores on clinically related questions (6.2% increase). Surveys were administered to the first-year students who participated in the video modules and fourth-year students who had completed the course prior to implementation of any clinical material. The response rate for the first-year students was 96% (115/120) and for the fourth-year students was 57% (68/120). The first-year students indicated a more positive perception of the physiology course and its importance for success on board examinations and their dental career than the fourth-year students. The students perceived that the most positive aspects of the modules were the clear applications of physiology to real-life dental situations, the interactive nature of the videos, and the improved student comprehension of course concepts. These results suggest that online modules may be used successfully to improve students' perceptions of the basic sciences and enhance their ability to apply basic science content to clinically important scenarios. PMID- 26632301 TI - Videotaped Feedback Method to Enhance Learning in Preclinical Operative Dentistry: An Experimental Study. AB - The aim of this study was to investigate if a videotaped feedback method enhanced teaching and learning outcomes in a preclinical operative laboratory setting for novice learners. In 2013, 60 dental students at a dental school in India were randomly assigned to two groups: control (n=30) and experimental (n=30). The control group prepared a Class II tooth preparation for amalgam after receiving a video demonstration of the exercise. The experimental group received the same video demonstration as the control group, but they also participated in a discussion and analysis of the control groups' videotaped performance and then performed the same exercise. The self-evaluation scores (SS) and examiner evaluation scores (ES) of the two groups were compared using the unpaired t-test. The experimental group also used a five-point Likert scale to rate each item on the feedback form. The means of SS (13.65+/-2.43) and ES (14.75+/-1.97) of the experimental group were statistically higher than the means of SS (11.55+/-2.09) and ES (11.60+/-1.82) of the control group. Most students in the experimental group perceived that this technique enhanced their learning experience. Within the limits of this study, the videotaped feedback using both ideal and non-ideal examples enhanced the students' performance. PMID- 26632302 TI - Effect of Video Triggering During Conventional Lectures on Final Grades of Dental Students in an Oral Biology Course: A Two-Year Retrospective Study. AB - The aim of this study was to analyze the effect of the inclusion of video triggers in conventional face-to-face lectures on the final grades of dental students in an oral biology course. The study consisted of two groups of students taking the course in two academic years at a dental school in Saudi Arabia: group 1, 2013-14 (control); and group 2, 2014-15. The total sample comprised 163 students (n=163; group 1: 71 and group 2: 92). Group 1 received lectures without any videos, whereas group 2 received lectures that included two to three videos of one to five minutes in duration with triggering effect (a video was shown every 10-15 minutes into the lecture). The final examination grades of the students were accessed retrospectively, and the data were compared with a chi square test. The results confirmed that a higher number of students who received video triggering during lectures (group 2) performed better than their counterparts who did not receive video triggers (group 1); the difference was statistically significant (p<0.05). Among the group 2 students, 26% achieved a grade of A, and 37% achieved a grade of B. In contrast, only 7% of the group 1 students obtained a grade of A, and 31% achieved a grade of B. These results suggest that video triggers may offer an advantage over conventional methods and their inclusion in lectures can be a way to enhance students' learning. PMID- 26632303 TI - Instant Messaging in Dental Education. AB - Instant messaging (IM) is when users communicate instantly via their mobile devices, and it has become one of the most preferred choices of tools to communicate amongst health professions students. The aim of this study was to understand how dental students communicate via IM, faculty members' perspectives on using IM to communicate with students, and whether such tools are useful in the learning environment. After free-associating themes on online communication, two draft topic guides for structured interviews were designed that focussed on mobile device-related communication activities. A total of 20 students and six faculty members at the University of Birmingham School of Dentistry agreed to take part in the interviews. Students were selected from years 1-5 representing each year group. The most preferred communication tools were emails, social networking, and IM. Emails were used for more formal messages, and IM and social networking sites were used for shorter messages. WhatsApp was the most used IM app because of its popular features such as being able to check if recipients have read and received messages and group work. The students reported that changes were necessary to improve their communication with faculty members. The faculty members reported having mixed feelings toward the use of IM to communicate with students. The students wished to make such tools a permanent part of their learning environment, but only with the approval of faculty members. The faculty members were willing to accept IM as a communication tool only if it is monitored and maintained by the university and has a positive effect on learning. PMID- 26632306 TI - Carbohydrates in diversity-oriented synthesis: challenges and opportunities. AB - Over the last decade, Diversity-Oriented Synthesis (DOS) has become a new paradigm for developing large collections of structurally diverse small molecules as probes to investigate biological pathways, and to provide a larger array of the chemical space. Drug discovery and chemical biology are taking advantage of DOS approaches to exploit highly-diverse and complex molecular platforms, producing advances in both target and ligand discovery. In this view, carbohydrates are attractive building blocks for DOS libraries, due to their stereochemical diversity and high density of polar functional groups, thus offering many possibilities for chemical manipulation and scaffold decoration. This review will discuss research contributions and perspectives on the application of carbohydrate chemistry to explore the accessible chemical space through appendage, stereochemical and scaffold diversity. PMID- 26632307 TI - Vaccination saves lives--dare we allow the anti-vaccine lobbyists to prevent it? PMID- 26632308 TI - Interventions for improving childhood vaccination coverage in low- and middle income countries. AB - 'Cochrane Corner' in the November SAMJ highlights a Cochrane review that evaluated the effects of interventions for improving childhood vaccination coverage in low- and middle-income countries. QUESTION: Which interventions increase the uptake of childhood vaccines in low and middle-income countries? BOTTOM LINE: Health education, home visits, and reminders probably increase the uptake of childhood vaccines in low and middle-income countries. PMID- 26632309 TI - Appropriate indications for positron emission tomography/computed tomography: College of Nuclear Physicians of the Colleges of Medicine of South Africa. AB - Individualised patient treatment approaches demand precise determination of initial disease extent combined with early, accurate assessment of response to treatment, which is made possible by positron emission tomography/computed tomography (PET/CT). PET is a non-invasive tool that provides tomographic images and quantitative parameters of perfusion, cell viability, and proliferation and/or metabolic activity of tissues. Fusion of the functional information with the morphological detail provided by CT as PET/CT can provide clinicians with a sensitive and accurate one-step whole-body diagnostic and prognostic tool, which directs and changes patient management. Three large-scale national studies published by the National Oncologic PET Registry in the USA have shown that imaging with PET changes the intended patient management strategy in 36.5% to 49% of cases, with consistent results across all cancer types. The proven clinical effectiveness and growing importance of PET/CT have prompted the College of Nuclear Physicians of South Africa, in collaboration with university hospitals, to develop a list of recommendations on the appropriate use of fluorine-18 fluorodeoxyglucose (18F-FDG) and non-18F-FDG PET/CT in oncology, cardiology, neurology and infection/inflammation. It is expected that other clinical situations will be added to these recommendations, provided that they are based upon solid clinical evidence. These recommendations are intended to offer advice regarding contemporary applications of PET/CT, as well as indicating novel developments and potential future indications. The CNP believes that these recommendations will serve an important and relevant role in advising referring physicians on the appropriate use of 18F-FDG and non-18F-FDG PET/CT. More promising clinical applications will be possible in the future, as newer PET tracers become more readily available. PMID- 26632310 TI - Efavirenz as a cause of ataxia in children. AB - Acute ataxia in childhood is often caused by toxin ingestion. With the increasing number of paediatric patients on antiretroviral medication, we are seeing more side-effects of these drugs. We report two cases of efavirenz toxicity causing ataxia. PMID- 26632311 TI - Child research in South Africa: How do the new regulations help? AB - Child research is governed by legal norms in the National Health Act (2003) and the Regulations. There is increasing harmony between the two on many issues, including the conditions under which children should be enrolled in research. The most striking disjuncture in the ethical-legal framework remains the allowable consent strategy for child research, where the law requires mandatory parental or legal guardian consent for all child research, while ethical guidelines afford research stakeholders the discretion to implement exceptions to this approach in specific justifiable circumstances. PMID- 26632312 TI - Screening for childhood hearing impairment in resource-constrained settings: Opportunities and possibilities. PMID- 26632313 TI - Time for 'basic antenatal care plus' in South Africa? PMID- 26632314 TI - Family planning in South Africa: Missing essentials and desirables. PMID- 26632315 TI - Patents and the quality, safety and efficacy of medicines. PMID- 26632316 TI - Pre-exposure prophylaxis for South African adolescents: What evidence? AB - Adolescents and young women, particularly in South Africa, are at increased risk of HIV acquisition. To date, we have had limited primary prevention options to offer. Oral pre-exposure prophylaxis (PrEP) is an additional prevention modality that has now been proven to reduce HIV acquisition in those who take it consistently during periods of HIV infection exposure. We review the PrEP evidence in adolescents and highlight some of the research gaps. Our recommendation is to increase the number of demonstration projects and other scale-up opportunities to offer oral PrEP to at-risk adolescents, and monitor carefully to answer the outstanding questions. PMID- 26632317 TI - School-based human papillomavirus vaccination: An opportunity to increase knowledge about cervical cancer and improve uptake of screening. AB - BACKGROUND: Poor knowledge about cervical cancer plays a role in limiting screening uptake. HPV vaccination provides an untested platform to distribute information that could possibly improve knowledge and screening coverage. OBJECTIVE: To measure changes in knowledge and screening uptake when information and screening opportunities were provided to mothers of adolescent HPV vaccine recipients. METHODS: During an HPV vaccine implementation project in the Western Cape (WC) and Gauteng Province (GP), South Africa, information about cervical cancer was provided to parents during a lecture, written information was distributed, and mothers were then invited to either screen at their clinic (WC) or use a self-screening kit (GP). A structured questionnaire was used to test cervical cancer knowledge and screening practices, comparing these before and after the project and between the two screening groups. RESULTS: Complete data for both questionnaires were available for 777 of 906 recruited women. Initial knowledge was poor, but on retesting 6 months later, knowledge about symptoms (p<0.005), screening (p<0.005) and vaccination (p<0.05) improved significantly after the information session and school-based HPV vaccination. In the second questionnaire, women reported significantly more screening and the last reported screening test was more recent. This improvement was more favourable in GP than in the WC (41% v. 26% reporting screening in the past 12 months). CONCLUSION: These results demonstrate how adolescent HPV vaccine programmes can help to control cervical cancer among mothers by offering information and screening. It is important not to lose this opportunity to educate mothers and their daughters and offer effective methods to prevent cervical cancer in both generations. PMID- 26632318 TI - Missed opportunities for immunisation in health facilities in Cape Town, South Africa. AB - BACKGROUND: Childhood immunisations are a cost-effective public health intervention for prevention of infectious diseases. Immunisation coverage is still suboptimal, however, which may result in disease outbreaks. Immunisation at every contact with a health facility is a strategy developed by the World Health Organization in order to improve immunisation coverage. OBJECTIVES: To estimate the prevalence of missed opportunities for immunisation at different levels of healthcare in the Western Cape Province, South Africa, and assess factors associated with missed opportunities. METHODS: The study included a health facility-based cross-sectional exit survey of caregivers with children up to 5 years of age, followed by a qualitative exploration of staff attitudes towards immunisation. RESULTS: The overall prevalence of missed opportunities for immunisation was 4.6%; 81.3% of caregivers brought Road-to-Health booklets (RTHBs) to consultations; and 56.0% of health workers asked to see the RTHBs during consultations. Children attending primary level facilities were significantly more likely to have their RTHBs requested than children attending a tertiary level facility. Lack of training and resources and heavy workloads were the main challenges reported at secondary/tertiary level facilities. CONCLUSION: Missed opportunities for immunisation at health facilities in Cape Town were low, probably reflecting good immunisation coverage among children accessing health facilities. Increased health worker support, particularly at secondary/tertiary levels of care, is needed to improve the use of RTHBs to provide immunisation. PMID- 26632319 TI - A profile of anti-vaccination lobbying on the South African internet, 2011-2013. AB - BACKGROUND: The South African Vaccination and Immunisation Centre receives many requests to explain the validity of internet-based anti-vaccination claims. Previous global studies on internet-based anti-vaccination lobbying had not identified anti-vaccination web pages originating in South Africa (SA). OBJECTIVE: To characterise SA internet-based anti-vaccination lobbying. METHODS: In 2011, searches for anti-vaccination content were performed using Google, Yahoo and MSN-Bing, limited to English-language SA web pages. Content analysis was performed on web pages expressing anti-vaccination sentiment about infant vaccination. This was repeated in 2012 and 2013 using Google, with the first 700 web pages per search being analysed. RESULTS: Blogs/forums, articles and e-shops constituted 40.3%, 55.2% and 4.5% of web pages, respectively. Authors were lay people (63.5%), complementary/alternative medicine (CAM) practitioners (23.1%), medical professionals practising CAM (7.7%) and medical professionals practising only allopathic medicine (5.8%). Advertisements appeared on 55.2% of web pages. Of these, 67.6% were sponsored by or linked to organisations with financial interests in discrediting vaccines, with 80.0% and 24.0% of web pages sponsored by these organisations claiming respectively that vaccines are ineffective and that vaccination is profit driven. The vast majority of web pages (92.5%) claimed that vaccines are not safe, and 77.6% of anti-vaccination claims originated from the USA. CONCLUSION: South Africans are creating web pages or blogs for local anti-vaccination lobbying. Research is needed to understand what influence internet-based anti-vaccination lobbying has on the uptake of infant vaccination in SA. PMID- 26632320 TI - Age of diagnosis of congenital hearing loss: Private v. public healthcare sector. AB - BACKGROUND: The age of diagnosis of congenital hearing loss is one of the most important determinants of communication outcome. A previous study by the lead author had evaluated the performance of the public health services in Bloemfontein, South Africa (SA), in this regard. This study aimed to examine whether the private health services in the same city were any better. OBJECTIVE: To determine whether the age of diagnosis of congenital hearing loss (CHL) in children seen in the private healthcare sector in Bloemfontein, Free State Province, SA, was lower than that in the public healthcare system in the same city. METHODS: A comparative study design was utilised and a retrospective database review conducted. Data obtained from this study in the private healthcare sector were compared with data from a previous study in the public healthcare sector using the same study design. RESULTS: Forty-eight children aged <6 years with disabling hearing impairment (DHI) were identified in the private healthcare sector during the study period; 33/47 (70.2%) did not undergo hearing screening at birth. The median age of diagnosis of DHI in the private healthcare sector was 2.24 years, and this was statistically significantly lower than the median age of diagnosis of 3.71 years in the public healthcare sector (p<0.0001; 95% confidence interval (CI) 0.99-2.0). The median age of diagnosis of congenital hearing loss (CHL) in the private healthcare sector was 3.01 years in children who were not screened at birth, and 1.25 years in those who were screened at birth. This difference was statistically significant (p<0.01; 95% CI 0.72-2.47). We also compared the median age of diagnosis of CHL in children from the private healthcare sector who were not screened at birth (median 3.01 years) with that in children in the public healthcare sector (median 3.71 years). This difference was statistically significant (p<0.01; 95% CI 0.41-1.56). CONCLUSIONS: Children in the Free State are diagnosed with CHL at a younger age in the private healthcare sector than in the public healthcare sector. With the social and economic benefits of early intervention in cases of DHI well established internationally, SA healthcare providers in both the public and private sectors need to develop screening, diagnostic and (re)habilitation services for children with hearing impairment. PMID- 26632321 TI - Evaluation of fetal MRI in a South African referral centre. AB - BACKGROUND: The Department of Radiology at Groote Schuur Hospital, Cape Town, South Africa, has been performing fetal magnetic resonance imaging (MRI) since 2007. Fetal MRI findings have not previously been analysed to correlate them with antenatal and postnatal findings. OBJECTIVES: To determine the most common indication for fetal MRI, and to correlate antenatal MRI with antenatal ultrasound (US), postnatal imaging and postmortem findings. METHODS: This was a retrospective study of imaging carried out between January 2006 and December 2011. Seventy fetal MRI cases with complete antenatal and postnatal medical records were included. Antenatal US and antenatal MRI were compared, and also compared with the postnatal imaging findings. Stata 12 was used to analyse the data, and Spearman's test to test the agreement between the results. RESULTS: Intracranial pathology was the most common indication for fetal MRI, with ventriculomegaly being the commonest indication determined from prenatal US. There was 72% agreement between antenatal US and fetal MRI. Postnatal findings showed 28% agreement with antenatal US and 39% agreement with fetal MRI. CONCLUSIONS: Intracranial pathology was the major indication for fetal MRI. There was good agreement between prenatal US and fetal MRI but poor agreement between antenatal and postnatal findings, largely as a result of resolution of ventriculomegaly. PMID- 26632322 TI - Depressive and post-traumatic stress symptoms following termination of pregnancy in South African women: A longitudinal study measuring the effects of chronic burden, crisis support and resilience. AB - BACKGROUND: Termination of pregnancy (TOP) remains a controversial issue, regardless of legislation. Access to services as well as psychological effects may vary across the world. OBJECTIVES AND METHODS: To better understand the psychological effects of TOP, this study describes the circumstances of 102 women who underwent a TOP from two socioeconomic sites in Johannesburg, South Africa, one serving women with few economic resources and the other serving women with adequate resources. The relationship between demographic characteristics, resilience and symptoms of post-traumatic stress disorder (PTSD) and depression before, 1 month after and 3 months after the procedure was also examined. RESULTS: Time since TOP, age, chronic burden, resilience and the interaction of site with religion and site with chronic burden were significant. In addition, site differences were found for religion and chronic burden in predicting depression scores. Women from both sites had significant decreases in depression scores over time. The interaction of time with site was not significant. Higher chronic burden scores correlated with higher depression scores. No variables were significant in the bivariate analysis for PTSD. CONCLUSION: Resilience, religion and chronic burden emerge as significant variables in women undergoing a first trimester TOP, and warrant further assessment in studies of this nature. PMID- 26632323 TI - Childhood cancer incidence in South Africa, 1987-2007. AB - BACKGROUND: Childhood cancer is an emerging problem in Africa. Its extent is hazy because data are scarce, but it should be addressed. This is the first report from the South African Children's Tumour Registry (SACTR), which covers the whole of South Africa (SA). It provides minimal estimates of cancer incidence and discusses the challenges of cancer surveillance and control in a child population in a middle-income country. Only about 2% of the African population is covered by cancer registries producing comparable incidence data. OBJECTIVE: To present and interpret incidence patterns and trends of childhood cancer over a 21-year period. The results should raise awareness of the problem of childhood cancer in an African population and provide sensible data for taking this problem in hand. METHODS: All eligible and validated cancer cases registered in the SACTR over the period 1987-2007 and classified according to the International Classification of Childhood Cancer were included. Population data were retrieved from official sources and estimated for the population subcategories. Incidence rates were standardised to the world standard and time trends were evaluated using joinpoint models, adjusting for sex and age. RESULTS: Based on the 11,699 cases, the overall age-standardised average annual incidence rate was 45 per million. Threefold differences in the overall incidence rates were observed between the ethnic groups, ranging from 116 for whites to 37 for black Africans, and they differed by diagnostic group. Differences between the nine provinces of SA relate to the ethnic composition and prevailing socioeconomic status. The overall incidence rate declined by 1.2% per year for the whole country (p<0.01). However, the decline was mainly observed during the first few years of the study period, after which rates stabilised or increased. CONCLUSIONS: Diagnosis and notification of childhood cancer should improve. The differences in incidence between ethnic groups suggest the priorities for cancer control. PMID- 26632324 TI - A method to predict different mechanisms for blood-brain barrier permeability of CNS activity compounds in Chinese herbs using support vector machine. AB - The blood-brain barrier (BBB), a highly selective barrier between central nervous system (CNS) and the blood stream, restricts and regulates the penetration of compounds from the blood into the brain. Drugs that affect the CNS interact with the BBB prior to their target site, so the prediction research on BBB permeability is a fundamental and significant research direction in neuropharmacology. In this study, we combed through the available data and then with the help of support vector machine (SVM), we established an experiment process for discovering potential CNS compounds and investigating the mechanisms of BBB permeability of them to advance the research in this field four types of prediction models, referring to CNS activity, BBB permeability, passive diffusion and efflux transport, were obtained in the experiment process. The first two models were used to discover compounds which may have CNS activity and also cross the BBB at the same time; the latter two were used to elucidate the mechanism of BBB permeability of those compounds. Three optimization parameter methods, Grid Search, Genetic Algorithm (GA), and Particle Swarm Optimization (PSO), were used to optimize the SVM models. Then, four optimal models were selected with excellent evaluation indexes (the accuracy, sensitivity and specificity of each model were all above 85%). Furthermore, discrimination models were utilized to study the BBB properties of the known CNS activity compounds in Chinese herbs and this may guide the CNS drug development. With the relatively systematic and quick approach, the application rationality of traditional Chinese medicines for treating nervous system disease in the clinical practice will be improved. PMID- 26632325 TI - Serum leptin, C-reactive protein, and cancer mortality in the NHANES III. AB - Adipokines, such as leptin, may affect cancer through its link with inflammation and obesity. We investigated the association between leptin, C-reactive protein, and risk of cancer death while accounting general and abdominal obesity. From the Third National Health and Examination Survey (NHANES III), we selected 5957 adult men and women with baseline measurements of serum leptin and CRP. Multivariable Cox regression was used to assess leptin and CRP levels (low, moderate, high) in relation to risk of cancer death. Stratification analyses were performed for obesity as defined by body mass index (BMI) and waist circumference. Fine and Gray regression was performed to account for death from cardiovascular disease and other causes as competing events. A total of 385 participants died of cancer during a mean follow-up of 18 years. After adjusting for BMI and waist circumference, an inverse association with log-transformed leptin was found for women, with a hazard ratio (HR) of 0.81 (95% confidence interval [CI]: 0.51-1.30) and 0.40 (95% CI: 0.24-0.68) for moderate and high compared to low levels of leptin, respectively; P(trend) = 0.0007). No association for leptin was observed in men, but higher CRP corresponded to increased risk of dying from cancer (HR: 2.98; 95% CI: 1.57-5.64 for the highest vs. lowest categories of CRP). Similar associations were observed with competing risk analysis also adjusted for BMI and waist circumference. Contrasting associations of serum leptin and CRP with cancer mortality may indicate sex-specific biological or environmental pathways linking obesity and cancer in men and women which warrant mechanistic investigations. PMID- 26632326 TI - Population tailored modification of tuberculosis specific interferon-gamma release assay. AB - OBJECTIVES: Blood-based Interferon-Gamma Release Assays (IGRA) identify Mycobacterium tuberculosis (MTB) sensitisation with increased specificity, but sensitivity remains impaired in human immunodeficiency virus (HIV) infected persons. The QuantiFERON-TB Gold In-Tube test contains peptide 38-55 of Rv2654c, based on data indicating differential recognition between tuberculosis patients and BCG vaccinated controls in Europe. We aimed to fine map the T cell response to Rv2654c with the view of improving sensitivity. METHODS: Interferon-gamma ELISpot assay was used in HIV uninfected persons with latent and active tuberculosis to map peptide epitopes of Rv2654c. A modified IGRA was tested in two further groups of 55 HIV uninfected and 44 HIV infected persons, recruited in South Africa. RESULTS: The most prominently recognised peptide was between amino acids 51-65. Using p51-65 to boost the QuantiFERON-TB Gold In-Tube assay, the quantitative performance of the modified IGRA increased from 1.83 IU/ml (IQR 0.30 7.35) to 2.83 (IQR 0.28-12.2; p = 0.002) in the HIV uninfected group. In the HIV infected cohort the percentage of positive responders increased from 57% to 64% but only after 3 months of ART (p = ns). CONCLUSIONS: Our data shows the potential to population tailor detection of MTB sensitization using specific synthetic peptides and interferon-gamma release in vitro. PMID- 26632327 TI - Multiple myeloma as a major cause of false-positive galactomannan tests in adult patients with cancer. AB - OBJECTIVES: The galactomannan (GM) test is a useful method for early diagnosis of invasive aspergillosis. Recently, multiple myeloma has newly been suggested to be related to false-positive results of GM. We performed a case-control study to validate this finding. METHODS: Electronic medical records were reviewed for patients admitted March through June 2014. Patients with false-positive GM results were selected as cases and those with negatives as controls. To verify the results of the four-month analysis, additional analysis was performed in multiple myeloma patients over a three-year period. RESULTS: There were 30 false positive and 316 negative cases during the four-month period. Among the factors evaluated, multiple myeloma was the only significant factor in the adjusted analysis (OR = 3.59, CI 1.28-10.04). In the three-year analysis of 145 multiple myeloma patients, 25.5% showed false-positive results, which was 3 times higher than overall. GM false-positivity was not related to serum monoclonal protein level or type of immunoglobulin. GM optical density indexes (ODIs) in all false positives were lower than 3.0. CONCLUSIONS: Multiple myeloma was a major cause of GM false-positivity in adult cancer patients. GM was false-positive in 25.5% of multiple myeloma patients with GM ODIs lower than 3.0. PMID- 26632328 TI - Molecular diagnosis of Legionella infections--Clinical utility of front-line screening as part of a pneumonia diagnostic algorithm. AB - OBJECTIVES: Urinary antigen testing for Legionella pneumophila serogroup 1 is the leading rapid diagnostic test for Legionnaires' Disease (LD); however other Legionella species and serogroups can also cause LD. The aim was to determine the utility of front-line L. pneumophila and Legionella species PCR in a severe respiratory infection algorithm. METHODS: L. pneumophila and Legionella species duplex real-time PCR was carried out on 1944 specimens from hospitalised patients over a 4 year period in Edinburgh, UK. RESULTS: L. pneumophila was detected by PCR in 49 (2.7%) specimens from 36 patients. During a LD outbreak, combined L. pneumophila respiratory PCR and urinary antigen testing had optimal sensitivity and specificity (92.6% and 98.3% respectively) for the detection of confirmed cases. Legionella species was detected by PCR in 16 (0.9%) specimens from 10 patients. The 5 confirmed and 1 probable cases of Legionella longbeachae LD were both PCR and antibody positive. CONCLUSIONS: Front-line L. pneumophila and Legionella species PCR is a valuable addition to urinary antigen testing as part of a well-defined algorithm. Cases of LD due to L. longbeachae might be considered laboratory-confirmed when there is a positive Legionella species PCR result and detection of L. longbeachae specific antibody response. PMID- 26632329 TI - Ongoing transmission of avian influenza A viruses in Hong Kong despite very comprehensive poultry control measures: A prospective seroepidemiology study. AB - OBJECTIVES: Stringent measures have been implemented in Hong Kong to prevent human infections due to avian influenza viruses (AIVs). Here, we report the seroprevalence of AIVs among high risk population. METHODS: In this prospective study, blood samples were collected in October and November 2013 and in July 2014 from workers at live poultry market (LPM) and pig/cattle slaughterhouse (SH) in Hong Kong. Serum antibody titers against A(H5N1), A(H7N9) and A(H9N2) were determined. RESULTS: When an hemagglutination inhibition (HI) titer of 40 was used as the cutoff, the A(H5N1) seropositive rate among LPM workers increased from 0% in 2013 to 37.8% in 2014 (P < 0.001) and the A(H9N2) seropositive rate increased from 10% to 55.6% (P < 0.001). There was no significant increase in A(H7N9) seropositive rate for LPM workers irrespective of cutoff titer. For SH workers, there was no significant increase in HI titer for any AIVs. Significantly more LPM workers had a >=4-fold increase in A(H5N1) HI titer from 2013 to 2014 than SH workers (60% vs 8.3%, P = 0.020). CONCLUSIONS: There was a significant increase of serum A(H5N1) and A(H9N2) HI titers among Hong Kong LPM workers between 2013 and 2014. Although we cannot exclude some degree of antibody cross-reactivity with other influenza viruses, our results suggest the occurrence of subclinical AIV infections in this population. PMID- 26632330 TI - Block of CDK1-dependent polyadenosine elongation of Cyclin B mRNA in metaphase-i arrested starfish oocytes is released by intracellular pH elevation upon spawning. AB - Meiotic progression requires the translation of maternal mRNAs in a strict temporal order. In isolated animal oocytes, translation of maternal mRNAs containing a cytoplasmic polyadenylation element (CPE), such as cyclin B, is activated by in vitro stimulation of meiotic resumption which induces phosphorylation of CPEB (CPE-binding protein) and elongation of their polyadenosine (poly(A)) tails; whether or not this model can be applied in vivo to oocytes arrested at metaphase of meiosis I in ovaries is unknown. In this study, we found that active CDK1 (cyclin-dependent kinase 1) phosphorylated CPEB in ovarian oocytes arrested at metphase I in the starfish body cavity, but phosphorylation of CPEB was not sufficient for elongation of cyclin B poly(A) tails. Immediately after spawning, however, mRNA was polyadenylated, suggesting that an increase in intracellular pH (pHi ) upon spawning triggers the elongation of poly(A) tails. Using a cell-free system made from maturing oocytes at metaphase I, we demonstrated that polyadenylation was indeed suppressed at pH below 7.0. These results suggest that a pH-sensitive process, functioning after CPEB phosphorylation, is blocked under physiologically low pHi (<7.0) in metaphase-I-arrested oocytes. The increase in pHi (>7.0) that occurs after spawning triggers polyadenylation of cyclin B mRNA and progression into meiosis II. PMID- 26632331 TI - Milk protein profiles in response to Streptococcus agalactiae subclinical mastitis in dairy cows. AB - The objective of this study was to investigate the milk protein profiles of normal milk and those of milk during the course of subclinical mastitis, caused by natural Streptococcus agalactiae infection. Two-dimensional gel electrophoresis and liquid chromatography mass spectrometry were used to assess protein profiles and to identify the proteins. The results showed that S. agalactiae subclinical mastitis altered the protein profiles of milk. Following Mascot database matching, 11 and 12 protein types were identified in the milk collected from healthy and S. agalactiae subclinical mastitic udders, respectively. The distinct presence of the antibacterial protein cathelicidin-1 was detected in infected milk samples, which in turn was highly correlated to the severity of subclinical mastitis as represented by the milk somatic cell count (r = 0.616), but not the bacterial count. The protein profile of milk reveals changes in the host response to S. agalactiae intramammary infection; cathelicidin-1 could therefore serve as a biomarker for the detection of subclinical mastitis in dairy cows. PMID- 26632332 TI - Prognostic Value of Ezrin in Various Cancers: A Systematic Review and Updated Meta-analysis. AB - More and more studies have investigated the effects of Ezrin expression level on the prognostic role in various tumors. However, the results remain controversial rather than conclusive. Here, we performed a systematic review and meta-analysis to evaluate the correlation of Ezrin expression with the prognosis in various tumors. the pooled hazard ratios (HR) with the corresponding 95% confidence intervals (95% CI) were calculated to evaluate the degree of the association. The overall results of fifty-five studies with 6675 patients showed that elevated Ezrin expression was associated with a worse prognosis in patients with cancers, with the pooled HRs of 1.86 (95% CI: 1.51-2.31, P < 0.001) for over survival (OS), 2.55 (95% CI: 2.14-3.05, P < 0.001) for disease-specific survival (DFS) and 2.02 (95% CI: 1.13-3.63, P = 0.018) for disease-specific survival (DSS)/metastasis-free survival (MFS) by the random, fixed and random effect model respectively. Similar results were also observed in the stratified analyses by tumor types, ethnicity background and sample source. This meta-analysis suggests that Ezrin may be a potential prognostic marker in cancer patients. High Ezrin is associated with a poor prognosis in a variety of solid tumors. PMID- 26632333 TI - Targeted gene disruption in Candida parapsilosis demonstrates a role for CPAR2_404800 in adhesion to a biotic surface and in a murine model of ascending urinary tract infection. AB - Candida parapsilosis is an emerging opportunistic pathogen, second in frequency only to C. albicans and commonly associated with both mucosal and systemic infections. Adhesion to biotic surfaces is a key step for the development of mycoses. The C. parapsilosis genome encodes 5 predicted agglutinin-like sequence proteins and their precise role in the adhesion process still remains to be elucidated. In this study, we focused on the putative adhesin Cpar2_404800, in view of its high homology to the most important adhesion molecule in C. albicans. Two independent lineages of C. parapsilosis CPAR2_404800 heterozygous and null mutants were obtained by site-specific deletion. CPAR2_404800 mutants did not differ from wild-type strain in terms of in vitro growth or in their ability to undergo morphogenesis. However, when compared for adhesion to a biotic surface, CPAR2_404800 null mutants exhibited a marked reduction in their adhesion to buccal epithelial cells (>60% reduction of adhesion index). Reintroduction of one copy of CPAR2_404800 gene in the null background restored wild type phenotype. A murine model of urinary tract infection was used to elucidate the in vivo contribution of CPAR2_404800. A 0.5 and 1 log10 reduction in colony forming unit numbers (per gram) was observed respectively in bladder and kidneys obtained from mice infected with null mutant compared to wild-type infected ones. Taken together, these findings provide the first evidence for a direct role of CPAR2_404800 in C. parapsilosis adhesion to host surfaces and demonstrate its contribution to the pathogenesis of murine urinary candidiasis. PMID- 26632335 TI - Prenatal ethanol exposure impairs temporal ordering behaviours in young adult rats. AB - Prenatal ethanol exposure (PNEE) causes significant deficits in functional (i.e., synaptic) plasticity in the dentate gyrus (DG) and cornu ammonis (CA) hippocampal sub-regions of young adult male rats. Previous research has shown that in the DG, these deficits are not apparent in age-matched PNEE females. This study aimed to expand these findings and determine if PNEE induces deficits in hippocampal dependent behaviours in both male and female young adult rats (PND 60). The metric change behavioural test examines DG-dependent deficits by determining whether an animal can detect a metric change between two identical objects. The temporal order behavioural test is thought to rely in part on the CA sub-region of the hippocampus and determines whether an animal will spend more time exploring an object that it has not seen for a larger temporal window as compared to an object that it has seen more recently. Using the liquid diet model of FASD (where 6.6% (v/v) ethanol is provided through a liquid diet consumed ad libitum throughout the entire gestation), we found that PNEE causes a significant impairment in the temporal order task, while no deficits in the DG-dependent metric change task were observed. There were no significant differences between males and females for either task. These results indicate that behaviours relying partially on the CA-region may be more affected by PNEE than those that rely on the DG. PMID- 26632334 TI - Recombinant Resilin-Based Bioelastomers for Regenerative Medicine Applications. AB - The outstanding elasticity, excellent resilience at high-frequency, and hydrophilic capacity of natural resilin have motivated investigations of recombinant resilin-based biomaterials as a new class of bio-elastomers in the engineering of mechanically active tissues. Accordingly, here the comprehensive characterization of modular resilin-like polypeptide (RLP) hydrogels is presented and their suitability as a novel biomaterial for in vivo applications is introduced. Oscillatory rheology confirmed that a full suite of the RLPs can be rapidly cross-linked upon addition of the tris(hydroxymethyl phosphine) cross linker, achieving similar in situ shear storage moduli (20 k +/- 3.5 Pa) across various material compositions. Uniaxial stress relaxation tensile testing of hydrated RLP hydrogels under cyclic loading and unloading showed negligible stress reduction and hysteresis, superior reversible extensibility, and high resilience with Young's moduli of 30 +/- 7.4 kPa. RLP hydrogels containing MMP sensitive domains are susceptible to enzymatic degradation by matrix metalloproteinase-1 (MMP-1). Cell culture studies revealed that RLP-based hydrogels supported the attachment and spreading (2D) of human mesenchymal stem cells and did not activate cultured macrophages. Subcutaneous transplantation of RLP hydrogels in a rat model, which to our knowledge is the first such reported in vivo analysis of RLP-based hydrogels, illustrated that these materials do not elicit a significant inflammatory response, suggesting their potential as materials for tissue engineering applications with targets of mechanically demanding tissues such as vocal fold and cardiovascular tissues. PMID- 26632336 TI - Dissociable hippocampal and amygdalar D1-like receptor contribution to discriminated Pavlovian conditioned approach learning. AB - Pavlovian conditioning is an elementary form of reward-related behavioral adaptation. The mesolimbic dopamine system is widely considered to mediate critical aspects of reward-related learning. For example, initial acquisition of positively-reinforced operant behavior requires dopamine (DA) D1 receptor (D1R) activation in the basolateral amygdala (BLA), central nucleus of the amygdala (CeA), and the ventral subiculum (vSUB). However, the role of D1R activation in these areas on appetitive, non-drug-related, Pavlovian learning is not currently known. In separate experiments, microinfusions of the D1-like receptor antagonist SCH-23390 (3.0 nmol/0.5 MUL per side) into the amygdala and subiculum preceded discriminated Pavlovian conditioned approach (dPCA) training sessions. D1-like antagonism in all three structures impaired the acquisition of discriminated approach, but had no effect on performance after conditioning was asymptotic. Moreover, dissociable effects of D1-like antagonism in the three structures on components of discriminated responding were obtained. Lastly, the lack of latent inhibition in drug-treated groups may elucidate the role of D1-like in reward related Pavlovian conditioning. The present data suggest a role for the D1 receptors in the amygdala and hippocampus in learning the significance of conditional stimuli, but not in the expression of conditional responses. PMID- 26632337 TI - GLYX-13 (rapastinel) ameliorates subchronic phencyclidine- and ketamine-induced declarative memory deficits in mice. AB - GLYX-13 (rapastinel), a tetrapeptide (Thr-Pro-Pro-Thr-amide), has been reported to have fast acting antidepressant properties in man based upon its N-methyl-D aspartate receptor (NMDAR) glycine site functional partial agonism. Ketamine, a non-competitive NMDAR antagonist, also reported to have fast acting antidepressant properties, produces cognitive impairment in rodents and man, whereas rapastinel has been reported to have cognitive enhancing properties in rodents, without impairing cognition in man, albeit clinical testing has been limited. The goal of this study was to compare the cognitive impairing effects of rapastinel and ketamine in novel object recognition (NOR), a measure of declarative memory, in male C57BL/6J mice treated with phencyclidine (PCP), another NMDAR noncompetitive antagonist known to severely impair cognition, in both rodents and man. C57BL/6J mice given a single dose or subchronic ketamine (30 mg/kg.i.p.) showed acute or persistent deficits in NOR, respectively. Acute i.v. rapastinel (1.0 mg/kg), did not induce NOR deficit. Pre-treatment with rapastinel significantly prevented acute ketamine-induced NOR deficit. Rapastinel (1.0 mg/kg, but not 0.3 mg/kg, iv) significantly reversed both subchronic ketamine- and subchronic PCP-induced NOR deficits. Rapastinel also potentiated the atypical antipsychotic drug with antidepressant properties, lurasidone, to restore NOR in subchronic ketamine-treated mice. These findings indicate that rapastinel, unlike ketamine, does not induce a declarative memory deficit in mice, and can prevent or reverse the ketamine-induced NOR deficit. Further study is required to determine if these differences translate during clinical use of ketamine and rapastinel as fast acting antidepressant drugs and if rapastinel could have non-ionotropic effects as an add-on therapy with antipsychotic/antidepressant medications. PMID- 26632338 TI - Nop2 is required for mammalian preimplantation development. AB - Nucleolar protein 2 (NOP2) is evolutionarily conserved from yeast to human, and has been found to play an important role in accelerating cell proliferation, cell cycle progression, and tumor aggressiveness. The expression pattern and function of Nop2 during early mammalian embryo development, however, has not been investigated. We identified Nop2 as an essential gene for development to the blastocyst stage while performing an RNA interference (RNAi)-based screen in mouse preimplantation embryos. Nop2 is expressed throughout preimplantation development, with highest mRNA and protein accumulation at the 8-cell and morula stages, respectively. RNAi-mediated knockdown of Nop2 results in embryos that arrest as morula. NOP2-deficient embryos exhibit reduced blastomere numbers, greatly increased apoptosis, and impaired cell-lineage specification. Furthermore, knockdown of Nop2 results in global reduction of all RNA species, including rRNA, small nuclear RNA, small nucleolar RNA, and mRNA. Taken together, our results demonstrate that Nop2 is an essential gene for blastocyst formation, and is required for RNA processing and/or stability in vivo during preimplantation embryo development in the mouse. PMID- 26632339 TI - Old friends, new story: The role of Slit2C signaling through PlexinA1. AB - Growth cone guidance is driven by attractive and repulsive signaling cues. Until recently, repulsive signaling by semaphorins was thought to be mediated through Plexin receptors, whereas Slits-induced repulsion was solely mediated through Robo receptors. In a recent report published in Nature Neuroscience, Celine Delloye-Bourgeois and colleagues (2015) combined phenotypic analyses of transgenic mouse lines and in vitro biochemical experiments to identify PlexinA1 as a novel receptor for Slits. Strikingly, they uncovered for the very first time that the Slit2C-terminal fragment possesses some unique biological activity as binding partner for PlexinA1. Even more excitingly, the signaling cascade triggered by SlitC binding to PlexinA1 mediates growth cone collapse of commissural axons both in vivo and ex vivo and nicely complements Robo-Slit signaling in the developing spinal cord midline to prevent midline recrossing. PMID- 26632340 TI - Rev-erbalpha modulates the hypothalamic orexinergic system to influence pleasurable feeding behaviour in mice. AB - The drive to eat is regulated by two compensatory brain pathways termed as homeostatic and hedonic. Hypothalamic orexinergic (ORX) neurons regulate metabolism, feeding and reward, thus controlling physiological and hedonic appetite. Circadian regulation of feeding, metabolism and rhythmic activity of ORX cells are driven by the brain suprachiasmatic clock. How the circadian clock impacts on ORX signalling and feeding-reward rhythms is, however, unknown. Here we used mice lacking the nuclear receptor REV-ERBalpha, a transcription repressor and a key component of the molecular clockwork, to study food-reward behaviour. Rev-Erbalpha mutant mice showed highly motivated behaviours to obtain palatable food, an increase in the intake and preference for tasty diets, and in the expression of the ORX protein in the hypothalamus. Palatable food intake was inhibited in animals treated with the ORX1R antagonist. Analyzing the Orx promoter, we found Retinoic acid-related Orphan receptor Response Element binding sites for Rev-Erbalpha. Furthermore, Rev-Erbalpha dampened the activation of Orx in vitro and in vivo. Our data provide evidence for a possible repressive role of Rev-Erbalpha in the regulation of ORX signalling, highlighting an implication of the circadian clockwork in modulating food-reward behaviours with an important impact for the central regulation of overeating. PMID- 26632341 TI - Daily update of motor predictions by physical activity. AB - Motor prediction, i.e., the ability to predict the sensory consequences of motor commands, is critical for adapted motor behavior. Like speed or force, the accuracy of motor prediction varies in a 24-hour basis. Although the prevailing view is that basic biological markers regulate this circadian modulation, behavioral factors such as physical activity, itself modulated by the alternation of night and day, can also regulate motor prediction. Here, we propose that physical activity updates motor prediction on a daily basis. We tested our hypothesis by up- and down-regulating physical activity via arm-immobilization and high-intensity training, respectively. Motor prediction was assessed by measuring the timing differences between actual and mental arm movements. Results show that although mental movement time was modulated during the day when the arm was unconstrained, it remained constant when the arm was immobilized. Additionally, increase of physical activity, via release from immobilization or intense bout of training, significantly reduced mental movement time. Finally, mental and actual times were similar in the afternoon in the unconstrained condition, indicating that predicted and actual movements match after sufficient amount of physical activity. Our study supports the view that physical activity calibrates motor predictions on a daily basis. PMID- 26632342 TI - Human parvovirus B19 VP1u Protein as inflammatory mediators induces liver injury in naive mice. AB - Human parvovirus B19 (B19V) is a human pathogen known to be associated with many non-erythroid diseases, including hepatitis. Although B19V VP1-unique region (B19 VP1u) has crucial roles in the pathogenesis of B19V infection, the influence of B19-VP1u proteins on hepatic injury is still obscure. This study investigated the effect and possible inflammatory signaling of B19-VP1u in livers from BALB/c mice that were subcutaneously inoculated with VP1u-expressing COS-7 cells. The in vivo effects of B19-VP1u were analyzed by using live animal imaging system (IVIS), Haematoxylin-Eosin staining, gel zymography, and immunoblotting after inoculation. Markedly hepatocyte disarray and lymphocyte infiltration, enhanced matrix metalloproteinase (MMP)-9 activity and increased phosphorylation of p38, ERK, IKK-alpha, IkappaB and NF-kappaB (p-p65) proteins were observed in livers from BALB/c mice receiving COS-7 cells expressing B19-VP1u as well as the significantly increased CRP, IL-1beta and IL-6. Notably, IFN-gamma and phosphorylated STAT1, but not STAT3, were also significantly increased in the livers of BALB/c mice that were subcutaneously inoculated with VP1u-expressing COS-7 cells. These findings revealed the effects of B19-VP1u on liver injury and suggested that B19-VP1u may have a role as mediators of inflammation in B19V infection. PMID- 26632343 TI - Periodic Nanoneedle and Buffer Zones Constructed on a Titanium Surface Promote Osteogenic Differentiation and Bone Calcification In Vivo. AB - Rapid and effective bone mineralization at the bone/implant interface is required for successful orthopedic and dental implants. In this study, two periodic microscale functionalized zones on titanium (MZT) are created, namely, nanoneedle zones and buffer zones. The aim of this design is to provide spatially regulated topographical cues on titanium to enhance the efficacy of bone regeneration. This goal is achieved using a versatile and effective technique in which nanoneedle structures are hydrothermally constructed on the surface of titanium sheets, after which selective laser irradiation is used to construct buffer zones. The zonal structures of the MZT overcome the suppressive effect of the nanoneedle film on osteoblasts. Additionally, the MZT exhibits zone-selective apatite deposition and protein adsorption. The accelerated in vitro osteoblast differentiation and nodule deposition on the MZT are confirmed. Elemental analysis of the bone nodules formed by the osteoblasts growing on the titanium and MZT demonstrates they have different compositions. Histological and scanning electron microscope analysis of the bone formation on in vivo implants shows that this process is also enhanced by the MZT implant. The concept of constructing functionalized zones on titanium implant could facilitate future research on improving the design of orthopedic and dental implant surfaces. PMID- 26632344 TI - Enzymatic monitoring of lignin and lignin derivatives biooxidation. AB - Lignin oxidation was enzymatically monitored by measuring methanol released during the reaction. The methanol was oxidized to formaldehyde and hydrogen peroxide, and the latter used to oxidize ABTS to a product measured spectrophotometrically. The efficiency was comparable to the commonly used gas chromatography method. The assay was fast and inexpensive. PMID- 26632345 TI - The complex interplay of physician, patient, and spouse in preoperative counseling for radical prostatectomy: a comparative mixed-method analysis of 30 videotaped consultations. AB - OBJECTIVES: Spouses of cancer patients play a crucial role in deciding on therapeutic choices. The aim of our study was to assess their role in counseling for radical prostatectomy. METHODS: We analyzed 30 videotaped preoperative consultations prior to radical prostatectomy. Thereof, 14 included the patients' female partner and 16 took place without partner attendance. We performed quantitative and qualitative conversation analysis to compare both settings. RESULTS: Mean age of patients was 61 (47-73) years; 13% (4/30) did not have a partner. Duration of preoperative consultations was 20 (10-32) min. Physicians spoke most of the time (93%, range 71-99%), followed by patients (7%, range 1 20%) and spouses (2%, range 0-8%). Patients whose spouse was present at the consultation tended to have a more averted posture (50% vs. 25%, p = 0.04) and tended to speak less often (5% vs. 8%, p = 0.02). In 4 of 14 (29%) consultations, the spouses tended to be more dominant, speaking more frequently. Qualitative analysis showed several examples of emotional support and helpful contributions by spouses. Difference of opinion occurred when pros and cons of a nerve-sparing approach were discussed. The spouses' impact appeared to influence the final decision of men contemplating a nerve-sparing approach in 1 of 14 conversations. CONCLUSIONS: Spouses appear to play a complex and sometimes ambivalent role in counseling for radical prostatectomy. Especially when discussing a nerve-sparing approach, urologist should focus on the patients' true needs while interacting with both partners. Personalized decision aids might help to identify possible conflicts in advance.Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26632346 TI - Histone deacetylase inhibitor valproic acid (VPA) promotes the epithelial mesenchymal transition of colorectal cancer cells via up regulation of Snail. AB - Histone deacetylase inhibitors (HDACIs) have been shown to have antiproliferative activity through cell-cycle arrest, differentiation, and apoptosis in colorectal cancer (CRC) cells. Our present study revealed that one HDAC inhibitor, valproic acid (VPA), can obviously promote in vitro motility of HCT-116 and SW480 cells. VPA treatment significantly down regulates the expression of epithelial markers E Cadherin (E-Cad) and Zona occludin-1(ZO-1) while up regulates the mesenchymal markers Vimentin (Vim) and N-cadherin (N-Cad), suggesting that VPA can trigger the epithelial-mesenchymal transition (EMT) of CRC cells. VPA treatment significantly increases the expression and nuclear localization of Snail, the key transcription factors of EMT. Snail knockdown by siRNAs obviously reverses VPA induced EMT of HCT-116 and SW480 cells. Further, VPA can decrease the ubiquitination, increase the acetylation, and then elevate the stabilization of Snail. VPA also increases the phosphorylation of Akt/GSK-3beta. The inhibitor of PI3K/Akt, LY2994002, significantly attenuates VPA induced phosphorylation of Akt and GSK-3beta and up regulation of Snail and Vim. Collectively, our data reveal that VPA can trigger the EMT of CRC cells via up regulation of Snail through AKT/GSK-3beta signals and post-transcriptional modification. It suggests that more attention should be paid when VPA used as a new anticancer drug for CRC patients. PMID- 26632347 TI - Anti-sense DNA d(GGCCCC)n expansions in C9ORF72 form i-motifs and protonated hairpins. AB - The G4C2 hexanucleotide repeat expansion mutation (HREM) in C9ORF72, represents the most common mutation associated with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Three main disease mechanisms have been proposed to date: C9ORF72 haploinsufficiency, RNA toxicity, and accumulation of dipeptide repeat proteins. Pure GC content of the HREM potentially enables the formation of various non-B DNA structures such as G-quadruplexes and i-motifs. These structures are proposed to act as promoters and regulatory elements affecting replication, transcription and translation of the surrounding region. G quadruplexes have already been shown on the G-rich sense DNA and RNA strands (G4C2)n, the structure of the anti-sense (G2C4)n strand remains unresolved. Similar C-rich sequences may, under acidic conditions, form i-motifs consisting of two parallel duplexes in a head to tail orientation held together by hemi protonated C(+)-C pairs. We show that d(G2C4)n repeats do form i-motif and protonated hairpins even under near-physiological conditions. Rather than forming a DNA duplex, i-motifs persist even in the presence of the sense strand. This preferential formation of G-quadruplex and i-motif/hairpin structures over duplex DNA, may explain HREM replicational and transcriptional instability. Furthermore, i-motifs/hairpins can represent a novel pharmacological target for C9ORF72 associated ALS and FTLD. PMID- 26632348 TI - The killing of macrophages by Corynebacterium ulcerans. AB - Corynebacterium ulcerans is an emerging pathogen transmitted by a zoonotic pathway with a very broad host spectrum to humans. Despite rising numbers of infections and potentially fatal outcomes, data on the molecular basis of pathogenicity are scarce. In this study, the interaction of 2 C. ulcerans isolates - one from an asymptomatic dog, one from a fatal case of human infection - with human macrophages was investigated. C. ulcerans strains were able to survive in macrophages for at least 20 hours. Uptake led to delay of phagolysosome maturation and detrimental effects on the macrophages as deduced from cytotoxicity measurements and FACS analyses. The data presented here indicate a high infectious potential of this emerging pathogen. PMID- 26632349 TI - Expecting the best and being prepared for the worst: structure, profiles, and 2 year temporal stability of dispositional optimism in women with breast cancer. AB - OBJECTIVES: Dispositional optimism is viewed as a key personality resource for resiliency and has been linked to adjustment among women with breast cancer. The aim was to examine (a) the psychometric proprieties of Life Orientation Test Revised (LOT-R), (b) the potential independence and co-occurrence of positive and negative dimensions of future outcome expectancies, (c) the longitudinal invariance of LOT-R and the temporal stability of dispositional optimism over 2 years following surgery, and (d) the predictive impact of optimism and pessimism on emotional distress among women with breast cancer. METHODS: Data from a prospective study (n = 750) of women with breast cancer were acquired shortly after surgery, and the women were followed up for 2 years. Assessments of LOT-R, Hospital Anxiety and Depression Scale, treatment-related, and demographic variables were subjected to structural equation modeling analysis. RESULTS: A bidimensional and temporarily invariant structure of LOT-R displayed acceptable fit indices. Three profiles of future expectancies consisting of optimists, pessimists, and ambiguous were identified. Temporal stability in optimism and pessimism over 2 years was established. Women with higher education displayed higher degrees of pessimism. Baseline dispositional optimism inversely predicted emotional distress at 2 years. CONCLUSIONS: The LOT-R should be approached as a bidimensional measure. Co-occurrence of optimism and pessimism may indicate a cautious defensive coping effort in women with breast cancer. The importance of systematic efforts to enhance optimism as well as the capacity to acknowledge both positive and negative future expectancies is emphasized.Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26632351 TI - Relating oxygen partial pressure, saturation and content: the haemoglobin-oxygen dissociation curve. AB - The delivery of oxygen by arterial blood to the tissues of the body has a number of critical determinants including blood oxygen concentration (content), saturation (S O2 ) and partial pressure, haemoglobin concentration and cardiac output, including its distribution. The haemoglobin-oxygen dissociation curve, a graphical representation of the relationship between oxygen satur-ation and oxygen partial pressure helps us to understand some of the principles underpinning this process. Historically this curve was derived from very limited data based on blood samples from small numbers of healthy subjects which were manipulated in vitro and ultimately determined by equations such as those described by Severinghaus in 1979. In a study of 3524 clinical specimens, we found that this equation estimated the S O2 in blood from patients with normal pH and S O2 >70% with remarkable accuracy and, to our knowledge, this is the first large-scale validation of this equation using clinical samples. Oxygen saturation by pulse oximetry (S pO2 ) is nowadays the standard clinical method for assessing arterial oxygen saturation, providing a convenient, pain-free means of continuously assessing oxygenation, provided the interpreting clinician is aware of important limitations. The use of pulse oximetry reduces the need for arterial blood gas analysis (S aO2 ) as many patients who are not at risk of hypercapnic respiratory failure or metabolic acidosis and have acceptable S pO2 do not necessarily require blood gas analysis. While arterial sampling remains the gold standard method of assessing ventilation and oxygenation, in those patients in whom blood gas analysis is indicated, arterialised capillary samples also have a valuable role in patient care. The clinical role of venous blood gases however remains less well defined. PMID- 26632350 TI - Ion channel expression and function in normal and osteoarthritic human synovial fluid progenitor cells. AB - Osteoarthritis (OA) is a chronic disease affecting the cartilage of over 15% of Canadians. Synovial fluid mesenchymal progenitor cells (sfMPCs) are present in joints and are thought to contribute to healing. OA sfMPCs have a greater proliferative ability but decreased chondrogenic potential. However, little is known about the factors influencing/regulating the differences between normal and OA sfMPCs. Recently, our lab has shown that sfMPC chondrogenic differentiation in vitro is favorably biased toward a similar osmotic environment as they experience in vivo. The current study now examines the expression and functionality of a variety of ion channels in sfMPCs derived from normal individuals and early OA patients. Results indicated that there is differential ion channel regulation at the functional level and expression level in early OA sfMPCs. All ion channels were upregulated in early OA compared to normal sfMPCs with the exception of KCNMA1 at the mRNA level. At the protein level, TRPV4 was over expressed in early OA sfMPCs, while KCNJ12 and KCNMA1 were unchanged between normal and early OA sfMPCs. At the functional level, the inward rectifying potassium channel was under expressed in early OA sfMPCs, however the membrane potential was unchanged between normal and early OA sfMPCs. In the synovial environment itself, a number of differences in ion concentration between normal and early OA synovial fluid were observed. These findings suggest that normal and OA progenitor cells demonstrate functional differences in how they interact with the synovial ion environment. PMID- 26632352 TI - Regulation of Isoprenoid Pheromone Biosynthesis in Bumblebee Males. AB - Males of the closely related species Bombus terrestris and Bombus lucorum attract conspecific females by completely different marking pheromones. MP of B. terrestris and B. lucorum pheromones contain mainly isoprenoid (ISP) compounds and fatty acid derivatives, respectively. Here, we studied the regulation of ISP biosynthesis in both bumblebees. RNA-seq and qRT-PCR analyses indicated that acetoacetyl-CoA thiolase (AACT), 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR), and farnesyl diphosphate synthase (FPPS) transcripts are abundant in the B. terrestris labial gland. Maximal abundance of these transcripts correlated well with AACT enzymatic activity detected in the LG extracts. In contrast, transcript abundances of AACT, HMGR, and FPPS in B. lucorum were low, and AACT activity was not detected in LGs. These results suggest that transcriptional regulation plays a key role in the control of ISP biosynthetic gene expression and ISP pheromone biosynthesis in bumblebee males. PMID- 26632353 TI - Treading the Line Between Sensational and Groundbreaking Science. PMID- 26632354 TI - "Editing" Genes: A Case Study About How Language Matters in Bioethics. AB - Metaphors used to describe new technologies mediate public understanding of the innovations. Analyzing the linguistic, rhetorical, and affective aspects of these metaphors opens the range of issues available for bioethical scrutiny and increases public accountability. This article shows how such a multidisciplinary approach can be useful by looking at a set of texts about one issue, the use of a newly developed technique for genetic modification, CRISPRcas9. PMID- 26632355 TI - CRISPR Critters and CRISPR Cracks. AB - This essay focuses on possible nonhuman applications of CRISPR/Cas9 that are likely to be widely overlooked because they are unexpected and, in some cases, perhaps even "frivolous." We look at five uses for "CRISPR Critters": wild de extinction, domestic de-extinction, personal whim, art, and novel forms of disease prevention. We then discuss the current regulatory framework and its possible limitations in those contexts. We end with questions about some deeper issues raised by the increased human control over life on earth offered by genome editing. PMID- 26632356 TI - Engineering Values Into Genetic Engineering: A Proposed Analytic Framework for Scientific Social Responsibility. AB - Recent experiments have been used to "edit" genomes of various plant, animal and other species, including humans, with unprecedented precision. Furthermore, editing the Cas9 endonuclease gene with a gene encoding the desired guide RNA into an organism, adjacent to an altered gene, could create a "gene drive" that could spread a trait through an entire population of organisms. These experiments represent advances along a spectrum of technological abilities that genetic engineers have been working on since the advent of recombinant DNA techniques. The scientific and bioethics communities have built substantial literatures about the ethical and policy implications of genetic engineering, especially in the age of bioterrorism. However, recent CRISPr/Cas experiments have triggered a rehashing of previous policy discussions, suggesting that the scientific community requires guidance on how to think about social responsibility. We propose a framework to enable analysis of social responsibility, using two examples of genetic engineering experiments. PMID- 26632357 TI - Human Germline CRISPR-Cas Modification: Toward a Regulatory Framework. AB - CRISPR germline editing therapies (CGETs) hold unprecedented potential to eradicate hereditary disorders. However, the prospect of altering the human germline has sparked a debate over the safety, efficacy, and morality of CGETs, triggering a funding moratorium by the NIH. There is an urgent need for practical paths for the evaluation of these capabilities. We propose a model regulatory framework for CGET research, clinical development, and distribution. Our model takes advantage of existing legal and regulatory institutions but adds elevated scrutiny at each stage of CGET development to accommodate the unique technical and ethical challenges posed by germline editing. PMID- 26632358 TI - Germline Manipulation and Our Future Worlds. AB - Two genetic technologies capable of making heritable changes to the human genome have revived interest in, and in some quarters a very familiar panic concerning, so-called germline interventions. These technologies are: most recently the use of CRISPR/Cas9 to edit genes in non-viable IVF zygotes and Mitochondrial Replacement Therapy (MRT) the use of which was approved in principle in a landmark vote earlier this year by the United Kingdom Parliament. The possibility of using either of these techniques in humans has encountered the most violent hostility and suspicion. However it is important to be aware that much of this hostility dates back to the fears associated with In Vitro Fertilization (IVF) and other reproductive technologies and by cloning; fears which were baseless at the time concerning both IVF and cloning the use of both of which have proved to be highly beneficial to humanity and which have been effectively regulated and controlled. This paper argues that CRISPR should by pursued through researh until it is safe enough for use in humans but there is no reason to suppose at this stage that such use will be unsafe or unethical (Collins 2015). PMID- 26632359 TI - CRISPR/Cas9 and Germline Modification: New Difficulties in Obtaining Informed Consent. PMID- 26632360 TI - CRISPR-Cas Gene Editing to Cure Serious Diseases: Treat the Patient, Not the Germ Line. PMID- 26632361 TI - Editing the Genome of the Human Germline: May Cool Heads Prevail. PMID- 26632362 TI - Genome Editing Technologies and Human Germline Genetic Modification: The Hinxton Group Consensus Statement. PMID- 26632363 TI - Cherchez la Femme: Reproductive CRISPR and Women's Choices. PMID- 26632364 TI - Human Germline Modification--A Missing Link. PMID- 26632365 TI - Modification of the Embryo's Genome: More Useful in Research Than in the Clinic. PMID- 26632366 TI - Genome Editing and Dialogic Responsibility: "What's in a Name?". PMID- 26632367 TI - The "Three-Parent Baby": A Case Study of How Language Frames the Ethical Debate Regarding an Emerging Technology. PMID- 26632368 TI - How Metaphors About the Genome Constrain CRISPR Metaphors: Separating the "Text" From Its "Editor". PMID- 26632369 TI - "Editing": A Productive Metaphor for Regulating CRISPR. PMID- 26632370 TI - Scientific Social Responsibility: Lessons From the Corporate Social Responsibility Movement. PMID- 26632371 TI - Scientific Responsibility: Should Analysis Start With the Scientists? PMID- 26632373 TI - Public Health and Advanced Maternal Age: An Imperfect but Justified Marriage. Response to Open Peer Commentaries on "Sleepwalking Into Infertility: The Need for a Public Health Approach Toward Advanced Maternal Age". PMID- 26632374 TI - Informed Consent, Libertarian Paternalism, and Nudging: A Response. PMID- 26632375 TI - Response to Open Peer Commentaries on "Looking for Trouble: Preventive Genomic Sequencing in the General Population and the Role of Patient Choice". PMID- 26632376 TI - Jessie W. Hirst, a Professor Who Challenged Prejudice towards Western Medicine. PMID- 26632377 TI - NOD-Like Receptors in Infection, Immunity, and Diseases. AB - Nucleotide-binding and oligomerization domain (NOD)-like receptors (NLRs) are pattern-recognition receptors similar to toll-like receptors (TLRs). While TLRs are transmembrane receptors, NLRs are cytoplasmic receptors that play a crucial role in the innate immune response by recognizing pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Based on their N-terminal domain, NLRs are divided into four subfamilies: NLRA, NLRB, NLRC, and NLRP. NLRs can also be divided into four broad functional categories: inflammasome assembly, signaling transduction, transcription activation, and autophagy. In addition to recognizing PAMPs and DAMPs, NLRs act as a key regulator of apoptosis and early development. Therefore, there are significant associations between NLRs and various diseases related to infection and immunity. NLR studies have recently begun to unveil the roles of NLRs in diseases such as gout, cryopyrin-associated periodic fever syndromes, and Crohn's disease. As these new associations between NRLs and diseases may improve our understanding of disease pathogenesis and lead to new approaches for the prevention and treatment of such diseases, NLRs are becoming increasingly relevant to clinicians. In this review, we provide a concise overview of NLRs and their role in infection, immunity, and disease, particularly from clinical perspectives. PMID- 26632378 TI - Recent Advances in Kawasaki Disease. AB - Kawasaki disease (KD) is characterized with acute systemic vasculitis, occurs predominantly in children between 6 months to 5 years of age. Patients with this disease recover well and the disease is self-limited in most cases. Since it can lead to devastating cardiovascular complications, KD needs special attention. Recent reports show steady increases in the prevalence of KD in both Japan and Korea. However, specific pathogens have yet to be found. Recent advances in research on KD include searches for genetic susceptibility related to KD and research on immunopathogenesis based on innate and acquired immunity. Also, search for etiopathogenesis and treatment of KD has been actively sought after using animal models. In this paper, the recent progress of research on KD was discussed. PMID- 26632380 TI - Anti-Proliferative and Apoptotic Activities of Mullerian Inhibiting Substance Combined with Calcitriol in Ovarian Cancer Cell Lines. AB - PURPOSE: This study aimed to investigate whether Mullerian inhibiting substance (MIS) in combination with calcitriol modulates proliferation and apoptosis of human ovarian cancer (OCa) cell lines (SKOV3, OVCAR3, and OVCA433) and identify the signaling pathway by which MIS mediates apoptosis. MATERIALS AND METHODS: OCa cell lines were treated with MIS in the absence or presence of calcitriol. Cell viability and proliferation were evaluated using the Cell Counting Kit-8 assay and apoptosis was evaluated by DNA fragmentation assay. Western blot and enzyme linked immunosorbent assay were used to determine the signaling pathway. RESULTS: The cells showed specific staining for the MIS type II receptor. Treatment of OCa cells with MIS and calcitriol led to dose- and time-dependent inhibition of cell growth and survival. The combination treatment significantly suppressed cell growth, down-regulated the expression of B-cell lymphoma 2 (Bcl-2), and up regulated the expressions of Bcl-2 associated X protein, caspase-3, and caspase-9 through the extracellular signal-regulated kinase signaling pathway. CONCLUSION: These results, coupled with a much-needed decrease in the toxic side effects of currently employed therapeutic agents, provide a strong rationale for testing the therapeutic potential of MIS, alone or in combination with calcitriol, in the treatment of OCa. PMID- 26632381 TI - Re-Irradiation of Hepatocellular Carcinoma: Clinical Applicability of Deformable Image Registration. AB - PURPOSE: This study aimed to evaluate whether the deformable image registration (DIR) method is clinically applicable to the safe delivery of re-irradiation in hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Between August 2010 and March 2012, 12 eligible HCC patients received re-irradiation using helical tomotherapy. The median total prescribed radiation doses at first irradiation and re-irradiation were 50 Gy (range, 36-60 Gy) and 50 Gy (range, 36-58.42 Gy), respectively. Most re-irradiation therapies (11 of 12) were administered to previously irradiated or marginal areas. Dose summation results were reproduced using DIR by rigid and deformable registration methods, and doses of organs-at risk (OARs) were evaluated. Treatment outcomes were also assessed. RESULTS: Thirty-six dose summation indices were obtained for three OARs (bowel, duodenum, and stomach doses in each patient). There was no statistical difference between the two different types of DIR methods (rigid and deformable) in terms of calculated summation SigmaD (0.1 cc, 1 cc, 2 cc, and max) in each OAR. The median total mean remaining liver doses (M(RLD)) in rigid- and deformable-type registration were not statistically different for all cohorts (p=0.248), although a large difference in M(RLD) was observed when there was a significant difference in spatial liver volume change between radiation intervals. One duodenal ulcer perforation developed 20 months after re-irradiation. CONCLUSION: Although current dose summation algorithms and uncertainties do not warrant accurate dosimetric results, OARs-based DIR dose summation can be usefully utilized in the re-irradiation of HCC. Appropriate cohort selection, watchful interpretation, and selective use of DIR methods are crucial to enhance the radio-therapeutic ratio. PMID- 26632379 TI - Intestinal Behcet's Disease: A True Inflammatory Bowel Disease or Merely an Intestinal Complication of Systemic Vasculitis? AB - Behcet's disease (BD) is a multi-systemic inflammatory disorder of an unknown etiology and shows a chronic recurrent clinical course. When the disease involves the alimentary tract, it is called intestinal BD because of its clinical importance. Intestinal BD is more frequently reported in East Asian countries than in Western or Middle Eastern countries. While any part of the gastrointestinal tract can be involved, the most common location of intestinal BD is the ileocecal area. A few, large, deep ulcerations with discrete border are characteristic endoscopic findings of intestinal BD. Currently, there is no single gold standard test or pathognomonic finding of intestinal BD. However, recently developed novel diagnostic criteria and a disease activity index have helped in assessing intestinal BD. As intestinal BD shares a lot of characteristics with inflammatory bowel disease, including genetic background, clinical manifestations, and therapeutic strategies, distinguishing between the two diseases in clinical practice is quite difficult. However, biologic agents such as anti-tumor necrosis factor alpha antibody shows a considerable efficacy similar to inflammatory bowel disease cases. It is important to distinguish and treat those two disease entities separately from the standpoint of precise medicine. Clinicians should require comprehensive knowledge regarding the similarities and differences between intestinal BD and inflammatory bowel disease for making an accurate clinical decision. PMID- 26632382 TI - Concomitance of P-gp/LRP Expression with EGFR Mutations in Exons 19 and 21 in Non Small Cell Lung Cancers. AB - PURPOSE: Traditional chemotherapy is the main adjuvant therapy for the treatment of non-small cell lung cancer (NSCLC). However, the emergence of multi-drug resistance (MDR) has greatly restricted the curative effect of chemotherapy. Therefore, it is necessary to find a method to treat MDR NSCLC clinically. It is worth investigating whether NSCLCs that are resistant to traditional chemotherapy can be effectively treated with tyrosine kinase inhibitors targeting epidermal growth factor receptor (EGFR). MATERIALS AND METHODS: The expression of P glycoprotein (P-gp) and lung resistance-related protein (LRP) was detected by immunohistochemistry, and mutations in EGFR (exons 19 and 21) and Kirsten rat sarcoma viral oncogene homolog (KRAS) (exon 2) were detected by high-resolution melting analysis (HRMA) of surgical NSCLC specimens from 127 patients who did not undergo traditional chemotherapy or radiotherapy. A Pearson chi-square test was performed to analyze the correlations between the expression of P-gp and LRP and mutations in EGFR and KRAS. RESULTS: The expression frequencies of P-gp and LRP were significantly higher in adenocarcinomas from non-smoking patients; the expression frequency of LRP was significantly higher in cancer tissue from female patients. The frequency of EGFR mutations was significantly higher in well to moderately differentiated adenocarcinomas from non-smoking female patients. The frequency of EGFR mutations in the cancers that expressed P-gp, LRP, or both P-gp and LRP was significantly higher than that in cancers that did not express P-gp or LRP. CONCLUSION: NSCLCs expressing P-gp/LRP bear the EGFR mutation in exon 19 or 21 easily. PMID- 26632383 TI - Prediction of Coronary Atherosclerotic Ostial Lesion with a Damping of the Pressure Tracing during Diagnostic Coronary Angiography. AB - PURPOSE: When performing coronary angiography (CAG), diagnostic catheter intubation to the ostium can cause damping of the pressure tracing. The aim of this study was to determine the predictors of atherosclerotic ostial stenosis in patients showing pressure damping during CAG. MATERIALS AND METHODS: In total, 2926 patients who underwent diagnostic CAG were screened in this study. Pressure damping was defined as an abrupt decline of the coronary blood pressure with a blunted pulse pressure after engagement of the diagnostic catheter. According to CAG and intravascular ultrasound (IVUS), we divided damped ostia into two groups: atherosclerotic ostial lesion group (true lesion group) and non-atherosclerotic ostium group (false lesion group). Clinical and angiographic characteristics were compared between the two groups. RESULTS: The overall incidence of pressure damping was 2.3% (68 patients and 76 ostia). Among the pressure damped ostia, 40.8% (31 of 76 ostia) were true atherosclerotic ostial lesions (true lesion group). The true lesion group had more frequent left main ostial damping and more percutaneous coronary interventions (PCIs) performed on non-ostial lesions, compared to the false lesion group. On multivariate logistic regression analysis, left main ostial damping [hazard ratio (HR) 4.11, 95% confidence interval (CI) 1.24-13.67, p=0.021] and PCI on non-ostial lesion (HR 5.34, 95% CI 1.34-21.27, p=0.018) emerged as independent predictors for true atherosclerotic ostial lesions in patients with pressure damping. CONCLUSION: Left main ostial damping and the presence of a non-ostial atherosclerotic lesion may suggest a significant true atherosclerotic lesion in the coronary ostium. PMID- 26632384 TI - Left Ventricular Filling Pressure as Assessed by the E/e' Ratio Is a Determinant of Atrial Fibrillation Recurrence after Cardioversion. AB - PURPOSE: Left ventricular (LV) filling pressure affects atrial fibrillation (AF) recurrence. We investigated the relationship between diastolic dysfunction and AF recurrence after cardioversion, and whether LV filling pressure was predictive of AF recurrence. MATERIALS AND METHODS: Sixty-six patients (mean 58+/-12 years) with newly diagnosed persistent AF were retrospectively enrolled. We excluded patients with left atrial (LA) diameters larger than 50 mm, thereby isolating the effect of LV filling pressure. We evaluated the differences between the patients with (group 1) and without AF recurrence (group 2). RESULTS: Group 1 showed increased LA volume index (LAVI) and E/e' compared to group 2 (p<0.05). During a mean follow-up period of 25+/-19 months, AF recurrence after cardioversion was 60.6% (40/66). The area under the receiver operating characteristics curve of E/e' for AF recurrence was 0.780 [95% confidence interval (CI): 0.657-0.903], and the optimal cut-off value of the E/e' was 9.15 with 75.0% of sensitivity and 73.1% of specificity. A Kaplan-Meier survival curve showed that the cumulative recurrence-free survival rate was significantly lower in patients with higher LV filling pressure (E/e'>9.15) compared with patients with lower LV filling pressure (E/e'<=9.15) (log rank p=0.008). Cox regression analysis revealed that E/e' [hazards ratio (HR): 1.100, 95% CI: 1.017-1.190] and LAVI (HR: 1.042, 95% CI: 1.002-1.084) were independent predictors for AF recurrence after cardioversion. CONCLUSION: LV filling pressure predicts the risk of AF recurrence in persistent AF patients after cardioversion. PMID- 26632385 TI - Clinical Significance of Additional Ablation of Atrial Premature Beats after Catheter Ablation for Atrial Fibrillation. AB - PURPOSE: The clinical significance of post-procedural atrial premature beats immediately after catheter ablation for atrial fibrillation (AF) has not been clearly determined. We hypothesized that the provocation of immediate recurrence of atrial premature beats (IRAPB) and additional ablation improves the clinical outcome of AF ablation. MATERIALS AND METHODS: We enrolled 200 patients with AF (76.5% males; 57.4+/-11.1 years old; 64.3% paroxysmal AF) who underwent catheter ablation. Post-procedure IRAPB was defined as frequent atrial premature beats (>=6/min) under isoproterenol infusion (5 MUg/min), monitored for 10 min after internal cardioversion, and we ablated mappable IRAPBs. Post-procedural IRAPB provocations were conducted in 100 patients. We compared the patients who showed IRAPB with those who did not. We also compared the IRAPB provocation group with 100 age-, sex-, and AF-type-matched patients who completed ablation without provocation (No-Test group). RESULTS: 1) Among the post-procedural IRAPB provocation group, 33% showed IRAPB and required additional ablation with a longer procedure time (p=0.001) than those without IRAPB, without increasing the complication rate. 2) During 18.0+/-6.6 months of follow-up, the patients who showed IRAPB had a worse clinical recurrence rate than those who did not (27.3% vs. 9.0%; p=0.016), in spite of additional IRAPB ablation. 3) However, the clinical recurrence rate was significantly lower in the IRAPB provocation group (15.0%) than in the No-Test group (28.0%; p=0.025) without lengthening of the procedure time or raising complication rate. CONCLUSION: The presence of post procedural IRAPB was associated with a higher recurrence rate after AF ablation. However, IRAPB provocation and additional ablation might facilitate a better clinical outcome. A further prospective randomized study is warranted. PMID- 26632386 TI - The Beneficial Effect of Renin-Angiotensin-Aldosterone System Blockade in Marfan Syndrome Patients after Aortic Root Replacement. AB - PURPOSE: In this study, we evaluated the long term beneficial effect of Renin Angiotensin-Aldosterone System (RAAS) blockade therapy in treatment of Marfan aortopathy. MATERIALS AND METHODS: We reviewed Marfan syndrome (MFS) patients who underwent aortic root replacement (ARR) between January 1996 and January 2011. All patients were prescribed beta-blockers indefinitely. We compared major aortic events including mortality, aortic dissection, and reoperation in patients without RAAS blockade (group 1, n=27) to those with (group 2, n=63). The aortic growth rate was calculated by dividing the diameter change on CT scans taken immediately post-operatively and the latest scan available. RESULTS: There were no differences in clinical parameters except for age which was higher in patients with RAAS blockade. In group 1, 2 (7%) deaths, 5 (19%) aortic dissections, and 7 (26%) reoperations occurred. In group 2, 3 (5%) deaths, 2 (3%) aortic dissections, and 3 (5%) reoperations occurred. A Kaplan-Meier plot demonstrated improved survival free from major aortic events in group 2. On multivariate Cox, RAAS blockade was an independent negative predictor of major aortic events (hazard ratio 0.38, 95% confidence interval 0.30-0.43, p=0.002). Mean diameter change in descending thoracic and supra-renal abdominal aorta was significantly higher in patients without RAAS blockade (p<0.05). CONCLUSION: In MFS patients who underwent ARR, the addition of RAAS blockade to beta-blocker was associated with reduction of aortic dilatation and clinical events. PMID- 26632387 TI - Comparative Evaluation of Several Gene Targets for Designing a Multiplex-PCR for an Early Diagnosis of Extrapulmonary Tuberculosis. AB - PURPOSE: Diagnosis of extrapulmonary tuberculosis (EPTB) poses serious challenges. A careful selection of appropriate gene targets is essential for designing a multiplex-polymerase chain reaction (M-PCR) assay. MATERIALS AND METHODS: We compared several gene targets of Mycobacterium tuberculosis, including IS6110, devR, and genes encoding MPB-64 (mpb64), 38kDa (pstS1), 65kDa (hsp65), 30kDa (fbpB), ESAT-6 (esat6), and CFP-10 (cfp10) proteins, using PCR assays on 105 EPTB specimens. From these data, we chose the two best gene targets to design an M-PCR. RESULTS: Among all gene targets tested, mpb64 showed the highest sensitivity (84% in confirmed cases and 77.5% in clinically suspected cases), followed by IS6110, hsp65, 38kDa, 30kDa, esat6, cfp10, and devR. We used mpb64+IS6110 for designing an M-PCR assay. Our M-PCR assay demonstrated a high sensitivity of 96% in confirmed EPTB cases and 88.75% in clinically suspected EPTB cases with a high specificity of 100%, taking clinical diagnosis as the gold standard. CONCLUSION: These M-PCR results along with the clinical findings may facilitate an early diagnosis of EPTB patients and clinical management of disease. PMID- 26632388 TI - Burkholderia Sepsis in Children as a Hospital-Acquired Infection. AB - PURPOSE: Hospital-acquired Burkholderia cepacia (B. cepacia) infection are not commonly recorded in patients without underlying lung disease, such as cystic fibrosis and chronic granulomatous disease. However, in 2014, B. cepacia appeared more frequently in pediatric blood samples than in any other year. In order to access this situation, we analyzed the clinical characteristics of B. cepacia infections in pediatric patients at our hospital. MATERIALS AND METHODS: We conducted a retrospective study of blood isolates of B. cepacia taken at our hospital between January 2004 and December 2014. Patient clinical data were obtained by retrospective review of electronic medical records. We constructed a dendrogram for B. cepacia isolates from two children and five adult patients. RESULTS: A total of 14 pediatric patients and 69 adult patients were identified as having B. cepacia bacteremia. In 2014, higher rates of B. cepacia bacteremia were observed in children. Most of them required Intensive Care Unit (ICU) care (12/14). In eleven children, sputum cultures were examined, and five of these children had the same strain of B. cepacia that grew out from their blood samples. Antibiotics were administered based on antibiotic sensitivity results. Four children expired despite treatment. Compared to children, there were no demonstrative differences in adults, except for history of ICU care. CONCLUSION: Although there were not many pediatric cases at our hospital, awareness of colonization through hospital-acquired infection and effective therapy for infection of B. cepacia is needed, as it can cause mortality and morbidity. PMID- 26632389 TI - Prediction of Cortical Defect Using C-Reactive Protein and Urine Sodium to Potassium Ratio in Infants with Febrile Urinary Tract Infection. AB - PURPOSE: We investigated whether C-reactive protein (CRP) levels, urine protein creatinine ratio (uProt/Cr), and urine electrolytes can be useful for discriminating acute pyelonephritis (APN) from other febrile illnesses or the presence of a cortical defect on 99mTc dimercaptosuccinic acid (DMSA) scanning (true APN) from its absence in infants with febrile urinary tract infection (UTI). MATERIALS AND METHODS: We examined 150 infants experiencing their first febrile UTI and 100 controls with other febrile illnesses consecutively admitted to our hospital from January 2010 to December 2012. Blood (CRP, electrolytes, Cr) and urine tests [uProt/Cr, electrolytes, and sodium-potassium ratio (uNa/K)] were performed upon admission. All infants with UTI underwent DMSA scans during admission. All data were compared between infants with UTI and controls and between infants with or without a cortical defect on DMSA scans. Using multiple logistic regression analysis, the ability of the parameters to predict true APN was analyzed. RESULTS: CRP levels and uProt/Cr were significantly higher in infants with true APN than in controls. uNa levels and uNa/K were significantly lower in infants with true APN than in controls. CRP levels and uNa/K were relevant factors for predicting true APN. The method using CRP levels, u-Prot/Cr, u-Na levels, and uNa/K had a sensitivity of 94%, specificity of 65%, positive predictive value of 60%, and negative predictive value of 95% for predicting true APN. CONCLUSION: We conclude that these parameters are useful for discriminating APN from other febrile illnesses or discriminating true APN in infants with febrile UTI. PMID- 26632390 TI - Associations between Single Nucleotide Polymorphisms of High Mobility Group Box 1 Protein and Clinical Outcomes in Korean Sepsis Patients. AB - PURPOSE: High mobility group box 1 (HMGB1) plays a central role in the pathogenesis of sepsis and multiple organ dysfunction syndromes. We investigated the associations of a single nucleotide polymorphism (SNP; rs1045411) in HMGB1 with various clinical parameters, severity, and prognosis in patients with sepsis, severe sepsis, or septic shock. MATERIALS AND METHODS: We enrolled 212 adult patients followed for 28 days. All patients were genotyped for rs1045411, and the serum levels of HMGB1 and several cytokines were measured. RESULTS: The proportions of patients according to genotype were GG (71.2%), GA (26.4%), and AA (2.4%). Among patients with chronic lung disease comorbidity, patients with a variant A allele had higher positive blood culture rates and higher levels of various cytokines [interleukin (IL)-1beta, IL-6, IL-10, IL-17, and tumor necrosis factor-alpha] than those with the GG genotype. In the analysis of those with diabetes as a comorbidity, patients with a variant A allele had higher blood culture and Gram-negative culture rates than those with GG genotypes; these patients also had a higher levels of IL-17. In the analysis of those with sepsis caused by a respiratory tract infection, patients with a variant A allele had higher levels of IL-10 and IL-17 (all p<0.05). This polymorphism had no significant impact on patient survival. CONCLUSION: The variant A allele of rs1045411 appears to be associated with a more severe inflammatory response than the GG genotype under specific conditions. PMID- 26632391 TI - HLA Allele Frequencies in 5802 Koreans: Varied Allele Types Associated with SJS/TEN According to Culprit Drugs. AB - PURPOSE: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are very serious forms of drug-induced cutaneous adverse reaction. SJS/TEN induced by certain drug is well known to be associated with some human leukocyte antigen (HLA) gene type. We aimed to explore HLA allele frequencies and their association with SJS/TEN according to culprit drugs in Korea. MATERIALS AND METHODS: We enrolled 5802 subjects who had results of HLA typing test from August 2005 to July 2014. Total 28 SJS/TEN patients were categorized based on culprit drugs (allopurinol, lamotrigine, carbamazepine) and identified the presence of HLA B*58:01, HLA-B*44:03, HLA-B*15:02, and HLA-A*31:01. RESULTS: HLA-A*24:02 (20.5%), HLA-B*44:03 (10.0%), and HLA-Cw*01:02 (17.1%) were the most frequent type in HLA A, -B, and -C genes, respectively. Allele frequencies of HLA-B*58:01, HLA B*44:03, HLA-A*31:01, and HLA-B*15:02 were 7.0%, 10.0%, 5.0%, and 0.3%, respectively. In 958 allopurinol users, 9 subjects (0.9%) were diagnosed with SJS/TEN. Among them, 8 subjects possessed HLA-B*58:01 allele. SJS/TEN induced by allopurinol was more frequently developed in subjects with HLA-B*58:01 than in subjects without it [odds ratio: 57.4; confidence interval (CI) 7.12-463.50; p<0.001]. Allopurinol treatment, based on screening by HLA-B*58:01 genotyping, could be more cost-effective than that not based on screening. HLA-B*44:03 may be associated with lamotrigine-induced SJS/TEN (odds ratio: 12.75; CI 1.03-157.14; p=0.053). Among carbamazepine users, only two patients experienced SJS/TEN and possessed neither HLA-B*15:02 nor HLA-A*31:03. CONCLUSION: HLA gene frequencies varied in Korea. Screening of HLA-B*58:01 before the use of allopurinol might be needed to anticipate probability of SJS/TEN. PMID- 26632392 TI - High Remission Rate of Chronic Immune Thrombocytopenia in Children: Result of 20 Year Follow-Up. AB - PURPOSE: This study examined the outcomes of children with chronic immune thrombocytopenia (ITP). MATERIALS AND METHODS: We retrospectively analyzed the medical records of all patients diagnosed with ITP from January 1992 to December 2011 at our institution. RESULTS: A total of 128 patients (64%) satisfied the criteria for newly diagnosed ITP, 31 (15%) for persistent ITP, and 41 (21%) for chronic ITP. The median age at diagnosis was 4.5 years (range, 1 month to 18 years). The median platelet count at diagnosis was 32*109/L. A comparison of the initial treatment data from 2001 to 2011 with those from 1992 to 2000 showed that the number of bone marrow examinations decreased, whereas observation increased. Chronic ITP presented at an older age than newly diagnosed and persistent ITP (6.6 years vs. 3.8 years vs. 4.1 years, respectively); however, the difference did not reach statistical significance (p=0.17). The probability of complete remission of chronic ITP was 50% and 76% at 2 and 5 years after diagnosis, respectively. Patients aged <1 year at diagnosis had a significantly better prognosis than did older patients (hazard ratio, 3.86; p=0.02). CONCLUSION: Children with chronic ITP showed a high remission rate after long-term follow-up. This study suggests that invasive treatments such as splenectomy in children with chronic ITP can be delayed for 4 to 5 years if thrombocytopenia and therapeutic medication do not affect the quality of life. PMID- 26632393 TI - Cholecystectomy for Prevention of Recurrence after Endoscopic Clearance of Bile Duct Stones in Korea. AB - PURPOSE: Cholecystectomy in patients with an intact gallbladder after endoscopic removal of stones from the common bile duct (CBD) remains controversial. We conducted a case-control study to determine the risk of recurrent CBD stones and the benefit of cholecystectomy for prevention of recurrence after endoscopic removal of stones from the CBD in Korean patients. MATERIALS AND METHODS: A total of 317 patients who underwent endoscopic CBD stone extraction between 2006 and 2012 were included. Possible risk factors for the recurrence of CBD stones including previous cholecystectomy history, bile duct diameter, stone size, number of stones, stone composition, and the presence of a periampullary diverticulum were analyzed. RESULTS: The mean duration of follow-up after CBD stone extraction was 25.4+/-22.0 months. A CBD diameter of 15 mm or larger [odds ratio (OR), 1.930; 95% confidence interval (CI), 1.098 to 3.391; p=0.022] and the presence of a periampullary diverticulum (OR, 1.859; 95% CI, 1.014 to 3.408; p=0.045) were independent predictive factors for CBD stone recurrence. Seventeen patients (26.6%) in the recurrence group underwent elective cholecystectomy soon after endoscopic extraction of CBD stones, compared to 88 (34.8%) in the non recurrence group; the difference was not statistically significant (p=0.212). CONCLUSION: A CBD diameter of 15 mm or larger and the presence of a periampullary diverticulum were found to be potential predictive factors for recurrence after endoscopic extraction of CBD stones. Elective cholecystectomy after clearance of CBD stones did not reduce the incidence of recurrent CBD stones in Korean patients. PMID- 26632394 TI - Hepatic Venous Pressure Gradient Predicts Long-Term Mortality in Patients with Decompensated Cirrhosis. AB - PURPOSE: The present study aimed to investigate the role of hepatic venous pressure gradient (HVPG) for prediction of long-term mortality in patients with decompensated cirrhosis. MATERIALS AND METHODS: Clinical data from 97 non critically-ill cirrhotic patients with HVPG measurements were retrospectively and consecutively collected between 2009 and 2012. Patients were classified according to clinical stages and presence of ascites. The prognostic accuracy of HVPG for death, survival curves, and hazard ratios were analyzed. RESULTS: During a median follow-up of 24 (interquartile range, 13-36) months, 22 patients (22.7%) died. The area under the receiver operating characteristics curves of HVPG for predicting 1-year, 2-year, and overall mortality were 0.801, 0.737, and 0.687, respectively (all p<0.01). The best cut-off value of HVPG for predicting long term overall mortality in all patients was 17 mm Hg. The mortality rates at 1 and 2 years were 8.9% and 19.2%, respectively: 1.9% and 11.9% with HVPG <=17 mm Hg and 16.2% and 29.4% with HVPG >17 mm Hg, respectively (p=0.015). In the ascites group, the mortality rates at 1 and 2 years were 3.9% and 17.6% with HVPG <=17 mm Hg and 17.5% and 35.2% with HVPG >17 mm Hg, respectively (p=0.044). Regarding the risk factors for mortality, both HVPG and model for end-stage liver disease were positively related with long-term mortality in all patients. Particularly, for the patients with ascites, both prothrombin time and HVPG were independent risk factors for predicting poor outcomes. CONCLUSION: HVPG is useful for predicting the long-term mortality in patients with decompensated cirrhosis, especially in the presence of ascites. PMID- 26632395 TI - Irritable Bowel Syndrome May Be Associated with Elevated Alanine Aminotransferase and Metabolic Syndrome. AB - PURPOSE: Recent studies have revealed close relationships between hepatic injury, metabolic pathways, and gut microbiota. The microorganisms in the intestine also cause irritable bowel syndrome (IBS). The aim of this study was to examine whether IBS was associated with elevated hepatic enzyme [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)], gamma-glutamyl transferase (gamma GT) levels, and metabolic syndrome (MS). MATERIALS AND METHODS: This was a retrospective, cross-sectional, case-control study. The case and control groups comprised subjects who visited our health promotion center for general check-ups from June 2010 to December 2010. Of the 1127 initially screened subjects, 83 had IBS according to the Rome III criteria. The control group consisted of 260 age- and sex-matched subjects without IBS who visited our health promotion center during the same period. RESULTS: Compared to control subjects, patients with IBS showed significantly higher values of anthropometric parameters (body mass index, waist circumference), liver enzymes, gamma-GT, and lipid levels. The prevalences of elevated ALT (16.9% vs. 7.7%; p=0.015) and gamma-GT (24.1% vs. 11.5%; p=0.037) levels were significantly higher in patients with IBS than in control subjects. A statistically significant difference was observed in the prevalence of MS between controls and IBS patients (12.7% vs. 32.5%; p<0.001). The relationships between elevated ALT levels, MS, and IBS remained statistically significant after controlling for potential confounding factors. CONCLUSION: On the basis of our study results, IBS may be an important condition in certain patients with elevated ALT levels and MS. PMID- 26632396 TI - Association between Toll-Like Receptor 9-1237T/C Polymorphism and the Susceptibility of Inflammatory Bowel Diseases: A Meta-Analysis. AB - PURPOSE: The -1237T/C polymorphism of the Toll-like receptor 9 (TLR9) gene has been implicated in the susceptibility of inflammatory bowel diseases (IBDs), but the results remain conflicting. We further investigated this association via meta analysis. MATERIALS AND METHODS: Multiple electronic databases were extensively searched until February, 2015. The strength of association was evaluated by calculating the pooled odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: A total of 2987 cases and 2388 controls from eight studies were analyzed. Overall, association was found between TLR9 -1237T/C polymorphism and the risk of IBDs when all the studies were pooled (recessive model, OR: 1.59, 95% CI: 1.02-2.47, p=0.04; homozygote comparison, OR: 1.62, 95% CI: 1.04-2.52, p=0.03; allele model, OR: 1.13, 95% CI: 1.00-1.27, p=0.05). Stratification by ethnicity indicated an association between TLR9 -1237T/C polymorphism and IBDs risk in Caucasians (recessive model, OR: 1.59, 95% CI: 1.02-2.47, p=0.04; homozygote comparison, OR: 1.62, 95% CI: 1.04-2.52, p=0.03; allele model, OR: 1.12, 95% CI: 1.00-1.27, p=0.05). When stratified by disease type, significant correlation were only found in the Crohn's disease subgroup (recessive model, OR: 1.69, 95% CI: 1.05-2.73, p=0.03; homozygote model, OR: 1.74, 95% CI: 1.07-2.82, p=0.02; allele model, OR: 1.15, 95% CI: 1.01-1.32, p=0.04). CONCLUSION: The present study suggested that the TLR9 -1237T/C polymorphism might act as a risk factor in the development of IBDs, particularly in Caucasians. PMID- 26632397 TI - Basal Forebrain Cholinergic Deficits Reduce Glucose Metabolism and Function of Cholinergic and GABAergic Systems in the Cingulate Cortex. AB - PURPOSE: Reduced brain glucose metabolism and basal forebrain cholinergic neuron degeneration are common features of Alzheimer's disease and have been correlated with memory function. Although regions representing glucose hypometabolism in patients with Alzheimer's disease are targets of cholinergic basal forebrain neurons, the interaction between cholinergic denervation and glucose hypometabolism is still unclear. The aim of the present study was to evaluate glucose metabolism changes caused by cholinergic deficits. MATERIALS AND METHODS: We lesioned basal forebrain cholinergic neurons in rats using 192 immunoglobulin G-saporin. After 3 weeks, lesioned animals underwent water maze testing or were analyzed by 18F-2-fluoro-2-deoxyglucose positron emission tomography. RESULTS: During water maze probe testing, performance of the lesioned group decreased with respect to time spent in the target quadrant and platform zone. Cingulate cortex glucose metabolism in the lesioned group decreased, compared with the normal group. Additionally, acetylcholinesterase activity and glutamate decarboxylase 65/67 expression declined in the cingulate cortex. CONCLUSION: Our results reveal that spatial memory impairment in animals with selective basal forebrain cholinergic neuron damage is associated with a functional decline in the GABAergic and cholinergic system associated with cingulate cortex glucose hypometabolism. PMID- 26632398 TI - Clinical and Pathological Heterogeneity of Korean Patients with CAPN3 Mutations. AB - PURPOSE: This study was designed to investigate the characteristics of Korean patients with calpainopathy. MATERIALS AND METHODS: Thirteen patients from ten unrelated families were diagnosed with calpainopathy via direct or targeted sequencing of the CAPN3 gene. Clinical, mutational, and pathological spectra were then analyzed. RESULTS: Nine different mutations, including four novel mutations (NM_000070: c.1524+1G>T, c.1789_1790inA, c.2184+1G>T, and c.2384C>T) were identified. The median age at symptom onset was 22 (interquartile range: 15-28). Common clinical findings were joint contracture in nine patients, winged scapula in four, and lordosis in one. However, we also found highly variable clinical features including early onset joint contractures, asymptomatic hyperCKemia, and heterogeneous clinical severity in three members of the same family. Four of nine muscle specimens revealed lobulated fibers, but three showed normal skeletal muscle histology. CONCLUSION: We identified four novel CAPN3 mutations and demonstrated clinical and pathological heterogeneity in Korean patients with calpainopathy. PMID- 26632399 TI - Impact of Angiotensin Converting Enzyme Inhibitor versus Angiotensin Receptor Blocker on Incidence of New-Onset Diabetes Mellitus in Asians. AB - PURPOSE: Angiotensin converting enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB) are associated with a decreased incidence of new-onset diabetes mellitus (NODM). The aim of this study was to compare the protective effect of ACEI versus ARBs on NODM in an Asian population. MATERIALS AND METHODS: We investigated a total of 2817 patients who did not have diabetes mellitus from January 2004 to September 2009. To adjust for potential confounders, a propensity score matched (PSM) analysis was performed using a logistic regression model. The primary end-point was the cumulative incidence of NODM, which was defined as having a fasting blood glucose >=126 mg/dL or HbA1c >=6.5%. Multivariable cox regression analysis was performed to determine the impact of ACEI versus ARB on the incidence of NODM. RESULTS: Mean follow-up duration was 1839+/-1019 days in all groups before baseline adjustment and 1864+/-1034 days in the PSM group. After PSM (C-statistics=0.731), a total 1024 patients (ACEI group, n=512 and ARB group, n=512) were enrolled for analysis and baseline characteristics were well balanced. After PSM, the cumulative incidence of NODM at 3 years was lower in the ACEI group than the ARB group (2.1% vs. 5.0%, p=0.012). In multivariate analysis, ACEI vs. ARB was an independent predictor of the lower incidence for NODM (odd ratio 0.37, confidence interval 0.17-0.79, p=0.010). CONCLUSION: In the present study, compared with ARB, chronic ACEI administration appeared to be associated with a lower incidence of NODM in a series of Asian cardiovascular patients. PMID- 26632400 TI - Development and Validation of Osteoporosis Risk-Assessment Model for Korean Men. AB - PURPOSE: The aim of the present study was to develop an osteoporosis risk assessment model to identify high-risk individuals among Korean men. MATERIALS AND METHODS: The study used data from 1340 and 1110 men >=50 years who participated in the 2009 and 2010 Korean National Health and Nutrition Examination Survey, respectively, for development and validation of an osteoporosis risk-assessment model. Osteoporosis was defined as T score <=-2.5 at either the femoral neck or lumbar spine. Performance of the candidate models and the Osteoporosis Self-assessment Tool for Asian (OSTA) was compared with sensitivity, specificity, and area under the receiver operating characteristics curve (AUC). A net reclassification improvement was further calculated to compare the developed Korean Osteoporosis Risk-Assessment Model for Men (KORAM-M) with OSTA. RESULTS: In the development dataset, the prevalence of osteoporosis was 8.1%. KORAM-M, consisting of age and body weight, had a sensitivity of 90.8%, a specificity of 42.4%, and an AUC of 0.666 with a cut-off score of -9. In the validation dataset, similar results were shown: sensitivity 87.9%, specificity 39.7%, and AUC 0.638. Additionally, risk categorization with KORAM-M showed improved reclassification over that of OSTA up to 22.8%. CONCLUSION: KORAM-M can be simply used as a pre-screening tool to identify candidates for dual energy X ray absorptiometry tests. PMID- 26632401 TI - Milk Consumption and Framingham Risk Score: Analysis of the Korea National Health and Nutrition Examination Survey Data (2008-2011). AB - PURPOSE: The benefit of milk intake remains controversial. The association between milk consumption and Framingham Risk Score (FRS) in a population consuming relatively low amounts of dairy products is undetermined. MATERIALS AND METHODS: A total of 13736 adults (5718 male and 8018 female) aged 20-80 years from the Korea National Health and Nutrition Examination Survey (2008-2011) were divided into groups according to milk consumption (rarely, monthly, weekly, and daily) and compared according to FRS after relevant variable adjustments. RESULTS: The mean FRS in males and females were 6.53 and 5.74, respectively. Males who consumed milk daily (15.9%) had a significantly lower FRS than males having milk rarely (31.6%) or monthly (17.4%; p=0.007). Females who consumed milk daily (22.3%) also had significantly lower FRS than rarely (29.8%), monthly (13.8%), or weekly (34%; p=0.001) consumers. In particular, males >=60 years old who consumed milk daily had a significantly lower FRS than males who consumed less milk (p<0.001). The odds ratio in this age group showed a significant and gradual increase in the weekly [OR=2.15; 95% confidence interval (CI) 1.14-4.03], monthly (OR=2.29; 95% CI 1.15-4.54), and rarely (OR=3.79; 95% CI 2.01-7.14) milk consumption groups when compared with the daily milk consumption group. CONCLUSION: Milk consumption was associated with a lower FRS in a low milk consuming population. In particular, daily milk consumption in males over 60 years old may be beneficial for those at risk for cardiovascular disease. PMID- 26632402 TI - Development of a Synthetic Surfactant Using a Surfactant Protein-C Peptide Analog: In Vitro Studies of Surface Physical Properties. AB - PURPOSE: Pulmonary surfactant (PS) replacement has been the gold standard therapy for neonatal respiratory distress syndrome; however, almost all commercial PSs contain animal proteins. We prepared a synthetic PS by using a human surfactant protein (SP) analog and evaluated its in vitro properties. MATERIALS AND METHODS: A peptide sequence (CPVHLKRLLLLLLLLLLLLLLLL) of human SP-C was chosen to develop the peptide analog (SPa-C). The new synthetic SP-C PS (sSP-C PS) was synthesized from SPa-C, dipalmitoyl phosphatidylcholine, phosphatidyl glycerol, and palmitic acid. Physical properties of the sSP-C PS were evaluated by measuring the maximum and minimum surface tensions (STs), surfactant spreading, and adsorption rate. In addition, we recorded an ST-area diagram. The data obtained on sSP-C PS were subsequently compared with those of purified natural bovine surfactant (PNBS), and the commercial product, Surfacten(r). RESULTS: The sSP-C PS and Surfacten(r) were found to have maximum ST values of 32-33 mN/m, whereas that of PNBS was much lower at 19 mN/m. The minimum ST values of all three products were less than 10 mN/m. The values that were measured for the equilibrium ST of rapidly spreading sSP-C PS, Surfacten(r), and PNBS were 27, 27, and 24 mN/m, respectively. The surface adsorptions were found to be the same for all three PSs (20 mN/m). ST area diagrams of sSP-C PS and Surfacten(r) revealed similar properties. CONCLUSION: In an in vitro experiment, the physical properties exhibited by sSP-C PS were similar to those of Surfacten(r). Further study is required to evaluate the in vivo efficacy. PMID- 26632403 TI - Smoking-Related Renal Histologic Injury in IgA Nephropathy Patients. AB - PURPOSE: Smoking reportedly exerts deleterious effects on renal function; however, its effects on histology have not been clarified in patients with IgA nephropathy (IgAN). MATERIALS AND METHODS: Renal histology was evaluated in a cohort of 397 patients diagnosed with IgAN according to smoking status and dose in relation to renal function. RESULTS: Among the study cohort, which was predominantly male (88.5%), 52 patients (13%) were current smokers. These current smokers demonstrated more frequent hypertension and higher serum creatinine levels than non/ex-smokers at the time of diagnosis, which was apparent with increased smoking dose. The percentages of global glomerulosclerosis and arteriolar hyalinosis increased with increased smoking dose, whereas tubulointerstitial fibrosis or arterial intimal thickening did not. Glomerular mesangial alpha-smooth muscle actin expression were similar between current and non/ex-smokers matched for age, gender, hypertension, and histologic severity, although the number of glomerular CD68+ cells was significantly fewer in smokers. Initial serum creatinine level, estimated glomerular filtration rate (eGFR), and global glomerulosclerosis were found to be risk factors of serum creatinine doubling in both smokers and non/ex-smokers by univariate analysis during a mean follow-up of 3.8 years. CONCLUSION: In addition to dose dependent renal functional decline and hypertension, smoking contributes to renal disease progression by eliciting microvascular injury in IgAN patients. PMID- 26632404 TI - Relationships between Isometric Muscle Strength, Gait Parameters, and Gross Motor Function Measure in Patients with Cerebral Palsy. AB - PURPOSE: This study investigated the correlation between isometric muscle strength, gross motor function, and gait parameters in patients with spastic cerebral palsy and to find which muscle groups play an important role for gait pattern in a flexed knee gait. MATERIALS AND METHODS: Twenty-four ambulatory patients (mean age, 10.0 years) with spastic cerebral palsy who were scheduled for single event multilevel surgery, including distal hamstring lengthening, were included. Preoperatively, peak isometric muscle strength was measured for the hip flexor, hip extensor, knee flexor, and knee extensor muscle groups using a handheld dynamometer, and three-dimensional (3D) gait analysis and gross motor function measure (GMFM) scoring were also performed. Correlations between peak isometric strength and GMFM, gait kinematics, and gait kinetics were analyzed. RESULTS: Peak isometric muscle strength of all muscle groups was not related to the GMFM score and the gross motor function classification system level. Peak isometric strength of the hip extensor and knee extensor was significantly correlated with the mean pelvic tilt (r=-0.588, p=0.003 and r=-0.436, p=0.033) and maximum pelvic obliquity (r=-0.450, p=0.031 and r=-0.419, p=0.041). There were significant correlations between peak isometric strength of the knee extensor and peak knee extensor moment in early stance (r=0.467, p=0.021) and in terminal stance (r=0.416, p=0.043). CONCLUSION: There is no correlation between muscle strength and gross motor function. However, this study showed that muscle strength, especially of the extensor muscle group of the hip and knee joints, might play a critical role in gait by stabilizing pelvic motion and decreasing energy consumption in a flexed knee gait. PMID- 26632405 TI - Radiologic Outcomes According to Varus Deformity in Minimally Invasive Surgery Total Knee Arthroplasty. AB - PURPOSE: To identify the accuracy of postoperative implant alignment in minimally invasive surgery total knee arthroplasty (MIS-TKA), based on the degree of varus deformity. MATERIALS AND METHODS: The research examined 627 cases of MIS-TKA from November 2005 to December 2007. The cases were categorized according to the preoperative degree of varus deformity in the knee joint in order to compare the postoperative alignment of the implant: less than 5 degrees varus (Group 1, 351 cases), 5 degrees to less than 10 degrees varus (Group 2, 189 cases), 10 degrees to less than 15 degrees varus (Group 3, 59 cases), and 15 degrees varus or more (Group 4, 28 cases). RESULTS: On average, the alignment of the tibial implant was 0.2+/-1.4 degrees , 0.1+/-1.3 degrees , 0.1+/-1.6 degrees , and 0.3+/-1.7 degrees varus, and the tibiofemoral alignment was 5.2+/ 1.9degrees, 4.7+/-1.9 degrees , 4.9+/-1.9 degrees , and 5.1+/-2.0 degrees valgus for Groups 1, 2, 3, and 4, respectively, in the preoperative stage, indicating no difference between the groups (p>0.05). With respect to the accuracy of the tibial implant alignment, 98.1%, 97.6%, 87.5%, and 86.7% of Groups 1, 2, 3, and 4, respectively, had 0+/-3 degrees varus angulation, demonstrating a reduced level of accuracy in Groups 3 and 4 (p<0.0001). There was no difference in terms of tibiofemoral alignment, with 83.9%, 82.9%, 85.4%, and 86.7% of each group, respectively, showing 6+/-3 degrees valgus angulation (p>0.05). CONCLUSION: Satisfactory component alignment was achieved in minimally invasive surgery in total knee arthroplasty, regardless of the degree of varus deformity. PMID- 26632406 TI - Relationship between Preoperative 18F-Fluorodeoxyglucose Uptake and Epidermal Growth Factor Receptor Status in Primary Colorectal Cancer. AB - PURPOSE: Both 18F-fluorodeoxyglucose (18F-FDG) uptake and epidermal growth factor receptor (EGFR) status are prognostic variables of colorectal cancer (CRC). The aim of this study was to investigate a possible association between 18F-FDG uptake on preoperative positron emission tomography/computed tomography (PET/CT) and EGFR status in primary CRC. MATERIALS AND METHODS: Records of 132 patients (66 men and 66 women; mean age=67.1+/-11.1 years) who underwent 18F-FDG PET/CT for CRC staging and subsequent bowel resection were reviewed. In primary lesions, 18F-FDG uptake was semiquantitatively evaluated in terms of maximum standardized uptake value (SUVmax), and EGFR status was determined by immunohistochemistry. Associations of clinicopathological parameters and EGFR status were analyzed by Pearson's chi-square test, multiple logistic regression, and receiver operating characteristic curves. RESULTS: Eighty-six patients (65.2%) showed EGFR expression. SUVmax was significantly lower in EGFR-negative tumors than in EGFR expressing tumors (10.0+/-4.2 vs. 12.1+/-2.1; p=0.012). It was the only significant parameter correlated with EGFR expression (odds ratio=2.457; relative risk=2.013; p=0.038). At the SUVmax threshold of 7.5, the sensitivity and specificity for predicting EGFR expression were 84.9% and 40.4%, respectively (area under the curve=0.624; p=0.019). CONCLUSION: Preoperative 18F-FDG uptake is slightly correlated with EGFR status in primary CRC. Preoperative SUVmax of 18F FDG may have a limited role in predicting EGFR expression in such tumors because of its poor specificity. PMID- 26632407 TI - Effect of Pneumoperitoneum on Oxidative Stress and Inflammation via the Arginase Pathway in Rats. AB - PURPOSE: Oxidative stress during CO2 pneumoperitoneum is reported to be associated with decreased bioactivity of nitric oxide (NO). However, the changes in endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS), and arginase during CO2 pneumoperitoneum have not been elucidated. MATERIALS AND METHODS: Thirty male Sprague-Dawley rats were randomized into three groups. After anesthesia induction, the abdominal cavities of the rats of groups intra-abdominal pressure (IAP)-10 and IAP-20 were insufflated with CO2 at pressures of 10 mm Hg and 20 mm Hg, respectively, for 2 hours. The rats of group IAP-0 were not insufflated. After deflation, plasma NO was measured, while protein expression levels and activity of eNOS, iNOS, arginase (Arg) I, and Arg II were analyzed with aorta and lung tissue samples. RESULTS: Plasma nitrite concentration and eNOS expression were significantly suppressed in groups IAP-10 and IAP-20 compared to IAP-0. While expression of iNOS and Arg I were comparable between the three groups, Arg II expression was significantly greater in group IAP-20 than in group IAP-0. Activity of eNOS was significantly lower in groups IAP-10 and IAP-20 than in group IAP-0, while iNOS activity was significantly greater in group IAP-20 than in groups IAP-0 and IAP-10. Arginase activity was significantly greater in group IAP-20 than in groups IAP-0 and IAP-10. CONCLUSION: The activity of eNOS decreases during CO2 pneumoperitoneum, while iNOS activity is significantly increased, a change that contributes to increased oxidative stress and inflammation. Moreover, arginase expression and activity is increased during CO2 pneumoperitoneum, which seems to act inversely to the NO system. PMID- 26632408 TI - Galpha12 Protects Vascular Endothelial Cells from Serum Withdrawal-Induced Apoptosis through Regulation of miR-155. AB - PURPOSE: Apoptosis of vascular endothelial cells is a type of endothelial damage that is associated with the pathogenesis of cardiovascular diseases such as atherosclerosis. Heterotrimeric GTP-binding proteins (G proteins), including the alpha 12 subunit of G protein (Galpha12), have been found to modulate cellular proliferation, differentiation, and apoptosis of numerous cell types. However, the role of Galpha12 in the regulation of apoptosis of vascular cells has not been elucidated. We investigated the role of Galpha12 in serum withdrawal-induced apoptosis of human umbilical vein endothelial cells (HUVECs) and its underlying mechanisms. MATERIALS AND METHODS: HUVECs were transfected with Galpha12 small interfering RNA (siRNA) to knockdown the endogenous Galpha12 expression and were serum-deprived for 6 h to induce apoptosis. The apoptosis of HUVECs were assessed by Western blotting and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. The expressions of microRNAs were analyzed by quantitative real-time PCR. RESULTS: Knockdown of Galpha12 with siRNA augmented the serum withdrawal-induced apoptosis of HUVECs and markedly repressed the expression of microRNA-155 (miR-155). Serum withdrawal-induced apoptosis of HUVECs was inhibited by the overexpression of miR-155 and increased significantly due to the inhibition of miR-155. Notably, the elevation of miR-155 expression prevented increased apoptosis of Galpha12-deficient HUVECs. CONCLUSION: From these results, we conclude that Galpha12 protects HUVECs from serum withdrawal induced apoptosis by retaining miR-155 expression. This suggests that Galpha12 might play a protective role in vascular endothelial cells by regulating the expression of microRNAs. PMID- 26632409 TI - Initial Serum Ammonia as a Predictor of Neurologic Complications in Patients with Acute Glufosinate Poisoning. AB - PURPOSE: Glufosinate poisoning can cause neurologic complications that may be difficult to treat due to delayed manifestation. Studies assessing possible predictors of complications are lacking. Although serum ammonia level is a potential predictor of severe neurotoxicity, it has only been assessed via case reports. Therefore, we investigated factors that predict neurologic complications in acute glufosinate-poisoned patients. MATERIALS AND METHODS: We conducted a retrospective review of 45 consecutive glufosinate-poisoning cases that were diagnosed in the emergency department (ED) of Wonju Severance Christian Hospital between May 2007 and July 2014. Patients with a Glasgow Coma Scale (GCS) score of <8, seizure, and/or amnesia were defined to a neurologic complication group. RESULTS: The neurologic complication group (29 patients, 64.4%) comprised patients with GCS<8 (27 patients, 60.0%), seizure (23 patients, 51.1%), and amnesia (5 patients, 11.1%). Non-neurologic complications included respiratory failure (14 patients, 31.1%), intubation and ventilator care (23 patients, 51.1%), shock (2 patients, 4.4%), pneumonia (16 patients, 35.6%), acute kidney injury (10 patients, 22.2%), and death (4 patients, 8.9%). Complications of GCS<8, seizure, respiratory failure, and intubation and ventilator care appeared during latent periods within 11 hrs, 34 hrs, 14 hrs, and 48 hrs, respectively. Initial serum ammonia was a predictor of neurologic complications [odds ratio 1.039, 95% confidence interval (1.001-1.078), p=0.046 and area under the curve 0.742]. CONCLUSION: Neurologic complications developed in 64.4% of patients with acute glufosinate poisoning. The most common complication was GCS<8. Initial serum ammonia level, which can be readily assessed in the ED, was a predictor of neurologic complications. PMID- 26632410 TI - alpha-Lipoic Acid Inhibits Expression of IL-8 by Suppressing Activation of MAPK, Jak/Stat, and NF-kappaB in H. pylori-Infected Gastric Epithelial AGS Cells. AB - The epithelial cytokine response, associated with reactive oxygen species (ROS), is important in Helicobacter pylori (H. pylori)-induced inflammation. H. pylori induces the production of ROS, which may be involved in the activation of mitogen activated protein kinases (MAPK), janus kinase/signal transducers and activators of transcription (Jak/Stat), and oxidant-sensitive transcription factor, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB), and thus, expression of interleukin-8 (IL-8) in gastric epithelial cells. alpha-lipoic acid, a naturally occurring thiol compound, is a potential antioxidant. It shows beneficial effects in treatment of oxidant-associated diseases including diabetes. The present study is purposed to investigate whether alpha-lipoic acid inhibits expression of inflammatory cytokine IL-8 by suppressing activation of MAPK, Jak/Stat, and NF-kappaB in H. pylori-infected gastric epithelial cells. Gastric epithelial AGS cells were pretreated with or without alpha-lipoic acid for 2 h and infected with H. pylori in a Korean isolate (HP99) at a ratio of 300:1. IL-8 mRNA expression was analyzed by RT-PCR analysis. IL-8 levels in the medium were determined by enzyme-linked immunosorbent assay. NF-kappaB-DNA binding activity was determined by electrophoretic mobility shift assay. Phospho specific and total forms of MAPK and Jak/Stat were assessed by Western blot analysis. ROS levels were determined using dichlorofluorescein fluorescence. As a result, H. pylori induced increases in ROS levels, mRNA, and protein levels of IL 8, as well as the activation of MAPK [extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun NH2-terminal kinase 1/2 (JNK1/2), p38], Jak/Stat (Jak1/2, Stat3), and NF-kappaB in AGS cells, which was inhibited by alpha-lipoic acid. In conclusion, alpha-lipoic acid may be beneficial for prevention and/or treatment of H. pylori infection-associated gastric inflammation. PMID- 26632411 TI - The Role of Virtual Surgical Planning in the Era of Robotic Surgery. AB - Among various surgical methods introduced to optimize esthetic results, robotic surgery has gradually expanded in scope. As incision, approach, and operation view in robotic surgery differ from existing surgical methods, we should consider reconstruction from a different perspective. We recently experienced two mandibular reconstruction cases after tumor ablative surgery with robotic neck dissection using the conventional reconstruction method and virtual surgical planning (VSP), respectively. We found that the conventional reconstruction method is inappropriate in modified facelift incision in robotic neck dissection because it provides limited surgical scope, restricts access to the defect area, and therefore, consumes considerable time before anastomosis. For these reasons, the authors consider VSP far more viable in the era of robotic surgery. PMID- 26632412 TI - Tectonic Lamellar Keratoplasty Using Cryopreserved Cornea in a Large Descemetocele. AB - We describe herein a case of an impending corneal perforation with a large descemetocele in a patient with previous penetrating keratoplasty (PKP) that subsequently was treated with an emergent lamellar keratoplasty using frozen preserved cornea. A 76-year-old male patient, who had a PKP, presented with a completely whitish and edematous graft accompanied by large epithelial defects. Although antibiotics and antiviral agents were tried for three days, the corneal stroma abruptly melted, except for the Descemet's membrane and endothelium. Cryopreserved corneal tissue that was kept at -80 degrees C was thawed and sutured on top of the remaining Descemet's membrane and endothelium. Pathological and microbiological tests were conducted using the remaining donor and recipient corneal tissues. After tectonic corneal transplantation on top of a large descemetocele, a healthy graft and relatively clear interfaces between graft-host junctions were maintained without serious adverse reactions throughout 6 month follow-up period. Microbiological evaluations of donor tissue at the time of thawing and tissue preparation were done, and the results were all negative. Tissue that was taken intraoperatively from the recipient cornea also showed negative microbiological results. In conclusion, tectonic lamellar keratoplasty, using cryopreserved corneal tissue, only onto the remaining Descemet's membrane and endothelium in an emergent condition, was a safe and effective treatment. PMID- 26632413 TI - Pulmonary Sarcoidosis Induced by Adalimumab: A Case Report and Literature Review. PMID- 26632414 TI - Retraction: Hydrogen Peroxide as an Effective Disinfectant for Pasteurella multocida. Yonsei Med J 2014;55:1152-6. AB - [This retracts the article DOI: 10.3349/ymj.2014.55.4.1152.]. PMID- 26632415 TI - Erratum to "Circulating Anti-Elastin Antibody Levels and Arterial Disease Characteristics: Associations with Arterial Stiffness and Atherosclerosis" by Lee SH, et al. (Yonsei Med J 2015;56:1545-51.). AB - [This corrects the article DOI: 10.3349/ymj.2015.56.6.1545.]. PMID- 26632416 TI - Repeated participation in pancreatic cancer surveillance by high-risk individuals imposes low psychological burden. AB - BACKGROUND: When assessing the feasibility of surveillance for pancreatic cancer (PC), it is important to address its psychological burden. The aim of this ongoing study is to evaluate the psychological burden of annual pancreatic surveillance for individuals at high risk to develop PC. METHODS: This is a multicenter prospective study. High-risk individuals who undergo annual pancreatic surveillance with magnetic resonance imaging (MRI) and endoscopic ultrasound (EUS) were invited to complete questionnaires to assess motivations for participating in surveillance, experiences with participation, perceived PC risk, topics of concern, and psychological distress. Questionnaires were sent after intake for participation (T1), after the first MRI and EUS (T2), and after the MRI and EUS 1 (T3), 2 (T4), and 3 years (T5) after first surveillance. RESULTS: In total, 140 out of 152 individuals returned one or more of the questionnaires (response 92%); 477 questionnaires were analyzed. The most frequently reported motivation for participating in surveillance was the possible early detection of (a precursor stage of) cancer (95-100%). Only a minority of respondents experienced MRI and EUS as uncomfortable (10% and 11%, respectively), and respondents dreaded their next EUS investigation less as surveillance progressed. Respondents' cancer worries decreased significantly over time, and both their anxiety and depression scores remained stable and low over the 3-year period of follow-up. CONCLUSIONS: The psychological burden of pancreatic surveillance is low at all assessments. Therefore, from a psychological point of view, participation of high-risk individuals in an annual pancreatic surveillance program is feasible.Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26632421 TI - Clinical asthma phenotypes in the real world: opportunities and challenges. AB - Asthma is a common, chronic and heterogeneous syndrome, affecting people of all ages, all races and both sexes. It may range from mild disease with barely noticeable symptoms, to very severe disease with constant symptoms that greatly hinder the life of the patient. Guidelines issued by various medical societies provide guidance on how to diagnose and manage asthmatic patients. It is now increasingly recognised that asthma management must be individualised, tailored not only to the severity of the disease but to the phenotypic characteristics of each patient. The aim of asthma treatment is control of asthma and the prevention of risk of exacerbations and fixed airflow limitation. Asthma control can be easily assessed clinically through simple screening tools such as the use of validated questionnaires and spirometry. The use of inflammatory biomarkers can be an alternative approach that, however, requires more time and resources. Asthma treatment involves the use of controllers, mainly inhaled corticosteroids and long-acting beta2-agonists, and relievers, mainly rapid-acting beta2 agonists. Controller medications reduce airway inflammation, lead to better symptom control and reduce the risk of future exacerbations. Reliever (rescue) medications alleviate symptoms and prevent exercise-induced bronchoconstriction. Treatment must be based on a "stepwise approach" in order to achieve good control of symptoms and to minimise future risks of exacerbations. That is, less treatment for mild disease, more treatment for severe, uncontrolled disease. Once good asthma control has been achieved and maintained, treatment should be stepped down. In severe asthmatics, phenotypic characterisation becomes more clinically useful and add-on treatment such as anti-immunoglobulin E monoclonal antibodies may be required. Despite our better understanding of asthma, there are still patients who will not respond to treatment and remain symptomatic. Dissemination of guidelines and national plans allowing early diagnosis of asthma as well as access to specialised primary and secondary care for asthmatic patients, personalised treatment and continuity of care may lead to excellence in care and controlled asthma for the majority of patients. Education of the patient in asthma is also very important, as in every chronic disease, as the patients live with the disease every day while they visit a healthcare professional a few times a year. Future planning for new treatments should focus on the needs of such severe asthma patients. PMID- 26632422 TI - Comparison of patient-reported need of psycho-oncologic support and the doctor's perspective: how do they relate to disease severity in melanoma patients? AB - OBJECTIVE: Psycho-neuro-immune research suggests an association between cancer outcomes and psychosocial distress. Objective criteria to determine patients' levels of distress are important to establish potential links to disease outcomes. METHODS: We compared three patient-reported with one doctor-reported measures of psycho-oncologic distress frequently used in routine cancer care and investigated associations with standard disease severity parameters in melanoma patients. We enrolled n = 361 patients, successively seen at two outpatient university clinics in Germany. In the naturalistic study, n = 222 patients had been diagnosed <180 days and were seen for the first time (Group I); n = 139 had been diagnosed >180 days and were in after-care (Group II). RESULTS: Across groups, only moderate associations were seen between patient- reported and doctor reported measures. Regarding clinical variables, disease severity and perceived need of psycho-oncologic support reported by patients or doctors showed hardly any association. After subgroup stratification, in patients of Group II, patient reported and doctor-reported instruments showed some small associations with disease parameters commonly linked to more rapid cancer progression in patients who are in cancer after-care. CONCLUSIONS: Overall, the few and low associations suggest that need of psycho-oncologic support and clinical variables were largely independent of each other and doctors' perception may not reflect the patient's view. Therefore, the assessment of the patient perspective is indispensable to ensure that melanoma patients receive appropriate support, as such need cannot be derived from other disease parameters or proxy report. More research is needed applying psychometrically robust instruments that are ideally combined with sensitive biomarkers to disentangle psycho-neuro-immune implications in melanoma patients. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26632423 TI - Red-Tuned Mn d-d Emission in Doped Semiconductor Nanocrystals. AB - Light-emitting Mn-doped semiconductor nanocrystals have been extensively studied for the last three decades for their intense and stable Mn d-d emission. In principle, this emission should be fixed at 585 nm (yellow), but recent studies have shown that the emission can be widely tuned even to 650 nm (red). This is a spectacular achievement as this would make Mn-doped nanocrystals efficient and tunable light emitters. Keeping these developments in view, the chemistry of the synthesis of these materials, their photophysical processes and the expected origins of their red emission are summarized in this Minireview. All the related important studies from 1992 onwards are chronologically discussed, and one particular case is elaborated on in detail. As these materials are potentially important for biology, and photovoltaic, sensing and light-emitting devices, this Minireview is expected to help researchers investigating the chemistry, physics and applications of these materials. PMID- 26632424 TI - Crossed views of burden and emotional distress of cancer patients and family caregivers during palliative care. AB - OBJECTIVE: Studies regarding natural caregivers' burden (CB) in palliative situations, as well as its determinants and consequences, have been numerous during the last 20 years. Yet, studies regarding how terminally ill cancer patients perceive their CB (self-perceived burden, SPB) are less common. This study aims to assess the links between CB and SPB evaluated by means of the very same items. It also aims at identifying the determinants of potential differences between CB and SPB and their consequences on emotional distress among both members of the dyad. METHODS: Sixty cancer patients from a palliative care unit and their principal natural caregiver completed questionnaires concerning the subjective burden of the caregiver, their own personal emotional distress and that of the other member of the dyad. RESULTS: Globally, patients had a good perception of their CB, although a little overestimated, except for their difficulties in managing their time. Caregivers overestimated patients' distress. The minimisation by patients of CB was a source of emotional distress for the latter, and the perception of being a burden to others was a source of depression for patients. These results did not depend on the nature of the relationship between patients and their caregivers. CONCLUSIONS: This data confirmed the need to study the experiences of the patient-caregiver dyad as well as their communication of their respective experiences, with a prospect to offer clinical interventions to optimise the quality of life and health of patients and their close relatives.Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26632425 TI - Interventional bronchoscopy in the management of thoracic malignancy. AB - Interventional bronchoscopy is a rapidly expanding field in respiratory medicine offering minimally invasive therapeutic and palliative procedures for all types of lung neoplasms. This field has progressed over the last couple of decades with the application of new technology. The HERMES European curriculum recommendations include interventional bronchoscopy skills in the modules of thoracic tumours and bronchoscopy [1]. However, interventional bronchoscopy is not available in all training centres and consequently, not all trainees will obtain experience unless they rotate to centres specifically offering such training. In this review, we give an overview of interventional bronchoscopic procedures used for the treatment and palliation of thoracic malignancy. These can be applied either with flexible or rigid bronchoscopy or a combination of both depending on the anatomical location of the tumour, the complexity of the case, bleeding risk, the operator's expertise and preference as well as local availability. Specialised anaesthetic support and appropriately trained endoscopy staff are essential, allowing a multimodality approach to meet the high complexity of these cases. PMID- 26632427 TI - Age-Dependent Changes of the Temporal Order--Causes and Treatment. AB - This review summarizes current knowledge on deteriorations in temporal order with advanced age. Changes of the overt rhythms will be described but also their putative causes and possible treatments of the disturbances. In aging animals and humans, all rhythm characteristics change. The most prominent changes are a decrease of circadian amplitude, leading to an extra-circadian dissemination (ECD), and a diminished ability to synchronize with the periodic environment. ECD is a shift from circadian to ultradian and infradian frequencies, accompanied by the loss of day-to-day phase stability. Responsiveness to photic and non-photic cues is decreased. As a consequence, both internal and external temporal order are disturbed not only under steady-state conditions but and even more markedly after changes in the periodic environment or following stressful events. Many of the changes seem to occur within the suprachiasmatic nucleus (SCN), the central circadian pacemaker, itself. The number of functioning neurons decreases with advancing age as does the coupling between them. Accordingly, the SCN generates a weaker and less stable circadian signal, insufficient to entrain peripheral oscillators properly or to regulate body functions rhythmically. However, age dependent disturbances in peripheral organs must also be considered. These changes may occur at different ages, thus causing further internal desynchronization. Several possibilities exist with regard to treating circadian disruptions or at least minimizing their consequences for health and fitness and preventing sleep disturbances. Benefits of bright light, melatonin and other chronobiotics, physical activity, social contacts and regular feeding schedules in preserving the temporal order of aged organisms are discussed. PMID- 26632426 TI - Excited-State Dynamics of a Two-Photon-Activatable Ruthenium Prodrug. AB - We present a new approach to investigate how the photodynamics of an octahedral ruthenium(II) complex activated through two-photon absorption (TPA) differ from the equivalent complex activated through one-photon absorption (OPA). We photoactivated a Ru(II) polypyridyl complex containing bioactive monodentate ligands in the photodynamic therapy window (620-1000 nm) by using TPA and used transient UV/Vis absorption spectroscopy to elucidate its reaction pathways. Density functional calculations allowed us to identify the nature of the initially populated states and kinetic analysis recovers a photoactivation lifetime of approximately 100 ps. The dynamics displayed following TPA or OPA are identical, showing that TPA prodrug design may use knowledge gathered from the more numerous and easily conducted OPA studies. PMID- 26632428 TI - Daily Melatonin Administration Attenuates Age-Dependent Disturbances of Cardiovascular Rhythms. AB - Increased blood pressure and reduced robustness of circadian rhythms are frequently reported in elderly subjects. The present study was aimed to investigate whether such changes can be reversed by daily melatonin ingestion. 97 normotensive and hypertensive volunteers of both genders and 63 to 91 years old participated. They lived in the Tyumen Elderly Veteran House on a self-chosen sleep-wake regimen to suit their personal convenience. The experiment lasted for three weeks. After one control week, part of the group (n=63) received 1.5 mg melatonin (Melaxen(TM)) each day at 22:30 h for two weeks. The other 34 subjects were placebo-treated. Systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) were measured using semi-automated devices at 03:00, 08:00, 11:00, 14:00, 17:00, 23:00 h each day of the first and the third week. Specially trained personnel made the measurements, taking care not to disturb subjects' sleep. Rhythm characteristics were estimated by means of single and population-mean cosinor analyses. Bingham test was used to compare rhythm parameters between groups and investigated physiologic variables. The 24-h HR rhythm was monophasic as described in other studies for young subjects though with a steeper increase in the morning. The daily SBP and DBP rhythms were bimodal. In reference to previously reported data of younger subjects, mean blood pressure of our cohort was elevated, particularly the nocturnal fall was less pronounced. Also, the overall SBP variability was higher as was the percentage of the 12-h component. Both values and also the SBP and DBP levels were reduced during melatonin treatment. The hypotensive effect of melatonin was most pronounced between 3:00 and 8:00 in the morning, i.e. at the time of the highest risk of adverse cardiovascular events, and in subjects with highest BP values before treatment. Moreover, the morning increase of HR was gentler what could have been of additional benefit. Melatonin has a direct hypotensive effect. Also, it stabilizes the internal temporal order enhancing the circadian component and the synchronization between rhythms of different physiological functions. This may further improve health and welfare of elderly subjects and particularly of those with hypertension. Taken together our data show the usefulness of melatonin for adjuvant medication. PMID- 26632429 TI - Age-Related Sleep Changes and its Implication in Neurodegenerative Diseases. AB - In the article authors discuss the current data on sleep changes with aging focusing on the influence of age-related degenerative changes in orexin containing and pacemaker brain areas. Pathophysiological mechanisms of sleep disturbances in Parkinson's and Alzheimer's diseases have much in common with normal age neurophysiological changes. Maintenance of the sleep-promoting systems function could positively modify the course of these diseases. PMID- 26632431 TI - Age-associated Advance of Sleep Times Relative to the Circadian Phase of Alertness-Sleepiness Rhythm: Can it be Explained by Changes in Ratios Between Strengths of the Underlying Oscillatory Processes? AB - The aging process is often associated with more or less prominent shifts of the entrained phases of behavioral and physiological rhythms at earlier clock hours, but the oscillatory mechanisms underlying these shifts have to be determined. The analysis of self-reports on home sleep times and self-scorings of sleepiness provided by 130 participants of sleep deprivation experiments revealed the difference between intro-individual (age-related) and inter-individual (gender- and chronotype-related) variation in phase angle between sleep timing and timing of nocturnal rise of sleepiness. A heterochronity of age-related changes in phase characteristics of the circadian rhythms was suggested for explaining this difference. In particular, a rhythm's strength might determine the rate of age related decline of its entrainment mechanism. In the case of a weak circadian rhythm, such as the homeostatic process underlying oscillations of slow wave activity in the sleep-wake cycle, a decline of the rhythm's strength might be already pronounced in middle aged adults. In contrast, a similar decline might occur much later in the cases of the homeostatic processes underlying stronger rhythms, such as the fluctuations of alertness-sleepiness, body temperature, melatonin secretion, etc. Moreover, the strength of a strong rhythm might become weaker earlier than that of the circadian pacemaker and, especially, earlier than decline of its ability to entrain to the light-dark cycle. Such sequence of changes in the circadian entrainment mechanisms might explain a general tendency to produce advance rather than delay shifts of entrained phases of circadian rhythms with progression of age from middle adulthood to elderly. PMID- 26632430 TI - Age-Related Sleep Disruption and Reduction in the Circadian Rhythm of Urine Output: Contribution to Nocturia? AB - Aging is associated with a marked increase in sleep complaints, and one factor causing sleep disruption is waking to void (nocturia). Urological surveys have found that few young adults report nocturia symptoms, but about half of those in their 60's and nearly 80% of older age groups are affected. Sleep surveys have found nocturia is a major cause of sleep disruption, with a majority of older adults with sleep disruption citing the need to void as the cause of their awakening. While much of the urological literature implies that nocturia causes sleep disruption, age-related changes in sleep depth and continuity may make it more likely that an older adult will wake in response to a filling bladder, or that an older adult will wake for another reason and then decide to void. There is also evidence that age-related changes in the amplitude of circadian rhythms contribute to nocturia. There is a well-described circadian rhythm in urine output, and evidence of circadian rhythmicity in some diuretic and anti-diuretic hormones. In this article, we describe how age-related changes in sleep depth and continuity and age-related changes in circadian rhythm amplitude may contribute to nocturia, and how nocturia in turn leads to sleep disruption. Better understanding of how changes in sleep and circadian rhythmicity impact nocturia may lead to improved treatments and better quality of life for older adults. PMID- 26632432 TI - Lounging with robots--social spaces of residents in care: A comparison trial. AB - AIMS: To investigate whether robots could reduce resident sleeping and stimulate activity in the lounges of an older persons' care facility. METHODS: Non randomised controlled trial over a 12-week period. The intervention involved situating robots in low-level and high-dependency ward lounges and a comparison with similar lounges without robots. A time sampling observation method was utilised to observe resident behaviour, including sleep and activities over periods of time, to compare interactions in robot and no robot lounges. RESULTS: The use of robots was modest; overall 13% of residents in robot lounges used the robot. Utilisation was higher in the low-level care lounges; on average, 23% used the robot, whereas in high-level care lounges, the television being on was the strongest predictor of sleep. CONCLUSION: This study found that having robots in lounges was mostly a positive experience. The amount of time residents slept during the day was significantly less in low-level care lounges that had a robot. PMID- 26632433 TI - Peptides to Target Tumor Vasculature and Lymphatics for Improved Anti Angiogenesis Therapy. AB - Cancer has become one of the leading causes of increased mortality. The currently employed diagnostic and therapeutic modality offers only minimal specificity towards cancerous cells and affects normal healthy cells. Targeted drug delivery systems have shown an improved efficiency in the diagnosis and treatment of various cancers, as the targeted molecules specifically reach the tumor cells without exerting any undesirable effects on the normal healthy cells. Recent findings have shown that disruption of blood vasculature and lymphatics is efficient in treating various cancers. As these vessels supply nutrient and oxygen, remove wastes and help in the metastasis; therapeutic agents targeting them will be highly useful. Of the various ligands used for targeting blood vasculature and lymphatics, peptides possess great advantage over other molecules. This review article is aimed at focusing the recent findings and developments on the peptides as targeting ligands for the improved anti angiogenesis therapy. PMID- 26632434 TI - Nanoparticles for Colorectal Cancer Targeted Drug Delivery and MR Imaging: Current Situation and Perspectives. AB - The application of nanoparticles (NPs) offers new prospects for the early detection and effective therapy of colorectal cancer (CRC). Various NPs have been designed and explored as diagnostic and/or therapeutic drug delivery vehicles. To achieve selective treatment and to reduce toxicity, these nanoparticles are usually endowed with targeting abilities. Passive targeting is based on the extravasation and enhanced permeability and retention effect of tumors, while active targeting always involves binding to specific ligands that are recognizable by CRC tissues, such as vascular endothelial growth factor, folate, monoclonal antibodies (mAbs), aptamers, and membrane penetrating peptides. In addition, contrast agents, such as gadolinium complexes and iron oxide particles, can be introduced into the delivery system to enable MR imaging and lesion detection. Furthermore, smart carriers have been gradually applied to the delivery system. These carriers are designed to respond to certain changes in the bio-environment and release encapsulated contents on demand, thus achieving effective drug concentrations at tumor sites. This review focuses on recent advances of NP technology for the targeted diagnosis and treatment of CRC and aims to unveil the emerging possibilities of using nanocarriers to enhance therapeutic applications. PMID- 26632435 TI - Targeting Tumors with Small Molecule Peptides. AB - Chemotherapeutic treatment of cancers is a challenging endeavor, hindered by poor selectivity towards tumorous tissues over healthy ones. Preferentially delivering a given drug to tumor sites necessitates the use of targeting elements, of which there are a wide range in development. In this Review, we highlight recent examples of peptide-based targeting ligands that have been exploited to selectively deliver a chemotherapeutic payload to specific tumor-associated sites such as the vasculature, lymphatics, or cell surface. The advantages and limitations of such approaches will be discussed with a view to potential future development. Additionally, we will also examine how peptide-based ligands can be used diagnostically in the detection and characterization of cancers through their incorporation into imaging agents. PMID- 26632436 TI - Targeted Delivery of Bleomycin: A Comprehensive Anticancer Review. AB - Despite being one of the most effective broad-spectrum chemotherapeutic agents in the treatment of cancers, the clinical applications of bleomycins (BLMs) have been limited due to their poor drug delivery abilities, and the side effect of causing lung fibrosis. With the increased therapeutics and the reduction of side effects, research and development of targeted drug delivery systems (TDDS) with BLMs have become essential for the expansive clinical usage of BLM-based therapeutics. This review summarizes the recent developments of various TDDS for BLMs, including techniques such as photochemical internalization, ultrasound, and micelle, liposome, and nanoparticle formation. The advantages and disadvantages for each delivery approach are outlined, along with the specific challenges associated with each delivery system. PMID- 26632437 TI - Fingolimod ameliorates the development of experimental autoimmune encephalomyelitis by inhibiting Akt-mTOR axis in mice. AB - Fingolimod is a new immunosuppressive agent approved by Food and Drug Administration (FDA) for treating multiple sclerosis (MS). It acts as a functional antagonist to downregulate the S1P1 receptor, which is known to signal through the Akt-mTOR pathway. We investigated the mechanism of fingolimod action in the classical animal model of MS: experimental autoimmune encephalomyelitis (EAE). Fingolimod treatment significantly reduced clinical scores and histopathology in this model, even when treatment was begun after the onset of pathology. The Akt-mTOR signaling pathway was shown to be activated in the EAE model, by measuring the abundance of downstream activation markers, pAkt and ps6k. And this pathway was inhibited when EAE mice were treated with fingolimod. Mice with EAE exhibited an increased frequency of Th1 cells in the spleen, with concomitant increases in the mRNA levels of Tbet and Ifng and increased IFN-gamma production by activated splenocytes; the frequency of Treg cells, as well as mRNA levels of Foxp3 and Tgfb, was reduced, as was TGF-beta production by activated splenocytes. After treatment with fingolimod, these parameters were reversed, suggesting that fingolimod treatment inhibits the Akt-mTOR axis in EAE, which affects the differentiation and function of Th1 and Treg cells. These results provide an insight into the mechanism of action of fingolimod treatment and may provide new ideas for treating EAE and MS. PMID- 26632438 TI - An In Silico Approach for Identification of Potential Anti-Mycobacterial Targets of Vasicine and Related Chemical Compounds. AB - Tuberculosis (TB) is known to mankind as one of the most pervasive and persistent of diseases since the early days of civilization. The growing resistance of the causative pathogen Mycobacterium tuberculosis to the standard drug regimen for TB poses further difficulty in its treatment and control. Screening of novel plant derived compounds with promising anti-tubercular activity has been cited as a prospective route for new anti-tubercular drug discovery and design. Justicia adhatoda L. is a perennial evergreen shrub which is widely mentioned in scientific literature on account of its potent anti-mycobacterial properties. In the present study, we have employed a series of computational methodologies to reveal the probable molecular interactions of vasicine, the principal alkaloid of Justicia adhatoda L., and two of its close natural derivatives- vasicinone and deoxyvasicine, with certain biological targets in M. tuberculosis. Targets were identified from literature and through a reverse Pharmacophore-based approach. Subsequent comparative molecular docking to identify the best ligand-target interactions revealed Antigen 85C of M. tuberculosis as the most potent biological target of vasicine on the basis of optimum molecular docking values. A chemogenomics approach was also employed to validate the molecular interactions between the same class of chemical compounds as vasicine and Antigen 85C. Further, a library of structural analogs of vasicine was created by bioiosterism based drug design to identify structural analogs with better inhibitory potential against Antigen 85C. PMID- 26632439 TI - An Integrated In Silico Method to Discover Novel Rock1 Inhibitors: Multi- Complex Based Pharmacophore, Molecular Dynamics Simulation and Hybrid Protocol Virtual Screening. AB - Rho-associated, coiled-coil containing protein kinase 1 (ROCK1) is an important regulator of focal adhesion, actomyosin contraction and cell motility. In this manuscript, a combination of the multi-complex-based pharmacophore (MCBP), molecular dynamics simulation and a hybrid protocol of a virtual screening method, comprised of multipharmacophore- based virtual screening (PBVS) and ensemble docking-based virtual screening (DBVS) methods were used for retrieving novel ROCK1 inhibitors from the natural products database embedded in the ZINC database. Ten hit compounds were selected from the hit compounds, and five compounds were tested experimentally. Thus, these results may provide valuable information for further discovery of more novel ROCK1 inhibitors. PMID- 26632440 TI - Bioactivity-Guided Isolation of Antiproliferative Sesquiterpene Lactones from Centaurea solstitialis L. ssp. solstitialis. AB - Centaurea solstitialis L. ssp. solstitialis (CSS) has been used as medicine for various diseases. In this work, root, stem and flower parts of the plant were separately extracted with methanol to execute bioassay-guided isolation. Antiproliferative activities of each extracts on C6 cells (Rat Brain tumor cells) and HeLa cells (human uterus carcinoma) were investigated in vitro. The methanol extract of stem exhibited the most antiproliferative activity therefore isolation of active compounds was carried out for stem of the plant. Methanol extract of stem was boiled at 97 degrees C for 2 hours in water and then hexane and ethyl acetate were extracted sequentially. Solstitialin A 1 and 15-dechloro-15 hydroxychlorojanerin 2 were isolated from ethyl acetate extract by column chromatography and identified by spectroscopic techniques. Solstitialin A 1 was isolated from CSS and 15-dechloro-15-hydroxychlorojanerin 2 was isolated from Saussurea lipschitz and Rhaponticum pulchrum previously. These two compounds exhibited very high antiproliferative activity on C6 and HeLa cells. IC50 and IC75 values of compound 1 were obtained as 10.78 and 53.65 against C6 cell and as 48.78 and 68.52 against HeLa, respectively. IC50 and IC75 values of compound 2 were determined as 432.43 and 109.79 against C6 cell. PMID- 26632441 TI - Pharmacophore-Based 3D-QSAR Modeling, Virtual Screening and Molecular Docking Analysis for the Detection of MERTK Inhibitors with Novel Scaffold. AB - MERTK plays an important role in cell biology and is correlated with many cancers, such as mantle cell lymphomas, pituitary adenomas, and T-cell acute lympholoblastic leukemia. So identification of new MERTK inhibitors is of extreme importance. In this study, 107 MERTK inhibitors with known activities were gathered to generate a ligand-based pharmacophore model (ADDHH.4), followed by building a 3D-QSAR model, which had high value of coefficient of determination (R(2)=0.9061) and high value of coefficient of determination (Q(2)=0.7442). For the pharmacophore model, two hydrogen bond donors (D), one hydrogen bond receptor (A), and two hydrophobic groups (H) were considered as the key elements contributing to ligand activity. The model then served to search a drug-like database with 1.5 million molecules, and 47832 hits were obtained. Subsequently, docking procedure was applied on these hits, and 840 compounds were obtained through high-throughput virtual screening (HTVS). Standard precision (SP), extra precision (XP) and rule of five were also used in virtual screening protocol. Finally, six candidates were identified as potential MERTK inhibitors, with the docking mode in MERTK analyzed. PMID- 26632442 TI - Thiazole-Based Thiazolidinones as Potent Antimicrobial Agents. Design, Synthesis and Biological Evaluation. AB - As a part of our ongoing project on the design and synthesis of new thiazole derivatives with antimicrobial activity, fourteen new ethyl 2-(2-((E)-((Z)-5-(4 benzyliden)- 4-oxothiazolidin-2-yliden)amino-4-yl)acetates, carrying halogens, methoxy and other groups were synthesized. Compounds were tested against eight Gram positive and negative bacteria as well as eight yeasts and mold by microdilution assay. All compounds showed good activity against all bacteria tested with MIC ranging between 2.3-39.8 umol/ml x 10(-2) and MBC of 9.2-79.6 umol/ml x 10(-2). As reference drugs Ampicillin (MIC 24.8-74.4 and MBC 37.2-124.0 umol/ml x 10(-2)) and Streptomycin (MIC 4,3-17.2 and MBC 8.6-51.6 umol/ml x 10( 2)) were used. The best activity was observed for 4-bromo derivative. All tested compounds showed excellent antifungal activity against all fungi tested with MIC in the range between 0.3-38.6 umol/ml x 10(-2) and MFC range of 0.6-77.2 umol/ml x 10(-2), better than that of reference drugs, Ketoconazole (MIC 38.0-475.0 and MFC 95.0-570 umol/ml x 10(-2)) and Bifonazole (MIC 48.0-64.0 and MFC 64.0-80.0 umol/ml x 10(-2)). The best activity was observed for 3-nitro derivative. It was found that among the 5-arylidene derivatives the inhibitory effect appears to be dependent on the substitution at the benzene ring. Fourteen new ethyl 2-(2-((E) ((Z)-5-(4-benzyliden)-4-oxothiazolidin-2-yliden)amino-4-yl)acetates were synthesized and evaluated for antibacterial and antifungal activity. PMID- 26632443 TI - Efficient Isothermal Titration Calorimetry Technique Identifies Direct Interaction of Small Molecule Inhibitors with the Target Protein. AB - Protein-protein interactions (PPI) play a critical role in regulating many cellular processes. Finding novel PPI inhibitors that interfere with specific binding of two proteins is considered a great challenge, mainly due to the complexity involved in characterizing multi-molecular systems and limited understanding of the physical principles governing PPIs. Here we show that the combination of virtual screening techniques, which are capable of filtering a large library of potential small molecule inhibitors, and a unique secondary screening by isothermal titration calorimetry, a label-free method capable of observing direct interactions, is an efficient tool for finding such an inhibitor. In this study we applied this strategy in a search for a small molecule capable of interfering with the interaction of the tumor-suppressor p53 and the E3-ligase MDM2. We virtually screened a library of 15 million small molecules that were filtered to a final set of 80 virtual hits. Our in vitro experimental assay, designed to validate the activity of mixtures of compounds by isothermal titration calorimetry, was used to identify an active molecule against MDM2. At the end of the process the small molecule (4S,7R)-4-(4-chlorophenyl)-5 hydroxy-2,7-dimethyl-N-(6-methylpyridin-2-yl)-4,6,7,8 tetrahydrIoquinoline-3 carboxamide was found to bind MDM2 with a dissociation constant of ~2 uM. Following the identification of this single bioactive compound, spectroscopic measurements were used to further characterize the interaction of the small molecule with the target protein. 2D NMR spectroscopy was used to map the binding region of the small molecule, and fluorescence polarization measurement confirmed that it indeed competes with p53. PMID- 26632444 TI - Effect of a traditional Chinese medicine prescription Quzhuotongbi decoction on hyperuricemia model rats studied by using serum metabolomics based on gas chromatography-mass spectrometry. AB - Morbidity of hyperuricemia has constantly increased in population in decades, and hyperuricemia has proved to be an important risk factor for gout, cardiovascular diseases and others. Many urate-lowering drugs have unfavorable side effects and drug interactions. Quzhuotongbi decoction (QZTBD) is an empirical traditional Chinese medicine prescription for clinical therapy of hyperuricemia without serious adverse effects. In the study, we investigated the effects of QZTBD on urate and other metabolites in the sera of hyperuricemia model rats. Hyperuricemia model was established by orally administering yeast extract paste, and allopurinol served as a positive control drug. Serum metabolomics was performed by using a gas chromatography-mass spectrometry (GC-MS) method. Student's t-test and the principal component analysis (PCA) were employed to find the metabolic perturbations in hyperuricemia model rats. The levels of urate, lactate, pyruvate and ornithine were significantly increased, and xanthine, glyconic acids (ribonate, galactonate), amino acids (aspartate, proline, glutamine, serine, pyroglutamate, glutamate) and glucose were down-regulated greatly in the model rats. It demonstrated that nucleotide metabolism, amino acid metabolism and glycolytic pathway were disturbed by yeast administration. An orthogonal signal correction-partial least-squares discriminant analysis (OSC-PLS DA) was performed to assess the effects of yeast administering and drug treatment. 11 significantly distinctive metabolites among four groups were defined according to the variable importance for project values (VIP>1) and univariate ANOVA (p value<0.05). As compared to the model rats, the serum uric acid levels were lowered markedly under the treatment of allopurinol or QZTBD. Aspartate and glutamine involved in purine metabolism, were raised to normal level as well. The different influences on xanthine, glutamate pyroglutamate and galactonate suggested there were different mechanisms of two drugs in urate lowering therapy. Our finding proved that QZTBD can efficiently lower the level of serum uric acid in a different way from allopurinol, which suggested that QZTBD based on the theory of TCM could be an effective therapeutic option for hyperuricemia. PMID- 26632445 TI - Laser-tuned whispering gallery modes in a solid-core microstructured optical fibre integrated with magnetic fluids. AB - A laser-assisted tuning method of whispering gallery modes (WGMs) in a cylindrical microresonator based on magnetic-fluids-infiltrated microstructured optical fibres (MFIMOFs, where MF and MOF respectively refer to magnetic fluid and microstructured optical fibre) is proposed, experimentally demonstrated and theoretically analysed in detail. The MFIMOF is prepared by infiltrating the air hole array of the MOF using capillary action effect. A fibre-coupling system is set up for the proposed MFIMOF-based microresonator to acquire an extinction ratio up to 25 dB and a Q-factor as large as 4.0 * 10(4). For the MF-infiltrated MOF, the light propagating in the fibre core region would rapidly spread out and would be absorbed by the MF-rod array cladding to induce significant thermal effect. This has been exploited to achieve a WGM resonance wavelength sensitivity of 0.034 nm/mW, which is ~20 times higher than it counterpart without MF infiltration. The wavelength response of the resonance dips exhibit linear power dependence, and owing to such desirable merits as ease of fabrication, high sensitivity and laser-assisted tunability, the proposed optical tuning approach of WGMs in the MFIMOF would find promising applications in the areas of optical filtering, sensing, and signal processing, as well as future all-optical networking systems. PMID- 26632447 TI - A composite scaffold of MSC affinity peptide-modified demineralized bone matrix particles and chitosan hydrogel for cartilage regeneration. AB - Articular cartilage injury is still a significant challenge because of the poor intrinsic healing potential of cartilage. Stem cell-based tissue engineering is a promising technique for cartilage repair. As cartilage defects are usually irregular in clinical settings, scaffolds with moldability that can fill any shape of cartilage defects and closely integrate with the host cartilage are desirable. In this study, we constructed a composite scaffold combining mesenchymal stem cells (MSCs) E7 affinity peptide-modified demineralized bone matrix (DBM) particles and chitosan (CS) hydrogel for cartilage engineering. This solid-supported composite scaffold exhibited appropriate porosity, which provided a 3D microenvironment that supports cell adhesion and proliferation. Cell proliferation and DNA content analysis indicated that the DBM-E7/CS scaffold promoted better rat bone marrow-derived MSCs (BMMSCs) survival than the CS or DBM/CS groups. Meanwhile, the DBM-E7/CS scaffold increased matrix production and improved chondrogenic differentiation ability of BMMSCs in vitro. Furthermore, after implantation in vivo for four weeks, compared to those in control groups, the regenerated issue in the DBM-E7/CS group exhibited translucent and superior cartilage-like structures, as indicated by gross observation, histological examination, and assessment of matrix staining. Overall, the functional composite scaffold of DBM-E7/CS is a promising option for repairing irregularly shaped cartilage defects. PMID- 26632448 TI - Assessment of liver fibrosis in primary biliary cholangitis: Comparison between indirect serum markers and fibrosis morphometry. AB - BACKGROUND: The accuracy of non-invasive methods for the quantification of liver fibrosis in primary biliary cholangitis (PBC) is still debated. AIMS: To determine the histo-morphometric measurement of fibrotic tissue and to explore the possible association between indirect markers (APRI, FORNS, FIB-4, and Lok) and morphometry. METHODS: Retrospective analysis of medical data from patients with PBC, on whom needle liver biopsy was performed as part of the diagnostic assessment. One section of each biopsy stained with Sirius red was used for calculating the percentage of collagen. Quantitative measure of fibrotic tissue (fibrosis morphometry) was calculated as a percentage of collagen content by digital image analysis. Morphometry results were divided into four groups reflecting Ludwig's staging and compared with values for indirect serum markers. RESULTS: 50 PBC patients were enrolled (86% females, mean age 57 +/- 12.30 years), 19 were Ludwig's stage I (38%), 14 stage II (28%), 12 stage III (24%), and five stage IV (10%). Morphometry results were significantly different among Ludwig stages (p<0.05). No significant differences were found for indirect serum markers. A significant correlation was found between morphometry results and indirect serum markers tested (p<0.05). CONCLUSION: In our cohort, the histo morphometric values of fibrotic tissue increased progressively with Ludwig's stages of PBC, while non-invasive markers did not. PMID- 26632446 TI - In situ vaccination: Cancer immunotherapy both personalized and off-the-shelf. AB - As cancer immunotherapy continues to benefit from novel approaches which cut immune 'brake pedals' (e.g. anti-PD1 and anti-CTLA4 antibodies) and push immune cell gas pedals (e.g. IL2, and IFNalpha) there will be increasing need to develop immune 'steering wheels' such as vaccines to guide the immune system specifically toward tumor associated antigens. Two primary hurdles in cancer vaccines have been: identification of universal antigens to be used in 'off-the-shelf' vaccines for common cancers, and 2) logistical hurdles of ex vivo production of individualized whole tumor cell vaccines. Here we summarize approaches using 'in situ vaccination' in which intratumoral administration of off-the-shelf immunomodulators have been developed to specifically induce (or amplify) T cell responses to each patient's individual tumor. Clinical studies have confirmed the induction of systemic immune and clinical responses to such approaches and preclinical models have suggested ways to further potentiate the translation of in situ vaccine trials for our patients. PMID- 26632450 TI - The first true deserticolous species of Buthus Leach, 1815 from Algeria (Scorpiones: Buthidae); Ecological and biogeographic considerations. AB - Since the early 2000s, the genus Buthus Leach, 1815 (family Buthidae) has been the subject of an important number of studies. These concerned particularly the species belonging to the 'Buthus occitanus' complex. A number of populations previously considered as subspecies or varieties of B. occitanus Leach were raised to the rank of species, but also many new species have been described. Most of the species considered in these studies come from North Africa, in particular from Morocco, Mauritania, Chad, Sudan and Egypt, but only two new species were recorded from Algeria. At present, one more new species of Buthus is described from the Algerian Saharan Desert, raising the number of confirmed Buthus in Algeria to five. Since most Buthus species from North Africa, and in particular those from Algeria, inhabit more mesic environments than the Saharan Central compartment, the new species appears as the first true deserticolous species found in this country. PMID- 26632449 TI - FGF coordinates air sac development by activation of the EGF ligand Vein through the transcription factor PntP2. AB - How several signaling pathways are coordinated to generate complex organs through regulation of tissue growth and patterning is a fundamental question in developmental biology. The larval trachea of Drosophila is composed of differentiated functional cells and groups of imaginal tracheoblasts that build the adult trachea during metamorphosis. Air sac primordium cells (ASP) are tracheal imaginal cells that form the dorsal air sacs that supply oxygen to the flight muscles of the Drosophila adult. The ASP emerges from the tracheal branch that connects to the wing disc by the activation of both Bnl-FGF/Btl and EGFR signaling pathways. Together, these pathways promote cell migration and proliferation. In this study we demonstrate that Vein (vn) is the EGF ligand responsible for the activation of the EGFR pathway in the ASP. We also find that the Bnl-FGF/Btl pathway regulates the expression of vn through the transcription factor PointedP2 (PntP2). Furthermore, we show that the FGF target gene escargot (esg) attenuates EGFR signaling at the tip cells of the developing ASP, reducing their mitotic rate to allow proper migration. Altogether, our results reveal a link between Bnl-FGF/Btl and EGFR signaling and provide novel insight into how the crosstalk of these pathways regulates migration and growth. PMID- 26632451 TI - Glucose-functionalized Au nanoprisms for optoacoustic imaging and near-infrared photothermal therapy. AB - Targeted imaging and tumor therapy using nanomaterials has stimulated research interest recently, but the high cytotoxicity and low cellular uptake of nanomaterials limit their bioapplication. In this paper, glucose (Glc) was chosen to functionalize Au nanoprisms (NPrs) for improving the cytotoxicity and cellular uptake of Au@PEG-Glc NPrs into cancer cells. Glucose is a primary source of energy at the cellular level and at cellular membranes for cell recognition. A coating of glucose facilitates the accumulation of Au@PEG-Glc NPrs in a tumor region much more than Au@PEG NPrs. Due to the high accumulation and excellent photoabsorbing property of Au@PEG-Glc NPrs, enhanced optoacoustic imaging of a tumor in vivo was achieved, and visualization of the tumor further guided cancer treatment. Based on the optical-thermal conversion performance of Au@PEG-Glc NPrs, the tumor in vivo was effectively cured through photothermal therapy. The current work demonstrates the great potential of Au@PEG-Glc NPrs in optoacoustic imaging and photothermal cancer therapy in future. PMID- 26632452 TI - Concise synthesis of rare pyrido[1,2-a]pyrimidin-2-ones and related nitrogen-rich bicyclic scaffolds with a ring-junction nitrogen. AB - Pyrido[1,2-a]pyrimidin-2-ones represent a pharmaceutically interesting class of heterocycles. The structurally related pyrido[1,2-a]pyrimidin-4-ones are associated with a broad range of useful biological properties. Furthermore, quinolizinone-type scaffolds of these sorts with a bridgehead nitrogen are expected to display interesting physico-chemical properties. However, pyrido[1,2 a]pyrimidin-2-ones are largely under-represented in current small molecule screening libraries and the physical and biological properties of the pyrido[1,2 a]pyrimidin-2-one scaffold have been poorly explored (indeed, the same can be said for unsaturated bicyclic compounds with a bridgehead nitrogen in general). Herein, we report the development of a new strategy for the concise synthesis of substituted pyrido[1,2-a]pyrimidin-2-ones from readily available starting materials. The synthetic route involved the acylation of the lithium amide bases of 2-aminopyridines with alkynoate esters to form alkynamides, which were then cyclised under thermal conditions. The use of lithium amide anions ensured excellent regioselectivity for the 2-oxo-isomer over the undesired 4-oxo-isomer, which offers a distinct advantage over some existing methods for the synthesis of pyrido[1,2-a]pyrimidin-2-ones. Notably, different aminoazines could also be employed in this approach, which enabled access to several very unusual bicyclic systems with higher nitrogen contents. This methodology thus represents an important contribution towards the synthesis of pyrido[1,2-a]pyrimidin-2-ones and other rare azabicycles with a ring-junction nitrogen. These heterocycles represent attractive structural templates for drug discovery. PMID- 26632453 TI - Paradoxical anaerobism in desert pupfish. AB - In order to estimate metabolic demands of desert pupfish for conservation purposes, we measured oxygen consumption in fish acclimated to the ecologically relevant temperatures of 28 or 33 degrees C. For these experiments, we used fish derived from a refuge population of Devils Hole pupfish (Cyprinodon diabolis). Measurement of routine oxygen consumption (VO2,routine) revealed some 33 degrees C-acclimated fish (10% of 295 assayed fish) periodically exhibited periods of no measurable oxygen consumption despite available ambient oxygen tensions that were above the critical PO2. We call this phenomenon paradoxical anaerobism. The longest observed continuous bout with no oxygen consumption was 149 min, although typical bouts were much shorter. Fish maintained normal posture and ventilation rate (>230 ventilations per minute) during paradoxical anaerobism. Fish rarely demonstrated a compensatory increase in oxygen use following a period of paradoxical anaerobism. In contrast, only one out of 262 sampled fish acclimated at 28 degrees C spontaneously demonstrated paradoxical anaerobism. Muscle lactate concentration was not elevated during periods of paradoxical anaerobism. However, the amount of ethanol released by the 33 degrees C-acclimated fish was 7.3 times greater than that released by the 28 degrees C acclimation group, suggesting ethanol may be used as an alternative end product of anaerobic metabolism. Exposure to exogenous ethanol, in concentrations as low as 0.1%, produced periods of paradoxical anaerobism even in 28 degrees C-acclimated fish. PMID- 26632454 TI - To boldly gulp: standard metabolic rate and boldness have context-dependent influences on risk-taking to breathe air in a catfish. AB - The African sharptooth catfish Clarias gariepinus has bimodal respiration, it has a suprabranchial air-breathing organ alongside substantial gills. We used automated bimodal respirometry to reveal that undisturbed juvenile catfish (N=29) breathed air continuously in normoxia, with a marked diurnal cycle. Air breathing and routine metabolic rate (RMR) increased in darkness when, in the wild, this nocturnal predator forages. Aquatic hypoxia (20% air saturation) greatly increased overall reliance on air breathing. We investigated whether two measures of risk taking to breathe air, namely absolute rates of aerial O2 uptake (MO2,air) and the percentage of RMR obtained from air (%MO2,air), were influenced by individual standard metabolic rate (SMR) and boldness. In particular, whether any influence varied with resource availability (normoxia versus hypoxia) or relative fear of predation (day versus night). Individual SMR, derived from respirometry, had an overall positive influence on MO2,air across all contexts but a positive influence on %MO2,air only in hypoxia. Thus, a pervasive effect of SMR on air breathing became most acute in hypoxia, when individuals with higher O2 demand took proportionally more risks. Boldness was estimated as time required to resume air breathing after a fearful stimulus in daylight normoxia (Tres). Although Tres had no overall influence on MO2,air or %MO2,air, there was a negative relationship between Tres and %MO2,air in daylight, in normoxia and hypoxia. There were two Tres response groups, 'bold' phenotypes with Tres below 75 min (N=13) which, in daylight, breathed proportionally more air than 'shy' phenotypes with Tres above 115 min (N=16). Therefore, individual boldness influenced air breathing when fear of predation was high. Thus, individual energy demand and personality did not have parallel influences on the emergent tendency to take risks to obtain a resource; their influences varied in strength with context. PMID- 26632455 TI - Stable isotope studies reveal pathways for the incorporation of non-essential amino acids in Acyrthosiphon pisum (pea aphids). AB - Plant roots incorporate inorganic nitrogen into the amino acids glutamine, glutamic acid, asparagine and aspartic acid, which together serve as the primary metabolites of nitrogen transport to other tissues. Given the preponderance of these four amino acids, phloem sap is a nutritionally unbalanced diet for phloem feeding insects. Therefore, aphids and other phloem feeders typically rely on microbial symbionts for the synthesis of essential amino acids. To investigate the metabolism of the four main transport amino acids by the pea aphid (Acyrthosiphon pisum), and its Buchnera aphidicola endosymbionts, aphids were fed defined diets with stable isotope-labeled glutamine, glutamic acid, asparagine or aspartic acid (U-(13)C, U-(15)N; U-(15)N; alpha-(15)N; or gamma-(15)N). The metabolic fate of the dietary (15)N and (13)C was traced using gas chromatography mass spectrometry (GC-MS). Nitrogen was the major contributor to the observed amino acid isotopomers with one additional unit mass (M+1). However, there was differential incorporation, with the amine nitrogen of asparagine being incorporated into other amino acids more efficiently than the amide nitrogen. Higher isotopomers (M+2, M+3 and M+4) indicated the incorporation of varying numbers of (13)C atoms into essential amino acids. GC-MS assays also showed that, even with an excess of dietary labeled glutamine, glutamic acid, asparagine or aspartic acid, the overall content of these amino acids in aphid bodies was mostly the product of catabolism of dietary amino acids and subsequent re synthesis within the aphids. Thus, these predominant dietary amino acids are not passed directly to Buchnera endosymbionts for synthesis of essential amino acids, but are rather are produced de novo, most likely by endogenous aphid enzymes. PMID- 26632456 TI - Observations on the spawning behavior, egg masses and paralarval development of the ommastrephid squid Todarodes pacificus in a laboratory mesocosm. AB - The spawning behavior of ommastrephid squids has never been observed under natural conditions. Previous laboratory observations of Japanese flying squid (Todarodes pacificus) suggest that pre-spawning females might rest on the continental shelf or slope before they ascend above the pycnocline to spawn, and that the egg masses might settle in the pycnocline. Here, two mesocosm experiments were conducted in a 300 m(3) tank that was 6 m deep to investigate this hypothesis. In the first experiment, a thermocline (2.5-3.5 m) was established in the tank by creating a thermally stratified (17-22 degrees C) water column. In the second experiment, the temperature was uniform (22 degrees C) at all depths. Prior to spawning, females did not rest on the tank floor. In the stratified water column, egg masses remained suspended in the thermocline, but in an unstratified water column, they settled on the tank bottom, collapsed and were infested by microbes, resulting in abnormal or nonviable embryos. Eleven females spawned a total of 18 egg masses (17-80 cm in diameter), indicating that females can spawn more than once when under stress. Paralarvae hatched at stage 30/31 and survived for up to 10 days, allowing us to observe the most advanced stage of paralarvae in captivity. Paralarvae survived after consumption of the inner yolk, suggesting they might have fed in the tank. PMID- 26632457 TI - Guineafowl with a twist: asymmetric limb control in steady bipedal locomotion. AB - In avian bipeds performing steady locomotion, right and left limbs are typically assumed to act out of phase, but with little kinematic disparity. However, outwardly appearing steadiness may harbor previously unrecognized asymmetries. Here, we present marker-based XROMM data showing that guineafowl on a treadmill routinely yaw away from their direction of travel using asymmetrical limb kinematics. Variation is most strongly reflected at the hip joints, where patterns of femoral long-axis rotation closely correlate to degree of yaw divergence. As yaw deviations increase, hip long-axis rotation angles undergo larger excursions and shift from biphasic to monophasic patterns. At large yaw angles, the alternately striding limbs exhibit synchronous external and internal femoral rotations of substantial magnitude. Hip coordination patterns resembling those used during sidestep maneuvers allow birds to asymmetrically modulate their mediolateral limb trajectories and thereby advance using a range of body orientations. PMID- 26632458 TI - [Clonal hematopoiesis in aplastic anemia]. PMID- 26632459 TI - [Chinese expert consensus on the laboratory practice of BCR- ABL tyrosine kinase domain mutation detection(2015)]. PMID- 26632460 TI - [A multicenter comparison study on the detection of BCR-ABL tyrosine kinase domain point mutation]. AB - OBJECTIVE: To investigate the accuracy and consistency of the detection of BCR ABL tyrosine kinase domain point mutation among different laboratories. METHODS: Every one of 6 laboratories prepared 10 cDNA samples from tyrosine kinase inhibitors resistant BCR-ABL (P210 or P190) positive patients'bone marrow or peripheral blood. Each cDNA sample was divided into 6 aliquots and delivered to the laboratories. All 6 laboratories tested BCR-ABL point mutations of 60 samples according to their own protocols. Peking University People's Hospital analyzed the comparison results based on both the reports and sequencing chromatogram from all laboratories. RESULTS: All laboratories reported the same nucleotide and corresponding amino acid mutations in 37 samples (61.7%). Of 60 samples, 53 had confirmed mutation types, and a total of 23 types were included; 1 had no mutation; mutation types of 6 samples could not be determined because of the big differences among chromatograms from different laboratories. Low percentages of mutants were significantly related to results inconsistency (P=0.008). Inconsistent result of one sample was caused by the unique chromatogram of the mutant L248V, and one by the non-coverage amplification of PCR product from different laboratories. Amplification was failed in 3 samples. Testing or sequencing mistakes occurred in 7 samples. The differences in the mutant percentages among laboratories were less than 20% in the 80.6% of samples with confirmed results. Low internal control gene copies (ABL<10 000) were significantly related to both failed amplification and big differences among chromatograms from different laboratories (P=0.005 and <0.001, respectively). CONCLUSION: Problems in the clinical routine detection of BCR-ABL point mutation could be exposed and improvement could be achieved by sample exchange and comparison. Low percentage of mutant is the main reason which causes the discrepancy of BCR-ABL point mutation results among different laboratories. PMID- 26632461 TI - [Expression of cMPO in 502 cases of acute myeloid leukemia (AML) and its diagnosis significance in AML subtypes]. AB - OBJECTIVE: To investigate the myeloperoxidase (cMPO) expression pattern by flow cytometry (FCM) in patients with acute myeloid leukemia (AML) and its role in classifying AML. METHODS: Eight- color multiparametric FCM with CD45/SSC gating was used to determine the cMPO expression in 502 AML patients. RESULTS: The positive rate of cMPO in all patients was 58.0%, in which the proportion of normal positivity, dim positivity and partial positivity was 21.5%, 34.1% and 2.4%, respectively. The remaining case (42.0%) were all negative. In AML with t (15;17)(q22;q12)/PMLRARalpha, the positive rate was the highest (100%) and the intensity was similar to that of the normal granular leukocytes, followed by AML with t (8;21(q22;q22/RUNX1-RUNX1T1, the positive rate was 91.4% and the intensity was mostly dim. AML with minimal differentiation and acute megakaryoblastic leukemia were all cMPO negative. The positive rates of cMPO in the remaining subtypes were between 22.7% and 76.2%. CONCLUSION: The positive rate and intensity of cMPO were significantly different among different subtypes of AML. PMID- 26632462 TI - [Combination antifungal therapy for invasive fungal disease in children with hematologic disease]. AB - OBJECTIVE: To evaluate antifungal combination strategy in children with hematologic diseases and invasive fungal disease( IFD). METHODS: A retrospective clinical study was performed based on 67 childhood patients with hematologic diseases and IFD who firstly accepted combination antifungal therapy for >= 7 days during January 2012 and December 2014. Of them, 11 cases received combination of echinocandin with azole, 10 cases received combination of echinocandin with amphotericin B, and 46 cases received combination of azole with amphotericin B. RESULTS: Overall response rate was 79.1%. Univariate analysis revealed that granulocyte recovery (P=0.031), status of underling disease (P=0.023) and the duration of the therapy (P=0.046) were significantly associated with efficacy. Multivariate analysis showed that the independent prognostic factor was the duration of combination antifungal therapy (OR=0.229, 95% CI 0.061 0.863, P=0.029). The response rates of echinocandin combined with azole, echinocandin combined with amphotericin B and azole combined with amphotericin B were 81.8%, 60.0% and 82.6%, respectively (P>0.05), and 12-week survival rates were 81.8%, 80.0% and 86.5%, respectively (P>0.05). The drug- related adverse reactions occurred 59 times in 34 patients. BUN increasing, hypokalemia and abnormal liver functions were considered the main side effects. CONCLUSION: For IFD in children with hematologic disease, to extend the duration of treatment (>= 14 days) could significantly improve the curative effect. Combinations of echinocandin with azole, echinocandin with amphotericin B and azole with amphotericin B can be used as a combination treatment options. Combination of Azole with amphotericin B is efficacious, safe and economic treatment option considering efficacy, survival rate, cost and dosage form. PMID- 26632463 TI - [Application of BIOMED- 2 standardized Ig gene rearrangement system in multiple myeloma]. AB - OBJECTIVE: To explore the application of BIOMED- 2 standardized immunoglobulin (Ig) gene rearrangement system in the diagnosis of multiple myeloma (MM), and the significance of clonality analysis by multiplex-PCR amplifications. METHODS: A total of 167 cases of MM bone marrow samples from 2009 to 2013, and 20 cases of reactive plasmacytosis used as the controls were included in this study. Multiplex-PCR amplifications were performed and the Ig gene rearrangements were analyzed using BIOMED-2 standardized clonality analysis system. RESULTS: 1 Of 167 MM cases, 107 showed IgH VH-JH rearrangement, 33 showed IgH DH-JH rearrangement, and 30% showed IgH DH-JH rearrangement in 60 IgH VH-JH rearrangement negative MM cases. The difference was statistically significant between IgH VH-JH rearrangement positive and negative cases (14.0% vs 30.0%, P=0.032). The total positive rate of IgH VH-JH, IgH DH-JH and IgK was 94.6%. The 20 reactive plasmacytosis (RP) cases showed negative Ig gene rearrangement. 2 of 167 MM cases, 9 (5.4%) showed clonal IgH rearrangement by agarose electrophoresis were confirmed as polyclonality by capillary electrophoresis. 3 Of 53 MM cases who have been detected by Ig gene rearrangement system and fluorescence in situ hybridization (FISH) for IgH simultaneously, 36 showed IgH rearrangement, 26 showed FISH IgH positive, and the difference was statistically significant (67.9% vs 49.1%, P=0.049). CONCLUSION: Combined detection of IgH VH- JH, IgH DH- JH and IgK could improve the positive rate of MM clonality dramatically, and measurement of IgH DH-JH rearrangement was more important in the IgH VH- JH negative cases. Ig gene rearrangement system was a faster and more sensitive method than FISH IgH. Application of BIOMED- 2 standardized immunoglobulin (Ig) gene rearrangement system is of significance for MM diagnosis. PMID- 26632464 TI - [Study of NK cells dysfunction in multiple myeloma patients]. AB - OBJECTIVE: To explore the mechanism of NK cell dysfunction in patients with multiple myeloma (MM). METHODS: The expression of inhibitory receptors (CD158a and CD158b) and activating receptors NKG2D and NCRs (NKp30, NKp44 and NKp46) on CD3-CD56+NK cell of 13 MM patients and 30 healthy controls were analyzed by flow cytometry. The concentration of soluble NKG2D ligands (MICA, MICB, ULBP1, ULBP2 and ULBP3) in serum was detected by enzyme- linked immunosorbent assay (ELISA), and the cytotoxicity of NK cell against MM cell line by flow cytometry. RESULTS: There are no significant differences of percentage and absolute number of NK cells, and the expression level of CD158a and CD158b between MM patients and healthy individuals (P>0.05). No NKp44 expression was detected on fresh isolated NK cells from both groups. There is no difference in inhibitor receptors expression between MM patients and healthy individuals but the expression of NKG2D, NKp30 and NKp46 on NK cells were higher in MM patients as compared with that in healthy individuals. The concentration of soluble NKG2D ligands in serum was higher in MM patients as compared with that in healthy individuals (P<0.05). Cultured healthy individual's NK cells with MM patient's serum could significantly decrease its cytotoxicity against MM cell line U266 cells [(38.5 +/ 6.5) % vs (25.4 +/- 5.9)%, P=0.044]. CONCLUSION: The higher level of soluble NKG2D ligands in serum may be the mechanism of NK cell dysfunction in MM patient. PMID- 26632465 TI - [Expression and prognostic value of COX- 2, p16(INK4A) and p53 in patients with classical Hodgkin lymphoma]. AB - OBJECTIVE: To investigate the expression level of COX-2, p16(INK4A) and p53 in patients with classic Hodgkin's lymphoma (cHL), and to evaluate their correlation with prognosis. METHODS: The clinical data and samples of 52 cHL cases were collected. Immunohistochemical staining was performed to analyze the proteins level mentioned above and in situ hybridization of EBV encoded RNA (EBER) to clarify the tumor EBV infection state. Correlation between the protein expression and prognosis of patients was analyzed. RESULTS: Of 52 cases, the male and female ratio was 1.6?1, the age was from 22 to 68 years old. All lesions located primarily in lymph nodes. All samples from 52 cases were stained with COX-2, p16(INK4A) and p53, and the positive expression of COX-2 was found in 28 cases (53.8%), that of p16(INK4A) in 25 cases (48.1%)and p53 in 42 cases (80.8%). All patients were divided into two groups according to differences in age (<40 years/ >= 40 years), gender (male/female), EBV infection (yes/no), B symptoms (yes/no), and the Ann Arbor staging (I-II/III-IV), the correlation with COX-2, p16(INK4A) and p53 expression were analyzed, and only p53 expression was correlated with Ann Arbor staging (P=0.027). The statistical analysis of correlations between COX- 2, p16(INK4A) and p53 showed that the expression of COX-2 was strongly correlated with p53 (P=0.008), and p16 (INK4A) was not related to either COX-2 or p53 (P=0.246 and 0.958). Kaplan- Meier univariate OS analysis using SPSS17.0 software showed that only COX-2 expression was an adverse prognostic factor for patients'event free survival (EFS) (P=0.003). Meanwhile COX-2 expression was a unique independent prognostic factor analyzed by COX proportional hazards regression model (HR=0.091, 95% CI 0.017-0.505, P=0.006). CONCLUSION: The expression rate of COX-2, p16 (INK4A) and p53 in the cHL were relatively high; and they were not statistically correlated with tumor EBV infection status; the COX-2 positive group had poor prognosis, but only event free survival time becomes statistically significant shorter. COX proportional hazard regression model was used to analyze the COX-2 expression as a independent adverse prognostic factors for EFS. PMID- 26632466 TI - [Clinical characteristics and survival of newly diagnosed multiple myeloma patients under 40 years old from single center and literature review]. AB - OBJECTIVE: To investigate the clinical characteristics and prognosis of very young patients with multiple myeloma (MM). METHODS: We retrospectively analyzed the clinical characteristics and outcome of 35 newly diagnosed MM patients 40 years old or younger during a period of 15 years and compared with published data from western countries. RESULTS: Our study demonstrated that these very young patients were more likely to be in advanced stage of International staging system, IgD isotype, hemoglobin<100 g/L, decreased platelets and deletion of 17p13. With a median follow-up of 17 months (1- 89 months), the median overall survival (OS) of this cohort was 33 months and progression-free survival (PFS) was 13 months, moreover 8 of 17 deaths occurred in the first year after diagnosis. In the univariate analysis, extramedullary infiltration, del (17p13)and renal impairment were associated with reduced PFS (P=0.031, P=0.015, P=000, respectively), while the last two factors also predicted inferior OS (P=0.015, P=0.001), but multivariate analysis showed that only renal impairment independently associated with inferior survival in COX model(PFS: HR=3.953, 95% CI 1.263-12.371, P=0.018; OS: HR=5.769, 95% CI 1.602- 20.771, P=0.007). CONCLUSION: Our research showed for the first time that the clinical characteristics and survival of MM patients <= 40 years old in China were different from that in western countries. The special attention should be paid to the patients with their diagnosis and treatment. PMID- 26632467 TI - [Effect of angular pyranocoumarin isolated from peucedanum praeruptorum on the proliferation and apoptosis of U266 cells]. AB - OBJECTIVE: To investigate the effects of angular pyranocoumarin (+/-) -4'-O- acetyl-3'-Oangeloyl- cis- khellactone (APC) extracted from peucedanum praeruptoruon on the proliferation and apoptosis of U266 cells, and to explore its related mechanism. METHODS: APC was extracted by petroleum ether technique, and its purity was tested by high performance liquid chromatography, and its chemical structure was identified by magnetic resonance spectroscopy. U266 cells were treated with APC in various concentrations (0, 10, 20, 30, 40 MUg/ml)for different durations(24 and 48 h). The inhibitive effect of APC on cell growth was detected by CCK-8 method. After U266 cells were incubated with APC(0, 10, 20, 30, 40 MUg/ml)for 24 h, the apoptosis of cells were observed by flow cytometry stained with Annexin V/PI and Hochest33342; the expression levels of caspase-3, 8, ERK, p-ERK, AKT and p-AKT protein were assayed by Western blot; the expression of hTERT mRNA was measured by RT-PCR. RESULTS: The purity of APC identified by magnetic resonance imaging was 98.8%. The proliferation of U266 cells was inhibited, and the apoptosis was induced in a time- and/or dose- dependent manner after treatment with APC. APC could upregulate the caspase- 8, 3 protein expression and downregulate the p- ERK, p-AKT protein expression along with the increase of APC dose. APC also could downregulate the hTERT mRNA expression. CONCLUSION: Angular pyranocoumarin APC could inhibit the proliferation and induce the apoptosis of U266 cells. The probable mechanism might be achieved by upregulating caspase-8, 3 protein expression and downregulating p-ERK, P-AKT protein and the hTERT mRNA expression. PMID- 26632468 TI - [Long- term outcome of thalidomide and cyclosporine in patients with IPSS low/intermediate- 1 myelodysplastic syndromes]. AB - OBJECTIVE: To investigate the long- term outcome of cyclosporin A (CsA) combined with thalidomide regime for Chinese patients with IPSS low/intermediate- 1 myelodysplastic syndromes (MDS) without del(5q)and the predictive variables which could impact the response to the therapy. METHODS: Seventy-six MDS patients who were treated with these drugs at a single institute in China were retrospectively analyzed. The polymorphism of cereblon gene, rs1672753, was detected in patients of this cohort by PCR and direct sequencing. RESULTS: A total of 53% of patients showed hematological improvement(HI)to the therapy. Thirty-one patients(31/73, 43%)achieved erythrocyte response(HI-E); 15 patients(15/50, 30%)achieved neutrophil response(HI-N); 18 patients(18/58, 31%)achieved platelet response(HI P). Twenty-seven of the 50 patients(46%)who were dependent on red blood cell transfusion achieved HI- E and became independent of transfusion. The median duration of response among the responders was 22 months (range, 1- 131 + months). Bone marrow blasts <=2% was the only factor associated with longer response duration in univariate analysis (P=0.010). There was no significant difference between the two groups of celeblon gene rs1672753 polymorphism either on the response rate or the response duration. The median survival of 67 patients without stem cell transplantation was 82 months. In multivariate analyses, factors significantly correlated with survival were IPSS-R(HR=3.461, 95%CI 1.126 10.639, P=0.030), age >= 60 y(HR=4.120, 95%CI 1.070-15.867, P=0.040)and HI N(HR=7.733, 95%CI 1.007-59.396, P=0.049). CONCLUSION: CsA combined with thalidomide regime could improve the anemia symptom in low/int-1 risk MDS patients without del(5q). The predictive value of cereblon gene polymorphism, rs1672753, could not be verified in this study. PMID- 26632469 TI - [The expression and role of the transcription factor C/EBPalpha in chronic myeloid leukemia]. AB - OBJECTIVE: To investigate the expression and the possible mechanism of the transcription factor C/EBPalpha in chronic myeloid leukemia(CML). METHODS: Bone marrow samples from 50 CML patients(including 33 patients in chronic phase, 7 in accelerated phase and 10 in blast crisis)and peripheral blood specimens of 20 healthy donors were collected. The expression of C/EBPalpha gene and the effect of Imatinib on its expression was detected by RT- PCR. C/EBPalpha gene was inserted into lentivirus expression vector pLVX- EGFP- 3FLAG- Puro by recombinant DNA technology to construct C/EBPalpha stable expression in K562 cells. Cell proliferation was assayed by CCK-8. The expressions of Foxo3a and Bim genes were detected by RT-PCR. RESULTS: The level of C/EBPalpha expression was significantly declined in CML patients compared with that of normal control group(P<0.01)and had negative correlation with bcr- abl expression(Spearman r=- 0.505, P<0.01). The stable K562- C/EBPalpha cell line was successfully established and confirmed by RT-PCR and Western blot. Cell proliferation ability was lower in the K562- C/EBPalpha group than that in the non- transfection and mock-vehicle groups. The expressions of Foxo3a and Bim genes were 1.06 +/- 0.06 and 0.53 +/- 0.07, respectively, which was higher than that of nontransfection and mock-vehicle groups(P<0.01, P<0.05). CONCLUSION: C/EBPalpha expression was decreased in CML patients, overexpression of C/EBPalpha could inhibit K562 cell growth. PMID- 26632470 TI - [CD4- CD8- TCRgammadelta+T cell large granular lymphocyte leukemia associated with beta- thalassemia minor: one case report and literature review]. PMID- 26632471 TI - [Cinobufagin treatment of relapsed or refractory hematological malignant tumor: 8 cases report and literatures review]. PMID- 26632472 TI - [Extramedullary plasmacytoma presented with multiple pulmonary plasmacytoma as first manifestation: a case report and literature review]. PMID- 26632473 TI - [The first tumor relapse after allogeneic hematopoietic stem cell transplantation in a therapy- related acute myeloid leukemia patient: a case report and literature review]. PMID- 26632474 TI - [Clinical efficacy observation of allogeneic hematopoietic stem cell transplantation in 16 patients with mixed phenotype acute leukemia]. PMID- 26632475 TI - [Development of immunodeficient mice/humanized mouse models and their applications in hematology research]. PMID- 26632476 TI - [Progress of bendamustine in the treatment of B cell non-Hodgkin lymphoma]. PMID- 26632477 TI - [Hepcidin for iron homeostasis and target therapy in ironrelated disorders]. PMID- 26632478 TI - [Report on treatment progresses of diffuse large B cell lymphoma in the 13th International Conference on Malignant Lymphoma]. PMID- 26632479 TI - 2015 - a seminal year for HIV biomedical prevention. PMID- 26632480 TI - Has the world ceased to care about HIV? And what can we do about it? PMID- 26632481 TI - [Gelatinous transformation of the bone marrow: A retrospective monocentric case series of 12 patients]. AB - PURPOSE: Gelatinous bone marrow transformation is a rare complication of unknown pathogenesis related to several underlying diseases. It is described as a focal loss of hematopoietic cells and a deposition of eosinophilic gelatinous substance rich in hyaluronic acid. We report a retrospective monocentric study followed by a literature review. METHODS: We have identified 12 patients with gelatinous transformation from 1999 to 2014. Clinical, biological and cytological data were collected. RESULTS: A bone marrow aspirate was performed for mild to severe pancytopenia (50%), less frequently for monocytopenia. Mean haemoglobin was 10.4g/dL, platelets 126.9G/L and leucocytes 3.82G/L. Gelatinous transformation was found in all patients. We have identified three hematologic malignancies, three cancers, three severe infections, two anorexia nervosa and one kidney injury. Ten patients had undernutrition, 9 out of the 12 patients died within a year due to advanced underlying disease and comorbidities. CONCLUSION: Gelatinous bone marrow transformation is found in various situations of severe undernutrition including anorexia nervosa, advanced cancers or severe sepsis, especially in HIV infection. The deposition of hyaluronic acid probably reduces haematopoiesis. Due to a complex inflammatory process, it alters the hematopoietic microenvironment and the bone marrow stroma. Severe undernutrition and other mechanisms are reviewed in this study. Gelatinous degeneration is still a rare disorder, indicative of an advanced underlying disease; its recognition could help guide investigations. PMID- 26632482 TI - [Appropriateness of the prescriptions of conventional versus new oral anticoagulants at discharge from a department of internal medicine]. AB - BACKGROUND: The recently introduced oral direct anticoagulants (ODAs), presumably safer, and with comparable efficacy to the vitamin K antagonists (VKAs), may reshape the world of anticoagulation medicine. This study aimed to assess the prescription appropriateness of ODAs and VKAs at discharge from hospital. METHODS: We performed a one year retrospective study between August 2012 and July 2013 in the department of internal medicine of a regional hospital (HVs Sion) using Electronic Medical Records. All patients receiving an ODA were included and matched to a patient treated with a VKA. The appropriateness of prescription at discharge was defined by an adequate indication and dosing, the absence of contraindication, a minimal risk of drug-drug interactions and no major bleeding or venous thromboembolism during the hospitalization. The bleeding risk was evaluated with the HAS-BLED score when the indication was atrial fibrillation (AF). RESULTS: Out of the 44patients included (22 with an ODA and 22 with a VKA), 38 received an appropriate prescription according to all criteria. Two patients had an inadequate dosing. A potential drug-drug interaction was detected in 3patients receiving a VKA and in 1patient receiving an ODA. No major contraindication was found, but a relative contraindication was discussed in 3cases. The majority of patients receiving an ODA for an AF had a minor bleeding risk. CONCLUSION: No significant difference was ascertained between the two groups regarding the appropriateness of prescription. Our results suggest that ODAs were cautiously used in our setting. PMID- 26632483 TI - Midwifery education in Central-Eastern Europe. AB - Problems in midwifery in many Central-Eastern European countries are very similar; it is possible to speak about the evolving Central-Eastern model of midwifery care. The educational models of this region have a relatively strong theoretical part; however, there is an insufficient practical dimension. Theoretical part of midwifery education in the universities is relatively autonomous and is slowly changing the professional identity of graduates. PMID- 26632484 TI - Palladium-catalyzed enolate arylation as a key C-C bond-forming reaction for the synthesis of isoquinolines. AB - The palladium-catalyzed coupling of an enolate with an ortho-functionalized aryl halide (an alpha-arylation) furnishes a protected 1,5-dicarbonyl moiety that can be cyclized to an isoquinoline with a source of ammonia. This fully regioselective synthetic route tolerates a wide range of substituents, including those that give rise to the traditionally difficult to access electron-deficient isoquinoline skeletons. These two synthetic operations can be combined to give a three-component, one-pot isoquinoline synthesis. Alternatively, cyclization of the intermediates with hydroxylamine hydrochloride engenders direct access to isoquinoline N-oxides; and cyclization with methylamine, gives isoquinolinium salts. Significant diversity is available in the substituents at the C4 position in four-component, one-pot couplings, by either trapping the in situ intermediate after alpha-arylation with carbon or heteroatom-based electrophiles, or by performing an alpha,alpha-heterodiarylation to install aryl groups at this position. The alpha-arylation of nitrile and ester enolates gives access to 3 amino and 3-hydroxyisoquinolines and the alpha-arylation of tert-butyl cyanoacetate followed by electrophile trapping, decarboxylation and cyclization, C4-functionalized 3-aminoisoquinolines. An oxime directing group can be used to direct a C-H functionalization/bromination, which allows monofunctionalized rather than difunctionalized aryl precursors to be brought through this synthetic route. PMID- 26632485 TI - Incidental 99mTc MDP uptake in the intestines and intravenous CT contrast. AB - AIM: We evaluated the association between intestinal visualization on bone scintigraphy and IV CT contrast in patients with breast cancer. PATIENTS, METHODS: 452 patients with breast cancer underwent a 99mTc methylene diphosphonate (MDP) bone scan for surveillance of bone metastasis. Presence, site and intensity of intestinal uptake were visually assessed. For patients with intestinal visualization, medical records were reviewed to identify the alleged potential causes. When IV CT contrast was administrated on the same day as bone scan, the time between IV CT contrast injection, 99mTc MDP administration and bone scan was assessed. RESULTS: Intestinal 99mTc MDP uptake was observed in 44 of the 452 patients (9.7%). Bone scans showed no thyroid or gastric uptake that suggested free pertechnetate. There were no patients with documented causes of intestinal uptake except for one patient with vesicoenteric fistula. Of the 452 patients, 149 (33.0%) underwent IV contrast-enhanced CT on the same day as bone scan. Forty of the 44 patients (90.9%) with intestinal uptake on bone scan underwent IV contrast-enhanced CT on the same day, whereas 109 of 408 (26.7%) patients without intestinal uptake on bone scintigraphy underwent IV contrast enhanced CT on the same day (p < 0.001). The patients who underwent IV contrast injection between Tc-99m MDP administration and acquisition of bone scans had significantly more frequent intestinal uptake than patients who underwent IV contrast injection either before 99mTc MDP administration or after bone scanning (42.4% vs. 1.8%, p < 0.001). CONCLUSIONS: IV CT contrast injection administered on the same day as bone scintigraphy is significantly associated with 99mTc MDP uptake in the intestines among patients with breast cancer. PMID- 26632486 TI - Neutralisation of the anti-coagulant effects of heparin by histones in blood plasma and purified systems. AB - Neutrophil extracellular traps (NETs) composed primarily of DNA and histones are a link between infection, inflammation and coagulation. NETs promote coagulation and approaches to destabilise NETs have been explored to reduce thrombosis and treat sepsis. Heparinoids bind histones and we report quantitative studies in plasma and purified systems to better understand physiological consequences. Unfractionated heparin (UFH) was investigated by activated partial thromboplastin time (APTT) and alongside low-molecular-weight heparins (LMWH) in purified systems with thrombin or factor Xa (FXa) and antithrombin (AT) to measure the sensitivity of UFH or LMWH to histones. A method was developed to assess the effectiveness of DNA and non-anticoagulant heparinoids as anti-histones. Histones effectively neutralised UFH, the IC50 value for neutralisation of 0.2 IU/ml UFH was 1.8 ug/ml histones in APTT and 4.6 ug/ml against 0.6 IU/ml UFH in a purified system. Histones also inhibited the activities of LMWHs with thrombin (IC50 6.1 and 11.0 ug/ml histones, for different LMWHs) or FXa (IC50 7.8 and 7.0 ug/ml histones). Direct interactions of UFH and LMWH with DNA and histones were explored by surface plasmon resonance, while rheology studies showed complex effects of histones, UFH and LMWH on clot resilience. A conclusion from these studies is that anticoagulation by UFH and LMWH will be compromised by high affinity binding to circulating histones even in the presence of DNA. A complete understanding of the effects of histones, DNA and heparins on the haemostatic system must include an appreciation of direct effects on fibrin and clot structure. PMID- 26632487 TI - Staphylococcal SSL5-induced platelet microparticles provoke proinflammatory responses via the CD40/TRAF6/NFkappaB signalling pathway in monocytes. AB - Pathogens-induced platelet activation contributes to inflammation in cardiovascular diseases, but underlying mechanisms remain elusive. Staphylococcal superantigen-like protein 5 (SSL5) is a known activator of platelets. Here we examined whether SSL5 is implicated in Staphylococcus aureus (S. aureus)-induced inflammation and potential mechanisms involved. As expected, we show that SSL5 activates human platelets and induces generation of platelet microparticles (PMPs). Flow cytometry and scanning electron microscopy studies demonstrate that SSL5-induced PMPs (SSL5-PMPs) bind to monocytes, causing aggregate formation. In addition, SSL5-PMPs provoke monocyte expression and release of inflammatory mediators, including interleukin-1beta (IL-1beta), tumour necrosis factor-alpha (TNFalpha), monocyte chemoattractant protein-1 (MCP-1) and matrix metalloproteinase-9 (MMP-9) in a dose- and time-dependent manner. SSL5-PMPs also enhance MCP-1-induced monocyte migration. Blockade of CD40 and CD40 ligand (CD40L) interactions with neutralising antibodies significantly reduce monocyte release of inflammatory mediators and migration induced by SSL5-PMPs. SiRNA mediated silencing of CD40 or TNF receptor (TNFR)-associated factor 6 (TRAF6) gene largely abrogates phosphorylation and nuclear translocation of NFkappaB (p65). In conclusion, SSL5 provokes the release of inflammatory mediators in monocytes, at least in part, via PMPs-mediated activation of the CD40/TRAF6/NFkappaB signalling pathway, though it normally inhibits leukocyte function. Our findings thus reveal a novel mechanism by which S. aureus induces inflammation. PMID- 26632488 TI - Comparative evaluation of Nabi and Beltsville extenders for cryopreservation of rooster semen. AB - Two experiments were conducted to evaluate the new rooster semen freezing extender which is containing a low level of glycerol and soybean lecithin as an alternative protective agent in the extender. The aim of the first experiment was to evaluate a new extender for freeze-thawing rooster semen known as "Nabi" extender compared to Beltsville. Second experiment was also performed to determine whether the Nabi extender has negative reactions on fertilization after artificial insemination (AI) or no. In the first experiment, post-thaw motion parameters, mitochondrial function and sperm apoptosis were analyzed using Sperm Class Analyzer (SCA), rhodamine-123 and Annexin-V, respectively for frozen-thawed semen in Nabi and Beltsville extender. Results showed that total motility, progressive motility, velocity parameters (VCL, VSL, VAP, LIN and STR) and live spermatozoa with active mitochondria were significantly higher in Nabi compare to Beltsville extender (P < 0.01). Also, the percentages of post-thawed live and early apoptotic spermatozoa were significantly higher in Nabi compared to Beltsville extender (14.46 +/- 0.95 vs. 19.27 +/- 0.95 and 14.83 +/- 4.51 vs. 39.27 +/- 4.51, respectively). For apoptotic spermatozoa, the percentages of post thawed late apoptotic spermatozoa were significantly lower in Nabi (29.66 +/- 3.11) compared to Beltsville extender (69.07 +/- 3.11), but the type of extender had no effect on the percentages of post-thawed necrotic spermatozoa. In the second experiment, 20 broiler breeder hens (Ross 308) were inseminated with thawed semen using the new freezing diluents or fresh semen for determination of fertility rate. Fertility rate with thawed semen (with Nabi extender) was lower compared to fresh semen (by approximately 8% points). It can be concluded that Nabi extender would improve post-thawed rooster sperm in vitro quality compared to Beltsville extender. The fertility rates of insemination in hens with freeze thaw sperm were comparable with fresh sperm. PMID- 26632489 TI - Genome editing in sea urchin embryos by using a CRISPR/Cas9 system. AB - Sea urchin embryos are a useful model system for investigating early developmental processes and the underlying gene regulatory networks. Most functional studies using sea urchin embryos rely on antisense morpholino oligonucleotides to knockdown gene functions. However, major concerns related to this technique include off-target effects, variations in morpholino efficiency, and potential morpholino toxicity; furthermore, such problems are difficult to discern. Recent advances in genome editing technologies have introduced the prospect of not only generating sequence-specific knockouts, but also providing genome-engineering applications. Two genome editing tools, zinc-finger nuclease (ZFN) and transcription activator-like effector nucleases (TALENs), have been utilized in sea urchin embryos, but the resulting efficiencies are far from satisfactory. The CRISPR (clustered regularly interspaced short palindromic repeat)-Cas9 (CRISPR-associated nuclease 9) system serves as an easy and efficient method with which to edit the genomes of several established and emerging model organisms in the field of developmental biology. Here, we apply the CRISPR/Cas9 system to the sea urchin embryo. We designed six guide RNAs (gRNAs) against the well-studied nodal gene and discovered that five of the gRNAs induced the expected phenotype in 60-80% of the injected embryos. In addition, we developed a simple method for isolating genomic DNA from individual embryos, enabling phenotype to be precisely linked to genotype, and revealed that the mutation rates were 67-100% among the sequenced clones. Of the two potential off target sites we examined, no off-target effects were observed. The detailed procedures described herein promise to accelerate the usage of CRISPR/Cas9 system for genome editing in sea urchin embryos. PMID- 26632491 TI - The association between initial manifestations of childhood-onset systemic lupus erythematosus and the survival. AB - INTRODUCTION: Childhood-onset systemic lupus erythematosus (cSLE) comprises 15 20% of patients with SLE. Although several studies have reported the outcomes of adult-onset SLE, few investigations have been conducted on cSLE in the Middle East. METHODS: In a retrospective study, all children with SLE admitted to our tertiary referral center between 1992 and 2011 were recruited. The clinical and laboratory data at the time of onset were recorded and analyzed. Kaplan-Meier analysis was used to calculate the survival rates. Cox regression analysis was applied to assess the predictors of mortality. RESULTS: One hundred and eighty eight children diagnosed with SLE were enrolled during the study period. Nine patients were censored due to loss to follow-up (6) and incomplete data (3 cases). Mean age of patients at the time of onset was 14.4 (3.05) years. Only 22 (11.8%) children were younger than 10 years at the time of disease onset. In total, 20 patients (11%) died, all after the first decade of life. The most common cause of death was lupus nephritis (10 patients, 50% of deaths) followed by infections (35%), cerebrovascular accidents (10%) and alveolar hemorrhage (5%). Cumulative survival rate after 5, 10, 15 and 20 years was 91, 87, 85, and 79%, respectively. Having hematuria or pleurisy at the time of SLE onset had a negative effect on survival in multivariate analysis. CONCLUSION: cSLE survival in Iran was comparable to that in other developing countries. Baseline presentation with hematuria predominantly increased the mortality rate in cSLE. Prospective and larger studies in future may unfold other aspects of cSLE. PMID- 26632490 TI - A three-dimensional study of alveologenesis in mouse lung. AB - Alveologenesis is the final step of lung maturation, which subdivides the alveolar region of the lung into smaller units called alveoli. Each of the nascent dividers serves as a new gas-exchange surface, and collectively they drastically increase the surface area for breathing. Disruption of alveologenesis results in simplification of alveoli, as is seen in premature infants diagnosed with bronchopulmonary dysplasia (BPD), a prevalent lung disease that is often associated with lifelong breathing deficiencies. To date, a majority of studies of alveologenesis rely on two-dimensional (2D) analysis of tissue sections. Given that an overarching theme of alveologenesis is thinning and extension of the epithelium and mesenchyme to facilitate gas exchange, often only a small portion of a cell or a cellular structure is represented in a single 2D plane. Here, we use a three-dimensional (3D) approach to examine the structural architecture and cellular composition of myofibroblasts, alveolar type 2 cells, elastin and lipid droplets in normal as well as BPD-like mouse lung. We found that 2D finger-like septal crests, commonly used to depict growing alveolar septae, are often artifacts of sectioning through fully established alveolar walls. Instead, a more accurate representation of growing septae are 3D ridges that are lined by platelet-derived growth factor receptor alpha (PDGFRA) and alpha smooth muscle actin (alpha-SMA)-expressing myofibroblasts, as well as the elastin fibers that they produce. Accordingly in 3D, both alpha-SMA and elastin were each found in connected networks underlying the 3D septal ridges rather than as isolated dots at the tip of 2D septal crests. Analysis through representative stages of alveologenesis revealed unappreciated dynamic changes in these patterns. PDGFRA expressing cells are only alpha-SMA-positive during the first phase of alveologenesis, but not in the second phase, suggesting that the two phases of septae formation may be driven by distinct mechanisms. Thin elastin fibers are already present in the alveolar region prior to alveologenesis, suggesting that during alveologenesis, there is not only new elastin deposition, but also extensive remodeling to transform thin and uniformly distributed fibers into thick cables that rim the nascent septae. Analysis of several genetic as well as hyperoxia-induced models of BPD revealed that the myofibroblast organization is perturbed in all, regardless of whether the origin of defect is epithelial, mesenchymal, endothelial or environmental. Finally, analysis of relative position of PDGFRA-positive cells and alveolar type 2 cells reveal that during alveologenesis, these two cell types are not always adjacent to one another. This result suggests that the niche and progenitor relationship afforded by their close juxtaposition in the adult lung may be a later acquired property. These insights revealed by 3D reconstruction of the septae set the foundation for future investigations of the mechanisms driving normal alveologenesis, as well as causes of alveolar simplification in BPD. PMID- 26632493 TI - Fatty acids, eicosanoids and PPAR gamma. AB - Peroxisome proliferator-activated receptor gamma (PPARgamma) belongs to the family of nuclear nuclear receptors and is mainly expressed in adipose tissue, hematopoietic cells and the large intestine. Contrary to other nuclear receptors that mainly bind a single specific ligand, there are numerous natural PPARgamma ligands, in particular fatty acids or their derivatives called eicosanoids. PPARgamma have pleiotropic functions: (i) glucose and lipid metabolism regulation, (ii) anti-inflammatory properties, (iii) oxidative stress inhibition, (iv) improvement of endothelial function. Its role has been mainly studied by the use synthetic agonists. In this review, we will focus on the effects of PPARgamma mediated through fatty acids and how these have beneficial health properties. PMID- 26632492 TI - Complement C5a inhibition improves late hemodynamic and inflammatory changes in a rat model of nonocclusive mesenteric ischemia. AB - BACKGROUND: Nonocclusive mesenteric ischemia (NOMI) can evolve in a variety of low-flow states. Although the mechanisms leading to NOMI-related intestinal necrosis are largely unknown, circumstantial evidence suggests that excessive vasoconstriction and complement activation both play important roles in this process. Because targeting of the circulatory malfunction of the splanchnic area could be of therapeutic relevance, we set out to investigate the long-term effects of treatment with a complement C5a antagonist in a rat model of partial aortic occlusion (PAO)-induced transient mesenteric hypoperfusion. METHODS: The mean arterial pressure of the splanchnic area was kept between 30 and 40 mm Hg by 60 minutes of PAO in anesthetized male Sprague-Dawley rats. C5a inhibitor acetyl peptide-A (AcPepA; 4 mg kg(-1) intravenously) or vehicle administration was initiated at the 45th minute of PAO. After 24 hours, the animals were reanesthetized to record the macrohemodynamics and ileal microcirculation, and plasma and tissue samples were taken for determination of high-mobility group box protein-1 (HMGB-1), endothelin-1, tumor necrosis factor (TNF)-alpha levels, and small intestinal leukocyte infiltration. Epithelial structural changes were visualized by in vivo confocal laser scanning endomicroscopy. RESULTS: At 24 hours after PAO, mean arterial pressure, heart rate, and cardiac output were significantly greater, the intestinal intramural microcirculation was significantly impaired, and plasma HMGB-1, endothelin-1, TNF-alpha levels, the degree of epithelial damage and leukocyte infiltration was increased. The AcPepA treatment moderated the hemodynamic and microcirculatory changes, and decreased inflammatory activation and histologic signs of mucosal damage. CONCLUSION: C5a inhibition ameliorated the potentially harmful local mesenteric hypoperfusion and global long-term inflammatory consequences of PAO. This approach is of promise for use in NOMI-associated situations. PMID- 26632494 TI - Coombs negative hemolytic anemia with Rheumatoid arthritis - a rare association. PMID- 26632495 TI - Boundedness of the solutions for certain classes of fractional differential equations with application to adaptive systems. AB - This paper presents the analysis of three classes of fractional differential equations appearing in the field of fractional adaptive systems, for the case when the fractional order is in the interval alpha ?(0,1] and the Caputo definition for fractional derivatives is used. The boundedness of the solutions is proved for all three cases, and the convergence to zero of the mean value of one of the variables is also proved. Applications of the obtained results to fractional adaptive schemes in the context of identification and control problems are presented at the end of the paper, including numerical simulations which support the analytical results. PMID- 26632496 TI - Systematic microcarrier screening and agitated culture conditions improves human mesenchymal stem cell yield in bioreactors. AB - Production of human mesenchymal stem cells for allogeneic cell therapies requires scalable, cost-effective manufacturing processes. Microcarriers enable the culture of anchorage-dependent cells in stirred-tank bioreactors. However, no robust, transferable methodology for microcarrier selection exists, with studies providing little or no reason explaining why a microcarrier was employed. We systematically evaluated 13 microcarriers for human bone marrow-derived MSC (hBM MSCs) expansion from three donors to establish a reproducible and transferable methodology for microcarrier selection. Monolayer studies demonstrated input cell line variability with respect to growth kinetics and metabolite flux. HBM-MSC1 underwent more cumulative population doublings over three passages in comparison to hBM-MSC2 and hBM-MSC3. In 100 mL spinner flasks, agitated conditions were significantly better than static conditions, irrespective of donor, and relative microcarrier performance was identical where the same microcarriers outperformed others with respect to growth kinetics and metabolite flux. Relative growth kinetics between donor cells on the microcarriers were the same as the monolayer study. Plastic microcarriers were selected as the optimal microcarrier for hBM MSC expansion. HBM-MSCs were successfully harvested and characterised, demonstrating hBM-MSC immunophenotype and differentiation capacity. This approach provides a systematic method for microcarrier selection, and the findings identify potentially significant bioprocessing implications for microcarrier based allogeneic cell therapy manufacture. PMID- 26632498 TI - The effect of induced hypertension on neurological outcome in forebrain ischaemia model in rats. AB - INTRODUCTION: The present study investigated the effects of induced hypertension on hippocampal cell death after forebrain ischaemia in rats. MATERIALS AND METHODS: In this study, forebrain ischaemia was induced in 20 Sprague-Dawley rats by clamping the bilateral common carotid arteries to induce systemic hypotension for 8min. All rats then underwent reperfusion during which the induced hypertension group (n=10) received intermittent intravenous injections of phenylephrine (5MUg) to maintain their mean arterial blood pressure at 20mmHg above baseline for 10min and the control group (n=10) did not receive any treatment. In both groups, the numbers of viable and apoptotic neuronal cells in the cornu ammonis 1 (CA1) area of the hippocampus were evaluated 7 days after the induction of ischaemia. RESULTS: The mean percentage of viable neuronal cells was higher in the induced hypertension group than in the control group (35% vs. 26%, respectively; p=0.004), but there was no significant difference in the proportion of apoptotic neuronal cells between the groups (57% vs. 43%, respectively; p=0.165). CONCLUSIONS: Induced hypertension significantly attenuated necrotic cell death in the hippocampal CA1 area, but apoptotic cell death was not affected. PMID- 26632499 TI - Medium to long term follow up of a consecutive series of 604 Exeter Trauma Stem Hemiarthroplasties (ETS) for the treatment of displaced intracapsular femoral neck fractures. AB - The aim of this study was to evaluate the medium to long term follow up results for the Exeter Trauma Stem (ETS) in the treatment of displaced femoral neck fractures. We retrospectively evaluated 604 consecutive cemented ETS hemiarthroplasties performed at our institution between 2007 and 2012. The range of follow up was 2-7 years with a mean follow-up of 4.1 years for the surviving patients. The mean age of the patient population was 84 years (range 46-106) with 81.3% female patients. 382 patients (63.2%) died within the follow up period. Postoperative superficial soft tissue infection occurred in 11 patients and deep prosthetic infection in 5 patients. Dislocation occurred in 11 patients and periprosthetic fracture occurred in 7 patients. 11 patients underwent Girdlestone excision arthroplasty and 6 patients were revised to total hip replacement. This paper represents the largest consecutive series for this implant, with the longest follow up currently available. The results confirm that the prosthesis is an excellent implant for these patients with a low risk of needing revision surgery. PMID- 26632497 TI - Aberrant protein trafficking in retinal degenerations: The initial phase of retinal remodeling. AB - Retinal trafficking proteins are involved in molecular assemblies that govern protein transport, orchestrate cellular events involved in cilia formation, regulate signal transduction, autophagy and endocytic trafficking, all of which if not properly controlled initiate retinal degeneration. Improper function and or trafficking of these proteins and molecular networks they are involved in cause a detrimental cascade of neural retinal remodeling due to cell death, resulting as devastating blinding diseases. A universal finding in retinal degenerative diseases is the profound detection of retinal remodeling, occurring as a phased modification of neural retinal function and structure, which begins at the molecular level. Retinal remodeling instigated by aberrant trafficking of proteins encompasses many forms of retinal degenerations, such as the diverse forms of retinitis pigmentosa (RP) and disorders that resemble RP through mutations in the rhodopsin gene, retinal ciliopathies, and some forms of glaucoma and age-related macular degeneration (AMD). As a large majority of genes associated with these different retinopathies are overlapping, it is imperative to understand their underlying molecular mechanisms. This review will discuss some of the most recent discoveries in vertebrate retinal remodeling and retinal degenerations caused by protein mistrafficking. PMID- 26632500 TI - Is AC TightRope fixation better than Bosworth screw fixation for minimally invasive operative treatment of Rockwood III AC joint injury? AB - INTRODUCTION: Injuries to the acromioclavicular (AC) joint are common in sports participants and may lead to instability or degenerative changes that require surgical intervention. Diagnostics include X-ray projections; MRI could also be a useful method. Surgical treatment of acute Rockwood type III AC dislocation varies on a case-by-case basis and includes coracoclavicular (CC) stabilisation with two techniques of minimal invasive fixation: the Bosworth screw and AC TightRope fixation (Arthrex, US). The aim of this study was to analyse whether there is a difference between these two surgical procedures in the quality of repair of CC ligaments by comparing preoperative and postoperative AC joint radiological and clinical findings. PATIENTS AND METHODS: In this study, we evaluated our 5 years' experience of surgical management of Rockwood type III AC dislocation. Radiological analyses included measurement of CC distance at the AC joint, X-ray and MRI evaluation of CC ligament scar tissue continuity; clinical outcome was assessed using the Constant Murley, Oxford Shoulder and DASH scores preoperatively and during 6 months of postoperative follow-up. RESULTS: A total of 68 patients with Rockwood type III AC dislocation were treated surgically with minimally invasive CC fixation using either the AC TightRope implant (34 patients, TR group) or the Bosworth screw (34 patients, BS group) in a prospective, randomised clinical trial. There was no statistically significant difference in radiological X-ray and MRI evaluations of postoperative results between the two groups of patients at the end of follow-up. Patients in the TR group reported significantly less inconvenience with treatment as the patients in the BS group had to undergo a second operation to remove the Bosworth screw. Postoperative recurrence of dislocation was observed in two patients in the TR group (5.88%) and in four patients in the BS group (11.76%) 6 months postoperatively. The difference between the two groups was not statistically significant (p=0.4). CONCLUSION: MRI could be a useful method to evaluate quality of repair of CC ligaments. The minimally invasive surgical techniques used in this study showed similar radiological and clinical efficacy in the treatment of acute Rockwood type III AC dislocation, but AC TightRope fixation provided patients with significantly more treatment satisfaction and less inconvenience than Bosworth screw fixation. PMID- 26632501 TI - Ubiquitous Chromatin Opening Elements (UCOEs) effect on transgene position and expression stability in CHO cells following methotrexate (MTX) amplification. AB - The requirement for complex therapeutic proteins has resulted in mammalian cells, especially CHO cells, being the dominant host for recombinant protein manufacturing. In creating recombinant CHO cell lines, the expression vectors integrate into various parts of the genome leading to variable levels of expression and stability of protein production. This makes mammalian cell line development a long and laborious process. Therefore, with the intention to accelerate process development of recombinant protein production in CHO systems, UCOEs are utilized to diminish instability of production by maintaining an open chromatin surrounding in combination with MTX amplification. Chromosome painting and FISH analysis were performed to provide detailed molecular evaluation on the location of amplified genes and its relationship to the productivity and stability of the amplified cell lines. In summary, cell lines generated with vectors containing UCOEs retained stable GFP expression with MTX present (but instability was observed in the absence of MTX). UCOE cell lines displayed a higher frequency of integration into >1 chromosome than non-UCOE group. Cell populations were more homogenous in terms of transgene location at the end of Long-term culture (LTC). Overall our findings suggest variation in eGFP fluorescence may be attributed to changes in transgene integration profile over LTC. PMID- 26632502 TI - Implant rates of cardiac implantable electrical devices in Europe: A systematic literature review. AB - BACKGROUND: In recent years, indications for cardiac implantable electrical devices (CIEDs) have broadened; however, budget constraints can significantly impact patient access to these life-saving health technologies. OBJECTIVE: To perform a systematic literature review on the implant rates of pacemakers, cardioverter-defibrillators, and cardiac resynchronization therapy devices in Europe over the last decade to provide insight into the possible reasons for differences across regions or countries. METHODS: Four electronic databases were searched to find studies describing CIED implant rates in Europe. Fifty-eight studies were included. RESULTS: An overview showed a recent rise in CIED implants, with large geographic differences. The ratio between the regions with the highest and lowest implant rates within the same country ranged between 1.3 and 3.4 for pacemakers and between 1.7 and 44.0 for defibrillators. The ratio between the countries with the highest and lowest implant rates ranged between 2.3 and 87.5 for pacemakers, between 3.1 and 1548.0 for defibrillators, and between 4.1 and 221.0 for resynchronization therapy devices. Implant rate variability appears to be influenced by health care, economic, demographic, and cultural factors. CONCLUSION: Publications on CIED implant rates in Europe show a wide variability within and across countries, the determinants of which are only partially investigated. Policy making should improve regarding equity of access to better care. PMID- 26632504 TI - Ultrastructural and morphological changes in Leishmania (Viannia) braziliensis treated with synthetic chalcones. AB - Cutaneous leishmaniasis has an estimated incidence of 1.5 million new cases per year and the treatment options available are old, expensive, toxic, and difficult to administer. Chalcones have shown good activity against several species of Leishmania. However few studies have discussed the mechanisms of action and drug target of this group of compounds in Leishmania. The synthetic chalcones that were evaluated in the present study were previously shown to exhibit activity against Leishmania (Viannia) braziliensis. The objective of the present study was to identify ultrastructural and morphological changes in L. (V.) braziliensis after treatment with three synthetic chalcones (1-3). Promastigotes were treated with chalcones 1-3 and evaluated by transmission and scanning electron microscopy. Cellular and nuclear morphology of the parasites, changes in membrane permeability, and DNA fragmentation in agarose electrophoresis gel were also investigated after exposure to synthetic chalcones. All three synthetic chalcones (1-3) induced ultrastructural alterations in mitochondria, intense vacuolization, two nuclei with rounding of parasites, and cellular and nuclear shrinkage. Chalcones 1-3 also induced no changes in membrane permeability, and presence of nucleosome-sized DNA fragments. Synthetic chalcones 1-3 induced ultrastructural and morphological changes, suggesting that chalcones 1-3 induce apoptosis-like cell death. Further studies should be conducted to elucidate other aspects of the action of these chalcones against Leishmania spp. and their use for the treatment of cutaneous leishmaniasis. PMID- 26632503 TI - Adjuvant-enhanced antibody and cellular responses to inclusion bodies expressing FhSAP2 correlates with protection of mice to Fasciola hepatica. AB - Fasciola hepatica saposin-like protein-2 (FhSAP2) is a protein differentially expressed in various developmental stages of F. hepatica. Recombinant FhSAP2 has demonstrated the induction of partial protection in mice and rabbits when it is administered subcutaneously (SC) in Freund's adjuvant. Because FhSAP2 is overexpressed in bacteria in the form of inclusion bodies (IBs), we isolated IBs expressing FhSAP2 and tested their immunogenicity when administered SC in mice emulsified in two different adjuvants: QS-21 and Montanide TM ISA720. Animals received three injections containing 20 MUg of protein two weeks apart and 4 weeks after the third injection, mice were infected with 10 F. hepatica metacercariae by oral route. The percentages of protection induced by FhSAP2-IBs were estimated to be between 60.0 and 62.5% when compared with adjuvant vaccinated, infected controls. By determining the levels of IgG1 and IgG2a antibodies and IL-4 and IFNgamma cytokines in the serum of experimental animals, it was found that both Th1 and Th2 immune responses were significantly increased in the FhSAP2-IBs vaccinated groups compared with the adjuvant-vaccinated, infected control groups. The adjuvant-vaccinated groups had significantly lower IgG1 to IgG2a ratios and lower IL-4 to IFNgamma ratios than the FhSAP2-IBs vaccinated animals, which is indicative of higher levels of Th2 immune responses. Irrespective to the adjuvant used, animals vaccinated with FhSAP2-IBs exhibited significantly higher survival percentage and less liver damage than the adjuvant control groups. This study suggests that FhSAP2 has potential as vaccine against F. hepatica and that the protection elicited by this molecule could be linked to a mechanism driven by the CD4-Th1 cells. PMID- 26632505 TI - Effects of glucosamine sulfate on the use of rescue non-steroidal anti inflammatory drugs in knee osteoarthritis: Results from the Pharmaco-Epidemiology of GonArthroSis (PEGASus) study. AB - BACKGROUND AND OBJECTIVE: The use of Symptomatic Slow-Acting Drugs in Osteoarthritis (SYSADOAs) may be expected to decrease the use of concomitant medications for rescue analgesia, including non-steroidal anti-inflammatory drugs (NSAIDs). The Pharmaco-Epidemiology of GonArthroSis (PEGASus) study was designed to assess this possibility. METHODS: PEGASus was a cohort study of continuous recruitment of patients with "dynamic" exposure to the investigated SYSADOA (crystalline glucosamine sulfate, glucosamine hydrochloride, chondroitin sulfate, diacerein, and avocado-soybean unsaponifiables, all at approved dosages). Investigators were rheumatologists or general practitioners randomly selected from French telephone lists. Patients diagnosed with knee osteoarthritis (OA) were recruited when consulting an investigator for a symptom flare and were prescribed, or not, one of the SYSADOAs as per clinical judgment. Follow-up visits were as per routine medical practice in the 12 months following enrollment, with telephone interviews after 1 month and at 4-month intervals thereafter up to 24 months. Use of NSAIDs was recorded, as well as the dynamism of treatment exposure consisting of continuing the prescribed SYSADOA, switching, discontinuation or initiation of a SYSADOA. Patient exposure was expressed in 2 month time units, with any NSAID use as Yes/No binary outcome during each unit. Odds ratios [OR and 95% confidence interval (CI)] of NSAID use were calculated for periods of exposure to each SYSADOA, by multivariate logistic regression for an 80% power and 95% confidence to see a decrease of at least 15%. RESULTS: This report consists of the full data pertaining to crystalline glucosamine sulfate, while results of other SYSADOAs were summarized as available from the French Health Authority (HAS) website (www.has-sante.fr). Of 6451 patients in the PEGASus cohort, 315 patients received crystalline glucosamine sulfate, they were exposed for 481 2-month time units and had an incident use of NSAIDs of 18.7%. In the control cohort (9237 time units) NSAID incident use was 23.8%. Crystalline glucosamine sulfate significantly decreased the risk of NSAID consumption by up to 36% (OR = 0.64; 95% CI: 0.45-0.92) in the primary analysis foreseen by the protocol; OR was 0.74 (95% CI: 0.54-1.01), i.e. at the very limit of significance, in a sensitivity analysis accounting for an extension of the study and of the control cohort. None of the other SYSADOAs showed any hint of a decrease in the use of NSAIDs. CONCLUSION: Crystalline glucosamine sulfate was the only SYSADOA that decreased the use of NSAIDs in this pharmaco-epidemiology study in patients with knee OA. PMID- 26632506 TI - Direct and indirect costs and resource use in dementia care: A cross-sectional study in patients living at home. AB - BACKGROUND: Due to the high prevalence of dementia, health care needs are increasing beyond existing formal resources. In Spain, it is the family that takes care of this disease. AIMS: To analyze the direct (health and non-health) and indirect economic costs related to care of people with dementia living with their informal caregiver in the home care/community environment, from the perspective of illness severity, associated comorbidity and social impact. DESIGN: Multicentric, descriptive study. SETTING: Three primary care public health centers associated with Hospital Clinic, Barcelona (Spain). PARTICIPANTS: Patients over 65 years old with a diagnosis of dementia, and included in a home care program. INCLUSION CRITERIA: People with a diagnosis of dementia made by a specialist neurologist; aged 65 years or older; a score <= 24 on the Mini-Mental State Examination, and identification of an informal caregiver. EXCLUSION CRITERIA: Patients unable to identify an informal caregiver, and those with primary psychiatric pathology or Korsakoff's syndrome. MEASUREMENTS: Use of Resources in Dementia to assess costs; Mini-Mental State Examination to evaluate cognitive capacity; Katz-Index to measure functional capacity; Neuropsychiatric Index for neuropsychiatric symptoms, and the Charlson-Index for comorbidity. Data collection took place between November, 2010 and April, 2012. RESULTS: The average estimated monthly care costs for people with dementia in the home setting are 1956.2? (SD 1463.9). Informal care was the major contributor to this with a mean estimated cost of 1214.86 (SD 902.68)?/month. Greater illness severity, dependency in activities of daily living, comorbidity and behavioral disturbance are associated with higher costs. Behavioral disturbance appeared as the only factor independently associated with cost in dementia care. The group of people with dementia with severe behavioral disturbance requires the most care resources with an average cost of 2545.2 (SD 1753.2)?/month. CONCLUSIONS: There is a direct association between dementia severity and increased costs. In addition, informal caregivers looking after people with dementia in Spain represent an important social cost. The independent factor associated with an increase in the total costs of patient care was neuropsychiatric symptoms. PMID- 26632507 TI - Overcoming low yields of plant-made antibodies by a protein engineering approach. AB - The commercial development of plant-based antibody production platforms is often limited by low and variable yields, but little is known about the factors that affect antibody accumulation during and after translation. Here, we present a strategy to identify yield-limiting regions in the transcript and protein. We exchanged variable heavy chain (VH) domain sequences between two human antibodies at structurally conserved positions, thus creating ten chimeric VH domains containing sequences from M12 (~1000 MUg/g leaf fresh weight [FW]) and 4E10 (~100 MUg/g FW). After transient expression in Nicotiana benthamiana leaves, we measured mRNA and protein levels by quantitative real-time PCR and surface plasmon resonance spectroscopy, respectively. Transcript levels were similar for all constructs, but antibody levels ranged from ~250 MUg/g to over 2000 MUg/g FW. Analysis of the expression levels showed that: i) 4E10 yields were only marginally increased by suppression of post-transcriptional gene silencing; ii) the CDR3 of 4E10 contains a protease site; and iii) a bipartite, yield-limiting region exists in the CDR2/CDR3. Our findings highlight the strong impact of cotranslational and posttranslational events on antibody yields and show that protein engineering is a powerful tool that can be used to overcome the remaining limitations affecting antibody production in plants. PMID- 26632508 TI - Characterization and crystal structure determination of beta-1,2-mannobiose phosphorylase from Listeria innocua. AB - Glycoside hydrolase family 130 consists of phosphorylases and hydrolases for beta mannosides. Here, we characterized beta-1,2-mannobiose phosphorylase from Listeria innocua (Lin0857) and determined its crystal structures complexed with beta-1,2-linked mannooligosaccharides. beta-1,2-Mannotriose was bound in a U shape, interacting with a phosphate analog at both ends. Lin0857 has a unique dimer structure connected by a loop, and a significant open-close loop displacement was observed for substrate entry. A long loop, which is exclusively present in Lin0857, covers the active site to limit the pocket size. A structural basis for substrate recognition and phosphorolysis was provided. PMID- 26632509 TI - Role of cytosolic and calcium independent phospholipases A(2) in insulin secretion impairment of INS-1E cells infected by S. aureus. AB - Cytosolic PLA2 (cPLA2) and Ca(2+)-independent PLA2 (iPLA2) play a significant role in insulin beta-cells secretion. Bacterial infections may be responsible of the onset of diabetes. The mechanism by which Staphylococcus aureus infection of INS-1 cells alters glucose-induced insulin secretion has been examined. After acute infection, insulin secretion and PLA2 activities significantly increased. Moreover, increased expressions of phospho-cPLA2, phospho-PKCalpha and phospho ERK 1/2 were observed. Chronic infection causes a decrease in insulin release and a significant increase of iPLA2 and COX-2 protein expression. Moreover, insulin secretion in infected cells could be restored using specific siRNAs against iPLA2 isoform and specific COX-2 inhibitor. PMID- 26632510 TI - Commitment of Annexin A2 in recruitment of microRNAs into extracellular vesicles. AB - Extracellular vesicles (EVs) contain microRNAs (miRNAs). However, the exact molecular mechanisms of the recruitment of miRNAs in EVs are not well characterized. Based on proteomic analysis, we identified that silencing of Annexin A2 (ANXA2) significantly decreased the amount of miRNAs in EVs. In addition, microarray analysis revealed that ANXA2 regulated the loading of miRNAs into EVs in a sequence independent manner. Lastly, immunoprecipitation analysis confirmed that ANXA2 could bind miRNAs in EVs in the presence of Ca(2+). These observations demonstrate that ANXA2 plays an important role in the packaging process of miRNAs into EVs. PMID- 26632511 TI - Uncoupling phototoxicity-elicited neural dysmorphology and death by insidious function and selective impairment of Ran-binding protein 2 (Ranbp2). AB - Morphological disintegration of neurons is coupled invariably to neural death. In particular, disruption of outer segments of photoreceptor neurons triggers photoreceptor death regardless of the pathological stressors. We show that Ranbp2(-/-)::Tg-Ranbp2(CLDm-HA) mice with mutations in SUMO-binding motif (SBM) of cyclophilin-like domain (CLD) of Ran-binding protein 2 (Ranbp2) expressed in a null Ranbp2 background lack untoward effects in photoreceptors in the absence of light-stress. However, compared to wild type photoreceptors, light-stress elicits profound disintegration of outer segments of Ranbp2(-/-)::Tg-Ranbp2(CLDm-HA) with paradoxical age-dependent resistance of photoreceptors to death and genotype independent activation of caspases. Ranbp2(-/-)::Tg-Ranbp2(CLDm-HA) exhibit photoreceptor death-independent changes in ubiquitin-proteasome system (UPS), but death-dependent increase of ubiquitin carrier protein 9(ubc9) levels. Hence, insidious functional impairment of SBM of Ranbp2's CLD promotes neuroprotection and uncoupling of photoreceptor degeneration and death against phototoxicity. PMID- 26632512 TI - Transplantation of VEGFl65-overexpressing vascular endothelial progenitor cells relieves endothelial injury after deep vein thrombectomy. AB - AIM: The purpose of this study was to explore the therapeutic efficacy of VEGF165 overexpressing vascular endothelial progenitor cells (EPCs) in post-thrombotic syndrome. MATERIALS AND METHODS: A thrombus model was developed to mimic the in vivo setting, and adenovirus transfection was used to overexpress VEGF165 in EPCs. These cells were transplanted into the animal model, and their ability to relieve endothelial injury was evaluated using haematoxylin and eosin staining, immunohistochemistry and scanning electron microscopy. RESULTS: Ferric chloride was used to build rat models of the inferior vena cava thrombosis, and HEK 293A cells were used to amplify adenovirus that overexpresses VEGF165. EPCs were infected with adenovirus, and this was confirmed by fluorescence microscopy. Transplantation of VEGH165-overexpressing EPCs into injured endothelial sites led to faster repair of the post-thrombotic tunica intima than wild-type EPCs. CONCLUSION: Transplantation of VEGF165-overexpressing EPCs was found to promote repair of the tunica intima, thus improving rehabilitation after surgery. PMID- 26632513 TI - Gestational hypertension, preeclampsia and intrauterine growth restriction induce dysregulation of cardiovascular and cerebrovascular disease associated microRNAs in maternal whole peripheral blood. AB - AIMS: To demonstrate that pregnancy-related complications are associated with alterations in cardiovascular and cerebrovascular microRNA expression. Gene expression of 29 microRNAs (miR-1-3p, miR-16-5p, miR-17-5p, miR-20a-5p, miR-20b 5p, miR-21-5p, miR-23a-3p, miR-24-3p, miR-26a-5p, miR-29a-3p, miR-92a-3p, miR-100 5p, miR-103a-3p, miR-122-5p, miR-125b-5p, miR-126-3p, miR-130b-3p, miR-133a-3p, miR-143-3p, miR-145-5p, miR-146a-5p, miR-181a-5p, miR-195-5p, miR-199a-5p, miR 210-3p, miR-221-3p, miR-342-3p, miR-499a-5p, and miR-574-3p) was assessed in maternal whole peripheral blood, compared between groups (39 gestational hypertension, 68 preeclampsia, 33 intrauterine growth restriction and 20 normal pregnancies) and correlated with the severity of the disease with respect to clinical signs, delivery date, and Doppler ultrasound parameters. Initially, selection and validation of endogenous controls for microRNA expression studies in patients affected by pregnancy-related complications have been carried out. RESULTS: The expression profile of microRNAs was different between pregnancy related complications and controls. The down-regulation of miR-100-5p, miR-125b 5p and miR-199a-5p was a common phenomenon shared between gestational hypertension, preeclampsia, and intrauterine growth restriction. Moreover, IUGR pregnancies induced down-regulation of miR-17-5p, miR-146a-5p, miR-221-3p and miR 574-3p in maternal circulation. Irrespective of the severity of the disease, preeclampsia was associated with the dysregulation of miR-100-5p and miR-125b-5p and IUGR with dysregulation of miR-199a-5p. Preeclampsia requiring termination of gestation before 34 weeks was associated with down-regulation of miR-146a-5p, miR 199a-5p and miR-221-3p. Weak negative correlation between miR-146a-5p and miR-221 3p expression and the pulsatility index in the umbilical artery was found. Additional microRNAs (miR-103a-3p, miR-126-3p, miR-195-5p and miR-499a-5p) showed a trend to down-regulation in appropriate pregnancy-related complications. CONCLUSION: Epigenetic changes are induced by pregnancy-related complications in maternal whole peripheral blood. PMID- 26632514 TI - Decreased levels of procoagulant phospholipids in bleeding patients treated by vitamin K antagonists. AB - International Normalized Ratio (INR) is currently used to monitor vitamin K antagonist therapy, and the bleeding incidence becomes exponential for INR>4.5. Inversely, more than 50% of patients with a supratherapeutic INR are asymptomatic. Therefore it could be of interest to identify patients with a higher bleeding risk. Microparticles derived from different cell types express procoagulant phospholipids (PPL) which can be evaluated by a chronometric coagulation assay where a shortening of the clotting times is associated with increased levels of PPL. In a series of 174 consecutive patients referred to our Emergency Department with an INR>5, median level of PPL was significantly (p=0.004) lower (38.2s) in the 119 asymptomatic patients than in patients with nonmajor (43.6s, n=35) or major bleeding (46.6s, n=19), indicating higher levels of procoagulant phospholipids in asymptomatic patients. By receiver operating characteristic curve analysis, a cut-off of 43.5s discriminated patients with higher haemorrhagic risk (area under the curve=0.648). In contrast, thrombomodulin levels, quantified either by immunological or functional assays were not significantly different between both groups. In conclusion, evaluation of PPL could be of interest to define the haemorrhagic risk of VKA- treated patients. PMID- 26632515 TI - Interconnectedness of global hemostasis assay parameters in simultaneously evaluated thrombin generation, fibrin generation and clot lysis in normal plasma. AB - BACKGROUND: Fluorogenic thrombin generation (TG) assays and turbidity-based fibrin generation (FG)- and fibrinolysis (FL)-resistance assays have been sought to assess bleeding and clotting disorders. Theoretically, TG, FG and FL tests should provide overlapping information because thrombin is responsible for FG and induces protection from FL. The relationships between TG, FG and FL parameters remain poorly investigated, partly because existing experimental systems do not permit simultaneous detection of both TG and FG in the same sample of plasma, and are instead tested in separate experiments. OBJECTIVES AND METHODS: We evaluated the potential benefits of a combined TG/FG/FL assay by testing responses of normal plasma to a wide range of tissue factor (TF) and tissue plasminogen activator (tPA) concentrations. Correlations between multiple parameters extracted from the TG and FG/FL curves were also compared. RESULTS: Rate of FG correlated well with TG peak height at all TF concentrations, but correlations between TG and FL parameters depended on the TF concentration. Without thrombomodulin, all FG/FL parameters at high TF could be predicted from TG parameters and no FL protection was observed. With thrombomodulin and high TF, TF dependent FL protection did not correlate with TF-dependent TG. The fluorogenic thrombin substrate did not interfere with optical density readings, and meaningful tPA concentrations did not interfere with TG readings. CONCLUSIONS: In normal plasma, TG, FG and FL parameters may provide interchangeable information. Evaluation of FL-resistance may provide additional data under special assay conditions, but the value of this information should be studied under disease conditions. PMID- 26632516 TI - Exhaustive and stable electromembrane extraction of acidic drugs from human plasma. AB - The first part of the current work systematically described the screening of different types of organic solvents as the supported liquid membrane (SLM) for electromembrane extraction (EME) of acidic drugs, including different alcohols, ketones, and ethers. Seven acidic drugs with a wide logP range (1.01-4.39) were selected as model substances. For the first time, the EME recovery of acidic drugs and system-current across the SLM with each organic solvent as SLM were investigated and correlated to relevant solvent properties such as viscosity and Kamlet and Taft solvatochromic parameters. Solvents with high hydrogen bonding acidity (alpha) and dipolarity-polarizability (pi*) were found to be successful SLMs, and 1-heptanol was the most efficient candidate, which provided EME recovery in the range of 94-110%. Both hydrogen bonding interactions, dipole dipole interactions, and hydrophobic interactions were involved in stabilizing the deprotonated acidic analytes (with high hydrogen bonding basicity and high dipole moment) during mass transfer across the SLM. The efficiency of the extraction normally decreased with increasing hydrocarbon chain length of the SLM, which was mainly due to increasing viscosity and decreasing alpha and pi* values. The system-current during EME was found to be dependent on the type and the volume of the SLM. In contact with human plasma, an SLM of pure 1-heptanol was unstable, and to improve stability, 1-heptanol was mixed with 2-nitrophenyl octyl ether (NPOE). With this SLM, exhaustive EME was performed from diluted human plasma, and the recoveries of five out of seven analytes were over 91% after 10min EME. This approach was evaluated using HPLC-UV, and the evaluation data were found to be satisfactory. PMID- 26632517 TI - Highly selective separation of enantiomers using a chiral porous organic cage. AB - Porous solids composed of shape-persistent organic cage molecules have attracted considerable attention due to their important applications such as molecular separation, heterogeneous catalysis, and gas storage. In this study, an imine linked porous organic cage (POC) CC10 diluted with a polysiloxane OV-1701 was explored as a novel stationary phase for high-resolution gas chromatography (GC). A wide variety of enantiomers belonging to different classes of organic compounds have been resolved on the coated capillary column, including chiral alcohols, esters, ketones, ethers, halohydrocarbons, epoxides, and organic acids. The fabricated column complements to commercial beta-DEX 120 column and our recently reported CC3-R column for separating enantiomers, which indicates that the excellent chiral recognition ability of CC10 is not only interesting academically, but also has potential for practical application. In addition, CC10 also exhibits good selectivity for the separation of n-alkanes, n-alcohols, Grob mixture, and positional isomers. This work also indicates that this type of chiral POCs will become a new class of chiral selector in the near future. PMID- 26632518 TI - Tailoring molecularly imprinted polymer beads for alternariol recognition and analysis by a screening with mycotoxin surrogates. AB - Molecularly imprinted porous polymer microspheres have been prepared for selective binding of alternariol (AOH), a phenolic mycotoxin produced by Alternaria fungi. In order to lead the synthesis of recognition materials, four original AOH surrogates have been designed, prepared and characterized. They bear different number of phenol groups in various positions and different degree of O methylation on the dibenzo[b,d]pyran-6-one skeleton. A comprehensive library of mixtures of basic, acidic or neutral monomers, with divinylbenzene or ethyleneglycol dimethacrylate as cross-linkers, were polymerized at a small scale in the presence of the four molecular mimics of the toxin molecule. This polymer screening has allowed selection of the optimal composition of the microbeads (N (2-aminoethyl)methacrylamide, EAMA, and ethylene glycol dimethacrylate). The latter are able to bind AOH in water-acetonitrile (80:20, v/v) with an affinity constant of 109+/-10mM(-1) and a total number of binding sites of 35+/-2MUmolg( 1), being alternariol monomethylether the only competitor species. Moreover, (1)H NMR titrations have unveiled a 1:2 surrogate-to-EAMA stoichiometry, the exact interaction sites and a binding constant of 1.5*10(4)M(-2). A molecularly imprinted solid phase extraction (MISPE) method has been optimized for selective isolation of the mycotoxin from aqueous samples upon a discriminating wash with 3mL of acetonitrile/water (20:80, v/v) followed by determination by HPLC with fluorescence detection. The method has been applied, in combination to ultrasound assisted extraction, to the analysis of AOH in tomato samples fortified with the mycotoxin at five concentration levels (33-110MUgkg(-1)), with recoveries in the range of 81-103% (RSD n=6). To the best of our knowledge, this is the first imprinted material capable of molecularly recognizing this widespread food contaminant. PMID- 26632519 TI - Polyclonal antibodies for specific detection of tobacco host cell proteins can be efficiently generated following RuBisCO depletion and the removal of endotoxins. AB - The production of biopharmaceutical proteins in plants requires efficient downstream processing steps that remove impurities such as host cell proteins (HCPs) and adventitious endotoxins produced by bacteria during transient expression. We therefore strived to develop effective routines for endotoxin removal from plant extracts and the subsequent use of the extracts to generate antibodies detecting a broad set of HCPs. At first, we depleted the superabundant protein ribulose-1,5-bisphosphate carboxylase/oxygenase (RuBisCO) for which PEG precipitation achieved the best results, preventing a dominant immune reaction against this protein. We found that a mixture of sera from rabbits immunized with pre-depleted or post-depleted extracts detected more HCPs than the individual sera used alone. We also developed a powerful endotoxin removal procedure using Polymyxin B for extracts from wild type plants or a combination of fiber-flow filtration and EndoTrap Blue for tobacco plants infiltrated with Agrobacterium tumefaciens. The antibodies we generated will be useful for quality and performance assessment in future process development and the methods we present can easily be transferred to other expression systems rendering them useful in the field of plant molecular farming. PMID- 26632521 TI - Lipid production of microalga Chlorella sorokiniana CY1 is improved by light source arrangement, bioreactor operation mode and deep-sea water supplements. AB - Microalgae-based biodiesel has been recognized as a sustainable and promising alternative to fossil diesel. High lipid productivity of microalgae is required for economic production of biodiesel from microalgae. This study was undertaken to enhance the growth and oil accumulation of an indigenous microalga Chlorella sorokiniana CY1 by applying engineering strategies using deep-sea water as the medium. First, the microalga was cultivated using LED as the immersed light source, and the results showed that the immersed LED could effectively enhance the oil/lipid content and final microalgal biomass concentration to 53.8% and 2.5 g/l, respectively. Next, the semi-batch photobioreactor operation with deep-sea water was shown to improve lipid content and microalgal growth over those from using batch and continuous cultures under similar operating conditions. The optimal replacement ratio was 50%, resulting in an oil/lipid content and final biomass concentration of 61.5% and 2.8 g/l, respectively. A long-term semi-batch culture utilizing 50%-replaced medium was carried out for four runs. The final biomass concentration and lipid productivity were 2.5 g/L and 112.2 mg/L/d, respectively. The fatty acid composition of the microalgal lipids was predominant by palmitic acid, stearic acid, oleic acid and linoleic acid, and this lipid quality is suitable for biodiesel production. This demonstrates that optimizing light source arrangement, bioreactor operation and deep-sea water supplements could effectively promote the lipid production of C. sorokiniana CY1 for the applications in microalgae-based biodiesel industry. PMID- 26632520 TI - Methotrexate Is Not Superior to Placebo for Inducing Steroid-Free Remission, but Induces Steroid-Free Clinical Remission in a Larger Proportion of Patients With Ulcerative Colitis. AB - BACKGROUND & AIMS: Parenteral methotrexate is an effective treatment for patients with Crohn's disease, but has never been adequately evaluated in patients with ulcerative colitis (UC). We conducted a randomized controlled trial to determine its safety and efficacy in patients with steroid-dependent UC. METHODS: We performed a double-blind, placebo-controlled trial to evaluate the efficacy of parenteral methotrexate (25 mg/wk) in 111 patients with corticosteroid-dependent UC at 26 medical centers in Europe from 2007 through 2013. Patients were given prednisone (10 to 40 mg/d) when the study began and were randomly assigned to groups (1:1) given placebo or methotrexate (intramuscularly or subcutaneously, 25 mg weekly) for 24 weeks. The primary end point was steroid-free remission (defined as a Mayo score <=2 with no item >1 and complete withdrawal of steroids) at week 16. Secondary endpoints included clinical remission (defined as a Mayo clinical subscore <=2 with no item >1) and endoscopic healing without steroids at weeks 16 and/or 24, remission without steroids at week 24, and remission at both weeks 16 and 24. RESULTS: Steroid-free remission at week 16 was achieved by 19 of 60 patients given methotrexate (31.7%) and 10 of 51 patients given placebo (19.6%)--a difference of 12.1% (95% confidence interval [CI]: -4.0% to 28.1%; P = .15). The proportion of patients in steroid-free clinical remission at week 16 was 41.7% in the methotrexate group and 23.5% in the placebo group, for a difference of 18.1% (95% CI: 1.1% to 35.2%; P = .04). The proportions of patients with steroid-free endoscopic healing at week 16 were 35% in the methotrexate group and 25.5% in the placebo group--a difference of 9.5% (95% CI: -7.5% to 26.5%; P = .28). No differences were observed in other secondary end points. More patients receiving placebo discontinued the study because of adverse events (47.1%), mostly caused by UC, than patients receiving methotrexate (26.7%; P = .03). A higher proportion of patients in the methotrexate group had nausea and vomiting (21.7%) than in the placebo group (3.9%; P = .006). CONCLUSIONS: In a randomized controlled trial, parenteral methotrexate was not superior to placebo for induction of steroid-free remission in patients with UC. However, methotrexate induced clinical remission without steroids in a significantly larger percentage of patients, resulting in fewer withdrawals from therapy due to active UC. ClinicalTrials.gov ID NCT00498589. PMID- 26632522 TI - Tissue Distribution of the 27.8 kDa Receptor and its Dynamic Expression in Response to Lymphocystis Disease Virus Infection in Flounder (Paralichthys olivaceus). AB - Lymphocystis disease virus (LCDV) enters and infects the gill cells of flounder (Paralichthys olivaceus) via a 27.8 kDa membrane protein receptor. In the present study, immunohistochemistry was performed to locate the tissue distribution of this molecule in healthy flounder and showed that it was widely distributed in the tissues tested. Indirect enzyme-linked immunosorbent assay (ELISA) showed that the expression of the receptor in healthy flounder was highest in the gills and stomach, then in the skin, intestine and liver, followed by the spleen, head kidney, heart, ovary and brain and finally the kidney. On LCDV infection, ELISA indicated that the expression of the receptor, as determined by ELISA, was significantly upregulated in all tissues of LCDV-infected flounder compared with controls, but this expression decreased over the 4 weeks post infection. In contrast, real-time quantitative polymerase chain reaction demonstrated that the copy number of the LCDV gene in the tissues increased with time post infection, and that viral loads were higher in the tissues with higher expressions of the receptor. These results point to a correlation between high expression of the 27.8 kDa receptor and efficient LCDV propagation. The wide tissue distribution of the receptor might be one reason why LCDV can infect various tissues leading to systemic infection. PMID- 26632523 TI - Endoscopic biopsy and EUS for the detection of pathologic complete response after neoadjuvant chemoradiotherapy in esophageal cancer: a systematic review and meta analysis. AB - BACKGROUND AND AIMS: Accurate determination of residual cancer status after neoadjuvant chemoradiotherapy (nCRT) for esophageal cancer could assist in selecting the optimal treatment strategy. The aim of this study was to review the evidence on the diagnostic accuracy of endoscopic biopsy and EUS after nCRT for detecting residual cancer at the primary tumor site (ypT+) and regional lymph nodes (ypN+) as opposed to a pathologic complete response (ypT0 and ypN0). METHODS: PubMed/Medline, Embase, and the Cochrane library were systematically searched. The analysis included diagnostic studies reporting on the accuracy of endoscopic biopsy or EUS in detecting residual cancer versus complete response after nCRT for esophageal cancer with histopathology as the reference standard. Bivariate random-effects models were used to estimate pooled sensitivities and specificities and examine sources of heterogeneity. RESULTS: Twenty-three studies comprising 12 endoscopic biopsy studies (1281 patients), 11 EUS studies reporting on ypT status (593 patients), and 10 EUS studies reporting on ypN status (602 patients), were included. Pooled estimates for sensitivity of endoscopic biopsy after nCRT for predicting ypT+ were 34.5% (95% confidence interval [CI], 26.0% 44.1%) and for specificity 91.0% (95% CI, 85.6%-94.5%). Pooled estimates for sensitivity of EUS after nCRT were 96.4% (95% CI, 91.7%-98.5%) and for specificity were 10.9% (95% CI, 3.5%-29.0%) for detecting ypT+, and 62.0% (95% CI, 46.0%-75.7%) and 56.7% (95% CI, 41.8%-70.5%) for detecting ypN+, respectively. CONCLUSIONS: Endoscopic biopsy after nCRT is a specific but not sensitive method for detecting residual esophageal cancer. Although EUS after nCRT yields a high sensitivity, only a limited number of patients will have negative findings at EUS with still a substantial false-negative rate. Furthermore, EUS provides only moderate accuracy for detecting residual lymph node involvement. Based on these findings, these endoscopic modalities cannot be used to withhold surgical treatment in test-negative patients after nCRT. ( CLINICAL TRIAL REGISTRATION NUMBER: CRD42015016527.). PMID- 26632524 TI - Contaminant cocktails: Interactive effects of fertiliser and copper paint on marine invertebrate recruitment and mortality. AB - Understanding interactive effects of contaminants is critical to predict how human activities change ecosystem structure and function. We examined independent and interactive effects of two contaminants (fertiliser and copper paint) on the recruitment, mortality, and total abundance of developing invertebrate communities in the field, 2, 4, 6, and 8 weeks after substrate submersion. Contaminants affected community structure differently, and produced an intermediate community in combination. Fertiliser increased recruitment and decreased mortality of active filter feeders (ascidians and barnacles), while copper paint decreased recruitment and increased mortality of some taxa. Contaminants applied together affected some taxa (e.g. Didemnid ascidians) antagonistically, as fertiliser mitigated adverse effects of copper paint. Recruitment of active filter feeders appears to be indicative of nutrient enrichment, and their increased abundance may reduce elevated nutrients in modified waterways. This study demonstrates the need to consider both independent and interactive effects of contaminants on marine communities in the field. PMID- 26632525 TI - Enhanced biodegradation of pyrene and indeno(1,2,3-cd)pyrene using bacteria immobilized in cinder beads in estuarine wetlands. AB - Two strains (Pseudomonas taiwanensis PYR1 and Acinetobacter baumannii INP1) were isolated from PAH-contaminated Liaohe estuarine wetland using enrichment. The cells of PYR1 and INP1 were immobilized in cinder beads for pyrene and indeno(1,2,3-cd)pyrene biodegradation in wetland. Biodegradation of pyrene and indeno(1,2,3-cd)pyrene in soils from wetland was carried out in pots using free cells as well as those immobilized in cinder beads to ascertain the role of bioaugmentation. Supported by the cinder beads, the immobilized cells degraded 70.7% and 80.9% of pyrene and indeno(1,2,3-cd)pyrene respectively after 30 days. While the free cells degraded only 58.2% and 55.3%. Additionally, microbial analysis with high-throughput sequencing revealed the changes of microbial communities in soil without and with cinder beads immobilized with strains. The result indicated that Gammaproteobacteria were dominant PAH-degrading groups during bioaugmentation. This effective approach can be used to treat other PAH contaminated wetlands by immobilizing different species of bacteria in cinder beads. PMID- 26632526 TI - Remote sensing of Qatar nearshore habitats with perspectives for coastal management. AB - A framework is proposed for utilizing remote sensing and ground-truthing field data to map benthic habitats in the State of Qatar, with potential application across the Arabian Gulf. Ideally the methodology can be applied to optimize the efficiency and effectiveness of mapping the nearshore environment to identify sensitive habitats, monitor for change, and assist in management decisions. The framework is applied to a case study for northeastern Qatar with a key focus on identifying high sensitivity coral habitat. The study helps confirm the presence of known coral and provides detail on a region in the area of interest where corals have not been previously mapped. Challenges for the remote sensing methodology associated with natural heterogeneity of the physical and biological environment are addressed. Recommendations on the application of this approach to coastal environmental risk assessment and management planning are discussed as well as future opportunities for improvement of the framework. PMID- 26632527 TI - Targeted next-generation sequencing revealed MYD88 deficiency in a child with chronic yersiniosis and granulomatous lymphadenitis. PMID- 26632528 TI - Kalkipyrone B, a marine cyanobacterial gamma-pyrone possessing cytotoxic and anti fungal activities. AB - Bioassay-guided fractionation of two marine cyanobacterial extracts using the H 460 human lung cancer cell line and the OVC-5 human ovarian cancer cell line led to the isolation of three related alpha-methoxy-beta, beta'-dimethyl-gamma pyrones each containing a modified alkyl chain, one of which was identified as the previously reported kalkipyrone and designated kalkipyrone A. The second compound was an analog designated kalkipyrone B. The third was identified as the recently reported yoshinone A, also isolated from a marine cyanobacterium. Kalkipyrone A and B were obtained from a field-collection of the cyanobacterium Leptolyngbya sp. from Fagasa Bay, American Samoa, while yoshinone A was isolated from a field-collection of cyanobacteria (cf. Schizothrix sp.) from Panama. One dimensional and two-dimensional NMR experiments were used to determine the overall structures and relative configurations of the kalkipyrones, and the absolute configuration of kalkipyrone B was determined by (1)H NMR analysis of diastereomeric Mosher's esters. Kalkipyrone A showed good cytotoxicity to H-460 human lung cancer cells (EC50=0.9MUM), while kalkipyrone B and yoshinone A were less active (EC50=9.0MUM and >10MUM, respectively). Both kalkipyrone A and B showed moderate toxicity to Saccharomyces cerevisiae ABC16-Monster strain (IC50=14.6 and 13.4MUM, respectively), whereas yoshinone A was of low toxicity to this yeast strain (IC50=63.8MUM). PMID- 26632529 TI - Differentiation between two "fang ji" herbal medicines, Stephania tetrandra and the nephrotoxic Aristolochia fangchi, using hyperspectral imaging. AB - Stephania tetrandra ("hang fang ji") and Aristolochia fangchi ("guang fang ji") are two different plant species used in Traditional Chinese Medicine (TCM). Both are commonly referred to as "fang ji" and S. tetrandra is mistakenly substituted and adulterated with the nephrotoxic A. fangchi as they have several morphological similarities. A. fangchi contains aristolochic acid, a carcinogen that causes urothelial carcinoma as well as aristolochic acid nephropathy (AAN). In Belgium, 128 cases of AAN was reported while in China, a further 116 cases with end-stage renal disease were noted. Toxicity issues associated with species substitution and adulteration necessitate the development of reliable methods for the quality assessment of herbal medicines. Hyperspectral imaging in combination with partial least squares discriminant analysis (PLS-DA) is suggested as an effective method to distinguish between S. tetrandra and A. fangchi root powder. Hyperspectral images were obtained in the wavelength region of 920-2514nm. Reduction of the dimensionality of the data was done by selecting the discrimination information range (964-1774nm). A discrimination model with a coefficient of determination (R(2)) of 0.9 and a root mean square error of prediction (RMSEP) of 0.23 was created. The constructed model successfully identified A. fangchi and S. tetrandra samples inserted into the model as an external validation set. In addition, adulteration detection was investigated by preparing incremental adulteration mixtures of S. tetrandra with A. fangchi (10 90%). Hyperspectral imaging showed the ability to accurately predict adulteration as low as 10%. It is evident that hyperspectral imaging has tremendous potential in the development of visual quality control methods which may prevent cases of aristolochic acid nephropathy in the future. PMID- 26632530 TI - The Leipzig Prospective Drug-Eluting Balloon-Registry - Outcome of 484 Consecutive Patients Treated for Coronary In-Stent Restenosis and De Novo Lesions Using Paclitaxel-Coated Balloons. AB - BACKGROUND: Drug-eluting balloons (DEB) are an alternative treatment of in-stent restenosis (ISR), but data regarding outcomes of DEB in de novo lesions are lacking. METHODS AND RESULTS: We investigated the effect of DEB on target lesion revascularization (TLR), procedural complications (coronary dissection/rupture, pericardial effusion, stent thrombosis, peri-interventional NSTEMI, stroke), major adverse cardiac and cerebrovascular events (all-cause mortality, myocardial infarction, TLR, stroke) in patients with ISR and de novo lesions in an all comers setting. Between April 2009 and October 2013, 484 consecutive patients (mean age 68.4 years; 77.9% male) were enrolled in a prospective registry. TLR rate was 4.9% at 12 months and 8.7% at long-term follow-up of 2.3 years. Subgroup analysis confirmed a TLR rate of 8.9% after DEB treatment of ISR in bare-metal stents (21/235 lesions), 13.0% in drug-eluting stents (21/161 lesions) and 0% for de novo lesions (0/76 lesions). At long-term follow-up, all-cause mortality/cardiac mortality was 8.7% (42/484)/3.3% (16/484) and MACCE rate was 18.4% (89/484 patients), with no differences between DEB for ISR compared with de novo lesions. CONCLUSIONS: DEB for ISR resulted in a low rate of TLR. Our data support DEB in ISR as an effective treatment option. DEB in small coronary vessels in our limited cohort appeared to be safe. Larger, randomized trials in small coronary vessels should be undertaken to verify the long-term results of the current trial. PMID- 26632531 TI - Lipoprotein(a) in Familial Hypercholesterolemia With Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Gain-of-Function Mutations. AB - BACKGROUND: It has been shown that serum lipoprotein(a) [Lp(a)] is elevated in familial hypercholesterolemia (FH) with mutation(s) of the LDL receptor (LDLR) gene. However, few data exist regarding Lp(a) levels in FH with gain-of-function mutations of the PCSK9 gene. METHODS AND RESULTS: We evaluated 42 mutation determined heterozygous FH patients with aPCSK9gain-of-function mutation (FH PCSK9, mean age 52, mean LDL-C 235 mg/dl), 198 mutation-determined heterozygous FH patients with aLDLRmutation (FH-LDLR, mean age 44, mean LDL-C 217 mg/dl), and 4,015 controls (CONTROL, mean age 56, mean LDL-C 109 mg/dl). We assessed their Lp(a), total cholesterol, triglycerides, HDL-C, LDL-C, use of statins, presence of hypertension, diabetes, chronic kidney disease, smoking, body mass index (BMI) and coronary artery disease (CAD). Multiple regression analysis showed that HDL C, use of statins, presence of hypertension, smoking, BMI, and Lp(a) were independently associated with the presence of CAD. Under these conditions, the serum levels of Lp(a) in patients with FH were significantly higher than those of the CONTROL group regardless of their causative genes, among the groups propensity score-matched (median Lp(a) 12.6 mg/dl [IQR:9.4-33.9], 21.1 mg/dl [IQR:11.7-34.9], and 5.0 mg/dl [IQR:2.7-8.1] in the FH-LDLR, FH-PCSK9, and CONTROL groups, respectively, P=0.002 for FH-LDLR vs. CONTROL, P=0.002 for FH PCSK9 vs. CONTROL). CONCLUSIONS: These data demonstrate that serum Lp(a) is elevated in patients with FH caused by PCSK9 gain-of-function mutations to the same level as that in FH caused by LDLR mutations. PMID- 26632532 TI - Is It Possible to Predict the Onset of "Heart Failure" in Hypertrophic Cardiomyopathy? PMID- 26632533 TI - Guidelines for Disaster Medicine for Patients With Cardiovascular Diseases (JCS 2014/JSH 2014/JCC 2014) - Digest Version . PMID- 26632534 TI - Pentraxin 3 and Platelet Activation in Obese Patients After Gastric Banding. AB - BACKGROUND: Circulating pentraxin 3 (PTX3), the main regulator of the inflammatory response, rapidly increases following cardiovascular events, and low PTX3 is associated with high body mass index. METHODS AND RESULTS: We conducted a 12-month longitudinal study, to test the hypothesis that laparoscopic adjustable gastric banding (LAGB)-induced weight loss was associated with changes in platelet activation markers and PTX3. Twelve obese patients, scheduled to undergo LAGB, were enrolled at the University Obesity Center. Urinary 11-dehydro thromboxane (Tx)B2excretion rate was measured on radioimmunoassay, and PTX3 and CD40L were determined on immunoassay. Plasma PTX3 increased by 178.8 and 214.9% (P<0.0001), respectively, 6 and 12 months after LAGB. High-sensitivity CRP decreased by 24 and 29.7% (P<0.0001), whereas CD40L decreased by 64.3 and 58.6% (P=0.002), respectively. Urinary 11-dehydro-TxB2decreased from 1,443 to 715 and 564 pg/mg creatinine, respectively 6 months and 12 months after LAGB (P<0.0001). PTX3 was inversely related to platelet activation markers, 11-dehydro-TxB2and CD40L. Moreover, multiple regression analysis on pooled data showed that plasma PTX3 was an independent predictor of urinary 11-dehydro-TxB2. CONCLUSIONS: There is an association between inflammation, platelet activation and metabolic dysfunction in obesity, and PTX3 is a key player within these circuits. PMID- 26632535 TI - Low-Normal Serum Sodium and Heart Failure-Related Events in Patients With Heart Failure With Preserved Left Ventricular Ejection Fraction. AB - BACKGROUND: Hyponatremia has been shown to be a prognostic factor in heart failure (HF) with preserved ejection fraction (HFpEF). Serum sodium (sNa) cut off, however, is not defined in HFpEF. Therefore, we investigated the relationship between sNa and HF-related events (cardiovascular death and hospitalization for HF decompensation) in HFpEF patients. METHODS AND RESULTS: We assessed cardiac function using echocardiography and measured sNa in HFpEF patients with New York Heart Association class II (n=321) or III (n=84) in a compensated condition after implementing medical therapy for HF. During a mean follow-up of 27 months, 73 patients developed HF-related events. On multivariate Cox hazard analysis including established predictors in HF, sNa level as a continuous variable was identified as an independent predictor for HF-related events in HFpEF (per 1.0 mmol/L: HR, 0.93; 95% CI: 0.87-0.98; P<0.01). Kaplan Meier analysis demonstrated significantly higher probability of HF-related events in the lower sNa group (sNa <140 mmol/L) than in the higher sNa group (sNa >=140 mmol/L; P<0.001, log-rank test). Further, the low-normal sNa group (135 mmol/L25 oocytes from about 40% (eCG-hCG) to 90%. The same protocol was also effective in other inbred (BALB/cA), outbred (ICR), and hybrid (B6D2F1) strains. In addition, B6 female mice aged over 1 yr ovulated 1.8-fold more oocytes by this protocol. Thus, estrous cycle synchronization followed by AIS-hCG yielded a broadly applicable, highly efficient superovulation. This protocol should promote the effective use of invaluable female mouse strains and decrease the numbers of animals euthanized. PMID- 26632611 TI - Age and Nursing Affect the Neonatal Porcine Uterine Transcriptome. AB - The lactocrine hypothesis for maternal programming of neonatal development was proposed to describe a mechanism through which milk-borne bioactive factors, delivered from mother to nursing offspring, could affect development of tissues, including the uterus. Porcine uterine development, initiated before birth, is completed postnatally. However, age- and lactocrine-sensitive elements of the neonatal porcine uterine developmental program are undefined. Here, effects of age and nursing on the uterine transcriptome for 48 h from birth (Postnatal Day [PND] = 0) were identified using RNA sequencing (RNAseq). Uterine tissues were obtained from neonatal gilts (n = 4 per group) within 1 h of birth and before feeding (PND 0), or 48 h after nursing ad libitum (PND 2N) or feeding a commercial milk replacer (PND 2R). RNAseq analysis revealed differentially expressed genes (DEGs) associated with both age (PND 2N vs. PND 0; 3283 DEGs) and nursing on PND 2 (PND 2N vs PND 2R; 896 DEGs). Expression of selected uterine genes was validated using quantitative real-time PCR. Bioinformatic analyses revealed multiple biological processes enriched in response to both age and nursing, including cell adhesion, morphogenesis, and cell-cell signaling. Age sensitive pathways also included estrogen receptor-alpha and hedgehog signaling cascades. Lactocrine-sensitive processes in nursed gilts included those involved in response to wounding, the plasminogen activator network and coagulation. Overall, RNAseq analysis revealed comprehensive age- and nursing-related transcriptomic differences in the neonatal porcine uterus and identified novel pathways and biological processes regulating uterine development. PMID- 26632609 TI - ALDH Enzyme Expression Is Independent of the Spermatogenic Cycle, and Their Inhibition Causes Misregulation of Murine Spermatogenic Processes. AB - Perturbations in the vitamin A metabolism pathway could be a significant cause of male infertility, as well as a target toward the development of a male contraceptive, necessitating the need for a better understanding of how testicular retinoic acid (RA) concentrations are regulated. Quantitative analyses have recently demonstrated that RA is present in a pulsatile manner along testis tubules. However, it is unclear if the aldehyde dehydrogenase (ALDH) enzymes, which are responsible for RA synthesis, contribute to the regulation of these RA concentration gradients. Previous studies have alluded to fluctuations in ALDH enzymes across the spermatogenic cycle, but these inferences have been based primarily on qualitative transcript localization experiments. Here, we show via various quantitative methods that the three well-known ALDH enzymes (ALDH1A1, ALDH1A2, and ALDH1A3), and an ALDH enzyme previously unreported in the murine testis (ALDH8A1), are not expressed in a stage-specific manner in the adult testis, but do fluctuate throughout juvenile development in perfect agreement with the first appearance of each advancing germ cell type. We also show, via treatments with a known ALDH inhibitor, that lowered testicular RA levels result in an increase in blood-testis barrier permeability, meiotic recombination, and meiotic defects. Taken together, these data further our understanding of the complex regulatory actions of RA on various spermatogenic events and, in contrast with previous studies, also suggest that the ALDH enzymes are not responsible for regulating the recently measured RA pulse. PMID- 26632612 TI - Metabolic and Endocrine Differences Between Dairy Cows That Do or Do Not Ovulate First Postpartum Dominant Follicles. AB - Most dairy cows develop the first dominant follicle postpartum within 2 wk after calving, but only about 40% of these follicles produce sufficient estradiol to stimulate ovulation despite having normal ultrasound appearance and growth. This study aimed to characterize metabolic, endocrine, and follicular fluid profiles of cows in which the first dominant follicle postpartum will become ovulatory and those with nonovulatory follicles. Luteinizing hormone pulse frequency, follicular fluid androstenedione, and follicular fluid estradiol concentrations were lower in nonovulatory cows suggesting that the function of theca cells is impaired. In addition, nonovulatory cows had more severe negative energy balance and greater insulin resistance postpartum. This study describes for the first time the steroid hormone profile of early postpartum follicles and shows that a steroidogenic defect most likely occurs in theca cells limiting the amount of androgen precursor available for estradiol production that impairs their ovulatory outcome. PMID- 26632614 TI - [Clinical analysis of 9 cases of liver failure with hemophagocytic syndrome]. PMID- 26632613 TI - Influence of riboflavin on the reduction of radionuclides by Shewanella oneidenis MR-1. AB - Uranium (as UO2(2+)), technetium (as TcO4(-)) and neptunium (as NpO2(+)) are highly mobile radionuclides that can be reduced enzymatically by a range of anaerobic and facultatively anaerobic microorganisms, including Shewanella oneidensis MR-1, to poorly soluble species. The redox chemistry of Pu is more complicated, but the dominant oxidation state in most environments is highly insoluble Pu(IV), which can be reduced to Pu(III) which has a potentially increased solubility which could enhance migration of Pu in the environment. Recently it was shown that flavins (riboflavin and flavin mononucleotide (FMN)) secreted by Shewanella oneidensis MR-1 can act as electron shuttles, promoting anoxic growth coupled to the accelerated reduction of poorly-crystalline Fe(III) oxides. Here, we studied the role of riboflavin in mediating the reduction of radionuclides in cultures of Shewanella oneidensis MR-1. Our results demonstrate that the addition of 10 MUM riboflavin enhances the reduction rate of Tc(VII) to Tc(IV), Pu(IV) to Pu(III) and to a lesser extent, Np(V) to Np(IV), but has no significant influence on the reduction rate of U(VI) by Shewanella oneidensis MR 1. Thus riboflavin can act as an extracellular electron shuttle to enhance rates of Tc(VII), Np(V) and Pu(IV) reduction, and may therefore play a role in controlling the oxidation state of key redox active actinides and fission products in natural and engineered environments. These results also suggest that the addition of riboflavin could be used to accelerate the bioremediation of radionuclide-contaminated environments. PMID- 26632615 TI - [Indocyanine green clearance test assessment of liver reserve function and estimation in patients with cirrhosis and liver failure]. PMID- 26632616 TI - [Hepatitis B virus X protein and methylation of the E-cadherin promoter in hepatocellular carcinoma]. PMID- 26632617 TI - [Inhibitory effect of mesima reshi UE-1 on biological behavior of human hepatic carcinoma cells in vitro]. PMID- 26632618 TI - [Portal vein thrombosis in cirrhosis: new insights into pathogenesis and diagnosis]. PMID- 26632619 TI - [MicroRNAs in biliary diseases]. PMID- 26632620 TI - [Progress of diffusion weighted imaging based on monoexponential and biexponential models as a clinical application for hepatic disease]. PMID- 26632621 TI - Jacobs and Stanfors reply. PMID- 26632623 TI - Preface. PMID- 26632622 TI - Reply. PMID- 26632631 TI - Toward an evidence-based implementation model and checklist for personalized dementia care in the community. AB - BACKGROUND: The aim was to develop an evidence-based model that focuses specifically on factors that enable the provision of personalized care to facilitate and promote the implementation of community-based personalized dementia care interventions. The model is based on our previous research and additional literature. METHODS: The theoretical model of adaptive implementation was used as a framework to structure our model. Facilitators and barriers considered relevant for personalized care were extracted from our studies and additional literature, and were synthesized into the new evidence-based implementation model and checklist for personalized dementia care in the community. RESULTS: Extraction of data led to a composition of an evidence-based model for the implementation of personalized psychosocial care interventions that incorporates core components of personalized care. The model addresses several issues, e.g. how personalized care interventions should be offered and to whom; whether these are able to adapt to personal characteristics and needs of clients and informal caregivers; and whether both organizational management and staff that provide the intervention support personalized care and are able to focus on providing individualized care. CONCLUSIONS: Our model provides a checklist for researchers, professional caregivers, and policy-makers who wish to develop, evaluate, or implement personalized care interventions. PMID- 26632632 TI - Short-term outcomes of local infiltration anaesthetic in total knee arthroplasty: a randomized controlled double-blinded controlled trial. AB - BACKGROUND: The primary objective of the study was to determine if local infiltration anaesthetic (LIA) reduced total length of hospital stay in total knee arthroplasty (TKA) patients. The study also examined whether LIA improves early pain management, patient satisfaction and range of motion in TKA patients. METHODS: We conducted a randomized controlled double-blinded study. Fifty patients undergoing TKA were randomized to receive either placebo or LIA at the time of surgery and on the first day post-operatively. Pain scores, level of satisfaction and range of motion were recorded preoperatively and post operatively. RESULTS: There was no statistical difference between the groups for length of stay, post-operative pain scores, satisfaction scores or range of motion 6 weeks post-operatively. CONCLUSION: This randomized double-blinded trial did not demonstrate a decrease in pain or reduction of length of stay due to local infiltration analgesia. PMID- 26632633 TI - Alcohol stimulates macrophage activation through caspase-dependent hepatocyte derived release of CD40L containing extracellular vesicles. AB - BACKGROUND & AIMS: The mechanisms by which hepatocyte exposure to alcohol activates inflammatory cells such as macrophages in alcoholic liver disease (ALD) are unclear. The role of released nano-sized membrane vesicles, termed extracellular vesicles (EV), in cell-to-cell communication has become increasingly recognized. We tested the hypothesis that hepatocytes exposed to alcohol may increase EV release to elicit macrophage activation. METHODS: Primary hepatocytes or HepG2 hepatocyte cell lines overexpressing ethanol-metabolizing enzymes alcohol dehydrogenase (HepG2(ADH)) or cytochrome P450 2E1 (HepG2(Cyp2E1)) were treated with ethanol and EV release was quantified with nanoparticle tracking analysis. EV mediated macrophage activation was monitored by analysing inflammatory cytokines and macrophage associated mRNA expression, immunohistochemistry, biochemical serum alanine aminotransferase and triglycerides analysis in our in vitro macrophage activation and in vivo murine ethanol feeding studies. RESULTS: Ethanol significantly increased EV release by 3.3-fold from HepG2(Cyp2E1) cells and was associated with activation of caspase 3. Blockade of caspase activation with pharmacological or genetic approaches abrogated alcohol-induced EV release. EV stimulated macrophage activation and inflammatory cytokine induction. An unbiased microarray-based approach and antibody neutralization experiments demonstrated a critical role of CD40 ligand (CD40L) in EV mediated macrophage activation. In vivo, wild-type mice receiving a pan-caspase, Rho kinase inhibitor or with genetic deletion of CD40 (CD40(-/-)) or the caspase-activating TRAIL receptor (TR(-/-)), were protected from alcohol induced injury and associated macrophage infiltration. Moreover, serum from patients with alcoholic hepatitis showed increased levels of CD40L enriched EV. CONCLUSION: In conclusion, hepatocytes release CD40L containing EV in a caspase dependent manner in response to alcohol exposure which promotes macrophage activation, contributing to inflammation in ALD. PMID- 26632635 TI - Insights into the diagnosis of hepatocellular carcinomas with hepatobiliary MRI. AB - The incidence of hepatocellular carcinomas (HCCs) has increased worldwide in line with an improved screening by high-resolution imaging of cirrhotic livers. Besides abdominal ultrasonography and computerised tomography, magnetic resonance imaging (MRI) is an important tool to detect HCCs. With commercialisation of MR hepatobiliary contrast agents that cross membrane transporters in hepatocytes or tumour cells, MRI adds new information to detect and characterise HCCs. When tumour cells lose organic anion transporting polypeptides (OATP1B1/B3) in cell membranes facing sinusoidal blood, tumours appear hypointense (decreased contrast agent concentrations) in comparison to surrounding normal or cirrhotic liver that retains OATP1B1/B3 expression. However, expression, regulation, and prognostic significance of transporter evolution along carcinogenesis are not completely known. Moreover, understanding signal intensities in focal lesions also relies on transport functions of cellular efflux transporters. This manuscript reviews all the publications that associate liver imaging with hepatobiliary contrast agents and expression of transporters. The regulation of transporters along carcinogenesis to anticipate the prognosis of focal lesions is also included. PMID- 26632634 TI - Hepatic stellate cell transdifferentiation involves genome-wide remodeling of the DNA methylation landscape. AB - BACKGROUND & AIMS: DNA methylation (5-mC) is an epigenetic mark that is an established regulator of transcriptional repression with an important role in liver fibrosis. Currently, there is very little knowledge available as to how DNA methylation controls the phenotype of hepatic stellate cell (HSC), the key cell type responsible for onset and progression of liver fibrosis. Moreover, recently discovered DNA hydroxymethylation (5-hmC) is involved in transcriptional activation and its patterns are often altered in human diseases. The aim of this study is to investigate the role of DNA methylation/hydroxymethylation in liver fibrosis. METHODS: Levels of 5-mC and 5-hmC were assessed by slot blot in a range of animal liver fibrosis models and human liver diseases. Expression levels of TET and DNMT enzymes were measured by qRT-PCR and Western blotting. Reduced representation bisulfite sequencing (RRBS) method was used to examine 5-mC and 5 hmC patterns in quiescent and in vivo activated rat HSC. RESULTS: We demonstrate global alteration in 5-mC and 5-hmC and their regulatory enzymes that accompany liver fibrosis and HSC transdifferentiation. Using RRBS, we show exact genomic positions of changed methylation patterns in quiescent and in vivo activated rat HSC. In addition, we demonstrate that reduction in DNMT3a expression leads to attenuation of pro-fibrogenic phenotype in activated HSC. CONCLUSIONS: Our data suggest that DNA 5-mC/5-hmC is a crucial step in HSC activation and therefore fibrogenesis. Changes in DNA methylation during HSC activation may bring new insights into the molecular events underpinning fibrogenesis and may provide biomarkers for disease progression as well as potential new drug targets. PMID- 26632636 TI - Candidate proteomic biomarkers for non-alcoholic fatty liver disease (steatosis and non-alcoholic steatohepatitis) discovered with mass-spectrometry: a systematic review. AB - CONTEXT: Non-alcoholic fatty liver disease (NAFLD) is characterized by lipid accumulation in the liver which is accompanied by a series of metabolic deregulations. There are sustained research efforts focusing upon biomarker discovery for NAFLD diagnosis and its prognosis in order investigate and follow up patients as minimally invasive as possible. OBJECTIVE: The objective of this study is to critically review proteomic studies that used mass spectrometry techniques and summarize relevant proteomic NAFLD candidate biomarkers. METHODS: Medline and Embase databases were searched from inception to December 2014. RESULTS: A final number of 22 records were included that identified 251 candidate proteomic biomarkers. Thirty-three biomarkers were confirmed - 14 were found in liver samples, 21 in serum samples, and two from both serum and liver samples. CONCLUSION: Some of the biomarkers identified have already been extensively studied regarding their diagnostic and prognostic capacity. However, there are also more potential biomarkers that still need to be addressed in future studies. PMID- 26632637 TI - Up-regulation of Proinflammatory Genes and Cytokines Induced by S100A8 in CD8+ T Cells in Lichen Planus. AB - Lichen planus (LP) is a chronic inflammatory mucocutaneous disease. The inflammatory status of LP may be related to S100A8 (myeloid-related protein 8; MRP8) activation of cytotoxic cells. The aims of this study were to evaluate S100A8 expression in skin lesions and the in vitro effects of S100A8 on CD8+ T cells and natural killer (NK) cells in LP. Increased levels of S100A8/S100A9 were detected in the skin lesions as well as in the sera of subjects with LP. S100A8 expression induced an increased cytotoxic response by peripheral blood CD8+CD107a+ T cells as well as by NK CD56bright cells in patients with LP. Increased expression of interleukin (IL)-1?, tumour necrosis factor (TNF) and IL 6 in the CD8+ T cells of patients with LP was induced by S100A8, in contrast to the control group that produced IL- 10 and interferon type I genes. These data suggest that, in individuals with LP, S100A8 may exert distinct immunomodulatory and cytotoxicity functions. PMID- 26632638 TI - Erythrokeratoderma Variabilis Caused by p.Gly45Glu in Connexin 31: Importance of the First Extracellular Loop Glycine Residue for Gap Junction Function. PMID- 26632640 TI - Vagal stimulation to suppress alternans: Are we saving lives or simply masking surrogate markers? PMID- 26632639 TI - Neural substrate of quality of life in patients with schizophrenia: a magnetisation transfer imaging study. AB - The aim of this study was to investigate the neural substrate underlying quality of life (QoL) and to demonstrate the microstructural abnormalities associated with impaired QoL in a large sample of patients with schizophrenia, using magnetisation transfer imaging. A total of 81 right-handed men with a diagnosis of schizophrenia and 25 age- and sex-similar healthy controls were included and underwent a 3T MRI with magnetization transfer ratio (MTR) to detect microstructural abnormalities. Compared with healthy controls, patients with schizophrenia had grey matter (GM) decreased MTR values in the temporal lobe (BA21, BA37 and BA38), the bilateral insula, the occipital lobe (BA17, BA18 and BA19) and the cerebellum. Patients with impaired QoL had lower GM MTR values relative to patients with preserved QoL in the bilateral temporal pole (BA38), the bilateral insula, the secondary visual cortex (BA18), the vermis and the cerebellum. Significant correlations between MTR values and QoL scores (p < 0.005) were observed in the GM of patients in the right temporal pole (BA38), the bilateral insula, the vermis and the right cerebellum. Our study shows that QoL impairment in patients with schizophrenia is related to the microstructural changes in an extensive network, suggesting that QoL is a bio-psychosocial marker. PMID- 26632641 TI - Monomorphic ventricular tachycardia in Brugada syndrome: True-true but related? PMID- 26632642 TI - Body Composition and Mortality Predictors in Hemodialysis Patients. AB - OBJECTIVE: To evaluate how different compartments of body composition can affect survival in hemodialysis (HD) patients. DESIGN: Multicenter longitudinal observational study of a cohort of patients in HD with 12 months of follow-up. SETTING: Patients from 34 Nephrocare dialysis units in Portugal were included. SUBJECTS: A total of 697 patients on maintenance HD during 4 hours 3 days per week were enrolled. INTERVENTION: Dry weight, presence of diabetes, body mass index (BMI), lean tissue index (LTI), fat tissue index (FTI), body cell mass index (BCMI), albumin and hydration status were recorded at baseline. In all patients, the assessment of body composition was carried out using the Body Composition Monitor (BCM; Fresenius Medical Care a Deutschland GmbH, Germany). MAIN OUTCOME MEASURE: Survival during a 12-month period of follow-up. RESULTS: Patient's mean (+/-standard deviation) age was 65.4 +/- 14.3 years, and median (interquartile range) HD vintage was 41 (19-81) months. Patients who died during the study period, had higher age (P < .001), lower dry weight (P = .001), BMI (P < .001), albumin (P < .001), LTI (P = .015), and also lower BCMI (P = .046). Patients with diabetes (P = .045), BMI < 18.5 kg/m(2) (P < .001), albumin < 4.0 g/dL (P < .001), relative overhydration >= 15% (P = .001), low FTI (P = .019), and also those in the lowest tertile of BCMI (P = .022) displayed a significantly worse survival. In the Cox regression analysis, the overall mortality of patient was related to low FTI, relative overhydration, BMI < 18.5 kg/m(2), BCMI <= 5.2 kg/m(2), and albumin < 4.0 g/dL. CONCLUSIONS: Several body composition parameters demonstrated to have an important role in predicting 1-year mortality in HD patients. Albumin, FTI, and BMI were useful predictors of mortality in these patients. PMID- 26632643 TI - Adverse health effects and histological changes in white sturgeon (Acipenser transmontanus) exposed to dietary selenomethionine. AB - It has been shown that selenium (Se) released to the aquatic environment can have devastating effects on local wildlife. White sturgeon (Acipenser transmontanus) have a life history particularly susceptible to contaminants, and their protection is of interest as they are culturally and economically important, and many populations are classified as endangered. During the present 72-d dietary study, multiple signs of decreased health and Se lethality were observed. Juvenile white sturgeon were given diets containing 1.4 MUg, 5.6 MUg, 22.4 MUg, or 104.4 MUg selenomethionine/g food (dry mass). Selenium accumulated in muscle and liver tissue in a dose-dependent manner. Edema causing exophthalmos developed within 15 d and 23 d, and lethal effects occurred in 54% and 22% of fish in the high- and medium-dose groups, respectively. Growth and hepatosomatic index were significantly lower in the high-dose group, which also had a high incidence of food avoidance. Histology of the liver revealed a dose-dependent increase in melanomacrophage aggregates and decrease of energy stores, which indicated toxicity. These results indicate that white sturgeon are susceptible to the effects of Se accumulation over relatively short time periods. This stresses the need for continued sturgeon research and studies looking into the environmental fate and regulation of released Se. Environ Toxicol Chem 2016;35:1741-1750. (c) 2015 SETAC. PMID- 26632644 TI - The Feasibility of Using Augmented Auditory Feedback From a Pressure Detecting Insole to Reduce the Knee Adduction Moment: A Proof of Concept Study. AB - The objective of this work was to conduct a proof of concept study utilizing auditory feedback from a pressure-detecting shoe insole to shift plantar pressure medially in order to reduce the knee adduction moment (KAM). When compared with normal walking, 32 healthy subjects significantly reduced their peak KAM using feedback (p < 0.001). When compared with medial thrust gait, an established gait modification, walking with pressure-based feedback was equally effective at reducing the peak KAM, yet it successfully mitigated other potentially detrimental gait measures such as the peak knee flexion moment (KFM), knee internal rotation moment (KIrM), and a reduction in speed. PMID- 26632645 TI - The interrelationship between dengue incidence and diurnal ranges of temperature and humidity in a Sri Lankan city and its potential applications. AB - BACKGROUND: Temperature, humidity, and other weather variables influence dengue transmission. Published studies show how the diurnal fluctuations of temperature around different mean temperatures influence dengue transmission. There are no published studies about the correlation between diurnal range of humidity and dengue transmission. OBJECTIVE: The goals of this study were to determine the correlation between dengue incidence and diurnal fluctuations of temperature and humidity in the Sri Lankan city of Kandy and to explore the possibilities of using that information for better control of dengue. DESIGN: We calculated the weekly dengue incidence in Kandy during the period 2003-2012, after collecting data on all of the reported dengue patients and estimated midyear populations. Data on daily maximum and minimum temperatures and night-time and daytime humidity were obtained from two weather stations, averaged, and converted into weekly data. The number of days per week with a diurnal temperature range (DTR) of >10 degrees C and <10 degrees C and the number of days per week with a diurnal humidity range (DHR) of >20 and <15% were calculated. Wavelet time series analysis was performed to determine the correlation between dengue incidence and diurnal ranges of temperature and humidity. RESULTS: There were negative correlations between dengue incidence and a DTR >10 degrees C and a DHR >20% with 3.3-week and 4-week lag periods, respectively. Additionally, positive correlations between dengue incidence and a DTR <10 degrees C and a DHR <15% with 3- and 4-week lag periods, respectively, were discovered. CONCLUSIONS: These findings are consistent with the results of previous entomological studies and theoretical models of DTR and dengue transmission correlation. It is important to conduct similar studies on diurnal fluctuations of humidity in the future. We suggest ways and means to use this information for local dengue control and to mitigate the potential effects of the ongoing global reduction of DTR on dengue incidence. PMID- 26632646 TI - Bactericidal Dendritic Polycation Cloaked with Stealth Material via Lipase Sensitive Intersegment Acquires Neutral Surface Charge without Losing Membrane Disruptive Activity. AB - Net cationicity of membrane-disruptive antimicrobials is necessary for their activity but may elicit immune attack when administered intravenously. By cloaking a dendritic polycation (G2) with poly(caprolactone-b-ethylene glycol) (PCL-b-PEG), we obtain a nanoparticle antimicrobial, G2-g-(PCL-b-PEG), which exhibits neutral surface charge but kills >99.9% of inoculated bacterial cells at <=8 MUg/mL. The observed activity may be attributed PCL's responsive degradation by bacterial lipase and the consequent exposure of the membrane-disruptive, bactericidal G2 core. Moreover, G2-g-(PCL-b-PEG) exhibits good colloidal stability in the presence of serum and insignificant hemolytic toxicity even at >=2048 MUg/mL. suggesting good blood compatibility required for intravenous administration. PMID- 26632647 TI - The protective effect of vildagliptin in chronic experimental cyclosporine A induced hepatotoxicity. AB - The study examined the effect of dipeptidyl peptidase-4 (DPP-4) inhibitor, vildagliptin, in cyclosporine (CsA)-induced hepatotoxicity. Rats were divided into 4 groups treated for 28 days: control (vehicle), vildagliptin (10 mg/kg, orally), CsA (20 mg/kg, s.c.), and CsA-vildagliptin group. Liver function was assessed by measuring serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyltransferase (gammaGT), lactate dehydrogenase (LDH), and albumin, and histopathological changes of liver were examined. Oxidative stress markers were evaluated. Assessment of nuclear factor kappa B (NF-kappaB) activity in hepatic nuclear extract, serum DPP-4, and expression of Bax and Bcl2 were also done. CsA-induced hepatotoxicity was evidenced by increase in serum levels of AST, ALT, and gammaGT; a decrease in serum albumin; and a significant alteration in hepatic architecture. Also, significant increase in thiobarbituric acid reactive substance (TBARS) and decrease in superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione (GSH) levels, increased expression Bax proteins with deceased expression of Bcl2, and increased hepatic activity of NF-kappaB and serum DPP-4 level were observed upon CsA treatment. Vildagliptin significantly improved all altered parameters induced by CsA administration. Vildagliptin has the potential to protect the liver against CsA-induced hepatotoxicity by reducing oxidative stress, DPP-4 activity, apoptosis, and inflammation. PMID- 26632648 TI - A Rigorous and Efficient Method To Reweight Very Large Conformational Ensembles Using Average Experimental Data and To Determine Their Relative Information Content. AB - Flexible polypeptides such as unfolded proteins may access an astronomical number of conformations. The most advanced simulations of such states usually comprise tens of thousands of individual structures. In principle, a comparison of parameters predicted from such ensembles to experimental data provides a measure of their quality. In practice, analyses that go beyond the comparison of unbiased average data have been impossible to carry out on the entirety of such very large ensembles and have, therefore, been restricted to much smaller subensembles and/or nondeterministic algorithms. Here, we show that such very large ensembles, on the order of 10(4) to 10(5) conformations, can be analyzed in full by a maximum entropy fit to experimental average data. Maximizing the entropy of the population weights of individual conformations under experimental chi(2) constraints is a convex optimization problem, which can be solved in a very efficient and robust manner to a unique global solution even for very large ensembles. Since the population weights can be determined reliably, the reweighted full ensemble presents the best model of the combined information from simulation and experiment. Furthermore, since the reduction of entropy due to the experimental constraints is well-defined, its value provides a robust measure of the information content of the experimental data relative to the simulated ensemble and an indication for the density of the sampling of conformational space. The method is applied to the reweighting of a 35,000 frame molecular dynamics trajectory of the nonapeptide EGAAWAASS by extensive NMR (3)J coupling and RDC data. The analysis shows that RDCs provide significantly more information than (3)J couplings and that a discontinuity in the RDC pattern at the central tryptophan is caused by a cluster of helical conformations. Reweighting factors are moderate and consistent with errors in MD force fields of less than 3kT. The required reweighting is larger for an ensemble derived from a statistical coil model, consistent with its coarser nature. We call the method COPER, for convex optimization for ensemble reweighting. Similar advantages of large-scale efficiency and robustness can be obtained for other ensemble analysis methods with convex targets and constraints, such as constrained chi(2) minimization and the maximum occurrence method. PMID- 26632649 TI - Facile Deep and Ultradeep Hydrodesulfurization by the [((i)Pr3P)Ni]5H6 Cluster Compared to Mononuclear Ni Sources. AB - The pentanuclear nickel cluster [((i)Pr3P)Ni]5H6 facilitates the room-temperature hydrodesulfurization of dibenzothiophene, 4-methyldibenzothiophene, and 4,6 dimethydibenzothiophene. These reactions provide the new tetranuclear nickel hydride sulfide [((i)Pr3P)Ni]4(MU-H)4(MU4-S) (1). In comparison, the dinuclear dinitrogen nickel complex [((i)Pr3P)2Ni]2(MU-N2) undergoes oxidative addition of the C-S bonds of dibenzothiophene and 4-methyl dibenzothiophene to provide the metallacycles Ni3(P(i)Pr3)3C12H8S (2) and Ni3(P(i)Pr3)3C13H10S (3), respectively, but 4,6-dimethydibenzothiophene is unreactive, even with heating to 70 degrees C for a week. The reaction of [((i)Pr3P)Ni]5H6 with SP(i)Pr3 in toluene provided [((i)Pr3P)Ni]5H6(S) (4), which was observed and characterized by NMR spectroscopy. The addition of vinyltrimethylsilane to 4 provided the best synthetic route to 1, with ((i)Pr3P)Ni(eta(2)-CH2?CHSiMe3)2 (5) generated as a byproduct. PMID- 26632650 TI - Enhanced Electrical Conductivity in Extruded Single-Wall Carbon Nanotube Wires from Modified Coagulation Parameters and Mechanical Processing. AB - Single-wall carbon nanotubes (SWCNTs) synthesized via laser vaporization have been dispersed using chlorosulfonic acid (CSA) and extruded under varying coagulation conditions to fabricate multifunctional wires. The use of high purity SWCNT material based upon established purification methods yields wires with highly aligned nanoscale morphology and an over 4* improvement in electrical conductivity over as-produced SWCNT material. A series of eight liquids have been evaluated for use as a coagulant bath, and each coagulant yielded unique wire morphology based on its interaction with the SWCNT-CSA dispersion. In particular, dimethylacetamide as a coagulant bath is shown to fabricate highly uniform SWCNT wires, and acetone coagulant baths result in the highest specific conductivity and tensile strength. A 2* improvement in specific conductivity has been measured for SWCNT wires following tensioning induced both during extrusion via increased coagulant bath depth and during solvent evaporation via mechanical strain, over that of as-extruded wires from shallower coagulant baths. Overall, combination of the optimized coagulation parameters has yielded acid-doped wires with the highest reported room temperature electrical conductivities to date of 4.1-5.0 MS/m and tensile strengths of 210-250 MPa. Such improvements in bulk electrical conductivity can impact the adoption of metal-free, multifunctional SWCNT materials for advanced cabling architectures. PMID- 26632652 TI - Total and High-density Lipoprotein Cholesterol in Adults: United States, 2011 2014. AB - KEY FINDINGS: High levels of total cholesterol and low levels of high-density lipoprotein (HDL) cholesterol (the "good cholesterol") are risk factors for coronary heart disease (1-3). During 2009-2010, 13.4% of adults had high total cholesterol and 21.3% had low HDL cholesterol (4). This report presents estimates of the percentage of adults with high total and low HDL cholesterol during 2011 2014, and trends in prevalence of high total and low HDL cholesterol from 2007 2008 to 2013-2014. Analysis is based on measured cholesterol only and does not account for cholesterol-lowering medication use. PMID- 26632651 TI - Novel Tacrine-Benzofuran Hybrids as Potent Multitarget-Directed Ligands for the Treatment of Alzheimer's Disease: Design, Synthesis, Biological Evaluation, and X ray Crystallography. AB - Twenty-six new tacrine-benzofuran hybrids were designed, synthesized, and evaluated in vitro on key molecular targets for Alzheimer's disease. Most hybrids exhibited good inhibitory activities on cholinesterases and beta-amyloid self aggregation. Selected compounds displayed significant inhibition of human beta secretase-1 (hBACE-1). Among the 26 hybrids, 2e showed the most interesting profile as a subnanomolar selective inhibitor of human acetylcholinesterase (hAChE) (IC50 = 0.86 nM) and a good inhibitor of both beta-amyloid aggregation (hAChE- and self-induced, 61.3% and 58.4%, respectively) and hBACE-1 activity (IC50 = 1.35 MUM). Kinetic studies showed that 2e acted as a slow, tight-binding, mixed-type inhibitor, while X-ray crystallographic studies highlighted the ability of 2e to induce large-scale structural changes in the active-site gorge of Torpedo californica AChE (TcAChE), with significant implications for structure based drug design. In vivo studies confirmed that 2e significantly ameliorates performances of scopolamine-treated ICR mice. Finally, 2e administration did not exhibit significant hepatotoxicity. PMID- 26632654 TI - Structure Tuning of Electrostatically Self-Assembled Nanoparticles through pH. AB - pH can be used to tune the self-assembly of cationic polyelectrolyte dendrimers and oppositely charged dyes and to produce particles with a desired shape and size in aqueous solution. We present fundamental insight into the effect of pH on electrostatic self-assembly of poly(amidoamine) dendrimers of generation 4 and di and trivalent anionic organic dyes. The solution pH is used as a key to turn on the interaction and to control the association by regulating the macroion charge. Stable and well-defined nanoparticles are formed in solution, being more stable at low pH where the dendrimer protonation is complete. Nanoparticle stability was correlated with zeta-potential measurements. We prove that the assemblies are electrostatically stabilized and elucidate the importance of the surface charge density. pH was also used as a key to nanoparticle dimension and shape. For example, smaller particles form at a lower pH. The nanostructures have been characterized using dynamic light scattering and small-angle neutron scattering. A "phase diagram" has been developed for each dye, showing the assembly size, shape, and instability regions dependent on the pH. Overall, a pH-responsive nanoparticle shape is a key step toward the design of novel smart therapeutic carrier systems. PMID- 26632653 TI - Conformational Fine-Tuning of Pore-Forming Peptide Potency and Selectivity. AB - To better understand the sequence-structure-function relationships that control the activity and selectivity of membrane-permeabilizing peptides, we screened a peptide library, based on the archetypal pore-former melittin, for loss-of function variants. This was accomplished by assaying library members for failure to cause leakage of entrapped contents from synthetic lipid vesicles at a peptide to-lipid ratio of 1:20, 10-fold higher than the concentration at which melittin efficiently permeabilizes the same vesicles. Surprisingly, about one-third of the library members are inactive under these conditions. In the negative peptides, two changes of hydrophobic residues to glycine were especially abundant. We show that loss-of-function activity can be completely recapitulated by a single residue change of the leucine at position 16 to glycine. Unlike the potently cytolytic melittin, the loss-of-function peptides, including the single-site variant, are essentially inactive against phosphatidylcholine vesicles and multiple types of eukaryotic cells. Loss of function is shown to result from a shift in the binding-folding equilibrium away from the active, bound, alpha helical state toward the inactive, unbound, random-coil state. Accordingly, the addition of anionic lipids to synthetic lipid vesicles restored binding, alpha helical secondary structure, and potent activity of the "negative" peptides. While nontoxic to mammalian cells, the single-site variant has potent bactericidal activity, consistent with the anionic nature of bacterial membranes. The results show that conformational fine-tuning of helical pore-forming peptides is a powerful way to modulate their activity and selectivity. PMID- 26632655 TI - Clinical efficacy and safety of laparoscopic nerve-sparing radical hysterectomy for locally advanced cervical cancer. AB - OBJECTIVE: To evaluate the feasibility and safety of laparoscopic nerve-sparing radical hysterectomy (LNRH) for locally advanced cervical cancer (LACC) after neoadjuvant chemotherapy (NACT). METHODS: 120 patients with stage Ib2 and IIa2 cervical cancer were treated with surgery combined with preoperative NACT in the Department of Obstetrics and Gynecology, PLA General Hospital. Eligible patients were divided into two groups according to surgery type: patients who underwent LNRH were assigned to one group, while the second group included patients who underwent laparoscopic radical hysterectomy (LRH) after administration of NACT. We compared these patients' general clinical information and surgical characteristics, and we assessed their bladder function and intestinal function recovery by questionnaire. RESULTS: No significant differences were found between the groups in patients' age or surgical characteristics. The mean duration of postoperative catheterization in the LNRH group was shorter than in the LRH group (P < 0.001). The intestinal and bladder function of patients in the LNRH group also recovered better than that of patients in the LRH group. CONCLUSION: LNRH is a feasible and safe procedure for LACC after NACT and reduces surgical complications. PMID- 26632657 TI - Flueggether A and Virosinine A, Anti-HIV Alkaloids from Flueggea virosa. AB - Two new alkaloids, flueggether A (1) and virosinine A (2), were isolated from a Chinese medicinal plant, Flueggea virosa. Their structures were assigned via spectroscopic methods with the absolute configurations of 1 and 2 being established by X-ray diffraction analysis and calculated electronic circular dichroism data, respectively. Compound 1 represents the first example with an ether bridge of Securinega alkaloid oligomers, and 2 bears a new heterocyclic backbone. Both alkaloids showed mild in vitro anti-HIV activity. PMID- 26632656 TI - Elucidating the Molecular Composition of Cartilage by Proteomics. AB - Articular cartilage consists of chondrocytes and two major components, a collagen rich framework and highly abundant proteoglycans. Most prior studies defining the zonal distribution of cartilage have extracted proteins with guanidine-HCl. However, an unextracted collagen-rich residual is left after extraction. In addition, the high abundance of anionic polysaccharide molecules extracted from cartilage adversely affects the chromatographic separation. In this study, we established a method for removing chondrocytes from cartilage sections with minimal extracellular matrix protein loss. The addition of surfactant to guanidine-HCl extraction buffer improved protein solubility. Ultrafiltration removed interference from polysaccharides and salts. Almost four-times more collagen peptides were extracted by the in situ trypsin digestion method. However, as expected, proteoglycans were more abundant within the guanidine-HCl extraction. These different methods were used to extract cartilage sections from different cartilage layers (superficial, intermediate, and deep), joint types (knee and hip), and disease states (healthy and osteoarthritic), and the extractions were evaluated by quantitative and qualitative proteomic analyses. The results of this study led to the identifications of the potential biomarkers of osteoarthritis (OA), OA progression, and the joint specific biomarkers. PMID- 26632658 TI - The Chinese Ebola Diagnostic and Treatment Center in Liberia as a model center. PMID- 26632659 TI - Emergence of a New Delhi metallo-beta-lactamase-1-producing Pseudomonas aeruginosa in Singapore. PMID- 26632660 TI - Comparison of the microbiological characteristics and virulence factors of ST131 and non-ST131 clones among extended-spectrum beta-lactamase-producing Escherichia coli causing bacteremia. AB - We evaluated the molecular epidemiology and microbiological characteristics of extended-spectrum beta-lactamase-producing Escherichia coli (ESBL-EC) isolates that cause bacteremia in Korean hospitals, focusing especially on ST131. Our data suggest that ST131 isolates possessed more virulence traits and showed more multidrug resistance patterns than non-ST131 isolates. Among CTX-M-15 producers, the frequency of serum resistance was significantly higher in ST131 than in non ST131. As in other parts of the world, the ESBL-EC ST131 clone has emerged and disseminated in both community and hospital settings in Korea, including in blood isolates in patients with bacteremia. PMID- 26632661 TI - Management of critical limb ischemia in the patient with diabetes. AB - Management of peripheral artery disease (PAD) and critical limb ischemia (CLI) in the patient with diabetes is an ever-important challenge for the vascular specialist. Patients with diabetes and CLI represent a unique subset--due to the different etiology, clinical presentation and outcomes compared to patients with CLI but no diabetes--and are at a high risk for the development of diabetic foot ulceration. The presence of PAD in a patient with diabetic foot ulceration is in turn associated with much poorer outcomes, including failure to heal wounds and, ultimately, increased risk of limb loss, as well as increased overall cardiovascular mortality. There remains a paucity of robust evidence as to the appropriate first-line method of revascularization in a patient with diabetes and CLI, however the clinical outcomes (following endovascular or open surgery) appear broadly similar and the decision of whether, when and how to revascularize should therefore be taken on an individual patient basis, in the context of a multi-disciplinary team. However, revascularization is only one part of the treatment of a patient with diabetes and ulceration and the outcomes of successful revascularization are not always predictable. The presence of infection, edema and neuropathy may also contribute to reduced perfusion and poor oxygenation and these factors should be addressed concurrently, along with aggressive medical management of cardiovascular risk factors. PMID- 26632662 TI - Notes from the Field: Increase in Human Cases of Tularemia--Colorado, Nebraska, South Dakota, and Wyoming, January-September 2015. AB - Tularemia is a rare, often serious disease caused by a gram-negative coccobacillus, Francisella tularensis, which infects humans and animals in the Northern Hemisphere. Approximately 125 cases have been reported annually in the United States during the last two decades. As of September 30, a total of 100 tularemia cases were reported in 2015 among residents of Colorado (n = 43), Nebraska (n = 21), South Dakota (n = 20), and Wyoming (n = 16) (Figure). This represents a substantial increase in the annual mean number of four (975% increase), seven (200%), seven (186%) and two (70%) cases, respectively, reported in each state during 2004-2014. PMID- 26632663 TI - Amino Acid Metaclusters: Implications of Growth Trends on Peptide Self-Assembly and Structure. AB - Ion-mobility mass spectrometry is utilized to examine the metacluster formation of serine, asparagine, isoleucine, and tryptophan. These amino acids are representative of different classes of noncharged amino acids. We show that they can form relatively large metaclusters in solution that are difficult or impossible to observe by traditional solution techniques. We further demonstrate, as an example, that the formation of Ser metaclusters is not an ESI artifact because large metaclusters can be detected in negative polarity and low concentration with similar cross sections to those measured in positive polarity and higher concentration. The growth trends of tryptophan and isoleucine metaclusters, along with serine, asparagine, and the previously studied phenylalanine, are balanced among various intrinsic properties of individual amino acids (e.g., hydrophobicity, size, and shape). The metacluster cross sections of hydrophilic residues (Ser, Asn, Trp) tend to stay on or fall below the isotropic model trend lines whereas those of hydrophobic amino acids (Ile, Phe) deviate positively from the isotropic trend lines. The growth trends correlate well to the predicted aggregation propensity of individual amino acids. From the metacluster data, we introduce a novel approach to score and predict aggregation propensity of peptides, which can offer a significant improvement over the existing methods in terms of accuracy. Using a set of hexapeptides, we show that the strong negative deviations of Ser metaclusters from the isotropic model leads a prediction of microcrystalline formation for the SFSFSF peptide, whereas the strong positive deviation of Ile leads to prediction or fibril formation for the NININI peptide. Both predictions are confirmed experimentally using ion mobility and TEM measurements. The peptide SISISI is predicted to only weakly aggregate, a prediction confirmed by TEM. PMID- 26632664 TI - Controversies in the pathophysiology and management of hyphema. AB - Traumatic hyphemas present dilemmas to physicians. There are numerous controversies pertaining to the optimal approach to traumatic hyphema and no standardized guidelines for its management. We address some of these controversies and present a pragmatic approach. We discuss various medical agents and surgical techniques available for treatment, along with the indications for their use. We address the complications associated with hyphema and how to diagnose and manage them and consider the management of hyphema in special situations such as in children and sickle-cell anemia and in rare clinical syndromes such as recurrent hyphema after placement of anterior chamber intraocular lenses. PMID- 26632667 TI - The Global Champion for End-of-Life Care: Who Are You? What Is Keeping You? PMID- 26632665 TI - Emerging Roles for MicroRNAs in Perioperative Medicine. AB - MicroRNAs (miRNAs) are small, non-protein-coding, single-stranded RNAs. They function as posttranscriptional regulators of gene expression by interacting with target mRNAs. This process prevents translation of target mRNAs into a functional protein. miRNAs are considered to be functionally involved in virtually all physiologic processes, including differentiation and proliferation, metabolism, hemostasis, apoptosis, and inflammation. Many of these functions have important implications for anesthesiology and critical care medicine. Studies indicate that miRNA expression levels can be used to predict the risk for eminent organ injury or sepsis. Pharmacologic approaches targeting miRNAs for the treatment of human diseases are currently being tested in clinical trials. The present review highlights the important biological functions of miRNAs and their usefulness as perioperative biomarkers and discusses the pharmacologic approaches that modulate miRNA functions for disease treatment. In addition, the authors discuss the pharmacologic interactions of miRNAs with currently used anesthetics and their potential to impact anesthetic toxicity and side effects. PMID- 26632668 TI - ISNCC Tobacco Position Statement. PMID- 26632666 TI - PTEN deficiency reprogrammes human neural stem cells towards a glioblastoma stem cell-like phenotype. AB - PTEN is a tumour suppressor frequently mutated in many types of cancers. Here we show that targeted disruption of PTEN leads to neoplastic transformation of human neural stem cells (NSCs), but not mesenchymal stem cells. PTEN-deficient NSCs display neoplasm-associated metabolic and gene expression profiles and generate intracranial tumours in immunodeficient mice. PTEN is localized to the nucleus in NSCs, binds to the PAX7 promoter through association with cAMP responsive element binding protein 1 (CREB)/CREB binding protein (CBP) and inhibits PAX7 transcription. PTEN deficiency leads to the upregulation of PAX7, which in turn promotes oncogenic transformation of NSCs and instates 'aggressiveness' in human glioblastoma stem cells. In a large clinical database, we find increased PAX7 levels in PTEN-deficient glioblastoma. Furthermore, we identify that mitomycin C selectively triggers apoptosis in NSCs with PTEN deficiency. Together, we uncover a potential mechanism of how PTEN safeguards NSCs, and establish a cellular platform to identify factors involved in NSC transformation, potentially permitting personalized treatment of glioblastoma. PMID- 26632670 TI - Oral Oncolytic Agents--A Need for Research to Enhance Patient Centeredness? PMID- 26632671 TI - A novel intranuclear RNA vector system for long-term stem cell modification. AB - Genetically modified stem and progenitor cells have emerged as a promising regenerative platform in the treatment of genetic and degenerative disorders, highlighted by their successful therapeutic use in inherent immunodeficiencies. However, biosafety concerns over insertional mutagenesis resulting from integrating recombinant viral vectors have overshadowed the widespread clinical applications of genetically modified stem cells. Here, we report an RNA-based episomal vector system, amenable for long-term transgene expression in stem cells. Specifically, we used a unique intranuclear RNA virus, borna disease virus (BDV), as the gene transfer vehicle, capable of persistent infections in various cell types. BDV-based vectors allowed for long-term transgene expression in mesenchymal stem cells (MSCs) without affecting cellular morphology, cell surface CD105 expression or the adipogenicity of MSCs. Similarly, replication-defective BDV vectors achieved long-term transduction of human induced pluripotent stem cells, while maintaining the ability to differentiate into three embryonic germ layers. Thus, the BDV-based vectors offer a genomic modification-free, episomal RNA delivery system for sustained stem cell transduction. PMID- 26632672 TI - Anti-dengue virus nonstructural protein 1 antibodies contribute to platelet phagocytosis by macrophages. AB - Thrombocytopenia is an important clinical manifestation of dengue disease. The hypotheses concerning the pathogenesis of thrombocytopenia include decreased production and increased destruction or consumption of platelets. We previously suggested a mechanism of molecular mimicry in which antibodies (Abs) directed against dengue virus (DENV) nonstructural protein 1 (NS1) cross-react with platelets. Furthermore, several lines of evidence show activation of endothelial cells (ECs) and macrophages are related to dengue disease severity. Previous studies also suggested that Ab-opsonised platelets facilitate the engulfment of platelets by macrophages. Here we show that TNF-alpha-activated ECs upregulate adhesion molecule expression to enhance the binding of platelets and macrophages and lead to anti-DENV NS1 Ab-mediated platelet phagocytosis. We further demonstrate that the interaction between macrophages and TNF-alpha-activated ECs requires binding of FcgammaR with the Fc region of platelet-bound anti-DENV NS1 Abs. Importantly, the binding of anti-DENV NS1 Abs to platelets did not interfere with platelet adhesion to ECs. The adhesion molecules ICAM-1 and beta3 integrin expressed on ECs as well as the FcgammaR expressed on macrophages were critical in anti-DENV NS1 Ab-mediated platelet phagocytosis on activated ECs. Moreover, anti-DENV NS1 Abs dramatically enhanced platelet engulfment by macrophages in a murine model of DENV infection. Our study provides evidence for a novel role for anti-DENV NS1 Abs in the pathogenesis of thrombocytopenia in dengue disease by enhancing platelet phagocytosis by macrophages. PMID- 26632673 TI - Is Surveillance of Uveal Melanoma Just a Screen? PMID- 26632675 TI - Copper-Catalyzed Borylative Cross-Coupling of Allenes and Imines: Selective Three Component Assembly of Branched Homoallyl Amines. AB - A copper-catalyzed three-component coupling of allenes, bis(pinacolato)diboron, and imines allows regio-, chemo-, and diastereoselective assembly of branched alpha,beta-substituted-gamma-boryl homoallylic amines, that is, products bearing versatile amino, alkenyl, and borane functionality. Alternatively, convenient oxidative workup allows access to alpha-substituted-beta-amino ketones. A computational study has been used to probe the stereochemical course of the cross coupling. PMID- 26632676 TI - Assessment of Vocal Fold Function Using Transcutaneous Laryngeal Ultrasonography and Flexible Laryngoscopy. AB - IMPORTANCE: Evaluation of preoperative and postoperative vocal fold function is important in patients undergoing thyroid or parathyroid surgical procedures. Transcutaneous laryngeal ultrasonography (TLUSG) has been proposed as a promising noninvasive technique and alternative to flexible fiberoptic laryngoscopy. OBJECTIVE: To determine whether TLUSG can be an alternative to flexible laryngoscopy in evaluating vocal fold function. DESIGN, SETTING, AND PARTICIPANTS: A prospective study was performed from March 1, 2013, to July 31, 2014. Patients who were scheduled to undergo thyroid or parathyroid surgery by a single surgeon at a North American, university-based tertiary care center and who agreed to undergo preoperative and postoperative TLUSG and flexible fiberoptic laryngoscopy were enrolled. Patients were divided into 2 groups: nonoverweight (body mass index [calculated as weight in kilograms divided by height in meters squared] <25) and overweight or obese (body mass index >= 25). Follow-up was completed on February 28, 2015, and data were analyzed from March 1, 2013, to February 28, 2015. INTERVENTIONS: Preoperative and postoperative TLUSG and flexible fiber optic laryngoscopic assessments of vocal fold function. MAIN OUTCOMES AND MEASURES: The findings of TLUSG and flexible fiber optic laryngoscopy were compared for all patients and each body mass index group to assess the accuracy of TLUSG in assessing vocal fold function. RESULTS: A total of 250 patients (500 vocal folds) underwent evaluation, of whom 208 (83.2%) were women and with a mean (SD) age of 52.7 (14.3) years. On flexible fiberoptic laryngoscopy findings, 13 patients had preoperative vocal fold paralysis (VFP), and 14 postoperative new incidents of VFP were identified. Only 7 (53.9%) of the preoperative cases of VFP and 15 (55.6%) of the postoperative cases of VFP were identified by TLUSG. The sensitivity, specificity, and accuracy of preoperative TLUSG were 53.8%, 50.5%, and 50.6%, respectively; for postoperative TLUSG, 55.6%, 38.7%, and 39.6%, respectively. In the nonoverweight group, the preoperative TLUSG sensitivity, specificity, and accuracy were 100%, 70.0%, and 70.5%, respectively; in the overweight-obese group, 45.4%, 43.4%, and 43.5%, respectively (odds ratio, 3.16; 95% CI, 2.06-4.84; P < .001). Postoperative visualization of the vocal folds was more challenging, with a sensitivity, specificity, and accuracy of 83.3%, 55.6%, and 56.8%, respectively, in the nonoverweight group, and 47.6%, 32.6%, and 33.4%, respectively, in the overweight obese group (odds ratio, 2.62; 95% CI, 1.75-3.94; P < .001). CONCLUSIONS AND RELEVANCE: When evaluation of vocal fold function is indicated in patients undergoing thyroid and parathyroid surgery, TLUSG should not be considered as an alternative to the current practice of flexible fiberoptic laryngoscopy. Adequate ultrasonographic visualization of the vocal folds and arytenoids is challenging, especially in overweight and obese patients and in the postoperative setting. PMID- 26632677 TI - The Effectiveness of ART Score in Selecting Patients for Transarterial Chemoembolization Retreatment: A Cohort Study in Taiwan. AB - The major issue in selecting patients for transarterial chemoembolization (TACE) lies in determining the optimal number of TACE sessions that may benefit patients before switching to other therapies. This is often a subjective decision not based on any standardized protocol. The ART (Assessment for Retreatment with Transarterial chemoembolization) score was recently developed to determine patients who may benefit from multiple sessions of TACE for treatment of hepatocellular carcinoma. The primary aim of the study was to validate the ART score in a Taiwanese cohort. The secondary aims were to evaluate overall survival and clinical determinants of improved survival in patients treated with multiple TACE sessions. The ART score, clinical characteristics, and outcomes of 82 patients with hepatocellular carcinoma who received multiple TACE sessions at Taipei Veterans General Hospital from September 2007 to July 2013 were analyzed. Among the 82 patients evaluated, 69.5% (n = 57) had an ART score of 0 to 1.5 and 34.1% (n = 25) had a score of >=2.5. The median overall survival was 23.1 months and the overall mortality rate was 62.2% (n = 51). The ART score was not associated with survival (P = 0.58). Multivariate Cox regression analysis revealed that tumor size >7.2 cm (hazard ratio 4.44, P < 0.001), aspartate transaminase (AST) level above 95 IU/L (hazard ratio 2.18, P = 0.02), AST increase more than 25% (hazard ratio 2.13, P = 0.02), 2nd/1st (pre-TACE) alpha fetoprotein ratio (hazard ratio 1.40, P = 0.001), and lack of radiological response to TACE (hazard ratio 2.21, P = 0.02) were independent clinical determinants of survival. The ART score was not found to be effective in selecting patients for TACE retreatment in our Taiwanese cohort. Large tumor size, high AST level, high 2nd/1st (pre-TACE) alpha-fetoprotein ratio, AST increase >25%, and lack of radiological response to TACE were independently associated with shorter survival after TACE therapy. PMID- 26632678 TI - Value of Neutrophil Counts in Predicting Surgery-Related Acute Kidney Injury and the Interaction of These Counts With Diabetes in Chronic Kidney Disease Patients With Hypertension: A Cohort Study. AB - As a component of routine blood cell analyses, the quantity of neutrophils present is a proven predictor of morbidity and mortality in several clinical settings. However, whether episodes of acute kidney injury (AKI) are associated with higher neutrophil counts in vulnerable groups, such as chronic kidney disease (CKD) patients with hypertension, are unknown. This study was conducted to investigate the relationship between neutrophil counts and the incidence of surgery-related AKI in CKD patients with hypertension.This was a retrospective cohort study of the relationship between neutrophils and surgery-related AKI. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using logistic regression models.In total, 119 (11.9%) of 998 patients experienced surgery-related AKI during hospitalization from October 2008 to February 2013. We divided patients into 4 quartiles according to their neutrophil counts. After adjusting for multiple covariates, the patients in the 4th quartile of neutrophil counts had greater ORs for AKI compared to those in the 1st quartile. The incidence of AKI increased 1.59-fold for those patients with neutrophil counts >=6.30 * 10/L. There was a positive linear association between the neutrophil count upon admission and the predicted probability of AKI. The cross-validation revealed a statistically significant predictive accuracy for AKI (area under the curve (AUC) = 0.68, 95% CI, 0.67-0.69). The interaction analyses revealed that higher neutrophil counts are associated with a heightened risk of AKI in the presence of diabetes (OR = 3.38, 95% CI, 1.06-10.80). There were no interactions between neutrophil counts and age (P = 0.371), sex (P = 0.335), estimated glomerular filtration rate (P = 0.487), systolic blood pressure (P = 0.950), diastolic blood pressure (P = 0.977), the presence of chronic heart failure (P = 0.226), or sepsis (P = 0.796).The neutrophil count upon admission, an index that is easily and rapidly measured, is valuable for the prediction of surgery-related AKI in CKD patients with hypertension, especially in those with diabetes. PMID- 26632679 TI - Evaluation of Degenerative Lumbar Scoliosis After Short Segment Decompression and Fusion. AB - The objective of this study was to investigate short segment decompression of degenerative lumbar scoliosis (DLS) and the efficiency of fusion treatment.After DLS surgery, the patients were retrospectively reviewed using the VAS (visual analog scale) and ODI (Oswestry Disability Index) to assess clinical outcomes. All patients underwent posterior lumbar decompressive laminectomy, pedicle screw internal fixation, and posterolateral bone graft fusion surgery. Radiographic measurements included the scoliotic Cobb angle, the fused Cobb angle, the anterior intervertebral angle (AIA), the sagittal intervertebral angle (SIA), and lumbar lordosis angle. The relationships between these parameters were examined by bivariate Pearson analysis and linear regression analysis.Preoperatively, the Cobb angle at the scoliotic segment was 15.4 degrees , which decreased to 10.2 degrees immediately following surgery (P < 0.05). The AIA significantly increased by the last follow-up (4.4 +/- 3.4) compared with pre- and postoperative values (2.5 +/- 2.8 and 2.2 +/- 2.4, respectively; P < 0.05). However, the scoliotic Cobb angle and the AIA did not correlate with the VAS or ODI scores. At the final follow-up, no patients had pseudoarthrosis or internal instrumentation-related complications.Short fusion surgical treatment results in limited DLS correction, with correction loss over time. The AIA between the upper adjacent segment and proximal fused vertebra continues to increase postoperatively, which does not exacerbate clinical symptoms, as reflected by the low reoperation rates for repairing degeneration at adjacent levels. PMID- 26632680 TI - Roentgenographic Evaluation of the Spine in Patients With Osteogenesis Imperfecta. AB - Osteogenesis imperfecta (OI) is a hereditary connective tissue disorder that leads to bone weakness and deformities, especially in the spine, which can lead to poor outcomes.The aim of this study was to find patterns and risk factors in spinal deformities in patients with OI.In a retrospective study, 70 patients with OI were selected. Radiographs of the spine were evaluated. We observed the presence or absence of the following changes: biconcave vertebrae, chest and vertebral deformities, unilateral rib, and thoracolumbar kyphosis. The greater curve was considered the primary one, and the secondary curve considered compensatory.In the study sample, we observed that the patients' ages ranged between 7 and 50 years, with a mean equal to 13 years, and 76% had scoliosis. In 68% of cases the main curve in the thoracic region was observed with the convexity to the right.The following was found in patients with OI: scoliosis, biconcave vertebrae, vertebral and chest deformity, unilateral rib, and thoracolumbar kyphosis. The thoracolumbar kyphosis is highly associated with thoracic hypokyphosis in patients with OI. PMID- 26632681 TI - Anterior Shoulder Dislocations in Busy Emergency Departments: The External Rotation Without Sedation and Analgesia (ERWOSA) Method May Be the First Choice for Reduction. AB - Shoulder joint is the most common joint requiring reduction by emergency physicians. Successful reduction is based on the overcoming of resistance of the shoulder muscles. Pain is the most important factor in resistance increase and sedation; analgesia and, in certain cases, intra-articular anesthesia are preferred for reduction. The external rotation (ER) method can provide successful reduction without causing an increase in muscle resistance if applied slowly and gently. The aim of this study was, therefore, to determine the usefulness of the ERWOSA method in the reduction of acute anterior shoulder dislocations (AASDs).This was a retrospective descriptive study. The records of patients admitted to the emergency department with anterior shoulder dislocation between 2009 and 2011 were reviewed for demographic data, sedation, analgesia, and discharge times. Patients were then divided into ERWOSA (n = 80) and external rotation and sedation-analgesia (ERASA, n = 59) groups, with regard to the application of SA (sedation-analgesia). The study data were analyzed using SPSS version 22.0 software for Windows. Numerical data were presented as mean +/- standard deviation and categorical data as rates.A total of 139 patients were included in the study. The patients' average age was 35 +/- 14 years, 108 (77.7%) were male. Successful reduction rates for 59 male and 21 female patients in the ERWOSA group were 83% and 66.7% (78.7% total success), respectively. Successful reduction rates for 49 male and 10 female patients in the ERASA group were 87.7% and 90% (88.1% total success), respectively. The length of stay of the ERWOSA and ERASA groups in emergency services were found to be significantly different, with 55 +/- 17 and 118 +/- 23 minutes for each group, respectively. There were no complications.The ER method can be used in reduction of anterior shoulder dislocations without sedation and analgesia, if applied slowly enough to overcome the resistance of shoulder muscles. The ERWOSA method causes both a significant decrease in the length of stay of patients in the emergency department results in negating the possibility of adverse drug effects. In busy emergency departments, male patients with anterior shoulder dislocation are particularly suitable candidates for ERWOSA. PMID- 26632682 TI - Promoting Diabetic Wound Therapy Using Biodegradable rhPDGF-Loaded Nanofibrous Membranes: CONSORT-Compliant Article. AB - The nanofibrous biodegradable drug-loaded membranes that sustainably released recombinant human platelet-derived growth factor (rhPDGF-BB) to repair diabetic wounds were developed in this work.rhPDGF-BB and poly(lactic-co-glycolic acid) (PLGA) were mixed in hexafluoroisopropyl alcohol, followed by the electrospinning of the solutions into biodegradable membranes to equip the nanofibrous membranes. An elution technique and an enzyme-linked immunosorbent assay kit were used to determine the rhPDGF-BB release rates in vitro and in vivo from this membrane. Eighteen Sprague-Dawley streptozotocin-induced diabetic rats were randomized into 3 groups: rhPDGF-BB-loaded nanofibrous membrane group, PLGA only membrane group, and conventional gauze sponge group for the wound associated with diabetes of rat in each group.The nanofibrous biodegradable membranes released effective concentrations of rhPDGF-BB for over 21 days. The nanofibrous rhPDGF-BB-loaded PLGA membranes contained more water and were further hydrophilic than PLGA only fibers. The rhPDGF-BB-loaded PLGA membranes considerably helped the diabetic wounds repairing. Furthermore, the proliferative cells and angiogenesis of rats associated with diabetes by rhPDGF-BB-loaded nanofibrous membranes were greater than those of other groups, owing to the increased matrix metalloproteinase 9.These biodegradable rhPDGF-BB-loaded membranes were effective in treating diabetic wounds as very advanced accelerators during the initial phases of wound healing process. PMID- 26632683 TI - Can Serum ST2 Levels Be Used as a Marker of Fibrosis in Chronic Hepatitis B Infection? AB - Interleukin 33 (IL-33) is a cytokine belonging to the IL-1 superfamily. Soluble ST2 (sST2) binds to IL-33 and by functioning as trap receptor inhibits signal sending to Th2 via transmembrane ST2. Because Th2-type cytokines play an important role in fibrosis, the aim of this study is to determine whether sST2 can be used as a marker of fibrosis in chronic hepatitis B (CHB) patients or not.The study included 19 healthy controls, 54 patients with CHB, and 14 patients with cirrhosis because of CHB. The aspartate aminotransferase-to-platelet ratio index (APRI) and fibrosis index based on the 4 factors (FIB-4) scores also calculated, and correlations between liver biopsies, sST2 levels, and these scores were analyzed in CHB and cirrhosis patients.The sST2 levels in patients with CHB were significantly higher than those in the control group subjects (median: 1133 pg/mL vs 762.5 pg/mL, respectively [P = 0.035]). In CHB patients, the METAVIR fibrosis score (stages from 0 to 4) showed a moderate correlation with serum sST2 level (r = 0.396, P = 0.004) and a weak correlation with FIB-4 score (r = 0.359, P = 0.008), but no correlation with APRI score (r = 0.253, P = 0.06). The under the curve value of serum sST2 was 0.68, and its prediction of significant fibrosis (METAVIR score >=2) in values >674 pg/mL had a sensitivity of 91.7% and specificity of 40% (P = 0.009). According to multiple logistic regression analysis, only METAVIR fibrosis stage was found to be an independent predictor of serum sST2 elevation in CHB patients (P = 0.04).The sST2 level can be used for differentiating significant fibrosis from mild fibrosis in CHB patients. However, the efficacy of this marker should be verified by larger studies in the future. PMID- 26632684 TI - Genome-wide Meta-analysis on the Sense of Smell Among US Older Adults. AB - Olfactory dysfunction is common among older adults and affects their safety, nutrition, quality of life, and mortality. More importantly, the decreased sense of smell is an early symptom of neurodegenerative diseases such as Parkinson disease (PD) and Alzheimer disease. However, the genetic determinants for the sense of smell have been poorly investigated. We here performed the first genome wide meta-analysis on the sense of smell among 6252 US older adults of European descent from the Atherosclerosis Risk in Communities (ARIC) study, the Health, Aging, and Body Composition (Health ABC) study, and the Religious Orders Study and the Rush Memory and Aging Project (ROS/MAP). Genome-wide association study analysis was performed first by individual cohorts and then meta-analyzed using fixed-effect models with inverse variance weights. Although no SNPs reached genome-wide statistical significance, we identified 13 loci with suggestive evidence for an association with the sense of smell (Pmeta < 1 * 10). Of these, 2 SNPs at chromosome 17q21.31 (rs199443 in NSF, P = 3.02 * 10; and rs2732614 in KIAA1267-LRRC37A, P = 6.65 * 10) exhibited cis effects on the expression of microtubule-associated protein tau (MAPT, 17q21.31) in 447 frontal-cortex samples obtained postmortem and profiled by RNA-seq (P < 1 * 10). Gene-based and pathway enrichment analyses further implicated MAPT in regulating the sense of smell in older adults. Similar results were obtained after excluding participants who reported a physician-diagnosed PD or use of PD medications. In conclusion, we provide preliminary evidence that the MAPT locus may play a role in regulating the sense of smell in older adults and therefore offer a potential genetic link between poor sense of smell and major neurodegenerative diseases. PMID- 26632685 TI - Transmission of Hepatitis B and C Virus Infection Through Body Piercing: A Systematic Review and Meta-Analysis. AB - Hepatitis B and hepatitis C are 2 types of potentially life-threatening liver diseases with high infection rate. Body piercing represents a progressively popular sociocultural phenomenon which is also a potential exposure approach for hepatitis B virus (HBV) and hepatitis C virus (HCV). Conclusions from those researches with statistically risk assessment of body piercing on HBV and HCV transmission are contradictory.Systematically analyze the association between body piercing and the risk of transmitting hepatitis B virus and hepatitis C virus for general population. Make evidence-based recommendations to the current practice and wake up public awareness of this health-threatening behavior.Comprehensive and high sensitivity search strategies were performed to exhaustively search related studies before 15 January 2015 (MEDLINE, EMBASE, WANFANG, CNKI datasets for published literatures, and Google and Google scholars for related grey articles). Two authors identified relevant studies for the review, abstracted data, and assessed literature quality independently and critically according to the selection criteria and quality assessment standard. Odds ratio (OR) and corresponding 95% confidence interval (CI) were used to estimate risk of HBV and HCV infection in relation to body piercing status. Subgroup analysis and sensitivity analysis were conducted to examine the source of heterogeneity and test the robust of the results.A total of 40 studies were included in this systematic review (10 for Hep-B, 26 for Hep-C, 4 for both Hep-B and Hep-C), the pooled OR (95% CI) for the association between body piercing and transmission of HBV/HCV is 1.80 (1.18, 2.75) and 1.83 (1.27, 2.64), respectively. Subgroup analysis suggested that highest risk of body piercing related to hepatitis C infection was for former soccer and veterans with OR of 4.63 (2.65, 8.10), while strongest association between body piercing and hepatitis B was for samples derived from students/community with OR of 2.40 (1.44, 4.02).The current systematic review and meta-analysis suggests that body piercing is significantly associated with the transmission of HBV as well as HCV, having body piercing probably can increase the risk of getting infected. Evidence from this study strongly recommends that comprehensive and effective programs should be established to provide safer piercing practice. PMID- 26632686 TI - Subscapularis Transthoracic Versus Posterolateral Approaches in the Surgical Management of Upper Thoracic Tuberculosis: A Prospective, Randomized Controlled Study. AB - The objective of the present study was to evaluate the clinical, radiological, and functional outcomes of a subscapularis transthoracic surgical approach and a posterolateral surgical approach with debridement, bone graft fusion, and internal fixation for the treatment of upper thoracic tuberculosis.There is currently debate over the best surgical approach for the treatment of upper thoracic tuberculosis. Traditionally, the subscapularis transthoracic approach has been preferred; however, the posterolateral approach has gained popularity in the past few years.A prospective, consecutive cohort of 43 upper thoracic tuberculosis patients with a mean age of 39 years (range: 20-52 years) was followed up for a minimum of 12 months (range: 12-60 months). Patients were randomly divided into 2 groups. Group A (n = 21) was treated by the subscapularis transthoracic approach and group B (n = 22) was treated by the posterolateral approach. All cases were evaluated for clinical, radiological, and functional outcomes. Intraoperative blood loss, operative duration, intraoperative and postoperative complications, hospital stay, the cure rate, fusion time, and the Frankel scale were used for clinical and functional evaluation, whereas the kyphosis angle was used for radiological evaluation.Grafted bones were fused by 10 months in all cases. There was no statistically significant difference between groups before surgery in terms of gender, age, segmental tuberculosis, erythrocyte sedimentation rate (ESR), Frankel scale, or Cobb's angle (P > 0.05). The average operative duration for Group B was lower than that of Group A. There were no significant differences in intraoperative blood loss, intraoperative and postoperative complications, hospital stay, grafted bone fusion time, or cure rate between groups (P > 0.05). The Cobb's angle correction rate for group B (68.5%) was significantly better than that of group A (30.9%). The neurological score showed significant postoperative improvement in both groups, with no significant difference between the groups.The subscapularis transthoracic approach and the posterolateral approach with debridement, bone graft fusion, and internal fixation are both sufficient and satisfactory for the surgical treatment of upper thoracic tuberculosis. However, the posterolateral approach is superior to the subscapularis transthoracic approach in terms of surgical trauma, operative time, and kyphosis correction. PMID- 26632688 TI - A 15-Year Time-series Study of Tooth Extraction in Brazil. AB - Tooth loss is considered to be a public health problem. Time-series studies that assess the influence of social conditions and access to health services on tooth loss are scarce.This study aimed to examine the time-series of permanent tooth extraction in Brazil between 1998 and 2012 and to compare these series in municipalities with different Human Development Index (HDI) scores and with different access to distinct primary and secondary care.The time-series study was performed between 1998 and 2012, using data from the Brazilian National Health Information System. Time-series study was performed between 1998 and 2012. Two annual rates of tooth extraction were calculated and evaluated separately according to 3 parameters: the HDI, the presence of a Dental Specialty Center, and coverage by Oral Health Teams. The time-series was analyzed using a linear regression model.An overall decrease in the tooth-loss tendencies during this period was observed, particularly in the tooth-extraction rate during primary care procedures. In the municipalities with an HDI that was lower than the median, the average tooth-loss rates were higher than in the municipalities with a higher HDI. The municipalities with lower rates of Oral Health Team coverage also showed lower extraction rates than the municipalities with higher coverage rates.In general, Brazil has shown a decrease in the trend to extract permanent teeth during these 15 years. Increased human development and access to dental services have influenced tooth-extraction rates. PMID- 26632689 TI - The Research of Feasibility and Efficacy of Radiofrequency Ablation in Treating Uterine Fibroids. AB - To explore the feasibility and efficacy of radiofrequency ablation in treating uterine fibroids.Ninety patients with multiple uterine fibroids, who had undergone hysterectomy were included in the study. After the uterus was resected, the temperature of 60, 80, 100 degrees C were adopted to ablate the in vitro fibroid with each temperature dealing with 30 patients. Simultaneously, 5 patients were included, whose in vivo fibroid were ablated with the temperature of 100 degrees C before the fibroids were removed after laparotomy. After the fibroids were ablated, the smooth muscle in the ablated center (group A), the ablated edge (group B) and 1 cm away from the ablated edge (group C) were taken. Then, the samples were stained with hematoxylin and eosin (HE) to examine the histopathological changes, and immunohistochemistry was performed to detect the expression of estrogen receptor (ER) and progesterone receptor (PR).After radiofrequency ablation, the ablated lesions were round, toast tan, and dry on gross appearance. There were no obvious tissue carbonization and there were distinct boundary from periphery tissue. In vitro: On automated analysis, the average optical density of ER and PR in group A, B, and C was lower than the control group (P < 0.05), and which were gradually raised with the increased distance to electrode. In the same treatment group, ER optical density was gradually decreased with the increased temperature among 3 different groups. The PR optical density was decreased with the increased temperature under different temperatures in group A and group B, there was significant difference among groups (P < 0.05). But in group C, there was no difference in PR expression among the temperature of 60, 80, and 100 degrees C (P > 0.05). In vivo: Compared with the control group, the average optical density of ER and PR were significantly different among group A, B, and C (P < 0.05), what's more, it was gradually raised with the increased distance to electrode.After radiofrequency ablation, the tissues displayed coagulative necrosis, and decreased ER and PR expression. Radiofrequency ablation may be considered a minimally invasive alternative for those women who wish to retain their reproductive potential. Eighty degree Celsius was expected to be the optimum temperature in radiofrequency ablation treatment of uterine fibroid. PMID- 26632687 TI - Platelet Count and Major Bleeding in Patients Receiving Vitamin K Antagonists for Acute Venous Thromboembolism, Findings From Real World Clinical Practice. AB - The outcome of patients with acute venous thromboembolism (VTE) and abnormal platelet count (PlC) at baseline has not been consistently studied. In real-world clinical practice, a number of patients with abnormal PlC receive vitamin K antagonists (VKAs) to treat acute VTE despite their higher risk of bleeding.We used the Registro Informatizado de Enfermedad TromboEmbolica registry database to compare the rate of major bleeding in patients receiving VKA for long-term therapy of acute VTE according to PlC levels at baseline. Patients were categorized as having very low (<100,000/MUL), low (100,000-150,000/MUL), normal (150,000-300,000/MUL), high (300,000-450,000/MUL), or very high (>450,000/MUL) PlC at baseline.Of 55,369 patients recruited as of January 2015, 37,000 (67%) received long-term therapy with VKA. Of these, 611 patients (1.6%) had very low PlC, 4006 (10.8%) had low PlC, 25,598 (69%) had normal PlC, 5801 (15.6%) had high PlC, and 984 (2.6%) had very high PlC at baseline. During the course of VKA therapy (mean, 192 days), there were no differences in the duration or intensity (as measured by international normalized ratio levels) of treatment between subgroups. The rate of major bleeding was 3.6%, 2.1%, 1.9%, 2.1%, and 3.7%, respectively, and the rate of fatal bleeding was 0.98%, 0.17%, 0.29%, 0.34%, and 0.50%, respectively. Patients with very low or very high PlC levels were more likely to have severe comorbidities.We found a nonlinear "U-shaped" relationship between PlC at baseline and major bleeding during therapy with VKA for VTE. Consistent alteration of PlC values at baseline suggested a greater frailty. PMID- 26632690 TI - End Stage Renal Disease as a Potential Risk Factor for Retinal Vein Occlusion. AB - End stage renal disease (ESRD) has been reported to be an important risk factor for systemic vascular disease. Retinal vein occlusion (RVO) is closely related with cardiovascular diseases; however, its association with ESRD had not been reported. The aim of the study was to investigate whether ESRD is a risk factor for RVO, including central retinal vein occlusion (CRVO) and branch retinal vein occlusion (BRVO). This population-based study is based on the longitudinal data from Taiwan National Health Insurance Research Database. The study cohort comprised 5344 patients with diagnosis of ESRD on hemodialysis or peritoneal dialysis during the period from January 1996 to December 2011. For each ESRD patient, we selected 20 non-ESRD patients matched on age and sex. Each ESRD patient and his/her controls were followed from the initiation of renal dialysis until either the diagnosis of RVO or censorship. Kaplan-Meier method was used to compare the hazard of RVO between cohorts. Stratified Cox proportional hazard models were applied to estimate the hazard ratio (HR) adjusted by the comorbidities of RVO including diabetes mellitus (DM), hypertension, hypercholesteremia, and hypertriglyceridemia. After stratifying by DM status, the statistics were applied again to examine the associations among the DM cohort and non-DM cohort.The 16-year RVO cumulative incidence for ESRD cohort was 2-fold to the non-ESRD (1.01% vs 0.46%). After matching with age, sex, hypertension, and hypercholesteremia, the adjusted HR was 1.46 (95% confidence interval = 1.07 2.01, P value = 0.018). By further excluding patients with DM, the adjusted HR escalated to 2.43 (95% confidence interval = 1.54-3.83, P < 0.001). In contrast, there was no significant risk of ESRD on RVO in the DM patients (HR = 1.03). We conclude that among the non-DM patients, ESRD cases had significantly higher RVO rate than the non-ESRD, which indicates that ESRD maybe a potential risk factor for the development of RVO in nondiabetic patients. PMID- 26632691 TI - Bone Mineral Density in Schizophrenia: An Update of Current Meta-Analysis and Literature Review Under Guideline of PRISMA. AB - Numerous reports have discussed bone mineral density (BMD) or the risk of osteoporosis in schizophrenia, but have yielded only controversial results.We conducted an update of meta-analysis to examine the overall change in BMD in patients with schizophrenia and the effect on BMD of different antipsychotic drugs.Electronic research through platform of PubMed.The inclusion criteria were as follows: articles with relevance to comparisons of BMD in patients with schizophrenia (SCHIZ) and healthy controls (HCs), or articles discussing comparisons of BMD in SCHIZ receiving prolactin-raising (PR) and prolactin sparing (PS) antipsychotics; articles about clinical trials.In the current meta analysis, we used the random-effect model to pool the results from 13 studies comparing BMD in SCHIZ and in HCs, and the results from 7 studies comparing BMD in patients receiving PR and PS.Our results revealed significantly lower BMD in SCHIZ than in HCs (P < 0.001). In the meta-regression, mean age of subjects modulated the difference in BMD between patients and control subjects (P < 0.001). In addition, the BMD in SCHIZ taking PR was significantly lower than in those taking PS (P = 0.006).Our study can only point to the phenomenon that BMD in SCHIZ is lower than that in HCs, and cannot reveal any possible pathophysiology or mechanism of this phenomenon. In addition, we could not rule out the possible effect of medication on BMD based on the results of the meta analysis of comparison of BMD in SCHIZ receiving PR and PS.The main result of our meta-analysis suggests that BMD is significantly lower in SCHIZ than in HCs. Our study emphasizes the importance of further screening for the risk of osteoporosis in young-aged schizophrenic patients, especially those taking PR, which are in high risk of fracture. PMID- 26632692 TI - Construction and Validation of a 14-Year Cardiovascular Risk Score for Use in the General Population: The Puras-GEVA Chart. AB - The current cardiovascular risk tables are based on a 10-year period and therefore, do not allow for predictions in the short or medium term. Thus, we are unable to take more aggressive therapeutic decisions when this risk is very high.To develop and validate a predictive model of cardiovascular disease (CVD), to enable calculation of risk in the short, medium and long term in the general population.Cohort study with 14 years of follow-up (1992-2006) was obtained through random sampling of 342,667 inhabitants in a Spanish region. MAIN OUTCOME: time-to-CVD. The sample was randomly divided into 2 parts [823 (80%), construction; 227 (20%), validation]. A stepwise Cox model was constructed to determine which variables at baseline (age, sex, blood pressure, etc) were associated with CVD. The model was adapted to a points system and risk groups based on epidemiological criteria (sensitivity and specificity) were established. The risk associated with each score was calculated every 2 years up to a maximum of 14. The estimated model was validated by calculating the C-statistic and comparison between observed and expected events.In the construction sample, 76 patients experienced a CVD during the follow-up (82 cases per 10,000 person years). Factors in the model included sex, diabetes, left ventricular hypertrophy, occupational physical activity, age, systolic blood pressure * heart rate, number of cigarettes, and total cholesterol. Validation yielded a C statistic of 0.886 and the comparison between expected and observed events was not significant (P: 0.49-0.75).We constructed and validated a scoring system able to determine, with a very high discriminating power, which patients will develop a CVD in the short, medium, and long term (maximum 14 years). Validation studies are needed for the model constructed. PMID- 26632693 TI - Associations of Il-1 Family-Related Polymorphisms With Gastric Cancer Risk and the Role of Mir-197 In Il-1f5 Expression. AB - To explore whether the roles of IL-1 family single nucleotide polymorphisms (SNPs) of the microRNA binding sites (miR-SNPs) in the 3' untranslated region (3' UTR) of their target genes in the progression of gastric cancer (GC) and verify the relationship between miR-197 with chronic inflammatory gene-IL1-F5 by microRNA target prediction, a case-control study which consisted of 500 cases and 500 frequency-matched healthy controls was conducted. Single nucleotide polymorphisms were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) or allele-specific PCR (AS-PCR). Association between SNPs and GC risk was evaluated by adjusted odds ratios (ORs) and 95% confidence intervals (CIs) in unconditional logistic regression analyses. Quantitative real-time (qRT) PCR assay and Western Blot analyses were performed to analyze the miR-197 expression and the IL1-F5 expression. The variant homozygote and heterozygote genotype of rs9005 in IL-1RN were significantly associated with increased risks of GC (ORadjusted [95%CI]: 1.71[1.04-2.81] and ORadjusted[95%CI]: 1.36 [1.04-1.78]). Compared with the wild heterozygote genotype, the variant heterozygote genotype of rs2472188 and rs2515401 in IL-1F5 polymorphisms were significantly associated with increased GC risks (ORadjusted [95%CI]: 1.51[1.15-1.99] and ORadjusted[95%CI]: 1.36[1.04-1.76]), but no significant differences existed in other 7 IL-1 family SNPs (rs2856836 in IL-1A, rs3732131 in IL-1R1, rs1135354 and rs3771157 in IL-18RA, rs3180235, rs957201 and rs2515402 in IL-1F5) with GC. The recombinant plasmid-pGenesil-1-miR-197 could upregulate the expression of miR-197 and downregulate the expression of IL-1F5 in human gastric cancer cell lines SGC-7901 and BGC-823 cells after transfection, and the miR-197 inhibitor could facilitate the expression of IL1-F5 after transfecting the same cell lines. These results suggested that SNPs in the IL-1 family genes play important roles in the development of GC and the IL-1F5 might be the target gene of miR-197, and miR-197 might negatively regulate its expression. PMID- 26632694 TI - Independent Association of Circulating Level of Chemerin With Functional and Early Morphological Vascular Changes in Newly Diagnosed Type 2 Diabetic Patients. AB - There is growing evidence that chemerin, a novel adipokine elevated in obesity and metabolic syndromes, plays a crucial role in advanced atherosclerosis. This study aimed to determine the chemerin levels in diabetes and evaluate the effects of increased chemerin on early atherosclerosis.A total of 245 newly diagnosed diabetic patients and 148 age-matched, healthy, normal glucose tolerant (NGT) controls were enrolled. Anthropometric measurements and plasma parameters were examined, including body mass index (BMI), waist circumference, blood pressure, glucose, lipid profiles, inflammation markers, adipokines, and cell adhesion molecules. Vascular healthy was measured with brachial flow-mediated dilatation (FMD) and carotid intima-media thickness (IMT).Compared with NGT controls, plasma chemerin levels were higher in diabetic patients (P < 0.01) and higher chemerin level was an independent risk factor of occurrence of diabetes even after metabolic profiles were adjusted (odds ratio [OR] = 1.352, 95% CI: 1.181-1.543, P < 0.01). In patients with type 2 diabetes, chemerin was positively associated with intercellular adhesion molecule-1 (ICAM-1), E-selectin, but not vascular adhesion molecule-1 (VCAM-1) and P-selectin. We also explored that plasma chemerin level was negatively associated with brachial FMD and positively with carotid IMT. Chemerin also retained a strong association with ICAM-1, FMD, and IMT even after adjusted for age, sex, and other risk factors (ICAM-1: r = 0.150, P = 0.024; FMD: r = -0.126, P = 0.001; IMT: r = 0.325, P < 0.001). By multiple linear regression analysis, plasma chemerin levels were related to ICAM-1 even after adjustments for conventional cardiovascular risk factors (beta = 0.192, P = 0.017). Moreover, logistic regression analysis showed that high chemerin level was an independent predictive variable for impaired endothelial function (OR = 1.066, 95% CI: 1.012-1.142, P = 0.048) and enhanced carotid vessel thickness (OR = 1.068, 95% CI: 1.021-1.148, P = 0.035) in diabetic patients.In summary, chemerin levels are independently associated with endothelial activation and early atherosclerosis in newly diagnosed type 2 diabetes. PMID- 26632695 TI - Refinement of Molecular Diagnostic Protocol of Auditory Neuropathy Spectrum Disorder: Disclosure of Significant Level of Etiologic Homogeneity in Koreans and Its Clinical Implications. AB - Auditory neuropathy spectrum disorder (ANSD) is a sensorineural hearing disorder caused by dysfunction of auditory neural conduction. ANSD has a heterogeneous etiology, including genetic factors; the response to cochlear implantation significantly varies depending on the etiology. The results of timely cochlear implantation for OTOF-related ANSD (DFNB9) have been reported to be good. Therefore, identifying the causative gene of ANSD, especially OTOF, is an important issue to rehabilitate these patients.Six sporadic ANSD subjects without anatomical abnormality of the cochlear nerve, including the 4 subjects that were previously reported to be without detectable OTOF mutation, were included. We performed targeted resequencing (TRS) of known deafness genes and multiphasic bioinformatics analyses of the data that ensured detection of capture failure and structural variations. Exclusion of SNP was also double checked. The TRS data previously obtained from 2 subjects were reanalyzed. Through this study, we detected 2 mutant alleles of OTOF from 5 (83.3%) of 6 ANSD subjects. All of the 5 subjects carried at least 1 mutant allele carrying p.R1939Q. This variant was categorized as a simple SNP (rs201326023) in the database and it resided in the exon with frequent capture failures, which previously led to exclusion of this variant from eligible candidacy mistakenly. In addition, we detected a structural variation within OTOF from a previously undiagnosed ANSD subject, which was the second structural variation reported in DFNB9 subjects to date.We identify a strong etiologic homogeneity of prelingual ANSD in case of the anatomically normal cochlear nerve in Koreans and now report DFNB9 as the single overwhelming cause. Multiphasic analysis of TRS data ensuring detection of capture failure and structural variations would be expected to reveal DFNB9 from a substantial portion of previously undiagnosed ANSD subjects in Koreans. Based on our results, we propose a novel strategy that incorporates imaging studies, prevalent mutation screening and multiphasic analysis of TRS data in a stepwise manner to correctly detect DFNB9 in Koreans. PMID- 26632696 TI - Efficacy of Enhanced External Counterpulsation in Patients With Chronic Refractory Angina on Canadian Cardiovascular Society (CCS) Angina Class: An Updated Meta-Analysis. AB - A growing number of patients with chronic artery disease suffer from angina, despite the optimal medical management (ie, beta-blockers, calcium channel blockers, and long-acting nitrates) and revascularization. Currently, enhanced external counterpulsation (EECP) therapy has been verified as a noninvasive, safe therapy for refractory angina. The study was designed to evaluate the efficacy of EECP in patients with chronic refractory angina according to Canadian Cardiovascular Society (CCS) angina class.We identified systematic literature through MEDLINE, EMBASE, the Cochrane Clinical Trials Register Database, and the ClinicalTrials. gov Website from 1990 to 2015. Studies were considered eligible if they were prospective and reported data on CCS class before and after EECP treatment. Meta-analysis was performed to assess the efficacy of EECP therapy by at least 1 CCS angina class improvement, and proportion along with the 95% confidence interval (CI) was calculated. Statistical heterogeneity was calculated by I statistic and the Q statistic. Sensitivity analysis was addressed to test the influence of trials on the overall pooled results. Subgroup analysis was applied to explore potential reasons for heterogeneity.Eighteen studies were enrolled in our meta-analysis. Pooled analysis showed 85% of patients underwent EECP had a reduction by at least one CCS class (95%CI 0.81-0.88, I = 58.5%, P < 0.001). The proportion of patients enrolled at primarily different studies with chronic heart failure (CHF) improved by at least 1 CCS class was about 84% after EECP (95%CI 0.81-0.88, I = 32.7%, P = 0.1668). After 3 large studies were excluded, the pooled proportion was 82% (95%CI 0.79-0.86, I = 18%, P = 0.2528). Funnel plot indicated that some asymmetry while the Begg and Egger bias statistic showed no publication bias (P = 0.1495 and 0.2859, respectively).Our study confirmed that EECP provided an effective treatment for patients who were unresponsive to medical management and/or invasive therapy. However, the long term benefits of EECP therapy needed further studies to evaluate in the management of chronic refractory angina. PMID- 26632697 TI - Association Between Polymorphisms of DRD2, COMT, DBH, and MAO-A Genes and Migraine Susceptibility: A Meta-Analysis. AB - Some epidemiological studies have investigated the relationship between genetic polymorphisms of DRD2, COMT, DBH, and MAO-A and migraine susceptibility, but the results are still inconsistent. Thus, our aim was to further assess the association through a meta-analysis.We examined 5 single nucleotide polymorphisms (SNPs) in 4 genes, including DRD2 rs1799732 and rs6275, DBH rs7239728, MAI-A VNTR, and COMT rs4680, and performed a meta-analysis of 11 published case-control studies including 3138 cases and 4126 controls. Odd ratios (ORs) with 95% confidence intervals (95% CIs) were used to evaluate the association between the 5 genetic polymorphisms and migraine susceptibility.There was no significant relationship between migraine susceptibility and 4 genetic polymorphisms of DRD2 rs1799732 and rs6275, DBH rs7239728, and MAO-A-VNTR. Nevertheless, decreased risk of migraine was observed to be in association with COMT rs4680 polymorphism in overall analysis (AA vs. GG + GA: OR = 0.76, 95% CI = 0.60-0.97, PHet > 0.642, I = 0), and in Caucasian group after subgroup analysis (AA vs. GG + GA: OR = 0.75, 95% CI = 0.58-0.96, PHet > 0.433, I = 0).Studied polymorphisms of DRD2, DBH, and MAO-A genes may not be associated with migraine susceptibility. However, COMT rs4680 polymorphism may decrease the risk of migraine, especially in Caucasians. The failure to evaluate environmental influence and provide adjusted effect size estimates highlights the need for additional studies in a large number to take these factors into consideration, thus better elucidating the role of the genes tested in migraine. PMID- 26632698 TI - A Prospective Randomized Study Comparing Mini-surgical Percutaneous Dilatational Tracheostomy With Surgical and Classical Percutaneous Tracheostomy: A New Method Beyond Contraindications. AB - Although percutaneous dilatational tracheostomy (PDT) is more accessible and less time-demanding compared with surgical tracheostomy (ST), it has its own limitations. We introduced a modified PDT technique and brought some surgical knowledge to the bedside to overcome some standard percutaneous dilatational tracheostomy relative contraindications. PDT uses a blind route of tracheal access that usually requires perioperational imaging guidance to protect accidental injuries. Moreover, there are contraindications in certain cases, limiting widespread PDT application. Different PDT modifications and devices have been represented to address the problem; however, these approaches are not generally popular among professionals due to limited accessibility and/or other reasons.We prospectively analyzed the double-blinded trial, patient and nurse head evaluating the complications, and collected data from 360 patients who underwent PDT, ST, or our modified mini-surgical PDT (msPDT, Hashemian method). These patients were divided into 2 groups-contraindicated to PDT-and randomization was done for msPDT or PDT in PDT-indicated group and msPDT or ST for PDT-contraindicated patients. The cases were compared in terms of pre and postoperational complications.Data analysis demonstrated that the mean value of procedural time was significantly lower in the msPDT group, either compared with the standard PDT or the ST group. Paratracheal insertion, intraprocedural hypoxemia, and bleeding were also significantly lower in the msPDT group compared with the standard PDT group. Other complications were not significantly different between msPDT and ST patients.The introduced msPDT represented a semiopen incision, other than blinded PDT route of tracheal access that allowed proceduralist to withdraw bronchoscopy and reduced the total time of procedure. Interestingly, the most important improvement was performing msPDT on PDT contraindicated patients with the complication rate comparable to surgical procedure. Supplements citation missing in the text. Please check supplements video in original manuscript. PMID- 26632699 TI - Significant Association Between Adiponutrin and Hepatocellular Carcinoma Risk. AB - ADPN I148M polymorphism has been consistently reported to play a role in liver associated diseases, such as alcoholic liver disease, chronic hepatitis C, and liver fat and fibrosis in nonalcoholic fatty liver disease. This significant association was also indicated in a series of hepatocellular carcinoma (HCC) studies, where the significance may be affected due to the small sample sizes. The aim of this study was to reexamine the ADPN-HCC association by use of meta analysis. Biweekly computer-based literature searches plus manual screening were undertaken in an effort to identify all studies that met the predefined inclusion criteria. The Mantel-Haenszel method was selected to estimate risk effects (odds ratio [OR] and 95% confidence interval [CI]). To examine reliability of the pooled risk effects, we additionally performed sensitivity analysis and publication bias tests. Ten studies (1335 HCC patients and 2927 HCC-free controls) were identified for the meta-analysis. We found significantly increased risk of HCC attributable to presence of ADPN I148M polymorphism, with the highest risk associated with the M/M genotype under the recessive model of inheritance (OR = 2.23, 95% CI = 1.87-2.67, between-study heterogeneity: P = 0.468). The significant increase persisted in Caucasian and African when data were stratified by ethnicity. Subgroup analysis according to source of controls revealed similar risk effects. Our meta-analysis indicates that I148M polymorphism in the ADPN gene may independently contribute to the progression of HCC irrespective of the etiologies. PMID- 26632700 TI - Delayed Intracerebral Hemorrhage Secondary to Ventriculoperitoneal Shunt: A Case Report and Literature Review. AB - The ventriculoperitoneal (VP) shunt is a routine procedure for cerebrospinal fluid (CSF) diversion, and is associated with many complications. A delayed hemorrhage after the VP shunt surgery, however, is quite rare. In this study, we report a case involving late-onset hemorrhage. The 67-year-old male patient with a history of head trauma and brain surgery underwent a VP shunt placement for hydrocephalus. The surgery course was uneventful and no bleeding was revealed in the first computed tomographic (CT) scan after the procedure. However, a massive intraparenchymal and intraventricular hemorrhage occurred 8 h following adjustment of the valve system on the 8th day after surgery.Erosion of the vasculature by catheter cannulation and a sudden reduction of CSF pressure after downregulation of the valve could be one of the possible causes of the intracerebral hemorrhage (ICH). PMID- 26632701 TI - The Clinical Course of Cirrhosis Patients Hospitalized for Acute Hepatic Deterioration: A Prospective Bicentric Study. AB - Patients with cirrhosis are vulnerable to acute hepatic insults and are more likely to develop rapid hepatic deterioration. The aim of this study is to describe the clinical course of patients with cirrhosis and hospitalized for acute hepatic deterioration (AHD).This is a prospective study involving 163 patients with cirrhosis and AHD. The occurrence of organ failures, systemic inflammatory response syndrome (SIRS), and infections during hospital stay were recorded and the relationship between organ failure and death or SIRS/infection was subsequently analyzed.Of 163 patients, 35 did not develop any organ failure during in-hospital follow-ups (90-day mortality: 0%); 84 had intrahepatic organ failures (IH-OFs, defined by liver and/or coagulation failure) (90-day mortality: 22.0%); and 44 patients developed extra-hepatic organ failures (EH-OFs, defined by kidney, cerebral, circulation, and respiratory failure) on the basis of IH-OF with a 90-day mortality of 90.9%. On multivariable analysis by a Cox proportion hazard model, age, WBC, presence of IH-OF, and EH-OF all predicted 90-day death. A logistic regression analysis identified SIRS being associated with the development of EH-OF. Furthermore, IH-OF at admission and infections occurred during the hospital stay were shown to be another 2 potential risk factors.The clinical course of cirrhosis patients with acute hepatic injury was characterized by 3 consecutive stages (AHD, IH-OF, and EH-OF), which provided a clear risk stratification. The PIRO criteria provided an accurate frame for prognostication of those patients. The systemic inflammatory response syndrome may be a target for blocking the progression to the EH-OF stage. PMID- 26632702 TI - Incidence and Risk Factors for Acute Kidney Injury Following Mannitol Infusion in Patients With Acute Stroke: A Retrospective Cohort Study. AB - Mannitol, an osmotic diuretic, is commonly used to treat patients with acute brain edema, but its use also increases the risk of developing acute kidney injury (AKI). In this study, we investigated the incidence and risk factors of mannitol-related AKI in acute stroke patients.A total of 432 patients (ischemic stroke 62.3%) >20 years of age who were admitted to the neurocritical care center in a tertiary hospital and received mannitol treatment were enrolled in this study. Clinical parameters including the scores of National Institutes of Health Stroke Scale (NIHSS) at admission, vascular risk factors, laboratory data, and concurrent nephrotoxic medications were registered. Acute kidney injury was defined as an absolute elevation in the serum creatinine (Scr) level of >=0.3 mg/dL from the baseline or a >=50% increase in Scr.The incidence of mannitol related AKI was 6.5% (95% confidence interval, 4.5%-9.3%) in acute stroke patients, 6.3% in patients with ischemic stroke, and 6.7% in patients with intracerebral hemorrhage. Multivariate analysis revealed that diabetes, lower estimated glomerular filtration rate at baseline, higher initial NIHSS score, and concurrent use of diuretics increased the risk of mannitol-related AKI. When present, the combination of these elements displayed an area under the receiver operating characteristic curve of 0.839 (95% confidence interval, 0.770-0.909). In conclusion, mannitol-related AKI is not uncommon in the treatment of acute stroke patients, especially in those with vulnerable risk factors. PMID- 26632703 TI - A Population-Based 16-Year Study on the Risk Factors of Surgical Site Infection in Patients after Bone Grafting: A Cross-Sectional Study in Taiwan. AB - Bone grafting is a commonly used orthopedic surgical procedure that will provide bone formation in bone defects or regions of defective bone healing. A major complication following bone grafting is a postoperative recipient graft site infection that is associated with substantial mortality and increased use of medical resources. The purpose of the study was to identify the risk factors associated with infection after bone-grafting surgery.Data from 1,303,347 patients listed in the Taiwan National Health Insurance Research Database (NHIRD) and admitted to hospitals from 1997 through 2012 who underwent primary bone grafting (mean age: 46.57 years old; mean length of hospital stay: 8.04 days) were analyzed. The incidence of infection by age, hospital stay, gender, income, chronic disease (tuberculosis [TB]; diabetes mellitus [DM]; acquired immunodeficiency syndrome [AIDS]), fracture complications (nonunion; delayed union fracture), types of graft and hospital was evaluated.Three percent of the patients developed a postoperative recipient graft site infection. Multivariable analysis revealed that patients were more likely to develop a post bone-grafting surgery infection if they were older, had a longer hospital stay, were male, had a lower income, or had comorbid TB, DM, or AIDS. Patients were more likely to develop an infection if they had a nonunion, an alloplast graft, or treated in a local clinic.Our findings should provide a clinically relevant reference for surgeons who perform bone grafting. Patients should be informed of the potential risks. PMID- 26632704 TI - Extranodal Rosai-Dorfman Disease as Isolated Lesion of the Tibia Diagnosed by Fine-Needle Aspiration Cytology: A Case Report. AB - Few studies have used fine-needle aspiration cytology for the purpose of isolated skeletal Rosai-Dorfman diseases (RDDs) diagnosis.Herein, we described an extremely rare case of a 56-year-old woman who presented to our hospital with an insidious onset of pain in the right proximal tibia.The provisional cytologic diagnosis of RDDs was confirmed by a computer tomography-guided core needle biopsy of the lesion. Subsequently, curettage and autogenous iliac crest bone graft were performed successfully. At the 4th year of follow-up her clinical symptoms disappeared, and there was no clinical evidence of lesion recurrence.Our case highlighted the role of fine-needle aspiration cytology with immunohistochemical studies in the diagnosis of RDDs and the characteristic features of isolated skeletal RDDs in an unusual location, the knowledge of which would help avoid missed or delayed diagnosis in the future. PMID- 26632705 TI - Association Between Colonic Diverticulosis and Erectile Dysfunction: A Nationwide Population-Based Study. AB - We investigated whether colonic diverticulosis (CD) is associated with an increased risk of the subsequent development of erectile dysfunction (ED).We identified 2879 patients, diagnosed with CD between 1998 and 2011 from the Taiwan National Health Insurance Research Database as the study cohort. Patients in a comparison cohort were frequency-matched with those in the CD cohort at a ratio of 1:4, frequency matched according to age (in 5-year bands) and year of CD diagnosis. The patients were followed-up until ED development, withdrawal from the National Health Insurance system, or the end of 2011. For both cohorts, the overall and age-specific incidence density rates of ED (per 1000 person-years) were calculated. The effects of age, CD, and other comorbidities on the risk of ED development were examined using Cox proportional hazards regression models.The average follow-up durations were 4.76 years and 4.97 years for the CD patients and comparison cohorts, respectively. The overall incidence of ED was 1.70-fold higher in the CD cohort than in the comparison cohort (2.92 and 1.71 per 1000 person-years, respectively). Colonic diverticulosis was an independent risk factor for subsequent ED development (adjusted HR [aHR] = 1.56, 95% confidence interval = 1.07-2.28) in a multivariate Cox proportional hazards regression model.In this large retrospective cohort study, CD was associated with future ED development. Additional studies are required for validating our results. PMID- 26632706 TI - Serine Protease Inhibitor Kazal Type 1 (SPINK1) c.194+2T > C Mutation May Predict Long-term Outcome of Endoscopic Treatments in Idiopathic Chronic Pancreatitis. AB - Endoscopic interventional is a commonly used treatment method for idiopathic chronic pancreatitis. Serine protease inhibitor Kazal type 1 (SPINK1) 194+2T>C mutation is most frequently observed in Chinese pancreatitis patients and influences the clinical course of idiopathic chronic pancreatitis patients. We conducted this study to determine the impacts of this mutation on the outcome of endoscopic treatments.In this study, we enrolled 423 patients. Among them, 101 idiopathic chronic pancreatitis patients without other relevant mutations had a successful endoscopic procedure and completed follow-up. Clinical characteristics including Izbicki pain score, exocrine and endocrine function, were evaluated. Genetic sequencing was conducted to detect SPINK1 194+2T>C mutations.The c.194+2T>C mutation was found in 58 (57.43%) patients. Factors relevant to pain relief are c.194+2T>C mutation (P = 0.011), severe pain before treatment (P = 0.005), and necessary subsequent endoscopic treatments (P < 0.001). More patients with the intronic mutation had deteriorated endocrine function (P = 0.001) relative to those patients without the mutation.Patients carrying the c.194+2T>C mutation were less likely to achieve pain relief through endoscopic treatments. They also have a higher risk of endocrine function deterioration. SPINK1 c.194+2T>C mutation may be applied as a pretreatment predictor in idiopathic chronic pancreatitis patients. PMID- 26632707 TI - Hybrid Strategy of Two-Level Cervical Artificial Disc and Intervertebral Cage: Biomechanical Effects on Tissues and Implants. AB - This numerical study aimed to evaluate tissue and implant responses to the hybrid surgery (HS) of cervical artificial disc replacement (C-ADR) and anterior cervical discectomy and fusion (ACDF).Four hybrid strategies of two-level C-ADR and ACDF were compared in terms of adjacent segment degeneration (ASD) and implant failure.The rotary C-ADR and semirigid ACDF have been extensively used in the multilevel treatment of cervical instability and degeneration, but the constrained mobility at the ACDF segments can induce postoperative ASD problems. Hybrid surgery of C-ADR and ACDF has been an alternative to provide the optimal tradeoff between surgical cost and ASD problems. The biomechanical effects of hybrid strategies warrant thorough investigation for the two-level instrumentation.Based on computed tomography imaging, a nonlinear C2-C7 model was developed and validated by cadaveric and numerical data. Four strategies of inserting the C-ADR and ACDF into the C4-C6 segments were systematically arranged as PP (2 peek cages), AA (2 artificial discs), PA, and AP. The biomechanical behavior of these 4 strategies was evaluated in terms of motion and stresses of discs, facet forces, stresses of C-ADR and ACDF, and C-ADR motion.The constrained mobility of the ACDF segment worsened the kinematic and mechanical demands of the adjacent segments and artificial discs. The C-ADR articulation provided higher mobility than the replaced disc of the intact construct, making it an effective buffer to accommodate the compensated mobility and load from the ACDF segment. Consequently, the ASD progression of the AA construct was most restricted, followed by the PA, AP, and PP construct.The PA strategy is a tradeoff to preserve mobility and reduce cost. The C-ADR of the PA construct preserves the mobility of the C5/C6 segment and shares the transferred motion and loads of the fused C4/C5 segment. The PA construct shows optimal biomechanical results for minimizing ASD and implant failure, whereas the AP strategy is only recommended when cranial degeneration is the major concern. PMID- 26632708 TI - Nonadherence of Oral Antihyperglycemic Medication Will Increase Risk of End-Stage Renal Disease. AB - Poor glycemic control is related to an increased risk of end-stage renal disease (ESRD). This study investigated the association between medication adherence and the risk of ESRD in patients with newly diagnosed diabetes mellitus.In this population-based cohort study, we used the Taiwan National Health Insurance Research Database (NHIRD) to identify 559,864 patients with newly diagnosed or treated diabetes mellitus who were ages from 20 to 85 years between 2001 and 2008. We identified 1695 patients with ESRD during the study period. The mean follow-up time of the patients with ESRD was 5.7 years. Time-dependent Cox proportional hazards regression was performed to estimate the hazard ratios for ESRD among the patients with newly diagnosed diabetes mellitus.After adjustment for various covariates, nonadherence to oral antihyperglycemic medication (OAM) was associated with a higher risk of ESRD compared with adherence to OAM (hazard ratio [HR], 1.11; 95% confidence interval [CI], 1.01-1.23). The effects of nonadherence to OAM on the risk of ESRD were significant for patients without hypertension, without gout, without chronic kidney disease, undergoing OAM polytherapy, and undergoing metformin polytherapy (HR [95% CIs], 1.18 [1.00 1.39], 1.13 [1.02-1.26], 1.17 [1.03-1.33], 1.22 [1.08-1.38], and 1.13 [1.02 1.25], respectively).In conclusion, nonadherence to OAM therapy is associated with ESRD. Adherence to medication therapy can prevent the progressive loss of renal function and ESRD for patients with diabetes. PMID- 26632709 TI - Protective Role of Glucagon-Like Peptide-1 Against High-Glucose-Induced Endothelial Oxidative Damage. AB - To investigate the protective effect of glucagon-like peptide-1 (GLP-1) against cell damage induced by high glucose.Human umbilical vein endothelial cells (HUVECs) were divided into control group (5.5 mmol/L) and high glucose groups (19, 33, or 47 mmol/L), which were cultured with different concentrations of glucose for 48 hours, respectively. Cell viability was measured with MTT assay. Levels of intracellular reactive oxygen species (ROS) were monitored by flow cytometry and apoptotic cell death was measured by staining with Annexin V-FITC and propidium iodide. Cultured cells were detected with intercellular adhesion molecule 1 (ICAM-1), VCAM-1, and JNK on protein.Compared with the control group, cell viability was decreased by 20% and 37%, respectively, when cultured under 33 and 47 mM, while increased in different GLP-1-treated groups (0.01 L, 0.1, 1, and 10 nmol/L). The GLP-1 treatment significantly reduced the ROS level of high glucose treatment group but not impact on the control group. Meanwhile, the level of apoptosis was elevated in the high glucose treatment group. Early apoptosis was significantly reversed in the GLP-1-treated group (0.1, 1, and 10 nmol/L). Late apoptosis was uniquely decreased in the GLP-1 concentrations of 10 nmol/L. Furthermore, GLP-1 could also reduce the protein levels of ICAM-1, VCAM-1, and phospho JNK in the endothelial cells with high glucose treatment.GLP-1 could inhibit cell apoptosis and reduce ROS generation and JNK-Bax signaling pathway activation, which were induced by high glucose treatment. PMID- 26632710 TI - Multiple Genetic Analysis System-Based Antibiotic Susceptibility Testing in Helicobacter pylori and High Eradication Rate With Phenotypic Resistance-Guided Quadruple Therapy. AB - Antibiotics resistance in Helicobacter pylori (H. pylori) is the major factor for eradication failure. Molecular tests including fluorescence in situ hybridization, PCR-restriction fragment length polymorphism, and dual priming oligonucleotide-PCR (DPO-PCR) play critical roles in the detection of antibiotic susceptibility; however, limited knowledge is known about application of multiple genetic analysis system (MGAS) in the area of H. pylori identification and antibiotics resistance detection.The aim of this study is to determine the antibiotics resistance using different molecular tests and evaluate the treatment outcomes of E-test-based genotypic resistance.A total of 297 patients with dyspepsia complaint were recruited for gastroscopies. Ninety patients with H. pylori culture positive were randomly divided into 2 groups (test group and control group). E-test, general PCR, and MGAS assay were performed in test group. Patients in control group were treated with empirical therapy (rabeprazole + bismuth potassium citrate + amoxicillin [AMX] + clarithromycin [CLR]), whereas patients in test group received quadruple therapy based on E-test results twice daily for 14 consecutive days. The eradication effect of H. pylori was confirmed by C-urea breath test after at least 4 weeks when treatment was finished.Rapid urease test showed 46.5% (128/297) patients with H. pylori infection, whereas 30.3% (90/297) patients were H. pylori culture positive. E-test showed that H. pylori primary resistance rate to CLR, AMX, metronidazole, tetracycline, and levofloxacin (LVX) was 40.0% (18/45), 4.4% (2/45), 53.3% (24/45), 0% (0/45), and 55.6% (25/45), respectively. In addition, there are many multidrug resistant (MDR) phenotypes, and the MDR strains have higher minimum inhibitory concentration than their single-drug resistant counterparts. Considering E-test as the reference test, the sensitivities of general PCR and MGAS in detecting CLR resistance were 83.3% (15/18) and 94.4% (17/18), whereas in detecting LVX resistance were 100% (25/25) and 83.3% (15/18), respectively. Finally, the eradication rate in test group was significantly higher than that in control group as demonstrated by intention-to-treat analysis and per-protocol analysis.MGAS is a promising assay for H. pylori identification and antibiotic susceptibility testing. Phenotypic resistance-guided quadruple therapy showed a high efficacy in treating patients with H. pylori infection. PMID- 26632711 TI - Molecular Analysis of Oral Bacteria in Heart Valve of Patients With Cardiovascular Disease by Real-Time Polymerase Chain Reaction. AB - Structural deficiencies and functional abnormalities of heart valves represent an important cause of cardiovascular morbidity and mortality, and a number of diseases, such as aortic stenosis, have been recently associated with infectious agents. This study aimed to analyze oral bacteria in dental plaque, saliva, and cardiac valves of patients with cardiovascular disease. Samples of supragingival plaque, subgingival plaque, saliva, and cardiac valve tissue were collected from 42 patients with heart valve disease. Molecular analysis of Streptococcus mutans, Prevotella intermedia, Porphyromonas gingivalis, and Treponema denticola was performed through real-time PCR. The micro-organism most frequently detected in heart valve samples was the S. mutans (89.3%), followed by P. intermedia (19.1%), P. gingivalis (4.2%), and T. denticola (2.1%). The mean decayed, missing, filled teeth (DMFT) was 26.4 +/- 6.9 (mean +/- SD), and according to the highest score of periodontal disease observed for each patient, periodontal pockets > 4 mm and dental calculus were detected in 43.4% and 34.7% of patients, respectively. In conclusion, oral bacteria, especially S. mutans, were found in the cardiac valve samples of patients with a high rate of caries and gingivitis/periodontitis. PMID- 26632712 TI - Human Papillomavirus Infections are Common and Predict Mortality in a Retrospective Cohort Study of Taiwanese Patients With Oral Cavity Cancer. AB - Human papillomavirus (HPV) infections are deemed to play a role in the pathogenesis of oral cavity cancer (OCC). However, their exact prevalence and clinical significance remain unclear. Herein, we investigated the prevalence and prognostic value of HPV infections in a large sample of Taiwanese OCC patients.This study was designed as a retrospective cohort study. Between 2004 and 2011, we identified 1002 consecutive patients with newly diagnosed OCC who were scheduled for standard treatment. HPV genotyping was performed in tumor specimens using polymerase chain reaction-based HPV blots. To investigate the temporal trends of HPV infections and their impact on 5-year overall survival (OS), patients were divided into 2 cohorts according to calendar periods: "2004 cohort" (2004-2007; n = 466) and "2008 cohort" (2008-2011; n = 536). Univariate and multivariate Cox regression models were also used to identify the independent predictors of OS in the 2 cohorts. A weighted risk score was assigned to each factor based on the range of their corresponding hazard ratios and validated in both cohorts using the c-statistic.The overall prevalence of HPV infections was 19%, with a trend toward decreasing rates from 2004 to 2011. In patients without risky oral habits, the 5-year OS rate of HPV-positive patients was significantly lower than that of HPV-negative cases (49% vs 80%; P = 0.021). In the 2004 cohort, multivariate analysis identified HPV16, pathological T3/T4, pathological N1/N2, and extracapsular spread as independent adverse prognostic factors for OS. In the 2008 cohort, pathological N1/N2, pathological stage III/IV, and histological tumor depth >8 mm were identified as independent adverse prognostic factors. Using a weighted grading system incorporating HPV16 infection, we devised a prognostic index that identified 4 distinct risk categories with 5-year OS rates ranging from 25% to 89% (c-statistic = 0.76) in the 2004 cohort. The validity of the index was internally confirmed in the 2008 cohort (c-statistic = 0.71).We conclude that HPV infections are common in Taiwanese OCC patients and predict 5-year OS. If independently validated, our composite prognostic score comprising HPV16 infection may be useful for allocating OCC patients to risk adapted therapies. PMID- 26632713 TI - Treatment of Clubfoot With Ponseti Method Using Semirigid Synthetic Softcast. AB - Randomized controlled clinical trial.The main purpose of the present study was to comparatively analyze the effectiveness, advantages, and the complications of using semirigid synthetic softcast with respect to plaster of Paris (POP) during the treatment of clubfoot deformity.The study group consisted of 196 babies (249 feet). A total of 133 feet treated by an orthopedic referral center using semirigid synthetic softcast were included in group A whereas the other 116 feet treated by another orthopedic clinic using POP cast were included in group B. The Pirani scores, number of cast applications, time period until Achilles tenotomy, any skin problems due to the cast itself, and/or cast removal were recorded. A final parent satisfaction score was also obtained.The mean Pirani sores were significantly improved from the first administration to the time before Achilles tenotomy in both groups. There was no significant difference according to the number of casts applied until tenotomy. The slippage of the cast and skin lesions was significantly more common in group B. Higher parent satisfaction levels were detected in group A.Semirigid softcast has been found as superior to POP in the aspects of parent satisfaction and cast-related complication rates. PMID- 26632714 TI - The Value of Restaging With Chest and Abdominal CT/MRI Scan After Neoadjuvant Chemoradiotherapy for Locally Advanced Rectal Cancer. AB - Little was known with regard to the value of preoperative systemic restaging for patients with locally advanced rectal cancer (LARC) treated with neoadjuvant chemoradiotherapy (CRT). This study was designed to evaluate the role of chest and abdominal computed tomography (CT) scan or magnetic resonance imaging (MRI) on preoperative restaging in LARC after neoadjuvant CRT and to assess the impact on treatment strategy.Between January 2007 and April 2013, 386 newly diagnosed consecutive patients with LARC who underwent neoadjuvant CRT and received restaging with chest and abdominal CT/MRI scan were included. Imaging results before and after CRT were analyzed.Twelve patients (3.1%) (6 liver lesions, 2 peritoneal lesions, 2 distant lymph node lesions, 1 lung lesions, 1 liver and lung lesions) were diagnosed as suspicious metastases on the restaging scan after radiotherapy. Seven patients (1.8%) were confirmed as metastases by pathology or long-term follow-up. The treatment strategy was changed in 5 of the 12 patients as a result of restaging CT/MRI findings. Another 10 patients (2.6%) who present with normal restaging imaging findings were diagnosed as metastases intra operatively. The sensitivity, specificity accuracy, negative predictive value, and positive predictive values of restaging CT/MRI was 41.4%, 98.6%, 58.3%, and 97.3%, respectively.The low incidence of metastases and minimal consequences for the treatment plan question the clinical value of routine restaging of chest and abdomen after neoadjuvant CRT. Based on this study, a routine restaging CT/MRI of chest and abdomen in patients with rectal cancer after neoadjuvant CRT is not advocated, carcino-embryonic antigen (CEA) -guided CT/MRI restaging might be an alternative. PMID- 26632715 TI - Cancer Incidence in Physicians: A Taiwan National Population-based Cohort Study. AB - Cancer has been the leading cause of death in Taiwan since 1982. Physicians have many health-related risk factors which may contribute to cancer, such as rotating night shift, radiation, poor lifestyle, and higher exposure risk to infection and potential carcinogenic drugs. However, the cancer risk in physicians is not clear. In Taiwan's National Health Insurance Research Database, we identified 14,889 physicians as the study cohort and randomly selected 29,778 nonmedical staff patients as the comparison cohort for this national population-based cohort study. Cox proportional-hazard regression was used to compare the cancer risk between physicians and comparisons. Physician subgroups were also analyzed. Physicians had a lower all-cancer risk than did the comparisons (hazard ratio [HR] 0.86, 95% confidence interval [CI] 0.76-0.97). In the sex-based analysis, male physicians had a lower all-cancer risk than did male comparisons (HR 0.82, 95% CI 0.73-0.94); and female physicians did not (HR 1.29, 95% CI 0.88-1.91). In the cancer-type analysis, male physicians had a higher risk of prostate cancer (HR 1.72, 95% CI 1.12-2.65) and female physicians had twice the risk of breast cancer (HR 2.00, 95% CI 1.11-3.62) than did comparisons. Cancer risk was not significantly associated with physician specialties. Physicians in Taiwan had a lower all-cancer risk but higher risks for prostate and breast cancer than did the general population. These new epidemiological findings require additional study to clarify possible mechanisms. PMID- 26632716 TI - Expression of LRIG1 is Associated With Good Prognosis for Human Non-small Cell Lung Cancer. AB - Somatic mutations, which are associated with a certain rate of response to targeted therapies, are ubiquitously found in human non-small cell lung cancer (NSCLC). However, it is largely unknown which group of patients may benefit from the respective treatments targeting different somatic mutations. Therefore, more effective prognostic and predictive markers are desperately needed for the treatment of NSCLC harboring different somatic mutations. The leucine-rich repeats and immunoglobulin-like domains (LRIG)-1 is a tumor suppressor gene that belongs to the LRIG family. LRIG1 expression has prognostic significance in various human cancers.In this study, we first used the quantitative polymerase chain reaction (qPCR) and immunohistochemical analysis of 36 and 182 NSCLC patient tissues to analyze the LRIG1 expression respectively. To investigate the prognostic value of LRIG1 in NSCLC, we examined the correlation between clinical features and overall survival (OS) with Cox proportional hazard regression. We also compared the sensitivity and specificity of LRIG1 in NSCLC prognosis by logistic regression to further evaluate the prognostic efficiency of LRIG1 in NSCLC.We found that the LRIG1 expression was associated with pathological type, differentiation status, and stage of NSCLC. The result showed that LRIG1 was an independent prognostic factor for OS of NSCLC patients. LRIG1 in combination with other clinicopathological risk factors was a stronger prognostic model than clinicopathological risk factors alone.Thus, the LRIG1 expression potentially offered a significant clinical value in directing personal treatment for NSCLC patients. PMID- 26632717 TI - 99mTc-MIBI Lung Scintigraphy in the Assessment of Pulmonary Involvement in Interstitial Lung Disease and Its Comparison With Pulmonary Function Tests and High-Resolution Computed Tomography: A Preliminary Study. AB - The differentiation of active inflammatory processes from an inactive form of the disease is of great value in the management of interstitial lung disease (ILD). The aim of this investigation was to assess the efficacy of 99mTc-methoxy isobutyl-isonitrile (99mTc-MIBI) scans in distinguishing the severity of the disease compared to radiological and clinical parameters.In total, 19 known cases of ILD were included in this study and were followed up for 1 year. Five patients without lung disease were considered as the control group. The patients underwent pulmonary function tests (PFTs) and high-resolution computed tomography scans, followed by 99mTc-MIBI scanning. The 99mTc-MIBI scans were analyzed either qualitatively (subjectively) or semiquantitatively.All 19 ILD patients demonstrated a strong increase in 99mTc-MIBI uptake in the lungs compared to the control group. The 99mTc-MIBI scan scores were higher in the patient group in both the early phase (0.24[0.19-0.31] vs 0.11[0.10-0.15], P < 0.05) and the delayed phase (0.15[0.09-0.27] vs 0.04[0.01-0.09], P < 0.05) compared with the control group. A positive correlation was detected between the 99mTc-MIBI scan and the high-resolution computed tomography (HRCT) scores (Spearman's correlation coefficient = 0.65, P < 0.02) in the early phase but not in the delayed phase in patients (P > 0.14). The 99mTc-MIBI scan scores were not significantly correlated with the PFT findings (P > 0.05). In total, 5 patients died and 14 patients were still alive over the 1-year follow-up period. There was also a significant difference between the uptake intensity of 99mTc-MIBI and the outcome in the early phase (dead: 0.32[0.29-0.43] vs alive: 0.21[0.18-0.24], P < 0.05) and delayed phase (dead: 0.27[0.22-0.28] vs alive: 0.10[0.07-0.19], P < 0.05).The washout rate was ~40 min starting from 20 min up to 60 min and this rate was significantly different in our 2 study groups (ILD: 46.61[15.61-50.39] vs NL: 70.91[27.09-116.36], P = 0.04).The present study demonstrated that 99mTc-MIBI lung scans might distinguish the severity of pulmonary involvement in early views, which were well correlated with HRCT findings. These results also revealed that 99mTc-MIBI lung scans might be used as a complement to other diagnostic and clinical examinations in terms of functional information in ILD; however, further investigations are strongly required. PMID- 26632718 TI - Genetic Variations in Key MicroRNAs are Associated With the Survival of Nonsmall Cell Lung Cancer. AB - MicroRNAs (miRNAs) are a class of small, noncoding RNA molecules involved in carcinogenesis. It has been identified that genetic variations in miRNAs contribute to cancer risk, prognosis, and survival. In the present study, we investigated whether single nucleotide polymorphisms (SNPs) of several key miRNAs (miR-184, miR-218, and miR-124) were associated with the prognosis of nonsmall cell lung cancer (NSCLC) in a clinical cohort study including 1001 cases. Cox proportional hazards regression models were used to estimate the hazard ratios (HRs) and their 95% confidence intervals (CIs). We found that 5 SNPs were associated with NSCLC survival (rs919968, rs3775815, rs4867902, and rs6122390 in an additive model: adjusted HR = 1.15, 95% CI = 1.02-1.29; adjusted HR = 0.78, 95% CI = 0.67-0.91, adjusted HR = 1.24, 95% CI = 1.09-1.41; adjusted HR = 1.21, 95% CI = 1.07-1.36, respectively; rs298206 in a dominant model: HR = 1.25, 95% CI = 1.05-1.49). Even after the Bonferroni correction, 3 SNPs remained significant (adjusted P = 0.010, 0.010, and 0.032 for rs3775815, rs4867902, and rs6122390, respectively). Additionally, the combined analysis of these 5 SNPs showed a significant locus-dosage effect between number of unfavorable alleles (rs919968 A, rs3775815-C, rs4867902-G, rs6122390-A, and rs298206-T) and death risk of NSCLC (P for trend < 0.001). A statistically significant multiplicative interaction was found between the genotypes of rs4867902 and surgical operation status (Pint = 0.013). These findings indicated that genetic variations in miRNAs (miR-184, miR 218, and miR-124) might be prognostic markers for NSCLC patients. PMID- 26632719 TI - Cardiac Mechanics in Isolated Bicuspid Aortic Valve Disease With Normal Ejection Fraction: A Study of Various Valvular Lesion Types. AB - Aortic stenosis (AS) and aortic regurgitation (AR) are associated with congenital isolated bicuspid aortic valve (BAV) disease. The chronic pressure overload of AS and the volume overload of AR are known to impair the left ventricular function. This study assessed whether two-dimensional speckle tracking echocardiography (2D STE) is capable of detecting the myocardial dysfunction associated with BAV caused by various aortic valve lesions in patients retaining normal ejection fraction (EF).Thirty-two isolated BAV patients and 20 healthy tricuspid aortic valve (TAV) volunteers were recruited. BAV patients were divided into 4 subgroups based on aortic valvular lesion types: normal function (NF) group, isolated AS group, isolated AR group, and a group who had both AS&AR. Myocardial strain and degree of twist were analyzed and compared between the BAV and TAV groups, as well as between valvular lesion groups and the NF group.Compared with healthy TAV controls, global radial strain (GRS), global circumferential strain (GCS), global longitudinal strain (GLS), and twist angle absolute values were lower in the BAV group (P < 0.05). The AS, AR, and AS&AR groups all demonstrated a significant decrease in GRS and GCS when compared with the TAV group. The AS and AS&AR groups demonstrated lower GLS than the TAV group, and the smallest degree of twist was detected in the AR group. There were no significant differences between the NF and TAV groups. The AR and AS&AR groups demonstrated significant differences in multiple parameters of cardiac mechanics compared with the NF group.2D-STE is able to detect altered cardiac mechanics associated with aortic lesion types in BAV patients with normal EF compared with normal TAV controls, and so can provide valuable information for clinical decision-making. PMID- 26632720 TI - Relation Between Hepatitis C Virus Exposure and Risk of Osteoporosis: A Nationwide Population-Based Study. AB - The effect of hepatitis C virus (HCV) exposure on bone mineral density without advanced liver disease remains debated. Thus, we assessed the relation between HCV exposure and the risk of osteoporosis.From 2000 to 2011, patients aged >20 years with HCV exposure were identified from the Longitudinal Health Insurance Database 2000. Of the 51,535 sampled patients, 41,228 and 10,307 patients were categorized as the comparison and the HCV exposure cohorts, respectively.The overall incidence of osteoporosis in the HCV exposure cohort was higher than in the comparison cohort (8.27 vs 6.19 per 1000 person-years; crude hazard ratio = 1.33, 95% confidence interval = 1.20-1.47). The incidence of osteoporosis, higher in women than in men, increased with age and comorbidity of hypertension, hyperlipidemia, and heart failure. The risk of developing osteoporosis was significantly higher in the HCV exposure cohort than in the comparison cohort after adjusting for age, sex, diabetes, hypertension, hyperlipidemia, heart failure, stroke, and cirrhosis. However, the risk of osteoporosis contributed by HCV decreased with age and the presence of comorbidity. Furthermore, the risk of osteoporotic fracture did not differ significantly between patients exposed to HCV and the comparison cohorts.HCV increases the risk of osteoporosis, but no detrimental effect on osteoporotic fracture was observed in this study. Furthermore, HCV may be less influential than other risk factors, such as hypertension, hyperlipidemia, and heart failure, in contributing to the development of osteoporosis. PMID- 26632721 TI - Sphincter of Oddi Dysfunction and the Formation of Adult Choledochal Cyst Following Cholecystectomy: A Retrospective Cohort Study. AB - To determine the causes underlying the formation of adult choledochal cyst.Anomalous pancreaticobiliary junction is the most widely accepted theory regarding the etiology of choledochal cyst. However, choledochal cysts have been found in patients in the absence of this anomaly. Because the number of adult patients with choledochal cyst is increasing, it is important to address this controversy.Bile amylase levels in the cysts of 27 patients (8 males and 19 females) who had undergone cholecystectomy were retrospectively evaluated.The average age of the 27 patients was 45.8 +/- 10.1 years and the majority (85.2%) were diagnosed with Todani type I cysts. None of the patients had dilatation of the common bile duct prior to surgery. There were 6 (22.2%) patients with anomalous pancreaticobiliary junction. However, amylase levels did not significantly differ between patients with and without this anomaly (P = 0.251). According to bile amylase levels, pancreatobiliary reflux was present in 21 (77.8%) patients. The mean amylase level significantly differed in patients with pancreatobiliary reflux (23,462 +/- 11,510 IU/L) and those without (235 +/- 103 IU/L) (P < 0.001). In patients with pancreatobiliary reflux, only 4 patients had anomalous pancreaticobiliary junction. That is, the majority of patients (17/21, 81%) having pancreatobiliary reflux did not have an anomalous junction of the pancreatic and biliary ducts.Since the only explanation for pancreatobiliary reflux in patients with a normal pancreaticobiliary junction is sphincter of Oddi dysfunction, we proposed that the formation of adult choledochal cyst is mainly due to sphincter of Oddi dysfunction. PMID- 26632722 TI - Relationship Between Forced Vital Capacity and Framingham Cardiovascular Risk Score Beyond the Presence of Metabolic Syndrome: The Fourth Korea National Health and Nutrition Examination Survey. AB - Impaired lung function is a risk factor for cardiovascular (CV) events. However, it has not been well established whether FVC reduction even within normal range is associated with cardiovascular disease (CVD) risk and whether reduced FVC is an independent relationship of CVD irrespective of metabolic syndrome. Thus, we aimed to explore the relationship between FVC and CV-event risk using the FRS beyond the presence of metabolic syndrome or abdominal obesity in a representative Korean population based on data from the nationwide Korea National Health and Nutrition Examination Survey (KNHANES IV).The study population included 9688 subjects >= 30 years of age with no previous diagnosis of CVD and obstructive lung disease. Using a logistic regression model and area under the curve (AUC) analysis, we evaluated the relationship between FVC quintiles and CV event risk using the Framingham Risk Score (FRS; >= 10% or >= 20%). In addition, we examined the effect of FVC on CV-event risk based on the presence of metabolic syndrome (MetS) and abdominal obesity.After adjusting for covariates, comparison of subjects in the lowest FVC (% pred) quintile (Q1) with those in the highest quintile (Q5) yielded an odds ratio (OR) of 2.27 (95% CI, 1.91-2.71) for intermediate and high risk, and 2.89 (95% CI, 2.31-3.61) for high risk. The ORs for cardiovascular risk using FRS also increased irrespective of the presence of abdominal obesity and MetS without significant interaction. Furthermore, the addition of FVC status to MetS status and abdominal obesity status significantly increased the AUC of the model predicting CV-event risk (P < 0.001 and P < 0.001).Our study demonstrates that FVC is inversely associated with 10-year CV event risk, irrespective of MetS and abdominal obesity in the general population without obstructive lung disease. Furthermore, the addition of FVC to MetS or abdominal obesity increased prediction of CVD event risks, implying a potential role of FVC to predict CV events. PMID- 26632723 TI - Good's Syndrome Patients Hospitalized for Infections: A Single-Center Retrospective Study. AB - Good's syndrome (GS) is a rare combination of thymoma and hypogammaglobulinemia, resulting in immunodeficiency. Patients with GS are highly susceptible to bacterial infection, particularly encapsulated bacterial infection in upper and lower respiratory tracts. Good's syndrome patients with moderate-to- severe infection are often hospitalized. Clinical features of GS patients remain to be characterized.Patients with the discharge diagnosis of GS and simultaneous infection from Peking Union Medical College Hospital between January 2001 and July 2015 were retrospectively analyzed.Among 14 hospitalized GS patients, 12 of them were admitted for severe infections. Mean patient age was 56.7 + 10.1 years. Average concentrations of serum IgG, IgA, and IgM were 2.3 + 1.9 g/L, 0.28 + 0.28 g/L, and 0.06 + 0.07 g/L, respectively. Respiratory and intestinal tracts were the most common sites for infection, which occurred in 7 and 4 patients, respectively. Pathogens identified in 10 patients included cytomegalovirus in 5 patients, Pneumocystis jirovecii, Clostridium difficile in 2 patients, Klebsiella pneumonia in 2 patients, and Streptococcus pneumonia and Hemophilus influenza in 1 patient. Ten patients were treated with antibiotics and immunoglobulin replacement. Only 1 patient who was on immunosuppressant therapy died from P. jirovecii pneumonia.Infection was the most frequent cause for hospitalization of GS patients. Both respiratory and intestinal tracts were the most common sites of infection. Cytomegalovirus and P. jirovecii represented 2 common opportunistic pathogens isolated from hospitalized GS patients with infections. PMID- 26632724 TI - Longitudinal Changes in the Brain Following Third Ventriculostomy in a Child With Hydrocephalus: A Case Report. AB - The goal of this study was to detect the long-term effect of shunting on the integrity of white matter in young children with hydrocephalus.The authors reported the case of a 6-month-old boy with hydrocephalus who was evaluated by diffusion tensor imaging (DTI) before and after a shunt operation.When compared with normal children, the structures of the corpus callosum, internal capsule, and corona radiata in the patient showed a decrease in fractional anisotropy and an increase in radial diffusivity values before the shunt operation. Following successful cerebrospinal fluid shunting, long-term follow-up DTI demonstrated a trend toward normalization of the fractional anisotropy and radial diffusivity values.Shunt treatment can prevent further damage to the brain and grossly reconstitute the distorted anatomy. DTI could be a useful tool in detecting longitudinal changes after a shunt operation. Further studies involving larger case numbers are needed to detect the long-term effect of shunting on the brains of children with hydrocephalus. PMID- 26632725 TI - Tubulointerstitial Nephritis and Uveitis Syndrome in an Elderly Man: Case Report and Literature Review. AB - Tubulointerstitial nephritis and uveitis (TINU) syndrome is a rare disease of unknown etiology defined by the combination of tubulointerstitial nephritis, uveitis, and biochemical abnormalities. It has been reported that TINU mainly affects adolescents and young women. Here we reported a special case regarding a 60-year-old man with acute renal failure due to TINU syndrome documented by renal biopsy.We present a rare case of an elderly patient, who had been suffering from a fever for 2 weeks, characterized by sudden onset and resolving spontaneously, and accompanied by extreme fatigue, loss of appetite, and shivering. Renal biopsy showed a tubulointerstitial nephritis, with polymorphonuclear infiltration and acute tubulitis. In the outpatient clinic, he was diagnosed with idiopathic bilateral anterior uveitis 1 month ago. Ophthalmological examination revealed anterior asymptomatic bilateral uveitis. Human leukocyte antigen (HLA) typing (HLA-DQA1*0101/0201 and HLA-DQB1*0303/0503) was found which supported the suspect of TINU syndrome. The patient was treated with oral prednisone (1 mg/kg) and continued for 8 weeks on tapering doses. Serum creatinine normalized within 3 and 6 months later renal function also recovered completely.This case highlights that TINU syndrome is probably an underdiagnosed disease responsible for some cases of idiopathic anterior uveitis in elderly male patients. It is of critical importance to be aware of this syndrome by nephrologist and ophthalmologists in this special population. Further studies are needed to elucidate clinical characteristic and pathogenesis of TINU syndrome in elderly population. PMID- 26632726 TI - A Novel Combination of Calprotectin and CXCL12 for Predicting Malignancy in Patients with Exudative Pleural Effusion. AB - Pleural effusion (PE) remains a significant challenge and public health problem, which needs novel noninvasive biomarkers for the precise diagnosis. The aim of this study was to further determine the clinical efficacy and diagnostic accuracy of a novel combination of calprotectin and CXCL12 for predicting malignancy in patients with exudative PE.Calprotectin and CXCL12 concentrations were measured in 95 individuals of exudative PE, with 39 malignant PE (MPE) and 56 benign PE (BPE). The accuracy of calprotectin and CXCL12 levels for discriminating MPE from BPE or tuberculous PE were evaluated using receiver-operating characteristic (ROC) curves. Univariate and multivariate logistic regression analyses were performed to test the association between calprotectin and CXCL12 levels and MPE.Calprotectin and CXCL12 levels of patients with MPE were significantly lower than that of BPE and tuberculous PE (P < 0.05). The area under the curve (AUC) of calprotectin and CXCL12 was 0.683 and 0.641 in MPE and BPE, and a combination of calprotectin <=500.19 ng/mL and CXCL12 <=6.11 ng/mL rendered a sensitivity and specificity of 48.72% and 78.57%, respectively. While in MPE and tuberculous PE, the AUC of calprotectin and CXCL12 was 0.696 and 0.690, and a combination of calprotectin <=421.73 ng/mL and CXCL12 <=3.71 ng/mL presented a sensitivity and specificity of 25.64% and 95.45%, respectively. Multivariate logistic regression demonstrated that both calprotectin and CXCL12 were independent predictors of MPE.Calprotectin and CXCL12 in pleural fluid are informative diagnostic biomarkers for predicting patients with MPE. PMID- 26632727 TI - Expression of Human Epidermal Growth Factor Receptor-2 in Resected Rectal Cancer. AB - The addition of trastuzumab to chemotherapy was demonstrated to be beneficial for advanced human epidermal growth factor receptor-2 (HER-2) positive gastric cancer. However, the HER-2 status of rectal cancer remains uncertain. This study aimed to determine the HER-2 expression in a large multicenter cohort of rectal cancer patients. The clinical and pathological features of 717 patients were retrospectively reviewed. All the patients were diagnosed with primary rectal adenocarcinoma without distant metastasis and took surgery directly without any preoperative anticancer treatment. HER-2 status was assessed on resected samples. A total of 99 cases with IHC3+ and 16 cases with IHC 2+ plus gene amplification were determined as HER-2 positive. 22.6% of HER-2 positive patients had local recurrence, whereas 16.9% of HER-2 negative patients did (P = 0.146). HER-2 positive tumors were more likely to have distant metastasis (P = 0.007). Univariate analysis revealed that pathological tumor stage, pathological node stage, positive margin, and lymphovascular invasion were significantly correlated with 5-year disease-free survival (DFS) and 5-year overall survival (OS). The patients with >10 dissected lymph nodes showed significantly longer OS (P = 0.045) but not DFS (P = 0.054). HER-2 negative patients had significantly better 5-year DFS (P < 0.001) and 5-year OS (P = 0.013) than those of the HER-2 positive patients. In the subgroup analysis for the early rectal cancer and locally advanced rectal cancer, HER-2 was also a poor predictor for survival. Multivariate analysis revealed that HER-2 was an independent prognostic factor for 5-year DFS (hazard ratio [HR] = 1.919, 95% confidence interval [CI] 1.415 2.605, P < 0.001) and for 5-year OS (HR = 1.549, 95% CI 1.097-2.186, P = 0.013). When the treatment was included in the analysis for locally advanced patients, HER-2 was a prognostic factor for 5-year DFS (P = 0.001) but not for 5-year OS (P = 0.106). This study confirmed that HER-2 was expressed in a part of patients with rectal cancers and might be used as a negative predictor. The results may support the trials to assess the efficacy of trastuzumab in treating HER-2 positive rectal cancer patients. PMID- 26632728 TI - Organophosphate Poisoning and Subsequent Acute Kidney Injury Risk: A Nationwide Population-Based Cohort Study. AB - Small numbers of the papers have studied the association between organophosphate (OP) poisoning and the subsequent acute kidney injury (AKI). Therefore, we used the National Health Insurance Research Database (NHIRD) to study whether patients with OP poisoning are associated with a higher risk to have subsequent AKI.The retrospective cohort study comprised patients aged >=20 years with OP poisoning and hospitalized diagnosis during 2000-2011 (N = 8924). Each OP poisoning patient was frequency-matched to 4 control patients based on age, sex, index year, and comorbidities of diabetes, hypertension, hyperlipidemia, chronic obstructive pulmonary disease, coronary artery disease, and stroke (N = 35,696). We conducted Cox proportional hazard regression analysis to estimate the effects of OP poisoning on AKI risk.The overall incidence of AKI was higher in the patients with OP poisoning than in the controls (4.85 vs 3.47/1000 person-years). After adjustment for age, sex, comorbidity, and interaction terms, patients with OP poisoning were associated with a 6.17-fold higher risk of AKI compared with the comparison cohort. Patients with highly severe OP poisoning were associated with a substantially increased risk of AKI.The study found OP poisoning is associated with increased risk of subsequent AKI. Future studies are encouraged to evaluate whether long-term effects exist and the best guideline to prevent the continuously impaired renal function. PMID- 26632729 TI - A Retrospective Study of 39 Patients Treated With Anterior Approach of Thoracic and Lumbar Spondylodiscitis: Clinical Manifestations, Anterior Surgical Treatment, and Outcome. AB - The aim of this study is to report our 39 patients treated with anterior debridement and autologous iliac bone grafting with or without anterior instrumentation, which is the presumed treatment of choice for thoracic or lumbar spondylodiscitis.Our patients underwent surgical treatment of spondylodiscitis using anterior debridement and autologous iliac bone grafting with or without anterior instrumentation and were analyzed with a mean follow-up of 8 years (range, 2-11 years). Kaneda 2-rod system instrumentation was used in 12 patients, in total. Clinical outcomes were assessed by the Frankel grade. Radiographic fusion was characterized based on 3-dimensional computed tomography.Of the whole group, 20 patients suffered from tuberculous spondylodiscitis and 19 suffered from hematogenous spondylodiscitis. Pathogens responsible for pyogenic infection included Staphylococcus aureus (4 patients), Pseudomonas aeruginosa (3 patients), and Brucella melitensis (1 patient). Fifteen patients had thoracic involvement, 20 had lumbar involvement, and 4 had thoracolumbar junction involvement. Preoperative neurological deficits were noted in 13 of the 39 patients. In terms of Frankel grade, 8 patients have improved, 4 have remained the same, and 1 patient has worsened during the follow-up period. Imaging-documented fusion was achieved in 23 of 27 patients in the graft group (85% fusion rate) and 11 of 12 patients in the graft + Kaneda instrumentation group (91% fusion rate).There was no instrumentation failure, loosening, or graft-related complication such as slippage or fracture of the graft. This approach demonstrated a good recovery rate of neurological functions and a high fusion rate. PMID- 26632730 TI - Interferon-Based Treatment of Hepatitis C Virus Infection Reduces All-Cause Mortality in Patients With End-Stage Renal Disease: An 8-Year Nationwide Cohort Study in Taiwan. AB - The long-term survival of end-stage renal disease (ESRD) patients with hepatitis C virus (HCV) infection who received interferon treatment has not been extensively evaluated.The HCV cohort was the ESRD patients with de novo HCV infection from 2004 to 2011; they were classified into treated and untreated groups according to interferon therapy records. Patients aged <20 years and those with a history of hepatitis B, kidney transplantation, or cancer were excluded. The control cohort included ESRD patients without HCV infection matched 4:1 to the HCV cohort by age, sex, and year of ESRD registration. We followed up all study participants until kidney transplantation, death, or the end of 2011, whichever came first. We assessed risk of all-cause mortality by using the multivariate Cox proportional hazard model with time-dependent covariate.In the HCV cohort, 134 patients (6.01%) received interferon treatment. Compared with the uninfected control cohort, the treated group had a lower risk of death (hazard ratio 0.47, 95% confidence interval [CI] 0.22-0.99). The untreated group had a 2.62-fold higher risk (95% CI 1.24-5.55) of death compared with the treated group. For the HCV cohort without cirrhosis or hepatoma, the risk of death in the treated group was further markedly reduced (hazard ratio 0.17, 95% CI 0.04-0.68) compared with that in the control cohort.For ESRD patients with HCV infection, receiving interferon treatment is associated with a survival advantage. Such an advantage is more prominent in HCV patients without cirrhosis or hepatoma. PMID- 26632731 TI - Novel Association Between the Reverse-Dipper Pattern of Ambulatory Blood Pressure Monitoring and Metabolic Syndrome in Men But Not in Women. AB - The aim of this study was to investigate the relationships between nocturnal variations in blood pressure (BP) and metabolic syndrome (MetS) in different gender.This cross-sectional study involved 509 hypertensive patients (254 males and 255 females, 45 to 75 years old) from September 2013 to March 2014. BP values were acquired from ambulatory BP monitoring (ABPM). The dipper pattern of BP was defined as 10% to 20% reduction of the mean systolic BP (SBP) values at night compared with the daytime values. The diagnosis of MetS was made according to NCEP ATP-III definition. Multivariate logistic regression analyses were used to explore the relationships between ABPM results and MetS.In our study, MetS were observed in 29.1% of male and 18.4% of female participants. The prevalence of MetS was higher in the patients with reverse-dipper pattern than in others. After multivariate logistic regression analysis, the reverse-dipper pattern of BP (odds ratio 2.298; P = 0.006) and 24-SBP (odds ratio 1.063; P = 0.021) were independently correlated with MetS in males. However, there was no association between MetS and BP reverse dipping in females.Our cross-sectional study showed that the reverse-dipper pattern of BP is associated with MetS in male, while the underlying mechanism deserves further investigation. PMID- 26632732 TI - Primary Gastrointestinal Lymphoma: A Retrospective Multicenter Clinical Study of 415 Cases in Chinese Province of Guangdong and a Systematic Review Containing 5075 Chinese Patients. AB - Primary gastrointestinal lymphoma (PGIL) is a rare malignant tumor without standard diagnosis and treatment methods. This study is aimed to systematically analyze its clinical characteristics and draw out an appropriate flow chart of diagnosis and treatment process for PGIL in China.This study retrospectively analyzed the clinicopathological characteristics, diagnostic approaches, prognostic factors, and therapeutic modalities in 415 cases of PGIL in Chinese province of Guangdong. A systematic review was conducted in 118 studies containing 5075 patients to further identify clinical manifestations and mortalities of therapeutic modalities.The most common clinical presentations were abdominal pain and bloody stools. Endoscopic biopsy was an important diagnostic means, and usually more than once to make a definite diagnosis. Retrospective multicenter clinical study showed that younger onset age (<60 years), female, one region involved, one lesion, early stage, International Prognostic Index (IPI <=1), normal lactate dehydrogenase (LDH), normal albumin, and nonemergency operation were significant prognostic factors for B-cell lymphoma; non-B symptom, tumor restricted to gastric or ileocecal region, one lesion, performance status (PS <=1), normal LDH, and nonsurgery alone were significant prognostic factors for T-cell lymphoma. Site of origin and IPI were independent prognostic factors for B-cell lymphoma; PS was the independent prognostic factor for T-cell lymphoma. And T-cell lymphoma had worse overall survival (OS) and progression free survival (PFS) than B-cell lymphoma. Among different therapeutic modalities, chemotherapy alone or combined with surgery showed better OS and PFS than surgery alone for diffuse large B-cell lymphoma (DLBCL) of stage I/II E and T-cell lymphoma. For DLBCL of stage III E/IV and mucosa-associated lymphoid tissue lymphoma, OS and PFS did not differ among different therapeutic groups. In meta analysis, surgery plus chemotherapy showed lowest mortality.Chemotherapy alone or combined with surgery may be the first-line treatment for DLBCL of stage I/II E and T-cell lymphoma. A flow chart of diagnosis and treatment process for PGIL was approximately drew out. PMID- 26632733 TI - Association Between Vitamin D Receptor rs731236 (Taq1) Polymorphism and Risk for Restless Legs Syndrome in the Spanish Caucasian Population. AB - Several recent works suggest a possible role of vitamin D deficiency in the etiology or restless legs syndrome (RLS). We analyzed the possible relationship of 2 common single nucleotide polymorphisms (SNPs) in the vitamin D3 receptor (VDR) gene with the risk for RLS.We studied the genotype and allelic variant frequencies of VDR rs2228570 and VDR rs731236 SNPs in 205 RLS patients and 445 healthy controls using a TaqMan essay.The frequencies of the rs731236AA genotype and the allelic variant rs731236A were significantly lower in RLS patients than in controls (P < 0.005 and < 0.01, respectively). Restless legs syndrome patients carrying the allelic variant rs731236G had an earlier age at onset, and those carrying the rs731236GG genotype had higher severity of RLS, although these data disappeared after multivariate analyses. None of the SNPs studied was related with the positivity of family history of RLS.These results suggest a modest, but significant association between VDR rs731236 SNP and the risk for RLS. PMID- 26632734 TI - Early Surgical Management of Large Scalp Infantile Hemangioma Using the TopClosure(r) Tension-Relief System. AB - Infantile hemangiomas (IHs) are the most common benign vascular neoplasms of infancy and childhood. The majority do not need medical intervention. However, large ulcerated scalp IHs may lead to fatal bleeding as well as severe cosmetic disfigurement that indicate early surgical excision, inflicting substantial surgical risks, with short- and long-term morbidity.The TopClosure Tension-Relief System (TRS) is an innovative skin stretching and wound closure-secure system that facilitates primary closure of relatively large skin defects. This system has been shown as a substitute for skin grafts, flaps, or tissue expanders.We describe a case of a giant IH of the scalp usually requiring a complex surgical approach, which was immediately primarily closed applying the TRS.A 3-day-old female infant presented with a giant scalp hemangioma at birth that rapidly grew in the neonatal period with early signs of ulceration. The patient underwent surgical resection of the giant scalp hemangioma with immediate primary closure of the defect using the TRS. Surgical procedure and postoperative period were uneventful.Early surgical resections of IHs at infancy carry substantial surgical risks and morbidity. This is the first reported case of early resection of a scalp hemangioma in the neonatal period, with successful immediate primary closure by application of stress-relaxation technique through the TRS. The application of the TopClosure TRS in this age group has significant advantages. It reduces the complexity and length of surgery, reducing blood loss, eliminating donor site morbidity, improving wound aesthetics, and minimizing the need for future reconstructive procedures. PMID- 26632735 TI - Differences in the Pathological Diagnosis and Repeat Craniotomy Rates in Cerebral Tumors Undergoing Biopsy or Resection in an Urban Versus Regional Center. AB - Primary intracranial tumors occur with an incidence of between 2.5 and 6 per 100,000 individuals. They require specialist expertise for investigation and management including input from radiology, pathology, neurosurgery, and oncology. Therefore, most patients with intracranial neoplasia are investigated and managed in larger hospitals. The geographically dispersed population of Australia has facilitated the development of neurosurgical units in regional areas. However, major metropolitan hospitals are over-represented compared with regional centers in most research cohorts. We therefore sought to investigate the spectrum of intracranial neoplasms undergoing biopsy and surgery at a major regional center in Australia and to compare the demographic and pathological features to similar cohorts treated in major metropolitan hospitals.We searched the pathological databases of both a major regional pathology provider and a major metropolitan pathology practice, which provides surgical pathology services for both a large private and a large public neurosurgical hospital, to identify all cerebral tumors undergoing biopsy or resection over a 14-year period (calendar years 2001 and 2014).In all, 3717 cerebral tumors were identified. Among them, 51% were from an urban private hospital, 33% from an urban public hospital, and 16% from a regional public hospital. Overall, one-third of them were neuroepithelial in origin, a quarter metastatic disease, a fifth meningeal, and one-tenth were pituitary adenomas. The regional center treated a higher proportion of metastatic tumors and less meningeal tumors compared with the urban center. Additionally, patients were less likely to undergo a second operation in the regional center (P < 0.001). The differences give an important insight into the burden of neurosurgical disease in regional Australia, and how it differs from that encountered in large metropolitan centers. PMID- 26632736 TI - A Simple Risk Model to Predict Survival in Patients With Carcinoma of Unknown Primary Origin. AB - Carcinoma of unknown primary origin (CUP) is characterized by diverse histological subtypes and clinical presentations, ranging from clinically indolent to frankly aggressive behaviors. This study aimed to identify prognostic factors of CUP and to develop a simple risk model to predict survival in a cohort of Asian patients.We retrospectively reviewed 190 patients diagnosed with CUP between 2007 and 2012 at a single medical center in Taiwan. The clinicopathological parameters and outcomes of our cohort were analyzed. A risk model was developed using multivariate logistic regression and a prognostic score was generated.The prognostic score was calculated based on 3 independent prognostic variables: the Eastern Cooperative Oncology Group (ECOG) scale (0 points if the score was 1, 2 points if it was 2-4), visceral organ involvement (0 points if no involvement, 1 point if involved), and the neutrophil-to-lymphocyte ratio (0 points if <=3, 1 point if >3). Patients were stratified into good (score 0), intermediate (score 1-2), and poor (score 3-4) prognostic groups based on the risk model. The median survival (95% confidence interval) was 1086 days (500 1617, n = 42), 305 days (237-372, n = 75), and 64 days (44-84, n = 73) for the good, intermediate, and poor prognostic groups, respectively. The c-statistics using the risk model and ECOG scale for the outcome of 1-year mortality were 0.80 and 0.70 (P = 0.038), respectively.In this study, we developed a simple risk model that accurately predicted survival in patients with CUP. This scoring system may be used to help patients and clinicians determine appropriate treatments. PMID- 26632737 TI - Epidemiology and Outcome of Severe Sepsis and Septic Shock in Surgical Intensive Care Units in Northern Taiwan. AB - Severe sepsis remains the leading cause of mortality in the critically ill. Local epidemiological studies on sepsis are of paramount importance to increase our knowledge about sepsis features and to improve patient care and prognosis.Adult patients (>=20 years) admitted to the surgical intensive care units with severe sepsis or septic shock from 2009 to 2010 were retrospectively retrieved and analyzed. The primary outcome of interest was 28-day mortality.Of 7795 admissions, 536 (6.9%) patients had severe sepsis. The most common sites of infection were the respiratory tract (38%) and abdomen (33%). Gram-negative bacteria, particularly Klebsiella pneumoniae (8.6%) and Escherichia coli (6.0%), were the major infecting micro-organisms, responsible for approximately two thirds of the severe sepsis episodes. The overall 28-day mortality rate was 61%, and a higher sequential organ failure assessment score and the use of mechanical ventilation were independently associated with a worse outcome.Admissions with severe sepsis are not uncommon and are associated with substantial 28-day mortality in surgical intensive care units in northern Taiwan. Establishment and optimization of each institutional sepsis care standard to improve the outcome of sepsis are warranted. PMID- 26632738 TI - Upper Gastrointestinal Symptoms Predictive of Candida Esophagitis and Erosive Esophagitis in HIV and Non-HIV Patients: An Endoscopy-Based Cross-Sectional Study of 6011 Patients. AB - Upper gastrointestinal (GI) symptoms are common in both HIV and non-HIV-infected patients, but the difference of GI symptom severity between 2 groups remains unknown. Candida esophagitis and erosive esophagitis, 2 major types of esophagitis, are seen in both HIV and non-HIV-infected patients, but differences in GI symptoms that are predictive of esophagitis between 2 groups remain unknown. We aimed to determine whether GI symptoms differ between HIV-infected and non-HIV-infected patients, and identify specific symptoms of candida esophagitis and erosive esophagitis between 2 groups.We prospectively enrolled 6011 patients (HIV, 430; non-HIV, 5581) who underwent endoscopy and completed questionnaires. Nine upper GI symptoms (epigastric pain, heartburn, acid regurgitation, hunger cramps, nausea, early satiety, belching, dysphagia, and odynophagia) were evaluated using a 7-point Likert scale. Associations between esophagitis and symptoms were analyzed by the multivariate logistic regression model adjusted for age, sex, and proton pump inhibitors.Endoscopy revealed GI organic diseases in 33.4% (2010/6.011) of patients. The prevalence of candida esophagitis and erosive esophagitis was 11.2% and 12.1% in HIV-infected patients, respectively, whereas it was 2.9% and 10.7 % in non-HIV-infected patients, respectively. After excluding GI-organic diseases, HIV-infected patients had significantly (P < 0.05) higher symptom scores for heartburn, hunger cramps, nausea, early satiety, belching, dysphagia, and odynophagia than non-HIV-infected patients. In HIV-infected patients, any symptom was not significantly associated with CD4 cell count. In multivariate analysis, none of the 9 GI symptoms were associated with candida esophagitis in HIV-infected patients, whereas dysphagia and odynophagia were independently (P < 0.05) associated with candida esophagitis in non-HIV-infected patients. However, heartburn and acid regurgitation were independently (P < 0.05) associated with erosive esophagitis in both patient groups. The internal consistency test using Cronbach's alpha revealed that the 9 symptom scores were reliable in both HIV (alpha, 0.86) and non-HIV-infected patients (alpha, 0.85).This large-scale endoscopy-based study showed that HIV infected patients have greater GI symptom scores compared with non-HIV-infected patients even after excluding GI-organic diseases. None of the upper GI symptoms predict candida esophagitis in HIV-infected patients, but dysphagia and odynophagia predict candida esophagitis in non-HIV-infected patients. Heartburn and acid regurgitation predict erosive esophagitis in both patient groups. PMID- 26632739 TI - Correlation Between Residual Displacement and Osteonecrosis of the Femoral Head Following Cannulated Screw Fixation of Femoral Neck Fractures. AB - The aim of the study was to introduce a new method for measuring the residual displacement of the femoral head after internal fixation and explore the relationship between residual displacement and osteonecrosis with femoral head, and to evaluate the risk factors associated with osteonecrosis of the femoral head in patients with femoral neck fractures treated by closed reduction and percutaneous cannulated screw fixation.One hundred and fifty patients who sustained intracapsular femoral neck fractures between January 2011 and April 2013 were enrolled in the study. All were treated with closed reduction and percutaneous cannulated screw internal fixation. The residual displacement of the femoral head after surgery was measured by 3-dimensional reconstruction that evaluated the quality of the reduction. Other data that might affect prognosis were also obtained from outpatient follow-up, telephone calls, or case reviews. Multivariate logistic regression analysis was applied to assess the intrinsic relationship between the risk factors and the osteonecrosis of the femoral head.Osteonecrosis of the femoral head occurred in 27 patients (18%). Significant differences were observed regarding the residual displacement of the femoral head and the preoperative Garden classification. Moreover, we found more or less residual displacement of femoral head in all patients with high quality of reduction based on x-ray by the new technique. There was a close relationship between residual displacement and ONFH.There exists limitation to evaluate the quality of reduction by x-ray. Three-dimensional reconstruction and digital measurement, as a new method, is a more accurate method to assess the quality of reduction. Residual displacement of the femoral head and the preoperative Garden classification were risk factors for osteonecrosis of the femoral head. High quality reduction was necessary to avoid complications. PMID- 26632740 TI - The Correlations Between MRI Perfusion, Diffusion Parameters, and 18F-FDG PET Metabolic Parameters in Primary Head-and-Neck Cancer: A Cross-Sectional Analysis in Single Institute. AB - This study aimed to investigate the relationships among parameters from dynamic contrast-enhanced (DCE) MRI, diffusion-weighted MRI (DWI), and F fluorodeoxyglucose (F-FDG) PET in patients with primary head-and-neck squamous cell carcinoma (HNSCC).A total of 34 patients with primary HNSCC underwent DCE MRI, DWI, and F-FDG PET before treatment. The perfusion parameters (Ktrans, Ktransmax, Kep, Ve, Vp, and AUC60) from DCE-MRI and ADC (ADCmean, ADCmin) values from DWI were calculated within the manually placed ROI around the main tumor. Standardized uptake value (SUVmax, SUVmean), metabolic tumor volume (MTV), and total lesion glycolysis (TLG = SUVmean * MTV) were calculated with thresholds of 3.0 SUV. The associations between parameters were evaluated by Pearson correlation analysis.Significant correlations were identified between Ktrans and Kep (r = 0.631), Ktrans and Ve (r = 0.603), Ktrans and ADCmean (r = 0.438), Ktransmax and Kep (r = 0.667), Ktransmax and Vp (r = 0.351), Ve and AUC60 (r = 0.364), Ve and ADCmean (r = 0.590), and Ve and ADCmin (r = 0.361). ADCmin was reversely correlated with TLG (r = -0.347). Tumor volume was significantly associated with Ktransmax (r = 0.348).The demonstrated relationships among parameters from DCE, DWI, and F-FDG PET suggest complex interactions among tumor biologic characteristics. Each diagnostic technique may provide complementary information for HNSCC. PMID- 26632741 TI - Pleural Empyema and Aortic Aneurysm: A Retrospective National Population-Based Cohort Study. AB - Pleural empyema (PE) may evolve into necrosis, fistula in the thorax, and sepsis; thus, it is also associated with high mortality.We investigated and analyzed the risk of aortic aneurysm (AA) in a cohort study of patients with PE.A total of 34,250 patients diagnosed with PE were identified as the PE cohort, and 137,000 patients without PE were selected randomly as the control group and matched by sex, age, and index year of PE diagnosis. Patients ages 20 years and younger with a history of AA were excluded. The risk of AA was analyzed using a Cox proportional hazards regression model.Excess risk of AA development was 1.69-fold higher in PE patients (adjusted hazard ratio [aHR] = 1.69; 95% confidence interval [CI] = 1.39-2.05) compared with non-PE patients. The patients with PE exhibited a greater adjusted risk of AA (aHR = 2.01; CI = 1.44-2.81) even if they did not have any of the 9 comorbidities included in our analysis (diabetes, hypertension, hyperlipidemia, chronic obstructive pulmonary disease, heart failure, cardiac artery disease, stroke, bacterial endocarditis, and rheumatic endocarditis). Compared with the patients without any of the 9 comorbidities or PE, the patients with only PE had a greater risk of developing AA (aHR = 2.00; CI = 1.43-2.79). The PE cohort had a significantly higher cumulative incidence of AA than the non-PE cohort did during 12 years of follow-up.In a large-scale cohort, patients with PE are linked with an increased risk of AA. PMID- 26632742 TI - Early Statin Use and the Progression of Alzheimer Disease: A Total Population Based Case-Control Study. AB - The protective effect of statin on Alzheimer disease (AD) is still controversial, probably due to the debate about when to start the use of statin and the lack of any large-scale randomized evidence that actually supports the hypothesis. The purpose of this study was to examine the protective effect of early statin use on mild-to-moderate AD in the total Taiwanese population.This was a total population based case-control study, using the total population of Taiwanese citizens seen in general medical practice; therefore, the findings can be applied to the general population. The study patients were those with newly diagnosed dementia (ICD-9 290.x) and prescribed any acetylcholinesterase inhibitors (AChEI) from the Taiwan National Health Insurance dataset in 1997 to 2008. The newly diagnosed eligible mild-to-moderate AD patients were traced from the dates of their index dates, which was defined as the first day to receive any AChEI treatment, back to 1 year (exposure period) to categorize them into AD with early statin use and without early statin use. Early statin use was defined as patients using statin before AChEI treatment. Alzheimer disease patients with early statin use were those receiving any statin treatment during the exposure period. Then, we used propensity-score-matched strategy to match these 2 groups as 1:1. The matched study patients were followed-up from their index dates. The primary outcome was the discontinuation of AChEI treatment, indicating AD progression.There were 719 mild-to-moderate AD-paired patients with early statin use and without early statin use for analyses. Alzheimer disease progression was statistically lower in AD patients with early statin use than those without (P = 0.00054). After adjusting for other covariates, mild-to-moderate AD patients with early stain use exhibited a 0.85-risk (95% CI = 0.76-0.95, P = 0.0066) to have AD progression than those without.Early statin use was significantly associated with a reduction in AD progression in mild-to-moderate AD patients. The future randomized trial studies can confirm our findings. PMID- 26632743 TI - Understanding the Differences Between Oncology Patients and Oncology Health Professionals Concerning Spirituality/Religiosity: A Cross-Sectional Study. AB - This study investigated whether spirituality/religiosity (S/R) plays an important role in the lives of cancer patients and in the work of health professionals who provide care for these patients. The correlations between spiritual quality of life (QOL) and the other QOL domain scores of patients and health professionals were also assessed. Moreover, QOL domain scores were compared between patients and health professionals. In this cross-sectional study, 1050 participants (525 oncology patients and 525 health professionals) were interviewed. Quality of life was assessed with the World Health Organization quality of life spiritual, religious, and personal beliefs (WHOQOL-SRPB). To compare the groups with respect to the instruments' domains, a quantile regression and an analysis of covariance model were used. The WHOQOL-Bref and WHOQOL-SRPB domains were correlated by performing Pearson and partial correlation tests. It was demonstrated that 94.1% of patients considered it important that health professionals addressed their spiritual beliefs, and 99.2% of patients relied on S/R to face cancer. Approximately, 99.6% of the patients reported that S/R support is necessary during cancer treatment; 98.3% of health professionals agreed that spiritual and religious support was necessary for oncology patients. Positive correlations between spiritual QOL and the other QOL domains were observed. When compared among themselves, patients exhibited significantly higher levels of spiritual QOL. In conclusion, S/R was an important construct in the minds of cancer patients and health professionals. Both groups often use S/R resources in their daily lives, which seems to positively affect their perceptions of QOL. Further studies are needed to determine how health professionals effectively address S/R during oncology practice. PMID- 26632744 TI - Scoliosis in a Patient With Gilbert Syndrome: A Case Report and Review of the Literature. AB - Gilbert syndrome (GS) is mainly characterized by intermittent unconjugated hyperbilirubinemia in the absence of hepatocellular disease or hemolysis. Little data are available on operative outcomes in GS patients with spinal deformity surgery.This study has presented a case of GS occurring in the patient with scoliosis.The patient was a 30-year-old female with scoliosis and GS. She was taken a correction form Thoracic 2 to Lumbar 1) levels by using the USS-II spinal system. At 2 years follow-up, the patient was well balanced and pain free. Plain radiographs demonstrated spine solid fusion without correction loss.Although complex scoliosis surgery can be performed safely in these patients with GS, careful perioperative managements including liver function and coagulation function are required. PMID- 26632745 TI - Ectopic Jejunal Variceal Rupture in a Liver Transplant Recipient Successfully Treated With Percutaneous Transhepatic Coil Embolization: A Case Report. AB - Here we present the rupture of ectopic jejunal varices developing in a liver transplant recipient without portal hypertension, which was successfully treated with percutaneous transhepatic coil embolization.A 48-year-old man with massive melena was admitted to our department. He had undergone liver transplantation for hepatitis B virus-related liver cirrhosis 8 months before, and his postoperative course was satisfactory except for an acute cellular rejection. No evidence of bleeding was detected by upper endoscopy or colonoscopy, but dynamic multidetector computed tomography of the whole abdomen revealed an intestinal varix protruding into the lumen of the jejunum with suspected extravasation. There was no evidence of portal venous stenosis or thrombosis. Immediately upon diagnosis of the ruptured ectopic jejunal varix, percutaneous transhepatic coil embolization was performed, achieving complete hemostasis. The portal venous pressure measured during the procedure was within normal limits. He was discharged from the hospital 11 days after embolization and remained in stable condition without re-bleeding 6 months after discharge.This is the first report of an ectopic intestinal variceal rupture in an uneventful liver transplant recipient that was successfully treated with interventional percutaneous transhepatic coil embolization. Clinicians encountering liver transplant recipients with melena should be aware of the possibility of late-onset rupture of ectopic varices, even in those having an uneventful post-transplant course without portal hypertension. PMID- 26632746 TI - Therapeutic Hypothermia and the Risk of Hemorrhage: A Systematic Review and Meta Analysis of Randomized Controlled Trials. AB - Current guidelines recommend a period of moderate therapeutic hypothermia (TH) for comatose patients after cardiac arrest to improve clinical outcomes. However, in-vitro studies have reported platelet dysfunction, thrombocytopenia, and coagulopathy, results that might discourage clinicians from applying TH in clinical practice. We aimed to quantify the risks of hemorrhage observed in clinical studies.Medline and Embase were searched from inception to October 2015.Randomized controlled trials (RCTs) comparing patients undergoing TH with controls were selected, irrespective of the indications for TH. There were no restrictions for language, population, or publication year.Data on study characteristics, which included patients, details of intervention, and outcome measures, were extracted.Forty-three trials that included 7528 patients were identified from 2692 potentially relevant references. Any hemorrhage was designated as the primary outcome and was reported in 28 studies. The pooled results showed no significant increase in hemorrhage risk associated with TH (risk difference [RD] 0.005; 95% confidence interval [CI] -0.001-0.011; I, 0%). Among secondary outcomes, patients undergoing TH were found to have increased risk of thrombocytopenia (RD 0.109; 95% CI 0.038-0.179; I 57.3%) and transfusion requirements (RD 0.021; 95% CI 0.003-0.040; I 0%). The meta-regression analysis indicated that prolonged duration of cooling may be associated with increased risk of hemorrhage.TH was not associated with increased risk of hemorrhage despite the increased risk of thrombocytopenia and transfusion requirements. Clinicians should cautiously assess each patient's risk-benefit profile before applying TH. PMID- 26632747 TI - Using the World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0) for Predicting Institutionalization of Patients With Dementia in Taiwan. AB - World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0) is an assessment tool and it has been applied for disability status assessment of Taiwanese dementia patients since July 2012. The aim of this study was to investigate the predicting accuracy of WHODAS 2.0 for institutionalization of dementia patients.Of these patients, 13,774 resided in a community and 4406 in a long-term care facility. Demographic data and WHODAS 2.0 standardized scores were analyzed using the Chi-square test and independent t test to compare patients with dementia in an institution with those in a community. The receiver operating characteristic (ROC) curve was applied to investigate accuracy in predicting institutionalization, and the optimal cutoff point was determined using the Youden index. Binary logistic regression was used to analyze variables to determine risk factors for the institutionalization of patients with dementia.WHODAS 2.0 scores in all domains were higher in patients with dementia in a long-term care facility than in those in a community (P < 0.01). The ROC curve showed moderate accuracy for all domains of WHODAS 2.0 (area under curve 0.6~0.8). Binary logistic regression revealed that the male gender, severity of disease, and standardized WHODAS 2.0 scores surpassing the cutoff values were risk factors for the institutionalization of patients with dementia.Although the accuracy of WHODAS 2.0 in predicting institutionalization is not considerably high for patients with dementia, our study found that the WHODAS 2.0 scores, the male gender, education status, urbanization level, and severity of disease were risk factors for institutionalization in long-term care facilities. PMID- 26632748 TI - Diagnostic Value of Presepsin for Sepsis: A Systematic Review and Meta-Analysis. AB - Several individual studies have reported the diagnostic accuracy of presepsin (sCD14-ST) for sepsis, but the results are inconsistent.The present systematic review and meta-analysis pooled data to better ascertain the value of circulatory presepsin as a biomarker for sepsis.Studies published in English before November 7, 2014 and assessing the diagnostic accuracy of presepsin for sepsis were retrieved from medical databases.The quality of eligible studies was assessed using a revised Quality Assessment for Studies of Diagnostic Accuracy (QUADAS-2). The overall diagnostic accuracy of presepsin for sepsis was pooled according to a bivariate model. Publication bias was assessed using Deek funnel plot asymmetry test.Eleven studies satisfied the inclusion criteria. The overall diagnostic sensitivity of presepsin for sepsis was 0.83 (95% CI: 0.77-0.88), and specificity was 0.78 (95% CI: 0.72-0.83). The area under the summary receiver operating characteristic curve was 0.88 (95% CI: 0.84-0.90). The pretest probability of sepsis was 0.56 among all subjects. When presepsin was introduced as the diagnostic test for sepsis, the posttest probabilities were 0.81 for a positive result and 0.19 for a negative. The major design deficits of the included studies were lack of prespecified thresholds and patient selection bias. The publication bias was negative.Presepsin is an effective adjunct biomarker for the diagnosis of sepsis, but is insufficient to detect or rule out sepsis when used alone. PMID- 26632749 TI - High Blood Pressure and All-Cause and Cardiovascular Disease Mortalities in Community-Dwelling Older Adults. AB - Although hypertension is common among older adults, the optimal blood pressure (BP) for survival in older adults remains unclear. We attempt to use a large cohort to assess the relationship between BP and mortality and to gain insight into what level of BP is required for optimal survival in older adults.A total of 77,389 community-dwelling adults, aged >=65 years, were followed between 2006 and 2010. Mortality was determined using matching cohort identifications with national death files. Cox proportional hazards regression models were used to evaluate the relationship of BP with all-cause, cardiovascular disease (CVD), and expanded-CVD mortalities.The mortality risks of the stage 2-3 hypertension group were substantial (all-cause mortality: hazard ratio [HR]: 1.23; 95% confidence interval [CI]: 1.10-1.37; CVDs mortality: HR: 1.31; 95% CI: 1.05-1.64; expanded CVDs mortality: HR: 1.40; 95% CI: 1.15-1.71). The cardiovascular and expanded cardiovascular mortality risks were lowest when systolic blood pressures were 120 to 129 mm Hg, and increased significantly when systolic blood pressures (SBPs) were >=160 mm Hg or diastolic BPs were >=90 mm Hg. A J-curve phenomenon for SBP on CVD and expanded-CVD mortality was observed. The impacts of stage 2-3 hypertension on mortality risks were significantly increased among women. The mortality risks of hypertension were not attenuated with older age.This study provides insight for identifying the optimal BP for survival in older adults, and extends the knowledge of the impacts of hypertension on mortality risks among women and the older adults. PMID- 26632750 TI - Severe Extra-Cerebral Anticoagulant-Related Bleeding in Intensive Care Unit: A Retrospective Study From 2000 to 2013. AB - Bleeding is the most frequent complication of anticoagulant therapy, responsible for a number of hospitalizations or deaths. However, studies describing the management and prognosis factors of extra-cerebral anticoagulant-related bleedings in intensive care unit (ICU) are lacking.Retrospective observational study in an 18-bed ICU in a tertiary teaching hospital. From January 2000 to December 2013, all consecutive patients, older than 18 years, admitted for severe anticoagulant-related bleeding (SAB) except intracerebral site were included.A total of 100 patients were included, the mean age was 77 +/- 11 years and 62% were women. SAB incidence in ICU doubled over 10 years (P = 0.03). In ICU, the average length of stay was 5 +/- 6 days and mortality was 30%. Nonsurviving patients had a higher SAPS II (78 +/- 24 vs 53 +/- 24, P < 0.0001), a higher SOFA (9.0 +/- 3.6 vs 4.7 +/- 3.4, P < 0.0001) and received more frequently support therapy such as mechanical ventilation (87% vs 16%, P < 0.0001) and vasopressors (90% vs 27%, P < 0.0001). The volume of blood-derived products transfused was more important in nonsurvivors mainly during the first 24 hours of resuscitation. Rapid anticoagulant reversal therapy was associated with better prognosis (ICU survivors 66% vs 39%, Fisher test P = 0.04). Anterior abdominal wall was identified as a frequent site of bleeding (22%) due to epigastric artery injury during subcutaneous injection of heparin and was associated with a large mortality (55%).Extra-cerebral SAB is a life-threatening complication that requires rapid resuscitation and anticoagulant reversal therapy. Injection of heparin should be done carefully in the subcutaneous tissue thereby avoiding artery injury. PMID- 26632751 TI - Incidence of and Risk Factors for Tuberculosis (TB) in Gastric Cancer Patients in an Area Endemic for TB: A Nationwide Population-based Matched Cohort Study. AB - To date, there have been few reports investigating the relationship between tuberculosis (TB) and gastric cancer.We conducted a nationwide population-based matched cohort study using data retrieved from Taiwan's National Health Insurance Research Database to determine the incidence of and risk factors for TB in patients diagnosed with gastric cancer. From 2000 to 2011, we identified 36,972 gastric cancer patients and normal subjects from the general population matched for age, sex, and comorbidities at a 1:1 ratio. The data were analyzed using Cox proportional hazards models.Compared with the matched cohort, gastric cancer patients exhibited a higher risk for TB (adjusted hazard ratio [HR] 2.25, 95% confidence interval [CI] 1.65-3.05, P < 0.001), and those with TB exhibited higher mortality (adjusted HR 1.59, 95% CI 1.41-1.79, P < 0.001). Old age (adjusted HR 2.40, 95% CI 1.92-2.99, P < 0.001), male sex (adjusted HR 2.13, 95% CI 1.76-2.57, P < 0.001), diabetes mellitus (adjusted HR 1.28, 95% CI 1.05-1.56, P = 0.013), and chronic obstructive pulmonary disease (COPD) (adjusted HR 1.44, 95% CI 1.19-1.75, P < 0.001) were identified as independent risk factors for TB in gastric cancer patients. Dyslipidemia was an independent protective factor for both TB (adjusted HR 2.13, 95% CI 1.73-2.62, P < 0.001) and mortality (adjusted HR 1.11, 95% CI 1.08-1.15, P < 0.001) in gastric cancer patients.Old age, male sex, diabetes mellitus, and COPD were independent risk factors for TB in gastric cancer. High-risk gastric cancer patients, especially those in TB-endemic areas, should be regularly screened for TB. PMID- 26632752 TI - Case Report of Thymoma Tumor Reduction Following Plasmapheresis. AB - For thymoma, multidisciplinary antitumor strategy is composed of surgery, chemotherapy, and radiotherapy. Meanwhile, ~20% to 25% of patients with thymoma have myasthenia gravis and plasmapheresis is recommended for thymoma-associated myasthenia gravis.We report a case that a 40-year-old woman with thymoma experiencing tumor relapse after surgery showed significant response to plasmapheresis.This is the first case of thymoma responded to plasmapheresis, which may guide the study of the etiology and pathogenesis of thymoma. PMID- 26632753 TI - New Cerebral Microbleeds After Mechanical Thrombectomy for Large-Vessel Occlusion Strokes. AB - The interval appearance of cerebral microbleeds (CMBs) after endovascular treatment has never been described. We investigated the frequency and predictors of new CMBs that developed shortly after mechanical thrombectomy for acute ischemic stroke, and its impact on clinical outcome.We retrospectively analyzed patients with large-vessel occlusion strokes treated with Merci Retriever, Penumbra System, or stent-retriever devices. Serial T2*-weighted gradient-recall echo (GRE) magnetic resonance imaging (MRI) before and 48 h after endovascular thrombectomy were assessed to identify new CMBs. We examined independent factors associated with new CMBs after mechanical thrombectomy. We analyzed the association of the presence, burden, and distribution of new CMBs with clinical outcome.A total of 187 consecutive patients with serial GRE were enrolled in this study. CMBs were evident in 36 (19.3%) patients before mechanical thrombectomy. New CMBs occurred in 41 (21.9%) patients after mechanical thrombectomy. Of the 68 new CMBs, 45 appeared in the lobar location, 18 in the deep location and 5 in the infratentorial location. The presence of baseline CMBs was associated with new CMBs after mechanical thrombectomy (OR 5.38; 95% CI 2.13-13.59; P < 0.001), no matter whether the patients were treated primarily with mechanical thrombectomy or with intravenous thrombolysis followed by mechanical thrombectomy. Patients with new CMBs did not have increased rates of hemorrhagic transformation, in hospital mortality, and modified Rankin Scale score 4 to 6 at discharge.New CMBs are common after mechanical thrombectomy in one-fifth of patients with acute ischemic stroke. Baseline CMBs before mechanical thrombectomy predicts the development of new CMBs. New CMBs after mechanical thrombectomy do not influence clinical outcome. PMID- 26632755 TI - Erratum for: A Simple and Sensitive LC-MS/MS Method for Determination of Four Major Active Diterpenoids from Andrographis paniculata in Human Plasma and Its Application to a Pilot Study. PMID- 26632754 TI - Long-Term Effects of a Very Low Carbohydrate Compared With a High Carbohydrate Diet on Renal Function in Individuals With Type 2 Diabetes: A Randomized Trial. AB - To compare the long-term effects of a very low carbohydrate, high-protein, low saturated fat (LC) diet with a traditional high unrefined carbohydrate, low-fat (HC) diet on markers of renal function in obese adults with type 2 diabetes (T2DM), but without overt kidney disease.One hundred fifteen adults (BMI 34.6 +/- 4.3 kg/m, age 58 +/- 7 years, HbA1c 7.3 +/- 1.1%, 56 +/- 12 mmol/mol, serum creatinine (SCr) 69 +/- 15 MUmol/L, glomerular filtration rate estimated by the Chronic Kidney Disease Epidemiology Collaboration formula (eGFR 94 +/- 12 mL/min/1.73 m)) were randomized to consume either an LC (14% energy as carbohydrate [CHO < 50 g/day], 28% protein [PRO], 58% fat [<10% saturated fat]) or an HC (53% CHO, 17% PRO, 30% fat [<10% saturated fat]) energy-matched, weight loss diet combined with supervised exercise training (60 min, 3 day/wk) for 12 months. Body weight, blood pressure, and renal function assessed by eGFR, estimated creatinine clearance (Cockcroft-Gault, Salazar-Corcoran) and albumin excretion rate (AER), were measured pre- and post-intervention.Both groups achieved similar completion rates (LC 71%, HC 65%) and reductions in weight (mean [95% CI]; -9.3 [-10.6, -8.0] kg) and blood pressure (-6 [-9, -4]/-6[-8, -5] mmHg), P >= 0.18. Protein intake calculated from 24 hours urinary urea was higher in the LC than HC group (LC 120.1 +/- 38.2 g/day, 1.3 g/kg/day; HC 95.8 +/- 27.8 g/day, 1 g/kg/day), P < 0.001 diet effect. Changes in SCr (LC 3 [1, 5], HC 1 [-1, 3] MUmol/L) and eGFR (LC -4 [-6, -2], HC -2 [-3, 0] mL/min/1.73 m) did not differ between diets (P = 0.25). AER decreased independent of diet composition (LC --2.4 [-6, 1.2], HC -1.8 [-5.4, 1.8] mg/24 h, P = 0.24); 6 participants (LC 3, HC 3) had moderately elevated AER at baseline (30-300 mg/24 h), which normalized in 4 participants (LC 2, HC 2) after 52 weeks.Compared with a traditional HC weight loss diet, consumption of an LC high protein diet does not adversely affect clinical markers of renal function in obese adults with T2DM and no preexisting kidney disease. PMID- 26632756 TI - Quality Evaluation of Zirconium Dioxide Frameworks Produced in Five Dental Laboratories from Different Countries. AB - PURPOSE: The aim of this study was to assess and compare quality as well as economic aspects of CAD/CAM high strength ceramic three-unit FDP frameworks ordered from dental laboratories located in emerging countries and Switzerland. MATERIAL AND METHODS: The master casts of six cases were sent to five dental laboratories located in Thailand (Bangkok), China (Peking and Shenzhen), Turkey (Izmir), and Switzerland (Bern). Each laboratory was using a different CAD/CAM system. The clinical fit of the frameworks was qualitatively assessed, and the thickness of the framework material, the connector height, the width, and the diameter were evaluated using a measuring sensor. The analysis of the internal fit of the frameworks was performed by means of a replica technique, whereas the inner and outer surfaces of the frameworks were evaluated for traces of postprocessing and damage to the intaglio surface with light and electronic microscopes. Groups (dental laboratories and cases) were compared for statistically significant differences using Mann-Whitney U-tests after Bonferroni correction. RESULTS: An acceptable clinical fit was found at 97.9% of the margins produced in laboratory E, 87.5% in B, 93.7% in C, 79.2% in A, and 62.5% in D. The mean framework thicknesses were not statistically significantly different for the premolar regions; however, for the molar area 4/8 of the evaluated sites were statistically significantly different. Circumference, surface, and width of the connectors produced in the different laboratories were statistically significantly different but not the height. There were great differences in the designs for the pontic and connector regions, and some of the frameworks would not be recommended for clinical use. Traces of heavy postprocessing were found in frameworks from some of the laboratories. The prices per framework ranged from US$177 to US$896. CONCLUSIONS: By ordering laboratory work in developing countries, a considerable price reduction was obtained compared to the price level in Switzerland. Despite the use of the standardized CAD/CAM chains of production in all laboratories, a large variability in the quality aspects, such as clinical marginal fit, connector and pontic design, as well as postprocessing traces was noted. Recommended sound handling of postprocessing was not applied in all laboratories. Dentists should be aware of the true and factitious advantages of CAD/CAM production chains and not lose control over the process. PMID- 26632758 TI - Color Bricks: Building Highly Organized and Strongly Absorbing Multicomponent Arrays of Terpyridyl Perylenes on Metal Oxide Surfaces. AB - Terpyridine-substituted perylenes containing cyclic anhydrides in the peri position were synthesized. The anhydride group served as an anchor for assembly of the terpyridyl-crowned chromophores as monomolecular layers on metal oxide surfaces. Further coordination with Zn(2+) ions allowed for layer-by-layer formation of supramolecular assemblies of perylene imides on the solid substrates. With properly selected anchor and linker molecules it was possible to build high quality structures of greater than ten successive layers by a simple and straightforward procedure. The prepared films were stable and had a broad spectral coverage and high absorbance. To demonstrate their potential use, the synthesized dyes were employed in solid-state dye-sensitized solar cells, and electron injection from the perylene antennas to titanium dioxide was observed. PMID- 26632757 TI - Depression and Oropharynx Cancer Outcome. AB - BACKGROUND: Studies have shown a modest relationship between depression and mortality in patients with cancer. Our study addressed methodological weaknesses in the literature by restricting the sample to patients with one cancer type, adjusting for factors known to affect outcome, and following up patients for a sufficient period. METHODS: We prospectively followed patients newly diagnosed with squamous cell oropharyngeal cancer from the start of radiation therapy until death or until date of last clinical visit. All patients were optimally treated with radiation and sometimes chemotherapy. After adjusting for tumor stage, treatment, comorbidities, smoking, excessive alcohol use, and demographic factors, we assessed the effects of baseline self-reported depression on overall survival and recurrence. RESULTS: One hundred thirty participants were followed for a median of 5 years. The average age was 56 years, and 83% were male. Eighteen participants died during the study and 15 experienced disease recurrence. Self-reported depression was associated with decreased overall survival duration (hazard ratio = 3.6, 95% confidence interval = 1.2-10.8) and disease recurrence (hazard ratio = 3.8, 95% confidence interval = 1.2-12.2) in multivariate analysis. In addition, smoking was associated with disease recurrence. CONCLUSIONS: Patients with oropharyngeal cancer may benefit from depression screening and evidence-based treatments, if appropriate. Future studies are needed to determine whether depression is an independent prognostic factor of outcome and to elucidate biobehavioral mechanisms involved in patients with oropharyngeal cancer. PMID- 26632759 TI - Aluminium alloyed iron-silicide/silicon solar cells: A simple approach for low cost environmental-friendly photovoltaic technology. AB - This work demonstrates the fabrication of silicide/silicon based solar cell towards the development of low cost and environmental friendly photovoltaic technology. A heterostructure solar cells using metallic alpha phase (alpha phase) aluminum alloyed iron silicide (FeSi(Al)) on n-type silicon is fabricated with an efficiency of 0.8%. The fabricated device has an open circuit voltage and fill-factor of 240 mV and 60%, respectively. Performance of the device was improved by about 7 fold to 5.1% through the interface engineering. The alpha phase FeSi(Al)/silicon solar cell devices have promising photovoltaic characteristic with an open circuit voltage, short-circuit current and a fill factor (FF) of 425 mV, 18.5 mA/cm(2), and 64%, respectively. The significant improvement of alpha-phase FeSi(Al)/n-Si solar cells is due to the formation p(+ )n homojunction through the formation of re-grown crystalline silicon layer (~5 10 nm) at the silicide/silicon interface. Thickness of the regrown silicon layer is crucial for the silicide/silicon based photovoltaic devices. Performance of the alpha-FeSi(Al)/n-Si solar cells significantly depends on the thickness of alpha-FeSi(Al) layer and process temperature during the device fabrication. This study will open up new opportunities for the Si based photovoltaic technology using a simple, sustainable, and los cost method. PMID- 26632760 TI - Uncovering the exercise-related proteome signature in skeletal muscle. AB - Exercise training has been recommended as a nonpharmacological strategy for the prevention and attenuation of skeletal muscle atrophy in distinct pathophysiological conditions. Despite the well-established phenotypic alterations, the molecular mechanisms underlying exercise-induced skeletal muscle remodeling are poorly characterized. Proteomics based on mass spectrometry have been successfully applied for the characterization of skeletal muscle proteome, representing a pivotal approach for the wide characterization of the molecular networks that lead to skeletal muscle remodeling. Nevertheless, few studies were performed to characterize the exercise-induced proteome remodeling of skeletal muscle, with only six research papers focused on the cross-talk between exercise and pathophysiological conditions. In order to add new insights on the impact of distinct exercise programs on skeletal muscle proteome, molecular network analysis was performed with bioinformatics tools. This analysis highlighted an exercise-related proteome signature characterized by the up-regulation of the capacity for ATP generation, oxygen delivery, antioxidant capacity and regulation of mitochondrial protein synthesis. Chronic endurance training up-regulates the tricarboxylic acid cycle and oxidative phosphorylation system, whereas the release of calcium ion into cytosol and amino acid metabolism are the biological processes up-regulated by a single bout of exercise. Other issues as exercise intensity, load, mode and regimen as well as muscle type also influence the exercise-induced proteome signature. The comprehensive analysis of the molecular networks modulated by exercise training in health and disease, taking in consideration all these variables, might not only support the therapeutic effect of exercise but also highlight novel targets for the development of enhanced pharmacological strategies. PMID- 26632761 TI - Evaluation of Adhesion Forces for the Manipulation of Micro-Objects in Submerged Environment through Deposition of pH Responsive Polyelectrolyte Layers. AB - Optimization of surface treatment for reversible adhesion of micro-objects in liquid environment for the need in microassembly processes is presented. A spherical borosilicate probe and planar oxidized silicon wafer substrates were modified by deposition of pH sensitive polyelectrolyte films through layer-by layer technique. Branched polyethylenimine (b-PEI) and poly(sodium styrenesulfonate) (PSS) were deposited in alternating manner on surfaces, and the influence of polyelectrolyte concentration, pH of deposition, and number of layers on the adhesion were successively examined. The multilayer buildup was followed by optical reflectometry (OR) and dissipative quartz crystal microbalance (QCM-D). The adhesion forces were monitored in aqueous environment at variable pH values by colloidal probe AFM microscopy. The thermodynamic work of adhesion was derived from the pull-off forces by using the Johnson-Kendall Roberts (JKR) model and compared to the work of adhesion determined from contact angle measurements. It was found out that they correlate well, however, the values accessed from JKR model were underestimated, which was attributed mainly to the effect of surface roughness. Obtained results have demonstrated that it is possible to achieve repeatable reversible adhesion with the change of pH of submerged environment by appropriately tailoring the surface properties and therefore the prevailing surface forces. PMID- 26632762 TI - Underlying Autoimmune Disease Is Not a Contraindication to the Use of Ipilimumab. PMID- 26632763 TI - Simultaneous fNIRS and thermal infrared imaging during cognitive task reveal autonomic correlates of prefrontal cortex activity. AB - Functional Near Infrared-Spectroscopy (fNIRS) represents a powerful tool to non invasively study task-evoked brain activity. fNIRS assessment of cortical activity may suffer for contamination by physiological noises of different origin (e.g. heart beat, respiration, blood pressure, skin blood flow), both task-evoked and spontaneous. Spontaneous changes occur at different time scales and, even if they are not directly elicited by tasks, their amplitude may result task modulated. In this study, concentration changes of hemoglobin were recorded over the prefrontal cortex while simultaneously recording the facial temperature variations of the participants through functional infrared thermal (fIR) imaging. fIR imaging provides touch-less estimation of the thermal expression of peripheral autonomic. Wavelet analysis revealed task-modulation of the very low frequency (VLF) components of both fNIRS and fIR signals and strong coherence between them. Our results indicate that subjective cognitive and autonomic activities are intimately linked and that the VLF component of the fNIRS signal is affected by the autonomic activity elicited by the cognitive task. Moreover, we showed that task-modulated changes in vascular tone occur both at a superficial and at larger depth in the brain. Combined use of fNIRS and fIR imaging can effectively quantify the impact of VLF autonomic activity on the fNIRS signals. PMID- 26632764 TI - Ultrafine Nanocrystalline CeO2@C-Containing NaAlH4 with Fast Kinetics and Good Reversibility for Hydrogen Storage. AB - A nanocrystalline CeO2@C-containing NaAlH4 composite is successfully synthesized in situ by hydrogenating a NaH-Al mixture doped with CeO2@C. Compared with NaAlH4 , the as-prepared CeO2@C-containing NaAlH4 composite, with a minor amount of excess Al, exhibits significantly improved hydrogen storage properties. The dehydrogenation onset temperature of the hydrogenated [NaH-Al-7 wt % CeO2@C] 0.04Al sample is 77 degrees C lower than that of the pristine sample because of a reduced kinetic barrier. More importantly, the dehydrogenated sample absorbs ~4.7 wt % hydrogen within 35 min at 100 degrees C and 10 MPa of hydrogen. Compositional and structural analyses reveal that CeO2 is converted to CeH2 during ball milling and that the newly formed CeH2 works with the excess of Al to synergistically improve the hydrogen storage properties of NaAlH4. Our findings will aid in the rational design of novel catalyst-doped complex hydride systems with low operating temperatures, fast kinetics, and long-term cyclability. PMID- 26632765 TI - Prognostic value of diastolic dysfunction in asymptomatic rheumatoid arthritis patients without cardiovascular risk factors. PMID- 26632766 TI - Interventions for smoking cessation in people diagnosed with lung cancer. AB - BACKGROUND: Lung cancer is one of the most common causes of death from cancer worldwide. Smoking induces and aggravates many health problems, including vascular diseases, respiratory illnesses and cancers. Tobacco smoking constitutes the most important risk factor for lung cancer. Most people with lung cancer are still active smokers at diagnosis or frequently relapse after smoking cessation. Quitting smoking is the most effective way for smokers to reduce the risk of premature death and disability. People with lung cancer may benefit from stopping smoking. Whether smoking cessation interventions are effective for people with lung cancer and whether one method of quitting is more effective than any other has not been systematically reviewed. OBJECTIVES: To determine the effectiveness of smoking cessation programmes for people with lung cancer. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (accessed via PubMed) and EMBASE up to 22 June 2015. We also searched the American Society of Clinical Oncology (ASCO) Annual Meeting proceedings, the lung cancer sections of the proceedings of the ESMO Congress, the lung cancer sections of the proceedings of the European Conference of Clinical Oncology (ECCO) Congress, the World Conference on Lung Cancer proceedings, the Society for Research on Nicotine and Tobacco Annual Meeting from 2013, the Food and Drug Administration website, the European Medicine Agency for drug registration website, the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) search portal, ClinicalTrials.gov, and the metaRegister of Controlled Trials (mRCT) to 1 July 2015. We applied no restriction on language of publication. SELECTION CRITERIA: We planned to include any randomised controlled trial (RCT) of any psychosocial or pharmacological smoking cessation intervention or combinations of both, compared with no intervention, a different psychosocial or pharmacological (or both) intervention or placebo for pharmacological interventions in people with lung cancer. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the studies from the initial search for potential trials for inclusion. We planned to use standard methodological procedures expected by Cochrane. We found no trials that met the inclusion criteria. MAIN RESULTS: We identified no RCTs that met our inclusion criteria. Among the 1052 records retrieved using our search strategy, we retrieved 13 studies for further investigation. We excluded 10 trials: five trials because we could not distinguish people with lung cancer from the other participants, or the participants were not people with lung cancer, four because they were not randomised, or RCTs. We excluded one trial because, though it was completed in 2004, no results are available. We assessed three ongoing trials for inclusion when data become available. AUTHORS' CONCLUSIONS: There were no RCTs that determined the effectiveness of any type of smoking cessation programme for people with lung cancer. There was insufficient evidence to determine whether smoking cessation interventions are effective for people with lung cancer and whether one programme is more effective than any other. People with lung cancer should be encouraged to quit smoking and offered smoking cessation interventions. However, due to the lack of RCTs, the efficacy of smoking cessation interventions for people with lung cancer cannot be evaluated and concluded. This systematic review identified a need for RCTs to explore these. PMID- 26632767 TI - A systematic review of primary active surveillance management of low-risk papillary carcinoma. AB - PURPOSE OF REVIEW: Active surveillance is close follow-up of neoplasms, with predetermined intervention triggers. We systematically reviewed the published English language literature on primary active surveillance of low-risk papillary thyroid cancer (PTC). RECENT FINDINGS: We searched seven electronic databases (1980-2015), supplemented with a hand search. Two reviewers independently screened 1715 citations and reviewed 32 full-text papers, ultimately including two papers. Data were independently abstracted. There were two Japanese single center, single-arm studies reporting on 1235 and 322 patients with PTC microcarcinoma (primary <=1 cm in diameter) confined to the thyroid. Mean study follow-up was of 5.0 and 6.5 years, respectively. Disease triggers for thyroidectomy included progression of the primary tumor or incident metastatic disease. The rates of thyroidectomy were 15.5% (191/1235) and 8.7% (28/322) in respective studies. The incidence of primary tumor enlargement >=3 mm in maximal diameter was 4.6% (58/1235) and 5.0% (16/322). The incidence of nodal metastases was 1.5% (19/1235) and 0.9% (3/322). There were neither reports of PTC-related death nor development of distant metastatic disease. Quality of life, psychosocial health, and economic outcomes were not reported. SUMMARY: In two Japanese single-arm studies, active surveillance of PTC microcarcinoma was relatively well tolerated; however, more long-term outcome research is needed. PMID- 26632768 TI - Revisiting robotic approaches to endocrine neoplasia: do the data support their continued use? AB - PURPOSE OF REVIEW: Although the advent of the robot has revolutionized the modern treatment of endocrine neoplasia, substantial controversies exist on its applicability, safety and benefits over the conventional laparoscopic operations. The present review aims to review the recent literature on various robotic approaches in treating thyroid, parathyroid, adrenal and pancreatic endocrine neoplasia and see whether its continued use should be supported. RECENT FINDINGS: In summary, the role of robotic thyroidectomy has been clearly established and should be continued by experienced surgeons on selected patients. Because of the limited availability of evidence, the feasibility of robotic parathyroidectomy has yet to be elucidated. With proven favorable perioperative outcomes, robotic adrenalectomy and pancreatectomy should be continued as potential alternatives to conventional surgery. SUMMARY: Robotic endocrine procedures still play a pivotal role in minimally invasive endocrine surgery with demonstrable safety and effectiveness. Future research should embark on prospective randomized-controlled trials on robotic endocrine procedures to collect higher level of evidence and long-term survival data. PMID- 26632770 TI - Tumor microenvironment in mycosis fungoides and Sezary syndrome. AB - PURPOSE OF REVIEW: Mycosis fungoides and Sezary syndrome arise from malignant T cells that reside in skin, and subsequently are capable of circulating between skin, lymph nodes, and blood. The pathophysiologic mechanisms that cause and result in different behaviors of the skin-homing-malignant T cells in different stages of cutaneous T-cell lymphoma (CTCL) are still unknown. It is hypothesized that the skin microenvironment which is composed by various immune cell subsets as well as their spatial distribution and T-cell interaction through different chemokines and cytokines have an important role in the development and pathogenesis of CTCL and will be addressed in this chapter. RECENT FINDINGS: Recent studies have discovered that malignant T cells in Sezary syndrome are of the central memory T-cell subset, whereas those in mycosis fungoides are nonrecirculating skin-resident effector memory T cells, and have shown a protumorigenic role of mast cells and macrophages in CTCL. In addition, it has been observed that malignant T cells may exhibit features of one of these three distinct phenotypes (forkhead box P3 + regulatory T-cell phenotype, Th2 phenotype, and Th17 phenotype) and are functionally exhausted through an increased expression of certain coinhibitory molecules, such as programmed death 1. SUMMARY: All these new findings could assist in the development of novel targeted therapies for CTCL. PMID- 26632769 TI - Single-cell approaches for molecular classification of endocrine tumors. AB - PURPOSE OF REVIEW: In this review, we summarize recent developments in single cell technologies that can be employed for the functional and molecular classification of endocrine cells in normal and neoplastic tissue. RECENT FINDINGS: The emergence of new platforms for the isolation, analysis, and dynamic assessment of individual cell identity and reactive behavior enables experimental deconstruction of intratumoral heterogeneity and other contexts where variability in cell signaling and biochemical responsiveness inform biological function and clinical presentation. These tools are particularly appropriate for examining and classifying endocrine neoplasias, as the clinical sequelae of these tumors are often driven by disrupted hormonal responsiveness secondary to compromised cell signaling. Single-cell methods allow for multidimensional experimental designs incorporating both spatial and temporal parameters with the capacity to probe dynamic cell signaling behaviors and kinetic response patterns dependent upon sequential agonist challenge. SUMMARY: Intratumoral heterogeneity in the provenance, composition, and biological activity of different forms of endocrine neoplasia presents a significant challenge for prognostic assessment. Single-cell technologies provide an array of powerful new approaches uniquely well suited for dissecting complex endocrine tumors. Studies examining the relationship between clinical behavior and tumor compositional variations in cellular activity are now possible, providing new opportunities to deconstruct the underlying mechanisms of endocrine neoplasia. PMID- 26632772 TI - Active-Site Engineering Expands the Substrate Profile of the Basidiomycete L Tryptophan Decarboxylase CsTDC. AB - Aromatic L-amino acid decarboxylases (AADCs) catalyze the release of CO2 from proteinogenic and non-proteinogenic L-amino acid substrates and are involved in pathways that biosynthesize neurotransmitters or bioactive natural products. In contrast to AADCs from animals and plants, fungal AADCs have received very little attention. Here, we report on the in vitro characterization of heterologously produced Ceriporiopsis subvermispora AADC, now referred to as CsTDC, which is the first characterized basidiomycete AADC. This study identified the enzyme as a decarboxylase that is strictly specific for L-tryptophan and 5-hydroxy-L tryptophan. The tdc gene was subjected to saturation mutagenesis so as to vary the key active site residue, Gly351. Aliphatic amino acid residues, L-serine, or L-threonine at position 351 added L-tyrosine and 3,4-dihydroxy-L-phenylalanine (L DOPA) decarboxylase activity while retaining stereospecificity and L-tryptophan decarboxylase activity. PMID- 26632773 TI - Adaptation of postural control while standing on a narrow unfixed base of support. AB - The purpose of this study was to investigate the adaptation with practice of postural control while standing on a rocker board. Thirteen healthy young adults participated. The participants were asked to stand in a sagittal plane on a rocker board with a semicircular base as steadily as possible for as long as they could. With practice, the duration of maintaining postural balance increased significantly and postural stability improved (P<0.05). Furthermore, the distances between center of pressure and the projection of center of mass decreased (P<0.05), although joint motion of the lower extremities did not change (P>0.05). This observation would be the consequence of a highly redundant human locomotor system. With practice, the central nervous system was able to shift the center of pressure position close to the accurate center of mass position. PMID- 26632774 TI - Foot-type analysis and plantar pressure differences between obese and nonobese adolescents during upright standing. AB - This study aimed to characterize the effect of obesity on foot-type and plantar pressure distribution in adolescents. Ten obese adolescents (obese group; BMI: 35.45+/-4.73 kg/m) and eight normal-weighted adolescents (control group; BMI: 18.67+/-2.46 kg/m) were recruited. Both groups were evaluated while standing using the Pedar-X in-shoe system. Foot-ground contact was characterized using contact area, peak of force and pressure calculated for the subareas of the foot. The analysis showed that obese participants had significantly higher area of contact in forefoot and midfoot (only in medial area) regions in comparison with the control group, whereas no statistically significant differences were observed for the rearfoot region. As far as the maximum pressure and force was concerned, similar results were obtained for both groups. Obese participants showed higher values for all the regions, with the exception of medial rearfoot area, for which the values were similar between the two groups. The analysis of foot-type distribution displayed that in the obese group high percentage of participants presented flat foot (70%) respect to cavus foot (20%) and normal foot (10%); on the contrary, in the control group, foot-types were markedly different, with 25% of participants with flat foot, 25% with cavus foot and 50% with normal foot. These results are important from a clinical perspective to develop and enhance the rehabilitative options in these patients and to avoid a worsening of their foot abnormalities. Untreated flat foot can in fact be disabling and over time can result in significant difficulties for the patient. PMID- 26632775 TI - The Electrochemical Synthesis of Polycationic Clusters. AB - As a new method for the synthesis of chalcogen polycationic clusters, the electrochemical dissolution of elemental tellurium in ionic liquids (IL) or in liquid SO2 is presented. ILs used are ethylmethylimidazolium triflate [OTf](-) and tetraalkylammonium triflylimide [NTf2](-). Tristriflylmethanide [CTf3](-) was used as [BuMeIm][CTf3] as the electrolyte in SO2. This allowed for the isolation of [Te4][CTf3]2, [Te6][OTf]4, and [Te8][NTf2]2 containing the square [Te4](2+), the prismatic [Te6](4+), and the novel barrelane-shaped [Te8](2+). The compounds are novel compositions as they do not contain the usual halometalate anions, but rather common weakly coordinating anions. The (125)Te NMR spectrum of an IL solution containing [Te8](2+) features only one broad signal at 2700 ppm. DFT calculations show that slight concerted displacements within the [Te8](2+) cluster lead to a fluxional molecular structure and a fast valence isomerism with a very low activation barrier of about 8 kJ mol(-1). PMID- 26632776 TI - Increased iron-stress resilience of maize through inoculation of siderophore producing Arthrobacter globiformis from mine. AB - Iron deficiency is common among graminaceous crops. Ecologically successful wild grasses from iron-limiting habitats are likely to harbour bacteria which secrete efficient high-affinity iron-chelating molecules (siderophores) to solubilize and mobilize iron. Such siderophore-producing rhizobacteria may increase the iron stress resilience of graminaceous crops. Considering this, 51 rhizobacterial isolates of Dichanthium annulatum from iron-limiting abandoned mine (~84% biologically unavailable iron) were purified and tested for siderophore production; and efficacy of Arthrobacter globiformis inoculation to increase iron stress resilience of maize and wheat was also evaluated. 16S rRNA sequence analyses demonstrated that siderophore-producing bacteria were taxonomically diverse (seven genera, nineteen species). Among these, Gram-positive Bacillus (eleven species) was prevalent (76.92%). A. globiformis, a commonly found rhizobacterium of graminaceous crops was investigated in detail. Its siderophore has high iron-chelation capacity (ICC: 13.0 +/- 2.4 MUM) and effectively dissolutes diverse iron-complexes (FeCl3 : 256.13 +/- 26.56 MUM/ml; Fe2 O3 red: 84.3 +/- 4.74 MUM/ml; mine spoil: 123.84 +/- 4.38 MUM/ml). Siderophore production (ICC) of A. globiformis BGDa404 also varied with supplementation of different iron complexes. In plant bioassay with iron-deficiency sensitive species maize, A. globiformis inoculation triggered stress-associated traits (peroxidase and proline) in roots, enhanced plant biomass, uptake of iron and phosphate, and protein and chlorophyll contents. However, in iron deficiency tolerant species wheat, growth improvement was marginal. The present study illustrates: (i) rhizosphere of D. annulatum colonizing abandoned mine as a "hotspot" of siderophore-producing bacteria; and (ii) potential of A. globiformis BGDa404 inoculation to increase iron-stress resilience in maize. A. globiformis BGDa404 has the potential to develop as bioinoculant to alleviate iron-stress in maize. PMID- 26632777 TI - Measurement of Blood Volume in Adult Rhesus Macaques (Macaca mulatta). AB - Most biomedical facilities that use rhesus macaques (Macaca mulatta) limit the amount of blood that may be collected for experimental purposes. These limits typically are expressed as a percentage of blood volume (BV), estimated by using a fixed ratio of blood (mL) per body weight (kg). BV estimation ratios vary widely among facilities and typically do not factor in variables known to influence BV in humans: sex, age, and body condition. We used indicator dilution methodology to determine the BV of 20 adult rhesus macaques (10 male, 10 female) that varied widely in body condition. We measured body composition by using dual energy X-ray absorptiometry, weight, crown-to-rump length, and body condition score. Two indicators, FITC-labeled hydroxyethyl starch (FITC-HES) and radioiodinated rhesus serum albumin ((125)I-RhSA), were injected simultaneously, followed by serial blood collection. Plasma volume at time 0 was determined by linear regression. BV was calculated from the plasma volume and Hct. We found that BV calculated by using FITC-HES was consistently lower than BV calculated by using (125)I-RhSA. Sex and age did not significantly affect BV. Percentage body fat was significantly associated with BV. Subjects categorized as having 'optimal' body condition score had 18% body fat and 62.1 mL/kg BV (by FITC-HES; 74.5 mL/kg by (125)I-RhSA). Each 1% increase in body fat corresponded to approximately 1 mL/kg decrease in BV. Body condition score correlated with the body fat percentage (R(2) = 0.7469). We provide an equation for calculating BV from weight and body condition score. PMID- 26632778 TI - Maternal Weight Gain as a Predictor of Litter Size in Swiss Webster, C57BL/6J, and BALB/cJ mice. AB - An important task facing both researchers and animal core facilities is producing sufficient mice for a given project. The inherent biologic variability of mouse reproduction and litter size further challenges effective research planning. A lack of precision in project planning contributes to the high cost of animal research, overproduction (thus waste) of animals, and inappropriate allocation of facility resources. To examine the extent daily prepartum maternal weight gain predicts litter size in 2 commonly used mouse strains (BALB/cJ and C57BL/6J) and one mouse stock (Swiss Webster), we weighed >= 25 pregnant dams of each strain or stock daily from the morning on which a vaginal plug (day 0) was present. On the morning when dams delivered their pups, we recorded the weight of the dam, the weight of the litter itself, and the number of pups. Litter sizes ranged from 1 to 7 pups for BALB/cJ, 2 to 13 for Swiss Webster, and 5 to 11 for C57BL/6J mice. Linear regression models (based on weight change from day 0) demonstrated that maternal weight gain at day 9 (BALB/cJ), day 11 (Swiss Webster), or day 14 (C57BL/6J) was a significant predictor of litter size. When tested prospectively, the linear regression model for each strain or stock was found to be accurate. These data indicate that the number of pups that will be born can be estimated accurately by using maternal weight gain at specific or stock-specific time points. PMID- 26632779 TI - A Practical Approach for Designing Breeding Groups to Maximize Genetic Diversity in a Large Colony of Captive Rhesus Macaques (Macaca mulatta). AB - Limited guidance is available on practical approaches for maintaining genetic diversity in large NHP colonies that support biomedical research, despite the fact that reduced diversity in these colonies is likely to compromise the application of findings in NHP to human disease. In particular, constraints related to simultaneously housing, breeding, and providing ongoing veterinary care for thousands of animals with a highly complex social structure creates unique challenges for genetic management in these colonies. Because the composition of new breeding groups is a critical component of genetic management, here we outline a 3-stage protocol for forming new breeding groups of NHP that is aimed at maximizing genetic diversity in the face of frequent restrictions on age, sex, and numbers of animals per breeding group. As an example application of this protocol, we describe optimal combinations of rhesus macaques from an analysis of candidate animals available for breeding in July 2013, selected from among the approximately 4000 macaques maintained at the Oregon National Primate Research Center. In addition, a simulation study to explore the genetic diversity in breeding groups formed by using this protocol, indicated an approximate 10 fold higher genome uniqueness, 50% lower mean kinship, and an 84-fold lower mean inbreeding coefficient among potential offspring within groups, when compared with a suboptimal group design. We conclude that this protocol provides a practical and effective approach to breeding group design for colony managers who want to prevent the loss of genetic diversity in large, semiisolated NHP colonies. PMID- 26632780 TI - Interactions Between Housing Density and Ambient Temperature in the Cage Environment: Effects on Mouse Physiology and Behavior. AB - To determine how housing density and ambient temperature interact to influence the physiology and behavior of mice, we systematically varied housing density (1 to 5 mice per cage) and ambient temperature (22, 26, or 30 degrees C) and measured effects on body weight, food intake, diurnal patterns of locomotor activity and core temperature, fecal corticosterone, and serum cytokine and adipokine panels. Temperatures inside cages housing 5 mice were 1 to 2 degrees C higher than the ambient temperature. As the housing density decreased, in-cage temperatures began to fall at a density of 2 or 3 mice per cage and did not differ from ambient temperature at 1 mouse per cage. Ambient temperature, but not housing density, significantly affected food intake. Although neither ambient temperature nor housing density affected core temperature or activity, hyperthermia and behavioral activation occurred during the 12-h period after cage change. Fecal concentrations of corticosterone metabolites and serum cytokines, chemokines, insulin, and leptin were not influenced by cage density and were only sporadically influenced by ambient temperature. Our data document that the number of mice housed per cage influences the intracage environmental conditions and that ambient temperature influences food intake even when temperatures are within or near recommended or thermoneutral ranges. We conclude that investigators should be cautious when changing the number of mice housed in a cage over the course of a study, because doing so significantly alters the cage environment to which remaining mice are exposed. PMID- 26632781 TI - Long-Term Provision of Environmental Resources Alters Behavior but not Physiology or Neuroanatomy of Male and Female BALB/c and C57BL/6 Mice. AB - Few studies have evaluated the long-term effects of providing environmental resources to mice. This consideration is important given that mice are often maintained in vivaria for months. We evaluated the effects of providing simple cage resources (wood wool, cotton nesting material, a plastic tunnel, and oat cereal) compared with standard housing (solid-bottom cage with hardwood chips) to group-housed adult male and female C57BL/6 and BALB/c mice (n = 20/sex/strain/group) over 6 mo to determine whether these resources had a lasting effect on animal physiology, anatomy, and behavior. Body weights increased in all groups over time but were proportionately higher in male and female BALB/c mice housed in resource-supplemented environments. Throughout the study, adding environmental resources had no effect on hematology and lymphocyte subsets, fecal corticoid metabolite levels, response to LPS injection, or dendritic spine length or density. Strain- or sex*environmentspecific changes occurred in dark-light activity and thermal nociceptive responses. Dominant agonistic behaviors, abnormal conspecific sexual behaviors, and social nonagonistic behaviors demonstrated sex and strain*environment interactions such that fewer maladaptive social behaviors were noted in mice that were provided with environmental resources. This association was particularly evident in male mice of both strains in resource-supplemented environments. A small but significant increase in brain weight:body weight ratios occurred in mice in resource-supplemented environments. Under the conditions evaluated here, consistent use of simple environmental resources had a positive long-term effect on the behavioral wellbeing of male and female BALB/c and C57BL/6 mice yet minimally affected other aspects of murine physiology and neuroanatomy. PMID- 26632782 TI - Effect of Enrichment Devices on Aggression in Manipulated Nude Mice. AB - Agonistic behavior in group-housed male mice is a recurring problem in many animal research facilities. Common management procedures, such as the removal of aggressors, are moderately successful but often fail, owing to recurrence of aggressive behavior among cagemates. Studies have incorporated enrichment devices to attenuate aggression, but such devices have had mixed results. However, these studies did not include research manipulations when assessing the benefits of various enrichment devices. We obtained 100 male athymic nude mice and studied the efficacy of various enrichment devices, including cotton squares, paper rolls, shredded paper, nylon bones, and a mouse house and wheel combination in the reduction of fighting during an ongoing study that involved randomization followed by prostate and intratibial injections. Groups were evaluated according to a numerical grading system for wound assessment. Examination of the data revealed that the enrichment devices had no effect on the presence of wounds, thus none of the devices tested affected fighting in nude mice. However, when mice began experimental use, fight wounds increased significantly at cage change and after randomization, reflecting a disruption of existing social hierarchies. Therefore, in the context of an actual research study that involves common manipulations, the specific enrichment device had less effect on aggression in male nude mice than did the destruction and reconstruction of social structures within each group. PMID- 26632783 TI - Characterization of Train-Induced Vibration and its Effect on Fecal Corticosterone Metabolites in Mice. AB - Excessive environmental vibrations can have deleterious effects on animal health and experimental results, but they remain poorly understood in the animal laboratory setting. The aims of this study were to characterize train-associated vibration in a rodent vivarium and to assess the effects of this vibration on the reproductive success and fecal corticosterone metabolite levels of mice. An instrumented cage, featuring a high-sensitivity microphone and accelerometer, was used to characterize the vibrations and sound in a vivarium that is near an active railroad. The vibrations caused by the passing trains are 3 times larger in amplitude than are the ambient facility vibrations, whereas most of the associated sound was below the audible range for mice. Mice housed in the room closest to the railroad tracks had pregnancy rates that were 50% to 60% lower than those of mice of the same strains but bred in other parts of the facility. To verify the effect of the train vibrations, we used a custom-built electromagnetic shaker to simulate the train-induced vibrations in a controlled environment. Fecal pellets were collected from male and female mice that were exposed to the simulated vibrations and from unexposed control animals. Analysis of the fecal samples revealed that vibrations similar to those produced by a passing train can increase the levels of fecal corticosterone metabolites in female mice. These increases warrant attention to the effects of vibration on mice and, consequently, on reproduction and experimental outcomes. PMID- 26632784 TI - Effect of Cage-Wash Temperature on the Removal of Infectious Agents from Caging and the Detection of Infectious Agents on the Filters of Animal Bedding-Disposal Cabinets by PCR Analysis. AB - Efficient, effective cage decontamination and the detection of infection are important to sustainable biosecurity within animal facilities. This study compared the efficacy of cage washing at 110 and 180 degrees F on preventing pathogen transmission. Soiled cages from mice infected with mouse parvovirus (MPV) and mouse hepatitis virus (MHV) were washed at 110 or 180 degrees F or were not washed. Sentinels from washed cages did not seroconvert to either virus, whereas sentinels in unwashed cages seroconverted to both agents. Soiled cages from mice harboring MPV, Helicobacter spp., Mycoplasma pulmonis, Syphacia obvelata, and Myocoptes musculinus were washed at 110 or 180 degrees F or were not washed. Sentinels from washed cages remained pathogen-free, whereas most sentinels in unwashed cages became infected with MPV and S. obvelata. Therefore washing at 110 or 180 degrees F is sufficient to decontaminate caging and prevent pathogen transmission. We then assessed whether PCR analysis of debris from the bedding disposal cabinet detected pathogens at the facility level. Samples were collected from the prefilter before and after the disposal of bedding from cages housing mice infected with both MPV and MHV. All samples collected before bedding disposal were negative for parvovirus and MHV, and all samples collected afterward were positive for these agents. Furthermore, all samples obtained from the prefilter before the disposal of bedding from multiply infected mice were pathogen-negative, and all those collected afterward were positive for parvovirus, M. pulmonis, S. obvelata, and Myocoptes musculinus. Therefore the debris on the prefilter of bedding-disposal cabinets is useful for pathogen screening. PMID- 26632785 TI - Comparison of Traditional and Integrated Digital Anesthetic Vaporizers. AB - Recent efforts have focused on mitigating anesthetic gas emissions during laboratory animal experiments. A recently developed, digitally controlled, integrated digital vaporizer (IDV) using a syringe pump has been designed to use and administer anesthetic gas to mice and rats more efficiently. The entire IDV system can be placed on a laboratory bench, requires fewer charcoal filters to act as passive scavengers when used at a low gas flow rate, and does not need compressed gas to operate, a requirement for traditional passive systems. The objective of this study was to compare isoflurane usage between a traditional vaporizer (TdV) and an IDV system at both the same settings and those recommended by the manufacturer. We used 10 C57BL/6 male mice and administered isoflurane through either nose cones or tracheal tubes connected to a pulsatile ventilator. The results showed that isoflurane usage is highly dependent on the flow rate of the carrier gas, but the IDV system was more precise and handled low flow rates (150 mL/min) better than did the TdV system. We observed only slight differences in heart rate, respiration rate, core body temperature, time to loss of the righting reflex, and recovery time between group averages for both systems when set to manufacturer-recommended settings. Although observed decreased levels of waste anesthetic gas at low flow rates are expected from the IDV system, further work is needed to assess environmental anesthetic gas levels and exposure to laboratory personnel. PMID- 26632786 TI - Pharmacokinetics and Antinociceptive Activity of Sustained-Release Buprenorphine in Sheep. AB - Buprenorphine is a potent analgesic commonly administered to alleviate pain in sheep used in research. Sustained-release buprenorphine (SRB) is an alternative to conventional buprenorphine hydrochloride (which must be injected repeatedly). To compare SRB with a typical conventional buprenorphine regimen (0.03 mg/kg every 8 h for 72 h), we used a simple 1:1 conversion to calculate a total SRB dose of 0.27 mg/kg per injection. The pharmacokinetics and thermal nociceptive effects of SRB were analyzed in 4 healthy adult sheep after a single intramuscular injection plus a washout period then a single subcutaneous injection. For both routes in all 4 sheep, plasma buprenorphine concentrations exceeded 0.1 ng/mL, considered the minimal threshold for therapeutic benefit, after 12 h and maintained a steady state for at least 72 h Likewise, for both routes in all sheep, thermal thresholds increased significantly between baseline and 12 h; lack of response persisted for at least 72 h. The average maximal plasma buprenorphine concentrations and bioavailability were similar for both routes. No clinical adverse effects occurred. Using a dose equivalent to the total course of conventional buprenorphine, this pilot study suggests that SRB is a well-tolerated, effective, and long-acting analgesic that can be administered as a single intramuscular or subcutaneous injection. SRB confers steady plasma concentrations and continuous analgesia in thermal nociception for at least 72 h. When compared with conventional buprenorphine, SRB has considerable advantages in improving wellbeing by minimizing handling-associated stress of repeated injection and limiting the likelihood of end-of-dose breakthrough pain. PMID- 26632787 TI - Intraperitoneal Injection of Ethanol for the Euthanasia of Laboratory Mice (Mus musculus) and Rats (Rattus norvegicus). AB - Compassion, professional ethics, and public sensitivity require that animals are euthanized humanely and appropriately under both planned and emergent situations. According to the 2013 AVMA Guidelines for the Euthanasia of Animals, intraperitoneal injection of ethanol is "acceptable with conditions" for use in mice. Because only limited information regarding this technique is available, we sought to evaluate ethanol by using ECG and high-definition video recording. Mice (n = 85) and rats (n = 16) were treated with intraperitoneal ethanol (70% or 100%), a positive-control agent (pentobarbital-phenytoin combination [Pe/Ph]), or a negative-control agent (saline solution). After injection, animals were assessed for behavioral and physiologic responses. Pain-assessment techniques in mice demonstrated that intraperitoneal injection of ethanol was not more painful than was intraperitoneal Pe/Ph. Median time to loss of consciousness for all mice that received ethanol or Pe/Ph was 45 s. Median time to respiratory arrest was 2.75, 2.25, and 2.63 min, and time (mean +/- SE) to cardiac arrest was 6.04 +/- 1.3, 2.96 +/- 0.6, and 4.03 +/- 0.5 min for 70% ethanol, 100% ethanol, and Pe/Ph, respectively. No mouse that received ethanol or Pe/Ph regained consciousness. Although successful in mice, intraperitoneal ethanol at the doses tested (9.2 to 20.1 g/kg) was unsuitable for euthanasia of rats (age, 7 to 8 wk) because of the volume needed and prolonged time to respiratory effects. For mice, intraperitoneal injection of 70% or 100% ethanol induced rapid and irreversible loss of consciousness, followed by death, and should be considered as "acceptable with conditions." PMID- 26632788 TI - Use of a Far-Infrared Active Warming Device in Guinea Pigs (Cavia porcellus). AB - Small mammals have difficulty maintaining body temperature under anesthesia. This hypothermia is a potential detriment not only to the health and comfort of the animal but also to the integrity of any treatment given or data gathered during the anesthetic period. Using an external warming device to assist with temperature regulation can mitigate these effects. In this study, we investigated the ability of an advanced warming device that uses far-infrared (FIR) heating and responds to real-time core temperature monitoring to maintain a normothermic core temperature in guinea pigs. Body temperatures were measured during 30 min of ketamine-xylazine general anesthesia with and without application of the heating device. The loss of core body heat from anesthetized guinea pigs under typical (unwarmed) conditions was significant, and this loss was almost completely mitigated by application of the FIR heating pad. The significant difference between the temperatures of the actively warmed guinea pigs as compared with the control group began as early as 14 min after anesthetic administration, leading to a 2.6 degrees C difference at 30 min. Loss of core body temperature was not correlated with animals' body weight; however, weight influences the efficiency of FIR warming slightly. These study results show that the FIR heating device accurately controls core body temperature in guinea pigs, therefore potentially alleviating the effects of body heat loss on animal physiology. PMID- 26632789 TI - Evaluation of Lacrimation Characteristics in Clinically Normal New Zealand White Rabbits by Using the Schirmer Tear Test I. AB - Rabbits are a common animal model in eye research and in safety testing of novel chemical agents. In addition, ocular disease is a routine presentation in clinical practice. However, few studies have quantitatively examined lacrimation kinetics in this species. This study used a noninvasive method of tear measurement (the Schirmer tear test, STT) to quantify values for basal and reflex tearing and to determine the kinetic nature of tear production in 76 New Zealand white rabbits. We obtained a value of 7.58 +/- 2.3 mm/min for the standard 1-min STT. Calculated values for mean residual tear volume and reflex tear flow were 1.95 MUL and 0.035 MUL/s, respectively. In addition, this study provides preliminary evidence for an interaction effect between eyes given that higher STT values were obtained from the second eye tested. PMID- 26632791 TI - Investigation of Blue Bedding in Cages Housing Treatment-Naive Hamsters. AB - During the acclimation phase of a preclinical safety study involving Syrian golden hamsters, some of the cages of treatment-naive animals were noted to contain blue-tinged bedding; the urine of these hamsters was not discolored. We sought to understand the underlying cause of this unusual finding to ensure that the study animals were healthy and free from factors that might confound the interpretation of the study. Analysis of extracts from the blue bedding by using HPLC with inline UV detection and high-resolution mass spectrometry indicated that the color was due to the presence of indigo blue. Furthermore, the indigo blue likely was formed through a series of biochemical events initiated by the intestinal metabolism of tryptophan to an indoxyl metabolite. We offer 2 hypotheses regarding the fate of the indoxyl metabolite: indigo blue formation through oxidative coupling in the liver or through urinary bacterial metabolism. PMID- 26632790 TI - Evaluation of Presurgical Skin Preparation Agents in African Clawed Frogs (Xenopus laevis). AB - Despite the routine collection of oocytes from African clawed frogs (Xenopus laevis) for use in research, few studies have evaluated methods for preparing their skin for surgery. We evaluated 3 skin preparatory agents by examining their antibacterial efficacy and the gross and microscopic appearance of Xenopus skin after exposure. Frogs (n = 14) were sedated and treated (contact time, 10 min) with 0.9% sterile NaCl on one-half of the ventrum and with 0.5% povidone-iodine or 0.75% chlorhexidine on the other half. Bacterial cultures were obtained before and after skin treatment; bacteria were identified by mass spectrometry. To assess inflammation and degenerative changes, the incision sites were photographed and biopsied at 0, 1, and 7 d after surgery. We isolated at least 22 genera of bacteria from the skin of our frog population (mean +/- SE, 5.21 +/- 0.82 genera per frog). Iodine (2.00 +/- 0.44 genera) and chlorhexidine (0.29 +/- 0.76 genera) both had greater antimicrobial activity than did saline. Skin erythema did not correlate with treatment group. Histologic evidence of epidermal degeneration and necrosis was greater on days 1 and 7 after chlorhexidine treatment than after iodine or saline. In addition, frogs treated with chlorhexidine had a higher incidence of clinical illness associated with the exposure site. In summary, although chlorhexidine has adequate antimicrobial activity against organisms on X. laevis skin, it leads to skin damage and subsequent clinical complications. We therefore do not recommend chlorhexidine as a preoperative preparation agent in Xenopus. PMID- 26632792 TI - Review of digital image security in Dermatology. AB - The inherently visual nature of dermatology naturally lends itself to photography. As technology has evolved, smartphone cameras have become ubiquitous and have the potential to improve education and patient care in dermatology. Although patients and physicians may agree that photography can improve patient care, there are certain risks involved with smartphone photography in the medical field. Perhaps most concerning is the number of dermatologists using smartphones to take unsecured images in their daily practice. A recent study revealed that 22% of surveyed dermatologists used smartphone cameras multiple times per day in their practice. Dermatologists may also overestimate patient comfort with smartphone use in clinical photography. We present a review of the use of smartphones in dermatology and address the potential lack of security and accompanying ethical dilemmas. PMID- 26632793 TI - Increased severity of itching, pain, and scaling in psoriasis patients is associated with increased disease severity, reduced quality of life, and reduced work productivity. AB - BACKGROUND: Psoriasis patients report that this disease can impact on their health-related quality of life (HR-QoL) and work productivity. It is important to understand how this is influenced by the clinical characteristics of psoriasis such as symptom severity. Common symptoms include itching, pain, and scaling but the psychosocial impact these features have on patients is not well understood. OBJECTIVE: To explore the impact of psoriasis symptoms (itching, pain, and scaling) on HR-QoL and work productivity. METHOD: Data were extracted from the Adelphi 2011 and 2013 Psoriasis Disease Specific Programmes - two real world surveys of US dermatologists and their psoriasis patients. HR-QoL was measured using the Dermatology Life Quality Index (DLQI) and EuroQOL 5-Dimension Health Questionnaire (EQ-5D). Work productivity loss was measured by the Work Productivity and Activity Impairment (WPAI) questionnaire. The impact of symptom severity (none, mild, moderate/severe) for itching, pain, and scaling on DLQI, EQ 5D, and WPAI scores were examined, controlling for differences in demographics and co-morbidities. RESULTS: Patient mean age was 44 years and 55% were male. Moderate/severe itching, pain, and scaling were experienced by 33%, 13%, and 41% of patients, respectively. Controlling for differences in demographics and co morbidities, increased symptom severity was associated with reduced HR-QoL. Accordingly, EQ-5D scores decreased with itching severity (moderate/severe vs. none: -0.07; 95% confidence interval [CI] =-0.09, -0.04), whereas DLQI scores increased (moderate/severe versus none: 4.9; CI = 3.9, 5.9) (both p<0.05). WPAI scores increased with itching severity, indicating increased work productivity loss (moderate/severe versus none: 17.6, CI = 11.8, 23.5, p<0.05). The same pattern was observed for pain and scaling. CONCLUSIONS: Among the patients studied, increased severity of psoriasis-related itching, pain, and scaling was associated with reduced health-related QoL and work productivity. PMID- 26632794 TI - A national survey of residents in combined Internal Medicine and Dermatology residency programs: educational experience and future plans. AB - IMPORTANCE: In response to a perceived erosion of medical dermatology, combined internal medicine and dermatology programs (med/derm) programs have been developed that aim to train dermatologists who take care of medically complex patients. Despite the investment in these programs, there is currently no data with regards to the potential impact of these trainees on the dermatology workforce. OBJECTIVE: To determine the experiences, motivations, and future plans of residents in combined med/derm residency programs. DESIGN, SETTING, AND PARTICIPANTS: We surveyed residents at all United States institutions with both categorical and combined training programs in spring of 2012. Respondents used visual analog scales to rate clinical interests, self-assessed competency, career plans, and challenges. MAIN OUTCOMES AND MEASURES: The primary study outcomes were comfort in taking care of patients with complex disease, future practice plans, and experience during residency. RESULTS: Twenty-eight of 31 med/derm residents (87.5%) and 28 of 91 (31%) categorical residents responded (overall response rate 46%). No significant differences were seen in self-assessed dermatology competency, or comfort in performing inpatient consultations, cosmetic procedures, or prescribing systemic agents. A trend toward less comfort in general dermatology was seen among med/derm residents. Med/derm residents were more likely to indicate career preferences for performing inpatient consultation and taking care of medically complex patients. Categorical residents rated their programs and experiences more highly. CONCLUSIONS AND RELEVANCE: Med/derm residents have stronger interests in serving medically complex patients. Categorical residents are more likely to have a positive experience during residency. Future work will be needed to ascertain career choices among graduates once data are available. PMID- 26632795 TI - IgM ocular cicatricial pemphigoid: a unique insight into the immune system. AB - A 42-year-old man with ocular erythema and scarring had a conjunctival biopsy revealing depostion of IgM and C3 without IgG at the epithelial basement membrane zone. Treatment with doxycyline, dapsone, and mycophenolate mofetil was unsuccessful and treatment with rituximab has led to partial remission of the conjunctival inflammation. He has undergone 4 cycles of rituximab treatment at intervals of 12 to 18 months. PMID- 26632796 TI - Scalp necrosis overlying a ventriculoperitoneal shunt: a case report and literature review. AB - BACKGROUND: The use of ventriculoperitoneal (VP) shunts has become ubiquitous in neurosurgery for the treatment of hydrocephalus. VP shunts work by creating a conduit for cerebrospinal fluid (CSF) to flow from the cerebral ventricles to the peritoneum and thus relieving pressure. Although typically safe, VP shunt complications are extremely common, occurring in up to 29% of adult cases and approximately half of pediatric cases. These complications may require patients to undergo several revisions throughout their lifetime Purpose: We describe a man who developed scalp necrosis overlying his VP shunt. We also summarize the potential complications of VP shunts. We discuss the presentation and pathogenesis of scalp necrosis in these patients. MATERIALS AND METHODS: A PubMed search of the following terms was performed and relevant citations were assessed: ventriculoperitoneal shunt, VP shunt, shunt complications, scalp necrosis, skin necrosis, ventriculoperitoneal shunt induced scalp necrosis, ventriculoperitoneal shunt induced skin necrosis. RESULTS: A 73-year-old man developed VP shunt induced scalp necrosis leading to loss of skin overlying the shunt valve. The patient was emergently referred to neurosurgery and admitted for revision of the shunt due to the significant risk for infection. The VP shunt was replaced with an external drain and a skin flap was used to repair the defect. CONCLUSION: VP shunts are devices that are frequently used for reducing intracranial pressure associated with hydrocephalus. The insertion of the shunt beneath the scalp sets the stage for potential pressure-induced scalp necrosis. The early recognition and diagnosis of VP shunt-induced scalp necrosis is essential to prevent infections and future complications. PMID- 26632797 TI - A case of Kaposi sarcoma in an immunocompetent, heterosexual Irish man: a discussion of etiology and viral transmission. AB - Four types of Kaposi sarcoma (KS) have been described, all of which are caused by human herpesvirus-8 (HHV-8). The incidence of KS in the United States is highest among HIV-positive homosexual men and elderly men of Eastern European, Jewish, or Mediterranean descent. However, few reports describe KS in HIV-negative, immunocompetent heterosexual men in the United States. HHV-8 is transmitted largely via saliva and close sexual contact, whereas there are only a handful of reports of transmission via blood and blood products. We report a case of an HIV negative, immunocompetent heterosexual man who acquired KS via blood transfusion. A 77-year-old immunocompetent, monogamously heterosexual, HIV-negative Irish man presented with a biopsy-proven KS lesion on the right thigh. Past surgical history included a coronary artery bypass graft, during which he received a blood transfusion from an unknown donor source. His ecchymotic KS lesions progressed while on doxycycline, intralesional vinblastine, and topical anti-angiogenic medications. The patient eventually achieved stabilization of KS lesions with acitretin. Our case report emphasizes the need to characterize the phenotype and transmission route of HHV-8 in heterosexual, immunocompetent patients in geographic regions with low HHV-8 seroprevalence. PMID- 26632798 TI - Infantile myofibroma: a firm, round plaque in an infant. AB - Infantile myofibroma is a rare fibromatous tumor that is variable in presentation and is frequently mistaken for hemangioma or rhabdomyosarcoma. We describe a 14 month-old male who presented with multiple, enlarging, firm lesions on the shoulder. Biopsy revealed a proliferation of small spindle cells with myxoid and hyalinized stroma infiltrating into the superficial adipose tissue. We provide a brief review of the clinical presentation, histopathologic features, management and recent advances in our understanding of this rare condition. PMID- 26632799 TI - C-MYC positive angiosarcoma of skin and breast following MammoSite(r) treatment. AB - Angiosarcoma of the skin and breast is a known complication of chronic lymphedema following mastectomy or external radiation therapy for breast cancer. We report a 68-year-old woman who presented with a 2.5 cm violaceous plaque on the skin of the right breast and a 3 cm mixed mass of the same breast by ultrasound 9 years after MammoSite(r) balloon brachytherapy. Biopsy of the skin lesion and the breast mass showed an infiltrating high grade angiosarcoma. The tumor cells in the skin and breast showed immunohistochemical reactivity for C-MYC. A total mastectomy confirmed the presence of high grade angiosarcoma in the skin and parenchyma of the breast and radiation changes in the breast parenchyma. Surgical margins were considered negative. The patient had cutaneous recurrence of angiosarcoma three months after the mastectomy. There have been only two other case reports in the literature of angiosarcoma on the skin following MammoSite(r) therapy. The c-myc mutation has been shown to be a specific mutation for angiosarcoma following radiation treatment. It is not found in atypical vascular lesions following irradiation or angiosarcoma unrelated to radiation treatment. PMID- 26632800 TI - Graphite oral tattoo: case report. AB - Pigmented oral lesions compose a large number of pathological entities, including exogenous pigmentat oral tattoos, such as amalgam and graphite tattoos. We report a rare case of a graphite tattoo on the palate of a 62-year-old patient with a history of pencil injury, compare it with amalgam tattoos, and determine the prevalence of oral tattoos in our Oral Pathology Service. We also compare the clinical and histological findings of grafite and amalgam tattoos. Oral tattoos affect women more frequently in the region of the alveolar ridge. Graphite tattoos occur in younger patients when compared with the amalgam type. Histologically, amalgam lesions represent impregnation of the reticular fibers of vessels and nerves with silver, whereas in cases of graphite tattoos, this impregnation is not observed, but it is common to observe a granulomatous inflammatory response, less evident in cases of amalgam tattoos. Both types of lesions require no treatment, but in some cases a biopsy may be done to rule out melanocytic lesions. PMID- 26632801 TI - Oral manifestations of connective tissue disease and novel therapeutic approaches. AB - Connective tissue diseases such as systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and Sjogren syndrome (SS) have presented many difficulties both in their diagnosis and treatment. Known causes for this difficulty include uncertainty of disease etiology, the multitude of clinical presentations, the unpredictable disease course, and the variable cell types, soluble mediators, and tissue factors that are believed to play a role in the pathogenesis of connective tissue diseases. The characteristic oral findings seen with these specific connective tissue diseases may assist with more swift diagnostic capability. Additionally, the recent use of biologics may redefine the success rate in the treatment and management of the disease. In this review we describe the oral manifestations associated with SLE, SSc, and SS and review the novel biologic drugs used to treat these conditions. PMID- 26632802 TI - Lichen planus pigmentosus in linear and zosteriform pattern along the lines of Blaschko. AB - Lichen planus pigmentosus (LPP) is a variant of lichen planus (LP) reported in various ethnic groups. It occurs predominantly in the third or fourth decade of life and is characterized by the insidious onset of dark-brown macules in sun exposed areas and flexural folds. Rarely, has it been described in a linear or segmental distribution. Herein we describe a case of LPP with lesions lateralized to right side of body along the lines of Blaschko, in a linear and zosteriform pattern. PMID- 26632803 TI - Novel mutation in the fumarate hydratase gene in a patient with Reed syndrome. AB - Reed syndrome is an autosomal dominant disorder characterized by cutaneous leiomyomas, uterine leiomyomas, and renal cell carcinoma caused by mutations in the fumarate hydratase gene. Dermatologic evaluation is often the first or only opportunity to discover the diagnosis of Reed syndrome in affected patients, which may prove to be life-saving. We present a 40-year-old woman with history of large uterine leiomyomas who presented with a two-year history of a pruritic papular eruption on the left neck refractory to topical corticosteroids. After histopathologic examination and genetic work-up, the patient was found to have a novel mutation in the fumarate hydratase gene and was subsequently diagnosed with Reed syndrome. PMID- 26632804 TI - Equestrian perniosis: A case report and review of the literature. AB - Equestrian perniosis is a rare form of perniosis that is predominantly seen in young female equestrians who ride in cold temperatures. Tight fitting clothing, age under 35 years, and smoking can contribute to the disease manifestation. The diagnosis can be determined from a thorough history and physical examination. However, a biopsy can be taken to confirm the diagnosis. Although many cases are self-limiting and resolve within a few days to weeks of diagnosis, nifedipinie can be considered as a therapeutic measure for persistent cases. Measures such as wearing loose fitting clothing and horseback riding in warmer temperatures and for shorter time periods can prevent recurrence. PMID- 26632805 TI - Painful plantar keratoderma and onychodystrophy in caucasian young woman. AB - Pachonychia congenita is an uncommon genodermatosis, classified among the disorders of keratinization and caused by mutation of certain keratin genes. The characteristic clinical triad is onychodystrophy, keratoderma, and plantar pain. In addition, the patients may present with epidermal cysts, steatocystomas, leukokeratosis, and deciduous teeth. PMID- 26632806 TI - Juvenile dermatomyositis with joint contractures and calcinosis cutis. AB - A 12-year-old boy presented to our department with firm papules on the fingers of both hands, erythematous scaly plaques on the dorsum of the hands and elbow, and deformities and limitation of motion in the joints of the hands and feet. His parents reported that the eruption started 6 years prior to presentation. He was previously diagnosed with psoriasis by physicians and acitretin treatment was given. However, he did not benefit from the treatment. PMID- 26632807 TI - LEOPARD Syndrome. AB - LEOPARD syndrome (LS) is an autosomal dominantly inherited or sporadic disorder of variable penetrance and expressivity. The acronym LEOPARD stands for its cardinal clinical features including Lentigines, Electrocardiographic conduction abnormalities, Ocular hypertelorism, Pulmonary stenosis, Abnormalities of genitalia, Retardation of growth, and Deafness. We present herein a patient with LEOPARD syndrome and distinctive features. It was noteworthy that our patient presented with the concern of generalized lentiginosis and subsequent evaluation revealed that the patient had LEOPARD syndrome. In this report we would like to highlight the importance of detailed clinical examination and appropriate imaging in patients with multiple lentigines. PMID- 26632808 TI - Increasing medical student exposure to clinical dermatology through participation in volunteer clinics. AB - Over the previous decade, several innovative teaching methods have been introduced to overcome the decreasing allotment of time dedicated to dermatology in U.S. medical school curricula. We report our experience of increasing medical student exposure to clinical dermatology thorough involvement in an extracurricular, volunteer-driven dermatology clinic. The clinic was well received by students and faculty. Our experience demonstrates that volunteer driven dermatology clinics may be an effective method of teaching and engendering a culture of community outreach among medical students and faculty. PMID- 26632809 TI - What are the most important factors that determine the overall quality of dermatology residency training: A resident survey. AB - Currently no broadly accepted and standardized objective ranking system for dermatology residency programs exist. A new ranking system was recently developed in an attempt to address this issue. However, it remains unclear if the algorithm employed is based on factors that have a tangible impact on the quality of training provided by dermatology residency programs [1]. Our authors surveyed all current dermatology residents in order to investigate the factors that they feel are most important in determining the strength of training provided by a residency program. PMID- 26632810 TI - Subungual hematoma: clinical appearance of resolution over time. AB - Subungual hemorrhage is usually a benign sign, often linked to a traumatic cause. However, it can also reveal a serious and chronic systemic disease. As we will show, subungual hemorrhage may be an indicator of the severity of diabetic microangiopathy. We report a case of subungual hemorrhage in diabetes. PMID- 26632811 TI - Terra firma-forme dermatosis: Case Series and dermoscopic features. AB - Terra firma-forme dermatosis (TFFD) is characterized by dirt-like skin lesions that disappear after rubbing with alcohol. We describe the dermoscopic features of TFFD before and after alcohol swabbing in six patients. All patients showed similar dermoscopic appearance with large polygonal plate-like brown scales arranged together giving a mosaic pattern. These features disappear completely after isopropyl alcohol swabbing of the lesions. In conclusion dermoscopy can assist in the evaluation of terra firma-forme dermatosis and the dermoscopic evaluation of other dirty dermatoses is recommended in the future to compare findings with TFFD. PMID- 26632812 TI - The Role of Palliative Surgery in Castration-Resistant Prostate Cancer. AB - Androgen deprivation therapy (ADT) with luteinizing hormone-releasing hormone (LHRH) analogues or antagonists represents the treatment of choice in men with metastatic prostate cancer (PCA). Depending on the serum concentration of the prostate-specific antigen (PSA) nadir, the survival might vary between 11 and 78 months. In castration-resistant PCA (CRPC), all new medical treatment options can induce complete and partial remissions in metastatic foci, but they have no profound effect on the prostate itself, as has been shown recently. About one third of all patients without local treatment of the primary will develop significant complications of the lower and upper urinary tract due to local progression of the PCA. In men with CRPC and lower urinary tract symptoms, palliative transurethral resection of the prostate (TURP) can be performed with a 60-70% success rate. Infiltration of the pelvic floor, the bladder neck and trigone, and the external urethral sphincter can make palliative radical surgery necessary. Bladder neck closure with continent vesicostomy, radical cystoprostatectomy with an incontinent urinary diversion, and anterior and posterior exenteration are individual therapeutic options in men with a good performance status and a considerable life expectancy. Symptomatic involvement of the upper urinary tract can be managed by the placement of endoluminal stents or a percutaneous nephrostomy in men with poor performance. In men with a good response to ADT and a good performance status, reconstructive ureteral surgery might be considered and the options of ureteral reimplantation, ureter ileal replacement, and a subcutaneous pyelovesical bypass have to be discussed. The indication to perform one of the above-mentioned surgical approaches needs to be discussed in a multidisciplinary tumor board. PMID- 26632813 TI - Clinical Significance of Fronto-Temporal Gray Matter Atrophy in Executive Dysfunction in Patients with Chronic Kidney Disease: The VCOHP Study. AB - BACKGROUND & OBJECTIVES: It is well known that cognitive impairment in patients with chronic kidney disease (CKD) is characterized by executive dysfunction, rather than memory dysfunction, although the precise mechanism of this remains to be elucidated. The purpose of the present study is to examine the correlation between gray matter volume (GMV) and executive function in CKD patients. DESIGN, SETTING, PARTICIPANTS, MEASUREMENTS: This cross-sectional study recruited 95 patients with non-dialysis-dependent CKD (NDD-CKD) with no history of cerebrovascular disease, who underwent brain magnetic resonance imaging (MRI) and Trail Making Test (TMT) in the VCOHP Study. The subjects underwent brain MRI and TMT part A (TMT-A) and part B (TMT-B). The segmentation algorithm from Statistical Parametric Mapping 8 software was applied to every T1-weighted MRI scan to extract tissue maps corresponding to gray matter, white matter, and cerebrospinal fluid. GMV was normalized by dividing by the total intracranial volume, calculated by adding GMV, white matter volume, and cerebrospinal fluid space volume. Then, normalized whole-brain GMV was divided into four categories of brain lobes; frontal, parietal, temporal, and occipital. We assessed the correlation between normalized GMV and TMT using multivariable regression analysis. RESULTS: Normalized whole-brain GMV was significantly inversely correlated to the scores of TMT-A, TMT-B, and DeltaTMT (TMT-B minus TMT-A). These correlations remained significant even after adjusting for relevant confounding factors. Normalized frontal and temporal GMV, but not parietal and occipital GMV, were significantly inversely correlated with TMT-A, TMT-B, and DeltaTMT using multivariable regression analysis. CONCLUSIONS: The present study demonstrates the correlation between normalized GMV, especially in the frontal and temporal lobes, and executive function, suggesting that fronto-temporal gray matter atrophy might contribute to executive dysfunction in NDD-CKD. PMID- 26632814 TI - Annual Temperature Reconstruction by Signal Decomposition and Synthesis from Multi-Proxies in Xinjiang, China, from 1850 to 2001. AB - We reconstructed the annual temperature anomaly series in Xinjiang during 1850 2001 based on three kinds of proxies, including 17 tree-ring width chronologies, one tree-ring delta13C series and two delta18O series of ice cores, and instrumental observation data. The low- and high-frequency signal decomposition for the raw temperature proxy data was obtained by a fast Fourier transform filter with a window size of 20 years, which was used to build a good relationship that explained the high variance between the temperature and the proxy data used for the reconstruction. The results showed that for 1850-2001, the temperature during most periods prior to the 1920s was lower than the mean temperature in the 20th century. Remarkable warming occurred in the 20th century at a rate of 0.85 degrees C/100a, which was higher than that during the past 150 years. Two cold periods occurred before the 1870s and around the 1910s, and a relatively warm interval occurred around the 1940s. In addition, the temperature series showed a warming hiatus of approximately 20 years around the 1970s, and a rapid increase since the 1980s. PMID- 26632815 TI - Correction: Impact of Replacing Smear Microscopy with Xpert MTB/RIF for Diagnosing Tuberculosis in Brazil: A Stepped-Wedge Cluster-Randomized Trial. PMID- 26632817 TI - Penehyclidine Hydrochloride Preconditioning Provides Cardioprotection in a Rat Model of Myocardial Ischemia/Reperfusion Injury. AB - To investigate the impacts and related mechanisms of penehyclidine hydrochloride (PHC) on ischemia/reperfusion (I/R)-induced myocardial injury. A rat model of myocardial I/R injury was established by the ligation of left anterior descending coronary artery for 30 min followed by 3 h perfusion. Before I/R, the rats were pretreated with or without PHC. Cardiac function was measured by echocardiography. The activities/levels of myocardial enzymes, oxidants and antioxidant enzymes were detected. Evans blue/TTC double staining was performed to assess infarct size. Cardiomyocyte apoptosis was evaluated by TUNEL assay. The release of inflammatory cytokines and inflammatory mediators was detected by ELISA. Western blot was performed to analyze the expression of COX-2, IkappaB, p IkappaB and NF-kappaB. Meanwhile, the rats were given a single injection of H-PHC before I/R. The effects of PHC on myocardial infarct and cardiac function were investigated after 7 days post-reperfusion. We found that PHC remarkably improved cardiac function, alleviated myocardial injury by decreasing myocardial enzyme levels and attenuated oxidative stress in a dose-dependent manner. Additionally, PHC preconditioning significantly reduced infarct size and the apoptotic rate of cardiomyocytes. Administration of PHC significantly decreased serum TNF-alpha, IL 1beta, IL-6 and PGE2 levels and myocardium COX-2 level. Meanwhile, the expression levels of p-IkappaB and NF-kappaB were downregulated, while IkappaB expression was upregulated. H-PHC also exerted long-term cardioprotection in a rat model of I/R injury by decreasing infarct size and improving cardiac function. These results suggest that PHC can efficiently protect the rats against I/R-induced myocardial injury. PMID- 26632816 TI - Transient Cerebral Ischemia Promotes Brain Mitochondrial Dysfunction and Exacerbates Cognitive Impairments in Young 5xFAD Mice. AB - Alzheimer's disease (AD) is heterogeneous and multifactorial neurological disorder; and the risk factors of AD still remain elusive. Recent studies have highlighted the role of vascular factors in promoting the progression of AD and have suggested that ischemic events increase the incidence of AD. However, the detailed mechanisms linking ischemic insult to the progression of AD is still largely undetermined. In this study, we have established a transient cerebral ischemia model on young 5xFAD mice and their non-transgenic (nonTg) littermates by the transient occlusion of bilateral common carotid arteries. We have found that transient cerebral ischemia significantly exacerbates brain mitochondrial dysfunction including mitochondrial respiration deficits, oxidative stress as well as suppressed levels of mitochondrial fusion proteins including optic atrophy 1 (OPA1) and mitofusin 2 (MFN2) in young 5xFAD mice resulting in aggravated spatial learning and memory. Intriguingly, transient cerebral ischemia did not induce elevation in the levels of cortical or mitochondrial Amyloid beta (Abeta)1-40 or 1-42 levels in 5xFAD mice. In addition, the glucose- and oxygen deprivation-induced apoptotic neuronal death in Abeta-treated neurons was significantly mitigated by mitochondria-targeted antioxidant mitotempo which suppresses mitochondrial superoxide levels. Therefore, the simplest interpretation of our results is that young 5xFAD mice with pre-existing AD-like mitochondrial dysfunction are more susceptible to the effects of transient cerebral ischemia; and ischemic events may exacerbate dementia and worsen the outcome of AD patients by exacerbating mitochondrial dysfunction. PMID- 26632818 TI - A New Scoring System Using Preoperative Factors and Contour Mapping for Predicting Postoperative Complications of Laparoscopic Gastrectomy. AB - BACKGROUND: Surgical risk assessment is becoming more important in the field of laparoscopic gastrectomy given the increasing complexity and technical demands of oncological procedures undertaken. However, no validated method for preoperative risk (PR) assessment has been reported. METHODS: Two-hundred fourteen patients who underwent laparoscopic gastrectomy between October 2011 and August 2014 were reviewed. Independent risk factors were examined by multivariate analysis and a PR score model was established. RESULTS: Thirty-six (16.8%) patients experienced postoperative complications. Multivariate analysis revealed that age >=75 years, American Society of Anesthesiologists score >=2, severe pulmonary disease, Brinkman index >=600, history of upper abdominal surgery and body mass index (BMI) were independent factors. Among these, BMI was strongly correlated with postoperative morbidity rate (r = 0.960). To permit risk prediction using BMI and the remaining 5 factors, a new PR score was established using 5 categorical variables. The new score was significantly correlated with the postoperative complication rate (r = 0.948), and its predictive value was superior to conventional risk scores such as E-PASS and POSSUM. A contour map was then created using BMI and this new PR score to more accurately stratify patients according to surgical risk prior to laparoscopic gastrectomy. CONCLUSIONS: A 2 dimensional risk estimation model was created to better estimate surgical risk and is a promising new tool for adequate surgical management. PMID- 26632819 TI - Antimicrobial Non-Susceptibility of Escherichia coli from Outpatients and Patients Visiting Emergency Rooms in Taiwan. AB - Longitudinal nationwide surveillance data on antimicrobial non-susceptibility and prevalence of extended-spectrum beta-lactamases (ESBLs) as well as AmpC beta lactamases producers among Escherichia coli from different sources in the community settings are limited. Such data may impact treatment practice. The present study investigated E. coli from outpatients and patients visiting emergency rooms collected by the Taiwan Surveillance of Antimicrobial Resistance (TSAR) program. A total of 3481 E. coli isolates were studied, including 2153 (61.9%) from urine and 1125 (32.3%) from blood samples. These isolates were collected biennially between 2002 and 2012 from a total of 28 hospitals located in different geographic regions of Taiwan. Minimum inhibitory concentrations (MIC) were determined using methods recommended by the Clinical Laboratory Standards Institute (CLSI). The prevalence and factors associated with the presence of ESBL and AmpC beta-lactamase-producers were determined. Significant increases in non-susceptibility to most beta-lactams and ciprofloxacin occurred during the study period. By 2012, non-susceptibility to cefotaxime and ciprofloxacin reached 21.1% and 26.9%, respectively. The prevalence of ESBL- and AmpC- producers also increased from 4.0% and 5.3%, respectively, in 2002-2004, to 10.7% for both in 2010-2012 (P < 0.001). The predominant ESBL and AmpC beta lactamase genes were CTX-M and CMY-types, respectively. Non-susceptibility of urine isolates to nitrofurantoin remained at around 8% and to fosfomycin was low (0.7%) but to cefazolin (based on the 2014 CLSI urine criteria) increased from 11.5% in 2002-2004 to 23.9% in 2010-2012 (P <0.001). Non-susceptibility of isolates from different specimen types was generally similar, but isolates from elderly patients were significantly more resistant to most antimicrobial agents and associated with the presence of ESBL- and AmpC- beta-lactamases. An additional concern is that decreased ciprofloxacin susceptibility (MIC 0.12-1 mg/L) was as high as 25% in isolates from all age groups, including those from pediatric patients. Our data indicated that there is a need to re-evaluate appropriate treatment selection for community-acquired infections in Taiwan. Identification of community reservoirs of multidrug-resistant E. coli is also warranted. PMID- 26632820 TI - Genomic Patterns of Positive Selection at the Origin of Rust Fungi. AB - Understanding the origin and evolution of pathogenicity and biotrophic life-style of rust fungi has remained a conundrum for decades. Research on the molecular mechanisms responsible for rust fungi evolution has been hampered by their biotrophic life-style until the sequencing of some rust fungi genomes. With the availability of multiple whole genomes and EST data for this group, it is now possible to employ genome-wide surveys and investigate how natural selection shaped their evolution. In this work, we employed a phylogenomics approach to search for positive selection and genes undergoing accelerated evolution at the origin of rust fungi on an assembly of single copy genes conserved across a broad range of basidiomycetes. Up to 985 genes were screened for positive selection on the phylogenetic branch leading to rusts, revealing a pervasive signal of positive selection throughout the data set with the proportion of positively selected genes ranging between 19.6-33.3%. Additionally, 30 genes were found to be under accelerated evolution at the origin of rust fungi, probably due to a mixture of positive selection and relaxation of purifying selection. Functional annotation of the positively selected genes revealed an enrichment in genes involved in the biosynthesis of secondary metabolites and several metabolism and transporter classes. PMID- 26632821 TI - Correlation of Aging and Segmental Choroidal Thickness Measurement using Swept Source Optical Coherence Tomography in Healthy Eyes. AB - PURPOSE: To assess and compare choroidal thickness changes related to aging, we determined whether changes are due to thinning of the choriocapillaris plus Sattler's (CS) layer and/or the large vessel layer in healthy eyes using swept source optical coherence tomography (SS-OCT) at a wavelength of 1,050-nm. METHODS: We studied 115 normal eyes of 115 healthy volunteers, all with refractive errors of less than -6 diopters. All 115 eyes underwent analysis of choroidal thickness at the fovea, the CS layer and the large choroidal vessel layer. In 68 of the 115 eyes, choroidal thickness was determined at five sites (the fovea, and superior, inferior, nasal, and temporal sites) using SS-OCT with an Early Treatment of Diabetic Retinopathy grid scan. RESULTS: Total choroidal thicknesses at each of the five sites were related to subject age (P<0.0001). The choroid was thinnest at the nasal site, followed by the temporal, inferior, superior and finally the subfoveal site itself. The total choroidal thickness at the nasal site was significantly less than those at the other four sites (p<0.05). The CS layer showed thinning which correlated with age (P<0.0001). The thickness of the choroidal large vessel layer also decreased with age (p = 0.02). Subfoveal choroidal thickness was calculated as follows: 443.89-2.98*age (MUm) (P<0.0001). CONCLUSION: Subfoveal choroidal thickness decreases by 2.98 MUm each year. Total choroidal thickness diminishes with age. The CS and large vessel layers of the choroid at the subfovea showed significant decreases, though only the former correlated strongly with age. PMID- 26632822 TI - Beyond Mortality: Sterility As a Neglected Component of Parasite Virulence. AB - Virulence is generally defined as the reduction in host fitness following infection by a parasite (see Box 1 for glossary) [1]. In general, parasite exploitation of host resources may reduce host survival (mortality virulence), decrease host fecundity (sterility virulence), or even have sub-lethal effects that disturb the way individuals interact within a community (morbidity) [2,3]. In fact, the virulence of many parasites involves a combination of these various effects (Box 2). In practice, however, virulence is most often defined as disease induced mortality [1, 4-6]. This is especially true in the theoretical literature, where the evolution of sterility virulence, morbidity, and mixed strategies of host exploitation have received relatively little attention. While the focus on mortality effects has allowed for easy comparison between models and, thus, rapid advancement of the field, we ask whether these theoretical simplifications have led us to inadvertently minimize the evolutionary importance of host sterilization and secondary virulence effects. As explicit theoretical work on morbidity is currently lacking (but see [7]), our aim in this Opinion piece is to discuss what is understood about sterility virulence evolution, its adaptive potential, and the implications for parasites that utilize a combination of host survival and reproductive resources. PMID- 26632823 TI - Estimated Costs for Delivery of HIV Antiretroviral Therapy to Individuals with CD4+ T-Cell Counts >350 cells/uL in Rural Uganda. AB - BACKGROUND: Evidence favoring earlier HIV ART initiation at high CD4+ T-cell counts (CD4>350/uL) has grown, and guidelines now recommend earlier HIV treatment. However, the cost of providing ART to individuals with CD4>350 in Sub Saharan Africa has not been well estimated. This remains a major barrier to optimal global cost projections for accelerating the scale-up of ART. Our objective was to compute costs of ART delivery to high CD4+count individuals in a typical rural Ugandan health center-based HIV clinic, and use these data to construct scenarios of efficient ART scale-up. METHODS: Within a clinical study evaluating streamlined ART delivery to 197 individuals with CD4+ cell counts >350 cells/uL (EARLI Study: NCT01479634) in Mbarara, Uganda, we performed a micro costing analysis of administrative records, ART prices, and time-and-motion analysis of staff work patterns. We computed observed per-person-per-year (ppy) costs, and constructed models estimating costs under several increasingly efficient ART scale-up scenarios using local salaries, lowest drug prices, optimized patient loads, and inclusion of viral load (VL) testing. FINDINGS: Among 197 individuals enrolled in the EARLI Study, median pre-ART CD4+ cell count was 569/uL (IQR 451-716). Observed ART delivery cost was $628 ppy at steady state. Models using local salaries and only core laboratory tests estimated costs of $529/$445 ppy (+/-VL testing, respectively). Models with lower salaries, lowest ART prices, and optimized healthcare worker schedules reduced costs by $100-200 ppy. Costs in a maximally efficient scale-up model were $320/$236 ppy (+/- VL testing). This included $39 for personnel, $106 for ART, $130/$46 for laboratory tests, and $46 for administrative/other costs. A key limitation of this study is its derivation and extrapolation of costs from one large rural treatment program of high CD4+ count individuals. CONCLUSIONS: In a Ugandan HIV clinic, ART delivery costs--including VL testing--for individuals with CD4>350 were similar to estimates from high-efficiency programs. In higher efficiency scale-up models, costs were substantially lower. These favorable costs may be achieved because high CD4+ count patients are often asymptomatic, facilitating more efficient streamlined ART delivery. Our work provides a framework for calculating costs of efficient ART scale-up models using accessible data from specific programs and regions. PMID- 26632824 TI - Smoking or My Job? US Media Coverage of Nonsmoker-Only Hiring Policies. AB - OBJECTIVES: Media advocacy plays a critical role in tobacco control, shaping the content of news in ways that generate public support for tobacco control. We examined US media coverage of nonsmoker-only hiring policies, which have little US public support, exploring the extent to which tobacco control advocates and experts have engaged the media on this controversial issue. METHODS: We searched online media databases (Lexis Nexis, Access World News, and Proquest) for articles published from 1995-2013, coding retrieved items through a collaborative, iterative process. We analyzed the volume, type, provenance, prominence, content and slant of coverage. RESULTS: We found 1,159 media items on nonsmoker-only hiring policies, most published in local newspapers in regions where such policies were enacted. The most common reason given for implementing such policies was to reduce healthcare costs. Most news items offered reasons both to support and oppose such policies; thus, the slant of the majority of news items was neutral or mixed. Tobacco control advocates or experts were infrequently cited or quoted in news items, and rarely authored opinion pieces. Those who expressed opinions were more likely to support than oppose nonsmoker only hiring policies, for economic and health reasons. Ethical concerns about the policies were seldom raised. CONCLUSIONS: As presented in the media, nonsmoker only hiring policies were primarily framed in terms of business cost savings and had little connection to health initiatives. Tobacco control advocates were rarely quoted and their positions were not consistent. Given their intrusiveness and the lack of strong evidence that such business policies actually do improve worker health, tobacco control advocates may feel that the status quo is preferable to engaging on a policy that the majority of Americans dislike. PMID- 26632826 TI - A one-dimensional chloride-bridged Pt(II)/Pt(IV) mixed-valence complex with a 4 [(4-hydroxyphenyl)diazenyl]benzenesulfonate counter-ion. AB - The title compound, catena-poly[[[bis(ethylenediamine-kappa(2)N,N')platinum(II)]- MU-chlorido-[bis(ethylenediamine)platinum(IV)]-MU-chlorido] tetrakis{4-[(4 hydroxyphenyl)diazenyl]benzenesulfonate} dihydrate], {[Pt(II)Pt(IV)Cl2(C2H8N2)4](HOC6H4N=NC6H4SO3)4.2H2O}n, has a linear chain structure composed of square-planar [Pt(en)2](2+) (en is ethylenediamine) and elongated octahedral trans-[PtCl2(en)2](2+) cations stacked alternately, bridged by Cl atoms, along the b axis. The Pt atoms are located on an inversion centre, while the Cl atoms are disordered over two sites and form a zigzag ...Cl-Pt(IV) Cl...Pt(II)... chain, with a Pt(IV)-Cl bond length of 2.3140 (14) A, an interatomic Pt(II)...Cl distance of 3.5969 (15) A and a Pt(IV)-Cl...Pt(II) angle of 170.66 (6) degrees . The structural parameter indicating the mixed-valence state of the Pt atom, expressed by delta = (Pt(IV)-Cl)/(Pt(II)...Cl), is 0.643. PMID- 26632827 TI - A new route for the synthesis of phosphate esters: 2,2'-[benzene-1,2 diylbis(oxy)]bis(5,5-dimethyl-1,3,2-dioxaphosphinane) 2,2'-dioxide. AB - Podand-type ligands are an interesting class of acyclic ligands which can form host-guest complexes with many transition metals and can undergo conformational changes. Organic phosphates are components of many biological molecules. A new route for the synthesis of phosphate esters with a retained six-membered ring has been used to prepare 2,2'-[benzene-1,2-diylbis(oxy)]bis(5,5-dimethyl-1,3,2 dioxaphosphinane) 2,2'-dioxide, C6H4{O[cyclo-P(O)OCH2CMe2CH2O]}2 or C16H24O8P2, (1), 2-[(2'-hydroxybiphenyl-2-yl)oxy]-5,5-dimethyl-1,3,2-dioxaphosphinane 2 oxide, [cyclo-P(O)OCH2CMe2CH2O](2,2'-OC6H4-C6H4OH), (2), and oxybis(5,5-dimethyl 1,3,2-dioxaphosphinane) 2,2'-dioxide, O[cyclo-P(O)OCH2CMe2CH2O]2, (3). Compound (1) is novel, whereas the results for compounds (2) and (3) have been reported previously, but we record here our results for compound (3), which we find are more precise and accurate than those currently reported in the literature. In (1), two cyclo-P(O)OCH2CMe2CH2O groups are linked through a catechol group. The conformations about the two catechol O atoms are quite different, viz. one C-C-O P torsion angle is -169.11 (11) degrees and indicates a trans arrangement, whereas the other C-C-O-P torsion angle is 92.48 (16) degrees , showing a gauche conformation. Both six-membered POCCCO rings have good chair-shape conformations. In both the trans and gauche conformations, the catechol O atoms are in the axial sites and the short P=O bonds are equatorially bound. PMID- 26632825 TI - Minor Loops in Major Folds: Enhancer-Promoter Looping, Chromatin Restructuring, and Their Association with Transcriptional Regulation and Disease. AB - The organization and folding of chromatin within the nucleus can determine the outcome of gene expression. Recent technological advancements have enabled us to study chromatin interactions in a genome-wide manner at high resolution. These studies have increased our understanding of the hierarchy and dynamics of chromatin domains that facilitate cognate enhancer-promoter looping, defining the transcriptional program of different cell types. In this review, we focus on vertebrate chromatin long-range interactions as they relate to transcriptional regulation. In addition, we describe how the alteration of boundaries that mark discrete regions in the genome with high interaction frequencies within them, called topological associated domains (TADs), could lead to various phenotypes, including human diseases, which we term as "TADopathies." PMID- 26632828 TI - Synthon preference in a hydrated beta-resorcylic acid structure and its cocrystal with thymine. AB - Multicomponent crystals or cocrystals play a significant role in crystal engineering, the main objective of which is to understand the role of intermolecular interactions and to utilize such understanding in the design of novel crystal structures. Molecules possessing carboxylic acid and amide functional groups are good candidates for forming cocrystals. beta-Resorcylic acid monohydrate, C7H6O4.H2O, (I), crystallizes in the triclinic space group P-1 with one beta-resorcylic acid molecule and one water molecule in the asymmetric unit. The cocrystal thymine-beta-resorcylic acid-water (1/1/1), C5H6N2O2.C7H6O4.H2O, (II), crystallizes in the orthorhombic space group Pca21, with one molecule each of thymine, beta-resorcylic acid and water in the asymmetric unit. All available donor and acceptor atoms in (I) and (II) are utilized for hydrogen bonding. The acid and amide functional groups are well known for the formation of self-complementary acid-acid and amide-amide homosynthons. In (I), an acid-acid homosynthon is observed, while in (II), an amide-acid heterosynthon is present. In (I), the beta-resorcylic acid molecule exhibits the expected intramolecular S(6) motif between the hydroxy and carbonyl O atoms, and an intermolecular R2(2)(8) dimer motif between the carboxylic acid groups; only the former motif is observed in (II). The water solvent molecule in (I) propagates the discrete dimers into two-dimensional hydrogen-bonded sheets. In (II), thymine and beta-resorcylic acid molecules do not form self complementary amide-amide and acid-acid homosynthons; instead, a thymine-beta resorcylic acid heterosynthon is observed. With the help of the water molecule, this heterosynthon is aggregated into a three-dimensional hydrogen-bonded network. The absence of thymine base pairing in (II) might be linked to the availability of additional functional groups and the preference of the donor and acceptor hydrogen-bond combinations. PMID- 26632829 TI - A novel crystal structure of {tris[4-(1H-pyrazol-3-yl-kappaN(2))-3-azabut-3 enyl]amine-kappaN}iron(II) bis(tetrafluoridoborate) methanol monosolvate featuring a low-spin configuration. AB - Mononuclear complexes are good model systems for evaluating the effects of different ligand systems on the magnetic properties of iron(II) centres. A novel crystal structure of the title compound, [Fe(C18H24N10)](BF4)2.CH3OH, with one molecule of methanol per formula unit exhibits a strictly sixfold coordination sphere associated with a low-spin configuration at the metal centre. The incorporated methanol solvent molecule promotes extended hydrogen-bonding networks between the tetrafluoridoborate anions and the cationic units. A less constrained crystal structure regarding close contacts between the tetrafluoridoborate anions and the cationic units allows a spin transition which is inhibited in the previously published hydrate of the title compound. PMID- 26632830 TI - Bis(2-{1-[(2,4,6-trimethylphenyl)imino]ethyl}pyrrol-1-ido kappa(2)N,N')nickel(II): a supramolecular structure formed by C-H...pi(arene) hydrogen bonds. AB - Nitrogen-based polydentate ligands are of interest owing to their flexible complexation to transition metal atoms. For the title compound, [Ni(C15H17N2)2], a transition metal complex formed by the coordination of two identical N,N' bidentate mono(imino)pyrrolyl ligands to an Ni(II) centre, an X-ray crystal diffraction study indicates that the two ligands show an inverted arrangement with respect to one another around the Ni(II) centre, which is located on a crystallographic inversion centre. The planes of the aromatic substituents at the imine N atoms of the ligands show dihedral angles of 85.91 (5) degrees with respect to the NiN4 plane. The Ni-N bond lengths are in the range 1.9072 (15) 1.9330 (15) A and the Nimino-Ni-Npyrrole bite angles are 83.18 (6) degrees . The Ni-Npyrrole bond is substantially shorter than the Ni-Nimino bond. Molecules are linked into an extensive network by means of intermolecular C-H...pi(arene) hydrogen bonds in which every molecule acts both as hydrogen-bond donor and acceptor. The supramolecular assembly takes the form of an infinite two dimensional sheet. PMID- 26632831 TI - A novel one-dimensional metal-organic framework with a MU-cyanido-argentate group: catena-poly[[(5,5'-dimethyl-2,2'-bipyridyl-kappa(2)N,N')silver(I)]-MU cyanido-kappa(2)N:C]. AB - The design and synthesis of metal coordination and supramolecular frameworks containing N-donor ligands and dicyanidoargentate units is of interest due to their potential applications in the fields of molecular magnetism, catalysis, nonlinear optics and luminescence. In the design and synthesis of extended frameworks, supramolecular interactions, such as hydrogen bonding, pi-pi stacking and van der Waals interactions, have been exploited for molecular recognition associated with biological activity and for the engineering of molecular solids.The title compound, [Ag(CN)(C12H12N2)]n, crystallizes with the Ag(I) cation on a twofold axis, half a cyanide ligand disordered about a centre of inversion and half a twofold-symmetric 5,5'-dimethyl-2,2'-bipyridine (5,5'-dmbpy) ligand in the asymmetric unit. Each Ag(I) cation exhibits a distorted tetrahedral geometry; the coordination environment comprises one C(N) atom and one N(C) atom from substitutionally disordered cyanide bridging ligands, and two N atoms from a bidentate chelating 5,5'-dmbpy ligand. The cyanide ligand links adjacent Ag(I) cations to generate a one-dimensional zigzag chain. These chains are linked together via weak nonclassical intermolecular interactions, generating a two dimensional supramolecular network. PMID- 26632832 TI - Five closely related 4-chloro-6,11-dihydro-5H-benzo[b]pyrimido[5,4-f]azepines: similar molecular structures but different supramolecular assemblies. AB - Dibenz[b,f]azepine (DBA) is a privileged 6-7-6 tricyclic ring system of importance in both organic and medicinal chemistry. Benzo[b]pyrimido[5,4 f]azepines (BPAs), which also contain a privileged 6-7-6 ring system, are less well investigated, probably because of a lack of straightforward and versatile methods for their synthesis. A simple and versatile synthetic approach to BPAs based on intramolecular Friedel-Crafts alkylation has been developed. A group of closely-related benzo[b]pyrimido[5,4-f]azepine derivatives, namely (6RS)-4-chloro 6,11-dimethyl-6,11-dihydro-5H-benzo[b]pyrimido[5,4-f]azepine, C14H14ClN3, (I), (6RS)-4-chloro-8-hydroxy-6,11-dimethyl-6,11-dihydro-5H-benzo[b]pyrimido[5,4 f]azepine, C14H14ClN3O, (II), (6RS)-4-chloro-8-methoxy-6,11-dimethyl-6,11-dihydro 5H-benzo[b]pyrimido[5,4-f]azepine, C15H16ClN3O, (III), and (6RS)-4-chloro-8 methoxy-6,11-dimethyl-2-phenyl-6,11-dihydro-5H-benzo[b]pyrimido[5,4-f]azepine, C21H20ClN3O, (IV), has been prepared and their structures compared with the recently published structure [Acosta-Quintero et al. (2015). Eur. J. Org. Chem. pp. 5360-5369] of (6RS)-4-chloro-2,6,8,11-tetramethyl-6,11-dihydro-5H benzo[b]pyrimido[5,4-f]azepine, (V). All five compounds crystallize as racemic mixtures and they have very similar molecular conformations, with the azepine ring adopting a boat-type conformation in each case, although the orientation of the methoxy substituent in each of (III) and (IV) is different. The supramolecular assemblies in (II) and (IV) depend upon hydrogen bonds of the O H...N and C-H...pi(arene) types, respectively, those in (I) and (V) depend upon pi-pi stacking interactions involving pairs of pyrimidine rings, and that in (III) depends upon a pi-pi stacking interaction involving pairs of phenyl rings. Short C-Cl...pi(pyrimidine) contacts are present in (I), (II) and (IV) but not in (III) or (V). PMID- 26632833 TI - A new two-dimensional extended adenine and thiophenecarboxylate mixed-ligand zinc(II) complex: synthesis, structure, thermostability and luminescent properties. AB - The design and preparation of crystalline polymeric materials has attracted increasing attention due to their diverse applications as functional materials in gas storage, separation, catalysis, sensing and photoluminescence. The judicious selection of organic linkers is critical for varying the coordination behaviour of the metal ions and determining the overall characteristics of the networks. A new adenine-based Zn(II) coordination polymer, [Zn(C6H2O4S)(C5H5N5)]n or [Zn(tdc)(9H-ade)] (H2tdc is thiophene-2,5-dicarboxylic acid and ade is adenine), has been prepared hydrothermally and the crystal structure exhibits in its packing two-dimensional (4,4) grid sheets parallel to the ab plane, featuring two distinct square cavities delimited by the two types of ligands and the Zn(II) ions with the dimensions 6.6 * 6.6 and 10.2 * 10.2 A (based on the Zn...Zn distance). The title complex shows enhanced photoluminescence at 378 nm compared to the free ligands, suggesting that the coordination of H2tdc or adenine to the metal centre effectively increases the rigidity of the ligands and reduces the energy loss by radiative decay of intraligand excited states. PMID- 26632834 TI - Structural characterization of the aquaporin inhibitor 2-nicotinamido-1,3,4 thiadiazole. AB - Nicotinamides are a class of compounds with a wide variety of applications, from use as antimicrobial agents to inhibitors of biological processes. These compounds are also cofactors, which are necessary components of metabolic processes. Structural modification gives rise to the activities observed. Similarly, 1,3,4-thiadiazoles have been shown to possess antioxidant, antimicrobial, or anti-inflammatory biological activity. To take advantage of each of the inherent characteristics of the two aforementioned functional groups, 2-nicotinamido-1,3,4-thiadiazole, C8H6N4OS, was synthesized. Since defining chemical connectivity is paramount in understanding biological activity, in this report, the structural characterization of 2-nicotinamido-1,3,4-thiadiazole has been carried out using X-ray crystallographic methods. The NMR-derived assignments were made possible by utilizing one- (1D) and two-dimensional (2D) NMR techniques. In addition, UV-Visible and IR spectroscopies, and elemental analysis were used to fully characterize the product synthesized by the one-step reaction between nicotinoyl chloride hydrochloride and 2-amino-1,3,4-thiadiazole. Computational parameters related to blood-brain barrier permeability are also presented. PMID- 26632835 TI - Mometasone furoate revisited, or how did the hydrate get in the bottle? AB - The redetermined structure of 9alpha,21-dichloro-11beta,17alpha-dihydroxy-16alpha methyl-3,20-dioxopregna-1,4-dien-17-yl furan-2-carboxylate monohydrate, C27H32Cl2O7.H2O, at 100 K has triclinic (P1) symmetry. The structure displays O H...O hydrogen bonding, which gives rise to infinite sheets extending parallel to the [110] plane. The previously published structure [Chen et al. (2005). J. Pharm. Sci. 94, 2496-2509] was determined at room temperature and no significant anomalous signal was present. Data for the structure presented in this study were collected at low temperature and the absolute configuration could be established based solely on anomalous diffraction. Another point of interest is that the structure determined in this study is that of the monohydrate, even though the crystal was harvested from a bottle of nasal spray that was supposed to contain exclusively crystals of the anhydrous form. PMID- 26632836 TI - A zwitterion produced by a strong intramolecular N->B interaction in 1-hydroxy-2 (pyridin-2-ylcarbonyl)benzo[d][1,2,3]diazaborinine. AB - 2-Acylated 2,3,1-benzodiazaborines can display unusual structures and reactivities. The crystal structure analysis of the boron heterocycle obtained by condensing 2-formylphenylboronic acid and picolinohydrazide reveals it to be an N >B-chelated zwitterionic tetracycle (systematic name: 1-hydroxy-11-oxo 9,10,17lambda(5)-triaza-1lambda(4)-boratetracyclo[8.7.0.0(2,7).0(12,17)]heptadeca 3,5,7,12,14,16-hexaen-17-ylium-1-uide), C13H10BN3O2, produced by the intramolecular addition of the Lewis basic picolinoyl N atom of 1-hydroxy-2 (pyridin-2-ylcarbonyl)benzo[d][1,2,3]diazaborinine to the boron heterocycle B atom acting as a Lewis acid. Neither of the other two pyridinylcarbonyl isomers (viz. nicotinoyl and isonicotinoyl) are able to adopt such a structure for geometric reasons. A favored yet reversible chelation equilibrium provides an explanation for the slow D2O exchange observed for the OH resonance in the (1)H NMR spectrum, as well as for its unusual upfield chemical shift. Deuterium exchange may take place solely in the minor open (unchelated) species present in solution. PMID- 26632837 TI - Novel one- and two-dimensional Zn(II) coordination polymers based on a versatile 3,6-bis(pyridin-4-yl)phenanthrene-9,10-dione ligand. AB - Two new Zn(II) coordination polymers, namely, catena-poly[[dibromidozinc(II)]-MU [3,6-bis(pyridin-4-yl)phenanthrene-9,10-dione-kappa(2)N:N']], [ZnBr2(C24H14N2O2)]n, (1), and poly[[bromido[MU3-10-hydroxy-3,6-bis(pyridin-4 yl)phenanthren-9-olato-kappa(3)N:N':O(9)]zinc(II)] hemihydrate], {[ZnBr(C24H15N2O2)].0.5H2O}n, (2), have been synthesized through hydrothermal reaction of ZnBr2 and a 60 degrees angular phenanthrenedione-based linker, i.e. 3,6-bis(pyridin-4-yl)phenanthrene-9,10-dione, in different solvent systems. Single-crystal analysis reveals that polymer (1) features one-dimensional zigzag chains connected by weak C-H...pi and pi-pi interactions to form a two dimensional network. The two-dimensional networks are further stacked in an ABAB fashion along the a axis through C-H...O hydrogen bonds. Layers A and B comprise left- and right-handed helical chains, respectively. Coordination polymer (2) displays a wave-like two-dimensional layered structure with helical chains. In this compound, there are two opposite helical -Zn-HL- chains [HL is 10-hydroxy 3,6-bis(pyridin-4-yl)phenanthren-9-olate] in adjacent layers. The layers are packed in an ABAB sequence and are further connected through O-H...Br and O-H...O hydrogen-bond interactions to form a three-dimensional framework. In (1) and (2), the mutidentate L and HL ligands exhibits different coordination modes. PMID- 26632838 TI - Oxidative degradation of the organometallic iron(II) complex [Fe{bis[3-(pyridin-2 yl)-1H-imidazol-1-yl]methane}(MeCN)(PMe3)](PF6)2: structure of the ligand decomposition product trapped via coordination to iron(II). AB - Iron is of interest as a catalyst because of its established use in the Haber Bosch process and because of its high abundance and low toxicity. Nitrogen heterocyclic carbenes (NHC) are important ligands in homogeneous catalysis and iron-NHC complexes have attracted increasing attention in recent years but still face problems in terms of stability under oxidative conditions. The structure of the iron(II) complex [1,1'-bis(pyridin-2-yl)-2,2-bi(1H-imidazole)-kappaN(3)][3,3' bis(pyridin-2-yl-kappaN)-1,1'-methanediylbi(1H-imidazol-2-yl kappaC(2))](trimethylphosphane-kappaP)iron(II) bis(hexafluoridophosphate), [Fe(C17H14N6)(C16H12N6)(C3H9P)](PF6)2, features coordination by an organic decomposition product of a tetradentate NHC ligand in an axial position. The decomposition product, a C-C-coupled biimidazole, is trapped by coordination to still-intact iron(II) complexes. Insights into the structural features of the organic decomposition products might help to improve the stability of oxidation catalysts under harsh conditions. PMID- 26632839 TI - Structures and packing of ferrocenylmethyl methacrylate and ferrocene-1,1' diylbis(methylene) dimethacrylate. AB - Electroactive metallocene polymers are of interest due to the possibility that they offer a muscle-like response, and in gel systems very large volume changes are possible. The ferrocenyl moiety exhibits physical and electrochemical stability of the neutral and oxidized forms and could be a candidate for use as the redox-active group in these materials. The title compounds, [Fe(C5H5)(C10H11O2)], (I), and [Fe(C10H11O2)2], (II), comprise a typical ferrocene core with coplanar and approximately eclipsed cyclopentadienyl (Cp) rings. In (I), there is a single methyl methacrylate substituent, with the other Cp ring unsubstituted. In (II), a methyl methacrylate substituent on each Cp ring completes the structure. In both compounds, there is an s-trans geometry of the vinyl and carbonyl components of the methacrylate group. Inversion dimers formed through C-H...O contacts dominate the crystal packing of both molecules. Weak C H...pi(ring) contacts and, in the case of (I), an unusual C-H...pi(alkene) contact further stabilize the structures. PMID- 26632840 TI - Structural aspects of two alpha-dihydrazones displaying a complete survey of intermolecular interactions. AB - The compounds (2'E,2'E)-2,2'-(propane-1,2-diylidene)bis[1-(2 nitrophenyl)hydrazine], C15H14N6O4, (I), and (2Z,3Z)-ethyl 3-[2-(2 nitrophenyl)hydrazinylidene]-2-[2-(4-nitrophenyl)hydrazinylidene]butanoate tetrahydrofuran hemisolvate, C18H18N6O6.0.5C4H8O, (II), are puzzling outliers deviating from a general synthetic route aimed at the preparation of substituted pyrazoles. Possible reasons for this outcome, which is exceptional in an otherwise firmly established synthetic procedure, are analyzed. Compound (I) is unsolvated, while compound (II) crystallizes with a tetrahydrofuran solvent molecule lying on an inversion centre. The ethoxycarbonyl chain of (II), in turn, appears disordered into two equally populated (50%) moieties. In both structures, a plethora of different commonly occurring weak intermolecular interactions [viz. pi(phenyl)...pi(phenyl), pi(C=N)...pi(C=N), pi(phenyl)...pi(C=N), N-H...O and C H...O] appear responsible for the crystal stability. Much less common are the short O(nitro)...O(nitro) contacts which are observed in the structure of (I), an example of unusual 'electron donor-acceptor' (EDA) interactions. PMID- 26632841 TI - The first N-terminal unprotected (Gly-Aib)n peptide: H-Gly-Aib-Gly-Aib-OtBu. AB - Glycine (Gly) is incorporated in roughly half of all known peptaibiotic (nonribosomally biosynthesized antibiotic peptides of fungal origin) sequences and is the residue with the greatest conformational flexibility. The conformational space of Aib (alpha-aminoisobutyric acid) is severely restricted by the second methyl group attached to the Calpha atom. Most of the crystal structures containing Aib are N-terminal protected. Deprotection of the N- or C terminus of peptides may alter the hydrogen-bonding scheme and/or the structure and may facilitate crystallization. The structure reported here for glycyl-alpha aminoisobutyrylglycyl-alpha-aminoisobutyric acid tert-butyl ester, C16H30N4O5, describes the first N-terminal-unprotected (Gly-Aib)n peptide. The achiral peptide could form an intramolecular hydrogen bond between the C=O group of Gly1 and the N-H group of Aib4. This hydrogen bond is found in all tetrapeptides and N terminal-protected tripeptides containing Aib, apart from one exception. In the present work, this hydrogen bond is not observed (N...O = 5.88 A). Instead, every molecule is hydrogen bonded to six other symmetry-related molecules with a total of eight hydrogen bonds per molecule. The backbone conformation starts in the right-handed helical region (and the left-handed helical region for the inverted molecule) and reverses the screw sense in the last two residues. PMID- 26632842 TI - A Global Analysis of Deforestation in Moist Tropical Forest Protected Areas. AB - Protected areas (PAs) have been established to conserve tropical forests, but their effectiveness at reducing deforestation is uncertain. To explore this issue, we combined high resolution data of global forest loss over the period 2000-2012 with data on PAs. For each PA we quantified forest loss within the PA, in buffer zones 1, 5, 10 and 15 km outside the PA boundary as well as a 1 km buffer within the PA boundary. We analysed 3376 tropical and subtropical moist forest PAs in 56 countries over 4 continents. We found that 73% of PAs experienced substantial deforestation pressure, with >0.1% a(-1) forest loss in the outer 1 km buffer. Forest loss within PAs was greatest in Asia (0.25% a(-1)) compared to Africa (0.1% a(-1)), the Neotropics (0.1% a(-1)) and Australasia (Australia and Papua New Guinea; 0.03% a(-1)). We defined performance (P) of a PA as the ratio of forest loss in the inner 1 km buffer compared to the loss that would have occurred in the absence of the PA, calculated as the loss in the outer 1 km buffer corrected for any difference in deforestation pressure between the two buffers. To remove the potential bias due to terrain, we analysed a subset of PAs (n = 1804) where slope and elevation in inner and outer 1 km buffers were similar (within 1 degrees and 100 m, respectively). We found 41% of PAs in this subset reduced forest loss in the inner buffer by at least 25% compared to the expected inner buffer forest loss (P<0.75). Median performance (P) of subset reserves was 0.87, meaning a reduction in forest loss within the PA of 13%. We found PAs were most effective in Australasia (P = 0.16), moderately successful in the Neotropics (P = 0.72) and Africa (p = 0.83), but ineffective in Asia (P = 1). We found many countries have PAs that give little or no protection to forest loss, particularly in parts of Asia, west Africa and central America. Across the tropics, the median effectiveness of PAs at the national level improved with gross domestic product per capita. Whilst tropical and subtropical moist forest PAs do reduce forest loss, widely varying performance suggests substantial opportunities for improved protection, particularly in Asia. PMID- 26632843 TI - Aetiology-Specific Estimates of the Global and Regional Incidence and Mortality of Diarrhoeal Diseases Commonly Transmitted through Food. AB - BACKGROUND: Diarrhoeal diseases are major contributors to the global burden of disease, particularly in children. However, comprehensive estimates of the incidence and mortality due to specific aetiologies of diarrhoeal diseases are not available. The objective of this study is to provide estimates of the global and regional incidence and mortality of diarrhoeal diseases caused by nine pathogens that are commonly transmitted through foods. METHODS AND FINDINGS: We abstracted data from systematic reviews and, depending on the overall mortality rates of the country, applied either a national incidence estimate approach or a modified Child Health Epidemiology Reference Group (CHERG) approach to estimate the aetiology-specific incidence and mortality of diarrhoeal diseases, by age and region. The nine diarrhoeal diseases assessed caused an estimated 1.8 billion (95% uncertainty interval [UI] 1.1-3.3 billion) cases and 599,000 (95% UI 472,000 802,000) deaths worldwide in 2010. The largest number of cases were caused by norovirus (677 million; 95% UI 468-1,153 million), enterotoxigenic Escherichia coli (ETEC) (233 million; 95% UI 154-380 million), Shigella spp. (188 million; 95% UI 94-379 million) and Giardia lamblia (179 million; 95% UI 125-263); the largest number of deaths were caused by norovirus (213,515; 95% UI 171,783 266,561), enteropathogenic E. coli (121,455; 95% UI 103,657-143,348), ETEC (73,041; 95% UI 55,474-96,984) and Shigella (64,993; 95% UI 48,966-92,357). There were marked regional differences in incidence and mortality for these nine diseases. Nearly 40% of cases and 43% of deaths caused by these nine diarrhoeal diseases occurred in children under five years of age. CONCLUSIONS: Diarrhoeal diseases caused by these nine pathogens are responsible for a large disease burden, particularly in children. These aetiology-specific burden estimates can inform efforts to reduce diarrhoeal diseases caused by these nine pathogens commonly transmitted through foods. PMID- 26632844 TI - Functional Metagenomics of the Bronchial Microbiome in COPD. AB - The course of chronic obstructive pulmonary disease (COPD) is frequently aggravated by exacerbations, and changes in the composition and activity of the microbiome may be implicated in their appearance. The aim of this study was to analyse the composition and the gene content of the microbial community in bronchial secretions of COPD patients in both stability and exacerbation. Taxonomic data were obtained by 16S rRNA gene amplification and pyrosequencing, and metabolic information through shotgun metagenomics, using the Metagenomics RAST server (MG-RAST), and the PICRUSt (Phylogenetic Investigation of Communities by Reconstruction of Unobserved States) programme, which predict metagenomes from 16S data. Eight severe COPD patients provided good quality sputum samples, and no significant differences in the relative abundance of any phyla and genera were found between stability and exacerbation. Bacterial biodiversity (Chao1 and Shannon indexes) did not show statistical differences and beta-diversity analysis (Bray-Curtis dissimilarity index) showed a similar microbial composition in the two clinical situations. Four functional categories showed statistically significant differences with MG-RAST at KEGG level 2: in exacerbation, Cell growth and Death and Transport and Catabolism decreased in abundance [1.6 (0.2 2.3) vs 3.6 (3.3-6.9), p = 0.012; and 1.8 (0-3.3) vs 3.6 (1.8-5.1), p = 0.025 respectively], while Cancer and Carbohydrate Metabolism increased [0.8 (0-1.5) vs 0 (0-0.5), p = 0.043; and 7 (6.4-9) vs 5.9 (6.3-6.1), p = 0.012 respectively]. In conclusion, the bronchial microbiome as a whole is not significantly modified when exacerbation symptoms appear in severe COPD patients, but its functional metabolic capabilities show significant changes in several pathways. PMID- 26632846 TI - Role of Focal Therapy with High-Intensity Focused Ultrasound in the Management of Clinically Localized Prostate Cancer. AB - Overtreatment of prostate cancer (PC) remains one of the main burdens in uro oncology. Focal therapy may be a reasonable alternative with less side effects and morbidity. Application of high-intensity focused ultrasound (HIFU) induces immediate and irreversible coagulation. The treatment leads to consecutive necrosis with sharply delineated margins, making HIFU a promising tool for the focal therapy of localized PC. Unlike radiation, the treatment leaves no collateral damage outside of the heated tissue, allowing repeated use of HIFU, if necessary. In case of non-organ-confined relapse, additional radical salvage therapy can be performed. This review gives an overview of the existing evidence on focal HIFU. Today, 3 HIFU devices are approved for the treatment of localized PC: SonablateTM, AblathermTM and the FocalOneTM device. In summary, the first published results of focal HIFU are promising. The quality of life and potency of the patients are well preserved. Therefore, HIFU treatment, and especially focal ablation of tumor foci, seems to be a safe alternative to standard treatment, with low side effects. The oncologic results seem satisfactory but need further follow-up to validate this practice of PC control. PMID- 26632845 TI - Newly Constructed Network Models of Different WNT Signaling Cascades Applied to Breast Cancer Expression Data. AB - INTRODUCTION: WNT signaling is a complex process comprising multiple pathways: the canonical beta-catenin-dependent pathway and several alternative non canonical pathways that act in a beta-catenin-independent manner. Representing these intricate signaling mechanisms through bioinformatic approaches is challenging. Nevertheless, a simplified but reliable bioinformatic WNT pathway model is needed, which can be further utilized to decipher specific WNT activation states within e.g. high-throughput data. RESULTS: In order to build such a model, we collected, parsed, and curated available WNT signaling knowledge from different pathway databases. The data were assembled to construct computationally suitable models of different WNT signaling cascades in the form of directed signaling graphs. This resulted in four networks representing canonical WNT signaling, non-canonical WNT signaling, the inhibition of canonical WNT signaling and the regulation of WNT signaling pathways, respectively. Furthermore, these networks were integrated with microarray and RNA sequencing data to gain deeper insight into the underlying biology of gene expression differences between MCF-7 and MDA-MB-231 breast cancer cell lines, representing weakly and highly invasive breast carcinomas, respectively. Differential genes up regulated in the MDA-MB-231 compared to the MCF-7 cell line were found to display enrichment in the gene set originating from the non-canonical network. Moreover, we identified and validated differentially regulated modules representing canonical and non-canonical WNT pathway components specific for the aggressive basal-like breast cancer subtype. CONCLUSIONS: In conclusion, we demonstrated that these newly constructed WNT networks reliably reflect distinct WNT signaling processes. Using transcriptomic data, we shaped these networks into comprehensive modules of the genes implicated in the aggressive basal-like breast cancer subtype and demonstrated that non-canonical WNT signaling is important in this context. The topology of these networks can be further refined in the future by integration with complementary data such as protein-protein interactions, in order to gain greater insight into signaling processes. PMID- 26632847 TI - Estimated Prevalence of Autism and Other Developmental Disabilities Following Questionnaire Changes in the 2014 National Health Interview Survey. AB - OBJECTIVES: The developmental disabilities questions in the 2014 National Health Interview Survey (NHIS) were changed from previous years, including question reordering and a new approach to asking about autism spectrum disorder (ASD). This report examines survey-based estimates of the lifetime prevalence of ASD, intellectual disability (ID), and any other developmental delay (other DD) following the inclusion of a standalone ASD question, the inclusion of specific diagnoses in the ASD question, and the ASD question preceding the other DD question, and compares them with estimates from previous years. METHODS: In NHIS, one child is randomly selected from each family to be the subject of detailed questions on health conditions, functional limitations, and health care utilization. Parents are asked if a doctor or health professional had ever told them that their child had each of a series of developmental disabilities. Prevalence estimates of ASD, ID, and other DD for children aged 3-17 years were calculated using data collected in 2011-2014. RESULTS: The estimated prevalence of ASD based on 2014 data was 2.24%, a significant increase from the estimated annualized prevalence of 1.25% based on 2011-2013 data. In contrast, the prevalence of other DD declined significantly from 4.84% based on 2011-2013 data to 3.57% based on 2014 data. The prevalence of ID did not significantly change from 2011-2013 (1.27%) to 2014 (1.10%). The prevalence of having any of the three conditions was constant across survey years. CONCLUSIONS: The revised question ordering and new approach to asking about developmental disabilities in the 2014 NHIS likely affected the prevalence estimates of these conditions. In previous years, it is likely that some parents of children diagnosed with ASD reported this developmental disability as other DD instead of, or in addition to, ASD. Following these changes, the 2014 ASD estimate was more similar to ASD prevalence estimates from other sources. PMID- 26632848 TI - National Influenza Vaccination Week--December 6-12, 2015. AB - The U.S. Department of Health and Human Services, CDC, state and local health departments, and other partners will observe National Influenza Vaccination Week (NIVW) during December 6-12, 2015, with educational and promotional activities across the country. PMID- 26632849 TI - Physiological determinants of wrestling success in elite Iranian senior and junior Greco-Roman wrestlers. AB - BACKGROUND: Fitness profile and the physiological determinants of wrestling success in Greco-Roman wrestlers were investigated. METHODS: The wrestlers from the Iranian National Greco-Roman Team (14 junior wrestlers and 12 senior wrestlers) participated in this study. The junior and senior wrestlers were divided into two groups of successful and less successful athletes based on their performance during the previous wrestling season. The wrestlers were evaluated for anthropometric measurements, flexibility, muscular endurance, explosive power, peak and mean power of upper and lower limbs, cardiovascular endurance, running speed, agility, and muscular strength. RESULTS: In senior wrestler, significant differences in favor of the successful wrestlers were found for relative grip strength (P<0.01), pull-ups (P<0.01), peak and mean anaerobic power of upper limbs (P<0.05), and oxygen consumption (O2) corresponding to ventilatory threshold (VT). The results of discriminant analysis revealed that the relative grip strength, pull-ups, and mean anaerobic power were the most important variables separating the groups. In junior wrestlers, the successful wrestlers had significantly more relative grip strength (P<0.01), pull-ups (P<0.01), peak and mean anaerobic power of upper limbs (P<0.05), and peak anaerobic power of lower limbs (P<0.05). However, the results of discriminant analysis showed that the model could not successfully determine group membership. CONCLUSIONS: In summary, muscular strength, muscular endurance, and anaerobic capacity are the most important variables in Greco-Roman wrestling and athletes must pay particular attention to improving these variables to be a successful wrestler. PMID- 26632850 TI - Geographic enrolment of the top 100 in athletics running events from 1996 to 2012. AB - BACKGROUND: It is widely accepted in the literature that athletes of West African origins achieve the best sprint performances, while athletes originating from East Africa are the most efficient at long distances. So far, no study has measured the evolution of these groups' contribution from 100 m to the marathon. METHODS: Speed, morphology and geographic origin of the top 100 male and female athletes (from 100 m to the marathon) were collected and analyzed over the 1996 2012 period. RESULTS: The amount of male sprinters (100, 200 and 400 m) originating from West Africa increased from 57.7% in 1996 to 72.3% in 2012, while female sprinters from West Africa increased from 55% to 65% over the same period. This contribution gradually increases from 400 m to 100 m for both sexes. For long-distance runs (3000 m, 10,000 m and marathon), male athletes from East Africa represented 32% in 1996 ; this proportion increased to 65.7% in 2012. It also increased over the same period from 9% to 39% for women. In addition, male and female sprinters originating from West Africa have a significantly higher Body Mass Index (BMI, P<0.05) than athletes of other geographic origin. Conversely, long distances runners' with an East African origin have a significantly lower BMI (P<0.05). CONCLUSIONS: Running best performances are dominated by a few groups including runners with West African ancestry for the sprint distances and East African runners for the long distances. This dominance strengthened from 1996 to 2012 for both sexes in parallel with a reduction of Caucasian and Asian athletes contribution and in relation to muscle mass repartition. PMID- 26632851 TI - An association of cocoa consumption with improved physical fitness and decreased muscle damage and oxidative stress in athletes. AB - BACKGROUND: Several studies have demonstrated the protective effects of cocoa consumption, due to its anti-inflammatory and antioxidant properties. Acute exercise induces oxidative stress and causes muscular damage during training. This study was designed to examine the effect of cocoa consumption on the markers of muscle damage, oxidative stress and physical fitness in professional soccer players. METHODS: Fifteen players (15-18 years old) were included in the study. Biochemical parameters, markers of muscle damage and oxidative stress, and physical performance were evaluated before and after cocoa consumption. Biochemical parameters determined the healthy metabolic status of the study group; biomarkers of muscle and oxidative damage were measured in blood to establish muscle and redox status. RESULTS: However, high levels of biomarkers of muscle damage were detected. Interestingly, cocoa consumption decreased the muscle damage biomarkers of CK and LDH by 39.4% and 23.03%, respectively. The redox status was modified by a decrease in oxidative damage (carbonyl groups, 26.31%; thiol groups, 27.52%; MDA, 32.42%) and an increase in total antioxidant capacity (15.98%) and GSH-Px activity (26.37%). In addition, we observed an increase in physical performance by 4% in the Cooper Test. CONCLUSIONS: Our findings suggest that a short period of cocoa consumption could be useful in maintaining a good physical fitness, due to the favourable effects on muscle and redox status in athletes during exhaustive exercise. PMID- 26632852 TI - Opthalmic outcomes should be included in future randomized control trials comparing carotid artery stenting vs. carotid endarterectomy in asymptomatic carotid disease. PMID- 26632853 TI - Sixteenth European Venous Forum Annual Meeting, St. Petersburg. PMID- 26632854 TI - Enhanced Bactericidal Activity of Silver Thin Films Deposited via Aerosol Assisted Chemical Vapor Deposition. AB - Silver thin films were deposited on SiO2-barrier-coated float glass, fluorine doped tin oxide (FTO) glass, Activ glass, and TiO2-coated float glass via AACVD using silver nitrate at 350 degrees C. The films were annealed at 600 degrees C and analyzed by X-ray powder diffraction, X-ray photoelectron spectroscopy, UV/vis/near-IR spectroscopy, and scanning electron microscopy. All the films were crystalline, and the silver was present in its elemental form and of nanometer dimension. The antibacterial activity of these samples was tested against Escherichia coli and Staphylococcus aureus in the dark and under UV light (365 nm). All Ag-deposited films reduced the numbers of E. coli by 99.9% within 6 h and the numbers of S. aureus by 99.9% within only 2 h. FTO/Ag reduced bacterial numbers of E. coli to below the detection limit after 60 min and caused a 99.9% reduction of S. aureus within only 15 min of UV irradiation. Activ/Ag reduced the numbers of S. aureus by 66.6% after 60 min and TiO2/Ag killed 99.9% of S. aureus within 60 min of UV exposure. More remarkably, we observed a 99.9% reduction in the numbers of E. coli within 6 h and the numbers of S. aureus within 4 h in the dark using our novel TiO2/Ag system. PMID- 26632855 TI - Assessment and Implications of Scattered Microbeam and Broadbeam Synchrotron Radiation for Bystander Effect Studies. AB - Synchrotron radiation is an excellent tool for investigating bystander effects in cell and animal models because of the well-defined and controllable configuration of the beam. Although synchrotron radiation has many advantages for such studies compared to conventional radiation, the contribution of dose exposure from scattered radiation nevertheless remains a source of concern. Therefore, the influence of scattered radiation on the detection of bystander effects induced by synchrotron radiation in biological in vitro models was evaluated. Radiochromic XRQA2 film-based dosimetry was employed to measure the absorbed dose of scattered radiation in cultured cells at various distances from a field exposed to microbeam radiotherapy and broadbeam X-ray radiation. The level of scattered radiation was dependent on the distance, dose in the target zone and beam mode. The number of gamma-H2AX foci in cells positioned at the same target distances was measured and used as a biodosimeter to evaluate the absorbed dose. A correlation of absorbed dose values measured by the physical and biological methods was identified. The gamma-H2AX assay successfully quantitated the scattered radiation in the range starting from 10 mGy and its contribution to the observed radiation-induced bystander effect. PMID- 26632856 TI - MicroRNA-145 Modulates Tumor Sensitivity to Radiation in Prostate Cancer. AB - Radiation therapy prior to surgery has increasingly become the standard of care for locally advanced prostate cancer, however tumor radioresistance remains a major clinical problem. While restoration of microRNA-145 (miR-145) expression reduces chemoradioresistance in glioblastoma and suppress prostate cancer proliferation, migration and invasion, the role of miR-145 in response to radiation therapy for prostate cancer is still unknown. The aim of this study was to investigate the role of miR-145 in determining the tumor response to radiation treatment in prostate cancer. Human prostate cancer cells LNCAP and PC3 were transfected with miR-145 mimic. Clonogenic assay was used to determine whether overexpression of miR-145 could alter radiation response in vitro. Immunofluorescence of gamma-H2AX and flow cytometric analysis of phosphorylated histone H3 were performed to investigate the potential mechanisms contributing to the enhanced radiation-induced cell killing induced by miR-145. In addition, a qPCR-based array was used to detect the possible miR-145-mediated regulated genes involved. Tumor growth delay assays and survival curves were then analyzed in an animal model to investigate whether miR-145 induced radiosensitivity in vivo. Furthermore, miR-145 expression was assessed in 30 prostate tumor tissue biopsies taken prior to neoadjuvant radiotherapy using miRNA arrays. Our current study suggested that ectopic expression of miR-145 significantly sensitized prostate cancer cells to radiation and we used gamma-H2AX phosphorylation as a surrogate marker of radiotherapy response versus miR-145 expression levels. We observed significantly more foci per cell in the group treated with miR-145 and radiation. In addition, mitotic catastrophe was significantly increased in cells receiving miR-145 and radiation. The above results suggest that miR-145 appears to reduced the efficiency of the repair of radiation-induced DNA double-strand breaks in cells. A detailed examination of the involvement of the DNA repair pathway showed that miR-145 reduced the expression of 10 genes involved in DNA repair according to a qPCR-based array data. Irradiation of subcutaneous PC3 tumors in mice treated with R11-miR-145 (a cellular permeable peptide, previously reported) resulted in an increase in radiation-induced tumor growth delay and lived the longest after combination treatment. Moreover, miR-145 expression was significantly increased in patients demonstrating good response (PSA < 2.0 ng/ml/year) to neoadjuvant radiotherapy, while expression of the miR-145 regulated DNA repair genes was significantly decreased. In conclusion, these data suggest a possible mechanism for miR-145 radiosensitivity, potentially through down regulating of DNA repair. This novel study shows a role for miR-145 in modulating radiosensitivity in vivo and highlights the need for further study investigating the potential role of miR-145 as both a predictive marker of response and a novel therapeutic agent with which to enhance the efficacy of radiation therapy. PMID- 26632857 TI - Whole-Lung Irradiation Results in Pulmonary Macrophage Alterations that are Subpopulation and Strain Specific. AB - Exposure of the lung to radiation produces injury and inflammatory responses that result in microenvironmental alterations, which can promote the development of pneumonitis and/or pulmonary fibrosis. It has been shown that after other toxic insults, macrophages become phenotypically polarized in response to microenvironmental signals, orchestrating the downstream inflammatory responses. However, their contribution to the development of the late consequences of pulmonary radiation exposure remains unclear. To address this issue, fibrosis prone C57BL/6J mice or pneumonitis-prone C3H/HeJ mice were whole-lung irradiated with 0 or 12.5 Gy and lung digests were collected between 3 and 26 weeks after radiation exposure. CD45(+) leukocytes were isolated and characterized by flow cytometry, and alveolar, interstitial and infiltrating macrophages were also detected. Ly6C, expressed by pro-inflammatory monocytes and macrophages, and mannose receptor (CD206), a marker of alternative activation, were assessed in each subpopulation. While the total number of pulmonary macrophages was depleted at 3 weeks after lung irradiation relative to age-matched controls in both C57 and C3H mice, identification of discrete subpopulations showed that this loss in cell number occurred in the alveolar, but not the interstitial or infiltrating, subsets. In the alveolar macrophages of both C57 and C3H mice, this correlated with a loss in the proportion of cells that expressed CD206 and F4/80. In contrast, in interstitial and infiltrating macrophages, the proportion of cells expressing these markers was increased at several time points after irradiation, with this response generally more pronounced in C3H mice. Radiation exposure was also associated with elevations in the proportion of alveolar and interstitial macrophage subpopulations expressing Ly6C and F4/80, with this response occurring at earlier time points in C57 mice. Although the radiation dose used in this study was not isoeffective for the inflammatory response in the two strains, the differences observed in the responses of these discrete macrophage populations between the fibrosis-prone versus pneumonitis-prone mice nonetheless suggest a possible role for these cells in the development of long-term consequences of pulmonary radiation exposure. PMID- 26632858 TI - Comparison of the transcutaneous bilirubinometers BiliCare and Minolta JM-103 in late preterm and term neonates. AB - OBJECTIVES: To assess the agreement of transcutaneous bilirubin (TcB) measurement with the BilicareTM System in comparison to TcB measured with JM-103TM and total serum bilirubin (TSB). METHODS: Caucasian infants with gestational age >=35 weeks with non-hemolytic jaundice received TcB measurement with both BilicareTM and JM 103TM devices. TSB was also obtained in infants at risk of phototherapy. RESULTS: We studied 458 infants measuring TcB with BilicareTM and JM-103TM, correlating the results and with TSB. The mean difference +/- 2SD between BilicareTM and JM 103TM TcB was 2.02 +/- 4.46 mg/dL and decreased from 2.88 +/- 3.17 to 1.20 +/- 4.55, and to -0.95 +/- 4.58 mg/dL at mild, moderate and high TcB values, respectively. CONCLUSIONS: BilicareTM and JM-103TM TcB measurements are well correlated, but BilicareTM over-estimates TcB for mild and moderate values and under-estimates it for high values compared to JM-103TM. This could increase the prescription of TSB measurements for less serious cases and decrease them in the most worrisome. PMID- 26632859 TI - General Protein Data Bank-Based Collective Variables for Protein Folding. AB - New, automated forms of data analysis are required to understand the high dimensional trajectories that are obtained from molecular dynamics simulations on proteins. Dimensionality reduction algorithms are particularly appealing in this regard as they allow one to construct unbiased, low-dimensional representations of the trajectory using only the information encoded in the trajectory. The downside of this approach is that a different set of coordinates are required for each different chemical system under study precisely because the coordinates are constructed using information from the trajectory. In this paper, we show how one can resolve this problem by using the sketch-map algorithm that we recently proposed to construct a low-dimensional representation of the structures contained in the protein data bank. We show that the resulting coordinates are as useful for analyzing trajectory data as coordinates constructed using landmark configurations taken from the trajectory and that these coordinates can thus be used for understanding protein folding across a range of systems. PMID- 26632860 TI - Colchicine for cardiovascular medicine. AB - Colchicine is an ancient drug with anti-inflammatory effects especially on neutrophils. These cells are critically involved in pericardial and atherosclerotic plaques inflammation, thus representing a new potential target for new therapies to treat and especially prevent cardiovascular events such as pericarditis, atrial fibrillation triggered by inflammation and ischemic vascular events. The aim of the present review is to briefly review the essential pharmacology and explore potential efficacy and safety of colchicine for new emerging cardiovascular indications. PMID- 26632862 TI - Synthesis, Biological Evaluation, and Utility of Fluorescent Ligands Targeting the MU-Opioid Receptor. AB - Fluorescently labeled ligands are useful pharmacological research tools for studying receptor localization, trafficking, and signaling processes via fluorescence imaging. They are also employed in fluorescent binding assays. This study is centered on the design, synthesis, and pharmacological evaluation of fluorescent probes for the opioid receptors, for which relatively few non peptidic fluorescent probes currently exist. The known MU-opioid receptor (MOR) partial agonist, buprenorphine, was structurally elaborated to include an amidoalkylamine linker moiety that was coupled with a range of fluorophores to afford new fluorescent probes. All compounds proved to be selective MOR antagonists. Confocal fluorescence microscopy studies revealed that the probe incorporating a sulfonated cyanine-5 fluorophore was the most appropriate for imaging studies. This ligand was subsequently employed in an automated fluorescence-based competition binding assay, allowing the pKi values of several well-known opioid ligands to be determined. Thus, this new probe will prove useful in future studies of MOR receptor pharmacology. PMID- 26632863 TI - Catalytic Asymmetric Iterative/Domino Aldehyde Cross-Aldol Reactions for the Rapid and Flexible Synthesis of 1,3-Polyols. AB - We report here catalytic asymmetric iterative and domino cross-aldol reactions between aldehydes, endowed with a high level of robustness, flexibility, and generality. A Cu(I)-DTBM-SEGPHOS complex catalyzes an asymmetric cross-aldol reaction between acceptor aldehydes and boron enolates derived from donor aldehydes, which are generated through Ir-catalyzed isomerization of allyloxyboronates. The unit process can be repeated using the aldol products in turn as acceptor substrates for the subsequent asymmetric aldol reaction. The donor aldehydes and stereoselectivity can be flexibly switched in a stepwise manner for the double-aldol reaction. Furthermore, asymmetric triple- and quadruple-aldol reactions are possible in one-pot using the appropriate amounts of donors and amine additives, rapidly elongating the carbon skeleton with controlling up to eight stereocenters. The method should be useful for straightforward synthesis of enantiomerically and diastereomerically enriched 1,3 polyols. PMID- 26632861 TI - Activation of Phosphorylase Kinase by Physiological Temperature. AB - In the six decades since its discovery, phosphorylase kinase (PhK) from rabbit skeletal muscle has usually been studied at 30 degrees C; in fact, not a single study has examined functions of PhK at a rabbit's body temperature, which is nearly 10 degrees C greater. Thus, we have examined aspects of the activity, regulation, and structure of PhK at temperatures between 0 and 40 degrees C. Between 0 and 30 degrees C, the activity at pH 6.8 of nonphosphorylated PhK predictably increased; however, between 30 and 40 degrees C, there was a dramatic jump in its activity, resulting in the nonactivated enzyme having a far greater activity at body temperature than was previously realized. This anomalous change in properties between 30 and 40 degrees C was observed for multiple functions, and both stimulation (by ADP and phosphorylation) and inhibition (by orthophosphate) were considerably less pronounced at 40 degrees C than at 30 degrees C. In general, the allosteric control of PhK's activity is definitely more subtle at body temperature. Changes in behavior related to activity at 40 degrees C and its control can be explained by the near disappearance of hysteresis at physiological temperature. In important ways, the picture of PhK that has emerged from six decades of study at temperatures of <=30 degrees C does not coincide with that of the enzyme studied at physiological temperature. The probable underlying mechanism for the dramatic increase in PhK's activity between 30 and 40 degrees C is an abrupt change in the conformations of the regulatory beta and catalytic gamma subunits between these two temperatures. PMID- 26632864 TI - XAS Investigation of Silver(I) Coordination in Copper(I) Biological Binding Sites. AB - Silver(I) is an unphysiological ion that, as the physiological copper(I) ion, shows high binding affinity for thiolate ligands; its toxicity has been proposed to be due to its capability to replace Cu(I) in the thiolate binding sites of proteins involved in copper homeostasis. Nevertheless, the nature of the Ag(I) thiolate complexes formed within cells is poorly understood, and the details of Ag(I) coordination in such complexes in physiologically relevant conditions are mostly unknown. By making use of X-ray absorption spectroscopy (XAS), we characterized the Ag(I) binding sites in proteins related to copper homeostasis, such as the chaperone Atox1 and metallothioneins (MTs), as well as in bioinspired thiolate Cu(I) chelators mimicking these proteins, in solution and at physiological pH. Different Ag(I) coordination environments were revealed: the Ag S bond length was found to correlate to the Ag(I) coordination number, with characteristic values of 2.40 and 2.49 A in AgS2 and AgS3 sites, respectively, comparable to the values reported for crystalline Ag(I)-thiolate compounds. The bioinspired Cu(I) chelator L(1) is proven to promote the unusual trigonal AgS3 coordination and, therefore, can serve as a reference compound for this environment. In the Cu(I)-chaperone Atox1, Ag(I) binds in digonal coordination to the two Cys residues of the Cu(I) binding loop, with the AgS2 characteristic bond length of 2.40 +/- 0.01 A. In the multinuclear Ag(I) clusters of rabbit and yeast metallothionein, the average Ag-S bond lengths are 2.48 +/- 0.01 A and 2.47 +/- 0.01 A, respectively, both indicative of the predominance of trigonal AgS3 sites. This work lends insight into the coordination chemistry of silver in its most probable intracellular targets and might help in elucidating the mechanistic aspects of Ag(I) toxicity. PMID- 26632865 TI - Targeted Metabolomics Approach To Detect the Misuse of Steroidal Aromatase Inhibitors in Equine Sports by Biomarker Profiling. AB - The use of anabolic androgenic steroids (AAS) is prohibited in both human and equine sports. The conventional approach in doping control testing for AAS (as well as other prohibited substances) is accomplished by the direct detection of target AAS or their characteristic metabolites in biological samples using hyphenated techniques such as gas chromatography or liquid chromatography coupled with mass spectrometry. Such an approach, however, falls short when dealing with unknown designer steroids where reference materials and their pharmacokinetics are not available. In addition, AASs with fast elimination times render the direct detection approach ineffective as the detection window is short. A targeted metabolomics approach is a plausible alternative to the conventional direct detection approach for controlling the misuse of AAS in sports. Because the administration of AAS of the same class may trigger similar physiological responses or effects in the body, it may be possible to detect such administrations by monitoring changes in the endogenous steroidal expression profile. This study attempts to evaluate the viability of using the targeted metabolomics approach to detect the administration of steroidal aromatase inhibitors, namely androst-4-ene-3,6,17-trione (6-OXO) and androsta-1,4,6-triene 3,17-dione (ATD), in horses. Total (free and conjugated) urinary concentrations of 31 endogenous steroids were determined by gas chromatography-tandem mass spectrometry for a group of 2 resting and 2 in-training thoroughbred geldings treated with either 6-OXO or ATD. Similar data were also obtained from a control (untreated) group of in-training thoroughbred geldings (n = 28). Statistical processing and chemometric procedures using principle component analysis and orthogonal projection to latent structures-discriminant analysis (OPLS-DA) have highlighted 7 potential biomarkers that could be used to differentiate urine samples obtained from the control and the treated groups. On the basis of this targeted metabolomic approach, the administration of 6-OXO and ATD could be detected for much longer relative to that of the conventional direct detection approach. PMID- 26632866 TI - Neuropeptidome of the Cephalopod Sepia officinalis: Identification, Tissue Mapping, and Expression Pattern of Neuropeptides and Neurohormones during Egg Laying. AB - Cephalopods exhibit a wide variety of behaviors such as prey capture, communication, camouflage, and reproduction thanks to a complex central nervous system (CNS) divided into several functional lobes that express a wide range of neuropeptides involved in the modulation of behaviors and physiological mechanisms associated with the main stages of their life cycle. This work focuses on the neuropeptidome expressed during egg-laying through de novo construction of the CNS transcriptome using an RNAseq approach (Illumina sequencing). Then, we completed the in silico analysis of the transcriptome by characterizing and tissue-mapping neuropeptides by mass spectrometry. To identify neuropeptides involved in the egg-laying process, we determined (1) the neuropeptide contents of the neurohemal area, hemolymph (blood), and nerve endings in mature females and (2) the expression levels of these peptides. Among the 38 neuropeptide families identified from 55 transcripts, 30 were described for the first time in Sepia officinalis, 5 were described for the first time in the animal kingdom, and 14 were strongly overexpressed in egg-laying females as compared with mature males. Mass spectrometry screening of hemolymph and nerve ending contents allowed us to clarify the status of many neuropeptides, that is, to determine whether they were neuromodulators or neurohormones. PMID- 26632867 TI - Room-Temperature Organocatalytic Cycloaddition of Azides with beta-Keto Sulfones: Toward Sulfonyl-1,2,3-triazoles. AB - Organocatalytic enamine-azide [3 + 2] cycloadditions between beta-keto sulfones and aryl azides can be performed at room temperature in good to excellent yields of products in the presence of catalytic amounts of pyrrolidine (5 mol %). The proposed organocatalytic methodology was found to be applicable to beta-keto arylsulfones containing a range of substituents. A wide variety of aryl azides also work. Basically, this constitutes a remarkably efficient protocol for the synthesis of novel 1,2,3-triazole compounds. PMID- 26632868 TI - Intracellular Generation of a Diterpene-Peptide Conjugate that Inhibits 14-3-3 Mediated Interactions. AB - Synthetic agents that disrupt intracellular protein-protein interactions (PPIs) are highly desirable for elucidating signaling networks and developing new therapeutics. However, designing cell-penetrating large molecules equipped with the many functional groups necessary for binding to large interfaces remains challenging. Here, we describe a rational strategy for the intracellular oxime ligation-mediated generation of an amphipathic bivalent inhibitor composed of a peptide and diterpene natural product, fusicoccin, which binds 14-3-3 protein with submicromolar affinity. Our results demonstrate that co-treatment of cells with small module molecules, the aldehyde-containing fusicoccin 1 and the aminooxy-containing peptide 2, generates the corresponding conjugate 3 in cells, resulting in significant cytotoxicity. In contrast, chemically synthesized 3 is not cytotoxic, likely due to its inability to penetrate cells. Compound 3, but not 1 or 2, disrupts endogenous 14-3-3/cRaf interactions, suggesting that cell death is caused by inhibition of 14-3-3 activity. These results suggest that intracellular generation of large-sized molecules may serve as a new approach for modulating PPIs. PMID- 26632869 TI - The impact of statin therapy on plasma levels of von Willebrand factor antigen. Systematic review and meta-analysis of randomised placebo-controlled trials. AB - Increased plasma levels of von Willebrand factor antigen (vWF:Ag) are associated with high risk of coronary artery disease. The effect of statin therapy on vWF:Ag levels remains uncertain. Therefore the aim of this meta-analysis was to evaluate the effect of statin therapy on vWF:Ag Levels. A systematic multiple-database search was carried out to identify randomized controlled trials (RCTs) that investigated the effect of statins on plasma vWF:Ag levels. Random-effect meta analysis of 21 treatment arms revealed a significant decrease in plasma vWF:Ag levels following statin therapy (SMD: -0.54, 95 %CI: -0.87, -0.21, p=0.001). In subgroup analyses, the greatest effect was observed with simvastatin (SMD: -1.54, 95 %CI: -2.92, -0.17, p=0.028) and pravastatin (SMD: -0.61, 95 %CI: -1.18, -0.04, p=0.035), but not with fluvastatin (SMD: -0.34, 95 %CI: -0.69, 0.02, p=0.065), atorvastatin (SMD: -0.23, 95 %CI: -0.57, 0.11, p=0.179) and rosuvastatin (SMD: 0.20, 95 % CI: -0.71, 0.30, p=0.431). The lowering effect of statins on plasma vWF:Ag levels was greater in the subset of studies lasting >= 12 weeks (SMD: 0.70, 95 %CI: -1.19, -0.22, p=0.005) compared with that of studies lasting < 12 weeks (SMD: -0.34, 95 %CI: -0.67, 0.003, p=0.052). Finally, low-intensity statin therapy was not associated with a significant reduction in vWF:Ag levels (SMD: 0.28, 95 %CI: -0.82, 0.27, p=0.320), but a significant effect was observed in high-intensity statin trials (SMD: -0.66, 95 %CI: -1.07, -0.24, p=0.002). This meta-analysis of available RCTs demonstrates a significant reduction in plasma vWF:Ag levels following statin therapy. PMID- 26632870 TI - Development and Suggestion of a Cardiac CTA Scoring System for the Prediction of Revascularization Success in Chronic Total Occlusions (CTO) of the Coronary Arteries. AB - OBJECTIVE: Analyzing occluded segments with computed tomography angiography (CTA) prior to percutaneous coronary intervention (PCI) increased revascularization success in chronic total occlusions (CTO). The aim of our study was to develop a scoring system for the prediction of PCI success in CTO. MATERIALS AND METHODS: 41 consecutive CTO patients (30 male; 63.1 years +/- 8.3 standard deviation) underwent CTA prior to PCI. All CTOs were categorized by two radiologists in consensus regarding the presence of special features and without knowledge of PCI outcome. All outcome criteria were evaluated. Afterwards one point was assigned for each unequally distributed outcome criteria per CTO and all points were added up to a single score. RESULTS: Severe calcifications (failure group 68.8 % vs. success group 28.0 %; p < 0.02) and intraluminal calcifications (68.8 %; 40.0 %), tortuosity (25.0 %; 0 %; p < 0.02), linear intrathrombus enhancement (37.5 %; 60.0 %) and distal vessel disease (68.8 %; 44.0 %) were unequally distributed. By adopting a threshold of 4 points or higher (maximum 5 points), the results were: sensitivity 31.3 %, specificity 100 %, negative predictive value (NPV) 69.4 % and positive predictive value (PPV) 100 %. The PCI complication rate was 9.8 % and the mean contrast media amount was 234.4 ml. CONCLUSION: With the suggested scoring system, based on five CTA criteria, PCI failure could be predicted with high PPV and specificity in our group of patients, but the NPV and sensitivity are low. However, 5 unsuccessful PCIs (13.2 %) could have been avoided and none would have been wrongly omitted. Regarding the complication rate during PCI and the high amounts of contrast media needed, a prediction system appears to be desirable and should be the object of large-scale trials. KEY POINTS: Single predictors of revascularization success in CTO have been identified. Success rates are improved by analyzing CTA data sets prior to revascularization approaches. Prediction of revascularization success via a scoring system based on five CTA criteria seems promising. Patient selection for the right treatment options might be improved in the future due to application of the scoring system. Also risks, complications, contrast media amounts and radiation doses might be reduced. PMID- 26632871 TI - Cloud-Based CT Dose Monitoring using the DICOM-Structured Report: Fully Automated Analysis in Regard to National Diagnostic Reference Levels. AB - PURPOSE: To implement automated CT dose data monitoring using the DICOM Structured Report (DICOM-SR) in order to monitor dose-related CT data in regard to national diagnostic reference levels (DRLs). MATERIALS AND METHODS: We used a novel in-house co-developed software tool based on the DICOM-SR to automatically monitor dose-related data from CT examinations. The DICOM-SR for each CT examination performed between 09/2011 and 03/2015 was automatically anonymized and sent from the CT scanners to a cloud server. Data was automatically analyzed in accordance with body region, patient age and corresponding DRL for volumetric computed tomography dose index (CTDIvol) and dose length product (DLP). RESULTS: Data of 36,523 examinations (131,527 scan series) performed on three different CT scanners and one PET/CT were analyzed. The overall mean CTDIvol and DLP were 51.3% and 52.8% of the national DRLs, respectively. CTDIvol and DLP reached 43.8% and 43.1% for abdominal CT (n=10,590), 66.6% and 69.6% for cranial CT (n=16,098) and 37.8% and 44.0% for chest CT (n=10,387) of the compared national DRLs, respectively. Overall, the CTDIvol exceeded national DRLs in 1.9% of the examinations, while the DLP exceeded national DRLs in 2.9% of the examinations. Between different CT protocols of the same body region, radiation exposure varied up to 50% of the DRLs. CONCLUSION: The implemented cloud-based CT dose monitoring based on the DICOM-SR enables automated benchmarking in regard to national DRLs. Overall the local dose exposure from CT reached approximately 50% of these DRLs indicating that DRL actualization as well as protocol-specific DRLs are desirable. The cloud-based approach enables multi-center dose monitoring and offers great potential to further optimize radiation exposure in radiological departments. KEY POINTS: * The newly developed software based on the DICOM Structured Report enables large-scale cloud-based CT dose monitoring * The implemented software solution enables automated benchmarking in regard to national DRLs * The local radiation exposure from CT reached approximately 50 % of the national DRLs * The cloud-based approach offers great potential for multi center dose analysis. PMID- 26632872 TI - Effect of Topological Structures on the Self-Assembly Behavior of Supramolecular Amphiphiles. AB - Three types of azobenzene-based telechelic guest polymers, PEG-azo, azo-PEG-azo, and PEG-azo4, were synthesized by a facile method. Subsequently, a series supramolecular amphiphiles with three distinct topological structures (hemitelechelic, ditelechelic, and quadritelechelic) were constructed through coupling with host polymer beta-cyclodextrin-poly(l-lactide) (beta-CD-PLLA) by combined host-guest complexation. Research on the self-assembly behavior of these amphiphiles demonstrated that the variation in self-assembly was tuned by the synergistic interaction of hydrophilicity and the curvature of the polymer chains, and very importantly, the topological structure of amphiphiles demonstrated effective control of the self-assembly behavior. PMID- 26632873 TI - Test-retest reliability of cuff pressure pain algometry in patients with knee osteoarthritis. PMID- 26632875 TI - Absence of Middle East respiratory syndrome coronavirus in Bactrian camels in the West Inner Mongolia Autonomous Region of China: surveillance study results from July 2015. PMID- 26632874 TI - DICER1 and microRNA regulation in post-traumatic stress disorder with comorbid depression. AB - DICER1 is an enzyme that generates mature microRNAs (miRNAs), which regulate gene expression post-transcriptionally in brain and other tissues and is involved in synaptic maturation and plasticity. Here, through genome-wide differential gene expression survey of post-traumatic stress disorder (PTSD) with comorbid depression (PTSD&Dep), we find that blood DICER1 expression is significantly reduced in cases versus controls, and replicate this in two independent cohorts. Our follow-up studies find that lower blood DICER1 expression is significantly associated with increased amygdala activation to fearful stimuli, a neural correlate for PTSD. Additionally, a genetic variant in the 3' un-translated region of DICER1, rs10144436, is significantly associated with DICER1 expression and with PTSD&Dep, and the latter is replicated in an independent cohort. Furthermore, genome-wide differential expression survey of miRNAs in blood in PTSD&Dep reveals miRNAs to be significantly downregulated in cases versus controls. Together, our novel data suggest DICER1 plays a role in molecular mechanisms of PTSD&Dep through the DICER1 and the miRNA regulation pathway. PMID- 26632876 TI - A phylogenetically distinct Middle East respiratory syndrome coronavirus detected in a dromedary calf from a closed dairy herd in Dubai with rising seroprevalence with age. AB - Middle East respiratory syndrome coronavirus (MERS-CoV) was detected by monoclonal antibody-based nucleocapsid protein-capture enzyme-linked immunosorbent assay (ELISA), RNA detection, and viral culture from the nasal sample of a 1-month-old dromedary calf in Dubai with sudden death. Whole genome phylogeny showed that this MERS-CoV strain did not cluster with the other MERS CoV strains from Dubai that we reported recently. Instead, it formed a unique branch more closely related to other MERS-CoV strains from patients in Qatar and Hafr-Al-Batin in Saudi Arabia, as well as the MERS-CoV strains from patients in the recent Korean outbreak, in which the index patient acquired the infection during travel in the eastern part of the Arabian Peninsula. Non-synonymous mutations, resulting in 11 unique amino acid differences, were observed between the MERS-CoV genome from the present study and all the other available MERS-CoV genomes. Among these 11 unique amino acid differences, four were found in ORF1ab, three were found in the S1 domain of the spike protein, and one each was found in the proteins encoded by ORF4b, ORF5, envelope gene, and ORF8. MERS-CoV detection for all other 254 dromedaries in this closed dairy herd was negative by nucleocapsid protein-capture ELISA and RNA detection. MERS-CoV IgG sero positivity gradually increased in dromedary calves with increasing age, with positivity rates of 75% at zero to three months, 79% at four months, 89% at five to six months, and 90% at seven to twelve months. The development of a rapid antigen detection kit for instantaneous diagnosis is warranted.Emerging Microbes & Infections (2015) 4, e74; doi:10.1038/emi.2015.74; published online 2 December 2015. PMID- 26632877 TI - When cells divide: Label-free multimodal spectral imaging for exploratory molecular investigation of living cells during cytokinesis. AB - In vivo, molecular-level investigation of cytokinesis, the climax of the cell cycle, not only deepens our understanding of how life continues, but it will also open up new possibilities of diagnosis/prognosis of cancer cells. Although fluorescence-based methods have been widely employed to address this challenge, they require a fluorophore to be designed for a specific known biomolecule and introduced into the cell. Here, we present a label-free spectral imaging approach based on multivariate curve resolution analysis of Raman hyperspectral data that enables exploratory untargeted studies of mammalian cell cytokinesis. We derived intrinsic vibrational spectra and intracellular distributions of major biomolecular components (lipids and proteins) in dividing and nondividing human colon cancer cells. In addition, we discovered an unusual autofluorescent lipid component that appears predominantly in the vicinity of the cleavage furrow during cytokinesis. This autofluorescence signal could be utilized as an endogenous probe for monitoring and visualizing cytokinesis in vivo. PMID- 26632878 TI - Cognitive and Affective Symptoms Experienced by Cancer Patients Receiving High Dose Intravenous Interleukin 2 Therapy: An Integrative Literature Review. AB - BACKGROUND: Alterations in cognitive/affective functioning are among the most challenging adverse effects experienced by 80% of patients with metastatic melanoma and metastatic renal cell carcinoma undergoing high-dose interleukin 2 (IL-2) therapy. OBJECTIVE: The purpose of this literature review is to describe what is known about IL-2-induced cognitive/affective symptoms, their prevalence, and level of severity and synthesize findings to determine areas for future research to address symptom management challenges. This review describes the IL-2 patient experience and the pathophysiology leading to these changes. METHODS: An online electronic search using PubMed was performed to identify relevant literature published between 1992 and 2015. Of the original 113 articles, information was extracted from 9 articles regarding cognitive symptoms, affective symptoms, sample size, research design, reliability, and validity. RESULTS: Our review suggests that the trajectories, breadth, and depth of cognitive/affective symptoms have yet to be described. Despite intervention studies designed to address the psychosocial complications of IL-2, an understanding of the level of altered cognitive/affective symptoms experienced by IL-2 patients remains unclear. CONCLUSION: Our literature review reveals a lack of standardization when assessing, reporting, and managing cognitive/affective symptoms. Patients/family members have reported cognitive/affective symptoms to be the most alarming and difficult symptoms, yet these symptoms are not adequately screened for, and patients were not informed about potential changes. IMPLICATIONS FOR PRACTICE: Assessing patients for cognitive/affective alterations is important to reduce anxiety while improving outcomes. Education about the illness trajectory (what to expect during/after treatment) can help care partners/patients set realistic shared expectations and increase coping. PMID- 26632879 TI - Comparison of Oncology Patients' and Their Family Caregivers' Attitudes and Concerns Toward Pain and Pain Management. AB - BACKGROUND: Both cancer patients and their family caregivers (FCs) report concerns about pain and pain management. When dyads share appraisal of the illness context, they may experience better dyadic adjustment. OBJECTIVE: The aim of this study was to compare oncology outpatients' and their FCs' attitudes and concerns toward pain and pain management. METHODS: In a cross-sectional study, outpatients with pain (n = 71) and their FCs completed the Barriers Questionnaire II, the Brief Pain Inventory, and information about demographic characteristics. Correlations and paired-samples t tests were calculated to evaluate agreement and differences in barrier scores between the patients and their FCs. RESULTS: Congruence was found in patients' and FCs' beliefs about pain and the use of analgesics on 4 of 7 subscales (ie, tolerance, immune system, side effects, distract the medical doctor) and on the Barriers Questionnaire II total score. Both patients and their FCs were most concerned about addiction. CONCLUSIONS: The concerns that both patients and their FCs have about pain and the use of analgesics may act as barriers to effective pain management. Fear of addiction may be an important barrier to cancer pain management. Only small differences were found in concerns between the patients and their FCs. IMPLICATIONS FOR PRACTICE: Patients and FCs need education about perceived barriers to effective pain management. They should be coached together to maintain or increase the congruence between them. PMID- 26632880 TI - Women Treated for Breast Cancer Experiences of Chemotherapy-Induced Pain: Memories, Any Present Pain, and Future Reflections. AB - BACKGROUND: Breast cancer survivors make up a growing population facing treatment that poses long-standing adverse effects including chemotherapy-related body function changes and/or pain. There is limited knowledge of patients' lived experiences of chemotherapy-induced pain (CHIP). OBJECTIVE: The aim of this study was to explore CHIP and any long-standing pain experiences in the lifeworld of breast cancer survivors. METHODS: Fifteen women participated in a follow-up interview a year after having experienced CHIP. They were interviewed from a lifeworld perspective; the interviews were analyzed through guided phenomenology reflection. RESULTS: A past perspective: CHIP is often described in metaphors, leads to changes in a patient's lifeworld, and impacts lived time. The women become entirely dependent on others but at the same time feel isolated and alone. Existential pain was experienced as increased vulnerability. Present perspective: Pain engages same parts of the body, but at a lower intensity than during CHIP. The pain creates time awareness. Expected normality in relationships/daily life has not yet been achieved, and a painful existence emerges in-between health and illness. Future perspective: There are expectations of pain continuing, and there is insecurity regarding whom to turn to in such cases. A painful awareness emerges about one's own and others' fragile existence. CONCLUSIONS: Experiencing CHIP can impact the lifeworld of women with a history of breast cancer. After CHIP, there are continued experiences of pain that trigger insecurity about whether one is healthy. IMPLICATIONS FOR PRACTICE: Cancer survivors would likely benefit from communication and information about and evaluation of CHIP. PMID- 26632881 TI - Healthcare Professionals' Knowledge of Family Psychosocial Problems in Pediatric Cancer: A Pilot Study. AB - BACKGROUND: Best practice guidelines for the treatment of cancer now advocate for a child- and family-centered model of care and a psychosocial model of risk prevention. However, healthcare professionals (HCPs) report a number of barriers preventing the implementation of psychosocial care, including an absence of tools to help identify psychosocial problems within the family. OBJECTIVES: The aims of this study are to (1) explore the psychometric properties of the Psychosocial Care Checklist (PCCL) and (2) test if the PCCL can differentiate the degree to which HCPs are aware of psychosocial problems within the family (patient, siblings, parents) of a child with cancer. METHODS: Thirty-seven HCPs caring for a child with cancer completed the PCCL at time 1 (2-4 weeks after diagnosis) and 29 HCPs completed the PCCL at time 2 (2-3 weeks after). RESULTS: The PCCL had strong test-retest reliability for all domains (alpha > .60) and strong internal consistency for the total PCCL (alpha = .91). Interrater reliability was moderate for the oncologist-nurse dyad with regard to sibling knowledge (r = 0.56) and total psychosocial knowledge (r = 0.65). Social workers were significantly more knowledgeable than both nurses and oncologists about total family problems (P = .01) and sibling problems (P = .03). CONCLUSIONS: Preliminary findings suggest that the PCCL has adequate test-retest reliability and validity and is useful in differentiating the degree to which HCPs are aware of psychosocial problems within the family, with social workers being the most knowledgeable. IMPLICATIONS FOR PRACTICE: Using the PCCL may help HCPs to identify psychosocial problems within the family and appropriately allocate psychosocial resources. PMID- 26632882 TI - Psychological Characteristics and Traits for Finding Benefit From Prostate Cancer: Correlates and Predictors. AB - BACKGROUND: Although beginning evidence suggests that the capacity to derive benefit from cancer-associated experiences may be influenced by some individual psychological characteristics and traits, little is known about predictors for finding benefit from prostate cancer. OBJECTIVE: The aim of this study was to explore the correlates and predictors for finding benefit from prostate cancer among a sample of men undergoing androgen deprivation. METHODS: Pearson correlation and multiple linear regression modeling were performed on data collected in an acute tertiary hospital outpatient setting (N = 209) between July 2011 and December 2013 to determine correlates and predictors for finding benefit from prostate cancer. RESULTS: Multiple linear regression modeling showed that while the 6 predictors of self-reported coping, depression, anxiety, distress, resilience, and hope explained 38% of the variance in finding benefit, coping provided the strongest and statistically significant predictive contribution. CONCLUSIONS: Self-reported coping was strongly predictive of finding benefit from prostate cancer, but questions remain about if subtypes of coping strategies can be more or less predictive of finding benefit. Self-reported levels of depression, anxiety, distress, resilience, and hope had a less predictive and nonsignificant role in finding benefit from prostate cancer and raise questions about their function in this subpopulation. IMPLICATIONS FOR PRACTICE: The findings suggest that coping strategies can maximize finding benefit from prostate cancer. Knowledge of influential coping strategies for finding benefit from prostate cancer can be immensely valuable to support men in rebuilding positive meaning amid a changed illness reality. Developing practice initiatives that foster positive meaning-making coping strategies seems valuable. PMID- 26632883 TI - Defective Ti2Nb10O27.1: an advanced anode material for lithium-ion batteries. AB - To explore anode materials with large capacities and high rate performances for the lithium-ion batteries of electric vehicles, defective Ti2Nb10O27.1 has been prepared through a facile solid-state reaction in argon. X-ray diffractions combined with Rietveld refinements indicate that Ti2Nb10O27.1 has the same crystal structure with stoichiometric Ti2Nb10O29 (Wadsley-Roth shear structure with A2/m space group) but larger lattice parameters and 6.6% O(2-) vacancies (vs. all O(2-) ions). The electronic conductivity and Li(+)ion diffusion coefficient of Ti2Nb10O27.1 are at least six orders of magnitude and ~2.5 times larger than those of Ti2Nb10O29, respectively. First-principles calculations reveal that the significantly enhanced electronic conductivity is attributed to the formation of impurity bands in Ti2Nb10O29-x and its conductor characteristic. As a result of the improvements in the electronic and ionic conductivities, Ti2Nb10O27.1 exhibits not only a large initial discharge capacity of 329 mAh g( 1) and charge capacity of 286 mAh g(-1) at 0.1 C but also an outstanding rate performance and cyclability. At 5 C, its charge capacity remains 180 mAh g(-1) with large capacity retention of 91.0% after 100 cycles, whereas those of Ti2Nb10O29 are only 90 mAh g(-1) and 74.7%. PMID- 26632884 TI - A novel polymorphism near HLA class II region is associated with spontaneous clearance of HCV and response to interferon treatment in Chinese patients. AB - A recent genome-wide association study (GWAS) has identified the single nucleotide polymorphism (SNP) rs4273729 in a 100-kbp region comprising human leukocyte antigens (HLAs) class II genes as an important predictor of hepatitis C virus (HCV) clearance in European and African populations. This study was to determine whether this polymorphism is also associated with spontaneous HCV clearance as well as response to interferon treatment in Chinese patients. Thus, 686 chronic HCV carriers, 432 individuals with spontaneous viral clearance and 243 patients with pegylated interferon-alpha and ribavirin (PEG IFN-alpha/RBV) treatment were genotyped. The rs4273729 GG genotype was strongly associated with spontaneous HCV clearance as well as better IFN/RBV treatment response compared with the GC/CC genotypes in Chinese Han population (additive model: odds ratio (OR)=0.62, 95% confidence interval (95% CI)=0.51-0.76; OR=0.58, 95% CI=0.38-0.88, respectively). Rs4273729, rs12980275, baseline HCV RNA and platelet level were independent predictors for sustained virological response (SVR). The area under the receiver-operating characteristic curve (AUC) was 0.578 when including rs4273729 alone, but the prediction value was improved significantly (AUC=0.733) when further including rs12980275, baseline viral load and baseline platelet level. In conclusion, the genetic variation of rs4273729 is associated with clearance of HCV in both the natural course and the treatment process in Chinese Han population. PMID- 26632885 TI - An epigenomic signature of postprandial hyperglycemia in peripheral blood leukocytes. AB - Postprandial hyperglycemia is known to be one of the earliest signs of abnormal glucose homeostasis associated with type 2 diabetes. This study aimed to assess clinical significance of a 1-h postprandial glucose level for the development of diabetes, and identify epigenetic biomarkers of postprandial hyperglycemia. We analyzed clinical data from the oral glucose tolerance tests for healthy subjects (n=4502). The ratio (Glu60/Glu0) of 1-h glucose levels to fasting glucose levels was significantly associated with an insulin sensitive index (QUICKI, quantitative insulin sensitivity check index) (beta=0.055, P=1.25E-04) as well as a risk of future pre-diabetic and diabetic conversion. Next, DNA methylation profile analyses of 24 matched pairs of the high and low Glu60/Glu0 ratio subjects showed that specific DNA methylation levels in the promoter region of an olfactory receptor gene (olfactory receptor gene family10 member A4, OR10A4) were associated with the Glu60/Glu0 ratios (beta=0.337, P=0.03). Moreover, acute oral glucose challenges decreased the DNA methylation levels of OR10A4 but not the global DNA methylation in peripheral leukocytes of healthy subjects (n=7), indicating that OR10A4 is a specific epigenomic target of postprandial hyperglycemia. This work suggests possible relevance of olfactory receptor genes to an earlier molecular biomarker of peripheral hyperglycemia and diabetic conversion. PMID- 26632886 TI - The African-387 C>T TGFB1 variant is functional and associates with the ophthalmoplegic complication in juvenile myasthenia gravis. AB - Although extraocular muscles are commonly affected by myasthenia gravis (MG) at presentation, a treatment-resistant ophthalmoplegic complication of MG (OP-MG) occurs in younger patients with African-genetic ancestry. In MG, pathogenic antibodies activate complement-mediated muscle damage and this may be potentiated in some OP-MG cases because of relative deficiency of decay-accelerating factor/CD55. Extending this argument, we hypothesized that OP-MG individuals may harbor African-specific polymorphisms in key genes influencing extraocular muscle remodeling. We screened the regulatory region of the transforming growth factor beta-1 (TGFB1) gene encoding the cytokine pivotal in muscle healing responses. We show the frequency of an African-specific polymorphism TGFB1 c.-387 T (rs11466316) among South Africans with African-genetic ancestry is higher than 1000 Genomes African controls (17.2% vs 4.8%; P<1 * 10(-7)), and associates with juvenile OP-MG (28%; P=0.043). Further, TGFB1 -387 C>T is functional because it represses the TGFB1 promoter construct basal activity by fivefold, and OP-MG fibroblasts (-387 C/T or T/T) have lower basal TGFB1 mRNA transcripts compared with controls (-387 C/C)(P=0.001). Co-transfections with Sp1 show less responsiveness of the -387 T promoter compared with wild-type -387 C (P=0.015). Our findings suggest that population-specific alleles may lower TGFB1 expression, thereby influencing OP-MG susceptibility by inhibiting extraocular muscle CD55 upregulation and/or altered endplate remodeling. PMID- 26632887 TI - Influence of Metastatic Status and Number of Removed Lymph Nodes on Survival of Patients With Squamous Esophageal Carcinoma. AB - The aim of this study was to determine the impact of lymph node (LN) metastasis conditions on the prognosis of patients with esophageal squamous carcinoma and the minimum number of LNs that should be removed to maximize overall postoperative survival among patients with this specific pathologic subtype. In this study, 312 patients with thoracic squamous esophageal carcinoma who received in-patient thoracic surgery by the same surgeon in our hospital from August 1, 2003 to December 31, 2009 were recruited. Subsequently, Kaplan-Meier methods were used to determine associations between LN metastasis conditions and mortality and between the numbers of LNs removed during esophagectomy and mortality. Cox regression models were used to adjust for potential confounding covariates. According to Kaplan-Meier analyses, the number of metastatic LNs was a good predictor for the prognosis of patients with esophageal squamous carcinoma and the dissection of >= 29 LNs during thoracic surgery significantly improved patient survival (P = 0.011).Lymph node metastasis rates may be a significant predictor for the prognosis of patients with esophageal squamous carcinoma. The number of LNs removed during esophagectomy is an independent predictor for the survival of patients with esophageal squamous carcinoma with maximal postoperative survival after the removal of >= 29 LNs. PMID- 26632888 TI - The Association of Losartan and Ramipril Therapy With Kidney and Cardiovascular Outcomes in Patients With Chronic Kidney Disease: A Chinese Nation-Wide Cohort Study in Taiwan. AB - The aim of this nation-wide cohort study was to assess the association of using an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin II receptor blocker (ARB) therapy on the prognosis of hypertensive patients with chronic kidney disease (CKD). We used Cox's proportional hazard regression model to estimate hazard ratios (HRs) for the risk of end-stage renal disease (ESRD), all cause mortality, cardiovascular mortality, and first hospitalization for cardiovascular disease (CVD) for losartan and ramipril versus conventional antihypertensive agents. In total, 136,266 hypertensive patients with CKD in Taiwan were followed up from 2001 to 2008. In an average follow-up of 5.9 years, 7364 (5.40%) patients reached ESRD, 4165 (3.06%) patients died, and 6163 (4.52%) patients had their first hospitalization for CVD. Use of losartan or ramipril was associated with a lower risk of the endpoints compared with the conventional group. In the losartan group, the risks of ESRD, all- and cardiovascular-cause mortality, and first hospitalization for CVD were decreased by 9.2% (P = 0.01), 24.6% (P < 0.001), 12.4% (P = 0.03), and 36.0% (P = 0.01), respectively. In the ramipril group, these risks decreased by 7.6% (P = 0.02) for ESRD, 56.9% (P < 0.001) for all-cause mortality, 7.5% (P = 0.04) for cardiovascular mortality, and 24.7% (P < 0.001) for first hospitalization. This study indicated that losartan and ramipril had distinct association on the prognosis of hypertensive patients with CKD, and was first to disclose that the mean time to reach each endpoint for patients in the losartan, ramipril, and conventional group was not significantly different. However, further study is needed to confirm results of the present study. PMID- 26632889 TI - Relation Between F-18 FDG Uptake of PET/CT and BRAFV600E Mutation in Papillary Thyroid Cancer. AB - BRAFV600E mutation and F-18 fluorodeoxyglucose (FDG) uptake are potential prognostic factors of papillary thyroid cancer (PTC). This study was performed to investigate the relationship between the BRAFV600E mutation and F-18 FDG uptake in PTC.We retrospectively included 169 PTC patients who underwent F-18 FDG positron emission tomography/computed tomography (PET/CT) before thyroidectomy from May 2009 to August 2012. Subjects were classified into overt PTC (>1 cm, n = 76) and papillary thyroid microcarcinoma (PTMC, n = 93) groups. Univariate and multivariate analyses were performed to assess the relationship between maximum standardized uptake value (SUVmax) of the primary tumors and clinicopathologic variables.The BRAFV600E mutation was detected in 82.2% (139/169). In all subjects, the BRAFV600E mutation and tumor size were independently related to SUVmax by multivariate analysis (P = 0.048 and P < 0.001, respectively). SUVmax was significantly higher in tumors with the BRAFV600E mutation than in those with wild-type BRAF (9.4 +/- 10.9 vs 5.0 +/- 4.1, P < 0.001). Similarly, in overt PTC group, the BRAFV600E mutation and tumor size were independently correlated with SUVmax (P = 0.032 and P = 0.001, respectively). By contrast, in PTMC group, only tumor size was significantly associated with SUVmax (P = 0.010). The presence of the BRAFV600E mutation is independently associated with high F-18 FDG uptake on preoperative PET/CT in patients with overt PTC, but this relationship was not evident in PTMC. This study provides a better understanding of the relationship between F-18 FDG uptake and BRAFV600E mutation in patients with PTC. PMID- 26632890 TI - Second Hepatectomy Improves Survival in Patients With Microvascular Invasive Hepatocellular Carcinoma Meeting the Milan Criteria. AB - Microvascular invasion (MVI) is a strong risk factor for patients with hepatocellular carcinoma (HCC) meeting the Milan criteria and who have received curative hepatectomy. The relevance of a second hepatectomy in patients with MVI positive recurrent HCC remains controversial. We had 329 cases of HCC hepatectomy meeting the Milan criteria and compared data on patient demographics, liver function, and tumor pathology between MVI-positive and MVI-negative group. We analyzed potential risk factors of overall survival (OS) and disease-free survival (DFS). Furthermore, newly developed pathological features following the second hepatectomy were also analyzed.The median OS and DFS were significantly superior in the MVI-negative group than in the MVI-positive group, 61 (10-81) versus 49 (11-82) months (P < 0.01) and 41 (7-75) versus 13 (3-69) months (P < 0.01), respectively. The presence of MVI and a total tumor diameter >3 cm were independent risk factors associated with both OS and DFS. Overall survival was significantly improved by a second hepatectomy in the MVI-positive group compared with the original MVI-positive group, 60 (26-82) versus 49 (11-82) months, respectively. This was now comparable to the MVI-negative group, 60 (26-82) versus 61 (10-81) months (P = 0.72). A second hepatectomy was consistently associated with better survival in the MVI-negative group as compared to the MVI positive group. A second hepatectomy improves survival in patients with MVI HCC meeting the Milan criteria. The biology of MVI may change following a second hepatectomy. The absence of MVI is a good prognostic sign for patients undergoing second hepatectomy. PMID- 26632891 TI - Few Outflow Problems With a Self-locating Catheter for Peritoneal Dialysis: A Randomized Trial. AB - We developed a technique for direct start of peritoneal dialysis. Using a coiled or straight Tenckhoff catheter often results in obstruction of flow. A self locating Wolfram catheter is on the market. It is not clarified if this results in a benefit.The primary aim of this study was to perform a randomized investigation to clarify if the use of a self-locating peritoneal dialysis (PD) catheter would result in different flow problems than a straight Tenckhoff catheter.A total of 61 insertions were made who were randomized and received either a straight Tenckhoff (n = 32) or a self-locating Wolfram catheter (n = 29). A previously described operation technique allowed immediate postoperative start of dialysis. Seven straight Tenckhoff catheters had to be changed into self locating catheters, and none vice versa, due to flow problems (P = 0.011). An early leakage resulted in temporarily postponed PD in 4 patients. This study showed that using the present operation technique the self-locating PD-catheter causes fewer obstruction episodes than a straight Tenckhoff catheter. This facilitates immediate postoperative start of PD. PMID- 26632892 TI - Fracture Risk After Bariatric Surgery: A 12-Year Nationwide Cohort Study. AB - Bariatric surgery has been shown to impair bone health. This study aimed to investigate the fracture risk in patients after bariatric surgery versus propensity score-matched controls. The authors used the National Health Insurance Research Database of Taiwan and identified 2064 patients who underwent bariatric surgery during 2001 to 2009. These patients were matched to 5027 obese patients who did not receive bariatric surgery, using propensity score matching accounting for age, sex, Charlson Comorbidity Index, diabetes, hypertension, hyperlipidemia and the year morbid obesity was diagnosed. The authors followed the surgical and control cohorts to death, any diagnosis of fracture, or December 31, 2012, whichever occurred first. Cox proportional hazard regression models were used to calculate relative rates of fractures in the surgical group and control group. At the end of the 12-year study period, there were 183 fractures in the surgical group (mean follow-up 4.8 years) and 374 fractures in the matched control group (mean follow-up 4.9 years). Overall, there was a 1.21-fold [95% confidence interval (CI): 1.02-1.43] significantly increased risk of fracture in the surgical group compared with the control group. Stratified by surgical procedures, malabsorptive procedures showed a significantly higher fracture risk (1.47, 95% CI: 1.01-2.15). The Kaplan-Meier estimated fracture rates were 1.60% at 1 year, 2.37% at 2 years, 1.69% at 5 years, and 2.06% after 5 years for the surgical patients, compared with 1.51%, 1.65%, 1.53%, and 1.42%, respectively, for the matched controls. Adjusted analysis showed a trend towards an increased fracture risk, 1 to 2 years after bariatric surgery. (1.42, 95% CI: 0.99-2.05). Bariatric surgery was significantly associated with an increased risk of fractures, mainly with malabsorptive procedures, with a trend of an increased fracture risk 1 to 2 years after surgery. These results provide further evidence for the adverse effects of bariatric surgery on the risk of fractures. PMID- 26632893 TI - A Randomized Controlled Study Comparing Reverse Hybrid Therapy and Standard Triple Therapy for Helicobacter pylori Infection. AB - Reverse hybrid therapy is an 1-step 2-phase treatment for Helicobacter pylori (H. pylori) infection with less cost than standard triple therapy. We conducted a randomized, controlled study to compare the efficacies of standard triple therapy and reverse hybrid therapy in the treatment of H. pylori infection. From October 2012 to March 2015, consecutive H. pylori-infected subjects were randomly allocated to receive either a reverse hybrid therapy (pantoprazole plus amoxicillin for 12 days and clarithromycin plus metronidazole for the initial 7 days) or a standard triple therapy (pantoprazole plus amoxicillin and clarithromycin for 12 days). H. pylori status was assessed 6 weeks after treatment. Additionally, antibiotic resistances and host CYP2C19 genotypes were examined and analyzed. A total of 440 H. pylori-infected patients were randomly assigned to receive either a reverse hybrid (n = 220) or a standard triple therapy (n = 220). The reverse hybrid group had a higher eradication rate than standard triple group either by intention-to-treat (93.6% vs. 86.8%; P = 0.016) or per-protocol analysis (95.7% vs. 88.3%; P = 0.005). The 2 patient groups exhibited similar frequencies of overall adverse events (14.1% vs. 9.5%) and drug compliance (96.8% vs. 98.6%). Clarithromycin resistance was an independent risk factor predicting eradication failure in standard triple group (P < 0.001), but not in reverse hybrid group. CYP2C19 genotypes did not affect the eradication rates in both groups. Reverse hybrid therapy can be considered for first-line treatment of H. pylori infection since the new therapy achieves a higher eradication rate than standard triple therapy with similar tolerability and less pharmaceutical cost. PMID- 26632894 TI - Association of ABO and Colton Blood Group Gene Polymorphisms With Hematological Traits Variation. AB - Hematological parameters are appraised routinely to determine overall human health and to diagnose and monitor certain diseases. In GWASs, more than 30 loci carrying common deoxyribonucleic acid (DNA) polymorphisms have been identified related to hematological traits. In this study, we investigated the contribution of ABO rs2073823 along with AQP1 rs1049305 and rs10244884 polymorphisms in hematological traits variation in a cohort of Iranian healthy individuals.Genomic DNA was extracted from peripheral blood of 168 healthy volunteer. Genotyping was performed by ARMS-PCR or PCR-RFLP and confirmed by DNA sequencing. Complete blood analyses were conducted for the participants. Significant association was observed between AQP1 rs1049305 and the hematological traits including hemoglobin, hematocrit, and platelet count (P = 0.012, 0.008, and 0.011, respectively). The AQP1 rs10244884 status was also significantly linked to hemoglobin and hematocrit levels in the study cohort (P = 0.015 and 0.041, respectively). Furthermore, ABO rs2073823 polymorphism was identified as a hemoglobin and hematocrit levels modifier (both with P = 0.004).AQP1 and ABO variants appear to predict hemoglobin and hematocrit levels but not other erythrocyte phenotype parameters including red blood cell counts and red blood cell indices. PMID- 26632896 TI - Survival Analyses for Patients With Surgically Resected Pancreatic Neuroendocrine Tumors by World Health Organization 2010 Grading Classifications and American Joint Committee on Cancer 2010 Staging Systems. AB - In 2010, World Health Organization (WHO) reclassified pancreatic neuroendocrine tumors (p-NETs) into 4 main groups: neuroendocrine tumor G1 (NET G1), neuroendocrine tumor G2 (NET G2), neuroendocrine carcinoma G3 (NEC G3), mixed adeno and neuroendocrine carcinoma (MANEC). Clinical value of these newly updated WHO grading criteria has not been rigorously validated. The authors aimed to evaluate the clinical consistency of the new 2010 grading classifications by WHO and the 2010 tumor-node metastasis staging systems by American Joint Committee on Cancer (AJCC) on survivals for patients with surgically resected p-NETs. Moreover, the authors would validate the prognostic value of both criteria for p NETs.The authors retrospectively collected the clinicopathologic data of 120 eligible patients who were all surgically treated and histopathologically diagnosed as p-NETs from January 2004 to February 2014 in our single institution. The new WHO criteria were assigned to 4 stratified groups with a respective distribution of 62, 35, 17, and 6 patients. Patients with NET G1 or NET G2 obtained a statistically better survival compared with those with NEC G3 or MANEC (P < 0.001). Survivals of NET G1 was also better than those of NET G2 (P = 0.023), whereas difference of survivals between NEC G3 and MANEC present no obvious significance (P = 0.071). The AJCC 2010 staging systems were respectively defined in 61, 36, 12, and 11 patients for each stage. Differences of survivals of stage I with stage III and IV were significant (P < 0.001), as well as those of stage II with III and IV (P < 0.001); whereas comparisons of stage I with stage II and stage III with IV were not statistically significant (P = 0.129, P = 0.286; respectively). Together with radical resection, these 2 systems were both significant in univariate and multivariate analysis (P < 0.05).The newly updated WHO 2010 grading classifications and the AJCC 2010 staging systems could consistently reflect the clinical outcome of patients with surgically resected p NETs. Meanwhile, both criteria could be independent predictors for survival analysis of p-NETs. PMID- 26632895 TI - Coronary CT Angiography in Heavily Calcified Coronary Arteries: Improvement of Coronary Lumen Visualization and Coronary Stenosis Assessment With Image Postprocessing Methods. AB - To compare the diagnostic value of coronary CT angiography (CCTA) with use of 2 image postprocessing methods (CCTA_S) and (CCTA_OS) and original data (CCTA_O) for the assessment of heavily calcified plaques. Fifty patients (41 men, 9 women; mean age 61.9 years +/- 9.1) with suspected coronary artery disease who underwent CCTA and invasive coronary angiography (ICA) examinations were included in the study. Image data were postprocessed with "sharpen" and smooth reconstruction algorithms in comparison with the original data without undergoing any image postprocessing to determine the effects on suppressing blooming artifacts due to heavy calcification in the coronary arteries. Minimal lumen diameter and degree of stenosis were measured and compared between CCTA_S, CCTA_OS, and CCTA_O with ICA as the reference method. The area under the curve (AUC) by receiver-operating characteristic curve analysis (ROC) was also compared among these 3 CCTA techniques. On a per-vessel assessment, the sensitivity, specificity, positive predictive value and negative predictive value, and 95% confidence interval (CI) were 100% (95% CI: 89%, 100%), 33% (95% CI: 22%, 45%), 41% (95% CI: 30%, 53%), 100% (95% CI: 85%, 100%) for CCTA_O, 94% (95% CI: 79%, 99%), 66% (95% CI: 54%, 77%), 57% (95% CI: 43%, 70%), and 95% (95% CI: 85%, 99%) for CCTA_S, 94% (95% CI: 79%, 99%), 44% (95% CI: 32%, 57%), 44% (95% CI: 32%, 57%), and 97% (95% CI: 79%, 99%) for CCTA_OS, respectively. The AUC by ROC curve analysis for CCTA_S showed significant improvement for detection of >50% coronary stenosis in left anterior descending coronary artery compared to that of CCTA_OS and CCTA_O methods (P < 0.05), with no significance differences for detection of coronary stenosis in the left circumflex and right coronary arteries (P > 0.05).CCTA with "sharpen" reconstruction reduces blooming artifacts from heavy calcification, thus, leading to significant improvement of specificity and positive predictive value of CCTA in patients with heavily calcified plaques. However, specificity is still moderate and additional functional imaging may be needed. PMID- 26632897 TI - Visceral Obesity Predicts Significant Fibrosis in Patients With Nonalcoholic Fatty Liver Disease. AB - Nonalcoholic fatty liver disease (NAFLD) is associated with visceral obesity. However, the association between visceral adipose tissue (VAT) area and fibrosis in NAFLD patients has not been completely established. This study was aimed to determine the relationship between the computed tomography-measured VAT area and significant fibrosis in NAFLD patients. A total of 324 NAFLD patients and 132 controls were evaluated by liver biopsy. NAFLD was diagnosed based on histological examinations and alcohol consumption <20 g/day. The NAFLD patients showed a higher age and gender-adjusted VAT area than the control group (86.1 +/- 2.3 vs 56.7 +/- 3.7, P < 0.001). The VAT area increased across the control, NAFLD without significant fibrosis, and NAFLD with significant fibrosis groups (54.9 +/ 3.5, 80.6 +/- 2.4, and 123.4 +/- 6.4, P < 0.001). This association persisted after adjusting for multiple confounders (P for trend = 0.028). A multivariate regression analysis demonstrated the VAT area was independently associated with NAFLD with significant fibrosis (F2-F4) (odds ratio [OR] 1.21 95% confidence interval [CI] 1.07-1.37 per 10 cm(2) increase of VAT area; OR 2.62 [per 1 - standard deviation (SD)] 95% CI 1.41-4.86). Moreover, a multivariate logistic regression analysis revealed the VAT area was independently associated with nonalcoholic steatohepatitis (NASH) in NAFLD (OR 1.17 95% CI 1.05-1.32 per 10 cm increase of VAT area; OR 2.21 [per 1 - SD] 95% CI 1.25-3.89). Increased VAT area is independently associated with NASH or significant fibrosis and VAT might be a central target for lifestyle modifications in NAFLD patients. PMID- 26632898 TI - Association of Tartrate-Resistant Acid Phosphatase-Expressed Macrophages and Metastatic Breast Cancer Progression. AB - Infiltrating neutrophils, lymphocytes, macrophages, and cytokines constitute a state of chronic inflammation within the tumor microenvironment. Tartrate resistant acid phosphatase 5a (TRACP5a) protein, a novel product of activated macrophage, is postulated to be a biomarker for systemic inflammatory burden in states of chronic inflammation. We aimed to investigate the clinical significance of TRACP5a expression in tumor-infiltrating macrophages and serum TRACP5a in patients with metastatic breast cancer (BC). We retrospectively analyzed the clinical data from 34 BC patients with confirmed skeletal/visceral metastasis upon or during first-line palliative treatment. Patients were stratified into 3 groups based on the therapeutic responses and follow-up disease course. The association of TRACP5a protein with other inflammatory and cancer biomarkers was assessed among the clinically distinct group of patients. Higher TRACP5a protein was significantly correlated with earlier disease progression and survival (P = 0.0045) in comparison to other inflammatory markers, CRP or IL-6. Patients with higher serum TRACP5a level and shorter survival and treatment refractoriness also had more TRACP+ tumor-infiltrating macrophages. Our data support a hypothesis that serum TRACP5a protein can potentially be a predictive and prognostic marker to evaluate disease progression and therapeutic response in BC patients with bone/visceral metastasis. The associations between overall survival and TRACP expression by macrophages require further prospective investigation. PMID- 26632899 TI - Outcome Comparisons Between Patients on Peritoneal Dialysis With and Without Polycystic Kidney Disease: A Nationwide Matched Cohort Study. AB - Polycystic kidney disease (PCKD) is the most common hereditary cause of end-stage renal disease. The complications associated with this disease may affect the performance of peritoneal dialysis (PD). The aim of this study was to compare the outcomes between patients on PD with PCKD and without PCKD.We extracted an incident cohort of adult (>= 20 years old) patients on long-term PD from the Taiwan National Health Insurance Research Database. Patients with PCKD were identified by specific diagnosis codes. We recorded baseline comorbidities, socioeconomic status, timing of referral to a nephrologist, prior hemodialysis history before PD, and the type of PD modalities. We compared the risk of death, technique failure, peritonitis, hospitalization, and outpatient visiting as well as overall medical expenditure between the patients with PCKD and a groups of patients without PCKD who were propensity-score matched (1:3). The analysis was carried out by various Cox regression models that considered competing risk and time-varying coefficients. We enrolled 139 patients with PCKD and 7739 patients without PCKD who started long-term PD between 1999 and 2010. Patients with PCKD were less comorbid and more often treated with automated PD. In the propensity score matched analysis, both overall survival and technique survival did not differ between the patients and the result was similar for hospitalization and peritonitis after adjusting for the application of automated PD. Furthermore, the overall annual medical expenditures were similar between the patients with and without PCKD. PD patients with PCKD are comparable to PD patients without PCKD in terms of risk of death, peritonitis, technique failure, and hospitalization in the present study. Furthermore, the medical expenses of the 2 groups after initiation of PD are also indistinguishable. PMID- 26632900 TI - Refractive Results Using a New Optical Biometry Device: Comparison With Ultrasound Biometry Data. AB - The aim of the study was to compare the measurements of optical (AL-Scan; Nidek Co., Ltd.) and ultrasonic (Echo Scan US-800; Nidek Co., Ltd.) biometry devices and to assess refractive results after cataract surgery. Eighty-one cataractous eyes of 81 patients were included in this study. Biometry was performed using the AL-Scan and an ultrasonic biometer (USB). Axial length (AL), keratometry (K) data, and intraocular lens (IOL) power calculations using the SRK/T formula were compared. Bland-Altman analysis was used to assess the extent of agreement between AL-Scan and USB data in terms of AL measurement and IOL power calculation. The K measurements of the AL-Scan were compared to autorefractor data (Canon Autorefractor RK-F1). The AL-Scan assessed the AL as longer (average difference 0.06 +/- 0.18 mm; ICC = 0.987; P < 0.001) and the IOL power as greater (average difference 0.19 +/- 0.66 D; ICC = 0.964; P < 0.001) than the USB. The AL Scan also measured average K values (average difference 0.25 +/- 0.25 D; ICC = 0.985; P < 0.001) greater than those given by the autorefractor. The postoperative mean absolute error was +0.30 +/- 0.04 D (minimum: -0.51 D, maximum +1.04 D). The postoperative mean K value change was 0.36 +/- 0.29 D (P < 0.05). The differences between measurements afforded by the AL-Scan and USB may be clinically acceptable. Keratometric changes that develop after cataract operations compromise the attainment of good refractive outcomes. PMID- 26632901 TI - The Tumor-immune Index is Correlated With the Prognosis of Patients After Curative Resection for Nonsmall Cell Lung Cancer. AB - We developed a novel tumor-immune index (TII) based on carcinoembryonic antigen levels, lymphocyte counts, and platelet counts, and explored its prognostic value in nonsmall cell lung cancer (NSCLC).The prognostic value of the TII was evaluated based on a retrospective study of 205 patients with early NSCLC, who underwent resection in the whole year of 2006, and validated in another group of 228 patients enrolled in the next year of 2007. The optimal cut-off point for the TII was 578 * 10(-9), and this value was used to stratify patients with NSCLC into low TII (<= 578 * 10(-9)) and high TII (>578 * 10(-9)) groups. Univariate and multivariate analyses revealed that high TII was an independent predictor for overall survival and recurrence-free survival in both the training and validation cohorts. The areas under the curve of the TII for survival and recurrence were significantly larger than those for tumor, node, metastasis (TNM) stage and carcinoembryonic antigen. In the subgroup analysis, the TII was also significantly correlated with overall survival (P = 0.001, P = 0.009, and P = 0.007 in the TNM I, II, and IIIa subgroups, respectively) and recurrence-free survival (P < 0.001, P = 0.006, and P = 0.014 in the TNM I, II, and IIIa subgroups, respectively). Similarly, for patients with N2-positive tumors, the overall survival and recurrence-free survival rates for patients in the high TII group were also significantly lower than the respective values for patients in the low TII group (P = 0.026 and P = 0.007, respectively). The TII can be used to distinguish patients with similar pathologies and stages into high and low-risk categories based on the probability of recurrence according to a convenient blood based test. PMID- 26632902 TI - Overweight Is a Major Contributor to Atherosclerosis in Systemic Lupus Erythematosus Patients at Apparent Low Risk for Cardiovascular Disease: A Cross Sectional Controlled Study. AB - Cardiovascular disease (CVD) is the main cause of death in systemic lupus erythematosus (SLE) patients. We aimed to determine whether overweight (defined as a body mass index [BMI] > 25 kg/m(2)) contributed to subclinical atherosclerosis in SLE patients at low risk for CVD according to traditional factors. Wall thickness of the internal carotid artery (ICWT) measured at the carotid bulb and carotid plaques were assessed in 49 SLE patients asymptomatic for CVD and 49 controls matched on Framingham score. Factors associated to ICWT were identified and multivariate analysis was performed.SLE patients and controls displayed a low 10-year risk for CVD according to Framingham score (mean 1.9 +/- 3.5 in SLE vs 1.8 +/- 3.2% in controls, P = 0.37). ICWT (P < 0.001) and number of patients with carotid plaques (P = 0.015) were, however, higher in SLE patients as compared to controls. In multivariable analysis, SLE was an independent risk for a carotid atherosclerosis (OR [95% confidence interval, CI]: 3.53 [1.36 9.14]; P = 0.009). Older age, higher BMI, and higher Framingham score were associated with atherosclerosis in SLE patients in univariate analysis. In multivariate analysis, only the association with overweight remained significant (OR [95% CI]: 4.13 [1.02-16.75]; P = 0.047). Overweight is a major contributor to atherosclerosis in SLE patients at apparent low risk for CVD. PMID- 26632903 TI - STROBE--Radiation Ulcer: An Overlooked Complication of Fluoroscopic Intervention: A Cross-Sectional Study. AB - With increasing numbers of percutaneous coronary intervention (PCI) and complex cardiac procedures, higher accumulated radiation dose in patient has been observed. We speculate cardiac catheter intervention induced radiation skin damage is no longer rare.To study the incidence of cardiac fluoroscopic intervention induced radiation ulcer. We retrospectively reviewed medical records of those who received cardiac fluoroscopic intervention in our hospital during 2012 to 2013 for any events of radiation ulcer. Only patients, whose clinical photos were available for reviewing, would be included for further evaluation. The diagnosis of radiation ulcers were made when there is a history of PCI with pictures proven skin ulcers, which presented typical characteristics of radiation injury. Nine patients with radiation ulcer were identified and the incidence was 0.34% (9/2570) per practice and 0.42% (9/2124) per patient. Prolonged procedure time, cumulative multiple procedures, right coronary artery occlusion with chronic total occlusion, obesity, and diabetes are frequent characteristics. The onset interval between the first skin manifestation and the latest radiation exposure varied from 3 weeks to 3 months. The histopathology studies failed to make diagnosis correctly in 5 out of 6 patients. To make thing worse, skin biopsy exacerbated the preexisting radiation dermatitis. Notably, all radiation ulcers were refractory to conventional wound care. Surgical intervention was necessary to heal the wound. Diagnosis of cardiac fluoroscopy intervention induced radiation skin damage is challenging and needs high index of clinical suspicion. Minimizing the radiation exposure by using new approaches is the most important way to prevent this complication. Patient education and a routine postprocedure dermatology follow up are mandatory in high-risk groups for both radiation skin damage and malignancies. This is a retrospective study, thus the true incidence of radiation ulcer caused by cardiac fluoroscopic intervention could be higher. PMID- 26632904 TI - Association of Paraoxonase 1 Gene Polymorphisms With the Risk of Hepatitis B Virus-related Liver Diseases in a Guangxi Population: A Case-control Study. AB - Paraoxonase 1 (PON1), a liver-induced glycoprotein enzyme responsible for antioxidant defense against reactive oxygen species and anti-inflammatory, has been linked to various cancers. The objective of this study was to explore the association of PON1 rs662 and rs705382 with the risk of chronic hepatitis B (CHB), hepatitis B virus-related liver cirrhosis (LC), and hepatocellular carcinoma (HCC) in patients living in the Guangxi region of southern China. The PON1 rs662 and rs705382 single-nucleotide polymorphisms (SNPs) were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 99 CHB patients, 84 LC patients, 258 HCC patients, and 221 healthy controls.Significant associations with CHB risk were observed for the rs705382 SNP after adjusting for sex, age, ethnicity, smoking, alcohol consumption, and body mass index. When stratified by sex and age, this positive association was significantly strengthened among men and individuals over 40 years old. Moreover, a decreased risk of LC was associated with the rs705382 CG and the combined GG + CG genotypes among women, with borderline statistical significance. In haplotype analyses, the haplotype GA was associated with a 1.68-fold increase in the risk of HCC.Our results showed that the PON1 rs705382 SNP might be a risk factor for CHB in Guangxi populations. PMID- 26632905 TI - Acute Pancreatitis Classifications: Basis and Key Goals. AB - To explore the efficacy of the revised Atlanta classification (RACAP) and the determinant-based classification of acute pancreatitis severity (DBCAPS) on the basis of clinical data and feedback from patients with acute pancreatitis (AP). The authors retrospectively investigated a total of 573 patients with AP admitted to our hospital between December 2011 and December 2014. The definitions of severity and local complications in AP using RACAP and DBCAPS are presented and common points and mutual differences between the 2 groups are analyzed and discussed. Classification according to RACAP and DBCAPS found 86 (15%) and 178 (31.1%) mild cases (P < 0.01), 269 (46.9%) and 176 (30.7%) moderate cases (P < 0.01), and 218 (38.0%) and 219 (38.2%) severe cases (P = 0.95), respectively. A major contribution of DBCAPS is the introduction of a new type of severe AP, critical AP, identified in 4 patients (0.7%). Complications were observed in 313 RACAP-defined cases and 153 DBCAPS-defined cases (P < 0.01). Among the 313 RACAP defined cases, acute peripancreatic fluid collection (236 patients, 75.40%), pancreatic pseudocysts (20 patients, 6.4%), acute necrotic collection (42 patients, 13.4%), and walled-off necrosis (15 patients, 4.8%) were observed. Among the 153 DBCAPS-defined cases, sterile peripancreatic necrosis (105 patients, 68.6%), sterile pancreatic necrosis (44 patients, 28.8%), infected peripancreatic necrosis (2 patients, 1.3%), and infected pancreatic necrosis (2/153 patients, 1.3%) were observed. Both classifications adopted organ failure and complications as determinants of severity. Revised Atlanta classification refined local complications and DBCAPS modified severity to include critical AP. In accordance with the demands of precision medicine, a combination of the 2 could be important for further clinical practice and scientific research. PMID- 26632906 TI - Association of Gallbladder Polyp and Stroke: A Nationwide, Population-Based Study. AB - Gallbladder polyp (GP) and stroke share several metabolic disorders as risk factors. We assessed the association between GP and subsequent stroke risk. From 2000 to 2011, patients with GP aged >20 years were identified from the Longitudinal Health Insurance Database 2000. Of the 15,975 examined patients, 12,780 and 3195 were categorized into the non-GP and GP cohorts, respectively. The relative risks of stroke were estimated using the Cox proportional hazard model after adjusting for age, sex, and comorbidities. The overall incidence of stroke was higher in the GP cohort than in the non-GP cohort (6.66 vs 5.20/1000 person-yr), with an incidence rate ratio (IRR) of 1.28 (95% confidence interval [CI] = 1.15-1.42). The risk of stroke was 1.32-fold (95% CI = 1.06-1.63) in patients with GP compared with patients without GP after adjusting for age, sex, income level, urbanization level, occupation and comorbidities of gallstone, alcohol-related illness, diabetes, hyperlipidemia, hypertension, obesity, COPD, coronary heart disease, and asthma. Furthermore, the stroke risk was higher among elderly patients (with 1-yr intervals; adjusted HR [aHR] = 1.06, 95% CI = 1.05 1.07), the male sex (aHR = 1.62, 95% CI = 1.35-1.96), lower income level (aHR = 1.37, 95% CI = 1.02-1.85 for level I; aHR = 1.62, 95% CI = 1.25-2.10 for level II), living in second urbanized areas (aHR = 1.28, 95% CI = 1.00-1.63), alcohol related illness (aHR = 1.56, 95% CI = 1.07-2.28), diabetes (aHR = 1.78, 95% CI = 1.41-2.24), and hypertension (aHR = 2.74, 95% CI = 2.19-3.42). GP is associated with stroke; however, GP may be less influential than other risk factors are, such as male sex, lower income level, alcohol-related illness, diabetes, and hypertension, on stroke development. Additional studies are required to clarify whether GP is a risk factor for or an epiphenomenon of stroke development. PMID- 26632907 TI - Transitional Care and Adherence of Adolescents and Young Adults After Kidney Transplantation in Germany and Austria: A Binational Observatory Census Within the TRANSNephro Trial. AB - Transition from child to adult-oriented care is widely regarded a challenging period for young people with kidney transplants and is associated with a high risk of graft failure. We analyzed the existing transition structures in Germany and Austria using a questionnaire and retrospective data of 119 patients transferred in 2011 to 2012. Most centers (73%) confirmed agreements on the transition procedure. Patients' age at transfer was subject to regulation in 73% (18 years). Median age at transition was 18.3 years (16.5-36.7). Median serum creatinine increased from 123 to 132 MUmol/L over the 12 month observation period before transfer (P = 0.002). A total of 25/119 patients showed increased creatinine >= 20% just before transfer. Biopsy proven rejection was found in 10/119 patients. Three patients lost their graft due to chronic graft nephropathy.Mean coefficient of variation (CoV%) of immunosuppression levels was 0.20 +/- 0.1. Increased creatinine levels >= 20% just before transfer were less frequently seen in patients with CoV < 0.20 (P = 0.007). The majority of pediatric nephrology centers have internal agreements on transitional care. More than half of the patients had CoV of immunosuppression trough levels consistent with good adherence. Although, 20% of the patients showed increase in serum creatinine close to transfer. PMID- 26632908 TI - Prevalence of Dyslipidemia Among Antiretroviral-Naive HIV-Infected Individuals in China. AB - Little is known about the epidemiological features of dyslipidemia among antiretroviral-naive HIV-infected individuals in China. We used a cross-sectional study design to estimate the prevalence of dyslipidemia in this population, and to identify risk factors associated with the presence of dyslipidemia. One thousand five hundred and eighteen antiretroviral-naive HIV-infected individuals and 347 HIV-negative subjects in China were enrolled during 2009 to 2010. Demographics and medical histories were recorded. After an overnight fast, serum samples were collected to measure lipid levels. Factors associated with the presence of dyslipidemia were analyzed by logistic regression. Mean total cholesterol (TC), low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL) levels were lower in HIV-positive than HIV-negative subjects, but mean triglyceride (TG) was higher in HIV-positive subjects. The overall prevalence of dyslipidemia in HIV-positive and HIV-negative groups did not differ (75.6% vs. 73.7%, P = 0.580). However, the prevalence of high TC (8.4% vs. 28.2%, P < 0.001) and high LDL (8.5% vs. 62.6%, P < 0.001) was lower in HIV positive than HIV-negative subjects, and the prevalence of high TG (33.9% vs. 17.0%, P < 0.001) and low HDL (59.6% vs. 11.2%, P < 0.001) was higher in HIV positive than HIV-negative subjects. Logistic analysis showed that HIV positivity was significantly associated with both an increased risk of high TG and low HDL and a decreased risk of high TC and high LDL. The mean levels of TC, of LDL and of HDL showed an increasing trend with increasing CD4 count in HIV-positive subjects. Multivariable logistic regression found that lower CD4 count was significantly associated with both an increased risk of high TG and low HDL and a decreased risk of high TC in HIV-positive subjects. Among antiretroviral-naive HIV-infected Chinese adults, there was a high prevalence of dyslipidemia characterized by high TG and low HDL, which was associated with lower CD4 counts. These data support the assessment of lipid profiles before and after initiation of antiretroviral therapy regardless of age. PMID- 26632909 TI - Prevalence and Risk Factors of Deep Vein Thrombosis in Patients Undergoing Lumbar Interbody Fusion Surgery: A Single-Center Cross-Sectional Study. AB - This cross-sectional study was designed to obtain the current prevalence of deep vein thrombosis (DVT) and analyze related risk factors in patients undergoing lumbar interbody fusion. Medical record data were collected from Department of Spinal Surgery, The Third Hospital of Hebei Medical University, between July 2014 and March 2015. Both univariate analysis and binary logistic regression analysis were performed to determine risk factors for DVT. A total of 995 patients were admitted into this study, including 484 men and 511 women, aged from 14 to 89 years old (median 50, IQR 19). The detection rate of lower limb DVT by ultrasonography was 22.4% (223/995) in patients undergoing lumbar interbody fusion. Notably, average VAS (visual analog scale) score in the first 3 days after surgery in the DVT group was more than that in the non-DVT group (Z = 21.69, P < 0.001). The logistic regression model was established as logit P = 13.257 + 0.056*X1 - 0.243*X8 + 2.085*X10 + 0.001*X12, (X1 = age; X8 = HDL; X10 = VAS; X12 = blood transfusion; x = 677.763, P < 0.001). In conclusion, advanced age, high postoperative VAS scores, and blood transfusion were risk factors for postoperative lower limb DVT. As well, the logistic regression model may contribute to an early evaluation postoperatively to ascertain the risk of lower limb DVT in patients undergoing lumbar interbody fusion surgery. PMID- 26632910 TI - Breast Cancer Subtype is Associated With Axillary Lymph Node Metastasis: A Retrospective Cohort Study. AB - The purpose of this study was to assess whether breast cancer subtype (BCS) as determined by estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 can predict the axillary lymph node metastasis in breast cancer. Patients who received breast conserving surgery or mastectomy and axillary lymph node dissection were identified from 2 cancer centers. The associations between clinicopathological variables and axillary lymph node involvement were evaluated in univariate and multivariate regression analyses. A total of 3471 patients met the inclusion criteria, and 53.0% had axillary lymph node metastases at diagnosis. Patients with hormone receptor (HR)-/human epidermal growth factor receptor 2 (HER2)- subtype had a higher grade disease and the lowest rate of lymphovascular invasion. Univariate and multivariable logistic regression analyses showed that BCS was significantly associated with lymph node involvement. Patients with the HR-/HER2- subtype had the lowest odds of having nodal positivity than those with other BCSs. HR+/HER2- (odds ratio [OR] 1.651, 95% confidence interval [CI]: 1.349-2.021, P < 0.001), HR+/HER2+ (OR 1.958, 95%CI 1.542-2.486, P < 0.001), and HR-/HER2+ (OR 1.525, 95%CI 1.181-1.970, P < 0.001) tumors had higher risk of nodal positivity than the HR-/HER2- subtype. The other independent predictors of nodal metastases included tumor size, tumor grade, and lymphovascular invasion. Breast cancer subtype can predict the presence of axillary lymph node metastasis in breast cancer. HR-/HER2- is associated with a reduced risk of axillary lymph node metastasis compared to other BCSs. Our findings may play an important role in guiding axillary treatment considerations if further confirmed in larger sample size studies. PMID- 26632911 TI - Single Shot Adductor Canal Block for Postoperative Analgesia of Pediatric Patellar Dislocation Surgery: A Case-Series Report. AB - Postoperative analgesia for the knee surgery in children can be challenging. Meanwhile acute pain management in pediatric patients is still often undertreated due to inadequate pain assessment or management. We reported the ultrasound guided single-injection adductor canal block (ACB) with 0.2% ropivacaine and dexmedetomidine (0.5 MUg/kg) in addition in a series of 6 children. Patients' age was range from 7 to 15 years old with right or left habitual patellar dislocation needing an open reduction and internal refixation. Pain assessments using Numeric Rating Scale scores on the operative limb were made preoperatively and at 12, 24, 36, and 48 h postoperatively at rest. Medication consumption was calculated as well. The possible complications, such as hemodynamic changes, nausea, vomiting, and dysesthesia, were also recorded at 12, 24, 36, and 48 h postoperatively at rest. The pain scores were low, and analgesic medication consumption was minimal. Meanwhile, no adverse events were recorded in any of the subject. Single injection ACB might be an optimal analgesia strategy for patellar dislocation surgery in pediatric patients. PMID- 26632912 TI - Association Between Family History and Hypertension Among Chinese Elderly. AB - This study aimed to evaluate the association between family history and prevalence of hypertension among Chinese community elderly, and also explore the gender difference. A population-based cross-sectional study was conducted in Miyun district of Beijing, in 2014. The family history information was obtained from each subject and was divided into 3 categories, no family history (FH0), 1 generation of first-degree relatives with hypertension (FH1), and 2 generations of first-degree relatives with hypertension (FH2). The prevalence of hypertension was 53.0%. Participants with positive family history had a significantly higher prevalence of hypertension (67.5%, 95% CI: 63.3-71.7) than those without (47.9%, 95% CI: 45.2-50.6), and even among participants without hypertension, the blood pressure levels were higher with positive FH. Multiple logistic regression analysis showed that a significantly linear-trend increase in hypertension according to family history of first degree relative numbers was observed in both genders (P for trend < 0.001). This study suggests that family history had not only a significant but also graded association with hypertension and with blood pressure levels, and this association exists even among those without hypertension. PMID- 26632915 TI - Thermal conductivities of single- and multi-layer phosphorene: a molecular dynamics study. AB - As a new two-dimensional (2D) material, phosphorene has drawn growing attention owing to its novel electronic properties, such as layer-dependent direct bandgaps and high carrier mobility. Herein we investigate the in-plane and cross-plane thermal conductivities of single- and multi-layer phosphorene, focusing on geometrical (sample size, orientation and layer number) and strain (compression and tension) effects. A strong anisotropy is found in the in-plane thermal conductivity with its value along the zigzag direction being much higher than that along the armchair direction. Interestingly, the in-plane thermal conductivity of multi-layer phosphorene is insensitive to the layer number, which is in strong contrast to that of graphene where the interlayer interactions strongly influence the thermal transport. Surprisingly, tensile strain leads to an anomalous increase in the in-plane thermal conductivity of phosphorene, in particular in the armchair direction. Both the in-plane and cross-plane thermal conductivities can be modulated by external strain; however, the strain modulation along the cross-plane direction is more effective and thus more tunable than that along the in-plane direction. Our findings here are of great importance for the thermal management in phosphorene-based nanoelectronic devices and for thermoelectric applications of phosphorene. PMID- 26632913 TI - Blood Pressure is Associated With Cerebral Blood Flow Alterations in Patients With T2DM as Revealed by Perfusion Functional MRI. AB - Type 2 diabetes mellitus (T2DM) and hypertension are both associated with cognitive impairment and brain function abnormalities. We investigated whether abnormal cerebral blood flow (CBF) patterns exists in T2DM patients and possible relationships between aberrant CBF and cognitive performance. Furthermore, we examined the influence of hypertension on CBF alterations in T2DM patients. T2DM patients (n = 38) and non-T2DM subjects (n = 40) were recruited from clinics, hospitals, and normal community health screenings. Cerebral blood flow images were collected and analyzed using arterial spin labeling perfusion functional magnetic resonance imaging (fMRI). Regions with major CBF differences between T2DM patients and non-T2DM controls were detected via 1-way ANOVA. The interaction effects between hypertension and T2DM for CBF alterations were also examined. Correlation analyses illustrated the association between CBF values and cognitive performance and between CBF and blood pressure. Compared with non-T2DM controls, T2DM patients exhibited decreased CBF, primarily in the visual area and the default mode network (DMN); decreased CBF in these regions was correlated with cognitive performance. There was a significant interaction effect between hypertension and diabetes for CBF in the precuneus and the middle occipital gyrus. Additionally, blood pressure correlated negatively with CBF in T2DM patients.T2DM patients exhibited reduced CBF in the visual area and DMN. Hypertension may facilitate a CBF decrease in the setting of diabetes. T2DM patients may benefit from blood pressure control to maintain their brain perfusion through CBF preservation. PMID- 26632916 TI - Blepharoptosis following ocular surgery: identifying risk factors. AB - PURPOSE OF REVIEW: To evaluate the incidence of blepharoptosis following ocular surgical procedures, to elucidate mechanisms for its cause, and to identify potential risk factors for ocular surgeons to avoid. RECENT FINDINGS: Postoperative blepharoptosis has been a poorly understood concept. In the search for a definitive cause, various technical components of surgery have been implicated. Recent research highlights the importance of individual anatomy and proposes new mechanisms for postoperative ptosis, including excessive eyelid tension from specula, topical prostaglandin analogue use, and direct trauma at the level of the tarsal plate. SUMMARY: Blepharoptosis is common following ocular surgery and can occur through multiple mechanisms. Certain individuals are at a higher risk for postoperative blepharoptosis, but all surgeons and patients undergoing ocular surgery should understand this risk when providing informed consent. Operative techniques can be adjusted to decrease rates of postoperative blepharoptosis. PMID- 26632917 TI - Ocular dominance, coexistent retinal disease, and refractive errors in patients with cataract surgery. AB - PURPOSE OF REVIEW: The purpose of this article is to highlight some common issues when planning cataract surgery in patients with preexisting ocular pathologies and to assess the role of ocular dominance in cataract surgery. RECENT FINDINGS: In addition to routine ocular examination, determination of ocular dominance and orthoptic evaluation for tropias, phorias, amblyopia, and diplopia can be helpful in planning for cataract surgery as these factors can affect postoperative outcomes. Although once controversial, cataract surgery by phacoemulsification is often a well tolerated and effective option for patients with coexistent retinal conditions including epiretinal membrane, age-related macular degeneration, diabetic retinopathy, and macular holes. SUMMARY: It is mandatory to recognize phorias, tropias, anisometropia, and amblyopia when planning cataract surgery. Visual potential, ocular dominance, refractive errors, and other retinal comorbidities influence cataract surgery planning and outcome. PMID- 26632918 TI - The economics of femtosecond laser-assisted cataract surgery. AB - PURPOSE OF REVIEW: Femtosecond lasers for use during cataract surgery carry significant purchase and use costs. The aim of this article is to help surgeons and surgery centers anticipate financial issues related to implementing femtosecond laser-assisted cataract surgery (FLACS). Such scenarios hopefully can help to inform decision making around the purchase and use of these lasers. RECENT FINDINGS: FLACS has several potential advantages over traditional phacoemulsification. However, although studies have demonstrated noninferiority of FLACS, there continues to be few data to support significantly improved visual outcomes. The literature does show a significantly higher cost for FLACS. As this cost can be passed on to patients under Medicare rules, there is the potential for increased physician revenue, which can be a motivator for adoption of this new technology. The magnitude of this increase is heavily influenced by the financial details of the implementation, like the cost of the laser, the volume of surgery performed, and the incremental increase in revenue. SUMMARY: A financial analysis should be performed prior to purchasing a femtosecond laser. This analysis can help predict if FLACS is going to be a financial windfall or a money loser. PMID- 26632920 TI - The Rendezvous Technique for Common Bile Duct Stones: A Meta-Analysis. AB - PURPOSE: This article aimed to clarify the effectiveness and the efficiency of the rendezvous technique for patients with common bile duct stones. METHODS: Four databases were searched on associations with rendezvous treatment. Six randomized controlled trials were evaluated for their success rate, stone clearance, morbidity, mortality, conversions, hospital stay, operating time, and hospitalization charges. RESULTS: This meta-analysis suggested no significant difference between the rendezvous group and the sequence group in the success rate and the stone clearance, but showed significant differences in the morbidity [odds ratio (OR)=0.54; 95% confidence intervals (CI), 0.30, 0.96], conversions (OR=0.40; 95% CI, 0.16, 0.97), the length of hospital stay (OR=-1.97; 95% CI, 2.29, -1.66), and the operating time (OR=12.95; 95% CI, 7.66, 18.24). CONCLUSIONS: The rendezvous technique is as effective as sequential endoscopic management for patients with common bile duct stones in its success rate and stone clearance, but the former is preferred in terms of morbidity, hospital stay, and hospitalization charges. PMID- 26632921 TI - Prospective Analysis of Laparoscopic Cholecystectomies Based on Postgraduate Resident Level. AB - BACKGROUND: Few studies have attempted to ascertain the safety of laparoscopic cholecystectomies (LC) based on resident postgraduate year. We hypothesize that there is no difference in complications based on resident level in LC. METHODS: We prospectively gathered data from 200 LC. Residents were classified as surgeon chief (SC), surgeon junior (SJ), or teaching assistant (TA/SJ). Outcomes included surgical complications and operative time based on resident level or ambulatory status. RESULTS: Average operating time was 65.17, 69.38, and 63.91 minutes for SC, SJ, and TA/SJ, respectively. Average operative time in the elective group was 62 versus 70.67 minutes in the emergent group (P=0.037). Five, 2, and 6 major complications occurred in the TA/SJ, and SC groups, respectively, (P=0.937). Major complications occurred in 9 of 97 emergent and 4 of 70 elective cases (P=0.396). CONCLUSION: With respect to time and morbidity in LC, we found all level of residents to be safe. PMID- 26632922 TI - Less Surgical Experience Has no Impact on Mortality and Morbidity After Laparoscopic Cholecystectomy: A Prospective Cohort Analysis. AB - BACKGROUND: The number of cholecystectomies required to be fully educated as a surgeon has not yet been established. The European Association for Endoscopic Surgery, however, claims that inadequate experience is a risk factor for bile duct injury. The objective was to investigate surgical experience as a risk factor after laparoscopic cholecystectomy. METHODS: A prospective cohort study using the Danish Cholecystectomy Database to generate a cohort including adults treated with laparoscopic cholecystectomy from 2006 to 2011. The relationship between surgeons' level of experience and outcomes were evaluated. RESULTS: Surgical inexperience was not a risk factor for mortality and morbidity. The risk of conversion was however higher when the patients were operated by more experienced surgeons with an odds ratio of 1.80 (95% confidence interval, 1.51 2.14). Surgical inexperience was not a risk factor for bile duct injury. CONCLUSION: We found that low surgical experience did not by itself increase the risk of mortality or morbidity. PMID- 26632923 TI - Paravertebral Catheter Placement, Under Direct Vision, for Postthoracotomy Analgesia. PMID- 26632924 TI - Strategy of Laparoscopic Partial Resection for Gastric Gastrointestinal Stromal Tumors According to the Growth Pattern. AB - Laparoscopic partial gastrectomy is the standard surgical treatment for gastric gastrointestinal stromal tumor (GIST). However, to reduce gastric deformation, the tumor margins should be secured so as to minimize the size of the resection as much as possible. This is the report on the 3 laparoscopic resection techniques for gastric GIST depending upon the growth pattern and location of the tumor, and their results. We performed laparoscopic partial gastrectomy for 41 gastric GISTs between 2004 and 2012. Simple resection was used on exophytic or small GISTs. Seromuscular resection was used on exoendophytic (intramural) and relatively small endophytic tumors. Transgastric resection was used in cases of large endophytic tumors. We performed simple resection on 24 lesions (58.5%), seromuscular resection on 14 lesions (34.1%), and transgastric resection on 3 lesions (7.3%). There were no intraoperative complications. Postoperative complications included 1 case (2.5%) of bleeding from the staple line. PMID- 26632925 TI - The use of botanical products and vitamins in sunscreens. AB - The use of botanical products and vitamins in skin care creams and sunscreens is prevalent. Herein we conduct an evaluation of sunscreens to quantitatively assess how often sunscreens incorporate botanically derived products and vitamins. The most commonly used botanicals products and vitamins are identified and stratified based on the sunscreen sun protection factor (SPF). The overall prevalence for the use of botanical agents and vitamins was 62% and 79%, respectively. Aloe vera and licorice root extracts were the most common botanical agents used in sunscreens. Retinyl palmitate was the most common vitamin derivative utilized in sunscreens. The prices of sunscreens significantly increased when more than one botanical product was added. Botanical products and vitamins are widely utilized in sunscreens and more research is needed to assess how their inclusion may enhance or alter the function of sunscreens. PMID- 26632926 TI - Skin simulators for dermatological procedures. AB - BACKGROUND: A variety of skin simulators are available on which to practice procedures; however, choice of a suboptimal substitute compromises realism and productive practice. OBJECTIVE: Skin simulators for basic dermatological procedures are reviewed. METHODS: The authors' anecdotal experience with various skin simulators for different procedures is shared. RESULTS: The following simulators are suggested: an unripe banana for elliptical excision, pork belly for undermining, pork belly for simple interrupted and buried suture, capped needle on a human shoulder for intramuscular injection, ripe tomato or hotdog with skin for intradermal injection, eggplant for shave biopsy, pork belly for punch biopsy, plastic tape over a dark surface for cryosurgery, and beef liver for electrosurgery. Flaps are best practiced with foam sandwiched between foam tape or artificial anatomical models created specifically for this purpose. LIMITATIONS: The utility of one simulator over another was not compared in a controlled study. CONCLUSION: Efficient, realistic skin simulators are readily available for practice, which should enhance the safety of the practitioner and improve outcomes of novices. PMID- 26632927 TI - Usefulness of a "puzzle" flap; more than an advancement flap for surgical reconstruction of nasal ala defects: Review of 10 cases. AB - Reconstructive surgery in nasal pyramid can be a challenge for surgeons. Moreover this anatomic area is one the most common sites for non-melanoma skin cancer. The "puzzle" flap was described to repair surgical defects located just on the nasal ala affecting melolabial sulcus. We have seen this flap can be also very useful to repair defects located on nasal sidewall and cheek without dysfunctional effects and with a good cosmetic result. PMID- 26632928 TI - Treatment of metastatic cutaneous Crohn disease with certolizumab. AB - Metastatic Crohn disease is a rare cutaneous manifestation of Crohn disease characterized by granulomatous lesions discontinuous with the diseased areas of the gastrointestinal tract. We report a case of a 32-year-old woman with history of Crohn disease who was admitted for treatment of cellulitis after presenting with a tender erythematous plaque of the left calf. Microbiological tests including tissue cultures were negative. A skin biopsy revealed granulomatous dermatitis consistent with metastatic cutaneous Crohn disease. Owing to concomitant perianal fistulas and abscesses and prior infusion reaction to infliximab, the patient was treated with certolizumab, a pegylated tumor necrosis factor (TNF) inhibitor combined with methotrexate resulting in complete resolution of the skin lesion. This case emphasizes the importance of recognizing this rare skin manifestation of Crohn disease and adds certolizumab as one of TNF inhibitors useful in the treatment of metastatic cutaneous Crohn disease. PMID- 26632929 TI - Unilateral nevoid trichoepitheliomas on the neck: an unfamiliar presentation. AB - Trichoepitheliomas are epidermal appendageal hamartomas, which usually present as solitary lesions; rarely multiple lesions may be present, mainly involving the centrofacial skin symmetrically. We report herein an adolescent male patient with multiple trichoepitheliomas, linearly arranged and dermatomal, present since birth, along the left side of the neck. PMID- 26632930 TI - Adalimumab-induced psoriatic alopecia/alopecia areata-like reaction in a patient with Crohn's disease. AB - Anti-tumor necrosis factor (anti-TNF) agents have been successfully used to treat both chronic idiopathic inflammatory bowel disease and other immune-mediated chronic diseases, but they can also induce a wide array of cutaneous reactions, including new-onset psoriasis and alopecia. We report a case of alopecia associated with psoriasiform skin lesions in a patient on adalimumab treatment for Crohn's disease. PMID- 26632931 TI - Persistent blaschkitis responsive to high potency topical steroids. AB - Blaschkitis is an acquired, rare dermatosis distributed along the lines of Blaschko. The papulovesicular eruption generally resolves in weeks and shows minimal response to topical steroids. Herein, we present a case of blaschkitis in an adult male who had lesions present for one year, which showed significant improvement after two weeks of topical clobetasol ointment. PMID- 26632932 TI - Hyperkeratotic variant of porokeratosis in a patient with Hepatitis C virus infection and a concomitant immunosuppressed state. AB - Porokeratoses are acquired and hereditary disorders of keratinization that share a distinctive lesion characterized by raised keratotic borders corresponding histologically to an angled column of parakeratotic cells, called a cornoid lamella. Although a precise mechanistic explanation is lacking, ultraviolet radiation and immunosuppressed states are considered causally-associated with most cases of acquired porokeratosis. Hepatitis C virus (HCV) infection has been proposed as a link between the immunosuppressed states and development of acquired porokeratosis. Among the various recognized clinical entities that constitute this group, rare cases of hyperkeratotic variants have been described that may pose a diagnostic challenge. Herein we describe a remarkable case of the hyperkeratotic variant of porokeratosis that occurred in a patient with known HIV and HCV infections and a coexisting therapy-related immunosuppressed state. We also provide a review of the relevant literature. PMID- 26632933 TI - A curious case of blue-green discoloration in a middle-aged indian man: Chromhidrosis. AB - INTRODUCTION: Chromhidrosis is a rare sweat gland disorder characterized by the excretion of colored sweat. It can be classified as apocrine, true eccrine, and pseudochromhidrosis. Amongst the different types of chromhidrosis, green chromhidrosis is extremely rare. We describe herein a case of blue green chromhidrosis induced by ingestion of homeopathic medicine. CASE REPORT: A middle aged man presented to us with blue green discoloration of hands and feet. There was a preceding history of ingestion of homeopathic medication. Histopathology from the involved skin showed greenish particles within eccrine glands. Initial blood copper level was high which returned to normal level after discontinuation of the homeopathic medicine. Spectrophotometry revealed high copper content of the green sweat. CONCLUSION: Our case emphasizes the importance of considering any type of ingested medicine, including homeopathic medicine, as a probable cause of chromhidrosis. PMID- 26632934 TI - Pressure-induced isomorphic sclerodermoid graft-versus-host disease from brassiere underwire and tight-fitting watch. AB - Sclerodermoid chronic graft-versus-host disease (scGVHD) is a rare form of cGVHD with an estimated prevalence of 3% to 11% in patients receiving allogeneic bone marrow transplants. scGVHD is believed to be an immune-mediated response characterized by aberrant T-cell function and dysregulation of tyrosine kinase cascades. Published literature on scGVHD is still limited and the mechanisms are yet to be fully understood. Thus, successful treatment of scGVHD remains largely unknown and many current options are hindered by potential side effects. This case provides an example of scGVHD localizing to areas of trauma and friction as a potential mechanism behind scGVHD and provides several case reports that document similar findings. PMID- 26632935 TI - Folliculocentric cutaneous presentation of disseminated Candida krusei infection in a patient with acute myeloid leukemia. AB - Candida krusei (C. krusei) is a multidrug-resistant opportunistic fungal pathogen that may cause disseminated infections in immunocompromised hosts. However, its clinical and histologic features are not well-characterized. We present a unique case to contribute to the growing knowledge base associated with this organism. During hospitalization for neutropenic fever, a 19-year-old man with acute myeloid leukemia, who underwent hematopoietic stem cell transplantation, developed a generalized folliculocentric eruption following initiation of antifungal therapy for newly diagnosed C. krusei fungemia. Despite adequate antifungal coverage and negative blood cultures, the follicular-based erythematous papules persisted. Biopsies demonstrated yeast within ruptured follicles, without angiotropism or involvement of the interfollicular dermis, subcutaneous tissue, or stratum corneum. Concurrent skin tissue cultures confirmed C. krusei. The patient remained febrile despite aggressive antifungal therapy, with relapse of leukemia and subsequent death. Our case is unusual given the development of cutaneous lesions following clearance of fungemia, with yeast limited to ruptured follicular lumina, possibly indicating a primary cutaneous source or early transfollicular/transepidermal elimination. Given the limited available descriptions of cutaneous histopathology for C. krusei, we seek to add to the understanding of its pathophysiology and aid in the diagnosis and treatment of this often fatal infection. PMID- 26632936 TI - Ungual squamous cell carcinoma mimicking a chronic paronychia: clinical, pathological and radiological correlation. AB - Squamous cell carcinoma is a malignant skin tumor that is rarely located in the nails. Its presentation, can sometimes be confused with an inflammatory process as onychomycosis or psoriatic onychopathy or other tumors as viral warts. We report the case of a 73-year-old woman with a locally invasive squamous cell carcinoma reaching the bone, simulating a chronic paronychia. PMID- 26632937 TI - Painful nodule in the caesarean section scar of a young woman. AB - Endometriosis is the presence of ectopic endometrial tissue outside the uterus and cutaneous endometriosis is a rare manifestation of this disease that may be found at the sites of surgical scars as a result of iatrogenic implantation. Herein we present a case of scar endometriosis in a 35-year-old woman. The scar was sustained following a remote caesarean section. PMID- 26632938 TI - Impact of the Pregnancy and Lactation Labeling Rule (PLLR) on Practicing Dermatologists. AB - On June 30th 2015, the FDA instituted a new system for the categorization of drug safety during pregnancy and lactation, known as the Pregnancy and Lactation Labeling Rule (PLLR), which replaces the "A, B, C, D, X" pregnancy labeling categories. The new rule will apply to all newly approved prescription medications, with a staggered phase-in for prescription drugs approved prior to the effective date. In this article, we provide a brief description of the major changes introduced by the PLLR and discuss the major implication of this new categorization system for clinical dermatologists. PMID- 26632939 TI - Extensive keloid formation after pemphigus vulgaris. AB - Pemphigus vulgaris is an immunobullous disease characterized by intraepidermal blister formation. These blisters eventually rupture, leaving erosions that are slow to heal, often leaving hyperpigmented patches, but no scars. We describe a case of a 67- year-old man with pemphigus vulgaris who suffered severe keloidal scarring after the pemphigus lesions became infected. His keloids were treated with intralesional corticosteroids with some improvement. Pemphigus vulgaris, a process confined to the epidermis, may lead to scarring in predisposed individuals, particularly if infection occurs. PMID- 26632940 TI - Paronychia-like cutaneous leishmaniasis. AB - Chronic paronychia is an inflammatory recalcitrant disorder affecting the nail folds. We report one patient with paronychia revealing ungueal leishmaniasis. A 34-year-old man, resident in the north of Morocco, presented with a 6-month history of an inflamed proximal nail fold of the left thumb, resistant to antibiotics and anti-fungal treatments. En bloc excision of the proximal nail fold was done. The histopathological exam showed epithelioid granulomas with giant cells and the presence of leshmania amastigotes, leading to the diagnosis of ungueal leishmaniasis. Clinical aspects of cutaneous leishmaniasis can be very misleading. The paronychial form is rarely described. In endemic areas it is necessary for the physician to be aware of atypical skin presentations of leishmaniasis. PMID- 26632941 TI - Failure of lichen planopilaris to respond to ustekinumab. AB - Lichen planopilaris failed to respond to ustekinumab after 10 months of treatment. PMID- 26632942 TI - Professional dermatology societies in the USA: an overview. AB - This is a concise overview in a table format for the current membership-based dermatology societies in the USA. The primary objective of these societies is to provide continuous medical education. These societies serve all health care providers in dermatology care, including physician assistants and nurses. There is a clear need for establishing more societies which focus on different aspect of dermatology. There is always a potential for improving the educational activities of these societies. PMID- 26632943 TI - Cutaneous myiasis of scalp in a young girl related to Musca domestica. AB - Cutaneous myiasis is a parasitic disease secondary to the presence of the larvae of certain insects, particularly diptera, in the skin of man or vertebrates [1]. Human myiasis is a rare clinical condition, but more frequently seen in tropical and subtropical areas. Hot humid climate with inadequate sanitary conditions favor the development of this condition. Dermatitis, psychiatric illnesses, leprosy, and diabetes are some contributory factors [2]. Treatment of myiasis, once diagnosed, is simple and rapid recovery is anticipated. PMID- 26632944 TI - Dermatologic health literacy in underserved communities: a case report of south Los Angeles middle schools. AB - BACKGROUND: The incidence of melanoma and other skin cancers has risen drastically in the United States. As with most types of cancer, the prognosis and survival rates are significantly improved with early diagnosis, but dismal for patients who present with advanced disease. It remains a fact that although melanoma is most common in Caucasian populations, ethnic minorities have a worse prognosis. Our hypothesis in this dermatologic health literacy study was that before necessary education, the required fund of knowledge with respect to skin cancer risk is lacking in several ethnic communities, but that intended compliance occurs when educational intervention occurs. METHODS: Three middle schools in South Los Angeles with predominantly Latino and African American youth were surveyed. Permission was obtained from the principals of the middle schools for the multi-day educational initiative. A total of 150 students were ultimately recruited and a pre-intervention survey administered. After preliminary review of the pre-intervention dermatologic health literacy results, a set of "core" learning concepts about sun safety were summarized and solidified for incorporation into the adolescent-appropriate sun safety protection pamphlet that was designed by designers at UCLA/Johnson & Johnson Health Care Institute. A full day of education on skin disease and the importance of sun protection from an early age was executed, followed three months later by a post-intervention visit that assessed compliance with the sun protection products and intended future use. RESULTS: Results from the pre- and post-intervention surveys/questionnaires were analyzed and interpreted. Of 150 pre-intervention surveys that were distributed, 54 identified as African American and 96 of whom identified as Latino. Of these, 75% of Latino students reported having a sunburn in the last year, whereas only 38.9% of African American students reported a sunburn. A total of 80% of the students reported as least some use of sunscreen in the 3 months prior to the post-intervention survey. Only 8% of African American students reported "everyday" use, whereas 24% of Latino students reported "everyday" use (P < 0.05). A total of 94% of the students intend to wear sunscreen in the future (89% of African American students and 97% of Latino students, with a P < 0.05 calculated using a two-sample t test). However, it should be noted that more than half (54%) of the total students reported that although they planned to apply the sunscreen daily, they deemed it too expensive, which might prevent consistent future use. CONCLUSIONS: Our hypothesis in this dermatologic health literacy study was that before necessary education, the required fund of knowledge with respect to skin cancer risk is lacking in several ethnic communities, but that intended compliance occurs when educational intervention occurs. The data, both quantitative and qualitative, demonstrate that our hypothesis is substantiated. PMID- 26632945 TI - Assignment of Milk Fat Fatty Acid Propyl Esters by GC-FID Analysis with the Aid of Ag-ion Solid-phase Extraction. AB - The recovery of short-chain fatty acids (FAs) in milk fat (MF) is improved when the analysis of the FA composition of MF by gas chromatography (GC) is conducted with the propyl or butyl ester derivatives, instead of the methyl esters. However, this approach complicates the detection of minor FAs, such as the minor positional isomers of 16:1, which represent <0.2% of the total content. In addition, the standards of these minor esters are not commercially available. In this study, with the aim to identify minor FAs, the fatty acid propyl esters (FAPEs) of MF were fractionated by Ag-ion solid phase extraction (Ag(+)-SPE) and analyzed by GC using a DB-23 capillary column. FAPEs were successfully fractionated mainly according to the degree of unsaturation by adjusting the elution conditions of the Ag(+)-SPE, and the minor FAPEs were easily determined without the aid of standard compounds. For example, by comparison of the GC profile of the saturated Ag(+)-SPE fraction with that of the original MF, minor FAs, such as iso-, anteiso-, and saturated FAs of 15:0 and 17:0, were expected to be eluted in this order. In addition, 16:1 propyl ester was co-eluted with iso 17:0 propyl ester under the GC conditions used in this study, as confirmed by the detection of the corresponding molecular ions (296 and 312, respectively) by GC MS. Moreover, 9c,11t-conjugated linoleic acid was found to elute between 18:3 and 20:0. To the best of our knowledge, this is the first report suggesting that the peak observed before that of cis-12:1 corresponds to trans-12:1. In conclusion, Ag(+)-SPE fractionation of FAPEs contributed to the identification of minor FAs in MF without the use of standard compounds. PMID- 26632946 TI - Physicochemical Properties and Fatty Acid Profiles of Elaeagnus mollis Diels Nut Oils. AB - The physicochemical properties, fatty acid profiles, content of tocopherol and sterol of the oils extracted from the nuts of Elaeagnus mollis Diels grown in different regions of China were studied in this work. The results indicated that the Elaeagnus mollis Diels nut oils contained about 0.2% sterols and the tocopherol contents were in the range of 119.6-128.6mg/100g. The nut oils were all rich in unsaturated fatty acids, especially oleic acid and linoleic acid. Furthermore, the main triacylglycerols species of the nut oils were all dilinoleoyl-monoolein (LOL), dioleoyl-monolinoleoyl (OLO) and trilinoleate (LLL). This work might be useful for developing applications for Elaeagnus mollis Diels nut oil. PMID- 26632947 TI - Composition of the Essential Oil of Allium neapolitanum Cirillo Growing Wild in Sicily and its Activity on Microorganisms Affecting Historical Art Crafts. AB - Essential oil of the aerial parts of Allium neapolitanum Cirillo collected in Sicily were analyzed by gas-chromatography-flame-ionization detection and gas chromatography-mass spectrometry. Nineteen compounds were identified in the oil and the main components were found to be (E)-chrysanthenyl acetate (28.1%), (Z) chrysanthenyl acetate (23.8%), (E)-beta-farnesene (9.6%), dimethyl trisulfide (9.6%), camphor (7.4%), methyl allyl disulfide (6.8%) and 1-methyl-3-allyl trisulfide (5.8%). The essential oil showed good antimicrobial activity against 11 strains of test microorganisms, including several species infesting historical material. PMID- 26632948 TI - Chemical Composition and Aroma Evaluation of Essential Oils from Skunk Cabbage (Symplocarpus foetidus). AB - Two sample preparation methods, namely hydrodistillation (HD) and solvent assisted flavor evaporation (SAFE), have been used to investigate the essential oils of the aerial parts (leaves and stems) of Symplocarpus foetidus, a plant with a characteristic odor, by gas chromatography mass spectrometry (GC-MS). Characteristic aroma-active compounds in the oils were detected by GC Olfactometry (GC-O) and aroma extract dilution analysis (AEDA). From the HD method, the main compounds in the oil were found to be p-vinyl-guaiacol (15.5%), 2-pentyl-furan (13.4%), and (Z)-ligustilide (9.5%). From the SAFE method, the main compounds were 2-butoxy-ethanol (49.6%), ethyl-pentanoate (4.5%), and mesitylene (4.0%). In HD oil, the most intense aroma-active compounds were 2 pentyl-furan (flavor dilution factor (FD) = 32, odor activity value (OAV) = 57), p-vinyl-guaiacol (FD = 16, OAV = 41), and dimethyl disulfide (FD = 16, OAV = 41). In SAFE oil, the main aroma-active compounds were 2-butoxy ethanol (FD = 32, OAV = 16), and 2-methoxy thiazole (FD = 32, OAV = 25). PMID- 26632949 TI - Is Saturday Night Retinopathy Being Reported More Frequently? PMID- 26632950 TI - Chemotherapy-Related Chronic Myelogenous Leukemia: A Case Series of Patients With Germ Cell Tumor. PMID- 26632951 TI - Five- and 10-Year Cause-Specific Survival Rates in Carcinoma of the Minor Salivary Gland. AB - IMPORTANCE: Previous studies of prognostic factors of carcinoma of the minor salivary gland (MSG) have been limited to single-institution studies and small case series. Thus, limited data are available to guide the head and neck oncologist in counseling patients on the prognosis and management of these malignant neoplasms. OBJECTIVE: To examine 5- and 10-year cause-specific survival (CSS) rates of MSG carcinomas across all histologic subtypes and head and neck tumor subsites. DESIGN, SETTING, AND PATIENTS: Retrospective, population-based study using National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) data from January 1, 1988, through December 31, 2009. The study included 5334 patients diagnosed as having MSG carcinoma and registered in the SEER database. Patients without follow-up, diagnostic confirmation, and/or race designation were excluded from the analysis (131 [2.4%]). Final follow-up was completed on December 31, 2009, and data were analyzed from August 5, 2013, to July 1, 2014. MAIN OUTCOMES AND MEASURES: Five- and 10-year CSS rates for US patients with MSG carcinoma. Cox proportional hazard models were used to estimate adjusted hazard ratios (HRs) and 95% CIs. RESULTS: Among the 5334 patients with MSG carcinoma included, the most common histologic subtypes included mucoepidermoid carcinoma (1568 [29.4%]), adenoid cystic carcinoma (1228 [23.0%]), and adenocarcinoma (1313 [24.6%]). The most frequent sites of primary tumor were the oral cavity (3132 [58.7%]) and pharynx (1130 [21.2%]). Five-year CSS rate was significantly worse for MSG malignant neoplasms located in the larynx (HR, 2.42; 95% CI, 1.67-3.50) and nasal cavity and/or paranasal sinus (HR, 1.73; 95% CI, 1.29-2.32). Being older than 75 years was associated with a significantly worse 5 year CSS rate (HR, 2.88; 95% CI, 2.05-4.06). Compared with no surgery, local tumor destruction (HR, 0.44; 95% CI, 0.30-0.64), partial surgery (HR, 0.33; 95% CI, 0.23-0.47), and total surgery (HR, 0.55; 95% CI, 0.41-0.74) were each found to be a significant positive prognostic factor. No differences were observed in the 5-year hazard of death for race/ethnicity, sex, diagnosis year, or socioeconomic status, and 10-year adjusted HRs were similar to the 5-year patterns. CONCLUSIONS AND RELEVANCE: This study, to date, represents the largest US survival analysis of carcinoma of the MSG. Prognosis is associated with histologic subtype, tumor subsite, age at diagnosis, grade, and surgical therapy. PMID- 26632952 TI - Forty-Year Trends in Tooth Loss Among American Adults With and Without Diabetes Mellitus: An Age-Period-Cohort Analysis. AB - INTRODUCTION: This study aimed to assess the trends in tooth loss among adults with and without diabetes mellitus in the United States and racial/ethnic disparities in tooth loss patterns, and to evaluate trends in tooth loss by age, birth cohorts, and survey periods. METHODS: Data came from 9 waves of the National Health and Nutrition Examination Survey (NHANES) from 1971 through 2012. The trends in the estimated tooth loss in people with and without diabetes were assessed by age groups, survey periods, and birth cohorts. The analytical sample was 37,609 dentate (ie, with at least 1 permanent tooth) adults aged 25 years or older. We applied hierarchical age-period-cohort cross-classified random-effects models for the trend analysis. RESULTS: The estimated number of teeth lost among non-Hispanic blacks with diabetes increased more with age than that among non Hispanic whites with diabetes (z = 4.05, P < .001) or Mexican Americans with diabetes (z = 4.38, P < .001). During 1971-2012, there was a significant decreasing trend in the number of teeth lost among non-Hispanic whites with diabetes (slope = -0.20, P < .001) and non-Hispanic blacks with diabetes (slope = -0.37, P < .001). However, adults with diabetes had about twice the tooth loss as did those without diabetes. CONCLUSION: Substantial differences in tooth loss between adults with and without diabetes and across racial/ethnic groups persisted over time. Appropriate dental care and tooth retention need to be further promoted among adults with diabetes. PMID- 26632953 TI - Tobacco Smoking in Islands of the Pacific Region, 2001-2013. AB - We provide an overview of tobacco smoking patterns in Pacific island countries and territories to facilitate monitoring progress toward the goal of a Tobacco Free Pacific by 2025. We examined data from 4 surveys conducted in the region between 2001 and 2013, including the STEPwise approach to surveillance for adults (25-64 years); the Global School-Based Student Health Survey and the Global Youth Tobacco Survey (students 13-15 years); and the Youth Risk Behavior Surveillance System (grade 9-12 students) in United States affiliated Pacific Islands (USAPIs). Adult smoking prevalence ranged from less than 5% of women in Vanuatu to almost 75% of men in Kiribati. Smoking prevalence among students (13-15 years) ranged between 5.6% and 52.1%. There were declines in smoking among youths in many USAPIs. To achieve the tobacco-free goal and reduce disease burden, accelerated action is needed to align national legislation with international agreements and build capacity for tobacco control at all levels. PMID- 26632954 TI - Adaptation of an Evidence-Based Colorectal Cancer Screening Program Using the Consolidated Framework for Implementation Research. AB - INTRODUCTION: Federally Qualified Health Centers (FQHCs) provide primary care to low-income and uninsured patients in the United States. FQHCs are required to report annual measurements and provide evidence of improvement for quality measures; effective methods to improve quality in FQHCs are needed. Systems of Support (SOS) is a proactive, mail-based, colorectal cancer screening program that was developed and tested in an integrated health care system. The objective of this study was to adapt SOS for use in an FQHC system, guided by the Consolidated Framework for Implementation Research (CFIR). METHODS: We conducted qualitative semi-structured interviews in 2014 with organizational leadership, medical staff, and nursing staff to identify facilitators of and barriers to implementation of SOS in an FQHC system. The interview guide was based on the CFIR framework. Interview transcripts were analyzed using Template Analysis. We adapted SOS and planned implementation strategies to address identified barriers. RESULTS: Facilitators of implementation of SOS were previous quality improvement experience and engagement of clinic and administrative leadership. Barriers to implementation were a more diverse patient population, a decentralized administrative structure, and communication challenges throughout the organization. Program adaptations focused on patient instructions and educational materials as well as elimination of follow-up phone calls. Implementation strategies included early and frequent engagement with organizational leadership and a smaller pilot program before organization-wide implementation. CONCLUSIONS: Use of CFIR identified facilitators of and barriers to implementation of the evidence-based colorectal cancer screening program. Program adaptations and implementation strategies based on this study may generalize to other FQHC systems that are considering implementation of a proactive, mail-based colorectal cancer screening program. PMID- 26632955 TI - A Mixed-Method Application of the Program Sustainability Assessment Tool to Evaluate the Sustainability of 4 Pediatric Asthma Care Coordination Programs. AB - INTRODUCTION: As part of a cross-site evaluation of the implementation of an evidence-based intervention for pediatric asthma care coordination into low income communities, we sought to understand the factors that influenced the programs' expected sustainability of the programs after external funding ended. METHODS: We administered the Center for Public Health Systems Science's Program Sustainability Assessment Tool, a 40-item instrument assessing 8 domains of sustainability capacity, to 12 key informants across 4 program sites. We developed open-ended probes for each domain. We examined patterns in site specific and overall domain scores, and coded qualitative data to identify challenges and strategies in each domain. RESULTS: Across sites, the domains of program evaluation (cross-site mean, 5.4 on a scale of 1-7) and program adaptation (mean, 5.2) had the highest ratings (indicating a strong finding during program evaluation) and funding stability had the lowest rating (mean, 2.7). Scores varied most across sites in the domains of strategic planning (SD, 0.9) and funding stability (SD, 0.9). Qualitative data revealed key challenges, including how implementation difficulties and externally led implementation can impede planning for sustainability. Program leaders discussed multiple strategies for enhancing capacity within each domain, including capitalizing on the interconnectedness of all domains, such as using evaluation and communication strategies to bolster internal political support throughout the implementation process. CONCLUSION: Findings indicating weak and strong domains were consistent with previous findings of studies that used the Program Sustainability Assessment Tool. The addition of qualitative probes yielded detailed data describing capacity strengths, weaknesses, and strategies to increase the likelihood that programs are sustained. PMID- 26632957 TI - QuickStats: Percentage of Uninsured Persons Aged <65 Years With No Health Insurance Coverage Because of Cost, by Race/Ethnicity--National Health Interview Survey, United States, 2004 and 2014. PMID- 26632956 TI - Formative Evaluation to Increase Availability of Healthy Snacks and Beverages in Stores Near Schools in Two Rural Oregon Counties, 2013. AB - INTRODUCTION: Children living in rural areas are at greater risk for obesity than their urban counterparts. Differences in healthy food access may contribute to this disparity. Most healthy food access initiatives target stores in urban areas. We conducted a formative evaluation to increase availability of healthy snacks and beverages in food stores near schools in rural Oregon. METHODS: We assessed availability of healthy snacks and beverages in food stores (n = 15) using the SNACZ (Students Now Advocating to Create Healthy Snacking Zones) checklist and conducted in-depth interviews with food store owners (n = 6). Frequency distributions were computed for SNACZ checklist items, and interview data were analyzed by using applied thematic analysis. RESULTS: Overall, availability of healthy snacks and beverages in study communities was low. Four interrelated themes regarding store owner perspectives on stocking healthy snacks and beverages emerged from the interviews: customer demand, space constraints, vendor influence, and perishability. CONCLUSION: In addition to working with food store owners, efforts to increase availability of healthy snacks and beverages in rural areas should engage young people, food buyers (eg, schools), and vendors as stakeholders for identifying strategies to increase demand for and availability of these items. Further research will be needed to determine which strategies or combinations of strategies are feasible to implement in the study communities. PMID- 26632958 TI - Psoriasis in melanoma patients: a prospective pilot study. AB - BACKGROUND: Melanoma is an immunogenic tumor and the presence of T-cell infiltrates within melanoma lesions may correlated with longer patient survival. Psoriasis is a chronic immune-mediated inflammatory disease, in which the role of T-cells is well established. The aim of our prospective pilot study was to investigate the relationship between melanoma and psoriasis examining 3 groups of patients: the melanoma-group (MG), the psoriasis-group (PG) and the control-group (CG). METHODS: Every patient underwent detailed anamnestic and clinical examination. Moreover, gene expression of interleukin-6 (IL-6), interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) was analyzed in all groups and in subjects affected by both melanoma and psoriasis (MP). RESULTS: Melanoma patients showed a lower frequency of psoriasis and positive family history (FH) of psoriasis respect to CG. Moreover, psoriatic patients presented fewer MN, and lower frequency of positive FH of melanoma than CG. IL-6 and IFN gamma were significantly increased in PG and reduced in MG. CONCLUSIONS: We propose a provocative hypothesis of a possible protective role of psoriasis for melanoma development. PMID- 26632959 TI - New therapeutic approaches in the treatment of anogenital lichen sclerosus: does photodynamic therapy represent a novel option? AB - BACKGROUND: Lichen sclerosus et atrophicus (LSA) is an inflammatory, mucocutaneous disorder that affects male and especially female with a debilitating impact on the quality of life. Common localization is the anogenital area. If not treated LSA can leave scars, functional impairment and can evolve in squamous cell carcinoma. The first line of treatment is represented by topical, ultra-potent corticosteroids, but often patients are unresponsive; moreover this therapy is frequently associated to relapses of the disease after discontinuation. METHODS: In this prospective observational study, the efficacy of three different treatments - topical calcineurin inhibitors, avocado and soya beans extracts, and methyl aminolevulinate photodynamic therapy (MAL-PDT) - was evaluated, and an effort has been made to define a therapeutic algorithm according to the severity of the disease. RESULTS: Of the 150 patients who were referred to the outpatient clinic for a dermatological and gynecological visit, 33 met the inclusion criteria. Sixteen (88%) patients showed an improvement of the lesion and a reduction of the itch; 3 (16.7%) patients with sever itch and fissurated lesions were evaluated for the MAL-PDT therapy. A total of 9 patients, after accurate examination of the lesions, were treated with MAL-PDT. The totality of the patients experienced a resolution of the lesions. CONCLUSIONS: In the early stages the use of ASE can represent a valid alternative that is well tolerated by the patients reducing the itching, dryness and improving the mucosal texture. The use of MAL-PDT represents a valid treatment in the moderate-severe stages of LSA. PMID- 26632960 TI - Robust Superhydrophobic Graphene-Based Composite Coatings with Self-Cleaning and Corrosion Barrier Properties. AB - Superhydrophobic surfaces for self-cleaning applications often suffer from mechanical instability and do not function well after abrasion/scratching. To address this problem, we present a method to prepare graphene-based superhydrophobic composite coatings with robust mechanical strength, self cleaning, and barrier properties. A suspension has been formulated that contains a mixture of reduced graphene oxide (rGO) and diatomaceous earth (DE) modified with polydimethylsiloxane (PDMS) that can be applied on any surface using common coating methods such as spraying, brush painting, and dip coating. Inclusion of TiO2 nanoparticles to the formulation shows further increase in water contact angle (WCA) from 159 +/- 2 degrees to 170 +/- 2 degrees due to the structural improvement with hierarchical surface roughness. Mechanical stability and durability of the coatings has been achieved by using a commercial adhesive to bond the superhydrophobic "paint" to various substrates. Excellent retention of superhydrophobicity was observed even after sandpaper abrasion and crosscut scratching. A potentiodynamic polarization study revealed excellent corrosion resistance (96.78%) properties, and an acid was used to provide further insight into coating barrier properties. The ease of application and remarkable properties of this graphene-based composite coating show considerable potential for broad application as a self-cleaning and protective layer. PMID- 26632961 TI - Genomics innovation: transforming healthcare, business, and the global economy. AB - The genomics revolution has generated an unprecedented number of assets to propel innovation. Initial availability of genomics-based applications show a significant potential to contribute addressing global challenges, such as human health, food security, alternative sources of energies, and environmental sustainability. In the last years, most developed and emerging nations have established bioeconomy agendas where genomics plays a major role to meet their local needs. Genomic medicine is one of the most visible areas where genomics innovation is likely to contribute to a more individualized, predictive, and preventive medical practice. Examples in agriculture, dairy and beef, fishery, aquaculture, and forests industries include the effective selection of genetic variants associated to traits of economic value. Some, in addition to producing more and better foods, already represent an important increase in revenues to their respective industries. It is reasonable to predict that genomics applications will lead to a paradigm shift in our ability to ease significant health, economic, and social burdens. However, to successfully benefit from genomics innovations, it is imperative to address a number of hurdles related to generating robust scientific evidence, developing lower-cost sequencing technologies, effective bioinformatics, as well as sensitive ethical, economical, environmental, legal, and social aspects associated with the development and use of genomics innovations. PMID- 26632962 TI - Improved Parameterization of Amine-Carboxylate and Amine-Phosphate Interactions for Molecular Dynamics Simulations Using the CHARMM and AMBER Force Fields. AB - Over the past decades, molecular dynamics (MD) simulations of biomolecules have become a mainstream biophysics technique. As the length and time scales amenable to the MD method increase, shortcomings of the empirical force fields, which have been developed and validated using relatively short simulations of small molecules, become apparent. One common artifact is aggregation of water-soluble biomolecules driven by artificially strong charge-charge interactions. Here, we report a systematic atom pair-specific refinement of Lennard-Jones parameters (NBFIX) describing amine-carboxylate and amine-phosphate interactions, which bring MD simulations of basic peptide-mediated nucleic acid assemblies and lipid bilayer membranes into better agreement with experimental data. As our refinement does not affect the existing parametrization of bonded interactions or alter the solvation free energies, it improves the realism of an MD simulation without introducing additional artifacts. PMID- 26632963 TI - Clinical Framework and Medical Countermeasure Use During an Anthrax Mass-Casualty Incident. AB - In 2014, CDC published updated guidelines for the prevention and treatment of anthrax (Hendricks KA, Wright ME, Shadomy SV, et al. Centers for Disease Control and Prevention expert panel meetings on prevention and treatment of anthrax in adults. Emerg Infect Dis 2014;20[2]. Available at http://wwwnc.cdc.gov/eid/article/20/2/13-0687_article.htm). These guidelines provided recommended best practices for the diagnosis and treatment of persons with naturally occurring or bioterrorism-related anthrax in conventional medical settings. An aerosolized release of Bacillus anthracis spores over densely populated areas could become a mass-casualty incident. To prepare for this possibility, the U.S. government has stockpiled equipment and therapeutics (known as medical countermeasures [MCMs]) for anthrax prevention and treatment. However, previously developed, publicly available clinical recommendations have not addressed the use of MCMs or clinical management during an anthrax mass-casualty incident, when the number of patients is likely to exceed the ability of the health care infrastructure to provide conventional standards of care and supplies of MCMs might be inadequate to meet the demand required. To address this gap, in 2013, CDC conducted a series of systematic reviews of the scientific literature on anthrax to identify evidence that could help clinicians and public health authorities set guidelines for intravenous antimicrobial and antitoxin use, diagnosis of anthrax meningitis, and management of common anthrax-specific complications in the setting of a mass-casualty incident. Evidence from these reviews was presented to professionals with expertise in anthrax, critical care, and disaster medicine during a series of workgroup meetings that were held from August 2013 through March 2014. In March 2014, a meeting was held at which 102 subject matter experts discussed the evidence and adapted the existing best practices guidance to a clinical use framework for the judicious, efficient, and rational use of stockpiled MCMs for the treatment of anthrax during a mass casualty incident, which is described in this report. This report addresses elements of hospital-based acute care, specifically antitoxins and intravenous antimicrobial use, and the diagnosis and management of common anthrax-specific complications during a mass-casualty incident. The recommendations in this report should be implemented only after predefined triggers have been met for shifting from conventional to contingency or crisis standards of care, such as when the magnitude of cases might lead to impending shortages of intravenous antimicrobials, antitoxins, critical care resources (e.g., chest tubes and chest drainage systems), or diagnostic capability. This guidance does not address primary triage decisions, anthrax postexposure prophylaxis, hospital bed or workforce surge capacity, or the logistics of dispensing MCMs. Clinicians, hospital administrators, state and local health officials, and planners can use these recommendations to assist in the development of crisis protocols that will ensure national preparedness for an anthrax mass-casualty incident. PMID- 26632964 TI - Thin Polymer Films with Continuous Vertically Aligned 1 nm Pores Fabricated by Soft Confinement. AB - Membrane separations are critically important in areas ranging from health care and analytical chemistry to bioprocessing and water purification. An ideal nanoporous membrane would consist of a thin film with physically continuous and vertically aligned nanopores and would display a narrow distribution of pore sizes. However, the current state of the art departs considerably from this ideal and is beset by intrinsic trade-offs between permeability and selectivity. We demonstrate an effective and scalable method to fabricate polymer films with ideal membrane morphologies consisting of submicron thickness films with physically continuous and vertically aligned 1 nm pores. The approach is based on soft confinement to control the orientation of a cross-linkable mesophase in which the pores are produced by self-assembly. The scalability, exceptional ease of fabrication, and potential to create a new class of nanofiltration membranes stand out as compelling aspects. PMID- 26632966 TI - Proceedings of the Musculoskeletal Health in the 21st Century Workshop. PMID- 26632965 TI - Optimization of a Novel Series of Ataxia-Telangiectasia Mutated Kinase Inhibitors as Potential Radiosensitizing Agents. AB - We previously reported a novel inhibitor of the ataxia-telangiectasia mutated (ATM) kinase, which is a target for novel radiosensitizing drugs. While our initial lead, compound 4, was relatively potent and nontoxic, it exhibited poor stability to oxidative metabolism and relatively poor selectivity against other kinases. The current study focused on balancing potency and selectivity with metabolic stability through structural modification to the metabolized site on the quinazoline core. We performed extensive structure-activity and structure property relationship studies on this quinazoline ATM kinase inhibitor in order to identify structural variants with enhanced selectivity and metabolic stability. We show that, while the C-7-methoxy group is essential for potency, replacing the C-6-methoxy group considerably improves metabolic stability without affecting potency. Promising analogues 20, 27g, and 27n were selected based on in vitro pharmacology and evaluated in murine pharmacokinetic and tolerability studies. Compound 27g possessed significantly improve pharmacokinetics relative to that of 4. Compound 27g was also significantly more selective against other kinases than 4. Therefore, 27g is a good candidate for further development as a potential radiosensitizer. PMID- 26632967 TI - Polychlorinated Biphenyls in a Temperate Alpine Glacier: 1. Effect of Percolating Meltwater on their Distribution in Glacier Ice. AB - In Alpine regions, glaciers act as environmental archives and can accumulate significant amounts of atmospherically derived pollutants. Due to the current climate-warming-induced accelerated melting, these pollutants are being released at correspondingly higher rates. To examine the effect of melting on the redistribution of legacy pollutants in Alpine glaciers, we analyzed polychlorinated biphenyls in an ice core from the temperate Silvretta glacier, located in eastern Switzerland. This glacier is affected by surface melting in summer. As a result, liquid water percolates down and particles are enriched in the current annual surface layer. Dating the ice core was a challenge because meltwater percolation also affects the traditionally used parameters. Instead, we counted annual layers of particulate black carbon in the ice core, adding the years with negative glacier mass balance, that is, years with melting and subsequent loss of the entire annual snow accumulation. The analyzed samples cover the time period 1930-2011. The concentration of indicator PCBs (iPCBs) in the Silvretta ice core follows the emission history, peaking in the 1970s (2.5 ng/L). High PCB values in the 1990s and 1930s are attributed to meltwater-induced relocation within the glacier. The total iPCB load at the Silvretta ice core site is 5 ng/cm(2). A significant amount of the total PCB burden in the Silvretta glacier has been released to the environment. PMID- 26632968 TI - Polychlorinated Biphenyls in a Temperate Alpine Glacier: 2. Model Results of Chemical Fate Processes. AB - We present results from a chemical fate model quantifying incorporation of polychlorinated biphenyls (PCBs) into the Silvretta glacier, a temperate Alpine glacier located in Switzerland. Temperate glaciers, in contrast to cold glaciers, are glaciers where melt processes are prevalent. Incorporation of PCBs into cold glaciers has been quantified in previous studies. However, the fate of PCBs in temperate glaciers has never been investigated. In the model, we include melt processes, inducing elution of water-soluble substances and, conversely, enrichment of particles and particle-bound chemicals. The model is validated by comparing modeled and measured PCB concentrations in an ice core collected in the Silvretta accumulation area. We quantify PCB incorporation between 1900 and 2010, and discuss the fate of six PCB congeners. PCB concentrations in the ice core peak in the period of high PCB emissions, as well as in years with strong melt. While for lower-chlorinated PCB congeners revolatilization is important, for higher-chlorinated congeners, the main processes are storage in glacier ice and removal by particle runoff. This study gives insight into PCB fate and dynamics and reveals the effect of snow accumulation and melt processes on the fate of semivolatile organic chemicals in a temperate Alpine glacier. PMID- 26632969 TI - Total Synthesis of (-)-Enigmazole A. AB - A highly convergent, stereocontrolled total synthesis of the architecturally complex marine sponge metabolite (-)-enigmazole A has been achieved. Highlights include an unprecedented late-stage large-fragment Petasis-Ferrier union/rearrangement, a multicomponent Type I Anion Relay Chemistry (ARC) tactic, and a dithiane-epoxide union in conjunction with an oxazole-directed stereoselective reduction. PMID- 26632970 TI - Influence of Cyclic Fatigue in Water on Screw Torque Loss of Long-Span One-Piece Implant-Supported Zirconia Frameworks. AB - PURPOSE: It is still unclear whether four, six, or more implants should be used when restoring fully edentulous maxillae. This research evaluated the in vitro screw torque loss of zirconia frameworks supported by six implants and cantilevered zirconia frameworks supported by four implants. MATERIALS AND METHODS: Computer aided design/computer-assisted machining was used to fabricate 10 one-piece frameworks. Standardized pressable porcelain crowns were fabricated and luted to the frameworks. Specimens were divided into two groups (n = 5): AO4, cantilevered 12-unit full-arch fixed dental prosthesis supported by four implants; AO6, 14-unit supported by six implants. An opposing mandibular dental arch was fabricated with bis-acrylic composite resin. Specimens were submitted to 200 N underwater cyclic load at 2-Hz frequency for 1 * 106 cycles in a controlled 37 degrees C temperature. A digital torque gauge assessed the initial and postload screw removal torque. Linear mixed-effects model was used for statistical analysis (alpha = 0.05). RESULTS: Significant screw torque loss was found for AO6 after cyclic loading (before: 36.20%/after: 52.82%; p < 0.05). Group AO6 (36.20%) presented lower preload loss before the cyclic loadings compared with AO4 (60.10%) (p < 0.05). CONCLUSIONS: Cyclic loading and lower implant-to-replaced-units ratio do not seem to compromise screw stability compared with higher implant-to-replaced-units ratio; however, a steep drop in preload was found before cyclic loading for both groups. PMID- 26632971 TI - Protein Adsorption Switch Constructed by a Pillar[5]arene-Based Host-Guest Interaction. AB - The interfacial properties of solid substrates are of importance for protein adsorption. Herein, we report a reversible protein adsorption switch based on the host-guest interaction of the butoxy pillar[5]arene and adipic acid. By the detector of the contact angle (CA), atomic force microscopy (AFM), and luminoscope on the silicon substrate, the intelligent protein switch exhibits excellent adsorptivity for BSA and switch performance by pH regulation. PMID- 26632972 TI - Proceedings of the 13(th) Congress of the Latin American Society for Sexual Medicine (SLAMS), Montevideo, Uruguay, August 13-16, 2015. PMID- 26632973 TI - Ortho-Trialkylstannyl Arylphosphanes by C-P and C-Sn Bond Formation in Arynes. AB - A novel and efficient approach to ortho-trialkylstannyl arylphosphanes by the reaction of arynes generated in situ with stannylated phosphanes (R3Sn-PR2) is described. Concurrent C-P and C-Sn bond formation occurs with high yields, and stannylated products are easily transformed into valuable ortho-substituted arylphosphanes. The reaction features high efficiency, good regioselectivity, and excellent practicality. PMID- 26632974 TI - Theoretical Prediction of Hydrogen Separation Performance of Two-Dimensional Carbon Network of Fused Pentagon. AB - Using the van-der-Waals-corrected density functional theory (DFT) and molecular dynamic (MD) simulations, we theoretically predict the H2 separation performance of a new two-dimensional sp(2) carbon allotropes-fused pentagon network. The DFT calculations demonstrate that the fused pentagon network with proper pore sizes presents a surmountable energy barrier (0.18 eV) for H2 molecule passing through. Furthermore, the fused pentagon network shows an exceptionally high selectivity for H2/gas (CO, CH4, CO2, N2, et al.) at 300 and 450 K. Besides, using MD simulations we demonstrate that the fused pentagon network exhibits a H2 permeance of 4 * 10(7) GPU at 450 K, which is much higher than the value (20 GPU) in the current industrial applications. With high selectivity and excellent permeability, the fused pentagon network should be an excellent candidate for H2 separation. PMID- 26632975 TI - There is more to risk and safety planning than dramatic risks: Mental health nurses' risk assessment and safety-management practice. AB - Risk assessment and safety planning are considered a cornerstone of mental health practice, yet limited research exists into how mental health nurses conceptualize 'risk' and how they engage with risk assessment and safety planning. The aim of the present study was to explore mental health nurses' practices and confidence in risk assessment and safety planning. A self-completed survey was administered to 381 mental health nurses in Ireland. The findings indicate that nurses focus on risk to self and risk to others, with the risk of suicide, self-harm, substance abuse, and violence being most frequently assessed. Risk from others and 'iatrogenic' risk were less frequently considered. Overall, there was limited evidence of recovery-oriented practice in relation to risk. The results demonstrate a lack of meaningful engagement with respect to collaborative safety planning, the identification and inclusion of protective factors, and the inclusion of positive risk-taking opportunities. In addition, respondents report a lack of confidence working with positive risk taking and involving family/carers in the risk-assessment and safety-planning process. Gaps in knowledge about risk-assessment and safety-planning practice, which could be addressed through education, are identified, as are the implications of the findings for practice and research. PMID- 26632976 TI - Mycotoxins Deoxynivalenol and Fumonisins Alter the Extrinsic Component of Intestinal Barrier in Broiler Chickens. AB - Deoxynivalenol (DON) and fumonisins (FBs) are secondary metabolites produced by Fusarium fungi that frequently contaminate broiler feed. The aim of this study was to investigate the impact of DON and/or FBs on the intestinal barrier in broiler chickens, more specifically on the mucus layer and antioxidative response to oxidative stress. One-day-old broiler chicks were divided into four groups, each consisting of eight pens of seven birds each, and were fed for 15 days either a control diet, a DON-contaminated diet (4.6 mg DON/kg feed), a FBs contaminated diet (25.4 mg FB1 + FB2/kg feed), or a DON+FBs-contaminated diet (4.3 mg DON and 22.9 mg FB1 + FB2/kg feed). DON and FBs affected the duodenal mucus layer by suppressing intestinal mucin (MUC) 2 gene expression and altering the mucin monosaccharide composition. Both mycotoxins decreased gene expression of the intestinal zinc transporter (ZnT)-1 and regulated intracellular methionine homeostasis, which are both important for preserving the cell's critical antioxidant activity. Feeding a DON- and/or FBs-contaminated diet, at concentrations close to the European Union maximum guidance levels (5 mg DON and 20 mg FB1 + FB2/kg feed) changes the intestinal mucus layer and several intestinal epithelial antioxidative mechanisms. PMID- 26632977 TI - Understanding the current anatomical competence landscape: Comparing perceptions of program directors, residents, and fourth-year medical students. AB - A mixed methods survey of fourth-year medical students, resident physicians, and residency program directors at the Indiana University School of Medicine gathered perceptions of anatomical competence-defined as the anatomical education necessary for effective clinical practice. The survey items explored numerous aspects of anatomical competence, including the most effective modes of instruction, perceptions of readiness for clinical practice, and specific suggestions for improving anatomical education during medical school and residency. The response rate was 46% for fourth-year medical students, 47% for residents (as graduates from 137 medical schools), and 71% for program directors. A majority of students and residents reported that their course in Gross Anatomy prepared them well for clinical practice; that cadaveric dissection was important in the early development of their anatomical competence; and that placing a greater emphasis on clinical relevance in medical school would have improved their anatomical competence even further. However, in terms of anatomical preparedness upon entering residency, the program directors rated their residents less prepared than the residents rated themselves. All three groups agreed that there is need for additional opportunities for anatomical educational during medical school and residency. Suggestions for improving anatomical education included the following: providing more opportunities for cadaveric dissection during medical school and residency; more consistent teaching of anatomy for clinical practice; more workshops that review anatomy; and better integration of anatomy with the teaching of other subjects during medical school. Anat Sci Educ 9: 307-318. (c) 2015 American Association of Anatomists. PMID- 26632978 TI - Deep venomics of the Pseudonaja genus reveals inter- and intra-specific variation. AB - Australian elapid venom remains an under-investigated resource of novel bioactive peptides. In this study, the venom gland transcriptomes and proteomes of the Australian western brown snakes, Pseudonaja aspidorhyncha and Pseudonaja nuchalis, were compared to Pseudonaja textilis. A deep venomics strategy incorporating high throughput 454 pyrosequencing gave a total of 200,911 raw reads for the three venoms. Subsequent annotation identified 5716 transcripts from 20 different toxin families with inter-specific variation between species observed in eight of the less abundant families. Integration of each venom proteome with the corresponding annotated reads identified 65 isoforms from six toxin families; high sequence coverage highlighted subtle differences between sequences and intra and inter-specific variation between species. High quality MS/MS data identified unusual glycoforms with natriuretic peptides from P. aspidorhyncha and P. nuchaliscontaining O-linked trisaccharides with high homology to the glycosylated region of TNPc. Molecular evolutionary assessments indicated the accelerated evolution of all toxin families with the exception of both natriuretic peptides and P. aspidorhyncha PLA2s that were found to be evolutionarily constrained under purifying selection pressures. This study has revealed a wide range of novel peptide sequences from six bioactive peptide families and highlights the subtle differences between toxins in these closely related species. BIOLOGICAL SIGNIFICANCE: Mining Australia's vastly untapped source of toxins from its venomous creatures has been significantly advanced by employing deep venomics methodology. Technological advances in transcriptome analysis using next generation sequencing platforms and proteome analysis by highly sensitive tandem mass spectrometry allowed a more comprehensive interrogation of three underinvestigated brown snake (Pseudonaja) venoms uncovering many novel peptide sequences that are unique to these closely related species. This generic strategy will provide invaluable information when applied to other venomous snakes for a deeper understanding of venom composition, envenomation, venom evolution, as well as identifying research tools and drug leads. PMID- 26632979 TI - Can Dispersion Forces Govern Aromatic Stacking in an Organic Solvent? AB - Experimental support for the dominance of van der Waals dispersion forces in aromatic stacking interactions occurring in organic solution is surprisingly limited. The size-dependence of aromatic stacking in an organic solvent was examined. The interaction energy was found to vary by about 7.5 kJ mol(-1) on going from a phenyl-phenyl to an anthracene-pyrene stack. Strikingly, the experimental data were highly correlated with dispersion energies determined using symmetry-adapted perturbation theory (SAPT), while the induction, exchange, electrostatic, and solvation energy components correlated poorly. Both the experimental data and the SAPT-dispersion energies gave high-quality correlations with the change in solvent accessible area upon complexation. Thus, the size dependence of aromatic stacking interactions is consistent with the dominance of van der Waals dispersion forces even in the presence of a competing polarizable solvent. PMID- 26632980 TI - Effects of the Affordable Care Act's young adult insurance expansion on prescription drug insurance coverage, utilization, and expenditures. AB - BACKGROUND: The US Affordable Care Act (ACA) extended the age of eligibility for young adults to remain on their parents' health insurance plans in order to address the disproportionate number of uninsured young adults in the United States. Effective September 23, 2010, the ACA has required all private health insurance plans to cover dependents until the age of 26. However, it is unknown whether the ACA dependent coverage expansion had an impact on prescription drug insurance or the use of prescription drugs. OBJECTIVES: To evaluate short-term changes in prescription health insurance coverage, prescription drug insurance coverage, prescription drug use, and prescription drug expenditures following implementation of the ACA young adult insurance expansion using national data from 2009 and 2011. RESULTS: Full-year health insurance coverage increased 4.9 percentage points during the study period, which was mainly due to increases in private health insurance among middle- and high-income young adults. In contrast, full-year prescription drug insurance coverage increased 5.5 percentage points and was primarily concentrated among high-income young adults. Although no significant short-term changes in overall prescription drug use were observed, a 30% decrease in out-of-pocket expenditures was seen among young adults. CONCLUSIONS: While the main goal of the ACA's young adult insurance expansion was to increase health insurance coverage among young adults, it also had the unintended positive effect of increasing coverage for prescription drug insurance. Additionally, young adults experienced substantial decreases in out-of pocket spending for prescription drugs. It is important for evaluations of health care policies to assess both intended and unintended outcomes to better understand the implications for the broader health system. PMID- 26632981 TI - One-Pot Homologation of Boronic Acids: A Platform for Diversity-Oriented Synthesis. AB - Formal homologation of sp(2)-hybridized boronic acids is achieved via cross coupling of boronic acids with conjunctive haloaryl BMIDA components in the presence of a suitably balanced basic phase. The utility of this approach to provide a platform for diversity-oriented synthesis in discovery medicinal chemistry is demonstrated in the context of the synthesis of a series of analogues of a BET bromodomain inhibitor. PMID- 26632982 TI - Bioactivity-based ultra-performance liquid chromatography-coupled quadrupole time of-flight mass spectrometry for NF-kappaB inhibitors identification in Chinese Medicinal Preparation Bufei Granule. AB - Traditional Chinese medicine (TCM) preparations have become effective treatments for many diseases. However, their active ingredients are still uncertain and difficult to identify. In this study, we propose a strategy that integrates ultra performance liquid chromatography/quadrupole-time-of-flight mass spectrometry (UPLC/Q-TOF-MS) and bioactive (NF-kappaB inhibitor) luciferase reporter assay systems for the rapid determination of various anti-inflammatory compounds of TCM preparations. In this way, Bufei Granule (BFG), a TCM preparation used for the clinical therapy of asthma, was analyzed by the two ways of component identification and activity detection. Potential anti-inflammatory constituents were screened by NF-kappaB activity assay systems and simultaneously identified according to the mass spectrometry data. Three structural types of NF-kappaB inhibitors (caffeic acid derivatives, flavonoids and Pentacyclic triterpenes) were characterized. Further cytokine detection confirmed the anti-inflammatory effects of the potential NF-kappaB inhibitors. Compared with conventional chromatographic separation and inhibitory activity detection, integrating UPLC/Q TOF-MS identification and virtual validation was more convenient and more reliable. This strategy clearly demonstrates that MS data-based fingerprinting is a meaningful tool not only in identifying constituents in complex matrix but also in directly screening for powerful trace ingredients in TCM preparations. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26632983 TI - Facilitated Anion Transport Induces Hyperpolarization of the Cell Membrane That Triggers Differentiation and Cell Death in Cancer Stem Cells. AB - Facilitated anion transport potentially represents a powerful tool to modulate various cellular functions. However, research into the biological effects of small molecule anionophores is still at an early stage. Here we have used two potent anionophore molecules inspired in the structure of marine metabolites tambjamines to gain insight into the effect induced by these compounds at the cellular level. We show how active anionophores, capable of facilitating the transmembrane transport of chloride and bicarbonate in model phospholipid liposomes, induce acidification of the cytosol and hyperpolarization of plasma cell membranes. We demonstrate how this combined effect can be used against cancer stem cells (CSCs). Hyperpolarization of cell membrane induces cell differentiation and loss of stemness of CSCs leading to effective elimination of this cancer cell subpopulation. PMID- 26632984 TI - The Evolving Theory of Evolutionary Radiations. AB - Evolutionary radiations have intrigued biologists for more than 100 years, and our understanding of the patterns and processes associated with these radiations continues to grow and evolve. Recently it has been recognized that there are many different types of evolutionary radiation beyond the well-studied adaptive radiations. We focus here on multifarious types of evolutionary radiations, paying special attention to the abiotic factors that might trigger diversification in clades. We integrate concepts such as exaptation, species selection, coevolution, and the turnover-pulse hypothesis (TPH) into the theoretical framework of evolutionary radiations. We also discuss other phenomena that are related to, but distinct from, evolutionary radiations that have relevance for evolutionary biology. PMID- 26632985 TI - Simple and Effective Way for Data Preprocessing Selection Based on Design of Experiments. AB - The selection of optimal preprocessing is among the main bottlenecks in chemometric data analysis. Preprocessing currently is a burden, since a multitude of different preprocessing methods is available for, e.g., baseline correction, smoothing, and alignment, but it is not clear beforehand which method(s) should be used for which data set. The process of preprocessing selection is often limited to trial-and-error and is therefore considered somewhat subjective. In this paper, we present a novel, simple, and effective approach for preprocessing selection. The defining feature of this approach is a design of experiments. On the basis of the design, model performance of a few well-chosen preprocessing methods, and combinations thereof (called strategies) is evaluated. Interpretation of the main effects and interactions subsequently enables the selection of an optimal preprocessing strategy. The presented approach is applied to eight different spectroscopic data sets, covering both calibration and classification challenges. We show that the approach is able to select a preprocessing strategy which improves model performance by at least 50% compared to the raw data; in most cases, it leads to a strategy very close to the true optimum. Our approach makes preprocessing selection fast, insightful, and objective. PMID- 26632986 TI - Advocacy interventions to reduce or eliminate violence and promote the physical and psychosocial well-being of women who experience intimate partner abuse. AB - BACKGROUND: Intimate partner abuse is common worldwide, damaging the short- and long-term physical, mental, and emotional health of survivors and children. Advocacy may contribute to reducing abuse, empowering women to improve their situation by providing informal counselling and support for safety planning and increasing access to different services. Advocacy may be a stand-alone service, accepting referrals from healthcare providers, or part of a multi-component (and possibly multi-agency) intervention provided by service staff or others. OBJECTIVES: To assess the effects of advocacy interventions within or outside healthcare settings in women who have experienced intimate partner abuse. SEARCH METHODS: In April 2015, we searched CENTRAL, Ovid MEDLINE, EMBASE, and 10 other databases. We also searched WHO ICTRP, mRCT, and UK Clinical Research Network (UKCRN), and examined relevant websites and reference lists with forward citation tracking of included studies. For the original review we handsearched six key journals. We also contacted first authors of eligible papers and experts in the field. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials comparing advocacy interventions for women with experience of intimate partner abuse versus no intervention or usual care (if advocacy was minimal and fewer than 20% of women received it). DATA COLLECTION AND ANALYSIS: Two review authors independently assessed risk of bias and undertook data extraction. We contacted authors for missing information needed to calculate statistics for the review and looked for adverse events. MAIN RESULTS: We included 13 trials involving 2141 participants aged 15 to 65 years, frequently having low socioeconomic status.The studies were quite heterogeneous in terms of methodology, study processes and design, including with regard to the duration of follow-up (postintervention to three years), although this was not associated with differences in effect. The studies also had considerable clinical heterogeneity in relation to staff delivering advocacy; setting (community, shelter, antenatal, healthcare); advocacy intensity (from 30 minutes to 80 hours); and abuse severity. Three trials evaluated advocacy within multi-component interventions. Eleven measured some form of abuse (eight scales), six assessed quality of life (three scales), and six measured depression (three scales). Countries and ethnic groups varied (one or more minority ethnic groups in the USA or UK, and local populations in Hong Kong and Peru). Setting was associated with intensity and duration of advocacy.Risk of bias was high in five studies, moderate in five, and low in three. The quality of evidence (considering multiple factors such as risk of bias, study size, missing data) was moderate to low for brief advocacy and very low for intensive advocacy. Incidence of abuse Physical abuseModerate quality pooled data from two healthcare studies (moderate risk of bias) and one community study (low risk of bias), all with 12-month follow-up data, showed no effect on physical abuse for brief (< 12 hours) advocacy interventions (standardised mean difference (SMD) 0.00, 95% confidence interval (CI) - 0.17 to 0.16; n = 558). One antenatal study (low risk of bias) showed an association between brief advocacy and reduced minor physical abuse at one year (mean difference (MD) change - 1.00, 95% CI - 1.82 to - 0.18; n = 110). An antenatal, multi-component study showed a greater likelihood of physical abuse ending (odds ratio (OR) 0.42, 95% CI 0.23 to 0.75) immediately after advocacy (number needed to treat (NNT) = 8); we cannot exclude impact from other components.Low to very low quality evidence from two intensive advocacy trials (12 hours plus duration) showed reduced severe physical abuse in women leaving a shelter at 24 months (OR 0.39, 95% CI 0.20 to 0.77; NNT = 8), but not at 12 or 36 months. Sexual abuseMeta-analysis of two studies (n = 239) showed no effect of advocacy on sexual abuse (SMD - 0.12, 95% CI - 0.37 to 0.14), agreeing with the change score (MD - 0.07, 95% CI - 0.30 to 0.16) from a third study and the OR (0.96, 95% CI 0.44 to 2.12) from a fourth antenatal, multi component study. Emotional abuseOne study in antenatal care, rated at low risk of bias, showed reduced emotional abuse at <= 12-month follow-up (MD (change score) 4.24, 95% CI - 6.42 to - 2.06; n = 110). Psychosocial health Quality of lifeMeta analysis of two studies (high risk of bias) showed intensive advocacy slightly improved overall quality of life of women recruited from shelters (MD 0.23, 95% CI 0.00 to 0.46; n = 343) at 12-month follow-up, with greater improvement in perceived physical quality of life from a primary care study (high risk of bias; MD 4.90, 95% CI 0.98 to 8.82) immediately postintervention. Depression Meta analysis of two studies in healthcare settings, one at high risk of bias and one at moderate risk, showed that fewer women developed depression (OR 0.31, 95% CI 0.15 to 0.65; n = 149; NNT = 4) with brief advocacy. One study at high risk of bias reported a slight reduction in depression in pregnant women immediately after the intervention (OR 0.51, 95% CI 0.20 to 1.29; n = 103; NNT = 8).There was no evidence that intensive advocacy reduced depression at <= 12-month follow-up (MD - 0.14, 95% CI - 0.33 to 0.05; 3 studies; n = 446) or at two years (SMD - 0.12, 95% CI - 0.36 to 0.12; 1 study; n = 265). Adverse effectsTwo women died, one who was murdered by her partner and one who committed suicide. No evidence links either death to study participation. AUTHORS' CONCLUSIONS: Results suggest some benefits from advocacy. However, most studies were underpowered. Clinical and methodological heterogeneity largely precluded pooling of trials. Therefore, there is uncertainty about the magnitude of benefit, the impact of abuse severity, and the setting.Based on the evidence reviewed, intensive advocacy may improve short-term quality of life and reduce physical abuse one to two years after the intervention for women recruited from domestic violence shelters or refuges. Brief advocacy may provide small short-term mental health benefits and reduce abuse, particularly in pregnant women and for less severe abuse. PMID- 26632988 TI - Increased inhibitor incidence in severe haemophilia A since 1990 attributable to more low titre inhibitors. AB - Many studies have reported an increased incidence of inhibitors in previously untreated patients (PUPs) with severe haemophilia A after the introduction of recombinant products. It was the objective of this study to investigate whether the inhibitor incidence has increased between 1990 and 2009 in an unselected cohort of PUPs with severe haemophilia A (FVIII< 1 %). Patients were consecutively recruited from 31 haemophilia treatment centres in 16 countries and followed until 50 exposure days or until inhibitor development. Inhibitor development was studied in five-year birth cohorts comparing cumulative incidences. Furthermore the risk for inhibitor development per five-year birth cohort was studied using multivariable Cox regression, adjusting for potential genetic and treatment-related confounders. A total of 926 PUPs were included with a total cumulative inhibitor incidence of 27.5 %. The inhibitor incidence increased from 19.5 % in 1990-1994 (lowest) to 30.9 % in 2000-2004 (highest; p value 0.011). Low titre inhibitor incidence increased from 3.1 % in 1990-1994 to 10.5 % in 2005-2009 (p-value 0.009). High titre inhibitor incidences remained stable over time. After 2000, risk of all inhibitor development was increased with adjusted hazard ratios 1.96 (95 % CI 1.06-2.83) in 2000-2004 and 2.34 (1.42 4.92) in 2005-2009. Screening for inhibitors was intensified over this 20-year study period from a median of 1.9 to 2.9 tests/year before 2000 to 2.7 to 4.3 tests/year after 2000. In conclusion, the cumulative inhibitor incidence has significantly increased between 1990 and 2009. The high titre inhibitor incidence has remained stable. PMID- 26632987 TI - Exposure to a glyphosate-based herbicide during pregnancy and lactation induces neurobehavioral alterations in rat offspring. AB - The impact of sub-lethal doses of herbicides on human health and the environment is a matter of controversy. Due to the fact that evidence particularly of the effects of glyphosate on the central nervous system of rat offspring by in utero exposure is scarce, the purpose of the present study was to assess the neurobehavioral effects of chronic exposure to a glyphosate-containing herbicide during pregnancy and lactation. To this end, pregnant Wistar rats were exposed through drinking water to 0.2% or 0.4% of a commercial formulation of glyphosate (corresponding to a concentration of 0.65 or 1.30g/L of glyphosate, respectively) during pregnancy and lactation and neurobehavioral alterations in offspring were analyzed. The postnatal day on which each pup acquired neonatal reflexes (righting, cliff aversion and negative geotaxis) and that on which eyes and auditory canals were fully opened were recorded for the assessment of sensorimotor development. Locomotor activity and anxiety levels were monitored via open field test and plus maze test, respectively, in 45- and 90-day-old offspring. Pups exposed to a glyphosate-based herbicide showed early onset of cliff aversion reflex and early auditory canal opening. A decrease in locomotor activity and in anxiety levels was also observed in the groups exposed to a glyphosate-containing herbicide. Findings from the present study reveal that early exposure to a glyphosate-based herbicide affects the central nervous system in rat offspring probably by altering mechanisms or neurotransmitter systems that regulate locomotor activity and anxiety. PMID- 26632989 TI - Magnitude and Origin of Electrical Noise at Individual Grain Boundaries in Graphene. AB - Grain boundaries (GBs) are undesired in large area layered 2D materials as they degrade the device quality and their electronic performance. Here we show that the grain boundaries in graphene which induce additional scattering of carriers in the conduction channel also act as an additional and strong source of electrical noise especially at the room temperature. From graphene field effect transistors consisting of single GB, we find that the electrical noise across the graphene GBs can be nearly 10 000 times larger than the noise from equivalent dimensions in single crystalline graphene. At high carrier densities (n), the noise magnitude across the GBs decreases as ?1/n, suggesting Hooge-type mobility fluctuations, whereas at low n close to the Dirac point, the noise magnitude could be quantitatively described by the fluctuations in the number of propagating modes across the GB. PMID- 26632990 TI - Dynamic Resting-State Functional Connectivity in Major Depression. AB - Major depressive disorder (MDD) is characterized by abnormal resting-state functional connectivity (RSFC), especially in medial prefrontal cortical (MPFC) regions of the default network. However, prior research in MDD has not examined dynamic changes in functional connectivity as networks form, interact, and dissolve over time. We compared unmedicated individuals with MDD (n=100) to control participants (n=109) on dynamic RSFC (operationalized as SD in RSFC over a series of sliding windows) of an MPFC seed region during a resting-state functional magnetic resonance imaging scan. Among participants with MDD, we also investigated the relationship between symptom severity and RSFC. Secondary analyses probed the association between dynamic RSFC and rumination. Results showed that individuals with MDD were characterized by decreased dynamic (less variable) RSFC between MPFC and regions of parahippocampal gyrus within the default network, a pattern related to sustained positive connectivity between these regions across sliding windows. In contrast, the MDD group exhibited increased dynamic (more variable) RSFC between MPFC and regions of insula, and higher severity of depression was related to increased dynamic RSFC between MPFC and dorsolateral prefrontal cortex. These patterns of highly variable RSFC were related to greater frequency of strong positive and negative correlations in activity across sliding windows. Secondary analyses indicated that increased dynamic RSFC between MPFC and insula was related to higher levels of recent rumination. These findings provide initial evidence that depression, and ruminative thinking in depression, are related to abnormal patterns of fluctuating communication among brain systems involved in regulating attention and self-referential thinking. PMID- 26632992 TI - Mid- and long-term runoff predictions by an improved phase-space reconstruction model. AB - In recent years, the phase-space reconstruction method has usually been used for mid- and long-term runoff predictions. However, the traditional phase-space reconstruction method is still needs to be improved. Using the genetic algorithm to improve the phase-space reconstruction method, a new nonlinear model of monthly runoff is constructed. The new model does not rely heavily on embedding dimensions. Recognizing that the rainfall-runoff process is complex, affected by a number of factors, more variables (e.g. temperature and rainfall) are incorporated in the model. In order to detect the possible presence of chaos in the runoff dynamics, chaotic characteristics of the model are also analyzed, which shows the model can represent the nonlinear and chaotic characteristics of the runoff. The model is tested for its forecasting performance in four types of experiments using data from six hydrological stations on the Yellow River and the Yangtze River. Results show that the medium-and long-term runoff is satisfactorily forecasted at the hydrological stations. Not only is the forecasting trend accurate, but also the mean absolute percentage error is no more than 15%. Moreover, the forecast results of wet years and dry years are both good, which means that the improved model can overcome the traditional ''wet years and dry years predictability barrier,'' to some extent. The model forecasts for different regions are all good, showing the universality of the approach. Compared with selected conceptual and empirical methods, the model exhibits greater reliability and stability in the long-term runoff prediction. Our study provides a new thinking for research on the association between the monthly runoff and other hydrological factors, and also provides a new method for the prediction of the monthly runoff. PMID- 26632993 TI - Tropical nature reserves are losing their buffer zones, but leakage is not to blame. AB - Tropical forests provide important ecosystem services to humanity, yet are threatened by habitat loss resulting from deforestation and land-use change. Although reserves are considered the cornerstones of conservation efforts in the tropics, their efficacy remains equivocal. One question that remains unresolved is whether leakage - the unanticipated displacement of deforestation from inside reserves into the unrestricted zones just beyond a reserve's administrative boundary - is common around tropical forest reserves, or whether the zones are acting as buffers between the protected area and the outside world. To resolve this question, we used the Landsat-derived Global Forest Change dataset to estimate deforestation rates between 2000 and 2012 inside and outside of 60 nature reserves spread across the tropics. Deforestation rates inside reserves (within 5km of the administrative boundary) were generally lower than those immediately outside the reserves (i.e. in buffer zones 0-10km from the boundary), suggesting that reserves are effective at protecting forests. We hypothesised that leakage would result in greater deforestation rates in reserve buffer zones than in the broader reserve landscapes, but such a pattern was observed in only five African sites, suggesting that leakage does not often occur on the edge of established reserves. However, roughly 80% of reserves experienced deforestation rates that increased gradually from their interiors to the outer periphery of their buffer zones. Thus, while leakage may not be a pervasive phenomenon around tropical reserves worldwide, tropical reserves are often losing their buffer zones, resulting in increased isolation that could have ramifications for ecosystem services provisioning and tropical conservation strategies. PMID- 26632991 TI - Early-Life Adversity Interacts with FKBP5 Genotypes: Altered Working Memory and Cardiac Stress Reactivity in the Oklahoma Family Health Patterns Project. AB - Exposure to stress during critical periods of development can have adverse effects on adult health behaviors, and genetic vulnerabilities may enhance these stress effects. We carried out an exploratory examination of psychological, physiological, and behavioral characteristics of 252 healthy young adults for the impact of early-life adversity (ELA) in relation to the G-to-A single nucleotide polymorphism (SNP), rs9296158, of the FKBP5 gene. FKBP5 is a molecular cochaperone that contributes to the functional status of the glucocorticoid receptor (GR) and to the quality of corticosteroid signaling. FKBP5 expression is upregulated by cortisol exposure during stressful episodes, with greater upregulation seen in A-allele carriers. As such, FKBP5 expression and GR function may be environmentally sensitive in A-allele carriers and therefore suitable for the study of gene-by-environment (G * E) interactions. Compared with FKBP5, GG homozygotes (N=118), A-allele carriers (N = 132) without psychiatric morbidity had progressively worse performance on the Stroop color-word task with increasing levels of ELA exposure (Genotype * ELA, F=5.14, P=0.007), indicating a G * E interaction on working memory in early adulthood. In addition, heart rate response to mental stress was diminished overall in AA/AG-allele carriers (F=5.15, P=0.024). Diminished working memory and attenuated autonomic responses to stress are both associated with risk for alcoholism and other substance use disorders. The present data suggest that FKBP5 in the GR pathway may be a point of vulnerability to ELA, as seen in this group of non-traumatized young adults. FKBP5 is accordingly a potential target for more extensive studies of the impact of ELA on health and health behaviors in adulthood. PMID- 26632994 TI - Proton Transfer of Guanine Radical Cations Studied by Time-Resolved Resonance Raman Spectroscopy Combined with Pulse Radiolysis. AB - The oxidation of guanine (G) is studied by using transient absorption and time resolved resonance Raman spectroscopies combined with pulse radiolysis. The transient absorption spectral change demonstrates that the neutral radical of G (G(*)(-H(+))), generated by the deprotonation of G radical cation (G(*+)), is rapidly converted to other G radical species. The formation of this species shows the pH dependence, suggesting that it is the G radical cation (G(*+))' formed from the protonation at the N7 of G(*)(-H(+)). On one hand, most Raman bands of (G(*+))' are up-shifted relative to those of G, indicating the increase in the bonding order of pyrimidine (Pyr) and imidazole rings. The (G(*+))' exhibits the characteristic CO stretching mode at ~1266 cm(-1) corresponding to a C-O single bond, indicating that the unpaired electron in (G(*+))' is localized on the oxygen of the Pyr ring. PMID- 26632995 TI - EFSUMB Guidelines on Interventional Ultrasound (INVUS), Part V. AB - The fifth section of the Guidelines on Interventional Ultrasound (INVUS) of the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) assesses the evidence for all the categories of endoscopic ultrasound-guided treatment reported to date. Celiac plexus neurolysis and block, vascular intervention, drainage of fluid collections, drainage of biliary and pancreatic ducts, and experimental tumor ablation techniques are discussed. For each topic, all current evidence has been extensively analyzed and summarized into major recommendations for reader consultation in clinical practice (long version). PMID- 26632996 TI - Multiple regimes of robust patterns between network structure and biodiversity. AB - Ecological networks such as plant-pollinator and host-parasite networks have structured interactions that define who interacts with whom. The structure of interactions also shapes ecological and evolutionary dynamics. Yet, there is significant ongoing debate as to whether certain structures, e.g., nestedness, contribute positively, negatively or not at all to biodiversity. We contend that examining variation in life history traits is key to disentangling the potential relationship between network structure and biodiversity. Here, we do so by analyzing a dynamic model of virus-bacteria interactions across a spectrum of network structures. Consistent with prior studies, we find plausible parameter domains exhibiting strong, positive relationships between nestedness and biodiversity. Yet, the same model can exhibit negative relationships between nestedness and biodiversity when examined in a distinct, plausible region of parameter space. We discuss steps towards identifying when network structure could, on its own, drive the resilience, sustainability, and even conservation of ecological communities. PMID- 26632997 TI - SAPHO and Monckeberg's sclerosis: two rare diseases and one patient. PMID- 26632998 TI - Structural Correspondence of the Oriented Attachment Growth Mechanism of Crystals of the Pharmaceutical Dirithromycin. AB - The oriented attachment (OA) mechanism is promising for designing novel nanomaterials, yet an intensive understanding of the relationship between the crystal structure and attachment orientation is still lacking. In this work, we report layered hexagonal crystals of the pharmaceutical dirithromycin (DIR) containing multiple layers fabricated via a solvothermal method for a certain period of time at 40 degrees C. These elongated hexagonal crystals experience an OA that is preferentially on the face (001) of the initial crystals to assemble the final crystals into layered stacks. Through agreement with molecular modeling calculations, we predicted the final crystal growth morphology and confirmed the favored attachment surface based on the energy change DeltaE following an OA event. These simulation results at the molecular level yielded good agreement with the crystal growth experiments. This study demonstrates the critical importance of combining experiments with a computational approach to understand the intrinsic molecular details of the OA growth mechanism of other compounds and to design nanomaterials with a desirable morphology and physical and chemical properties. PMID- 26632999 TI - Association of inflammatory cytokine gene polymorphisms with inflammatory bowel disease in a Moroccan cohort. AB - The purpose of this study was to investigate whether common variants in inflammatory and immune response genes influence inflammatory bowel disease (IBD) risk among Moroccan patients. Using a candidate gene approach, 10 single nucleotide polymorphisms mapping on six genes (MIF_rs755622, TNFA_rs1800629, IL6_rs2069840, IL6R_rs2228145, IL6ST_rs2228044, IL17A (rs2275913, rs4711998, rs7747909, rs8193036, rs3819024)) were assessed in 510 subjects grouped in 199 IBD and 311 healthy controls. Genotyping was performed with the TaqMan allelic discrimination technology. The results were analyzed using PLINK software. The frequency of allele A for TNFA rs1800629 was significantly higher in ulcerative colitis (UC) patients compared with controls (30.16 vs 16.72%; P=0.0005; odds ratio (OR)=2.15; 95% confidence interval (CI)=1.39-3.32). Statistically significant association to UC was also found under dominant AA+AG vs GG (OR=1.85, 95% CI=1.07-3.21; P=0.02) and recessive models (OR=8.38; 95% CI=2.86-24.53; P=0.0001). In the same way, an association of TNFA rs1800629 variant was observed with IBD under recessive model AA vs AG+GG (OR=4.10; 95% CI=1.56-10.76; P=0.004). No evidence of significant associations was found for the remaining investigated polymorphisms. Our data suggest that TNFA gene promoter polymorphism participates in determining IBD susceptibility in Moroccan patients. PMID- 26633000 TI - A Toll-like receptor-1 variant and its characteristic cellular phenotype is associated with severe malaria in Papua New Guinean children. AB - Genetic factors are likely to contribute to low severe malaria case fatality rates in Melanesian populations, but association studies can be underpowered and may not provide plausible mechanistic explanations if significant associations are detected. In preparation for a genome-wide association study, 29 candidate single-nucleotide polymorphisms (SNPs) with minor allele frequencies >5% were examined in a case-control study of 504 Papua New Guinean children with severe malaria. In parallel, an immunological substudy was performed on convalescent peripheral blood mononuclear cells (PBMCs) from cases and controls. Following stimulation with a Toll-like receptor (TLR) 1/2 agonist, effector cytokines and chemokines were assayed. The only significant genetic association observed involved a nonsynonymous SNP (TLR1rs4833095) in the TLR1 gene. A recessive (TT) genotype was associated with reduced odds of severe malaria of 0.52 (95% confidence interval (0.29-0.90), P=0.006). Concentrations of pro-inflammatory cytokines interleukin-1beta and tumour necrosis factor alpha were significantly higher in severe malaria cases compared with healthy controls, but lower in children with the protective recessive (TT) genotype. A genetic variant in TLR1 may contribute to the low severe malaria case fatality rates in this region through a reduced pro-inflammatory cellular phenotype. PMID- 26633002 TI - Liposome Bupivacaine for Postsurgical Analgesia in Patients Undergoing Robotically Assisted Cardiac Surgery. AB - OBJECTIVE: Despite the advantages of robotically assisted cardiac surgery over conventional open sternotomy, robotically assisted surgery may be associated with substantial postsurgical pain arising from multiple incisions and access ports. This single-site, retrospective chart review evaluated the impact of liposome bupivacaine compared with bupivacaine HCl on postsurgical pain management in patients undergoing robotically assisted endoscopic cardiac surgery. METHODS: Sequential patient cohorts undergoing robotically assisted cardiac surgery received either 0.25% bupivacaine HCl (100 mg in 40 mL, n = 30) or liposome bupivacaine (266 mg in 20 mL, expanded to 40 mL with 0.9% sterile normal saline, n = 30) intraoperatively via equal-volume infiltration across port sites. Outcome measures, collected from the day of surgery through postoperative day 3, were daily and total use of opioid analgesics (converted to morphine equivalents), pain intensity (11-point numeric rating scale), and incidence of postoperative nausea and vomiting. RESULTS: Median length of hospital stay was 4 days in the liposome bupivacaine group and 3 days in the bupivacaine HCl group. Patients receiving liposome bupivacaine had numerically lower mean pain scores (at six of seven time points), reduced mean opioid consumption, and a reduced incidence of postoperative nausea and vomiting compared with those receiving bupivacaine HCl, although none of the differences reached statistical significance. CONCLUSIONS: Results from this small retrospective, observational study suggest that liposome bupivacaine may improve postsurgical pain relief and reduce postsurgical opioid consumption, in comparison with bupivacaine HCl, in patients undergoing robotically assisted cardiac surgery. Larger prospective studies of liposome bupivacaine in this setting are warranted. PMID- 26633001 TI - Targeted exosome-mediated delivery of opioid receptor Mu siRNA for the treatment of morphine relapse. AB - Cell-derived exosomes have been demonstrated to be efficient carriers of small RNAs to neighbouring or distant cells, highlighting the preponderance of exosomes as carriers for gene therapy over other artificial delivery tools. In the present study, we employed modified exosomes expressing the neuron-specific rabies viral glycoprotein (RVG) peptide on the membrane surface to deliver opioid receptor mu (MOR) siRNA into the brain to treat morphine addiction. We found that MOR siRNA could be efficiently packaged into RVG exosomes and was associated with argonaute 2 (AGO2) in exosomes. These exosomes efficiently and specifically delivered MOR siRNA into Neuro2A cells and the mouse brain. Functionally, siRNA-loaded RVG exosomes significantly reduced MOR mRNA and protein levels. Surprisingly, MOR siRNA delivered by the RVG exosomes strongly inhibited morphine relapse via the down-regulation of MOR expression levels. In conclusion, our results demonstrate that targeted RVG exosomes can efficiently transfer siRNA to the central nervous system and mediate the treatment of morphine relapse by down-regulating MOR expression levels. Our study provides a brand new strategy to treat drug relapse and diseases of the central nervous system. PMID- 26633003 TI - Beating-Heart Sliding Arch Aortoplasty for Arch Hypoplasia Beyond Infancy. AB - Hypoplasia of the aortic arch commonly accompanies coarctation of the aorta and should be addressed at the time of coarctation repair to prevent residual gradient. Using a novel technique, McKenzie et al performed an ascending sliding arch aortoplasty to correct hypoplasia using native aortic tissue. This procedure was accomplished with an arrested heart and uses the fact that the ascending aorta associated with the hypoplastic arch is typically elongated. We have furthered the development of the ascending sliding arch aortoplasty by performing the entire procedure without inducing cardiac arrest. PMID- 26633005 TI - Androgen Deprivation Therapy in Prostate Cancer - Current Status in M1 Patients. AB - Androgen deprivation therapy is the cornerstone treatment for metastatic prostate cancer. It can be done either surgically or medically. Luteinizing hormone releasing hormone agonists and antagonist are the most effective drugs, with different side effects and modes of action, but no clear efficacy differences. Adding a non-steroidal antiandrogen adds a marginal benefit but also significant side effects and costs. Non-steroidal antiandrogens should not be used as monotherapy. In most patients with metastases, immediate castration is the standard of care. The intermittent modality is apparently non-inferior to the continuous one, with some other benefits. Upfront chemotherapy added to castration should be considered as the new standard of care in many metastatic patients. Castration leads to many adverse effects, some potentially life threatening such as cardiovascular side effects. PMID- 26633006 TI - [3 + 2]-Annulations of N-alkyl-3-substituted indoles with quinone monoketals catalysed by Bronsted acids. AB - An organocatalytic dearomative [3 + 2]-annulation of N-alkyl-3-alkylindoles with quinone monoketals is developed. The reaction provides a mild and straightforward way to various benzofuro[2,3-b]indolines of potential biological and pharmaceutical interest in moderate to good yields. Moreover, when 3 phenylindole, a problematic substrate in previous relevant studies, was used as the substrate under the otherwise same reaction conditions, a novel 1,2-shift of the phenyl group occurred followed by aromatization to provide 2,3-diaryl indoles useful for cancer therapy studies in moderate yields. PMID- 26633007 TI - New Developments in the Management of Prostate Cancer. PMID- 26633008 TI - Refining Our Understanding of Howiesons Poort Lithic Technology: The Evidence from Grey Rocky Layer in Sibudu Cave (KwaZulu-Natal, South Africa). AB - The detailed technological analysis of the youngest Howiesons Poort occupation in Sibudu Cave, layer Grey Rocky, has shown the importance of blade production (with different knapping methods involved), but also of flaking methods in coarse grained rock types. Moreover, new strategies of bifacial production and microlithism were important. Grey Rocky lithic technology shows a really versatile example of reduction strategies that were highly influenced by the characteristics of the rock types. This lithic assemblage is another example of the technological variability linked to the Howiesons Poort technocomplex. The reasons for this variability are still difficult to elucidate. Discrepancies between sites might be for different reasons: diachronic variations, functional variations, organizational variations or maybe different regional variations within what has been recognized traditionally and typologically as Howiesons Poort. The technological comparison of the Grey Rocky assemblage with assemblages from other Howiesons Poort sites demonstrates that there are common technological trends during the late Pleistocene, but they still need to be properly circumscribed chronologically. On the one hand, Howiesons Poort characteristics such as the bifacial production in quartz are reminiscent of production in some Still Bay or pre-Still Bay industries and the flake production or the prismatic blade production described here could be a point in common with pre-Still Bay and post-Howiesons Poort industries. On the other hand, the detailed analysis of the Grey Rocky lithics reinforces the particular character of this Howiesons Poort technocomplex, yet it also shows clear technological links with other Middle Stone Age assemblages. PMID- 26633009 TI - A Proteomics Approach to Investigate miR-153-3p and miR-205-5p Targets in Neuroblastoma Cells. AB - MicroRNAs are key regulators associated with numerous diseases. In HEK293 cells, miR-153-3p and miR-205-5p down-regulate alpha-synuclein (SNCA) and Leucine-rich repeat kinase 2 (LRRK2), two key proteins involved in Parkinson's disease (PD). We have used two-dimensional gel electrophoresis (2D-PAGE) coupled to mass spectrometry (MS) to identify a spectrum of miR-153-3p and miR-205-5p targets in neuronal SH-SY5Y cells. We overexpressed and inhibited both microRNAs in SH-SY5Y cells and through comparative proteomics profiling we quantified ~240 protein spots from each analysis. Combined, thirty-three protein spots were identified showing significant (p-value < 0.05) changes in abundance. Modulation of miR-153 3p resulted in seven up-regulated proteins and eight down-regulated proteins. miR 205 modulation resulted in twelve up-regulated proteins and six down-regulated proteins. Several of the proteins are associated with neuronal processes, including peroxiredoxin-2 and -4, cofilin-1, prefoldin 2, alpha-enolase, human nucleoside diphosphate kinase B (Nm23) and 14-3-3 protein epsilon. Many of the differentially expressed proteins are involved in diverse pathways including metabolism, neurotrophin signaling, actin cytoskeletal regulation, HIF-1 signaling and the proteasome indicating that miR-153-3p and miR-205-5p are involved in the regulation of a wide variety of biological processes in neuroblastoma cells. PMID- 26633010 TI - National Studies as a Component of the World Health Organization Initiative to Estimate the Global and Regional Burden of Foodborne Disease. AB - BACKGROUND: The World Health Organization (WHO) initiative to estimate the global burden of foodborne diseases established the Foodborne Diseases Burden Epidemiology Reference Group (FERG) in 2007. In addition to global and regional estimates, the initiative sought to promote actions at a national level. This involved capacity building through national foodborne disease burden studies, and encouragement of the use of burden information in setting evidence-informed policies. To address these objectives a FERG Country Studies Task Force was established and has developed a suite of tools and resources to facilitate national burden of foodborne disease studies. This paper describes the process and lessons learned during the conduct of pilot country studies under the WHO FERG initiative. FINDINGS: Pilot country studies were initiated in Albania, Japan and Thailand in 2011 and in Uganda in 2012. A brief description of each study is provided. The major scientific issue is a lack of data, particularly in relation to disease etiology, and attribution of disease burden to foodborne transmission. Situation analysis, knowledge translation, and risk communication to achieve evidence-informed policies require specialist expertise and resources. CONCLUSIONS: The FERG global and regional burden estimates will greatly enhance the ability of individual countries to fill data gaps and generate national estimates to support efforts to reduce the burden of foodborne disease. PMID- 26633011 TI - The Epidemiology of Hip and Major Osteoporotic Fractures in a Dutch Population of Community-Dwelling Elderly: Implications for the Dutch FRAX(r) Algorithm. AB - BACKGROUND: Incidence rates of non-hip major osteoporotic fractures (MOF) remain poorly characterized in the Netherlands. The Dutch FRAX(r) algorithm, which predicts 10-year probabilities of hip fracture and MOF (first of hip, humerus, forearm, clinical vertebral), therefore incorporates imputed MOF rates. Swedish incidence rate ratios for hip fracture to MOF (Malmo 1987-1996) were used to perform this imputation. However, equality of these ratios between countries is uncertain and recent evidence is scarce. Aims were to estimate incidence rates of hip fracture and MOF and to compare observed MOF rates to those predicted by the imputation method for the Netherlands. METHODS: Using hospitalisation and general practitioner records from the Dutch PHARMO Database Network (2002-2011) we calculated age-and-sex-specific and age-standardized incidence rates (IRs) of hip and other MOFs (humerus, forearm, clinical vertebral) and as used in FRAX(r). Observed MOF rates were compared to those predicted among community-dwelling individuals >=50 years by the standardized incidence ratio (SIR; 95% CI). RESULTS: Age-standardized IRs (per 10,000 person-years) of MOF among men and women >=50 years were 25.9 and 77.0, respectively. These numbers were 9.3 and 24.0 for hip fracture. Among women 55-84 years, observed MOF rates were significantly higher than predicted (SIR ranged between 1.12-1.50, depending on age). In men, the imputation method performed reasonable. CONCLUSION: Observed MOF incidence was higher than predicted for community-dwelling women over a wide age-range, while it agreed reasonable for men. As miscalibration may influence treatment decisions, there is a need for confirmation of results in another data source. Until then, the Dutch FRAX(r) output should be interpreted with caution. PMID- 26633013 TI - Silent or Vocalizing Rats Copulate in a Similar Manner. AB - Both male and female rats produce 50 kHz ultrasonic vocalizations (USVs) in the presence of a sexual partner and during copulation. Previous studies showed that USVs have no incentive value for rats. In this study, we evaluated the role of USVs in behavior during copulation. Three groups of rats were used: sham males paired with sham females, devocalized females paired with sham males, and sham females paired with devocalized males. During the copulation test, the USVs emitted by the sham rat were recorded and the sexual behavior of both the male and the female were observed. The results revealed that devocalized and sham females showed similar patterns of sexual behavior and no difference was found in the copulatory behavior of devocalized and sham males. Also the behavior of the partner of a sham rat was comparable to the partner of a devocalized rat. In addition, almost no changes in USVs emission were found in the 5 seconds before and/or after a copulatory behavior. It can be concluded that USVs play no important role in rat copulatory behavior at least in sexually naive rats. PMID- 26633012 TI - The Mammalian "Obesogen" Tributyltin Targets Hepatic Triglyceride Accumulation and the Transcriptional Regulation of Lipid Metabolism in the Liver and Brain of Zebrafish. AB - Recent findings indicate that different Endocrine Disrupting Chemicals (EDCs) interfere with lipid metabolic pathways in mammals and promote fat accumulation, a previously unknown site of action for these compounds. The antifoulant and environmental pollutant tributyltin (TBT), which causes imposex in gastropod snails, induces an "obesogenic" phenotype in mammals, through the activation of the nuclear receptors retinoid X receptor (RXR) and peroxisome proliferator activated receptor gamma (PPARgamma). In teleosts, the effects of TBT on the lipid metabolism are poorly understood, particularly following exposure to low, environmental concentrations. In this context, the present work shows that exposure of zebrafish to 10 and 50 ng/L of TBT (as Sn) from pre-hatch to 9 months of age alters the body weight, condition factor, hepatosomatic index and hepatic triglycerides in a gender and dose related manner. Furthermore, TBT modulated the transcription of key lipid regulating factors and enzymes involved in adipogenesis, lipogenesis, glucocorticoid metabolism, growth and development in the brain and liver of exposed fish, revealing sexual dimorphic effects in the latter. Overall, the present study shows that the model mammalian obesogen TBT interferes with triglyceride accumulation and the transcriptional regulation of lipid metabolism in zebrafish and indentifies the brain lipogenic transcription profile of fish as a new target of this compound. PMID- 26633014 TI - Estimating the Burden of Febrile Illnesses. PMID- 26633015 TI - Antiretroviral Therapy, Especially Efavirenz, Is Associated with Low Bone Mineral Density in HIV-Infected South Africans. AB - PURPOSE: We determined the prevalence and correlates of low bone mineral density (BMD) in HIV-infected South Africans as there is a paucity of such data from Africa. METHODS: BMD and serum 25-hydroxyvitamin D were measured in HIV-positive participants on antiretroviral therapy (ART) and in those not yet on ART (ART naive). RESULTS: We enrolled 444 participants [median age 35(IQR: 30, 40) years; 77% women]. BMD was low (z score <-2SD) in 17% and 5% of participants at the lumbar spine and total hip, respectively. Total hip [0.909 (SD 0.123) vs 0.956 (SD 0.124) g/cm2, p = 0.0001] and neck of femur BMD [0.796 (SD 0.130) vs 0.844 (SD 0.120) g/cm2, p = 0.0001] were lower in the ART, compared to the ART-naive group. Vitamin D deficiency was present in 15% of participants and was associated with efavirenz use [adjusted OR 2.04 (95% CI 1.01 to 4.13)]. In a multivariate linear regression, exposure to efavirenz or lopinavir-based ART was associated with lower total hip BMD, whereas higher weight, being male and higher vitamin D concentration were associated with higher total hip BMD (adjusted R2 = 0.28). Age, weight, sex, and the use of efavirenz-based ART were independently associated with lumbar spine BMD (adjusted R2 = 0.13). CONCLUSIONS: Vitamin D status, use of efavirenz or lopinavir/ritonavir, weight, age and sex are significantly associated with lower BMD in this young cohort of HIV-infected South Africans. PMID- 26633016 TI - Soluble TRAIL Concentration in Serum Is Elevated in People with Hypercholesterolemia. AB - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a multi functional cytokine, which is involved in the pathophysiological processes of cardiovascular and metabolic diseases. Previously, we demonstrated that TRAIL stimulated lipid uptake and foam cell formation in macrophages in vitro. Several clinical studies have suggested that the serum concentration of TRAIL may be increased in humans with elevated blood cholesterol; however, the current data appear to be inconclusive in this regard. In the present study, we examined the relationships between the serum TRAIL concentration and cholesterol levels in 352 generally healthy subjects undergoing the routine annual health check. We showed that there were significant correlations between TRAIL concentration and levels of total and low-density lipoprotein cholesterols. The level of TRAIL was significantly elevated in subjects with hypercholesterolemia, although this relationship might be also associated with changes of other metabolic factors. Moreover, we showed that the level of blood cholesterol was significantly higher in subjects in the upper quartile of serum TRAIL. In conclusion, our data demonstrate that the serum TRAIL concentration is elevated in people with hypercholesterolemia. PMID- 26633017 TI - Association between Thiopurine S-Methyltransferase Polymorphisms and Azathioprine Induced Adverse Drug Reactions in Patients with Autoimmune Diseases: A Meta Analysis. AB - PURPOSE: Azathioprine (AZA) is widely used as an immunosuppressive drug in autoimmune diseases, but its use is limited by significant adverse drug reactions (ADRs). Thiopurine S-methyltransferase (TPMT) is an important enzyme involved in AZA metabolism. Several clinical guidelines recommend determining TPMT genotype or phenotype before initiating AZA therapy. Although several studies have investigated the association between TPMT polymorphisms and AZA-induced ADRs, the results are inconsistent. The purpose of this study is to evaluate whether there is an association between TPMT polymorphisms and AZA-induced ADRs using meta analysis. METHODS: We explored PubMed, Web of Science and Embase for articles on TPMT polymorphisms and AZA-induced ADRs. Studies that compared TPMT polymorphisms with-ADRs and without-ADRs in patients with autoimmune diseases were included. Relevant outcome data from all the included articles were extracted and the pooled odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were calculated using Revman 5.3 software. RESULTS: Eleven published studies, with a total of 651 patients with autoimmune diseases, investigated associations between TPMT polymorphisms and AZA-induced ADRs, were included in this meta-analysis. Our meta-analysis demonstrated that TPMT polymorphisms were significantly associated with AZA-induced overall ADRs, bone marrow toxicity and gastric intolerance; pooled ORs were 3.12 (1.48-6.56), 3.76 (1.97-7.17) and 6.43 (2.04-20.25), respectively. TPMT polymorphisms were not associated with the development of hepatotoxicity; the corresponding pooled OR was 2.86 (95%CI: 0.32-25.86). However, the association in GI subset could be driven by one single study. After this study was excluded, the OR was 2.11 (95%CI: 0.36-12.42); namely, the association became negative. CONCLUSIONS: Our meta-analysis demonstrated an association of TPMT polymorphisms with overall AZA-induced ADRs, bone marrow toxicity and gastric intolerance, but not with hepatotoxicity. The presence of the normal TPMT genotypes cannot preclude the development of ADRs during AZA treatment, TPMT genotyping prior to commencing AZA therapy cannot replace, may augment, the current practice of regular monitoring of the white blood cell. Because of small sample sizes, large and extensive exploration was required to validate our findings. PMID- 26633018 TI - Traveling into Outer Space: Unanswered Questions about Fungal Extracellular Vesicles. PMID- 26633020 TI - Importance of Proton-Coupled Electron Transfer from Natural Phenolic Compounds in Superoxide Scavenging. AB - The superoxide O2(.-) scavenging reaction of (+)-catechin (Cat), quercetin (Que), rutin, and alpha-tocopherol (alpha-TOH) as natural phenolic compounds is investigated on the basis of electrochemical and ESR spectral measurements with the aid of density functional theory (DFT) calculations. Reversibility of the O2/O2(.-) redox couple is significantly affected by the presence of the phenolic compounds. The catechol moiety of Cat, Que, and rutin plays an essential role in concerted proton-coupled electron transfer (PCET) to HO2(.) derived from O2(.-) to give H2O2 and the corresponding o-benzoquinone radical anions. On the other hand, the presence of alpha-TOH causes sequential electron and proton transfers to HO2(.) to give H2O2 and the alpha-tocopheroxyl radical. These electron transfers in the presence of the phenolic compounds are inferred from the ESR spectral measurements. The DFT calculation results suggest that the O2(.-) scavenging reaction of the natural phenolic compounds proceeds efficiently with the one-step concerted PCET or sequential PCET mechanism. PMID- 26633019 TI - Divergent RNA Localisation Patterns of Maternal Genes Regulating Embryonic Patterning in the Butterfly Pararge aegeria. AB - The maternal effect genes responsible for patterning the embryo along the antero posterior (AP) axis are broadly conserved in insects. The precise function of these maternal effect genes is the result of the localisation of their mRNA in the oocyte. The main developmental mechanisms involved have been elucidated in Drosophila melanogaster, but recent studies have shown that other insect orders often diverge in RNA localisation patterns. A recent study has shown that in the butterfly Pararge aegeria the distinction between blastodermal embryonic (i.e. germ band) and extra-embryonic tissue (i.e. serosa) is already specified in the oocyte during oogenesis in the ovariole, long before blastoderm cellularisation. To examine the extent by which a female butterfly specifies and patterns the AP axis within the region fated to be the germ band, and whether she specifies a germ plasm, we performed in situ hybridisation experiments on oocytes in P. aegeria ovarioles and on early embryos. RNA localisation of the following key maternal effect genes were investigated: caudal (cad), orthodenticle (otd), hunchback (hb) and four nanos (nos) paralogs, as well as TDRD7 a gene containing a key functional domain (OST-HTH/LOTUS) shared with oskar. TDRD7 was mainly confined to the follicle cells, whilst hb was exclusively zygotically transcribed. RNA of some of the nos paralogs, otd and cad revealed complex localisation patterns within the cortical region prefiguring the germ band (i.e. germ cortex). Rather interestingly, otd was localised within and outside the anterior of the germ cortex. Transcripts of nos-O formed a distinct granular ring in the middle of the germ cortex possibly prefiguring the region where germline stem cells form. These butterfly RNA localisation patterns are highly divergent with respect to other insects, highlighting the diverse ways in which different insect orders maternally regulate early embryogenesis of their offspring. PMID- 26633021 TI - Development and Assessment of a Nomogram to Propose the Initial Dosage Regimen of a Meropenem Infusion Based on Serum Creatinine and Age Using a Monte Carlo Simulation. AB - A conventional nomogram, based on serum creatinine (sCr) and age, was developed in order to determine the correct initial dosage regimen for meropenem (MEPM) infusions in elderly patients with severe community-acquired pneumonia (CAP), using a target minimum inhibitory concentration (MIC) of 2 mg/L. A correlation between age and actual bodyweight (BW) in a development cohort of 44 males and 45 females was performed by linear regression using the least-squares method (male: y=-0.4676x+80.281, R(2)=0.4888; female: y=-0.4373x+77.502, R(2)=0.3194). There were no significant differences between actual BW and the BW (e-BW) estimated using this equation in this cohort (male: e-BW 41.6+/-3.1 kg, BW 41.7+/-3.5 kg, p=0.93; female: e-BW 39.5+/-2.1 kg, BW 39.5+/-3.7 kg, p=0.20). By integrating these equations using the Monte Carlo simulation method, a dosage regime was calculated which would have an 80% probability of maintaining plasma drug levels above the MIC for more than 40% of the time (>40%TAM), using only the age and sCr of individual patients. This relationship was summarized as a nomogram. The nomogram was validated using an independent validation cohort (n=28) of patients. An optimized dosage regimen could be predicted in 84 patients (94.4%) in the development cohort and 25 patients (89.3%) in the validation cohort. This nomogram may be a useful tool for clinicians and pharmacists in determining an initial MEPM regimen in elderly patients with severe CAP, based only on age and sCr. PMID- 26633022 TI - Novel 2,7-Substituted (S)-1,2,3,4-Tetrahydroisoquinoline-3-carboxylic Acids: Peroxisome Proliferator-Activated Receptor gamma Partial Agonists with Protein Tyrosine Phosphatase 1B Inhibition. AB - A novel series of 2,7-substituted 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives were synthesized and biologically evaluated. (S)-2-(2 Furylacryloyl)-7-[2-(2-methylindane-2-yl)-5-methyloxazol-4-yl]methoxy-1,2,3,4 tetrahydroisoquinoline-3-carboxylic acid tert-butylamine salt (13jE) was identified as a potent human peroxisome proliferator-activated receptor gamma (PPARgamma)-selective agonist (EC50=85 nM) and human protein-tyrosine phosphatase 1B (PTP-1B) inhibitor (IC50=1.0 uM). Compound 13jE partially activated PPARgamma, but not PPARalpha or PPARdelta, and antagonized farglitazar, a full PPARgamma agonist. Cmax after the oral administration of 13jE at 10 mg/kg was 28.6 ug/mL (53 uM) in male Sprague-Dawley (SD) rats. Repeated administration of 13jE and rosiglitazone for 14 d at 10 mg/kg/d decreased plasma glucose and triglyceride levels significantly in male KK-A(y) mice. Rosiglitazone, but not 13jE, significantly increased the plasma volume and liver weight. In conclusion, 13jE showed stronger hypoglycemic and hypolipidemic effects and weaker hemodilution and hepatotoxic effects than rosiglitazone, suggesting that its safer efficacy may be due to its partial PPARgamma agonism and PTP-1B inhibition. PMID- 26633023 TI - Discovery of Potent Antiproliferative Agents Targeting EGFR Tyrosine Kinase Based on the Pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-amine Scaffold. AB - A series of pyridothieno[3,2-d]pyrimidin-4-amines was designed and synthesized as congeners to the classical 4-anilinoquinazolines as ATP-competitive epidermal growth factor receptor (EGFR) inhibitors. Compound 5a exhibited the most potent and selective inhibitory activity against EGFR with an IC50 value of 36.7 nM. Moreover, compounds 4b and 5a showed remarkable cell growth inhibition against leukemia, central nervous system cancer, and non-small cell lung cancer cell lines that overexpress EGFR, with growth inhibition of 50% (GI50) values of around 10 nM in the full U.S. National Cancer Institute 60 cell panel assay. Cell cycle studies indicated that compounds 4b and 5a induced significant cell cycle arrest in the S-phase and G0/G1, respectively, in addition to boosting P27(kip) expression. Compound 5a did not alter the viability of placental trophoblasts, which reflects its safety for normal cells. The standard COMPARE analyses demonstrated considerable correlation levels between compounds 4b and 5a and erlotinib, with pyridinium chlorochromate (PCC) values of 0.707 and 0.727, respectively. PMID- 26633024 TI - Design, Synthesis, Biological Evaluation, and Antioxidant and Cytotoxic Activity of Heteroatom-Substituted 1,4-Naphtho- and Benzoquinones. AB - In the present paper, we report the synthesis, characterization, and biological evaluation as antifungal, antibacterial, antioxidant, and cytotoxic/anticancer agents of N-, S-, O-substituted-1,4-naphtho- and 2,5-bis(amino-substituted)-1,4 benzoquinone derivatives. In the synthesized compounds, antimicrobial activity at low concentrations against Escherichia coli B-906, Staphylococcus aureus 209-P, and Mycobacterium luteum B-917 bacteria and Candida tenuis VKM Y-70 and Aspergillus niger F-1119 fungi in comparison with controls was identified. 2-(N Diphenylmethylpiperazin-1-yl)-3-chloro-1,4-naphthoquinone 9a was the most potent, with a minimum inhibitory concentration value of 3.9 ug/mL against test culture M. luteum. The synthesized compounds were screened for their antioxidant capacity using the cupric-reducing antioxidant capacity (CUPRAC) method. 2,2'-[1-(2 Aminoethyl)piperazin-1-yl]-3,3'-dichloro-bis(1,4-naphthoquinone) 10 showed the highest antioxidant capacity, with a 0.455 CUPRAC-trolox equivalent antioxidant capacity (TEAC) coefficient. Other parameters of antioxidant activity (scavenging effects on OH(.), O2(.-), and H2O2) of these compounds were also determined. The cytotoxic activity of the compounds was investigated by employing the sulforhodamine B cell viability assay against A549 (lung), MCF-7 (breast), DU145 (prostate), and HT-29 (colon) cancer cell lines. Compound 10 exhibited the most powerful cytotoxic activity at a concentration of 20 uM against all cell lines. In addition to the strongest antioxidant activity of compound 10, it also had lowest IC50 values (<3 uM), warranting further in vivo studies due to its anticancer activity. PMID- 26633025 TI - Adsorption of As(III) from Aqueous Solutions by Novel Fe-Mg Type Hydrotalcite. AB - Morphological and chemical evaluation of Fe-Mg hydrotalcite (Fe-HT) was performed using scanning electron microscopy, X-ray diffraction analysis, and electron microanalysis for application as an adsorbent for water treatment. The adsorption of arsenic III (As(III)) on Fe-HT was evaluated via examination of the effect of the contact time and analysis of the adsorption isotherm. The amount of As(III) adsorbed increased slightly with increasing temperature. The results of the adsorption isotherm studies suggested that As(III) adsorption can be well described by both the Freundlich and Langmuir equations. The adsorption of As(III) on Fe-HT reached equilibrium within 24 h, and the adsorption kinetic data fit the pseudo-second-order kinetic model better than the pseudo-first-order model. The amount of As(III) present on the surface of Fe-HT increased after As(III) adsorption, and the crystalline structure of Fe-HT was maintained after adsorption of As(III). The (003) and (006) peaks in the X-ray diffraction patterns were attributed to basal reflections, and these peaks shifted from respective 2theta values of 10.86 and 21.94 degrees to 11.12 and 22.52 degrees , indicating exchange of As(III) with chloride ions in Fe-HT with consequent narrowing of the inter-layer spacing. Collectively, these results suggest that Fe HT is prospectively useful for the adsorption of As(III) from aqueous solutions. PMID- 26633026 TI - Crotocascarins I-K: Crotofolane-Type Diterpenoids, Crotocascarin gamma, Isocrotofolane Glucoside and Phenolic Glycoside from the Leaves of Croton cascarilloides. AB - From the 1-BuOH-soluble fraction of a methanol (MeOH) extract of the leaves of Croton cascarilloides, crotofolanes: crotocascarins I-K, nor-crotofolane: crotocascarin gamma, isocrotofolane glucoside and phenolic glycoside were isolated by a combination of various separation techniques. Their structures were elucidated mainly from the NMR spectroscopic evidence. The structure of crotocascarin K was first elucidated by spectroscopic analysis and then was confirmed by X-ray crystallographic analysis. Its absolute structure was finally determined by the modified Mosher's method. Isocrotofolane glucoside was found to possess a new skeleton, however, its absolute structure remains to be determined. PMID- 26633027 TI - Multicomponent Reactions of Acetoacetanilide Derivatives with Aromatic Aldehydes and Cyanomethylene Reagents to Produce 4H-Pyran and 1,4-Dihydropyridine Derivatives with Antitumor Activities. AB - The multi-component reaction of either acetoacetanilide derivative 1a or b with any of the aldehyde derivatives 2a-d and malononitrile 3 in the presence of triethylamine as a catalyst gave the 4H-pyran derivatives 4a-g, respectively. Carrying the same reaction but using a catalytic amount of ammonium acetate gave the 1,4-dihydropyridine derivatives 5a-f, respectively. The use of ethyl cyanoacetate instead of malononitrile in the presence of a catalytic amount of triethylamine gave the 4H-pyran derivatives 7a-d, respectively. Compound 4e was used to synthesize 1,4-dihydropyridine 9a-c and arylhydraone 11a-e derivatives were synthesized from 4a and e. The anti-tumor evaluations of the newly synthesized products were tested against six human cancer and normal cell lines. The results showed that compounds 4a, b, f, 5d, f, 9 and 11a-d had optimal cytotoxic effect against cancer cell lines with IC50<550 nM. The toxicity of the most active compounds was further measured against shrimp larvae. PMID- 26633028 TI - New Glabretal Triterpenes from the Immature Fruits of Poncirus trifoliata and Their Selective Cytotoxicity. AB - Two new glabretal triterpenes, pancastatins A (1) and B (2), were isolated from the immature fruits of Poncirus trifoliata. Their chemical structures were elucidated by spectroscopic analyses including one- and two-dimensional NMR and high-resolution electrospray ionization mass spectrometry. Compounds 1 and 2 exhibited selective cytotoxicity against PANC-1 pancreatic cancer cells under low glucose stress conditions. PMID- 26633029 TI - Investigation of Physicochemical Drug Properties to Prepare Fine Globular Granules Composed of Only Drug Substance in Fluidized Bed Rotor Granulation. AB - The effect of some drug properties (wettability and particle size distribution) on granule properties (mean particle size, particle size distribution, sphericity, and granule strength) were investigated in a high (>97%) drug-loading formulation using fluidized bed rotor granulation. Three drugs: acetaminophen (APAP); ibuprofen (IBU); and ethenzamide (ETZ) were used as model drugs based on their differences in wettability and particle size distribution. Granules with mean particle sizes of 100-200 um and a narrow particle size distribution (PSD) could be prepared regardless of the drug used. IBU and ETZ granules showed a higher sphericity than APAP granules, while APAP and ETZ granules exhibited higher granule strength than IBU. The relationship between drug and granule properties suggested that the wettability and the PSD of the drugs were critical parameters affecting sphericity and granule strength, respectively. Furthermore, the dissolution profiles of granules prepared with poorly water-soluble drugs (IBU and ETZ) showed a rapid release (80% release in 20 min) because of the improved wettability with granulation. The present study demonstrated for the first time that fluidized bed rotor granulation can prepare high drug-loaded (>97%) globular granules with a mean particle size of less than 200 um and the relationship between physicochemical drug properties and the properties of the granules obtained could be readily determined, indicating the potential for further application of this methodology to various drugs. PMID- 26633030 TI - Effect of Chaenomeles sinensis Extract on Choline Acetyltransferase Activity and Trimethyltin-Induced Learning and Memory Impairment in Mice. AB - The aim of this study was to search for a novel choline acetyltransferase (ChAT) activator from plants traditionally grown in Korea. An ethanol extract from Chaenomeles sinensis Koehne showed the highest ChAT-activating effect in vitro in an assay that used human neuroblastoma cells and [(14)C]acetyl-CoA. The active compound was speculated to be stearic acid methyl ester (SAME). In an in vivo experiment, C. sinensis extract and SAME improved trimethyltin (TMT)-induced deficits in learning and memory in mice as assessed by a Y-maze behavioral test and a passive avoidance test. The C. sinensis extract might attenuate the TMT induced brain disorder. This study suggests that SAME from C. sinensis might be useful in the treatment of Alzheimer's disease. PMID- 26633031 TI - New 2-Benzoxazolinone Derivatives with Cytotoxic Activities from the Roots of Acanthus ilicifolius. AB - Four new 2-benzoxazolinone-type alkaloids (acanthosides A-D) along with three known ones were isolated from the roots of Acanthus ilicifolius. Their structures were established by detailed interpretation of one dimensional (1D)- and two dimensional (2D)-NMR as well as high-resolution electrospray ionization (ESI)-MS data. The antiproliferative activities of these compounds were evaluated in vitro against three cultured cancer cell lines. The new compounds exhibited different levels of cytotoxicity against the HepG2, HeLa, and A-549 cancer cell lines with IC50 range 7.8-26.6 uM. In comparison with known compounds, the new isolates displayed better cytotoxic activities, which was attributable to the presence of substituted benzoyl moiety in their structures. PMID- 26633032 TI - Long-Term Patterns in the Population Dynamics of Daphnia longispina, Leptodora kindtii and Cyanobacteria in a Shallow Reservoir: A Self-Organising Map (SOM) Approach. AB - The recognition of long-term patterns in the seasonal dynamics of Daphnia longispina, Leptodora kindtii and cyanobacteria is dependent upon their interactions, the water temperature and the hydrological conditions, which were all investigated between 1999 and 2008 in the lowland Sulejow Reservoir. The biomass of cyanobacteria, densities of D. longispina and L. kindtii, concentration of chlorophyll a and water temperature were assessed weekly from April to October at three sampling stations along the longitudinal reservoir axis. The retention time was calculated using data on the actual water inflow and reservoir volume. A self-organising map (SOM) was used due to high interannual variability in the studied parameters and their often non-linear relationships. Classification of the SOM output neurons into three clusters that grouped the sampling terms with similar biotic states allowed identification of the crucial abiotic factors responsible for the seasonal sequence of events: cluster CL-ExSp (extreme/spring) corresponded to hydrologically unstable cold periods (mostly spring) with extreme values and highly variable abiotic factors, which made abiotic control of the biota dominant; cluster CL-StSm (stable/summer) was associated with ordinary late spring and summer and was characterised by stable non-extreme abiotic conditions, which made biotic interactions more important; and the cluster CL-ExSm (extreme/summer), was associated with late spring/summer and characterised by thermal or hydrological extremes, which weakened the role of biotic factors. The significance of the differences between the SOM sub-clusters was verified by Kruskal-Wallis and post-hoc Dunn tests. The importance of the temperature and hydrological regimes as the key plankton-regulating factors in the dam reservoir, as shown by the SOM, was confirmed by the results of canonical correlation analyses (CCA) of each cluster. The demonstrated significance of hydrology in seasonal plankton dynamics complements the widely accepted pattern proposed by the plankton succession model for lakes, the PEG (Plankton Ecology Group), and may be useful for the formulation of management decisions in dam reservoirs. PMID- 26633033 TI - Effects of the Change in Working Status on the Health of Older People in Japan. AB - BACKGROUND: Working at old ages is regarded as a good way to keep one's health according to the idea of productive aging. However, there is not enough evidence yet whether retirement is good or bad, or the kind of effects it has on the health of older adults aged 65 and over. We examined it by using a recent data of Wako city, a suburb area near Tokyo in Japan. METHODS: One thousand seven hundred sixty-eight participants answered to 3 waves of survey questionnaires: 2008, 2010, and 2012, successively. We considered 3 indicators of health; self-rated health, mental health (GDS15) and HLFC (Higher-Level Functional Capacity: TMIG IC). In cross-sectional analysis, we compared these 3 indicators by three groups: full-time worker, part-time worker, and non-worker. In longitudinal analysis, we compared these three indicators by two groups: subjects who successively worked in 2008, 2010, 2012, and subjects who worked in 2008 but retired before 2010. We used one-way and two way repeated measures ANCOVA for these analyses, respectively. RESULTS: It was significantly clear that retirement worsened both mental health and HLFC in people aged 65 years and over; especially, mental health worsened rapidly and HLFC gradually. However, these indicators didn't worsen in subjects who changed from full-time jobs to part-time jobs. Quitting from part-time jobs deteriorated mental health gradually and HLFC moderately compared to full-time jobs. CONCLUSION: The results support the activity theory that older adults who quit from full-time jobs deteriorated both mental health and HLFC, though at different speeds. If they make a transit to part-time jobs, the deterioration would be moderate. It shows that working is an effective way of social participation for older people aged 65 years and over in Japan. PMID- 26633034 TI - Pharmacokinetic Study of Adjuvant Gemcitabine Therapy for Biliary Tract Cancer following Major Hepatectomy (KHBO1101). AB - BACKGROUND: Biliary tract cancer (BTC) patients who have undergone surgical resection with major hepatectomy cannot tolerate the standard gemcitabine regimen (1,000 mg/m2 on days 1, 8, and 15 every 4 weeks) due to severe toxicities such as myelosuppression. Our dose-finding study of adjuvant gemcitabine therapy for biliary tract cancer following major hepatectomy determined that the recommended dose is 1,000 mg/m2 on days 1 and 15 every 4 weeks. Here, we evaluate the pharmacokinetics and pharmacodynamics of gemcitabine in these subjects. METHODS: We evaluated BTC patients scheduled to undergo surgical resection with major hepatectomy followed by gemcitabine therapy. A pharmacokinetic evaluation of gemcitabine and its main metabolite, 2',2'-difluorodeoxyuridine (dFdU), was conducted at the initial administration of gemcitabine, which was given by intravenous infusion over 30 min at a dose of 800-1,000 mg/m2. Physical examination and adverse events were monitored for 12 weeks. RESULTS: Thirteen patients were enrolled from August 2011 to January 2013, with 12 ultimately completing the pharmacokinetic study. Eight patients had hilar cholangiocarcinoma, three had intrahepatic cholangiocarcinoma, and one had superficial spreading type cholangiocarcinoma. The median interval from surgery to first administration of gemcitabine was 65.5 days (range, 43-83 days). We observed the following toxicities: neutropenia (n = 11, 91.7%), leukopenia (n = 10, 83.3%), thrombocytopenia (n = 6, 50.0%), and infection (n = 5, 41.7%). Grade 3 or 4 neutropenia was observed in 25% (n = 3) of patients. There were differences in clearance of gemcitabine and dFdU between our subjects and the subjects who had not undergone hepatectomy. CONCLUSION: Major hepatectomy did not affect the pharmacokinetics of gemcitabine or dFdU. TRIAL REGISTRATION: UMIN-CTR in (JPRN) UMIN000005109. PMID- 26633035 TI - Global Survey of Corneal Transplantation and Eye Banking. AB - IMPORTANCE: Corneal transplantation restores visual function when visual impairment caused by a corneal disease becomes too severe. It is considered the world's most frequent type of transplantation, but, to our knowledge, there are no exhaustive data allowing measurement of supply and demand, although such data are essential in defining local, national, and global strategies to fight corneal blindness. OBJECTIVE: To describe the worldwide situation of corneal transplantation supply and demand. DESIGN, SETTING, AND PARTICIPANTS: Data were collected between August 2012 and August 2013 from a systematic review of published literature in parallel with national and international reports on corneal transplantation and eye banking. In a second step, eye bank staff and/or corneal surgeons were interviewed on their local activities. Interviews were performed during international ophthalmology or eye-banking congresses or by telephone or email. Countries' national supply/demand status was classified using a 7-grade system. Data were collected from 148 countries. MAIN OUTCOMES AND MEASURES: Corneal transplantation and corneal procurements per capita in each country. RESULTS: In 2012, we identified 184,576 corneal transplants performed in 116 countries. These were procured from 283,530 corneas and stored in 742 eye banks. The top indications were Fuchs dystrophy (39% of all corneal transplants performed), a primary corneal edema mostly affecting elderly individuals; keratoconus (27%), a corneal disease that slowly deforms the cornea in young people; and sequellae of infectious keratitis (20%). The United States, with 199.10-6 corneal transplants per capita, had the highest transplantation rate, followed by Lebanon (122.10-6) and Canada (117.10-6), while the median of the 116 transplanting countries was 19.10-6. Corneas were procured in only 82 countries. Only the United States and Sri Lanka exported large numbers of donor corneas. About 53% of the world's population had no access to corneal transplantation. CONCLUSIONS AND RELEVANCE: Our survey globally quantified the considerable shortage of corneal graft tissue, with only 1 cornea available for 70 needed. Efforts to encourage cornea donation must continue in all countries, but it is also essential to develop alternative and/or complementary solutions, such as corneal bioengineering. PMID- 26633036 TI - LncRNA-HIT Functions as an Epigenetic Regulator of Chondrogenesis through Its Recruitment of p100/CBP Complexes. AB - Gene expression profiling in E 11 mouse embryos identified high expression of the long noncoding RNA (lncRNA), LNCRNA-HIT in the undifferentiated limb mesenchyme, gut, and developing genital tubercle. In the limb mesenchyme, LncRNA-HIT was found to be retained in the nucleus, forming a complex with p100 and CBP. Analysis of the genome-wide distribution of LncRNA-HIT-p100/CBP complexes by ChIRP-seq revealed LncRNA-HIT associated peaks at multiple loci in the murine genome. Ontological analysis of the genes contacted by LncRNA-HIT-p100/CBP complexes indicate a primary role for these loci in chondrogenic differentiation. Functional analysis using siRNA-mediated reductions in LncRNA-HIT or p100 transcripts revealed a significant decrease in expression of many of the LncRNA HIT-associated loci. LncRNA-HIT siRNA treatments also impacted the ability of the limb mesenchyme to form cartilage, reducing mesenchymal cell condensation and the formation of cartilage nodules. Mechanistically the LncRNA-HIT siRNA treatments impacted pro-chondrogenic gene expression by reducing H3K27ac or p100 activity, confirming that LncRNA-HIT is essential for chondrogenic differentiation in the limb mesenchyme. Taken together, these findings reveal a fundamental epigenetic mechanism functioning during early limb development, using LncRNA-HIT and its associated proteins to promote the expression of multiple genes whose products are necessary for the formation of cartilage. PMID- 26633037 TI - Neurotoxic Effects of Anthracycline- vs Nonanthracycline-Based Chemotherapy on Cognition in Breast Cancer Survivors. AB - IMPORTANCE: Chemotherapy exposure is a known risk factor for cancer-related cognitive impairments. Anthracycline-based regimens are commonly used chemotherapies that have been shown to be associated with cognitive impairment and brain changes in clinical studies. OBJECTIVE: To directly compare the effects of anthracycline and nonanthracycline regimens on cognitive status and functional brain connectivity. DESIGN, SETTING, AND PARTICIPANTS: In this observational study, we retrospectively examined cognitive and resting state functional magnetic resonance imaging data acquired from 62 primary breast cancer survivors (mean [SD] age, 54.7 [8.5] years) who were more than 2 years off-therapy, on average. Twenty of these women received anthracycline-based chemotherapy as part of their primary treatment, 19 received nonanthracycline regimens, and 23 did not receive any chemotherapy. Participants were enrolled at a single academic institution (Stanford University) from 2008 to 2014, and the study analyses were performed at this time. MAIN OUTCOMES AND MEASURES: Cognitive status was measured using standardized neuropsychological tests, and functional brain connectivity was evaluated using resting state functional magnetic resonance imaging with a focus on the brain's default mode network. RESULTS: The anthracycline group demonstrated significantly lower verbal memory performance including immediate recall (F = 3.73; P = .03) and delayed recall (F = 11.11; P < .001) as well as lower left precuneus connectivity (F = 7.48; P = .001) compared with the other 2 groups. Patient-reported outcomes related to cognitive dysfunction (F = 7.27; P = .002) and psychological distress (F = 5.64; P = .006) were similarly elevated in both chemotherapy groups compared with the non-chemotherapy-treated controls. CONCLUSIONS AND RELEVANCE: These results suggest that anthracyclines may have greater negative effects than nonanthracycline regimens on particular cognitive domains and brain network connections. Both anthracycline and nonanthracycline regimens may have nonspecific effects on other cognitive domains as well as certain patient reported outcomes. Further research is needed to identify potential methods for protecting the brain against the effects of various chemotherapeutic agents. PMID- 26633039 TI - Rigid Esophagoscopy for Head and Neck Cancer Staging and the Incidence of Synchronous Esophageal Malignant Neoplasms. AB - IMPORTANCE: Rigid esophagoscopy (RE) was once an essential part of the evaluation of patients with head and neck squamous cell carcinoma (HNSCC) due to the high likelihood of identifying a synchronous malignant neoplasm in the esophagus. Given recent advances in imaging and endoscopic techniques and changes in the incidence of esophageal cancer, the current role for RE in HNSCC staging is unclear. OBJECTIVE: To analyze the current role of RE in evaluating patients with HNSCC, and to determine the incidence of synchronous esophageal malignant neoplasms in patients with HNSCC. DESIGN, SETTING, AND PARTICIPANTS: In this retrospective study performed at an academic tertiary care center, 582 patients were studied who had undergone RE for HNSCC staging from July 1, 2004, through October 31, 2012. To assess the incidence of synchronous esophageal malignant neoplasms, a literature review was performed, and the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) data set was queried. MAIN OUTCOMES AND MEASURES: The primary outcome measure was the incidence of synchronous esophageal malignant neoplasms, as measured by retrospective review at our institution, SEER data set analysis, and literature review. Secondary outcome measures were RE complications and nonmalignant findings during RE. RESULTS: A total of 601 staging REs were performed in 582 patients. The mean age was 60.2 years and 454 (78.0%) were men. There were 9 complications (1.5%), including 1 esophageal perforation (0.2%). Rigid esophagoscopy was aborted in 50 cases. Of the 551 completed REs, no abnormal findings were noted in 523 patients (94.9%), and nonmalignant pathologic findings were identified in 28 patients (5.1%). No synchronous primary esophageal carcinomas were detected. The incidence of synchronous esophageal malignant neoplasms found on screening endoscopy based on literature review and on SEER data set analysis was very low and has decreased from 1980 to 2010 in North America. The incidence reported in South America and Asia was relatively high. CONCLUSIONS AND RELEVANCE: Rigid esophagoscopy is safe, but the utility is low for cancer staging and for detection of nonmalignant esophageal disease. Review of the literature and analysis of a large national cancer data set indicate that the incidence of synchronous esophageal malignant neoplasms in patients with HNSCC is low and has been decreasing during the past 3 decades. Thus, screening esophagoscopy should be limited to patients with HNSCC who are at high risk for synchronous esophageal malignant neoplasms. PMID- 26633038 TI - Invariant NKT cells are expanded in peripheral blood but are undetectable in salivary glands of patients with primary Sjogren's syndrome. AB - OBJECTIVES: Invariant NKT (iNKT) cells play a role in regulating the function of autoreactive B cells before their entry into germinal centres. Absence and/or reduction of iNKT cells have been demonstrated in patients with systemic lupus erythematosus (SLE) together with an increase of autoreactive B cell activity. Primary Sjogren's syndrome (pSS) is a systemic autoimmune disease in which lymphocyte infiltration and organisation in lymphoid structures of inflamed salivary glands occurs. The aim of the study was to investigate the percentage and function of iNKT in the salivary glands and peripheral blood of patients with pSS. METHODS: Minor salivary gland biopsies were obtained from patients with pSS and with non-specific chronic sialoadenitis (nSS). Flow cytometry analysis of CD1d/alpha-GalactosylCeramide (alpha-GalCer) tetramer positive cells, producing IFN-gamma and IL-17, and quantitative gene expression analysis by TaqMan real time PCR for Valpha24 were performed on salivary glands biopsies and peripheral blood samples obtained from patients and controls. Flow cytometry and immunofluorescence analysis for autoreactive B lymphocytes and ELISA for anti-SSA antibodies (Ab) detection were also performed. RESULTS: An increase of iNKT was detected ex vivo in peripheral blood of pSS patients; after alpha-GalCer stimulation this subset produce IL-17 and IFN-iNKT were undetectable in the salivary glands of pSS patients and anti-SSA specific B cells were found in target tissue. Invariant NKT cells were able to inhibit autoantibody production by B cells obtained from salivary glands of pSS. CONCLUSIONS: Impaired iNKT migration to inflamed sites might induce the activation of autoreactive B cells specific for SSA-antigen in salivary glands of pSS patients. PMID- 26633040 TI - Assisted Reproductive Technology Surveillance - ?United States, 2013. AB - PROBLEM/CONDITION: Since the first U.S. infant conceived with assisted reproductive technology (ART) was born in 1981, both the use of ART and the number of fertility clinics providing ART services have increased steadily in the United States. ART includes fertility treatments in which eggs or embryos are handled in the laboratory (i.e., in vitro fertilization [IVF] and related procedures). Women who undergo ART procedures are more likely than women who conceive naturally to deliver multiple-birth infants. Multiple births pose substantial risks to both mothers and infants, including obstetric complications, preterm delivery, and low birthweight infants. This report provides state specific information for the United States (including Puerto Rico) on ART procedures performed in 2013 and compares infant outcomes that occurred in 2013 (resulting from ART procedures performed in 2012 and 2013) with outcomes for all infants born in the United States in 2013. REPORTING PERIOD COVERED: 2013. DESCRIPTION OF SYSTEM: In 1996, CDC began collecting data on ART procedures performed in fertility clinics in the United States as mandated by the Fertility Clinic Success Rate and Certification Act of 1992 (FCSRCA) (Public Law 102-493). Data are collected through the National ART Surveillance System (NASS), a web based data collection system developed by CDC. This report includes data from 52 reporting areas (the 50 states, the District of Columbia [DC], and Puerto Rico). RESULTS: In 2013, a total of 160,521 ART procedures (range: 109 in Wyoming to 20,299 in California) with the intent to transfer at least one embryo were performed in 467 U.S. fertility clinics and were reported to CDC. These procedures resulted in 53,252 live-birth deliveries (range: 47 in Alaska to 6,979 in California) and 66,691 infants (range: 61 in Alaska to 8,649 in California). Nationally, the total number of ART procedures performed per million women of reproductive age (15-44 years), a proxy measure of the ART usage rate, was 2,521 (range: 352 in Puerto Rico to 7,688 in DC). ART use exceeded the national rate in 13 reporting areas (California, Connecticut, Delaware, Hawaii, Illinois, Maryland, Massachusetts, New Hampshire, New Jersey, New York, Rhode Island, Virginia, and DC). Nationally, among ART transfer procedures in patients using fresh embryos from their own eggs, the average number of embryos transferred increased with increasing age of the woman (1.8 among women aged <35 years, 2.0 among women aged 35-37 years, and 2.5 among women aged >37 years). Among women aged <35 years, who typically are considered to be good candidates for elective single embryo transfer (eSET) procedures, the national eSET rate was 21.4% (range: 4.0% in Idaho to 77.5% in Delaware). In 2013, ART contributed to 1.6% of all infants born in the United States (range: 0.2% in Puerto Rico to 4.8% in Massachusetts) and 18.7% of all multiple-birth infants (range: 4.5% in Puerto Rico to 35.7% in Massachusetts), including 18.5% of all twin infants (range: 4.5% in Mississippi to 35.3% in Massachusetts) and 25.2% of all triplet and higher order infants (range: 0% in several reporting areas to 51.5% in New Jersey). Multiple-birth deliveries were higher among infants conceived with ART (41.1%; range: 20.4% in Delaware to 61.6% in Wyoming) than among all infants born in the total birth population (only 3.5%; range: 1.8% in Puerto Rico to 4.5% in Massachusetts and New Jersey). Approximately 39% of ART-conceived infants were twin infants, and 2% were triplet and higher-order infants. ART-conceived twins accounted for approximately 95.4% of all ART-conceived infants born in multiple deliveries. Nationally, infants conceived with ART contributed to 5.8% of all low birthweight (<2,500 grams) infants (range: 0.9% in Puerto Rico to 15.1% in Massachusetts). Among ART-conceived infants, 29.1% were low birthweight (range: 18.3% in Delaware to 42.6% in Louisiana), compared with 8.0% among all infants (range: 5.8% in Alaska to 11.5% in Mississippi). ART-conceived infants contributed to 4.6% of all preterm (<37 weeks) infants (range: 0.6% in Puerto Rico to 13.3% in Massachusetts). Preterm birth rates were higher among infants conceived with ART (33.6%; range: 22.3% in DC to 50.7% in Louisiana) than among all infants born in the total birth population (11.4%; range: 8.8% in California to 16.6% in Mississippi). The percentage of ART-conceived infants who were low birthweight was 9.0% (range: 5.1% in Mississippi to 19.7% in Puerto Rico) among singletons and 56.3% (range: 48.3% in Maine to 72.4% in Puerto Rico) among twins; the corresponding percentages among all infants born were 6.3% for singletons (range: 4.6% in Alaska to 9.6% in Mississippi and Puerto Rico) and 55.3% for twins (range: 43.6% in Alaska to 65.6% in Mississippi). The percentage of ART conceived infants who were preterm varied from 13.3% (range: 8.7% in Rhode Island to 26.9% in West Virginia) among singletons to 61.0% (range: 47.8% in DC to 78.8% in Oklahoma) among twins; the corresponding percentages among all infants were 10.1% for singletons (range: 6.8% in Vermont to 14.8% in Mississippi) and 56.6% for twins (range: 44.7% in New Hampshire to 68.9% in Louisiana). INTERPRETATION: The percentage of infants conceived with ART varied considerably by reporting area. In most reporting areas, multiple births from ART contributed to a substantial proportion of all twins, triplets, and higher-order infants born, and the low birthweight and preterm infant birth rates were disproportionately higher among ART-conceived infants than among the overall birth population. Although women aged <35 years are typically considered good candidates for eSET, on average two embryos were transferred per ART procedure with women in this group, increasing the overall multiple-birth rates in the United States. Compared with ART-conceived singletons, ART-conceived twins were approximately four-and-a-half times more likely to be born preterm, and approximately six times more likely to be born with low birthweight. Singleton infants conceived with ART had slightly higher rates of preterm delivery and low birthweight than all singleton infants born in the United States. ART use per population unit was geographically variable, with 13 reporting areas showing ART use above the national rate. Of the four states (Illinois, Massachusetts, New Jersey, and Rhode Island) with comprehensive statewide-mandated health insurance coverage for ART procedures (i.e., coverage for at least four cycles of IVF), two states (Massachusetts and New Jersey) had rates of ART use exceeding twice the national level. This type of mandated insurance has been associated with greater use of ART and likely accounts for some of the difference in per capita ART use observed among states. PUBLIC HEALTH ACTIONS: Reducing the number of embryos transferred per ART procedure and increasing use of eSET, when clinically appropriate (typically for women aged <35 years), could help reduce multiple births, particularly ART conceived twin infants, and related adverse consequences of ART. Because twins account for the majority of ART-conceived multiple births, improved patient education and counseling on the maternal and infant health risks of having twins is needed. Although ART contributes to high rates of multiple births, other factors not investigated in this report (e.g., delayed childbearing and non-ART fertility treatments) also contribute to multiple births and warrant further study. PMID- 26633041 TI - Hot issues in female and male hormonal contraception. AB - In recent years a number of significant developments in the field of female hormonal contraception have been made which have produced new formulations and delivery systems providing high efficacy, safety and important non-contraceptive benefits. In particular long-acting reversible contraception (LARC) formulations have been demonstrated to ensure extremely high efficacy in typical use, minimal contraindications, optimal safety in all women thereby representing the best option for most women of all ages. Their effectiveness is not reliant upon user adherence and their ability to reduce unintended pregnancies and abortions has been proven. Unfortunately the same considerations cannot be made for male hormonal contraception. Although a large number of men are interested and would welcome the opportunity to use male contraceptive methods, no safe, effective and reversible methods are available on the market. Current methods available for men are limited to condoms and vasectomy. Highly effective prototype regimens have been developed but the pharmaceutical industry is unwilling to pursue further development and market these products. Of all new approaches to male contraception, hormonal methods are the closest to clinical application. These are based on the reversible suppression of luteinizing hormone and follicle stimulating hormone with subsequent reversible inhibition of spermatogenesis and consequent replacement to maintain androgen dependent physiological functions. Most approaches tested combination regimens such as testosterone and a progestin or testosterone and a GnRH analog. PMID- 26633042 TI - Robotic versus laparoscopic surgery in gynecology: which should we use? AB - This review of the literature aims at assessing the safety and effectiveness of robotic versus laparoscopic surgery in benign and malignant gynecological diseases. Robotic-assisted laparoscopy is already widely used in the United States and Europe for the main gynecological procedure - hysterectomy - and has proved feasible and comfortable for other benign and malignant gynecological procedures. However, the clinical effectiveness and safety of robotic surgery compared with standard laparoscopy have not been undoubtedly established. We reviewed the literature by searching in the Ovid/MEDLINE, PubMed, Cochrane Library, and Google Scholar databases for all the articles published from January 1995 to September 2015. More rigorous experimental studies are needed, that compare robotic-assisted surgery and laparoscopic surgery for gynecological diseases. However, current data seem to encourage the use of minimally-invasive surgery to treat benign and malignant gynecological diseases. PMID- 26633043 TI - Hydrothermal Synthesis and Processing of Barium Titanate Nanoparticles Embedded in Polymer Films. AB - Barium titanate nanoparticles embedded in flexible polymer films were synthesized using hydrothermal processing methods. The resulting films were characterized with respect to material composition, size distribution of nanoparticles, and spatial location of particles within the polymer film. Synthesis conditions were varied based on the mechanical properties of the polymer films, ratio of polymer to barium titanate precursors, and length of aging time between initial formulations of the solution to final processing of nanoparticles. Block copolymers of poly(styrene-co-maleic anhydride) (SMAh) were used to spatially separate titanium precursors based on specific chemical interactions with the maleic anhydride moiety. However, the glassy nature of this copolymer restricted mobility of the titanium precursors during hydrothermal processing. The addition of rubbery butadiene moieties, through mixing of the SMAh with poly(styrene butadiene-styrene) (SBS) copolymer, increased the nanoparticle dispersion as a result of greater diffusivity of the titanium precursor via higher mobility of the polymer matrix. Additionally, an aminosilane was used as a means to retard cross-linking in polymer-metalorganic solutions, as the titanium precursor molecules were shown to react and form networks prior to hydrothermal processing. By adding small amounts of competing aminosilane, excessive cross-linking was prevented without significantly impacting the quality and composition of the final barium titanate nanoparticles. X-ray diffraction and X-ray photoelectron spectroscopy were used to verify nanoparticle compositions. Particle sizes within the polymer films were measured to be 108 +/- 5 nm, 100 +/- 6 nm, and 60 +/- 5 nm under different synthetic conditions using electron microscopy. Flexibility of the films was assessed through measurement of the glass transition temperature using dynamic mechanical analysis. Dielectric permittivity was measured using an impedance analyzer. PMID- 26633045 TI - Effect of gamma irradiation on phenol content, antioxidant activity and biological activity of black maca and red maca extracts (Lepidium meyenii walp). AB - This study was performed to determine the effects of gamma irradiation on UV spectrum on maca, total content of polyphenols, 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical-scavenging activities and in vivo biological activities of red and black maca extracts (Lepidium meyenii). Adult mice of the strain Swiss aged 3 months and weighing 30-35 g in average were used to determine biological activities. Daily sperm production, effect on testosterone-induced prostate hyperplasia and forced swimming test were used to determine the effect of irradiation on biological activities of maca extracts. Irradiation did not show differences in UV spectrum but improves the amount of total polyphenols in red maca as well as in black maca extracts. In both cases, black maca extract has more content of polyphenols than red maca extract (p < 0.01). Gamma irradiation significantly increased the antioxidant capacity (p < 0.05). No difference was observed in daily sperm production when irradiated and nonirradiated maca extract were administered to mice (p > 0.05). Black maca extract but not red maca extract has more swimming endurance capacity in the forced swimming test. Irradiation of black maca extract increased the swimming time to exhaustion (p < 0.05). This is not observed with red maca extract (p > 0.05). Testosterone enanthate (TE) increased significantly the ventral prostate weight. Administration of red maca extract in animals treated with TE prevented the increase in prostate weight. Irradiation did not modify effect of red maca extract on prostate weight (p > 0.05). In conclusion, irradiation does not alter the biological activities of both black maca and red maca extracts. It prevents the presence of microorganisms in the extracts of black or red maca, but the biological activities were maintained. PMID- 26633046 TI - Prevalence of Obesity Among Adults and Youth: United States, 2011-2014. AB - KEY FINDINGS: Obesity is associated with health risks (1,2). Monitoring the prevalence of obesity is relevant for public health programs that focus on reducing or preventing obesity. No significant changes were seen in either adult or childhood obesity prevalence in the United States between 2003-2004 and 2011 2012 (3). This report provides the most recent national data on obesity prevalence by sex, age, and race and Hispanic origin, using data for 2011- 2014. Overall prevalence estimates from 1999-2000 through 2013-2014 are also presented. PMID- 26633047 TI - Prevalence of Cholesterol Treatment Eligibility and Medication Use Among Adults- United States, 2005-2012. AB - A high blood level of low-density lipoprotein cholesterol (LDL-C) remains a major risk factor for atherosclerotic cardiovascular disease (ASCVD), although data from 2005 through 2012 has shown a decline in high cholesterol (total and LDL cholesterol) along with an increase in the use of cholesterol-lowering medications. The most recent national guidelines (published in 2013) from the American College of Cardiology and the American Heart Association (ACC/AHA) expand previous recommendations for reducing cholesterol to include lifestyle modifications and medication use as part of complete cholesterol management and to lower risk for ASCVD. Because changes in cholesterol treatment guidelines might magnify existing disparities in care and medication use, it is important to describe persons currently eligible for treatment and medication use, particularly as more providers implement the 2013 ACC/AHA guidelines. To understand baseline estimates of U.S. adults on or eligible for cholesterol treatment, as well as to identify sex and racial/ethnic disparities, CDC analyzed data from the 2005-2012 National Health and Nutrition Examination Surveys (NHANES). Because the 2013 ACC/AHA guidelines focus on initiation or continuation of cholesterol treatment, adults meeting the guidelines' eligibility criteria as well as adults who were currently taking cholesterol-lowering medication were assessed as a group. Overall, 36.7% of U.S. adults or 78.1 million persons aged >=21 years were on or eligible for cholesterol treatment. Within this group, 55.5% were currently taking cholesterol-lowering medication, and 46.6% reported making lifestyle modifications, such as exercising, dietary changes, or controlling their weight, to lower cholesterol; 37.1% reported making lifestyle modifications and taking medication, and 35.5% reported doing neither. Among adults on or eligible for cholesterol-lowering medication, the proportion taking cholesterol-lowering medication was higher for women than men and for non Hispanic whites (whites) than Mexican-Americans and non-Hispanic blacks (blacks). Further efforts by clinicians and public health practitioners are needed to implement complementary and targeted patient education and disease management programs to reduce sex and racial/ethnic disparities among adults eligible for treatment of cholesterol. PMID- 26633044 TI - Current and future directions in the treatment and prevention of drug-induced liver injury: a systematic review. AB - While the pace of discovery of new agents, mechanisms and risk factors involved in drug-induced liver injury (DILI) remains brisk, advances in the treatment of acute DILI seems slow by comparison. In general, the key to treating suspected DILI is to stop using the drug prior to developing irreversible liver failure. However, predicting when to stop is an inexact science, and commonly used ALT monitoring is an ineffective strategy outside of clinical trials. The only specific antidote for acute DILI remains N-acetylcysteine (NAC) for acetaminophen poisoning, although NAC is proving to be beneficial in some cases of non acetaminophen DILI in adults. Corticosteroids can be effective for DILI associated with autoimmune or systemic hypersensitivity features. Ursodeoxycholic acid, silymarin and glycyrrhizin have been used to treat DILI for decades, but success remains anecdotal. Bile acid washout regimens using cholestyramine appear to be more evidenced based, in particular for leflunomide toxicity. For drug induced acute liver failure, the use of liver support systems is still investigational in the United States and emergency liver transplant remains limited by its availability. Primary prevention appears to be the key to avoiding DILI and the need for acute treatment. Pharmacogenomics, including human leukocyte antigen genotyping and the discovery of specific DILI biomarkers offers significant promise for the future. This article describes and summarizes the numerous and diverse treatment and prevention modalities that are currently available to manage DILI. PMID- 26633048 TI - Searching for Saddle Points by Using the Nudged Elastic Band Method: An Implementation for Gas-Phase Systems. AB - A new implementation of the Nudged Elastic Band (NEB) optimization method is presented. This approach uses a global procedure that yields the whole reaction path, and thus it provides an alternative to the sequential optimization of the transition state and consequent calculation of the minimum energy path. Furthermore the algorithm is very useful when one is not sure if a saddle point exists, because it can be used to eliminate the possibility of a saddle point when one does not exist. Three different versions of the NEB algorithm have been implemented. The influences of various parameters and methodological choices on the performance of the method have been studied, and the quality of the results is assessed by comparison with the saddle point and minimum energy path calculations sequential method. Recommendations are made for algorithmic choices and default parameters. PMID- 26633049 TI - Empirical Valence-Bond Models for Reactive Potential Energy Surfaces Using Distributed Gaussians. AB - A new method for constructing empirical valence bond potential energy surfaces for reactions is presented. Building on the generalized Gaussian approach of Chang-Miller, V12(2)(q) is represented by a Gaussian times a polynomial at the transition state and generalized to handle any number of data points on the potential energy surface. The method is applied to two model surfaces and the HCN isomerization reaction. The applications demonstrate that the present method overcomes the divergence problems encountered in some other approaches. The use of Cartesian versus internal or redundant internal coordinates is discussed. PMID- 26633050 TI - Acceleration of Classical Mechanics by Phase Space Constraints. AB - In this article phase space constrained classical mechanics (PSCCM), a version of accelerated dynamics, is suggested to speed up classical trajectory simulations of slow chemical processes. The approach is based on introducing constraints which lock trajectories in the region of the phase space close to the dividing surface, which separates reactants and products. This results in substantial (up to more than 2 orders of magnitude) speeding up of the trajectory simulation. Actual microcanonical rates are calculated by introducing a correction factor equal to the fraction of the phase volume which is allowed by the constraints. The constraints can be more complex than previously used boosting potentials. The approach has its origin in Intramolecular Dynamics Diffusion Theory, which shows that the majority of nonstatistical effects are localized near the transition state. An excellent agreement with standard trajectory simulation at high energies and Monte Carlo Transition State Theory at low energies is demonstrated for the unimolecular dissociation of methyl nitrite, proving that PSCCM works both in statistical and nonstatistical regimes. PMID- 26633051 TI - Molecular Dynamics Simulation of Argon, Krypton, and Xenon Using Two-Body and Three-Body Intermolecular Potentials. AB - We have performed the molecular dynamics simulation to obtain energy and pressure of argon, krypton, and xenon at different temperatures using a HFD-like potential which has been obtained with an inversion of viscosity data at zero pressure. The contribution of three-body dispersion resulting from third-order triple-dipole interactions has been computed using an accurate simple relation between two-body and three-body interactions developed by Marcelli and Sadus. Our results indicate that this simple three-body potential which was originally used in conjunction with the BFW potential is also valid when used with the HFD-like potential. This appears to support the conjecture that the relationship is independent of the two body potential. The energy and pressure obtained are in good overall agreement with the experiment, especially for argon. A comparison of our simulated results with HMSA and ODS integral equations and a molecular simulation have been also included. PMID- 26633052 TI - Elucidating the Conformational Dependence of Calculated pKa Values. AB - The variability within calculated protein residue pKa values calculated using Poisson-Boltzmann continuum theory with respect to small conformational fluctuations is investigated. As a general rule, sites buried in the protein core have the largest pKa fluctuations but the least amount of conformational variability; conversely, sites on the protein surface generally have large conformational fluctuations but very small pKa fluctuations. These results occur because of the heterogeneous or uniform nature of the electrostatic microenvironments at the protein core or surface, respectively. Atypical surface sites with large pKa fluctuations occur at the interfaces between significant anionic and cationic potentials. PMID- 26633053 TI - Increasing the Efficiency of Free Energy Calculations Using Parallel Tempering and Histogram Reweighting. AB - Free energy calculations from molecular simulations using thermodynamic integration or free energy perturbation require long simulation times to achieve sufficient precision. If entropic and enthalpic components of the free energy are desired, then the computational requirements are larger still. Here we present how parallel tempering (PT) Monte Carlo and weighted histogram analysis method (WHAM) can be used to improve the efficiency of free energy calculations. For both methods, which can be used separately or together, simulations at more than one temperature are performed. The same additional temperatures are often used to determine entropy changes. The results, for the aqueous solvation of n-butane and methane, show noticeable improvement in the precision of the free energy and entropy changes. The PT and WHAM methods can give similar error bars as conventional molecular dynamics in half the simulation time. The methods offer an efficient procedure for calculating free energy, entropy, and enthalpy changes in which free energy calculations are performed in parallel for a small number of closely spaced temperatures (for example, as here, at three temperatures: 298 K and 298 +/- 15 K), and WHAM is used to enhance the data at each temperature. PMID- 26633054 TI - The Structure of Liquid Benzene. AB - The interactions of aromatic groups have been identified as playing a crucial role in many systems of interest. Unfortunately, conventional atom-centered force fields provide only an approximate representation of these molecules owing to their failure to consider the quadrupole moment arising from the pi electrons. In this paper the structure of liquid benzene, the prototypical aromatic system, is investigated using a novel approach to Monte Carlo simulation, parametrized against experimental thermodynamic data, which incorporates an explicit representation of the aromatic pi electrons. In contrast to previous simulations of liquid benzene it is found that a perpendicular arrangement of benzene molecules is preferred to a parallel arrangement. This result is in good agreement with experimental data. PMID- 26633055 TI - Trisilaallene and the Relative Stability of Si3H4 Isomers. AB - A theoretical quantum-mechanical study of trisilaallene, H2Si [Formula: see text] Si [Formula: see text] SiH2, and of 15 other Si3H4 isomers was carried out using ab initio and DFT methods with a variety of basis sets. Values given below are at B3LYP/6-31G(d,p). Unlike H2C [Formula: see text] C [Formula: see text] CH2 which is linear, H2Si [Formula: see text] Si [Formula: see text] SiH2 is highly bent at the central silicon atom, with a SiSiSi bending angle of 69.4 degrees . The Si [Formula: see text] Si bond length is 2.269 A, longer than a regular Si [Formula: see text] Si double bond (2.179 A) but shorter than a Si-Si single bond (2.351 A). The distance between the terminal silicon atoms is 2.583 A, significantly longer than a Si-Si single bond. The geometry and electronic properties of H2Si [Formula: see text] Si [Formula: see text] SiH2 are similar to those of the corresponding trisilacyclopropylidene, which is only 2.7 kcal/mol higher in energy. A barrier of only 0.1 kcal/mol separates trisilacyclopropylidene and trisilaallene which can be described as bond-stretch isomers. Sixteen minima were located on the Si3H4 PES, most of them within a narrow energy range of ca. 10 kcal/mol. Six of the Si3H4 isomers are analogous to the classic C3H4 minima structures; however, the other Si3H4 isomers do not have carbon analogues, and they are characterized by hydrogen-bridged structures. PMID- 26633056 TI - Covalency in Highly Polar Bonds. Structure and Bonding of Methylalkalimetal Oligomers (CH3M)n (M = Li-Rb; n = 1, 4). AB - We have carried out a theoretical investigation of the methylalkalimetal monomers CH3M and tetramers (CH3M)4 with M = Li, Na, K, and Rb and, for comparison, the methyl halides CH3X with X = F, Cl, Br, and I, using density functional theory (DFT) at BP86/TZ2P. Our purpose is to determine how the structure and thermochemistry (e.g., C-M bond lengths and strengths, oligomerization energies) of organoalkalimetal compounds depend on the metal atom and to understand the emerging trends in terms of quantitative Kohn-Sham molecular orbital (KS-MO) theory. The C-M bond becomes longer and weaker, both in the monomers and tetramers, if one descends the periodic table from Li to Rb. Quantitative bonding analysis shows that this trend is not only determined by decreasing electrostatic attraction but also, even to a larger extent, by the weakening in orbital interactions. The latter become less stabilizing along Li-Rb because the bond overlap between the singly occupied molecular orbitals (SOMOs) of CH3(*) and M(*) radicals decreases as the metal ns atomic orbital (AO) becomes larger and more diffuse. Thus, the C-M bond behaves as a typical electron-pair bond between the methyl radical and alkalimetal atom, and, in that respect, it is covalent. It is also shown that such an electron-pair bond can still be highly polar, in agreement with the large dipole moment. Interestingly, the C-M bond becomes less polar in the methylalkalimetal tetramers because metal-metal interactions stabilize the alkalimetal orbitals and, in that way, make the alkalimetal effectively less electropositive. PMID- 26633057 TI - Heisenberg Exchange in Dinuclear Manganese Complexes: A Density Functional Theory Study. AB - This work presents a systematic investigation of the performance of broken symmetry density functional theory for the evaluation of Heisenberg exchange constants. We study dinuclear Mn(IV)-Mn(IV) complexes with bis(MU-oxo), bis(MU oxo)(MU-carboxylato), and tris(MU-oxo) cores for this purpose, as these are of fundamental biological interest as well as being potential precursors for molecular magnets based on manganese complexes, the so-called Mn12 magnets. The obtained results indicate that quantitative agreement with available experimental data for the Heisenberg exchange constants can be achieved for most of the investigated complexes but also that there are significant failures for some compounds. We evaluate factors influencing the accuracy of obtained results and examine effects of different mappings between broken symmetry and Heisenberg Hamiltonian states in an attempt to formulate a reliable recipe for the evaluation of magnetic coupling in these complexes. An assessment of the bonding situation in the molecular system under investigation is found crucial in choosing the appropriate scheme for evaluation of the Heisenberg exchange constants. PMID- 26633058 TI - Computational Characterization of Metal Binding Groups for Metalloenzyme Inhibitors. AB - The mode of action of many pest or disease control agents involves inhibition of some metalloenzyme that is essential for the survival of the target organism. These inhibitors typically consist of a functional group that is capable of a primary binding interaction with the metal and a scaffold that is capable of secondary interactions with the remainder of the enzyme. To characterize the binding ability of various metal binding groups (BGs), we have performed electronic structure calculations on ligand displacement reactions in a model system related to the metalloenzyme, peptide deformylase: E-M-R + BG -> E-M-BG + R. Here E represents a model coordination environment for the metal M, and R is a reference ligand (e.g., water) that may be displaced by a metal binding group. Since the oxidation state of many of the metals considered allows for multiple spin states, we also studied the influence of spin state on the coordination environment. Qualitative considerations of electronic structure inspired by the calculations provide an understanding of binding energy trends across a variety of ligands for a given metal and across a variety of metals for a given ligand. PMID- 26633059 TI - CuNO2 and Cu(+)NO2 Revisited: A Comparative ab Initio and DFT Study. AB - We have reinvestigated CuNO2 and Cu(+)NO2 at ab initio as well as at pure and hybrid DFT levels of approximation employing large ANO basis sets. The systems were fully optimized using the CCSD(T), QCISD(T), BPW91, PBE, PBE0, and B3LYP methods. Several stationary points (minima and transition structures) were found on the related potential energy surfaces (PES). The C2v bidentate eta(2)-O,O isomer is calculated to be the most stable species on the CuNO2 PES, followed by two monodentate isomers [Formula: see text] the Cs eta(1)-O and C2v eta(1)-N species which are higher in energy by 12 and 14 kcal/mol, respectively, at CCSD(T)/Basis-II (where Basis-II is 21s15p10d6f4g/8s7p5d3f2g for Cu; 14s9p4d3f/5s4p3d2f for O and N). On the Cu(+)NO2 PES, the Cs monodentate eta(1)-O trans (0 kcal/mol) and cis (+3 kcal/mol at CCSD(T)/Basis-II) isomers are found, followed by the C2v monodentate eta(1)-N isomer (+14 kcal/mol at CCSD/Basis-II). In contrast to the pure DFT, the hybrid DFT methods perform reasonably well for predicting the relative stabilities (except for eta(1)-N of CuNO2) and structures; however, their predictions of the bond dissociation energies are less reliable (for CuNO2 the difference is as much as 10 kcal/mol compared to the CCSD(T) values). The performance of the QCISD(T) method was analyzed, and, furthermore, the issue of symmetry breaking was investigated. PMID- 26633060 TI - Assessment of Model Chemistries for Noncovalent Interactions. AB - In the present study, we report tests of 57 model chemistry methods for calculating binding energies of 31 diverse van der Waals molecules arranged in five databases of noncovalent interaction energies. The model chemistries studied include wave function theory (WFT), density functional theory (DFT), and combined wave function-density-functional-theory (CWFDFT), and they include methods whose computational effort scales (for large systems) as N(7), N(6), N(5), and N(4), where N is the number of atoms. The model chemistries include 2 CWFDFT N(7) models, 4 multilevel WFT N(7) models, 5 single-level WFT N(7) models, 4 CWFDFT N(6) models, 3 multilevel WFT N(6) models, 11 single-level WFT N(6) models, 5 CWFDFT N(5) models, 10 single-level WFTN(5) models, 4 multilevel WFT N(5) models, 4 single-level DFT N(4) models, and 5 single-level WFT N(4) models. We draw the following conclusions based on the mean absolute errors in 31 noncovalent binding energies: (1) MCG3-MPW gives the best performance for predicting the binding energies of these noncovalent complexes. (2) MCQCISD-MPWB and MCQCISD-MPW are the best two N(6) methods. (3) M05-2X is the best single-level method for these noncovalent complexes. These four methods should facilitate useful calculations on a wide variety of practical applications involving hydrogen bonding, charge transfer complexes, dipole interactions, weak (dispersion-like) interactions, and pi...pi stacking. If a user is interested in only a particular type of noncovalent interactions, though, some other methods, may be recommended for especially favorable performance/cost ratios. For example, BMC-CCSD has an outstanding performance for hydrogen bonding, and PWB6K has an outstanding cost adjusted performance for dipole interaction calculations on very large systems. We also show that M05-2X performs well for interactions of amino acid pair residues. PMID- 26633061 TI - On the Angular Dependence of the Vicinal Fluorine-Fluorine Coupling Constant in 1,2-Difluoroethane: Deviation from a Karplus-like Shape. AB - The angular dependence of the vicinal fluorine-fluorine coupling constant, (3)JFF, for 1,2-difluoroethane has been investigated with several polarization propagator methods. (3)JFF and its four Ramsey contributions were calculated using the random phase approximation (RPA), its multiconfigurational generalization, and both second-order polarization propagator approximations (SOPPA and SOPPA(CCSD)), using locally dense basis sets. The geometries were optimized for each dihedral angle at the level of density functional theory using the B3LYP functional and fourth-order Moller-Plesset perturbation theory. The resulting coupling constant curves were fitted to a cosine series with 8 coefficients. Our results are compared with those obtained previously and values estimated from experiment. It is found that the inclusion of electron correlation in the calculation of (3)JFF reduces the absolute values. This is mainly due to changes in the FC contribution, which for dihedral angles around the trans conformation even changes its sign. This sign change is responsible for the breakdown of the Karplus-like curve. PMID- 26633062 TI - Calculation of Nuclear Spin-Spin Coupling Constants of Molecules with First and Second Row Atoms in Study of Basis Set Dependence. AB - This paper proposes a systematic way to modify standard basis sets for use in NMR spin-spin coupling calculations, which allows the high sensitivity of this property to the basis set to be handled in a manner which remains computationally feasible. The new basis set series is derived by uncontracting a standard basis set, such as correlation-consistent aug-cc-pVTZ, and extending it by systematically adding tight s and d functions. For elements in different rows of the periodic table, different progressions of functions are added. The new basis sets are shown to approach the basis set limit for calculations on a range of molecules containing hydrogen and first and second row atoms. PMID- 26633063 TI - Accurate Treatment of Energetics and Geometry of Carbon and Hydrocarbon Compounds within Tight-Binding Model. AB - We show that a simple noniterative tight-binding model can provide reliable estimates of energetics and geometries of molecules with C-C and C-H bonds. The mean absolute error in heats of formation, ~4.6 kcal/mol, is essentially smaller than those found in previous tight-binding schemes. The internal consistency of the calculated heats of formation enables the reliable prediction of bond dissociation energies and isomerization enthalpies. The model gives accurate molecular geometries of hydrocarbons; the mean absolute errors in bond lengths and bond angles are 0.015 A and 1.4 degrees , respectively. The calculated vibration frequencies agree reasonably well with experimental values. The method has proven to be transferable to complex carbon and hydrocarbon systems. The good performance of the model and its computational efficiency make it promising for simulations of carbon and hydrocarbon systems. PMID- 26633064 TI - Parametrization of Atomic Energies to Improve Small Basis Set Density Functional Thermochemistry. AB - Enthalpies of formation predicted with density functional theory and small basis sets can be greatly improved by treating the atomic energies as empirical parameters. When a variety of functionals and small basis sets are used, the root mean-square error in enthalpies of formation is reduced by a factor of approximately two for the least improved functional/basis set pair, with significantly larger reductions for other functionals, especially LSDA. When the 3-21G* and 3-21+G* basis sets are used with nonempirical functionals, it is possible to achieve accuracy greater than that of PM3, which was primarily designed to reproduce enthalpies of formation. In addition to decreasing statistical errors, our procedure can also remove qualitative errors in density functional/basis set pairs that fail for the prediction of enthalpies of formation. PMID- 26633065 TI - AM1/d Parameters for Magnesium in Metalloenzymes. AB - AM1/d parameters are derived for magnesium, optimized for modeling reactions in metalloenzymes. The parameters are optimized with a Monte Carlo procedure so as to reproduce the geometries and energies of a training set calculated with density functional theory. The training set consists of compounds with magnesium coordinated to the oxygen atom of typical biological ligands. Optimization of AM1 parameters without extension to d functions leaves serious errors. The new AM1/d parameters provide a clear improvement in accuracy compared to the standard semiempirical methods AM1 and MNDO/d and will be particularly useful for modeling reactions in large biological systems at low computational cost. PMID- 26633066 TI - Development of a Parametrized Force Field To Reproduce Semiempirical Geometries. AB - Here we describe the development of a classical force field parameter set to reproduce the geometry of proteins minimized at the semiempirical quantum mechanical level. The overall goal of the development of this new force field is to provide an inexpensive, yet reliable, method to arrive at geometries that are more consistent with a semiempirical treatment of protein structures. Since the minimization of a large number of protein structures at the semiempirical level can become cost-prohibitive, a "preminimization" with an appropriately parametrized classical treatment could potentially lead to more computationally efficient methods for studying protein structures through semiempirical means. Here we demonstrate that this force field allows for more rapid and stable geometry optimizations at the semiempirical level and can aid in the adoption of quantum mechanical calculations for large biological systems. PMID- 26633067 TI - Hybrid Density Functional Methods Empirically Optimized for the Computation of (13)C and (1)H Chemical Shifts in Chloroform Solution. AB - Two hybrid generalized-gradient approximation density functionals, WC04 and WP04, are optimized for the prediction of (13)C and (1)H chemical shifts, respectively, using a training set of 43 molecules in chloroform solution. Tests on molecules not included in the training set, namely six stereoisomeric methylcyclohexanols and a beta-lactam antibiotic, indicate the models to be robust and moreover to provide results more accurate than those from equivalent B3LYP, PBE1, or mPW1PW91 calculations, particularly for the prediction of downfield resonances in nuclear magnetic resonance spectra. However, linear regression of the B3LYP, PBE1, and mPW1PW91 predicted values on the experimental data improves the accuracy of those models so that they are comparable to WC04 and WP04. PMID- 26633068 TI - Adsorption of Benzene on Copper, Silver, and Gold Surfaces. AB - The adsorption of benzene on the Cu(111), Ag(111), Au(111), and Cu(110) surfaces at low coverage is modeled using density-functional theory (DFT) using periodic slab models of the surfaces as well as using both DFT and complete-active-space self-consistent field theory with second-order Moller-Plesset perturbation corrections (CASPT2) for the interaction of benzene with a Cu13 cluster model for the Cu(110) surface. For the binding to the (111) surfaces, key qualitative features of the results such as weak physisorption, the relative orientation of the adsorbate on the surface, and surface potential changes are in good agreement with experimental findings. Also, the binding to Cu(110) is predicted to be much stronger than that to Cu(111) and much weaker than that seen in previous calculations for Ni(110), as observed. However, a range of physisorptive-like and chemisorptive-like structures are found for benzene on Cu(110) that are roughly consistent with observed spectroscopic data, with these structures differing dramatically in geometry but trivially in energy. For all systems, the bonding is found to be purely dispersive in nature with minimal covalent character. As dispersive energies are reproduced very poorly by DFT, the calculated binding energies are found to dramatically underestimate the observed ones, while CASPT2 calculations indicate that there is no binding at the Hartree-Fock level and demonstrate that the expected intermolecular correlation (dispersive) energy is of the correct order to explain the experimental binding-energy data. DFT calculations performed for benzene on Cu(110) and for benzene on the model cluster indicate that this cluster is actually too reactive and provides a poor chemical model for the system. PMID- 26633069 TI - Effect of the f-Orbital Delocalization on the Ligand-Field Splitting Energies in Lanthanide-Containing Elpasolites. AB - The ligand-field induced splitting energies of f-levels in lanthanide-containing elpasolites are derived using the first-principles universal orbital-free embedding formalism [Wesolowski and Warshel, J. Phys. Chem. 1993, 97, 8050]. In our previous work concerning chloroelpasolite lattice (Cs2NaLnCl6), embedded orbitals and their energies were obtained using an additional assumption concerning the localization of embedded orbitals on preselected atoms leading to rather good ligand-field parameters. In this work, the validity of the localization assumption is examined by lifting it. In variational calculations, each component of the total electron density (this of the cation and that of the ligands) spreads over the whole system. It is found that the corresponding electron densities remain localized around the cation and the ligands, respectively. The calculated splitting energies of f-orbitals in chloroelpasolites are not affected noticeably in the whole lanthanide series. The same computational procedure is used also for other elpasolite lattices (Cs2NaLnX6, where X=F, Br, and I) [Formula: see text] materials which have not been fabricated or for which the ligand-field splitting parameters are not available. PMID- 26633070 TI - Simulation of Actuation by Polymeric Polyelectrolyte Helicenes. AB - The potential of several peripherally substituted [6.3.1] helicenes to serve as linear actuators was investigated using molecular dynamics calculations. Reversible extension upon ionization of pendant functionality was observed in three of four cases. The largest extensions were obtained for molecules with amino groups or ionized phosphate groups attached directly to the helical backbone (extensions of 176 +/- 4% and 184 +/- 4%, respectively). Electrostatic forces and swelling drive the actuation. PMID- 26633071 TI - QM/MM Models of the O2-Evolving Complex of Photosystem II. AB - This paper introduces structural models of the oxygen-evolving complex of photosystem II (PSII) in the dark-stable S1 state, as well as in the reduced S0 and oxidized S2 states, with complete ligation of the metal-oxo cluster by amino acid residues, water, hydroxide, and chloride. The models are developed according to state-of-the-art quantum mechanics/molecular mechanics (QM/MM) hybrid methods, applied in conjunction with the X-ray crystal structure of PSII from the cyanobacterium Thermosynechococcus elongatus, recently reported at 3.5 A resolution. Manganese and calcium ions are ligated consistently with standard coordination chemistry assumptions, supported by biochemical and spectroscopic data. Furthermore, the calcium-bound chloride ligand is found to be bound in a position consistent with pulsed electron paramagnetic resonance data obtained from acetate-substituted PSII. The ligation of protein ligands includes monodentate coordination of D1-D342, CP43-E354, and D1-D170 to Mn(1), Mn(3), and Mn(4), respectively; eta(2) coordination of D1-E333 to both Mn(3) and Mn(2); and ligation of D1-E189 and D1-H332 to Mn(2). The resulting QM/MM structural models are consistent with available mechanistic data and also are compatible with X-ray diffraction models and extended X-ray absorption fine structure measurements of PSII. It is, therefore, conjectured that the proposed QM/MM models are particularly relevant to the development and validation of catalytic water oxidation intermediates. PMID- 26633072 TI - Atomic Charge Parameters for the Finite Difference Poisson-Boltzmann Method Using Electronegativity Neutralization. AB - An optimization of Rappe and Goddard's charge equilibration (QEq) method of assigning atomic partial charges is described. This optimization is designed for fast and accurate calculation of solvation free energies using the finite difference Poisson-Boltzmann (FDPB) method. The optimization is performed against experimental small molecule solvation free energies using the FDPB method and adjusting Rappe and Goddard's atomic electronegativity values. Using a test set of compounds for which experimental solvation energies are available and a rather small number of parameters, very good agreement was obtained with experiment, with a mean unsigned error of about 0.5 kcal/mol. The QEq atomic partial charge assignment method can reflect the effects of the conformational changes and solvent induction on charge distribution in molecules. In the second section of the paper we examined this feature with a study of the alanine dipeptide conformations in water solvent. The different contributions to the energy surface of the dipeptide were examined and compared with the results from fixed CHARMm charge potential, which is widely used for molecular dynamics studies. PMID- 26633073 TI - Molecular Modeling the Reaction Mechanism of Serine-Carboxyl Peptidases. AB - We performed molecular modeling on the mechanism of serine-carboxyl peptidases, a novel class of enzymes active at acidic pH and distinguished by the conserved triad of amino acid residues Ser-Glu-Asp. Catalytic cleavage of a hexapeptide fragment of the oxidized B-chain of insulin by the Pseudomonas sedolisin, a member of the serine-carboxyl peptidases family, was simulated. Following motifs of the crystal structure of the sedolisin-inhibitor complex (PDB accession code 1NLU ) we designed the model enzyme-substrate (ES) complex and performed quantum mechanical-molecular mechanical calculations of the energy profile along a reaction route up to the acylenzyme (EA) complex through the tetrahedral intermediate (TI). The energies and forces were computed by using the PBE0 exchange-correlation functional and the basis set 6-31+G** in the quantum part and the AMBER force field parameters in the molecular mechanical part. Analysis of the ES, TI, and AE structures as well as of the corresponding transition states allows us to scrutinize the chemical transformations catalyzed by sedolisin. According to the results of simulations, the reaction mechanism of serine-carboxyl peptidases should be viewed as a special case of carboxyl (aspartic) proteases, with the nucleophilic water molecule being replaced by the Ser residue. The catalytic triad Ser-Glu-Asp in sedolisin functions differently compared to the well-known triad Ser-His-Asp of serine proteases, despite the structural similarity of sedolisin and the serine proteases member, subtilisin. PMID- 26633074 TI - Theoretical Study on the Structure and the Frequency of Isomers of the Naphthalene Dimer. AB - The structures of the naphthalene monomer and dimer were investigated with performing vibrational analysis. The MP2 optimization showed that the naphthalene monomer has a nonplanar geometry in the 6-31G, 6-31G*, 6-31+G*, and 6-311G basis sets, while it has a planar geometry in the 6-31G*(0.25) and Dunning's correlation consistent basis sets. The MP2/cc-pVDZ calculation showed the presence of the four stable isomers, which were part of the isomers in the previous MP2/6-31G* calculation (Walsh, T. R. Chem. Phys. Lett. 2002, 363, 45). The presence of extra structures in the MP2/6-31G* calculation is attributed to a poor description of the potential energy surface, which is evident from the nonplanar structure of the monomer in the MP2/6-31G* calculation. The relative stability among the isomers in the MP2/cc-pVDZ calculation without counterpoise correction was maintained in both the single-point calculation at the MP2/aug-cc pVDZ//MP2/cc-pVDZ level and the counterpoise-corrected optimization at the MP2/cc pVDZ level. The relative stability among the isomers suggested an enhancement of the pi-pi interaction in the structure with lower symmetry, which could be explained using a molecular-orbital model. The vibrational analysis in MP2/cc pVDZ without the counterpoise correction suggested that the isomers of the naphthalene dimer were distinguishable by the observation of the infrared spectrum in the low-frequency region (150-600 cm(-)(1)). PMID- 26633075 TI - Monitoring Biopolymer Degradation by Taylor Dispersion Analysis. AB - This work aims at demonstrating the interest of modern Taylor dispersion analysis (TDA), performed in narrow internal diameter capillary, for monitoring biopolymer degradations. Hydrolytic and enzymatic degradations of dendrigraft poly-l-lysine taken as model compounds have been performed and monitored by TDA at different degradation times. Different approaches for the data processing of the taylorgrams are compared, including simple integration of the taylorgram, curve fitting with a finite number of Gaussian peaks, cumulant-like method and Constrained Regularized Linear Inversion approach. Valuable information on the kinetics of the enzymatic/hydrolytic degradation reactions and on the degradation process can be obtained by TDA. PMID- 26633076 TI - Effects of Cyclization on Peptide Backbone Dynamics. AB - Despite the widespread use of cyclization as a structure optimization tool in peptide chemistry, little is known about the effect of cyclization on peptide internal dynamics. In this work, we used a combination of multifield NMR relaxation and molecular dynamics techniques to study both monocyclic and polycyclic peptides that have promising biopharmaceutical properties, namely, VH, SFTI-1, and cVc1.1, and their less constrained analogues to study the effects of backbone cyclization (which forms a macrocycle) and disulfide-bond cyclization (which forms internal cycles). We confirmed that backbone cyclization contributes to the rigidity of the monocyclic VH. Interestingly, however, backbone cyclization of the bicyclic SFTI-1 had a limited effect on rigidity, with changes in internal dynamics localized around the ligation site. This suggests that the disulfide bond, which creates an internal cycle, has an insulating effect, protecting the internal cycle from external motional effects. An insulating effect was also observed for the polycyclic cVc1.1: The rigidity of the core was not enhanced by macrocyclization. Additionally, we found that disulfide bonds provide a greater contribution to overall rigidity than macrocyclization. Overall, our results suggest that, although backbone cyclization can improve rigidity, there is a complex interplay between dynamics and cyclization, particularly for polycyclic systems. PMID- 26633077 TI - Controlling range expansion in habitat networks by adaptively targeting source populations. AB - Controlling the spread of invasive species, pests, and pathogens is often logistically limited to interventions that target specific locations at specific periods. However, in complex, highly connected systems, such as marine environments connected by ocean currents, populations spread dynamically in both space and time via transient connectivity links. This results in nondeterministic future distributions of species in which local populations emerge dynamically and concurrently over a large area. The challenge, therefore, is to choose intervention locations that will maximize the effectiveness of the control efforts. We propose a novel method to manage dynamic species invasions and outbreaks that identifies the intervention locations most likely to curtail population expansion by selectively targeting local populations most likely to expand their future range. Critically, at any point during the development of the invasion or outbreak, the method identifies the local intervention that maximizes the long-term benefit across the ecosystem by restricting species' potential to spread. In so doing, the method adaptively selects the intervention targets under dynamically changing circumstances. To illustrate the effectiveness of the method we applied it to controlling the spread of crown-of-thorns starfish (Acanthaster sp.) outbreaks across Australia's Great Barrier Reef. Application of our method resulted in an 18-fold relative improvement in management outcomes compared with a random targeting of reefs in putative starfish control scenarios. Although we focused on applying the method to reducing the spread of an unwanted species, it can also be used to facilitate the spread of desirable species through connectivity networks. For example, the method could be used to select those fragments of habitat most likely to rebuild a population if they were sufficiently well protected. PMID- 26633078 TI - Neuroprotective Effect of Lycopene Against PTZ-induced Kindling Seizures in Mice: Possible Behavioural, Biochemical and Mitochondrial Dysfunction. AB - Oxidative stress and mitochondrial dysfunction are the major contributing factors in the pathophysiology of various neurological disorders. Recently, antioxidant therapies aimed at reducing oxidative stress gained a considerable attention in epilepsy treatment. Lycopene, a carotenoid antioxidant, has received scientific interest in recent years. So, the present study has been designed to evaluate the neuroprotective effect of lycopene against the pentylenetetrazol (PTZ)-induced kindling epilepsy. Laca mice received lycopene (2.5, 5 and 10 mg/kg) and sodium valproate for a period of 29 days and PTZ (40 mg/kg i.p (Intraperitoneal)) injection on alternative days. Various behavioural (kindling score), biochemical parameters (lipid peroxidation, superoxide dismutase, reduced glutathione, catalase and nitrite) and mitochondrial enzyme complex activities (I, II and IV) were assessed in the brain. Results depicted that repeated administration of a sub-convulsive dose of PTZ (40 mg/kg) significantly increased kindling score, oxidative damage and impaired mitochondrial enzyme complex activities (I, II and IV) as compared with naive animals. Lycopene (5 and 10 mg/kg) and sodium valproate (100 mg/kg) treatment for a duration of 29 days significantly attenuated kindling score, reversed oxidative damage and restored mitochondrial enzyme complex activities (I, II and IV) as compared with control. Thus, present study demonstrates the neuroprotective potential of lycopene in PTZ-induced kindling in mice. PMID- 26633079 TI - Ultrafine Metal Phosphide Nanocrystals in Situ Decorated on Highly Porous Heteroatom-Doped Carbons for Active Electrocatalytic Hydrogen Evolution. AB - In spite of being technologically feasible, electrochemical water reduction to facilitate hydrogen production is confronted with issues mainly due to the lack of affordable and efficient catalysts for the water reduction half reaction. Reported herein is the fabrication of metal phosphides nanocrystals uniformly loaded on highly porous heteroatom-modified carbons through one-step carbonization-phosphization methodology. Remarkably, the well-structured porosity and the increased electrochemically accessible active sites ensure the high catalytic efficiency for electrochemical hydrogen evolution in acidic medium in terms of small onset potentials (33 mV) and large cathodic current density (0.481 mA cm(-2)), even comparable to the state-of-the-art Pt/C benchmark. The easily prepared composite catalysts of structural and textural peculiarities may serve as promising non-noble metal catalysts for realistic hydrogen evolution. PMID- 26633080 TI - Predictable Outcomes with Porcelain Laminate Veneers: A Clinical Report. AB - This clinical report describes how to achieve predictable outcomes for anterior teeth esthetic restorations with porcelain laminate veneers by associating the digital planning and design of the restoration with interim restorations. The previous digital smile design of the restoration eliminates the communication barrier with the patient and assists the clinician throughout patient treatment. Interim restorations (diagnostic mock-ups) further enhance communication with the patient and prevent unnecessary tooth reduction for conservative tooth preparation. Adequate communication between patient and clinician contributes to successful definitive restorations and patient satisfaction with the final esthetic outcome. PMID- 26633081 TI - Discussing Sexual Dysfunction with Chronic Kidney Disease Patients: Practice Patterns in the Office of the Nephrologist. AB - INTRODUCTION: Sexual dysfunction (SD) is a common problem in patients suffering from chronic kidney disease (CKD). Sexual health remains a difficult subject to detect and discuss. Although many studies have been performed on the incidence of SD, little is known about practice patterns when it concerns quality of life (QoL)-related questions such as SD in the nephrologists' practice. AIM: The aim of this study was to determine to which extent nephrologists, important renal care providers, discuss SD with their patients and their possible barriers toward discussing this subject. METHODS: A 50-item questionnaire was sent to all Dutch nephrologists (n = 312). MAIN OUTCOME MEASURES: The survey results. RESULTS: The response rate of the survey was 34.5%. Almost all responders (96.4%) stated to address SD in less than half of their new patients. The most important barrier not to discuss SD was patients not expressing their concern regarding SD spontaneously (70.8%). Other important barriers were: "the lack of a suitable moment to discuss" (61.9%) and "insufficient time" (46.9%). Eighty-five percent of the nephrologists stated that insufficient attention was paid to SD and treatment options during their training. Sixty-five percent of the respondents stated to be in need of extending their knowledge on the discussing of SD. CONCLUSIONS: Dutch nephrologists do not discuss problems with sexual function routinely. The lack of knowledge, suitable education, and insufficient time are factors causing undervaluation of SD in CKD patients. Implementation of competent sexual education and raising awareness among nephrologists on the importance of paying attention to SD could improve care and QoL for patients with CKD. More research should be performed among patients and other renal care providers to develop an adequate method to enhance our current system. PMID- 26633083 TI - Sequestration and metabolism of host cell arginine by the intraerythrocytic malaria parasite Plasmodium falciparum. AB - Human erythrocytes have an active nitric oxide synthase, which converts arginine into citrulline and nitric oxide (NO). NO serves several important functions, including the maintenance of normal erythrocyte deformability, thereby ensuring efficient passage of the red blood cell through narrow microcapillaries. Here, we show that following invasion by the malaria parasite Plasmodium falciparum the arginine pool in the host erythrocyte compartment is sequestered and metabolized by the parasite. Arginine from the extracellular medium enters the infected cell via endogenous host cell transporters and is taken up by the intracellular parasite by a high-affinity cationic amino acid transporter at the parasite surface. Within the parasite arginine is metabolized into citrulline and ornithine. The uptake and metabolism of arginine by the parasite deprive the erythrocyte of the substrate required for NO production and may contribute to the decreased deformability of infected erythrocytes. PMID- 26633082 TI - Imaging Glycosylation In Vivo by Metabolic Labeling and Magnetic Resonance Imaging. AB - Glycosylation is a ubiquitous post-translational modification, present in over 50% of the proteins in the human genome, with important roles in cell-cell communication and migration. Interest in glycome profiling has increased with the realization that glycans can be used as biomarkers of many diseases, including cancer. We report here the first tomographic imaging of glycosylated tissues in live mice by using metabolic labeling and a gadolinium-based bioorthogonal MRI probe. Significant N-azidoacetylgalactosamine dependent T1 contrast was observed in vivo two hours after probe administration. Tumor, kidney, and liver showed significant contrast, and several other tissues, including the pancreas, spleen, heart, and intestines, showed a very high contrast (>10-fold). This approach has the potential to enable the rapid and non-invasive magnetic resonance imaging of glycosylated tissues in vivo in preclinical models of disease. PMID- 26633084 TI - ADRB2 polymorphisms in allergic asthma in Han Chinese children. AB - BACKGROUND: Single-nucleotide polymorphisms (SNPs) in the human beta2 adrenergic receptor (ADRB2) gene have been linked to pathogenesis of and treatment responses in asthma. In China, where asthma is common, little information exists regarding ADRB2 variants and their effects on asthma. The current study sought to investigate the relationship between variations in ADRB2 and childhood asthma. METHODS: Blood samples were collected from 298 pediatric asthma cases treated in our hospital from July 2013 to September 2014; 304 samples were collected from healthy children for a control group. Six loci (at base positions -47, 79, -2387, 46, 523, and 491) of ADRB2 were genotyped using the TaqMan probe assay; SHEsis was used to determine haplotypes. Allele frequencies and genotype distributions were compared between groups using chi square and t tests. RESULTS: No significant differences in genotype or allele frequencies were found between the groups for the polymorphic loci -2387 bp (T>C), 46 bp (G>A), and 523 bp (C>A) (p > 0.05). However, genotype frequencies for the ADRB2 SNPs at -47 bp (C>T) and 79 bp (G>C) differed significantly between asthma and control groups (p < 0.05). Further, linkage disequilibrium was found between these 2 SNPs (D' = 0.990, r(2) = 0.962), as well as between SNPs at 46 and 523 bp (D' = 0.985, r(2) = 0.607). Finally, of the 4 haplotypes analyzed in these samples (haplotypes III, IV, IX, and XI), the frequency of haplotype III was significantly lower in the asthma group than the control group (p < 0.05; odds ratio [OR] = 0.72; 95% confidence interval [CI], 0.48 to 0.97). CONCLUSION: Variations of ADRB2 at base positions 47 (C>T) and 79 (G>C), as well as haplotype III, may contribute to susceptibility to childhood asthma. PMID- 26633085 TI - Zintl Clusters as Wet-Chemical Precursors for Germanium Nanomorphologies with Tunable Composition. AB - [Ge9](4-) Zintl clusters are used as soluble germanium source for a bottom-up fabrication of Ge nanomorphologies such as inverse opal structures with tunable composition. The method is based on the assembly and oxidation of [Ge9 ](4-) clusters in a template mold using SiCl4 , GeCl4 , and PCl3 leading to Si and P containing Ge phases as shown by X-ray diffraction, Raman spectroscopy, and energy-dispersive X-ray analysis. [Ge9](4-) clusters are retained using ethylenediamine (en) as a transfer medium to a mold after removal of the solvent if water is thoroughly excluded, but are oxidized to amorphous Ge in presence of water traces. (1)H NMR spectroscopy reveals the oxidative deprotonation of en by [Ge9](4-). Subsequent annealing leads to crystalline Ge. As an example for wet chemical synthesis of complex Ge nanomorphologies, we describe the fabrication of undoped and P-doped inverse opal-structured Ge films with a rather low oxygen contents. The morphology of the films with regular volume porosity is characterized by SEM, TEM, and grazing incidence small-angle X-ray scattering. PMID- 26633086 TI - Detection and Quantitative Analysis of the Non-cytotoxic allo-Tenuazonic Acid in Tomato Products by Stable Isotope Dilution HPLC-MS/MS. AB - Tenuazonic acid (1) is a mycotoxin produced mainly by fungi of the genus Alternaria. It occurs in a variety of agricultural products. allo-Tenuazonic acid (2) is an isomer of 1 that is not chromatographically separated from 1 in most analytical methods. Therefore, both isomers are quantitated as a sum parameter. In this study a QuEChERS (quick, easy, cheap, effective, rugged and safe) based stable isotope dilution HPLC-MS/MS method including the chromatographic separation of both isomers was developed and applied to 20 tomato products from the German market. All products showed contamination with both toxins. 1 was found in a range from 5.3 +/- 0.1 to 550 +/- 15 MUg/kg (average = 120 MUg/kg) and 2 in a range from 1.5 +/- 0.4- to 270 +/- 0.8 MUg/kg (average = 58 MUg/kg). 2 represents 7.0-44% of the sum of both isomers (average = 29%). This is the first reported occurrence of 2 in food samples. To evaluate and compare the cytotoxicities of 1 and 2, both compounds were isolated from a synthetic racemic mixture. 1 showed moderate cytotoxic effects on HT-29 cells starting at 100 MUM, whereas 2 exhibited no activity. 2 was not produced in liquid cultures of Alternaria alternata in yeast extract sucrose (YES) medium, but could be detected in small amounts in tomato puree inoculated with the fungus. PMID- 26633087 TI - Happy New Year!!!! PMID- 26633088 TI - Synergistic Effect of a Physiological Ratio of Estradiol and Testosterone in the Treatment of Early-stage Atherosclerosis. AB - BACKGROUND AND AIMS: Clinical trials and epidemiological data suggest that estrogen replacement therapy (ERT) fails to reduce cardiovascular events in postmenopausal women with coronary heart disease (CHD). The high concentration of estrogen supplementation may increase the risk of thrombosis and result in testosterone deficiency, which is considered the main reason for failure. Thus, we hypothesized that a physiologic dosage of estradiol combined with testosterone may become a new therapeutic strategy in postmenopausal women with CHD. METHODS AND RESULTS: We used human umbilical vein endothelial cells (HUVECs) and female C57BL/6 mice as the experimental subjects. With the HUVECs, we found an appropriate E2/T ratio of 5:1 (5*10(-8) mol/L estradiol and 10(-8) mol/L testosterone), which has a significant anti-apoptotic effect on HUVECs by inducing a C-reactive protein. In the in vivo study, we verified the beneficial effects of the defined appropriate E2/T ratio in mice with early stage atherosclerosis. We found that replacement therapy with the defined appropriate E2/T ratio had beneficial effects of reducing the lipid lesions, reducing the formation of foam cells, reducing endothelial injury, modulating the coagulation system function and inhibiting inflammation and was significantly more effective than either estradiol or testosterone supplementation alone. CONCLUSION: The present study demonstrated that estradiol and testosterone have a synergistic effect on early stage atherosclerosis, and replacement therapy with the defined appropriate E2/T ratio can significantly suppress the development of atherosclerosis through reducing the lipid lesions, reducing the formation of foam cells, reducing endothelial injury, modulating the coagulation system function and inhibiting inflammation. PMID- 26633089 TI - Generalized pruritus preceding paraneoplastic neuropathy. AB - Paraneoplastic syndromes are a group of rare disorders involving non-metastatic systemic effects accompanying malignancies, and occur remotely from the tumor itself. Chronic pruritus lasting more than 6 weeks can be from paraneoplastic origin. A 65-year-old woman was admitted for generalized pruritus lasting for 1 month, despite treatment with prednisolone, levocetirizine and hydroxyzine. General examination was normal. Biological data and gastroscopy were normal. One month later, the patient was readmitted for worsening of her pruritus and walking impairment, revealing a severe sensory neuropathy. Blood anti-Hu antibodies returned positive at a level of 400 (normal <100). Bronchoscopy and bronchial biopsies revealed small-cell lung carcinoma. To our knowledge, the association of generalized pruritus and paraneoplastic neuropathy has been rarely reported. Our observation raises the question of a pathophysiological continuum between pruritus and neuropathy in a paraneoplastic context. PMID- 26633090 TI - Pregabalin and gabapentin for the treatment of sciatica. AB - Whilst pregabalin (PGB) and gabapentin (GBP) are both used to treat neuropathic pain, their relative role in sciatica is unclear. Our aim was to extensively review the roles of PGB and GBP in treating sciatica. The efficacy, side effects (SE) profile and cost of PGB and GBP in neuropathic pain states were reviewed with special reference to sciatica. Eleven articles matched the criteria: seven systematic reviews, one retrospective cross-sectional study, one placebo controlled-crossover study, one randomized placebo-controlled double-blind study and one case report. GBP and PGB appeared to demonstrate comparable efficacy and SE. However, the amount and quality of evidence was low, and only indirect comparisons were available. Importantly, no direct "head-to-head" study existed. Globally, costs varied widely (by up to 31 times) and unpredictably (PGB cheaper than GBP, or vice versa). Formulary regulator rulings were globally disparate; however, many exclusively favoured the more expensive drug (whether GBP or PGB). No studies assessed PGB-GBP interchange. Weak evidence suggests that efficacy and SE with GBP and PGB are probably similar; however, firm conclusions are precluded. Despite weak data, and having cited minor titration, but definite cost, advantages, UK National Institute for Health and Clinical Excellence favoured PGB over GBP. Given that no evidence supports unhindered PGB-GBP interchange, neither drug should probably be favoured. Prospective "head-to-head" studies are urgently required to provide robust evidence-based knowledge for choice of GBP or PGB in sciatica. PMID- 26633091 TI - Heterotopic ossification associated with myelopathy following cervical disc prosthesis implantation. AB - This case report presents a 37-year-old man with clinical signs of myelopathy almost 9 years after implantation of a Bryan disc prosthesis (Medtronic Sofamor Danek, Memphis, TN, USA) for C5/C6 soft disc herniation. As demonstrated on MRI and CT scan, spinal cord compression was caused by bony spurs due to heterotopic ossification posterior to the still moving prosthesis. The device, as well as the ectopic bone deposits, had to be removed because of myelopathy and its imminent aggravation. Conversion to anterior spondylodesis was performed. PMID- 26633092 TI - Scalable hospital at home with virtual physician visits: pilot study. AB - OBJECTIVES: To evaluate the safety, feasibility, and efficacy of a substitutive Hospital at Home (HaH) model where physician care was provided via 2-way biometrically enhanced tele-video for a 34-day care episode. STUDY DESIGN: Prospective, nonrandomized, quasi-experiment. METHODS: Using medical record and patient survey data, we compared patients cared for in HaH (n = 50) versus the traditional acute care hospital (n = 52). RESULTS: Patients in HaH had substantial contact with the HaH physician, as well as in-person visits with nurse practitioners and other care providers. HaH patients were more satisfied with their care in multiple domains and met illness-specific quality standards at similar rates to hospital comparison patients. Functional outcomes were notable for a trend toward improvements in activities of daily living among HaH patients. Compared with hospital patients at 90 days after discharge, HaH patients were less likely to experience a hospital readmission (adjusted odds ratio, 0.39; 95% CI, 0.21-0.72). CONCLUSIONS: This pilot study suggests that a scalable substitutive model of HaH using biometrically enhanced 2-way tele-video, virtual physician visits, and caring for patients over a 34-day episode is safe, feasible, highly satisfactory, and may be associated with substantial reductions in hospital readmissions. PMID- 26633093 TI - Health coaching by medical assistants improves patients' chronic care experience. AB - OBJECTIVES: We sought to test the hypothesis that training medical assistants to provide health coaching would improve patients' experience of care received and overall satisfaction with their clinic. STUDY DESIGN: Randomized controlled trial. METHODS: Low-income English- or Spanish-speaking patients aged 18 to 75 years with poorly controlled type 2 diabetes, hypertension, and/or hyperlipidemia were randomized to receive either a health coach or usual care for 12 months. Patient care experience was measured using the Patient Assessment of Chronic Illness Care (PACIC) scale at baseline and at 12 months. Patient overall satisfaction with the clinic was assessed with a single item asking if they would recommend the clinic to a friend or family member. PACIC and satisfaction scores were compared between study arms using generalized estimating equations to account for clustering at the clinician level. RESULTS: PACIC scores were available from baseline and at 12 months on 366 (76%) of the 441 patients randomized. At baseline, patients receiving health coaching were similar to those in the usual care group with respect to demographic and other characteristics, including mean PACIC scores (3.00 vs 3.06) and the percent who would "definitely recommend" their clinic (73% and 73%, respectively). At 12 months, coached patients had a significantly higher mean PACIC score (3.82 vs 3.13; P < .001) and were more likely to report they would definitely recommend their clinic (85% vs 73%; P = .002). CONCLUSIONS: Using medical assistants trained in health coaching significantly improved the quality of care that low-income patients with poorly controlled chronic disease reported receiving from their healthcare team. PMID- 26633094 TI - Medication adherence and healthcare disparities: impact of statin co-payment reduction. AB - OBJECTIVES: Minority patients have lower rates of cardiovascular medication adherence, which may be amenable to co-payment reductions. Our objective was to evaluate the effect of race on adherence changes following a statin co-payment reduction intervention. STUDY DESIGN: Retrospective analysis. METHODS: The intervention was implemented by a large self-insured employer. Eligible individuals in the intervention cohort (n = 1961) were compared with a control group of employees of other companies without such a policy (n = 37,320). As a proxy for race, we categorized patients into tertiles based on the proportion of black residents living in their zip code of residence. Analyses were performed using difference-in-differences design with generalized estimating equations. RESULTS: Prior to the new co-payment policy, adherence rates were higher for individuals living in areas with fewer black residents. In multivariable models adjusting for demographic factors, clinical covariates and baseline trends, the co-payment reduction increased adherence by 2.0% (P = .14), 2.1% (P = .15) and 6% (P < .0001) for intervention patients living in areas with the bottom, middle and top tertiles of the proportion of black residents. These results persisted after adjusting for income. CONCLUSIONS: Co-payment reduction for statins preferentially improved adherence among patients living in communities with a higher proportion of black residents. Further research is needed on the impact of value-based insurance design programs on reducing racial disparities in cardiovascular care. PMID- 26633095 TI - Integrated Medicare and Medicaid managed care and rehospitalization of dual eligibles. AB - OBJECTIVES: Healthcare expenditures for dually eligible individuals covered by both Medicare and Medicaid constitute a disproportionate share of spending for the 2 programs. Fragmentation, inefficiency, and low-quality care have been long standing issues for this population. The objective of this study was to conduct an early evaluation of an innovative program that coordinates benefits for elderly dual eligibles. STUDY DESIGN: Longitudinal cohort study. METHODS: Comparable sources of administrative claims from 2007 to 2009 were used to examine differences in 30-day rehospitalization between dual eligibles in Massachusetts participating in Senior Care Options (SCO), an integrated managed care program, and dual eligibles in Medicare fee-for-service. Multivariable logistic regression models with county and time fixed effects were used for estimation. RESULTS: We found no statistically significant effect of SCO on rehospitalization, an area where coordinated care would be expected to make a substantial difference. CONCLUSIONS: Our results suggest that coordinating the financing and delivery of services through an integrated managed program may not sufficiently address the problems of inefficiency and fragmentation in care for hospitalized dual eligible enrollees. PMID- 26633096 TI - Solutions for filling gaps in accountable care measure sets. AB - OBJECTIVES: A primary objective of accountable care is to support providers in reforming care to improve outcomes and lower costs. Gaps in accountable care measure sets may cause missed opportunities for improvement and missed signals of problems in care. Measures to balance financial incentives may be particularly important for high-cost conditions or specialty treatments. This study explored gaps in measure sets for specific conditions and offers strategies for more comprehensive measurement that do not necessarily require more measures. STUDY DESIGN: A descriptive analysis of measure gaps in accountable care programs and proposed solutions for filling the gaps. METHODS: We analyzed gaps in 2 accountable care organization measure sets for 20 high-priority clinical conditions by comparing the measures in those sets with clinical guidelines and assessing the use of outcome measures. Where we identified gaps, we looked for existing measures to address the gaps. Gaps not addressed by existing measures were considered areas for measure development or measurement strategy refinement. RESULTS: We found measure gaps across all 20 conditions, including those conditions that are commonly addressed in current measure sets. In addition, we found many gaps that could not be filled by existing measures. Results across all 20 conditions informed recommendations for measure set improvement. CONCLUSIONS: Addressing all gaps in accountable care measure sets with more of the same types of measures and approaches to measurement would require an impractical number of measures and would miss the opportunity to use better measures and innovative approaches. Strategies for effectively filling measure gaps include using preferred measure types such as cross-cutting, outcome, and patient-reported measures. Program implementers should also apply new approaches to measurement, including layered and modular models. PMID- 26633097 TI - Delivering value by focusing on patient experience. AB - The use of patient experience as a quality metric in healthcare remains controversial. Clinicians have expressed concern that incentives focused on patient experience may lead to lower quality care. However, empirical evidence from the United States and abroad suggests that hospitals and ambulatory care providers with higher patient satisfaction scores also perform better on clinical process and outcome measures. While it may be that high-performing providers simply have more resources to devote to both patient experience and the technical aspects of care, we suspect that these providers' performance is also driven by a conscious commitment to quality. As the country shifts toward new payment models, we should encourage this type of commitment to quality. Perhaps most importantly, improving the patient experience will build trust in the healthcare system, guard against withholding of services in the face of changing provider incentives, and promote collaboration between clinicians and patients. Therefore, patient experience measures should play a critical role in how we judge high-quality, value-based care. PMID- 26633098 TI - The path to value through the use of holistic care. PMID- 26633099 TI - Sensitive method for the determination of rocilinostat in small volume mouse plasma by LC-MS/MS and its application to a pharmacokinetic study in mice. AB - A highly sensitive, specific and rapid LC-ESI-MS/MS method has been developed and validated for the quantification of rocilinostat in small volume mouse plasma (20 MUL) using vorinostat as an internal standard (IS) as per regulatory guidelines. Sample preparation was accomplished through a protein precipitation procedure with acetonitrile. Chromatography was achieved on Prodigy ODS-2 column using a binary gradient using mobile phase A (0.2% formic acid in water) and B (acetonitrile) at a flow rate of 0.38 mL/min. The total chromatographic run time was 4.1 min and the elution of rocilinostat and IS occurred at ~3.2 and 2.9 min, respectively. A linear response function was established in the concentration range of 0.28-1193 ng/mL in mouse plasma. The intra- and inter-day accuracy and precisions were in the ranges of 3.12-8.93 and 6.41-11.6%, respectively. This novel method has been applied to a pharmacokinetic study in mice. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26633100 TI - Butelase 1: A Versatile Ligase for Peptide and Protein Macrocyclization. AB - Macrocyclization is a valuable tool for drug design and protein engineering. Although various methods have been developed to prepare macrocycles, a general and efficient strategy is needed. Here we report a highly efficient method using butelase 1 to macrocyclize peptides and proteins ranging in sizes from 26 to >200 residues. We achieved cyclizations that are 20,000 times faster than sortase A, the most widely used ligase for protein cyclization. The reactions completed within minutes with up to 95% yields. PMID- 26633101 TI - Effect of the inadequacy of antibiotic therapy in the Emergency Department on hospital stays. AB - INTRODUCTION: The main objective of the study was to determine the frequency of patients receiving inappropriate empiric antibiotic therapy and to assess the impact in terms of increase length of hospital stay, 30-day re-admissions, and 30 day mortality. METHODS: An observational retrospective cohort study was conducted over a one-month period that included all patients hospitalised from an Emergency Department (ED) due to infection. Demographic variables, comorbidity, multi resistance risk factors, site of infection, microbiological findings, and antibiotic prescribed in ED were collected. Outcomes were length of hospital stay, 30-day re-admissions, and 30-day mortality. RESULTS: A total of 376 patients were included, with a mean age of 71.1 (SD 21) years. The most frequent causes were respiratory (45.7%) and urine (23.9%) infections. The number of patients with length of stay over the median (>=9 days) was 165 (46.1%), with re admissions 74 (19.7%), and mortality at 30 days 44 (11.7%). There was inappropriate antibiotic treatment in 42 (11.2%) cases. After adjusting for demographic data, comorbidity, risk factors for multidrug resistant organism, presence of sepsis criteria in ED, and site of infection, inappropriate treatment was associated with an extended length of hospital stay (OR 2.22; 95% CI; 1.07 4.60; P=.032), but did not to an increase in mortality (P=.271) or re-admission (P=.784) at 30 days. CONCLUSION: The inappropriate empirical antibiotic therapy in patients admitted from the ED leads to an extended hospital stay, but did not increase mortality or readmission. PMID- 26633102 TI - Mycophenolic acid versus azathioprine as primary immunosuppression for kidney transplant recipients. AB - BACKGROUND: Modern immunosuppressive regimens after kidney transplantation usually use a combination of two or three agents of different classes to prevent rejection and maintain graft function. Most frequently, calcineurin-inhibitors (CNI) are combined with corticosteroids and a proliferation-inhibitor, either azathioprine (AZA) or mycophenolic acid (MPA). MPA has largely replaced AZA as a first line agent in primary immunosuppression, as MPA is believed to be of stronger immunosuppressive potency than AZA. However, treatment with MPA is more costly, which calls for a comprehensive assessment of the comparative effects of the two drugs. OBJECTIVES: This review of randomised controlled trials (RCTs) aimed to look at the benefits and harms of MPA versus AZA in primary immunosuppressive regimens after kidney transplantation. Both agents were compared regarding their efficacy for maintaining graft and patient survival, prevention of acute rejection, maintaining graft function, and their safety, including infections, malignancies and other adverse events. Furthermore, we investigated potential effect modifiers, such as transplantation era and the concomitant immunosuppressive regimen in detail. SEARCH METHODS: We searched Cochrane Kidney and Transplant's Specialised Register (to 21 September 2015) through contact with the Trials' Search Co-ordinator using search terms relevant to this review. SELECTION CRITERIA: All RCTs about MPA versus AZA in primary immunosuppression after kidney transplantation were included, without restriction on language or publication type. DATA COLLECTION AND ANALYSIS: Two authors independently determined study eligibility, assessed risk of bias and extracted data from each study. Statistical analyses were performed using the random effects model and the results were expressed as risk ratio (RR) for dichotomous outcomes and mean difference (MD) for continuous outcomes with 95% confidence intervals (CI). MAIN RESULTS: We included 23 studies (94 reports) that involved 3301 participants. All studies tested mycophenolate mofetil (MMF), an MPA, and 22 studies reported at least one outcome relevant for this review. Assessment of methodological quality indicated that important information on factors used to judge susceptibility for bias was infrequently and inconsistently reported.MMF treatment reduced the risk for graft loss including death (RR 0.82, 95% CI 0.67 to 1.0) and for death-censored graft loss (RR 0.78, 95% CI 0.62 to 0.99, P < 0.05). No statistically significant difference for MMF versus AZA treatment was found for all-cause mortality (16 studies, 2987 participants: RR 0.95, 95% CI 0.70 to 1.29). The risk for any acute rejection (22 studies, 3301 participants: RR 0.65, 95% CI 0.57 to 0.73, P < 0.01), biopsy-proven acute rejection (12 studies, 2696 participants: RR 0.59, 95% CI 0.52 to 0.68) and antibody-treated acute rejection (15 studies, 2914 participants: RR 0.48, 95% CI 0.36 to 0.65, P < 0.01) were reduced in MMF treated patients. Meta-regression analyses suggested that the magnitude of risk reduction of acute rejection may be dependent on the control rate (relative risk reduction (RRR) 0.34, 95% CI 0.10 to 1.09, P = 0.08), AZA dose (RRR 1.01, 95% CI 1.00 to 1.01, P = 0.10) and the use of cyclosporin A micro-emulsion (RRR 1.27, 95% CI 0.98 to 1.65, P = 0.07). Pooled analyses failed to show a significant and meaningful difference between MMF and AZA in kidney function measures.Data on malignancies and infections were sparse, except for cytomegalovirus (CMV) infections. The risk for CMV viraemia/syndrome (13 studies, 2880 participants: RR 1.06, 95% CI 0.85 to 1.32) was not statistically significantly different between MMF and AZA treated patients, whereas the likelihood of tissue-invasive CMV disease was greater with MMF therapy (7 studies, 1510 participants: RR 1.70, 95% CI 1.10 to 2.61). Adverse event profiles varied: gastrointestinal symptoms were more likely in MMF treated patients and thrombocytopenia and elevated liver enzymes were more common in AZA treatment. AUTHORS' CONCLUSIONS: MMF was superior to AZA for improvement of graft survival and prevention of acute rejection after kidney transplantation. These benefits must be weighed against potential harms such as tissue-invasive CMV disease. However, assessment of the evidence on safety outcomes was limited due to rare events in the observation periods of the studies (e.g. malignancies) and inconsistent reporting and definitions (e.g. infections, adverse events). Thus, balancing benefits and harms of the two drugs remains a major task of the transplant physician to decide which agent the individual patient should be started on. PMID- 26633104 TI - [Heteroresistance in Vancomycin-Intermediate Staphylococcus aureus (VISA), susceptible or resistant?]. PMID- 26633103 TI - Dose-dependent effects of isoflurane on regional activity and neural network function: A resting-state fMRI study of 14 rhesus monkeys: An observational study. AB - The dose-dependent effect of isoflurane on cerebral regional activity and functional connectivity (FC) in 14 rhesus monkeys was investigated using resting state functional MRI. Amplitude of low-frequency fluctuations (ALFF) decreased in the cerebellum, visual cortex, and cortico-subcortical network when the isoflurane dose changed from 1.0 to 1.3 MAC. ALFF decreased in the arousal system, cerebellum, sensory, visual areas, cortico-subcortical network and default mode network and increased in the bilateral dorsal prefrontal cortices, frontal eye fields and motor-related areas from 1.0 to 1.6 MAC. FC of the default mode network, frontal-parietal, cortico-subcortical, motor, sensory, auditory and visual areas was reduced when isoflurane increased from 1.0 to 1.3 MAC. FC decreased in more widespread areas, especially in regions of cortico-subcortical networks and limbic systems, when isoflurane further increased from 1.0 to 1.6 MAC. Both dose-dependent decreased and increased ALFF were separately observed, while FC deteriorated as the anesthesia deepened. These results suggest that changes continue to occur past the loss of consciousness, and the dose-dependent effects of isoflurane are different with regard to regional function and neural network integration. PMID- 26633105 TI - [Quinolones. Nowadays perspectives and mechanisms of resistance]. AB - Quinolones are a family of synthetic broad-spectrum antimicrobial drugs whose target is the synthesis of DNA. They directly inhibit DNA replication by interacting with two enzymes; DNA gyrase and topoisomerase IV. They have been widely used for the treatment of several community and hospital acquired infections, in the food processing industry and in the agricultural field, making the increasing incidence of quinolone resistance a frequent problem associated with constant exposition to diverse microorganisms. Resistance may be achieved by three non-exclusive mechanisms; through chromosomic mutations in the Quinolone Resistance-Determining Regions of DNA gyrase and topoisomerase IV, by reducing the intracytoplasmic concentrations of quinolones actively or passively and by Plasmid-Mediated Quinolones-Resistance genes, [Qnr determinant genes of resistance to quinolones, variant gene of the aminoglycoside acetyltransferase (AAC(6')-Ib-c)] and encoding genes of efflux pumps (qepA and oqxAB)]. The future of quinolones is uncertain, however, meanwhile they continue to be used in an irrational way, increasing resistance to quinolones should remain as an area of primary priority for research. PMID- 26633106 TI - [Clinical features and prognostic factors of meningococcal disease: a case series study in Chile during the 2012-2013 outbreak]. AB - INTRODUCTION: Meningococcal disease (MD) is a major global problem because of its case fatality rate and sequels. Since 2012 cases of serogroup W have increased in Chile, with nonspecific clinical presentation, high case fatality rate and serious consequences. OBJECTIVE: To characterize the evolution and outcome of MD cases between January 2012 and March 2013 in Chile. MATERIAL AND METHODS: Case series considering 149 MD cases of 7 regions. A questionnaire was applied and clinical records were reviewed, including individual, agent, clinical course and healthcare process variables. The analysis allowed to obtain estimates of the OR as likelihood of dying. RESULTS: 51.5% was meningococcemia, the case fatality rate reached 27%, prevailing serogroup W (46.6%). Factors that increased the probability of dying: > age, belonging to indigenous people, having lived a stressful event, having diarrhea, impaired consciousness, cardiovascular symptoms, low oxygen saturation and low Glasgow coma scale score. DISCUSSION: The case fatality rate exceeded normal levels and was higher in serogroup W. Increasing in this serogroup, associated to the increased presence of nonspecific symptoms or rapid progression to septicemia, hit a health system accustomed to more classic meningococcal disease presentation, which could partly explain the observed increased fatality rate. PMID- 26633107 TI - [Outbreak due to Serratia marcescens associated with intrinsic contamination of aqueous chlorhexidine]. AB - Serratia marcescens is a widely distributed gram-negative rod, often associated to nosocomial infections. Some outbreaks linked to contaminated antiseptic solutions have been reported. In this study we report a nosocomial outbreak of surgical site infection and catheter insertion site infection due to S. marcescens. 33 patients with positive cultures were studied after an index case was identified. Epidemiological, microbiological and molecular analysis demostrated an intrinsic contamination of alcohol free chlorhexidine solution as causal factor. Positive cultures were associated with 13 clinical infections, 9 colonized patients, 6 pseudobacteremia episodes and 5 patients without documented exposure. Hospital and national recall of contaminated chlorhexidine solution was performed after this study. Intrinsic contamination of antiseptic solutions is an infrequent cause of nosocomial infections with major epidemiological relevance. PMID- 26633108 TI - [Clinic and epidemiologic description of Clostridium difficile infection in a pediatric population]. AB - BACKGROUND: Clostridium difficile (CUj-associated disease (CDAD) and the role of the hypervirulent strain NAP1 have not been well characterized in Pediatrics. AIMS: To describe clinical features of CDAD, and to estimate NAP1 frequency and association with disease severity in Pediatrics. METHODS: Descriptive, transversal surveillance of diarrheal episodes in Chilean children, hospitalized between February 2012 and December 2013, positive for CD by molecular diagnosis. RESULTS: A total of 66 episodes of diarrhea with identification of CD occurred thougout the study period in children between 1 month and 19 years of age of which 39% were younger than one year old. CD acquisition was predominantly nosocomial and the most common risk factors were: presence of comorbidities (98.6%), use of antibiotics (93.9%), proton pump inhibitors (84.8%), invasive mechanic ventilation (54.5%), feeding tube (48.5%) and immunosuppression (40.9%). Clinical course was mostly mild, but 12 cases presented an unfavorable course, of which 3/26 occurred in children less than one year. Only one case was positive for NAP1 and had a mild course. CONCLUSION: Diarrhea with identification of CD was present throughout all pediatric ages, including children less than one year old. Analytical and longitudinal studies are required to better characterize the pathogenic role of CD in this age group. CDAD occurred mostly in patients with risk factors, and the clinical course was predominantly mild. PMID- 26633109 TI - [Leptospirosis frequency and socio-demographic characteristics associated in febrile patients from northern Peru]. AB - INDRODUCTION: Leptospirosis is a frequent cause of febrile illness around the world, particularly in tropical and subtropical areas such as Peru. OBJECTIVE: To estimate the frequency and socio-demographic characteristics associated with leptospirosis in febrile patients in northern Peru. MATERIALS AND METHODS: A cross sectional study was conducted from January to December 2014 in 143 fever cases admitted to the Hospital Regional Lambayeque, Peru. Structured for socio demographic information and sanitation questionnaire was used. Serum samples were examined to quantitatively determine the presence of IgM antibodies to leptospira using ELISA IgM. RESULTS: The frequency was 26.6% (95% CI 19.3 to 33.8) and independently associated features were: be between 20-54 years (OR: 3.36, 95% CI 1.17 to 9, 64), work in agriculture-livestock (OR: 6.15, 95% CI 1.99 to 19.05),contact with animals (OR: 4,13, IC 95%: 1,76-9,65) and consumption of unsafe water(OR: 3,33, IC 95%: 1,49-7,43). CONCLUSIONS: This study reveals a high frequency of leptospirosis among febrile patients from northern Peru. These results indicate the need to investigate routinely leptospirosis in febrile patients, especially those exhibiting risk characteristics. PMID- 26633110 TI - [In vitro antibacterial activity of Chilean propolis against Helicobacter pylori]. AB - INTRODUCTION: Propolis is a natural product derived from beekeeping. It has anesthetic, anti-inflammatory, immune-stimulant and antibacterial properties on grampositive and gramnegative bacteria. However, little is known regarding its activity on Helicobacter pylori. This bacteria colonizes about half of the world's population and is associated with chronic gastritis, peptic ulcer and gastric cancer. OBJECTIVE: The aim of this study was to evaluate the inhibitory activity of 22 propolis extracts from nine of the 11 beekeeping Chilean regions on 10 strains of H. pylori isolated from gastric mucosa. METHODS: The antibacterial activity of the extracts was determined using the well diffusion method and diffusion disks. RESULTS: 100% of the extracts were active on the tested strains, showing inhibition halos equal to or greater than 15 mm by both methods. CONCLUSIONS: Our results show an effective anti H. pylori activity of propolis. However, additional microbiological studies are needed before a potential clinical utility of these natural products is warranted. PMID- 26633111 TI - [Toxoplasmosis, a parasitic zoonoses prevalent in Chile: count and challenges]. AB - BACKGROUND: Toxoplasmosis, cosmopolitan parasitic zoonosis often found in humans, is transmitted mainly by food and water, and is considered a significant risk of morbidity and mortality in pregnant women, newborns and immunocompromised patients. OBJECTIVE: To identify the information about this zoonosis and its first reports in Chile. MATERIALS AND METHODS: Review of publications in Pubmed, Mesh search of systematic reviews, case studies, cross-sectional studies, systematic reviews, meta-analysis and specialty publications. In addition, other publications in parasitology journals were analyzed. CONCLUSIONS: There are reports of the presence of this disease in Chile for 60 years. During this time several differences in prevalence depending on geographic location, age and education level of the population have been detected. There is low epidemiological vigilance and lack of specific official preventive measures for this disease, despite the possible introduction of new parasite genotypes of an increased virulence and pathogenicity in the country through the importation of meat. New enigmas have arisen in relation to this disease associating it with Alzheimer, Parkinson's disease, autism, learning disabilities, among others. PMID- 26633112 TI - [Clostridium difficile associated diarrhea in children]. AB - INTRODUCTION: Clostridium difficile is the most commonly isolated organism in antimicrobial and health care-associated diarrhea and is growing in relevance in community-acquired infections. It is a Gram-positive bacillus acquired via the fecal-oral route in the community and in hospital setting. EPIDEMIOLOGY: 0.6 to 2.1% worldwide incidence, mortality ~ 1-5%. COLONIZATION: High rates of asymptomatic colonization in healthy people, 37% in children: its presence in stools is of controversial significance. Risk factors in children are prior exposure to antibiotics, recent hospitalization, immunosuppression or inflammatory bowel disease. CLINICAL MANIFESTATIONS: Secondary to intestinal involvement due to toxin production, ranging from asymptomatic colonization to fulminant disease. DIAGNOSIS: Clinical diagnostic criteria plus high sensitivity and specificity laboratory certification. Recommendations AAP (American Academy of Pediatrics): under 1 year, avoid routine study, only in Hirschsprung disease and/or nosocomial outbreak, 1-3 year, a (+) result suggests C. difficile associated diarrhea (CDAD) is possible, and in children older than 3 years interpretation is equal to adults. MANAGEMENT: Antimicrobial suspension, oral metronidazole as first line in mild to moderate CDAD, and oral or enema vancomycin or associated with intravenous metronidazole only in severe cases. Duration 10 days. PREVENTION: Antimicrobial control programs and environmental management. CONCLUSION: Given the increasing complexity of pediatric patients it is important to deepen the knowledge on this microorganism and its clinical manifestations, as its incidence, morbidity and mortality are increasing. PMID- 26633113 TI - [Pertussis vaccines: acellular versus whole cell. Perhaps a return to the past?]. AB - The resurgence of pertussis in the world and in our country has questioned the effectiveness of cellular and acellular vaccines. The reason why pertussis has not been controlled or eliminated after 70 years of implementation of the vaccination is probably multifactorial. This article, on the basis of questions and answers, describes the benefits and limitations of both cellular and acellular vaccines and suggests new strategies of vaccination in childhood. It is a fact that the currently applied vaccination does not eliminate the circulation of Bordetella pertussis in the community. Perhaps the introduction of vaccines with live B. pertussis, inhalation, will be able to eliminate the disease around the world. PMID- 26633114 TI - [Nephronia in pediatrics: part of the spectrum of upper urinary tract infections. Clinical cases and review of the literature]. AB - Nephronia or focal acute nephritis corresponds to a localized inflammatory non liquefactive kidney infection which may involve parenchyma of one or more renal lobes. It has been suggested that nephronia is part of the spectrum of upper urinary tract infections between acute pyelonephritis and renal abscess. It is associated with a prolonged clinical course, higher levels of inflammatory markers and an increased risk of renal scarring, compared to pyelonephritis. Ultrasound plays a useful role. Nephronia is an under-diagnosed condition, thus, clinical suspicion is important for early diagnosis and appropriate treatment. We present three paediatric cases, and a review of the literature. PMID- 26633115 TI - [Candida parapsilosis complex]. PMID- 26633116 TI - [Infectious diseases in the genomic era]. AB - Next generation sequencing (NGS) technologies have arrived, changing research and infectious disease research into a new era, the "genomic era". Currently, the developed world is introducing NGS in a number of applications, including clinical diagnostics, epidemiology, and microbiology. In developing countries NGS is being progressively introduced. Technologies currently available allow to sequence the whole genome of bacterial and viral strains for an approximate cost of $100 USD, which is highly cost savings compared to old-technologies for genome sequencing. Here we review recent publication of whole genome sequencing used for, (i) tracking of foodborne outbreaks, with emphasis in Salmonella and Listeria monocytogenes, (ii) building genomic databases for Governments, (iii) investigating nosocomial infections, and (iv) clinical diagnosis. The genomic era is here to stay and researchers should use these "massive databases" generated by this technology to decrease infectious diseases and thus improve health of humans and animals. PMID- 26633117 TI - [Notes about other epidemics in Colonial Chile]. AB - In chronicles or in the historiography of the Colony in Chile there are few references about epidemics different to smallpox; like typhus, typhoid fever, dysentery, etc. Almost all, fast spreading in the country and some with high lethality, which led to overflowing the capacity of hospitals in the Chilean colonial period. PMID- 26633118 TI - [Hip tuberculosis. Case report and literature review]. AB - Osteoarticular tuberculosis is a rare complication of the disseminated disease and appears, in different series, between 10% to 20%, trough hematogenous spread. Tuberculosis hip involvement is less than 10% of all the cases of osteoarticular tuberculosis. The diagnosis is confirmed by the detection of Mycobacterium tuberculosis in samples obtained from joint fluid or synovial membrane biopsy by direct examination and culture, in order to perform antimicrobial susceptibility testing. Here, we present a patient infected with the human immunodeficiency virus (HIV) who developed a disseminated tuberculosis with affection of the hip in the context of the immunodeficiency related with the retrovirus. PMID- 26633119 TI - [Severe neutropenia as side effect of medical treatment in nontuberculous mycobacterial adenitis]. AB - Non-tuberculous mycobacterial adenitis is getting more common in our environment. Epidemiologic studies and clinical trials published nowadays are limited. We present a 2-years-old boy diagnosed of Mycobacterium intracellulare adenitis and severe neutropenia as side effect of combined treatment with oral azythromycin and rifabutin, which recovers after suspending the second one. Liver metabolism of macrolide seems to increase other drugs toxicity, in this case, rifabutin. The patient eventually needed surgery due to persistence of the adenitis despite treatment with antibiotics. PMID- 26633120 TI - [Isolation of Staphylococcus aureus hetero-resistant to vancomycin (hVISA) in the Regional Hospital of Concepcion, Chile]. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is widely distributed in hospital environments, causing serious infections, mainly the bloodstream, surgical site infection and pneumonia. Vancomycin (VAN) is the antibiotic of choice for treating severe MRSA infections; however, nowadays worldwide resistant strains (VRSA), with intermediate susceptibility (VISA) and decreased susceptibility or hetero-resistance to VAN (hVISA) have been reported, related to treatment failure and increased mortality. This report describes the first confirmed isolation of MRSA with hVISA phenotype in a public hospital in Chile. PMID- 26633121 TI - [Isolation frequency of the Mycobacterium genus in urine samples]. AB - Kidney infections caused by Mycobacterium genus are torpid and chronic evolution. In this study were analyzed 177 urine samples (included 110 from HIV patients) received between January 2006 and July 2014 in the National Reference Laboratory of Tuberculosis at Tropical Medicine Institute "Pedro Kouri" (IPK). The results were 17 isolates Mycobacterium tuberculosis, and 30 isolates of nontuberculous mycobacteria were detected. This study confirms the diagnostic importance of these infections especially in HIV/AIDS patients. PMID- 26633122 TI - [Hymenolepis nana infection: associated factors with this parasitism in a health area of Southern Spain]. AB - Hymenolepis nana is the most common tapeworm in humans; prevalence rates of 0.1% 58% have been reported. The aim of this study was to determine the prevalence in a health area of Southern Spain and identify the demographic variables potentially associated with increased rates of hymenolepiasis in this area. A retrospective study was performed with patients, who had H. nana eggs in fecal samples during january 2000 to december 2013. Parasitological diagnosis relied on microscopic detection in concentrated stool samples. During the study period, 73.660 stool samples were analyzed. H. nana eggs were observed in 158 patients (31 female) with a mean age of 18,9 years. The prevalence during the study period was 0,21% and 61% of the infected patients had more than one intestinal parasite. In conclusion, the prevalence of parasitism by H. nana in our population was higher than the national average and higher in adults than in children due to the characteristics of our population. PMID- 26633123 TI - [Transgressions to the HIV voluntary counseling and testing in Peru: the case of the requirement for civil marriage]. PMID- 26633125 TI - Redox-Dependent Franck-Condon Blockade and Avalanche Transport in a Graphene Fullerene Single-Molecule Transistor. AB - We report transport measurements on a graphene-fullerene single-molecule transistor. The device architecture where a functionalized C60 binds to graphene nanoelectrodes results in strong electron-vibron coupling and weak vibron relaxation. Using a combined approach of transport spectroscopy, Raman spectroscopy, and DFT calculations, we demonstrate center-of-mass oscillations, redox-dependent Franck-Condon blockade, and a transport regime characterized by avalanche tunnelling in a single-molecule transistor. PMID- 26633126 TI - Helicobacter pylori eradication: gastric cancer prevention. AB - INTRODUCTION: The principal effect of Helicobacter pylori infection is lifelong chronic gastritis, affecting up to 20% of younger adults but 50% to 80% of adults born in resource-rich countries before 1950. METHODS AND OUTCOMES: We conducted a systematic overview, aiming to answer the following clinical question: What are the effects of H pylori eradication treatment on the risk of developing gastric cancer? We searched: Medline, Embase, The Cochrane Library, and other important databases up to July 2014 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). RESULTS: At this update, searching of electronic databases retrieved 208 studies. After deduplication and removal of conference abstracts, 166 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 124 studies and the further review of 42 full publications. Of the 42 full articles evaluated, one systematic review was added at this update. We performed a GRADE evaluation for two PICO combinations. CONCLUSIONS: In this systematic overview, we categorised the efficacy for one intervention based on information about the effectiveness and safety of H pylori eradication treatment for the prevention of gastric cancer. PMID- 26633127 TI - SIFT missense predictions for genomes. AB - The SIFT (sorting intolerant from tolerant) algorithm helps bridge the gap between mutations and phenotypic variations by predicting whether an amino acid substitution is deleterious. SIFT has been used in disease, mutation and genetic studies, and a protocol for its use has been previously published with Nature Protocols. This updated protocol describes SIFT 4G (SIFT for genomes), which is a faster version of SIFT that enables practical computations on reference genomes. Users can get predictions for single-nucleotide variants from their organism of interest using the SIFT 4G annotator with SIFT 4G's precomputed databases. The scope of genomic predictions is expanded, with predictions available for more than 200 organisms. Users can also run the SIFT 4G algorithm themselves. SIFT predictions can be retrieved for 6.7 million variants in 4 min once the database has been downloaded. If precomputed predictions are not available, the SIFT 4G algorithm can compute predictions at a rate of 2.6 s per protein sequence. SIFT 4G is available from http://sift-dna.org/sift4g. PMID- 26633128 TI - Accelerated gas-liquid visible light photoredox catalysis with continuous-flow photochemical microreactors. AB - In this protocol, we describe the construction and use of an operationally simple photochemical microreactor for gas-liquid photoredox catalysis using visible light. The general procedure includes details on how to set up the microreactor appropriately with inlets for gaseous reagents and organic starting materials, and it includes examples of how to use it to achieve continuous-flow preparation of disulfides or trifluoromethylated heterocycles and thiols. The reported photomicroreactors are modular, inexpensive and can be prepared rapidly from commercially available parts within 1 h even by nonspecialists. Interestingly, typical reaction times of gas-liquid visible light photocatalytic reactions performed in microflow are lower (in the minute range) than comparable reactions performed as a batch process (in the hour range). This can be attributed to the improved irradiation efficiency of the reaction mixture and the enhanced gas liquid mass transfer in the segmented gas-liquid flow regime. PMID- 26633129 TI - Antibody-coupled siRNA as an efficient method for in vivo mRNA knockdown. AB - Knockdown of genes by RNA interference (RNAi) in vitro requires methods of transfection or transduction, both of which have limited impact in vivo. As a virus-free approach, we chemically coupled cell surface receptors internalizing antibodies to the short interfering RNA (siRNA) carrier peptide protamine using the bispecific cross-linker sulfo-SMCC (sulfosuccinimidyl 4-(N maleimidomethyl)cyclohexane-1-carboxylate). First, protamine was conjugated amino terminally to sulfo-SMCC, and then this conjugate was coupled via cysteine residues to the IgG backbone to carry siRNA. This complex can efficiently find, bind and internalize into receptor-positive cells in vitro and in vivo, which can be checked by flow cytometry, fluorescence microscopy and western blotting. This method obtains results similar to those of siRNA targeting molecules engineered by genetic fusions between receptor-binding and siRNA carrier units, with the advantage of using readily available purified proteins without the need for engineering, expression and purification of respective constructs. The procedure for coupling the complex takes ~ 2 d, and the functional assays take ~ 2 weeks. PMID- 26633131 TI - Phonon Mode Transformation Across the Orthohombic-Tetragonal Phase Transition in a Lead Iodide Perovskite CH3NH3PbI3: A Terahertz Time-Domain Spectroscopy Approach. AB - We study the temperature-dependent phonon modes of the organometallic lead iodide perovskite CH3NH3PbI3 thin film across the terahertz (0.5-3 THz) and temperature (20-300 K) ranges. These modes are related to the vibration of the Pb-I bonds. We found that two phonon modes in the tetragonal phase at room temperature split into four modes in the low-temperature orthorhombic phase. By use of the Lorentz model fitting, we analyze the critical behavior of this phase transition. The carrier mobility values calculated from the low-temperature phonon mode frequencies, via two theoretical approaches, are found to agree reasonably with the experimental value (~2000 cm(2) V(-1) s(-1)) from a previous time-resolved THz spectroscopy work. Thus, we have established a possible link between terahertz phonon modes and the transport properties of perovskite-based solar cells. PMID- 26633130 TI - Fast and easy phosphopeptide fractionation by combinatorial ERLIC-SCX solid-phase extraction for in-depth phosphoproteome analysis. AB - Mass spectrometry-based phosphoproteomic analysis is a powerful method for gaining a global, unbiased understanding of cellular signaling. Its accuracy and comprehensiveness stands or falls with the quality and choice of the applied phosphopeptide prefractionation strategy. This protocol covers a powerful but simple and rapid strategy for phosphopeptide prefractionation. The combinatorial use of two distinct chromatographic techniques that address the inverse physicochemical properties of peptides allows for superior fractionation efficiency of multiple phosphorylated peptides. In the first step, multiphosphorylated peptides are separated according to the number of negatively charged phosphosites by electrostatic repulsion-hydrophilic interaction chromatography (ERLIC). A subsequent strong cation exchange (SCX) step separates mostly singly phosphorylated peptides in the ERLIC flow-through according to their positive charge. The presented strategy is inexpensive and adaptable to large and small amounts of starting material, and it allows highly multiplexed sample preparation. Because of its implementation as solid-phase extraction, the entire workflow takes only 2 h to complete. PMID- 26633132 TI - The critical role of IL-6 in the pathogenesis of Takayasu arteritis. AB - OBJECTIVES: To investigate T cell subsets and immune cytokine profiles in untreated Takayasu arteritis (TAK) patients and the underlying immunopathological mechanism. METHODS: We enrolled 50 untreated TAK patients and 40 age-matched controls (20 healthy controls, 20 untreated SLE patients). Enzyme-linked immunosorbent assays (ELISAs) were used to define cytokine profiles in all patients, and flow cytometry was performed for 9 TAK patients and 12 healthy controls. Hematoxylin and eosin (Handamp;E) staining and immunohistochemistry (IHC) were performed in aortic tissues of 9 TAK and 9 atherosclerosis patients; clinical data were also collected. RESULTS: Circulating CD4(+) T cells were more frequent in TAK patients (p<0.05). Frequencies of Th1, Th2, and Th17 cells were higher, whereas Treg cells were reduced in TAK. Significantly higher levels of IL 6 and lower levels of IFN-gamma, IL-4, and IL-17 were detected in TAK patients (p<0.05). By H & E staining, thickened vascular walls with proliferation of collagen fibre were observed in most patients. Inflammatory sites with infiltrating macrophages, lymphocytes, and neutrophils were located in adventitia. IHC revealed T cells (mainly CD4(+) T cells) in vascular lesions. Additionally, IL-6 was positive throughout the vascular wall in most specimens, whereas IFN-gamma, IL-12, and IL-17 were detected in inflammatory sites of active patients. IL-6 levels were positively related to ESR, CRP, and Kerr scores (p<0.05). CONCLUSIONS: Significantly increased levels of IL-6 were detected in peripheral blood and aortic tissues of untreated patients. IL-6 might be a sensitive biomarker to assess disease activity and could be critical in the immunopathogenesis of TAK. PMID- 26633133 TI - Tuning the Wettability of Halloysite Clay Nanotubes by Surface Carbonization for Optimal Emulsion Stabilization. AB - The carbonization of hydrophilic particle surfaces provides an effective route for tuning particle wettability in the preparation of particle-stabilized emulsions. The wettability of naturally occurring halloysite clay nanotubes (HNT) is successfully tuned by the selective carbonization of the negatively charged external HNT surface. The positively charge chitosan biopolymer binds to the negatively charged external HNT surface by electrostatic attraction and hydrogen bonding, yielding carbonized halloysite nanotubes (CHNT) on pyrolysis in an inert atmosphere. Relative to the native HNT, the oil emulsification ability of the CHNT at intermediate levels of carbonization is significantly enhanced due to the thermodynamically more favorable attachment of the particles at the oil-water interface. Cryogenic scanning electron microscopy (cryo-SEM) imaging reveals that networks of CHNT attach to the oil-water interface with the particles in a side on orientation. The concepts advanced here can be extended to other inorganic solids and carbon sources for the optimal design of particle-stabilized emulsions. PMID- 26633135 TI - Carriage of Class 1 and Class 2 Integron in Multidrug Resistant Pseudomonas aeruginosa Isolated from Burn Patients in Tehran Hospitals, Iran. AB - Objective: To investigate the antimicrobial susceptibility patterns of Pseudomonas aeruginosa clinical isolates and their associations with the existence of integrons. Methods: During a 12-month study, 140 clinically significant Pseudomonas aeruginosa isolates were collected from patients hospitalized in the burn ward of different hospitals in Tehran. Pseudomonas aeruginosa isolates were identified using standard laboratory procedures. Antimicrobial susceptibility testing was performed for 13 antimicrobial agents according to the standard Kirby-Bauer disk diffusion method and Clinical and Laboratory Standards Institute (CLSI) guidelines. The frequency of Class 1, 2 and 3 integrons was detected using a polymerase chain reaction (PCR) method. Results: The resistance rates of Pseudomonas aeruginosa isolates to 13 antimicrobial agents were between 34.7% and 90.8%. Ceftriaxone and imipenem had good activity against the isolates. Of 140 tested isolates, 91 (65%) were multidrug resistant. The most predominant resistance profile among the isolates included resistance to 10 (12.14%), 9 (12.14%) and 8 (12.14%) antibiotics. Class 1 and 2 integrons were detected in 57.2% (56/98) and 30.6% (30/98) of tested Pseudomonas aeruginosa isolates, respectively. Of 98 (70%) integron positive isolates, only 12 (12.2%) isolates were positive for both classes of integrons. Resistance of the isolates to cefotaxime, aztreonam, imipenem, tobramycin, ticarcillin, ciprofloxacin and cloxacillin was observed to be significantly associated with the existence of integrons. Conclusion: These data confirmed high prevalence of Class 1 integrons among Pseudomonas aeruginosa isolates from burn patients in this study. Based on these results, integrons may play an important role in the possible transmission of resistance genes to the clinical Pseudomonas aeruginosa isolates. PMID- 26633136 TI - Prevalence of Congenital Malformations in Grenada. AB - Objectives: To determine the prevalence of congenital malformations in Grenada for the period January 2000-December 2004. Methods: The study included neonates diagnosed with congenital malformations as well as those who were part of the Grenada Heart Foundation for the same time period. Patient delivery records from the three government hospitals were reviewed. Parents were contacted and a questionnaire administered to obtain demographic and maternal history related to the birth. Results: The prevalence of birth defects was 0.78% (95%CI: 0.61, 0.98) for the five-year period among the 9004 live births. Cardiovascular malformations were the most prevalent (0.32%; 95% CI: 0.22, 0.45%), with abnormalities of the genitourinary system being the least prevalent (0.04%; 95% CI: 0.01, 0.11%). Conclusion: The prevalence of congenital malformations in Grenada is low in comparison to other developed and developing countries. PMID- 26633137 TI - Computed Tomography Identifies Hepatic Portal Venous Gas Caused by Severe Diarrhoea. AB - Aim: To use computed tomography (CT) to diagnose the reasons for hepatic portal venous gas (HPVG) in the case of an elderly male patient. Methods: This is a case study of an elderly male patient who suffered acute, obvious abdominal pain accompanied with stop of exhaust defecation following three days of diarrhoea, abdominal distention and emesis. The patient also developed asthma, which gradually became severe. The patient was admitted to the hospital where he underwent a physical examination and a CT scan. Results: The CT results confirmed that the patient was suffering from HPVG caused by severe diarrhoea. The CT scan showed obvious expansion and pneumatosis in the enteric cavity and subcutaneous emphysema in the intestinal wall. Also, the intrahepatic portal branches and small branches of veins in the mesentery were filled with a high density of gas. The combination of many factors led to HPVG. Gastrointestinal mucosa and pressure accompanied with intestinal septic infection were the main factors. The case report revealed that gas in the enteric cavity went into the submucosa, then into the small branches of veins in the mesentery and finally into the intrahepatic portal vein system. Conclusions: Computed examination revealed the imaging features of HPVG. Hepatic portal venous gas suggested the growth of enteric cavity pressure, the damage of intestinal mucosa and intestinal infection, providing references for clinical diagnosis. PMID- 26633138 TI - Bilateral Septic Neonatal Orchiepididymitis - Case Report. AB - Neonatal epididymo-orchitis is a rare condition, causing testicular pain in neonatal boys. It represents epididymo-testicular inflammation which commonly coexists with urinary tract infections and malformations. The idiopathic type is extremely rare. We present a case of a seven-day old male neonate with advanced septic form of idiopathic orchiepididymitis and no associated urinary tract anomalies. The boy was hospitalized with signs of sepsis, anterior abdominal wall phlegmona and bilateral acute scrotum. Colour Doppler echosonography indicated epididymo-testicular inflammation with increased vascular flow. The patient underwent surgical exploration of both scrota in order to evacuate purulent content and fibrin. Cultures of Enterobacter spp were detected in hemiscrotal pus. Prompt administration of antibiotics was done. The postoperative course was uneventful. We suggest that every male baby must be very meticulously examined by a neonatologist in the early postnatal period, in order to prevent infertility. PMID- 26633139 TI - Case Report of Patient with Relapse of B-cell Lymphoma in the Breast Parenchyma. AB - We present a patient with relapse of B-cell non-Hodgkin's lymphoma in the breast that was clinically presented as a primary breast cancer. A 72-year old female was treated with chemotherapy and monoclonal antibodies (anti-CD20) due to diffuse large B-cell non-Hodgkin's lymphoma. Complete remission was achieved. Three years later, she was presented with a palpable left breast lump in the perimammillar area of the left breast, dimensions up to 3 cm. Laboratory results were within normal range. Mammography re-vealed a solitary, bilobulated, non calcified mass of the left breast. On ultrasound, the lesion was hypo-echoic with blurred edges, with posterior acoustic enhancement, measuring 2 * 3 * 7 * 2 cm. Histological findings of ultrasound-guided fine needle aspiration and core needle biopsy were corre-spondent to diffuse large B-cell lymphoma. Pathohistological report showed cells with CD20+/Bcl- 2+/Bcl-6-/MUM-1+/CD3- imunophenotype. The breast parenchyma was infiltrated with B-cell lym-phoma. After diagnosis was confirmed, radiotherapy was initiated. Repeat ultrasound studies showed complete regression of the left breast lesion as did positron emission tomography- computed tomography (PET/CT) scan three months after therapy. In conclusion, the relapse of lymphoma in the breast is very rare. In patients previously treated for lymphoma, differential diagnosis should always include relapse, although it clinically presents itself as a primary breast cancer. PMID- 26633140 TI - Dose-dependent Hallucinations Due to Baclofen in a Patient with Spastic Cervical Spinal Cord Injury. PMID- 26633141 TI - SBOL Visual: A Graphical Language for Genetic Designs. AB - Synthetic Biology Open Language (SBOL) Visual is a graphical standard for genetic engineering. It consists of symbols representing DNA subsequences, including regulatory elements and DNA assembly features. These symbols can be used to draw illustrations for communication and instruction, and as image assets for computer aided design. SBOL Visual is a community standard, freely available for personal, academic, and commercial use (Creative Commons CC0 license). We provide prototypical symbol images that have been used in scientific publications and software tools. We encourage users to use and modify them freely, and to join the SBOL Visual community: http://www.sbolstandard.org/visual. PMID- 26633142 TI - Cord blood telomere length in Latino infants: relation with maternal education and infant sex. AB - OBJECTIVE: Telomere length (TL) has important consequences for early disease and lifelong health. However, few studies have examined determinants of TL at birth. STUDY DESIGN: Here we test associations between cord blood TL and parental and birth factors associated with exposure to stress and indicative of healthy intrauterine life in Latino infants. We tested associations that were significant in bivariate analysis in a multivariate regression model to identify independent predictors for shorter TL at birth. RESULT: Two novel and independent predictors emerged in our analysis of 54 infants. Female gender was associated with longer TL by ~350 base pairs (adjusted beta-coefficient for male gender=-369.57, (95% confidence interval, -718.21 to (-)20.92), P=0.02); rho=-0.26, P=0.057). Increased maternal high-school education, as indicated by a high-school diploma or additional education beyond high school, was also associated with longer TL, by ~500 base pairs (adjusted beta-coefficient for high-school diploma or greater=505.68 (95% confidence interval, 151.69 to 859.68), P<0.01); rho=0.36, P<0.01). Increasing head circumference trended towards statistical significance in association with longer TL (adjusted beta-coefficient = 7.33; 95% confidence interval -0.52 to 15.18; P=0.07). When we removed all infants who had been exposed to high oxidative stress in pregnancy including those exposed to maternal hypertension, preeclampsia, gestational diabetes, and those who were low birth weight or preterm birth (n=7), increasing birth weight percentile was associated with longer TL (adjusted beta-coefficient=8.04 (95% confidence interval 0.07 to 16.00), P=0.048). CONCLUSION: Shorter TL at birth is associated with being male, low maternal education (less than a high school degree), and a trend towards lower birth weight and head circumference. Given the critical role of long TL in predicting health and disease, these findings contribute to the growing literature attempting to understand determinants of TL. PMID- 26633143 TI - What impact do essential newborn care practices have on neonatal mortality in low and lower-middle income countries? Evidence from Bangladesh. AB - OBJECTIVE: To assess the impact of essential newborn care (ENC) practices on the mortality of neonates delivered at home in Bangladesh. STUDY DESIGN: This study used cross-sectional data from the 2011 Bangladesh Demographic and Health Survey. Adjusted logistic regression model was used to examine the effect of ENC practices on neonatal mortality based on 3190 live-born infants. RESULT: Delayed bathing (72 h after delivery) significantly contributed to reducing neonatal mortality. A significant but counterintuitive relation was observed between the dry cord care and neonatal deaths. CONCLUSION: Neonatal mortality may be reduced through emphasizing delayed bathing. Specific guidelines on the cleanliness of the fabric used to dry and wrap newborns, as well as emphasizing the use of clean delivery kits and initiation of immediate and exclusive breastfeeding, may improve neonatal outcomes. Further, the ENC guidelines in Bangladesh should include the application of topical antiseptics to the cord stump. PMID- 26633144 TI - Empirical estimation of the normative blood pressure in infants <28 weeks gestation using a massive data approach. AB - OBJECTIVE: To determine the expected systolic, mean and diastolic blood pressures at birth and respective rates of change during the first 72 h of life in infants born at <28 weeks estimated gestational age (EGA) with a favorable short-term outcome, defined as survival to 14 days with grade II or less intraventricular hemorrhage (IVH). STUDY DESIGN: Systolic, mean and diastolic blood pressures were continuously sampled at 0.5 Hz via umbilical artery catheter from birth through 72 h. The raw data were aligned by postnatal hour and underwent error correction. For each infant, the mean values of systolic, mean and diastolic blood pressure were calculated for each postnatal hour. The slope and intercept of best-fit line for each of the three blood pressure parameters was then calculated. Infants that received inotropic medications, died in the first 14 days of life, or had IVH grade III or IV were excluded. RESULT: Using 11.9 million valid data points from 35 infants (mean EGA=25.7 +/- 1.5 weeks, mean birth weight=865 +/- 201 g), we found independent associations of African-American race (P<0.01) and a complete course of antenatal steroids (P<0.01) with higher blood pressures at birth and a slower rate of increase. Acute chorioamnionitis was independently associated (P=0.02) with lower blood pressures at birth and a faster rate of increase. EGA and birth weight were not independently predictive of blood pressure parameters. CONCLUSION: We found that (i) the estimated mean blood pressure at birth is ~33 mmHg in a cohort of very preterm infants, (ii) blood pressure gradually increases with postnatal age, (iii) systolic blood pressure increases at a faster rate than diastolic blood pressure, (iv) race, antenatal steroid exposure and chorioamnionitis are independent modulators of blood pressure whereas EGA and birth weight are not. PMID- 26633145 TI - Randomized trial of laryngeal mask airway versus endotracheal intubation for surfactant delivery. AB - OBJECTIVE: To compare the effectiveness of surfactant delivery via endotracheal tube (ETT) using an intubation-surfactant-rapid extubation approach with premedication) vs laryngeal mask airway (LMA) in preventing the need for mechanical ventilation in preterm neonates with moderate respiratory distress syndrome (RDS). STUDY DESIGN: Moderately preterm infants diagnosed with RDS, receiving nasal continuous positive airway pressure with FiO2 0.30 to 0.60, were randomized to two groups at age 3 to 48 h. Those in the ETT group were intubated following premedication with atropine and morphine, whereas the LMA group received only atropine. Both groups received calfactant before a planned reinstitution of nasal continuous positive airway pressure, and had equivalent pre-specified criteria for subsequent mechanical ventilation and surfactant retreatment. The primary outcome was failure of surfactant treatment strategy to avoid mechanical ventilation; we differentiated early from late failures to assess the contribution of potential mechanisms such as respiratory depression versus less-effective surfactant delivery. Secondary outcomes addressed efficacy and safety end points. RESULT: Sixty-one patients were randomized, one excluded and 30 analyzed in each group, with similar baseline characteristics. Failure rate was 77% in the ETT group and 30% in the LMA group (P<0.001). The difference was related to early failure, as late failure rates did not differ between groups. FiO2 decrease after surfactant and rates of adverse events were similar between groups. CONCLUSION: Surfactant therapy through an LMA decreases the proportion of newborns with moderate RDS who require mechanical ventilation, when compared with a standard endotracheal intubation procedure with sedation. The efficacy of surfactant in decreasing RDS severity appears similar with both methods. Morphine premedication likely contributed to early post-surfactant failures. PMID- 26633146 TI - A retrospective comparison of VLBW outcomes before and after implementing new delivery room guidelines at a regional tertiary care center. AB - OBJECTIVE: To evaluate the impact of implemented protocol changes on delivery room interventions and very low birth weight (VLBW) health outcomes. STUDY DESIGN: Retrospective study comparing birth characteristics, interventions and health outcomes of VLBW infants born in a tertiary care center before (calendar years 2008 to 2009) and after (calendar years 2012 to 2013) implementing new protocols using Chi-square analyses. RESULT: Four hundred and nine were born before and 303 after changes were implemented. Postimplementation infants had more use of antenatal steroids (P=0.02), gestational age ?24 weeks (P=0.03) and birth weights between 501 and 750 g (P=0.04) and less oxygen administration (P=0.002), face mask ventilation (P=0.0001), surfactant use (P=0.0001), chest compressions (P=0.0001), intubation (P=0.002), epinephrine use (P=0.011), hypothermia (P=0.0001) and discharges home on supplemental oxygen (P=0.05). CONCLUSION: Changes creating a new delivery team, adopting new delivery practice guidelines and updating delivery room equipment resulted in positive outcomes for delivery room practices and patient outcomes. PMID- 26633147 TI - A retrospective analysis of the effect of human milk on prevention of necrotizing enterocolitis and postnatal growth. AB - OBJECTIVE: The objective of this study is to determine whether the use of donor human milk (DHM) in very low birth weight (VLBW, ?1500 g) neonates in a large neonatal intensive care unit (NICU) affected the rate of necrotizing enterocolitis (NEC) or impacted growth. STUDY DESIGN: This was a retrospective chart review of 550 VLBW neonates following the introduction of DHM as the preferred diet if maternal breast milk (MBM) was not available. Demographics, growth parameters, incidence of NEC or death and days of DHM or MBM were extracted from charts. RESULT: Compared with infants who received human milk (HM) on fewer than 50% of hospital days, neonates who received HM on ?50% of hospital days had equivalent growth outcomes but lower rates of NEC (NEC 3.4 vs 13.5%, P<0.001) and mortality (1.0 vs 4.2%, P=0.017). Growth and NEC rates were inversely correlated with the duration of exposure to HM. CONCLUSION: HM should always be the diet of choice in preterm infants. DHM is a safe alternative, if MBM is not available. Although the use of HM is associated with lower rates of NEC, growth rates were significantly lower in infants with significant HM intake. The decline in growth rates following the introduction of DHM should draw attention to optimize fortification of all HM feedings. PMID- 26633148 TI - Multifaceted role of beta-arrestins in inflammation and disease. PMID- 26633150 TI - Outcomes of a Bystander Intervention Community Health Service-Learning Project. AB - The purpose of this article is to describe the integration of a college bystander intervention service-learning project into an entry-level community clinical course in a prelicensure program and its outcomes. Two years of data from 118 students showed that students helped improve campus safety while growing as professionals and gaining leadership and health promotion skills. Approximately one-third of the students described a specific incident in which they intervened in an ambiguous situation. PMID- 26633149 TI - Organochlorine pesticides (OCPs) in wetland soils under different land uses along a 100-year chronosequence of reclamation in a Chinese estuary. AB - Soil profiles were collected at a depth of 30 cm in ditch wetlands (DWs), riverine wetlands (RiWs) and reclaimed wetlands (ReWs) along a 100-year chronosequence of reclamation in the Pearl River Delta. In total, 16 OCPs were measured to investigate the effects of wetland reclamation and reclamation history on OCP levels. Our results showed that average ?DDTs, HCB, MXC, and ?OCPs were higher in surface soils of DWs compared to RiWs and ReWs. Both D30 and D20 soils contained the highest ?OCP levels, followed by D40 and D100 soils; lower ?OCP levels occurred in D10 soils. Higher ?OCP levels were observed in the younger RiWs than in the older ones, and surface soils exhibited higher ?OCP concentrations in the older ReWs compared with younger ReWs. The predominant percentages of gamma-HCH in ?HCHs (>42%) and aldrin in ?DRINs (>46%) in most samples reflected the recent use of lindane and aldrin. The presence of dominant DDT isomers (p,p'-DDE and p,p'-DDD) indicated the historical input of DDT and significant aerobic degradation of the compound. Generally, DW soils had a higher ecotoxicological risk of OCPs than RiW and ReW soils, and the top 30 cm soils had higher ecotoxicological risks of HCHs than of DDTs. PMID- 26633151 TI - Stimulation of Cauda Equina With a Figure-of-Eight Magnetic Coil. AB - PURPOSE: To record responses in the abductor hallucis muscle after lumbosacral stimulation with a figure-of-eight magnetic coil. To compare magnetic stimulation (MS), electrical stimulation (ES), and the peripheral motor conduction time. METHODS: M and F waves and compound muscle action potentials were recorded after L1 MS, S1 MS, and L1 ES. RESULTS: The compound muscle action potential latency on L1 MS was 26.9 +/- 2.6 milliseconds and on L1 ES was 25.6 +/- 2.2 milliseconds, and the peripheral motor conduction time was 27.0 +/- 2.5 milliseconds (analysis of variance P = 0.0008). The compound muscle action potential amplitude was 12 +/ 11% of M-wave on L1 MS, 32 +/- 18% on S1 MS, and 31 +/- 17% on L1 ES. CONCLUSIONS: Dorsal MS reliably elicits responses in the abductor hallucis muscle. The latency of compound muscle action potentials on L1 MS is comparable to peripheral motor conduction time. A potential drawback of MS may be too weak stimulation at the proximal end of the cauda equina. PMID- 26633152 TI - Foreword. PMID- 26633153 TI - Sepsis and Septic Shock: Lingering Questions. AB - Sepsis and septic shock are major health conditions in the United States, with a high incidence and mortality. The Surviving Sepsis Campaign, which was formed in 2002, formulates guidelines for the management of severe sepsis and septic shock and has actually demonstrated a reduction in mortality with institution of "sepsis bundles." Despite this, some elements of the guidelines have been questioned, and recent data suggest that strict compliance with bundles and protocols may not be necessary. Still, prompt recognition and treatment of sepsis and septic shock remain of utmost importance. PMID- 26633154 TI - Back to Fundamentals: Using High- and Low-Fidelity Simulation to Provide Reinforcement of Preventative Measures for Sepsis. AB - Health care-associated infections result in a staggering number of preventable patient deaths per year. Numerous point-of-practice initiatives and action plans have been implemented, requiring ongoing and continuing education for practicing clinicians. Equally important is the implementation of prevention practices and protocols throughout programs responsible for preparing health care providers. The use of simulation as an experiential form of learning is effective in nursing education as fundamental concepts and best practices in sepsis prevention are repeated and reinforced. PMID- 26633155 TI - Incorporating Interprofessional Evidenced-Based Sepsis Simulation Education for Certified Nursing Assistants (CNAs) and Licensed Care Providers Within Long-term Care Settings for Process and Quality Improvement. AB - Improving resident safety and quality of care by maximizing interdisciplinary communication among long-term care providers is essential in meeting the goals of the United States' Federal Health care reform. The new Triple Aim goals focus on improved patient outcomes, increasing patient satisfaction, and decreased health care costs, thus providing consumers with quality, efficient patient-focused care. Within the United States, sepsis is the 10th leading cause of death with a 28.6% mortality rate in the elderly, increasing to 40% to 60% in septic shock. As a result of the Affordable Care Act, the Centers for Medicare & Medicaid services supported the Interventions to Reduce Acute Care Transfers 3.0 program to improve health care quality and prevent avoidable rehospitalization by improving assessment, documentation, and communication among health care providers. The Interventions to Reduce Acute Care Transfers 3.0 tools were incorporated in interprofessional sepsis simulations throughout 19 long-term care facilities to encourage the early recognition of sepsis symptoms and prompt communication of sepsis symptoms among interdisciplinary teams. As a result of this simulation training, many long-term care organizations have adopted the STOP and WATCH and SBAR tools as a venue to communicate resident condition changes. PMID- 26633156 TI - Don't Go Chasing Waterfalls: Excessive Fluid Resuscitation in Severe Sepsis and Septic Shock. AB - Aggressive fluid resuscitation is the mainstay therapy in modern sepsis management. Its efficacy was demonstrated in the landmark study by Emmanuel Rivers in 2001. However, more recent evidence largely shows that a positive fluid balance increases mortality in critically ill patients with sepsis. This article examines the theoretical benefits of fluid resuscitation and physiological responses to it that may negatively affect patients' outcome. PMID- 26633157 TI - Glycocalyx in Sepsis Resuscitation. AB - Starling's forces are fundamental to our understanding of physiology. Based on his findings, hydrostatic pressure and oncotic pressure are crucial factors in the movement of intravascular and extravascular fluid. However, new literatures on endothelial glycocalyx, a layer of protective glycoprotein within the vasculature that was first discovered in the 1980s, are reshaping our standard models of Starling's forces. This article examines the nature of the endothelial glycocalyx and why understanding it may change the way we resuscitate patients with sepsis. PMID- 26633158 TI - Bathing With 2% Chlorhexidine Gluconate: Evidence and Costs Associated With Central Line-Associated Bloodstream Infections. AB - In a coordinated national effort reported by the Agency for Healthcare Research and Quality, the use of 2% chlorhexidine gluconate (CHG) has reduced the central line-associated bloodstream infection (CLABSI) rate by 40%. Conversely, a recent randomized clinical trial determined that chlorhexidine bathing did not reduce the CLABSI rate. The objectives of this study were to conduct meta-analysis and clarify the effectiveness of 2% CHG bathing by nurses on CLABSIs in adult intensive care unit patients and to determine the contributing costs attributable to CLABSIs and 2% CHG bathing. Eligible studies that included the outcome of bloodstream infection rate for central lines were considered. A rigorous systematic review protocol and software tools available from the Joanna Briggs Institute via OvidSP were used. Agency for Healthcare Research and Quality tools assisted with identifiable CHG bathing costs. Four studies were included in the meta-analysis for the outcome of primary bloodstream infections, and 2 studies narratively supported the meta-analysis. A relative risk of 0.46 with 95% confidence interval (0.34-0.63) was determined. This significant effect is seen in an overall z-score of 4.84 (P < .0001). This meta-analysis supports that 2% CHG reduces CLABSIs. The estimated cost increase of 2% CHG-impregnated cloths is $4.10 versus nonmedicated bathing cloths. The cost associated with a single CLABSI is 10 times more than the cost of using 2% CHG-impregnated cloths. Nursing provides significant influence for the prevention of CLABSIs in critical care via evidence-based best practices. PMID- 26633159 TI - Financial Implications of Sepsis Prevention, Early Identification, and Treatment: A Population Health Perspective. AB - Each day an estimated 2000 to 3000 new cases of sepsis are identified and treated in US hospitals. Despite the enormity of the problem, less than one-half of all US adults have heard of sepsis. This article reviews the financial costs of sepsis in the United States, examining the evidence for its economic impact across both hospitals and nursing homes. A brief description of payment models and government programs to promote more coordinated care between hospitals and nursing homes is provided to highlight areas where advances in sepsis care may be incentivized and sustained in new systems emerging in response to the Affordable Care Act. Finally, the costs of sepsis care to the Medicare program in a specific health care market (Pittsburgh) are estimated to highlight the challenges and opportunities for interorganizational collaborative strategies in value-based models of care delivery. PMID- 26633160 TI - Sepsis Resuscitation: Consensus and Controversies. AB - Sepsis is a malignant intravascular inflammation representing the body's response to overwhelming and life-threatening infection. Sepsis can result in tissue damage, organ failure, and death. Critical care nurses are at the forefront for identifying sepsis and initiating the early goal-directed therapies that are known to improve survival. Among key factors in the successful resuscitation and stabilization of the septic patient are fluid management, establishment and maintenance of a secure airway, judicious use of pharmacological agents, and dynamic adjustments in therapy based on nuances detected in data from clinical monitoring. PMID- 26633161 TI - An Integrative Review of Pain Resource Nurse Programs. AB - Mismanaged pain challenges health care systems. In the early 1990s, pain resource nurse programs were developed by Ferrell and colleagues. Variations of the model have existed for more than 20 years. While results of these programs have been disseminated, conclusive evidence has not been examined via a synthesis of the literature. A structured systematic search using multiple databases was conducted for research studies published 2005-2012. The search identified 11 studies on effective use of a pain resource nurse and/or a pain resource nurse program. The results revealed wide variations existing in program design, research methodology, practice settings, and reported outcomes. Overall, the strength of the evidence on pain resource nurse programs was determined to range from low to moderate quality for making generalizable conclusions. However, 4 key elements were identified as integral to effective pain resource nurse programs and useful for the program design and development: leadership commitment and active involvement in embedding a culture of effective pain management throughout the organization; addressing staff-related and organization-related challenges and barriers to pain management; a combination of strategies to overcome these barriers; and collaborative multidisciplinary teamwork and communication. Specific recommendations are provided for program implementation. Although the evidence was inconclusive, useful information exists to create the design of effective pain resource nurse programs. Collaborative multisite studies on the long-term effects of pain resource nurse programs are recommended. PMID- 26633162 TI - Docking study and biological evaluation of pyrrolidine-based iminosugars as pharmacological chaperones for Gaucher disease. AB - We report on the synthesis and biological evaluation of a series of alpha-1-C alkylated 1,4-dideoxy-1,4-imino-d-arabinitol (DAB) derivatives as pharmacological chaperones for Gaucher disease. The parent compound, DAB, did not show inhibition of human beta-glucocerebrosidase but showed moderate intestinal alpha-glucosidase inhibition; in contrast, extension of alpha-1-C-alkyl chain length gave a series of highly potent and selective inhibitors of the beta-glucocerebrosidase. Our design of alpha-1-C-tridecyl-DAB (5j) produced a potent inhibitor of the beta glucocerebrosidase, with IC50 value of 0.77 MUM. A molecular docking study revealed that the alpha-1-C-tridecyl group has a favorable interaction with the hydrophobic pocket and the sugar analogue part (DAB) interacted with essential hydrogen bonds formed to Asp127, Glu235 and Glu340. Furthermore, alpha-1-C tridecyl-DAB (5j) displayed enhancement of activity at an effective concentration 10-times lower than isofagomine. alpha-1-C-Tridecyl-DAB therefore provides the first example of a pyrrolidine iminosugar as a new class of promising pharmacological chaperones with the potential for treatment of Gaucher disease. PMID- 26633163 TI - Glycemic index, glycemic load and invasive breast cancer incidence in postmenopausal women: The PREDIMED study. AB - The objective of this study was to evaluate the prospective associations between dietary glycemic index (GI) and glycemic load (GL) and the risk for invasive breast cancer incidence in postmenopausal women at high cardiovascular disease (CVD) risk. This study was conducted within the framework of the PREvencion con DIeta MEDiterranea (PREDIMED) study, a nutritional intervention trial for primary cardiovascular prevention. We included 4010 women aged between 60 and 80 years who were initially free from breast cancer but at high risk for CVD disease. Dietary information was collected using a validated 137-item food frequency questionnaire. We assigned GI values using the International Tables of GI and GL values. Cases were ascertained through yearly consultation of medical records and through consultation of the National Death Index. Only cases confirmed by results from cytology tests or histological evaluation were included. We estimated multivariable-adjusted hazard ratios for invasive breast cancer risk across tertiles of energy-adjusted dietary GI/GL using Cox regression models. We repeated our analyses using yearly repeated measures of GI/GL intakes. No associations were found between baseline dietary GI/GL and invasive breast cancer incidence. The multivariable hazard ratio and 95% confidence interval (CI) for the top tertile of dietary GI was 1.02 (95% CI: 0.42-2.46) and for dietary GL was 1.00 (95% CI: 0.44-2.30) when compared with the bottom tertile. Repeated-measures analyses yielded similar results. In sensitivity analyses, no significant associations were observed for women with obesity or diabetes. Dietary GI and GL did not appear to be associated with an increased risk for invasive breast cancer in postmenopausal women at high CVD risk. PMID- 26633164 TI - Diagnosis of prostate cancer by analyzing oxidative stress in human seminal plasma: developing unsophisticated tools for noninvasive prostate cancer diagnosis. AB - Prostate-specific antigen blood testing has improved early detection of prostate cancer (PCa); however, PCa mortality has not decreased accordingly and a prostate biopsy is still required for a definitive diagnosis. Proteomic biomarker screening in easily available body fluids such as seminal plasma is now increasingly being proposed as a solution to improve PCa detection and prognosis. PCa cells typically produce high levels of reactive oxygen species (ROS). In this study, we therefore investigated ROS levels in semen samples from patients with a negative or a positive prostate biopsy to predict PCa diagnosis. Multiple clinicopathological parameters (digital rectal examination, prostate-specific antigen scoring, prostate biopsy, and ROS levels) of patients examined for PCa were measured. No significant differences in ROS levels were detected in relation to PCa diagnosis. Although seminal plasma is a well-suited medium for prostate related biomarkers, no significant differences in ROS levels were observed between the patient groups. Comparison with ROS levels encountered in semen of larger patient groups is the next logical step. PMID- 26633165 TI - Influence of primary care professionals on early detection of breast cancer: different perception between family physicians and nursing professionals. AB - The aim of this study was to assess the level of self-perceived influence on early detection of breast cancer among nurses and family physicians (FP) working in primary care and to identify the factors associated with a lower perception in each group. In the Autonomous Community of Madrid, an online questionnaire on cancer prevention was sent to a random sample of primary care professionals (3586 FP and nurses). The data included sex, age, profession, years in primary care, specific postgraduate training, and opinions and attitudes toward cancer prevention. A descriptive analysis was carried out. Factors associated with a low/null self-perceived influence on early detection of breast cancer were analyzed separately for FP and nurses with multivariate logistic regression models. In all, 76.4% of the participants considered that their influence on the early detection of breast cancer was enough/high. FP attributed to themselves a higher influence than nurses (enough/high: 86.0 vs. 64.6%, P<0.01), and a lower perception was associated with a low/null perceived utility of their individual intervention [odds ratio (OR): 6.42, 95% confidence interval (CI) 2.77-14.85]. Among nurses, also associated with this low/null perceived utility [adjusted odds ratio (aOR): 2.81, 95% CI 1.37-5.77] were the absence of postgraduate training in the matter (aOR: 2.56, 95% CI 1.05-6.25), and a low/null perception of feasibility of prevention programs in their centers (aOR: 1.93, 95% CI 1.25 2.98). Primary care professionals perceive their activity in the early detection of breast cancer as relevant, especially FP. To increase knowledge of the utility of individual interventions, specific training and improvement of the feasibility of these programs could enhance this perception. PMID- 26633166 TI - A Cost-Utility Model of Care for Peristomal Skin Complications. AB - PURPOSE: The aim of this study was to evaluate the economic and humanistic implications of using ostomy components to prevent subsequent peristomal skin complications (PSCs) in individuals who experience an initial, leakage-related PSC event. DESIGN: Cost-utility analysis. METHODS: We developed a simple decision model to consider, from a payer's perspective, PSCs managed with and without the use of ostomy components over 1 year. The model evaluated the extent to which outcomes associated with the use of ostomy components (PSC events avoided; quality-adjusted life days gained) offset the costs associated with their use. RESULTS: Our base case analysis of 1000 hypothetical individuals over 1 year assumes that using ostomy components following a first PSC reduces recurrent events versus PSC management without components. In this analysis, component acquisition costs were largely offset by lower resource use for ostomy supplies (barriers; pouches) and lower clinical utilization to manage PSCs. The overall annual average resource use for individuals using components was about 6.3% ($139) higher versus individuals not using components. Each PSC event avoided yielded, on average, 8 additional quality-adjusted life days over 1 year. CONCLUSIONS: In our analysis, (1) acquisition costs for ostomy components were offset in whole or in part by the use of fewer ostomy supplies to manage PSCs and (2) use of ostomy components to prevent PSCs produced better outcomes (fewer repeat PSC events; more health-related quality-adjusted life days) over 1 year compared to not using components. PMID- 26633167 TI - Gleason Score 6 - Prostate Cancer or Benign Variant? AB - The leading motivation behind wanting to call a 'malignant' prostate lesion 'benign' is the evidence of indolent prostate cancer that is not associated with a fatal outcome and in part makes therapeutic measures such as surgery and radiotherapy appear like overtreatment for some or possibly the majority of such patients. The present article reviews the definitions of 'precancerous lesion' and 'cancer' from a histopathologic point of view as the basis and gold standard for diagnosis. It is clear that with the 2 modifications implemented since its first publication, the Gleason score as the grading system for prostate cancer has shifted towards a low malignant subgroup diagnosed as Gleason 6. The recommendation of the International Society of Urological Pathology to change the Gleason score to a 5-tiered system, starting with grade group 1, is presented here, and may help doctor-patient communication especially in the active surveillance setting. PMID- 26633168 TI - Dual CD4/CD8-positive Ichthyosiform Mycosis Fungoides with Lymph Node, Peripheral Blood and Cardiac Involvement: A Case Report. PMID- 26633169 TI - Telephone Transmission and Earwitnesses: Performance on Voice Parades Controlled for Voice Similarity. AB - The effect of telephone transmission on a listener's ability to recognise a speaker in a voice parade is investigated. A hundred listeners (25 per condition) heard 1 of 5 'target' voices, then returned a week later for a voice parade. The 4 conditions were: target exposure and parade both at studio quality; exposure and parade both at telephone quality; studio exposure with telephone parade, and vice versa. Fewer correct identifications followed from telephone exposure and parade (64%) than from studio exposure and parade (76%). Fewer still resulted for studio exposure/telephone parade (60%) and, dramatically, only 32% for telephone exposure/studio parade. Certain speakers were identified more readily than others across all conditions. Confidence ratings reflected this effect of speaker, but not the effect of exposure/parade condition. PMID- 26633170 TI - The Impact of the Invasive Alien Plant, Impatiens glandulifera, on Pollen Transfer Networks. AB - Biological invasions are a threat to the maintenance of ecological processes, including pollination. Plant-flower visitor networks are traditionally used as a surrogated for pollination at the community level, despite they do not represent the pollination process, which takes place at the stigma of plants where pollen grains are deposited. Here we investigated whether the invasion of the alien plant Impatiens glandulifera (Balsaminaceae) affects pollen transfer at the community level. We asked whether more alien pollen is deposited on the stigmas of plants on invaded sites, whether deposition is affected by stigma type (dry, semidry and wet) and whether the invasion of I. glandulifera changes the structure of the resulting pollen transfer networks. We sampled stigmas of plants on 10 sites invaded by I. glandulifera (hereafter, balsam) and 10 non-invaded control sites. All 20 networks had interactions with balsam pollen, although significantly more balsam pollen was found on plants with dry stigmas in invaded areas. Balsam pollen deposition was restricted to a small subset of plant species, which is surprising because pollinators are known to carry high loads of balsam pollen. Balsam invasion did not affect the loading of native pollen, nor did it affect pollen transfer network properties; networks were modular and poorly nested, both of which are likely to be related to the specificity of pollen transfer interactions. Our results indicate that pollination networks become more specialized when moving from the flower visitation to the level of pollen transfer networks. Therefore, caution is needed when inferring pollination from patterns of insect visitation or insect pollen loads as the relationship between these and pollen deposition is not straightforward. PMID- 26633171 TI - Money Affects Theory of Mind Differently by Gender. AB - Theory of Mind (ToM)--the ability to understand other's thoughts, intentions, and emotions--is important for navigating interpersonal relationships, avoiding conflict, and empathizing. Prior research has identified many factors that affect one's ToM ability, but little work has examined how different kinds of monetary incentives affect ToM ability. We ask: Does money affect ToM ability? If so, how does the effect depend on the structure of monetary incentives? How do the differences depend on gender? We hypothesize that money will affect ToM ability differently by gender: monetary rewards increase males' motivation to express ToM ability while simultaneously crowding out females' motivation. This prediction is confirmed in an experiment that varies the structure of monetary rewards for correct answers in the Reading the Mind in the Eyes Test (RMET). RMET scores decrease for females and increase for males with individual payments, and this effect is stronger with competitively-structured payments. RMET scores do not significantly change when monetary earnings go to a charity. Whether money improves or hinders ToM ability, and, hence, success in social interactions, thus depends on the interaction of gender and monetary incentive structure. PMID- 26633172 TI - Physiologic Stresses Reveal a Salmonella Persister State and TA Family Toxins Modulate Tolerance to These Stresses. AB - Bacterial persister cells are considered a basis for chronic infections and relapse caused by bacterial pathogens. Persisters are phenotypic variants characterized by low metabolic activity and slow or no replication. This low metabolic state increases pathogen tolerance to antibiotics and host immune defenses that target actively growing cells. In this study we demonstrate that within a population of Salmonella enterica serotype Typhimurium, a small percentage of bacteria are reversibly tolerant to specific stressors that mimic the macrophage host environment. Numerous studies show that Toxin-Antitoxin (TA) systems contribute to persister states, based on toxin inhibition of bacterial metabolism or growth. To identify toxins that may promote a persister state in response to host-associated stressors, we analyzed the six TA loci specific to S. enterica serotypes that cause systemic infection in mammals, including five RelBE family members and one VapBC member. Deletion of TA loci increased or decreased tolerance depending on the stress conditions. Similarly, exogenous expression of toxins had mixed effects on bacterial survival in response to stress. In macrophages, S. Typhimurium induced expression of three of the toxins examined. These observations indicate that distinct toxin family members have protective capabilities for specific stressors but also suggest that TA loci have both positive and negative effects on tolerance. PMID- 26633173 TI - A Chemical and Enzymatic Approach to Study Site-Specific Sumoylation. AB - A variety of cellular pathways are regulated by protein modifications with ubiquitin-family proteins. SUMO, the Small Ubiquitin-like MOdifier, is covalently attached to lysine on target proteins via a cascade reaction catalyzed by E1, E2, and E3 enzymes. A major barrier to understanding the diverse regulatory roles of SUMO has been a lack of suitable methods to identify protein sumoylation sites. Here we developed a mass-spectrometry (MS) based approach combining chemical and enzymatic modifications to identify sumoylation sites. We applied this method to analyze the auto-sumoylation of the E1 enzyme in vitro and compared it to the GG remnant method using Smt3-I96R as a substrate. We further examined the effect of smt3-I96R mutation in vivo and performed a proteome-wide analysis of protein sumoylation sites in Saccharomyces cerevisiae. To validate these findings, we confirmed several sumoylation sites of Aos1 and Uba2 in vivo. Together, these results demonstrate that our chemical and enzymatic method for identifying protein sumoylation sites provides a useful tool and that a combination of methods allows a detailed analysis of protein sumoylation sites. PMID- 26633174 TI - Novel Applications for Oxalate-Phosphate-Amine Metal-Organic-Frameworks (OPA MOFs): Can an Iron-Based OPA-MOF Be Used as Slow-Release Fertilizer? AB - A porous iron-based oxalate-phosphate-amine metal-organic framework material (OPA MOF) was investigated as a microbially-induced slow-release nitrogen (N) and phosphorus (P) fertilizer. Seedling growth, grain yields, nutrient uptake of wheat plants, and soil dynamics in incubated soil, were investigated using OPA MOF vs standard P (triple-superphosphate) and N (urea) fertilizers in an acidic Ferralsol at two application rates (equivalent 120 and 40 kg N ha(-1)). While urea hydrolysis in the OPA-MOF treatment was rapid, conversion of ammonium to nitrate was significantly inhibited compared to urea treatment. Reduced wheat growth in OPA-MOF treatments was not caused by N-deficiency, but by limited P bioavailability. Two likely reasons were slow P-mobilisation from the OPA-MOF or rapid P-binding in the acid soil. P-uptake and yield in OPA-MOF treatments were significantly higher than in nil-P controls, but significantly lower than in conventionally-fertilised plants. OPA-MOF showed potential as enhanced efficiency N fertilizer. However, as P-bioavailability was insufficient to meet plant demands, further work should determine if P-availability may be enhanced in alkaline soils, or whether central ions other than Fe, forming the inorganic metal-P framework in the MOF, may act as a more effective P-source in acid soils. PMID- 26633175 TI - Occurrence of Priming in the Degradation of Lignocellulose in Marine Sediments. AB - More than 50% of terrestrially-derived organic carbon (terrOC) flux from the continents to the ocean is remineralised in the coastal zone despite its perceived high refractivity. The efficient degradation of terrOC in the marine environment could be fuelled by labile marine-derived material, a phenomenon known as "priming effect", but experimental data to confirm this mechanism are lacking. We tested this hypothesis by treating coastal sediments with 13C lignocellulose, as a proxy for terrOC, with and without addition of unlabelled diatom detritus that served as the priming inducer. The occurrence of priming was assessed by the difference in lignocellulose mineralisation between diatom amended treatments and controls in aerobic sediment slurries. Priming of lignocellulose degradation was observed only at the initial stages of the experiment (day 7) and coincided with overall high microbial activity as exemplified by total CO2 production. Lignocellulose mineralisation did not differ consistently between diatom treatments and control for the remaining experimental time (days 14-28). Based on this pattern, we hypothesize that the faster initiation of lignocellulose mineralisation in diatom-amended treatments is attributed to the decomposition of accessible polysaccharide components within the lignocellulose complex by activated diatom degraders. The fact that diatom degraders contributed to lignocellulose degradation was also supported by the different patterns in 13C-enrichment of phospholipid fatty acids between treatments. Although we did not observe differences between treatments in the total quantity of respired lignocellulose at the end of the experiment, differences in timing could be important in natural ecosystems where the amount of time that a certain compound is subject to aerobic degradation before burial to deeper anoxic sediments may be limited. PMID- 26633176 TI - Trachoma and Yaws: Common Ground? PMID- 26633177 TI - Modelling Water Uptake Provides a New Perspective on Grass and Tree Coexistence. AB - Root biomass distributions have long been used to infer patterns of resource uptake. These patterns are used to understand plant growth, plant coexistence and water budgets. Root biomass, however, may be a poor indicator of resource uptake because large roots typically do not absorb water, fine roots do not absorb water from dry soils and roots of different species can be difficult to differentiate. In a sub-tropical savanna, Kruger Park, South Africa, we used a hydrologic tracer experiment to describe the abundance of active grass and tree roots across the soil profile. We then used this tracer data to parameterize a water movement model (Hydrus 1D). The model accounted for water availability and estimated grass and tree water uptake by depth over a growing season. Most root biomass was found in shallow soils (0-20 cm) and tracer data revealed that, within these shallow depths, half of active grass roots were in the top 12 cm while half of active tree roots were in the top 21 cm. However, because shallow soils provided roots with less water than deep soils (20-90 cm), the water movement model indicated that grass and tree water uptake was twice as deep as would be predicted from root biomass or tracer data alone: half of grass and tree water uptake occurred in the top 23 and 43 cm, respectively. Niche partitioning was also greater when estimated from water uptake rather than tracer uptake. Contrary to long-standing assumptions, shallow grass root distributions absorbed 32% less water than slightly deeper tree root distributions when grasses and trees were assumed to have equal water demands. Quantifying water uptake revealed deeper soil water uptake, greater niche partitioning and greater benefits of deep roots than would be estimated from root biomass or tracer uptake data alone. PMID- 26633178 TI - Chemotherapy with Gemcitabine and Cisplatin for Advanced Ductal Adenocarcinoma of the Prostate: Clinical Courses of Two Patients. AB - Ductal adenocarcinoma is an unusual variant of adenocarcinoma of the prostate with a poorly understood natural history, and its treatment is not well defined. Ductal adenocarcinoma is often diagnosed at an advanced stage, because no specific tumor markers are known. Docetaxel has been used for acinar adenocarcinoma of the prostate, a common type of prostate cancer, but it is largely ineffective for ductal adenocarcinoma. Earlier studies suggested that the chemotherapy with gemcitabine and cisplatin might be effective for ductal adenocarcinoma. Here we report two patients with ductal adenocarcinoma of the prostate that did not respond to docetaxel, but responded to the gemcitabine/cisplatin chemotherapy. Patient 1 was a 59-year-old man who had lung metastasis despite androgen deprivation therapy with undetectable levels of prostate-specific antigen and who presented with brain metastasis during docetaxel chemotherapy. Pathological examination of the resected brain tumor revealed ductal adenocarcinoma with positive immunostaining for carcinoembryonic antigen. The gemcitabine/cisplatin chemotherapy achieved partial response of the lung metastasis with serum carcinoembryonic antigen levels decreasing from 11.4 ng/mL to 2.9 ng/mL. Patient 2 was a 69-year-old man with lung metastasis. Local progression appeared during androgen deprivation therapy, and the subsequent transurethral biopsy revealed ductal adenocarcinoma with positive immunostaining for neuron-specific enolase. Bone and distant lymph node metastasis appeared despite docetaxel chemotherapy. Six courses of the gemcitabine/cisplatin chemotherapy achieved partial response of metastatic lesions, with serum neuron specific enolase levels decreasing from 118 ng/mL to 2.6 ng/mL. The gemcitabine/cisplatin chemotherapy is a potential option for treatment of advanced ductal adenocarcinoma of the prostate. PMID- 26633179 TI - Clinicopathologica Epidemiological Characteristics and Change Tendencies of Renal Cell Carcinoma in Shanxi Province of China from 2005 to 2014. AB - OBJECTIVES: RCC is the most common solid renal malignancy in adults worldwide. To provide the insight of clinicopathologica epidemiological characteristics and change tendencies of renal cell carcinoma (RCC), 2154 cases were collected from Shanxi Province of China, including diagnose time, age, gender, tumor size, Fuhrman grade, tumor stage, tumor location, local advance or distant metastasis and first symptom from 2005 to 2014. This retrospectively investigation, as its general objective, was to analyze the clinicopathologica epidemiological characteristics and the change tendencies of RCC. METHODS: Between 2005 and 2014, 2154 patients who were diagnosed with RCC in three large tertiary hospitals at Shanxi Province were included. The patients' demographic features, pathological diagnoses and metastatic statuses were analyzed. Statistics methods include the chi-squared test, analysis of variance, Spearman's correlation analysis, Logistic regression and ARIMA modeling. RESULTS: Of the 2154 included patients, the constituent ratio of female /male was 63.1% and 36.9%, with the median age of 57 years old. Fuhrman grade distributions differed significantly between males and females (p = 0.024). Also, a significant difference in tumor size was found by different clinical stages (p < 0.001), with a linear correlation (p < 0.001). Moreover, Spearman's analysis indicated tumor grade has a negative correlation with female (p = 0.009) and a positive correlation with tumor size (p = 0.000). It was found that the tumor diameter is bigger in the left side (p = 0.022). Furthermore, the metastasis rate was higher in the bigger tumor (p < 0.001) and the left-sided tumors (p = 0.027). Logistic regression also showed that tumor size is a risk factor for metastasis (OR = 1.724). The risk of local advance or distant metastasis in the left kidney was 1.6-fold greater than that of the right kidney. From 2005 to 2014 the number of RCC cases gradually increased (mainly for pathological grade II and III, but grade I and IV), while the average tumor size decreased, showing the severity increase mildly. Base on the results of a time series analysis-prediction the average RCC size would continue to decrease from the first quarter of 2015 to the fourth quarter of 2016. CONCLUSIONS: The cases of RCC increased from 2005 to 2014 with clear cell type as the main pathological type in this population. The characteristics in the constituent ratios of the RCC vary depending on gender, pathological grade, tumor size, and location, which may be the important factors impacting treatment and prognosis. PMID- 26633180 TI - VdCYC8, Encoding CYC8 Glucose Repression Mediator Protein, Is Required for Microsclerotia Formation and Full Virulence in Verticillium dahliae. AB - Verticillium dahliae is the primary causal agent for Verticillium wilt disease on a diverse array of economically important crops, including cotton. In previous research, we obtained the low-pathogenicity mutant T286 from the T-DNA insertional mutant library of the highly virulent isolate Vd080 derived from cotton. In this study, the target disrupted gene VdCYC8 was identified by TAIL PCR, encoding a homolog of CYC8 proteins involved in glucose repression. The deletion mutant DeltaCYC8 exhibited several developmental deficiencies, including reduced microsclerotia formation, reduced sporulation, and slower growth. Moreover, compared with the wild type strain Vd080, the pathogenicity of strain DeltaCYC8 was significantly decreased on cotton seedlings. However, the complementary mutants DeltaCYC8-C led to restoration of the wild type phenotype or near wild type levels of virulence on cotton. Interestingly, pathogenicity of the strains was correlated with VdCYC8 gene expression levels in complemented mutants. Gene expression analyses in the wild type strain Vd080, the DeltaCYC8-45 strain, and complemented strain DeltaCYC8-C26 indicated that VdCYC8 regulates the transcription levels of several genes in V. dahliae that have roles in melanin and production. PMID- 26633181 TI - PD-L1 Blockade Differentially Impacts Regulatory T Cells from HIV-Infected Individuals Depending on Plasma Viremia. AB - Blocking the PD-1/PD-L1 pathway has emerged as a potential therapy to restore impaired immune responses in human immunodeficiency virus (HIV)-infected individuals. Most reports have studied the impact of the PD-L1 blockade on effector cells and neglected possible effects on regulatory T cells (Treg cells), which play an essential role in balancing immunopathology and antiviral effector responses. The aim of this study was to define the consequences of ex vivo PD-L1 blockade on Treg cells from HIV-infected individuals. We observed that HIV infection led to an increase in PD-1+ and PD-L1+ Treg cells. This upregulation correlated with disease progression and decreased under antiretroviral treatment. Treg cells from viremic individuals had a particularly high PD-1 expression and impaired proliferative capacity in comparison with Treg cells from individuals under antiretroviral treatment. PD-L1 blockade restored the proliferative capacity of Treg cells from viremic individuals but had no effect on its suppressive capacity. Moreover, it increased the viral production in cell cultures from viremic individuals. This increase in viral production correlated with an increase in Treg cell percentage and a reduction in the CD4/Treg and CD8/Treg cell ratios. In contrast to the effect of the PD-L1 blockade on Treg cells from viremic individuals, we did not observe a significant effect on the proliferative capacity of Treg cells from individuals in whom viremia was controlled (either spontaneously or by antiretroviral treatment). However, PD-L1 blockade resulted in an increased proliferative capacity of HIV-specific-CD8 T cells in all subjects. Taken together, our findings suggest that manipulating PD L1 in vivo can be expected to influence the net gain of effector function depending on the subject's plasma viremia. PMID- 26633182 TI - Hepatic Ultrasonography for Surveillance in Patients With Uveal Melanoma. AB - IMPORTANCE: There is a lack of information regarding the role of systemic surveillance in patients with primary uveal melanoma. OBJECTIVE: To evaluate the utility of serial hepatic ultrasonography (USG) for detection of asymptomatic liver metastases in patients undergoing surveillance after primary treatment of uveal melanoma. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study reviewing data from patients with primary uveal melanoma treated between October 2003 and October 2012 at a multispecialty tertiary care center. Patients were managed using a standardized protocol. Initial staging was done with contrast enhanced computed tomography of the chest, abdomen, and pelvis. This was followed by periodic surveillance with hepatic USG and liver function tests scheduled every 6 months for the first 5 years and annually thereafter. Abnormal surveillance hepatic USG findings were categorized as (1) cyst or hemangioma, (2) indeterminate lesion, (3) suspicious for metastasis, or (4) consistent with metastasis. If indicated, hepatic USG abnormalities were confirmed by additional imaging modalities (confirmatory scans) such as computed tomography or magnetic resonance imaging. Liver biopsy was performed only if the confirmatory scan was positive. MAIN OUTCOMES AND MEASURES: Sensitivity, specificity, and positive predictive value of hepatic USG for detecting asymptomatic liver metastases. RESULTS: In 263 patients (121 men, 142 women; mean [SD] age at diagnosis, 61.1 [13.9] years), a total of 1390 hepatic USGs were performed, with a mean of 5.3 per patient (range, 1-17 per patient). Overall, 86 hepatic USGs of 71 patients (27%) were reported as abnormal. Of the 13 lesions identified as a cyst/hemangioma and 17 as indeterminate, 1 was found to be metastatic in each group (8% and 6%, respectively). Of 36 patients with findings suspicious for metastasis, 23 (64%) had metastasis confirmed. All 5 patients (100%) with findings consistent with metastasis had biopsy-proven metastasis. The sensitivity, specificity, and positive predictive value of hepatic USG for findings that were indeterminate or suspicious for metastasis were 96% (95% CI, 80%-99%), 88% (95% CI, 83%-91%), and 45% (95% CI, 33%-59%), respectively. Specificity of the confirmatory scan was greater than that of hepatic USG (93% [95% CI, 89%-96%] vs 88% [95% CI, 83%-91%], respectively; P < .001). Only 4 of 30 patients (13%) with metastasis had abnormal findings on simultaneous liver function tests. CONCLUSIONS AND RELEVANCE: A stepwise surveillance protocol based on serial hepatic USGs followed by confirmatory scans offers high likelihood of detecting asymptomatic metastases in patients with primary uveal melanoma. PMID- 26633183 TI - Correction: A New Extension of the Binomial Error Model for Responses to Items of Varying Difficulty in Educational Testing and Attitude Surveys. PMID- 26633184 TI - Ipilimumab Therapy in Patients With Advanced Melanoma and Preexisting Autoimmune Disorders. AB - IMPORTANCE: Ipilimumab and other immune therapies are effective treatment options for patients with advanced melanoma but cause frequent immune-related toxic effects. Autoimmune diseases are common, and the safety and efficacy of ipilimumab therapy in patients with preexisting autoimmune disorders is not known. OBJECTIVE: To determine the safety and efficacy of ipilimumab therapy in patients with advanced melanoma with preexisting autoimmune disorders. DESIGN, SETTING, AND PARTICIPANTS: Retrospective review of patients with advanced melanoma and preexisting autoimmune disorders who received ipilimumab at 9 academic tertiary referral centers from January 1, 2012, through August 1, 2015. The data analysis was performed on August 24, 2015. EXPOSURE: Ipilimumab therapy. MAIN OUTCOMES AND MEASURES: Safety, in terms of frequency of autoimmune flares and conventional immune-related adverse events (irAEs), and efficacy, in terms of response rates and overall survival, were evaluated descriptively. RESULTS: Of the 30 patients who received ipilimumab (17 [57%] male; median [range] age, 59.5 [30-80] y), 6 had rheumatoid arthritis, 5 had psoriasis, 6 had inflammatory bowel disease, 2 had systemic lupus erythematosus, 2 had multiple sclerosis, 2 had autoimmune thyroiditis, and 7 had other conditions. Thirteen patients (43%) were receiving immunosuppressive therapy at the time of initiation of ipilimumab therapy, most commonly low-dose prednisone or hydroxychloroquine. With ipilimumab treatment, 8 patients (27%) experienced exacerbations of their autoimmune condition necessitating systemic treatment; all were managed with corticosteroids. Conventional grade 3 to 5 irAEs occurred in 10 patients (33%) and were reversible with corticosteroids or with infliximab therapy in 2 cases. One patient with baseline psoriasis died of presumed immune-related colitis after a 1-week delay prior to reporting symptoms. Fifteen patients (50%) had neither autoimmune disease flares nor irAEs. Six patients experienced an objective response (20%), including 1 with a durable complete response. CONCLUSIONS AND RELEVANCE: To our knowledge, this is the largest series of patients with preexisting autoimmune disease treated with immune checkpoint inhibitors. Ipilimumab was clinically active and was associated with exacerbations of autoimmune disease and conventional ipilimumab-induced irAEs that were readily manageable with standard therapies when started in a timely fashion. Ipilimumab therapy may be considered in this setting with vigilant clinical monitoring. PMID- 26633185 TI - Serum levels of granzyme B decrease in patients with rheumatoid arthritis responding to abatacept. AB - OBJECTIVES: A possible role of granzyme B (GZMB) in the pathogenesis of joint erosions in rheumatoid arthritis (RA) has been suggested. Since CD28neg T-cells may be an important source of GZMB, and we have previously shown that co stimulation blockade by abatacept can prevent the generation of the CD28neg T cell populations, we evaluated the effect of abatacept therapy on GZMB serum levels in patients with RA. METHODS: The serum levels of GZMB were evaluated by an indirect solid-phase enzyme immunoassay before the start of treatment with abatacept (T0) in 53 patients with RA and after 6 months of therapy (T6) in 25 patients. RESULTS: At T0, GZMB serum levels were correlated with disease activity measured by DAS28-CRP (p=0.0022) and percentages of circulating CD4+CD28neg and CD8+CD28neg T-cells (p=0.007; p=0.031). The levels of GZMB in 18 patients with a moderate or good EULAR clinical response to ABA significantly decreased from T0 to T6 (p=0.023), whereas no variation was observed in 7 non responders. The variation of GZMB levels was directly correlated with that of DAS28-PCR (p=0.040), but not with those of circulating CD28-neg T-cell subsets. CONCLUSIONS: Costimulation blockade by ABA can decrease the serum levels of GZMB in RA patients responding to the treatment, suggesting that this might be one of the mechanism by which abatacept can prevent radiographic erosions. However, the lack of correlation of such decrease with the numbers of circulating CD28-neg T cells suggests that these cells probably are not the main source of serum GZMB. PMID- 26633186 TI - Addressing Saddle Nose Deformity. PMID- 26633188 TI - Treatment of neonates with meconium aspiration syndrome by proportional assist ventilation and synchronized intermittent mandatory ventilation: a comparison study. AB - BACKGROUND: This study aimed to compare the relevant clinical parameters of neonates with MAS who are supported by proportion assisted ventilation (PAV) and synchronized intermittent mandatory ventilation (SIMV). METHODS: Forty neonates diagnosed as MAS who required mechanical ventilation were divided randomly into PAV group and SIMV group (N.=20). The respiratory rate (RR), heart rate (HR), peak inspiratory pressure (PIP), mean arterial blood pressure (MABP), arterial-to alveolar oxygen tension ratio (a/APO2), fraction of inspiration oxygen (FiO2), mean airway pressure (MAP) and tidal volume (VT) were measured before the ventilation, 1,12, 24, 48 hours after the ventilation and before weaning. RESULTS: We observed no significant differences in the mechanical ventilation time, oxygen supply time, hospital stay between PAV and SIMV groups. In addition, we found no significant differences in HR, MABP, a/APO2 and FiO2 at every time point between two groups (P>0.05). However, we observed significant differences in RR, MAP, PIP and VT at every time point between two groups (P<0.05). CONCLUSIONS: PAV and SIMV might be a useful ventilator mode to support the neonates with MAS who require ventilation. To achieve the same effect, PAV adopts rapid shallow breathing pattern, with smaller tidal volume and lower MAP and PIP. PMID- 26633189 TI - Clinical analysis of perioperative nursing of coarctation of the aorta. AB - AIM: To explore the treatment experience of the perioperative nursing of coarctation of the aorta. METHODS: From June 2012 to December 2013, a total of 15 Children diagnosed with coarctation of the aorta were retrospectively studied and sorted into the observation group in our hospital. Also, 12 children admitted between January 2010 and December 2012 was sorted into control group. Combined intravenous anesthesia and cardiopulmonary bypass were conducted on all the children. Children in observation group underwent perioperative nursing, including preoperative nursing (evaluating disease conditions, improving pre operative preparation and pre-operative discussion) and postoperative nursing (transferred into ICU, respiratory management, circulation system management, nutrition support nursing, using intravenous drugs). Children in the control group were treated with common nursing. Clinical effects of both groups were compared. RESULTS: 14 out of 15 cases in the treatment group were cured and discharged from the hospital after a 6~12-month follow-up. All patients had good prognosis, except one case quit the treatment and left hospital for obstinate low output syndrome. CONCLUSION: With the improvement in the skills of a repair operation, extracorporeal circulation and monitoring as well as nursing, the restenosis incident rate and morality rate were effectively reduced. Meanwhile, taking an initiative for comprehensive prevention nursing measures during peri operation is an important guarantee to a successful operation and prognosis. PMID- 26633187 TI - Arthropod Distribution in a Tropical Rainforest: Tackling a Four Dimensional Puzzle. AB - Quantifying the spatio-temporal distribution of arthropods in tropical rainforests represents a first step towards scrutinizing the global distribution of biodiversity on Earth. To date most studies have focused on narrow taxonomic groups or lack a design that allows partitioning of the components of diversity. Here, we consider an exceptionally large dataset (113,952 individuals representing 5,858 species), obtained from the San Lorenzo forest in Panama, where the phylogenetic breadth of arthropod taxa was surveyed using 14 protocols targeting the soil, litter, understory, lower and upper canopy habitats, replicated across seasons in 2003 and 2004. This dataset is used to explore the relative influence of horizontal, vertical and seasonal drivers of arthropod distribution in this forest. We considered arthropod abundance, observed and estimated species richness, additive decomposition of species richness, multiplicative partitioning of species diversity, variation in species composition, species turnover and guild structure as components of diversity. At the scale of our study (2 km of distance, 40 m in height and 400 days), the effects related to the vertical and seasonal dimensions were most important. Most adult arthropods were collected from the soil/litter or the upper canopy and species richness was highest in the canopy. We compared the distribution of arthropods and trees within our study system. Effects related to the seasonal dimension were stronger for arthropods than for trees. We conclude that: (1) models of beta diversity developed for tropical trees are unlikely to be applicable to tropical arthropods; (2) it is imperative that estimates of global biodiversity derived from mass collecting of arthropods in tropical rainforests embrace the strong vertical and seasonal partitioning observed here; and (3) given the high species turnover observed between seasons, global climate change may have severe consequences for rainforest arthropods. PMID- 26633190 TI - Tele-rehabilitation in developmental dyslexia: methods of implementation and expected results. AB - : Developmental Dyslexia is a disorder, highly frequent in the school population, for which the recommended rehabilitation procedures are not well defined. This study aimed to automatize reading decoding skills by using an innovative system for rehabilitation, based on a tele- rehabilitation method. It requires an intensive home-exercise with the supervision, by web, of the clinician. The study had three main aims: to diffuse knowledge on new methods for rehabilitation of reading difficulties; to verify whether an intensive and simplified exercise, targeted to the automation of reading, is suitable for different subgroups of dyslexic children; to define the treatment effects on basic cognitive functions underlying reading. METHODS: 25 children, grouped according to the neuropsychological and anamnestic profiles, took part to the treatment by the software Reading Trainer(r). RESULTS: Both speed and accuracy of reading decoding increased significantly after treatment, independently from the functional neuropsychological profile or the history of oral language delay. These changes were specific to decoding and not associated with improvements in reading comprehension or spelling skills. However, there was a "cascade effect" of the treatment efficacy on those basic cognitive functions considered precursors of the ability to read, with significant improvements in rapid lexical access, phonological processing and visual attention. CONCLUSIONS: This study provides information on the efficacy of new tools for tele-rehabilitation of specific reading disorders. PMID- 26633192 TI - Microscopic Investigation of Grain Boundaries in Organolead Halide Perovskite Solar Cells. AB - Grain boundaries (GBs) play an important role in organic-inorganic halide perovskite solar cells, which have generally been recognized as a new class of materials for photovoltaic applications. To definitely understand the electrical structure and behavior of GBs, here we present Kelvin probe force microscopy and conductive atomic force microscopy (c-AFM) measurements of both typical and inverted planar organolead halide perovskite solar cells. By comparing the contact potential difference (CPD) of these two devices in the dark and under illumination, we found that a downward band bending exists in GBs that predominantly attract photoinduced electrons. The c-AFM measurements observed that higher photocurrents flow through GBs when a low bias overcomes the barrier created by the band bending, indicating that GBs act as effective charge dissociation interfaces and photocurrent transduction pathways rather than recombination sites. PMID- 26633191 TI - A Qualitative Study of Prescription Contraception Use: The Perspectives of Users, General Practitioners and Pharmacists. AB - BACKGROUND: The oral contraceptive pill (OCP) remains the most popular form of prescription contraception in many countries, despite adherence difficulties for many. Uptake of long acting reversible contraceptives (LARCs), which are less reliant on user adherence, remains low. The aim of this study was to explore the experiences of, and attitudes towards, prescription contraception amongst samples of contraception users, general practitioners (GPs) and pharmacists. METHODOLOGY AND FINDINGS: We conducted a qualitative study using semi-structured interviews with 18 contraception users, 18 GPs and 9 pharmacists. The study took place in Galway, Republic of Ireland between June and September 2014. Thematic analysis was used to analyse the data. Overall, contraception users were more familiar with the OCP, and all the women interviewed began their prescription contraception journey using this method. All participants identified episodes of poor adherence throughout the reproductive life course. The identified barriers for use of LARCs were lack of information, misconceptions, lack of access and high cost. In contrast, GPs believed that adherence to the OCP was good and stated they were more likely to prescribe the OCP than other methods, as they were most familiar with this option. Barriers to prescribing LARCSs were time, cost to practice, training and deskilling. Pharmacists also believed that adherence to the OCP was generally good and that their role was limited to dispensing medication and providing information when asked. DISCUSSION AND CONCLUSION: There are contrasting perspectives between contraception service providers and contraceptive users. Training for healthcare providers is required to support informed contraceptive choice and adherence. It is necessary to address the practice barriers of cost and lack of time, to promote better communication around adherence issues and prescription contraception options. There is a need for more easily-accessible public health information to promote awareness on all methods of prescription contraception. PMID- 26633193 TI - Random Tagging Genotyping by Sequencing (rtGBS), an Unbiased Approach to Locate Restriction Enzyme Sites across the Target Genome. AB - Genotyping by sequencing (GBS) is a restriction enzyme based targeted approach developed to reduce the genome complexity and discover genetic markers when a priori sequence information is unavailable. Sufficient coverage at each locus is essential to distinguish heterozygous from homozygous sites accurately. The number of GBS samples able to be pooled in one sequencing lane is limited by the number of restriction sites present in the genome and the read depth required at each site per sample for accurate calling of single-nucleotide polymorphisms. Loci bias was observed using a slight modification of the Elshire et al. METHOD: some restriction enzyme sites were represented in higher proportions while others were poorly represented or absent. This bias could be due to the quality of genomic DNA, the endonuclease and ligase reaction efficiency, the distance between restriction sites, the preferential amplification of small library restriction fragments, or bias towards cluster formation of small amplicons during the sequencing process. To overcome these issues, we have developed a GBS method based on randomly tagging genomic DNA (rtGBS). By randomly landing on the genome, we can, with less bias, find restriction sites that are far apart, and undetected by the standard GBS (stdGBS) method. The study comprises two types of biological replicates: six different kiwifruit plants and two independent DNA extractions per plant; and three types of technical replicates: four samples of each DNA extraction, stdGBS vs. rtGBS methods, and two independent library amplifications, each sequenced in separate lanes. A statistically significant unbiased distribution of restriction fragment size by rtGBS showed that this method targeted 49% (39,145) of BamH I sites shared with the reference genome, compared to only 14% (11,513) by stdGBS. PMID- 26633194 TI - RAB-10 Regulates Dendritic Branching by Balancing Dendritic Transport. AB - The construction of a large dendritic arbor requires robust growth and the precise delivery of membrane and protein cargoes to specific subcellular regions of the developing dendrite. How the microtubule-based vesicular trafficking and sorting systems are regulated to distribute these dendritic development factors throughout the dendrite is not well understood. Here we identify the small GTPase RAB-10 and the exocyst complex as critical regulators of dendrite morphogenesis and patterning in the C. elegans sensory neuron PVD. In rab-10 mutants, PVD dendritic branches are reduced in the posterior region of the cell but are excessive in the distal anterior region of the cell. We also demonstrate that the dendritic branch distribution within PVD depends on the balance between the molecular motors kinesin-1/UNC-116 and dynein, and we propose that RAB-10 regulates dendrite morphology by balancing the activity of these motors to appropriately distribute branching factors, including the transmembrane receptor DMA-1. PMID- 26633195 TI - Hepatitis B immune status in adolescents vaccinated during infancy: A retrospective cohort study from a pediatric practice in Germany. AB - In Germany, vaccination of infants against hepatitis B is recommended since 1995. However, data on long-term immunity is sparse and the necessity of a booster dose remains uncertain. Aims of this study were to assess the long-term persistence of antibodies to the hepatitis B surface antigen (anti-HBs) after immunization during infancy and the effect of a subsequent hepatitis B booster vaccination during adolescence on anti-HBs levels. Patients from a private pediatric practice who had received a full vaccination course of hepatitis B as infants and who were quantitatively tested for anti-HBs during adolescence (pre-booster levels) were included. In those participants who received a hepatitis B booster, post-booster anti-HBs levels were measured. Univariate analyses were conducted to determine factors associated with pre- and post-booster anti-HBs levels, respectively. 106 participants (53% male) were included in the study. At an average of 13.7 y after primary vaccination, 14% of participants had an anti-HBs level of >=100 IU/l, while 46% were at 10-99 IU/l and 40% had anti-HBs levels of <10 IU/l. In total, 34 received a booster vaccination. Of those, 97% (33/34) had post-booster anti HBs levels >= 100 IU/l, which were independent from pre-booster levels. No other patient characteristics were associated with pre-booster or post-booster anti HBs>= 100 IU/l. Although almost half of study participants showed low anti-HBs levels at follow-up, robust responses to booster vaccination suggest that adolescents who received the full vaccination course during infancy are still protected against hepatitis B infection. PMID- 26633196 TI - Polymorphisms of anti-Mullerian hormone signaling pathway in healthy Singapore women: population differences, endocrine effects and reproductive outcomes. AB - In order to study the association of genetic polymorphisms of anti-Mullerian hormone (AMH) signaling pathway with endocrine changes and pregnancy outcomes, a total of 213 women of reproductive ages were recruited according to our inclusion and exclusion criteria between November 2011 and September 2014 in Singapore. Genotyping studies were performed using a minor groove binder primer/probe Taqman assay. The allele frequencies of the AMH Ile(49)Ser and AMHR2 -482A > G polymorphisms were analyzed in relation to female reproductive hormone levels, ovarian parameters, menstrual cycle lengths and pregnancy outcomes. AMH Ser allele frequency and AMHR2 G allele frequency of our Singapore population were compared with those of other populations reported in HapMap. The genotype distributions and allele frequencies for the AMH Ile(49)Ser and AMHR2 -482A > G polymorphisms were not associated with estradiol (E2) levels, ovarian parameters, menstrual cycle length, or pregnancy outcomes in our cohort. Our findings suggest that genetic variants in the AMH signal transduction pathway have population differences but do not appear to have significant effects on ovarian, endocrine, metabolic parameters and reproductive outcomes. PMID- 26633197 TI - Hypertension Prevalence and Control Among Adults: United States, 2011-2014. AB - KEY FINDINGS: Hypertension is a public health challenge in the United States because it directly increases the risk for cardiovascular disease (1). National and regional health initiatives, including Healthy People 2020, the Million Hearts Initiative, and the Community Preventive Services Task Force, have sought to increase public awareness of the health benefits of improving blood pressure control (2-4). This report presents updated estimates for the prevalence and control of hypertension in the United States for 2011-2014. PMID- 26633198 TI - Dynamic Formation and Breaking of Disulfide Bonds in Molecular Dynamics Simulations with the UNRES Force Field. AB - Many proteins contain disulfide bonds that are usually essential for maintaining function and a stable structure. Several algorithms attempt to predict the arrangement of disulfide bonds in the context of protein structure prediction, but none can simulate the entire process of oxidative folding, including dynamic formation and breaking of disulfide bonds. In this work, a potential function developed to model disulfide bonds is coupled with the united-residue (UNRES) force field, and used in both canonical and replica exchange molecular dynamics simulations to produce complete oxidative folding pathways. The potential function is obtained by introducing a transition barrier that separates the bonded and nonbonded states of the half-cystine residues. Tests on several helical proteins show that improved predictions are obtained when dynamic disulfide-bond formation and breaking are considered. The effect of the disulfide bonds on the folding kinetics is also investigated, particularly their role in stabilizing folding intermediates, resulting in slower folding. PMID- 26633199 TI - Theoretical Investigation of Tautomeric Equilibria for Isonicotinic Acid, 4 Pyridone, and Acetylacetone in Vacuo and in Solution. AB - Tautomeric equilibria have been theoretically calculated for isonicotinic acid (neutral and zwitterionic forms), the 4-pyridone/4-hydroxypyridine system, and the keto-enol transformation for acetylacetone in vacuo and in tetrahydrofuran, methanol, and water solvents. Solvent, basis set, and cavity model effects have been studied in the integral equation formalism for the polarizable continuum model (IEF-PCM)/B3LYP framework, as well as the effect of the procedure, CHELPG or RESP, applied in fitting atomic charges to the in-solution molecular electrostatic potential (ELPO). The in-solution optimized geometries obtained at the IEF-PCM/B3LYP/6-31G* and 6-311++G** levels differ moderately but deviate from their gas-phase counterparts. Atomic charges fitted to the in-solution ELPO show small variations in the considered solvents, as well as when the united-atom cavity model, or a model with explicit consideration of polar hydrogens and scaled Bondi radii, has been applied. In contrast, the fitting procedure considerably affects the derived charges producing more separated atomic charges when the CHELPG rather than the RESP procedure is utilized. The fitted charges increase up to 20% in absolute value when the basis set is enlarged from 6-31G* to 6-311++G** in the IEF-PCM/B3LYP calculations. The relative free energy, calculated as DeltaGtot = DeltaEint + DeltaG(solv) + DeltaGthermal + (symmetry correction), in an ab initio/density funtional theory (DFT) + free energy perturbation (FEP)/Monte Carlo (MC) approximation strongly depends on the accepted value for the relative internal energy, DeltaEint, of the tautomers. DeltaEint is to be calculated at the IEF-PCM/QCISD(T)/cc-pVTZ//IEF-PCM/B3LYP/6 31G* level for the isonicotinic acid tautomers for producing relative free energies in aqueous solution close to experimental values. In other solvents, for this system and for the other two tautomeric equilibria, calculation of DeltaEint at the IEF-PCM/B3LYP/6-31G* level produces DeltaGtot in agreement up to 1 kcal/mol with the experimental values. FEP/MC DeltaG(solv) calculations provide robust results with RESP charges derived by a fit to the in-solution ELPO generated at the IEF-PCM/B3LYP/6-31G* level. Molecular dynamics simulations pointed out that isonicotinic acid forms a dimeric zwitterion in tetrahydrofuran, in contrast to what happens in aqueous solution, and this structural peculiarity was interpreted as the reason for the failure of the ab initio/DFT + FEP/MC method in this particular solution. PMID- 26633200 TI - Factors Contributing to the Accuracy of Harmonic Force Field Calculations for Water. AB - An analysis of the major factors affecting the accuracy of harmonic force field computations of water is presented. By systematically varying the level of approximation in the basis set, treatment of electron correlation, core electron correlation, and relativistic correction, the underlying sources of error in the computation of harmonic vibrational frequencies for water were quantified. The convergence error due to wavefunction description with a cc-pVQZ basis set in the absence of electron correlation was 1.6 cm(-1), as determined from extending the Hartree-Fock computations to larger basis sets. The convergence error due to neglecting higher-order electronic correlation terms than are included at the CCSD(T) level using the cc-pVTZ basis set was estimated to be 4.7 cm(-1), as determined from frequency calculations up to CCSDTQ for water and literature results up to CCSDTQP for diatomic molecules. The convergence error due to omitting higher-order diffuse functions than included in aug-cc-pVQZ was found to be 3.7 cm(-1), as determined by adding more diffuse functions in larger basis sets. The error associated with neglecting core electron correlation effects (i.e., "freezing" core electrons) was 5.0 cm(-1) and with neglecting relativistic effects was 2.2 cm(-1). Due to a cancellation among these various sources of error, the harmonic frequencies for H2O computed using the CCSD(T)/aug-cc-pVQZ model chemistry were on average within 2 cm(-1) of experimentally inferred vibrational frequencies. PMID- 26633201 TI - Comparison of Semiempirical ZILSH and DFT Calculations of Exchange Constants in the Single Molecule Magnet [Fe8O2(OH)12(tacn)6](8.). AB - The exchange constants describing magnetic interactions between high spin Fe(3+) ions in the complex [Fe8O2(OH)12(tacn)6](8+) have been estimated with the semiempirical ZILSH method, and the results compared to those of DFT calculations and experimental magnetic studies. The ZILSH method provides more accurate estimates of the exchange constants than the DFT calculations, particularly for the "body-body" interaction within the central Fe4 "butterfly" unit of the complex. This interaction is found to be antiferromagnetic, which contrasts with the DFT description but is in agreement with experimental studies on smaller Fe4 butterfly complexes and known empirical correlations between exchange constants and structural parameters. The ground-state wavefunction obtained by diagonalizing the Heisenberg spin Hamiltonian matrix has a spin of ten, in agreement with previous experimental and theoretical studies. Spin alignments in the ground state demonstrate how spin frustration can lead to nonzero spin in complexes with exclusively antiferromagnetic exchange interactions. PMID- 26633202 TI - Lone-Pair Orientation Effect of an alpha-Oxygen Atom on (1)JCC NMR Spin-Spin Coupling Constants in o-Substituted Phenols. Experimental and DFT Study. AB - The well-known N lone-pair orientation effect on (1)JCC spin-spin coupling constants (SSCCs) in oximes and their derivatives was used to study how negative hyperconjugative interactions of type LP1(O) -> sigma*CC depend on ortho interactions involving the OH group. This study demanded the following analyses: (i) a qualitative estimation of how (1)JCC SSCCs are affected by hyperconjugative interactions, (ii) a study of similar stereochemical effects to those in oximes, but in (1)JC1C2 and (1)JC1C6in a series of 2-substituted phenols, and (iii) a quantitative estimation, with the natural bond order approach, of some key electron delocalization interactions. A few unexpected results are quoted. LP1(O) -> sigma*CC interactions are affected by proximity interactions as follows: (a) they are enhanced by hydrogen bonds transferring charge into the (O-H)* antibonding orbital; (b) they are enhanced by proximity interactions of type LP1(O)...H-C; (c) they are inhibited by interactions of type LP(O1)...H-O. Consequences of these observations are discussed. PMID- 26633203 TI - Extension of the Core-Valence-Rydberg B3LYP Functional to Core-Excited-State Calculations of Third-Row Atoms. AB - A modified core-valence-Rydberg Becke's three-parameter exchange (B3) + Lee-Yang Parr (LYP) correlation (CVR-B3LYP) functional is proposed in order to calculate core-excitation energies of third-row atoms with reasonable accuracy. The assessment of conventional exchange-correlation functionals shows that the appropriate portions of Hartree-Fock (HF) exchange for core-excited-state calculations depend on shells: 70% and 50% for K-shell and L-shell excitations, respectively. Therefore, the modified CVR-B3LYP functional is designed to use the appropriate portions of HF exchange, 70%, 50%, and 20%, for K-shell, L-shell, and valence regions separately. Time-dependent density functional theory calculations with the modified CVR-B3LYP functional yield both K-shell and L-shell excitation energies with reasonable accuracy. The modified CVR-B3LYP also provides valence excitation energies and standard enthalpies of formation accurately. Thus, the modified CVR-B3LYP describes all of the K-shell, L-shell, and valence electrons appropriately. PMID- 26633204 TI - CASCI Reference Wave Functions for Multireference Perturbation Theory Built from Hartree-Fock or Kohn-Sham Orbitals. AB - The MRMP2 method and many similar variants of multireference perturbation theory have a potentially wide range of applicability. However they typically require a CASSCF calculation to define the reference wave function. It is worthwhile to investigate whether 'simpler' orbitals than those obtained from the full CASSCF procedure can provide useful accuracy. In this study we investigate six reactions taken from the Zhao-Gonzalez-Garcia-Truhlar database and investigate the MRMP2 procedure when used with a variety of different orbital sets in order to assess the reliability of such procedures. The results are encouraging and suggest that multireference perturbation theory may be used, for some systems, with the simplified procedures presented here. PMID- 26633205 TI - Critical Role of the Correlation Functional in DFT Descriptions of an Agostic Niobium Complex. AB - In previous studies of the agostic bonding in Tp(Me2)NbCl(R'CCR' ')(R), we have made use of a hybrid QM/MM protocol (B3LYP:UFF) where the QM partition ([Nb(Cl)(iPr)(HCCH)(NHCH2)3](+)) was rather small, but the optimized structures were nevertheless in apparently good agreement with experiment. In attempting to improve this model by expanding the size of the QM region, we were surprised to discover that a full QM treatment of the whole molecule using the B3LYP functional failed to locate an agostic structure of any kind. A systematic assessment of density functionals reveals that the poor performance of B3LYP in these systems is typical of all DFT methods that do not obey the uniform electron gas (UEG) correlation limit. Those that do obey the UEG limit, in contrast, provide an excellent description of the agostic structure when the complete ligand system is treated at the QM level. The apparently good performance of our original (B3LYP:UFF) hybrid method can be traced to a cancellation of errors: the B3LYP functional underestimates the intrinsic strength of the agostic interaction relative to competing Nb-Cl pi bonding, but this is offset by an additional but unphysical electrostatic component to the agostic bond introduced by the presence of a positive charge in the QM region. PMID- 26633206 TI - Kernel Energy Method: The Interaction Energy of the Collagen Triple Helix. AB - There is a rapid growth in computational difficulty with the number of atoms when quantum mechanics is applied to the study of biological molecules. This difficulty may be alleviated in two different ways. One is the advance of parallel supercomputers. And the second is the use of a quantum crystallographic formalism based upon quantum kernels. The kernel methodology is well suited for parallel computation. Recently published articles have applied these advances to calculate the quantum mechanical ab initio molecular energy of peptides, protein (insulin), DNA, and RNA. The results were found to have high accuracy. This paper shows that it is possible to use the full power of ab initio quantum mechanics to calculate the interaction of long chain molecules of biological and medicinal interest. Such molecules may contain thousands or even tens of thousands of atoms. In the approach presented here the computational difficulty of representing a molecule increases only modestly with the number of atoms. The calculations are simplified by representing a full molecule by smaller "kernels" of atoms. The general case is illustrated by a specific example using an important protein, viz., a triple helix collagen molecule of known molecular structure. In order for such a molecule to be a stable helix, the overall interactions among the chains must be attractive. The results show that such interactions are accurately represented by application of the KEM to this triple helix. PMID- 26633207 TI - Electrostatically Embedded Many-Body Correlation Energy, with Applications to the Calculation of Accurate Second-Order Moller-Plesset Perturbation Theory Energies for Large Water Clusters. AB - The electrostatically embedded many-body expansion (EE-MB), previously applied to the total electronic energy, is here applied only to the electronic correlation energy (CE), combined with a Hartree-Fock calculation on the entire system. The separate treatment of the Hartree-Fock and correlation energies provides an efficient way to approximate correlation energy for extended systems. We illustrate this here by calculating accurate Moller-Plesset second-order perturbation theory (MP2) energies for a series of clusters ranging in size from 5 to 20 water molecules. In this new method, called EE-MB-CE, where MB is pairwise additive (PA) or three-body (3B), the full Hartree-Fock energy of a system of N monomers is calculated (i.e., the many-body expansion is carried out to the Nth order), while the EE-MB method is used to calculate the correlation energy of the system. We find that not only does this new method lead to better energetics than the original EE-MB method but also that one is able to obtain excellent agreement with full MP2 calculations by considering only a two-body expansion of the correlation energy, leading to a considerable savings in computational time as compared to the three-body expansion. Additionally, we propose the use of a cutoff to further reduce the number of two-body terms that must be calculated, and we show that if a cutoff of 6 A is used, then one can eliminate up to 44% of the pairs and still calculate energies to within 0.1% of the net interaction energy of the full cluster. PMID- 26633208 TI - Parameter Calibration of Transition-Metal Elements for the Spin-Polarized Self Consistent-Charge Density-Functional Tight-Binding (DFTB) Method: Sc, Ti, Fe, Co, and Ni. AB - Recently developed parameters for five first-row transition-metal elements (M = Sc, Ti, Fe, Co, and Ni) in combination with H, C, N, and O as well as the same metal (M-M) for the spin-polarized self-consistent-charge density-functional tight-binding (DFTB) method have been calibrated. To test their performance a couple sets of compounds have been selected to represent a variety of interactions and bonding schemes that occur frequently in transition-metal containing systems. The results show that the DFTB method with the present parameters in most cases reproduces structural properties very well, but the bond energies and the relative energies of different spin states only qualitatively compared to the B3LYP/SDD+6-31G(d) density functional (DFT) results. An application to the ONIOM(DFT:DFTB) indicates that DFTB works well as the low level method for the ONIOM calculation. PMID- 26633209 TI - Parallel Calculation of Coupled Cluster Singles and Doubles Wave Functions Using Array Files. AB - A new parallel implementation of the Coupled Cluster Singles and Doubles (CCSD) and related wave functions (e.g Quadratic Configuration Interaction, QCI, and Coupled Electron Pair, CEPA) is described, based on the Array Files middleware. The program can handle large basis sets, even without utilizing symmetry, on modest distributed memory workstation clusters. High computational efficiency is achieved by formulating all major operations in terms of matrix multiplications. Timings are provided for systems with 50-228 valence electrons and up to 1144 basis functions, with little or no symmetry. Our largest calculation (QCISD/aug cc-pVQZ for the parallel displaced benzene dimer) uses 1512 basis functions. Calculations on the benzene dimer show that the usual procedure of estimating the effect of basis set enlargement from second-order Moller-Plesset (MP2) calculations is less reliable than previously assumed. Replacing the weak pair amplitudes in CCSD/QCISD calculations by MP2 amplitudes affects the calculated energy only slightly. PMID- 26633210 TI - Self-Consistent Polarization of the Boundary in the Redistributed Charge and Dipole Scheme for Combined Quantum-Mechanical and Molecular-Mechanical Calculations. AB - The recently developed redistributed charge (RC) and redistributed charge and dipole (RCD) schemes are electrostatic-embedding schemes to treat a quantum mechanical/molecular- mechanical (QM/MM) boundary that passes through covalent bonds. In the RC and RCD schemes, the QM subsystem is polarized by the MM subsystem, but the MM subsystem is not polarized by the QM one; this results in an unbalanced treatment of the electrostatic interactions. In the work reported here, we developed improved schemes, namely, the polarized-boundary RC scheme (PBRC) and the polarized-boundary RCD (PBRCD) scheme, by adding self-consistent mutual polarization of the boundary region of the MM subsystem to the previous schemes. The mutual polarizations are accounted for in the polarized-boundary calculations by adjusting the boundary-region MM point charges according to the principles of electronegativity equalization and charge conservation until the charge distributions in both the QM subsystem and the polarizable region of the MM subsystem converge. In particular, we implemented three literature parametrizations of electronegativity equalization: the original electronegativity equalization method (EEM) by Mortier and co-workers, the charge equalization (QEq) method proposed by Rappe and Goddard, and a modified version of the QEq method by Bakowies and Thiel. The PBRC and PBRCD schemes were tested by calculating proton affinities for small organic compounds and capped amino acids. As compared to full-QM calculations, the PBRC and PBRCD schemes produced more accurate proton affinities, on average, than the original RC and RCD methods; the mean unsigned error in proton affinities is reduced from about 5 kcal/mol to 3 kcal/mol with little change in geometry. The improvement is encouraging and illustrates the importance of mutual polarization of the QM and MM subsystems in treating reactions where noticeable charge transfer occurs in the QM subsystem. PMID- 26633211 TI - What Is the Limit of Atom Encapsulation for Icosahedral Carboranes? AB - The stability of endohedral carboranes X@{1,n-C2B10H12} (X = Li(+), Be(2+); n = 2, 7, 12) and X@{CB11H12(-)} (X = Li(+), Be(2+)) is studied using electronic structure calculations with the B3LYP/6-311+G(d,p) model. Our calculations suggest that all endohedral compounds are local energy minima; for the exohedral complexes X...cage, the global energy minimum always corresponds to the X atom above a triangular face of the icosahedron. In the latter the X atom is furthest apart from the carbon atoms of the cage. As opposite to exohedral {Be(2+)...cage} complexes, no global energy minima were found for exohedral complexes {Li(+)...cage} whereby a carbon atom is present in the triangular face of the icosahedron below the Li(+) cation. PMID- 26633212 TI - QM-MM Investigation of the Reaction of Peroxynitrite with Carbon Dioxide in Water. AB - We have investigated the reaction of peroxynitrite with carbon dioxide in aqueous solution by means of combined quantum-classical (QM-MM) molecular dynamics simulations. In our QM-MM scheme, the reactant was modeled using density functional theory with a Gaussian basis set, and the solvent was described using the mean-field TIP4P force field. The free energy profile of this reaction has been computed using umbrella sampling and multiple steering molecular dynamics (MSMD) schemes. Umbrella sampling methods turned out to be much more efficient than MSMD schemes, due to the possibility of employing a combination of classical and QM-MM thermalization schemes. We found the presence of a significant barrier in the free energy profile associated with the reaction in solution, which is not present in vacuum, that may be ascribed to the significant charge redistribution upon reaction and the concomitant solvation pattern changes. PMID- 26633213 TI - Understanding Rate Accelerations for Diels-Alder Reactions in Solution Using Enhanced QM/MM Methodology. AB - The Diels-Alder reactions of cyclopentadiene with 1,4-naphthoquinone, methyl vinyl ketone, and acrylonitrile have been investigated using QM/MM calculations in water, methanol, acetonitrile, and hexane. This extends an earlier AM1-based QM/MM study (J. Phys. Chem. B 2002, 106, 8078) that only investigated the reactions in water and utilized gas-phase optimized structures as starting points for computations of one-dimensional potentials of mean force (PMFs). Presently, the stationary points were located automatically in multiple solvents by computing two-dimensional PMFs, and the QM method is now PDDG/PM3. The resultant geometries are improved, and relative free energies of activation are well reproduced, e.g., DeltaG(?) for the reaction with naphthoquinone is computed to increase upon transfer from water to methanol, acetonitrile, and hexane by 3.2, 4.1, and 5.1 kcal/mol, while the experimental values are 3.4, 4.0, and 5.0 kcal/mol. Ab initio MP2/6-311+G(2d,p) calculations using the CPCM continuum solvent model on gas-phase CBS-QB3 geometries were also found to yield accurate DeltaG(?) values in water. However, only the QM/MM methodology reproduced the large rate increases in proceeding from aprotic solvents to water. The dominant factors for the rate variations are enhanced hydrogen bonding for the polarized transition states and reduction in hydrophobic surface area. PMID- 26633214 TI - The Gradient Curves Method: An Improved Strategy for the Derivation of Molecular Mechanics Valence Force Fields from ab Initio Data. AB - A novel force-field development strategy is proposed that tackles the well-known difficulty of parameter correlations arising in a conventional least-squares optimization. In the first step of the new gradient curves method (GCM), continuity criteria are imposed to transform the raw multidimensional ab initio training data to distinct sets of one-dimensional data, each associated with an individual energy term. In the second step, the transformed data suggest suitable analytical expressions, and the parameters in these expressions are fitted to the transformed data; that is, one does not have to postulate a priori analytical expressions for the force-field energy terms. This approach facilitates the derivation of valence terms. Benchmarks have been performed on a set of small molecules. The results show that the new method yields physically acceptable energy terms exactly when a conventional parametrization would suffer from parameter correlations, that is, when an increasing number of redundant internal coordinates is used in the force-field model. The generic treatment of parameter correlations in the proposed method facilitates an intuitive physical interpretation of the individual terms in the force-field expression, which is a prerequisite for the transferability of force-field models. PMID- 26633215 TI - Molecular Dynamics and Free Energy Study of the Conformational Equilibria in the UUUU RNA Hairpin. AB - A series of molecular dynamics (MD) simulations was performed to elucidate the thermodynamic basis for the relative stabilities of hairpin, duplex, and single stranded forms of the 5'-CGC(UUUU)GCG-3' oligonucleotide. According to a recent NMR study this sequence exhibits dynamic conformational equilibrium in aqueous solution in the vicinity of room temperature. Free energy calculations using the molecular mechanics-Poisson Boltzmann-surface area (MM-PB/SA) approach support a shift in the conformational equilibrium from duplex to hairpin as the temperature is increased from 276 to 300 K, in agreement with the NMR results. The effect of added salt on the relative stabilities of RNA conformers is also reproduced by our calculations. The calculated DeltaH degrees for the equilibrium between hairpin and single stranded forms is estimated to be -23.4 kcal/mol, in reasonable agreement with experimental values. Our results reveal that the conformational equilibrium strongly depends on the solute entropy and the electrostatic interactions modulated by added salt. Simulations of hairpin loop conducted at two different temperatures converged to the same lowest energy loop conformation. This conformer is stabilized by favorable van der Waals interactions as a result of U5-U6-U7 base stacking, a hydrogen bond between the U4 base and the phosphate linking U6 and U7, and hydrogen bonds involving the 2'OH groups at U4 and U6. However, the sugar pucker of the four uridines in the lowest energy conformer is different from that reported by a NMR study. While the NMR study found that U5 and U7 adopt the C2'-endo conformation, the simulation results suggests that overall the structure with the U5 and U7 in the C3'-endo conformation is thermodynamically more stable than the structure containing the C2'-endo pucker by approximately 8 kcal/mol. Calculations based on the MM-PB/SA scheme show that although the electrostatic solvation free energy favors the C2' endo conformation for the U5 and U7 riboses, it is offset by the less favorable intramolecular electrostatic and van der Waals energies. To enhance the conformational sampling, a replica exchange molecular dynamics (REMD) simulation was conducted in a generalized Born (GB) continuum solvent for the hairpin loop. This simulation indicates that the stable loop structure observed in the explicit solvent simulations corresponds to the free energy minimum. It also reveals that while the U4, U5, and U6 sugar rings are predominantly in the C3'-endo conformation, there is considerable variation in the sugar pucker of the U7 ribose ring. PMID- 26633216 TI - Continuous Fractional Component Monte Carlo: An Adaptive Biasing Method for Open System Atomistic Simulations. AB - A new open system Monte Carlo procedure designed to overcome difficulties with insertion and deletion of molecules is introduced. The method utilizes gradual insertions and deletions of molecules through the use of a continuous coupling parameter and an adaptive bias potential. The method draws upon concepts from previous open system molecular dynamics and expanded ensemble Monte Carlo techniques and is applied to both the grand canonical and osmotic ensembles. It is shown to yield correct results for the volumetric properties of the Lennard Jones fluid and water as well as the phase behavior of the CO2-ethanol binary system. PMID- 26633217 TI - AMBER Force Field Parameters for the Naturally Occurring Modified Nucleosides in RNA. AB - Classical molecular dynamics (MD) simulations are useful for characterizing the structure and dynamics of biological macromolecules, ultimately, resulting in elucidation of biological function. The AMBER force field is widely used and has well-defined bond length, bond angle, partial charge, and van der Waals parameters for all the common amino acids and nucleotides, but it lacks parameters for many of the modifications found in nucleic acids and proteins. Presently there are 107 known naturally occurring modifications that play important roles in RNA stability, folding, and other functions. Modified nucleotides are found in almost all transfer RNAs, ribosomal RNAs of both the small and large subunits, and in many other functional RNAs. We developed force field parameters for the 107 modified nucleotides currently known to be present in RNA. The methodology used for deriving the modified nucleotide parameters is consistent with the methods used to develop the Cornell et al. force field. These parameters will improve the functionality of AMBER so that simulations can now be readily performed on diverse RNAs having post-transcriptional modifications. PMID- 26633218 TI - On the Use of Elevated Temperature in Simulations To Study Protein Unfolding Mechanisms. AB - In protein unfolding simulations, elevated temperature, significantly exceeding the melting temperature Tm, provides an important means to accelerate unfolding to a computationally accessible time range. This procedure is based on the assumption that protein thermal unfolding has Arrhenius behavior and therefore that increasing temperature does not alter the protein unfolding pathways. However, in nature, proteins can show non-Arrhenius behavior and, in practice, overly fast unfolding in high-temperature simulations can result in difficulties in identifying unfolding intermediates and distinguishing their relative stabilities. In this paper, we describe simulations of two WW domains, small protein domains that have a three-stranded beta-sheet structure. Simulations were carried out at several temperatures ranging from 300 K to 500 K, starting from folded structures. The results demonstrate the temperature dependence of the unfolding pathways, showing that to obtain unfolding pathways corresponding to those observed in experiments, the elevation of the simulation temperature has to be controlled. Based on trajectory analysis, we proposed a qualitative criterion for judging when an elevated temperature is acceptable or not, namely, that the temperature must be such that the native folded state is sampled substantially before protein unfolding begins. While depending on force field parameters and protein fold complexity, this criterion can be quantified to obtain the upper bound of an "acceptable elevated temperature", which was observed to be dependent on the thermostabilities of the two WW domain proteins. PMID- 26633219 TI - Solvatochromic Shifts of the n -> pi* Transition of Acetone from Steam Vapor to Ambient Aqueous Solution: A Combined Configuration Interaction QM/MM Simulation Study Incorporating Solvent Polarization. AB - A hybrid quantum mechanical and molecular mechanical potential is used in Monte Carlo simulations to examine the solvent effects on the electronic excitation energy of the n -> pi(*) transition of acetone in ambient and supercritical water fluid, in which the temperature is in the range of 25-500 degrees C with pressures of 1-2763 atm. In the present study, the acetone molecule is described by the AM1 Hamiltonian, and the water molecules are treated classically. Two sets of calculations are performed. The first involves the TIP4P model for water, and the second employs a polarizable model, POL2, for the solvent. The first calculation yields the excitation energy by using the static ground-state solvent charge distribution obtained from QM-CI/MM calculations. The latter takes into account the effect of solvent polarization following the solute electronic excitation. The trend of the computed n -> pi(*) blue-shifts for acetone as function of the fluid density is in good agreement with experimental results. The present simulations of acetone in the supercritical, near supercritical, dense liquid, and ambient water fluids reveal that the solvatochromic shifts are dominated by the electrostatic interactions between acetone and water molecules during the solute excitation. Additionally, the solvent charge redistribution following the solute electronic excitation has a small correlation (0 to -37 cm( 1)) to the total solvatochromic shift and decreases linearly with water density. Both the solvatochromic shift and solvent polarization correction are more obvious in the ambient water than in the supercritical water because the solvent stabilization of the ground state over the excited state is more significant in the former condition. PMID- 26633220 TI - Solid-Liquid Interfacial Free Energy of Water: A Molecular Dynamics Simulation Study. AB - The superheating-undercooling hysteresis method and molecular dynamics simulation [Luo et al. Phys. Rev. B 2003, 68, 134206] were applied to estimate solid-liquid interfacial free energy (gamma) of model water at ambient pressure. Two models of water were selected, the TIP4P-Ew and TIP5P-Ew, which are the improved TIP4P and TIP5P model (for the use with Ewald technique), respectively. The calculated gamma at 1 bar is 37 mJ/m(2) for TIP4P-Ew and 42 mJ/m(2) for TIP5P-Ew, consistent with a previous direct MD simulation (39 mJ/m(2)), as well as within the range of measured values (25-44 mJ/m(2)). PMID- 26633221 TI - Combined QM/MM Molecular Dynamics Study on a Condensed-Phase SN2 Reaction at Nitrogen: The Effect of Explicitly Including Solvent Polarization. AB - In a previous combined QM/MM molecular dynamics (MD) study from our laboratory on the identity SN2 reaction between a chloride anion and an amino chloride in liquid dimethyl ether (DME), an increase in the free energy activation barrier was observed in the condensed phase when compared to the gas-phase activation energy. Here we reproduce these findings, but when comparing the condensed-phase potential of mean force (PMF) with the free energy profile in the gas phase (obtained from Monte Carlo simulations), we observe a smaller solvent effect on the activation barrier of the reaction. In a next step, we introduce an explicit description of electronic polarization in the MM (solvent) part of the system. A polarizable force field for liquid DME was developed based on the charge-on spring (COS) model, which was calibrated to reproduce thermodynamic properties of the nonpolarizable model in classical MD simulations. The COS model was implemented into the MNDO/GROMOS interface in a special version of the QM/MM software ChemShell, which was used to investigate the effect of solvent polarization on the free energy profile of the reaction under study. A higher activation barrier was obtained using the polarizable solvent model than with the nonpolarizable force field, due to a better solvation of and a stronger polarization of solvent molecules around the separate reactants. The obtained PMFs were subjected to an energy-entropy decomposition of the relative solvation free energies of the reactant complex along the reaction coordinate, to investigate in a quantitative manner whether the solvent (polarization) effects are mainly due to favorable QM-MM (energetic) interactions. PMID- 26633222 TI - Basis Set Superposition Error along the Free-Energy Surface of the Water Dimer. AB - In this article we review the behavior of static plane wave basis set calculations in comparison to Gaussian basis set calculations. This was done in the framework of density functional theory for description of hydrogen bonds with the water dimer as an example. Furthermore we carried out molecular dynamics simulations enforcing the self-dissociation reaction of the water dimer to study the influence of the basis set onto the reaction. Not surprisingly, we find strongly varying results of the calculated forces for a chosen cutoff along the reaction coordinates. The basis set superposition errors of the dimer interaction energy are analyzed along the free-energy surface, i.e., along the trajectories. Based on the analysis along the trajectories a qualitative and quantitative estimate depending on the particular point of the free-energy surface can be provided. Namely, at the intermolecular O...H distance close to the equilibrium geometry the errors are smaller than at shorter O...H distances. However, the distribution at the equilibrium distance is more unsymmetrical than the distribution at short distances. It is wider, and the standard deviation is larger than at shorter distances where the basis set superposition error is larger. PMID- 26633223 TI - Theoretical Studies on Optical and Electronic Properties of Propionic-Acid Terminated Silicon Quantum Dots. AB - The origin and stability of photoluminescence (PL) are critical issues for silicon nanoparticles to be used as biological probes. Optical and electronic properties of propionic-acid (PA) -terminated silicon quantum dots (SiQDs) were studied using the density-functional tight-binding method. We find that the adsorbed PA molecules slightly affect the structure of silicon core. The PA adsorption does not change the optical properties of SiQDs, while it substantially decreases the ionization potentials in the excited state and results in some new active orbitals with adjacent energies around the Fermi energy level. Accordingly, the modified surface of SiQDs can serve as a reaction substrate to oxygen and solvent molecules, which is responsible for the increase in both PL stability and water solubility. PMID- 26633224 TI - Establishing Effective Simulation Protocols for beta- and alpha/beta-Mixed Peptides. I. QM and QM/MM Models. AB - A quantum mechanical (QM) model for non-natural beta- and alpha/beta-mixed peptides is investigated using an approximate density functional method (called SCC-DFTB). In the gas phase the predictions of the model for cyclic and acyclic dipeptides and several acyclic heptapeptides are compared to ab initio B3LYP and LMP2 calculations. The SCC-DFTB reproduces the global minimum of the configurations with the root-mean-square (rms) error in the key dihedral angles of less than 14 degrees. The relative energies of different conformers are also well described in general, with the typical rms error of 2-3 kcal/mol relative to LMP2 energies at either B3LYP or LMP2 optimized structures. The dipole moments are reproduced with a systematic underestimate of less than 15%. The QM model is also used with a molecular mechanical (MM) model of the solvent. For a tetrameric alpha/beta-peptide in water, the SCC-DFTB/MM energies are well correlated with B3LYP/6-31+G**/MM single point energies for a wide range of structures sampled in 2 ns of SCC-DFTB/MM molecular dynamics. For an octameric alpha/beta-peptide in methanol the predicted structures are in qualitative agreement with experimental NOE data. These results suggest that the SCC-DFTB model provides a fairly accurate representation of the structure and thermodynamics of these peptides. PMID- 26633225 TI - Molecular Dynamics Simulations of Proteins: Can the Explicit Water Model Be Varied? AB - In molecular mechanics simulations of biological systems, the solvation water is typically represented by a default water model which is an integral part of the force field. Indeed, protein nonbonding parameters are chosen in order to obtain a balance between water-water and protein-water interactions and hence a reliable description of protein solvation. However, less attention has been paid to the question of whether the water model provides a reliable description of the water properties under the chosen simulation conditions, for which more accurate water models often exist. Here we consider the case of the CHARMM protein force field, which was parametrized for use with a modified TIP3P model. Using quantum mechanical and molecular mechanical calculations, we investigate whether the CHARMM force field can be used with other water models: TIP4P and TIP5P. Solvation properties of N-methylacetamide (NMA), other small solute molecules, and a small protein are examined. The results indicate differences in binding energies and minimum energy geometries, especially for TIP5P, but the overall description of solvation is found to be similar for all models tested. The results provide an indication that molecular mechanics simulations with the CHARMM force field can be performed with water models other than TIP3P, thus enabling an improved description of the solvent water properties. PMID- 26633226 TI - Atomic Charge Calculation of Metallobiomolecules in Terms of the ABEEM Method. AB - Applying the atom-bond electronegativity equalization method (ABEEM) to metallobiomolecules, the ABEEM parameters for transition metals (V, Cr, Mn, Fe, Co, Ni, Cu, and Zn) were calibrated through linear regression and least-squares optimization by choosing more than 300 training molecules. The quality of the ABEEM charge calculated in terms of the optimized electronegativity and hardness parameters for the training set is assessed by comparison with B3LYP/6-31G* charges. For a check, the ABEEM charges of some large metallobiomolecules have been calculated, and the obtained results correlate quite well to those calculated with the B3LYP/6-31G* method. The linear correlation coefficients R are all over 0.98. This shows that the ABEEM method can predict the charge distributions of large metallobiomolecules with high accuracy. PMID- 26633227 TI - Molecular Dynamics of Organophosphorous Hydrolases Bound to the Nerve Agent Soman. AB - The organophosphorous hydrolase (OPH) from Pseudomonas diminuta is capable of degrading extremely toxic organophosphorous compounds with a high catalytic turnover and broad substrate specificity. Although the natural substrate for OPH is unknown, its triple-mutant H254G/H257W/L303T exhibits a 3 order of magnitude increase in catalytic efficiency and modified stereospecificity toward the most toxic SpSc enantiomer of soman. Molecular dynamics simulations and binding free energy calculations have been undertaken for the wild-type and triple-mutant H254G/H257W/L303T enzymes bound to the SpSc-soman enantiomer. Comparison of the simulations indicates that substrate binding induces conformational changes of the loops near the active site. The coordination of the zinc cations in the active site of OPH differs between the free enzyme and the complexes. This suggests that the active site of OPH can accommodate several catalytically active coordination geometries, consistent with the fact that the enzymatic activity of the wild-type OPH can be enhanced by alterations to the metal content of the enzyme. It is also argued that the enhanced efficiency of the triple mutant is determined by enzyme-transition-state complementarity. These results provide a qualitative, molecular-level explanation for the 3 order of magnitude increase in catalytic efficiency of the triple-mutant toward SpSc-soman. PMID- 26633228 TI - Homoleptic Carbonyls of the Second-Row Transition Metals: Evaluation of Hartree Fock and Density Functional Theory Methods. AB - The homoleptic mono- and multinuclear carbonyls for Mo, Tc, Ru, and Rh, namely, Mo(CO)6, Ru(CO)5, Tc2(CO)10, Ru3(CO)12, Rh4(CO)12, and Rh6(CO)16, are investigated theoretically by the Hartree-Fock method and three density functional theory (DFT) methods, i.e., BP86, B3LYP, and MPW1PW91, along with the SDD ECP basis sets. The results predicted by all the methods are basically in agreement with each other. The MPW1PW91 and BP86 methods predict geometric parameters and vibrational spectra, respectively, closest to the experimental values. For Ru3(CO)12 the relative energies of the D3h isomer with only terminal CO groups and the C2v isomer with two bridging CO groups are within 3 kcal/mol of each other with the lower energy isomer depending upon the computational method used. For Rh4(CO)12 the global minimum is predicted to have C3v symmetry, with three bridging and nine terminal carbonyls, in accord with experiment. The Rh6(CO)16 structure has Td symmetry and satisfies the Wade-Mingos rules for an octahedral cluster. Using the MPW1PW91 method the Rh-Rh distances in Rh4(CO)12 are found to be 2.692 A and 2.750 A and those in Rh6(CO)16 to be 2.785 A. PMID- 26633229 TI - Sparkle/PM3 Parameters for the Modeling of Neodymium(III), Promethium(III), and Samarium(III) Complexes. AB - The Sparkle/PM3 model is extended to neodymium(III), promethium(III), and samarium(III) complexes. The unsigned mean error, for all Sparkle/PM3 interatomic distances between the trivalent lanthanide ion and the ligand atoms of the first sphere of coordination, is 0.074 A for Nd(III); 0.057 A for Pm(III); and 0.075 A for Sm(III). These figures are similar to the Sparkle/AM1 ones of 0.076 A, 0.059 A, and 0.075 A, respectively, indicating they are all comparable models. Moreover, their accuracy is similar to what can be obtained by present-day ab initio effective potential calculations on such lanthanide complexes. Hence, the choice of which model to utilize will depend on the assessment of the effect of either AM1 or PM3 on the quantum chemical description of the organic ligands. Finally, we present a preliminary attempt to verify the geometry prediction consistency of Sparkle/PM3. Since lanthanide complexes are usually flexible, we randomly generated 200 different input geometries for the samarium complex QIPQOV which were then fully optimized by Sparkle/PM3. A trend appeared in that, on average, the lower the total energy of the local minima found, the lower the unsigned mean errors, and the higher the accuracy of the model. These preliminary results do indicate that attempting to find, with Sparkle/PM3, a global minimum for the geometry of a given complex, with the understanding that it will tend to be closer to the experimental geometry, appears to be warranted. Therefore, the sparkle model is seemingly a trustworthy semiempirical quantum chemical model for the prediction of lanthanide complexes geometries. PMID- 26633230 TI - Toward the Prediction of Organic Hydrate Crystal Structures. AB - Lattice energy minimization studies on four ordered crystal structures of ice and 22 hydrates of approximately rigid organic molecules (along with 11 corresponding anhydrate structures) were used to establish a model potential scheme, based on the use of a distributed multipole electrostatic model, that can reasonably reproduce the crystal structures. Transferring the empirical repulsion-dispersion potentials for organic oxygen and polar hydrogen atoms to water appears more successful for modeling ice phases than using common water potentials derived from liquid properties. Lattice energy differences are reasonable but quite sensitive to the exact conformation of water and the organic molecule used in the rigid molecule modeling. This potential scheme was used to test a new approach of predicting the crystal structure of 5-azauracil monohydrate (an isolated site hydrate) based on seeking dense crystal packings of 66 5-azauracil...water hydrogen-bonded clusters, derived from an analysis of hydrate hydrogen bond geometries involving the carbonyl- and aza-group acceptors in the Cambridge Structural Database. The known structure was found within 5 kJ mol(-1) of the global minimum in static lattice energy and as the third most stable structure, within 1 kJ mol(-1), when thermal effects at ambient temperature were considered. Thus, although the computational prediction of whether an organic molecule will crystallize in a hydrated form poses many challenges, the prediction of plausible structures for hydrogen-bonded monohydrates is now possible. PMID- 26633231 TI - Sugar Folding: A Novel Structural Prediction Tool for Oligosaccharides and Polysaccharides 1. AB - This paper is the first in a series of two articles where we report the development of fast sugar structure prediction software (FSPS). To the best of our knowledge, this is the first automated tool for the systematic study of conformations of complex oligosaccharides in solution. In contrast to previously developed molecular builders such as POLYS (Engelsen, S. B.; Cros, S.; Mackie, W.; Perez, S. Biopolymers 1996, 39, 417-433) where only information about the minimum energy conformation of disaccharide pairs is considered in order to build larger oligosaccharides, this tool is based on a systematic search of dihedral conformational space, optimization of structures using implicit solvation models, explicit molecular dynamics simulations, NOE calculations, and a very powerful substructure recognition algorithm and database. Our FSPS can rapidly find minimum-energy conformers and rank them according to different criteria. Two such criteria are the energy of the conformers in implicit solvent and the root-mean square deviation (RMSD) of computed NOEs with respect to experimental data. Even though experimental NOEs may result from an average over conformers instead of a single structure, we find that sorting according to NOE RMSD constitutes a better estimator for the global free-energy minimum structure in explicit solvent (i.e., the most likely structure in solution). In contrast, the lowest-energy structure in implicit solvent does not usually correspond to the free-energy minimum. A harmonic approximation to compute free energies of each conformer does not appear to reverse this conclusion, indicating that either explicit hydrogen bonding to the solvent or anharmonic effects in the free energy or both are fundamentally important. In the first article, we discuss our methodology and study, as a proof of concept, a simple substituted disaccharide. In the second article, we focus on two complex human milk oligosaccharides. PMID- 26633232 TI - Sugar Folding: A Novel Structural Prediction Tool for Oligosaccharides and Polysaccharides 2. AB - This is the second in a set of two articles where we describe our newly developed scheme to predict conformations of complex oligosaccharides in solution. We apply our fast sugar conformation prediction tool to the case of two complex human milk oligosaccharides LNF-1 and LND-1. As described in detail in the first paper, our protocol initially delivers a set of "unique structures" corresponding to important minima on the potential-energy landscape of a complex sugar using an implicit solvent model. The nuclear Overhauser effect ranking of individual conformations provides a suitable way for comparison with available experiments. The structures obtained agree well with earlier computational predictions but are obtained at a significantly lower computational cost. Sugar conformations corresponding to stable energy minima not found by earlier molecular dynamics studies were also detected using our methodology. In order to evaluate the effects of explicit solvation and thermal fluctuations on several different predicted conformers, we also performed short-time molecular dynamics simulations in an explicit solvent. PMID- 26633233 TI - CDC Grand Rounds: Prevention and Control of Skin Cancer. AB - Skin cancer is the most common cancer in the United States, and most cases are preventable. Persons with certain genetic risk factors, including having a lighter natural skin color; blue or green eyes; red or blonde hair; dysplastic nevi or a large number of common moles; and skin that burns, freckles, or reddens easily or becomes painful after time in the sun, have increased risk for skin cancer. Persons with a family or personal history of skin cancer, especially melanoma, are also at increased risk. Although these genetic factors contribute to individual risk, most skin cancers are also strongly associated with ultraviolet (UV) radiation exposure. Most UV exposure comes from the sun, although some persons use UV-emitting indoor tanning devices (e.g., beds, booths, and lamps). PMID- 26633234 TI - Mechanism of Efficient Proton Conduction in Diphosphoric Acid Elucidated via First-Principles Simulation and NMR. AB - Diphosphoric acid (H4P2O7) is the first condensation product of phosphoric acid (H3PO4), the compound with the highest intrinsic proton conductivity in the liquid state. It exists at higher temperature (T > 200 degrees C) and lower relative humidity (RH ~ 0.01%) and shows significant ionic conductivity under these conditions. In this work, ab initio molecular dynamics simulations of a pure H4P2O7 model system and NMR spectroscopy on nominal H4P2O7 (which contains significant amounts of ortho- and triphosphoric acid in thermodynamic equilibrium) were performed to reveal the nature and underlying mechanisms of the ionic conductivity. The central oxygen of the molecule is found to be excluded from any hydrogen bonding, which has two interesting consequences: (i) compared to H3PO4, the acidity of H4P2O7 is severely increased, and (ii) the condensation reaction only leads to a minor decrease in hydrogen bond network frustration, which is thought to be one of the features enabling high proton conductivity. A topological analysis of diphosphoric acid's hydrogen bond network shows remarkable similarities to that of phosphonic acid (H3PO3). The hydrogen bonding facilitates protonic polarization fluctuations (Zundel polarization) extending over several molecules (Grotthuss chains), the other important ingredient for efficient structural diffusion of protons. At T = 160 degrees C, this is estimated to make a conductivity contribution of about 0.1 S/cm, which accounts for half of the total ionic conductivity (sigma ~ 0.2 S/cm). The other half is suggested to result from diffusion of charged phosphate species (vehicle mechanism) that are present in high concentration, resembling conduction in ionic liquids. PMID- 26633235 TI - Characteristics of Farm Equipment-Related Crashes Associated With Injury in Children and Adolescents on Farm Equipment. AB - PURPOSE: Operating or riding on farm equipment is one of the leading causes of farm-related injuries and fatalities among children and adolescents. The aim of this study is to examine environment, crash, vehicle, and occupant characteristics and the probability of injury, given a crash, in youth under age 18 on farm equipment. METHOD: Data from the Departments of Transportation on farm equipment-related crashes across 9 Midwestern states from 2005-2010 were used. Odds ratios were calculated using logistic regression to assess the relationship between environment, crash, vehicle, and occupant characteristics and the probability of injury, given a crash. FINDINGS: A total of 434 farm equipment related crashes involved 505 child or adolescent occupants on farm equipment: 198 passengers and 307 operators. Passengers of farm equipment had 4.1 higher odds of injury than operators. Occupants who used restraints had significantly lower odds of injury than those who did not. Furthermore, occupants on farm equipment that was rear-ended or sideswiped had significantly lower odds of injury compared to occupants on farm equipment involved in noncollision crashes. Likewise, occupants on farm equipment that was impacted while turning had significantly lower odds of injury compared to those on equipment that was impacted while moving straight. CONCLUSION: Precautions should be taken to limit or restrict youth from riding on or operating farm equipment. These findings reiterate the need to enforce policies that improve safety measures for youth involved in or exposed to agricultural tasks. PMID- 26633236 TI - Speciation Dynamics of Phosphorus during (Hydro)Thermal Treatments of Sewage Sludge. AB - (Hydro)thermal treatments of sewage sludge from wastewater treatment process can significantly reduce waste volume and transform sludge into valuable products such as pyrochar and hydrochar. Given the global concern with phosphorus (P) resource depletion, P recycling/reclamation from or direct soil application of the derived chars can be potential P recycling practices. In order to evaluate P recyclability as well as the selection and optimization of treatment techniques, it is critical to understand the effects of different treatment techniques and conditions on P speciation and distribution. In the present study, we systematically characterized P speciation in chars derived from thermal (i.e., pyrolysis) and hydrothermal treatments of municipal sewage sludge using complementary chemical extraction and nuclear magnetic resonance (NMR) spectroscopy methods. P species in the raw activated sludge was dominated by orthophosphate and long-chain polyphosphates, whereas increased amounts of pyrophosphate and short-chain polyphosphates formed after pyrolysis at 250-600 degrees C. In contrast, hydrothermal treatments resulted in the production of only inorganic orthophosphate in the hydrochar. In addition to the change of molecular speciation, thermal treatments also altered the physical state and extractability of different P species in the pyrochars from pyrolysis, with both total P and polyphosphate being less extractable with increasing pyrolysis temperature. Results from this study suggest that P speciation and availability in sludge-derived chars are tunable by varying treatment techniques and conditions, and provide fundamental knowledge basis for the design and selection of waste management strategies for better nutrient (re)cycling and reclamation. PMID- 26633237 TI - Effect of Resveratrol Treatment on the Pharmacokinetics of Diclofenac in Healthy Human Volunteers. AB - The purpose of the present study was to assess the effect of resveratrol (RSV) treatment on the pharmacokinetics of diclofenac (DIC) in healthy human volunteers. The open-label, two period, sequential study was conducted in 12 healthy human volunteers. A single dose of RSV 500 mg was administered daily for 10 days during treatment phase. A single dose of DIC 100 mg was administered during control and after treatment phases under fasting conditions. The blood samples were collected after DIC dosing and analyzed by HPLC. Treatment with RSV significantly enhanced maximum plasma concentration (Cmax) (1.73 to 2.91 ug/mL), area under the curve (AUC) (5.05 to 9.95 g h/mL), half life (T1/2) (1.12 to 1.76 h) and significantly decreased elimination rate constant (Kel ) (0.71 to 0.41 h( 1)), apparent oral clearance (CL/F) (14.58 to 6.48 L/h) of DIC as compared to control. The geometric mean ratios for Cmax, AUC, T1/2, Kel and CL/F of DIC were 1.75, 2.12, 1.65, 0.61 and 0.47, respectively were outside the limits of 0.8 1.25, which indicates clinically significant interaction between DIC and RSV. The results suggest that the altered pharmacokinetics of DIC might be attributed to RSV mediated inhibition of CYP2C9 enzyme. Therefore, combination therapy of DIC along with RSV may represent a novel approach to reduce dosage and results in reduced gastrointestinal side effects of DIC. PMID- 26633238 TI - Facile Synthesis of Lithium Sulfide Nanocrystals for Use in Advanced Rechargeable Batteries. AB - This work reports a new method of synthesizing anhydrous lithium sulfide (Li2S) nanocrystals and demonstrates their potential as cathode materials for advanced rechargeable batteries. Li2S is synthesized by reacting hydrogen sulfide (H2S) with lithium naphthalenide (Li-NAP), a thermodynamically spontaneous reaction that proceeds to completion rapidly at ambient temperature and pressure. The process completely removes H2S, a major industrial waste, while cogenerating 1,4 dihydronaphthalene, itself a value-added chemical that can be used as liquid fuel. The phase purity, morphology, and homogeneity of the resulting nanopowders were confirmed by X-ray diffraction and scanning electron microscopy. The synthesized Li2S nanoparticles (100 nm) were assembled into cathodes, and their performance was compared to that of cathodes fabricated using commercial Li2S micropowders (1-5 MUm). Electrochemical analyses demonstrated that the synthesized Li2S were superior in terms of (dis)charge capacity, cycling stability, output voltage, and voltage efficiency. PMID- 26633239 TI - Abstracts of The Asian Pacific Society of Respirology 20th Congress, December 3 6, 2015, Kuala Lumpur, Malaysia. PMID- 26633240 TI - CT perfusion in acute stroke calls: A pictorial review and differential diagnoses. AB - CT perfusion is increasingly utilised in hyperacute stroke to facilitate diagnosis and patient selection for reperfusion therapies. This review article demonstrates eight examples of how CT perfusion can be used to diagnose stroke mimics and small volume infarcts, which can be easily missed on non-contrast CT, and to suggest the presence of an ischaemic penumbra. Radiologists involved in stroke management must understand the importance of rapid imaging acquisition and be confident in the prospective interpretation of this powerful diagnostic tool as we move into a new era of hyperacute stroke care. PMID- 26633241 TI - Synthesis of Multiply Substituted Polycyclic Aromatic Hydrocarbons by Iridium Catalyzed Annulation of Ring-Fused Benzocyclobutenol with Alkyne through C-C Bond Cleavage. AB - The first iridium-catalyzed intermolecular cyclization between alkynes and ring fused benzocyclobutenols (RBCB) through C-C bond cleavage is described. A variety of elusive polycyclic aromatic hydrocarbons (PAHs) with multiple substituents are obtained in good yields under mild conditions. This procedure provides a unique and expeditious tool for the synthesis of PAHs. PMID- 26633242 TI - SETAC publications have global impact. PMID- 26633243 TI - A self-administered test of taste function using "Taste Strips". AB - BACKGROUND: Assessment of gustatory function with impregnated taste strips is an established and validated method. In clinical routine, application of the tests is often limited due to lack of time or costs associated with administering the test. The aim of the study was to develop a procedure suitable for self administration of the "Taste Strips" test. METHODS: The investigated participants (n = 65; 22 males, 43 females; mean age 36.7 +/- 19.2 years; range, 20 to 83 years) were tested twice in a randomized crossover procedure. On 1 occasion, an examiner administered the established and validated "Taste Strips" test. On another occasion, test subjects administered the taste strips themselves. Results of both test methods were compared. RESULTS: The mean score (+/- standard deviation [SD]) of the assisted taste test (11.6 +/- 2.6) was significantly lower compared to the mean self-administered taste test that yielded 12.3 +/- 2.6 points (Wilcoxon test: z = 2.836; p < 0.01). Comparison of mean values showed minimal difference of the tested procedures of 0.7 +/- 1.9 points with a significant positive correlation of test results (r65 = 0.734; p < 0.01). CONCLUSION: Although a small difference between test results was observed, the new test procedure seems to be an adequate screening tool for assessment of taste function with less personnel effort, leading to improved management of patients with chemosensory disorders. PMID- 26633244 TI - An Online Health Prevention Intervention for Youth with Addicted or Mentally Ill Parents: Experiences and Perspectives of Participants and Providers from a Randomized Controlled Trial. AB - BACKGROUND: Mental illnesses affect many people around the world, either directly or indirectly. Families of persons suffering from mental illness or addiction suffer too, especially their children. In the Netherlands, 864,000 parents meet the diagnostic criteria for a mental illness or addiction. Evidence shows that offspring of mentally ill or addicted parents are at risk for developing mental disorders or illnesses themselves. The Kopstoring course is an online 8-week group course with supervision by 2 trained psychologists or social workers, aimed to prevent behavioral and psychological problems for children (aged 16 to 25 years) of parents with mental health problems or addictions. The course addresses themes such as roles in the family and mastery skills. An online randomized controlled trial (RCT) was conducted to assess the effectiveness of the Kopstoring course. OBJECTIVE: The aim was to gain knowledge about expectations, experiences, and perspectives of participants and providers of the online Kopstoring course. METHODS: A process evaluation was performed to evaluate the online delivery of Kopstoring and the experiences and perspectives of participants and providers of Kopstoring. Interviews were performed with members from both groups. Participants were drawn from a sample from the Kopstoring RCT. RESULTS: Thirteen participants and 4 providers were interviewed. Five main themes emerged from these interviews: background, the requirements for the intervention, experience with the intervention, technical aspects, and research aspects. Overall, participants and providers found the intervention to be valuable because it was online; therefore, protecting their anonymity was considered a key component. Most barriers existed in the technical sphere. Additional barriers existed with conducting the RCT, namely gathering informed consent and gathering parental consent in the case of minors. CONCLUSIONS: This study provides valuable insight into participants' and providers' experiences and expectations with the online preventive intervention Kopstoring. It also sheds light on the process of the online provision of Kopstoring and the accompanying RCT. The findings of this study may partly explain dropout rates when delivering online interventions. The change in the (financial) structure of the youth mental health care system in the Netherlands has financial implications for the delivery of prevention programs for youth. Lastly, there are few RCTs that assess the effectiveness and cost effectiveness of online prevention programs in the field of (youth) mental health care and not many process evaluations of these programs exist. This hampers a good comparison between online interventions and the expectations and experiences of the participants and providers. TRIAL REGISTRATION: Nederlands Trial Register: NTR1982; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=1982 (Archived by WebCite(r) at http://www.webcitation.org/6d8xYDQbB). PMID- 26633246 TI - O2 Activation and Double C-H Oxidation by a Mononuclear Manganese(II) Complex. AB - A Mn(II) complex, [Mn(dpeo)2](2+) (dpeo=1,2-di(pyridin-2-yl)ethanone oxime), activates O2, with ensuing stepwise oxidation of the methylene group in the ligands providing an alkoxide and ultimately a ketone group. X-ray crystal structure analysis of an intermediate homoleptic alkoxide Mn(III) complex shows tridentate binding of the ligand via the two pyridyl groups and the newly installed alkoxide moiety, with the oxime group no longer coordinated. The structure of a Mn(II) complex of the final ketone ligand, cis-[MnBr2(hidpe)2] (hidpe=2-(hydroxyimino)-1,2-di(pyridine-2-yl)ethanone) shows that bidentate oxime/pyridine coordination has been resumed. H2(18)O and (18)O2 labeling experiments suggest that the inserted O atoms originate from two different O2 molecules. The progress of the oxygenation was monitored through changes in the resonance-enhanced Raman bands of the oxime unit. PMID- 26633245 TI - Multiple Binding Poses in the Hydrophobic Cavity of Bee Odorant Binding Protein AmelOBP14. AB - In the first step of olfaction, odorants are bound and solubilized by small globular odorant binding proteins (OBPs) which shuttle them to the membrane of a sensory neuron. Low ligand affinity and selectivity at this step enable the recognition of a wide range of chemicals. Honey bee Apis mellifera's OBP14 (AmelOBP14) binds different plant odorants in a largely hydrophobic cavity. In long molecular dynamics simulations in the presence and absence of ligand eugenol, we observe a highly dynamic C-terminal region which forms one side of the ligand-binding cavity, and the ligand drifts away from its crystallized orientation. Hamiltonian replica exchange simulations, allowing exchanges of conformations sampled by the real ligand with those sampled by a noninteracting dummy molecule and several intermediates, suggest an alternative, quite different ligand pose which is adopted immediately and which is stable in long simulations. Thermodynamic integration yields binding free energies which are in reasonable agreement with experimental data. PMID- 26633247 TI - The effectiveness of exercise programmes in patients with multiple myeloma: A literature review. AB - A limited number of clinical studies have investigated the effectiveness of participation in exercise training programmes for patients with multiple myeloma (MM), exploring the different biomedical, physical, psychological and quality of life. The aim of this literature review is to evaluate current quantitative and qualitative evidence concerning the effectiveness of participation in exercise programmes for patients with MM in improving physiological and/or psychological status. A literature search encompassing studies published between January 1998 and July 2013 was conducted through ten electronic databases. This search was further expanded through citation chaining, manual grey literature searches, and peer review consultation. In total, seven interventional studies were identified and appraised using Critical Appraisal Skill Programme (CASP) or Centre for Evidence-Based Management of Amsterdam (CEBMa). Though the majority of the studies presented encouraging data, however, three studies that implemented individualized exercise interventions for patients at different stages of MM and myeloablative treatment showed mixed results. In conclusion, the effectiveness of participation in exercise programmes remains unclear for patients with MM, as the studies reviewed were flawed by relatively weak methodological approaches. PMID- 26633248 TI - Meat consumption and cancer risk: a critical review of published meta-analyses. AB - Dietary habits play a substantial role for increasing or reducing cancer risk. We performed a critical review of scientific literature, to describe the findings of meta-analyses that explored the association between meat consumption and cancer risk. Overall, 42 eligible meta-analyses were included in this review, in which meat consumption was assumed from sheer statistics. Convincing association was found between larger intake of red meat and cancer, especially with colorectal, lung, esophageal and gastric malignancies. Increased consumption of processed meat was also found to be associated with colorectal, esophageal, gastric and bladder cancers. Enhanced intake of white meat or poultry was found to be negatively associated with some types of cancers. Larger beef consumption was significantly associated with cancer, whereas the risk was not increased consuming high amounts of pork. Our analysis suggest increased risk of cancer in subjects consuming large amounts of red and processed meat, but not in those with high intake of white meat or poultry. PMID- 26633249 TI - GABA mechanisms of the nucleus of the solitary tract regulates the cardiovascular and sympathetic effects of moxonidine. AB - The antihypertensive drugs moxonidine and clonidine are alpha2-adrenoceptor and imidazoline (I1) agonists. Previous results from our laboratory have shown that moxonidine can act in the commissural nucleus of the solitary tract (commNTS). In addition, some studies have shown that GABA or glutamate receptor blockade in the RVLM blunted the hypotension produced by these antihypertensive agents in spontaneously hypertensive rats. Therefore, in the present study we verify whether the cardiovascular and sympathetic effects produced by moxonidine in the commNTS are dependent on GABAergic or glutamatergic mechanisms. Mean arterial pressure (MAP) and splanchnic sympathetic nerve activity (sSNA) were recorded in urethane-anesthetized, and artificially-ventilated male Wistar rats (250-350 g). Injection of the GABAA antagonist bicuculline (25 pmol/50 nL) into the commNTS reduced the hypotension as well as the sympathoinhibition elicited by moxonidine. Prior injection of the glutamate receptor antagonist kynurenic acid (2.5 nmol/50 nL) into the commNTS was not effective in reducing the hypotension and sympathoinhibition elicited by moxonidine. Therefore, we conclude that the hypotensive and sympathoinhibitory effects elicited by microinjection of moxonidine into the commNTS are dependent on GABA receptors, but not ionotropic glutamate receptors. PMID- 26633250 TI - Impact of weekly feedback on test ordering patterns. AB - OBJECTIVES: We examined the impact of weekly feedback reports on the test ordering behavior of internal medicine residents. STUDY DESIGN: Retrospective analysis of a performance improvement effort. METHODS: In a large, urban, academic medical center, we extracted raw data on every inpatient laboratory test ordered by all internal medicine residents during two 26-week time periods. The pre-intervention phase established baseline ordering volume as each resident rotated through the various clinical services. The intervention consisted of a 1 hour educational seminar detailing the potential harm and costs of laboratory overutilization followed by the post intervention phase, which consisted of weekly feedback reports graphically illustrating individual versus group ordering patterns, where the identity of individual residents was protected. The total numbers of tests ordered during the 2 phases were compared using an independent t test. RESULTS: During the post intervention phase, we observed a net reduction of 21% in tests ordered-an average of 941 tests per week-with the greatest reduction in the chemistry section of the laboratory, followed by hematology, coagulation, and all others combined. This reduction in test volume corresponded to a $1.3 million reduction in charges. CONCLUSIONS: Providing physicians-in-training with a weekly feedback report detailing their test ordering volume in comparison with those of their peers is an effective method for reducing laboratory overutilization. Benefits to our approach include maintaining physician autonomy without alteration of existing infrastructure or disclosure of test fees. PMID- 26633251 TI - Testing novel patient financial incentives to increase breast cancer screening. AB - OBJECTIVES: To examine the effects of 3 types of low-cost financial incentives for patients, including a novel "person-centered" approach on breast cancer screening (mammogram) rates. STUDY DESIGN: Randomized controlled trial with 4 arms: 3 types of financial incentives ($15 gift card, entry into lottery for $250 gift card, and a person-centered incentive with choice of $15 gift card or lottery) and a control group. Sample included privately insured Tufts Health Plan members in Massachusetts who were women aged 42 to 69 years with no mammogram claim in >= 2.6 years. METHODS: A sample of 4700 eligible members were randomized to 4 study arms. The control group received a standard reminder letter and the incentive groups received a reminder letter plus an incentive offer for obtaining a mammogram within the next 4 months. Bivariate tests and multivariate logistic regression were used to assess the incentives' impact on mammogram receipt. Data were analyzed for 4427 members (after exclusions such as undeliverable mail). RESULTS: The percent of members receiving a mammogram during the study was 11.7% (gift card), 12.1% (lottery), 13.4% (person-centered/choice), and 11.9% (controls). Differences were not statistically significant in bivariate or multivariate full-sample analyses. In exploratory subgroup analyses of members with a mammogram during the most recent year prior to the study-defined gap, person-centered incentives were associated with a higher likelihood of mammogram receipt. CONCLUSIONS: None of the low-cost incentives tested had a statistically significant effect on mammogram rates in the full sample. Exploratory findings for members who were more recently screened suggest that they may be more responsive to person-centered incentives. PMID- 26633252 TI - Community pharmacy automatic refill program improves adherence to maintenance therapy and reduces wasted medication. AB - OBJECTIVES: Automatic prescription refill programs are a popular means of improving medication adherence. A concern is the potential for prescription drug wastage and unnecessary healthcare spending. We evaluated the impact of an automatic refill program on patterns of medication use. STUDY DESIGN: Retrospective propensity score matched cohort study with multivariable generalized linear modeling. METHODS: The setting of the study was a pharmacy benefit manager administering benefits for patients of retail pharmacies. Participants included patients on medication for chronic conditions; those receiving a 30-day supply (n = 153,964) and a 90-day supply (n = 100,394) were analyzed separately. The intervention was the automatic prescription refill program. Measures included medication possession ratio (MPR) and average days excess at the time of refill. The results are reported across 11 therapeutic classes. RESULTS: Overall, patients receiving 30-day supplies of medication in the automatic refill program had an MPR that was 3 points higher than those not in the refill program; among those receiving 90-day fills and in the refill program, the MPR was 1.4 points higher (P < .001 for both 30- and 90-day fills). The MPR was higher for members in the refill program across all therapeutic classes. Limiting our analysis to members receiving more than 365 days of medication, we found that patients who received 30-day fills and enrolled in the automatic refill program had 2.5 fewer days' oversupply than those in the control group, whereas automatic refill patients receiving 90-day supplies had 2.18 fewer days' oversupply than the controls (P < .001 for both 30- and 90-day fills). CONCLUSIONS: For this pharmacy provider, automatic refill programs result in improved adherence without adding to medication oversupply. PMID- 26633253 TI - Medicare Advantage: what explains its robust health? AB - The Medicare Advantage (MA) program continues to grow and thrive, despite plan payment cuts imposed through the Affordable Care Act. What explains this surprising outcome (one that is strikingly different than the experience of MA plans in the late 1990s, when payment cuts led to dramatic shrinkage in enrollment and curtailment of plans)? This analysis argues that a combination of factors, including the way payment cuts were imposed, the plan offerings, the characteristics of beneficiaries, and the way they make choices together explain the program's current health. Understanding these factors is important for MA, Medicare, and, more generally, for participants in new payment models. PMID- 26633254 TI - Medicare's Bundled Payments for Care Improvement initiative: expanding enrollment suggests potential for large impact. AB - OBJECTIVES: Aiming to encourage care coordination and cost efficiency, the Center for Medicare and Medicaid Innovation (CMMI) launched the Bundled Payments for Care Improvement (BPCI) initiative in 2013. To help gauge the program's potential impact and generalizability, we describe early and current participants. STUDY DESIGN: We examined the cross-sectional association between BPCI participation and providers' structural and cost characteristics. METHODS: Using data from October 2013 and June 2014, we quantified changes in BPCI participation. We described structural differences between participating and nonparticipating hospitals using t tests and chi2 tests, and we used the Cochrane-Armitage test to assess whether participants were more likely be in higher 90-day episode cost quintiles than their peers at baseline (2009-2010). RESULTS: Overall (risk bearing and non-risk-bearing) participation in BPCI increased from about 400 in October 2013 to more than 2000 in June 2014-attributable, in part, to Model 2, the most comprehensive of the 4 models offered by CMMI for provider participation. Model 2 hospitals increasingly resemble eligible but nonparticipating hospitals. For the most commonly chosen condition of hip replacement, Model 2 hospitals were not costlier than their peers. Hospitals used to make up 97% of Model 2 participants, but physician practices now comprise a substantial number of Model 2 participants. However, most BPCI participants have not yet begun to bear financial risk. Risk-bearing Model 2 hospitals are a smaller and less representative group, with higher baseline costs for hip replacement than their peers. CONCLUSIONS: Growing participation in BPCI suggests strong interest in bundled payments. The long-term impact of BPCI will depend on CMMI's ability to persuade interested but non-risk-bearing participants to bear risk. PMID- 26633255 TI - Physician response to patient request for unnecessary care. AB - OBJECTIVES: Evaluating unnecessary US medical practices, and the strategies that reduce them, are increasingly recognized as crucial to healthcare financing sustainability. Provider factors are known to affect unnecessary medical practices, yet little is known about how physician responses to patient requests for unnecessary care affect these practices. Among primary care physicians (PCPs), we investigated 2 types of unnecessary medical practices triggered by patient requests: a) unnecessary specialty referrals and b) prescriptions for brand-name drugs when generic alternatives are available. STUDY DESIGN AND METHODS: We used data from a survey of a nationally representative sample of 840 US PCPs in 2009. Response rates for family practice (n = 274), internal medicine (n = 257), and pediatrics (n = 309) were 67.5%, 60.8%, and 72.7%, respectively. RESULTS: In response to patient requests, 51.9% of PCPs reported making unnecessary specialty referrals and 38.7% prescribed brand-name drugs. Family physicians (odds ratio [OR], 2.77; 95% CI, 1.77-4.34) and internal medicine physicians (OR, 4.51; 95% CI, 2.87-7.06) were more likely than pediatricians to prescribe brand-name drugs. PCP specialty was similarly associated with unnecessary referrals. Other predictors of acquiescence to patient requests included interactions with drug/device representatives, more years of clinical experience, seeing fewer safety net patients, and solo/2-person practice organizations. Area-level Medicare spending was not associated with the 2 unnecessary practices. CONCLUSIONS: Many PCPs reported acquiescing to patient requests for unnecessary care. Provider and organizational factors predicted this behavior. Policies aimed at reducing such practice could improve care quality and lower cost. Patient and physician incentives that can potentially reduce unnecessary medical practices warrant exploration. PMID- 26633256 TI - Moving risk to physicians. PMID- 26633257 TI - Total Synthesis of (+)-Cytosporolide A via a Biomimetic Hetero-Diels-Alder Reaction. AB - The first total synthesis of (+)-cytosporolide A was achieved by a biomimetic hetero-Diels-Alder reaction of (-)-fuscoatrol A with o-quinone methide generated from (+)-CJ-12,373. The dienophile, highly oxygenated caryophyllene sesquiterpenoid (-)-fuscoatrol A, was synthesized from the synthetic intermediate in our previous total synthesis of (+)-pestalotiopsin A. The o-quinone methide precursor, isochroman carboxylic acid (+)-CJ-12,373, was synthesized through a Kolbe-Schmitt reaction and an oxa-Pictet-Spengler reaction. The hetero-Diels Alder reaction of these two compounds proceeded with complete chemo-, regio-, and stereoselectivity to produce the complicated pentacyclic ring system of the cytosporolide skeleton. This total synthesis unambiguously demonstrates that natural cytosporolide A has the structure previously suggested. PMID- 26633259 TI - Correction to "Adsorption and Separation of Small Hydrocarbons on the Flexible, Vanadium-Containing MOF, COMOC-2". PMID- 26633258 TI - A mass spectrometric insight into the origins of benign gynecological disorders. AB - Applications of mass spectrometry (MS) are rapidly expanding and encompass molecular and cellular biology. MS aids in the analysis of in vivo global molecular alterations, identifying potential biomarkers which may improve diagnosis and treatment of various pathologies. MS has added new dimensionality to medical research. Pioneering gynecologists now study molecular mechanisms underlying female reproductive pathology with MS-based tools. Although benign gynecologic disorders including endometriosis, adenomyosis, leiomyoma, and polycystic ovarian syndrome (PCOS) carry low mortality rates, they cause significant physical, mental, and social detriments. Additionally, some benign disorders are unfortunately associated with malignancies. MS-based technology can detect malignant changes in formerly benign proteomes and metabolomes with distinct advantages of speed, sensitivity, and specificity. We present the use of MS in proteomics and metabolomics, and summarize the current understanding of the molecular pathways concerning female reproductive anatomy. Highlight discoveries of novel protein and metabolite biomarkers via MS-based technology, we underscore the clinical application of these techniques in the diagnosis and management of benign gynecological disorders. (c) 2015 Wiley Periodicals, Inc. Mass Spec Rev 36:450-470, 2017. PMID- 26633260 TI - A Novel Strategy through Combining iRGD Peptide with Tumor-Microenvironment Responsive and Multistage Nanoparticles for Deep Tumor Penetration. AB - Despite the great achievements that nanomedicines have obtained so far, deep penetration of nanomedicines into tumors is still a major challenge in tumor treatment. The enhanced permeability and retention (EPR) effect was the main theoretical foundation for using nanomedicines to treat solid tumor. However, the antitumor efficiency is modest because the tumor is heterogeneous, with dense collagen matrix, abnormal tumor vasculature, and lymphatic system. Nanomedicines could only passively accumulate near leaky site of tumor vessels, and they cannot reach the deep region of tumor. To enhance further the tumor penetration efficiency, we developed a novel strategy of coadministering cell-homing penetration peptide iRGD with size-shrinkable and tumor-microenvironment responsive multistage system (DOX-AuNPs-GNPs) to overcome these barriers. First, iRGD could specifically increase the permeability of tumor vascular and tumor tissue, leading to more DOX-AuNPs-GNPs leaking out from tumor vasculature. Second, the multistage system passively accumulated in tumor tissue and shrank from 131.1 to 46.6 nm to reach the deep region of tumor. In vitro, coadministering iRGD with DOX-AuNPs-GNPs showed higher cellular uptake and apoptosis ratio. In vivo, coadministering iRGD with DOX-AuNPs-GNPs presented higher penetration and accumulation in tumor than giving DOX-AuNPs-GNPs alone, leading to the best antitumor efficiency in 4T1 tumor-bearing mouse model. PMID- 26633261 TI - SFC-APLI-(TOF)MS: Hyphenation of Supercritical Fluid Chromatography to Atmospheric Pressure Laser Ionization Mass Spectrometry. AB - Atmospheric-pressure laser ionization mass spectrometry (APLI-MS) is a powerful method for the analysis of polycyclic aromatic hydrocarbon (PAH) molecules, which are ionized in a selective and highly sensitive way via resonance-enhanced multiphoton ionization. APLI was presented in 2005 and has been hyphenated successfully to chromatographic separation techniques like high performance liquid chromatography (HPLC) and gas chromatography (GC). In order to expand the portfolio of chromatographic couplings to APLI, a new hyphenation setup of APLI and supercritical-fluid chromatography (SFC) was constructed and aim of this work. Here, we demonstrate the first hyphenation of SFC and APLI in a simple designed way with respect to different optimization steps to ensure a sensitive analysis. The new setup permits qualitative and quantitative determination of native and also more polar PAH molecules. As a result of the altered ambient characteristics within the source enclosure, the quantification of 1 hydroxypyrene (1-HP) in human urine is possible without prior derivatization. The limit of detection for 1-HP by SFC-APLI-TOF(MS) was found to be 0.5 MUg L(-1), which is lower than the 1-HP concentrations found in exposed persons. PMID- 26633262 TI - Corticosteroids for treating sepsis. AB - BACKGROUND: Sepsis occurs when an infection is complicated by organ failures as defined by a sequential organ failure assessment (SOFA) score of two or higher. Sepsis may be complicated by impaired corticosteroid metabolism. Giving corticosteroids may benefit patients. The original review was published in 2004 and was updated in 2010 and again in 2015. OBJECTIVES: To examine the effects of corticosteroids on death at one month in patients with sepsis, and to examine whether dose and duration of corticosteroids influence patient response to this treatment. SEARCH METHODS: We searched the Central Register of Controlled Trials (CENTRAL; 2014, Issue 10), MEDLINE (October 2014), EMBASE (October 2014), Latin American Caribbean Health Sciences Literature (LILACS; October 2014) and reference lists of articles, and we contacted trial authors. The original searches were performed in August 2003 and in October 2009. SELECTION CRITERIA: We included randomized controlled trials of corticosteroids versus placebo or supportive treatment in patients with sepsis. DATA COLLECTION AND ANALYSIS: All review authors agreed on the eligibility of trials. One review author extracted data, which were checked by the other review authors, and by the primary author of the paper when possible. We obtained some missing data from trial authors. We assessed the methodological quality of trials. MAIN RESULTS: We identified nine additional studies since the last update, for a total of 33 eligible trials (n = 4268 participants). Twenty-three of these 33 trials were at low risk of selection bias, 22 were at low risk of performance and detection bias, 27 were at low risk of attrition bias and 14 were at low risk of selective reporting.Corticosteroids reduced 28-day mortality (27 trials; n = 3176; risk ratio (RR) 0.87, 95% confidence interval (CI) 0.76 to 1.00; P value = 0.05, random-effects model). The quality of evidence for this outcome was downgraded from high to low for imprecision (upper limit of 95% CI = 1) and for inconsistency (significant heterogeneity across trial results). Heterogeneity was related in part to the dosing strategy. Treatment with a long course of low-dose corticosteroids significantly reduced 28-day mortality (22 trials; RR 0.87, 95% CI 0.78 to 0.97; P value = 0.01, fixed-effect model). The quality of evidence was downgraded from high to moderate for inconsistency (owing to non-significant effects shown by one large trial). Corticosteroids also reduced mortality rate in the intensive care unit (13 trials; RR 0.82, 95% CI 0.68 to 1.00; P value = 0.04, random-effects model) and at the hospital (17 trials; RR 0.85, 95% CI 0.73 to 0.98; P value = 0.03, random-effects model). Quality of the evidence for in-hospital mortality was downgraded from high to moderate for inconsistency and imprecision (upper limit of 95% CI for RR approaching 1). Corticosteroids increased the proportion of shock reversal by day seven (12 trials; RR 1.31, 95% CI 1.14 to 1.51; P value = 0.0001) and by day 28 (seven trials; n = 1013; RR 1.11, 95% CI 1.02 to 1.21; P value = 0.01) and reduced the SOFA score by day seven (eight trials; mean difference (MD) -1.53, 95% CI -2.04 to -1.03; P value < 0.00001, random-effects model) and survivors' length of stay in the intensive care unit (10 trials; MD 2.19, 95% CI -3.93 to -0.46; P value = 0.01, fixed-effect model) without inducing gastroduodenal bleeding (19 trials; RR 1.24, 95% CI 0. 92 to 1.67; P value = 0.15, fixed-effect model), superinfection (19 trials; RR 1.02, 95% CI 0.87 to 1.20; P value = 0.81, fixed-effect model) or neuromuscular weakness (three trials; RR 0.62, 95% CI 0.21 to 1.88; P value = 0.40, fixed-effect model). Corticosteroid increased the risk of hyperglycaemia (13 trials; RR 1.26, 95% CI 1.16 to 1.37; P value < 0.00001, fixed-effect model) and hypernatraemia (three trials; RR 1.64, 95% CI 1.28 to 2.09; P value < 0.0001, fixed-effect model). AUTHORS' CONCLUSIONS: Overall, low-quality evidence indicates that corticosteroids reduce mortality among patients with sepsis. Moderate-quality evidence suggests that a long course of low-dose corticosteroids reduced 28-day mortality without inducing major complications and led to an increase in metabolic disorders. PMID- 26633263 TI - Rosuvastatin enhances anti-inflammatory and inhibits pro-inflammatory functions in cultured microglial cells. AB - Microglial activation results in profound morphological, functional and gene expression changes that affect the pro- and anti-inflammatory mechanisms of these cells. Although statins have beneficial effects on inflammation, they have not been thoroughly investigated for their ability to affect microglial functions. Therefore the effects of rosuvastatin, one of the most commonly prescribed drugs in cardiovascular therapy, either alone or in combination with bacterial lipopolysaccharide (LPS), were profiled in pure microglial cultures derived from the forebrains of 18-day-old rat embryos. To reveal the effects of rosuvastatin on a number of pro- and anti-inflammatory mechanisms, we performed morphometric, functional and gene expression studies relating to cell adhesion and proliferation, phagocytosis, pro- and anti-inflammatory cytokine (IL-1beta, tumor necrosis factor alpha (TNF-alpha) and IL-10, respectively) production, and the expression of various inflammation-related genes, including those related to the above morphological parameters and cellular functions. We found that microglia could be an important therapeutic target of rosuvastatin. In unchallenged (control) microglia, rosuvastatin inhibited proliferation and cell adhesion, but promoted microspike formation and elevated the expression of certain anti inflammatory genes (Cxcl1, Ccl5, Mbl2), while phagocytosis or pro- and anti inflammatory cytokine production were unaffected. Moreover, rosuvastatin markedly inhibited microglial activation in LPS-challenged cells by affecting both their morphology and functions as it inhibited LPS-elicited phagocytosis and inhibited pro-inflammatory cytokine (IL-1beta, TNF-alpha) production, concomitantly increasing the level of IL-10, an anti-inflammatory cytokine. Finally, rosuvastatin beneficially and differentially affected the expression of a number of inflammation-related genes in LPS-challenged cells by inhibiting numerous pro inflammatory and stimulating several anti-inflammatory genes. Since the microglia could elicit pro-inflammatory responses leading to neurodegeneration, it is important to attenuate such mechanisms and promote anti-inflammatory properties, and develop prophylactic therapies. By beneficially regulating both pro- and anti inflammatory microglial functions, rosuvastatin may be considered as a prophylactic agent in the prevention of inflammation-related neurological disorders. PMID- 26633264 TI - Impaired implicit learning and feedback processing after stroke. AB - The ability to learn is assumed to support successful recovery and rehabilitation therapy after stroke. Hence, learning impairments may reduce the recovery potential. Here, the hypothesis is tested that stroke survivors have deficits in feedback-driven implicit learning. Stroke survivors (n=30) and healthy age matched control subjects (n=21) learned a probabilistic classification task with brain activation measured using functional magnetic resonance imaging in a subset of these individuals (17 stroke and 10 controls). Stroke subjects learned slower than controls to classify cues. After being rewarded with a smiley face, they were less likely to give the same response when the cue was repeated. Stroke subjects showed reduced brain activation in putamen, pallidum, thalamus, frontal and prefrontal cortices and cerebellum when compared with controls. Lesion analysis identified those stroke survivors as learning-impaired who had lesions in frontal areas, putamen, thalamus, caudate and insula. Lesion laterality had no effect on learning efficacy or brain activation. These findings suggest that stroke survivors have deficits in reinforcement learning that may be related to dysfunctional processing of feedback-based decision-making, reward signals and working memory. PMID- 26633265 TI - Dynamics of directional coupling underlying spike-wave discharges. AB - PURPOSE: Spike and wave discharges (SWDs), generated within cortico-thalamo cortical networks, are the electroencephalographic biomarker of absence epilepsy. The current work aims to identify mechanisms of SWD initiation, maintenance and termination by the analyses of dynamics and directionality of mutual interactions between the neocortex and various functionally different thalamic nuclei. METHODS: Local-field potential recordings of 16 male Wistar Albino Glaxo from Rijswijk (WAG/Rij) rats, equipped with electrodes targeting layer 4-6 of the somatosensory cortex, rostral and caudal reticular thalamic nuclei (rRTN and cRTN), ventro-posteromedial (VPM), anterior (ATN) and posterior (PO) thalamic nuclei, were obtained. 3s epochs prior to SWD onset, after SWD onset, prior to SWD offset and after SWD offset were analyzed with newly developed time-variant adapted nonlinear Granger causality. RESULTS: A gradual increase in coupling toward SWD onset between cortico-cortical pairs appears as early as 2s preictally. Next first unidirectional increase in coupling is noticed in a restricted number of cortico-thalamic and thalamo-cortical channel pairs, which turn into bidirectional coupling approaching SWD onset, and a gradual increase of intrathalamic coupling. Seizure onset is characterized by a coupling decrease for more than a second in a majority of channel pairs, only the cortex kept driving the cRTN. Intrathalamically the cRTN drives the PO, VPM and ATN. Most channel pairs no longer show differences in coupling with baseline during SWD maintenance, a major exception is the unidirectional coupling between cortex and cRTN. Toward the end of SWDs, more and more channel pairs show an increase in often bidirectional coupling, this increase suddenly vanishes at SWD offset. CONCLUSION: The initiation of SWD is due to a gradual increase in intracortical coupling, followed by a selective increase in first unidirectional and later bidirectional coupling between the cortex and thalamus and also intrathalamically. Once the network is oscillating, coupling decreases in most of the channel pairs, although the cortex keeps its influence on the cRTN. The SWD is dampened by a gradual increase in coupling strength and in the number of channel pairs that influence each other; the latter might represent an endogenous brake of SWDs. PMID- 26633266 TI - Human recognition memory and conflict control: An event-related potential study. AB - The relationship between recognition memory and cognitive control is an important research topic. The current study investigated how conflict control influences an individual's emotional memory. During the encoding phase, participants were required to judge the affective valence of a Chinese Chengyu word (either positive or negative) in a modified Simon paradigm and to remember the word. Half of the words were presented in the congruent condition and the other half were displayed in the incongruent condition. During the retrieval phase, participants were instructed to make an 'old/new judgment' and decide whether the word had been presented previously. Electrophysiological responses were recorded using the event-related potential (ERP) technique. The behavioral results of retrieval processes showed that participants remembered more positive than negative words when they were encoded in the congruent condition. The electrophysiological results revealed that the retrieval of words encoded in the incongruent condition elicited less negative frontal negativity (FN) and early posterior negativity (EPN) amplitudes than those encoded in the congruent condition. The retrieval of words encoded in the incongruent condition induced greater late positive complex (LPC) amplitudes, relative to those encoded in the congruent condition on the left hemisphere. It was also observed that the recognition of positive words induced faster LPC responses than negative words when they were encoded in the incongruent condition. The present electrophysiological study illustrates that emotional memory processes may be affected by conflict control. PMID- 26633267 TI - [The harm to others from drinking: A population study]. AB - BACKGROUND: Alcohol can harm both drinkers and their human environment. Most of research in Chile has focused on the drinker. This work focuses on the damage to others. Governmental expenditures due to drinking are estimated to quadruple the income earned through taxation. AIM: To report the results of a population survey conducted in Chile in 2013 to assess the harm done to others from drinking by a known or unknown drinker. MATERIAL AND METHODS: A household survey of a sample of 1500 subjects living in urban areas, predominantly over 50.000 inhabitants, was conducted by trained interviewers. RESULTS: A significant number of respondents reported that the effect of alcohol consumption by third parties was somewhat (18.7%) or very negative (14.8%). The most frequent negative effects were verbal abuse (37.4%), being bullied (17.4%), feeling fearful at home or in a private meeting (19.6%) and family problems (16.9%). CONCLUSIONS: About one third of Chileans surveyed have suffered negative effects due to alcohol consumption of a known or unknown drinker. This finding signals the need of designing public policies addressed to minimize or prevent collateral effects of drinking. PMID- 26633268 TI - [Association between serotonin transporter and monoamine oxidase A gene polymorphisms and depression]. AB - BACKGROUND: Serotonin plays a central role regulating mood and on the development of depressive disorders. AIM: To study whether 5HTTLPR functional polymorphisms in the serotonin transporter gene or the Monoamine oxidase A gene (uMAOA) were risk markers for depression. MATERIAL AND METHODS: The Composite International Diagnostic Interview (CIDI) was applied to 1,062 consultants in primary health care centers aged between 18 and 75 years to establish the diagnosis of depression. A sample of saliva was obtained for DNA extraction and genetic analyses. RESULTS: No association between the presence of depressive disorders and 5HTTLPR (ss) or uMAOA (3/3) risk genotypes was found. Psychological abuse and the presence of two or more life events were found to be predictors of depression in the studied sample. CONCLUSIONS: In this study, 5HTTLPR and uMAOA polymorphisms were not risk factors for depression. However, psychological abuse and the presence of two or more life events were risk factors for depressive disorders. PMID- 26633269 TI - [Hemoglobin variants in Colombian patients referred to discard hemoglobinopathies]. AB - BACKGROUND: Oxygen transport is altered in hemoglobinopathies. AIM: To study the distribution of hemoglobinopathies in Andean subjects without African ancestry. MATERIAL AND METHODS: We analyzed blood samples of 1,407 subjects aged 18 to 59 years (58% females), living in the central Andean region of Colombia, referred to discard hemoglobinopathies. The frequency and type of hemoglobinopathy was established by capillary and agarose gel electrophoresis. RESULTS: The frequency of hemoglobinopathies was 34.5% and higher among females. The structural variants found were: AS-heterozygous hemoglobin (8.1%), homozygous SS (3.7%), heterozygous SC (2.2%), AC heterozygotes (0.5%) and heterozygous AE (0.3%). Quantitative variants found were Hb A-Beta thalassemia (13.91%) and Hb H (0.06%), Beta thalassemia heterozygotes C (0.88%), S-Beta thalassemia heterozygotes (6.07%) and compound heterozygous SC/Beta thalassemia (0.25%), with a persistence of fetal hemoglobin 0. Composite thalassemia was also found in 31%. All techniques showed good correlation and capillary electrophoresis demonstrated a greater detection of hemoglobin variants. CONCLUSIONS: The frequency of hemoglobin variants in the analyzed population was high, which is an important public health indicator. The most common hemoglobin variant was HbA/Increased structural Hb A2 and the mos frequent structural hemoglobinopathy was sickle cell trait. Capillary electrophoresis can discern any Hb variants present in the population. PMID- 26633270 TI - [Results of acute myeloid leukemia treatment. Analysis of 63 patients between 2010-2014]. AB - BACKGROUND: Acute myeloid leukemia (AML) is the most common acute leukemia in adults, emphasizing its high recurrence rate despite hematopoietic cell transplantation (HCT). AIM: To report the results of AML treatment at the Catholic University of Chile Clinical Hospital. PATIENTS AND METHODS: Review of medical records of patients with AML. RESULTS: 63 patients, median age 55.4 years (range:16-89), treated between 2010 and 2014. Admission laboratory values showed (median values): leukocytes 45.989/mm3, hemoglobin 9.1 g/dl, platelets 75.548/mm3, peripheral blood blasts 38% and bone marrow blasts 74%. According to cytogenetic risk classification we observed the following groups: favorable 8% (n = 5), intermediate 51% (n = 32), unfavorable 13% (n = 8) and unknown 28% (n = 17). Seventy five percent of patients received induction chemotherapy and 25% palliative care. Median survival of treated and palliative care patients was 27.3 and 1 month respectively. Induction chemotherapy (IC) mortality (ICM) was 4.2%. Seventy percent (n = 33) of patients who received IC had complete response (CR) with a 3-year relapse free survival (RFS) of 25% and overall survival (OS) of 31%. Multivariate analysis demonstrated that achievement of CR, cytogenetic risk group and receiving consolidation chemotherapy were significantly associated with better RFS and OS. CONCLUSIONS: AML treatment with standard chemotherapy in our center achieves similar results to what has been described in international series regarding induction rates and ICM, however RFS and OS are still very low, especially in intermediate and high cytogenetic risk groups. PMID- 26633272 TI - [Endoscopic submucosal dissection in early gastric cancer: Experience in 16 patients]. AB - BACKGROUND: Endoscopic submucosal dissection (ESD) is a minimally invasive procedure that allows curative treatment of early gastric cancer (EGC) in selected patients. AIM: To report our initial experience with ESD. MATERIAL AND METHODS: Analysis of prospective data from 16 patients aged 61 to 84 years, who underwent ESD between December 2011 and June 2014. Tumor type, operative time, hospitalization length, oncologic outcomes, complications and short-term follow up were registered. RESULTS: En-block resection was achieved in all cases. The median operative time was 135 min (range: 50-320 min). Specimens' median size was 3.5 cm (range: 3-10). All the resections were R0. In 14 patients ESD was considered curative. In two patients, ESD was considered potentially non-curative due to the presence pathological risk factors for lymph-node metastases in the biopsy specimen. Both patients underwent laparoscopic gastrectomy with lymph-node dissection. There was one case of gastric wall perforation that was repaired by laparoscopic suture. There was no mortality. The median follow-up time was 15 months (range: 2-30 months). CONCLUSIONS: ESD is a feasible and safe procedure in our institution with good results in this initial experience. PMID- 26633271 TI - [Characterization of pesticide exposures reported between 2006 and 2013 to a poison information center in Chile]. AB - BACKGROUND: Pesticides are widely used to increase crop yields and vector control. However, both acute and chronic exposure have health consequences. There is paucity of information about the global occurrence of pesticide poisonings. AIM: To characterize the reports of pesticide exposures received by a University Poison Information Center. MATERIAL AND METHODS: All pesticide exposures reported in Chile between 2006 and 2013 were analyzed. A data-collection sheet provided by the International Programme on Chemical Safety of the World Health Organization, was used to collect information. RESULTS: In the study period, 13,181 reports were analyzed. The main age groups exposed were preschoolers and adults. Sixty one percent of exposures occurred accidentally and 24.8% were suicide attempts. Exposures to acetylcholinesterase inhibitors was reported in 29.3% of cases, to superwarfarin rodenticides in 28.5% and to pyrethroids in 24.0%. An increased risk of suicide attempts with pesticides was observed among women, when compared with men (odds ratio: 1.5; 95% confidence intervals: 1.4-1.6; p < 0.001). The risk was higher among teenage girls. CONCLUSIONS: The amount of cases under acetyl cholinesterase inhibitor exposure, the most toxic pesticides currently in use should be highlighted. Workers should be educated and all cases should be reported to take actions aiming at reducing these events. PMID- 26633273 TI - [Work activity of medical graduates at the University of Chile: Analysis per campus and graduation year]. AB - BACKGROUND: The University promotes practices and values that influence their students in the pursuit of their occupational interests. AIM: To determine working activity features of medical graduates from the University of Chile and their relationship with undergraduate characteristics. MATERIAL AND METHODS: Medical graduates of the University of Chile were invited to complete a survey using a virtual server. The survey collected demographic, socioeconomic, work and guild characteristics. Undergraduate data, as campus and graduation years were obtained. RESULTS: The survey was completed by 333 physicians (167 men) aged 29 +/- 2 years, graduated from 2007 to 2010. Ninety four percent had a paid work, 59% were employed in public hospitals and 28% in primary care health centers. The predominant type of work activity was performed in the public health service (55%), while 17% worked in private health services. Activity in public health services or primary care were significantly associated with the pursuit of undergraduate clinical activities in specific campuses of the University. CONCLUSIONS: The employment rate of medical graduates was high. Differences observed by graduation campus and type of work may be due to the modeling that students receive from teachers. PMID- 26633274 TI - [CEACLIN, an instrument suited to identify medical students' strategies to learn in pre-clerkship years]. AB - BACKGROUND: Upon the beginning of pre-clerkship years, medical students must develop strategies to learn from experience and to improve their relational skills to communicate with patients. AIM: To develop an instrument to identify the strategies used by medical students to learn in clinical contexts. MATERIAL AND METHODS: Using a Delfi technique to reach consensus, a national panel of students and clinical teachers from 15 Chilean medical schools analyzed an 80 item questionnaire built from perceptions of Chilean students and teachers from one medical school. After two Delfi rounds and a pilot application, a 48-item questionnaire was obtained. Its reliability and construct validity were assessed by Cronbach alpha coefficient and factor analysis, respectively, on the base of an application to 336 medical students. RESULTS: The questionnaire developed, named CEACLIN, is highly reliable (alpha= 0.84). Its inner structure is made of eleven factors: Autonomy, Solving doubts and problems, Searching and organizing information, Proactivity, Reaching to others, Paying attention and emotions, Searching for trust, Evading burden, Coping with burden, Motivation and Postponing the personal life. All together, these factors account for 47.4 % of the variance. CONCLUSIONS: CEACLIN is a valid, reliable and easy to use instrument suited to identify students' strategies to learn in pre-clerkship years. Many of its items allude to concepts of theories of experiential learning and motivation. We hope that CEACLIN will be of value to medical students and clinical teachers to improve the learning and teaching of clinical reasoning and communication skills. PMID- 26633275 TI - [Translation and cultural adaptation of the Composite Physical Function for its use in Chile]. AB - Aging is directly related with loss of physical independency. Composite Physical Function questionnaire (CPF) assess, throw 12 items, a range of daily life activities in order to determine dependency levels in elderly. However, there is not a Spanish version of this instrument. AIM: To translate and culturally adapt the CPF to Spanish for its use in Chilean elderly. METHOD: Standardized international methodology was used in this study, which consisted in double direct translation to Spanish, harmonization of versions and back-translation to English. Acceptability and familiarity of the obtained version was analyzed using probing and paraphrasing methods using a sample of 20 older adults aged from 65 to 80 years old. RESULTS: All items were clear and understandable, although minor adaptations needed to be done in order to improve the understandability of two items. These adaptations consisted in adding information in brackets at the end of the sentence. CONCLUSION: Spanish version of the CPF questionnaire was obtained to its use in Chile. This questionnaire has been proved to be understandable and adapted to its use in Chilean older adults. Its ease of use makes this questionnaire potentially useful in future researches and surveys. PMID- 26633276 TI - [Molecular diagnosis as a strategy for differential diagnosis and at early ages of neurofibromatosis type 1 (NF1)]. AB - Neurofibromatosis type 1 (NF1), is a haploinsufficient and multisystemic disease, caused by inherited or sporadic mutations in the NF1 gene. Its incidence is one in 2,500 to 3,000 individuals, it has an autosomal dominant pattern of inheritance, high clinical variability, complete penetrance and age-dependent complications. Neurofibromin is the product of the NF1 gene and is believed to act as a tumor suppressor since the loss of its function has been associated with benign and malignant tumors in neural crest-derived tissues. Only two correlations between clinical phenotype and mutant alleles in the NF1 gene have been observed. The established criteria for disease diagnosis are very efficient in adults and children older than 3 years of age, but not for children under this age. Mutational analysis is therefore recommended to confirm the disease in young children with a negative family history. A pathogenic mutation in the NF1 should be added to the list of diagnostic criteria. Mutational analysis is also recommended for differential diagnosis and for prenatal or pre-implantation genetic diagnosis, taking into consideration the family history and the type of method to be applied. Molecular studies of this disease using different complimentary molecular techniques and bioinformatics tools have characterized NF1 gene mutations at both the DNA and mRNA levels, increasing the mutational spectrum. Consequently, about 1,289 defects have been reported to date, mainly nonsense/missense mutations, deletions and splice site defects. PMID- 26633277 TI - [Presumed consent and reciprocity as means to increase organ availability for transplantation]. AB - Chile became the third country in the world (after Israel and Singapore) to introduce the rule of reciprocity to receive an allograft. This means that if an individual opts for not being an organ donor, loses priority to receive a transplant. Despite the difficulties associated with its implementation, the recent Chilean reform that also incorporated the presumed consent, should be studied by those countries that are trying to overcome the severe lack of organ availability for transplantation. PMID- 26633278 TI - [Rethinking the selection of medical students, considering non-cognitive skills]. AB - In Chile the only requirement to study medicine is to obtain an academic achievement score over a certain cutoff value. However, the literature states that this type of selection is insufficient, since the medical profession requires cognitive and non-cognitive skills. These abilities are associated with better adaptation and academic success, as well as less dropping out. Therefore, those skills should be considered in the selection process to assure that the education goals are met. The aim of this study was to review the existing literature regarding the selection and evaluation criteria for students who are applying to medical schools. It was evident that Chilean medical schools need to establish appropriate criteria to ensure a more inclusive and fair admission. They need to design a system of admission with solid evidence of validity and reliability, complementary to the current form of student selection. This system should be considered common to all schools of medicine and, in turn, consider the sensibilities of the particular mission of each school, since academic, cognitive, inter- and intrapersonal aspects may vary among them. PMID- 26633279 TI - [Smoking among undergraduate university students]. AB - BACKGROUND: Smoking is one of the major Public Health problems worldwide. AIM: To study the frequency of tobacco smoking among undergraduate students of a Chilean university. MATERIAL AND METHODS: An opinion survey was sent by e-mail to all undergraduate students of a university, registering gender, age, study years, study area, smoking behavior, motivation (reason for smoking), intention to quit and tobacco law perception. RESULTS: 1,008 (57% females) out of 11,679 surveys were answered back. Prevalence of active smoking among respondents was 36%, without association with gender, age or years of study. However, students from scientific areas had a lower prevalence. Seventy seven percent of smokers manifested the intention to quit the habit or have started quitting already. Ninety six percent were acquainted with the tobacco law and by 73% agreed with it. CONCLUSIONS: Smoking is highly prevalent among university students. It is necessary to develop strategies for smoking cessation within universities that may prevent or reduce tobacco smoking among students. PMID- 26633280 TI - [Mitral valve repair for degenerative mitral insufficiency: likelihood of success, early and-long term results at 20 years]. AB - BACKGROUND: The 2014 Guidelines for the Management of Patients with Valvular Heart Disease require to know the probability of success and operative mortality of Mitral Valve Repair (MVR) for Degenerative Mitral Insufficiency (DMI) at a given institution. AIM: To assess the probability of success, operative mortality and long-term results of MVR for DMI. PATIENTS AND METHODS: The database of the Cardiovascular Surgery Service was reviewed for the period December 1991 to December 2013. Long-term survival information was obtained from death certificate records of the Chilean Identification Service. RESULTS: One hundred forty seven patients with DMI were identified, all operated by one author (RZ). In 28 (19%) the mitral valve was replaced, including three patients in whom a MVR was intended without success. A successful MVR was performed in 119 patients (81%). The probability of a successful MVR was 97.5% (119 of 122). Prolapsed posterior leaflet was present in 81% and annulus dilatation in 60% of cases. The most frequent surgical procedures were quadrilateral resection (83%) and chordal transfer (13%). A mitral annuloplasty was performed in 92% of cases. Operative mortality was 0.8%. At the end of a 9.9 (0 - 22.7) years follow-up, 87 patients (73%) were alive and mean survival was 16.9 years. Survival rates at 5, 10, 15 and 20 years were 91%, 78%, 71% and 50%, respectively. Six patients were re operated, due to mitral valve dysfunction in three. Mean re-operation free survival was 21.4 years. Echocardiographic follow-up was 75% completed at an average of 64 months; 84% of cases had no or only 1+ mitral regurgitation. CONCLUSIONS: In our experience, MVR for DMI had an operative mortality below 1% and a probability of success greater than 95%, with excellent long-term results. PMID- 26633281 TI - [Primary cutaneous anaplastic large cell lymphoma: Report of one case]. AB - Primary cutaneous anaplastic large cell lymphoma (PCALCL) is within the spectrum of cutaneous CD30-positive lymphoproliferative disorders. It presents as localized or multifocal tumors or plaques and carries an excellent long-term prognosis even in cases with regional and/or ipsilateral lymph node involvement or in cases of recurrent disease. We report a 34 year-old female with a thigh lesion. Skin biopsy confirmed the diagnosis of PCALCL. The patient was strictly monitored but no treatment was instituted and the tumor regressed spontaneously. After 24 months of follow-up the patient remains free of disease without new lesions. PMID- 26633282 TI - [Are the consultant strategy and health objectives aligned with the reality of population ageing?]. PMID- 26633283 TI - [How many undergraduate medical students are involved in medical research?]. PMID- 26633284 TI - [How many undergraduate medical students are involved in medical research? A reply]. PMID- 26633285 TI - [Obese but malnourished: a serious problem in Latin America]. PMID- 26633286 TI - Conformationally Locked Tolans, beta-Sheet Structures, and Photophysical Properties. AB - Conformationally locked tetrasubstituted tolans were synthesized by introducing a tether on the tolan. To demonstrate the utilities of these motifs, a beta-hairpin structure (15) was synthesized, and its additional stabilizing effects were evaluated. Moreover, the photophysical properties of cyclic tolans and their beta sheet structure were investigated. The fluorescence quantum yield of cyclic tolan 12 is >1000 times stronger than its congener 1 in CH3CN. PMID- 26633287 TI - Cytokines in disease: Genetic variation affects IL-6 response in synovial fibroblasts. PMID- 26633289 TI - Imaging: Whole-body MRI undresses polymyalgia rheumatica. PMID- 26633288 TI - Targeting of proangiogenic signalling pathways in chronic inflammation. AB - Angiogenesis is de novo capillary outgrowth from pre-existing blood vessels. This process not only is crucial for normal development, but also has an important role in supplying oxygen and nutrients to inflamed tissues, as well as in facilitating the migration of inflammatory cells to the synovium in rheumatoid arthritis, spondyloarthritis and other systemic autoimmune diseases. Neovascularization is dependent on the balance of proangiogenic and antiangiogenic mediators, including growth factors, cytokines, chemokines, cell adhesion molecules and matrix metalloproteinases. This Review describes the various intracellular signalling pathways that govern these angiogenic processes and discusses potential approaches to interfere with pathological angiogenesis, and thereby ameliorate inflammatory disease, by targeting these pathways. PMID- 26633292 TI - Collective Strength, Collective Action. PMID- 26633290 TI - Targeting GM-CSF in inflammatory diseases. AB - Granulocyte-macrophage colony stimulating factor (GM-CSF) is a growth factor first identified as an inducer of differentiation and proliferation of granulocytes and macrophages derived from haematopoietic progenitor cells. Later studies have shown that GM-CSF is involved in a wide range of biological processes in both innate and adaptive immunity, with its production being tightly linked to the response to danger signals. Given that the functions of GM-CSF span multiple tissues and biological processes, this cytokine has shown potential as a new and important therapeutic target in several autoimmune and inflammatory disorders - particularly in rheumatoid arthritis. Indeed, GM-CSF was one of the first cytokines detected in human synovial fluid from inflamed joints. Therapies that target GM-CSF or its receptor have been tested in preclinical studies with promising results, further supporting the potential of targeting the GM-CSF pathway. In this Review, we discuss our expanding view of the biology of GM-CSF, outline what has been learnt about GM-CSF from studies of animal models and human diseases, and summarize the results of early phase clinical trials evaluating GM CSF antagonism in inflammatory disorders. PMID- 26633291 TI - Type I/II cytokines, JAKs, and new strategies for treating autoimmune diseases. AB - Cytokines are major drivers of autoimmunity, and biologic agents targeting cytokines have revolutionized the treatment of immune-mediated diseases. Despite the effectiveness of these drugs, they do not induce complete remission in all patients, prompting the development of alternative strategies - including targeting of intracellular signal transduction pathways downstream of cytokines. Many cytokines that bind type I and type II cytokine receptors are critical regulators of immune-mediated diseases and employ the Janus kinase (JAK) and signal transducer and activator of transcription (STAT) pathway to exert their effect. Pharmacological inhibition of JAKs blocks the actions of type I/II cytokines, and within the past 3 years therapeutic JAK inhibitors, or Jakinibs, have become available to rheumatologists. Jakinibs have proven effective for the treatment of rheumatoid arthritis and other inflammatory diseases. Adverse effects of these agents are largely related to their mode of action and include infections and hyperlipidemia. Jakinibs are currently being investigated for a number of new indications, and second-generation selective Jakinibs are being developed and tested. Targeting STATs could be a future avenue for the treatment of rheumatologic diseases, although substantial challenges remain. Nonetheless, the ability to therapeutically target intracellular signalling pathways has already created a new paradigm for the treatment of rheumatologic disease. PMID- 26633293 TI - Coherent Spin Dynamics in Molecular Cr8Zn Wheels. AB - Controlling and understanding transitions between molecular spin states allows selection of the most suitable ones for qubit encoding. Here we present a detailed investigation of single crystals of a polynuclear Cr8Zn molecular wheel using 241 GHz electron paramagnetic resonance (EPR) spectroscopy in high magnetic field. Continuous wave spectra are well reproduced by spin Hamiltonian calculations, which evidence that transitions in correspondence to a well-defined anticrossing involve mixed states with different total spin. We studied, by means of spin echo experiments, the temperature dependence of the dephasing time (T2) down to 1.35 K. These results are reproduced by considering both hyperfine and intermolecular dipolar interactions, evidencing that the dipolar contribution is completely suppressed at the lowest temperature. Overall, these results shed light on the effects of the decoherence mechanisms, whose understanding is crucial to exploit chemically engineered molecular states as a resource for quantum information processing. PMID- 26633294 TI - Health Canada Warning on Citalopram and Escitalopram--Its Effects on Prescribing in Consultation-Liaison Psychiatry. AB - BACKGROUND: Reports have suggested that citalopram and escitalopram may prolong the QTc interval, leading Health Canada to issue a warning to limit their dosages in 2012. Little is known about the effects of this warning and similar ones (e.g., by the Food and Drug Administration) on antidepressant prescribing in inpatients with acute medical illness, who are theoretically at high risk of QTc prolongation. The main objective of our study is to examine the effect of the Health Canada warning on citalopram/escitalopram prescribing patterns in the consultation-liaison (C-L) psychiatry setting. METHODS: We performed a retrospective cohort study including 275 randomly selected inpatients with medical illness assessed by the psychiatric C-L team of a large Canadian academic hospital between 2008 and 2014. We grouped patients based on whether they were assessed by the C-L team before or after the citalopram Health Canada warning. Our primary outcome was change in citalopram/escitalopram prescribing patterns. RESULTS: We found that of patients seen before the Health Canada warning, a significantly higher number were prescribed citalopram/escitalopram (44.1% vs. 22.3%, chi(2) = 14.835, p < 0.001), even after controlling for confounders. However, the percentage of patients using a citalopram/escitalopram dose exceeding those recommended by the Health Canada warning was similar in both groups (8.9% vs. 12.1%, chi(2) = 0.233, p = 0.63). CONCLUSIONS: Overall, C-L psychiatrists were less likely to prescribe citalopram/escitalopram following the Health Canada warning, which did not translate into safer dosing. Clinicians should not avoid prescribing citalopram/escitalopram appropriately in medically vulnerable inpatients when benefits outweigh disadvantages. PMID- 26633295 TI - Mortality in children with Kawasaki disease: 20 years of experience from a tertiary care centre in North India. AB - Kawasaki disease (KD) is a common vasculitic disorder of childhood. Reported mortality in KD in Japan is 0.014%. We report the clinical and laboratory profile of 4 children who succumbed to KD during the period January 1994 to March 2015 at the Paediatric Allergy Immunology Unit, Advanced Paediatrics Centre, Post Graduate Institute of Medical Education and Research Centre, Chandigarh, India. A total of 460 children were diagnosed with KD based on the American Heart Association criteria. Male to female ratio was 1.96:1 and 106 children were aged 2 years or less. Children with KD received 2 g/kg of intravenous immunoglobulin (IVIg). In addition, aspirin was administered in doses of 30-50 mg/kg/day during the acute phase and 3-5 mg/kg/day thereafter. 2-D echocardiography was carried out once during the acute phase and approximately 6-8 weeks later on follow-up. Four children (2 boys, 2 girls) died during this period and their details were analysed from their clinical records. All 4 were under 2 years of age and had had significant delays in diagnosis and referral. Symptomatic myocarditis was noted in 2 children, while 2 of them had thrombocytopenia. We report a mortality of 0.87% in children with KD. Delays in diagnosis and referral contributed significantly to this mortality. To the best of our knowledge, this is the first report on mortality in KD from any developing nation. PMID- 26633296 TI - Computational Identification of Mechanistic Factors That Determine the Timing and Intensity of the Inflammatory Response. AB - Timely resolution of inflammation is critical for the restoration of homeostasis in injured or infected tissue. Chronic inflammation is often characterized by a persistent increase in the concentrations of inflammatory cells and molecular mediators, whose distinct amount and timing characteristics offer an opportunity to identify effective therapeutic regulatory targets. Here, we used our recently developed computational model of local inflammation to identify potential targets for molecular interventions and to investigate the effects of individual and combined inhibition of such targets. This was accomplished via the development and application of computational strategies involving the simulation and analysis of thousands of inflammatory scenarios. We found that modulation of macrophage influx and efflux is an effective potential strategy to regulate the amount of inflammatory cells and molecular mediators in both normal and chronic inflammatory scenarios. We identified three molecular mediators - tumor necrosis factor-alpha (TNF-alpha), transforming growth factor-beta (TGF-beta), and the chemokine CXCL8 - as potential molecular targets whose individual or combined inhibition may robustly regulate both the amount and timing properties of the kinetic trajectories for neutrophils and macrophages in chronic inflammation. Modulation of macrophage flux, as well as of the abundance of TNF-alpha, TGF beta, and CXCL8, may improve the resolution of chronic inflammation. PMID- 26633297 TI - Genetic Deletion of the Stromal Cell Marker CD248 (Endosialin) Protects against the Development of Renal Fibrosis. AB - BACKGROUND: Tissue fibrosis and microvascular rarefaction are hallmarks of progressive renal disease. CD248 is a transmembrane glycoprotein expressed by key effector cells within the stroma of fibrotic kidneys including pericytes, myofibroblasts and stromal fibroblasts. In human disease, increased expression of CD248 by stromal cells predicts progression to end-stage renal failure. We therefore, hypothesized that the genetic deletion of the CD248 gene would protect against fibrosis following kidney injury. METHODS: Using the unilateral ureteral obstruction (UUO) model of renal fibrosis, we investigated the effect of genetic deletion of CD248 on post obstructive kidney fibrosis. RESULTS: CD248 null mice were protected from fibrosis and microvascular rarefaction following UUO. Although the precise mechanism is not known, this may to be due to a stabilizing effect of pericytes with less migration and differentiation of pericytes toward a myofibroblast phenotype in CD248-/- mice. CD248-/- fibroblasts also proliferated less and deposited less collagen in vitro. CONCLUSION: These studies suggest that CD248 stromal cells have a pathogenic role in renal fibrosis and that targeting CD248 is effective at inhibiting both microvascular rarefaction and renal fibrosis through modulation of pericyte and stromal cell function. PMID- 26633298 TI - High-Risk Prostate Cancer: Role of Radical Prostatectomy and Radiation Therapy. AB - Up to 12% of European men aged 55-69 years diagnosed with prostate cancer have high-risk disease and thus are at increased risk of mortality. There remains a lack of consensus on definitive treatment for prostate cancer, although both radiation therapy and radical prostatectomy are frequently utilized. Furthermore, the different types of radiation and surgical options also increase the complexity of deciding on a single treatment, as does the use of multimodal treatment plans. Here, we provide an overview of radiation therapy and radical prostatectomy in treating high-risk prostate cancer. PMID- 26633300 TI - Correction: Hypoxia Preconditioned Mesenchymal Stem Cells Prevent Cardiac Fibroblast Activation and Collagen Production via Leptin. PMID- 26633299 TI - Chronic Nicotine Exposure In Vivo and In Vitro Inhibits Vitamin B1 (Thiamin) Uptake by Pancreatic Acinar Cells. AB - Thiamin (vitamin B1), a member of the water-soluble family of vitamins, is essential for normal cellular functions; its deficiency results in oxidative stress and mitochondrial dysfunction. Pancreatic acinar cells (PAC) obtain thiamin from the circulation using a specific carrier-mediated process mediated by both thiamin transporters -1 and -2 (THTR-1 and THTR-2; encoded by the SLC19A2 and SLC19A3 genes, respectively). The aim of the current study was to examine the effect of chronic exposure of mouse PAC in vivo and human PAC in vitro to nicotine (a major component of cigarette smoke that has been implicated in pancreatic diseases) on thiamin uptake and to delineate the mechanism involved. The results showed that chronic exposure of mice to nicotine significantly inhibits thiamin uptake in murine PAC, and that this inhibition is associated with a marked decrease in expression of THTR-1 and THTR-2 at the protein, mRNA and hnRNAs level. Furthermore, expression of the important thiamin-metabolizing enzyme, thiamin pyrophosphokinase (TPKase), was significantly reduced in PAC of mice exposed to nicotine. Similarly, chronic exposure of cultured human PAC to nicotine (0.5 MUM, 48 h) significantly inhibited thiamin uptake, which was also associated with a decrease in expression of THTR-1 and THTR-2 proteins and mRNAs. This study demonstrates that chronic exposure of PAC to nicotine impairs the physiology and the molecular biology of the thiamin uptake process. Furthermore, the study suggests that the effect is, in part, mediated through transcriptional mechanism(s) affecting the SLC19A2 and SLC19A3 genes. PMID- 26633302 TI - MRI-Only Based Radiotherapy Treatment Planning for the Rat Brain on a Small Animal Radiation Research Platform (SARRP). AB - Computed tomography (CT) is the standard imaging modality in radiation therapy treatment planning (RTP). However, magnetic resonance (MR) imaging provides superior soft tissue contrast, increasing the precision of target volume selection. We present MR-only based RTP for a rat brain on a small animal radiation research platform (SARRP) using probabilistic voxel classification with multiple MR sequences. Six rat heads were imaged, each with one CT and five MR sequences. The MR sequences were: T1-weighted, T2-weighted, zero-echo time (ZTE), and two ultra-short echo time sequences with 20 MUs (UTE1) and 2 ms (UTE2) echo times. CT data were manually segmented into air, soft tissue, and bone to obtain the RTP reference. Bias field corrected MR images were automatically segmented into the same tissue classes using a fuzzy c-means segmentation algorithm with multiple images as input. Similarities between segmented CT and automatic segmented MR (ASMR) images were evaluated using Dice coefficient. Three ASMR images with high similarity index were used for further RTP. Three beam arrangements were investigated. Dose distributions were compared by analysing dose volume histograms. The highest Dice coefficients were obtained for the ZTE UTE2 combination and for the T1-UTE1-T2 combination when ZTE was unavailable. Both combinations, along with UTE1-UTE2, often used to generate ASMR images, were used for further RTP. Using 1 beam, MR based RTP underestimated the dose to be delivered to the target (range: 1.4%-7.6%). When more complex beam configurations were used, the calculated dose using the ZTE-UTE2 combination was the most accurate, with 0.7% deviation from CT, compared to 0.8% for T1-UTE1-T2 and 1.7% for UTE1-UTE2. The presented MR-only based workflow for RTP on a SARRP enables both accurate organ delineation and dose calculations using multiple MR sequences. This method can be useful in longitudinal studies where CT's cumulative radiation dose might contribute to the total dose. PMID- 26633301 TI - DNA Packaging Specificity of Bacteriophage N15 with an Excursion into the Genetics of a Cohesive End Mismatch. AB - During DNA replication by the lambda-like bacteriophages, immature concatemeric DNA is produced by rolling circle replication. The concatemers are processed into mature chromosomes with cohesive ends, and packaged into prohead shells, during virion assembly. Cohesive ends are generated by the viral enzyme terminase, which introduces staggered nicks at cos, an approx. 200 bp-long sequence containing subsites cosQ, cosN and cosB. Interactions of cos subsites of immature concatemeric DNA with terminase orchestrate DNA processing and packaging. To initiate DNA packaging, terminase interacts with cosB and nicks cosN. The cohesive ends of N15 DNA differ from those of lambda at 2/12 positions. Genetic experiments show that phages with chromosomes containing mismatched cohesive ends are functional. In at least some infections, the cohesive end mismatch persists through cyclization and replication, so that progeny phages of both allelic types are produced in the infected cell. N15 possesses an asymmetric packaging specificity: N15 DNA is not packaged by phages lambda or 21, but surprisingly, N15-specific terminase packages lambda DNA. Implications for genetic interactions among lambda-like bacteriophages are discussed. PMID- 26633303 TI - No Evidence for Enrichment in Schizophrenia for Common Allelic Associations at Imprinted Loci. AB - Most genetic studies assume that the function of a genetic variant is independent of the parent from which it is inherited, but this is not always true. The best known example of parent-of-origin effects arises with respect to alleles at imprinted loci. In classical imprinting, characteristically, either the maternal or paternal copy is expressed, but not both. Only alleles present in one of the parental copies of the gene, the expressed copy, is likely to contribute to disease. It has been postulated that imprinting is important in central nervous system development, and that consequently, imprinted loci may be involved in schizophrenia. If this is true, allowing for parent-of-origin effects might be important in genetic studies of schizophrenia. Here, we use genome-wide association data from one of the world's largest samples (N = 695) of parent schizophrenia-offspring trios to test for parent-of-origin effects. To maximise power, we restricted our analyses to test two main hypotheses. If imprinting plays a disproportionate role in schizophrenia susceptibility, we postulated a) that alleles showing robust evidence for association to schizophrenia from previous genome-wide association studies should be enriched for parent-of-origin effects and b) that genes at loci imprinted in humans or mice should be enriched both for genome-wide significant associations, and in our sample, for parent-of origin effects. Neither prediction was supported in the present study. We have shown, that it is unlikely that parent-of-origin effects or imprinting play particularly important roles in schizophrenia, although our findings do not exclude such effects at specific loci nor do they exclude such effects among rare alleles. PMID- 26633304 TI - Calcium Nodules as a Proxy for Quaternary Paleoclimate Change on China's Loess Plateau. AB - Different proxies have been used to investigate Quaternary paleoclimate change. Here, we used weathering of calcium nodules in paleosols on China's Loess Plateau as a proxy for Quaternary paleoclimate changes to provide an alternative indicator of these changes. Paleosol and carbonate nodules were collected from Luochuan and Lantian counties in Shaanxi Province, China. We found that this approach allowed quantitative reconstruction of temperature, rainfall, soil mineral composition, and the effects of weathering and leaching. The changes in carbonate content in the loess and paleosol sequences were controlled by alternating dry and wet climatic conditions. Nodule formation conditions were directly affected by the leaching and migration of elements. The loess and paleosol sequences developed calcium nodules, and their formation was closely related to the rainfall and leaching characteristics of the paleoclimate. The paleoclimate and soil minerals affected the vegetation types and directly influenced changes in the soil. During formation of the calcium nodules, the surface vegetation evolved slowly, and the number of species and quantity of vegetation both decreased. PMID- 26633305 TI - A Review of the Role of Food and the Food System in the Transmission and Spread of Ebolavirus. AB - The current outbreak of Ebola virus disease (EVD) centered in West Africa is the largest in history, with nearly ten times more individuals contracting the disease than all previous outbreaks combined. The details of human-to-human and zoonotic ebolavirus transmission have justifiably received the largest share of research attention, and much information exists on these topics. However, although food processing-in the form of slaughtering and preparing wildlife for consumption (referred to as bushmeat)-has been implicated in EVD outbreaks, the full role of food in EVD spread is poorly understood and has been little studied. A literature search was undertaken to assess the current state of knowledge regarding how food can or may transmit ebolaviruses and how the food system contributes to EVD outbreak and spread. The literature reveals surprising preliminary evidence that food and the food system may be more implicated in ebolavirus transmission than expected and that further research is urgently needed. PMID- 26633306 TI - Leukoreduction for the prevention of adverse reactions from allogeneic blood transfusion. AB - BACKGROUND: A blood transfusion is an acute intervention, implemented to solve life and health-threatening conditions on a short-term basis. However, blood transfusions have adverse events, some of them potentially related to immune modulation or to a direct transmission of infectious agents (e.g. cytomegalovirus). Leukoreduction is a process in which the white blood cells are intentionally reduced in packed red blood cells (PRBCs) in order to reduce the risk of adverse reactions. The potential benefits of leukoreduced PRBCs in all types of transfused patients for decreasing infectious and non-infectious complications remain unclear. OBJECTIVES: To determine the clinical effectiveness of leukoreduction of packed red blood cells for preventing adverse reactions following allogeneic blood transfusion. SEARCH METHODS: We ran the most recent search on 10th November 2015. We searched the Cochrane Injuries Group's Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL, the Cochrane Library), MEDLINE (OvidSP), Embase(OvidSP), CINAHL Plus (EBSCO), LILACS (BIREME), and clinical trials registers. In addition, we checked the reference lists of all relevant trials and reviews identified in the literature searches. SELECTION CRITERIA: Randomised clinical trials including patients of all ages requiring PRBC allogeneic transfusion. Any study was eligible for inclusion, regardless of the length of participant follow-up or country where the study was performed. The primary outcome was transfusion-related acute lung injury (TRALI). Secondary outcomes were death from any cause, infection from any cause, non-infectious complications and any other adverse event. DATA COLLECTION AND ANALYSIS: At least two review authors independently performed study selection, 'Risk of bias' assessments and data extraction. We estimated pooled relative risk for dichotomous outcomes, and we measured statistical heterogeneity using I2 statistic. The random-effects model was used to synthesise results. We conducted a trial sequential analysis to assess the risk of random errors in cumulative meta-analyses. MAIN RESULTS: Thirteen studies, most including adult patients, met the eligibility criteria. We found no clear evidence of an effect of leukoreduced PRBC versus non-leukoreduced PRBC in patients that were randomised to receive transfusion for the following outcomes: TRALI: RR 0.96, 95% CI 0.67 to 1.36, P = 0.80 from one trial reporting data on 1864 trauma patients. The accrued information of 1864 participants constituted only 28.5% of the diversity-adjusted required information size (DARIS) of 6548 participants. The quality of evidence was low. Death from any cause: RR 0.81, 95% CI 0.58 to 1.12, I2 statistic = 63%, P = 0.20 from nine trials reporting data on 6485 cardiovascular surgical patients, gastro-oncology surgical patients, trauma patients and HIV infected patients. The accrued information of 6485 participants constituted only 55.3% of the DARIS of 11,735 participants. The quality of evidence was very low. Infection from any cause: RR 0.80, 95% CI 0.62 to 1.03, I2 statistic = 84%, P = 0.08 from 10 trials reporting data on 6709 cardiovascular surgical patients, gastro-oncology surgical patients, trauma patients and HIV infected patients. The accrued information of 6709 participants constituted only 60.6% of the DARIS of 11,062 participants. The quality of evidence was very low. Adverse events: The only adverse event reported as an adverse event was fever (RR 0.81, 95% CI 0.64 to 1.02; I2 statistic= 0%, P = 0.07). Fever was reported in two trials on 634 cardiovascular surgical and gastro-oncology surgical patients. The accrued information of 634 participants constituted only 84.4% of the DARIS of 751 participants. The quality of evidence was low. Incidence of other non infectious complications: This outcome was not assessed in any included trial. AUTHORS' CONCLUSIONS: There is no clear evidence for supporting or rejecting the routine use of leukoreduction in all patients requiring PRBC transfusion for preventing TRALI, death, infection, non-infectious complications and other adverse events. As the quality of evidence is very low to low, more evidence is needed before a definitive conclusion can be drawn. PMID- 26633307 TI - Transcriptional and Proteomic Profiling of Aspergillus flavipes in Response to Sulfur Starvation. AB - Aspergillus flavipes has received considerable interest due to its potential to produce therapeutic enzymes involved in sulfur amino acid metabolism. In natural habitats, A. flavipes survives under sulfur limitations by mobilizing endogenous and exogenous sulfur to operate diverse cellular processes. Sulfur limitation affects virulence and pathogenicity, and modulates proteome of sulfur assimilating enzymes of several fungi. However, there are no previous reports aimed at exploring effects of sulfur limitation on the regulation of A. flavipes sulfur metabolism enzymes at the transcriptional, post-transcriptional and proteomic levels. In this report, we show that sulfur limitation affects morphological and physiological responses of A. flavipes. Transcription and enzymatic activities of several key sulfur metabolism genes, ATP-sulfurylase, sulfite reductase, methionine permease, cysteine synthase, cystathionine beta- and gamma-lyase, glutathione reductase and glutathione peroxidase were increased under sulfur starvation conditions. A 50 kDa protein band was strongly induced by sulfur starvation, and the proteomic analyses of this protein band using LC-MS/MS revealed similarity to many proteins involved in the sulfur metabolism pathway. PMID- 26633309 TI - Assimilation of the seabird and ship drift data in the north-eastern sea of Japan into an operational ocean nowcast/forecast system. AB - At the present time, ocean current is being operationally monitored mainly by combined use of numerical ocean nowcast/forecast models and satellite remote sensing data. Improvement in the accuracy of the ocean current nowcast/forecast requires additional measurements with higher spatial and temporal resolution as expected from the current observation network. Here we show feasibility of assimilating high-resolution seabird and ship drift data into an operational ocean forecast system. Data assimilation of geostrophic current contained in the observed drift leads to refinement in the gyre mode events of the Tsugaru warm current in the north-eastern sea of Japan represented by the model. Fitting the observed drift to the model depends on ability of the drift representing geostrophic current compared to that representing directly wind driven components. A preferable horizontal scale of 50 km indicated for the seabird drift data assimilation implies their capability of capturing eddies with smaller horizontal scale than the minimum scale of 100 km resolved by the satellite altimetry. The present study actually demonstrates that transdisciplinary approaches combining bio-/ship- logging and numerical modeling could be effective for enhancement in monitoring the ocean current. PMID- 26633308 TI - Melamine Impairs Female Fertility via Suppressing Protein Level of Juno in Mouse Eggs. AB - Melamine is an organic nitrogenous compound widely used as an industrial chemical, and it has been recently reported by us that melamine has a toxic effect on the female reproductive system in mice, and renders females subfertile; the molecular basis, however, has not been adequately assessed. In the present study, we explore the underlying mechanism regarding how melamine compromises fertility in the mouse. The data showed that melamine exposure significantly impaired the fertilization capability of the egg during in vitro fertilization. To further figure out the cause, we analyzed ovastacin localization and protein level, the sperm binding ability of zona pellucida, and ZP2 cleavage status in unfertilized eggs from melamine fed mice, and no obvious differences were found between control and treatment groups. However, the protein level of Juno on the egg plasma membrane in the high-dose feeding group indeed significantly decreased compared to the control group. Thus, these data suggest that melamine compromises female fertility via suppressing Juno protein level on the egg membrane. PMID- 26633310 TI - A Population-based Investigation of Circadian Rhythm of Intraocular Pressure in Habitual Position Among Healthy Subjects: The Handan Eye Study. AB - PURPOSE: (1) To investigate the reference value of peak-trough difference in circadian rhythm of intraocular pressure (IOP) in habitual position and (2) to compare the IOP parameters among 3 age groups. MATERIALS AND METHODS: Habitual IOP of healthy subjects sampled from the population in the Handan Eye Study was measured every 2 hours in the seated position during light-wake period (7:30 AM, 9:30 AM, 11:30 AM, 1:30 PM, 3:30 PM, 5:30 PM, 7:30 PM, 9:30 PM) and in the supine position during dark-sleep period (11:30 PM, 1:30 AM, 3:30 AM, 5:30 AM). Blood pressure and heart rate were obtained subsequently at each IOP measurement. RESULTS: Two hundred six healthy subjects were included in the final analyses (n=20, 30 to 39 y old; n=95, 40 to 49 y old; n=91, 50 to 59 y old). For peak trough difference (7.2+/-2.3 mm Hg; 6.8 to 7.5 mm Hg, 95% confidence interval) in habitual position, the reference value was described as median 7.0 mm Hg, 25th percentile 5.5 mm Hg, and 95th percentile 11.5 mm Hg. No significant differences in peak-trough difference, acrophase (cosine-fit analysis derived peak timing) and amplitude (half distance between the cosine-fit maximum and minimum) were found among the 3 age groups. In the cosine model, the nocturnal acrophase (3:49+/-0.53 AM; 3:42 to 3:55 AM, 95% confidence interval) was detected for the entire group. Furthermore, 106 subjects (52%) had a nocturnal peak pattern, 36 subjects (17%) had a diurnal peak pattern, and 64 subjects (31%) had no evident pattern. CONCLUSIONS: In habitual position, 75% of healthy subjects from a population-based investigation had IOP variation >5.5 mm Hg and 95% subjects had <11.5 mm Hg variation. Aging may not influence the circadian habitual IOP rhythm. PMID- 26633311 TI - Correction: From Innovation to Diversification: A Simple Competitive Model. PMID- 26633312 TI - Technological Application of Maltodextrins According to the Degree of Polymerization. AB - Maltodextrin (MX) is an ingredient in high demand in the food industry, mainly for its useful physical properties which depend on the dextrose equivalent (DE). The DE has however been shown to be an inaccurate parameter for predicting the performance of the MXs in technological applications, hence commercial MXs were characterized by mass spectrometry (MS) to determine their molecular weight distribution (MWD) and degree of polymerization (DP). Samples were subjected to different water activities (aw). Water adsorption was similar at low aw, but radically increased with the DP at higher aw. The decomposition temperature (Td) showed some variations attributed to the thermal hydrolysis induced by the large amount of adsorbed water and the supplied heat. The glass transition temperature (Tg) linearly decreased with both, aw and DP. The microstructural analysis by X ray diffraction showed that MXs did not crystallize with the adsorption of water, preserving their amorphous structure. The optical micrographs showed radical changes in the overall appearance of the MXs, indicating a transition from a glassy to a rubbery state. Based on these characterizations, different technological applications for the MXs were suggested. PMID- 26633313 TI - When Phosphosugars Meet Gold: Synthesis and Catalytic Activities of Phostones and Polyhydroxylated Phosphonite Au(I) Complexes. AB - The synthesis and characterization of P-chiral phosphonite-, phosphonate- and thiophosphonate-Au(I) complexes are reported. These novel ligands for Au(I) are based on glycomimetic phosphorus scaffolds, obtained from the chiral pool. The catalytic activities of these complexes are shown in the cyclization of allenols and the hydroamination of 2-(2-propynyl)aniline combined with an organocatalyzed reduction to the corresponding 2-phenyl tetrahydroquinoline. All described gold complexes present excellent catalytic activities. PMID- 26633314 TI - Stereo- and Regiocontrolled Syntheses of Exomethylenic Cyclohexane beta-Amino Acid Derivatives. AB - Cyclohexane analogues of the antifungal icofungipen [(1R,2S)-2-amino-4 methylenecyclopentanecarboxylic acid] were selectively synthesized from unsaturated bicyclic beta-lactams by transformation of the ring olefinic bond through three different regio- and stereocontrolled hydroxylation techniques, followed by hydroxy group oxidation and oxo-methylene interconversion with a phosphorane. Starting from an enantiomerically pure bicyclic beta-lactam obtained by enzymatic resolution of the racemic compound, an enantiodivergent procedure led to the preparation of both dextro- and levorotatory cyclohexane analogues of icofungipen. PMID- 26633315 TI - Iridium-Catalyzed Asymmetric Ring-Opening of Oxabenzonorbornadienes with N Substituted Piperazine Nucleophiles. AB - Iridium-catalyzed asymmetric ring-opening of oxabenzonorbornadienes with N substituted piperazines was described. The reaction afforded the corresponding ring-opening products in high yields and moderate enantioselectivities in the presence of 2.5 mol % [Ir(COD)Cl]2 and 5.0 mol % (S)-p-Tol-BINAP. The effects of various chiral bidentate ligands, catalyst loading, solvent, and temperature on the yield and enantioselectivity were also investigated. A plausible mechanism was proposed to account for the formation of the corresponding trans-ring opened products based on the X-ray structure of product 2i. PMID- 26633316 TI - Argentatin B Inhibits Proliferation of Prostate and Colon Cancer Cells by Inducing Cell Senescence. AB - Argentatin B has been shown to inhibit the growth of colon HCT-15, and prostate PC-3 cancer cells. However, the mechanism by which argentatin B inhibits cell proliferation is still unknown. We aimed to investigate the mechanism by which argentatin B inhibits cell proliferation. The cell cycle was studied by flow cytometry. Apoptosis was evaluated by Annexin-V-Fluos, and Hoechst 33342 dye staining. Cell senescence was evaluated by proliferation tests, and staining for SA-beta-galactosidase. Senescence-related proteins (PCNA, p21, and p27) were analyzed by Western blotting. Potential toxicity of argentatin B was evaluated in CD-1 mice. Its effect on tumor growth was tested in a HCT-15 and PC-3 xenograft model. Argentatin B induced an increment of cells in sub G1, but did not produce apoptosis. Proliferation of both cell lines was inhibited by argentatin B. Forty three percent HCT-15, and 66% PC-3 cells showed positive SA-beta-galactosidase staining. The expression of PCNA was decreased, p21 expression was increased in both cell lines, but p27 expression increased only in PC-3 cells after treatment. Administration of argentatin B to healthy mice did not produce treatment associated pathologies. However, it restricted the growth of HCT-15 and PC-3 tumors. These results indicate that treatment with argentatin B induces cell senescence. PMID- 26633317 TI - Antioxidant Phytochemicals for the Prevention and Treatment of Chronic Diseases. AB - Overproduction of oxidants (reactive oxygen species and reactive nitrogen species) in the human body is responsible for the pathogenesis of some diseases. The scavenging of these oxidants is thought to be an effective measure to depress the level of oxidative stress of organisms. It has been reported that intake of vegetables and fruits is inversely associated with the risk of many chronic diseases, and antioxidant phytochemicals in vegetables and fruits are considered to be responsible for these health benefits. Antioxidant phytochemicals can be found in many foods and medicinal plants, and play an important role in the prevention and treatment of chronic diseases caused by oxidative stress. They often possess strong antioxidant and free radical scavenging abilities, as well as anti-inflammatory action, which are also the basis of other bioactivities and health benefits, such as anticancer, anti-aging, and protective action for cardiovascular diseases, diabetes mellitus, obesity and neurodegenerative diseases. This review summarizes recent progress on the health benefits of antioxidant phytochemicals, and discusses their potential mechanisms in the prevention and treatment of chronic diseases. PMID- 26633318 TI - Apigenin Attenuates Melanoma Cell Migration by Inducing Anoikis through Integrin and Focal Adhesion Kinase Inhibition. AB - Apigenin, a nonmutagenic flavonoid, has been found to have antitumor properties and is therefore particularly relevant for the development of chemotherapeutic agents for cancers. In this study, time- and dose-dependent cell viability and cytotoxicity were assessed to determine the effects of apigenin on A2058 and A375 melanoma cells. Melanoma cells were pretreated with different concentrations of apigenin and analyzed for morphological changes, anoikis induction, cell migration, and levels of proteins associated with apoptosis. Apigenin reduced integrin protein levels and inhibited the phosphorylation of focal adhesion kinase (FAK) and extracellular signal-regulated kinase (ERK1/2), which induce anoikis in human cutaneous melanoma cells. Apigenin exhibited dose-dependent inhibition of melanoma cell migration, unlike untreated controls. Furthermore, apigenin treatment increased apoptotic factors such as caspase-3 and cleaved poly(ADP-ribose) polymerase in a dose-dependent manner, demonstrating the metastasis of melanoma cells. Our results provide a new insight into the mechanisms by which apigenin prevents melanoma metastasis by sensitizing anoikis induced by the loss of integrin proteins in the FAK/ERK1/2 signaling pathway. These findings elucidate the related mechanisms and suggest the potential of apigenin in developing clinical treatment strategies against malignant melanoma. PMID- 26633319 TI - Improved Antioxidant Capacity of Optimization of a Self-Microemulsifying Drug Delivery System for Resveratrol. AB - The use of nano-encapsulated resveratrol (RSV) in self-micro-emulsified drug delivery systems (SMEDDS) formulations was investigated. Self-emulsifying grading tests were used to establish the optimal ratio of oil, surfactant, and co surfactant. The optimized system was further investigated for the droplet size and zeta potential at the different medium pH values by a Malvern Zetasizer and transmission electron microscopy (TEM). The antioxidant capacity and cytotoxicity of the formulation were detected by DCFH-DA and a CCK-8 assays. The results showed that the nano-emulsion based on ethyl oleate, Tween-80, and PEG-400 (35:40:25, w/w/w) was the most stable formulation due to the small droplet size (approximately 50 nm) and high zeta potential in a neutral environment. Furthermore, this formulation also exhibited a greater antioxidant capacity with less toxicity than free RSV. Taken together, considering these results and the simple fabrication process, this formulation could be used to deliver nutritional food supplements in a stable, efficient, and safe manner. PMID- 26633320 TI - A Copper-Based Metal-Organic Framework as an Efficient and Reusable Heterogeneous Catalyst for Ullmann and Goldberg Type C-N Coupling Reactions. AB - A highly porous metal-organic framework (Cu-TDPAT), constructed from a paddle wheel type dinuclear copper cluster and 2,4,6-tris(3,5-dicarboxylphenylamino) 1,3,5-triazine (H6TDPAT), has been tested in Ullmann and Goldberg type C-N coupling reactions of a wide range of primary and secondary amines with halobenzenes, affording the corresponding N-arylation compounds in moderate to excellent yields. The Cu-TDPAT catalyst could be easily separated from the reaction mixtures by simple filtration, and could be reused at least five times without any significant degradation in catalytic activity. PMID- 26633321 TI - Dihydrochalcone Compounds Isolated from Crabapple Leaves Showed Anticancer Effects on Human Cancer Cell Lines. AB - Seven dihydrochalcone compounds were isolated from the leaves of Malus crabapples, cv. "Radiant", and their chemical structures were elucidated by UV, IR, ESI-MS, 1H-NMR and (13)C-NMR analyses. These compounds, which include trilobatin (A1), phloretin (A2), 3-hydroxyphloretin (A3), phloretin rutinoside (A4), phlorizin (A5), 6''-O-coumaroyl-4'-O-glucopyranosylphloretin (A6), and 3''' methoxy-6''-O-feruloy-4'-O-glucopyranosyl-phloretin (A7), all belong to the phloretin class and its derivatives. Compounds A6 and A7 are two new rare dihydrochalcone compounds. The results of a MTT cancer cell growth inhibition assay demonstrated that phloretin and these derivatives showed significant positive anticancer activities against several human cancer cell lines, including the A549 human lung cancer cell line, Bel 7402 liver cancer cell line, HepG2 human ileocecal cancer cell line, and HT-29 human colon cancer cell line. A7 had significant effects on all cancer cell lines, suggesting potential applications for phloretin and its derivatives. Adding a methoxyl group to phloretin dramatically increases phloretin's anticancer activity. PMID- 26633322 TI - Metabolic Characteristics in Meal of Black Rapeseed and Yellow-Seeded Progeny of Brassica napus-Sinapis alba Hybrids. AB - Breeding of yellow-seeded rapeseed (Brassica napus) is preferred over black seeded rapeseed for the desirable properties of the former. This study evaluated the metabolites and nutritive values of black-seeded rapeseed meal and yellow seeded meal from the progeny of a B. napus-Sinapis alba hybrid. Yellow-seed meal presented higher protein (35.46% vs. 30.29%), higher sucrose (7.85% vs. 7.29%), less dietary fiber (26.19% vs. 34.63%) and crude fiber (4.56% vs. 8.86%), and less glucosinolates (22.18 vs. 28.19 MUmol/g) than black-seeded one. Amounts of ash (3.65% vs. 4.55%), phytic acid (4.98% vs. 5.60%), and total polyphenols (2.67% vs. 2.82%) were decreased slightly in yellow-seeded meal compared with black-seeded meal. Yellow-seeded meal contained more essential amino acids than black-seeded meal. Levels of the mineral elements Fe, Mn, and Zn in yellow-seeded meal were higher than black-seeded meal. By contrast, levels of P, Ca, and Mg were lower in yellow-seeded meal. Moreover, yellow-seeded meal showed lower flavonol (kaempferol, quercetin, isorhamnetin, and their derivatives) content than black-seeded meal. Comparison of metabolites between yellow and black rapeseed confirmed the improved nutritional value of meal from yellow-seeded B. napus, and this would be helpful to the breeding and improvement of rapeseed for animal feeding. PMID- 26633323 TI - Characterization of Global Transcriptome Using Illumina Paired-End Sequencing and Development of EST-SSR Markers in Two Species of Gynostemma (Cucurbitaceae). AB - Gynostemma pentaphyllum is an important medicinal herb of the Cucurbitaceae family, but limited genomic data have hindered genetic studies. In this study, transcriptomes of two closely-related Gynostemma species, Gynostemma cardiospermum and G. pentaphyllum, were sequenced using Illumina paired-end sequencing technology. A total of 71,607 nonredundant unigenes were assembled. Of these unigenes, 60.45% (43,288) were annotated based on sequence similarity search with known proteins. A total of 11,059 unigenes were identified in the Kyoto Encyclopedia of Genes and Genomes Pathway (KEGG) database. A total of 3891 simple sequence repeats (SSRs) were detected in 3526 nonredundant unigenes, 2596 primer pairs were designed and 360 of them were randomly selected for validation. Of these, 268 primer pairs yielded clear products among six G. pentaphyllum samples. Thirty polymorphic SSR markers were used to test polymorphism and transferability in Gynostemma. Finally, 15 SSR makers that amplified in all 12 Gynostemma species were used to assess genetic diversity. Our results generated a comprehensive sequence resource for Gynostemma research. PMID- 26633324 TI - Hydrothermal Conversion of Giant Reed to Furfural and Levulinic Acid: Optimization of the Process under Microwave Irradiation and Investigation of Distinctive Agronomic Parameters. AB - The hydrothermal conversion of giant reed (Arundo donax L.) to furfural (FA) and levulinic acid (LA) was investigated in the presence of dilute hydrochloric acid. FA and LA yields were improved by univariate optimization of the main reaction parameters: concentration of the acid catalyst, solid/liquid ratio of the reaction mixture, hydrolysis temperature, and reaction time. The catalytic performances were investigated adopting the efficient microwave (MW) irradiation, allowing significant energy and time savings. The best FA and LA yields were further confirmed using a traditionally heated autoclave reactor, giving very high results, when compared with the literature. Hydrolysis temperature and time were the main reaction variables to be carefully optimized: FA formation needed milder reaction conditions, while LA more severe ones. The effect of the crop management (e.g., harvest time) on FA/LA production was discussed, revealing that harvest time was not a discriminating parameter for the further optimization of both FA and LA production, due to the very high productivity of the giant reed throughout the year. The promising results demonstrate that giant reed represents a very interesting candidate for a very high contemporary production of FA and LA of up to about 70% and 90% of the theoretical yields, respectively. PMID- 26633325 TI - Factors Influencing Oral Bioavailability of Thai Mango Seed Kernel Extract and Its Key Phenolic Principles. AB - Mango seed kernel extract (MSKE) and its key components (gallic acid, GA; methyl gallate, MG; and pentagalloyl glucopyranose, PGG) have generated interest because of their pharmacological activities. To develop the potential use of the key components in MSKE as natural therapeutic agents, their pharmacokinetic data are necessary. Therefore, this study was performed to evaluate the factors affecting their oral bioavailability as pure compounds and as components in MSKE. The in vitro chemical stability, biological stability, and absorption were evaluated in Hanks' Balanced Salt Solution, Caco-2 cell and rat fecal lysates, and the Caco-2 cell model, respectively. The in vivo oral pharmacokinetic behavior was elucidated in Sprague-Dawley rats. The key components were unstable under alkaline conditions and in Caco-2 cell lysates or rat fecal lysates. The absorptive permeability coefficient followed the order MG > GA > PGG. The in vivo results exhibited similar pharmacokinetic trends to the in vitro studies. Additionally, the co-components in MSKE may affect the pharmacokinetic behaviors of the key components in MSKE. In conclusion, chemical degradation under alkaline conditions, biological degradation by intestinal cell and colonic microflora enzymes, and low absorptive permeability could be important factors underlying the oral bioavailability of these polyphenols. PMID- 26633326 TI - Comparative Pharmacokinetics Study of Icariin and Icariside II in Rats. AB - To explore the pharmacokinetic properties of icariin (ICA) and icariside II (ICA II) following intragastric and intravenous administration in rats, a rapid and sensitive method by using ultra-performance liquid chromatography-tandem mass spectroscopy (UPLC-MS/MS) was developed and validated for the simultaneous quantification of ICA and ICA II in rat plasma. The quantification was performed by using multiple reaction monitoring of the transitions m/z 677.1/531.1 for ICA, 515.1/369.1 for ICA II and 463.1/301.1 for diosmetin-7-O-beta-d-glucopyranoside (IS). The assay showed linearity over the concentration range of 1.03-1032 ng/mL, with correlation coefficients of 0.9983 and 0.9977. Intra- and inter-day precision and accuracy were within 15%. The lower limit of quantification for both ICA and ICA II was 1.03 ng/mL, respectively. The recovery of ICA and ICA II was more than 86.2%. The LC-MS/MS method has been successfully used in the pharmacokinetic studies of ICA and ICA II in rats. The results indicated that 91.2% of ICA was transformed into ICA II after oral administration by rats, whereas only 0.4% of ICA was transformed into ICA II after intravenous administration. A comparison of the pharmacokinetics of ICA and ICA II after oral administration revealed that the Cmax and AUC0-t of ICA II were 3.8 and 13.0 times higher, respectively, than those of ICA. However, after intravenous administration, the Cmax and AUC0-t of ICA II were about only 12.1% and 4.2% of those of ICA. These results suggest that ICA and ICA II have distinct pharmacokinetic properties, and the insights obtained facilitate future pharmacological action studies. PMID- 26633327 TI - Mitochondrion-Targeted Peptide SS-31 Inhibited Oxidized Low-Density Lipoproteins Induced Foam Cell Formation through both ROS Scavenging and Inhibition of Cholesterol Influx in RAW264.7 Cells. AB - Foam cell formation as a result of imbalance of modified cholesterol influx and efflux by macrophages is a key to the occurrence and development of atherosclerosis. Oxidative stress is thought to be involved in the pathogenesis of atherosclerosis. SS-31 is a member of the Szeto-Schiller (SS) peptides shown to specifically target the inner mitochondrial membrane to scavenge reactive oxygen species. In this study, we investigated whether SS-31 may provide protective effect on macrophage from foam cell formation in RAW264.7 cells. The results showed that SS-31 inhibited oxidized low-density lipoproteins (ox-LDL) induced foam cell formation and cholesterol accumulation, demonstrated by intracellular oil red O staining and measurement of cholesterol content. The mechanism was revealed that SS-31 did not only significantly attenuated ox-LDL induced generation of reactive oxygen species (ROS) and increased the activities of superoxide dismutases, but also dose-dependently inhibited the expression of CD36 and LOX-1, two scavenger receptors of ox-LDL, while the expression of ATP binding cassette A1 and G1, playing a pivotal role in cholesterol efflux, was not affected. As a result, SS-31 decreased pro-inflammatory cytokines such as interleukin 6 and tumor necrosis factor alpha, suggesting the prevention of inflammatory responses. In conclusion, our results demonstrate that SS-31 provides a beneficial effect on macrophages from foam cell formation, likely, through both ROS scavenging and inhibition of cholesterol influx. Therefore, SS 31 may potentially be of therapeutic relevance in prevention of human atherogenesis. PMID- 26633328 TI - Oligonucleotide Functionalised Microbeads: Indispensable Tools for High Throughput Aptamer Selection. AB - The functionalisation of microbeads with oligonucleotides has become an indispensable technique for high-throughput aptamer selection in SELEX protocols. In addition to simplifying the separation of binding and non-binding aptamer candidates, microbeads have facilitated the integration of other technologies such as emulsion PCR (ePCR) and Fluorescence Activated Cell Sorting (FACS) to high-throughput selection techniques. Within these systems, monoclonal aptamer microbeads can be individually generated and assayed to assess aptamer candidate fitness thereby helping eliminate stochastic effects which are common to classical SELEX techniques. Such techniques have given rise to aptamers with 1000 times greater binding affinities when compared to traditional SELEX. Another emerging technique is Fluorescence Activated Droplet Sorting (FADS) whereby selection does not rely on binding capture allowing evolution of a greater diversity of aptamer properties such as fluorescence or enzymatic activity. Within this review we explore examples and applications of oligonucleotide functionalised microbeads in aptamer selection and reflect upon new opportunities arising for aptamer science. PMID- 26633329 TI - Evaluation of Antimicrobial Efficiency of New Polymers Comprised by Covalently Attached and/or Electrostatically Bound Bacteriostatic Species, Based on Quaternary Ammonium Compounds. AB - In the present work a detailed study of new bacteriostatic copolymers with quaternized ammonium groups introduced in the polymer chain through covalent attachment or electrostatic interaction, was performed. Different copolymers have been considered since beside the active species, the hydrophobic/hydrophilic nature of the co-monomer was also evaluated in the case of covalently attached bacteriostatic groups, aiming at achieving permanent antibacterial activity. Homopolymers with quaternized ammonium/phosphonium groups were also tested for comparison reasons. The antimicrobial activity of the synthesized polymers after 3 and 24 h of exposure at 4 and 22 degrees C was investigated on cultures of Gram-negative (P. aeruginosa, E. coli) and Gram-positive (S. aureus, E. faecalis) bacteria. It was found that the combination of the hydrophilic monomer acrylic acid (AA), at low contents, with the covalently attached bacteriostatic group vinyl benzyl dimethylhexadecylammonium chloride (VBCHAM) in the copolymer P(AA-co VBCHAM88), resulted in a high bacteriostatic activity against P. aeruginosa and E. faecalis (6 log reduction in certain cases). Moreover, the combination of covalently attached VBCHAM units with electrostatically bound cetyltrimethylammonium 4-styrene sulfonate (SSAmC16) units in the P(SSAmC16-co VBCHAMx) copolymers led to efficient antimicrobial materials, especially against Gram-positive bacteria, where a log reduction between 4.9 and 6.2 was verified. These materials remain remarkably efficient even when they are incorporated in polysulfone membranes. PMID- 26633330 TI - Synthesis, Characterization and Reactions of (Azidoethynyl)trimethylsilane. AB - Synthesis of azido(trimethylsilyl)acetylene (6) was performed by treating the iodonium salt 5 with highly soluble hexadecyltributylphosphonium azide (QN3) at 40 degrees C. Although this product is very unstable, it can nevertheless be trapped by the click reaction with cyclooctyne to give the corresponding 1,2,3 triazole, and also directly characterized by 1H- and (13)C-NMR data as well as IR spectra, which were measured in solution at low temperature and in the gas phase. The thermal or photochemical decay of azide 6 leads to cyano(trimethylsilyl)carbene. This is demonstrated not only by quantum chemical calculations, but also by the trapping reactions with the help of isobutene. PMID- 26633331 TI - Isoeugenin, a Novel Nitric Oxide Synthase Inhibitor Isolated from the Rhizomes of Imperata cylindrica. AB - Phytochemical studies on the constituents of the rhizomes of Imperata cylindrica (Gramineae) were performed using high-performance liquid chromatography (HPLC). We also aimed to search for any biologically active substance capable of inhibiting nitric oxide (NO) formation in lipopolysaccharide (LPS)-activated macrophage 264.7 cells, by testing four compounds isolated from this plant. Four compounds, including a new chromone, isoeugenin, along with ferulic acid, p coumaric acid, and caffeic acid were isolated and identified by NMR spectroscopy. The structure of isoeugenin was determined as 7-hydroxy-5-methoxy-2 methylchromone by the 2D-NMR technique. Among the four compounds, isoeugenin has the lowest IC50 value on the inhibition of NO production in LPS-activated macrophage RAW264.7 cells (IC50, 9.33 MUg/mL). In addition, isoeugenin significantly suppressed the LPS-induced expressions of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and proinflammatory cytokines mRNA levels. Taken together, these results suggest that the anti-inflammatory activity of isoeugenin is associated with the down-regulation of iNOS, COX-2, and pro inflammatory cytokines in RAW264.7 cells. Accordingly, our results suggest that the new chromone isoegenin should be considered a potential treatment for inflammatory disease. PMID- 26633332 TI - Synthesis and Physicochemical Characterization of the Process-Related Impurities of Olmesartan Medoxomil. Do 5-(Biphenyl-2-yl)-1-triphenylmethyltetrazole Intermediates in Sartan Syntheses Exist? AB - During the process development for multigram-scale synthesis of olmesartan medoxomil (OM), two principal regioisomeric process-related impurities were observed along with the final active pharmaceutical ingredient (API). The impurities were identified as N-1- and N-2-(5-methyl-2-oxo-1,3-dioxolen-4 yl)methyl derivatives of OM. Both compounds, of which N-2 isomer of olmesartan dimedoxomil is a novel impurity of OM, were synthesized and fully characterized by differential scanning calorimetry (DSC), infrared spectroscopy (IR), nuclear magnetic resonance spectroscopy (NMR) and high-resolution mass spectrometry/electrospray ionization (HRMS/ESI). Their 1H, (13)C and (15)N nuclear magnetic resonance signals were fully assigned. The molecular structures of N-triphenylmethylolmesartan ethyl (N-tritylolmesartan ethyl) and N tritylolmesartan medoxomil, the key intermediates in OM synthesis, were solved and refined using single-crystal X-ray diffraction (SCXRD). The SCXRD study revealed that N-tritylated intermediates of OM exist exclusively as one of the two possible regioisomers. In molecular structures of these regioisomers, the trityl substituent is attached to the N-2 nitrogen atom of the tetrazole ring, and not to the N-1 nitrogen, as has been widely reported up to the present. This finding indicates that the reported structural formula of N-tritylolmesartan ethyl and N-tritylolmesartan medoxomil, as well as their systematic chemical names, must be revised. The careful analysis of literature spectroscopic data for other sartan intermediates and their analogs with 5-(biphenyl-2-yl)tetrazole moiety showed that they also exist exclusively as N-2-trityl regioisomers. PMID- 26633333 TI - A GC-MS Based Metabonomics Study of Rheumatoid Arthritis and the Interventional Effects of the Simiaowan in Rats. AB - Simiaowan (SMW) is a famous Chinese prescription widely used in clinical treatment of rheumatoid arthritis (RA). The aim of the present study is to determine novel biomarkers to increase the current understanding of RA mechanisms, as well as the underlying therapeutic mechanism of SMW, in RA-model rats. Plasma extracts from control, RA model, and SMW-treated rats were analyzed by gas chromatography coupled with mass spectrometry (GC-MS). An orthogonal partial least-square discriminant analysis (OPLS-DA) model was created to detect metabolites that were expressed in significantly different amounts between the RA model and the control rats and investigate the therapeutic effect of SMW. Metabonomics may prove to be a valuable tool for determining the efficacy of complex traditional prescriptions. PMID- 26633334 TI - Analysis of Chemical Constituents in Wuzi-Yanzong-Wan by UPLC-ESI-LTQ-Orbitrap MS. AB - Wuzi-Yanzong-Wan (WZYZW), a classical traditional Chinese medicine (TCM) prescription containing Fructus Lych, Semen Cuscutae (fried), Fructus Rubi, Fructus Schisandrae chinensis (steamed) and Semen Plantaginis (fried with salt), is widely used to treat impotence, sterility, spermatorrhea, premature ejaculation, lumbago and post-micturation dribble. However, the chemical profile of WZYZW has not been established yet. In this work, a rapid and sensitive method for systematically screening and identifying the chemical constituents of WZYZW in both positive and negative ion modes using Ultra-Performance LC coupled with ESI-linear ion trap-Orbitrap tandem mass spectrometry (UPLC-ESI-LTQ-Orbitrap-MS) has been developed. Based on the chromatographic and spectrometric data, and referring to the literature, we could tentatively identify 106 compounds, including organic acids, flavonoids, phenylpropanoids, alkaloids and terpenoids. Fourteen ingredients from Fructus Lych were identified, while 10 ingredients were from Semen Cuscutae (fried), 33 ingredients were from Fructus Rubi, 37 ingredients were from Fructus Schisandrae chinensis (steamed), and 20 ingredients were from Semen Plantaginis (fried with salt). The results may provide essential data for further quality control, pharmacological research and clinical evaluation of WZYZW. Furthermore, this study indicates the developed approach based on UPLC-ESI-LTQ-Orbitrap-MS is suitable for characterizing the chemical profiles of TCM prescriptions. This is the first report to provide a comprehensive analysis of the chemical constituents of WZYZW. PMID- 26633335 TI - Soluble Epoxide Hydrolase Inhibitory Activity of Selaginellin Derivatives from Selaginella tamariscina. AB - Selaginellin derivatives 1-3 isolated from Selaginella tamariscina were evaluated for their inhibition of soluble epoxide hydrolase (sEH) to demonstrate their potential for the treatment of cardiovascular disease. All selaginellin derivatives (1-3) inhibited sEH enzymatic activity and PHOME hydrolysis, in a dose-dependent manner, with IC50 values of 3.1 +/- 0.1, 8.2 +/- 2.2, and 4.2 +/- 0.2 MUM, respectively. We further determined that the derivatives function as non competitive inhibitors. Moreover, the predicted that binding sites and interaction between 1-3 and sEH were solved by docking simulations. According to quantitative analysis, 1-3 were confirmed to have high content in the roots of S. tamariscina; among them, selaginellin 3 exhibited the highest content of 189.3 +/ 0.0 MUg/g. PMID- 26633336 TI - Synthesis of a Stable Primary-Alkyl-Substituted Selenenyl Iodide and Its Hydrolytic Conversion to the Corresponding Selenenic Acid. AB - A primary-alkyl-substituted selenenyl iodide was successfully synthesized through oxidative iodination of a selenol with N-iodosuccinimide by taking advantage of a cavity-shaped steric protection group. The selenenyl iodide exhibited high thermal stability and remained unchanged upon heating at 100 degrees C for 3 h in [D8]toluene. The selenenyl iodide was reduced to the corresponding selenol by treatment with dithiothreitol. Hydrolysis of the selenenyl iodide under alkaline conditions afforded the corresponding selenenic acid almost quantitatively, corroborating the chemical validity of the recent proposal that hydrolysis of a selenenyl iodide to a selenenic acid is potentially involved in the catalytic mechanism of an iodothyronine deiodinase. PMID- 26633337 TI - Accurate Mass GC/LC-Quadrupole Time of Flight Mass Spectrometry Analysis of Fatty Acids and Triacylglycerols of Spicy Fruits from the Apiaceae Family. AB - The triacylglycerol (TAG) structure and the regio-stereospecific distribution of fatty acids (FA) of seed oils from most of the Apiaceae family are not well documented. The TAG structure ultimately determines the final physical properties of the oils and the position of FAs in the TAG molecule affects the digestion; absorption and metabolism; and physical and technological properties of TAGs. Fixed oils from the fruits of dill (Anethum graveolens), caraway (Carum carvi), cumin (Cuminum cyminum), coriander (Coriandrum sativum), anise (Pimpinella anisum), carrot (Daucus carota), celery (Apium graveolens), fennel (Foeniculum vulgare), and Khella (Ammi visnaga), all from the Apiaceae family, were extracted at room temperature in chloroform/methanol (2:1 v/v) using percolators. Crude lipids were fractionated by solid phase extraction to separate neutral triacylglycerols (TAGs) from other lipids components. Neutral TAGs were subjected to transesterification process to convert them to their corresponding fatty acids methyl esters (FAMES) using 1% boron trifluoride (BF3) in methanol. FAMES were analyzed by gas chromatography-quadrupole time of flight (GC-QTOF) mass spectrometry. Triglycerides were analyzed using high performance liquid chromatography-quadrupole time of flight (LC-QTOF) mass spectrometry. Petroselinic acid was the major fatty acid in all samples ranging from 57% of the total fatty acids in caraway up to 82% in fennel. All samples contained palmitic (16:0), palmitoleic (C16:1n-9), stearic (C18:0), petroselinic (C18:1n-12), linoleic (C18:2n-6), linolinic (18:3n-3), and arachidic (C20:0) acids. TAG were analyzed using LC-QTOF for accurate mass identification and mass spectrometry/mass spectrometry (MS/MS) techniques for regiospesific elucidation of the identified TAGs. Five major TAGs were detected in all samples but with different relative concentrations in all of the tested samples. Several other TAGs were detected as minor components and were present in some samples and absence in the others. Regiospecific analysis showed a non-random fatty acids distribution. Petroselinic acid was predominantly located at the sn-1 and sn-3 positions. PMID- 26633338 TI - DFT Studies on the Stereoselectivity of alpha-Silyloxy Diazoalkane Cycloadditions. AB - The intramolecular [3+2] cycloaddition (32CA) of alkene-tethered alpha silyloxydiazoalkanes provides variable stereoselectivity in generating bicyclic pyrazolines where the silyloxy group is either syn or anti to the newly formed pyrazoline ring. To elucidate the origin of the stereoselectivity, density functional theory (DFT) calculations were carried out for the energy of each transition state structure (TSs) and product. Steric effects were identified as the major determining factors in the diastereoselectivity of the 32CA reaction with regards to substrate structure (cyclic or acyclic alpha silyloxydiazoalkanes). PMID- 26633339 TI - Enrichment and Purification of Polyphenol Extract from Sphallerocarpus gracilis Stems and Leaves and in Vitro Evaluation of DNA Damage-Protective Activity and Inhibitory Effects of alpha-Amylase and alpha-Glucosidase. AB - An efficient preparative separation method for Sphallerocarpus gracilis stems and leaves polyphenols (SGslP) was established in this study. An X-5 macroporous adsorption resin was selected for the purification of the SGslP, and the polyphenol content of the purified SGslP (PSGslP) was increased 5.11-fold from 8.29% to 42.38% after one treatment run. The chemical composition of the PSGslP was analyzed by HPLC-MS/MS, and the predominant compounds were found to be luteolin-7-glucoside, acacetin-7-acetyglycoside and its isomers. In addition, the PSGslP was evaluated in vitro to determine the DNA damage-protective activity and inhibitory effects of alpha-amylase and alpha-glucosidase. The results indicated that the PSGslP exhibited significant protective activities against both ROO* and *OH radical-induced DNA damage. Moreover, the PSGslP exerted a dose-dependent inhibition effect on alpha-glucosidase but no inhibitory effect on alpha-amylase. These findings indicate that the Sphallerocarpus gracilis stems and leaves are good natural sources of antioxidants and are potent inhibitors of alpha glucosidase activity and are potential anti-diabetic inhibitor. PMID- 26633340 TI - An Effective Synthesis Method for Tilorone Dihydrochloride with Obvious IFN-alpha Inducing Activity. AB - Tilorone dihydrochloride (1) has great potential for inducing interferon against pathogenic infection. In this paper, we describe a convenient preparation method for 2,7-dihydroxyfluoren-9-one (2), which is a usual pharmaceutical intermediate for preparing tilorone dihydrochloride (1). In the novel method, methyl esterification of 4,4'-dihydroxy-[1,1'-biphenyl]-2-carboxylic acid (4) was carried out under milder conditions with higher yield and played an important role in the preparation of compound 2. The structures of the relative intermediates and target compound were characterized by melting point, IR, MS, and 1H-NMR. Furthermore, the synthesized tilorone dihydrochloride exhibited an obvious effect on induction of interferon-alpha (IFN-alpha) in mice within 12 h, and the peak level was observed until 24 h. This fruitful work has resulted in tilorone dihydrochloride becoming available in large-scale and wide application in clinics, which has a good pharmaceutical development prospects. PMID- 26633341 TI - Synthesis and Biological Evaluation of Norcantharidin Derivatives Possessing an Aromatic Amine Moiety as Antifungal Agents. AB - Based on the structure of naturally produced cantharidin, different arylamine groups were linked to the norcantharidin scaffold to provide thirty six compounds. Their structures were confirmed by melting point, 1H-NMR, (13)C-NMR and HRMS-ESI studies. These synthetic compounds were tested as fungistatic agents against eight phytopathogenic fungi using the mycelium growth rate method. Of these thirty six derivatives, seven displayed stronger antifungal activity than did norcantharidin, seven showed higher activity than did cantharidin and three exhibited more significant activity than that of thiabendazole. In particular, 3 (3'-chloro-phenyl)carbamoyl norcantharidate II-8 showed the most significant fungicidal activity against Sclerotinia fructigena and S. sclerotiorum, with IC50 values of 0.88 and 0.97 MUg/mL, respectively. The preliminary structure-activity relationship data of these compounds revealed that: (1) the benzene ring is critical for the improvement of the spectrum of antifungal activity (3 phenylcarbamoyl norcantharidate II-1 vs norcantharidin and cantharidin); (2) among the three sites, including the C-2', C-3' and C-4' positions of the phenyl ring, the presence of a halogen atom at the C-3'position of the benzene ring caused the most significant increase in antifungal activity; (3) compounds with strongly electron-drawing or electron-donating groups substitutions were found to have a poor antifungal activity; and (4) compared with fluorine, bromine and iodine, chlorine substituted at the C-3' position of the benzene ring most greatly promoted fungistatic activity. Thus, compound II-8 has emerged as new lead structure for the development of new fungicides. PMID- 26633342 TI - Technological Aspects of Chemoenzymatic Epoxidation of Fatty Acids, Fatty Acid Esters and Vegetable Oils: A Review. AB - The general subject of the review is analysis of the effect of technological parameters on the chemoenzymatic epoxidation processes of vegetable oils, fatty acids and alkyl esters of fatty acids. The technological parameters considered include temperature, concentration, amount of hydrogen peroxide relative to the number of unsaturated bonds, the amounts of enzyme catalysts, presence of solvent and amount of free fatty acids. Also chemical reactions accompanying the technological processes are discussed together with different technological options and significance of the products obtained. PMID- 26633343 TI - Two New Flavonol Glycosides from Polygala sibirica L. var megalopha Fr. AB - Two new flavonol glycosides, named polygalin H (1) and polygalin I (2), as well as the known compound polygalin D (3), were isolated from the whole plant of Polygala sibirica L. var megalopha Fr. Their structures were elucidated on the basis of spectroscopic data analysis. These flavonol glycosides exhibited strong inhibitory activities against xanthine oxidase in vitro. Their half-maximal inhibitory concentrations (IC50) were calculated, which were 9.48, 8.31, 16.00 MUM, respectively. PMID- 26633344 TI - Synthesis and Biological Evaluation of Curcumin Derivatives with Water-Soluble Groups as Potential Antitumor Agents: An in Vitro Investigation Using Tumor Cell Lines. AB - Three series of curcumin derivatives including phosphorylated, etherified, and esterified products of curcumin were synthesized, and their anti-tumor activities were assessed against human breast cancer MCF-7, hepatocellular carcinoma Hep-G2, and human cervical carcinoma HeLa cells. Compared with curcumin, compounds 3, 8, and 9 exhibited stronger antitumor cell line growth activities against HeLa cells. Compound 12 also showed higher antitumor cell line growth activities on MCF-7 cells than curcumin. Among them, 4-((1E,6E)-7-(4-Hydroxy-3-methoxyphenyl) 3,5-dioxohepta-1,6-dienyl)-2-methoxyphenyl dihydrogen phosphate(3) showed the strongest activity with an half maximal inhibitory concentration (IC50) of 6.78 uM against HeLa cells compared with curcumin with an IC50 of 17.67 uM. Stabilities of representatives of the three series were tested in rabbit plasma in vitro, and compounds 3 and 4 slowly released curcumin in plasma. The effect of compound 3 on HeLa cell apoptosis was determined by examining morphological changes by DAPI (4',6-diamidino-2-phenylindole) staining as well as Annexin V FITC/ Propidium Iodide (PI) double staining and flow cytometry. The results showed that 3 induced cellular apoptosis in a dose-dependent manner. Together our findings show that 3 merits further investigation as a new potential antitumor drug candidate. PMID- 26633345 TI - The Novel Multiple Inner Primers-Loop-Mediated Isothermal Amplification (MIP LAMP) for Rapid Detection and Differentiation of Listeria monocytogenes. AB - Here, a novel model of loop-mediated isothermal amplification (LAMP), termed multiple inner primers-LAMP (MIP-LAMP), was devised and successfully applied to detect Listeria monocytogenes. A set of 10 specific MIP-LAMP primers, which recognized 14 different regions of target gene, was designed to target a sequence in the hlyA gene. The MIP-LAMP assay efficiently amplified the target element within 35 min at 63 degrees C and was evaluated for sensitivity and specificity. The templates were specially amplified in the presence of the genomic DNA from L. monocytogenes. The limit of detection (LoD) of MIP-LAMP assay was 62.5 fg/reaction using purified L. monocytogenes DNA. The LoD for DNA isolated from serial dilutions of L. monocytogenes cells in buffer and in milk corresponded to 2.4 CFU and 24 CFU, respectively. The amplified products were analyzed by real time monitoring of changes in turbidity, and visualized by adding Loop Fluorescent Detection Reagent (FD), or as a ladder-like banding pattern on gel electrophoresis. A total of 48 pork samples were investigated for L. monocytogenes by the novel MIP-LAMP method, and the diagnostic accuracy was shown to be 100% when compared to the culture-biotechnical method. In conclusion, the MIP-LAMP methodology was demonstrated to be a reliable, sensitive and specific tool for rapid detection of L. monocytogenes strains. PMID- 26633346 TI - Characterization of Amorphous and Co-Amorphous Simvastatin Formulations Prepared by Spray Drying. AB - In this study, spray drying from aqueous solutions, using the surface-active agent sodium lauryl sulfate (SLS) as a solubilizer, was explored as a production method for co-amorphous simvastatin-lysine (SVS-LYS) at 1:1 molar mixtures, which previously have been observed to form a co-amorphous mixture upon ball milling. In addition, a spray-dried formulation of SVS without LYS was prepared. Energy dispersive X-ray spectroscopy (EDS) revealed that SLS coated the SVS and SVS-LYS particles upon spray drying. X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC) showed that in the spray-dried formulations the remaining crystallinity originated from SLS only. The best dissolution properties and a "spring and parachute" effect were found for SVS spray-dried from a 5% SLS solution without LYS. Despite the presence of at least partially crystalline SLS in the mixtures, all the studied formulations were able to significantly extend the stability of amorphous SVS compared to previous co-amorphous formulations of SVS. The best stability (at least 12 months in dry conditions) was observed when SLS was spray-dried with SVS (and LYS). In conclusion, spray drying of SVS and LYS from aqueous surfactant solutions was able to produce formulations with improved physical stability for amorphous SVS. PMID- 26633347 TI - Determination of Solubility Parameters of Ibuprofen and Ibuprofen Lysinate. AB - In recent years there has been a growing interest in formulating solid dispersions, which purposes mainly include solubility enhancement, sustained drug release and taste masking. The most notable problem by these dispersions is drug carrier (in)solubility. Here we focus on solubility parameters as a tool for predicting the solubility of a drug in certain carriers. Solubility parameters were determined in two different ways: solely by using calculation methods, and by experimental approaches. Six different calculation methods were applied in order to calculate the solubility parameters of the drug ibuprofen and several excipients. However, we were not able to do so in the case of ibuprofen lysinate, as calculation models for salts are still not defined. Therefore, the extended Hansen's approach and inverse gas chromatography (IGC) were used for evaluating of solubility parameters for ibuprofen lysinate. The obtained values of the total solubility parameter did not differ much between the two methods: by the extended Hansen's approach it was deltat = 31.15 MPa(0.5) and with IGC it was deltat = 35.17 MPa(0.5). However, the values of partial solubility parameters, i.e., deltad, deltap and deltah, did differ from each other, what might be due to the complex behaviour of a salt in the presence of various solvents. PMID- 26633348 TI - Amphiphilic Lipopeptide-Mediated Transport of Insulin and Cell Membrane Penetration Mechanism. AB - Arginine octamer (R8) and its derivatives were developed in this study for the enhanced mucosal permeation of insulin. R8 was substituted with different aminos, then modified with stearic acid (SA). We found that the SAR6EW-insulin complex had stronger intermolecular interactions and higher complex stability. The amphiphilic lipopeptide (SAR6EW) was significantly more efficient for the permeation of insulin than R8 and R6EW both in vitro and in vivo. Interestingly, different cellular internalization mechanisms were observed for the complexes. When the effectiveness of the complexes in delivering insulin in vivo was examined, it was found that the SAR6EW-insulin complex provided a significant and sustained (six hours) reduction in the blood glucose levels of diabetic rats. The improved absorption could be the comprehensive result of stronger intermolecular interactions, better enzymatic stability, altered internalization pathways, and increased transportation efficacy. In addition, no sign of toxicity was observed after consecutive administrations of SAR6EW. These results demonstrate that SAR6EW is a promising epithelium permeation enhancer for insulin and suggest that the chemical modification of cell-penetrating peptides is a feasible strategy to enhance their potential. PMID- 26633349 TI - Oral Administration of Achyranthis radix Extract Prevents TMA-induced Allergic Contact Dermatitis by Regulating Th2 Cytokine and Chemokine Production in Vivo. AB - Allergic contact dermatitis (ACD) remains a major skin disease in many countries, necessitating the discovery of novel and effective anti-ACD agents. In this study, we investigated the preventive effects of Achyranthis radix extract (AcRE) on trimellitic anhydride (TMA)-induced dermatitis and the potential mechanism of action involved. Oral administration of AcRE and prednisolone (PS) significantly suppressed TMA-induced increases in ear and epidermal thickness, and IgE expression. In addition, abnormal expression of IL-1beta and TNF-alpha protein and mRNA was also significantly attenuated by oral administration of AcRE. Treatment with AcRE also significantly suppressed TMA-induced IL-4 and IL-13 cytokines and mRNA expression in vivo. Moreover, AcRE strongly suppressed TMA induced IL-4 and IL-5 production in draining lymph nodes, as well as OVA-induced IL-4 and IL-5 expression in primary cultured splenocytes. Interestingly, AcRE suppressed IL-4-induced STAT6 phosphorylation in both primary cultured splenocytes and HaCaT cells, and TMA-induced GATA3 mRNA expression ex vivo. AcRE also suppressed TMA-mediated CCL11 and IL-4-induced CCL26 mRNA expression and infiltration of CCR3 positive cells. The major compounds from AcRE were identified as gentisic acid (0.64 +/- 0.2 MUg/g dry weight of AcRE), protocatechuic acid (2.69 +/- 0.1 MUg/g dry weight of AcRE), 4-hydroxybenzoic acid (5.59 +/- 0.3 MUg/g dry weight of AcRE), caffeic acid (4.21 +/- 0.1 MUg/g dry weight of AcRE), and ferulic acid (14.78 +/- 0.4 +/- 0.3 MUg/g dry weight of AcRE). Taken together, these results suggest that AcRE has potential for development as an agent to prevent and treat allergic contact dermatitis. PMID- 26633350 TI - Simultaneous Determination of Eight Ginsenosides in Rat Plasma by Liquid Chromatography-Electrospray Ionization Tandem Mass Spectrometry: Application to Their Pharmacokinetics. AB - A high-performance liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) method was successfully developed and validated for the identification and determination of eight ginsenosides: ginsenoside Rg1 (1); 20(S)-ginsenoside Rh1 (2); 20(S)-ginsenoside Rg2 (3); 20(R)-ginsenoside Rh1 (4); 20(R)-ginsenoside Rg2 (5); ginsenoside Rd (6); 20(S)-ginsenoside Rg3 (7); and 20(R)-ginsenoside Rg3 (8) in rat plasma. The established rapid method had high linearity, selectivity, sensitivity, accuracy, and precision. The method has been used successfully to study the pharmacokinetics of abovementioned eight ginsenosides for the first time. After an oral administration of total saponins in the stems-leaves of Panax ginseng C. A. Meyer (GTSSL) at a dose of 400 mg/kg, the ginsenosides 6, 7, and 8, belonging to protopanaxadiol-type saponins, exhibited relatively long tmax values, suggesting that they were slowly absorbed, while the ginsenosides 1-5, belonging to protopanaxatriol-type saponins, had different tmax values, which should be due to their differences in the substituted groups. Compounds 2 and 4, 3 and 5, 7 and 8 were three pairs of R/S epimerics at C-20, which was interesting that the t1/2 of 20(S)-epimers were always longer than those of 20(R)-epimers. This pharmacokinetic identification of multiple ginsenosides of GTSSL in rat plasma provides a significant basis for better understanding the clinical application of GTSSL. PMID- 26633351 TI - Influence of Pre-Fermentation Treatments on Wine Volatile and Sensory Profile of the New Disease Tolerant Cultivar Solaris. AB - Solaris is a new disease tolerant cultivar increasingly cultivated in cool climate regions. In order to explore the winemaking processes' potential to make different styles of Solaris wines, the effects of different pre-fermentation treatments (direct press after crushing, whole cluster press, cold maceration, and skin fermentation) on the volatile profile, chemical, and sensory properties of Solaris wines were investigated. Cold maceration treatment for 24 h and fermentation on skin led to wines with lower acidity and higher glycerol and total polyphenol indexes. Sensory analysis showed that cold maceration enhanced "apricot" and "apple" flavor while skin fermentation gave rise to increased "rose" and "elderflower" flavor. The PLS regression model revealed that fruity flavor of cold macerated wines was related to a combination of esters while beta damascenone and linalool were correlated to the "rose" and "elderflower" flavor. This study provides information about pre-fermentation techniques that allowed the possibility of obtaining wines with different styles. PMID- 26633352 TI - Influence of Excipients and Spray Drying on the Physical and Chemical Properties of Nutraceutical Capsules Containing Phytochemicals from Black Bean Extract. AB - Black beans (Phaseolus vulgaris L.) are a rich source of flavonoids and saponins with proven health benefits. Spray dried black bean extract powders were used in different formulations for the production of nutraceutical capsules with reduced batch-to-batch weight variability. Factorial designs were used to find an adequate maltodextrin-extract ratio for the spray-drying process to produce black bean extract powders. Several flowability properties were used to determine composite flow index of produced powders. Powder containing 6% maltodextrin had the highest yield (78.6%) and the best recovery of flavonoids and saponins (>56% and >73%, respectively). The new complexes formed by the interaction of black bean powder with maltodextrin, microcrystalline cellulose 50 and starch exhibited not only bigger particles, but also a rougher structure than using only maltodextrin and starch as excipients. A drying process prior to capsule production improved powder flowability, increasing capsule weight and reducing variability. The formulation containing 25.0% of maltodextrin, 24.1% of microcrystalline cellulose 50, 50% of starch and 0.9% of magnesium stearate produced capsules with less than 2.5% weight variability. The spray drying technique is a feasible technique to produce good flow extract powders containing valuable phytochemicals and low cost excipients to reduce the end-product variability. PMID- 26633353 TI - Symmetry Breaking of B2N((-, 0, +)): An Aspect of the Electric Potential and Atomic Charges. AB - In this study, the three forms of B2N((-, 0, +))-radical, anion and cation-have been compared in terms of electric potential and atomic charges, ESP, rather than the well-known cut of the potential energy surface (PES). We have realized that the double minimum of the BNB radical is related to the lack of the correct permutational symmetry of the wave function and charge distribution. The symmetry breaking (SB) for B2N((0, +)) exhibits energy barrier in the region of (5-150) cm(-1). The SB barrier goes through a dynamic change with no centrosymmetric form which depends on the wave function or charge distribution. In spite of A ~ 2 Sigma g + exited state, the B ~ 2 ? g excited configuration contributes to the ground state ( B ~ 2 ? g - X ~ 2 Sigma u + ) for forming radicals. The SB did not occur for the anion form (B2N((-))) in any electrostatic potential and charges distribution. Finally, we have modified the Columbic term of the Schrodinger equation to define the parameters "alphaalpha' and betabeta'" in order to investigate the SBs subject. PMID- 26633356 TI - Therapeutic Potential of Cell Penetrating Peptides (CPPs) and Cationic Polymers for Chronic Hepatitis B. AB - Chronic hepatitis B virus (HBV) infection remains a major health problem worldwide. Because current anti-HBV treatments are only virostatic, there is an urgent need for development of alternative antiviral approaches. In this context, cell-penetrating peptides (CPPs) and cationic polymers, such as chitosan (CS), appear of particular interest as nonviral vectors due to their capacity to facilitate cellular delivery of bioactive cargoes including peptide nucleic acids (PNAs) or DNA vaccines. We have investigated the ability of a PNA conjugated to different CPPs to inhibit the replication of duck hepatitis B virus (DHBV), a reference model for human HBV infection. The in vivo administration of PNA-CPP conjugates to neonatal ducklings showed that they reached the liver and inhibited DHBV replication. Interestingly, our results indicated also that a modified CPP (CatLip) alone, in the absence of its PNA cargo, was able to drastically inhibit late stages of DHBV replication. In the mouse model, conjugation of HBV DNA vaccine to modified CS (Man-CS-Phe) improved cellular and humoral responses to plasmid-encoded antigen. Moreover, other systems for gene delivery were investigated including CPP-modified CS and cationic nanoparticles. The results showed that these nonviral vectors considerably increased plasmid DNA uptake and expression. Collectively promising results obtained in preclinical studies suggest the usefulness of these safe delivery systems for the development of novel therapeutics against chronic hepatitis B. PMID- 26633355 TI - Therapeutic Targets for Neurodevelopmental Disorders Emerging from Animal Models with Perinatal Immune Activation. AB - Increasing epidemiological evidence indicates that perinatal infection with various viral pathogens enhances the risk for several psychiatric disorders. The pathophysiological significance of astrocyte interactions with neurons and/or gut microbiomes has been reported in neurodevelopmental disorders triggered by pre- and postnatal immune insults. Recent studies with the maternal immune activation or neonatal polyriboinosinic polyribocytidylic acid models of neurodevelopmental disorders have identified various candidate molecules that could be responsible for brain dysfunction. Here, we review the functions of several candidate molecules in neurodevelopment and brain function and discuss their potential as therapeutic targets for psychiatric disorders. PMID- 26633354 TI - Old Things New View: Ascorbic Acid Protects the Brain in Neurodegenerative Disorders. AB - Ascorbic acid is a key antioxidant of the Central Nervous System (CNS). Under brain activity, ascorbic acid is released from glial reservoirs to the synaptic cleft, where it is taken up by neurons. In neurons, ascorbic acid scavenges reactive oxygen species (ROS) generated during synaptic activity and neuronal metabolism where it is then oxidized to dehydroascorbic acid and released into the extracellular space, where it can be recycled by astrocytes. Other intrinsic properties of ascorbic acid, beyond acting as an antioxidant, are important in its role as a key molecule of the CNS. Ascorbic acid can switch neuronal metabolism from glucose consumption to uptake and use of lactate as a metabolic substrate to sustain synaptic activity. Multiple evidence links oxidative stress with neurodegeneration, positioning redox imbalance and ROS as a cause of neurodegeneration. In this review, we focus on ascorbic acid homeostasis, its functions, how it is used by neurons and recycled to ensure antioxidant supply during synaptic activity and how this antioxidant is dysregulated in neurodegenerative disorders. PMID- 26633357 TI - ITSN2L Interacts with and Negatively Regulates RABEP1. AB - Intersectin-2Long (ITSN2L) is a multi-domain protein participating in endocytosis and exocytosis. In this study, RABEP1 was identified as a novel ITSN2L interacting protein using a yeast two-hybrid screen from a human brain cDNA library and this interaction, specifically involving the ITSN2L CC domain and RABEP1 CC3 regions, was further confirmed by in vitro GST (glutathione-S transferase) pull-down and in vivo co-immunoprecipitation assays. Corroboratively, we observed that these two proteins co-localize in the cytoplasm of mammalian cells. Furthermore, over-expression of ITSN2L promotes RABEP1 degradation and represses RABEP1-enhanced endosome aggregation, indicating that ITSN2L acts as a negative regulator of RABEP1. Finally, we showed that ITSN2L and RABEP1 play opposite roles in regulating endocytosis. Taken together, our results indicate that ITSN2L interacts with RABEP1 and stimulates its degradation in regulation of endocytosis. PMID- 26633358 TI - Polar Glycosylated and Lateral Non-Glycosylated Flagella from Aeromonas hydrophila Strain AH-1 (Serotype O11). AB - Polar and but not lateral flagellin proteins from Aeromonas hydrophila strain AH 1 (serotype O11) were found to be glycosylated. Top-down mass spectrometry studies of purified polar flagellins suggested the presence of a 403 Da glycan of mass. Bottom-up mass spectrometry studies showed the polar flagellin peptides to be modified with 403 Da glycans in O-linkage. The MS fragmentation pattern of this putative glycan was similar to that of pseudaminic acid derivative. Mutants lacking the biosynthesis of pseudaminic acid (pseB and pseI homologues) were unable to produce polar flagella but no changes were observed in lateral flagella by post-transcriptional regulation of the flagellin. Complementation was achieved by reintroduction of the wild-type pseB and pseI. We compared two pathogenic features (adhesion to eukaryotic cells and biofilm production) between the wild type strain and two kinds of mutants: mutants lacking polar flagella glycosylation and lacking the O11-antigen lipopolysaccharide (LPS) but with unaltered polar flagella glycosylation. Results suggest that polar flagella glycosylation is extremely important for A. hydrophila AH-1 adhesion to Hep-2 cells and biofilm formation. In addition, we show the importance of the polar flagella glycosylation for immune stimulation of IL-8 production via toll-"like" receptor 5 (TLR5). PMID- 26633359 TI - Characterization of Aspartate Kinase from Corynebacterium pekinense and the Critical Site of Arg169. AB - Aspartate kinase (AK) is the key enzyme in the biosynthesis of aspartate-derived amino acids. Recombinant AK was efficiently purified and systematically characterized through analysis under optimal conditions combined with steady state kinetics study. Homogeneous AK was predicted as a decamer with a molecular weight of ~48 kDa and a half-life of 4.5 h. The enzymatic activity was enhanced by ethanol and Ni(2+). Moreover, steady-state kinetic study confirmed that AK is an allosteric enzyme, and its activity was inhibited by allosteric inhibitors, such as Lys, Met, and Thr. Theoretical results indicated the binding mode of AK and showed that Arg169 is an important residue in substrate binding, catalytic domain, and inhibitor binding. The values of the kinetic parameter Vmax of R169 mutants, namely, R169Y, R169P, R169D, and R169H AK, with l-aspartate as the substrate, were 4.71-, 2.25-, 2.57-, and 2.13-fold higher, respectively, than that of the wild-type AK. Furthermore, experimental and theoretical data showed that Arg169 formed a hydrogen bond with Glu92, which functions as the entrance gate. This study provides a basis to develop new enzymes and elucidate the corresponding amino acid production. PMID- 26633360 TI - Metagenomic Analysis of Upwelling-Affected Brazilian Coastal Seawater Reveals Sequence Domains of Type I PKS and Modular NRPS. AB - Marine environments harbor a wide range of microorganisms from the three domains of life. These microorganisms have great potential to enable discovery of new enzymes and bioactive compounds for industrial use. However, only ~1% of microorganisms from the environment can currently be identified through cultured isolates, limiting the discovery of new compounds. To overcome this limitation, a metagenomics approach has been widely adopted for biodiversity studies on samples from marine environments. In this study, we screened metagenomes in order to estimate the potential for new natural compound synthesis mediated by diversity in the Polyketide Synthase (PKS) and Nonribosomal Peptide Synthetase (NRPS) genes. The samples were collected from the Praia dos Anjos (Angel's Beach) surface water-Arraial do Cabo (Rio de Janeiro state, Brazil), an environment affected by upwelling. In order to evaluate the potential for screening natural products in Arraial do Cabo samples, we used KS (keto-synthase) and C (condensation) domains (from PKS and NRPS, respectively) to build Hidden Markov Models (HMM) models. From both samples, a total of 84 KS and 46 C novel domain sequences were obtained, showing the potential of this environment for the discovery of new genes of biotechnological interest. These domains were classified by phylogenetic analysis and this was the first study conducted to screen PKS and NRPS genes in an upwelling affected sample. PMID- 26633361 TI - The Importance of Caveolin-1 as Key-Regulator of Three-Dimensional Growth in Thyroid Cancer Cells Cultured under Real and Simulated Microgravity Conditions. AB - We recently demonstrated that the CAV1 gene was down-regulated, when poorly differentiated thyroid FTC-133 cancer cells formed spheroids under simulated microgravity conditions. Here, we present evidence that the caveolin-1 protein is involved in the inhibition of spheroid formation, when confluent monolayers are exposed to microgravity. The evidence is based on proteins detected in cells and their supernatants of the recent spaceflight experiment: "NanoRacks-CellBox Thyroid Cancer". The culture supernatant had been collected in a special container adjacent to the flight hardware incubation chamber and stored at low temperature until it was analyzed by Multi-Analyte Profiling (MAP) technology, while the cells remaining in the incubation chamber were fixed by RNAlater and examined by mass spectrometry. The soluble proteins identified by MAP were investigated in regard to their mutual interactions and their influence on proteins, which were associated with the cells secreting the soluble proteins and had been identified in a preceding study. A Pathway Studio v.11 analysis of the soluble and cell-associated proteins together with protein kinase C alpha (PRKCA) suggests that caveolin-1 is involved, when plasminogen enriched in the extracellular space is not activated and the vascular cellular adhesion molecule (VCAM-1) mediated cell-cell adhesion is simultaneously strengthened and activated PRKCA is recruited in caveolae, while the thyroid cancer cells do not form spheroids. PMID- 26633362 TI - RpoN Regulates Virulence Factors of Pseudomonas aeruginosa via Modulating the PqsR Quorum Sensing Regulator. AB - The alternative sigma factor RpoN regulates many cell functions, such as motility, quorum sensing, and virulence in the opportunistic pathogen Pseudomonas aeruginosa (P. aeruginosa). P. aeruginosa often evolves rpoN-negative variants during the chronic infection in cystic fibrosis patients. It is unclear how RpoN interacts with other regulatory mechanisms to control virulence of P. aeruginosa. In this study, we show that RpoN modulates the function of PqsR, a quorum sensing receptor regulating production of virulence factors including the phenazine pyocyanin. The ?rpoN mutant is able to synthesize 4-quinolone signal molecule HHQ but unable to activate PqsR and Pseudomonas quinolone signal (pqs) quorum sensing. The ?rpoN mutant produces minimal level of pyocyanin and is unable to produce the anti-staphylococcal agents. Providing pqsR in trans in the ?rpoN mutant restores its pqs quorum sensing and virulence factor production to the wild-type level. Our study provides evidence that RpoN has a regulatory effect on P. aeruginosa virulence through modulating the function of the PqsR quorum sensing regulator. PMID- 26633363 TI - Gene Expression Profiles of Main Olfactory Epithelium in Adenylyl Cyclase 3 Knockout Mice. AB - Adenylyl Cyclase 3 (AC3) plays an important role in the olfactory sensation signaling pathway in mice. AC3 deficiency leads to defects in olfaction. However, it is still unknown whether AC3 deficiency affects gene expression or olfactory signal transduction pathways within the main olfactory epithelium (MOE). In this study, gene microarrays were used to screen differentially expressed genes in MOE from AC3 knockout (AC3(-/-)) and wild-type (AC3(+/+)) mice. The differentially expressed genes identified were subjected to bioinformatic analysis and verified by qRT-PCR. Gene expression in the MOE from AC3(-/-) mice was significantly altered, compared to AC3(+/+) mice. Of the 41266 gene probes, 3379 had greater than 2-fold fold change in expression levels between AC3(-/-) and AC3(+/+) mice, accounting for 8% of the total gene probes. Of these genes, 1391 were up regulated, and 1988 were down regulated, including 425 olfactory receptor genes, 99 genes that are specifically expressed in the immature olfactory neurons, 305 genes that are specifically expressed in the mature olfactory neurons, and 155 genes that are involved in epigenetic regulation. Quantitative RT-PCR verification of the differentially expressed epigenetic regulation related genes, olfactory receptors, ion transporter related genes, neuron development and differentiation related genes, lipid metabolism and membrane protein transport etc. related genes showed that P75NTR, Hinfp, Gadd45b, and Tet3 were significantly up-regulated, while Olfr370, Olfr1414, Olfr1208, Golf, Faim2, Tsg101, Mapk10, Actl6b, H2BE, ATF5, Kirrrel2, OMP, Drd2 etc. were significantly down-regulated. In summary, AC3 may play a role in proximal olfactory signaling and play a role in the regulation of differentially expressed genes in mouse MOE. PMID- 26633364 TI - Carbon Ion Irradiated Neural Injury Induced the Peripheral Immune Effects in Vitro or in Vivo. AB - Carbon ion radiation is a promising treatment for brain cancer; however, the immune system involved long-term systemic effects evoke a concern of complementary and alternative therapies in clinical treatment. To clarify radiotherapy caused fundamental changes in peripheral immune system, examinations were performed based on established models in vitro and in vivo. We found that brain-localized carbon ion radiation of neural cells induced complex changes in the peripheral blood, thymus, and spleen at one, two, and three months after its application. Atrophy, apoptosis, and abnormal T-cell distributions were observed in rats receiving a single high dose of radiation. Radiation downregulated the expression of proteins involved in T-cell development at the transcriptional level and increased the proportion of CD3+CD4(-)CD8+ T-cells in the thymus and the proportion of CD3+CD4+CD8(-) T-cells in the spleen. These data show that brain irradiation severely affects the peripheral immune system, even at relatively long times after irradiation. In addition, they provide valuable information that will implement the design of biological-based strategies that will aid brain cancer patients suffering from the long-term side effects of radiation. PMID- 26633366 TI - Myricetin Attenuates Depressant-Like Behavior in Mice Subjected to Repeated Restraint Stress. AB - Increasing evidence has shown that oxidative stress may be implicated in chronic stress-induced depression. Several flavonoids with anti-oxidative effects have been proved to be anti-depressive. Myricetin is a well-defined flavonoid with the anti-oxidative, anti-inflammatory, anti-apoptotic, and neuroprotective properties. The aim of the present study is to investigate the possible effects of chronic administration of myricetin on depressant-like behaviors in mice subjected to repeated restraint (4 h/day) for 21 days. Our results showed that myricetin administration specifically reduced the immobility time in mice exposed to chronic stress, as tested in both forced swimming test and tail suspension test. Myricetin treatment improved activities of glutathione peroxidase (GSH-PX) in the hippocampus of stressed mice. In addition, myricetin treatment decreased plasma corticosterone levels of those mice subjected to repeated restraint stress. The effects of myricetin on the brain-derived neurotrophic factor (BDNF) levels in hippocampus were also investigated. The results revealed that myricetin normalized the decreased BDNF levels in mice subjected to repeated restraint stress. These findings provided more evidence that chronic administration of myricetin improves helpless behaviors. The protective effects of myricetin might be partially mediated by an influence on BDNF levels and might be attributed to myricetin-mediated anti-oxidative stress in the hippocampus. PMID- 26633367 TI - Neuropeptide Trefoil Factor 3 Reverses Depressive-Like Behaviors by Activation of BDNF-ERK-CREB Signaling in Olfactory Bulbectomized Rats. AB - The trefoil factors (TFFs) are a family of three polypeptides, among which TFF1 and TFF3 are widely distributed in the central nervous system. Our previous study indicated that TFF3 was a potential rapid-onset antidepressant as it reversed the depressive-like behaviors induced by acute or chronic mild stress. In order to further identify the antidepressant-like effect of TFF3, we applied an olfactory bulbectomy (OB), a classic animal model of depression, in the present study. To elucidate the mechanism underlying the antidepressant-like activity of TFF3, we tested the role of brain-derived neurotrophic factor (BDNF)-extracellular signal related kinase (ERK)-cyclic adenosine monophosphate response element binding protein (CREB) signaling in the hippocampus in the process. Chronic systemic administration of TFF3 (0.1 mg/kg, i.p.) for seven days not only produced a significant antidepressant-like efficacy in the OB paradigm, but also restored the expression of BDNF, pERK, and pCREB in the hippocampal CA3. Inhibition of BDNF or extracellular signal-related kinase (ERK) signaling in CA3 blocked the antidepressant-like activity of TFF3 in OB rats. Our findings further confirmed the therapeutic effect of TFF3 against depression and suggested that the normalization of the BDNF-ERK-CREB pathway was involved in the behavioral response of TFF3 for the treatment of depression. PMID- 26633365 TI - MiRNAs and Other Epigenetic Changes as Biomarkers in Triple Negative Breast Cancer. AB - Triple negative breast cancer (TNBC) is characterised by the lack of receptors for estrogen (ER), progesterone (PR), and human epidermal growth factor 2 (HER2). Since it cannot be treated by current endocrine therapies which target these receptors and due to its aggressive nature, it has one of the worst prognoses of all breast cancer subtypes. The only treatments remain chemo- and/or radio therapy and surgery and because of this, novel biomarkers or treatment targets are urgently required to improve disease outcomes. MicroRNAs represent an attractive candidate for targeted therapies against TNBC, due to their natural ability to act as antisense interactors and regulators of entire gene sets involved in malignancy and their superiority over mRNA profiling to accurately classify disease. Here we review the current knowledge regarding miRNAs as biomarkers in TNBC and their potential use as therapeutic targets in this disease. Further, we review other epigenetic changes and interactions of these changes with microRNAs in this breast cancer subtype, which may lead to the discovery of new treatment targets for TNBC. PMID- 26633368 TI - Cytidine 5'-Diphosphocholine (Citicoline) in Glaucoma: Rationale of Its Use, Current Evidence and Future Perspectives. AB - Cytidine 5'-diphosphocholine or citicoline is an endogenous compound that acts in the biosynthetic pathway of phospholipids of cell membranes, particularly phosphatidylcholine, and it is able to increase neurotrasmitters levels in the central nervous system. Citicoline has shown positive effects in Parkinson's disease and Alzheimer's disease, as well as in amblyopia. Glaucoma is a neurodegenerative disease currently considered a disease involving ocular and visual brain structures. Neuroprotection has been proposed as a valid therapeutic option for those patients progressing despite a well-controlled intraocular pressure, the main risk factor for the progression of the disease. The aim of this review is to critically summarize the current evidence about the effect of citicoline in glaucoma. PMID- 26633369 TI - Thrombophilia and Pregnancy Complications. AB - There is a paucity of strong evidence associated with adverse pregnancy outcomes and thrombophilia in pregnancy. These problems include both early (recurrent miscarriage) and late placental vascular-mediated problems (fetal loss, pre eclampsia, placental abruption and intra-uterine growth restriction). Due to poor quality case-control and cohort study designs, there is often an increase in the relative risk of these complications associated with thrombophilia, particularly recurrent early pregnancy loss, late fetal loss and pre-eclampsia, but the absolute risk remains very small. It appears that low-molecular weight heparin has other benefits on the placental vascular system besides its anticoagulant properties. Its use is in the context of antiphospholipid syndrome and recurrent pregnancy loss and also in women with implantation failure to improve live birth rates. There is currently no role for low-molecular weight heparin to prevent late placental-mediated complications in patients with inherited thrombophilia and this may be due to small patient numbers in the studies involved in summarising the evidence. There is potential for low-molecular weight heparin to improve pregnancy outcomes in women with prior severe vascular complications of pregnancy such as early-onset intra-uterine growth restriction and pre-eclampsia but further high quality randomised controlled trials are required to answer this question. PMID- 26633371 TI - Characterization of Morphological and Cellular Events Underlying Oral Regeneration in the Sea Anemone, Nematostella vectensis. AB - Cnidarians, the extant sister group to bilateria, are well known for their impressive regenerative capacity. The sea anemone Nematostella vectensis is a well-established system for the study of development and evolution that is receiving increased attention for its regenerative capacity. Nematostella is able to regrow missing body parts within five to six days after its bisection, yet studies describing the morphological, cellular, and molecular events underlying this process are sparse and very heterogeneous in their experimental approaches. In this study, we lay down the basic framework to study oral regeneration in Nematostella vectensis. Using various imaging and staining techniques we characterize in detail the morphological, cellular, and global molecular events that define specific landmarks of this process. Furthermore, we describe in vivo assays to evaluate wound healing success and the initiation of pharynx reformation. Using our described landmarks for regeneration and in vivo assays, we analyze the effects of perturbing either transcription or cellular proliferation on the regenerative process. Interestingly, neither one of these experimental perturbations has major effects on wound closure, although they slightly delay or partially block it. We further show that while the inhibition of transcription blocks regeneration in a very early step, inhibiting cellular proliferation only affects later events such as pharynx reformation and tentacle elongation. PMID- 26633370 TI - Maize-Pathogen Interactions: An Ongoing Combat from a Proteomics Perspective. AB - Maize (Zea mays L.) is a host to numerous pathogenic species that impose serious diseases to its ear and foliage, negatively affecting the yield and the quality of the maize crop. A considerable amount of research has been carried out to elucidate mechanisms of maize-pathogen interactions with a major goal to identify defense-associated proteins. In this review, we summarize interactions of maize with its agriculturally important pathogens that were assessed at the proteome level. Employing differential analyses, such as the comparison of pathogen resistant and susceptible maize varieties, as well as changes in maize proteomes after pathogen challenge, numerous proteins were identified as possible candidates in maize resistance. We describe findings of various research groups that used mainly mass spectrometry-based, high through-put proteomic tools to investigate maize interactions with fungal pathogens Aspergillus flavus, Fusarium spp., and Curvularia lunata, and viral agents Rice Black-streaked Dwarf Virus and Sugarcane Mosaic Virus. PMID- 26633372 TI - Molecular Evolution of the TET Gene Family in Mammals. AB - Ten-eleven translocation (TET) proteins, a family of Fe(2+)- and 2-oxoglutarate dependent dioxygenases, are involved in DNA demethylation. They also help regulate various cellular functions. Three TET paralogs have been identified (TET1, TET2, and TET3) in humans. This study focuses on the evolution of mammalian TET genes. Distinct patterns in TET1 and TET2 vs. TET3 were revealed by codon-based tests of positive selection. Results indicate that TET1 and TET2 genes have experienced positive selection more frequently than TET3 gene, and that the majority of codon sites evolved under strong negative selection. These findings imply that the selective pressure on TET3 may have been relaxed in several lineages during the course of evolution. Our analysis of convergent amino acid substitutions also supports the different evolutionary dynamics among TET gene subfamily members. All of the five amino acid sites that are inferred to have evolved under positive selection in the catalytic domain of TET2 are localized at the protein's outer surface. The adaptive changes of these positively selected amino acid sites could be associated with dynamic interactions between other TET-interacting proteins, and positive selection thus appears to shift the regulatory scheme of TET enzyme function. PMID- 26633373 TI - Simultaneous Analysis of SEPT9 Promoter Methylation Status, Micronuclei Frequency, and Folate-Related Gene Polymorphisms: The Potential for a Novel Blood Based Colorectal Cancer Biomarker. AB - One challenge in colorectal cancer (CRC) is identifying novel biomarkers to be introduced in screening programs. The present study investigated the promoter methylation status of the SEPT9 gene in peripheral blood samples of subjects' positive fecal occult blood test (FOBT). In order to add new insights, we investigated the association between SEPT9 promoter methylation and micronuclei frequency, and polymorphisms in the folate-related pathway genes. SEPT9 promoter methylation, micronuclei frequency, and genotypes were evaluated on 74 individuals' FOBT positive. Individuals were subjected to a colonoscopy that provided written informed consent for study participation. SEPT9 promoter methylation status was significantly lower in the CRC group than controls (p = 0.0006). In contrast, the CaCo2 cell-line, analyzed as a tissue specific model of colon adenocarcinoma, showed a significantly higher percentage of SEPT9 promoter methylation compared to the CRC group (p < 0.0001). Linear regression analysis showed an inverse correlation between micronuclei frequency and the decrease in the methylation levels of SEPT9 promoter region among CRC patients (beta = 0.926, p = 0.0001). With regard to genotype analysis, we showed the involvement of the DHFR polymorphism (rs70991108) in SEPT9 promoter methylation level in CRC patients only. In particular, the presence of at least one 19 bp del allele significantly correlates with decreased SEPT9 promoter methylation, compared to the 19 bp ins/ins genotype (p = 0.007). While remaining aware of the strengths and limitations of the study, this represents the first evidence of a novel approach for the early detection of CRC, using SEPT9 promoter methylation, micronuclei frequency and genotypes, with the potential to improve CRC risk assessment. PMID- 26633374 TI - Cloning and Expression Analysis of Vvlcc3, a Novel and Functional Laccase Gene Possibly Involved in Stipe Elongation. AB - Volvariella volvacea, usually harvested in its egg stage, is one of the most popular mushrooms in Asia. The rapid transition from the egg stage to elongation stage, during which the stipe stretches to almost full length leads to the opening of the cap and rupture of the universal veil, and is considered to be one of the main factors that negatively impacts the yield and value of V. volvacea. Stipe elongation is a common phenomenon in mushrooms; however, the mechanisms, genes and regulation involved in stipe elongation are still poorly understood. In order to study the genes related to the stipe elongation, we analyzed the transcription of laccase genes in stipe tissue of V. volvacea, as some laccases have been suggested to be involved in stipe elongation in Flammulina velutipes. Based on transcription patterns, the expression of Vvlcc3 was found to be the highest among the 11 laccase genes. Moreover, phylogenetic analysis showed that VvLCC3 has a high degree of identity with other basidiomycete laccases. Therefore, we selected and cloned a laccase gene, named Vvlcc3, a cDNA from V. volvacea, and expressed the cDNA in Pichia pastoris. The presence of the laccase signature L1-L4 on the deduced protein sequence indicates that the gene encodes a laccase. Phylogenetic analysis showed that VvLCC3 clusters with Coprinopsis cinerea laccases. The ability to catalyze ABTS (2,2'-Azino-bis(3 ethylbenzothiazoline-6-sulfonic acid) oxidation proved that the product of the Vvlcc3 gene was a functional laccase. We also found that the expression of the Vvlcc3 gene in V. volvacea increased during button stage to the elongation stage; it reached its peak in the elongation stage, and then decreased in the maturation stage, which was similar to the trend in the expression of Fv-lac3 and Fv-lac5 in F. velutipes stipe tissue. The similar trend in expression level of these laccase genes of F. velutipes suggested that this gene could be involved in stipe elongation in V. volvacea. PMID- 26633375 TI - DAG/PKCdelta and IP3/Ca2+/CaMK IIbeta Operate in Parallel to Each Other in PLCgamma1-Driven Cell Proliferation and Migration of Human Gastric Adenocarcinoma Cells, through Akt/mTOR/S6 Pathway. AB - Phosphoinositide specific phospholipase Cgamma (PLCgamma) activates diacylglycerol (DAG)/protein kinase C (PKC) and inositol 1,4,5-trisphosphate (IP3)/Ca(2+)/calmodulin-dependent protein kinase II (CaMK II) axes to regulate import events in some cancer cells, including gastric adenocarcinoma cells. However, whether DAG/PKCdelta and IP3/Ca(2+)/CaMK IIbeta axes are simultaneously involved in PLCgamma1-driven cell proliferation and migration of human gastric adenocarcinoma cells and the underlying mechanism are not elucidated. Here, we investigated the role of DAG/PKCdelta or CaMK IIbeta in PLCgamma1-driven cell proliferation and migration of human gastric adenocarcinoma cells, using the BGC 823 cell line. The results indicated that the inhibition of PKCdelta and CaMK IIbeta could block cell proliferation and migration of BGC-823 cells as well as the effect of inhibiting PLCgamma1, including the decrease of cell viability, the increase of apoptotic index, the down-regulation of matrix metalloproteinase (MMP) 9 expression level, and the decrease of cell migration rate. Both DAG/PKCdelta and CaMK IIbeta triggered protein kinase B (Akt)/mammalian target of rapamycin (mTOR)/S6 pathway to regulate protein synthesis. The data indicate that DAG/PKCdelta and IP3/Ca(2+)/CaMK IIbeta operate in parallel to each other in PLCgamma1-driven cell proliferation and migration of human gastric adenocarcinoma cells through Akt/mTOR/S6 pathway, with important implication for validating PLCgamma1 as a molecular biomarker in early gastric cancer diagnosis and disease surveillance. PMID- 26633376 TI - Effects of PMMA and Cross-Linked Dextran Filler for Soft Tissue Augmentation in Rats. AB - This study was conducted for evaluation of the ability to maintain efficacy and biocompatibility of cross-linked dextran in hydroxypropyl methylcellulose (DiHM) and cross-linked dextran mixed with PMMA in hydroxypropyl methylcellulose (PDiHM), compared with hyaluronic acid (HA) filler. Saline and HA solution was administered in the negative and positive control groups, and DiHM and PDiHM were administered in the test groups (n = 10 in each group). The site of cranial subcutaneous injection was the mid-point of the interpupillary line, and the site of intraoral submucosal injection was the ridge crest 2 mm below the cervical line of the mandibular left incisor. Before and immediately after filler injection, intraoral photos and lateral cephalometric radiographs were taken for analysis and comparison of the effect of the filler on the injection sites. The filler injected areas were converted into sequential size changes (%) of the baseline. Histomorphologic examination was performed after 12 weeks. The smallest value in the filler injected area was observed during the experimental period in the normal saline group (p < 0.001), which was almost absorbed at 4 weeks (7.19% +/- 12.72%). The HA group exhibited a steady decrease in sequential size and showed a lower value than the DiHM and PDiHM groups (saline < HA < DHiM, PDHiM, p < 0.001). DiHM and PDiHM tended to increase for the first 4 weeks and later decreased until 12 weeks. In this study on DiHM and PDiHM, there was no histological abnormality in cranial skin and oral mucosa. DiHM and PDiHM filler materials with injection system provide an excellent alternative surgical method for use in oral and craniofacial fields. PMID- 26633377 TI - Repositioning of Thiourea-Containing Drugs as Tyrosinase Inhibitors. AB - Tyrosinase catalyzes two distinct sequential reactions in melanin biosynthesis: The hydroxylation of tyrosine to dihydroxyphenylalanine (DOPA) and the oxidation of DOPA to dopaquinone. Developing functional modulators of tyrosinase is important for therapeutic and cosmetic purposes. Given the abundance of thiourea moiety in known tyrosinase inhibitors, we studied other thiourea-containing drugs as potential tyrosinase inhibitors. The thiourea-containing drugs in clinical use were retrieved and tested for their ability to inhibit tyrosinase. We observed that methimazole, thiouracil, methylthiouracil, propylthiouracil, ambazone, and thioacetazone inhibited mushroom tyrosinase. Except for methimazole, there was limited information regarding the activity of other drugs against tyrosinase. Both thioacetazone and ambazone significantly inhibited tyrosinase, with IC50 of 14 and 15 MUM, respectively. Ambazone decreased melanin content without causing cellular toxicity at 20 MUM in B16F10 cells. The activity of ambazone was stronger than that of kojic acid both in enzyme and melanin content assays. Kinetics of enzyme inhibition assigned the thiourea-containg drugs as non competitive inhibitors. The complex models by docking simulation suggested that the intermolecular hydrogen bond via the nitrogen of thiourea and the contacts via thione were equally important for interacting with tyrosinase. These data were consistent with the results of enzyme assays with the analogues of thiourea. PMID- 26633378 TI - Plants as Factories for Human Pharmaceuticals: Applications and Challenges. AB - Plant molecular farming (PMF), defined as the practice of using plants to produce human therapeutic proteins, has received worldwide interest. PMF has grown and advanced considerably over the past two decades. A number of therapeutic proteins have been produced in plants, some of which have been through pre-clinical or clinical trials and are close to commercialization. Plants have the potential to mass-produce pharmaceutical products with less cost than traditional methods. Tobacco-derived antibodies have been tested and used to combat the Ebola outbreak in Africa. Genetically engineered immunoadhesin (DPP4-Fc) produced in green plants has been shown to be able to bind to MERS-CoV (Middle East Respiratory Syndrome), preventing the virus from infecting lung cells. Biosafety concerns (such as pollen contamination and immunogenicity of plant-specific glycans) and costly downstream extraction and purification requirements, however, have hampered PMF production from moving from the laboratory to industrial application. In this review, the challenges and opportunities of PMF are discussed. Topics addressed include; transformation and expression systems, plant bioreactors, safety concerns, and various opportunities to produce topical applications and health supplements. PMID- 26633379 TI - Parallel Reaction Monitoring: A Targeted Experiment Performed Using High Resolution and High Mass Accuracy Mass Spectrometry. AB - The parallel reaction monitoring (PRM) assay has emerged as an alternative method of targeted quantification. The PRM assay is performed in a high resolution and high mass accuracy mode on a mass spectrometer. This review presents the features that make PRM a highly specific and selective method for targeted quantification using quadrupole-Orbitrap hybrid instruments. In addition, this review discusses the label-based and label-free methods of quantification that can be performed with the targeted approach. PMID- 26633380 TI - Transcriptomic Response to Nitric Oxide Treatment in Larix olgensis Henry. AB - Larix olgensis Henry is an important coniferous species found in plantation forests in northeastern China, but it is vulnerable to pathogens. Nitric oxide (NO) is an important molecule involved in plant resistance to pathogens. To study the regulatory role of NO at the transcriptional level, we characterized the transcriptomic response of L. olgensis seedlings to sodium nitroprusside (SNP, NO donor) using Illumina sequencing and de novo transcriptome assembly. A significant number of putative metabolic pathways and functions associated with the unique sequences were identified. Genes related to plant pathogen infection (FLS2, WRKY33, MAPKKK, and PR1) were upregulated with SNP treatment. This report describes the potential contribution of NO to disease resistance in L. olgensis as induced by biotic stress. Our results provide a substantial contribution to the genomic and transcriptomic resources for L. olgensis, as well as expanding our understanding of the involvement of NO in defense responses at the transcriptional level. PMID- 26633381 TI - New Whitening Constituents from Taiwan-Native Pyracantha koidzumii: Structures and Tyrosinase Inhibitory Analysis in Human Epidermal Melanocytes. AB - Nontoxic natural products useful in skin care cosmetics are of considerable interest. Tyrosinase is a rate-limiting enzyme for which its inhibitor is useful in developing whitening cosmetics. Pyracantha koidzumii (Hayata) Rehder is an endemic species in Taiwan that exhibits tyrosinase-inhibitory activity. To find new active natural compounds from P. koidzumii, we performed bioguided isolation and studied the related activity in human epidermal melanocytes. In total, 13 compounds were identified from P. koidzumii in the present study, including two new compounds, 3,6-dihydroxy-2,4-dimethoxy-dibenzofuran (9) and 3,4-dihydroxy-5 methoxybiphenyl-2'-O-beta-d-glucopyranoside (13), as well as 11 known compounds. The new compound 13 exhibited maximum potency in inhibiting cellular tyrosinase activity, the protein expression of cellular tyrosinase and tyrosinase-related protein-2, as well as the mRNA expression of Paired box 3 and microphthalmia associated transcription factor in a concentration-dependent manner. In the enzyme kinetic assay, the new compound 13 acted as an uncompetitive mixed-type inhibitor against the substrate l-3,4-dihydroxyphenylalanine and had a Km value against this substrate of 0.262 mM, as calculated using the Lineweaver-Burk plots. Taken together, our findings show compound 13 exhibits tyrosinase inhibition in human melanocytes and compound 13 may be a potential candidate for use in cosmetics. PMID- 26633383 TI - Overexpression of X-Box Binding Protein 1 (XBP1) Correlates to Poor Prognosis and Up-Regulation of PI3K/mTOR in Human Osteosarcoma. AB - Increasing evidence demonstrates that dysregulation of XBP1 function contributes to tumorigenesis in some cancers. However, little is known about the role of XBP1 in the progression of osteosarcoma (OS). The expression of XBP1 in OS samples was measured by quantitative RT-PCR and Western blotting assays. Cell cycle analysis and cell counting kit 8 (CCK8) assays were performed to determine the effects of XBP1 expression on cells growth capacity. Cell apoptosis coassay was applied to determine cell survival. The expression of genes affected by XBP1 was examined by quantitative RT-RCR and validated by Western blotting assays. XBP1 was overexpressed in OS clinical samples compared with corresponding non-cancerous tissues. Overexpression of XBP1 was significantly associated with advanced clinical stages, high degree of malignancy and low tumor necrosis rate. Furthermore, hypoxia activated XBP1, and silencing XBP1 significantly enhanced OS cell apoptosis. Knock-down of XBP1 resulted in inhibition of OS growth. Most importantly, knockdown of XBP1 led to down-regulation of PIK3R3 and mTOR. Taken together, XBP1 is up-regulated and has a pro-tumor effect in OS with activation of PI3K/mTOR signaling. Thus, targeting XBP1 may provide a new potential therapeutic method for OS. PMID- 26633384 TI - Cloning of the Major Capsid Protein (MCP) of Grouper Iridovirus of Taiwan (TGIV) and Preliminary Evaluation of a Recombinant MCP Vaccine against TGIV. AB - Fish iridoviruses cause systemic diseases with high mortality in various species of wild and farm-raised fish, resulting in severe economic losses. In 1998, we isolated a new epizootic iridovirus in cultured grouper (Epinephelus sp.) in Taiwan, thus named as grouper iridovirus of Taiwan (TGIV). We report here the cloning of TGIV major capsid protein (MCP). Phylogenetic analysis of the iridoviral MCPs confirmed the classification of TGIV into the Megalocytivirus genus. Recombinant TGIV MCP and GIV MCP were then generated to produce polyclonal antibodies. Western blot analysis revealed that the two antisera were species specific, indicating no common epitope shared by the MCPs of the two viruses. We further assayed the potency of a subunit vaccine containing recombinant TGIV MCP. The vaccine effectively protected grouper from TGIV infection. The result demonstrated that MCP is a suitable antigen for anti-TGIV vaccines. PMID- 26633382 TI - Induced Pluripotency and Gene Editing in Disease Modelling: Perspectives and Challenges. AB - Embryonic stem cells (ESCs) are chiefly characterized by their ability to self renew and to differentiate into any cell type derived from the three main germ layers. It was demonstrated that somatic cells could be reprogrammed to form induced pluripotent stem cells (iPSCs) via various strategies. Gene editing is a technique that can be used to make targeted changes in the genome, and the efficiency of this process has been significantly enhanced by recent advancements. The use of engineered endonucleases, such as homing endonucleases, zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs) and Cas9 of the CRISPR system, has significantly enhanced the efficiency of gene editing. The combination of somatic cell reprogramming with gene editing enables us to model human diseases in vitro, in a manner considered superior to animal disease models. In this review, we discuss the various strategies of reprogramming and gene targeting with an emphasis on the current advancements and challenges of using these techniques to model human diseases. PMID- 26633385 TI - Mutations of Glucose-6-Phosphate Dehydrogenase Durham, Santa-Maria and A+ Variants Are Associated with Loss Functional and Structural Stability of the Protein. AB - Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzymopathy in the world. More than 160 mutations causing the disease have been identified, but only 10% of these variants have been studied at biochemical and biophysical levels. In this study we report on the functional and structural characterization of three naturally occurring variants corresponding to different classes of disease severity: Class I G6PD Durham, Class II G6PD Santa Maria, and Class III G6PD A+. The results showed that the G6PD Durham (severe deficiency), and the G6PD Santa Maria and A+ (less severe deficiency) (Class I, II and III, respectively) affect the catalytic efficiency of these enzymes, are more sensitive to temperature denaturing, and affect the stability of the overall protein when compared to the wild type WT-G6PD. In the variants, the exposure of more and buried hydrophobic pockets was induced and monitored with 8 Anilinonaphthalene-1-sulfonic acid (ANS) fluorescence, directly affecting the compaction of structure at different levels and probably reducing the stability of the protein. The degree of functional and structural perturbation by each variant correlates with the clinical severity reported in different patients. PMID- 26633386 TI - Gga-miR-101-3p Plays a Key Role in Mycoplasma gallisepticum (HS Strain) Infection of Chicken. AB - Mycoplasma gallisepticum (MG), one of the most pathogenic Mycoplasma, has caused tremendous economic loss in the poultry industry. Recently, increasing evidence has suggested that micro ribonucleic acids (miRNAs) are involved in microbial pathogenesis. However, little is known about potential roles of miRNAs in MG infection of chicken. In the present study, using miRNA Solexa sequencing we have found that gga-miR-101-3p was up-regulated in the lungs of MG-infected chicken embryos. Moreover, gga-miR-101-3p regulated expression of the host enhancer of zeste homolog 2 (EZH2) through binding to the 3' un-translated region (3'-UTR) of EZH2 gene. Over-expression of gga-miR-101-3p significantly inhibited EZH2 expression and hence inhibited proliferation of chicken embryonic fibroblast (DF 1 cells) by blocking the G1-to-S phase transition. Similar results were obtained in MG-infected chicken embryos and DF-1 cells, where gga-miR-101-3p was significantly up-regulated, while EZH2 was significantly down-regulated. This study reveals that gga-miR-101-3p plays an important role in MG infection through regulation of EZH2 expression and provides a new insight into the mechanisms of MG pathogenesis. PMID- 26633387 TI - Genome-Wide Identification and Analysis of the VQ Motif-Containing Protein Family in Chinese Cabbage (Brassica rapa L. ssp. Pekinensis). AB - Previous studies have showed that the VQ motif-containing proteins in Arabidopsis thaliana and Oryza sativa play an important role in plant growth, development, and stress responses. However, little is known about the functions of the VQ genes in Brassica rapa (Chinese cabbage). In this study, we performed genome-wide identification, characterization, and expression analysis of the VQ genes in Chinese cabbage, especially under adverse environment. We identified 57 VQ genes and classified them into seven subgroups (I-VII), which were dispersedly distributed on chromosomes 1 to 10. The expansion of these genes mainly contributed to segmental and tandem duplication. Fifty-four VQ genes contained no introns and 50 VQ proteins were less than 300 amino acids in length. Quantitative real-time PCR showed that the VQ genes were differentially expressed in various tissues and during different abiotic stresses and plant hormone treatments. This study provides a comprehensive overview of Chinese cabbage VQ genes and will benefit the molecular breeding for resistance to stresses and disease, as well as further studies on the biological functions of the VQ proteins. PMID- 26633389 TI - Omics-Based Comparative Transcriptional Profiling of Two Contrasting Rice Genotypes during Early Infestation by Small Brown Planthopper. AB - The small brown planthopper (SBPH) is one of the destructive pests of rice. Although different biochemical pathways that are involved in rice responding to planthopper infestation have been documented, it is unclear which individual metabolic pathways are responsive to planthopper infestation. In this study, an omics-based comparative transcriptional profiling of two contrasting rice genotypes, an SBPH-resistant and an SBPH-susceptible rice line, was assessed for rice individual metabolic pathways responsive to SBPH infestation. When exposed to SBPH, 166 metabolic pathways were differentially regulated; of these, more than one-third of metabolic pathways displayed similar change patterns between these two contrasting rice genotypes; the difference of change pattern between these two contrasting rice genotypes mostly lies in biosynthetic pathways and the obvious difference of change pattern lies in energy metabolism pathways. Combining the Pathway Tools Omics Viewer with the web tool Venn, 21 and 6 metabolic pathways which potentially associated with SBPH resistance and susceptibility, respectively were identified. This study presents an omics-based comparative transcriptional profiling of SBPH-resistant and SBPH-susceptible rice plants during early infestation by SBPH, which will be very informative in studying rice-insect interaction. The results will provide insight into how rice plants respond to early infestation by SBPH from the biochemical pathways perspective. PMID- 26633390 TI - Next-Generation Sequencing Workflow for NSCLC Critical Samples Using a Targeted Sequencing Approach by Ion Torrent PGMTM Platform. AB - Next-generation sequencing (NGS) is a cost-effective technology capable of screening several genes simultaneously; however, its application in a clinical context requires an established workflow to acquire reliable sequencing results. Here, we report an optimized NGS workflow analyzing 22 lung cancer-related genes to sequence critical samples such as DNA from formalin-fixed paraffin-embedded (FFPE) blocks and circulating free DNA (cfDNA). Snap frozen and matched FFPE gDNA from 12 non-small cell lung cancer (NSCLC) patients, whose gDNA fragmentation status was previously evaluated using a multiplex PCR-based quality control, were successfully sequenced with Ion Torrent PGMTM. The robust bioinformatic pipeline allowed us to correctly call both Single Nucleotide Variants (SNVs) and indels with a detection limit of 5%, achieving 100% specificity and 96% sensitivity. This workflow was also validated in 13 FFPE NSCLC biopsies. Furthermore, a specific protocol for low input gDNA capable of producing good sequencing data with high coverage, high uniformity, and a low error rate was also optimized. In conclusion, we demonstrate the feasibility of obtaining gDNA from FFPE samples suitable for NGS by performing appropriate quality controls. The optimized workflow, capable of screening low input gDNA, highlights NGS as a potential tool in the detection, disease monitoring, and treatment of NSCLC. PMID- 26633388 TI - Current Status of Herbal Medicines in Chronic Liver Disease Therapy: The Biological Effects, Molecular Targets and Future Prospects. AB - Chronic liver dysfunction or injury is a serious health problem worldwide. Chronic liver disease involves a wide range of liver pathologies that include fatty liver, hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. The efficiency of current synthetic agents in treating chronic liver disease is not satisfactory and they have undesirable side effects. Thereby, numerous medicinal herbs and phytochemicals have been investigated as complementary and alternative treatments for chronic liver diseases. Since some herbal products have already been used for the management of liver diseases in some countries or regions, a systematic review on these herbal medicines for chronic liver disease is urgently needed. Herein, we conducted a review describing the potential role, pharmacological studies and molecular mechanisms of several commonly used medicinal herbs and phytochemicals for chronic liver diseases treatment. Their potential toxicity and side effects were also discussed. Several herbal formulae and their biological effects in chronic liver disease treatment as well as the underlying molecular mechanisms are also summarized in this paper. This review article is a comprehensive and systematic analysis of our current knowledge of the conventional medicinal herbs and phytochemicals in treating chronic liver diseases and on the potential pitfalls which need to be addressed in future study. PMID- 26633392 TI - Optimisation in the Design of Environmental Sensor Networks with Robustness Consideration. AB - This work proposes the design of Environmental Sensor Networks (ESN) through balancing robustness and redundancy. An Evolutionary Algorithm (EA) is employed to find the optimal placement of sensor nodes in the Region of Interest (RoI). Data quality issues are introduced to simulate their impact on the performance of the ESN. Spatial Regression Test (SRT) is also utilised to promote robustness in data quality of the designed ESN. The proposed method provides high network representativeness (fit for purpose) with minimum sensor redundancy (cost), and ensures robustness by enabling the network to continue to achieve its objectives when some sensors fail. PMID- 26633391 TI - Diversity and Inheritance of Intergenic Spacer Sequences of 45S Ribosomal DNA among Accessions of Brassica oleracea L. var. capitata. AB - Ribosomal DNA (rDNA) of plants is present in high copy number and shows variation between and within species in the length of the intergenic spacer (IGS). The 45S rDNA of flowering plants includes the 5.8S, 18S and 25S rDNA genes, the internal transcribed spacer (ITS1 and ITS2), and the intergenic spacer 45S-IGS (25S-18S). This study identified six different types of 45S-IGS, A to F, which at 363 bp, 1121 bp, 1717 bp, 1969 bp, 2036 bp and 2111 bp in length, respectively, were much shorter than the reported reference IGS sequences in B. oleracea var. alboglabra. The shortest two IGS types, A and B, lacked the transcription initiation site, non-transcribed spacer, and external transcribed spacer. Functional behavior of those two IGS types in relation to rRNA synthesis is a subject of further investigation. The other four IGSs had subtle variations in the transcription termination site, guanine-cytosine (GC) content, and number of tandem repeats, but the external transcribed spacers of these four IGSs were quite similar in length. The 45S IGSs were found to follow Mendelian inheritance in a population of 15 F1s and their 30 inbred parental lines, which suggests that these sequences could be useful for development of new breeding tools. In addition, this study represents the first report of intra-specific (within subspecies) variation of the 45S IGS in B. oleracea. PMID- 26633393 TI - Throughput Maximization for Sensor-Aided Cognitive Radio Networks with Continuous Energy Arrivals. AB - We consider a Sensor-Aided Cognitive Radio Network (SACRN) in which sensors capable of harvesting energy are distributed throughout the network to support secondary transmitters for sensing licensed channels in order to improve both energy and spectral efficiency. Harvesting ambient energy is one of the most promising solutions to mitigate energy deficiency, prolong device lifetime, and partly reduce the battery size of devices. So far, many works related to SACRN have considered single secondary users capable of harvesting energy in whole slot as well as short-term throughput. In the paper, we consider two types of energy harvesting sensor nodes (EHSN): Type-I sensor nodes will harvest ambient energy in whole slot duration, whereas type-II sensor nodes will only harvest energy after carrying out spectrum sensing. In the paper, we also investigate long-term throughput in the scheduling window, and formulate the throughput maximization problem by considering energy-neutral operation conditions of type-I and -II sensors and the target detection probability. Through simulations, it is shown that the sensing energy consumption of all sensor nodes can be efficiently managed with the proposed scheme to achieve optimal long-term throughput in the window. PMID- 26633394 TI - UAV Control on the Basis of 3D Landmark Bearing-Only Observations. AB - The article presents an approach to the control of a UAV on the basis of 3D landmark observations. The novelty of the work is the usage of the 3D RANSAC algorithm developed on the basis of the landmarks' position prediction with the aid of a modified Kalman-type filter. Modification of the filter based on the pseudo-measurements approach permits obtaining unbiased UAV position estimation with quadratic error characteristics. Modeling of UAV flight on the basis of the suggested algorithm shows good performance, even under significant external perturbations. PMID- 26633395 TI - Process Mining Methodology for Health Process Tracking Using Real-Time Indoor Location Systems. AB - The definition of efficient and accurate health processes in hospitals is crucial for ensuring an adequate quality of service. Knowing and improving the behavior of the surgical processes in a hospital can improve the number of patients that can be operated on using the same resources. However, the measure of this process is usually made in an obtrusive way, forcing nurses to get information and time data, affecting the proper process and generating inaccurate data due to human errors during the stressful journey of health staff in the operating theater. The use of indoor location systems can take time information about the process in an unobtrusive way, freeing nurses, allowing them to engage in purely welfare work. However, it is necessary to present these data in a understandable way for health professionals, who cannot deal with large amounts of historical localization log data. The use of process mining techniques can deal with this problem, offering an easily understandable view of the process. In this paper, we present a tool and a process mining-based methodology that, using indoor location systems, enables health staff not only to represent the process, but to know precise information about the deployment of the process in an unobtrusive and transparent way. We have successfully tested this tool in a real surgical area with 3613 patients during February, March and April of 2015. PMID- 26633396 TI - Enhanced Two-Factor Authentication and Key Agreement Using Dynamic Identities in Wireless Sensor Networks. AB - Key agreements that use only password authentication are convenient in communication networks, but these key agreement schemes often fail to resist possible attacks, and therefore provide poor security compared with some other authentication schemes. To increase security, many authentication and key agreement schemes use smartcard authentication in addition to passwords. Thus, two-factor authentication and key agreement schemes using smartcards and passwords are widely adopted in many applications. Vaidya et al. recently presented a two-factor authentication and key agreement scheme for wireless sensor networks (WSNs). Kim et al. observed that the Vaidya et al. scheme fails to resist gateway node bypassing and user impersonation attacks, and then proposed an improved scheme for WSNs. This study analyzes the weaknesses of the two-factor authentication and key agreement scheme of Kim et al., which include vulnerability to impersonation attacks, lost smartcard attacks and man-in-the middle attacks, violation of session key security, and failure to protect user privacy. An efficient and secure authentication and key agreement scheme for WSNs based on the scheme of Kim et al. is then proposed. The proposed scheme not only solves the weaknesses of previous approaches, but also increases security requirements while maintaining low computational cost. PMID- 26633397 TI - Electromagnetic Modelling of Fiber Sensors for Low-Cost and High Sensitivity Temperature Monitoring. AB - An accurate design of an innovative fiber optic temperature sensor is developed. The sensor is based on a cascade of three microstructured optical fibers (MOFs). In the first one a suitable cascade of long period gratings is designed into the core. A single mode intermediate and a rare-earth activated Fabry-Perot optical cavity are the other two sensor MOF sections. An exhaustive theoretic feasibility investigation is performed employing computer code. The complete set-up for temperature monitoring can be obtained by utilizing only a low cost pump diode laser at 980 nm wavelength and a commercial optical power detector. The simulated sensitivity S = 315.1 MUW/ degrees C and the operation range DeltaT = 100 degrees C is good enough for actual applications. PMID- 26633398 TI - Temperature Effects on the Wind Direction Measurement of 2D Solid Thermal Wind Sensors. AB - For a two-dimensional solid silicon thermal wind sensor with symmetrical structure, the wind speed and direction information can be derived from the output voltages in two orthogonal directions, i.e., the north-south and east west. However, the output voltages in these two directions will vary linearly with the ambient temperature. Therefore, in this paper, a temperature model to study the temperature effect on the wind direction measurement has been developed. A theoretical analysis has been presented first, and then Finite Element Method (FEM) simulations have been performed. It is found that due to symmetrical structure of the thermal wind sensor, the temperature effects on the output signals in the north-south and east-west directions are highly similar. As a result, the wind direction measurement of the thermal wind sensor is approximately independent of the ambient temperature. The experimental results fit the theoretical analysis and simulation results very well. PMID- 26633400 TI - Improved PPP Ambiguity Resolution Considering the Stochastic Characteristics of Atmospheric Corrections from Regional Networks. AB - With the increased availability of regional reference networks, Precise Point Positioning (PPP) can achieve fast ambiguity resolution (AR) and precise positioning by assimilating the satellite fractional cycle biases (FCBs) and atmospheric corrections derived from these networks. In such processing, the atmospheric corrections are usually treated as deterministic quantities. This is however unrealistic since the estimated atmospheric corrections obtained from the network data are random and furthermore the interpolated corrections diverge from the realistic corrections. This paper is dedicated to the stochastic modelling of atmospheric corrections and analyzing their effects on the PPP AR efficiency. The random errors of the interpolated corrections are processed as two components: one is from the random errors of estimated corrections at reference stations, while the other arises from the atmospheric delay discrepancies between reference stations and users. The interpolated atmospheric corrections are then applied by users as pseudo-observations with the estimated stochastic model. Two data sets are processed to assess the performance of interpolated corrections with the estimated stochastic models. The results show that when the stochastic characteristics of interpolated corrections are properly taken into account, the successful fix rate reaches 93.3% within 5 min for a medium inter-station distance network and 80.6% within 10 min for a long inter-station distance network. PMID- 26633399 TI - Identification of Chinese Herbs Using a Sequencing-Free Nanostructured Electrochemical DNA Biosensor. AB - Due to the nearly identical phenotypes and chemical constituents, it is often very challenging to accurately differentiate diverse species of a Chinese herbal genus. Although technologies including DNA barcoding have been introduced to help address this problem, they are generally time-consuming and require expensive sequencing. Herein, we present a simple sequencing-free electrochemical biosensor, which enables easy differentiation between two closely related Fritillaria species. To improve its differentiation capability using trace amounts of DNA sample available from herbal extracts, a stepwise electrochemical deposition of reduced graphene oxide (RGO) and gold nanoparticles (AuNPs) was adopted to engineer a synergistic nanostructured sensing interface. By using such a nanofeatured electrochemical DNA (E-DNA) biosensor, two Chinese herbal species of Fritillaria (F. thunbergii and F. cirrhosa) were successfully discriminated at the DNA level, because a fragment of 16-mer sequence at the spacer region of the 5S-rRNA only exists in F. thunbergii. This E-DNA sensor was capable of identifying the target sequence in the range from 100 fM to 10 nM, and a detection limit as low as 11.7 fM (S/N = 3) was obtained. Importantly, this sensor was applied to detect the unique fragment of the PCR products amplified from F. thunbergii and F. cirrhosa, respectively. We anticipate that such a direct, sequencing-free sensing mode will ultimately pave the way towards a new generation of herb-identification strategies. PMID- 26633401 TI - Multiple-Point Temperature Gradient Algorithm for Ring Laser Gyroscope Bias Compensation. AB - To further improve ring laser gyroscope (RLG) bias stability, a multiple-point temperature gradient algorithm is proposed for RLG bias compensation in this paper. Based on the multiple-point temperature measurement system, a complete thermo-image of the RLG block is developed. Combined with the multiple-point temperature gradients between different points of the RLG block, the particle swarm optimization algorithm is used to tune the support vector machine (SVM) parameters, and an optimized design for selecting the thermometer locations is also discussed. The experimental results validate the superiority of the introduced method and enhance the precision and generalizability in the RLG bias compensation model. PMID- 26633402 TI - Effect of Pore Size and Film Thickness on Gold-Coated Nanoporous Anodic Aluminum Oxide Substrates for Surface-Enhanced Raman Scattering Sensor. AB - A sensitive surface enhanced Raman scattering chemical sensor is demonstrated by using inexpensive gold-coated nanoporous anodic aluminum oxide substrates. To optimize the performance of the substrates for sensing by the Surface-enhanced Raman scattering (SERS) technique, the size of the nanopores is varied from 18 nm to 150 nm and the gold film thickness is varied from 30 nm to 120 nm. The sensitivity of gold-coated nanoporous surface enhanced Raman scattering sensor is characterized by detecting low concentrations of Rhodamine 6G laser dye molecules. The morphology of the SERS substrates is characterized by atomic force microscopy. Optical properties of the nanoporous SERS substrates including transmittance, reflectance, and absorbance are also investigated. Relative signal enhancement is plotted for a range of substrate parameters and a detection limit of 10(-6) M is established. PMID- 26633403 TI - Simulated and Real Sheet-of-Light 3D Object Scanning Using a-Si:H Thin Film PSD Arrays. AB - A MATLAB/SIMULINK software simulation model (structure and component blocks) has been constructed in order to view and analyze the potential of the PSD (Position Sensitive Detector) array concept technology before it is further expanded or developed. This simulation allows changing most of its parameters, such as the number of elements in the PSD array, the direction of vision, the viewing/scanning angle, the object rotation, translation, sample/scan/simulation time, etc. In addition, results show for the first time the possibility of scanning an object in 3D when using an a-Si:H thin film 128 PSD array sensor and hardware/software system. Moreover, this sensor technology is able to perform these scans and render 3D objects at high speeds and high resolutions when using a sheet-of-light laser within a triangulation platform. As shown by the simulation, a substantial enhancement in 3D object profile image quality and realism can be achieved by increasing the number of elements of the PSD array sensor as well as by achieving an optimal position response from the sensor since clearly the definition of the 3D object profile depends on the correct and accurate position response of each detector as well as on the size of the PSD array. PMID- 26633404 TI - A Single Eu-Doped In2O3 Nanobelt Device for Selective H2S Detection. AB - Eu-doped In2O3 nanobelts (Eu-In2O3 NBs) and pure In2O3 nanobelts (In2O3 NBs) are synthesized by the carbon thermal reduction method. Single nanobelt sensors are fabricated via an ion beam deposition system with a mesh-grid mask. The gas sensing response properties of the Eu-In2O3 NB device and its undoped counterpart are investigated with several kinds of gases (including H2S, CO, NO2, HCHO, and C2H5OH) at different concentrations and different temperatures. It is found that the response of the Eu-In2O3 NB device to 100 ppm of H2S is the best among these gases and the sensitivity reaches 5.74, which is five times that of pure In2O3 NB at 260 degrees C. We also found that the former has an excellent sensitive response and great selectivity to H2S compared to the latter. Besides, there is a linear relationship between the response and H2S concentration when its concentration changes from 5 to 100 ppm and from 100 to 1000 ppm. The response/recovery time is quite short and remains stable with an increase of H2S concentration. These results mean that the doping of Eu can improve the gas sensing performance of In2O3 NB effectually. PMID- 26633405 TI - A Network Topology Control and Identity Authentication Protocol with Support for Movable Sensor Nodes. AB - It is expected that in the near future wireless sensor network (WSNs) will be more widely used in the mobile environment, in applications such as Autonomous Underwater Vehicles (AUVs) for marine monitoring and mobile robots for environmental investigation. The sensor nodes' mobility can easily cause changes to the structure of a network topology, and lead to the decline in the amount of transmitted data, excessive energy consumption, and lack of security. To solve these problems, a kind of efficient Topology Control algorithm for node Mobility (TCM) is proposed. In the topology construction stage, an efficient clustering algorithm is adopted, which supports sensor node movement. It can ensure the balance of clustering, and reduce the energy consumption. In the topology maintenance stage, the digital signature authentication based on Error Correction Code (ECC) and the communication mechanism of soft handover are adopted. After verifying the legal identity of the mobile nodes, secure communications can be established, and this can increase the amount of data transmitted. Compared to some existing schemes, the proposed scheme has significant advantages regarding network topology stability, amounts of data transferred, lifetime and safety performance of the network. PMID- 26633406 TI - Assessment of the Contribution of BeiDou GEO, IGSO, and MEO Satellites to PPP in Asia-Pacific Region. AB - In contrast to the US Global Positioning System (GPS), the Russian Global Navigation Satellite System (GLONASS) and the European Galileo, the developing Chinese BeiDou satellite navigation system (BDS) consists of not only Medium Earth Orbit (MEO), but also Geostationary Orbit (GEO) as well as Inclined Geosynchronous Orbit (IGSO) satellites. In this study, the Precise Point Positioning (PPP) and PPP with Integer Ambiguity Resolution (IAR) are obtained. The contributions of these three different types of BDS satellites to PPP in Asia Pacific region are assessed using data from selected 20 sites over more than four weeks. By using various PPP cases with different satellite combinations, in general, the largest contribution of BDS IGSO among the three kinds of BDS satellites to the reduction of convergence time and the improvement of positioning accuracy, particularly in the east direction, is identified. These PPP cases include static BDS only solutions and static/kinematic ambiguity-float and -fixed PPP with the combination of GPS and BDS. The statistical results demonstrate that the inclusion of BDS GEO and MEO satellites can improve the observation condition and result in better PPP performance as well. When combined with GPS, the contribution of BDS to the reduction of convergence time is, however, not as significant as that of GLONASS. As far as the positioning accuracy is concerned, GLONASS improves the accuracy in vertical component more than BDS does, whereas similar improvement in horizontal component can be achieved by inclusion of BDS IGSO and MEO as GLONASS. PMID- 26633407 TI - Optimized Design of the SGA-WZ Strapdown Airborne Gravimeter Temperature Control System. AB - The temperature control system is one of the most important subsystems of the strapdown airborne gravimeter. Because the quartz flexible accelerometer based on springy support technology is the core sensor in the strapdown airborne gravimeter and the magnet steel in the electromagnetic force equilibrium circuits of the quartz flexible accelerometer is greatly affected by temperature, in order to guarantee the temperature control precision and minimize the effect of temperature on the gravimeter, the SGA-WZ temperature control system adopts a three-level control method. Based on the design experience of the SGA-WZ-01, the SGA-WZ-02 temperature control system came out with a further optimized design. In 1st level temperature control, thermoelectric cooler is used to conquer temperature change caused by hot weather. The experiments show that the optimized stability of 1st level temperature control is about 0.1 degrees C and the max cool down capability is about 10 degrees C. The temperature field is analyzed in the 2nd and 3rd level temperature control using the finite element analysis software ANSYS. The 2nd and 3rd level temperature control optimization scheme is based on the foundation of heat analysis. The experimental results show that static accuracy of SGA-WZ-02 reaches 0.21 mGal/24 h, with internal accuracy being 0.743 mGal/4.8 km and external accuracy being 0.37 mGal/4.8 km compared with the result of the GT-2A, whose internal precision is superior to 1 mGal/4.8 km and all of them are better than those in SGA-WZ-01. PMID- 26633408 TI - Node Non-Uniform Deployment Based on Clustering Algorithm for Underwater Sensor Networks. AB - A node non-uniform deployment based on clustering algorithm for underwater sensor networks (UWSNs) is proposed in this study. This algorithm is proposed because optimizing network connectivity rate and network lifetime is difficult for the existing node non-uniform deployment algorithms under the premise of improving the network coverage rate for UWSNs. A high network connectivity rate is achieved by determining the heterogeneous communication ranges of nodes during node clustering. Moreover, the concept of aggregate contribution degree is defined, and the nodes with lower aggregate contribution degrees are used to substitute the dying nodes to decrease the total movement distance of nodes and prolong the network lifetime. Simulation results show that the proposed algorithm can achieve a better network coverage rate and network connectivity rate, as well as decrease the total movement distance of nodes and prolong the network lifetime. PMID- 26633410 TI - A Primer on Autonomous Aerial Vehicle Design. AB - There is a large amount of research currently being done on autonomous micro aerial vehicles (MAV), such as quadrotor helicopters or quadcopters. The ability to create a working autonomous MAV depends mainly on integrating a simultaneous localization and mapping (SLAM) solution with the rest of the system. This paper provides an introduction for creating an autonomous MAV for enclosed environments, aimed at students and professionals alike. The standard autonomous system and MAV automation are discussed, while we focus on the core concepts of SLAM systems and trajectory planning algorithms. The advantages and disadvantages of using remote processing are evaluated, and recommendations are made regarding the viability of on-board processing. Recommendations are made regarding best practices to serve as a guideline for aspirant MAV designers. PMID- 26633409 TI - Microfluidics Integrated Biosensors: A Leading Technology towards Lab-on-a-Chip and Sensing Applications. AB - A biosensor can be defined as a compact analytical device or unit incorporating a biological or biologically derived sensitive recognition element immobilized on a physicochemical transducer to measure one or more analytes. Microfluidic systems, on the other hand, provide throughput processing, enhance transport for controlling the flow conditions, increase the mixing rate of different reagents, reduce sample and reagents volume (down to nanoliter), increase sensitivity of detection, and utilize the same platform for both sample preparation and detection. In view of these advantages, the integration of microfluidic and biosensor technologies provides the ability to merge chemical and biological components into a single platform and offers new opportunities for future biosensing applications including portability, disposability, real-time detection, unprecedented accuracies, and simultaneous analysis of different analytes in a single device. This review aims at representing advances and achievements in the field of microfluidic-based biosensing. The review also presents examples extracted from the literature to demonstrate the advantages of merging microfluidic and biosensing technologies and illustrate the versatility that such integration promises in the future biosensing for emerging areas of biological engineering, biomedical studies, point-of-care diagnostics, environmental monitoring, and precision agriculture. PMID- 26633411 TI - Electronic Tongue Response to Chemicals in Orange Juice that Change Concentration in Relation to Harvest Maturity and Citrus Greening or Huanglongbing (HLB) Disease. AB - In an earlier study, an electronic tongue system (e-tongue) has been used to differentiate between orange juice made from healthy fruit and from fruit affected by the citrus greening or Huanglongbing (HLB) disease. This study investigated the reaction of an e-tongue system to the main chemicals in orange juice that impact flavor and health benefits and are also impacted by HLB. Orange juice was spiked with sucrose (0.2-5.0 g/100 mL), citric acid (0.1%-3.0% g/100 mL) and potassium chloride (0.1-3.0 g/100 mL) as well as the secondary metabolites nomilin (1-30 ug/mL), limonin (1-30 ug/mL), limonin glucoside (30-200 ug/mL), hesperidin (30-400 ug/mL) and hesperetin (30-400 ug/mL). Performance of Alpha MOS sensor sets #1 (pharmaceutical) and #5 (food) were compared for the same samples, with sensor set #1 generally giving better separation than sensor set #5 for sucrose, sensor set #5 giving better separation for nomilin and limonin, both sets being efficient at separating citric acid, potassium chloride, hesperitin and limonin glucoside, and neither set discriminating hesperidin efficiently. Orange juice made from fruit over the harvest season and from fruit harvested from healthy or HLB-affected trees were separated by harvest maturity, disease state and disease severity. PMID- 26633412 TI - Event-Based Control Strategy for Mobile Robots in Wireless Environments. AB - In this paper, a new event-based control strategy for mobile robots is presented. It has been designed to work in wireless environments where a centralized controller has to interchange information with the robots over an RF (radio frequency) interface. The event-based architectures have been developed for differential wheeled robots, although they can be applied to other kinds of robots in a simple way. The solution has been checked over classical navigation algorithms, like wall following and obstacle avoidance, using scenarios with a unique or multiple robots. A comparison between the proposed architectures and the classical discrete-time strategy is also carried out. The experimental results shows that the proposed solution has a higher efficiency in communication resource usage than the classical discrete-time strategy with the same accuracy. PMID- 26633413 TI - GNSS Single Frequency, Single Epoch Reliable Attitude Determination Method with Baseline Vector Constraint. AB - For Global Navigation Satellite System (GNSS) single frequency, single epoch attitude determination, this paper proposes a new reliable method with baseline vector constraint. First, prior knowledge of baseline length, heading, and pitch obtained from other navigation equipment or sensors are used to reconstruct objective function rigorously. Then, searching strategy is improved. It substitutes gradually Enlarged ellipsoidal search space for non-ellipsoidal search space to ensure correct ambiguity candidates are within it and make the searching process directly be carried out by least squares ambiguity decorrelation algorithm (LAMBDA) method. For all vector candidates, some ones are further eliminated by derived approximate inequality, which accelerates the searching process. Experimental results show that compared to traditional method with only baseline length constraint, this new method can utilize a priori baseline three-dimensional knowledge to fix ambiguity reliably and achieve a high success rate. Experimental tests also verify it is not very sensitive to baseline vector error and can perform robustly when angular error is not great. PMID- 26633414 TI - Improving GLONASS Precise Orbit Determination through Data Connection. AB - In order to improve the precision of GLONASS orbits, this paper presents a method to connect the data segments of a single station-satellite pair to increase the observation continuity and, consequently, the strength of the precise orbit determination (POD) solution. In this method, for each GLONASS station-satellite pair, the wide-lane ambiguities derived from the Melbourne-Wubbena combination are statistically tested and corrected for phase integer offsets and then the same is carried out for the narrow-lane ambiguities calculated from the POD solution. An experimental validation was carried out using one-month GNSS data of a global network with 175 IGS stations. The result shows that, on average, 27.1% of the GLONASS station-satellite pairs with multiple data segments could be connected to a single long observation arc and, thus, only one ambiguity parameter was estimated. Using the connected data, the GLONASS orbit overlapping RMS at the day boundaries could be reduced by 19.2% in ideal cases with an averaged reduction of about 6.3%. PMID- 26633415 TI - Low Complexity HEVC Encoder for Visual Sensor Networks. AB - Visual sensor networks (VSNs) can be widely applied in security surveillance, environmental monitoring, smart rooms, etc. However, with the increased number of camera nodes in VSNs, the volume of the visual information data increases significantly, which becomes a challenge for storage, processing and transmitting the visual data. The state-of-the-art video compression standard, high efficiency video coding (HEVC), can effectively compress the raw visual data, while the higher compression rate comes at the cost of heavy computational complexity. Hence, reducing the encoding complexity becomes vital for the HEVC encoder to be used in VSNs. In this paper, we propose a fast coding unit (CU) depth decision method to reduce the encoding complexity of the HEVC encoder for VSNs. Firstly, the content property of the CU is analyzed. Then, an early CU depth decision method and a low complexity distortion calculation method are proposed for the CUs with homogenous content. Experimental results show that the proposed method achieves 71.91% on average encoding time savings for the HEVC encoder for VSNs. PMID- 26633416 TI - Pupil and Glint Detection Using Wearable Camera Sensor and Near-Infrared LED Array. AB - This paper proposes a novel pupil and glint detection method for gaze tracking system using a wearable camera sensor and near-infrared LED array. A novel circular ring rays location (CRRL) method is proposed for pupil boundary points detection. Firstly, improved Otsu optimal threshold binarization, opening-and closing operation and projection of 3D gray-level histogram are utilized to estimate rough pupil center and radius. Secondly, a circular ring area including pupil edge inside is determined according to rough pupil center and radius. Thirdly, a series of rays are shot from inner to outer ring to collect pupil boundary points. Interference points are eliminated by calculating gradient amplitude. At last, an improved total least squares is proposed to fit collected pupil boundary points. In addition, the improved total least squares developed is utilized for the solution of Gaussian function deformation to calculate glint center. The experimental results show that the proposed method is more robust and accurate than conventional detection methods. When interference factors such as glints and natural light reflection are located on pupil contour, pupil boundary points and center can be detected accurately. The proposed method contributes to enhance stability, accuracy and real-time quality of gaze tracking system. PMID- 26633417 TI - A Novel Hybrid Intelligent Indoor Location Method for Mobile Devices by Zones Using Wi-Fi Signals. AB - The increasing use of mobile devices in indoor spaces brings challenges to location methods. This work presents a hybrid intelligent method based on data mining and Type-2 fuzzy logic to locate mobile devices in an indoor space by zones using Wi-Fi signals from selected access points (APs). This approach takes advantage of wireless local area networks (WLANs) over other types of architectures and implements the complete method in a mobile application using the developed tools. Besides, the proposed approach is validated by experimental data obtained from case studies and the cross-validation technique. For the purpose of generating the fuzzy rules that conform to the Takagi-Sugeno fuzzy system structure, a semi-supervised data mining technique called subtractive clustering is used. This algorithm finds centers of clusters from the radius map given by the collected signals from APs. Measurements of Wi-Fi signals can be noisy due to several factors mentioned in this work, so this method proposed the use of Type-2 fuzzy logic for modeling and dealing with such uncertain information. PMID- 26633418 TI - Abnormal Condition Monitoring of Workpieces Based on RFID for Wisdom Manufacturing Workshops. AB - Radio Frequency Identification (RFID) technology has been widely used in many fields. However, previous studies have mainly focused on product life cycle tracking, and there are few studies on real-time status monitoring of workpieces in manufacturing workshops. In this paper, a wisdom manufacturing model is introduced, a sensing-aware environment for a wisdom manufacturing workshop is constructed, and RFID event models are defined. A synthetic data cleaning method is applied to clean the raw RFID data. The Complex Event Processing (CEP) technology is adopted to monitor abnormal conditions of workpieces in real time. The RFID data cleaning method and data mining technology are examined by simulation and physical experiments. The results show that the synthetic data cleaning method preprocesses data well. The CEP based on the Rifidi((r)) Edge Server technology completed abnormal condition monitoring of workpieces in real time. This paper reveals the importance of RFID spatial and temporal data analysis in real-time status monitoring of workpieces in wisdom manufacturing workshops. PMID- 26633419 TI - Development of a Wireless and Passive SAW-Based Chemical Sensor for Organophosphorous Compound Detection. AB - A new wireless and passive surface acoustic wave (SAW)-based chemical sensor for organophosphorous compound (OC) detection is presented. A 434 MHz reflective delay line configuration composed by single phase unidirectional transducers (SPUDTs) and three shorted reflectors was fabricated on YZ LiNbO3 piezoelectric substrate as the sensor element. A thin fluoroalcoholpolysiloxane (SXFA) film acted as the sensitive interface deposited onto the SAW propagation path between the second and last reflectors of the SAW device. The first reflector was used for the temperature compensation utilizing the difference method. The adsorption between the SXFA and OC molecules modulates the SAW propagation, especially for the time delay of the SAW, hence, the phase shifts of the reflection peaks from the corresponding reflectors can be used to characterize the target OC. Prior to the sensor fabrication, the coupling of modes (COM) and perturbation theory were utilized to predict the SAW device performance and the gas adsorption. Referring to a frequency-modulated continuous wave (FMCW)-based reader unit, the developed SAW chemical sensor was wirelessly characterized in gas exposure experiments for dimethylmethylphosphonate (DMMP) detection. Sensor performance parameters such as phase sensitivity, repeatability, linearity, and temperature compensation were evaluated experimentally. PMID- 26633420 TI - Passive Sensor Integration for Vehicle Self-Localization in Urban Traffic Environment. AB - This research proposes an accurate vehicular positioning system which can achieve lane-level performance in urban canyons. Multiple passive sensors, which include Global Navigation Satellite System (GNSS) receivers, onboard cameras and inertial sensors, are integrated in the proposed system. As the main source for the localization, the GNSS technique suffers from Non-Line-Of-Sight (NLOS) propagation and multipath effects in urban canyons. This paper proposes to employ a novel GNSS positioning technique in the integration. The employed GNSS technique reduces the multipath and NLOS effects by using the 3D building map. In addition, the inertial sensor can describe the vehicle motion, but has a drift problem as time increases. This paper develops vision-based lane detection, which is firstly used for controlling the drift of the inertial sensor. Moreover, the lane keeping and changing behaviors are extracted from the lane detection function, and further reduce the lateral positioning error in the proposed localization system. We evaluate the integrated localization system in the challenging city urban scenario. The experiments demonstrate the proposed method has sub-meter accuracy with respect to mean positioning error. PMID- 26633421 TI - An Adaptive Channel Access Method for Dynamic Super Dense Wireless Sensor Networks. AB - Super dense and distributed wireless sensor networks have become very popular with the development of small cell technology, Internet of Things (IoT), Machine to-Machine (M2M) communications, Vehicular-to-Vehicular (V2V) communications and public safety networks. While densely deployed wireless networks provide one of the most important and sustainable solutions to improve the accuracy of sensing and spectral efficiency, a new channel access scheme needs to be designed to solve the channel congestion problem introduced by the high dynamics of competing nodes accessing the channel simultaneously. In this paper, we firstly analyzed the channel contention problem using a novel normalized channel contention analysis model which provides information on how to tune the contention window according to the state of channel contention. We then proposed an adaptive channel contention window tuning algorithm in which the contention window tuning rate is set dynamically based on the estimated channel contention level. Simulation results show that our proposed adaptive channel access algorithm based on fast contention window tuning can achieve more than 95 % of the theoretical optimal throughput and 0 . 97 of fairness index especially in dynamic and dense networks. PMID- 26633422 TI - Tracking Multiple Video Targets with an Improved GM-PHD Tracker. AB - Tracking multiple moving targets from a video plays an important role in many vision-based robotic applications. In this paper, we propose an improved Gaussian mixture probability hypothesis density (GM-PHD) tracker with weight penalization to effectively and accurately track multiple moving targets from a video. First, an entropy-based birth intensity estimation method is incorporated to eliminate the false positives caused by noisy video data. Then, a weight-penalized method with multi-feature fusion is proposed to accurately track the targets in close movement. For targets without occlusion, a weight matrix that contains all updated weights between the predicted target states and the measurements is constructed, and a simple, but effective method based on total weight and predicted target state is proposed to search the ambiguous weights in the weight matrix. The ambiguous weights are then penalized according to the fused target features that include spatial-colour appearance, histogram of oriented gradient and target area and further re-normalized to form a new weight matrix. With this new weight matrix, the tracker can correctly track the targets in close movement without occlusion. For targets with occlusion, a robust game-theoretical method is used. Finally, the experiments conducted on various video scenarios validate the effectiveness of the proposed penalization method and show the superior performance of our tracker over the state of the art. PMID- 26633423 TI - Camera Calibration for Water-Biota Research: The Projected Area of Vegetation. AB - Imaging systems have an indisputable role in revealing vegetation posture under diverse flow conditions, image sequences being generated with off the shelf digital cameras. Such sensors are cheap but introduce a range of distortion effects, a trait only marginally tackled in hydraulic studies focusing on water vegetation dependencies. This paper aims to bridge this gap by presenting a simple calibration method to remove both camera lens distortion and refractive effects of water. The effectiveness of the method is illustrated using the variable projected area, computed for both simple and complex shaped objects. Results demonstrate the significance of correcting images using a combined lens distortion and refraction model, prior to determining projected areas and further data analysis. Use of this technique is expected to increase data reliability for future work on vegetated channels. PMID- 26633424 TI - Sensing Home: A Cost-Effective Design for Smart Home via Heterogeneous Wireless Networks. AB - The aging population has inspired the marketing of advanced real time devices for home health care, more and more wearable devices and mobile applications, which have emerged in this field. However, to properly collect behavior information, accurately recognize human activities, and deploy the whole system in a real living environment is a challenging task. In this paper, we propose a feasible wireless-based solution to deploy a data collection scheme, activity recognition model, feedback control and mobile integration via heterogeneous networks. We compared and found a suitable algorithm that can be run on cost-efficient embedded devices. Specifically, we use the Super Set Transformation method to map the raw data into a sparse binary matrix. Furthermore, designed front-end devices of low power consumption gather the living data of the habitant via ZigBee to reduce the burden of wiring work. Finally, we evaluated our approach and show it can achieve a theoretical time-slice accuracy of 98%. The mapping solution we propose is compatible with more wearable devices and mobile apps. PMID- 26633425 TI - Microelectromechanical Resonant Accelerometer Designed with a High Sensitivity. AB - This paper describes the design and experimental evaluation of a silicon micro machined resonant accelerometer (SMRA). This type of accelerometer works on the principle that a proof mass under acceleration applies force to two double-ended tuning fork (DETF) resonators, and the frequency output of two DETFs exhibits a differential shift. The dies of an SMRA are fabricated using silicon-on-insulator (SOI) processing and wafer-level vacuum packaging. This research aims to design a high-sensitivity SMRA because a high sensitivity allows for the acceleration signal to be easily demodulated by frequency counting techniques and decreases the noise level. This study applies the energy-consumed concept and the Nelder Mead algorithm in the SMRA to address the design issues and further increase its sensitivity. Using this novel method, the sensitivity of the SMRA has been increased by 66.1%, which attributes to both the re-designed DETF and the reduced energy loss on the micro-lever. The results of both the closed-form and finite element analyses are described and are in agreement with one another. A resonant frequency of approximately 22 kHz, a frequency sensitivity of over 250 Hz per g, a one-hour bias stability of 55 MUg, a bias repeatability (1sigma) of 48 MUg and the bias-instability of 4.8 MUg have been achieved. PMID- 26633426 TI - Cytotoxic Effects of Tropodithietic Acid on Mammalian Clonal Cell Lines of Neuronal and Glial Origin. AB - The marine metabolite tropodithietic acid (TDA), produced by several Roseobacter clade bacteria, is known for its broad antimicrobial activity. TDA is of interest not only as a probiotic in aquaculture, but also because it might be of use as an antibacterial agent in non-marine or non-aquatic environments, and thus the potentially cytotoxic influences on eukaryotic cells need to be evaluated. The present study was undertaken to investigate its effects on cells of the mammalian nervous system, i.e., neuronal N2a cells and OLN-93 cells as model systems for nerve cells and glia. The data show that in both cell lines TDA exerted morphological changes and cytotoxic effects at a concentration of 0.3-0.5 ug/mL (1.4-2.4 uM). Furthermore, TDA caused a breakdown of the mitochondrial membrane potential, the activation of extracellular signal-regulated kinases ERK1/2, and the induction of the small heat shock protein HSP32/HO-1, which is considered as a sensor of oxidative stress. The cytotoxic effects were accompanied by an increase in intracellular Ca(2+)-levels, the disturbance of the microtubule network, and the reorganization of the microfilament system. Hence, mammalian cells are a sensitive target for the action of TDA and react by the activation of a stress response resulting in cell death. PMID- 26633427 TI - Influence of Temperature on Growth and Production of Pectenotoxin-2 by a Monoclonal Culture of Dinophysis caudata. AB - The effects of temperature on growth and production of Lipophilic Toxins (LT) by a monoclonal culture of Dinophysis caudata was studied. The cell density of D. caudata increased significantly with increasing temperature, and was the highest under 27, 30, and 32.5 degrees C. Temperature affected the average specific growth rate (u) during the exponential growth phase (EG), which increased from 15 degrees C to 30 degrees C, and then decreased at 32.5 degrees C. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) revealed that this strain of D. caudata produced only pectenotoxin-2 (PTX-2) whose concentration increased significantly with incubation period, except at 32.5 degrees C. It was significantly different between temperatures <=18 degrees C, >=21 degrees C, and 32.5 degrees C. The cellular toxin production (CTP, pg.cell(-1).day(-1)) showed variation with growth phase and temperature, except at 32.5 degrees C. The average net toxin production (Rtox) was not affected by temperature. During EG, the average specific toxin production rate (utox) increased significantly with increase in temperature, reaching a peak of 0.66 +/- 0.01 day(-1) at 30 degrees C, and then decreased. Over the entire growth span, utox was significantly correlated to u, and this correlation was most significant at 27 and 30 degrees C. During EG, utox was affected by both temperature and growth. This study shows that temperature affects growth and toxin production of this strain of D. caudata during EG. In addition, a positive correlation was found between toxin production and growth. PMID- 26633429 TI - The 9th European Conference on Marine Natural Products. AB - The 9th European Conference on Marine Natural Products (ECMNP) in Glasgow follows its predecessors in La Toja (2013), Tjarno (2011), Porto (2009), Ischia (2007), Paris (2005), Elmau (2002), Santiago de Compostela (1999), and Athens (1997). [...]. PMID- 26633428 TI - Briarenolides U-Y, New Anti-Inflammatory Briarane Diterpenoids from an Octocoral Briareum sp. (Briareidae). AB - Five new 13,14-epoxybriarane diterpenoids, briarenolides U-Y (1-5), were isolated from the octocoral Briareum sp. The structures of briaranes 1-5 were elucidated by spectroscopic methods. Briarenolides U-Y (1-5) were found to significantly inhibit the expression of the pro-inflammatory inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) protein of the lipopolysaccharide (LPS) stimulated RAW264.7 macrophage cells. PMID- 26633430 TI - The MARINA Risk Assessment Strategy: A Flexible Strategy for Efficient Information Collection and Risk Assessment of Nanomaterials. AB - An engineered nanomaterial (ENM) may actually consist of a population of primary particles, aggregates and agglomerates of various sizes. Furthermore, their physico-chemical characteristics may change during the various life-cycle stages. It will probably not be feasible to test all varieties of all ENMs for possible health and environmental risks. There is therefore a need to further develop the approaches for risk assessment of ENMs. Within the EU FP7 project Managing Risks of Nanoparticles (MARINA) a two-phase risk assessment strategy has been developed. In Phase 1 (Problem framing) a base set of information is considered, relevant exposure scenarios (RESs) are identified and the scope for Phase 2 (Risk assessment) is established. The relevance of an RES is indicated by information on exposure, fate/kinetics and/or hazard; these three domains are included as separate pillars that contain specific tools. Phase 2 consists of an iterative process of risk characterization, identification of data needs and integrated collection and evaluation of data on the three domains, until sufficient information is obtained to conclude on possible risks in a RES. Only data are generated that are considered to be needed for the purpose of risk assessment. A fourth pillar, risk characterization, is defined and it contains risk assessment tools. This strategy describes a flexible and efficient approach for data collection and risk assessment which is essential to ensure safety of ENMs. Further developments are needed to provide guidance and make the MARINA Risk Assessment Strategy operational. Case studies will be needed to refine the strategy. PMID- 26633431 TI - Low Levels of Awareness of Lead Hazards among Pregnant Women in a High Risk- Johannesburg Neighbourhood. AB - BACKGROUND: The widespread use of lead and elevated risk of lead exposure in South African children justifies a need for high levels of awareness of the sources, exposure pathways, and measures to reduce this risk in children. This study aimed to determine the levels of knowledge of lead hazards among pregnant women in an area where children had already been established to be at a high risk of lead exposure and poisoning. METHODS: Following informed consent, a structured questionnaire was administered to 119 pregnant women attending antenatal clinic services at Rahima Moosa Mother and Child Hospital, west of central Johannesburg. Questions were asked about social, demographic and residential characteristics, as well as knowledge, perceptions, behaviours and practices in relation to child lead hazards. CONCLUSION: Overall awareness of the dangers of lead in pregnancy was low (11%). Amongst those who had heard of it, only 15% thought that lead could cause detrimental health effects. A consequence of this low level of awareness of lead hazards is a high potential for the participants and their children to unwittingly be exposed to environmental lead from various sources, thereby undermining preventative approaches. PMID- 26633432 TI - Spatial Evaluation of Heavy Metals Concentrations in the Surface Sediment of Taihu Lake. AB - With regard to the size of China's freshwater lakes, Taihu Lake ranks third and it plays an important role in the supply of drinking water, flood prevention, farming and navigation, as well as in the travelling industry. The problem of environmental pollution has attracted widespread attention in recent years. In order to understand the levels, distribution and sources of heavy metals in sediments of Taihu Lake, random selection was carried out to obtain 59 samples of surface sediment from the entire lake and study the concentrations of Pb, Cd, Cu, Zn, Cr and Ni. Toxic units were also calculated to normalize the toxicities caused by various heavy metals. As a result, Cd and Cu in sediment were considered lower than the effect range low (ERL) at all regions where samples were gathered, while Pb and Ni were categorized into ERL-effect range median (ERM) at over 22% of the regions where samples were obtained. Nevertheless, all average concentrations of the samples were below the level of potential effect. According to the findings of this research, significant spatial heterogeneity existed in the above heavy metals. In conclusion, the distribution areas of heavy metals with higher concentrations were mainly the north bays, namely Zhushan Bay, Meiliang Bay as well as Gonghu Bay. The distribution areas of Cu, Zn, Cr and Ni with higher concentration also included the lake's central region, whereas the uniform distribution areas of those with lower concentrations were the lake's southeast region. In addition, it was most probable that the spatial distribution of heavy metals was determined by river inputs, whereas atmospheric precipitation caused by urban and traffic contamination also exerted considerable effects on the higher concentrations of Pb and Cd. Through evaluating the total amount of toxic units (SigmaTU), it was found that higher toxicity existed primarily in the north bays and central region of the lake. If the heavy metals were sorted by the reduction of mean heavy metal toxic units in Taihu Lake in descending order, it would be Pb, Cr, Ni, Cd, Zn and Cu. Generally speaking, these result of analyses are conducive to alleviating the contamination of heavy metals in Taihu Lake. PMID- 26633433 TI - Indoor Air Contamination from Hazardous Waste Sites: Improving the Evidence Base for Decision-Making. AB - At hazardous waste sites, volatile chemicals can migrate through groundwater and soil into buildings, a process known as vapor intrusion. Due to increasing recognition of vapor intrusion as a potential indoor air pollution source, in 2015 the U.S. Environmental Protection Agency (EPA) released a new vapor intrusion guidance document. The guidance specifies two conditions for demonstrating that remediation is needed: (1) proof of a vapor intrusion pathway; and (2) evidence that human health risks exceed established thresholds (for example, one excess cancer among 10,000 exposed people). However, the guidance lacks details on methods for demonstrating these conditions. We review current evidence suggesting that monitoring and modeling approaches commonly employed at vapor intrusion sites do not adequately characterize long-term exposure and in many cases may underestimate risks. On the basis of this evidence, we recommend specific approaches to monitoring and modeling to account for these uncertainties. We propose a value of information approach to integrate the lines of evidence at a site and determine if more information is needed before deciding whether the two conditions specified in the vapor intrusion guidance are satisfied. To facilitate data collection and decision-making, we recommend a multi-directional community engagement strategy and consideration of environment justice concerns. PMID- 26633434 TI - Healthy versus Unhealthy Suppliers in Food Desert Neighborhoods: A Network Analysis of Corner Stores' Food Supplier Networks. AB - BACKGROUND: Products in corner stores may be affected by the network of suppliers from which storeowners procure food and beverages. To date, this supplier network has not been well characterized. METHODS: Using network analysis, we examined the connections between corner stores (n = 24) in food deserts of Baltimore City (MD, USA) and their food/beverage suppliers (n = 42), to determine how different store and supplier characteristics correlated. RESULTS: Food and beverage suppliers fell into two categories: Those providing primarily healthy foods/beverages (n = 15) in the healthy supplier network (HSN) and those providing primarily unhealthy food/beverages (n = 41) in the unhealthy supplier network (UHSN). Corner store connections to suppliers in the UHSN were nearly two times greater (t = 5.23, p < 0.001), and key suppliers in the UHSN core were more diverse, compared to the HSN. The UHSN was significantly more cohesive and densely connected, with corner stores sharing a greater number of the same unhealthy suppliers, compared to HSN, which was less cohesive and sparsely connected (t = 5.82; p < 0.001). Compared to African Americans, Asian and Hispanic corner storeowners had on average -1.53 (p < 0.001) fewer connections to suppliers in the HSN (p < 0.001). CONCLUSIONS: Our findings indicate clear differences between corner stores' HSN and UHSN. Addressing ethnic/cultural differences of storeowners may also be important to consider. PMID- 26633435 TI - A Comparative Study on the Uptake and Toxicity of Nickel Added in the Form of Different Salts to Maize Seedlings. AB - In soil ecotoxicological studies, a toxic metal is usually added in the form of either an inorganic or organic salt with relatively high solubility. Nitrate, chloride, acetate, or sulfate are commonly considered as valid options for that aim. However, recent studies have shown that different salts of the same metal at the same cationic concentration may exhibit different toxicities to plants and soil organisms. This information should be considered when selecting data to use for developing toxicological criteria for soil environment. A comparative study was carried out to evaluate the toxicity of five nickel (Ni) salts: NiCl2, NiSO4, Ni(II)-citrate, Ni(CH3COO)2, and Ni(II)-EDTA (ethylenediaminetetraacetate), on maize seedlings. The plant metrics used were plant height, shoot and root biomass, leaf soluble sugars and starch, and the Ni contents of the shoots and roots. The results indicated that when Ni was added to the soil, toxicity varied with the selected anionic partner with the following toxicity ranking NiSO4 < Ni(CH3COO)2 < Ni(II)-citrate < NiCl2 < Ni(II)-EDTA. Taking the plant-height metric as an example, the effective concentrations for 50% inhibition (EC50) were 3148 mg.kg(-1) for NiSO4, 1315 mg.kg(-1) for NiCl2, and 89 mg.kg(-1) for Ni(II) EDTA. Compared with the Ni in the other salts, that in Ni(II)-EDTA was taken up the most efficiently by the maize roots and, thus, resulted in the greatest toxic effects on the plants. Nickel generally reduced leaf soluble sugars, which indicated an effect on plant carbohydrate metabolism. The outcome of the study demonstrates that different salts of the same metal have quite different ecotoxicities. Therefore, the anionic counterpart of a potentially toxic metal cation must be taken into account in the development of ecotoxicological criteria for evaluating the soil environment, and a preferred approach of leaching soil to reduce the anionic partner should also be considered. PMID- 26633436 TI - The Associations of Job Stress and Organizational Identification with Job Satisfaction among Chinese Police Officers: The Mediating Role of Psychological Capital. AB - Police officers' job satisfaction is an important issue for police force management, but insufficient research exists on the topic, especially in China. This study aimed to examine the associations of job stress and organizational identification with job satisfaction among Chinese police officers, and particularly the mediating role of psychological capital (PsyCap). A cross sectional study was conducted in Liaoning Province of China during the period of September-October 2014. A set of self-administered questionnaires was distributed to 2514 police officers, and complete responses were obtained from 2226 participants. The associations among variables in relation to job satisfaction were validated by structural equation modeling. Job stress was negatively associated with job satisfaction, while organizational identification and PsyCap were positively associated with job satisfaction among Chinese police officers. PsyCap mediated the associations of job stress and organizational identification with job satisfaction. Interventions to improve Chinese police officers' job satisfaction should be developed in the future, especially the enhancement of PsyCap. PMID- 26633437 TI - Assessment of the Phytotoxicity of Metal Oxide Nanoparticles on Two Crop Plants, Maize (Zea mays L.) and Rice (Oryza sativa L.). AB - In this study, the phytotoxicity of seven metal oxide nanoparticles(NPs)-titanium dioxide (nTiO2), silicon dioxide (nSiO2), cerium dioxide (nCeO2), magnetite (nFe3O4), aluminum oxide (nAl2O3), zinc oxide (nZnO) and copper oxide (nCuO)-was assessed on two agriculturally significant crop plants (maize and rice). The results showed that seed germination was not affected by any of the seven metal oxide NPs. However, at the concentration of 2000 mg.L(-1), the root elongation was significantly inhibited by nCuO (95.73% for maize and 97.28% for rice), nZnO (50.45% for maize and 66.75% for rice). On the contrary, minor phytotoxicity of nAl2O3 was only observed in maize, and no obvious toxic effects were found in the other four metal oxide NPs. By further study we found that the phytotoxic effects of nZnO, nAl2O3 and nCuO (25 to 2000 mg.L(-)1) were concentration dependent, and were not caused by the corresponding Cu(2+), Zn(2+) and Al(3+) ions (0.11 mg.L( )1, 1.27 mg.L(-)1 and 0.74 mg.L(-)1, respectively). Furthermore, ZnO NPs (<50 nm) showed greater toxicity than ZnO microparticles(MPs)(<5 MUm) to root elongation of both maize and rice. Overall, this study provided valuable information for the application of engineered NPs in agriculture and the assessment of the potential environmental risks. PMID- 26633438 TI - Occurrence and Profiles of the Artificial Endocrine Disruptor Bisphenol A and Natural Endocrine Disruptor Phytoestrogens in Urine from Children in China. AB - BACKGROUND: Exposure to artificial or natural endocrine disruptors, such as bisphenol A (BPA) and phytoestrogens has been demonstrated to have health effects, especially in children. Biomonitoring of BPA and phytoestrogens in human urine can be used to assess the intake levels of these compounds. METHODS: In this study, BPA and phytoestrogens in urine specimens (n = 256) collected from children in China were measured by liquid chromatography (LC)-tandem mass spectrometry (MS/MS). RESULTS: BPA was detected in most specimens, with a geometric mean concentration of 1.58 ng/mL. For the first time, levels of urinary phytoestrogens in Chinese children were reported. Daidzein and enterolactone are the typical isoflavones and lignans compounds in urine, respectively. CONCLUSIONS: Relatively high levels of urinary BPA indicate an increasing risk of BPA exposure to Chinese children. Urinary concentrations of daidzein in Chinese children are higher when compared with those reported in the U.S. children, while concentrations of urinary enterolactone and enterodiols are significantly lower. This suggests a significant difference in phytoestrogen intake between the children from China and from the U.S. PMID- 26633439 TI - Epidemiology of Unintentional Child Injuries in the Makwanpur District of Nepal: A Household Survey. AB - Secondary sources of information indicate that the proportion of child deaths due to injuries is increasing in Nepal. This study aimed to describe the epidemiology of unintentional injuries in children, explore risk factors and estimate the burden faced by families and the community in the Makwanpur district. We conducted a household survey in Makwanpur, covering 3441 households. Injuries that occurred during the 12 months before the survey and required treatment or caused the child to be unable to take part in usual activities for three or more days were included. We identified 193 cases of non-fatal unintentional child injuries from 181 households and estimated an annual rate of non-fatal injuries of 24.6/1000 children; rates for boys were double (32.7/1000) that for girls (16.8/1000). The rates were higher among the children of age groups 1-4 years and 5-9 years. Falls were the most common cause of non-fatal child injuries followed by burns in preschool children and road traffic injuries were the most likely cause in adolescence. Mean period of disability following injury was 25 days. The rates and the mechanisms of injury vary by age and gender. Falls and burns are currently the most common mechanisms of injury amongst young children around rural homes. PMID- 26633440 TI - Feasibility of Measuring Tobacco Smoke Air Pollution in Homes: Report from a Pilot Study. AB - Tobacco smoke air pollution (TSAP) measurement may persuade parents to adopt smoke-free homes and thereby reduce harm to children from tobacco smoke in the home. In a pilot study involving 29 smoking families, a Sidepak was used to continuously monitor home PM(2.5) during an 8-h period, Sidepak and/or Dylos monitors provided real-time feedback, and passive nicotine monitors were used to measure home air nicotine for one week. Feedback was provided to participants in the context of motivational interviews. Home PM(2.5) levels recorded by continuous monitoring were not well-accepted by participants because of the noise level. Also, graphs from continuous monitoring showed unexplained peaks, often associated with sources unrelated to indoor smoking, such as cooking, construction, or outdoor sources. This hampered delivery of a persuasive message about the relationship between home smoking and TSAP. By contrast, immediate real time PM(2.5) feedback (with Sidepak or Dylos monitor) was feasible and provided unambiguous information; the Dylos had the additional advantages of being more economical and quieter. Air nicotine sampling was complicated by the time-lag for feedback and questions regarding shelf-life. Improvement in the science of TSAP measurement in the home environment is needed to encourage and help maintain smoke-free homes and protect vulnerable children. Recent advances in the use of mobile devices for real-time feedback are promising and warrant further development, as do accurate methods for real-time air nicotine air monitoring. PMID- 26633441 TI - The Geographic Distribution of Liver Cancer in Canada Does Not Associate with Cyanobacterial Toxin Exposure. AB - BACKGROUND: The incidence of liver cancer has been increasing in Canada over the past decade, as has cyanobacterial contamination of Canadian freshwater lakes and drinking water sources. Cyanotoxins released by cyanobacteria have been implicated in the pathogenesis of liver cancer. OBJECTIVE: To determine whether a geographic association exists between liver cancer and surrogate markers of cyanobacterial contamination of freshwater lakes in Canada. METHODS: A negative binomial regression model was employed based on previously identified risk factors for liver cancer. RESULTS: No association existed between the geographic distribution of liver cancer and surrogate markers of cyanobacterial contamination. As predicted, significant associations existed in areas with a high prevalence of hepatitis B virus infection, large immigrant populations and urban residences. DISCUSSION AND CONCLUSIONS: The results of this study suggest that cyanobacterial contamination of freshwater lakes does not play an important role in the increasing incidence of liver cancer in Canada. PMID- 26633442 TI - Relationship Between Job Burnout and Neuroendocrine Indicators in Soldiers in the Xinjiang Arid Desert: A Cross-Sectional Study. AB - The purpose of this study was to explore the relationship between job burnout and neuroendocrine indicators in soldiers living in a harsh environment. Three hundred soldiers stationed in the arid desert and 600 in an urban area were recruited. They filled in the Chinese Maslach Burnout Inventory questionnaire. One hundred soldiers were randomly selected from each group to measure their levels of noradrenaline, serotonin, heat shock protein (HSP)-70, adrenocorticotropic hormone, and serum cortisol. Job burnout was more common in soldiers from urban areas than those from rural areas. Job burnout was significantly higher among soldiers stationed in the arid desert than those in urban areas. For soldiers in the arid desert, the levels of HSP-70, serum cortisol, and adrenocorticotropic hormone were significantly higher than in soldiers in urban areas. Correlation analyses showed that the degree of job burnout was weakly negatively correlated with the level of HSP-70. Being an only child, HSP-70 levels, cortisol levels, and ACTH levels were independently associated with job burnout in soldiers stationed in the arid desert. A higher level of job burnout in soldiers stationed in arid desert and a corresponding change in neuroendocrine indicators indicated a correlation between occupational stress and neurotransmitters. PMID- 26633443 TI - Delayed Numerical Chromosome Aberrations in Human Fibroblasts by Low Dose of Radiation. AB - Radiation-induced genomic instability refers to a type of damage transmitted over many generations following irradiation. This delayed impact of radiation exposure may pose a high risk to human health and increases concern over the dose limit of radiation exposure for both the public and radiation workers. Therefore, the development of additional biomarkers is still needed for the detection of delayed responses following low doses of radiation exposure. In this study, we examined the effect of X-irradiation on delayed induction of numerical chromosomal aberrations in normal human fibroblasts irradiated with 20, 50 and 100 cGy of X rays using the micronucleus-centromere assay. Frequencies of centromere negative- and positive-micronuclei, and aneuploidy of chromosome 1 and 4 were analyzed in the surviving cells at 28, 88 and 240 h after X-irradiation. X-irradiation increased the frequency of micronuclei (MN) in a dose-dependent manner in the cells at all measured time-points, but no significant differences in MN frequency among cell passages were observed. Aneuploid frequency of chromosomes 1 and 4 increased with radiation doses, and a significantly higher frequency of aneuploidy was observed in the surviving cells analyzed at 240 h compared to 28 h. These results indicate that low-dose of X-irradiation can induce delayed aneuploidy of chromosomes 1 and 4 in normal fibroblasts. PMID- 26633444 TI - Applying Rank Sum Ratio (RSR) to the Evaluation of Feeding Practices Behaviors, and Its Associations with Infant Health Risk in Rural Lhasa, Tibet. AB - To evaluate the status of feeding practices and analyze the association between feeding practice and health status among Tibetan infants, a cross-sectional survey of 386 women with children aged under 24 months was conducted in rural areas surrounding Lhasa, Tibet. All participants were selected using simple random sampling and were interviewed face-to-face by trained interviewers. Mothers were interviewed to collect information on their feeding practices. A feeding practices index was created using the rank sum ratio method. Most of the infants had been or were being breastfed at the time of the interview. The feeding practices index was significantly and inversely associated with the prevalence of acute upper respiratory infection, and the odds ratio for the qualified feeding practices index vs. the non-qualified feeding practices index was 0.43 (95% confidence interval: 0.20-0.94). There were no measurable associations observed between acute upper respiratory infection, diarrhea, and the feeding practices index after controlling for selected factors. The method of rank sum ratio provides a flexible way to evaluate feeding practices and is easy to understand. Furthermore, appropriate infant feeding practices might play a protective role in Tibetan infants' health. PMID- 26633445 TI - GIS and Remote Sensing Use in the Exploration of Lyme Disease Epidemiology. AB - Given the relatively recent recognition of Lyme disease (LD) by CDC in 1990 as a nationally notifiable infectious condition, the rise of reported human cases every year argues for a better understanding of its geographic scope. The aim of this inquiry was to explore research conducted on spatiotemporal patterns of Lyme disease in order to identify strategies for implementing vector and reservoir targeted interventions. The focus of this review is on the use of GIS-based methods to study populations of the reservoir hosts, vectors and humans in addition to the spatiotemporal interactions between these populations. New GIS based studies are monitoring occurrence at the macro-level, and helping pinpoint areas of occurrence at the micro-level, where spread within populations of reservoir hosts, clusters of infected ticks and tick to human transmission may be better understood. PMID- 26633446 TI - A Predictive Risk Model for A(H7N9) Human Infections Based on Spatial-Temporal Autocorrelation and Risk Factors: China, 2013-2014. AB - This study investigated the spatial distribution, spatial autocorrelation, temporal cluster, spatial-temporal autocorrelation and probable risk factors of H7N9 outbreaks in humans from March 2013 to December 2014 in China. The results showed that the epidemic spread with significant spatial-temporal autocorrelation. In order to describe the spatial-temporal autocorrelation of H7N9, an improved model was developed by introducing a spatial-temporal factor in this paper. Logistic regression analyses were utilized to investigate the risk factors associated with their distribution, and nine risk factors were significantly associated with the occurrence of A(H7N9) human infections: the spatial-temporal factor phi (OR = 2546669.382, p < 0.001), migration route (OR = 0.993, p < 0.01), river (OR = 0.861, p < 0.001), lake(OR = 0.992, p < 0.001), road (OR = 0.906, p < 0.001), railway (OR = 0.980, p < 0.001), temperature (OR = 1.170, p < 0.01), precipitation (OR = 0.615, p < 0.001) and relative humidity (OR = 1.337, p < 0.001). The improved model obtained a better prediction performance and a higher fitting accuracy than the traditional model: in the improved model 90.1% (91/101) of the cases during February 2014 occurred in the high risk areas (the predictive risk > 0.70) of the predictive risk map, whereas 44.6% (45/101) of which overlaid on the high risk areas (the predictive risk > 0.70) for the traditional model, and the fitting accuracy of the improved model was 91.6% which was superior to the traditional model (86.1%). The predictive risk map generated based on the improved model revealed that the east and southeast of China were the high risk areas of A(H7N9) human infections in February 2014. These results provided baseline data for the control and prevention of future human infections. PMID- 26633447 TI - Physiological and Psychological Effects of a Forest Therapy Program on Middle Aged Females. AB - The natural environment is increasingly recognized as an effective counter to urban stress, and "Forest Therapy" has recently attracted attention as a relaxation and stress management activity with demonstrated clinical efficacy. The present study assessed the physiological and psychological effects of a forest therapy program on middle-aged females. Seventeen Japanese females (62.2 +/- 9.4 years; mean +/- standard deviation) participated in this experiment. Pulse rate, salivary cortisol level, and psychological indices were measured on the day before forest therapy and on the forest therapy day. Pulse rate and salivary cortisol were significantly lower than baseline following forest therapy, indicating that subjects were in a physiologically relaxed state. Subjects reported feeling significantly more "comfortable," "relaxed," and "natural" according to the semantic differential (SD) method. The Profile of Mood State (POMS) negative mood subscale score for "tension-anxiety" was significantly lower, while that for "vigor" was significantly higher following forest therapy. Our study revealed that forest therapy elicited a significant (1) decrease in pulse rate, (2) decrease in salivary cortisol levels, (3) increase in positive feelings, and (4) decrease in negative feelings. In conclusion, there are substantial physiological and psychological benefits of forest therapy on middle aged females. PMID- 26633448 TI - Prediction of Indoor Air Exposure from Outdoor Air Quality Using an Artificial Neural Network Model for Inner City Commercial Buildings. AB - NO2 and particulate matter are the air pollutants of most concern in Ireland, with possible links to the higher respiratory and cardiovascular mortality and morbidity rates found in the country compared to the rest of Europe. Currently, air quality limits in Europe only cover outdoor environments yet the quality of indoor air is an essential determinant of a person's well-being, especially since the average person spends more than 90% of their time indoors. The modelling conducted in this research aims to provide a framework for epidemiological studies by the use of publically available data from fixed outdoor monitoring stations to predict indoor air quality more accurately. Predictions are made using two modelling techniques, the Personal-exposure Activity Location Model (PALM), to predict outdoor air quality at a particular building, and Artificial Neural Networks, to model the indoor/outdoor relationship of the building. This joint approach has been used to predict indoor air concentrations for three inner city commercial buildings in Dublin, where parallel indoor and outdoor diurnal monitoring had been carried out on site. This modelling methodology has been shown to provide reasonable predictions of average NO2 indoor air quality compared to the monitored data, but did not perform well in the prediction of indoor PM2.5 concentrations. Hence, this approach could be used to determine NO2 exposures more rigorously of those who work and/or live in the city centre, which can then be linked to potential health impacts. PMID- 26633449 TI - Association of PAEs with Precocious Puberty in Children: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Precocious puberty (PP) currently affects 1 in 5000 children and is 10 times more common in girls. Existing studies have tried to detect an association between phathalic acid esters (PAEs) and PP, but the results did not reach a consensus. OBJECTIVE: To estimate the association between PAEs and children with PP based on current evidence. METHODS: Databases including PubMed (1978 to March 2015), OVID (1946 to March 2015), Web of Science (1970 to March 2015), EBSCO (1976 to March 2015), CNKI (1979 to March 2015), WANFANG DATA (1987 to March 2015), CBM (1978 to March 2015) and CQVIP (1989 to March 2015) were searched to identify all case-control studies that determined the exposure and concentration of PAEs and their metabolites in children with PP. Meta-analysis of the pooled standard mean difference (SMD) and odds ratio (OR) with 95% confidence intervals (CI) were calculated. RESULTS: A total of 14 studies involving 2223 subjects were finally included. The pooled estimates showed that PP was associated with di-(2-ethylhexyl)-phthalate (DEHP) exposure (OR: 3.90, 95% CI: 2.77 to 5.49). Besides, the concentration of DEHP (SMD: 1.73, 95% CI: 0.54 to 2.91) and di-n-butyl phthalate (DBP) (SMD: 4.31, 95% CI: 2.67 to 5.95) in the PP group were significantly higher than those in the control group, respectively, while no difference was detected between case and control groups in either serum or urinary concentration of mono-(2-ethylhexyl)-phthalate (MEHP), monobutyl phthalate (MBP), mono(2-ethyl-5-oxohexyl) phthalate(MEOHP), mono-(2-ethyl-5 carboxypentyl) phthalate (MECPP), monomethyl phthalate (MMP), monobenzyl phthalate (MBzP) or monoethyl phthalate (MEP). CONCLUSIONS: Exposure of DEHP and DBP might be associated with PP risk for girls, however, there is no evidence to show an association between the exposure to most PAE metabolites and PP. Given the moderate strength of the results, well-designed cohort studies with large sample size should be performed in future. PMID- 26633450 TI - Accidental Water Pollution Risk Analysis of Mine Tailings Ponds in Guanting Reservoir Watershed, Zhangjiakou City, China. AB - Over the past half century, a surprising number of major pollution incidents occurred due to tailings dam failures. Most previous studies of such incidents comprised forensic analyses of environmental impacts after a tailings dam failure, with few considering the combined pollution risk before incidents occur at a watershed-scale. We therefore propose Watershed-scale Tailings-pond Pollution Risk Analysis (WTPRA), designed for multiple mine tailings ponds, stemming from previous watershed-scale accidental pollution risk assessments. Transferred and combined risk is embedded using risk rankings of multiple routes of the "source-pathway-target" in the WTPRA. The previous approach is modified using multi-criteria analysis, dam failure models, and instantaneous water quality models, which are modified for application to multiple tailings ponds. The study area covers the basin of Gutanting Reservoir (the largest backup drinking water source for Beijing) in Zhangjiakou City, where many mine tailings ponds are located. The resultant map shows that risk is higher downstream of Gutanting Reservoir and in its two tributary basins (i.e., Qingshui River and Longyang River). Conversely, risk is lower in the midstream and upstream reaches. The analysis also indicates that the most hazardous mine tailings ponds are located in Chongli and Xuanhua, and that Guanting Reservoir is the most vulnerable receptor. Sensitivity and uncertainty analyses are performed to validate the robustness of the WTPRA method. PMID- 26633451 TI - Awareness of Cytomegalovirus Infection among Pregnant Women in Geneva, Switzerland: A Cross-sectional Study. AB - BACKGROUND: Cytomegalovirus (CMV) is the most frequent cause of congenital infection and commonly associated with sensorineural deficit. At present, there is neither prophylaxis nor treatment during pregnancy. The objective of this study was to evaluate the level of awareness regarding CMV infection and its consequences in women delivering at the University of Geneva Hospitals (Geneva, Switzerland). METHODS: The study consisted of a validated questionnaire completed by women in the immediate postpartum period. RESULTS: The questionnaire was completed by 59% (314/528) of delivering women. Only 39% (123/314) knew about CMV and 19.7% (62/314) had received information about preventive measures. Women were more aware about other congenital diseases, such as toxoplasmosis (87%); human immunodeficiency virus (99%); syphilis (85.5%); rubella (92.3%); and group B Streptococcus (63%). Factors associated with CMV awareness were Swiss nationality, high education level, employment in health care or with children, and being followed by an obstetrician. Regarding quality of information, few were aware of the main CMV complications (deafness, 25.2%; mental retardation, 34.5%). Among those informed about CMV, most (74.6%) knew about preventive measures. Among these, 82.5% thought that these were easily applicable. CONCLUSIONS: Most women were unaware of CMV infection and its potential risks during pregnancy. It is crucial to improve CMV information given to pregnant women to prevent the risks for the fetus/newborn. PMID- 26633452 TI - Impact of Heat and Cold on Total and Cause-Specific Mortality in Vadu HDSS--A Rural Setting in Western India. AB - Many diseases are affected by changes in weather. There have been limited studies, however, which have examined the relationship between heat and cold and cause-specific mortality in low and middle-income countries. In this study, we aimed to estimate the effects of heat and cold days on total and cause-specific mortality in the Vadu Health and Demographic Surveillance System (HDSS) area in western India. We used a quasi-Poisson regression model allowing for over dispersion to examine the association of total and cause-specific mortality with extreme high (98th percentile, >39 degrees C) and low temperature (2nd percentile, <25 degrees C) over the period January 2003 to December 2012. Delays of 0 and 0-4 days were considered and relative risks (RR) with 95% confidence intervals (CI) were calculated. Heat was significantly associated with daily deaths by non-infectious diseases (RR = 1.57; CI: 1.18-2.10). There was an increase in the risk of total mortality in the age group 12-59 years on lag 0 day (RR = 1.43; CI: 1.02-1.99). A high increase in total mortality was observed among men at lag 0 day (RR = 1.38; CI: 1.05-1.83). We did not find any short-term association between total and cause-specific mortality and cold days. Deaths from neither infectious nor external causes were associated with heat or cold. Our results showed a strong and rather immediate relationship between high temperatures and non-infectious disease mortality in a rural population located in western India, during 2003-2012. This study may be used to develop targeted interventions such as Heat Early Warning Systems in the area to reduce mortality from extreme temperatures. PMID- 26633453 TI - Effects of 90-Day Feeding of Transgenic Maize BT799 on the Reproductive System in Male Wistar Rats. AB - BT799 is a genetically modified (GM) maize plant that expresses the Cry1Ac gene from Bacillus thuringiensis (Bt). The Cry1Ac gene was introduced into maize line Zhen58 to encode the Bt crystal protein and thus produce insect-resistant maize BT799. Expression of Bt protein in planta confers resistance to Lepidopteran pests and corn rootworms. The present study was designed to investigate any potential effects of BT799 on the reproductive system of male rats and evaluate the nutritional value of diets containing BT799 maize grain in a 90-day subchronic rodent feeding study. Male Wistar rats were fed with diets containing BT799 maize flours or made from its near isogenic control (Zhen58) at a concentration of 84.7%, nutritionally equal to the standard AIN-93G diet. Another blank control group of male rats were treated with commercial AIN-93G diet. No significant differences in body weight, hematology and serum chemistry results were observed between rats fed with the diets containing transgenic BT799, Zhen58 and the control in this 13-week feeding study. Results of serum hormone levels, sperm parameters and relative organ/body weights indicated no treatment-related side effects on the reproductive system of male rats. In addition, no diet related changes were found in necropsy and histopathology examinations. Based on results of the current study, we did not find any differences in the parameters tested in our study of the reproductive system of male rats between BT799 and Zhen58 or the control. PMID- 26633454 TI - Biosorption Potential of Bacillus salmalaya Strain 139SI for Removal of Cr(VI) from Aqueous Solution. AB - The present study investigated the biosorption capacity of live and dead cells of a novel Bacillus strain for chromium. The optimum biosorption condition was evaluated in various analytical parameters, including initial concentration of chromium, pH, and contact time. The Langmuir isotherm model showed an enhanced fit to the equilibrium data. Live and dead biomasses followed the monolayer biosorption of the active surface sites. The maximum biosorption capacity was 20.35 mg/g at 25 degrees C, with pH 3 and contact time of 50 min. Strain 139SI was an excellent host to the hexavalent chromium. The biosorption kinetics of chromium in the dead and live cells of Bacillus salmalaya (B. salmalaya) 139SI followed the pseudo second-order mechanism. Scanning electron microscopy and fourier transform infrared indicated significant influence of the dead cells on the biosorption of chromium based on cell morphological changes. Approximately 92% and 70% desorption efficiencies were achieved using dead and live cells, respectively. These findings demonstrated the high sorption capacity of dead biomasses of B. salmalaya 139SI in the biosorption process. Thermodynamic evaluation (DeltaG0, DeltaH0, and DeltaS0) indicated that the mechanism of Cr(VI) adsorption is endothermic; that is, chemisorption. Results indicated that chromium accumulation occurred in the cell wall of B. salmalaya 139SI rather than intracellular accumulation. PMID- 26633455 TI - Assessing the Acceptability and Usability of an Internet-Based Intelligent Health Assistant Developed for Use among Turkish Migrants: Results of a Study Conducted in Bremen, Germany. AB - The Internet offers a new chance for health professionals to reach population groups not usually reached through traditional information channels, for example, migrants. Criticism has, however, been raised that most health information on the Internet is not easy to read and lacks cultural sensitivity. We developed an Internet-based bilingual health assistant especially for Turkish migrants in Germany, tested its acceptance, and evaluated its usability in a participatory research design with families with and without Turkish migrant background. The interactive health assistant covered the following: nutrition, physical activity, overweight, diabetes, as well as pregnancy and pregnancy support. The idea of an Internet-based health assistant was generally accepted by all participants of the evaluation study, as long as it would be incorporated in existing appliances, such as smartphones. The bilingual nature of the assistant was welcomed especially by first generation migrants, but migrant participants also indicated that not all health information needed to be made available in a culture-specific way. The participants were least satisfied with the nutrition component, which they felt should include recipes and ingredients from the culture of origin, as well as specific aspects of food preparation. PMID- 26633456 TI - Differential Effects of Temperature Extremes on Hospital Admission Rates for Respiratory Disease between Indigenous and Non-Indigenous Australians in the Northern Territory. AB - The health gap between Indigenous and non-Indigenous Australians may be exacerbated by climate change if temperature extremes have disproportionate adverse effects on Indigenous people. To explore this issue, we analysed the effect of temperature extremes on hospital admissions for respiratory diseases, stratified by age, Indigenous status and sex, for people living in two different climates zones in the Northern Territory during the period 1993-2011. We examined admissions for both acute and chronic respiratory diagnoses, controlling for day of the week and seasonality variables. Our analysis showed that: (1) overall, Indigenous hospital admission rates far exceeded non-Indigenous admission rates for acute and chronic diagnoses, and Top End climate zone admission rates exceeded Central Australia climate zone admission rates; (2) extreme cold and hot temperatures were associated with inconsistent changes in admission rates for acute respiratory disease in Indigenous and non-Indigenous children and older adults; and (3) no response to cold or hot temperature extremes was found for chronic respiratory diagnoses. These findings support our two hypotheses, that extreme hot and cold temperatures have a different effect on hospitalisations for respiratory disease between Indigenous and non-Indigenous people, and that these health risks vary between the different climate zones. We did not, however, find that there were differing responses to temperature extremes in the two populations, suggesting that any increased vulnerability to climate change in the Indigenous population of the Northern Territory arises from an increased underlying risk to respiratory disease and an already greater existing health burden. PMID- 26633457 TI - Screening for Elevated Blood Lead Levels in Children: Assessment of Criteria and a Proposal for New Ones in France. AB - The decline in children's Blood Lead Levels (BLL) raises questions about the ability of current lead poisoning screening criteria to identify those children most exposed. The objectives of the study were to evaluate the performance of current screening criteria in identifying children with blood lead levels higher than 50 ug/L in France, and to propose new criteria. Data from a national French survey, conducted among 3831 children aged 6 months to 6 years in 2008-2009 were used. The sensitivity and specificity of the current criteria in predicting blood lead levels higher than or equal to 50 ug/L were evaluated. Two predictive models of BLL above 44 ug/L (for lack of sufficient sample size at 50 ug/L) were built: the first using current criteria, and the second using newly identified risk factors. For each model, performance was studied by calculating the area under the ROC (Receiver Operating Characteristic) curve. The sensitivity of current criteria for detecting BLL higher than or equal to 50 ug/L was 0.51 (0.26; 0.75) and specificity was 0.66 (0.62; 0.70). The new model included the following criteria: foreign child newly arrived in France, mother born abroad, consumption of tap water in the presence of lead pipes, pre-1949 housing, period of construction of housing unknown, presence of peeling paint, parental smoking at home, occupancy rates for housing and child's address in a cadastral municipality or census block comprising more than 6% of housing that is potentially unfit and built pre-1949. The area under the ROC curve was 0.86 for the new model, versus 0.76 for the current one. The lead poisoning screening criteria should be updated. The risk of industrial, occupational and hobby-related exposure could not be assessed in this study, but should be kept as screening criteria. PMID- 26633458 TI - Fractal Characteristics of Soil Retention Curve and Particle Size Distribution with Different Vegetation Types in Mountain Areas of Northern China. AB - Based on fractal theory, the fractal characteristics of soil particle size distribution (PSD) and soil water retention curve (WRC) under the five vegetation types were studied in the mountainous land of Northern China. Results showed that: (1) the fractal parameters of soil PSD and soil WRC varied greatly under each different vegetation type, with Quercus acutissima Carr. and Robina pseudoacacia Linn. mixed plantation (QRM) > Pinus thunbergii Parl. and Pistacia chinensis Bunge mixed plantation (PPM) > Pinus thunbergii Parl. (PTP) > Juglans rigia Linn. (JRL) > abandoned grassland (ABG); (2) the soil fractal dimensions of woodlands (QRM, PPM, PTP and JRL) were significantly higher than that in ABG, and mixed forests (QRM and PPM) were higher than that in pure forests (PTP and JRL); (3) the fractal dimension of soil was positively correlated with the silt and clay content but negatively correlated with the sand content; and (4) the fractal dimension of soil PSD was positively correlated with the soil WRC. These indicated that the fractal parameters of soil PSD and soil WRC could act as quantitative indices to reflect the physical properties of the soil, and could be used to describe the influences of the Return Farmland to Forests Projects on soil structure. PMID- 26633459 TI - Inhibition Profiling of Retroviral Protease Inhibitors Using an HIV-2 Modular System. AB - Retroviral protease inhibitors (PIs) are fundamental pillars in the treatment of HIV infection and acquired immunodeficiency syndrome (AIDS). Currently used PIs are designed against HIV-1, and their effect on HIV-2 is understudied. Using a modular HIV-2 protease cassette system, inhibition profiling assays were carried out for protease inhibitors both in enzymatic and cell culture assays. Moreover, the treatment-associated resistance mutations (I54M, L90M) were introduced into the modular system, and comparative inhibition assays were performed to determine their effect on the susceptibility of the protease. Our results indicate that darunavir, saquinavir, indinavir and lopinavir were very effective HIV-2 protease inhibitors, while tipranavir, nelfinavir and amprenavir showed a decreased efficacy. I54M, L90M double mutation resulted in a significant reduction in the susceptibility to most of the inhibitors with the exception of tipranavir. To our knowledge, this modular system constitutes a novel approach in the field of HIV-2 protease characterization and susceptibility testing. PMID- 26633460 TI - Incomplete LPS Core-Specific Felix01-Like Virus vB_EcoM_VpaE1. AB - Bacteriophages represent a valuable source for studying the mechanisms underlying virus-host interactions. A better understanding of the host-specificity of viruses at the molecular level can promote various phage applications, including bacterial diagnostics, antimicrobial therapeutics, and improve methods in molecular biology. In this study, we describe the isolation and characterization of a novel coliphage, vB_EcoM_VpaE1, which has different host specificity than its relatives. Morphology studies, coupled with the results of genomic and proteomic analyses, indicate that vB_EcoM_VpaE1 belongs to the newly proposed genus Felix01likevirus in the family Myoviridae. The genus Felix01likevirus comprises a group of highly similar phages that infect O-antigen-expressing Salmonella and Escherichia coli (E. coli) strains. Phage vB_EcoM_VpaE1 differs from the rest of Felix01-like viruses, since it infects O-antigen-deficient E. coli strains with an incomplete core lipopolysaccharide (LPS). We show that vB_EcoM_VpaE1 can infect mutants of E. coli that contain various truncations in their LPS, and can even recognize LPS that is truncated down to the inner-core oligosaccharide, showing potential for the control of rough E. coli strains, which usually emerge as resistant mutants upon infection by O-Ag-specific phages. Furthermore, VpaE1 can replicate in a wide temperature range from 9 to 49 degrees C, suggesting that this virus is well adapted to harsh environmental conditions. Since the structural proteins of such phages tend to be rather robust, the receptor-recognizing proteins of VpaE1 are an attractive tool for application in glycan analysis, bacterial diagnostics and antimicrobial therapeutics. PMID- 26633461 TI - Fluorescent Protein-Tagged Sindbis Virus E2 Glycoprotein Allows Single Particle Analysis of Virus Budding from Live Cells. AB - Sindbis virus (SINV) is an enveloped, mosquito-borne alphavirus. Here we generated and characterized a fluorescent protein-tagged (FP-tagged) SINV and found that the presence of the FP-tag (mCherry) affected glycoprotein transport to the plasma membrane whereas the specific infectivity of the virus was not affected. We examined the virions by transmission electron cryo-microscopy and determined the arrangement of the FP-tag on the surface of the virion. The fluorescent proteins are arranged icosahedrally on the virus surface in a stable manner that did not adversely affect receptor binding or fusion functions of E2 and E1, respectively. The delay in surface expression of the viral glycoproteins, as demonstrated by flow cytometry analysis, contributed to a 10-fold reduction in mCherry-E2 virus titer. There is a 1:1 ratio of mCherry to E2 incorporated into the virion, which leads to a strong fluorescence signal and thus facilitates single-particle tracking experiments. We used the FP-tagged virus for high resolution live-cell imaging to study the spatial and temporal aspects of alphavirus assembly and budding from mammalian cells. These processes were further analyzed by thin section microscopy. The results demonstrate that SINV buds from the plasma membrane of infected cells and is dispersed into the surrounding media or spread to neighboring cells facilitated by its close association with filopodial extensions. PMID- 26633462 TI - Stem Cell-Based Cell Carrier for Targeted Oncolytic Virotherapy: Translational Opportunity and Open Questions. AB - Oncolytic virotherapy for cancer is an innovative therapeutic option where the ability of a virus to promote cell lysis is harnessed and reprogrammed to selectively destroy cancer cells. Such treatment modalities exhibited antitumor activity in preclinical and clinical settings and appear to be well tolerated when tested in clinical trials. However, the clinical success of oncolytic virotherapy has been significantly hampered due to the inability to target systematic metastasis. This is partly due to the inability of the therapeutic virus to survive in the patient circulation, in order to target tumors at distant sites. An early study from various laboratories demonstrated that cells infected with oncolytic virus can protect the therapeutic payload form the host immune system as well as function as factories for virus production and enhance the therapeutic efficacy of oncolytic virus. While a variety of cell lineages possessed potential as cell carriers, copious investigation has established stem cells as a very attractive cell carrier system in oncolytic virotherapy. The ideal cell carrier desire to be susceptible to viral infection as well as support viral infection, maintain immunosuppressive properties to shield the loaded viruses from the host immune system, and most importantly possess an intrinsic tumor homing ability to deliver loaded viruses directly to the site of the metastasis-all qualities stem cells exhibit. In this review, we summarize the recent work in the development of stem cell-based carrier for oncolytic virotherapy, discuss the advantages and disadvantages of a variety of cell carriers, especially focusing on why stem cells have emerged as the leading candidate, and finally propose a future direction for stem cell-based targeted oncolytic virotherapy that involves its establishment as a viable treatment option for cancer patients in the clinical setting. PMID- 26633464 TI - Identification of a New Ribonucleoside Inhibitor of Ebola Virus Replication. AB - The current outbreak of Ebola virus (EBOV) in West Africa has claimed the lives of more than 15,000 people and highlights an urgent need for therapeutics capable of preventing virus replication. In this study we screened known nucleoside analogues for their ability to interfere with EBOV replication. Among them, the cytidine analogue beta-d-N4-hydroxycytidine (NHC) demonstrated potent inhibitory activities against EBOV replication and spread at non-cytotoxic concentrations. Thus, NHC constitutes an interesting candidate for the development of a suitable drug treatment against EBOV. PMID- 26633463 TI - Natural Products as Tools for Defining How Cellular Metabolism Influences Cellular Immune and Inflammatory Function during Chronic Infection. AB - Chronic viral infections like those caused by hepatitis C virus (HCV) and human immunodeficiency virus (HIV) cause disease that establishes an ongoing state of chronic inflammation. While there have been tremendous improvements towards curing HCV with directly acting antiviral agents (DAA) and keeping HIV viral loads below detection with antiretroviral therapy (ART), there is still a need to control inflammation in these diseases. Recent studies indicate that many natural products like curcumin, resveratrol and silymarin alter cellular metabolism and signal transduction pathways via enzymes such as adenosine monophosphate kinase (AMPK) and mechanistic target of rapamycin (mTOR), and these pathways directly influence cellular inflammatory status (such as NF-kappaB) and immune function. Natural products represent a vast toolkit to dissect and define how cellular metabolism controls cellular immune and inflammatory function. PMID- 26633465 TI - Rapid Construction of Stable Infectious Full-Length cDNA Clone of Papaya Leaf Distortion Mosaic Virus Using In-Fusion Cloning. AB - Papaya leaf distortion mosaic virus (PLDMV) is becoming a threat to papaya and transgenic papaya resistant to the related pathogen, papaya ringspot virus (PRSV). The generation of infectious viral clones is an essential step for reverse-genetics studies of viral gene function and cross-protection. In this study, a sequence- and ligation-independent cloning system, the In-Fusion((r)) Cloning Kit (Clontech, Mountain View, CA, USA), was used to construct intron-less or intron-containing full-length cDNA clones of the isolate PLDMV-DF, with the simultaneous scarless assembly of multiple viral and intron fragments into a plasmid vector in a single reaction. The intron-containing full-length cDNA clone of PLDMV-DF was stably propagated in Escherichia coli. In vitro intron-containing transcripts were processed and spliced into biologically active intron-less transcripts following mechanical inoculation and then initiated systemic infections in Carica papaya L. seedlings, which developed similar symptoms to those caused by the wild-type virus. However, no infectivity was detected when the plants were inoculated with RNA transcripts from the intron-less construct because the instability of the viral cDNA clone in bacterial cells caused a non sense or deletion mutation of the genomic sequence of PLDMV-DF. To our knowledge, this is the first report of the construction of an infectious full-length cDNA clone of PLDMV and the splicing of intron-containing transcripts following mechanical inoculation. In-Fusion cloning shortens the construction time from months to days. Therefore, it is a faster, more flexible, and more efficient method than the traditional multistep restriction enzyme-mediated subcloning procedure. PMID- 26633467 TI - Alphacoronaviruses Detected in French Bats Are Phylogeographically Linked to Coronaviruses of European Bats. AB - Bats are a reservoir for a diverse range of viruses, including coronaviruses (CoVs). To determine the presence of CoVs in French bats, fecal samples were collected between July and August of 2014 from four bat species in seven different locations around the city of Bourges in France. We present for the first time the presence of alpha-CoVs in French Pipistrellus pipistrellus bat species with an estimated prevalence of 4.2%. Based on the analysis of a fragment of the RNA-dependent RNA polymerase (RdRp) gene, phylogenetic analyses show that alpha-CoVs sequences detected in French bats are closely related to other European bat alpha-CoVs. Phylogeographic analyses of RdRp sequences show that several CoVs strains circulate in European bats: (i) old strains detected that have probably diverged a long time ago and are detected in different bat subspecies; (ii) strains detected in Myotis and Pipistrellus bat species that have more recently diverged. Our findings support previous observations describing the complexity of the detected CoVs in bats worldwide. PMID- 26633466 TI - Potential for Improving Potency and Specificity of Reovirus Oncolysis with Next Generation Reovirus Variants. AB - Viruses that specifically replicate in tumor over normal cells offer promising cancer therapies. Oncolytic viruses (OV) not only kill the tumor cells directly; they also promote anti-tumor immunotherapeutic responses. Other major advantages of OVs are that they dose-escalate in tumors and can be genetically engineered to enhance potency and specificity. Unmodified wild type reovirus is a propitious OV currently in phase I-III clinical trials. This review summarizes modifications to reovirus that may improve potency and/or specificity during oncolysis. Classical genetics approaches have revealed reovirus variants with improved adaptation towards tumors or with enhanced ability to establish specific steps of virus replication and cell killing among transformed cells. The recent emergence of a reverse genetics system for reovirus has provided novel strategies to fine-tune reovirus proteins or introduce exogenous genes that could promote oncolytic activity. Over the next decade, these findings are likely to generate better optimized second-generation reovirus vectors and improve the efficacy of oncolytic reotherapy. PMID- 26633468 TI - Evidence for Oncolytic Virotherapy: Where Have We Got to and Where Are We Going? AB - The last few years have seen an increased interest in immunotherapy in the treatment of malignant disease. In particular, there has been significant enthusiasm for oncolytic virotherapy, with a large amount of pre-clinical data showing promise in animal models in a wide range of tumour types. How do we move forward into the clinical setting and translate something which has such potential into meaningful clinical outcomes? Here, we review how the field of oncolytic virotherapy has developed thus far and what the future may hold. PMID- 26633471 TI - Second International Congress on Chocolate and Cocoa in Medicine Held in Barcelona, Spain, 25-26th September 2015. PMID- 26633470 TI - Chronic Zinc Deficiency Alters Chick Gut Microbiota Composition and Function. AB - Zinc (Zn) deficiency is a prevalent micronutrient insufficiency. Although the gut is a vital organ for Zn utilization, and Zn deficiency is associated with impaired intestinal permeability and a global decrease in gastrointestinal health, alterations in the gut microbial ecology of the host under conditions of Zn deficiency have yet to be studied. Using the broiler chicken (Gallus gallus) model, the aim of this study was to characterize distinct cecal microbiota shifts induced by chronic dietary Zn depletion. We demonstrate that Zn deficiency induces significant taxonomic alterations and decreases overall species richness and diversity, establishing a microbial profile resembling that of various other pathological states. Through metagenomic analysis, we show that predicted Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways responsible for macro- and micronutrient uptake are significantly depleted under Zn deficiency; along with concomitant decreases in beneficial short chain fatty acids, such depletions may further preclude optimal host Zn availability. We also identify several candidate microbes that may play a significant role in modulating the bioavailability and utilization of dietary Zn during prolonged deficiency. Our results are the first to characterize a unique and dysbiotic cecal microbiota during Zn deficiency, and provide evidence for such microbial perturbations as potential effectors of the Zn deficient phenotype. PMID- 26633469 TI - Viral Infection at High Magnification: 3D Electron Microscopy Methods to Analyze the Architecture of Infected Cells. AB - As obligate intracellular parasites, viruses need to hijack their cellular hosts and reprogram their machineries in order to replicate their genomes and produce new virions. For the direct visualization of the different steps of a viral life cycle (attachment, entry, replication, assembly and egress) electron microscopy (EM) methods are extremely helpful. While conventional EM has given important information about virus-host cell interactions, the development of three dimensional EM (3D-EM) approaches provides unprecedented insights into how viruses remodel the intracellular architecture of the host cell. During the last years several 3D-EM methods have been developed. Here we will provide a description of the main approaches and examples of innovative applications. PMID- 26633473 TI - Internal Fat and Cardiometabolic Risk Factors Following a Meal-Replacement Regimen vs. Comprehensive Lifestyle Changes in Obese Subjects. AB - The aim of the present study was to investigate the effect of a meal-replacement regimen vs. comprehensive lifestyle changes in overweight or obese subjects on intra-abdominal fat stores (Magnetic Resonance Imaging (MRI) measurements) and cardiometabolic risk factors. Forty-two obese men (n = 18) and women (n = 24) (age 49 +/- 8 years; weight 96.3 +/- 12.1 kg; BMI 32.7 +/- 2.3 kg/m2) were selected for this randomized parallel-group design investigation. Subjects in the lifestyle group (LS-G; n = 22) received dietary counselling sessions and instructions how to increase physical activity. In the meal replacement group (MR G; n = 20) meals were replaced by a low-calorie drink high in soy protein. After six months, subjects in the LS-G lost 8.88 +/- 6.24 kg and subjects in the MR-G lost 7.1 +/- 2.33 kg; p < 0.01 for changes within groups; no significant differences were found between the groups. Lean body mass remained constant in both intervention groups. MRI analyses showed that internal fat was significantly reduced in both groups to a comparable amount; the higher fat loss in the LS-G in the abdominal area was due to a higher reduction in subcutaneous fat. Both interventions significantly reduced components of the cardiometabolic risk profile and leptin levels. The decrease in the adipokines fetuin A and resistin was more pronounced in the MR-G. In conclusion, both interventions significantly reduced body weight, total fat mass and internal abdominal fat while preserving lean body mass. The reduction in the adipokines fetuin A and resistin was more pronounced in the meal replacement group suggesting an additional effect of soy protein components. PMID- 26633472 TI - Effect of Replacing Animal Protein with Plant Protein on Glycemic Control in Diabetes: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. AB - Previous research on the effect of replacing sources of animal protein with plant protein on glycemic control has been inconsistent. We therefore conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to assess the effect of this replacement on glycemic control in individuals with diabetes. We searched MEDLINE, EMBASE, and Cochrane databases through 26 August 2015. We included RCTs >= 3-weeks comparing the effect of replacing animal with plant protein on HbA1c, fasting glucose (FG), and fasting insulin (FI). Two independent reviewers extracted relevant data, assessed study quality and risk of bias. Data were pooled by the generic inverse variance method and expressed as mean differences (MD) with 95% confidence intervals (CIs). Heterogeneity was assessed (Cochran Q-statistic) and quantified (I2-statistic). Thirteen RCTs (n = 280) met the eligibility criteria. Diets emphasizing a replacement of animal with plant protein at a median level of ~35% of total protein per day significantly lowered HbA1c (MD = -0.15%; 95%-CI: -0.26, -0.05%), FG (MD = -0.53 mmol/L; 95% CI: -0.92, -0.13 mmol/L) and FI (MD = -10.09 pmol/L; 95%-CI: -17.31, -2.86 pmol/L) compared with control arms. Overall, the results indicate that replacing sources of animal with plant protein leads to modest improvements in glycemic control in individuals with diabetes. Owing to uncertainties in our analyses there is a need for larger, longer, higher quality trials. TRIAL REGISTRATION: ClinicalTrials.gov registration number: NCT02037321. PMID- 26633474 TI - The Emerging Role of Disturbed CoQ Metabolism in Nonalcoholic Fatty Liver Disease Development and Progression. AB - Although non-alcoholic fatty liver disease (NAFLD), characterised by the accumulation of triacylglycerol in the liver, is the most common liver disorder, the causes of its development and progression to the more serious non-alcoholic steatohepatitis (NASH) remain incompletely understood. Oxidative stress has been implicated as a key factor in both these processes, and mitochondrial dysfunction and inflammation are also believed to play a part. Coenzyme Q (CoQ) is a powerful antioxidant found in all cell membranes which has an essential role in mitochondrial respiration and also has anti-inflammatory properties. NAFLD has been shown to be associated with disturbances in plasma and liver CoQ concentrations, but the relationship between these changes and disease development and progression is not yet clear. Dietary supplementation with CoQ has been found to be hepatoprotective and to reduce oxidative stress and inflammation as well as improving mitochondrial dysfunction, suggesting that it may be beneficial in NAFLD. However, studies using animal models or patients with NAFLD have given inconclusive results. Overall, evidence is now emerging to indicate that disturbances in CoQ metabolism are involved in NAFLD development and progression to NASH, and this highlights the need for further studies with human subjects to fully clarify its role. PMID- 26633475 TI - Maternal Low Quality Protein Diet Alters Plasma Amino Acid Concentrations of Weaning Rats. AB - Several studies have indicated the influence of a maternal low protein diet on the fetus. However, the effect of a maternal low quality protein diet on fetal growth and development is largely unknown. Wistar rats (11 weeks old) were mated and maintained on either a chow diet with 20% casein (n = 6) as the control group (C), or a low quality protein diet with 20% wheat gluten (n = 7) as the experimental group (WG) through gestation and lactation. Maternal body weights were similar in both groups throughout the study. Birth weights were not influenced by maternal diet and offspring body weights during lactation were similar between the groups. Offspring's plasma amino acid profiles showed that plasma methionine, glutamine and lysine were significantly lower and aspartic acid, ornithine and glycine-proline were significantly higher in the WG. Plant based protein comprises an important part of protein intake in developing countries. It is well-known that these diets can be inadequate in terms of essential amino acids. The current study shows differential effects of a maternal low quality protein diet on the offspring's plasma amino acids. Future studies will examine further aspects of the influence of maternal low quality protein diets on fetal growth and development. PMID- 26633476 TI - Study of Anti-Fatigue Effect in Rats of Ferrous Chelates Including Hairtail Protein Hydrolysates. AB - The ability of ferrous chelates including hairtail protein hydrolysates to prevent and reduce fatigue was studied in rats. After hydrolysis of hairtail surimi with papain, the hairtail protein hydrolysates (HPH) were separated into three groups by range of relative molecular weight using ultrafiltration membrane separation. Hairtail proteins were then chelated with ferrous ions, and the antioxidant activity, the amino acid composition and chelation rate of the three kinds of ferrous chelates including hairtail protein hydrolysates (Fe-HPH) were determined. Among the three groups, the Fe-HPH chelate showing the best conditions was selected for the anti-fatigue animal experiment. For it, experimental rats were randomly divided into seven groups. Group A was designated as the negative control group given distilled water. Group B, the positive control group, was given glutathione. Groups C, D and E were designated as the Fe HPH chelate treatment groups and given low, medium, and high doses, respectively. Group F was designated as HPH hydrolysate treatment group, and Group G was designated as FeCl2 treatment group. The different diets were orally administered to rats for 20 days. After that time, rats were subjected to forced swimming training after 1 h of gavage. Rats given Fe-FPH chelate had higher haemoglobin regeneration efficiency (HRE), longer exhaustive swimming time and higher SOD activity. Additionally, Fe-FPH chelate was found to significantly decrease the malondialdehyde content, visibly enhance the GSH-Px activity in liver and reduce blood lactic acid of rats. Fe-HPH chelate revealed an anti-fatigue effect, similar to or better than the positive control substance and superior to HPH or Fe when provided alone. PMID- 26633477 TI - Dietary Nitrates, Nitrites, and Nitrosamines Intake and the Risk of Gastric Cancer: A Meta-Analysis. AB - The potential associations between dietary consumption of nitrates, nitrites, and nitrosamines and gastric cancer risk have been investigated by several studies, but yielded inconclusive results. We conducted a meta-analysis to provide a quantitative assessment of their relationships. Relevant articles were identified by a systematic literature searching of PubMed and Embase databases prior to August 2015. Random-effects models were employed to pool the relative risks. A total of 22 articles consisting of 49 studies-19 studies for nitrates, 19 studies for nitrites, and 11 studies for N-nitrosodimethylamine (NDMA)-were included. The summary relative risk of stomach cancer for the highest categories, compared with the lowest, was 0.80 (95% confidence interval (CI), 0.69-0.93) for dietary nitrates intake, 1.31 (95% CI, 1.13-1.52) for nitrites, and 1.34 (95% CI, 1.02 1.76) for NDMA (p for heterogeneity was 0.015, 0.013 and <0.001, respectively). The study type was found as the main source of heterogeneity for nitrates and nitrites. The heterogeneity for NDMA could not be eliminated completely through stratified analysis. Although significant associations were all observed in case control studies, the cohort studies still showed a slight trend. The dose response analysis indicated similar results as well. High nitrates intake was associated with a weak but statistically significant reduced risk of gastric cancer. Whereas increased consumption of nitrites and NDMA seemed to be risk factors for cancer. Due to the lack of uniformity for exposure assessment across studies, further prospective researches are warranted to verify these findings. PMID- 26633478 TI - Recognising and Managing Refractory Coeliac Disease: A Tertiary Centre Experience. AB - Refractory coeliac disease (RCD) is a rare complication of coeliac disease (CD) and involves malabsorption and villous atrophy despite adherence to a strict gluten-free diet (GFD) for at least 12 months in the absence of another cause. RCD is classified based on the T-cells in the intra-epithelial lymphocyte (IEL) morphology into type 1 with normal IEL and type 2 with aberrant IEL (clonal) by PCR (polymerase chain reaction) for T cell receptors (TCR) at the beta/gamma loci. RCD type 1 is managed with strict nutritional and pharmacological management. RCD type 2 can be complicated by ulcerative jejunitis or enteropathy associated lymphoma (EATL), the latter having a five-year mortality of 50%. Management options for RCD type 2 and response to treatment differs across centres and there have been debates over the best treatment option. Treatment options that have been used include azathioprine and steroids, methotrexate, cyclosporine, campath (an anti CD-52 monoclonal antibody), and cladribine or fluadribine with or without autologous stem cell transplantation. We present a tertiary centre's experience in the treatment of RCD type 2 where treatment with prednisolone and azathioprine was used, and our results show good response with histological recovery in 56.6% of treated individuals. PMID- 26633479 TI - Greater Calcium Intake is Associated with Better Bone Health Measured by Quantitative Ultrasound of the Phalanges in Pediatric Patients Treated with Anticonvulsant Drugs. AB - We aimed to investigate and compare the effects of chronic antiepileptic therapy on bone health in pediatric patients using quantitative ultrasound of the phalanges (QUS) and controlling for potential confounding factors, particularly nutrient intake. The amplitude-dependent speed of sound (Ad-SoS) was measured in 33 epileptic children and 32 healthy children aged 6.5 +/- 3.1 and 6.3 +/- 1.1 (mean +/- SD) years, respectively. There were no significant differences in the demographics such as age, weight and height between epileptic children and the control group children. None of the children in the epileptic or the treatment group were found to have a vitamin D deficiency. There were no significant differences in laboratory tests between groups. Lower QUS figures were found in the epileptic children (p = 0.001). After further adjustment for potential confounders such age, height, weight, calcium intake, vitamin D intake, physical activity and sex, the differences remained significant (p < 0.001). After further classification of the participants based on the tertile of calcium intake, no significant differences were found between patients and healthy controls in the greatest tertile of calcium intake (p = 0.217). We conclude that anticonvulsant therapy using valproate may lead to low bone mass in children and that an adequate intake of calcium might counteract such deleterious effects. PMID- 26633480 TI - Gestational Vitamin 25(OH)D Status as a Risk Factor for Receptive Language Development: A 24-Month, Longitudinal, Observational Study. AB - Emerging data suggest that vitamin D status during childhood and adolescence can affect neurocognitive development. The purpose of this study was to investigate whether gestational 25(OH)D status is associated with early childhood cognitive and receptive language development. The Conditions Affecting Neurocognitive Development and Learning in Early Childhood Study (CANDLE) study enrolled 1503 mother-child dyads during the second trimester of healthy singleton pregnancies from Shelby County TN. Among 1020 participants of the total CANDLE cohort for whom 25(OH)D levels were available, mean gestational 25(OH)D level during the second trimester was 22.3 ng/mL (range 5.9-68.4), with 41.7% of values <20 ng/dL. Cognitive and language scaled scores increased in a stair-step manner as gestational 25(OH)D levels in the second trimester rose from <20 ng/dL, through 20-29.99 ng/dL, to >=30 ng/dL. When controlling for socioeconomic status, race, use of tobacco products, gestational age of the child at birth, and age at the 2 year assessment, the gestational 25(OH)D was positively related to receptive language development (p < 0.017), but not cognitive or expressive language. PMID- 26633481 TI - A Randomized Controlled Trial Investigating the Effects of a Special Extract of Bacopa monnieri (CDRI 08) on Hyperactivity and Inattention in Male Children and Adolescents: BACHI Study Protocol (ANZCTRN12612000827831). AB - Clinical diagnoses of Attention Deficit Hyperactivity Disorder (ADHD) and the use of prescription medications for its treatment have increased in recent years. Current treatments may involve the administration of amphetamine-type substances, a treatment path many parents are apprehensive to take. Therefore, alternative pharmacological treatments are required. Few nutritional or pharmacological alternatives that reduce ADHD associated symptoms (hyperactivity and inattention) have been subjected to rigorous clinical trials. Bacopa monnieri is a perennial creeping herb. CDRI 08 is a special extract of Bacopa monnieri which has been subjected to hundreds of scientific studies and has been shown in human randomized controlled trials (RCTs) to improve memory, attention, and mood. It is hypothesised that chronic administration of CDRI 08 will improve attention, concentration and behaviour in children with high levels of hyperactivity and/or inattention. This paper reports the protocol for the first 16-week, randomized, placebo-controlled, double-blind, parallel groups trial examining the efficacy and safety of CDRI 08 in male children aged 6-14 years with high levels of inattention and hyperactivity. The primary outcome variable will be the level of hyperactivity and inattention measured by the Conners' Parent Rating Scale (CPRS). Secondary outcome variables include cognition, mood, sleep, and EEG. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN12612000827831. PMID- 26633482 TI - Protective Effect of Vanillic Acid against Hyperinsulinemia, Hyperglycemia and Hyperlipidemia via Alleviating Hepatic Insulin Resistance and Inflammation in High-Fat Diet (HFD)-Fed Rats. AB - Excess free fatty acid accumulation from abnormal lipid metabolism results in the insulin resistance in peripheral cells, subsequently causing hyperinsulinemia, hyperglycemia and/or hyperlipidemia in diabetes mellitus (DM) patients. Herein, we investigated the effect of phenolic acids on glucose uptake in an insulin resistant cell-culture model and on hepatic insulin resistance and inflammation in rats fed a high-fat diet (HFD). The results show that vanillic acid (VA) demonstrated the highest glucose uptake ability among all tested phenolic acids in insulin-resistant FL83B mouse hepatocytes. Furthermore, rats fed HFD for 16 weeks were orally administered with VA daily (30 mg/kg body weight) at weeks 13 16. The results show that levels of serum insulin, glucose, triglyceride, and free fatty acid were significantly decreased in VA-treated HFD rats (p < 0.05), indicating the protective effects of VA against hyperinsulinemia, hyperglycemia and hyperlipidemia in HFD rats. Moreover, VA significantly reduced values of area under the curve for glucose (AUCglucose) in oral glucose tolerance test and homeostasis model assessment-insulin resistance (HOMA-IR) index, suggesting the improving effect on glucose tolerance and insulin resistance in HFD rats. The Western blot analysis revealed that VA significantly up-regulated expression of hepatic insulin-signaling and lipid metabolism-related protein, including insulin receptor, phosphatidylinositol-3 kinase, glucose transporter 2, and phosphorylated acetyl CoA carboxylase in HFD rats. VA also significantly down regulated hepatic inflammation-related proteins, including cyclooxygenase-2 and monocyte chemoattractant protein-1 expressions in HFD rats. These results indicate that VA might ameliorate insulin resistance via improving hepatic insulin signaling and alleviating inflammation pathways in HFD rats. These findings also suggest the potential of VA in preventing the progression of DM. PMID- 26633483 TI - An Assessment of the Potential Impact of Fortification of Staples and Condiments on Micronutrient Intake of Young Children and Women of Reproductive Age in Bangladesh. AB - Bangladesh has experienced rapid economic growth and achieved major health improvements in the past decade, but malnutrition rates remain high. A nationally representative study conducted in 2011 assessed the dietary habits of 841 children 24-59 months old; 1428 children 6-14 years old; and 1412 non-pregnant, non-lactating women. The study's objective was to assess dietary intakes of key micronutrients and the consumption pattern of potentially fortifiable foods, and then to model the potential impact of fortification of key staple foods. The current intakes of several micronutrients, namely, iron, zinc, folate, vitamin A and vitamin B12, were found to be insufficient to meet the needs of Bangladesh's children and women. The fortification of rice with iron and zinc and edible oil with vitamin A has the potential to fill a significant part of the nutrient gap, as these are consumed widely and in significant amounts. Wheat flour and sugar are not as promising food vehicles in the Bangladeshi context, as they were consumed by a smaller portion of the population and in smaller amounts. In conclusion, fortification of rice and oil is recommended to address the large gap in micronutrient intakes. PMID- 26633484 TI - High Prevalence of Vitamin D Deficiency in Infertile Women Referring for Assisted Reproduction. AB - A comprehensive analysis of the vitamin D status of infertile women is the first step in understanding hypovitaminosis impact on reproductive potential. We sought to determine vitamin D profiles of women attending an infertility center and to investigate non-dietary determinants of vitamin D status in this population. In this cross-sectional analysis, a cohort of 1072 women (mean age +/- standard deviation 36.3 +/- 4.4 years) attending an academic infertility center was used to examine serum 25-hydroxy-vitamin D (25(OH)D) levels in relation to demographic characteristics, seasons and general health risk factors. Both unadjusted and adjusted levels of serum 25(OH)D were examined. Median 25(OH)D concentration was below 30 ng/mL for 89% of the entire year. Over the whole year, 6.5% of patients had 25(OH)D levels <=10 ng/mL, 40.1% <=20 ng/mL, and 77.4% <=30 ng/mL. Global solar radiation was weakly correlated with 25(OH)D levels. At multivariable analysis, 25(OH)D levels were inversely associated with BMI; conversely, 25(OH)D levels were positively associated with height and endometriosis history. Serum 25(OH)D levels are highly deficient in women seeking medical help for couple's infertility. Levels are significantly associated with body composition, seasonal modifications and causes of infertility. Importantly, this deficiency status may last during pregnancy with more severe consequences. PMID- 26633485 TI - Growing Strong and Healthy with Mister Bone: An Educational Program to Have Strong Bones Later in Life. AB - Optimal peak bone mass and bone health later in life are favored by a sufficient calcium intake in infancy, childhood and adolescence. The purpose of this study was to test a new educational program created to monitor and to improve calcium and vitamin D intake in children. Nutritional habits in children were evaluated through a food frequency questionnaire (FFQ) to assess the intake of calcium, vitamin D, dairy products, and total caloric energy at baseline and after seven months of exposure to a unique educational program applied between November 2013 and May 2014 in 176 schoolchildren (48% male, 52% female) attending the fourth and fifth grades of two selected primary schools in Florence, Italy. A significant increase of calcium (from 870 +/- 190 to 1100 +/- 200 mg/day, p < 0.05), and vitamin D (from 3.6 +/- 1.53 to 4.1 +/- 2 ug/day) intake in children was documented after the educational program. The amount of specific foods important for bone health consumed, such as milk and vegetables, increased significantly, both in male and female children (p < 0.05). The proposed educational program appears to be effective in modifying calcium intake in children, with a significant increase in the consumption of dairy products and vegetables, but without a significant change in the total caloric intake. PMID- 26633486 TI - Proceedings of the 2015 Meeting of the Australasian Section of the American Oil Chemists' Society (AAOCS). PMID- 26633487 TI - Gliadin-Specific T-Cells Mobilized in the Peripheral Blood of Coeliac Patients by Short Oral Gluten Challenge: Clinical Applications. AB - Celiac disease (CD) is a common lifelong food intolerance triggered by dietary gluten affecting 1% of the general population. Gliadin-specific T-cell lines and T-cell clones obtained from intestinal biopsies have provided great support in the investigation of immuno-pathogenesis of CD. In the early 2000 a new in vivo, less invasive, approach was established aimed to evaluate the adaptive gliadin specific T-cell response in peripheral blood of celiac patients on a gluten free diet. In fact, it has been demonstrated that three days of ingestion of wheat containing food induces the mobilization of memory T lymphocytes reactive against gliadin from gut-associated lymphoid tissue into peripheral blood of CD patients. Such antigen-specific T-cells releasing interferon-gamma can be transiently detected by using the enzyme-linked immunospot (ELISPOT) assays or by flow cytometry tetramer technology. This paper discusses the suitability of this in vivo tool to investigate the repertoire of gluten pathogenic peptides, to support CD diagnosis, and to assess the efficacy of novel therapeutic strategies. A systematic review of all potential applications of short oral gluten challenge is provided. PMID- 26633488 TI - Concord Grape Juice Polyphenols and Cardiovascular Risk Factors: Dose-Response Relationships. AB - Pure fruit juices provide nutritional value with evidence suggesting some of their benefits on biomarkers of cardiovascular disease risk may be derived from their constituent polyphenols, particularly flavonoids. However, few data from clinical trials are available on the dose-response relationship of fruit juice flavonoids to these outcomes. Utilizing the results of clinical trials testing single doses, we have analyzed data from studies of 100% Concord grape juice by placing its flavonoid content in the context of results from randomized clinical trials of other polyphenol-rich foods and beverages describing the same outcomes but covering a broader range of intake. We selected established biomarkers determined by similar methods for measuring flow-mediated vasodilation (FMD), blood pressure, platelet aggregation, and the resistance of low density lipoprotein cholesterol (LDL) to oxidation. Despite differences among the clinical trials in the treatment, subjects, and duration, correlations were observed between the dose and FMD. Inverse dose-response relationships, albeit with lower correlation coefficients, were also noted for the other outcomes. These results suggest a clear relationship between consumption of even modest serving sizes of Concord grape juice, flavonoid intake, and effects on risk factors for cardiovascular disease. This approach to dose-response relationships may prove useful for testing other individual foods and beverages. PMID- 26633489 TI - Copper-2 Ingestion, Plus Increased Meat Eating Leading to Increased Copper Absorption, Are Major Factors Behind the Current Epidemic of Alzheimer's Disease. AB - It has become clear that copper toxicity is playing a major role in Alzheimer's disease; but why is the brain copper toxicity with cognition loss in Alzheimer's disease so much different clinically than brain copper toxicity in Wilson's disease, which results in a movement disorder? Furthermore, why is the inorganic copper of supplement pills and in drinking water so much more damaging to cognition than the organic copper in food? A recent paper, which shows that almost all food copper is copper-1, that is the copper-2 of foods reverts to the reduced copper-1 form at death or harvest, gives new insight into these questions. The body has an intestinal transport system for copper-1, Ctr1, which channels copper-1 through the liver and into safe channels. Ctr1 cannot absorb copper-2, and some copper-2 bypasses the liver, ends up in the blood quickly, and is toxic to cognition. Humans evolved to handle copper-1 safely, but not copper 2. Alzheimer's is at least in part, a copper-2 toxicity disease, while Wilson's is a general copper overload disease. In this review, we will show that the epidemiology of the Alzheimer's epidemic occurring in developed, but not undeveloped countries, fits with the epidemiology of exposure to copper-2 ingestion leached from copper plumbing and from copper supplement pill ingestion. Increased meat eating in developed countries is also a factor, because it increases copper absorption, and thus over all copper exposure. PMID- 26633490 TI - Anti-Diabetic Effects of Madecassic Acid and Rotundic Acid. AB - Anti-diabetic effects of madecassic acid (MEA) and rotundic acid (RA) were examined. MEA or RA at 0.05% or 0.1% was supplied to diabetic mice for six weeks. The intake of MEA, not RA, dose-dependently lowered plasma glucose level and increased plasma insulin level. MEA, not RA, intake dose-dependently reduced plasminogen activator inhibitor-1 activity and fibrinogen level; as well as restored antithrombin-III and protein C activities in plasma of diabetic mice. MEA or RA intake decreased triglyceride and cholesterol levels in plasma and liver. Histological data agreed that MEA or RA intake lowered hepatic lipid droplets, determined by ORO stain. MEA intake dose-dependently declined reactive oxygen species (ROS) and oxidized glutathione levels, increased glutathione content and maintained the activity of glutathione reductase and catalase in the heart and kidneys of diabetic mice. MEA intake dose-dependently reduced interleukin (IL)-1beta, IL-6, tumor necrosis factor-alpha and monocyte chemoattractant protein-1 levels in the heart and kidneys of diabetic mice. RA intake at 0.1% declined cardiac and renal levels of these inflammatory factors. These data indicated that MEA improved glycemic control and hemostatic imbalance, lowered lipid accumulation, and attenuated oxidative and inflammatory stress in diabetic mice. Thus, madecassic acid could be considered as an anti-diabetic agent. PMID- 26633491 TI - Processed Food Contributions to Energy and Nutrient Intake Differ among US Children by Race/Ethnicity. AB - This study determined and compared the mean daily intake of energy and nutrients from processed foods by level of processing (minimally processed; processed for preservation, nutrient enhancement, and freshness; mixtures of combined ingredients; ready-to-eat processed foods; and prepared foods/meals) among non Hispanic white, non-Hispanic black, and Mexican American US children. Data from participants 2-18 years old (n = 10,298) of the nationally representative cross sectional National Health and Nutrition Examination Survey 2003-2008 with a complete one day, 24-h dietary recall were used to determine mean intake of energy and nutrients recommended for increase and decrease, as per the 2010 Dietary Guidelines for Americans, among child race/ethnic groups by category of food processing. Regression analysis was used to estimate and compare covariate adjusted (gender, age, and poverty-income-level) least square means (p < 0.05/3 race/ethnic groups). All children, regardless of race or ethnicity consumed processed foods. Approximately 66% to 84% of total daily energy, saturated fat, cholesterol, fiber, total sugar, added sugars, calcium, vitamin D, potassium, and sodium intake are contributed by one of the five categories of processed foods. Clinicians and policy should primarily advise consideration of the energy and nutrient composition of foods, rather than the processing level, when selecting a healthy diet for children. PMID- 26633492 TI - Change in Metabolic Profile after 1-Year Nutritional-Behavioral Intervention in Obese Children. AB - Research findings are inconsistent about improvement of specific cardio-metabolic variables after lifestyle intervention in obese children. The aim of this trial was to evaluate the effect of a 1-year intervention, based on normocaloric diet and physical activity, on body mass index (BMI), blood lipid profile, glucose metabolism and metabolic syndrome. Eighty-five obese children aged >=6 years were analyzed. The BMI z-score was calculated. Fasting blood samples were analyzed for lipids, insulin and glucose. The homeostatic model assessment of insulin resistance (HOMA-IR) was calculated and insulin resistance was defined as HOMA-IR >3.16. HOMA-beta%, quantitative insulin sensitivity check index and triglyceride glucose index were calculated. The metabolic syndrome was defined in accordance with the International Diabetes Federation criteria. At the end of intervention children showed a reduction (mean (95% CI)) in BMI z-score (-0.58 (-0.66; 0.50)), triglycerides (-0.35 (-0.45; -0.25) mmol/L) and triglyceride glucose index (-0.29 (-0.37; -0.21)), and an increase in HDL cholesterol (0.06 (0.01; 0.11) mmol/L). Prevalence of insulin resistance declined from 51.8% to 36.5% and prevalence of metabolic syndrome from 17.1% to 4.9%. Nutritional-behavioral interventions can improve the blood lipid profile and insulin sensitivity in obese children, and possibly provide benefits in terms of metabolic syndrome. PMID- 26633493 TI - Single Nucleotide Polymorphisms in the FADS Gene Cluster but not the ELOVL2 Gene are Associated with Serum Polyunsaturated Fatty Acid Composition and Development of Allergy (in a Swedish Birth Cohort). AB - Exposure to polyunsaturated fatty acids (PUFA) influences immune function and may affect the risk of allergy development. Long chain PUFAs are produced from dietary precursors catalyzed by desaturases and elongases encoded by FADS and ELOVL genes. In 211 subjects, we investigated whether polymorphisms in the FADS gene cluster and the ELOVL2 gene were associated with allergy or PUFA composition in serum phospholipids in a Swedish birth-cohort sampled at birth and at 13 years of age; allergy was diagnosed at 13 years of age. Minor allele carriers of rs102275 and rs174448 (FADS gene cluster) had decreased proportions of 20:4 n-6 in cord and adolescent serum and increased proportions of 20:3 n-6 in cord serum as well as a nominally reduced risk of developing atopic eczema, but not respiratory allergy, at 13 years of age. Minor allele carriers of rs17606561 in the ELOVL2 gene had nominally decreased proportions of 20:4 n-6 in cord serum but ELOVL polymorphisms (rs2236212 and rs17606561) were not associated with allergy development. Thus, reduced capacity to desaturase n-6 PUFAs due to FADS polymorphisms was nominally associated with reduced risk for eczema development, which could indicate a pathogenic role for long-chain PUFAs in allergy development. PMID- 26633494 TI - Associations of Child Temperament with Child Overweight and Breakfast Habits: A Population Study in Five-Year-Olds. AB - This study examines the associations of child temperament with overweight/obesity and breakfast habits. Participants were 17,409 five-year-olds whose mothers partake in the Norwegian Mother and Child Cohort Study (MoBa), and completed a questionnaire at the child's 5th birthday. Temperament was assessed as externalizing, internalizing and sociable temperament. Breakfast habits differentiated between "every day", "4 to 6 times a week", and "0 to 3 times a week". The child's weight status was determined by Body Mass Index-percentiles and categorized as normal weight versus overweight/obese. Children with externalizing temperament had higher odds of being overweight and higher odds of not eating breakfast daily. Children high in internalizing temperament had higher odds of not eating breakfast daily, but not of being overweight. Children with average scores of sociability were more prone to being overweight but had normal breakfast habits. All results were adjusted for key confounders. That five-year olds high in externalizing temperament had a higher risk to be overweight adds important information to the literature. The association of externalizing temperament with child breakfast habits so early in life is intriguing, as parents mostly control eating patterns in children that young. Mechanisms mediating this association should be explored. PMID- 26633495 TI - Recent Advances in Research on Widow Spider Venoms and Toxins. AB - Widow spiders have received much attention due to the frequently reported human and animal injures caused by them. Elucidation of the molecular composition and action mechanism of the venoms and toxins has vast implications in the treatment of latrodectism and in the neurobiology and pharmaceutical research. In recent years, the studies of the widow spider venoms and the venom toxins, particularly the alpha-latrotoxin, have achieved many new advances; however, the mechanism of action of the venom toxins has not been completely clear. The widow spider is different from many other venomous animals in that it has toxic components not only in the venom glands but also in other parts of the adult spider body, newborn spiderlings, and even the eggs. More recently, the molecular basis for the toxicity outside the venom glands has been systematically investigated, with four proteinaceous toxic components being purified and preliminarily characterized, which has expanded our understanding of the widow spider toxins. This review presents a glance at the recent advances in the study on the venoms and toxins from the Latrodectus species. PMID- 26633496 TI - Use of Monoclonal Antibodies in the Sensitive Detection and Neutralization of Botulinum Neurotoxin Serotype B. AB - Botulinum neurotoxins (BoNT) are some of nature's most potent toxins. Due to potential food contamination, and bioterrorism concerns, the development of detection reagents, therapeutics and countermeasures are of urgent interest. Recently, we have developed a sensitive electrochemiluminescent (ECL) immunoassay for BoNT/B, using monoclonal antibodies (mAbs) MCS6-27 and anti-BoNT/B rabbit polyclonal antibodies as the capture and detector. The ECL assay detected as little as 1 pg/mL BoNT/B in the buffer matrix, surpassing the detection sensitivities of the gold standard mouse bioassays. The ECL assay also allowed detection of BoNT/B in sera matrices of up to 100% sera with negligible matrix effects. This highly-sensitive assay allowed the determination of the biological half-lives of BoNT/B holotoxin in vivo. We further tested the toxin neutralization potential of our monoclonal antibodies using the mouse systemic and oral intoxication models. A combination of mAbs protected mice in both pre- and post-exposure models to lethal doses of BoNT/B. MAbs were capable of increasing survival of animals when administered even 10 h post-intoxication in an oral model, suggesting a likely time for BoNT/B complexes to reach the blood stream. More sensitive detection assays and treatments against BoNT intoxication will greatly enhance efforts to combat botulism. PMID- 26633497 TI - Biodegradation of Ochratoxin A by Bacterial Strains Isolated from Vineyard Soils. AB - Ochratoxin A (OTA) is a mycotoxin with a main nephrotoxic activity contaminating several foodstuffs. In the present report, five soil samples collected from OTA contaminated vineyards were screened to isolate microorganisms able to biodegrade OTA. When cultivated in OTA-supplemented medium, OTA was converted in OTalpha by 225 bacterial isolates. To reveal clonal relationships between isolates, molecular typing by using an automated rep-PCR system was carried out, thus showing the presence of 27 different strains (rep-PCR profiles). The 16S-rRNA gene sequence analysis of an isolate representative of each rep-PCR profiles indicated that they belonged to five bacterial genera, namely Pseudomonas, Leclercia, Pantoea, Enterobacter, and Acinetobacter. However, further evaluation of OTA-degrading activity by the 27 strains revealed that only Acinetobacter calcoaceticus strain 396.1 and Acinetobacter sp. strain neg1, consistently conserved the above property; their further characterization showed that they were able to convert 82% and 91% OTA into OTalpha in six days at 24 degrees C, respectively. The presence of OTalpha, as the unique OTA-degradation product was confirmed by LC-HRMS. This is the first report on OTA biodegradation by bacterial strains isolated from agricultural soils and carried out under aerobic conditions and moderate temperatures. These microorganisms might be used to detoxify OTA contaminated feed and could be a new source of gene(s) for the development of a novel enzymatic detoxification system. PMID- 26633498 TI - Comments on Ekino et al. Cloning and Characterization of a Unique Cytotoxic Protein Parasporin-5 Produced by Bacillus thuringiensis A1100 Strain. Toxins 2014, 6, 1882-1895. PMID- 26633499 TI - Response to Leopoldo Palma. Comments on Ekino et al. Cloning and Characterization of a Unique Cytotoxic Protein Parasporin-5 Produced by Bacillus thuringiensis A1100 Strain. Toxins 2014, 6, 1882-1895. PMID- 26633500 TI - A Venom Gland Extracellular Chitin-Binding-Like Protein from Pupal Endoparasitoid Wasps, Pteromalus Puparum, Selectively Binds Chitin. AB - Chitin-binding proteins (CBPs) are present in many species and they act in a variety of biological processes. We analyzed a Pteromalus puparum venom apparatus proteome and transcriptome and identified a partial gene encoding a possible CBP. Here, we report cloning a full-length cDNA of a sequence encoding a chitin binding-like protein (PpCBP) from P. puparum, a pupal endoparasitoid of Pieris rapae. The cDNA encoded a 96-amino-acid protein, including a secretory signal peptide and a chitin-binding peritrophin-A domain. Phylogenetic analysis of chitin binding domains (CBDs) of cuticle proteins and peritrophic matrix proteins in selected insects revealed that the CBD of PpCBP clustered with the CBD of Nasonia vitripennis. The PpCBP is specifically expressed in the venom apparatus of P. puparum, mostly in the venom gland. PpCBP expression was highest at day one after adult eclosion and much lower for the following five days. We produced a recombinant PpCBP and binding assays showed the recombinant protein selectively binds chitin but not cellulose in vitro. We infer that PpCBP serves a structural role in the venom reservoir, or may be injected into the host to help wound healing of the host exoskeleton. PMID- 26633501 TI - Biological and Enzymatic Characterization of Proteases from Crude Venom of the Ant Odontomachus bauri. AB - Hymenoptera venoms constitute an interesting source of natural toxins that may lead to the development of novel therapeutic agents. The present study investigated the enzymatic and biological characteristics of the crude venom of the ant Odontomachus bauri. Its crude venom presents several protein bands, with higher staining for six proteins with gelatinolytic activity (17, 20, 26, 29, 43 and 48 kDa). The crude venom showed high proteolytic activity on azocasein at optimal pH 8.0 and 37 degrees C. In the presence of protease inhibitors as aprotinin, leupeptin and EDTA, the azocaseinolytic activity was reduced by 45%, 29% and 9%, respectively, suggesting that the enzymes present in the crude venom belong to the three classes of proteases, with the serine proteases in greater intensity. The crude venom degraded the fibrinogen alpha-chain faster than the beta-chain, while the fibrinogen gamma-chain remained unchanged. In biological assays, O. bauri venom showed hemolytic and coagulant activity in vitro, and defibrinating activity in vivo. In addition, the venom showed antimicrobial activity against Staphylococcus aureus and Escherichia coli as well as antiparasitic activity on Toxoplasma gondii infection in vitro. In that sense, this study sheds perspectives for pharmacological applications of O. bauri venom enzymes. PMID- 26633502 TI - Temporal Variation and Association of Aflatoxin B1 Albumin-Adduct Levels with Socio-Economic and Food Consumption Factors in HIV Positive Adults. AB - The association between aflatoxin exposure and alteration in immune responses observed in humans suggest that aflatoxin could suppress the immune system and work synergistically with HIV to increase disease severity and progression to AIDS. No longitudinal study has been conducted to assess exposure to aflatoxin (AF) among HIV positive individuals. We examined temporal variation in AFB1 albumin adducts (AF-ALB) in HIV positive Ghanaians, and assessed the association with socioeconomic and food consumption factors. We collected socioeconomic and food consumption data for 307 HIV positive antiretroviral naive adults and examined AF-ALB levels at recruitment (baseline) and at six (follow-up 1) and 12 (follow-up 2) months post-recruitment, by age, gender, socioeconomic status (SES) and food consumption patterns. Generalized linear models were used to examine the influence of socioeconomic and food consumption factors on changes in AF-ALB levels over the study period, adjusting for other covariates. AF-ALB levels (pg/mg albumin) were lower at baseline (mean AF-ALB: 14.9, SD: 15.9), higher at six months (mean AF-ALB: 23.3, SD: 26.6), and lower at 12 months (mean AF-ALB: 15.3, SD: 15.4). Participants with the lowest SES had the highest AF-ALB levels at baseline and follow up-2 compared with those with higher SES. Participants who bought less than 20% of their food and who stored maize for less than two months had lower AF-ALB levels. In the adjusted models, there was a statistically significant association between follow up time and season (dry or rainy season) on AF-ALB levels over time (p = 0.04). Asymptomatic HIV-positive Ghanaians had high plasma AF-ALB levels that varied according to season, socioeconomic status, and food consumption patterns. Steps need to be taken to ensure the safety and security of the food supply for the population, but in particular for the most vulnerable groups such as HIV positive people. PMID- 26633503 TI - Assimilation, Accumulation, and Metabolism of Dinophysistoxins (DTXs) and Pectenotoxins (PTXs) in the Several Tissues of Japanese Scallop Patinopecten yessoensis. AB - Japanese scallops, Patinopecten yessoensis, were fed with the toxic dinoflagellate Dinophysis fortii to elucidate the relative magnitude of assimilation, accumulation, and metabolism of diarrhetic shellfish toxins (DSTs) and pectenotoxins (PTXs). Three individual scallops were separately exposed to cultured D. fortii for four days. The average cell number of D. fortii assimilated by each individual scallop was 7.7 * 105. Dinophysistoxin-1 (DTX1), pectenotoxin-2 (PTX2) and their metabolites were analyzed by liquid chromatography tandem mass spectrometry (LC/MS/MS) and the toxin content in individual tissues (digestive gland, adductor muscle, gill, gonad, mantle, and the others), feces and the seawater medium were quantified. Toxins were almost exclusively accumulated in the digestive gland with only low levels being detected in the gills, mantles, gonads, and adductor muscles. DTX1 and PTX2 were the dominant toxins in the D. fortii cells fed to the scallops, whereas the dominant toxins detected in the digestive gland of scallops were PTX6 and esterified acyl-O-DTX1 (DTX3). In other tissues PTX2 was the dominant toxin observed. The ratio of accumulated to assimilated toxins was 21%-39% and 7%-23% for PTXs and DTXs respectively. Approximately 54%-75% of PTX2 and 52%-70% of DTX1 assimilated by the scallops was directly excreted into the seawater mainly without metabolic transformation. PMID- 26633504 TI - Interaction of Citrinin with Human Serum Albumin. AB - Citrinin (CIT) is a mycotoxin produced by several Aspergillus, Penicillium, and Monascus species. CIT occurs worldwide in different foods and drinks and causes health problems for humans and animals. Human serum albumin (HSA) is the most abundant plasma protein in human circulation. Albumin forms stable complexes with many drugs and xenobiotics; therefore, HSA commonly plays important role in the pharmacokinetics or toxicokinetics of numerous compounds. However, the interaction of CIT with HSA is poorly characterized yet. In this study, the complex formation of CIT with HSA was investigated using fluorescence spectroscopy and ultrafiltration techniques. For the deeper understanding of the interaction, thermodynamic, and molecular modeling studies were performed as well. Our results suggest that CIT forms stable complex with HSA (logK ~ 5.3) and its primary binding site is located in subdomain IIA (Sudlow's Site I). In vitro cell experiments also recommend that CIT-HSA interaction may have biological relevance. Finally, the complex formations of CIT with bovine, porcine, and rat serum albumin were investigated, in order to test the potential species differences of CIT-albumin interactions. PMID- 26633505 TI - Risk Assessment of Deoxynivalenol by Revisiting Its Bioavailability in Pig and Rat Models to Establish Which Is More Suitable. AB - Due to its toxic properties, high stability, and prevalence, the presence of deoxynivalenol (DON) in the food chain is a major threat to food safety and therefore a health risk for both humans and animals. In this study, experiments were carried out with sows and female rats to examine the kinetics of DON after intravenous and oral administration at 100 ug/kg of body weight. After intravenous administration of DON in pigs, a two-compartment model with rapid initial distribution (0.030 +/- 0.019 h) followed by a slower terminal elimination phase (1.53 +/- 0.54 h) was fitted to the concentration profile of DON in pig plasma. In rats, a short elimination half-life (0.46 h) and a clearance of 2.59 L/h/kg were estimated by sparse sampling non-compartmental analysis. Following oral exposure, DON was rapidly absorbed and reached maximal plasma concentrations (Cmax) of 42.07 +/- 8.48 and 10.44 +/- 5.87 ug/L plasma after (t(max)) 1.44 +/- 0.52 and 0.17 h in pigs and rats, respectively. The mean bioavailability of DON was 70.5% +/- 25.6% for pigs and 47.3% for rats. In the framework of DON risk assessment, these two animal models could be useful in an exposure scenario in two different ways because of their different bioavailability. PMID- 26633506 TI - Phylloseptin-PBa--A Novel Broad-Spectrum Antimicrobial Peptide from the Skin Secretion of the Peruvian Purple-Sided Leaf Frog (Phyllomedusa Baltea) Which Exhibits Cancer Cell Cytotoxicity. AB - Antimicrobial peptides from amphibian skin secretion display remarkable broad spectrum antimicrobial activity and are thus promising for the discovery of new antibiotics. In this study, we report a novel peptide belonging to the phylloseptin family of antimicrobial peptides, from the skin secretion of the purple-sided leaf frog, Phyllomedusa baltea, which was named Phylloseptin-PBa. Degenerate primers complementary to putative signal peptide sites of frog skin peptide precursor-encoding cDNAs were designed to interrogate a skin secretion derived cDNA library from this frog. Subsequently, the peptide was isolated and identified using reverse phase HPLC and MS/MS fragmentation. The synthetic replicate was demonstrated to have activity against S. aureus, E. coli and C. albicans at concentrations of 8, 128 and 8 mg/L, respectively. In addition, it exhibited anti-proliferative activity against the human cancer cell lines, H460, PC3 and U251MG, but was less active against a normal human cell line (HMEC). Furthermore, a haemolysis assay was performed to assess mammalian cell cytotoxicity of Phylloseptin-PBa. This peptide contained a large proportion of alpha-helical domain, which may explain its antimicrobial and anticancer activities. PMID- 26633507 TI - Computational Studies of Venom Peptides Targeting Potassium Channels. AB - Small peptides isolated from the venom of animals are potential scaffolds for ion channel drug discovery. This review article mainly focuses on the computational studies that have advanced our understanding of how various toxins interfere with the function of K+ channels. We introduce the computational tools available for the study of toxin-channel interactions. We then discuss how these computational tools have been fruitfully applied to elucidate the mechanisms of action of a wide range of venom peptides from scorpions, spiders, and sea anemone. PMID- 26633508 TI - MC-LR Exposure Leads to Subfertility of Female Mice and Induces Oxidative Stress in Granulosa Cells. AB - Health risk of human exposure to microcystin-leucine arginine (MC-LR) has aroused more and more attention over the past few decades. In the present study, MC-LR was orally administered to female mice at 0, 1, 10 and 40 MUg/L for three and six months. We found that chronic exposure to MC-LR at environmental levels could stimulate follicle atresia and lead to decreased developmental follicles, accompanied by a reduction of gonadosomatic index (GSI). In line with the irregular gonadal hormone level and estrus cycles, subfertility of female mice was also confirmed by analyzing numbers of litters and pups. The in vitro study suggested that granulosa cells could uptake MC-LR and should be the target of the toxicant. Oxidative stress in granulose cells induced by MC-LR promoted follicle atresia and eventually leads to female subfertility. PMID- 26633509 TI - Multi-Toxic Endpoints of the Foodborne Mycotoxins in Nematode Caenorhabditis elegans. AB - Aflatoxins B1 (AFB1), deoxynivalenol (DON), fumonisin B1 (FB1), T-2 toxin (T-2), and zearalenone (ZEA) are the major foodborne mycotoxins of public health concerns. In the present study, the multiple toxic endpoints of these naturally occurring mycotoxins were evaluated in Caenorhabditis elegans model for their lethality, toxic effects on growth and reproduction, as well as influence on lifespan. We found that the lethality endpoint was more sensitive for T-2 toxicity with the EC50 at 1.38 mg/L, the growth endpoint was relatively sensitive for AFB1 toxic effects, and the reproduction endpoint was more sensitive for toxicities of AFB1, FB1, and ZEA. Moreover, the lifespan endpoint was sensitive to toxic effects of all five tested mycotoxins. Data obtained from this study may serve as an important contribution to knowledge on assessment of mycotoxin toxic effects, especially for assessing developmental and reproductive toxic effects, using the C. elegans model. PMID- 26633510 TI - Mass Spectrometry-Based Method of Detecting and Distinguishing Type 1 and Type 2 Shiga-Like Toxins in Human Serum. AB - Shiga-like toxins (verotoxins) are responsible for the virulence associated with a variety of foodborne bacterial pathogens. Direct detection of toxins requires a specific and sensitive technique. In this study, we describe a mass spectrometry based method of analyzing the tryptic decapeptides derived from the non-toxic B subunits. A gene encoding a single protein that yields a set of relevant peptides upon digestion with trypsin was designed. The (15)N-labeled protein was prepared by growing the expressing bacteria in minimal medium supplemented with (15)NH4Cl. Trypsin digestion of the (15)N-labeled protein yields a set of (15)N-labeled peptides for use as internal standards to identify and quantify Shiga or Shiga like toxins. We determined that this approach can be used to detect, quantify and distinguish among the known Shiga toxins (Stx) and Shiga-like toxins (Stx1 and Stx2) in the low attomole range (per injection) in complex media, including human serum. Furthermore, Stx1a could be detected and distinguished from the newly identified Stx1e in complex media. As new Shiga-like toxins are identified, this approach can be readily modified to detect them. Since intact toxins are digested with trypsin prior to analysis, the handling of intact Shiga toxins is minimized. The analysis can be accomplished within 5 h. PMID- 26633511 TI - The Role of Rho GTPases in Toxicity of Clostridium difficile Toxins. AB - Clostridium difficile (C. difficile) is the main cause of antibiotic-associated diarrhea prevailing in hospital settings. In the past decade, the morbidity and mortality of C. difficile infection (CDI) has increased significantly due to the emergence of hypervirulent strains. Toxin A (TcdA) and toxin B (TcdB), the two exotoxins of C. difficile, are the major virulence factors of CDI. The common mode of action of TcdA and TcdB is elicited by specific glucosylation of Rho GTPase proteins in the host cytosol using UDP-glucose as a co-substrate, resulting in the inactivation of Rho proteins. Rho proteins are the key members in many biological processes and signaling pathways, inactivation of which leads to cytopathic and cytotoxic effects and immune responses of the host cells. It is supposed that Rho GTPases play an important role in the toxicity of C. difficile toxins. This review focuses on recent progresses in the understanding of functional consequences of Rho GTPases glucosylation induced by C. difficile toxins and the role of Rho GTPases in the toxicity of TcdA and TcdB. PMID- 26633512 TI - Membrane-Binding Mechanism of Clostridium perfringens Alpha-Toxin. AB - Clostridium perfringens alpha-toxin is a key mediator of gas gangrene, which is a life-threatening infection that manifests as fever, pain, edema, myonecrosis, and gas production. Alpha-toxin possesses phospholipase C and sphingomyelinase activities. The toxin is composed of an N-terminal domain (1-250 aa, N-domain), which is the catalytic site, and a C-terminal domain (251-370 aa, C-domain), which is the membrane-binding site. Immunization of mice with the C-domain of alpha-toxin prevents the gas gangrene caused by C. perfringens, whereas immunization with the N-domain has no effect. The central loop domain (55-93 aa), especially H....SW(84)Y(85)....G, plays an important role in the interaction with ganglioside GM1a. The toxin binds to lipid rafts in the presence of a GM1a/TrkA complex, and metabolites from phosphatidylcholine to diacylglycerol through the enzymatic activity of alpha-toxin itself. These membrane dynamics leads to the activation of endogenous PLCgamma-1 via TrkA. In addition, treatment with alpha toxin leads to the formation of diacylglycerol at membrane rafts in ganglioside deficient DonQ cells; this in turn triggers endocytosis and cell death. This article summarizes the current the membrane-binding mechanism of alpha-toxin in detail. PMID- 26633513 TI - Aberrant GLI1 Activation in DNA Damage Response, Carcinogenesis and Chemoresistance. AB - The canonical hedgehog (HH) pathway is a multicomponent signaling cascade (HH, protein patched homolog 1 (PTCH1), smoothened (SMO)) that plays a pivotal role during embryonic development through activation of downstream effector molecules, namely glioma-associated oncogene homolog 1 (GLI1), GLI2 and GLI3. Activation of GLIs must be tightly regulated as they modulate target genes which control tissue patterning, stem cell maintenance, and differentiation during development. However, dysregulation or mutations in HH signaling leads to genomic instability (GI) and various cancers, for example, germline mutation in PTCH1 lead to Gorlin syndrome, a condition where patients develop numerous basal cell carcinomas and rarely rhabdomyosarcoma (RMS). Activating mutations in SMO have also been recognized in sporadic cases of medulloblastoma and SMO is overexpressed in many other cancers. Recently, studies in several human cancers have shown that GLI1 expression is independent from HH ligand and canonical intracellular signaling through PTCH and SMO. In fact, this aberrantly regulated GLI1 has been linked to several non-canonical oncogenic growth signals such as Kirsten rat sarcoma viral oncogene homolog (KRAS), avian myelocytomatosis virus oncogene cellular homolog (C-MYC), transforming growth factor beta (TGFbeta), wingless-type MMTV integration site family (WNT) and beta-catenin. Recent studies from our lab and other independent studies demonstrate that aberrantly expressed GLI1 influences the integrity of several DNA damage response and repair signals, and if altered, these networks can contribute to GI and impact tumor response to chemo- and radiation therapies. Furthermore, the ineffectiveness of SMO inhibitors in clinical studies argues for the development of GLI1-specific inhibitors in order to develop effective therapeutic modalities to treat these tumors. In this review, we focus on summarizing current understanding of the molecular, biochemical and cellular basis for aberrant GLI1 expression and discuss GLI1 mediated HH signaling on DNA damage responses, carcinogenesis and chemoresistance. PMID- 26633514 TI - The Microenvironment in Gliomas: Phenotypic Expressions. AB - The microenvironment of malignant gliomas is described according to its definition in the literature. Beside tumor cells, a series of stromal cells (microglia/macrophages, pericytes, fibroblasts, endothelial cells, normal and reactive astrocytes) represents the cell component, whereas a complex network of molecular signaling represents the functional component. Its most evident expressions are perivascular and perinecrotic niches that are believed to be the site of tumor stem cells or progenitors in the tumor. Phenotypically, both niches are not easily recognizable; here, they are described together with a critical revision of their concept. As for perinecrotic niches, an alternative interpretation is given about their origin that regards the tumor stem cells as the residue of those that populated hyperproliferating areas in which necroses develop. This is based on the concept that the stem-like is a status and not a cell type, depending on the microenvironment that regulates a conversion of tumor non-stem cells and tumor stem cells through a cell reprogramming. PMID- 26633515 TI - Paclitaxel Through the Ages of Anticancer Therapy: Exploring Its Role in Chemoresistance and Radiation Therapy. AB - Paclitaxel (Taxol((r))) is a member of the taxane class of anticancer drugs and one of the most common chemotherapeutic agents used against many forms of cancer. Paclitaxel is a microtubule-stabilizer that selectively arrests cells in the G2/M phase of the cell cycle, and found to induce cytotoxicity in a time and concentration-dependent manner. Paclitaxel has been embedded in novel drug formulations, including albumin and polymeric micelle nanoparticles, and applied to many anticancer treatment regimens due to its mechanism of action and radiation sensitizing effects. Though paclitaxel is a major anticancer drug which has been used for many years in clinical treatments, its therapeutic efficacy can be limited by common encumbrances faced by anticancer drugs. These encumbrances include toxicities, de novo refraction, and acquired multidrug resistance (MDR). This article will give a current and comprehensive review of paclitaxel, beginning with its unique history and pharmacology, explore its mechanisms of drug resistance and influence in combination with radiation therapy, while highlighting current treatment regimens, formulations, and new discoveries. PMID- 26633516 TI - Molecular and Cytogenetic Characterization of New Wheat-Dasypyrum breviaristatum Derivatives with Post-Harvest Re-Growth Habit. AB - A novel Dasypyrum species, Dasypyrum breviaristatum, serves as a valuable source of useful genes for wheat improvement. The development and characterization of new wheat-D. breviaristatum introgression lines is important to determine the novel gene(s) on specific chromosome(s). We first used multi-color fluorescence in situ hybridization (FISH) to identify the individual D. breviaristatum V(b) chromosomes in a common wheat-D. breviaristatum partial amphiploid, TDH-2. The FISH patterns of D. breviaristatum chromosomes were different from those of D. villosum chromosomes. Lines D2146 and D2150 were selected from a cross between wheat line MY11 and wheat-D. breviaristatum partial amphiploid TDH-2, and they were characterized by FISH and PCR-based molecular markers. We found that D2150 was a monosomic addition line for chromosome 5V(b) of D. breviaristatum, while D2146 had the 5V(b)L chromosome arm translocated with wheat chromosome 5AS. Molecular marker analysis confirmed that the introduced D. breviaristatum chromosome 5V(b)L translocation possessed a duplicated region homoeologous to 5AS, revealing that the 5AS.5V(b)L translocation may not functionally compensate well. The dwarfing and the pre-harvest re-growth habits observed in the wheat-D. breviaristatum chromosome 5V(b) derivatives may be useful for future development of perennial growth wheat lines. PMID- 26633517 TI - Daptomycin-Nonsusceptible Staphylococcus aureus: The Role of Combination Therapy with Daptomycin and Gentamicin. AB - Reduced susceptibility to daptomycin in Staphylococcus aureus has now been described, leading to clinical failures. Here we determined the impact of daptomycin and gentamicin combination therapy on bactericidal activity and resistance emergence using daptomycin-susceptible and -resistant isolates with mutations linked to previous daptomycin or vancomycin exposure. Enhanced killing of S. aureus was observed when gentamicin was combined with daptomycin, most commonly with daptomycin concentrations below the peak serum free-drug concentrations achieved with standard dosing. Synergy was seen with daptomycin susceptible isolates and with isolates resistant to vancomycin and daptomycin. Combination therapy also prevented the emergence of resistance. Daptomycin and gentamicin combination therapy may provide the synergy required to prevent emergence of resistance when daptomycin levels are below peak serum concentrations as would be found in deep-seated, complicated infections. PMID- 26633518 TI - Origins and Early Evolution of the tRNA Molecule. AB - Modern transfer RNAs (tRNAs) are composed of ~76 nucleotides and play an important role as "adaptor" molecules that mediate the translation of information from messenger RNAs (mRNAs). Many studies suggest that the contemporary full length tRNA was formed by the ligation of half-sized hairpin-like RNAs. A minihelix (a coaxial stack of the acceptor stem on the T-stem of tRNA) can function both in aminoacylation by aminoacyl tRNA synthetases and in peptide bond formation on the ribosome, indicating that it may be a vestige of the ancestral tRNA. The universal CCA-3' terminus of tRNA is also a typical characteristic of the molecule. "Why CCA?" is the fundamental unanswered question, but several findings give a comprehensive picture of its origin. Here, the origins and early evolution of tRNA are discussed in terms of various perspectives, including nucleotide ligation, chiral selectivity of amino acids, genetic code evolution, and the organization of the ribosomal peptidyl transferase center (PTC). The proto-tRNA molecules may have evolved not only as adaptors but also as contributors to the composition of the ribosome. PMID- 26633520 TI - Early Onset of Laying and Bumblefoot Favor Keel Bone Fractures. AB - Numerous studies have demonstrated influences of hybrid, feed, and housing on prevalence of keel bone fractures, but influences of behavior and production on an individual level are less known. In this longitudinal study, 80 white and brown laying hens were regularly checked for keel bone deviations and fractures while egg production was individually monitored using Radio Frequency Identification (RFID) from production until depopulation at 65 weeks of age. These focal birds were kept in eight pens with 20 hens per pen in total. About 62% of the hens had broken keel bones at depopulation. The occurrence of new fractures was temporally linked to egg laying: more new fractures occurred during the time when laying rates were highest. Hens with fractured keel bones at depopulation had laid their first egg earlier than hens with intact keel bones. However, the total number of eggs was neither correlated with the onset of egg laying nor with keel bone fractures. All birds with bumblefoot on both feet had a fracture at depopulation. Hens stayed in the nest for a longer time during egg laying during the ten days after the fracture than during the ten days before the fracture. In conclusion, a relationship between laying rates and keel bone fractures seems likely. PMID- 26633521 TI - A Review of Different Stunning Methods for Poultry-Animal Welfare Aspects (Stunning Methods for Poultry). AB - Electrical water bath stunning is the most commonly used method for poultry stunning prior to slaughter, but has been questioned on animal welfare and product quality grounds. Controlled atmosphere stunning (CAS) methods, involving a variety of gas mixtures, have become increasingly common, at least in Europe. CAS methods have been perceived as an improvement from an animal welfare perspective, partly because birds can be stunned without prior shackling, and are generally considered to result in improved product quality compared to water bath stunning. However, there would still be an interest in alternative stunning methods especially for small to medium size poultry slaughterhouses. This review presents an overview of the modes of action and the technical aspects of poultry stunning methods, including novel and emerging stunning technologies. PMID- 26633522 TI - Artificially Increased Yolk Hormone Levels and Neophobia in Domestic Chicks. AB - In birds there is compelling evidence that the development and expression of behavior is affected by maternal factors, particularly via variation in yolk hormone concentrations of maternal origin. In the present study we tested whether variation in yolk hormone levels lead to variation in the expression of neophobia in young domestic chicks. Understanding how the prenatal environment could predispose chicks to express fear-related behaviors is essential in order to propose preventive actions and improve animal welfare. We simulated the consequences of a maternal stress by experimentally enhancing yolk progesterone, testosterone and estradiol concentrations in hen eggs prior to incubation. The chicks from these hormone-treated eggs (H) and from sham embryos (C) that received the vehicle-only were exposed to novel food, novel object and novel environment tests. H chicks approached a novel object significantly faster and were significantly more active in a novel environment than controls, suggesting less fearfulness. Conversely, no effect of the treatment was found in food neophobia tests. Our study highlights a developmental influence of yolk hormones on a specific aspect of neophobia. The results suggest that increased yolk hormone levels modulate specifically the probability of exploring novel environments or novel objects in the environment. PMID- 26633523 TI - How Farm Animals React and Perceive Stressful Situations Such As Handling, Restraint, and Transport. AB - An animal that has been carefully acclimated to handling may willingly re-enter a restrainer. Another animal may have an intense agitated behavioral reaction or refuse to re-enter the handling facility. Physiological measures of stress such as cortisol may be very low in the animal that re-enters willingly and higher in animals that actively resist restraint. Carefully acclimating young animals to handling and restraint can help improve both productivity and welfare by reducing fear stress. Some of the topics covered in this review are: How an animal perceives handling and restraint, the detrimental effects of a sudden novel event, descriptions of temperament and aversion tests and the importance of good stockmanship. PMID- 26633519 TI - Antimicrobial Mechanisms of Macrophages and the Immune Evasion Strategies of Staphylococcus aureus. AB - Habitually professional phagocytes, including macrophages, eradicate microbial invaders from the human body without overt signs of infection. Despite this, there exist select bacteria that are professional pathogens, causing significant morbidity and mortality across the globe and Staphylococcus aureus is no exception. S. aureus is a highly successful pathogen that can infect virtually every tissue that comprises the human body causing a broad spectrum of diseases. The profound pathogenic capacity of S. aureus can be attributed, in part, to its ability to elaborate a profusion of bacterial effectors that circumvent host immunity. Macrophages are important professional phagocytes that contribute to both the innate and adaptive immune response, however from in vitro and in vivo studies, it is evident that they fail to eradicate S. aureus. This review provides an overview of the antimicrobial mechanisms employed by macrophages to combat bacteria and describes the immune evasion strategies and some representative effectors that enable S. aureus to evade macrophage-mediated killing. PMID- 26633524 TI - Preliminary Validation and Reliability Testing of the Montreal Instrument for Cat Arthritis Testing, for Use by Veterinarians, in a Colony of Laboratory Cats. AB - Subtle signs and conflicting physical and radiographic findings make feline osteoarthritis (OA) challenging to diagnose. A physical examination-based assessment was developed, consisting of eight items: Interaction, Exploration, Posture, Gait, Body Condition, Coat and Claws, (joint) Palpation-Findings, and Palpation-Cat Reaction. Content (experts) and face (veterinary students) validity were excellent. Construct validity, internal consistency, and intra- and inter rater reliability were assessed via a pilot and main study, using laboratory housed cats with and without OA. Gait distinguished OA status in the pilot ( p = 0.05) study. In the main study, no scale item achieved statistically significant OA detection. Forelimb peak vertical ground reaction force (PVF) correlated inversely with Gait (Rho s = -0.38 ( p = 0.03) to -0.41 ( p = 0.02)). Body Posture correlated with Gait, and inversely with forelimb PVF at two of three time points (Rho s = -0.38 ( p = 0.03) to -0.43 ( p = 0.01)). Palpation (Findings, Cat Reaction) did not distinguish OA from non-OA cats. Palpation-Cat Reaction (Forelimbs) correlated inversely with forelimb PVF at two time points (Rho s = -0.41 ( p = 0.02) to -0.41 ( p = 0.01)), but scores were highly variable, and poorly reliable. Gait and Posture require improved sensitivity, and Palpation should be interpreted cautiously, in diagnosing feline OA. PMID- 26633527 TI - Immune Response of Multiparous Hyper-Immunized Sows against Peptides from Non Structural and Structural Proteins of PRRSV. AB - The purpose of this study was to evaluate the humoral and cellular responses of commercial multiparous and hyper-immunized sows against peptides from non structural (nsp) and structural proteins of porcine reproductive and respiratory syndrome virus (PRRSV). We selected sows with different numbers of parities from a commercial farm. Management practices on this farm include the use of the MLV commercial vaccine four times per year, plus two vaccinations during the acclimation period. The humoral response was evaluated via the antibody recognition of peptides from nsp and structural proteins, and the cellular response was assessed by measuring the frequency of peptide and PRRSV-specific IFN-gamma-secreting cells (IFNgamma-SC). Our results show that sows with six parities have more antibodies against peptides from structural proteins than against peptides from nsp. The analysis of the cellular response revealed that the number of immunizations did not affect the frequency of IFNgamma-SC and that the response was stronger against peptides from structural proteins (M protein) than against nsp (nsp2). In summary, these results demonstrate that multiparous, hyper-immunized sows have a stronger immune humoral response to PRRSV structural peptides than nsp, but no differences in IFNgamma-SC against the same peptides were observed. PMID- 26633525 TI - Models and Methods to Investigate Acute Stress Responses in Cattle. AB - There is a growing appreciation within the livestock industry and throughout society that animal stress is an important issue that must be addressed. With implications for animal health, well-being, and productivity, minimizing animal stress through improved animal management procedures and/or selective breeding is becoming a priority. Effective management of stress, however, depends on the ability to identify and quantify the effects of various stressors and determine if individual or combined stressors have distinct biological effects. Furthermore, it is critical to determine the duration of stress-induced biological effects if we are to understand how stress alters animal production and disease susceptibility. Common stress models used to evaluate both psychological and physical stressors in cattle are reviewed. We identify some of the major gaps in our knowledge regarding responses to specific stressors and propose more integrated methodologies and approaches to measuring these responses. These approaches are based on an increased knowledge of both the metabolic and immune effects of stress. Finally, we speculate on how these findings may impact animal agriculture, as well as the potential application of large animal models to understanding human stress. PMID- 26633528 TI - Synthesis and Characterization of Cellulose-Based Hydrogels to Be Used as Gel Electrolytes. AB - Cellulose-based hydrogels, obtained by tuned, low-cost synthetic routes, are proposed as convenient gel electrolyte membranes. Hydrogels have been prepared from different types of cellulose by optimized solubilization and crosslinking steps. The obtained gel membranes have been characterized by infrared spectroscopy, scanning electron microscopy, thermogravimetric analysis, and mechanical tests in order to investigate the crosslinking occurrence and modifications of cellulose resulting from the synthetic process, morphology of the hydrogels, their thermal stability, and viscoelastic-extensional properties, respectively. Hydrogels liquid uptake capability and ionic conductivity, derived from absorption of aqueous electrolytic solutions, have been evaluated, to assess the successful applicability of the proposed membranes as gel electrolytes for electrochemical devices. To this purpose, the redox behavior of electroactive species entrapped into the hydrogels has been investigated by cyclic voltammetry tests, revealing very high reversibility and ion diffusivity. PMID- 26633526 TI - Pedunculopontine Gamma Band Activity and Development. AB - This review highlights the most important discovery in the reticular activating system in the last 10 years, the manifestation of gamma band activity in cells of the reticular activating system (RAS), especially in the pedunculopontine nucleus, which is in charge of waking and rapid eye movement (REM) sleep. The identification of different cell groups manifesting P/Q-type Ca(2+) channels that control waking vs. those that manifest N-type channels that control REM sleep provides novel avenues for the differential control of waking vs. REM sleep. Recent discoveries on the development of this system can help explain the developmental decrease in REM sleep and the basic rest-activity cycle. PMID- 26633529 TI - The Position of Abeta22-40 and Abeta1-42 in Anionic Lipid Membranes Containing Cholesterol. AB - Amyloid-beta peptides interact with cell membranes in the human brain and are associated with neurodegenerative diseases, such as Alzheimer's disease. An emerging explanation of the molecular mechanism, which results in neurodegeneration, places the cause of neurotoxicity of the amyloid- peptides on their potentially negative interaction with neuronal membranes. It is known that amyloid-beta peptides interact with the membrane, modifying the membrane's structural and dynamic properties. We present a series of X-ray diffraction experiments on anionic model lipid membranes containing various amounts of cholesterol. These experiments provide experimental evidence for an interaction of both the full length amyloid-beta1-42 peptide, and the peptide fragment amyloid-beta22-40 with anionic bilayer containing cholesterol. The location of the amyloid-beta peptides was determined from these experiments, with the full length peptide embedding into the membrane, and the peptide fragment occupying 2 positions-on the membrane surface and embedded into the membrane core. PMID- 26633530 TI - Co-Utilization of Glucose and Xylose for Enhanced Lignocellulosic Ethanol Production with Reverse Membrane Bioreactors. AB - Integrated permeate channel (IPC) flat sheet membranes were examined for use as a reverse membrane bioreactor (rMBR) for lignocellulosic ethanol production. The fermenting organism, Saccharomyces cerevisiae (T0936), a genetically-modified strain with the ability to ferment xylose, was used inside the rMBR. The rMBR was evaluated for simultaneous glucose and xylose utilization as well as in situ detoxification of furfural and hydroxylmethyl furfural (HMF). The synthetic medium was investigated, after which the pretreated wheat straw was used as a xylose-rich lignocellulosic substrate. The IPC membrane panels were successfully used as the rMBR during the batch fermentations, which lasted for up to eight days without fouling. With the rMBR, complete glucose and xylose utilization, resulting in 86% of the theoretical ethanol yield, was observed with the synthetic medium. Its application with the pretreated wheat straw resulted in complete glucose consumption and 87% xylose utilization; a final ethanol concentration of 30.3 g/L was obtained, which corresponds to 83% of the theoretical yield. Moreover, complete in situ detoxification of furfural and HMF was obtained within 36 h and 60 h, respectively, with the rMBR. The use of the rMBR is a promising technology for large-scale lignocellulosic ethanol production, since it facilitates the co-utilization of glucose and xylose; moreover, the technology also allows the reuse of the yeast for several batches. PMID- 26633531 TI - Claudin 1 in Breast Cancer: New Insights. AB - Claudin 1 is a small transmembrane protein responsible for maintaining the barrier function that exists between epithelial cells. A tight junction protein that regulates the paracellular transport of small ions across adjacent cells, claudin 1 maintains cellular polarity and plays a major role in cell-cell communication and epithelial cell homeostasis. Long considered to be a putative tumor suppressor in human breast cancer, new studies suggest a role much more complex. While most invasive breast cancers exhibit a down regulation or absence of claudin 1, some aggressive subtypes that exhibit high claudin 1 levels have now been described. Furthermore, a causal role for claudin 1 in breast cancer progression has recently been demonstrated in some breast cancer cell lines. In this review we highlight new insights into the role of claudin 1 in breast cancer, including its involvement in collective migration and epithelial mesenchymal transition (EMT). PMID- 26633532 TI - Microfluidic Impedimetric Cell Regeneration Assay to Monitor the Enhanced Cytotoxic Effect of Nanomaterial Perfusion. AB - In the last decade, the application of nanomaterials (NMs) in technical products and biomedicine has become a rapidly increasing market trend. As the safety and efficacy of NMs are of utmost importance, new methods are needed to study the dynamic interactions of NMs at the nano-biointerface. However, evaluation of NMs based on standard and static cell culture end-point detection methods does not provide information on the dynamics of living biological systems, which is crucial for the understanding of physiological responses. To bridge this technological gap, we here present a microfluidic cell culture system containing embedded impedance microsensors to continuously and non-invasively monitor the effects of NMs on adherent cells under varying flow conditions. As a model, the impact of silica NMs on the vitality and regenerative capacity of human lung cells after acute and chronic exposure scenarios was studied over an 18-h period following a four-hour NM treatment. Results of the study demonstrated that the developed system is applicable to reliably analyze the consequences of dynamic NM exposure to physiological cell barriers in both nanotoxicology and nanomedicine. PMID- 26633533 TI - Fish Peroxiredoxins and Their Role in Immunity. AB - Peroxiredoxins (Prxs) are a family of antioxidant enzymes that protect cells from oxidative damage. In addition, Prxs may act as modulators of inflammation, protect against cell death and tumour progression, and facilitate tissue repair after damage. The most studied roles of Prx1 and Prx2 are immunological. Here we present a review on the effects of some immunostimulant treatments and bacterial, viral, or parasitic infections on the expression of fish Prxs at the gene and/or protein level, and point to their important role in immunity. The Prxs show antioxidant activity as well as a protective effect against infection. Some preliminary data are presented about the role of fish Prx1 and Prx2 in virus resistance although further studies are needed before the role of fish Prx in immunity can be definitively defined. PMID- 26633534 TI - Biology of Bony Fish Macrophages. AB - Macrophages are found across all vertebrate species, reside in virtually all animal tissues, and play critical roles in host protection and homeostasis. Various mechanisms determine and regulate the highly plastic functional phenotypes of macrophages, including antimicrobial host defenses (pro inflammatory, M1-type), and resolution and repair functions (anti inflammatory/regulatory, M2-type). The study of inflammatory macrophages in immune defense of teleosts has garnered much attention, and antimicrobial mechanisms of these cells have been extensively studied in various fish models. Intriguingly, both similarities and differences have been documented for the regulation of lower vertebrate macrophage antimicrobial defenses, as compared to what has been described in mammals. Advances in our understanding of the teleost macrophage M2 phenotypes likewise suggest functional conservation through similar and distinct regulatory strategies, compared to their mammalian counterparts. In this review, we discuss the current understanding of the molecular mechanisms governing teleost macrophage functional heterogeneity, including monopoetic development, classical macrophage inflammatory and antimicrobial responses as well as alternative macrophage polarization towards tissues repair and resolution of inflammation. PMID- 26633536 TI - VGLUTs and Glutamate Synthesis-Focus on DRG Neurons and Pain. AB - The amino acid glutamate is the principal excitatory transmitter in the nervous system, including in sensory neurons that convey pain sensation from the periphery to the brain. It is now well established that a family of membrane proteins, termed vesicular glutamate transporters (VGLUTs), serve a critical function in these neurons: they incorporate glutamate into synaptic vesicles. VGLUTs have a central role both under normal neurotransmission and pathological conditions, such as neuropathic or inflammatory pain. In the present short review, we will address VGLUTs in the context of primary afferent neurons. We will focus on the role of VGLUTs in pain triggered by noxious stimuli, peripheral nerve injury, and tissue inflammation, as mostly explored in transgenic mice. The possible interplay between glutamate biosynthesis and VGLUT-dependent packaging in synaptic vesicles, and its potential impact in various pain states will be presented. PMID- 26633537 TI - Examination of the Fractalkine and Fractalkine Receptor Expression in Fallopian Adenocarcinoma Reveals Differences When Compared to Ovarian Carcinoma. AB - Fallopian adenocarcinoma is a rare malignancy arising in the epithelium of the fallopian tube. Fallopian tube epithelium has been proposed as a tissue origin for high-grade serous ovarian carcinoma, the deadliest gynecologic malignancy. Given the commonalities in dissemination and treatment of these malignancies, we contemplated the possibility of similar patterns of gene expression underlying their progression. To reveal potential similarities or differences in the gene expression of fallopian adenocarcinoma and high-grade serous ovarian carcinoma, we tested expression of the fractalkine receptor (CX3CR1) and its ligand, fractalkine (CX3CL1), in the specimens of normal and pathologic fallopian tube using immunohistochemistry. Our data show that CX3CR1 is expressed in the normal, cancer adjacent normal, inflammatory, and malignant fallopian epithelium. CX3CL1 was expressed only by the normal and cancer adjacent normal fallopian tube epithelium; its expression was largely lost in the inflammatory and malignant fallopian epithelium. In opposite, both CX3CR1 and CX3CL1 are expressed in high grade serous ovarian carcinoma. These findings are consistent with an idea that fallopian adenocarcinoma and high-grade serous ovarian carcinoma, although currently thought to arise from the same organ, may not share similar molecular characteristics. PMID- 26633535 TI - A Novel Aspect of Tumorigenesis-BMI1 Functions in Regulating DNA Damage Response. AB - BMI1 plays critical roles in maintaining the self-renewal of hematopoietic, neural, intestinal stem cells, and cancer stem cells (CSCs) for a variety of cancer types. BMI1 promotes cell proliferative life span and epithelial to mesenchymal transition (EMT). Upregulation of BMI1 occurs in multiple cancer types and is associated with poor prognosis. Mechanistically, BMI1 is a subunit of the Polycomb repressive complex 1 (PRC1), and binds the catalytic RING2/RING1b subunit to form a functional E3 ubiquitin ligase. Through mono-ubiquitination of histone H2A at lysine 119 (H2A-K119Ub), BMI1 represses multiple gene loci; among these, the INK4A/ARF locus has been most thoroughly investigated. The locus encodes the p16INK4A and p14/p19ARF tumor suppressors that function in the pRb and p53 pathways, respectively. Its repression contributes to BMI1-derived tumorigenesis. BMI1 also possesses other oncogenic functions, specifically its regulative role in DNA damage response (DDR). In this process, BMI1 ubiquitinates histone H2A and gammaH2AX, thereby facilitating the repair of double-stranded DNA breaks (DSBs) through stimulating homologous recombination and non-homologous end joining. Additionally, BMI1 compromises DSB-induced checkpoint activation independent of its-associated E3 ubiquitin ligase activity. We review the emerging role of BMI1 in DDR regulation and discuss its impact on BMI1-derived tumorigenesis. PMID- 26633538 TI - Mast Cell Proteases 6 and 7 Stimulate Angiogenesis by Inducing Endothelial Cells to Release Angiogenic Factors. AB - Mast cell proteases are thought to be involved with tumor progression and neo vascularization. However, their exact role is still unclear. The present study was undertaken to further elucidate the function of specific subtypes of recombinant mouse mast cell proteases (rmMCP-6 and 7) in neo-vascularization. SVEC4-10 cells were cultured on Geltrex(r) with either rmMCP-6 or 7 and tube formation was analyzed by fluorescence microscopy and scanning electron microscopy. Additionally, the capacity of these proteases to induce the release of angiogenic factors and pro and anti-angiogenic proteins was analyzed. Both rmMCP-6 and 7 were able to stimulate tube formation. Scanning electron microscopy showed that incubation with the proteases induced SVEC4-10 cells to invade the gel matrix. However, the expression and activity of metalloproteases were not altered by incubation with the mast cell proteases. Furthermore, rmMCP-6 and rmMCP-7 were able to induce the differential release of angiogenic factors from the SVEC4-10 cells. rmMCP-7 was more efficient in stimulating tube formation and release of angiogenic factors than rmMCP-6. These results suggest that the subtypes of proteases released by mast cells may influence endothelial cells during in vivo neo-vascularization. PMID- 26633539 TI - Genotypic Diversity within a Single Pseudomonas aeruginosa Strain Commonly Shared by Australian Patients with Cystic Fibrosis. AB - In cystic fibrosis (CF), Pseudomonas aeruginosa undergoes intra-strain genotypic and phenotypic diversification while establishing and maintaining chronic lung infections. As the clinical significance of these changes is uncertain, we investigated intra-strain diversity in commonly shared strains from CF patients to determine if specific gene mutations were associated with increased antibiotic resistance and worse clinical outcomes. Two-hundred-and-one P. aeruginosa isolates (163 represented a dominant Australian shared strain, AUST-02) from two Queensland CF centres over two distinct time-periods (2001-2002 and 2007-2009) underwent mexZ and lasR sequencing. Broth microdilution antibiotic susceptibility testing in a subset of isolates was also performed. We identified a novel AUST-02 subtype (M3L7) in adults attending a single Queensland CF centre. This M3L7 subtype was multi-drug resistant and had significantly higher antibiotic minimum inhibitory concentrations than other AUST-02 subtypes. Prospective molecular surveillance using polymerase chain reaction assays determined the prevalence of the 'M3L7' subtype at this centre during 2007-2009 (170 patients) and 2011 (173 patients). Three-year clinical outcomes of patients harbouring different strains and subtypes were compared. MexZ and LasR sequences from AUST-02 isolates were more likely in 2007-2009 than 2001-2002 to exhibit mutations (mexZ: odds ratio (OR) = 3.8; 95% confidence interval (CI): 1.1-13.5 and LasR: OR = 2.5; 95%CI: 1.3 5.0). Surveillance at the adult centre in 2007-2009 identified M3L7 in 28/509 (5.5%) P. aeruginosa isolates from 13/170 (7.6%) patients. A repeat survey in 2011 identified M3L7 in 21/519 (4.0%) P. aeruginosa isolates from 11/173 (6.4%) patients. The M3L7 subtype was associated with greater intravenous antibiotic and hospitalisation requirements, and a higher 3-year risk of death/lung transplantation, than other AUST-02 subtypes (adjusted hazard ratio [HR] = 9.4; 95%CI: 2.2-39.2) and non-AUST-02 strains (adjusted HR = 4.8; 95%CI: 1.4-16.2). This suggests ongoing microevolution of the shared CF strain, AUST-02, was associated with an emerging multi-drug resistant subtype and possibly poorer clinical outcomes. PMID- 26633540 TI - Systematic Structural Analyses of Attachment Organelle in Mycoplasma pneumoniae. AB - Mycoplasma pneumoniae, a human pathogenic bacterium, glides on host cell surfaces by a unique and unknown mechanism. It forms an attachment organelle at a cell pole as a membrane protrusion composed of surface and internal structures, with a highly organized architecture. In the present study, we succeeded in isolating the internal structure of the organelle by sucrose-gradient centrifugation. The negative-staining electron microscopy clarified the details and dimensions of the internal structure, which is composed of terminal button, paired plates, and bowl complex from the end of cell front. Peptide mass fingerprinting of the structure suggested 25 novel components for the organelle, and 3 of them were suggested for their involvement in the structure through their subcellular localization determined by enhanced yellow fluorescent protein (EYFP) tagging. Thirteen component proteins including the previously reported ones were mapped on the organelle systematically for the first time, in nanometer order by EYFP tagging and immunoelectron microscopy. Two, three, and six specific proteins localized specifically to the terminal button, the paired plates, and the bowl, respectively and interestingly, HMW2 molecules were aligned parallel to form the plate. The integration of these results gave the whole image of the organelle and allowed us to discuss possible gliding mechanisms. PMID- 26633541 TI - Subvalvular Pannus Overgrowth after Mosaic Bioprosthesis Implantation in the Aortic Position. AB - PURPOSE: Although pannus overgrowth by itself was not the pathology of structural valve deterioration (SVD), it might be related to reoperation for SVD of the bioprostheses. METHODS: We retrospectively reviewed patients undergoing reoperation for SVD after implantation of the third-generation Mosaic aortic bioprosthesis and macroscopic appearance of the explanted valves was examined to detect the presence of pannus. RESULTS: There were 10 patients and the age for the initial aortic valve replacement was 72 +/- 10 years old. The duration of durability was 9.9 +/- 2.0 years. Deteriorated valve presented stenosis (valvular area of 0.96 +/- 0.20 cm(2); pressure gradient of 60 +/- 23 mmHg). Coexisting regurgitant flow was detected in two cases. Macroscopically, subvalvular pannus overgrowth was detected in 8 cases (80%). The proportion of overgrowth from the annulus was almost even and pannus overgrowth created subvalvular membrane, which restricted the area especially for each commissure. In contrast, opening and mobility of each leaflet was not severely limited and pannus overgrowth would restrict the area, especially for each commissure. In other two cases with regurgitation, tear of the leaflet on the stent strut was detected and mild calcification of each leaflet restricted opening. CONCLUSION: In patients with the Mosaic aortic bioprosthesis, pannus overgrowth was the major cause for reoperation. PMID- 26633543 TI - Economic evaluation of whole-genome sequencing in healthy individuals: what can we learn from CEAs of whole-body CT screening? PMID- 26633542 TI - Clinical application of whole-exome sequencing across clinical indications. AB - PURPOSE: We report the diagnostic yield of whole-exome sequencing (WES) in 3,040 consecutive cases at a single clinical laboratory. METHODS: WES was performed for many different clinical indications and included the proband plus two or more family members in 76% of cases. RESULTS: The overall diagnostic yield of WES was 28.8%. The diagnostic yield was 23.6% in proband-only cases and 31.0% when three family members were analyzed. The highest yield was for patients who had disorders involving hearing (55%, N = 11), vision (47%, N = 60), the skeletal muscle system (40%, N = 43), the skeletal system (39%, N = 54), multiple congenital anomalies (36%, N = 729), skin (32%, N = 31), the central nervous system (31%, N = 1,082), and the cardiovascular system (28%, N = 54). Of 2,091 cases in which secondary findings were analyzed for 56 American College of Medical Genetics and Genomics-recommended genes, 6.2% (N = 129) had reportable pathogenic variants. In addition to cases with a definitive diagnosis, in 24.2% of cases a candidate gene was reported that may later be reclassified as being associated with a definitive diagnosis. CONCLUSION: Our experience with our first 3,040 WES cases suggests that analysis of trios significantly improves the diagnostic yield compared with proband-only testing for genetically heterogeneous disorders and facilitates identification of novel candidate genes.Genet Med 18 7, 696-704. PMID- 26633544 TI - The global prevalence of HFE and non-HFE hemochromatosis estimated from analysis of next-generation sequencing data. AB - PURPOSE: The prevalence of HFE-related hereditary hemochromatosis (HH) among European populations has been well studied. There are no prevalence data for atypical forms of HH caused by mutations in HFE2, HAMP, TFR2, or SLC40A1. The purpose of this study was to estimate the population prevalence of these non-HFE forms of HH. METHODS: A list of HH pathogenic variants in publically available next-generation sequence (NGS) databases was compiled and allele frequencies were determined. RESULTS: Of 161 variants previously associated with HH, 43 were represented among the NGS data sets; an additional 40 unreported functional variants also were identified. The predicted prevalence of HFE HH and the p.Cys282Tyr mutation closely matched previous estimates from similar populations. Of the non-HFE forms of iron overload, TFR2-, HFE2-, and HAMP-related forms are predicted to be rare, with pathogenic allele frequencies in the range of 0.00007 to 0.0005. Significantly, SLC40A1 variants that have been previously associated with autosomal-dominant ferroportin disease were identified in several populations (pathogenic allele frequency 0.0004), being most prevalent among Africans. CONCLUSION: We have, for the first time, estimated the population prevalence of non-HFE HH. This methodology could be applied to estimate the population prevalence of a wide variety of genetic disorders.Genet Med 18 6, 618 626. PMID- 26633545 TI - Molecular diagnostic experience of whole-exome sequencing in adult patients. AB - PURPOSE: Whole-exome sequencing (WES) is increasingly used as a diagnostic tool in medicine, but prior reports focus on predominantly pediatric cohorts with neurologic or developmental disorders. We describe the diagnostic yield and characteristics of WES in adults. METHODS: We performed a retrospective analysis of consecutive WES reports for adults from a diagnostic laboratory. Phenotype composition was determined using Human Phenotype Ontology terms. RESULTS: Molecular diagnoses were reported for 17.5% (85/486) of adults, which is lower than that for a primarily pediatric population (25.2%; P = 0.0003); the diagnostic rate was higher (23.9%) for those 18-30 years of age compared to patients older than 30 years (10.4%; P = 0.0001). Dual Mendelian diagnoses contributed to 7% of diagnoses, revealing blended phenotypes. Diagnoses were more frequent among individuals with abnormalities of the nervous system, skeletal system, head/neck, and growth. Diagnostic rate was independent of family history information, and de novo mutations contributed to 61.4% of autosomal dominant diagnoses. CONCLUSION: Early WES experience in adults demonstrates molecular diagnoses in a substantial proportion of patients, informing clinical management, recurrence risk, and recommendations for relatives. A positive family history was not predictive, consistent with molecular diagnoses often revealed by de novo events, informing the Mendelian basis of genetic disease in adults.Genet Med 18 7, 678-685. PMID- 26633547 TI - Generating and evaluating evidence of the clinical utility of molecular diagnostic tests in oncology. AB - PURPOSE: Enthusiasm for molecular diagnostic (MDx) testing in oncology is constrained by the gaps in required evidence regarding its impact on patient outcomes (clinical utility (CU)). This effectiveness guidance document proposes recommendations for the design and evaluation of studies intended to reflect the evidence expectations of payers, while also reflecting information needs of patients and clinicians. METHODS: Our process included literature reviews and key informant interviews followed by iterative virtual and in-person consultation with an expert technical working group and an advisory group comprising life sciences industry experts, public and private payers, patients, clinicians, regulators, researchers, and other stakeholders. RESULTS: Treatment decisions in oncology represent high-risk clinical decision making, and therefore the recommendations give preference to randomized controlled trials (RCTs) for demonstrating CU. The guidance also describes circumstances under which alternatives to RCTs could be considered, specifying conditions under which test developers could use prospective-retrospective studies with banked biospecimens, single-arm studies, prospective observational studies, or decision-analytic modeling techniques that make a reasonable case for CU. CONCLUSION: Using a process driven by multiple stakeholders, we developed a common framework for designing and evaluating studies of the clinical validity and CU of MDx tests, achieving a balance between internal validity of the studies and the relevance, feasibility, and timeliness of generating the desired evidence.Genet Med 18 8, 780-787. PMID- 26633546 TI - Accelerating matchmaking of novel dysmorphology syndromes through clinical and genomic characterization of a large cohort. AB - PURPOSE: Dysmorphology syndromes are among the most common referrals to clinical genetics specialists. Inability to match the dysmorphology pattern to a known syndrome can pose a major diagnostic challenge. With an aim to accelerate the establishment of new syndromes and their genetic etiology, we describe our experience with multiplex consanguineous families that appeared to represent novel autosomal recessive dysmorphology syndromes at the time of evaluation. METHODS: Combined autozygome/exome analysis of multiplex consanguineous families with apparently novel dysmorphology syndromes. RESULTS: Consistent with the apparent novelty of the phenotypes, our analysis revealed a strong candidate variant in genes that were novel at the time of the analysis in the majority of cases, and 10 of these genes are published here for the first time as novel candidates (CDK9, NEK9, ZNF668, TTC28, MBL2, CADPS, CACNA1H, HYAL2, CTU2, and C3ORF17). A significant minority of the phenotypes (6/31, 19%), however, were caused by genes known to cause Mendelian phenotypes, thus expanding the phenotypic spectrum of the diseases linked to these genes. The conspicuous inheritance pattern and the highly specific phenotypes appear to have contributed to the high yield (90%) of plausible molecular diagnoses in our study cohort. CONCLUSION: Reporting detailed clinical and genomic analysis of a large series of apparently novel dysmorphology syndromes will likely lead to a trend to accelerate the establishment of novel syndromes and their underlying genes through open exchange of data for the benefit of patients, their families, health care providers, and the research community.Genet Med 18 7, 686-695. PMID- 26633548 TI - Observed and expected frequencies of structural hemoglobin variants in newborn screening surveys in Africa and the Middle East: deviations from Hardy-Weinberg equilibrium. AB - PURPOSE: Our objective was to compare observed and expected genotype proportions from newborn screening surveys of structural hemoglobin variants. METHODS: We conducted a systematic review of newborn screening surveys of hemoglobins S and C in Africa and the Middle East. We compared observed frequencies to those expected assuming Hardy-Weinberg equilibrium (HWE). Significant deviations were identified by an exact test. The fixation index FIS was calculated to assess excess homozygosity. We compared newborn estimates corrected and uncorrected for HWE deviations using demographic data. RESULTS: Sixty samples reported genotype counts for hemoglobin variants in Africa and the Middle East. Observed and expected counts matched in 27%. The observed number of sickle cell anemia (SCA) individuals was higher than expected in 42 samples, reaching significance (P < 0.05) in 24. High FIS values were common across the study regions. The estimated total number of newborns with SCA, corrected based on FIS, was 33,261 annual births instead of 24,958 for the 38 samples across sub-Saharan Africa and 1,109 annual births instead of 578 for 12 samples from the Middle East. CONCLUSION: Differences between observed and expected genotype frequencies are common in surveys of hemoglobin variants in the study regions. Further research is required to identify and quantify factors responsible for such deviations. Estimates based on HWE might substantially underestimate the annual number of SCA-affected newborns (up to one-third in sub-Saharan Africa and one-half in the Middle East). PMID- 26633549 TI - Absolute Quantification of Human Liver Phosphorus-Containing Metabolites In Vivo Using an Inhomogeneous Spoiling Magnetic Field Gradient. AB - PURPOSE: Absolute concentrations of high-energy phosphorus (31P) metabolites in liver provide more important insight into physiologic status of liver disease compared to resonance integral ratios. A simple method for measuring absolute concentrations of 31P metabolites in human liver is described. The approach uses surface spoiling inhomogeneous magnetic field gradient to select signal from liver tissue. The technique avoids issues caused by respiratory motion, chemical shift dispersion associated with linear magnetic field gradients, and increased tissue heat deposition due to radiofrequency absorption, especially at high field strength. METHODS: A method to localize signal from liver was demonstrated using superficial and highly non-uniform magnetic field gradients, which eliminate signal(s) from surface tissue(s) located between the liver and RF coil. A double standard method was implemented to determine absolute 31P metabolite concentrations in vivo. 8 healthy individuals were examined in a 3 T MR scanner. RESULTS: Concentrations of metabolites measured in eight healthy individuals are: gamma-adenosine triphosphate (ATP) = 2.44 +/- 0.21 (mean +/- sd) mmol/l of wet tissue volume, alpha-ATP = 3.2 +/- 0.63 mmol/l, beta-ATP = 2.98 +/- 0.45 mmol/l, inorganic phosphates (Pi) = 1.87 +/- 0.25 mmol/l, phosphodiesters (PDE) = 10.62 +/- 2.20 mmol/l and phosphomonoesters (PME) = 2.12 +/- 0.51 mmol/l. All are in good agreement with literature values. CONCLUSIONS: The technique offers robust and fast means to localize signal from liver tissue, allows absolute metabolite concentration determination, and avoids problems associated with constant field gradient (linear field variation) localization methods. PMID- 26633550 TI - Trehalose Accumulation Triggers Autophagy during Plant Desiccation. AB - Global climate change, increasingly erratic weather and a burgeoning global population are significant threats to the sustainability of future crop production. There is an urgent need for the development of robust measures that enable crops to withstand the uncertainty of climate change whilst still producing maximum yields. Resurrection plants possess the unique ability to withstand desiccation for prolonged periods, can be restored upon watering and represent great potential for the development of stress tolerant crops. Here, we describe the remarkable stress characteristics of Tripogon loliiformis, an uncharacterised resurrection grass and close relative of the economically important cereals, rice, sorghum, and maize. We show that T. loliiformis survives extreme environmental stress by implementing autophagy to prevent Programmed Cell Death. Notably, we identified a novel role for trehalose in the regulation of autophagy in T.loliiformis. Transcriptome, Gas Chromatography Mass Spectrometry, immunoblotting and confocal microscopy analyses directly linked the accumulation of trehalose with the onset of autophagy in dehydrating and desiccated T. loliiformis shoots. These results were supported in vitro with the observation of autophagosomes in trehalose treated T. loliiformis leaves; autophagosomes were not detected in untreated samples. Presumably, once induced, autophagy promotes desiccation tolerance in T.loliiformis, by removal of cellular toxins to suppress programmed cell death and the recycling of nutrients to delay the onset of senescence. These findings illustrate how resurrection plants manipulate sugar metabolism to promote desiccation tolerance and may provide candidate genes that are potentially useful for the development of stress tolerant crops. PMID- 26633551 TI - Anaemia and low body mass index are associated with increased cardiovascular disease in patients with Takayasu arteritis. AB - OBJECTIVES: Despite the high prevalence of cardiovascular disease (CVD) among patients with Takayasu arteritis (TA), few studies have identified its clinical correlates. The aim of this study was to analyse the prevalence of CVD and its association with traditional CV risk factors and disease-related variables in patients with TA. METHODS: A total of 262 consecutive patients with a diagnosis of TA between January 2009 and July 2013 were included in this study. The primary outcome was CVD, defined as the presence of a previous history of myocardial infarction, angina, coronary disease, coronary bypass surgery, coronary angioplasty, and stroke. Multivariate logistic regression analysis was used to determine the relationship of conventional CV risk factors and TA-related variables to the presence of CVD. RESULTS: CVD was present in 64 (24.4%) of patients with TA. Of the total cohort, 16 (6.1%) had a history of myocardial infarction, 31 (11.8%) had angina and 24 (9.2%) had stroke. Multivariate logistic regression analysis revealed that anaemia (OR, 2.449; 95% CI: 1.167-5.141, p=0.018), low body mass index (OR, 0.821; 95% CI: 0.723-0.932, p=0.002), advancing age (OR, 1.050; 95% CI: 1.013-1.088, p=0.007), hyperlipidaemia (OR, 3.792; 95% CI: 1.647-8.727, p=0.002), and family history of CVD (OR, 2.915; 95% CI: 1.188-7.153, p=0.019) were significantly associated with the presence of CVD. CONCLUSIONS: Our study suggests that in addition to traditional CV risk factors, anaemia and low body mass index are independently associated with increased CVD in patients with TA. PMID- 26633552 TI - Plasma C1q/TNF-related protein 9: a promising biomarker for diabetic renal vascular injury. AB - BACKGROUND: Adipocytokines are associated with the pathophysiology of type 2 diabetes (T2DM). METHODS: We analyzed the relationship between levels of the plasma C1q/tumor necrosis factor-related protein 9 (CTRP9) and other adipocytokines or the endothelial function in patients with T2DM, and analyzed their trending manner. RESULTS: CTRP9 was detected in plasma from 14 out of a total of 28 patients. The values were not normally distributed. In comparing between groups in which CTRP9 was or was not detected, there were statistically significant differences in the high molecular weight adiponectin (HAN) and the urinary albumin/creatinine ratio (ACR). This indicates that both CTRP9 and HAN reflect the pathophysiology of renal involvement in T2DM. HAN correlated with Body Mass Index, ACR, and homeostasis model assessment of insulin resistance. However, CTRP9 did not correlate with HAN or any other parameters. CONCLUSIONS: CTRP9 independently trends in a different manner from HAN, and may reflect diabetic renal vascular risk in association with atherosclerosis and abnormal glucose metabolism besides of impaired vaso-relaxation in patients with T2DM. PMID- 26633553 TI - Changing practice of pelvic lymph node dissection in management of primary bladder cancer. AB - BACKGROUND: Surgical management of bladder cancer has seen a significant period of change over the last decade. This has largely been driven by recognition of the importance of pelvic lymph node dissection (PLND) - yet debate still continues regarding the extent of dissection required. Our aim was to ascertain how the practice of PLND has evolved over the last decade in the setting of bladder cancer and cystectomy at a tertiary referral centre. METHODS: Analysis of a retrospectively collected database including all cystectomies conducted at a tertiary centre in the last 10 years. Cases of non-primary bladder cancer were excluded. Histopathology records were scanned for data regarding PLND. Extent of PLND was defined according to levels. These were numbered level 1 (perivesical, pelvic and obturator), level 2 (internal and external iliac) and level 3 (common iliac). Trends in extent of dissection and number of nodes harvested were assessed. RESULTS: One hundred and thirty cases of primary bladder cancer undergoing cystectomy were identified. Dissection to level 3 has increased from zero cases in 2005-2008 to 40% of cases in 2013-2015. We have seen a corresponding rise in number of lymph nodes collected. Increasing extent of dissection has improved staging by identifying positive nodes that would otherwise be missed. CONCLUSIONS: The extent of PLND has increased over time. The current standard template at our institution includes a bilateral dissection of perivesical, obturator, internal iliac, external iliac and common iliac LN. This change has resulted in more accurate staging and increased total lymph node yield. PMID- 26633554 TI - How Does Cause of Death Contribute to the Hispanic Mortality Advantage in the United States? AB - KEY FINDINGS: The Hispanic population in the United States has lower overall mortality and higher life expectancy at birth than the non-Hispanic white and non Hispanic black populations. The expectation has been that the Hispanic population should exhibit a mortality profile that is similar to that of the non-Hispanic black population, not one that is advantaged relative to the non-Hispanic white population (1-4). In this report, differences in the leading causes of death between the Hispanic and non-Hispanic white and black populations are explored to determine how they contributed to the life expectancy advantage of the Hispanic population in 2013. PMID- 26633555 TI - Phylogeographic Structure of the White-Footed Mouse and the Deer Mouse, Two Lyme Disease Reservoir Hosts in Quebec. AB - Modification of a species range is one of many consequences of climate change and is driving the emergence of Lyme disease in eastern Canada. The primary reservoir host of the bacteria responsible for Lyme disease, Borrelia burgdorferi, is the white-footed mouse (Peromyscus leucopus), whose range is rapidly shifting north into southern Quebec. The deer mouse, P. maniculatus, is occurring over most Quebec province and is a less competent host for B. burgdorferi. Here, we compared the phylogeographic structure of both Peromyscus species in Quebec. Using a combination of multiple mitochondrial DNA markers and phylogeographic methods, we detected an ongoing and rapid expansion of P. leucopus, while P. maniculatus appears more stable. Haplotype and populations networks indicated that populations of P. maniculatus exhibit more genetic structure than P. leucopus across the study area. Furthermore, significant and consistent genetic divergences between populations of the two species on both sides of the St. Lawrence River suggest that distinct lineages of P. leucopus and P. maniculatus with different ancestral origins colonized Southern Quebec following the Last Glacial Maximum. The phylogeographic structure of pathogens is expected to mirror the structure observed in their reservoir hosts. As different strains of Borrelia burgdorferi may be associated with different levels of pathogenicity and immune responses of their hosts, our results are helpful at better understanding the pattern of spread of Lyme disease in a zone of emergence, and associated risk for human populations. PMID- 26633556 TI - Ethics of Placebo Procedures in Ophthalmic Surgical Trials. PMID- 26633557 TI - FAT4 functions as a tumour suppressor in gastric cancer by modulating Wnt/beta catenin signalling. AB - BACKGROUND: FAT4, a cadherin-related protein, was shown to function as a tumour suppressor; however, its role in human gastric cancer remains largely unknown. Here, we investigated the role of FAT4 in gastric cancer and examined the underlying molecular mechanisms. METHODS: The expression of FAT4 was evaluated by immunohistochemistry, western blotting, and qRT-PCR in relation to the clinicopathological characteristics of gastric cancer patients. The effects of FAT4 silencing on cell proliferation, migration, and invasion were assessed by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium) assay, and migration and invasion assays in gastric cancer cell lines in vitro and in a mouse xenograft model in vivo. RESULTS: Downregulation of FAT4 expression in gastric cancer tissues compared with adjacent normal tissues was correlated with lymph-node metastasis and poor survival. Knockdown of FAT4 promoted the growth and invasion of gastric cancer cells via the activation of Wnt/beta-catenin signalling, and induced epithelial-to-mesenchymal transition (EMT) in gastric cancer cells, as demonstrated by the upregulation and downregulation of mesenchymal and epithelial markers. Silencing of FAT4 promoted tumour growth and metastasis in a gastric cancer xenograft model in vivo. CONCLUSIONS: FAT4 has a tumour suppressor role mediated by the modulation of Wnt/beta-catenin signalling, providing potential novel targets for the treatment of gastric cancer. PMID- 26633558 TI - Risk prediction tools for cancer in primary care. AB - Numerous risk tools are now available, which predict either current or future risk of a cancer diagnosis. In theory, these tools have the potential to improve patient outcomes through enhancing the consistency and quality of clinical decision-making, facilitating equitable and cost-effective distribution of finite resources such as screening tests or preventive interventions, and encouraging behaviour change. These potential uses have been recognised by the National Cancer Institute as an 'area of extraordinary opportunity' and an increasing number of risk prediction models continue to be developed. The data on predictive utility (discrimination and calibration) of these models suggest that some have potential for clinical application; however, the focus on implementation and impact is much more recent and there remains considerable uncertainty about their clinical utility and how to implement them in order to maximise benefits and minimise harms such as over-medicalisation, anxiety and false reassurance. If the potential benefits of risk prediction models are to be realised in clinical practice, further validation of the underlying risk models and research to assess the acceptability, clinical impact and economic implications of incorporating them in practice are needed. PMID- 26633559 TI - Increased sensitivity to platinum drugs of cancer cells with acquired resistance to trabectedin. AB - BACKGROUND: In order to investigate the mechanisms of acquired resistance to trabectedin, trabectedin-resistant human myxoid liposarcoma (402-91/T) and ovarian carcinoma (A2780/T) cell lines were derived and characterised in vitro and in vivo. METHODS: Resistant cell lines were obtained by repeated exposures to trabectedin. Characterisation was performed by evaluating drug sensitivity, cell cycle perturbations, DNA damage and DNA repair protein expression. In vivo experiments were performed on A2780 and A2780/T xenografts. RESULTS: 402-91/T and A2780/T cells were six-fold resistant to trabectedin compared with parental cells. Resistant cells were found to be hypersensitive to UV light and did not express specific proteins involved in the nucleotide excision repair (NER) pathway: XPF and ERCC1 in 402-91/T and XPG in A2780/T. NER deficiency in trabectedin-resistant cells was associated with the absence of a G2/M arrest induced by trabectedin and with enhanced sensitivity (two-fold) to platinum drugs. In A2780/T, this collateral sensitivity, confirmed in vivo, was associated with an increased formation of DNA interstrand crosslinks. CONCLUSIONS: Our finding that resistance to trabectedin is associated with the loss of NER function, with a consequent increased sensitivity to platinum drugs, provides the rational for sequential use of these drugs in patients who have acquired resistance to trabectedin. PMID- 26633560 TI - Novel CAD-ALK gene rearrangement is drugable by entrectinib in colorectal cancer. AB - BACKGROUND: Activated anaplastic lymphoma kinase (ALK) gene fusions are recurrent events in a small fraction of colorectal cancers (CRCs), although these events have not yet been exploited as in other malignancies. METHODS: We detected ALK protein expression by immunohistochemistry and gene rearrangements by fluorescence in situ hybridisation in the ALKA-372-001 phase I study of the pan Trk, ROS1, and ALK inhibitor entrectinib. One out of 487 CRCs showed ALK positivity with a peculiar pattern that prompted further characterisation by targeted sequencing using anchored multiplex PCR. RESULTS: A novel ALK fusion with the carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD) gene (CAD-ALK fusion gene) was identified. It resulted from inversion within chromosome 2 and the fusion of exons 1-35 of CAD with exons 20 29 of ALK. After failure of previous standard therapies, treatment of this patient with the ALK inhibitor entrectinib resulted in a durable objective tumour response. CONCLUSIONS: We describe the novel CAD-ALK rearrangement as an oncogene and provide the first evidence of its drugability as a new molecular target in CRC. PMID- 26633561 TI - Metabolic markers in blood can separate prostate cancer from benign prostatic hyperplasia. AB - BACKGROUND: An individualised risk-stratified screening for prostate cancer (PCa) would select the patients who will benefit from further investigations as well as therapy. Current detection methods suffer from low sensitivity and specificity, especially for separating PCa from benign prostatic conditions. We have investigated the use of metabolomics analyses of blood samples for separating PCa patients and controls with benign prostatic hyperplasia (BPH). METHODS: Blood plasma and serum samples from 29 PCa patient and 21 controls with BPH were analysed by metabolomics analysis using magnetic resonance spectroscopy, mass spectrometry and gas chromatography. Differences in blood metabolic patterns were examined by multivariate and univariate statistics. RESULTS: By combining results from different methodological platforms, PCa patients and controls were separated with a sensitivity and specificity of 81.5% and 75.2%, respectively. CONCLUSIONS: The combined analysis of serum and plasma samples by different metabolomics measurement techniques gave successful discrimination of PCa and controls, and provided metabolic markers and insight into the processes characteristic of PCa. Our results suggest changes in fatty acid (acylcarnitines), choline (glycerophospholipids) and amino acid metabolism (arginine) as markers for PCa compared with BPH. PMID- 26633562 TI - Syntheses and cellular investigations of di-aspartate and aspartate-lysine chlorin e(6) conjugates. AB - Chlorin e6 is a tricarboxylic acid degradation product of chlorophyll a. Four chlorin e6 bis(amino acid) conjugates were regioselectively synthesized bearing two aspartate conjugates in the 13(1),17(3)- and 15(2),17(3)-positions, or at the 13(1),15(2)via an ethylene diamine linker. One additional conjugate bearing two different amino acids, lysine at 13(1)via an ethylene diamine linker and an aspartate at 15(2)via a beta-alanine linker was also synthesized. The cytotoxicity and uptake of four di(amino acid) chlorin e6 conjugates were investigated in human HEp2 cells, and compared with chlorin e6. The most cytotoxic and most taken up conjugates were the zwitterionic 13(1),15(2) disubstituted conjugates 28 and 33; these also localized in multiple organelles. In contrast, the anionic 13(1),17(3)- and 15(2),17(3)-di-aspartyl chlorin e6 conjugates 12 and 13 showed low dark cytoxicity and lower phototoxicity compared with chlorin e6. PMID- 26633563 TI - Salicylic acid-induced superoxide generation catalyzed by plant peroxidase in hydrogen peroxide-independent manner. AB - It has been reported that salicylic acid (SA) induces both immediate spike and long lasting phases of oxidative burst represented by the generation of reactive oxygen species (ROS) such as superoxide anion radical (O2(*-)). In general, in the earlier phase of oxidative burst, apoplastic peroxidase are likely involved and in the late phase of the oxidative burst, NADPH oxidase is likely involved. Key signaling events connecting the 2 phases of oxidative burst are calcium channel activation and protein phosphorylation events. To date, the known earliest signaling event in response to exogenously added SA is the cell wall peroxidase-catalyzed generation of O2(*-) in a hydrogen peroxide (H2O2)-dependent manner. However, this model is incomplete since the source of the initially required H2O2 could not be explained. Based on the recently proposed role for H2O2-independent mechanism for ROS production catalyzed by plant peroxidases (Kimura et al., 2014, Frontiers in Plant Science), we hereby propose a novel model for plant peroxidase-catalyzed oxidative burst fueled by SA. PMID- 26633564 TI - Regulation of grain yield in rice under well-watered and drought stress conditions by GUDK. AB - Increasing the grain yield of cereals, which is stable under unfavorable environmental stress, is a major objective to sustain production and feed the growing world population. Recently, we functionally characterized a receptor-like cytoplasmic kinase, named GROWTH UNDER DROUGHT KINASE (GUDK), revealing its role in regulating grain yield under well-watered and drought stress conditions by transphosphorylating the OsAP37 transcription factor. GUDK is induced under several stresses and its loss-of-function increased the sensitivity of rice seedlings to salinity, osmotic stress, and abscisic acid treatment. In addition to reduced tolerance of gudk mutant plants to drought stress at vegetative stage, a significant reduction in grain yield was observed under well-watered and drought stress conditions at reproductive stage. Gene co-expression analysis supports the role of GUDK in regulating important biological processes both under control and stress conditions. Thus, our results suggest that GUDK has the potential to regulate grain yield both under favorable and unfavorable conditions. PMID- 26633565 TI - Partly transparent young legume pods: Do they mimic caterpillars for defense and simultaneously enable better photosynthesis? AB - Being partly or fully transparent as a defense from predation is mostly known in various groups of aquatic animals and various terrestrial arthropods. Plants, being photosynthetic and having cell walls made of various polymers, cannot be wholly transparent. In spite of these inherent limitations, some succulent plant species of arid zones have partially transparent "windows" in order to perform photosynthesis in their below-ground leaves, as defense from herbivores as well as for protection from harsh environmental conditions. Similarly, transparent "windows" or even wholly transparent leaves are found in certain thick or thin, above-ground organs irrespective of aridity. The young pods of various wild annual Mediterranean legume species belonging to the genera Lathyrus, Pisum and Vicia are partly transparent and may therefore look like caterpillars when viewed with back illumination. I propose that this character serves 2 functions: (1) being a type of defensive caterpillar mimicry that may reduce their consumption by various herbivores in that very sensitive stage, and (2) simultaneously allowing better photosynthesis in the rapidly growing seeds and pods. Unlike animals that are transparent for either defensive or aggressive crypsis, in the case of young legume pods it allows them to visually mimic caterpillars for defense. PMID- 26633567 TI - Overexpression of AtPTPA in Arabidopsis increases protein phosphatase 2A activity by promoting holoenzyme formation and ABA negatively affects holoenzyme formation. AB - AtPTPA is a critical regulator for the holoenzyme assembling of protein phosphatase 2A (PP2A) in Arabidopsis. Characterization of AtPTPA improves our understanding of the function and regulation of PP2A in eukaryotes. Further analysis of AtPTPA-overexpressing plants indicates that AtPTPA increases PP2A activity by promoting PP2A's AC dimer formation, thereby holoenzyme assembling. Plant hormone abscisic acid (ABA) reduces PP2A enzyme activity by negatively affects PP2A's AC dimer formation. Therefore, AtPTPA is a positive factor that promotes PP2A holoenzyme assembly, and ABA is a negative factor that prevents PP2A holoenzyme assembly. PMID- 26633566 TI - Regulatory roles of serotonin and melatonin in abiotic stress tolerance in plants. AB - Understanding the physiological and biochemical basis of abiotic stress tolerance in plants has always been one of the major aspects of research aiming to enhance plant productivity in arid and semi-arid cultivated lands all over the world. Growth of stress-tolerant transgenic crops and associated agricultural benefits through increased productivity, and related ethical issues, are also the major concerns of current research in various laboratories. Interesting data on the regulation of abiotic stress tolerance in plants by serotonin and melatonin has accumulated in the recent past. These two indoleamines possess antioxidative and growth-inducing properties, thus proving beneficial for stress acclimatization. Present review shall focus on the modes of serotonin and melatonin-induced regulation of abiotic stress tolerance in plants. Complex molecular interactions of serotonin and auxin-responsive genes have suggested their antagonistic nature. Data from genomic and metabolomic analyses of melatonin-induced abiotic stress signaling have lead to an understanding of the regulation of stress tolerance through the modulation of transcription factors, enzymes and various signaling molecules. Melatonin, nitric oxide (NO) and calmodulin interactions have provided new avenues for research on the molecular aspects of stress physiology in plants. Investigations on the characterization of receptors associated with serotonin and melatonin responses, are yet to be undertaken in plants. Patenting of biotechnological inventions pertaining to serotonin and melatonin formulations (through soil application or foliar spray) are expected to be some of the possible ways to regulate abiotic stress tolerance in plants. The present review, thus, summarizes the regulatory roles of serotonin and melatonin in modulating the signaling events accompanying abiotic stress in plants. PMID- 26633568 TI - Potassium Postdeposition Treatment-Induced Band Gap Widening at Cu(In,Ga)Se2 Surfaces--Reason for Performance Leap? AB - Direct and inverse photoemission were used to study the impact of alkali fluoride postdeposition treatments on the chemical and electronic surface structure of Cu(In,Ga)Se2 (CIGSe) thin films used for high-efficiency flexible solar cells. We find a large surface band gap (E(g)(Surf), up to 2.52 eV) for a NaF/KF postdeposition treated (PDT) absorber significantly increases compared to the CIGSe bulk band gap and to the Eg(Surf) of 1.61 eV found for an absorber treated with NaF only. Both the valence band maximum (VBM) and the conduction band minimum shift away from the Fermi level. Depth-dependent photoemission measurements reveal that the VBM decreases with increasing surface sensitivity for both samples; this effect is more pronounced for the NaF/KF-PDT CIGSe sample. The observed electronic structure changes can be linked to the recent breakthroughs in CIGSe device efficiencies. PMID- 26633569 TI - Minimally Invasive Approach to the Lingual and Hypoglossal Nerves in the Adult Rat. AB - Surgical manipulation of the sensory and motor nerves of the rat tongue is often employed in studies evaluating the oral cavity functions of mastication and deglutition. A noninvasive, atraumatic approach that will then facilitate sufficient manipulation of these structures is required. In this study, we detail an approach that consistently allows identification of the hypoglossal (motor) and lingual (sensory) nerves of the rat. Six Wistar rats (250-500 g) were anesthetized and dissected either as fresh tissue (N = 3) or following transcardial perfusion with 4% paraformaldehyde (N = 3). Both fixed and non-fixed specimens of the rat head and neck were incised in the right submandibular region. The first animal in each group was used to gain a basic understanding of the regional muscular anatomy with reference to the hypoglossal and lingual nerves. Subsequent animals were used for the development of an efficient and minimally invasive approach to these nerves. The resultant approach begins as an incision through skin and platysma, followed by medial reflection of the digastric muscle. This allows visualization of the hypoglossal nerve in the region of the bifurcation of the common trunk into medial and lateral subdivisions. Next, the lingual nerve dissection is approached by reflection rostrally of the transversus mandibularis muscle and a caudal reflection of the mylohyoid muscle. This dissection reveals the geniohyoid muscle which when separated bluntly using forceps, exposes the lingual nerve. The anatomical approach described and illustrated herein will aid investigators in consistent identification of these two nerves as fundamental methods of their projects. PMID- 26633571 TI - The Genomic Grade Assay Compared With Ki67 to Determine Risk of Distant Breast Cancer Recurrence. AB - IMPORTANCE: The Genomic Grade Index (GGI) was previously developed, evaluated on frozen tissue, and shown to be prognostic in early breast cancer. To test the GGI in formalin-fixed, paraffin-embedded breast cancer tumors, a quantitative reverse transcriptase polymerase chain reaction assay was developed and named the Genomic Grade (GG). The GG assay has the potential to increase the clinical application of the GGI, but robust demonstration of the clinical validity of the GG assay is required. OBJECTIVE: To evaluate the prognostic ability of the GG assay to detect breast cancer recurrence compared with centrally reviewed immunohistochemical testing of Ki67 antigen proliferation. DESIGN, SETTING, AND PARTICIPANTS: This is an internationally collaborative substudy of a large phase 3 4-arm adjuvant trial. Patients had endocrine receptor-positive, node-positive, or node-negative nonmetastatic primary breast cancer. Patients included in this study had available formalin-fixed, paraffin-embedded samples of their primary tumors and were randomized to either a 5-year tamoxifen monotherapy arm or a 5-year letrozole monotherapy arm. Associations between either GG assay results or log2 transformed Ki67 data and survival end points were evaluated using Cox regression models stratified for chemotherapy use; the 2 vs 4 arm randomization option; and endocrine therapy assignment with and without adjustment for clinicopathological parameters, including centrally reviewed histological grade, hormone receptors, and ERBB2 (formerly HER2 or HER2/neu). The likelihood ratio statistic was used to assess the added prognostic value. INTERVENTIONS: Central evaluation and comparison, blinded for clinical information, of the GG assay, breast cancer histological grade, and Ki67. MAIN OUTCOMES AND MEASURES: Distant recurrence-free interval (DRFI). RESULTS: Genomic Grade assay data were obtained in 883 breast cancer samples (62%). At a median follow-up of 8.1 years, 84 (10%) had distant recurrences. Increasing GG or Ki67 were both significantly associated with lower DRFI and added independent prognostic information to the clinicopathological prognostic factors. In patients with early node-negative breast cancer who were endocrine-only treated, 38% were GG1 with a 10-year DRFI of 99% (95% CI, 97% 100%), and 18% were histological grade 1 with a 10-year DRFI of 100% (95% CI, 100%-100%). For GG equivocal patients, the 10-year DRFI was 94% (95% CI, 90% 98%), and for GG3 patients, the 10-year DRFI was 87% (95% CI, 80%-94%). CONCLUSIONS AND RELEVANCE: Either the GG assay or centrally reviewed Ki67 significantly improves clinicopathological models to determine distant recurrence of breast cancer. Compared with the histological grade, the GG assay can identify a higher proportion of endocrine-only treated patients with very low risk of distant recurrence at 10 years. TRIAL REGISTRATION: clinicaltrials.gov Identifiers: NCT00004205 and NCT00004205. PMID- 26633572 TI - Fast Crystallization and Improved Stability of Perovskite Solar Cells with Zn2SnO4 Electron Transporting Layer: Interface Matters. AB - Here we report that mesoporous ternary oxide Zn2SnO4 can significantly promotes the crystallization of hybrid perovskite layers and serves as an efficient electron transporting material in perovskite solar cells. Such devices exhibit an energy conversion efficiency of 13.34%, which is even higher than that achieved with the commonly used TiO2 in the similar experimental conditions (9.1%). Simple one-step spin coating of CH3NH3PbI3-xClx on Zn2SnO4 is found to lead to rapidly crystallized bilayer perovskite structure without any solvent engineering. Furthermore, ultrafast transient absorption measurement reveals efficient charge transfer at the Zn2SnO4/perovskite interface. Most importantly, solar cells with Zn2SnO4 as the electron-transporting material exhibit negligible electrical hysteresis and exceptionally high stability without encapsulation for over one month. Besides underscoring Zn2SnO4 as a highly promising electron transporting material for perovskite solar cells, our results demonstrate the significant role of interfaces on improving the perovskite crystallization and photovoltaic performance. PMID- 26633573 TI - Hydrophilic Association in a Dilute Glutamine Solution Persists Independent of Increasing Temperature. AB - Recent studies suggest that hydrophilic interactions play an important role in controlling self-assembly in biological processes. To explore the effect of temperature on this interaction, we extend our previous work on the glutamine water system at 24 degrees C (at a mole ratio of 1 glutamine to 269 water molecules) and present additional neutron diffraction data, at the same concentration, at 37 and 60 degrees C, using hydrogen/deuterium substitution on the water and glutamine, coupled with further extensive empirical potential structure refinement computer simulations. Taking all the possible hydrophilic couplings between glutamine molecules into account, we find that nearly one-fifth of the glutamines in solution are linked by hydrogen bonds at any one time. This number contrasts strongly with the ~3-4% fraction found in the same simulation with random packing and no hydrogen bonds. Within the uncertainties imposed by dilute solution statistics, we find no temperature dependence in these values. The clusters are highly transitory, forming and disappearing rapidly as the simulations proceed. Hydrophobic association of the alkyl groups on glutamine without concomitant hydrophilic association of the charged head and side-chain groups is only weakly observed. PMID- 26633574 TI - Notes from the Field: Carbapenem-resistant Enterobacteriaceae Producing OXA-48 like Carbapenemases--United States, 2010-2015. AB - Carbapenem-resistant Enterobacteriaceae (CRE) are bacteria that are often resistant to most classes of antibiotics and cause health care-associated infections with high mortality rates. Among CRE, strains that carry plasmid encoded carbapenemase enzymes that inactivate carbapenem antibiotics are of greatest public health concern because of their potential for rapid global dissemination, as evidenced by the increasing distribution of CRE that produce the Klebsiella pneumoniae carbapenemase and the New Delhi metallo-beta-lactamase. Newly described resistance in Enterobacteriaceae, such as plasmid-mediated resistance to the last-line antimicrobial colistin, recently detected in China, and resistance to the newly approved antimicrobial, ceftazidime-avibactam, identified from a U.S. K. pneumoniae carbapenemase-producing isolate, highlight the continued urgency to delay spread of CRE. Monitoring the emergence of carbapenemases is crucial to limiting their spread; identification of patients carrying carbapenemase-producing CRE should result in the institution of transmission-based precautions and enhanced environmental cleaning to prevent transmission.* The OXA-48 carbapenemase was first identified in Enterobacteriaceae in Turkey in 2001, and OXA-48-like variants have subsequently been reported around the world. The first U.S. reports of OXA-48-like carbapenemases were published in 2013 and included retrospectively identified isolates from 2009 and two isolates collected in 2012 from patients in Virginia who had recently been hospitalized outside the United States. Although there are limited additional published reports from the United States, CDC continues to receive reprots of these organisms. This report describes patients identified as carrying CRE producing OXA-48-like carbapenemases in the United States during June 2010-August 2015. PMID- 26633575 TI - Addressing Saddle Nose Deformity--Reply. PMID- 26633576 TI - Analysis of O(6)-[4-(3-Pyridyl)-4-oxobut-1-yl]-2'-deoxyguanosine and Other DNA Adducts in Rats Treated with Enantiomeric or Racemic N'-Nitrosonornicotine. AB - (S)-N'-Nitrosonornicotine [(S)-NNN] and racemic NNN are powerful oral and esophageal carcinogens in the F344 rat, whereas (R)-NNN has only weak activity. Tumor formation in these tissues of rats treated with racemic NNN was far greater than the sum of the activities of the individual enantiomers. We hypothesized that metabolites of (R)-NNN enhanced levels of DNA adducts produced by (S)-NNN. A test of that hypothesis necessitated the development of a novel liquid chromatography-nanoelectrospray ionization-high resolution tandem mass spectrometry method for the analysis of O(6)-[4-(3-pyridyl)-4-oxobut-1-yl]-2' deoxyguanosine (O(6)-POB-dGuo), a highly mutagenic DNA adduct not previously quantified in rats treated with NNN. The new method, with a limit of detection of 6.5 amol for diluted standard and 100 amol for DNA samples, was applied in this study. Groups of nine F344 rats were treated with doses as follows: 7 ppm (R) NNN, 7 ppm (S)-NNN, and 14 ppm racemic NNN; 14 ppm (R)-NNN, 14 ppm (S)-NNN, and 28 ppm racemic NNN; or 28 ppm (R)-NNN, 28 ppm (S)-NNN, and 56 ppm racemic NNN for 5 weeks, and tissues were analyzed for DNA adducts. We found statistically significant, but modest, synergistic enhancement of levels of O(6)-POB-dGuo in the esophagus but not the oral cavity of rats treated with racemic NNN (low and median doses only) compared to the sum of the amounts formed in these tissues of rats treated with (S)-NNN or (R)-NNN. There was no synergy in the formation of other POB-DNA adducts of NNN in oral cavity and esophagus, nor was there any evidence for synergy in nasal respiratory and olfactory epithelium, lung, or liver. Our results provide the first quantitation of O(6)-POB-dGuo in DNA from tissues of rats treated with NNN and evidence for synergy in DNA adduct formation as one possible mechanism by which (R)-NNN enhances the carcinogenicity of (S) NNN in rats. PMID- 26633577 TI - Geographic Variation in Treatment and Outcomes Among Patients With AMI: Investigating Urban-Rural Differences Among Hospitalized Patients. AB - BACKGROUND: The value of early invasive revascularization for patients suffering acute myocardial infarction (AMI) is well known. However, access to revascularization services varies geographically and demographically. Previous studies have not examined the influence of rural residence on revascularization rates and outcomes among patients hospitalized with AMI. METHODS: Our retrospective cohort study included patients hospitalized in Washington State with a primary diagnosis of AMI from 2009 to 2012. Urban or rural residence was determined using rural-urban commuting area (RUCA) codes. Multivariable models were used to evaluate geographic variation in rates of invasive versus medical management, in-hospital mortality, rehospitalization, and subsequent revascularization procedures. RESULTS: Our study included 25,156 urban dwellers and 2,770 rural residents. Adjusted models found rural patients to be at increased odds of undergoing invasive revascularization during the initial episode of AMI care (OR = 1.11; 95% CI: 1.01-1.21; P = .02) compared to urban dwelling patients. Rural patients were more likely to be transferred for care (OR = 4.28; 95% CI: 3.93-4.66; P < .001) and more likely to undergo coronary artery bypass grafting (CABG) (OR = 1.55; 95% CI: 1.35-1.78; P < .001) compared to the urban cohort. We found no significant geographic cohort differences in in hospital mortality or subsequent revascularization rates. CONCLUSION: Our findings suggest that despite limited access to cardiac care facilities, rural patients are accessing revascularization services. However, rural residents are more likely to undergo CABG during their index admission. High transfer rates suggest that rural regions rely on effective transfer networks to access invasive cardiac services. PMID- 26633578 TI - Enhanced Retention of Chemotactic Bacteria in a Pore Network with Residual NAPL Contamination. AB - Nonaqueous-phase liquid (NAPL) contaminants are difficult to eliminate from natural aquifers due, in part, to the heterogeneous structure of the soil. Chemotaxis enhances the mixing of bacteria with contaminant sources in low permeability regions, which may not be readily accessible by advection and dispersion alone. A microfluidic device was designed to mimic heterogeneous features of a contaminated groundwater aquifer. NAPL droplets (toluene) were trapped within a fine pore network, and bacteria were injected through a highly conductive adjacent macrochannel. Chemotactic bacteria (Pseudomonas putida F1) exhibited greater accumulation near the pore network at 0.5 m/day than both the nonchemotactic control and the chemotactic bacteria at a higher groundwater velocity of 5 m/day. Chemotactic bacteria accumulated in the vicinity of NAPL droplets, and the accumulation was 15% greater than a nonchemotactic mutant. Indirect evidence showed that chemotactic bacteria were retained within the contaminated low-permeability region longer than nonchemotactic bacteria at 0.25 m/day. This retention was diminished at 5 m/day. Numerical solutions of the bacterial-transport equations were consistent with the experimental results. Because toluene is degraded by P. putida F1, the accumulation of chemotactic bacteria around NAPL sources is expected to increase contaminant consumption and improve the efficiency of bioremediation. PMID- 26633579 TI - First Total Synthesis of Gliomasolide C and Formal Total Synthesis of Sch 725674. AB - Syntheses of two 14-membered macrolides Sch-725674 and Gliomasolide C are described here. The first total synthesis of Gliomasolide C, the short synthesis of Sch-725674, and regioselective Wacker oxidation of internal olefin are the highlights of this disclosure. In addition, a key macrocycle with orthogonal functionalities was designed and synthesized on a gram scale for the generation of analogues. PMID- 26633580 TI - High-Rate LiTi2(PO4)3@N-C Composite via Bi-nitrogen Sources Doping. AB - Mesoporous LiTi2(PO4)3@nitrogen-rich doped carbon composites have been synthesized by a novel bi-nitrogen sources doping strategy. Tripolycyanamide (C3H6N6) and urea are proposed for the first time as both nitrogen and carbon sources to achieve a homogeneous nitrogen-doped carbon coating layer via an in situ method. The electrode delivers ultrahigh rate performance and outstanding cycling stability in lithium ion batteries (LIBs). In an organic electrolyte system, the electrode demonstrates high discharge capacities of 120 mAh g(-1) and 87 mAh g(-1) at 20C and 50C, respectively. Moreover, 89.5% of initial discharge capacity is retained after 1000 cycles at 10C. When used as an anode for aqueous LIBs, the electrode also demonstrates superior rate capability with the discharge capacity of 103 mAh g(-1) at 10C, corresponding to 84% of that at 1C. Outstanding cycling stability with capacity retention of 91.2% after 100 cycles at 30 mA g( 1) and 90.4% over 400 cycles at 150 mA g(-1) are also demonstrated. The uniform nitrogen-rich carbon coating and unique mesoporous structure play important roles in effectively suppressing the charge-transfer resistance and facilitating Li ion/electron diffusion, thus leading to the superior electrochemical properties. PMID- 26633581 TI - Utility of CT-cisternogram for radiosurgery in trigeminal neuralgia: A not-to-be forgotten technique. AB - Radiosurgery (RS) is a well-established ablative therapy for trigeminal neuralgia (TGN). Successful RS requires the delivery of an extremely high dose of radiation to a small cisternal portion of the nerve, which lies amidst critical structures. This study describes the utility of CT-cisternogram in RS targeting for TGN. We report on patients with TGN who required CT-cisternogram for target identification for CyberKnife (CK) RS at our institution between September 2010 and April 2015. CT-cisternogram is a well-tolerated procedure that adds useful information to RS planning. Illustrative cases with complex anatomy and MRI artifacts related to postoperative changes and Teflon implant are described. CT cisternogram is a complementary imaging modality that is useful in some patients, for RS target delineation. PMID- 26633582 TI - Active gas aspiration versus simple gas evacuation to reduce shoulder pain after diagnostic laparoscopy: A randomized controlled trial. AB - AIM: To evaluate the effectiveness of active gas aspiration to reduce postoperative shoulder pain in infertile women undergoing day-case diagnostic laparoscopy. MATERIAL AND METHODS: Seventy four infertile women undergoing diagnostic laparoscopy during July 2013 to February 2014 were randomized to an active gas aspiration or simple gas evacuation (control) group at the end of the surgery. Postoperative shoulder and wound pain were assessed using a visual analog scale at 6, 12 and 24 h after surgery. Consumption of rescue analgesics and adverse events were recorded. RESULTS: There were 37 patients in each group. The shoulder pain scores of the active gas aspiration group showed lower pain intensity than the simple gas evacuation group, with statistically significant results at at all time points. There was no significant difference in surgical wound pain. The proportion of patients who required postoperative rescue analgesics was lower in the study than in control group (43.2% vs. 67.6%, P = 0.035). There was no significant difference in adverse events until 24 h after surgery. CONCLUSIONS: Active gas aspiration provided a significantly superior effect on postoperative shoulder pain relief after diagnostic laparoscopy when compared to simple gas evacuation, without any adverse events. PMID- 26633583 TI - Light-Regulated Polymerization under Near-Infrared/Far-Red Irradiation Catalyzed by Bacteriochlorophyll a. AB - Photoregulated polymerizations are typically conducted using high-energy (UV and blue) light, which may lead to undesired side reactions. Furthermore, as the penetration of visible light is rather limited, the range of applications with such wavelengths is likewise limited. We herein report the first living radical polymerization that can be activated and deactivated by irradiation with near infrared (NIR) and far-red light. Bacteriochlorophyll a (Bachl a) was employed as a photoredox catalyst for photoinduced electron transfer/reversible addition fragmentation chain transfer (PET-RAFT) polymerization. Well-defined polymers were thus synthesized within a few hours under NIR (lambda=850 nm) and far-red (lambda=780 nm) irradiation with excellent control over the molecular weight (M(n)/M(w)<1.25). Taking advantage of the good penetration of NIR light, we showed that the polymerization also proceeded smoothly when a translucent barrier was placed between light source and reaction vessel. PMID- 26633584 TI - A single diamagnetic catalyCEST MRI contrast agent that detects cathepsin B enzyme activity by using a ratio of two CEST signals. AB - CatalyCEST MRI can detect enzyme activity by monitoring the change in chemical exchange with water after a contrast agent is cleaved by an enzyme. Often these molecules use paramagnetic metals and are delivered with an additional non responsive reference molecule. To improve this approach for molecular imaging, a single diamagnetic agent with enzyme-responsive and enzyme-unresponsive CEST signals was synthesized and characterized. The CEST signal from the aryl amide disappeared after cleavage of a dipeptidyl ligand with cathepsin B, while a salicylic acid moiety was largely unresponsive to enzyme activity. The ratiometric comparison of the two CEST signals from the same agent allowed for concentration independent measurements of enzyme activity. The chemical exchange rate of the salicylic acid moiety was unchanged after enzyme catalysis, which further validated that this moiety was enzyme-unresponsive. The temperature dependence of the chemical exchange rate of the salicylic acid moiety was non Arrhenius, suggesting a two-step chemical exchange mechanism for salicylic acid. The good detection sensitivity at low saturation power facilitates clinical translation, along with the potentially low toxicity of a non-metallic MRI contrast agent. The modular design of the agent constitutes a platform technology that expands the variety of agents that may be employed by catalyCEST MRI for molecular imaging. PMID- 26633588 TI - Quadriceps and Hamstring Strength Recovery During Early Neuromuscular Rehabilitation After ACL Hamstring-Tendon Autograft Reconstruction. AB - CONTEXT: There is lack of information related to quadriceps and hamstring strength recovery during the early period of rehabilitation after anterior cruciate ligament reconstruction (ACLR) using hamstring-tendon graft (HTG). OBJECTIVE: To investigate quadriceps and hamstring isometric strength at 4-, 8-, and 12-wk time points after ACLR and to document the strength changes of these muscles over time. DESIGN: Longitudinal study. PARTICIPANTS: 24 patients (age 28.1 +/- 8.1 y) who underwent unilateral single-bundle anatomic ACLR with 4 strand semitendinosus and gracilis tendon graft. MAIN OUTCOME MEASURES: The isometric strength of quadriceps and hamstring muscles was measured on an isokinetic dynamometer at a 60 degrees knee-flexion angle 4, 8, and 12 wk after surgery. RESULTS: Quadriceps and hamstring strength significantly increased over time for both the involved limb (quadriceps F2,46 = 58.3, P < .001; hamstring F2,46 = 35.7, P < .001) and uninvolved limb (quadriceps F2,46 = 17.9, P < .001; hamstring F2,46 =56.9, P = .001). Quadriceps and hamstring indexes significantly changed from 4 wk (QI 57.9, HI 54.4) to 8 wk (QI 78.8, HI 69.9) and from 8 wk to 12 wk (QI 82, HI 75.7) (P < .001); however, there was no difference between indexes at the 12-wk time point (P = .17). CONCLUSIONS: The results of this study serve as a reference for clinicians while directing a rehabilitation protocol for HTG ACLR patients to better appreciate expected strength changes of the muscles in the early phase of recovery. PMID- 26633585 TI - Five-year analysis from phase 2 trial of "sandwich" chemoradiotherapy in newly diagnosed, stage IE to IIE, nasal type, extranodal natural killer/T-cell lymphoma. AB - The "sandwich" protocol, was first proposed by us and comprised of l asparaginase, vincristine, and prednisone chemotherapy with radiotherapy, results in 2-year overall survival and progression-free survival rates that surpass traditional therapies for patients with newly diagnosed, stage IE-IIE, nasal type, extranodal natural killer/T-cell lymphoma. The results had been published by cancer. These patients were followed up over a median period of 67 months, for which updates and the results of prognostic factors analyses are presented. The 5 year overall survival and progress-free survival rates were both 64%. The highest rates of death occurred during the first 6 months, and between the second and third year after enrollment. The initial therapeutic response (odds ratio = 5.83; P = 0.001) and B symptoms (odds ratio = 6.13; P = 0.043) were significant prognostic factors for overall survival. However, the international prognostic index was not significant for progress-free survival and overall survival. There were no severe long-term side effects. These results indicate that the "sandwich" protocol may benefit the long-term survival of patients with newly diagnosed stage IE-IIE, nasal type, extranodal natural killer/T-cell lymphoma. However, additional studies with larger samples are required to confirm these results. This study is registered at www.Chictr.org (ChicTR-TNC-09000394). PMID- 26633589 TI - Postoperative Rehabilitation After Hip Arthroscopy: A Search for the Evidence. AB - CONTEXT: Hip arthroscopy has become an increasingly popular option for active individuals with recalcitrant hip pain. Conditions that may be addressed through hip arthroscopy include labral pathology, femoral acetabular impingement, capsular hyperlaxity, ligamentum teres tears, and the presence of intra-articular bodies. Although the body of literature examining operative procedures has grown, there is a paucity of evidence specifically on the efficacy of postoperative rehabilitation programs. To date, there are no systematic reviews that have evaluated the available evidence on postoperative rehabilitation. OBJECTIVE: To evaluate the available evidence on postoperative rehabilitation programs after arthroscopy of the hip joint. EVIDENCE ACQUISITION: A search of the PubMed, CINAHL, SPORTDiscus, ProQuest, and Google Scholar databases was conducted in January 2014 according the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for reporting systematic reviews. EVIDENCE SYNTHESIS: Six studies met the inclusion criteria and were either case series or case reports (level 4 evidence) that described a 4- or 5-phase postoperative rehabilitation program. The available evidence supports a postoperative period of restricted weight bearing and mobility; however, the specific interventions in the postoperative phases are variable with no comparison trials. CONCLUSION: This review identified a paucity of evidence on postoperative rehabilitation after hip arthroscopy. Existing reports are descriptive in nature, so the superiority of a particular approach cannot be determined. One can surmise from existing studies that a 4- to 5-stage program with an initial period of weight-bearing and mobility precautions is efficacious in regard to function, patient satisfaction, and return to competitive-level athletics. Clinicians may consider such a program as a general guideline but should individualize treatment according to the surgical procedure and surgeon guidelines. Future research should focus on comparative trials to determine the effect of specific postoperative rehabilitation designs. PMID- 26633590 TI - Computational Prediction and Biochemical Analyses of New Inverse Agonists for the CB1 Receptor. AB - Human cannabinoid type 1 (CB1) G-protein coupled receptor is a potential therapeutic target for obesity. The previously predicted and experimentally validated ensemble of ligand-free conformations of CB1 [Scott, C. E. et al. Protein Sci. 2013 , 22 , 101 - 113 ; Ahn, K. H. et al. Proteins 2013 , 81 , 1304 1317] are used here to predict the binding sites for known CB1-selective inverse agonists including rimonabant and its seven known derivatives. This binding pocket, which differs significantly from previously published models, is used to identify 16 novel compounds expected to be CB1 inverse agonists by exploiting potential new interactions. We show experimentally that two of these compounds exhibit inverse agonist properties including inhibition of basal and agonist induced G-protein coupling activity, as well as an enhanced level of CB1 cell surface localization. This demonstrates the utility of using the predicted binding sites for an ensemble of CB1 receptor structures for designing new CB1 inverse agonists. PMID- 26633591 TI - A Usual G-Protein-Coupled Receptor in Unusual Membranes. AB - G-protein-coupled receptors (GPCRs) are the largest family of membrane-bound receptors and constitute about 50% of all known drug targets. They offer great potential for membrane protein nanotechnologies. We report here a charge interaction-directed reconstitution mechanism that induces spontaneous insertion of bovine rhodopsin, the eukaryotic GPCR, into both lipid- and polymer-based artificial membranes. We reveal a new allosteric mode of rhodopsin activation incurred by the non-biological membranes: the cationic membrane drives a transition from the inactive MI to the activated MII state in the absence of high [H(+)] or negative spontaneous curvature. We attribute this activation to the attractive charge interaction between the membrane surface and the deprotonated Glu134 residue of the rhodopsin-conserved ERY sequence motif that helps break the cytoplasmic "ionic lock". This study unveils a novel design concept of non biological membranes to reconstitute and harness GPCR functions in synthetic systems. PMID- 26633593 TI - Proton Magnetic Resonance Imaging for Initial Assessment of Isolated Mycobacterium avium Complex Pneumonia. AB - RATIONALE: Computed tomographic (CT) radiography is the reference standard for imaging Mycobacterium avium complex (MAC) lung infection. Magnetic resonance imaging (MRI) has been shown to be comparable to CT for characterizing other pulmonary inflammatory conditions, but has not been rigorously tested for imaging MAC pneumonia. OBJECTIVES: To determine the feasibility of pulmonary MRI for imaging MAC pneumonia and to assess the degree of agreement between MRI and CT for assessing the anatomic features and lobar extent of MAC lung infections. METHODS: Twenty-five subjects with culture-confirmed MAC pneumonia and no identified coinfecting organisms were evaluated by thoracic MRI and then by chest CT imaging performed up to 1 week later. After deidentification, first the MRI and then the CT scans were scored 2 weeks apart by two chest radiologists working independently of one another. Discrepancies were resolved by a third chest radiologist. The scans were scored for bronchiectasis, consolidation or atelectasis, abscess or sacculation, nodules, and mucus plugging using a three point lobar scale (absent, <50% of lobe, and >50% of lobe). Agreement analyses and ordinary least products regressions were performed. MEASUREMENTS AND MAIN RESULTS: A fixed bias was found between total CT and MRI scores, with CT scoring higher on average (median difference: 4 on a scale of 48; interquartile range: 3, 6). Fixed biases were found for bronchiectasis and consolidation or atelectasis subscale scores. Both fixed and proportional biases were found between CT and MRI mucus plugging scores. No bias was found between CT and MRI nodule scores. There was nearly perfect lobar percent agreement for more conspicuous findings such as consolidation or atelectasis and abscess or sacculation. CONCLUSIONS: In this exploratory study of 25 adult patients with culture-proven MAC lung infection, we found moderate agreement between MRI and CT for assessing the anatomic features and lobar extent of disease. Given the feasibility of chest MRI for this condition, future work is warranted to assess the clinical impact of MRI compared with CT in assessing progression of untreated MAC infection and response to treatment over time. PMID- 26633594 TI - Chain Walking as a Strategy for Carbon-Carbon Bond Formation at Unreactive Sites in Organic Synthesis: Catalytic Cycloisomerization of Various 1,n-Dienes. AB - Carbon-carbon bond formation at unreactive sp(3)-carbons in small organic molecules via chain walking was achieved for the palladium-catalyzed cycloisomerization of 1,n-dienes. Various 1,n-dienes (n = 7-14) such as those containing cyclic alkenes, acyclic internal alkenes, and a trisubstituted alkene can be used for the chain-walking cycloisomerization/hydrogenation process, and five-membered ring compounds including simple cyclopentane and pyrrolidine derivatives can easily be prepared. Chain walking over a tertiary carbon was also found to be possible in the cycloisomerization. It is not necessary for the linker portion of the diene to contain a quaternary center, and diene substrates with two alkene moieties linked by a tertiary carbon or a nitrogen atom can also be used as substrates. Column chromatography using silica gel containing silver nitrate was found to be effective for isolating some of the cycloisomerization products without hydrogenation. Deuterium-labeling experiments provided direct evidence to show that the reaction proceeds via a chain-walking mechanism. PMID- 26633592 TI - Instrumental variable approaches to identifying the causal effect of educational attainment on dementia risk. AB - PURPOSE: Education is an established correlate of cognitive status in older adulthood, but whether expanding educational opportunities would improve cognitive functioning remains unclear given limitations of prior studies for causal inference. Therefore, we conducted instrumental variable (IV) analyses of the association between education and dementia risk, using for the first time in this area, genetic variants as instruments as well as state-level school policies. METHODS: IV analyses in the Health and Retirement Study cohort (1998 2010) used two sets of instruments: (1) a genetic risk score constructed from three single-nucleotide polymorphisms (SNPs; n = 7981); and (2) compulsory schooling laws (CSLs) and state school characteristics (term length, student teacher ratios, and expenditures; n = 10,955). RESULTS: Using the genetic risk score as an IV, there was a 1.1% reduction in dementia risk per year of schooling (95% confidence interval, -2.4 to 0.02). Leveraging compulsory schooling laws and state school characteristics as IVs, there was a substantially larger protective effect (-9.5%; 95% confidence interval, -14.8 to -4.2). Analyses evaluating the plausibility of the IV assumptions indicated estimates derived from analyses relying on CSLs provide the best estimates of the causal effect of education. CONCLUSIONS: IV analyses suggest education is protective against risk of dementia in older adulthood. PMID- 26633595 TI - Surface Mechanical and Rheological Behaviors of Biocompatible Poly((D,L-lactic acid-ran-glycolic acid)-block-ethylene glycol) (PLGA-PEG) and Poly((D,L-lactic acid-ran-glycolic acid-ran-epsilon-caprolactone)-block-ethylene glycol) (PLGACL PEG) Block Copolymers at the Air-Water Interface. AB - Air-water interfacial monolayers of poly((D,L-lactic acid-ran-glycolic acid) block-ethylene glycol) (PLGA-PEG) exhibit an exponential increase in surface pressure under high monolayer compression. In order to understand the molecular origin of this behavior, a combined experimental and theoretical investigation (including surface pressure-area isotherm, X-ray reflectivity (XR) and interfacial rheological measurements, and a self-consistent field (SCF) theoretical analysis) was performed on air-water monolayers formed by a PLGA-PEG diblock copolymer and also by a nonglassy analogue of this diblock copolymer, poly((D,L-lactic acid-ran-glycolic acid-ran-caprolactone)-block-ethylene glycol) (PLGACL-PEG). The combined results of this study show that the two mechanisms, i.e., the glass transition of the collapsed PLGA film and the lateral repulsion of the PEG brush chains that occur simultaneously under lateral compression of the monolayer, are both responsible for the observed PLGA-PEG isotherm behavior. Upon cessation of compression, the high surface pressure of the PLGA-PEG monolayer typically relaxes over time with a stretched exponential decay, suggesting that in this diblock copolymer situation, the hydrophobic domain formed by the PLGA blocks undergoes glass transition in the high lateral compression state, analogously to the PLGA homopolymer monolayer. In the high PEG grafting density regime, the contribution of the PEG brush chains to the high monolayer surface pressure is significantly lower than what is predicted by the SCF model because of the many-body attraction among PEG segments (referred to in the literature as the "n-cluster" effects). The end-grafted PEG chains were found to be protein resistant even under the influence of the "n-cluster" effects. PMID- 26633596 TI - Automated Assessment of Right Ventricular Volumes and Function Using Three Dimensional Transesophageal Echocardiography. AB - Assessment of right ventricular (RV) function is known to be of diagnostic value in patients with RV dysfunction. Because of its complex anatomic shape, automated determination of the RV volume is difficult and strong reliance on geometric assumptions is not desired. A method for automated RV assessment was developed using three-dimensional (3-D) echocardiography without relying on a priori knowledge of the cardiac anatomy. A 3-D adaptive filtering technique that optimizes the discrimination between blood and myocardium was applied to facilitate endocardial border detection. Filtered image data were incorporated in a segmentation model to automatically detect the endocardial RV border. End systolic and end-diastolic RV volumes, as well as ejection fraction, were computed from the automatically segmented endocardial surfaces and compared against reference volumes manually delineated by two expert cardiologists. The results reported good performance in terms of correlation and agreement with the results from the reference volumes. PMID- 26633597 TI - Revealing Intermolecular Interaction and Surface Restructuring of an Aromatic Thiol Assembling on Au(111) by Tip-Enhanced Raman Spectroscopy. AB - Controlling the packing structure and revealing the intermolecular interaction of self-assembled monolayers (SAMs) on solid surfaces are crucial for manipulating its properties. We utilized tip-enhanced Raman spectroscopy (TERS) to address the challenge in probing the subtle change of the intermolecular interaction during the assembly of a pyridine-terminated aromatic thiol on the single crystal Au(111) surface that cannot produce enhanced Raman signal, together with electrochemical methods to study the charge transfer properties of SAM. We observed that the aromatic C?C bond stretching vibration can be a marker to monitor the strength of the intermolecular interaction of SAMs, because this Raman peak is very sensitive to the intermolecular pi-pi stacking. Our results indicate that the SAM experiences a surface restructuring after the formation of a densely packed monolayer. We propose that the intermolecular electrostatic repulsion governs the restructuring when the packing density is high. The correlated TERS and electrochemical studies also suggest that the intermolecular interaction may have some impact on the charge transfer properties of SAM. This study provides a molecular-level insight into understanding and exploiting the intermolecular interactions toward better control over the assembling process and tuning the electrical properties of aromatic thiols. PMID- 26633598 TI - Risk of bias assessment should not go beyond reporting assessment. PMID- 26633599 TI - Appropriate statistical methods were infrequently used in cluster-randomized crossover trials. AB - OBJECTIVE: To assess the design and statistical methods used in cluster randomized crossover (CRXO) trials. STUDY DESIGN AND SETTING: We undertook a systematic review of CRXO trials. Searches of MEDLINE, EMBASE, and CINAHL Plus; and citation searches of CRXO methodological articles were conducted to December 2014. We extracted data on design characteristics and statistical methods for sample size, data analysis, and handling of missing data. RESULTS: Ninety-one trials including 139 end point analyses met the inclusion criteria. Trials had a median of nine clusters [interquartile range (IQR), 4-21] and median cluster period size of 30 individuals (IQR, 14-77); 58 (69%) trials had two periods, and 27 trials (30%) included the same individuals in all periods. A rationale for the design was reported in only 25 trials (27%). A sample size justification was provided in 53 (58%) trials. Only nine (10%) trials accounted appropriately for the design in their sample size calculation. Ten of the 12 cluster-level analyses used a method that accounted for the clustering and multiple-period aspects of the design. In contrast, only 4 of the 127 individual-level analyses used a potentially appropriate method. CONCLUSIONS: There is a need for improved application of appropriate analysis and sample size methods, and reporting, in CRXO trials. PMID- 26633600 TI - A full competing risk analysis of hospital-acquired infections can easily be performed by a case-cohort approach. AB - OBJECTIVES: We provide a case-cohort approach and show that a full competing risk analysis is feasible even in a reduced data set. Competing events for hospital acquired infections are death or discharge from the hospital because they preclude the observation of such infections. STUDY DESIGN AND SETTING: Using surveillance data of 6,568 patient admissions (full cohort) from two Spanish intensive care units, we propose a case-cohort approach which uses only data from a random sample of the full cohort and all infected patients (the cases). We combine established methodology to study following measures: event-specific as well as subdistribution hazard ratios for all three events (infection, death, and discharge), cumulative hazards as well as incidence functions by risk factor, and also for all three events. RESULTS: Compared with the values from the full cohort, all measures are well approximated with the case-cohort design. For the event of interest (infection), event-specific and subdistribution hazards can be estimated with the full efficiency of the case-cohort design. So, standard errors are only slightly increased, whereas the precision of estimated hazards of the competing events is inflated according to the size of the subcohort. CONCLUSION: The case-cohort design provides an appropriate sampling design for studying hospital-acquired infections in a reduced data set. Potential effects of risk factors on the competing events (death and discharge) can be evaluated. PMID- 26633601 TI - Prognostic Tests for Estrogen Receptor-Positive Breast Cancer: Need for Global Consideration and Further Evolution. PMID- 26633602 TI - Hibernation in the pygmy slow loris (Nycticebus pygmaeus): multiday torpor in primates is not restricted to Madagascar. AB - Hibernation and short daily torpor are states of energy conservation with reduced metabolism and body temperature. Both hibernation, also called multiday torpor, and daily torpor are common among mammals and occur in at least 11 orders. Within the primates, there is a peculiar situation, because to date torpor has been almost exclusively reported for Malagasy lemurs. The single exception is the African lesser bushbaby, which is capable of daily torpor, but uses it only under extremely adverse conditions. For true hibernation, the geographical restriction was absolute. No primate outside of Madagascar was previously known to hibernate. Since hibernation is commonly viewed as an ancient, plesiomorphic trait, theoretically this could mean that hibernation as an overwintering strategy was lost in all other primates in mainland Africa, Asia, and the Americas. However, we hypothesized that a good candidate species for the use of hibernation, outside of Madagascar should be the pygmy slow loris (Nycticebus pygmaeus), a small primate inhabiting tropical forests. Here, we show that pygmy slow lorises exposed to natural climatic conditions in northern Vietnam during winter indeed undergo torpor lasting up to 63 h, that is, hibernation. Thus, hibernation has been retained in at least one primate outside of Madagascar. PMID- 26633603 TI - Respiratory monitoring with electrical impedance tomography for lung protective ventilation and alveolar recruitment maneuver in a patient with a single lung transplant and early graft dysfunction. AB - A case is presented on a patient who underwent left single lung transplantation for emphysema type COPD. There was early graft dysfunction gradeiii during the immediate postoperative period, which required the implantation of an extracorporeal membrane oxygenator (ECMO). Respirator ventilatory parameters were adjusted to avoid lung distension, low tidal volume (Vc) (280ml), high respiratory rates (20rpm), and a positive pressure at end expiration (PEEP) level of 8cmH2O. On monitoring the pulmonary tidal volume distribution by bedside electrical impedance tomography (EIT), it was noted that most of the tidal volume was distributed in the native lung emphysema. An alveolar recruitment manoeuvre was performed, under control of the EIT, that enabled the current volume and distribution and the pressures required to ventilate the transplanted lung to be observed. PMID- 26633604 TI - Evolution of regional oxygen saturation in the peri-operative of thoracic surgery and its relationship with central venous saturation. AB - OBJECTIVE: To study the relationship between the values of SvcO2 and SrcO2 in lung resection with one lung ventilation (OLV) and changes in these variables and mean arterial pressure (MAP) and arterial oxygen saturation (SpO2) during the perioperative period. MATERIAL AND METHODS: Prospective, observational study of 25 patients in whom pulmonary resection was performed with OLV. The values of MAP, SpO2, SvO2, and SrcO2 were recorded at 6 different times: 1)baseline; 2)double-lung ventilation before the OLV (VBP1); 3)during OLV; 4)after double lung ventilation (VBP2); 5)30minutes after surgery, and 6)6hours after surgery. RESULTS: The SrcO2 showed a significant increase from baseline to starting ventilation (65.72+/-9.05% vs 70.44+/-7.24%; P<.01). There were no significant changes in their values at the different intraoperative times. Post-operatively, as in the case of the SvcO2, a significant decrease (P<.001) of its value compared with the previous value was observed. CONCLUSIONS: SrcO2 showed a significant increase after induction of anaesthesia and initiation of mechanical ventilation compared to baseline, and a significant decrease at the end of surgery after extubation in the immediate postoperative period. Being a tissue monitoring, non-invasive technique and with continuous values it can alert the clinician of changes in the ratio of oxygen consumption (VO2) to oxygen delivery (DO2) at times of greatest risk, such as OLV, extubation, and the early postoperative period. PMID- 26633605 TI - Severe cefepime-induced status epilepticus treated with haemofiltration. AB - Neurotoxicity caused by cefepime may occur predominantly in patients with impaired renal function. A case of a cefepime-induced non-convulsive status epilepticus (NCSE) is presented. A 65-year-old woman suffered a severe NCSE due to cefepime in the presence of acute renal failure, requiring coma induction with sodium thiopental. A serious interaction between valproic acid (VPA) and meropenem was also produced after changing cefepime to meropenem. Continuous veno venous haemofiltration was employed to improve cefepime clearance, and the patient progressively regained her previous mental condition. In conclusion, the cefepime dose must be adjusted according to renal function in order to avoid toxicity in patients with renal failure. Electroencephalogram should be considered in cases of acute confusional state in patients receiving cefepime, to achieve early detection of NCSE. Continuous renal replacement therapy may be successfully employed in severe cases in order to accelerate cefepime removal. Likewise, meropenem should not be used concomitantly with VPA. PMID- 26633607 TI - Paediatricians' most embarrassing moments. PMID- 26633606 TI - Reliability and validity of the Spanish version of the modified Yale Preoperative Anxiety Scale. AB - INTRODUCTION AND OBJECTIVE: To minimise preoperative stress and increase child cooperation during induction of anaesthesia is one of the most important perioperative objectives. The modified Yale Preoperative Anxiety Scale was developed to evaluate anxiety. The aim of this study was to translate into Spanish, and validate the psychometric properties of the Spanish version of this scale. MATERIAL AND METHODS: The Spanish translation of the scale was performed following the World Health Organisation guidelines. During induction of anaesthesia, 81 children aged 2 to 12 years were recorded. Two observers evaluated the recordings independently. Content validity index of modified Yale Preoperative Anxiety Scale Spanish version was assessed. Weighted Kappa was calculated to measure interobserver agreement, and the Pearson correlation between the Induction Compliance Checklist and the modified Yale Preoperative Anxiety Scale was determined. RESULTS: The Spanish version obtained high content validity (0.91 to 0.98). Reliability analysis using weighted Kappa statistics revealed that interobserver agreement ranged from 0.54 to 0.75. Concurrent validity was high (r=0.94; P<.001). CONCLUSIONS: Validated assessment tools are needed to evaluate interventions to reduce child preoperative anxiety. The Spanish version of the modified Yale Preoperative Anxiety Scale evaluated in this study has shown good psychometric properties of reliability and validity. PMID- 26633608 TI - Human papillomavirus vaccination crisis in Japan. AB - The European Academy of Paediatrics (EAP) is gravely concerned about the human papillomavirus (HPV) vaccination crisis in Japan and particularly about the negative position taken by governmental authorities. Given that the HPV vaccine is both safe and effective, there is no recognizable reason to date to withhold this lifesaving and cost effective public health measure from a population. Therefore, the EAP strongly encourages the Japanese health authorities to actively support HPV vaccination for the future health of their children and adolescents. PMID- 26633609 TI - How the system failed Dylan: About the effects of fragmented community child health-care services on patient safety. PMID- 26633610 TI - Tricyclic antidepressants - third-line treatment for attention deficit hyperactivity disorder in school-aged children. PMID- 26633611 TI - Intravenous immunoglobulin in acute Sydenham's chorea: A systematic review. AB - Sydenham's chorea (SC) is a major manifestation seen in 25% of patients with acute rheumatic fever. SC is the prototypic autoimmune neurological disorder, which has a less appreciated associated risk of psychiatric morbidity. We undertook a systematic review to examine whether the use of intravenous immunoglobulin affects clinical recovery and morbidity. PMID- 26633612 TI - Headache, hypertension and seizures. PMID- 26633613 TI - Infant born with a linear and whorled papulovesicular rash with eosinophilia. PMID- 26633620 TI - Implications of circumcision complications for hospital policy. PMID- 26633621 TI - Human parechovirus central nervous system infection: A rare cause of neonatal encephalitis. PMID- 26633622 TI - Long-term costs and outcomes in psoriatic arthritis patients not responding to conventional therapy treated with tumour necrosis factor inhibitors: the extension of the Psoriatic Arthritis Cost Evaluation (PACE) study. AB - OBJECTIVES: Poor information on long-term outcomes and costs on tumour necrosis factor (TNF) inhibitors in psoriatic arthritis (PsA) are available. Our aim was to evaluate long-term costs and benefits of TNF- inhibitors in PsA patients with inadequate response to conventional treatment with traditional disease-modifying anti-rheumatic drugs (tDMARDs). METHODS: Fifty-five out of 107 enrolled patients included in the study at one year, completed the 5-year follow-up period. These patients were enrolled in 8 of 9 centres included in the study at one year. Patients aged older than 18 years, with different forms of PsA and failure or intolerance to tDMARDs therapy were treated with anti-TNF agents. Information on resource use, health-related quality of life (HRQoL), disease activity, function and laboratory values were collected at baseline and through the 5 years of therapy. Costs (expressed in Euro 2011) and utility (measured by EQ-5D instrument) before TNF inhibitor therapy and after 1 and 5 years were compared. RESULTS: The majority of patients (46 out of 55; 83.6%) had a predominant or exclusive peripheral arthritis and 16.4% had predominant or exclusive axial involvement. There was a statistically significant improvement of the most important clinical variables after 1 year of follow-up. These improvements were maintained also after 5 years. The direct costs increased by approximately ?800 per patient-month after 1 year, the indirect costs decreased by ?100 and the overall costs increased by more than ?700 per patient-month due to the cost of TNF inhibitor therapy. Costs at 5 year were similar to the costs at 1 year. The HRQoL parameters showed the same trends of the clinical variables. EQ-5D VAS, EQ 5D utility and SF-36 PCS score showed a significant improvement after 1 year, maintained at 5 years. SF-36 MCS showed an improvement only at 5 years. CONCLUSIONS: The results of our study suggest that TNF blockers have long-term efficacy. The higher cost of TNF inhibitor therapy was balanced by a significant improvement of HRQoL, stable at 5 years of follow-up. Our results need to be confirmed in larger samples of patients. PMID- 26633623 TI - HIV: Cure by killing. PMID- 26633625 TI - Corrigendum: Identification of the pollen self-incompatibility determinant in Papaver rhoeas. PMID- 26633624 TI - Signal integration by Ca(2+) regulates intestinal stem-cell activity. AB - Somatic stem cells maintain tissue homeostasis by dynamically adjusting proliferation and differentiation in response to stress and metabolic cues. Here we identify Ca(2+) signalling as a central regulator of intestinal stem cell (ISC) activity in Drosophila. We show that dietary L-glutamate stimulates ISC division and gut growth. The metabotropic glutamate receptor (mGluR) is required in ISCs for this response, and for an associated modulation of cytosolic Ca(2+) oscillations that results in sustained high cytosolic Ca(2+) concentrations. High cytosolic Ca(2+) concentrations induce ISC proliferation by regulating Calcineurin and CREB-regulated transcriptional co-activator (Crtc). In response to a wide range of dietary and stress stimuli, ISCs reversibly transition between Ca(2+) oscillation states that represent poised or activated modes of proliferation, respectively. We propose that the dynamic regulation of intracellular Ca(2+) levels allows effective integration of diverse mitogenic signals in ISCs to adapt their proliferative activity to the needs of the tissue. PMID- 26633626 TI - Microbiomes: Curating communities from plants. PMID- 26633627 TI - Corrigendum: Domains of genome-wide gene expression dysregulation in Down's syndrome. PMID- 26633629 TI - Planetary science: How the Solar System didn't form. PMID- 26633628 TI - Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. AB - In recent years, several associations between common chronic human disorders and altered gut microbiome composition and function have been reported. In most of these reports, treatment regimens were not controlled for and conclusions could thus be confounded by the effects of various drugs on the microbiota, which may obscure microbial causes, protective factors or diagnostically relevant signals. Our study addresses disease and drug signatures in the human gut microbiome of type 2 diabetes mellitus (T2D). Two previous quantitative gut metagenomics studies of T2D patients that were unstratified for treatment yielded divergent conclusions regarding its associated gut microbial dysbiosis. Here we show, using 784 available human gut metagenomes, how antidiabetic medication confounds these results, and analyse in detail the effects of the most widely used antidiabetic drug metformin. We provide support for microbial mediation of the therapeutic effects of metformin through short-chain fatty acid production, as well as for potential microbiota-mediated mechanisms behind known intestinal adverse effects in the form of a relative increase in abundance of Escherichia species. Controlling for metformin treatment, we report a unified signature of gut microbiome shifts in T2D with a depletion of butyrate-producing taxa. These in turn cause functional microbiome shifts, in part alleviated by metformin-induced changes. Overall, the present study emphasizes the need to disentangle gut microbiota signatures of specific human diseases from those of medication. PMID- 26633631 TI - Functional overlap of the Arabidopsis leaf and root microbiota. AB - Roots and leaves of healthy plants host taxonomically structured bacterial assemblies, and members of these communities contribute to plant growth and health. We established Arabidopsis leaf- and root-derived microbiota culture collections representing the majority of bacterial species that are reproducibly detectable by culture-independent community sequencing. We found an extensive taxonomic overlap between the leaf and root microbiota. Genome drafts of 400 isolates revealed a large overlap of genome-encoded functional capabilities between leaf- and root-derived bacteria with few significant differences at the level of individual functional categories. Using defined bacterial communities and a gnotobiotic Arabidopsis plant system we show that the isolates form assemblies resembling natural microbiota on their cognate host organs, but are also capable of ectopic leaf or root colonization. While this raises the possibility of reciprocal relocation between root and leaf microbiota members, genome information and recolonization experiments also provide evidence for microbiota specialization to their respective niche. PMID- 26633630 TI - Corrigendum: A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma. PMID- 26633632 TI - Replication stress activates DNA repair synthesis in mitosis. AB - Oncogene-induced DNA replication stress has been implicated as a driver of tumorigenesis. Many chromosomal rearrangements characteristic of human cancers originate from specific regions of the genome called common fragile sites (CFSs). CFSs are difficult-to-replicate loci that manifest as gaps or breaks on metaphase chromosomes (termed CFS 'expression'), particularly when cells have been exposed to replicative stress. The MUS81-EME1 structure-specific endonuclease promotes the appearance of chromosome gaps or breaks at CFSs following replicative stress. Here we show that entry of cells into mitotic prophase triggers the recruitment of MUS81 to CFSs. The nuclease activity of MUS81 then promotes POLD3-dependent DNA synthesis at CFSs, which serves to minimize chromosome mis-segregation and non-disjunction. We propose that the attempted condensation of incompletely duplicated loci in early mitosis serves as the trigger for completion of DNA replication at CFS loci in human cells. Given that this POLD3-dependent mitotic DNA synthesis is enhanced in aneuploid cancer cells that exhibit intrinsically high levels of chromosomal instability (CIN(+)) and replicative stress, we suggest that targeting this pathway could represent a new therapeutic approach. PMID- 26633633 TI - Dense magnetized plasma associated with a fast radio burst. AB - Fast radio bursts are bright, unresolved, non-repeating, broadband, millisecond flashes, found primarily at high Galactic latitudes, with dispersion measures much larger than expected for a Galactic source. The inferred all-sky burst rate is comparable to the core-collapse supernova rate out to redshift 0.5. If the observed dispersion measures are assumed to be dominated by the intergalactic medium, the sources are at cosmological distances with redshifts of 0.2 to 1 (refs 10 and 11). These parameters are consistent with a wide range of source models. One fast burst revealed circular polarization of the radio emission, but no linear polarization was detected, and hence no Faraday rotation measure could be determined. Here we report the examination of archival data revealing Faraday rotation in the fast radio burst FRB 110523. Its radio flux and dispersion measure are consistent with values from previously reported bursts and, accounting for a Galactic contribution to the dispersion and using a model of intergalactic electron density, we place the source at a maximum redshift of 0.5. The burst has a much higher rotation measure than expected for this line of sight through the Milky Way and the intergalactic medium, indicating magnetization in the vicinity of the source itself or within a host galaxy. The pulse was scattered by two distinct plasma screens during propagation, which requires either a dense nebula associated with the source or a location within the central region of its host galaxy. The detection in this instance of magnetization and scattering that are both local to the source favours models involving young stellar populations such as magnetars over models involving the mergers of older neutron stars, which are more likely to be located in low-density regions of the host galaxy. PMID- 26633634 TI - Biodiversity: Recovery as nitrogen declines. PMID- 26633635 TI - Grassland biodiversity bounces back from long-term nitrogen addition. AB - The negative effect of increasing atmospheric nitrogen (N) pollution on grassland biodiversity is now incontrovertible. However, the recent introduction of cleaner technologies in the UK has led to reductions in the emissions of nitrogen oxides, with concomitant decreases in N deposition. The degree to which grassland biodiversity can be expected to 'bounce back' in response to these improvements in air quality is uncertain, with a suggestion that long-term chronic N addition may lead to an alternative low biodiversity state. Here we present evidence from the 160-year-old Park Grass Experiment at Rothamsted Research, UK, that shows a positive response of biodiversity to reducing N addition from either atmospheric pollution or fertilizers. The proportion of legumes, species richness and diversity increased across the experiment between 1991 and 2012 as both wet and dry N deposition declined. Plots that stopped receiving inorganic N fertilizer in 1989 recovered much of the diversity that had been lost, especially if limed. There was no evidence that chronic N addition has resulted in an alternative low biodiversity state on the Park Grass plots, except where there has been extreme acidification, although it is likely that the recovery of plant communities has been facilitated by the twice-yearly mowing and removal of biomass. This may also explain why a comparable response of plant communities to reduced N inputs has yet to be observed in the wider landscape. PMID- 26633636 TI - Barcoding reveals complex clonal dynamics of de novo transformed human mammary cells. AB - Most human breast cancers have diversified genomically and biologically by the time they become clinically evident. Early events involved in their genesis and the cellular context in which these events occur have thus been difficult to characterize. Here we present the first formal evidence of the shared and independent ability of basal cells and luminal progenitors, isolated from normal human mammary tissue and transduced with a single oncogene (KRAS(G12D)), to produce serially transplantable, polyclonal, invasive ductal carcinomas within 8 weeks of being introduced either subrenally or subcutaneously into immunodeficient mice. DNA barcoding of the initial cells revealed a dramatic change in the numbers and sizes of clones generated from them within 2 weeks, and the first appearance of many 'new' clones in tumours passaged into secondary recipients. Both primary and secondary tumours were phenotypically heterogeneous and primary tumours were categorized transcriptionally as 'normal-like'. This system challenges previous concepts that carcinogenesis in normal human epithelia is necessarily a slow process requiring the acquisition of multiple driver mutations. It also presents the first description of initial events that accompany the genesis and evolution of malignant human mammary cell populations, thereby contributing new understanding of the rapidity with which heterogeneity in their properties can develop. PMID- 26633637 TI - Welcome to the preexposure prophylaxis revolution. PMID- 26633638 TI - Current concepts for PrEP adherence in the PrEP revolution: from clinical trials to routine practice. AB - PURPOSE OF REVIEW: The review describes the current understanding of adherence to oral preexposure prophylaxis (PrEP), methods for adherence measurement, approaches to supporting PrEP adherence, and guidance for defining PrEP adherence goals within the larger context of HIV prevention. RECENT FINDINGS: PrEP adherence has generally been higher in recent trials, open-label extensions, and demonstration projects compared with the initial clinical trials; potential explanations include known PrEP efficacy and different motivations to take PrEP. Recent studies have explored adherence monitoring through electronic pill containers, short message service (SMS), and drug concentrations in hair and dried blood spots. The few PrEP adherence interventions developed to date include combinations of enhanced counseling, feedback of objective adherence measurement, and SMS. Conceptualization of PrEP adherence is evolving. The goal is not 100% adherence indefinitely, as it was in clinical trials. PrEP adherence should be defined with respect to HIV exposure, which varies over time by sexual behavior and use of other prevention strategies. SUMMARY: PrEP adherence beyond clinical trials has generally been high enough to achieve reliable HIV prevention. Future efforts to measure and support PrEP adherence should focus on the context of risk for HIV acquisition, accounting for dynamic behaviors and choices among HIV prevention options. PMID- 26633639 TI - Promise and pitfalls of pre-exposure prophylaxis for female sex workers. AB - PURPOSE OF REVIEW: We explore the potential benefits of integrating preexposure prophylaxis (PrEP) into combination HIV prevention for female sex workers (FSWs) and the likely challenges to implementation. RECENT FINDINGS: Evidence for the biological effectiveness of PrEP in women who can adhere to daily dosing is strong. FSWs in many countries bear the brunt of the HIV epidemic. Current combination prevention approaches enable many FSWs to remain HIV-free, but in some settings FSWs are unable to mitigate their risk. PrEP provides a new prevention tool for these women. To benefit, HIV-negative FSWs need to perceive that they are at risk, be motivated and able to take PrEP daily and to attend health services for prescription refill and clinical monitoring. FSWs face particular structural challenges to PrEP uptake and use, including stigmatizing health services; fear of disclosure to other FSWs and clients; fear of the authorities; lack of social support; substance use; unplanned travel and risk compensation many of which can be addressed through combination prevention approaches. SUMMARY: For those FSWs who are unable to mitigate their HIV risk, PrEP, if adequately supported and integrated with combination prevention, may empower them to remain HIV-free. PMID- 26633640 TI - Should we fear resistance from tenofovir/emtricitabine preexposure prophylaxis? AB - PURPOSE OF REVIEW: To review current data on HIV-1 resistance arising from the use of fixed dose combination tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) for preexposure prophylaxis (PrEP) to prevent HIV-1 infection. RECENT FINDINGS: Resistance to tenofovir (TNV) or FTC is infrequently selected by TDF/FTC PrEP if started before HIV-1 infection has occurred, but is much more common when inadvertently started during undiagnosed acute infection. Mathematical modeling predicts that the number of HIV-1 infections averted by the use of PrEP far exceeds the increase in drug-resistant infections that could occur from PrEP. Studies in macaques show that TNV-resistant virus but not FTC resistant virus can cause breakthrough infection despite TDF/FTC PrEP. FTC resistance with M184 V/I occurs more frequently than TFV resistance with K65R in seroconverters from clinical trials of TDF/FTC PrEP. SUMMARY: The benefit of preventing HIV-1 infections with TDF/FTC PrEP far outweighs the risk of drug resistant infection, provided PrEP is not started in persons with undiagnosed HIV 1 infection. We should respect but not fear HIV-1 resistance from TDF/FTC PrEP and recognize that most TNV or FTC resistance will arise from its use for antiretroviral therapy (ART). Preventing ART failure or detecting it early is most important for preventing the spread of HIV-1 resistance to TDF/FTC and preserving its effectiveness for both PrEP and ART. PMID- 26633641 TI - Nondaily preexposure prophylaxis for HIV prevention. AB - PURPOSE OF REVIEW: To discuss nondaily preexposure prophylaxis (PrEP) modalities that may provide advantages compared with daily PrEP in cost and cumulative toxicity, but may have lower adherence forgiveness. RECENT FINDINGS: Animal models have informed our understanding of early viral transmission events, which help guide event-driven PrEP dosing strategies. These models indicate early establishment of viral replication in rectal or cervicovaginal tissues, so event driven PrEP should rapidly deliver high mucosal drug concentrations within hours of the potential exposure event. Macaque models have demonstrated the high biological efficacy for event-driven dosing of oral tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) against both vaginal and rectal virus transmission. In humans, the IPERGAY study demonstrated 86% efficacy for event-driven oral TDF/FTC dosing among men who have sex with men (MSM), while no similar efficacy data are available on women or heterosexual men. The HPTN 067 study showed that certain MSM populations adhere well to nondaily PrEP, whereas other populations of women adhere more poorly to nondaily versus daily regimens. Pharmacokinetic studies following oral TDF/FTC dosing in humans indicate that TFV-diphosphate (the active form of TFV) accumulates to higher concentrations in rectal versus cervicovaginal tissue, but nonadherence in trials complicates the interpretation of differential mucosal drug concentrations. SUMMARY: Event-driven dosing for TFV based PrEP has promise for HIV prevention in MSM. Future research of event-driven PrEP in women and heterosexual men should be guided by a better understanding of the importance of mucosal drug concentrations for PrEP efficacy and its sensitivity to adherence. PMID- 26633642 TI - Ethical considerations regarding oral preexposure prophylaxis in HIV prevention trials. AB - PURPOSE OF REVIEW: Although substantial evidence supports oral preexposure prophylaxis with tenofovir disoproxil fumarate and emtricitabine (OPTF) for the primary prevention of HIV infection in certain settings, assessing whether other promising HIV prevention interventions are safe and effective as well as determining optimal prevention strategies necessitates research. However, given the established safety and efficacy of OPTF, it is necessary to determine when and how is it ethically acceptable to conduct this research, which is the focus of this review. RECENT FINDINGS: Although they are somewhat intertwined, questions regarding OPTF in research can be considered in two broad categories: use in a comparison arm and as a standard of prevention. Major statements addressing these issues are described and recent literature directed at the particular issue of OPTF in research is reviewed and critiqued. SUMMARY: There is now arguably a rebuttable presumption for the use of OPTF as a comparator or as part of the standard of prevention in much future HIV prevention research. However, making such determinations necessitates taking into account scientific considerations, the modality being evaluated, acceptability, adherence, and the local context. Doing so should be optimized by robust stakeholder engagement. PMID- 26633643 TI - The promise and pitfalls of long-acting injectable agents for HIV prevention. AB - PURPOSE OF REVIEW: Preexposure prophylaxis for HIV prevention is highly effective when taken as prescribed. Adherence to required dosing regimens for protection may pose challenges. Long-acting agents for HIV prevention may have the potential to improve adherence via favorable pharmacokinetics supportive of infrequent dosing. This review focuses on the potential benefits and considerations for the study and use of 2 long-acting injectable agents, cabotegravir (GSK1265744LA, CAB LA) and rilpivirine (TMC278LA, RPV LA), for use as chemoprophylaxis for HIV prevention. RECENT FINDINGS: Oral RPV is United States Food and Drug Administration approved for HIV treatment (in combination with other antiretrovirals). Both CAB LA and RPV LA are currently in phase 2a safety/tolerability/pharmacokinetic studies in anticipation and support of future efficacy evaluation. Both agents have favorable pharmacokinetics, and use is complicated by injection site reactions. SUMMARY: Long-acting injectable formulations, if safe and well tolerated, may improve pharmacokinetic coverage of exposures to HIV infection. Complexities around safety, tolerability, and starting/stopping protocols require careful consideration. PMID- 26633645 TI - Mirrored STDP Implements Autoencoder Learning in a Network of Spiking Neurons. AB - The autoencoder algorithm is a simple but powerful unsupervised method for training neural networks. Autoencoder networks can learn sparse distributed codes similar to those seen in cortical sensory areas such as visual area V1, but they can also be stacked to learn increasingly abstract representations. Several computational neuroscience models of sensory areas, including Olshausen & Field's Sparse Coding algorithm, can be seen as autoencoder variants, and autoencoders have seen extensive use in the machine learning community. Despite their power and versatility, autoencoders have been difficult to implement in a biologically realistic fashion. The challenges include their need to calculate differences between two neuronal activities and their requirement for learning rules which lead to identical changes at feedforward and feedback connections. Here, we study a biologically realistic network of integrate-and-fire neurons with anatomical connectivity and synaptic plasticity that closely matches that observed in cortical sensory areas. Our choice of synaptic plasticity rules is inspired by recent experimental and theoretical results suggesting that learning at feedback connections may have a different form from learning at feedforward connections, and our results depend critically on this novel choice of plasticity rules. Specifically, we propose that plasticity rules at feedforward versus feedback connections are temporally opposed versions of spike-timing dependent plasticity (STDP), leading to a symmetric combined rule we call Mirrored STDP (mSTDP). We show that with mSTDP, our network follows a learning rule that approximately minimizes an autoencoder loss function. When trained with whitened natural image patches, the learned synaptic weights resemble the receptive fields seen in V1. Our results use realistic synaptic plasticity rules to show that the powerful autoencoder learning algorithm could be within the reach of real biological networks. PMID- 26633646 TI - Systemic Medical Treatment in Men with Metastatic Castration-Resistant Prostate Cancer: Recommendations for Daily Routine. AB - The approval or clinical evaluation of several new agents - cabazitaxel, abiraterone acetate, enzalutamide, sipuleucel-T, and radium-223 - has significantly changed the management of patients with metastatic castration resistant prostate cancer (mCRPC) prior to or after docetaxel-based chemotherapy. All of these agents have resulted in a significant survival benefit as compared to their control group. However, treatment responses might differ depending on the associated comorbidities and the extent and biological aggressiveness of the disease. Furthermore, treatment-associated side effects differ between the various drugs. As new drugs become approved, new treatment strategies and markers to best select which patients will best respond to which drug are needed. It is the aim of the current article to i) summarize the data of established treatment options in mCRPC, ii) highlight new developments in medical treatment, iii) provide clinically useful algorithms for the daily routine, and iv) point out future developments in medical treatment. PMID- 26633647 TI - A Systematic Review of the Application And Correlates of YFAS-Diagnosed 'Food Addiction' in Humans: Are Eating-Related 'Addictions' a Cause for Concern or Empty Concepts? AB - The proposition of so-called 'food addiction' (FA) in the scientific literature has stimulated a recent surge in research and debate. The concept of FA is controversial, and opinion is divided. Many of the findings depend upon the use of a single instrument called the Yale Food Addiction Scale (YFAS). This review systematically examined FA, as defined by the YFAS, reported in 40 experimental human studies published in or after 2009. The results indicated that much of the literature makes the supposition that food addiction is an accepted neurobiological disease, consistent with substance use disorders; an interpretation based on very limited data. This raises the question as to whether those individuals who meet the YFAS criteria for diagnosis are truly 'addicted' to food or if they experience significant impairment to their psychological wellbeing and quality of life as would be expected in clinically recognised addictive disorders. At the present time, little research has investigated the extent to which a psychometric self-assessment of FA symptomatology can elucidate a harmful relationship with target foods in the diet. A positive YFAS diagnosis is usually positively associated with BMI and strongly linked with the presence of binge eating, but certain exceptions within the literature were revealed. Further clarification is required as to whether so-called FA is sufficiently different to existing conditions and traits to warrant classification as a distinctive disease phenotype rather than an expression of strong habits and preferences. PMID- 26633648 TI - Experimental Crossing of Two Distinct Species of Leopard Geckos, Eublepharis angramainyu and E. macularius: Viability, Fertility and Phenotypic Variation of the Hybrids. AB - Hybridization between distinct species of animals and subsequent genetic introgression plays a considerable role in the speciation process and the emergence of adaptive characters. Fitness of between-species hybrids usually sharply decreases with the divergence time of the concerned species and the divergence depth, which still allows for a successful crossing differs among principal clades of vertebrates. Recently, a review of hybridization events among distinct lizard species revealed that lizards belong to vertebrates with a highly developed ability to hybridize. In spite of this, reliable reports of experimental hybridizations between genetically fairly divergent species are only exceptional. Here, we show the results of the crossing of two distinct allopatric species of eyelid geckos possessing temperature sex determination and lacking sex chromosomes: Eublepharis macularius distributed in Pakistan/Afghanistan area and E. angramainyu, which inhabits Mesopotamia and adjacent areas. We demonstrated that F1 hybrids were viable and fertile, and the introgression of E. angramainyu genes into the E. macularius genome can be enabled via a backcrossing. The examined hybrids (except those of the F2 generation) displayed neither malformations nor a reduced survival. Analyses of morphometric and coloration traits confirmed phenotypic distinctness of both parental species and their F1 hybrids. These findings contrast with long-term geographic and an evolutionary separation of the studied species. Thus, the occurrence of fertile hybrids of comparably divergent species, such as E. angramainyu and E. macularius, may also be expected in other taxa of squamates. This would violate the current estimates of species diversity in lizards. PMID- 26633649 TI - Antimicrobial Resistance in Escherichia coli Recovered from Feedlot Cattle and Associations with Antimicrobial Use. AB - The objectives of this study were to estimate the prevalence of antimicrobial resistance (AMR) and to investigate the associations between exposures to antimicrobial drugs (AMDs) and AMR in fecal non-type specific Escherichia coli (NTSEC) recovered from a large population of feedlot cattle. Two-stage random sampling was used to select individually identified cattle for enrollment, which were sampled at arrival and then a second time later in the feeding period. Advanced regression techniques were used to estimate resistance prevalences, and to investigate associations between AMD exposures in enrolled cattle and penmates and AMR identified in NTSEC recovered from the second sample set. Resistance was most commonly detected to tetracycline, streptomycin, and sulfisoxazole, and was rarely identified for critically important AMDs. All cattle were exposed to AMDs in feed, and 45% were treated parenterally. While resistance prevalence generally increased during the feeding period, most AMD exposures were not significantly associated with AMR outcomes. Exposures of enrolled cattle to tetracycline were associated with increased resistance to tetracycline and trimethoprim sulfa, while beta-lactam exposures were associated with decreased likelihood of detecting streptomycin resistance. Pen-level AMD exposure measures were not associated with resistance outcomes. These findings suggest that tetracycline treatment of feedlot cattle can be associated with modest increases in risk for recovery of resistant NTSEC, but the numerous treatments with an advanced macrolide (tulathromycin) were not associated with detectable increases in resistance in NTSEC. All cattle were exposed to in-feed treatments of tetracycline and this could limit the ability to identify the full impact of these exposures, but these exposures varied for enrolled cattle varied, providing an opportunity to evaluate a dose response. While AMD exposures were not associated with detectably increased risks for resistance to critically important AMDs, rare resistance outcomes and infrequent exposure to other important AMDs (e.g., cephalosporins) limited our ability to rigorously investigate questions regarding factors that can influence resistance to these important AMDs. PMID- 26633650 TI - Crisis intervention for people with severe mental illnesses. AB - BACKGROUND: A particularly difficult challenge for community treatment of people with serious mental illnesses is the delivery of an acceptable level of care during the acute phases of severe mental illness. Crisis-intervention models of care were developed as a possible solution. OBJECTIVES: To review the effects of crisis-intervention models for anyone with serious mental illness experiencing an acute episode compared to the standard care they would normally receive. If possible, to compare the effects of mobile crisis teams visiting patients' homes with crisis units based in home-like residential houses. SEARCH METHODS: We searched the Cochrane Schizophrenia Group's Study-Based Register of Trials. There is no language, time, document type, or publication status limitations for inclusion of records in the register. This search was undertaken in 1998 and then updated 2003, 2006, 2010 and September 29, 2014. SELECTION CRITERIA: We included all randomised controlled trials of crisis-intervention models versus standard care for people with severe mental illnesses that met our inclusion criteria. DATA COLLECTION AND ANALYSIS: We independently extracted data from these trials and we estimated risk ratios (RR) or mean differences (MD), with 95% confidence intervals (CI). We assessed risk of bias for included studies and used GRADE to create a 'Summary of findings' table. MAIN RESULTS: The update search September 2014 found no further new studies for inclusion, the number of studies included in this review remains eight with a total of 1144 participants. Our main outcomes of interest are hospital use, global state, mental state, quality of life, participant satisfaction and family burden. With the exception of mental state, it was not possible to pool data for these outcomes.Crisis intervention may reduce repeat admissions to hospital (excluding index admissions) at six months (1 RCT, n = 369, RR 0.75 CI 0.50 to 1.13, high quality evidence), but does appear to reduce family burden (at six months: 1 RCT, n = 120, RR 0.34 CI 0.20 to 0.59, low quality evidence), improve mental state (Brief Psychiatric Rating Scale (BPRS) three months: 2 RCTs, n = 248, MD -4.03 CI -8.18 to 0.12, low quality evidence), and improve global state (Global Assessment Scale (GAS) 20 months; 1 RCT, n = 142, MD 5.70, -0.26 to 11.66, moderate quality evidence). Participants in the crisis-intervention group were more satisfied with their care 20 months after crisis (Client Satisfaction Questionnaire (CSQ-8): 1 RCT, n = 137, MD 5.40 CI 3.91 to 6.89, moderate quality evidence). However, quality of life scores at six months were similar between treatment groups (Manchester Short Assessment of quality of life (MANSA); 1 RCT, n = 226, MD -1.50 CI -5.15 to 2.15, low quality evidence). Favourable results for crisis intervention were also found for leaving the study early and family satisfaction. No differences in death rates were found. Some studies suggested crisis intervention to be more cost-effective than hospital care but all numerical data were either skewed or unusable. We identified no data on staff satisfaction, carer input, complications with medication or number of relapses. AUTHORS' CONCLUSIONS: Care based on crisis intervention principles, with or without an ongoing homecare package, appears to be a viable and acceptable way of treating people with serious mental illnesses. However only eight small studies with unclear blinding, reporting and attrition bias could be included and evidence for the main outcomes of interest is low to moderate quality. If this approach is to be widely implemented it would seem that more evaluative studies are still needed. PMID- 26633651 TI - Discrimination of Multiple Coronal Stop Contrasts in Wubuy (Australia): A Natural Referent Consonant Account. AB - Native speech perception is generally assumed to be highly efficient and accurate. Very little research has, however, directly examined the limitations of native perception, especially for contrasts that are only minimally differentiated acoustically and articulatorily. Here, we demonstrate that native speech perception may indeed be more difficult than is often assumed, where phonemes are highly similar, and we address the nature and extremes of consonant perception. We present two studies of native and non-native (English) perception of the acoustically and articulatorily similar four-way coronal stop contrast /t t [symbol: see text] t/ (apico-alveolar, apico-retroflex, lamino-dental, lamino alveopalatal) of Wubuy, an indigenous language of Australia. The results show that all listeners find contrasts involving /t/ easy to discriminate, but that, for both groups, contrasts involving /t t [symbol: see text]/ are much harder. Where the two groups differ, the results largely reflect native language (Wubuy vs English) attunement as predicted by the Perceptual Assimilation Model. We also observe striking perceptual asymmetries in the native listeners' perception of contrasts involving the latter three stops, likely due to the differences in input frequency. Such asymmetries have not previously been observed in adults, and we propose a novel Natural Referent Consonant Hypothesis to account for the results. PMID- 26633652 TI - Are Interferon-Free Direct-Acting Antivirals for the Treatment of HCV Enough to Control the Epidemic among People Who Inject Drugs? AB - BACKGROUND: Widely access to interferon-free direct-acting antiviral regimens (IFN-free DAA) is poised to dramatically change the impact of the HCV epidemic among people who inject drugs (PWID). We evaluated the long-term effect of increasing HCV testing, treatment and engagement into harm-reduction activities, focused on active PWID, on the HCV epidemic in British Columbia (BC), Canada. METHODS: We built a compartmental model of HCV disease transmission stratified by disease progression, transmission risk, and fibrosis level. We explored the effect of: (1) Increasing treatment rates from 8 to 20, 40 and 80 per 1000 infected PWID/year; (2) Increasing treatment eligibility based on fibrosis level; (3) Maximizing the effect of testing by performing it immediately upon ending the acute phase; (4) Increasing access to harm-reduction activities to reduce the risk of re-infection; (5) Different HCV antiviral regimens on the Control Reproduction Number Rc. We assessed the impact of these interventions on incidence, prevalence and mortality from 2016 to 2030. RESULTS: Of all HCV antiviral regimens, only IFN-free DAAs offered a high chance of disease elimination (i.e. Rc < 1), but it would be necessary to substantially increase the current low testing and treatment rates. Assuming a treatment rate of 80 per 1000 infected PWID per year, coupled with a high testing rate, the incidence rate, at the end of 2030, could decrease from 92.9 per 1000 susceptible PWID per year (Status Quo) to 82.8 (by treating only PWID with fibrosis level F2 and higher) or to 65.5 (by treating PWID regardless of fibrosis level). If PWID also had access to increased harm-reduction activities, the incidence rate further decreased to 53.1 per 1000 susceptible PWID per year. We also obtained significant decreases in prevalence and mortality at the end of 2030. CONCLUSIONS: The combination of increased access to HCV testing, highly efficacious antiviral treatment and harm-reduction programs can substantially decrease the burden of the HCV epidemic among PWID. However, unless we increase the current levels of treatment and testing, the HCV epidemic among PWID in BC, and in other parts of the world with similar epidemiological background, will remain a substantial public health concern for many years. PMID- 26633653 TI - Opposing Effects of Zac1 and Curcumin on AP-1-Regulated Expressions of S100A7. AB - ZAC, an encoding gene mapped at chromosome 6q24-q25 within PSORS1, was previously found over-expressed in the lower compartment of the hyperplastic epidermis in psoriatic lesions. Cytokines produced in the inflammatory dermatoses may drive AP 1 transcription factor to induce responsive gene expressions. We demonstrated that mZac1 can enhance AP-1-responsive S100A7 expression of which the encoding gene was located in PSORS4 with HaCaT keratinocytes. However, the mZac1-enhanced AP-1 transcriptional activity was suppressed by curcumin, indicating the anti inflammatory property of this botanical agent and is exhibited by blocking the AP 1-mediated cross-talk between PSORS1 and PSORS4. Two putative AP-1-binding sites were found and demonstrated to be functionally important in the regulation of S100A7 promoter activity. Moreover, we found curcumin reduced the DNA-binding activity of AP-1 to the recognition element located in the S100A7 promoter. The S100A7 expression was found to be upregulated in the lesioned epidermis of atopic dermatitis and psoriasis, which is where this keratinocyte-derived chemoattractant engaged in the pro-inflammatory feedback loop. Understanding the regulatory mechanism of S100A7 expression will be helpful to develop therapeutic strategies for chronic inflammatory dermatoses via blocking the reciprocal stimuli between the inflammatory cells and keratinocytes. PMID- 26633655 TI - The Rho GTPase Family Genes in Bivalvia Genomes: Sequence, Evolution and Expression Analysis. AB - BACKGROUND: Rho GTPases are important members of the Ras superfamily, which represents the largest signaling protein family in eukaryotes, and function as key molecular switches in converting and amplifying external signals into cellular responses. Although numerous analyses of Rho family genes have been reported, including their functions and evolution, a systematic analysis of this family has not been performed in Mollusca or in Bivalvia, one of the most important classes of Mollusca. RESULTS: In this study, we systematically identified and characterized a total set (Rho, Rac, Mig, Cdc42, Tc10, Rnd, RhoU, RhoBTB and Miro) of thirty Rho GTPase genes in three bivalve species, including nine in the Yesso scallop Patinopecten yessoensis, nine in the Zhikong scallop Chlamys farreri, and twelve in the Pacific oyster Crassostrea gigas. Phylogenetic analysis and interspecies comparison indicated that bivalves might possess the most complete types of Rho genes in invertebrates. A multiple RNA-seq dataset was used to investigate the expression profiles of bivalve Rho genes, revealing that the examined scallops share more similar Rho expression patterns than the oyster, whereas more Rho mRNAs are expressed in C. farreri and C. gigas than in P. yessoensis. Additionally, Rho, Rac and Cdc42 were found to be duplicated in the oyster but not in the scallops. Among the expanded Rho genes of C. gigas, duplication pairs with high synonymous substitution rates (Ks) displayed greater differences in expression. CONCLUSION: A comprehensive analysis of bivalve Rho GTPase family genes was performed in scallop and oyster species, and Rho genes in bivalves exhibit greater conservation than those in any other invertebrate. This is the first study focusing on a genome-wide characterization of Rho GTPase genes in bivalves, and the findings will provide a valuable resource for a better understanding of Rho evolution and Rho GTPase function in Bivalvia. PMID- 26633658 TI - The American Ambulance in Paris, 1914-1917. Part I: The Creation of the American Ambulance. PMID- 26633656 TI - Environmental Transmission of Typhoid Fever in an Urban Slum. AB - BACKGROUND: Enteric fever due to Salmonella Typhi (typhoid fever) occurs in urban areas with poor sanitation. While direct fecal-oral transmission is thought to be the predominant mode of transmission, recent evidence suggests that indirect environmental transmission may also contribute to disease spread. METHODS: Data from a population-based infectious disease surveillance system (28,000 individuals followed biweekly) were used to map the spatial pattern of typhoid fever in Kibera, an urban informal settlement in Nairobi Kenya, between 2010 2011. Spatial modeling was used to test whether variations in topography and accumulation of surface water explain the geographic patterns of risk. RESULTS: Among children less than ten years of age, risk of typhoid fever was geographically heterogeneous across the study area (p = 0.016) and was positively associated with lower elevation, OR = 1.87, 95% CI (1.36-2.57), p <0.001. In contrast, the risk of typhoid fever did not vary geographically or with elevation among individuals more than ten years of age [corrected]. CONCLUSIONS: Our results provide evidence of indirect, environmental transmission of typhoid fever among children, a group with high exposure to fecal pathogens in the environment. Spatially targeting sanitation interventions may decrease enteric fever transmission. PMID- 26633657 TI - Primordial Follicle Transplantation within Designer Biomaterial Grafts Produce Live Births in a Mouse Infertility Model. AB - The gonadotoxic effects of chemotherapy and radiation may result in premature ovarian failure in premenopausal oncology patients. Although autotransplantation of ovarian tissue has led to successful live births, reintroduction of latent malignant cells inducing relapse is a significant concern. In this report, we investigated the design of biomaterial grafts for transplantation of isolated ovarian follicles as a means to preserve fertility. Primordial and primary ovarian follicles from young female mice were extracted and encapsulated into biomaterials for subsequent transplantation into adult mice. Among the formulations tested, aggregated follicles encapsulated within fibrin had enhanced survival and integration with the host tissue following transplantation relative to the fibrin-alginate and fibrin-collagen composites. All mice transplanted with fibrin-encapsulated follicles resumed cycling, and live births were achieved only for follicles transplanted within VEGF-loaded fibrin beads. The extent to which these procedures reduce the presence of metastatic breast cancer cells among the isolated follicles was evaluated, with significantly reduced numbers of cancer cells present relative to intact ovaries. This ability to obtain live births by transplanting isolated primordial and primary follicles, while also reducing the risk of re-seeding disease relative to ovarian tissue transplantation, may ultimately provide a means to preserve fertility in premenopausal oncology patients. PMID- 26633659 TI - Should Military Care Providers Force-Feed Detainees? PMID- 26633660 TI - SEVAK Project in India and Guyana Modeled After the Independent Duty Corpsman of the U.S. Navy. PMID- 26633661 TI - 26-Year-Old Man With Shortness of Breath After Open Ocean Swim. PMID- 26633662 TI - Adventures in Convoy Ops: The Perspective of a Registered Nurse Who Found Himself on the Front Line. PMID- 26633663 TI - Needle Thoracotomy in Trauma. AB - Tension pneumothorax is one of the leading causes of preventable death in trauma patients. Needle thoracotomy (NT) is the currently accepted first-line intervention but has not been well validated. In this review, we have critically discussed the evidence for NT procedure, re-examined the recommendations by the Advanced Trauma Life Support organization and investigated the safest and most effective way of NT. The current evidence to support the use of NT is limited. However, when used, it should be applied in the 2nd intercostal space at midclavicular line using a catheter length of at least 4.5 cm. Alternative measures should be studied for better prehospital management of tension pneumothorax. PMID- 26633664 TI - Radiographic Changes and Fracture in Patients Having Received Bisphosphonate Therapy for >= 5 Years at a Single Institution. AB - INTRODUCTION: Bisphosphonates have been shown to reduce the incidence of vertebral fractures, as well as intertrochanteric and femoral neck fractures; however, data also demonstrate the association of prolonged use and atypical femur fractures. We intend to report the incidence of atypical femur fractures and cortical irregularities in patients from a single institution having received prolonged bisphosphonate therapy. METHODS: A retrospective review of the pharmaceutical database was performed for all patients who were prescribed bisphosphonates at a single institution from 2002 to 2012. People taking bisphosphonates for >= 5 years were included. Those identified as having adequate radiographs with visualization of at least 5-cm distal to the lesser trochanter were selected. Radiographs were reviewed for evidence of atypical femur fractures or lateral cortical beaking. Medical records were retrospectively reviewed to determine any prodromal symptoms or clinical risk factors. RESULTS: A total of 7,671 patients were identified between the years of 2002 and 2012 as having been prescribed bisphosphonates at a single institution. Of these, 1,684 were using bisphosphonates for >= 5 years (2002-2007). 396 patients taking bisphosphonates for greater than 5 years had adequate radiographs. In total, 8 patients (2.02%) had positive findings; 7 were females. More specifically, 2 (0.51%) patients had incomplete subtrochanteric fractures while 6 (1.52%) demonstrated lateral cortical beaking. DISCUSSION/CONCLUSION: Over 2% of patients at our institution having received bisphosphonate therapy for >= 5 years demonstrated cortical irregularities or have already experienced an atypical femur fracture. These findings could call into question the need for radiographic screening for patients on prolonged bisphosphonate therapy. PMID- 26633665 TI - Survey of Retired Military Pharmacist's Transition to a Civilian Pharmacy Career Path. AB - PURPOSE: To explore variables relevant to transition to civilian pharmacy career path for retiring military pharmacists. METHODS: A cross-sectional survey was designed to collect information from retired military pharmacists including demographics, military service information, postretirement employment and perceptions of transition, satisfaction, level of responsibility, work environment, rewards (level of financial compensation, opportunities for professional development and career advancement, health benefits), and level of supervisory support. The questionnaire also included additional items asking about their perception of their military experience, transition to civilian work and the impact the military career had on their personal and family life. RESULTS: Respondents included 140 retired pharmacists from the U.S. Army, Navy, Air Force, or Coast Guard. Factors found to be significant predictors of transition to civilian career included: bureaucracy in current job, time elapsed since retirement, extent to which an individual misses military structure and chain of command, access to military facilities and Veterans Administration benefits, and reporting little or no stress in committed long-term personal relationship while in the military. CONCLUSION: Findings suggest that the majority of retired military pharmacists perceived the transition to civilian professional sector was about what they expected or easier than expected. PMID- 26633666 TI - Identification of Fall Prevention Strategies for the Military: A Review of the Literature. AB - In the U.S. Army, falls have historically been among the top five causes of hospitalization and a leading cause of nonbattle injuries in military operations overseas. OBJECTIVE: For safety and public health professionals, commanders, and supervisors looking to address this problem, a literature review was conducted to identify and summarize existing fall prevention strategies applicable to a working-age population. METHODS: A total of nine literature databases were searched for articles published from 1970 to 2011. Article titles and abstracts were screened to select original research with an injury or noninjury outcome. Intervention studies were reviewed in detail and quality scored by 3 public health scientists. RESULTS: The search identified over 2,200 articles. Of these, 525 met inclusion criteria and were reviewed in more detail, resulting in identification of 9 interventions. Nearly all of the identified interventions had been implemented in occupational environments. Study quality was rated and scores ranged from 4.5 to 8.0 (maximum 10 points). CONCLUSIONS: Few intervention studies were identified. Multifaceted programs showed the greatest promise for translation to military environments. Additional evaluation research is greatly needed to further efforts to address this leading military public health problem. PMID- 26633667 TI - Relationships Between Physical Fitness, Demands of Flight Duty, and Musculoskeletal Symptoms Among Military Pilots. AB - Although the mechanisms of G-induced stresses on the spinal structure of military pilots are well understood, less is known about relationships between the intensity of physical activity, fitness, occupational musculoskeletal symptoms, and the degree of resulting disabilities. During an aeromedical examination, Finnish military pilots answered a questionnaire on their flying experience, the occurrence of flight duty-related pain, the degree of resulting disabilities, and the intensity of physical activity they conducted. 195 males were selected for further analysis. They were divided into three groups, designated high G, low G, and HQ, according to their current flight duty profile. 93% of pilots who had passed fighter lead-in training reported flight duty-induced musculoskeletal disorders. The high-G group exhibited the highest aerobic capacity (p < 0.001) and muscular fitness scores (p < 0.001). The fittest individuals suffered markedly fewer disabilities than their less fit counterparts (p = 0.005). Flight hour accumulation among the subjects in the high-G group was associated (p = 0.010) with the occurrence of flight duty-induced disabilities. The fittest pilots flew aircraft that induce the heaviest accelerations. They also reported more musculoskeletal pain than the other pilots. Yet they seemed to experience fewer disabilities, which highlights the importance of physical training in the maintenance of operational readiness. PMID- 26633669 TI - Research on U.S. Military Women: Recruitment and Retention Challenges and Strategies. AB - OBJECTIVES: To examine literature on recruitment and retention of military women in research studies as an underrepresented, and potentially marginalized, population. METHODS: A literature search was conducted to examine challenges, identify potential barriers and facilitators, and to inform strategies for recruitment and retention of military women in research studies. This search was supplemented by findings in military-specific databases and discussions with Military Women's Health Research Interest Group subject matter experts. RESULTS: Ten articles addressed research recruitment and retention challenges and strategies in marginalized/underrepresented populations, providing an effective context to inform research recruitment and retention in military settings. Research with military women is often challenged by logistical, cultural, social, ethical, and methodological issues, which may hinder exploration of potentially sensitive issues. DISCUSSION: Researchers must consider military-specific challenges to conducting research that include lengthy deployments, unpredictable military exercises, and foreign assignments, in accessing research participants. A case example shows strategies used in a military cervical cancer screening study. CONCLUSION: There are few published articles specific to research recruitment and retention in female military populations. Available resources broadly address recruitment challenges for Veterans, marginalized, hard-to access, and transient research participants, which may provide guidance and strategies for success when applied to military populations. PMID- 26633668 TI - Suboptimal Nutritional Characteristics in Male and Female Soldiers Compared to Sports Nutrition Guidelines. AB - The purpose of this study was to evaluate the nutrient intake of male and female Soldiers in the 101 st Airborne Division (Air Assault) compared to sports nutrition standards for athletes, and to identify suboptimal eating characteristics that may impair physical performance and jeopardize military readiness. Male and female Soldiers from the 101 st Airborne Division (Air Assault) completed a 24-hour dietary recall and nutrition history questionnaire before anthropometric and body composition measurements were taken. Compared to sports nutrition guidelines, Soldiers of the 101 st under consume carbohydrates (males: 3.9 +/- 2.0 vs. 5.0 g/kg, p < 0.001; females: 4.0 +/- 2.1 vs. 5.0 g/kg, p = 0.001), male Soldiers eat too much fat (32.4% of kcal vs. <30% of kcal, p = 0.000) and saturated fat (males: 10.5 +/- 3.9% of kcal vs. 10.0% of kcal, p = 0.044), and both males and females follow a meal pattern that may not optimize energy availability throughout the day. Eating too much fat and under fueling carbohydrate may negatively impact the adaptations to physical training and compromise overall health. Although Soldiers continue to participate in arduous training programs, future research should be aimed at determining the energy and macronutrient needs to fuel and recover from specific types of military training. PMID- 26633670 TI - Investigation of Self-Reported Musculoskeletal Injuries on Post-Deployment Health Assessment Forms for Aeromedical Evacuation Personnel. AB - Musculoskeletal injuries (MSIs) are a concern for the military community because of medical expenses, possible disability, and separation from the military. This study investigated the prevalence of MSIs in deployed aeromedical evacuation (AE) populations reported on Post-Deployment Health Assessment (PDHA) forms. A secondary aim was to examine the relationship between the occurrence of self reported MSIs on PDHAs and a subsequent medical diagnosis. Flight nurses (Air Force Specialty Code [AFSC] 46F) and AE technicians (AETs) (AFSC 4N0 with a flight duty badge) who completed a PDHA during 2008-2010 were investigated. Data from the test population were compared with a control group of deployed ground based counterparts. During this time period, 1,366 and 1,959 PDHAs were completed by the AE nursing and AET groups, respectively. At least 1 MSI was reported by 18% of AE nurse and 19% of AET compared with 23% of non-AE nurse and 25% of non AET PDHAs. Of these individuals with reported MSIs, 35% and 44% of AE nurse and AET PDHAs, respectively, had a diagnosis matching their MSIs. Identifying the prevalence of MSIs in the unique AE environment can lead to the development of preventative and ergonomic solutions, minimizing the risk of MSIs and improving mission success. PMID- 26633671 TI - Age and Aortic Diameters in Pilots. AB - BACKGROUND: Pilots are exposed to various physical and hemodynamic stresses during flight. Aortic dilatation may be one of the important consequences of flight-related stress. In this study, we evaluated whether or not variation in aortic diameter was associated with the type of aircraft and the age of pilots. MATERIALS AND METHODS: Medical records of 87 jet aircraft pilots (JP) (mean age = 30.0 +/- 7.0 years) and 65 non-jet aircraft pilots (NJP) (mean age = 32.63 +/- 5.7) were reviewed. Echocardiographic diameters of the aortic sinus (AoS) and ascending aorta (AoAsc) were measured using standard echo probe positions. RESULTS: Aortic diameters were not statistically different between JP and NJP. Regression analysis revealed that the diameters of the AoS (R = 0.484, R(2) = 0.234, p < 0.001) and AoAsc (R = 0.514, R(2) = 0.264, p < 0.001) were significantly associated with age in the JP group. Whereas, there was not any relationship found between age and the diameters of the AoS and AoAsc in the NJP group. CONCLUSION: Jet pilots had aortic enlargement as they became older in contrast to the NJP group. Although the aortic diameters were not within the critical ranges in the JP group, these results could suggest that flight-related stresses might result in acute aortic syndromes in the long term. PMID- 26633672 TI - A Wearable Device Providing a Visual Fixation Point for the Alleviation of Motion Sickness Symptoms. AB - OBJECTIVES: Motion sickness (MS) can be problematic for many military operations. Some pharmaceutical countermeasures are effective but can lead to side effects. Non-pharmaceutical countermeasures vary in effectiveness and can require time to be beneficial (e.g., desensitization). Previous research suggests that visual fixation can alleviate MS symptoms. In the current experiment we tested the effectiveness of a user-worn device that provides a visual fixation point that moves with the user. METHODS: Fourteen subjects viewed the interior of a rotating optokinetic drum (60 degrees /s) through a visor that displayed either a clear view of the scene (control) or the scene with a fixation point (experimental). After 5 minutes of viewing, symptoms were assessed using (1) the Simulator Sickness Questionnaire that yields four scores (total, nausea, oculomotor, and disorientation) and (2) a 0 to 10 MS overall scale. RESULTS: Viewing the fixation point resulted in significantly lower scores for all measures. Control condition scores were as much as 400% higher than when the fixation point was viewed. CONCLUSIONS: A wearable device that presents a visual fixation point that moves with the user may reduce MS. The device's portability suggests that it may be suitable for some military operations, and additional research in the field is warranted. PMID- 26633673 TI - The Surprising Origins of a World War II-Era Mural That Was Nearly Lost. PMID- 26633674 TI - Unusual Late Presentation of Hemophilia A in an Active Duty U.S. Marine Following Open Shoulder Surgery. AB - Hemophilia A is clotting disorder affecting 8:100,000 males in the United States. It is an X-linked recessive genetic disorder, although about one-third of cases occur spontaneously without known family history. Because of the risk of uncontrolled hemorrhage on the battlefield, hemophilia and other bleeding disorders exclude individuals from service in the U.S. military. We report a case of an active duty U.S. Marine whose underlying diagnosis of Hemophilia A was discovered and treated by a multidisciplinary team of orthopedic surgeons and hematologists following recurrent hematomas after open rotator cuff surgery. The patient gave informed consent for publication. PMID- 26633675 TI - Palliative Cryotherapy of Aggressive Endobronchial Parotid Carcinoma ex Pleomorphic Adenoma: A Case Report. AB - Carcinoma ex pleomorphic adenoma is a rare salivary gland malignancy with a poor prognosis that can metastasize to the lungs. Endobronchial metastasis and associated bronchoscopic characteristics have not been described in the literature. Cryotherapy is a safe and efficacious palliative treatment option for obstructive bronchial tumors that can be performed with flexible bronchoscopy. We report the successful use of cryotherapy for the palliation of an aggressive parotid malignancy with extraordinary endobronchial metastases and describe bronchoscopic characteristics of this unique entity. PMID- 26633676 TI - Autologous Internal Iliac Artery Graft in a Popliteal Artery Injury Defect in War Surgery. AB - A 23-year-old Afghan National Policeman sustained a right popliteal artery injury secondary to a ground-based blast. Initial treatment was an application of a tourniquet, and after triage at a local civilian hospital a shunt was placed, 3 hours after the initial injury, and then was transferred to Kabul for definitive care, 24 hours after injury. Extensive trauma to both legs precluded use of greater saphenous vein as a graft. To avoid an above-the-knee amputation, a branch of the internal iliac artery was harvested for grafting. Postoperative computed tomography angiography indicated the presence of excellent flow, and he was discharged fully ambulatory on postoperative day 17. Autologous arterial grafting has only been used infrequently, and in this case represents innovation in a low-resource environment. Surgical training in Afghanistan has seen great strides at the National Hospital. If this patient were treated at any other facility, he likely would have had a high amputation. Without advising or direction of coalition surgeons, the Afghan Trauma Team independently made the decision to harvest the artery and salvage the limb, and this is one example of how coalition support has bolstered the confidence of Afghan surgeons to develop unconventional solutions to conventional problems. PMID- 26633677 TI - A Heavy Protection. AB - The wearing of individual protective elements has revolutionized the typology of war wounds. The benefit/risk ratio is particularly satisfying, but several side effects with minor consequences are described, calling for further ergonomic development from manufacturers of these protective elements. This case report describes a meralgia paresthetica by compression of the lateral cutaneous thigh nerve because of the wearing of bulletproof vest. A symptomatic treatment was introduced, and 2 months after the apparition of the symptoms, the patient's condition has improved, with only a slight hypoesthesia remaining. PMID- 26633678 TI - 6'6" United States Marine Seeks Treatment for Gynecomastia Only to Learn It Is All in His Head. AB - Growth Hormone (GH) excess is an uncommon cause of gynecomastia encountered in primary care. Adults with GH excess (acromegaly) have a 72% increase in mortality compared with the general population, which is reversible with early detection and intervention. Currently, however, the diagnosis of acromegaly is often delayed up to 12 years because of the subtle onset of symptoms. We present an active duty male diagnosed with acromegaly after presenting to his primary care provider with chronic gynecomastia. The most common cause of GH excess is a pituitary somatotroph adenoma; however, it is important to remember that magnetic resonance imaging of the pituitary does not distinguish between functioning and nonfunctioning tumors. Subsequently, the diagnosis of GH excess is based on biochemical studies, not imaging. PMID- 26633679 TI - Beware of the Beetle: A Case Report of Severe Vesicating Dermatitis. AB - INTRODUCTION: Outbreaks of Paederus dermatitis have been documented worldwide. A case of Paederus dermatitis from Ethiopia is presented to highlight the importance of this clinical entity in the deployed setting. CASE PRESENTATION: A 31-year-old male presented with a 3- day history of scattered areas of a purulent, vesicating erythematous rash to his mid-back and neck. The largest of these measured 5 * 7 cm with erythematous borders and an erosive center. One to 2 days prior, 15 troops reported similar and less severe vesicating lesions to their extremities and backs. All patients participated in the same outdoor recreational event. A survey of the event's location revealed signs of the Paederus beetle. DISCUSSION: Although a known phenomenon, there are no literature reports of Paederus dermatitis within AFRICOM. Crushing the Paederus beetle against the skin causes an intense rash because of paederin in the hemolymph. Most present with typical linear lesions likely caused by brushing off the beetle from the skin. Fortunately, patients respond favorably to topical steroid treatment. CONCLUSION: Paederus beetle exposure in the deployed setting can impact force health. Increased awareness among providers and personnel should mitigate potential exposure and limit the morbidity associated with this beetle. PMID- 26633681 TI - Effects of Increased Nitrogen Availability on C and N Cycles in Tropical Forests: A Meta-Analysis. AB - Atmospheric N deposition is predicted to increase four times over its current status in tropical forests by 2030. Our ability to understand the effects of N enrichment on C and N cycles is being challenged by the large heterogeneity of the tropical forest biome. The specific response will depend on the forest's nutrient status; however, few studies of N addition appear to incorporate the nutrient status in tropical forests, possibly due to difficulties in explaining how this status is maintained. We used a meta-analysis to explore the consequences of the N enrichment on C and N cycles in tropical montane and lowland forests. We tracked changes in aboveground and belowground plant C and N and in mineral soil in response to N addition. We found an increasing trend of plant biomass in montane forests, but not in lowland forests, as well as a greater increase in NO emission in montane forest compared with lowland forest. The N2O and NO emission increase in both forest; however, the N2O increase in lowland forest was significantly even at first time N addition. The NO emission increase showed be greater at first term compared with long term N addition. Moreover, the increase in total soil N, ammonium, microbial N, and dissolved N concentration under N enrichment indicates a rich N status of lowland forests. The available evidence of N addition experiments shows that the lowland forest is richer in N than montane forests. Finally, the greater increase in N leaching and N gas emission highlights the importance of study the N deposition effect on the global climate change. PMID- 26633680 TI - Patient Preferences for Biologicals in Psoriasis: Top Priority of Safety for Cardiovascular Patients. AB - Patients with psoriasis are often affected by comorbidities, which largely influence treatment decisions. Here we performed conjoint analysis to assess the impact of comorbidities on preferences of patients with moderate-to-severe psoriasis for outcome (probability of 50% and 90% improvement, time until response, sustainability of success, probability of mild and severe adverse events (AE), probability of ACR 20 response) and process attributes (treatment location, frequency, duration and delivery method) of biologicals. The influence of comorbidities on Relative Importance Scores (RIS) was determined with analysis of variance and multivariate regression. Among the 200 participants completing the study, 22.5% suffered from psoriatic arthritis, 31.5% from arterial hypertension, 15% from cardiovascular disease (myocardial infarction, stroke, coronary artery disease, and/or arterial occlusive disease), 14.5% from diabetes, 11% from hyperlipidemia, 26% from chronic bronchitis or asthma and 12.5% from depression. Participants with psoriatic arthritis attached greater importance to ACR 20 response (RIS = 10.3 vs. 5.0, p<0.001; beta = 0.278, p<0.001) and sustainability (RIS = 5.8 vs. 5.0, p = 0.032) but less value to time until response (RIS = 3.4 vs. 4.8, p = 0.045) than those without arthritis. Participants with arterial hypertension were particularly interested in a low risk of mild AE (RIS 9.7 vs. 12.1; p = 0.033) and a short treatment duration (RIS = 8.0 vs. 9.6, p = 0.002). Those with cardiovascular disease worried more about mild AE (RIS = 12.8 vs. 10, p = 0.027; beta = 0.170, p = 0.027) and severe AE (RIS = 23.2 vs. 16.2, p = 0.001; beta = 0.203, p = 0.007) but cared less about time until response (beta = -0.189, p = 0.013), treatment location (beta = 0.153, p = 0.049), frequency (beta = -0.20, p = 0.008) and delivery method (beta = -0.175, p = 0.023) than others. Patients' concerns should be addressed in-depth when prescribing biologicals to comorbid patients, keeping in mind that TNF antagonists may favourably influence cardiovascular risk. PMID- 26633682 TI - Correction: Investigating the Relationships among Stressors, Stress Level, and Mental Symptoms for Infertile Patients: A Structural Equation Modeling Approach. PMID- 26633683 TI - Insulin degludec (Tresiba)--a new long-acting insulin for diabetes. PMID- 26633684 TI - Drugs past their expiration date. PMID- 26633685 TI - Deoxycholic acid (Kybella) for double chin. PMID- 26633686 TI - Ferric citrate (Auryxia) for hyperphosphatemia. PMID- 26633687 TI - Nivolumab (Opdivo) plus ipilimumab (Yervoy) for metastatic melanoma. PMID- 26633688 TI - Nocebo Effect of Informed Consent in Interventional Procedures. PMID- 26633689 TI - Sensitization and Serological Biomarkers in Knee Osteoarthritis Patients With Different Degrees of Synovitis. AB - OBJECTIVE: Synovitis is a frequent condition in knee osteoarthritis (KOA) and has been associated with pain. This study investigated the links between the pressure hyperalgesia, the clinical pain, the degree of the synovitis, inflammatory biomarkers, and tissue-specific biomarkers in KOA patients. MATERIALS AND METHODS: Fifty-eight KOA patients and 33 pain-free controls participated in this study. The patients were magnetic resonance imaging scanned, and the Boston-Leeds OA Knee Score (BLOKS, 0 to 3) was used to assess the degree of synovitis. The maximal knee pain intensity over the last 24 hours was scored on a visual analog scale (VAS). The pressure pain thresholds (PPTs) were assessed over the KOA affected knee. Serological biomarkers were measured in fasting serum: high sensitive C-reactive protein, matrix metalloproteinase-mediated degradation of CRP, and matrix metalloproteinase-mediated collagen type I, II, and III degradation (C1M [connective tissue], C2M [cartilage], C3M [synovial membrane]). RESULTS: Compared with controls, the KOA patients showed increased levels of C1M (P<0.02), C2M (P<0.001), and high-sensitive C-reactive protein (P<0.02), decreased level of C3M (P<0.03), and reduced PPTs (P<0.03). Patients with no (BLOKS 0) and moderate to severe (BLOKS 2&3) synovitis had significantly lower PPTs compared with mild synovitis (BLOKS 1). Significantly negative correlations were found between VAS and PPTs. No correlations were found between BLOKS and the VAS, PPT, or biomarkers. DISCUSSION: Patients without and with moderate to severe synovitis demonstrated local pressure hyperalgesia and increased degrees of: (1) systemic inflammation, (2) connective tissue degradation, (3) cartilage degradation, and (4) decreased synovial membrane degradation as compared with controls. PMID- 26633690 TI - The Effects of Anesthetic Technique on Postoperative Opioid Consumption in Ankle Fracture Surgery. AB - OBJECTIVES: To investigate the impact of common anesthetic techniques on postoperative opioid consumption in ankle fracture surgery. MATERIALS AND METHODS: We performed a retrospective cohort study on 622 patients with isolated ankle fractures undergoing primary reconstructive surgery. Patients were identified by consecutive screening in the years 2008 to 2011. Our primary endpoint was the difference in the 24-hour postoperative opioid consumption after general anesthesia (GA) compared with different regional anesthesia modalities. Secondary endpoints were length of stay in the postanesthesia care unit, risk of postoperative nausea and vomiting, and postoperative length of hospital stay. RESULTS: Opioid consumption in 4 anesthesia groups (equipotent doses of IV morphine) was as follows: GA: 21.9 mg (95% confidence interval [CI]+/-1.2), GA+peripheral nerve block (PNB): 16.3 mg (95% CI+/-1.1), spinal anesthesia (SA): 17.1 mg (95% CI+/-0.9), and SA+PNB: 14.6 mg (95% CI+/-1.0). We found significant differences between "GA" and all other groups (P<=0.01). The most pronounced difference is seen when GA is compared with SA+PNB, with a 33.4% opioid reduction in the latter group. DISCUSSION: Regional anesthesia modalities reduce postoperative opioid consumption in ankle fracture surgery in comparison with GA. A benefit of PNBs is possibly due to an improved pain profile. Our study is retrospective and cannot predict the exact magnitude of this benefit. PMID- 26633691 TI - Functional Status, Quality of Life, and Costs Associated With Fibromyalgia Subgroups: A Latent Profile Analysis. AB - OBJECTIVES: Although fibromyalgia syndrome (FM) is considered a heterogeneous condition, there is no generally accepted subgroup typology. We used hierarchical cluster analysis and latent profile analysis to replicate Giesecke's classification in Spanish FM patients. The second aim was to examine whether the subgroups differed in sociodemographic characteristics, functional status, quality of life, and in direct and indirect costs. MATERIALS AND METHODS: A total of 160 FM patients completed the following measures for cluster derivation: the Center for Epidemiological Studies-Depression Scale, the Trait Anxiety Inventory, the Pain Catastrophizing Scale, and the Control over Pain subscale. Pain threshold was measured with a sphygmomanometer. In addition, the Fibromyalgia Impact Questionnaire-Revised, the EuroQoL-5D-3L, and the Client Service Receipt Inventory were administered for cluster validation. RESULTS: Two distinct clusters were identified using hierarchical cluster analysis ("hypersensitive" group, 69.8% and "functional" group, 30.2%). In contrast, the latent profile analysis goodness-of-fit indices supported the existence of 3 FM patient profiles: (1) a "functional" profile (28.1%) defined as moderate tenderness, distress, and pain catastrophizing; (2) a "dysfunctional" profile (45.6%) defined by elevated tenderness, distress, and pain catastrophizing; and (3) a "highly dysfunctional and distressed" profile (26.3%) characterized by elevated tenderness and extremely high distress and catastrophizing. We did not find significant differences in sociodemographic characteristics between the 2 clusters or among the 3 profiles. The functional profile was associated with less impairment, greater quality of life, and lower health care costs. DISCUSSION: We identified 3 distinct profiles which accounted for the heterogeneity of FM patients. Our findings might help to design tailored interventions for FM patients. PMID- 26633692 TI - Immunohistochemical analyses of cell cycle progression and gene expression of biliary epithelial cells during liver regeneration after partial hepatectomy of the mouse. AB - The liver has a remarkable regeneration capacity, and, after surgical removal of its mass, the remaining tissue undergoes rapid regeneration through compensatory growth of its constituent cells. Although hepatocytes synchronously proliferate under the control of various signaling molecules from neighboring cells, there have been few detailed analyses on how biliary cells regenerate for their cell population after liver resection. The present study was undertaken to clarify how biliary cells regenerate after partial hepatectomy of mice through extensive analyses of their cell cycle progression and gene expression using immunohistochemical and RT-PCR techniques. When expression of PCNA, Ki67 antigen, topoisomerase IIalpha and phosphorylated histone H3, which are cell cycle markers, was immunohistochemically examined during liver regeneration, hepatocytes had a peak of the S phase and M phase at 48-72 h after resection. By contrast, biliary epithelial cells had much lower proliferative activity than that of hepatocytes, and their peak of the S phase was delayed. Mitotic figures were rarely detectable in biliary cells. RT-PCR analyses of gene expression of biliary markers such as Spp1 (osteopontin), Epcam and Hnf1b demonstrated that they were upregulated during liver regeneration. Periportal hepatocytes expressed some of biliary markers, including Spp1 mRNA and protein. Some periportal hepatocytes had downregulated expression of HNF4alpha and HNF1alpha. Gene expression of Notch signaling molecules responsible for cell fate decision of hepatoblasts to biliary cells during development was upregulated during liver regeneration. Notch signaling may be involved in biliary regeneration. PMID- 26633693 TI - Binding and Oligomerization of Modified and Native Bt Toxins in Resistant and Susceptible Pink Bollworm. AB - Insecticidal proteins from Bacillus thuringiensis (Bt) are used extensively in sprays and transgenic crops for pest control, but their efficacy is reduced when pests evolve resistance. Better understanding of the mode of action of Bt toxins and the mechanisms of insect resistance is needed to enhance the durability of these important alternatives to conventional insecticides. Mode of action models agree that binding of Bt toxins to midgut proteins such as cadherin is essential for toxicity, but some details remain unresolved, such as the role of toxin oligomers. In this study, we evaluated how Bt toxin Cry1Ac and its genetically engineered counterpart Cry1AcMod interact with brush border membrane vesicles (BBMV) from resistant and susceptible larvae of Pectinophora gossypiella (pink bollworm), a global pest of cotton. Compared with Cry1Ac, Cry1AcMod lacks 56 amino acids at the amino-terminus including helix alpha-1; previous work showed that Cry1AcMod formed oligomers in vitro without cadherin and killed P. gossypiella larvae harboring cadherin mutations linked with >1000-fold resistance to Cry1Ac. Here we found that resistance to Cry1Ac was associated with reduced oligomer formation and insertion. In contrast, Cry1AcMod formed oligomers in BBMV from resistant larvae. These results confirm the role of cadherin in oligomerization of Cry1Ac in susceptible larvae and imply that forming oligomers without cadherin promotes toxicity of Cry1AcMod against resistant P. gossypiella larvae that have cadherin mutations. PMID- 26633694 TI - Lipid Fingerprinting in Mild versus Severe Forms of Gestational Diabetes Mellitus. AB - The blood serum lipid profile of women with Gestational Diabetes Mellitus (GDM) is still under study. There are no data on the serum lipid profile of GDM patients with more severe (insulin treated) compared to milder forms (diet treated) GDM. The aim of our study was to analyze the blood serum lipid profile of patients with milder versus more severe forms of GDM and to compare these findings with those of healthy pregnant women. This cross-sectional analytical study included 30 insulin-treated GDM, 30 diet-only GDM and 30 healthy pregnant women. Serum lipid was extracted from the 90 participants and their lipid profiles were analyzed by lipid fingerprinting using liquid-chromatography-mass spectrometry. A total of 143 parent ions were differentially represented in each of the three groups, belonging to the following classes: Glycerophospholipids, Sterol Lipids, Sphingolipids, Prenol Lipids, Fatty Acyls and Glycerolipids. There were significant differences in the lipid profiles of healthy pregnant women compared to GDM patients and also between milder versus more severe forms of GDM. There are marked differences in lipid fingerprinting between healthy pregnant women compared to those with GDM in the third trimester. Moreover, the lipid profile of women with more severe forms of GDM differs considerably from that of women with milder forms of GDM. These findings may be useful to help clarify the pathogenesis of milder and more severe forms of GDM. PMID- 26633698 TI - Epidemiology of Takayasu's arteritis in Turkey. AB - OBJECTIVES: To estimate the prevalence and incidence of Takayasu arteritis (TA) among the residents of the city of Izmir, the third largest metropolis in Turkey. METHODS: Five tertiary care teaching hospitals, which were the only ones that provided rheumatology specialty care during the study period in the city of Izmir from 2006 through 2010, were invited to take part in the present study. A case search was performed electronically in the information systems of these hospitals using The International Classification of Diseases Tenth Revision (ICD-10) code for Takayasu arteritis (M31.4). The diagnosis was confirmed through chart review by a rheumatologist according to the 1990 American College of Rheumatology (ACR) criteria. Annual prevalence was calculated based on the number of patients that were alive at the end of 2010. Age- and sex-adjusted prevalence rates were standardised according to the 2010 Turkish population, based on 2010 Turkish Census. RESULTS: A total of 41 patients were confirmed to have TA and also to live within the targeted area. The annual prevalence was estimated as 12.8 (95% CI 12.0-13.6) per million; 23.5/million (95% CI 21.9-25.0) in females and 1.9/million (95% CI 1.5-2.4) in males. The prevalence was higher 8.8/million (95% CI 7.7-10.0) in the population >40 years of age. During the study period, the mean annual incidence of TA was estimated as 1.11/million (95% CI 0.54-1.67). CONCLUSIONS: The first epidemiologic study of TA in a Turkish population suggests that TA is a relatively common vasculitis in Turkey. PMID- 26633699 TI - Variation in Operating Characteristics of Residential Care Communities, by Size of Community: United States, 2014. AB - KEY FINDINGS: Assisted living and similar residential care communities provide services to individuals who cannot live independently but generally do not require the skilled level of care provided by nursing homes. In 2014, there were 30,200 residential care communities nationwide (1). This report presents the most current national estimates of residential care community operating characteristics and compares these characteristics by community bed size. State level estimates for the characteristics presented in this report are available from http://www.cdc.gov/nchs/nsltcp/nsltcp_products.htm. PMID- 26633700 TI - Impact of metabolic comorbidities on outcomes of patients with acute pancreatitis: a scoping review. AB - With the increasing prevalence of metabolic comorbidities, their impact on outcomes of patients with acute pancreatitis needs to be considered. Metabolic comorbidities, such as diabetes mellitus, obesity, and metabolic syndrome, have been shown to have a role to play in the course of disease. This scoping review aims to map published clinical studies that have investigated the impact of metabolic comorbidities on outcomes in patients with acute pancreatitis. PMID- 26633695 TI - An Evolution-Based Screen for Genetic Differentiation between Anopheles Sister Taxa Enriches for Detection of Functional Immune Factors. AB - Nucleotide variation patterns across species are shaped by the processes of natural selection, including exposure to environmental pathogens. We examined patterns of genetic variation in two sister species, Anopheles gambiae and Anopheles coluzzii, both efficient natural vectors of human malaria in West Africa. We used the differentiation signature displayed by a known coordinate selective sweep of immune genes APL1 and TEP1 in A. coluzzii to design a population genetic screen trained on the sweep, classified a panel of 26 potential immune genes for concordance with the signature, and functionally tested their immune phenotypes. The screen results were strongly predictive for genes with protective immune phenotypes: genes meeting the screen criteria were significantly more likely to display a functional phenotype against malaria infection than genes not meeting the criteria (p = 0.0005). Thus, an evolution based screen can efficiently prioritize candidate genes for labor-intensive downstream functional testing, and safely allow the elimination of genes not meeting the screen criteria. The suite of immune genes with characteristics similar to the APL1-TEP1 selective sweep appears to be more widespread in the A. coluzzii genome than previously recognized. The immune gene differentiation may be a consequence of adaptation of A. coluzzii to new pathogens encountered in its niche expansion during the separation from A. gambiae, although the role, if any of natural selection by Plasmodium is unknown. Application of the screen allowed identification of new functional immune factors, and assignment of new functions to known factors. We describe biochemical binding interactions between immune proteins that underlie functional activity for malaria infection, which highlights the interplay between pathogen specificity and the structure of immune complexes. We also find that most malaria-protective immune factors display phenotypes for either human or rodent malaria, with broad specificity a rarity. PMID- 26633701 TI - BRAFp.V600E, p.V600K, and p.V600R Mutations in Malignant Melanoma: Do They Also Differ in Immunohistochemical Assessment and Clinical Features? AB - INTRODUCTION: Although the detection of BRAF p.V600E mutation by immunohistochemistry was clearly described in melanoma, discordant evidences were reported for the detection of p.V600K and p.V600R mutations. The aim of the study was to evaluate the efficacy of BRAFp.V600E, p.V600K, and p.V600R detection by immunohistochemistry in melanoma. MATERIALS AND METHODS: Immunohistochemistry with VE1 antibody was performed on 18 tissue samples of metastatic melanomas with known BRAF mutational status. RESULTS: The concordance rate of immunohistochemistry was 100% for p.V600E mutation. In contrast, the 7 p.V600K mutated melanomas were scored as negative. p.V600K-mutated melanomas were significantly associated with older age, male sex, and worst clinical outcome. CONCLUSIONS: Immunohistochemistry could efficaciously be adopted as a first step for the detection of BRAFp.V600E mutation in the initial selection of patients with advanced melanomas as candidates for BRAF inhibitors. It should be followed by molecular techniques in p.V600E-negative melanomas, for the specific search of p.V600K and other non-p.V600E BRAF mutations. PMID- 26633702 TI - Stepwise Protocol for Cytospin-enhanced Smearing for Scraped Corneal Epithelial Cells. AB - Proteins and antigens present on the cell surface are usually determined by immunofluorescence staining. Uniform distribution of cells is required to appreciate the presence of surface proteins. Improper smearing or crushing of the corneal epithelial cells can potentially destroy the cellular integrity. Thus a simplified, systemic method was designed to smear the cells scraped from the cornea. The procedure includes trypsinisation for dissociation of corneal epithelial cells and cytospinning for concentrating the cells in a smear. The standardized protocol was found to be efficient in maintaining the integrity of the corneal epithelial cells and also the distribution of the cells in the smear. PMID- 26633703 TI - Limited Utility of p63 in the Sole Evaluation of Suspected Oropharyngeal Squamous Cell Carcinoma: A Cautionary Tale! PMID- 26633704 TI - What Are the Major Determinants in the Success of Smoking Cessation: Results from the Health Examinees Study. AB - Understanding mechanisms underlying smoking-related factors should be prioritized in establishing smoking prevention and cessation policy. The aim of this study was to identify factors significantly associated with smoking initiation and/or smoking cessation as well as the most important determinants of successful smoking cessation in a developed non-Western setting. Based on multiple logistic regression models, the odds ratios (ORs) for smoking initiation and cessation were estimated among males (N = 24,490) who had participated in the Health Examinees (HEXA) study. The Cox proportional hazards regression model was used to assess the association between selected predictors of smoking cessation and the likelihood of reaching this goal. Finally, Kaplan-Meier curves were constructed to illustrate the distribution of time from age at smoking initiation to age at smoking cessation. We found that the ORs for successfully quitting smoking increased with age, married status, educational achievement, having a non-manual job, drinking cessation and disease morbidity. Those exposed to secondhand smoking showed less likelihood of quitting smoking. A continual decrease in the ORs for successfully quitting smoking was observed according to increased smoking duration, smoking dose per day and lifetime tobacco exposure (ptrend <0.001). Among the selected predictors, lifetime tobacco exposure, educational attainment, alcohol drinking status and birth cohort were the major determinants in the success of smoking cessation. Our findings suggest that lifetime tobacco exposure, educational attainment, alcohol drinking status and birth cohort can determine success in smoking cessation. Public interventions promoting a smoke free environment are needed to reinforce discouraging the initiation of, reducing, and quitting cigarette smoking. PMID- 26633706 TI - An Unusual Outcome After Mastoidectomy. Endolymphatic sac tumor. PMID- 26633705 TI - World Health Organization Estimates of the Global and Regional Disease Burden of 11 Foodborne Parasitic Diseases, 2010: A Data Synthesis. AB - BACKGROUND: Foodborne diseases are globally important, resulting in considerable morbidity and mortality. Parasitic diseases often result in high burdens of disease in low and middle income countries and are frequently transmitted to humans via contaminated food. This study presents the first estimates of the global and regional human disease burden of 10 helminth diseases and toxoplasmosis that may be attributed to contaminated food. METHODS AND FINDINGS: Data were abstracted from 16 systematic reviews or similar studies published between 2010 and 2015; from 5 disease data bases accessed in 2015; and from 79 reports, 73 of which have been published since 2000, 4 published between 1995 and 2000 and 2 published in 1986 and 1981. These included reports from national surveillance systems, journal articles, and national estimates of foodborne diseases. These data were used to estimate the number of infections, sequelae, deaths, and Disability Adjusted Life Years (DALYs), by age and region for 2010. These parasitic diseases, resulted in 48.4 million cases (95% Uncertainty intervals [UI] of 43.4-79.0 million) and 59,724 (95% UI 48,017-83,616) deaths annually resulting in 8.78 million (95% UI 7.62-12.51 million) DALYs. We estimated that 48% (95% UI 38%-56%) of cases of these parasitic diseases were foodborne, resulting in 76% (95% UI 65%-81%) of the DALYs attributable to these diseases. Overall, foodborne parasitic disease, excluding enteric protozoa, caused an estimated 23.2 million (95% UI 18.2-38.1 million) cases and 45,927 (95% UI 34,763-59,933) deaths annually resulting in an estimated 6.64 million (95% UI 5.61-8.41 million) DALYs. Foodborne Ascaris infection (12.3 million cases, 95% UI 8.29-22.0 million) and foodborne toxoplasmosis (10.3 million cases, 95% UI 7.40 14.9 million) were the most common foodborne parasitic diseases. Human cysticercosis with 2.78 million DALYs (95% UI 2.14-3.61 million), foodborne trematodosis with 2.02 million DALYs (95% UI 1.65-2.48 million) and foodborne toxoplasmosis with 825,000 DALYs (95% UI 561,000-1.26 million) resulted in the highest burdens in terms of DALYs, mainly due to years lived with disability. Foodborne enteric protozoa, reported elsewhere, resulted in an additional 67.2 million illnesses or 492,000 DALYs. Major limitations of our study include often substantial data gaps that had to be filled by imputation and suffer from the uncertainties that surround such models. Due to resource limitations it was also not possible to consider all potentially foodborne parasites (for example Trypanosoma cruzi). CONCLUSIONS: Parasites are frequently transmitted to humans through contaminated food. These estimates represent an important step forward in understanding the impact of foodborne diseases globally and regionally. The disease burden due to most foodborne parasites is highly focal and results in significant morbidity and mortality among vulnerable populations. PMID- 26633707 TI - Personality and Situation Predictors of Consistent Eating Patterns. AB - INTRODUCTION: A consistent eating style might be beneficial to avoid overeating in a food-rich environment. Eating consistency entails maintaining a similar dietary pattern across different eating situations. This construct is relatively under-studied, but the available evidence suggests that eating consistency supports successful weight maintenance and decreases risk for metabolic syndrome and cardiovascular disease. Yet, personality and situation predictors of consistency have not been studied. METHODS: A community-based sample of 164 women completed various personality tests, and 139 of them also reported their eating behaviour 6 times/day over 10 observational days. We focused on observations with meals (breakfast, lunch, or dinner). The participants indicated if their momentary eating patterns were consistent with their own baseline eating patterns in terms of healthiness or size of the meal. Further, participants described various characteristics of each eating situation. RESULTS: Eating consistency was positively predicted by trait self-control. Eating consistency was undermined by eating in the evening, eating with others, eating away from home, having consumed alcohol and having undertaken physical exercise. Interactions emerged between personality traits and situations, including punishment sensitivity, restraint, physical activity and alcohol consumption. CONCLUSION: Trait self-control and several eating situation variables were related to eating consistency. These findings provide a starting point for targeting interventions to improve consistency, suggesting that a focus on self-control skills, together with addressing contextual factors such as social situations and time of day, may be most promising. This work is a first step to provide people with the tools they need to maintain a consistently healthy lifestyle in a food-rich environment. PMID- 26633709 TI - Curcumin hormesis mediates a cross-talk between autophagy and cell death. PMID- 26633708 TI - Molecular mechanism by which acyclic retinoid induces nuclear localization of transglutaminase 2 in human hepatocellular carcinoma cells. AB - Nuclear accumulation of transglutaminase 2 (TG2) is an important step in TG2 dependent cell death. However, the underlying molecular mechanisms for nuclear translocation of TG2 are still poorly understood. In this study, we demonstrated that acyclic retinoid (ACR) induced nuclear accumulation of TG2 in JHH-7 cells, a hepatocellular carcinoma (HCC) leading to their apoptosis. We further demonstrated molecular mechanism in nuclear-cytoplasmic trafficking of TG2 and an effect of ACR on it. We identified a novel 14-amino acid nuclear localization signal (NLS) (466)AEKEETGMAMRIRV(479) in the 'C' domain and a leucine-rich nuclear export signal (NES) (657)LHMGLHKL(664) in the 'D' domain that allowed TG2 to shuttle between the nuclear and cytosolic milieu. Increased nuclear import of GAPDH myc-HIS fused with the identified NLS was observed, confirming its nuclear import ability. Leptomycin B, an inhibitor of exportin-1 as well as point mutation of all leucine residues to glutamine residues in the NES of TG2 demolished its nuclear export. TG2 formed a trimeric complex with importin-alpha and importin-beta independently from transamidase activity which strongly suggested the involvement of a NLS-based translocation of TG2 to the nucleus. ACR accelerated the formation of the trimeric complex and that may be at least in part responsible for enhanced nuclear localization of TG2 in HCC cells treated with ACR. PMID- 26633710 TI - Genetic ablation of homeodomain-interacting protein kinase 2 selectively induces apoptosis of cerebellar Purkinje cells during adulthood and generates an ataxic like phenotype. AB - Homeodomain-interacting protein kinase 2 (HIPK2) is a multitalented coregulator of an increasing number of transcription factors and cofactors involved in cell death and proliferation in several organs and systems. As Hipk2(-/-) mice show behavioral abnormalities consistent with cerebellar dysfunction, we investigated whether Hipk2 is involved in these neurological symptoms. To this aim, we characterized the postnatal developmental expression profile of Hipk2 in the brain cortex, hippocampus, striatum, and cerebellum of mice by real-time PCR, western blot analysis, and immunohistochemistry. Notably, we found that whereas in the brain cortex, hippocampus, and striatum, HIPK2 expression progressively decreased with age, that is, from postnatal day 1 to adulthood, it increased in the cerebellum. Interestingly, mice lacking Hipk2 displayed atrophic lobules and a visibly smaller cerebellum than did wild-type mice. More important, the cerebellum of Hipk2(-/-) mice showed a strong reduction in cerebellar Purkinje neurons during adulthood. Such reduction is due to the activation of an apoptotic process associated with a compromised proteasomal function followed by an unpredicted accumulation of ubiquitinated proteins. In particular, Purkinje cell dysfunction was characterized by a strong accumulation of ubiquitinated beta catenin. Moreover, our behavioral tests showed that Hipk2(-/-) mice displayed muscle and balance impairment, indicative of Hipk2 involvement in cerebellar function. Taken together, these results indicate that Hipk2 exerts a relevant role in the survival of cerebellar Purkinje cells and that Hipk2 genetic ablation generates cerebellar dysfunction compatible with an ataxic-like phenotype. PMID- 26633712 TI - Bcl-2 together with PI3K p110alpha regulates cell morphology and cell migration. PMID- 26633711 TI - Akt inhibition attenuates rasfonin-induced autophagy and apoptosis through the glycolytic pathway in renal cancer cells. AB - Rasfonin is a fungal secondary metabolite with demonstrated antitumor effects. However, the underlying mechanism of the regulatory role in autophagy initiated by rasfonin is largely unknown. Moreover, the function of Akt to positively mediate the induced autophagy remains elusive. In the present study, we observed that rasfonin induced autophagy concomitant with the upregulation of Akt phosphorylation. Both the inhibition of Akt by small molecule inhibitors and genetic modification partially reduced rasfonin-dependent autophagic flux and PARP-1 cleavage. The overexpression of myrAkts (constant active form) promoted rasfonin-induced apoptosis and autophagy in a cell type- and Akt isoform-specific manner. Using quantitative PCR and immunoblotting, we observed that rasfonin increased the expression of glycolytic gene PFKFB3, and this increased expression can be suppressed in the presence of Akt inhibitor. The inhibition of PFKFB3 suppressed rasfonin-activated autophagy with enhanced PARP-1 cleavage. In the case of glucose uptake was disrupted, which mean the glycolytic pathway was fully blocked, the rasfonin-induced autophagy and PARP-1 cleavage were downregulated. Collectively, these results demonstrated that Akt positively regulated rasfonin enhanced autophagy and caspase-dependent apoptosis primarily through affecting the glycolytic pathway. PMID- 26633713 TI - NFAT4-dependent miR-324-5p regulates mitochondrial morphology and cardiomyocyte cell death by targeting Mtfr1. AB - Emerging evidence suggest that the abnormal mitochondrial fission participates in pathogenesis of cardiac diseases, including myocardial infarction and heart failure. However, the molecular components regulating mitochondrial network in heart remain largely unidentified. Here we report that NFAT4, miR-324-5p and mitochondrial fission regulator 1 (Mtfr1) function in one signaling axis that regulates mitochondrial morphology and cardiomyocyte cell death. Knocking down Mtfr1 suppresses mitochondrial fission, apoptosis and myocardial infarction. Mtfr1 is a direct target of miR-324-5p, and miR-324-5p attenuates mitochondrial fission, cardiomyocyte apoptosis and myocardial infarction by suppressing Mtfr1 translation. Finally, we show that transcription factor NFAT4 inhibits miR-324-5p expression. Knockdown of NFAT4 suppresses mitochondrial fission and protects cardiomyocyte from apoptosis and myocardial infarction. Our study defines the NFAT4/ miR-324-5p/Mtfr1 axis, which participates in the regulation of mitochondrial fission and cardiomyocyte apoptosis, and suggests potential new treatment avenues for cardiac diseases. PMID- 26633714 TI - Macrophage migration inhibitory factor has a permissive role in concanavalin A induced cell death of human hepatoma cells through autophagy. AB - Concanavalin A (ConA) is a lectin and T-cell mitogen that can activate immune responses. In recent times, ConA-induced cell death of hepatoma cells through autophagy has been reported and its therapeutic effect was confirmed in a murine in situ hepatoma model. However, the molecular mechanism of ConA-induced autophagy is still unclear. As macrophage migration inhibitory factor (MIF), which is a proinflammatory cytokine, can trigger autophagy in human hepatoma cells, the possible involvement of MIF in ConA-induced autophagy was investigated in this study. We demonstrated that cell death is followed by an increment in MIF expression and secretion in the ConA-stimulated human hepatoma cell lines, HuH-7 and Hep G2. In addition, ConA-induced autophagy and cell death of hepatoma cells were blocked in the presence of an MIF inhibitor. Knockdown of endogenous MIF by small hairpin RNA confirmed that MIF is required for both ConA-induced autophagy and death of hepatoma cells. Furthermore, signal pathway studies demonstrated that ConA induces signal transducer and activator of transcription 3 (STAT3) phosphorylation to trigger MIF upregulation, which in turn promotes Bcl 2/adenovirus E1B 19 kDa-interacting protein 3 (BNIP3)-dependent autophagy. By using a murine in situ hepatoma model, we further demonstrated that MIF contributes to anti-hepatoma activity of ConA by regulating STAT3-MIF-BNIP3 dependent autophagy. In summary, our findings uncover a novel role of MIF in lectin-mediated anti-hepatoma activities by regulating autophagy. PMID- 26633715 TI - Be resistant to apoptosis: a host factor from gingival fibroblasts. PMID- 26633717 TI - Loss of serum response factor induces microRNA-mediated apoptosis in intestinal smooth muscle cells. AB - Serum response factor (SRF) is a transcription factor known to mediate phenotypic plasticity in smooth muscle cells (SMCs). Despite the critical role of this protein in mediating intestinal injury response, little is known about the mechanism through which SRF alters SMC behavior. Here, we provide compelling evidence for the involvement of SRF-dependent microRNAs (miRNAs) in the regulation of SMC apoptosis. We generated SMC-restricted Srf inducible knockout (KO) mice and observed both severe degeneration of SMCs and a significant decrease in the expression of apoptosis-associated miRNAs. The absence of these miRNAs was associated with overexpression of apoptotic proteins, and we observed a high level of SMC death and myopathy in the intestinal muscle layers. These data provide a compelling new model that implicates SMC degeneration via anti apoptotic miRNA deficiency caused by lack of SRF in gastrointestinal motility disorders. PMID- 26633718 TI - Socs1 and Socs3 degrades Traf6 via polyubiquitination in LPS-induced acute necrotizing pancreatitis. AB - Mechanisms involved in inflammatory development during acute pancreatitis (AP) are largely vague, especially in the transformation of acute edematous pancreatitis (AEP) into acute necrotizing pancreatitis (ANP). This current study aims to investigate the functions of Traf6 in different AP models in vitro and in vivo, and to identify the possible regulatory mechanism in the progression of inflammation from mild to severe. Our data revealed that the level of Traf6 expression was significantly increased in the mild AP induced by caerulein, and the upregulation of Traf6 played a protective role in acinar cells against caerulein-induced apoptosis. In contrast, only Traf6 protein but not mRNA was downregulated in the severe ANP induced by combination treatment of caerulein and LPS. Mechanistic studies showed that LPS upregulated the levels of Socs1 and Socs3 expressions in acinar cells, Socs1 and Socs3 interacted Traf6 directly and degraded Traf6 protein via polyubiquitination, thereby counteracted the protective function of Traf6. In vivo study further showed that combination treatment of caerulein and LPS failed to induce an ANP model in the TLR4 knockout mice, and the level of Traf6 expression in the pancreatic tissues remained the same as that from the acute edematous pancreatitis (AEP) mouse. Taken together, our study reveals that Traf6 functioned as a protective factor in the progression of AP, and LPS-induced Socs1 and Socs3 exacerbate mild AP to severe AP, which provides evidence for developing a new therapeutic target to combat AP. PMID- 26633719 TI - Happy 30th Anniversary--Holistic Nursing Practice! PMID- 26633716 TI - Neuroblastoma: oncogenic mechanisms and therapeutic exploitation of necroptosis. AB - Neuroblastoma (NB) is the most common extracranial childhood tumor classified in five stages (1, 2, 3, 4 and 4S), two of which (3 and 4) identify chemotherapy resistant, highly aggressive disease. High-risk NB frequently displays MYCN amplification, mutations in ALK and ATRX, and genomic rearrangements in TERT genes. These NB subtypes are also characterized by reduced susceptibility to programmed cell death induced by chemotherapeutic drugs. The latter feature is a major cause of failure in the treatment of advanced NB patients. Thus, proper reactivation of apoptosis or of other types of programmed cell death pathways in response to treatment is relevant for the clinical management of aggressive forms of NB. In this short review, we will discuss the most relevant genomic rearrangements that define high-risk NB and the role that destabilization of p53 and p73 can have in NB aggressiveness. In addition, we will propose a strategy to stabilize p53 and p73 by using specific inhibitors of their ubiquitin-dependent degradation. Finally, we will introduce necroptosis as an alternative strategy to kill NB cells and increase tumor immunogenicity. PMID- 26633720 TI - Bioelectrodynamics: A New Patient Care Strategy for Nursing, Health, and Wellness. AB - Bioelectrodynamics is an interdisciplinary subject that offers a pathway for nursing to develop a new patient care strategy in health care. The application of bioenergy to living organisms has the potential to advance medical science in the areas of prevention, cancer, wound care, pain, and many other chronic diseases. PMID- 26633721 TI - A Case Report of Sanguis Draconis for Treating a Patient With Refractory Wound Dehiscence After Breast Cancer Chemotherapy. AB - Breast cancer is one of the most common female malignant tumors. According to data statistics, the incidence of breast cancer was 7% to 10% for a variety of malignant tumors, being only lower than that of uterine cancer. The methods of treating breast cancer are given priority over operative treatment and combined with chemotherapy and radiotherapy. However, exosmosis of chemotherapeutic drugs is a common complication of chemotherapy. Exosmosis of drugs can stimulate local organs to induce acute inflammatory reaction and necrosis, which finally lead to wound infection and difficulty in healing. In December 2013, a patient with full thickness wound (an area of 5 * 3 cm) dehiscence at the completion of the second phase of chemotherapy for left breast cancer after radical operation was admitted to our department. Her wound had healed after radical operation. The patient followed an integrative therapy treatment protocol that consisted of an external application of a phytomedicine called Sanguis Draconis and combined with a series of conventional treatments, including 3M Transparent Dressing moist therapy, increase in nutrition, and prevention therapies for infection. The patient's integrative treatment program resulted in complete wound healing, and the successful completion of the late 6 courses of chemotherapy. The article describes the nursing experiences associated with this case study. PMID- 26633722 TI - A Systematic Literature Review Toward the Characterization of Comfort. AB - Comfort integrates the taxonomies and the classifications of nursing knowledge. Its meaning is not yet clear, although it is an important construct from which theories are developed. This article aims to analyze comfort in nursing scientific literature. The results highlight a particular interest in comfort at crisis situations such as illness, palliative care, or intensive care. Comforting seems to be a complex intervention. More studies are needed to achieve its operational assimilation and implementation in clinical practice, as well as the evaluation of its efficiency and effectiveness. PMID- 26633723 TI - Nurses' Perceptions of Futile Care: A Qualitative Study. AB - Health care professionals believe that futile care must not be provided; however, there is no clear agreement over the definition and the manifestations of futile care. The aim of this study was to explore Iranian nurses' perceptions of futile care. In this qualitative exploratory study, the conventional content analysis approach was used for collecting and analyzing the study data. Three main themes were extracted from the data: nonfutility of care: care tantamount with outcome; sense of burnout; and subjectivity and relativity of medical futility concept. PMID- 26633724 TI - Cultural Safety: An Evolutionary Concept Analysis. AB - Healing occurs in a safe milieu, and patients feel safe when service providers view them as whole persons, recognizing the multiple underlying factors that cause illness. Cultural safety can lead to service delivery in this way, but most nurses have no clear understanding of this concept. This study aimed to clarify cultural safety on the basis of Rodgers' evolutionary concept analysis. Cultural sensitivity and cultural awareness are the antecedents of cultural safety. These concepts include a nurse's flexibility toward his or her patients with different perspectives, creating an atmosphere free from intimidation and judgment of the patients, with an overall promotion of health in multicultural communities. PMID- 26633725 TI - Managing Ulcerative Colitis in the Adolescent: Highlighting the Developmental and Self-management Needs. AB - Ulcerative colitis (UC) is a lifelong disease that peaks in diagnosis between the ages of 15 to 25 years, making UC a significant chronic disease among adolescents that could affect the adolescents throughout their life. This article provides an overview of the role of nurse practitioners as health care providers in managing adolescent patients with UC with a holistic approach that encompasses the physical aspects of the disease, as well as developmental and psychosocial needs. By describing the influence that developmental stage and psychological stress have on patients with UC, the nurse practitioners can facilitate evidence-based and holistic care for adolescents and promote self-management. PMID- 26633726 TI - Presence: A Step Closer to Spiritual Care in Nursing. AB - This article argues that while not all nurses are comfortable with spiritual care, nurses may be comfortable with enacting presence. Presence, an encompassing element in spiritual care, might be a more accessible first step for nurses toward spiritual care. To further highlight this viewpoint, the nature, consequences, and cultivation of presence are also discussed. PMID- 26633727 TI - Echinacea purpurea: A Proprietary Extract of Echinacea purpurea Is Shown to be Safe and Effective in the Prevention of the Common Cold. AB - The research study in this review represents the largest clinical trial to date that evaluated the safety and efficacy of Echinacea purpurea for prophylactic treatment of the common cold, in addition to investigating its risk-benefit in a long-term treatment period. The clinical application of the proprietary standardized Echinacea purpurea extract(Echinaforce) demonstrated efficacy as a preventive cold treatment option over a 4-month duration. This study showed that Echinacea's long-term prevention was associated with a reduction in the total number of cold episodes, a reduction in the number of days with colds, and a reduction in cold episodes requiring additional medication. Furthermore, the Echinacea test agent inhibited virally confirmed colds, exhibited maximal effects on recurrent infections, and demonstrated that its preventive effects increased relative to therapy compliance and adherence to the protocol. In summary, Echinacea purpurea when taken as recommended for the prevention of the common cold appears to provide a positive risk to benefit ratio. PMID- 26633728 TI - The Whole Self As a Sexually Diverse Being: Authentic Holism. PMID- 26633729 TI - Prematurity and fetal lung response after tracheal occlusion in fetuses with severe congenital diaphragmatic hernia. AB - OBJECTIVE: To evaluate the independent association of fetal pulmonary response and prematurity to postnatal outcomes after fetal tracheal occlusion for congenital diaphragmatic hernia. METHODS: Fetal pulmonary response, prematurity (<37 weeks at delivery) and extreme prematurity (<32 weeks at delivery) were evaluated and compared between survivors and non-survivors at 6 months of life. Multivariable analysis was conducted with generalized linear mixed models for variables significantly associated with survival in univariate analysis. RESULTS: Eighty-four infants were included, of whom 40 survived (47.6%) and 44 died (52.4%). Univariate analysis demonstrated that survival was associated with greater lung response (p=0.006), and the absence of extreme preterm delivery (p=0.044). In multivariable analysis, greater pulmonary response after FETO was an independent predictor of survival (aOR 1.87, 95% CI 1.08-3.33, p=0.023), whereas the presence of extreme prematurity was not statistically associated with mortality after controlling for fetal pulmonary response (aOR 0.52, 95% CI 0.12 2.30, p=0.367). CONCLUSION: Fetal pulmonary response after FETO is the most important factor associated with survival, independently from the gestational age at delivery. PMID- 26633730 TI - Diazaoxatriangulenium: synthesis of reactive derivatives and conjugation to bovine serum albumin. AB - The azaoxa-triangulenium dyes are characterised by emission in the red and a long fluorescence lifetime (up to 25 ns). These properties have been widely explored for the azadioxatrianguelnium (ADOTA) dye. Here, the syntheses of reactive maleimide and NHS-ester forms of the diazaoxatriangulenium (DAOTA) system are reported. The DAOTA fluorophore was conjugated to bovine serum albumin (BSA) and investigated in comparison to the corresponding ADOTA-BSA conjugate. It was found that the fluorescence of DAOTA experienced a significantly higher degree of solvent quenching if compared to ADOTA as non-conjugated dyes in aqueous solution, while the fluorescence quenching observed upon conjugation to BSA was significantly reduced for DAOTA when compared to ADOTA. The differences in observed quenching for the conjugates can be explained by the different electronic structures of the dyes, which renders DAOTA significantly less prone to reductive photoinduced electron transfer (PET) quenching from e.g. tryptophan. We conclude that DAOTA, with emission in the red and inherent resistance to PET quenching, is an ideal platform for the development of long fluorescence lifetime probes for time-resolved imaging and fluorescence polarisation assay. PMID- 26633732 TI - Mechanic Insight into Aggregation of Lysozyme by Ultrasensitive Differential Scanning Calorimetry and Sedimentation Velocity. AB - Folding and aggregation of proteins profoundly influence their functions. We have investigated the effects of thermal history, concentration and pH on the denaturation and refolding of lysozyme by using ultrasensitive differential scanning calorimetry (US-DSC) and sedimentation velocity (SV) via analytical ultracentrifugation (AUC). The former is sensitive to small energy change whereas the latter can differentiate the oligomers such as dimer and trimer from individual protein molecules. Our studies reveal that the degree of denaturation irreversibility increases as heating times increases. The denaturation temperature (Td) and enthalpy change (DeltaH) are influenced by heating rate since the denaturation is not in equilibrium during the heating. We can obtain Td and DeltaH in equilibrium by extrapolation of heating rate to zero. In a dilute solution, no aggregation but unfolding happens in the denaturation. However, when the concentration is above a critical value (~15.0 mg/mL), lysozyme molecules readily form trimers or other oligomers. Lysozyme molecules unfold into stretched chains at pH > 6.0, which would further forms large aggregates. The formation of aggregates makes the refolding of lysozyme impossible. PMID- 26633733 TI - Palbociclib (PD0332991)-a Selective and Potent Cyclin-Dependent Kinase Inhibitor: A Review of Pharmacodynamics and Clinical Development. AB - IMPORTANCE: Palbociclib (PD0332991) is a newly developed drug that received breakthrough designation and recent US Food and Drug Administration approval in combination with endocrine therapy in the treatment of hormone receptor positive, ERBB2-negative (formerly HER2 or HER2/neu) breast cancer in the first-line metastatic setting. OBJECTIVE: Herein we describe the preclinical and translational data and early- and late-phase clinical trials in which palbociclib has been investigated in a broad array of tumor types. We discuss the pharmacodynamics, pharmacokinetics, toxic effects, and clinical response rates. EVIDENCE REVIEW: On March 1, 2015, we conducted a review of the literature describing the development of palbociclib. We used the PubMed search terms "PD0332991," "palbociclib," and "CDK4/6 inhibitor" to find all published articles of interest, without limitation as to publication date. FINDINGS: Palbociclib is a potent and specific oral cyclin-dependent kinase (CDK) 4/6 inhibitor that has strong preclinical data to support its activity in retinoblastoma protein expressing tumors. Phase 1 trials have demonstrated safety, and phase 2 trials have shown single-agent activity in mantle-cell lymphoma, breast cancer, liposarcoma, and teratoma with reversible neutropenia as the main toxic effect. Addition of palbociclib to endocrine therapy improves progression-free survival in endocrine therapy-naive and endocrine therapy-resistant metastatic settings. CONCLUSIONS AND RELEVANCE: Palbociclib is well tolerated and has therapeutic potential for multiple cancers, including breast cancer, where its efficacy has been demonstrated alone and in combination with endocrine therapy. Additional combinations of palbociclib with endocrine therapy, chemotherapy, and targeted therapy have potential in various tumors, and phase 3 trials are under way. PMID- 26633734 TI - Synthesis and Characterization of 4,11-Diaminoanthra[2,3-b]furan-5,10-diones: Tumor Cell Apoptosis through tNOX-Modulated NAD(+)/NADH Ratio and SIRT1. AB - A series of new 4,11-diaminoanthra[2,3-b]furan-5,10-dione derivatives with different side chains were synthesized. Selected 2-unsubstituted derivatives 11 14 showed high antiproliferative potency on a panel of mammalian tumor cell lines including multidrug resistance variants. Compounds 11-14 utilized multiple mechanisms of cytotoxicity including inhibition of Top1/Top2-mediated DNA relaxation, reduced NAD(+)/NADH ratio through tNOX inhibition, suppression of a NAD(+)-dependent sirtuin 1 (SIRT1) deacetylase activity, and activation of caspase-mediated apoptosis. Here, for the first time, we report that tumor associated NADH oxidase (tNOX) and SIRT1 are important cellular targets of antitumor anthracene-9,10-diones. PMID- 26633735 TI - Periorbital and Midfacial Volume Enhancement With Cannula. PMID- 26633736 TI - Unilateral elbow flexion fatigue modulates corticospinal responsiveness in non fatigued contralateral biceps brachii. AB - Exercise-induced fatigue can change motor performance in non-exercised muscles. The objective was to investigate unilateral elbow flexion (EF) fatigue effects on the maximal voluntary force (MVC) and corticospinal excitability of contralateral non-exercised biceps brachii (BB). Transcranial magnetic, transmastoid electrical, and brachial plexus electrical stimulation were used to elicit motor evoked potentials (MEP), cervicomedullary motor evoked potentials (CMEP), and compound muscle action potentials in the contralateral non-exercised BB of 12 participants before and after (i) two bouts of 100-s unilateral EF (fatigue) or (ii) control. Three stimuli were evoked every 1.5 s during a series of 6-s isometric EF at 100%, 50%, and 5% of MVC. The non-exercised EF MVC force, electromyographic activity, and voluntary activation were not significantly different between fatigue and control. Non-exercised BB MEP and CMEP amplitudes during 100% MVCs demonstrated significantly higher (P = 0.03) and lower values (P = 0.01), respectively, after fatigue compared with control. There was no difference between the two conditions for MEP and CMEP amplitudes during 50% and 5% MVCs. Unilateral exercise-induced EF fatigue did not lead to cross-over central fatigue to the contralateral homologous muscle but enhanced the supraspinal responsiveness (MEP/CMEP) of the neural circuitries supplying central commands to non-exercised muscles at higher contraction intensity. PMID- 26633737 TI - Efficient Synthesis of Primary Nitrocarbamates of Sugar Alcohols: From Food to Energetic Materials. AB - The synthesis of various new polyvalent nitrocarbamates derived from sugar alcohols was accomplished by an economically benign two-step synthesis. The precursor carbamates were synthesized with the reagent chlorosulfonyl isocyanate (CSI) and further nitrated using mixed acid. The starting materials, sugar alcohols, are renewable biomass, mainly used in food and cosmetic industry. The structures of one carbamate and one nitrocarbamate were exemplary described by single-crystal X-ray-analysis. The heat of formation is calculated by the use of isodesmic reactions and the energetic performance data were estimated. All compounds were fully characterized by elemental analysis, vibrational spectroscopy, (1)H, (13)C, and (14/15)N NMR spectroscopy and thermal analysis (DSC). The nitrocarbamates exhibit good detonation performance and have significantly lower sensitivities compared to the commonly used nitrate ester explosive PETN. PMID- 26633739 TI - Probing the Evaporation Dynamics of Ethanol/Gasoline Biofuel Blends Using Single Droplet Manipulation Techniques. AB - Using blends of bioethanol and gasoline as automotive fuel leads to a net decrease in the production of harmful emission compared to the use of pure fossil fuel. However, fuel droplet evaporation dynamics change depending on the mixing ratio. Here we use single particle manipulation techniques to study the evaporation dynamics of ethanol/gasoline blend microdroplets. The use of an electrodynamic balance enables measurements of the evaporation of individual droplets in a controlled environment, while optical tweezers facilitate studies of the behavior of droplets inside a spray. Hence, the combination of both methods is perfectly suited to obtain a complete picture of the evaporation process. The influence of adding varied amounts of ethanol to gasoline is investigated, and we observe that droplets with a greater fraction of ethanol take longer to evaporate. Furthermore, we find that our methods are sensitive enough to observe the presence of trace amounts of water in the droplets. A theoretical model, predicting the evaporation of ethanol and gasoline droplets in dry nitrogen gas, is used to explain the experimental results. Also a theoretical estimation of the saturation of the environment, with other aerosols, in the tweezers is carried out. PMID- 26633738 TI - Randomized trial of ultrasound-indicated cerclage in singleton women without lower genital tract inflammation. AB - AIM: This is the first report of a randomized trial of cerclage on pure cervical shortening without vaginosis or cervicitis. The objective of our multicenter randomized controlled trial was to assess the benefits of ultrasound-indicated cervical cerclage in the mid-trimester to prevent preterm birth in women who have no signs of infection or inflammation of the lower genital tract. MATERIAL AND METHODS: Women with a short cervical length < 25 mm between 16 and 26 weeks of gestation were randomly assigned to receive a Shirodkar cerclage, McDonald cerclage, or bedrest (no cerclage). Before being randomly assigned to one of the three groups, all women were screened for infection/inflammation of the lower genital tract; those with positive results were excluded from the study. The ratio of preterm delivery as a primary end-point was evaluated in the groups. RESULTS: A total of 106 singleton patients with a short cervical length were assessed for study eligibility; 106 patients were randomized to the three treatment options. Ultimately, 98 patients (in the Shirodkar [n = 34], McDonald [n = 34] and bedrest [n = 30] groups) were analyzed. No differences in preterm delivery or perinatal outcomes were found between the three groups. Significantly fewer patients in the Shirodkar group required hospitalization for treatment of threatened preterm labor when compared to patients in the bedrest group. CONCLUSION: For women with a short cervical length < 25 mm between 16 and 26 weeks of gestation, Shirodkar cerclage might be considered to reduce the occurrence of threatened preterm labor. PMID- 26633740 TI - T-Cell Receptor Binding Affects the Dynamics of the Peptide/MHC-I Complex. AB - The recognition of peptide/MHC by T-cell receptors is one of the most important interactions in the adaptive immune system. A large number of computational studies have investigated the structural dynamics of this interaction. However, to date only limited attention has been paid to differences between the dynamics of peptide/MHC with the T-cell receptor bound and unbound. Here we present the first large-scale molecular dynamics simulation study of this type investigating HLA-B*08:01 in complex with the Epstein-Barr virus peptide FLRGRAYGL and all possible single-point mutations (n = 172). All of the simulations were performed with and without the LC 13 T-cell receptor for a simulation time of 100 ns, yielding 344 simulations and a total simulation time of 34 400 ns. Our study is 2 orders of magnitude larger than the average T-cell receptor/peptide/MHC molecular dynamics simulation study. This data set provides reliable insights into alterations of the peptide/MHC-I dynamics caused by the presence of the T-cell receptor. We found that simulations in the presence of T-cell receptors have more hydrogen bonds between the peptide and MHC, altered flexibility patterns in the MHC helices and the peptide, a lower MHC groove width range, and altered solvent accessible surface areas. This indicates that without a T-cell receptor the MHC binding groove can open and close, while the presence of the T-cell receptor inhibits these breathing-like motions. PMID- 26633741 TI - pH and Glutathione Dual-Responsive Dynamic Cross-Linked Supramolecular Network on Mesoporous Silica Nanoparticles for Controlled Anticancer Drug Release. AB - A dynamic cross-linked supramolecular network of poly(glycidyl methacrylate)s derivative chains was constructed on mesoporous silica nanoparticles via disulfide bond and ion-dipole interactions between cucurbit[7]urils and protonated diamines in the polymer chains. This kind of multifunctional organic inorganic hybrid material with pH- and glutathione- (GSH-) stimuli responsiveness can be applied to anticancer drug delivery and controlled release. Good release performance toward doxorubicin hydrochloride (DOX) was achieved under the simulative tumor intracellular environment (pH = 5.0, CGSH = 2-10 mM). Significantly, the release amount of DOX increased upon lowering the solution pH value and increasing the concentration of GSH, as demonstrated by a series of controlled release experiments. Furthermore, the DOX-loaded hybrid nanomaterials displayed apparent cell-growth inhibition effects to cancer cell lines, as evidenced by MTT assay and confocal laser scanning microscopy. PMID- 26633742 TI - Mechanistic Studies on the Photoallergy Mediated by Fenofibric Acid: Photoreactivity with Serum Albumins. AB - The photoreactivity of fenofibric acid (FA) in the presence of human and bovine serum albumins (HSA and BSA, respectively) has been investigated by steady-state irradiation, fluorescence, and laser flash photolysis (LFP). Spectroscopic measurements allowed for the determination of a 1:1 stoichiometry for the FA/SA complexes and pointed to a moderate binding of FA to the proteins; by contrast, the FA photoproducts were complexed more efficiently with SAs. Covalent photobinding to the protein, which is directly related to the photoallergic properties of the drug, was detected after long irradiation times and was found to be significantly higher in the case of BSA. Intermolecular FA-amino acid and FA-albumin irradiations resulted in the formation of photoproducts arising from coupling between both moieties, as indicated by mass spectrometric analysis. Mechanistic studies using model drug-amino acid linked systems indicated that the key photochemical step involved in photoallergy is formal hydrogen atom transfer from an amino acid residue to the excited benzophenone chromophore of FA or (more likely) its photoproducts. This results in the formation of caged radical pairs followed by C-C coupling to give covalent photoaducts. PMID- 26633744 TI - Porphyrin Nanodroplets: Sub-micrometer Ultrasound and Photoacoustic Contrast Imaging Agents. AB - A novel class of all-organic nanoscale porphyrin nanodroplet agents is presented which is suitable for multimodality ultrasound and photoacoustic molecular imaging. Previous multimodality photoacoustic-ultrasound agents are either not organic, or not yet demonstrated to exhibit enhanced accumulation in leaky tumor vasculature, perhaps because of large diameters. In the current study, porphyrin nanodroplets are created with a mean diameter of 185 nm which is small enough to exhibit the enhanced permeability and retention effect. Porphyrin within the nanodroplet shell has strong optical absorption at 705 nm with an estimated molar extinction coefficient >5 * 10(9) m(-1) cm(-1) , allowing both ultrasound and photoacoustic contrast in the same nanoparticle using all organic materials. The potential of nanodroplets is that they may be phase-changed into microbubbles using high pressure ultrasound, providing ultrasound contrast with single-bubble sensitivity. Multispectral photoacoustic imaging allows visualization of nanodroplets when injected intratumorally in an HT1080 tumor in the chorioallantoic membrane of a chicken embryo. Intravital microscopy imaging of Hep3-GFP and HT1080-GFP tumors in chicken embryos determines that nanodroplets accumulated throughout or at the periphery of tumors, suggesting that porphyrin nanodroplets may be useful for enhancing the visualization of tumors with ultrasound and/or photoacoustic imaging. PMID- 26633745 TI - Indoor Pollutant Hexabromocyclododecane Has a Modest Immunomodulatory Effect on House Dust Mite Induced Allergic Asthma in Mice. AB - Hexabromocyclododecane (HBCD) has been recognized as an indoor pollutant. HBCD is added as a flame retardant to many consumer products and leaches from the products into house dust. HBCD might be potentially hazardous to the airways because of inhalation of house dust. Sensitization to house dust mite (HDM) is a risk factor for the development of allergic asthma. In this study, we examined whether HBCD can affect the immune response to HDM allergens. Bone-marrow-derived dendritic cells (BMDCs) were exposed simultaneously to HBCD and HDM in vitro. HBCD enhanced oxidative stress in HDM-pulsed BMDCs, which was accompanied by a higher production of Interleukin (IL)-6 and -10. Adoptive transfer of HDM/HBCD exposed BMDCs into naive mice resulted in enhanced levels of IL-17A after inhalational challenge with HDM. Direct mucosal exposure to HBCD during HDM inhalation enhanced IL-4 or IL-17A production, depending on the HDM extract used, but did not aggravate the eosinophilic airway inflammation or airway hyper reactivity. Our results indicate that exposure to HBCD can have a mild immune modulating effect by enhancing the inflammatory cytokine production in response to inhaled HDM in mice. PMID- 26633747 TI - Effect of continuous positive airway pressure on nocturnal urine production in patients with obstructive sleep apnea syndrome. AB - AIM: The aim of this study was to identify the clinical features of patients with obstructive sleep apnea syndrome (OSAS) and investigate the impact of continuous positive airway pressure (CPAP) treatment on nocturnal urine volume. MATERIALS AND METHODS: This study enrolled 53 patients with moderate-to-severe OSAS and an apnea-hypoxia index of >20/hr. Data were collected on serum brain natriuretic peptide (BNP) level, International Prostate Symptom Score-Quality of Life (IPSS QOL) score, Overactive Bladder Symptom Score (OABSS), International Consultation on Incontinence Modular Questionnaire-Nocturia QOL (ICIQ-NQOL) score, Epworth Sleepiness Scale (ESS) score, and the frequency volume chart. Only patients who continued CPAP treatment for 3 months were included in the analysis. RESULTS: In total, 40 patients (33 men and 7 women) completed the study (75.5%). The mean age was 56.9 years. The night-time frequency to void was significantly decreased from 2.1 to 1.2 after CPAP treatment (P < 0.01). The mean scores as assessed by ESS, IPSS-QOL, OABSS, and ICIQ-NQOL significantly improved after CPAP (P < 0.01). The mean diastolic blood pressure significantly decreased after CPAP treatment. However, there was no significant change in the BNP level before and after CPAP treatment. In the frequency volume chart, hours of undisturbed sleep, total nocturnal voided volume, and nocturnal polyuria index significantly improved after CPAP treatment (P < 0.05). However, 24-hr voided volume and mean voided volume during night-time did not change after CPAP treatment. CONCLUSION: CPAP treatment decreases night-time urinary frequency by reducing nocturnal urine production and improves QOL in patients with OSAS. Neurourol. Urodynam. 36:376 379, 2017. (c) 2015 Wiley Periodicals, Inc. PMID- 26633746 TI - Noncovalent Modulation of the Inverse Temperature Transition and Self-Assembly of Elastin-b-Collagen-like Peptide Bioconjugates. AB - Stimuli-responsive nanostructures produced with peptide domains from the extracellular matrix offer great opportunities for imaging and drug delivery. Although the individual utility of elastin-like (poly)peptides and collagen-like peptides in such applications has been demonstrated, the synergistic advantages of combining these motifs in short peptide conjugates have surprisingly not been reported. Here, we introduce the conjugation of a thermoresponsive elastin-like peptide (ELP) with a triple-helix-forming collagen-like peptide (CLP) to yield ELP-CLP conjugates that show a remarkable reduction in the inverse transition temperature of the ELP domain upon formation of the CLP triple helix. The lower transition temperature of the conjugate enables the facile formation of well defined vesicles at physiological temperature and the unexpected resolubilization of the vesicles at elevated temperatures upon unfolding of the CLP domain. Given the demonstrated ability of CLPs to modify collagens, our results not only provide a simple and versatile avenue for controlling the inverse transition behavior of ELPs, but also suggest future opportunities for these thermoresponsive nanostructures in biologically relevant environments. PMID- 26633748 TI - Synthesis of 10 nm beta-NaYF4:Yb,Er/NaYF4 Core/Shell Upconversion Nanocrystals with 5 nm Particle Cores. AB - A new method is presented for preparing gram amounts of very small core/shell upconversion nanocrystals without additional codoping of the particles. First, ca. 5 nm beta-NaYF4:Yb,Er core particles are formed by the reaction of sodium oleate, rare-earth oleate, and ammonium fluoride, thereby making use of the fact that a high ratio of sodium to rare-earth ions promotes the nucleation of a large number of beta-phase seeds. Thereafter, a 2 nm thick NaYF4 shell is formed by using 3-4 nm particles of alpha-NaYF4 as a single-source precursor for the beta phase shell material. In contrast to the core particles, however, these alpha phase particles are prepared with a low ratio of sodium to rare-earth ions, which efficiently suppresses an undesired nucleation of beta-NaYF4 particles during shell growth. PMID- 26633749 TI - Effects of clamping procedures on central venous pressure during liver resection. AB - BACKGROUND: Various clamping procedures are used to decrease bleeding during liver resections but their effect on central venous pressure (CVP) remains unclear. The aim of this study was to assess the variations of the CVP during two different clamping procedures. METHODS: We retrospectively reviewed 29 patients (19 males, 10 females) who had Pringle maneuver (PM) and clamping of the inferior vena cava below the liver (IVCC) during major liver resections. RESULTS: Mean decrease of the CVP after PM, IVCC, and PM+IVCC was 0.84 +/- 1.37, 2.17 +/- 2.13 and 3.17 +/- 2.56 cmH20, respectively (P=0.02, P<0.0001 and P<0.0001, respectively). IVCC was more effective in inducing a decrease of the CVP than PM alone (P<0.05). The combination of both PM and IVCC induced the greatest decrease but not to a level of significance compared to IVCC alone (P=0.25). CONCLUSION: IVCC remains the more efficient procedure to lower the CVP. However, although PM is commonly used to control vascular inflow within the liver its significant influence on the CVP could participate to the reduction of bleeding during liver resections. PMID- 26633750 TI - Ankle-Dorsiflexion Range of Motion After Ankle Self-Stretching Using a Strap. AB - CONTEXT: A variety of ankle self-stretching exercises have been recommended to improve ankle-dorsiflexion range of motion (DFROM) in individuals with limited ankle dorsiflexion. A strap can be applied to stabilize the talus and facilitate anterior glide of the distal tibia at the talocrural joint during ankle self stretching exercises. Novel ankle self-stretching using a strap (SSS) may be a useful method of improving ankle DFROM. OBJECTIVE: To compare the effects of 2 ankle-stretching techniques (static stretching versus SSS) on ankle DFROM. DESIGN: Randomized controlled clinical trial. SETTING: University research laboratory. PATIENTS OR OTHER PARTICIPANTS: Thirty-two participants with limited active dorsiflexion (<20 degrees ) while sitting (14 women and 18 men) were recruited. MAIN OUTCOME MEASURE(S): The participants performed 2 ankle self stretching techniques (static stretching and SSS) for 3 weeks. Active DFROM (ADFROM), passive DFROM (PDFROM), and the lunge angle were measured. An independent t test was used to compare the improvements in these values before and after the 2 stretching interventions. The level of statistical significance was set at alpha = .05. RESULTS: Active DFROM and PDFROM were greater in both stretching groups after the 3-week interventions. However, ADFROM, PDFROM, and the lunge angle were greater in the SSS group than in the static-stretching group (P < .05). CONCLUSIONS: Ankle SSS is recommended to improve ADFROM, PDFROM, and the lunge angle in individuals with limited DFROM. PMID- 26633751 TI - From Beetles in Nature to the Laboratory: Actuating Underwater Locomotion on Hydrophobic Surfaces. AB - The controlled wetting and dewetting of surfaces is a primary mechanism used by beetles in nature, such as the ladybird and the leaf beetle for underwater locomotion.1 Their adhesion to surfaces underwater is enabled through the attachment of bubbles trapped in their setae-covered legs. Locomotion, however, is performed by applying mechanical forces in order to move, attach, and detach the bubbles in a controlled manner. Under synthetic conditions, however, when a bubble is bound to a surface, it is nearly impossible to maneuver without the use of external stimuli. Thus, actuated wetting and dewetting of surfaces remain challenges. Here, electrowetting-on-dielectric (EWOD) is used for the manipulation of bubble-particle complexes on unpatterned surfaces. Bubbles nucleate on catalytic Janus disks adjacent to a hydrophobic surface. By changing the wettability of the surface through electrowetting, the bubbles show a variety of reactions, depending on the shape and periodicity of the electrical signal. Time-resolved (MUs) imaging of bubble radial oscillations reveals possible mechanisms for the lateral mobility of bubbles on a surface under electrowetting: bubble instability is induced when electric pulses are carefully adjusted. This instability is used to control the surface-bound bubble locomotion and is described in terms of the change in surface energy. It is shown that a deterministic force applied normal can lead to a random walk of micrometer-sized bubbles by exploiting the phenomenon of contact angle hysteresis. Finally, bubble use in nature for underwater locomotion and the actuated bubble locomotion presented in this study are compared. PMID- 26633752 TI - Genetic Polymorphism of CHRM2 in COPD: Clinical Significance and Therapeutic Implications. AB - Chronic Obstructive Pulmonary Disease (COPD) is a common preventable and treatable disease, characterized by persistent airflow limitation not fully reversible. However, a number of patients with COPD respond to bronchodilator agents. Some studies have shown polymorphisms in the b2-adrenergic (ADRb2) and muscarinic M2 and M3 receptors (CHRM) that may participate in the modulation of the receptor responses. This study was designed to investigate the existence and the role of adrenergic and muscarinic receptor polymorphisms and their functional impact in COPD. Eighty-two patients with COPD and 17 healthy smokers were recruited and screened for ADRb2 (T164I and R175R), for CHRM2 (rs1824024) and for CHRM3 (-513C/A and -492C/T). Among the polymorphisms studied our results was not able to demonstrate statistically significant association between the polymorphisms studied and COPD risk. Contrarily, we identified, in our COPD population, a significant association with the CHRM2 (rs1824024) polymorphism and disease severity, with lower lung function test values, frequent exacerbations, and poor response to anti-cholinergic drugs. These results suggest the potential role of receptor polymorphism assessment to discriminate newly COPD phenotypes. J. Cell. Physiol. 231: 1745-1751, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26633753 TI - Correction to "Ni Mg Mixed Metal Oxides for p-Type Dye-Sensitized Solar Cells". PMID- 26633754 TI - Integration of Ultraviolet Photodissociation with Proton Transfer Reactions and Ion Parking for Analysis of Intact Proteins. AB - We report the implementation of proton transfer reactions (PTR) and ion parking on an Orbitrap mass spectrometer. PTR/ion parking allows charge states of proteins to be focused into a single lower charge state via sequential deprotonation reactions with a proton scavenging reagent, in this case, a nitrogen-containing adduct of fluoranthene. Using PTR and ion parking, we evaluate the charge state dependence of fragmentation of ubiquitin (8.6 kDa), myoglobin (17 kDa), and carbonic anhydrase (29 kDa) upon higher energy collisional dissociation (HCD) or ultraviolet photodissociation (UVPD). UVPD exhibited less charge state dependence, thus yielding more uniform distributions of cleavages along the protein backbone and consequently higher sequence coverage than HCD. HCD resulted in especially prominent cleavages C-terminal to amino acids containing acidic side-chains and N-terminal to proline residues; UVPD did not exhibit preferential cleavage adjacent to acidic residues but did show enhancement next to proline and phenylalanine. PMID- 26633755 TI - Imaging Brain Networks After Cancer and Chemotherapy: Advances Toward Etiology and Unanswered Questions. PMID- 26633756 TI - Clostridium difficile carriage in healthy pregnant women in China. AB - Infection with Clostridium difficile has been shown to have particularly poor outcomes for pregnant women, including an increased risk of death. The purpose of this study was to investigate the prevalence, genotypic distribution, and characterization of C. difficile strains isolated from pregnant women without diarrhea in China. As part of this study, 3.7% (37 out of 1009) of samples acquired from pregnant females tested positive for C. difficile. Of these positive samples, 27.0% (10) were toxigenic isolates containing both toxin A and toxin B genes (A+B+), 13.5% (5) of the variant strains contained the toxin B gene (A-B+) only, while the rest were non-toxigenic isolates (59.5%, 22 isolates). Among the non-pregnant women without diarrhea tested, 1.4% (9 of 651) contained toxigenic isolates (all of which were A+B+). Sixteen different sequence types (STs) were isolated during the course of this study. ST-37 (ribotype 017) and ST 54 (ribotype 012) were the most frequent toxigenic types observed in pregnant women. All strains showed susceptibility to the antibiotics metronidazole and vancomycin. The resistance rates of toxigenic C. difficile strains isolated from pregnant females to clindamycin, erythromycin, moxifloxacin, levofloxacin, and rifampicin were 20%, 46.7%, 13.6%, 46.7% and 13.3%, respectively. There was no significant difference between resistance rates of toxigenic and non-toxigenic strains with respect to their susceptibility to these antibiotics. However, when compared with the same data from non-pregnant women, toxigenic strains from pregnant women showed lower resistance rates to clindamycin (P < 0.05). PMID- 26633757 TI - Copper N-Heterocyclic Carbene: A Catalyst for Aerobic Oxidation or Reduction Reactions. AB - Copper N-heterocyclic carbene complexes can be readily used as catalysts for both aerobic oxidation of alcohols to aldehydes and reduction of imines to amines. Our methodology is universal for aromatic substrates and shows versatile tolerance to potential cascade reactions. A one-pot tandem synthetic strategy could afford useful imines and secondary amines via an oxidation-reduction strategy. PMID- 26633758 TI - Miniaturized Swimming Soft Robot with Complex Movement Actuated and Controlled by Remote Light Signals. AB - Powering and communication with micro robots to enable complex functions is a long-standing challenge as the size of robots continues to shrink. Physical connection of wires or components needed for wireless communication are complex and limited by the size of electronic and energy storage devices, making miniaturization of robots difficult. To explore an alternative solution, we designed and fabricated a micro soft swimming robot with both powering and controlling functions provided by remote light, which does not carry any electronic devices and batteries. In this approach, a polymer film containing azobenzene chromophore which is sensitive to ultra-violet (UV) light works as "motor", and the UV light and visible light work as "power and signal lines". Periodically flashing UV light and white light drives the robot flagellum periodically to swing to eventually push forward the robot in the glass tube filled with liquid. The gripper on robot head can be opened or closed by lights to grab and carry the load. This kind of remotely light-driven approach realizes complex driving and controlling of micro robotic structures, making it possible to design and fabricate even smaller robots. It will have great potential among applications in the micro machine and robot fields. PMID- 26633759 TI - In vivo gamma-aminobutyric acid measurement in rats with spectral editing at 4.7T. AB - PURPOSE: To evaluate the feasibility of spectral editing for quantification of gamma-aminobutyric acid (GABA) in the rat brain and to determine whether altered GABA concentration in the ventral striatum is a neural endophenotype associated with trait-like impulsive behavior. MATERIALS AND METHODS: Spectra were acquired at 4.7T for 23 male Lister-hooded rats that had been previously screened for extremely low and high impulsivity phenotypes on an automated behavioral task (n = 11 low-impulsive; n = 12 high-impulsive). Voxels of 3 * 7 * 4 mm(3) (84 MUL) centered bilaterally across the ventral striatum were used to evaluate GABA concentration ratios. RESULTS: Quantifiable GABA signals in the ventral striatum were obtained for all rats. Mean-edited GABA to n-acetyl aspartate (NAA) ratios in the ventral striatum were 0.22 (95% confidence interval [CI] [0.18, 0.25]). Mean GABA/NAA ratios in this region were significantly decreased by 28% in high impulsive rats compared to low-impulsive rats (P = 0.02; 95% CI [-53%, -2%]). CONCLUSION: These findings demonstrate that spectral editing at 4.7T is a feasible method to assess in vivo GABA concentrations in the rat brain. The results show that diminished GABA content in the ventral striatum may be a neural endophenotype associated with impulsivity. J. Magn. Reson. Imaging 2016;43:1308 1312. PMID- 26633760 TI - Synthesis of WS2xSe2-2x Alloy Nanosheets with Composition-Tunable Electronic Properties. AB - Two-dimensional (2D) layered transition metal dichalcogenides (TMDs) have recently emerged as a new class of atomically thin semiconductors for diverse electronic, optoelectronic, and valleytronic applications. To explore the full potential of these 2D semiconductors requires a precise control of their band gap and electronic properties, which represents a significant challenge in 2D material systems. Here we demonstrate a systematic control of the electronic properties of 2D-TMDs by creating mixed alloys of the intrinsically p-type WSe2 and intrinsically n-type WS2 with variable alloy compositions. We show that a series of WS2xSe2-2x alloy nanosheets can be synthesized with fully tunable chemical compositions and optical properties. Electrical transport studies using back-gated field effect transistors demonstrate that charge carrier types and threshold voltages of the alloy nanosheet transistors can be systematically tuned by adjusting the alloy composition. A highly p-type behavior is observed in selenium-rich alloy, which gradually shifts to lightly p-type, and then switches to lightly n-type characteristics with the increasing sulfur atomic ratio, and eventually evolves into highly n-doped semiconductors in sulfur-rich alloys. The synthesis of WS2xSe2-2x nanosheets with tunable optical and electronic properties represents a critical step toward rational design of 2D electronics with tailored spectral responses and device characteristics. PMID- 26633762 TI - Longitudinal patient pathways in clinical education: a medical student's perspective. PMID- 26633761 TI - Individual Differences Among Children in Sucrose Detection Thresholds: Relationship With Age, Gender, and Bitter Taste Genotype. AB - BACKGROUND: Little research has focused on whether there are individual differences among children in their sensitivity to sweet taste and, if so, the biological correlates of such differences. OBJECTIVES: Our goal was to understand how variations in children's sucrose detection thresholds relate to their age and gender, taste genotype, body composition, and dietary intake of added sugars. METHODS: Sucrose detection thresholds in 7- to 14-year-old children were tested individually using a validated, two-alternative, forced-choice, paired-comparison tracking method. Five genetic variants of taste genes were assayed: TAS1R3 and GNAT3 (sweet genes; one variant each) and the bitter receptor gene TAS2R38 (three variants). All children were measured for body weight and height. A subset of these children were measured for the percentage of body fat and waist circumference and provided added sugar intake by 24-hour dietary recall. RESULTS: Sucrose thresholds ranged from 0.23 to 153.8 mM with most of the children completing the threshold task (216/235; 92%). Some children were biologically related (i.e., siblings), and for the genetic analysis, one sibling from each family was studied. Variants in the bitter but not the sweet genes were related to sucrose threshold and sugar intake; children with two bitter-sensitive alleles could detect sucrose at lower concentrations (F(2,165) = 4.55, p = .01; rs1726866) and reported eating more added sugar (% kcal; F(2, 62) = 3.64, p = .03) than did children with less sensitive alleles. Age, gender, and indices of obesity also were related to child-to-child differences in sucrose threshold; girls were more sensitive than boys (t(214) = 2.0, p = .05), older children were more sensitive than younger children (r(214) = -.16, p = .02), and fatter (r(84) = -.22, p = .05) or more centrally obese children (r(84) = -.26, p = .02) were more sensitive relative to others. DISCUSSION: Inborn differences in bitter sensitivity may affect childhood dietary sugar intake with long-term health consequences. There may be a more complex interplay between the developing bitter and sweet taste systems than previously understood. PMID- 26633763 TI - Health-seeking behaviour, diagnostics and transmission dynamics in the control of visceral leishmaniasis in the Indian subcontinent. AB - Countries in the Indian subcontinent have committed to reducing the incidence of kala-azar, a clinical manifestation of visceral leishmaniasis, to below 1 in 10,000 by 2020. We address the role of timing of use and accuracy of diagnostics in kala-azar control and elimination. We use empirical data on health-seeking behaviour and health-system performance from the Indian state of Bihar, Bangladesh and Nepal to parameterize a mathematical model. Diagnosis of cases is key to case management, control and surveillance. Treatment of cases prevents onward transmission, and we show that the differences in time to diagnosis in these three settings explain the observed differences in incidence. Shortening the time from health-care seeking to diagnosis is likely to lead to dramatic reductions in incidence in Bihar, bringing the incidence down to the levels seen in Bangladesh and Nepal. The results emphasize the importance of maintaining population and health-system awareness, particularly as transmission and disease incidence decline. We explore the possibility of diagnosing patients before the onset of clinical kala-azar (before 14 days fever), and show that this could have a marked impact on incidence, even for a moderately sensitive test. However, limited specificity (that results in false positives) is a major barrier to such a strategy. Diagnostic tests of high specificity used at an early stage of active infection, even if sensitivity is only moderate, could have a key role in the control of kala-azar, and prevent its resurgence when paired with the passive health-care system and tests of high sensitivity, such as the test for rK39 antibody response. PMID- 26633765 TI - Expanding the role of diagnostic and prognostic tools for infectious diseases in resource-poor settings. PMID- 26633764 TI - The role of rapid diagnostics in managing Ebola epidemics. AB - Ebola emerged in West Africa around December 2013 and swept through Guinea, Sierra Leone and Liberia, giving rise to 27,748 confirmed, probable and suspected cases reported by 29 July 2015. Case diagnoses during the epidemic have relied on polymerase chain reaction-based tests. Owing to limited laboratory capacity and local transport infrastructure, the delays from sample collection to test results being available have often been 2 days or more. Point-of-care rapid diagnostic tests offer the potential to substantially reduce these delays. We review Ebola rapid diagnostic tests approved by the World Health Organization and those currently in development. Such rapid diagnostic tests could allow early triaging of patients, thereby reducing the potential for nosocomial transmission. In addition, despite the lower test accuracy, rapid diagnostic test-based diagnosis may be beneficial in some contexts because of the reduced time spent by uninfected individuals in health-care settings where they may be at increased risk of infection; this also frees up hospital beds. We use mathematical modelling to explore the potential benefits of diagnostic testing strategies involving rapid diagnostic tests alone and in combination with polymerase chain reaction testing. Our analysis indicates that the use of rapid diagnostic tests with sensitivity and specificity comparable with those currently under development always enhances control, whether evaluated at a health-care-unit or population level. If such tests had been available throughout the recent epidemic, we estimate, for Sierra Leone, that their use in combination with confirmatory polymerase chain-reaction testing might have reduced the scale of the epidemic by over a third. PMID- 26633766 TI - Evaluating the impact of pulse oximetry on childhood pneumonia mortality in resource-poor settings. AB - It is estimated that pneumonia is responsible for 15% of childhood deaths worldwide. Recent research has shown that hypoxia and malnutrition are strong predictors of mortality in children hospitalized for pneumonia. It is estimated that 15% of children under 5 who are hospitalized for pneumonia have hypoxaemia and that around 1.5 million children with severe pneumonia require oxygen treatment each year. We developed a deterministic compartmental model that links the care pathway to disease progression to assess the impact of introducing pulse oximetry as a prognostic tool to distinguish severe from non-severe pneumonia in under-5 year olds across 15 countries with the highest burden worldwide. We estimate that, assuming access to supplemental oxygen, pulse oximetry has the potential to avert up to 148,000 deaths if implemented across the 15 countries. By contrast, integrated management of childhood illness alone has a relatively small impact on mortality owing to its low sensitivity. Pulse oximetry can significantly increase the incidence of correctly treated severe cases as well as reduce the incidence of incorrect treatment with antibiotics. We also found that the combination of pulse oximetry with integrated management of childhood illness is highly cost-effective, with median estimates ranging from US$2.97 to $52.92 per disability-adjusted life year averted in the 15 countries analysed. This combination of substantial burden reduction and favourable cost-effectiveness makes pulse oximetry a promising candidate for improving the prognosis for children with pneumonia in resource-poor settings. PMID- 26633767 TI - Understanding the incremental value of novel diagnostic tests for tuberculosis. AB - Tuberculosis is a major source of global mortality caused by infection, partly because of a tremendous ongoing burden of undiagnosed disease. Improved diagnostic technology may play an increasingly crucial part in global efforts to end tuberculosis, but the ability of diagnostic tests to curb tuberculosis transmission is dependent on multiple factors, including the time taken by a patient to seek health care, the patient's symptoms, and the patterns of transmission before diagnosis. Novel diagnostic assays for tuberculosis have conventionally been evaluated on the basis of characteristics such as sensitivity and specificity, using assumptions that probably overestimate the impact of diagnostic tests on transmission. We argue for a shift in focus to the evaluation of such tests' incremental value, defining outcomes that reflect each test's purpose (for example, transmissions averted) and comparing systems with the test against those without, in terms of those outcomes. Incremental value can also be measured in units of outcome per incremental unit of resource (for example, money or human capacity). Using a novel, simplified model of tuberculosis transmission that addresses some of the limitations of earlier tuberculosis diagnostic models, we demonstrate that the incremental value of any novel test depends not just on its accuracy, but also on elements such as patient behaviour, tuberculosis natural history and health systems. By integrating these factors into a single unified framework, we advance an approach to the evaluation of new diagnostic tests for tuberculosis that considers the incremental value at the population level and demonstrates how additional data could inform more-effective implementation of tuberculosis diagnostic tests under various conditions. PMID- 26633768 TI - Sustainable HIV treatment in Africa through viral-load-informed differentiated care. AB - There are inefficiencies in current approaches to monitoring patients on antiretroviral therapy in sub-Saharan Africa. Patients typically attend clinics every 1 to 3 months for clinical assessment. The clinic costs are comparable with the costs of the drugs themselves and CD4 counts are measured every 6 months, but patients are rarely switched to second-line therapies. To ensure sustainability of treatment programmes, a transition to more cost-effective delivery of antiretroviral therapy is needed. In contrast to the CD4 count, measurement of the level of HIV RNA in plasma (the viral load) provides a direct measure of the current treatment effect. Viral-load-informed differentiated care is a means of tailoring care so that those with suppressed viral load visit the clinic less frequently and attention is focussed on those with unsuppressed viral load to promote adherence and timely switching to a second-line regimen. The most feasible approach to measuring viral load in many countries is to collect dried blood spot samples for testing in regional laboratories; however, there have been concerns over the sensitivity and specificity of this approach to define treatment failure and the delay in returning results to the clinic. We use modelling to synthesize evidence and evaluate the cost-effectiveness of viral load-informed differentiated care, accounting for limitations of dried blood sample testing. We find that viral-load-informed differentiated care using dried blood sample testing is cost-effective and is a recommended strategy for patient monitoring, although further empirical evidence as the approach is rolled out would be of value. We also explore the potential benefits of point-of-care viral load tests that may become available in the future. PMID- 26633770 TI - Comparison of diagnostics for the detection of asymptomatic Plasmodium falciparum infections to inform control and elimination strategies. AB - The global burden of malaria has been substantially reduced over the past two decades. Future efforts to reduce malaria further will require moving beyond the treatment of clinical infections to targeting malaria transmission more broadly in the community. As such, the accurate identification of asymptomatic human infections, which can sustain a large proportion of transmission, is becoming a vital component of control and elimination programmes. We determined the relationship across common diagnostics used to measure malaria prevalence - polymerase chain reaction (PCR), rapid diagnostic test and microscopy - for the detection of Plasmodium falciparum infections in endemic populations based on a pooled analysis of cross-sectional data. We included data from more than 170,000 individuals comparing the detection by rapid diagnostic test and microscopy, and 30,000 for detection by rapid diagnostic test and PCR. The analysis showed that, on average, rapid diagnostic tests detected 41% (95% confidence interval = 26 66%) of PCR-positive infections. Data for the comparison of rapid diagnostic test to PCR detection at high transmission intensity and in adults were sparse. Prevalence measured by rapid diagnostic test and microscopy was comparable, although rapid diagnostic test detected slightly more infections than microscopy. On average, microscopy captured 87% (95% confidence interval = 74-102%) of rapid diagnostic test-positive infections. The extent to which higher rapid diagnostic test detection reflects increased sensitivity, lack of specificity or both, is unclear. Once the contribution of asymptomatic individuals to the infectious reservoir is better defined, future analyses should ideally establish optimal detection limits of new diagnostics for use in control and elimination strategies. PMID- 26633769 TI - Systematic review and meta-analysis of community and facility-based HIV testing to address linkage to care gaps in sub-Saharan Africa. AB - HIV testing and counselling is the first crucial step for linkage to HIV treatment and prevention. However, despite high HIV burden in sub-Saharan Africa, testing coverage is low, particularly among young adults and men. Community-based HIV testing and counselling (testing outside of health facilities) has the potential to reduce coverage gaps, but the relative impact of different modalities is not well assessed. We conducted a systematic review of HIV testing modalities, characterizing community (home, mobile, index, key populations, campaign, workplace and self-testing) and facility approaches by population reached, HIV positivity, CD4 count at diagnosis and linkage. Of 2,520 abstracts screened, 126 met eligibility criteria. Community HIV testing and counselling had high coverage and uptake and identified HIV-positive people at higher CD4 counts than facility testing. Mobile HIV testing reached the highest proportion of men of all modalities examined (50%, 95% confidence interval (CI) = 47-54%) and home with self-testing reached the highest proportion of young adults (66%, 95% CI = 65-67%). Few studies evaluated HIV testing for key populations (commercial sex workers and men who have sex with men), but these interventions yielded high HIV positivity (38%, 95% CI = 19-62%) combined with the highest proportion of first time testers (78%, 95% CI = 63-88%), indicating service gaps. Community testing with facilitated linkage (for example, counsellor follow-up to support linkage) achieved high linkage to care (95%, 95% CI = 87-98%) and antiretroviral initiation (75%, 95% CI = 68-82%). Expanding home and mobile testing, self testing and outreach to key populations with facilitated linkage can increase the proportion of men, young adults and high-risk individuals linked to HIV treatment and prevention, and decrease HIV burden. PMID- 26633775 TI - Infectious Enthusiasm. PMID- 26633771 TI - Assessing the impact of next-generation rapid diagnostic tests on Plasmodium falciparum malaria elimination strategies. AB - Mass-screen-and-treat and targeted mass-drug-administration strategies are being considered as a means to interrupt transmission of Plasmodium falciparum malaria. However, the effectiveness of such strategies will depend on the extent to which current and future diagnostics are able to detect those individuals who are infectious to mosquitoes. We estimate the relationship between parasite density and onward infectivity using sensitive quantitative parasite diagnostics and mosquito feeding assays from Burkina Faso. We find that a diagnostic with a lower detection limit of 200 parasites per microlitre would detect 55% of the infectious reservoir (the combined infectivity to mosquitoes of the whole population weighted by how often each individual is bitten) whereas a test with a limit of 20 parasites per microlitre would detect 83% and 2 parasites per microlitre would detect 95% of the infectious reservoir. Using mathematical models, we show that increasing the diagnostic sensitivity from 200 parasites per microlitre (equivalent to microscopy or current rapid diagnostic tests) to 2 parasites per microlitre would increase the number of regions where transmission could be interrupted with a mass-screen-and-treat programme from an entomological inoculation rate below 1 to one of up to 4. The higher sensitivity diagnostic could reduce the number of treatment rounds required to interrupt transmission in areas of lower prevalence. We predict that mass-screen-and-treat with a highly sensitive diagnostic is less effective than mass drug administration owing to the prophylactic protection provided to uninfected individuals by the latter approach. In low-transmission settings such as those in Southeast Asia, we find that a diagnostic tool with a sensitivity of 20 parasites per microlitre may be sufficient for targeted mass drug administration because this diagnostic is predicted to identify a similar village population prevalence compared with that currently detected using polymerase chain reaction if treatment levels are high and screening is conducted during the dry season. Along with other factors, such as coverage, choice of drug, timing of the intervention, importation of infections, and seasonality, the sensitivity of the diagnostic can play a part in increasing the chance of interrupting transmission. PMID- 26633776 TI - Neurologic Complications of Human Immunodeficiency Virus Infection. AB - PURPOSE OF REVIEW: Neurologic complications of human immunodeficiency virus (HIV) infection remain common, despite effective antiretroviral treatment (ART). Neurologic manifestations may be due to opportunistic infection, immune reconstitution, or the virus itself, posing diagnostic challenges for the neurologist. Neurologists are also asked to comment on the use of immunomodulatory agents in these patients and to manage long-term complications, such as neurocognitive disorders and peripheral neuropathy or the associated comorbidities. RECENT FINDINGS: HIV enters the central nervous system (CNS) soon after infection and can cause atrophy of the brain within 3 months of infection. As patients are living longer, comorbidities such as stroke associated with metabolic syndrome, hepatitis C, and drug abuse are important contributory factors to the neurologic and neuropsychiatric manifestations of HIV infection. Immune-mediated syndromes are increasingly being recognized in patients with HIV infection on antiretroviral therapy. This includes a subacute T-cell-mediated encephalitis called CNS-immune reconstitution inflammatory syndrome, fulminant multiple sclerosis-like lesions, and unmasking of underlying opportunistic infections with profound inflammatory reaction. Our understanding of the most appropriate antiretrovirals for treating or preventing CNS HIV replication continues to improve. Major efforts are being made to understand how the CNS reservoirs are established and maintained, and new approaches are being developed to develop a functional cure or eradicate the virus. SUMMARY: This article reviews the neurologic complications caused by HIV infection, associated comorbidities, or antiretroviral drugs that are commonly encountered by neurologists. PMID- 26633777 TI - Central Nervous System Infections With Immunomodulatory Therapies. AB - PURPOSE OF REVIEW: Serious central nervous system infections may occur in the setting of immunomodulatory drug use. It is important for neurologists to be aware of the incidence, diagnosis, management, and treatment of these infections. RECENT FINDINGS: Infectious disease has long been recognized as a complication of broad immunosuppression. However, the frequency with which infectious disease is observed appears to be lower and the spectrum of infectious complications narrower with immunomodulatory drugs, a class of agents having a more restricted effect on the immune system. An increasingly broad spectrum of immunomodulating agents has been used in the treatment of neurologic disorders, particularly in the management of multiple sclerosis. The recognition of progressive multifocal leukoencephalopathy (PML) in association with the use of natalizumab, an alpha4beta1 integrin inhibitor used in the treatment of multiple sclerosis, heralded concerns about infections associated with the use of immunomodulatory therapy. While the observation of PML with natalizumab remains the most striking example to date, other immunomodulatory treatments may also be associated with an increased risk of PML. Furthermore, other infectious diseases, including herpes simplex virus, varicella-zoster virus, and tuberculosis, are also associated with the use of immunomodulatory agents. The use of screening tests, careful monitoring, and immunization and the initiation of prophylactic treatment to address potential infectious complications associated with use of immunomodulatory therapies is evolving; at the same time, the armamentarium of neuroimmunodulatory therapies continues to expand. SUMMARY: A comprehensive understanding of natalizumab-associated PML is illustrative of the potential pathogenic effects of immunomodulatory agents that lead to infectious complications, as well as the recognition and potential treatment strategies of these complications. The current knowledge of immunotherapy-associated PML incidence, clinical and radiographic features, and management are discussed in detail in this article. Increased risk of herpetic and other infectious complications has also been encountered with immunomodulation. Strategies in relation to minimizing risk and decreasing chances of encountering infectious complications associated with the use of such therapies, including those related to PML, tuberculosis, herpes simplex virus, and varicella-zoster virus, are highlighted. PMID- 26633778 TI - Arbovirus Infections. AB - PURPOSE OF REVIEW: Arbovirus (arthropod-borne virus) infections are increasingly important causes of neurologic disease in the United States through both endemic transmission and travel-associated infections. This article reviews the major arbovirus infections that can cause neurologic disease likely to be encountered in the United States. RECENT FINDINGS: West Nile virus continues to be an important cause of epidemic encephalitis, while emerging arbovirus infections such as dengue and chikungunya have rapidly expanded their geographic distribution. As emerging arboviruses expand in new geographic regions, neurologic abnormalities are reported in new patient populations. SUMMARY: Emerging arbovirus infections are increasingly important causes of neurologic disease throughout the world and in the United States. While no US Food and Drug Administration (FDA)-approved therapy is yet available for these infections, prompt recognition and diagnosis from the consulting neurologist will ensure appropriate supportive care for the patient. PMID- 26633780 TI - Tropical Neuroinfectious Diseases. AB - PURPOSE OF REVIEW: This article discusses the assessment of the patient presenting with neurologic symptoms who has lived in or traveled through tropical or subtropical regions and reviews selected nervous system infections prevalent in the tropics and subtropics, with discussion of the epidemiology, clinical features, recommended diagnostic testing, and management. RECENT FINDINGS: Increasing travel, emigration, and population growth all facilitate the global spread of tropical neurologic infections. Neurologists worldwide should be aware of the spectrum of neurologic manifestations as well as the most appropriate approach to diagnosis and management of these infections. SUMMARY: Although many infectious tropical diseases affecting the nervous system are preventable or treatable, the burden of disease remains high, with significant socioeconomic costs associated with managing acute manifestations and chronic, often debilitating, neurologic sequelae. Tropical infections of the nervous system are often transmitted in regions where people live in poverty and where access to adequate health care is limited. As with most infections of the nervous system, timely access to proper treatment is of utmost importance, as delays are typically associated with worse outcome. PMID- 26633781 TI - Fungal Infections of the Central Nervous System. AB - PURPOSE OF REVIEW: This article summarizes current knowledge on the epidemiology, clinical presentations, diagnosis, and management of selected fungal infections of the central nervous system (CNS). Key syndromes, differential diagnoses, and therapeutic interventions according to host immune status and exposure are reviewed. RECENT FINDINGS: Advancements in imaging of the brain and spinal cord, and molecular DNA and antigen-based laboratory diagnostics afford improved sensitivity for CNS mycoses. Newer therapeutic strategies may improve outcomes if provided early and host immunosuppression is abrogated. Adjunctive corticosteroid use for disabling neuroinflammation and cerebral edema in the setting of microbiological control may be considered. In addition, nonspecific presentations and absence of fevers in patients without human immunodeficiency virus suggest that screening for Cryptococcus meningitis be performed in all patients with subcortical dementias using a simple CSF or serum antigen test. SUMMARY: CNS fungal infections comprise a wide spectrum of clinical syndromes, including abscesses, meningitis/meningoencephalitis, focal masses, stroke/vasculitides, immune reconstitution inflammatory syndrome (IRIS), and spinal pathologies such as arachnoiditis. The main etiologies include Aspergillus, Cryptococcus, Candida, Mucorales, dematiaceous molds, and dimorphic endemic fungi, with the route of acquisition being respiratory or traumatic inoculation with subsequent spread hematogenously or contiguously. Proper management focuses on early effective antifungal therapy and surgery for large or compressive mass lesions. While adjunctive recombinant cytokine or growth factor use has been supported in certain hosts with refractory infections, IRIS-like reactions may occur, suggesting alternative approaches such as high-dose pulse corticosteroids followed by taper. PMID- 26633779 TI - Prion Diseases. AB - PURPOSE OF REVIEW: This article presents an update on the clinical aspects of human prion disease, including the wide spectrum of their presentations. RECENT FINDINGS: Prion diseases, a group of disorders caused by abnormally shaped proteins called prions, occur in sporadic (Jakob-Creutzfeldt disease), genetic (genetic Jakob-Creutzfeldt disease, Gerstmann-Straussler-Scheinker syndrome, and fatal familial insomnia), and acquired (kuru, variant Jakob-Creutzfeldt disease, and iatrogenic Jakob-Creutzfeldt disease) forms. This article presents updated information on the clinical features and diagnostic methods for human prion diseases. New antemortem potential diagnostic tests based on amplifying prions in order to detect them are showing very high specificity. Understanding of the diversity of possible presentations of human prion diseases continues to evolve, with some genetic forms progressing slowly over decades, beginning with dysautonomia and neuropathy and progressing to a frontal-executive dementia with pathology of combined prionopathy and tauopathy. Unfortunately, to date, all human prion disease clinical trials have failed to show survival benefit. A very rare polymorphism in the prion protein gene recently has been identified that appears to protect against prion disease; this finding, in addition to providing greater understanding of the prionlike mechanisms of neurodegenerative disorders, might lead to potential treatments. SUMMARY: Sporadic Jakob-Creutzfeldt disease is the most common form of human prion disease. Genetic prion diseases, resulting from mutations in the prion-related protein gene (PRNP), are classified based on the mutation, clinical phenotype, and neuropathologic features and can be difficult to diagnose because of their varied presentations. Perhaps most relevant to this Continuum issue on neuroinfectious diseases, acquired prion diseases are caused by accidental transmission to humans, but fortunately, they are the least common form and are becoming rarer as awareness of transmission risk has led to implementation of measures to prevent such occurrences. PMID- 26633782 TI - Bacterial Infections of the Central Nervous System. AB - PURPOSE OF REVIEW: Bacterial infections of the central nervous system are neurologic emergencies. Prompt recognition and treatment are essential not only to prevent mortality, but also to decrease neurologic sequelae. This article focuses on the two most common central nervous system bacterial infections, bacterial meningitis and spinal epidural abscess. RECENT FINDINGS: Two outbreaks of serogroup B meningococcal disease have occurred on US college campuses. The meningococcal vaccine given to young adults does not contain serogroup B. SUMMARY: In bacterial meningitis and in bacterial spinal epidural abscess, the identification of and eradication of the pathogen with antimicrobial therapy is the easy part. It is the recognition of the disorder, the understanding of which diagnostic studies to obtain and their limitations, and the management of the neurologic complications that require the expertise of a neurologist. PMID- 26633783 TI - Varicella-Zoster Virus Infections. AB - PURPOSE OF REVIEW: This article describes the clinical features and laboratory and imaging abnormalities of the protean neurologic disorders produced by varicella-zoster virus (VZV) reactivation. Diseases include not only zoster, but also chronic pain (postherpetic neuralgia), meningoencephalitis and cerebellitis, single or multiple cranial nerve palsies (polyneuritis cranialis), myelopathy (myelitis and spinal cord infarction), and VZV vasculopathy of intracerebral and extracerebral arteries that causes ischemic or hemorrhagic stroke, aneurysm, subarachnoid and intracerebral hemorrhage, arterial ectasia, and dissection. The article addresses accurate diagnosis of VZV infection of the nervous system in the absence of rash, and optimal treatment. RECENT FINDINGS: All neurologic disorders produced by VZV can occur in the absence of rash. Diagnosis is confirmed by the presence of VZV DNA or anti-VZV antibodies in CSF. Based on evidence from recent studies, VZV has been implicated as a cause of giant cell arteritis. SUMMARY: Clinicians must be aware that VZV reactivation produces multiple disorders of the central nervous system (CNS) and peripheral nervous system, often without rash. Rapid virologic verification and prompt treatment with antiviral agents can lead to complete recovery, even in patients with protracted disease. PMID- 26633784 TI - Herpes Simplex Virus Infections of the Central Nervous System. AB - PURPOSE OF THE REVIEW: This article summarizes knowledge of herpes simplex virus (HSV) infections of the central nervous system (CNS). Disease pathogenesis, detection of DNA polymerase chain reaction (PCR) for diagnosis and prognosis, and approaches to therapy warrant consideration. RECENT FINDINGS: HSV infection of the CNS is one of few treatable viral diseases. Clinical trials indicate that outcome following neonatal herpes simplex virus type 2 (HSV-2) infections of the CNS is significantly improved when 6 months of suppressive oral acyclovir therapy follows IV antiviral therapy. In contrast, herpes simplex virus type 1 (HSV-1) infections of the brain do not benefit from extended oral antiviral therapy. This implies a difference in disease pathogenesis between HSV-2 and HSV-1 infections of the brain. PCR detection of viral DNA in the CSF is the gold standard for diagnosis. Use of PCR is now being adopted as a basis for determining the duration of therapy in the newborn. SUMMARY: HSV infections are among the most common encountered by humans; seropositivity occurs in 50% to 90% of adult populations. Herpes simplex encephalitis, however, is an uncommon result of this infection. Since no new antiviral drugs have been introduced in nearly 3 decades, much effort has focused on learning how to better use acyclovir and how to use existing databases to establish earlier diagnosis. PMID- 26633785 TI - Neurosyphilis. AB - PURPOSE OF REVIEW: This article reviews the etiology, clinical manifestations, diagnosis, and treatment of neurosyphilis, with a focus on issues of particular relevance to neurologists. RECENT FINDINGS: The number of cases of infectious syphilis in the United States has steadily increased since 2000. The highest rates are among men who have sex with men, and approximately half of these individuals are infected with human immunodeficiency virus (HIV). Neurosyphilis is a serious complication of syphilis that can develop at any time in the course of syphilis. Two neuroimaging patterns should alert the neurologist to a diagnosis of neurosyphilis: cerebral gummas, which are dural-based lesions that can mimic meningiomas, and medial temporal lobe abnormalities that can mimic herpes encephalitis. Penicillin G is the recommended treatment for neurosyphilis, but ceftriaxone may be an acceptable alternative. SUMMARY: The diagnosis of neurosyphilis can be challenging. A sound understanding of the clinical manifestations and the strengths and limitations of diagnostic tests are essential tools for the neurologist. PMID- 26633786 TI - Lyme Neuroborreliosis. AB - PURPOSE OF REVIEW: Lyme disease, caused by the spirochete Borrelia burgdorferi, is the most common tick-borne illness in the United States and Europe. Lyme disease usually begins with the characteristic skin lesion, erythema migrans, at the site of the tick bite. Following hematogenous dissemination, neurologic, cardiac, and/or rheumatologic involvement may occur. Neurologic involvement occurs in up to 15% of untreated B. burgdorferi infection and neurologists should be familiar with its diagnosis and management. RECENT FINDINGS: The most common early neurologic manifestations of Lyme disease are cranial neuropathy (particularly facial palsy), lymphocytic meningitis, and radiculoneuritis, which often occur in combination. Late neuroborreliosis occurs much less frequently than early disease. A combination of clinical and laboratory findings is recommended for the diagnosis of Lyme neuroborreliosis. Treatment with recommended antibiotic regimens is effective in Lyme neuroborreliosis, and patients with early disease usually have excellent outcomes. Recovery is slower and may be incomplete in patients with late disease. SUMMARY: Nervous system involvement occurs in up to 15% of patients with untreated B. burgdorferi infection. This article reviews clinical aspects of the diagnosis and treatment of Lyme neuroborreliosis, with focus on the United States. PMID- 26633787 TI - Quarantine, Isolation, and Health Care Workers. AB - Although Ebola virus disease and other hemorrhagic fevers are not generally considered infectious diseases of the nervous system, neurologists may be asked to participate in the management of patients with these and other dangerous communicable illnesses, including possible bioterrorism agents. It is essential for all health professionals to understand the public health, legal, and ethical frameworks behind autonomy-limiting interventions such as quarantine and isolation. Health care professionals represent the front line of defense during public health emergencies. They are often disproportionately affected by the illnesses themselves as well as by the public health interventions intended to prevent spread. The global health crisis caused by the spread of Ebola virus disease has been instructional for examining these ethical issues. PMID- 26633788 TI - Prevention and Management of Health Care-Associated Infections. AB - Health care-associated infections (formerly called hospital-acquired infections or nosocomial infections) are a major public health concern. They place an enormous burden on the health care system, prolong hospitalization, and increase health care costs. Neurologists act as primary providers in the hospital or the clinic for patients with multiple comorbidities. We must be aware of the burden of health care-associated infections, their common types, risk factors, and various prevention strategies. Common strategies can be applied in day-to-day practice to help prevent health care-associated infections. PMID- 26633789 TI - Coding of Neuroinfectious Diseases. AB - Accurate coding is an important function of neurologic practice. This contribution to Continuum is part of an ongoing series that presents helpful coding information along with examples related to the issue topic. Tips for diagnosis coding, Evaluation and Management coding, procedure coding, or a combination are presented, depending on which is most applicable to the subject area of the issue. PMID- 26633790 TI - Appendix A: Summary of Evidence-based Guideline for Clinicians: Antiepileptic Drug Selection for People With HIV/AIDS. PMID- 26633791 TI - Appendix B: Summary of Evidence-based Guideline for Clinicians: Treatment of Parenchymal Neurocysticercosis. PMID- 26633792 TI - Appendix C: Practice Parameter: Diagnosis of Patients With Nervous System Lyme Borreliosis (Lyme Disease). PMID- 26633793 TI - Appendix D: Summary of Evidence-based Guideline for Clinicians: Treatment of Nervous System Lyme Disease. PMID- 26633797 TI - Patient Management Problem. PMID- 26633800 TI - Correction: Efficient "Shotgun" Inference of Neural Connectivity from Highly Sub sampled Activity Data. PMID- 26633801 TI - Gender, Race, and Age at Diagnosis as Risk Factors for Metastasis or Recurrence among 1,657 Thyroid Cancer Patients Treated with Radioiodine across 40 Years in Singapore. AB - BACKGROUND: To obtain descriptive data on Singaporean thyroid cancer patients treated with radioiodine and to assess gender, race, and age at diagnosis as risk factors for metastasis or recurrence. METHODS: This is a retrospective study of all thyroid cancer patients treated with radioiodine of any prescribed activity at our institution. Data collected included: age at diagnosis, gender, race, histopathological type, duration of follow-up, and metastasis at diagnosis (locoregional or distant) or recurrence at any time. Gender, race, and age at diagnosis were analyzed for possible associations with metastasis or recurrence. RESULTS: A total of 1,657 thyroid cancer patients were treated with radioiodine across a 40-year period; mean follow-up 6.4 +/- 6.9 years (median 4.2 years). 656 (39.6%) patients had metastasis or recurrence over the duration of their follow up. Male gender (odds ratio (OR) 1.38; p = 0.006), Malay race (OR 1.71; p < 0.0001), and age at diagnosis of > 46 years (OR 1.31; p = 0.007) were significantly associated with metastasis or recurrence. CONCLUSION: Male gender, Malay race, and age at diagnosis of > 46 years were significant risk factors for metastasis or recurrence in Singaporean thyroid cancer patients treated with radioiodine. PMID- 26633802 TI - Subpial transection surgery for epilepsy. AB - BACKGROUND: Nearly 30% of patients with epilepsy continue to have seizures in spite of using several antiepileptic drug (AED) regimens. Such patients are regarded as having refractory, or uncontrolled, epilepsy. No definition of uncontrolled, or medically refractory, epilepsy has been universally accepted, but for the purposes of this review, we will consider seizures as drug resistant if they have failed to respond to a minimum of two AEDs. It is believed that early surgical intervention may prevent seizures at a younger age, which, in turn, may improve the intellectual and social status of children. Many types of surgery are available for treatment of refractory epilepsy; one such procedure is known as subpial transection. OBJECTIVES: To determine the benefits and adverse effects of subpial transection for partial-onset seizures and generalised tonic clonic seizures in children and adults. SEARCH METHODS: We searched the Cochrane Epilepsy Group Specialised Register (29 June 2015), the Cochrane Central Register of Controlled Trials (CENTRAL; May 2015, Issue 5) and MEDLINE (1946 to 29 June 2015). We imposed no language restrictions. SELECTION CRITERIA: We considered all randomised and quasi-randomised parallel-group studies, whether blinded or non blinded. DATA COLLECTION AND ANALYSIS: Two review authors (BK and SR) independently screened trials identified by the search. The same two review authors planned to independently assess the methodological quality of studies. When studies were identified for inclusion, one review author would have extracted the data, and the other would have verified the data. MAIN RESULTS: We found no relevant studies. AUTHORS' CONCLUSIONS: We found no evidence to support or refute use of subpial transection surgery for patients with medically refractory epilepsy. Well-designed randomised controlled trials are needed to guide clinical practice. PMID- 26633803 TI - A Prospective Study on the Clinical and Microbiological Spectrum of Endophthalmitis in a Specific Region in Denmark. AB - PURPOSE: To study the clinical and microbiological spectrum of endophthalmitis with emphasis on clinical features, visual outcomes and risks of surgical complications. METHODS: A prospective observational study was conducted between 2012 and 2013 in a specific region in Denmark. Patients were clinically examined before, during and after surgical intervention for endophthalmitis. RESULTS: Fifty eyes with endophthalmitis were included. Endophthalmitis after cataract surgery (post-cataract), anti-VEGF (vascular endothelial growth factor) intravitreal injections (post-injection) and cases of endogenous endophthalmitis were responsible for 40, 28 and 18% of all cases, respectively. There was no difference in the microbiological spectrum in post-cataract patients and post injection patients, but patients with post-cataract endophthalmitis presented statistically significantly more frequently with hypopyon and fibrin in the anterior chamber. Between 20 and 25% of post-cataract and post-injection endophthalmitis patients developed a surgical complication after primary surgical intervention for endophthalmitis, and this was statistically significantly associated with a poor visual outcome. There was no statistically significant difference in the risk of surgical complications in phakic and pseudophakic eyes with post-injection endophthalmitis. Of the 8 patients with endogenous endophthalmitis, 67% developed a surgical complication, and these patients had a high mortality. The visual outcome in the most common types of endophthalmitis was good, with 60% of post-cataract patients achieving a visual outcome >= 0.5, and 64% of post-injection patients only had a mild vision loss (1-14 ETDRS letters) or even gained vision. CONCLUSIONS: The endophthalmitis cases had a broad clinical spectrum. Surprisingly, endogenous endophthalmitis accounted for almost one fifth of all cases. Patients with post-cataract endophthalmitis had a clinically different presentation than patients with post-injection endophthalmitis. In general, the bacteria were low-virulent and the visual outcomes good, but a substantial part of the patients developed a surgical complication which was associated with a poor visual outcome. PMID- 26633804 TI - Quantifying crustal thickness over time in magmatic arcs. AB - We present global and regional correlations between whole-rock values of Sr/Y and La/Yb and crustal thickness for intermediate rocks from modern subduction-related magmatic arcs formed around the Pacific. These correlations bolster earlier ideas that various geochemical parameters can be used to track changes of crustal thickness through time in ancient subduction systems. Inferred crustal thicknesses using our proposed empirical fits are consistent with independent geologic constraints for the Cenozoic evolution of the central Andes, as well as various Mesozoic magmatic arc segments currently exposed in the Coast Mountains, British Columbia, and the Sierra Nevada and Mojave-Transverse Range regions of California. We propose that these geochemical parameters can be used, when averaged over the typical lifetimes and spatial footprints of composite volcanoes and their intrusive equivalents to infer crustal thickness changes over time in ancient orogens. PMID- 26633805 TI - HLA-G 3'UTR Polymorphisms Impact the Prognosis of Stage II-III CRC Patients in Fluoropyrimidine-Based Treatment. AB - An important hallmark of CRC is the evasion of immune surveillance. HLA-G is a negative regulator of host's immune response. Overexpression of HLA-G protein in primary tumour CRC tissues has already been associated to worse prognosis; however a definition of the role of immunogenetic host background is still lacking. Germline polymorphisms in the 3'UTR region of HLA-G influence the magnitude of the protein by modulating HLA-G mRNA stability. Soluble HLA-G has been associated to 3'UTR +2960 Ins/Ins and +3035 C/T (lower levels) and +3187 G/G (high levels) genotypes. HLA-G 3'UTR SNPs have never been explored in CRC outcome. The purpose of this study was to investigate if common HLA-G 3'UTR polymorphisms have an impact on DFS and OS of 253 stage II-III CRC patients, after primary surgery and ADJ-CT based on FL. The 3'UTR was sequenced and SNPs were analyzed for their association with survival by Kaplan-Meier and multivariate Cox models; results underwent internal validation using a resampling method (bootstrap analysis). In a multivariate analysis, we estimated an association with improved DFS in Ins allele (Ins/Del +Ins/Ins) carriers (HR 0.60, 95% CI 0.38-0.93, P = 0.023) and in patients with +3035 C/T genotype (HR 0.51, 95% CI 0.26-0.99, P = 0.045). The +3187 G/G mutated carriers (G/G vs A/A+A/G) were associated to a worst prognosis in both DFS (HR 2.46, 95% CI 1.19-5.05, P = 0.015) and OS (HR 2.71, 95% CI 1.16-6.63, P = 0.022). Our study shows a prognostic and independent role of 3 HLA-G 3'UTR SNPs, +2960 14-bp INDEL, +3035 C>T, and +3187 A>G. PMID- 26633806 TI - Randomized Controlled Trial of Zoledronic Acid plus Chemotherapy versus Chemotherapy Alone as Neoadjuvant Treatment of HER2-Negative Primary Breast Cancer (JONIE Study). AB - PURPOSE: Zoledronic acid (ZOL) is a nitrogen-containing bisphosphonate that induces osteoclast apoptosis and inhibits bone resorption by inhibiting the mevalonate pathway. Its benefit for the prevention of skeletal complications due to bone metastases has been established. However, the antitumor efficacy of ZOL, although suggested by multiple preclinical and clinical studies, has not yet been clinically proven. We performed the present randomized Phase 2 trial to investigate the antitumor effect of ZOL with chemotherapy (CT). METHODS: Asian patients with HER2-negative invasive breast cancer were randomly assigned to either the CT or CT+ZOL (CTZ) group. One hundred and eighty-eight patients were randomized to either the CT group (n = 95) or the CTZ group (n = 93) from March 2010 to April 2012, and 180 patients were assessed. All patients received four cycles of FEC100 (fluorouracil 500 mg/m2, epirubicin 100 mg/m2, and cyclophosphamide 500 mg/m2), followed by 12 cycles of paclitaxel at 80 mg/m2 weekly. ZOL (4 mg) was administered three to four times weekly for 7 weeks to the patients in the CTZ group. The primary endpoint was the pathological complete response (pCR) rate, which was defined as no invasive cancer in the breast tissue specimen. Safety was assessed in all patients who received at least one dose of the study drug. RESULTS: This randomized controlled trial indicated that the rates of pCR in CTZ group (14.8%) was doubled to CT group (7.7%), respectively (one-sided chi-square test, p = 0.068), though the additional efficacy of zoledronic acid was not demonstrated statistically. The pCR rate in postmenopausal patients was 18.4% and 5.1% in the CTZ and CT groups, respectively (one-sided Fisher's exact test, p = 0.071), and that in patients with triple negative breast cancer was 35.3% and 11.8% in the CTZ and CT groups, respectively (one-sided Fisher's exact test, p = 0.112). Thus the addition of ZOL to neoadjuvant CT has potential anticancer benefits in postmenopausal patients and patients with triple-negative breast cancer. Further investigation is warranted. TRIAL REGISTRATION: University Hospital Medical Information Network. UMIN000003261. PMID- 26633807 TI - Developing a Method to Test the Validity of 24 Hour Time Use Diaries Using Wearable Cameras: A Feasibility Pilot. AB - Self-report time use diaries collect a continuous sequenced record of daily activities but the validity of the data they produce is uncertain. This study tests the feasibility of using wearable cameras to generate, through image prompted interview, reconstructed 'near-objective' data to assess their validity. 16 volunteers completed the Harmonised European Time Use Survey (HETUS) diary and used an Autographer wearable camera (recording images at approximately 15 second intervals) for the waking hours of the same 24-hour period. Participants then completed an interview in which visual images were used as prompts to reconstruct a record of activities for comparison with the diary record. 14 participants complied with the full collection protocol. We compared time use and number of discrete activities from the diary and camera records (using 10 classifications of activity). In terms of aggregate totals of daily time use we found no significant difference between the diary and camera data. In terms of number of discrete activities, participants reported a mean of 19.2 activities per day in the diaries, while image prompted interviews revealed 41.1 activities per day. The visualisations of the individual activity sequences reveal some potentially important differences between the two record types, which will be explored at the next project stage. This study demonstrates the feasibility of using wearable cameras to reconstruct time use through image prompted interview in order to test the concurrent validity of 24-hour activity time-use budgets. In future we need a suitably powered study to assess the validity and reliability of 24-hour time use diaries. PMID- 26633808 TI - The Molecular Cytogenetic Characterization of Pistachio (Pistacia vera L.) Suggests the Arrest of Recombination in the Largest Heteropycnotic Pair HC1. AB - This paper represents the first molecular cytogenetic characterization of the strictly dioecious pistachio tree (Pistacia vera L.). The karyotype was characterized by fluorescent in situ hybridization (FISH) with probes for 5S and 45S rDNAs, and the pistachio specific satellite DNAs PIVE-40, and PIVE-180, together with DAPI-staining. PIVE-180 has a monomeric unit of 176-178 bp and high sequence homology between family members; PIVE-40 has a 43 bp consensus monomeric unit, and is most likely arranged in higher order repeats (HORs) of two units. The P. vera genome is highly heterochromatic, and prominent DAPI positive blocks are detected in most chromosomes. Despite the difficulty in classifying chromosomes according to morphology, 10 out of 15 pairs (2n = 30) could be distinguished by their unique banding patterns using a combination of FISH probes. Significantly, the largest pair, designated HC1, is strongly heteropycnotic, shows differential condensation, and has massive enrichment in PIVE-40 repeats. There are two types of HC1 chromosomes (type-I and type-II) with differing PIVE-40 hybridization signal. Only type-I/II heterozygotes and type-I homozygotes individuals were found. We speculate that the differentiation between the two HC1 chromosomes is due to suppression of homologous recombination at meiosis, reinforced by the presence of PIVE-40 HORs and differences in PIVE-40 abundance. This would be compatible with a ZW sex-determination system in the pistachio tree. PMID- 26633809 TI - Relationship between Initial Telomere Length, Initial Telomerase Activity, Age, and Replicative Capacity of Nucleus Pulposus Chondrocytes in Human Intervertebral Discs: What Is a Predictor of Replicative Potential? AB - There is evidence that telomere length (TL), telomerase activity (TA), and age are related to the replicative potential of human nucleus pulposus chondrocytes (NPCs). However, it has not yet been established if any of these factors can serve as predictors of the replicative potential of NPCs. To establish predictors of the replicative potential of NPCs, we evaluated potential relationships between replicative capacity of NPCs, initial TL (telomere length at the first passage), initial TA (telomerase activity at the first passage), and age. Nucleus pulposus specimens were obtained from 14 patients of various ages undergoing discectomy. NPCs were serially cultivated until the end of their replicative lifespans. Relationships among cumulative population doubling level (PDL), initial TL, initial TA, and age were analyzed. Initial TA was negatively correlated with age (r = -0.674, P = 0.008). However, no correlation between initial TL and age was observed. Cumulative PDL was also negatively correlated with age (r = -0.585, P = 0.028). Although the cumulative PDL appeared to increase with initial TL or initial TA, this trend was not statistically significant. In conclusion, age is the sole predictor of the replicative potential of human NPCs, and replicative potential decreases with age. Initial TL and initial TA are not predictors of replicative potential, and can serve only as reference values. PMID- 26633810 TI - Development and Evaluation of a Parenting Resilience Elements Questionnaire (PREQ) Measuring Resiliency in Rearing Children with Developmental Disorders. AB - We developed a parenting resilience elements questionnaire (PREQ) measuring the degree to which mothers possess elements that aid in adapting to challenges and difficulties related to children with developmental disorders (DD). A total of 424 parents of children with DD were recruited from five medical institutes. Psychometric properties of PREQ were evaluated using data of 363 mothers of children with DD. Furthermore, multiple regression analysis was performed, predicting depressive symptoms and parenting behavior with PREQ subscales, a general health questionnaire, and the total difficulties score of a strength and difficulties questionnaire. Factor analysis revealed three reliable factors: "knowledge of the child's characteristics," "perceived social supports," and "positive perceptions of parenting." Moreover, multiple regression analysis showed that "knowledge of the child's characteristics" was associated with parenting behavior, whereas "perceived social supports" predicted depressive symptoms; "positive perceptions of parenting" influenced both parenting behavior and depressive symptoms. These findings indicated that the PREQ may be used as a scale measuring resiliency in mothers of children with DD and is useful for evaluating their parenting ability in clinical interventions. PMID- 26633811 TI - Cortex commands the performance of skilled movement. AB - Mammalian cerebral cortex is accepted as being critical for voluntary motor control, but what functions depend on cortex is still unclear. Here we used rapid, reversible optogenetic inhibition to test the role of cortex during a head fixed task in which mice reach, grab, and eat a food pellet. Sudden cortical inhibition blocked initiation or froze execution of this skilled prehension behavior, but left untrained forelimb movements unaffected. Unexpectedly, kinematically normal prehension occurred immediately after cortical inhibition, even during rest periods lacking cue and pellet. This 'rebound' prehension was only evoked in trained and food-deprived animals, suggesting that a motivation gated motor engram sufficient to evoke prehension is activated at inhibition's end. These results demonstrate the necessity and sufficiency of cortical activity for enacting a learned skill. PMID- 26633814 TI - Relationships Between 3 Classification Systems in Brachial Plexus Birth Palsy. AB - BACKGROUND: The Mallet scale, Active Movement Scale (AMS), and Toronto Test are validated for use in children with brachial plexus birth palsy (BPBP). However, the inability to compare these evaluation systems has led to difficulty gauging treatment efficacy and interpreting available literature in which multiple scoring systems are reported. Given the critical importance of physical examination, we compared 3 scoring systems to clarify statistical relationships between current validated evaluation methods. METHODS: The medical records of children with BPBP treated at a single institution over a 14-year period were retrospectively reviewed. Modified Mallet, AMS, and Toronto scores were recorded throughout the entire period. Data were included if at least 2 complete scoring systems were documented during the same examination session. Spearman correlation coefficients were calculated for all composite and subscore combinations. A concordance table was constructed for select variables found to be highly correlated. RESULTS: Total single-session score combinations were as follows: 157 Mallet and AMS, 325 AMS and Toronto, and 143 Mallet and Toronto. Composite AMS and Toronto scores were found to have a strong correlation (r=0.928, P<0.001). A concordance table comparing these variables revealed that a Toronto score of 3.5 is concordant to an AMS score of 45. Modified Mallet scores had only a moderate correlation with composite AMS (r=0.512, P<0.001) and Toronto (r=0.458, P<0.001) scores. Specifically regarding the modified Mallet score, maneuvers requiring external rotation had stronger correlations with the composite modified Mallet score than maneuvers highlighting internal rotation. CONCLUSIONS: Modified Mallet scores do not correlate well with AMS or Toronto scores and should be utilized separately when managing children with BPBP. Similarly, AMS and Toronto scores are inadequate to guide clinical decisions for which the literature cites Mallet scores as outcome measures, and vice versa. Lastly, Mallet scores should incorporate an isolated internal rotation component to adequately assess midline function. LEVEL OF EVIDENCE: Diagnostic level III. PMID- 26633812 TI - An extracellular biochemical screen reveals that FLRTs and Unc5s mediate neuronal subtype recognition in the retina. AB - In the inner plexiform layer (IPL) of the mouse retina, ~70 neuronal subtypes organize their neurites into an intricate laminar structure that underlies visual processing. To find recognition proteins involved in lamination, we utilized microarray data from 13 subtypes to identify differentially-expressed extracellular proteins and performed a high-throughput biochemical screen. We identified ~50 previously-unknown receptor-ligand pairs, including new interactions among members of the FLRT and Unc5 families. These proteins show laminar-restricted IPL localization and induce attraction and/or repulsion of retinal neurites in culture, placing them in an ideal position to mediate laminar targeting. Consistent with a repulsive role in arbor lamination, we observed complementary expression patterns for one interaction pair, FLRT2-Unc5C, in vivo. Starburst amacrine cells and their synaptic partners, ON-OFF direction-selective ganglion cells, express FLRT2 and are repelled by Unc5C. These data suggest a single molecular mechanism may have been co-opted by synaptic partners to ensure joint laminar restriction. PMID- 26633815 TI - Esophageal Perforation Caused by a Posterior Pedicle Screw: A Case Report. AB - BACKGROUND: Posterior spinal instrumented fusion has received widespread acceptance in adolescent idiopathic scoliosis (AIS) treatment, there have been some potential complications resulted from screw misplacement. Esophagus is one of the vital structures close to the upper thoracic vertebras and is at risk for potential injury. METHODS: A 15-year-old girl who underwent posterior instrumented fusion for AIS was admitted to our department 10 years later with a complaint of dysphagia due to an esophageal perforation from a malpositioned T4 pedicle screw (PS). After implant removal and nasogastric tube placement, oral feeding was started after 3 days and the patient was discharged from hospital after 1 week. RESULTS: In 12 weeks, the esophageal perforation healed without complications. CONCLUSIONS: This is the first case report of esophageal perforation by a posterior PS in an AIS patient. Esophagus is close to the upper thoracic vertebras and an anterior cortical perforation can cause esophageal injury if longer than 35 mm PSs are used. This unusual but potential complication must be kept in mind in scoliosis surgery. LEVEL OF EVIDENCE: Level IV-case report. PMID- 26633813 TI - Multipotent versus differentiated cell fate selection in the developing Drosophila airways. AB - Developmental potentials of cells are tightly controlled at multiple levels. The embryonic Drosophila airway tree is roughly subdivided into two types of cells with distinct developmental potentials: a proximally located group of multipotent adult precursor cells (P-fate) and a distally located population of more differentiated cells (D-fate). We show that the GATA-family transcription factor (TF) Grain promotes the P-fate and the POU-homeobox TF Ventral veinless (Vvl/Drifter/U-turned) stimulates the D-fate. Hedgehog and receptor tyrosine kinase (RTK) signaling cooperate with Vvl to drive the D-fate at the expense of the P-fate while negative regulators of either of these signaling pathways ensure P-fate specification. Local concentrations of Decapentaplegic/BMP, Wingless/Wnt, and Hedgehog signals differentially regulate the expression of D-factors and P factors to transform an equipotent primordial field into a concentric pattern of radially different morphogenetic potentials, which gradually gives rise to the distal-proximal organization of distinct cell types in the mature airway. PMID- 26633816 TI - The Surgical Management of Osteochondritis Dissecans of the Knee in the Skeletally Immature: A Survey of the Pediatric Orthopaedic Society of North America (POSNA) Membership. AB - BACKGROUND: While the characteristics of osteochondritis dissecans (OCD) of the knee that require surgery to heal have been described, several surgical techniques/procedures exist with no consensus established regarding timing of treatment and specific surgical intervention. In this study, we aim to determine current trends in surgical treatment for OCD lesions in the skeletally immature who have failed 6 months of nonoperative management by surveying a large cohort of orthopaedic surgeons. METHODS: An electronic survey designed using REDCap to capture surgeon treatment preferences for OCD lesions was distributed to members of the Pediatric Orthopaedic Society of North America (POSNA). The survey inquired about treating physicians' training and demographics. It then offered a series of clinical vignettes alongside imaging describing patients with varying degrees of severity of OCD following nonoperative treatment. Surgeons were prompted to select from a variety of multiple-choice-based options for further patient management. Standard descriptive statistics were used to summarize and compare the responses. RESULTS: Of the 129 POSNA members completing the pediatric survey, 97.7% were attending level orthopaedic surgeons, the majority identifying with an academic institution and treating mostly skeletally immature patients. In the skeletally immature population, the majority would treat intact, stable OCD lesions with drilling in a retroarticular or transarticular manner. Preferred treatment for unstable, salvageable lesions was screw fixation using bioabsorble materials or metal with variable pitch with no bone graft. The majority of respondents would treat unstable, unsalvageable OCD lesions with chondroplasty and osteochondral transplant/transfer or microfracture/drilling. CONCLUSIONS: The POSNA membership appears to agree on principle in terms of treatment modalities for various stages of OCD lesions in the skeletally immature, whereas individual techniques of achieving these principles may vary. Members endorse drilling for stable intact lesions; fixation for unstable, salvageable lesions; and "defect fill" for unsalvageable lesions. CLINICAL SIGNIFICANCE: OCD surgical treatment patterns can be used in future studies to determine which techniques are most effective for given indications, with the goal of designing a research-proven optimal treatment regimen for skeletally immature patients. PMID- 26633817 TI - Long-term Results After Extensive Soft Tissue Release in Very Severe Congenital Clubfeet. AB - BACKGROUND: The purpose of this study was to determine the long-term results, at an average follow-up of 22 years, in 66 patients (105 clubfeet) with very severe congenital idiopathic clubfeet according to the Dimeglio-Bensahel scale. METHODS: Patients were treated with an extensive soft tissue release in infancy. Results of the treatment were assessed according to the 100-point system of Ghanem Seringe. At the latest follow-up, all participants were evaluated with regard to pain and the overall function of the lower extremities. At the latest follow-up, anteroposterior and lateral radiographs of the affected foot and the contralateral normal foot, when applicable, were performed. RESULTS: In total, 92% of the patients were satisfied. The mean functional score of Ghanem-Seringe was 70.4 points. No foot had an excellent result, 19 feet had a good result, 16 had a fair result, and 70 had a poor result. A total of 86 feet were painful after strenuous activities or during walking. Eleven patients walked with a limp. In total, 82 feet were stiff. Ankle dorsiflexion and plantar flexion averaged 4.0+/-4.5 degrees and 19.9+/-10.7 degrees. Bone deformations such as flattening of the talar dome were observed in 93 feet. Among these feet, the Ghanem score was significantly lower (P<0.05). Necrosis of the navicular was present in 28 feet and subluxation in 82 feet. In total, 32 feet had moderate osteoarthritis. DISCUSSION: Results revealed that despite anatomically and radiologically imperfect clubfeet, most patients demonstrated satisfaction. Satisfaction was not significantly correlated with residual deformity, but with the sensation of a normal gait by the patient and the high initial Dimeglio-Bensahel score. Female patients were significantly less satisfied than male patients because they were more constrained in their social life than boys. Their main dissatisfaction was the atrophy of the calf. We noted several residual deformations. Plantar release seems to contribute to the high rate of overcorrection in our series. Extensive posterolateral and plantar releases in very severe clubfeet was responsible for sequelae, morphologic, anatomic, and functional, especially in adulthood. Deterioration of results over time was confirmed by our series. LEVEL OF EVIDENCE: Level IV. PMID- 26633818 TI - The Fate of the Iliopsoas Muscle in Long-term Follow-up After Open Reduction With a Medial Approach in Developmental Dysplasia of the Hip. Part 2: Isokinetic Muscle Strength Evaluation. AB - BACKGROUND: The impact on long-term weakness of hip flexion of complete iliopsoas tenotomy during open reduction of developmental hip dysplasia with a medial approach has not yet been fully clarified. The purpose of this study was to investigate the isokinetic muscle strength (IMS) of hip flexor and extensor muscles in these patients and also to analyze the effect of spontaneous reattachment of the iliopsoas muscle on IMS measurements. METHODS: The study included 20 patients. Earlier magnetic resonance imaging examination of all the patients revealed spontaneous reattachment of the iliopsoas in 18 (90%) patients. IMS measurements were performed at 60 and 150 degrees/s. The peak torque, total work (TW), average power (AP), work fatigue, and agonist to antagonist muscle ratio of the operated and nonoperated hips were recorded separately for flexors and extensors. The effect of iliopsoas reattachment on IMS was also evaluated. RESULTS: The mean follow-up period was 16.65+/-2.16 (13 to 20) years. Total work (P=0.013) and average power (P=0.009) of the flexor muscles and work fatigue of the extensor muscles (P=0.030) of the operated hip were significantly decreased when compared with the nonoperated hips at 150 degrees/s. There was no significant difference between the flexor muscles of the operated and nonoperated hips (P<0.05) at 60 degrees/s and extensor muscles (P<0.05) at 150 degrees/s. In addition, patients without reattachment had lower IMS in the operated hips. DISCUSSION: Flexor muscle strength was decreased in the operated hip against low resistance in long-term follow-up after iliopsoas tenotomy. This may reflect that hip muscle strength was decreased after prolonged activities such as sports. However, in forceful activities flexor muscle strength was retained due to iliopsoas reattachment. On the basis of this study we thought that spontaneous reattachment of the iliopsoas tendon substantially preserves muscle strength. Nonetheless possible efforts should be made to surgically reattach the psoas tendon to preserve strength of the muscle. LEVEL OF EVIDENCE: Therapeutic level IV. PMID- 26633819 TI - Pediatric Traumatic Amputations in the United States: A 5-Year Review. AB - BACKGROUND: Pediatric traumatic amputations are devastating injuries capable of causing permanent physical and psychological sequelae. Few epidemiologic reports exist for guidance of prevention strategies. The objective of this study is to review the recent trends in pediatric traumatic amputations using a national databank. METHODS: A review of all pediatric (age, 0 to 17 y) amputee patients was performed using the National Trauma Data Bank from 2007 to 2011. Data including demographics, location of amputation, and mechanism of injury were analyzed. RESULTS: In the analysis 2238 patients were identified. The majority of amputations occurred in the youngest (0 to 5 y) and oldest (15 to 17 y) age groups with a 3:1 male to female ratio. The most common amputation locations were finger (54%) and toe (20%). A caught between mechanism (16.3%) was most common overall followed by machinery, powered lawn mowers, motor vehicle collisions, firearms, and off-road vehicles. Males were statistically more likely to have an amputation and lawnmower injuries were statistically associated with lower extremity amputations in children 5 years old and below. Motor vehicle injuries were the most common cause of adolescent amputations. Firearm-related amputations occurred predominantly in adolescents, whereas off-road vehicle amputations occurred in all ages. CONCLUSIONS: Common trends in pediatric amputations are relatively unchanged over the last decade. Young children sustain more finger amputations from a caught between objects mechanism, whereas adolescents sustain serious amputations from higher energy mechanisms such as firearms-related and motor vehicle-related injuries. Lawnmower-related amputations continue to most significantly affect younger children despite increased public awareness. Improved prevention strategies targeting age and mechanism-related trends are necessary to prevent these costly and debilitating injuries. LEVEL OF EVIDENCE: Level IV. PMID- 26633820 TI - The Fate of the Neuromuscular Hip After Spinal Fusion. AB - BACKGROUND: The goals of treatment of neuromuscular scoliosis are to achieve a balanced spine and level pelvis with most constructs including pelvic fixation. However, the pelvis can become a stiff "end vertebra" that prevents compensatory mechanisms to adjust to hip deformities in this patient population. The purpose of this study is to determine the frequency of hip pathology and surgery after spinal fusion in this patient population. METHODS: We performed a retrospective chart and radiographic review of cerebral palsy patients who underwent posterior spinal fusion (PSF) at our institution from 2005 to 2011. We collected radiographic data of preoperative and postoperative pelvic obliquity and hip reduction status and position (up, level, down). We further evaluated patients requiring hip surgery (containment or salvage). RESULTS: Of 47 patients with an average follow-up of 3.5 years after spinal fusion, 21 (45%) underwent a hip procedure. Thirty-eight patients (81%) demonstrated or developed hip subluxation/dislocation. Hip pathology occurred more often in the up hip, but the pathologic down hip more often underwent a hip surgery. Eight new hip subluxation/dislocations occurred after spine surgery. Three (38%) of the new postoperative subluxation/dislocations required hip surgery; all had pelvic obliquity <6 degrees. Eleven patients underwent hip surgery before PSF, 7 were varus femoral osteotomies for subluxation, whereas 5 hips required salvage. In follow-up after PSF, none of these had a new dislocation. Ten patients required hip surgery after PSF at a mean of 1.6 years after PSF. Eight patients had a salvage procedure for painful hip and 2 varus femoral osteotomies for subluxations. CONCLUSIONS: In our cerebral palsy patients who underwent PSF, 45% of these patients required a hip procedure. In the patients who had containment before PSF, the hips maintained reduction after spinal fixation. After correction of pelvic obliquity, 17% of patients had new-onset hip subluxation/dislocation after PSF. Postoperative subluxation/dislocation was not dependent on whether the hip was up or down preoperatively. LEVEL OF EVIDENCE: IV, Retrospective. PMID- 26633821 TI - Incentives Increase Participation in Mass Dog Rabies Vaccination Clinics and Methods of Coverage Estimation Are Assessed to Be Accurate. AB - In this study we show that incentives (dog collars and owner wristbands) are effective at increasing owner participation in mass dog rabies vaccination clinics and we conclude that household questionnaire surveys and the mark-re sight (transect survey) method for estimating post-vaccination coverage are accurate when all dogs, including puppies, are included. Incentives were distributed during central-point rabies vaccination clinics in northern Tanzania to quantify their effect on owner participation. In villages where incentives were handed out participation increased, with an average of 34 more dogs being vaccinated. Through economies of scale, this represents a reduction in the cost per-dog of $0.47. This represents the price-threshold under which the cost of the incentive used must fall to be economically viable. Additionally, vaccination coverage levels were determined in ten villages through the gold-standard village wide census technique, as well as through two cheaper and quicker methods (randomized household questionnaire and the transect survey). Cost data were also collected. Both non-gold standard methods were found to be accurate when puppies were included in the calculations, although the transect survey and the household questionnaire survey over- and under-estimated the coverage respectively. Given that additional demographic data can be collected through the household questionnaire survey, and that its estimate of coverage is more conservative, we recommend this method. Despite the use of incentives the average vaccination coverage was below the 70% threshold for eliminating rabies. We discuss the reasons and suggest solutions to improve coverage. Given recent international targets to eliminate rabies, this study provides valuable and timely data to help improve mass dog vaccination programs in Africa and elsewhere. PMID- 26633822 TI - Corticosteroid Therapy for Management of Hemolysis, Elevated Liver Enzymes, and Low Platelet Count (HELLP) Syndrome: A Meta-Analysis. AB - BACKGROUND Hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome is a severe condition of pregnancy that is associated with significant morbidity and mortality. Corticoteroid (CORT) therapy is common in the management of HELLP syndrome. This study evaluates the efficacy of CORT therapy to patients with HELLP Syndrome. MATERIAL AND METHODS A literature search was carried out in multiple electronic databases. Meta-analyses of means difference and odds ratio were carried under the random-effects model. RESULTS Fifteen studies (675 CORT treated and 787 control HELLP patients) were included. CORT treatment significantly improved platelet count (mean difference between CORT treated and controls in changes from baseline, MD: 38.08 [15.71, 60.45]*109; p=0.0009), lactic dehydrogenase (LDH) levels (MD: -440 [-760, -120] IU/L; p=0.007), and alanine aminotransferase (ALT) levels (MD: -143.34 [-278.69, -7.99] IU/L; p=0.04) but the decrease in aspartate aminotransferase (AST) levels was not statistically significant (MD: -48.50 [-114.32, 17.32] IU/L; p=0.15). Corticosteroid treatment was also associated with significantly less blood transfusion rate (odds ratio, OR: 0.42 [0.24, 0.76]; p=0.004) and hospital/ICU stay (MD: -1.79 [-3.54, -0.05] days; p=0.04). Maternal mortality (OR: 1.27 [0.45, 3.60]; p=0.65), birth weight (MD: 0.09 [-0.11, 0.28]; p=0.38) and the prevalence of morbid conditions (OR: 0.79 [0.58, 1.08]; p=0.14) did not differ significantly between both groups. CONCLUSIONS Corticosteroid administration to HELLP patients improves platelet count, and the serum levels of LDH and ALT, and reduces hospital/ICU stay and blood transfusion rate, but is not significantly associated with better maternal mortality and overall morbidity. PMID- 26633823 TI - Prevention of Diet-Induced Obesity Effects on Body Weight and Gut Microbiota in Mice Treated Chronically with Delta9-Tetrahydrocannabinol. AB - OBJECTIVE: Acute administration of cannabinoid CB1 receptor agonists, or the ingestion of cannabis, induces short-term hyperphagia. However, the incidence of obesity is lower in frequent cannabis users compared to non-users. Gut microbiota affects host metabolism and altered microbial profiles are observed in obese states. Gut microbiota modifies adipogenesis through actions on the endocannabinoid system. This study investigated the effect of chronic THC administration on body weight and gut microbiota in diet-induced obese (DIO) and lean mice. METHODS: Adult male DIO and lean mice were treated daily with vehicle or THC (2mg/kg for 3 weeks and 4 mg/kg for 1 additional week). Body weight, fat mass, energy intake, locomotor activity, whole gut transit and gut microbiota were measured longitudinally. RESULTS: THC reduced weight gain, fat mass gain and energy intake in DIO but not lean mice. DIO-induced changes in select gut microbiota were prevented in mice chronically administered THC. THC had no effect on locomotor activity or whole gut transit in either lean or DIO mice. CONCLUSIONS: Chronic THC treatment reduced energy intake and prevented high fat diet-induced increases in body weight and adiposity; effects that were unlikely to be a result of sedation or altered gastrointestinal transit. Changes in gut microbiota potentially contribute to chronic THC-induced actions on body weight in obesity. PMID- 26633824 TI - A Population-Based Acute Meningitis and Encephalitis Syndromes Surveillance in Guangxi, China, May 2007-June 2012. AB - OBJECTIVES: Acute meningitis and encephalitis (AME) are common diseases with the main pathogens being viruses and bacteria. As specific treatments are different, it is important to develop clinical prediction rules to distinguish aseptic from bacterial or fungal infection. In this study we evaluated the incidence rates, seasonal variety and the main etiologic agents of AME, and identified factors that could be used to predict the etiologic agents. METHODS: A population-based AME syndrome surveillance system was set up in Guigang City, Guangxi, involving 12 hospitals serving the study communities. All patients meeting the case definition were investigated. Blood and/or cerebrospinal fluid were tested for bacterial pathogens using culture or RT-PCR and serological tests for viruses using enzyme-linked immunosorbent assays. Laboratory testing variables were grouped using factor analysis. Multinomial logistic regression was used to predict the etiology of AME. RESULTS: From May 2007 to June 2012, the annual incidence rate of AME syndrome, and disease specifically caused by Japanese encephalitis (JE), other viruses, bacteria and fungi were 12.55, 0.58, 4.57, 0.45 and 0.14 per 100,000 population, respectively. The top three identified viral etiologic agents were enterovirus, mumps virus, and JE virus, and for bacteria/fungi were Streptococcus sp., Cryptococcus neoformans and Staphylococcus sp. The incidence of JE and other viruses affected younger populations and peaked from April to August. Alteration of consciousness and leukocytosis were more likely to be caused by JE, bacteria and fungi whereas CSF inflammation was associated with bacterial/fungal infection. CONCLUSIONS: With limited predictive validity of symptoms and signs and routine laboratory tests, specific tests for JE virus, mumps virus and enteroviruses are required to evaluate the immunization impact and plan for further intervention. CSF bacterial culture cannot be omitted in guiding clinical decisions regarding patient treatment. PMID- 26633825 TI - Sodium Fluoride Affects DNA Methylation of Imprinted Genes in Mouse Early Embryos. AB - Fluorine is reported to affect embryonic development, but the underlining mechanism is unclear. The modification of DNA methylation of the H19 and Peg3 genes is important in embryonic development. Therefore, the effect of fluorine on methylation of H19 and Peg3 during early mouse embryos was studied. It was shown that the H19 gene was significantly downmethylated in E2.5, E3.5, and E4.5 embryos from pregnant mice treated with 120 mg/l NaF in drinking water for 48 h. But methylation of both H19 and Peg3 genes was disrupted when the parent male mice were treated with NaF for 35 days. H19 DNA methylation decreased significantly, while Peg3 was almost completely methylated. However, when pregnant mice, mated with NaF-treated male mice, were again treated with NaF for 48 h, either H19 or Peg3 methylation in the embryos decreased significantly. In addition, the mRNA level of H19 considerably increased in E3.5 and E4.5 embryos from NaF-treated pregnant mice. Further, the expression of DNMT1 decreased significantly after NaF treatment. Conclusively, we demonstrated that fluorine may adversely affect early embryonic development by disrupting the methylation of H19 and Peg3 through downregulation of DNMT1. PMID- 26633826 TI - Correction: Distinct Yellowfin Tuna (Thunnus albacares) Stocks Detected in Western and Central Pacific Ocean (WCPO) Using DNA Microsatellites. PMID- 26633827 TI - Variation in Residential Care Community Resident Characteristics, by Size of Community: United States, 2014. AB - KEY FINDINGS: Residents of residential care communities are persons who cannot live independently but generally do not require the skilled care provided by nursing homes. There were 835,200 current residents in residential care communities in 2014 (1,2). "Current residents" refers to those who were living in the community on the day of data collection (as opposed to the total number of residents who lived in the community at some time during the calendar year). This report presents national estimates of selected characteristics of current residents in 2014 and compares these characteristics by community bed size. State level estimates for these characteristics are available online at: http:// www.cdc.gov/nchs/nsltcp/nsltcp_products.htm. PMID- 26633828 TI - Moving toward a gene therapy for Huntington's disease. PMID- 26633829 TI - Estimation of D-Arabinose by Gas Chromatography/Mass Spectrometry as Surrogate for Mycobacterial Lipoarabinomannan in Human Urine. AB - Globally, tuberculosis is slowly declining each year and it is estimated that 37 million lives were saved between 2000 and 2013 through effective diagnosis and treatment. Currently, diagnosis relies on demonstration of the bacteria, Mycobacterium tuberculosis (Mtb), in clinical specimens by serial sputum microscopy, culture and molecular testing. Commercial immunoassay lateral flow kits developed to detect Mtb lipoglycan lipoarabinomannan (LAM) in urine as a marker of active TB exhibit poor sensitivity, especially in immunocompetent individuals, perhaps due to low abundance of the analyte. Our present study was designed to develop methods to validate the presence of LAM in a quantitative fashion in human urine samples obtained from culture-confirmed TB patients. Herein we describe, a consolidated approach for isolating LAM from the urine and quantifying D-arabinose as a proxy for LAM, using Gas Chromatography/Mass Spectrometry. 298 urine samples obtained from a repository were rigorously analyzed and shown to contain varying amounts of LAM-equivalent ranging between ~10-40 ng/mL. To further substantiate that D-arabinose detected in the samples originated from LAM, tuberculostearic acid, the unique 10-methyloctadecanoic acid present at the phosphatidylinositol end of LAM was also analyzed in a set of samples and found to be present confirming that the D-arabinose was indeed derived from LAM. Among the 144 samples from culture-negative TB suspects, 30 showed presence of D-arabinose suggesting another source of the analyte, such as disseminated TB or from non-tuberculosis mycobacterium. Our work validates that LAM is present in the urine samples of culture-positive patients in small but readily detectable amounts. The study further substantiates LAM in urine as a powerful biomarker for active tuberculosis. PMID- 26633830 TI - No Evidence That Gratitude Enhances Neural Performance Monitoring or Conflict Driven Control. AB - It has recently been suggested that gratitude can benefit self-regulation by reducing impulsivity during economic decision making. We tested if comparable benefits of gratitude are observed for neural performance monitoring and conflict driven self-control. In a pre-post design, 61 participants were randomly assigned to either a gratitude or happiness condition, and then performed a pre-induction flanker task. Subsequently, participants recalled an autobiographical event where they had felt grateful or happy, followed by a post-induction flanker task. Despite closely following existing protocols, participants in the gratitude condition did not report elevated gratefulness compared to the happy group. In regard to self-control, we found no association between gratitude- operationalized by experimental condition or as a continuous predictor--and any control metric, including flanker interference, post-error adjustments, or neural monitoring (the error-related negativity, ERN). Thus, while gratitude might increase economic patience, such benefits may not generalize to conflict-driven control processes. PMID- 26633831 TI - World Health Organization Estimates of the Global and Regional Disease Burden of 22 Foodborne Bacterial, Protozoal, and Viral Diseases, 2010: A Data Synthesis. AB - BACKGROUND: Foodborne diseases are important worldwide, resulting in considerable morbidity and mortality. To our knowledge, we present the first global and regional estimates of the disease burden of the most important foodborne bacterial, protozoal, and viral diseases. METHODS AND FINDINGS: We synthesized data on the number of foodborne illnesses, sequelae, deaths, and Disability Adjusted Life Years (DALYs), for all diseases with sufficient data to support global and regional estimates, by age and region. The data sources included varied by pathogen and included systematic reviews, cohort studies, surveillance studies and other burden of disease assessments. We sought relevant data circa 2010, and included sources from 1990-2012. The number of studies per pathogen ranged from as few as 5 studies for bacterial intoxications through to 494 studies for diarrheal pathogens. To estimate mortality for Mycobacterium bovis infections and morbidity and mortality for invasive non-typhoidal Salmonella enterica infections, we excluded cases attributed to HIV infection. We excluded stillbirths in our estimates. We estimate that the 22 diseases included in our study resulted in two billion (95% uncertainty interval [UI] 1.5-2.9 billion) cases, over one million (95% UI 0.89-1.4 million) deaths, and 78.7 million (95% UI 65.0-97.7 million) DALYs in 2010. To estimate the burden due to contaminated food, we then applied proportions of infections that were estimated to be foodborne from a global expert elicitation. Waterborne transmission of disease was not included. We estimate that 29% (95% UI 23-36%) of cases caused by diseases in our study, or 582 million (95% UI 401-922 million), were transmitted by contaminated food, resulting in 25.2 million (95% UI 17.5-37.0 million) DALYs. Norovirus was the leading cause of foodborne illness causing 125 million (95% UI 70-251 million) cases, while Campylobacter spp. caused 96 million (95% UI 52-177 million) foodborne illnesses. Of all foodborne diseases, diarrheal and invasive infections due to non-typhoidal S. enterica infections resulted in the highest burden, causing 4.07 million (95% UI 2.49-6.27 million) DALYs. Regionally, DALYs per 100,000 population were highest in the African region followed by the South East Asian region. Considerable burden of foodborne disease is borne by children less than five years of age. Major limitations of our study include data gaps, particularly in middle- and high-mortality countries, and uncertainty around the proportion of diseases that were foodborne. CONCLUSIONS: Foodborne diseases result in a large disease burden, particularly in children. Although it is known that diarrheal diseases are a major burden in children, we have demonstrated for the first time the importance of contaminated food as a cause. There is a need to focus food safety interventions on preventing foodborne diseases, particularly in low- and middle-income settings. PMID- 26633833 TI - Diminished Smell in a Teenaged Girl. Isolated anosmia. PMID- 26633832 TI - Inter-kingdom Signaling by the Legionella Quorum Sensing Molecule LAI-1 Modulates Cell Migration through an IQGAP1-Cdc42-ARHGEF9-Dependent Pathway. AB - Small molecule signaling promotes the communication between bacteria as well as between bacteria and eukaryotes. The opportunistic pathogenic bacterium Legionella pneumophila employs LAI-1 (3-hydroxypentadecane-4-one) for bacterial cell-cell communication. LAI-1 is produced and detected by the Lqs (Legionella quorum sensing) system, which regulates a variety of processes including natural competence for DNA uptake and pathogen-host cell interactions. In this study, we analyze the role of LAI-1 in inter-kingdom signaling. L. pneumophila lacking the autoinducer synthase LqsA no longer impeded the migration of infected cells, and the defect was complemented by plasmid-borne lqsA. Synthetic LAI-1 dose dependently inhibited cell migration, without affecting bacterial uptake or cytotoxicity. The forward migration index but not the velocity of LAI-1-treated cells was reduced, and the cell cytoskeleton appeared destabilized. LAI-1 dependent inhibition of cell migration involved the scaffold protein IQGAP1, the small GTPase Cdc42 as well as the Cdc42-specific guanine nucleotide exchange factor ARHGEF9, but not other modulators of Cdc42, or RhoA, Rac1 or Ran GTPase. Upon treatment with LAI-1, Cdc42 was inactivated and IQGAP1 redistributed to the cell cortex regardless of whether Cdc42 was present or not. Furthermore, LAI-1 reversed the inhibition of cell migration by L. pneumophila, suggesting that the compound and the bacteria antagonistically target host signaling pathway(s). Collectively, the results indicate that the L. pneumophila quorum sensing compound LAI-1 modulates migration of eukaryotic cells through a signaling pathway involving IQGAP1, Cdc42 and ARHGEF9. PMID- 26633834 TI - Calcium Electroporation: Evidence for Differential Effects in Normal and Malignant Cell Lines, Evaluated in a 3D Spheroid Model. AB - BACKGROUND: Calcium electroporation describes the use of high voltage electric pulses to introduce supraphysiological calcium concentrations into cells. This promising method is currently in clinical trial as an anti-cancer treatment. One very important issue is the relation between tumor cell kill efficacy-and normal cell sensitivity. METHODS: Using a 3D spheroid cell culture model we have tested the effect of calcium electroporation and electrochemotherapy using bleomycin on three different human cancer cell lines: a colorectal adenocarcinoma (HT29), a bladder transitional cell carcinoma (SW780), and a breast adenocarcinoma (MDA MB231), as well as on primary normal human dermal fibroblasts (HDF-n). RESULTS: The results showed a clear reduction in spheroid size in all three cancer cell spheroids three days after treatment with respectively calcium electroporation (p<0.0001) or electrochemotherapy using bleomycin (p<0.0001). Strikingly, the size of normal fibroblast spheroids was neither affected after calcium electroporation nor electrochemotherapy using bleomycin, indicating that calcium electroporation, like electrochemotherapy, will have limited adverse effects on the surrounding normal tissue when treating with calcium electroporation. The intracellular ATP level, which has previously been shown to be depleted after calcium electroporation, was measured in the spheroids after treatment. The results showed a dramatic decrease in the intracellular ATP level (p<0.01) in all four spheroid types-malignant as well as normal. CONCLUSION: In conclusion, calcium electroporation seems to be more effective in inducing cell death in cancer cell spheroids than in a normal fibroblast spheroid, even though intracellular ATP level is depleted in all spheroid types after treatment. These results may indicate an important therapeutic window for this therapy; although further studies are needed in vivo and in patients to investigate the effect of calcium electroporation on surrounding normal tissue when treating tumors. PMID- 26633835 TI - Nine- to Twelve-Month Anti-Tuberculosis Treatment Is Associated with a Lower Recurrence Rate than 6-9-Month Treatment in Human Immunodeficiency Virus-Infected Patients: A Retrospective Population-Based Cohort Study in Taiwan. AB - BACKGROUND: Human immunodeficiency virus (HIV)-infected patients are at an increased risk of tuberculosis (TB) and its recurrence following completion of anti-TB treatment. We investigated whether extending anti-TB treatment to 9 months or longer reduces TB recurrence. METHODS: HIV-infected patients who were diagnosed with pulmonary TB between 1997 and 2009 and who received anti-TB treatment for a duration between 5.5 and 12.5 months were identified from the National Health Insurance Research Database in Taiwan. Those who received any non fluoroquinolone second-line anti-TB drug for >28 days were excluded. Factors associated with TB recurrence within 2 years after completion of anti-TB treatment were explored using Cox regression analysis. Sensitivity analysis was performed for a subpopulation fulfilling strict diagnostic criteria for HIV infection. RESULTS: TB recurrence was observed in 18 (3.5%) of 508 HIV-infected patients. The recurrence rate declined from 5.4% to 1.0% after the implementation of directly observed therapy, short course (DOTS) in 2006 (p = 0.014). The recurrence rate was 5.9%, 5.2%, and 1.6% in patients who received anti-TB treatment for <195, 195-270, and >270 days, respectively (p = 0.066). Cox regression analysis revealed that TB diagnosed in the DOTS era (hazard ratio [HR]: 0.18 [0.04-0.77]) and anti-TB treatment for >270 days (HR: 0.24 [0.06 0.89]) were associated with a reduced risk of TB recurrence. Sensitivity analysis of 449 selected patients revealed that anti-TB treatment for >270 days was a significant factor. CONCLUSION: In Taiwan, the 2-year TB recurrence rate in HIV infected patients declined after implementation of DOTS. The risk of TB recurrence in HIV-infected patients can be further reduced by extending anti-TB treatment to 9-12.5 months. PMID- 26633838 TI - [Focussing on the Individual--Opportunities for a Personalised Psychiatry and Psychotherapy]. PMID- 26633836 TI - Effects of dabigatran on the cellular and protein phase of coagulation in patients with coronary artery disease on dual antiplatelet therapy with aspirin and clopidogrel. Results from a prospective, randomised, double-blind, placebo controlled study. AB - There is growing interest in understanding the effects of adding an oral anticoagulant in patients on dual antiplatelet therapy (DAPT). Vitamin K antagonists (VKAs) and clopidogrel represent the most broadly utilised oral anticoagulant and P2Y12 receptor inhibitor, respectively. However, VKAs can interfere with clopidogrel metabolism via the cytochrome P450 (CYP) system which in turn may result in an increase in platelet reactivity. Dabigatran is a direct acting (anti-II) oral anticoagulant which does not interfere with CYP and has favourable safety and efficacy profiles compared with VKAs. The pharmacodynamic (PD) effects on platelet reactivity and clot kinetic of adjunctive dabigatran therapy in patients on DAPT are poorly explored. In this prospective, randomised, double-blind, placebo-controlled PD study, patients (n=30) on maintenance DAPT with aspirin and clopidogrel were randomised to either dabigatran 150 mg bid or placebo for seven days. PD testing was performed before and after treatment using four different assays exploring multiple pathways of platelet aggregation and fibrin clot kinetics: light transmittance aggregometry (LTA), multiple electrode aggregometry (MEA), kaolin-activated thromboelastography (TEG) and turbidimetric assays. There were no differences in multiple measures of platelet reactivity investigating purinergic and non-purinergic signaling pathways assessed by LTA, MEA and TEG platelet mapping. Dabigatran significantly increased parameters related to thrombin activity and thrombus generation, and delayed fibrin clot formation, without affecting clot structure or fibrinolysis. In conclusion, in patients on DAPT with aspirin and clopidogrel, adjunctive dabigatran therapy is not associated with modulation of profiles of platelet reactivity as determined by several assays assessing multiple platelet signalling pathways. However, dabigatran significantly interferes with parameters related to thrombin activity and delays fibrin clot formation. PMID- 26633839 TI - [Mixed Episodes in Bipolar Disorders--Changes in DSM-5 and Treatment Recommendations]. AB - Mixed episodes in the course of affective disorders are challenging for any psychiatrist, because they are often characterized by a complicated and difficult treatment course (e. g. higher suicide rates) and a worse treatment outcome. In DSM-5, one of the main changes is that the diagnosis of a mixed episode was disestablished and replaced with affective episodes with so called "mixed features". This alteration markedly reduces the diagnostic threshold. The available literature on pharmacological treatment of mixed episodes is not sufficient; however, treatment with atypical antipsychotics, especially olanzapine and aripiprazole and the mood stabilizers valproate and carmabazepine has proved to be beneficial. PMID- 26633840 TI - [Psychiatric Day Clinics--Evidence for and Importance of Patient-Centered Care]. AB - OBJECTIVE: The aim of the study was to summarize and evaluate the recent literature on treatment in psychiatric day clinics, and to assess the importance of such clinics in the current healthcare system. METHOD: We conducted a systematic review of recent studies in order to compare the efficacy and cost effectiveness of day clinics in relation to in- and outpatient treatment. RESULTS: The evidence is still sparse and inconclusive. CONCLUSION: Psychiatric day clinics act as a link between inpatient and outpatient treatment in community mental healthcare. However, evidence in support of the efficacy and cost effectiveness of day clinics is still sparse. PMID- 26633841 TI - [Forensic Implications of Sleep-Associated Behavior Disorders]. AB - Parasomnias represent a category of disorders that involve complex behaviors or emotional experiences, arising from or occurring during sleep, which might be also associated with (incomplete) awakening. These phenomena are classified as REM- or Non-REM-parasomnias. In particular the latter, including confusional arousal, sleepwalking and sleep terrors but also REM-sleep behavior disorder might result in criminal consequences. Using polysomnography, the pathophysiological mechanisms of these disorders have been investigated thoroughly. Nevertheless, in German literature, forensic implications of complex behaviors arising from sleep disorders have only been described insufficiently. Here we describe the most relevant parasomnias and also how to proceed in the context of forensic assessments. PMID- 26633842 TI - [Cognitive Function in Patients Before and After Micro-neurosurgical Resection of Frontal Brain Tumors]. AB - Patients with lesions of the prefrontal cortex as a result of frontal brain tumors (intra- and extra-axial) can show impairments of executive functions 1 2 3 4. Although there are a large number of psychological tests, the detection of impairments of relevant everyday executive functions in these patients is still extremely difficult. In 30 patients with lesions of the prefrontal cortex, the executive functions were tested with the Behavioral Assessment of Dysexecutive Syndrome (BADS) and 21 patients were also followed up postoperatively. Additionally, if possible, the Wisconsin Card Sorting Test (WCST), a widely used executive function test, and the Wechsler Adult Intelligence Scale (WAIS) for general cognitive performance were conducted. Pre- and postoperatively, a total of 16 patients were followed up with all three tests. The aim was to investigate the neuropsychological assessment pre- and postoperatively, to evaluate it in terms of deficits and changes in performance and to ensure that no new relevant everyday cognitive deficits arose. Preoperatively, only one patient, who could not be tested post-surgery, showed a reduced overall profile value in the BADS. In all tested patients, there was no evidence of deterioration of cognitive status 8 - 12 weeks postoperatively. Further investigations using fMRI should be used to clarify whether the results obtained should be interpreted as neuroplastic adaptations of prefrontal cognitive functions or as a failure to detect deficits due to a lack of sensitivity of the tests used. PMID- 26633843 TI - [Remember, Avert, Prevent: Franz Ludwig Berthold Kihn--A Typology of "Euthanasia"]. AB - BACKGROUND: The current debate on assisted suicide provides the occasion for calling to mind the role of Berthold Kihn as a psychiatrist under National Socialism. With a historical presentation of a typology of euthanasia, the Academic Psychiatry of Erlangen together with the Medical Ethics would like to sensitize discussions on assisted suicide by drawing attention to the start and end of Kihn's scientific career. METHOD: Relevant archive material, primary and secondary literature were analyzed and evaluated. RESULTS: As Assistant and Senior Physician at the Psychiatric and Neurological Hospital of the University of Erlangen, Kihn lectured on "the elimination of the inferiors". As Director of the Psychiatric and Neurological Hospital of Jena University, Kihn selected psychiatric patients to be murdered under the "T4 action". Kihn participated in drafting a "Euthanasia Law". Despite his involvement in the murder of mentally ill, Kihn returned to Erlangen as a "Soviet Zone refugee", where a Denazification Court considered him a "hanger-on". Kihn was reintegrated in the academic faculty of the Friedrich-Alexander-University and headed a private clinic. On 21.01.1963, the State's Attorney Nuremberg-Fuerth dropped the criminal procedure against Kihn -officially due to a lack of proof of punishable guilt. DISCUSSION: An appropriate medical historical contextualization can represent an important condition for an adequate medical ethical debate on physician-assisted suicide and the involvement of psychiatrists. FINAL COMMENT: The analysis of Kihn's patterns of thought and argumentation can help sensitize those involved in debates on physician-assisted suicide and highlights the critical role of psychiatry as a discipline in this context. PMID- 26633844 TI - [State-of-the-art Treatment of Acute Stroke]. AB - This article gives an overview about diagnostic imaging and treatment options of acute patients with ischemic and hemorrhagic stroke with emphasis on evidence from relevant studies published in the last 2 years. A computed tomography of the brain with CT-angiography should be the minimal standard imaging modality in acute ischemic stroke patients. Diffusion-weighted/imaging-fluid-attenuated inversion recovery (FLAIR)-mismatch magnetic resonance imaging can be useful in patients with wake-up stroke to select patients for recanalisation therapies. Systemic thrombolysis with rt-PA within 4.5 hours after symptom onset and mechanical thrombectomy with stent retrievers within 6 hours and proven occlusion of a large vessel in the anterior brain circulation are both evidence-based treatments. In contrast, there are no major therapeutic advances in patients with hemorrhagic stroke. The systolic blood pressure should be lowered < 140 mm Hg in these patients within one hour. Both acute ischemic and hemorrhagic stroke and patients with a transient ischemic attack should be monitored and treated on a stroke unit due to an improved outcome. A prophylactic antibiotic treatment and very early mobilization during the first 24 hours is not recommended in acute stroke patients. PMID- 26633845 TI - Recurrent Vitreous Hemorrhage Despite Pars Plana Vitrectomy, Laser, and Injections. PMID- 26633846 TI - Stereodynamics in the Collisional Autoionization of Water, Ammonia, and Hydrogen Sulfide with Metastable Rare Gas Atoms: Competition Between Intermolecular Halogen and Hydrogen Bonds. AB - Recent experiments on the title subject, performed with a high-resolution crossed beam apparatus, have provided the total ionization cross sections as a function of the collision energy between noble gas atoms, electronically excited in their metastable states (Ng*), and H2 O, H2 S, and NH3 reagents, as well as the emitted electron energy spectra. This paper presents a rationalization of all the experimental findings in a unifying picture to cast light on the basic chemical properties of Ng* under conditions of great relevance both from a fundamental and from an applied point of view. The importance of this investigation is that it isolates the selective role of the intermolecular halogen and hydrogen bonds, to assess their anisotropic effects on the stereodynamics of the promoted ionization reactions, and to model energy transfer and reactivity in systems of applied interest, such as planetary atmospheres, plasmas, lasers, and flames. PMID- 26633849 TI - Avoiding Carbothermal Reduction: Distillation of Alkoxysilanes from Biogenic, Green, and Sustainable Sources. AB - The direct depolymerization of SiO2 to distillable alkoxysilanes has been explored repeatedly without success for 85 years as an alternative to carbothermal reduction (1900 degrees C) to Si(met) , followed by treatment with ROH. We report herein the base-catalyzed depolymerization of SiO2 with diols to form distillable spirocyclic alkoxysilanes and Si(OEt)4. Thus, 2-methyl-2,4 pentanediol, 2,2,4-trimethyl-1,3-pentanediol, or ethylene glycol (EGH2) react with silica sources, such as rice hull ash, in the presence of NaOH (10%) to form H2O and distillable spirocyclic alkoxysilanes [bis(2-methyl-2,4-pentanediolato) silicate, bis(2,2,4-trimethyl-1,3-pentanediolato) silicate or Si(eg)2 polymer with 5-98% conversion, as governed by surface area/crystallinity. Si(eg)2 or bis(2-methyl-2,4-pentanediolato) silicate reacted with EtOH and catalytic acid to give Si(OEt)4 in 60% yield, thus providing inexpensive routes to high-purity precipitated or fumed silica and compounds with single Si-C bonds. PMID- 26633851 TI - Preparative isolation of a cytotoxic principle of a forest mushroom Suillus luteus by sodium dodecyl sulfate based "salting-in" countercurrent chromatography. AB - In the course of screening new anticancer natural products, an edible forest mushroom Suillus luteus (L. Ex Franch). Gray was found to have potent cytotoxicity against several human cancer cells. However, the lipophilic sample made some countercurrent chromatography solvent systems emulsify, which caused difficulties in the separation of its cytotoxic components. Here, we found that the addition of an organic salt sodium dodecyl sulfate could efficiently shorten the settling time of the mushroom sample solutions by eliminating the emulsification of two-phase solvent systems. Moreover, we found that sodium dodecyl sulfate could play a new "salting-in" role and made the partition coefficients of the solutes decrease with the increased concentrations. Thus, a sodium dodecyl sulfate based salting-in countercurrent chromatography method has been successfully established for the first time for preparative isolation of a cytotoxic principle of the mushroom. The active component was identified as isosuillin. Whole results indicated that sodium dodecyl sulfate could be used as an efficient salting-in reagent for two-phase solvent system selection and targeted countercurrent chromatography isolation. It is very useful for current natural products isolation and drug discovery. PMID- 26633852 TI - Intermittent sacral neuromodulation for idiopathic urgency urinary incontinence in women. AB - AIMS: SNM has been proven to be effective in the treatment of refractory UUI. Total costs and patient burden due to regular battery changes may prevent broad implementation of this treatment. The aim was to achieve a minimal improvement of 50% in incontinence episodes compared to pre-SNM by using iSNM. METHODS: This prospective cohort study was performed in women with UUI receiving treatment with SNM for a minimum of 6 months. The neurostimulator was programmed to 8 hr "on" and 16 hr "off" per day for 12 weeks. Prior to iSNM, data were collected during no SNM and cSNM. Bladder diaries and various patient reported outcome measures were collected at predetermined time points: 1-5 weeks, and 8, 12, and 16 weeks. Nonparametric tests were used for the statistical analysis. RESULTS: Of the 19 patients 63% showed an improvement of >50% of incontinence episodes during iSNM compared to pre-SNM. Bladder diary parameters showed a difference between pre-SNM and iSNM median (P-value); incontinence episodes/24 hr, 4.1-1.0 (P = 0.04), incontinence severity, 2.0-1.0 (P = 0.001), voiding episodes/24 hr, 13.0-8.0 (P = 0.001), and voided volume, 149-219 ml (P = 0.04). The UDI-6, 50.0-27.8 (P = 0.03), and the IIQ-7 scores, 50.0-9.5 (P = 0.04) also showed a significant improvement. No difference was demonstrated between iSNM and cSNM. CONCLUSIONS: Compared to pre-SNM parameters, iSNM shows an improvement in both objective and subjective outcomes. Specifically no difference was found between iSNM and cSNM, indicating that iSNM could be a feasible and cost-effective alternative. Neurourol. Urodynam. 36:385-389, 2017. (c) 2015 Wiley Periodicals, Inc. PMID- 26633853 TI - Controllable Synthesis of Ultrathin Transition-Metal Hydroxide Nanosheets and their Extended Composite Nanostructures for Enhanced Catalytic Activity in the Heck Reaction. AB - We report an effective and universal approach for the preparation of ultrathin single- or multiple-component transition-metal hydroxide (TMH) nanosheets with thickness below 5 nm. The unique synthesis benefits from the gradual decomposition of the preformed metal-boron (M-B, M=Fe, Co, Ni, NiCo) composite nanospheres which facilitates the formation of ultrathin nanosheets by the oxidation of the metal and the simultaneous release of boron species. The high specific surface area of the sheets associated with their ultrathin nature promises a wide range of applications. For example, we demonstrate the remarkable adsorption ability of Pb(II) and As(V) in waste water by the ultrathin FeOOH nanosheets. More interestingly, the process can be extended simply to the synthesis of composite structures of metal alloy hollow shells encapsulated by TMH nanosheets, which show excellent catalytic activity in the Heck reaction. PMID- 26633854 TI - Elevated red cell distribution width contributes to a poor prognosis in patients with esophageal carcinoma. AB - BACKGROUND: The red cell distribution width (RDW) has also been reported to reliably reflect the inflammation and nutrition status and predict the prognosis across several types of cancer, however, the prognostic value of RDW in esophageal carcinoma has seldom been studied. METHODS: A retrospective study was performed to assess the prognostic value of RDW in patients with esophageal carcinoma by the Kaplan-Meier analysis and multivariate Cox regression proportional hazard model. All enrolled patients were divided into high RDW group (?15%) and low RDW group (<15%) according to the detected RDW values. RESULTS: Clinical and laboratory data from a total of 179 patients with esophageal carcinoma were retrieved. With a median follow-up of 21months, the high RDW group exhibited a shorter disease-free survival (DFS) (p<0.001) and an unfavorable overall survival (OS) (p<0.001) in the univariate analysis. The multivariate analysis revealed that elevated RDW at diagnosis was an independent prognostic factor for shorter PFS (p=0.043, HR=1.907, 95% CI=1.020-3.565) and poor OS (p=0.042, HR=1.895, 95% CI=1.023-3.508) after adjustment with other cancer related prognostic factors. CONCLUSION: The present study suggests that elevated preoperative RDW(?15%) at the diagnosis may independently predict poorer disease free and overall survival among patients with esophageal carcinoma. PMID- 26633855 TI - Hs-CRP in stroke: A meta-analysis. AB - BACKGROUND: Studies on high-sensitivity C-reactive protein (hs-CRP) and stroke risk have yielded conflicting results. OBJECTIVE: To determine whether elevated baseline hs-CRP presents an independent risk for different kinds of strokes by conducting a meta-analysis. METHODS: The PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure and Wanfang databases were systematically searched for prospective observational studies published until January 2015. Studies reporting hs-CRP levels and adjusted risk estimates of different stroke subtypes by hs-CRP were selected. Pooled results were expressed as adjusted risk ratios (RRs), with corresponding 95% confidence intervals (CI) for the highest versus the lowest hs-CRP category. RESULTS: Twelve studies involving 2269 strokes, of which 2436 were ischemic and 655 were hemorrhagic, were identified from 66,560 participants. When comparing the highest with the lowest hs-CRP category, the pooled RR of ischemic strokes was 1.46 (95% CI 1.27-1.67) in a fixed-effect model. The pooled RRs of all strokes and hemorrhagic stroke were 1.23 (95% CI: 0.997-1.51) and 0.82 (95% CI 0.59-1.13), respectively. The risk of ischemic strokes seemed higher in men (RR 1.66; 95% CI 1.23-2.24). CONCLUSIONS: Elevated baseline hs-CRP levels are independently associated with excessive ischemic stroke risk but exhibit no clear effect on hemorrhagic stroke. PMID- 26633856 TI - Salivary markers of kidney function - Potentials and limitations. AB - Saliva can be collected non-invasively, repeatedly and without trained personnel. It is a promising diagnostic body fluid with clinical use in endocrinology and dentistry. For decades, it is known that saliva contains also urea, creatinine and other markers of renal function. Clinical studies have shown that the salivary concentrations of these markers could be useful for the assessment of kidney function without the need of blood collection. This article summarizes the clinical and experimental data on the use of saliva as a diagnostic fluid in nephrology and points out the advantages, pitfalls, technical requirements and future perspective for the use of saliva as a novel potential diagnostic biofluid. PMID- 26633857 TI - Intracortical Microstimulation Parameters Dictate the Amplitude and Latency of Evoked Responses. AB - BACKGROUND: Microstimulation of brain tissue plays a key role in a variety of sensory prosthetics, clinical therapies and research applications. However, the effects of stimulation parameters on the responses they evoke remain widely unknown. OBJECTIVE: We aimed to investigate the contribution of each stimulation parameter to the response and identify interactions existing between parameters. METHODS: Parameters of the constant-current, biphasic square waveform were examined in acute terminal experiments under ketamine anaesthesia. The motor cortex of 7 Sprague-Dawley rats was stimulated while recording motor evoked potentials (MEP) from the forelimb. Intracortical microstimulation (ICMS) parameters were systematically tested in a pair-wise fashion to observe the influence of each parameter on the amplitude and latency of the MEP. RESULTS: The amplitude of the MEP increased continually with stimulus amplitude (p < 0.001) and pulse duration (p = 0.001) throughout the range tested. Increases were also observed when stimuli were raised from low to moderate values of frequency (p = 0.022) and train duration (p = 0.045), after which no further excitation occurs. The latency of MEP initiation decreased when stimulus amplitude (p = 0.037) and frequency (p = 0.001) were raised from low to moderate values, after which the responses plateaued. MEP latencies were further reduced by increasing the pulse duration (p = 0.011), but train duration had no effect. CONCLUSIONS: Our data indicate that MEP amplitude and onset latency can be modulated by alterations to a number of stimulus parameters, even in restrictive paradigms, and suggest that the parameters of the standard ICMS signal used for evoking movements from the motor cortex can be further optimized. PMID- 26633858 TI - Control of sturgeon sperm motility: Antagonism between K+ ions concentration and osmolality. AB - Spermatozoa are stored in a quiescent state in the male reproductive tract and motility is induced in response to various environmental stimuli, such as change of osmolality (general case) and a decrease of extracellular K+ in fish from Acipenseridae family. This study was aimed to investigate the relationship between osmolality and extracellular K+ concentration in controlling sperm motility in sturgeon. Pre-incubation of sturgeon sperm for 5s in hypertonic solutions of glycerol, NaCl, or sucrose (each of 335 mOsm/kg osmolality) prepares sturgeon spermatozoa to become fully motile in presence of high concentration of K+ ions (15 mM), which has previously been demonstrated to fully repress motility. Furthermore, presence of 0.5mM KCl during the high osmolality pre incubation exposure completely prevented subsequent spermatozoa activation in a K+-rich media. Manipulating the transport of K+ ions by the presence of K+ ionophore (valinomycin), it was concluded that once an efflux of K+ ions, the precursor of sturgeon sperm motility activation, is taking place, spermatozoa then become insensitive to a large extracellular K+ concentration. PMID- 26633859 TI - Insomnia in Adults With Chronic Hepatitis B, Liver Failure, and Cirrhosis: A Case Control Study. AB - PURPOSE: To determine the frequency and socio-demographic/clinical correlates of insomnia in patients with chronic hepatitis B, hepatitis B virus (HBV)-related liver failure, and cirrhosis. DESIGN AND METHODS: Up to 120 patients with HBV related diseases and 40 matched healthy controls were recruited. Depressive and anxiety symptoms, early, middle, and late insomnia were measured. FINDINGS: The frequency of >=1 type of insomnia was 64.2% in patients and 35.0% in controls; frequencies of early, middle, and late insomnia in patients were 39.2%, 42.5%, and 48.3%, respectively, compared to 22.5%, 10.0%, and 25.0% in controls. Urban residency was independently associated with less insomnia of any type, accounting for 22.6% of the variance. PRACTICE IMPLICATIONS: A considerable proportion of patients with HBV-related diseases suffer from insomnia that warrants more attention in clinical practice. PMID- 26633860 TI - Structural Analysis of FRIGIDA Flowering-Time Regulator. PMID- 26633861 TI - Structural Aspects of Multistep Phosphorelay-Mediated Signaling in Plants. AB - The multistep phosphorelay (MSP) is a central signaling pathway in plants integrating a wide spectrum of hormonal and environmental inputs and controlling numerous developmental adaptations. For the thorough comprehension of the molecular mechanisms underlying the MSP-mediated signal recognition and transduction, the detailed structural characterization of individual members of the pathway is critical. In this review we describe and discuss the recently known crystal and nuclear magnetic resonance structures of proteins acting in MSP signaling in higher plants, focusing particularly on cytokinin and ethylene signaling in Arabidopsis thaliana. We discuss the range of functional aspects of available structural information including determination of ligand specificity, activation of the receptor via its autophosphorylation, and downstream signal transduction through the phosphorelay. We compare the plant structures with their bacterial counterparts and show that although the overall similarity is high, the differences in structural details are frequent and functionally important. Finally, we discuss emerging knowledge on molecular recognition mechanisms in the MSP, and mention the latest findings regarding structural determinants of signaling specificity in the Arabidopsis MSP that could serve as a general model of this pathway in all higher plants. PMID- 26633862 TI - Smoking and its associations with sociodemographic and clinical characteristics and quality of life in patients with schizophrenia treated in primary care in China. AB - OBJECTIVE: Maintenance treatment for clinically stable patients with schizophrenia is usually provided by Chinese primary care physicians, but no study has investigated smoking rates in this population. This study investigated the rate of smoking and its associations with sociodemographic and clinical characteristics and quality of life (QOL) in patients with schizophrenia treated in primary care in China. METHODS: This was a cross-sectional, community-based survey. A total of 621 schizophrenia patients were recruited from 22 primary care services in Guangzhou, China, in 2013. Patients' sociodemographic and clinical characteristics, smoking status, and QOL were recorded. RESULTS: The frequency of current smoking was 23.8% in the whole sample; 41.5% for men and 2.5% for women. Multiple logistic regression analysis revealed that male gender, married status, alcohol use, older age at onset, fewer major medical conditions, lower education level and more hospitalizations were independently associated with current smoking. CONCLUSION: The frequency of smoking in Chinese schizophrenia patients treated by primary care physicians is lower than most figures reported from Western and Chinese psychiatric settings. PMID- 26633863 TI - Assessment of psychosocial factors and predictors of psychopathology in a sample of heart transplantation recipients: a prospective 12-month follow-up. AB - BACKGROUND AND OBJECTIVES: In the last decades, researchers of heart transplantation (HT) programs have attempted to identify the existence of psychosocial factors that might influence the clinical outcome before and after the transplantation. The first objective of this study is the prospective description of changes in psychiatric and psychosocial factors in a sample of HT recipients through a 12-month follow-up. The second goal is to identify predictors of psychopathology 1 year after HT. METHODS: Pretransplant baseline assessment consisted of clinical form; Hospital Anxiety and Depression Scale (HADS); Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Structured Clinical Interview; Coping questionnaire (COPE); Five Factors Inventory Revised; Apgar-Family questionnaire and Multidimensional Health Locus of Control (MHLC). The assessment 1 year after HT consisted of HADS, COPE, Apgar Family and MHLC. RESULTS: The sample included 78 recipients. During the waiting list period, 32.1% of them had a psychiatric disorder; personality factors profile was similar to the general population, and they showed adaptive coping strategies. Some changes in psychosocial factors were observed at 12 months after the surgery: lower scores of anxiety and depression, less necessity of publicly venting of feelings and a trend to an internal locus of control. Neuroticism and Disengagement pre-HT were predictors of psychopathology in the follow-up assessment. CONCLUSIONS: Pretransplant psychosocial screening is important and enables to find out markers of emotional distress like Neuroticism or Disengagement coping styles to identify patients who might benefit from psychiatric and psychological interventions. Successful HT involved some positive changes in psychosocial factors 12 months after the surgery beyond physical recovery. PMID- 26633864 TI - Towards Explaining International Differences in Health Care Performance: Results of the EuroHOPE Project. PMID- 26633865 TI - Comparative Analysis of Treatment Costs in EUROHOPE. AB - This study examines the challenges of estimating risk-adjusted treatment costs in international comparative research, specifically in the European Health Care Outcomes, Performance, and Efficiency (EuroHOPE) project. We describe the diverse format of resource data and challenges of converting these data into resource use indicators that allow meaningful cross-country comparisons. The three cost indicators developed in EuroHOPE are then described, discussed, and applied. We compare the risk-adjusted mean treatment costs of acute myocardial infarction for four of the seven countries in the EuroHOPE project, namely, Finland, Hungary, Norway, and Sweden. The outcome of the comparison depends on the time perspective as well as on the particular resource use indicator. We argue that these complementary indicators add to our understanding of the variation in resource use across countries. PMID- 26633866 TI - Parameter Heterogeneity In Breast Cancer Cost Regressions - Evidence From Five European Countries. AB - We investigate parameter heterogeneity in breast cancer 1-year cumulative hospital costs across five European countries as part of the EuroHOPE project. The paper aims to explore whether conditional mean effects provide a suitable representation of the national variation in hospital costs. A cohort of patients with a primary diagnosis of invasive breast cancer (ICD-9 codes 174 and ICD-10 C50 codes) is derived using routinely collected individual breast cancer data from Finland, the metropolitan area of Turin (Italy), Norway, Scotland and Sweden. Conditional mean effects are estimated by ordinary least squares for each country, and quantile regressions are used to explore heterogeneity across the conditional quantile distribution. Point estimates based on conditional mean effects provide a good approximation of treatment response for some key demographic and diagnostic specific variables (e.g. age and ICD-10 diagnosis) across the conditional quantile distribution. For many policy variables of interest, however, there is considerable evidence of parameter heterogeneity that is concealed if decisions are based solely on conditional mean results. The use of quantile regression methods reinforce the need to consider beyond an average effect given the greater recognition that breast cancer is a complex disease reflecting patient heterogeneity. PMID- 26633867 TI - Individual and Regional-level Factors Contributing to Variation in Length of Stay After Cerebral Infarction in Six European Countries. AB - Using patient-level data for cerebral infarction cases in 2007, gathered from Finland, Hungary, Italy, the Netherlands, Scotland and Sweden, we studied the variation in risk-adjusted length of stay (LoS) of acute hospital care and 1-year mortality, both within and between countries. In addition, we analysed the variance of LoS and associations of selected regional-level factors with LoS and 1-year mortality after cerebral infarction. The data show that LoS distributions are surprisingly different across countries and that there is significant deviation in the risk-adjusted regional-level LoS in all of the countries studied. We used negative binomial regression to model the individual-level LoS, and random intercept models and ordinary least squares regression for the regional-level analysis of risk-adjusted LoS, variance of LoS, 1-year risk adjusted mortality and crude mortality for a period of 31-365 days. The observed variations between regions and countries in both LoS and mortality were not fully explained by either patient-level or regional-level factors. The results indicate that there may exist potential for efficiency gains in acute hospital care of cerebral infarction and that healthcare managers could learn from best practices. PMID- 26633868 TI - European Regional Differences in All-Cause Mortality and Length of Stay for Patients with Hip Fracture. AB - The objective of this study was to compare healthcare performance for the surgical treatment of hip fractures across and within Finland, Hungary, Italy, the Netherlands, Norway, Scotland, and Sweden. Differences in age-adjusted and sex-adjusted 30-day and one-year all-cause mortality rates following hip fracture, as well as the length of stay of the first hospital episode in acute care and during a follow up of 365 days, were investigated, and associations between selected country-level and regional-level factors with mortality and length of stay were assessed. Hungary showed the highest one-year mortality rate (mean 39.7%) and the lowest length of stay in one year (12.7 days), whereas Italy had the lowest one-year mortality rate (mean 19.1 %) and the highest length of stay (23.3 days). The observed variations were largely explained by country specific effects rather than by regional-level factors. The results show that there should still be room for efficiency gains in the acute treatment of hip fracture, and clinicians, healthcare managers, and politicians should learn from best practices. This study demonstrates that an international comparison of acute hospital care is possible using pooled individual-level administrative data. PMID- 26633869 TI - Variations and Determinants of Mortality and Length of Stay of Very Low Birth Weight and Very Low for Gestational Age Infants in Seven European Countries. AB - The EuroHOPE very low birth weight and very low for gestational age infants study aimed to measure and explain variation in mortality and length of stay (LoS) in the populations of seven European nations (Finland, Hungary, Italy (only the province of Rome), the Netherlands, Norway, Scotland and Sweden). Data were linked from birth, hospital discharge and mortality registries. For each infant basic clinical and demographic information, infant mortality and LoS at 1 year were retrieved. In addition, socio-economic variables at the regional level were used. Results based on 16,087 infants confirm that gestational age and Apgar score at 5 min are important determinants of both mortality and LoS. In most countries, infants admitted or transferred to third-level hospitals showed lower probability of death and longer LoS. In the meta-analyses, the combined estimates show that being male, multiple births, presence of malformations, per capita income and low population density are significant risk factors for death. It is essential that national policies improve the quality of administrative datasets and address systemic problems in assigning identification numbers at birth. European policy should aim at improving the comparability of data across jurisdictions. PMID- 26633870 TI - Acute Myocardial Infarction, Use of Percutaneous Coronary Intervention, and Mortality: A Comparative Effectiveness Analysis Covering Seven European Countries. AB - Percutaneous coronary interventions (PCI) on acute myocardial infarction (AMI) patients have increased substantially in the last 12-15 years because of its clinical effectiveness. The expansion of PCI treatment for AMI patients raises two questions: How did PCI utilization rates vary across European regions, and which healthcare system and regional characteristic variables correlated with the utilization rate? Were the differences in use of PCI associated with differences in outcome, operationalized as 30-day mortality? We obtained our results from a dataset based on the administrative information systems of the populations of seven European countries. PCI rates were highest in the Netherlands, followed by Sweden and Hungary. The probability of receiving PCI was highest in regions with their own PCI facilities and in healthcare systems with activity-based reimbursement systems. Thirty-day mortality rates differed considerably between the countries with the highest rates in Hungary, Scotland, and Finland. Mortality was lowest in Sweden and Norway. The associations between PCI and mortality were remarkable in all age groups and across most countries. Despite extensive risk adjustment, we interpret the associations both as effects of selection and treatments. We observed a lower effect of PCI in the higher age groups in Hungary. PMID- 26633871 TI - Socio-economic Inequality in the Use of Procedures and Mortality Among AMI Patients: Quantifying the Effects Along Different Paths. AB - It is not known whether inequality in access to cardiac procedures translates into inequality in mortality. In this paper, we use a path analysis model to quantify both the direct effect of socio-economic status on mortality and the indirect effect of socio-economic status on mortality as mediated by the provision of cardiac procedures. The study links microdata from the Finnish and Norwegian national patient registers describing treatment episodes with data from prescription registers, causes-of-death registers and registers covering education and income. We show that socio-economic variables affect access to percutaneous coronary intervention in both countries, but that these effects are only moderate and that the indirect effects of the socio-economic factors on mortality through access to percutaneous coronary intervention are minor. The direct effects of income and education on mortality are significantly larger. We conclude that the socio-economic gradient in the use of percutaneous coronary intervention adds to socio-economic differences in mortality to little or no extent. PMID- 26633872 TI - Outcome, Use of Resources and Their Relationship in the Treatment of AMI, Stroke and Hip Fracture at European Hospitals. AB - The aim of the present study was to compare the quality (survival), use of resources and their relationship in the treatment of three major conditions (acute myocardial infarction (AMI), stroke and hip fracture), in hospitals in five European countries (Finland, Hungary, Italy, Norway and Sweden). The comparison of quality and use of resources was based on hospital-level random effects models estimated from patient-level data. After examining quality and use of resources separately, we analysed whether a cost-quality trade-off existed between the hospitals. Our results showed notable differences between hospitals and countries in both survival and use of resources. Some evidence would support increasing the horizontal integration: higher degrees of concentration of regional AMI care were associated with lower use of resources. A positive relation between cost and quality in the care of AMI patients existed in Hungary and Finland. In the care of stroke and hip fracture, we found no evidence of a cost-quality trade-off. Thus, the cost-quality association was inconsistent and prevailed for certain treatments or patient groups, but not in all countries. PMID- 26633873 TI - Costs and Quality at the Hospital Level in the Nordic Countries. AB - This article develops and analyzes patient register-based measures of quality for the major Nordic countries. Previous studies show that Finnish hospitals have significantly higher average productivity than hospitals in Sweden, Denmark, and Norway and also a substantial variation within each country. This paper examines whether quality differences can form part of the explanation and attempts to uncover quality-cost trade-offs. Data on costs and discharges in each diagnosis related group for 160 acute hospitals in 2008-2009 were collected. Patient register-based measures of quality such as readmissions, mortality (in hospital or outside), and patient safety indices were developed and case-mix adjusted. Productivity is estimated using bootstrapped data envelopment analysis. Results indicate that case-mix adjustment is important, and there are significant differences in the case-mix adjusted performance measures as well as in productivity both at the national and hospital levels. For most quality indicators, the performance measures reveal room for improvement. There is a weak but statistical significant trade-off between productivity and inpatient readmissions within 30 days but a tendency that hospitals with high 30-day mortality also have higher costs. Hence, no clear cost-quality trade-off pattern was discovered. Patient registers can be used and developed to improve future quality and cost comparisons. PMID- 26633874 TI - A Window on Geographic Variation in Health Care: Insights from EuroHOPE. AB - The aim of EuroHOPE was to provide new evidence on the performance of healthcare systems, using a disease-based approach, linkable patient-level data and internationally standardized methods. This paper summarizes its main results. In the seven EuroHOPE countries, the Acute Myocardial Infarction (AMI), stroke and hip fracture patient populations were similar with regard to age, sex and comorbidity. However, non-negligible geographic variation in mortality and resource use was found to exist. Survival rates varied to similar extents between countries and regions for AMI, stroke, hip fracture and very low birth weight. Geographic variation in length of stay differed according to type of disease. Regression analyses showed that only a small part of geographic variation could be explained by demand and supply side factors. Furthermore, the impact of these factors varied between countries. The findings show that there is room for improvement in performance at all levels of analysis and call for more in-depth disease-based research. In using international patient-level data and a standardized methodology, the EuroHOPE approach provides a promising stepping stone for future investigations in this field. Still, more detailed patient and provider information, including outside of hospital care, and better data sharing arrangements are needed to reach a more comprehensive understanding of geographic variations in health care. PMID- 26633875 TI - CD19-Targeted CAR T Cells: A New Tool in the Fight against B Cell Malignancies. AB - Adoptive cell immunotherapy is a novel tool in the fight against cancer. Serving both effector and memory functions for the immune system, T cells make an obvious candidate for adoptive cell immunotherapy. By modifying native T cells with a chimeric antigen receptor (CAR), these cells can theoretically be targeted against any extracellular antigen. To date, the best-studied and clinically validated CAR T cells recognize CD19, a cell surface molecule on B cells and B cell malignancies. These CD19-directed T cells have shown clinical utility in chronic lymphocytic leukemia, acute lymphoblastic leukemia (ALL), and non Hodgkin's lymphomas, with some patients achieving long-term disease remissions after treatment. This review will briefly summarize the current data supporting the use of adoptively transferred CAR T cells for the treatment of CD19-positive malignancies. Given these exciting results, the Food and Drug Administration has granted a 'breakthrough' designation for several variations of CD19-directed CAR T cells for treatment of adult and pediatric relapsed/refractory ALL. PMID- 26633876 TI - Electrical Impedance and Expression of Tight Junction Components of the Nasal Turbinate and Polyp. AB - PURPOSE: We investigated the electrical impedance and expression of tight junction components of the turbinate mucosa, nasal polyp, and normal skin. PROCEDURES: The inferior turbinate and nasal polyp of patients with chronic rhinosinusitis and the postauricular skin of patients with otitis media were examined. Electrical impedance was measured in vivo using a tissue conductance meter. Expressions of claudin-1 and tricellulin were examined by fluorescence immunohistochemistry and quantitative RT-PCR. RESULTS: Electrical impedance was higher in the skin than in the turbinate and polyp, but did not differ between the turbinate and polyp. Immunoreactivities for claudin-1 and tricellulin were seen in the epithelial/epidermal layer. Expression of claudin-1 was higher in the skin than in the turbinate and polyp. The polyp tended to show higher expression of claudin-1 but showed lower expression of tricellulin than the turbinate. The ratio of claudin-1 to tricellulin was highest in the skin and lowest in the turbinate. The correlation between expressions of the two tight junction components was strongly positive in the skin (r = 0.964) and negative (r = 0.527) in the turbinate and polyp. CONCLUSIONS: These results suggest that the roles of claudin-1 and tricellulin in barrier function may be complementary, and may thereby maintain a constant level of permeability of the mucosal tissues. PMID- 26633877 TI - Turtle Dorsal Cortex Pyramidal Neurons Comprise Two Distinct Cell Types with Indistinguishable Visual Responses. AB - A detailed inventory of the constituent pieces in cerebral cortex is considered essential to understand the principles underlying cortical signal processing. Specifically, the search for pyramidal neuron subtypes is partly motivated by the hypothesis that a subtype-specific division of labor could create a rich substrate for computation. On the other hand, the extreme integration of individual neurons into the collective cortical circuit promotes the hypothesis that cellular individuality represents a smaller computational role within the context of the larger network. These competing hypotheses raise the important question to what extent the computational function of a neuron is determined by its individual type or by its circuit connections. We created electrophysiological profiles from pyramidal neurons within the sole cellular layer of turtle visual cortex by measuring responses to current injection using whole-cell recordings. A blind clustering algorithm applied to these data revealed the presence of two principle types of pyramidal neurons. Brief diffuse light flashes triggered membrane potential fluctuations in those same cortical neurons. The apparently network driven variability of the visual responses concealed the existence of subtypes. In conclusion, our results support the notion that the importance of diverse intrinsic physiological properties is minimized when neurons are embedded in a synaptic recurrent network. PMID- 26633878 TI - Fentanyl Enhances Hepatotoxicity of Paclitaxel via Inhibition of CYP3A4 and ABCB1 Transport Activity in Mice. AB - Fentanyl, a potent opioid analgesic that is used to treat cancer pain, is commonly administered with paclitaxel in advanced tumors. However, the effect of fentanyl on the hepatotoxicity of paclitaxel and its potential mechanism of action is not well studied. The purpose of this study was to investigate the effect of fentanyl on the hepatotoxicity of paclitaxel and its potential mechanisms of action. Pharmacokinetic parameters of paclitaxel were tested using reversed phase high-performance liquid chromatography (RP-HPLC). Aspartate transaminase (AST), alanine aminotransferase (ALT), and mouse liver histopathology were examined. Moreover, the cytotoxicity of anti-carcinogens was examined using 1-(4, 5-dimethylthiazol-2-yl)-3,5-diphenylformazan (MTT), and the intracellular accumulation of doxorubicin and rhodamine 123 was detected by flow cytometry. Furthermore, the expression of ABCB1 and the activity of ABCB1 ATPase and CYP3A4 were also examined. In this study, the co-administration of fentanyl and paclitaxel prolonged the half-life (t1/2) of paclitaxel from 1.455 hours to 2.344 hours and decreased the clearance (CL) from 10.997 ml/h to 7.014 ml/h in mice. Fentanyl significantly increased the levels of ALT in mice to 88.2 U/L, which is more than 2-fold higher than the level detected in the control group, and it increased the histological damage in mouse livers. Furthermore, fentanyl enhanced the cytotoxicity of anti-carcinogens that are ABCB1 substrates and increased the accumulation of doxorubicin and rhodamine 123. Additionally, fentanyl stimulated ABCB1 ATPase activity and inhibited CYP3A4 activity in the liver microsomes of mice. Our study indicates that the obvious hepatotoxicity during this co-administration was due to the inhibition of CYP3A4 activity and ABCB1 transport activity. These findings suggested that the accumulation-induced hepatotoxicity of paclitaxel when it is combined with fentanyl should be avoided. PMID- 26633879 TI - Nanobodies: site-specific labeling for super-resolution imaging, rapid epitope mapping and native protein complex isolation. AB - Nanobodies are single-domain antibodies of camelid origin. We generated nanobodies against the vertebrate nuclear pore complex (NPC) and used them in STORM imaging to locate individual NPC proteins with <2 nm epitope-label displacement. For this, we introduced cysteines at specific positions in the nanobody sequence and labeled the resulting proteins with fluorophore-maleimides. As nanobodies are normally stabilized by disulfide-bonded cysteines, this appears counterintuitive. Yet, our analysis showed that this caused no folding problems. Compared to traditional NHS ester-labeling of lysines, the cysteine-maleimide strategy resulted in far less background in fluorescence imaging, it better preserved epitope recognition and it is site-specific. We also devised a rapid epitope-mapping strategy, which relies on crosslinking mass spectrometry and the introduced ectopic cysteines. Finally, we used different anti-nucleoporin nanobodies to purify the major NPC building blocks - each in a single step, with native elution and, as demonstrated, in excellent quality for structural analysis by electron microscopy. The presented strategies are applicable to any nanobody and nanobody-target. PMID- 26633880 TI - Untwisting the Caenorhabditis elegans embryo. AB - The nematode Caenorhabditis elegans possesses a simple embryonic nervous system with few enough neurons that the growth of each cell could be followed to provide a systems-level view of development. However, studies of single cell development have largely been conducted in fixed or pre-twitching live embryos, because of technical difficulties associated with embryo movement in late embryogenesis. We present open-source untwisting and annotation software (http://mipav.cit.nih.gov/plugin_jws/mipav_worm_plugin.php) that allows the investigation of neurodevelopmental events in late embryogenesis and apply it to track the 3D positions of seam cell nuclei, neurons, and neurites in multiple elongating embryos. We also provide a tutorial describing how to use the software (Supplementary file 1) and a detailed description of the untwisting algorithm (Appendix). The detailed positional information we obtained enabled us to develop a composite model showing movement of these cells and neurites in an 'average' worm embryo. The untwisting and cell tracking capabilities of our method provide a foundation on which to catalog C. elegans neurodevelopment, allowing interrogation of developmental events in previously inaccessible periods of embryogenesis. PMID- 26633881 TI - Synergistic integration of Netrin and ephrin axon guidance signals by spinal motor neurons. AB - During neural circuit assembly, axonal growth cones are exposed to multiple guidance signals at trajectory choice points. While axonal responses to individual guidance cues have been extensively studied, less is known about responses to combination of signals and underlying molecular mechanisms. Here, we studied the convergence of signals directing trajectory selection of spinal motor axons entering the limb. We first demonstrate that Netrin-1 attracts and repels distinct motor axon populations, according to their expression of Netrin receptors. Quantitative in vitro assays demonstrate that motor axons synergistically integrate both attractive or repulsive Netrin-1 signals together with repulsive ephrin signals. Our investigations of the mechanism of ephrin-B2 and Netrin-1 integration demonstrate that the Netrin receptor Unc5c and the ephrin receptor EphB2 can form a complex in a ligand-dependent manner and that Netrin-ephrin synergistic growth cones responses involve the potentiation of Src family kinase signaling, a common effector of both pathways. PMID- 26633882 TI - Mouse models of human PIK3CA-related brain overgrowth have acutely treatable epilepsy. AB - Mutations in the catalytic subunit of phosphoinositide 3-kinase (PIK3CA) and other PI3K-AKT pathway components have been associated with cancer and a wide spectrum of brain and body overgrowth. In the brain, the phenotypic spectrum of PIK3CA-related segmental overgrowth includes bilateral dysplastic megalencephaly, hemimegalencephaly and focal cortical dysplasia, the most common cause of intractable pediatric epilepsy. We generated mouse models expressing the most common activating Pik3ca mutations (H1047R and E545K) in developing neural progenitors. These accurately recapitulate all the key human pathological features including brain enlargement, cortical malformation, hydrocephalus and epilepsy, with phenotypic severity dependent on the mutant allele and its time of activation. Underlying mechanisms include increased proliferation, cell size and altered white matter. Notably, we demonstrate that acute 1 hr-suppression of PI3K signaling despite the ongoing presence of dysplasia has dramatic anti-epileptic benefit. Thus PI3K inhibitors offer a promising new avenue for effective anti epileptic therapy for intractable pediatric epilepsy patients. PMID- 26633884 TI - Observations on the Inactivation Efficacy of a MALDI-TOF MS Chemical Extraction Method on Bacillus anthracis Vegetative Cells and Spores. AB - A chemical (ethanol; formic acid; acetonitrile) protein extraction method for the preparation of bacterial samples for matrix assisted laser desorption ionisation time-of-flight mass spectrometry (MALDI-TOF MS) identification was evaluated for its ability to inactivate bacterial species. Initial viability tests (with and without double filtration of the extract through 0.2 MUM filters), indicated that the method could inactivate Escherichia coli MRE 162 and Klebsiella pneumoniae ATCC 35657, with or without filtration, but that filtration was required to exclude viable, avirulent, Bacillus anthracis UM23CL2 from extracts. Multiple, high stringency, viability experiments were then carried out on entire filtered extracts prepared from virulent B. anthracis Vollum vegetative cells and spores ranging in concentration from 10(6)-10(8) cfu per extract. B. anthracis was recovered in 3/18 vegetative cell extracts and 10/18 spore extracts. From vegetative cell extracts B. anthracis was only recovered from extracts that had undergone prolonged Luria (L)-broth (7 day) and L-agar plate (a further 7 days) incubations. We hypothesise that the recovery of B. anthracis in vegetative cell extracts is due to the escape of individual sub-lethally injured cells. We discuss our results in view of working practises in clinical laboratories and in the context of recent inadvertent releases of viable B. anthracis. PMID- 26633883 TI - Methodological Framework for World Health Organization Estimates of the Global Burden of Foodborne Disease. AB - BACKGROUND: The Foodborne Disease Burden Epidemiology Reference Group (FERG) was established in 2007 by the World Health Organization to estimate the global burden of foodborne diseases (FBDs). This paper describes the methodological framework developed by FERG's Computational Task Force to transform epidemiological information into FBD burden estimates. METHODS AND FINDINGS: The global and regional burden of 31 FBDs was quantified, along with limited estimates for 5 other FBDs, using Disability-Adjusted Life Years in a hazard- and incidence-based approach. To accomplish this task, the following workflow was defined: outline of disease models and collection of epidemiological data; design and completion of a database template; development of an imputation model; identification of disability weights; probabilistic burden assessment; and estimating the proportion of the disease burden by each hazard that is attributable to exposure by food (i.e., source attribution). All computations were performed in R and the different functions were compiled in the R package 'FERG'. Traceability and transparency were ensured by sharing results and methods in an interactive way with all FERG members throughout the process. CONCLUSIONS: We developed a comprehensive framework for estimating the global burden of FBDs, in which methodological simplicity and transparency were key elements. All the tools developed have been made available and can be translated into a user friendly national toolkit for studying and monitoring food safety at the local level. PMID- 26633885 TI - Pharmacogenetic Risk Stratification in Angiotensin-Converting Enzyme Inhibitor Treated Patients with Congestive Heart Failure: A Retrospective Cohort Study. AB - BACKGROUND: Evidence for pharmacogenetic risk stratification of angiotensin converting enzyme inhibitor (ACEI) treatment is limited. Therefore, in a cohort of ACEI-treated patients with congestive heart failure (CHF), we investigated the predictive value of two pharmacogenetic scores that previously were found to predict ACEI efficacy in patients with ischemic heart disease and hypertension, respectively. Score A combined single nucleotide polymorphisms (SNPs) of the angiotensin II receptor type 1 gene (rs275651 and rs5182) and the bradykinin receptor B1 gene (rs12050217). Score B combined SNPs of the angiotensin converting enzyme gene (rs4343) and ABO blood group genes (rs495828 and rs8176746). METHODS: Danish patients with CHF enrolled in the previously reported Echocardiography and Heart Outcome Study were included. Subjects were genotyped and categorized according to pharmacogenetic scores A and B of <=1, 2 and >=3 each, and followed for up to 10 years. Difference in cumulative incidences of cardiovascular death and all-cause death were assessed by the cumulative incidence estimator. Survival was modeled by Cox proportional hazard analyses. RESULTS: We included 667 patients, of whom 80% were treated with ACEIs. Differences in cumulative incidences of cardiovascular death (P = 0.346 and P = 0.486) and all-cause death (P = 0.515 and P = 0.486) were not significant for score A and B, respectively. There was no difference in risk of cardiovascular death or all-cause death between subjects with score A <=1 vs. 2 (HR 1.03 [95% CI 0.79-1.34] and HR 1.11 [95% CI 0.88-1.42]), score A <=1 vs. >=3 (HR 0.80 [95% CI 0.59-1.08] and HR 0.91 [95% CI 0.70-1.20]), score B <=1 vs. 2 (HR 1.02 [95% CI 0.78-1.32] and HR 0.98 [95% CI 0.77-1.24]), and score B <=1 vs. >=3 (HR 1.03 [95% CI 0.75-1.41] and HR 1.05 [95% CI 0.79-1.40]), respectively. CONCLUSIONS: We found no association between either of the analyzed pharmacogenetic scores and fatal outcomes in ACEI-treated patients with CHF. PMID- 26633886 TI - Non-Invasive Pregnancy Diagnosis in Big Cats using the PGFM (13,14-dihydro-15 keto-PGF2alpha) Assay. AB - Non-invasive monitoring of hormones using feces has become a vital tool for reproductive management and reliable pregnancy diagnosis in big cats. Previous studies described the PGF2alpha metabolite (PGFM) as an indicator of pregnancy in various feline species. The present study aimed to standardize pregnancy detection in big cats like the tiger (Panthera tigris), jaguar (Panthera onca) and lion (Panthera leo) using fecal samples. High-performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometry (LCMS) were performed to identify PGFM in feces. An EIA developed against 9alpha,11alpha dihydroxy-15-oxo-prost-5-en-1-oic acid-BSA was used to assay PGFM in fecal samples of the Bengal tiger, Asiatic lion and jaguar. The PGFM levels increased after 9 weeks of pregnancy and remained elevated until parturition. All animals showed elevated levels of PGFM in the last trimester of pregnancy, thus making PGFM a reliable tool for pregnancy diagnosis during this period that can be useful in captive breeding programs in these species. PMID- 26633887 TI - Synthesis and biological evaluation of 3-(4-fluorophenyl)-1H-pyrazole derivatives as androgen receptor antagonists. AB - A novel series of 3-(4-fluorophenyl)-1H-pyrazole derivatives were synthesized and evaluated for their antiproliferative activity against two prostate cancer cell lines (LNCaP and PC-3) and androgen receptor target gene prostate-specific antigen (PSA) inhibitory activity in LNCaP cells. Several compounds showed potent antiproliferative activity against LNCaP cells and showed a promising PSA downregulation rate. Among these, compound 10e selectively inhibited LNCaP cell growth with an IC50 value of 18 MUmol/l and showed a PSA downregulation rate of 46%, which was better than the lead compound T3. PMID- 26633888 TI - Observation of hepatotoxicity during long-term gefitinib administration in patients with non-small-cell lung cancer. AB - To observe drug-induced hepatotoxicity by long-term gefitinib administration in the treatment of non-small-cell lung cancer. The data of 101 patients with locally advanced or metastatic non-small-cell lung cancer, for which gefitinib had been used orally for 3 months or longer, were retrospectively analyzed. The median duration of gefitinib administration was 14 months (3-60 months). Forty patients (39.6%) developed abnormal hepatic function, among whom 30 patients (29.7%) had grade I hepatotoxicity, six patients (5.9%) had grade II, and four patients (4.0%) had grade III, respectively. The median time from starting gefitinib oral therapy to developing liver dysfunction was 4 months (1-23 months) for the entire cohort. The incidence of hepatotoxicity in the group with a duration of more than 14 months was much higher than that in the group with a duration of less than 14 months (52.0 vs. 27.5%, P=0.012). In thirty-two patients (32/40), abnormal liver function resolved with hepatoprotective treatment, whereas eight patients (8/40) had persistent grade I hepatotoxicity until the last follow-up. Our study showed that long-term gefitinib-induced hepatotoxicity was a common adverse event, especially for the cohort with a duration of longer than 14 months. In most patients with hepatotoxicity, normal liver function was restored and discontinuation of gefitinib was not necessary. PMID- 26633889 TI - Viral Hepatitis Among Non-Hispanic Asian Adults in the United States, 2011-2014. AB - KEY FINDINGS: Hepatitis A (HAV), B (HBV), and C (HCV) viruses are common types of viral hepatitis. HBV and HCV infection can lead to liver disease, cancer, and serious health consequences. HAV and HBV infections are high among Asian persons, especially those born outside the United States (1-3). This report provides 2011- 2014 National Health and Nutrition Examination Survey (NHANES) estimates on prevalence of antibody to HAV (from infection or immunization), past or current HBV infection, and current HCV infection, by race and Hispanic origin. PMID- 26633890 TI - Molecular Epidemiology of Amoebiasis: A Cross-Sectional Study among North East Indian Population. AB - BACKGROUND: Epidemiological studies carried out using culture or microscopy in most of the amoebiasis endemic developing countries, yielded confusing results since none of these could differentiate the pathogenic Entamoeba histolytica from the non-pathogenic Entamoeba dispar and Entamoeba moshkovskii. The Northeastern part of India is a hot spot of infection since the climatic conditions are most conducive for the infection and so far no systemic study has been carried out in this region. METHODOLOGY/PRINCIPAL FINDINGS: Following a cross-sectional study designed during the period 2011-2014, a total of 1260 fecal samples collected from the Northeast Indian population were subjected to microscopy, fecal culture and a sensitive and specific DNA dot blot screening assay developed in our laboratory targeting the Entamoeba spp. Further species discrimination using PCR assay performed in microscopy, culture and DNA dot blot screening positive samples showed E. histolytica an overall prevalence rate of 11.1%, 8.0% and 13.7% respectively. In addition, infection rates of nonpathogenic E. dispar and E. moshkovskii were 11.8% (95% CI = 10.2, 13.8) and 7.8% (95% CI = 6.4, 9.4) respectively. The spatial distributions of infection were 18.2% (107/588) of Assam, 11.7% (23/197) of Manipur, 10.2% (21/207) of Meghalaya, and 8.2% (22/268) of Tripura states. Association study of the disease with demographic features suggested poor living condition (OR = 3.21; 95% CI = 1.83, 5.63), previous history of infection in family member (OR = 3.18; 95% CI = 2.09, 4.82) and unhygienic toilet facility (OR = 1.79; 95% CI = 1.28, 2.49) as significant risk factors for amoebiasis. Children in age group <15 yr, participants having lower levels of education, and daily laborers exhibited a higher infection rate. CONCLUSIONS/SIGNIFICANCE: Despite the importance of molecular diagnosis of amoebiasis, molecular epidemiological data based on a large sample size from endemic countries are rarely reported in the literature. Improved and faster method of diagnosis employed here to dissect out the pathogenic from the nonpathogenic species would help the clinicians to prescribe the appropriate anti amoebic drug. PMID- 26633891 TI - Wild Edible Fruit of Prunus nepalensis Ser. (Steud), a Potential Source of Antioxidants, Ameliorates Iron Overload-Induced Hepatotoxicity and Liver Fibrosis in Mice. AB - The antioxidant and restoration potentials of hepatic injury by Prunus nepalensis Ser. (Steud), a wild fruit plant from the Northeastern region of India, were investigated. The fruit extract (PNME) exhibited excellent antioxidant and reducing properties and also scavenged the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical (IC50 = 30.92 +/- 0.40 MUg/ml). PNME demonstrated promising scavenging potency, as assessed by the scavenging of different reactive oxygen and nitrogen species. Moreover, the extract revealed an exceptional iron chelation capacity with an IC50 of 25.64 +/- 0.60 MUg/ml. The extract induced significant improvement of hepatic injury and liver fibrosis against iron overload induced hepatotoxicity in mice in a dose-dependent manner, and this effect was supported by different histopathological studies. The phytochemical constitutions and their identification by HPLC confirmed the presence of purpurin, tannic acid, methyl gallate, reserpine, gallic acid, ascorbic acid, catechin and rutin. The identified compounds were investigated for their individual radical scavenging and iron chelation activity; some compounds exhibited excellent radical scavenging and iron chelation properties, but most were toxic towards normal cells (WI-38). On the other hand, crude PNME was found to be completely nontoxic to normal cells, suggesting its feasibility as a safe oral drug. The above study suggests that different phytochemicals in PNME contributed to its free radical scavenging and iron chelation activity; however, further studies are required to determine the pathway in which PNME acts to treat iron-overload diseases. PMID- 26633892 TI - Effect of Tendon Vibration on Hemiparetic Arm Stability in Unstable Workspaces. AB - Sensory stimulation of wrist musculature can enhance stability in the proximal arm and may be a useful therapy aimed at improving arm control post-stroke. Specifically, our prior research indicates tendon vibration can enhance stability during point-to-point arm movements and in tracking tasks. The goal of the present study was to investigate the influence of forearm tendon vibration on endpoint stability, measured at the hand, immediately following forward arm movements in an unstable environment. Both proximal and distal workspaces were tested. Ten hemiparetic stroke subjects and 5 healthy controls made forward arm movements while grasping the handle of a two-joint robotic arm. At the end of each movement, the robot applied destabilizing forces. During some trials, 70 Hz vibration was applied to the forearm flexor muscle tendons. 70 Hz was used as the stimulus frequency as it lies within the range of optimal frequencies that activate the muscle spindles at the highest response rate. Endpoint position, velocity, muscle activity and grip force data were compared before, during and after vibration. Stability at the endpoint was quantified as the magnitude of oscillation about the target position, calculated from the power of the tangential velocity data. Prior to vibration, subjects produced unstable, oscillating hand movements about the target location due to the applied force field. Stability increased during vibration, as evidenced by decreased oscillation in hand tangential velocity. PMID- 26633893 TI - The Divergent Intracellular Lifestyle of Francisella tularensis in Evolutionarily Distinct Host Cells. PMID- 26633894 TI - The Role of ARX in Human Pancreatic Endocrine Specification. AB - The in vitro differentiation of human embryonic stem cells (hESCs) offers a model system to explore human development. Humans with mutations in the transcription factor Aristaless Related Homeobox (ARX) often suffer from the syndrome X-linked lissencephaly with ambiguous genitalia (XLAG), affecting many cell types including those of the pancreas. Indeed, XLAG pancreatic islets lack glucagon and pancreatic polypeptide-positive cells but retain somatostatin, insulin, and ghrelin-positive cells. To further examine the role of ARX in human pancreatic endocrine development, we utilized genomic editing in hESCs to generate deletions in ARX. ARX knockout hESCs retained pancreatic differentiation capacity and ARX knockout endocrine cells were biased toward somatostatin-positive cells (94% of endocrine cells) with reduced pancreatic polypeptide (rarely detected), glucagon (90% reduced) and insulin-positive (65% reduced) lineages. ARX knockout somatostatin-positive cells shared expression patterns with human fetal and adult delta-cells. Differentiated ARX knockout cells upregulated PAX4, NKX2.2, ISL1, HHEX, PCSK1, PCSK2 expression while downregulating PAX6 and IRX2. Re-expression of ARX in ARX knockout pancreatic progenitors reduced HHEX and increased PAX6 and insulin expression following differentiation. Taken together these data suggest that ARX plays a key role in pancreatic endocrine fate specification of pancreatic polypeptide, somatostatin, glucagon and insulin positive cells from hESCs. PMID- 26633895 TI - Antiviral Protection via RdRP-Mediated Stable Activation of Innate Immunity. AB - For many emerging and re-emerging infectious diseases, definitive solutions via sterilizing adaptive immunity may require years or decades to develop, if they are even possible. The innate immune system offers alternative mechanisms that do not require antigen-specific recognition or a priori knowledge of the causative agent. However, it is unclear whether effective stable innate immune system activation can be achieved without triggering harmful autoimmunity or other chronic inflammatory sequelae. Here, we show that transgenic expression of a picornavirus RNA-dependent RNA polymerase (RdRP), in the absence of other viral proteins, can profoundly reconfigure mammalian innate antiviral immunity by exposing the normally membrane-sequestered RdRP activity to sustained innate immune detection. RdRP-transgenic mice have life-long, quantitatively dramatic upregulation of 80 interferon-stimulated genes (ISGs) and show profound resistance to normally lethal viral challenge. Multiple crosses with defined knockout mice (Rag1, Mda5, Mavs, Ifnar1, Ifngr1, and Tlr3) established that the mechanism operates via MDA5 and MAVS and is fully independent of the adaptive immune system. Human cell models recapitulated the key features with striking fidelity, with the RdRP inducing an analogous ISG network and a strict block to HIV-1 infection. This RdRP-mediated antiviral mechanism does not depend on secondary structure within the RdRP mRNA but operates at the protein level and requires RdRP catalysis. Importantly, despite lifelong massive ISG elevations, RdRP mice are entirely healthy, with normal longevity. Our data reveal that a powerfully augmented MDA5-mediated activation state can be a well-tolerated mammalian innate immune system configuration. These results provide a foundation for augmenting innate immunity to achieve broad-spectrum antiviral protection. PMID- 26633896 TI - World Health Organization Global Estimates and Regional Comparisons of the Burden of Foodborne Disease in 2010. AB - Illness and death from diseases caused by contaminated food are a constant threat to public health and a significant impediment to socio-economic development worldwide. To measure the global and regional burden of foodborne disease (FBD), the World Health Organization (WHO) established the Foodborne Disease Burden Epidemiology Reference Group (FERG), which here reports their first estimates of the incidence, mortality, and disease burden due to 31 foodborne hazards. We find that the global burden of FBD is comparable to those of the major infectious diseases, HIV/AIDS, malaria and tuberculosis. The most frequent causes of foodborne illness were diarrheal disease agents, particularly norovirus and Campylobacter spp. Diarrheal disease agents, especially non-typhoidal Salmonella enterica, were also responsible for the majority of deaths due to FBD. Other major causes of FBD deaths were Salmonella Typhi, Taenia solium and hepatitis A virus. The global burden of FBD caused by the 31 hazards in 2010 was 33 million Disability Adjusted Life Years (DALYs); children under five years old bore 40% of this burden. The 14 subregions, defined on the basis of child and adult mortality, had considerably different burdens of FBD, with the greatest falling on the subregions in Africa, followed by the subregions in South-East Asia and the Eastern Mediterranean D subregion. Some hazards, such as non-typhoidal S. enterica, were important causes of FBD in all regions of the world, whereas others, such as certain parasitic helminths, were highly localised. Thus, the burden of FBD is borne particularly by children under five years old-although they represent only 9% of the global population-and people living in low-income regions of the world. These estimates are conservative, i.e., underestimates rather than overestimates; further studies are needed to address the data gaps and limitations of the study. Nevertheless, all stakeholders can contribute to improvements in food safety throughout the food chain by incorporating these estimates into policy development at national and international levels. PMID- 26633897 TI - Nestin Positive Bone Marrow Derived Cells Responded to Injury Mobilize into Peripheral Circulation and Participate in Skin Defect Healing. AB - Exogenously infused mesenchymal stem cells (MSCs) are thought to migrate to injury site through peripheral blood stream and participate in tissue repair. However, whether and how endogenous bone marrow MSCs mobilized to circulating and targeted to tissue injury has raised some controversy, and related studies were restricted by the difficulty of MSCs identifying in vivo. Nestin, a kind of intermediate filament protein initially identified in neuroepithelial stem cells, was recently reported as a credible criteria for MSCs in bone marrow. In this study, we used a green fluorescent protein (GFP) labeled bone marrow replacement model to trace the nestin positive bone marrow derived cells (BMDCs) of skin defected-mice. We found that after skin injured, numbers of nestin+ cells in peripheral blood and bone marrow both increased. A remarkable concentration of nestin+ BMDCs around skin wound was detected, while few of these cells could be observed in uninjured skin or other organs. This recruitment effect could not be promoted by granulocyte colony-stimulating factor (G-CSF), suggests a different mobilization mechanism from ones G-CSF takes effect on hematopoietic cells. Our results proposed nestin+ BMDCs as mobilized candidates in skin injury repair, which provide a new insight of endogenous MSCs therapy. PMID- 26633898 TI - Beneficial Effects of Evogliptin, a Novel Dipeptidyl Peptidase 4 Inhibitor, on Adiposity with Increased Ppargc1a in White Adipose Tissue in Obese Mice. AB - Although dipeptidyl peptidase 4 (DPP4) is an adipokine known to positively correlate with adiposity, the effects of pharmacological DPP4 inhibition on body composition have not been fully understood. This study was aimed to assess the effects of DPP4 inhibitors on adiposity for the first time in the established obese mice model. The weight loss effects of multiple DPP4 inhibitors were compared after a 4 week treatment in diet-induced obese mice. In addition, a 2 week study was performed to explore and compare the acute effects of evogliptin, a novel DPP4 inhibitor, and exenatide, a glucagon-like peptide-1 (GLP-1) analogue, on whole body composition, energy consumption, various plasma adipokines and gene expression in white adipose tissue (WAT). After the 4 week treatment, weight loss and blood glucose reductions were consistently observed with multiple DPP4 inhibitors. Moreover, after 2-week treatment, evogliptin dose dependently reduced whole body fat mass while increasing the proportion of smaller adipocytes. However, insulin sensitivity or plasma lipid levels were not significantly altered. In addition to increased active GLP-1 levels by plasma DPP4 inhibition, evogliptin also enhanced basal metabolic rate without reduction in caloric intake, in contrast to exenatide; this finding suggested evogliptin's effects may be mediated by pathways other than via GLP-1. Evogliptin treatment also differentially increased Ppargc1a expression, a key metabolic regulator, in WAT, but not in skeletal muscle and brown adipose tissue. The increased expression of the downstream mitochondrial gene, Cox4i1, was also suggestive of the potential metabolic alteration in WAT by DPP4 inhibitors. We are the first to demonstrate that pharmacological DPP4 inhibition by evogliptin directly causes fat loss in established obese mice. In contradistinction to exenatide, the fat loss effect of DPP4 inhibitor is partly attributed to enhanced energy expenditure along with metabolic changes in WAT. These results provide insight into the regulation of energy storage in WAT caused by DPP4 inhibition. PMID- 26633900 TI - Cervical Cancer Screening: Defining the Need for Research. AB - With the development of a National Cancer Plan published in 2012, Germany has followed the recommendations of the WHO and the EU. The first area of action listed in Germany's National Cancer Plan is improving the early detection of cancer. Both citizens and medical specialists are encouraged to take responsibility themselves and contribute to the efforts being made to meet the challenge of cancer. Screening for cervical cancer has long been an integral part of the German Directive for the Early Detection of Cancer and now - following the recommendations given in the European Guideline - an organised screening approach shall be developed to maximise the benefits and minimise the risks through a partial reorganisation of existing structures. Before this can be rolled out nationwide, it will be necessary to check the feasibility and suitability of new contents and organisational structures. The Federal Joint Committee which is largely responsible for the process according to the draft law on the implementation of the National Cancer Plan has emphasised the importance of evidence-based medicine and of collaboration between the autonomous governing bodies within the healthcare system to obtain viable results. For medical specialists, the follow-on question is which areas will need more research in future. New process steps need to be developed and verified to see whether they offer evidence which will support defined approaches or whether such evidence needs to be newly compiled, e.g. by testing invitation procedures for screening in trial schemes. The experience gained during the implementation of the existing directive on early detection of cancer should be integrated into the new process. Research initiated by specialists could encourage the development of a new version of the Directive for the Early Detection of Cancer suitable for the Germany's healthcare system. PMID- 26633899 TI - The Association of Human Apolipoprotein C-III Sialylation Proteoforms with Plasma Triglycerides. AB - INTRODUCTION: Apolipoprotein C-III (apoC-III) regulates triglyceride (TG) metabolism. In plasma, apoC-III exists in non-sialylated (apoC-III0a without glycosylation and apoC-III0b with glycosylation), monosialylated (apoC-III1) or disialylated (apoC-III2) proteoforms. Our aim was to clarify the relationship between apoC-III sialylation proteoforms with fasting plasma TG concentrations. METHODS: In 204 non-diabetic adolescent participants, the relative abundance of apoC-III plasma proteoforms was measured using mass spectrometric immunoassay. RESULTS: Compared with the healthy weight subgroup (n = 16), the ratios of apoC III0a, apoC-III0b, and apoC-III1 to apoC-III2 were significantly greater in overweight (n = 33) and obese participants (n = 155). These ratios were positively correlated with BMI z-scores and negatively correlated with measures of insulin sensitivity (Si). The relationship of apoC-III1 / apoC-III2 with Si persisted after adjusting for BMI (p = 0.02). Fasting TG was correlated with the ratio of apoC-III0a / apoC-III2 (r = 0.47, p<0.001), apoC-III0b / apoC-III2 (r = 0.41, p<0.001), apoC-III1 / apoC-III2 (r = 0.43, p<0.001). By examining apoC-III concentrations, the association of apoC-III proteoforms with TG was driven by apoC-III0a (r = 0.57, p<0.001), apoC-III0b (r = 0.56. p<0.001) and apoC-III1 (r = 0.67, p<0.001), but not apoC-III2 (r = 0.006, p = 0.9) concentrations, indicating that apoC-III relationship with plasma TG differed in apoC-III2 compared with the other proteoforms. CONCLUSION: We conclude that apoC-III0a, apoC-III0b, and apoC III1, but not apoC- III2 appear to be under metabolic control and associate with fasting plasma TG. Measurement of apoC-III proteoforms can offer insights into the biology of TG metabolism in obesity. PMID- 26633901 TI - Uterine Fibroid Embolisation - Potential Impact on Fertility and Pregnancy Outcome. AB - The current standard therapy to treat myomas in women wishing to have children consists of minimally invasive surgical myomectomy. Uterine artery embolisation (UAE) has also been discussed as another minimally invasive treatment option to treat myomas. This review evaluates the literature of the past 10 years on fibroid embolisation and its impact on fertility and pregnancy. Potential problems associated with UAE such as radiation exposure of the ovaries, impairment of ovarian function and the impact on pregnancy and child birth are discussed in detail. Previously published reports of at least 337 pregnancies after UAE were evaluated. The review concludes that UAE to treat myomas can only be recommended in women with fertility problems due to myomas who refuse surgery or women with an unacceptably high surgical risk, because the evaluated case reports and studies show that UAE significantly increases the risk of spontaneous abortion; there is also evidence of pathologically increased levels for other obstetric outcome parameters. There are still very few prospective studies which provide sufficient evidence for a definitive statement on the impact of UAE therapy on fertility rates and pregnancy outcomes. PMID- 26633902 TI - Treatment of Iron Deficiency in Women. AB - Iron deficiency with and without anaemia is a common cause of morbidity, particularly in women. Iron deficiency is generally the result of an imbalance between iron loss and iron absorption. In women with symptoms suspicious for iron deficiency, it is important to confirm or exclude the suspicion using proper tests. The use of serum ferritin levels is considered the gold standard for diagnosis. Although the ideal ferritin levels are not unknown the current consent is that levels < 40 ng/ml indicate iron deficiency, which needs to be treated in symptomatic patients. However, symptoms can already occur at ferritin levels of < 100 ng/ml and treatment must be adapted to the individual patient. Iron supplementation is only indicated in symptomatic patients diagnosed with iron deficiency whose quality of life is affected. It is important to treat iron deficiency together with its causes or risk factors. For example, blood loss from hypermenorrhea should be reduced. Women also need to receive information about the benefits of an iron-rich diet. If oral treatment with iron supplements is ineffective, parenteral iron administration is recommended. PMID- 26633903 TI - Joint Statement by the Gynecologic Radiology Study Group (AGR), the German Society for Gynecology and Obstetrics (DGGG), the German Society for Senology (DGS) and the Professional Association of Gynecologists (BVF). PMID- 26633904 TI - An efficacy trial of 'Steps to Your Health', a health promotion programme for adults with intellectual disability. AB - OBJECTIVE: Although there are evaluation and effectiveness studies of health promotion interventions for adults with intellectual disabilities (ID), randomized efficacy trials of such interventions are lacking. DESIGN: A randomized active control intervention trial. SETTING: The participants attended the health promotion classes in local disability agency service facilities. Method: We enrolled 443 individuals and randomly assigned them to one of two eight-week participatory classes. The 'Steps to Your Health' (STYH) classes emphasized moderate to vigorous physical activity (MVPA), healthy eating and body mass index (BMI) reduction. The control intervention focused on hygiene and safety. RESULTS: We did not find a statistically significant difference in mean MVPA or BMI change between completers of the STYH group compared to the control group one year after the intervention was completed. We did find that participation in STYH classes had a non-significant association with odds of reduction in BMI (odds ratio [OR] 2.87, 95% confidence interval [CI] 0.91-9.11) and completers who lived in group homes were more likely than their counterparts who lived with families or in apartments to decrease their BMI (OR 4.61; 95% CI 1.14-18.64). CONCLUSIONS: This trial did not demonstrate a significant effect of STYH participation on change in mean minutes of MVPA or mean BMI 12 months after classes ended, although there was a non-significant association with odds of reduction of BMI (p = 0.07). This study has implications for design of intervention studies in people with intellectual disability (ID). PMID- 26633906 TI - Loss of gamma-tubulin, GCP-WD/NEDD1 and CDK5RAP2 from the Centrosome of Neurons in Developing Mouse Cerebral and Cerebellar Cortex. AB - It has been recently reported that the centrosome of neurons does not have microtubule nucleating activity. Microtubule nucleation requires gamma-tubulin as well as its recruiting proteins, GCP-WD/NEDD1 and CDK5RAP2 that anchor gamma tubulin to the centrosome. Change in the localization of these proteins during in vivo development of brain, however, has not been well examined. In this study we investigate the localization of gamma-tubulin, GCP-WD and CDK5RAP2 in developing cerebral and cerebellar cortex with immunofluorescence. We found that gamma tubulin and its recruiting proteins were localized at centrosomes of immature neurons, while they were lost at centrosomes in mature neurons. This indicated that the loss of microtubule nucleating activity at the centrosome of neurons is due to the loss of gamma-tubulin-recruiting proteins from the centrosome. RT-PCR analysis revealed that these proteins are still expressed after birth, suggesting that they have a role in microtubule generation in cell body and dendrites of mature neurons. Microtubule regrowth experiments on cultured mature neurons showed that microtubules are nucleated not at the centrosome but within dendrites. These data indicated the translocation of microtubule-organizing activity from the centrosome to dendrites during maturation of neurons, which would explain the mixed polarity of microtubules in dendrites. PMID- 26633905 TI - Increased Expression of Osteopontin in the Degenerating Striatum of Rats Treated with Mitochondrial Toxin 3-Nitropropionic Acid: A Light and Electron Microscopy Study. AB - The mycotoxin 3-nitropropionic acid (3NP) is an irreversible inhibitor that induces neuronal damage by inhibiting mitochondrial complex II. Neurodegeneration induced by 3NP, which is preferentially induced in the striatum, is caused by an excess influx and accumulation of calcium in mitochondria. Osteopontin (OPN) is a glycosylated phosphoprotein and plays a role in the regulation of calcium precipitation in the injured brain. The present study was designed to examine whether induction of OPN protein is implicated in the pathogenesis of 3NP-induced striatal neurodegeneration. We observed overlapping regional expression of OPN, the neurodegeneration marker Fluoro-Jade B, and the microglial marker ionized calcium-binding adaptor molecule 1 (Iba1) in the 3NP-lesioned striatum. OPN expression was closely associated with the mitochondrial marker NADH dehydrogenase (ubiquinone) flavoprotein 2 in the damaged striatum. In addition, immunoelectron microscopy demonstrated that OPN protein was specifically localized to the inner membrane and matrix of the mitochondria in degenerating striatal neurons, and cell fragments containing OPN-labeled mitochondria were also present within activated brain macrophages. Thus, our study revealed that OPN expression is associated with mitochondrial dysfunction produced by 3NP induced alteration of mitochondrial calcium homeostasis, suggesting that OPN is involved in the pathogenesis of striatal degeneration by 3NP administration. PMID- 26633907 TI - Coated Glass Slides TACAS Are Applicable to Heat-Assisted Immunostaining and In Situ Hybridization at the Electron Microscopy Level. AB - We performed pre-embedding electron microscopic study for visualizing the antigen and genome of severe fever with thrombocytopenia syndrome (SFTS) virus in the cytoplasm of macrophages of the human splenic red pulp, both requesting preheating treatment of sections. To pursue this, coated glass slides with unique characteristics are needed. Namely, during staining they must prevent detaching off sections, but after staining the sections must be transferred to epoxy resin. Aminopropyltriexoxysilane-coated glass slides, widely used for immunostaining, were resistant to transfer to epoxy resin. In contrast, coated glass slides designated as Thinlayer Advanced Cytology Assay System (TACAS) were suitable for this purpose. The technique is also applicable to the coated glass slide requiring cytology practice, in which immunocytochemical evaluation is needed after cell transfer to another glass slide. PMID- 26633908 TI - Intensive Immunofluorescence Staining Methods for Low Expression Protein: Detection of Intestinal Stem Cell Marker LGR5. AB - Leucine-rich repeat-containing G-protein coupled receptor 5, or LGR5, is a molecule that recognizes stem cells in multiple organs and also in colon cancer. Previously, we have developed monoclonal antibodies specific to LGR5 protein that can be used for immunofluorescence staining, but because a very low level of LGR5 protein is expressed, the visualization technique needed to be enhanced. To develop procedures to detect LGR5 protein in various specimens by immunofluorescence staining, we evaluated the Alexa-labeled streptavidin biotin (LSAB), the Qdot, and the tyramide methods. The detection sensitivity was highest in the tyramide method followed by the Qdot method, whereas subcellular localization of the protein was most clear in the Qdot method, because the Qdot method gave a high S/N ratio that could show a low background. Thus, the tyramide method is superior to the Q-dot method for intensifying the signal of a low expression protein, and the Qdot method is superior to the tyramide method for identifying the subcellular localization of the target protein. The results of the present study will be helpful in providing more insight into the pathophysiological roles of LGR5-positive cancer stem cells and in developing therapeutic approaches for targeting cancer stem cells. PMID- 26633909 TI - Building a Playground: General Guidelines for Creating Educational Web Sites for Children. AB - PURPOSE: Since 2004, the number of children online has increased 18%, compared with a 10% increase in total users. Not only do children represent a growing segment of Internet users, much of what they do online has a specific purpose: education. To help technical communicators create educational Web sites for children, we offer a set of guidelines to direct the design process. METHOD: Nine children participated in a usability test of the CARES Playground, an educational Web site geared toward 7- to 9-year-olds. The site was designed by a group of graduate students in professional writing based on a review of the (admittedly limited) literature dealing with designing Web sites for children. This paper matches common themes from existing literature to the results of the usability tests. RESULTS: Since all the information on designing Web sites for children emerged from the literature of designing Web sites for adults, the themes of navigation, appearance, and content are not unfamiliar. However, the interpretation of those common issues for children-as well as the children's reaction to them-may be surprising. CONCLUSION: Technical communicators need to be conscious and deliberate when designing Web sites for children. To ensure that educational Web sites are able to meet their learning goals, careful consideration of children's developmental abilities and Web preferences must be considered. We present several guidelines as a starting point, though further research is needed to confirm and expand upon them. PMID- 26633910 TI - MINDING THEIR OWN BUSINESS: MARRIED WOMEN AND CREDIT IN EARLY EIGHTEENTH-CENTURY LONDON. AB - Taking a micro-historical approach, this paper explores the business activities of Elizabeth Carter and Elizabeth Hatchett, two married women who operated together as pawnbrokers in London in the early decades of the eighteenth century. Based on a protracted inheritance dispute through which their extensive dealings come to light, the discussion assesses married women's lending and investment strategies in a burgeoning metropolitan economy; the networks through which women lenders operated; and the extent to which wives could sidestep the legal conventions of 'coverture' which restricted their ownership of moveable property. It is argued that the moneylending and asset management activities of women like Carter and Hatchett were an important part of married women's work that did not simply consolidate neighbourhood ties but that placed them at the heart of the early modern economy. PMID- 26633911 TI - Social Movements, Organizations, and Fields: a Decade of Theoretical Integration. PMID- 26633912 TI - A Mastery Rubric: guiding curriculum design, admissions and development of course objectives. AB - This article describes a 'Mastery Rubric' (MR) used to design both the curriculum and the assessments in a new two-year certificate programme intended to train physicians in clinical research skills. The MR for clinical research skills is built around a set of core research skills: critical review of literature; articulation of research objective; development of research design; development of analysis plan; implementation of the study; implementation of the analysis plan and presentation of results. Four distinct levels of performance are described for each skill: beginning, novice, competent and proficient. This rubric outlines and provides a path to mastery of the clinical research skills the certificate programme was designed and funded to target. Using the rubric to design the curriculum ensures that courses will provide instruction in key domains, promotes assessment that demonstrates development in the target skills and knowledge, and encourages reflection and cognitive self-monitoring in the students. It is a flexible, criterion-referenced definition of 'success' for students as well as the programme itself. The criteria are characterised in terms of the skills, habits of mind and organisational principles that can foster excellence in clinical research, but the approach can be generalised. PMID- 26633913 TI - Image-based Reconstruction of 3D Myocardial Infarct Geometry for Patient Specific Applications. AB - Accurate reconstruction of the three-dimensional (3D) geometry of a myocardial infarct from two-dimensional (2D) multi-slice image sequences has important applications in the clinical evaluation and treatment of patients with ischemic cardiomyopathy. However, this reconstruction is challenging because the resolution of common clinical scans used to acquire infarct structure, such as short-axis, late-gadolinium enhanced cardiac magnetic resonance (LGE-CMR) images, is low, especially in the out-of-plane direction. In this study, we propose a novel technique to reconstruct the 3D infarct geometry from low resolution clinical images. Our methodology is based on a function called logarithm of odds (LogOdds), which allows the broader class of linear combinations in the LogOdds vector space as opposed to being limited to only a convex combination in the binary label space. To assess the efficacy of the method, we used high-resolution LGE-CMR images of 36 human hearts in vivo, and 3 canine hearts ex vivo. The infarct was manually segmented in each slice of the acquired images, and the manually segmented data were downsampled to clinical resolution. The developed method was then applied to the downsampled image slices, and the resulting reconstructions were compared with the manually segmented data. Several existing reconstruction techniques were also implemented, and compared with the proposed method. The results show that the LogOdds method significantly outperforms all the other tested methods in terms of region overlap. PMID- 26633914 TI - Initial testing of a 3D printed perfusion phantom using digital subtraction angiography. AB - Perfusion imaging is the most applied modality for the assessment of acute stroke. Parameters such as Cerebral Blood Flow (CBF), Cerebral Blood volume (CBV) and Mean Transit Time (MTT) are used to distinguish the tissue infarct core and ischemic penumbra. Due to lack of standardization these parameters vary significantly between vendors and software even when provided with the same data set. There is a critical need to standardize the systems and make them more reliable. We have designed a uniform phantom to test and verify the perfusion systems. We implemented a flow loop with different flow rates (250, 300, 350 ml/min) and injected the same amount of contrast. The images of the phantom were acquired using a Digital Angiographic system. Since this phantom is uniform, projection images obtained using DSA is sufficient for initial validation. To validate the phantom we measured the contrast concentration at three regions of interest (arterial input, venous output, perfused area) and derived time density curves (TDC). We then calculated the maximum slope, area under the TDCs and flow. The maximum slope calculations were linearly increasing with increase in flow rate, the area under the curve decreases with increase in flow rate. There was 25% error between the calculated flow and measured flow. The derived TDCs were clinically relevant and the calculated flow, maximum slope and areas under the curve were sensitive to the measured flow. We have created a systematic way to calibrate existing perfusion systems and assess their reliability. PMID- 26633915 TI - High Serum Level of beta2-Microglobulin in Late Posttransplant Period Predicts Subsequent Decline in Kidney Allograft Function: A Preliminary Study. AB - BACKGROUND: Identification of patients at risk for kidney allograft (KAG) failure beyond the first posttransplant year is an unmet need. We aimed to determine whether serum beta-2-microglobulin (beta2MG) in the late posttransplant period could predict a decline in KAG function. METHODS: We assessed a value of single measurement of serum beta2MG at one to seventeen years after transplantation in predicting the estimated glomerular filtration rate (eGFR) and the decline in eGFR over a period of two years in 79 recipients of KAG. RESULTS: At baseline serum beta2MG concentration was higher (P = 0.011) in patients with allograft dysfunction: 8.67 +/- 2.48 ug/mL versus those with satisfactory graft function: 6.67 +/- 2.13 ug/mL. Higher beta2MG independently predicted the lower eGFR, the drop in eGFR by >=25% after one and two years, and the value of negative eGFR slope. When combined with proteinuria and acute rejection, serum beta2MG had excellent power in predicting certain drop in eGFR after one year (AUC = 0.910). In conjunction with posttransplant time serum beta2MG had good accuracy in predicting certain eGFR drop after two years (AUC = 0.821). CONCLUSIONS: Elevated serum beta2MG in the late posttransplant period is useful in identifying patients at risk for rapid loss of graft function. PMID- 26633916 TI - Tanzanian men's gender attitudes, HIV knowledge, and risk behaviours. AB - This study uses data from the 2004-05 Tanzanian Demographic and Health Survey to examine whether men's traditional gender role attitudes contribute to their sexual risk behaviours for HIV. Logistic regression with random effects were used to analyze effects on risk behaviours at last sex (partners being drunk and condom use) with the three most recent sexual relationships. Men's traditional gender attitudes increased risky sexual behaviours (e.g., not using a condom) even when they had accurate knowledge regarding HIV risks. The impact of men's gender attitudes and HIV knowledge on risky sexual behaviours did not vary by relationship type. Unexpectedly, condom use was more likely when either partner was drunk compared to neither being drunk, though the protective impact of HIV knowledge remained. Overall, these findings suggest that traditional gender attitudes present barriers to preventing HIV/AIDS that even increased knowledge about HIV risks may not overcome. PMID- 26633917 TI - The relationship between distribution of body fat mass and carotid artery intima media thickness in Korean older adults. AB - [Purpose] The aim of this study was to examine the relationships between the amount and distribution of body fat and the carotid intima-media thickness to explore whether coronary artery disease risk may be mediated through effects on the amount of fat mass in older adults. [Subjects and Methods] A total of 200 elderly females was participated. The percentage of body fat mass was measured by the bioelectrical impedance analysis method, and the carotid intima-media thickness was measured by B-mode ultrasound. Analysis of covariance was performed to assess independent associations between the four categories of percentage of body fat mass and the carotid intima-media thickness after multivariate adjustment. Logistic regression analyses were utilized to calculate odds ratios and 95% confidence intervals for examining independent associations between percentage of body fat mass and the estimated risk of coronary artery disease. [Results] Analysis of covariance showed that the carotid intima-media thickness was significantly thick in both obesity and overweight groups. When multivariate adjusted OR for the estimated risk of coronary artery disease, the odds ratios for the obesity and overweight groups were 3.0 (95% confidence interval, 1.1 to 8.7) and 2.5 (95% confidence interval, 1.0 to 6.1), respectively. [Conclusion] This study demonstrates that elderly females with a high body fat mass are more likely to have the estimated risk of CAD than who fit body fat mass in elderly female. PMID- 26633918 TI - Retraction: Effect of exercise at light loads with manipulative resistance on infraspinatus, trapezius (upper fiber) and deltoid (middle fiber) muscle activities in shoulder joint elevation. AB - [This retracts the article on p. 627 in vol. 27.]. PMID- 26633919 TI - Gender Differences in the Behavioral Symptom Severity of Prader-Willi Syndrome. AB - OBJECTIVES: This study measured gender differences in Prader-Willi syndrome (PWS) in regard to the severity of behavioral symptoms. METHODS: The Food Related Problem Questionnaire (FRPQ), the Aberrant Behavior Checklist Japanese Version, the Childhood Routines Inventory, the Pervasive Developmental Disorders Autism Society Japan Rating Scale, and Japanese ADHD-RS were administered to PWS patients (45 males aged 6 to 58 and 37 females aged 6 to 45). To examine the effects that gender and genotype have on the severity of each symptom, two-way ANOVAs were conducted. RESULTS: Significant interactions were found only in regard to FRPQ scores, such as FRPQ total score (F(1, 78) = 8.43, p < 0.01). The FRPQ of male deletion (DEL) individuals was higher than that of female DEL and male mUPD. The FRPQ of male maternal uniparental disomy (mUPD) was lower than that of female mUPD. CONCLUSIONS: In terms of problem behaviors, routines, autistic behaviors, and hyperactivity, no significant differences were found. Food-related behaviors in DEL were more severe in males, although those in mUPD were less severe in males. PMID- 26633921 TI - Is Public Health System in LMICs Ready to Respond to the Ever Growing NCDs? PMID- 26633920 TI - Identification of Anti-Long Chain Saturated Fatty Acid IgG Antibodies in Serum of Patients with Type 2 Diabetes. AB - High levels of serum long chain saturated fatty acids (LCSFAs) have been associated with inflammation in type 2 diabetes. Dietary SFAs can promote inflammation, the secretion of IgG antibodies, and secretion of the proinflammatory cytokine IL-1beta. This study characterizes anti-LCSFA IgG antibodies from patients with type 2 diabetes. Serum samples from several cohorts with type 2 diabetes were analyzed for the presence of anti-LCSFA IgG, the cytokine IL-1beta, and nonesterified fatty acids. Anti-LCSFA IgG was isolated from patient samples and used for in vitro characterization of avidity and specificity. A cohort participating in En Balance, a diabetes health education program that improved diabetes management, tested positive for anti-LCSFA IgG. Following the 3-month program, the cohort showed a significant reduction in anti LCSFA IgG levels. Anti-LCSFA antibodies isolated from these patients demonstrated high avidity, were specific for long chain SFAs, and correlated with serum fatty acids in patients with managed type 2 diabetes. Interestingly, anti-LCSFA IgG neutralized PA-induced IL-1beta secretion by dendritic cells. Our data shows that nonesterified SFAs are recognized by IgG antibodies present in human blood. The identification of anti-LCSFA IgG antibodies in human sera establishes a basis for further exploration of lipid induced immune responses in diabetic patients. PMID- 26633922 TI - Socio-Economic, Demographic and Lifestyle Determinants of Overweight and Obesity among Adults of Northeast India. AB - BACKGROUND: Overweight and obesity are the accumulation of high body adiposity, which can have detrimental health effects and contribute to the development of numerous preventable non-communicable diseases. This study aims to evaluate the effect of socio-economic, demographic and lifestyle factors on the prevalence of overweight and obesity among adults belonging to the Rengma-Naga population of North-east India. METHODS: This cross-sectional study was conducted among 826 Rengma-Naga individuals (males: 422; females: 404) aged 20-49 years from the Karbi Anglong District of Assam, using a two-stage stratified random sampling. The socio-economic, demographic and lifestyle variables were recorded using structured schedules. Height and weight were recorded and the Body Mass Index (BMI) was calculated using standard procedures and equation. The WHO (2000) cut off points were utilized to assess the prevalence of overweight (BMI >=23.00 24.99 kg/m(2)) and obesity (BMI >=25.00 kg/m(2)). The data were analysed using ANOVA, chi-square analysis and binary logistic regression analysis using SPSS (version 17.0). RESULTS: The prevalence of overweight and obesity were 32.57% (males: 39.34%; females: 25.50%) and 10.77% (males: 9.95%; females: 11.63%), respectively. The binary logistic regression analysis showed that age groups (e.g., 40-49 years), education (>=9(th) standard), part-time occupation and monthly income (>=Rs.10000) were significantly associated with overweight and obesity (p<0.05). CONCLUSIONS: Age, education occupation and income appear to have higher associations with overweight and obesity among adults. Suitable healthcare strategies and intervention programmes are needed for combating such prevalence in population. PMID- 26633923 TI - Sexual and Contraceptive Practices among Female Undergraduates in a Nigerian Tertiary Institution. AB - BACKGROUND: The reproductive health of adolescents and young women is integral to the wellbeing of a society. This study was carried out to determine current sexual practices and contraceptive usage among female undergraduate students in a Southwest Nigerian tertiary institution. METHODS: It was a cross-sectional questionnaire based survey of female university undergraduates. Pre-tested questionnaire was used to elicit information on socio-demographic variables and sexual and contraceptive practices. Frequency tables were generated and univariate and multivariate logistic regressions were used to determine factors that influenced sexual and contraceptive practices. SPSS software version 16.0 was used for analysis. RESULTS: Of 350 students sampled, 306 completed the questionnaire. One hundred and eighty six (60.8%) students were currently sexually active. The mean age of sexual debut was 19.11 years. Sixty-six (35.5%) had more than one sexual partners. Contraceptive knowledge was 100%, but consistent use was 34.4%. A third of the respondents had sex for material rewards and/or under the influence of alcohol and recreational drugs. Students who were less than 20 years old (Adjusted OR: 3.52; 95%CI=2.10-6.82) were more likely to be sexually active while those from polygamous/separated families (Adjusted OR: 0.32; 95% CI=0.18-0.58) were less likely to be sexually active. CONCLUSION: There is a high level of sexual activity and low contraceptive use among female undergraduate students in Southwest Nigeria. More reproductive health education and promotion is necessary to safeguard their sexual health. PMID- 26633924 TI - Impact of Oral Health on The Quality of Life of Elementary School Teachers. AB - BACKGROUND: The success of preventive school health programs is largely dependent on teachers who are role models to pupils and pivotal to implementation. It is therefore important to understand the perception of school teachers about the impact of oral health on their daily activities. The aim of this study was to assess oral health related quality of life of elementary school teachers by evaluating the impact of oral conditions like dental caries and periodontal disease on their daily performances and school work. METHODS: This was a descriptive cross sectional study in which 407 teachers were selected through multistage random sampling technique. Data were collected with structured interviewer-administered Oral Impact on Daily Performances (OIDP) questionnaires and by clinical oral examinations. Data were collated and analysed with SPSS. RESULTS: The prevalence of reporting of impacts on daily performances was 39.1% with eating and enjoying food being the most commonly impacted activity. Impacts on daily performances were more likely to be reported by teachers with better education (p = 0.019). Teachers with caries had higher odds of reporting impacts as a result of oral health status (CI: 1.04, 5.64, p = 0.040). The severity of periodontal disease found on clinical examination was not related to reporting of impacts on quality of life (p > 0.05). CONCLUSIONS: The oral health status of school teachers impacted significantly on their daily performance and school work when they experienced pain. Painless but highly prevalent oral lesions were, however, not perceived to influence their quality of life. PMID- 26633925 TI - Cytopathological Examination and Epidemiological Study of Cervicitis in Commercial Sex Workers (CSWs) in Coal City (Enugu), Nigeria. AB - BACKGROUND: llicit sexual behavior by commercial sex workers (CSW) may have a disproportionate impact on the reproductive health of a woman that often leads to cervicitis. This study aimed at examining the cytopathology, patterns, prevalence and burden of cervicitis in CSW in Enugu metropolis, Nigeria. METHODS: Cervical smear was collected from the endocervix of about one hundred and eighteen (n=118) CSWs between November, 2014 and February, 2015 using the liquid-based cytology (LBC) method. Smears were processed and stained by the modified Papanicolaou method. Leftover samples were tested for sexually transmitted diseases, especially N. gonorrhea, and C. trachomatis using ligase chain reaction and nucleic acid amplification test. A randomized sampling design was used for data collection. RESULTS: Cytopathological examination of cervicitis in CSWs showed a moderate infection, and moderately severe to chronic inflammatory cells. The epidemiological study revealed that acute cervicitis are predominant 7(5.9%) and 2(1.7%) are chronic cervicitis. The prevalence of CSWs living with cervicitis in Enugu, Nigeria (7.6%), is significantly affected by age and working duration as CSWs. Also, Chlamydia trachomatis is the solely associated pathogen implicated in cervicitis group (n=9). Candidiasis infection (n=12) and T. vaginalis (n=3) are observed in non-cervicitis group (n=109) while the association between C. trachomatis and cervicitis infection is statistically significant (P= 0.0221). CONCLUSIONS: Acute cervicitis was prevalent with a preponderance of 4:1 in CSWs in Enugu, Nigeria. C. trachomatis infection was the most prevalent etiologic agent of cervicitis in this study. Further molecular study of LBC smears from CSWs using PCR is strongly recommended. PMID- 26633926 TI - Motivation and Factors Affecting It among Health Professionals in the Public Hospitals, Central Ethiopia. AB - BACKGROUND: Motivation is an individual's degree of willingness to exert and maintain an effort towards organizational goals. This study assessed motivational status and factors affecting it among health professionals in public hospitals of West Shoa Zone, Oromia Region. METHOD: Facility based cross-sectional survey was employed. All health professionals who served at least for 6 months in Ambo, Gedo and Gindeberet hospitals were included. Self-administered Likert scale type questionnaire was used. Data were analyzed using SPSS version 20. Mean motivation calculated as percentage of maximum scale score was used. Bivariate and multiple linear regression analyses were done to see the independent effects of explanatory variables. RESULTS: The overall motivation level of health professionals was 63.63%. Motivation level of health professionals varied among the hospitals. Gindeberet Hospital had lower motivation score as compared to Ambo Hospital (B = -0.54 and 95% CI; -0.08,-0.27). The mean motivation score of health professionals who got monthly financial benefit was significantly higher than those who did not (B = 0.71 and 95% CI; 0.32, 1.10). Environmental factors had higher impact on doctors' motivation compared to nurses' (B = 0.51 and 95% CI; 0.10, 0.92). Supervisor-related factors highly varied in motivation relative to other variables. CONCLUSIONS: Motivation of health professionals was affected by factors related to supervisor, financial benefits, job content and hospital location. Efforts should be made to provide financial benefits to health professionals as appropriate especially, to those who did not get any such benefits. Officially recognizing best performance is also suggested. PMID- 26633927 TI - The Relationship Between Life Course Factors, Parental Demographics, Dental Coping Beliefs and Its Influence on Adolescents Dental Visit: a Cross Sectional Study. AB - BACKGROUND: Oral Disease is a multifactorial one that includes behavioral and cultural components, and the severity of the disease depends on regularity of dental visits. The purpose of the study was to evaluate the relationship between parental demographics, life course factors, dental coping beliefs with the recent dental attendance among adolescents in Udupi Taluk. METHODS: Three hundred and fifty adolescents aged 16-19 years from four randomly selected schools in Udupi Taluk participated in this cross sectional study. Information was obtained regarding their parental demographics, their early life course, dental coping beliefs and recent dental attendance. Bivariate followed by multiple logistic regression analysis was performed to elicit variables which predict recent dental attendance. RESULTS: Out of the 324 adolescents who completed the questionnaire, 25.3% reported visiting a dentist within a period of one year. Childhood dental visit, childhood dental experience, housing, internal and external locus of control and self-efficacy were significantly associated with recent dental visit (p<0.05). Participants who lived in cement/brick houses were 4.3 times more likely to visit a dentist within one year compared to those living in hut/mud/combined houses (p<0.05). Adolescents with lower external (OR= 0.11, P<0.003) and low internal (OR=0.05, P<0.001) locus of control had lower odds of visiting a dentist within a year when compared with those having higher locus of control. CONCLUSION: Childhood financial hardships, childhood dental visits and experiences and dental coping beliefs affect dental attendance pattern during adolescence. These factors should be considered while tailoring interventions to promote the oral health and dental attendance behaviors of adolescents. PMID- 26633928 TI - Febrile Convulsion among Hospitalized Children Aged Six Months to Five Years and Its Association With Haemoglobin Electrophoretic Pattern. AB - BACKGROUND: Febrile convulsion and sickle cell disease are common in tropical countries and both are associated with significant morbidity and mortality. Worldwide, Nigeria has the highest prevalence of sickle cell disease. However, there is a dearth of knowledge on the haemoglobin electrophoresis in patients with febrile convulsions. METHODS: This was a hospital based, descriptive, cross sectional study of the relationship between haemoglobin genotype and febrile convulsion at the University of Ilorin Teaching Hospital over a period of 12 months. A self-designed pretested questionnaire was administered on the subjects, and necessary examinations and investigations were conducted. RESULTS: Of a total of 1675 children admitted into the emergency paediatric unit during the study period, children aged 6 months-5 years that presented with febrile convulsions were 167(10%). Of this, 1,212 were aged 6 months-5 years. Thus, the age specific, hospital-based prevalence was 13.8%. The M:F was 1.1:1. Their Haemoglobin genotype distribution was AA 131(78.4%), AS 23(13.8%), AC 6(3.6%), SS 6(3.6%), and 1(0.6%) SC. The mean age of the sickle cell disease patients was higher at 46.0+/-13.5 months compared to 29.2+/-15.4 months in the non-sickle cell disease patients (p=0.005). The mean packed cell volume in subjects with sickle cell anaemia was 8.8+/-1.5%; the only case of haemoglobin SC had packed cell volume of 20%, while the non-sickle cell disease patients had a normal PCV. Malaria was present in 80.4% of them. CONCLUSION: Febrile convulsion remains a common cause of hospitalisation. It is uncommon in haemoglobin SS where severe anaemia is always an accompanying derangement. The packed cell volume is nearly normal in children with normal haemoglobin genotype. PMID- 26633929 TI - Clinical and Biomarkers Difference in Prepartum and Postpartum Eclampsia. AB - BACKGROUND: There is a large body of literature which assessed the incidence and risk factors of eclampsia, but little was done in assessing the association of clinical features and biological markers with prepartum and postpartum eclampsia. METHODS: A total of 361 eclamptic women admitted to three teaching hospitals between 2008 and 2013 were included in this analysis. A comparative analysis was done for several clinical and biological variables to assess their association with prepartum and postpartum eclampsia. RESULTS: The overall incidence of eclampsia was 1.2% (prepartum 71% and postpartum 29%). The majority of women with prepartum eclampsia were young, primigravida, more hypertensive, symptomatic and proteinuric. Conversely, the majorities of the women with post-partum eclampsia were adult, multiparous, carrying pregnancy to term, anemic, thrombocytopenic, and with hepatic dysfunction. The commonest severity symptom (headache) was less common in postpartum eclamptic women. CONCLUSION: The incidence of eclampsia was among the highest in the world. And, the analysis has shown that the clinical and biochemical spectrum of prepartum and postpartum eclampsia were apparently different. The majority of the women who developed postpartum eclampsia were multiparous and adult. Derangement of biomarkers was also more common in women with postpartum eclampsia. PMID- 26633930 TI - The Ahmed Glaucoma Valve in Refractory Glaucoma: Experiences in Southwest Ethiopia. AB - BACKGROUND: The management of refractory glaucoma is a challenging task for any glaucoma surgeon. This study is aimed to evaluate the efficacy of Ahmed Glaucoma Valve implantation in refractory glaucomas in South-West Ethiopia. METHODS: A retrospective review was conducted on the charts of consecutive patients treated with Ahmed glaucoma valve implantation at Jimma University Specialized Hospital between August 2012 and August 2014. Success was defined as Intraocular Pressure (IOP) less than 22 mm Hg and greater than 5mm Hg at 6 months, with at least 30% reduction from baseline, without medical therapy (complete success) or either with or without medication (qualified successes). RESULTS: A total of 12 eyes of 11 patients were included. The mean age of patients was 40.7 (SD= 19.0) years; 63.6% of them were males. The main types of glaucoma were pseudoexfoliative (3 eyes), uveitic (2 eyes), chronic angle closure (2 eyes) and Juvenile Open Angle (JOAG) (2 eyes). The mean IOP was reduced from preoperative level (32.75+/-7.14 mmHg) to (15.75 +/-4.35 mmHg) at six postoperative months, (P<0.001); 66.7% eyes had complete successes while 83.3% had qualified success. Intra-operative complications were encountered in 2(16.7%) eyes, while 5/12 (41.7%) eyes had post operative complications-hypotony (one with choroidal effusion) and progression of cataract in 2 eyes each. Hypertensive phase was diagnosed in 2(16.7%) eyes. CONCLUSION: The Ahmed glaucoma valve implant appears to be effective and relatively safe for treating complicated glaucomas with success rate comparable with those reported from other studies. KEYWORDS: Ahmed glaucoma valve, refractory glaucoma, complications, Ethiopia. PMID- 26633931 TI - Intraoperative Use of Epsilon Amino Caproic Acid and Tranexamic Acid in Surgeries Performed Under Cardiopulmonary Bypass: a Comparative Study To Assess Their Impact On Reopening Due To Postoperative Bleeding. AB - BACKGROUND: Open heart surgeries under cardiopulmonary bypass are associated with excessive perioperative bleeding that often requires reoperation. Antifibrinolytics like epsilon aminocaproic acid and tranexamic acid are widely used to control bleeding. There are limited studies primarily showing the impact of these drugs on the incidence of reopening following open heart surgical procedures. The goal of this study was to compare incidence of reopening following open heart surgeries in patients who were administered either epsilon amino caproic acid or tranexamic acid for control of perioperative bleeding. METHODS: A prospective, randomized, controlled trial was performed among seventy eight patients of either sex in the age group of 18 to 65 years scheduled for open heart surgeries under cardiopulmonary bypass. They were randomly allocated into three groups where group A (n=26) received epsilon aminocaproic acid, group B (n=26) received tranexamic acid and group C (control group, n=26) received intravenous 0.9% normal saline. Patients had similar anaesthetic protocols, and were monitored for twenty-four hours postoperatively to assess reopening rates because of excessive bleeding. RESULTS: Two patients in each group receiving either tranexamic acid or epsilon aminocaproic acid had excessive bleeding requiring reopening after surgery whereas three patients in the control group had undergone reopening for excessive bleeding (p>0.05). CONCLUSIONS: Epsilon aminocaproic acid and tranexamic acid exhibit similar and comparable effect to placebo on incidence of reopening for excessive bleeding following open heart surgeries under cardiopulmonary bypass. PMID- 26633932 TI - Challenges in the Management of Mucopolysaccharidosis Type II (Hunter's Syndrome) in a Developing Country: a Case Report. AB - BACKGROUND: Mucopolysaccharidosis type II (Hunter's syndrome) is an X-linked chromosomal storage disorder due to deficiency of the lysosomal enzyme iduronate 2-sulfatase with patients rarely living till adulthood. Failure to identify patients early could contribute to an increased morbidity as identified in this case report. CASE DETAILS: An eight year old patient with Hunter's syndrome identified five years after disease onset with severe cardiovascular complications exemplifies the challenges faced in resource-limited countries towards making diagnosis and treatment of rare conditions. Elevated urinary glycosaminoglycans levels or a strong clinical suspicion of Hunter's syndrome, as identified in the index case, is a prerequisite for enzyme activity testing. Urinary mucopolysaccharide(MPS) level was 69.6 mg/mmol(normal range is 0.0 - 11.6 mg/mmol), and the confirming MPS electrophoresis analysis showed elevated heparan sulphate in the urine sample. Enzyme activity testing, with absent or very low iduronate-2-sulfatase activity, is diagnostic. However, the scarce availability and high cost of these tests is another constraint in making a diagnosis. CONCLUSION: Identification and management of mucopolysaccharidosis type II pose a problem in resource-constrained countries due to late presentation, lack of facility for diagnosis and treatment, cost and expertise required for the management. PMID- 26633933 TI - Cerebral Vein Thrombosis Post CABG Precipitated by Malposition of Subclavian Central Catheter in Protein C & S Deficiency Patient. AB - BACKGROUND: Cerebral venous thrombosis is an uncommon disorder in the general population. However, it has a higher frequency among patients younger than 40 years , patients with thrombophilia and patients that have foreign body such as catheter in their veins or arterial system. CASE DETAILS: In this case report, we described the clinical and radiological findings of a patient who developed cerebral vein thrombosis post coronary artery bypass grafting secondary undiagnosed protein C and S deficiency which was precipitated by malposition of subclavian central catheter into internal jugular vein. CONCLUSION: We emphasis the importance of radiological veiw of central vein catheter position just after or at the time of cannulation of central vein, not at some hours later as in our case. PMID- 26633934 TI - The Largest Reported Dissecting Aneurysm of Ascending Aorta Following Aortic Valve Replacement Accompanied by Superior Vena Cava Syndrome. AB - BACKGROUND: Ascending aortic dissection (AAD) is a rare and serious complication of aortic valve replacement. Multiple risk factors such as connective tissue disease, aortic wall thinning, aortic diameter, calcification of wall, structural features of aortic wall and associated diseases have been considered as a predisposing factor for the occurrences of AAD. Preoperative recognition of these variables with proper intra intra operative logic judgment may decrease the incidence of this complication. CASE DETAILS: We herein present a huge ascending aorta with dissecting aneurysm (AAD) with a large intra-operative diameter (15 cm) that has not been recorded in the medical literature so far. He presented with dyspnea, chest pain and amazing symptom of superior vena cava syndrome. The patient underwent open heart surgery with resection of ascending aorta aneurysm with classic Bentall operation. The post-operative period was associated with uneventful course and the patient was discharged with good condition on 12(th) post-operative day. CONCLUSION: A six months' follow-up revealed abolishment of chest pain and superior vena cava (SVC) syndrome and good prosthetic composite graft function with no recurrence of pseudo aneurysm or dissection. PMID- 26633935 TI - A Meta-Analysis of Bilateral Essure(r) Procedural Placement Success Rates on First Attempt. AB - Background: The Essure(r) (Bayer HealthCare Pharmaceuticals, Leverkusen, Germany) female sterilization procedure entails using a hysteroscope to guide a microinsert into the Fallopian tube openings. Failed placement can lead to patient dissatisfaction, repeat procedures, unintended or ectopic pregnancy, perforation of internal organs, or need for subsequent medical interventions. Additional interventions increase women's health risks, and costs for patients and the health care industry. Demonstrated successful placement rates are 63% 100%. To date, there have not been any systematic analyses of variables associated with placement rates. Objectives: The aims of this review were: (1) to estimate the average rate of successful bilateral Essure microinsert placement on first attempt; and (2) to identify variables associated with successful placement. Materials and Methods: A meta-analysis was conducted on 64 published studies and 19 variables. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, all published studies between November 2001 and February 2015 were reviewed. The studies were taken from from PubMed and Google Scholar, and by using the the "snowball" method that reported variables associated with successful bilateral Essure placement rates. Results: The weighted average rate of successful bilateral microinsert placement on first attempt was 92% (0.92 [95% confidence interval: 0.904-0.931]). Variables associated with successful placements were: (1) newer device models; (2) higher body mass index; and (3) a higher percent of patients who received local anesthesia. Conclusions: The data gathered for this review indicate that the highest bilateral success rates may be obtained by utilizing the newest Essure device model with local anesthesia in heavier patients. More standardized data reporting in published Essure studies is recommended. (J GYNECOL SURG 31:308). PMID- 26633937 TI - Erratum: Randomized comparative trial of cervical block protocols for pain management during hysteroscopic removal of polyps and myomas [Erratum]. PMID- 26633936 TI - Youth in contexts of political violence: A developmental approach to the study of youth identity and emotional security in their communities. AB - Going beyond the association between youth exposure to political violence and psychopathology, the current paper examines within-person change in youth strength of identity with their ethno-political group and youth reports of the insecurity in their communities. Conceptually related but growing out of different paradigms, both group identity and emotional insecurity have been examined as key variables impacting youth responses to threats from other group members. The goal of the current study is to review previous studies examining these two key variables and to contribute new analyses, modeling within-person change in both variables and examining co-variation in their growth The current paper uses data from 823 Belfast adolescents over 4 years. The results suggest youth are changing linearly over age in both constructs and that there are ethno political group differences in how youth are changing. The results also indicate that change in insecurity is related to strength of identity at age 18, and strength of identity and emotional insecurity are related at age 18. Implications and directions for future work in the area of youth and political violence are discussed. PMID- 26633939 TI - The Identification of Prognostic Factors and Survival Statistics of Conventional Central Chondrosarcoma. AB - Introduction. Chondrosarcomas are malignant bone tumors that are characterized by the production of chondroid tissue. Since radiation therapy and chemotherapy have limited effect on chondrosarcoma, treatment of most patients depends on surgical resection. We conducted this study to identify independent predictive factors and survival characteristics for conventional central chondrosarcoma and dedifferentiated central chondrosarcoma. Methods. A systematic literature review was performed in September 2014 using the Pubmed, Embase, and Cochrane databases. Subsequent to a beforehand-composed selection procedure we included 13 studies, comprising a total of 1114 patients. Results. The prognosis of central chondrosarcoma is generally good for the histologically low-grade tumors. Prognosis for the high-grade chondrosarcoma and the dedifferentiated chondrosarcoma is poor with lower survival rates. Poor prognostic factors in conventional chondrosarcoma for overall survival are high-grade tumors and axial/pelvic tumor location. In dedifferentiated chondrosarcoma the percentage of dedifferentiated component has significant influence on disease-free survival. Conclusion. Despite the fact that there are multiple prognostic factors identified, as shown in this study, there is a need for prospective and comparative studies. The resulting knowledge about prognostic factors and survival can give direction in the development of better therapies. This could eventually lead to an evidence-based foundation for treating chondrosarcoma patients. PMID- 26633938 TI - Homogenous Good Outcome in a Heterogeneous Group of Tumors: An Institutional Series of Outcomes of Superficial Soft Tissue Sarcomas. AB - Introduction. Superficial soft tissue sarcomas (S-STS) are generally amenable to wide excision. We hypothesized that local recurrence (LR) should be low, even without radiation therapy (RT), and sought to examine the contribution of depth to LR and OS. Methods. Patients with S-STS were retrospectively reviewed. Demographics, tumor features, treatment received, and outcomes were analyzed. Results. 103 patients were identified. Median age was 55 years; 53% of patients were female. Tumor site was 39% in trunk, 38% in the lower extremity, 14% in the upper extremity, and 9% in other locations. The most common histology was 36% leiomyosarcoma. Median tumor size was 2.8 cm (range 0.2-14 cm). Sixty-six percent of tumors were of intermediate/high grade. RT was administered preoperatively in 6% of patients and postoperatively in 15% of patients. An R0 resection was accomplished in 92%. At a median follow-up of 34.2 months (range 2.3-176), 9 patients had a LR (8.7%). Tumor size and grade were not associated with LR. OS was not associated with any tumor or patient variables on univariate analysis. Conclusions. LR was low for S-STS, even with large or high grade tumors and selective use of RT. Surgical resection alone may be adequate therapy for most patients. Superficial location seems to supersede other factors imparting a good prognosis for this group of tumors. PMID- 26633940 TI - Registered Nurse to Bachelor of Science in Nursing: nesting a fast-track to traditional generic program, teachings from nursing education in Burkina Faso. AB - BACKGROUND: Nursing education has evolved over time to fit societies' increasing care needs. Innovations in nursing education draw thorny debates on potential jeopardy in the quality, safety, and efficacy of nurse graduates. Accelerated nursing education programs have been among landmark strategic changes to address the persistent bedside nurse shortage. Despite the dearth of empirical studies in sub-Saharan Africa (SSA), the National School of Public Health of Burkina Faso has developed a State Diploma Nursing (SDN) fast-track program. With innovative features, the program is nested into the traditional SDN program. This study investigates preliminary outcomes of the implemented policy using the initial cohort that went through the program. Comparison of the traditional generic program and the fast-track one is drawn to inform nursing education policy. METHODS: The study was conducted in the three campuses delivering the SDN program. Data collected from a representative sample included 255 students from the 2006-2009 cohort, after concluding the program. Surveyed students were assessed according to the program entry status. Outcomes were measured using students' academic performance. Besides descriptive analysis, bivariate t-test, F test, and multivariate ordinary least square regression (OLSR) were employed to determine the comparative pattern between the traditional generic and the newly nested fast-track program. Students' varied statuses (private pre-registration, state pre-registration, private post-registration, and state post-registration) were kept to better outline the findings trend. RESULTS: A fifth (19.6 %) of surveyed students were enrolled in the fast-track stream from which, one third (33.7 %) consisted of post-registered students. Fast-track students comparatively achieved the best academic performance (mean: 73.68/100, SD: 5.52). Multivariate OLSR confirmed that fast-track students performed better (beta: 5.559, p < 0.001), and further informed differences between campuses. Students entry status also displayed significant differences, yet the academic performance of post registered students from traditional generic versus fast-track was similar (p = 0.409). CONCLUSION: Findings suggest that fast-track program students performed better than the ones from the traditional generic program. The uniqueness and success of this mixed nursing program experience sheds light for nursing educators engaged in policy making. The study results can serve as a crucial foundation for policymakers to alleviate the nurse shortage in SSA. PMID- 26633941 TI - Different co-sensitizations could determine different risk assessment in peach allergy? Evaluation of an anaphylactic biomarker in Pru p 3 positive patients. AB - BACKGROUND: In Italy, the nsLTP (Pru p 3) has been identified as the most frequent cause of food allergy and anaphylaxis. In order to estimate the risk assessment in peach allergy, we investigated the presence of correlations between the levels of sIgE to Pru p 3 with the severity of the clinical symptoms in two Pru p 3 positive populations from two different areas of Italy. METHODS: 133 consecutively Pru p 3 positive patients were recruited from South Italy, where the prevalence of PR-10 and profilin sensitization is low, and from North-East Italy, where the sensitization to pathogenesis related protein -10 (PR-10) and profilin is higher. Skin prick test (SPT) to peach extract and sIgE to peach panallergens were performed. RESULTS: All 133 patients were positive to SPT to peach extract and to sIgE to Pru p 3. The North-East population was simultaneously positive to Pru p 1 (42.8 %) and Pru p 4 (12.7 %), while no Southern patients were positive to PR-10 or to profilin. A significant difference in the levels of sIgE to Pru p 3 was found only in South Italy Pru p 3 + patients vs. asymptomatic patients (p = 0.01) and in mild reactions vs. severe reactions (p = 0.0008). In South Italy patients, it was also found a significant correlation between the severity of the clinical reaction and the levels of sIgE to Pru p 3 (p = 0.001). CONCLUSION: Level of sIgE to Pru p 3 indicates the possibility of development a severe food allergic reaction. Pru p 3 positive patients from different geographical areas and with different co-sensitizations to Pru p 1 and/or Pru p 4 could have a different risk assessment in peach allergy. PMID- 26633944 TI - Mental Health Outcomes of Drug Conflict Among University Students at the U.S. Mexico Border. AB - The purpose of this cross-sectional study was to investigate to what extent young adults with close ties to Mexico were at greater risk for self-reported negative mental health outcomes than comparison groups during drug-related armed conflict from 2008 through 2012, and the effect of type and number of traumatic events on mental health outcomes. Using the Harvard Trauma Questionnaire and the Hopkins Symptom Checklist, 202 university students living in the El Paso-Ciudad Juarez border region were surveyed for symptoms of depression, anxiety, and posttraumatic stress. Students with close ties to Mexico reported symptoms of anxiety and posttraumatic stress at significantly higher rates compared with those without connection to Mexico, but there was no significant difference in rates of depression. Although more than a third of participants reported experiencing 5 or more traumatic events connected with the drug war, being confined to home had the most significant effect. Frequency of traumatic events reported by students as well as rates of anxiety and posttraumatic stress symptoms were higher among students with greater connection to Mexico. Rates of clinically-significant depressive symptoms among all students were higher than expected for U.S. adults but comparable with all U.S. college students. This study presents important new data on the mental health effects of Mexico's drug war. PMID- 26633945 TI - Translating Nature to Nurture: Back to the Future for "New" Epilepsy Therapies. AB - An emerging strategy for finding new epilepsy therapies is focused on botanicals (as illustrated by recent attention to medical marijuana), given their centuries old traditions of use in treatment of convulsive seizures, contemporary anecdotal reports of efficacy in persons with epilepsy, and identification of underlying mechanisms of action that are relevant to epilepsy. Hundreds of plant extracts have been found to block seizures in acute animal seizure models, with actions that include effects on GABA receptors and voltage-gated ion channels as well as anti-inflammatory and neuroprotective effects. While existing published clinical studies of botanicals and seizure control are generally of inadequate quality to determine safety and efficacy, recent developments at the FDA may encourage sponsors to develop and commercialize botanicals for epilepsy. PMID- 26633942 TI - Gender-specific effects of intrauterine growth restriction on the adipose tissue of adult rats: a proteomic approach. AB - BACKGROUND: Intrauterine growth restriction (IUGR) may program metabolic alterations affecting physiological functions and lead to diseases in later life. The adipose tissue is an important organ influencing energy homeostasis. The present study was aimed at exploring the consequences of IUGR on the retroperitoneal adipose tissue of adult male and female rats, using a proteomic approach. METHODS AND RESULTS: Pregnant Wistar rats were fed with balanced chow, either ad libitum (control group) or restricted to 50 % of control intake (restricted group) during the whole gestation. The offspring were weaned to ad libitum chow and studied at 4 months of age. Retroperitoneal fat was analyzed by two-dimensional gel electrophoresis followed by mass spectrometry. Both male and female restricted groups had low body weight at birth and at weaning but normal body weight at adulthood. The restricted males had normal fat pads weight and serum glucose levels, with a trend to hyperinsulinemia. The restricted females had increased fat pads weight with normal glucose and insulin levels. The restricted males showed up-regulated levels of proteasome subunit alpha type 3, branched-chain-amino-acid aminotransferase, elongation 1- alpha 1, fatty acid synthase levels, cytosolic malate dehydrogenase and ATP synthase subunit alpha. These alterations point to increased proteolysis and lipogenesis rates and favoring of ATP generation. The restricted females showed down-regulated levels of L-lactate dehydrogenase perilipin-1, mitochondrial branched-chain alpha-keto acid dehydrogenase E1, and transketolase. These findings suggest impairment of glycemic control, stimulation of lipolysis and inhibition of proteolysis, pentose phosphate pathway and lipogenesis rates. In both genders, several proteins involved in oxidative stress and inflammation were affected, in a pattern compatible with impairment of these responses. CONCLUSIONS: The proteomic analysis of adipose tissue showed that, although IUGR affected pathways of substrate and energy metabolism in both males and females, important gender differences were evident. While IUGR males displayed alterations pointing to a predisposition to later development of obesity, the alterations observed in IUGR females pointed to a metabolic status of established obesity, in agreement with their increased fat pads mass. PMID- 26633946 TI - Finding the Lesser of Two Evils: Treating Refractory Status Epilepticus. PMID- 26633947 TI - PRES-ing for Answers About Long-Term Seizure Risk in Patients With Posterior Reversible Encephalopathy Syndrome. PMID- 26633948 TI - Prediction of Postsurgical Neuropsychological Outcome: Increasing Options. PMID- 26633949 TI - SUDEP Prevention "Position Statement". PMID- 26633950 TI - The Limits Between Focal and Generalized Epilepsy. PMID- 26633951 TI - Bottom-of-Sulcus Dysplasia as an Epileptic Syndrome: The Power of Clinical Correlation. PMID- 26633952 TI - Limiting Retinal Toxicity of Vigabatrin in Children With Infantile Spasms. PMID- 26633953 TI - Parent Versus Child Informants: Who Do We Choose? PMID- 26633954 TI - The Expanding SCN8A-Related Epilepsy Phenotype. PMID- 26633955 TI - Vaccination Triggers, Rather Than Causes, Seizures. PMID- 26633956 TI - 3D for Define Implantation Targets, Distinguish Eloquent Cortex, or Desist From Invasive Monitoring. PMID- 26633957 TI - "Fold Here"-Chemical Correctors in the Treatment of Epilepsy. PMID- 26633958 TI - Watch Out, No Brakes! Impaired Inhibition Results in Hyperexcitable Networks. PMID- 26633959 TI - Primed for Problems: Stress Confers Vulnerability to Epilepsy and Associated Comorbidities. PMID- 26633960 TI - The Art of Setting Limits: Lessons from GABAergic Interneuron Transplantation. PMID- 26633961 TI - Losing Touch With Your Astrocytes Can Cause Epilepsy. PMID- 26633962 TI - Clearly, Graphene is the New Gold. PMID- 26633963 TI - What Are We Communicating When We Present the Diagnosis of PNES? PMID- 26633964 TI - Navigating the maze of requirements for obtaining approval of non-interventional studies (NIS) in the European Union. AB - OBJECTIVE: The purpose of this article is to give an overview of the complexities and unexpected regulatory requirements for obtaining approval of multinational and multicentre non-interventional studies (NIS) in the European Union (EU). METHODS: The websites of national competent authorities (CAs), ethics committees (ECs) and data protection (DP) authorities were consulted to find regulations and guidance information related to the authorisation of NIS in various member states of the EU. RESULTS: Many additional hurdles, neither disclosed nor clear in the various regulations/guidances for NIS, were identified. Although approval from the CA is not needed for NIS, in many countries request of CA opinion is nevertheless recommended, prior to submission to the EC, to obtain confirmation that the planned NIS does not fall in the interventional trial category. Clinical trial insurance was required in some countries. In countries like Belgium and Italy, the multicentre NIS required the approval from a central EC and local ECs as a single central EC opinion was not considered sufficient. The EC document requirements for submission and the fees were extremely variable among all member states. Additional approvals from data protection authorities and insurance companies were required in some countries. CONCLUSIONS: The process of obtaining approval for multicentre and multinational NIS is time consuming due to lack of transparency and the different regulatory requirements among member states. The EU pharmacovigilance legislation and clinical trial regulation No 536/2014 is a step forward in providing a regulatory framework for PASS (post-authorisation safety studies) and low intervention clinical trials, but since regulation No 536/2014 excludes NIS, it will be difficult to enforce harmonization of requirements for approval of NIS among member states. PMID- 26633965 TI - Autoimmune thyroiditis associated with neuromyelitis optica (NMO). AB - Neuromyelitis optica (NMO or Devic's syndrome) is a rare relapsing demyelinating disease of the central nervous system (CNS) that mainly affects the spinal cord and optic nerves and shares many clinical and radiological features with multiple sclerosis. The association of NMO with other autoimmune diseases was reported, but very few reports described association with autoimmune thyroid disease. Early differentiation between NMO and multiple sclerosis is very important as the natural course and treatment regimens differ significantly. We report a case of a 50-year-old woman who was admitted initially with vomiting, hiccups and paraesthesias but was not diagnosed with NMO and presented with a severe progression of the disease. The patient was also diagnosed to have autoimmune thyroiditis with lymphocytic infiltration of the thyroid which progressed from hyperthyroidism to hypothyroidism. NMO diagnosis was established with seropositivity for NMO-IgG and MRI showing longitudinally extensive spinal cord lesions (3 or more spinal segments). In spite of treatment, the response was poor due to lack of early diagnosis and aggressive immunosuppressant therapy. PMID- 26633966 TI - Expression of Npas4 mRNA in Telencephalic Areas of Adult and Postnatal Mouse Brain. AB - The transcription factor neuronal PAS domain-containing protein 4 (Npas4) is an inducible immediate early gene which regulates the formation of inhibitory synapses, and could have a significant regulatory role during cortical circuit formation. However, little is known about basal Npas4 mRNA expression during postnatal development. Here, postnatal and adult mouse brain sections were processed for isotopic in situ hybridization using an Npas4 specific cRNA antisense probe. In adults, Npas4 mRNA was found in the telencephalon with very restricted or no expression in diencephalon or mesencephalon. In most telencephalic areas, including the anterior olfactory nucleus (AON), piriform cortex, neocortex, hippocampus, dorsal caudate putamen (CPu), septum and basolateral amygdala nucleus (BLA), basal Npas4 expression was detected in scattered cells which exhibited strong hybridization signal. In embryonic and neonatal brain sections, Npas4 mRNA expression signals were very low. Starting at postnatal day 5 (P5), transcripts for Npas4 were detected in the AON, CPu and piriform cortex. At P8, additional Npas4 hybridization was found in CA1 and CA3 pyramidal layer, and in primary motor cortex. By P13, robust mRNA expression was located in layers IV and VI of all sensory cortices, frontal cortex and cingulate cortex. After onset of expression, postnatal spatial mRNA distribution was similar to that in adults, with the exception of the CPu, where Npas4 transcripts became gradually restricted to the most dorsal part. In conclusion, the spatial distribution of Npas4 mRNA is mostly restricted to telencephalic areas, and the temporal expression increases with developmental age during postnatal development, which seem to correlate with the onset of activity-driven excitatory transmission. PMID- 26633967 TI - Emotion Analysis of Telephone Complaints from Customer Based on Affective Computing. AB - Customer complaint has been the important feedback for modern enterprises to improve their product and service quality as well as the customer's loyalty. As one of the commonly used manners in customer complaint, telephone communication carries rich emotional information of speeches, which provides valuable resources for perceiving the customer's satisfaction and studying the complaint handling skills. This paper studies the characteristics of telephone complaint speeches and proposes an analysis method based on affective computing technology, which can recognize the dynamic changes of customer emotions from the conversations between the service staff and the customer. The recognition process includes speaker recognition, emotional feature parameter extraction, and dynamic emotion recognition. Experimental results show that this method is effective and can reach high recognition rates of happy and angry states. It has been successfully applied to the operation quality and service administration in telecom and Internet service company. PMID- 26633968 TI - Epidemiological, Clinical, and Paraclinic Aspect of Cutaneous Sarcoidosis in Black Africans. AB - The specific objectives were to identify the epidemiology of cutaneous sarcoidosis and describe the clinical and laboratory aspects of the disease. Materials and Methods. We performed a descriptive cross-sectional study involving 24 referred cases of cutaneous sarcoidosis in 25 years (1990-2014) collected at Venereology Dermatology Department of the University Hospital of Treichville (Abidjan) both in consultation and in hospitalization. Results. The hospital frequency was one case per year. The average age was 42 years, ranging from 9 to 64. The sex ratio was 1. The shortest time interval between the appearance of the skin lesion and consultation of Dermatology Department at CHU Treichville was 3 months. The elementary lesions were represented primarily by a papule (18 cases), placard (3 cases), and nodule (2 cases) and mainly sat on the face and neck in 8 cases (38%). Extra cutaneous lesions were dominated by ganglion and respiratory involvement with 5 cases each followed by musculoskeletal damage in 3 cases. Chest radiography showed abnormality in 13 cases (54%). The pulmonary function test performed in 13 patients found 7 cases (54%) having restrictive ventilatory syndrome and 6 cases (46%) being normal. A tuberculin anergy was found in 11 cases (61%). PMID- 26633969 TI - Anti-Inflammation Property of Syzygium cumini (L.) Skeels on Indomethacin-Induced Acute Gastric Ulceration. AB - Indomethacin, nonsteroidal anti-inflammatory drug (NSAIDs), induced gastric damage and perforation through the excess generation of reactive oxygen species (ROS). Syzygium cumini (L.) Skeels is commonly used as a medicinal plant and is claimed to have antioxidant activities. The effects of Syzygium cumini (L.) Skeels aqueous extract (SCC) on antifree radical, anti-inflammation, and antiulcer of SCC on indomethacin induced acute gastric ulceration were determined in our study. Scavenging activity at 50% of SCC is higher than ascorbic acid in in vitro study. Mice treated with indomethacin revealed mucosal hemorrhagic lesion and inhibited mucus content. Pretreatment with SCC caused discernible decrease in indomethacin induced gastric lesion and lipid peroxide content. In addition, oxidized glutathione (GSSG), glutathione peroxidase (GPx), nitric oxide (NO) levels, and gastric wall mucus were restored on acute treated mice model. Indomethacin induced inflammation by activated inducible nitric oxide synthase (iNOS) and tumor necrosis factor-alpha (TNF-alpha) proinflammatory cytokines to release large amount of ROS/RNS which were ameliorated in mice pretreatment with SCC. SCC showed restoration of the imbalance of oxidative damage leading to amelioration of cyclooxygenase enzyme (COX). In conclusion, SCC acts as an antioxidant, anti-inflammation, and antiulcer against indomethacin. PMID- 26633970 TI - Association among Fibrinolytic Proteins, Metabolic Syndrome Components, Insulin Secretion, and Resistance in Schoolchildren. AB - We investigated the role of urokinase plasminogen activator (uPA) and its soluble receptors (suPAR) and plasminogen activator inhibitor-1 (PAI-1) in metabolic syndrome (MetS) components, insulin secretion, and resistance in schoolchildren. We enrolled 387 children, aged 10.3 +/- 1.5 years, in Taipei. Anthropometry, fibrinolytic proteins, MetS components, insulin secretion, and resistance were measured. Subjects were divided into normal, overweight, and obese groups. Finally, the relationship between fibrinolytic proteins and metabolic syndrome in boys and girls was analyzed. In boys, PAI-1 was positively associated with body mass index (BMI) percentile, hypertriglyceride, insulin secretion, and resistance. In girls, PAI-1 was positively associated with obesity, hypertriglyceridemia, and insulin secretion. In girls, uPA was positively associated with insulin secretion. suPAR was positively associated with high sensitivity C-reactive protein in both boys and girls, and with BMI percentile and body fat in girls. The obese boys had higher suPAR and PAI-1 levels than the normal group. The obese girls had higher uPA, suPAR, and PAI-1 than the normal group. Boys and girls with MetS had higher PAI-1. Fibrinolytic proteins, especially PAI-1, are associated with MetS components and insulin secretion in children. Fibrinolytic proteins changes were more likely to occur in girls than in boys. PMID- 26633971 TI - Evaluation of Osteogenic and Cementogenic Potential of Periodontal Ligament Fibroblast Spheroids Using a Three-Dimensional In Vitro Model of Periodontium. AB - The aim of this study was to develop a three-dimensional in vitro model of periodontium to investigate the osteogenic and cementogenic differentiation potential of the periodontal ligament fibroblast (PDLF) spheroids within a dentin membrane complex. PDLFs were cultured in both spheroid forms and monolayers and were seeded onto two biological collagen-based and synthetic membranes. Cell membrane composites were then transferred onto dentin slices with fibroblasts facing the dentin surface and further cultured for 20 days. The composites were then processed for histology and immunohistochemical analyses for osteocalcin, Runx2, periostin, and cementum attachment protein (CAP). Both membranes seeded with PDLF-derived cells adhered to dentin and fibroblasts were present at the dentin interface and spread within both membranes. All membrane-cell-dentine composites showed positive staining for osteocalcin, Runx2, and periostin. However, CAP was not expressed by any of the tissue composites. It can be concluded that PDLFs exhibited some osteogenic potential when cultured in a 3D matrix in the presence of dentin as shown by the expression of osteocalcin. However the interaction of cells and dentin in this study was unable to stimulate cementum formation. The type of membrane did not have a significant effect upon differentiation, but fibroblast seeded-PGA membrane demonstrated better attachment to dentin than the collagen membrane. PMID- 26633972 TI - Oral Health Status of the Elderly at Tonga, West Region, Cameroon. AB - Objectives. The aim of this study was to determine the oral health status of elderly persons in Tonga, West Region of Cameroon. Methodology. This is a cross sectional study of persons of at least 65 years, living in Tonga village, West Region of Cameroon. Results. A total of 183 persons aged between 65 and 94 years, mean age of 73 years +/-7 s.d., 83 (45,4%) males, and 100 (54,6%) females participated in the study. The most represented age range was 65-74 years (60.1%); 86 (47.3%) and elders above 65 constituted 1.8% of the total population. More than a third 117 (41.4%) had visible dental plaque, 117 (48,6%) had periodontal pockets >4 mm, 153 (54,1%) had teeth with total crown destruction, 70 (38.3%) had not lost a tooth, 23 (12.6%) had lost 1 tooth, 19 (10.4%) have lost at least 2 teeth, 100 (55.7%) were partially edentulous at the maxilla and 98 (53.6%) at the mandible, 2 (1.1%) were completely edentulous at the maxilla and 3 (1.6%) at the mandible, and 3.8% had removable dentures. The mean DMF index was 6.11 and 69.4% had dental caries. Risk factors to dental caries were toothbrushing and tobacco consumption while dental plaque was associated to pocket depth of 4-6 mm. Barriers to oral health care included ignorance 47 (25.7%), financial difficulties 124 (67.8%), and distance to the nearest clinic 12 (6.5%). Conclusion. The oral status of the elderly was generally poor. PMID- 26633974 TI - Improving the Measurement of Disease Activity for Patients with Rheumatoid Arthritis: Validation of an Electronic Version of the Routine Assessment of Patient Index Data 3. AB - Introduction. An electronic Routine Assessment of Patient Index Data 3 (RAPID 3) was incorporated into our electronic health records (EHRs) which did not replicate the visual presentation of the paper version. This study validated the electronic RAPID 3 compared to the paper version. Methods. Rheumatoid arthritis (RA) patients (n = 50) completed both the electronic RAPID 3 online in the week prior to and a paper version on the day of their clinic visit. Results. Paired t test showed no significant difference (p value = 0.46) between versions. Conclusion. The electronic version of RAPID 3 is valid and can be easily integrated in care of RA patients. PMID- 26633973 TI - Gastric Antral Vascular Ectasia in Systemic Sclerosis: Current Concepts. AB - Introduction. Gastric antral vascular ectasia (GAVE) is a rare entity with unique endoscopic appearance described as "watermelon stomach." It has been associated with systemic sclerosis but the pathophysiological changes leading to GAVE have not been explained and still remain uncertain. Methods. Databases Medline, Scopus, Embase, PubMed, and Cochrane were searched for relevant papers. The main search words were "Gastric antral vascular ectasia," "Watermelon Stomach," "GAVE," "Scleroderma," and "Systemic Sclerosis." Fifty-four papers were considered for this review. Results. GAVE is a rare entity in the spectrum of manifestations of systemic sclerosis with unknown pathogenesis. Most patients with systemic sclerosis and GAVE present with asymptomatic anemia, iron deficiency anemia, or heavy acute gastrointestinal bleeding. Symptomatic therapy and endoscopic ablation are the first-line of treatment. Surgical approach may be recommended for patients who do not respond to medical or endoscopic therapies. Conclusion. GAVE can be properly diagnosed and treated. Early diagnosis is key in the management of GAVE because it makes symptomatic therapies and endoscopic approaches feasible. A high index of suspicion is critical. Future studies and a critical review of the current findings about GAVE are needed to understand the role of this condition in systemic sclerosis. PMID- 26633975 TI - Jugular Venous Catheterization: A Case of Knotting. AB - A 79-year-old woman, diagnosed for cancer of the ovary, had a central catheter that was placed with difficulty through the right internal jugular vein intraoperatively. After oophorectomy, it was realized that the catheter was knotted. Thus, the central venous catheter was removed successfully using a traction technique in the operating room. Central venous catheter use may result in various complications, although it has been used as an invasive method for hemodynamic monitoring and fluid and drug infusion. Here, we present catheter knotting in a case with solutions for this complication, under literature review. PMID- 26633976 TI - Identification of New Rat Bone Marrow-Derived Population of Very Small Stem Cell with Oct-4A and Nanog Expression by Flow Cytometric Platforms. AB - Very small embryonic-like stem cells (VSELs) represent a unique rare population of adult stem cells (SCs) sharing several structural, genetic, biochemical, and functional properties with embryonic SCs and have been identified in several adult murine and human tissues. However, rat bone marrow- (BM-) derived SCs closely resembling murine or human VSELs have not been described. Thus, we employed multi-instrumental flow cytometric approach including classical and imaging cytometry and we established that newly identified population of nonhematopoietic cells expressing CD106 (VCAM-I) antigen contains SCs with very small size, expressing markers of pluripotency (Oct-4A and Nanog) on both mRNA and protein levels that indicate VSEL population. Based on our experience in both murine and human VSEL isolation procedures by fluorescence-activated cell sorting (FACS), we also optimized sorting protocol for separation of CD45(-)/Lin( )/CD106(+) rat BM-derived VSELs from wild type and eGFP-expressing rats, which are often used as donor animals for cell transplantations in regenerative studies in vivo. Thus, this is a first study identifying multiantigenic phenotype and providing sorting protocols for isolation VSELs from rat BM tissue for further examining of their functional properties in vitro as well as regenerative capacity in distinct in vivo rat models of tissue injury. PMID- 26633977 TI - Human Very Small Embryonic-Like Stem Cells Are Present in Normal Peripheral Blood of Young, Middle-Aged, and Aged Subjects. AB - The purpose of our study was to determine whether the number of human very small embryonic-like stem cells (huVSELs) would vary depending on the age of humans. HuVSELs frequency was evaluated into the steady-state (SS) peripheral blood (PB) of healthy volunteers using flow cytometry analysis. Their numbers were compared with volunteers' age. Blood samples were withdrawn from 28 volunteers (age ranging from 20 to 70 years), who were distributed among three groups of age: "young" (mean age, 27.8 years), "middle" (mean age, 49 years), and "older" (mean age, 64.2 years). Comparing the three groups, we did not observe any statistically significant difference in huVSELs numbers between them. The difference in mRNA expression for PSC markers as SSEA-4, Oct-4, Nanog, and Sox2 between the three groups of age was not statistically significant. A similar frequency of huVSELs into the SS-PB of young, middle-aged, and aged subjects may indicate that the VSELs pool persists all along the life as a reserve for tissue repair in case of minor injury and that there is a continuous efflux of these cells from the BM into the PB. PMID- 26633978 TI - Oral Allergy Syndrome: An Update for Stomatologists. AB - Oral allergy syndrome (OAS) is an allergic reaction in the oral cavity subsequent to the consumption of food such as fruits, nuts, and vegetables. It occurs mainly due to homology of proteins of pollen to the proteins of fruits and vegetables. In OAS, the immune system produces antibodies that are directed against the proteins of pollen and structurally similar proteins in food, hence, resulting in allergic symptoms limited mainly to the oral cavity. In this review, we have summarized the etiopathogenesis, clinical features, diagnosis, and management of OAS as an update for stomatologists. PMID- 26633979 TI - An investigation of cancer rates in the Argentia region, Newfoundland and Labrador: an ecological study. AB - BACKGROUND: The Argentia region of Newfoundland and Labrador, Canada, was home to a US naval base during a 40-year period between the 1940s and the 1990s. Activities on the base resulted in contamination of the soil and groundwater in the region with chemicals such as heavy metals and dioxins, and residents have expressed concern about higher rates of cancer in their community. This study investigated the rate of cancer diagnosis that is disproportionately high in the Argentia region. METHODS: Cases of cancer diagnosed between 1985 and 2011 were obtained for the Argentia region, two comparison communities, and the province of Newfoundland and Labrador. Crude and age-standardized incidence rates of cancer diagnosis were calculated and compared. The crude incidence rate was adjusted for differences in age demographics using census data, and age-standardized incidence rates were compared. RESULTS: Although the Argentia region had a higher crude rate of cancer diagnosis, the age-standardized incidence rate did not differ significantly from the comparison communities or the provincial average. Argentia has an aging population, which may have influenced the perception of increased cancer diagnosis in the community. CONCLUSIONS: We did not detect an increased burden of cancer in the Argentia region. PMID- 26633981 TI - Thyroid Cancer Epidemic: A Peril or an Alarm? PMID- 26633980 TI - Anxiety Symptoms During Adolescence Predicts Salivary Cortisol in Early Adulthood Among Blacks; Sex differences. AB - BACKGROUND: Although the link between psychological distress and altered cortisol level has been already shown; very limited information exists about this association among Black youth. OBJECTIVES: We tested sex differences in predictive role of symptoms of anxiety during adolescence on annual decline in morning salivary cortisol levels in early adulthood among Black youth. PATIENTS AND METHODS: Data came from wave 1 (year 1994), wave 6 (year 2000), and wave 7 (year 2001) of the Flint adolescent study. In this study 176 Black youth (85 males and 91 females) were followed for 7 years from mean age of 15 at baseline to 22 at the end of follow up. Linear regression was used for data analysis with change in salivary cortisol from 2000 to 2001 as the dependent variable, symptoms of anxiety, at 1994 as independent variable, age, number of employed parents, depressive symptoms and alcohol use at 1994 as controls, and sex as the moderator. RESULTS: Higher level of anxiety symptoms at 1994 was predictive of a higher decline in morning salivary cortisol from 2000 to 2001 for all youths, while the effects of baseline socio-economics, depressive symptoms, and alcohol use were controlled. Among female participants, anxiety symptoms at 1994 were predictive of a greater decline in morning salivary cortisol level from 2000 to 2001. The association was not found among males. CONCLUSIONS: Our findings suggest sex differences in the predictive role of anxiety symptoms during adolescence on the annual decline in cortisol level during early adulthood. While most research on this topic is among White middle class individuals, our findings shed more light on the longitudinal links between psychological distress and the hypothalamus-pituitary-adrenal (HPA) axis function among Black youth. PMID- 26633982 TI - Rapid Levothyroxine Absorption Testing: A Case Series of Nonadherent Patients. AB - BACKGROUND: Nonadherence to levothyroxine therapy is one cause of persistent hypothyroidism. To distinguish nonadherence from malabsorption, a levothyroxine absorption test is required. Typically, this test measures the serum free thyroxine (FT4) response to 1000 mcg of oral levothyroxine over 4 to 24 hours. Published data indicate that serum levels of FT4 are at or near their peak 2 hours after levothyroxine ingestion. OBJECTIVES: We present the successful completion of 2-hour levothyroxine absorption testing in 3 patients as a retrospective case series. PATIENTS AND METHODS: Serum levels of thyroid stimulating hormone (TSH), FT4, and free triiodothyronine (FT3) were drawn at 0, 60, and 120 minutes after 1000 mcg of oral levothyroxine. RESULTS: In all 3 cases, baseline thyroid function indicated the patients had taken their prescribed doses of levothyroxine prior to the absorption test. Despite high baseline levels both FT3 and FT4 increased during each absorption test, providing more evidence of adequate levothyroxine absorption. Subsequently, patients achieved normal TSH levels on lower doses of levothyroxine. CONCLUSIONS: Levothyroxine absorption testing over 2 hours may offer a more rapid alternative to the commonly used longer protocols to rule out malabsorption. Scheduling a levothyroxine absorption test may induce some patients to start adhering to levothyroxine therapy. PMID- 26633983 TI - Baseline Religion Involvement Predicts Subsequent Salivary Cortisol Levels Among Male But not Female Black Youth. AB - BACKGROUND: Compared to Whites, Blacks are exposed to higher levels of chronic stress in the United States. As a result, major Black-White differences exist in the baseline and response of cortisol. Yet, the potential association between baseline religiosity and subsequent cortisol levels of Blacks are not known. OBJECTIVES: In the current study we aimed to determine the association between baseline religious behaviors and daytime salivary cortisol level among male and female Black youth. MATERIALS AND METHODS: With a longitudinal design, data came from wave 1 (1994) and wave 6 (2000) of a cohort from an urban area in the Midwest of the United States. The study followed 227 Black adolescents (109 males and 118 females) for six years. Socio-demographics and religious behaviors (frequency of participation in religious activities) were measured at baseline. Base morning cortisol level at wave 6 was the outcome. We fitted a linear regression model to test the association between baseline religiosity at wave 1 and cortisol level at wave 6, while baseline age, socio-economics, and psychological symptoms were controlled. RESULTS: In the pooled sample, frequency of participation in religious activities at baseline was negatively associated with mean cortisol level at follow up (r = -0.29, P > 0.01) among all, males (r = -0.38, P > 0.01), but not females (r = -.20, P > 0.05). Frequency of participation in religious activities remained a significant predictor of subsequent cortisol level (b = -0.283, 95% CI = -.107 - -0.022) while the effect of age, socioeconomics, and psychological symptoms were controlled. We could only find such an association among male Black youth (b = -0.368, 95% CI = -0.148 - 0.024) but not female Black youth (b = -0.229, 95% CI = -.113 - 0.011). CONCLUSIONS: Religiosity has been used as a coping mechanism among Blacks. Religiosity may also be related to stress regulation among Black youth. Future studies need to test complex associations between race, sex, religiosity, chronic stress, coping, and function of hypothalamo-pituitary-adrenal (HPA). It is not known whether male Black youth who are and those who are not religious differently cope with stress associated with daily discrimination and living in disadvantaged neighborhoods. PMID- 26633984 TI - Combination therapy in type 2 diabetes mellitus: adding empagliflozin to basal insulin. AB - Type 2 diabetes mellitus (T2DM) management is complex, with few patients successfully achieving recommended glycemic targets with monotherapy, most progressing to combination therapy, and many eventually requiring insulin. Sodium glucose cotransporter 2 (SGLT2) inhibitors are an emerging class of antidiabetes agents with an insulin-independent mechanism of action, making them suitable for use in combination with any other class of antidiabetes agents, including insulin. This review evaluates a 78-week, randomized, double-blind, placebo controlled trial investigating the impact of empagliflozin, an SGLT2 inhibitor, as add-on to basal insulin in patients with inadequate glycemic control on basal insulin, with or without metformin and/or a sulfonylurea. Empagliflozin added on to basal insulin resulted in significant and sustained reductions in glycated hemoglobin (HbA1c) levels compared with placebo. Empagliflozin has previously been shown to induce weight loss, and was associated with sustained weight loss in this study. This combination therapy was well tolerated, with similar levels of hypoglycemic adverse events in the empagliflozin and placebo groups over the 78-week treatment period. Urinary tract infections and genital infections, side effects associated with SGLT2 inhibitors, were reported more commonly in the empagliflozin group; however, such events led to treatment discontinuation in very few patients. These findings suggest that, with their complementary mechanisms of action, empagliflozin added on to basal insulin may be a useful treatment option in patients on basal insulin who need additional glycemic control without weight gain. PMID- 26633985 TI - Effect of Electroacupuncture on Cell Apoptosis and ERK Signal Pathway in the Hippocampus of Adult Rats with Cerebral Ischemia-Reperfusion. AB - Background. EA therapy is a traditional therapeutic approach for alleviation of cerebral I/R-induced brain injury. We investigated the effect of EA on MCAO rat model to examine the mechanism of apoptosis in the rat hippocampus. Methods. 200 male Sprague-Dawley rats were randomly divided into sham, I/R, EA, ERK inhibitor (PD), and ERK inhibitor+EA (PD+EA) groups. Each group was subdivided into 5 groups according to different time points. Locomotor behaviors were evaluated using neurological scales and morphological examination was performed using HE staining. Apoptosis index of neural cells in local infarcted area was measured by TUNEL and p-ERK expression was detected using immunohistochemistry technique and western blot analysis. Results. Neurological deficit scores and neural apoptosis in the EA group were lower than I/R group at the same time points, respectively. At different time points, p-ERK level was increased in the ischemic hippocampal CA1 in the EA group as compared to I/R group; the increased level was increased most at 1 day, 3 days, and 1 week (p < 0.01). Conclusion. EA alleviates neurological deficit, reduces apoptosis index, and simultaneously upregulates the expression of p-ERK signal pathway in rats subjected to I/R injury. PMID- 26633986 TI - Assessment of Antifungal Activity of Bakuchiol on Oral-Associated Candida spp. AB - Bakuchiol is an active component of Psoralea glandulosa and Psoralea corylifolia, used in traditional Chinese medicine. The study aimed at investigating the antifungal activity of bakuchiol on planktonic and biofilm forms of orally associated Candida species. The antifungal susceptibility testing was determined by the broth micro dilution technique. Growth kinetics and cell surface hydrophobicity (CSH) of Candida were measured to assess the inhibitory effect of bakuchiol on Candida planktonic cells. Biofilm biomass and cellular metabolic activity were quantitatively estimated by the crystal violet (CV) and the 2,3 bis(2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino)carbonyl]-2H-tetrazolium hydroxide (XTT) assays. All Candida strains have been shown to be susceptible to bakuchiol with the MIC ranges from 12.5 to 100 MUg/mL. Significant decrease in specific growth rates and viable counts demonstrates the inhibitory effect of bakuchiol on Candida planktonic cells. A brief exposure to bakuchiol also reduced CSH of Candida (P < 0.05), indicating altered surface properties of yeast cells towards hydrophobic interfaces. Biofilm biomass and cell metabolic activity were mostly decreased, except for C. glabrata (P = 0.29). The antifungal properties of bakuchiol on Candida species in this in vitro study may give insights into the application in therapeutic strategy against Candida infections. PMID- 26633987 TI - The Triterpenoid Betulin Protects against the Neuromuscular Effects of Bothrops jararacussu Snake Venom In Vivo. AB - We confirmed the ability of the triterpenoid betulin to protect against neurotoxicity caused by Bothrops jararacussu snake venom in vitro in mouse isolated phrenic nerve-diaphragm (PND) preparations and examined its capability of in vivo protection using the rat external popliteal/sciatic nerve-tibialis anterior (EPSTA) preparation. Venom caused complete, irreversible blockade in PND (40 MUg/mL), but only partial blockade (~30%) in EPSTA (3.6 mg/kg, i.m.) after 120 min. In PND, preincubation of venom with commercial bothropic antivenom (CBA) attenuated the venom-induced blockade, and, in EPSTA, CBA given i.v. 15 min after venom also attenuated the blockade (by ~70% in both preparations). Preincubation of venom with betulin (200 MUg/mL) markedly attenuated the venom-induced blockade in PND; similarly, a single dose of betulin (20 mg, i.p., 15 min after venom) virtually abolished the venom-induced decrease in contractility. Plasma creatine kinase activity was significantly elevated 120 min after venom injection in the EPSTA but was attenuated by CBA and betulin. These results indicate that betulin given i.p. has a similar efficacy as CBA given i.v. in attenuating the neuromuscular effects of B. jararacussu venom in vivo and could be a useful complementary measure to antivenom therapy for treating snakebite. PMID- 26633988 TI - Determinants of late presentation to HIV/AIDS care in Southern Tigray Zone, Northern Ethiopia: an institution based case-control study. AB - BACKGROUND: Late diagnosis and presentation to human immune deficiency virus (HIV)/acquired immune deficiency syndrome care reduce the benefits of antiretroviral therapy and increase the risk of HIV transmission. OBJECTIVES: This study was conducted to identify determinants of late presentation to HIV care among people living with HIV in Southern Tigray, Northern Ethiopia. METHODS: An institution based un-matched case-control (1:2 ratios) supported with qualitative data was conducted in Southern Tigray Zone from March 1 to April 30, 2014. Individuals with HIV enrolled from six randomly selected health facilities were included in the study. Cases were people living with HIV who had cluster of differentiation four count <350 cells/MUl or World Health Organization stages 3 or 4. A total of 442 study participants were included by systematic sampling techniques. Bivariable and multivariable binary logistic regression model was used to identify associated factors. Odds ratio with 95 % CI was computed to assess the strength of the associations. RESULT: Age categories, 25-29 years [AOR 3, 95 % CI (1.2-8.1)] and 35-39 years [AOR 4.1, 95 % CI (1.4-12.5)], having two [AOR 6, 95 % CI (1.3-28)] and more [AOR 5.2, 95 % CI (1.1-24.8)] lifetime sexual partners, poor social support [AOR 2.3, 95 % CI (1.26-4.30)], second (next to lowest) wealth quintile [AOR 3.3, 95 % CI 91.3-8.5)], fear of stigma [AOR 4.4, 95 % CI (2.2-8.3)], fear of losing job [AOR 6.8, 95 % CI (1.8-24.5)], and reported severe illness [AOR 4.3, 95 % CI (2.26-8)] were identified to be the risk factors for late presentation. CONCLUSION: Low socio-economic status and social support, fear of stigma were potential risk factors for late presentation. Efforts towards promoting early care seeking should target on these factors in the study area and other similar settings. PMID- 26633989 TI - Combined intervention with pioglitazone and n-3 fatty acids in metformin-treated type 2 diabetic patients: improvement of lipid metabolism. AB - BACKGROUND: The marine n-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) exert numerous beneficial effects on health, but their potency to improve treatment of type 2 diabetic (T2D) patients remains poorly characterized. We aimed to evaluate the effect of a combination intervention using EPA + DHA and the insulin-sensitizing drug pioglitazone in overweight/obese T2D patients already treated with metformin. METHODS: In a parallel-group, four arm, randomized trial, 69 patients (66 % men) were assigned to 24-week intervention using: (i) corn oil (5 g/day; Placebo), (ii) pioglitazone (15 mg/day; Pio), (iii) EPA + DHA concentrate (5 g/day, containing ~2.8 g EPA + DHA; Omega-3), or (iv) pioglitazone and EPA + DHA concentrate (Pio& Omega-3). Data from 60 patients were used for the final evaluation. At baseline and after intervention, various metabolic markers, adiponectin and cytokines were evaluated in serum using standard procedures, EPA + DHA content in serum phospholipids was evaluated using shotgun lipidomics and mass spectrometry, and hyperinsulinemic euglycemic clamp and meal test were also performed. Indirect calorimetry was conducted after the intervention. Primary endpoints were changes from baseline in insulin sensitivity evaluated using hyperinsulinemic-euglycemic clamp and in serum triacylglycerol concentrations in fasting state. Secondary endpoints included changes in fasting glycemia and glycated hemoglobin (HbA1c), changes in postprandial glucose, free fatty acid and triacylglycerol concentrations, metabolic flexibility assessed by indirect calorimetry, and inflammatory markers. RESULTS: Omega-3 and Pio& Omega-3 increased EPA + DHA content in serum phospholipids. Pio and Pio& Omega-3 increased body weight and adiponectin levels. Both fasting glycemia and HbA1c were increased by Omega-3, but were unchanged by Pio& Omega-3. Insulin sensitivity was not affected by Omega-3, while it was improved by Pio& Omega-3. Fasting triacylglycerol concentrations and inflammatory markers were not significantly affected by any of the interventions. Lipid metabolism in the meal test and metabolic flexibility were additively improved by Pio& Omega-3. CONCLUSION: Besides preventing a modest negative effect of n-3 fatty acids on glycemic control, the combination of pioglitazone and EPA + DHA can be used to improve lipid metabolism in T2D patients on stable metformin therapy. TRIAL REGISTRATION: EudraCT number 2009-011106-42. PMID- 26633990 TI - Attachment, recalled parental rearing, and ADHD symptoms predict emotion processing and alexithymia in adults with ADHD. AB - BACKGROUND: The aim of the aricle is to study the relationship between attachment, parental rearing behavior, and (infant and current) ADHD symptoms with emotion processing and alexithymia in adults with ADHD. METHODS: Attachment, parental behavior, and ADHD variables were tested for predictive value regarding emotion processing and alexithymia in the total sample, the pooled ADHD groups (with inattentive type and combined type, each with n = 26) and a control group (n = 26). Comparisons were performed between the pooled ADHD groups and the control group, and between the ADHD subtype groups regarding all emotion processing and alexithymia, and attachment-related measures. RESULTS: Emotion processing/alexithymia parameters were mainly predicted by early or current attachment-related features, and, to a lesser extent, by childhood or current ADHD symptoms, primarily in the ADHD groups. CONCLUSIONS: The findings suggest partly specific and possibly causal relationships between attachment-related features and current emotion processing/alexithymia in adults with ADHD. The results confirm the necessity for further study of the multiple interactions between infant and parental ADHD symptoms, aversive parenting, and attachment with respect to emotional functioning in adult ADHD. PMID- 26633991 TI - Exponentially Fitted Two-Derivative Runge-Kutta Methods for Simulation of Oscillatory Genetic Regulatory Systems. AB - Oscillation is one of the most important phenomena in the chemical reaction systems in living cells. The general purpose simulation algorithms fail to take into account this special character and produce unsatisfying results. In order to enhance the accuracy of the integrator, the second-order derivative is incorporated in the scheme. The oscillatory feature of the solution is captured by the integrators with an exponential fitting property. Three practical exponentially fitted TDRK (EFTDRK) methods are derived. To test the effectiveness of the new EFTDRK methods, the two-gene system with cross-regulation and the circadian oscillation of the period protein in Drosophila are simulated. Each EFTDRK method has the best fitting frequency which minimizes the global error. The numerical results show that the new EFTDRK methods are more accurate and more efficient than their prototype TDRK methods or RK methods of the same order and the traditional exponentially fitted RK method in the literature. PMID- 26633992 TI - Evaluation of lime and hydrothermal pretreatments for efficient enzymatic hydrolysis of raw sugarcane bagasse. AB - BACKGROUND: Ethanol production from sugarcane bagasse requires a pretreatment step to disrupt the cellulose-hemicellulose-lignin complex and to increase biomass digestibility, thus allowing the obtaining of high yields of fermentable sugars for the subsequent fermentation. Hydrothermal and lime pretreatments have emerged as effective methods in preparing the lignocellulosic biomass for bioconversion. These pretreatments are advantageous because they can be performed under mild temperature and pressure conditions, resulting in less sugar degradation compared with other pretreatments, and also are cost-effective and environmentally sustainable. In this study, we evaluated the effect of these pretreatments on the efficiency of enzymatic hydrolysis of raw sugarcane bagasse obtained directly from mill without prior screening. In addition, we evaluated the structure and composition modifications of this bagasse after lime and hydrothermal pretreatments. RESULTS: The highest cellulose hydrolysis rate (70 % digestion) was obtained for raw sugarcane bagasse pretreated with lime [0.1 g Ca(OH)2/g raw] for 60 min at 120 degrees C compared with hydrothermally pretreated bagasse (21 % digestion) under the same time and temperature conditions. Chemical composition analyses showed that the lime pretreatment of bagasse promoted high solubilization of lignin (30 %) and hemicellulose (5 %) accompanied by a cellulose accumulation (11 %). Analysis of pretreated bagasse structure revealed that lime pretreatment caused considerable damage to the bagasse fibers, including rupture of the cell wall, exposing the cellulose-rich areas to enzymatic action. CONCLUSION: We showed that lime pretreatment is effective in improving enzymatic digestibility of raw sugarcane bagasse, even at low lime loading and over a short pretreatment period. It was also demonstrated that this pretreatment caused alterations in the structure and composition of raw bagasse, which had a pronounced effect on the enzymes accessibility to the substrate, resulting in an increase of cellulose hydrolysis rate. These results indicate that the use of raw sugarcane bagasse (without prior screening) pretreated with lime (cheaper and environmentally friendly reagent) may represent a cost reduction in the cellulosic ethanol production. PMID- 26633993 TI - Preservation of microbial communities enriched on lignocellulose under thermophilic and high-solid conditions. AB - BACKGROUND: Microbial communities enriched from diverse environments have shown considerable promise for the targeted discovery of microorganisms and enzymes for bioconversion of lignocellulose to liquid fuels. While preservation of microbial communities is important for commercialization and research, few studies have examined storage conditions ideal for preservation. The goal of this study was to evaluate the impact of preservation method on composition of microbial communities enriched on switchgrass before and after storage. The enrichments were completed in a high-solid and aerobic environment at 55 degrees C. Community composition was examined for each enrichment to determine when a stable community was achieved. Preservation methods included cryopreservation with the cryoprotective agents DMSO and glycerol, and cryopreservation without cryoprotective agents. Revived communities were examined for their ability to decompose switchgrass under high-solid and thermophilic conditions. RESULTS: High throughput 16S rRNA gene sequencing of DNA extracted from enrichment samples showed that the majority of the shift in composition of the switchgrass-degrading community occurred during the initial three 2-week enrichments. Shifts in community structure upon storage occurred in all cryopreserved samples. Storage in liquid nitrogen in the absence of cryoprotectant resulted in variable preservation of dominant microorganisms in enriched samples. Cryopreservation with either DMSO or glycerol provided consistent and equivalent preservation of dominant organisms. CONCLUSIONS: A stable switchgrass-degrading microbial community was achieved after three 2-week enrichments. Dominant microorganisms were preserved equally well with DMSO and glycerol. DMSO-preserved communities required more incubation time upon revival to achieve pre-storage activity levels during high-solid thermophilic cultivation on switchgrass. Despite shifts in the community with storage, the samples were active upon revival under thermophilic and high-solid conditions. The results suggest that the presence of microorganisms may be more important than their relative abundance in retaining an active microbial community. PMID- 26633994 TI - Transcriptional program for nitrogen starvation-induced lipid accumulation in Chlamydomonas reinhardtii. AB - BACKGROUND: Algae accumulate lipids to endure different kinds of environmental stresses including macronutrient starvation. Although this response has been extensively studied, an in depth understanding of the transcriptional regulatory network (TRN) that controls the transition into lipid accumulation remains elusive. In this study, we used a systems biology approach to elucidate the transcriptional program that coordinates the nitrogen starvation-induced metabolic readjustments that drive lipid accumulation in Chlamydomonas reinhardtii. RESULTS: We demonstrate that nitrogen starvation triggered differential regulation of 2147 transcripts, which were co-regulated in 215 distinct modules and temporally ordered as 31 transcriptional waves. An early stage response was triggered within 12 min that initiated growth arrest through activation of key signaling pathways, while simultaneously preparing the intracellular environment for later stages by modulating transport processes and ubiquitin-mediated protein degradation. Subsequently, central metabolism and carbon fixation were remodeled to trigger the accumulation of triacylglycerols. Further analysis revealed that these waves of genome-wide transcriptional events were coordinated by a regulatory program orchestrated by at least 17 transcriptional regulators, many of which had not been previously implicated in this process. We demonstrate that the TRN coordinates transcriptional downregulation of 57 metabolic enzymes across a period of nearly 4 h to drive an increase in lipid content per unit biomass. Notably, this TRN appears to also drive lipid accumulation during sulfur starvation, while phosphorus starvation induces a different regulatory program. The TRN model described here is available as a community-wide web-resource at http://networks.systemsbiology.net/chlamy portal. CONCLUSIONS: In this work, we have uncovered a comprehensive mechanistic model of the TRN controlling the transition from N starvation to lipid accumulation. The program coordinates sequentially ordered transcriptional waves that simultaneously arrest growth and lead to lipid accumulation. This study has generated predictive tools that will aid in devising strategies for the rational manipulation of regulatory and metabolic networks for better biofuel and biomass production. PMID- 26633995 TI - Functionally distinct patterns of nucleosome remodeling at enhancers in glucocorticoid-treated acute lymphoblastic leukemia. AB - BACKGROUND: Precise nucleosome positioning is an increasingly recognized feature of promoters and enhancers, reflecting complex contributions of DNA sequence, nucleosome positioning, histone modification and transcription factor binding to enhancer activity and regulation of gene expression. Changes in nucleosome position and occupancy, histone variants and modifications, and chromatin remodeling are also critical elements of dynamic transcriptional regulation, but poorly understood at enhancers. We investigated glucocorticoid receptor associated (GR) nucleosome dynamics at enhancers in acute lymphoblastic leukemia. RESULTS: For the first time, we demonstrate functionally distinct modes of nucleosome remodeling upon chromatin binding by GR, which we term central, non central, phased, and minimal. Central and non-central remodeling reflect nucleosome eviction by GR and cofactors, respectively. Phased remodeling involves nucleosome repositioning and is associated with rapidly activated enhancers and induction of gene expression. Minimal remodeling sites initially have low levels of enhancer-associated histone modification, but the majority of these regions gain H3K4me2 or H3K27Ac to become de novo enhancers. Minimal remodeling regions are associated with gene ontologies specific to decreased B cell number and mTOR inhibition and may make unique contributions to glucocorticoid-induced leukemia cell death. CONCLUSIONS: Our findings form a novel framework for understanding the dynamic interplay between transcription factor binding, nucleosome remodeling, enhancer function, and gene expression in the leukemia response to glucocorticoids. PMID- 26633996 TI - Insertional Achilles tendinopathy is associated with arthritic changes of the posterior calcaneal cartilage: a retrospective study. AB - BACKGROUND: To characterize the histological changes within the posterior calcaneal cartilage in patients with insertional Achilles tendinopathy (IAT) and test the relationships between severity of the histological changes and level of functional impairment. METHODS: Sixteen posterior calcaneal wall specimens of patients with IAT who had posterior calcaneal ostectomy were investigated. Hematoxylin-eosin stain, Toluidine-blue stain, Polarized light microscopy, and Masson Trichrome stain were used to characterize histological changes. Changes within the posterior calcaneal wall cartilage were graded according to Osteoarthritis Research Society International (OARSI) criteria. Functional scores were completed at the time of surgery according to the American Orthopedic Foot and Ankle Society (AOFAS) Ankle-Hindfoot score. RESULTS: Mean age of patients was 48.9 years. Histological findings within the posterior calcaneal wall cartilage specimens were consistent with arthritic changes. OARSI grading indicated Grade 2 changes in one specimen, mean AOFAS score 60; Grade 3 changes in three specimens, AOFAS score 73.7 +/- 2.5; Grade 4 changes in four specimens, AOFAS score 44 +/- 21.4; Grade 5 changes in eight specimens, AOFAS score 48 +/- 9.9. Higher OARSI grades were correlated with lower AOFAS scores (rho = -0.65, p < 0.01). CONCLUSIONS: Degenerative arthritic changes of the posterior calcaneal wall cartilage characterize patients with IAT and the severity of such changes is directly correlated to the degree of functional impairment. PMID- 26633999 TI - An Editor's farewell. AB - At the end of his mandate as Breathe Chief Editor, James Paton reflects on the previous 3 years http://ow.ly/RctU8. PMID- 26633998 TI - A new insight into the role of plasma fibrinogen in the development of metabolic syndrome from a prospective cohort study in urban Han Chinese population. AB - BACKGROUND: Elevated levels of fibrinogen may contribute to a prothrombotic state. Cross-sectional studies suggest fibrinogen possibly linked with MetS/its components, while results of cohort studies remain controversial. Thus, this study was designed to identify the association of plasma fibrinogen with metabolic syndrome (MetS) and further to clarify the role of fibrinogen in the development of MetS. METHODS: A large-scale prospective cohort study was conducted in routine health check-up population. 6209 participants free of MetS at baseline were included in the original cohort, with annually routine health check-up for incident MetS from 2005 to 2011. Then, 4 pre-MetS sub-cohorts, with overweight, hypertension, hyperglycemia and dyslipidemia at baseline respectively, were also created from the original cohort. Various strategies of Cox model analysis were performed for attempting to confirm the role of fibrinogen in the development of MetS. RESULTS: Total MetS incidence density was 75.58 per 1000 person-years. Cox regression analysis by adjusting for potential confounders as well as four MetS components showed a significant effect of fibrinogen on MetS just in female, with risk ratio (RR) (95 % CI) of 1.48 (1.02, 2.13) for Q4 vs. Q1. Further analysis in the 4 pre-MetS female sub-cohorts revealed this significant effect only in overweight sub-cohort, with RR (95 % CI) of 1.97 (1.20, 3.23), but no significant interaction of overweight with fibrinogen on MetS was revealed in original female cohort. Then, stratification analysis among the 4 sub-groups of fibrinogen quartiles showed that effects of overweight on MetS were different among the 4 sub-groups of fibrinogen quartiles, with RR of 2.98 for Q1, 4.40 for Q2, 3.93 for Q3, and 4.82 for Q4 respectively. CONCLUSIONS: Fibrinogen was associated with MetS just in overweight sub-cohort of female individuals, and fibrinogen might be a potential modifier in the pathway from overweight to MetS. PMID- 26633997 TI - High-quality and universal empirical atomic charges for chemoinformatics applications. AB - BACKGROUND: Partial atomic charges describe the distribution of electron density in a molecule and therefore provide clues to the chemical behaviour of molecules. Recently, these charges have become popular in chemoinformatics, as they are informative descriptors that can be utilised in pharmacophore design, virtual screening, similarity searches etc. Especially conformationally-dependent charges perform very successfully. In particular, their fast and accurate calculation via the Electronegativity Equalization Method (EEM) seems very promising for chemoinformatics applications. Unfortunately, published EEM parameter sets include only parameters for basic atom types and they often miss parameters for halogens, phosphorus, sulphur, triple bonded carbon etc. Therefore their applicability for drug-like molecules is limited. RESULTS: We have prepared six EEM parameter sets which enable the user to calculate EEM charges in a quality comparable to quantum mechanics (QM) charges based on the most common charge calculation schemes (i.e., MPA, NPA and AIM) and a robust QM approach (HF/6-311G, B3LYP/6-311G). The calculated EEM parameters exhibited very good quality on a training set ([Formula: see text]) and also on a test set ([Formula: see text]). They are applicable for at least 95 % of molecules in key drug databases (DrugBank, ChEMBL, Pubchem and ZINC) compared to less than 60 % of the molecules from these databases for which currently used EEM parameters are applicable. CONCLUSIONS: We developed EEM parameters enabling the fast calculation of high quality partial atomic charges for almost all drug-like molecules. In parallel, we provide a software solution for their easy computation (http://ncbr.muni.cz/eem_parameters). It enables the direct application of EEM in chemoinformatics. PMID- 26634000 TI - "Take the active option" to support Healthy Lungs for Life. AB - ERS/ELF say "take the active option" for Healthy Lungs for Life http://ow.ly/R1WaX. PMID- 26634001 TI - ERS/EBAP European Accreditation of Training Centres in Adult Respiratory Medicine: how could it benefit your centre? AB - Find out about the benefits of the ERS/EBAP European Accreditation of Training Centres in Adult Respiratory Medicine http://ow.ly/R0dXo. PMID- 26634002 TI - A sanguine experience: Case Report. AB - A 68-year-old man presents at A&E with breathlessness but no chest pain, haemoptysis or sputum production http://ow.ly/R029n. PMID- 26634003 TI - Pulmonary rehabilitation: Patient and healthcare professional perspective. AB - A patient and healthcare professional from The Netherlands give an overview of the pulmonary rehabilitation process http://ow.ly/R0iTI. PMID- 26634004 TI - Juniors' voice at the ERS International Congress, Amsterdam 2015: Juniors' Voice. AB - Junior member activities at the ERS International Congress 2015 http://ow.ly/R2oIn. PMID- 26634005 TI - How to optimise patient and public involvement in your research: Doing science. AB - This paper considers how best to achieve patient and public involvement in research and how to get the most out of it http://ow.ly/R0hwV. PMID- 26634006 TI - Hot topics from the Assemblies. AB - Mannitol improves mucus clearance in non-cystic fibrosis (CF) bronchiectasis and improves mucus clearance and pulmonary function test results in patients with CF. It is not clear to what extent inhaled mannitol has an impact on exacerbation rates and quality of life in patients with non-CF bronchiectasis. PMID- 26634007 TI - GPs Meet Rare Lung Disorders Task Force factsheet: pulmonary arterial hypertension. AB - ERS GPs Meet Rare Lung Disorders Task Force factsheet: pulmonary arterial hypertension http://ow.ly/RlcYz. PMID- 26634008 TI - Exercise and air quality: 10 top tips. AB - When exercising in a town or city, make use of parks, public spaces and trails with low emission zones as much as possible. A growing amount of research is showing that greenspaces contribute to our health and wellbeing. PMID- 26634010 TI - Giant Congenital Pelvic AVM Causing Cardiac Failure, Diplegia, and Neurogenic Bladder. AB - BACKGROUND: Pelvic arteriovenous malformations (AVMs) are uncommon lesions and only a rare number of male cases have been reported. Their clinical presentations are variable and imaging modalities have an important place in diagnosis and treatment planning. CASE REPORT: We present the imaging findings of a giant congenital pelvic AVM that was diagnosed in a 30-year-old male patient eight years ago and which progressed despite follow-up and treatment, causing cardiac failure, diplegia, and neurogenic bladder. CONCLUSIONS: Pelvic AVMs are uncommon lesions and they can present with various symptoms based on their locations and sizes. Delays in the diagnosis and treatment can cause local and systemic complications. Imaging is very important in the diagnosis of pelvic AVM. PMID- 26634009 TI - Epigenetic inactivation of the extracellular matrix metallopeptidase ADAMTS19 gene and the metastatic spread in colorectal cancer. AB - BACKGROUND: ADAMTS19 encodes a member of the ADAMTS (a disintegrin and metalloproteinase domain with thrombospondin motifs) protein family with emerging roles in carcinogenesis and metastasis. ADAMTS shares several distinct protein modules including a propeptide region, a metalloproteinase domain, a disintegrin like domain, and a thrombospondin type 1 (TS) motif. In a previous work, we found ADAMTS19 frequently hypermethylated in colorectal cancer (CRC). We explored the association of methylation with tumor genotype and phenotype. RESULTS: The methylation status of the CpG island in the promoter of ADAMTS19 was determined in 252 colorectal, 65 pancreatic, 33 breast and 169 ovarian primary tumors, 70 CRC metastases, and 10 CRC cell lines. Tumor-specific methylation of ADAMTS19 was significantly more frequent in gastrointestinal than in gynecological cancers (odds ratio (OR) = 2.9, confidence interval (CI) = (1.9-4.7), p = 5.2 * 10(-7)) and was independent of the methylation of adjacent loci in CRC. Hypermethylation associated with CRC with mutated BRAF oncogene (OR = 10.1, CI = (3.1-42.9), p = 6.3 * 10(-6)) and with the mucinous phenotype in CRC (OR = 2.1, CI = (1.1-4.1), p = 0.023) and ovarian cancer (OR = 60, CI = (16-346), p = 4 * 10(-16)). Methylation was significantly more frequent in CRC metastases homing to the ovary and omentum than in those homing to the liver and lung (OR = 6.1, CI = (1.8 22.2), p = 0.001). Differentiating local from distant metastatic spread, methylation negatively associated with tumor progression (p = 0.031) but positively with depth of invasion (p = 0.030). Hypermethylation associated with transcriptional repression in CRC cell lines, and treatment with 5'-AZA-2' deoxycytidine led to reactivation of mRNA expression. shRNA-mediated silencing of ADAMTS19 had no effect on the in vitro proliferation rate of CRC cells but significantly diminished their collective migration speed (56 %, p = 3.3 * 10( 4)) and potential to migrate in collagen I (64 %, p = 4.3 * 10(-10)). CONCLUSIONS: Our results highlight the frequent involvement of ADAMTS19 epigenetic silencing in CRC and mucinous ovarian cancer. The mechanistic preferences for the target organ of metastatic spread may lead to the development of diagnostic CRC biomarkers. The association with the mucinous phenotype also may have diagnostic applications for ovarian cancer. PMID- 26634011 TI - Large Gastric Perforation Sealed by Splenic Lysis: Emphasis on Indirect Signs - A Rare Case Report. AB - BACKGROUND: Gastric perforation is a life-threatening condition, requiring early and reliable discovery. The delay before surgical treatment is a strong determinant of poor outcome, associated complications and hospitalization costs. By using ultrasound and multi-detector computed tomography (MDCT) we can further evaluate undiagnosed cases of silent gastric perforations presenting with non specific acute abdomen. Here we bring forth the role of a radiologist in cases of perforation which present with indirect signs involving the organs forming the stomach bed, like the spleen, pancreas and kidney. CASE REPORT: A 25-year-old male patient presented with an acute onset of severe upper abdominal pain radiating to the back and vomiting. MDCT of the abdomen was done which revealed atrophic pancreas with organized collection in the sub-capsular location indenting the superior pole of the left kidney. Spleen was not visualized. The most striking imaging finding in that case was destruction of the splenic parenchyma with protrusion of the remaining tissue into the stomach lumen. The hypothesis behind this was a cascade of events which started with gastric perforation, spillage of highly destructive gastric juice over the stomach bed and finally becoming silent with rapid sealing of the defect by the omentum and the spleen. CONCLUSIONS: Acute abdomen is a diagnostic challenge to a clinician and radiologist with gastric perforation being a great mimicker of other urgent abdominal pathologies. To avoid a delayed diagnosis or a misdiagnosis, familiarity with typical and atypical imaging features is essential as in our case of splenic lysis. It acted as the 2(nd) policeman and provided a great clue to solve the diagnostic dilemma. PMID- 26634012 TI - Right Liver Lobe Hypoplasia and Related Abnormalities. AB - BACKGROUND: Hypoplasia and agenesis of the liver lobe is a rare abnormality. It is associated with biliary system abnormalities, high location of the right kidney, and right colon interposition. These patients are prone to gallstones, portal hypertension and possible surgical complications because of anatomical disturbance. CASE REPORT: Magnetic resonance imaging features of a rare case of hypoplasia of the right lobe of the liver in a sigmoid cancer patient are presented. CONCLUSIONS: Hypoplasia of the right liver should not be confused with liver atrophy; indeed, associations with other coexistent abnormalities are also possible. Awareness and familiarity with these anomalies are necessary to avoid fatal surgical and interventional complications. PMID- 26634013 TI - Microfluidic assembly kit based on laser-cut building blocks for education and fast prototyping. AB - Here, we present an inexpensive rapid-prototyping method that allows researchers and children to quickly assemble multi-layered microfluidic devices from easily pre-fabricated building blocks. We developed low-cost (<$2) kits based on laser cut acrylic building block pieces and double-sided tape that allow users to generate water droplets in oil, capture living cells, and conduct basic phototaxis experiments. We developed and tested a 90-min lesson plan with children aged 12-14 yr and provide here the instructions for teachers to replicate these experiments and lessons. All parts of the kit are easy to make or order. We propose to use such easy to fabricate kits in labs with no access to current microfluidic tools as well as in classroom environments to get exposure to the powerful techniques of microfluidics. PMID- 26634014 TI - On-chip recalcification of citrated whole blood using a microfluidic herringbone mixer. AB - In vitro assays of platelet function and coagulation are typically performed in the presence of an anticoagulant. The divalent cation chelator sodium citrate is among the most common because its effect on coagulation is reversible upon reintroduction of divalent cations. Adding divalent cations into citrated blood by batch mixing leads to platelet activation and initiation of coagulation after several minutes, thus limiting the time blood can be used before spontaneously clotting. In this work, we describe a herringbone microfluidic mixer to continuously introduce divalent cations into citrated blood. The mixing ratio, defined as the ratio of the volumetric flow rates of citrated blood and recalcification buffer, can be adjusted by changing the relative inlet pressures of these two solutions. This feature is useful in whole blood assays in order to account for differences in hematocrit, and thus viscosity. The recalcification process in the herringbone mixer does not activate platelets. The advantage of this continuous mixing approach is demonstrated in microfluidic vascular injury model in which platelets and fibrin accumulate on a collagen-tissue factor surface under flow. Continuous recalcification with the herringbone mixer allowed for flow assay times of up to 30 min, more than three times longer than the time achieved by batch recalcification. This continuous mixer allows for measurements of thrombus formation, remodeling, and fibrinolysis in vitro over time scales that are relevant to these physiological processes. PMID- 26634015 TI - Hydrodynamic self-focusing in a parallel microfluidic device through cross filtration. AB - The flow focusing is a fundamental prior step in order to sort, analyze, and detect particles or cells. The standard hydrodynamic approach requires two fluids to be injected into the microfluidic device: one containing the sample and the other one, called the sheath fluid, allows squeezing the sample fluid into a narrow stream. The major drawback of this approach is the high complexity of the layout for microfluidic devices when parallel streams are required. In this work, we present a novel parallelized microfluidic device that enables hydrodynamic focusing in each microchannel using a single feed flow. At each of the parallel channels, a cross-filter region is present that allows removing fluid from the sample fluid. This fluid is used to create local sheath fluids that hydrodynamically pinch the sample fluid. The great advantage of the proposed device is that, since only one inlet is needed, multiple parallel micro-channels can be easily introduced into the design. In the paper, the design method is described and the numerical simulations performed to define the optimal design are summarized. Moreover, the operational functionality of devices tested by using both polystyrene beads and Acute Lymphoid Leukemia cells are shown. PMID- 26634016 TI - Surface modification on polydimethylsiloxane-based microchannels with fragmented poly(l-lactic acid) nanosheets. AB - Surface modification is a critical issue in various applications of polydimethylsiloxane (PDMS)-based microfluidic devices. Here, we describe a novel method through which PDMS-based microchannels were successfully modified with fragmented poly(l-lactic acid) (PLLA) nanosheets through a simple patchwork technique that exploited the high level of adhesiveness of PLLA nanosheets. Compared with other surface modification methods, our method required neither complicated chemical modifications nor the use of organic solvents that tend to cause PDMS swelling. The experimental results indicated that the modified PDMS exhibited excellent capacity for preventing the adhesion and activation of platelets. This simple yet efficient method can be used to fabricate the special PDMS microfluidic devices for biological, medical, and even hematological purposes. PMID- 26634017 TI - Complete genome sequence of Salinicoccus halodurans H3B36, isolated from the Qaidam Basin in China. AB - Salinicoccus halodurans H3B36 is a moderately halophilic bacterium isolated from a sediment sample of Qaidam Basin at 3.2 m vertical depth. Strain H3B36 accumulate N (alpha)-acetyl-alpha-lysine as compatible solute against salinity and heat stresses and may have potential applications in industrial biotechnology. In this study, we sequenced the genome of strain H3B36 using single molecule, real-time sequencing technology on a PacBio RS II instrument. The complete genome of strain H3B36 was 2,778,379 bp and contained 2,853 protein coding genes, 12 rRNA genes, and 61 tRNA genes with 58 tandem repeats, six minisatellite DNA sequences, 11 genome islands, and no CRISPR repeat region. Further analysis of epigenetic modifications revealed the presence of 11,000 m4C type modified bases, 7,545 m6A-type modified bases, and 89,064 other modified bases. The data on the genome of this strain may provide an insight into the metabolism of N (alpha)-acetyl-alpha-lysine. PMID- 26634018 TI - Complete genome of Pseudomonas chlororaphis strain UFB2, a soil bacterium with antibacterial activity against bacterial canker pathogen of tomato. AB - Strain UFB2 was isolated from a soybean field soil in Mississippi and identified as a member of Pseudomonas chlororaphis. Strain UFB2 has a broad-spectrum antimicrobial activity against common soil-borne pathogens. Plate assays showed that strain UFB2 was especially efficient in inhibiting the growth of Clavibacter michiganensis 1-07, the causal agent of the devastating bacterial canker of tomato. Here, the complete genome sequence of P. chlororaphis strain UFB2 is reported and described. The strain UFB2 genome consists of a circular chromosome of 6,360,256 bp of which 87.86 % are protein-coding bases. Genome analysis revealed multiple gene islands encoding various secondary metabolites such as 2,4 diacetylphloroglucinol. Further genome analysis will provide more details about strain UFB2 antibacterial activities mechanisms and the use of this strain as a potential biocontrol agent. PMID- 26634019 TI - Genome sequence of a dissimilatory Fe(III)-reducing bacterium Geobacter soli type strain GSS01(T). AB - Strain GSS01(T) (=KCTC 4545=MCCC 1 K00269) is the type strain of the species Geobacter soli. G. soli strain GSS01(T) is of interest due to its ability to reduce insoluble Fe(III) oxides with a wide range of electron donors. Here we describe some key features of this strain, together with the whole genome sequence and annotation. The genome of size 3,657,100 bp contains 3229 protein coding and 54 RNA genes, including 2 16S rRNA genes. The genome of strain GSS01(T)contains 76 predicted cytochrome genes, 24 pilus assembly protein genes and several other genes, which were proposed to be related to the reduction of insoluble Fe(III) oxides. The genes associated with the electron donors and acceptors of strain GSS01(T) were predicted in the genome. Information gained from its sequence will be relevant to the future elucidation of extracellular electron transfer mechanism during the reduction of Fe(III) oxides. PMID- 26634020 TI - Guest Editor John Cooke Lends Expertise on Special Cardiovascular Regeneration Issue. PMID- 26634021 TI - Mechanisms of Atherosclerosis: New Insights and Novel Therapeutic Approaches. PMID- 26634022 TI - New Insights Into Tobacco-Induced Vascular Disease: Clinical Ramifications. AB - Tobacco smoke contains more than 4,000 compounds. These include phenols, carbonyls, and nitrosamines that may be irritants and carcinogens; particulate matter such as tars; volatiles and gases such as carbon monoxide; and nicotine. Many of these compounds may contribute to the adverse health effects of tobacco. For example, recent findings have shown that the angiogenic and proliferative effects of nicotine are mediated by activation of nicotinic receptors on the vascular cells. Nicotine-induced activation of vascular cells may contribute to pathological neovascularization in cancer, age-related macular degeneration, and atherosclerosis. This review focuses on how nicotine adversely affects cardiovascular health and highlights intriguing new data about nicotine's potent angiogenic and proliferative properties. PMID- 26634023 TI - AIBP: A Novel Molecule at the Interface of Cholesterol Transport, Angiogenesis, and Atherosclerosis. AB - Cardiovascular disease, which is often driven by hypercholesterolemia and subsequent coronary atherosclerosis, is the number-one cause of morbidity and mortality in the United States. Based on long-term epidemiological studies, high density lipoprotein cholesterol (HDL-C) levels are inversely correlated with risk for coronary artery disease (CAD). HDL-mediated reverse cholesterol transport (RCT) is responsible for cholesterol removal from the peripheral tissues and return to the liver for final elimination.1 In atherosclerosis, intraplaque angiogenesis promotes plaque growth and increases plaque vulnerability. Conceivably, the acceleration of RCT and disruption of intraplaque angiogenesis would inhibit atherosclerosis and reduce CAD. We have identified a protein called apoA-I binding protein (AIBP) that augments HDL functionality by accelerating cholesterol efflux. Furthermore, AIBP inhibits vascular endothelial growth factor receptor 2 activation in endothelial cells and limits angiogenesis.2 The following discusses the prospect of using AIBP as a novel therapeutic approach for the treatment of CAD. PMID- 26634025 TI - Telomerase Therapy to Reverse Cardiovascular Senescence. AB - Cellular senescence of endothelial cells plays an important role in the development of vascular lesions that ultimately lead to an atherosclerotic plaque. This review focuses on the age-related changes of endothelial and vascular smooth muscle cells that contribute to vascular disease and discusses potential new targets that could rejuvenate the vascular system and thereby prevent or delay atherosclerosis. PMID- 26634024 TI - Endothelium-Derived Nitric Oxide as an Antiatherogenic Mechanism: Implications for Therapy. AB - Endothelium-derived nitric oxide (eNO) is a multifunctional signaling molecule critically involved in the maintenance of metabolic and cardiovascular homeostasis. In addition to its role as a potent endogenous vasodilator, eNO suppresses key processes in vascular lesion formation and opposes atherogenesis. This review discusses eNO as an antiatherogenic molecule and highlights factors that influence its bioavailability and therapeutic approaches to restore or enhance its levels. PMID- 26634026 TI - Therapeutic Transdifferentiation: A Novel Approach for Ischemic Syndromes. AB - The technological development of induced pluripotent stem cells (iPSCs) has overcome many of the limitations of adult and embryonic stem cells. We have found that activation of innate immunity signaling is necessary for this process, as it facilitates epigenetic plasticity in cells by a process called transflammation. More recently, we have discovered that transflammation also facilitates the transdifferentiation of cells directly from one somatic cell type to another. This insight may lead to a promising therapeutic pathway that avoids reverting cells all the way back to pluripotency before achieving a cell type of interest. While there is much therapeutic promise to transflammation and transdifferentiation, there is also evidence that transdifferentiation plays a role in some pathological conditions, including atherosclerosis. Ultimately, better understanding of transflammation will facilitate the development of regenerative therapies. PMID- 26634027 TI - High-Density Lipoprotein Processing and Premature Cardiovascular Disease. AB - High plasma concentrations of low-density lipoprotein-cholesterol (LDL-C) are a well-accepted risk factor for cardiovascular disease (CVD), and the statin class of hypolipidemic drugs has emerged as an effective means of lowering LDL-C and reducing CVD risk. In contrast, the role of plasma high-density lipoproteins (HDL) in protection against atherosclerotic vascular disease is the subject of considerable controversy. Although the inverse correlation between plasma HDL-C and CVD is widely acknowledged, reduction of CVD risk by interventions that increase HDL-C have not been uniformly successful. Several studies of large populations have shown that the first step in reverse cholesterol transport (RCT), the transfer of cholesterol from the subendothelial space of the arterial wall via the plasma compartment to the liver for disposal, is impaired in patients with CVD. Here we review HDL function, the mechanisms by which HDL supports RCT, and the role of RCT in preventing CVD. PMID- 26634028 TI - ANA-Negative Lupus Presenting with Heart Failure and Severe Valvular Dysfunction: Case Report and Review of the Literature. AB - Antinuclear antibody (ANA) negative lupus is an important subset of the systemic lupus erythematosus (SLE) disease spectrum. Since the introduction of human cell line for ANA assay, the occurrence of true ANA-negative SLE has been a rare clinical phenomenon. The nature of cardiac involvement in ANA-negative SLE is not well understood, although any cardiac involvement, including valvular dysfunction, should be considered as a presenting manifestation of SLE irrespective of serology status. Early recognition and intervention appears to be associated with decreased morbidity. The following report describes our first case of ANA-negative SLE with an initial presentation of severe cardiac valvular dysfunction and heart failure. It also characterizes the spectrum of disease severity in ANA-negative SLE and demonstrates how aggressive SLE therapy can improve cardiac disease. PMID- 26634029 TI - A New Differential Diagnosis: Synthetic Cannabinoids-Associated Acute Renal Failure. AB - Synthetic cannabinoids (SCs) are herbal blends that use plant material with varying concentrations of synthetic analogues of cannabinoids. These products are sold as incense or potpourri and are labeled "Not for human use." Even so, rates of abuse are rapidly increasing worldwide, especially in the young adult population. An extensive network of users exists, and the products can easily be ordered on the Internet under various brand names, including the most popular ones, "K2" and "Spice." Not much is known about their spectrum of toxicity and no specific antidote is available at present. Renal failure is a rare complication associated with SC abuse. We describe a case of acute kidney injury associated with use of SCs and present a review of the current literature, including the history and some key pharmacologic and epidemiologic findings related to synthetic cannabinoid compounds. PMID- 26634030 TI - Mucoepidermoid Carcinoma of the Tracheobronchial Tree. AB - Primary salivary type lung cancers are extremely rare intrathoracic malignancies. Mucoepidermoid tumor is one of the salivary gland tumors that originates from submucosal glands of the tracheobronchial tree. These are very slow-growing low grade malignant tumors. Surgery is the mainstay of treatment and rarely requires adjuvant therapy. In this case report we describe a 65-year-old woman who presented with a solitary cough yet on further investigation was found to have a mucoepidermoid tumor originating from the hilum of the left lung. PMID- 26634031 TI - Prosthetic Mitral Valve Thrombosis. PMID- 26634032 TI - Quadricuspid Aortic Valve. PMID- 26634033 TI - Administration of Anesthesia to Patients with Renal Failure. PMID- 26634035 TI - Crystal Cathedral, Crystal Horse and Crystal Hyacinth. PMID- 26634036 TI - Fragile. PMID- 26634037 TI - Albert E. Raizner Receives Master Interventionalist Designation. PMID- 26634038 TI - Use of blood based biomarkers in the evaluation of Crohn's disease and ulcerative colitis. AB - Despite significant improvements in our understanding of Crohn's disease (CD) and ulcerative colitis (UC) in recent years, questions remain regarding the best approaches to assessment and management of these chronic diseases during periods of both relapse and remission. Various serologic biomarkers have been used in the evaluation of patients with both suspected and documented inflammatory bowel disease (IBD), and while each has potential utility in the assessment of patients with IBD, potential limitation remain with each method of assessment. Given these potential shortcomings, there has been increased interest in other means of evaluation of patients with IBD, including an expanding interest in the role of gene expression profiling. Among patients with IBD, gene expression profiles obtained from whole blood have been used to differentiate active from inactive CD, as well as to differentiate between CD, UC, and non-inflammatory diarrheal conditions. There are many opportunities for a non-invasive, blood based test to aid in the assessment of patients with IBD, particularly when considering more invasive means of evaluation including endoscopy with biopsy. Furthermore, as the emphasis on personalized medicine continues to increase, the potential ability of gene expression analysis to predict patient response to individual therapies offers great promise. While whole blood gene expression analysis may not completely replace more traditional means of evaluating patients with suspected or known IBD, it does offer significant potential to expand our knowledge of the underlying genes involved in the development of these diseases. PMID- 26634039 TI - Endoscopic resection of tumors in the lower digestive tract. AB - As endoscopic technology has developed and matured, the endoscopic resection of gastrointestinal tract polyps has become a widely used treatment. Colorectal polyps are the most common type of polyp, which are best managed by early resection before the polyp undergoes malignant transformation. Methods for treating colorectal tumors are numerous, including argon plasma coagulation, endoscopic mucosal resection, endoscopic submucosal dissection, and laparoscopic endoscopic cooperative surgery. In this review, we will highlight several currently used clinical endoscopic resection methods and how they are selected based on the characteristics of the targeted tumor. Specifically, we will focus on laparoscopic-endoscopic cooperative surgery. PMID- 26634040 TI - Endoscopic submucosal dissection vs laparoscopic colorectal resection for early colorectal epithelial neoplasia. AB - AIM: To compare the short term outcome of endoscopic submucosal dissection (ESD) with that of laparoscopic colorectal resection (LC) for the treatment of early colorectal epithelial neoplasms that are not amenable to conventional endoscopic removal. METHODS: This was a retrospective cohort study. The clinical data of all consecutive patients who underwent ESD for endoscopically assessed benign lesions that were larger than 2 cm in diameter from 2009 to 2013 were collected. These patients were compared with a cohort of controls who underwent LC from 2005 to 2013. Lesions that were proven to be malignant by initial endoscopic biopsies were excluded. Mid and lower rectal lesions were not included because total mesorectal excision, which bears a more complicated postoperative course, is not indicated for lesions without histological proof of malignancy. Both ESD and LC were performed by the same surgical unit with a standardized technique. The patients were managed according to a standard protocol, and they were closely monitored for complications after the procedures. All hospital records were reviewed, and the following data were compared between the ESD and LC groups: patient demographics, size and location of the lesions, procedure time, short term clinical outcomes and pathology results. RESULTS: From 2005 to 2013, 65 patients who underwent ESD and 55 patients who underwent LC were included in this study. The two groups were similar in terms of sex (P = 0.41) and American Society of Anesthesiologist class (P = 0.58), although patients in the ESD group were slightly older (68.6 +/- 9.4 vs 64.6 +/- 9.9, P = 0.03). ESD could be accomplished with a shorter procedure time (113 +/- 66 min vs 153 +/- 43 min, P < 0.01) for lesions of comparable size (3.0 +/- 1.2 cm vs 3.4 +/- 1.4 cm, P = 0.22) and location (colon/rectum: 59/6 vs colon/rectum: 52/3, P = 0.43). ESD appeared to be associated with a lower short-term complication rate, but the difference did not reach statistical significance (10.8% vs 23.6%, P = 0.06). In the LC arm, a total of 22 complications occurred in 13 patients. A total of 7 complications occurred in the ESD arm, including 5 perforations and 2 episodes of bleeding. All perforations were observed during the procedure and were successfully managed by endoscopic clipping without emergency surgical intervention. Patients in the ESD arm had a faster recovery than patients in the LC arm, which included shorter time to resume normal diet (2 d vs 4 d, P = 0.01) and a shorter hospital stay (3 d vs 6 d, P < 0.01). CONCLUSION: ESD showed better short-term clinical outcomes in this study. Further prospective randomized studies will be required to evaluate the efficacy and superiority of colorectal ESD over LC. PMID- 26634041 TI - Feasibility of cold snare polypectomy in Japan: A pilot study. AB - AIM: To investigate the feasibility of cold snare polypectomy (CSP) in Japan. METHODS: The outcomes of 234 non-pedunculated polyps smaller than 10 mm in 61 patients who underwent CSP in a Japanese referral center were retrospectively analyzed. The cold snare polypectomies were performed by nine endoscopists with no prior experience in CSP using an electrosurgical snare without electrocautery. RESULTS: CSPs were completed for 232 of the 234 polyps. Two (0.9%) polyps could not be removed without electrocautery. Immediate postpolypectomy bleeding requiring endoscopic hemostasis occurred in eight lesions (3.4%; 95%CI: 1.1% 5.8%), but all were easily managed. The incidence of immediate bleeding after CSP for small polyps (6-9 mm) was significantly higher than that of diminutive polyps (<= 5 mm; 15% vs 1%, respectively). Three (5%) patients complained of minor bleeding after the procedure but required no intervention. The incidence of delayed bleeding requiring endoscopic intervention was 0.0% (95%CI: 0.0%-1.7%). In total, 12% of the resected lesions could not be retrieved for pathological examination. Tumor involvement in the lateral margin could not be histologically assessed in 70 (40%) lesions. CONCLUSION: CSP is feasible in Japan. However, immediate bleeding, retrieval failure and uncertain assessment of the lateral tumor margin should not be underestimated. Careful endoscopic diagnosis before and evaluation of the tumor residue after CSP are recommended when implementing CSP in Japan. PMID- 26634042 TI - Duodenal polyposis secondary to portal hypertensive duodenopathy. AB - Portal hypertensive duodenopathy (PHD) is a recognized, but uncommon finding of portal hypertension in cirrhotic patients. Lesions associated with PHD include erythema, erosions, ulcers, telangiectasia, exaggerated villous pattern and duodenal varices. However, duodenal polyposis as a manifestation of PHD is rare. We report a case of a 52-year-old man who underwent esophagogastroduodenoscopy and was found with multiple small duodenal polyps ranging in size from 1-8 mm. Biopsy of the representative polyps revealed polypoid fragments of duodenal mucosa with villiform hyperplasia lined by reactive duodenal/gastric foveolar epithelium and underlying lamina propria showed proliferating ectatic and congested capillaries. The features were diagnostic of polyps arising in the setting of PHD. PMID- 26634043 TI - The role of drinking in new and existing friendships across high school settings. AB - We use 9 Add Health high schools with longitudinal network data to assess whether adolescent drinkers choose friends who drink, prefer friends whose friends drink, if selection differs between new and existing friendships, and between schools. Utilizing dynamic social network models that control for friend influences on individual alcohol use, the results show that drinkers do not strongly prefer friends who drink. Instead, they favor close friends whose friends' drink, suggesting that alcohol matters for selection on the social groups and environments that friends connect each other to. The role of alcohol use differs by whether friendships are new or existing, however, with bridging connections being less stable. Moreover, selection processes, and the implications of alcohol use for friendship, vary in important ways between schools. PMID- 26634044 TI - Antioxidant activity and anti-inflammatory activity of ethanol extract and fractions of Doenjang in LPS-stimulated RAW 264.7 macrophages. AB - BACKGROUND/OBJECTIVES: Fermentation can increase functional compounds in fermented soybean products, thereby improving antioxidant and/or anti inflammatory activities. We investigated the changes in the contents of phenolics and isoflavones, antioxidant activity and anti-inflammatory activity of Doenjang during fermentation and aging. MATERIALS/METHODS: Doenjang was made by inoculating Aspergillus oryzae and Bacillus licheniformis in soybeans, fermenting and aging for 1, 3, 6, 8, and 12 months (D1, D3, D6, D8, and D12). Doenjang was extracted using ethanol, and sequentially fractioned by hexane, dichloromethane (DM), ethylacetate (EA), n-butanol, and water. The contents of total phenolics, flavonoids and isoflavones, 2,2-diphenyl-1 picryl hydrazyl (DPPH) radical scavenging activity, and ferric reducing antioxidant power (FRAP) were measured. Anti-inflammatory effects in terms of nitric oxide (NO), prostaglandin (PG) E2 and pro-inflammatory cytokine production and inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 expressions were also measured using LPS treated RAW 264.7 macrophages. RESULTS: Total phenolic and flavonoid contents showed a gradual increase during fermentation and 6 months of aging and were sustained thereafter. DPPH radical scavenging activity and FRAP were increased by fermentation. FRAP was further increased by aging, but DPPH radical scavenging activity was not. Total isoflavone and glycoside contents decreased during fermentation and the aging process, while aglycone content and its proportion increased up to 3 or 6 months of aging and then showed a slow decrease. DM and EA fractions of Doenjang showed much higher total phenolic and flavonoid contents, and DPPH radical scavenging activity than the others. At 100 ug/mL, DM and EA fractions of D12 showed strongly suppressed NO production to 55.6% and 52.5% of control, respectively, and PGE2 production to 25.0% and 28.3% of control with inhibition of iNOS or COX-2 protein expression in macrophages. CONCLUSIONS: Twelve month-aged Doenjang has potent antioxidant and anti-inflammatory activities with high levels of phenolics and isoflavone aglycones, and can be used as a beneficial food for human health. PMID- 26634045 TI - Sonchus asper extract inhibits LPS-induced oxidative stress and pro-inflammatory cytokine production in RAW264.7 macrophages. AB - BACKGROUND/OBJECTIVES: Sonchus asper is used extensively as an herbal anti inflammatory for treatment of bronchitis, asthma, wounds, burns, and cough; however, further investigation is needed in order to understand the underlying mechanism. To determine its mechanism of action, we examined the effects of an ethyl acetate fraction (EAF) of S. asper on nitric oxide (NO) production and prostaglandin-E2 levels in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. MATERIALS/METHODS: An in vitro culture of RAW264.7 macrophages was treated with LPS to induce inflammation. RESULTS: Treatment with EAF resulted in significant suppression of oxidative stress in RAW264.7 macrophages as demonstrated by increased endogenous superoxide dismutase (SOD) activity and intracellular glutathione levels, decreased generation of reactive oxygen species and lipid peroxidation, and restoration of the mitochondrial membrane potential. To confirm its anti-inflammatory effects, analysis of expression of inducible NO synthase, cyclooxygenase-2, tumor necrosis factor-alpha, and the anti inflammatory cytokines IL-1beta and IL-6 was performed using semi-quantitative RT PCR. EAF treatment resulted in significantly reduced dose-dependent expression of all of these factors, and enhanced expression of the antioxidants MnSOD and heme oxygenase-1. In addition, HPLC fingerprint results suggest that rutin, caffeic acid, and quercetin may be the active ingredients in EAF. CONCLUSIONS: Taken together, findings of this study imply that the anti-inflammatory effect of EAF on LPS-stimulated RAW264.7 cells is mediated by suppression of oxidative stress. PMID- 26634046 TI - Cytoprotective effect of rhamnetin on miconazole-induced H9c2 cell damage. AB - BACKGROUND/OBJECTIVES: Reactive oxygen species (ROS) formation is closely related to miconazole-induced heart dysfunction. Although rhamnetin has antioxidant effects, it remained unknown whether it can protect against miconazole-induced cardiomyocyte apoptosis. Thus, we investigated the effects of rhamnetin on miconazole-stimulated H9c2 cell apoptosis. MATERIALS/METHODS: Cell morphology was observed by inverted microscope and cell viability was determined using a WelCountTM cell proliferation assay kit. Miconazole-induced ROS production was evaluated by fluorescence-activated cell sorting with 6-carboxy-2',7' dichlorofluoroscein diacetate (H2DCF-DA) stain. Immunoblot analysis was used to determine apurinic/apyrimidinic endonuclease 1 (APE/Ref-1) and cleaved cysteine aspartic protease (caspase) 3 expression. NADPH oxidase levels were measured using real-time polymerase chain reaction. RESULTS: Miconazole (3 and 10 uM) induced abnormal morphological changes and cell death in H9c2 cells. Rhamnetin enhanced the viability of miconazole (3 uM)-treated cells in a dose-dependent manner. Rhamnetin (1 and 3 uM) treatment downregulated cleaved caspase 3 and upregulated APE/Ref-1 expression in miconazole-stimulated cells. Additionally, rhamnetin significantly reduced ROS generation. CONCLUSIONS: Our data suggest that rhamnetin may have cytoprotective effects in miconazole-stimulated H9c2 cardiomyocytes via ROS inhibition. This effect most likely occurs through the upregulation of APE/Ref-1 and attenuation of hydrogen peroxide levels. PMID- 26634047 TI - The micosporine-like amino acids-rich aqueous methanol extract of laver (Porphyra yezoensis) inhibits adipogenesis and induces apoptosis in 3T3-L1 adipocytes. AB - BACKGROUND/OBJECTIVES: Increased mass of adipose tissue in obese persons is caused by excessive adipogenesis, which is elaborately controlled by an array of transcription factors. Inhibition of adipogenesis by diverse plant-derived substances has been explored. The aim of the current study was to examine the effects of the aqueous methanol extract of laver (Porphyra yezoensis) on adipogenesis and apoptosis in 3T3-L1 adipocytes and to investigate the mechanism underlying the effect of the laver extract. MATERIALS/METHODS: 3T3-L1 cells were treated with various concentrations of laver extract in differentiation medium. Lipid accumulation, expression of adipogenic proteins, including CCAAT enhancer binding protein alpha, peroxisome proliferator-activated receptor gamma, fatty acid binding protein 4, and fatty acid synthase, cell viability, apoptosis, and the total content and the ratio of reduced to oxidized forms of glutathione (GSH/GSSG) were analyzed. RESULTS: Treatment with laver extract resulted in a significant decrease in lipid accumulation in 3T3-L1 adipocytes, which showed correlation with a reduction in expression of adipogenic proteins. Treatment with laver extract also resulted in a decrease in the viability of preadipocytes and an increase in the apoptosis of mature adipocytes. Treatment with laver extract led to exacerbated depletion of cellular glutathione and abolished the transient increase in GSH/GSSG ratio during adipogenesis in 3T3-L1 adipocytes. CONCLUSION: Results of our study demonstrated that treatment with the laver extract caused inhibition of adipogenesis, a decrease in proliferation of preadipocytes, and an increase in the apoptosis of mature adipocytes. It appears that these effects were caused by increasing oxidative stress, as demonstrated by the depletion and oxidation of the cellular glutathione pool in the extract-treated adipocytes. Our results suggest that a prooxidant role of laver extract is associated with its antiadipogenic and proapoptotic effects. PMID- 26634048 TI - Bioconversion of Citrus unshiu peel extracts with cytolase suppresses adipogenic activity in 3T3-L1 cells. AB - BACKGROUND/OBJECTIVES: Citrus flavonoids have a variety of physiological properties such as anti-oxidant, anti-inflammation, anti-cancer, and anti obesity. We investigated whether bioconversion of Citrus unshiu with cytolase (CU C) ameliorates the anti-adipogenic effects by modulation of adipocyte differentiation and lipid metabolism in 3T3-L1 cells. MATERIALS/METHODS: Glycoside forms of Citrus unshiu (CU) were converted into aglycoside forms with cytolase treatment. Cell viability of CU and CU-C was measured at various concentrations in 3T3L-1 cells. The anti-adipogenic and lipolytic effects were examined using Oil red O staining and free glycerol assay, respectively. We performed real time-polymerase chain reaction and western immunoblotting assay to detect mRNA and protein expression of adipogenic transcription factors, respectively. RESULTS: Treatment with cytolase decreased flavanone rutinoside forms (narirutin and hesperidin) and instead, increased flavanone aglycoside forms (naringenin and hesperetin). During adipocyte differentiation, 3T3-L1 cells were treated with CU or CU-C at a dose of 0.5 mg/ml. Adipocyte differentiation was inhibited in CU-C group, but not in CU group. CU-C markedly suppressed the insulin-induced protein expression of CCAAT/enhancer-binding protein alpha (C/EBPalpha) and peroxisome proliferator-activated receptor gamma (PPARgamma) as well as the mRNA levels of CEBPalpha, PPARgamma, and sterol regulatory element binding protein 1c (SREBP1c). Both CU and CU-C groups significantly increased the adipolytic activity with the higher release of free glycerol than those of control group in differentiated 3T3-L1 adipocytes. CU-C is particularly superior in suppression of adipogenesis, whereas CU-C has similar effect to CU on stimulation of lipolysis. CONCLUSIONS: These results suggest that bioconversion of Citrus unshiu peel extracts with cytolase enhances aglycoside flavonoids and improves the anti-adipogenic metabolism via both inhibition of key adipogenic transcription factors and induction of adipolytic activity. PMID- 26634049 TI - Antiobesity effects of the water-soluble fraction of the ethanol extract of Smilax china L. leaf in 3T3-L1 adipocytes. AB - BACKGROUND/OBJECTIVES: Several medicinal properties of Smilax china L. have been studied including antioxidant, anti-inflammatory, and anti-cancer effects. However, the antiobesity activity and mechanism by which the water-soluble fraction of this plant mediates its effects are not clear. In the present study, we investigated the lipolytic actions of the water-soluble fraction of Smilax china L. leaf ethanol extract (wsSCLE) in 3T3-L1 adipocytes. MATERIALS/METHODS: The wsSCLE was identified by measuring the total polyphenol and flavonoid content. The wsSCLE was evaluated for its effects on cell viability, lipid accumulation, glycerol, and cyclic adenosine monophosphate (cAMP) contents. In addition, western blot analysis was used to evaluate the effects on protein kinase A (PKA), PKA substrates (PKAs), and hormone-sensitive lipase (HSL). For the lipid accumulation assay, 3T3-L1 adipocytes were treated with different doses of wsSCLE for 9 days starting 2 days post-confluence. In other cell experiments, mature 3T3-L1 adipocytes were treated for 24 h with wsSCLE. RESULTS: Results showed that treatment with wsSCLE at 0.05, 0.1, and 0.25 mg/mL had no effect on cell morphology and viability. Without evidence of toxicity, wsSCLE treatment decreased lipid accumulation compared with the untreated adipocyte controls as shown by the lower absorbance of Oil Red O stain. The wsSCLE significantly induced glycerol release and cAMP production in mature 3T3-L1 cells. Furthermore, protein levels of phosphorylated PKA, PKAs, and HSL significantly increased following wsSCLE treatment. CONCLUSION: These results demonstrate that the potential antiobesity activity of wsSCLE is at least in part due to the stimulation of cAMP-PKA-HSL signaling. In addition, the wsSCLE-stimulated lipolysis induced by the signaling is mediated via activation of the beta adrenergic receptor. PMID- 26634050 TI - Effects of developmental iron deficiency and post-weaning iron repletion on the levels of iron transporter proteins in rats. AB - BACKGROUND/OBJECTIVES: Iron deficiency in early life is associated with developmental problems, which may persist until later in life. The question of whether iron repletion after developmental iron deficiency could restore iron homeostasis is not well characterized. In the present study, we investigated the changes of iron transporters after iron depletion during the gestational-neonatal period and iron repletion during the post-weaning period. MATERIALS/METHODS: Pregnant rats were provided iron-deficient (< 6 ppm Fe) or control (36 ppm Fe) diets from gestational day 2. At weaning, pups from iron-deficient dams were fed either iron-deficient (ID group) or control (IDR group) diets for 4 week. Pups from control dams were continued to be fed with the control diet throughout the study period (CON). RESULTS: Compared to the CON, ID rats had significantly lower hemoglobin and hematocrits in the blood and significantly lower tissue iron in the liver and spleen. Hepatic hepcidin and BMP6 mRNA levels were also strongly down-regulated in the ID group. Developmental iron deficiency significantly increased iron transporters divalent metal transporter 1 (DMT1) and ferroportin (FPN) in the duodenum, but decreased DMT1 in the liver. Dietary iron repletion restored the levels of hemoglobin and hematocrit to a normal range, but the tissue iron levels and hepatic hepcidin mRNA levels were significantly lower than those in the CON group. Both FPN and DMT1 protein levels in the liver and in the duodenum were not different between the IDR and the CON. By contrast, DMT1 in the spleen was significantly lower in the IDR, compared to the CON. The splenic FPN was also decreased in the IDR more than in the CON, although the difference did not reach statistical significance. CONCLUSIONS: Our findings demonstrate that iron transporter proteins in the duodenum, liver and spleen are differentially regulated during developmental iron deficiency. Also, post-weaning iron repletion efficiently restores iron transporters in the duodenum and the liver but not in the spleen, which suggests that early-life iron deficiency may cause long term abnormalities in iron recycling from the spleen. PMID- 26634051 TI - Effects of natural raw meal (NRM) on high-fat diet and dextran sulfate sodium (DSS)-induced ulcerative colitis in C57BL/6J mice. AB - BACKGROUND/OBJECTIVES: Colitis is a serious health problem, and chronic obesity is associated with the progression of colitis. The aim of this study was to determine the effects of natural raw meal (NRM) on high-fat diet (HFD, 45%) and dextran sulfate sodium (DSS, 2% w/v)-induced colitis in C57BL/6J mice. MATERIALS/METHODS: Body weight, colon length, and colon weight-to-length ratio, were measured directly. Serum levels of obesity-related biomarkers, triglyceride (TG), total cholesterol (TC), low density lipoprotein (LDL), high density lipoprotein (HDL), insulin, leptin, and adiponectin were determined using commercial kits. Serum levels of pro-inflammatory cytokines including tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, and IL-6 were detected using a commercial ELISA kit. Histological study was performed using a hematoxylin and eosin (H&E) staining assay. Colonic mRNA expressions of TNF alpha, IL-1beta, IL-6, inducible nitric oxide synthase (iNOS), and cyclooxygenase 2 (COX-2) were determined by RT-PCR assay. RESULTS: Body weight and obesity related biomarkers (TG, TC, LDL, HDL, insulin, leptin, and adiponectin) were regulated and obesity was prevented in NRM treated mice. NRM significantly suppressed colon shortening and reduced colon weight-to-length ratio in HFD+DSS induced colitis in C57BL/6J mice (P < 0.05). Histological observations suggested that NRM reduced edema, mucosal damage, and the loss of crypts induced by HFD and DSS. In addition, NRM decreased the serum levels of pro-inflammatory cytokines, TNF-alpha, IL-1beta, and IL-6 and inhibited the mRNA expressions of these cytokines, and iNOS and COX-2 in colon mucosa (P < 0.05). CONCLUSION: The results suggest that NRM has an anti-inflammatory effect against HFD and DSS-induced colitis in mice, and that these effects are due to the amelioration of HFD and/or DSS-induced inflammatory reactions. PMID- 26634052 TI - Estrogen deprivation and excess energy supply accelerate 7,12 dimethylbenz(a)anthracene-induced mammary tumor growth in C3H/HeN mice. AB - BACKGROUND/OBJECTIVES: Obesity is a risk factor of breast cancer in postmenopausal women. Estrogen deprivation has been suggested to cause alteration of lipid metabolism thereby creating a cellular microenvironment favoring tumor growth. The aim of this study is to investigate the effects of estrogen depletion in combination with excess energy supply on breast tumor development. MATERIALS/METHODS: Ovariectomized (OVX) or sham-operated C3H/HeN mice at 4 wks were provided with either a normal diet or a high-fat diet (HD) for 16 weeks. Breast tumors were induced by administration of 7,12-dimethylbenz(a)anthracene once a week for six consecutive weeks. RESULTS: Study results showed higher serum concentrations of free fatty acids and insulin in the OVX+HD group compared to other groups. The average tumor volume was significantly larger in OVX+HD animals than in other groups. Expressions of mammary tumor insulin receptor and mammalian target of rapamycin proteins as well as the ratio of pAKT/AKT were significantly increased, while pAMPK/AMPK was decreased in OVX+HD animals compared to the sham operated groups. Higher relative expression of liver fatty acid synthase mRNA was observed in OVX+HD mice compared with other groups. CONCLUSIONS: These results suggest that excess energy supply affects the accelerated mammary tumor growth in estrogen deprived mice. PMID- 26634053 TI - Evaluation of the efficacy of nutritional screening tools to predict malnutrition in the elderly at a geriatric care hospital. AB - BACKGROUND/OBJECTIVES: Malnutrition in the elderly is a serious problem, prevalent in both hospitals and care homes. Due to the absence of a gold standard for malnutrition, herein we evaluate the efficacy of five nutritional screening tools developed or used for the elderly. SUBJECTS/METHODS: Elected medical records of 141 elderly patients (86 men and 55 women, aged 73.5 +/- 5.2 years) hospitalized at a geriatric care hospital were analyzed. Nutritional screening was performed using the following tools: Mini Nutrition Assessment (MNA), Mini Nutrition Assessment-Short Form (MNA-SF), Geriatric Nutritional Risk Index (GNRI), Malnutrition Universal Screening Tool (MUST) and Nutritional Risk Screening 2002 (NRS 2002). A combined index for malnutrition was also calculated as a reference tool. Each patient evaluated as malnourished to any degree or at risk of malnutrition according to at least four out of five of the aforementioned tools was categorized as malnourished in the combined index classification. RESULTS: According to the combined index, 44.0% of the patients were at risk of malnutrition to some degree. While the nutritional risk and/or malnutrition varied greatly depending on the tool applied, ranging from 36.2% (MUST) to 72.3% (MNA-SF). MUST showed good validity (sensitivity 80.6%, specificity 98.7%) and almost perfect agreement (k = 0.81) with the combined index. In contrast, MNA-SF showed poor validity (sensitivity 100%, specificity 49.4%) and only moderate agreement (k = 0.46) with the combined index. CONCLUSIONS: MNA-SF was found to overestimate the nutritional risk in the elderly. MUST appeared to be the most valid and useful screening tool to predict malnutrition in the elderly at a geriatric care hospital. PMID- 26634054 TI - Consumer attitudes, barriers, and meal satisfaction associated with sodium reduced meal intake at worksite cafeterias. AB - BACKGROUND/OBJECTIVES: Targeting consumers who consume lunches at their worksite cafeterias would be a valuable approach to reduce sodium intake in South Korea. To assess the relationships between socio-demographic factors, consumer satisfaction, attitudes, barriers and the frequency of sodium-reduced meal intake. SUBJECTS/METHODS: We implemented a cross-sectional research, analyzing data from 738 consumers aged 18 years or older (327 males and 411 females) at 17 worksite cafeterias in South Korea. We used the ordinary least squares regression analysis to determine the factors related to overall satisfaction with sodium reduced meal. General linear models with LSD tests were employed to examine the variables that differed by the frequency of sodium-reduced meal intake. RESULTS: Most subjects always or usually consumed the sodium-reduced meal (49%), followed by sometimes (34%) and rarely or never (18%). Diverse menus, taste and belief in the helpfulness of the sodium-reduced meal significantly increased overall satisfaction with the sodium-reduced diet (P < 0.05). We found importance of needs in the following order: 1) 'menu diversity' (4.01 points), 2) 'active promotion' (3.97 points), 3) 'display of nutrition labels in a visible location' (3.96 points), 4) 'improvement of taste' (3.88 points), and 5) 'education of sodium-reduction self-care behaviors' (3.82 points). CONCLUSION: Dietitians could lead consumers to choose sodium-reduced meals by improving their taste and providing diverse menus for the sodium-reduced meals at worksite cafeterias. PMID- 26634055 TI - Dietary intake of fats and fatty acids in the Korean population: Korea National Health and Nutrition Examination Survey, 2013. AB - BACKGROUND/OBJECTIVES: The aim of this study was to estimate average total fat and fatty acid intakes as well as identify major food sources using data from the Korea National Health and Nutrition Examination Survey (KNHANES) VI-1 (2013). SUBJECTS/METHODS: Total fat and fatty acid intakes were estimated using 24-hour dietary recall data on 7,048 participants aged >= 3 years from the KNHANES VI-1 (2013). Data included total fat, saturated fatty acid (SFA), monounsaturated fatty acid (MUFA), polyunsaturated fatty acid (PUFA), n-3 fatty acid (n-3 FA), and n-6 fatty acid (n-6 FA) levels. Population means and standard errors of the mean were weighted in order to produce national estimates and separated based on sex, age, income, as well as residential region. Major food sources of fat, SFA, MUFA, PUFA, n-3 FA, and n-6 FA were identified based on mean consumption amounts of fat and fatty acids in each food. RESULTS: The mean intake of total fat was 48.0 g while mean intakes of SFA, MUFA, PUFA, n-3 FA, and n-6 FA were 14.4 g, 15.3 g, 11.6 g, 1.6 g, and 10.1 g, respectively. Intakes of MUFA and SFA were each higher than that of PUFA in all age groups. Pork was the major source of total fat, SFA, and MUFA, and soybean oil was the major source of PUFA. Milk and pork were major sources of SFA in subjects aged 3-11 years and >= 12 years, respectively. Perilla seed oil and soybean oil were main sources of n-3 FA in subjects aged >= 50 years and aged < 50 years, respectively. CONCLUSIONS: Estimation of mean fatty acid intakes of this study using nationally represented samples of the Korean population could be useful for developing and evaluating national nutritional policies. PMID- 26634056 TI - Trends in adherence to dietary recommendations among Korean type 2 diabetes mellitus patients. AB - BACKGROUND/OBJECTIVES: The current study examined trends in adherence to dietary recommendations and compared the levels of adherence between diagnosed and undiagnosed subjects with type 2 diabetes mellitus (T2DM) in Korea over the past 14 years. SUBJECTS/METHODS: Data were collected from the 1998-2012 Korea National Health and Nutrition Examination Surveys (KNHANES). Diagnosed diabetes was defined as giving a positive response to questions about awareness of the disease, a physician's diagnosis of diabetes, or medical treatment for diabetes, whereas undiagnosed diabetes was defined as having a fasting glucose level >= 126 mg/dl. Assessment of adherence level was based on 6 components of dietary guidelines, considering meal patterns and intake levels of calories, carbohydrates, vegetable/seaweed, sodium, and alcohol. The participants received 1 point if they met the criteria for each of the 6 components, and the total possible score ranged from 0 to 6 points. Multivariate generalized linear regression was performed, taking into account the complex survey design. RESULTS: Among all diabetic patients aged 30 years or older, the proportion of diagnosed diabetes increased dramatically, from 40.9% in 1998 to 75.9% in 2012 (P for trend < 0.001). The overall adherence levels to dietary recommendations were low and did not significantly differ between diagnosed and undiagnosed subjects with T2DM for all survey years. Several improvements were observed, including increased adherence to maintaining sufficient vegetable/seaweed consumption (increased from 0.12 to 0.16 points) and limiting sodium intake (increased from 0.12-0.13 points to 0.19-0.24 points; P for trend < 0.001), while adherence to maintaining moderate alcohol consumption decreased. CONCLUSIONS: Analysis of data collected by the KNHANES indicates that Korean T2DM patients have poor adherence to dietary recommendations and maintenance of a healthy lifestyle, regardless of disease awareness. This finding suggests that development of practical, evidence-based guidelines is necessary and that provision and expansion of educational programs for T2DM patients is critical after diagnosis. PMID- 26634057 TI - The effect of providing nutritional information about fast-food restaurant menus on parents' meal choices for their children. AB - BACKGROUND/OBJECTIVES: To encourage healthier food choices for children in fast food restaurants, many initiatives have been proposed. This study aimed to examine the effect of disclosing nutritional information on parents' meal choices for their children at fast-food restaurants in South Korea. SUBJECTS/METHODS: An online experimental survey using a menu board was conducted with 242 parents of children aged 2-12 years who dined with them at fast-food restaurants at least once a month. Participants were classified into two groups: the low-calorie group (n = 41) who chose at least one of the lowest calorie meals in each menu category, and the high-calorie group (n = 201) who did not. The attributes including perceived empowerment, use of provided nutritional information, and perceived difficulties were compared between the two groups. RESULTS: The low calorie group perceived significantly higher empowerment with the nutritional information provided than did the high-calorie group (P = 0.020). Additionally, the low-calorie group was more interested in nutrition labeling (P < 0.001) and considered the nutritional value of menus when selecting restaurants for their children more than did the high-calorie group (P = 0.017). The low-calorie group used the nutritional information provided when choosing meals for their children significantly more than did the high-calorie group (P < 0.001), but the high calorie group had greater difficulty using the nutritional information provided (P = 0.012). CONCLUSIONS: The results suggest that improving the empowerment of parents using nutritional information could be a strategy for promoting healthier parental food choices for their children at fast-food restaurants. PMID- 26634058 TI - Attenuating effect of Lactobacillus brevis G101 on the MSG symptom complex in a double-blind, placebo-controlled study. AB - BACKGROUND/OBJECTIVES: Lactobacillus brevis G101 suppresses the absorption of monosodium glutamate (MSG) from the intestine into the blood in mice. Therefore, the attenuating effect of orally administered G101 on monosodium glutamate (MSG) symptom complex was investigated in humans. MATERIALS/METHODS: Capsules (300 mg) containing Lactobacillus brevis G101 (1*10(10) CFU/individual) or maltodextrin (placebo) was orally administered in 30 respondents with self-recognized monosodium glutamate (MSG) symptom complex for 5 days and the rice with black soybean sauce containing 6 g MSG (RBSM) was ingested 30 min after the final administration. Thereafter, the MSG symptom complex (rated on a 5-point scale: 1, none; 5, strong) was investigated in a double blind placebo controlled study. The intensity of the MSG symptom complex was significantly reduced in respondents of the G101 intake group (2.87 +/- 0.73) compared to that in those treated with the placebo (3.63 +/- 1.03) (P = 0.0016). Respondents in the placebo group exhibited more of the various major conditions of the MSG symptom complex than in the G101 intake group. Although there was no significant difference in the appearance time of the MSG symptom complex between subjects orally administered G101 and those administered the placebo, its disappearance in < 3 h was observed in 69.9% of subjects in the G101 treatment group and in 38.0% of subjects in the placebo group (P = 0.0841). CONCLUSIONS: Oral administration of Lactobacillus brevis G101 may be able to reduce the intensity of the MSG symptom complex. PMID- 26634059 TI - A Mini Overview of Isolation, Characterization and Application of Amniotic Fluid Stem Cells. AB - Amniotic fluid represents rich sources of stem cells that can be used in treatments for a wide range of diseases. Amniotic fluid- stem cells have properties intermediate between embryonic and adult mesenchymal stem cells which make them particularly attractive for cellular regeneration and tissue engineering. Furthermore, scientists are interested in these cells because they come from the amniotic fluid that is routinely discarded after birth. In this review we give a brief introduction of amniotic fluid followed by a description of the cells present within this fluid and aim to summarize the all existing isolation methods, culturing, characterization and application of these cells. Finally, we elaborate on the differentiation and potential for these cells to promote regeneration of various tissue defects, including fetal tissue, the nervous system, heart, lungs, kidneys, bones, and cartilage in the form of table. PMID- 26634060 TI - Adipose Tissue - Adequate, Accessible Regenerative Material. AB - The potential use of stem cell based therapies for the repair and regeneration of various tissues offers a paradigm shift that may provide alternative therapeutic solutions for a number of diseases. The use of either embryonic stem cells (ESCs) or induced pluripotent stem cells in clinical situations is limited due to cell regulations and to technical and ethical considerations involved in genetic manipulation of human ESCs, even though these cells are highly beneficial. Mesenchymal stem cells seen to be an ideal population of stem cells in particular, Adipose derived stem cells (ASCs) which can be obtained in large number and easily harvested from adipose tissue. It is ubiquitously available and has several advantages compared to other sources as easily accessible in large quantities with minimal invasive harvesting procedure, and isolation of adipose derived mesenchymal stem cells yield a high amount of stem cells which is essential for stem cell based therapies and tissue engineering. Recently, periodontal tissue regeneration using ASCs has been examined in some animal models. This method has potential in the regeneration of functional periodontal tissues because various secreted growth factors from ASCs might not only promote the regeneration of periodontal tissues but also encourage neovascularization of the damaged tissues. This review summarizes the sources, isolation and characteristics of adipose derived stem cells and its potential role in periodontal regeneration is discussed. PMID- 26634061 TI - Planarians: an In Vivo Model for Regenerative Medicine. AB - The emergence of regenerative medicine has raised the hope of treating an extraordinary range of disease and serious injuries. Understanding the processes of cell proliferation, differentiation and pattern formation in regenerative organisms could help find ways to enhance the poor regenerative abilities shown by many other animals, including humans. Recently, planarians have emerged as an attractive model in which to study regeneration. These animals are considering as in vivo plate, during which we can study the behavior and characristics of stem cells in their own niche. A variety of characteristic such as: simplicity, easy to manipulate experimentally, the existence of more than 100 years of literature, makes these animals an extraordinary model for regenerative medicine researches. Among planarians free-living freshwater hermaphrodite Schmidtea mediterranea has emerged as a suitable model system because it displays robust regenerative properties and, unlike most other planarians, it is a stable diploid with a genome size of about 4.8*10(8) base pairs, nearly half that of other common planarians. Planarian regeneration involves two highly flexible systems: pluripotent neoblasts that can generate any new cell type and muscle cells that provide positional instructions for the regeneration of anybody region. neoblasts represent roughly 25~30 percent of all planarian cells and are scattered broadly through the parenchyma, being absent only from the animal head tips and the pharynx. Two models for neo-blast specification have been proposed; the naive model posits that all neoblasts are stem cells with the same potential and are a largely homogeneous population. PMID- 26634062 TI - Induction of Spermatogenesis by Bone Marrow-derived Mesenchymal Stem Cells in Busulfan-induced Azoospermia in Hamster. AB - BACKGROUND: Bone marrow-derived mesenchymal stem cells (BM-MSCs) have potential of differentiation and they secrete anti-inflammatory cytokines and growth factors which make them appropriate for cell therapy. AIM OF THE WORK: Were to evaluate the healing effect of BM-MSCs transplantation on germinal cells of busulfan-induced azoospermic hamsters. MATERIAL AND METHODS: In the present experimental case control study, BM-MSCs were isolated from bone marrow of donor albino hamsters. Five mature male recipient hamsters received two doses of 10 mg/kg of busulfan with 21 days interval to stop endogenous spermatogenesis. After induction of azoospermia, right testis of hamsters was injected with 10(6) BM MSCs via efferent duct and the left one remained as azoospermia control testis. Five normal mature hamsters were selected as normal intact control. After 35 days, testes and epididymis of three groups were removed for histological evaluation. RESULTS: Histomorphological analyses of BM-MSCs treated testes and epididymis showed the epithelial tissue of seminiferous tubules had normal morphology and spermatozoa were present in epididymis tubes. Spermatogenesis was observed in most cell-treated seminiferous tubules. The untreated seminiferous tubules were empty. CONCLUSION: Transplanted BM-MSCs could successfully induce spermatogenesis in seminiferous tubules of azoospermic hamster. Therefore, BM MSCs can be an attractive candidate in cell transplantation of azoospermia. PMID- 26634063 TI - Role of Endogenous Bone Marrow Stem Cells Mobilization in Repair of Damaged Inner Ear in Rats. AB - BACKGROUND AND OBJECTIVES: The utilization of the stem cells is widely used in the last few years in different fields of medicine, either by external transplantation or endogenous mobilization, most of these studies still experimental on animals; few were tried on human as in the spinal cord injury or myocardial infarction. As regard its use in the inner ear, stem cell transplantation was examined in many previous studies, while the mobilization idea is a new method to be experimented in inner ear hair cell regeneration. The present work assessed the possibility of mobilizing endogenous bone marrow derived stem cells (SCs) in rats using granulocyte colony stimulating factor (G CSF) to induce regeneration and repair to experimentally damaged inner ear hair cells by Amikacin injection. METHODS: The study included thirty adult Sprague Dawley male rats. Experimental induction of inner ear damage was done by repeated intratympanic injection of amikacin sulfate. Mobilization of bone marrow SCs was provoked by subcutaneous injection of GCSF. Cochlear integrity, induction of hearing loss and functional recovery of sensory hearing loss were assessed using Distortion Product Otoacoustic Emission (DPOAEs). The morphological alteration and recovery of the organ of Corti was assessed histologically using the light and scanning electron microscopes. RESULTS: After six month duration, there was improvement in 50% of the sensorineural DPOAE results. Functional recovery coincided with the repair of structural components of organ of Corti. CONCLUSIONS: SCs mobilization by G-CSF is a promising alternative method for replacement therapy in sensorineural hearing loss. PMID- 26634064 TI - Cryopreservation of Human Wharton's Jelly-derived Mesenchymal Stem Cells Following Controlled Rate Freezing Protocol Using Different Cryoprotectants; A Comparative Study. AB - OBJECTIVES: To compare the effect of three different cryoprotectants on basic stem cell characteristics for the possibility of using well defined, dimethyl sulfoxide (DMSO) and serum free freezing solutions to cryopreserve human Wharton's jelly-derived mesenchymal stem cells (WJMSCs) following controlled rate freezing protocol. METHODS: The mesenchymal stem cells isolated from human Wharton's jelly were cryopreserved using 10% DMSO, 10% polyvinylpyrrolidone (PVP) and a cocktail solution comprising of 0.05 M glucose, 0.05 M sucrose and 1.5 M ethylene glycol following controlled rate freezing protocol. We investigated the post-thaw cell viability, morphology, proliferation capacity, basic stem cell characteristics, in vitro differentiation potential and apoptosis-related gene expression profile before and after cryopreservation. RESULTS: The cryoprotectant 10% DMSO has shown higher post-thaw cell viability of 81.2+/-0.58% whereas 10% PVP and cocktail solution have shown 62.87+/-0.35% and 72.2+/-0.23%, respectively at 0 h immediately thawing. The cell viability was further reduced in all the cryopreserved groups at 24 h later post-thaw culture. Further, the complete elimination of FBS in cryoprotectants has resulted in drastic reduction in cell viability. Cryopreservation did not alter the basic stem cell characteristics, plasticity and multipotency except proliferation rate. The expression of pro apoptotic BAX and p53 genes were higher whilst p21 was lower in all the cryopreserved groups when compare to the control group of WJMSCs. CONCLUSION: Although 10% DMSO has shown higher post-thaw cell viability compare to 10% PVP and cocktail solution, the present study indicates the feasibility of developing a well-defined DMSO free cryosolution which can improve storage and future broad range applications of WJMSCs in regenerative medicine without losing their basic stem cell characteristics. PMID- 26634065 TI - Therapeutic Effect of Adipose Derived Stem Cells versus Atorvastatin on Amiodarone Induced Lung Injury in Male Rat. AB - BACKGROUND AND OBJECTIVES: Amiodarone (AM), a class 3 antiarrhythmic drug, has been associated with variety of adverse effects, the most serious of which is pulmonary toxicity. Ator (A) is a statin, known for their immunomodulatory and anti-inflammatory activities. Recent studies provide evidence of potential therapeutic effect of statins on lung injury. Adipose derived stem cells (ADSCs) have shown great promise in the repair of various tissues. The present study aimed at investigating and comparing the possible therapeutic effect of A and ADSCs on AM induced lung injury in albino rats. METHODS AND RESULTS: 34 adult male albino rats were divided into 5 groups: control group (Gp I), A group (Gp II) received 10 mg/kg of A orally 6 days (d)/week (w) for 4 weeks (ws), AM group (Gp III) received 30 mg/kg of AM orally 6 d/w for 4 ws, AM&A group (Gp IV) received AM for 4ws then A for other 4 ws and AM&SCs group (Gp V) received AM for 4 ws then injected with 0.5 ml ADSCs on 2 successive days intravenously (IV). Histological, histochemical, immunohistochemical and morphometric studies were performed. Group III displayed bronchiolitis obliterans, thickened interalveolar septa (IAS) and thickened vascular wall which were proven morphometrically. Increased area% of collagen fibers and apoptotic changes were recorded. All findings regressed on A administration and ADSCs therapy. CONCLUSION: Ator proved a definite ameliorating effect on the degenerative, inflammatory, apoptotic and fibrotic changes induced by AM. ADSCs administration denoted more remarkable therapeutic effect compared to A. PMID- 26634066 TI - Comparative Histological Study on the Therapeutic Effect of Green Tea and Stem Cells in Alzheimer's Disease Complicating Experimentally Induced Diabetes. AB - BACKGROUND AND OBJECTIVES: Alzheimer's disease (AD) is a devastating neurodegenerative disorder. Increasing evidence implicates diabetes mellitus (DM) as a risk factor for AD. Green tea (GT) has several beneficial effects attributed to its anti-oxidant phenolic compounds. Adipose tissue is a rich source of adipose-derived mesenchymal stem cells (ADSCs). This study was designed to evaluate and compare the possible therapeutic effect of green tea extract (GTE) and ADSCs on AD complicating induced DM in male rat. METHODS: 31 adult male albino rats were divided into 5 groups. Group I (Control), Group II received GTE, 50 mg/kg daily orally for 4 weeks, Group III received a single intraperitoneal injection of Streptozotocin (STZ), 50 mg/kg, Group IV: received STZ followed by GTE and Group V: received STZ followed by human ADSCs (hADSCs) intravenously. RESULTS: Multiple acidophilic masses, deformed neurons, Congo red +ve masses and Caspase 3 +ve neurons were seen in group III, became few in group IV and occasional in group V. Multiple Prussian blue +ve cells were detected in group V. Some CD44 +ve cells were noticed in group III, became multiple in groups IV and V. The mean area of neurons exhibiting acidophilic cytoplasm, mean area of amyloid plaques and mean area % of Caspase 3 +ve cells indicated a significant increase in group III. The mean area % of CD44 +ve cells recorded a significant increase in group IV. CONCLUSIONS: hADSCs exerted a more marked therapeutic effect on the neurodegenerative changes complicating DM and corresponding to AD. PMID- 26634067 TI - A Novel Cell Therapy Method for Recovering after Brain Stroke in Rats. AB - BACKGROUND: Nowadays, stroke leads to a significant part of the adult mortality and morbidity and also it could result in some neurological deficits in the patients' lives. Cell therapy has opened a new approach to treat the brain ischemia and reduce its terrible effects on the patients' lives. There are several articles which show that the cell therapy could be beneficial for treating brain stroke. In this study, we have planned to present a new cell therapy method for stroke by administration of Mesenchymal stem cells and differentiated neural stem cells without astrocytes. METHOD AND MATERIALS: The Mesenchymal stem cells were isolated from tibia and femur of a 250~300 g rat and they were cultured in DMEM/F12, 10% fetal bovine serum, 1% Pen/Strep. Neural stem cells were isolated from 14 days rat embryo ganglion eminence and were cultured in NSA media containing Neurobasal, 2% B27, bFGF 10 ng/ml and EGF 20 ng/ml after 5 days they formed some neurospheres. The isolated neural stem cells were differentiated to neural lineages by adding 5% fetal bovine serum to their culture media. After 48 hours the astrocytes were depleted by using MACS kit. RESULTS: The group that received Mesenchymal stem cells systemically and differentiated neural stem cells without astrocytes had the best neurological outcomes and the least infarct volume and apoptosis. It could be understood that this cell therapy method might cause almost full recovery after brain stoke. CONCLUSION: Using combination cell therapy with Mesenchymal stem cells and differentiated neural stem cells with removed astrocyte could provide a novel method for curing brain stroke. PMID- 26634068 TI - Possible Therapeutic Effect of Stem Cell in Atherosclerosis in Albino Rats. A Histological and Immunohistochemical Study. AB - BACKGROUND: Atherosclerosis is the leading cause of death worldwide. there are no effective approaches to regressing atherosclerosis due to not fully understood mechanisms. Recently, stem cell-based therapies have held promises to various diseases, including vascular diseases. AIM: The present study aimed at investigating the possible effect of cord blood mesenchymal stem cell (MSC) therapy on atherosclerosis. MATERIAL AND METHODS: Eighty adult male albino rats were divided into control group (I), atherogenic group (II): subjected to high cholesterol fed diet (200~300 mg/kg body weight) for 12 weeks and 1.8 million units of vitamin D / kg of diet for 6 weeks. Stem cell therapy group (III): injected with stem cells in the tail vein following confirmation of atherosclerosis. Histological, Immunohistochemical and morphometric studies were performed were conducted. RESULTS: Atherogenic group (II) showed increased aortic thickness, intimal proliferation, smooth muscle proliferation and migration. Increased area % of collagen fibers, iNOS and vimentin immunoreactions were recorded and proved morphometrically. All findings regressed on stem cell therapy. CONCLUSION: A definite therapeutic effect of mesenchymal stem cells was found on atherosclerosis. PMID- 26634070 TI - Fibrin Scaffolds Designing in order to Human Adipose-derived Mesenchymal Stem Cells Differentiation to Chondrocytes in the Presence of TGF-beta3. AB - BACKGROUND AND OBJECTIVES: One of the most cellular source used for cartilage tissue engineering are mesenchymal stem cells (MSCs). In present study, human MSCs were used as cellular source. Since scaffold plays an important role in tissue engineering the aim of this study is to assess fibrin scaffold ability in chondrogenic differentiation of adipose-derived mesenchymal stem cells (ADMSCs). METHODS: ADMSCs were isolated and cultured in DMEM medium supplemented with 10% FBS. Also ADMSCs expanded and characterised by flow cytometry. ADMSCs expressed CD44, CD90, CD105 but not CD34. After trypsinization, cells were entered within the fibrin scaffold. Then, chondrogenic medium was added to the scaffold. Seven days after cell culture, cell viability and proliferation were assessed by MTT test. Finally, 14 days after the ending of chondrogenic differentiation, analysis of chondrogenic genes expression was evaluated by RT-PCR and Real time PCR. Also, formation and development of chondrocyte cells was analysed by histological and immunohistochemistry evaluations. RESULTS: Viability and proliferation as well as chondrogenic genes expression within fibrin scaffold increased significantly compared with control group (cells free scaffold). Also, histological and immunohistochemistry evaluation showed that chondrocyte cells and collagen type II are formed on fibrin scaffold. CONCLUSIONS: Fibrin is a suitable scaffold for chondrogenic differentiation of ADMSCs. PMID- 26634069 TI - Autologous Stem Cells Transplantation in Egyptian Patients with Liver Cirrhosis on Top of Hepatitis C Virus. AB - BACKGROUND AND OBJECTIVES: Use of pluripotent stem cells is an ideal solution for liver insufficiencies. This work aims is to evaluate the safety and feasibility of autologous stem cells transplantation (SCT) in Egyptian patients of liver cirrhosis on top of hepatitis C virus (HCV). SUBJECTS AND RESULTS: 20 patients with HCV induced liver cirrhosis were divided into 2 groups. Group I: included 10 patients with liver cirrhosis Child score >=9, for whom autologous stem cell transplantation was done using granulocyte colony stimulating factor (G-CSF) for stem cells mobilization. Separation and collection of the peripheral blood stem cells was done by leukapheresis. G-CSF mobilized peripheral blood mononuclear cells (G-CSF PB-MNCs) were counted by flow cytometry. Stem cell injection into the hepatic artery was done. Group II: included 10 patients with HCV induced liver cirrhosis as a control group. Follow up and comparison between both groups were done over a follow up period of 6 months. The procedure was well tolerated. Mobilization was successful and the total number of G-CSF PB-MNCs in the harvests ranged from 25*10(6) to 191*10(6). There was improvement in the quality of life, serum albumin, total bilirubin, liver enzymes and the Child-Pugh score of group I over the first two-three months after the procedure. CONCLUSION: SCT in HCV induced liver cirrhosis is a safe procedure. It can improve the quality of life and hepatic functions transiently with no effect on the life expectancy or the fate of the liver cirrhosis. PMID- 26634071 TI - FGF8 is Essential for Functionality of Induced Neural Precursor Cell-derived Dopaminergic Neurons. AB - Induced neural precursor cells (iNPCs) are one source of transplantable dopaminergic neurons used in cell therapy for Parkinson's disease. In the present study, we demonstrate that iNPCs can be generated by transducing Brn2, Ascl1, Myt1L and Bcl-xL in a culture supplemented with several mitogens and subsequently can be differentiated to dopaminergic neurons (DA). However, studies have shown that iDA and/or iNPC-derived DA neurons using various conversion protocols have low efficiency. Here, we show that early exposure of FGF8 to fibroblasts efficiently improves differentiation of DA neurons. So our study demonstrates that FGF8 is a critical factor for generation of iNPC-derived DA neurons. PMID- 26634072 TI - Autologous Stem Cell Application in Periodontal Regeneration Technique (SAI-PRT) Using PDLSCs Directly From an Extracted Tooth...An Insight. AB - Periodontal regeneration represents the ultimate goal of periodontal therapy. The current regenerative techniques have limited success rates especially in advanced periodontal defects. Currently the research is focused on novel cell-based approaches for periodontal regeneration to overcome the limitations of existing treatment. The human clinical trial on stem cells based periodontal regeneration is promising. The plethora of animal studies provide sound evidence to support the belief that periodontal ligament stem cells (PDLSCs) can be used for periodontal regeneration. The direct application of autologous periodontal stem cells in treatment of intrabony defects is attempted for the first time in periodontal literature. Stem cell Application in Periodontal Regeneration Technique (SAI-PRT) using direct PDLSCs has overcome the limitations and concerns of ex- vivo stem cell culture methods like high cost, technique sensitivity, loss of stemness during cell passage, genetic manipulation and tumorigenic potential. Clinical feasibility, success and cost effectiveness over currently available techniques are encouraging. The clinical utility of this novel idea is recommended. PMID- 26634073 TI - Therapeutic hypothermia for elevated intracranial pressure in traumatic brain injury: does it do more harm than good? PMID- 26634074 TI - Propofol as a controlled substance: poison or remedy. PMID- 26634076 TI - T test as a parametric statistic. AB - In statistic tests, the probability distribution of the statistics is important. When samples are drawn from population N (u, sigma(2)) with a sample size of n, the distribution of the sample mean X should be a normal distribution N (u, sigma(2)/n). Under the null hypothesis u = u0, the distribution of statistics [Formula: see text] should be standardized as a normal distribution. When the variance of the population is not known, replacement with the sample variance s (2) is possible. In this case, the statistics [Formula: see text] follows a t distribution (n-1 degrees of freedom). An independent-group t test can be carried out for a comparison of means between two independent groups, with a paired t test for paired data. As the t test is a parametric test, samples should meet certain preconditions, such as normality, equal variances and independence. PMID- 26634077 TI - The combination of sugammadex and neostigmine can reduce the dosage of sugammadex during recovery from the moderate neuromuscular blockade. AB - BACKGROUND: Sugammadex is a novel neuromuscular reversal agent, but its associated hypersensitivity reaction and high cost have been obstacles to its widespread use. In the interest of reducing the necessary dosage of sugammadex, the reversal time of the combined use of sugammadex and neostigmine from moderate neuromuscular blockade were investigated. METHODS: The patients enrolled ranged in age from 18 to 65 years old with American Society of Anesthesiologists class 1 or 2. The subjects were randomly assigned into one of the four groups (Group S2, S1, SN, and N; n = 30 per group). The reversal agents of each groups were as follows: S2 - sugammadex 2 mg/kg, S1 - sugammadex 1 mg/kg, SN - sugammadex 1 mg/kg + neostigmine 50 ug/kg + glycopyrrolate 10 ug/kg, N - neostigmine 50 ug/kg + glycopyrrolate 10 ug/kg. The time to recovery of the train-of-four (TOF) ratio was checked in each group. RESULTS: The time to 90% recovery of TOF ratio was 182.6 +/- 88.9, 371.1 +/- 210.4, 204.3 +/- 103.2, 953.2 +/- 379.7 sec in group S2, S1, SN and N, respectively. Group SN showed a significantly shorter recovery time than did group S1 and N (P < 0.001). However, statistically significant differences between the S2 and SN groups were not be observed (P = 0.291). No hypersensitivity reactions occurred in all groups. CONCLUSIONS: For the reversal from rocuronium-induced moderate neuromuscular blockade, the combined use of sugammadex and neostigmine may be helpful to decrease the recovery time and can also reduce the required dosage of sugammadex. However, the increased incidence of systemic muscarinic side effects must be considered. PMID- 26634075 TI - Postreperfusion syndrome during liver transplantation. AB - As surgical and graft preservation techniques have improved and immunosuppressive drugs have advanced, liver transplantation (LT) is now considered the gold standard for treating patients with end-stage liver disease worldwide. However, despite the improved survival following LT, severe hemodynamic disturbances during LT remain a serious issue for the anesthesiologist. The greatest hemodynamic disturbance is postreperfusion syndrome (PRS), which occurs at reperfusion of the donated liver after unclamping of the portal vein. PRS is characterized by marked decreases in mean arterial pressure and systemic vascular resistance, and moderate increases in pulmonary arterial pressure and central venous pressure. The underlying pathophysiological mechanisms of PRS are complex. Moreover, risk factors associated with PRS are not fully understood. Rapid and appropriate treatment with vasopressors, volume replacement, or venesection must be provided depending on the cause of the hemodynamic disturbance when hemodynamic instability becomes profound after reperfusion. The negative effects of PRS on postoperative early morbidity and mortality are clear, but the effect of PRS on postoperative long-term mortality remains a matter of debate. PMID- 26634078 TI - Effects of a fentanyl-propofol mixture on propofol injection pain: a randomized clinical trial. AB - BACKGROUND: Propofol injection pain is a common problem that can be very distressing for patients. We compared the effects of injection with saline followed by injection with a fentanyl-propofol mixture, injection with fentanyl followed by a propofol injection, and injection with saline followed by propofol alone on propofol injection pain. METHODS: The patients were assigned randomly to one of three groups. A rubber tourniquet was placed on the forearm to produce venous occlusion for 1 min. Before anesthesia induction, group C (control, n = 50) and group M (fentanylpropofol mixture, n = 50) received 5 ml of isotonic saline, while group F (fentanyl, n = 50) received 2 ug/kg of fentanyl. After the tourniquet was released, groups C and F received 5 ml of propofol and group M received 5 ml of a mixture containing 20 ml of propofol and 4 ml of fentanyl. At 10 s after the study drugs were given, a standard question about the comfort of the injection was asked of the patient. We used a verbal rating scale to evaluate propofol injection pain. Statistical analyses were performed with Student's t tests and Fisher's exact tests; P < 0.05 was considered to indicate statistical significance. RESULTS: The demographic data were similar among the groups. In group M, the number of patients reporting propofol injection pain was significantly lower than in groups F and C (both P < 0.001). No patient in group F or M experienced severe pain, whereas 24 patients (48%) had severe pain in group C (both P < 0.001). CONCLUSIONS: This study shows that a fentanyl-propofol mixture was more effective than fentanyl pretreatment or a placebo in preventing propofol injection pain. PMID- 26634079 TI - Risk factors associated with outcomes of hip fracture surgery in elderly patients. AB - BACKGROUND: Hip fracture surgery on elderly patients is associated with a high incidence of morbidity and mortality. The aim of this study is to identify the risk factors related to the postoperative mortality and complications following hip fracture surgery on elderly patients. METHODS: In this retrospective study, the medical records of elderly patients (aged 65 years or older) who underwent hip fracture surgery from January 2011 to June 2014 were reviewed. A total of 464 patients were involved. Demographic data of the patients, American Society of Anesthesiologists physical status, preoperative comorbidities, type and duration of anesthesia and type of surgery were collected. Factors related to postoperative mortality and complications; as well as to intensive care unit admission were analyzed using logistic regression. RESULTS: The incidence of postoperative mortality, cardiovascular complications, respiratory complications and intensive care unit (ICU) admission were 1.7, 4.7, 19.6 and 7.1%, respectively. Postoperative mortality was associated with preoperative respiratory comorbidities, postoperative cardiovascular complications (P < 0.05). Postoperative cardiovascular complications were related to frequent intraoperative hypotension (P <0.05). Postoperative respiratory complications were related to age, preoperative renal failure, neurological comorbidities, and bedridden state (P < 0.05). ICU admission was associated with the time from injury to operation, preoperative neurological comorbidities and frequent intraoperative hypotension (P < 0.05). CONCLUSIONS: Adequate treatment of respiratory comorbidities and prevention of cardiovascular complications might be the critical factors in reducing postoperative mortality in elderly patients undergoing hip fracture surgery. PMID- 26634080 TI - Clinical efficacy of the classic laryngeal mask airway in elderly patients: a comparison with young adult patients. AB - BACKGROUND: The elderly have been reported to show anatomical and physiologic changes in the upper airway, which might affect the supraglottic airway (SGA) performance in geriatric populations. This study aimed to evaluate the clinical efficacy of the classic laryngeal mask airway (LMA-C) in the elderly compared with young adult patients. METHODS: Fifty patients aged 65-85 years (elderly group) and 50 patients aged 20-40 years (young group) who were scheduled for surgery using the LMA-C for general anesthesia were enrolled in this prospective, non-randomized, comparative study. Manipulations required during insertion, success rate, insertion time, oropharyngeal leak pressure, gastric insufflation, and intraoperative inadequate ventilation with the LMA-C were assessed. Fiberoptic evaluation was used to determine the position of the LMA-C. RESULTS: In the elderly group, the insertion success rate on the first attempt was significantly lower than that in the young group (84 vs. 96%, P = 0.02). The insertion time in the elderly group was significantly longer than that in the young group (28.5 +/- 19.6 vs. 22.2 +/- 6.4 seconds, P = 0.001). However, there was no difference in oropharyngeal leak pressure or fiberoptic grade between the two groups after proper placement of the LMA-C. During the surgery, inadequate ventilation events occurred more frequently in the elderly group than in the young group (31.3 vs. 4.0%, P < 0.001). CONCLUSIONS: The clinical efficacy of the LMA-C in elderly patients was inferior to that in young adult patients. Therefore, further studies are required to determine the type of SGA that can provide excellent clinical efficacy in the geriatric population. PMID- 26634081 TI - Effective dose of dexmedetomidine to induce adequate sedation in elderly patients under spinal anesthesia. AB - BACKGROUND: During sedation with dexmedetomidine, a dose adjustment may be needed based on the invasiveness of the procedure, the patient's general condition, and their age. We aim here to determine the effective dose (ED) of dexmedetomidine to induce an adequate depth of sedation in elderly patients undergoing spinal anesthesia. METHODS: In this study, 47 patients aged 65 years or older, American Society of Anesthesiologists physical status I or II, undergoing spinal anesthesia were included. Patients were randomly allocated into group I, II, III, IV or V according to the dexmedetomidine loading dose of 0.1, 0.3, 0.5, 0.7 and 1.0 ug/kg, respectively. After spinal anesthesia, the assigned loading dose of dexmedetomidine was infused intravenously for 10 minutes, after which infusion was maintained at a rate of 0.3 ug/kg/h for the next 10 minutes in all groups. We assessed the depth of sedation with the Ramsay sedation scale every five minutes and measured vital signs and the oxygen saturation. The ED50 and ED95 of dexmedetomidine to obtain adequate sedation (Ramsay sedation score >= 3) upon the completion of the loading dose were calculated with logistic regression. RESULTS: The ED50 and ED95 of dexmedetomidine for adequate sedation were 0.29 ug/kg (95% confidence intervals [CI] 0.14-0.44) and 0.86 ug/kg (95% CI 0.52-1.20), respectively. Hypotension was frequent in groups IV, V compared to groups I, II, III (31.6 vs. 3.6%, P = 0.013). CONCLUSIONS: ED95 of dexmedetomidine loading dose for adequate sedation is 0.86 ug/kg. However, dose higher than 0.5 ug/kg can lead to hemodynamic instability. PMID- 26634082 TI - Postoperative pain, nausea and vomiting among pre- and postmenopausal women undergoing cystocele and rectocele repair surgery. AB - BACKGROUND: Postoperative nausea and vomiting (PONV) and postoperative pain are among the most common side-effects of surgery. Many factors, such as a change in the level of sex hormones, are reported to affect these complications. This study aimed to evaluate the probable effects of the menopause on PONV and postoperative pain. METHODS: Prospective study, in which a total number of 144 female patients undergoing cystocele or rectocele repair surgery under standardized spinal anesthesia were included. Patients were divided into two equally sized sample groups of pre- and postmenopausal women (n = 72). The occurrence of PONV, the severity of pain as assessed by visual analog scale (VAS) pain score, and the quantity of morphine and metoclopramide required were recorded at 2, 4, 6, 12, 18 and 24 h after surgery. RESULTS: The mean VAS pain score and the mean quantity of morphine required was higher among premenopausal women (P = 0.006). Moreover, these patients required more morphine for their pain management during the first 24 h after surgery compared to postmenopausal women (P < 0.0001). No difference was observed between the two groups regarding the incidence of PONV (P = 0.09 and P = 1.00 for nausea and vomiting, respectively) and the mean amount of metoclopramide required (P = 0.38). CONCLUSIONS: Premenopausal women are more likely to suffer from postoperative pain after cystocele and rectocele repair surgery. Further studies regarding the measurement of hormonal changes among surgical patients in both pre- and postmenopausal women are recommended to evaluate the effects on PONV and postoperative pain. PMID- 26634083 TI - Clinical and psychological characteristics of propofol abusers in Korea: a survey of propofol abuse in 38, non-healthcare professionals. AB - BACKGROUND: The aim of this study is to investigate the characteristics of propofol abuse based on the results of a survey analysis of abusers among non healthcare professionals in Korea. METHODS: Thirty-eight propofol abusers were questioned between October and December 2010, and were enrolled and voluntarily participated in a structured survey consisting of an interview and completing a previously prepared questionnaire. The questionnaire was divided into three distinct parts: part 1 dealt with the history of propofol abuse; part 2 highlighted the problems caused by propofol abuse; and part 3 enquired regarding demographics of abusers. RESULTS: Thirty-one (81.6%) of the 38 interviewees abused propofol for more than one year. During the last 12 months, 34 (89.0%) received propofol at two or three times a week. The minimum and maximum amounts of propofol (median, range) administered each time were 500 (100, 1000) and 2000 (500, 4000) mg, respectively. Stress relief and the maintenance of a sense of well-being were quoted the most important reasons for the first-time administration of propofol and its subsequent abuse, respectively. The majority of abusers (36.0, 97.3%) reported a sense of pleasure or euphoria at the time of their propofol injection. Withdrawal symptoms occurred in five abusers (13.2%). Thirteen (36.1%) reported disruptions in their work life. None of the respondents had previously admitted to and or reported abuse of any other controlled substances. CONCLUSIONS: These results provided reference data for the regulation of propofol in Korea as a controlled substance and may also be of interest to international agencies in other countries. PMID- 26634084 TI - Vagolytic atropine attenuates cerebral vasodilation response during acute orthostatic hypotension. AB - BACKGROUND: Atropine is an anticholinergic drug which is commonly used in clinical practice. The effect of parasympathetic block with atropine on dynamic cerebrovascular regulation remains unclear. This study was aimed to identify effects of vagolytic atropine on cerebrovascular response during acute orthostatic hypotension in humans. METHODS: Continuous middle cerebral blood flow velocity (CBFV, transcranial Doppler) and arterial blood pressure (ABP, Finometer) were measured during a sit-to-stand procedure in 10 healthy subjects with placebo and vagolytic (10 ug/kg) doses of atropine. Cerebral vascular tone was assessed by cerebrovascular resistance (CVR = ABP / CBFV). Dynamic cerebral autoregulation was also assessed by transfer function analysis of ABP and CBFV. RESULTS: During the standing session, ABP fell to a similar extent in both groups by an average of 23 to 25 mmHg (26% to 29%). CBFV also fell in all subjects but significantly more in vagolytic atropine (-15.0 +/- 7.0 cm/s) compared with placebo (-12.0 +/- 5.8 cm/s, P < 0.05). CVR was decreased significantly in the placebo group during posture change (1.56 +/- 0.44 vs. 1.38 +/- 0.38, P < 0.05), in contrast, lesser decreased in the atropine group (1.60 +/- 0.50 vs. 1.53 +/- 0.42, P = 0.193). Transfer function coherence in the very-low-frequency range was significantly increased in the atropine group during the standing session (0.55 +/- 0.14), compared with the sitting session (0.45 +/- 0.14, P = 0.006). CONCLUSIONS: These data present that vagolytic atropine attenuates cerebral vasodilation response to acute orthostatic hypotension, suggesting the use of atropine may need care in patients with cerebrovascular disease with vagal impairment. PMID- 26634085 TI - Ultrasound-guided central cluster approach for the supraclavicular brachial plexus block: a case series. AB - There are many different approaches to ultrasound-guided supraclavicular brachial plexus block (US-SCBPB), and each has a different success rate and complications. The most commonly performed US-SCBPB is the corner pocket approach in which the needle is advanced very close to the subclavian artery and pleura. Therefore, it may be associated with a risk of subclavian artery puncture or pneumothorax. We advanced the needle into the central part of the neural cluster after penetrating the sheath of the brachial plexus in US-SCBPB. We refer to this new method as the "central cluster approach." In this approach, the needle does not have to advance close to the subclavian artery or pleura. The aim of this study was to evaluate the clinical outcomes of the central cluster approach in US-SCBPB. PMID- 26634086 TI - Anesthetic management of a patient with polycythemia vera undergoing emergency repair of a type-A aortic dissection and concomitant coronary artery bypass grafting: a case report. AB - Polycythemia vera is a chronic progressive myeloproliferative disease characterized by increased circulating red blood cells, and the hyperviscosity of the blood can lead to an increased risk of arterial thrombosis. In a previous survey regarding postoperative outcomes in polycythemia vera patients, an increased risk of both vascular occlusive and hemorrhagic complications have been reported. Aortic surgery involving cardiopulmonary bypass may be associated with the development of a coagulopathy, and as a result, the occurrence of thrombotic complications should be avoided after coronary anastomosis. Thus, optimizing the hemostatic balance is an important concern for anesthesiologists. However, only a few cases of anesthetic management in polycythemia vera patients undergoing concomitant aorta and coronary arterial bypass surgery have ever been reported. Here, we experience a polycythemia vera patient who underwent an emergency repair of a type-A aortic dissection and concomitant coronary artery bypass grafting, and report this case with a review of the relevant literature. PMID- 26634087 TI - Bronchoconstriction following instillation of phenylephrine eye drops in premature infants with bronchopulmonary dysplasia: two cases report. AB - Premature infants requiring an ophthalmic examination or even surgery for retinopathy of prematurity (ROP) have a high prevalence of co-existing bronchopulmonary dysplasia (BPD). Reactive airway is one of the clinical presentations of BPD. We report two cases of bronchoconstriction following instillation of mydriatic eye drops. One occurred during induction of anesthesia for laser photocoagulation and the other before screening of ROP. The most likely cause in each case was phenylephrine eye drops. We recommend that the minimal dosage of phenylephrine needed to attain proper mydriasis should be instilled to infant patients, and the possibility of bronchoconstriction occurrence kept in mind, especially for infants with low body weight with BPD. PMID- 26634088 TI - Management of cardiac arrest in a parturient with Eisenmenger's syndrome and complete atrioventricular block during Cesarean section: a case report. AB - A 26-year-old parturient with Eisenmenger's syndrome and complete atrioventricular block was presented for emergency Cesarean section due to preterm labor. Ventricular tachycardia (VT), which progressed to ventricular fibrillation (VF), started immediately after the incision. Cardiopulmonary resuscitation with electric shocks was given by anesthesiologists while the obstetrician delivered the baby between the shocks. A cardiac surgeon was ready for extracorporeal membrane oxygenation institution in case of emergency but spontaneous circulation of the patient returned after the 3rd shock and the delivery of the baby. The newborn's Apgar score was 4 at 1 minute and 8 at 5 minutes. An implantable cardioverter-defibrillator was inserted before the discharge because the patient had recurrent episodes of VT and VF postoperatively. PMID- 26634089 TI - Recurrence of herpes zoster in a young woman with IgG3 deficiency. PMID- 26634090 TI - The Association between Atopic Dermatitis and Depressive Symptoms in Korean Adults: The Fifth Korea National Health and Nutrition Examination Survey, 2007 2012. AB - BACKGROUND: Atopic dermatitis (AD) is characterized by pruritic and eczematous skin lesions, which often cause depressive symptoms, anxiety, stress, sleep disturbances, social withdrawal, and stigmatization. METHODS: In total, 23,442 subjects (434 AD patients and 23,008 control subjects) aged 19 years or older and without a history of major medical illness or depressive disorders were selected from The Fifth Korea National Health and Nutrition Examination Survey 2007-2012. Following the initial selection, 2,170 age- and sex-matched control subjects were selected using 1:5 propensity score matching. Multiple logistic regression analysis was performed to identify the presence of depressive symptoms of at least 2 weeks in duration. RESULTS: The demographic, socioeconomic, and clinical characteristics of AD patients and control subjects were presented and compared, and some variables differed significantly between groups. Presence of depressive symptoms was set as dependent variable, and multiple logistic regression analysis was performed as follows: (1) unadjusted; (2) with alcohol use, exercise status, smoking status, and body mass index (BMI) adjusted for; and (3) with alcohol use, exercise status, smoking status, marital status, occupation, BMI, total caloric intake, history of hypertension, and history of diabetes mellitus adjusted for. Depressive symptoms were significantly higher (odds ratios, 1.46, 1.40, and 1.36; 95% confidence intervals, 1.09-1.95, 1.0.4-1.88, and 1.01-1.85, respectively) in AD patients relative to those of matched controls. CONCLUSION: AD and clinical depression interact closely, and causal relationships between the two conditions have frequently been observed. Physicians should consider mental health interventions cautiously. It is particularly important that primary care physicians provide comprehensive, continuous long-term care. PMID- 26634091 TI - Physical Activity Level of Korean Adults with Chronic Diseases: The Korean National Health and Nutritional Examination Survey, 2010-2012. AB - BACKGROUND: Proper physical activities are known to be helpful in the prevention and management of chronic diseases. However, the physical activity level of patients with chronic diseases is low. Therefore, this study aimed to investigate the physical activity compliance of patients with hypertension, diabetes, and dyslipidemia in Korea. METHODS: This study analyzed the 2010-2012 Fifth Korean National Health and Nutrition Examination Survey data. We included 13,873 individuals in the analysis. The level of physical activity compliance was measured by performing multivariate logistic regression analyses. RESULTS: In the univariate analysis, the subjects with hypertension or diabetes tended to comply with the physical activity guidelines less faithfully than their healthy counterparts. The proportion of subjects with hypertension who were insufficiently physically active was 65.4% among the men and 75.8% among the women. For diabetes, the proportions were 66.7% and 76.8%, respectively. No significant difference was found between the subjects with dyslipidemia and their healthy counterparts. In the multivariate logistic regression analysis, no significant difference in physical activity compliance was observed between the subjects with hypertension, diabetes, or dyslipidemia and their healthy counterparts for both sexes. CONCLUSION: The patients with hypertension or diabetes tended to have lower physical activity prevlaence than their healthy counterparts. However, for dyslipidemia, no significant difference was found between the two groups. Given the significance of physical activities in the management of chronic diseases, the physical activities of these patients need to be improved. PMID- 26634092 TI - Associations between Metabolic Syndrome and Inadequate Sleep Duration and Skipping Breakfast. AB - BACKGROUND: The prevalence of metabolic syndrome is increasing worldwide, and previous studies have shown that inadequate sleep duration and skipping breakfast may be related to metabolic syndrome. Therefore, we investigated the effects of inadequate sleep and skipping breakfast on metabolic syndrome using data from the Korea National Health and Nutrition Examination Survey (KNHANES) IV & V reports (2007-2009 and 2010-2012, respectively). METHODS: The sample included 12,999 subjects who participated in the KNHANES IV & V. Sleep duration and breakfast eating were self-reported, and metabolic syndrome was defined according to the modified National Cholesterol Education Program Adult Treatment Panel III guidelines. Subjects were divided into 12 groups according to breakfast eating and sleep duration patterns, and multiple logistic regression analyses adjusted for age, sex, household income, education level, smoking status, alcohol drinking, physical activity, and total daily energy intake were conducted. RESULTS: In subjects under 50 years of age, sleeping less than 6 hours was significantly associated with increased metabolic syndrome except among those who ate breakfast on only 1 of the past 2 days. In subjects over 50 years of age, sleeping less than 6 hours was significantly associated with a decreased risk of metabolic syndrome among those who ate breakfast on both days. CONCLUSION: In conclusion, significant associations between metabolic syndrome and sleep duration were identified, and these associations differed according to age group. PMID- 26634093 TI - Efficacy of Vitamin C Supplements in Prevention of Cancer: A Meta-Analysis of Randomized Controlled Trials. AB - BACKGROUND: Previous randomized controlled trials (RCTs) have reported inconsistent findings regarding the association between vitamin C supplementation and the risk of cancer. METHODS: We performed a meta-analysis of RCTs to investigate the efficacy of vitamin C supplements for prevention of cancer. We searched the PubMed, EMBASE, and Cochrane Library databases in November 2014 using common keywords related to vitamin C supplements and cancer. RESULTS: Among 785 articles, a total of seven trials were identified, which included 62,619 participants; 31,326 and 31,293 were randomized to vitamin C supplementation and control or placebo groups, respectively, which were included in the final analysis. A fixed-effects meta-analysis of all seven RCTs revealed no significant association between vitamin C supplementation and cancer (relative risk, 1.00; 95% confidence intervals, 0.95-1.05). Similarly, subgroup meta-analysis by dose of vitamin C administered singly or in combination with other supplements, follow up period, methodological quality, cancer mortality, gender, smoking status, country, and type of cancer also showed no efficacy of vitamin C supplementation for cancer prevention. CONCLUSION: This meta-analysis shows that there is no evidence to support the use of vitamin C supplements for prevention of cancer. PMID- 26634094 TI - Development of the Perceived Stress Inventory: A New Questionnaire for Korean Population Surveys. AB - BACKGROUND: Given emerging evidence of the association between stress and disease, practitioners need a tool for measuring stress. Several instruments exist to measure perceived stress; however, none of them are applicable for population surveys because stress conceptualization can differ by population. The aim of this study was to develop and validate the Perceived Stress Inventory (PSI) and its short version for use in population surveys and clinical practice in Korea. METHODS: From a pool of perceived stress items collected from three widely used instruments, 20 items were selected for the new measurement tool. Nine of these items were selected for the short version. We evaluated the validity of the items using exploratory factor analysis of the preliminary data. To evaluate the convergent validity of the PSI, 387 healthy people were recruited and stratified on the basis of age and sex. Confirmatory analyses and examination of structural stability were also carried out. To evaluate discriminatory validity, the PSI score of a group with depressive symptoms was compared with that of a healthy group. A similar comparison was also done for persons with anxious mood. RESULTS: Exploratory factor analysis supported a three-factor construct (tension, depression, and anger) for the PSI. Reliability values were satisfactory, ranging from 0.67 to 0.87. Convergent validity was confirmed through correlation with the Perceived Stress Scale, Center for Epidemiologic Studies Depression Scale, and State-Trait Anxiety Inventory. People with depressive or anxious mood had higher scores than the healthy group on the total PSI, all three dimensions, and the short version. CONCLUSION: The long and short versions of the PSI are valid and reliable tools for measuring perceived stress. These instruments offer benefits for stress research using population-based surveys. PMID- 26634095 TI - The Effects of Alcohol on Quality of Sleep. AB - BACKGROUND: Alcohol is traditionally known to have a relaxing effect. However, persons who consume alcohol in excessive amounts suffer from poor sleep quality and patients with alcohol use disorders commonly report insomnia. In this study, we aimed to evaluate the effects of alcohol use on sleep quality. METHODS: A questionnaire-based cross-sectional survey was conducted with 234 men and 159 women who had visited a general hospital. We used structured questionnaires, including Alcohol Use Disorder Identification Test-Korean revised version (AUDIT KR) and the Pittsburgh Sleep Quality Index-Korean version (PSQI-K). We analyzed the association between scores for all subcategories of the PSQI-K and the AUDIT KR and then analyzed the correlation between AUDIT-KR and global PSQI-K scores. RESULTS: The global PSQI-K score for men was positively correlated with the AUDIT KR score (P=0.008) after adjusting for age, chronic disease, tobacco use, exercise, depression, and anxiety. The AUDIT-KR score was significantly associated with subjective sleep quality (P=0.005), sleep duration (P=0.047), and sleep disturbance (P=0.048); it was not associated with sleep latency, sleep efficiency, or daytime dysfunction. Sleep disturbances due to snoring were significantly associated with total AUDIT-KR score (P=0.008). There was no correlation between the global PSQI-K and AUDIT-KR scores for women (P=0.333). However, daytime dysfunction showed a significant association with total AUDIT-KR score (P=0.048). CONCLUSION: Men with higher AUDIT-KR scores tended to suffer from poor sleep quality. AUDIT-KR scores showed significant correlations with subjective sleep quality, sleep duration, and sleep disturbances in men. PMID- 26634096 TI - Fast Eating Speed Increases the Risk of Endoscopic Erosive Gastritis in Korean Adults. AB - BACKGROUND: Fast eating or overeating can induce gastrointestinal diseases such as gastritis. However, the association between gastritis and speed of eating is unclear. The aim of this study was to determine whether eating speed is associated with increased risk of endoscopic erosive gastritis (EEG). METHODS: We carried out a cross-sectional study involving 10,893 adults who underwent a general health checkup between 2007 and 2009. Two groups, EEG patients and EEG free patients, were compared by using the t-test and the chi-square test. Multiple logistic regression analyses were performed to investigate the association between eating speed and EEG. RESULTS: The group with EEG had a higher proportion of males, average age, body mass index, and percentages of current smokers and risky drinkers than those without EEG. After adjusting for anthropometric, social, and endoscopic parameters, the group with the highest eating speed (<5 min/meal) had 1.7 times higher risk for EEG than the group with the lowest eating speed (>=15 min/meal) (odds ratio, 1.71; 95% confidence interval, 1.20-2.45). CONCLUSION: High eating speed is an independent risk factor for EEG. Our results indicate the need for further studies to clarify the role of eating speed in gastritis. PMID- 26634097 TI - The Association between Stress Level in Daily Life and Age at Natural Menopause in Korean Women: Outcomes of the Korean National Health and Nutrition Examination Survey in 2010-2012. AB - BACKGROUND: Although several risk factors associated with reduced age at natural menopause (ANM) have been investigated, the results are inconsistent. Excessive stress, which leads to elevation of stress hormones, can also negatively affect reproductive ability, including by accelerating menopause. However, a direct association between stress level and ANM has not yet been demonstrated. Therefore, the object of this study was to investigate the association between stress level and ANM in Korean women. METHODS: Study participants were Korean women between 40 and 70 years old who were in natural menopause during the 5th Korean National Health and Nutrition Examination Survey (n=3,176). The level of stress in daily life was estimated based on data from the mental health topics of the survey. We used the t-test and one-way analysis of variance to analyze the correlation between stress level and ANM. Regression (beta) coefficients calculated by multiple regression analysis were used to estimate various factors affecting ANM. RESULTS: Women who experienced a high level of stress in daily life had a lower mean ANM than women with a low stress level (50.17+/-3.7 and 50.58+/-3.5 years, respectively), with a statistically significant correlation (P<0.05). This correlation was still observed after adjusting for age, body mass index, menstrual regularity, and personal income (P<0.05 for variables). CONCLUSION: In Korean women between 40 and 70 years of age who are in natural menopause, there is a statistically significant correlation between stress level and ANM. In particular, women who experience a high level of stress in daily life have reduced ANM. PMID- 26634098 TI - Association of 10-Year Atherosclerotic Cardiovascular Disease Risk Score with Carotid Intima-Media Thickness and Plaque. AB - BACKGROUND: The aim of this study was to determine the association between carotid intima-media thickness (IMT) and newly developed 10-year atherosclerotic cardiovascular disease (ASCVD) risk score. METHODS: Participants were 201 Korean adults who underwent carotid ultrasonography at the Health Promotion Center of the Eulji General Hospital. We obtained information about medical history and lifestyle, and conducted laboratory tests. Carotid IMT by B-mode ultrasonography was measured. Carotid injury was considered present when the maximum carotid IMT was >=0.9 mm or when arteriosclerotic plaques were detected. The 10-year ASCVD risk score was calculated using the 2013 American College of Cardiology/American Heart Association guidelines. RESULTS: Men had higher 10-year ASCVD risk score than did women (mean+/-standard deviation: 7.15+/-6.04 vs. 2.53+/-3.67, respectively; P<0.001). Ten-year ASCVD risk was significantly correlated with right maximum carotid IMT (r=0.307), left maximum carotid IMT (r=0.230), right mean carotid IMT (r=0.322), and left mean carotid IMT (r=0.264). The group with high 10-year ASCVD risk were at even higher risk of carotid injury than were the group with low 10-year ASCVD risk (odds ratio, 2.201; 95% confidence interval, 1.162-4.1706; P=0.019). Only 10-year ASCVD risk score was significantly associated with carotid injury (odds ratio, 4.104; 95% confidence interval, 1.570 10.729). Variables that were not included in the 10-year ASCVD risk score were not significantly associated with carotid injury. CONCLUSION: The findings of this study suggest that 10-year ASCVD risk score is associated with carotid injury. PMID- 26634099 TI - Differences in Factors Associated with Albuminuria according to Gender and Comorbidities of Hypertension and Diabetes. AB - BACKGROUND: This study examined the differences in factors associated with albuminuria according to gender and comorbidities of hypertension (HTN) and diabetes mellitus (DM). METHODS: We included 3,859 participants aged 20 to 79 years (55% female) from the 5th Korea National Health and Nutrition Examination Survey. Participants were excluded if they took antihypertensive or anti-diabetic medication, had chronic renal failure, had malignant tumor, were pregnant or menstruating during the health examination, or had missing urine albumin data. Albuminuria was defined by the participant's urine albumin-creatinine ratio (uACR). Relationships between dependent and independent variables were analyzed using the Pearson's correlation test and simple linear regression. Due to possible muticollinearity, multiple linear regression analysis was used to determine whether the association between the dependent and independent variables of interest remained significant after adjustment for other potentially confounding independent variables. RESULTS: The variables significantly correlated with uACR were different between the genders and between subjects with HTN or DM as a comorbidity. In the multiple linear regression models, hemoglobin A1c (P=0.01) was positively associated with uACR in men without HTN and DM. In men with HTN or DM, systolic blood pressure and fasting glucose (P<0.01) were positively associated with uACR. In women with HTN or DM, waist circumference (P=0.011) and gamma-glutamyl transpeptidase (P<0.001) were positively correlated with uACR (P<0.05) and glucose level (P=0.019) was negatively correlated with uACR. CONCLUSION: The study suggested factors correlated with albuminuria were different for men and women according to comorbidities such as HTN and DM. PMID- 26634100 TI - Correlation of Arterial Stiffness and Bone Mineral Density by Measuring Brachial Ankle Pulse Wave Velocity in Healthy Korean Women. AB - BACKGROUND: An association between arterial stiffness and osteoporosis has previously been reported. Therefore, we investigated the relationship between arterial stiffness, measured by brachial-ankle pulse wave velocity, and bone mineral density in a sample of healthy women undergoing routine medical checkup. METHODS: We retrospectively reviewed the medical charts of 135 women who had visited the Health Promotion Center (between May 2009 and December 2012). Brachial-ankle pulse wave velocity was measured using an automatic wave analyzer. Bone mineral density of the lumbar spine (L1-L4) and femur was measured by dual energy X-ray absorptiometry. Metabolic syndrome was defined according to National Cholesterol Education Program-Adult Treatment Panel III criteria, using body mass index >25 kg/m(2) instead of waist circumference >88.9 cm. RESULTS: Pearson's correlation analysis revealed significant inverse relationships between pulse wave velocity and bone mineral density of the lumbar spine (r=-0.335, P<0.001), femur neck (r=-0.335, P<0.001), and total femur (r=-0.181, P=0.04). Pulse wave velocity showed the strongest association with age (r=0.586, P<0.001). Multiple regression analysis identified an independent relationship between pulse wave velocity and lumbar spine bone mineral density in women after adjusting for age, metabolic syndrome, body mass index, smoking status, alcohol intake, and exercise (r=-0.229, P=0.01). CONCLUSION: This study confirmed an association between arterial stiffness and bone mineral density in women. PMID- 26634101 TI - Factors Associated with Fatigue in Korean Gastric Cancer Survivors. AB - BACKGROUND: Gastric cancer is the second most common cancer in Korea. Fatigue is a common symptom among cancer survivors. The aim of this study was to identify factors associated with fatigue in gastric cancer survivors. METHODS: Data were analyzed from 199 gastric cancer survivors who visited a cancer survivor outpatient clinic from July 2013 to June 2014. Patients were surveyed using a questionnaire containing a fatigue severity scale (FSS) and questions regarding associated symptoms. Participants were divided into fatigue (FSS) and non-fatigue groups based on FSS scores (>=4 and <4, respectively). Age, sex, weight, body mass index, cancer stage, pathology, surgery type, chemotherapy, radiotherapy, comorbid disease, family history of cancer, smoking, alcohol consumption, exercise, and laboratory results were investigated. RESULTS: The fatigue and non fatigue groups contained 42 and 157 survivors, respectively. Their mean age was 58 years, and the mean post-operative period was 6.58 years. Arthralgia (odds ratio [OR], 12.95; 95% confidence interval [CI], 3.21-52.34), dyspnea (OR, 10.54; 95% CI, 2.94-37.80), dyspepsia (OR, 8.26; 95% CI, 2.63-25.96), changed bowel habits (OR, 4.56; 95% CI, 1.09-19.11), anemia (OR, 3.18; 95% CI, 1.26-8.05), and regular exercise (OR, 0.31; 95% CI, 0.12-0.77) were significantly associated with fatigue in gastric cancer survivors, while weight, treatment, and depressive mood were not. CONCLUSION: Arthralgia, dyspnea, dyspepsia, bowel habit change, anemia, and regular exercise are associated with fatigue in gastric cancer survivors. PMID- 26634103 TI - Association between Parity and Blood Pressure in Korean Women: Korean National Health and Nutrition Examination Survey, 2010-2012. AB - BACKGROUND: Pregnancy considerably alters cardiovascular dynamics, and thereby affects the transition of blood pressure after delivery in women. We aimed to analyze the association between parity and blood pressure in Korean adult women. METHODS: We included 8,890 women who participated in Korean National Health and Nutrition Examination Survey between 2010 and 2012. We divided the population according to the menopause status and analyzed the association between parity and blood pressure by using multiple regression analysis, and on hypertension, by using logistic regression analysis. RESULTS: Systolic and diastolic blood pressures were significantly associated with parity in premenopausal women (beta= 0.091 [P<0.001] and beta=-0.069 [P<0.001], respectively). In the analysis that excluded women receiving antihypertensive medication, the systolic and diastolic blood pressure of postmenopausal women were significantly associated with parity (beta=-0.059 [P=0.022] and beta=-0.054 [P=0.044], respectively). Parity was found to prevent hypertension after adjustment for confounders in postmenopausal women (odds ratio, 0.55; 95% confidence interval, 0.310-0.985). CONCLUSION: We found that parity prevented hypertension in Korean women. PMID- 26634102 TI - The Correlation between the Triglyceride to High Density Lipoprotein Cholesterol Ratio and Computed Tomography-Measured Visceral Fat and Cardiovascular Disease Risk Factors in Local Adult Male Subjects. AB - BACKGROUND: We studied the association between the triglyceride to high-density lipoprotein cholesterol ratio and computed tomography-measured visceral fat as well as cardiovascular risk factors among Korean male adults. METHODS: We measured triglycerides, high density lipoprotein cholesterol, body mass, waist circumference, fasting plasma glucose, hemoglobin A1c, systolic blood pressure, diastolic blood pressure, visceral fat, and subcutaneous fat among 372 Korean men. The visceral fat and subcutaneous fat areas were measured by computed tomography using a single computed tomography slice at the L4-5 lumbar level. We analyzed the association between the triglyceride to high density lipoprotein cholesterol ratio and visceral fat as well as cardiovascular risk factors. RESULTS: A positive correlation was found between the triglyceride to high density lipoprotein cholesterol ratio and variables such as body mass index, waist circumference, fasting plasma glucose, hemoglobin A1c, visceral fat, and the visceral-subcutaneous fat ratio. However, there was no significant correlation between the triglyceride to high density lipoprotein cholesterol ratio and subcutaneous fat or blood pressure. Multiple logistic regression analyses revealed significant associations between a triglyceride to high density lipoprotein cholesterol ratio >=3 and diabetes, a body mass index >=25 kg/m(2), a waist circumference >=90 cm, and a visceral fat area >=100 cm(2). The triglyceride to high density lipoprotein cholesterol ratio was not significantly associated with hypertension. CONCLUSION: There were significant associations between the triglyceride to high density lipoprotein cholesterol ratio and body mass, waist circumference, diabetes, and visceral fat among a clinical sample of Korean men. In the clinical setting, the triglyceride to high density lipoprotein cholesterol ratio may be a simple and useful indicator for visceral obesity and cardiovascular disease. PMID- 26634105 TI - Comments on Statistical Issues in November 2015. PMID- 26634104 TI - Health-Related Quality of Life and Cardiovascular Disease Risk in Korean Adults. AB - BACKGROUND: Health-related quality of life (HRQoL) is considered an important outcome measure in chronic diseases, in particular cardiovascular disease (CVD), which is known to be associated with impaired HRQoL. However, few studies have examined HRQoL in individuals at high risk of CVD. METHODS: Using the Fifth Korea National Health and Nutrition Examination Survey 2010-2012, we analyzed data from 10,307 adults aged >=30 years. The study subjects were stratified into 3 groups on the basis of their Framingham risk score-a 10-year estimate of CVD risk: <10.0% (low risk), 10.0%-19.9% (moderate risk), and >=20.0% (high risk). The EuroQol-5D (EQ-5D) was used to evaluate HRQoL. RESULTS: A significantly higher proportion of high-risk subjects than low-risk participants had impaired HRQoL (defined as the lowest quartile of the EQ-5D index); this held true even after adjustment for confounding factors in multivariable logistic regression analysis (men: odds ratio [OR], 1.62; 95% confidence interval [CI], 1.24-2.11; women: OR, 1.46; 95% CI, 1.02-2.08). In terms of the 5 EQ-5D dimensions, a 10-year CVD risk >=20.0% was significantly associated with self-reported problems of mobility in men (OR, 3.15; 95% CI, 2.02-4.90), and of mobility (OR, 1.56; 95% CI, 1.09-2.24), self-care (OR, 2.14; 95% CI, 1.09-4.22), and usual activity problems (OR, 1.80; 95% CI, 1.17-2.78) in women. CONCLUSION: A high CVD risk is associated with impaired HRQoL. After adjustment for demographic and clinical factors, a 10-year CVD risk >=20.0% is an independent predictor of impaired HRQoL in the general population; in particular, of mobility problems in men, and of mobility, self care, and usual activity problems in women. PMID- 26634106 TI - Verification of ALDH Activity as a Biomarker in Colon Cancer Stem Cells-Derived HT-29 Cell Line. AB - BACKGROUND: Recent evidence has suggested that epithelial cancers including colorectal cancer (CRC) have driven by a small population of self-renewing, multi potent cells termed cancer stem cells (CSCs) which could be responsible for recurrence of cancer. Aldehyde dehydrogenase 1 (ALDH1) activity has used as a functional stem cell biomarker to isolate CSCs in different cancers such as colorectal cancer. OBJECTIVES: The main aim of this research was to determine the utility of ALDH1 activity along with CD44 and EPCAM in identifying stem cell-like cells in human HT-29 colonic adenocarcinoma cell line. MATERIALS AND METHODS: In this experimental study, colon CSCs biomarkers including CD44, EPCAM and ALDH1 in colonospheres and parent cells have analyzed by flow cytometry. The expression levels of stemness genes in spheroid and parental cells have investigated using SYBR Green real-time PCR. In addition, in vivo xenografts assay has performed to determine tumorigenic potential of tumor spheroid cells in nude mice. RESULTS: According to results, over 92% of spheroids were CD44+/EpCAM+, while parent cells only have expressed 38% of CD44/EpCAM biomarkers (P < 0.001). Controversially, ALDH activity was about 2-fold higher in the parent cells than spheroid cells (P < 0.05). In comparison with the parental cells, expression levels of ''stemness'' genes, like Sox2, Oct4, Nanog, C-myc, and Klf4 have significantly increased in colonosphere cells (P < 0.05). Further, administration of 2500 spheroids could be sufficient to initiate tumor growth in nude mice, while 1x106 of parental cells has needed to form tumor. CONCLUSIONS: For the first time, we have shown that colonospheres with low ALDH1 activity has indicated increased tumorigenic potential and stemness properties. So, it hasn't seemed that ALDH1 could become a useful biomarker to identify CSCs population in HT-29 cell line. PMID- 26634107 TI - Immunotherapy in Multiple Myeloma Using Cancer-Testis Antigens. AB - CONTEXT: Multiple myeloma (MM) is a B-cell malignancy characterized by monoclonal expansion of abnormal plasma cells in the bone marrow. It accounts for 10% of hematological malignancies. Although patients respond to a wide range of anticancer modalities, relapse occurs in a significant number of the cases. Immunotherapeutic approaches have been evolved to tackle this problem. Cancer testis antigens CTAs as a group of tumor-associated antigens are appropriate targets for cancer immunotherapy as they have restricted expression pattern in normal tissues except for testis which is an immune-privileged site. Expression of these antigens has been assessed in different malignancies including MM. EVIDENCE ACQUISITION: We performed a computerized search of the MEDLINE/PubMed databases with key words: multiple myeloma, cancer-testis antigen, and cancer stem cell and immunotherapy. RESULTS: Several CTAs including NY-ESO-1, MAGE and GAGE family have been shown to be expressed in MM patients. Cellular and humoral immune responses against these antigens have been detected in MM patients. CONCLUSIONS: The frequent and high expression level of CTAs in MM patients shows that these antigens can be applied as cancer biomarkers as well as targets for immunotherapy in these patients. PMID- 26634108 TI - First Experience of Intraoperative Radiation Therapy in Cerebral High Grade Glioma in Iran: A Report of Three Cases and Literature Review. AB - INTRODUCTION: Among the high grade cerebral gliomas, Glioblastoma multiform for instance, would be the main pattern of local recurrence causes clinical deterioration and deaths. This has observed 2 - 3 cm upon the initial lesion. During the period of 2 - 4 weeks post-surgery, remaining tumor cells have re grown until radiochemotherapy has initiated. So it has seemed clear that improved local control could hopefully translate into improved survival. As a matter of fact, mass reduction has insufficiently achieved in almost every case of GBM as that the tumor cell number has not fallen below a "threshold" that tumor control might achieve by the host immune system. Intraoperative Radiation therapy has been one of those add-on therapies, which has performed during or directly after resection and cleared the tumor cavity from microscopically remaining cells. Although IORT has presented a novel and feasible principle, the method faced a number of technical and geometrical errors and limitations, which has decreased its potential in the reports of previous studies. Examples could be mentioned as incomplete target volume coverage that seemed as the greatest influence on survival, due to irradiation with an inadequate electron cone size, due to angle errors, or inadequately low energies. In contrast to the previously used forward beaming electron cones, spherical irradiation sources were specifically attractive in brain tumor IORT, even in post resection cavities with normal complex shapes. CASE PRESENTATION: We have been reporting 3 cases of high grade gliomas, one recurrent GBM, one primary glioma grade III, and the last one recurrent Rhabdoid GBM, which have been fulfilling our entrance criteria of IORT procedure, by using spherical applicators, which has been increasingly discussed in recent studies. CONCLUSIONS: It was the first experience of intraoperative radiation therapy for cerebral malignant tumours in Iran. Finally, we had a brief overview on the past and present IORT strategies in the treatment of GBM. PMID- 26634109 TI - Head and Neck Squamous Cell Carcinoma in Iran: Clinico-Pathological and Treatment Related Factors Influencing Survival. AB - BACKGROUND: Evidences about survival of the patients with head and neck squamous cell carsinoma (HNSCC) have been scant in our region. OBJECTIVES: The aim of current study was to determine clinico-pathological and treatment-related factors, influencing outcome of these patients. PATIENTS AND METHODS: We have reviewed all patients with a new diagnosis of HNSCC admitted between 2008 and 2014 in "Jorjani Cancer Center", Tehran, Iran. Overall survival (OS) and event free survival (EFS) of the patients, and their relation with demographic and clinico-pathological factors have been analyzed. RESULTS: Among 119 included patients, 90 were male and 29 were female with mean age of 58 years. Larynx was the most common primary tumor site (55% of all patients). With a median follow-up period of 28 months, OS and EFS of the study patients was 61.2% and 52.4%, respectively. Tumor stage was the only parameter has significantly influenced the patients' OS. Patients with normal BMIs had significantly higher mean EFS compared with patients with bellow or above normal BMIs. Surgical treatment modalities have resulted in the same prognosis as non-surgical approaches. CONCLUSIONS: Our study seems to be the first that investigated outcome of Iranian patients with head and neck cancer and its influencing factors. PMID- 26634110 TI - Substrate-Dependent Activity of ERK and MEK Proteins in Breast Cancer (MCF7), and Kidney Embryonic (Hek-293) Cell Lines, Cultured on Different Substrates. AB - BACKGROUND: Breast cancer has been one of the most common types of cancer, as the leading cause of women death in world. Breast cancer has known as a heterogenic disease that the clinical path in different patients would be very different. Since the current classification has not covered the diverse clinical course of breast cancer, lots of efforts has done to find new biological markers. Integrins are hetero dimmer proteins of alpha and beta subunits on cell membrane. After binding to extra cellular matrix (ECM), integrins activate MAPK pathway that regulated different activities like survival, differentiation, migration, immunologic response. The interaction of integrins and ECM have a key role in cancer cell activities like survival and metastasis. OBJECTIVES: In this study the expression of alphavbeta3 integrin, substrate -dependent morphology and ERK and p-ERK activation was compared in MCF7 and Hek-293 cells lines. MATERIALS AND METHODS: The expression of alphavbeta3 integrin was assayed by flow cytometry. These cell lines were cultured on pre-covered plates with fibronectin (FN), fibrinogen (Fg) or collagen (Col) and the expression of ERK and p-ERK proteins was assessed in attached and free cells for each substrate after 1 hour incubation. The morphology of the cells have examined under an inverted phase contrast microscope at 15 min, 1 hour, 3 hours, 5 hours and 1 day of incubatioon. RESULTS: Different substrate induced the expression ERK or p-ERK differently in the two cell lines. In MCF7 cells, substrates induced the expression of ERK in all the attached cells but free cells in BSA, collagen and Fg showed a lower expression of ERK. In comparison with Hek-293 cells althought all the attached cells have expressed ERK peotein but only free cells in collagen plates showed the expression of ERK. None of the cell lines has shown any expression of ERK and p-ERK in attached or free cells except for the Hek-293 free cells in collagen platees that have shown a weak signal for p-ERK. CONCLUSIONS: Overall the breast cancer cell lines MCF7 and Hek-293 cells have differently responded on similar substrates regarding morpology or ERK and MEK expressions. PMID- 26634111 TI - Cardiac Involvement in Non-Hodgkin Lymphoma, an Incidental Large Atrial Mass: A Case Report. AB - INTRODUCTION: Cardiac involvement as an initial presentation of malignant lymphoma has been a rare occurrence. CASE PRESENTATION: We have reported a 78 year old man with complaint of abdominal pain and vomiting. In patients preoperative evaluation for surgical management of an intra-abdominal mass, a large intracardiac mass has found incidentally during the echocardiography. Pathologic biopsy of right atrial mass that has removed by open heart surgery shown: non Hodgkin-B cell lymphoma. Bone marrow biopsy was taken and was positive for lymphomatous involvement. CONCLUSIONS: The patient has treated by CHOP chemotherapy regiment successfully and after completion of treatment, there was complete response. PMID- 26634112 TI - Construction and Validation the Lifestyle Questionnaire Related to Cancer. AB - BACKGROUND: Healthy lifestyle is a significant factor in cancer etiologic and prevention of cancer. There are instruments to measure a healthy life style, but the lifestyle questionnaires only examine one or a few more aspects of lifestyle. OBJECTIVES: The purpose of this study was to construct a comprehensive instrument to examine all aspects of lifestyle related to cancer. MATERIALS AND METHODS: This study was a cross-sectional study that was conducted in Yazd city in Iran. A questionnaire was designed to assess and measure various aspects of lifestyle related to cancer using similar studies. Researchers used the Cronbach's alpha and test-retest method to determine the reliability. Also, construct validity was determined using the factor analysis method in SPSS 16 software. RESULTS: Face validity was examined using a panel of experts. Cronbach's alpha for the whole scale was appropriate (alpha = 0.87). Also, Cronbach's alpha for all dimensions of questionnaire was acceptable (perfect score). Test-retest method was used to determine the reliability. The results indicated that ICC was in the range of 0.84 to 0.94. Based on the obtained results of factor analysis method, 8 dimensions of the questionnaire were extracted (physical health, physical activity and exercise, mental health, drug and alcohol avoidance, balanced consumption of food, environmental pollutants and harmful substances, weight control and nutrition, and reproductive health). CONCLUSIONS: This study showed that the present questionnaire can be used as a valid and reliable tool for collecting data about the lifestyle of people related to cancer. PMID- 26634113 TI - Preventing and Therapeutic Effect of Propolis in Radiotherapy Induced Mucositis of Head and Neck Cancers: A Triple-Blind, Randomized, Placebo-Controlled Trial. AB - BACKGROUND: Mucositis is one of the acute complications of radiotherapy which can ulcerate oral mucosa and cause severe pain and discomfort which can affect oral normal function. Propolis is a natural source of flavenoid which has antiulcer, antibacterial, antifungal, healing and anti-inflammatory effects. Using such an affordable compound without any bad smell or taste that has reasonable price can help the radiotherapy undergoing patients. OBJECTIVES: Our goal is assessing the preventing and therapeutic effect of propolis in radiotherapy induced mucositis in patients with head and neck cancer. PATIENTS AND METHODS: In a randomized triple blind clinical trial, 20 patient were selected randomly to swish and swallow 15 ml of water based extract of propolis mouth wash 3 times a day in the case group (n = 10) and 15 ml placebo mouth wash in control group (n = 10). we use NIC-CTC scale for determining mucositis grading. RESULTS: We use T-test, Man Whitney, Chi-square, and Friedman as analyzing tests. Case group had significantly (P < 0.05) lower grade of mucositis in all of the follow-ups, but xerostomia is not significantly different in two groups (P > 0.05). CONCLUSIONS: This is a pilot study which shows water based extract of propolis efficiently prevents and heals radiotherapy induced mucositis. PMID- 26634114 TI - An Investigation of the Growth Inhibitory Capacity of Several Medicinal Plants From Iran on Tumor Cell Lines. AB - BACKGROUND: Traditional herbal medicine is a valuable resource that provides new drugs for cancer treatment. OBJECTIVES: In this study we aim to screen and investigate the in vitro anti-tumor activities of ten species of plants commonly grown in Southern Iran. MATERIALS AND METHODS: We used the MTT colorimetric assay to evaluate the cytotoxic activities of the methanol extracts of these plants on various tumor cell lines. The IC50 was calculated as a scale for this evaluation. RESULTS: Satureja bachtiarica, Satureja hortensis, Thymus vulgaris, Thymus daenensis and Mentha lonigfolia showed the inhibitoriest effects on Jurkat cells with > 80% inhibition at 200 ug/mL. Satureja hortensis (IC50: 66.7 ug/mL) was the most effective. These plants also strongly inhibited K562 cell growth; Satureja bachtiarica (IC50: 28.3 ug/mL), Satureja hortensis (IC50: 52 ug/mL) and Thymus vulgaris (IC50: 87 ug/mL) were the most effective extracts. Cichorium intybus, Rheum ribes, Alhagi pseudalhagi and Glycyrrihza glabra also showed notable effects on the leukemia cell lines. The Raji cell line was mostly inhibited by Satureja bachtiarica and Thymus vulgaris with approximately 40% inhibition at 200ug/ml. The influence of these extracts on solid tumor cell lines was not strong. Fen cells were mostly affected by Glycyrrihza glabra (IC50: 182 ug/mL) and HeLa cells by Satureja hortensis (31.6% growth inhibitory effect at 200 ug/mL). CONCLUSIONS: Leukemic cell lines were more sensitive to the extracts than the solid tumor cell lines; Satureja hortensis, Satureja bachtiarica, Thymus vulgaris, Thymus daenensis and Mentha lonigfolia showed remarkable inhibitory potential. PMID- 26634115 TI - Cost-Utility Analysis of IEV Drug Regimen Versus ESHAP Drug Regimen for the Patients With Relapsed and Refractory Hodgkin and Non-Hodgkin's Lymphoma in Iran. AB - BACKGROUND: Chemotherapy for lymph nodes cancer is often composed of several drugs that are used in a treatment program. OBJECTIVES: The aim of this study was to perform a cost-utility analysis of IEV regimen (ifosfamide, epirubicin and etoposide) versus ESHAP regimen (etoposide, methylprednisolone, high-dose cytarabine, and cisplatin) in patients with lymphoma in the south of Iran. PATIENTS AND METHODS: This was a cost-utility analysis done as a cross-sectional study in the south of Iran. Using decision tree, expected costs, quality adjusted life years (QALYs) and the incremental cost-effectiveness ratio (ICER) were estimated. In addition, the robustness of results was examined by sensitivity analysis. RESULTS: The results of this study indicated that the total lymphoma patients were about 65 people that 27 patients received IEV regimen and 38 patients ESHAP (43 patients with Hodgkin's and 22 with non-Hodgkin lymphoma). The results of decision tree showed that in the IEV arm, the expected cost was $20952.93 and the expected QALYs was 3.89 and in the ESHAP arm, the expected cost was $31691.74 and the expected QALYs was 3.86. Based on the results of the study, IEV regimen was cost-effective alternative to the ESHAP regimen. CONCLUSIONS: According to the results of this study, it is recommended that oncologists use IEV instead of ESHAP in the treatment of patients with lymphoma and because of high costs of IEV drug costs, it is suggested that IEV drugs should be covered by insurance. PMID- 26634116 TI - The Role of Family and Care Givers of Cancer Survivors in Patient Management. PMID- 26634118 TI - Treating chronic spontaneous urticaria using a brief 'whole person' treatment approach: a proof-of-concept study. AB - BACKGROUND: Chronic spontaneous urticaria (CSU) poses problems with respect to high prevalence, reduced quality of life, lack of long term efficacy, and expense of current treatments for severe intractable symptoms. There have been many reports suggesting 'stress' factors may be implicated, but there are no studies that explore the efficacy of treatments including a psychological perspective. A whole person treatment approach (WPTA), which addresses psychological factors has been used, with effect, for 6 years in the Auckland City Hospital Immunology Department. FINDINGS: In a pilot study to demonstrate feasibility of recruitment and treatment of CSU patients in a time-limited, whole person treatment approach, within a conventional immunology department, four patients (three CSU and one idiopathic angioedema) were recruited into a brief WPTA course based in non dualistic concepts of mind and body connectedness, and utilising psychotherapy derived listening skills for up to 10 h long sessions, once per week. Treatment efficacy rating, using Urticaria Activity Score and the Urticaria Severity Score, and reduction of drug usage, showed patients experienced long term resolution of urticaria and cessation of hospitalisation for angioedema and came off regular antihistamine medication. CONCLUSIONS: A clinician treating chronic spontaneous urticaria in an Immunology department, using a whole person treatment paradigm, can safely explore unique meanings and emotional states, in a process acceptable to patients, resulting in a significant clinical benefit for symptoms. A much larger study comparing the outcome of WPTA versus standard treatment alone is warranted. PMID- 26634117 TI - Elusive sources of variability of dystrophin rescue by exon skipping. AB - BACKGROUND: Systemic delivery of anti-sense oligonucleotides to Duchenne muscular dystrophy (DMD) patients to induce de novo dystrophin protein expression in muscle (exon skipping) is a promising therapy. Treatment with Phosphorodiamidate morpholino oligomers (PMO) lead to shorter de novo dystrophin protein in both animal models and DMD boys who otherwise lack dystrophin; however, restoration of dystrophin has been observed to be highly variable. Understanding the factors causing highly variable induction of dystrophin expression in pre-clinical models would likely lead to more effective means of exon skipping in both pre-clinical studies and human clinical trials. METHODS: In the present study, we investigated possible factors that might lead to the variable success of exon skipping using morpholino drugs in the mdx mouse model. We tested whether specific muscle groups or fiber types showed better success than others and also correlated residual PMO concentration in muscle with the amount of de novo dystrophin protein 1 month after a single high-dose morpholino injection (800 mg/kg). We compared the results from six muscle groups using three different methods of dystrophin quantification: immunostaining, immunoblotting, and mass spectrometry assays. RESULTS: The triceps muscle showed the greatest degree of rescue (average 38+/-28 % by immunostaining). All three dystrophin detection methods were generally concordant for all muscles. We show that dystrophin rescue occurs in a sporadic patchy pattern with high geographic variability across muscle sections. We did not find a correlation between residual morpholino drug in muscle tissue and the degree of dystrophin expression. CONCLUSIONS: While we found some evidence of muscle group enhancement and successful rescue, our data also suggest that other yet-undefined factors may underlie the observed variability in the success of exon skipping. Our study highlights the challenges associated with quantifying dystrophin in clinical trials where a single small muscle biopsy is taken from a DMD patient. PMID- 26634119 TI - Implementation of an antimicrobial stewardship program targeting residents with urinary tract infections in three community long-term care facilities: a quasi experimental study using time-series analysis. AB - BACKGROUND: Asymptomatic bacteriuria in the elderly commonly results in antibiotic administration and, in turn, contributes to antimicrobial resistance, adverse drug events, and increased costs. This is a major problem in the long term care facility (LTCF) setting, where residents frequently transition to and from the acute-care setting, often transporting drug-resistant organisms across the continuum of care. The goal of this study was to assess the feasibility and efficacy of antimicrobial stewardship programs (ASPs) targeting urinary tract infections (UTIs) at community LTCFs. METHODS: This was a quasi-experimental study targeting antibiotic prescriptions for UTI using time-series analysis with 6-month retrospective pre-intervention and 6-month intervention period at three community LTCFs. The ASP team (infectious diseases (ID) pharmacist and ID physician) performed weekly prospective audit and feedback of consecutive prescriptions for UTI. Loeb clinical consensus criteria were used to assess appropriateness of antibiotics; recommendations were communicated to the primary treating provider by the ID pharmacist. Resident outcomes were recorded at subsequent visits. Generalized estimating equations using segmented regression were used to evaluate the impact of the ASP intervention on rates of antibiotic prescribing and antibiotic resistance. RESULTS: One-hundred and four antibiotic prescriptions for UTI were evaluated during the intervention, and recommendations were made for change in therapy in 40 (38 %), out of which 10 (25 %) were implemented. Only eight (8 %) residents started on antibiotics for UTI met clinical criteria for antibiotic initiation. An immediate 26 % decrease in antibiotic prescriptions for UTI during the ASP was identified with a 6 % reduction continuing through the intervention period (95 % Confidence Interval ([CI)] for the difference: -8 to -3 %). Similarly, a 25 % immediate decrease in all antibiotic prescriptions was noted after introduction of the ASP with a 5 % reduction continuing throughout the intervention period (95 % CI: -8 to -2 %). No significant effect was noted on resistant organisms or Clostridium difficile. CONCLUSION: Weekly prospective audit and feedback ASP in three community LTCFs over 6 months resulted in antibiotic utilization decreases but many lost opportunities for intervention. PMID- 26634120 TI - Development of the European Health Interview Survey - Physical Activity Questionnaire (EHIS-PAQ) to monitor physical activity in the European Union. AB - BACKGROUND: A domain-specific physical activity questionnaire (EHIS-PAQ) was developed in the framework of the second wave of the European Health Interview Survey (EHIS). This article presents the EHIS-PAQ and describes its development and evaluation processes. METHODS: Research institutes from Belgium, Estonia and Germany participated in the Improvement of the EHIS (ImpEHIS) Grant project issued by Eurostat. The instrument development process comprised a non-systematic literature review and a systematic HIS/HES database search for physical activity survey questions. The developed EHIS-PAQ proposal was reviewed by survey experts. Cognitive testing of the EHIS-PAQ was conducted in Estonia and Germany. The EHIS PAQ was further tested in a pilot survey in Belgium, Estonia and Germany in different modes of data collection, face-to-face paper and pencil interview (PAPI) and computer assisted telephone interview (CATI). RESULTS: The EHIS-PAQ is a rather pragmatic tool aiming to evaluate how far the population is physically active in specific public health relevant settings. It assesses work-related, transport-related and leisure-time physical activity in a typical week. Cognitive testing revealed that the EHIS-PAQ worked as intended. The pilot testing showed the feasibility of using the EHIS-PAQ in an international health interview survey setting in Europe. It will be implemented in all 28 European Union Member States via European Union implementing regulation in the period between 2013 and 2015. This will be a first opportunity to get comparable data on domain-specific physical activity in all 28 EU MS and to publish indicators at the EU level. CONCLUSIONS: The EHIS-PAQ is a short, domain-specific PA questionnaire based on PA questions which have been used in large-scale health interview surveys before. It was designed by considering the respondents' perspective in answering PA questions. PMID- 26634121 TI - Concept review of dry powder inhalers: correct interpretation of published data. AB - Dry powder inhalers (DPIs) are widely used in the clinical practice for delivering therapeutics to patients with lung diseases, such as chronic obstructive pulmonary disease. An overview of current DPIs available on the market from high resistance to low resistance has been reported in a recent review article. We assessed this concept review article and believe this letter provides important additional information regarding the correct interpretation of the data on low resistance DPIs. PMID- 26634122 TI - Modeling workplace contact networks: The effects of organizational structure, architecture, and reporting errors on epidemic predictions. AB - Face-to-face social contacts are potentially important transmission routes for acute respiratory infections, and understanding the contact network can improve our ability to predict, contain, and control epidemics. Although workplaces are important settings for infectious disease transmission, few studies have collected workplace contact data and estimated workplace contact networks. We use contact diaries, architectural distance measures, and institutional structures to estimate social contact networks within a Swiss research institute. Some contact reports were inconsistent, indicating reporting errors. We adjust for this with a latent variable model, jointly estimating the true (unobserved) network of contacts and duration-specific reporting probabilities. We find that contact probability decreases with distance, and that research group membership, role, and shared projects are strongly predictive of contact patterns. Estimated reporting probabilities were low only for 0-5 min contacts. Adjusting for reporting error changed the estimate of the duration distribution, but did not change the estimates of covariate effects and had little effect on epidemic predictions. Our epidemic simulation study indicates that inclusion of network structure based on architectural and organizational structure data can improve the accuracy of epidemic forecasting models. PMID- 26634123 TI - Chronic stress does not impair liver regeneration in rats. AB - BACKGROUND: Although wound healing is a simple regenerative process that is critical after surgery, it has been shown to be impaired under psychological stress. The liver has a unique capacity to regenerate through highly complex mechanisms. The aim of this study was to investigate the effects of chronic stress, which may induce a depression-like state, on the complex process of liver regeneration in rats. METHODS: Twenty rats were included in this study. The animals received either a standard housing protocol or were subjected to a Chronic Mild Stress (CMS) stress paradigm. All rats underwent a 70 % partial hepatectomy (PHx). The animals were evaluated on postoperative day 2 or 4. Blood samples were collected to examine circulating markers of inflammation and liver cell damage. Additionally, liver tissues were sampled to evaluate liver weight and regeneration rate. RESULTS: None of the animals died during the study. There were no differences between in body weight, liver weight, liver regeneration rate or biochemical markers at any time during the study. CONCLUSION: The results of this study indicate that stress and the induction of depression-like state do not affect the process of liver regeneration after 70 % hepatectomy in rats. PMID- 26634124 TI - Incidence and risk factors of delirium in multi-center Thai surgical intensive care units: a prospective cohort study. AB - BACKGROUND: Delirium in intensive care units increases morbidity and mortality risk. The incidence and risk factors of delirium vary among studies. This study therefore aimed to determine the incidence and risk factors of delirium in Thai university-based surgical intensive care units. METHODS: A multi-center, prospective cohort study was conducted. All patients who had been admitted to surgical intensive care units (SICU) between April 2011 and January 2012 were enrolled. Delirium was diagnosed using the Intensive Care Delirium Screening Checklists (ICDSC). The univariable and multivariable risk regression analyses were analyzed and presented as risk ratio (RR) and 95 % confidence interval (CI). RESULTS: The overall incidence of delirium was 3.6 % (162 of 4450, 95 % CI 3.09 4.19 %) whilst the incidences of delirium for patients being admitted <=48 and >48 h were 0.7 % (21 of 2967, 95 % CI 0.41-1.01 %) and 8.3 % (141 of 1685, 95 % CI 7.04-9.68 %), respectively. The incidence of delirium on each study site was significantly different (range between 0 and 13.9 %, P < 0.001). Delirious patients had a significantly higher age (65.3 +/- 15.6 versus 61.8 +/- 17.3 years, P = 0.013), higher Acute Physiology and Chronic Health Evaluation II score (APACHE II score) (16 (12-23) versus 10 (7-15), P < 0.001), and higher sequential organ failure assessment score (5 (2-8) versus 2 (1-5), P < 0.001). The median duration of delirium was 3 (1-5) days. Delirious patients had significantly longer duration of ICU stay (8 (5-19) versus 2 (1-4), P < 0.001) and higher ICU mortality rate (23.5 versus 8.1 %, P < 0.001). Sepsis (RR = 3.70, 95 % CI 2.33 5.90, P < 0.001), exposure to sedative medications (RR = 3.54, 95 % CI 2.13-5.87, P < 0.001), higher APACHE II score (RR = 2.79, 95 % CI 1.98-3.95, P < 0.001), thoracic surgery (RR = 1.74, 95 % CI 1.09-2.78, P = 0.021), and emergency surgery (RR = 1.70, 95 % CI 1.09-2.65, P = 0.019) were independent risk factors of delirium in SICU. CONCLUSIONS: Sepsis, exposure to sedative medications, higher APACHE II score, thoracic surgery, and emergency surgery were independent risk factors of delirium in Thai university-based surgical intensive care units. PMID- 26634125 TI - Therapeutic dilemma in the management of a patient with the clinical picture of TTP and severe B12 deficiency. AB - BACKGROUND: Idiopathic thrombotic thrombocytopenic purpura (TTP) is a rare hematological emergency characterized by the pentad of microangiopathic hemolytic anemia, thrombocytopenia, neurological symptoms, renal injury, and fever that is invariably fatal if left untreated. Prompt intervention with plasma exchange minimizes mortality and is the cornerstone of therapy. Rare reports have described "pseudo-TTP" driven by extreme hematologic abnormalities resulting from deficiency of vitamin B12. Distinguishing between these entities can pose a diagnostic and therapeutic challenge. CASE PRESENTATION: A 77 year old female presented with altered mental status, renal insufficiency, thrombocytopenia and evidence of microangiopathic hemolytic anemia, suggesting TTP. Workup demonstrated macrocytosis and reticulocytopenia, and B12 level was unmeasurably low. Other elements of her clinical presentation, including volume loss and bleeding suggested a multifactorial pathogenesis could be contributing to her laboratory abnormalities, reducing the likelihood that she had TTP. The risks and benefits of treating aggressively with therapeutic plasma exchange (TPE) for TTP were considered given the diagnostic possibilities. The patient received TPE initially, with rapid de-escalation after her clinical response suggested "pseudo TTP" from B12 deficiency was the driving the process. B12 supplementation corrected her hematologic abnormalities and she remains well two years after presenting. CONCLUSIONS: TTP is a rare condition with fatal consequences if left untreated. Guidelines recommend TPE even if there is uncertainty about the diagnosis of TTP. B12 deficiency is common, though not typically associated with severe hematologic abnormalities. We compare the presenting characteristics of all thirteen cases of pseudo-TTP reported in the literature with those from patients in case series of TTP to suggest a set of parameters that can help clinicians distinguish between pseudo-TTP and TTP and guide decision making regarding intervention. Evaluation of all TTP cases should include a B12, methylmalonic acid level and reticulocyte count. Reticulocytopenia suggests B12 deficiency. Finally an LDH level above 2500 IU/L is relatively uncommon in TTP and should suggest consideration of B12 deficiency. PMID- 26634126 TI - Applicability of models to estimate traffic noise for urban roads. AB - BACKGROUND: Traffic noise is a highly relevant environmental impact in cities. Models to estimate traffic noise, in turn, can be useful tools to guide mitigation measures. In this paper, the applicability of models to estimate noise levels produced by a continuous flow of vehicles on urban roads is investigated. The aim is to identify which models are more appropriate to estimate traffic noise in urban areas since several models available were conceived to estimate noise from highway traffic. RESULTS: First, measurements of traffic noise, vehicle count and speed were carried out in five arterial urban roads of a brazilian city. Together with geometric measurements of width of lanes and distance from noise meter to lanes, these data were input in several models to estimate traffic noise. The predicted noise levels were then compared to the respective measured counterparts for each road investigated. In addition, a chart showing mean differences in noise between estimations and measurements is presented, to evaluate the overall performance of the models. Measured Leq values varied from 69 to 79 dB(A) for traffic flows varying from 1618 to 5220 vehicles/h. Mean noise level differences between estimations and measurements for all urban roads investigated ranged from -3.5 to 5.5 dB(A). CONCLUSIONS: According to the results, deficiencies of some models are discussed while other models are identified as applicable to noise estimations on urban roads in a condition of continuous flow. Key issues to apply such models to urban roads are highlighted. PMID- 26634127 TI - Bilateral hippocampal stroke secondary to acute cocaine intoxication. AB - Hippocampal infarction is a rare complication of cocaine use, with only two cases previously reporting this association. We present a 44-year-old male who developed a persistent amnesic syndrome following cocaine intoxication. Examination identified no other neurological deficits. Subsequent MRI brain revealed high FLAIR signals and diffusion restriction in the hippocampus and centrum semiovale bilaterally, consistent with infarction. These findings were in keeping with the results of formal neuropsychological testing where deficits in both verbal and visual episodic memory and learning capacity were identified, consistent with hippocampal dysfunction. In contrast to previous reports, this presentation occurred in the absence of other vascular risk factors or hypoxic insults. PMID- 26634128 TI - Oro-facial swelling: ultrasonographic aid in the diagnosis. AB - Oro-facial swellings are frequently encountered in clinical practice. The aim of this report is to unveil the uncommon manifestation of a common clinical problem and the help of ultrasonographic imaging in the diagnosis. PMID- 26634129 TI - Etanercept-associated myelitis. PMID- 26634130 TI - Kleine-Levin syndrome with comorbid iron deficiency anemia. AB - Kleine-Levin syndrome (KLS) is a rare chronic sleep disorder of unknown etiopathology, which typically occurs in adolescent males. Although the severity of symptoms and disease course varies between the KLS patients, it usually resolves spontaneously, but sometime comorbid conditions may worsen the symptoms. Herein, we report a case of KLS who presented with severe episodic hypersomnia. During episodes, the patient used to sleep as long as 20 h in a day, affecting his daily living activities. All the relevant investigations including electroencephalography, magnetic resonance imaging of brain and cerebrospinal fluid analysis were normal except for severe iron deficiency anemia (IDA). In our patient, the severity of symptoms worsened due to coexistent IDA. The treatment of IDA along with modafinil decreased the severity of symptoms and shortened the hospital stay during episodes. This might be the first case report of KLS with comorbid IDA. PMID- 26634131 TI - Priapism and clozapine use in a patient with hypochondriacal delusional syndrome. AB - Priapism is a urological emergency that results in a penile or clitoral engorgement, having several triggers by the use of medications, including psychiatric drugs, such as antipsychotics and antidepressants. The most common priapism presentation is the ischemic type that can result in the fibrosis of corporus cavernosus, with a significant risk of persistent erectile dysfunction. It is believed that, in the case of antipsychotic use, priapism is mediated by an imbalance in alpha-1-adrenergic blocking, with large variation affinity for alpha 1-adrenergic receptors among antipsychotics. This case report contributes to the study of this rare but severe side effect. Priapism can limit both treatment adherence and the reproductive future of our patients. We describe a case report of a patient with a delusional hypochondriac syndrome who had multiple priapism episodes using clozapine 50 mg/daily. In conclusion, we make brief comments on priapism management, a hard clinical dilemma. PMID- 26634132 TI - A 'Y-shaped' soft tissue ossification in fibrodysplasia ossificans progressiva. PMID- 26634133 TI - Polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes (POEMS syndrome): a paraneoplastic syndrome. AB - POEMS syndrome (Crow-Fukase syndrome) is a rare paraneoplastic disorder. It is characterized by peripheral neuropathy, elevated vascular endothelial growth factors (VEGFs), monoclonal gammopathy, sclerotic bone lesions and Castleman disease. Other important clinical features are organomegaly, edema, ascites, papilledema, endocrinopathy, skin changes and thrombocytosis. A high index of suspicion, a detailed clinical history and examination followed by appropriate laboratory investigations like VEGF level, radiological skeletal survey and bone marrow biopsy are required to diagnose POEMS syndrome. We report a case of POEMS syndrome who presented with insidious onset, progressive sensorimotor polyneuropathy, pedal edema, ascites, hepatomegaly, skin changes and hypothyroidism. X-ray of the pelvis showed osteosclerotic lesions. Immunoelectrophoresis using the immunofixation method revealed lambda chain monoclonal gammopathy. The patient was given radiotherapy, followed by a combination therapy of melphalan and dexamethasone. We emphasize the importance of recognizing a challenging diagnosis of a rare disease, which is shown to be treatment responsive. PMID- 26634134 TI - An isolated case of first metatarsal tuberculosis. AB - An apparently healthy adolescent presented to us with multiple discharging sinuses from his right foot for the past 1 year. All serological parameters were within normal limits. X-ray picture revealed an expansile osteolytic lesion of first metatarsal. Tissue biopsy and PCR confirmed it be of tubercular etiology. The incidence of isolated occurrence of metatarsal tuberculosis is very rare and the diagnostic dilemma it brings about is briefly discussed in the following report. PMID- 26634135 TI - Insomnia and exacerbation of anxiety associated with high-EPA fish oil supplements after successful treatment of depression. AB - A 54-year-old male consulted his general practitioner for increasing general anxiety and mild panic attacks despite effective treatment for recurrent major depressive disorder, which included a fish oil supplement enriched in eicosapentaenoic acid (EPA). The patient would awaken suddenly at night with shortness of breath and overwhelming worry. During the daytime, he felt a general, nonspecific anxiety and frequently experienced sympathetic activation upon confronting routine challenges. He also experienced dyspnea-induced feelings of panic. He reported that he stopped taking the fish oil supplements after several more months of symptoms, and his anxiety and insomnia then largely disappeared. Several weeks later, he resumed consumption of high-EPA fish oil at the prior dosage for 2 days. On both nights, the patient reported nighttime awakening similar to the previous episodes, followed by daytime agitation. Since halting the fish oil supplements, the anxiety and insomnia have not returned and his depression remains in remission. PMID- 26634136 TI - Biliary ascariasis: radiological clue to diagnosis. AB - Ascariasis is caused by Ascaris lumbricoides. It is the most common helminthic infection seen worldwide. Ascariasis is an endemic disease in our country. This is due to the prevailing poor sanitary conditions and low level of education. Biliary ascariasis is an uncommon cause of obstructive jaundice. We report a case of biliary ascariasis in a young labourer who presented with acute abdominal pain. PMID- 26634137 TI - Case of acquired or pseudo-Pelger-Huet anomaly. AB - Pelger-Huet anomaly (PHA) is a rare benign autosomal-dominant anomaly with an incidence of ~1 in 6000. It does not cause neutrophilia, but it can cause a false increase in band forms. It should be differentiated from acquired or pseudo Pelger-Huet anomaly (PPHA), which has similar morphology, however; it is associated with different pathological states like Myelodysplastic syndrome, as well as with certain infections and drugs. We report a case of a 67-year-old Caucasian gentleman with past medical history of rheumatoid arthritis, type II diabetes mellitus and hypothyroidism, who presented with 1 day history of fever (101 degrees F) and night sweats. Medications include ibuprofen, methotrexate, hydroxychloroquine and levothyroxine. Patient denied any other symptoms. His work up showed normal WBC count (8.6) and increase in bands (24%). The patient was admitted for further evaluation. During the next 2 days, the patient did not have any fever or any new symptoms. Peripheral blood smear was done as part of his work-up for bandemia, showed findings suggestive of PHA. Ibuprofen was discontinued. Follow-up few weeks later showed normal blood smear. Diagnosis of PPHA was made. The presented case showed that we should think of PHA?PPHA in any case with normal total WBC count and significant shift to the lift with no apparent explanation. Looking at smears directly under the microscopes is crucial to make diagnosis. PMID- 26634138 TI - Cytological diagnosis of bancroftian filariasis presented as a subcutaneous swelling in the cubital fossa: an unusual presentation. AB - Filariasis is a disabling parasitic disease and the prevalence of lymphatic filariasis caused by Wuchereria bancrofti is quite high in India. However, W. bancrofti presenting as a subcutaneous swelling and a demonstration of microfilariae in cytological smears from upper extremity lesions is extremely rare. We report a case of 20-year-old male who presented with a small subcutaneous swelling near medial aspect of the left cubital fossa. The wet mount preparation showed many motile microfilariae. Cytology smears revealed a large number of sheathed microfilariae with the tail tip free of nucleus, identified as W. bancrofti without significant inflammatory cell infiltrate. Indirect ELISA was highly positive for specific recombinant W. bancrofti filarial antigen (WL-L2). The role of cytology cannot be underestimated in clinically unanticipated cases of bancroftian filariasis, especially with the amicrofilaremic state. Filariasis should always be considered in the differential diagnosis during cytological evaluation of any swelling, especially in endemic areas. PMID- 26634139 TI - CPT-11/bevacizumab for the treatment of refractory brain metastases in patients with HER2-neu-positive breast cancer. AB - Nervous system relapse of patients with advanced HER2-neu-positive breast cancer is an increasing problem, with one-third of women developing brain metastases. Standard therapies using steroids, surgery and radiotherapy do not provide a lasting response. We evaluated CPT-11 and bevacizumab, which can both cross the blood-brain barrier, as combination therapy to treat HER2-neu-positive breast cancer with brain metastases. PMID- 26634140 TI - Myeloma-associated systemic amyloidosis masquerading as NASH-associated cirrhosis and diabetic microvascular complications. AB - Authors describe the case of a 60-year-old diabetic man who presented with jaundice, ascites and significant weight loss over a period of 2 months. Physical examination revealed firm hepatomegaly with ascites. On evaluation, nephropathy, axonal neuropathy, carpal tunnel syndrome and decompensated cryptogenic liver disease with portal hypertension were found fitting with the diagnosis of diabetic nephropathy and neuropathy and nonalcoholic steato-hepatitis-associated cirrhosis, respectively. It was only after tissue diagnosis and serum protein electrophoresis that a definitive diagnosis of myeloma-related amyloidosis was made. This case emphasizes the fact that due to nonspecific initial presentation and multisystem involvement, a high index of suspicion and prompt use of appropriate tests including tissue diagnosis may be required to diagnose amyloid light-chain amyloidosis, which may be a rare presenting feature of myeloma. It should be differentiated from a commoner multisystem disease like diabetes and its complications. PMID- 26634141 TI - Tuberculosis of the thyroid gland: two case reports. AB - Tuberculosis of the thyroid gland is a rare entity even in countries like India where tuberculosis is endemic. The patients may present with thyroid swelling, inflammation and very rarely thyroid dysfunction. Caseous necrosis and epithelioid cell granulomas on fine-needle aspiration cytology and histopathological examination are diagnostic. We present two cases of thyroid gland tuberculosis. One patient had subclinical thyrotoxicosis with presentation mimicking acute bacterial thyroiditis. The other patient had a solitary thyroid nodule with normal thyroid function. Involvement of other organs was absent in both cases. Proper diagnosis may avoid unnecessary surgical interventions. PMID- 26634142 TI - Oncogenic osteomalacia caused by occult nasal mesenchymal tumor: a monster in the cave. AB - Authors describe a case of oncogenic osteomalacia in a 35-year-old man, who presented with a 2-year history of generalized pain and progressive weakness of lower limbs, eventually became bedbound. At admission, he had severe hip pain resulting from bilateral femoral neck fractures. Laboratory investigations revealed hypophosphatemia, hyperphosphaturia, normocalcemia, elevated alkaline phosphatase and normal serum levels of parathormone and 25-hydroxyvitamin D. Serum fibroblast growth factor 23 (FGF23) level was elevated. A radiographic skeletal survey showed osteoporosis and insufficiency fractures of the femoral neck. A whole-body functional imaging failed to reveal any areas of increased activity. However, on computed tomography and magnetic resonance imaging of the head and neck region, a tumor was discovered at left nasal cavity. The tumor was surgically removed. After surgery, his symptoms were relieved and biochemical parameters normalized. We stress that careful clinical examination including nose and paranasal sinuses may be rewarding in cases with hypophosphatemic osteomalacia. PMID- 26634143 TI - Yersinia pseudotuberculosis aortitis in a patient with diverticulosis and polycystic kidney disease. AB - An 81-year-old gentleman with chronic kidney disease presented with pyrexia and a new systolic cardiac murmur. Investigations revealed infective aortitis of a pre existing aortic aneurysm graft repair. Peripheral blood cultures were positive for Yersinia pseudotuberculosis and the patient was successfully treated with an extended course of antibiotics. Abdominal imaging also revealed progressive bilateral polycystic kidney disease with associated diverticular disease, which was postulated as the source of the Y. pseudotuberculosis. An autosomal dominant polycystic kidney disease may present late in life and extra-renal manifestations of this disease are an important cause of morbidity. PMID- 26634144 TI - Guillain-Barre syndrome mimics primary biliary cirrhosis-related myopathy. AB - Guillain-Barre syndrome (GBS) is an immune-mediated disorder characterized by acute polyneuropathy, ascending paralysis and post infectious polyneuritis. Two thirds of patients present with a history of recent upper respiratory tract or gastrointestinal infection. The clinical history, neurologic examination and laboratory assessment allow for a straightforward diagnosis in the majority of cases. However, primary biliary cirrhosis (PBC) is known to cause clinically detectable muscular weakness. It is therefore critical to differentiate between PBC-associated muscular weakness and GBS-induced paralysis. Here, we report a patient with a longstanding history of PBC who developed progressive weakness and respiratory failure due to GBS, which clinically mimicked PBC myopathy. This is the first reported association between GBS and PBC. PMID- 26634145 TI - An unexpected cause of hypertrophic myocardium. PMID- 26634146 TI - Nitric oxide inhibition strategies. AB - Nitric oxide is involved in many physiologic processes. There are efforts, described elsewhere in this volume, to deliver nitric oxide to tissues as a therapy. Nitric oxide also contributes to pathophysiologic processes. Inhibiting nitric oxide or its production can thus also be of therapeutic benefit. This article addresses such inhibitory strategies. PMID- 26634147 TI - MRI with intrathecal MRI gadolinium contrast medium administration: a possible method to assess glymphatic function in human brain. AB - Recently, the "glymphatic system" of the brain has been discovered in rodents, which is a paravascular, transparenchymal route for clearance of excess brain metabolites and distribution of compounds in the cerebrospinal fluid. It has already been demonstrated that intrathecally administered gadolinium (Gd) contrast medium distributes along this route in rats, but so far not in humans. A 27-year-old woman underwent magnetic resonance imaging (MRI) with intrathecal administration of gadobutrol, which distributed throughout her entire brain after 1 and 4.5 h. MRI with intrathecal Gd may become a tool to study glymphatic function in the human brain. PMID- 26634148 TI - Adoptive transfer of immune subsets prior to MCAO does not exacerbate stroke outcome in splenectomized mice. AB - The peripheral immune response contributes to neurologic impairment after stroke and the extent of initial damage is greater in males than females. We have previously shown that spleen cells directly contribute to ischemic damage in males, as splenectomy prior to experimental stroke eliminates the sex differences in infarct volume. This study aims to determine which specific subset of immune cells exert pathogenic effects when injected 24 hours before MCAO induction into splenectomized male and female WT mice. The results demonstrate that CD4/CD8/CD11b treated mice had no significant effect on infarct volumes vs. vehicle-treated control mice after MCAO. However, there were significant alterations to the resident peripheral immune composition. These results suggest that there are regulatory factors resulting from splenectomy or other possible influences that inhibit peripheral immune cell contribution to neuroinflammation and thus contributing to differential effects of the spleen on stroke outcome in males and female mice. PMID- 26634149 TI - Clinical Variation of Plasmodium falciparum eba-175, ama-1, and msp-3 Genotypes in Young Children Living in a Seasonally High Malaria Transmission Setting in Burkina Faso. AB - The association between P. falciparum eba-175, ama-1, and msp-3 polymorphism in the pathogenicity of malaria disease was investigated. We therefore compared the prevalence of different alleles between symptomatic and asymptomatic malarial children under five years of age living in Burkina Faso. Blood filter papers were collected during the 2008 malaria transmission season from 228 symptomatic and 199 asymptomatic children under five years of age. All patients were living in the rural area of Sapone at about 50 km from Ouagadougou, the capital city of Burkina Faso. P. falciparum parasite DNA was extracted using QIAGEN kits and the alleles diversity was assessed by a nested PCR. PCR products were then digested by restriction enzymes based on already described polymorphic regions of the eba 175, ama-1, and msp-3 genes. The individual alleles eba-175_FCR3 and msp-3_K1 frequencies were statistically higher (p < 0.0001) in the asymptomatic group compared to the symptomatic ones. No statistically significant difference was noted in the prevalence of ama-1-3D7, ama-1-K1, and ama-1-HB3 genotypes between the two groups (p > 0.05). The comparative analysis of P. falciparum genotypes indicated that the polymorphism in eba-175 and msp-3 genotypes varied between asymptomatic and symptomatic clinical groups and may contribute to the pathogenesis of malaria. PMID- 26634150 TI - Optical Coherence Tomography Angiography in Central Serous Chorioretinopathy. AB - Purpose. To analyze optical coherence tomography angiography (OCTA) findings in eyes with central serous chorioretinopathy (CSC) and to compare them with those obtained with multimodal imaging. Methods. A series of consecutive patients diagnosed with CSC, underwent OCTA and multimodal imaging, including spectral domain OCT, fluorescein, and indocyanine green angiography. OCTA images were performed at three main depth intervals: automatically segmented outer retina, manually adjusted outer retina, and automatically segmented choriocapillaris. Results. Thirty-three eyes of 32 consecutive patients were analyzed. OCTA showed 3 main anomalies at the choriocapillaris: the presence of dark areas (19/33 eyes) which were frequently associated with serous retinal detachment, presence of dark spots (7/33 eyes) which were frequently associated with retinal pigment epithelium detachment, and presence of abnormal vessels (12/33 eyes) which were frequently, but not systematically, associated with choroidal neovascularization, as confirmed by multimodal imaging. Conclusions. OCTA revealed dark areas and dark spots, which were commonly observed. An abnormal choroidal pattern was also observed in one-third of cases, even when multimodal imaging did not evidence any choroidal neovascularization. Abnormal choroidal vessels should be interpreted with caution, and we could assume that this pathological choroidal vascular pattern observed in many CSC cases could be distinct from CNV. PMID- 26634151 TI - Assessment of Corneal Biomechanical Properties by CorVis ST in Patients with Dry Eye and in Healthy Subjects. AB - Purpose. To investigate corneal biomechanical properties in patients with dry eye and in healthy subjects using Corneal Visualization Scheimpflug Technology (CorVis ST). Methods. Biomechanical parameters were measured using CorVis ST in 28 eyes of 28 patients with dry eye (dry eye group) and 26 normal subjects (control group). The Schirmer I test value, tear film break-up time (TBUT), and corneal staining score (CSS) were recorded for each eye. Biomechanical properties were compared between the two groups and bivariate correlation analysis was used to assess the relationship between biomechanical parameters and dry eye signs. Results. Only one of the ten biomechanical parameters was significantly different between the two groups. Patients in the dry eye group had significantly lower highest concavity time (HC-time) (P = 0.02) than the control group. Correlation analysis showed a significant negative correlation between HC-time and CSS with marginal P value (rho = -0.39, P = 0.04) in the dry eye group. Conclusions. The corneal biomechanical parameter of HC-time is reduced in dry eyes compared to normal eyes. There was also a very weak but significant negative correlation between HC-time and CSS in the dry eye group, indicating that ocular surface damage can give rise to a more compliant cornea in dry eyes. PMID- 26634152 TI - Color Doppler Imaging Analysis of Ocular Blood Flow Velocities in Normal Tension Glaucoma Patients: A Meta-Analysis. AB - Background. To evaluate the potential diagnostic value of CDI of retrobulbar hemodynamic changes in NTG patients. Methods. Relevant publications which included PSV, EDV, and RI of OA, CRA, NPCA, and TPCA in NTG patients and normal controls measured by CDI were retrieved from the Cochrane Central Register of Controlled Trials, PubMed, the ISI Web of Knowledge, and EMBASE from 1990 to 2014. Subgroup analyses were made based on IOP-lowering medications uses. Result. In OA, there was significant decrease of PSV with moderate heterogeneity (P < 0.00001, I (2) = 49%) and significant decrease of EDV with significant heterogeneity (P = 0.0005, I (2) = 87%) in NTG patients. In CRA, similar results of PSV (P < 0.00001, I (2) = 42%) and EDV (P < 0.00001, I (2) = 80%) were detected. Significant decrease of PSV and EDV with significant heterogeneity was also found in both NPCA (P < 0.0001, I (2) = 70%; P < 0.0001, I (2) = 76%; resp.) and TPCA (P < 0.00001, I (2) = 54%; P < 0.00001, I (2) = 65%; resp.). Statistically significant increases of RI were found in CRA (P = 0.0002, I (2) = 89%) and TPCA (P = 0.02, I (2) = 81%) with significant heterogeneities, though RI in OA (P = 0.25, I (2) = 94%) and in NPCA (P = 0.15, I (2) = 86%) showed no statistical changes with significant heterogeneities. Conclusions. Ischemic change of retrobulbar hemodynamics is one of the important manifestations of NTG. Hemodynamic parameters measured by CDI might be potential diagnostic tools for NTG. PMID- 26634154 TI - Differential Expression of Tyrosine Hydroxylase Protein and Apoptosis-Related Genes in Differentiated and Undifferentiated SH-SY5Y Neuroblastoma Cells Treated with MPP(.). AB - The human neuroblastoma SH-SY5Y cell line has been used as a dopaminergic cell model for Parkinson's disease research. Whether undifferentiated or differentiated SH-SY5Y cells are more suitable remains controversial. This study aims to evaluate the expression of apoptosis-related mRNAs activated by MPP(+) and evaluate the differential expression of tyrosine hydroxylase (TH) in undifferentiated and retinoic acid- (RA-) induced differentiated cells. The western blot results showed a gradual decrease in TH in undifferentiated cells and a gradual increase in TH in differentiated cells from days 4 to 10 after cell plating. Immunostaining revealed a gradual increase in TH along with neuritic outgrowth in differentiated cells on days 4 and 7 of RA treatment. For the study on cell susceptibility to MPP(+) and the expression of apoptosis-related genes, MTT assay showed a decrease in cell viability to approximately 50% requiring 500 and 1000 MUM of MPP(+) for undifferentiated and RA-differentiated cells, respectively. Using real-time RT-PCR, treatment with 500 MUM MPP(+) led to significant increases in the Bax/Bcl-2 ratio, p53, and caspase-3 in undifferentiated cells but was without significance in differentiated cells. In conclusion, differentiated cells may be more suitable, and the shorter duration of RA differentiation may make the SH-SY5Y cell model more accessible. PMID- 26634155 TI - Alternative Methods to Treat Nausea and Vomiting from Cancer Chemotherapy. AB - Chemotherapy Induced Nausea and Vomiting (CINV) is among the most intensive side effects and critical concerns for patients with cancer. Most of these patients experience nausea and vomiting after chemotherapy. Sometimes, this is so annoying that it may prevent them from continuing the therapy. With the recent advances, a variety of therapeutic methods are innovated and applied to control CINV. Among them, the main methods include medicinal therapy, relaxation, and herbal therapy. Yet, using dexamethasone together with massage therapy and ginger is identified as the most effective method. PMID- 26634156 TI - Adipsin Is Associated with Multiple Sclerosis: A Follow-Up Study of Adipokines. AB - Background and Objective. The role of adipokines in regulation of immune responses has been recognized, but very little is known about their impact on multiple sclerosis (MS). In this study, we analysed whether the major adipokines are differentially expressed in plasma of patients with different MS subtypes and clinically isolated syndrome (CIS) and explored their association with major disease characteristics. Methods. The levels of adiponectin, adipsin, leptin, and resistin in the plasma of 80 patients with different subtypes of MS and CIS were followed up annually over the two years. The data obtained were correlated with disease activity, EDSS and volumes of T1-weighted lesions (T1-LV), and fluid attenuation inversion recovery lesions (FLAIR-LV) on MRI. Results. In MS group, a correlation was found between the level of adipsin and EDSS score at baseline (r = 0.506, p < 0.001). In RRMS, the levels of adipsin correlated with EDSS scores (r = 0.542, p = 0.002), T1-LV (r = 0.410, p = 0.034), and FLAIR-LV (r = 0.601, p = 0.0001) at baseline and an increase in the T1-LV over the follow-up (r = 0.582, p = 0.003). Associations with other adipokines were not detected. Conclusion. Our exploratory study provides novel insights on the impact of adipokines in MS and suggests that adipsin exerts predictive potential as a biomarker of neurodegeneration. PMID- 26634157 TI - The Morphofunctional Effect of the Transplantation of Bone Marrow Stromal Cells and Predegenerated Peripheral Nerve in Chronic Paraplegic Rat Model via Spinal Cord Transection. AB - Functional recovery following spinal cord injury (SCI) is limited by poor axonal and cellular regeneration as well as the failure to replace damaged myelin. Employed separately, both the transplantation of the predegenerated peripheral nerve (PPN) and the transplantation of bone marrow stromal cells (BMSCs) have been shown to promote the regrowth and remyelination of the damaged central axons in SCI models of hemisection, transection, and contusion injury. With the aim to test the effects of the combined transplantation of PPN and BMSC on regrowth, remyelination, and locomotor function in an adult rat model of spinal cord (SC) transection, 39 Fischer 344 rats underwent SC transection at T9 level. Four weeks later they were randomly assigned to traumatic spinal cord injury (TSCI) without treatment, TSCI + Fibrin Glue (FG), TSCI + FG + PPN, and TSCI + FG + PPN + BMSCs. Eight weeks after, transplantation was carried out on immunofluorescence and electron microscope studies. The results showed greater axonal regrowth and remyelination in experimental groups TSCI + FG + PPN and TSCI + FG + PPN + BMSCs analyzed with GAP-43, neuritin, and myelin basic protein. It is concluded that the combined treatment of PPN and BMSCs is a favorable strategy for axonal regrowth and remyelination in a chronic SC transection model. PMID- 26634158 TI - Mitral Subvalvular Aneurysm in a Patient with Chagas Disease and Recurrent Episodes of Ventricular Tachycardia. AB - Subvalvular left ventricular aneurysm is a rare disease of obscure origin suggesting unique causes such as congenital, traumatic, and inflammatory or infectious diseases. Its mortality is closely related to heart failure, mitral insufficiency, thromboembolic phenomena, and cardiac arrhythmias. Although association with coronary artery disease is not described, the compression of epicardial vessels by the aneurysm may lead to ischemic manifestations. We report here a case of mitral subvalvular left ventricular aneurysm of probable chagasic origin, in a patient with normal left ventricular function evolving with repeated episodes of monomorphic ventricular tachycardia, despite noninducible electrophysiological testing and the use of optimal medical treatment, including amiodarone. The indication for implantable cardioverter-defibrillator in patients with Chagas cardiomyopathy and segmental wall motion abnormalities but without global systolic dysfunction remains unclear in literature, even in the presence of complex ventricular arrhythmias. A brief review of the literature on morphological features, diagnosis, prognosis, and treatment will be also discussed. PMID- 26634153 TI - Dysfunctional High-Density Lipoprotein: An Innovative Target for Proteomics and Lipidomics. AB - High-Density Lipoprotein-Cholesterol (HDL-C) is regarded as an important protective factor against cardiovascular disease, with abundant evidence of an inverse relationship between its serum levels and risk of cardiovascular disease, as well as various antiatherogenic, antioxidant, and anti-inflammatory properties. Nevertheless, observations of hereditary syndromes featuring scant HDL-C concentration in absence of premature atherosclerotic disease suggest HDL-C levels may not be the best predictor of cardiovascular disease. Indeed, the beneficial effects of HDL may not depend solely on their concentration, but also on their quality. Distinct subfractions of this lipoprotein appear to be constituted by specific protein-lipid conglomerates necessary for different physiologic and pathophysiologic functions. However, in a chronic inflammatory microenvironment, diverse components of the HDL proteome and lipid core suffer alterations, which propel a shift towards a dysfunctional state, where HDL-C becomes proatherogenic, prooxidant, and proinflammatory. This heterogeneity highlights the need for further specialized molecular studies in this aspect, in order to achieve a better understanding of this dysfunctional state; with an emphasis on the potential role for proteomics and lipidomics as valuable methods in the search of novel therapeutic approaches for cardiovascular disease. PMID- 26634159 TI - Effectiveness of an Innovative Pulsed Electromagnetic Fields Stimulation in Healing of Untreatable Skin Ulcers in the Frail Elderly: Two Case Reports. AB - Introduction. Recalcitrant skin ulcers are a major burden in elderly patients. Specifically, chronic wounds result in significant morbidity and mortality and have a profound economic impact. Pulsed electromagnetic fields (PEMFs) have proved to be a promising therapy for wound healing. Here we describe the first reported case of an innovative PEMF therapy, Emysimmetric Bilateral Stimulation (EBS), used to successfully treat refractory skin ulcers in two elderly and fragile patients. Case Presentation. Two elderly patients developed multiple chronic skin ulcerations. Despite appropriate treatment, the ulcers showed little improvement and the risk of amputation was high. Both patients underwent daily EBS therapy and standard dressing. After few weeks of treatment, major improvements were observed and all ulcers had healed. Conclusion. In patients with refractory ulceration, EBS therapy may be of real benefit in terms of faster healing. This case supports the supportive role for PEMFs in the treatment of skin ulceration in diabetes and is suggestive of a potential benefit of EBS in this clinical condition. PMID- 26634160 TI - Primary Hyperoxaluria Diagnosed Based on Bone Marrow Biopsy in Pancytopenic Adult with End Stage Renal Disease. AB - Inborn errors of metabolism cause increase of metabolites in serum and their deposition in various organs including bone marrow. Primary hyperoxaluria (PH) is a rare inborn error in the pathway of glyoxylate metabolism which causes excessive oxalate production. The disease is characterized by widespread deposition of calcium oxalate (oxalosis) in multiple organs. Urinary tract including renal parenchyma is the initial site of deposition followed by extrarenal organs such as bone marrow. This case report introduces a 54-year-old woman with end stage renal disease presenting with debilitating fatigue and pancytopenia. The remarkable point in her past medical history was recurrent episodes of nephrolithiasis, urolithiasis, and urinary tract infection since the age of 5 years and resultant end stage renal disease in adulthood in the absence of appropriate medical evaluation and treatment. She had an unsuccessful renal transplantation with transplant failure. The patient underwent bone marrow biopsy for evaluation of pancytopenia. Microscopic study of bone marrow biopsy led to the diagnosis of primary hyperoxaluria. PMID- 26634161 TI - Robot-Assisted Laparoscopic Partial Colpectomy and Intracorporeal Ileal Conduit Urinary Diversion (Bricker) for Cervical Adenocarcinoma Recurrence. AB - Ileal conduit urinary diversion (Bricker) is a standard surgical open procedure. The Da Vinci robot allowed precision for this surgical procedure, especially for intracorporeal suturing. Meanwhile, few reports of robot-assisted laparoscopic ileal conduit diversion (Bricker) are described in the literature. We report the case of a 69-year-old patient with a vaginal recurrence of cervical adenocarcinoma associated with vesicovaginal fistula treated by robot-assisted laparoscopic partial colpectomy and ileal conduit urinary diversion (Bricker). The robot-assisted laparoscopic procedure followed all surgical steps of the open procedure. Postoperative period was free of complications. PMID- 26634162 TI - Urothelial Superior Vena Cava Syndrome with Limited Response to Radiation Therapy. AB - Radiation therapy (RT) is the standard of care for cases of superior vena cava (SVC) syndrome secondary to metastatic adenopathy. Histologies vary in radiosensitivity and response time, making alternative therapies such as chemotherapy and/or intravenous stenting preferable alternative options for certain diagnoses. Metastatic urothelial carcinoma is a particularly rare cause of SVC syndrome with only 3 cases reported in the literature. Consequently, optimal management remains challenging, particularly in cases of high tumor burden. Here we present a case of highly advanced metastatic urothelial cancer with SVC syndrome and tracheal compression. The patient started urgent RT but expired midway through her treatment course due to systemic progression of disease, requiring SVC and tracheal stenting. The authors review the literature including discussion of the few other known cases of SVC syndrome due to urothelial carcinoma and a review of this histology's response to RT. This experience suggests, that in cases of SVC syndrome with widespread advanced disease, stenting and chemotherapy with or without RT may be the most important initial treatment plan, depending on goals of care. PMID- 26634164 TI - Submandibular Lateral Ectopic Thyroid Tissue: Ultrasonography, Computed Tomography, and Scintigraphic Findings. AB - Ectopic thyroid can be encountered anywhere between the base of tongue and pretracheal region. The most common form is euthyroid neck mass. Herein, we aimed to present the findings of a female case with ectopic thyroid tissue localized in the left submandibular region. A 44-year-old female patient, who underwent bilateral subtotal thyroidectomy four years ago with the diagnosis of multinodular goiter, was admitted to our hospital due to a mass localized in the left submandibular area that gradually increased in the last six months. Neck ultrasonography, contrast-enhanced computed tomography, and scintigraphic examination were performed on the patient. On thyroid scintigraphy with Tc-99m pertechnetate, thyroid tissue activity uptake showing massive radioactivity was observed in the normal localization of the thyroid gland and in the submandibular localization. The focus in the submandibular region was excised. Pathological examination of the specimen showed normal thyroid follicle cells with no signs of malignancy. The submandibular mass is a rarely encountered lateral ectopic thyroid tissue. Accordingly, ectopic thyroid tissue should also be considered in the differential diagnosis of masses in the submandibular region. PMID- 26634163 TI - Clinicopathological and Targeted Exome Gene Features of a Patient with Metastatic Acinic Cell Carcinoma of the Parotid Gland Harboring an ARID2 Nonsense Mutation and CDKN2A/B Deletion. AB - We describe the presentation, treatment, clinical outcome, and targeted genome analysis of a metastatic salivary acinic cell carcinoma (AciCC). A 71-year-old male presented with a 3 cm right tail of a parotid lesion, first detected as a nodule by the patient seven months earlier. He had a right total parotidectomy with cranial nerve VII resection, right facial nerve resection and grafting, resection of the right conchal cartilage, and right modified radical neck dissection. The primary tumor revealed AciCC with two distinct areas: a well differentiated component with glandular architecture and a dedifferentiated component with infiltrative growth pattern associated with prominent stromal response, necrosis, perineural invasion, and cellular pleomorphism. Tumor staging was pT4 N0 MX. Immunohistochemistry staining showed pankeratin (+), CD56 (-), and a Ki67 proliferation index of 15%. Upon microscopic inspection, 49 local lymph nodes resected during parotidectomy were negative for cancer cells. Targeted sequencing of the primary tumor revealed deletions of CDKN2A and CDKN2B, a nonsense mutation in ARID2, and single missense mutations of unknown significance in nine other genes. Despite postoperative localized radiation treatment, follow up whole body PET/CT scan showed lung, soft tissue, bone, and liver metastases. The patient expired 9 months after resection of the primary tumor. PMID- 26634165 TI - Community-Acquired Pneumonia and Empyema Caused by Citrobacter koseri in an Immunocompetent Patient. AB - Citrobacter species, belonging to the family Enterobacteriaceae, are environmental organisms commonly found in soil, water, and the intestinal tracts of animals and humans. Citrobacter koseri is known to be an uncommon but serious cause of both sporadic and epidemic septicemia and meningitis in neonates and young infants. Most cases reported have occurred in immunocompromised hosts. The infections caused by Citrobacter are difficult to treat with usual broad spectrum antibiotics owing to rapid generation of mutants and have been associated with high death rates in the past. We believe this is the first case described in the literature of a community-acquired pneumonia and empyema caused by Citrobacter koseri in an immunocompetent adult patient. PMID- 26634166 TI - Severe Respiratory Distress in a Child with Pulmonary Idiopathic Hemosiderosis Initially Presenting with Iron-Deficiency Anemia. AB - Idiopathic pulmonary hemosiderosis (IPH) is a rare cause of alveolar hemorrhage in children but should be considered in children with anemia of unknown origin who develop respiratory complications. It is commonly characterized by the triad of recurrent hemoptysis, diffuse parenchymal infiltrates, and iron-deficiency anemia. Pathogenesis is unclear and diagnosis may be difficult along with a variable clinical course. A 6-year-old boy was admitted to the hospital with a severe iron-deficiency anemia, but he later developed severe acute respiratory failure and hemoptysis requiring intubation and mechanical ventilation. The suspicion of IPH led to the use of immunosuppressive therapy with high dose of corticosteroids with rapid improvement in clinical condition and discharge from hospital. PMID- 26634167 TI - Malignant Peripheral Nerve Sheath Tumor: MRI and CT Findings. AB - This is a case report of a 56-year-old male with hypertension who presented with urinary retention and bowel incontinence. CT and MRI of the abdomen and pelvis showed a large complex cystic and solid enhancing mass in the right presacral space. Pathology biopsy result showed malignant peripheral nerve sheath tumor (MPNST) with extensive necrosis. The diagnosis of MPNST is extremely difficult due to the lack of (1) conclusive immunohistochemistry or unique chromosomal anomaly, (2) universal distinctive histopathology, and (3) clinical criteria. The clinical, radiologic, and histologic presentation of MPNST is important in its diagnosis. A rare case of MPNST that produced urinary retention and bowel incontinence is presented that may aid clinicians in the diagnosis of this rare clinical entity. Motor weakness, central enhancement, and immunohistochemistry may assist in the diagnosis of MPNST and differentiation between benign peripheral nerve sheath tumor (BPNST) and MPNST. PMID- 26634168 TI - Enterohepatic Migration of Fish Bone Resulting in Liver Abscess. AB - Liver abscess formation due to enterohepatic migration of a foreign body is extremely rare. Foreign body ingestion is generally an unconscious and painless event, thus complicating preoperative diagnosis in most patients. We report the case of a 61-year-old man who presented with secondary peritonitis from a ruptured hepatic abscess after an ingested fish bone migrated into the liver. PMID- 26634169 TI - ELISA-Based Crossmatching Allowing the Detection of Emerging Donor-Specific Anti HLA Antibodies through the Use of Stored Donors' Cell Lysates. AB - About forty years ago the complement-dependent crossmatch assay (CDC-CM) was developed as standard procedure in order to select recipients without donor specific antibodies directed against human leukocyte antigens of their given donors since the negative outcome of pretransplant crossmatching represents one of the most important requirements for a successful kidney graft survival. However, as a functional assay the CDC-CM strongly depends on the availability of donors' isolated lymphocytes and in particular on their vitality highly limiting its applicability for recipients treated with special drugs and therapeutic antibodies or suffering from underlying autoimmune diseases. In the great majority of these cases ELISA-based crossmatching has been demonstrated to be an adequate alternative procedure nevertheless leading to valid results. With these case reports we show for the first time that ELISA-based crossmatching is suitable to demonstrate the upcoming donor-specific anti-HLA antibodies as a consequence of allografting using deep-frozen deceased donor's material such as blood or spleen detergent lysate. Thus, this ELISA-based procedure first provides the option to routinely perform crossmatching using stored material of deceased donors in order to substitute or at least to complement virtual crossmatching, that is, the comparison of the recipients' anti-HLA antibody specificities with the donors' historically identified HLA types. PMID- 26634170 TI - Laparoscopic Management of a Complex Adrenal Cyst. AB - Adrenal cysts are rare, and their clinical management remains controversial. We report a case involving an adrenal cyst with a complicated appearance on radiological studies. Unenhanced computed tomography revealed a unilocular, noncalcified, hypoattenuating mass with a thin wall in the left adrenal gland. The lesion gradually increased in size from 10 to 50 mm at two-year follow-up. On contrast-enhanced magnetic resonance imaging, a mural nodule with contrast enhancement was observed. The entire adrenal gland was excised en bloc via a lateral transperitoneal laparoscopic approach without violating the principles of surgical oncology. The pathological diagnosis was an adrenal pseudocyst. Laparoscopic adrenalectomy is a safe option for the treatment of complex adrenal cysts, while maintaining the benefits of minimal invasiveness. PMID- 26634171 TI - Screening for Mild Cognitive Impairment in Parkinson's Disease: Comparison of the Italian Versions of Three Neuropsychological Tests. AB - Mild cognitive impairment (MCI) is frequent in Parkinson's disease (PD). Recently proposed criteria for MCI in PD (PD-MCI) indicate level I diagnosis based on abbreviated assessment and level II based on comprehensive neuropsychological evaluation. The study explored the sensitivity and specificity of the Italian versions of three neuropsychological tests for level I diagnosis of PD-MCI. We recruited 100 consecutive PD patients. After screening for inclusion criteria, 43 patients were included. The sensitivity and specificity of the Mini Mental State Examination (MMSE), the Montreal Cognitive Assessment (MoCA), and the Addenbrooke's Cognitive Examination Revised (ACE-R) in comparison to level II diagnosis of PD-MCI were examined. PD-MCI was diagnosed (level II) in 51% of patients. Disease duration was significantly longer and PD motor scales were more severely impaired in MCI group. The receiver-operator characteristics curve documented nonsignificant difference in the performance of the three tests, with slight advantage of MMSE (corrected data). The time of administration favored MMSE. In Italian-speaking PD patients, MMSE might represent a good screening tool for PD-MCI, because of the shorter time of administration and the performance comparable to those of MoCA and ACE-R. Further studies are needed to validate the new PD-MCI criteria across different languages and cultures. PMID- 26634173 TI - Enhancement of Solubility of Lamotrigine by Solid Dispersion and Development of Orally Disintegrating Tablets Using 3(2) Full Factorial Design. AB - Present investigation deals with the preparation and evaluation of orally disintegrating tablets (ODTs) of lamotrigine using beta-cyclodextrin and PVP-K30 as polymers for the preparation of solid dispersion which help in enhancement of aqueous solubility of this BCS CLASS-II drug and sodium starch glycolate (SSG) and crospovidone as a superdisintegrating agent, to reduce disintegration time. The ODTs were prepared by direct compression method. Nine formulations were developed with different ratios of superdisintegrating agents. All the formulations were evaluated for disintegration time, weight variation, hardness, friability, drug content uniformity, wetting time, and in vitro drug release study. In vitro drug release study was performed using United States Pharmacopoeia (USP) type 2 dissolution test apparatus employing paddle stirrer at 50 rpm using 900 mL of 0.1 N HCl maintained at 37 degrees C +/- 0.5 degrees C as the dissolution medium. On the basis of evaluation parameters formulations were prepared using beta-CD 1 : 1 solid dispersion. Then 3(2) full factorial design was applied using SSG and crospovidone in different ratios suggested by using design expert 8.0.7.1 and optimized formulation was prepared using amount of SSG and crospovidone as suggested by the software. The optimized formulation prepared had disintegrating time of 15 s, wetting time of 24 s, and % friability of 0.55. PMID- 26634172 TI - Prognostic Significance of N-Glycolyl GM3 Ganglioside Expression in Non-Small Cell Lung Carcinoma Patients: New Evidences. AB - The prognostic role of N-glycolyl GM3 ganglioside (NeuGcGM3) expression in non small cell lung carcinoma (NSCLC) still remains controversial. In this study, the NeuGcGM3 expression was reevaluated using an increased number of NSCLC cases and the 14F7 Mab (a highly specific IgG1 raised against NeuGcGM3). An immunohistochemical score integrating the percentage of 14F7-positive cells and the intensity of reaction was applied to reassess the relationship between NeuGcGM3 expression, some clinicopathological features, and the overall survival (OS) of NSCLC patients. The double and the triple expression of NeuGcGM3 with the epidermal growth factor receptor (EGFR) and/or its ligand, the epidermal growth factor (EGF), were also evaluated. NeuGcGM3 expression correlates with both S Phase fraction (p = 0.006) and proliferation index (p = 0.000). Additionally, NeuGcGM3 expression was associated with a poor OS of patients in both univariate (p = 0.020) and multivariate (p = 0.010) analysis. Moreover, the double and/or the triple positivity of tumors to NeuGcGM3, EGFR, and/or EGF permitted us to identify phenotypes of NSCLC with a more aggressive biological behavior. Our results are in agreement with the negative prognostic significance of NeuGcGM3 expression in NSCLC patients. However, standardization of techniques to determine the expression of NeuGcGM3 in NSCLC as well as the implementation of a universal scoring system is recommended. PMID- 26634174 TI - Healthcare Adherence Among Patients Who Report the Self-Sabotage of their Own Medical Care. PMID- 26634175 TI - Resident and Patient Responses to the Institution of Required Narcotic Agreements in an Internal Medicine Outpatient Clinic. PMID- 26634176 TI - Placental Barrier and Autism Spectrum Disorders: The Role of Prolactin and Dopamine on the Developing Fetal Brain. AB - Dopamine and prolactin exhibit opposite effects on lactation. However, a possible role for increased prolactin/dopamine ratio in postpartum mood and thought disorders and as a prognostic indicator of the mother's future mental health has not been well investigated. Postpartum depression is a serious condition with potentially devastating outcomes for both the mother and the infant. Early detection and treatment of this condition can have impressive results. Treatment options include antidepressant medications for mood disorders and use of antipsychotics and electroconvulsive therapy to address postpartum psychosis. Although there are obvious benefits of such treatments on the welfare of the mother and her child, broader implications of these treatments on lactation and child growth and development are not known. This review article explores a possible link between in-utero exposure to a high maternal prolactin/dopamine ratio and subsequent development of autism spectrum disorders. We hypothesize that a comprehensive, biologically oriented approach to the use of psychotropics in the regulation of neurotransmission during pre- and postpartum periods may result in better outcomes in this population. PMID- 26634177 TI - The Effect of Carnitine Supplementation on Hyperammonemia and Carnitine Deficiency Treated with Valproic Acid in a Psychiatric Setting. AB - OBJECTIVE: The aim of this study was to investigate the effect of levocarnitine (active isoform of carnitine, L-Carnitine) supplementation on serum ammonia and carnitine levels simultaneously, and their clinical outcomes in valproic acid treated psychiatric subjects. DESIGN: This was a propsective study of 22 psychiatric patients. METHOD: A fixed dose of levocarnitine was coadministrated over a period of three months in subjects with valproic acid-induced hyperammonemia. Serum ammonia, valproic acid, and carnitine concentrations were measured, and psychiatric symptoms were recorded at baseline and one, two, and three months. Sequential change of the levels of serum ammonia, valproic acid, free carnitine, acylcarnitine, total carnitine, ratios of acylcarnitine/free carnitine, and the scores of Brief Psychotic Rating Scale, Clinical Global Impression-Severity scale, and the Global Assessment of Functioning scale were compared within total subjects and two groups divided by the effectiveness of levocarnitine supplementation against baseline hyperammonemia. RESULTS: Within total subjects, free carnitine, acylcarnitine, and total carnitine levels were significantly increased without statistical change in serum ammonia, valproic acid levels, and acylcarnitine/free carnitine ratio, while a part of Brief Psychotic Rating Scale scores was decreased. Acylcarnitine levels were significantly increased at all points in the levocarnitine effective group and not in the noneffective group. Acylcarnitine/free carnitine ratio increased in the levocarnitine effective group and decreased in the noneffective group, which was confirmed by negative correlation between the ratio of serum ammonia levels at three months to serum ammonia levels at baseline and the ratio of acylcarnitine/free carnitine levels at three months to acylcarnitine/free carnitine levels at baseline. CONCLUSION: In valproic acid-treated psychiatric patients, carnitine supplementation resulted in overall improvement in mental status. Improvement of hyperammonemia and carnitine deficiency in this group may be related to mitochondrial function. PMID- 26634178 TI - Electroconvulsive Therapy Intervention for Parkinson's Disease. AB - BACKGROUND: Electroconvulsive therapy is an established means to improve function in a variety of psychiatric and neurologic conditions, particularly for patients who remain treatment-refractory. Parkinson's disease is a neurodegenerative disorder that sometimes does not respond well to conventional pharmacotherapies. Reports have indicated that electroconvulsive therapy may be an effective and safe treatment for those patients with Parkinson's disease who are not optimally responding to first-line treatments. Despite these reports, however, electroconvulsive therapy is not often used by clinicians in patients with treatment-resistant Parkinson's disease, perhaps due to stigma, lack of knowledge regarding its safety and efficacy, and/or inability to predict the duration of therapeutic benefit. OBJECTIVE: Our objective was to determine if the available literature on ECT supports it as a safe and effective treatment option in patients with treatment-refractory Parkinson's disease. CONCLUSION: Motoric improvement induced by electroconvulsive therapy has been documented for decades in persons with Parkinson's disease. Efficacy and safety are reported following electroconvulsive therapy in people with Parkinson's disease who have sub-optimal response to medicines or experience the "on/off" phenomenon to L-dopa. Electroconvulsive therapy is an effective option for acute and maintenance treatment of Parkinson's disease in select patients. Inability to predict how long the beneficial effects of ECT therapy will last in patients with Parkinson's disease may be a reason why this treatment is underutilized by clinicians. More research is warranted to clarify parameters for application and duration of therapeutic benefit in individuals with difficult-to-treat Parkinson's disease. PMID- 26634179 TI - Autism in the Son of a Woman with Mitochondrial Myopathy and Dysautonomia: A Case Report. AB - The relationship between autism spectrum disorders and mitochondrial dysfunction, including mitochondrial myopathies and other mitochondrial diseases, is an area of ongoing research. All autism spectrum disorders are known to be heritable, via genetic and/or epigenetic mechanisms, but specific modes of inheritance are not well characterized. Nevertheless, autism spectrum disorders have been linked to many specific genes associated with mitochondrial function, especially to genes involved in mitochondrial tRNA and the electron transport chain, both particularly vulnerable to point mutations, and clinical research also supports a relationship between the two pathologies. Although only a small minority of patients with autism have a mitochondrial disease, many patients with mitochondrial myopathies have autism spectrum disorder symptoms, and these symptoms may be the presenting symptoms, which presents a diagnostic challenge for clinicians. The authors report the case of a 15-year-old boy with a history of autism spectrum disorder and neurocardiogenic syncope, admitted to the inpatient unit for self-injury, whose young mother, age 35, was discovered to suffer from mitochondrial myopathy, dysautonomia, neurocardiogenic syncope, Ehler Danlos syndrome, and other uncommon multisystem pathologies likely related to mitochondrial dysfunction. This case illustrates the need for a high index of suspicion for mitochondrial disease in patients with autism, as they have two orders of magnitude greater risk for such diseases than the general population. The literature shows that mitochondrial disease is underdiagnosed in autism spectrum disorder patients and should not be viewed as a "zebra" (i.e., an obscure diagnosis that is made when a more common explanation is more likely). PMID- 26634180 TI - Aripiprazole for Treatment of Apathy. AB - OBJECTIVE: The objective of this article is to present a case of improved outcome of apathy syndrome with aripiprazole. CASE SUMMARY: A 42-year-old man with depression and seizure disorder had significant apathy that did not respond to carbamazepine, sertraline, and topiramate. Apathy was assessed using Apathy Evaluation Scale. Discontinuation of carbamazepine did not alleviate apathy. Aripiprazole, a novel antipsychotic with partial agonistic activity at dopamine D2 receptors, was introduced and the dose adjusted to 15mg a day. The patient showed significant improvement in apathy after six weeks of therapy with aripiprazole. DISCUSSION: Depression is often mistaken for apathy, which is different in symptoms, presentation, and treatment options. Selective serotonin reuptake inhibitors are known to cause or increase symptoms of apathy in some patients. Recent evidence suggests that dopamine receptor agonists can be helpful in treatment of apathy. Apathy significantly improved in this patient after initiation of aripiprazole. CONCLUSION: Aripiprazole may be useful for treatment of apathy syndrome. Its role in treatment of apathy requires further investigation in clinical trials. PMID- 26634181 TI - A Simple Chi-Square Statistic for Testing Homogeneity of Zero-Inflated Distributions. AB - Zero-inflated distributions are common in statistical problems where there is interest in testing homogeneity of two or more independent groups. Often, the underlying distribution that has an inflated number of zero-valued observations is asymmetric, and its functional form may not be known or easily characterized. In this case, comparisons of the groups in terms of their respective percentiles may be appropriate as these estimates are nonparametric and more robust to outliers and other irregularities. The median test is often used to compare distributions with similar but asymmetric shapes but may be uninformative when there are excess zeros or dissimilar shapes. For zero-inflated distributions, it is useful to compare the distributions with respect to their proportion of zeros, coupled with the comparison of percentile profiles for the observed non-zero values. A simple chi-square test for simultaneous testing of these two components is proposed, applicable to both continuous and discrete data. Results of simulation studies are reported to summarize empirical power under several scenarios. We give recommendations for the minimum sample size which is necessary to achieve suitable test performance in specific examples. PMID- 26634182 TI - Reducing Friction on Skin at Risk: The Use of 3MTM CavilonTM No Sting Barrier Film. AB - Objective: To compare the coefficient of friction (CoF) of skin against fabric when the skin is covered with a liquid barrier film versus a silicone dressing, relative to a bare skin baseline. Approach: A laboratory instrument allowing the measurement of friction between two surfaces was used to compare the CoF between a fabric representing bed linen (100% cotton) and the skin of two laboratory operators, either bare (dry or hydrated) or covered with a liquid barrier film or a silicone dressing. Results: The CoF of hydrated skin was over twice the value found for dry skin. The liquid barrier film product reduced the CoF of hydrated skin to a greater extent than the silicone dressing. Innovation and Conclusion: Silicone dressings have recently been promoted to help prevent pressure ulcers. Published data have shown that their CoF is lower than other dressings, but the data were not compared to bare skin. We found that a liquid barrier film provided a greater reduction in the CoF of skin against linen than a silicone dressing. In the context of preventative use (e.g., application on intact skin) to reduce the risk of pressure ulcers, applying a liquid barrier film may reduce friction better than a silicone dressing. PMID- 26634183 TI - The Management of Diabetic Foot Ulcers with Porcine Small Intestine Submucosa Tri Layer Matrix: A Randomized Controlled Trial. AB - Objective: This study demonstrates that superior outcomes are possible when diabetic foot ulcers (DFU) are managed with tri-layer porcine small intestine submucosa (SIS). Approach: Patients with DFU from 11 centers participated in this prospective randomized controlled trial. Qualified subjects were randomized (1:1) to either SIS or standard care (SC) selected at the discretion of the Investigator and followed for 12 weeks or complete ulcer closure. Results: Eighty two subjects (41 in each group) were evaluable in the intent-to-treat analysis. Ulcers managed with SIS had a significantly greater proportion closed by 12 weeks than for the Control group (54% vs. 32%, p=0.021) and this proportion was numerically higher at all visits. Time to closure for ulcers achieving closure was 2 weeks earlier for the SIS group than for SC. Median reduction in ulcer area was significantly greater for SIS at each weekly visit (all p values<0.05). Review of reported adverse events found no safety concerns. Innovation: These data support the use of tri-layer SIS for the effective management of DFU. Conclusion: In this randomized controlled trial, SIS was found to be associated with more rapid improvement, and a higher likelihood of achieving complete ulcer closure than those ulcers treated with SC. PMID- 26634184 TI - Abductor Hallucis: Anatomical Variation and Its Clinical Implications in the Reconstruction of Chronic Nonhealing Ulcers and Defects of Foot. AB - Abductor hallucis (AH) is an intrinsic muscle of sole of the foot. It is commonly used in the coverage of ankle and heel defects and chronic nonhealing ulcers of the foot; its use is reported to have a favorable long-term outcome. The muscle's apt bulk and size, its simple surgical isolation, absence of donor-site defect, unvaried anatomy, and long neurovascular pedicle are some of the advantages that make it a promising muscle flap. During routine cadaver dissection in the Department of Anatomy of Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry, India, we identified an anatomical variation in AH in both feet of a 45-year-old embalmed male Indian cadaver. The variant muscle had innumerable proximal attachments, a majority of them arising atypically in the form of tough tendinous slips from the medial intermuscular septum at the junction of central and tibial components of plantar aponeurosis, the medial surface of first metatarsal and the intermuscular septum separating AH from the flexor hallucis brevis. The tendon: muscle ratio was 1.76, higher than the normal reported ratio of 0.56+/-0.07. This article highlights the variation noted and its implication for clinicians. On Internet search, we did not come across the variations described in our article. Findings of the anatomical variation reported in this article could benefit surgeons who decide to use AH flaps in the future. PMID- 26634185 TI - Biophysical Approaches for Oral Wound Healing: Emphasis on Photobiomodulation. AB - Significance: Oral wounds can lead to significant pain and discomfort as well as affect overall general health due to poor diet and inadequate nutrition. Besides many biological and pharmaceutical methods being investigated, there is growing interest in exploring various biophysical devices that utilize electric, magnetic, ultrasound, pressure, and light energy. Recent Advances: Significant insight into mechanisms of these biophysical devices could provide a clear rationale for their clinical use. Preclinical studies are essential precursors in determining physiological mechanisms and elucidation of causal pathways. This will lead to development of safe and effective therapeutic protocols for clinical wound management. Critical Issues: Identification of precise events initiated by biophysical devices, specifically photobiomodulation-the major focus of this review, offers promising avenues in improving oral wound management. The primary phase responses initiated by the interventions that distinctly contribute to the therapeutic response must be clearly delineated from secondary phase responses. The latter events are a consequence of the wound healing process and must not be confused with causal mechanisms. Future Direction: Clinical adoption of these biophysical devices needs robust and efficacious protocols that can be developed by well-designed preclinical and clinical studies. Elucidation of the precise molecular mechanisms of these biophysical approaches could determine optimization of their applications for predictive oral wound care. PMID- 26634186 TI - Fabrication of a Flexible Amperometric Glucose Sensor Using Additive Processes. AB - This study details the use of printing and other additive processes to fabricate a novel amperometric glucose sensor. The sensor was fabricated using a Au coated 12.7 MUm thick polyimide substrate as a starting material, where micro-contact printing, electrochemical plating, chloridization, electrohydrodynamic jet (e jet) printing, and spin coating were used to pattern, deposit, chloridize, print, and coat functional materials, respectively. We have found that e-jet printing was effective for the deposition and patterning of glucose oxidase inks with lateral feature sizes between ~5 to 1000 MUm in width, and that the glucose oxidase was still active after printing. The thickness of the permselective layer was optimized to obtain a linear response for glucose concentrations up to 32 mM and no response to acetaminophen, a common interfering compound, was observed. The use of such thin polyimide substrates allow wrapping of the sensors around catheters with high radius of curvature ~250 MUm, where additive and microfabrication methods may allow significant cost reductions. PMID- 26634187 TI - Characterization of the Cellular Output of a Point-of-Care Device and the Implications for Addressing Critical Limb Ischemia. AB - Critical limb ischemia (CLI) is a terminal disease with high morbidity and healthcare costs due to limb loss. There are no effective medical therapies for patients with CLI to prevent amputation. Cell-based therapies are currently being investigated to address this unmet clinical need and have shown promising preliminary results. The purpose of this study was to characterize the output of a point-of-care cell separator (MarrowStim P.A.D. Kit), currently under investigation for the treatment of CLI, and compare its output with Ficoll-based separation. The outputs of the MarrowStim P.A.D. Kit and Ficoll separation were characterized using an automated hematology analyzer, colony-forming unit (CFU) assays, and tubulogenesis assays. Hematology analysis indicated that the MarrowStim P.A.D. Kit concentrated the total nucleated cells, mononuclear cells, and granulocytes compared with baseline bone marrow aspirate. Cells collected were positive for VEGFR-2, CD3, CD14, CD34, CD45, CD56, CD105, CD117, CD133, and Stro-1 antigen. CFU assays demonstrated that the MarrowStim P.A.D. Kit output a significantly greater number of mesenchymal stem cells and hematopoietic stem cells compared with cells output by Ficoll separation. There was no significant difference in the number of endothelial progenitor cells output by the two separation techniques. Isolated cells from both techniques formed interconnected nodes and microtubules in a three-dimensional cell culture assay. This information, along with data currently being collected in large-scale clinical trials, will help instruct how different cellular fractions may affect the outcomes for CLI patients. PMID- 26634188 TI - Molecular Profiling of Multiplexed Gene Markers to Assess Viability of Ex Vivo Human Colon Explant Cultures. AB - Human colon tissue explant culture provides a physiologically relevant model system to study human gut biology. However, the small (20-30 mg) and complex tissue samples used present challenges for monitoring tissue stability, viability, and provision of sufficient tissue for analyses. Combining molecular profiling with explant culture has potential to overcome such limitations, permitting interrogation of complex gene regulation required to maintain gut mucosa in culture, monitor responses to culture environments and interventions. Human ex vivo colon explant gene expression profiles were assayed using an in house custom-designed hCellMarkerPlex assay at culture time points 0, 1, 2, 4, and 14 h. Characteristic profiles of epithelial cell markers linked to differentiation, cellular polarization, and apoptosis were correlated with visible histochemical changes in explant epithelium during culture and tissue donors. The GenomeLab System provides effective assay of multiple targets not possible from small tissue samples with conventional gene expression technology platforms. This is advantageous to increase the utility of the ex vivo human colon model in applications to interrogate this complex and dynamic tissue environment for use in analytical testing. PMID- 26634190 TI - Expression of Placental Members of the Human Growth Hormone Gene Family Is Increased in Response to Sequential Inhibition of DNA Methylation and Histone Deacetylation. AB - The genes coding for human (h) chorionic somatomammotropin (CS), hCS-A and hCS-B, and placental growth hormone (GH-V), hGH-V, are located at a single locus on chromosome 17. Efficient expression of these placental genes has been linked to local regulatory (5' P and 3' enhancer) sequences and a remote locus control region (LCR), in part, through gene transfer in placental and nonplacental tumor cells. However, low levels of endogenous hCS/GH-V transcripts are reported in the same cells compared with term placenta, suggesting that chromatin structure, or regulatory region accessibility, versus transcription factor availability contributes to the relatively low levels. To assess individual hCS-A, CS-B, and GH-V gene expression in placental and nonplacental tumor cells and the effect of increasing chromatin accessibility by inhibiting DNA methylation and histone deacetylation using 5-aza-2'-deoxycytidine (azadC) and trichostatin A (TSA). Low levels of hCS-A, CS-B, and GH-V were detected in placental and nonplacental tumor cells compared with term placenta. A significant >5-fold increase in activity was seen in placental, but not nonplacental, cells transfected with hybrid hCS promoter luciferase genes containing 3' enhancer sequences. Pretreatment of placental JEG-3 cells with azadC resulted in a >10-fold increase in hCS-A, CS-B, and GH-V RNA levels with TSA treatment compared with TSA treatment alone. This effect was specific as reversing the treatment regimen did not have the same effect. An assessment of hyperacetylated H3/H4 in JEG-3 cells treated with azadC and TSA versus TSA alone revealed significant increases consistent with a more open chromatin structure, including the hCS 3' enhancer sequences and LCR. These observations suggest that accessibility of remote and local regulatory regions required for efficient placental hGH/CS expression can be restricted by DNA methylation and histone acetylation status. This includes restricting access of the hCS 3' enhancer sequences to available placental enhancer transcription factors. PMID- 26634191 TI - Maximal Usage Trial: An Overview of the Design of Systemic Bioavailability Trial for Topical Dermatological Products. AB - Dermatologic diseases can present in varying forms and severity, ranging from the individual lesion and up to almost total skin involvement. Pharmacokinetic assessment of topical drug products has previously been plagued by bioanalytical assay limitations and the lack of a standardized study design. Since the mid 1990's the US Food and Drug Administration has developed and implemented a pharmacokinetic maximal usage trial (MUsT) design to help address these issues. The MUsT design takes into account the following elements: the enrollment of patients rather than normal volunteers, the frequency of dosing, duration of dosing, use of highest proposed strength, total involved surface area to be treated at one time, amount applied per square centimeter, application method and site preparation, product formulation, and use of a sensitive bioanalytical method that has been properly validated. This paper provides a perspective of pre MUsT study designs and a discussion of the individual elements that make up a MUsT. PMID- 26634189 TI - Tissue Engineering a Biological Repair Strategy for Lumbar Disc Herniation. AB - The intervertebral disc is a critical part of the intersegmental soft tissue of the spinal column, providing flexibility and mobility, while absorbing large complex loads. Spinal disease, including disc herniation and degeneration, may be a significant contributor to low back pain. Clinically, disc herniations are treated with both nonoperative and operative methods. Operative treatment for disc herniation includes removal of the herniated material when neural compression occurs. While this strategy may have short-term advantages over nonoperative methods, the remaining disc material is not addressed and surgery for mild degeneration may have limited long-term advantage over nonoperative methods. Furthermore, disc herniation and surgery significantly alter the mechanical function of the disc joint, which may contribute to progression of degeneration in surrounding tissues. We reviewed recent advances in tissue engineering and regenerative medicine strategies that may have a significant impact on disc herniation repair. Our review on tissue engineering strategies focuses on cell-based and inductive methods, each commonly combined with material based approaches. An ideal clinically relevant biological repair strategy will significantly reduce pain and repair and restore flexibility and motion of the spine. PMID- 26634192 TI - Mammalian Mss51 is a skeletal muscle-specific gene modulating cellular metabolism. AB - BACKGROUND: The transforming growth factor beta (TGF-beta) signaling pathways modulate skeletal muscle growth, regeneration, and cellular metabolism. Several recent gene expression studies have shown that inhibition of myostatin and TGF beta1 signaling consistently leads to a significant reduction in expression of Mss51, also named Zmynd17. The function of mammalian Mss51 is unknown although a putative homolog in yeast is a mitochondrial translational activator. OBJECTIVE: The objective of this work was to characterize mammalian Mss51. METHODS: Quantitative RT-PCR and immunoblot of subcellular fractionation were used to determine expression patterns and localization of Mss51. The CRISPR/Cas9 system was used to reduce expression of Mss51 in C2C12 myoblasts and the function of Mss51 was evaluated in assays of proliferation, differentiation and cellular metabolism. RESULTS: Mss51 was predominantly expressed in skeletal muscle and in those muscles dominated by fast-twitch fibers. In vitro, its expression was upregulated upon differentiation of C2C12 myoblasts into myotubes. Expression of Mss51 was modulated in response to altered TGF-beta family signaling. In human muscle, Mss51 localized to the mitochondria. Its genetic disruption resulted in increased levels of cellular ATP, beta-oxidation, glycolysis, and oxidative phosphorylation. CONCLUSIONS: Mss51 is a novel, skeletal muscle-specific gene and a key target of myostatin and TGF-beta1 signaling. Unlike myostatin, TGF-beta1 and IGF-1, Mss51 does not regulate myoblast proliferation or differentiation. Rather, Mss51 appears to be one of the effectors of these growth factors on metabolic processes including fatty acid oxidation, glycolysis and oxidative phosphorylation. PMID- 26634193 TI - Measurement Scales of Suicidal Ideation and Attitudes: A Systematic Review Article. AB - BACKGROUND: The main aim of this study was to accumulate research evidence that introduce validated scales to measure suicidal attitudes and ideation and provide an empirical framework for adopting a relevant assessment tool in studies on suicide and suicidal behaviors. METHODS: Medical Subject Headings' (MeSH) terms were used to search Ovid Medline, PROQUEST, Wiley online library, Science Direct and PubMed for the published articles in English that reported application of an scale to measure suicidal attitudes and ideation from January 1974 onward. RESULTS: Fourteen suicidal attitude scale and 15 scales for assessing suicidal ideation were identified in this systematic review. No gold standard approach was recognized to study suicide related attitudes and ideations. CONCLUSION: Special focus on generally agreed dimensions of suicidal ideation and attitudes and cross cultural validation of the introduced scales to be applicable in different ethnic and socially diverse populations could be a promising area of research for scholars. PMID- 26634194 TI - Acceptability of Physician Directed Academic Detailing to Increase Colorectal Cancer Screening: an Application of the RESPECT Approach. AB - BACKGROUND: In developing effective interventions to increase colorectal cancer (CRC) screening in at risk populations, a necessary first requirement is feasibility. This paper describes how the RESPECT approach to health education guided the conceptualization and implementation of physician-directed academic detailing (AD) to increase practice-wide CRC screening uptake. METHODS: Physician directed AD was one intervention component in a large educational randomized controlled trial to increase CRC screening uptake. Study participants, primarily urban minority, were aged 50 or older, insured for CRC screening with no out-of pocket expense and out of compliance with current screening recommendations. The trial was conducted in the New York City metropolitan area. Participants identified their primary care physician; 564 individuals were recruited, representing 459 physician practices. Two-thirds of the physician practices were randomized to receive AD. The RESPECT approach, modified for AD, comprises: 1) Rapport, 2) Educate, but don't overwhelm, 3) Start with physicians where they are, 4) Philosophical orientation based on a humanistic approach to education, 5) Engagement of the physician and his/her office staff, 6) Care and show empathy, and 7) Trust. Feasibility was assessed as rate of AD delivery. RESULTS: The AD was delivered to 283 (92.5%) of the 306 practices assigned to receive it; 222/283 (78.4%) delivered to the doctor. CONCLUSION: The AD was feasible and acceptable to implement across a range of clinical settings. The RESPECT approach offers a framework for tailoring educational efforts, allowing flexibility, as opposed to strict adherence to a highly structured script or a universal approach. PMID- 26634195 TI - Levels of Some Heavy Metals in Raw Cow's Milk from Selected Milk Production Sites in Iran: Is There any Health Concern? AB - BACKGROUND: The aim of this study was to evaluate the content of mercury (Hg), arsenic (As), nickel (Ni) and tin (Sn) in raw cow's milk of traditional and industrial sites from 8 different sites in Arak City, Markazi Province, Iran. METHODS: In this cross sectional study, a total of 32 samples were collected from sub-cities of Arak, Iran via subjective sampling method. Both industrial and traditional dairy farms were selected for sampling. Twenty-five gram of each sample was turned to ash in ovens for metal analyses including Hg, As, Ni and Sn by anatomic absorption spectrometer. RESULTS: The residue amounts of Hg and As were lower than permissible limit suggested by Codex Alimentarius, but for Ni and Sn it was higher only in one of the collection sites. The average concentra-tion of Hg was significantly higher (P<0.05) in traditional farms as compared to industrial farms. Be-sides, amounts of Sn was significantly high in the traditional farms (P<0.05). Further, a high contents Ni was detected in industrial farms (P<0.05). CONCLUSION: High Sn and Ni contents of some milk samples from this region might be potentially hazardous to consumers. Further, none of the other metals tested crossed permissible levels. PMID- 26634196 TI - Vitamin D Status in Preeclamptic and Non-preeclamptic Pregnant Women: A Case Control Study in the North West of Iran. AB - BACKGROUND: There are few studies on the vitamin D status in preeclamptic women. The objective of this case-control study was to determine vitamin D status, in preeclamptic women and compare it with that of healthy pregnant controls. METHODS: Forty preeclamptic women, aged 18 to 45yr and forty age- and pregnancy weight-matched healthy controls participated in the study. Serum 25-hydroxy vitamin D (25(OH)D) levels were measured and its levels of <10, 10-30, 30-90 and >90 nanogram per milliliter (ng/ml) were considered as vitamin D deficiency, insufficiency, sufficiency, and toxicity, respectively. RESULTS: Sixty and forty percent of preeclamptic women were vitamin D deficient and insufficient, while in the control group they were 10% and 90%, respectively. No significant difference was found in the median intake of vitamin D between preeclamptic and non preeclamptic women (1.45 and 1.20ug/day respectively), but serum 25(OH)D concentration was significantly lower in preeclamptic cases compared to controls (10.09 +/- 6.66 and 15.73 +/- 5.85ng /ml respectively, P= 0.002) . CONCLUSION: Vitamin D deficiency is common among preeclamptic and non-preeclamptic pregnant women in the north-west of Iran. Preeclampsia can cause decreasing of serum level of 25(OH)D. PMID- 26634197 TI - Advertising Violent Toys in Weekly Circulars of Popular Retailers in the United States. AB - BACKGROUND: Violence is a pervasive problem in the United States. Toys, far from trivial playthings, are a reflection of society, including its beliefs and values. The purpose of this study was to describe the extent to which violent toys are marketed in online weekly flyers of popular retailers, how the violence is manifested, and whether violent toys are marketed differentially to boys and girls. METHODS: For this cross-sectional observational study, online circulars from 5 major retailers were downloaded and examined each week for 14 weeks during the fall of 2014. For each retailer, the total number of toys, as well as the total number of violent and non-violent toys, was recorded. In addition, each violent toy was categorized into one of five groups: picturing a figure with a weapon, a figure with intent to strike (with fists drawn or an angry face), a toy with a violent name, a toy that was a weapon itself, or a set of toys that included two or more of these criteria. RESULTS: A total number of 3,459 toys were observed, of which 1,053 (30%) were deemed violent. Of the violent toys, 95% were marketed to boys (n=1,003) versus 5% to girls (n=50). The most prevalent violent category was a figure with a weapon such as a sword, knife or gun (29%), followed by figures with fists out and aggressive faces (26%). CONCLUSION: Parents should be mindful of toy retailer"s marketing of violent toys, especially toward boys, and the potential for those toys to de-sensitize their children to violence. PMID- 26634198 TI - The Technical Quality of Delivered Care for People with Inflammatory Bowel Disease in Tabriz Gastroenterology Clinics. AB - BACKGROUND: The Inflammatory Bowel Disease (IBD) is considered as one of the chronic diseasesre-quiring complicated treatment. This study aimed to assess technical quality of providing care for pa-tients with IBD. METHODS: This cross sectional study was conducted on 94 people with IBD using interviews and simple random sampling methods in Gastroenterology, Endoscopy and clinic of Imam Reza Hospital and Golgasht Clinic in Tabriz in 2012. The data collection tool was a researcher-designed questionnaire whose validity and reliability had been confirmed. In order to investigate the statistical relationship between the background variables and compliance with the standards the Chi-square test was applied using SPSS 17 Software. RESULTS: "visit by the physician" and "diet advice by the dietitian" have had the highest and the lowest levels of compliance with the standard respectively, and "the care related to the disease exacerbation" and "the care provided by the other physicians" were not compatible with the standards in 80% of the cases. Data analyses also showed that there was a significant relationship between participant's age, job, education and the smoking status and compliance of some care with the relevant standards (P<0.05). CONCLUSION: The results indicate a substantial gap between provided care for the people with IBD and the relevant standards. This indicates the areas that need of improvement and requires the serious attention of the authorities. PMID- 26634199 TI - The Effect of Road Traffic Noise on Reaction Time. AB - BACKGROUND: Traffic noise is one of the main important sources in urban noise pollution, which causes various physiological and psychological effects that can cause disturbs in performance, sleep disturbances, hearing loss and impact on job performance. This study was conducted to verify the impact of road traffic noise on reaction time in terms of extraversion and sex. METHODS: Traffic noise was measured and recorded in 10 arterial streets in Tehran, and then the recorded noise was emitted towards participants in an acoustic room. The participants were 80 (40 cases and 40 controls) students. Personality type was determined by Eysenck Personality Inventory (EPI) questioner. Reaction time before and after exposure to traffic noise was measured. RESULTS: Reaction time before exposure to traffic noise did not differ (P=0.437) significantly between introverts and extraverts. However, it was increased significantly in both groups after exposure to traffic noise (P<0.01). Introvert's reaction time was more increased than that of extraverts. CONCLUSION: Traffic noise augmented reaction time of both males and females. This study also revealed that exposure to traffic noise leads to increase in reaction time. PMID- 26634200 TI - Lentil Sprouts Effect On Serum Lipids of Overweight and Obese Patients with Type 2 Diabetes. AB - BACKGROUND: The present study aimed to determine the effect of lentil sprouts [LS] on lipid profiles in overweight and obese patients with type 2 diabetes. METHODS: Forty- eight overweight and obese type 2 diabetic patients, September and November2013, 30-65 years, participated in this clinical trial and randomly divided into two groups; LS group and controls. Patients in control group received conventional drug therapy, while patients in LS group received 60 g LS daily during 8 weeks along with routine medication. Significant differences among and between the groups were determined by independent t-test and paired sample t test using SPSS software. The patients were blinded for the treatment. In this trial the effect of LS on serum lipid profiles were inves-tigated. RESULTS: Thirty-nine patients completed the study. After 8 weeks, serum levels of HDL-C was higher in the LS group compared to control group (48.3 +/-1.9 vs. 42.8+/-1.7, P<0.03). TG and ox-LDL were lower in the LS group compared to controls [(127+/ 13.4 vs. 170+/- 12.4.P<0.01) and (83.3+/-29.1 vs. 98.7+/-28.2.P<0.6)]. CONCLUSIONS: LS consumption could have favorable effect on serum lipid profiles. PMID- 26634201 TI - The Association between the Risk of Premenstrual Syndrome and Vitamin D, Calcium, and Magnesium Status among University Students: A Case Control Study. AB - BACKGROUND: Premenstrual syndrome (PMS) is one of major health problems in childbearing age women. Herein, we compared the nutritional status of vitamin D, calcium (Ca) and magnesium (Mg) in young students affected by PMS with those of normal participants. METHODS: This study was conducted on 62 students aged 20-25 yr in the city of Abadan (31 PMS cases and 31 controls). All participants completed four or more criteria according to the Utah PMS Calendar 3. Age, height, body mass index (BMI), serum Ca, Mg and vitamin D levels and a 24-hour food recall questionnaire were recorded. RESULTS: Vitamin D serum levels were lower than the normal range in the two groups. The odds ratios (CI 95%) of having PMS based on serum Ca and Mg concentrations were 0.81(0.67 - 0.89) and 0.86 (0.72 - 0.93), respectively. Based on serum levels, 855 of all participants showed vitamin D deficiency and more than one-third of the PMS cases were Mg deficient (P<0.05). In addition, there were signifi-cant differences in dietary intake of Ca and Mg, and potassium but not vitamin D in the two groups. Dietary intakes of Ca and Mg were quite below the recommendation in all participants. CONCLUSION: Vitamin D, Ca and Mg nutritional status are compromised in PMS subjects. Because PMS is a prevalent health problem among young women, it merits more attention regarding improvement of their health and nutritional status. PMID- 26634202 TI - Influence of Sorghum Kafirin on Serum Lipid Profile and Antioxidant Activity in Hyperlipidemic Rats (In Vitro and In Vivo Studies). AB - The aim of this study was to compare in vitro the antioxidant potential of sorghum kafirin and sorghum flour and their influence on lipids and antioxidant capacity in rats. The antioxidant activity in sorghum kafirin extract measured by the DPPH and TEAC methods was increased 30 and 65 times, respectively, compared to that of its counterpart, sorghum flour. According to electrophoresis assay, the kafirins tert-butanol extract showed a high proportion of alpha-kafirin monomers, and its amino acid composition revealed higher hydrophobic amino acid content such as alanine, isoleucine, leucine, tyrosine and phenylalanine than sorghum flour extract. Diets supplemented with sorghum kafirin extract have improved lipid metabolism and increased the serum antioxidant potential (67%) especially in rats fed with added cholesterol. The bioactive peptides generated from kafirin in vivo hydrolysis appear to be associated with the positive effect on serum lipids and antioxidant activity. According to these results, sorghum kafirin extract at the levels used in this study apparently could be used for prevention of atherosclerosis and other chronic diseases. PMID- 26634203 TI - Clinical Outcomes and Urodynamic Effects of Tailored Transvaginal Mesh Surgery for Pelvic Organ Prolapse. AB - OBJECTIVE: To evaluate the clinical outcomes and urodynamic effects of tailored anterior transvaginal mesh surgery (ATVM) and tailored posterior transvaginal mesh surgery (PTVM). METHODS: We developed ATVM for the simultaneous correction of cystocele and stress urinary incontinence and PTVM for the simultaneous correction of enterocoele, uterine prolapse, vaginal stump prolapse, and rectocele. RESULTS: A total of 104 women enrolled. The median postsurgical follow up was 25.5 months. The anatomic cure rate was 98.1% (102/104). Fifty-eight patients underwent urodynamic studies before and after surgeries. The pad weight decreased from 29.3 +/- 43.1 to 6.4 +/- 20.9 g at 3 months. Among the 20 patients with ATVM, 13 patients had objective stress urinary incontinence (SUI) at baseline while 8 patients came to have no demonstrated SUI (NDSUI), and 2 improved after surgery. Among the 38 patients who underwent ATVM and PTVM, 24 had objective SUI at baseline while 18 came to have NDSUI, and 2 improved after surgery. Mesh extrusion (n = 4), vaginal hematoma (n = 3), and voiding difficulty (n = 2) were noted postoperatively. Quality of life was substantially improved. CONCLUSIONS: Our findings document the advantages of these two novel pelvic reconstructive surgeries for pelvic organ prolapse, which had a positive impact on quality of life. ATVM surgery additionally provided an anti-incontinence effect. This clinical trial is registered at ClinicalTrials.gov (NCT02178735). PMID- 26634204 TI - New Insights in the Diagnosis and Treatment of Heart Failure. AB - Cardiovascular disease is the leading cause of mortality in the US and in westernized countries with ischemic heart disease accounting for the majority of these deaths. Paradoxically, the improvements in the medical and surgical treatments of acute coronary syndrome are leading to an increasing number of "survivors" who are then developing heart failure. Despite considerable advances in its management, the gold standard for the treatment of end-stage heart failure patients remains heart transplantation. Nevertheless, this procedure can be offered only to a small percentage of patients who could benefit from a new heart due to the limited availability of donor organs. The aim of this review is to evaluate the safety and efficacy of innovative approaches in the diagnosis and treatment of patients refractory to standard medical therapy and excluded from cardiac transplantation lists. PMID- 26634206 TI - New Insight in the Assessment of Atrial Size and Function. PMID- 26634205 TI - Genetic Variations in ABCG2 Gene Predict Breast Carcinoma Susceptibility and Clinical Outcomes after Treatment with Anthracycline-Based Chemotherapy. AB - The genetic variants of the ATP-binding cassette, subfamily G, member 2 (ABCG2) are known to be involved in developing cancer risk and interindividual differences in chemotherapeutic response. The polymorphisms in ABCG2 gene were genotyped by using PCR-RFLP assays. We found that ABCG2 G34A GA/AA genotype, C421A AA genotype, and haplotypes 34A-421C and 34G-421A were significantly associated with increased risk for developing breast carcinoma. Furthermore, ABCG2 C421A AA homozygote had a significant enhanced therapeutic response in patients with neoadjuvant anthracycline-based chemotherapy. Moreover, ABCG2 G34A AA genotype carriers displayed a longer OS in ER positive patients or PR positive patients after postoperative anthracycline-based chemotherapy. These results suggested that the ABCG2 polymorphisms might be a candidate pharmacogenomic factor to assess susceptibility and prognosis for breast carcinoma patients. PMID- 26634207 TI - Some Biochemical and Hematological Parameters among Petrol Station Attendants: A Comparative Study. AB - OBJECTIVE: To describe selected biochemical and hematological parameters (blood picture, liver enzymes, and kidney functions) in petrol station attendants in Mansoura city. METHODS: This is a comparative cross-sectional study. The exposed group included 102 petrol station attendants. They were compared to a matched group of healthy 102 male service and office workers at the Faculty of Medicine, Mansoura University. The results of blood picture, liver enzymes, and kidney functions were compared between both groups. RESULTS: Mean Red Blood Cells (RBCs) count, hemoglobin level, and Hematocrit (HCT) level were significantly lower in petrol station attendants than the comparison group. All other blood picture parameters showed nonsignificant difference between both groups. Liver enzymes, renal functions, serum albumin, and total protein showed statistically nonsignificant difference between both groups except for alanine aminotransferase (ALT) which was significantly higher in petrol station attendants. CONCLUSIONS: Some laboratory parameters among petrol station attendants showed changes that could be attributed to workplace exposure and should be given attention at preemployment and periodic medical examination. PMID- 26634208 TI - Comparison of the Clinical Characteristics and Outcome of Benign and Malignant Eyelid Tumors: An Analysis of 4521 Eyelid Tumors in a Tertiary Medical Center. AB - We retrospectively reviewed the clinical features and outcome of benign and malignant eyelid tumors from 1995 to 2015 in a tertiary medical center. Among 4,521 histologically confirmed eyelid tumors, 4,294 (95.0%) were benign tumors and 227 (5.0%) were malignant tumors. The mean age at diagnosis was significantly higher in patients with malignant lid tumors than those with benign lid tumors (72.5 and 55.4 years, resp., p < 0.001). The most common benign eyelid tumors were intradermal nevus (21.1%), followed by seborrheic keratosis (12.6%) and xanthelasma (11.2%). The most common malignant eyelid tumors were basal cell carcinomas (57.8%), followed by sebaceous gland carcinomas (21.1%) and squamous cell carcinomas (10.1%). There was a relative male predominance (63.4% and 49.2%, resp., p < 0.001) and higher recurrence rate (11.9% and 4.4%, resp., p < 0.001) in malignant lid tumors as compared with those of benign lid tumors. Twenty-two patients (9.7%) received orbital exenteration/enucleation. Eight patients (3.5%) with malignant lid tumors died of disease. Patients with eyelid melanoma were associated with a high mortality rate (25.0%). It is important to differentiate between benign and malignant eyelid tumors, because they may cause cosmetic disfigurement and severe morbidity, especially in those with malignant eyelid tumors. PMID- 26634209 TI - Effect of Diet and Exercise on the Peripheral Immune System in Young Balb/c Mice. AB - Although diet and exercise clearly have an influence on immune function, studies are scarce on the effect caused by exercise and the consumption of a carbohydrate rich or fat-rich diet on the peripheral immune system. The aim of the present study was to evaluate the effect of exercise and the two aforementioned unbalanced diets on young Balb/c mice, especially in relation to BMI, the level of glucose, and the percentage of lymphocyte subpopulations in peripheral blood. The changes found were then related to the synthesis of leptin and adiponectin as well as the production of oxidative stress. The increase in BMI found with the carbohydrate-rich and fat-rich diets showed correlation with the levels of leptin and adiponectin. An increase in leptin and a decrease in adiponectin directly correlated with an increase in total lymphocytes and CD4+ cells and with a decrease in B cells. The increase in leptin also correlated with an increase in CD8+ cells. Glycemia and oxidative stress increased with the two unbalanced diets, negatively affecting the proliferation of total lymphocytes and the percentage of B cells, apparently by causing alterations in proteins through carbonylation. These alterations caused by an unbalanced diet were not modified by moderate exercise. PMID- 26634210 TI - Expression and Prognostic Significance of Macrophage Inflammatory Protein-3 Alpha and Cystatin A in Nasopharyngeal Carcinoma. AB - This study aims to investigate the expression of macrophage inflammatory protein 3 alpha (MIP-3alpha) and cystatin A in nasopharyngeal carcinoma (NPC) and their association with clinical characteristics and prognosis. Primary tumor specimens from 114 NPC patients and associated clinical follow-up data were collected, and the expression of MIP-3alpha and cystatin A proteins was investigated by immunohistochemistry. Expression of MIP-3alpha was significantly associated with TNM stage in patients with NPC (P < 0.05). NPC patients with positive expression of MIP-3alpha exhibited shorter median overall survival (OS) and distant metastasis-free survival (DMFS), compared with patients with negative expression (OS: 50.5 months versus 59.0 months, P = 0.013; DMFS: 50.1 months versus 60.2 months, P = 0.003). NPC patients with positive expression of cystatin A exhibited shorter median OS, local recurrence-free survival (LRFS), and DMFS, compared with patients with negative expression (OS: 51.1 months versus 60.0 months, P = 0.004; LRFS: 54.5 months versus 59.5 months, P = 0.036; DMFS: 52.3 months versus 58.8 months, P = 0.036). Both MIP-3alpha and cystatin A overexpressions in NPC tumor tissues were strong independent factors of poor prognosis in NPC patients. MIP 3alpha and cystatin A expressions may be valuable prognostic markers in NPC patients. PMID- 26634211 TI - Psychosocial Factors and Workers' Health and Safety. PMID- 26634212 TI - The Influence of alpha-Lipoic Acid and Garlic Administration on Biomarkers of Oxidative Stress and Inflammation in Rabbits Exposed to Oxidized Nutrition Oils. AB - We hypothesized that addition of substances with antioxidant activity could decrease the concentrations of biomarkers of oxidative stress and inflammatory process, thus inhibiting nonalcoholic steatohepatitis development. We investigated the influence of alpha-lipoic acid (ALA) and garlic administration on the development of adverse changes in rabbit liver and serum under oxidative stress conditions induced with HFD from oxidized oils. We determined 8-hydroxy-2' deoxyguanosine (8 OHdG) and malondialdehyde (MDA) in liver homogenates, total oxidant status (TOS), lipid peroxides (LOO) and tumor necrosis factor alpha (TNFalpha) in blood serum, and TNFalpha and IL-1alpha genes expression in liver. The results indicate that the intake of dietary ALA and garlic was significantly associated with decreases of 8 OHdG and MDA levels in rabbits' liver tissue as well as TOS and LOO levels in rabbits' serum. Similarly, TNFalpha and IL-1alpha gene expressions were suppressed due to ALA and garlic supplementation. The histopathological analysis confirmed that HFD results in liver disorder leading to steatosis. This adverse effect of HFD was ameliorated by the supplementation of ALA and garlic. The obtained results indicate a beneficial effect of ALA and garlic administration by reducing the oxidative stress intensity and the levels of some proinflammatory cytokines in rabbits fed HFD. PMID- 26634213 TI - Using Weighted Sparse Representation Model Combined with Discrete Cosine Transformation to Predict Protein-Protein Interactions from Protein Sequence. AB - Increasing demand for the knowledge about protein-protein interactions (PPIs) is promoting the development of methods for predicting protein interaction network. Although high-throughput technologies have generated considerable PPIs data for various organisms, it has inevitable drawbacks such as high cost, time consumption, and inherently high false positive rate. For this reason, computational methods are drawing more and more attention for predicting PPIs. In this study, we report a computational method for predicting PPIs using the information of protein sequences. The main improvements come from adopting a novel protein sequence representation by using discrete cosine transform (DCT) on substitution matrix representation (SMR) and from using weighted sparse representation based classifier (WSRC). When performing on the PPIs dataset of Yeast, Human, and H. pylori, we got excellent results with average accuracies as high as 96.28%, 96.30%, and 86.74%, respectively, significantly better than previous methods. Promising results obtained have proven that the proposed method is feasible, robust, and powerful. To further evaluate the proposed method, we compared it with the state-of-the-art support vector machine (SVM) classifier. Extensive experiments were also performed in which we used Yeast PPIs samples as training set to predict PPIs of other five species datasets. PMID- 26634214 TI - Optimization of Arundo donax Saccharification by (Hemi)cellulolytic Enzymes from Pleurotus ostreatus. AB - An enzymatic mixture of cellulases and xylanases was produced by Pleurotus ostreatus using microcrystalline cellulose as inducer, partially characterized and tested in the statistical analysis of Arundo donax bioconversion. The Plackett-Burman screening design was applied to identify the most significant parameters for the enzymatic hydrolysis of pretreated A. donax. As the most significant influence during the enzymatic hydrolysis of A. donax was exercised by the temperature ( degrees C), pH, and time, the combined effect of these factors in the bioconversion by P. ostreatus cellulase and xylanase was analyzed by a 3(3) factorial experimental design. It is worth noting that the best result of 480.10 mg of sugars/gds, obtained at 45 degrees C, pH 3.5, and 96 hours of incubation, was significant also when compared with the results previously reached by process optimization with commercial enzymes. PMID- 26634215 TI - New Methods in Exploring Old Topics: Case Studying Brittle Diabetes in the Family Context. AB - BACKGROUND: In questing for a more refined quantitative research approach, we revisited vector autoregressive (VAR) modeling for the analysis of time series data in the context of the so far poorly explored concept of family dynamics surrounding instable diabetes type 1 (or brittle diabetes). METHOD: We adopted a new approach to VAR analysis from econometrics referred to as the optimized multivariate lag selection process and applied it to a set of raw data previously analyzed through standard approaches. RESULTS: We illustrated recurring psychosomatic circles of cause and effect relationships between emotional and somatic parameters surrounding glycemic control of the child's diabetes and the affective states of all family members. CONCLUSION: The optimized multivariate lag selection process allowed for more specific, dynamic, and statistically reliable results (increasing R(2) tenfold in explaining glycemic variability), which were derived from a larger window of past explanatory variables (lags). Such highly quantitative versus historic more qualitative approaches to case study analysis of psychosomatics surrounding diabetes in adolescents were reflected critically. PMID- 26634217 TI - The Association of the GABRP Polymorphisms with Systemic Lupus Erythematosus. AB - Gamma-aminobutyric acid receptor subunit pi (GABRP) is involved in inhibitory synaptic transmission in the central nervous system. This gene encodes multisubunit chloride channels and is also expressed in numerous nonneuronal tissues such as the uterus and the ovaries. This study was aimed to validate whether the polymorphisms in the GABRP gene are associated with the susceptibility to systematic lupus erythematosus (SLE). The genotype frequencies of the rs929763, rs732157, and rs3805455 of the GABRP gene in SLE patients were significantly different from those of the control group (P < 0.0001, P = 0.05 and 0.002, resp.). Additional analysis showed that the genotype of the rs929763 and rs3805455 of the GABRP gene were also significantly associated with female SLE patients (P < 0.0001, P = 0.005, resp.). Two haplotype frequencies including a major haplotype of GABRP SNPs were more significantly different between the SLE patients and the healthy controls (P = 0.038 and 4.2E - 24, resp.). These results suggest that the polymorphisms in the GABRP gene might be associated with the susceptibility to SLE and the haplotype of GABRP SNPs is useful genetic marker for SLE. PMID- 26634218 TI - Durable Sustained Virologic Response After Oral Directly Acting Antiviral Therapy Despite Immunosuppressive Treatment. AB - Treatment for hepatitis C has evolved from interferon-based therapy to all oral, directly acting antiviral (DAA) therapy. The influence of immunosuppression on maintaining sustained virologic response (SVR) in patients who have been treated with these directly acting agents is unknown. In this study, we report sustained hepatitis C virus (HCV) suppression in 3 patients undergoing various immunosuppressive treatments after achieving SVR with DAA therapy. Three patients, who were enrolled in 1 of 2 single-center National Institutes of Health clinical trials, achieved SVR12. Each patient had undergone between 6 and 24 weeks of DAA therapy with or without ribavirin. Immunosuppression was varied among the 3 patients. Therapy included adalimumab, carboplatin/irinotecan, or capecitabine. In all 3 cases, patients maintained HCV RNA levels below detection after immunosuppression. All patients had undetectable viral load and normalized liver-related enzymes during immunosuppressive therapy. This report suggests that SVR as a result of novel DAA therapy is durable and likely not affected by immunosuppressive therapy. Larger studies are required to confirm these results, but findings are promising for the treatment of large numbers of HCV-infected patients who may require subsequent immunosuppressive or immunomodulating therapies. PMID- 26634216 TI - fMLP-Induced IL-8 Release Is Dependent on NADPH Oxidase in Human Neutrophils. AB - N-Formyl-methionyl-leucyl-phenylalanine (fMLP) and platelet-activating factor (PAF) induce similar intracellular signalling profiles; but only fMLP induces interleukin-8 (IL-8) release and nicotinamide adenine dinucleotide phosphate reduced (NADPH) oxidase activity in neutrophils. Because the role of ROS on IL-8 release in neutrophils is until now controversial, we assessed if NADPH oxidase is involved in the IL-8 secretions and PI3K/Akt, MAPK, and NF-kappaB pathways activity induced by fMLP. Neutrophils were obtained from healthy volunteers. IL-8 was measured by ELISA, IL-8 mRNA by qPCR, and ROS production by luminol-amplified chemiluminescence, reduction of ferricytochrome c, and FACS. Intracellular pH changes were detected by spectrofluorescence. ERK1/2, p38 MAPK, and Akt phosphorylation were analysed by immunoblotting and NF-kappaB was analysed by immunocytochemistry. Hydroxy-3-methoxyaceto-phenone (HMAP), diphenyleneiodonium (DPI), and siRNA Nox2 reduced the ROS and IL-8 release in neutrophils treated with fMLP. HMAP, DPI, and amiloride (a Na(+)/H(+) exchanger inhibitor) inhibited the Akt phosphorylation and did not affect the p38 MAPK and ERK1/2 activity. DPI and HMAP reduced NF-kappaB translocation induced by fMLP. We showed that IL-8 release induced by fMLP is dependent on NADPH oxidase, and ROS could play a redundant role in cell signalling, ultimately activating the PI3K/Akt and NF kappaB pathways in neutrophils. PMID- 26634219 TI - Risk Factors for Sexual Transmission of Hepatitis C Virus Among Human Immunodeficiency Virus-Infected Men Who Have Sex With Men: A Case-Control Study. AB - Background. Since 2000, incidence of sexually acquired hepatitis C virus (HCV) infection has increased among human immunodeficiency virus (HIV)-infected men who have sex with men (MSM). To date, few case-control and cohort studies evaluating HCV transmission risk factors were conducted in this population, and most of these studies were initially designed to study HIV-related risk behavior and characteristics. Methods. From 2009 onwards, HIV-infected MSM with acute HCV infection and controls (HIV-monoinfected MSM) were prospectively included in the MOSAIC (MSM Observational Study of Acute Infection with hepatitis C) study at 5 large HIV outpatient clinics in the Netherlands. Written questionnaires were administered, covering sociodemographics, bloodborne risk factors for HCV infection, sexual behavior, and drug use. Clinical data were acquired through linkage with databases from the Dutch HIV Monitoring Foundation. For this study, determinants of HCV acquisition collected at the inclusion visit were analyzed using logistic regression. Results. Two hundred thirteen HIV-infected MSM (82 MSM with acute HCV infection and 131 MSM without) were included with a median age of 45.7 years (interquartile range [IQR], 41.0-52.2). Receptive unprotected anal intercourse (adjusted odds ratio [aOR], 5.01; 95% confidence interval [CI], 1.63 15.4), sharing sex toys (aOR, 3.62; 95% CI, 1.04-12.5), unprotected fisting (aOR, 2.57; 95% CI, 1.02-6.44), injecting drugs (aOR, 15.62; 95% CI, 1.27-192.6), sharing straws when snorting drugs (aOR, 3.40; 95% CI, 1.39-8.32), lower CD4 cell count (aOR, 1.75 per cubic root; 95% CI, 1.19-2.58), and recent diagnosis of ulcerative sexually transmitted infection (aOR, 4.82; 95% CI, 1.60-14.53) had significant effects on HCV acquisition. Conclusions. In this study, both sexual behavior and biological factors appear to independently increase the risk of HCV acquisition among HIV-infected MSM. PMID- 26634220 TI - Public Awareness of Sepsis Is Low in Sweden. AB - Background. Sepsis is a serious and common condition with high mortality and morbidity. The public awareness, knowledge, and perception of sepsis in Sweden are unknown. Methods. A survey was performed using an online interview distributed to adults, aged 18-74, between March 6 and 9, 2015. Results. A total of 1001 people responded to the survey. Twenty-one percent of participants had heard of sepsis, whereas more than 86% had heard of each of the other conditions listed; for example, stroke (95%), chronic obstructive pulmonary disease (COPD) (95%), and leukemia (92%). Of those who had heard of sepsis, 93% responded that it is an infection or blood poisoning in an open question. The respondents who had heard of each disease estimated its mortality. For sepsis, the mortality was estimated at an average of 30%, which was at the same level as estimated mortalities for prostate and breast cancer but lower than for stroke, COPD, and leukemia. Conclusions. The awareness and knowledge of sepsis is low. The mortality for sepsis is not as overestimated as for many other diseases. The lack of awareness of sepsis might be a target to improve the outcome for sepsis patients by reducing the prehospital delay and hence enable early interventions. An increased general awareness might also raise interest for funding for research in this area and for its priority in healthcare support. PMID- 26634221 TI - Strategies employed by sexual minority adolescents to cope with minority stress. AB - Sexual minority adolescents (SMA) experience disparities in health and behavioral health outcomes, including high rates of depression, anxiety, self-harm, substance use, HIV risk behavior, suicidal ideation, and suicide attempts. These outcomes are commonly attributed to minority stress. Stress experiences are different for SMA than their adult counterparts. For example, disclosing their sexual orientation may be more likely to result in homelessness because these youth more often live with parents or other family members. Although stress in this population has been explored in previous research, very little is known about how SMA cope. Relying upon an adolescent coping model, this study examined the coping strategies, responses, and resources of SMA related to stress. Forty eight racially and ethnically diverse SMA (age 14-19) were recruited for 90 minute tape-recorded interviews. The semi-structured interviews were guided by a life history calendar. Recordings were transcribed verbatim and entered into QSR NVivo. All transcripts were coded by two members of the research team and went through a consensus process. Forty-three unique coping statements emerged that fit with the Compas model of adolescent coping. SMA cope with minority stress in similar ways to heterosexual youth coping with general stress, but findings suggest that SMA may also use different kinds of coping resources. Although further research is needed, the present study identified a variety of ways SMA cope with stress and can inform future research on the development interventions. PMID- 26634222 TI - Mice lacking integrin beta3 expression exhibit altered response to chronic stress. AB - Recent studies indicate multiple roles for integrin alphavbeta3 in adult neurons, including response to pharmacological agents such as cocaine and selective serotonin reuptake inhibitors. In this study, we examined the role of the integrin beta3 gene (Itgb3) in the response to environmental stimuli by subjecting Itgb3+/+ and Itgb3-/- mice to unpredictable chronic mild stressors. We found that genetic abrogation of integrin beta3 expression elicits an exaggerated vulnerability to chronic unpredictable stress in the open field test. In this test, chronic stress elicited significant decreases in stereotypic behavior and horizontal locomotor activity, including increases in anxiety behaviors. Mild chronic stress led to reductions in dopamine turnover in midbrains of Itgb3+/+, but not Itgb3-/- mice, suggesting a disruption of stress-dependent regulation of DA homeostasis. Chronic stress elicited altered synaptic expression of syntaxin and synaptophysin in midbrains of Itgb3-/- mice, when compared to Itgb3+/+. Semi quantitative Western blot studies revealed that the synaptic expression, but not total tissue expression, of multiple signaling proteins is correlated with integrin alphav levels in the midbrain. Moreover, loss of integrin beta3 expression modifies this correlation network. Together, these findings demonstrate that Itgb3-/- mice display a pattern of changes indicating disrupted regulation of midbrain synaptic systems involved in conferring resilience to mild stressors. PMID- 26634223 TI - Physiological phenotyping of dementias using emotional sounds. AB - INTRODUCTION: Emotional behavioral disturbances are hallmarks of many dementias but their pathophysiology is poorly understood. Here we addressed this issue using the paradigm of emotionally salient sounds. METHODS: Pupil responses and affective valence ratings for nonverbal sounds of varying emotional salience were assessed in patients with behavioral variant frontotemporal dementia (bvFTD) (n = 14), semantic dementia (SD) (n = 10), progressive nonfluent aphasia (PNFA) (n = 12), and AD (n = 10) versus healthy age-matched individuals (n = 26). RESULTS: Referenced to healthy individuals, overall autonomic reactivity to sound was normal in Alzheimer's disease (AD) but reduced in other syndromes. Patients with bvFTD, SD, and AD showed altered coupling between pupillary and affective behavioral responses to emotionally salient sounds. DISCUSSION: Emotional sounds are a useful model system for analyzing how dementias affect the processing of salient environmental signals, with implications for defining pathophysiological mechanisms and novel biomarker development. PMID- 26634224 TI - Retinal microvascular network attenuation in Alzheimer's disease. AB - INTRODUCTION: Cerebral small-vessel disease has been implicated in the development of Alzheimer's disease (AD). The retinal microvasculature enables the noninvasive visualization and evaluation of the systemic microcirculation. We evaluated retinal microvascular parameters in a case-control study of AD patients and cognitively normal controls. METHODS: Retinal images were computationally analyzed and quantitative retinal parameters (caliber, fractal dimension, tortuosity, and bifurcation) measured. Regression models were used to compute odds ratios (OR) and confidence intervals (CI) for AD with adjustment for confounders. RESULTS: Retinal images were available in 213 AD participants and 294 cognitively normal controls. Persons with lower venular fractal dimension (OR per standard deviation [SD] increase, 0.77 [CI: 0.62-0.97]) and lower arteriolar tortuosity (OR per SD increase, 0.78 [CI: 0.63-0.97]) were more likely to have AD after appropriate adjustment. DISCUSSION: Patients with AD have a sparser retinal microvascular network and retinal microvascular variation may represent similar pathophysiological events within the cerebral microvasculature of patients with AD. PMID- 26634225 TI - Comparative Evaluation of the Impact of Subacute Exposure of Smokeless Tobacco and Tobacco Smoke on Rat Testis. AB - This study investigated the effects of 30-day exposure to tobacco smoke (TS), smokeless tobacco (ST), and nicotine on reproductive parameters and oxidative biomarkers in prepubertal and adult male rats. Sperm motility was reduced by 77.5 and 89.0% in TS and ST exposed prepubertal rats and 71.1 and 86.4% in adult rats, respectively. Sperm count was also reduced by 64.7 and 89.9% in prepubertal rats and 64.9 and 47.0% in adult rats, respectively. Nicotine decreased sperm motility (82.2%) and count (62.6%) in prepubertal rats but caused no effect in adult rats. There were no changes in sperm morphology; testosterone was decreased, while LH and FSH were increased in exposed rats, when compared with control. Malondialdehyde levels in testes of exposed rats were increased, and GSH, SOD, and catalase were altered. Results indicate that subacute exposure of tobacco products alters sperm characteristics in a rank order of ST > TS > nicotine, which may be linked to increase in oxidative stress in the testis. PMID- 26634227 TI - Predictors of Obstructive Sleep Apnea Risk among Blacks with Metabolic Syndrome. AB - INTRODUCTION: Identification of risk factors for obstructive sleep apnea (OSA) is important to enable comprehensive intervention to reduce OSA-related cardiovascular disease (CVD). The metabolic syndrome outcome study (MetSO) provides a unique opportunity to address these factors. This study investigated risk of OSA among blacks with metabolic syndrome. METHODS: The present study utilized data from MetSO, an NIH-funded cohort study of blacks with metabolic syndrome. A total of 1,035 patients provided data for the analysis. These included sociodemographic factors, health risks, and medical history. Physician diagnosed conditions were obtained using an electronic medical record system (Allscripts, Sunrise Enterprise). Patients were diagnosed with metabolic syndrome using criteria articulated in the joint interim statement for harmonizing the metabolic syndrome. Patients with a score >=6 on the Apnea Risk Evaluation System (ARES) questionnaire were considered at risk for OSA. Obesity is defined by body mass index (BMI >= 30 kg/m2). RESULTS: Of the 1,035 patients screened in the MetSO cohort, 48.9% were at high risk for OSA. Using multivariate-adjusted logistic regression analysis, we observed that obesity was the strongest predictor of OSA risk (OR=1.59, 95%CI=1.24-2.04, p<0.0001). This finding remained significant even after adjustment for known covariates including blood pressure, low-density lipoprotein, high-density lipoprotein, and glucose levels (OR=1.44, 95%CI=1.11-1.86, p<0.001). CONCLUSION: Blacks in the MetSO cohort are at greater OSA risk, relative to the adult population in developed countries. Consistent with previous observations, obesity proved the strongest independent predictor of OSA risk among blacks with metabolic syndrome. PMID- 26634226 TI - Social Stress Engages Neurochemically-Distinct Afferents to the Rat Locus Coeruleus Depending on Coping Strategy. AB - Stress increases vulnerability to psychiatric disorders, partly by affecting brain monoamine systems, such as the locus coeruleus (LC)-norepinephrine system. During stress, LC activity is coregulated by corticotropin-releasing factor (CRF) and endogenous opioids. This study identified neural circuitry that regulates LC activity of intruder rats during the resident-intruder model of social stress. LC afferents were retrogradely labeled with Fluorogold (FG) and rats were subjected to one or five daily exposures to an aggressive resident. Sections through the nucleus paragigantocellularis (PGi) and central amygdalar nucleus (CNA), major sources of enkephalin (ENK) and CRF LC afferents, respectively, were immunocytochemically processed to detect c-fos, FG, and CRF or ENK. In response to a single exposure, intruder rats assumed defeat with a relatively short latency (SL). LC neurons, PGI-ENK LC afferents, and CNA-CRF LC afferents were activated in these rats as indicated by increased c-fos expression. With repeated stress, rats exhibited either a SL or long latency (LL) to defeat and these strategies were associated with distinct patterns of neuronal activation. In SL rats, LC neurons were activated, as were CNA-CRF LC afferents but not PGI-ENK LC afferents. LL rats had an opposite pattern, maintaining activation of PGi-ENK LC afferents but not CNA-CRF LC afferents or LC neurons. Together, these results indicate that the establishment of different coping strategies to social stress is associated with changes in the circuitry that regulates activity of the brain norepinephrine system. This may underlie differential vulnerability to the consequences of social stress that characterize these different coping strategies. PMID- 26634228 TI - An Examination of Ethical Issues Surrounding a Research Project: "The Role of Anxiety and Sleep Deprivation on Excessive Gestational Weight Gain". PMID- 26634229 TI - Mining Missing Hyperlinks from Human Navigation Traces: A Case Study of Wikipedia. AB - Hyperlinks are an essential feature of the World Wide Web. They are especially important for online encyclopedias such as Wikipedia: an article can often only be understood in the context of related articles, and hyperlinks make it easy to explore this context. But important links are often missing, and several methods have been proposed to alleviate this problem by learning a linking model based on the structure of the existing links. Here we propose a novel approach to identifying missing links in Wikipedia. We build on the fact that the ultimate purpose of Wikipedia links is to aid navigation. Rather than merely suggesting new links that are in tune with the structure of existing links, our method finds missing links that would immediately enhance Wikipedia's navigability. We leverage data sets of navigation paths collected through a Wikipedia-based human computation game in which users must find a short path from a start to a target article by only clicking links encountered along the way. We harness human navigational traces to identify a set of candidates for missing links and then rank these candidates. Experiments show that our procedure identifies missing links of high quality. PMID- 26634230 TI - The phenotypic and genomic diversity of Aspergillus strains producing glucose dehydrogenase. AB - Twelve Aspergillus sp. strains producing glucose dehydrogenase were identified using ITS region sequencing. Based on the sequences obtained, the genomic relationship of the analyzed strains was investigated. Moreover, partial gdh gene sequences were determined and aligned. The amplified fragment length polymorphism (AFLP) method was applied for genomic fingerprinting of twelve Aspergillus isolates. Using one PstI restriction endonuclease and five selective primers in an AFLP assay, 556 DNA fragments were generated, including 532 polymorphic bands. The AFLP profiles were found to be highly specific for each strain and they unambiguously distinguished twelve Aspergilli fungi. The AFLP-based dendrogram generated by the UPGMA method grouped all the Aspergillus fungi studied into two major clusters. All the Aspergillus strains were also characterized using Biolog FF MicroPlates to obtain data on C-substrate utilization and mitochondrial activity. The ability to decompose various substrates differed among the analyzed strains up to three folds. All of the studied strains mainly decomposed carbohydrates. PMID- 26634231 TI - Synergistic hemolysins of coagulase-negative staphylococci (CoNS). AB - A total of 104 coagulase negative staphylococci, belonging to S. capitis, S. hominis, S. haemolyticus and S. warneri, originating from the collection of the Department of Pharmaceutical Microbiology (ZMF), Medical University of Lodz, Poland, were tested for their synergistic hemolytic activity. 83% of strains produced delta-hemolysin, however, the percentage of positive strains of S. haemolyticus, S. warneri, S. capitis and S. hominis was different - 98%, 78%, 75% and 68%, respectively. Highly pure hemolysins were obtained from culture supernatants by protein precipitation with ammonium sulphate (0-70% of saturation) and extraction by using a mixture of organic solvents. The purity and molecular mass of hemolysins was determined by TRIS/Tricine PAGE. All CoNS hemolysins were small peptides with a molar mass of about 3.5 kDa; they possessed cytotoxic activity against the line of human foreskin fibroblasts ATCC Hs27 and lysed red cells from different mammalian species, however, the highest activity was observed when guinea pig, dog and human red blood cells were used. The cytotoxic effect on fibroblasts occurred within 30 minutes. The S. cohnii ssp. urealyticus strain was used as a control. The antimicrobial activity was examined using hemolysins of S. capitis, S. hominis, S. cohnii ssp. cohnii and S. cohnii ssp. urealyticus. Hemolysins of the two S. cohnii subspecies did not demonstrate antimicrobial activity. Cytolysins of S. capitis and S. hominis had a very narrow spectrum of action; out of 37 examined strains, the growth of only Micrococcus luteus, Corynebacterium diphtheriae and Pasteurella multocida was inhibited. PMID- 26634232 TI - Immune response gene polymorphisms in tuberculosis. AB - Tuberculosis (TB), an infectious disease caused by Mycobacterium tuberculosis (M.tb), remains a leading public health problem in most parts of the world. Despite the discovery of the bacilli over 100 years ago, there are still many unanswered questions about the host resistance to TB. Although one third of the world's population is infected with virulent M.tb, no more than 5-10% develop active disease within their lifetime. A lot of studies suggest that host genetic factors determine the outcome of M.tb-host interactions, however, specific genes and polymorphisms that govern the development of TB are not completely understood. Strong evidence exists for genes encoding pattern recognition receptors (TLR, CD14), C-type lectins, cytokines/chemokines and their receptors (IFN-gamma, TNF-alpha, IL-12, IL-10, MCP-1, MMP-1), major histocompatibility complex (MHC) molecules, vitamin D receptor (VDR), and proton-coupled divalent metal ion transporters (SLC11A1). Polymorphisms in these genes have a diverse influence on the susceptibility to or protection against TB among particular families, ethnicities and races. In this paper, we review recent discoveries in genetic studies and correlate these findings with their influence on TB susceptibility. PMID- 26634233 TI - Assembly of single molecular magnets from dinuclear to 2D Dy-compounds with significant change of relaxation energy barriers. AB - A dinuclear Dy(III) compound (1) was structurally and magnetically characterized, displaying a single-molecule magnet (SMM) behavior with a relaxation energy barrier of 21(1) K. Interestingly, by only adding a suitable substituent on the ligand in , as an SMM building unit, can be further assembled into a two dimensional (2D) framework (2), which possesses a typical SMM behavior and a high relaxation energy barrier of 68(2) K. The result implied that the assembly of an SMM can effectively tune the energy barrier. To our knowledge, a cluster-based SMM assembled into a new 2D framework with SMM behavior is seldom reported. PMID- 26634234 TI - Hydroamination of diphenylbutadiyne with secondary N-methyl-anilines using the dipotassium tetrakis(2,6-diisopropylanilino)calciate precatalyst. AB - The approved precatalyst [K2Ca{N(H)Dipp}4] was employed to study the hydroamination of diphenylbutadiyne with N-methyl-anilines in tetrahydrofuran at room temperature. The hydroamination occurs regioselectively within a few hours yielding (N-methyl)-(N-aryl)-1,4-diphenylbut-1-ene-3-yne-1-ylamine with phenyl (1a), 4-tolyl (1b) and 4-fluorophenyl groups (1c). In all cases a mixture of E- and Z-isomers is obtained. The second hydroamination step requires drastically extended reaction times and is successful only for the reaction of diphenylbutadiyne with N-methyl-aniline and N-methyl-4-fluoroaniline giving 1,4 diphenyl-1,4-bis(N-methyl-anilino)buta-1,3-diene [R = H (2a) and F (2c)]; a mixture of E,E-, E,Z- and Z,Z-isomers is obtained. The X-ray structures of E-1a, E-1b and E-1c show a slightly shortened N-C bond to the alkene moieties. Due to enhanced steric strain the anilino units of Z,Z-2c and Z,Z-3 turn away from the butadiene unit and consequently, the lone pair at the planar nitrogen atoms slightly interacts with the adjacent aryl groups. PMID- 26634235 TI - Group 13 metal complexes containing the bis-(4-methylbenzoxazol-2-yl)-methanide ligand. AB - To focus on the high importance of low-valent main group metal complexes, which can be applied to catalytic transformations, this article deals with the promising new ligand system (4-MeNCOC6H3)2CH2 (1). It is patterned on the well known nacnac ligand and further development of the parent bisheterocyclo methanes. In comparison with the results of previous studies based on the bisheterocyclo methanes (NCOC6H4)2CH2 and (NCOC6H4)2CH2 derivative 1 was modified by adding a methyl group to the annulated benzene perimeters to enhance the steric protection of a potentially coordinated main group metal cation. On reaction of 1 with group 13 trimethyl reagents and dialkyl aluminium halides the ligand backbone gets deprotonated and the two endocyclic nitrogen donor atoms coordinate with the remaining organometallic fragment to form a six-membered metalla heterocycle. The synthesis of [Me2Al{(4-MeNCOC6H3)2CH}] (2), [Me2Ga{(4 MeNCOC6H3)2CH}] (3), [Me2In{(4-MeNCOC6H3)2CH}] (4), [ClMeAl{(4-MeNCOC6H3)2CH}] (5), [IMeAl{(4-MeNCOC6H3)2CH}] (6) and [IEtAl{(4-MeNCOC6H3)2CH}] (7) could be accomplished. A structural comparison of those metallated species based on single crystal X-ray analyses identifies them as ideal precursors generating new low valent main group complexes. PMID- 26634236 TI - BMP4: a Possible Key Factor in Differentiation of Auditory Neuron-Like Cells from Bone-Derived Mesenchymal Stromal Cells. AB - BACKGROUND: Previous studies have shown that BMP4 may play an important part in the development of auditory neurons (ANs), which are degenerated in sensorineural hearing loss. However, whether BMP4 can promote sensory fate specification from mesenchymal stromal cells (MSCs) is unknown so far. METHODS: MSCs isolated from Sprague-Dawley (SD) rats were confirmed by expression of MSC markers using flow cytometry and adipogenesis/osteogenesis using differentiation assays. MSCs treated with a complex of neurotrophic factors (BMP4 group and non-BMP4 group) were induced into auditory neuron-like cells, then the differences between the two groups were analyzed in morphological observation, cell growth curve, qRT PCR, and immunofluorescence. RESULTS: Flow cytometric analysis showed that the isolated cells expressed typical MSC surface markers. After adipogenic and osteogenic induction, the cells were stained by oil red O and Alizarin Red. The neuronal induced cells were in the growth plateau and had special forms of neurons. In the presence of BMP4, the inner ear genes NF-M, Neurog1, GluR4, NeuroD, Calretinin, NeuN, Tau, and GATA3 were up-regulated in MSCs. CONCLUSIONS: MSCs have the capacity to differentiate into auditory neuron-like cells in vitro. As an effective inducer, BMP4 may play a key role in transdifferentiation. PMID- 26634237 TI - Mentoring. PMID- 26634238 TI - The Authors respond. PMID- 26634239 TI - Expanded Access to Non-VA Care Through the Veterans Choice Program. Interim final rule. AB - The Department of Veterans Affairs (VA) revises its medical regulations that implement section 101 of the Veterans Access, Choice, and Accountability Act of 2014 (hereafter referred to as "the Choice Act"), which requires VA to establish a program to furnish hospital care and medical services through eligible non-VA health care providers to eligible veterans who either cannot be seen within the wait-time goals of the Veterans Health Administration (VHA) or who qualify based on their place of residence (hereafter referred to as the "Veterans Choice Program" or the "Program"). These regulatory revisions are required by the most recent amendments to the Choice Act made by the Construction Authorization and Choice Improvement Act of 2014, and by the Surface Transportation and Veterans Health Care Choice Improvement Act of 2015. The Construction Authorization and Choice Improvement Act of 2014 amended the Choice Act to define additional criteria that VA may use to determine that a veteran's travel to a VA medical facility is an "unusual or excessive burden," and the Surface Transportation and Veterans Health Care Choice Improvement Act of 2015 amended the Choice Act to cover all veterans enrolled in the VA health care system, remove the 60-day limit on an episode of care, modify the wait-time and 40-mile distance eligibility criteria, and expand provider eligibility based on criteria as determined by VA. This interim final rule revises VA regulations consistent with the changes made to the Choice Act as described above. PMID- 26634240 TI - How High is America's Health Care Cost Burden? Findings from the Commonwealth Fund Health Care Affordability Tracking Survey, July-August 2015. AB - One-quarter of privately insured working-age adults have high health care cost burdens relative to their incomes in 2015, according to the Commonwealth Fund Health Care Affordability Index, a comprehensive measure of consumer health care costs. This figure, which is based on a nationally representative sample of people with private insurance who are mainly covered by employer plans, is statistically unchanged from 2014. When looking specifically at adults with low incomes, more than half have high cost burdens. In addition, when privately insured adults were asked how they rated their affordability, greater shares reported their premiums and deductible costs were difficult or impossible to afford than the Index would suggest. Health plan deductibles and copayments had negative effects on many people's willingness to get needed health care or fill prescriptions. In addition, many consumers are confused about which services are free to them and which count toward their deductible. PMID- 26634241 TI - Evaluating the Impact of Health Insurance Industry Consolidation: Learning from Experience. AB - Research shows consolidation in the private health insurance industry leads to premium increases, even though insurers with larger local market shares generally obtain lower prices from health care providers. Additional research is needed to understand how to protect against harms and unlock benefits from scale. Data on enrollment, premiums, and costs of commercial health insurance--by insurer, plan, customer segment, and local market--would help us understand whether, when, and for whom consolidation is harmful or beneficial. Such transparency is common where there is a strong public interest and substantial public regulation, both of which characterize this vital sector. PMID- 26634242 TI - Intrauterine Growth Retardation (IUGR) as a Novel Condition of Insulin-Like Growth Factor-1 (IGF-1) Deficiency. AB - Insulin-like growth factor 1 (IGF-1) is an anabolic hormone with several biological activities, such as proliferation, mitochondrial protection, cell survival, tissue growth and development, anti-inflammatory, antioxidant, antifibrogenic and antiaging. This hormone plays an important role in embryological and postnatal states, being essential for normal foetal and placental growth and differentiation. During gestation, the placenta is one of the major sources of IGF-1, among other hormones. This intrauterine organ expresses IGF-1 receptors and IGF-1 binding proteins (IGFBPs), which control IGF 1 activities. Intrauterine growth restriction (IUGR) is the second most frequent cause of perinatal morbidity and mortality, defined as the inability to achieve the expected weight for gestational age. Different studies have revealed that IUGR infants have placental dysfunction and low circulating levels of insulin, IGF-1, IGF-2 and IGFBPs. Such data suggest that IGF-1 deficiency in gestational state may be one of the major causes of foetal growth retardation. The aim of this review is to study the epidemiology, physiopathology and possible causes of IUGR. Also, it intends to study the possible role of the placenta as an IGF-1 target organ. The purpose is to establish if IUGR could be considered as a novel condition of IGF-1 deficiency and if its treatment with low doses of IGF-1 could be a suitable therapeutic strategy. PMID- 26634243 TI - Examining mortality among formerly homeless adults enrolled in Housing First: An observational study. AB - BACKGROUND: Adults who experience prolonged homelessness have mortality rates 3 to 4 times that of the general population. Housing First (HF) is an evidence based practice that effectively ends chronic homelessness, yet there has been virtually no research on premature mortality among HF enrollees. In the United States, this gap in the literature exists despite research that has suggested chronically homeless adults constitute an aging cohort, with nearly half aged 50 years old or older. METHODS: This observational study examined mortality among formerly homeless adults in an HF program. We examined death rates and causes of death among HF participants and assessed the timing and predictors of death among HF participants following entry into housing. We also compared mortality rates between HF participants and (a) members of the general population and (b) individuals experiencing homelessness. We supplemented these analyses with a comparison of the causes of death and characteristics of decedents in the HF program with a sample of adults identified as homeless in the same city at the time of death through a formal review process. RESULTS: The majority of decedents in both groups were between the ages of 45 and 64 at their time of death; the average age at death for HF participants was 57, compared to 53 for individuals in the homeless sample. Among those in the HF group, 72% died from natural causes, compared to 49% from the homeless group. This included 21% of HF participants and 7% from the homeless group who died from cancer. Among homeless adults, 40% died from an accident, which was significantly more than the 14% of HF participants who died from an accident. HIV or other infectious diseases contributed to 13% of homeless deaths compared to only 2% of HF participants. Hypothermia contributed to 6% of homeless deaths, which was not a cause of death for HF participants. CONCLUSIONS: Results suggest HF participants face excess mortality in comparison to members of the general population and that mortality rates among HF participants are higher than among those reported among members of the general homeless population in prior studies. However, findings also suggest that causes of death may differ between HF participants and their homeless counterparts. Specifically, chronic diseases appear to be more prominent causes of death among HF participants, indicating the potential need for integrating medical support and end-of-life care in HF. PMID- 26634244 TI - Erratum to: Fine-grained information extraction from German transthoracic echocardiography reports. PMID- 26634246 TI - Frailty still matters to health and survival in centenarians: the case of China. AB - BACKGROUND: Frailty indicates accumulated vulnerability of adverse health outcomes in later life. Its robustness in predicting dependent living, falls, comorbidity, disability, health change, mortality, and health care utilization at older ages is well-documented. However, almost no studies have ever attempted to examine its robustness in centenarians, mainly due to data unavailability. This study examines prevalence of frailty in centenarians and its predictive powers on subsequent mortality and health conditions. METHODS: We use a sample of 4434 centenarians from the 2002, 2005, 2008, and 2011 waves of the Chinese Longitudinal Healthy Longevity Survey (CLHLS), with elders in three younger age groups 65-79, 80-89, and 90-99 as comparisons. Frailty is measured by a cumulative deficit index (DI) that is constructed from 39 variables covering physical and cognitive function, disease conditions, psychological well-being, and other health dimensions. Survival analysis is conducted to examine how frailty is associated with subsequent mortality at an average follow-up length of 3.7 years (2.6 years for deceased persons died in 2002-2011 and 7.6 years for survived persons at the 2011 wave). Logistic regressions are applied to examine how frailty is associated with subsequent physical and cognitive functions, disease conditions, and self-rated health with an average follow-up length of 3.0 years. RESULTS: The study reveals that centenarians are frailer than younger elders. The DI scores increase from less than 0.1 at ages 65-79 to over 0.30 in centenarians. Women are frailer than men at all ages. However, there is a great variation in frailty among all age groups. We also find that each additional increase of 0.01 score of the DI is associated with 1.6 % higher mortality risk (95 % CI: 1.014-1.018) in female centenarians and 1.4 % higher mortality risk (95 % CI: 1.010-1.018) in male centenarians, although these associations are weaker than those in other three younger age groups. CONCLUSIONS: Frailty still plays an important role in determining subsequent health outcomes and mortality in centenarians. PMID- 26634247 TI - Impaired aldehyde dehydrogenase 1 subfamily member 2A-dependent retinoic acid signaling is related with a mesenchymal-like phenotype and an unfavorable prognosis of head and neck squamous cell carcinoma. AB - BACKGROUND: An inverse correlation between expression of the aldehyde dehydrogenase 1 subfamily A2 (ALDH1A2) and gene promoter methylation has been identified as a common feature of oropharyngeal squamous cell carcinoma (OPSCC). Moreover, low ALDH1A2 expression was associated with an unfavorable prognosis of OPSCC patients, however the causal link between reduced ALDH1A2 function and treatment failure has not been addressed so far. METHODS: Serial sections from tissue microarrays of patients with primary OPSCC (n = 101) were stained by immunohistochemistry for key regulators of retinoic acid (RA) signaling, including ALDH1A2. Survival with respect to these regulators was investigated by univariate Kaplan-Meier analysis and multivariate Cox regression proportional hazard models. The impact of ALDH1A2-RAR signaling on tumor-relevant processes was addressed in established tumor cell lines and in an orthotopic mouse xenograft model. RESULTS: Immunohistochemical analysis showed an improved prognosis of ALDH1A2(high) OPSCC only in the presence of CRABP2, an intracellular RA transporter. Moreover, an ALDH1A2(high)CRABP2(high) staining pattern served as an independent predictor for progression-free (HR: 0.395, p = 0.007) and overall survival (HR: 0.303, p = 0.002), suggesting a critical impact of RA metabolism and signaling on clinical outcome. Functionally, ALDH1A2 expression and activity in tumor cell lines were related to RA levels. While administration of retinoids inhibited clonogenic growth and proliferation, the pharmacological inhibition of ALDH1A2-RAR signaling resulted in loss of cell-cell adhesion and a mesenchymal like phenotype. Xenograft tumors derived from FaDu cells with stable silencing of ALDH1A2 and primary tumors from OPSCC patients with low ALDH1A2 expression exhibited a mesenchymal-like phenotype characterized by vimentin expression. CONCLUSIONS: This study has unraveled a critical role of ALDH1A2-RAR signaling in the pathogenesis of head and neck cancer and our data implicate that patients with ALDH1A2(low) tumors might benefit from adjuvant treatment with retinoids. PMID- 26634248 TI - Clinicians' overestimation of febrile child risk assessment. AB - We aimed to estimate clinicians' based risk thresholds at which febrile children would be managed as serious bacterial infections (SBI) to determine influencing characteristics and to compare thresholds with prediction model (Feverkidstool) risk estimates. Twenty-one video vignettes of febrile children visiting the emergency department (ED) were assessed by 42 (40.4 %) international paediatricians/paediatric emergency clinicians. Questions were related to clinical risk scores of the child having SBI and SBI management decisions on visual analogue scales. Feverkidstool risk scores were based on clinical signs/symptoms and C-reactive protein. Amongst vignettes assigned to SBI management, the median risk was 60 % (interquartile range (IQR) 30.0-80.5) and 16.0 % (IQR 5.0-32.0) when vignettes were not managed as SBI. Ill appearance and aberrant circulatory signs were the most influencing factors, as age and duration of fever were the least influencing factors on SBI management decisions. Feverkidstool risk scores varied from 13 % (IQR 7.7-28.1) for SBI management to 7.3 % (IQR 5.7-16.3) for no SBI management. CONCLUSION: Clinicians assigned high risk scores to children who they would have managed as SBI, mostly influenced by ill appearance and aberrant circulation. In contrast to SBI risk assessment of the Feverkidstool, clinicians' appeared to apply a more stepwise assessment of the risk of presence/absence of SBI at different steps in the diagnostic and therapeutic process. Uniform risk thresholds at which one should start SBI management in febrile children remains unclear; risk thresholds at which we refrained from SBI management were more consistent. WHAT IS KNOWN: *Only a small proportion of febrile children presenting to the emergency department will have serious bacterial infections (SBI) and uniform risk thresholds to start or withhold SBI treatment are not known. *The low prevalence of SBI and consequently the low exposure of clinicians to these infections make them rely more on alarming signs or clinical decision rules. What is New: *Previously identified model predictors for SBI appeared to be significantly influencing factors in clinicians' febrile child management in emergency care. *Clinicians' wielded higher risk thresholds regarding SBI febrile child management than reflected by the clinical prediction model while smaller differences in risk thresholds between clinical and model prediction were observed when clinicians refrained from SBI management. PMID- 26634250 TI - Comment on: "Regorafenib: Start Low and Go Slow". PMID- 26634249 TI - High level of interleukin-32 gamma in the joint of ankylosing spondylitis is associated with osteoblast differentiation. AB - BACKGOUND: The formation of bony spurs and ankylosis is a key pathognomic feature in ankylosing spondylitis (AS) and results in functional impairment. The aim of this study was to investigate the role of IL-32gamma in osteoblast (OB) differentiation and its association with the pathogenesis of AS. METHODS: The concentration and expression of IL-32gamma were evaluated in synovial fluid and tissue from patients with AS, rheumatoid arthritis (RA) and osteoarthritis (OA), using enzyme-linked immunosorbent assay and immunohistochemistry. To establish whether IL-32gamma affects OB differentiation, we used calvarial cells of IL 32gamma transgenic (TG) mice or wild-type (WT) mice. To elucidate the mechanism of osteoblastogenesis, levels of regulators were assayed in IL-32gamma TG mice and in primary OBs after IL-32gamma stimulation. RESULTS: The IL-32gamma levels were higher in the synovial fluid of AS patients compared with RA or OA patients and the expression of IL-32 was higher in AS synovia than in RA or OA synovia. Additional IL-32gamma stimulation in precursor cells enhanced OB differentiation potentially and IL-32gamma TG mice showed higher rates of OB differentiation than WT mice. IL-32gamma reduced the expression of DKK-1, a negative regulator, in both WT precursor cells and human OBs and the constitutive expression of DKK-1 was suppressed in calvarial cells from IL-32gamma TG mice. CONCLUSIONS: The elevated level of IL-32gamma in AS joint could enhance OB differentiation via DKK 1 suppression. Therefore, IL-32gamma might be a putative molecular target to prevent the abnormal bone formation in AS. PMID- 26634245 TI - A genome-wide association study identifies risk loci for spirometric measures among smokers of European and African ancestry. AB - BACKGROUND: Pulmonary function decline is a major contributor to morbidity and mortality among smokers. Post bronchodilator FEV1 and FEV1/FVC ratio are considered the standard assessment of airflow obstruction. We performed a genome wide association study (GWAS) in 9919 current and former smokers in the COPDGene study (6659 non-Hispanic Whites [NHW] and 3260 African Americans [AA]) to identify associations with spirometric measures (post-bronchodilator FEV1 and FEV1/FVC). We also conducted meta-analysis of FEV1 and FEV1/FVC GWAS in the COPDGene, ECLIPSE, and GenKOLS cohorts (total n = 13,532). RESULTS: Among NHW in the COPDGene cohort, both measures of pulmonary function were significantly associated with SNPs at the 15q25 locus [containing CHRNA3/5, AGPHD1, IREB2, CHRNB4] (lowest p-value = 2.17 * 10(-11)), and FEV1/FVC was associated with a genomic region on chromosome 4 [upstream of HHIP] (lowest p-value = 5.94 * 10( 10)); both regions have been previously associated with COPD. For the meta analysis, in addition to confirming associations to the regions near CHRNA3/5 and HHIP, genome-wide significant associations were identified for FEV1 on chromosome 1 [TGFB2] (p-value = 8.99 * 10(-9)), 9 [DBH] (p-value = 9.69 * 10(-9)) and 19 [CYP2A6/7] (p-value = 3.49 * 10(-8)) and for FEV1/FVC on chromosome 1 [TGFB2] (p value = 8.99 * 10(-9)), 4 [FAM13A] (p-value = 3.88 * 10(-12)), 11 [MMP3/12] (p value = 3.29 * 10(-10)) and 14 [RIN3] (p-value = 5.64 * 10(-9)). CONCLUSIONS: In a large genome-wide association study of lung function in smokers, we found genome-wide significant associations at several previously described loci with lung function or COPD. We additionally identified a novel genome-wide significant locus with FEV1 on chromosome 9 [DBH] in a meta-analysis of three study populations. PMID- 26634251 TI - Liver ChIP-seq analysis in FGF19-treated mice reveals SHP as a global transcriptional partner of SREBP-2. AB - BACKGROUND: Fibroblast growth factor-19 (FGF19) is an intestinal hormone that mediates postprandial metabolic responses in the liver. The unusual orphan nuclear receptor, small heterodimer partner (SHP), acts as a co-repressor for many transcriptional factors and has been implicated in diverse biological pathways including FGF19-mediated repression of bile acid synthesis. To explore global functions of SHP in mediating FGF19 action, we identify genome-wide SHP binding sites in hepatic chromatin in mice treated with vehicle or FGF19 by ChIP seq analysis. RESULTS: The overall pattern of SHP binding sites between these two groups is similar, but SHP binding is enhanced at the sites by addition of FGF19. SHP binding is detected preferentially in promoter regions that are enriched in motifs for unexpected non-nuclear receptors. We observe global co-localization of SHP sites with published sites for SREBP-2, a master transcriptional activator of cholesterol biosynthesis. FGF19 increases functional interaction between endogenous SHP and SREBP-2 and inhibits SREBP-2 target genes, and these effects were blunted in SHP-knockout mice. Furthermore, FGF19-induced phosphorylation of SHP at Thr-55 is shown to be important for its functional interaction with SREBP 2 and reduction of liver/serum cholesterol levels. CONCLUSION: This study reveals SHP as a global transcriptional partner of SREBP-2 in regulation of sterol biosynthetic gene networks and provides a potential mechanism for cholesterol lowering action of FGF19. PMID- 26634252 TI - Evidence-based diagnosis and treatment of macrophage activation syndrome in systemic juvenile idiopathic arthritis. AB - BACKGROUND: Macrophage activation syndrome (MAS) is a severe and potentially lethal complication of several inflammatory diseases but seems particularly linked to systemic juvenile idiopathic arthritis (sJIA). Standardized diagnostic and treatment guidelines for MAS in sJIA are currently lacking. The aim of this systematic literature review was to evaluate currently available literature on diagnostic criteria for MAS in sJIA and provide an overview of possible biomarkers for diagnosis, disease activity and treatment response and recent advances in treatment. METHODS: A systematic literature search was performed in MEDLINE, EMBASE and Cochrane. 495 papers were identified. Potentially relevant papers were selected by 3 authors after which full text screening was performed. All selected papers were evaluated by at least two independent experts for validity and level of evidence according to EULAR guidelines. RESULTS: 27 papers were included: 7 on diagnosis, 9 on biomarkers and 11 on treatment. Systematic review of the literature confirmed that there are no validated diagnostic criteria for MAS in sJIA. The preliminary Ravelli criteria, with the addition of ferritin, performed well in a large retrospective case-control study. Recently, an international consortium lead by PRINTO proposed a new set of diagnostic criteria able to distinguish MAS from active sJIA and/or infection with superior performance. Other promising diagnostic biomarkers potentially distinguish MAS complicating sJIA from primary and virus-associated hemophagocytic lymphohistiocytosis. The highest level of evidence for treatment comes from case series. High dose corticosteroids with or without cyclosporine A were frequently reported as first-line therapy. From the newer treatment modalities, promising responses have been reported with anakinra. CONCLUSION: MAS in sJIA seems to be diagnosed best by the recently proposed PRINTO criteria, although prospective validation is needed. Novel promising biomarkers for sJIA related MAS are in need of prospective validation as well, and are not widely available yet. Currently, treatment of MAS in sJIA relies more on experience than evidence based medicine. Taking into account the severity of MAS and the scarcity of evidence, early expert consultation is recommended as soon as MAS is suspected. PMID- 26634253 TI - Diagnosis of rotator cuff tears using 3-Tesla MRI versus 3-Tesla MRA: a systematic review and meta-analysis. AB - OBJECTIVE: To compare the diagnostic accuracy of magnetic resonance imaging (MRI), 2-dimensional magnetic resonance arthrogram (MRA) and 3-dimensional isotropic MRA in the diagnosis of rotator cuff tears when performed exclusively at 3-T. MATERIALS AND METHODS: A systematic review was undertaken of the Cochrane, MEDLINE and PubMed databases in accordance with the PRISMA guidelines. Studies comparing 3-T MRI or 3-T MRA (index tests) to arthroscopic surgical findings (reference test) were included. Methodological appraisal was performed using QUADAS 2. Pooled sensitivity and specificity were calculated and summary receiver-operating curves generated. Kappa coefficients quantified inter-observer reliability. RESULTS: Fourteen studies comprising 1332 patients were identified for inclusion. Twelve studies were retrospective and there were concerns regarding index test bias and applicability in nine and six studies respectively. Reference test bias was a concern in all studies. Both 3-T MRI and 3-T MRA showed similar excellent diagnostic accuracy for full-thickness supraspinatus tears. Concerning partial-thickness supraspinatus tears, 3-T 2D MRA was significantly more sensitive (86.6 vs. 80.5 %, p = 0.014) but significantly less specific (95.2 vs. 100 %, p < 0.001). There was a trend towards greater accuracy in the diagnosis of subscapularis tears with 3-T MRA. Three-Tesla 3D isotropic MRA showed similar accuracy to 3-T conventional 2D MRA. CONCLUSION: Three-Tesla MRI appeared equivalent to 3-T MRA in the diagnosis of full- and partial-thickness tears, although there was a trend towards greater accuracy in the diagnosis of subscapularis tears with 3-T MRA. Three-Tesla 3D isotropic MRA appears equivalent to 3-T 2D MRA for all types of tears. PMID- 26634254 TI - Signal intensity loss of the intervertebral discs in the cervical spine of young patients on fluid sensitive sequences. AB - OBJECTIVE: To evaluate the signal intensity (SI) of the intervertebral discs of the cervical spine on magnetic resonance (MR) fluid sensitive sequences, and correlate this to secondary signs of degeneration on MR and radiographs as well as to age. MATERIAL AND METHODS: A total of 265 patients aged >=16 with back pain (>=3-months, <2-year, onset <45-years) from the SPondyloArthritis Caught Early (SPACE) cohort were included. Sagittal 1.5 T MR images and lateral radiographs of the cervical spine were independently evaluated by two readers for: SI of the intervertebral discs using a grading system based of Pfirrmann (grade 1 normal/bright SI; 2 inhomogeneous/bright SI; 3 inhomogeneous/mildly decreased SI; 4 inhomogeneous/markedly decreased SI; 5 signal void), disc herniation and Modic changes (MRI) and disc space narrowing, osteophytes and sclerosis (radiograph). Readers were blinded for clinical information. Descriptive statistics were used for characteristics and prevalence of findings, and regression analysis was used for age and grades. RESULTS: Of 265 patients (36% male, mean age 30), 221 (83%) patients had 1 to 6 discs (median 4) with decreased SI. Of 1,590 discs, 737 (46%) were grade 1; 711 (45%) grade 2; 133 (8%) grade 3; 8 (1%) grade 4 and 1 (0%) grade 5. Secondary signs of degeneration were rare and seen predominantly in C5 C7 and appear to be related to signal loss grade 3 and 4. CONCLUSION: Low signal intensity of intervertebral discs in absence of secondary degenerative signs in the cervical spine on fluid sensitive MR images might be pre-existing and part of the natural course. PMID- 26634255 TI - [New therapy option for type 2 diabetes mellitus: EMPA-REG study]. PMID- 26634256 TI - Evidence that exposure to progesterone alone is a sufficient stimulus to cause a precipitous rise in the immunomodulatory protein the progesterone induced blocking factor (PIBF). AB - PURPOSE: To determine if exposure to progesterone alone is sufficient to increase the production of the immunomodulatory protein known as the progesterone induced blocking factor (PIBF). Also to determine what method of progesterone delivery or form of P best stimulates PIBF secretion. METHODS: Serum samples from patients with infertility and paid volunteers were evaluated for both PIBF and progesterone at various times during the follicular phase and the luteal phase in both natural cycles and cycles involving embryo transfer after endogenous and exogenous progesterone exposure and after various synthetic progestins. PIBF was measured by a non-commercial research ELISA assay. Comparisons were made of serum PIBF before and after exposure to progesterone, 17-hydroxyprogesterone, and oral contraceptives. PIBF was also measured before and after transfer of embryos. RESULTS: Progesterone alone without exposure to the fetal allogeneic stimulus was able to produce a marked increase in serum PIBF. Neither a synthetic progestin (19-nortestosterone derivative) nor 17-hydroxyprogesterone caused an increase in PIBF. Some PIBF is generally detected even in the follicular phase. CONCLUSIONS: A previous concept considered that an allogeneic stimulus, e.g., from the fetal semi-allograft, was necessary to induce de novo progesterone receptors in gamma delta T cells, which, in turn, when exposed to a high concentration of progesterone, would secrete high levels of PIBF. These data show that exposure to an allogeneic stimulus is not needed to cause a marked rise in PIBF, merely progesterone alone is sufficient. PMID- 26634257 TI - Is the wrong question being asked in infertility research? AB - A persistent finding is that assisted reproductive technology (ART) is associated with compromised birth outcomes, including higher risks for prematurity, low birthweight, and congenital malformations, even among singletons. Over the past decade, our research group, the Massachusetts Outcome Study of Assisted Reproductive Technology (MOSART), has evaluated pregnancy and birth outcomes among three groups of women, those women treated with ART, those with indicators of subfertility but without ART treatment, and fertile women. We have also explored the influence of infertility-related diagnoses on outcomes for women and infants. Over the course of our research, we have changed our perspective from an original focus on ART treatment parameters as the primary cause of excess morbidity to one centered instead on the underlying infertility-related diagnoses. This paper summarizes the research findings from our group that support this change in focus for infertility-based research from a primary emphasis on ART treatment to greater attention to the contribution of preexisting pathology underlying the infertility and suggests directions for future analyses. PMID- 26634258 TI - Evaluation of Chest X-ray and Thoracic Computed Tomography in Patients with Suspected Tuberculosis. AB - OBJECTIVE: To investigate if there is any correlation between positive findings detected by posterior-anterior (PA) chest radiograph and thoracic computerized tomography (CT) in cases with suspected lung tuberculosis (TB) due to positive tuberculin skin test (TST) results. METHODS: This is a retrospective evaluation of the medical files of patients who visited the Department of Pediatrics, Istanbul University, Istanbul Faculty of Medicine from 2006, through 2011 as outpatients and had positive TST (>15 mm) results. RESULTS: A total of 326 patients were included in the study; 45.7 % (n = 149) were girls, and the mean age was 9.0 +/- 4.1 y (range: 1-17 y). In total, 14.4 % (n = 47) had TB findings, all of which were in the form of hilar lymphadenopathy. Among the 47 cases with TB findings in PA chest X-ray, 45 (95.7 %) also had findings in thoracic CT. Only 2 (4.3 %) patients had normal thoracic CT results although their PA chest X-ray results were positive. CONCLUSIONS: Evaluation for pulmonary TB in children with positive isolated TSTs should be made primarily with PA chest X-ray. A routine thoracic CT scan is not necessary for asymptomatic patients with only hilar lymphadenopathy findings in PA chest radiographs. PMID- 26634259 TI - Uttarakhand Disaster 2013: A Report on Psychosocial Adversities Experienced by Children and Adolescents. AB - OBJECTIVE: To report the psychosocial adversities faced by children and adolescents in the Uttarkashi, district of Uttarakhand, experienced immediately after the Himalayan Tsunami in June 2013. Also to discuss issues pertinent to the disaster management including the needs of the disaster affected areas and future challenges. METHODS: This is a cross sectional observational report from the community assessment and interventions that were carried out as part of the disaster relief work by National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore within 1 mo of the disaster. Assessments and interventions were done by a team consisting of psychiatry resident, clinical psychologist, psychiatric social worker and a nurse. All diagnosis were made using International Classification of Diseases 10 (ICD 10) and the data was analysed using descriptive statistics and chi-square tests. RESULTS: A total of 300 children were screened; the mean age of the sample was 11.5 y and 65(32.5%) were boys. Two hundred (66.7%) children/adolescents reported one or the other psychosocial adversities attributable to the disaster. Psychological distress was present in 54/300 (18%) of the individuals. Loss of shelter and loss of playing space were the social issues having a statistically significant association with psychological distress signals such as feelings of anxiety, helplessness, insecurity, grief and uncertainty. Stress induced diagnosable psychiatric disorder was not present in any child or adolescent, however stress related psychiatric symptoms were present in around 13%. CONCLUSIONS: Himalayan tsunami of Uttarakhand in 2013 was associated with considerable psychosocial adversities among the resident children and adolescents. As children are a vulnerable population, a public health approach towards assessment and management of the psychosocial adversities in this population is urgently required at the state and national levels. PMID- 26634260 TI - Identification of Y-Chromosome Sequences in Turner Syndrome. AB - OBJECTIVES: To investigate the presence of Y-chromosome sequences and determine their frequency in patients with Turner syndrome. METHODS: The study included 23 patients with Turner syndrome from Brazil, who gave written informed consent for participating in the study. Cytogenetic analyses were performed in peripheral blood lymphocytes, with 100 metaphases per patient. Genomic DNA was also extracted from peripheral blood lymphocytes, and gene sequences DYZ1, DYZ3, ZFY and SRY were amplified by Polymerase Chain Reaction. RESULTS: The cytogenetic analysis showed a 45,X karyotype in 9 patients (39.2 %) and a mosaic pattern in 14 (60.8 %). In 8.7 % (2 out of 23) of the patients, Y-chromosome sequences were found. This prevalence is very similar to those reported previously. The initial karyotype analysis of these patients did not reveal Y-chromosome material, but they were found positive for Y-specific sequences in the lymphocyte DNA analysis. CONCLUSION: The PCR technique showed that 2 (8.7 %) of the patients with Turner syndrome had Y-chromosome sequences, both presenting marker chromosomes on cytogenetic analysis. PMID- 26634262 TI - Medicine Safety Monitoring in Pediatric Population in India. PMID- 26634261 TI - Mutation Analysis of TBX1 in Children with Conotruncal Heart Anomalies. PMID- 26634263 TI - Transient Zebra-like Hyperpigmentation in a Healthy Newborn. PMID- 26634264 TI - Imaging in Pediatric Demyelinating and Inflammatory Diseases of the Brain- Part 1. AB - Imaging plays an important role in the diagnosis, management, prognostication and follow up of pediatric demyelinating and inflammatory diseases of the brain and forms an integral part of the diagnostic criteria. Conventional and advanced MR imaging is the first and only reliable imaging modality. This article reviews the typical and atypical imaging features of common and some uncommon demyelinating and inflammatory diseases with emphasis on the criteria for categorization. Imaging protocols and the role of advanced imaging techniques are also covered appropriately. PMID- 26634265 TI - Kawasaki Disease: Experience from Developing Countries. PMID- 26634266 TI - Bile Duct Perforation due to Inspissated Bile Presenting as Refractory Ascites. AB - Non hepatic origin of refractory ascites is not a rarity. Hemolytic anemias are known to cause inspissated bile and biliary obstruction. Distal biliary obstruction can lead to biliary perforation. The authors report a case of hereditary spherocytosis leading to inspissated bile causing bile duct perforation and biliary ascites. A high index of suspicion for biliary ascites should be kept in a child with refractory ascites in the setting of progressive ascites with decreasing bilirubin. Ascitic fluid bilirubin analysis will clinch the diagnosis. Surgical repair is the optimal management. PMID- 26634267 TI - Phenotypic Variations in the 22q11 Deletion Syndrome - Study in a South Indian Population. PMID- 26634268 TI - Unsuccessful Retrieval of Impacted Foreign Body Bronchus: Think about Fogarty Catheter. PMID- 26634270 TI - Breastfeeding Duration and Authoritative Feeding Practices in First-Time Mothers. AB - BACKGROUND: Longer breastfeeding duration appears to have a protective effect against childhood obesity. This effect may be partially mediated by maternal feeding practices during the first years of life. However, the few studies that have examined links between breastfeeding duration and subsequent feeding practices have yielded conflicting results. OBJECTIVE: Using a large sample of first-time mothers and a newly validated, comprehensive measure of maternal feeding (the Feeding Practices and Structure Questionnaire), this study examined associations between breastfeeding duration and maternal feeding practices at child age 24 months. METHODS: Mothers (n = 458) enrolled in the NOURISH trial provided data on breastfeeding at child age 4, 14, and 24 months, and on feeding practices at 24 months. Structural equation modeling was used to examine associations between breastfeeding duration and 5 nonresponsive and 4 structure related "authoritative" feeding practices, adjusting for a range of maternal and child characteristics. RESULTS: The model showed acceptable fit (chi(2)/df = 1.68; root mean square error of approximation = .04, comparative fit index = .91, and Tucker-Lewis index = .89) and longer breastfeeding duration was negatively associated with 4 out of 5 nonresponsive feeding practices and positively associated with 3 out of 4 structure-related feeding practices. Overall, these results suggest that mothers who breastfeed longer reported using more appropriate feeding practices. CONCLUSION: These data demonstrate an association between longer breastfeeding duration and authoritative feeding practices characterized by responsiveness and structure, which may partly account for the apparent protective effect of breastfeeding on childhood obesity. PMID- 26634271 TI - Selective Toxicity of Investigational Ixazomib for Human Leukemia Cells Expressing Mutant Cytoplasmic NPM1: Role of Reactive Oxygen Species. AB - PURPOSE: This study was performed to determine whether the investigational proteasome inhibitor ixazomib demonstrated selective antineoplastic activity against acute myelogenous leukemia cells expressing a mutated nucleophosmin-1 gene and to gain a better understanding of its mechanisms of action. EXPERIMENTAL DESIGN: The cytotoxic effects of ixazomib treatment were analyzed in human acute myelogenous leukemia (AML) cell lines and primary AML samples expressing wild type or mutated NPM1 (NPMc(+)). The potential roles of oxidative stress in mediating cytotoxic activity were determined using flow cytometry, enzyme-based assays, and Western blots. RESULTS: Apoptosis induced by ixazomib was abrogated by knockdown of NPM1/NPMc(+)expression using an inducible shRNA construct and enhanced by NPMc(+)overexpression. Cytotoxicity was associated with superoxide generation and was reduced by the addition of the antioxidant N-acetylcysteine. AML cells expressing NPMc(+)had significantly reduced levels of intracellular glutathione and NADPH associated with reduced antioxidant responses to drug treatment. Treatment of 3 patients with relapsed NPMc(+)AML resulted in an antileukemic effect in 1 patient as demonstrated by a marked reduction of leukemic blasts in the peripheral blood. Efficacy was associated with superoxide generation, reduced glutathione levels, and reduced mRNA and protein expression of antioxidant effectors in responding cells. CONCLUSIONS: In this study, a direct association was observed between NPMc(+)expression in AML, reduced antioxidant responses, and enhanced sensitivity to an oral proteasome inhibitor that induces oxidative stress. These data suggest that intracellular determinants of antioxidant responses may be good predictors of therapeutic response to ixazomib. PMID- 26634272 TI - The Effects of a Warm or Chilly Climate Toward Socioeconomic Diversity on Academic Motivation and Self-Concept. AB - Persistent academic achievement gaps exist between university students from high and low socioeconomic status (SES) backgrounds. The current research proposes that the extent to which a university is perceived as actively supporting versus passively neglecting students from diverse socioeconomic backgrounds can influence low-SES students' academic motivation and self-concepts. In Experiments 1 and 2, low-SES students exposed to cues suggestive of an institution's warmth toward socioeconomic diversity demonstrated greater academic efficacy, expectations, and implicit associations with high academic achievement compared with those exposed to cues indicating institutional chilliness. Exploring the phenomenology underlying these effects, Experiment 3 demonstrated that warmth cues led low-SES students to perceive their socioeconomic background as a better match with the rest of the student body and to perceive the university as more socioeconomically diverse than did chilliness cues. Contributions to our understanding of low-SES students' psychological experiences in academic settings and practical implications for academic institutions are discussed. PMID- 26634273 TI - Just relax and concentrate on your breathing. PMID- 26634274 TI - Transdermal delivery of oxybutynin chloride proniosomal gels for the treatment of overactive bladder. AB - CONTEXT: Overactive bladder (OAB) is a common problem and anticholinergic drugs are first-line therapy, but they have side effects. OBJECTIVE: Development of oxybutynin chloride (OC) proniosomal gels and analyses of its efficacy for OAB treatment. MATERIALS AND METHODS: Phase separation coacervation was used to prepare proniosomal gels using various non-ionic surfactants, lipids, soy lecithin and isopropyl alcohol. Gels were characterized with regard to entrapment efficiency (EE), vesicle size, surface morphology (using environmental scanning electron microscopy [E-SEM]), stability, attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy, in vitro skin permeation, in vivo animal studies and histopathology. RESULTS AND DISCUSSION: EE was 87-92%, vesicle size was 0.38-5.0 MUm, and morphology showed some loosened pores in proniosomes after hydration. ATR-FTIR spectroscopy showed no significant shifts in peaks corresponding to OC and excipients. Most formulations exhibited >50% permeation but the cholesterol-containing formulations P3 (Span 20:Span 60 [1:1]) and P4 [Tween 20:Tween 80 (1:1)] had the highest percent cumulative permeation. P3 and P4 also showed faster recovery of cholinergic effects on salivary glands than oral formulations. P3 and P4 had pronounced therapeutic effects in reduction of urinary frequency and demonstrated improvements in bladder morphology (highly regenerative surface of the transitional epithelium). CONCLUSION: These results suggest that OC could be incorporated into proniosomal gels for transdermal delivery in the treatment of OAB. PMID- 26634275 TI - Efforts to improve US hospital safety stalled in 2014, report finds. PMID- 26634276 TI - The Loneliness Curriculum of Psychiatric Training. PMID- 26634278 TI - A novel approach for monitoring volatile anesthetic concentration during cardiopulmonary bypass. PMID- 26634279 TI - Chasing myocardial outcomes: perioperative myocardial infarction and cardiac troponin. AB - Perioperative myocardial infarction represents the most common cardiovascular complication following non-cardiac surgery, but frequently presents without the usual clinical signs and symptoms consistent with acute coronary syndrome. Given the silent nature of this event, a clinician's reliance on risk stratification tools and cardiac specific biomarkers to assist in the identification of at-risk individuals is heightened in the perioperative setting. Although cardiac troponin elevations following non-cardiac surgery have been consistently linked to increased mortality, uncertainty remains over how to clinically intervene to prevent harm. This decision is further complicated by the increasing sensitivity of the newest generation of cardiac biomarker immunoassays. In this narrative review, the growing body of evidence surrounding cardiac troponin elevations in the perioperative setting, how the evidence has been integrated into recent clinical practice guidelines, and its implications for the detection of perioperative myocardial infarction are discussed. PMID- 26634277 TI - Regulation of Sphingolipid Biosynthesis by the Morphogenesis Checkpoint Kinase Swe1. AB - Sphingolipid (SL) biosynthesis is negatively regulated by the highly conserved endoplasmic reticulum-localized Orm family proteins. Defective SL synthesis in Saccharomyces cerevisiae leads to increased phosphorylation and inhibition of Orm proteins by the kinase Ypk1. Here we present evidence that the yeast morphogenesis checkpoint kinase, Swe1, regulates SL biosynthesis independent of the Ypk1 pathway. Deletion of the Swe1 kinase renders mutant cells sensitive to serine palmitoyltransferase inhibition due to impaired sphingoid long-chain base synthesis. Based on these data and previous results, we suggest that Swe1 kinase perceives alterations in SL homeostasis, activates SL synthesis, and may thus represent the missing regulatory link that controls the SL rheostat during the cell cycle. PMID- 26634280 TI - Interscapular pain associated with neuraxial labour analgesia: a case series. AB - PURPOSE: Some labouring women with neuraxial labour analgesia experience severe upper back pain, typically between the scapulae. This pain may complicate management of neuraxial analgesia/anesthesia, and it may also have important implications for the mode of delivery. This case series describes the clinical course and management of three patients who developed interscapular pain associated with neuraxial labour analgesia. PRINCIPAL FINDINGS: Neuraxial labour analgesia was initiated in all patients with a combined spinal-epidural technique and maintained via patient-controlled epidural analgesia. Two patients were nulliparous. One patient experienced interscapular pain during initiation of epidural anesthesia for Cesarean delivery after 19 hr of maintenance of labour analgesia with local anesthetic/opioid solution. The other two patients experienced interscapular pain during routine maintenance of epidural labour analgesia. In two patients, the epidural space was identified using loss of resistance to air. Another patient recalled experiencing interscapular pain with her prior labour epidural. Management of these patients included decreasing the epidural infusion rate, increasing the concentration of local anesthetic in the epidural infusion solution, administration of epidural opioids, and replacement of the epidural catheter. All patients eventually experienced relief of their interscapular pain. CONCLUSIONS: While little is understood about the etiology of this unique anesthetic complication, it may have important clinical consequences, including inadequate analgesia, inability to provide timely epidural anesthesia, and an increased risk of Cesarean delivery. Future work should characterize at risk patients, delineate effective treatment strategies, and identify any associated long-term consequences. PMID- 26634283 TI - Performance and carbon turnover in fast- and slow-growing broilers submitted to cyclic heat stress and fed on high-protein diets. AB - Two experiments were conducted to test the hypothesis that when using similar protein/amino acid diets and environment temperature conditions, the performance and carbon turnover in muscle and liver tissues, as measured by the incorporation of stable isotopes ((13)C/(12)C), must be different between fast-growing Cobb 500(r) and slow-growing Label Rouge broilers. For both experiments (Cobb and Label Rouge), 21-d-old birds were distributed in a completely randomised, 3 * 3 factorial design; three environmental temperatures (cyclic heat stress ad libitum, 22 degrees C ad libitum, and 22 degrees C restricted) and three crude protein concentrations (189.1, 210 and 220 g/kg CP) were used. The Cobb 500(r) had better performance with higher concentrations of crude protein. Cyclic heat stress (a temperature factor), negatively affected this genetic strain's performance. For the Label Rouge birds, the crude protein concentrations in the diet presented inconsistent results and cyclic heat stress did not affect the performance. The carbon turnover rate was affected in the Cobb 500(r) strain, with a high protein content reducing carbon turnover in the evaluated tissues (liver and muscles). Feed intake had a greater impact on carbon turnover rates than cyclic heat stress. The Label Rouge birds were not affected by the evaluated factors, suggesting that genetic improvement has a leading role on tissue carbon turnover. There is a genetic influence on carbon turnover in the liver and muscle tissues of broiler chickens. In addition, genetically fast-growing broilers are more susceptible to variations in diet composition and environmental temperature than less rapidly growing animals. PMID- 26634281 TI - Prefrontal control and predictors of cognitive behavioral therapy response in social anxiety disorder. AB - Generalized social anxiety disorder (gSAD) is associated with aberrant anterior cingulate cortex (ACC) response to threat distractors. Perceptual load has been shown to modulate ACC activity such that under high load, when demands on processing capacity is restricted, individuals with gSAD exhibit compensatory activation to threat distractors yet under low load, there is evidence of reduced activation. It is not known if neural predictors of response to cognitive behavioral therapy (CBT), based on such emotional conflict resolution, interact with demands on controlled processes. Prior to CBT, 32 patients with gSAD completed an fMRI task involving a target letter in a string of identical targets (low perceptual load) or a target letter in a mixed letter string (high perceptual load) superimposed on fearful, angry and neutral face distractors. Whole-brain voxel-wise analyses revealed better CBT outcome was predicted by more frontopartial activity that included dorsal ACC (dACC) and insula to threat (vs neutral) distractors during high, but not low, perceptual load. Psychophysiological interaction analysis with dACC as the seed region revealed less connectivity with dorsolateral prefrontal cortex to threat distractors during high load. Results indicate patients with less regulatory capability when demands on higher-order control are great may benefit more from CBT. PMID- 26634284 TI - Patient-Based Long-Term Results of the Surgical Treatment of Congenital Talipes Equinovarus. AB - Long-term results of surgical treatment for congenital talipes equinovarus are documented in the literature but mainly in correlation with clinical and radiographic objective criteria. We present a retrospective study of 48 patients who underwent surgical correction (extended Cincinnati type "a la carte" approach) in our department with an average of 17 years' follow-up. Patients were interviewed and completed a validated disease specific instrument, which evaluates foot function as well as patients' satisfaction, the use of orthotics, shoe size, and the impact of this operation in their adult life. Parameters such as gender, age at first surgery, side affected, and the number of procedures were also studied. According to our findings, the greater the age at last surgery, the worse the outcome. Quality-of-life issues were expressed at a higher rate among women and by patients that underwent multiple surgeries. Unilateral correction has a correlation with the shoe size. Even if a "successful" surgical correction is achieved, residual symptoms may alter walking ability, self-image, and shoe wearing in adult life. It would be valuable to continue to follow these patients up over time. LEVELS OF EVIDENCE: Therapeutic, Level IV: Case series. PMID- 26634285 TI - A Prospective Study of Mortality and Trauma-Related Risk Factors Among a Nationally Representative Sample of Vietnam Veterans. AB - Because Vietnam veterans comprise the majority of all living veterans and most are now older adults, the urgency and potential value of studying the long-term health effects of service in the Vietnam War, including effects on mortality, is increasing. The present study is the first prospective mortality assessment of a representative sample of Vietnam veterans. We used one of the longest follow-up periods to date (spanning older adulthood) and conducted one of the most comprehensive assessments of potential risk factors. Vital status and cause of death were ascertained for the 1,632 veterans who fought in the Vietnam theater (hereafter referred to as theater veterans) and for 716 Vietnam War-era veterans (hereafter referred to as era veterans) who participated in the National Vietnam Veterans Readjustment Study (1987-2011). As of April 2011, 16.0% (95% confidence interval: 13.1, 19.0) of all Vietnam veterans who were alive in the 1980s were deceased. Male theater veterans with a high probability of posttraumatic stress disorder (PTSD) were nearly 2 times more likely to have died than were those without PTSD, even after adjustment for sociodemographic and other characteristics. A high level of exposure to war zone stress was independently associated with mortality for both male and female theater veterans after adjustment for sociodemographic characteristics, PTSD, and physical comorbid conditions. Theater veterans with a high level of exposure to war zone stress and a high probability of PTSD had the greatest mortality risk (adjusted hazard ratio = 2.34, 95% confidence interval: 1.24, 4.43). PMID- 26634286 TI - Transatrial Endocardial Placement of Epicardial Pacing Lead. AB - We report a technique wherein an epicardial pacing lead was placed transatrially to achieve optimal pacing in a patient with a complex venous anatomy. PMID- 26634287 TI - Rhubarb decreased the systemic exposure of cyclosporine, a probe substrate of P glycoprotein and CYP 3A. AB - 1. Rhubarb, rhizome of Rheum palmatum L. (RP), is an important herb in clinical Chinese medicine. 2. Cyclosporine (CSP) is an immunosuppressant with narrow therapeutic window. The oral bioavailability of CSP was associated with P glycoprotein (P-gp) and CYP 3A4. CSP was used as a probe substrate to investigate the in vivo modulation effects of RP on P-gp and CYP 3A. 3. Rats were orally administered 2.5 mg/kg of CSP with and without 0.25 and 1.0 g/kg of RP. The blood CSP concentration was determined by a specific monoclonal fluorescence polarization immunoassay. 4. Both dosages of RP significantly decreased the Cmax and AUC0-t of CSP in rats. Mechanism studies indicated that RP activated the functions of P-gp and CYP 3A. 5. RP ingestion reduced the systemic exposure of CSP through activating P-gp and CYP 3A. PMID- 26634288 TI - Comparative Studies of Three Pairs of alpha- and gamma-Conjugated Folic Acid Derivatives Labeled with Fluorine-18. AB - The folate receptor (FR) is upregulated in various epithelial cancer types (FR alpha-isoform), while healthy tissues show only restricted expression. FR targeted imaging using folate radiopharmaceuticals is therefore a promising approach for the detection of FR-positive cancer tissue. Almost all folate-based radiopharmaceuticals have been prepared by conjugation at the gamma-carboxylic functionality of the glutamate moiety of folic acid. In this work, three pairs of fluorinated alpha- and gamma-conjugated folate derivatives were synthesized and their in vitro and in vivo properties compared. The syntheses of all six regioisomers were obtained in good chemical yields using a multistep synthetic approach including the highly selective Cu(I)-catalyzed 1,3-dipolar cycloaddition. The radiosyntheses of the alpha- and gamma-conjugated (18)F labeled folate derivatives were accomplished in moderate to good radiochemical yields, high radiochemical purities (>95%), and specific activities ranging from 25 to 196 GBq/MUmol. In vitro, all folate derivatives showed high binding affinity to the FR-alpha (IC50 = 1.4-2.2 nM). In vivo PET imaging and biodistribution studies in FR-positive KB tumor-bearing mice demonstrated similar FR-specific tumor uptake for both regioisomers of each pair of compounds. However, FR-unspecific liver uptake was significantly lower for the alpha regioisomers compared to the corresponding gamma-regioisomers. In contrast, kidney uptake was up to 50% lower for the gamma-regioisomers than for the alpha regioisomers. These results show that the site of conjugation in the glutamyl moiety of folic acid has a significant impact on the in vivo behavior of (18)F based radiofolates, but not on their in vitro FR-binding affinity. These findings may potentially stimulate new directions for the design of novel (18)F-labeled folate-based radiotracers. PMID- 26634289 TI - Risk factors associated with competing mortality among patients with head and neck cancer in Japan. AB - Conclusions This study demonstrated a high incidence of competing mortality in patients with head and neck cancer (HNC). It identified age to be an independent prognostic factor for non-cancer mortality. These findings contribute to the appropriate treatment selection in clinical settings and study design in clinical trials. Objectives To investigate the incidences of second primary cancer (SPC) and non-cancer mortalities among patients with HNC and reveal the determinant factors for these mortalities. Methods This study reviewed the records of 334 patients with HNC between 2006-2012. The cumulative incidences of HNC, non cancer, and SPC mortalities were estimated. A Fine and Gray regression model was used to investigate factors associated with cancer and non-cancer mortalities. Results The 5-year cumulative incidences of HNC, SPC, and non-cancer mortalities were 28.0%, 2.5%, and 6.5%, respectively. In univariate analysis, the factors associated with SPC mortality were tumor site and comorbidity, whereas those associated with non-cancer mortality were age, gender, and comorbidity. In multivariate analysis, age (sub-distribution hazard ratio = 2.59) was the independent risk factor for non-cancer mortality. PMID- 26634290 TI - Bioaccumulation of metallic trace elements and organic pollutants in marine sponges from the South Brittany Coast, France. AB - The purpose of this study was to compare the accumulation of metallic and organic pollutants in marine sponges with the oyster Crassostrea gigas used as sentinel species. The concentrations of 12 Metallic Trace Elements (MTEs), 16 Polycyclic Aromatic Hydrocarbons (PAHs), 7 PolyChlorinated Biphenyls (PCBs), and 3 organotin derivatives were measured in 7 marine sponges collected in the Etel River (South Brittany, France). Results indicated Al, Co, Cr, Fe, Pb, and Ti particularly accumulated in marine sponges such as Hymeniacidon perlevis and Raspailia ramosa at higher levels compared to oysters. At the opposite, Cu and Zn accumulated significantly at higher concentrations in oysters. Among PAHs analyzed, benzo(a)pyrene bioaccumulated in H. perlevis at levels up to 17-fold higher than in oysters. In contrast, PCBs bioaccumulated preferentially in oysters. Significant differences exist in the abilities of marine phyla and sponge species to accumulate organic and metallic pollutants however, among the few sponge species studied, H. perlevis showed impressive bioaccumulation properties. The use of this species as bioindicator and/or bioremediator near shellfish farming areas is also discussed. PMID- 26634291 TI - A Cyan Fluorescent Reporter Expressed from the Chloroplast Genome of Marchantia polymorpha. AB - Recently, the liverwort Marchantia polymorpha has received increasing attention as a basal plant model for multicellular studies. Its ease of handling, well characterized plastome and proven protocols for biolistic plastid transformation qualify M. polymorpha as an attractive platform to study the evolution of chloroplasts during the transition from water to land. In addition, chloroplasts of M. polymorpha provide a convenient test-bed for the characterization of genetic elements involved in plastid gene expression due to the absence of mechanisms for RNA editing. While reporter genes have proven valuable to the qualitative and quantitative study of gene expression in chloroplasts, expression of green fluorescent protein (GFP) in chloroplasts of M. polymorpha has proven problematic. We report the design of a codon-optimized gfp varian, mturq2cp, which allowed successful expression of a cyan fluorescent protein under control of the tobacco psbA promoter from the chloroplast genome of M. polymorpha. We demonstrate the utility of mturq2cp in (i) early screening for transplastomic events following biolistic transformation of M. polymorpha spores; (ii) visualization of stromules as elements of plastid structure in Marchantia; and (iii) quantitative microscopy for the analysis of promoter activity. PMID- 26634292 TI - Fetal growth restriction but not preterm birth is a risk factor for severe hypospadias. AB - BACKGROUND: Hypospadias has multifactorial causes and occurs at a high frequency among very low-birthweight infants. Placental insufficiency is hypothesized to be one cause of hypospadias; that is, decreased human chorionic gonadotropin (hCG) secretion caused by placental insufficiency is suspected to result in abnormal male external genitalia, but there is little direct evidence to support this. The aim of this study was therefore to identify the features of hypospadias and to clarify the male genital abnormalities caused by fetal growth restriction (FGR). METHODS: We reviewed the clinical data of boys who underwent hypospadias repair between 2005 and 2011 at Kyoto University Hospital. RESULTS: Twenty boys were included in this study. Fifteen (75%) of the subjects were preterm or low birthweight infants. Thirteen (65%) had FGR, 60% of whom had severe hypospadias regardless of gestational age. In addition, 92% of the FGR infants also had other genital anomalies, such as cryptorchidism, bifid scrotum, or micropenis. In contrast, only 14% and 43% of the non-FGR infants had severe hypospadias or genital anomalies other than hypospadias, respectively. Placental histopathology was available in eight FGR infants, in seven of whom it was suggestive of blood flow deficiency such as infarction and single umbilical artery. CONCLUSIONS: Infants with FGR have a high incidence of hypospadias. FGR caused by placental dysfunction, but not low birthweight, is a risk factor for severe hypospadias associated with multiple genital anomalies. PMID- 26634293 TI - Muscle networks: Connectivity analysis of EMG activity during postural control. AB - Understanding the mechanisms that reduce the many degrees of freedom in the musculoskeletal system remains an outstanding challenge. Muscle synergies reduce the dimensionality and hence simplify the control problem. How this is achieved is not yet known. Here we use network theory to assess the coordination between multiple muscles and to elucidate the neural implementation of muscle synergies. We performed connectivity analysis of surface EMG from ten leg muscles to extract the muscle networks while human participants were standing upright in four different conditions. We observed widespread connectivity between muscles at multiple distinct frequency bands. The network topology differed significantly between frequencies and between conditions. These findings demonstrate how muscle networks can be used to investigate the neural circuitry of motor coordination. The presence of disparate muscle networks across frequencies suggests that the neuromuscular system is organized into a multiplex network allowing for parallel and hierarchical control structures. PMID- 26634294 TI - Probe Intracellular Trafficking of a Polymeric DNA Delivery Vehicle by Functionalization with an Aggregation-Induced Emissive Tetraphenylethene Derivative. AB - Characteristic aggregation-induced quenching of pi-fluorophores imposed substantial hindrance to their utilization in nanomedicine for insight into microscopic intracellular trafficking of therapeutic payload. To address this obstacle, we attempted to introduce a novel aggregation-induced emission (AIE) fluorophore into the cationic polymer, which was further used for formulation of a gene delivery carrier. Note that the selective restriction of the intramolecular rotation of the AIE fluorophore through its covalent bond to the polymer conduced to immense AIE. Furthermore, DNA payload labeled with the appropriate fluorophore as the Forster resonance energy transfer (FRET) acceptor verified a facile strategy to trace intracellular DNA releasing activity relying on the distance limitation requested by FRET (AIE fluorophore as FRET donor). Moreover, the hydrophobic nature of the AIE fluorophore appeared to promote colloidal stability of the constructed formulation. Together with other chemistry functionalization strategies (including endosome escape), the ultimate formulation exerted dramatic gene transfection efficiency. Hence, this report manifested a first nanomedicine platform combining AIE and FRET for microscopic insight into DNA intracellular trafficking activity. PMID- 26634295 TI - Neuromodulation of fast-spiking and non-fast-spiking hippocampal CA1 interneurons by human cerebrospinal fluid. AB - KEY POINTS: How the brain extracellular fluid influences the activity of GABAergic interneurons in vivo is not known. This issue is examined in the hippocampal brain slice by comparing GABAergic interneuron activity in human versus artificial cerebrospinal fluid. Human cerebrospinal fluid (hCSF) substantially increases the excitability of fast-spiking and non-fast-spiking CA1 interneurons. CA1 pyramidal cells are even more strongly excited by hCSF. The tonic excitation of pyramidal cells, in combination with an increased responsiveness of interneurons to excitatory input, is likely to promote the generation of synchronized network activity in the hippocampus. ABSTRACT: GABAergic interneurons intricately regulate the activity of hippocampal and neocortical networks. Their function in vivo is likely to be tuned by neuromodulatory substances in the brain extracellular fluid. However, in vitro investigations of GABAergic interneuron function do not account for such effects, as neurons are kept in artificial extracellular fluid. To examine the neuromodulatory influence of brain extracellular fluid on GABAergic activity, we recorded from fast-spiking and non-fast-spiking CA1 interneurons, as well as from pyramidal cells, in the presence of human cerebrospinal fluid (hCSF), using a matched artificial cerebrospinal fluid (aCSF) as control. We found that hCSF increased the frequency of spontaneous firing more than twofold in the two groups of interneurons, and more than fourfold in CA1 pyramidal cells. hCSF did not affect the resting membrane potential of CA1 interneurons but caused depolarization in pyramidal cells. The increased excitability of interneurons and pyramidal cells was accompanied by reductions in after-hyperpolarization amplitudes and a left-shift in the frequency-current relationships. Our results suggest that ambient concentrations of neuromodulators in the brain extracellular fluid powerfully influence the excitability of neuronal networks. PMID- 26634296 TI - Traumatic dental injury in permanent teeth: knowledge and management in a group of Brazilian school teachers. AB - BACKGROUND/AIM: School is a place with a high frequency of dental trauma, and several studies have shown that teachers' knowledge in how to act during acute dental emergencies is lacking. Therefore, this study aimed to assess the knowledge and actions of a group of Brazilian school teachers relative to dental trauma in permanent teeth. MATERIALS AND METHODS: A cross-sectional, observational study, from 27, schools randomized by lot was performed. All 205 teachers in the 27 schools answered a structured and self-administered questionnaire. The questionnaire contained questions about the participants' education level, work experience and first-aid training, as well as knowledge about and attitudes towards dental trauma in permanent teeth as well as their experience in dental emergency situations. RESULTS: Of the 205 teachers, 91.2% reported having no knowledge about dental trauma and 16.6% of teachers had seen cases of acute dental trauma. Among the 205 teachers, 23.9% had received first aid training and 4.1% had been educated in dental trauma. Regarding actions of acute injuries to permanent teeth, the teachers showed a significant error rate. No association was found between the level of education and first-aid training or experience with dental trauma. In relation to the experience of the teacher, association was found when managing trauma to soft tissue. CONCLUSION: The knowledge and actions of Brazilian schoolteachers in relation to care of acute injuries in permanent teeth were inconsistent and based on unfounded concepts, beliefs and intuition, and lack of training. Continuing education of teachers in oral care due to a dental trauma should be a good plan of action. PMID- 26634298 TI - Siltuximab: a targeted therapy for idiopathic multicentric Castleman disease. AB - Human herpes virus-8 (HHV-8)-negative or idiopathic multicentric Castleman disease (iMCD) is a rare and deadly disorder that sits at the nexus of hematology/oncology, virology and immunology. Management of iMCD has been challenging due to limited understanding of etiology and pathogenesis and few treatment options. The recent approvals in North America, Europe and Brazil of siltuximab, a monoclonal antibody against IL-6, for iMCD now provide a safe and effective therapy that targets a key aspect of pathogenesis. In the first ever randomized, placebo-controlled trial in iMCD, siltuximab significantly reduced disease burden and symptoms in a large portion (34%) of patients. The optimal dose is 11 mg/kg intravenously every 3 weeks. At this time, duration of treatment is often life-long or until treatment failure. Additional research is needed to identify biomarkers that may assist with predicting treatment effectiveness in iMCD and to investigate the role of siltuximab in HHV-8-positive MCD and pediatric iMCD patients. PMID- 26634297 TI - Concurrent BMP7 and FGF9 signalling governs AP-1 function to promote self-renewal of nephron progenitor cells. AB - Self-renewal of nephron progenitor cells (NPCs) is governed by BMP, FGF and WNT signalling. Mechanisms underlying cross-talk between these pathways at the molecular level are largely unknown. Here we delineate the pathway through which the proliferative BMP7 signal is transduced in NPCs in the mouse. BMP7 activates the MAPKs TAK1 and JNK to phosphorylate the transcription factor JUN, which in turn governs transcription of AP-1-element containing G1-phase cell cycle regulators such as Myc and Ccnd1 to promote NPC proliferation. Conditional inactivation of Tak1 or Jun in cap mesenchyme causes identical phenotypes characterized by premature depletion of NPCs. While JUN is regulated by BMP7, we find that its partner FOS is regulated by FGF9. We demonstrate that BMP7 and FGF9 coordinately regulate AP-1 transcription to promote G1-S cell cycle progression and NPC proliferation. Our findings identify a molecular mechanism explaining the important cooperation between two major NPC self-renewal pathways. PMID- 26634299 TI - Relationships between the duration of illness and the current status of diabetes in elderly patients with type 2 diabetes mellitus. AB - AIMS: The aim of the present study was to clarify the relationships between the duration of diabetes and the current statuses of diabetes in elderly (aged >=65 years) patients with type 2 diabetes. METHODS: Clinical characteristics were cross-sectionally examined in 1436 patients (684 elderly and 752 non-elderly) with type 2 diabetes. RESULTS: As the duration of diabetes increased, the patients' age, frequency of receiving insulin therapy and glycated hemoglobin value increased in both the elderly and non-elderly groups, whereas the urinary C peptide immunoreactivity and glomerular filtration rate decreased. The duration of diabetes (years) was significantly associated with the prevalence of diabetic retinopathy (OR 1.05, 95% CI 1.03-1.07, P < 0.01), nephropathy (OR 1.03, 95% CI 1.01-1.05, P < 0.01) and neuropathy (OR 1.08, 95% CI 1.05-1.12, P < 0.01), but not with cerebrovascular disease (OR 1.01, 95% CI 0.99-1.03, P = 0.38), coronary heart disease (OR 1.02, 95% CI 1.00-1.04, P = 0.09) or peripheral artery disease (OR 1.02, 95%CI 0.99-1.05, P = 0.12) in the elderly patients after adjusting for the traditional risk factors of diabetic angiopathies. In contrast, the duration of diabetes showed a significant association with the prevalence of both diabetic micro- and macroangiopathies in the non-elderly patients. CONCLUSIONS: It should be noted that atherosclerotic diseases are present in the clinical setting for the management of elderly diabetic patients independent of the duration of diabetes. Geriatr Gerontol Int 2017; 17: 24-30. PMID- 26634300 TI - Identification and comparative analysis of complement C3-associated microRNAs in immune response of Apostichopus japonicus by high-throughput sequencing. AB - MicroRNAs (miRNAs) are important effectors in mediating host-pathogen interaction. In this report, coelomocytes miRNA libraries of three Japanese sea cucumbers Apostichopus japonicus were built by Illumina((r)) Hiseq2000 from different time points after lipopolysaccharide challenge (at time 0 h, 6 h and 12 h). The clean data received from high throughput sequencing were used to sequences analysis. Referenced to the Strongylocentrotus purpuratus genome, 38 conserved miRNAs were found, and three miRNA candidates were predicted by software. According to the evidence resulting from the expression of AjC3, expressing levels of spu-miR-133, spu-miR-137 and spu-miR-2004 altered along with the expression of AjC3 changing at different time points after LPS injection. Thus, we speculated that the three miRNAs may have influence on A. japonicus complement C3. The spu-miR-137 and miR-137 gene family in miRBase were analyzed by bioinformatics. There is an obvious discrepancy between invertebrates and vertebrates. The first and ninth nucleotides in invertebrate miR-137 are offset compared vertebrate miR-137. Importantly, this is the first attempt to map the stage of immune response regulome in echinoderms, which might be considered as information for elucidating the intrinsic mechanism underlying the immune system in this species. PMID- 26634301 TI - Apelin: an antithrombotic factor that inhibits platelet function. AB - Apelin peptide and its receptor APJ are directly implicated in various physiological processes ranging from cardiovascular homeostasis to immune signaling. Here, we show that apelin is a key player in hemostasis with an ability to inhibit thrombin- and collagen-mediated platelet activation. Mice lacking apelin displayed a shorter bleeding time and a prothrombotic profile. Their platelets exhibited increased adhesion and a reduced occlusion time in venules, and displayed a higher aggregation rate after their activation by thrombin compared with wild-type platelets. Consequently, human and mouse platelets express apelin and its receptor APJ. Apelin directly interferes with thrombin-mediated signaling pathways and platelet activation, secretion, and aggregation, but not with ADP and thromboxane A2-mediated pathways. IV apelin administration induced excessive bleeding and prevented thrombosis in mice. Taken together, these findings suggest that apelin and/or APJ agonists could potentially be useful adducts in antiplatelet therapies and may provide a promising perspective for patients who continue to display adverse thrombotic events with current antiplatelet therapies. PMID- 26634302 TI - CRISPR/Cas9-mediated conversion of human platelet alloantigen allotypes. AB - Human platelet alloantigens (HPAs) reside on functionally important platelet membrane glycoproteins and are caused by single nucleotide polymorphisms in the genes that encode them. Antibodies that form against HPAs are responsible for several clinically important alloimmune bleeding disorders, including fetal and neonatal alloimmune thrombocytopenia and posttransfusion purpura. The HPA-1a/HPA 1b alloantigen system, also known as the Pl(A1)/Pl(A2) polymorphism, is the most frequently implicated HPA among whites, and a single Leu33Pro amino acid polymorphism within the integrin beta3 subunit is responsible for generating the HPA-1a/HPA-1b alloantigenic epitopes. HPA-1b/b platelets, like those bearing other low-frequency platelet-specific alloantigens, are relatively rare in the population and difficult to obtain for purposes of transfusion therapy and diagnostic testing. We used CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR associated protein 9) gene-editing technology to transform Leu33 (+) megakaryocytelike DAMI cells and induced pluripotent stem cells (iPSCs) to the Pro33 allotype. CD41(+) megakaryocyte progenitors derived from these cells expressed the HPA-1b (Pl(A2)) alloantigenic epitope, as reported by diagnostic NciI restriction enzyme digestion, DNA sequencing, and western blot analysis using HPA-1b-specific human maternal alloantisera. Application of CRISPR/Cas9 technology to genetically edit this and other clinically-important HPAs holds great potential for production of designer platelets for diagnostic, investigative, and, ultimately, therapeutic use. PMID- 26634303 TI - Persistent replication of a hepatitis C virus genotype 1b-based chimeric clone carrying E1, E2 and p6 regions from GB virus B in a New World monkey. AB - The development of effective hepatitis C virus (HCV) vaccines is essential for the prevention of further HCV dissemination, especially in developing countries. Therefore the aim of this study is to establish a feasible and immunocompetent surrogate animal model of HCV infection that will help in evaluation of the protective efficacy of newly developing HCV vaccine candidates. To circumvent the narrow host range of HCV, an HCV genotype 1b-based chimeric clone carrying E1, E2 and p6 regions from GB virus B (GBV-B), which is closely related to HCV, was generated. The chimera between HCV and GBV-B, named HCV/G, replicated more efficiently as compared with the HCV clone in primary marmoset hepatocytes. Furthermore, it was found that the chimera persistently replicated in a tamarin for more than 2 years after intrahepatic inoculation of the chimeric RNA. Although relatively low (<200 copies/mL), the viral RNA loads in plasma were detectable intermittently during the observation period. Of note, the chimeric RNA was found in the pellet fraction obtained by ultracentrifugation of the plasma at 73 weeks, indicating production of the chimeric virus. Our results will help establish a novel non-human primate model for HCV infection on the basis of the HCV/G chimera in the major framework of the HCV genome. PMID- 26634304 TI - Multifractal analysis of weighted networks by a modified sandbox algorithm. AB - Complex networks have attracted growing attention in many fields. As a generalization of fractal analysis, multifractal analysis (MFA) is a useful way to systematically describe the spatial heterogeneity of both theoretical and experimental fractal patterns. Some algorithms for MFA of unweighted complex networks have been proposed in the past a few years, including the sandbox (SB) algorithm recently employed by our group. In this paper, a modified SB algorithm (we call it SBw algorithm) is proposed for MFA of weighted networks. First, we use the SBw algorithm to study the multifractal property of two families of weighted fractal networks (WFNs): "Sierpinski" WFNs and "Cantor dust" WFNs. We also discuss how the fractal dimension and generalized fractal dimensions change with the edge-weights of the WFN. From the comparison between the theoretical and numerical fractal dimensions of these networks, we can find that the proposed SBw algorithm is efficient and feasible for MFA of weighted networks. Then, we apply the SBw algorithm to study multifractal properties of some real weighted networks - collaboration networks. It is found that the multifractality exists in these weighted networks, and is affected by their edge-weights. PMID- 26634305 TI - Clinical importance of faecal calprotectin variability in inflammatory bowel disease: intra-individual variability and standardisation of sampling procedure. AB - OBJECTIVE: Faecal (f-) calprotectin is a biomarker of intestinal inflammation. Previous studies have described intra-individual day-to-day variability of this biomarker in patients with inflammatory bowel disease (IBD) and morning samples have been suggested for standardisation purposes. With this project, we investigated if day-to-day variability differed from diurnal variability. Additionally, we evaluated a new extraction method for f-calprotectin analysis. METHODS: Fifty patients provided three faeces samples from morning - evening - morning on two consecutive days. Nineteen patients provided two faeces samples from the same bowel movement, one conventional spot sample, and one sample with a device for patient-administered sampling and extraction. RESULTS: The two morning samples differentiated between mucosal inflammation and mucosal healing with same level of agreement as the two samples from the same day (kappa 0.76), using an f calprotectin cut-off level of 259 MUg/g. Although large intra-individual variation in f-calprotectin values, there were no significant day-to-day (p = 0.096) or diurnal variation (p = 0.78). Used by laboratory technicians, the new extraction device correlated significantly with the conventional extraction method (p < 0.001), Spearman's rank correlation coefficient 0.95. Of the 19 patients testing patient administered extraction, two patients provided samples leading to considerably higher f-calprotectin levels than conventional sampling procedure. CONCLUSIONS: The reliability of f-calprotectin morning samples is equal to the reliability of samples from different bowel movements on the same day. The new extraction method is reliable when used by laboratory technicians, but larger studies are recommended to evaluate patient administered extraction. PMID- 26634306 TI - Zeta potentials of polydimethylsiloxane surfaces modified by polybrene of different concentrations. AB - Zeta potential is an important parameter for characterizing the electrokinetic properties of a solid-liquid interface. In this paper, zeta potentials of polydimethylsiloxane surfaces modified by polybrene (PB) solutions of different concentrations in Phosphate buffer solution and pure water were reported. The zeta potentials were measured by an induction current method. The measurements were validated both by a calibration curve based on the data reported in the published papers and by comparing the zeta potential determined by using the Smoluchowski equation and the measured velocity of the electrokinetic motion of particles in a microchannel. PMID- 26634307 TI - Guiding principles for the development of legislation regulating the doctor patient relationship and end-of-life decisions: a joint effort by believers and non-believers. PMID- 26634308 TI - Endogenous opioids contribute to insensitivity to pain in humans and mice lacking sodium channel Nav1.7. AB - Loss-of-function mutations in the SCN9A gene encoding voltage-gated sodium channel Nav1.7 cause congenital insensitivity to pain in humans and mice. Surprisingly, many potent selective antagonists of Nav1.7 are weak analgesics. We investigated whether Nav1.7, as well as contributing to electrical signalling, may have additional functions. Here we report that Nav1.7 deletion has profound effects on gene expression, leading to an upregulation of enkephalin precursor Penk mRNA and met-enkephalin protein in sensory neurons. In contrast, Nav1.8-null mutant sensory neurons show no upregulated Penk mRNA expression. Application of the opioid antagonist naloxone potentiates noxious peripheral input into the spinal cord and dramatically reduces analgesia in both female and male Nav1.7 null mutant mice, as well as in a human Nav1.7-null mutant. These data suggest that Nav1.7 channel blockers alone may not replicate the analgesic phenotype of null mutant humans and mice, but may be potentiated with exogenous opioids. PMID- 26634309 TI - The Malat1 long non-coding RNA is upregulated by signalling through the PERK axis of unfolded protein response during flavivirus infection. AB - Flavivirus infection causes host cell death by initiation of an unfolded protein response (UPR). UPR is initiated following activation of three ER-membrane resident sensors, PERK, IRE1alpha and ATF6, which are otherwise kept inactive through association with the ER-chaperone GRP78. Activation precedes cellular and molecular changes that act to restore homeostasis but might eventually initiate apoptosis. These changes involve influencing function of multiple genes by either transcriptional or post-transcriptional or post-translational mechanisms. Transcriptional control includes expression of transcription factor cascades, which influence cognate gene expression. Malat1 is a long non-coding RNA which is over-expressed in many human oncogenic tissues and regulates cell cycle and survival. In this report, for the first time we show activation of Malat1 following infection by two flaviviruses, both of which activate the UPR in host cells. The temporal kinetics of expression was restricted to later time points. Further, Malat1 was also activated by pharmacological inducer of UPR, to a similar degree. Using drugs that specifically inhibit or activate the PERK or IRE1alpha sensors, we demonstrate that signalling through the PERK axis activates this expression, through a transcriptional mechanism. To our knowledge, this is the first report of an UPR pathway regulating the expression of an lncRNA. PMID- 26634310 TI - Gold Catalyzed Synthesis of Substituted Furan by Intermolecular Cascade Reaction of Propargyl Alcohol and Alkyne. AB - Using a combination of triazole-gold (TA-Au) and copper catalysts, the substituted furan was achieved in one pot through a three-step reaction cascade. The reaction tolerates a large substrate scope with simple starting materials. The desired di-, tri-, and tetrasubstituted furans were prepared in good to excellent yields. PMID- 26634311 TI - Associations with violent and homicidal behaviour among men with schizophrenia. AB - Objective We aimed to assess the risk factors associated with homicidal behaviour in male patients diagnosed with schizophrenia. Methods In a period of 1 year, male schizophrenia cases between 18-65 years of age (n = 210) were included. The clinical evaluation included the Positive and Negative Syndrome Scale (PANSS) and Overt Aggression Scale (OAS). The patients were divided into three groups in terms of violent behaviour history: (1) homicide group (n = 30), (2) a violent act resulting in serious injury (n = 71), (3) control group (patients without a history of a violent act) (n = 109). Results Lower level of education, rural residence, being unemployed and living alone were found to be significantly more common in patients who had committed a violent act compared to the schizophrenia patients in the control group. In order to explore the predictive value of several factors associated with violent behaviour, a logistic regression model was used, and variables (shorter duration of education, living alone, and lack of insight) significantly predicted the presence of violent behaviour (murder and/or injury) (chi(2)=31.78, df = 12, p = 0.001). Conclusions In order to be able to determine causality of homicidal acts in schizophrenia patients, our significant findings between homicidal violence, non-homicidal violence and the control group would merit further attention and exploration in further studies. PMID- 26634312 TI - Vaccines and Kawasaki disease. AB - The distinctive immune system characteristics of children with Kawasaki disease (KD) could suggest that they respond in a particular way to all antigenic stimulations, including those due to vaccines. Moreover, treatment of KD is mainly based on immunomodulatory therapy. These factors suggest that vaccines and KD may interact in several ways. These interactions could be of clinical relevance because KD is a disease of younger children who receive most of the vaccines recommended for infectious disease prevention. This paper shows that available evidence does not support an association between KD development and vaccine administration. Moreover, it highlights that administration of routine vaccines is mandatory even in children with KD and all efforts must be made to ensure the highest degree of protection against vaccine-preventable diseases for these patients. However, studies are needed to clarify currently unsolved issues, especially issues related to immunologic interference induced by intravenous immunoglobulin and biological drugs. PMID- 26634313 TI - Type and location of findings in dental panoramic tomographs in 7-12-year-old orthodontic patients. AB - OBJECTIVE: The Radiation and Nuclear Safety Authority in Finland has paid attention to the large numbers of dental panoramic tomographs (DPTs), particularly in 7-12-year-old children. The majority of these radiographs are taken for orthodontic reasons. Because of the high radiosensitivity of children, the size of the irradiated field should be carefully chosen to yield the necessary diagnostic information at the lowest possible dose. The purpose of the present study was, therefore, to assess the outcome of DPTs within this age group in terms of type and location of pathological findings. It was also hypothesized that DPTs of orthodontic patients rarely display unrestored caries. MATERIALS AND METHODS: Four hundred and forty-one DPTs, taken of 7-12-year-old children in 2010 2014, were randomly sampled. The 413 of them (94%) that had been taken for orthodontic reasons were analysed. RESULTS: All pathologic findings were restricted to the tooth-bearing area and there was no pathology in the bone structure or any incidental findings in the region of temporomandibular joint. Unlike hypothesized, 27% of the orthodontic DPTs showed caries in deciduous teeth and 16% in permanent teeth. A sub-sample of 229 DPTs, analysed for developmental dental and occlusal problems, most commonly displayed crowding (50%), positional anomalies and local problems with tooth eruption (32%), as well as hyperodontia (15%). CONCLUSION: Inclusion of only the actual area of interest in the image field should be considered case-specifically as a means to reduce the radiation dose. PMID- 26634314 TI - Micelle-Induced Self-Assembling Protein Nanowires: Versatile Supramolecular Scaffolds for Designing the Light-Harvesting System. AB - Organic nanoparticle induced self-assembly of proteins with periodic nanostructures is a promising and burgeoning strategy to develop functional biomimetic nanomaterials. Cricoid proteins afford monodispersed and well-defined hollow centers, and can be used to multivalently interact with geometrically symmetric nanoparticles to form one-dimensional protein nanoarrays. Herein, we report that core-cross-linked micelles can direct cricoid stable protein one (SP1) to self-assembling nanowires through multiple electrostatic interactions. One micelle can act as an organic nanoparticle to interact with two central concaves of SP1 in an opposite orientation to form a sandwich structure, further controlling the assembly direction to supramolecular protein nanowires. The reported versatile supramolecular scaffolds can be optionally manipulated to develop multifunctional integrated or synergistic biomimetic nanomaterials. Artificial light-harvesting nanowires are further developed to mimic the energy transfer process of photosynthetic bacteria for their structural similarity, by means of labeling donor and acceptor chromophores to SP1 rings and spherical micelles, respectively. The absorbing energy can be transferred within the adjacent donors around the ring and shuttling the collected energy to the nearby acceptor chromophore. The artificial light-harvesting nanowires are designed by mimicking the structural characteristic of natural LH-2 complex, which are meaningful in exploring the photosynthesis process in vitro. PMID- 26634315 TI - 'B line' in heart failure: a not so easy issue. PMID- 26634316 TI - Treatments for erectile dysfunction in spinal cord lesioned patients. Are there alternatives to phosphodiesterase type 5 inhibitors? PMID- 26634318 TI - Treatments for erectile dysfunction in spinal cord patients: Alternatives to phosphodiesterase type 5 inhibitors? A review study. PMID- 26634319 TI - The effect of functional electrical stimulation cycling on late functional improvement in patients with chronic incomplete spinal cord injury. PMID- 26634320 TI - Functional impact of multidisciplinary outpatient program on patients with chronic complete spinal cord injury. PMID- 26634321 TI - Review of dietetic service provision and activity in spinal cord injury centres: a multicentre survey in the UK and Republic of Ireland. PMID- 26634322 TI - Effects of interval aerobic training combined with strength exercise on body composition, glycaemic and lipid profile and aerobic capacity of obese rats. AB - The purpose of this study was to investigate the effects of interval aerobic training combined with strength exercise in the same training session on body composition, and glycaemic and lipid profile in obese rats. Sixteen lean Zucker rats and sixteen obese Zucker rats were randomly divided into exercise and sedentary subgroups (4 groups, n = 8). Exercise consisted of interval aerobic training combined with strength exercise in the same training session. The animals trained 60 min/day, 5 days/week for 8 weeks. Body composition, lipid and glycaemic profiles and inflammatory markers were assessed. Results showed that fat mass was reduced in both lean and obese rats following the exercise training (effect size (95% confidence interval (CI)) = 1.8 (0.5-3.0)). Plasma low-density lipoprotein-cholesterol and fasting glucose were lower in the exercise compared to the sedentary groups (d = 2.0 (0.7-3.2) and 1.8 (0.5-3.0), respectively). Plasma insulin was reduced in exercise compared to sedentary groups (d = 2.1 (0.8 3.4)). Some exercise * phenotype interactions showed that the highest decreases in insulin, homeostatic model assessment-insulin resistance, fasting and postprandial glucose were observed in the obese + exercise group (all, P < 0.01). The findings of this study suggest that interval aerobic training combined with strength exercise would improve body composition, and lipid and glycaemic profiles, especially in obese rats. PMID- 26634323 TI - Tenants with additional needs: when housing first does not solve homelessness. AB - BACKGROUND: At Home/Chez-Soi was a 24 month randomized controlled trial of Housing First (HF) conducted in five Canadian cities. AIMS: This article attempts to identify the characteristics of participants who experienced housing instability one year after entering HF. METHODS: Those defined as experiencing housing instability were housed <50% of the last 9 months of the first year, excluding time in institutions, unless they were housed 100% of the past 3 months. RESULTS: Only 13.5% of HF participants (n = 157/1162) met criteria for housing instability. Several variables were significant predictors of instability in between-group comparisons and multiple regression analyses: residence in Winnipeg, cumulative lifetime homelessness, percent of previous 3 months spent in jail, and community psychological integration; while residence in Moncton and a diagnosis of PTSD or panic disorder predicted stability. The predictive models were weak, identifying correctly only 3.8% of individuals that failed to achieve housing stability. CONCLUSIONS: It is not possible to predict confidently at baseline who will experience early housing instability in HF. There are certain individual characteristics that might be considered risk factors. Providing HF to all individuals who qualify for a HF program remains the most valid way to administer admission to housing. PMID- 26634331 TI - Population genetic study of 34 X-Chromosome markers in 5 main ethnic groups of China. AB - As a multi-ethnic country, China has some indigenous population groups which vary in culture and social customs, perhaps as a result of geographic isolation and different traditions. However, upon close interactions and intermarriage, admixture of different gene pools among these ethnic groups may occur. In order to gain more insight on the genetic background of X-Chromosome from these ethnic groups, a set of X-markers (18 X-STRs and 16 X-Indels) was genotyped in 5 main ethnic groups of China (HAN, HUI, Uygur, Mongolian, Tibetan). Twenty-three private alleles were detected in HAN, Uygur, Tibetan and Mongolian. Significant differences (p < 0.0001) were all observed for the 3 parameters of heterozygosity (Ho, He and UHe) among the 5 ethnic groups. Highest values of Nei genetic distance were always observed at HUI-Uygur pairwise when analyzed with X-STRs or X-Indels separately and combined. Phylogenetic tree and PCA analyses revealed a clear pattern of population differentiation of HUI and Uygur. However, the HAN, Tibetan and Mongolian ethnic groups were closely clustered. Eighteen X-Indels exhibited in general congruent phylogenetic signal and similar cluster among the 5 ethnic groups compared with 16 X-STRs. Aforementioned results proved the genetic polymorphism and potential of the 34 X-markers in the 5 ethnic groups. PMID- 26634333 TI - Crossover behavior of the thermal conductance and Kramers' transition rate theory. AB - Kramers' theory frames chemical reaction rates in solution as reactants overcoming a barrier in the presence of friction and noise. For weak coupling to the solution, the reaction rate is limited by the rate at which the solution can restore equilibrium after a subset of reactants have surmounted the barrier to become products. For strong coupling, there are always sufficiently energetic reactants. However, the solution returns many of the intermediate states back to the reactants before the product fully forms. Here, we demonstrate that the thermal conductance displays an analogous physical response to the friction and noise that drive the heat current through a material or structure. A crossover behavior emerges where the thermal reservoirs dominate the conductance at the extremes and only in the intermediate region are the intrinsic properties of the lattice manifest. Not only does this shed new light on Kramers' classic turnover problem, this result is significant for the design of devices for thermal management and other applications, as well as the proper simulation of transport at the nanoscale. PMID- 26634332 TI - Comprehensive red blood cell and platelet antigen prediction from whole genome sequencing: proof of principle. AB - BACKGROUND: There are 346 serologically defined red blood cell (RBC) antigens and 33 serologically defined platelet (PLT) antigens, most of which have known genetic changes in 45 RBC or six PLT genes that correlate with antigen expression. Polymorphic sites associated with antigen expression in the primary literature and reference databases are annotated according to nucleotide positions in cDNA. This makes antigen prediction from next-generation sequencing data challenging, since it uses genomic coordinates. STUDY DESIGN AND METHODS: The conventional cDNA reference sequences for all known RBC and PLT genes that correlate with antigen expression were aligned to the human reference genome. The alignments allowed conversion of conventional cDNA nucleotide positions to the corresponding genomic coordinates. RBC and PLT antigen prediction was then performed using the human reference genome and whole genome sequencing (WGS) data with serologic confirmation. RESULTS: Some major differences and alignment issues were found when attempting to convert the conventional cDNA to human reference genome sequences for the following genes: ABO, A4GALT, RHD, RHCE, FUT3, ACKR1 (previously DARC), ACHE, FUT2, CR1, GCNT2, and RHAG. However, it was possible to create usable alignments, which facilitated the prediction of all RBC and PLT antigens with a known molecular basis from WGS data. Traditional serologic typing for 18 RBC antigens were in agreement with the WGS-based antigen predictions, providing proof of principle for this approach. CONCLUSION: Detailed mapping of conventional cDNA annotated RBC and PLT alleles can enable accurate prediction of RBC and PLT antigens from whole genomic sequencing data. PMID- 26634334 TI - Progress Is Made by People--They Earn Our Recognition! PMID- 26634335 TI - Installation of a Rigid EDTA-Like Motif into a Protein alpha-Helix for Paramagnetic NMR Spectroscopy with Cobalt(II) Ions. AB - Coupling two copies of an iminodiacetic acid-cysteine hybrid ligand to a pair of cysteine residues positioned in an i, i+4 arrangement within a protein alpha helix leads to generation of an EDTA-like metal ion-binding motif. Rigid binding of a Co(II) ion by this motif produces pseudo-contact shifts suitable for paramagnetic NMR structural studies. PMID- 26634336 TI - Tunable lasing in cholesteric liquid crystal elastomers with accurate measurements of strain. AB - We report wide range and reversible tuning of the selective reflection band of a single crystal cholesteric liquid crystal elastomer (CLCE). The tuning is the result of mechanical shortening of the helical pitch achieved by imposing a uniform uniaxial strain along the helical axis. On doping the CLCE sample with a laser dye, we observe lasing from the CLCE in both glassy and rubbery states. By changing the cholesteric pitch, mechanical compression provides tuning of the laser emission from the dye doped CLCE over a significant part of the fluorescence band of the laser dye. In this work we demonstrate for the first time that both the CLCE pitch and the lasing wavelength are linearly dependent on the strain imposed on the CLCE film. PMID- 26634337 TI - Exercise left ventricular ejection fraction predicts events in right bundle branch block. AB - OBJECTIVE: Interpretation of the electrocardiogram (ECG) during exercise is not easy in patients with right bundle branch block (RBBB). Also, the value of exercise echocardiography (ExE) for predicting outcome in them has not been addressed. We sought to assess its prognostic value in patients with RBBB and known/suspected coronary disease. DESIGN: Retrospective analysis of data on 703 patients with RBBB who were submitted to a clinically-indicated ExE. The end points were overall mortality and combined myocardial infarction and cardiovascular mortality. RESULTS: During follow-up (4.1 +/- 4.5 years) there were 130 deaths and 108 combined events. Independent predictors of combined events were history of coronary artery disease (hazard ratio [HR] = 2.37, 95% Confidence Interval [CI] = 1.24-4.52, p = 0.009) resting wall motion score index (HR = 2.14, 95% CI = 1.12-4.10, p = 0.02), metabolic equivalents (HR = 0.89, 95% CI = 0.93-0.97, p = 0.007), Delta in double product with exercise (HR = 0.96, 95% CI = 0.92-1.00, p = 0.036) and Delta in left ventricular ejection fraction (LVEF) with exercise (HR = 0.97, 95% CI = 0.94-0.99, p = 0.01). Neither positive clinical nor ECG exercise testing was predictive. Combined event rates were 3.3% in patients with DeltaLVEF > 5%, 4.7% in those with DeltaLVEF between 1-5% and 8.2% in those with no increase (Delta < 1%). CONCLUSIONS: A decrease in LVEF during exercise is predictive of serious events in patients with RBBB. PMID- 26634338 TI - Alcohol Consumption and Long-Term Labor Market Outcomes. AB - This paper examines whether alcohol consumption is related to long-term labor market outcomes. We use twin data for Finnish men and women matched to register based individual information on employment and earnings. The twin data allow us to account for the shared environmental and genetic factors. The quantity of alcohol consumption was measured by weekly average consumption using self reported data from three surveys (1975, 1981 and 1990). The average of an individual's employment months and earnings were measured in adulthood over the period 1990-2009. The models that account for the shared environmental and genetic factors reveal that former drinkers and heavy drinkers both have almost 20% lower earnings compared with moderate drinkers. On average, former drinkers work annually approx. 1 month less over the 20-year observation period. These associations are robust to the use of covariates, such as education, pre-existing health endowment and smoking. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26634339 TI - Single-laboratory validation of a saponification method for the determination of four polycyclic aromatic hydrocarbons in edible oils by HPLC-fluorescence detection. AB - An analytical method is reported for the determination of four polycyclic aromatic hydrocarbons (benzo[a]pyrene (BaP), benz[a]anthracene (BaA), benzo[b]fluoranthene (BbF) and chrysene (CHR)) in edible oils (sesame, maize, sunflower and olive oil) by high-performance liquid chromatography. Sample preparation is based on three steps including saponification, liquid-liquid partitioning and, finally, clean-up by solid phase extraction on 2 g of silica. Guidance on single-laboratory validation of the proposed analysis method was taken from the second edition of the Eurachem guide on method validation. The lower level of the working range of the method was determined by the limits of quantification of the individual analytes, and the upper level was equal to 5.0 ug kg(-1). The limits of detection and quantification of the four PAHs ranged from 0.06 to 0.12 ug kg(-1) and from 0.13 to 0.24 ug kg(-1). Recoveries of more than 84.8% were achieved for all four PAHs at two concentration levels (2.5 and 5.0 ug kg(-1)), and expanded relative measurement uncertainties were below 20%. The performance of the validated method was in all aspects compliant with provisions set in European Union legislation for the performance of analytical methods employed in the official control of food. The applicability of the method to routine samples was evaluated based on a limited number of commercial edible oil samples. PMID- 26634340 TI - Severe falciparum malaria complicated by prolonged haemolysis and rhinomaxillary mucormycosis after parasite clearance: a case report. AB - BACKGROUND: Severe falciparum malaria may be complicated by prolonged haemolysis and recurrent fever after parasite clearance. However, their respective etiologies are unclear and challenging to diagnose. We report the first case of severe falciparum malaria followed by prolonged haemolytic anaemia and rhinomaxillary mucormycosis in a previously healthy adult male. CASE PRESENTATION: A 30-year old Bangladeshi man was admitted with severe falciparum malaria complicated by hyperlactataemia and haemoglobinuria. Prior to admission he was treated with intravenous quinine and upon admission received intravenous artesunate and empiric ceftriaxone. Thirty hours later the peripheral parasitaemia cleared with resolution of fever and haemoglobinuria. Despite parasite clearance, on day 3 the patient developed recurrent fever and acute haemolytic anaemia requiring seven blood transfusions over six days with no improvement of his haemoglobin or haemoglobinuria. On day 10, he was treated with high-dose dexamethasone and meropenem with discontinuation of the ceftriaxone. Two days later the haemoglobinuria resolved. Ceftriaxone-induced haemolysis was the suspected final diagnosis. On day 16, the patient had progressively worsening right-sided facial pain and swelling; a necrotic ulceration of the hard palate was observed. Rhinomaxillary mucormycosis was diagnosed supported by microscopy findings. The patient initially responded to treatment with urgent surgical debridement, itraconazole, followed by two weeks of amphotericin B deoxycholate, however was subsequently lost to follow up. CONCLUSIONS: This case highlights the range of potential alternative aetiologies of acute, prolonged haemolysis and recurrent fever following parasite clearance in severe falciparum malaria. It emphasizes the importance of a high degree of suspicion for alternative causes of haemolysis in order to avoid unnecessary treatments, including blood transfusion and steroids. It is critical to consider and identify common invasive bacterial and rare opportunistic co-infections as a cause of fever in severe malaria patients remaining febrile after parasite clearance to promote antimicrobial stewardship and prompt emergency care. PMID- 26634341 TI - Cigarette smoke exposure impairs reverse cholesterol transport which can be minimized by treatment of hydrogen-saturated saline. AB - BACKGROUND: Cigarette smoke (CS) exposure impaired plasma lipid profiles by modification of apolipoproteins. Hydrogen (H2) has been proved effective on reducing oxidative stress or improving HDL functionalities in animal models or metabolic syndrome volunteers. This study was undertaken to explore the effects of CS exposure on reverse cholesterol transport (RCT) and the antioxidative effects of H2 treatment against CS exposure in mice transgenic for human cholesteryl ester transfer protein (CETP). METHODS: [(3)H]-cholesterol-laden macrophages were injected intraperitoneally into mice, and the samples of blood, bile, liver, and feces were collected for radioactivity determination to evaluate RCT. [(3)H]-cholesterol-laden macrophages were incubated with HDL isolated from different groups of mice, and the samples of cell medium supernatants were collected for evaluating the HDL functionality to elicit cholesterol efflux. RESULTS: CS exposure significantly decreased plasma HDL cholesterol level (HDL-C) by 22% and increased LDL cholesterol level (LDL-C) by 21% compared with the control group (p < 0.05, p < 0.01), while H2 treatment significantly improved the CS-impaired levels of TC, LDL-C and HDL-C by 10, 27 and 31%, respectively, compared with the CS group (p < 0.05, p < 0.01 and p < 0.05). Besides, CS exposure significantly decreased [(3)H] tracer concentrations in liver, bile and feces by 17, 35 and 48%, respectively, compared with the control group (p < 0.05 for liver and feces), while H2 treatment significantly improved them by 21, 72% and 89%, respectively, compared with the CS group (all p < 0.05). Furthermore, CS exposure significantly decreased the HDL functionality to elicit cholesterol efflux by 26% (p < 0.05), while H2 treatment also improved it by 32% (p < 0.05). We did not find any significant alterations in protein expressions of RCT involved genes. CONCLUSIONS: These findings provided direct evidence supporting the notion that CS exposure in vivo impairs plasma lipid profiles, HDL functionalities and macrophage-to-feces RCT pathway in CETP transgenic mice, all of which can be minimized by treatment of H2-saturated saline. PMID- 26634342 TI - SIGIRR participates in negative regulation of LPS response and tolerance in human bladder epithelial cells. AB - BACKGROUND: The innate immune response of urinary tract is critically important in the defense to microbial attack. Toll-like receptor 4 (TLR4) controls initial mucosal response to uropathogenic Escherichia coli (UPEC). However, excessive and dysfunctional TLR signaling may result in severe inflammation and inappropriate tissue damage. Previous studies have demonstrated that single immunoglobulin IL 1R-related receptor/Toll IL-1 receptor 8 (SIGIRR/TIR8) is a member of the toll interleukin-1 receptor (TIR) family that can negatively modulate TLR4 mediated signaling, but its role in the innate immunity of urinary tract infection remains incompletely defined. In this study, we investigated its cellular distribution and mechanisms involved within the human bladder epithelial cells after LPS stimulation. RESULTS: Immunostaining, reverse transcription PCR and Western blot results showed that SIGIRR was constitutively expressed in the human bladder epithelial cell lines and was downregulated after LPS stimulation. To further define the role of SIGIRR, cells were transiently transfected with SIGIRR siRNA and stimulated with LPS. SIGIRR gene silencing augmented chemokine expression in response to LPS, as indicated by increased levels of IL-6 and IL-8 secretions in the supernatants compared with negative control siRNA. Furthermore, LPS tolerance, a protective mechanism against second LPS stimulation, was significantly reduced in SIGIRR siRNA transfected cells. Moreover, transient gene silencing augmented LPS-induced NF-kappaB and MAPK activation. CONCLUSIONS: In conclusion, our results suggest that SIGIRR plays an important role in the negative regulation of LPS response and tolerance in human bladder epithelial cells, possibly through its impact on TLR-mediated signaling. PMID- 26634344 TI - Statistical considerations for stopping systemic lupus erythematosus clinical trials earlier. AB - Group sequential designs are used to potentially shorten randomized clinical trials and thereby reduce subject burden, improve safety, and save time and resources. Clinical trials comparing treatments for systemic lupus erythematosus (SLE) might adopt such designs if the ordinal outcome scales for SLE, such as the Systemic Lupus Activity Measure and Systemic Lupus Erythematosus Disease Activity Index, were more like continuous outcome scales with interval properties. After describing the basic features of sequential trials and highlighting some major issues in their design, we propose approaches that mitigate these issues. In particular, high-speed computing has accelerated advances in sequential design, making available a variety of designs that can be implemented with minimal technical support. The challenge now is to understand the concepts behind such flexible designs and then to apply them to improve studies of SLE. PMID- 26634343 TI - An organizational perspective on the long-term sustainability of a nursing best practice guidelines program: a case study. AB - BACKGROUND: Many healthcare innovations are not sustained over the long term, wasting costly implementation efforts and often desperately-needed initial improvements. Although there have been advances in knowledge about innovation implementation, there has been considerably less attention focused on understanding what happens following the early stages of change. Research is needed to determine how to improve the 'staying power' of healthcare innovations. As almost no empirical knowledge exists about innovation sustainability in nursing, the purpose of our study was to understand how a nursing best practice guidelines (BPG) program was sustained over a long-term period in an acute healthcare centre. METHODS: We conducted a qualitative descriptive case study to examine the program's sustainability at the nursing department level of the organization. The organization was a large, urban, multi-site acute care centre in Canada. The patient safety-oriented BPG program, initiated in 2004, consisted of an organization-wide implementation of three BPGs: falls prevention, pressure ulcer prevention, and pain management. Data were collected eight years following program initiation through 14 key informant interviews, document reviews, and observations. We developed a framework for the sustainability of healthcare innovations to guide data collection and content analysis. RESULTS: Program sustainability entailed a combination of three essential characteristics: benefits, institutionalization, and development. A constellation of 11 factors most influenced the long-term sustainability of the program. These factors were innovation-, context-, leadership-, and process-related. Three key interactions between factors influencing program sustainability and characteristics of program sustainability accounted for how the program had been sustained. These interactions were between: leadership commitment and benefits; complementarity of leadership actions and both institutionalization and development; and a reflection-and-course-correction strategy and development. CONCLUSIONS: Study findings indicate that the successful initial implementation of an organizational program does not automatically lead to longer-term program sustainability. The persistent, complementary, and aligned actions of committed leaders, in a variety of roles across a health centre department, seem necessary. Organizational leaders should consider a broad conceptualization of sustainability that extends beyond program institutionalization and/or program benefits. The development of an organizational program may be necessary for its long-term survival. PMID- 26634345 TI - M(3)-S: a genotype calling method incorporating information from samples with known genotypes. AB - BACKGROUND: A key challenge in analyzing high throughput Single Nucleotide Polymorphism (SNP) arrays is the accurate inference of genotypes for SNPs with low minor allele frequencies. A number of calling algorithms have been developed to infer genotypes for common SNPs, but they are limited in their performance in calling rare SNPs. The existing algorithms can be broadly classified into three categories, including: population-based methods, SNP-based methods, and a hybrid of the two approaches. Despite the relatively better performance of the hybrid approach, it is still challenging to analyze rare SNPs. RESULTS: We propose to utilize information from samples with known genotypes to develop a two stage genotyping procedure, namely M(3)-S, for rare SNP calling. This new approach can improve genotyping accuracy through clearly defining the boundaries of genotype clusters from samples with known genotypes, and enlarge the call rate by combining the simulated data based on the inferred genotype clusters information with the study population. CONCLUSIONS: Applications to real data demonstrates that this new approach M(3)-S outperforms existing methods in calling rare SNPs. PMID- 26634346 TI - Diagnostic accuracy of nasal nitric oxide for establishing diagnosis of primary ciliary dyskinesia: a meta-analysis. AB - BACKGROUND: To date, diagnosis of Primary Ciliary Dyskinesia (PCD) remains difficult and challenging. We systematically evaluated the diagnostic performance of nasal Nitric Oxide (nNO) measurement for the detection of PCD, using either velum-closure (VC) or non-velum-closure (non-VC) techniques. METHODS: All major electronic databases were searched from inception until March 2015 using appropriate terms. The sensitivity and specificity of nNO measurement was calculated in PCD patients diagnosed by transmission electron microscopy, high speed video-microscopy or genetic testing. Summary receiver operating characteristic (HSROC) curves were drawn using the parameters of the fitted models. RESULTS: Twelve studies provided data for 13 different populations, including nine case-control (n = 793) and four prospective cohorts (n = 392). The overall sensitivity of nNO measured by VC techniques was 0.95 (95 % CI 0.91 0.97), while specificity was 0.94 (95 % CI 0.88-0.97). The positive likelihood ratio (LR+) of the test was 15.8 (95 % CI 8.1-30.6), whereas the negative likelihood ratio (LR-) was 0.06 (95 % CI 0.04-0.09). For non-VC techniques, the overall sensitivity of nNO measurement was 0.93 (95 % CI 0.89-0.96) whereas specificity was 0.95 (95 % CI 0.82-0.99). The LR+ of the test was 18.5 (95 % CI 4.6-73.8) whereas the LR- was 0.07 (95 % CI 0.04-0.12). CONCLUSIONS: Diagnostic accuracy of nNO measurement both with VC and non-VC maneuvers is high and can be effectively employed in the clinical setting to detect PCD even in young children, thus potentiating early diagnosis. Measurement of nNO merits to be part of a revised diagnostic algorithm with the most efficacious combination of tests to achieve PCD diagnosis. PMID- 26634347 TI - Two-dimensional imaging in hyperbolic media-the role of field components and ordinary waves. AB - We study full vector imaging of two dimensional source fields through finite slabs of media with extreme anisotropy, such as hyperbolic media. For this, we adapt the exact transfer matrix method for uniaxial media to calculate the two dimensional transfer functions and point spread functions for arbitrary vector fields described in Cartesian coordinates. This is more convenient for imaging simulations than the use of the natural, propagation direction-dependent TE/TM basis, and clarifies which field components contribute to sub-diffraction imaging. We study the effect of ordinary waves on image quality, which previous one-dimensional approaches could not consider. Perfect sub-diffraction imaging can be achieved if longitudinal fields are measured, but in the more common case where field intensities or transverse fields are measured, ordinary waves cause artefacts. These become more prevalent when attempting to image large objects with high resolution. We discuss implications for curved hyperbolic imaging geometries such as hyperlenses. PMID- 26634348 TI - Ccr2 deletion dissociates cavity size and tau pathology after mild traumatic brain injury. AB - BACKGROUND: Millions of people experience traumatic brain injury (TBI) as a result of falls, car accidents, sports injury, and blast. TBI has been associated with the development of neurodegenerative conditions such as Alzheimer's disease (AD) and chronic traumatic encephalopathy (CTE). In the initial hours and days, the pathology of TBI comprises neuronal injury, breakdown of the blood-brain barrier, and inflammation. At the cellular level, the inflammatory reaction consists of responses by brain-resident microglia, astrocytes, and vascular elements as well as infiltration of peripheral cells. After TBI, signaling by chemokine (C-C motif) ligand 2 (CCL2) to the chemokine (C-C motif) receptor 2 (CCR2) is a key regulator of brain infiltration by monocytes. METHODS: We utilized mice with one or both copies of Ccr2 disrupted by red fluorescent protein (RFP, Ccr2 (RFP/+) and Ccr2 (RFP/RFP) ). We subjected these mice to the mild lateral fluid percussion model of TBI and examined several pathological outcomes 3 days later in order to determine the effects of altered monocyte entry into the brain. RESULTS: Ccr2 deletion reduced monocyte infiltration, diminished lesion cavity volume, and lessened axonal damage after mild TBI, but the microglial reaction to the lesion was not affected. We further examined phosphorylation of the microtubule-associated protein tau, which aggregates in brains of people with TBI, AD, and CTE. Surprisingly, Ccr2 deletion was associated with increased tau mislocalization to the cell body in the cortex and hippocampus by tissue staining and increased levels of phosphorylated tau in the hippocampus by Western blot. CONCLUSIONS: Disruption of CCR2 enhanced tau pathology and reduced cavity volume in the context of TBI. The data reveal a complex role for CCR2(+) monocytes in TBI, as monitored by cavity volume, axonal damage, and tau phosphorylation. PMID- 26634349 TI - Predicting habits of vegetable parenting practices to facilitate the design of change programmes. AB - OBJECTIVE: Habit has been defined as the automatic performance of a usual behaviour. The present paper reports the relationships of variables from a Model of Goal Directed Behavior to four scales in regard to parents' habits when feeding their children: habit of (i) actively involving child in selection of vegetables; (ii) maintaining a positive vegetable environment; (iii) positive communications about vegetables; and (iv) controlling vegetable practices. We tested the hypothesis that the primary predictor of each habit variable would be the measure of the corresponding parenting practice. DESIGN: Internet survey data from a mostly female sample. Primary analyses employed regression modelling with backward deletion, controlling for demographics and parenting practices behaviour. SETTING: Houston, Texas, USA. SUBJECTS: Parents of 307 pre-school (3-5 year-old) children. RESULTS: Three of the four models accounted for about 50 % of the variance in the parenting practices habit scales. Each habit scale was primarily predicted by the corresponding parenting practices scale (suggesting validity). The habit of active child involvement in vegetable selection was also most strongly predicted by two barriers and rudimentary self-efficacy; the habit of maintaining a positive vegetable environment by one barrier; the habit of maintaining positive communications about vegetables by an emotional scale; and the habit of controlling vegetable practices by a perceived behavioural control scale. CONCLUSIONS: The predictiveness of the psychosocial variables beyond parenting practices behaviour was modest. Discontinuing the habit of ineffective controlling parenting practices may require increasing the parent's perceived control of parenting practices, perhaps through simulated parent-child interactions. PMID- 26634350 TI - Heat Shock Factor 1-Regulated miRNAs Can Target Huntingtin and Suppress Aggregates of Mutant Huntingtin. AB - BACKGROUND: Heat shock factor 1 (HSF1) is the master regulator of chaperone network in mammalian cells and can protect cells from adverse effects of misfolded proteins by rapidly inducing expression of multiple heat shock proteins (HSPs) and other cytoprotective proteins. HSF1 also regulates transcription of microRNAs (miRNAs) in heat shock-dependent manner and these miRNAs are likely to regulate diverse cellular processes by acting as downstream effectors of HSF1. METHODS: The study was aimed at understanding the effect of HSF1-regulated miRNAs on huntingtin expression and Huntington's Disease (HD) pathogenesis, if any. The cumulative effect of all HSF1-regulated miRNAs on huntingtin expression was measured by quantitative real-time PCR and luciferase reporter assay and effect of miRNAs on mutant huntingtin aggregates was determined by aggregate counting assay. RESULTS: Our study reveals that HSF1-regulated miRNAs cumulatively target huntingtin and reduce its expression in HD cell model. We also identify 4 huntingtin-targeting miRNAs viz. miR-125b, miR-146a, miR-150 and miR-214 as candidate miRNAs responsible for observed inhibitory effect of HSF1 on huntingtin expression. We further demonstrate that HSF1-regulated miRNAs together can suppress aggregates of mutant huntingtin in cell model of HD. CONCLUSION: We conclude that the protective effect of HSF1 in the context of HD is a consequence of synergistic induction of HSPs and HSF1-regulated huntingtin-targeting miRNAs. Moreover, the suppressive effect of HSF1-regulated miRNAs on mutant huntingtin aggregates indicates their potential as therapeutic agents for the treatment of HD. PMID- 26634351 TI - Modeling the habitat suitability for the arbovirus vector Aedes albopictus (Diptera: Culicidae) in Germany. AB - Climatic changes raise the risk of re-emergence of arthropod-borne virus outbreaks globally. These viruses are transmitted by arthropod vectors, often mosquitoes. Due to increasing worldwide trade and tourism, these vector species are often accidentally introduced into many countries beyond their former distribution range. Aedes albopictus, a well-known disease vector, was detected for the first time in Germany in 2007, but seems to have failed establishment until today. However, the species is known to occur in other temperate regions and a risk for establishment in Germany remains, especially in the face of predicted climate change. Thus, the goal of the study was to estimate the potential distribution of Ae. albopictus in Germany. We used ecological niche modeling in order to estimate the potential habitat suitability for this species under current and projected future climatic conditions. According to our model, there are already two areas in western and southern Germany that appear suitable for Ae. albopictus under current climatic conditions. One of these areas lies in Baden-Wuerttemberg, the other in North-Rhine Westphalia in the Ruhr region. Furthermore, projections under future climatic conditions show an increase of the modeled habitat suitability throughout Germany. Ae. albopictus is supposed to be better acclimated to colder temperatures than other tropical vectors and thus, might become, triggered by climate change, a serious threat to public health in Germany. Our modeling results can help optimizing the design of monitoring programs currently in place in Germany. PMID- 26634352 TI - Initial antifungal strategy does not correlate with mortality in patients with candidemia. AB - The incidence of Candida bloodstream infections (BSIs) has increased over time, especially in medical wards. The objective of this study was to evaluate the impact of different antifungal treatment strategies on 30-day mortality in patients with Candida BSI not admitted to intensive care units (ICUs) at disease onset. This prospective, monocentric, cohort study was conducted at an 1100-bed university hospital in Rome, Italy, where an infectious disease consultation team was implemented. All cases of Candida BSIs observed in adult patients from November 2012 to April 2014 were included. Patients were grouped according to the initial antifungal strategy: fluconazole, echinocandin, or liposomal amphotericin B. Cox regression analysis was used to identify risk factors significantly associated with 15-day and 30-day mortality. During the study period, 130 patients with candidemia were observed (58 % with C. albicans, 7 % with C. glabrata, and 23 % with C. parapsilosis). The first antifungal drug was fluconazole for 40 % of patients, echinocandin for 57.0 %, and liposomal amphotericin B for 4 %. During follow-up, 33 % of patients died. The cumulative mortality 30 days after the candidemia episode was 30.8 % and was similar among groups. In the Cox regression analysis, clinical presentation was the only independent factor associated with 15-day mortality, and Acute Physiology and Chronic Health Evaluation (APACHE) II score and clinical presentation were the independent factors associated with 30-day mortality. No differences in 15-day and 30-day mortality were observed between patients with and without C. albicans candidemia. In patients with candidemia admitted to medical or surgical wards, clinical severity but not the initial antifungal strategy were significantly correlated with mortality. PMID- 26634354 TI - [Abdominal magnetic resonance imaging]. PMID- 26634364 TI - Edited Volumes 36/1 (2014). PMID- 26634353 TI - Clonal relationship between human and avian ciprofloxacin-resistant Escherichia coli isolates in North-Eastern Algeria. AB - The objectives of this study were to determine rates, patterns, and mechanisms of antibiotic resistance, and to assess connections between chicken commensal, human commensal, and pathogenic ciprofloxacin-resistant Escherichia coli isolates. All E. coli isolates collected from chickens, their farmers, and patients in the Constantine region (North-east Algeria) were analyzed for bla and plasmid mediated quinolone resistance (PMQR) gene contents, phylogroups, Rep-PCR profiles, and multilocus sequence types. A high prevalence of resistance to fluoroquinolones (51.4 % to ciprofloxacin) was recorded in avian isolates. Of these, 22.2 % carried the aac(6')-Ib-cr gene, whereas lower resistance levels to these antibiotics were recorded in chicken farmers' isolates. None of the commensal isolates harbored the qnr, qepA, or oqxAB genes. One human pathogenic isolate was ertapenem-resistant and harbored the bla OXA-48 gene, 84 showed an extended-spectrum beta-lactamase phenotype, with bla CTX-M-15 gene prevalent in 87.2 % of them. Seventy isolates were resistant to fluoroquinolones, with aac(6') Ib-cr present in 72.8 %, qnrB in 5.7 %, and qnrS in 10 %. Three Rep-PCR profiles were common to chicken commensal and human pathogenic isolates (phylogroups D and B1; ST21, ST48, and ST471 respectively); one was found in both chicken and chicken-farmer commensal strains (D; ST108), while another profile was identified in a chicken-farmer commensal strain and a human pathogenic one (B1; ST19). These findings suggest clonal and epidemiologic links between chicken and human ciprofloxacin-resistant E. coli isolates and the important role that poultry may play in the epidemiology of human E. coli infections in the Constantine region. PMID- 26634366 TI - Increased interhemispheric resting-state functional connectivity after sleep deprivation: a resting-state fMRI study. AB - Several functional imaging studies have investigated the regional effects of sleep deprivation (SD) on impaired brain function; however, potential changes in the functional interactions between the cerebral hemispheres after SD are not well understood. In this study, we used a recently validated approach, voxel mirrored homotopic connectivity (VMHC), to directly examine the changes in interhemispheric homotopic resting-state functional connectivity (RSFC) after SD. Resting-state functional MRI (fMRI) was performed in 28 participants both after rest wakefulness (RW) and a total night of SD. An interhemispheric RSFC map was obtained by calculating the Pearson correlation (Fisher Z transformed) between each pair of homotopic voxel time series for each subject in each condition. The between-condition differences in interhemispheric RSFC were then examined at global and voxelwise levels separately. Significantly increased global VMHC was found after sleep deprivation; specifically, a significant increase in VMHC was found in specific brain regions, including the thalamus, paracentral lobule, supplementary motor area, postcentral gyrus and lingual gyrus. No regions showed significantly reduced VMHC after sleep deprivation. Further analysis indicates that these findings did not depend on the various sizes of smoothing kernels that were adopted in the preprocessing steps and that the differences in these regions were still significant with or without global signal regression. Our data suggest that the increased VMHC might reflect the compensatory involvement of bilateral brain areas, especially the bilateral thalamus, to prevent cognitive performance deterioration when sleep pressure is elevated after sleep deprivation. Our findings provide preliminary evidence of interhemispheric correlation changes after SD and contribute to a better understanding of the neural mechanisms of SD. PMID- 26634365 TI - Major Histocompatibility Complex Class II Deficiency due to a Novel Mutation in RFXANK in a Child of Mexican Descent. PMID- 26634367 TI - In memoriam Prof. Paolo Biassoni (1929-2015). PMID- 26634368 TI - The role of dietary potassium in hypertension and diabetes. AB - Potassium is an essential mineral which plays major roles for the resting membrane potential and the intracellular osmolarity. In addition, for several years, it has been known that potassium also affects endothelial and vascular smooth muscle functions and it has been repeatedly shown that an increase in potassium intake shifts blood pressure to a more preferable level. Meanwhile, the blood pressure lowering effects of potassium were presented in several intervention trials and summarized in a handful of meta-analyses. Furthermore, accumulating epidemiological evidence from, especially, the last decade relates low dietary potassium intake or serum potassium levels to an increased risk for insulin resistance or diabetes. However, intervention trials are required to confirm this association. So, in addition to reduction of sodium intake, increasing dietary potassium intake may positively affect blood pressure and possibly also glucose metabolism in many populations. This concise review not only summarizes the studies linking potassium to blood pressure and diabetes but also discusses potential mechanisms involved, like vascular smooth muscle relaxation and endothelium-dependent vasodilation or stimulation of insulin secretion in pancreatic beta-cells, respectively. PMID- 26634369 TI - High intake of dietary tyramine does not deteriorate glucose handling and does not cause adverse cardiovascular effects in mice. AB - Tyramine is naturally occurring in food and induces pressor responses. Low tyramine diets are recommended for patients treated with MAO inhibitors to avoid the fatal hypertensive crisis sadly known as "cheese effect". Hence, tyramine intake is suspected to have toxicological consequences in humans, while its administration to type 1 diabetic rodents has been reported to improve glucose tolerance. We investigated in mice whether prolonged tyramine ingestion could alter glucose homeostasis, insulin sensitivity, adipose tissue physiology or cardiovascular functions. Tyramine was added at 0.04 or 0.14 % in the drinking water since this was estimated to increase by 10- to 40-fold the spontaneous tyramine intake of control mice fed a standard diet. Ten to 12 weeks of such tyramine supplementation did not influence body weight gain, adiposity or food consumption. Both doses (reaching approx. 300 and 1100 MUmol tyramine/kg bw/day) decreased nonfasting blood glucose but did not modify glucose tolerance or fasting levels of glucose, insulin or circulating lipids. Blood pressure was not increased in tyramine-drinking mice, while only the higher tested dose moderately increased heart rate without change in its variability. Markers of cardiac tissue injury or oxidative stress remained unaltered, except an increased hydrogen peroxide production in heart preparations. In isolated adipocytes, tyramine inhibited lipolysis similarly in treated and control groups, as did insulin. The lack of serious adverse cardiovascular effects of prolonged tyramine supplementation in normoglycemic mice together with the somewhat insulin-like effects found on adipose cells should lead to reconsider favourably the risk/benefit ratio of the intake of this dietary amine. PMID- 26634370 TI - Cold stress increases reactive oxygen species formation via TRPA1 activation in A549 cells. AB - Reactive oxygen species (ROS) are responsible for lung damage during inhalation of cold air. However, the mechanism of the ROS production induced by cold stress in the lung is still unclear. In this work, we measured the changes of ROS and the cytosolic Ca(2+) concentration ([Ca(2+)]c) in A549 cell. We observed that cold stress (from 20 to 5 degrees C) exposure of A549 cell resulted in an increase of ROS and [Ca(2+)]c, which was completely attenuated by removing Ca(2+) from medium. Further experiments showed that cold-sensing transient receptor potential subfamily member 1 (TRPA1) agonist (allyl isothiocyanate, AITC) increased the production of ROS and the level of [Ca(2+)]c in A549 cell. Moreover, HC-030031, a TRPA1 selective antagonist, significantly inhibited the enhanced ROS and [Ca(2+)]c induced by AITC or cold stimulation, respectively. Taken together, these data demonstrated that TRPA1 activation played an important role in the enhanced production of ROS induced by cold stress in A549 cell. PMID- 26634372 TI - Intensive care unit outcome in the elderly. PMID- 26634373 TI - The practice of mediation to resolve clinical, bioethical, and medical malpractice disputes. AB - Mediation is a voluntary process whereby a neutral and impartial third party-t-he mediator--is present to facilitate communication and negotiation between the disputing parties so that amicable settlements can be agreed. Being confidential and non-adversarial in nature, the mediation process and skills are particularly applicable in clinical practice to facilitate challenging communications following adverse events, to assist bioethical decision making and to resolve disputes. Mediation is also a more effective and efficient means of dispute resolution in medical malpractice claims when compared with civil litigation. Health care mediation teams should be set up at individual facilities to provide education and consultation services to frontline staff and patients. At a community level, the Government, the mediation community, and the health care professionals should join forces to promote mediation as a means to settle medical malpractice claims outside of the courtroom. PMID- 26634371 TI - Structural studies of UBXN2A and mortalin interaction and the putative role of silenced UBXN2A in preventing response to chemotherapy. AB - Overexpression of the oncoprotein mortalin in cancer cells and its protein partners enables mortalin to promote multiple oncogenic signaling pathways and effectively antagonize chemotherapy-induced cell death. A UBX-domain-containing protein, UBXN2A, acts as a potential mortalin inhibitor. This current study determines whether UBXN2A effectively binds to and occupies mortalin's binding pocket, resulting in a direct improvement in the tumor's sensitivity to chemotherapy. Molecular modeling of human mortalin's binding pocket and its binding to the SEP domain of UBXN2A followed by yeast two-hybrid and His-tag pull down assays revealed that three amino acids (PRO442, ILE558, and LYS555) within the substrate-binding domain of mortalin are crucial for UBXN2A binding to mortalin. As revealed by chase experiments in the presence of cycloheximide, overexpression of UBXN2A seems to interfere with the mortalin-CHIP E3 ubiquitin ligase and consequently suppresses the C-terminus of the HSC70-interacting protein (CHIP)-mediated destabilization of p53, resulting in its stabilization in the cytoplasm and upregulation in the nucleus. Overexpression of UBXN2A causes a significant inhibition of cell proliferation and the migration of colon cancer cells. We silenced UBXN2A in the human osteosarcoma U2OS cell line, an enriched mortalin cancer cell, followed by a clinical dosage of the chemotherapeutic agent 5-fluorouracil (5-FU). The UBXN2A knockout U2OS cells revealed that UBXNA is essential for the cytotoxic effect achieved by 5-FU. UBXN2A overexpression markedly increased the apoptotic response of U2OS cells to the 5-FU. In addition, silencing of UBXN2A protein suppresses apoptosis enhanced by UBXN2A overexpression in U2OS. The knowledge gained from this study provides insights into the mechanistic role of UBXN2A as a potent mortalin inhibitor and as a potential chemotherapy sensitizer for clinical application. PMID- 26634374 TI - Churg-Strauss syndrome from an orthopaedic perspective. AB - Churg-Strauss syndrome, which has been frequently described by physicians in the literature, is a small and medium-sized vessel systemic vasculitis typically associated with asthma, lung infiltrates, and hypereosinophilia. We report a case of Churg-Strauss syndrome with presenting symptoms of bilateral lower limb weakness and numbness only. The patient was admitted to an orthopaedic ward for management and a final diagnosis was reached following sural nerve biopsy. The patient's symptoms responded promptly to steroid treatment and she was able to walk with a stick 3 weeks following admission. This report emphasises the need to be aware of this syndrome when managing patients with neurological deficit in order to achieve prompt diagnosis and treatment. PMID- 26634375 TI - Extrapulmonary involvement associated with Mycoplasma pneumoniae infection. AB - Mycoplasma pneumoniae infection usually presents with upper and lower respiratory tract infection. Extrapulmonary involvement is not uncommon, however. We report two cases of predominantly extrapulmonary manifestations of Mycoplasma pneumoniae infection without significant pulmonary involvement. Both cases were diagnosed by serology. These cases illustrate the diversity of clinical presentations of Mycoplasma pneumoniae infection. Clinicians should maintain a high index of suspicion. PMID- 26634376 TI - Food avoidance does not improve childhood eczema. PMID- 26634377 TI - Phlebosclerotic colitis: radiological findings of an uncommon entity. PMID- 26634378 TI - The nail points to the diagnosis. Fong disease or hereditary osteo onychodysplasia. PMID- 26634379 TI - Immaterial Boys? A Large-Scale Exploration of Gender-Based Differences in Child Sexual Exploitation Service Users. AB - Child sexual exploitation is increasingly recognized nationally and internationally as a pressing child protection, crime prevention, and public health issue. In the United Kingdom, for example, a recent series of high-profile cases has fueled pressure on policy makers and practitioners to improve responses. Yet, prevailing discourse, research, and interventions around child sexual exploitation have focused overwhelmingly on female victims. This study was designed to help redress fundamental knowledge gaps around boys affected by sexual exploitation. This was achieved through rigorous quantitative analysis of individual-level data for 9,042 users of child sexual exploitation services in the United Kingdom. One third of the sample were boys, and gender was associated with statistically significant differences on many variables. The results of this exploratory study highlight the need for further targeted research and more nuanced and inclusive counter-strategies. PMID- 26634380 TI - Slow walking speed may be early sign of Alzheimer's in older people, study finds. PMID- 26634382 TI - Explaining laboratory test results to patients: what the clinician needs to know. PMID- 26634381 TI - ESMO-ESGO-ESTRO Consensus Conference on Endometrial Cancer: diagnosis, treatment and follow-up. AB - The first joint European Society for Medical Oncology (ESMO), European SocieTy for Radiotherapy & Oncology (ESTRO) and European Society of Gynaecological Oncology (ESGO) consensus conference on endometrial cancer was held on 11-13 December 2014 in Milan, Italy, and comprised a multidisciplinary panel of 40 leading experts in the management of endometrial cancer. Before the conference, the expert panel prepared three clinically relevant questions about endometrial cancer relating to the following four areas: prevention and screening, surgery, adjuvant treatment and advanced and recurrent disease. All relevant scientific literature, as identified by the experts, was reviewed in advance. During the consensus conference, the panel developed recommendations for each specific question and a consensus was reached. Results of this consensus conference, together with a summary of evidence supporting each recommendation, are detailed in this article. All participants have approved this final article. PMID- 26634383 TI - Comparing high-dimensional confounder control methods for rapid cohort studies from electronic health records. AB - AIMS: Electronic health records (EHR), containing rich clinical histories of large patient populations, can provide evidence for clinical decisions when evidence from trials and literature is absent. To enable such observational studies from EHR in real time, particularly in emergencies, rapid confounder control methods that can handle numerous variables and adjust for biases are imperative. This study compares the performance of 18 automatic confounder control methods. METHODS: Methods include propensity scores, direct adjustment by machine learning, similarity matching and resampling in two simulated and one real-world EHR datasets. RESULTS & CONCLUSIONS: Direct adjustment by lasso regression and ensemble models involving multiple resamples have performance comparable to expert-based propensity scores and thus, may help provide real-time EHR-based evidence for timely clinical decisions. PMID- 26634384 TI - Recent developments in brain tumor predisposing syndromes. AB - The etiologies of brain tumors are in the most cases unknown, but improvements in genetics and DNA screening have helped to identify a wide range of brain tumor predisposition disorders. In this review we are discussing some of the most common predisposition disorders, namely: neurofibromatosis type 1 and 2, schwannomatosis, rhabdoid tumor predisposition disorder, nevoid basal cell carcinoma syndrome (Gorlin), tuberous sclerosis complex, von Hippel-Lindau, Li Fraumeni and Turcot syndromes. Recent findings from the GLIOGENE collaboration and the newly identified glioma causing gene POT1, will also be discussed. Genetics. We will describe these disorders from a genetic and clinical standpoint, focusing on the difference in clinical symptoms depending on the underlying gene or germline mutation. Central nervous system (CNS) tumors. Most of these disorders predispose the carriers to a wide range of symptoms. Herein, we will focus particularly on tumors affecting the CNS and discuss improvements of targeted therapy for the particular disorders. PMID- 26634385 TI - 5-Fluorouracil enteric-coated nanoparticles for improved apoptotic activity and therapeutic index in treating colorectal cancer. AB - 5-Fluorouracil (5-FU) is one among the anti-cancer agents in FOLFORINOX treatment along with oxaliplatin and irinotecan for the treatment of colorectal cancer. Despite its potential activity on the tumor cells, it lacks site specificity partly attributed by its biodistribution to healthy cells resulting in toxic effects to healthy cells. Therefore, we have formulated 5-fluorouracil enteric coated nanoparticles (5-FUEC) to localize the drug in the colon area that enables its prolonged presence in target area in a sustained manner. The current work emphasizes on enhanced anti-cancer activity of 5-FUEC sequencing its apoptotic activity on HCT 116 colorectal cancer cell lines in vitro. MTT assay exhibited 5.5-fold decrease in IC50 value of nanoparticles comparable to 5-FU. Nuclear fragmentation with irregular edges in nucleus of cells justified its improved activity. Furthermore, flow cytometric analysis confirms the majority of cells gated in early apoptotic (39.75%) and late apoptotic phase (36.25%). Acridine orange/ethidium bromide staining (AO/EB) exhibited cells with red fluorescence (indicating apoptosis) comparable to the control and 5-FU. gamma-Scintigraphic studies determined the applicability and feasibility of the enteric coating with mean gastric emptying time, mean intestinal transit time and mean colon arrival time of 1.89 +/- 0.03, 2.15 +/- 0.05 and 4.03 +/- 0.27 h, respectively. Moreover, nanoparticulate approach was found significant in reducing tumor size and volume in xenograft tumor models in vivo along with sustained release. These superior anti-cancer activities exhibited by 5-FUEC indicated that it could be a potential alternative to chemotherapy for colorectal cancer. PMID- 26634386 TI - Recent prospective of nanofiber scaffolds fabrication approaches for skin regeneration. AB - The largest organ of human body is skin, which acting as a barrier with immunologic, sensorial and protective functions. It is always in exposure to the external environment, which can result many different types of damage and injury with loss of variable volumes of extracellular matrix (ECM). For the treatment of skin lesions and damages, several approaches are now accessible, such as the application of allografts, autografts, and tissue-engineered substitutes, wound dressings and nanofiber scaffolds approaches. Even though proven clinically effective, these methods are still characterized by main drawbacks such as patient inadequate vascularization, morbidity, the inability to reproduce skin appendages, low adherence to the wound bed and high manufacturing costs. Advanced approaches based on nanofiber scaffolds approaches offer a permanent, viable and effective substitute to explain the drawbacks of skin regeneration and repair by combining growth factors, cells, and biomaterials and advanced biomanufacturing methods. This review details recent advances of nanofiber scaffolds in skin regeneration and repair strategies, and describes a synthesis method of nanofiber scaffolds. PMID- 26634387 TI - Commentary concerning the review by Mitchell et al. (2014): curiosities in drug metabolism (Xenobiotica 2014; 44:666-76). PMID- 26634388 TI - Inactivating frameshift mutation of PBRM1, a putative tumour suppressor gene, in colorectal cancers. PMID- 26634389 TI - Effects of autonomous motivational priming on motivation and affective responses towards high-intensity interval training. AB - This study examined the effect of autonomous motivational priming on motivation, attitudes and intentions towards high-intensity interval training (HIT). Participants (N = 42) performed a graded exercise test to determine their peak aerobic power (WPEAK). At a subsequent testing session, participants were randomised to complete either an autonomous or neutral motivational priming task followed by a 10 * 1 HIT exercise protocol, alternating 1-min bouts of hard (70% WPEAK) and light (12.5% WPEAK) exercises for 20 min. Participants primed with autonomous motivation reported greater enjoyment, P = .009, etap(2) = .16, and perceived competence, P = .005, etap(2) = .18, post-exercise compared to those in the neutral priming condition. Participants in the autonomous motivational priming condition also reported more positive attitudes, P = .014, etap(2) = .14, towards HIT; however, there was no difference between the conditions for task motivation during HIT or intentions, P = .53, etap(2) = .01, to engage in HIT. These findings highlight autonomous motivational priming as a method of enhancing affective and motivational experiences regarding HIT. PMID- 26634390 TI - Eveningness and poor sleep quality independently contribute to self-reported depression severity in psychiatric inpatients with affective disorder. AB - Background Chronotype and insomnia have been related to the development and to an unfavourable course of depression. However, the mutual relationship of both risk factors is as yet unclear, especially in acute, clinically manifest depressive disorders. Aims The present study was carried out to elucidate the separate direct and indirect influence of chronotype and poor sleep quality on depression severity in patients hospitalized for depression. Methods Depression severity (BDI-II), chronotype (Morningness-Eveningness Questionnaire), and subjective sleep quality (Pittsburgh Sleep Quality Index total score) were assessed concurrently in inpatients with a depressive syndrome and insomnia during routine treatment. Correlations, multiple regression and bootstrapping methods for testing mediation models were applied to assess the independent direct and indirect effects of chronotype and sleep quality on depression severity, after adjusting for effects of age and gender. Results Data from 57 consecutively admitted patients (88% with major depression) were analyzed (68% women, mean age 41 +/- 13 years). Significant correlations between morningness-eveningness (p <0.05) or sleep quality (p <0.01) and depression severity were found; in a multiple regression model comprising chronotype, sleep quality, age and gender, only chronotype (p <0.05) and sleep disturbances (p <0.01) remained as independent significant concurrent predictors of depression severity (R(2) = 0.184, p <0.01). Two mediation models revealed no significant results. Conclusions Eveningness and poor subjective sleep quality were independently and directly associated with higher depression severity in inpatients with depressive syndromes. Chronotype and sleep quality should be taken into account not only in risk assessment and prevention but also in hospitalized patients to develop and improve treatment options. PMID- 26634391 TI - St. John's wort and its component hyperforin alleviate experimental autoimmune encephalomyelitis through expansion of regulatory T-cells. AB - Multiple sclerosis (MS) is a central nervous system disorder mainly characterized by inflammation, demyelination and axonal injury. Anti-inflammatory agents can be used to ameliorate the disease process. Hypericum perforatum L or St. John's wort is widely used as an anti-depressant and anti-inflammatory remedy in traditional and herbal medicine. Based on St. John's wort properties, the therapeutic potentials of an H. perforatum extract (HPE) and a single component, hyperforin were evaluated for effectiveness against MOG35-55-induced experimental autoimmune encephalomyelitis (EAE), an animal model for human multiple sclerosis. Female C57BL/6 mice were immunized with specific antigen MOG35-55 and then administered different doses of hyperforin or HPE post-immunization. Clinical symptoms/other relevant parameters were assessed daily. Histological analysis of the spinal cord was performed. T-cell proliferative activity was also evaluated using a BrdU assay. The effect of hyperforin on regulatory T-cells (Treg cells) was assessed using flow cytometry. The results indicate hyperforin and HPE reduced the incidence and severity of EAE, an outcome that closely correlated with an inhibition of pathological features (leukocyte infiltration and demyelination) and antigen-specific T-cell proliferation. The study also showed that hyperforin caused increased Treg cell levels in the spleen. These results indicated that hyperforin and HPE could attenuate EAE autoimmune responses by inhibiting immune cell infiltration and expansion of Treg cell and could eventually be considered as a potential candidate for use in the treatment of MS. PMID- 26634392 TI - Factors that influence the development of avulsion of the levator ani muscle in eutocic deliveries: 3-4D transperineal ultrasound study. AB - INTRODUCTION: Levator ani muscle (LAM) lesions are the most frequent injuries of the pelvic floor during delivery. Ten to 36% of women report this lesion during their first delivery. Many risk factors have been proposed but very few evaluate the aspects that can influence during natural vaginal delivery. METHOD: A prospective observational trial was conducted involving 74 primiparous women following vaginal delivery. Maternal, fetal and obstetric characteristics were analyzed. A transperineal three or four-dimensional (3D-4D) ultrasound was offered six months after delivery in order to evaluate avulsions and anomalies of the hiatus. RESULTS: Seventy four women were included, three of them did not show up for ultrasound evaluation. Sixty two (87.3%) demonstrated no avulsion in comparison with nine (12.7%) who did. Five of these lesions were unilateral and four bilateral. Mean newborn weight was 3193 g in the "no avulsion group" versus 3470 g in the "avulsion" group (p=0.025). DISCUSSION: According to the results, the most important risk factor established, for avulsion during natural childbirth, was the newborn weight. This contrasts with many other authors who have established that birth weight has no impact on these lesions. CONCLUSIONS: The most important factor intervening in the avulsion of LAM during natural vaginal delivery is the newborn weight. Patients with diagnosed avulsions present an enlarged urogenital hiatus during valsalva and maximal contraction. PMID- 26634393 TI - Molecular analysis of microbial community in arsenic-rich groundwater of Kolsor, West Bengal. AB - Bacterial community composition within the highly arsenic (As) contaminated groundwater from Kolsur, West Bengal was analyzed over a period of 3 years using 16S rRNA gene clone library and Denaturing Gradient Gel Electrophoresis (DGGE). Molecular phylogenetic study revealed abundance of alpha-Proteobacteria (56%) and Firmicutes (29%) along with members of beta-Proteobacteria, Verrucomicrobia and Sphingobacteria as relatively minor groups. Along with consistent physicochemical environment, a stable microbial community structure comprising of bacterial genera Agrobacterium-Rhizobium, Ochrobactrum, Pseudomonas, Anoxybacillus and Penibacillus was recorded over the three years study period. Presence of cytosolic arsenate reductase (arsC) gene was observed within the microbial community. Phylogenetic analyses revealed that all the arsC sequences were closely related to the same gene from gamma-proteobacterial members while the community was consisted of mainly alpha-proteobacterial groups. Such phylogenetic incongruence between 16S rRNA and arsC genes possibly indicated horizontal gene transfer (HGT) of the ars genes within the groundwater community. Overall, the study reported a nearly stable geomicrobial environment and genetic determinant related to As homeostasis gene, and provided a better insight on biogeochemistry of As contaminated aquifer of West Bengal. PMID- 26634394 TI - Thermotolerant alkaline protease enzyme from Bacillus licheniformis A10: purification, characterization, effects of surfactants and organic solvents. AB - In this study, the extracellular thermostable alkaline protease out of A10 strain was purified 1.38-fold with 9.44% efficiency through the ammonium sulfate precipitation-dialysis and DE52 anion exchange chromatography methods. The molecular weight of the enzyme in question along with sodium dodecyl sulfate polyacrylamide gel electrophoresis was determined to be approximately 40.55 kDa, whereas the optimum pH and temperature ratings were identified as 9.0 and 70 degrees C, respectively. It was seen that the enzyme had remained stable between pH 7.5-10.5 range, protecting more than 90% of its activity in the wake of 1 h incubation at 60-70 degrees C. It was also observed that the enzyme enhanced its activity in the presence of Mg(2+), Mn(2+), K(+), while Fe(2+), Ni(2+), Zn(2+), Ag(+ )and Co(2+ ) decreased the activity. Ca(2+), however, did not cause any change in the activity. The enzyme was seen to have been totally inhibited by phenylmethylsulfonyl fluoride, therefore, proved to be a serine alkaline protease. PMID- 26634395 TI - Rehabilitation of Bells' palsy from a multi-team perspective. AB - Conclusions Defectively healed facial paralysis causes difficulties to talk and eat, involuntary spasms (synkinesis), and cosmetic deformities which can give rise both to severe psychological and physical trauma. A team consisting of Ear Nose-Throat specialists, Plastic surgeons and Physiotherapists can offer better care, treatment and outcome for patients suffering from Bells' palsy. Objectives Patients suffering from Bells' palsy from all ENT hospitals in Sweden and the University Hospital in Helsinki has been included. Methods Results have been drawn and statistically processed for different outcomes from a prospective, double blind cross over study. Results from a pilot surgical study and therapeutic results from physiotherapy studies have been included. Ideas concerning different kinds of surgery will be reviewed and the role of physiotherapy discussed. Results According to common results, treatment with Prednisolone enhances the recovery rate and should, if possible, be used early in the course. Sunnybrook grading at 1 month after onset most accurately predicts non-recovery at 12 months in Bells' palsy and a risk factor curve will be presented in order to predict outcome and selection of patients for undergoing facial surgery. This report is focusing on how to handle patients with Bells' palsy from a multi-rehabilitation team point of view, and what will be recommended to provide these patients with the best clinical and surgical help. PMID- 26634396 TI - Reducing outcome measures in mental health: a systematic review of the methods. AB - BACKGROUND: Traditionally, classical test theory (CTT) has been used for instrument development and various methods have since been proposed for reducing outcome measures to shorter versions. These reduction methods have not previously been compared in mental or physical health. AIM: To identify and compare the various methods used to develop brief versions of outcome measures from existing measures in mental health. METHOD: A systematic review of the literature in Embase, Medline, PsychInfo and from a grey literature was done. Search strategies were developed in each database to identify all relevant literature based on the inclusion criteria. Each paper identified was briefly described and then assessed using a bespoke assessment checklist developed by the authors. Methods for reducing outcome measures found across all studies were compared. RESULTS: Ten papers were identified. Five methods were used for scale reduction: Rasch analysis (RA), exploratory factor analysis (EFA), graded response models (GRMs), all-subset regression, and regression. RA was the most widely used process. CONCLUSION: The Rasch model (RM) is the only model where "'specific objectivity"' is a defining property of the model. This property is necessary for constructing scales in line with the fundamental principles of measurement. PMID- 26634397 TI - Tumor necrosis factor-alpha driven inflammation in alpha-1 antitrypsin deficiency: a new model of pathogenesis and treatment. AB - Alpha-1 antitrypsin (AAT) deficiency (AATD) has traditionally been thought of as a genetic disorder characterized by lung destruction and early emphysema in a low AAT, and high neutrophil elastase (NE) environment in the lungs of affected individuals. Recently, a growing body of evidence has emerged to support the hypothesis that tumor necrosis factor alpha (TNF-alpha) is essential in the pathogenesis of both genetic AATD and non-genetic chronic obstructive pulmonary disease (COPD). Reports have highlighted the importance of TNF-alpha driven immune cell dysfunction in the development of lung disease in AATD. The authors discuss the role of AAT as a key modulator of TNF-alpha signaling firstly in the setting of AATD and secondly in other conditions where AAT augmentation therapy has potential utility as a novel therapy. PMID- 26634398 TI - Use of digital images to aid in the decision-making for acute upper extremity trauma referral. AB - This study evaluated the use of digital smartphone images in the decision-making for acute upper extremity trauma referrals. Surgeons (n = 15) were presented with ten upper limb trauma scenarios for consideration of immediate transfer. Based on verbal history and with additional images, participants were asked questions regarding diagnosis, injured tissues, recommended management and diagnostic and treatment confidence. Statistical analyses evaluated confidence level changes and relationships between confidence levels and independent variables. Confidence levels for diagnosis and treatment were increased with the provision of smartphone images, and this was statistically significant. The decision to transfer was changed in 22%. The photographs were more useful for amputation versus non-amputation injuries (diagnosis and treatment) and hand versus forearm injuries (diagnosis), and these differences reached statistical significance. Smartphone digital images were shown to be useful for decision-making in acute upper extremity trauma referrals. This improved communication may have implications for health cost savings and patient burden by minimizing unnecessary acute transfers. LEVEL OF EVIDENCE: Diagnostic Level III. PMID- 26634399 TI - Percutaneous fixation of distal radial fractures with and without plaster splint immobilization. PMID- 26634400 TI - Patient satisfaction and non-UK educated nurses: a cross-sectional observational study of English National Health Service Hospitals. AB - OBJECTIVES: To examine whether patient satisfaction with nursing care in National Health Service (NHS) hospitals in England is associated with the proportion of non-UK educated nurses providing care. DESIGN: Cross-sectional analysis using data from the 2010 NHS Adult Inpatient Survey merged with data from nurse and hospital administrator surveys. Logistic regression models with corrections for clustering were used to determine whether the proportions of non-UK educated nurses were significantly related to patient satisfaction before and after taking account of other hospital, nursing and patient characteristics. SETTING: 31 English NHS trusts. PARTICIPANTS: 12,506 patients 16 years of age and older with at least one overnight stay that completed a satisfaction survey; 2962 bedside care nurses who completed a nurse survey; and 31 NHS trusts. MAIN OUTCOME MEASURE: Patient satisfaction. RESULTS: The percentage of non-UK educated nurses providing bedside hospital care, which ranged from 1% to 52% of nurses, was significantly associated with patient satisfaction. After controlling for potential confounding factors, each 10-point increase in the percentage of non-UK educated nurses diminished the odds of patients reporting good or excellent care by 12% (OR=0.88), and decreased the odds of patients agreeing that they always had confidence and trust in nurses by 13% (OR=0.87). Other indicators of patient satisfaction also revealed lower satisfaction in hospitals with higher percentages of non-UK educated nurses. CONCLUSIONS: Use of non-UK educated nurses in English NHS hospitals is associated with lower patient satisfaction. Importing nurses from abroad to substitute for domestically educated nurses may negatively impact quality of care. PMID- 26634401 TI - Depression and risk of hospitalisations and rehospitalisations for ambulatory care-sensitive conditions in Denmark: a population-based cohort study. AB - OBJECTIVE: Hospitalisations for ambulatory care-sensitive conditions (ACSCs), a group of chronic and acute illnesses considered not to require inpatient treatment if timely and appropriate ambulatory care is received, and early rehospitalisations are common and costly. We sought to determine whether individuals with depression are at increased risk of hospitalisations for ACSCs, and rehospitalisation for the same or another ACSC, within 30 days. DESIGN: National, population-based cohort study. SETTING: Denmark. PARTICIPANTS: 5,049,353 individuals >= 18 years of age between 1 January 2005 and 31 December 2013. MEASUREMENTS: Depression was ascertained via psychiatrist diagnoses in the Danish Psychiatric Central Register or antidepressant prescription redemption from the Danish National Prescription Registry. Hospitalisations for ACSCs and rehospitalisations within 30 days were identified using the Danish National Patient Register. RESULTS: Overall, individuals with depression were 2.35 times more likely to be hospitalised for an ACSC (95% CI 2.32 to 2.37) versus those without depression after adjusting for age, sex and calendar period, and 1.45 times more likely after adjusting for socioeconomic factors, comorbidities and primary care utilisation (95% CI 1.43 to 1.46). After adjusting for ACSC predisposing comorbidity, depression was associated with significantly greater risk of hospitalisations for all chronic (eg, angina, diabetes complications, congestive heart failure exacerbation) and acute ACSCs (eg, pneumonia) compared to those without depression. Compared to those without depression, persons with depression were 1.21 times more likely to be rehospitalised within 30 days for the same ACSC (95% CI 1.18 to 1.24) and 1.19 times more likely to be rehospitalised within 30 days for a different ACSC (95% CI 1.15 to 1.23). CONCLUSIONS: Individuals with depression are at increased risk of hospitalisations for ACSCs, and once discharged are at elevated risk of rehospitalisations within 30 days for ACSCs. PMID- 26634402 TI - Safflower Yellow regulates microglial polarization and inhibits inflammatory response in LPS-stimulated Bv2 cells. AB - Activated microglia, especially polarized M1 cells, produce pro-inflammatory cytokines and free radicals, thereby contributing directly to neuroinflammation and various brain disorders. Given that excessive or chronic neuroinflammation within the central nervous system (CNS) exacerbates neuronal damage, molecules that modulate neuroinflammation are candidates as neuroprotective agents. In this study, we provide evidence that Safflor yellow (SY), the main active component in the traditional Chinese medicine safflower, modulates inflammatory responses by acting directly on BV2 microglia. LPS stimulated BV2 cells to upregulate expression of TLR4-Myd88 and MAPK-NF-kappaB signaling pathways and to release IL 1beta, IL-6, TNF-alpha, and COX-2. However, SY treatment inhibited expression of TLR4-Myd88 and p-38/p-JNK-NF-kappaB, downregulated expression of iNOS, CD16/32, and IL-12, and upregulated CD206 and IL-10. In conclusion, our results demonstrate that SY exerts an anti-inflammatory effect on BV2 microglia, possibly through TLR-4/p-38/p-JNK/NF-kappaB signaling pathways and the conversion of microglia from inflammatory M1 to an anti-inflammatory M2 phenotype. PMID- 26634403 TI - Refractory chronic spontaneous urticaria and permanent atrial fibrillation associated with dental infection: Mere coincidence or something more to it? AB - Controversy surrounds the role of dental infection/inflammation in the oral cavity in chronic spontaneous urticaria (CSU) and atrial fibrillation (AF), which is mainly due to scarce literature in this area. Therefore, this case report and review of literature illustrate a possible association between the acute-phase response (APR) and clinical conditions, such as CSU and dental infection/inflammation of oral cavity and AF.We describe a 36-year-old man with an 8-year history of difficult-to-treat, uncontrolled CSU, co-existent with dental infection/inflammatory processes of oral cavity and permanent atrial fibrillation (AF). In the presented case, the most likely triggering or aggravating/maintaining factor of the symptoms was the inflammation/dental infection of the oral cavity because of rapid reduction of the urticarial symptoms, drug doses, and serum CRP levels after the dental therapy. Dental treatment may have a beneficial effect on the systemic inflammatory response, reducing/normalizing the circulating levels of APR markers. APR activation appears to worsen CSU course, early identification and treatment of infectious/inflammatory foci in the oral cavity would form the mainstay of supportive therapy for CU probably through reduction of the systemic inflammatory burden. APR associated with infectious/inflammatory foci in the oral cavity could be taken into account as a predisposing agents to AF. PMID- 26634404 TI - Dip-in Indicators for Visual Differentiation of Fuel Mixtures Based on Wettability of Fluoroalkylchlorosilane-Coated Inverse Opal Films. AB - We have developed the dip-in indicator based on the inverse opal film (IOF) for visual differentiation of organic liquid mixtures, such as oil/gasoline or ethanol/gasoline fuel mixtures. The IOF consists of a three-dimensional porous structure with a highly ordered periodic arrangement of nanopores. The specularly reflected light at the interface of the nanopores and silica walls contributes to the structural color of the IOF film. This color disappears when the nanopores are infiltrated by a liquid with a similar refractive index to silica. The disappearance of the structural color provides a means to differentiate various liquid fuel mixtures based on their wettability of the nanopores in the IOF-based indicators. For differentiation of various liquid mixtures, we tune the wettability threshold of the indicator in such a way that it is wetted (color disappears) by one liquid but is not wetted by the other (color remains). Although colorimetric differentiation of liquids based on IOF wettability has been reported, differentiation of highly similar liquid mixtures require complicated readout approaches. It is known that the IOF wettability is controlled by multiple surface properties (e.g., oleophobicity) and structural properties (e.g., neck angle and film thickness) of the nanostructure. Therefore, we aim to exploit the combined tuning of these properties for differentiation of fuel mixtures with close compositions. In this study, we have demonstrated that, for the first time, the IOF-based dip-in indicator is able to detect a slight difference in the fuel mixture composition (i.e., 0.4% of oil content). Moreover, the color/no-color differentiation platform is simple, powerful, and easy-to read. This platform makes the dip-in indicator a promising tool for authentication and determination of fuel composition at the point-of-purchase or point-of-use. PMID- 26634405 TI - Vibrational Calculations of Higher-Order Weakly Bound Complexes: The He3,4I2 Cases. AB - The structure and relative stability of higher-order He3,4I2 clusters are investigated by carrying out full-dimensional quantum calculations within the multiconfiguration time-dependent Hartree framework. The full interaction between the I2 molecule and the He atoms is based on analytical three-body ab initio He I2 potentials obtained from high level ab initio calculations plus the He-He interaction. The low-lying minima on the potential surfaces are found to be very close in energy with the He atoms in a ring encircling the dopant for the global minimum structure, while for the local minima one or two of the He atoms prefer the linear arrangements along the I2-axis. Such classical description on the basis of the potential energy landscape is corrected by including anharmonic quantum effects, present in highly floppy systems, by carrying out full dimensional quantum calculations. The potential energy operator was constructed by natural potential fits, while a mode combination scheme was employed to optimize the computational cost of the improved relaxation calculations. The obtained results predict the relative stability of the He3,4I2 isomers at zero temperature and provide benchmark data on binding energies and structural properties of these van der Waals systems. The (2,1) and (2,2), involving two He atoms in the T-shape and one or two He atoms in the linear configurations, respectively, are found to be the most stable isomers, although extremely close in energy with the (3,0) and (4,0) ones as predicted by classical optimizations. Comparison with experimental data on similar systems at low temperatures is also discussed. This analysis indicates once more the importance of quantum delocalization and the need of accurate quantum-mechanical treatments to characterize such doped helium nanosystems. PMID- 26634406 TI - Model Studies on the Antioxidative Effect of Polyphenols in Thermally Treated D Glucose/L-Alanine Solutions with Added Metal Ions. AB - The influence of different polyphenolic compounds (PPs) on the Maillard reaction in a d-glucose/l-alanine model system with or without metal ions was studied under various reaction conditions. At temperatures up to 100 degrees C the PPs showed pro-oxidative effects due to their reducing effects on metal ions. This can be explained by a combined redox cycling mechanism of metals and PPs that promotes oxidation in the Maillard reaction. The antioxidative capacities of the PPs were measured with three different assays and correlated directly with their pro-oxidative effects on d-glucosone formation. The degree of the pro-oxidative effect depended not only on the PPs' reducing potential and their antioxidative ability but also on their concentration, the temperature, and the pH value of the model system. At low pH values and temperatures, the PPs were more stable and therefore showed an increased pro-oxidative tendency. In contrast, some of the used PPs were almost completely degraded at temperatures of 130 degrees C, and the formed polymers were able to complex metal ions. In the absence of these catalyzing ions, the oxidation ratio of d-glucose to d-glucosone was decreased. PMID- 26634407 TI - Auxiliary-Directed Pd-Catalyzed gamma-C(sp(3))-H Bond Activation of alpha Aminobutanoic Acid Derivatives. AB - New bidentate auxiliaries derived from the isoxazole-3-carboxamide and oxazole-4 carboxamide moieties were used for Pd-catalyzed C(sp(3))-H bond activation. The results show that, when placed on a primary amine compound, 5-methylisoxazole-3 carboxamide (MICA) directs Pd-catalyzed activation of inert gamma-C(sp(3))-H bonds for C-C bond formation. Selective and efficient arylation and alkylation of several alpha-aminobutanoic acid derivatives led to various gamma-substituted non natural amino acids. The MICA directing group can be conveniently removed and recovered under very mild conditions. PMID- 26634408 TI - Exposing the Alkanesulfonate Monooxygenase Protein-Protein Interaction Sites. AB - The alkanesulfonate monooxygenase enzymes (SsuE and SsuD) catalyze the desulfonation of diverse alkanesulfonate substrates. The SsuE enzyme is an NADPH dependent FMN reductase that provides reduced flavin to the SsuD monooxygenase enzyme. Previous studies have highlighted the presence of protein-protein interactions between SsuE and SsuD thought to be important in the flavin transfer event, but the putative interaction sites have not been identified. Protected sites on specific regions of SsuE and SsuD were identified by hydrogen-deuterium exchange mass spectrometry. An alpha-helix on SsuD containing conserved charged amino acids showed a decrease in percent deuteration in the presence of SsuE. The alpha-helical region of SsuD is part of an insertion sequence and is adjacent to the active site opening. A SsuD variant containing substitutions of the charged residues showed a 4-fold decrease in coupled assays that included SsuE to provide reduced FMN, but there was no activity observed with an SsuD variant containing a deletion of the alpha-helix under similar conditions. Desulfonation by the SsuD deletion variant was only observed with an increase in enzyme and substrate concentrations. Although activity was observed under certain conditions, there were no protein-protein interactions observed with the SsuD variants and SsuE in pull-down assays and fluorimetric titrations. The results from these studies suggest that optimal transfer of reduced flavin from SsuE to SsuD requires defined protein-protein interactions, but diffusion can occur under specified conditions. A basis is established for further studies to evaluate the structural features of the alkanesulfonate monooxygenase enzymes that promote desulfonation. PMID- 26634409 TI - Enhanced Li-S Batteries Using Amine-Functionalized Carbon Nanotubes in the Cathode. AB - The rechargeable lithium-sulfur (Li-S) battery is an attractive platform for high energy, low-cost electrochemical energy storage. Practical Li-S cells are limited by several fundamental issues, including the low conductivity of sulfur and its reduction compounds with Li and the dissolution of long-chain lithium polysulfides (LiPS) into the electrolyte. We report on an approach that allows high-performance sulfur-carbon cathodes to be designed based on tethering polyethylenimine (PEI) polymers bearing large numbers of amine groups in every molecular unit to hydroxyl- and carboxyl-functionalized multiwall carbon nanotubes. Significantly, for the first time we show by means of direct dissolution kinetics measurements that the incorporation of CNT-PEI hybrids in a sulfur cathode stabilizes the cathode by both kinetic and thermodynamic processes. Composite sulfur cathodes based the CNT-PEI hybrids display high capacity at both low and high current rates, with capacity retention rates exceeding 90%. The attractive electrochemical performance of the materials is shown by means of DFT calculations and physical analysis to originate from three principal sources: (i) specific and strong interaction between sulfur species and amine groups in PEI; (ii) an interconnected conductive CNT substrate; and (iii) the combination of physical and thermal sequestration of LiPS provided by the CNT=PEI composite. PMID- 26634410 TI - Trends in the exploitation of South Atlantic shark populations. AB - Approximately 25% of globally reported shark catches occur in Atlantic pelagic longline fisheries. Strong declines in shark populations have been detected in the North Atlantic, whereas in the South Atlantic the situation is less clear, although fishing effort has been increasing in this region since the late 1970s. We synthesized information on shark catch rates (based on 871,177 sharks caught on 86,492 longline sets) for the major species caught by multiple fleets in the South Atlantic between 1979 and 2011. We complied records from fishing logbooks of fishing companies, fishers, and onboard observers that were supplied to Brazilian institutions. By using exploratory data analysis and literature sources, we identified 3 phases of exploitation in these data (Supporting Information). From 1979 to 1997 (phase A), 5 fleets (40 vessels) fished mainly for tunas. From 1998 to 2008 (phase B), 20 fleets (100 vessels) fished for tunas, swordfishes, and sharks. From 2008 to 2011 (phase C), 3 fleets (30 vessels) fished for multiple species, but restrictive measures were implemented. We used generalized linear models to standardize catch rates and identify trends in each of these phases. Shark catch rates increased from 1979 to 1997, when fishing effort was low, decreased from 1998 to 2008, when fishing effort increased substantially, and remained stable or increased from 2008 to 2011, when fishing effort was again low. Our results indicate that most shark populations affected by longlines in the South Atlantic are currently depleted, but these populations may recover if fishing effort is reduced accordingly. In this context, it is problematic that comprehensive data collection, monitoring, and management of these fisheries ceased after 2012. Concurrently with the fact that Brazil is newly identified by FAO among the largest (and in fastest expansion) shark sub products consumer market worldwide. PMID- 26634413 TI - Factors associated with the effect of pulmonary rehabilitation on physical activity in patients with chronic obstructive pulmonary disease. AB - AIM: Although the effects of pulmonary rehabilitation (PR) have been well defined for chronic obstructive pulmonary disease (COPD), it remains controversial whether PR improves physical activity (PA). The purpose of the present study was to identify factors associated with the effect of PR on PA. METHODS: This was a prospective study of 29 patients with COPD. They underwent pulmonary rehabilitation twice weekly for 12 weeks, and were assessed using the hospital anxiety and depression score, 6-min walk distance (6MWD), and the St. George Respiratory Questionnaire (SGRQ) before and after they underwent PR. The PA of patients was measured by a three-axis accelerometer. Physical activity level (PAL) was calculated by dividing each patient's total energy expenditure by basal metabolic rate. Correlations between changes in PAL after PR and 6MWD, St. George Respiratory Questionnaire, and hospital anxiety and depression score scores, and clinical parameters, including forced expiratory volume in 1 s were determined. RESULTS: 6MWD was significantly increased, but PAL was unchanged after PR. PAL was positively correlated with 6MWD, but not with percent predicted forced expiratory volume in 1 s nor St. George Respiratory Questionnaire scores before PR. The increase in PAL was negatively correlated with changes in hospital anxiety and depression score anxiety and depression scores, but was not correlated with the change in 6MWD. CONCLUSIONS: A PR program for COPD patients improved results of the 6MWD, but not PAL. Increased PAL was associated with improvements in anxiety and depression, but not with increased exercise capacity. Treating the depression and anxiety of patients with COPD might not only reduce emotional distress, but also improve their PAL. Geriatr Gerontol Int 2017; 17: 17 23. PMID- 26634412 TI - Pyrimidine Triazole Thioether Derivatives as Toll-Like Receptor 5 (TLR5)/Flagellin Complex Inhibitors. AB - Protein-protein interactions have been regarded as "undruggable" despite their importance in many biological processes. The complex formed between host toll like receptor 5 (TLR5) and flagellin, a globular protein that is the main component of a bacterial flagellum, plays a vital role in a number of pathogen defenses, immunological diseases and cancers. Through high-throughput screening, we identified two hits with a common pharmacophore, which were used to successfully develop a series of small-molecule probes as novel inhibitors of flagellin binding to TLR5. In a multitude of assays, 4-((4-benzyl-5-(pyridin4yl) 4H-1,2,4-triazol-3-yl)thio)pyrido[3',2':4,5]thieno[3,2-d]pyrimidine (TH1020) was identified as a potent antagonist of TLR5 signaling with promising activity (IC50 =0.85+/-0.12 MUm) and specificity. Furthermore, TH1020 was shown to repress the expression of downstream TNF-alpha signaling pathways mediated by the TLR5/flagellin complex formation. Based on molecular docking simulation, TH1020 is suggested to compete with flagellin and disrupt its association with TLR5. TH1020 provides a much-needed molecular probe for studying this important protein protein interaction and a lead compound for identifying novel therapeutics targeting TLR5. PMID- 26634414 TI - Comprehensive characterization of the effects of ellagic acid and urolithins on colorectal cancer and key-associated molecular hallmarks: MicroRNA cell specific induction of CDKN1A (p21) as a common mechanism involved. AB - SCOPE: Ellagitannins, ellagic acid, and the colonic metabolites urolithins (Uros) exhibit anticancer effects against colon cells, but a comprehensive molecular analysis has not been done. Herein, we used a panel of cell lines to first time evaluate the antiproliferative properties and accompanying molecular responses of two ellagitannin metabolites mixtures mimicking the situation in vivo and of each individual metabolite. METHODS AND RESULTS: We examined cell growth, cell cycle, apoptosis, and the expression of related genes and microRNAs (miRs) in a panel of nonmalignant and malignant colon cell lines. Regardless of the composition, the mixed metabolites similarly inhibited proliferation, induced cycle arrest, and apoptosis. All the metabolites contributed to these effects, but Uro-A, isourolithin A, Uro-C, and Uro-D were more potent than Uro-B and ellagic acid. Despite molecular differences between the cell lines, we discerned relevant changes in key cancer markers and corroborated the induction of CDKN1A (cyclin dependent kinase inhibitor 1A gene (p21, Cip1); encoding p21) as a common step underlying the anticancer properties of Uros. Interestingly, cell-unique downregulation of miR-224 or upregulation of miR-215 was found associated with CDKN1A induction. CONCLUSION: Physiologically relevant mixtures of Uros exert anticancer effects against colon cancer cells via a common CDKN1A upregulatory mechanism. Other associated molecular responses are however heterogeneous and mostly cell-specific. PMID- 26634415 TI - Bringing meaning to user involvement in mental health care planning: a qualitative exploration of service user perspectives. AB - BACKGROUND: Service users wish to be involved in care planning but typically feel marginalized in this process. Qualitative explorations of the barriers and enablers of user involvement in mental health care planning are limited. QUESTION: How is user involvement in care planning conceptualized by service users and how can meaningful involvement be instilled in the care planning process? METHODS: In 2013, we conducted five focus groups (n = 27) and 23 individual interviews with current or recent adult users of secondary care mental health services (n = 27) in England. Eight users participated in both. Data were analysed using Framework Analysis. Results Ten themes emerged from the data: these themes encompassed procedural elements (connection; contribution; currency; care consolidation; and consequence), service user characteristics (capacity and confidence) and professional enablers (consultation; choice; and clarity of expression). Procedural elements were discussed most frequently in service user discourse. DISCUSSION: The process of care planning, centred on the user clinician relationship, is key to user involvement. IMPLICATIONS FOR PRACTICE: Users describe a common model of meaningful involvement in care planning. Their requests, summarized through a 10C framework of care planning involvement, provide clear direction for improving service users satisfaction with care planning and enhancing the culture of services. PMID- 26634416 TI - RETROSPECTIVE EVALUATION OF INTERFRACTION URETERAL MOVEMENT IN DOGS UNDERGOING RADIATION THERAPY TO ELUCIDATE APPROPRIATE SETUP MARGINS. AB - Radiation-induced ureteral damage can result in serious complications (i.e., hydronephrosis). Also, ureters can be included in planning target volume (PTV) such as ureteral invasion of urinary bladder carcinoma. Therefore, knowing the interfractional movement of the ureters is critical for creation of appropriate planning organs at risk (pOAR) and PTV. This retrospective and descriptive study of 17 dogs with genitourinary carcinomas that underwent intensity-modulated, image-guided radiation therapy (IM-IGRT) was conducted to describe the movement and calculate suggested pOAR/PTV expansions at three locations (at the levels of third lumbar vertebra, immediately cranial to vesicoureteral junction [VUJ], and midway between those two) and from two perspectives: during a course of (1) IM IGRT, where position verification is performed using soft tissue registration when the dogs underwent clinical IM-IGRT; (2) radiation therapy whereby position verification is performed using planar radiography with a corresponding bony registration. This registration was performed by fusing the radiation planning computed tomography (CT) and cone-beam CTs using bony landmarks. With soft tissue registration, findings supported the use of larger pOAR expansion (0.7-1.8 cm) for the mid region of the ureters compared to the areas near VUJ (0.7-1.1 cm). With bony registration, findings supported the use of larger pOAR/PTV expansions (1.6-1.7 cm) for dorsal direction bilaterally at areas near VUJ compared to those with soft tissue registration (0.9-1.0 cm). The results of this study should help radiation oncologists use appropriate ureter expansions for specific patient orientations and positioning verification methods. PMID- 26634417 TI - Response to: Hyperkalaemia in heart failure: binding the patient to improved treatment? PMID- 26634418 TI - Chemo- and Regioselective Ethynylation of Tryptophan-Containing Peptides and Proteins. AB - Ethynylation of various tryptophan-containing peptides and a single model protein was achieved using Waser's reagent, 1-[(triisopropylsilyl)ethynyl]-1,2 benziodoxol-3(1 H)-one (TIPS-EBX), under gold(I) catalysis. It was demonstrated by NMR that the ethynylation occurred selectively at the C2-position of the indole ring of tryptophan. Further, MS/MS showed that the tryptophan residues could be modified selectively with ethynyl functionalities even when the tryptophan was present as a part of the protein. Finally, the terminal alkyne was used to label a model peptide with a fluorophore by means of copper-catalyzed click chemistry. PMID- 26634419 TI - Acetylsalicylic Acid Daily vs Acetylsalicylic Acid Every 3 Days in Healthy Volunteers: Effect on Platelet Aggregation, Gastric Mucosa, and Prostaglandin E2 Synthesis. AB - Substantial platelet inhibition was observed 3 days after a single administration of acetylsalicylic acid 81 mg to healthy volunteers. Here we investigate prostaglandin E2 (PGE2 ) antrum concentrations and gastrointestinal symptoms in two treatment groups: one receiving losartan and acetylsalicylic acid every day and the other receiving losartan every day and acetylsalicylic acid every 3 days. Twenty-eight healthy volunteers from both sexes received either 50 mg losartan and acetylsalicylic acid 81 mg daily or 50 mg losartan and acetylsalicylic acid 81 every 3 days with placebo on the other days. Therapy was delivered for 30 days for both groups. Gastric endoscopy was performed before and after treatment period. Biopsies were collected for PGE2 quantification. Platelet function tests were carried out before and during treatment and TXB2 release on platelet rich plasma was measured. The every 3 day low-dose acetylsalicylic acid regimen produced complete inhibition of platelet aggregation compared to the daily treatment. Thromboxane B2 release was substantially abolished for both groups during treatment. There was no significant difference on the endoscopic score of both treatment groups after the 30-day treatment (P = .215). There was over 50% suppression of antrum PGE2 content on volunteers receiving acetylsalicylic acid daily (P = .0016), while for the every 3 day dose regimen there was no significant difference between pre and post-treatment antrum PGE2 dosages (P = .4193). Since PGE2 is involved in gastric healing, we understand that this new approach could be safer and as efficient as the standard daily therapy on a long term basis. PMID- 26634420 TI - Rigid and remodelled: cerebrovascular structure and function after experimental high-thoracic spinal cord transection. AB - High-thoracic or cervical spinal cord injury (SCI) is associated with several critical clinical conditions related to impaired cerebrovascular health, including: 300-400% increased risk of stroke, cognitive decline and diminished cerebral blood flow regulation. The purpose of this study was to examine the influence of high-thoracic (T3 spinal segment) SCI on cerebrovascular structure and function, as well as molecular markers of profibrosis. Seven weeks after complete T3 spinal cord transection (T3-SCI, n = 15) or sham injury (Sham, n = 10), rats were sacrificed for either middle cerebral artery (MCA) structure and function assessments via ex vivo pressure myography, or immunohistochemical analyses. Myogenic tone was unchanged, but over a range of transmural pressures, inward remodelling occurred after T3-SCI with a 40% reduction in distensibility (both P < 0.05), and a 33% reduction in vasoconstrictive reactivity to 5-HT trending toward significance (P = 0.09). After T3-SCI, the MCA had more collagen I (42%), collagen III (24%), transforming growth factor beta (47%) and angiotensin II receptor type 2 (132%), 27% less elastin as well as concurrent increased wall thickness and reduced lumen diameter (all P < 0.05). Sympathetic innervation (tyrosine hydroxylase-positive axon density) and endothelium dependent dilatation (carbachol) of the MCA were not different between groups. This study demonstrates profibrosis and hypertrophic inward remodelling within the largest cerebral artery after high-thoracic SCI, leading to increased stiffness and possibly impaired reactivity. These deleterious adaptations would substantially undermine the capacity for regulation of cerebral blood flow and probably underlie several cerebrovascular clinical conditions in the SCI population. PMID- 26634429 TI - Study of intact virus-like particles of human papillomavirus by capillary electrophoresis. AB - Virus-like particles of human papillomavirus (HPV-VLP), resulting from the self assembly of the capsid proteins (L1 or L1 and L2), have been widely used to study HPV as they are similar to the native virion. Moreover, two prophylactic vaccines, Gardasil((r)) and Cervarix((r)), are based on HPV-VLP L1. Analytical techniques currently used to characterize HPV-VLP, such as SDS-PAGE, Western blot, ELISA, are time-consuming and semiquantitative. In this study, CE was evaluated for the analysis of intact HPV16-VLP. The usefulness of capillary inner wall coating as well as various BGEs, pH, and detergent additives were investigated. Reproducible HPV-VLP analysis in CE was achieved using poly(ethylene oxide)-coated capillary and a BGE containing high salt concentration and low SDS concentration. The developed method enables HPV-VLP detection in less than 10 min (migration times RSD: 1.6%). The identity of HPV VLP peak was confirmed by comparison with a sample obtained from a wild-type baculovirus and with VLP-based vaccine, Gardasil((r)) , after adjuvant dissolution. Finally, we applied the developed methodology to VLP-based vaccines, demonstrating that CE could be successfully used for vaccine quality control. PMID- 26634421 TI - Vinculin controls talin engagement with the actomyosin machinery. AB - The link between extracellular-matrix-bound integrins and intracellular F-actin is essential for cell spreading and migration. Here, we demonstrate how the actin binding proteins talin and vinculin cooperate to provide this link. By expressing structure-based talin mutants in talin null cells, we show that while the C terminal actin-binding site (ABS3) in talin is required for adhesion complex assembly, the central ABS2 is essential for focal adhesion (FA) maturation. Thus, although ABS2 mutants support cell spreading, the cells lack FAs, fail to polarize and exert reduced force on the surrounding matrix. ABS2 is inhibited by the preceding mechanosensitive vinculin-binding R3 domain, and deletion of R2R3 or expression of constitutively active vinculin generates stable force independent FAs, although cell polarity is compromised. Our data suggest a model whereby force acting on integrin-talin complexes via ABS3 promotes R3 unfolding and vinculin binding, activating ABS2 and locking talin into an actin-binding configuration that stabilizes FAs. PMID- 26634430 TI - Hepatic steatosis depresses alpha-1-antitrypsin levels in human and rat acute pancreatitis. AB - Hepatic steatosis (HS) can exacerbate acute pancreatitis (AP). This study aimed to investigate the relation between alpha1-antitrypsin (AAT) and acute pancreatitis when patients have HS. Using proteomic profiling, we identified 18 differently expressed proteins pots in the serum of rats with or without HS after surgical establishment of AP. AAT was found to be one of the significantly down regulated proteins. AAT levels were significantly lower in hepatic steatosis acute pancreatitis (HSAP) than in non-HSAP (NHSAP) (P < 0.001). To explore the clinical significance of these observations, we measured the levels of AAT in the serum of 240 patients with HSAP, NHSAP, fatty liver disease (FLD), or no disease. Compared with healthy controls, serum AAT levels in patients with NHSAP were significantly higher (P < 0.01), while in patients with HSAP serum AAT levels were significantly lower (P < 0.01). Further studies showed that acute physiology and chronic health evaluation (APACHE-II) scores were negatively correlated with serum AAT levels (r = -0.85, P < 0.01). In conclusion, low serum levels of AAT in patients with HSAP are correlated with disease severity and AAT may represent a potential target for therapies aiming to improve pancreatitis. PMID- 26634431 TI - 3D visualization of XFEL beam focusing properties using LiF crystal X-ray detector. AB - Here, we report, that by means of direct irradiation of lithium fluoride a (LiF) crystal, in situ 3D visualization of the SACLA XFEL focused beam profile along the propagation direction is realized, including propagation inside photoluminescence solid matter. High sensitivity and large dynamic range of the LiF crystal detector allowed measurements of the intensity distribution of the beam at distances far from the best focus as well as near the best focus and evaluation of XFEL source size and beam quality factor M(2). Our measurements also support the theoretical prediction that for X-ray photons with energies ~10 keV the radius of the generated photoelectron cloud within the LiF crystal reaches about 600 nm before thermalization. The proposed method has a spatial resolution ~0.4-2.0 MUm for photons with energies 6-14 keV and potentially could be used in a single shot mode for optimization of different focusing systems developed at XFEL and synchrotron facilities. PMID- 26634432 TI - Glycosylation of Dentin Matrix Protein 1 is critical for osteogenesis. AB - Proteoglycans play important roles in regulating osteogenesis. Dentin matrix protein 1 (DMP1) is a highly expressed bone extracellular matrix protein that regulates both bone development and phosphate metabolism. After glycosylation, an N-terminal fragment of DMP1 protein was identified as a new proteoglycan (DMP1 PG) in bone matrix. In vitro investigations showed that Ser(89) is the key glycosylation site in mouse DMP1. However, the specific role of DMP1 glycosylation is still not understood. In this study, a mutant DMP1 mouse model was developed in which the glycosylation site S(89) was substituted with G(89) (S89G-DMP1). The glycosylation level of DMP1 was down-regulated in the bone matrix of S89G-DMP1 mice. Compared with wild type mice, the long bones of S89G DMP1 mice showed developmental changes, including the speed of bone remodeling and mineralization, the morphology and activities of osteocytes, and activities of both osteoblasts and osteoclasts. These findings indicate that glycosylation of DMP1 is a key posttranslational modification process during development and that DMP1-PG functions as an indispensable proteoglycan in osteogenesis. PMID- 26634433 TI - Contribution of human and climate change impacts to changes in streamflow of Canada. AB - Climate change exerts great influence on streamflow by changing precipitation, temperature, snowpack and potential evapotranspiration (PET), while human activities in a watershed can directly alter the runoff production and indirectly through affecting climatic variables. However, to separate contribution of anthropogenic and natural drivers to observed changes in streamflow is non trivial. Here we estimated the direct influence of human activities and climate change effect to changes of the mean annual streamflow (MAS) of 96 Canadian watersheds based on the elasticity of streamflow in relation to precipitation, PET and human impacts such as land use and cover change. Elasticities of streamflow for each watershed are analytically derived using the Budyko Framework. We found that climate change generally caused an increase in MAS, while human impacts generally a decrease in MAS and such impact tends to become more severe with time, even though there are exceptions. Higher proportions of human contribution, compared to that of climate change contribution, resulted in generally decreased streamflow of Canada observed in recent decades. Furthermore, if without contributions from retreating glaciers to streamflow, human impact would have resulted in a more severe decrease in Canadian streamflow. PMID- 26634434 TI - Learning-induced synaptic potentiation in implanted neural precursor cell-derived neurons. AB - Neuronal loss caused by neurodegenerative diseases, traumatic brain injury and stroke results in cognitive dysfunctioning. Implantation of neural stem/precursor cells (NPCs) can improve the brain function by replacing lost neurons. Proper synaptic integration following neuronal differentiation of implanted cells is believed to be a prerequisite for the functional recovery. In the present study, we characterized the functional properties of immortalized neural progenitor HiB5 cells implanted into the rat hippocampus with chemically induced lesion. The implanted HiB5 cells migrated toward CA1 pyramidal layer and differentiated into vGluT1-positive glutamatergic neurons with morphological and electrophysiological properties of endogenous CA1 pyramidal cells. Functional synaptic integration of HiB5 cell-derived neurons was also evidenced by immunohistochemical and electrophysiological data. Lesion-caused memory deficit was significantly recovered after the implantation when assessed by inhibitory avoidance (IA) learning. Remarkably, IA learning preferentially produced long-term potentiation (LTP) at the synapses onto HiB5 cell-derived neurons, which occluded paring protocol-induced LTP ex vivo. We conclude that the implanted HiB5 cell-derived neurons actively participate in learning process through LTP formation, thereby counteracting lesion-mediated memory impairment. PMID- 26634435 TI - Aquaporin7 plays a crucial role in tolerance to hyperosmotic stress and in the survival of oocytes during cryopreservation. AB - Hyperosmotic stress may induce apoptosis of different cells. However, oocytes show tolerance to osmotic stress during cryopreservation by vitrification, which is an assisted reproductive technique. The underlying mechanism is still not understood. Here, we demonstrated that hyperosmosis produced by high concentrations of cryoprotectants, including DMSO, ethylene glycol and sucrose, significantly upregulated the protein levels of aquaporin (AQP) 7, but not AQP3 and AQP9, in mouse oocytes. Knockdown of AQP7 expression by siRNA-injection significantly reduced the survival of oocytes after vitrification. In oocytes, AQP7 was shown to bind with F-actin, a protein involved in almost all biological events. Moreover, we found that hyperosmosis could upregulate the phosphorylation levels of CPE-binding protein (CPEB) and Aurora A. Inhibition of the PI3K and PKC pathways blocked the hyperosmosis-induced upregulation of AQP7 and the phosphorylation of CPEB and Aurora A in oocytes. In conclusion, hyperosmosis could upregulate the expression of AQP7 via Aurora A/CPEB phosphorylation mediated by the PI3K and PKC pathways, and upregulation of AQP7 plays an important role in improving of tolerance to hyperosmotic stress and survival of oocytes during cryopreservation by vitrification. PMID- 26634437 TI - Systematic pan-cancer analysis of tumour purity. AB - The tumour microenvironment is the non-cancerous cells present in and around a tumour, including mainly immune cells, but also fibroblasts and cells that comprise supporting blood vessels. These non-cancerous components of the tumour may play an important role in cancer biology. They also have a strong influence on the genomic analysis of tumour samples, and may alter the biological interpretation of results. Here we present a systematic analysis using different measurement modalities of tumour purity in >10,000 samples across 21 cancer types from the Cancer Genome Atlas. Patients are stratified according to clinical features in an attempt to detect clinical differences driven by purity levels. We demonstrate the confounding effect of tumour purity on correlating and clustering tumours with transcriptomics data. Finally, using a differential expression method that accounts for tumour purity, we find an immunotherapy gene signature in several cancer types that is not detected by traditional differential expression analyses. PMID- 26634436 TI - Clinical correlation between HBV infection and concomitant bacterial infections. AB - Bacterial infections are common in patients suffering viral hepatitis and critical for prognosis. However, any correlation between HBV and concomitant bacterial infections is not well characterized. A retrospective study was conducted from Jan 2012 to Jan 2014 on 1333 hospitalized patients infected with bacteria. Among them, 491 HBV-infected patients were co-infected with E. coli (268), S. aureus (61), P. aeruginosa (64) or K. pneumoniae (98). A group of 300 complication-free chronically HBV-infected patients were controls. We found that HBV DNA levels were elevated in patients with each of the bacterial infections (all P < 0.05). ALT and HBeAg were strong determinants of high HBV DNA concentration. Patterns of determinants varied in infections by Gram-positive and Gram-negative bacteria. Patients with HBV DNA >= 2000 IU/mL had higher rates of all four concomitant bacterial infections (all P < 0.001). All types of strains isolated from HBV-positive patients showed less resistance to tested antimicrobials. The HBV DNA serum concentrations were inversely correlated to the number of ineffective antimicrobials in E. coli, P. aeruginosa and K. pneumoniae infections (P = 0.022, 0.017 and 0.016, respectively), but not S. aureus (P = 0.194). In conclusion, bacterial infections are associated with a high level of HBV replication, which, in turn, has a significant positive impact on bacterial resistance to antimicrobials. These correlations vary between Gram-negative and Gram-positive bacteria. PMID- 26634438 TI - Dynamical excitation of the tropical Pacific Ocean and ENSO variability by Little Ice Age cooling. AB - Tropical Pacific Ocean dynamics during the Medieval Climate Anomaly (MCA) and the Little Ice Age (LIA) are poorly characterized due to a lack of evidence from the eastern equatorial Pacific. We reconstructed sea surface temperature, El Nino Southern Oscillation (ENSO) activity, and the tropical Pacific zonal gradient for the past millennium from Galapagos ocean sediments. We document a mid-millennium shift (MMS) in ocean-atmosphere circulation around 1500-1650 CE, from a state with dampened ENSO and strong zonal gradient to one with amplified ENSO and weak gradient. The MMS coincided with the deepest LIA cooling and was probably caused by a southward shift of the intertropical convergence zone. The peak of the MCA (900-1150 CE) was a warm period in the eastern Pacific, contradicting the paradigm of a persistent La Nina pattern. PMID- 26634439 TI - Cytoplasmic protein aggregates interfere with nucleocytoplasmic transport of protein and RNA. AB - Amyloid-like protein aggregation is associated with neurodegeneration and other pathologies. The nature of the toxic aggregate species and their mechanism of action remain elusive. Here, we analyzed the compartment specificity of aggregate toxicity using artificial beta-sheet proteins, as well as fragments of mutant huntingtin and TAR DNA binding protein-43 (TDP-43). Aggregation in the cytoplasm interfered with nucleocytoplasmic protein and RNA transport. In contrast, the same proteins did not inhibit transport when forming inclusions in the nucleus at or around the nucleolus. Protein aggregation in the cytoplasm, but not the nucleus, caused the sequestration and mislocalization of proteins containing disordered and low-complexity sequences, including multiple factors of the nuclear import and export machinery. Thus, impairment of nucleocytoplasmic transport may contribute to the cellular pathology of various aggregate deposition diseases. PMID- 26634440 TI - Fetal liver hematopoietic stem cell niches associate with portal vessels. AB - Whereas the cellular basis of the hematopoietic stem cell (HSC) niche in the bone marrow has been characterized, the nature of the fetal liver niche is not yet elucidated. We show that Nestin(+)NG2(+) pericytes associate with portal vessels, forming a niche promoting HSC expansion. Nestin(+)NG2(+) cells and HSCs scale during development with the fractal branching patterns of portal vessels, tributaries of the umbilical vein. After closure of the umbilical inlet at birth, portal vessels undergo a transition from Neuropilin-1(+)Ephrin-B2(+) artery to EphB4(+) vein phenotype, associated with a loss of periportal Nestin(+)NG2(+) cells and emigration of HSCs away from portal vessels. These data support a model in which HSCs are titrated against a periportal vascular niche with a fractal like organization enabled by placental circulation. PMID- 26634442 TI - Graphene Distributed Amplifiers: Generating Desirable Gain for Graphene Field Effect Transistors. AB - Ever since its discovery, graphene bears great expectations in high frequency electronics due to its irreplaceably high carrier mobility. However, it has long been blamed for the weakness in generating gains, which seriously limits its pace of development. Distributed amplification, on the other hand, has successfully been used in conventional semiconductors to increase the amplifiers' gain bandwidth product. In this paper, distributed amplification is first applied to graphene. Transmission lines phase-synchronize paralleled graphene field-effect transistors (GFETs), combining the gain of each stage in an additive manner. Simulations were based on fabricated GFETs whose fT ranged from 8.5 GHz to 10.5 GHz and fmax from 12 GHz to 14 GHz. A simulated four-stage graphene distributed amplifier achieved up to 4 dB gain and 3.5 GHz bandwidth, which could be realized with future IC processes. A PCB level graphene distributed amplifier was fabricated as a proof of circuit concept. PMID- 26634441 TI - Structure and membrane remodeling activity of ESCRT-III helical polymers. AB - The endosomal sorting complexes required for transport (ESCRT) proteins mediate fundamental membrane remodeling events that require stabilizing negative membrane curvature. These include endosomal intralumenal vesicle formation, HIV budding, nuclear envelope closure, and cytokinetic abscission. ESCRT-III subunits perform key roles in these processes by changing conformation and polymerizing into membrane-remodeling filaments. Here, we report the 4 angstrom resolution cryogenic electron microscopy reconstruction of a one-start, double-stranded helical copolymer composed of two different human ESCRT-III subunits, charged multivesicular body protein 1B (CHMP1B) and increased sodium tolerance 1 (IST1). The inner strand comprises "open" CHMP1B subunits that interlock in an elaborate domain-swapped architecture and is encircled by an outer strand of "closed" IST1 subunits. Unlike other ESCRT-III proteins, CHMP1B and IST1 polymers form external coats on positively curved membranes in vitro and in vivo. Our analysis suggests how common ESCRT-III filament architectures could stabilize different degrees and directions of membrane curvature. PMID- 26634443 TI - An observational study of the quality of care for chronic kidney disease: a Buffalo and Albany, New York metropolitan area study. AB - BACKGROUND: The database of a major regional health insurer was employed to identify the number and frequency of covered patients with chronic kidney disease (CKD). We then examined the characteristics of their care as defined, in part, by the frequency of physician visits and specialty referral, the characteristics of laboratory testing and total costs as indices of the quality of care of the subject population. METHODS: This retrospective, cross-sectional study analyzed insurance claims, laboratory results and medication prescription data. Patients with two estimated glomerular filtration rate readings below 60 ml/min/1.73 m(2) (n = 20,388) were identified and classified by CKD stage. RESULTS: The prevalence of CKD stages 3a and above was 12 %. Vascular comorbidities were common with prevalence increasing steadily from stage 3a through stage 5. Only 55.6 % of stage 4 CKD patients had claims for nephrology visits within one year of their index date. Fifty-nine percent of patients had claims for renin-angiotensin system (RAS) blockers. Twenty-five percent of patients in stage 3a CKD filled a prescription for non-steroidal anti-inflammatory drugs. Fifty-two percent of patients who developed end-stage renal disease received their first dialysis treatment as inpatients. CONCLUSIONS: The pattern of medical practice observed highlights apparent deficiencies in the care of CKD patients including inappropriate medication use, delayed nephrology referral, and a lack of preparation for dialysis. This study shows the potential value of using large patient databases available through insurers to assess and likely improve regional CKD care. PMID- 26634444 TI - Metabolomic profiles delineate mycolactone signature in Buruli ulcer disease. AB - Infection of human skin with Mycobacterium ulcerans, the causative agent of Buruli ulcer, is associated with the systemic diffusion of a bacterial macrolide named mycolactone. Patients with progressive disease show alterations in their serum proteome, likely reflecting the inhibition of secreted protein production by mycolactone at the cellular level. Here, we used semi-quantitative metabolomics to characterize metabolic perturbations in serum samples of infected individuals, and human cells exposed to mycolactone. Among the 430 metabolites profiled across 20 patients and 20 healthy endemic controls, there were significant differences in the serum levels of hexoses, steroid hormones, acylcarnitines, purine, heme, bile acids, riboflavin and lysolipids. In parallel, analysis of 292 metabolites in human T cells treated or not with mycolactone showed alterations in hexoses, lysolipids and purine catabolites. Together, these data demonstrate that M. ulcerans infection causes systemic perturbations in the serum metabolome that can be ascribed to mycolactone. Of particular importance to Buruli ulcer pathogenesis is that changes in blood sugar homeostasis in infected patients are mirrored by alterations in hexose metabolism in mycolactone-exposed cells. PMID- 26634445 TI - Effects of the N terminus of mouse DNA polymerase kappa on the bypass of a guanine-benzo[a]pyrenyl adduct. AB - DNA polymerase kappa (Polkappa), one of the typical member of the Y-family DNA polymerases, has been demonstrated to bypass the 10S(+)-trans-anti-benzo[a]pyrene diol epoxide-N(2)-deoxyguanine adducts (BPDE-dG) efficiently and accurately. A large structural gap between the core and little finger as well as an N-clasp domain are essential to its unique translesion capability. However, whether the extreme N-terminus of Polkappa is required for its activity is unclear. In this work, we constructed two mouse Polkappa deletions, which have either a catalytic core (mPolkappa1-516) or a core without the first 21-residues (mPolkappa22-516), and tested their activities in the replication of normal and BPDE-DNA. These two Polkappa deletions are nearly as efficient as the full length protein (Polkappa1 852) in normal DNA synthesis. However, steady-state kinetics reveals a significant reduction in efficiency of dCTP incorporation opposite the lesion by Polkappa22-516, along with increased frequencies for misinsertion compared with Polkappa1-852 The next nucleotide insertion opposite the template C immediately following the BPDE-dG was also examined, and the bypass differences induced by deletions were highlighted in both insertion and extension step. We conclude that the extreme N-terminal part of Polkappa is required for the processivity and fidelity of Polkappa during translesion synthesis of BPDE-dG lesions. PMID- 26634446 TI - Limitation of tuning the antibody-antigen reaction by changing the value of pH and its consequence for hyperthermia. AB - Distribution of the isoelectric point (pI) was calculated for the hypervariable regions of Fab fragments of the antibody molecules, which structure is annotated in the structural antibody database SabDab. The distribution is consistent with the universal for all organisms dividing the proteome into two sets of acidic and basic proteins. It shows the additional fine structure in a form of the narrow sized peaks of pI values. This is an explanation why a small change of the environmental pH can have a strong effect on the antibody-antigen affinity. To show this, a typical enzyme-linked immunospecific assay experiment for testing the reaction of goat anti-human IgA antibodies with human IgA immunoglobulins of saliva as antigens was modified in such a way that Fe3O4magnetic nanoparticles were added to PBS buffer. The magnetic nanoparticles were remotely heated by the radio frequency magnetic field providing the local change of temperature and pH. It was observed that short times of the heating were significantly increasing the antibody-antigen binding strength while it was not the case for a longer time. The finding discussed in the study can be useful for biopharmaceuticals using antibodies, the immunoassay techniques as well as for control over the use of hyperthermia. PMID- 26634448 TI - Colloidal crystal based plasma polymer patterning to control Pseudomonas aeruginosa attachment to surfaces. AB - Biofilm formation on medical implants and subsequent infections are a global problem. A great deal of effort has focused on developing chemical contrasts based on micro- and nanopatterning for studying and controlling cells and bacteria at surfaces. It has been known that micro- and nanopatterns on surfaces can influence biomolecule adsorption, and subsequent cell and bacterial adhesion. However, less focus has been on precisely controlling patterns to study the initial bacterial attachment mechanisms and subsequently how the patterning influences the role played by biomolecular adsorption on biofilm formation. In this work, the authors have used colloidal self-assembly in a confined area to pattern surfaces with colloidal crystals and used them as masks during allylamine plasma polymer (AAMpp) deposition to generate highly ordered patterns from the micro- to the nanoscale. Polyethylene glycol (PEG)-aldehyde was grafted to the plasma regions via "cloud point" grafting to prevent the attachment of bacteria on the plasma patterned surface regions, thereby controlling the adhesive sites by choice of the colloidal crystal morphology. Pseudomonas aeruginosa was chosen to study the bacterial interactions with these chemically patterned surfaces. Scanning electron microscope, x-ray photoelectron spectroscopy (XPS), atomic force microscopy, and epifluorescence microscopy were used for pattern characterization, surface chemical analysis, and imaging of attached bacteria. The AAMpp influenced bacterial attachment because of the amine groups displaying a positive charge. XPS results confirm the successful grafting of PEG on the AAMpp surfaces. The results showed that PEG patterns can be used as a surface for bacterial patterning including investigating the role of biomolecular patterning on bacterial attachment. These types of patterns are easy to fabricate and could be useful in further applications in biomedical research. PMID- 26634447 TI - Intestinal M cells. AB - We have an enormous number of commensal bacteria in our intestine, moreover, the foods that we ingest and the water we drink is sometimes contaminated with pathogenic microorganisms. The intestinal epithelium is always exposed to such microbes, friend or foe, so to contain them our gut is equipped with specialized gut-associated lymphoid tissue (GALT), literally the largest peripheral lymphoid tissue in the body. GALT is the intestinal immune inductive site composed of lymphoid follicles such as Peyer's patches. M cells are a subset of intestinal epithelial cells (IECs) residing in the region of the epithelium covering GALT lymphoid follicles. Although the vast majority of IEC function to absorb nutrients from the intestine, M cells are highly specialized to take up intestinal microbial antigens and deliver them to GALT for efficient mucosal as well as systemic immune responses. I will discuss recent advances in our understanding of the molecular mechanisms of M-cell differentiation and functions. PMID- 26634449 TI - Estimation of indices of health service readiness with a principal component analysis of the Tanzania Service Provision Assessment Survey. AB - BACKGROUND: Service Provision Assessment (SPA) surveys have been conducted to gauge primary health care and family planning clinical readiness throughout East and South Asia as well as sub-Saharan Africa. Intended to provide useful descriptive information on health system functioning to supplement the Demographic and Health Survey data, each SPA produces a plethora of discrete indicators that are so numerous as to be impossible to analyze in conjunction with population and health survey data or to rate the relative readiness of individual health facilities. Moreover, sequential SPA surveys have yet to be analyzed in ways that provide systematic evidence that service readiness is improving or deteriorating over time. METHODS: This paper presents an illustrative analysis of the 2006 Tanzania SPA with the goal of demonstrating a practical solution to SPA data utilization challenges using a subset of variables selected to represent the six building blocks of health system strength identified by the World Health Organization (WHO) with a focus on system readiness to provide service. Principal Components Analytical (PCA) models extract indices representing common variance of readiness indicators. Possible uses of results include the application of PCA loadings to checklist data, either for the comparison of current circumstances in a locality with a national standard, for the ranking of the relative strength of operation of clinics, or for the estimation of trends in clinic service quality improvement or deterioration over time. RESULTS: Among hospitals and health centers in Tanzania, indices representing two components explain 32% of the common variance of 141 SPA indicators. For dispensaries, a single principal component explains 26% of the common variance of 86 SPA indicators. For hospitals/HCs, the principal component is characterized by preventive measures and indicators of basic primary health care capabilities. For dispensaries, the principal component is characterized by very basic newborn care as well as preparedness for delivery. CONCLUSIONS: PCA of complex facility survey data generates composite scale coefficients that can be used to reduce indicators to indices for application in comparative analyses of clinical readiness, or for multi-level analysis of the impact of clinical capability on health outcomes or on survival. PMID- 26634450 TI - Enzyme mechanism prediction: a template matching problem on InterPro signature subspaces. AB - BACKGROUND: We recently reported that one may be able to predict with high accuracy the chemical mechanism of an enzyme by employing a simple pattern recognition approach: a k Nearest Neighbour rule with k = 1 (k1NN) and 321 InterPro sequence signatures as enzyme features. The nearest-neighbour rule is known to be highly sensitive to errors in the training data, in particular when the available training dataset is small. This was the case in our previous study, in which our dataset comprised 248 enzymes annotated against 71 enzymatic mechanism labels from the MACiE database. In the current study, we have carefully re-analysed our dataset and prediction results to "explain" why a high variance k1NN rule exhibited such remarkable classification performance. RESULTS: We find that enzymes with different chemical mechanism labels in this dataset reside in barely overlapping subspaces in the feature space defined by the 321 features selected. These features contain the appropriate information needed to accurately classify the enzymatic mechanisms, rendering our classification problem a basic look-up exercise. This observation dovetails with the low misclassification rate we reported. CONCLUSION: Our results provide explanations for the "anomaly"-a basic nearest-neighbour algorithm exhibiting remarkable prediction performance for enzymatic mechanism despite the fact that the feature space was large and sparse. Our results also dovetail well with another finding we reported, namely that InterPro signatures are critical for accurate prediction of enzyme mechanism. We also suggest simple rules that might enable one to inductively predict whether a novel enzyme possesses any of our 71 predefined mechanisms. PMID- 26634451 TI - DHOEM: a statistical simulation software for simulating new markers in real SNP marker data. AB - BACKGROUND: Numerous simulation tools based on specific assumptions have been proposed to simulate populations. Here we present a simulation tool named DHOEM (densification of haplotypes by loess regression and maximum likelihood) which is free from population assumptions and simulates new markers in real SNP marker data. The main objective of DHOEM is to generate a new population, which incorporates real and simulated SNP by statistical learning from an initial population, which match the realized features of the latter. RESULTS: To demonstrate DHOEM's abilities, we used a sample of 704 haplotypes for 12 chromosomes with 8336 SNP from a synthetic population, used for breeding upland rice in Latin America. The distributions of allele frequencies, pairwise SNP LD coefficients and data structures, before and after marker densification of the associated marker data set, were shown to be in relatively good agreement at moderate degrees of marker densification. DHOEM is a user-friendly tool that allows the user to specify the level of marker density desired, with a user defined minor allele frequency (MAF) limit, which is produced in a reasonable computation time. CONCLUSIONS: DHOEM is a user-friendly and useful tool for simulation and methodological studies in quantitative genetics and breeding. PMID- 26634452 TI - The use of corticosteroids in patients with COPD or asthma does not decrease lung squamous cell carcinoma. AB - BACKGROUND: Asthma and COPD (chronic obstructive pulmonary disease) lead to persistent airway inflammation and are associated with lung cancer. The objective of the study was to assess the relationship between inhaled (ICS) and oral corticosteroid (OCS) use, and risk of lung squamous cell carcinoma (SqCC). METHODS: This study was a nested case-control study. Patients with newly diagnosed asthma or COPD between 2003 and 2010 were identified from the National Health Insurance Database. Cases were defined as patients diagnosed with SqCC after enrollment. For each case, four control individuals who were randomly matched for sex and age and date diagnosis of asthma or COPD were selected. RESULTS: From the 1,672,455 eligible participants, 793 patients with SqCC were matched with 3,172 controls. The odds ratios (ORs) of SqCC in men who received high and low-dose ICS were 2.18 (95 %CI, 1.56-3.04) and 1.77 (1.22-2.57), respectively. Similarly, the ORs were 1.46 (95 %CI, 1.16-1.84) and 1.55 (95 %CI, 1.22-1.98) for men who were placed on low and high dose OCS. However, there was no significant association between cumulative ICS and/or OCS and risk of SqCC in women. Recent dose increase in corticosteroid was significantly associated with risk of SqCC. Specifically, among men, the ORs for SqCC were 8.08 (95 %CI, 3.22 20.30) for high-dose ICS + OCS, 4.49 (95 % CI, 2.05-9.85) for high-dose ICS, and 3.54 (95 % CI, 2.50-5.01) for high-dose OCS treatments, respectively. The OR for SqCC in women who received high-dose OCS was 6.72 (95 %CI, 2.69-16.81). CONCLUSION: Corticosteroid use did not decrease SqCC in patients with asthma or COPD. Recent dose increase in corticosteroids was associated with SqCC. PMID- 26634453 TI - Botulinum neurotoxin type A in the treatment of classical Trigeminal Neuralgia (BoTN): study protocol for a randomized controlled trial. AB - BACKGROUND: Trigeminal neuralgia is characterized by paroxysmal facial pain attacks. Adequate prophylactic drug therapy is often limited by the lack of efficacy and intolerance due to central nervous system side effects. Subcutaneous injections of botulinum toxin type A are a promising treatment option for patients with unsatisfactory response to drug therapy or neurosurgical intervention. Its effects are expected to last for at least 3 months, so it could be a potential long-term treatment. This is the study protocol of a prospective, placebo-controlled, double blind clinical trial investigating the add-on therapy of subcutaneous administration of botulinum toxin type A injections to standard treatment in therapy-refractory classical trigeminal neuralgia. METHODS AND DESIGN: BoTN is a prospective, double blind, placebo-controlled trial with a randomized withdrawal design in which a single blind phase is followed by a double blind phase (see also Methods and design). Eligible patients with classical trigeminal neuralgia who are otherwise refractory to medical and neurosurgical treatment will receive subcutaneous injections of botulinum toxin type A into injection sites of the affected trigeminal branch. In the first phase all patients will receive botulinum toxin type A in a single blinded intervention. Twelve weeks later therapy responders will be allocated to the verum or placebo (saline) arm in a double blind, randomized manner. These injections will be performed at the same sites as the first injections. This trial will be conducted in a tertiary outpatient clinic specialized in the treatment of headache and facial pain. There will be three investigators performing the injections who are experienced in the treatment of headache and facial pain and trained in botulinum toxin type A injections. DISCUSSION: BoTN is designed to assess the efficacy and safety of subcutaneous botulinum toxin type A injections in addition to standard prophylactic treatment in therapy-refractory trigeminal neuralgia. TRIAL REGISTRATION NUMBER: EU Clinical Trials Register: EudraCT-No: 2014-001959-24 https://www.clinicaltrialsregister.eu/ctr search/rest/download/trial/2014-001959-24/DE Date of trial registration 26 August 2014. PMID- 26634454 TI - Molecular cloning of Peking duck Toll-like receptor 3 (duTLR3) gene and its responses to reovirus infection. AB - BACKGROUND: Toll-like receptors (TLRs) play an important role in detecting pathogen-associated molecular patterns (PAMPs). Among the TLRs, TLR3 is involved in the recognition of double-stranded RNA. This study was designed to explore the relationship between duTLR3 and duck reovirus (DRV) infection. METHODS: In this study, we cloned and performed a molecular characterization of the complete sequence of Peking duck TLR3 (duTLR3). The expression level of duTLR3 was also determined, along with the relative levels of Mx and IFN-alpha mRNA after DRV infection. RESULTS: The duTLR3 gene is 2776-bp long and encodes an 895-amino-acid long protein. Sequence analysis of the product revealed the complete transcript of Peking duck TLR3, including the 88-bp 5'UTR, the 2688-bp coding sequence (ORF), and the 76-bp 3'UTR and poly(A) tail. DuTLR3 was found to share a high amino acid sequence similarity with TLR3 from Jing ding duck (99.6 %), Muscovy duck (97.1 %) and chicken (86.3 %). Additionally, the tissue distribution of duTLR3 suggested that it was abundantly expressed in various tissues, especially in the trachea, esophagus and pancreatic gland. Duck reovirus (DRV) infection resulted in high mRNA expression levels of duTLR3 in the spleen, liver, lung and brain. CONCLUSION: These results suggest that duTLR3 may play an important role in anti-viral defense mechanisms. PMID- 26634455 TI - Molecular cloning, polymorphisms, and expression analysis of the RERG gene in indigenous Chinese goats. AB - The current study aimed to investigate the coding sequence, polymorphisms, and expression of the RERG gene in indigenous Chinese goats. cDNA of RERG, obtained through reverse transcription PCR was analyzed using bioinformatic techniques. Polymorphisms in the exon regions of the RERG gene were identified and their associations with growth traits in three varieties of indigenous Chinese goats were investigated. Expression of the RERG gene in three goat breeds of the same age was detected using real-time quantitative PCR. The results revealed that the cDNA of RERG, which contained a complete open reading frame of 20-620 bp, was 629 bp in length. The associated accession numbers in GenBank are JN672576, JQ917222, and JN580309 for the QianBei Ma goat, the GuiZhou white goat, and the GuiZhou black goat, respectively. Four consistent SNP sites were found in the exon regions of the RERG gene for the three goat breeds. mRNA expression of the RERG gene differed between different tissues in adult goats of same age. The highest expression was observed in lung and spleen tissues, while the lowest expression was recorded in thymus gland tissue. In addition, the expression of the RERG gene in the muscle of Guizhou white goat, GuiZhou black goat, and QianBei Ma goat decreased sequentially. Our results lay the foundations for further investigation into the role of the RERG gene in goat growth traits. PMID- 26634456 TI - Technological value of SPECT/CT fusion imaging for the diagnosis of lower gastrointestinal bleeding. AB - The aim of this study was to assess the clinical value of diagnosing and locating lower gastrointestinal (GI) bleeding using single photon emission computed tomography (SPECT)/computed tomography (CT) fusion imaging with 99mTc labeled red blood cells ((99m)Tc-RBC). Fifty-six patients with suspected lower GI bleeding received a preoperative intravenous injection of (99m)Tc-RBC and each underwent planar, SPECT/CT imaging of the lower abdominal region. The location and path of lower GI bleeding were diagnosed by contrastive analysis of planar and SPECT/CT fusion imaging. Among the 56 patients selected, there were abnormalities in concentrated radionuclide activity with planar imaging in 50 patients and in SPECT/CT fusion imaging in 52 patients. Moreover, bleeding points that were coincident with the surgical results were evident with planar imaging in 31 patients and with SPECT/CT fusion imaging in 48 patients. The diagnostic sensitivity of planar imaging and SPECT/CT fusion imaging were 89.3% (50/56) and 92.9% (52/56), respectively, and the difference was not statistically significant (chi(2) = 0.11, P > 0.05). The corresponding positional accuracy values were 73.8% (31/42) and 92.3% (48/52), and the difference was statistically significant (chi(2) = 4.63, P < 0.05). (99m)Tc- RBC SPECT/CT fusion imaging is an effective, simple, and accurate method that can be used for diagnosing and locating lower GI bleeding. PMID- 26634457 TI - Genetic association of productive and reproductive traits with stayability in Nellore cattle: analysis using Bayesian models. AB - We evaluated the genetic association of growth traits [weight adjusted to 205 days of age (W205), 365 days of age (W365), and 550 days of age (W550); weight gain between 205 days of age and 365 days of age (WG1) and between 365 days of age and 550 days of age (WG2)] and reproductive traits [age at first calving (AFC); first calving interval (FCI)] with stayability in the herd (STAY), using Bayesian inference in linear and threshold models. We defined STAY as the probability of a cow calving three or more times before the age of 76 months, given that she had calved at least once. We assigned binary codes (0, failure; 1, success) to each female. We used a sire model for analysis and formed different contemporary groups for the investigated traits. We analyzed the results by applying a two-trait sire model that included STAY (threshold trait) and linear traits (W205, W365, W550, WG1, WG2, AFC, and FCI). We used Gibbs sampling to estimate variance components and heritabilities. In all the analyses, we found that the mean heritability estimates for STAY were of moderate magnitude (0.20 0.25). The mean heritabilities for W205, W365, W550, WG1, WG2, AFC, and FCI were 0.20, 0.23, 0.39, 0.08, 0.14, 0.12, and 0.11, respectively. We observed wide variation in the posterior distributions of genetic correlations; however, with the exception of those obtained for the reproductive traits, the mean estimates were of low magnitude. Selection for WG2 can results in favorable correlated response in STAY. PMID- 26634458 TI - Multidrug resistance gene (MDR1) polymorphisms may not be directly associated with response to imatinib in chronic myeloid leukemia. AB - Our study aimed to investigate the association between multidrug resistance (MDR1) gene polymorphisms and the response to imatinib (IM) in chronic myeloid leukemia (CML). An electronic databases in PubMed, Cochrane Library, Wanfang, China National Knowledge Infrastructure, and VIP were searched using combinations of keywords relating to MDR1 polymorphisms and the response to IM in CML. Studies retrieved from database searches were screened using stringent inclusion and exclusion criteria. The Comprehensive Meta-analysis 2.0 software was utilized for all statistical analyses. In total, 186 studies were initially retrieved, and 10 studies, involving 987 CML patients, were eventually included in this meta analysis. Results of our study revealed no significant associations between MDR1 rs1045642, rs1128503, and rs2032582 polymorphisms and major molecular response and complete molecular response in CML patients. Significant differences were observed in the genotype frequencies of MDR1 rs1128503 under homozygous, heterozygous, and recessive models, between CML patients sensitive and resistant to IM. A significant difference in genotype frequencies of MDR1 rs2032582 was also observed under allele, homozygous, heterozygous, and recessive models between CML patients sensitive and resistant to IM. In conclusion, based on our meta-analysis, the MDR1 polymorphisms, rs1045642, rs1128503, and rs2032582, are not directly correlated with the curative effect of IM treatment of CML patients. PMID- 26634459 TI - Leptin receptor expression and Gln223Arg polymorphism as prognostic markers in oral and oropharyngeal cancer. AB - The leptin gene product is released into the blood stream, passes through the blood-brain barrier, and finds the leptin receptor (LEPR) in the central nervous system. This hormone regulates food intake, hematopoiesis, inflammation, immunity, differentiation, and cell proliferation. The LEPR Gln223Arg polymorphism has been reported to alter receptor function and expression, both of which have been related with prognostics in several tumor types. Furthermore, several studies have shown a relationship between the Gln223Arg polymorphism and tumor development, and its role in oral and oropharyngeal squamous cell carcinoma is now well understood. In this study, 315 DNA samples were used for LEPR Gln223Arg genotyping and 87 primary oral and oropharyngeal squamous cell carcinomas were used for immunohistochemical expression analysis, such that a relationship between these and tumor development and prognosis could be established. Homozygous LEPR Arg223 was found to be associated with a 2-fold reduction in oral and oropharyngeal cancer risk. In contrast, the presence of the Arg223 allele in tumors was associated with worse disease-free and disease specific survival. Low LEPR expression was found to be an independent risk factor, increasing the risk for lymph node metastasis 4-fold. In conclusion, the Gln223Arg polymorphism and LEPR expression might be valuable markers for oral and oropharyngeal cancer, suggesting that LEPR might serve as a potential target for future therapies. PMID- 26634460 TI - Targeting exogenous GDNF gene to the bovine somatic cell beta-casein locus for the production of transgenic bovine animals. AB - Considerable attention is currently being directed toward methods for producing recombinant human proteins in the mammary glands of genetically modified transgenic livestock. However, the expression of inserted genes in transgenic animals is variable and often very low because of the randomness of the site of transgene integration. One possible strategy to avoid the expression problem associated with random integration is to use site-specific integration by targeting integration to a high expression locus and, thereby, to improve expression of the transferred gene. In the present study, we focused on glial cell line-derived neurotrophic factor (GDNF), a novel type of neurotrophic factor first cloned in 1993. Research has shown that GDNF may have potential applications in the treatment of Parkinson's disease and other diseases of the central nervous system since it acts as a protective factor for central dopaminergic neurons. Here, we constructed a gene targeting vector to knock-in the human GDNF gene at the bovine beta-casein gene locus as a first step to producing transgenic animals with a high level of expression of human GDNF protein in their mammary glands. Bovine fetal fibroblast cells were transfected with linearized pNRTCNbG by electroporation. Three cell clones were identified with successful targeting to the beta-casein locus; and were confirmed using both polymerase chain reaction analysis and sequencing. Gene-targeted cells were used as nuclear donors; a total of 161 embryos were reconstructed, 23 of which developed to the blastocyst stage. These blastocysts were transferred to 8 recipient cows, but no offspring were obtained. PMID- 26634461 TI - Hematological markers and biochemical profiles in terms of gender and age of captive collared peccaries (Tayassu tajacu) in eastern Amazon. AB - Complete blood counts and blood biochemical analyses are laboratory tests that allow the monitoring of physiological condition, nutrition, and health in free living or captive wild animals. When interpreting these tests, it is essential to compare the results with reference ranges that are suitable for the species. Few studies have been conducted on the hematological and biochemical characteristics of Tayassu tajacu, particularly for animals raised in the Amazon biome. The objectives of this study were to evaluate the influence of age and gender on the hematological and biochemical profiles of captive T. tajacu, and to establish reference intervals for these parameters. Complete blood counts and biochemical analyses were performed using manual methods and semi-automatic equipment, respectively. There were significant differences in relation to age in hematocrit and hemoglobin levels, and mean cell volumes, in captive T. tajacu. No basophils were observed, and the neutrophil:lymphocyte ratio was less than 1. Levels of total protein, urea, phosphorus, and alkaline phosphatase were significantly affected by age (P < 0.05). Gender did not affect any of the results. The hematological and biochemical parameters for this species were determined, and may be used as reference ranges for captive T. tajacu. PMID- 26634462 TI - Physical mapping of 18S and 5S rDNA loci and histone H3 gene in grasshopper species of the subfamily Gomphocerinae (Acrididae). AB - In this study, fluorescence in situ hybridization (FISH) analysis was used to determine and compare the numbers and chromosomal locations of two multigene families (rDNA and histone H3) in four Neotropical species of gomphocerine grasshoppers. FISH using the 18S rDNA probe identified a single site on the S9 chromosome of Amblytropidia sp and Cauratettix borelli, a single site on chromosome M6 of Compsacris pulcher, and two sites (chromosomes L1 and L2) in Orphulella punctata. By contrast, FISH with a 5S rDNA probe identified dispersion of this sequence in the genomes of the four species, with evidence of intraspecific variations. Amblytropidia sp had six to eight FISH signals on autosomal chromosomes, while C. pulcher exhibited a signal only on the M5 bivalent. The histone H3 gene was less variable and was restricted to a single pair in all species. The conservation of the numbers and locations of 18S rDNA and H3 genes in conjunction with data from the literature was useful for evaluating karyotype evolution in this subfamily. The variation in the number and sizes of 5S rDNA sites indicates a process of recent dispersion that might have been mediated by transposition. PMID- 26634463 TI - Angiotensin II type 1 receptor gene A1166C polymorphism and breast cancer susceptibility. AB - Numerous studies have evaluated the association between the angiotensin II type-1 receptor (AGTR1) gene A1166C polymorphism and breast cancer risk. However, the specific association is controversial. The aim of the present study was to derive a more precise estimation of the relationship. A comprehensive research was conducted of the PubMed and the Google Scholar databases through February 2015. Data were assessed using STATA version 12.0. Pooled odds ratios with 95%CIs were derived from the fixed-effect or random-effect models. A total of 911 patients with breast cancer and 1284 controls from 5 case-control studies were included in this meta-analysis. The meta-analysis results showed no significant association between the AGTR1 gene A1166C polymorphism and breast cancer risk. Similarly, in the subgroup analysis regarding ethnicity, no associations were observed. Heterogeneity and publication bias were not observed in this meta-analysis. The A1166C polymorphism in the AGTR1 gene may not be a risk factor for breast cancer. Further, large, and well-designed studies are needed to confirm this conclusion. PMID- 26634464 TI - Differential expression of microRNAs may regulate pollen development in Brassica oleracea. AB - MicroRNAs (miRNAs) are a class of non-coding endogenous negative regulators that regulate gene expression at both the transcriptional and post-transcriptional levels. However, little is known about the expression characteristics of miRNAs during pollen development in Brassica oleracea. In this study, five known and three novel miRNAs were identified and their expression patterns were compared in the flower buds of B. oleracea using stem-loop reverse transcription polymerase chain reaction (RT-PCR) and quantitative real-time PCR. The results revealed that the eight miRNAs were constantly expressed during pollen development but exhibited different expression patterns during the five developmental stages of the flower buds between the cytoplasmic male sterile (CMS) line and its fertile maintainer. The highest miRNA expression levels occurred at the uninucleate microspore stage in the fertile line Bo01-12B and at the bicellular pollen stage in the CMS line Bo01-12A. Potential target genes for the miRNAs were predicted and analyzed, and suggested that miRNAs are involved in the regulation of target genes related to pollen development. The results of this study further our understanding of the regulatory role of miRNAs in pollen development. PMID- 26634465 TI - Cultivar identification and genetic relationship of pineapple (Ananas comosus) cultivars using SSR markers. AB - The genetic relationships among 27 pineapple [Ananas comosus (L.) Merr.] cultivars and lines were examined using 16 simple sequence repeat (SSR) markers. The number of alleles per locus of the SSR markers ranged from 2 to 6 (average 3.19), for a total of 51 alleles. Similarity coefficients were calculated on the basis of 51 amplified bands. A dendrogram was created according to the 16 SSR markers by the unweighted pair-group method. The banding patterns obtained from the SSR primers allowed most of the cultivars and lines to be distinguished, with the exception of vegetative clones. According to the dendrogram, the 27 pineapple cultivars and lines were clustered into three main clusters and four individual clusters. As expected, the dendrogram showed that derived cultivars and lines are closely related to their parental cultivars; the genetic relationships between pineapple cultivars agree with the genealogy of their breeding history. In addition, the analysis showed that there is no obvious correlation between SSR markers and morphological characters. In conclusion, SSR analysis is an efficient method for pineapple cultivar identification and can offer valuable informative characters to identify pineapple cultivars in Taiwan. PMID- 26634466 TI - Structure and polymorphism of novel X-chromosome short tandem repeat loci in a Chinese Han population. AB - Recently, 5 novel X-chromosome short tandem repeat (X-STR) loci with high degrees of polymorphism were examined. In this study, we investigated the genetic distribution of these loci in a Chinese Han population. The 5 X-STR loci were successfully examined by polyacrylamide gel electrophoresis in a total of 200 unrelated Shaanxi Han individuals (100 males and 100 females). Hardy-Weinberg equilibrium tests revealed no significant deviation from expected values (P > 0.05) for all 5 X-STR loci in the Shaanxi Han population.The loci were named DXS p11.3, DXS-q12, DXS-q13.3, DXS-q22.1, and DXS-q25 and were found to contain 6, 8, 7, 7, and 5 alleles, respectively. In addition, 17, 21, 18, 19, and 11 genotypes, respectively, were detected in the female samples. The heterozygosities of the 5 X-STR loci were 0.75, 0.74, 0.74, 0.72, and 0.56, respectively. The polymorphic information contents of the 5 X-STR loci were 0.70, 0.69, 0.69, 0.68, and 0.51, respectively. The individual discrimination values of the 5 X-STR loci were 0.88, 0.86, 0.88, 0.87, and 0.74, respectively. Five new X-chromosome STR loci with high degrees of polymorphism were observed in our lab. The results of this study are important for forensic individual identification, paternity identification, and population genetics research. PMID- 26634467 TI - Applying DNA barcodes for identification of economically important species in Brassicaceae. AB - Brassicaceae is a large plant family of special interest; it includes many economically important crops, herbs, and ornamentals, as well as model organisms. The taxonomy of the Brassicaceae has long been controversial because of the poorly delimited generic boundaries and artificially circumscribed tribes. Despite great effort to delimitate species and reconstruct the phylogeny of Brassicaceae, little research has been carried out to investigate the applicability and effectiveness of different DNA regions as barcodes - a recent aid for taxonomic identification - to identify economically important species in Brassicaceae. In this study, we evaluated the feasibility of five intensively recommended regions [rbcL, matK, trnH-psbA, internal transcribed spacer (ITS), ITS2] as candidate DNA barcodes to discriminate economic species of Brassicaceae in China and try to establish a new digital identification method for economic plants of Brassicaceae. All sequences of 58 samples from 27 economic species (Brassicaceae) in China were assessed in the success rates of PCR amplifications, intra- and inter-specific divergence, DNA barcoding gaps, and efficiency of identification. Compared with other markers, ITS showed superiority in species discrimination with an accurate identification of 67.2% at the species level. Consequently, as one of the most popular phylogenetic markers, our study indicated that ITS was a powerful but not perfect barcode for Brassicaceae identification. We further discuss the discrimination power of different loci due to inheritance pattern, polyploidization and hybridization in species-specific evolution. Further screening of other nuclear genes related to species isolation as plant barcode candidates is also proposed. PMID- 26634468 TI - Effects of choice of month of treatment and parity order on bovine superovulation traits. AB - In this study, the performance of 300 Changbaishan Black cattle treated for superovulation from June to September was evaluated to determine the optimal conditions and herds for bovine embryo production. Data analysis revealed that cattle treated in July and August had higher numbers of available embryos (NAE), M1 embryos (NM1), and total embryos (NTE), as well as a higher percentage of M1 embryos (PM1). The temperature and precipitation observed during July and August were greater than those seen in the other two months; strong correlations were observed between these traits and the choice of month of treatment. In addition, multiparous cattle showed a better performance, higher NTE, NAE, NM1, and PM1 values, higher percentages of available embryos, and a lower percentage of degenerated embryos. The co-efficient correlation analysis showed that the month chosen for the treatment did not affect the superovulation traits of nulliparous cattle; however, the choice of the month affected multiparous cattle. Multiparous and nulliparous cattle exhibited many significant differences when treated in July and in August. In addition, the superovulatory traits of multiparous cattle, and not the nulliparous cattle, were strongly correlated to the choice of month of treatment. The results suggested that superovulation is more effective during a period with appropriate environmental temperature and humidity, and that multiparous cattle are more suitable for morula production. PMID- 26634469 TI - Effects of kinase insert domain receptor (KDR) gene silencing on the sensitivity of A549 cells to erlotinib. AB - We investigated the effects of kinase insert domain receptor (KDR) gene silencing on the proliferation of A549 cells and their sensitivity to erlotinib. A KDR small interfering RNA (siRNA) sequence was designed and synthesized; then, it was transfected into A549 cells using Lipofectamine(TM) 2000. KDR mRNA and protein expression after KDR gene silencing was detected by reverse transcription polymerase chain reaction and western blotting; the A549 cell cycle was detected by flow cytometry. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and colony formation assay were performed to determine the sensitivity of A549 cells to erlotinib after KDR gene silencing. After 48h of KDR gene silencing, there was a significant decrease in KDR gene and protein expression (P < 0.05). The A549 cell cycle was arrested at the G0/G1 phase, and the number of cells in the S phase decreased; the difference was statistically significant (P < 0.05). In the KDR gene silencing group, the sensitivity of A549 cells to erlotinib was significantly enhanced (P < 0.05). KDR siRNA can significantly silence the KDR gene in A549 cells, inhibit the proliferation of A549 cells, and enhance their sensitivity to erlotinib. PMID- 26634470 TI - Indirect selection of industrial tomato genotypes rich in zingiberene and resistant to Tuta absoluta Meyrick. AB - Obtaining tomato cultivars resistant to pests through interspecific crosses between commercial cultivars and wild accessions is an important tool in integrated pest management. The aim of this study was to select tomato genotypes with high zingiberene (ZGB) levels that are resistant to the South American tomato moth (Tuta absoluta Meyrick) and to estimate genetic parameters of ZGB inheritance from the interspecific cross Solanum lycopersicum cultivar 'Redencao' x Solanum habrochaites var. hirsutum (PI-127826 accession). F2 plants with different ZGB contents were selected and submitted to a tomato moth resistance test. ZGB content exhibits high broad sense heritability, with incomplete dominance of lower ZGB content. Furthermore, the level of ZGB in leaflets was estimated to be controlled by two genes. These results show that high ZGB levels are effective at conferring resistance to the South American tomato moth. PMID- 26634471 TI - Detection of CK19, LUNX, and KS1/4 mRNA expression in the peripheral blood for diagnosis of micrometastases in patients with non-small cell lung cancer and their clinical implications. AB - The expression of CK19, LUNX, and KS1/4 mRNA biomarkers was detected in the peripheral blood of non-small cell lung cancer (NSCLC) patients to investigate the feasibility of indicating lung cancer micrometastases. Micrometastases were identified in the peripheral blood of 32 NSCLC patients, 15 benign pulmonary disease (BPD) patients, and 10 healthy volunteers by reverse transcriptase polymerase chain reaction. The detection rates of CK19, LUNX, and KS1/4 mRNA positive cells in the peripheral blood obtained from the NSCLC group were 34.4% (11/32), 37.5% (12/32), and 25% (8/32), respectively. CK19, LUNX, and KS1/4 mRNA positive cells were detected in 6.6% (1/15), 0.0% (0/15), and 13.3% (2/15) of the patients with BPD, respectively. However, the healthy group did not express any of the three markers. The expression of CK19, LUNX, and KS1/4 mRNA was significantly higher in the NSCLC group than that in the healthy and BPD groups (P < 0.05). CK19 and LUNX mRNA may be ideal biomarkers indicating micrometastases in patients with NSCLC; however, the diagnostic applicability of KS1/4 mRNA remains uncertain. The rate of expression of CK19 was not correlated with the clinicopathological characteristics (P > 0.05). The rate of expression of LUNX and KS1/4 was closely related to the clinical stage (P < 0.05), and not related to the clinical characteristics of the disease (age, gender, smoking history, pathological type, histologic classification, and differentiation; P > 0.05). PMID- 26634472 TI - Analysis of an "off-ladder" allele at the Penta D short tandem repeat locus. AB - Kinship testing of a father and his son from Guangxi, China, the location of the Zhuang minority people, was performed using the PowerPlex(r) 18D System with a short tandem repeat typing kit. The results indicated that both the father and his son had an off-ladder allele at the Penta D locus, with a genetic size larger than that of the maximal standard allelic ladder. To further identify this locus, monogenic amplification, gene cloning, and genetic sequencing were performed. Sequencing analysis demonstrated that the fragment size of the Penta D-OL locus was 469 bp and the core sequence was [AAAGA]21, also called Penta D-21. The rare Penta D-21 allele was found to be distributed among the Zhuang population from the Guangxi Zhuang Autonomous Region of China; therefore, this study improved the range of DNA data available for this locus and enhanced our ability for individual identification of gene loci. PMID- 26634473 TI - Role of survivin in the pathogenesis of papillary thyroid carcinoma. AB - The purpose of this study was to assess the correlation between the survivin gene and the occurrence and pathogenesis of papillary thyroid carcinoma (PTC). Sixty patients with PTC and no preoperative chemotherapy were recruited for the study and 30 thyrophyma patients receiving operative treatment in Drum Tower Hospital (Nanjing, China) were included as the control group. The protein expression levels of survivin were assessed by immunoblotting and immunohistochemical analysis of tissues from both patient groups. For survivin gene knockdown experiments, two target sequences were selected based on the mRNA sequence of survivin and two pairs of siRNA interference sequences were designed and synthesized accordingly. The siRNAs were shown to be successfully transfected into SW579 carcinoma cells and the resulting survivin knockdown was assessed by RT-PCR and immunofluorescence. Survivin was shown by immunohistochemistry to be distributed in the cytoplasm of PTC and thyrophyma cells, with the signal being significantly stronger in PTC cells than in thyrophyma cells and statistical analysis of immunostaining data further showed survivin to be more highly expressed (P < 0.05) in the PTC tissue than in the thyrophyma tissue. Transfection of SW579 cells with siRNA was found to be effective in knocking down the expression levels of survivin: 87.3 and 76.2% knockdown was achieved with sh Survivin-1 and sh-Survivin-2, respectively. The findings reported here show that survivin is highly expressed in PTC and may therefore play a role in the occurrence, lymph node metastasis, and clinical staging of PTC. PMID- 26634474 TI - Molecular cloning and characterization of GbMECT and GbMECP gene promoters from Ginkgo biloba. AB - Ginkgolides are key pharmaceutical components in Ginkgo biloba. Using the cDNA sequence of the MECP and MECT genes to design primers, we obtained the promoters of these genes from Ginkgo genomic DNA using the genome walking method. The two promoters were 744 and 982 bp in length, respectively. The cis-elements of the GbMECPs and GbMECT promoters were predicted and analyzed using the plant cis acting regulatory element database. We found major cis-elements in the sequence of the GbMECT and GbMECPs promoters. The GbMECP promoter contains six TATA boxes and eight CAAT boxes. The GbMECT contains five TATA boxes and seven CAAT boxes. Furthermore, some cis-elements in the promoters of GbMECPs and GbMECT included hormone and light-regulated elements, UB-B-induced elements, and stress-related dehydration-responsive elements. Expression analysis results showed that the MECP gene is mainly involved in responses to CCC (cycocel) and UV-B, and that MECT is mainly involved in responses to wounding treatment. These results also showed that the expression model was consistent with the cis-elements present. During the annual growth cycle, the level of GbMECPs was significantly correlated with terpene lactones accumulation in leaves. A fitted quadratic curve showed the best model for correlating GbMECPs with terpene lactones in leaves. These results will help us to understand the transcriptional regulatory mechanisms involved in key gene expression and ginkgolide accumulation in G. biloba. PMID- 26634475 TI - Keratins 17 and 19 expression as prognostic markers in oral squamous cell carcinoma. AB - Five-year survival rates for oral squamous cell carcinoma (OSCC) are 30% and the mortality rate is 50%. Immunohistochemistry panels are used to evaluate proliferation, vascularization, apoptosis, HPV infection, and keratin expression, which are important markers of malignant progression. Keratins are a family of intermediate filaments predominantly expressed in epithelial cells and have an essential role in mechanical support and cytoskeleton formation, which is essential for the structural integrity and stability of the cell. In this study, we analyzed the expressions of keratins 17 and 19 (K17 and K19) by immunohistochemistry in tumoral and non-tumoral tissues from patients with OSCC. The results show that expression of these keratins is higher in tumor tissues compared to non-tumor tissues. Positive K17 expression correlates with lymph node metastasis and multivariate analysis confirmed this relationship, revealing a 6 fold increase in lymph node metastasis when K17 is expressed. We observed a correlation between K17 expression with disease-free survival and disease specific death in patients who received surgery and radiotherapy. Multivariate analysis revealed that low expression of K17 was an independent marker for early disease relapse and disease-specific death in patients treated with surgery and radiotherapy, with an approximately 4-fold increased risk when compared to high K17 expression. Our results suggest a potential role for K17 and K19 expression profiles as tumor prognostic markers in OSCC patients. PMID- 26634476 TI - Association of the CYP4F2 rs2108622 genetic polymorphism with hypertension: a meta-analysis. AB - Previous case-control studies on the relationship between the CYP4F2 gene rs2108622 polymorphism and hypertension have produced contrasting results. In this study, we aimed to further evaluate the relationship between the CYP4F2 gene rs2108622 polymorphism and hypertension. We selected four case-control studies related to the CYP4F2 gene rs2108622 polymorphism and hypertension by searching PubMed, EMBase, the Chinese Biomedical Literature Database, and the Wanfang database. We utilized the Cochran Q-test and the I2 index to measure the heterogeneity across studies. To merge the odds ratio (OR) and the 95% confidence interval (95%CI), we utilized the fixed and random-effect models during the analyses. The present study included 1878 patients with hypertension and 1512 healthy control subjects. By meta-analysis, we did not find any association of the CYP4F2 gene rs2108622 polymorphism with hypertension in either genotype or allele distribution [AA+AG vs GG: OR = 1.18, 95%CI (0.91-1.54), P = 0.21; GG+AG vs AA: OR = 0.91, 95%CI (0.80-1.05), P = 0.20; A allele vs G allele: OR = 1.04, 95%CI (0.93-1.16), P = 0.53]. We concluded that the CYP4F2 gene rs2108622 polymorphism was not associated with hypertension. PMID- 26634477 TI - Investigation of AZF microdeletions in patients with Klinefelter syndrome. AB - We investigated azoospermia region microdeletions in male infertility patients with Klinefelter syndrome (KFS), as well as the association between azoospermia symptoms in patients with KFS and Y chromosome microdeletion polymorphisms. A total of 111 cases with male infertility confirmed to have KFS (47, XXY) and 94 fertile men were included in this study. Peripheral blood was drawn and DNA was extracted from these samples. Multiplex polymerase chain reaction was performed to screen the partial deletions of 25 sequence-tagged sites on the Y chromosome. In 111 cases with KFS, 1 case contained the AZFb+d+c deletion. The Gr/Gr deletion was identified in 12 KFS cases and 5 control cases. In addition, the b2/b3 deletion was identified in 13 KFS cases and 6 control cases. There were no significant differences in phenotype and genotype of the 2 partial AZFc deletions between patients and controls (P > 0.05). Our results suggest that patients with KFS may also have Y chromosome microdeletions to varying degrees and that the gr/gr deletion and b2/b3 deletion may not play a role in the susceptible genetic background of azoospermia in patients with KFS in the Sichuan population. PMID- 26634478 TI - Effect of CYP3A5 gene polymorphisms on tacrolimus concentration/dosage ratio in adult liver transplant patients. AB - We examined the influence of the cytochrome P450 3A5 (CYP3A5) genes in both donors and recipients on the concentration-dosage ratio (C/D) of tacrolimus in Chinese liver transplant patients. Fifty-one adult liver transplant patients who received tacrolimus were included in this study. The CYP3A5 polymorphism in donors and recipients was determined at the time of transplantation, and tacrolimus-based immunosuppressive therapy was started based on each patient's genetic constitution. The relationship between the C/D of tacrolimus for 3 months after surgery and the CYP3A5 genotype was analyzed. A stepwise regression model was used to analyze the relationship between C/D of tacrolimus and genotype, time course, age, and liver weight in liver transplant patients. Three months after liver transplantation, C/D was both affected by the CYP3A5 genotype of both the donors and the recipients. The C/D of tacrolimus in patients with the CYP3A5*1 allele or carrying CYP3A5*1 allele in the liver was lower than that in CYP3A5*3/*3 patients with the CYP3A5*3/*3 genotype in the liver (P < 0.01). The CYP3A5*1 genotype in donors as well as in patients both contributes to interindividual variation in the C/D of tacrolimus in adult liver transplantation. PMID- 26634479 TI - Improvements in neuroelectrophysiological and rear limb functions in rats with spinal cord injury after Schwann cell transplantation in combination with a C5a receptor antagonist. AB - We measured the effect of Schwann cell transplantation and complement factor 5a (C5a) receptor antagonist on nerve function recovery in rats with spinal cord injury. Experimental spinal cord injury was induced in eighty Wistar rats and these were randomly divided into four treatment groups: culture medium and saline injection (control group), Schwann cell injection (cell transplantation group), C5a receptor antagonist injection (C5a receptor antagonist group), and both Schwann cell and C5a receptor antagonist injections (combination group). Rear limb functional recovery was assessed 1, 2, 4, 6, and 8 weeks after the spinal cord injury with the tilt table test and the Basso, Beattie, Bresnahan scale. Sex determining region Y (SRY) gene expression was measured at week 4 and horseradish peroxidase (HRP) labeling was used at week 8 to further assess the recovery of neuroelectrophysiological functions. The rear limb functional assessment showed that the combination group had better outcomes than the cell transplantation and C5a receptor antagonist groups. All treatment groups had better outcomes than control. Only the cell transplantation and combination groups showed SRY expression. The number of HRP-positive nerve fibers in the different groups ranked as follows: combination group > cell transplantation and C5a receptor antagonist > control. The refractory period and amplitude of the induced potential in the combination group were significantly greater than in the other three groups. These results suggest that the combination of Schwann cell transplantation and the C5a receptor antagonist enhances the regeneration of injured synapses and improves limb function and electrophysiology. PMID- 26634480 TI - Identification and characterization of polymorphic microsatellite loci in the red crowned crane. AB - We isolated and characterized microsatellite loci for the red-crowned crane (Grus japonensis) from a microsatellite-enriched database, which was obtained using high-throughput sequencing technology. We designed primer sets for 445 microsatellite loci and after initial screening, 34 loci were genotyped in 31 red crowned cranes. The number of observed alleles ranged from 3 to 10. Observed and expected heterozygosities ranged from 0.197 to 0.935 and 0.453 to 0.887, respectively; the mean polymorphic information content was 0.663. Loci Lia10943, Lia60455, Lia48514, Lia62171, Lia1059, and Lia5286 deviated from expectation of the Hardy-Weinberg equilibrium; however, significant linkage disequilibrium was not observed among the 34 loci. Using these 34 markers, we successfully completed parental identification for 19 cranes. The probability of exclusion for 7 selected loci (Lia271333, Lia3745, Lia11091, Lia45761, Lia16468, Lia21909, and Lia22355) was >0.9977 and analyses with more loci increased the combination efficiency. These 34 markers were also proven to be efficient for individual identification. We recommend that this marker system be used in the systematic control of pedigree management and future genetic variation studies of red crowned cranes. PMID- 26634481 TI - Methylation-sensitive amplified polymorphism-based genome-wide analysis of cytosine methylation profiles in Nicotiana tabacum cultivars. AB - This study aimed to investigate cytosine methylation profiles in different tobacco (Nicotiana tabacum) cultivars grown in China. Methylation-sensitive amplified polymorphism was used to analyze genome-wide global methylation profiles in four tobacco cultivars (Yunyan 85, NC89, K326, and Yunyan 87). Amplicons with methylated C motifs were cloned by reamplified polymerase chain reaction, sequenced, and analyzed. The results show that geographical location had a greater effect on methylation patterns in the tobacco genome than did sampling time. Analysis of the CG dinucleotide distribution in methylation sensitive polymorphic restriction fragments suggested that a CpG dinucleotide cluster-enriched area is a possible site of cytosine methylation in the tobacco genome. The sequence alignments of the Nia1 gene (that encodes nitrate reductase) in Yunyan 87 in different regions indicate that a C-T transition might be responsible for the tobacco phenotype. T-C nucleotide replacement might also be responsible for the tobacco phenotype and may be influenced by geographical location. PMID- 26634482 TI - Homology-based analysis of the GRAS gene family in tobacco. AB - Members of the GRAS gene family are important transcriptional regulators. In this study, 21 GRAS genes were identified from tobacco, and were classified into eight subgroups according to the classification of Arabidopsis thaliana. Here, we provide a preliminary overview of this gene family in tobacco, describing the gene structure, gene expression, protein motif organization, phylogenetic analysis, and comparative analysis in tobacco, Arabidopsis, and rice. Using the sequences of 21 GRAS genes in Arabidopsis to search against the American tobacco genome database, 21 homologous GRAS genes in tobacco were identified. Sequence analysis indicates that these GRAS proteins have five conserved domains, which is consistent with their counterparts in other plants. Phylogenetic analyses divided the GRAS gene family into eight subgroups, each of which has distinct conserved domains and biological functions. Furthermore, the expression pattern of these 21 GRAS genes reveals that most are expressed in all six tissues studied; however, some have tissue specificity. Taken together, this comprehensive analysis will provide a rich resource to assist in the study of GRAS protein functions in tobacco. PMID- 26634483 TI - Novel polymorphic microsatellite markers for Bellamya and their application in population genetics of three species. AB - Bellamya is a widely distributed freshwater snail genus in China; however, its genetic diversity is completely unknown. Sixty-five novel microsatellite loci were isolated and characterized from a microsatellite-enriched library of Bellamya aeruginosa genomic DNA. Most of the 65 loci were successfully amplified. We found high polymorphic information content values for these loci, ranging from 0.235 to 0.892. There were 3 to 12 alleles per locus, and the HE and HO varied from 0.425 to 0.953 and 0.026 to 1.000, respectively. Fifteen loci deviated significantly from Hardy-Weinberg equilibrium after Bonferroni's correction. All 65 SSR markers were tested in an additional five Bellamya species, and 96.9% of the 325 locus/taxon combinations tested resulted in cross-species amplification. Seven polymorphic microsatellite markers were randomly selected for comparison among nine populations of three species. All populations had moderate to high genetic diversity. In genetic distance-based cluster analysis, the populations of B. aeruginosa and B. dispiralis formed species-based clusters, whereas populations of B. angularia did not. The three examined Bellamya species could be differentiated using SSR markers. These microsatellite loci should be useful for genetic diversity analysis, analysis of phylogenetic relationship, and species delimitation of Bellamya. PMID- 26634485 TI - Establishment of a hepatocyte steatosis model using Chang liver cells. AB - The objective of this study was to explore the experimental conditions for hepatocellular steatosis models of Chang liver cells induced by oleic acid (OA). For that, Chang liver cells were induced by different concentrations of OA for different periods. The MTT assay was used to detect hepatic cell activity, the Oil Red O staining was used to observe intracellular lipid droplets accumulation, and the glycerol phosphate oxidase method was used to detect the triglyceride (TG) content in the Chang liver cell. The hepatocellular steatosis models of Chang liver cell were established successfully by inducing with 0.2 mM OA for 24h. TG content in model cells was 379.98 +/- 23.19 mg/g, which is significantly different from control cells (185.03 +/- 12.68 mg/g; P < 0.01). These were considered proper conditions for establishing hepatocellular steatosis models of Chang liver cells, producing a reliable model for nonalcoholic fatty liver disease research. PMID- 26634484 TI - Association of adiponectin gene polymorphisms with hypertensive disorder complicating pregnancy and disorders of lipid metabolism. AB - The aim of this study was to determine whether single nucleotide polymorphisms (SNPs) in APM1 contribute to disorders of lipid metabolism in hypertensive disorder complicating pregnancy (HDCP). The study included 178 pregnant women with HDCP and 243 healthy pregnant controls. Using PCR-restriction fragment length polymorphism, we detected the frequencies of genotypes, alleles, and haplotypes of two SNPs, +45T>G (rs2241766) and +276G>T (rs1501299), in APM1. We found that the SNP +276 TT genotype was significantly associated with protection against HDCP compared to the pooled G genotypes. The genotype and allele frequency distributions of SNP +276 were significantly different between the cases and controls. Single-point genotype and allele distributions in SNP +45 were not statistically different between the groups. The pooled G haplotypes were significantly overrepresented in the case group compared to the TT haplotype. Plasma adiponectin (APN) concentration was determined by enzyme-linked immunosorbent assay, and we found that APN levels in cases were significantly lower than those in controls. Using the clinical data, we evaluated the correlation between the two SNPs and HDCP development, and revealed an association between the two SNPs and disorders of lipid metabolism in patients with HDCP. Except for fasting insulin levels, which was higher in cases than in controls, there were no significant differences in the other clinical data between the two groups. PMID- 26634486 TI - Relationship between perioperative cardiovascular risk factors and bone marrow cells from patients undergoing coronary artery bypass grafting surgery. AB - Cell therapy through the implantation of autologous bone marrow cells has long been used in clinical trials for the treatment of ischemic heart diseases. However, as the outcomes of cell implantation vary among patients, risk factors that might influence the level and function of bone marrow progenitor cells should be determined, to identify patients who would benefit the most from this treatment. We collected clinical and laboratory data from 44 patients scheduled to undergo sternotomy for coronary artery bypass grafting (CABG). Bone marrow was aspirated from the sternum during the operation, and bone marrow mononuclear cells (BMMNCs) were isolated through density centrifugation. A negative correlation was observed between the number of BMMNCs and age (N = 44, r = 0.788, P = 0.001). The level of CD34+ cells in BMMNCs was 0.94 +/- 0.39%, CD133+ cells 0.46 +/- 0.28%, and CD34+CD133+ cells 0.53 +/- 0.26%. The levels of CD34+ and CD133+ cells in diabetic patients were significantly lower than those in nondiabetic patients. Female gender, advanced age, and poor heart function were related with reduced progenitor cell clonogenic function. A positive correlation was observed between the level of CD34+ cells and BMMNC migration ability. Aging and diabetes were the major risk factors that influence the level and function of bone marrow resident progenitor cells in patients with coronary heart disease undergoing CABG. Further study is needed to determine whether these two factors can influence the outcome of bone marrow cell therapy for ischemic heart disease. PMID- 26634488 TI - Association of CD226 polymorphisms with the susceptibility to type 1 diabetes in Chinese children. AB - Polymorphisms in the CD226 gene have been reported to be associated with autoimmune diseases. The aim of our study was to investigate the association between two single nucleotide polymorphisms (SNPs) (rs763361 and rs727088) in the CD226 gene and the risk for developing type 1 diabetes (T1D) in Chinese Han children. This case-control study included a total of 152 Chinese children with T1D and 304 matched-pair, healthy controls based on age and gender. The genetic variants of the rs763361 and rs727088 SNPs in the CD226 gene were determined using the polymerase chain reaction and restriction fragment length polymorphism method. The CD226 rs763361 polymorphism increased the risk of T1D in the genotype [P < 0.001, odds ratio (OR) = 3.9, 95% confidence interval (CI) = 2.24-6.76], dominant (P < 0.001, OR = 2.1, 95%CI = 1.40-3.14), and recessive (P < 0.001, OR = 0.5, 95%CI = 0.30-0.84) models. Additionally, the carriers of the T allele were more susceptible to T1D (P < 0.001, OR = 2.1, 95%CI = 1.58-2.79). Carriers of the T allele who were younger than 10 years of age at disease onset had an increased risk of T1D than those who were older at the disease onset. However, there was no association between the CD226 rs727088 SNP and risk for developing T1D. These findings revealed that CD226 rs763361 polymorphism was significantly associated with susceptibility to T1D and that the presence of the T allele might be a genetic factor for susceptibility to T1D. PMID- 26634487 TI - Molecular characterization of accessions of Cratylia argentea (Camaratuba) using ISSR markers. AB - Cratylia argentea (Desv.) Kuntze (Fabaceae) is a drought-tolerant, perennial legume found primarily in Brazil, Bolivia, and Peru. The shrub is well adapted to acid soils and exhibits high productivity and nutritional value, characteristics that would favor its use as a dry season animal forage supplement in semiarid regions. In plant improvement programs, the production of elite hybrids with superior traits is generally achieved by crossing parents that exhibit the highest level of genetic divergence. Therefore, the aim of the present study was to assess genetic diversity among 13 accessions of C. argentea from the same population maintained in the active germplasm bank of Embrapa Meio-Norte using inter-simple sequence repeat (ISSR) markers. Genetic similarities between C. argentea accessions were estimated from Jaccard coefficients, and a dendrogram was constructed using the unweighted pair group method with arithmetic average (UPGMA). The set of 15 primers selected for ISSR analysis generated a total of 313 loci of which 79.23% were polymorphic. The mean number of bands per primer was 20.87, and the amplicons ranged from 280 to 3000 bp in size. Primers UBC834 and UBC827 generated the largest number of polymorphic loci and exhibited 90.91 and 100% polymorphism, respectively. The coefficients of genetic similarity among accessions varied between 0.49 and 0.73. UPGMA cluster analysis allowed the identification of four genotypic groups and demonstrated the existence of considerable variability within the collection. Potential progenitors were selected that would offer good possibilities of obtaining unusual and favorable combinations of genes in a plant breeding program. PMID- 26634489 TI - Swine leukocyte antigen class II genes (SLA-DRA, SLA-DRB1, SLA-DQA, SLA-DQB1) polymorphism and genotyping in Guizhou minipigs. AB - The swine leukocyte antigen (SLA) complex harbors highly polymorphic gene clusters encoding glycoproteins that are involved in responses to vaccines, infectious disease, and production performance. Pigs with well-defined SLA class II genes are useful for the study of disease, immunology, and vaccines. In this study, we analyzed four SLA class II genes (SLA-DRA, SLA-DRB1, SLA-DQA, SLA-DQB1) in 22 founder Guizhou minipigs using a sequence-based typing method. Twelve alleles were detected, compared with the SLA class II allele sequences in the GenBank, and one of twelve alleles was found to be novel in Guizhou minipigs. There are four SLA II haplotypes, and one of them has been previously reported in Meishan pigs. Furthermore, based on sequence information of these alleles, we developed a simple SLA typing method implemented to SLA-typing for unknown offspring of Guizhou minipigs, relying on designed twelve sequence specific primers that could discriminate between each other. According to the combination of sequence-based typing and PCR-SSP, we were able to rapidly check SLA typing of Guizhou breeding stock and identified four SLA haplotypes in the herd. Therefore, SLA-defined Guizhou minipigs will be useful as animal models for xenotransplantation and immunological research. PMID- 26634490 TI - Association between alcohol dehydrogenase 1C gene *1/*2 polymorphism and pancreatitis risk: a meta-analysis. AB - Numerous studies have focused on the relationship be-tween alcohol dehydrogenase 1C gene (ADH1C) *1/*2 polymorphism (Ile350Val, rs698, also known as ADH1C *1/*2) and pancreatitis risk, but the results have been inconsistent. Thus, we conducted a meta-anal-ysis to more precisely estimate this association. Relevant publications were searched in several widely used databases and 9 eligible studies were included in the meta-analysis. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate the strength of the association. Significant associations between ADH1C *1/*2 poly-morphism and pancreatitis risk were observed in both overall meta-analysis for 12 vs 22 (OR = 1.53, 95%CI = 1.12-2.10) and 11 + 12 vs 22 (OR = 1.44, 95%CI = 1.07-1.95), and the chronic alcoholic pancre-atitis subgroup for 12 vs 22 (OR = 1.64, 95%CI = 1.17-2.29) and 11 + 12 vs 22 (OR = 1.53, 95%CI = 1.11-2.11). Significant pancreatitis risk variation was also detected in Caucasians for 11 + 12 vs 22 (OR = 1.45, 95%CI = 1.07-1.98). In conclusion, the ADH1C *1/*2 polymorphism is likely associated with pancreatitis risk, particularly chronic alcoholic pancreatitis risk, with the *1 allele functioning as a risk factor. PMID- 26634491 TI - Proteome analysis of tobacco leaves reveals dynamic changes in protein expression among different cultivation areas. AB - The leaves of tobacco plants were used to analyze differences in protein content of tobacco grown in the four main flue-cured tobacco-producing areas of Sichuan Province, China. An improved protein extraction method, isoelectric focusing/sodium dodecyl sulfate-polyacrylamide gel electrophoresis two dimensional gel electrophoretic separation, was used to extract and separate total protein from tobacco leaves. Proteomic maps with relatively high resolution and repeatability were produced. At isoelectric points 4 to 7 and molecular weight ranging from 20-100 kDa, we detected 1032, 1030, 1019, and 1011 clearly visible protein spots in tobacco leaves from the four study areas. Proteome comparison between these protein spots showed that 119 spots with a greater than 2-fold change in expression quantity contributed to the variation in expression. Of which, 115 were successfully identified and annotated. According to the annotation results, these proteins participate in photosynthesis, energy metabolism, mineral nutrition, terpene metabolism, defensive reaction, and other physiological and biochemical processes. This study preliminarily explains the effects of ecological conditions on the physiological metabolism of tobacco leaves and how such effects directly or indirectly contribute to tobacco leaf quality. PMID- 26634492 TI - Weak cation magnetic separation technology and MALDI-TOF-MS in screening serum protein markers in primary type I osteoporosis. AB - We investigated weak cation magnetic separation technology and matrix-assisted laser desorption ionization-time of flight-mass spectrometry (MALDI-TOF-MS) in screening serum protein markers of primary type I osteoporosis. We selected 16 postmenopausal women with osteoporosis and nine postmenopausal women as controls to find a new method for screening biomarkers and establishing a diagnostic model for primary type I osteoporosis. Serum samples were obtained from controls and patients. Serum protein was extracted with the WCX protein chip system; protein fingerprints were examined using MALDI-TOF-MS. The preprocessed and model construction data were handled by the ProteinChip system. The diagnostic models were established using a genetic arithmetic model combined with a support vector machine (SVM). The SVM model with the highest Youden index was selected. Combinations with the highest accuracy in distinguishing different groups of data were selected as potential biomarkers. From the two groups of serum proteins, 123 cumulative MS protein peaks were selected. Significant intensity differences in the protein peaks of 16 postmenopausal women with osteoporosis were screened. The difference in Youden index between the four groups of protein peaks showed that the highest peaks had mass-to-charge ratios of 8909.047, 8690.658, 13745.48, and 15114.52. A diagnosis model was established with these four markers as the candidates, and the model specificity and sensitivity were found to be 100%. Two groups of specimens in the SVM results on the scatterplot were distinguishable. We established a diagnosis model, and provided a new serological method for screening and diagnosis of osteoporosis with high sensitivity and specificity. PMID- 26634493 TI - A novel frameshift deletion in the COL1A1 gene identified in a Chinese family with osteogenesis imperfecta. AB - Osteogenesis imperfecta (OI) is a genetically heterogeneous group of disorders, characterized by abnormal bone fragility, blue sclera, deafness, joint laxity, and soft-tissue dysplasia. The purpose of this study was to elucidate the genetic or molecular basis for OI type IA in a Chinese family. We evaluated the members of a family, in which six individuals are affected with increased bone fragility and blue sclera. Results of exome sequencing revealed a novel 1-bp deletion (c.2329delG, p.A777fs) in exon 33 of the COL1A1 gene in two affected individuals, but not in a control family member without OI. The variation co-segregated with the disease in all the OI patients but not in the unaffected family members. The mutation caused a frameshift alteration after codon 777, leading to premature termination of the COL1A1 protein. Thus, our findings identified a novel frameshift deletion c.2329delG (p.A777fs) in the COL1A1 gene, which is associated with OI type IA in a Chinese family. PMID- 26634494 TI - Isolation of Pantoea ananatis from sugarcane and characterization of its potential for plant growth promotion. AB - Each year, approximately 170 million metric tons of chemical fertilizer are consumed by global agriculture. Furthermore, some chemical fertilizers contain toxic by-products and their long-term use may contaminate groundwater, lakes, and rivers. The use of plant growth-promoting bacteria may be a cost-effective strategy for partially replacing conventional chemical fertilizers, and may become an integrated plant nutrient solution for sustainable crop production. The main direct bacteria-activated mechanisms of plant growth promotion are based on improvement of nutrient acquisition, siderophore biosynthesis, nitrogen fixation, and hormonal stimulation. The aim of this study was to isolate and identify bacteria with growth-promoting activities from sugarcane. We extracted the bacterial isolate SCB4789F-1 from sugarcane leaves and characterized it with regard to its profile of growth-promoting activities, including its ability to colonize Arabidopsis thaliana. Based on its biochemical characteristics and 16S rDNA sequence analysis, this isolate was identified as Pantoea ananatis. The bacteria were efficient at phosphate and zinc solubilization, and production of siderophores and indole-3-acetic acid in vitro. The isolate was characterized by Gram staining, resistance to antibiotics, and use of carbon sources. This is the first report on zinc solubilization in vitro by this bacterium, and on plant growth promotion following its inoculation into A. thaliana. The beneficial effects to plants of this bacterium justify future analysis of inoculation of economically relevant crops. PMID- 26634495 TI - Cloning and characterization of up-regulated HbSINA4 gene induced by drought stress in Tibetan hulless barley. AB - Hulless barley is an important crop cereal in Tibetan, China. Drought is a major abiotic stress in barley production. In this study, we cloned the drought-related HbSINA4 gene from the variety 'Himalaya 10' and analyzed its expression patterns under different drought and rehydration conditions. The cDNA of HbSINA4 was 1052 bp long, including an open reading frame of 771 bp that encoded a protein of 256 amino acids. The molecular weight of HbSINA4 protein was predicted to be 29.53 kDa and the theoretical pI was 8.32. Bioinformatic analysis showed that the HbSINA4 gene contained a protein kinase domain profile family signature motif, with high similarity to that of Oryza sativa and Brachypodium distachyon. Real time polymerase chain reaction (PCR) assays revealed that gene expression declined rapidly with increasing drought stress; in contrast, its expression increased after rehydration treatment. Therefore, the HbSINA4 gene responds to the drought stress and plays an important role in barely drought resistance. Furthermore, our results provide information which may be useful in other temperate crop studies and in aiding resistance to drought. PMID- 26634496 TI - Discovery and characterization of a first set of polymorphic microsatellite markers in Siganus oramin. AB - Nine microsatellite DNA markers were developed and characterized for Siganus oramin by the 5'-anchored polymerase chain reaction technique. A total of 42 alleles were identified in 30 individuals, and the number of alleles per locus ranged from 3 to 7, with an average of 4.7. The observed and expected heterozygosity per locus ranged from 0.5333 to 1.0000 and from 0.5254 to 0.8474, respectively, with an average of 0.7422 and 0.6906, respectively. A significant deviation from the Hardy-Weinberg equilibrium was detected at one microsatellite locus after a Bonferroni's correction (P < 0.0056). No significant linkage disequilibrium was found between any of the pairs of the nine loci. The microsatellite loci developed in this study will improve our understanding of the genetic background of S. oramin. PMID- 26634497 TI - Characterization and significance of MUC1 and c-myc expression in elderly patients with papillary thyroid carcinoma. AB - The aim of this study was to examine the expression of mucin 1 (MUC1) and c-myc and the significance thereof in elderly patients with papillary thyroid carcinoma. The expression levels of MUC1 and c-myc were examined by immunohistochemical methods in 58 patients with papillary thyroid carcinoma, 35 with nodular goiter, and 30 subjects with normal thyroid tissue. The positive rate of MUC1 detection in papillary thyroid carcinoma was 77.6% (45/58), while it was 90.0% (9/10) in those with infiltration and 88.2% (15/17) in those with lymphatic metastasis. The positive rate of c-myc was 81.0% (47/58) in those with papillary thyroid carcinoma and 100.0% (17/17) in those with lymphatic metastasis. These results demonstrated that there were differences in MUC1 and c myc expression in benign and papillary thyroid carcinoma and that these differences were related to thyroid cancer lymphatic metastasis. PMID- 26634498 TI - Genome-wide association study of growth traits in the Jinghai Yellow chicken. AB - Growth is one of the most economically important traits in the poultry industry. In this study, we identified single-nucleotide polymorphisms (SNPs) and candidate genes associated with growth traits of the Jinghai Yellow chicken. Genome-wide association studies were conducted using the Illumina 60 K SNP Chicken array to genotype 400 Jinghai Yellow chickens. For each bird, the body weights at hatching and at 2, 4, 6, 8, 12, 14, and 16 weeks were recorded. The SNPs that were significantly associated with the growth traits were identified using the general linear regression model. The results revealed a total of 18 SNPs that reached Bonferroni genome-wide significance (P < 1.80E-6). Three proximal genes (BTRC, NLK, and NF1) were found to participate in the Wnt-signaling pathway and mitogen activated protein kinase signaling pathway. Haplotype analysis identified 19 significant haplotypes and identified a region 152.4-156.3M on GGA1 affecting 3 growth traits (BW4, BW14, and BW16). These results may help identify the exact locations of body weight quantitative trait loci on a genome level and indicate variants that can be used for subsequent investigations for Jinghai Yellow chicken. PMID- 26634499 TI - Genetic dissimilarity and selection of putative mutants of Terra Maranhao plantain cultivar using the Ward-MLM strategy. AB - The objective of this study was to evaluate genetic variability and select putative mutants of Terra Maranhao plantain cultivar (AAB genome) subjected to gamma radiation based on agronomic data and inter simple sequence repeat molecular marker profiles using the Ward-MLM strategy. A total of 233 irradiated plants and 41 controls were assessed. The agronomic and molecular data were subjected to the Ward-MLM statistical algorithm in the SAS program. Cluster analysis was performed by the average distance method (UPGMA), based on the distance matrix of the Gower algorithm, and the cophenetic correlation coefficient calculated using the R software. The distance between the putative mutants ranged from 0.321 to 0.524, with an average distance of 0.426, and a cophenetic correlation coefficient of 0.79. Three putative mutants, which were selected based on the best agronomic traits and low height, will undergo further evaluation in the next stages of the banana breeding program at Embrapa. These results describe the first attempt of using combined data of Terra Maranhao plantain cultivar for the purpose of selecting mutants and assessing genetic variability. PMID- 26634500 TI - Effect of wilfortrine on human hepatic cancer HepG2 cell proliferation potential in vitro. AB - Liver cancers are characterized by high morbidity and mortality owing to few effective drugs for its treatment. Wilfortrine has several pharmacological effects, including an inhibitory effect on liver cancer cell proliferation. However, whether wilfortrine can induce liver cancer cell apoptosis has not been elucidated. We investigated the role of wilfortrine on liver cancer cell HepG2 apoptosis and analyzed its possible mechanisms to provide a theoretical basis for clinical analysis of liver cancer pathogenesis. The liver cancer cell line HepG2 was treated with 40 mM wilfortrine for 48 h. Flow cytometry was applied to detect HepG2 cell apoptosis and cell cycle changes. Western blot was used to analyze Bcl 2 and Bax expression. The HepG2 cell apoptosis rate increased significantly after treatment with wilfortrine, especially the early apoptosis rate (P < 0.05). However, wilfortrine did not change the cell cycle of HepG2 cells. After wilfortrine treatment, Bcl- 2 expression decreased significantly (P < 0.05); on the contrary, Bax expression increased noticeably compared with the control group (P < 0.05). Wilfortrine can induce liver cancer cell HepG2 apoptosis, but with no effect on the cell cycle, mainly by promoting Bax expression and inhibiting anti apoptotic protein Bcl-2 expression. PMID- 26634502 TI - Elevated serum homocysteine level in the development of diabetic peripheral neuropathy. AB - The development of diabetic peripheral neuropathy (DPN) is always followed by changes in vascular endothelial cells that are related to the reactivity of the homocysteine (Hcy) sulfhydryl group. In this meta-analysis, we investigated the association of Hcy with the pathogenesis and progression of DPN. We screened the Embase, Ovid, PubMed, Web of Science, Wangfang, and China National Knowledge Infrastructure databases. All analyses were performed by using the STATA software, version 12.0 (StataCorp, College Station, TX, USA) and the Comprehensive Meta-analysis 2.0 software (Biostatic Inc., Englewood, NJ, USA). The standardized mean difference (SMD) and 95% confidence interval (95%CI) were further calculated. The electronic literature search identified six articles that included 603 patients with DPN and 687 healthy controls. The pooled SMD of those six studies revealed that increased serum levels of Hcy may be correlated with DPN (SMD = 1.23, 95%CI: 1.09-1.36, P < 0.001). Subgroup analysis according to ethnicity indicated that high serum Hcy levels might be an important risk factor for DPN in both Asian and Caucasian populations (Asians: SMD = 0.62, 95%CI: 0.45 0.79, P < 0.001; Caucasians: SMD = 2.32, 95%CI: 2.10-2.55, P < 0.001; respectively). Elevated serum levels of Hcy indicate the risk of development of DPN in patients, suggesting that Hcy levels could be used as a marker for new therapeutic approaches to DPN. PMID- 26634501 TI - Genetic and biogeographical relationships among species of Astyanax (Teleostei, Characidae) in Brazilian river basins. AB - The genetic relationships among 17 species of Astyanax from the Iguacu River and adjacent river basins in Brazil were examined using nucleotide sequences of the mitochondrial cytochrome b gene (cytb). Congruent trees were constructed using neighbor-joining, maximum-likelihood, and Bayesian methods. The resulting clades suggest that at least three major groups share similar origins with the endemic species of the Iguacu River. The results indicate that Astyanax is polyphyletic in this location, which suggests that Astyanax did not diversify from a single ancestral group that was isolated when the Iguacu River basin formed. Astyanax bifasciatus shares an origin with some species of the altiparanae-bimaculatus complex, while A. minor originated from the same group as A. aff. paranae, A. fasciatus, and A. bockmanni. The third group includes A. dissimilis, Astyanax sp F, and A. serratus that are endemic species to the Iguacu River basin. Geological and hydrological events that influenced the biogeographical patterns of these species are discussed. PMID- 26634503 TI - Multivariate analysis of backcross progeny of Passiflora L. (Passifloraceae) for pre-breeding genotype selection. AB - The Ward-MLM procedure was used to evaluate genetic variation in four backcross progenies and in their parents, hybrid F1 HD13 and donor parent Passiflora sublanceolata. Sixteen quantitative descriptors and five qualitative characteristics of relevance to ornamental flower production were assessed. Using the pseudo-F and pseudo-T2 criteria, we identified four groups among these plants in two evaluation periods. In both evaluations, the BC1 plants showed greater dissimilarity to their recurrent parent, but showed high genetic similarity with the P. sublanceolata parent. The first two canonical variables produced by the Ward-MLM procedure accounted for over 90% of the variation in both evaluation periods, enabling the representation of diversity through two-dimensional graphics. Groups II and IV were formed in the first assessment period. Groups I and IV formed in the second period and showed plants with selection potential. We found that it was essential to use both qualitative and quantitative variables for this analysis. Assessments of quantitative descriptors indicate that the selection of BC1 plants can be performed in any of the four progenies. Because of the similarities observed for some floral descriptors between BC1 and the P. sublanceolata parent, a second generation backcross was not recommended. However, the selection of BC1 plants for evaluation and direct use as an ornamental cultivar, or as a resource in other breeding programs, can be recommended. PMID- 26634504 TI - Molecular cloning and expression analysis of jasmonic acid dependent but salicylic acid independent LeWRKY1. AB - Various plant genes can be activated or inhibited by phytohormones under conditions of biotic and abiotic stress, especially in response to jasmonic acid (JA) and salicylic acid (SA). Interactions between JA and SA may be synergistic or antagonistic, depending on the stress condition. In this study, we cloned a full-length cDNA (LeWRKY1, GenBank accession No. FJ654265) from Lycopersicon esculentum by rapid amplification of cDNA ends. Sequence analysis showed that this gene is a group II WRKY transcription factor. Analysis of LeWRKY1 mRNA expression in various tissues by qRT-PCR showed that the highest and lowest expression occurred in the leaves and stems, respectively. In addition, LeWRKY1 expression was induced by JA and Botrytis cinerea Pers., but not by SA. PMID- 26634505 TI - Analysis of gene expression patterns and levels in maize hybrids and their parents. AB - Heterosis has greatly contributed to conventional plant breeding and is widely used to increase crop plant productivity. However, although some studies have explored the mechanisms of heterosis at the genomic and transcriptome level, these mechanisms still remain unclear. The growth and development of maize seedlings and immature embryos have an important impact on subsequent production. This study investigated differentially expressed genes (DEGs) between parents and reciprocal hybrids in the seedling leaves, roots, and immature embryo 15 days after pollination using amplified fragment length polymorphism (AFLP)-based transcript profiling (cDNA-AFLP). We isolated 180, 170, and 108 genes from the leaves, roots, and immature embryos, respectively, that were differentially expressed between hybrids and parents. Sequencing and functional analysis revealed that 107 transcript-derived fragments in the roots and leaves and 90 in the immature embryos were involved in known functions, whereas many DEGs had roles in plant growth and development, photosynthesis, signal transduction, and seed germination. Quantitative reverse-transcription polymerase chain reaction analysis of relative expression levels between reciprocal hybrids and both parental genotypes of selected genes produced results that were consistent with cDNA-AFLP. We validated the expression patterns of 15 selected genes related to heterosis formation and revealed that most showed non-additive expression in one or both hybrids, including dominant, underdominant, and overdominant expression. This indicates that gene-regulatory interactions among parental alleles play an important role in heterosis during the early developmental stages of maize. PMID- 26634506 TI - Isolation and characterization of new microsatellite markers in red tail prawn, Fenneropenaeus penicillatus, an endangered species in China. AB - Until recently, Fenneropenaeus penicillatus was considered a commercial shrimp species. However, in 2005, it was included on the Red List as an endangered species by the Chinese government. In this study, 19 new microsatellite markers in F. penicillatus were developed and tested in samples of 32 wild individuals from Nanao, China. Twelve loci were polymorphic and 7 were monomorphic. Of the 12 polymorphic loci, the number of alleles per locus ranged from 3 to 6, with an average of 4.42 alleles per locus. The polymorphism information content ranged from 0.302 to 0.670, with a mean of 0.4817. The observed and expected heterozygosities ranged from 0.2250 to 0.8889 and from 0.1111 to 0.7750, respectively. Significant deviations from Hardy-Weinberg equilibrium (HWE, adjusted P < 0.0042) after a Bonferroni correction were observed in 3 loci (NA-9, NA-57, and NA-64), whereas the other 9 loci were in HWE. These new microsatellite markers will be useful in further research on the population genetic structure of F. penicillatus. PMID- 26634507 TI - Evaluation of genetic divergence among clones of conilon coffee after scheduled cycle pruning. AB - Coffea canephora genotypes from the breeding program of Instituto Capixaba de Pesquisa e Extensao Rural were evaluated, and genetic diversity was estimated with the aim of future improvement strategies. From an initial group of 55 genotypes, 18 from the region of Castelo, ES, were selected, and three clones of the cultivars "Vitoria" and "robusta tropical." Upon completion of the scheduled cycle pruning, 17 morphoagronomic traits were measured in the 22 genotypes selected. The principal components method was used to evaluate the contributions relative to the traits. The genetic dissimilarity matrix was obtained through Mahalanobis generalized distance, and genotypes were grouped using the hierarchical method based on the mean of the distances. The most promising clones of Avaliacao Castelo were AC02, AC03, AC12, AC13, AC22, AC24, AC26, AC27, AC28, AC29, AC30, AC35, AC36, AC37, AC39, AC40, AC43, and AC46. These methods detected high genetic variability, grouping, by similarity, the genotypes in five groups. The trait that contributed the least to genetic divergence was the number of leaves in plagiotropic branches; however, this was not eliminated, because discarding it altered the groups. There are superior genotypes with potential for use in the next stages of the breeding program, aimed at both the composition of clonal variety and hybridizations. PMID- 26634508 TI - Association of the LMNA gene single nucleotide polymorphism rs4641 with bdilated cardiomyopathy. AB - Recently, studies on the pathogenesis of dilated cardiomyopathy (DCM) have focused on the underlying molecular biology and the association between single nucleotide polymorphisms (SNPs) and disease. This study was designed to explore the association between the rs4641 SNP of the LMNA gene and DCM in order to identify a new gene locus related to DCM. Polymerase chain reaction-restriction fragment length polymorphism and DNA sequencing were employed to detect and genotype rs4641 in 198 patients with DCM and 160 healthy controls. Genotype and allele frequencies were compared to discover their relationship and logistic regression was used to assess the risk of DCM associated with the polymorphic variants. In the DCM group, the frequencies of the TC and TT genotypes and the T allele of rs4641 were remarkably higher than those in the control group (P < 0.01). According to risk analysis, taking the CC genotype as a reference, both the TC and TT genotypes increased the risk of DCM pathogenesis, with OR (95%CI) values of 5.957 (2.903- 12.222) and 6.424 (2.156-19.141), respectively. Taking the C allele as the reference, presence of the T allele was found to increase DCM risk, with OR (95%CI) of 5.295 (3.121-8.983). These results suggested that the C to T mutation at the rs4641 locus of LMNA could enhance the risk of DCM, and that rs4641 represented a genetic susceptibility locus. Therefore, it was concluded that the LMNA rs4641 SNP was associated with DCM risk, which indicated that LMNA is a susceptibility gene for DCM. PMID- 26634509 TI - Correlation between chromosomal polymorphisms and male infertility in a Northeast Chinese population. AB - The aim of this study was to evaluate the correlation between chromosomal polymorphisms and male infertility. The patients were diagnosed with azoospermia or oligospermiaby a semen analysis. Chromosomal analysis was performed on peripheral blood lymphocytes obtained from the patients, with standard G-banding and C-banding. Y chromosome microdeletions were detected by multiplex polymerase chain reaction (PCR) amplification. The parents of 35 polymorphic probands were also subjected to chromosomal analysis, and their detailed reproductive histories were surveyed. The frequency of autosomal polymorphisms did not differ significantly among the infertile patients and fertile control individuals. The frequency of the Yqh-variant increased with the decrease in sperm count; this appeared at a significantly higher frequency in the azoospermia group (57.2 vs 24.3 vs 0%). The results of PCR amplification indicated that 32.14% of the patients with Yqh +/- had microdeletions in the Y chromosome. The parents of the probands with the same chromosomal polymorphisms as the probands (among the 35 recalled families) did not show any adverse reproductive history. We observed no significant correlations between autosomal polymorphisms and male infertility. However, we observed a significant increase in the frequency of Yqh- in the azoospermic patients. This may be attributed to Y chromosome microdeletions, although the association between Y chromosome microdeletions and Y chromosome variants remains to be elucidated. PMID- 26634510 TI - G-395A polymorphism in the promoter region of the KLOTHO gene and hypertension among elderly (90 years and older) Chinese individuals. AB - The aim of this study was to examine the possible associations between the KLOTHO G-395A gene polymorphism and hypertension in Chinese nonagenarians and centenarians. The G-395A (rs1207568) in the promoter region of the KLOTHO gene was genotyped using a standard TaqMan allelic discrimination assay. We included 710 participants aged 93.5 +/- 3.2 years in the analyses. The expression of the A allele of the KLOTHO G-395A polymorphism was significantly downregulated in the hypertension group compared to the control group (0.137 vs 0.200, P < 0.001). The genotype distribution of the G-395A polymorphism between the hypertension and control groups was significantly different in women and smokers, and not in men or non-smokers. The mean systolic blood pressure, percentage of hypertension, and percentage of isolated systolic hypertension was significantly higher in the group with the GG genotype than in the group with the GA+AA genotype. Subjects expressing the GA+AA genotype demonstrated a significantly lower risk of hypertension even after adjusting for age, gender, and other relevant risk factors compared to the population expressing the GG genotype (odds ratio, 0.68; 95% confidence interval: 0.49 to 0.95).The -395A allele of the KLOTHO gene may be a protective genetic factor for hypertension in the Chinese population. PMID- 26634511 TI - Protective effects against and potential mechanisms underlying the effect of magnesium isoglycyrrhizinate in hypoxia-reoxygenation injury in rat liver cells. AB - We examined the protective effects of magnesium isoglycyrrhizinate (MgIG) on hypoxia-reoxygenation injury in rat liver cells. Rat liver cells in the logarithmic growth phase were divided into the hypoxia-reoxygenation injury model group and MgIG pretreatment group (0.01, 0.1, 1, 10, 100 mg/mL). After 24-h pretreatment, we detected the effects of MgIG on liver cell viability using the methyl thiazolyl tetrazolium (MTT) assay at 6-h hypoxia and 4-h reoxygenation. After 24-h pretreatment, liver cells were randomly divided into the hypoxia reoxygenation injury model group and low-, moderate-, and high-MgIG-concentration groups (0.1, 1, 10 mg/mL, respectively), and hypoxia and reoxygenation were simulated for 6 and 4 h, respectively. Cell morphology was observed by light microscopy. Nuclear factor-kB gene expression was analyzed by quantitative reverse transcription-polymerase chain reaction. MTT results showed that MgIG (0.1, 1, 10 mg/mL) improved the A-value of anoxia-reoxygenation injury in liver cells (P < 0.01) compared with that of the model group. Cells did not survive when the MgIG concentration was 100 mg/mL. At an MgIG concentration lower than 0.01 mg/mL, the A-value of the MTT group was higher than that of the model group (P > 0.05). Nuclear factor-kB mRNA expression (0.597 +/- 0.062, 0.248 +/- 0.067, 0.141 +/- 0.029) in the low-, moderate-, and high-concentration groups was lower than that in the model group (P < 0.01). MgIG reduced hypoxia-reoxygenation injury of liver cells, indicating that it improved hepatic cell activity, inhibited lipid peroxidation and inflammatory reactions, and decreased nuclear factor-kB mRNA expression. PMID- 26634512 TI - MiR-577 inhibits pancreatic beta-cell function and survival by targeting fibroblast growth factor 21 (FGF-21) in pediatric diabetes. AB - Pancreatic beta-cell dysfunction is a central component of the pathogenesis of pediatric diabetes. MicroRNA (miRNA) have become one of the most encouraging and fruitful fields in biological research, and have been implicated as new players in the pathogenesis of diabetes and diabetes-associated complications. The role of miRNA in diabetes begins with the development of pancreatic islets. Fibroblast growth factor (FGF)-21 enhances glucose uptake in adipocytes, protecting transgenic animals from diet-induced obesity when overexpressed, and lowers blood glucose and triglyceride levels in diabetic animals (when administered); therefore, it is a good way to treat diabetes. However, the mechanism of miRNA in regulation of FGF21 is not known. In this study, FGF-21 was predicted to be the target of miR-577. Therefore, we investigated the effects of miR-577 on beta-cell function and survival by targeting FGF-21. We demonstrated that, although FGF-21 does not acutely stimulate insulin secretion in isolated islets from normal rats, it increases insulin secretion and insulin content in diabetic islets and protects beta-cells from apoptosis via the activation of extracellular signal regulated kinase 1/2 and Akt signaling pathways. PMID- 26634513 TI - Quantitative candidate gene association studies of metabolic traits in Han Chinese type 2 diabetes patients. AB - Recent genome-wide association studies have identified many loci associated with type 2 diabetes mellitus (T2DM), hyperuricemia, and obesity in various ethnic populations. However, quantitative traits have been less well investigated in Han Chinese T2DM populations. We investigated the association between candidate gene single nucleotide polymorphisms (SNPs) and metabolic syndrome-related quantitative traits in Han Chinese T2DM subjects. Unrelated Han Chinese T2DM patients (1975) were recruited. Eighty-six SNPs were genotyped and tested for association with quantitative traits including lipid profiles, blood pressure, body mass index (BMI), serum uric acid (SUA), glycated hemoglobin (HbA1c), plasma glucose [fasting plasma glucose (FPG)], plasma glucose 120 min post-OGTT (P2PG; OGTT = oral glucose tolerance test), and insulin resistance-related traits. We found that CAMTA1, ABI2, VHL, KAT2B, PKHD1, ESR1, TOX, SLC30A8, SFI1, and MYH9 polymorphisms were associated with HbA1c, FPG, and/or P2PG; GCK, HHEX, TCF7L2, KCNQ1, and TBX5 polymorphisms were associated with insulin resistance-related traits; ABCG2, SLC2A9, and PKHD1 polymorphisms were associated with SUA; CAMTA1, VHL, KAT2B, PON1, NUB1, SLITRK5, SMAD3, FTO, FANCA, and PCSK2 polymorphisms were associated with blood lipid traits; CAMTA1, SPAG16, TOX, KCNQ1, ACACB, and MYH9 polymorphisms were associated with blood pressure; and UBE2E3, SPAG16, SLC2A9, CDKAL1, CDKN2A/B, TCF7L2, SMAD3, and PNPLA3 polymorphisms were associated with BMI (all P values <0.05). Some of the candidate genes were associated with metabolic and anthropometric traits in T2DM in Han Chinese. Although none of these associations reached genome-wide significance (P < 5 x 10(-8)), genes and loci identified in this study are worthy of further replication and investigation. PMID- 26634514 TI - 729G/C polymorphism in Toll-like receptor 4 results in increased susceptibility to bladder cancer. AB - In this study, the association between the 729G/C polymorphism in Toll-like receptor 4 (TLR4) and the risk of bladder cancer was investigated. A total of 376 patients with bladder cancer and 380 healthy volunteers from the Third Xiangya Hospital of Central South University (China) were enrolled in this study between January 2008 and February 2014. The TLR4-729G/C polymorphism was detected by the polymerase chain reaction-restriction fragment length polymorphism assay. There was a significant difference in the distribution of the TLR4-729G/C genotype between bladder cancer patients and healthy controls (P < 0.001). Our analysis showed that the GC genotype (OR = 2.99; 95%CI = 1.01-4.81, P = 0.046) and CC genotype (OR = 3.67; 95%CI = 2.11-7.27, P = 0.017) were significantly associated with increased bladder cancer risk when the GG genotype served as a reference. Furthermore, carriers of the C allele had a significantly increased risk of developing bladder cancer (OR = 3.89; 95%CI = 2.88-8.53; P = 0.009). Our results suggest a correlation between the TLR4-729G/C polymorphism and the risk of developing bladder cancer in this Chinese population. PMID- 26634515 TI - Purification, characterization, and heterologous expression of an antifungal protein from the endophytic Bacillus subtilis strain Em7 and its activity against Sclerotinia sclerotiorum. AB - An antifungal protein exhibiting a high activity against Sclerotinia sclerotiorum in vivo was purified by ammonium sulfate precipitation, hydrophobic chromatography, and gel filtration chromatography from the culture filtrate of the endophytic Bacillus subtilis strain Em7. The protein was characterized as a beta-1,3-1,4-glucanase according to amino acid analysis, and showed excellent properties in thermal stability and acid resistance. At the same time, the antifungal protein was cloned and heterologously expressed in Escherichia coli BL21. The recombinant protein was purified and showed similar enzymatic properties to the native protein, exhibiting strong inhibitory activity against S. sclerotiorum. This shows that the beta-1,3-1,4-glucanase may play a very important role in B. subtilis Em7 biocontrol function. In addition, many physiochemical properties of the native and purified recombinant protein were compared, including the effect of pH, temperature, metal cations, substrate specificity, and kinetic parameters. All parameters were similar between the native and recombinant purified protein, indicating that the purified recombinant protein has potential for industrial applications. PMID- 26634516 TI - RUNX3 gene polymorphisms and haplotypes in Mexican patients with colorectal cancer. AB - We analyzed a possible association between RUNX3 gene polymorphisms and haplotypes in Mexican patients with colorectal cancer (CRC). Genomic DNA samples were obtained from the peripheral blood of 176 Mexican patients with CRC at diagnosis and from 195 individuals that formed the control group. The polymorphisms were detected by polymerase chain reaction-restriction fragment length polymorphism. Association was estimated by odds ratio (OR). The haplotypes and linkage disequilibrium were established using the Arlequin v3.5 software. We found that the RUNX3 polymorphisms analyzed were in Hardy-Weinberg equilibrium. The RUNX3 rs2236852 AA genotype and A allele showed association with CRC (OR = 0.39, 95%CI = 0.21-0.73, P < 0.01; OR = 0.65, 95%CI = 0.49-0.87, P < 0.01, respectively), while the rs6672420, rs11249206, and rs760805 polymorphisms did not show significant association with CRC. The TA haplotype (SNPs rs760805 and rs2236852) showed an increased risk for CRC (OR = 2.52, 95%CI = 1.47-4.30, P < 0.001). In conclusion, we found that the AA genotype and A allele of rs2236852 polymorphism confer a decreased CRC risk, while the TA haplotype appears to increase the risk of CRC development in Mexican patients. PMID- 26634517 TI - VDAC2 involvement in the stress response pathway in Arabidopsis thaliana. AB - The voltage-dependent anion channel (VDAC) is the major transport protein in the outer membrane of mitochondria, and is involved in the formation of a permeable transition pore and metabolite transport. In this study, we explored the role of Arabidopsis thaliana VDAC2 (AtVDAC2) in the signal transduction pathway in Arabidopsis under salt stress. We investigated the germination rates of AtVDAC2 transgenic lines under salicylic acid (SA) treatment, and found that AtVDAC2 can affect the sensitivity of Arabidopsis to SA. Furthermore, the stomatal apertures of AtVDAC2 transgenic Arabidopsis were calculated. Results showed that the over expression lines showed the obvious stomatal closure, while in the antisense lines, no obvious changes in stomatal apertures were found. In addition, we also detected the expression levels of salt stress and SA response-associated genes in transgenic plants and found that AtVDAC2 affected the expression of these genes. Our study investigated the role of AtVDAC2 in SA and salt stress response in Arabidopsis; our observations provide some helpful information for better understanding the direct and downstream functions of AtVDAC. PMID- 26634518 TI - Association of polymorphism in ICAM-1 (K469E) and cytology parameters in patients' initial blood test with acute ischemic stroke. AB - Acute ischemic stroke (AIS) has become a serious health problem in many countries because of its poor outcome and worsening epidemic trend. Early identification of genetic risk factors and physiological indicators for stroke occurrence may help to reduce the incidence of stroke. Therefore, we conducted a case-control study including 50 AIS patients and 50 healthy individuals from a Chinese population to explore the association between AIS and patient complete blood profiles and the association between AIS and the genetic polymorphism K469E in intercellular adhesion molecule-1 (ICAM-1). Compared to the control group, AIS patients showed a high percentage of mononuclear cells, low platelet count, low ratio of platelet to lymphocyte count, high frequency of the 469K allele, and low frequency of the 469E allele. White blood cell count, percentage of neutrophils, percentage of lymphatic cells, platelet distribution width, mean platelet volume, and platelet hematocrit levels showed no significant differences between the 2 groups and between different genotypes. Our results suggested an association of elevated levels of mononuclear cells and reduced platelet count with higher AIS risk. Our results also supported the hypothesis that the KK genotype at the K469E locus in ICAM-1 is a risk factor for AIS. PMID- 26634519 TI - XRCC1 rs25487 polymorphism is associated with lung cancer risk in epidemiologically susceptible Chinese people. AB - Base excision repair (BER) plays an important role in maintaining genome integrity and anti-cancer drug resistance. Single nu-cleotide polymorphisms (SNPs) in BER genes were detected in 500 lung cancer patients and 500 cancer-free controls. A logistic regression model was applied to analyze the relationship between lung cancer susceptibility and BER SNPs coupled with a wide range of epidemiological factors in a Chinese population. SNPs including rs25487 in the X ray repair cross-complementing group 1 gene, rs1052133 in the 8-oxoguanine DNA gly-cosylase gene, and rs1136410 in the poly (ADP-ribose) polymerase 1 gene were identified. Multivariate analysis showed that the rs25487-AG geno-type was associated with a higher incidence of lung cancer compared with the GG genotype. The rs25487 SNP was associated with the pathological distribution of lung cancer. Moreover, rs1052133-GG was associated with early age of lung cancer onset compared with the CC genotype. Our data demonstrated that the SNPs rs25487 and rs1052133 are risk factors for lung cancer in epidemiologically susceptible Chinese people. PMID- 26634521 TI - Association between serum angiopoietin-2 concentration and clinicopathological parameters in patients with colorectal cancer. AB - We examined the expression of angiopoietin-2 in serum samples from patients diagnosed with colorectal cancer and healthy volunteers and investigated the feasibility of using angiopoietin-2 as a potential diagnostic colorectal cancer biomarker. Enzyme-linked immunosorbent assays were used to measure the levels of angiopoietin-2 in patients with colorectal cancer and healthy control subjects. Correlations between serum angiopoietin-2 levels and clinicopathological factors were investigated. A receiver operating characteristic curve was used to predict cut-off values of the markers. Serum concentrations of angiopoietin-2 were significantly higher in patients with colorectal cancer than in controls (2896 +/ 1273 vs 1554 +/- 991 pg/mL, P = 0.004). Serum angiopoietin-2 expression levels were significantly positively correlated with TNM stage (P = 0.003), lymph node involvement (P = 0.04), and distant metastases (P = 0.005). Receiver operating characteristic curve analysis revealed that serum level of angiopoietin-2 was a potential biomarker for differentiating colorectal cancer patients from controls and had a receiver operating characteristic area under the curve of 0.859 (95% confidence interval = 0.740-0.978). At a cut-off value of 2710 pg/mL, the sensitivity was 79.3% and the specificity was 82.4%. Our results suggest that angiopoietin-2 can be used as a diagnostic biomarker for colorectal cancer in clinical practice. Additional studies are needed to clarify the detailed mechanism of angiopoietin-2 in the carcinogenesis and metastasis of colorectal cancer. PMID- 26634520 TI - Efficacy and safety of nucleoside analogues in preventing vertical transmission of the hepatitis B virus from father to infant. AB - We examined the efficacy and safety of nucleoside analogues in preventing the vertical transmission of hepatitis B virus (HBV) from father to infant. We included 201 patients who visited the liver clinic of our hospital. The patients were positive for HBV surface antigen (HBsAg), HBeAg, anti-HBc, and HBV DNA; 189 patients (94%) had abnormal liver function. In all couples, the fathers were HBV DNA-negative and had normal liver function, and the mothers were anti-HB-positive before pregnancy. The control group comprised 188 couples who visited our hospital during the same time period. The fathers in the control group were positive for HBsAg, HBeAg, anti-HBc, and HBV DNA. The mothers were HBsAg-negative and anti-HBs-positive. No infants in the case group were HBsAg-positive and HBV DNA-positive, and all were anti-HBs-positive, indicating that father to infant HBV vertical transmission was prevented in the case group. In the control group, 147 of 188 newborns (78.2%) were anti-HBs-positive at birth, 28 (14.9%) were HBV DNA-positive, and 19 (10.1%) were HBsAg-positive. A significant difference was observed between the two groups. No statistically significant difference was observed in the gestational age, birth weight, birth length, 1-min and 8-min Apgar score, jaundice, other internal and surgical diseases, delivery mode, and other birth information between the neonates born to couples in the case and control groups; there were no fetal malformations and stillbirths in the two groups. Our results showed that administration of antiretroviral therapy to HBV DNA-positive fathers before pregnancy can cause a decrease in the viral load and prevent father to infant HBV vertical transmission. The use of antiviral nucleoside analogues before pregnancy was safe in fathers, and the fathers who wanted children could continue to use anti-viral therapy. The sample size in our study was small, and further studies with a large sample size and longer follow up time are required for determining the use of nucleoside analogues from the point view of prenatal and postnatal care. PMID- 26634522 TI - Relationship between HLA-DP gene polymorphisms and the risk of hepatocellular carcinoma: a meta-analysis. AB - The association between the HLA-DP single nucleotide polymorphisms (SNPs) rs3077 and rs9277535 and hepatocellular carcinoma (HCC) has been reported, but results have been inconclusive and controversial. Therefore, to investigate the relationship between these HLA-DP SNPs and HCC susceptibility, a meta-analysis of studies published before January 2014 was carried out using the PubMed and Google Scholar databases. Odds ratios (ORs) and 95% confidence intervals (CI) were calculated for HLA-DP alleles, and for co-dominant, dominant, and recessive genotype models of each SNP, based on fixed- or random-effects models. A total of nine studies from six published articles were included. The association study between rs3077 and HCC susceptibility was performed in four independent comparisons that contained 1871 cases with hepatitis B virus (HBV)-related HCC and 3207 carriers with persistent HBV. Association between rs9277535 and HCC susceptibility was examined in five separate comparisons that contained 2017 cases and 3930 carriers. Our analysis indicated a significant association of rs3077 and rs9277535 with HCC susceptibility, suggesting that rs3077 might act beneficially against HCC susceptibility (A vs G: OR = 0.884, 95%CI = 0.803-0.973, P = 0.012; GA vs GG: OR = 0.842, 95%CI = 0.733-0.967, P = 0.015; AA+GA vs GG: OR = 0.848, 95%CI = 0.744-0.968, P = 0.014), and that rs9277535 might promote HCC susceptibility (AA vs GA: OR = 1.202, 95%CI = 1.011-1.428, P = 0.037). This study suggested that HLA-DP rs3077 and rs9277535 polymorphisms are associated with HCC susceptibility in the Asian population. PMID- 26634523 TI - Dihydromyricetin induces cell apoptosis via a p53-related pathway in AGS human gastric cancer cells. AB - The aim of the present study was to determine the anti-proliferative and pro apoptotic effects of dihydromyricetin (DHM) on the AGS human gastric cancer cells and their underlying mechanisms. The effects of DHM on AGS cells were evaluated by using 3-(4, 5-di-methylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), lactate dehydrogenase, and Annexin V/propidium iodide (PI) double-staining assays. The underlying mechanisms were determined by using quantitative real-time polymerase chain reaction. The results demonstrated that DHM significantly (P < 0.05) inhibited AGS cell proliferation and induced cell cytotoxicity in a dose- and time-dependent manner. Additionally, Annexin V/PI double-staining assay showed that DHM promoted cell apoptosis in both, early and late stages. Furthermore, DHM also regulated the expression of apoptotic genes such as p53 and B-cell lymphoma-2 (bcl-2) in a dose- and time-dependent manner. In conclusion, this is the first report demonstrating the anticancer and pro-apoptosis effects of DHM on AGS human gastric cancer cells. The results strongly suggest that DHM may be a potential therapeutic candidate for the treatment of gastric cancer. PMID- 26634524 TI - Morphology and photosynthetic enzyme activity of maize phosphoenolpyruvate carboxylase transgenic rice. AB - The morphology and photosynthetic enzyme activity were studied in maize phosphoenolpyruvate carboxylase transgenic rice and non-transgenic rice. The results showed that compared with non-transgenic rice, phosphoenolpyruvate carboxylase transgenic rice was taller and had a stronger stalk, wider leaves, and more exuberant root system, with increased photosynthetic enzyme activity and improved yield components. Therefore, given the superiority of this plant type and heterosis, this is a novel breeding strategy for rice for the introduction of C4 photosynthesis genes into high-yielding rice. PMID- 26634525 TI - Physiological evaluation of the responses of Larix olgensis families to drought stress and proteomic analysis of the superior family. AB - The conifer Larix olgensis has been analyzed to delineate physiological and proteomic changes that occur under drought stress. Studies of the deleterious effects of drought in the larch families have mainly focused on photosynthesis. In the present study, when the intensity of drought was increased, plant height was inhibited as both POD and MDA levels increased, which indicates oxidative stress. Two-dimensional gel electrophoresis analysis detected 23 significantly differentially expressed proteins, of which 18 were analyzed by peptide mass fingerprinting by using MALDI-TOF/TOF. Eight spots were found to be up-regulated, while the other 10 spots were down-regulated during drought stress. The proteins that were induced by drought treatment have been implicated in the physiological changes that occurred. These results could provide additional information that could lead to a better understanding of the molecular basis of drought sensitivity in larch plants. PMID- 26634526 TI - Effects of gemcitabine on radiosensitization, apoptosis, and Bcl-2 and Bax protein expression in human pancreatic cancer xenografts in nude mice. AB - The aim of this study was to evaluate the radiosensitizing effects of gemcitabine towards human pancreatic cancer xenografts. A human pancreatic cancer xenograft model was established in nude mice, 36 of which were randomly divided into 6 treatment groups. Tumors were measured every 2 days, and the tumor volumes, growth delays, and inhibition rates were compared to evaluate the gemcitabine enhancement factor. The apoptotic index was determined by terminal deoxynucleotidyl transferase dUTP nick end-labeling assay, and apoptosis inhibitory protein Bcl-2 and apoptosis-related protein Bax expression were detected by immunohistochemistry. Compared with the control group, xenograft growth was significantly inhibited in the 25 (G25) and 50 mg/kg gemcitabine (G50) groups (P < 0.05). In the 25 (G25R) and 50 (G50R) mg/kg gemcitabine + radiotherapy groups, local tumor growth was significantly inhibited, with inhibition rates of 88.22 and 91.23%, respectively, significantly higher than those of the simple radiotherapy (SR), G25, and G50 groups (44.11, 72.88, and 77.53%, respectively; P < 0.05). The tumor growth delay in the G25R and G50R groups were 9 and 15 days, respectively, higher than the SR, G25, and G50 groups (each 4 days, P < 0.05). The apoptosis of tumor cells in the intervention groups significantly increased, and the apoptotic index among the intervention groups exhibited significant differences (P < 0.05). The immunohistochemical results indicated that Bcl-2 was downregulated to different degrees in the intervention groups, whereas Bax was upregulated (P < 0.05). Therefore, gemcitabine appears to enhance the radiotherapeutic sensitivity of human pancreatic cancer xenografts significantly. PMID- 26634527 TI - Correlation between non-metastatic protein 23 expression and clinicopathological features of colorectal cancer in Asians. AB - The current meta-analysis was performed to investigate the association between non-metastatic protein 23 (NM23) expression, tumor pathology, and disease prognosis in colorectal cancer (CRC) among Asians. English and Chinese language based electronic databases (e.g., PubMed, EBSCO, Ovid, Springerlink, Wiley, Web of Science, Wanfang databases, China National Knowledge Infrastructure, VIP databases) were searched using search terms to identify published studies relevant to NM23 and CRC with immunohistochemistry. In total, 289 studies were identified through database searches, and 16 cohort studies (4 studies in English, 12 in Chinese) were chosen for meta-analysis, which included 1592 CRC patients. The results revealed that NM23 protein expression in CRC tissue was higher in patients with Dukes stages A and B than in patients with Dukes stages C and D. The NM23 protein was expressed at higher levels in well- and moderately differentiated tumors than in poorly differentiated tumors. The 5-year survival rate was also higher in CRC patients with NM23-positive tumors than in CRC patients with NM23-negative tumors. Significantly, 5-year tumor relapse and metastasis were lower in patients with NM23-positive tumors than in CRC patients with NM23-negative tumors. The findings suggest that NM23 expression status is associated with tumor aggressiveness and survival in CRC among Asians. Importantly, CRC patients with NM23-positive tumors had a better prognosis, and thus NM23 expression maybe used as a key prognostic indicator for CRC. PMID- 26634528 TI - SET8 expression is associated with overall survival in gastric cancer. AB - SET8, a member of the SET domain-containing methyl-transferase, has been implicated in various biological processes. In this study, SET8 was immunostained in 100 samples of gastric cancer tissues and semi-quantified using the HSCORE method to determine the predictive value of SET8 expression levels for gastric cancer outcome. The relationship between SET8 expression and the 5-year survival rate of gastric cancer patients was assessed. High expression of SET8 was associated with a shorter survival time in gastric cancer patients, and the level of SET8 expression was found to be an independent predictor of gastric cancer outcome (relative risk = 1.939; 95% confidence interval = 1.025-3.668; P = 0.042). Analysis of SET8 levels may help in the identification of patient subgroups that are at high risk for poor disease outcomes. PMID- 26634529 TI - Genetic differentiation of Octopus minor (Mollusca, Cephalopoda) off the northern coast of China as revealed by amplified fragment length polymorphisms. AB - Octopus minor (Sasaki, 1920) is an economically important cephalopod that is found in the northern coastal waters of China. In this study, we investigated genetic differentiation in fishery populations using amplified fragment length polymorphisms (AFLPs). A total of 150 individuals were collected from five locations: Dalian (DL), Yan-tai (YT), Qingdao (QD), Lianyungang (LY), and Zhoushan (ZS), and 243 reproducible bands were amplified using five AFLP primer combinations. The percentage of polymorphic bands ranged from 53.33 to 76.08%. Nei's genetic identity ranged from 0.9139 to 0.9713, and the genetic distance ranged from 0.0291 to 0.0900. A phylogenetic tree was constructed using the unweighted pair group method with arithmetic mean, based on the genetic distance. The DL and YT populations originated from one clade, while the QD, LY, and ZS populations originated from another. The results indicate that the O. minor stock consisted of two genetic populations with an overall significantly analogous FST value (0.1088, P < 0.05). Most of the variance was within populations. These findings will be important for more sustainable octopus fisheries, so that this marine resource can be conserved for its long-term utilization. PMID- 26634530 TI - Differential expression of peroxisome proliferator-activated receptor gamma, fatty acid synthase, and hormone-sensitive lipase in fat-tailed and thin-tailed sheep breeds. AB - Tail fat content affects meat quality, and it varies in different sheep breeds. Theoretically, lipid metabolism contributes to variation in tail fat content. Tail length, tail width, and tail girth were measured in live Tong sheep (with both short fat tail and long fat tail), Shaanbei fine wool sheep (long thin tail), Tan sheep (short fat tail), Kazakh sheep (hip fat tail), and Tibetan sheep (short thin tail). The expression levels of genes related to tail adipose tissue lipid metabolism were investigated, which included lipogenetic genes (PPARgamma and FAS) and lipolytic gene (HSL). Differences were observed (P < 0.05) in PPARgamma mRNA expression levels in the different breeds; FAS mRNA expression levels did not differ (P > 0.05) in Tong sheep with short fat tail, Tong sheep with long fat tail, Shaanbei fine wool sheep, and Tibetan sheep; HSL mRNA expression levels were not different (P > 0.05) in Tong sheep. PPARgamma and HSL protein expression levels differed (P < 0.05) between the different breeds; FAS protein expression levels were different (P < 0.05) in Tong sheep with long fat tails, Tan sheep, Kazakh sheep, and Tibetan sheep, but did not differ (P > 0.05) in Tong sheep with short fat tails and Shaanbei fine wool sheep. These results provide useful information to further understand the function of PPARgamma, FAS, and HSL in sheep tail lipid metabolism, which should be applicable to studies on the regulation of fat deposition and improvement of meat quality. PMID- 26634531 TI - A meta-analysis to evaluate the effectiveness of real-time PCR for diagnosing novel coronavirus infections. AB - Novel coronavirus (nCoV) belongs to the Coronaviridae family, which includes the virus that causes SARS, or severe acute respiratory syndrome. However, infection source, transmission route, and host of nCoV have not yet been thoroughly characterized. In some cases, nCoV presented a limited person-to-person transmission. Therefore, early diagnosis of nCoV may be of importance for reducing the spread of disease in public. Methods for nCoV diagnosis involve smear dyeing inspection, culture identification, and real-time PCR detection, all of which are proved highly effective. Here, we performed a meta-analysis to evaluate the effectiveness of real-time PCR for diagnosing nCoV infection. Fifteen articles conformed to the inclusion and exclusion criteria for further meta-analysis on the basis of a wide range of publications searched from databases involving PubMed, EMBASE, Web of Science, Medline, ISI. We analyzed the stability and publication bias as well as examined the heterogeneity inspection of real-time PCR detection in contrast to smear staining and culture identification. The fixed-effect model was adopted in our meta-analysis. Our result demonstrated that the combination of real-time PCR and smear diagnostics yielded an odds ratio (OR) = 1.91, 95% confidence interval (CI) = 1.51-2.41, Z = 5.43, P < 0.05, while the combination of real-time PCR and culture identification yielded OR = 2.44, 95%CI = 1.77-3.37, Z = 5.41, P < 0.05. Therefore, we propose real-time PCR as an efficient method that offers an auxiliary support for future nCoV diagnosis. PMID- 26634532 TI - Protective effect of interleukin-10 and recombinant human keratinocyte growth factor-2 on ventilation-induced lung injury in rats. AB - A rat model of ventilation-induced lung injury (VILI) during anesthesia was generated to investigate the potential role and possible mechanism of interleukin 10 (IL-10) and recombinant human keratinocyte growth factor-2 (rhKGF-2) in protecting anesthetized rats against VILI. A total of 50 male SD rats were randomly divided into 5 groups (N = 10 each): control, VILI, IL-10, rhKGF-2, and IL-10 + rhKGF-2. The VILI (model) group was generated via ventilation, with a tidal volume of 20 mL/kg. Rats in the IL-10 and rhKGF-2 groups received 8 mg/kg IL-10 and 5 mg/kg rhKGF-2, respectively, prior to ventilation. The rats in the IL 10 + rhKGF-2 group received both 8 mg/kg IL-10 and 5 mg/kg rhKGF-2 72 h before ventilation. The total number of nucleated cells and neutrophils in the bronchial alveolar lavage fluid was quantified, and the pathological changes in the pulmonary tissues examined by hematoxylin and eosin staining. The transcript and protein levels of surfactant protein C (SP-C) in lung tissues were detected by real-time polymerase chain reaction and western blot analyses. The SP-C mRNA expression in both IL-10 and rhKGF-2 groups was similar to that in the VILI group. However, this was significantly elevated in the combined treatment group (P < 0.05), indicating that IL-10 and rhKGF-2 could synergistically protect the lung tissue from VILI via the enhancement of SP-C mRNA expression in lung tissues. The protein assay showed a decreased level of infiltration and activation of inflammatory cells, in addition to increased expression of SP-C, thereby confirming the efficacy of this treatment in preventing VILI during anesthesia. PMID- 26634533 TI - Matrix metalloproteinase-3 gene polymorphism and its mRNA expression in rheumatoid arthritis. AB - Matrix metalloproteinase-3 (MMP-3) can mediate the occurrence and development of rheumatoid arthritis (RA). The MMP3 promoter gene exhibits polymorphism with 5A/6A alleles. We investigated the correlation between the expression of MMP3 gene polymorphism and RA to provide an objective basis for prognosis evaluation. We enrolled 80 RA patients and 80 healthy subjects. Enzyme-linked immunosorbent assay was used to detect MMP-3 serum levels, pyrosequencing was used to test MMP3 genotypes, and real-time polymerase chain reaction determined MMP-3 mRNA expression levels. Compared with the control group, the serum level of MMP-3 in the RA patients increased significantly (P < 0.05). The serum level of MMP-3 in RA patients in the active period was markedly elevated compared with that in patients in the relief period (P < 0.05). There was no statistically significant difference between MMP3 gene frequency distribution in the RA patients and the control group (P > 0.05). MMP-3 mRNA expression in the RA patients was markedly upregulated compared with the control group (P < 0.05), while RA patients in the active period exhibited higher MMP-3 mRNA expression (P < 0.05). There was no significant difference in MMP-3 mRNA expression between RA patients with or without the 6A/6A genotype (P > 0.05). RA patients exhibited higher serum MMP-3 levels and mRNA expression, which were more obvious in the active period. MMP-3 is associated with the occurrence and development of RA bone erosion, and its serum level and mRNA expression can be treated as important predictors of joint damage. PMID- 26634534 TI - Clinical and cytogenetic results of a series of amniocentesis cases from Northeast China: a report of 2500 cases. AB - The aims of this study were to demonstrate the clinical and cytogenetic results of amniocentesis (AS) cases in Northeast China, to compare the incidence of different kinds of chromosomal abnormalities, and to study the association between the detection rate of chromosomal abnormalities and different indications for prenatal diagnosis. Cytogenetic analysis was performed on long-term tissue cultures of 2500 second-trimester amniotic fluid samples. The most common indication for genetic AS was abnormal maternal serum-screening test (69.56%), followed by advanced maternal age (15.04%). Chromosomal abnormality was detected in 206 (8.24%) of the 2500 samples. The detection rate of abnormal karyotypes was 62.5% in the group in which one member of the couple was a carrier of a chromosome abnormality; in the group having a positive result from noninvasive prenatal testing, the frequency was 50%. To determine the origin of fetal chromosome abnormal karyotype, 45 fetuses were analyzed. Of these, 20 were found to be de novo abnormalities and 25 were familial. The frequency and proportion of abnormal karyotypes varied substantially across different maternal AS indications. Knowing the origin and type of chromosomal abnormality would help determine termination or continuation of the pregnancy. PMID- 26634535 TI - A genome-wide analysis of the ultimate pH in swine. AB - Meat pH is an important factor influencing meat quality traits in swine. This study evaluated a large number of genetic variants that covered all of the swine chromosomal regions. Approximately 68,000 single nucleotide polymorphisms (SNPs), found on Illumina Porcine SNP chips, were tested for associations with meat pH values. A genome-wide association study (GWAS) found that 19 SNPs on Sus scrofa chromosome 4 were significantly associated with pH. Two major candidate genomic regions were defined: a 1.08-Mb region (at nucleotide 30118313 to 31207050) contained 10 significant SNPs, based on an effect value of 5.0; and a 2.7-Mb genomic region (at nucleotide 73293076 to 76023681) contained 9 significant SNPs. Three putative genes--PKHD1L1, VCPIP1, and LOC102166532--were identified by GWAS near significant SNPs. These genes may account for variations in pH levels. Three pseudogenes and two non-coding RNAs were also detected by GWAS analysis. Estimations of expected and observed P values for pH revealed significant departures from the null hypothesis. A total of 9 haplotype blocks (HB) were constructed: HBs 1, 3, and 5 showed significant effects on pH24 and pH45, whereas an association was not confirmed between pH24 and HBs 4, 6, and 8. Findings from this study indicate that the three genes identified may influence pH of pig meat. PMID- 26634536 TI - Genomic survey and gene expression analysis of the VDAC gene family in rice. AB - The voltage-dependent anion channel (VDAC), also known as a mitochondrial porin, plays an important role in the regulation of metabolic and energetic functions of mitochondria, as well as in mitochondria-mediated apoptosis. Cytoplasmic male sterility (CMS) is of major economic importance for commercial hybrid production and a research model for the interaction be-tween nuclear and cytoplasmic genomes. Recent research has revealed that CMS is associated with programmed cell death. Here, we used the Honglian (HL)-CMS line of rice (Oryza sativa) as material to investigate the association of O. sativa VDAC (OsVDAC) expression to CMS. Eight VDACs were extracted from rice in this study. Bioinformatic analysis of the rice VDACs was conducted at the DNA, cDNA, and protein level. Expression patterns of OsVDACs were analyzed in different organs and during different stages of pollen development using sterile line YuetaiA (YTA), and its maintainer line YuetaiB (YTB). Differential expression of OsVDACs between YTA and YTB was observed, suggesting that VDACs may be involved in the formation of HL-CMS. PMID- 26634537 TI - Population genetic structure in Phyla scaberrima from Mexico and Colombia assessed by AFLP markers and implications for conservation. AB - Phyla scaberrima (Verbenaceae) is a herbaceous perennial species that is distributed from Mexico (center of origin) to Colombia, growing in forest and swamp edges or grasslands from sea level up to an altitude of 1800 m. The chemical properties and uses in popular medicine have drastically affected the population size of this species. In this study, we investigated genetic variability in populations of P. scaberrima using AFLP markers. Three AFLP primer combinations rendered a total of 997 markers in a sample of 131 individuals from five populations, including two populations from Mexico and three from Colombia. The average percentage of polymorphic loci, gene diversity and Shannon-Wiener index were 46.62, 0.0695, and 0.119, respectively. Analysis of molecular variance showed that the distribution of the genetic variability within populations (85.41%) was higher than between groups (8.11%) and between populations (6.48%). Principal coordinate analysis and Bayesian analysis for the K number of clusters showed that the individuals were dispersed in five (K= 5) clusters. The low levels of genetic diversity observed in these populations demonstrated that the populations from Mexico and Colombia need urgent management to recover their genetic variability. PMID- 26634538 TI - A study of the association between the connexin 40 rs35594137 polymorphism and atrial fibrillation in Xinjiang Chinese Han and Uygur populations. AB - Atrial fibrillation (AF) occurrence has a known genetic component. Many reports have revealed a correlation between gene mutation and AF, involving genes related to ion channels, connexin (Cx), and those within the angiotensin system. In this study, the correlation between the Cx 40 polymorphism (rs35594137) and AF was investigated in patients with AF in the Xinjiang, Turpan, and Kashi regions and in controls. The AF cohort included 122 patients (58 Han and 64 Uygur). The control subjects were recruited according to the 1:1 corresponding method and matched for age and gender. Polymerase chain reaction-restriction enzyme fragment length polymorphism was used to analyze Cx 40 (rs35594137) genotype and allele distributions. Compared with the control group, A allele and A allele frequency were higher in the promoter region of Cx 40 (rs35594137) site (P < 0.05). In the Uygur population, the distribution of rs35594137 genotype and allele frequencies was not significantly different (P > 0.05) from the AF and control groups of Chinese Han origin. The confounding factors, including coronary heart disease, hypertension, smoking, and drinking, were evaluated by multivariate conditional logistic regression analysis. Cx 40 (rs35594137) differences between AF and control groups of Han origin were not significant (P > 0.05), but were statistically significant in the Uygur population (P < 0.05). These results demonstrated that Cx 40 (rs35594137) was associated with AF. In the Uygur population, Cx 40 (rs35594137) should be considered as an independent risk factor for patients with AF, who might have racial differences in rs35594137 variant frequencies. PMID- 26634539 TI - Diversity of arthropod community in transgenic poplar-cotton ecosystems. AB - Poplar-cotton agro-ecosystems are the main agricultural planting modes of plain cotton fields in China. Here, we performed a systematic survey of the diversity and population of arthropod communities in four different combination of poplar cotton eco-systems, including I) non-transgenic poplar and non-transgenic cotton fields; II) non-transgenic poplar and transgenic cotton fields [Bacillus thuringiensis (Bt) cotton]; III) Bt transgenic poplar (high insect resistant strain Pb29) and non-transgenic cotton; and IV) transgenic poplar and transgenic cotton fields, over a period of 3 years. Based on the statistical methods used to investigate community ecology, the effects of transgenic ecosystems on the whole structure of the arthropod community, on the structure of arthropods in the nutritive layer, and on the similarity of arthropod communities were evaluated. The main results were as follows: the transgenic poplar-cotton ecosystem has a stronger inhibitory effect on insect pests and has no impact on the structure of the arthropod community, and therefore, maintains the diversity of the arthropod community. The character index of the community indicated that the structure of the arthropod community of the transgenic poplar-cotton ecosystem was better than that of the poplar-cotton ecosystem, and that system IV had the best structure. As for the abundance of nutritional classes, the transgenic poplar-cotton ecosystem was also better than that of the non-transgenic poplar-cotton ecosystem. The cluster analysis and similarity of arthropod communities between the four different transgenic poplar-cotton ecosystems illustrated that the structure of the arthropod community excelled in the small sample of the transgenic poplar-cotton ecosystems. PMID- 26634540 TI - Effect of specific silencing of EMMPRIN on the growth and cell cycle distribution of MCF-7 breast cancer cells. AB - The extracellular matrix metalloproteinase inducer (EMMPRIN, CD147) is a member of the immunoglobulin family and shows increased expression in tumor cells. We examined the effect of RNAi-mediated EMMPRIN gene silencing induced by lentiviral on the growth and cycle distribution of MCF-7 breast cancer cells. Lentiviral expressing EMMPRIN-short hairpin RNA were packaged to infect MCF-7 cells. The inhibition efficiency of EMMPRIN was validated by real-time fluorescent quantitation polymerase chain reaction and western blotting. The effect of EMMPRIN on cell proliferation ability was detected using the MTT assay and clone formation experiments. Changes in cell cycle were detected by flow cytometry. EMMPRIN-short hairpin RNA-packaged lentiviral significantly down-regulated EMMPRIN mRNA and protein expression, significantly inhibited cell proliferation and in vitro tumorigenicity, and induced cell cycle abnormalities. Cells in the G0/G1 and G2/M phases were increased, while cells in the S phase were decreased after infection of MCF-7 cells for 3 days. The EMMPRIN gene facilitates breast cancer cell malignant proliferation by regulating cell cycle distribution and may be a molecular target for breast cancer gene therapy. PMID- 26634542 TI - Distribution of constitutive heterochromatin in Pachycoris torridus (Hemiptera, Scutelleridae) with different chromatic patterns. AB - The stink bug Pachycoris torridus is a pest of great agricultural importance due to its records on culture of physic nut (Jatropha curcas), which is the raw material for biodiesel production. An interesting feature of this insect is its high phenotypic variability, a characteristic that resulted in it being classified as a new species on eight separate occasions. In the suborder Heteroptera, the heterochromatin pattern is specific and often allows species to be differentiated. To confirm whether there is differentiation between specimens of P. torridus with different color patterns (yellow, orange, brown, and red), samples were analyzed cytogenetically using the C-banding method. During meiotic prophase, the four color patterns analyzed showed a large heterochromatic chromocenter, consisting of a combination of both sex chromosomes (X and Y). Thus, the present study reports chromosomal homogeneity in different color patterns of P. torridus and highlights the importance of this tool in the description of new species. PMID- 26634541 TI - Effect of atorvastatin on plasma NT-proBNP and inflammatory cytokine expression in patients with heart failure. AB - The aim of this study was to explore the effect of atorvastatin intervention on plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) and inflammatory cytokine levels in patients with heart failure (HF). One hundred and twenty-three HF patients were selected from our hospital and randomly divided into control (N = 61) and observation (N = 62) groups; the former received conventional treatment, while the latter were given conventional treatment combined with atorvastatin. Plasma NT-proBNP, inflammatory cytokines [high-sensitive C-reactive protein (hs-CRP), interleukin (IL)-6, IL-10] and cardiac function [left ventricular end-diastolic dimension (LVEDD), left ventricular ejection fraction (LVEF), end-diastolic maximum flow rate ratio (E/A)] were compared among groups. The effective rate of treating HF significantly increased after atorvastatin treatment. The plasma NT-proBNP, IL-6, IL-10, hs-CRP, and LVEDD levels significantly decreased (P < 0.05), while the LVEF and E/A levels significantly increased (P < 0.05) in the observation group compared to the control group and before intervention. The NT-proBNP and cytokine levels significantly differed among patients with different classes of heart function (P < 0.05); the NT-proBNP and cytokine levels increased with the severity of heart function. Pearson's correlation analysis revealed a negative correlation between the NT-proBNP and inflammatory cytokine levels and LVEF and E/A values, and a positive correlation between these factors and LVEDD (P < 0.05). In conclusion, atorvastatin significantly improves cardiac function; the mechanism atorvastatin action was related to the decrease in plasma NT-proBNP and inflammatory cytokine levels. PMID- 26634543 TI - Microbiological quality and bacterial diversity of the tropical oyster Crassostrea rhizophorae in a monitored farming system and from natural stocks. AB - Microbiological evaluation is one of the most important parameters for analyzing the viability of an oyster farming system, which addresses public health and ecological concerns. Here, the microbiological quality of the oyster Crassostrea rhizophorae cultivated in a monitored environment and from natural beds in Bahia, northeastern Brazil, was determined. Bacterial diversity in oysters was measured by polymerase chain reaction-denaturing gradient gel electrophoresis. Sequence analysis revealed that most bacterial species showed similarity with uncultured or unidentified bacteria from environmental samples, and were clustered into the phylum Proteobacteria. Diverse bacteria from cultivated (monitored) oyster samples were grouped in the same cluster with a high similarity index (above 79%). Microbiological analyses revealed that these oysters did not contain pathogens. These results reflect the natural balance of the microbial communities essential to the maintenance of health and in inhibiting pathogen colonization in the oyster. On the other hand, bacterial diversity of samples from native stocks in extractive areas displayed a similarity index varying between 55 and 77%, and all samples were clustered separately from each other and from the cluster of samples derived from the cultivation area. Microbiological analyses showed that oysters from the extractive area were not fit for human consumption. This reflected a different composition of the microbial community in this area, probably resulting from anthropic impact. Our study also demonstrated that low temperatures and high rainfall limits the bacterial concentration in tropical oysters. This is the first study analyzing the total bacterial community profiles of the oyster C. rhizophorae. PMID- 26634544 TI - Influence of suppression of CapG gene expression by siRNA on the growth and metastasis of human prostate cancer cells. AB - This study investigated CapG gene expression in prostate cancer cell lines; in addition, we explored the effects of CapG suppression on DU145 cell growth, and the underlying mechanism with which CapG affects DU145 cell growth and invasiveness. The expression of CapG and 18 related genes in DU145 cells was analyzed by flow cytometry, quantitative polymerase chain reaction (qPCR), CCK8 assay, western blot, and the trans-well assay. DU145 cells were transfected with designed small interfering RNA (siRNA). CapG expression was quantified by qPCR and western blot. DU145 cell proliferation and invasiveness was analyzed using the CCK8, flow cytometric, and trans-well assays. CapG, TMPRSS1, EGFR, ETS-1, ERBB2, AKT, Cyclin D1, P21, Bcl-2, and Bak1 gene and Bcl-2, Cyclin D1, and CapG protein expressions were significantly lower in the siRNA group compared to the negative control group (P < 0.05). The proliferation of CapG siRNA DU145 cells was lower than that of the two control groups, 48 h after transfection. The cell inhibition rate was 24.5, 35.4, and 16,5% at 24, 48, and 72 h, respectively. The growth curve indicated that CapG siRNA DU145 cells showed a significantly slower proliferation rate (P < 0.05). The trans-well assay showed a significant decrease in the migratory and invasive capacities of DU145 cells in the siRNA group (P < 0.05). The suppression of CapG expression caused a significant decrease in the proliferation, invasiveness, and metastasis of DU145 cells. The mechanism with which CapG, with other oncogenes, influences cancer cell cycle remains to be elucidated. PMID- 26634545 TI - Identification of a novel mutation of the EDA gene in X-linked hypohidrotic ectodermal dysplasia. AB - This study aimed to identify the disease-causing mutation in the ectodysplasin A (EDA) gene in a Chinese family affected by X-linked hypohidrotic ectodermal dysplasia (XLHED). A family clinically diagnosed with XLHED was investigated. For mutation analysis, the coding region of EDA of 2 patients and 7 unaffected members of the family was sequenced. The detected mutation in EDA was investigated in 120 normal controls. A missense mutation (c.878T>G) in EDA was detected in 2 patients and 3 female carriers, but not in 4 unaffected members of the family. The mutation was not found in the 120 healthy controls and has not been reported previously. Our findings indicate that a novel mutation (c.878T>G) of EDA is associated with XLHED and adds to the repertoire of EDA mutations. PMID- 26634546 TI - A genome-wide association study of growth trait-related single nucleotide polymorphisms in Chinese Yancheng chickens. AB - Chicken (Gallus gallus) growth traits are important economic traits, and many studies have been conducted on genetic selection for body weight. However, most of these studies have detected functional chromosome mutations or regions by conventional molecular markers or gene chips. In this study, we performed a new genome-wide association study using specific-locus amplified fragment sequencing (SLAF-seq) technology in purebred Yancheng chickens. Single nucleotide polymorphisms (SNPs) that were significantly associated with phenotypic traits were identified by GAPIT-compressed mixed linear models. Eighteen SNP markers reached 5% Bonferroni genome-wide significance. A region spanning 72.3 to 82.1 Mb on GGA4 had a strong influence on growth traits. Four genes (FAM184B, KCNIP4, MIR15A, and GLI3) were closely associated with body weight. Some SNPs were coincident with previously reported quantitative trait locus regions. Our results would promote the researches of Chinese chickens and accelerate the utilization of Chinese chicken, specially Yancheng chicken. PMID- 26634547 TI - LITAF, HHEX, and DUSP1 expression in mesenchymal stem cells from patients with psoriasis. AB - Psoriasis is a common chronic relapsing inflammatory skin disease, in which mesenchymal stem cells (MSCs) have been hypothesized to play an important role in abnormal localized inflammation and vascular proliferation observed in skin lesions. Previous studies have revealed abnormal gene expression patterns, DNA methylation status, and cytokine secretion of MSCs in psoriatic skin lesions, as well as some gene expression abnormalities related to inflammation and angiogenesis. We further verified the gene and protein expressions of inflammation-related lipopolysaccharide-induced tumor necrosis factor-alpha transcription factor (LITAF), dual-specificity protein phosphatase 1 (DUSP1), and angiogenesis-related hematopoietically expressed homeobox (HHEX) in MSCs derived from the skin lesions of psoriasis patients. The gene expression of LITAF, DUSP1, and HHEX in dermal MSCs was measured at the mRNA level using reverse transcription-polymerase chain reaction and the corresponding protein expression levels were analyzed by western blotting analysis. The gene and protein expression levels of LITAF, HHEX, and DUSP1 in dermal MSCs were significantly lower in psoriasis patients compared to controls. Amplification and western blotting results were consistent with our previously reported gene chip data. Our results suggest that dermal MSCs in psoriatic skin lesions may be involved in the development, progression, and regulation of localized inflammatory abnormalities by reducing the expression of LITAF, HHEX, and DUSP1, which are related to inflammation and angiogenesis. PMID- 26634548 TI - Polymorphisms in CYP17, COMT, and ESR1 genes in women after menopause and association with bone mineral density. AB - In this study, we evaluated genetic factors related to the mineral density during post-menopause. We evaluated 110 women in the first 5 years post-menopause, without previous hormone replacement therapy. Cytochrome P450 17 (CYP17) (rs743572), catechol-O-methyl transferase (COMT) (rs4680), and estrogen receptor 1 (ESR1) (rs9322331) were examined for the presence of polymorphisms. Clinical data were collected by anamnesis; all patients had the osseous densitometry examined using a lunar instrument to determine mineral osseous densitometry in the lumbar column (L2-L4). CYP17, COMT, and ESR1 genotyping was carried out by polymerase chain reaction with DNA collected from buccal swabs. The average age was 51.96 years. The average weights of the patients in control and osteopenia groups were 70.25 +/- 12.00 and 62.45 +/- 11.64, respectively (P = 0.001) and body mass index (P = 0.006; control: 29.43 +/- 5.25; osteopenia: 26.72 +/- 4.57). Related to CYP17 polymorphisms, 28.18% of women were TT (wild-type homozygous), 60% were TC (heterozygous), and 11.82% were CC (mutated homozygous). Related to COMT polymorphisms, 53.64% of women were GG (wild-type homozygous), 37.27% were GA (heterozygous), and 9.09% were AA (mutated homozygous). Related to ESR1, 53.64% of women were CC (wild-type homozygous), 40.91% were CT (heterozygous), and 5.45% were TT (mutated homozygous). The ESR1 variant allele was significantly higher in the osteopenia group when compared with women in the normal group (P = 0.02). ESR1 may be associated with low mineral osseous densitometry, while CYP17 and COMT gene polymorphisms were not associated with mineral osseous densitometry. PMID- 26634549 TI - Association between TNF-alpha rs1799724 and rs1800629 polymorphisms and the risk of Crohn's disease. AB - We investigated the associations between 2 major tumor necrosis factor-alpha (TNF alpha) polymorphisms, rs1799724 C>T and rs1800629 G>A, and the susceptibility to Crohn's disease (CD) using a meta-analysis framework. The PubMed, EBSCO, Ovid, Wiley, Web of Science, WANFANG, and VIP databases (last updated search in October 2014) were comprehensively searched for relevant published studies. The studies retrieved from database searches were filtered based on inclusion and exclusion criteria, and the resultant data extracted from the selected studies were analyzed using the Comprehensive Meta-analysis 2.0 software. Eleven case-control studies, containing 2000 CD patients and 3499 healthy controls, were identified as relevant to this meta-analysis. Data extracted from these 11 studies were analyzed to understand the role of the 2 TNF-alpha polymorphisms in CD. We found that the TNF-alpha rs1799724 C>T polymorphism increased the susceptibility to CD (allele model: OR = 1.293, 95%CI = 1.090-1.534, P = 0.003; dominant model: OR = 1.258, 95%CI = 1.031-1.534, P = 0.024). In contrast, we found no significant association between the TNF-alpha rs1800629 G>A polymorphism and CD susceptibility (allele model: OR = 1.005, 95%CI = 0.864-1.170, P = 0.945; dominant model: OR = 0.962, 95%CI = 0.809-1.145, P = 0.667). This meta-analysis showed that the TNF-alpha rs1799724 C>T polymorphism is associated with CD susceptibility, while the TNF-alpha rs1800629 G>A polymorphism appeared to have no correlation with the susceptibility to CD. PMID- 26634550 TI - Transcriptional profiles of emasculated flowers of black locust (Robinia pseudoacacia) determined using the cDNA-AFLP technique. AB - Black locust (Robinia pseudoacacia) is a tree in the subfamily Faboideae, native to North America, that has been naturalized and widely planted in temperate Europe and Asia. Black locust has important ecological and economic value, but its quality needs improvement. Hybridization programs are important for black locust breeding, but the low rate of fruit set after controlled pollination limits both its breeding and that of other monoclinous plant species that share this problem. In this study, we investigated gene expression in emasculated black locust flowers using the cDNA-amplified fragment length polymorphism technique to determine why the rate of fruit set is low after controlled pollination. Flowers that were emasculated after being frozen in liquid nitrogen were used as controls. Changes in the flower transcriptome were more dramatic at 5 h after emasculation than at 48 h. Injury caused by emasculation decreased the expression levels of genes associated with metabolism, growth regulation, signal transduction, and photosynthesis, and it increased the expression of genes related to stress-response metabolism, signal transduction, and promotion of senescence. The changes in the expression levels of these genes had negative effects on sugar metabolism, protein metabolism, lipid metabolism, energy metabolism, matter transport, signal transduction, osmotic regulation, pH regulation, and photosynthesis. Thus, emasculation accelerated flower senescence, resulting in low fruit set. PMID- 26634551 TI - Relationship between the HLA-G 14 bp insertion/deletion polymorphism and susceptibility to autoimmune disease: a meta-analysis. AB - Numerous studies have investigated the potential relationship between the human leukocyte antigen (HLA)-G 14-bp insertion/deletion (INS/DEL) polymorphisms and autoimmune disease (AID). However, published results are inconclusive. Our aim was to determine whether the 14-bp INS/DEL polymorphism in the HLA-G gene contributes to the risk of AID. A systemic literature search of the PubMed and EMBASE databases was conducted to identify eligible studies investigating the association of the HLA-G 14-bp INS/DEL polymorphism with AID. Our analysis included 11 publications involving a total of 6462 individuals. Overall, no significant association between the HLA-G 14-bp INS/DEL polymorphism and AID was detected in any comparison model. Further subgroup analyses based on AID types and ethnicity also revealed no significant associations. Our results suggest that the HLA-G 14-bp INS/DEL polymorphism is unrelated to the development of AID. Further studies including larger sample sizes are warranted to confirm these results. PMID- 26634552 TI - Mutational characterization of the P3H1/CRTAP/CypB complex in recessive osteogenesis imperfecta. AB - Osteogenesis imperfecta (OI) is a genetic disease characterized by bone deformities and fractures. Most cases are caused by autosomal dominant mutations in the type I collagen genes COL1A1 and COL1A2; however, an increasing number of recessive mutations in other genes have been reported. The LEPRE1, CRTAP, and PPIB genes encode proteins that form the P3H1/CRTAP/CypB complex, which is responsible for posttranslational modifications of type I collagen. In general, mutations in these genes lead to severe and lethal phenotypes of recessive OI. Here, we describe sixteen genetic variations detected in LEPRE1, CRTAP, and PPIB from 25 Brazilian patients with OI. Samples were screened for mutations on single strand conformation polymorphism gels and variants were determined by automated sequencing. Seven variants were detected in patients but were absent in control samples. LEPRE1 contained the highest number of variants, including the previously described West African allele (c.1080+1G>T) found in one patient with severe OI as well as a previously undescribed p.Trp675Leu change that is predicted to be disease causing. In CRTAP, one patient carried the c.558A>G homozygous mutation, predicted as disease causing through alteration of a splice site. Genetic variations detected in the PPIB gene are probably not pathogenic due to their localization or because of their synonymous effect. This study enhances our knowledge about the mutational pattern of the LEPRE1, CRTAP, and PPIB genes. In addition, the results strengthen the proposition that LEPRE1 should be the first gene analyzed in mutation detection studies in patients with recessive OI. PMID- 26634553 TI - Association between HLA-DRB1 alleles and tuberculosis: a meta-analysis. AB - Although a number of studies have reported that human leukocyte antigen (HLA) DRB1 alleles may be correlated with tuberculosis (TB), most were based on small samples or inconsistent and unclear results. Here, we present a meta-analysis to investigate the relationship between HLA-DRB1 alleles and TB susceptibility. We gathered relevant information from published studies on the association between HLA-DRB1 alleles and TB susceptibility through a systematic research. Data from eligible fifteen studies were included in the meta-analyses. Each dataset was statistically analyzed to evaluate the HLA-DRB1 alleles by calculating the respective odds ratios (ORs) and 95% confidence intervals (CIs). The results revealed that frequencies of two DRB1 alleles were significantly decreased in TB: DRB1*03 (P = 0.016, OR = 0.78, 95%CI = 0.67-0.95) and DRB1*07 (P = 0.017, OR = 0.81, 95%CI = 0.68-0.96). Thus, our data indicate that DRB1*03 and DRB1*07 may provide protective effects against TB susceptibility. However, well-designed studies with large sample sizes are required for better understanding of this association. PMID- 26634554 TI - Role of interleukin-10 gene polymorphisms in the development of coronary artery disease in Chinese population. AB - The aim of this study was to investigate the association between three common SNPs (-1082A/G, -819T/C, and -592A/C) in the interleukin 10 (IL-10) gene, and the development of coronary artery disease. Between January 2013 and December 2014, 272 patients with coronary artery disease and control subjects (each) were recruited for this study from the Huaihe Hospital of Henan University. The IL-10 1082A/G, -819T/C and -592A/C gene polymorphisms were analyzed using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. Logistic regression analyses revealed an association between the AA and GA+AA genotypes of IL-10-1082G/A and an elevated risk of coronary artery disease, compared to the GG genotype [adjusted odds ratio (OR) = 2.31 and 1.49; 95% confidence interval (CI) = 1.29-4.19 and 1.04-2.12, respectively]. The AG+GG genotype was associated with a moderately increased risk of coronary artery disease in smokers (adjusted OR = 2.74; 95% CI = 1.01-3.01). In conclusion, the AA and GA+AA genotypes of IL-10-1082G/A were associated with an elevated risk of coronary artery disease; the IL-10-1082G/A gene polymorphism also interacted with the tobacco smoking habits, contributing to the development of coronary artery disease. PMID- 26634556 TI - Effect of different compounds on the induction of laccase production by Agaricus blazei. AB - Laccases are polyphenol oxidases produced by many fungi and have many applications in textile, food and beverage, and pulp and paper industries. Laccase production can be induced using aromatic or phenolic compounds that mostly affect the transcription of laccase-encoding genes. In this study, we analyzed laccase and biomass production by Agaricus blazei in the presence of different concentrations of nitrogen, copper, and inducers such as pyrogallol, veratryl alcohol, xylidine, vanillin, guaiacol, and ethanol. Laccase production by A. blazei U2-4 reached 43.8 U/mL in the presence of 2.8 g/L nitrogen and 150 MUM copper. However, addition of copper to the cultivation medium decreased biomass production. Different compounds differentially induced laccase production by A. blazei. Moreover, different concentrations of these inducers exerted different effects on laccase activity. Ethanol (1.0 mM), guaiacol (0.5 mM), and vanillin (0.5 mM) were the best inducers and increased laccase activity by 120% (A. blazei U2-2), 30% (A. blazei U2-3), and 9% (A. blazei U2-4), respectively. In contrast, pyrogallol and xylidine decreased laccase activity but increased biomass production. PMID- 26634555 TI - Investigation of the association between interleukin-10 polymorphisms and risk of acute pancreatitis in a Chinese population. AB - We conducted a case-control study to investigate the possible association between three common single nucleotide polymorphisms in interleukin-10 (IL-10) and the development of acute pancreatitis in a Chinese population. Between January 2013 and December 2014, 255 patients with acute pancreatitis and 255 control subjects were recruited for the study. Genotyping of IL-10 rs1800896, rs1800871, and rs1800872 was performed using polymerase chain reaction coupled with restriction fragment length polymorphism. Using logistic regression analysis, we found that the AA genotype of IL-10 rs1800896 was correlated with an increased risk of acute pancreatitis in a codominant model (OR = 2.44, 95%CI = 1.28-4.77). In a dominant model, we found that the GA+AA genotype of IL-10 rs1800896 was associated with an elevated risk of acute pancreatitis (OR = 1.51, 95%CI = 1.05-2.18). In a recessive model, the AA genotype of IL-10 rs1800896 was correlated with an increased risk of acute pancreatitis (OR = 1.98, 95%CI = 1.06-3.77). In conclusion, IL-10 rs1800896 was correlated with an increased risk of acute pancreatitis in codominant, dominant, and recessive models. PMID- 26634557 TI - Genetic diversity in three natural populations of Pitcairnia flammea (l.) John (Bromeliaceae) estimated by ISSR markers. AB - Bromeliads are greatly represented in the Atlantic Forest, although many species are threatened with extinction owing to habitat fragmentation and intense extraction for ornamental purposes. Therefore, it is necessary to conduct studies generating knowledge about genetic diversity and the distribution of this diversity among and within natural populations to establish conservation strategies. These studies can be performed with the use of molecular markers. Molecular markers are advantageous for studies of natural populations, for conservation programs, and to aid in properly classifying plant species. This study aimed to evaluate the genetic diversity among and within natural populations of Pitcairnia flammea, occurring in three fragments of the Atlantic Forest in the southern State of Espirito Santo through the use of inter-simple sequence repeat (ISSR) markers. DNA samples from 55 individuals were amplified with 18 ISSR primers, generating 180 bands, 159 of which were polymorphic. The Shannon genetic diversity index ranged from 0.348 to 0.465, with an average of 0.412. The Bayesian approach for the molecular data indicated the existence of two genetic groups. Analysis of molecular variance indicated the existence of 90.3% diversity within the population and 9.74% among populations. The amount of genetic differentiation of populations was moderate (0.0974), indicating that gene flow rates may be enough to counteract the effects of genetic drift. Greater genetic variability found in population B indicates that this area is an important source of genetic variability. PMID- 26634558 TI - Accurate description of phages and their genomes--Genet. Mol. Res. 14 (1): 190 198 "Bioinformatic analysis of phage AB3, a phiKMV-like virus infecting Acinetobacter baumannii". PMID- 26634559 TI - High altitude pulmonary edema and hypoxia-related genes--Genet. Mol. Res. 14 (3): 11562-11572 "Correlation between single nucleotide polymorphisms in hypoxia related genes and susceptibility to acute high-altitude pulmonary edema". PMID- 26634560 TI - It's all good on the surface: care coordination experiences of migrant cancer patients in Australia. AB - PURPOSE: Migrants diagnosed with cancer in Australia have high unmet need and poorer psychosocial outcomes than comparable Australian-born patients. It is possible that migrants also experience worse coordination of their cancer care. The purpose of this study was to describe migrant patients' experience of care coordination to inform the development of items for inclusion in a cancer care coordination questionnaire sensitive to the specific cultural needs of these patients. METHODS: Eighteen Chinese (Mandarin and Cantonese), Arabic and Macedonian patients and carers from two metropolitan cancer centres in Sydney, Australia, were recruited. Two focus groups and 11 telephone interviews were conducted in the participants' own language. A semi-structured interview format was utilised to qualitatively explore participants' experiences of cancer care coordination during treatment. Themes were identified using a thematic analysis. RESULTS: Cancer care was generally perceived to be well coordinated. Four themes were identified that impacted on the quality of care coordination as a direct result of a patient's migrant status: (1) the impact of language on understanding and information access, (2) the role of interpreters and (3) access to services and (4) understanding the roles and responsibilities of the team. CONCLUSIONS: Despite their care generally being well coordinated, migrants require additional assistance such as information in a form appropriate to their language proficiency and understanding of the new health system. Development of a culturally specific measure of cancer care coordination will enable evaluation of future strategies to improve care. PMID- 26634561 TI - Chemotherapy-induced neuropathy in multiple myeloma: influence on quality of life and development of a questionnaire to compose common toxicity criteria grading for use in daily clinical practice. AB - PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) may negatively influence multiple myeloma (MM) patients' health-related quality of life (HRQOL). Dose modification is the only way to minimize CIPN. To measure CIPN in daily practice, the Indication for Common Toxicity Criteria (CTC) Grading of Peripheral Neuropathy Questionnaire (ICPNQ) was developed which can be completed within five minutes by the patient. The aims of this study were to (1) perform a psychometric evaluation of the ICPNQ and (2) examine the prevalence of CIPN and its influence on HRQOL in population-based MM patients. METHODS: One hundred fifty-six MM patients, diagnosed between 2000 and 2014, completed the ICPNQ, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Chemotherapy-Induced Peripheral Neuropathy 20 (EORTC QLQ-CIPN20), and EORTC QLQ C30 (65 % response). RESULTS: The psychometric analyses showed a Cronbach's alpha of 0.84, 0.74, and 0.61 for, respectively, the sensory, motoric, and autonomic subscales of the ICPNQ. Test-retest reliability and construct validity were good for all subscales. Overall, 65 % of patients reported grade 2-3 neuropathy according to the ICPNQ. Patients with the highest CTC grades (grade 2 with neuropathic pain and grade 3 (38 %)) according to the ICPNQ reported significantly worse scores on all EORTC QLQ-CIPN20 subscales compared to patients with lower CTC grades (p <= 0.002). In addition, they reported statistically significant and clinically relevant worse HRQOL scores on almost all EORTC QLQ C30 subscales. CONCLUSIONS: CIPN is a common side effect in MM patients, which has a negative impact on HRQOL. The ICPNQ is a valid instrument to distinguish the highest CIPN CTC grades from the lower CTC grades necessary to decide on dose modifications of chemotherapy in daily clinical practice. PMID- 26634562 TI - Play-based procedural preparation and support intervention for cranial radiation. AB - PURPOSE: The primary objective of this study was to examine the relationship between play-based procedural preparation and support intervention and use of sedation in children with central nervous system (CNS) tumors during radiation therapy. The secondary objective was to analyze the cost-effectiveness of the intervention compared to costs associated with daily sedation. METHODS: A retrospective chart review was conducted, and 116 children aged 5-12 years met criteria for inclusion. Outcome measures included the total number of radiation treatments received, the number of treatments received with and without sedation, and the type and duration of interventions, which consisted of developmentally appropriate play, education, preparation, and distraction provided by a certified child life specialist. RESULTS: The results of univariate analyses showed that age, tumor location, and total number and duration of interventions were significantly associated with sedation use during radiation therapy. Multivariate analyses showed that, after adjustment for age, tumor location, and craniospinal radiation, a significant relationship was found between the total number and duration of the interventions and sedation use. The implementation of a play based procedural preparation and support intervention provided by a certified child life specialist significantly reduced health-care costs by decreasing the necessity of daily sedation. CONCLUSIONS: Support interventions provided by child life specialists significantly decreased both sedation use and the cost associated with daily sedation during cranial radiation therapy in children with CNS tumors. This study supports the value of the child life professional as a play-based developmental specialist and a crucial component of cost-effective healthcare. PMID- 26634563 TI - Patient Survival and Technique Failure in Continuous Ambulatory Peritoneal Dialysis Patients with Prior Stroke. AB - ? BACKGROUND: To investigate patient survival and technical failure of patients with prior stroke receiving continuous ambulatory peritoneal dialysis (CAPD) in Southern China. ? METHODS: This was a retrospective study. All subjects were recruited from the peritoneal dialysis center in The First Affiliated Hospital of Sun Yat-sen University from 1 January 2006 to 31 December 2010. All eligible patients were assigned to stroke group and non-stroke group according to a history of stroke before receiving CAPD. The primary outcomes were all-cause mortality and death-censored technical failure. Cox regression was used to estimate risk factors of all-cause mortality and death-censored technique failure. ? RESULTS: Of the 1,068 recruited patients, 75 (7.0%) patients had a previous history of stroke. The all-cause mortality and death-censored technique failure were significantly higher in the stroke group compared with the non stroke group, respectively (odds ratio [OR] 2.67, 95% confidence interval [CI] 1.59 - 4.46 and OR 2.52, 95% CI 1.19 - 5.34). Older age (changed by 10 years, hazard ratio [HR] 1.90, 95% CI 1.07 - 3.38), lower body mass index (BMI 18.5 - 23.9 vs < 18.5 kg/m(2) reference, HR 0.17, 95% CI 0.05 - 0.55) and time to the first episode of peritonitis (HR 0.93, 95% CI 0.89 - 0.96) were independently associated with increased risk of all-cause mortality in patients with prior stroke. In addition, time to the first episode of peritonitis was associated with decreased risk of death-censored technique failure (HR 0.91, 95% CI 0.84 - 0.99) in those with prior stroke. ? CONCLUSIONS: Continuous ambulatory peritoneal dialysis patients with prior stroke had high rates of all-cause mortality and technique failure compared with those without prior stroke. Older age, lower BMI, and time to the first episode of peritonitis were independent risk factors of all cause mortality in patients with prior stroke. PMID- 26634564 TI - Is Peritonitis Risk Increased in Elderly Patients on Peritoneal Dialysis? Report from the French Language Peritoneal Dialysis Registry (RDPLF). AB - ? INTRODUCTION: This study was carried out to examine whether or not elderly patients on peritoneal dialysis (PD) had an increased risk of peritonitis. ? METHODS: This was a retrospective cohort study based on data from the French Language Peritoneal Dialysis Registry. We analyzed 8,396 incident patients starting PD between January 2003 and December 2010. The end of the observation period was 31 December 2012. Patients were separated into 2 age groups: up to 75 and over of 75 years old. ? RESULTS: Among 8,396 patients starting dialysis there were 3,173 patients older than 75. When using a Cox model, no association was found between age greater than 75 years and increased risk of peritonitis (hazard ratio [HR]: 0.97 [0.88 - 1.07]). Diabetes (HR: 1.14 [1.01 - 1.28] and continuous ambulatory PD (HR: 1.13 [1.04 - 1.23]) were significantly associated with a higher risk of peritoneal infection whereas nurse-assisted PD was associated with a lower risk of peritonitis (HR: 0.85 [0.78 - 0.94]. In the analysis restricted to the 3,840 self-care PD patients, there was no association between age older than 75 years and risk of peritonitis. ? CONCLUSION: The risk of peritonitis is not increased in elderly patients on PD in a country where assisted PD is available. PMID- 26634565 TI - Equivalent Fall Risk in Elderly Patients on Hemodialysis and Peritoneal Dialysis. AB - ? BACKGROUND: Accidental falls are common in the hemodialysis (HD) population. The high fall rate has been attributed to a combination of aging, kidney disease related morbidity, and HD treatment-related hazards. We hypothesized that patients maintained on peritoneal dialysis (PD) would have fewer falls than those on chronic HD. The objective of this study was to compare the falls risk between cohorts of elderly patients maintained on HD and PD, using prospective data from a large academic dialysis facility. ? METHODS: Patients aged 65 years or over on chronic in-hospital HD and PD at the University Health Network were recruited. Patients were followed biweekly, and falls occurring within the first year recorded. Fall risk between the 2 groups was compared using both crude and adjusted Poisson lognormal random effects modeling. ? RESULTS: Out of 258 potential patients, 236 were recruited, assessed at baseline, and followed biweekly for falls. Of 74 PD patients, 40 (54%) experienced 86 falls while 76 out of 162 (47%) HD patients experienced a total of 305 falls (crude fall rate 1.25 vs 1.60 respectively, odds ratio [OR] falls in PD patients 0.78, 95% confidence interval [CI] 0.61 - 0.92, p = 0.04). After adjustment for differences in comorbidity, number of medications, and other demographic differences, PD patients were no less likely to experience accidental falls than HD patients (OR 1.63, 95% CI 0.88 - 3.04, p = 0.1). ? CONCLUSIONS: We conclude that accidental falls are equally common in the PD population and the HD population. These data argue against post-HD hypotension as the sole contributor to the high fall risk in the dialysis population. PMID- 26634566 TI - Prevalence of Cognitive Impairment Among Peritoneal Dialysis Patients, Impact on Peritonitis and Role of Assisted Dialysis. AB - ? BACKGROUND: Chronic renal failure and aging are suggested as risk factors for cognitive impairment (CI). We studied the prevalence of CI among peritoneal dialysis (PD) patients using Montreal Cognitive Assessment (MoCA), its impact on PD-related peritonitis in the first year, and the potential role of assisted PD. ? METHODS: One hundred fourteen patients were newly started on PD between February 2011 and July 2013. Montreal Cognitive Assessment was performed in the absence of acute illness. Data on patient characteristics including demographics, comorbidities, blood parameters, dialysis adequacy, presence of helpers, medications, and the number PD-related infections were collected. ? RESULTS: The age of studied patients was 59+/-15.0 years, and 47% were female. The prevalence of CI was 28.9%. Patients older than 65 years old (odds ratio [OR] 4.88, confidence interval [CI] 1.79 - 13.28 p = 0.002) and with an education of primary level or below (OR 4.08, CI 1.30 - 12.81, p = 0.016) were independent risk factors for CI in multivariate analysis. Patients with PD-related peritonitis were significantly older (p < 0.001) and more likely to have CI as defined by MoCA (p = 0.035). After adjustment for age, however, CI was not a significant independent risk factor for PD-related peritonitis among self-care PD patients (OR 2.20, CI 0.65 - 7.44, p = 0.20). When we compared patients with MoCA-defined CI receiving self-care and assisted PD, there were no statistically significant differences between the 2 groups in terms of age, MoCA scores, or comorbidities. There were also no statistically significant differences in 1-year outcome of PD related peritonitis rates or exit-site infections. ? CONCLUSION: Cognitive impairment is common among local PD patients. Even with CI, peritonitis rate in self-care PD with adequate training is similar to CI patients on assisted PD. PMID- 26634567 TI - Long-Term Exit-Site Gentamicin Prophylaxis and Gentamicin Resistance in a Peritoneal Dialysis Program. AB - ? BACKGROUND: Daily gentamicin cream exit-site prophylaxis reduces peritoneal dialysis (PD)-related gram-negative infections. However, there is a concern about the potential for increasing gentamicin resistance with the long-term use of prophylactic gentamicin. This study evaluated the incidence of gentamicin resistant PD-related infections over more than 2 decades. ? METHODS: Study data on prevalent PD patients were retrieved from a prospectively maintained institutional review board (IRB)-approved PD registry at a single center from January 1, 1991, to December 31, 2000, and January 1, 2004, to December 31, 2013. The rates of gram-negative infections, fungal infections and those infections with organisms resistant to gentamicin were examined for the 2 periods. Period 1 from 1991 to 2000 when S. aureus prophylaxis consisted initially of oral rifampin to treat nasal carriage with S. aureus, and was then daily exit-site mupirocin ointment for all PD patients, was compared to the period from 2004 to 2013 when daily exit-site gentamicin cream was prescribed as prophylaxis (Period 2). ? RESULTS: The study included a total of 444 PD patients (265 and 179 in Period 1 and Period 2, respectively). No significant difference was noted in demographics between the 2 periods except race. The gram-negative exit-site infection rates for Period 1 and Period 2 were 0.109 versus 0.027 (p < 0.0001). Gram-negative peritonitis rates were similar. There were 3 episodes of gentamicin-resistant infections in each period. Fungal infections remained consistently low. ? CONCLUSION: Despite a decade of exit-site gentamicin prophylaxis, gentamicin resistant PD-related infections and fungal infections remained very low and similar to the prior period. PMID- 26634568 TI - Migraine incidence in 5 years: a population-based prospective longitudinal study in Turkey. AB - BACKGROUND: The incidence of migraine has been investigated only in a few studies worldwide and it is not known in our country. We, therefore, aimed to estimate the migraine incidence in a previously accomplished population-based prevalence study sample of 5323 individuals in the year 2008. METHODS: The former Turkish headache prevalence study has been completed as a nationwide, randomized, home based study of face-to-face examination by physicians trained for headache diagnosis by using ICHD criteria. Five years after this study an optimized survey including 50 questions was performed to estimate the migraine incidence in migraine-free individuals in the previous study, with a 56.4 % responder rate. Two validation studies for this survey were performed prior and after the study each in 100 subjects by comparing the gold standard of expert diagnosis of headache, showing high rate of reliability (Crohnbach alpha: 0.911 and 0.706, respectively). RESULTS: Migraine incidence was estimated as 2.38 % (2.98 % in women and 1.93 % in men) per year in 2563 migraine-free individuals; if the population at risk is defined as the group without any headaches, the migraine incidence decreased to 1.99 %. The chronic migraine (CM) incidence [without medication overuse (MOH)] was 0.066 % and that of MOH was 0.259 %. We found a significant burden of the disease on the occupational functionality as well as on social and family life, even in the early years of the migraine. The family history of headaches especially in the fathers could be useful to predict new cases of migraine, besides the well-known risk factor, diagnosis of depression, whereas income and education did not seem to relate to migraine onset. CONCLUSIONS: Our study with a large population-based nation-wide sample, using ICHD-II criteria, with structured headache interviews as well as blinded re validation of the questionnaire diagnoses showed a 2.38 % incidence rate of migraine in Turkey, higher than most of the other previous reports; a finding which could be related to genetic factors and also to the methodological differences in the study designs. Moreover the incidence of CM was found to be 0.066 %. PMID- 26634570 TI - Treatment of gastrointestinal autonomic neuropathy. AB - The symptoms caused by gastrointestinal autonomic neuropathy in diabetes mellitus is important to highlight since it affects a large proportion of people with diabetes, regardless of whether this is type 1 or type 2. Gastroparesis and general signs of bowel dysfunction, such as constipation, diarrhoea and abdominal pain are most often encountered and involve both pharmacological and non pharmacological treatment options. This mini-review summarises a presentation given at the 'Diagnosis and treatment of autonomic diabetic neuropathy in the gut' symposium at the 2015 annual meeting of the EASD. It is accompanied by another mini-review on a topic from this symposium (by Azpiroz and Malagelada, DOI: 10.1007/s00125-015-3831-1 ) and a commentary by the Session Chair, Peter Kempler (DOI: 10.1007/s00125-015-3826-y ). PMID- 26634569 TI - Repeated tender point injections of granisetron alleviate chronic myofascial pain -a randomized, controlled, double-blinded trial. AB - BACKGROUND: Serotonin (5-HT) mediates pain by peripheral 5-HT3-receptors. Results from a few studies indicate that intramuscular injections of 5-HT3-antagonists may reduce musculoskeletal pain. The aim of this study was to investigate if repeated intramuscular tender-point injections of the 5-HT3-antagonist granisetron alleviate pain in patients with myofascial temporomandibular disorders (M-TMD). METHODS: This prospective, randomized, controlled, double blind, parallel-arm trial (RCT) was carried out during at two centers in Stockholm, Sweden. The randomization was performed by a researcher who did not participate in data collection with an internet-based application ( www.randomization.com ). 40 patients with a diagnose of M-TMD according to the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) were randomized to receive repeated injections, one week apart, with either granisetron (GRA; 3 mg) or isotonic saline as control (CTR). RESULTS: The median weekly pain intensities decreased significantly at all follow-ups (1-, 2-, 6 months) in the GRA-group (Friedman test; P < 0.05), but not in the CTR-group (Friedman-test; P > 0.075). The numbers needed to treat (NNT) were 4 at the 1- and 6-month follow-ups, and 3.3 at the 2-month follow-up in favor of granisetron. CONCLUSIONS: Repeated intramuscular tender-point injections with granisetron provide a new pharmacological treatment possibility for myofascial pain patients with repeated intramuscular tender-point injections with the serotonin type 3 antagonist granisetron. It showed a clinically relevant pain reducing effect in the temporomandibular region, both in a short- and long-term aspect. TRIAL REGISTRATION: European Clinical Trials Database 2005-006042-41 as well as at Clinical Trials NCT02230371 . PMID- 26634571 TI - The non-canonical NF-kappaB pathway is induced by cytokines in pancreatic beta cells and contributes to cell death and proinflammatory responses in vitro. AB - AIMS/HYPOTHESIS: Activation of the transcription factor nuclear factor (NF) kappaB by proinflammatory cytokines plays an important role in beta cell demise in type 1 diabetes. Two main signalling pathways are known to activate NF-kappaB, namely the canonical and the non-canonical pathways. Up to now, studies on the role of NF-kappaB activation in beta cells have focused on the canonical pathway. The aim of this study was to investigate whether cytokines activate the non canonical pathway in beta cells, how this pathway is regulated and the consequences of its activation on beta cell fate. METHODS: NF-kappaB signalling was analysed by immunoblotting, promoter reporter assays and real-time RT-PCR, after knockdown or overexpression of key genes/proteins. INS-1E cells, FACS purified rat beta cells and the human beta cell line EndoC-betaH1 exposed to cytokines were used as models. RESULTS: IL-1beta plus IFN-gamma induced stabilisation of NF-kappaB-inducing kinase and increased the expression and cleavage of p100 protein, culminating in the nuclear translocation of p52, the hallmark of the non-canonical signalling. This activation relied on different crosstalks between the canonical and non-canonical pathways, some of which were beta cell specific. Importantly, cytokine-mediated activation of the non canonical pathway controlled the expression of 'late' NF-kappaB-dependent genes, regulating both pro-apoptotic and inflammatory responses, which are implicated in beta cell loss in early type 1 diabetes. CONCLUSIONS/INTERPRETATION: The atypical activation of the non-canonical NF-kappaB pathway by proinflammatory cytokines constitutes a novel 'feed-forward' mechanism that contributes to the particularly pro-apoptotic effect of NF-kappaB in beta cells. PMID- 26634572 TI - The Effect of Ethnicity on Human Axillary Odorant Production. AB - Previous findings from our laboratory highlighted marked ethnic differences in volatile organic compounds (VOCs) from cerumen among individuals of Caucasian, East Asian, and African-American descent, based, in part, on genetic differences in a gene that codes for a transport protein, which is a member of the ATP binding cassette transporter, sub-family C, member 11 (ABCC11). In the current work, we hypothesized that axillary odorants produced by East Asians would differ markedly from those obtained from individuals of European or African descent based on the pattern of ethnic diversity that exists in ABCC11. Using gas chromatography/mass spectrometry (GC/MS) we examined differences in axillary odorant VOCs among 30 individuals of African-American, Caucasian, and East Asian descent with respect to their ABCC11 genotype. While no qualitative differences in the type of axillary odorants were observed across ethnic groups, we found that characteristic axillary odorants varied quantitatively with respect to ethnic origin. We propose that ABCC11 is not solely responsible for predicting the relative amounts of volatiles found in axillary secretions and that other biochemical pathways must be involved. PMID- 26634575 TI - [Antiurolithiasic effect of a plant mixture of Herniaria glabra, Agropyron repens, Equisetum arvense and Sambucus nigra (Herbensurina(r)) in the prevention of experimentally induced nephrolithiasis in rats]. AB - OBJECTIVE: To determine the effect of a botanical formulation of Herniaria glabra, Agropyron repens, Equisetum arvense, and Sambucus nigra as a preventive agent in an experimentally induced nefrolithiasis model in rats. METHODS: Six groups of six Wistar male rats each were induced for nefrolithiasis by treatment with 0.75% ethylene glycol (EG) and 1% ammonium chloride for three days and then EG only for 15 days. One group was treated with placebo (control group) and the other groups (treated groups) were treated with 30 mg/Kg, 60 mg/Kg, 125 mg/Kg, 250 mg/Kg and 500 mg/Kg of the plant extract formulation (PEF). 24-h urine and water samples were collected one day before EG administration and at 7, 13 and 18 days to determine diuresis, crystalluria and urine biochemistry. The kidneys were removed for histological analysis. The phytochemical characterization of PEF and each of its component plant extracts was performed using gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry. RESULTS: Animals treated with 125 mg/Kg of the PEF had statistically significantly lower calcium oxalate crystals deposits content compared to the control group. All PEF doses statistically significantly decreased the number of microcalcifications compared to the control group. Furthermore, the number of kidneys affected by subcapsular fibrosis was statistically significantly higher in control group than in treated groups with the PEF. The diuresis of the 125 mg/Kg and 500 mg/Kg PEF-treated groups was statistically significantly higher than that of the control group. A phytochemical analysis demonstrated the presence of flavonoids, dicarboxylic acids and saponins. CONCLUSION: Treatment with PEF prevents deposits of calcium oxalate crystals formation and of microcalcifications in the kidney, and reduces the risk of fibrosis subcapsular. 125 mg/Kg of PEF is the dose that has a greater effect on the studied parameters. PMID- 26634573 TI - Salicylic Acid Treatment Increases the Levels of Triterpene Glycosides in Black Cohosh (Actaea Racemosa) Rhizomes. AB - Black cohosh (Actaea racemosa) serves as the host plant for the Appalachian azure butterfly, Celastrina neglectamajor. Overharvesting of Black cohosh for the dietary supplement industry may result in its extirpation, and may also cause the elimination of the dependent butterfly. One way to increase or maintain the number of host plants in forested environments would be to reduce the number harvested, for example by increasing the levels of the desired metabolites in Black cohosh rhizomes. The secondary metabolites actein and deoxyactein are triterpene glycosides and are among the compounds associated with the putative activity of Black cohosh extracts. Acetein and deoxyacetein are used to standardize Black cohosh supplements. To gain an understanding of mechanisms that may control actein and deoxyactein accumulation, Black cohosh rhizomes were treated with exogenous salicylic acid, jasmonic acid, or ethylene, or were mechanically wounded. Salicylic acid treatment significantly increased the levels of actein and deoxyactein in the rhizome of Black cohosh, suggesting that the synthesis of triterpene glycosides is controlled in part by salicylic acid. Using salicylic acid or related chemicals to increase the levels of actein and deoxyactein in rhizomes may help supply the supplement industry and, simultaneously, help conserve Black cohosh and species dependent upon it. PMID- 26634576 TI - Seasonal preponderance in testicular torsion: is it a myth? AB - OBJECTIVE: In this study, we aimed to investigate the relation of testicular torsion and weather conditions, and to report results from Turkey, a country located between temperate and sub-tropical climate zones. METHODS: A total of 56 patients that had surgery with the diagnosis of testicular torsion in Ankara Education and Research Hospital Urology Clinic between 2005 and 2014 were included in the study. Age of the patient, side of torsion, date and time at onset of pain, scrotal exploration time, ischemia duration, degree of cord torsion, the surgical procedure performed, and scrotal Doppler ultrasound (USG) findings at the time of diagnosis and 1 month after surgery were retrospectively analyzed. The web archives of Turkish Republic Meteorology General Directorate was used to determine the seasonal and mean temperatures at the time of diagnosis. The data were analyzed with SPSS v. 16 statistical package program using Chi-square, Mann- Whitney U and Wilcoxon tests. RESULTS: The mean age of 56 males included in the study was 18.88 +/- 0.73 years. Right testicular torsion was seen in 23, and left testicular torsion was seen in 33 patients. Testicular arterial flow was absent in 37, arterial flow was moderately decreased in 12, and significantly decreased in 7 patients on Doppler USG. Detorsion procedure was performed in 46 patients while 10 patients had orchiectomy. Nine patients were admitted in summer, 14 in fall, 15 in winter, and 18 in spring. The mean air temperature at the time of admittance was 9.31 +/- 1.05 degrees C. The prevalence of testicular torsion was not found different among the seasons (p=0.39). The analysis of air temperature at the time of admittance of the patients revealed that it was below 15 degrees C in 40 patients while it was above 15 degrees C in 16 patients, with a significant difference in between (p=0.002). CONCLUSIONS: The prevalence of testicular torsion did not change in relation with the seasons. However, it was determined that its prevalence was directly proportional to the air temperature, and increased particularly below 15 degrees C. PMID- 26634577 TI - [IgG4-Related Retroperitoneal fibrosis]. AB - OBJECTIVE: To report two new cases of IgG4-related retroperitoneal fibrosis, a recently described pathology. METHODS: We analyze two cases diagnosed in our center and performed a literature review. RESULT: IgG4 related disease is a recently described entity that includes previously not related pathologies. The clinical manifestations are highly variable and its presentation is usually subacute. The treatment of choice is glucocorticoids. In our first case the outcome was favorable with corticosteroids and azathioprine. However, the second case required surgery on 2 occasions with radical nephrectomy. The diagnosis of the latter was made nine years after the onset of symptoms when the biopsy was reviewed; at that moment immunosuppressive therapy was not started. CONCLUSIONS: It is very important to know and diagnose this disease because of the good response to treatment that prevents complications. PMID- 26634578 TI - [Buccal mucosa graft augmented anastomotic urethroplasty for the treatment of bulbar urethral strictures]. AB - OBJECTIVE: To report our outcomes with the use of buccal mucosal graft anastomotic urethroplasty to reconstruct complex anterior urethral strictures. METHODS: Between October 2007 and January 2011 we conducted a retrospective review of a series of 65 patients from 2 different centers. We analyzed demographic data, surgical outcomes and complications. RESULTS: Patient mean age was 50.09 years (range: 25 to 75), mean stricture length was 3.95 cm (range: 3 to 7 cm) and mean follow-up 33.13 months (range: 12.7 to 52.77). Eighty percent of patients had prior treatments, mainly direct visual internal urethrotomy (DVIU) and urethral dilatation. Most frequent etiologies were iatrogenic in 46.15% of patients and idiopathic in 35.38% of patients. Success rate was achieved in 96.92% of patients; only 2 patients presented recurrence and were treated successfully with one DVIU. Clavien Dindo I-II complications were found in 59% of patients. No patient had chronic sequels. CONCLUSION: Augmented anastomotic urethroplasty using dorsal onlay buccal mucosa graft enables correction, in one time, of long segment urethral strictures with severe spongiofibrosis and/or obliterated lumen. Our outcomes are comparable with those of previously reported in international series. PMID- 26634580 TI - TRYPTASE AND HISTAMINE MAY SUPPORT ORAL FOOD CHALLENGE IN THE DIAGNOSIS OF ALLERGY. AB - Allergen-specific immunoglobulin E (IgE) reactions lead to acute degranulation of mast cells and basophils and release of stored mediators, particularly tryptase and histamine, which can be measured in vitro after reactions. The aim of this study was to investigate the utility of serum tryptase and plasma histamine during oral food challenge (OFC) in 103 children with suspected food allergy, in order to support the diagnosis of a IgE-mediated reaction. Blood samples for serum tryptase and plasma histamine were collected before the OFC and after the onset of allergic symptoms or after 60 minutes from test completion. Serum tryptase and plasma histamine were measured by a fluoroenzyme immunoassay (ImmunoCAP; ThermoFisher, Uppsala, Sweden) according to the manufacturer?s instructions. A correlation between serum tryptase and plasma histamine distributions was observed after OFC (p=0.0035). A correlation was also observed for both serum tryptase and plasma histamine before and after OFC (p less than0.0001). Subjects with positive response to OFC had significantly higher values (p = 0.0375) of serum tryptase compared to subjects with negative response. The plasma histamine distribution showed a significant difference between measurements before and after OFC, both in the complete population (p less than 0.0001), and considering the response (negative OFC: p less than 0.0001; positive OFC: p=0.0181). The diagnostic work-up of IgE- mediated food allergy may include determination of serum tryptase and plasma histamine, in order to support the results of OFC. These markers are strongly related to the same IgE-mediated mechanism and, as they can be both easily measured, can confirm the allergic nature of a reaction in the real-life setting of food allergy. PMID- 26634579 TI - Surgeons changing the approach for total hip arthroplasty from posterior to direct anterior with fluoroscopy should consider potential excessive cup anteversion and flexion implantation of the stem in their early experience. AB - PURPOSE: Many reports outline the benefits derived from using the direct anterior approach (DAA) in primary total hip arthroplasty (THA); however, the learning curve for the DAA has not been well documented, and the complications associated with the DAA during this learning curve seem relatively high. The aim of this study was to investigate implant positioning in primary THA, when the surgeon was a novice at the DAA, and had previously used the standard posterior approach (PA). PATIENTS AND METHODS: We investigated implant positioning in the first 80 consecutive THA cases performed by two senior surgeons using the DAA (with fluoroscopic assistance), and compared them to the same two surgeons' previous 80 respective THA cases performed using their previous standard posterior approach. RESULTS: Cup positioning accuracy was higher for the DAA (p < 0.001) but greater cup anteversion (19.3 degrees +/- 11.0 using the PA vs 27.6 degrees +/- 6.3 using DAA, p < 0.0001) was also demonstrated. A total of 69.3 % of cups in the DAA group were positioned with an anteversion angle greater than their target angle. In the DAA group the stem was more frequently positioned in flexion and less frequently in neutral than for the PA group. CONCLUSIONS: Although fluoroscopic assistance seemed to decrease complications such as femoral fracture, surgeons changing from PA to DAA for THA should consider potential excessive cup anteversion and flexion implantation of the stem in their early experience with DAA. PMID- 26634581 TI - ALMOND MILK: A POTENTIAL THERAPEUTIC WEAPON AGAINST COW?S MILK PROTEIN ALLERGY. AB - Food allergy is defined as an adverse health effect arising from a specific immune response that occurs reproducibly following exposure to a given food. Cow?s milk protein allergy results from an immunological reaction to one or more milk proteins. The principle key in the treatment of cow?s milk protein allergy is the dietary elimination of cow?s milk protein. Although hydrolyzed and elemental formulas are appropriate replacements, other milk products, including almond milk adequately integrated, could be administered. Here, in the light of encouraging results from our study, we focused on the anti-inflammatory and anti oxidant properties of almond milk and we also believe that almond milk might be considered as a potential alternative in cow?s milk protein allergy treatment. PMID- 26634582 TI - ATOPIC DERMATITIS: EXPRESSION OF IMMUNOLOGICAL IMBALANCE. AB - Atopic dermatitis is a chronic relapsing-remitting inflammatory skin condition, characterized by a skin barrier dysfunction resulting in epidermal damage and altered permeability to allergens and microbes. Although pathogenesis of atopic dermatitis is complex and still not fully understood, it has been hypothesized that genetic predisposition, environmental factors, and skin barrier dysfunction are involved. Innate and adaptive immune system has also a pivotal role in the development, maintenance and flare-up of atopic dermatitis. The immune pathogenesis of atopic dermatitis is determined by the impairment of different T helper cells, of their cytokine secretion profiles as well as of their specific receptor. In this review, we focus on the current knowledge of the etiopathogenetic pathways of atopic dermatitis in relationship to the critical role of the innate and adaptive immune system, providing a unifying view. PMID- 26634583 TI - ATOPIC DERMATITIS: IS THERE A ROLE FOR PROBIOTICS? AB - Atopic dermatitis (AD) is a chronic inflammatory skin disease that commonly presents during early childhood. In the last decades the prevalence of AD has increased, especially in western societies. This frequently relapsing inflammatory condition has a strong impact on the quality of life of patients and families. The recent advances in the understanding of this disease have paved the way for the development of new strategies for the prevention and treatment of AD. Among the new therapeutic options, there is increasing interest in the potential benefit of probiotic supplementation. It has been widely demonstrated that the human microbiota plays a fundamental role not only in the maintenance of intestinal homeostasis through the interaction between microorganisms and the innate immune system, but also in the microbiota-mediated development of adaptive immunity. In addition, several studies have demonstrated that probiotics are able to influence the composition of gut microbiota and may exert immunomodulatory effects. According to these promising results, the possible application of probiotics in the therapeutic management of allergic diseases has been investigated in many studies. In particular, a considerable body of literature has been published analyzing the effects of probiotics on patients with AD. In order to shed light on frequently conflicting results, we reviewed the data regarding the application of probiotics in AD, with the aim to provide a state-of the-art assessment of the most important studies exploring the role of probiotics both in the prevention and treatment of AD. PMID- 26634584 TI - CHILDHOOD IDIOPATHIC NEPHROTIC SYNDROME AND ATOPIC DISEASES: IS THERE A RELATIONSHIP? AB - Nephrotic syndrome is a condition of massive proteinuria that leads to hypoalbuminaemia and oedema. In the pediatric age, the most common form of nephrotic syndrome is childhood idiopathic nephrotic syndrome (CINS). Although the etiological mechanisms underlying CINS are still unclear, the disease is considered to be immune-mediated. Several studies have previously reported a possible association between CINS and atopy, with the latter defined as abnormal immunoglobulin-E response on the background of a T-helper 2 (Th2)-driven immune system. In fact, both experimental and clinical studies have suggested that idiopathic nephrotic syndrome can be associated and/or triggered by a wide array of atopic diseases, though this remains a highly controversial topic. Exposure to inhalant-allergens (and/or introduction of food-allergens) has been previously correlated with the onset and/or the relapse of CINS in some children and a significant worse response to steroid therapy has been also described in reports of CINS associated to concomitant atopic diseases. In this review, we analyzed previous studies with the aim to clarify, basing on the existent literature, the association between atopy and idiopathic nephrotic syndrome. Additionally, we also speculated on the underlying immunological pathways that could potentially make some children prone to both CINS and atopic diseases. PMID- 26634585 TI - CYSTIC FIBROSIS AND ANTIBIOTIC HYPERSENSITIVITY: PRESENT KNOWLEDGE AND PRACTICAL APPROACH. AB - Cystic fibrosis is one of the most common fatal genetic diseases (1 in 2500 births). The defect causing the disease is localized on the 7q31 gene, which codifies for the CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) transmembrane protein. CFTR is a chloride channel localized on the epithelial cells of the mucosa of the respiratory tract, pancreatic ducts, biliary tree, intestine, vas deferens and sweat glands. More than 2000 different mutations are currently known; some are prominent or relatively frequent, ranging from one population to another. The most frequent complications of cystic fibrosis are those affecting the bronchial tree. Patients suffer from recurrent lung infections, which involve a progressive loss of lung function. The pulmonary infections are frequent or chronic and limit the quality of life of patients. In addition to being enormously exposed to antibiotics, they have many more opportunities to develop hypersensitivity reactions to these molecules. Only a complete allergy work-up with a detailed analysis of the clinical history, skin tests and provocation test can show if the patient has actually experienced an allergic hypersensitivity reaction. Desensitization is to be considered as a treatment that may help patients benefit from antibiotic treatment in those cases in which they have a proven allergy to a certain molecule. PMID- 26634586 TI - EMERGING AND FUTURE THERAPIES FOR ALLERGIC RHINITIS. AB - Allergic rhinitis (AR) is one of the most common diseases and represents a global health problem, currently affecting up to 30% of the general population, with a continuously increasing prevalence and significant comorbidities and complications. To date, the mainstay of current treatment strategies of AR includes allergen avoidance, pharmacotherapy and allergen-specific immunotherapy, as defined by Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines for both adults and children. The aim of this review is to provide an update on all emerging and future therapeutic options for the treatment of AR. PMID- 26634587 TI - EXHALED BREATH TEMPERATURE IN ASTHMATIC CHILDREN. AB - Asthma is characterized by chronic inflammation of airways. Currently, no traditional method allows an easy daily evaluation of the degree of airway inflammation. Measuring inflammatory biomarkers in the breath is a very attractive approach to monitor asthma inflammation. In recent years, the measurement of exhaled breath temperature (EBT) has been proposed as a method capable of detecting the inflammatory status of the airways. The objective of this study is to strengthen the role of EBT in the diagnosis and monitoring of asthma. The study sample was represented by a group of 40 patients, of both sexes, aged 6-15 years. The elective criteria for submitting patients to EBT determination were abstaining from drugs in the preceding 24 h, fasting for at least 2 h, physical resting for at least 30 minutes, a body temperature between 35-37 degrees C. The temperature in the room of the surveys ranged from 18 to 25 degrees C. The EBT values of asthmatic patients were higher [(median (IQR): 29.77 degrees C (30.67 degrees C to 29.38 degrees C) range 28.46 degrees C min-max 34.78 degrees C] than those of non-asthmatic ones (median (IQR): 28.22 degrees C (29.09 degrees C-27.7 degrees C), range 27.09 degrees C min-max 30.07 degrees C] and this difference was highly significant (p less than 0.001). Furthermore, no significant difference was found between the EBT values of the following groups of patients: those exposed and not exposed to passive smoking, those receiving and not receiving leukotriene drugs, those receiving and not receiving specific immunotherapy, monoallergic patients and poliallergic ones, those sensitized and not sensitized to house dust, perennial allergic patients and seasonal allergic ones. In addition, the evaluation of the correlation of EBT values with body temperature (r=0.119, p=0.464) and ambient temperature (r=-304, p = 0.057) did not show any significant correlation. Finally, no statistically significant correlation was demonstrated between EBT values and FEV1 (r=-0055, p=0.81, Fig. 4). In conclusion, the data of the present study further support the hypothesis that EBT can be considered a good method for monitoring asthma. PMID- 26634588 TI - HIGH-MOBILITY GROUP BOX 1 IN ALLERGIC AND NON ALLERGIC UPPER AIRWAY INFLAMMATION. AB - High mobility group box 1, an evolutionary ancient protein conserved in the eukaryotic kingdom, exerts intra- and extra- cellular functions, orchestrating a homeostatic defensive response in challenged tissues. Its action associated with various inflammatory cells is essential for the occurrence, progression, and persistence of asthma, rhinitis, and nasal polyposis. The recent discovery of High mobility group box 1, as a critical mediator of inflammation, stimulated an increasing interest in the field of inflammation research, suggesting new therapies for atopic and non-atopic inflammatory processes. PMID- 26634590 TI - Mannitol bronchial challenge test in asthmatic children. AB - Bronchial asthma is a chronic inflammatory disease characterized by bronchial obstruction, usually reversible spontaneously or after therapy, bronchial hyperreactivity and accelerated decrease of lung function that may possibly evolve into irreversible obstruction of the respiratory tract. Bronchial provocation tests can be used in order to assess the presence and degree of bronchial hyper reactivity. The recently introduced mannitol powder inhalation indirect test seems to have an interesting and promising role, especially in childhood, because of its high diagnostic specificity, easiness of execution and best standardization. In this study the authors focused on the significance and clinical use of mannitol bronchial challenge test in asthmatic children. PMID- 26634589 TI - ALLERGIC RHINITIS AND ADENOID HYPERTROPHY IN CHILDREN: IS ADENOIDECTOMY ALWAYS REALLY USEFUL? AB - Allergic rhinitis (AR) and adenoid hypertrophy (AH) are common in children and are often associated with each other. Recent studies have shown improvement of respiratory symptoms and reduction in the adenoid volume after anti-allergic medical therapy (intranasal corticosteroids, antihistamines). The aim of our retrospective study is to evaluate the effectiveness of adenoidectomy on respiratory symptoms in pediatric patients with AR. We recruited 404 pediatric patients with AR, and we divided them into 4 groups (1. intermittent-mild rhinitis; 2. intermittent-moderate/severe rhinitis; 3. persistent-mild rhinitis; 4. persistent-moderate/severe rhinitis), using ARIA classification. For each patient we evaluated: age at onset of AR; family history of allergy; the presence of other allergic diseases; serum total IgE values; skin prick test (SPT) results; presence of AH evaluated by rhino-laringeal fibroscopy; adenoidectomy and its efficacy on respiratory symptoms. Our data show an association between AR and AH: 90 of 404 (22%) children with AR had AH of a degree greater than 2nd. A significant percentage (80%) of children suffering from AR did not present satisfactory benefits from adenoidectomy. They reported persistence or recurrence of rhinitic symptoms after surgery or only partial benefits, especially of recurrent respiratory tract infections and nasal obstruction. The local allergic persistent inflammation on nasal mucosa and adenoid tissue is probably the cause of the unsatisfactory results of adenoidectomy, therefore surgery cannot be the first therapeutic step for these children. It is important to extinguish the local inflammation by medical anti-allergic therapy to obtain improvements of nasal symptoms and to prevent adenoid regrowth. PMID- 26634591 TI - PRIMARY NOCTURNAL ENURESIS IN CHILDREN WITH ALLERGIC RHINITIS AND SEVERE ADENOTONSILLAR HYPERTROPHY: A SINGLE CENTER PILOT STUDY. AB - Nocturnal enuresis is defined as intermittent urinary incontinence during sleep that occurs at least twice a week for three consecutive months. There is no unifying etiology for nocturnal enuresis in the pediatric population and the disorder is likely to be multifactorial. We aimed to investigate the relationship between primary nocturnal enuresis, allergic rhinitis, and related complications in a paediatric case series from a single Center. We retrospectively reviewed and prospectively followed-up at our Institution (i) 32 children (14 females, 18 males; mean age 6.31+/-1.21 yrs) affected by allergic rhinitis with adenoidal hypertrophygrade I-II (group A) and (ii) 27 children (11 females, 16 males; mean age 6.52+/-1.33 yrs) affected by allergic rhinitis with adenoidal hypertrophy grade III-IV (group B). Allergic rhinitis was diagnosed on the basis of (a) typical nasal symptoms due to atopic sensitization (e.g., rhinorrhea , itching, sneezing fits, and nasal congestion and obstruction) and (b) positive skin prick testing and/or increased level of total serum IgE. We identified discrepancies between group A and group B in terms of risk of primary nocturnal enuresis. In fact, only 1 child of group A (3.12%) reported uncomplicated primary nocturnal enuresis; conversely, 6 children of group B (22.22%) showed a history of uncomplicated primary nocturnal enuresis (p=0.040). There was no statistically significant difference between the two groups in terms of atopic sensitization and serum total IgE levels (p=0.43). Allergic rhinitis may potentially influence the onset and the natural history of nocturnal enuresis in some children. Children with allergic rhinitis and more severe respiratory manifestations, seem to be more prone to developing primary nocturnal enuresis, likely due to potential multi-factorial causes (e.g., sleep disorders, chronic phlogosis, immune deregulation). PMID- 26634592 TI - PROBIOTICS AND ALLERGIC RESPIRATORY DISEASES. AB - Probiotics are able to restore microbiome and the normal intestinal permeability, improve the immunological function of gut barrier and reduce the intestinal inflammatory response and the production of pro-inflammatory cytokine characteristics of local and systemic allergic inflammation. Clinical studies have demonstrated the efficacy of probiotics in the treatment of various clinical conditions such as atopic dermatitis and food allergies and in the primary prevention of atopy. Recent studies have shown that oral administration of certain probiotic exerts therapeutic effects in the treatment of allergic respiratory diseases such as asthma and rhinitis. PMID- 26634593 TI - SAFETY AND EFFICACY OF SUBLINGUAL SPECIFIC IMMUNOTHERAPY TO HOUSE DUST MITE USING A DIFFERENT DOSAGE: A PILOT STUDY. AB - The aim of this randomized open study was to evaluate the safety and efficacy of different dosages (2000 UI vs 4000 UI) of sublingual immunotherapy (SLIT) in patients with allergic diseases such as asthma associated to rhinitis and rhinoconjunctivitis sensitized to house dust mites. We enrolled 61 patients with a history of allergic asthma, and a positive skin prick test for Dermatophagoides (D.) pteronyssinus/farinae. Patients were randomly assigned to receiving SLIT at dosage of 2000 UI (Group A) or 4000 UI (Group B) maintenance dose. We evaluated: subjective symptoms using a Visual Analogic Scale (VAS), the amount of prescribed symptomatic drugs, bronchial reactivity to methacoline and side effects using a specific questionnaire. A significant improvement in symptoms, assessed by VAS, was observed with both SLIT doses with no significant differences between groups. The provocation dose of methacoline inducing a 20% fall of FEV1 significantly increased after 12 months only in the 4000 UI dose group. In conclusion, both monomeric allergoid dosages of SLIT (2000 UI and 4000 UI) are a safe and efficacy option to reduce symptoms in patients with allergic asthma caused by house dust mites. Moreover, both dosages are efficacious even to protect against airway reactivity but it seems that monomeric allergoid of SLIT at higher dosage (4000 UI) is better than at the lower dosage (2000 UI). PMID- 26634594 TI - RELATION OF BODY MASS INDEX WITH IgE LEVELS, ALLERGIC SENSITIZATION AND LUNG FUNCTION IN ASTHMATIC CHILDREN: OUR EXPERIENCE AND REVISION OF LITERATURE. AB - In recent decades, there has been an increase in the prevalence of asthma and obesity in pediatric age. In this regard several studies have provided controversial data to demonstrate the link between Body Mass Index (BMI) and asthma, both in adults and in children. In this prospective study we evaluated the relationship between body mass index value, total IgE immunoglobulin E levels, skin prick test (SPT) sensitization and lung function in children affected by asthma. According to the analysis of data on the comparison of normal weight patients versus overweight/obese patients, there was no significant difference in the values of FEV1 (86%+/-12 vs 90%+/-19), FVC (81%+/-11 vs 88%+/ 18), skin prick tests (22.72% vs 36.66%) and total IgE values (192.22+/-368.28 vs 503+/-914.04). We carried out a sub-analysis to study the difference between three groups of patients: normal weight, overweight and obese. Obese patients showed higher total IgE values than normal-weight patients with a statistically significant difference. Conversely, there was no significant difference between the normal weight group and the obese group in the respiratory function tests and the SPT. Moreover, we found a higher value of total IgE in female overweight/obese compared with normal weight, while there was no significant difference in relation to parameters of lung function and SPT. However, the same analysis in the male sample did not show any statistically significant difference. This study confirms the higher incidence of atopy in obese children, especially in female gender, but not a direct relationship with either allergens sensitization or abnormal lung function. PMID- 26634595 TI - PROBIOTICS AND INFLAMMATORY BOWEL DISEASES. AB - Intestinal microbiota is composed by symbiotic innocuous bacteria and potential pathogens also called pathobionts. Even if the mechanism of action of intestinal bacteria remain still unknown, specific microbial species seem to have important role in the maintenance of immunological equilibrium in the gut through the direct interaction with immune cells. Some studies have found a dysregulated interaction between the intestinal bacteria, the gut barrier, and the intestinal associated immune system in Inflammatory Bowel Disease (IBD) patients and in the pathogenesis of these pathologies. In IBD patients some Butyrate producing bacteria, as Faecalibacterium Prausnitzii, are under represented and this could be related with their chronic inflammatory state. PMID- 26634596 TI - SERUM YKL-40 IN CHILDREN WITH ASTHMA. AB - Asthma is one of the most common chronic diseases in children. To date the diagnosis of asthma is mainly clinical, based on the clinical history, a careful physical examination and lung function tests. However, symptoms are often not specific and lung function tests are not very sensitive. In order to find a solution to this problem new biomarkers of airway inflammation are being developed. YKL-40 is a chitinase-like protein that has a role in the inflammation and tissue remodeling in several human diseases. The aim of this study is to evaluate serum levels of YKL40 in children with intermittent or persistent asthma. We performed a cross-sectional analysis of serum samples from a cohort of patients with asthma and healthy controls. Patients with asthma were stratified according to four levels of asthma severity (mild intermittent, mild persistent, moderate persistent, and severe persistent). The analysis of serum samples was performed with the use of a commercially available enzyme-linked immune-adsorbent assay (ELISA) kit (Quidel). The minimum detection limit of the assay for YKL-40 is 15.6 ng per milliliter (ng/ml). Our data showed that circulating YKL-40 levels are significantly higher in patients with asthma than healthy subjects (36+/-18.6 vs 14:41+/-2.88, p= 0.001). Furthermore, we found significantly higher values of YKL-40 in both groups of children with intermittent asthma (p less than 0.001) and persistent asthma (p less than 0.001) than healthy controls. However, no correlation was found with duration and severity of asthmatic disease (r = 0:18, p= 0:33, r = 0.28 P = 0:13, respectively). Our data allow us to suggest that YKL 40 represents a useful biomarker of asthma in children with intermittent or persistent asthma. PMID- 26634597 TI - SUBLINGUAL IMMUNOTHERAPY IN CHILDREN: STATE OF ART. AB - Allergic immunotherapy (AIT) today represents a therapeutic practice for the treatment of allergic diseases such as rhinitis or asthma and is recognized as the only treatment able to modify the natural history of the disease. Administering gradually increasing doses of the causative allergen, AIT, has the objective of achieving immune tolerance against allergens. One of the administration routes most used in clinical practice is represented by the sublingual route. Current research on sublingual immunotherapy (SLIT) is focused on confirming the efficacy for all the different relevant allergens, on a better definition of allergen extracts and the improvement of their immunological properties and safety, on the identification of best treatment regimens, and on the possibility of extending the clinical indications. The aim of this review is to describe the most recent step in the field of SLIT development. PMID- 26634598 TI - VITAMIN D AND BRONCHIAL INFLAMMATION IN ASTHMATIC CHILDREN. AB - The role of the vitamin D in calcium homeostasis and bone metabolism is well known. In recent years it has been recognized that in addition to the traditional functions, vitamin D modulates a variety of processes such as host defense, inflammation and immunity. Epidemiological data indicate that low levels of vitamin D in serum are associated with impaired lung function and increased incidence of inflammatory diseases, infectious diseases and cancer. The authors studied the correlation among vitamin D levels, allergic inflammation, lung function and control of asthma and found a significant decrease of FeNO values (p= 0.0018) in children with vitamin D levels>30 ng/ml. These findings confirm that vitamin D plays a major role in bronchial inflammation. PMID- 26634599 TI - SERUM AND BAL YKL-40 LEVELS IN DIFFERENT INFLAMMATORY LUNG DISEASES: AN UPDATE. AB - YKL-40 (also called chitinase 3-like-1 or human cartilage glycoprotein 39) is a chitinase-like protein belonging to the family 18 of glycosyl hydrolase (GH18). This protein is involved in the inflammatory process acting as pro-inflammatory cytokine secreted by neutrophils, activated human macrophages, vascular smooth muscle cells and cancer cells. It has been shown that YKL-40 has a role in pathological tissue remodeling and development of fibrosis of several diseases. To date, the biological and pathophysiological function of YKL-40 protein in pulmonary diseases is still unclear. This review focuses on the role of YKL-40 in diagnosis and monitoring of different lung diseases in order to assess whether this protein could be used as biomarker of specific conditions featured by inflammation and fibrosis. A comprehensive review of the literature using PubMed database, with appropriate terms, was undertaken for articles in English published since 1997. The literature search was undertaken in October 2014. PMID- 26634600 TI - ATOPIC DERMATITIS: MELATONIN AS POTENTIAL TREATMENT. AB - Atopic dermatitis (AD) is a chronic relapsing-remitting inflammatory skin disorder, characterized by a skin barrier dysfunction resulting in epidermal damage and altered permeability to allergens and microbes. Traditionally, the immunological mechanism involving the Th1-Th2 paradigm is considered central in the pathogenesis of AD. However, oxidative stress is, currently, recognized as a fundamental predisposing stimulus for AD. Several therapeutic approaches have been proposed as treatment, including the use of melatonin. This indolamine, through widespread expression and pleiotropic activity of the cutaneous melatoninergic system, may counteract environmental and endogenous stressors, regulate the immune response, decrease oxidative stress, and, finally, promote skin integrity. In the light of its pleiotropic effects, melatonin could represent a potential and alternative therapeutic approach in patients with AD. PMID- 26634601 TI - WALNUT SENSITIZATION IN PEDIATRIC AGE: A PRELIMINARY STUDY. AB - Walnut consumption has recently become a healthy dietary habit worldwide, due to its positive benefits in reducing cholesterol levels and oxidative stress; this has resulted in an increase in individual consumption, global production and risk of developing sensitization and allergy. In general, clinical manifestations of walnut allergy are frequently severe and systemic potentially life-threatening, leading to anaphylaxis both in the pediatric and adult populations. In light of these findings, we performed a preliminary study considering the walnut native allergen and the recombinant Jug r1 in order to evaluate their role in atopic diseases. PMID- 26634602 TI - beta2-AGONISTS IN CHILDHOOD ASTHMA. AB - beta2-agonists reduce airflow limitation by improving airway diameter as a consequence of a direct action on airway smooth muscle. beta;2-agonists can be broadly classified according to their duration of action: short-acting beta2 agonists (SABAs), including albuterol, terbutaline and fenoterol, have pharmacodynamics half?lives between 2 and 6 h and long-acting beta2-agonists (LABAs), including salmeterol and formoterol, require twice daily treatment. SABAs are often used ?as needed? for asthma exacerbations and before exercise in the presence of exercise-induced bronchospasm. LABAs provide longer symptom control, which is a particularly useful feature for preventing night-time symptoms. There are two main LABAs, salmeterol and formoterol. This review focused on the recent data published on this topic. PMID- 26634603 TI - The relationship between interfragmentary movement and cell differentiation in early fracture healing under locking plate fixation. AB - Interfragmentary movement (IFM) at the fracture site plays an important role in fracture healing, particularly during its early stage, via influencing the mechanical microenvironment of mesenchymal stem cells within the fracture callus. However, the effect of changes in IFM resulting from the changes in the configuration of locking plate fixation on cell differentiation has not yet been fully understood. In this study, mechanical experiments on surrogate tibia specimens, manufactured from specially formulated polyurethane, were conducted to investigate changes in IFM of fractures under various locking plate fixation configurations and loading magnitudes. The effect of the observed IFM on callus cell differentiation was then further studied using computational simulation. We found that during the early stage, cell differentiation in the fracture callus is highly influenced by fracture gap size and IFM, which in turn, is highly sensitive to locking plate fixation configuration. The computational model predicted that a small gap size (e.g. 1 mm) under a relatively flexible configuration of locking plate fixation (larger bone-plate distances and working lengths) could experience excessive strain and fluid flow within the fracture site, resulting in excessive fibrous tissue differentiation and delayed healing. By contrast, a relatively flexible configuration of locking plate fixation was predicted to improve cartilaginous callus formation and bone healing for a relatively larger gap size (e.g. 3 mm). If further confirmed by animal and human studies, the research outcome of this paper may have implications for orthopaedic surgeons in optimising the application of locking plate fixations for fractures in clinical practice. PMID- 26634604 TI - On beam quality and flatness of radiotherapy megavoltage photon beams. AB - Ratio of percentage depth dose (PDD) at two depths, PDD at a depth of 10 cm (PDD10), and beam flatness are monitored regularly for radiotherapy beams for quality assurance. The purpose of this study is to understand the effects of changes in one of these parameters on the other. Is it possible to monitor only the beam flatness and not PDD? The investigation has two components. Naturally occurring i.e., unintended changes in PDD ratio and in-plane flatness for 6 and 10 MV photon beams for one particular Siemens Artiste Linac are monitored for a period of about 4 years. Secondly, deliberate changes in the beam parameters are induced by changing the bending magnet current (BMI). Relationships between various beam parameters for unintended changes as well as deliberate changes are characterized. Long term unintentional changes of PDD ratio are found to have no systematic trend. The flatness in the inplane direction for 6 and 10 MV beams show slow increase of 0.43 and 0.75% respectively in about 4 years while the changes in the PDD ratio show no such trend. Over 10% changes in BMI are required to induce changes in the beam quality indices at 2% level. PDD ratio for the 10 MV beam is found to be less sensitive, while the depth of maximum dose, d(max), is more sensitive to the changes in BMI compared to the 6 MV beam. Tolerances are more stringent for PDD10 than PDD ratio for the 10 MV beam. PDD ratio, PDD10, and flatness must be monitored independently. Furthermore, off axis ratio alone cannot be used to monitor flatness. The effect of beam quality change in the absolute dose is clinically insignificant. PMID- 26634605 TI - Cancer immunosurveillance: role of patrolling monocytes. AB - Classical inflammatory monocytes and their derivative macrophages promote tumor metastasis whereas CD8(+) T and NK cells restrict tumor growth. In a recent paper published in Science, Hanna and colleagues demonstrate that another monocyte population, nonclassical patrolling monocytes, is enriched in the microvasculature of tumor-challenged lung and reduces tumor metastasis by recruiting NK cells. PMID- 26634606 TI - Genetic lineage tracing identifies in situ Kit-expressing cardiomyocytes. AB - Cardiac cells marked by c-Kit or Kit, dubbed cardiac stem cells (CSCs), are in clinical trials to investigate their ability to stimulate cardiac regeneration and repair. These studies were initially motivated by the purported cardiogenic activity of these cells. Recent lineage tracing studies using Kit promoter to drive expression of the inducible Cre recombinase showed that these CSCs had highly limited cardiogenic activity, inadequate to support efficient cardiac repair. Here we reassess the lineage tracing data by investigating the identity of cells immediately after Cre labeling. Our instant lineage tracing approach identifies Kit-expressing cardiomyocytes, which are labeled immediately after tamoxifen induction. In combination with long-term lineage tracing experiments, these data reveal that the large majority of long-term labeled cardiomyocytes are pre-existing Kit-expressing cardiomyocytes rather than cardiomyocytes formed de novo from CSCs. This study presents a new interpretation for the contribution of Kit(+) cells to cardiomyocytes and shows that Kit genetic lineage tracing over estimates the cardiogenic activity of Kit(+) CSCs. PMID- 26634607 TI - Three unsuccessful treatments of Helicobacter pylori infection by a highly virulent strain with quadruple antibiotic resistance. AB - We report a case of an adult patient undergoing three unsuccessful Helicobacter pylori treatments, including proton pump inhibitor (PPI), bismuth subcitrate, metronidazole and tetracycline in 2012, PPI, amoxicillin and clarithromycin in 2013, and PPI, amoxicillin and rifampin in 2014. Following the first treatment, the isolate was metronidazole and ciprofloxacin/levofloxacin resistant. After the second treatment, the isolate was resistant to metronidazole, ciprofloxacin/levofloxacin and rifampin, developing secondary clarithromycin resistance by A2143G mutation and was susceptible only to tetracycline. After the third treatment, the patient still remained H. pylori positive. Patient's strain was highly virulent (cagA (+) , cagE (+) and vacA s1a/m1/i1). The evolution of the patient's disease was from gastroesophageal reflux disease in 2012 to two duodenal ulcers in 2015. Briefly, the infecting strain showed quadruple antibiotic resistance and a transient amoxicillin resistance. Triple clarithromycin-based treatment induced secondary clarithromycin resistance by A2143G mutation, while rifampin resistance caused the third treatment failure. Several options for the next treatment regimens are discussed. PMID- 26634608 TI - Exploration of the antioxidant system and photosynthetic system of a marine algicidal Bacillus and its effect on four harmful algal bloom species. AB - A novel marine bacterium, strain B1, initially showed 96.4% algicidal activity against Phaeocystis globosa. Under this situation, 3 other harmful algal species (Skeletonema costatum, Heterosigma akashiwo, and Prorocentrum donghaiense) were chosen to study the algicidal effects of strain B1, and the algicidal activities were 91.4%, 90.7%, and 90.6%, respectively. To explore the algicidal mechanism of strain B1 on these 4 harmful algal species, the characteristics of the antioxidant system and photosynthetic system were studied. Sensitivity to strain B1 supernatant, enzyme activity, and gene expression varied with algal species, while the algicidal patterns were similar. Strain B1 supernatant increased malondialdehyde contents; decreased chlorophyll a contents; changed total antioxidant and superoxide dismutase activity; and restrained psbA, psbD, and rbcL genes expression, which eventually resulted in the algal cells death. The algicidal procedure was observed using field emission scanning electron microscopy, which indicated that algal cells were lysed and cellular substances were released. These findings suggested that the antioxidant and photosynthetic system of these 4 algal species was destroyed under strain B1 supernatant stress. This is the first report to explore and compare the mechanism of a marine Bacillus against harmful algal bloom species of covered 4 phyla. PMID- 26634609 TI - Necrotizing sialometaplasia of the lacrimal sac mimicking squamous cell carcinoma: Necrotizing dacyocystometaplasia. AB - INTRODUCTION: Necrotizing sialometaplasia is thought to represent an inflammatory reaction directed against an ischemic insult or local trauma within a glandular tissue and is most commonly observed in the minor salivary glands of the oral mucosa. The importance of this condition arises from the fact that its clinical and histological aspects may raise issues of differential diagnosis with malignant neoplasms. The authors present a case of necrotizing sialometaplasia involving the lacrimal sac simulating a well-differentiated squamous cell carcinoma. CASE: A 52-year-old man presented with epiphora in the left eye after having sustained an orbital blowout fracture during a motor vehicle accident. During subsequent external dacryocystorhinostomy, an abnormal lacrimal sac mucosa was observed and analyzed histologically revealing a well-differentiated squamous cell carcinoma. However, the subsequent biopsies of the lacrimal sac were negative for malignancy; in view of these findings, two pathologists reviewed the first specimen and immunohistochemical staining was performed allowing us to arrive at a diagnosis of necrotizing sialometaplasia. We suggest the term necrotizing dacryocystometaplasia for the involvement at this site. CONCLUSION: Although exceedingly unusual, necrotizing dacryocystomeplasia should be considered in patients presenting with epiphora in the appropriate clinical context. Notably, this condition can be mistaken for a malignant disease, presenting a diagnostic challenge both clinically and histopathologically. PMID- 26634610 TI - The Child-care Food and Activity Practices Questionnaire (CFAPQ): development and first validation steps. AB - OBJECTIVE: To develop and validate a questionnaire to measure food-related and activity-related practices of child-care staff, based on existing, validated parenting practices questionnaires. DESIGN: A selection of items from the Comprehensive Feeding Practices Questionnaire (CFPQ) and the Preschooler Physical Activity Parenting Practices (PPAPP) questionnaire was made to include items most suitable for the child-care setting. The converted questionnaire was pre-tested among child-care staff during cognitive interviews and pilot-tested among a larger sample of child-care staff. Factor analyses with Varimax rotation and internal consistencies were used to examine the scales. Spearman correlations, t tests and ANOVA were used to examine associations between the scales and staff's background characteristics (e.g. years of experience, gender). SETTING: Child care centres in the Netherlands. SUBJECTS: The qualitative pre-test included ten child-care staff members. The quantitative pilot test included 178 child-care staff members. RESULTS: The new questionnaire, the Child-care Food and Activity Practices Questionnaire (CFAPQ), consists of sixty-three items (forty food related and twenty-three activity-related items), divided over twelve scales (seven food-related and five activity-related scales). The CFAPQ scales are to a large extent similar to the original CFPQ and PPAPP scales. The CFAPQ scales show sufficient internal consistency with Cronbach's alpha ranging between 0.53 and 0.96, and average corrected item-total correlations within acceptable ranges (0.30-0.89). Several of the scales were significantly associated with child-care staff's background characteristics. CONCLUSIONS: Scale psychometrics of the CFAPQ indicate it is a valid questionnaire that assesses child-care staff's practices related to both food and activities. PMID- 26634611 TI - Totality of the evidence at work: The first U.S. biosimilar. AB - On March 6(th) 2015, the Food and Drug Administration (FDA) approved filgrastim sndz (Zarxio) as the first biosimilar in the United States (US) for all indications of the reference product. Filgrastim-sndz is a biosimilar of Amgen's Neupogen and is mainly used to treat neutropenia in cancer patients receiving chemotherapy. This article presents a summary of the analytical and clinical studies submitted by Sandoz and describes how the information was integrated to provide the 'totality of the evidence' leading to the approval of the biosimilar. PMID- 26634612 TI - Development, validation and application of an HPLC method for reduced vitamin C qualification in HBOCs solution. AB - A rapid and sensitive high-performance liquid chromatography (HPLC) method for vitamin C (Vc) determination was developed in hemoglobin-based oxygen carriers (HBOCs) solution. After polymerized hemoglobin precipitation, Vc could be tested out within 5 min. The standard curve was linear in Vc quantity of 0.00-3.00 MUg. Vc recovery was 103.56-108.68%, and relative standard deviation values of the repeatability and precision were below 1.00%. The limits of detection and limits of quantification were 0.002 ppm and 0.01 ppm, respectively. Furthermore, the application of established HPLC methods in methemoglobin reduction by Vc under different pH indicated that higher pH values could accelerate the reduction. This study suggested the potential application of established HPLC method in HBOCs research and development. PMID- 26634613 TI - The permeability characteristics and interaction of the main components from Zhizi Bopi decoction in the MDCK cell model. AB - 1. Although emerging evidence indicates the therapeutic effects of Zhizi Bopi Decoction, the extent to which essential ingredients are absorbed and the possible synergistic actions are poorly understood. 2. In this study, MDCK cell model was used to determine the bi-directional permeability and interaction between the main components (geniposide, berberine and glycyrrhizic acid) of Zhizi Bopi Decoction. 3. The transport of the active ingredients was concentration-dependent in both directions. Moreover, the Papp (AP-BL) values of berberine and glycyrrhizic acid were significantly reduced when co-incubation with an ATP inhibitor. Additionally, uptake of berberine, glycyrrhizic acid were clearly inhibited by the inhibitors of P-glycoprotein and MRP2, indicating that P gp and MRP2 may be involved in the transport of berberine and glycyrrhizic acid, respectively. However, it was found that geniposide may be purely passive diffusion. Furthermore, the combined incubation of geniposide with berberine and glycyrrhizic acid had a powerful sorbefacient effect than use of a single drug alone which may be regulated by tight junctions. 4. In summary, our study provides useful information for pharmacological applications of Zhizi Bopi Decoction and offers new insights into this ancient decoction for further researches, especially in drug synergism. PMID- 26634614 TI - Global refugee total reached almost 60 million in 2014, highest since WWII. PMID- 26634615 TI - Who benefits more from hemodynamically guided hypotensive therapy? The experience from two randomized, prospective and controlled trials. AB - OBJECTIVES: Arterial hypertension (AH) may be related to fluid retention, increased vascular resistance or hyperdynamic heart function. Impedance cardiography (ICG) is shown to be useful in the individualization of antihypertensive therapy but little is known about who most benefits from this therapeutic approach. The aim of this analysis was to estimate the effectiveness of ICG-guided antihypertensive therapy with respect to baseline blood pressure (BP) from the perspective of 12 weeks' observation in randomized, prospective and controlled trials. METHODS: This analysis involved 272 patients (average age: 44.1 +/- 10.8 years) with AH. After baseline evaluation, including: office BP measurement (systolic, SBP; diastolic, DBP; mean, MBP) and ambulatory BP monitoring (mean 24-h SBP, mean 24-h DBP) the subjects were randomly assigned to groups of empiric [GE] and ICG-guided antihypertensive therapy [HD]. The results were evaluated separately in subgroups derived from median of MBP (110 mmHg): with slightly increased ('SI_BP') and more increased BP ('MI_BP'). The comparative analysis included absolute change in BP (d_OSBP, d_ODBP, d_24-h SBP, d_24-h DBP) and the percentage of patients with reduction of BP ? 10 mmHg (d10_OSBP, d10_ODBP, d10_24-h SBP, d10_24-h DBP). RESULTS: ICG-guided therapy was shown to be superior to the empiric approach, especially in MI_BP. In this subgroup, the BP reduction in HD was higher than in GE: d_OSBP (23.3 +/- 10.8 versus 18.5 +/- 13.9 mmHg; p = 0.035), d_ODBP (16.0 +/- 6.3 versus 11.6 +/- 9.6 mmHg; p = 0.003), d_24-h SBP (17.7 +/- 10.8 versus 13.1 +/- 13.1 mmHg; p = 0.035). This benefit was also confirmed by a higher percentage of patients with significant BP reduction: d10_OSBP (87.7% versus 69.1%; p = 0.012), d10_ODBP (69.2% versus 47.3%; p = 0.012) and d10_24-h SBP (72.3% versus 52.7%; p = 0.012). The comparison in the SI_BP subgroup did not reveal such significant differences. CONCLUSIONS: The hemodynamically guided pharmacotherapy results in greater BP reduction. This effect is more pronounced in patients with higher baseline BP, while in those with slightly increased BP the empiric approach seems comparable to ICG. PMID- 26634616 TI - Letting go of yesterday: Effect of distraction on post-event processing and anticipatory anxiety in a socially anxious sample. AB - According to cognitive models, post-event processing (PEP) is a key factor in the maintenance of social anxiety. Given that decreasing PEP can be challenging for socially anxious individuals, it is important to identify potentially useful strategies. Although distraction may help to decrease PEP, the findings have been equivocal. The primary purpose of this study was to examine whether a brief distraction period immediately following a speech would lead to less PEP the next day. The secondary aim was to examine the effect of distraction following an initial speech on anticipatory anxiety for a second speech, via reductions in PEP. Participants (N = 77 undergraduates with elevated social anxiety; 67.53% female) delivered a speech and were randomly assigned to a distraction, rumination, or control condition. The following day, participants reported levels of PEP in relation to the first speech, as well as anxiety regarding a second, upcoming speech. As expected, those in the distraction condition reported less PEP than those in the rumination and control conditions. Additionally, distraction following the first speech was indirectly related to anticipatory anxiety for the second speech, via PEP. Distraction may represent a potentially useful strategy for reducing PEP and other maladaptive processes that may maintain social anxiety. PMID- 26634617 TI - Health and Safety Executive's failed record on occupational medicine. PMID- 26634618 TI - Telepsychiatry integration of mental health services into rural primary care settings. AB - From a population health perspective, the mental health care system in the USA faces two fundamental challenges: (1) a lack of capacity and (2) an inequitable geographic distribution of services. Telepsychiatry can help address the equity problem, and if applied thoughtfully, can also help address the capacity problem. In this paper we describe how telepsychiatry can be used to address the capacity and equity challenges related to the delivery of mental health services in rural areas. Five models of telepsychiatry are described, including (1) the traditional telepsychiatry referral model, (2) The telepsychiatry collaborative care model, (3) the telepsychiatry behavioural health consultant model, (4) the telepsychiatry consultation-liaison model, and (5) the telepsychiatry curbside consultation model. The strong empirical evidence for the telepsychiatry collaborative care model is presented along with two case studies of telepsychiatry consultation in the context of the telepsychiatry collaborative care model. By placing telepsychiatrists and tele-therapists in consultation roles, telepsychiatry collaborative care has the potential to leverage scarce specialist mental health resources to reach more patients, thereby allowing these providers to have a greater population level impact compared to traditional referral models of care. Comparative effectiveness trials are needed to identify which models of telepsychiatry are the most appropriate for patients with complex psychiatric disorders. PMID- 26634619 TI - ANAMMOX-like performances for nitrogen removal from ammonium-sulfate-rich wastewater in an anaerobic sequencing batch reactor. AB - Ammonium removal by the ANaerobic AMonium OXidation (ANAMMOX) process was observed through the Sulfate-Reducing Ammonium Oxidation (SRAO) process. The same concentration of ammonium (100 mg N L(-1)) was applied to two anaerobic sequencing batch reactors (AnSBRs) that were inoculated with the same activated sludge from the Vermicelli wastewater treatment process, while nitrite was fed in ANAMMOX and sulfate in SRAO reactors. In SRAO-AnSBR, in substrates that were fed with a ratio of NH4(+)/SO4(2-) at 1:0.4 +/- 0.03, a hydraulic retention time (HRT) of 48 h and without sludge draining, the Ammonium Removal Rate (ARR) was 0.02 +/- 0.01 kg N m(-3).d(-1). Adding specific ANAMMOX substrates to SRAO-AnSBR sludge in batch tests results in specific ammonium and nitrite removal rates of 0.198 and 0.139 g N g(-1) VSS.d, respectively, indicating that the ANAMMOX activity contributes to the removal of ammonium in the SRAO process using the nitrite that is produced from SRAO. Nevertheless, the inability of ANAMMOX to utilize sulfate to oxidize ammonium was also investigated in batch tests by augmenting enriched ANAMMOX culture in SRAO-AnSBR sludge and without nitrite supply. The time course of sulfate in a 24-hour cycle of SRAO-AnSBR showed an increase in sulfate after 6 h. For enriched SRAO culture, the uptake molar ratio of NH4(+)/SO4(2-) at 8 hours in a batch test was 1:0.82 lower than the value of 1:0.20 +/- 0.09 as obtained in an SRAO-AnSBR effluent, while the stoichiometric ratio of 1:0.5 that includes the ANAMMOX reaction was in this range. After a longer operation of more than 2 years without sludge draining, the accumulation of sulfate and the reduction of ammonium removal were observed, probably due to the gradual increase in the sulfur denitrification rate and the competitive use of nitrite with ANAMMOX. The 16S rRNA gene PCR-DGGE (polymerase chain reaction denaturing gradient gel electrophoresis) and PCR cloning analyses resulted in the detection of the ANAMMOX bacterium (Candidatus Brocadia sinica JPN1) Desulfacinum subterraneum belonging to the genus Desulfacinum and bacteria that are involved in sulfur metabolism (Pseudomonas aeruginosa strain SBTPe-001 and Paracoccus denitrificans strain IAM12479) in SRAO-AnSBR. PMID- 26634620 TI - Kinetic and docking studies of cytosolic/tumor-associated carbonic anhydrase isozymes I, II and IX with some hydroxylic compounds. AB - A series of hydroxylic compounds (1-10, NK-154 and NK-168) have been assayed for the inhibition of three physiologically relevant carbonic anhydrase isozymes, the cytosolic isozymes I, II and tumor-associated isozyme IX. The investigated compounds showed inhibition constants in the range of 0.068-4003, 0.012-9.9 and 0.025-115 MUm at the hCA I, hCA II and hCA IX enzymes, respectively. In order to investigate the binding mechanisms of these inhibitors, in silico studies were also applied. Molecular docking scores of the studied compounds are calculated using scoring algorithms, namely Glide/induced fit docking. The inhibitory potencies of the novel compounds were analyzed at the human isoforms hCA I, hCA II and hCA IX as targets and the KI values were calculated. PMID- 26634621 TI - The role of transcription factors of neurosensory cells in non-syndromic sensorineural hearing loss with or without inner ear malformation. AB - CONCLUSIONS: Previous studies have stated the roles and correlation of the four TFs (Sox2, Atoh1, Neurog1, and Neurod1) in the development of neurosensory cells. but whether they are inherited pathogenic factors to cause non-syndromic sensorineural hearing loss is unknown so far. This is the first time for screening the Sox2, Atoh1, Neurog1, and Neurod1 genes in children with NSHL. The c.133A > G in Neurod1 gene is a polymorphism, which is not associated with NSHL. Although these genes are the recognized TFs for modulating the development and transformation of NSCs, they may not be the inherited pathogenic factors to cause congenital severe or profound NSHL directly. OBJECTIVE: To investigate the effect of the transcription factors (TFs) for the development of neurosensory cells (NSCs) and to explore the genetic etiology of congenital profound non-syndromic sensorineural hearing loss (NSHL). METHODS: Children with NSHL, from multi national and regional group, and control group were recruited to screen for the most common mutations for non-syndromic deafness among East Asian (mtDNA 12S rRNA: 1555A > G, 1494C > T; SLC26A4: IVS7-2 A > G, 2168 C > T). And mutational analysis of the coding regions in Sox2, Atoh1 and Neurog1, Neurod1 genes were performed. RESULTS: Only the c.133A > G (p. Ala45Thr) in the Neurod1 gene was detected in this study. The allele frequencies of this variant were 88.00% and 84.88% in the inner ear malformation group and the normal inner ear group, respectively, while 90.85% of children in the control group carried c.133A > G. This variant existed in every group commonly and had no significant difference among them. No variant in the other two TFs was detected in this cohort. PMID- 26634622 TI - Multispecies toxicity test for silver nanoparticles to derive hazardous concentration based on species sensitivity distribution for the protection of aquatic ecosystems. AB - With increasing concerns about the release of silver nanoparticles (AgNPs) into the environment and the risks they pose to ecological and human health, a number of studies of AgNP toxicity to aquatic organisms have been conducted. USEPA and EU JRC have published risk assessment reports for AgNPs. However, most previous studies have focused on the adverse effects of AgNPs on individual species. Hazardous concentration (HC) of AgNPs for protection of aquatic ecosystems that are based on species sensitivity distributions (SSDs) have not yet been derived because sufficient data have not been available. In this study, we conducted multispecies toxicity tests, including acute assays using eight species from five different taxonomic groups (bacteria, algae, flagellates, crustaceans and fish) and chronic assays using six species from four different taxonomic groups (algae, flagellates, crustaceans and fish). Using the results of these assays, we used a SSD approach to derive an AgNP aquatic HC5 (Hazard concentrations at the 5% species) of 0.614 MUg/L. To our knowledge, this is the first report of a proposed HC of AgNPs for the protection of aquatic ecosystems that is based on SSDs and uses chronic toxicity data. PMID- 26634623 TI - Maternal azithromycin administration eradicates intra-amniotic Ureaplasma infection: The first human case report. PMID- 26634625 TI - Microfluidic Generation of Porous Microcarriers for Three-Dimensional Cell Culture. AB - Inspired by the microstructure of the stem cell niche, which is generally composed of adjacent cell protection layers and an extracellular matrix (ECM), we present novel microfluidic porous microcarriers for cell culture that consist of external-internal connected scaffold structures and biopolymer matrix fillers. The biomimetic scaffold structure of the porous microcarriers not only avoids the imposition of shear forces on the encapsulated cells but also provides a confined microenvironment for cell self-assembly, whereas the biopolymers in the porous cores of the microcarriers can act as an ECM microenvironment to promote the formation of multicellular spheroid aggregates for biomedical applications. PMID- 26634624 TI - The impact of vitamin D on asthmatic human airway smooth muscle. AB - Asthma is a chronic heterogeneous disorder, which involves airway inflammation, airway hyperresponsiveness (AHR) and airway remodeling. The airway smooth muscle (ASM) bundle regulates the broncho-motor tone and plays a critical role in AHR as well as orchestrating inflammation. Vitamin D deficiency has been linked to increased severity and exacerbations of symptoms in asthmatic patients. It has been shown to modulate both immune and structural cells, including ASM cells, in inflammatory diseases. Given that current asthma therapies have not been successful in reversing airway remodeling, vitamin D supplementation as a potential therapeutic option has gained a great deal of attention. Here, we highlight the potential immunomodulatory properties of vitamin D in regulating ASM function and airway inflammation in bronchial asthma. PMID- 26634627 TI - Reaction Dynamics of CN Radicals in Acetonitrile Solutions. AB - The bimolecular reactions that follow 267 nm ultraviolet photolysis of ICN in acetonitrile solution have been studied using transient absorption spectroscopy on the picosecond time scale. Time-resolved electronic absorption spectroscopy (TEAS) in the ultraviolet and visible spectral regions observes rapid production and loss (with a decay time constant of 0.6 +/- 0.1 ps) of the photolytically generated free CN radicals. Some of these radicals convert to a solvated form which decays with a lifetime of 8.5 +/- 2.1 ps. Time-resolved vibrational absorption spectroscopy (TVAS) reveals that the free and solvated CN-radicals undergo geminate recombination with I atoms to make ICN and INC, H atom abstraction reactions, and addition reactions to solvent molecules to make C3H3N2 radical species. These radical products have a characteristic absorption band at 2036 cm(-1) that shifts to 2010 cm(-1) when ICN is photolyzed in CD3CN. The HCN yield is low, suggesting the addition pathway competes effectively with H atom abstraction from CH3CN, but the delayed growth of the C3H3N2 radical band is best described by reaction of solvated CN radicals through an unobserved intermediate species. Addition of methanol or tetrahydrofuran as a cosolute promotes H atom abstraction reactions that produce vibrationally hot HCN. The combination of TEAS and TVAS measurements shows that the rate-limiting process for production of ground-state HCN is vibrational cooling, the rate of which is accelerated by the presence of methanol or tetrahydrofuran. PMID- 26634629 TI - "My Partner Will Change": Cognitive Distortion in Battered Women in Bolivia. AB - This study examines the role of cognitive distortion in women's decision to stay with or leave their violent partner in a sample of Bolivian women. Our study is based on a consistency model: Cognitive distortion is assumed to play an important role in maintaining cognitive consistency under threatening conditions. Eighty victims of partner violence aged 18 to 62 years who sought help in a legal institution were longitudinally assessed three times over a time period of 6 months. Measures were taken from previous studies and culturally adapted through qualitative interviews. Nearly half of the participants decreased their intention to leave the violent partner in the time span of 1 month between the first and second interview. Women who had decreased their leaving intention had concurrently increased their cognitive distortion: They blamed their partner less, were more convinced that they could stop the violence themselves, and were more likely to believe that their partner would change. Cognitive distortion was not observed among women who remained stable in their intention to leave. Women whose intention of leaving decreased and who displayed more cognitive distortion after 1 month were more likely to live with the violent partner 6 months later than women whose leaving intention remained stable or increased. Socio demographic variables were not related to cognitive distortion or stay-leave decisions in this study. We conclude that cognitive distortion plays a role for women's decision to stay, enhancing their risk of re-victimization. PMID- 26634628 TI - Use of Autometallography in Studies of Nanosilver Distribution and Toxicity. AB - With the increasing use of and interest in nanoparticles in medicine and technology, the tissue and cell-specific localization of the particles are important considerations when the nanomaterials find their way into biological systems. This brief communication shows the utility of autometallography in determining the location of metal deposition at the light microscopic level. Although primarily focusing on studies of the toxicity and deposition of silver nanoparticles, use of autometallography to localize zinc and other metals at the tissue and subcellular localization is also recognized. PMID- 26634630 TI - The Association Between Social Support and Stages of Change in Survivors of Intimate Partner Violence. AB - For survivors of intimate partner violence (IPV), it is often difficult to take steps to establish safety and obtain a violence free life. Researchers have applied stage of change theory to aid in understanding the experience of survivors, as well as, the factors that can help women who desire to make changes in or break free from a violent relationship. Social support is one factor that can be helpful to IPV survivors who are attempting to make changes in their relationship. The purpose of the current study was to examine the differences in social support experienced by women who are at varying points in the process of change. Shelter residents ( N = 191) participated in this cross-sectional non experimental study. Analyses demonstrated five distinct clusters or profiles of change among study participants and were labeled by the authors as follows: preparticipation, decision making, engagement, ambivalent, and action. All forms of social support (i.e., structural, functional, and satisfaction) were generally higher for individuals more engaged in the process of change. More specifically, differences were noted between the action and decision-making clusters and the engagement and decision-making clusters. These findings suggest that it is vital that clinicians working with survivors of IPV not only assess but also tailor interventions to meet survivors where they are in the process of change. Further, interventions that foster survivors' abilities to develop reliable and satisfying social support networks will be beneficial for survivors of IPV. PMID- 26634631 TI - Identification and evaluation of the chemical similarity of Yindan xinnaotong samples by ultra high performance liquid chromatography with quadrupole time-of flight mass spectrometry fingerprinting. AB - Yindan xinnaotong, a compound preparation used in traditional Chinese medicine, is composed of eight herbs: Ginkgo biloba leaf (yinxingye), Salvia miltiorrhizae (danshen), Herba gynostemmatis (jiaogulan), Erigerontis herba (dengzhanxixin), Allii sativi bulbus (dasuan), Notoginseng radixe rhizoma (sanqi), Crataegi fructus (shanzha), and Borneolum (tianranbingpian). Yindan xinnaotong is primarily used to treat cardiovascular and cerebrovascular diseases. However, to date, no scientific methods have been established to assess the quality of Yindan xinnaotong. Therefore, a combinatorial method was developed based on chemical constituent identification and fingerprint analysis to assess the consistency of Yindan xinnaotong quality. In this study, ultra high performance liquid chromatography coupled with time-of-flight mass spectrometry was used to identify the chemical components of Yindan xinnaotong soft capsules. Approximately 74 components were detected, of which 70, including flavonoids, ginkgolide, phenolic acid, diterpenoid tanshinones, and ginsenoside, were tentatively identified. A fingerprint analysis was also conducted to evaluate the uniformity of the quality of Yindan xinnaotong soft capsules. Ten batches of Yindan xinnaotong soft capsules were analyzed. All of the resulting chromatograms were imported into the "Similarity Evaluation System for Chromatographic Fingerprints of TCM" (Chinese Pharmacopoeia Commission, version 2004A). The similarity scores of common peaks from these samples ranged from 0.903-1.000, indicating that samples from different batches were highly correlated. PMID- 26634632 TI - Treatment of subchondral cysts in patients with haemophilia. AB - INTRODUCTION: The haemophilic arthropathy is a disabling disease that causes chronic pain and functional limitation, due to recurrent intra-articular bleeding, with impaired quality of life. OBJECTIVE: The aim of this work is to present our 24-year experience in the treatment of subchondral cysts filled with hydroxyapatite coralline in patients with haemophilia. PATIENTS AND METHOD: Thirty-seven male patients with forty-nine cystic lesions were treated and evaluated between 1990 and 2014. Thirty four patients were haemophilia type A, three were haemophilia type B, two patients had inhibitors to factor VIII. The average age was 23.6 years. The average follow-up was 10 years. The lesions were located: twenty-four in the tibia (49%), six in the talus (12.2%), seven in the ulna (14.4%), five in the humerus (10.2%), five in the femur (10.2%) and two in the distal radius (4%). In all patients' radiographs, Computed Tomography and Magnetic Resonance Imaging were performed before surgery. The lesions were treated when the injury was greater than 15% of the joint area, and when the joint area was greater than 1 cm of diameter. Surgical technique consisted of aspirating the cyst contents and refilling it with hydroxyapatite coralline. RESULTS: In forty-eight cysts, restitution of bone structure was achieved by impaction of hydroxyapatite coralline. The average time of bone restoration was 10 months. Only one patient required a second intervention. CONCLUSION: The treatment of subchondral cyst in PWH by aspiration and filling with hydroxyapatite coralline allows bone restoration and delays deterioration of the joint treated. PMID- 26634633 TI - Radiographic evaluation of nursing- and healthcare-associated pneumonia. AB - AIM: Radiographic testing has an important role in the diagnosis and evaluation of pneumonia. The aim of the present study was to evaluate the usefulness of computed tomography (CT), in comparison with chest roentography (CR), in the diagnosis and evaluation of nursing- and healthcare-associated pneumonia (NHCAP) . METHODS: The utility of CT in the diagnosis of NHCAP was compared with that of CR in a prospective study of patients who visited the emergency room in Nissan Tamagawa Hospital, Tokyo, Japan, with clinical symptoms that were indicative of NHCAP. We also evaluated whether particular CT findings were risk factors for NHCAP-associated mortality. RESULTS: A total of 162 patients with suspected NHCAP were included in the study. The 162 patients included 147 (90.6%) patients who were diagnosed with NHCAP based on the detection of pneumonic infiltration on CT. In contrast, CR was not capable of recognizing pneumonic infiltration in 15 of the 147 (10.2%) patients. A multivariable analysis which was carried out to determine the risk factors for NHCAP-associated mortality, showed that oxygen desaturation had the greatest odds ratio, followed by a blood urea nitrogen level of >=21 mg/dL and the detection of bilateral pneumonic infiltration by CT. CONCLUSIONS: We herein show that CT is superior to CR for the diagnosis and evaluation of NHCAP. The present study will provide a foundation for further studies to clarify whether the use of CT in the diagnosis and evaluation of NHCAP can improve the clinical outcome of patients with NHCAP. Geriatr Gerontol Int 2017; 17: 41-47. PMID- 26634634 TI - Impurity-Mediated Early Condensation of a Charge Density Wave in an Atomic Wire Array. AB - We directly show how impurity atoms induce the condensation of a representative electronic phase, the charge density wave (CDW) phase, in atomic scale with scanning tunneling microscopy. Oxygen impurity atoms on the self-assembled metallic atomic wire array on a silicon crystal condense the CDW locally above the pristine transition temperature. More interestingly, the CDW along the wires is induced not by a single atomic impurity but by the cooperation of multiple impurities. First-principles calculations disclose the mechanism of the cooperation as the coherent superposition of the local lattice strain induced by impurities, stressing the coupled electronic and lattice degrees of freedom for the CDW. This opens the possibility of the strain engineering over electronic phases of atomic-scale systems. PMID- 26634635 TI - Total Synthesis of Peniphenones A-D via Biomimetic Reactions of a Common o Quinone Methide Intermediate. AB - The total synthesis of peniphenones A-D has been achieved via Michael reactions between appropriate nucleophiles and a common o-quinone methide intermediate. This strategy, which was based on a biosynthetic hypothesis, minimized the use of protecting groups and thus facilitated concise syntheses of the natural products. The most complex target, the benzannulated spiroketal peniphenone A, was synthesized enantioselectively in nine linear steps from commercially available starting materials. PMID- 26634637 TI - Importance of lethal control of invasive predators for island conservation. PMID- 26634638 TI - Fighting Cancer with Transition Metal Complexes: From Naked DNA to Protein and Chromatin Targeting Strategies. AB - Many transition metal complexes have unique physicochemical properties that can be efficiently exploited in medicinal chemistry for cancer treatment. Traditionally, double-stranded DNA has been assumed to be the main binding target; however, recent studies have shown that nucleosomal DNA as well as proteins can act as dominant molecular binding partners. This has raised new questions about the molecular determinants that govern DNA versus protein binding selectivity, and has offered new ways to rationalize their biological activity and possible side effects. To address these questions, molecular simulations at an atomistic level of detail have been used to complement, support, and rationalize experimental data. Herein we review some relevant studies-focused on platinum and ruthenium compounds-to illustrate the power of state-of-the-art molecular simulation techniques and to demonstrate how the interplay between molecular simulations and experiments can make important contributions to elucidating the target preferences of some promising transition metal anticancer agents. This contribution aims at providing relevant information that may help in the rational design of novel drug-discovery strategies. PMID- 26634639 TI - Induction of pancreatic beta cell gene expression in mesenchymal stem cells. AB - Transdifferentiattion potential of mesenchymal stem cells (MSCs) into insulin producing cells (IPCs) has been suggested recently. In our recent works, we demonstrated the high performance of mouse neonate pancreas extract (MPE) in the production of functional IPCs from carcinoma stem cells. In this study, MPE was used to generate IPCs from MSCs without any genetic manipulation. To this end, bone marrow MSCs were isolated and characterized. In order to differentiate, MSCs were induced by selection of nestin-expressing cells and treatment with 100 MUg/mL MPE. Morphological features of the differenti-ated cells were confirmed by dithizone staining. Immunoreactivity to insulin receptor beta, proinsulin, insulin, and C-peptide was observed by immunoflourescence. We also quantified glucose-dependent insulin production and secretion by ELISA. Real-time PCR indicated the expressions of beta cell-related genes, PDX-1, INS1, INS2, EP300, and CREB1, in IPC cells. Possible pathways governed by CREB1, EP300, and PDX-1 transcription factors in differentiation of MSCs to IPCs were determined based on Gene Set Enrichment (GSE) approach at P = 0.05. Pathway discovery highlighted the negative regulatory effects of MIR124-2, HDAC5 protein, REST, and NR0B2 transcription factors on expression of CREB1, EP300, and PDX-1 and inhabitation of IPC differentiations. In contrast, a crosstalk between FOXA2 and TCF7L2 transcription factors, DNA-PK complex, KAT2B protein positively interacting with PDX-1, CREB1, EP300 resulted in the induction of IPC and following insulin production. In conclusion, we report an efficient, simple, and easy method for production of functional IPCs from MSCs by MPE treatment. PMID- 26634640 TI - Hexameric Capsules Studied by Magic Angle Spinning Solid-State NMR Spectroscopy: Identifying Solvent Molecules in Pyrogallol[4]arene Capsules. AB - Powders of pyrogallol[4]arene hexamers were produced by evaporation from organic solvents and were studied, for the first time, by magic angle spinning solid state NMR (MAS ssNMR). Evaporation selectively removed non-encapsulated solvent molecules leaving stable hexameric capsules encapsulating solvent molecules. After exposure of the powder to solvent vapors, (1)H/(13)C heteronuclear correlation MAS ssNMR experiments were used to assign the signals of the external and encapsulated solvent molecules. The formed capsules were stable for months and the process of solvent encapsulation was reversible. According to the ssNMR experiments, the encapsulated solvent molecules occupy different sites and those sites differ in their mobility. The presented approach paves the way for studying guest exchange, guest affinity, and gas storage in hexamers of this type in the solid state. PMID- 26634641 TI - Triphenylphosphine-Mediated Deoxygenative Reduction of CF3 SO2 Na and Its Application for Trifluoromethylthiolation of Aryl Iodides. AB - We report herein a practical method for taming Langlois' reagent CF3 SO2 Na to generate CuSCF3 by a triphenylphospine-mediated deoxygenative reduction process. This chemistry highlights a novel utilization of the inherent CF3 S skeleton of Langlois' reagent as a CF3 S feedstock under mild conditions. The CuSCF3 intermediate generated by this protocol can react with a wide array of supporting ligands to furnish several air-stable [LCu(SCF3 )] complexes as valuable trifluoromethylthiolating agents. In addition, the CuSCF3 intermediate can be directly employed for the trifluoromethylthiolation of (hetero)aryl iodides with operational simplicity and atomic efficiency. PMID- 26634642 TI - Pharmacokinetics, Pharmacodynamics, Safety, and Clinical Activity of Multiple Doses of RCT-18 in Chinese Patients With Systemic Lupus Erythematosus. AB - RCT-18 is a novel recombinant fusion protein that blocks the activity of a B lymphocyte stimulator and a proliferation-inducing ligand. This was a randomized, single-blind, and placebo-controlled phase 1 study in 12 patients with systemic lupus erythematosus. Eligible patients were randomized 3:1 to receive multiple subcutaneous doses of RCT-18 for 4 weeks (180 mg, once weekly) or placebo and monitored over an 84-day observation period for pharmacokinetics, pharmacodynamics, immunogenicity, safety, and clinical activity. After multiple dose RCT-18, the maximal serum concentration (Cmax ) of total and free RCT-18 was reached within 1 to 2 days. Mean elimination half-life for total RCT-18 and free RCT-18 was 11.4 to 26.4 days and 2.4 to 26.5 days, respectively. Slight accumulation was found after multiple subcutaneous administrations. The average accumulation ratios of AUC and Cmax after the fourth administration of RCT-18 were 2.0 and 1.7 for total RCT-18, and 1.8 and 1.6 for free RCT-18. The formation and elimination of BLyS-RCT-18 complex were much slower, with a time to Cmax of 14 to 46 days. Pharmacokinetic characteristics of RCT-18 in SLE patients were similar to those in patients with rheumatoid arthritis. No positive reaction was detected in the immunogenicity assessments. RCT-18 was biologically active, according to serum immunoglobulin and B-cell levels. Treatment-related IgM and IgA reduction was found during this study. CD19(+) , IgD(+) , and CD27(+) B-cell counts were increased after administration and decreased subsequently. SLE patients treated with RCT-18 were more prone to infections, including moderate and severe infections. Lower dosages of RCT-18 should be considered in further clinical development. PMID- 26634643 TI - Mechanisms of 5-HT1A receptor-mediated transmission in dorsal raphe serotonin neurons. AB - KEY POINTS: In the dorsal raphe nucleus, it is known that serotonin release activates metabotropic 5-HT1A autoreceptors located on serotonin neurons that leads to an inhibition of firing through the activation of G-protein-coupled inwardly rectifying potassium channels. We found that in mouse brain slices evoked serotonin release produced a 5-HT1A receptor-mediated inhibitory postsynaptic current (IPSC) that resulted in only a transient pause in firing. While spillover activation of receptors contributed to evoked IPSCs, serotonin reuptake transporters prevented pooling of serotonin in the extrasynaptic space from activating 5-HT1A -IPSCs. As a result, the decay of 5-HT1A -IPSCs was independent of the intensity of stimulation or the probability of transmitter release. These results indicate that evoked serotonin transmission in the dorsal raphe nucleus mediated by metabotropic 5-HT1A autoreceptors may occur via point to-point synapses rather than by paracrine mechanisms. ABSTRACT: In the dorsal raphe nucleus (DRN), feedback activation by Galphai/o -coupled 5-HT1A autoreceptors reduces the excitability of serotoninergic neurons, which decreases serotonin release both locally within the DRN and in projection regions. Serotonin transmission within the DRN is thought to occur via transmitter spillover and paracrine activation of extrasynaptic receptors. Here, we tested the volume transmission hypothesis in mouse DRN brain slices by recording 5-HT1A receptor-mediated inhibitory postsynaptic currents (5-HT1A -IPSCs) generated by the activation of G-protein-coupled inwardly rectifying potassium channels (GIRKs). We found that in the DRN of ePET1-EYFP mice, which selectively express enhanced yellow fluorescent protein in serontonergic neurons, the local release of serotonin generated 5-HT1A -IPSCs in serotonin neurons that rose and fell within a second. The transient activation of 5-HT1A autoreceptors resulted in brief pauses in neuron firing that did not alter the overall firing rate. The duration of 5-HT1A -IPSCs was primarily shaped by receptor deactivation due to clearance via serotonin reuptake transporters. Slowing diffusion with dextran prolonged the rise and reduced the amplitude the IPSCs and the effects were potentiated when uptake was inhibited. By examining the decay kinetics of IPSCs, we found that while spillover may allow for the activation of extrasynaptic receptors, efficient uptake by serotonin reuptake transporters (SERTs) prevented the pooling of serotonin from prolonging the duration of transmission when multiple inputs were active. Together the results suggest that the activation of 5-HT1A receptors in the DRN results from the local release of serotonin rather than the extended diffusion throughout the extracellular space. PMID- 26634644 TI - A highly reversible room-temperature lithium metal battery based on crosslinked hairy nanoparticles. AB - Rough electrodeposition, uncontrolled parasitic side-reactions with electrolytes and dendrite-induced short-circuits have hindered development of advanced energy storage technologies based on metallic lithium, sodium and aluminium electrodes. Solid polymer electrolytes and nanoparticle-polymer composites have shown promise as candidates to suppress lithium dendrite growth, but the challenge of simultaneously maintaining high mechanical strength and high ionic conductivity at room temperature has so far been unmet in these materials. Here we report a facile and scalable method of fabricating tough, freestanding membranes that combine the best attributes of solid polymers, nanocomposites and gel-polymer electrolytes. Hairy nanoparticles are employed as multifunctional nodes for polymer crosslinking, which produces mechanically robust membranes that are exceptionally effective in inhibiting dendrite growth in a lithium metal battery. The membranes are also reported to enable stable cycling of lithium batteries paired with conventional intercalating cathodes. Our findings appear to provide an important step towards room-temperature dendrite-free batteries. PMID- 26634645 TI - Charge Transport in Organic and Polymeric Semiconductors for Flexible and Stretchable Devices. AB - An ultimate goal of organic electronics is to fabricate large-area electronic devices and circuits on flexible and stretchable substrates. To achieve this target, understanding and/or tuning of the processes that determine charge transport is therefore of paramount importance for the development of high performance devices, e.g., organic field-effect transistors (OFETs). Significant progress in this field is summarized here, with particular focus on the new insights of charge transport under certain strain effects in flexible and stretchable OFETs. PMID- 26634646 TI - Liquid chromatography-electron ionization tandem mass spectrometry with the Direct-EI interface in the fast determination of diazepam and flunitrazepam in alcoholic beverages. AB - This is the first application based on electron ionization (EI) using a Direct-EI LC interface and MS/MS to detect unequivocally target compounds in a very small real sample. The determination and quantification of benzodiazepines in very small residues of beverages, collected at the scene of drug-facilitated crimes are mandatory in legal procedures. A specific and sensitive analytical instrumentation is needed, involving little or no sample preparation. Here, a direct flow injection analysis of alcoholic beverages spiked with commercially available drugs containing diazepam and flunitrazepam is presented. The method proposed is very fast and requires neither sample preparation nor chromatographic separation. Linearity (R(2) ) was between 0.9977 and 0.9992; LOD and LOQ spanned from 0.01 to 0.02 ng/MUL and from 0.1 to 0.5 ng/MUL, respectively; intra- and interday repeatabilities were between 1 and 8%. No matrix effects were observed from the comparison of the linear regression curves obtained in real fortified samples and in pure ethanol. Vodka, whisky, and white wine specimens were fortified with commercial drugs, Valium((r)) and Rohypnol((r)) , at two different concentrations (20 and 50 ng/MUL) to simulate the typical amounts found in adulterated real samples and analyzed to demonstrate the method applicability to forensic analyses. PMID- 26634647 TI - Understanding the Unique Electronic Properties of Nano Structures Using Photoemission Theory. AB - Newly emerging experimental techniques such as nano-ARPES are expected to provide an opportunity to measure the electronic properties of nano-materials directly. However, the interpretation of the spectra is not simple because it must consider quantum mechanical effects related to the measurement process itself. Here, we demonstrate a novel approach that can overcome this problem by using an adequate simulation to corroborate the experimental results. Ab initio calculation on arbitrarily-shaped or chemically ornamented nano-structures is elaborately correlated to photoemission theory. This correlation can be directly exploited to interpret the experimental results. To test this method, a direct comparison was made between the calculation results and experimental results on highly-oriented pyrolytic graphite (HOPG). As a general extension, the unique electronic structures of nano-sized graphene oxide and features from the experimental result of black phosphorous (BP) are disclosed for the first time as supportive evidence of the usefulness of this method. This work pioneers an approach to intuitive and practical understanding of the electronic properties of nano-materials. PMID- 26634648 TI - The Assembling of Poly (3-Octyl-Thiophene) on CVD Grown Single Layer Graphene. AB - The interface between organic semiconductor and graphene electrode, especially the structure of the first few molecular layers at the interface, is crucial for the device properties such as the charge transport in organic field effect transistors. In this work, we have used scanning tunneling microscopy to investigate the poly (3-octyl-thiophene) (P3OT)-graphene interface. Our results reveal the dynamic assembling of P3OT on single layer graphene. As on other substrates the epitaxial effect plays a role in determining the orientation of the P3OT assembling, however, the inter-thiophene distance along the backbone is consistent with that optimized in vaccum, no compression was observed. Adsorption of P3OT on ripples is weaker due to local curvature, which has been verified both by scanning tunneling microscopy and density functional theory simulation. Scanning tunneling microscopy also reveals that P3OT tends to form hairpin folds when meets a ripple. PMID- 26634649 TI - Distinct predictive performance of Rac1 and Cdc42 in cell migration. AB - We propose a new computation-based approach for elucidating how signaling molecules are decoded in cell migration. In this approach, we performed FRET time lapse imaging of Rac1 and Cdc42, members of Rho GTPases which are responsible for cell motility, and quantitatively identified the response functions that describe the conversion from the molecular activities to the morphological changes. Based on the identified response functions, we clarified the profiles of how the morphology spatiotemporally changes in response to local and transient activation of Rac1 and Cdc42, and found that Rac1 and Cdc42 activation triggers laterally propagating membrane protrusion. The response functions were also endowed with property of differentiator, which is beneficial for maintaining sensitivity under adaptation to the mean level of input. Using the response function, we could predict the morphological change from molecular activity, and its predictive performance provides a new quantitative measure of how much the Rho GTPases participate in the cell migration. Interestingly, we discovered distinct predictive performance of Rac1 and Cdc42 depending on the migration modes, indicating that Rac1 and Cdc42 contribute to persistent and random migration, respectively. Thus, our proposed predictive approach enabled us to uncover the hidden information processing rules of Rho GTPases in the cell migration. PMID- 26634650 TI - Characterization of Pseudooxynicotine Amine Oxidase of Pseudomonas putida S16 that Is Crucial for Nicotine Degradation. AB - Pseudooxynicotine amine oxidase (Pnao) is essential to the pyrrolidine pathway of nicotine degradation of Pseudomonas putida strain S16, which is significant for the detoxification of nicotine, through removing the CH3NH2 group. However, little is known about biochemical mechanism of this enzyme. Here, we characterized its properties and biochemical mechanism. Isotope labeling experiments provided direct evidence that the newly introduced oxygen atom in 3 succinoylsemialdehyde-pyridine is derived from H2O, but not from O2. Pnao was very stable at temperatures below 50 degrees C; below this temperature, the enzyme activity increased as temperature rose. Site-directed mutagenesis studies showed that residue 180 is important for its thermal stability. In addition, tungstate may enhance the enzyme activity, which has rarely been reported before. Our findings make a further understanding of the crucial Pnao in nicotine degradation. PMID- 26634651 TI - APOL1 Genotype, Kidney and Cardiovascular Disease, and Death in Older Adults. AB - OBJECTIVE: We sought to evaluate the cardiovascular impact of coding variants in the apolipoprotein L1 gene APOL1 that protect against trypanosome infection but have been associated with kidney disease among African Americans. APPROACH AND RESULTS: As part of the Cardiovascular Health Study, a population-based cohort of Americans aged >=65 years, we genotyped APOL1 polymorphisms rs73885319 and rs71785153 and examined kidney function, subclinical atherosclerosis, and incident cardiovascular disease and death over 13 years of follow-up among 91 African Americans with 2 risk alleles, 707 other African Americans, and 4964 white participants. The high-risk genotype with 2 risk alleles was associated with 2-fold higher levels of albuminuria and lower ankle-brachial indices but similar carotid intima-media thickness among African Americans. Median survival among high-risk African Americans was 9.9 years (95% confidence interval [CI], 8.7-11.9), compared with 13.6 years (95% CI, 12.5-14.3) among other African Americans and 13.3 years (95% CI, 13.0-13.6) among whites (P=0.03). The high-risk genotype was also associated with increased risk for incident myocardial infarction (adjusted hazard ratio 1.8; 95% CI, 1.1-3.0) and mortality (adjusted hazard ratio 1.3; 95% CI 1.0-1.7). Albuminuria and risk for myocardial infarction and mortality were nearly identical between African Americans with 0 to 1 risk alleles and whites. CONCLUSIONS: APOL1 genotype is associated with albuminuria, subclinical atherosclerosis, incident myocardial infarction, and mortality in older African Americans. African Americans without 2 risk alleles do not differ significantly in risk of myocardial infarction or mortality from whites. APOL1 trypanolytic variants may account for a substantial proportion of the excess risk of chronic disease in African Americans. PMID- 26634652 TI - Valve Endothelial Cell-Derived Tgfbeta1 Signaling Promotes Nuclear Localization of Sox9 in Interstitial Cells Associated With Attenuated Calcification. AB - OBJECTIVE: Aortic valve disease, including calcification, affects >2% of the human population and is caused by complex interactions between multiple risk factors, including genetic mutations, the environment, and biomechanics. At present, there are no effective treatments other than surgery, and this is because of the limited understanding of the mechanisms that underlie the condition. Previous work has shown that valve interstitial cells within the aortic valve cusps differentiate toward an osteoblast-like cell and deposit bone like matrix that leads to leaflet stiffening and calcific aortic valve stenosis. However, the mechanisms that promote pathological phenotypes in valve interstitial cells are unknown. APPROACH AND RESULTS: Using a combination of in vitro and in vivo tools with mouse, porcine, and human tissue, we show that in valve interstitial cells, reduced Sox9 expression and nuclear localization precedes the onset of calcification. In vitro, Sox9 nuclear export and calcific nodule formation is prevented by valve endothelial cells. However, in vivo, loss of Tgfbeta1 in the endothelium leads to reduced Sox9 expression and calcific aortic valve disease. CONCLUSIONS: Together, these findings suggest that reduced nuclear localization of Sox9 in valve interstitial cells is an early indicator of calcification, and therefore, pharmacological targeting to prevent nuclear export could serve as a novel therapeutic tool in the prevention of calcification and stenosis. PMID- 26634653 TI - Antithrombotic Effects of Nur77 and Nor1 Are Mediated Through Upregulating Thrombomodulin Expression in Endothelial Cells. AB - OBJECTIVE: Thrombomodulin is highly expressed on the lumenal surface of vascular endothelial cells (ECs) and possesses potent anticoagulant, antifibrinolytic, and anti-inflammatory activities in the vessel wall. However, the regulation of thrombomodulin expression in ECs remains largely unknown. APPROACHES AND RESULTS: In this study, we characterized nuclear receptor 4A family as a novel regulator of thrombomodulin expression in vascular ECs. We demonstrated that both nuclear receptors 4A, Nur77 and Nor1, robustly increase thrombomodulin mRNA and protein levels in human vascular ECs and in mouse liver tissues after adenovirus-mediated transduction of Nur77 and Nor1 cDNAs. Moreover, Nur77 deficiency and knockdown of Nur77 and Nor1 expression markedly attenuated the basal and vascular endothelial growth factor165-stimulated thrombomodulin expression. Mechanistically, we found that Nur77 and Nor1 increase thrombomodulin expression by acting through 2 different mechanisms. We showed that Nur77 barely affects thrombomodulin promoter activity, but significantly increases thrombomodulin mRNA stability, whereas Nor1 enhances thrombomodulin expression mainly through induction of Kruppel-like factors 2 and 4 in vascular ECs. Furthermore, we demonstrated that both Nur77 and Nor1 significantly increase protein C activity and inhibit tumor necrosis factor alpha-induced prothrombotic effects in human ECs. Deficiency of Nur77 increases susceptibility to arterial thrombosis, whereas enhanced expression of Nur77 and Nor1 protects mice from arterial thrombus formation. CONCLUSIONS: Our results identified nuclear receptors 4A as novel regulators of thrombomodulin expression and function in vascular ECs and provided a proof-of-concept demonstration that targeted increasing expression of Nur77 and Nor1 in the vascular endothelium might represent a novel therapeutic approach for the treatment of thrombotic disorders. PMID- 26634654 TI - Effects of Long-Term Type I Interferon on the Arterial Wall and Smooth Muscle Progenitor Cells Differentiation. AB - OBJECTIVE: Patients with systemic lupus erythematosis are at risk for premature atherosclerosis and half of the patients with systemic lupus erythematosis have elevated type I interferon (IFN-I) levels. We hypothesized that IFN-I would induce premature atherosclerosis by increasing the number of smooth muscle progenitor cells (SMPC) in the bloodstream and promoting atherosclerotic lesions within the vasculature. APPROACH AND RESULTS: SMPC isolated from wild-type and IFN receptor knockout animals were cultured in medium+/-IFN-I. In vivo, we used electroporation to generate stable IFN-I expression for as long as 4 months. The number of SMPC was determined in mice that expressed IFN-I and in control mice and sections from the bifurcation of the abdominal aorta were analyzed 3 months after electroporation of an IFN-I expression plasmid or a control plasmid. Adding IFN-I to the media increased the number of cultured wild-type SMPC and increased mRNA for SM22, but had no effect on SMPC isolated from IFN receptor knockout mice. Our in vivo results demonstrated a positive relationship between the preatherosclerotic-like lesions and endothelial damage. Although, there were no significant differences in smooth muscle cell density or thickness of the medial layer between groups, the IFN-I-expressing mice had a significant increase in preatherosclerotic-like lesions and immature smooth muscle cells, cells that expressed CD34 and smooth muscle alpha-actin; but lacked smooth muscle myosin heavy chain. CONCLUSIONS: IFN-I seems to enhance SMPC number in vitro. In vivo IFN-I expression may maintain SMPC in an immature state. These immature smooth muscle cells could give rise to macrophages and eventually foam cells. PMID- 26634657 TI - Arc of instability or arc of opportunity? PMID- 26634655 TI - LRP1 Regulates Retinal Angiogenesis by Inhibiting PARP-1 Activity and Endothelial Cell Proliferation. AB - OBJECTIVE: We recently demonstrated that low-density lipoprotein receptor-related protein 1 (LRP1) is required for cardiovascular development in zebrafish. However, what role LRP1 plays in angiogenesis remains to be determined. To better understand the role of LRP1 in endothelial cell function, we investigated how LRP1 regulates mouse retinal angiogenesis. APPROACH AND RESULTS: Depletion of LRP1 in endothelial cells results in increased retinal neovascularization in a mouse model of oxygen-induced retinopathy. Specifically, retinas in mice lacking endothelial LRP1 have more branching points and angiogenic sprouts at the leading edge of the newly formed vasculature. Increased endothelial proliferation as detected by Ki67 staining was observed in LRP1-deleted retinal endothelium in response to hypoxia. Using an array of biochemical and cell biology approaches, we demonstrate that poly(ADP-ribose) polymerase-1 (PARP-1) directly interacts with LRP1 in human retinal microvascular endothelial cells. This interaction between LRP1 and PARP-1 decreases under hypoxic condition. Moreover, LRP1 knockdown results in increased PARP-1 activity and subsequent phosphorylation of both retinoblastoma protein and cyclin-dependent kinase 2, which function to promote cell cycle progression and angiogenesis. CONCLUSIONS: Together, these data reveal a pivotal role for LRP1 in endothelial cell proliferation and retinal neovascularization induced by hypoxia. In addition, we demonstrate for the first time the interaction between LRP1 and PARP-1 and the LRP1-dependent regulation of PARP-1-signaling pathways. These data bring forth the possibility of novel therapeutic approaches for pathological angiogenesis. PMID- 26634656 TI - Innate Immune Molecule Surfactant Protein D Attenuates Sepsis-induced Acute Pancreatic Injury through Modulating Apoptosis and NF-kappaB-mediated Inflammation. AB - Sepsis causes multiple-organ dysfunction including pancreatic injury, thus resulting in high mortality. Innate immune molecule surfactant protein D (SP-D) plays a critical role in host defense and regulating inflammation of infectious diseases. In this study we investigated SP-D functions in the acute pancreatic injury (API) with C57BL/6 Wild-type (WT) and SP-D knockout (KO) mice in cecal ligation and puncture (CLP) model. Our results confirm SP-D expression in pancreatic islets and intercalated ducts and are the first to explore the role of pancreatic SP-D in sepsis. CLP decreased pancreatic SP-D levels and caused severe pancreatic injury with higher serum amylase 24 h after CLP. Apoptosis and neutrophil infiltration were increased in the pancreas of septic KO mice (p < 0.05, vs septic WT mice), with lower Bcl-2 and higher caspase-3 levels in septic KO mice (p < 0.05). Molecular analysis revealed increased NF-kappaB-p65 and phosphorylated IkappaB-alpha levels along with higher serum levels of TNF-alpha and IL-6 in septic KO mice compared to septic WT mice (p < 0.01). Furthermore, in vitro islet cultures stimulated with LPS produced higher TNF-alpha and IL-6 (p < 0.05) from KO mice compared to WT mice. Collectively, these results demonstrate SP-D plays protective roles by inhibiting apoptosis and modulating NF-kappaB mediated inflammation in CLP-induced API. PMID- 26634658 TI - Conversations between anthropology and psychiatry: drawing out the best from interdisciplinarity in global mental health. AB - OBJECTIVES: Conversations between anthropologists and psychiatrists have led to new theoretical trajectories, research agendas and clinical practices as social scientists and medical practitioners forged new understandings about the interaction of culture, personhood and illness. However, the demands of global mental health, coupled with health service provision requirements, mean that mental health interventions set up with the best intentions can fail to take into account the knowledge and expertise that social sciences can contribute to a programme's success. In this paper, I reflect on conversations between an anthropologist and mental health professionals in direct reference to data analysis of an AusAID mental health capacity-building programme undertaken in the Pacific region. CONCLUSIONS: Social and cultural perspectives embedded within programmes can provide richer, more contextualised interventions. In drawing on the combined expertise of anthropology and psychiatry, new taken-for-granted reference points embedding cultural approaches form the basis for delivery of global mental health programmes. These perspectives include: Locating mental health programmes within development critiques. Situating the subjects of development within contextualised settings, acknowledging and respecting local knowledge, understandings and practices. A focus on interdisciplinarity as the basis for future practice in global mental health projects. PMID- 26634659 TI - Cultural diversity and mental health. AB - OBJECTIVE: Cultural diversity and its impact on mental health has become an increasingly important issue in a globalised world where the interactions between cultures continue to grow exponentially. This paper presents critical areas in which culture impacts on mental health, such as how health and illness are perceived, coping styles, treatment-seeking patterns, impacts of history, racism, bias and stereotyping, gender, family, stigma and discrimination. CONCLUSIONS: While cultural differences provide a number of challenges to mental health policy and practice they also provide a number of opportunities to work in unique and effective ways towards positive mental health. Ethno-specific approaches to mental health that incorporate traditional and community-based systems can provide new avenues for working with culturally diverse populations. PMID- 26634660 TI - Mental health in the island nations of the Western Pacific: a rapid review of the literature. AB - OBJECTIVES: The aim of the study was to identify mental-health-relevant literature accessible to policy makers and healthcare workers in the island nations of the Western Pacific. METHODS: Material collated to support the inaugural Leadership in Mental Health: Island Nations course held in Cairns in May 2015 was used as the basis of a "rapid review". RESULTS: The rapid review considered 303 documents identified by a search carried out using James Cook University's OneSearch, Google Scholar, and the authors' knowledge. Search terms included mental health and the like, and terms with Pacific and current Pacific island country names. Findings were classified by region/country, year of release/publication, mental health issue addressed, peer-reviewed or grey literature, and type of study. Almost half of the findings had been released in the previous five years. However, only 36% were peer-reviewed publications and only 3.6% of the findings were intervention studies. CONCLUSIONS: There is limited easily accessible documentation to confidently direct practice or policies regarding which strategies are likely to be effective in responding to the high rates of mental ill-health experienced in the Pacific island nations, or to plan for increases as a consequence of rapid social and demographic changes that are transforming Pacific island societies. PMID- 26634661 TI - Burden of mental and substance use disorders in Indigenous Australians and Oceania. AB - OBJECTIVE: Mental and substance use disorders are responsible for significant health loss across the globe. In this review, the burden of disease attributable to mental and substance use disorders in Indigenous Australians and Pacific Island countries was described and compared. METHODS: For Indigenous Australians, findings from the burden of disease and injury study by Begg and colleagues were summarised. These were then compared to the findings of the Global Burden of Disease Study 2010, which reported results for Oceania, a region consisting of Pacific Island countries. Results for mental and substance use disorder burden were described in terms of disability-adjusted life years, years lived with disability and years of life lost to due to premature mortality. RESULTS: Mental and substance use disorders were the leading cause of non-fatal burden (i.e. disability) in both Indigenous Australia and Oceania. Furthermore, in Oceania mental and substance use disorders are projected to cause more disability than all communicable diseases combined by 2050. CONCLUSION: Mental and substance use disorders contribute significantly to health loss for both Indigenous Australians and Pacific Island populations. These findings indicate a substantial need to prioritise these disorders in terms of policy, services and research. PMID- 26634662 TI - A longitudinal study of health outcomes for people released from prison in Fiji: the HIP-Fiji project. AB - OBJECTIVE: To examine the health of prisoners and ex-prisoners in Fiji, including risk behaviours, service access and HIV status. METHODS: Longitudinal study of 198 men and women recruited prior to release from prison in Fiji, interviewed in the weeks preceding release, and again 1 and 4 months post-release. Dried blood spot samples taken at baseline were tested for HIV. RESULTS: Eighty percent of participants completed at least one follow-up interview. The prevalence of HIV was low (1%), despite evidence of widespread STI and BBV risk behaviours. A history of risky substance use was normative and more than a third reported high psychological distress prior to release. Fewer than one in four reported accessing health care within a month of release from prison. CONCLUSIONS: The health needs of this population are significant but differ in important ways from those of incarcerated populations in other countries. Further research is needed to inform evidence-based care for prisoners and ex-prisoners in Pacific Island nations. PMID- 26634663 TI - Mental health issues from rising sea level in a remote coastal region of the Solomon Islands: current and future. AB - OBJECTIVE: There is little published research about mental health and climate change in the Pacific, including Solomon Islands. Solomon Islands has one of the highest rates of sea-level rise globally. The aim of this research was to document mental health issues related to sea-level rise for people in East Malaita, Solomon Islands. METHOD: A cross-sectional study was carried out in six low-lying villages in East Malaita, Solomon Islands. The researcher travelled to villages by dugout canoe. In addition to quantitative, closed-ended questions, open-ended questions with villagers explored individual and community responses to rising sea level. RESULTS: Of 60 people asked, 57 completed the questionnaire. Of these, 90% reported having seen a change in the weather patterns. Nearly all participants reported that sea-level rise is affecting them and their family and is causing fear and worry on a personal and community level. Four themes emerged from the qualitative analysis: experience of physical impacts of climate change; worry about the future; adaptation to climate change; government response needed. CONCLUSION: Given predictions of ongoing sea-level rise in the Pacific it is essential that more research is conducted to further understand the human impact of climate change for small island states which will inform local, provincial and national-level mental health responses. PMID- 26634664 TI - Resuscitating the National Mental Health Policy in the Maldives. AB - OBJECTIVES: This article summarises the experiences and challenges in resuscitating the National Mental Health Policy in the Maldives, a developing island nation in the Indian Ocean. CONCLUSIONS: The most significant challenge included stigma and poor awareness around mental health at all levels, compounded by the lack of established mental health advocacy groups. The broad scope of mental health in the policy without accompanying detailed plans and lack of local research may have also been barriers. The background of political instability and its consequences on the health sector have also been significant barriers to political endorsement. Persevering with advocating for mental health and improving awareness will be crucial to ensure that resuscitation attempts are successful. PMID- 26634665 TI - Rich Country, Poor People: the challenges of providing psychiatric services in the public and the private sectors in Papua New Guinea. AB - OBJECTIVE: To describe some of the challenges in the provision of psychiatric services in Papua New Guinea. CONCLUSION: Many of the challenges faced when providing mental health care are not clinical in nature, but rather a combination of social, cultural, economic and infrastructural factors that hinder the adequate provision of, and access to, psychiatric services in Papua New Guinea. PMID- 26634666 TI - Capacity building for Pacific Island countries: the challenges and benefits of developing a postgraduate clinical training programme. AB - OBJECTIVES: To describe the development of a postgraduate clinical training programme in mental health for the Pacific region by the Fiji National University (FNU), the challenges and benefits. CONCLUSIONS: The establishment of FNU's one year full-time postgraduate diploma in mental health (PGDMH) has resulted in graduates across the Pacific in all three main regions of Oceania trained as frontline practitioners in mental health. Most of the graduates hold key mental health positions in their respective countries. The PGDMH provides culturally relevant and sensitive training in settings and with resources similar to the graduates' homelands. Challenges relate mainly to the sustainability of the programme, selection of candidates, addressing the needs of stakeholders and teaching in an evolving, under-resourced mental health service. The ongoing challenge continues to be the maintenance of a symbiotic co-existence that results in mutual benefits for both the University and stakeholders without jeopardizing the integrity of the programme or the independence of the University. PMID- 26634667 TI - Implementation Science for closing the treatment gap for mental disorders by translating evidence base into practice: experiences from the PRIME project. AB - OBJECTIVE: This paper utilizes the experience of PRIME (Programme for Improving Mental health care) to exemplify how implementation science provides key insights and approaches to closing the treatment gap for mental disorders. CONCLUSION: The real-world application of strategies described in the implementation science literature, accompanied by use of alternative, rigorous evaluation methods to assess their impact on patient outcomes, can help in closing the mental health treatment gap in disadvantaged populations. PMID- 26634668 TI - Evaluation of a Leadership in Mental Health course for Pacific Island Nation delegates. AB - OBJECTIVE: We report the background to and preliminary evaluation of the Leadership in Mental Health: Island Nations course, run for the first time in Cairns in conjunction with Creating Futures 2015. CONCLUSION: The course was well attended and well received, with increased confidence in key areas demonstrated and concerns regarding local application identified. In addition to positive comments, content and delivery issues were raised. Future opportunities for expanding upon this initial course are discussed. PMID- 26634669 TI - Strengthening research capacity in the Pacific: an example from the Atoifi Health Research Group, Solomon Islands. AB - OBJECTIVE: To provide an example of one model of research capacity building for mental health from a remote setting in Solomon Islands. METHODS: The Atoifi Health Research Group is building health research capacity with a health service on the remote east coast of Malaita, Solomon Islands. The group uses a 'learn-by doing' approach embedded in health service and community-level health projects. The group is eclectic in nature and deliberately engages a variety of partners to discover culturally informed methods of collecting, analysing and disseminating research findings. RESULTS: Key successes of the Atoifi Health Research Group are: that it was initiated by Solomon Islanders with self-expressed desire to learn about research; the learn-by-doing model; inclusion of community people to inform questions and socio-cultural appropriateness; and commitment to ongoing support by international researchers. CONCLUSIONS: Given different social, cultural, economic, geographic, spiritual and service contexts across the Pacific, locally appropriate approaches need to be considered. Such approaches challenge the orthodox approach of centralized investment to replicate specialist driven approaches of funder nations. Increasing expertise at all levels through participatory capacity building models that define and address local problems may be more sustainable and responsive to local mental health contexts. PMID- 26634670 TI - Insider-Outsider reflections from a Native Hawaiian researcher and the use of community-based participatory approaches. AB - OBJECTIVES: There is an increasing interest in conducting research within indigenous communities among indigenous and non-indigenous researchers alike. This paper offers the critical reflections of one Native Hawaiian researcher and the process of engaging in research as both an insider-outsider. CONCLUSIONS: Community-based, participatory research (CBPR) offers one model for outsiders to work effectively with indigenous communities, but CBPR also offers valuable principles for insiders who desire to work with their own communities. PMID- 26634671 TI - Healthy phoning: Papua New Guinea's first ever health call centre. AB - OBJECTIVE: The paper reports on the establishment of Papua New Guinea's first ever health call centre. METHOD: Details of the phone calls received during the first nine weeks of the call centre's operation are presented. RESULTS: The data on phone call rates and types indicate a slight increase in utilisation of the service over the initial period. A total of 113 health-related phone calls were received during the first nine weeks of the call centre's operation. Most of these calls were from the public, while a small number were from rural health workers. Prank calls and calls enquiring about the service were also received. During establishment, mental health was not considered and calls that may fall into this category have not been logged separately. CONCLUSIONS: Further analysis would need to be undertaken to determine the effectiveness of the health call centre model in the Papua New Guinea context. Scripts, protocols and analysis regarding mental health may need to be developed. PMID- 26634672 TI - Alternative approaches to well-being and engagement in Vanuatu. AB - OBJECTIVES: This article describes some innovative approaches to understanding, measuring and attributing value to traditional wisdom in Vanuatu. METHODS: The article uses decolonising methodologies to privilege indigenous perspectives. In particular, the study features the use of endogenous practices, such as sand drawing, as a vehicle for facilitating community engagement in the research. RESULTS: The results of the project reveal that, in the context of broad structural support for customary practices, communities leveraging traditional wisdom into commercial realms are able to generate livelihoods and maintain cultural heritage transmission. CONCLUSIONS: Local communities report increased pride and pleasure in the resurgence and innovation of cultural practices. PMID- 26634673 TI - Art and mental health in Samoa. AB - OBJECTIVES: To pilot an art and mental health project with Samoan and Australian stakeholders. The aim of this project was to provide a voice through the medium of art for people experiencing mental illness, and to improve the public understanding in Samoa of mental illness and trauma. METHODS: Over 12 months, a series of innovative workshops were held with Samoan and Australian stakeholders, followed by an art exhibition. These workshops developed strategies to support the promotion and understanding of mental health in Samoa. Key stakeholders from both art making and mental health services were engaged in activities to explore the possibility of collaboration in the Apia community. RESULTS: The project was able to identify the existing resources and community support for the arts and mental health projects, to design a series of activities aimed to promote and maintain health in the community, and to pilot these programs with five key organizations. CONCLUSIONS: This project demonstrates the potential for art and mental health projects to contribute to both improving mental health and to lowering the personal and social costs of mental ill health for communities in Samoa. PMID- 26634674 TI - 'Forgotten': a personal comment and communique on West Papuan refugees. AB - OBJECTIVE: To raise awareness of the ongoing human rights violations of the Indigenous residents of West Papua and their mental health consequences. METHOD: The author, herself a refugee from West Papua, provides a summary comment from a presentation to the Leadership in Mental Health: Island Nations course, based on personal experience in West Papua and Papua New Guinea, and a telephone survey of West Papuan refugees resident in Australia. RESULT: A communique in solidarity from all course delegates was produced and is included. CONCLUSION: Human rights violations continue in West Papua, and the plight of its indigenous residents and West Papuan refugees in Papua New Guinea and Australia are dire and should not be 'forgotten'. PMID- 26634678 TI - Body mass index and risk of subtypes of head-neck cancer: the Netherlands Cohort Study. AB - Low body mass index (BMI) has been associated with risk of head-neck cancer (HNC), but prospective data are scarce. We investigated the association between BMI, BMI at age 20 years and change in BMI during adulthood with risk of HNC and HNC subtypes. 120,852 participants completed a questionnaire on diet and other cancer risk factors, including anthropometric measurements, at baseline in 1986. After 20.3 years of follow-up, 411 HNC (127 oral cavity cancer (OCC), 84 oro /hypopharyngeal cancer (OHPC), and 197 laryngeal cancer (LC)) cases and 3,980 subcohort members were available for case-cohort analysis using Cox proportional hazards models. BMI at baseline was inversely associated with risk of HNC overall, with a multivariate rate ratio of 3.31 (95% CI 1.40-7.82) for subjects with a BMI < 18.5 kg/m(2), compared to participants with a BMI of 18.5 to 25 kg/m(2). Among HNC subtypes, this association was strongest for OCC and OHPC. The association between BMI at age 20 and HNC risk appeared to be positive. In this large prospective cohort study, we found an inverse association between BMI at baseline and HNC risk. For BMI at age 20, however, a positive rather than inverse association was found. PMID- 26634679 TI - An update on hepatitis C virus. AB - Chronic hepatitis caused by hepatitis C virus infection is one of the leading causes of liver cirrhosis and hepatocellular carcinoma globally. Over the last few years, there have been significant advances in our understanding of the immunopathogenesis of this infection, as well as revolutionary developments in the therapeutic armamentarium. The introduction of a number of new oral antiviral agents is already delivering major benefits to patients as they are generally well tolerated and are associated with excellent response rates in the majority. Nonetheless, a number of clinical scenarios remain challenging and research is ongoing in these areas. In this update, we review developments in both basic as well as translational research in the field. PMID- 26634680 TI - Clinical implications of the global multidrug-resistant tuberculosis epidemic. AB - Multidrug-resistant tuberculosis (MDR TB) is a significant threat to global health estimated to account for nearly half a million new cases and over 200,000 deaths in 2013. The number of MDR TB cases in the UK has risen over the last 15 years, with ever more complex clinical cases and associated challenging public health and societal implications. In this review, we provide an overview of the epidemiology of MDR TB globally and in the UK, outline the clinical management of MDR TB and summarise recent advances in diagnostics and prospects for new treatment. PMID- 26634681 TI - Understanding and intervening in HIV-associated tuberculosis. AB - HIV-associated tuberculosis can present as extremes, ranging from acute life threatening disseminated disease to occult asymptomatic infection. Both ends of this spectrum have distinct pathological correlates and require specific diagnostic and treatment approaches. Novel therapeutics, targeting both pathogen and host, are needed to augment pathogen clearance. In latent tuberculosis infection, enhancement of immune activation could be desirable. Antiretroviral therapy augments the beneficial effects of antitubercular therapy. However, in the context of high bacillary burden, antiretroviral therapy can also result in pathology (tuberculosis immune reconstitution inflammatory syndrome). In the immune reconstituting patient, modulation of immune activation controls tissue destruction. Interventions should also be appropriate and sustainable within the programmatic setting. PMID- 26634682 TI - Time dictates: emerging clinical analyses of the impact of circadian rhythms on diagnosis, prognosis and treatment of disease. AB - Since the advent of modern molecular tools, researchers have extensively shown that essential cellular machineries have robust circadian (roughly 24 hours) variations in their pace. This molecular rhythmicity translates directly into time-of-day-dependent variation in physiology in most organ systems, which in turn provides the mechanistic rationale for why timing on a daily basis should matter in many aspects of human health. However, these basic science findings have been slow to move from bench to bedside because clinical studies are still lacking to demonstrate the importance of timing. Therefore, it has not been clear how physicians should incorporate knowledge of natural 24-hour rhythms into routine practice. This review is a brief summary of results from recently completed clinical studies on hypertension, myocardial infarction, diabetes mellitus, and adrenal dysfunction that highlights new evidence for the emerging importance of circadian rhythms in diagnosis, prognosis and treatment of disease. PMID- 26634683 TI - Vitamin D--what is normal according to latest research and how should we deal with it? AB - Vitamin D deficiency is a public health concern. Mediated by classical endocrine effects, vitamin D deficiency is causally linked with bone and calcium disorders. Non-endocrine actions of vitamin D are also widely recognised and these effects are mediated by local tissue activation of vitamin D bringing about intracrine effects in non-classical sites. Supported by large volumes of observational studies linking low circulating vitamin D with negative outcomes for many common disease states, there is growing interest that vitamin D may be central to the pathology and outcomes of many common diseases, including cardiovascular, cancer and autoimmune conditions. This article explores the quality of evidence linking vitamin D and various disease outcomes, and furthermore describes some of the cellular and molecular mechanisms of vitamin D action that may help explain some of the incongruity of data observed in observational versus interventional studies of vitamin D supplementation. PMID- 26634684 TI - Advances in pathogenesis and treatment of systemic sclerosis. AB - Systemic sclerosis is the most severe disease within the scleroderma spectrum and is a major medical challenge with high mortality and morbidity. There have been advances in understanding of pathogenesis that reflect the interplay between immune-inflammatory processes and vasculopathy and fibrosis. It can be regarded as a disease of connective tissue repair and this leads to organ-based complications. However the aetiology and triggering events remain to be elucidated. Treatment is available for many aspects of the disease although the available therapies are not curative and some complications remain very challenging, especially non-lethal manifestations such as fatigue, calcinosis and anorectal dysfunction. Immunosuppression is now established as a beneficial approach but balancing risk and benefit is vital, especially for powerful approaches such as autologous stem cell transplantation. PMID- 26634685 TI - Epigenetic mechanisms and drug discovery in rheumatology. AB - There is a growing understanding of the epigenetic mechanisms that regulate gene expression in healthy conditions and a realisation that dysregulation of these mechanisms is an underlying factor in many human diseases. We discuss studies demonstrating that small molecule inhibitors of epigenetic regulatory proteins can block pathogenic mechanisms associated with rheumatoid arthritis, focusing on the effects of these inhibitors on synovial fibroblasts-fibroblast-like synoviocytes. PMID- 26634686 TI - Polycystic ovary syndrome: insight into pathogenesis and a common association with insulin resistance. AB - Polycystic ovary syndrome (PCOS) is a common condition that typically develops in reproductive-age women. The cardinal clinical and biochemical characteristics of PCOS include reproductive dysfunction and hyperandrogenic features. PCOS is also strongly associated with obesity based on data from epidemiological and genetic studies. Accordingly, PCOS often becomes manifest in those women who carry a genetic predisposition to its development, and who also gain weight. The role of weight gain and obesity in the development of PCOS is mediated at least in part, through worsening of insulin resistance. Compensatory hyperinsulinaemia that develops in this context disrupts ovarian function, with enhanced androgen production and arrest of ovarian follicular development. Insulin resistance also contributes to the strong association of PCOS with adverse metabolic risk, including dysglycaemia, dyslipidaemia and fatty liver. Conversely, modest weight loss of just 5% body weight with improvement in insulin sensitivity, frequently results in clinically meaningful improvements in hyperandrogenic, reproductive and metabolic features. Future developments of novel therapies for obese women with PCOS should focus on promotion of weight loss and improvement in insulin sensitivity. In this context, therapies that complement lifestyle changes such as dietary modification and exercise, particularly during the maintenance phase of weight loss are important. Putative novel targets for therapy in PCOS include human brown adipose tissue. PMID- 26634687 TI - An overview of the genetics, mechanisms and management of NAFLD and ALD. AB - Alcoholic liver disease (ALD) and, increasingly, non-alcoholic fatty liver disease (NAFLD) are common causes of advanced liver disease in many developed countries including the UK. Both diseases share parallel natural histories, progressing from steatosis, to steatohepatitis and fibrosis/cirrhosis; and are characterised by substantial interindividual variation in disease outcome. This article will provide an overview of disease mechanisms, genetic modifiers and management, focusing principally on NAFLD, while drawing parallels between the two conditions where appropriate. PMID- 26634688 TI - Future mechanistic strategies for tackling fibrosis--an unmet need in liver disease. AB - Standardised mortality rates for liver disease in the UK have increased 400% since 1970. However, evidence from a large number of animal models and clinical trials indicates that liver fibrosis and even cirrhosis are potentially reversible if the underlying cause can be successfully removed. Nevertheless, in a significant number of patients cure of the underlying disease may not result in fibrosis regression, and no antifibrotic drug has been licenced by the United States Food and Drug Administration or the European Medicines Agency. Dissection of the mechanistic pathways and regulatory factors that characterise matrix remodelling and architectural repair during fibrosis regression are revealing novel therapeutic approaches to induce liver repair. Points of attack in the fibrotic cascade include promoting the loss of hepatic myofibroblasts, inhibiting profibrogenic properties of myofibroblasts, stimulating degradation of accumulated liver scar tissue, targeting the immune response, and cell-based therapies. Therapeutic candidates are now being evaluated in early-phase human trials but translation into the clinic will require careful patient selection and stratification, and the definition and validation of clinically meaningful endpoints. PMID- 26634689 TI - Sarcopenia and frailty: new challenges for clinical practice. AB - Sarcopenia and frailty are important conditions that become increasingly prevalent with age. Sarcopenia is the loss of muscle mass and function, and frailty can be defined as multi-system impairment associated with increased vulnerability to stressors. There is overlap between the two conditions, especially in terms of the physical aspects of the frailty phenotype: low grip strength, gait speed and muscle mass. These measures have been associated with a wide range of ageing outcomes and can be assessed in the clinical setting. In terms of intervention, there is evidence for the benefit of resistance exercise programmes, although these may not always be feasible. Considerable research into the use of medicines, both existing and new, as well as dietary supplements is ongoing. Finally in order to prevent or delay the development of these conditions, an additional approach is to consider aetiological factors operating across the life course. PMID- 26634690 TI - Recent advances in the pathogenesis and treatment of osteoporosis. AB - Over recent decades, the perception of osteoporosis has changed from that of an inevitable consequence of ageing, to that of a well characterised and treatable chronic non-communicable disease, with major impacts on individuals, healthcare systems and societies. Characterisation of its pathophysiology from the hierarchical structure of bone and the role of its cell population, development of effective strategies for the identification of those most appropriate for treatment, and an increasing armamentarium of efficacious pharmacological therapies, have underpinned this evolution. Despite this marked progress, individuals who experience a fragility fracture remain under-treated in many areas of the world, and there is substantial need for investment both in secondary and primary prevention globally. In this brief article, we give an overview of the pathogenesis of osteoporosis, and summarise current and future approaches to its assessment and treatment. PMID- 26634691 TI - V1 neurons respond to luminance changes faster than contrast changes. AB - Luminance and contrast are two major attributes of objects in the visual scene. Luminance and contrast information received by visual neurons are often updated simultaneously. We examined the temporal response properties of neurons in the primary visual cortex (V1) to stimuli whose luminance and contrast were simultaneously changed by 50 Hz. We found that response tuning to luminance changes precedes tuning to contrast changes in V1. For most V1 neurons, the onset time of response tuning to luminance changes was shorter than that to contrast changes. Most neurons carried luminance information in the early response stage, while all neurons carried both contrast and luminance information in the late response stage. The early luminance response suggests that cortical processing for luminance is not as slow as previously thought. PMID- 26634692 TI - Dual functions of Rap1 are crucial for T-cell homeostasis and prevention of spontaneous colitis. AB - Rap1-GTP activates leukocyte function-associated antigen-1 (LFA-1) to induce arrest on the high endothelial venule (HEV). Here we show that Rap1-GDP restrains rolling behaviours of T cells on the peripheral lymph node addressin (PNAd), P selectin and mucosal addressin cell adhesion molecule-1 (MadCAM-1) by inhibiting tether formation. Consequently, Rap1 deficiency impairs homing of naive T cells to peripheral lymph nodes, but accelerates homing of TH17 and TH1 cells to the colon, resulting in spontaneous colitis with tumours. Rap1-GDP associates with and activates lymphocyte-oriented kinase, which phosphorylates ERM (ezrin, radixin and moesin) in resting T cells. Phosphomimetic ezrin reduces the rolling of Rap1-deficient cells, and thereby decreases their homing into the colon. On the other hand, chemokines activate Rap1 at the plasma membrane within seconds, and Rap1-GTP binds to filamins, which diminishes its association with the beta2 chain of LFA-1 and results in LFA-1 activation. This Rap1-dependent regulation of T-cell circulation prevents the onset of colitis. PMID- 26634693 TI - Cyclosporine A protects podocytes by regulating WAVE1 phosphorylation. AB - Accumulating evidence suggests that podocytes are direct targets of many classic antiproteinuric drugs. The immunosuppressive drug cyclosporine A (CsA), which is a calcineurin inhibitor, is used to treat proteinuric kidney diseases. One novel mechanism by which CsA reduces proteinuria is by directly stabilizing the podocyte cytoskeleton. Previous studies showed that calcineurin can directly regulate WAVE1 within mouse striatal slices. In this study, WAVE1 was expressed in podocytes and was localized in the podocyte cell bodies and foot processes (FPs). WAVE1 expression increased in both in vivo and in vitro models of puromycin aminonucleoside (PAN)-induced podocyte injury. CsA restored WAVE1 expression and also partially rescued the disordered F-actin arrangement after PAN injury. Co-immunoprecipitation assays showed that calcineurin directly interacted with WAVE1 and regulated WAVE1 phosphorylation in podocytes. Synaptopodin is a well-characterized target of CsA. WAVE1 overexpression and synaptopodin knockdown experiments directly demonstrated that WAVE1 expression is not dependent on synaptopodin expression, and vice versa. Overexpression of WAVE1 using a WAVE1 plasmid disrupted F-actin structure and promoted podocyte migration compared with the empty vector group. Therefore, WAVE1 may be a novel molecular target for the maintenance of podocyte FPs and for antiproteinuric treatment in the future. PMID- 26634694 TI - The influence of input and output modality on following instructions in working memory. AB - Following instructions is an important component of learning and has been shown to rely on working memory. This study examined the ability to follow instructions within working memory under varying input and output modalities. In Experiment 1, participants heard, read, or viewed demonstration of short sequences of instructions, and recalled either by oral repetition or physical enactment. There was a significant main effect of encoding, showing superior recall performance when instructions were demonstrated relative to spoken or written presentation. Experiment 2 examined whether recall is further improved when instructions are presented both in spoken and demonstrated form, relative to single modality presentation. The advantage for demonstration over spoken instructions was replicated, and dual input was superior to spoken instructions. However, dual input did not bring extra benefit compared to demonstration of instructions. We also observed a significant enacted-retrieval recall advantage. These findings suggest effects of both input and output modalities on the ability to remember and follow instructions in working memory. Outcomes substantially inform the underexplored but important new area of action-based working memory and its links to embodied cognition, with implications for pedagogic practice. PMID- 26634696 TI - Erratum to: Genome-wide transcriptional and physiological responses to drought stress in leaves and roots of two willow genotypes. PMID- 26634695 TI - Towards a midwifery profession in Bangladesh--a systems approach for a complex world. AB - BACKGROUND: The midwifery profession is crucial for a functioning health system aiming at improved maternal and child health outcomes. Complex Adaptive Systems (CAS) can be used as a tool to understand actors' interactions in the system around midwifery profession for improved maternal and child health. The purpose of this study is to explore how actors connect to promote the Bangladesh's midwifery profession. METHODS: An explorative study based on the framework of CAS was performed. Data were collected through semi-structured interviews with 16 key persons representing nine different organisations promoting the establishment of the midwifery profession. Qualitative analysis was used. RESULTS: Findings show that the actors were intertwined and driving towards a common goal; to save lives through education and deployment of 3000 midwives. The unique knowledge contributions of everyone involved were giving the system strength and power to perform. Collaboration was seen as more could be achieved compared to what an individual organisation could do. Significant results of this were that two midwifery curricula and faculty development had been produced. Although collaboration was mostly seen as something positive to move the system forward, the approach to reach the set goal varied with different interests, priorities and concerns, both on individual organisational level as well as at system level. Frequent struggles of individual philosophies versus organisational mandates were seen as competing interests for advancing the national priorities. It would appear that newcomers with innovative ideas were denied access on the same terms as other actors. CONCLUSIONS: This study illustrates that CAS thinking can be used as a metaphor to understand how to adapt more emergent ways of working instead of the traditional planned approaches to change and develop in order to deal better with a more complex world. Through examining how actors connect for establishing a midwifery profession, offers insights of shared interests towards stepping up efforts for a competent midwifery profession in Bangladesh and elsewhere. Good relationships, where everyone's expertise and innovations, are used to the full, are crucial for establishing a strong midwifery profession and thus improved maternal and child health. PMID- 26634697 TI - Multiple susceptibility loci at chromosome 11q23.3 are associated with plasma triglyceride in East Asians. AB - Genetic studies of plasma TG levels have identified associations with multiple candidate loci on chromosome11q23.3, which harbors a number of genes, including BUD13, ZNF259, and APOA5-A4-C3-A1. This study aimed to examine whether these multiple candidate genes on the 11q23.3 regions exert independent effects on TG levels or whether their effects are confounded by linkage disequilibrium (LD). We performed a genome-wide association study and consequent fine-mapping analyses on TG levels in two Korean population-based cohorts: the Korea Association Resource study (n = 8,223) and the Healthy Twin study (n = 1,735). A total of 301 loci reached genome-wide significance level in pooled analysis, including 10 SNPs with weak LD (r(2) < 0.06) clustered on 11q23.3: ApoA5 (rs651821, rs2075291); ZNF259 (rs964184, rs603446); BUD13 (rs11216126); Apoa4 (rs7396851); SIK3 (rs12292858); PCSK7 (rs199890178); PAFAH1B2 (rs12420127), and SIDT2 (rs2269399). When the inter dependence between alleles was examined using conditional models, five loci on BUD13, ZNF259, and ApoA5 showed possible independent associations. A haplotype analysis using five SNPs revealed both hyper- and hypotriglyceridemic haplotypes, which are relatively common in Koreans (haplotype frequency 0.08-0.22). Our findings suggest the presence of multiple functional loci on 11q23.3, which might exert their effects on plasma TG level independently or through complex interactions between functional loci. PMID- 26634698 TI - IBD or strongyloidiasis? AB - INTRODUCTION: Strongyloides has been shown to infrequently mimic inflammatory bowel disease (IBD) or to disseminate when a patient with IBD and unrecognized strongyloides is treated with immunosupression. CASE REPORT: A man from Ecuador, living in Spain for years, with a history of type 2 diabetes mellitus and psoriasis treated with topical corticosteroids, was admitted to the hospital with an 8-month history of diarrhoea. Blood tests showed hyperglycemia, hyponatremia, elevated CRP and faecal calprotectin. Colonoscopy suggested IBD. The patient improved with steroids, pending biopsy results, and he was discharged. Biopies were compatible with IBD, but careful examination revealed strongyloides. He was given a prescription of albendazole. He had to be readmitted due to SIADH, which resolved with fluid restriction. Upon discharge albendazole was prescribed again. The patient skipped most of the out-patient-clinic visits. He returned a year later on 10 mg/week methotrexate, asymptomatic, with 20% eosinophilia, and admitting he had never taken the strongyloides treatment for economical reasons. He then received a week of oral albendazol at the hospital. Biopsies and blood cell count were afterwards normal (eosinophils 3.1%) and serology for strongyloides antibodies was negative. DISCUSSION: This case is of interest for four rarely concurring reasons. It's a worm infection that mimics IBD; the infection was diagnosed by colon biopsy; the infection caused a SIADH; and, most interestingly, even though the patient is on immunosupression, he remains asymptomatic. PMID- 26634700 TI - Erratum to: Molecular phylogeny of the subfamily Stevardiinae Gill, 1858 (Characiformes: Characidae): classification and the evolution of reproductive traits. PMID- 26634699 TI - Effect of Cyclooxygenase(COX)-1 and COX-2 inhibition on furosemide-induced renal responses and isoform immunolocalization in the healthy cat kidney. AB - BACKGROUND: The role of cyclooxygenase(COX)-1 and COX-2 in the saluretic and renin-angiotensin responses to loop diuretics in the cat is unknown. We propose in vivo characterisation of isoform roles in a furosemide model by administering non-steroidal anti-inflammatory drugs (NSAIDs) with differing selectivity profiles: robenacoxib (COX-2 selective) and ketoprofen (COX-1 selective). RESULTS: In this four period crossover study, we compared the effect of four treatments: placebo, robenacoxib once or twice daily and ketoprofen once daily concomitantly with furosemide in seven healthy cats. For each period, urine and blood samples were collected at baseline and within 48 h of treatment starting. Plasma renin activity (PRA), plasma and urinary aldosterone concentrations, glomerular filtration rate (GFR) and 24 h urinary volumes, electrolytes and eicosanoids (PGE2, 6-keto-PGF1alpha, TxB2), renal injury biomarker excretions [N acetyl-beta-D-glucosaminidase (NAG) and Gamma-Glutamyltransferase] were measured. Urine volume (24 h) and urinary sodium, chloride and calcium excretions increased from baseline with all treatments. Plasma creatinine increased with all treatments except placebo, whereas GFR was significantly decreased from baseline only with ketoprofen. PRA increased significantly with placebo and once daily robenacoxib and the increase was significantly higher with placebo compared to ketoprofen (10.5 +/- 4.4 vs 4.9 +/- 5.0 ng ml(-1) h(-1)). Urinary aldosterone excretion increased with all treatments but this increase was inhibited by 75 % with ketoprofen and 65 % with once daily robenacoxib compared to placebo. Urinary PGE2 excretion decreased with all treatments and excretion was significantly lower with ketoprofen compared to placebo. Urinary TxB2 excretion was significantly increased from baseline only with placebo. NAG increased from baseline with all treatments. Immunohistochemistry on post-mortem renal specimens, obtained from a different group of cats that died naturally of non renal causes, suggested constitutive COX-1 and COX-2 co-localization in many renal structures including the macula densa (MD). CONCLUSIONS: These data suggest that both COX-1 and COX-2 could generate the signal from the MD to the renin secreting cells in cats exposed to furosemide. Co-localization of COX isoenzymes in MD cells supports the functional data reported here. PMID- 26634701 TI - Mitigating aflatoxin exposure to improve child growth in Eastern Kenya: study protocol for a randomized controlled trial. AB - BACKGROUND: While the few studies that have looked at the association between stunting and aflatoxin exposure have found surprisingly large effects, the results remain inconclusive due to a lack of randomized controlled studies. This protocol describes a non-blinded, cluster-randomized controlled trial with the specific objective of testing the impact of reduced aflatoxin exposure on (individual) child linear growth. METHODS/DESIGN: Participants were recruited from among households containing women in the last 5 months of pregnancy in 28 maize-growing villages within Meru and Tharaka-Nithi Counties in Kenya. Households in villages assigned to the intervention group are offered rapid testing of their stored maize for the presence of aflatoxin each month; any maize found to contain more than 10 ppb aflatoxin is replaced with an equal amount of maize that contains less than this concentration of the toxin. They are also offered the opportunity to buy maize that has been tested and found to contain less than 10 ppb aflatoxin at local shops. Clusters (villages) were allocated to the intervention group (28 villages containing 687 participating households) or control group (28 villages containing 536 participating households) using a random number generator. The trial, which is funded by United Kingdom (UK) aid from the UK government, the Global Food Security Portal, and the Ministry for Foreign Affairs of Finland, is currently ongoing. DISCUSSION: This study is the first randomized controlled trial (RCT) to test for a causal impact of aflatoxin exposure on child growth. Whether or not this relationship is found, its results will have implications for the prioritization of aflatoxin control efforts by governments in affected regions, as well as international donors. TRIAL REGISTRATION: American Economic Association RCT Registry # 0000105 . Initial registration date: 6 November 2013, last updated 30 December 2014. PMID- 26634703 TI - Redundant Publication-How to Avoid Duplication. PMID- 26634702 TI - Dynamic expression of viral and cellular microRNAs in infectious mononucleosis caused by primary Epstein-Barr virus infection in children. AB - BACKGROUND: Epstein-Barr virus (EBV) was the first virus identified to encode microRNAs (miRNAs). Both of viral and human cellular miRNAs are important in EBV infection. However, the dynamic expression profile of miRNAs during primary EBV infection was unknown. This study aimed to investigate the dynamic expression profile of viral and cellular miRNAs in infectious mononucleosis (IM) caused by primary EBV infection. METHODS: The levels of viral and cellular miRNAs were measured in fifteen pediatric IM patients at three different time-points. Fifteen healthy children who were seropositive for EBV were enrolled in the control group. Relative expression levels of miRNAs were detected by quantitative real time PCR (qPCR) assay. RESULTS: EBV-miR-BHRF1-1, 1-2-3P, miR-BART13-1, 19-3p, 11 3P, 12-1, and 16-1 in IM patients of early phase were significantly higher than in healthy children. Most cellular miRNAs of B cells, such as hsa-miR-155-5p, 34a-5p, -18b-5p, -181a-5p, and -142-5p were up-regulated; while most of cellular miRNAs of CD8 + T cells, such as hsa-miR-223, -29c-3p, -181a, -200a-3p, miR-155 5p, -146a, and -142-5p were down-regulated in IM patients. With disease progression, nearly all of EBV-miRNAs decreased, especially miR-BHRF1, but at a slower rate than EBV DNA loads. Most of the cellular miRNAs of B cells, including hsa-miR-134-5p, -18b-5p, -34a-5p, and -196a-5p increased with time. However, most of the cellular miRNAs of CD8 + T cells, including hsa-let-7a-5p, -142-3p, -142 5p, and -155-5p decreased with time. Additionally, hsa-miR-155-5p of B cells and hsa-miR-18b-5p of CD8+ T cells exhibited a positive correlation with miR-BHRF1-2 5P and miR-BART2-5P (0.96 <= r <= 0.99, P < 0.05). Finally, hsa-miR-181a-5p of B cells had positive correlation with miR-BART4-3p, 4-5P, 16-1, and 22 (0.97 <= r <= 0.99, P < 0.05). CONCLUSIONS: Our study is the first to describe the expression profile of viral and cellular miRNAs in IM caused by primary EBV infection. These results might be the basis of investigating the pathogenic mechanism of EBV-related diseases and bring new insights into their diagnosis and treatment. PMID- 26634704 TI - [In Process Citation]. PMID- 26634705 TI - [Spine surgery in a combat support hospital]. AB - BACKGROUND AND AIM: From July 2007 to October 2014, neurosurgical services have been continuously available in a multinational Role 3 combat support hospital in Mazar-e-Sharif (MeS), Afghanistan. In this paper, we analyze a 7-year operative and outpatient spinal surgery caseload experience. MATERIALS AND METHODS: The overall annual and monthly caseloads were determined. Additionally, the surgical cases were differentiated relating to the strength of the indication, the location of the surgical site, and the origin of the patients. The outpatient caseload and spectrum of the years 2012 and 2013 were also analyzed. RESULTS: A total of 341 surgeries were performed and 188 of them were spinal surgeries (55.1 %). The vast majority of surgeries were performed for degenerative diseases (127/188; 67.6 %). The proportion of fractures and penetrating injuries (61/188; 32.4%) increased over the observation period. Eighty percent of the immediate and urgent surgeries (within 12 h; n = 70) were performed for these indications. 19.8 % of the surgeries were done as an emergency, whereas 17.3 % had delayed urgency, and 62.9 % were elective procedures. Of the 1026 outpatient consultations documented, 82 % of them were related to spinal diseases. CONCLUSIONS: The overall caseload in addition to the distribution of location, strength of indication, and patient origin for MeS are significantly lower than that reported by other International Security Assistance Force (ISAF) nations in eastern and southern Afghanistan. In addition, the rate of elective surgeries and those carried out in civilian Afghan patients is highest in MeS. In comparison with MeS, none of the other ISAF military hospitals shows such a strong concentration of degenerative spinal conditions in their surgical spectrum. Nevertheless, the changing pattern of spine-related diagnoses and surgical therapies in the current conflict represents a challenge for future educational and material planning in comparable missions. PMID- 26634706 TI - A Validated High-Throughput Fluorometric Method for Determination of Omeprazole in Quality Control Laboratory via Charge Transfer Sensitized Fluorescence. AB - A high-throughput 96-microwell plate fluorometric method was developed and validated to determine omeprazole (OMZ) in its dosage forms. The method was based on the charge-transfer (CT) sensitized fluorescence reaction of OMZ with 2, 3 dichloro-5, 6-dicyano-1, 4-benzoquinone (DDQ). This fluorescence reaction provided a new approach for simple, sensitive and selective determinations of OMZ in pharmaceutical preparations. In the present method, the fluorescence reaction was carried out in 96-microwell plates as reaction vessels in order to increase the automation of the methodology and the efficiency of its use in quality control laboratories. All factors affecting the fluorescence reaction were carefully studied and the conditions were optimized. The stoichiometry of the fluorescence reaction between OMZ and DDQ was determined and the reaction mechanism was suggested. Under the optimum conditions, the linear range was 100 6000 ng/ml with the lowest LOD of 33 ng/ml. Analytical performance of the proposed assay, in terms of accuracy and precision, was statistically validated and the results were satisfactory; RSD was <2.6 % and the accuracy was 98.6-101.6 %. The method was successfully applied to the analysis of OMZ in its dosage forms; the recovery values were 98.26-99.60 +/- 0.95-2.22 %. The developed methodology may provide a safer, automated and economic tool for the analysis of OMZ in quality control laboratories. PMID- 26634707 TI - Studies on Structural, Morphological and Optical Properties of Chemically Deposited CdS(1-x)Se(x) Thin Films. AB - The thin films of CdS(1-x)Se(x) were successfully deposited over glass substrates by chemical bath deposition technique. Cadmium acetate, thiourea and sodium selenosulfate were used as source materials for Cd(2+), S(2-) and Se(2-) ions, while 2-mercaptoethanol was used as capping agent. The various deposition conditions such as precursor concentration, deposition temperature, pH and deposition time were optimized for the deposition of CdS(1-x)Se(x) thin films of good quality and the films were annealed at 200 degrees and 300 degrees C. The structural, morphological, chemical and optical properties were examined by various characterization techniques and discussed in detail. The optical band gap of CdS(1-x)Se(x) thin film samples were estimated and found in the range from 2.11 to 1.79 eV for as-deposited and annealed thin films. PMID- 26634708 TI - Aggressive B cell Lymphoma: Optimal Therapy for MYC-positive, Double-Hit, and Triple-Hit DLBCL. AB - OPINION STATEMENT: Approximately 10% of cases of diffuse large B cell lymphoma (DLBCL) harbor a MYC rearrangement and this has been associated with an inferior outcome following standard therapy across many different studies. Double-hit and triple-hit lymphomas harbor concurrent rearrangements of MYC and BCL2 and/or BCL6 and are also associated with a very aggressive course and poor clinical outcome. It is unclear and there is lack of consensus on how these diseases should be approached therapeutically. They are characterized typically by high tumor proliferation and likely require Burkitt lymphoma-type strategies and several retrospective studies suggest that more intensive approaches than rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) may be beneficial. One challenge in this respect is that most patients with these diseases are older than 60 years and generally have poor tolerability of regimens typically used in Burkitt lymphoma. Dose-adjusted EPOCH-R is an alternative effective immunochemotherapy platform for DLBCL and is effective in Burkitt lymphoma, and retrospective studies suggest that it is effective and feasible in patients with DLBCL that harbors a MYC rearrangement with or without a BCL-2 translocation (double-hit). A multicenter study of this approach in MYC rearranged DLBCL is ongoing and preliminary results are very encouraging. There is a lack of consensus on the role of consolidation stem cell transplantation in patients who achieve a good response to initial therapy but at this point in time, no (retrospective) studies have demonstrated any benefit. These diseases are also associated with a high rate of CNS involvement and progression and checking for cerebrospinal fluid by cytology and flow cytometry at initial diagnosis should be considered. In summary, based on retrospective data and preliminary prospective data (as more mature data is awaited), while Burkitt-type regimens may be feasible in young patients, DA-EPOCH-R is a reasonable approach for patients with these diseases, particularly for those over the age of 60 years. CNS prophylaxis is a reasonable consideration (depending on clinical characteristics) given that the rate of CNS progression is high. Many exciting new small molecule inhibitors such as BCL-2 and MYC inhibitors are in development and are exciting for these diseases and attempts are underway to combine them with effective immunochemotherapy platforms. PMID- 26634709 TI - Blepharokeratoconjunctivitis in childhood: corneal involvement and visual outcome. AB - PURPOSE: The main objective of this study is to describe the prevalence, degree and risk of corneal involvement, and visual impact in a pediatric population with blepharokeratoconjunctivitis (BKC). METHODS: Retrospective, observational, case control study. Clinical records of patients <=16 years old with BKC seen between 2006 and 2012 were reviewed. The prevalence and relative risk of corneal involvement was evaluated between patients with and without corneal affection through a univariate and multivariate analysis with logistic regression. Visual acuity at presentation and at last follow-up visit was also analyzed. RESULTS: One hundred and fourteen children with BKC, with a male-to-female ratio of 1 : 1 and a mean age at diagnosis of 9.13 years. The mean follow-up time was 26.4 (+/ 25) months. Corneal involvement was present in 39.5% of patients, varying from superficial punctate keratitis to perforation. Corneal changes were not seen in children under 4 years old. The risk of corneal affection was greater in patients with photophobia, hordeolum, female gender and asymmetric disease (OR of 2.69, 11.6, 2.35 and 2.77, respectively). The mean best-corrected visual acuity at presentation was 0.20 (corneal affected group), compared to 0.11 (unaffected group; P=0.02). CONCLUSIONS: Our study showed an older age at time of diagnosis and a worse visual outcome in patients with BKC and corneal disease compared with previous reports. Early diagnosis and detection of risk factors for corneal involvement, as well as adequate treatment, is mandatory to prevent serious long term visual repercussions in children with BKC. PMID- 26634710 TI - Risk factors for contact lens-related microbial keratitis in Singapore. AB - PURPOSE: To investigate independent risk factors for contact lens-related microbial keratitis in Singapore and estimate their impact on disease load. METHODS: Cases were contact lens wearers presenting to Singapore National Eye Centre with microbial keratitis between 2008 and 2010. Community contact lens wearers were recruited as controls. All wearers completed a previously validated questionnaire describing contact lens wear history, hygiene and compliance habits, and demographics. Risk factors significant in univariate analysis (P<0.2) were evaluated in a multivariate model. RESULTS: In all, 58 cases of microbial keratitis and 152 contemporaneous controls were identified. When controlling for other variables, Chinese had a 7 * lower risk compared with other races (95% CI: 2.3-21.3, P=0.001). Those aged between 25 and 44 years were at 3 * increased risk compared with younger wearers (95% CI: 1.1-9.6, P=0.04). Occasional overnight contact lens wear (less often than one night per week) was associated with a 4 * higher risk (95% CI: 1.2-15.4, P=0.03) compared with daily use. Not washing hands before handling was associated with a 13 * increased risk (95% CI: 1.9-84.8, P=0.008). Use of multipurpose solution A carried a 16 * higher risk compared with hydrogen peroxide (95% CI: 1.5-174.0, P=0.02). The combined PAR% for modifiable risk factors (occasional overnight wear, not washing of hands, and MPS A) was 82%. CONCLUSIONS: Consistent with previous findings, independent risk factors for contact lens-related microbial keratitis include poor hand hygiene, occasional overnight wear, and type of lens care solution. Prolonged overnight or extended contact lens use was infrequent in this population. PMID- 26634711 TI - Ranibizumab for the treatment of wet AMD: a summary of real-world studies. AB - Data from real-world studies of ranibizumab in neovascular (wet) age-related macular degeneration suggest that outcomes in clinical practice fail to match those seen in clinical trials. These real-world studies follow treatment regimens that differ from the fixed dosing used in the pivotal clinical trial programme. To better understand the effectiveness of ranibizumab in clinical practice, we conducted a comprehensive evaluation of 12-month outcomes reported in peer reviewed 'real-world' publications. Key measures included in our analysis were mean change in visual acuity (VA) and the proportion of patients gaining >=15 letters or losing <=15 letters. Twenty studies were eligible for inclusion in our study, with 18 358 eyes having sufficient data for analysis of 12-month outcomes. Mean baseline VA ranged from 48.8 to 61.6 Early Treatment Diabetic Retinopathy Study letters. Mean change in VA was between -2.0 and +5.5 letters, with a grand mean of +2.9+/-3.2, and a weighted mean (adjusted for the number of eyes in the study) of +1.95. Eleven studies reported that 19+/-7.5 (mean value) of patients gained >=15 letters, while in 12 studies the mean percentage of patient losing <=15 letters was 89+/-6.5%. Our comprehensive analysis of real-world ranibizumab study data confirm that patient outcomes are considerably poorer than those reported in randomised control trials of both fixed and pro re nata regimens. PMID- 26634712 TI - Which tonometry in eyes with keratoconus? AB - AIMS: To compare intraocular pressure (IOP) measurements obtained with Goldmann applanation tonometery (GAT), dynamic contour tonometry (DCT), tonopen (TP), and ocular response analyzer (ORA), and to determine the influence of Amsler grade and central corneal thickness (CCT) on the IOP readings in eyes with keratoconus that are classified into four groups according to the Amsler-Krumeich classification. METHODS: All eyes with keratoconus were separated into four groups using Amsler-Krumeich classification for keratoconus. IOP was measured in 202 eyes of 202 patients with keratoconus using GAT, DCT, TP, and ORA. RESULTS: The IOP differences revealed no significant difference among the Amsler degree in the DCT and corneal-compensated IOP (IOPcc) measurements (P>0.05 for all). There was no statistically significant difference in terms of IOP differences between GAT and IOPcc (P>0.05), TP and Goldmann-correlated measure of IOP (IOPg; P>0.05) in the Amsler I, while the IOP measurements revealed significant difference among the measurements of the four different tonometers in the Amsler II, Amsler III, and Amsler IV (P<0.05 for all). CONCLUSIONS: There was no significant association between DCT IOP or IOPcc and CCT in eyes with keratoconus; no statistically significant difference was found between keratoconus stages and the control group in terms of the IOP analyzed with these two techniques. These two techniques may be the most stable in the measurement of IOP in different keratoconus stages. However, no IOP technique can be used interchangeably with other techniques in the follow-up of keratoconus patients. PMID- 26634713 TI - How safe is the light during ophthalmic diagnosis and surgery. AB - The light used when undertaking ophthalmic diagnosis or ophthalmic surgery can be hazardous and the need to address this from a clinical and practicable point of view is discussed. Not all patients are equally at risk. Age and health are risk factors that need to be taken into account, the aged eye being more at risk as is the eye with existing disease. The risk of photochemical damage to the retina is increased as a result of patients being examined with different ophthalmic instruments during a 24-h period. The ways in which the clinician needs to address these safety issues is discussed bearing in mind the guidelines that are being developed. PMID- 26634714 TI - Introduction to the special issue on energy materials. PMID- 26634715 TI - Metal-organic frameworks: the pressure is on. AB - Metal-organic frameworks (MOFs) demonstrate a wide variety of behavior in their response to pressure, including anomalous mechanical properties, negative linear compressibility, pressure-induced crystal-to-crystal and crystal-to-amorphous structural transitions. The discovery of framework materials combining novel pressure responses and high mechanical stability is key in the quest for applications of MOFs at the industrial level. PMID- 26634716 TI - Structural studies of metal-organic frameworks under high pressure. AB - Over the last 10 years or so, the interest and number of high-pressure studies has increased substantially. One area of growth within this niche field is in the study of metal-organic frameworks (MOFs or coordination polymers). Here we present a review on the subject, where we look at the structural effects of both non-porous and porous MOFs, and discuss their mechanical and chemical response to elevated pressures. PMID- 26634717 TI - Structure and spectroscopy of CuH prepared via borohydride reduction. AB - Copper(I) hydride (cuprous hydride, CuH) was the first binary metal hydride to be discovered (in 1844) and is singular in that it is synthesized in solution, at ambient temperature. There are several synthetic paths to CuH, one of which involves reduction of an aqueous solution of CuSO4.5H2O by borohydride ions. The product from this procedure has not been extensively characterized. Using a combination of diffraction methods (X-ray and neutron) and inelastic neutron scattering spectroscopy, we show that the CuH from the borohydride route has the same bulk structure as CuH produced by other routes. Our work shows that the product consists of a core of CuH with a shell of water and that this may be largely replaced by ethanol. This offers the possibility of modifying the properties of CuH produced by aqueous routes. PMID- 26634718 TI - Crystal engineering on superpolyhedral building blocks in metal-organic frameworks applied in gas adsorption. AB - Two metal-organic frameworks [PCN-426(Ni) and PCN-427(Cu)] have been designed and synthesized to investigate the structure predictability using a SBB (supermolecular building blocks) approach. Tetratopic ligands featuring 120 degrees angular carboxylate moieties were coordinated with a [Ni3(MU3-O)] cluster and a [Cu2O2] unit, respectively. As topologically predicted, 4-connected networks with square coordination adopted the nbo net for the Ni-MOF and ssb net for the Cu-MOF. PCN-426(Ni) was augmented with 12-connected octahedral SBBs, while PCN-427(Cu) was constructed with tetragonal open channels. After a CO2 supercritical drying procedure, the PCN-426(Ni) possessed a Brunauer-Emmett Teller (BET) surface area as high as 3935 m(2) g(-1) and impressively high N2 uptake of 1500 cm(3) g(-1). This work demonstrates the generalization of the SBB strategy, finding an alternative to inconvenient synthetic processes to achieve the desired structural features. PMID- 26634719 TI - The crystal chemistry of inorganic metal borohydrides and their relation to metal oxides. AB - The crystal structures of inorganic homoleptic metal borohydrides are analysed with respect to their structural prototypes found amongst metal oxides in the inorganic databases such as Pearson's Crystal Data [Villars & Cenzual (2015). Pearson's Crystal Data. Crystal Structure Database for Inorganic Compounds, Release 2014/2015, ASM International, Materials Park, Ohio, USA]. The coordination polyhedra around the cations and the borohydride anion are determined, and constitute the basis of the structural systematics underlying metal borohydride chemistry in various frameworks and variants of ionic packing, including complex anions and the packing of neutral molecules in the crystal. Underlying nets are determined by topology analysis using the program TOPOS [Blatov (2006). IUCr CompComm. Newsl. 7, 4-38]. It is found that the Pauling rules for ionic crystals apply to all non-molecular borohydride crystal structures, and that the latter can often be derived by simple deformation of the close-packed anionic lattices c.c.p. and h.c.p., by partially removing anions and filling tetrahedral or octahedral sites. The deviation from an ideal close packing is facilitated in metal borohydrides with respect to the oxide due to geometrical and electronic considerations of the BH4(-) anion (tetrahedral shape, polarizability). This review on crystal chemistry of borohydrides and their similarity to oxides is a contribution which should serve materials engineers as a roadmap to design new materials, synthetic chemists in their search for promising compounds to be prepared, and materials scientists in understanding the properties of novel materials. PMID- 26634720 TI - Intrinsic flexibility of porous materials; theory, modelling and the flexibility window of the EMT zeolite framework. AB - Framework materials have structures containing strongly bonded polyhedral groups of atoms connected through their vertices. Typically the energy cost for variations of the inter-polyhedral geometry is much less than the cost of distortions of the polyhedra themselves - as in the case of silicates, where the geometry of the SiO4 tetrahedral group is much more strongly constrained than the Si-O-Si bridging angle. As a result, framework materials frequently display intrinsic flexibility, and their dynamic and static properties are strongly influenced by low-energy collective motions of the polyhedra. Insight into these motions can be obtained in reciprocal space through the 'rigid unit mode' (RUM) model, and in real-space through template-based geometric simulations. We briefly review the framework flexibility phenomena in energy-relevant materials, including ionic conductors, perovskites and zeolites. In particular we examine the 'flexibility window' phenomenon in zeolites and present novel results on the flexibility window of the EMT framework, which shed light on the role of structure-directing agents. Our key finding is that the crown ether, despite its steric bulk, does not limit the geometric flexibility of the framework. PMID- 26634721 TI - Using neutron powder diffraction and first-principles calculations to understand the working mechanisms of porous coordination polymer sorbents. AB - Metal-organic frameworks (MOFs) are promising solid sorbents, showing gas selectivity and uptake capacities relevant to many important applications, notably in the energy sector. To improve and tailor the sorption properties of these materials for such applications, it is necessary to gain an understanding of their working mechanisms at the atomic and molecular scale. Specifically, it is important to understand how features such as framework porosity, topology, chemical functionality and flexibility underpin sorbent behaviour and performance. Such information is obtained through interrogation of structure function relationships, with neutron powder diffraction (NPD) being a particularly powerful characterization tool. The combination of NPD with first principles density functional theory (DFT) calculations enables a deep understanding of the sorption mechanisms, and the resulting insights can direct the future development of MOF sorbents. In this paper, experimental approaches and investigations of two example MOFs are summarized, which demonstrate the type of information and the understanding into their functional mechanisms that can be gained. Such information is critical to the strategic design of new materials with targeted gas-sorption properties. PMID- 26634722 TI - Lithium chromium pyrophosphate as an insertion material for Li-ion batteries. AB - Lithium chromium pyrophosphate (LiCrP2O7) and carbon-coated LiCrP2O7 (LiCrP2O7/C) were synthesized by solid-state and sol-gel routes, respectively. The materials were characterized by X-ray diffraction (XRD), thermogravimetric analysis (TGA), scanning electron microscopy (SEM) and conductivity measurements. LiCrP2O7 powder has a conductivity of ~ 10(-8) S cm(-1), ~ 10(4) times smaller than LiCrP2O7/C (~ 10(-4) S cm(-1)). LiCrP2O7/C is electrochemically active, mainly between 1.8 and 2.2 V versus Li(+)/Li (Cr(3+)/Cr(2+) redox couple), whereas LiCrP2O7 has limited electrochemical activity. LiCrP2O7/C delivers a reversible specific charge up to ~ 105 mAh g(-1) after 100 cycles, close to the theoretical limit of 115 mAh g( 1). Operando XRD experiments show slight peak shifts between 2.2 and 4.8 V versus Li(+)/Li, and a reversible amorphization between 1.8 and 2.2 V versus Li(+)/Li, suggesting an insertion reaction mechanism. PMID- 26634723 TI - Structural diversity in hybrid organic-inorganic lead iodide materials. AB - The structural chemistry of hybrid organic-inorganic lead iodide materials has become of increasing significance for energy applications since the discovery and development of perovskite solar cells based on methylammonium lead iodide. Seven new hybrid lead iodide compounds have been synthesized and structurally characterized using single-crystal X-ray diffraction. The lead iodide units in materials templated with bipyridyl, 1,2-bis(4-pyridyl)ethane, 1,2-di(4 pyridyl)ethylene and imidazole adopt one-dimensional chain structures, while crystallization from solutions containing piperazinium cations generates a salt containing isolated [PbI6](4-) octahedral anions. Templating with 4 chlorobenzylammonium lead iodide adopts the well known two-dimensional layered perovskite structure with vertex shared sheets of composition [PbI4](2-) separated by double layers of organic cations. The relationships between the various structures determined, their compositions, stability and hydrogen bonding between the protonated amine and the iodide ions of the PbI6 octahedra are described. PMID- 26634724 TI - Type II Bi1 - xWxO1.5 + 1.5x: a (3 + 3)-dimensional commensurate modulation that stabilizes the fast-ion conducting delta phase of bismuth oxide. AB - The Type II phase in the Bi1 - xWxO1.5 + 1.5x system is shown to have a (3 + 3) dimensional modulated delta-Bi2O3-related structure, in which the modulation vector E 'locks in' to a commensurate value of 1/3. The structure was refined in a 3 * 3 * 3 supercell against single-crystal Laue neutron diffraction data. Ab initio calculations were used to test and optimize the local structure of the oxygen sublattice around a single mixed Bi/W site. The underlying crystal chemistry was shown to be essentially the same as for the recently refined (3 + 3)-dimensional modulated structure of Type II Bi1 - xNbxO1.5 + x (Ling et al., 2013), based on a transition from fluorite-type to pyrochlore-type via the appearance of W4O18 'tetrahedra of octahedra' and chains of corner-sharing WO6 octahedra along <110>F directions. The full range of occupancies on this mixed Bi/W site give a hypothetical solid-solution range bounded by Bi23W4O46.5 (x = 0.148) and Bi22W5O48 (x = 0.185), consistent with previous reports and with our own synthetic and analytical results. PMID- 26634725 TI - Spinel materials for Li-ion batteries: new insights obtained by operando neutron and synchrotron X-ray diffraction. AB - In the last few decades Li-ion batteries changed the way we store energy, becoming a key element of our everyday life. Their continuous improvement is tightly bound to the understanding of lithium (de)intercalation phenomena in electrode materials. Here we address the use of operando diffraction techniques to understand these mechanisms. We focus on powerful probes such as neutrons and synchrotron X-ray radiation, which have become increasingly familiar to the electrochemical community. After discussing the general benefits (and drawbacks) of these characterization techniques and the work of customization required to adapt standard electrochemical cells to an operando diffraction experiment, we highlight several very recent results. We concentrate on important electrode materials such as the spinels Li1 + xMn2 - xO4 (0 <= x <= 0.10) and LiNi0.4Mn1.6O4. Thorough investigations led by operando neutron powder diffraction demonstrated that neutrons are highly sensitive to structural parameters that cannot be captured by other means (for example, atomic Debye Waller factors and lithium site occupancy). Synchrotron radiation X-ray powder diffraction reveals how LiMn2O4 is subject to irreversibility upon the first electrochemical cycle, resulting in severe Bragg peak broadening. Even more interestingly, we show for the first time an ordering scheme of the elusive composition Li0.5Mn2O4, through the coexistence of Mn(3+):Mn(4+) 1:3 cation ordering and lithium/vacancy ordering. More accurately written as Li0.5Mn(3+)0.5Mn(4+)1.5O4, this intermediate phase loses the Fd?overline 3m symmetry, to be correctly described in the P213 space group. PMID- 26634726 TI - Polymorph engineering of CuMO2 (M = Al, Ga, Sc, Y) semiconductors for solar energy applications: from delafossite to wurtzite. AB - The cuprous oxide based ternary delafossite semiconductors have been well studied in the context of p-type transparent conducting oxides. CuAlO2, CuGaO2 and CuInO2 represent a homologous series where the electronic properties can be tuned over a large range. The optical transparency of these materials has been associated with dipole forbidden transitions, which are related to the linear O-Cu-O coordination motif. The recent demonstration that these materials can be synthesized in tetrahedral structures (wurtzite analogues of the chalcopyrite lattice) opens up a new vista of applications. We investigate the underlying structure-property relationships (for Group 3 and 13 metals), from the perspective of first principles materials modelling, towards developing earth-abundant photoactive metal oxides. All materials studied possess indirect fundamental band gaps ranging from 1 to 2 eV, which are smaller than their delafossite counterparts, although in all cases the difference between direct and indirect band gaps is less than 0.03 eV. PMID- 26634727 TI - Disorder in the composite crystal structure of the manganese 'disilicide' MnSi1.73 from powder X-ray diffraction data. AB - The crystal structure of the higher manganese silicide MnSi1.7 (known in the literature as HMS) is investigated in samples with different compositions obtained by different techniques at temperatures not higher than 1273 K. Powder X ray diffraction was applied. The crystal structure is described as incommensurate composite. In addition to the ordered model already known in the literature, the partial disorder in the silicon substructure was detected and described introducing an additional atomic site with a different modulation function. PMID- 26634728 TI - Oxyanion induced variations in domain structure for amorphous cobalt oxide oxygen evolving catalysts, resolved by X-ray pair distribution function analysis. AB - Amorphous thin film oxygen evolving catalysts, OECs, of first-row transition metals show promise to serve as self-assembling photoanode materials in solar driven, photoelectrochemical 'artificial leaf' devices. This report demonstrates the ability to use high-energy X-ray scattering and atomic pair distribution function analysis, PDF, to resolve structure in amorphous metal oxide catalyst films. The analysis is applied here to resolve domain structure differences induced by oxyanion substitution during the electrochemical assembly of amorphous cobalt oxide catalyst films, Co-OEC. PDF patterns for Co-OEC films formed using phosphate, Pi, methylphosphate, MPi, and borate, Bi, electrolyte buffers show that the resulting domains vary in size following the sequence Pi < MPi < Bi. The increases in domain size for CoMPi and CoBi were found to be correlated with increases in the contributions from bilayer and trilayer stacked domains having structures intermediate between those of the LiCoOO and CoO(OH) mineral forms. The lattice structures and offset stacking of adjacent layers in the partially stacked CoMPi and CoBi domains were best matched to those in the LiCoOO layered structure. The results demonstrate the ability of PDF analysis to elucidate features of domain size, structure, defect content and mesoscale organization for amorphous metal oxide catalysts that are not readily accessed by other X-ray techniques. PDF structure analysis is shown to provide a way to characterize domain structures in different forms of amorphous oxide catalysts, and hence provide an opportunity to investigate correlations between domain structure and catalytic activity. PMID- 26634729 TI - Microwave-assisted synthesis and electrochemical evaluation of VO2 (B) nanostructures. AB - Understanding how intercalation materials change during electrochemical operation is paramount to optimizing their behaviour and function and in situ characterization methods allow us to observe these changes without sample destruction. Here we first report the improved intercalation properties of bronze phase vanadium dioxide VO2 (B) prepared by a microwave-assisted route which exhibits a larger electrochemical capacity (232 mAh g(-1)) compared with VO2 (B) prepared by a solvothermal route (197 mAh g(-1)). These electrochemical differences have also been followed using in situ X-ray absorption spectroscopy allowing us to follow oxidation state changes as they occur during battery operation. PMID- 26634730 TI - Structure-property relationships in lithium superionic conductors having a Li10GeP2S12-type structure. AB - The crystal structures of the superionic conductors Li9.81Sn0.81P2.19S12 and Li10.35Si1.35P1.65S12, both having a Li10GeP2S12 (LGPS)-type structure, were determined by neutron diffraction analysis over the temperature range 12-800 K. The maximum entropy method was also employed to clarify the lithium distribution in these materials. The Sn system showed one-dimensional diffusion in the c direction over a wide temperature range, even though the Ge-based system typically exhibits three-dimensional conduction at higher temperatures. The ionic conduction mechanisms of analogous Si, Ge and Sn phases with LGPS-type structures are discussed on the basis of the observed structural parameter changes. PMID- 26634731 TI - Closing the gap between electron and X-ray crystallography. AB - The development of a proper refinement algorithm that takes into account dynamical scattering guarantees, for electron crystallography, results approaching X-rays in terms of precision, accuracy and reliability. The combination of such dynamical refinement and electron diffraction tomography establishes a complete pathway for the structure characterization of single sub micrometric crystals. PMID- 26634732 TI - Structure refinement using precession electron diffraction tomography and dynamical diffraction: tests on experimental data. AB - The recently published method for the structure refinement from three-dimensional precession electron diffraction data using dynamical diffraction theory [Palatinus et al. (2015). Acta Cryst. A71, 235-244] has been applied to a set of experimental data sets from five different samples - Ni2Si, PrVO3, kaolinite, orthopyroxene and mayenite. The data were measured on different instruments and with variable precession angles. For each sample a reliable reference structure was available. A large series of tests revealed that the method provides structure models with an average error in atomic positions typically between 0.01 and 0.02 A. The obtained structure models are significantly more accurate than models obtained by refinement using kinematical approximation for the calculation of model intensities. The method also allows a reliable determination of site occupancies and determination of absolute structure. Based on the extensive tests, an optimal set of the parameters for the method is proposed. PMID- 26634733 TI - Structural chemistry and number theory amalgamized: crystal structure of Na11Hg52. AB - The recently elucidated crystal structure of the technologically important amalgam Na11Hg52 is described by means of a method employing some fundamental concept of number theory, namely modular arithmetical (congruence) relations observed between a slightly idealized set of atomic coordinates. In combination with well known ideas from group theory, regarding lattice-sublattice transformations, these allow for a deeper mutual understanding of both and provide the structural chemist with a slightly different kind of spectacles, thus enabling a distinct viw on complex crystal structures in general. PMID- 26634734 TI - Crystal chemistry of hydrothermally grown ternary alkali rare earth fluorides. AB - The structural variations of several alkali metal rare earth fluoride single crystals are summarized. Two different stoichiometric formulations are considered, namely those of ARE2F7 and ARE3F10 (A = K, Rb, Cs; RE = Y, La-Lu), over a wide range of ionic radii of both the alkali and rare earth (RE) ions. Previously reported and several new single-crystal structures are considered. The new single crystals are grown using hydrothermal methods and the structures are compared with literature reports of structures grown from both melts and hydrothermal fluids. The data reported here are combined with the literature data to gain a greater understanding of structural subtleties surrounding these systems. The work underscores the importance of the size of the cations to the observed structure type and also introduces synthetic technique as a contributor to the same. New insights based on single-crystal structure analysis in the work introduce a new disordered structure type in the case of ARE2F7, and examine the trends and boundaries of the ARE3F10 stoichiometry. Such fundamental structural information is useful in understanding the potential applications of these compounds as optical materials. PMID- 26634735 TI - On the transferability of electron density in binary vanadium borides VB, V3B4 and VB2. AB - Binary vanadium borides are suitable model systems for a systematic analysis of the transferability concept in intermetallic compounds due to chemical intergrowth in their crystal structures. In order to underline this structural relationship, topological properties of the electron density in VB, V3B4 and VB2 reconstructed from high-resolution single-crystal X-ray diffraction data as well as derived from quantum chemical calculations, are analysed in terms of Bader's Quantum Theory of Atoms in Molecules [Bader (1990). Atoms in Molecules: A Quantum Theory, 1st ed. Oxford: Clarendon Press]. The compounds VB, V3B4 and VB2 are characterized by a charge transfer from the metal to boron together with two predominant atomic interactions, the shared covalent B-B interactions and the polar covalent B-M interactions. The resembling features of the crystal structures are well reflected by the respective B-B interatomic distances as well as by rho(r) values at the B-B bond critical points. The latter decrease with an increase in the corresponding interatomic distances. The B-B bonds show transferable electron density properties at bond critical points depending on the respective bond distances. PMID- 26634736 TI - Photocrystallography and IR spectroscopy of light-induced linkage NO isomers in [RuBr(NO)2(PCyp3)2]BF4. AB - One single photo-induced linkage NO isomer (PLI) is detected and characterized in the dinitrosyl pentacoordinated compound [RuBr(NO)2(PCyp3)2]BF4 by a combination of photocrystallographic and IR analysis. In the ground state, the molecule adopts a trigonal-bipyramidal structure with the two NO ligands almost linear with angles Ru-N1-O1 = 168.92 (16), Ru-N2-O2 = 166.64 (16) degrees , and exactly equal distances of Ru-N = 1.7838 (17) and O-N = 1.158 (2) A. After light irradiation of 405 nm at T = 10 K, the angle of Ru-N2-O2 changes to 114.2 (6) degrees by rotation of the O atom towards the Br ligand with increased distances of Ru-N2 = 1.992 (6) and N2-O2 = 1.184 (8) A, forming a bent kappaN bonded configuration. Using IR spectroscopy, the optimal wavelength and maximum population of 39 (1)% of the PLI is determined. In the ground state (GS), the two symmetric nus(NO) and asymmetric nuas(NO) vibrations are measured at 1820 and 1778 cm(-1), respectively. Upon photo-irradiation, the detection of only one new vibrational nu(NO) stretching band at 1655 cm(-1), assigned to the antisymmetric coupled vibration mode and shifted to lower wavenumbers by -123 cm(-1), supports the photocrystallographic result. These experimental results are supported by additional DFT calculations, which reproduce the structural parameters and vibrational properties of both the ground state and the photo-induced linkage isomer well. Especially the experimentally characterized molecular structure of the PLI state corresponds to an energy minimum in the calculations; the stabilization of the bent kappaN bonded configuration of the PLI state originates from specific intramolecular orbital overlap. PMID- 26634737 TI - Crystal behavior of potassium bromate under compression. AB - We report on high-pressure angle-dispersive X-ray diffraction data up to 15 GPa and ab initio total-energy calculations up to 242 GPa for KBrO3. No phase transition was found below 15 Pa in contrast to previously reported data. Its experimental bulk modulus in the quasi-hydrostatic regime is B0 = 18.8 (9) GPa with a bulk modulus pressure derivative B'0 = 8.2 (4). However, according to our ab initio calculations, KBrO3 significantly reduces its rhombohedral distortion via small cooperative movements of the atoms and the structure progressively approaches the cubic symmetry, where the KBr subarray would adopt a topology similar to that of the corresponding B2-type bromide. This rearrangement of atoms is directly related to the Buerger's mechanism of the B1-B2 phase transition for halides, confirming that cations (second neighbors) do not arrange in an arbitrary way. The O atoms forming the [BrO3] pyramidal units move smoothly with pressure to the center of the [K8] cube faces, where electron localization function calculations present their maxima in other B2-type compounds, eventually adopting the perovskite-type structure at P ? 152 GPa. Our data on KBrO3 has been compared with chemically substituted isostructural halates, providing new insights on the compressibility of this family of compounds. PMID- 26634738 TI - A temperature-induced order-disorder phase transition in a 4-substituted 4,2':6',4''-terpyridine. AB - Crystals of 4'-(isoquinolin-4-yl)-4,2':6',4''-terpyridine (iqtp), C24H16N4, grown from an ethanol solution, undergo a reversible first-order single-crystal to single-crystal phase transition at Tc in the range 273-275 K, from a disordered higher-temperature phase [form (I)] in the space group P21/c, with one single molecule in the asymmetric unit, to an ordered lower-temperature one [form (II)] in the space group P21/n, with two independent molecules in the asymmetric unit. There is a group-subgroup relationship linking (I)-(II), due to cell doubling and the disappearance of a number of symmetry operations. In addition to X-ray diffraction, the transition has been monitored by Raman spectroscopy and differential scanning calorimetry, the latter disclosing an enthalpy change of 0.72 (6) kJ mol(-1). Variations of the unit-cell parameters with temperature between 170 and 293 K are presented. The evolution of diffraction spots in the vicinity of the transition temperature shows the coexistence of both phases, confirming the first-order character of the transition. Structural details of both phases are analyzed and intermolecular interactions compared in order to investigate the mechanism of the phase transition. A three-dimensional Hirshfeld surface analysis was performed to corroborate the significant changes in the intermolecular features. PMID- 26634739 TI - Evaluation of Aneurysm Neck Angle Change After Endovascular Aneurysm Repair Clinical Investigations. AB - PURPOSE: To evaluate the aneurysm neck angle changes and post-endovascular aneurysm repair (EVAR) complications. METHODS: We retrospectively analyzed 72 cases of elective EVAR for abdominal aortic aneurysm among 109 consecutive cases from December 2005 to April 2014. Patients were divided into angulated and non angulated groups. The angulated group was defined as neck angulation >=60 degrees . Neck angle was evaluated pre- and post-EVAR during short- (within 1 month), mid (3-6 months), and long-term (>1 year) follow-up. Aneurysm sac diameter change, aneurysm neck morphology other than angulation, endoleaks, and other post procedural complications were also documented. RESULTS: A total of 34 patients were enrolled in the angulated group. There were no statistical differences in age, sex, follow-up duration, and aneurysm neck profile between the two groups (p > 0.05). Both groups showed statistically significant and consistent decreases in angulation during the follow-up period (p < 0.01). The angulated group revealed 22.45 % more straightening than the non-angulated group. Recoil of the Endurant device occurred in the angulated group. No statistically significant intergroup differences were observed in any endoleaks, complications, or re-intervention rates (p > 0.05). Pre-EVAR angle was the only predictor for post-procedural angle change (p < 0.001). CONCLUSION: EVAR is applicable for patients with highly angulated aneurysm neck and provides consistent neck straightening over long-term follow-up. Recoil was evident in the angulated group using the Endurant device. PMID- 26634740 TI - Renal Sympathetic Denervation by CT-Guided Ethanol Injection: A Phase II Pilot Trial of a Novel Technique. AB - OBJECTIVES: CT-guided ethanol-mediated renal sympathetic denervation in treatment of therapy-resistant hypertension was performed to assess patient safety and collect preliminary data on treatment efficacy. MATERIALS AND METHODS: Eleven patients with therapy-resistant hypertension (blood pressure of >160 mmHg despite three different antihypertensive drugs including a diuretic) and following screening for secondary causes were enrolled in a phase II single arm open label pilot trial of CT-guided neurolysis of sympathetic renal innervation. Primary endpoint was safety, and secondary endpoint was a decrease of the mean office as well as 24-h systolic blood pressure in follow-up. Follow-up visits at 4 weeks, 3, and 6 months included 24-h blood pressure assessments, office blood pressure, laboratory values, as well as full clinical and quality of life assessments. RESULTS: No toxicities >=3 degrees occurred. Three patients exhibited worsened kidney function in follow-up analyses. When accounting all patients, office systolic blood pressure decreased significantly at all follow-up visits (maximal mean decrease -41.2 mmHg at 3 months). The mean 24-h systolic blood pressure values decreased significantly at 3 months, but not at 6 months (mean: -9.7 and 6.3 mmHg, respectively). Exclusion of five patients who had failed catheter-based endovascular denervation and/or were incompliant for antihypertensive drug intake revealed a more pronounced decrease of 24-h systolic blood pressure (mean: -18.3 and -15.2 mmHg at 3 and 6 months, p = 0.03 and 0.06). CONCLUSION: CT-guided sympathetic denervation proved to be safe and applicable under various anatomical conditions with more renal arteries and such of small diameter. PMID- 26634741 TI - Adult stem cell lineage tracing and deep tissue imaging. AB - Lineage tracing is a widely used method for understanding cellular dynamics in multicellular organisms during processes such as development, adult tissue maintenance, injury repair and tumorigenesis. Advances in tracing or tracking methods, from light microscopy-based live cell tracking to fluorescent label tracing with two-photon microscopy, together with emerging tissue clearing strategies and intravital imaging approaches have enabled scientists to decipher adult stem and progenitor cell properties in various tissues and in a wide variety of biological processes. Although technical advances have enabled time controlled genetic labeling and simultaneous live imaging, a number of obstacles still need to be overcome. In this review, we aim to provide an in-depth description of the traditional use of lineage tracing as well as current strategies and upcoming new methods of labeling and imaging. PMID- 26634742 TI - Downregulation of pyrroline-5-carboxylate reductase-2 induces the autophagy of melanoma cells via AMPK/mTOR pathway. AB - Melanoma is the most aggressive form of skin cancer and causes 50,000 deaths annually worldwide. The roles of proline-dependent process and autophagy have both been reported in studies on melanoma. In the present study, we focused on the effect of pyrroline-5-carboxylate reductase-2 (PYCR2) on inducing autophagy process in melanoma. The expression of PYCR2 was regulated by an RNAi technique, and the cell proliferation of A375 cell line was determined by methyl thiazolyl tetrazolium test; the effect of PYCR2 on the apoptosis process and AMPK/mTOR pathway was evaluated by flow cytometry assay and Western blot. It was found that silence of PYCR2 resulted in the decrease of proliferative ability and activation of AMPK/mTOR-induced autophagy of A375 cells. PYCR2 silencing also activated AMPK/mTOR pathway in another melanoma cell line, CHL-1. However, the overexpression of PYCR2 seemed to make no difference to the cell viability and targeted pathway. Our results offered a preliminary illustration on the mechanism of the PYCR2-dependent autophagy and showed that PYCR2 was a potential therapeutic target of melanoma. PMID- 26634743 TI - The growth arrest-specific transcript 5 (GAS5): a pivotal tumor suppressor long noncoding RNA in human cancers. AB - Long noncoding RNAs (lncRNAs), which refer to a group of RNAs with length more than 200 nucleotides and limited protein-coding potential, play a widespread role in regulating biological processes, such as cell differentiation, proliferation, apoptosis, and migration. LncRNAs are dysregulated in multiple cancers, playing an either oncogenic or tumor-suppressive role. LncRNA GAS5 is a recently identified tumor suppressor involved in several cancers, like breast cancer, prostate cancer, lung cancer, and colorectal cancer. The low-expression pattern confers tumor cells elevated capacity of proliferation and predicts poorer prognosis. Existing studies mirror that lncRNA GAS5 promises to be a novel diagnostic biomarker, therapy target, as well as prognostic biomarker. In this review, we will summarize the current knowledge about this vital lncRNA, from its discovery, characteristics, and biological function to molecular mechanism in various neoplasms. PMID- 26634745 TI - Regulation of osteosarcoma cell invasion through osteopontin modification by miR 4262. AB - Osteopontin (OPN) is a phosphorylated glycoprotein that plays a critical role in the invasion of osteosarcoma (OS), the most common primary malignant bone tumor. Since microRNAs (miRNAs) have been well documented as key players in the tumorigenesis, cancer cell growth, and metastases, determination of the involved miRNAs that may regulate OPN-mediated OS cell invasion appears to be one important question in the current understanding and therapeutic strategies for OS. Here, we found that the levels of miR-4262 were significantly decreased and the levels of OPN were significantly increased in OS specimens, compared to the paired adjacent non-tumor tissue. Moreover, miR-4262 and OPN inversely correlated in OS specimens. The 5-year survival of the patients with lower miR-4262 levels in the resected OS was worse than that of patients with high miR-4262 levels. Bioinformatics analyses showed that miR-4262 targeted the 3'-UTR of OPN mRNA to inhibit its translation, which was proved by luciferase reporter assay. Furthermore, miR-4262 overexpression inhibited OPN-mediated cell invasion, while miR-4262 depletion increased OPN-mediated cell invasion in OS cells, in both a transwell cell invasion assay and a scratch wound healing assay. Together, our data suggest that suppression of miR-4262 in OS cells may promote OPN-mediated cancer invasion, highlighting miR-4262 as an intriguing therapeutic target to prevent OS metastases. PMID- 26634744 TI - The roles of microRNAs in Wilms' tumors. AB - Wilms' tumor is the most common renal tumor in children in which diffusely anaplastic or unfavorable histology foreshadows poor prognosis. MicroRNAs are small, non-coding RNAs that negatively regulate gene expression at the posttranscriptional level. Accumulating evidence shows that microRNA dysregulation takes part in the pathogenesis of many renal diseases, such as chronic kidney diseases, polycystic kidney disease, renal fibrosis, and renal cancers. In Wilms' tumor, dysregulation of some key oncogenic or tumor suppressing microRNAs, such as miR-17~92 cluster, miR-185, miR-204, and miR-483, has been documented. In this review, we will summarize current evidence on the role of dysregulated microRNAs in the development of Wilms' tumor. PMID- 26634746 TI - Inactivation of Lactobacillus rhamnosus GG by fixation modifies its probiotic properties. AB - Probiotics are microorganisms that have beneficial effects on the host and are safe for oral intake in a suitable dose. However, there are situations in which the administration of living microorganisms poses a risk for immunocompromised host. The objective of this study was to evaluate the influence of several fixation methods on selected biological properties of Lactobacillus rhamnosus GG that are relevant to its probiotic action. Fixation of the bacterial cells with ethanol, 2-propanol, glutaraldehyde, paraformaldehyde, and heat treatment resulted in a significant decrease of alkaline phosphatase, peroxidase, and beta galactosidase activities. Most of the fixation procedures reduced bacterial cell hydrophobicity and increased adhesion capacity. The fixation procedures resulted in a different perception of the bacterial cells by enterocytes, which was shown as changes in gene expression in enterocytes. The results show that some procedures of inactivation allow a fraction of the enzymatic activity to be maintained. The adhesion properties of the bacterial cells were enhanced, but the response of enterocytes to fixed cells was different than to live bacteria. Inactivation allows maintenance and modification of some of the properties of the bacterial cells. PMID- 26634747 TI - Acta updates. PMID- 26634748 TI - Compulsory calorie-labelling of menu items is not a panacea for the obesity epidemic. A response to 'Compulsory calorie labelling of foods' by Nikolaou and Lean. PMID- 26634749 TI - Development of a Robust Method for Simultaneous Quantification of Polymer (HPMC) and Surfactant (Dodecyl beta-D-Maltoside) in Nanosuspensions. AB - This report describes the development of a chromatographic method for the simultaneous quantification of a polymer, hydroxypropyl methylcellulose (HPMC), and a surfactant, dodecyl beta-D-maltoside (DM), that are commonly used in the physical stabilization of pharmaceutical formulations such as nanosuspensions and solid dispersions. These excipients are often challenging to quantify due to the lack of chromophores. A reverse phase size exclusion chromatography (SEC) with evaporative light scattering detector (ELSD) technique was utilized to develop an accurate and robust assay for the simultaneous quantification of HPMC and DM in a nanosuspension formulation. The statistical design of experiments was used to determine the influence of critical ELSD variables including temperature, pressure, and gain on accuracy, precision, and sensitivity of the assay. A robust design space was identified where it was determined that an increase in the temperature of the drift tube and gain of the instrument increased the accuracy and precision of the assay and a decrease in the nebulizer pressure value increased the sensitivity of the assay. In the optimized design space, response data showed that the assay could quantify HPMC and DM simultaneously with good accuracy, precision, and reproducibility. Overall, SEC-ELSD proved to be a powerful technique for the simultaneous quantification of HPMC and DM. This technique can be used to quantify the amount of HPMC and DM in nanosuspensions, which is critical to understanding their effects on the physical stability of nanosuspensions. PMID- 26634750 TI - Recent in vivo advances in cell-penetrating peptide-assisted drug delivery. AB - INTRODUCTION: Delivery of macromolecular drugs is an important field in medical research. However, macromolecules are usually unable to cross the cell membrane without the assistance of a delivery system. Cell penetrating peptides (CPPs) are unique tools to gain access to the cell interior and deliver a bioactive cargo into the cytosol or nucleus. In addition to macromolecular delivery, CPPs have been used to deliver smaller bioactive molecules. Therefore CPPs have become an intensive field of research for medical treatment. AREAS COVERED: In this review, we highlight studies that include CPP in vivo disease models. We review different strategies and approaches that have been used, with specific attention on recent publications. The approaches that have been used include CPP-cargo covalent conjugation strategies and nanoparticle strategies. Various additional strategies have been used to achieve disease targeting, including active targeting, passive targeting, and combined active/passive strategies. As a result, delivery of various types of molecule has been achieved, including small drug molecules, proteins and nucleic acid-based macromolecules (e.g. siRNA, antisense nucleotides and plasmid DNA). EXPERT OPINION: Despite recent advances in the field, confusions surrounding CPP internalization mechanisms and intracellular trafficking are hindering the development of new and more efficient vectors. Nevertheless, the recent increase in the number of publications containing in vivo CPP utilization looks promising that the number of clinical trials would also increase in the near future. PMID- 26634751 TI - Nineteen Whole-Genome Assemblies of Yersinia pestis subsp. microtus, Including Representatives of Biovars caucasica, talassica, hissarica, altaica, xilingolensis, and ulegeica. AB - The etiologic agent of plague, Yersinia pestis, includes two subspecies, of which Y. pestis subsp. microtus contains the strains that cause only occasional diseases in humans that are not accompanied by human-to-human transmission. Here, we report the draft genome sequences of 19 Y. pestis strains (across 6 biovars of Y. pestis subsp. microtus). PMID- 26634752 TI - Draft Genome Sequence of Agreia bicolorata Strain AC-1804, a Producer of Large Amounts of Carotenoid Pigments, Isolated from Narrow Reed Grass Infected by the Phytoparasitic Nematode. AB - Here, we report the draft genome sequence of Agreia bicolorata strain AC-1804, isolated from narrow reed grass galls induced by a plant-parasitic nematode which is able to produce large amounts of carotenoid pigments. The draft genome sequence of 3,919,485 bp provides a resource for carotenoid pathway research. PMID- 26634753 TI - Draft Genome Sequence of Vibrio owensii Strain SH-14, Which Causes Shrimp Acute Hepatopancreatic Necrosis Disease. AB - We sequenced Vibrio owensii strain SH-14, which causes serious acute hepatopancreatic necrosis disease (AHPND) in shrimp. Sequence analysis showed a large extrachromosomal plasmid, which encoded pir toxin genes and shared highly sequence similarity with the one observed in AHPND-causing Vibrio parahaemolyticus strains. The results suggest that this plasmid appears to play an important role in shrimp AHPND. PMID- 26634754 TI - Complete Genome Sequence of Polypropylene Glycol- and Polyethylene Glycol Degrading Sphingopyxis macrogoltabida Strain EY-1. AB - Strain EY-1 was isolated from a microbial consortium growing on a random polymer of ethylene oxide and propylene oxide. Strain EY-1 grew on polyethylene glycol and polypropylene glycol and identified as Sphingopyxis macrogoltabida. Here, we report the complete genome sequence of Sphingopyxis macrogoltabida EY-1. The genome of strain EY-1 is comprised of a 4.76-Mb circular chromosome, and five plasmids. The whole finishing was conducted in silico, with aids of computational tools GenoFinisher and AceFileViewer. Strain EY-1 is available from Biological Resource Center, National Institute of Technology and Evaluation (Tokyo, Japan) (NITE). PMID- 26634755 TI - Draft Genome Sequence of Komagataeibacter intermedius Strain AF2, a Producer of Cellulose, Isolated from Kombucha Tea. AB - Here, we present the draft genome sequence of Komagataeibacter intermedius strain AF2, which was isolated from Kombucha tea and is capable of producing cellulose, although at lower levels compared to another bacterium from the same environment, K. rhaeticus strain AF1. PMID- 26634756 TI - Genome Sequence of the Acetogenic Bacterium Oxobacter pfennigii DSM 3222T. AB - Here, we report the draft genome sequence of Oxobacter pfennigii DSM 3222(T), an anaerobic, acetogenic, carbon monoxide-oxidizing, and butyrate-producing bacterium. The genome consists of a chromosome with a size of 4.49 Mbp. PMID- 26634757 TI - Draft Genome Sequences of Three Mycobacterium chimaera Respiratory Isolates. AB - Mycobacterium chimaera is an opportunistic human pathogen implicated in both pulmonary and cardiovascular infections. Here, we report the draft genome sequences of three strains isolated from human respiratory specimens. PMID- 26634758 TI - High-Quality Draft Genome Sequence of Kallotenue papyrolyticum JKG1T Reveals Broad Heterotrophic Capacity Focused on Carbohydrate and Amino Acid Metabolism. AB - The draft genome of Kallotenue papyrolyticum JKG1(T), a member of the order Kallotenuales, class Chloroflexia, consists of 4,475,263 bp in 4 contigs and encodes 4,010 predicted genes, 49 tRNA-encoding genes, and 3 rRNA operons. The genome is consistent with a heterotrophic lifestyle including catabolism of polysaccharides and amino acids. PMID- 26634759 TI - Genome Sequence of Rapid Beer-Spoiling Isolate Lactobacillus brevis BSO 464. AB - The genome of brewery-isolate Lactobacillus brevis BSO 464 was sequenced and assembly produced a chromosome and eight plasmids. This bacterium tolerates dissolved CO2/pressure and can rapidly spoil packaged beer. This genome is useful for analyzing the genetics associated with beer spoilage by lactic acid bacteria. PMID- 26634760 TI - Characterization and Sequencing of a Genotype VIId Newcastle Disease Virus Isolated from Laying Ducks in Jiangsu, China. AB - We report here the complete genome sequence and biological characterization of a virulent Newcastle disease virus (NDV) strain, NDV/duck/Jiangsu/JSD0812/2008, isolated from laying ducks in Jiangsu Province, China. The genome is 15,192 nucleotides in length and is classified in subgenotype VIId of genotype VII, class II. PMID- 26634761 TI - The 474-Kilobase-Pair Complete Genome Sequence of CeV-01B, a Virus Infecting Haptolina (Chrysochromulina) ericina (Prymnesiophyceae). AB - We report the complete genome sequence of CeV-01B, a large double-stranded DNA virus infecting the unicellular marine phytoplankton Haptolina (formerly Chrysochromulina) ericina. CeV-01B and its closest relative Phaeocystis globosa virus define an emerging subclade of the Megaviridae family with smaller genomes and particles than the originally described giant Mimiviridae infecting Acanthamoeba. PMID- 26634762 TI - Complete Genome Sequence of Genotype Ib Newcastle Disease Virus Isolated from a Mallard (Anas platyrhynchos) in Russia. AB - We report here the complete genome sequence of a Newcastle disease virus isolate, NDV/Yakutiya/mallard/852/2011, isolated from a mallard in Russia. On the basis of phylogenetic analysis, this strain was clustered into class II genotype Ib. PMID- 26634763 TI - Molecular Characteristics of H6N6 Influenza Virus Isolated from Pigeons in Guangxi, Southern China. AB - Here, we report the complete genome sequence of an H6N6 avian influenza virus (AIV) isolated from a pigeon in Guangxi, southern China, in 2014. The eight RNA segment genes shared a high nucleotide identity (97 to 99%) with H6N6 subtypes of AIV isolated from ducks in the regions around Guangxi Province. The finding of this study will help us understand the ecology and molecular characteristics of H6 avian influenza virus in wild birds in southern China. PMID- 26634764 TI - Draft Whole-Genome Sequence of Serratia marcescens Strain RM66262, Isolated from a Patient with a Urinary Tract Infection. AB - Serratia marcescens strains are ubiquitous bacteria isolated from environmental niches and also constitute emergent nosocomial opportunistic pathogens. Here, we report on the draft genome sequence of S. marcescens strain RM66262, which was isolated from a patient with urinary tract infection in the Bacteriology Service of the Rosario National University, Rosario, Argentina. PMID- 26634765 TI - Finished Annotated Genome Sequence of Burkholderia pseudomallei Strain Bp1651, a Multidrug-Resistant Clinical Isolate. AB - Burkholderia pseudomallei strain Bp1651, a human isolate, is resistant to all clinically relevant antibiotics. We report here on the finished genome sequence assembly and annotation of the two chromosomes of this strain. This genome sequence may assist in understanding the mechanisms of antimicrobial resistance for this pathogenic species. PMID- 26634766 TI - Draft Genome Sequence of the Marine Pathogen Vibrio coralliilyticus RE22. AB - Vibrio coralliilyticus RE22 is a causative agent of vibriosis in larval bivalves. We report here the draft genome sequence of V. coralliilyticus RE22 and describe additional virulence factors that may provide insight into its mechanism of pathogenicity. PMID- 26634767 TI - A study of the association between atmospheric particulate matter and blood pressure in the population. AB - This systematic review and meta-analysis was conducted to assess the association between the level of atmospheric particulate matter (PM) and the increase in blood pressure (BP) for different exposure terms (<= 7 vs > 7 days) and age groups (< 65 vs >= 65 years). Some databases were searched to investigate the association between increased atmospheric PM (diameter < 2.5 mm [PM2.5] or < 10 mm [PM10]) and BP (systolic blood pressure [SBP] and diastolic blood pressure [DBP]). Among a total of 719 identified articles, 68 were reviewed in depth, of which only 20 satisfied the inclusion criteria. A significant association was found between PM10 levels and higher BP. The beta values were 0.270mmHg (95% confidence interval [CI] 0.068-0.482) for SBP and 0.215mmHg (95% CI 0.058-0.372) for DBP. These beta values mean that, for every 10 mg/m(3) increase in PM10, SBP increased by 0.270mmHg and DBP by 0.215 mmHg. Subgroup analyses were conducted for different exposure terms and age groups. A positive association was seen between PM2.5 and SBP. The beta value of SBP was 0.495mmHg (95% CI 0.03-0.96) with every 10 mg/m(3) increase in PM2.5. There were no significant associations in both age groups and non-older groups. There was no significant association between PM2.5 and DBP, either in the overall effect or in the subgroup effects. In conclusion, significant associations were found between higher BP and higher PM10 levels, but the association between BP and levels of PM2.5 levels was unclear. PMID- 26634768 TI - Prion protein gene sequence and chronic wasting disease susceptibility in white tailed deer (Odocoileus virginianus). AB - The sequence of the prion protein gene (PRNP) affects susceptibility to spongiform encephalopathies, or prion diseases in many species. In white-tailed deer, both coding and non-coding single nucleotide polymorphisms have been identified in this gene that correlate to chronic wasting disease (CWD) susceptibility. Previous studies examined individual nucleotide or amino acid mutations; here we examine all nucleotide polymorphisms and their combined effects on CWD. A 626 bp region of PRNP was examined from 703 free-ranging white tailed deer. Deer were sampled between 2002 and 2010 by hunter harvest or government culling in Illinois and Wisconsin. Fourteen variable nucleotide positions were identified (4 new and 10 previously reported). We identified 68 diplotypes comprised of 24 predicted haplotypes, with the most common diplotype occurring in 123 individuals. Diplotypes that were found exclusively among positive or negative animals were rare, each occurring in less than 1% of the deer studied. Only one haplotype (C, odds ratio 0.240) and 2 diplotypes (AC and BC, odds ratios of 0.161 and 0.108 respectively) has significant associations with CWD resistance. Each contains mutations (one synonymous nucleotide 555C/T and one nonsynonymous nucleotide 286G/A) at positions reported to be significantly associated with reduced CWD susceptibility. Results suggest that deer populations with higher frequencies of haplotype C or diplotypes AC and BC might have a reduced risk for CWD infection--while populations with lower frequencies may have higher risk for infection. Understanding the genetic basis of CWD has improved our ability to assess herd susceptibility and direct management efforts within CWD infected areas. PMID- 26634769 TI - Short-term estriol administration modulates hypothalamo-pituitary function in patients with functional hypothalamic amenorrhea (FHA). AB - OBJECTIVE: To evaluate the influence of short-term estriol administration (10 d) on the hypothalamus-pituitary function and gonadotropins secretion in patients affected by functional hypothalamic amenorrhea (FHA). STUDY DESIGN: Controlled clinical study on patients with FHA (n = 12) in a clinical research environment. INTERVENTION(S): Hormonal determinations and gonadotropin (luteinizing hormone [LH] and FSH) response to a gonadotropin-releasing hormone (GnRH) bolus (10 MUg) at baseline condition and after 10 d of therapy with 2 mg/d of estriol per os. MAIN OUTCOME MEASURE(S): Measurements of plasma LH, FSH, prolactin, estradiol, androstenedione, 17alpha-hydroxyprogesterone, insulin, cortisol, thyroid stimulating hormone, free triiodothyronine, and free thyroxine. RESULT(S): After treatment, the FHA patients showed a statistically significant increase of both LH and FSH plasma levels and the significant increase of their responses to the GnRH bolus. CONCLUSION(S): Estriol short-term therapy modulates within 10 d of administration the neuroendocrine control of the hypothalamus-pituitary unit and induces the recovery of both gonadotropins synthesis and secretion in hypogonadotropic patients with FHA. PMID- 26634770 TI - Purification and properties of 4-methyl-5-hydroxyethylthiazole kinase from Escherichia coli. AB - 4-Methyl-5-hydroxyethylthiazole kinase (ThiM) participates in thiamin biosynthesis as the key enzyme in its salvage pathway. We purified and characterized ThiM from Escherichia coli. It has broad substrate specificity toward various nucleotides and shows a preference for dATP as a phosphate donor over ATP. It is activated by divalent cations, and responds more strongly to Co(2+) than to Mg(2+). PMID- 26634771 TI - The soluble receptor ST2 is positively associated with occupational exposure to radiation. AB - Purpose Radiation exposure, besides the risk of cancer, may also increase the risk of non-cancer diseases, including cardiovascular disease (CVD). This study investigates whether the soluble form of the ST2 receptor (sST2), an emerging prognostic marker in patients with CVD, can be used to monitor the CVD risk in individuals occupationally exposed to radiation. Materials and methods sST2 in blood plasma from 69 individuals, 45 workers from the nuclear industry and 24 controls, was analyzed using enzyme-linked assay (ELISA). Total antioxidant status (TAS) of blood plasma and levels of reactive oxygen species (ROS) in lymphocytes were determined by colorimetric and fluorescence assays. Results The data suggest a 5-fold increase in the number of subjects with sST2 levels above the clinical threshold and a 10-fold increase in the number of subjects with TAS levels outside the reference range in the exposed group when compared to the group of non-exposed individuals. The strongest up-regulation of TAS was measured in the group of younger workers with cumulative doses not exceeding 50 mSv. Conclusion The present study may represent an initial step towards the establishment of sST2 as a biomarker for CVD risk estimation in the context of radiation exposure. PMID- 26634772 TI - Overall Postneonatal Mortality and Rates of SIDS. AB - BACKGROUND: Reductions in sudden infant death syndrome (SIDS) are commonly attributed to modifications in infant sleep environments. Approaches to diagnosis in sudden infant death, death scene investigations, the prevalence of intrinsic risk factors for SIDS, and the potential influence of treatment-related factors on infant vulnerability have also changed. Understanding all contributory factors may help reduce residual SIDS rates. METHODS: We analyzed US Mortality Multiple Causes Records for 1983 to 2012 to compare SIDS postneonatal mortality rates with a projection applying non-SIDS mortality changes, using those changes as a proxy measure for alterations in intrinsic risk. Composites of neglect-related, unknown, and circumstantial respiratory diagnoses were measured, as was a cumulative composite of unexplained infant death diagnoses. Cluster analysis with leading causes of postneonatal mortality and SIDS mortality rates for low birth weight infants were also examined. RESULTS: SIDS and non-SIDS postneonatal mortality rates were concordant over time. Important variance was seen 1994 to 1996, coinciding with Back-to-Sleep initiation. Other variance, eliminated in the cumulative composite, appeared related to differences in diagnostic practices. Changes in SIDS rates resembled changes in mortality from congenital malformations, respiratory distress of the newborn, and diseases of the circulatory system. SIDS rates for low birth weight infants followed broader postneonatal trends. CONCLUSIONS: SIDS mortality followed trends in overall postneonatal mortality, including effects of changes in the infant sleep environment and diagnostic classification. Preventing asphyxia risk in the sleep environment must be coupled with efforts to understand intrinsic biological pathways, some potentially associated with other categories of infant and perinatal mortality. PMID- 26634773 TI - SIDS Risk: It's More Than Just the Sleep Environment. PMID- 26634774 TI - A Low-Literacy Asthma Action Plan to Improve Provider Asthma Counseling: A Randomized Study. AB - BACKGROUND AND OBJECTIVES: The use of written asthma action plans (WAAPs) has been associated with reduced asthma-related morbidity, but there are concerns about their complexity. We developed a health literacy-informed, pictogram- and photograph-based WAAP and examined whether providers who used it, with no training, would have better asthma counseling quality compared with those who used a standard plan. METHODS: Physicians at 2 academic centers randomized to use a low-literacy or standard action plan (American Academy of Allergy, Asthma and Immunology) to counsel the hypothetical parent of child with moderate persistent asthma (regimen: Flovent 110 MUg 2 puffs twice daily, Singulair 5 mg daily, Albuterol 2 puffs every 4 hours as needed). Two blinded raters independently reviewed counseling transcriptions. PRIMARY OUTCOME MEASURES: medication instructions presented with times of day (eg, morning and night vs number of times per day) and inhaler color; spacer use recommended; need for everyday medications, even when sick, addressed; and explicit symptoms used. RESULTS: 119 providers were randomly assigned (61 low literacy, 58 standard). Providers who used the low-literacy plan were more likely to use times of day (eg, Flovent morning and night, 96.7% vs 51.7%, P < .001; odds ratio [OR] = 27.5; 95% confidence interval [CI], 6.1-123.4), recommend spacer use (eg, Albuterol, 83.6% vs 43.1%, P < .001; OR = 6.7; 95% CI, 2.9-15.8), address need for daily medications when sick (93.4% vs 34.5%, P < .001; OR = 27.1; 95% CI, 8.6-85.4), use explicit symptoms (eg, "ribs show when breathing," 54.1% vs 3.4%, P < .001; OR = 33.0; 95% CI, 7.4-147.5). Few mentioned inhaler color. Mean (SD) counseling time was similar (3.9 [2.5] vs 3.8 [2.6] minutes, P = .8). CONCLUSIONS: Use of a low-literacy WAAP improves the quality of asthma counseling by helping providers target key issues by using recommended clear communication principles. PMID- 26634775 TI - Antioxidant Potential of the Methanol Extract of Parquetina nigrescens Mediates Protection Against Intestinal Ischemia-Reperfusion Injury in Rats. AB - Parquetina nigrescens is a medicinal herb with recognized antioxidant properties and potential to alleviate conditions associated with oxidative stress, including gastric ulcers. We investigated the protective potential of methanol extract of Parquetina nigrescens (MEPN) against ischemia-reperfusion injury in the intestine of rats. Thirty (30) male Wistar albino rats were randomly assigned into five groups with Group I made up of control rats and Group II consisting of rats experimentally subjected to ischemia and reperfusion (IR) by clamping of the superior mesenteric artery (SMA) for 30 minutes and 45 minutes, respectively. Groups III and IV rats also had IR, but were initially pre-treated with MEPN at 500 mg/kg and 1000 mg/kg respectively, for seven days. Rats in Group V were also pre-treated with Vitamin C, for seven days, before induction of IR. The results showed marked reduction in intestinal epithelial lesions in groups treated with MEPN, compared to the IR group which had severe villi erosion, inflammatory cell infiltration and hemorrhages. There were significant increases in Malondialdehyde (MDA) and significant reductions in reduced glutathione (GSH) and Glutathione S transferase (GST) activity with IR injury, while pre-treatment with either MEPN or Vitamin C prevented these effects. Increases in Glutathione peroxidase (GPX), Catalase (CAT) and Superoxide dismutase (SOD) with IR provided evidence for adaptive responses to oxidative injury during IR and preservation of enzyme activity by MEPN and Vitamin C. Taken together, Parquetina nigrescens provided considerable alleviation of intestinal injury produced by IR, at values much as effective as that offered by Vitamin C. PMID- 26634776 TI - Health and Safety Executive's response to article on the demise of occupational medicine. PMID- 26634777 TI - Chirp-Coded Ultraharmonic Imaging with a Modified Clinical Intravascular Ultrasound System. AB - Imaging plaque microvasculature with contrast-enhanced intravascular ultrasound (IVUS) could help clinicians evaluate atherosclerosis and guide therapeutic interventions. In this study, we evaluated the performance of chirp-coded ultraharmonic imaging using a modified IVUS system (iLabTM, Boston Scientific/Scimed) equipped with clinically available peripheral and coronary imaging catheters. Flow phantoms perfused with a phospholipid-encapsulated contrast agent were visualized using ultraharmonic imaging at 12 MHz and 30 MHz transmit frequencies. Flow channels with diameters as small as 0.8 mm and 0.5 mm were visualized using the peripheral and coronary imaging catheters. Radio frequency signals were acquired at standard IVUS rotation speed, which resulted in a frame rate of 30 frames/s. Contrast-to-tissue ratios up to 17.9 +/- 1.11 dB and 10.7 +/- 2.85 dB were attained by chirp-coded ultraharmonic imaging at 12 MHz and 30 MHz transmit frequencies, respectively. These results demonstrate the feasibility of performing ultraharmonic imaging at standard frame rates with clinically available IVUS catheters using chirp-coded excitation. PMID- 26634778 TI - Ospemifene for the treatment of postmenopausal vulvar and vaginal atrophy: recommendations for clinical use. AB - INTRODUCTION: Vulvar vaginal atrophy (VVA), a component of genitourinary syndrome of menopause, is a chronic, progressive medical condition that results from estrogen deficiency at menopause. Ospemifene is a nonhormonal, estrogen receptor agonist/antagonist (ERAA) FDA-approved for the treatment of moderate to severe dyspareunia, a symptom of VVA, due to menopause. AREAS COVERED: PubMed was searched from inception to March 2015 with keywords ospemifene and vulvar vaginal atrophy; no other similar clinical reviews were found. This is a comprehensive review describing the clinical safety and efficacy of ospemifene for the treatment of dyspareunia and VVA. Preclinical and clinical data suggesting further potential use or benefits of ospemifene for women's health will also be reviewed. EXPERT OPINION: Ospemifene is an approved oral option for postmenopausal women seeking treatment for VVA with bothersome dyspareunia, particularly for those who have tried and failed over-the-counter options or do not want vaginal therapies. Further clinical studies are needed to evaluate the preclinical and early clinical findings of antagonistic to neutral effect on breast tissue and positive effect on bone, which, in the future, may support the use of ospemifene to prevent bone loss or treat VVA in women at high risk or with breast cancer. PMID- 26634779 TI - Challenging times for occupational medicine. PMID- 26634780 TI - New insights in the acute toxic/genotoxic effects of CuO nanoparticles in the in vivo Drosophila model. AB - Metal oxide nanoparticles are highly reactive from the biological point of view and, for this reason, it exists important reservations in regard human health impact. We used Drosophila as a promising in vivo model to diagnose the biological effects of copper oxide nanoparticles (CuO-NPs). Due to the potential role of ions release the effects of CuO-NPs were compared with those induced by copper sulfate, CuSO4. A wide battery of approaches has been used including toxicity, cell and body internalization, induction of reactive oxygen species (ROS) as well as changes in gene expression, related to both general stress and alterations in the intestinal barrier, and genotoxicity. The obtained results show that CuO-NPs have the ability to be distributed inside midgut cells and translocate to the general body compartment (internal hemolymph) interacting with hemocytes. Its exposure leads to reduced larval growth, decreased flies viability, delaying their emergency periods, especially at higher doses (2 and 10 mM). Moreover, deregulation of stress genes including antioxidant genes, and genes involved in wound healing were also observed. In this point it should be emphasized the novelty of using genes such as Duox, Upd3, PPO2, and Hml to determine injury on the intestinal barrier. On the other hand, CuO-NPs had non genotoxic potential, in agreement with their inability to increase ROS production. In general dissolved copper produced higher toxic/genotoxic effects than those induced by CuO-NPs which would indicate that copper ions alone are more important in inducing harmful effects than copper nanoparticles itself. PMID- 26634781 TI - Subjective and objective voice evaluation in Sjogren's syndrome. AB - Objective The aim of this study is to assess the subjective and objective aspects of voice in Sjogren's syndrome. Methods The study enrolled 10 women with Sjogren's syndrome and 12 healthy women. Maximum phonation time, fundamental frequency, jitter, shimmer, and noise-to-harmonics ratio were determined during acoustic voice analysis. The Stroboscopy Evaluation Rating Form was used for the laryngostroboscopic evaluation. A subjective evaluation was performed using the Turkish version of Voice Handicap Index-10. Results The mean age of the Sjogren's syndrome and control groups was 46 +/- 13.89 and 41.27 +/- 6.99 years, respectively, and did not differ (P = 0.131). In the laryngostroboscopic evaluation, the smoothness and straightness of vocal folds, regularity, and glottal closure differed significantly. In the acoustic and aerodynamic analyses, none of the parameters differed statistically, while the Sjogren's syndrome group had significantly higher Voice Handicap Index-10 scores than the controls. Conclusion Sjogren's syndrome affects the voice and voice quality. PMID- 26634782 TI - Will new drugs change the standard of care for patients with mantle cell lymphoma? AB - Mantle Cell lymphoma is a heterogeneous malignancy that has different subtypes with variable levels of aggressiveness. Research on the pathobiology of this disease is helping us understand the etiology for this heterogeneity and has the potential to guide future therapeutic options. The availability of the Ki67 proliferation index and the use of the MIPI score can help determine which of the numerous therapeutic options might be utilized. Minimal Residual Disease testing can act as a guide as to the potential benefit of maintenance therapy. This article discusses the current standard of care for Mantle Cell lymphoma and our current understanding of the pathobiology of the disease leading to strategies to improve patient outcomes with some of the newer targeted agents. PMID- 26634783 TI - The role of immune mechanisms in alcoholic and nonalcoholic steatohepatitis: a 2015 update. AB - So far, innate immune mechanisms have been recognized as the main responsible for the evolution of both alcoholic steatohepatitis (ASH) and nonalcoholic steatohepatitis (NASH). However, increasing evidence points toward the possible role of adaptive immune responses, as an additional factor in promoting hepatic inflammation in steatohepatitis. In this article, we discuss recent data involving circulating antibodies and lymphocyte-mediated responses in sustaining the progression of ASH and NASH to fibrosis, as well as the possible mechanisms implicated in favoring the onset of adaptive immunity in the setting of steatohepatitis. PMID- 26634784 TI - Protease-Activable Cell-Penetrating Peptide-Protoporphyrin Conjugate for Targeted Photodynamic Therapy in Vivo. AB - In this paper, we aimed to develop a conjugate of matrix metalloproteinases-2 (MMP-2)-sensitive activable cell-penetrating peptide (R9GPLGLAGE8, ACPP) with protoporphyrin (PpIX) for tumor-targeting photodynamic therapy. In normal tissue, the cell-penetrating function of polycationic CPP (R9) would be blocked by a polyanionic peptide (E8) through intramolecular electrostatic attraction. Once exposed to MMP-2 existing at the tumor site, proteolysis of the oligopeptide linker (GPLGLAG) between the CPP and the polyanionic peptide would dissociate the inhibitory polyanions and release CPP-PpIX for photodynamic therapy (PDT). It was found that after tail vein injection the ACPP-PpIX conjugate could accumulate effectively at the tumor site with the fluorescence enhancement which was beneficial for tumor diagnosis and image-guided PDT. After further administration with irradiation, both the solid tumor size and weight had a significant suppression (reduced by more than 90%) with a low systemic toxicity. This ACPP PpIX conjugate delivery system activated by MMP-2 would be a promising strategy for tumor-targeted treatment. PMID- 26634785 TI - Selective Tuning of a Particular Chemical Reaction on Surfaces through Electrical Resonance: An ab Initio Molecular Dynamics Study. AB - We used ab initio molecular dynamics (AIMD) to investigate the effect of a monochromatic oscillating electric field in resonance with a particular molecular vibration on surfaces. As a case study, AIMD simulations were carried out for hydroxyl functional groups on graphene. When the frequency of the applied field matches with the C-OH vibration frequency, the amplitude is monotonically amplified, leading to a complete desorption from the surface, overcoming the substantial barrier. This suggests the possibility of activating a particular bond without damaging the remaining surface. We extended this work to the case of the amination of sp(2)-bonded carbon surfaces and discussed the general perspective that, in general, an unfavorable chemical process can be activated by applying an external electric field with an appropriate resonance frequency. PMID- 26634786 TI - The voltage-gated potassium channel Kv1.3 is a promising multitherapeutic target against human pathologies. AB - INTRODUCTION: The voltage-dependent potassium channel Kv1.3 is mainly present in the nervous and immune systems. In leukocytes, Kv1.3 fine-tunes the activation and proliferation of the immune response. However, Kv1.3 is also present in other tissues where its physiological role is still under investigation. Thus, Kv1.3 alterations have been related to several human diseases. AREAS COVERED: In this work, the authors highlight the role of Kv1.3 in various pathologies and the potential use of Kv1.3 blockers as safe pharmacological tools. The limited repertoire of K(+) channels in leukocytes and its expression pattern makes Kv1.3 crucial for effector memory T cell physiology and it is therefore a good pharmacological target for chronic inflammatory diseases. Moreover, Kv1.3 has been related to insulin sensitivity, cell proliferation and apoptosis. In this scenario, Kv1.3 activity is also implicated in non-insulin-dependent type II diabetes mellitus, obesity and cancer. EXPERT OPINION: Fortunately, Kv1.3 is characterized by a very selective and potent pharmacology that has been demonstrated to ameliorate autoimmune and metabolic symptoms in disease-animal models without major side effects. Moreover, Kv1.3 blockers are showing positive results in preclinical trials. Considering this evidence, the implication of Kv1.3 in a wide repertoire of human pathologies indicates this channel is an important therapeutic target. PMID- 26634787 TI - Recombination, Solvation and Reaction of CN Radicals Following Ultraviolet Photolysis of ICN in Organic Solvents. AB - The fates of CN radicals produced by ultraviolet (UV) photolysis of ICN in various organic solvents have been examined by transient electronic and vibrational absorption spectroscopy (TEAS and TVAS). Near-UV and visible bands in the TEAS measurement enable direct observation of the CN radicals and their complexes with the solvent molecules. Complementary TVAS measurements probe the products of CN-radical reactions. Geminate recombination to form ICN and INC is a minor pathway on the 150 fs -1300 ps time scales of our experiments in the chosen organic solvents; nonetheless, large infrared transition dipole moments permit direct observation of INC that is vibrationally excited in the C=N stretching mode. The time constants for INC vibrational cooling range from 30 ps in tetrahydrofuran (THF) to 1400 ps in more weakly interacting solvents such as chloroform. The major channel for CN removal in the organic solvents is reaction with solvent molecules, as revealed by depletion of solvent absorption bands and growth of product bands in the TVA spectra. HCN is a reaction product of hydrogen atom abstraction in most of the photoexcited solutions, and forms with vibrational excitation in both the C-H and C=N stretching modes. The vibrational cooling rate of the C=N stretch in HCN depends on the solvent, and follows the same trend as the cooling rate of the C=N stretch in INC. However, in acetonitrile solution an additional reaction pathway produces C3H3N2(*) radicals, which release HCN on a much longer time scale. PMID- 26634788 TI - Preparation and Characterization of Coaxial Electrospun Fibers Containing Triclosan for Comparative Study of Release Properties with Amoxicillin and Epicatechin. AB - The optimal conditions for the fibers preparation of cellulose acetate (CA) and poly(vinyl pyrrolidone) (PVP) containing triclosan within the fiber were successfully found; the physicochemical characteristics of these fibrous membranes were corroborated by FTIR spectroscopy, thermal analysis, mechanical tests, SEM , and TEM analysis. The formation of composite fibers of CA and PVP containing triclosan at the core of the fiber was evidenced. A comparative study of the release properties of amoxicillin, epicatechin or triclosan embedded into fibers CA/PVP/CA was performed. As more interactions of the drug with CA or PVP occur, slower release of the drug into the release medium takes place. Regarding the drug delivery system design, it is important to consider the possible molecular interactions between the material components and predict how fast or slow the drug will be delivered into the corresponding medium. PMID- 26634789 TI - Wound Healing Effect of an in Situ Forming Hydrogel Loading Curcumin-Phospholipid Complex. AB - Wound is one of most commonly clinical diseases. Curcumin is known to improve wound healing but its bioavailability and therapeutic efficiency are very low. Here we firstly report the application of phospholipid complexes to wound healing. A curcumin-phospholipid complex (CPC) was prepared with a solvent evaporation method. The X-ray diffraction showed that the CPC was amorphous, which was further demonstrated with the electron microscopy. Furthermore, the CPC was loaded into a poloxamer in situ forming hydrogel (ISG). The CPC ISG showed higher erosion rates than the curcumin ISG due to the amorphous structure of CPC, which could lead to increase in curcumin dissolution. The CPC ISG showed higher wound healing effect than the control on the rat skin wound model especially in the early phase. The epidermal recovery was highly improved by the CPC ISG compared to the control. The CPC ISG is a promising formulation as an effective wound healing dressing. PMID- 26634790 TI - Preparation and in vitro/in vivo Evaluation of Lacidipine by Adsorption onto Fumed Silica Using Supercritical Carbon Dioxide. AB - The aim of this study was to design a silica-supported solid dispersion of lacidipine (LCDP) to enhance the dissolution rate and oral absorption using supercritical CO2 (scCO2) as a solvent. The formulation was characterized using differential scanning calorimetry, powder X-ray diffraction, scanning electron microscopy and fourier transformed infrared spectroscopy. In the dissolution test, LCDP-scCO2 formulation showed a significantly enhanced dissolution compared with LCDPsilica physical mixture and a faster dissolution rate than Lacipil(r) under different dissolution conditions. In an in vivo test, the area under concentration-time curve and Cmax of LCDP-scCO2 formulation was 9.23 and 23.78 fold greater than LCDP-silica physical mixture (1:15, w/w), respectively, whereas the corresponding values were 1.92 and 2.80 fold greater than Lacipil(r), respectively. Our results showed that the solid dispersion prepared by supercritical fluids technology is a feasible method to enhance the oral bioavailability of LCDP. PMID- 26634791 TI - Last Advances in Nanocarriers-Based Drug Delivery Systems for Colorectal Cancer. AB - Colorectal cancer is the third most common type of cancer in both, men and women. The development of metastasis is very frequent, especially in patients with advanced stage, who require intensive chemotherapy that often results in poor response and significant morbidity. The undesirable effects of intensive chemotherapy on normal cells and the development of multidrug resistance are two of the main causes of treatment failure. Recent advances in nanotechnology allow to target cancer cells using cytotoxic drugs without affecting normal cells. Nanocarriers such as liposomes, polymeric nanoparticles and carbon nanotubes, among others, are able to improve drug distribution and bioavailability, cytotoxic concentration in the tumor mass and drug delivery to tumor tissue and, at the same time, reduce side effects. Current research studies are being conducted to develop new biomaterials that improve the characteristics of these nanomolecules. Several preclinical assays have disclosed the efficacy of nanotherapy in colon cancer, although further clinical trials will be necessary to demonstrate its efficacy. This review discusses the current status and the potential advantages of using nanocarrier-based drug delivery systems for colorectal cancer. PMID- 26634792 TI - Studies of the separation performance of silanized silica gel for simulated distillation. AB - We present the results of investigations of the chromatographic (sorptive) properties of silanized silica gel as a stationary phase for gas chromatography used for simulated distillation. Commercially available silanized sorbent (particle diameter range 63-200 MUm, average pore size 60 A) was sieved to obtain the 80-100 mesh fraction (180-150 MUm). The obtained results revealed that silanized silica gel allows the complete separation of a mixture of n- and iso alkanes in the C1 -C7 range. Such a separation is achieved with a temperature program starting with an initial temperature of 50C, which is advantageous because the gas chromatograph oven does not have to be cooled below room temperature. The use of temperature programming with a final temperature of 300C ensures separation and elution of all mixture components from C1 to n-C28 in one run. This study confirms the applicability of silanized silica gel as a stationary phase for the investigation of distillation temperature distribution of gasoline and diesel fuel based on the simulated distillation procedure according to ASTM D2887. The deviations of individual points of distillation curve obtained using ASTM D2887 and columns packed with silanized silica gel were within the reproducibility range of the standard procedure. PMID- 26634793 TI - Childhood physical activity body contact risk: feasibility of a novel technique for objective measurements of impact speed, frequency, and intentionality. AB - INTRODUCTION: Children at risk for bleeding injuries are restricted from body contact during physical activity but current recommendations are based on expert opinion. AIM: Evaluate high-speed digital video recording as an objective measure of body contact risk during physical activity. METHODS: Observational study of physical activities among healthy children, grouped according to participation in teams (vs. individual) and on their perceived risk of injury (high/low). High speed digital video recordings documented the collision target (floor/ground/ice, people, wall, equipment), estimated speed, and impact rates for team and individual activities, with and without expected body contact. RESULTS: Among 348 participating children (3-16 years, 51% female), 32% to 78% experienced at least one contact. Impact type varied significantly (chi-square, p < 0.001) by activity category. Unstructured and Team high risk activity impacts were primarily with the floor/ground, whereas Individual low risk activities were characterized by equipment impacts. Impact speeds were typically 1.0 to 2.1 m s(-1) . Higher impact speeds occurred during instructional classes (2.1 m s(-1) ), unstructured free swim (1.9 m s(-1) ) and ball hockey (1.7 m s(-1) ). Impact rates were higher during Team high risk and Team low risk sports (3.0 and 1.8 impacts per minute, respectively) compared to Individual (high or low risk) or Unstructured activities (0.2-0.3 impacts per minute). CONCLUSIONS: High speed video recordings of childhood physical activity are a feasible method for characterizing the frequency, type, direction and speed of impacts. Quantifying the impacts that occur during childhood physical activity could inform the guidelines for physical activity participation among children with identified bleeding risks. PMID- 26634795 TI - Dissecting the cyclic di-guanylate monophosphate signalling network regulating motility in Salmonella enterica serovar Typhimurium. PMID- 26634796 TI - Leonuketal, a Spiroketal Diterpenoid from Leonurus japonicus. AB - An architecturally complex spiroketal diterpenoid, leonuketal (1), was isolated from the aerial parts of the plant Leonurus japonicus. This compound possessed an unprecedented tetracyclic skeleton that comprised a bridged spiroketal moiety fused with a ketal-gamma-lactone unit. The structure and absolute configuration were determined by spectroscopic analyses, a modified Mosher's method, and ECD (electronic circular dichroism) calculations. Leonuketal (1) showed significant vasorelaxant activity against KCl-induced contraction of rat aorta, with the EC50 value of 2.32 MUM. PMID- 26634797 TI - Inhibition of the osteogenic differentiation of mesenchymal stem cells derived from the offspring of rats treated with caffeine during pregnancy and lactation. AB - Caffeine is an alkaloid that is widely consumed due to its presence in drugs, coffee, tea, and chocolate. This compound passes to offspring through the placenta and milk; can cause teratogenic mutations; and reduces the formation, growth, and mass of bone. Because mesenchymal stem cells (MSCs) are responsible for generating the entire skeleton, we hypothesized that these cells are targets of caffeine. This study evaluated the osteogenic differentiation of MSCs derived from the offspring of rats treated with caffeine during pregnancy and lactation. Twenty-four adult Wistar rats were randomly divided into four groups, including one control group and three experimental groups treated with 25, 50, or 100 mg/kg of caffeine. At weaning, three 21-day-old pups from each dam in each group were euthanized for extraction of bone marrow cells for in vitro tests. Caffeine doses of 50 and 100 mg/kg significantly reduced the activity of alkaline phosphatase at 7, 14, and 21 days and the expression of collagen I at 21 days. However, the expression of gene transcripts for alkaline phosphatase, Runx-2, and bone sialoprotein, as well as the synthesis of mineralization nodules, decreased significantly in all groups treated with caffeine. The expression of osteocalcin was significantly reduced only in the group treated with 50 mg/kg caffeine. The caffeine that passes from the mother to the offspring during pregnancy and lactation reduces the osteogenic differentiation of MSCs. We propose that this reduction in the osteogenic potential of MSCs may be involved in the pathogenesis of osteopenia resulting from caffeine consumption. PMID- 26634798 TI - Absolute Configuration Assignment of a Paraconic Acid Derivative via Vibrational Circular Dichroism Spectroscopy and Density Functional Theory Calculation. AB - Density functional theory calculation of the vibrational circular dichroism spectrum was used to assign the absolute configuration of an all-carbon quaternary beta-stereocenter of a gamma-butyrolactone recently synthesized through an asymmetric organocatalytic tandem aldol/lactonization sequence. Comparison with the experimental spectrum is satisfactory, on account of the fact that spectroscopic features are weak due to the presence of multiple conformers. As a result, the (R) absolute configuration was assigned to the (+) optical isomer. PMID- 26634799 TI - Spectrum of epidemiological and clinical findings in patients with heart failure with preserved ejection fraction stratified by study design: a systematic review. AB - BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) represents a major global and economic burden, but its epidemiological, clinical, and outcome data have varied according to study design. METHODS AND RESULTS: We conducted a systematic review of published HFpEF clinical trials and observational studies (community-based studies and registries) from August 1998 to July 2013 using PubMed and EMBASE databases. Two independent investigators manually screened and extracted relevant data. We included 62 articles (19 describing clinical trials, 12 describing community-based observational studies, and 31 describing registries). The ejection fraction (EF) cut-off values ranged widely for HFpEF from >40% to >55%. However, differences in EF cut-offs were not clearly associated with incidence and prevalence data across studies. Of all patients with heart failure in community studies, 33-84% had HFpEF, which tended to be higher than reported in registries. The HFpEF patients in included studies were primarily older, white (>70%) patients with hypertension (~50-90%) and coronary artery disease (up to 60%). All-cause mortality and all-cause hospitalizations ranged from 13% to 23% (26-50 months follow-up) and 55% to 67% (37-50 months follow-up), respectively, in clinical trials; cardiovascular causes accounted for 70% of both outcomes. All-cause mortality tended to be higher in registries than in clinical trials and community-based observational studies up to 5 years into follow-up. CONCLUSIONS: Important differences in EF thresholds, epidemiological indices, clinical profiles, treatment patterns, and outcomes exist across contemporary HFpEF clinical trials, observational studies, and registries. Precision in definition and inclusion of more uniform populations may facilitate improved profiling of HFpEF patients. PMID- 26634800 TI - Glycometabolic reprogramming associated with the initiation of human dental pulp stem cell differentiation. AB - Glycometabolism, particularly mitochondrial oxidative phosphorylation (OXPHOS) and glycolysis, plays a central role in cell life activities. Glycometabolism can be reprogrammed to maintain the stemness or to induce the differentiation of stem cells, thereby regulating tissue repair and regeneration. However, research on the glycometabolism of human dental pulp stem cells (hDPSCs) remains scarce. Here, we investigated the relationship between glycometabolic reprogramming and initiation of hDPSC differentiation. We found the differentiation of hDPSCs commenced on day 3 when cells were cultured in mineralized medium. When cell differentiation commenced, mitochondria became elongated with well-developed cristae, and the oxygen consumption rate of mitochondria was enhanced, manifested as an increase in basal respiration, mitochondrial ATP production, and maximal respiration. Interestingly, glycolytic enzyme activities, glycolysis capacity, and glycolysis reserve were also upregulated at this time to match the powerful bioenergetic demands. More importantly, hDPSCs derived from different donors or cultured in various oxygen environments showed similar glycometabolic changes when they began to differentiate. Thus, glycometabolic reprogramming accompanies initiation of hDPSC differentiation and could potentially play a role in the regulation of dental pulp repair. PMID- 26634801 TI - Utilizing an o-Quinone Methide in Asymmetric Transfer Hydrogenation: Enantioselective Synthesis of Brosimine A, Brosimine B, and Brosimacutin L. AB - A concise and highly enantioselective synthesis of the flavonoids brosimine A, brosimine B, and brosimacutin L is reported for the first time. The key transformation is a single-step conversion of a flavanone into a flavan by means of an asymmetric transfer hydrogenation/deoxygenation cascade. PMID- 26634802 TI - Management of aneurysmal subarachnoid haemorrhage with intracerebral hematoma: Is there an indication for coiling first? Study of 44 cases. AB - BACKGROUND: Aneurysmal subarachnoid haemorrhage (ASH) with intracerebral hematoma (ICH) has a poor prognosis. The treatment is to secure the aneurysm and do an ICH evacuation. OBJECTIVE: The aim of the study was to determine if aneurysm coiling followed by ICH evacuation is a viable alternative treatment compared to exclusive surgery, regardless of the clinical or paraclinical presentations. METHODS: A retrospective study was conducted between 2004 and 2014, which included 44 patients. The patients were divided up in four groups. Two were principal groups: The clipped group (aneurysm clipping with ICH evacuation) and the coiled group (aneurysm coiling, followed by ICH evacuation); and two were subgroups of the latter: Aneurysm coiling with ICH evacuation after 24 hours and ICH evacuation followed by aneurysm coiling. We studied the demographic and radiologic characteristics, and the 3-month outcome. RESULTS: We included 17 patients in the coiled group: The outcome was better for the patients with World Federation of Neurosurgery (WFNS) scores of 1, 2 and 3; compared to the patients with WFNS scores 4 and 5. We included 16 patients in the clipped group: The outcome was better, compared the coiled group, for those patients with WFNS scores 4 and 5. Six patients were treated with aneurysm coiling, followed by ICH evacuation after 24 hours: 33% had a good outcome. Five patients were treated by ICH evacuation, followed by aneurysm coiling: None had a good outcome. CONCLUSIONS: It was necessary to realise a prospective study to compare the outcomes of patients with WFNS scores of 1, 2 or 3; between those with aneurysm coiling followed by ICH evacuation and aneurysm clipping with ICH evacuation, to determine the potential of using the coiling first, for these patients. PMID- 26634803 TI - Endovascular coiling of small intracranial aneurysms using a very soft bare platinum coil: A comparison of the packing performance of new and old HyperSoft(r) helical coils. AB - AIMS: Soft and small coils are known to be appropriate for the treatment of small aneurysms. The purpose of this study was to determine whether the new HyperSoft(r) helical coil, which is softer and smaller than its predecessors, has any effect on the packing performance in a matched-pair study with an old HyperSoft(r) helical coil. MATERIALS AND METHODS: Thirty-six consecutive patients harboring 43 cerebral aneurysms treated with new HyperSofts were included in this study. Forty-one aneurysms treated with old HyperSofts were identified from our database as matched controls based on similar volumes and locations. Packing attenuation, adverse events during the procedures, and angiographic occlusions were observed and compared between the two groups. RESULTS: The mean packing density was significantly higher in the new HyperSoft(r) group compared to the control group (35.5% vs. 26.9%), and a larger proportion of the aneurysms embolized with the 1.5 mm size coil, which has higher packing density. There was no difference in immediate and midterm angiographic outcomes. There was no difference in the rate of intraprocedural perforation, but there was no intraprocedural rupture related to the 1.5 mm coil. CONCLUSIONS: The use of new HyperSoft(r) helical coils allows higher packing density comparable with the old technology. New HyperSoft(r) coils, especially those with 1.5 mm loop diameter, can be expected to fill smaller residual spaces in small aneurysms and may be helpful in preventing recanalization. PMID- 26634804 TI - Antidiabetic Effects of Simple Phenolic Acids: A Comprehensive Review. AB - Diabetes mellitus (DM) has become a major public health threat across the globe. Current antidiabetic therapies are based on synthetic drugs that very often have side effects. It has been widely acknowledged that diet plays an important role in the management of diabetes. Phenolic acids are widely found in daily foods such as fruits, vegetables, cereals, legumes, and wine and they provide biological, medicinal, and health properties. Simple phenolic acids have been shown to increase glucose uptake and glycogen synthesis, improve glucose and lipid profiles of certain diseases (obesity, cardiovascular diseases, DM, and its complication). The current review is an attempt to list out the antidiabetic effects of simple phenolic acids from medicinal plants and botanical foods. PMID- 26634805 TI - Increased Risk of Adverse Renal Outcome Following Polyethylene Glycol Bowel Preparation Compared to Sodium Picosulfate. PMID- 26634808 TI - A Packaged Self-Powered System with Universal Connectors Based on Hybridized Nanogenerators. AB - A packaged self-powered system by hybridizing nanogenerators (PSNGS) is demonstrated. The performance of the PSNGS is tested in a biofluid and used for powering an electronic thermometer. Select waterproof universal connectors are designed and fabricated for energy and signal transmission. This PSNGS and the connectors can significantly advance the development of self-powered implanted medical devices and wearable/portable electronics. PMID- 26634806 TI - Mammalian SRP receptor switches the Sec61 translocase from Sec62 to SRP-dependent translocation. AB - Two distinct pathways deliver secretory proteins to the Sec61 protein translocase in the endoplasmic reticulum membrane. The canonical pathway requires the signal recognition particle (SRP) and its cognate receptor (SR), and targets ribosome associated proteins to the Sec translocase. The SRP-independent pathway requires the Sec translocase-associated ER membrane protein Sec62 and can be uncoupled from translation. Here we show that SR switches translocons to SRP-dependent translocation by displacing Sec62. This activity localizes to the charged linker region between the longin and GTPase domains of SRalpha. Using truncation variants, crosslinking and translocation assays reveals two elements with distinct functions as follows: one rearranges the translocon, displacing Sec62 from Sec61. A second promotes ribosome binding and is conserved between all eukaryotes. These specific regions in SRalpha reprogramme the Sec translocon and facilitate recruitment of ribosome-nascent chain complexes. Overall, our study identifies an important function of SR, which mechanistically links two seemingly independent modes of translocation. PMID- 26634807 TI - Stem cell-derived astrocytes: are they physiologically credible? AB - Astrocytes are now increasingly acknowledged as having fundamental and sophisticated roles in brain function and dysfunction. Unravelling the complex mechanisms that underlie human brain astrocyte-neuron interactions is therefore an essential step on the way to understanding how the brain operates. Insights into astrocyte function to date have almost exclusively been derived from studies conducted using murine or rodent models. Whilst these have led to significant discoveries, preliminary work with human astrocytes has revealed a hitherto unknown range of astrocyte types with potentially greater functional complexity and increased neuronal interaction with respect to animal astrocytes. It is becoming apparent, therefore, that many important functions of astrocytes will only be discovered by direct physiological interrogation of human astrocytes. Recent advancements in the field of stem cell biology have provided a source of human-based models. These will provide a platform to facilitate our understanding of normal astrocyte functions as well as their role in CNS pathology. A number of recent studies have demonstrated that stem cell-derived astrocytes exhibit a range of properties, suggesting that they may be functionally equivalent to their in vivo counterparts. Further validation against in vivo models will ultimately confirm the future utility of these stem cell-based approaches in fulfilling the need for human-based cellular models for basic and clinical research. In this review we discuss the roles of astrocytes in the brain and highlight the extent to which human stem cell-derived astrocytes have demonstrated functional activities that are equivalent to those observed in vivo. PMID- 26634809 TI - 1,4-Dihydropyridine derivatives without Ca2+-antagonist activity up-regulate Psma6 mRNA expression in kidneys of intact and diabetic rats. AB - Impaired degradation of proteins by the ubiquitin-proteasome system (UPS) is observed in numerous pathologies including diabetes mellitus (DM) and its complications. Dysregulation of proteasomal degradation might be because of altered expression of genes and proteins involved in the UPS. The search for novel compounds able to normalize expression of the UPS appears to be a topical problem. A novel group of 1,4-dihydropyridine (1,4-DHP) derivatives lacking Ca2+ antagonists activities, but capable to produce antidiabetic, antioxidant and DNA repair enhancing effects, were tested for ability to modify Psma6 mRNA expression levels in rat kidneys and blood in healthy animals and in rats with streptozotocin (STZ) induced DM. Psma6 gene was chosen for the study, as polymorphisms of its human analogue are associated with DM and cardiovascular diseases. 1,4-DHP derivatives (metcarbatone, etcarbatone, glutapyrone, J-9-125 and AV-153-Na) were administered per os for three days (0.05 mg/kg and/or 0.5 mg/kg). Psma6 gene expression levels were evaluated by quantitative PCR. Psma6 expression was higher in kidneys compared to blood. Induction of diabetes caused increase of Psma6 expression in kidneys, although it was not changed in blood. Several 1,4-DHP derivatives increased expression of the gene both in kidneys and blood of control and model animals, but greater impact was observed in kidneys. The observed effect might reflect coupling of antioxidant and proteolysis promoting activities of the compounds. PMID- 26634810 TI - Enzyme-guided DNA Sewing Architecture. AB - With the advent of nanotechnology, a variety of nanoarchitectures with varied physicochemical properties have been designed. Owing to the unique characteristics, DNAs have been used as a functional building block for novel nanoarchitecture. In particular, a self-assembly of long DNA molecules via a piece DNA staple has been utilized to attain such constructs. However, it needs many talented prerequisites (e.g., complicated computer program) with fewer yields of products. In addition, it has many limitations to overcome: for instance, (i) thermal instability under moderate environments and (ii) restraint in size caused by the restricted length of scaffold strands. Alternatively, the enzymatic sewing linkage of short DNA blocks is simply designed into long DNA assemblies but it is more error-prone due to the undeveloped sequence data. Here, we present, for the first time, a comprehensive study for directly combining DNA structures into higher DNA sewing constructs through the 5'-end cohesive ligation of T4 enzyme. Inspired by these achievements, the synthesized DNA nanomaterials were also utilized for effective detection and real-time diagnosis of cancer specific and cytosolic RNA markers. This generalized protocol for generic DNA sewing is expected to be useful in several DNA nanotechnology as well as any nucleic acid-related fields. PMID- 26634811 TI - Theoretical assessment of feasibility to sequence DNA through interlayer electronic tunneling transport at aligned nanopores in bilayer graphene. AB - Fast, cost effective, single-shot DNA sequencing could be the prelude of a new era in genetics. As DNA encodes the information for the production of proteins in all known living beings on Earth, determining the nucleobase sequences is the first and necessary step in that direction. Graphene-based nanopore devices hold great promise for next-generation DNA sequencing. In this work, we develop a novel approach for sequencing DNA using bilayer graphene to read the interlayer conductance through the layers in the presence of target nucleobases. Classical molecular dynamics simulations of DNA translocation through the pore were performed to trace the nucleobase trajectories and evaluate the interaction between the nucleobases and the nanopore. This interaction stabilizes the bases in different orientations, resulting in smaller fluctuations of the nucleobases inside the pore. We assessed the performance of a bilayer graphene nanopore setup for the purpose of DNA sequencing by employing density functional theory and non equilibrium Green's function method to investigate the interlayer conductance of nucleobases coupling simultaneously to the top and bottom graphene layers. The obtained conductance is significantly affected by the presence of DNA in the bilayer graphene nanopore, allowing us to analyze DNA sequences. PMID- 26634812 TI - Extracellular vesicle long noncoding RNA as potential biomarkers of liver cancer. AB - Analysis of extracellular vesicles (EV) and their contents may be useful as disease biomarkers if they reflect the contents of cells of origin, differ between normal and diseased tissue and can be reliably detected. An increasing number of long noncoding RNA (lncRNA) are being reported to be aberrantly expressed in human cancers. These tumor-associated lncRNA may have potential as new biomarkers of disease. In this review, we highlight lncRNAs that are commonly associated with hepatocellular cancer, and summarize their potential biological roles and underlying molecular mechanisms. While lncRNA can be detected in the circulation, their low expression within circulating vesicles will require the use of highly sensitive detection technologies such as digital polymerase chain reaction or next-generation sequencing. While the integrity and functional role of tumor-specific lncRNAs within EV have yet to be established, their presence or enrichment within tumor cell-derived EV offers promise for their potential as disease biomarkers. PMID- 26634813 TI - Silicon etching using only Oxygen at high temperature: An alternative approach to Si micro-machining on 150 mm Si wafers. AB - Using a combination of low-pressure oxygen and high temperatures, isotropic and anisotropic silicon (Si) etch rates can be controlled up to ten micron per minute. By varying the process conditions, we show that the vertical-to-lateral etch rate ratio can be controlled from 1:1 isotropic etch to 1.8:1 anisotropic. This simple Si etching technique combines the main respective advantages of both wet and dry Si etching techniques such as fast Si etch rate, stiction-free, and high etch rate uniformity across a wafer. In addition, this alternative O2-based Si etching technique has additional advantages not commonly associated with dry etchants such as avoiding the use of halogens and has no toxic by-products, which improves safety and simplifies waste disposal. Furthermore, this process also exhibits very high selectivity (>1000:1) with conventional hard masks such as silicon carbide, silicon dioxide and silicon nitride, enabling deep Si etching. In these initial studies, etch rates as high as 9.2 MUm/min could be achieved at 1150 degrees C. Empirical estimation for the calculation of the etch rate as a function of the feature size and oxygen flow rate are presented and used as proof of concepts. PMID- 26634814 TI - CB1 cannabinoid receptor enrichment in the ependymal region of the adult human spinal cord. AB - Cannabinoids are involved in the regulation of neural stem cell biology and their receptors are expressed in the neurogenic niches of adult rodents. In the spinal cord of rats and mice, neural stem cells can be found in the ependymal region, surrounding the central canal, but there is evidence that this region is largely different in adult humans: lacks a patent canal and presents perivascular pseudorosettes, typically found in low grade ependymomas. Using Laser Capture Microdissection, Taqman gene expression assays and immunohistochemistry, we have studied the expression of endocannabinoid system components (receptors and enzymes) at the human spinal cord ependymal region. We observe that ependymal region is enriched in CB1 cannabinoid receptor, due to high CB1 expression in GFAP+ astrocytic domains. However, in human spinal cord levels that retain central canal patency we found ependymal cells with high CB1 expression, equivalent to the CB1(HIGH) cell subpopulation described in rodents. Our results support the existence of ependymal CB1(HIGH) cells across species, and may encourage further studies on this subpopulation, although only in cases when central canal is patent. In the adult human ependyma, which usually shows central canal absence, CB1 may play a different role by modulating astrocyte functions. PMID- 26634815 TI - Low-temperature synthesis of high-ordered anatase TiO2 nanotube array films coated with exposed {001} nanofacets. AB - High-ordered anatase TiO2 nanotube array films coated with exposed high-reactive {001} nanofacets were fabricated by a modified hydrothermal method using amorphous anodic TiO2 nanotube arrays (ATONAs) as starting materials. It was found that the reaction between gas phase HF and solid ATONAs played a key role in the transformation process from amorphous to anatase TiO2, and the TiO2 tubular structure kept unchanged during the surface modification with an exposed {001} facets up to 76.5%, which could be attributed to the low reaction temperature of 130 degrees C. Our study provided a novel route for the facile preparation of {001} facets exposed anatase TiO2. PMID- 26634816 TI - Direct Observation of the Biaxial Stress Effect on Efficiency Droop in GaN-based Light-emitting Diode under Electrical Injection. AB - Light-emitting diode (LED) efficiency has attracted considerable interest because of the extended use of solid-state lighting. Owing to lack of direct measurement, identification of the reasons for efficiency droop has been restricted. A direct measurement technique is developed in this work for characterization of biaxial stress in GaN-based blue LEDs under electrical injection. The Raman shift of the GaN E2 mode evidently decreases by 4.4 cm(-1) as the driving current on GaN-based LEDs increases to 700 mA. Biaxial compressive stress is released initially and biaxial tensile stress builds up as the current increases with respect to the value of stress-free GaN. First-principles calculations reveal that electron accumulation is responsible for the stress variation in InxGa1-xN/GaN quantum wells, and then reduces the transition probability among quantum levels. This behavior is consistent with the measured current-dependent external quantum efficiency. The rule of biaxial stress-dependent efficiency is further validated by controlling the biaxial stress of GaN-based LEDs with different sapphire substrate thicknesses. This work provides a method for direct observation of the biaxial stress effect on efficiency droop in LEDs under electrical injection. PMID- 26634817 TI - Real-space collapse of a polariton condensate. AB - Microcavity polaritons are two-dimensional bosonic fluids with strong nonlinearities, composed of coupled photonic and electronic excitations. In their condensed form, they display quantum hydrodynamic features similar to atomic Bose Einstein condensates, such as long-range coherence, superfluidity and quantized vorticity. Here we report the unique phenomenology that is observed when a pulse of light impacts the polariton vacuum: the fluid which is suddenly created does not splash but instead coheres into a very bright spot. The real-space collapse into a sharp peak is at odd with the repulsive interactions of polaritons and their positive mass, suggesting that an unconventional mechanism is at play. Our modelling devises a possible explanation in the self-trapping due to a local heating of the crystal lattice, that can be described as a collective polaron formed by a polariton condensate. These observations hint at the polariton fluid dynamics in conditions of extreme intensities and ultrafast times. PMID- 26634818 TI - The genome sequence of Sea-Island cotton (Gossypium barbadense) provides insights into the allopolyploidization and development of superior spinnable fibres. AB - Gossypium hirsutum contributes the most production of cotton fibre, but G. barbadense is valued for its better comprehensive resistance and superior fibre properties. However, the allotetraploid genome of G. barbadense has not been comprehensively analysed. Here we present a high-quality assembly of the 2.57 gigabase genome of G. barbadense, including 80,876 protein-coding genes. The double-sized genome of the A (or At) (1.50 Gb) against D (or Dt) (853 Mb) primarily resulted from the expansion of Gypsy elements, including Peabody and Retrosat2 subclades in the Del clade, and the Athila subclade in the Athila/Tat clade. Substantial gene expansion and contraction were observed and rich homoeologous gene pairs with biased expression patterns were identified, suggesting abundant gene sub-functionalization occurred by allopolyploidization. More specifically, the CesA gene family has adapted differentially temporal expression patterns, suggesting an integrated regulatory mechanism of CesA genes from At and Dt subgenomes for the primary and secondary cellulose biosynthesis of cotton fibre in a "relay race"-like fashion. We anticipate that the G. barbadense genome sequence will advance our understanding the mechanism of genome polyploidization and underpin genome-wide comparison research in this genus. PMID- 26634819 TI - Glial expression of Swiss cheese (SWS), the Drosophila orthologue of neuropathy target esterase (NTE), is required for neuronal ensheathment and function. AB - Mutations in Drosophila Swiss cheese (SWS) or its vertebrate orthologue neuropathy target esterase (NTE), respectively, cause progressive neuronal degeneration in Drosophila and mice and a complex syndrome in humans that includes mental retardation, spastic paraplegia and blindness. SWS and NTE are widely expressed in neurons but can also be found in glia; however, their function in glia has, until now, remained unknown. We have used a knockdown approach to specifically address SWS function in glia and to probe for resulting neuronal dysfunctions. This revealed that loss of SWS in pseudocartridge glia causes the formation of multi-layered glial whorls in the lamina cortex, the first optic neuropil. This phenotype was rescued by the expression of SWS or NTE, suggesting that the glial function is conserved in the vertebrate protein. SWS was also found to be required for the glial wrapping of neurons by ensheathing glia, and its loss in glia caused axonal damage. We also detected severe locomotion deficits in glial sws-knockdown flies, which occurred as early as 2 days after eclosion and increased further with age. Utilizing the giant fibre system to test for underlying functional neuronal defects showed that the response latency to a stimulus was unchanged in knockdown flies compared to controls, but the reliability with which the neurons responded to increasing frequencies was reduced. This shows that the loss of SWS in glia impairs neuronal function, strongly suggesting that the loss of glial SWS plays an important role in the phenotypes observed in the sws mutant. It is therefore likely that changes in glia also contribute to the pathology observed in humans that carry mutations in NTE. PMID- 26634821 TI - Searching for the definition of macrosomia through an outcome-based approach in low- and middle-income countries: a secondary analysis of the WHO Global Survey in Africa, Asia and Latin America. AB - BACKGROUND: No consensus definition of macrosomia currently exists among researchers and obstetricians. We aimed to identify a definition of macrosomia that is more predictive of maternal and perinatal mortality and morbidity in low- and middle-income countries. METHODS: We conducted a secondary data analysis using WHO Global Survey on Maternal and Perinatal Health data on Africa and Latin America from 2004 to 2005 and Asia from 2007 to 2008. We compared adverse outcomes, which were assessed by the composite maternal mortality and morbidity index (MMMI) and perinatal mortality and morbidity index (PMMI) in subgroups with birthweight (3000-3499 g [reference group], 3500-3999 g, 4000-4099 g, 4100-4199 g, 4200-4299 g, 4300-4399 g, 4400-4499 g, 4500-4999 g) or country-specific birthweight percentile for gestational age (50(th)-74(th) percentile [reference group], 75(th)-89(th), 90(th)-94(th), 95(th)-96(th), and >=97(th) percentile). Two-level logistic regression models were used to estimate odds ratios of MMMI and PMMI. RESULTS: A total of 246,659 singleton term births from 363 facilities in 23 low- and middle-income countries were included. Adjusted odds ratios (aORs) for intrapartum caesarean sections exceeded 2.0 when birthweight was greater than 4000 g (2.00 [95% CI: 1.68, 2.39], 2.42 [95% CI: 2.02, 2.89], 2.01 [95% CI: 1.74, 2.33] in Africa, Asia and Latin America, respectively). aORs of MMMI reached 2.0 when birthweight was greater than 4000 g, 4500 g in Asia and Africa, respectively. aORs of PMMI approached to 2.0 (1.78 [95% CI: 1.16, 2.74]) when birthweight was greater than 4500 g in Latin America. When birthweight was at the 90(th) percentile or higher, aORs of MMMI and PMMI increased, but none exceeded 2.0. CONCLUSIONS: The population-specific definition of macrosomia using birthweight cut-off points irrespective of gestational age (4500 g in Africa and Latin America, 4000 g in Asia) is more predictive of maternal and perinatal adverse outcomes, and simpler to apply compared to the definition based on birthweight percentile for a given gestational age. PMID- 26634822 TI - Laparoscopic cholecystectomy under spinal anaesthesia vs. general anaesthesia: a meta-analysis of randomized controlled trials. AB - BACKGROUND: Laparoscopic Cholecystectomy (LC) is conventionally performed under general anaesthesia (GA), but there are multiple studies which have found spinal anaesthesia (SA) as a safe alternative. This meta-analysis was performed after adding many recent randomized controlled trials (RCTs) to clarify this issue. METHODS: Relevant articles published in English were identified by searching PubMed, Embase, Web of Knowledge, and the Cochrane Controlled Trial Register from January 1, 2000 to December 1, 2014. Reference lists of the retrieved articles were reviewed to identify additional articles. Primary outcomes (postoperative pain scores) and secondary outcomes (operating time (OT) and postoperative complications) were pooled. Quantitative variables were calculated using the weighted mean difference (WMD), and qualitative variables were pooled using odds ratios (OR). RESULTS: Seven appropriate RCTs were identified from 912 published articles. Seven hundred and twelve patients were treated, 352 in SA group and 360 in GA group. LC under SA was superior to LC under GA in postoperative pain within 12 h (visual analogue score (VAS) in 2-4 h, WMD = -1.61, P = 0.000; VAS in 6-8 h, WMD = -1.277, P = 0.015) and postoperative complications (postoperative nausea and vomiting (PONV) WMD = 0.427, P = 0.001; Overall Morbidity WMD = 0.691, P = 0.027). The GA group was superior to SA group in postoperative urinary retention (WMD = 4.273, P = 0.022). There were no significant differences in operating time (WMD = 0.184, P = 0.141) between two groups. CONCLUSIONS: SA as the sole anaesthesia technique is feasible, safe for elective LC. PMID- 26634820 TI - SerpinB3 and Yap Interplay Increases Myc Oncogenic Activity. AB - SerpinB3 has been recently described as an early marker of liver carcinogenesis, but the potential mechanistic role of this serpin in tumor development is still poorly understood. Overexpression of Myc often correlates with more aggressive tumour forms, supporting its involvement in carcinogenesis. Yes-associated protein (Yap), the main effector of the Hippo pathway, is a central regulator of proliferation and it has been found up-regulated in hepatocellular carcinomas. The study has been designed to investigate and characterize the interplay and functional modulation of Myc by SerpinB3 in liver cancer. Results from this study indicate that Myc was up-regulated by SerpinB3 through calpain and Hippo dependent molecular mechanisms in transgenic mice and hepatoma cells overexpressing human SerpinB3, and also in human hepatocellular carcinomas. Human recombinant SerpinB3 was capable to inhibit the activity of Calpain in vitro, likely reducing its ability to cleave Myc in its non oncogenic Myc-nick cytoplasmic form. SerpinB3 indirectly increased the transcription of Myc through the induction of Yap pathway. These findings provide for the first time evidence that SerpinB3 can improve the production of Myc through direct and indirect mechanisms that include the inhibition of generation of its cytoplasmic form and the activation of Yap pathway. PMID- 26634825 TI - Oviposition Behavior in Aedes aegypti and Aedes albopictus (Diptera: Culicidae) in Response to the Presence of Heterospecific and Conspecific Larvae. AB - In mosquitoes, location of suitable sites for oviposition requires a set of visual, tactile, and olfactory cues that influences females before laying their eggs. The ability of gravid females to distinguish among potential oviposition sites that will or will not support the growth, development, and survival of their progeny is critical. Aedes aegypti (L.) and Aedes albopictus (Skuse) share ecological niches, being highly competitive in larval stage. We studied the oviposition behavior of both species in the presence of larvae of one or the other species (heterospecific or conspecific larvae). The number of eggs laid by gravid females on oviposition sites (water with different or the same species of Aedes larvae) were compared. The presence and density of heterospecific or conspecific larvae had a positive or negative effect on the ovipositional responses, measured as an oviposition activity index. For both species, the oviposition was not affected by heterospecific larvae with densities between 10 and 100 larvae in water, but a strong attractant behavior was observed for a density of 500 larvae in water. For Ae. albopictus in the presence of larvae of the same species (conspecific oviposition), we observed an attractant effect for larvae density of 10 but not for 100 or 500 larvae in water. Instead, for Ae. aegypti, we observed attraction only for 100 larvae, not for 10 or 500 larvae. Results presented here provide an additional insight about oviposition behavior responses of gravid females in the presence of conspecific and heterospecific larvae in breeding sites. PMID- 26634824 TI - Clinical-pathological findings of otitis media and media-interna in calves and (clinical) evaluation of a standardized therapeutic protocol. AB - BACKGROUND: The aims of this field trial were to describe the clinical-pathologic findings in calves with otitis media (OM) and media-interna (OMI), to evaluate, through the development of a scoring system, the effectiveness of a standardized therapeutic protocol, and to identify the causative pathogens and their possible correlation with concurrent respiratory disease. All animals underwent physical and neurological examinations at three experimental time points: at diagnosis/beginning of treatment (T0), 1 week (T1) and 2 weeks (T2) after therapy was started, respectively. Follow-up telephone interviews with animal owners were conducted 1 month later. The therapeutic protocol consisted of tulathromycin (Draxxin(r); Zoetis), oxytetracycline hydrochloride (Terramicina 100(r); Zoetis), and carprofen (Rimadyl(r); Zoetis). RESULTS: Twenty-two calves were enrolled. Physical and otoscopic examination at T0 revealed monolateral and bilateral otorrhea in 16 and 6 calves, respectively, with peripheral vestibular system involvement in calves presenting with neurological signs (n = 17; 77 %). A significant improvement of clinical and neurological scores was observed in 20 (90 %) calves, a full recovery in only 1 (5 %). One calf worsened between T0 and T1 and it was removed from the study. None of the other animals showed a worsening of clinical conditions and/or required further treatments at one month follow up. Mycoplasma bovis was isolated in 89 % of the affected ears either alone or together with P. multocida (n = 5), Streptococcus spp. (n = 1), Staphylococcus spp. (n = 1), and Pseudomonas spp. (n = 1). M. bovis either alone or together with these bacteria was also isolated from the upper and/or lower respiratory tract in 19 (86 %) calves. CONCLUSIONS: This is the first prospective study to evaluate the effectiveness of a standardized therapeutic protocol for the treatment of OM/OMI in calves. The therapy led to clinical improvement in the majority of the calves. Persistence of mild clinical-neurological signs did not compromise productive performance. The numerical scoring system for clinical and neurological signs permitted objective evaluation of response to therapy. M. bovis was the pathogen most often isolated. This finding should be considered in the treatment of OM/OMI in calves. Moreover, respiratory tract infection should not be underrated, since it is one of the major risk factors for the development of OM/OMI. PMID- 26634826 TI - Image findings of cranial nerve pathology on [18F]-2- deoxy-D-glucose (FDG) positron emission tomography with computerized tomography (PET/CT): a pictorial essay. AB - This article aims to increase awareness about the utility of (18)F -FDG-PET/CT in the evaluation of cranial nerve (CN) pathology. We discuss the clinical implication of detecting perineural tumor spread, emphasize the primary and secondary (18)F -FDG-PET/CT findings of CN pathology, and illustrate the individual (18)F -FDG-PET/CT CN anatomy and pathology of 11 of the 12 CNs. PMID- 26634827 TI - A voyage to Terra Australis: human-mediated dispersal of cats. AB - BACKGROUND: Cats have been transported as human commensals worldwide giving rise to many feral populations. In Australia, feral cats have caused decline and extinction of native mammals, but their time of introduction and origin is unclear. Here, we investigate hypotheses of cat arrival pre- or post-European settlement, and the potential for admixture between cats of different invasion events. We analyse the genetic structure and diversity of feral cats from six locations on mainland Australia, seven Australian islands and samples from Southeast Asia and Europe using microsatellite and mitochondrial DNA data. RESULTS: Our results based on phylogeographic model selection are consistent with a European origin of cats in Australia. We find genetic distinctiveness of Australian mainland samples compared with Dirk Hartog Island, Flinders Island, Tasman Island and Cocos (Keeling) Island samples, and genetic similarities between some of the island populations. Historical records suggest that introduction of cats to these islands occurred at the time of European exploration and/or in connection with the pearling, whaling and sealing trades early in the 19th century. On-going influx of domestic cats into the feral cat population is apparently causing the Australian mainland populations to be genetically differentiated from those island populations, which likely are remnants of the historically introduced cat genotypes. CONCLUSION: A mainly European origin of feral cats in Australia, with possible secondary introductions from Asia following the initial establishment of cats in Australia is reasonable. The islands surrounding Australia may represent founding populations and are of particular interest. The results of the study provide an important timeframe for the impact of feral cats on native species in Australia. PMID- 26634829 TI - An unusual initial presentation of mantle cell lymphoma arising from the lymphoid stroma of warthin tumor. AB - BACKGROUND: Warthin tumors presenting concomitantly with a lymphoma is vanishingly rare with only 15 reported cases in English literature. Herein, we report an unusual initial presentation of a mantle cell lymphoma involving the lymphoid stroma of a Warthin tumor. CASE PRESENTATION: A seventy-seven year old otherwise healthy gentleman with a 50-pack year smoking history presents with a slowly enlarging left cheek mass. CT scan of the neck demonstrated a left parotid gland tumor measuring 3.4 cm in greatest dimension. He underwent a left superficial parotidectomy, with subsequent histopathologic examination revealing a Warthin tumor with extensive expansion of the lymphoid stroma. Flow cytometric, immunohistochemical, and cytogenetic studies of the stromal component of the tumor confirmed the presence of a mantle cell lymphoma. Clinical staging demonstrated stage IVa disease, and was considered to be at low to intermediate risk due to the slow growth of the parotid lesion. The patient is undergoing close follow up with repeat PET-CT scans at six months. CONCLUSION: To the best of our knowledge, this is the first well documented collision tumor between mantle cell lymphoma and a Warthin tumor. This case also brings to light the significance of thorough evaluation of the lymphoid component of Warthin tumor. PMID- 26634828 TI - Clinical outcomes and neural correlates of 20 sessions of repetitive transcranial magnetic stimulation in severe and enduring anorexia nervosa (the TIARA study): study protocol for a randomised controlled feasibility trial. AB - BACKGROUND: Anorexia nervosa (AN) is a serious mental disorder with multiple comorbidities and complications. In those with a severe and enduring form of the illness (SEED-AN), treatment responsivity is poor and the evidence base limited. Thus, there is a need for novel treatment strategies. This paper describes the theoretical background and protocol of a feasibility randomised controlled trial (RCT) of real versus sham (placebo) therapeutic repetitive transcranial magnetic stimulation (rTMS) in SEED-AN. The aim of this trial is to obtain information that will guide decision making and protocol development in relation to a future large-scale RCT of rTMS in this group of patients, and also to assess the preliminary efficacy and neural correlates of rTMS treatment. DESIGN: Forty-four adults from the community with a DSM-5 diagnosis of AN, an illness duration>3 years and a previous course of unsuccessful treatment will be randomly allocated to receive 20 sessions of either real or sham rTMS, in a parallel group design. As this is a feasibility study, no primary outcome has been defined and a broad range of outcome variables will be examined. These include weight/body mass index (BMI), eating disorder psychopathology, other psychopathology (for example, depression, anxiety), quality of life, neuropsychological processes (such as self regulation, attentional bias and food choice behaviour), neuroimaging measures (that is, changes in brain structure or function), tolerability and acceptability of rTMS, and additional service utilisation. The feasibility of conducting a large-scale RCT of rTMS and the appropriateness of rTMS as a treatment for SEED AN will be evaluated through: assessment of recruitment and retention rates, acceptability of random allocation, blinding success (allocation concealment), completion of treatment sessions and research assessments (baseline, post treatment and follow-up assessments). The acceptability and tolerability of the treatment will be assessed via semi-structured interviews. DISCUSSION: The effect sizes generated and other findings from this trial will inform a future large scale RCT with respect to decisions on primary outcome measures and other aspects of protocol development. Additionally, results from this study will provide a preliminary indication of the efficacy of rTMS treatment for AN, the neural correlates of the illness, and potential biomarkers of clinical response. TRIAL REGISTRATION: ISRCTN14329415 . Date of registration: 23 July 2015. PMID- 26634830 TI - Clinical and radiographic outcomes of a trabecular titaniumTM acetabular component in hip arthroplasty: results at minimum 5 years follow-up. AB - BACKGROUND: Aim of this prospective study was to evaluate mid-term clinical and radiographic outcomes in total hip arthroplasty using an acetabular cup made of an innovative biomaterial, Trabecular TitaniumTM, whose highly porous structure and mechanical properties have been designed to mimic those of the natural bone, thus promoting a more physiological load transfer and a more durable fixation. METHODS: Between September 2007 and November 2009, 134 total hip replacements and eight revisions were carried out using DELTA-TT primary cups (Lima Corporate, Villanova di San Daniele del Friuli, Italy) in 133 consecutive patients. Mean age was 57.5 +/- 14.7 SD (18-92) years. Diagnosis was primarily hip osteoarthritis in 85 (63 %) cases, developmental dysplasia of the hip (DDH) in 24 (18 %) and hip avascular necrosis (AVN) in 10 (7 %). All the revision procedures were due to aseptic loosening of the original implant. Approval of the Institutional Review Board of the IRCCS Policlinico San Matteo in Pavia was obtained for this study. RESULTS: Mean follow-up was 72.7 +/- 7.9 SD (60-86) months. Average Harris Hip Score (HHS) significantly increased from 44.2 +/- 5.4 SD (35-52) preoperatively to 95.9 +/- 3.5 SD (88-100) at the last follow-up. No major post-operative complications were observed. 99.3 % of the acetabular components were radiographically stable at the last follow-up, without any radiolucent lines, sclerotic areas or periprosthetic osteolysis. Kaplan-Meier survival rate was 99.3 % at 5 years (95 % confidence interval). CONCLUSIONS: This first account on the mid-term clinical performance of the DELTA-TT cup shows primary and secondary stability, thus representing an optimal solution for patients with high demands or affected by severe hip conditions. PMID- 26634831 TI - Screen time exposure and reporting of headaches in young adults: A cross sectional study. AB - Objective The objective of this article is to investigate whether excessive screen time exposure is associated with non-migraine headache and migraine in young adults. Background Increased levels of television time have been associated with increased risk of headache. However, time spent using newer electronic devices with a screen (smartphone, tablet) has not been examined yet. Methods We conducted a cross-sectional study among 4927 participants of the French i-Share cohort. Demographic characteristics, screen time exposure (computers, tablets, smartphones and television) as well as headache/migraine symptoms were recorded in a standardized questionnaire. Multinomial logistic regression models were used to evaluate the association between screen time exposure and headache status. Results Participants had a mean age of 20.8 years and 75.5% were female. The multivariable model showed that students in the highest screen time exposure quintile had an increased risk for migraine. The odds ratio (OR) (95% confidence interval (CI)) was 1.37 (1.14 to 1.66) for migraine when compared with students without headache and with low screen time exposure. This association was somewhat stronger for migraine without aura (OR = 1.50, 95% CI 1.19 to 1.89). We found no significant association between screen time exposure and non-migraine headache. Conclusion High levels of screen time exposure are associated with migraine in young adults. No significant association was found with non-migraine headache. PMID- 26634832 TI - Association of depressive symptoms with allodynia in patients with migraine: A cross-sectional study. AB - Aims Migraine and depression have a strong association. We aimed to determine whether this relationship was particularly evident in migraineurs with allodynia. Methods A cross-sectional study was carried out of 98 consecutive patients with episodic migraine presenting for their first evaluation in an outpatient clinic. The participants completed a demographic questionnaire, the Allodynia Symptom Checklist and the Hospital Anxiety and Depression Scale (HADS). Results Among the migraineurs, 75 (77%) reported allodynia. Allodynia was associated with higher median HADS-Anxiety (9 vs. 6, p = 0.038) and HADS-Depression (6 vs. 4, p = 0.014) scores. In a multiple regression model, the HADS-Depression scores were independently associated with allodynia (odds ratio 1.236, 95% confidence interval 1.046-1.461). An increased severity of allodynia correlated with higher depression scores ( r = 0.224; p = 0.027). Conclusion Anxious and depressive symptoms are more common in migraineurs with allodynia than in those without allodynia. Further studies are necessary to clarify the relationship between depressive symptoms and allodynia, as well as its therapeutic implications in migraine. PMID- 26634833 TI - Headaches in patients with previous head injuries: A population-based historical cohort study (HUNT). AB - Background Headache attributed to head injury is claimed to be among the most common secondary headache disorders, yet available epidemiological evidence is scarce. We evaluated the prevalence of headache among individuals previously exposed to head injury by a comparison to an uninjured control group. Methods This population-based historical cohort study used data from hospital records on previous exposure to head injury linked to a large epidemiological survey with data on headache occurrence. Participants without head injury, according to hospital records, were used as controls. The head injuries were classified according to the Head Injury Severity Scale (HISS) and the International Classification of Headache Disorders (ICHD-3 beta). Binary logistic regression was performed to investigate the association between headache and head injury, controlling for potential confounders. Results The exposed group consisted of 940 individuals and the control group of 38,751 individuals. In the multivariate analyses, adjusting for age, sex, anxiety, depression and socioeconomic status, there were significant associations between mild head injury and any headache, migraine, chronic daily headache and medication overuse headache. Conclusion Headache was more likely among individuals previously referred to a hospital for a mild head injury compared to uninjured controls. PMID- 26634834 TI - Poor man's fluorescence and equipment. PMID- 26634836 TI - Neonatal mortality and outcome at the end of the first year of life in early onset urea cycle disorders--review and meta-analysis of observational studies published over more than 35 years. AB - BACKGROUND: For urea cycle disorders (UCD), proportions and mortality of early onset (EO) patients, as well as outcome at one year of life show large variability. We aimed to integrate available evidence to create benchmarks for new diagnostic and therapeutic strategies. METHODS: Medline search for reports published between 1978 and Dec 22, 2014 was completed by hand search. Random effects meta-analysis was done for four UCDs, deficiency of carbamylphosphate synthetase 1 (CPS1D), male/female ornithine transcarbamylase (OTCDm/f), argininosuccinate synthetase (ASSD) and lyase (ASLD). Effects of publication year and geographic area were analysed by meta-regression. RESULTS: Twenty-four publications report onset time (n = 1542 patients), survival of EO (n = 665 patients) and outcome at one year of life (n = 172 patients). Proportions for EO manifestation (95% confidence interval) were: CPS1D = 0.75 (0.61;0.88); OTCDm = 0.52 (0.39;0.65); OTCDf = 0.07 (0.03;0.11); ASSD = 0.65 (0.57;0.73); ASLD = 0.60 (0.44;0.77); for surviving EO patients: CPS1D = 0.64 (0.50;0.79); OTCDm = 0.40 (0.16;0.64); OTCDf = 0.57 (0.29;0.85); ASSD = 0.67 (0.48;0.86); ASLD = 0.81 (0.68;0.94); and for normal outcome at one year for survivors: CPS1D = 0.20 (0.07;0.38); OTCDm = 0.15 (0.00;0.39); OTCDf no data; ASSD = 0.36 (0.13;0.60); ASLD = 0.36 (0.17;0.58). Between study variation was large. Year of publication had no effect. Studies from Europe showed lower survival rates than those from Japan or USA. CONCLUSIONS: UCDs, except for OTCDf, have high risks of EO disease manifestation and, except for ASLD, of neonatal death. No improvement of survival was observed over more than three decades. Geographic variation remains to be explained. This comprehensive description of the natural history of EO UCDs should be considered by scientists, clinicians, health policy makers and guideline developers. PMID- 26634838 TI - Vaginal birth and pelvic floor dysfunction revisited: Can cesarean delivery be protective? PMID- 26634839 TI - Immunological aspects of sport nutrition. AB - Prolonged bouts of exercise and heavy training regimens are associated with depression of immune system functions that can increase the risk of picking up opportunistic infections such as the common cold and influenza. Some common sport nutrition practices including high-carbohydrate diets and carbohydrate ingestion during exercise, training with low-glycogen stores, intentional dieting for weight loss, ingestion of high-dose antioxidant supplements and protein ingestion post exercise may influence immune system status in athletes. In order to maintain robust immunity, athletes need to consume a well-balanced diet that is sufficient to meet their requirements for energy, carbohydrate, protein and micronutrients. Dietary deficiencies of protein and specific micronutrients are well known to be potential causes of immune dysfunction and an adequate intake of some essential minerals including iron and zinc and the vitamins A, D, E, B6 and B12 are important to maintain a healthy immune function. Vitamin D may be a particular concern as recent studies have emphasised its importance in limiting infection episode incidence and duration in both the general population and in athletes and many individuals exhibit inadequate vitamin D status during the winter months. There is only limited evidence that individual amino acids, beta glucans, herbal extracts and zinc are capable of boosting immunity or reducing infection risk in athletes. The ingestion of carbohydrate during exercise and daily consumption of probiotics, vitamin D3, bovine colostrum and plant polyphenol containing supplements or foodstuffs currently offer the best chance of success, particularly for those individuals who are prone to illness. PMID- 26634840 TI - Enzymatic Hydrolysis of Hydrotropic Pulps at Different Substrate Loadings. AB - Enzymatic hydrolysis of cellulosic raw materials to produce nutrient broths for microbiological synthesis of ethanol and other valuable products is an important field of modern biotechnology. Biotechnological processing implies the selection of an effective pretreatment technique for raw materials. In this study, the hydrotropic treatment increased the reactivity of the obtained substrates toward enzymatic hydrolysis by 7.1 times for Miscanthus and by 7.3 times for oat hulls. The hydrotropic pulp from oat hulls was more reactive toward enzymatic hydrolysis compared to that from Miscanthus, despite that the substrates had similar compositions. As the initial substrate loadings were raised during enzymatic hydrolysis of the hydrotropic Miscanthus and oat hull pulps, the concentration of reducing sugars increased by 34 g/dm(3) and the yield of reducing sugars decreased by 31 %. The findings allow us to predict the efficiency of enzymatic hydrolysis of hydrotropic pulps from Miscanthus and oat hulls when scaling up the process by volume. PMID- 26634841 TI - Envisaging the Regulation of Alkaloid Biosynthesis and Associated Growth Kinetics in Hairy Roots of Vinca minor Through the Function of Artificial Neural Network. AB - Artificial neural network based modeling is a generic approach to understand and correlate different complex parameters of biological systems for improving the desired output. In addition, some new inferences can also be predicted in a shorter time with less cost and labor. As terpenoid indole alkaloid pathway in Vinca minor is very less investigated or elucidated, a strategy of elicitation with hydroxylase and acetyltransferase along with incorporation of various precursors from primary shikimate and secoiridoid pools via simultaneous employment of cyclooxygenase inhibitor was performed in the hairy roots of V. minor. This led to the increment in biomass accumulation, total alkaloid concentration, and vincamine production in selected treatments. The resultant experimental values were correlated with algorithm approaches of artificial neural network that assisted in finding the yield of vincamine, alkaloids, and growth kinetics using number of elicits. The inputs were the hydroxylase/acetyltransferase elicitors and cyclooxygenase inhibitor along with various precursors from shikimate and secoiridoid pools and the outputs were growth index (GI), alkaloids, and vincamine. The approach incorporates two MATLAB codes; GRNN and FFBPNN. Growth kinetic studies revealed that shikimate and tryptophan supplementation triggers biomass accumulation (GI = 440.2 to 540.5); while maximum alkaloid (3.7 % dry wt.) and vincamine production (0.017 +/- 0.001 % dry wt.) was obtained on supplementation of secologanin along with tryptophan, naproxen, hydrogen peroxide, and acetic anhydride. The study shows that experimental and predicted values strongly correlate each other. The correlation coefficient for growth index (GI), alkaloids, and vincamine was found to be 0.9997, 0.9980, 0.9511 in GRNN and 0.9725, 0.9444, 0.9422 in FFBPNN, respectively. GRNN provided greater similarity between the target and predicted dataset in comparison to FFBPNN. The findings can provide future insights to calculate growth index, alkaloids, and vincamine in combination to different elicits. PMID- 26634842 TI - The Bioconversion of Pretreated Cashew Apple Bagasse into Ethanol by SHF and SSF Processes. AB - Ethanol production from acidic-alkaline pretreated cashew apple bagasse (CAB-OH) was investigated using separated hydrolysis and fermentation (SHF) and simultaneous saccharification and fermentation (SSF) processes. First, a screening of Kluyveromyces strains was conducted by SHF and a maximum ethanol concentration of 24.1 g L(-1) was obtained using Kluyveromyces marxianus ATCC36907, which presented similar profiles when compared to results obtained by a Saccharomyces strain. The effect of temperature on ethanol production conducted by SHF using K. marxianus ATCC36907 was investigated, and the maximum ethanol yield (YE/G) was obtained at 40 degrees C (0.46 g g(-1)) using a synthetic medium. In the SHF using CAB-OH hydrolysate, the maximum ethanol concentration obtained was 24.9 g L(-1), 5.92 g L(-1) h(-1) of productivity, and ethanol yield of 0.43 g g(-1) at 40 degrees C. Afterwards, K. marxianus ATCC36907 was used in the bioconversion of CAB-OH by SSF, and an ethanol concentration of 41.41 +/- 0.2 g L(-1) was obtained using 10 % CAB-OH at 40 degrees C, 150 rpm and 24 h, resulting in a Y'E/G of 0.50 gE gG (-1) and an efficiency of 98.4 %, in the process conducted with cellobiase supplementation. SHF and SSF processes using CAB-OH and K. marxianus ATCC36907 can be used to ethanol production, but the SSF process required only one step to achieve the same production. PMID- 26634843 TI - Development and validation of an automated and marker-free CT-based spatial analysis method (CTSA) for assessment of femoral hip implant migration: In vitro accuracy and precision comparable to that of radiostereometric analysis (RSA). AB - BACKGROUND AND PURPOSE: We developed a marker-free automated CT-based spatial analysis (CTSA) method to detect stem-bone migration in consecutive CT datasets and assessed the accuracy and precision in vitro. Our aim was to demonstrate that in vitro accuracy and precision of CTSA is comparable to that of radiostereometric analysis (RSA). MATERIAL AND METHODS: Stem and bone were segmented in 2 CT datasets and both were registered pairwise. The resulting rigid transformations were compared and transferred to an anatomically sound coordinate system, taking the stem as reference. This resulted in 3 translation parameters and 3 rotation parameters describing the relative amount of stem-bone displacement, and it allowed calculation of the point of maximal stem migration. Accuracy was evaluated in 39 comparisons by imposing known stem migration on a stem-bone model. Precision was estimated in 20 comparisons based on a zero migration model, and in 5 patients without stem loosening. RESULTS: Limits of the 95% tolerance intervals (TIs) for accuracy did not exceed 0.28 mm for translations and 0.20 degrees for rotations (largest standard deviation of the signed error (SD(SE)): 0.081 mm and 0.057 degrees ). In vitro, limits of the 95% TI for precision in a clinically relevant setting (8 comparisons) were below 0.09 mm and 0.14 degrees (largest SD(SE): 0.012 mm and 0.020 degrees ). In patients, the precision was lower, but acceptable, and dependent on CT scan resolution. INTERPRETATION: CTSA allows detection of stem-bone migration with an accuracy and precision comparable to that of RSA. It could be valuable for evaluation of subtle stem loosening in clinical practice. PMID- 26634844 TI - Campylobacter jejuni sequence types show remarkable spatial and temporal stability in Blackbirds. AB - BACKGROUND: The zoonotic bacterium Campylobacter jejuni has a broad host range but is especially associated with birds, both domestic and wild. Earlier studies have indicated thrushes of the genus Turdus in Europe to be frequently colonized with C. jejuni, and predominately with host-associated specific genotypes. The European Blackbird Turdus merula has a large distribution in Europe, including some oceanic islands, and was also introduced to Australia by European immigrants in the 1850s. METHODS: The host specificity and temporal stability of European Blackbird C. jejuni was investigated with multilocus sequence typing in a set of isolates collected from Sweden, Australia, and The Azores. RESULTS: Remarkably, we found that the Swedish, Australian, and Azorean isolates were genetically highly similar, despite extensive spatial and temporal isolation. This indicates adaptation, exquisite specificity, and stability in time for European Blackbirds, which is in sharp contrast with the high levels of recombination and mutation found in poultry-related C. jejuni genotypes. CONCLUSION: The maintenance of host specific signals in spatially and temporally separated C. jejuni populations suggests the existence of strong purifying selection for this bacterium in European Blackbirds. PMID- 26634845 TI - Veterinary syndromic surveillance in practice: costs and benefits for governmental organizations. AB - BACKGROUND: We describe a veterinary syndromic surveillance system developed in Sweden based on laboratory test requests. MATERIALS AND METHODS: The system is a desktop application built using free software. RESULTS: Development took 1 year. During the first year of operation, utility was demonstrated by the detection of statistically significant increases in the number of laboratory submissions. The number of false alarms was considered satisfactory in order to achieve the desired sensitivity. DISCUSSION: Besides the demonstrated benefit for disease surveillance, the system contributed to improving data quality and communication between the diagnostic departments and the epidemiology department. PMID- 26634846 TI - Comparison of Additive Manufactured and Conventional 316L Stainless Steels ERRATUM. PMID- 26634847 TI - Dendritic polyglycerol sulfate attenuates murine graft-versus-host disease. AB - Graft-versus-host disease (GvHD) is a severe immune reaction commonly occurring after hematopoietic stem cell transplantation. The outcome of patients who do not respond to the currently used immunosuppressive drugs is poor, thus there is an urgent need for the evaluation of new therapies. Heparin has a well-known anti inflammatory effect and heparin analogues with a low anticoagulant effect are interesting candidates as new anti-inflammatory drugs. We explored the therapeutic potential of dendritic polyglycerol sulfates (dPGS), a novel class of heparin derivatives, on murine acute GvHD in vivo. The therapeutic effect of dPGS on murine GvHD was more intense after intravenous application compared to subcutaneous injection. An increased survival rate and improved clinical scores were observed in mice treated with 5 mg/kg once a week. In these animals, there was a reduction in the percentage of CD4(+) and CD8(+) T cells, which are the main effectors of GvHD. In addition, dPGS treatment decreased the number of tumor necrosis factor alpha (TNFalpha)-producing T cells. Increasing the dose of dPGS reversed the positive effect on survival as well as the clinical score, which indicates a small therapeutic range. Here, we report for the first time that dPGS have a significant immunosuppressive in vivo effect in a mouse model of severe acute GvHD. Therefore, we propose to study dPGS as promising candidates for the development of potential new drugs in the treatment of steroid-refractory GvHD patients first in larger animals and later in humans. PMID- 26634848 TI - Predicting recurrence of non-muscle-invasive bladder cancer after transurethral resection. AB - AIM: To determine clinical prognostic factors and their impact on the risk of recurrence of newly discovered non-muscle-invasive bladder cancer. METHODS: The study included 120 patients of both sexes aged 45-80 years with newly discovered non-muscle-invasive bladder cancer. All the patients were treated surgically by transurethral electro resection (TUER). The outcome of patients with and without recurrence was followed at intervals of three months after surgery, the total of two years. For monitoring the probability of early recurrence the criteria of the European Organization for Research and Treatment of Cancer (EORTC) were used. RESULTS: The average age of the patients was 65.9 years, 79 (79.2%) males and 21 (20.8%) females. The total of 67 (55.8%) patients had a recurrence during the period of monitoring. The average time to the first and fourth recurrence was 15.4 and 23.9 months, respectively. Numbers of tumors and a degree of invasion had a significant prognostic impact on the risk of recurrence. The EORTC score was a highly significant predictor of recurrence (OR=1.237; p < 0.001). CONCLUSION: Based on available clinical and pathological prognostic factors and by stratification of patients into three disease risk groups it is possible to predict the possibility of disease. Individual approach and recommendations for the treatment using EORTC risk tables should improve the quality of treatment. PMID- 26634849 TI - Factors affecting mortality in emergency surgery in cases of complicated colorectal cancer. AB - AIM: To evaluate retrospectively demographic, clinical and histopathological variables effective on mortality in patients who had undergone emergency surgery due to complicated colorectal cancer. METHODS: A total of 39 patients underwent urgent surgical interventions due to complicated colorectal cancer at the Department of General Surgery, Dursun Odabas Medical Center, between January 2010 and January 2015. Thirty three of these were included in the study. Six patients were excluded because complete medical records had been missing. Medical records of the 33 cases were retrospectively reviewed. RESULTS: There were 14 (42.5%) male and 19 (57.5%) female patients. Mean age was 60 years (range: 32- 83 years); 14 (42.5%) patients were less than 60 years old , while 19 (57.5%) were 60 years old or older. Operations were performed due to perforation (39.3%) and obstruction (60.6%) in 13 and 20 patients, respectively. Tumor localization was in the right and transverse colon in nine (21.2%) and in the left colon in 24 cases (72.7%). Eleven (33.3%) patients underwent resection and anastomosis, 13 (39.3%) resection and ostomy, and nine (27.2%) patients underwent ostomy alone without any resection. Postoperative mortality occurred in nine cases (27.2%). CONCLUSIONS: High mortality should be expected in females older than 60 years with a left sided colon tumor or with another synchronous tumor and in perforated tumors. Unnecessary major resections should be avoided and primary pathology should be in the focus of treatment in order to decrease the mortality and morbidity rates. PMID- 26634850 TI - Efficacy and safety of iris-supported phakic lenses (Verisyse) for treating moderately high myopia. AB - AIM: To evaluate efficacy and safety of iris-supported phakic lenses (Verisyse) for treating moderately high myopia. METHODS: This prospective clinical study included 40 eyes from 29 patients, who underwent implantation of Verisyse for correction of myopia from -6.00 to -14.50 diopters (D) in the Eye Clinic ''Svjetlost'', Sarajevo, from January 2011 to January 2014. Uncorrected distance visual acuity (UDVA), manifest residual spherical equivalent(MRSE), postoperative astigmatism, intraocular pressure(IOP), endothelial cell (EC) density were evaluated at one, three, six and twelve months. Corrected visual acuity (CDVA), index of safety and efficacy were evaluated after 12 months. RESULTS: Out of 29 patients 15 were males and 14 females, with mean age of 27.9 +/- 5.0. After 12 months 77.5% eyes had UDVA >= 0.5 and 32.5% had UDVA >= 0.8. Mean MRSE was 0.55D +/-0.57D and mean postoperative astigmatism -0.86D +/- 0.47D. Efficacy index was 1.09 +/- 0.19 and safety index 1.18 +/- 0.21. One eye(2.5%) lost two Snellen lines and three eyes (7.5%) one line, 11 eyes (27.5%) gained one line, and five eyes (15.5%) gained two lines. EC loss after 12 months was 7.59 +/- 3.05%. There was no significant change of IOP after one year follow up. CONCLUSION: Implantation of iris-supported phakic lenses (Verisyse) for treating moderately high myopia is an efficient and safe procedure. PMID- 26634851 TI - RNA processing-associated molecular mechanisms of neurodegenerative diseases. AB - Dysfunctions of RNA processing and mutations of RNA binding proteins (RBPs) play a fundamental role in the pathogenesis of many neurodegenerative diseases. To elucidate the function of RNA processing and RBPs mutations in neuronal cells and to increase our understanding on the pathogenic mechanisms of neurodegeneration, I have reviewed recent advances on RNA processing-associated molecular mechanisms of neurodegenerative diseases, including RBPs-mediated dysfunction of RNA processing, dysfunctional microRNA (miRNA)-based regulation of gene expression, and oxidative RNA modification. I have focused on neurodegeneration induced by RBPs mutations, by dysfunction of miRNA regulation, and by the oxidized RNAs within neurons, and discuss how these dysfunctions have pathologically contributed to neurodegenerative diseases. The advances overviewed above will be valuable to basic investigation and clinical application of target diagnostic tests and therapies. PMID- 26634852 TI - Safety of oral tenofovir disoproxil fumarate-based pre-exposure prophylaxis for HIV prevention. AB - INTRODUCTION: Tenofovir disoproxil fumarate (TDF)-based pre-exposure prophylaxis is a novel HIV prevention strategy for individuals at increased sexual risk for HIV infection. For any biomedical prevention intervention, the bar for tolerating adverse effects in healthy persons is high compared to therapeutic interventions. AREAS COVERED: We provide a concise summary of the clinical safety of TDF-based pre-exposure prophylaxis with focus on TDF-related effects on tolerability, kidney function, bone density, HIV resistance, sexual and reproductive health. The evidence base for this review is derived from a literature search of both randomized and observational studies evaluating efficacy and safety of TDF-based PrEP, TDF alone or in combination with emtricitabine, identified from PUBMED and EMBASE electronic databases, clinicaltrials.gov and major HIV conferences. EXPERT OPINION: TDF-based pre-exposure prophylaxis is a potent intervention against HIV acquisition when taken which is generally safe and well tolerated. The risk of the small, non-progressive, and reversible decline in glomerular filtration rate and bone mineral density as well as the potential selection for drug resistance associated with PrEP are outweighed, at the population level and broadly for individuals, by PrEP's substantial reduction in the risk of HIV infection. PMID- 26634853 TI - The Expression of Notch 1 and Notch 3 in Gallbladder Cancer and Their Clinicopathological Significance. AB - Gallbladder cancers (GBCs) are highly malignant gastrointestinal cancers. The biological makers for the prognosis and targeting therapy of GBCs have not been established. The protein expression of Notch 1 and Notch 3 in 46 squamous cell/adenosquamous carcinomas (SC/ASCs) and 80 adenocarcinomas (AC) was measured using immunohistochemistry. Positive Notch 1 and Notch 3 expression in both SC/ASC and AC was significantly associated with large tumor size, invasion, metastasis, and low surgical curability (P < 0.05 or P < 0.01). Univariate Kaplan Meier analysis showed that positive Notch 1 and Notch 3 expression was significantly associated with mean survival of SC/ASC and AC patients (P < 0.01 or P < 0.001). Multivariate Cox regression analysis showed that positive Notch 1 and Notch 3 expression, as well as low differentiation, large tumor size, high TNM stage, invasion, lymph node metastasis, and surgical curability are independent poor-prognostic factors in both SC/ASC and AC patients. Positive Notch 1 and Notch 3 expression is closely correlated with severe clinicopathological characteristics and poor prognosis in both SC/ASC and AC patients. PMID- 26634855 TI - "Do it All by Myself": A Salutogenic Approach of Masculine Health Practice Among Farming Men Coping With Stress. AB - Farming is often considered one of the most stressful occupations. At the same time, farming men symbolically represent a strong, traditional, or hegemonic form of masculinity based on stoicism, resourcefulness, and resilience to adversity. A contrast is observed between this social representation and their health status, marked by higher levels of stress, social isolation, psychological distress, and suicide than many other subgroups of men. A salutogenic approach was taken in this study to enable the investigation of the social contexts in which farming men positively engage in health-promoting behaviors that may prevent or ameliorate mental health problems. A focus was placed on how farming men cope with stress on their own, and the relationship of this to their popular image of being resourceful and resilient. Thirty-two individual in-depth interviews with farming men and a focus group with five key informants working in rural areas within the Province of Quebec, Canada, were carried out. Self-distraction and cognitive strategies emerged as the most relevant for participants. Notably, taking work breaks conflicted with the discourse of the "relentless worker" that farmers are expected to be. Pathways to positive coping and recovery implied an ambivalence between contemplation of strategies aligned with negative aspects of traditional masculinity norms in North America and strategies aligned with more positive, progressive aspects of these norms based on the importance of family and work life balance. Health promotion and future research should investigate how various positive masculine practices can be aligned with farmers' health and well-being and that of their family. PMID- 26634854 TI - Hispanic Male's Perspectives of Health Behaviors Related to Weight Management. AB - Hispanic males have the highest prevalence of overweight and obesity among men in the United States; yet are significantly underrepresented in weight loss research. The purpose of the current study was to examine Hispanic male's perspectives of health behaviors related to weight management to refine the methodologies to deliver a gender-sensitive and culturally sensitive weight loss intervention. From October 2014 to April 2015, semistructured interviews were conducted with 14 overweight Hispanic men of ages 18 to 64 years. The interviews lasted approximately 60 minutes. Participants also completed a brief questionnaire and body weight/height were measured. Grounded in a deductive process, a preliminary codebook was developed based on the topics included in the interview guides. A thematic analysis facilitated the identification of inductive themes and the finalization of the codebook used for transcript analysis. Four overarching themes were identified: (a) general health beliefs of how diet and physical activity behaviors affect health outcomes, (b) barriers to healthy eating and physical activity, (c) motivators for change, and (d) viable recruitment and intervention approaches. Future research should examine feasible and appropriate recruitment and intervention strategies identified by Hispanic males to improve weight management in this vulnerable group. PMID- 26634856 TI - Masculine Traits and Depressive Symptoms in Older and Younger Men and Women. AB - Evidence suggests that men who strongly endorse masculine traits display an atypical presentation of depression, including more externalizing symptoms (e.g., anger or substance use), but fewer typical, internalizing symptoms (e.g., depressed mood or crying). This phenomenon has not been adequately explored in older adults or women. The current study used the externalizing subscale of the Masculine Depression Scale in older and younger men and women to detect atypical symptoms. It was predicted that individuals who more strongly endorsed masculine traits would have higher scores on the measure of externalizing symptoms relative to a measure of typical depressive symptoms Center for Epidemiologic Studies Depression Scale. It was anticipated that results would differ by age-group but not by gender. Multigroup path analysis was used to test the hypothesis. The hypothesized path model, in which endorsement of masculine traits was associated with lower scores on the Center for Epidemiologic Studies-Depression Scale and with scores on the externalizing, but not internalizing, factor of the Masculine Depression Scale, fit the data well. Results differed significantly by age-group and gender. Masculine individuals reported lower levels of typical depressive symptoms relative to externalizing symptoms, but further research is needed within age- and gender groups. Results are consistent with the gendered responding framework and suggest that current assessment tools, which tend to focus on internalizing symptoms of depression, may not detect depression in individuals who endorse masculine traits. PMID- 26634858 TI - Adherence and Persistence Patterns in Medication Use Among Men With Lower Urinary Tract Symptoms/Benign Prostatic Hyperplasia. AB - Medication adherence and persistence patterns among patients with lower urinary tract symptoms/benign prostatic hyperplasia (LUTS/BPH) were analyzed. Electronic medical records of patients from the Reliant Medical Group were examined to evaluate adherence and persistence patterns. A total of 1,807 patients with LUTS/BPH were included in the study, and the number of patients at least 50 years of age was 1,748/1,807 (97%). Overall, 15.77% of patients were prescribed index prescription once, and no patients on combination alpha-blocker and 5-alpha reductase inhibitor therapies were prescribed their index prescriptions once. For all patients with LUTS/BPH, the mean number of prescriptions filled was 6.26, and the percentage of men persisting on index therapy for >=4 years was 48%. Patients with LUTS/BPH showed a high proportion of both adherent and persistent treatment patterns, especially among patients taking combination therapy. The long follow up time in our study provides evidence that patients are experiencing sufficient symptom relief to tolerate the challenges of remaining adherent and persistent. PMID- 26634857 TI - Recommendations for Treating Males: An Ethical Rationale for the Inclusion of Testicular Self-Examination (TSE) in a Standard of Care. AB - The phrase "standard of care" is primarily a legal term representing what procedure a reasonable person (i.e., health practitioner) would administer to patients across similar circumstances. One major concern for health practitioners is delivering and advocating for treatments not defined as a standard of care. While providing such treatments may meet certain ethical imperatives, doing so may unwittingly trigger medical malpractice litigation fears from practitioners. Apprehension to deviate, even slightly, from the standard of care may (seem to) put the practitioner at significant risk for litigation, which, in turn, may limit options for treatment and preventive measures recommended by the practitioner. Specific to testicular treatment, certain guidelines exist for cancer, torsion, vasectomy, and scrotal masses, among others. As it relates to screening, practitioner examination is expected for patients presenting with testicular abnormalities. Testicular self-examination (TSE) advocacy, however, is discouraged by the U.S. Preventive Services Task Force, which may prompt a general unwillingness among health practitioners to promote the behavior. Considering the benefits TSE has beyond cancer detection, and the historical support it has received among health practitioners, it is paramount to consider the ethical implications of its official "exclusion" from preventive health and clinical care recommendations (i.e., standard of care). Since good ethics should lead practitioner patient care guidelines, not fear of increased malpractice risks, we recommend the development of a standard of care for counseling males to perform TSE. PMID- 26634859 TI - Effects of Two Different Dosages of Sildenafil on Patients With Erectile Dysfunction. AB - To investigate the effects of two different dosages of sildenafil on patients with erectile dysfunction (ED), a total of 3,674 patients with ED were recruited to answer questionnaires designed specifically for this study. There were 977 patients in the 50 mg group and there were 2,697 patients in the 100 mg group. Both 50 mg and 100 mg of sildenafil therapy increased the ED patients' average monthly frequency of sexual intercourse, improved erectile function state in self assessment, and elevated sexual satisfaction and enjoyment. Despite a higher rate of concomitant diseases, patients in the higher dosage of sildenafil group had a better outcome in the average monthly frequency of sexual intercourse and sexual enjoyment compared with those in the lower dosage. Such a study might be helpful for health care providers to choose sildenafil dosage for patients with ED. PMID- 26634860 TI - Opinions and Attitudes About Vasectomy of Married Couples Living in Turkey. AB - This study was conducted as a descriptive study, designed to determine the opinions and attitudes of married couples living in Turkey about vasectomy. The sample consisted of 350 women. Researchers used a questionnaire to collect data. Descriptive statistics and chi-square analysis were used. The results showed that 14% of women and 43.0% of men were of the opinion that undergoing a vasectomy procedure was a sin. Chi-square analysis determined statistically significant differences between the male and female groups ( p < .05). More than 88.0% of the men were not willing to have vasectomy and 35.4% thought that vasectomy had a negative effect on marriage and sexual health. In addition, 58.9% thought that vasectomy had a negative effect on men's health. Women were more likely than men to see vasectomy as merely a cultural taboo instead of a sin. Sociocultural factors, such as ideas that contraception is the woman's responsibility, that sterilized men lose status in society, or that sterilized men lose authority in the family, as well as misconceptions about vasectomy such as concerns about sexual functioning, psychological effects, and effects on physical strength, were determined to be the main barriers for vasectomy use in Turkish culture. The study recommends determining strategies for overcoming sociocultural barriers by raising awareness and increasing the utilization of vasectomy. Couple-specific family planning programs can make an important contribution toward improving awareness of the benefits of vasectomy. PMID- 26634861 TI - Barriers and Motivators to Participating in mHealth Research Among African American Men. AB - Most African American (AA) men own a smartphone, which positions them to be targeted for a variety of programs, services, and health interventions using mobile devices (mHealth). The goal of this study was to assess AA men's use of technology and the barriers and motivators to participating in mHealth research. A self-administered survey was completed by 311 men. Multinomial logistic regression examined associations between three age groups (18-29 years, 30-50 years, and 51+ years), technology access, and motivators and barriers to participating in mHealth research. Sixty-five percent of men owned a smartphone and a laptop. Men aged 18 to 29 years were more likely willing to use a health app and smartwatch/wristband monitor than older men ( p < .01). Men aged 18 to 29 years were also more likely than older men to be motivated to participate for a free cell phone/upgraded data plan and contribution to the greater good ( p < .05). Older men were more likely than younger ones to be motivated to become more educated about the topic ( p < .05). Younger men were more likely than older ones to report lack of interest in the topic as a barrier to participating ( p < .01), while older men were more likely than younger ones to cite lack of research targeted to minority communities as a barrier ( p < .05). This study suggests that culturally tailored mHealth research using smartphones may be of interest to AA men interested in risk reduction and chronic disease self-management. Opportunities also exist to educate AA men about the topic at hand and why minority men are being targeted for the programs and interventions. PMID- 26634862 TI - Serum periostin in biliary atresia. PMID- 26634863 TI - Iatrogenic and sporadic Creutzfeldt-Jakob disease in 2 sisters without mutation in the prion protein gene. AB - Human genetic prion diseases have invariably been linked to alterations of the prion protein (PrP) gene PRNP. Two sisters died from probable Creutzfeldt-Jakob disease (CJD) in Switzerland within 14 y. At autopsy, both patients had typical spongiform change in their brains accompanied by punctuate deposits of PrP. Biochemical analyses demonstrated proteinase K-resistant PrP. Sequencing of PRNP showed 2 wild-type alleles in both siblings. Retrospectively, clinical data revealed a history of dural transplantation in the initially deceased sister, compatible with a diagnosis of iatrogenic CJD. Clinical and familial histories provided no evidence for potential horizontal transmission. This observation of 2 siblings suffering from CJD without mutations in the PRNP gene suggests potential involvement of non-PRNP genes in prion disease etiology. PMID- 26634864 TI - Naproxen sodium decreases prostaglandins secretion from cultured human endometrial stromal cells modulating metabolizing enzymes mRNA expression. AB - Dysmenorrhea, defined as painful cramps occurring immediately before or during the menstrual period, is a common symptom of different gynecological diseases. An acute uterine inflammatory response driven by prostaglandins (PGs) is responsible for painful symptoms. Progesterone withdrawal is responsible for activation of cyclooxygenase (COX-2) enzyme and decrease of hydroxyprostaglandin dehydrogenase (HPDG) with consequent increased secretion of PGs secretion, inducing uterine contractility and pain. The most widely used drugs for the treatment of pelvic pain associated with menstrual cycle are non steroidal anti-inflammatory drugs (NSAIDs). The uterine site of action of these drugs is still not defined and the present study evaluated the effect of naproxen sodium in cultured human endometrial stromal cells (HESC) collected from healthy women. PGE2 release was measured by ELISA; COX-2 and HPDG mRNA expression were assessed by qRT-PCR. Naproxen sodium did not affect HESC vitality. Naproxen sodium significantly decreased PGE2 secretion (p < 0.01) and COX-2 mRNA expression (p < 0.01). TNF alpha induced PGE2 release was reduced in presence of naproxen sodium (p < 0.05), in association with decreased COX-2 and increased HPDG mRNAs expression. Naproxen sodium decreases endometrial PGE2 release induced by inflammatory stimulus acting on endometrial COX-2 and HPDG expression, suggesting endometrial synthesis of prostaglandins as a possible target for reduction of uterine inflammatory mechanism in dysmenorrhea. PMID- 26634865 TI - Isomaltodextrin, a highly branched alpha-glucan, increases rat colonic H2 production as well as indigestible dextrin. AB - Colonic hydrogen (H2) protects against inflammation-induced oxidative stress. We examined the effect of a new highly branched alpha-glucan, isomaltodextrin (IMD), on colonic H2 production in rats. Rats were fed a 16.7% IMD, 8.8% indigestible dextrin (ID), or 10.4% high amylose cornstarch diet (Expt. 1), were fed diets containing 3.3-16.7% IMD (Expt. 2), or were fed diets containing 16.7% IMD or 5.2% fructooligosaccharide (FOS) (Expt. 3), for 14 days. Compared with the control group, feeding IMD or other alpha-glucans dose dependently and significantly increased H2 excretion and portal H2 concentration. The ability of IMD to increase H2 production was not inferior to that of FOS. The cecal Firmicutes/Bacteroidetes ratio in the IMD group was 5-14% of that in the control group. The cecal abundance of bifidobacteria was significantly greater in the IMD group than in the control group. Taken together, IMD, as well as other alpha glucans, significantly increased colonic H2 production in a dose-dependent manner. PMID- 26634866 TI - Post-irradiation viability and cytotoxicity of natural killer cells isolated from human peripheral blood using different methods. AB - Purpose We compared the pre- and post-irradiation viability and cytotoxicity of human peripheral natural killer cell (NK) populations obtained using different isolation methods. Material and methods Three methods were used to enrich total NK cells from buffy coats: (I) a Ficoll-Paque gradient, plastic adherence and a nylon wool column; (II) a discontinuous Percoll gradient; or (III) the Dynal NK cell isolation kit. Subsequently, CD16(+) and CD56(+) NK cell subsets were collected using (IV) flow cytometry or (V) magnetic-activated cell sorting (MACS) NK cell isolation kits. The yield, viability, purity and cytotoxicity of the NK cell populations were measured using trypan blue exclusion, flow cytometry using propidium iodide and (51)Cr release assays after enrichments as well as viability and cytotoxicity after a single radiation dose. Results The purity of the preparations, as measured by the CD16(+) and CD56(+) cell content, was equally good between methods I-III (p = 0.323), but the content of CD16(+) and CD56(+) cells using these methods was significantly lower than that using methods IV and V (p = 0.005). The viability of the cell population enriched via flow cytometry (85.5%) was significantly lower than that enriched via other methods (99.4-98.0%, p = 0.003). The cytotoxicity of NK cells enriched using methods I-III was significantly higher than that of NK cells enriched using methods IV and V (p = 0.000). In vitro the NK cells did not recover cytotoxic activity following irradiation. In addition, we detected considerable inter-individual variation in yield, cytotoxicity and radiation sensitivity between the NK cells collected from different human donors. Conclusions The selection of the appropriate NK cell enrichment method is very important for NK cell irradiation studies. According to our results, the Dynal and MACS NK isolation kits best retained the killing capacity and the viability of irradiated NK cells. PMID- 26634867 TI - Chemical Composition of Golden Berry Leaves Against Hepato-renal Fibrosis. AB - The role of Physalis peruviana (golden berry) as functional food against hepato renal fibrosis induced by carbon tetrachloride (CCl4) was evaluated. The chemical composition of leaves referred the presence of withanolides and flavonoids. Two compounds, ursolic acid and lupeol, were isolated and their structures were elucidated by different spectral analysis techniques. The biological evaluation was conducted on different animal groups; control rats, control orally treated with plant extract (500 mg/kg body weight twice a week for six consecutive weeks), CCl4 (0.5 ml/kg body weight diluted to 1:9 (v/v) in olive oil and injected intraperitoneally) group, CCl4 treated with plant extract and CCl4 treated with silymarin as a reference herbal drug. The evaluation was done through measuring oxidative stress markers; malondialdehyde (MDA), superoxide dismutase (SOD) and nitric oxide (NO). Liver function indices; aspartate and alanine aminotransferases (AST & ALT), alkaline phosphatase (ALP), gamma glutamyl transferase (GGT), bilirubin and total hepatic protein were also estimated. Kidney disorder biomarkers; creatinine, urea and serum protein were also evaluated. The results revealed plant safety and decrease in NO, MDA, IgG, ALP, tissue protein, bilirubin, creatinine and urea levels. Increase in SOD, AST, ALT, GGT and serum protein levels were observed. Improvement in liver and kidney histopathological architectures were also seen. In conclusion, Physalis peruviana recorded a significant protective role in liver and kidney against fibrosis. Further studies are needed to evaluate its isolated compounds and its use in pharmacological applications and clinical uses. PMID- 26634868 TI - IFN-gamma for Friedreich ataxia: present evidence. AB - IFN-gamma-1b is currently US FDA approved as an orphan drug for the treatment of chronic granulomatous disease and severe malignant osteopetrosis. It is administered via subcutaneous injection and is a potential therapy for Friedreich ataxia (FRDA), a rare degenerative neurological condition. Ongoing Phase II and III trials in both adults and children with FRDA were preceded by a small Phase I, open-label trial in children that showed that IFN-gamma-1b was reasonably well tolerated and improved overall neurological function as measured by the Friedreich Ataxia Rating Scale after 12 weeks of treatment, though the primary outcome measure of frataxin level showed no improvement. Although there is an established dose of IFN-gamma-1b prescribed for the current indications, the efficacy and tolerability of these dose levels in the FRDA population remains the subject of ongoing investigation. PMID- 26634869 TI - Woman who was granted right to refuse kidney dialysis dies. PMID- 26634870 TI - Harmful effects of silver nanoparticles on a complex detrital model system. AB - The rapid proliferation of silver nanoparticles (AgNP) in industry and the environment requires realistic toxicity assessments based on approaches that consider the biological complexity of ecosystems. Here we assessed the acute toxicity of carbonate-coated AgNP and, for comparison, AgNO3 (Ag(+)) by using a model system consisting of decomposing plant litter and the associated fungal and bacterial decomposers as central players in the functioning of stream ecosystems. Little variation in size and surface charge during the experiment indicated that the AgNP used were essentially stable. AgNP disrupted bacterial growth (<=83% reduction in protein biosynthesis, EC50 = 0.3 MUM), clearly affected fungal growth (<=61% reduction in ergosterol synthesis, EC50 = 47 MUM) with both endpoints more sensitive to AgNP than to Ag(+). Fungal reproduction, in contrast, was stimulated by AgNP, but not Ag(+), at concentrations up to 25 MUM. Both AgNP and Ag(+ )also stimulated extracellular alkaline phosphatase but reduced leucine aminopeptidase, whereas beta-glucosidase was stimulated by AgNP and reduced by Ag(+). Importantly, the provision of cysteine, a chelating ligand that complexes free Ag(+), failed to alleviate AgNP toxicity to microbial growth, clearly demonstrating particle-mediated toxicity independent of the presence of ionic silver. This contrasts with the observed inhibition of leucine aminopeptidase by Ag(+), which accounted for 2-6% of the total silver in treatments receiving AgNP. These results show that although outcomes of AgNP and Ag(+ )exposure assessed by different functional endpoints vary widely, AgNP strongly interferes with bacterial growth and a range of other microbial processes, resulting in severe consequences for natural microbial communities and ecosystem functioning. PMID- 26634871 TI - A biologically active delivery material with dried-rehydrated vesicles containing the anti-inflammatory diclofenac for potential wound healing. AB - Chronic wounds usually remain in the inflammatory phase of the healing process during several months or even years. Hence, a continuous research has been resulting in the development of wound dressings with improved performance. Herein, we report a delivery system for cutaneous wound healing, consisting of a textile material (non-woven gauzes) covered with lipidic vesicles containing diclofenac, a non-steroidal anti-inflammatory drug (NSAID). This study also aims to compare the entrapment efficiency data with previous works and confirm that this parameter and drug amount are not directly correlated. A method of dehydration-rehydration of the liposomes presenting different sizes and lamellarities was used to assess the best conditions to attain the highest drug entrapment efficiency. Optimum conditions for the NSAID release were achieved with high phospholipid concentrations and dried-rehydrated vesicles (DRVs) prepared from multilamellar liposomes (MLVs). A chemical activation of the gauzes was performed to enhance the vesicles attachment, also contributing to a higher drug amount in the surrounding media. In spite of the entrapment efficiency being lower comparatively with other values presented by us previously, the diclofenac concentration was considerably higher in this formulation. Entrapment efficiency is, therefore, not sufficient per se to define the real amount of drug contained in the formulation. The cytocompatibility assessment in human skin fibroblasts showed that DRVs from MLVs and DRVs from large unilamellar liposomes (LUVs) with less than 750 MUM of egg-yolk phosphatidylcholine (EPC), containing diclofenac, were not cytotoxic after 72 h of contact, greatly implying potential for their application in the chronic wounds healing. PMID- 26634872 TI - Author's reply to Jennings. PMID- 26634873 TI - Nivolumab for advanced non-small cell lung cancer: an evaluation of a phase III study. AB - Lung cancer still remains associated with a high mortality rate and more efficacious therapies are needed in order to improve the disease outcome. Nivolumab is a monoclonal antibody which blocks the programmed death-1 receptor which is currently evaluated in phase III clinical trials in advanced lung cancer. Here, we evaluate the results of a phase III study in which nivolumab efficacy and safety were compared to those of docetaxel. Nivolumab was able to improve survival and progression-free survival and exhibited a very good safety profile. Further clinical data are needed in order to better position this therapy among the existing methods. The promising results support the use of this therapy as a stand-alone approach. PMID- 26634874 TI - Kidney transplantation, bioengineering and regeneration: an originally immunology based discipline destined to transition towards ad hoc organ manufacturing and repair. AB - Kidney transplantation (KT), as a modality of renal replacement therapy (RRT), has been shown to be both economically and functionally superior to dialysis for the treatment of end-stage renal disease (ESRD). Progress in KT is limited by two major barriers: a) a chronic and burgeoning shortage of transplantable organs and b) the need for chronic immunosuppression following transplantation. Although ground-breaking advances in transplant immunology have improved patient survival and graft durability, a new pathway of innovation is needed in order to overcome current obstacles. Regenerative medicine (RM) holds the potential to shift the paradigm in RRT, through organ bioengineering. Manufactured organs represent a potentially inexhaustible source of transplantable grafts that would bypass the need for immunosuppressive drugs by using autologous cells to repopulate extracellular matrix (ECM) scaffolds. This overview discusses the current status of renal transplantation while reviewing the most promising innovations in RM therapy as applied to RRT. PMID- 26634875 TI - An Efficient and Facile Method for the Synthesis of Benzimidazoisoquinoline Derivatives via a Multicomponent Reaction. AB - Two series of benzimidazoisoquinoline and fused benzimidazoisoquinoline benzimidazole derivatives have been synthesized using an efficient one-pot procedure. This process involves an intramolecular nucleophilic substitution reaction and provides facile access to two series of complexes and potentially interesting biologically active scaffolds. PMID- 26634876 TI - Stem cell transcription factor NANOG in cancers--is eternal youth a curse? AB - INTRODUCTION: Targeting cancer stem cells can be a more effective approach to treat cancer. NANOG is one of the key factors for maintaining the self-renewal ability and pluripotency of stem cells, including cancer stem cells. Overexpression of NANOG has been observed in various human malignancies. Several reports have suggested that NANOG contributes to carcinogenesis by initiating and preserving cancer stem cells. It is obvious that NANOG is also involved in establishing other hallmarks of cancer such as uncontrolled cell growth, chemoresistance, metastasis, and immune evasion. AREAS COVERED: This review will discuss the molecular properties and oncogenic roles of NANOG. The idea of using agents that inhibit the transcription factor to treat cancer is presented. Interfering with NANOG-mediated transcriptions using small interfering RNA, transcription factor decoy, genome editing, and small-molecule inhibitors may provide novel strategies to target cancer stem cells. EXPERT OPINION: As a pivotal controller in cancer stem cell maintenance and a positive regulator of various oncogenic pathways, NANOG may be an important target for cancer therapy. However, as a transcription factor, it is inherently difficult to target by pharmacological means. Novel approaches need to be explored before the inhibition of NANOG can be applied in a clinical setting. PMID- 26634877 TI - Unique Phase Behaviors in the Gemini Surfactant/EAN Binary System: The Role of the Hydroxyl Group. AB - The hydroxyl group in the spacer of a cationic Gemini surfactant (12-3OH-12) caused dramatic changes of the phase behaviors in a protic ionic liquid (EAN). Here, the effects of the hydroxyl group on micellization and lyotropic liquid crystal formation were investigated through the surface tension, small-angle X ray scattering, polarized optical microscopy, and rheological measurements. With the hydroxyl group in the spacer, the critical micellization concentration of 12 3OH-12 was found to be lower than that of the homologue without hydroxyl (12-3 12) and the 12-3OH-12 molecules packed more densely at the air/EAN interface. It was then interesting to observe a coexistence of two separated phases at wide concentration and temperature ranges in this 12-3OH-12/EAN system. Such a micellar phase separation was rarely observed in the ionic surfactant binary system. With the increase of surfactant concentration, the reverse hexagonal and bicontinuous cubic phases appeared in sequence, whereas only a reverse hexagonal phase was found in 12-3-12/EAN system. But, the hexagonal phases formed with 12 3OH-12 exhibited lower viscoelasticity and thermostability than those observed in 12-3-12/EAN system. Such unique changes in phase behaviors of 12-3OH-12 were ascribed to their enhanced solvophilic interactions of 12-3OH-12 and relatively weak solvophobic interactions in EAN. PMID- 26634879 TI - Evaluation of the economic feasibility of a processing plant for steelmaking slag. AB - The utilisation of steelmaking slag as recycled aggregate for concretes is a widely investigated solution for mitigating the expenditure and environmental impacts of its storage. The Brazilian steel industry is investing in research and slag reprocessing practices, aiming to reuse most of its metallic fraction and properly allocate the non-metallic fraction, saving energy and reducing mining impacts. Research results demonstrate the technical and environmental feasibility of steel slag aggregates for civil construction. However, it is essential to evaluate whether the processing of the slag is economically feasible for this purpose. Economic analysis of the processing of steel slag was conducted through simulation - Monte Carlo method - in which it is possible to determine the risks and uncertainties inherent to the project. The costs that comprise the proposed project, from design through construction and operation itself, were estimated at US$2.8 million. The result of the simulation indicates economic feasibility of the project with 98% certainty, and an estimated profit of around 42%. PMID- 26634880 TI - Relationship between Structural Relaxation, Shear Viscosity, and Ionic Conduction of LiPF6/Propylene Carbonate Solutions. AB - The structure and dynamics of the solutions of LiPF6 in propylene carbonate over a concentration range of 0-3 mol/kg are studied with neutron spin echo spectroscopy, alternating-current (AC) conductometry, and shear impedance spectroscopy. The neutron diffraction shows a prepeak at ~10 nm(-1) in addition to the main peak at ~14 nm(-1) when the concentration of the salt is no less than 2 mol/kg. Compared with the frequency-dependent shear viscosity and AC conductivity, the relaxation of the shear stress agrees with that expected from the structural relaxation of the main peak. On the other hand, the relaxation of the conductivity is slower than the shear relaxation at all the concentrations, and the former approximately matches with the relaxation of the prepeak at the highest concentration, 3 mol/kg, which is several times slower than that of the main peak. The possible contribution of the prepeak structure to the ionic conduction is discussed. PMID- 26634881 TI - Gynaecological and obstetrical bleeding in women with factor XI deficiency - a systematic review. AB - INTRODUCTION: Menstrual bleeding, pregnancy and delivery present an intrinsic haemostatic challenge to women with bleeding disorders such as factor XI (FXI) deficiency. AIM: To provide a systematic overview of studies on gynaecological and obstetrical bleeding problems in women with FXI deficiency. METHODS: We searched MEDLINE, EMBASE and the Cochrane library for studies that present original data on the incidence of and treatment options for gynaecological and obstetrical bleeding in FXI-deficient women. RESULTS: We identified 27 studies, including a total of 372 women with FXI deficiency. All studies were observational, no interventional treatment studies were found. Most patients had a mild deficiency (FXI >= 20 IU dL-1 ). Heavy menstrual bleeding (HMB) was reported in 7-67%. In 7/19 (37%) women who underwent gynaecological procedures, a bleeding complication occurred, including in 2/7 hysterectomies (29%). About 3 20% of reported pregnancies ended in a miscarriage; of these miscarriages 0-25% (4/23 miscarriages) were complicated by bleeding. Terminations of pregnancies (TOP) were complicated by bleeding in 4 out of 11 cases (36%). In 90 out of 498 (18%) deliveries a postpartum haemorrhage (PPH) was reported, ranging from 0 to 50% in individual studies. In 21% (66/321) of deliveries, prophylaxis was given. This was associated with 9% (6/66) PPH, compared to 19% in deliveries without prophylaxis (84/432). Epidural analgesia was performed without complications in 44 patients. CONCLUSION: Women with FXI deficiency have a clearly increased risk of HMB, and of bleeding complications after miscarriage, TOP and delivery. No high quality data are available regarding prophylactic treatment. PMID- 26634882 TI - Improved wound management at lower cost: a sensible goal for Australia. AB - Chronic wounds cost the Australian health system at least US$2.85 billion per year. Wound care services in Australia involve a complex mix of treatment options, health care sectors and funding mechanisms. It is clear that implementation of evidence-based wound care coincides with large health improvements and cost savings, yet the majority of Australians with chronic wounds do not receive evidence-based treatment. High initial treatment costs, inadequate reimbursement, poor financial incentives to invest in optimal care and limitations in clinical skills are major barriers to the adoption of evidence based wound care. Enhanced education and appropriate financial incentives in primary care will improve uptake of evidence-based practice. Secondary-level wound specialty clinics to fill referral gaps in the community, boosted by appropriate credentialing, will improve access to specialist care. In order to secure funding for better services in a competitive environment, evidence of cost effectiveness is required. Future effort to generate evidence on the cost effectiveness of wound management interventions should provide evidence that decision makers find easy to interpret. If this happens, and it will require a large effort of health services research, it could be used to inform future policy and decision-making activities, reduce health care costs and improve patient outcomes. PMID- 26634883 TI - Molecular Engineering of Aqueous Soluble Triarylboron-Compound-Based Two-Photon Fluorescent Probe for Mitochondria H2S with Analyte-Induced Finite Aggregation and Excellent Membrane Permeability. AB - Hydrogen sulfide (H2S) is a multifunctional signaling molecule that participates in many important biological processes. Herein, by functionalizing triarylboron with cyclen and diphenylamine, we synthesized TAB-1, TAB-2, and TAB-3 for H2S recongnization by rational design of molecular structures. Among them, aqueous soluble TAB-2 possesses excellent properties, including large two-photon action cross section, membrane permeability and can effectively complex with Cu(2+). The complex of TAB-2-Cu(2+) can selectively detect H2S with an instant response and mitochondria targeted. Moreover, the H2S-induced finite aggregation of indicators enhances their photostability and causes variation of the fluorescence lifetime. TAB-2-Cu(2+) has also been successfully applied for the mitochondria H2S imaging in NIH/3T3 fibroblast cells by TPM and FLIM. PMID- 26634884 TI - Extension of Pyrrolopyrrole pi-System: Approach to Constructing Hexacyclic Nitrogen-Containing Aromatic Systems. AB - A facile three-step approach to synthesizing quinoline-fused pyrrolopyrroles is reported. The crucial step in this synthesis is the condensation of 2-aminophenyl substituted pyrrolopyrroles with aromatic aldehydes. The resulting hexacyclic ladder-type dyes strongly absorb UV radiation and exhibit fluorescence at 450-510 nm. The presence of pyridine-type and pyrrole-type nitrogen atoms is important for the electronic properties of this almost planar heterocycle. These heteroatoms, along with the addition of moderate electron-withdrawing and electron-accepting substituents, provide a means for fine-tuning of the emission characteristics of the polycyclic conjugates. PMID- 26634887 TI - Towards the Limits of Vibrational Circular Dichroism Spectroscopy: VCD Spectra of Some Alkyl Vinylethers. AB - Three alkyl vinylethers from our collection of chiral samples were investigated through VCD spectroscopy, in combination with Density Functional Theory (DFT) calculations. Despite the simplicity of the compounds, reproducing all the spectral features is an involved task, since the many significantly populated conformers contribute to the total VCD spectrum with bands which often have opposite signatures. Nevertheless, we show that certain bands can be satisfactorily reproduced by calculation and therefore they may be employed for the determination of absolute configuration in these and similar compounds, for which no simple alternative method is available. PMID- 26634886 TI - Carotid artery thickness is associated with chronic use of highly active antiretroviral therapy in patients infected with human immunodeficiency virus: A 3.0 Tesla magnetic resonance imaging study. AB - OBJECTIVES: While patients with HIV infection have an elevated stroke risk, ultrasound studies of carotid artery wall thickness have reported variable results. We hypothesized that subjects with HIV infection on chronic highly active antiretroviral therapy (HAART) would have increased carotid artery wall thickness by magnetic resonance imaging (MRI). METHODS: This cross-sectional study compared carotid artery wall thickness between 26 individuals infected with HIV on chronic HAART and 20 controls, without HIV infection but with similar cardiovascular risk factors, using 3.0-T noncontrast MRI. Inclusion criteria included male gender, age 35-55 years, and chronic HAART (>= 3 years) among HIV seropositive subjects; those with known cardiovascular disease or diabetes were excluded. RESULTS: Between subjects with HIV infection and controls, there were no differences in mean (+/-SD) age (47.8 +/- 5.0 vs. 47.8 +/- 4.7 years, respectively; P = 0.19) or cardiovascular risk factors (P > 0.05 for each). Mean (+/-SD) wall thickness was increased in those with HIV infection vs. controls for the left (0.88 +/- 0.08 vs. 0.83 +/- 0.08 mm, respectively; P = 0.03) and right (0.90 +/- 0.10 vs. 0.85 +/- 0.07 mm, respectively; P = 0.046) common carotid arteries. Among individuals with HIV infection, variables associated with increased mean carotid artery wall thickness included lipoaccumulation [+0.09 mm; 95% confidence interval (CI) 0.03-0.14 mm; P = 0.003], Framingham risk score >= 5% (+0.07 mm; 95% CI 0.01-0.12; P = 0.02 mm), and increased duration of protease inhibitor therapy (+0.03 mm per 5 years; 95% CI 0.01-0.06 mm; P = 0.02). CONCLUSIONS: Individuals with HIV infection on chronic HAART had increased carotid artery wall thickness as compared to similar controls. In subjects with HIV infection, the presence of lipoaccumulation and longer duration of protease inhibitor therapy were associated with greater wall thickness. PMID- 26634888 TI - Nanocomposite versus Mesocomposite for Osteogenic Differentiation of Tonsil Derived Mesenchymal Stem Cells. AB - Injectable inorganic/organic composite systems consisting of well-defined mesocrystals (4-8 MUm) of calcium phosphate and polypeptide thermogel significantly enhance the osteogenic differentiation of the tonsil derived mesenchymal stem cells (TMSCs). Compared to composite systems incorporating nanoparticles (10-100 nm) or pure hydrogel systems, osteogenic biomarkers including alkaline phosphatase (ALP), bone morphogenetic protein 2, and osteocalcin are highly expressed at both the mRNA level and the protein level in the mesocrystal composite systems. ALP activity of differentiated cells is also significantly higher in the mesocomposite systems compared to the nanocomposite systems or the pure hydrogel systems. The mesocomposite systems provide not only hard surfaces for binding the cells/proteins by the inorganic mesocrystals but also a soft matrix for holding the cells by the hydrogel. Through the current research, (1) a novel method of preparing mesocrystals is developed, (2) TMSCs are proved as a new resource of stem cells, and (3) the mesocomposite systems are proved to be a promising tool in controlling stem cell differentiation. (4) Finally, the research emphasizes the significance of mesoscience as a new perspective of science in controlling cell and material interfaces. PMID- 26634889 TI - Optimizing clinical use of biomarkers in high-risk acute heart failure patients. AB - AIM: The clinical value of single biomarkers at single time-points to predict outcomes in patients with acute heart failure (AHF) is limited. We performed a multimarker, multi-time-point analysis of biomarkers for the prediction of post discharge clinical outcomes in high-risk AHF patients. METHODS AND RESULTS: A set of 48 circulating biomarkers were measured in the PROTECT trial which enrolled 2033 patients with AHF. Associations between baseline levels of biomarkers and outcomes (30-day all-cause mortality, 30-day death or rehospitalization for renal/cardiovascular causes and 180-day all-cause mortality) were evaluated. Prognostic accuracies of baseline, days 2 or 3, 7, and 14 biomarker measurements were estimated and compared utilizing a time-dependent area under the curve (AUC) analysis. Forty-four biomarkers were significantly associated with outcomes, but 42 had limited prognostic value (C-index < 0.70). However, multimarker models combining best-performing biomarkers from different clusters had a much stronger prognostic value. Combining blood urea nitrogen (BUN), chloride, interleukin (IL) 6, cTnI, sST-2 and VEGFR-1 into a clinical model yielded a 11% increase in C index to 0.84 and 0.78 for 30-day and 180-day all-cause mortality, respectively, and cNRI of 0.86 95% CI [0.55-1.11] and 0.76 95% CI [0.57-0.87]. Prognostic gain was modest for the 30-day death/rehospitalization for cardiovascular or renal causes endpoint. Comparative time-dependent AUC analysis indicated that late measurements provided superior accuracy for the prediction of all-cause mortality over 180 days, with few exceptions including BUN and galectin-3. However, the predictive value of most biomarkers showed a diminishing pattern over time irrespective of moment of measurement. CONCLUSIONS: Multimarker models significantly improve risk prediction. Subsequent measurements, beyond admission, are needed for majority of biomarkers to maximize prognostic value over time, particularly in the long term. PMID- 26634890 TI - Magnesium regulates neural stem cell proliferation in the mouse hippocampus by altering mitochondrial function. AB - In the adult brain, neural stem cells from the subgranular zone (SGZ) of the hippocampus and the subventricular zone (SVZ) of the cortex progress through the following five developmental stages: radial glia-like cells, neural progenitor cells, neuroblasts, immature neurons, and mature neurons. These developmental stages are linked to both neuronal microenvironments and energy metabolism. Neurogenesis is restricted and has been demonstrated to arise from tissue microenvironments. We determined that magnesium, a key nutrient in cellular energy metabolism, affects neural stem cell (NSC) proliferation in cells derived from the embryonic hippocampus by influencing mitochondrial function. Densities of proliferating cells and NSCs both showed their highest values at 0.8 mM [Mg(2+) ]o , whereas lower proliferation rates were observed at 0.4 and 1.4 mM [Mg(2+) ]o . The numbers and sizes of the neurospheres reached the maximum at 0.8 mM [Mg(2+) ]o and were weaker under both low (0.4 mM) and high (1.4 mM) concentrations of magnesium. In vitro experimental evidence demonstrates that extracellular magnesium regulates the number of cultured hippocampal NSCs, affecting both magnesium homeostasis and mitochondrial function. Our findings indicate that the effect of [Mg(2+) ]o on NSC proliferation may lie downstream of alterations in mitochondrial function because mitochondrial membrane potential was highest in the NSCs in the moderate [Mg(2+) ]o (0.8 mM) group and lower in both the low (0.4 mM) and high (1.4 mM) [Mg(2+) ]o groups. Overall, these findings demonstrate a new function for magnesium in the brain in the regulation of hippocampal neural stem cells: affecting their cellular energy metabolism. PMID- 26634891 TI - Force-Induced Reversal of beta-Eliminations: Stressed Disulfide Bonds in Alkaline Solution. AB - Understanding the impact of tensile forces on disulfide bond cleavage is not only crucial to the breaking of cross-linkers in vulcanized materials such as strained rubber, but also to the regulation of protein activity by disulfide switches. By using ab initio simulations in the condensed phase, we investigated the response of disulfide cleavage by beta-elimination to mechanical stress. We reveal that the rate-determining first step of the thermal reaction, which is the abstraction of the beta-proton, is insensitive to external forces. However, forces larger than about 1 nN were found to reshape the free-energy landscape of the reaction so dramatically that a second channel is created, where the order of the reaction steps is reversed, turning beta-deprotonation into a barrier-free follow-up process to C-S cleavage. This transforms a slow and force-independent process with second-order kinetics into a unimolecular reaction that is greatly accelerated by mechanical forces. PMID- 26634892 TI - Gastrodin Ameliorates Oxidative Stress and Proinflammatory Response in Nonalcoholic Fatty Liver Disease through the AMPK/Nrf2 Pathway. AB - This study was designed to investigate the antioxidative, antiinflammatory and metabolism-regulating effects of gastrodin (GSTD) in the treatment of nonalcoholic fatty liver disease (NAFLD). Oleic acid (OA) was used to induce steatosis in HL-7702 cells; a high-fat or high-fat and high-cholesterol diet was used to induce NAFLD in mice and rats. Our results showed that GSTD significantly increased hepatic superoxide dismutase (SOD) but decreased reactive oxygen species (ROS)/malondialdehyde (MDA) and reduced the mRNA levels of proinflammatory cytokines both in vitro and in vivo. GSTD promoted the phosphorylation of nuclear factor erythroid-2-related factor-2 (Nrf2) at serine (Ser) 40, stimulated its nuclear translocation and increased hepatic expression of heme oxygenase-1 (HO-1). GSTD activated AMP-activated protein kinase (AMPK), suppressed hepatic steatosis, lowered serum triglyceride (TG)/glucose and decreased body weight gain in animals with NAFLD. The stimulating effects of GSTD on the Nrf2 pathway as well as its antioxidative/antiinflammatory activities were abolished by compound C in OA-treated HL-7702 cells. In summary, our results demonstrate that GSTD activates the AMPK/Nrf2 pathway, ameliorates oxidative stress/proinflammatory response and improves lipid metabolism in NAFLD. Our findings may support the future clinical application of GSTD for the treatment of NAFLD to reduce hepatic steatosis, oxidative stress and proinflammatory response. PMID- 26634893 TI - Mitigating the Effects of Nonadherence in Clinical Trials. AB - Accounting for subject nonadherence and eliminating inappropriate subjects in clinical trials are critical elements of a successful study. Nonadherence can increase variance, lower study power, and reduce the magnitude of treatment effects. Inappropriate subjects (including those who do not have the illness under study, fail to report exclusionary conditions, falsely report medication adherence, or participate in concurrent trials) confound safety and efficacy signals. This paper, a product of the International Society for CNS Clinical Trial Methodology (ISCTM) Working Group on Nonadherence in Clinical Trials, explores and models nonadherence in clinical trials and puts forth specific recommendations to identify and mitigate its negative effects. These include statistical analyses of nonadherence data, novel protocol design, and the use of biomarkers, subject registries, and/or medication adherence technologies. PMID- 26634894 TI - In situ X-ray diffraction and the evolution of polarization during the growth of ferroelectric superlattices. AB - In epitaxially strained ferroelectric thin films and superlattices, the ferroelectric transition temperature can lie above the growth temperature. Ferroelectric polarization and domains should then evolve during the growth of a sample, and electrostatic boundary conditions may play an important role. In this work, ferroelectric domains, surface termination, average lattice parameter and bilayer thickness are simultaneously monitored using in situ synchrotron X-ray diffraction during the growth of BaTiO3/SrTiO3 superlattices on SrTiO3 substrates by off-axis radio frequency magnetron sputtering. The technique used allows for scan times substantially faster than the growth of a single layer of material. Effects of electric boundary conditions are investigated by growing the same superlattice alternatively on SrTiO3 substrates and 20 nm SrRuO3 thin films on SrTiO3 substrates. These experiments provide important insights into the formation and evolution of ferroelectric domains when the sample is ferroelectric during the growth process. PMID- 26634896 TI - Preferential Excitation of the Hybrid Magnetic-Electric Mode as a Limiting Mechanism for Achievable Fundamental Magnetic Resonance in Planar Aluminum Nanostructures. AB - Aluminum is a promising candidate for light at the nanoscale in the ultraviolet (UV); however, the realization of magnetic resonance in the UV range remains challenging due to stringent dimensional requirements arising from the intrinsic loss caused by the interband transition. Here, the mode interaction with the aluminum interband transition and preferential excitation of the hybrid magnetic electric mode, as discovered in ultrasmall Al resonators, are reported. PMID- 26634895 TI - Modulatory and plastic effects of kinins on spinal cord networks. AB - KEY POINTS: Inflammatory kinins are released following spinal cord injury or neurotrauma. The effects of these kinins on ongoing locomotor activity of central pattern generator networks are unknown. In the present study, kinins were shown to have short- and long-term effects on motor networks. The short-term effects included direct depolarization of interneurons and motoneurons in the ventral horn accompanied by modulation of transient receptor potential vanilloid 1 sensitive nociceptors in the dorsal horn. Over the long-term, we observed a bradykinin-mediated effect on promoting plasticity in the spinal cord. In a model of spinal cord injury, we observed an increase in microglia numbers in both the dorsal and ventral horn and, in a microglia cell culture model, we observed bradykinin-induced expression of glial-derived neurotrophic factor. ABSTRACT: The expression and function of inflammatory mediators in the developing spinal cord remain poorly characterized. We discovered novel, short and long-term roles for the inflammatory nonapeptide bradykinin (BK) and its receptor bradykinin receptor B2 (B2R) in the neuromodulation of developing sensorimotor networks following a spinal cord injury (SCI), suggesting that BK participates in an excitotoxic cascade. Functional expression of B2R was confirmed by a transient disruptive action of BK on fictive locomotion generated by a combination of NMDA, 5-HT and dopamine. The role of BK in the dorsal horn nociceptive afferents was tested using spinal cord attached to one-hind-limb (HL) preparations. In the HL preparations, BK at a subthreshold concentration induced transient disruption of fictive locomotion only in the presence of: (1) noxious heat applied to the hind paw and (2) the heat sensing ion channel transient receptor potential vanilloid 1 (TRPV1), known to be restricted to nociceptors in the superficial dorsal horn. BK directly depolarized motoneurons and ascending interneurons in the ventrolateral funiculus. We found a key mechanism for BK in promoting long-term plasticity within the spinal cord. Using a model of neonatal SCI and a microglial cell culture model, we examined the role of BK in inducing activation of microglia and expression of glial-derived neurotrophic factor (GDNF). In the neonatal SCI model, we observed an increase in microglia numbers and increased GDNF expression restricted to microglia. In the microglia cell culture model, we observed a BK induced increased expression of GDNF via B2R, suggesting a novel mechanism for BK spinal-mediated plasticity. PMID- 26634897 TI - South African adolescents' beliefs about depression. AB - PURPOSE: This study explores the depression literacy in adolescents in South Africa. METHOD: A semi-structured questionnaire was administered to 2,050 students from disadvantaged secondary schools in Johannesburg region. RESULT: A total of 90.9% reported depression as an illness, and 41.4% considered it a sign of weakness. Parents and siblings followed by friends and teachers were the preferred support options. The indicators of depression identified were socialisation pattern changes (24.6%), sad mood (23.6%), sleeping and eating pattern changes (18.3%), irritable behaviour (12.5%) and other health risk behaviours (9.7%). CONCLUSION: The majority considered depression an illness. An improvement in adolescent mental health literacy will increase access to help when needed. PMID- 26634899 TI - Differential effect of DJ-1/PARK7 on development of natural and induced regulatory T cells. AB - Regulatory T cells (Tregs) are essential for maintaining an effective immune tolerance and a homeostatic balance of various other immune cells. To manipulate the immune response during infections and autoimmune disorders, it is essential to know which genes or key molecules are involved in the development of Tregs. Transcription factor Foxp3 is required for the development of Tregs and governs most of the suppressive functions of these cells. Inhibited PI3K/AKT/mTOR signalling is critical for Foxp3 stability. Previous studies have suggested that DJ-1 or PARK7 protein is a positive regulator of the PI3K/AKT/mTOR pathway by negatively regulating the activity of PTEN. Thus, we hypothesised that a lack of DJ-1 could promote the development of Tregs. As a result, loss of DJ-1 decreased the total CD4(+) T cell numbers but increased the fraction of thymic and peripheral nTregs. In contrast, Foxp3 generation was not augmented following differentiation of DJ-1-deficient naive CD4(+) T cells. DJ-1-deficient-iTregs were imperfect in replication, proliferation and more prone to cell death. Furthermore, DJ-1 deficient iTregs were less sensitive to pSmad2 and pStat5 signalling but had activated AKT/mTOR signalling. These observations reveal an unexpected differential role of DJ-1 in the development of nTregs and iTregs. PMID- 26634900 TI - The most sensitive inputs to cutaneous representing regions of primary somatosensory cortex do not change with behavioral training. AB - Learning a sensory detection task leads to an increased primary sensory cortex response to the detected stimulus, while learning a sensory discrimination task additionally leads to a decreased sensory cortex response to the distractor stimulus. Neural responses are scaled up, and down, in strength, along with concomitant changes in receptive field size. The present work considers neural response properties that are invariant to learning. Data are drawn from two animals that were trained to detect and discriminate spatially separate taps delivered to positions on the skin of their fingers. Each animal was implanted with electrodes positioned in area 3b, and responses were derived on a near daily basis over 84 days in animal 1 and 202 days in animal 2. Responses to taps delivered in the receptive field were quantitatively measured each day, and receptive fields were audiomanually mapped each day. In the subset of responses that had light cutaneous receptive fields, a preponderance of the days, the most sensitive region of the field was invariant to training. This skin region was present in the receptive field on all, or nearly all, occasions in which the receptive field was mapped, and this region constituted roughly half of the most sensitive region. These results suggest that maintaining the most sensitive inputs as dominant in cortical receptive fields provide a measure of stability that may be transformationally useful for minimizing reconstruction errors and perceptual constancy. PMID- 26634901 TI - Passive heating following the prematch warm-up in soccer: examining the time course of changes in muscle temperature and contractile function. AB - This study examined changes in muscle temperature, electrically evoked muscle contractile properties, and voluntary power before and after a soccer specific active warm-up and subsequent rest period. Ten amateur soccer players performed two experimental sessions that involved performance of a modified FIFA 11+ soccer specific warm-up, followed by a 12.5-min rest period where participants were required to wear either normal clothing or a passive electrical heating garment was applied to the upper thigh muscles. Assessments around the warm-up and cool down included measures of maximal torque, rate of torque development, muscle temperature (Tm), and electrically evoked measures of quadriceps contractile function. Tm was increased after the warm-up by 3.2 +/- 0.7 degrees C (P < 0.001). Voluntary and evoked rates of torque development increased after the warm up between 20% and 30% (P < 0.05), despite declines in both maximal voluntary torque and voluntary activation (P < 0.05). Application of a passive heating garment in the cool-down period after the warm-up did not effect variables measured. While Tm was reduced by 1.4 +/- 0.4 degrees C after the rest period (P < 0.001), this value was still higher than pre warm-up levels. Voluntary and evoked rate of torque development remained elevated from pre warm-up levels at the end of the cool-down (P < 0.05). The soccer specific warm-up elevated muscle temperature by 3.2 degrees C and was associated with concomitant increases of between 20% and 30% in voluntary rate of torque development, which seems explained by elevations in rate-dependent measures of intrinsic muscle contractile function. Application of a passive heating garment did not attenuate declines in muscle temperature during a 12.5-min rest period. PMID- 26634902 TI - TNF causes changes in glomerular endothelial permeability and morphology through a Rho and myosin light chain kinase-dependent mechanism. AB - A key function of the endothelium is to serve as a regulated barrier between tissue compartments. We have previously shown that tumor necrosis factor (TNF) plays a crucial role in lipopolysaccharide (LPS)-induced acute kidney injury, in part by causing injury to the renal endothelium through its receptor TNFR1. Here, we report that TNF increased permeability to albumin in primary culture mouse renal endothelial cells, as well as human glomerular endothelial cells. This process occurred in association with changes in the actin cytoskeleton and was associated with gaps between previously confluent cells in culture and decreases in the tight junction protein occludin. This process was dependent on myosin light chain activation, as seen by its prevention with Rho-associated kinase and myosin light chain kinase (MLCK) inhibitors. Surprisingly, permeability was not blocked by inhibition of apoptosis with caspase inhibitors. Additionally, we found that the renal glycocalyx, which plays an important role in barrier function, was also degraded by TNF in a Rho and MLCK dependent fashion. TNF treatment caused a decrease in the size of endothelial fenestrae, dependent on Rho and MLCK, although the relevance of this to changes in permeability is uncertain. In summary, TNF-induced barrier dysfunction in renal endothelial cells is crucially dependent upon the Rho/MLCK signaling pathway. PMID- 26634903 TI - Epoetin beta pegol alleviates oxidative stress and exacerbation of renal damage from iron deposition, thereby delaying CKD progression in progressive glomerulonephritis rats. AB - The increased deposition of iron in the kidneys that occurs with glomerulopathy hinders the functional and structural recovery of the tubules and promotes progression of chronic kidney disease (CKD). Here, we evaluated whether epoetin beta pegol (continuous erythropoietin receptor activator: CERA), which has a long half-life in blood and strongly suppresses hepcidin-25, exerts renoprotection in a rat model of chronic progressive glomerulonephritis (cGN). cGN rats showed elevated urinary total protein excretion (uTP) and plasma urea nitrogen (UN) from day 14 after the induction of kidney disease (day 0) and finally declined into end-stage kidney disease (ESKD), showing reduced creatinine clearance with glomerulosclerosis, tubular dilation, and tubulointerstitial fibrosis. A single dose of CERA given on day 1, but not on day 16, alleviated increasing uTP and UN, thereby delaying ESKD. In the initial disease phase, CERA significantly suppressed urinary 8-OHdG and liver-type fatty acid-binding protein (L-FABP), a tubular damage marker. CERA also inhibited elevated plasma hepcidin-25 levels and alleviated subsequent iron accumulation in kidneys in association with elevated urinary iron excretion and resulted in alleviation of growth of Ki67-positive tubular and glomerular cells. In addition, at day 28 when the exacerbation of uTP occurs, a significant correlation was observed between iron deposition in the kidney and urinary L-FABP. In our study, CERA mitigated increasing kidney damage, thereby delaying CKD progression in this glomerulonephritis rat model. Alleviation by CERA of the exacerbation of kidney damage could be attributable to mitigation of tubular damage that might occur with lowered iron deposition in tubules. PMID- 26634904 TI - Glicentin-related pancreatic polypeptide inhibits glucose-stimulated insulin secretion from the isolated pancreas of adult male rats. AB - Peptides derived from the glucagon gene Gcg, for example, glucagon and glucagon like peptide 1 (GLP-1), act as physiological regulators of fuel metabolism and are thus of major interest in the pathogenesis of diseases, such as type-2 diabetes and obesity, and their therapeutic management. Glicentin-related pancreatic polypeptide (GRPP) is a further, 30 amino acid Gcg-derived peptide identified in human, mouse, rat, and pig. However, the potential glucoregulatory function of this peptide is largely unknown. Here, we synthesized rat GRPP (rGRPP) and a closely related peptide, rat GRPP-like peptide (rGRPP-LP), and investigated their actions in the liver and pancreas of adult male rats by employing isolated-perfused organ preparations. Rat GRPP and rGRPP-LP did not affect glucose output from the liver, but both elicited potent inhibition of glucose-stimulated insulin secretion (GSIS) from the rat pancreas. This action is unlikely to be mediated by glucagon or GLP-1 receptors, as rGRPP and rGRPP-LP did not stimulate cyclic adenosine monophosphate (cAMP) production from the glucagon or GLP-1 receptors, nor did they antagonize glucagon- or GLP-1-stimulated cAMP production at either receptor. GRPP and GRPP-LP may be novel regulators of insulin secretion, acting through an as-yet undefined receptor. PMID- 26634905 TI - Secretome identification of immune cell factors mediating metastatic cell homing. AB - Metastatic cell homing is a complex process mediated in part by diffusible factors secreted from immune cells found at a pre-metastatic niche. We report on connecting secretomics and TRanscriptional Activity CEll aRray (TRACER) data to identify functional paracrine interactions between immune cells and metastatic cells as novel mediators of homing. Metastatic breast cancer mouse models were used to generate a diseased splenocyte conditioned media (D-SCM) containing immune cell secreted factors. MDA-MB-231 metastatic cell activity including cell invasion, migration, transendothelial migration, and proliferation were increased in D-SCM relative to control media. Our D-SCM secretome analysis yielded 144 secreted factor candidates that contribute to increased metastatic cell activity. The functional mediators of homing were identified using MetaCore software to determine interactions between the immune cell secretome and the TRACER identified active transcription factors within metastatic cells. Among the 5 candidate homing factors identified, haptoglobin was selected and validated in vitro and in vivo as a key mediator of homing. Our studies demonstrate a novel systems biology approach to identify functional signaling factors associated with a cellular phenotype, which provides an enabling tool that complements large scale protein identification provided by proteomics. PMID- 26634906 TI - Evolution of crystal and electronic structures of magnesium dicarbide at high pressure. AB - Carbon-based compounds exhibit unexpected structures and electronic behavior at high pressure arising from various bonding features of carbon (e.g., sp, sp(2) and sp(3) C-C bonds). Here we report evolution of crystal structures of MgC2 in a wide pressure range of 0-200 GPa as predicted through ab-initio calculations in combination with an unbiased swarm structure search. Three pressure-induced structural transformations are unraveled, following the phase sequence of ambient pressure P42/mnm (alpha-phase) -> Cmcm (beta-phase) -> C2m (gamma-phase) -> EuGe2 type P-3m1 (delta-phase), where significant C-C bonding modifications from C-C dimer to quasi 1-dimensionzigzag chain, to polymerized ribbon and then to winkled quasi 2- dimension graphite sheet are evident. The predicted beta- and gamma phases with sp(2) C-C hybridization are metals, while the delta- phase characterized by a sp(3)C-C hybridization is a narrow-gap semiconductor with a band gap of 0.667 eV. Strong electron-phonon couplings in the compressed beta- and gamma- phases arepredicted with beta-phase showing a high superconducting critical temperature of 11.2 K. The current results indicate that pressure is effective in tuning the crystal and electronic structures of MgC2, which is expected to have impact on physical properties for potential applications. PMID- 26634907 TI - Collective punishment is more effective than collective reward for promoting cooperation. AB - Collective punishment and reward are usually regarded as two potential mechanisms to explain the evolution of cooperation. Both scenarios, however, seem problematic to understand cooperative behavior, because they can raise the second order free-rider problem and many organisms are not able to discriminate less cooperating individuals. Even though they have been proved to increase cooperation, there has been a debate about which one being more effective. To address this issue, we resort to the N-player evolutionary snowdrift game (NESG), where a collective punishment/reward mechanism is added by allowing some players to display punishment/reward towards all remaining players. By means of numerous simulations and analyses, we find that collective punishment is more effective in promoting cooperation for a relatively high initial frequency of cooperation or for a relatively small group. When the intensity of punishment exceeds a certain threshold, a stable state of full cooperation emerges for both small and large groups. In contrast, such state does not appear for large groups playing a NESG with reward mechanism. In the case of mutualistic interactions, finally, our results show the new payoff with collective punishment/reward can lead to the coexistence of cooperators and defectors when discrimination between these two is not possible. PMID- 26634908 TI - Reduced GeO2 Nanoparticles: Electronic Structure of a Nominal GeOx Complex and Its Stability under H2 Annealing. AB - A nominal GeOx (x <= 2) compound contains mixtures of Ge, Ge suboxides, and GeO2, but the detailed composition and crystallinity could vary from material to material. In this study, we synthesize GeOx nanoparticles by chemical reduction of GeO2, and comparatively investigate the freshly prepared sample and the sample exposed to ambient conditions. Although both compounds are nominally GeOx, they exhibit different X-ray diffraction patterns. X-ray absorption fine structure (XAFS) is utilized to analyse the detailed structure of GeOx. We find that the two initial GeOx compounds have entirely different compositions: the fresh GeOx contains large amorphous Ge clusters connected by GeOx, while after air exposure; the Ge clusters are replaced by a GeO2-GeOx composite. In addition, the two GeOx products undergo different structural rearrangement under H2 annealing, producing different intermediate phases before ultimately turning into metallic Ge. In the fresh GeOx, the amorphous Ge remains stable, with the GeOx being gradually reduced to Ge, leading to a final structure of crystalline Ge grains connected by GeOx. The air-exposed GeOx on the other hand, undergoes a GeO2->GeOx->Ge transition, in which H2 induces the creation of oxygen vacancies at intermediate stage. A complete removal of oxides occurs at high temperature. PMID- 26634910 TI - Glioma: Tumour cell teamwork. PMID- 26634909 TI - Two Distinct Moral Mechanisms for Ascribing and Denying Intentionality. AB - Philosophers and legal scholars have long theorized about how intentionality serves as a critical input for morality and culpability, but the emerging field of experimental philosophy has revealed a puzzling asymmetry. People judge actions leading to negative consequences as being more intentional than those leading to positive ones. The implications of this asymmetry remain unclear because there is no consensus regarding the underlying mechanism. Based on converging behavioral and neural evidence, we demonstrate that there is no single underlying mechanism. Instead, two distinct mechanisms together generate the asymmetry. Emotion drives ascriptions of intentionality for negative consequences, while the consideration of statistical norms leads to the denial of intentionality for positive consequences. We employ this novel two-mechanism model to illustrate that morality can paradoxically shape judgments of intentionality. This is consequential for mens rea in legal practice and arguments in moral philosophy pertaining to terror bombing, abortion, and euthanasia among others. PMID- 26634911 TI - Non-additive effects of litter diversity on greenhouse gas emissions from alpine steppe soil in Northern Tibet. AB - While litter decomposition is a fundamental ecological process, previous studies have mainly focused on the decay of single species. In this study, we conducted a litter-mixing experiment to investigate litter diversity effects on greenhouse gas (GHG) emissions from an alpine steppe soil in Northern Tibet. Significant non additive effects of litter diversity on GHG dynamics can be detected; these non additive effects were the result of species composition rather than species richness. Synergistic effects were frequent for CO2 and N2O emissions, as they were found to occur in 70.5% and 47.1% of total cases, respectively; antagonistic effects on CH4 uptake predominated in 60.3% of the cases examined. The degree of synergism and antagonism may be significantly impacted by litter chemical traits, such as lignin and N, lignin:N ratio, and total phenols during decomposition (P < 0.05). In addition, the relationship between chemical traits and litter-mixing effects changed over incubation time. Our study provides an opportunity to gain insight into the relationship between litter diversity and soil ecological processes. The results indicate that higher plant diversity may generally enhance CO2 and N2O emissions while inhibiting CH4 uptake; meanwhile, the direction and strength of non-additive effects appear to be related to litter chemical traits. PMID- 26634912 TI - The Long Noncoding RNA IFNG-AS1 Promotes T Helper Type 1 Cells Response in Patients with Hashimoto's Thyroiditis. AB - The long noncoding (lnc) RNA-Ifng-AS1 plays an essential role in the transcription of the gene encoding IFN-gamma by Th1 cells, and its human ortholog, IFNG-AS1, is expressed in human Th1 cells. However, IFNG-AS1 contributing to Th1 cells' response in Hashimoto's thyroiditis (HT) patients has not been reported. Twenty-eight HT patients and 20 healthy controls were enrolled in the study. The proportion of circulating Th1 cells and the level of T-bet, IFNG mRNA were increased in HT patients, the expression of IFNG-AS1 was upregulated and positively correlated with the proportion of circulating Th1 cells or T-bet, and IFNG expression, or serum level of anti-thyroglobulin antibody/thyroperoxidase antibody in HT patients. IFNG-AS1 regulated the expression of IFNG at both transcriptional and translational level in human CD4(+) T cells. Furthermore, strong positive correlations between the increased transcript level of IFNG-AS1 and the increased transcript level of T-bet or IFNG were revealed in thyroid tissues from HT patients. Our results indicate that enhanced expression of lncRNA-IFNG-AS1 contributes to Th1 cell response in HT patients and may be involved in the pathogenesis of HT. PMID- 26634913 TI - Interactive media for parental education on managing children chronic condition: a systematic review of the literature. AB - BACKGROUND: Although some research has examined the use of games for the education of pediatric patients, the use of technology for parental education seems like an appropriate application as it has been a part of the popular culture for at least 30 years. The main objective of this systematic review is to examine the literature for research evaluating the use of interactive media in the education of parents of children with chronic conditions. METHODS: We searched the MEDLINE, PSYCHINFO, CINAHL, Cochrane database of systematic reviews and EMBASE databases from 1986 to 2014 seeking original investigations on the use of interactive media and video games to educate parents of children with chronic conditions. Cohort studies, randomized control trials, and observational studies were included in our search of the literature. Two investigators reviewed abstracts and full texts as necessary. The quality of the studies was assessed using the GRADE guidelines. Overall trend in the results and the degree of certainty in the results were considered when assessing the body of literature pertaining to our focused questions. RESULTS: Our initial search identified 4367 papers, but only 12 fulfilled the criterion established for final analysis, with the majority of the studies having flaws that reduced their quality. These papers reported mostly positive results supporting the idea that parent education is possible through interactive media. CONCLUSION: We found limited evidence of the effectiveness of using serious games and or interactive media to educate parents of children with chronic conditions. PMID- 26634914 TI - Emergency medical services transport delays for suspected stroke and myocardial infarction patients. AB - BACKGROUND: Prehospital delays in receiving emergency care for suspected stroke and myocardial infarction (MI) patients have significant impacts on health outcomes. Use of Emergency Medical Services (EMS) has been shown to reduce these delays. However, disparities in EMS transport delays are thought to exist. Therefore the objective of this study was to investigate and identify disparities in EMS transport times for suspected stroke and MI patients. METHODS: Over 3,900 records of suspected stroke and MI patients, reported during 2006-2009, were obtained from two EMS agencies (EMS 1 & EMS 2) in Tennessee. Summary statistics of transport time intervals were computed. Multivariable logistic models were used to identify predictors of time intervals exceeding EMS guidelines. RESULTS: Only 66 and 10 % of suspected stroke patients were taken to stroke centers by EMS 1 and 2, respectively. Most (80-83 %) emergency calls had response times within the recommended 10 min. However, over 1/3 of the calls had on-scene times exceeding the recommended 15 min. Predictors of time intervals exceeding EMS guidelines were EMS agency, patient age, season and whether or not patients were taken to a specialty center. The odds of total transport time exceeding EMS guidelines were significantly lower for patients not taken to specialty centers. Noteworthy was the 72 % lower odds of total time exceeding guidelines for stroke patients served by EMS 1 compared to those served by EMS 2. Additionally, for every decade increase in age of the patient, the odds of on-scene time exceeding guidelines increased by 15 and 19 % for stroke and MI patients, respectively. CONCLUSION: In this study, prehospital delays, as measured by total transport time exceeding guideline was influenced by season, EMS agency responsible, patient age and whether or not the patient is transported to a specialty center. The magnitude of the delays associated with some of the factors are large enough to be clinically important although others, though statistically significant, may not be large enough to be clinically important. These findings should be useful for guiding future studies and local health initiatives that seek to reduce disparities in prehospital delays so as to improve health services and outcomes for stroke and MI patients. PMID- 26634915 TI - Seasonal Occurrence of Uroleucon nigrotuberculatum (Hemiptera: Aphididae) in Northern Kyushu and Mechanisms of Its Summer Disappearance. AB - Regulation mechanisms of insect population dynamics are important for conservation biology and insect pest management. The aphid Uroleucon nigrotuberculatum (Olive), native to North America, was introduced into Japan in the late 1980s. A previous study revealed that, in Japan, the aphid population densities increased in spring, but they suddenly disappeared from low-elevation areas in midsummer (called "summer disappearance"). However, the aphids were found continuously in a mountainous area throughout the season. Field investigations and field and laboratory experiments were conducted to clarify the mechanism of such population dynamics. Although the number of aphids increased in spring, they rapidly decreased in lowland and mountainous areas in early summer. Both top-down and bottom-up effects seemed to contribute to the rapid decline because the density of predators peaked in the growing season and the host plant height reached 60-80 cm, which suppressed the reproduction of aphids in our laboratory experiment. Then the aphids disappeared from lowland areas in midsummer when the maximum air temperature reached 35 degrees C there. The laboratory experiment revealed that the aphid does not survive at 35 degrees C. In addition, our field experiment in summer showed that U. nigrotuberculatum disappeared regardless of the presence or absence of an aphidophagous coccinellid, and the aphids did not disappear even on the tall plant treatment in the laboratory experiment. These results strongly suggest that high temperature in lowland areas causes the summer disappearance of U. nigrotuberculatum. Therefore, the population density of U. nigrotuberculatum is regulated by different factors between seasons and altitudes. PMID- 26634917 TI - An immune-modulating diet increases the regulatory T cells and reduces T helper 1 inflammatory response in Leishmaniosis affected dogs treated with standard therapy. AB - BACKGROUND: Clinical appearance and evolution of Canine Leishmaniosis (CL) are the consequence of complex interactions between the parasite and the genetic and immunological backgrounds. We investigated the effect of an immune-modulating diet in CL. Dogs were treated with anti- Leishmania pharmacological therapy combined with standard diet (SD Group) or with the immune-modulating diet (IMMD Group). CD3+ CD4+ Foxp3+ Regulatory T cells (Treg) and CD3+ CD4+ IFN-gamma + T helper 1 (Th1) were analyzed by flow cytometry. RESULTS: All sick dogs showed low platelet number at diagnosis (T0). A platelet increase was observed after six months (T6) SD Group, with still remaining in the normal range at twelve months (T12). IMMD Group showed an increase in platelet number becoming similar to healthy dogs at T6 and T12. An increase of CD4/CD8 ratio was revealed in SD Group after three months (T3), while at T6 and at T12 the values resembled to T0. The increase in CD4/CD8 ratio at T3 was maintained at T6 and T12 in IMMD Group. A reduction in the percentage of Treg of all sick dogs was observed at T0. A recovery of Treg percentage was observed only at T3 in SD Group, while this effect disappeared at T6 and T12. In contrast, Treg percentage became similar to healthy animals in IMDD Group at T3, T6 and T12. Sick dogs showed an increase of Th1 cells at T0 as compared with healthy dogs. We observed the occurrence of a decrease of Th1 cells from T3 to T12 in SD Group, although a trend of increase was observed at T6 and T12. At variance, IMMD Group dogs showed a progressive decrease of Th1 cells, whose levels became similar to healthy controls at T6 and T12. CONCLUSION: The immune-modulating diet appears to regulate the immune response in CL during the standard pharmacological treatment. The presence of nutraceuticals in the diet correlates with the decrease of Th1 cells and with the increase of Treg in sick dogs. Therefore, the administration of the specific dietary supplement improved the clinical response to the standard treatment in a model of CL. PMID- 26634918 TI - Surveying and benchmarking techniques to analyse DNA gel fingerprint images. AB - DNA fingerprinting is a genetic typing technique that allows the analysis of the genomic relatedness between samples, and the comparison of DNA patterns. The analysis of DNA gel fingerprint images usually consists of five consecutive steps: image pre-processing, lane segmentation, band detection, normalization and fingerprint comparison. In this article, we firstly survey the main methods that have been applied in the literature in each of these stages. Secondly, we focus on lane-segmentation and band-detection algorithms-as they are the steps that usually require user-intervention-and detect the seven core algorithms used for both tasks. Subsequently, we present a benchmark that includes a data set of images, the gold standards associated with those images and the tools to measure the performance of lane-segmentation and band-detection algorithms. Finally, we implement the core algorithms used both for lane segmentation and band detection, and evaluate their performance using our benchmark. As a conclusion of that study, we obtain that the average profile algorithm is the best starting point for lane segmentation and band detection. PMID- 26634920 TI - Community-acquired pneumonia: pneumococcal vaccine. AB - INTRODUCTION: In the Northern Hemisphere about 12/1000 people per year (on average) contract pneumonia while living in the community, with most cases caused by Streptococcus pneumoniae. Mortality ranges from about 5% to 35% depending on severity of disease, with a worse prognosis in older people, men, and people with chronic diseases. METHODS AND OUTCOMES: We conducted a systematic overview, aiming to answer the following clinical question: What are the effects of pneumococcal vaccine to prevent community-acquired pneumonia? We searched: Medline, Embase, The Cochrane Library, and other important databases up to April 2014 (Clinical Evidence overviews are updated periodically; please check our website for the most up-to-date version of this overview). RESULTS: At this update, searching of electronic databases retrieved 651 studies. After deduplication and removal of conference abstracts, 403 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 348 studies and the further review of 55 full publications. Of the 55 full articles evaluated, eight systematic reviews and one RCT were added at this update. In addition, one RCT was added to the Comment section. We performed a GRADE evaluation for five PICO combinations. CONCLUSIONS: In this systematic overview, we categorised the efficacy for two intervention based on information about the effectiveness and safety of conjugated vaccine and polysaccharide vaccine. PMID- 26634919 TI - Progress and challenges in bioinformatics approaches for enhancer identification. AB - Enhancers are cis-acting DNA elements that play critical roles in distal regulation of gene expression. Identifying enhancers is an important step for understanding distinct gene expression programs that may reflect normal and pathogenic cellular conditions. Experimental identification of enhancers is constrained by the set of conditions used in the experiment. This requires multiple experiments to identify enhancers, as they can be active under specific cellular conditions but not in different cell types/tissues or cellular states. This has opened prospects for computational prediction methods that can be used for high-throughput identification of putative enhancers to complement experimental approaches. Potential functions and properties of predicted enhancers have been catalogued and summarized in several enhancer-oriented databases. Because the current methods for the computational prediction of enhancers produce significantly different enhancer predictions, it will be beneficial for the research community to have an overview of the strategies and solutions developed in this field. In this review, we focus on the identification and analysis of enhancers by bioinformatics approaches. First, we describe a general framework for computational identification of enhancers, present relevant data types and discuss possible computational solutions. Next, we cover over 30 existing computational enhancer identification methods that were developed since 2000. Our review highlights advantages, limitations and potentials, while suggesting pragmatic guidelines for development of more efficient computational enhancer prediction methods. Finally, we discuss challenges and open problems of this topic, which require further consideration. PMID- 26634921 TI - Population structure and genetic diversity in the nannandrous moss Homalothecium lutescens: does the dwarf male system facilitate gene flow? AB - BACKGROUND: Nannandry is a sexual system where males ("dwarf males") are much smaller than the conspecific females. Dwarf males occur in a wide range of unrelated organisms but the evolutionary advantages of this condition are poorly understood. The dwarf male sexual system results in differences in the mode of dispersal and establishment as well as the life span between males and females. Such differences must have profound effects on the population dynamics and genetic structures. We have studied four populations of the nannandrous moss Homalothecium lutescens in southern Sweden. We genotyped dwarf males and female shoots with the aim of describing the genetic diversity and structure of the populations. RESULTS: Dwarf males were most related to their host shoot, then their colony (within 0.5 m(2)) and then the rest of the population, which suggests restricted spore dispersal. However, a few dwarf males in each population appeared to originate from other colonies and sometimes even other populations. Genetic diversity of dwarf males was generally high but showed no tendency to be consistently higher or lower than female genetic diversity within the four populations. CONCLUSIONS: Although most dwarf males have local origin, sporadic dispersal events occur. The ability of the dwarf males to establish in high numbers in mature colonies facilitates gene flow between populations as well as increases the potential to accumulate genetic diversity within populations. PMID- 26634922 TI - The impact of a computerized decision aid on empowering pregnant women for choosing vaginal versus cesarean section delivery: study protocol for a randomized controlled trial. AB - BACKGROUND: Cesarean delivery on maternal request (CDMR) is one of the main reasons for cesarean delivery in Iran, and women often need help in making a decision about the delivery options available to them. The main objective of this study is to evaluate the effect of a computerized decision aid (CDA) system on empowering pregnant women in choosing an appropriate mode of delivery. This CDA contrasts the advantages and disadvantages of vaginal versus cesarean section delivery in terms of their value to the individual woman. METHODS/DESIGN: The protocol concerns a randomized trial study that will be performed among Iranian women. Four hundred pregnant women will be recruited from two private and two public prenatal centers in Mashhad, Iran. They will be randomly assigned to either an intervention or a control group. The designed CDA will be provided to the intervention group, whereas the control group will only receive routine care. The CDA provides educational contents as well as some recommendations. The CDA's knowledge base is obtained from the results of studies on predictors of cesarean delivery. The CDA's software will be installed on women's computers for use at home. The two primary outcomes for the study are O'Connor's Decisional Conflict Scale and knowledge as measured by true/false questions. Actual mode of delivery (vaginal versus cesarean) will be compared in the two groups. DISCUSSION: We investigate the effect of a CDA on empowering pregnant women in terms of reducing their decisional conflict as well as on improving their clinical knowledge pertaining to mode of delivery. TRIAL REGISTRATION: This trial is registered with the Iran Trial Registrar under registration number IRCT2015093010777N4 and registration date 26 October 2015. PMID- 26634923 TI - The evolution of social networks through the implementation of evidence-informed decision-making interventions: a longitudinal analysis of three public health units in Canada. AB - BACKGROUND: We studied the evolution of information-seeking networks over a 2 year period during which an organization-wide intervention was implemented to promote evidence-informed decision-making (EIDM) in three public health units in Ontario, Canada. We tested whether engagement of staff in the intervention and their EIDM behavior were associated with being chosen as information source and how the trend of inter-divisional communications and the dominance of experts evolved over time. METHODS: Local managers at each health unit selected a group of staff to get engage in Knowledge Broker-led workshops and development of evidence summaries to address local public health problems. The staff were invited to answer three online surveys (at baseline and two annual follow-ups) including name generator questions eliciting the list of the staff they would turn to for help integrating research evidence into practice. We used stochastic actor-oriented modeling to study the evolution of networks. We tested the effect of engagement in the intervention, EIDM behavior scores, organizational divisions, and structural dynamics of social networks on the tendency of staff to select information sources, and the change in its trend between year 1 and year 2 of follow-up. RESULTS: In all the three health units, and especially in the two units with higher levels of engagement in the intervention, the network evolved towards a more centralized structure, with an increasing significance of already central staff. The staff showed greater tendencies to seek information from peers with higher EIDM behavior scores. In the public health unit that had highest engagement and stronger leadership support, the engaged staff became more central. In all public health units, the engaged staff showed an increasing tendency towards forming clusters. The staff in the three public health units showed a tendency towards limiting their connections within their divisions. CONCLUSIONS: The longitudinal analysis provided us with a means to study the microstructural changes in public health units, clues to the sustainability of the implementation. The hierarchical transformation of networks towards experts and formation of clusters among staff who were engaged in the intervention show how implementing organizational interventions to promote EIDM may affect the knowledge flow and distribution in health care communities, which may lead to unanticipated consequences. PMID- 26634924 TI - Practicability for robot-aided measurement of knee stability in-vivo. AB - BACKGROUND: For the analysis of different treatments concerning anterior cruciate ligament (ACL) rupture, objective methods for the quantification of knee stability are needed. Therefore, a new method for in-vivo stability measurement using a robotic testing system should be developed and evaluated. METHODS: A new experimental setting was developed using a KUKA robot and a custom-made chair for the positioning and fixation of the participants. The tibia was connected to the robot via a Vacoped shoe and magnetic buttons, providing adequate safety. Anterior tibial translation and internal tibial rotation were measured on both legs of 40 healthy human subjects at 30 degrees , 60 degrees and 90 degrees of flexion, applying anterior forces of 80 N and internal torques of 4 Nm, respectively. RESULTS: While the mean differences between the right and left leg measured for anterior tibial translation were within an acceptable range (<1.5 mm), the absolute values were substantially large (38-40.5 mm). For mean internal tibial rotation, between 17.5 and 20 degrees were measured at the different sides and flexion angles, with a maximal difference of 0.75 degrees . High reproducibility of the measurements could be demonstrated for both, anterior tibial translation (ICC(3,1) = 0.97) and internal tibial rotation (ICC(3,1) = 0.94). CONCLUSIONS: Excellent results were achieved for internal tibial rotation, almost reproducing current in-vitro studies, but too large anterior tibial translation was measured due to soft-tissue compression. Therefore, high potential for the analysis of ACL related treatments concerning rotational stability is seen for the proposed method, but further optimization is necessary to enhance this method for the reliable measurement of anterior tibial translation. PMID- 26634925 TI - An Anti-EGFR IgA That Displays Improved Pharmacokinetics and Myeloid Effector Cell Engagement In Vivo. AB - Antibodies of IgA isotype effectively engage myeloid effector cells for cancer immunotherapy. Here, we describe preclinical studies with an Fc engineered IgA2m(1) antibody containing the variable regions of the EGFR antibody cetuximab. Compared with wild-type IgA2m(1), the engineered molecule lacked two N glycosylation sites (N166 and N337), two free cysteines (C311 and C472), and contained a stabilized heavy and light chain linkage (P221R mutation). This novel molecule displayed improved production rates and biochemical properties compared with wild-type IgA. In vitro, Fab- and Fc-mediated effector functions, such as inhibition of ligand binding, receptor modulation, and engagement of myeloid effector cells for antibody-dependent cell-mediated cytotoxicity, were similar between wild-type and engineered IgA2. The engineered antibody displayed lower levels of terminal galactosylation leading to reduced asialoglycoprotein-receptor binding and to improved pharmacokinetic properties. In a long-term in vivo model against EGFR-positive cancer cells, improved serum half-life translated into higher efficacy of the engineered molecule, which required myeloid cells expressing human FcalphaRI for its full efficacy. However, Fab-mediated effector functions contributed to the in vivo efficacy because the novel IgA antibody demonstrated therapeutic activity also in non-FcalphaRI transgenic mice. Together, these results demonstrate that engineering of an IgA antibody can significantly improve its pharmacokinetics and its therapeutic efficacy to inhibit tumor growth in vivo. PMID- 26634926 TI - Bereavement Is Associated with an Increased Risk of HPV Infection and Cervical Cancer: An Epidemiological Study in Sweden. AB - Grief over the loss of a family member may cause physical and mental illness, but an association between bereavement and cancer risk has not been established. Based on the Swedish National Cervical Screening Register (1969-2011) including 14,011,269 smears from 2,466,107 women, we conducted two nested case-control studies to examine the associations of bereavement (i.e., loss of a family member due to death) with abnormal cytology (390,310 first abnormal and 1,951,319 normal smears) and in situ/invasive cervical cancer (75,128 case and 375,640 control women), both individually matched on year of birth and screening adherence. Among 1,696 of the control women, we further investigated bereavement in association with human papillomavirus (HPV) infection, both HPV16 and other HPV types. Bereavement was consistently associated with a 4% to 9% increased risk for first abnormal cytology, in situ and invasive cervical cancer (all P < 0.02). The associations became stronger when multiple losses, loss of child, sibling or spouse, and loss due to unnatural cause were analyzed separately (P for trend or difference < 0.0001), and for women with high screening adherence (P for difference < 0.05). Among 1,696 women who had not developed cervical cancer, we further investigated the link between bereavement and HPV infection. Bereavement was associated with a 62% increased risk of HPV16 infection, high viral load, and recurrent infection, and was also more strongly associated with HPV infections designated as high-risk compared with low-risk determinants of cervical carcinogenesis. Collectively, our findings demonstrate that bereavement is associated with an increased risk of developing cervical cancer. Further, they suggest that this association may be attributed to stress-induced oncogenic HPV infections. PMID- 26634927 TI - Anticonvulsant Activity of Hydroalcoholic Extract of Citrullus colocynthis Fruit: Involvement of Benzodiazepine and Opioid Receptors. AB - This study investigated the anticonvulsant activity of Citrullus colocynthis fruit extract used traditionally in the treatment of convulsion. Albino mice were pretreated with extract in different doses (10, 25, 50, and 100 mg/kg), prior to injection of pentylenetetrazole. Animals received pretreatments with naloxone and flumazenil to further clarify the mechanisms of anticonvulsant action. The total flavonoid content of Citrullus colocynthis extract was also determined. Citrullus colocynthis hydroalcoholic extract with doses 25 and 50 mg/kg prolonged the onset of seizures and decreased the duration compared with control group. Pretreatment by flumazenil could inhibit the effect of Citrullus colocynthis on latency of seizure to some extent and administration of naloxone significantly inhibited changes in latency and duration of seizure produced by Citrullus colocynthis This study showed that Citrullus colocynthis has significant anticonvulsant effect in pentylenetetrazole-induced seizures in mice, and these effects may be related to its effect on gamma-aminobutyric acid-ergic and opioid systems. These results confirmed the traditional use of Citrullus colocynthis in Iranian traditional medicine. PMID- 26634928 TI - Localization of the human neonatal Fc receptor (FcRn) in human nasal epithelium. AB - The airway epithelium is a central player in the defense against pathogens including efficient mucociliary clearance and secretion of immunoglobulins, mainly polymeric IgA, but also IgG. Pulmonary administration of therapeutic antibodies on one hand, and intranasal immunization on the other, are powerful tools to treat airway infections. In either case, the airway epithelium is the primary site of antibody transfer. In various epithelia, bi-polar transcytosis of IgG and IgG immune complexes is mediated by the human neonatal Fc receptor, FcRn, but FcRn expression in the nasal epithelium had not been demonstrated, so far. We prepared affinity-purified antibodies against FcRn alpha-chain and confirmed their specificity by Western blotting and immunofluorescence microscopy. These antibodies were used to study the localization of FcRn alpha-chain in fixed nasal tissue. We here demonstrate for the first time that ciliated epithelial cells, basal cells, gland cells, and endothelial cells in the underlying connective tissue express the receptor. A predominant basolateral steady state distribution of the receptor was observed in ciliated epithelial as well as in gland cells. Co localization of FcRn alpha-chain with IgG or with early sorting endosomes (EEA1 positive) but not with late endosomes/lysosomes (LAMP-2-positive) in ciliated cells was observed. This is indicative for the presence of the receptor in the recycling/transcytotic pathway but not in compartments involved in lysosomal degradation supporting the role of FcRn in IgG transcytosis in the nasal epithelium. PMID- 26634929 TI - The DnaJ-like zinc finger domain protein ORANGE localizes to the nucleus in etiolated cotyledons of Arabidopsis thaliana. AB - Vitamin A deficiency (VAD) is a worldwide health problem. Overexpression of the DnaJ-like zinc finger domain protein ORANGE (OR) is a novel strategy for the biofortification of pro-vitamin A carotenoids in different staple crops to alleviate VAD. In plants, OR triggers the differentiation from non-pigmented plastids into carotenoid-accumulating plastids. There are different reports on the subcellular localization of this protein in either chloroplasts or the nucleus, both of which were supported by confocal observation and protein-protein interaction results. In this work, we studied the subcellular localization of OR in the cotyledons of germinating seedlings whose plastids were transitioning from non-pigmented proplastids into carotenoid-accumulating etioplasts in the dark, and then into chloroplasts upon illumination. Our Western blot analysis identified two bands of the Arabidopsis OR protein (AtOR) from the chloroplast fraction of the mature leaves (i.e., a 34-kDa form corresponding to the full length peptide and a 30-kDa form suggesting the removal of the N-terminal chloroplast transit peptide). We found that the full-length AtOR was predominantly localized in the nucleus in etiolated cotyledons, although its abundance decreased upon illumination. Our bioinformatics analysis indicated a nuclear localization signal (NLS) after the N-terminal chloroplast transit peptide. When we substituted different N-terminal regions of AtOR with the green fluorescent protein, our confocal observations demonstrated that this NLS was sufficient to target AtOR to the nucleus. Our results demonstrate that AtOR is a dual-targeted protein that mainly localizes in the nucleus in etiolated cotyledons. PMID- 26634930 TI - Quantitating aortic regurgitation by cardiovascular magnetic resonance: significant variations due to slice location and breath holding. AB - OBJECTIVES: Compare variability in flow measurements by phase contrast MRI, performed at different locations in the aorta and pulmonary artery (PA) using breath-held (BH) and free-breathing (FB) sequences. METHODS: Fifty-seven patients with valvular heart disease, confirmed by echocardiography, were scanned using BH technique at 3 locations in the ascending aorta (SOV = sinus of Valsalva, STJ = sinotubular junction, ASC = ascending aorta at level of right pulmonary artery) and 2 locations in PA. Single FB measurement was obtained at STJ for aorta. Obtained metrics (SV = stroke volume, FV = forward volume, BV = backward volume, RF = regurgitant fraction) were evaluated separately for patients with aortic regurgitation (AR, n = 31) and mitral regurgitation (n = 26). RESULTS: No difference was noted between the two measurements in the PA. Significant differences were noted in measured SV at different aortic locations. SV measurements obtained at ASC correlated best with the measurements obtained in the PA. Strongest correlation of AR was measured at the STJ. CONCLUSION: Measurements of flow volumes by phase contrast MRI differ depending on slice location. When using stroke volumes to calculate pulmonary to systemic blood flow ratio (Qp/Qs), ASC should be used. For quantifying aortic regurgitation, measurement should be obtained at STJ. KEY POINTS: * Aortic regurgitation can be accurately measured by MRI. * Aortic regurgitation measurement by MRI varies according to the location where measured. * Aortic regurgitation can also be measured by MRI without breath hold. PMID- 26634931 TI - Identification of Imaging Predictors Discriminating Different Primary Liver Tumours in Patients with Chronic Liver Disease on Gadoxetic Acid-enhanced MRI: a Classification Tree Analysis. AB - OBJECTIVES: To identify predictors for the discrimination of intrahepatic cholangiocarcinoma (IMCC) and combined hepatocellular-cholangiocarcinoma (CHC) from hepatocellular carcinoma (HCC) for primary liver cancers on gadoxetic acid enhanced MRI among high-risk chronic liver disease (CLD) patients using classification tree analysis (CTA). METHODS: A total of 152 patients with histopathologically proven IMCC (n = 40), CHC (n = 24) and HCC (n = 91) were enrolled. Tumour marker and MRI variables including morphologic features, signal intensity, and enhancement pattern were used to identify tumours suspicious for IMCC and CHC using CTA. RESULTS: On CTA, arterial rim enhancement (ARE) was the initial splitting predictor for assessing the probability of tumours being IMCC or CHC. Of 43 tumours that were classified in a subgroup on CTA based on the presence of ARE, non-intralesional fat, and non-globular shape, 41 (95.3 %) were IMCCs (n = 29) or CHCs (n = 12). All 24 tumours showing fat on MRI were HCCs. The CTA model demonstrated sensitivity of 84.4 %, specificity of 97.8 %, and accuracy of 92.3 % for discriminating IMCCs and CHCs from HCCs. CONCLUSIONS: We established a simple CTA model for classifying a high-risk group of CLD patients with IMCC and CHC. This model may be useful for guiding diagnosis for primary liver cancers in patients with CLD. KEY POINTS: * Arterial rim enhancement was the initial splitting predictor on CTA. * CTA model achieved high sensitivity, specificity, and accuracy for discrimination of tumours. * This model may be useful for guiding diagnosis of primary liver cancers. PMID- 26634932 TI - Inductively Coupled Plasma Zoom-Time-of-Flight Mass Spectrometry. AB - A zoom-time-of-flight mass spectrometer has been coupled to an inductively coupled plasma (ICP) ionization source. Zoom-time-of-flight mass spectrometry (zoom-TOFMS) combines two complementary types of velocity-based mass separation. Specifically, zoom-TOFMS alternates between conventional, constant-energy acceleration (CEA) TOFMS and energy-focused, constant-momentum acceleration (CMA) (zoom) TOFMS. The CMA mode provides a mass-resolution enhancement of 1.5-1.7* over CEA-TOFMS in the current, 35-cm ICP-zoom-TOFMS instrument geometry. The maximum resolving power (full-width at half-maximum) for the ICP-zoom-TOFMS instrument is 1200 for CEA-TOFMS and 1900 for CMA-TOFMS. The CMA mode yields detection limits of between 0.02 and 0.8 ppt, depending upon the repetition rate and integration time-compared with single ppt detection limits for CEA-TOFMS. Isotope-ratio precision is shot-noise limited at approximately 0.2% relative standard deviation (RSD) for both CEA- and CMA-TOFMS at a 10 kHz repetition rate and an integration time of 3-5 min. When the repetition rate is increased to 43.5 kHz for CMA, the shot-noise limited, zoom-mode isotope-ratio precision is improved to 0.09% RSD for the same integration time. PMID- 26634934 TI - The Role of beta-Carboline Alkaloids in the Pathogenesis of Essential Tremor. AB - Essential tremor (ET) is one of the most prevalent neurological disorders in the world. Environmental factors have been implicated in the pathogenesis of ET. In particular, epidemiological studies have suggested that neurotoxic agents, especially beta-carboline alkaloids (betaCAs), might be generated through Maillard-type reaction. betaCAs are molecules which are members of a large group of heterocyclic amines (HCAs, the so-called products of cooking meat). betaCAs are highly tremorogenic in animals, producing a marked generalized action tremor soon after systemic administration in a wide range of laboratory animals such as mice, rats and monkeys. Administration of betaCAs remains currently the main experimental model of ET. We review the pathogenesis of ET, with a focus on the biochemistry of betaCAs, their occurrence and biological activity, their endogenous biosynthesis, their formation in food, their toxicokinetics and their neurotoxicity. We highlight open questions regarding the effects of betaCAs in humans. PMID- 26634935 TI - Nonredundant roles of keratinocyte-derived IL-34 and neutrophil-derived CSF1 in Langerhans cell renewal in the steady state and during inflammation. AB - IL-34 and colony-stimulating factor 1 (CSF1) are two alternative ligands for the CSF1 receptor that play nonredundant roles in the development, survival, and function of tissue macrophages and Langerhans cells (LCs). In this study, we investigated the spatio-temporal production of IL-34 and its impact on skin LCs in the developing embryo and adult mice in the steady state and during inflammation using Il34(LacZ) reporter mice and newly generated inducible Il34 knockout mice. We found that IL-34 is produced in the developing skin epidermis of the embryo, where it promotes the final differentiation of LC precursors. In adult life, LCs required IL-34 to continually self-renew in the steady state. However, during UV-induced skin damage, LC regeneration depended on neutrophils infiltrating the skin, which produced large amounts of CSF1. We conclude that LCs require IL-34 when residing in fully differentiated and anatomically intact skin epidermis, but rely on neutrophil-derived CSF1 during inflammation. Our demonstration that neutrophils are an important source of CSF1 during skin inflammation may exemplify a mechanism through which neutrophils promote their subsequent replacement with mononuclear phagocytes. PMID- 26634936 TI - Lyme disease: time for a new approach? PMID- 26634933 TI - Animal Models of Bone Loss in Inflammatory Arthritis: from Cytokines in the Bench to Novel Treatments for Bone Loss in the Bedside-a Comprehensive Review. AB - Throughout life, bone is continuously remodelled. Bone is formed by osteoblasts, from mesenchymal origin, while osteoclasts induce bone resorption. This process is tightly regulated. During inflammation, several growth factors and cytokines are increased inducing osteoclast differentiation and activation, and chronic inflammation is a condition that initiates systemic bone loss. Rheumatoid arthritis (RA) is a chronic inflammatory auto-immune disease that is characterised by active synovitis and is associated with early peri-articular bone loss. Peri-articular bone loss precedes focal bone erosions, which may progress to bone destruction and disability. The incidence of generalised osteoporosis is associated with the severity of arthritis in RA and increased osteoporotic vertebral and hip fracture risk. In this review, we will give an overview of different animal models of inflammatory arthritis related to RA with focus on bone erosion and involvement of pro-inflammatory cytokines. In addition, a humanised endochondral ossification model will be discussed, which can be used in a translational approach to answer osteoimmunological questions. PMID- 26634937 TI - Decreased lung function in 7-year-old children with early-life organophosphate exposure. AB - BACKGROUND: Organophosphate pesticides are heavily used in agriculture, and adverse associations with respiratory health in occupational settings have been reported. However, most of the evidence comes from studies where there were no biomarkers of exposure and no objective outcome measurement. Non-occupational chronic effects among residents living in agricultural communities are less well described. OBJECTIVE: To evaluate associations between early-life organophosphate exposure and lung function of children living in an agricultural community. METHODS: Participants were 279 children from the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) longitudinal birth cohort. The area under the curve for organophosphate exposure was determined by urinary diethyl and dimethyl dialkylphosphate metabolites of organophosphate pesticides, which were measured five times during childhood (6-60 months). Spirometry was performed at age 7 years. Regression models controlled for maternal smoking during pregnancy, season of birth, particulate matter concentrations with aerodynamic diameter <=2.5 MUm (PM2.5), breast feeding duration, mould and pets at home, distance of home from a highway, food insecurity, maternal education, season of spirometry, sex, height and technician. RESULTS: Childhood diethyl, dimethyl and total dialkylphosphate concentrations were associated with significant decreases in lung function at age 7. Specifically, we found lower FEV1, (L/s) (beta=-0.16, 95% CI -0.30 to -0.02, p=0.03) and FVC (L) (beta=-0.17, 95% CI -0.34 to 0.01, p=0.06) per 10-fold increase of total dialkylphosphate levels. CONCLUSIONS: Early life organophosphate exposure as assessed by dialkylphosphate concentrations was adversely associated with 7-year-old children's lung function. PMID- 26634938 TI - Premature Progesterone Elevation Does Not Affect Pregnancy Outcome in High Responder Patients Undergoing Short-Interval Coasting in IVF Cycles. AB - BACKGROUND We aimed to present the relationship between premature progesterone elevation (PPE) and clinical outcomes in high-responder patients who had a coasting period of <4 days in length due to their high risk of developing ovarian hyperstimulation syndrome (OHSS) and who were treated with a long-acting gonadotropin-releasing hormone agonist (GnRH-agonist) protocol in in vitro fertilization-embryo transfer (IVF-ET) cycles. MATERIAL AND METHODS This retrospective study was conducted at the University Hospital Assisted Reproductive Technology Center. The outcomes of 101 patients undergoing IVF- intracytoplasmic sperm injection (ICSI) cycles who showed a high response to COH (estradiol >4000 pg/ml and/or >20 follicles each >=10 mm in diameter and at least 20% >=15 mm) and who were coasted for <4 days were evaluated. Number of oocytes, 2 pronuclei (PN) embryos, implantation rate, and live birth rate were measured. RESULTS The incidence of PPE was 32.6%. Compared with those without PPE, patients with PPE had a higher number of oocytes retrieved. Total mature and fertilized oocytes and the mean number of embryos transferred were not significantly different between groups. Live birth rates (41.9% vs. 38.7%) and implantation rates (26.5% vs. 23%) were also not significantly divergent in the PPE and non PPE groups, respectively. CONCLUSIONS P concentrations >=1.3 ng/ml on the day of human chorionic gonadotropin (hCG) administration, designated in this study as PPE, does not appear to be related to adverse effects in terms of clinical outcomes in high-responder patients undergoing coasting <4 days due to their high risk of developing OHSS treated with a long-acting GnRH-a protocol in IVF-embryo transfer cycles. PMID- 26634939 TI - The Differential Diagnosis of Thrombocytopenia in Pregnancy. AB - BACKGROUND: Thrombocytopenia is, after anemia, the second most common abnormality of the complete blood count in pregnancy, with a reported frequency of 6.6% to 11.2%. It has many causes. Thrombocytopenia should be diagnostically evaluated as early as possible in pregnancy, so that the obstetrical management can be accordingly planned to minimize harm to the mother and child. As the various underlying diseases share clinical features and laboratory findings, the differential diagnosis is often a difficult interdisciplinary challenge. METHODS: In this article, we review pertinent literature (2000-January 2015) retrieved by a selective search in PubMed. RESULTS: Gestational thrombocytopenia is the most common type, accounting for 75% of cases, followed by severe pre-eclampsia/HELLP syndrome (hemolysis, elevated liver enzymes, low platelet count) in 15-22% and autoimmune thrombocytopenia (ITP) in 1-4%. Gestational thrombocytopenia and ITP differ in the bleeding history, the severity of thrombocytopenia, the frequency of neo - natal thrombocytopenia, and the rate of normalization of the platelet count after delivery. The HELLP syndrome and rarer microangiopathic hemolytic anemias (e.g., thrombotic thrombocytopenic purpura) can be differentiated on the basis of their main clinical features, such as hypertension/proteinuria and upper abdominal pain, the severity of hemolysis and thrombocytopenia, the degree of transaminase elevation, and the rapidity of postpartum remission of the clinical and laboratory findings. A stepwise diagnostic procedure should be followed to distinguish further causes, e.g., to differentiate thrombocytopenia due to infection, autoimmune disease, or drugs from thrombocytopenia due to a rare hereditary disease. CONCLUSION: The early interdisciplinary evaluation of thrombocytopenia in pregnancy is a prerequisite for the optimal care of the mother and child. The development of evidence-based recommendations for interdisciplinary management should be a goal for the near future. PMID- 26634940 TI - Indirect Comparisons and Network Meta-Analyses. AB - BACKGROUND: Systematic reviews provide a structured summary of the results of trials that have been carried out on any particular subject. If the data from multiple trials are sufficiently homogenous, a meta-analysis can be performed to calculate pooled effect estimates. Traditional meta-analysis involves groups of trials that compare the same two interventions directly (head to head). Lately, however, indirect comparisons and network metaanalyses have become increasingly common. METHODS: Various methods of indirect comparison and network meta-analysis are presented and discussed on the basis of a selective review of the literature. The main assumptions and requirements of these methods are described, and a checklist is provided as an aid to the evaluation of published indirect comparisons and network meta-analyses. RESULTS: When no head-to-head trials of two interventions are available, indirect comparisons and network metaanalyses enable the estimation of effects as well as the simultaneous analysis of networks involving more than two interventions. Network meta-analyses and indirect comparisons can only be useful if the trial or patient characteristics are similar and the observed effects are sufficiently homogeneous. Moreover, there should be no major discrepancy between the direct and indirect evidence. If trials are available that compare each of two treatments against a third one, but not against each other, then the third intervention can be used as a common comparator to enable a comparison of the other two. CONCLUSION: Indirect comparisons and network metaanalyses are an important further development of traditional meta-analysis. Clear and detailed documentation is needed so that findings obtained by these new methods can be reliably judged. PMID- 26634941 TI - NICE guidance on menopause: cognitive behavioural therapy is an effective non hormonal intervention for managing vasomotor symptoms. PMID- 26634942 TI - Evaluation of the acceptability of intravaginal prasterone ovule administration using an applicator. AB - The objective of the study is to evaluate the acceptability of the intravaginal administration of ovules/suppositories of DHEA (dehydroepiandrosterone, prasterone) for the treatment of vulvovaginal atrophy (VVA) in women with moderate to severe dyspareunia who were administered daily for 12 weeks intravaginal 0.50% (6.5 mg) DHEA or placebo. There were a total of 373 women in the per-protocol population who responded to the questionnaire for both treatment groups. While it was planned that the applicator would be evaluated as suitable if at least 80% of participants have a global score <= 2 units, 99% and 100% of participants had a score <= 2 units in the placebo and DHEA groups, respectively, for the global score (mean of 5 questions). When asked about like and dislike the technique of drug administration, 284 comments were positive, while 114 women gave no comment. About 92-94% of women indicated that they were very confident to be able use the applicator successfully in the future. The survey shows a high degree of satisfaction and of confidence to use the applicator successfully in the future. PMID- 26634943 TI - Measurement properties of a patient-reported outcome measure assessing psoriasis severity: The psoriasis symptoms and signs diary. AB - BACKGROUND: Collecting reliable and valid symptom information from patients is critical for assessing psoriasis severity in clinical research. OBJECTIVE: To evaluate measurement properties of a new patient-reported outcome (PRO), the Psoriasis Symptoms and Signs Diary (PSSD). METHODS: One hundred six US patients with moderate-to-severe plaque psoriasis completed two versions of the PSSD [a 24 hour recall (PSSD-24h) and 7-day recall (PSSD-7d)] using a 0-10 numerical rating scale. Reliability (test-retest and internal consistency), validity (convergent, divergent and known-groups), responsiveness, and version equivalence were evaluated. Minimally important difference was estimated. RESULTS: Based on exploratory factor analysis and clinical input, symptom, sign, and total severity scores were established. Internal consistency (Cronbach's alpha >= 0.944) and test-retest reliability (intraclass correlation coefficients >= 0.824) were acceptable. Correlations with Dermatology Life Quality Index (DLQI) (0.489 to 0.644) indicated convergent validity, while low correlations (< 0.30) with several Short Form (SF)-36 scales indicated divergent validity. PSSD scores differed when patients were categorized by Body Surface Area, DLQI, and Psoriasis Area Severity Index scores. PSSD-24h and PSSD-7d versions were equivalent (Pearson correlations >= 0.953). LIMITATIONS: PSSD responsiveness should be evaluated in patients receiving treatment. CONCLUSION: The PSSD is reliable and valid in measuring symptoms/signs of patients with moderate-to-severe plaque psoriasis. PMID- 26634944 TI - The evolving understanding of small HER2-positive breast cancers: matching management to outcomes. AB - Systemic therapy for small (stage I) HER2-positive breast cancers has long posed a dilemma for clinicians, as the majority of these patients were excluded from the large adjuvant trastuzumab trials. However in the decade since those trials were reported, data have accumulated to suggest that recurrence risk for these small but biologically aggressive tumors is nontrivial. In this review, we summarize data from numerous cohort studies describing the outcomes of small HER2 positive tumors, mostly in the absence of HER2-directed therapy. We then examine the potential impact of HER2-directed treatment in this population, culminating in the recently published prospective study of paclitaxel/trastuzumab therapy. The landscape of next generation anti-HER2 therapies is quickly evolving; a role for some of these agents in the small HER2-positive subpopulation may also be on the horizon. PMID- 26634945 TI - Current and emerging triplet combination therapies for relapsed and refractory multiple myeloma. AB - Despite significant improvement in outcomes have been observed for multiple myeloma (MM) patients over the past 10-15 years, mainly due to the introduction of novel agents targeting the tumor clone and the bone marrow microenvironment, treatment of refractory and/or relapsed (RR) disease remains a challenge, particularly for patients who have failed prior bortezomib- and lenalidomide based therapies. More recently, new drugs with different mechanisms of action, including second generation proteasome inhibitors, third generation immunomodulatory drugs, histone deacetylase inhibitors and monoclonal antibodies, have been developed and are under investigation, further increasing treatment options for RRMM patients. Overall, novel agent-based triplet combinations demonstrated superior response rates and prolonged disease control when compared with two-drug regimens in several randomized clinical trials, without adding any relevant additional toxicity. Salvage triplet therapies are likely to play a key role in overcoming drug-resistance and hold promise to further improve long-term outcomes of RRMM patients. PMID- 26634946 TI - Nanoparticle-Induced Gelation of Bimodal Slurries with Highly Size-Asymmetric Particles: Effect of Surface Chemistry and Concentration. AB - A systematic study has been performed to investigate the effect of surface potential of nanoparticles on the rheological behavior of bimodal suspensions, using a model system consisting of polystyrene latex (primary size ~530 nm) and alumina-coated silica (primary size ~12 nm) particles. The surface potential of small particles was tuned by varying the solution pH, causing them to be repulsive to each other, attractive to each other, and oppositely charged to the large particles, while the large particles remained electrostatically stabilized. We found that the rheological properties could be dramatically changed from viscous to gel-like depending on the surface potential and concentration of small particles. A colloidal gel was induced by small particles when the small particles had the opposite charge to the large particles and a volume fraction of 10(-4) < phismall < 10(-3), and when the small particles were attractive to each other above a critical threshold, phismall > 10(-4). Cryo-SEM distinguished the gel structures to be either short bridging gels produced by oppositely charged small particles or long bridging gels or dense gels produced by attractive small particles. On the basis of this rheological behavior and microstructure, we prepared a phase diagram of highly size-asymmetric bimodal colloids with respect to the surface chemistry and concentration of small particles. PMID- 26634947 TI - Cartilage oligomeric matrix protein and hyaluronic acid are sensitive serum biomarkers for early cartilage lesions in the knee joint. AB - The purpose of this study was to evaluate the relationship between five previously established serum osteoarthritis biomarkers and the severity of cartilage lesions in the knee. Cartilage damage (classified according to the Outerbridge scoring system) and serum concentrations of cartilage oligomeric matrix protein (COMP), collagen type II C-telopeptide (CTX-II), matrix metalloproteinase-3 (MMP-3), collagen type III N-propeptide, (PIIINP), and hyaluronic acid (HA) were determined in 79 patients who underwent knee arthroscopy or total knee replacement. HA and COMP concentrations were significantly higher in the Outerbridge score 1 and 2 groups, respectively. These results suggest that serum COMP and HA concentrations can be used to predict early cartilage lesions in the knee. PMID- 26634948 TI - Safety considerations of septic shock treatment. AB - INTRODUCTION: The management of sepsis essentially relies on effective resuscitation with fluids and vasopressors, appropriate and adequate antimicrobial therapy, and organ support. Any of these interventions can have beneficial but also harmful effects. AREAS COVERED: We focus on the key hemodynamic signs of sepsis and discuss the potential safety risks associated with the management of each of them, including optimizing arterial pressure, cardiac output and oxygen delivery. We also underline the importance of the timing of interventions. EXPERT OPINION: Patients with septic shock are heterogeneous, making it particularly difficult to provide therapeutic recommendations that are safe and effective for all. A personalized medicine approach should be used with treatment decisions carefully considered and the risks and benefits of each intervention balanced in each individual patient. PMID- 26634949 TI - Effects of Added Zinc on Skeletal Muscle Morphometrics and Gene Expression of Finishing Pigs Fed Ractopamine-HCL. AB - Finishing pigs (n = 320) were used in a 35-day study to determine the effects of ractopamine-HCl (RAC) and supplemental Zinc (Zn) level on loin eye area (LEA) and gene expression. Pens were randomly allotted to the following treatments for the final 35 days on feed: a corn-soybean meal diet (CON), a diet with 10 ppm RAC (RAC+), and RAC diet plus added Zn at 75, 150, or 225 ppm. Sixteen pigs per treatment were randomly selected for collection of serial muscle biopsies and carcass data on day 0, 8, 18, and 32 of the treatment phase. Compared to CON carcasses, RAC+ carcasses had 12.6% larger (P = 0.03) LEA. Carcasses from RAC diets with added Zn had a tendency for increased (quadratic, P < 0.10) LEA compared to the RAC+ carcasses. Compared to RAC+ pigs, relative expression of IGF1 decreased with increasing levels of Zn on day 8 and 18 of treatment, but expression levels were similar on day 32 due to Zn treatments increasing in expression while the RAC+ treatment decreased (Zn quadratic * day quadratic, P = 0.04). A similar trend was detected for the expression of beta1-receptor where expression levels in the RAC+ pigs were greater than Zn supplemented pigs on day 8 and 18 of the experiment, but the magnitude of difference between the treatments was reduced on day 32 due to a decrease in expression by RAC+ pigs and an increase in expression by the Zn pigs (Zn quadratic * day quadratic, P = 0.01). The ability of Zn to prolong the expression of these two genes may be responsible for the tendency of Zn to increase LEA in RAC supplemented pigs. PMID- 26634950 TI - Preparation of Carboxymethyl Chitosan Microspheres and Their Application in Hemostasis. AB - OBJECTIVE: Chitosan (CS) is currently used as a hemostatic agent in emergencies and in military settings. However, its application is limited owing to its poor hydrophilia at neutral pH. Carboxymethyl chitosan (CMCS) is an important, water soluble derivative of CS. In this study, we prepared CS and CMCS microspheres (CSMs and CMCSMs, respectively) and evaluated their hemostatic effect. METHODS: To prepare the microspheres of various sizes, we used the emulsion cross-linking technique. CMCSMs were also loaded with etamsylate (DIC). Clotting time in vitro and in a hepatic injury model was examined to evaluate the hemostatic effect. RESULTS: CMCSMs swelled more and clotted faster than did CSMs. CMCSMs loaded with DIC had no effect on hemostasis. CONCLUSIONS: Both increasing material hydrophilicity and expanding the contact area promoted clotting, whereas chemical cross-linking hampered it because of decreased swelling. CMCSMs are promising candidates for the production of effective hemostatic agents. (Disaster Med Public Health Preparedness. 2017;11:660-667). PMID- 26634951 TI - Synonymous codon usage pattern in mitochondrial CYB gene in pisces, aves, and mammals. AB - Cytochrome b (CYB) protein plays an important role in complex III of the mitochondrial oxidative phosphorylation. Codon usage is the phenomenon of non uniform usage of synonymous codons. In the present study, we report the pattern of codon usage in MT-CYB gene using various codon usage parameters. Nucleotide composition such as % of C and T was higher than A and G in pisces. In aves, % of A and C was higher than T and G but in mammals, A and T was higher than C and G. Heat map shows that AT-ending codons were mostly negative and GC-ending codons were mostly positive. From the heat map based on RSCU values, it is evident that codon usage prefers A/C at the third codon position and it was less towards T/G in its third codon position. The codons absent in pisces were AGT (except Toxotes chatareus), TGT, and CAG (except Elasma zonatum). The codons such as AGT (except Falco peregrinus), CGT (except Vidua chalybeata), and ACG (except Aythya americana) were absent in aves whereas, in mammals, the absent codons were namely CAG (except Canis familiaris) and ACG (except Rattus norvegicus). Codon usage bias was low in pisces, aves, and mammals. The frequency of leucine was the highest in the amino acid and cysteine was the lowest. Correlation analysis further suggests that mutation pressure is mainly responsible for codon usage pattern. Natural selection might also play a vital role in codon usage pattern but it was weaker than mutation pressure. PMID- 26634952 TI - Assessment of chromosomal aberration in the bone marrow cells of Swiss Albino mice treated by 4-methylimidazole. AB - 4-Methylimidazole (4-MEI) is formed during the production of certain caramel coloring agents used in many food and drink products. It may also be formed during the cooking, roasting, or other processing of some foods and beverages. So it was unintentionally consumed in worldwide. This study was aimed to investigate the genotoxic and cytotoxic effects of 4-MEI using chromosome aberration (CA) and mitotic index (MI) in Swiss Albino mice. In this research, CA and MI of the mouse bone marrow cells were analyzed after treating the animals with 4-MEI (100, 130 and 160 mg/kg) for 12 h and 24 h treatment times. All data were analyzed using statistical methods. 4-MEI significantly increased the percentage of CAs at all concentrations for 12 h and at highest concentration for 24 h treatment periods. 4-MEI at highest concentration for 12 h and at all concentrations for 24 h decreased the MI in comparison with control. Genotoxic and cytotoxic effects of 4 MEI at 24 h treatment periods were concentration dependent. Consequently, it can be said that 4-MEI have genotoxic and cytotoxic effect in mouse. PMID- 26634953 TI - Routine knee arthroscopic surgery for the painful knee in middle-aged and old patients--time to abandon ship. PMID- 26634954 TI - The value of inflammatory markers to diagnose and monitor diabetic foot osteomyelitis. AB - In this study, we assessed the effectiveness of inflammatory markers to diagnose and monitor the treatment of osteomyelitis in the diabetic foot. We evaluated 35 consecutive patients admitted to our hospital with infected foot ulcers. Patients were divided in two groups based on the results of bone culture and histopathology: osteomyelitis and no osteomyelitis. The erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), procalcitonin (PCT), interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor alpha (TNFalpha), monocyte chemotactic protein-1 (MCP-1) and macrophage inflammatory protein-1 alpha (MIP1alpha) were measured at baseline after 3 and 6 weeks of standard therapy. PCT levels in the osteomyelitis group were significantly higher at baseline than in the group with no osteomyelitis (P = 0.049). There were no significant differences between the two groups in the levels of the other markers. CRP, ESR, PCT and IL-6 levels significantly declined in the group with osteomyelitis after starting therapy, while MCP-1 increased (P = 0.002). TNFalpha and MIP1alpha levels were below range in 80 out of 97 samples and therefore not reported. Our results suggest that PCT might be useful to distinguish osteomyelitis in infected foot ulcers. CRP, ESR, PCT and IL-6 are valuable when monitoring the effect of therapy. PMID- 26634955 TI - Endocrine therapy in premenopausal women with breast cancer: a critical appraisal of current evidence. AB - Nearly 60% of all breast cancer premenopausal women are diagnosed with a hormone receptor positive tumor and, therefore, are candidates for adjuvant hormonal therapy. Treatment with tamoxifen for at least 5 years has been for a long time the standard of care, as it is associated with overall positive clinical outcomes. However, in the last decade, a number of studies on adjuvant endocrine therapy in premenopausal women with hormone receptor positive breast cancer have been published, adding a bulk of evidence to existing knowledge in this field. A critical appraisal of their results appears necessary in order to put the recently collected data into the current framework of treatment, and to discuss the several issues that remain open. Here, we review the most recent evidence on the following: the optimal duration of tamoxifen treatment, results of the studies comparing tamoxifen alone to tamoxifen plus ovarian function suppression (OFS), results of the studies comparing tamoxifen plus OFS to aromatase inhibitors plus OFS. PMID- 26634956 TI - Efficacy and tolerability of buccal buprenorphine in opioid-naive patients with moderate to severe chronic low back pain. AB - OBJECTIVES: Buprenorphine HCl buccal film has been developed for treating chronic pain utilizing BioErodible MucoAdhesive (BEMA((r))) delivery technology. Buccal buprenorphine (BBUP; Belbuca(TM), Endo Pharmaceuticals) was evaluated for the management of moderate to severe chronic low back pain (CLBP) requiring around the-clock analgesia in a multicenter, double-blind, placebo-controlled, enriched enrollment, randomized-withdrawal study in opioid-naive patients. METHODS: Patients (n = 749) were titrated to a dose of BBUP (range, 150-450 ug every 12 h) that was generally well tolerated and provided adequate analgesia for >=14 days, and then randomized to BBUP (n = 229) or placebo (n = 232), respectively. The primary efficacy variable was the change from baseline to week 12 of double-blind treatment in the mean of daily average pain intensity scores (numeric rating scale from 0 [no pain] to 10 [worst pain imaginable]). RESULTS: Patients were experiencing moderate to severe pain at study entry: mean (SD) = 7.15 (1.05). Following titration, pain was reduced to the mild range; 2.81 (1.07). After randomization, mean (SD) pain scores increased from baseline to week 12 more with placebo (1.59 [2.04]) versus BBUP: (0.94 [1.85]) with a significant between-group difference (-0.67 [95% CI: -1.07 to -0.26]; p = 0.0012). A significantly larger percentage of patients receiving BBUP versus placebo had >=30% pain reduction (63% vs 47%; p = 0.0012). During double-blind treatment, the most frequent adverse events (AEs) with BBUP were nausea (10%), constipation (4%) and vomiting (4%). The most common AEs with placebo were nausea (7%), upper respiratory tract infection (4%), headache (3%) and diarrhea (3%). CONCLUSIONS: These findings demonstrate the efficacy and tolerability of BBUP among opioid-naive patients requiring around-the-clock opioid treatment for CLBP. PMID- 26634957 TI - Androgen receptor gene polymorphism influence fat accumulation: A longitudinal study from adolescence to adult age. AB - To determine the influence of androgen receptor CAG and GGN repeat polymorphisms on fat mass and maximal fat oxidation (MFO), CAG and GGN repeat lengths were measured in 128 young boys, from which longitudinal data were obtained in 45 of them [mean +/- SD: 12.8 +/- 3.6 years old at recruitment, and 27.0 +/- 4.8 years old at adult age]. Subjects were grouped as CAG short (CAGS ) if harboring repeat lengths <= 21, the rest as CAG long (CAGL ); and GGN short (GGNS ) if GGN repeat lengths <= 23, or long if > 23 (GGNL ). CAGS and GGNS were associated with lower adiposity than CAGL or GGNL (P < 0.05). There was an association between the logarithm of CAG repeats polymorphism and the changes of body mass (r = 0.34, P = 0.03). At adult age, CAGS men showed lower accumulation of total body and trunk fat mass, and lower resting metabolic rate (RMR) and MFO per kg of total lean mass compared with CAGL (P < 0.05). GGNS men also showed lower percentage of body fat (P < 0.05). In summary, androgen receptor CAG and GGN repeat polymorphisms are associated with RMR, MFO, fat mass, and its regional distribution in healthy male adolescents, influencing fat accumulation from adolescence to adult age. PMID- 26634958 TI - Dewetting of S1-Pocket via Water Channel upon Thrombin-Substrate Association Reaction. AB - Upon protein-substrate association reaction, dewetting of the substrate-binding pocket is one of the rate-limiting processes. However, understanding the microscopic mechanism still remains challenging because of practical limitations of experimental methodologies. We have addressed the problem here by using molecular dynamics (MD) simulation of the thrombin-substrate association reaction. During the MD simulation, ArgP1 in a substrate accessed thrombin's substrate-binding pocket and formed specific hydrogen bonds (H-bonds) with Asp189 in thrombin, while the catalytic serine of thrombin was still away from the substrate's active site. It is assumed that the thrombin-substrate association reaction is regulated by a stepwise mechanism. Furthermore, in the earlier stage of ArgP1 access to the pocket, we observed that ArgP1 was spatially separated from Asp189 by two water molecules in the pocket. These water molecules transferred from the pocket, followed by the specific H-bond formation between thrombin and the substrate. Interestingly, they were not evacuated directly from the pocket to the bulk solvent, but moved to the water channel of thrombin. This observation indicates that the channel plays functional roles in dewetting upon the association reaction. PMID- 26634959 TI - Bioluminescence Probe for Detecting Hydrogen Sulfide in Vivo. AB - Considering that hydrogen sulfide (H2S) is an endogenous signaling molecule involved in numerous biological processes, a method for monitoring H2S as a powerful tool for investigating its complicated functions and mechanisms is urgently demanded. Herein, a bioluminescent turn-on probe was reported based on caged strategy for the detection of H2S in vitro and in vivo. This probe will help us understand the intricate contribution of H2S to a variety of physiological and pathological processes. PMID- 26634960 TI - Aryl(trifluoroethyl)iodonium Triflimide and Nitrile Solvent Systems: A Combination for the Stereoselective Synthesis of Armed 1,2-trans-beta-Glycosides at Noncryogenic Temperatures. AB - Armed thioglycosides can be activated with aryl(trifluoroethyl)iodonium triflimide in 2:1 CH2Cl2/pivalonitrile or a solvent combination of CH2Cl2, acetonitrile, isobutyronitrile, and pivalonitrile (6:1:1:1) at 0 degrees C for glycosylation reactions that proceed in good yield and moderate to excellent selectivity (up to 25:1 beta/alpha). Comparison to other common glycosylation promoters reveals that both the mixed solvent and the iodonium salt promoter are required for stereoselectivity. PMID- 26634961 TI - How do patients and professionals differentiate between intra-articular joint bleeds and acute flare-ups of arthropathy in patients with haemophilia? AB - INTRODUCTION: The overlap in symptoms between joint bleeds and flare-ups of haemophilia arthropathy (HA) creates difficulties in differentiating between the two conditions. Diagnosis of haemarthrosis is currently empirically made based upon clinical presentations. However, no standard diagnostic criteria are available. To offer appropriate treatment, rapid and accurate diagnosis is essential. Additionally, adequate differentiation can decrease health costs significantly. AIM: The aim of this study was to identify signs and symptoms to differentiate between an intra-articular joint bleed and an acute flare-up of HA in patients with haemophilia and make an initial proposal of items to include in a diagnostic criteria set. METHODS: Six focus group interviews with a total of 13 patients and 15 professionals were carried out. The focus groups were structured following the Nominal Group Technique (NGT). RESULTS: The most important signs and symptoms used to differentiate between joint bleeds and HA were (i) course of the symptoms, (ii) cause of the complaints, (iii) joint history, (iv) type of pain and (v) degree of impairments in range of motion. CONCLUSION: This qualitative study provides insight into signs and symptoms that are currently used to differentiate between joint bleeds and flare-ups of HA. Results of this study can be used to develop a valid and standardized clinical diagnostic criteria set to differentiate between these two conditions. Further research is necessary to validate the signs and symptoms found in this study. PMID- 26634962 TI - Elevated placenta growth factor levels in the early second-trimester amniotic fluid are associated with preterm delivery. AB - OBJECTIVE: The purpose of this study was to determine how angiogenesis-related factors correlate with preterm delivery. METHODS: A cohort of 382 pregnant women undergoing early second-trimester genetic amniocentesis was enrolled and followed up until delivery, and the amniotic fluid was collected and stored as a nested case-control study. Cases with preterm delivery (n = 31) were compared with matched controls with term delivery (n = 62). The amniotic fluid concentrations of placenta growth factor (PlGF), angiogenins, angiopoietin-2, soluble fms-like tyrosine kinase and soluble endoglin were determined using enzyme-linked immunosorbent assays. RESULTS: Women who delivered preterm had a higher amniotic PlGF concentration compared with the control group (median 12.6 pg/ml versus 6.1 pg/ml; p=0.027). Other angiogenesis-related factors did not show any differences between case and control groups. The odds ratio for preterm delivery based on amniotic fluid PlGF was 1.031 (95% confidence interval: 1.002-1.061; p=0.035). Additionally, when the cases were subdivided into early preterm, late preterm and term groups, PlGF values between the early preterm and term delivery groups were significantly different (median 16.6 pg/ml versus 6.1 pg/ml; Bonferroni-adjusted p=0.018). CONCLUSION: Amniotic fluid PlGF levels in the early second trimester of pregnancy are associated with preterm delivery. PMID- 26634963 TI - Photoinduced Atom Transfer Radical Polymerization with ppm-Level Cu Catalyst by Visible Light in Aqueous Media. AB - Photoinduced ATRP was successfully performed in aqueous media. Polymerization of oligo(ethylene oxide) methyl ether methacrylate (OEOMA) in the presence of CuBr2 catalyst and tris(2-pyridylmethyl)amine ligand when irradiated with visible light of 392 nm wavelength at 0.9 mW/cm(2) intensity was well controlled. Linear semi logarithmic kinetic plots and molecular weights increasing with conversion were observed. Polymers of OEOMA were synthesized with low dispersity (Mw/Mn = 1.12) using only 22 ppm of copper catalyst in the presence of excess bromide anions in highly diluted (90% v/v) aqueous media. The effects of copper concentration, salt, and targeted degrees of polymerization were investigated. The polymerization could be directly regulated by external stimulation, i.e., switching the irradiation on/off, with a good retention of chain-end functionality, as proved by clean chain extension of the OEOMA polymers. This new system could enable applications for controlled aqueous radical polymerization due to its low catalyst loading in the absence of any other chemicals. PMID- 26634964 TI - Liver ergothioneine accumulation in a guinea pig model of non-alcoholic fatty liver disease. A possible mechanism of defence? AB - L-ergothioneine (ET), a putative antioxidant compound acquired by animals through dietary sources, has been suggested to accumulate in certain cells and tissues in the body that are predisposed to high oxidative stress. In the present study, we identified an elevation of ET in the liver of a guinea pig model of non-alcoholic fatty liver disease (NAFLD), elucidated a possible mechanism for the increased uptake and investigated the possible role for this accumulation. This increase in liver ET levels correlated with cholesterol accumulation and disease severity. We identified an increase in the transcriptional factor, RUNX1, which has been shown to upregulate the expression of the ET-specific transporter OCTN1, and could consequently lead to the observable elevation in ET. An increase was also seen in heat shock protein 70 (HSP70) which seemingly corresponds to ET elevation. No significant increase was observed in oxidative damage markers, F2-isoprostanes, and protein carbonyls, which could possibly be attributed to the increase in liver ET through direct antioxidant action, induction of HSP70, or by chelation of Fe(2+), preventing redox chemistry. The data suggest a novel mechanism by which the guinea pig fatty liver accumulates ET via upregulation of its transporter, as a possible stress response by the damaged liver to further suppress oxidative damage and delay tissue injury. Similar events may happen in other animal models of disease, and researchers should be aware of the possibility. PMID- 26634965 TI - Non-steroidal mineralocorticoid receptor antagonism for the treatment of cardiovascular and renal disease. AB - Pharmaceutical antagonism of the mineralocorticoid receptor (MR) can protect against organ damage caused by elevated aldosterone levels in patients experiencing heart failure (HF), chronic kidney disease (CKD), primary aldosteronism, and hypertension. While traditional steroid-based MR antagonists effectively reduce mortality rates and extend patient survival, their broad application has been limited by significant side effects, most notably hyperkalaemia. Recently, finerenone (BAY 94-8862) has emerged as a next generation non-steroidal dihydropyridine-based MR antagonist designed to minimize off-target effects while maintaining potent efficacy. In this review, the outcomes of finerenone therapy in several diseases associated with MR activity are explored. The (pre-) clinical efficacy of finerenone is compared with that of traditional steroid-based MR antagonists. Finally, recent and ongoing clinical trials using finerenone to treat chronic HF, CKD, and diabetic nephropathy are discussed. Taken together, pre-clinical and clinical evidence suggests that finerenone may achieve equivalent organ-protective effects with reduced levels of electrolyte disturbance compared with traditional steroid-based MR antagonists. This supports further clinical development of finerenone for the treatment of cardiovascular and renal disease. PMID- 26634966 TI - Electron-induced dissociation (EID) for structure characterization of glycerophosphatidylcholine: determination of double-bond positions and localization of acyl chains. AB - Glycerophospholipids are a highly abundant and diverse collection of biologically relevant lipids, and distinction between isomeric and isobaric species is a fundamental aspect for confident identification. The ability to confidently assign a unique structure to a glycerophospholipid of interest is dependent on determining the number and location of the points of unsaturation and assignment of acyl chain position. The use of high-energy electrons (>20 eV) to induce gas phase dissociation of intact precursor ions results in diagnostic product ions for localizing double-bond positions and determining acyl chain assignment. We describe a high-resolution, tandem mass spectrometry method for structure characterization of glycerophospholipids using electron-induced dissociation (EID). Furthermore, the inclusion of nomenclature to systematically assign bond cleavage sites with acyl chain position and double-bond location enables a uniform platform for lipid identification. The EID methodology detailed here combines novel application of an electron-based dissociation technique with high resolution mass spectrometry that facilitates a new experimental approach for lipid biomarker discovery and validation. PMID- 26634967 TI - Elucidating collision induced dissociation products and reaction mechanisms of protonated uracil by coupling chemical dynamics simulations with tandem mass spectrometry experiments. AB - In this study we have coupled mixed quantum-classical (quantum mechanics/molecular mechanics) direct chemical dynamics simulations with electrospray ionization/tandem mass spectrometry experiments in order to achieve a deeper understanding of the fragmentation mechanisms occurring during the collision induced dissociation of gaseous protonated uracil. Using this approach, we were able to successfully characterize the fragmentation pathways corresponding to ammonia loss (m/z 96), water loss (m/z 95) and cyanic or isocyanic acid loss (m/z 70). Furthermore, we also performed experiments with isotopic labeling completing the fragmentation picture. Remarkably, fragmentation mechanisms obtained from chemical dynamics simulations are consistent with those deduced from isotopic labeling. PMID- 26634968 TI - Medium-sized phosphorus cluster cations P+ 2m+1 (6 <= m <= 32) studied by collision-induced dissociation mass spectrometry. AB - Medium-sized phosphorus cluster cations were generated by laser ablation of red phosphorus and investigated by the method of collision-induced dissociation mass spectrometry. Experimental results show that the primary dissociation channels of phosphorus cluster cations of P(+) 2m+1 (6 <= m <= 11) are all characterized by the loss of P4 unit. For larger cluster cations, their dissociation pathways were more complex. For those magic cations of P(+) 8k+1 observed previously, their dissociation pathways progressively change from the loss of P4 unit (for k = 3) to the loss of P8 unit (for k = 4, 5). A new dissociation pathway characterized by the loss of P10 unit was also indentified for larger cations of P(+) 8k+1 (6 <= k <= 8). Theoretical calculation also shows that, for cations of P(+) 2m+1 (4 <= m <= 10), the dissociation channel characterized by the loss of P4 unit is more energetically favorable than other dissociation channels, which is in good agreement with the experimental results. PMID- 26634969 TI - Characterization of dehydroascorbate-mediated modification of glutaredoxin by mass spectrometry. AB - Ascorbate is as a potent antioxidant in vivo protecting the organism against oxidative stress. In this process, ascorbate is oxidized in two steps to dehydroascorbate (DHA), which if not efficiently reduced back to ascorbate decomposes irreversibly to a complex mixture of products. We demonstrate that a component of this mixture specifically reacts with the thiol group of cysteine residues at physiological pH to give a protein adduct involving the addition of a 5-carbon fragment of DHA (+112 Da). Incubations of glutaredoxin-1 expressed in Escherichia coli and dehydroascorbate revealed abundant adducts of +112, +224 and +336 Da due to the addition of one, two and three conjugation products of DHA, respectively. ESI-MS of carbamidomethylated glutaredoxin-1 before incubation with DHA, deuterium exchange together with tandem mass spectrometry analysis and LC ESIMS/MS of modified peptides confirmed structure and sites of modification in the protein. Modification of protein thiols by a DHA-derived product can be involved in oxidative stress-mediated cellular toxicity. PMID- 26634970 TI - Experimental and simulation investigation of ion transfer in different sampling capillaries. AB - Atmospheric pressure interfaces were a fundamental structure for transferring air generated ions into the vacuum manifold of a mass spectrometer. This work is devoted to the characterization of ion transfer in metal capillaries through both experimental and simulated investigations. The impact of capillary configurations on ion transmission efficiency was evaluated using an electrospray mass spectrometer with various bent capillaries as the transfer devices. In addition, a numerical model has been set up by coupling the SIMION 8.0 and the computational flow dynamics for simulation study of ion migration in the complex atmospheric system. The transfer efficiency was found to be highly affected by the variation in electric field and the capillary geometry, revealing that the hydrodynamic and electric force were both dominant and interactional during the transmission process. The consistency of the results from the experimental analysis and simulation modeling proved the validity of the model, which was helpful for understanding ion activity in transfer capillaries. PMID- 26634971 TI - MALDI imaging reveals lipid changes in the skin of leprosy patients before and after multidrug therapy (MDT). AB - Leprosy still represents a health problem in several countries. Affecting skin and peripheral nerves, it may lead to permanent disabilities. Disturbances on skin lipid metabolism in leprosy were already observed; however, the localization and distribution of lipids could not be accessed. The role of lipids on infectious disease has been fully addressed only recently, as they directly influence immune response. Matrix-assisted laser desorption/ionization imaging mass spectrometry provides a powerful tool to localize and identify lipids in tissues. The aim of this work was to study and compare the changes in lipid distribution of skin biopsies taken from leprosy patients before and after multidrug therapy (MDT). Different species of phosphatidic acid, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, sphingomyelin and phosphatidylcholine were detected. Differences in skin lipid signal intensities, as well as in their localization, were observed before and after MDT in every patient. In general, lipid distribution in the skin after MDT had a pattern similar to control skin samples, where most of the lipids were located in the upper part of the dermis and epidermis. This study opens paths to a better understanding of lipid functions in leprosy pathogenesis and immune response. PMID- 26634972 TI - Separation and characterization of oxidized isomeric lipid-peptide adducts by ion mobility mass spectrometry. AB - Phospholipids are major components of cell membranes and lipoprotein complexes. They are prone to oxidation by endogenous and exogenous reactive oxygen species yielding a large variety of modified lipids including small aliphatic and phospholipid bound aldehydes and ketones. These carbonyls are strong electrophiles that can modify proteins and, thereby, alter their structures and functions triggering various pathophysiological conditions. The analysis of lipid protein adducts by liquid chromatography-MS is challenged by their mixed chemical nature (polar peptide and hydrophobic lipid), low abundance in biological samples, and formation of multiple isomers. Thus, we investigated traveling wave ion mobility mass spectrometry (TWIMS) to analyze lipid-peptide adducts generated by incubating model peptides corresponding to the amphipathic beta1 sheet sequence of apolipoprotein B-100 with 1-palmitoyl-2-(oxo-nonanoyl)-sn glycerophosphatidylcholine (PONPC). The complex mixture of peptides, lipids, and peptide-lipid adducts was separated by TWIMS, which was especially important for the identification of two mono-PONPC-peptide isomers containing Schiff bases at different lysine residues. Moreover, TWIMS separated structural conformers of one peptide-lipid adduct possessing most likely different orientations of the hydrophobic sn-1 fatty acyl residue and head group of PONPC, relative to the peptide backbone. PMID- 26634973 TI - Which cations form upon CSI or ESI of solutions of Grignard reagents? PMID- 26634974 TI - A new approach to live reaction monitoring using active flow technology in ultra high-speed HPLC with mass spectral detection. AB - A new type of chromatography column referred to as a parallel segmented flow (PSF) column enables ultra-high-speed high-performance liquid chromatography-MS to be undertaken. This occurs because the separation efficiency obtained on PSF columns has been shown in prior studies to be superior to conventional columns, and the flow stream is split radially inside the outlet end fitting of the column, rather than in an axial post-column flow stream split. As a result, the flow through the column can be five times higher than the flow through the MS. In this work, the degradation of amino acids in dilute nitric acid was used to illustrate the process. Separations were obtained in less than 12 s, although the reinjection process was initiated 6 s after the previous injection. The degradation rate constant of tryptophan, in the presence of tyrosine and phenylalanine, was determined. PMID- 26634975 TI - Linear ion trap with added octopole field component: the property and method. AB - It is well known that superimposition of some positive octopole field will benefit the performance of ion trap mass analyzer. In the radial-ejection linear ion trap (LIT), adding some octopole field component to the main quadrupole field is usually accomplished by stretching the ejection rod pair. In this study, the effect of octopole potential and some other higher order potential on the performance of LIT mass analyzer is investigated. A simple and effective method, which is to add some octopole component by building a LIT with a pair of rectangular electrodes and a pair of semi-circular electrodes, is reported. Its properties were studied by numerical simulations and experiments. The results showed that a certain amount of positive octopole component could be produced by simply adjusting the position and width of the rectangular electrodes. A resolution of over 1200 at m/z 609 (~1600 Da/s) was observed in this type of LIT. They also performed tandem mass spectrometry well. The device with optimum geometry for ion ejection from rectangular electrodes provided comparable performance to that for ion ejection from semi-circular electrodes. This type of LIT design is easy for fabrication and assembly. PMID- 26634976 TI - Markers of mesterolone abuse in sulfate fraction for doping control in human urine. AB - This manuscript describes the direct detection of mesteroloe sulfo-conjugated metabolites by liquid chromatography/quadrupole/time of flight mass spectrometry (LC/Q/TOFMS) with special focus on evaluation of their retrospective detectability and their structure elucidation. A comparison of their long-term detectability, with the mesterolone main metabolite (1alpha-methyl-5alpha androstan-3alpha-ol-17-one) excreted in glucuronide fraction and detected by gas chromatography/high resolution mass spectrometry (GC/HRMS), is also presented. Studies on mesterolone were performed with samples obtained from two excretion studies after single oral administration of Proviron(c) by healthy volunteers. Potential sulfate metabolites were detected in post administration samples after liquid-liquid extraction (LLE) with ethyl acetate and LC/TOFMS analysis, in negative mode. Twelve mesterolone sulfate metabolites from the first excretion study and nine from the second were subsequently confirmed by LC/Q/TOFMS. Finally, six mesterolone sulfate metabolites were considered important taking into account their abundance and long-term detectability, encoded as M1, M2, M4, M5, M6 and M7. The proposed mesterolone sulfate metabolites M1, M2, M4 and M5 (excreted as sulfates) have the same retrospectivity with the main mesterolone metabolite, excreted in glucuronide fraction. For metabolite characterization, LC fractionation was performed. The metabolites were identified and characterized by GC/MS, after solvolysis and derivatization. Combined mass spectra data from trimethyl-silyl (TMS), TMS-enolTMS and methoxime-TMS derivatives were taken into account for the characterization of these metabolites. It was concluded that M1 is 1alpha-methyl-5alpha-androstan-3beta-ol-17 one, M2 is 1alpha-methyl-5alpha androstan-3alpha-ol-17 one, M4 is 1alpha-methyl-5a-androstan-3beta, 16z-diol-17 one, M5 is 1alpha-methyl-5alpha-androstan-17z,4xi-diol-3one, M6 is 1alpha-methyl 5alpha-androstan-3z,6z-diol-17-one and M7 is 4z-hydroxy-1alpha-methyl-5alpha androstan-3,17-dione. PMID- 26634977 TI - Mono-, di- and trimethylated homologues of isoprenoid tetraether lipid cores in archaea and environmental samples: mass spectrometric identification and significance. AB - Higher homologues of widely reported C(86) isoprenoid diglycerol tetraether lipid cores, containing 0-6 cyclopentyl rings, have been identified in (hyper)thermophilic archaea, representing up to 21% of total tetraether lipids in the cells. Liquid chromatography-tandem mass spectrometry confirms that the additional carbon atoms in the C(87-88) homologues are located in the etherified chains. Structures identified include dialkyl and monoalkyl ('H-shaped') tetraethers containing C(40-42) or C(81-82) hydrocarbons, respectively, many representing novel compounds. Gas chromatography-mass spectrometric analysis of hydrocarbons released from the lipid cores by ether cleavage suggests that the C(40) chains are biphytanes and the C(41) chains 13-methylbiphytanes. Multiple isomers, having different chain combinations, were recognised among the dialkyl lipids. Methylated tetraethers are produced by Methanothermobacter thermautotrophicus in varying proportions depending on growth conditions, suggesting that methylation may be an adaptive mechanism to regulate cellular function. The detection of methylated lipids in Pyrobaculum sp. AQ1.S2 and Sulfolobus acidocaldarius represents the first reported occurrences in Crenarchaeota. Soils and aquatic sediments from geographically distinct mesotemperate environments that were screened for homologues contained monomethylated tetraethers, with di- and trimethylated structures being detected occasionally. The structural diversity and range of occurrences of the C(87-89) tetraethers highlight their potential as complementary biomarkers for archaea in natural environments. PMID- 26634978 TI - Heterocyclic ring cleavage upon collision-induced dissociation of deprotonated 3 hydroxy-1,2,5-oxadiazoles (3-hydroxyfurazans). AB - A series of 4-substituted 3-hydroxyfurazans were subjected to electrospray ionization tandem mass spectrometry. At low collision energy, oxyisocyanate ([O=C=N-O](-), m/z 58) was formed as the predominant product ion from each deprotonated 3-hydroxyfurazan, indicating cleavage of the heterocyclic ring. The facile energetics of this characteristic fragmentation process was confirmed by density functional computations. PMID- 26634979 TI - Combining UV photodissociation action spectroscopy with electron transfer dissociation for structure analysis of gas-phase peptide cation-radicals. AB - We report the first example of using ultraviolet (UV) photodissociation action spectroscopy for the investigation of gas-phase peptide cation-radicals produced by electron transfer dissociation. z-Type fragment ions (?) Gly-Gly-Lys(+), coordinated to 18-crown-6-ether (CE), are generated, selected by mass and photodissociated in the 200-400 nm region. The UVPD action spectra indicate the presence of valence-bond isomers differing in the position of the Calpha radical defect, (alpha-Gly)-Gly-Lys(+) (CE), Gly-(alpha-Gly)-Lys(+) (CE) and Gly-Gly (alpha-Lys(+))(CE). The isomers are readily distinguishable by UV absorption spectra obtained by time-dependent density functional theory (TD-DFT) calculations. In contrast, conformational isomers of these radical types are calculated to have similar UV spectra. UV photodissociation action spectroscopy represents a new tool for the investigation of transient intermediates of ion electron reactions. Specifically, z-type cation radicals are shown to undergo spontaneous hydrogen atom migrations upon electron transfer dissociation. PMID- 26634980 TI - In Memoriam Urs Peter Schlunegger: 27 September 1934 - 28 September 2015. PMID- 26634982 TI - Development of Bifunctional Inhibitors of Polo-Like Kinase 1 with Low-Nanomolar Activities Against the Polo-Box Domain. AB - Polo-like kinase 1 (Plk1), a validated cancer target, harbors a protein-protein interaction domain referred to as the polo-box domain (PBD), in addition to its enzymatic domain. Although functional inhibition either of the enzymatic domain or of the PBD has been shown to inhibit Plk1, so far there have been no reports of bifunctional agents with the potential to target both protein domains. Here we report the development of Plk1 inhibitors that incorporate both an ATP competitive ligand of the enzymatic domain, derived from BI 2536, and a functional inhibitor of the PBD, based either on the small molecule poloxin-2 or on a PBD-binding peptide. Although these bifunctional agents do not seem to bind both protein domains simultaneously, the most potent compound displays low nanomolar activity against the Plk1 PBD, with excellent selectivity over the PBDs of Plk2 and Plk3. Our data provide insights into challenges and opportunities relating to the optimization of Plk1 PBD ligands as potent Plk1 inhibitors. PMID- 26634983 TI - Estimation of Filling and Afterload Conditions by Pump Intrinsic Parameters in a Pulsatile Total Artificial Heart. AB - A physiological control algorithm is being developed to ensure an optimal physiological interaction between the ReinHeart total artificial heart (TAH) and the circulatory system. A key factor for that is the long-term, accurate determination of the hemodynamic state of the cardiovascular system. This study presents a method to determine estimation models for predicting hemodynamic parameters (pump chamber filling and afterload) from both left and right cardiovascular circulations. The estimation models are based on linear regression models that correlate filling and afterload values with pump intrinsic parameters derived from measured values of motor current and piston position. Predictions for filling lie in average within 5% from actual values, predictions for systemic afterload (AoPmean , AoPsys ) and mean pulmonary afterload (PAPmean ) lie in average within 9% from actual values. Predictions for systolic pulmonary afterload (PAPsys ) present an average deviation of 14%. The estimation models show satisfactory prediction and confidence intervals and are thus suitable to estimate hemodynamic parameters. This method and derived estimation models are a valuable alternative to implanted sensors and are an essential step for the development of a physiological control algorithm for a fully implantable TAH. PMID- 26634984 TI - Major advances in physiology: celebrating a centenary of contributions by women. Introduction. PMID- 26634985 TI - Meet Our Associate Editor. PMID- 26634987 TI - Enhancing the magnetic anisotropy of maghemite nanoparticles via the surface coordination of molecular complexes. AB - Superparamagnetic nanoparticles are promising objects for data storage or medical applications. In the smallest--and more attractive--systems, the properties are governed by the magnetic anisotropy. Here we report a molecule-based synthetic strategy to enhance this anisotropy in sub-10-nm nanoparticles. It consists of the fabrication of composite materials where anisotropic molecular complexes are coordinated to the surface of the nanoparticles. Reacting 5 nm gamma-Fe2O3 nanoparticles with the [Co(II)(TPMA)Cl2] complex (TPMA: tris(2 pyridylmethyl)amine) leads to the desired composite materials and the characterization of the functionalized nanoparticles evidences the successful coordination--without nanoparticle aggregation and without complex dissociation- of the molecular complexes to the nanoparticles surface. Magnetic measurements indicate the significant enhancement of the anisotropy in the final objects. Indeed, the functionalized nanoparticles show a threefold increase of the blocking temperature and a coercive field increased by one order of magnitude. PMID- 26634988 TI - Functional coupling of diverse voltage-gated Ca(2+) channels underlies high fidelity of fast dendritic Ca(2+) signals during burst firing. AB - KEY POINTS: In neurons, the Ca(2+) signal associated with the dendritic back propagating action potential codes a chemical message to the different dendritic sites, playing a crucial role in electrical signalling, synaptic transmission and synaptic plasticity. The study of the underlying Ca(2+) current, mediated by different types of voltage-gated Ca(2+) channels, cannot be achieved by using the patch clamp technique. In this article, we used a recently developed cutting-edge optical technique to investigate the physiological behaviour of local Ca(2+) currents along the apical dendrite of CA1 hippocampal pyramidal neurons. We directly measure, for the first time, the synergistic activation and deactivation of the diverse dendritic voltage-gated Ca(2+) channels operating during bursts of back-propagating action potentials to precisely control the Ca(2+) signal. We demonstrate that the Ca(2+) loss via high-voltage-activated channels is compensated by the Ca(2+) entry via the other channels translating in high fidelity of Ca(2+) signalling. ABSTRACT: In CA1 hippocampal pyramidal neurons, the dendritic Ca(2+) signal associated with somatic firing represents a fundamental activation code for several proteins. This signal, mediated by voltage-gated Ca(2+) channels (VGCCs), varies along the dendrites. In this study, using a recent optical technique based on the low-affinity indicator Oregon Green 488 BAPTA-5N, we analysed how activation and deactivation of VGCCs produced by back-propagating action potentials (bAPs) along the apical dendrite shape the Ca(2+) signal at different locations in CA1 hippocampal pyramidal neurons of the mouse. We measured, at multiple dendritic sites, the Ca(2+) transients and the changes in membrane potential associated with bAPs at 50 MUs temporal resolution and we estimated the kinetics of the Ca(2+) current. We found that during somatic bursts, the bAPs decrease in amplitude along the apical dendrite but the amplitude of the associated Ca(2+) signal in the initial 200 MUm dendritic segment does not change. Using a detailed pharmacological analysis, we demonstrate that this effect is due to the perfect compensation of the loss of Ca(2+) via high-voltage-activated (HVA) VGCCs by a larger Ca(2+) component via low-voltage-activated (LVA) VGCCs, revealing a mechanism coupling the two VGCC families of K(+) channels. More distally, where the bAP does not activate HVA VGCCs, the Ca(2+) signal is variable during the burst. Thus, we demonstrate that HVA- and LVA-VGCCs operate synergistically to stabilise Ca(2+) signals associated with bAPs in the most proximal 200 MUm dendritic segment. PMID- 26634989 TI - Extremely Stretchable Electroluminescent Devices with Ionic Conductors. AB - An extremely stretchable electroluminescent device is fabricated based on alternating-current electroluminescent (ACEL) materials and ionic conductors. The stretchable ACEL device possesses extremely high stretchability, and can be linearly stretched to 700% with the luminance being maintained at 70% of the initial value before stretching. The ACEL device can be repetitively stretched to 400% with stable emission behavior. PMID- 26634990 TI - Dressing an existential wound (DEW) - a new model for long-term care following disasters. AB - BACKGROUND: Presence, concern, compassion and universal or ontological unity between human beings have emerged as crucial to the healthy development of people who have experienced disasters. AIM AND OBJECTIVES: The aim of this article was to present a new model for long-term care following disasters. The objective of the model was to contribute to the readiness for long-term care following disasters in professionals and nonprofessionals as a result of their understanding of the model. DESIGN: A longitudinal qualitative study of Swedish tourists affected by the South East Asian tsunami in 2004 is the empirical base for this clinical model, which was developed within the framework of caring science. METHODS: A hermeneutic method was used. RESULTS: The model is based on the assumption that life issues are an important aspect of long-term follow-up after a disaster. The term 'life issues' refers to the following: existential questioning of life's content, values and priorities; people's relationships with each other; and the importance of health, suffering, love and death. Life issues also refer to the way in which survivors form a new understanding of life after a disaster experience. Existential care is based on a charitable attitude of compassion and mercy towards one's fellows, be they professionals, families or wider society. By presenting eight theses, the model provides an approach based on compassion that works as an existential dressing for survivors of disaster. CONCLUSIONS: The model gives a knowledge base and approach for the long-term care of survivors, including practical advice. PMID- 26634991 TI - Electrolithography--A New and Versatile Process for Nano Patterning. AB - We report a new lithography technique based on electromigration driven material transport for drawing patterns at nanometer scales in ambient conditions. We use a thin metal film as a masking layer and a polymer layer beneath it as a pattern transfer layer. The desired pattern is drawn in the metal layer by etching the metal with a conducting scanning probe assisted by liquid electromigration. The pattern drawn on the metal layer is transferred to the polymer layer by etching the polymer with an appropriate solvent. Subsequently, the pattern is transferred to the desired material layer using a film deposition technique followed by conventional lift-off process. Using this simple technique, we have achieved pattern resolutions of 9 nm on the polymer and 40 nm on transferring the pattern to another material. Based on the ease of use and process costs, this technique promises to be competitive to e-beam lithography that employs high energy and ultra-high vacuum, or the industrial standard ultra-violet light photolithography that employs extremely expensive implements to reach nano-scale resolutions. We also demonstrate direct mask writing using this technique and explain the fundamentals behind the workings of the developed method. PMID- 26634992 TI - Single Particle Dynamic Imaging and Fe3+ Sensing with Bright Carbon Dots Derived from Bovine Serum Albumin Proteins. AB - In this work, we demonstrated a convenient and green strategy for the synthesis of highly luminescent and water-soluble carbon dots (Cdots) by carbonizing carbon precursors, i.e., Bovine serum albumin (BSA) nanoparticles, in water solution. Without post surface modification, the as-synthesized Cdots exhibit fluorescence quantum yield (Q.Y.) as high as 34.8% and display superior colloidal stability not only in concentrated salt solutions (e.g. 2 M KCl) but also in a wide range of pH solutions. According to the FT-IR measurements, the Cdots contain many carboxyl groups, providing a versatile route for further chemical and biological functionalization. Through conjugation of Cdots with the transacting activator of transcription (TAT) peptide (a kind of cell penetration peptide (CPP)) derived from human immunodeficiency virus (HIV), it is possible to directly monitor the dynamic interactions of CPP with living cell membrane at single particle level. Furthermore, these Cdots also exhibit a dosage-dependent selectivity toward Fe(3+) among other metal ions, including K(+), Na(+), Mg(2+), Hg(2+), Co(2+), Cu(2+), Pb(2+) and Al(3+). We believed that the Cdots prepared by this strategy would display promising applications in various areas, including analytical chemistry, nanomedicine, biochemistry and so on. PMID- 26634993 TI - Improving Protein Fold Recognition by Deep Learning Networks. AB - For accurate recognition of protein folds, a deep learning network method (DN Fold) was developed to predict if a given query-template protein pair belongs to the same structural fold. The input used stemmed from the protein sequence and structural features extracted from the protein pair. We evaluated the performance of DN-Fold along with 18 different methods on Lindahl's benchmark dataset and on a large benchmark set extracted from SCOP 1.75 consisting of about one million protein pairs, at three different levels of fold recognition (i.e., protein family, superfamily, and fold) depending on the evolutionary distance between protein sequences. The correct recognition rate of ensembled DN-Fold for Top 1 predictions is 84.5%, 61.5%, and 33.6% and for Top 5 is 91.2%, 76.5%, and 60.7% at family, superfamily, and fold levels, respectively. We also evaluated the performance of single DN-Fold (DN-FoldS), which showed the comparable results at the level of family and superfamily, compared to ensemble DN-Fold. Finally, we extended the binary classification problem of fold recognition to real-value regression task, which also show a promising performance. DN-Fold is freely available through a web server at http://iris.rnet.missouri.edu/dnfold. PMID- 26634994 TI - Comparing photosynthetic characteristics of Isoetes sinensis Palmer under submerged and terrestrial conditions. AB - Crassulacean acid metabolism (CAM) is widespread in terrestrial and aquatic species, plastic in response to environmental changes. Isoetes L. is one of the earliest basal vascular plants and CAM is popular in this genus. Isoetes sinensis Palmer is an amphibious species, alternating frequently between terrestrial and aquatic environments. Given this, we investigated and compared photosynthetic characteristics over a diurnal cycle under submerged condition (SC) and terrestrial condition (TC). The results suggest that I. sinensis possesses a stronger CAM capacity under SC. Compared with under TC, titratable acidity levels and organic acid concentrations were more enriched under SC, whereas soluble sugar or starch and protein levels were lower under SC. Transcript analyses for nine photosynthetic genes revealed that CAM-associated genes possessed high transcripts under SC, but C3-related transcripts were highly expressed under TC. In addition, the enzyme activity measurements demonstrated that PEPC activity over a diurnal cycle was slightly higher under SC, whereas Rubisco activity during the daytime was greater under TC. This comprehensive study probably facilitates general understandings about the CAM photosynthetic characteristics of Isoetes in response to the environmental changes. PMID- 26634995 TI - Prevention of Dielectric Breakdown of Nanopore Membranes by Charge Neutralization. AB - To achieve DNA sequencing using a solid-state nanopore, it is necessary to reduce the electric noise current. The noise current can be decreased by reducing the capacitance (C) of the nanopore device. However, we found that an electric-charge difference (DeltaQ) between the electrolyte in one chamber and the electrolyte in another chamber occurred. For low capacitance devices, this electric-charge imbalance can lead to unexpectedly high voltage (DeltaV = DeltaQ/C) which disrupted the membrane when the two electrolytes were independently poured into the chambers. We elucidated the mechanism for the generation of initial defects and established new procedures for preventing the generation of defects by connecting an electric bypass between the chambers. PMID- 26634997 TI - Spectra of weighted scale-free networks. AB - Much information about the structure and dynamics of a network is encoded in the eigenvalues of its transition matrix. In this paper, we present a first study on the transition matrix of a family of weight driven networks, whose degree, strength, and edge weight obey power-law distributions, as observed in diverse real networks. We analytically obtain all the eigenvalues, as well as their multiplicities. We then apply the obtained eigenvalues to derive a closed-form expression for the random target access time for biased random walks occurring on the studied weighted networks. Moreover, using the connection between the eigenvalues of the transition matrix of a network and its weighted spanning trees, we validate the obtained eigenvalues and their multiplicities. We show that the power-law weight distribution has a strong effect on the behavior of random walks. PMID- 26634998 TI - Chronic Disease Diagnosis as a Teachable Moment for Health Behavior Changes Among Middle-Aged and Older Adults. AB - OBJECTIVE: To examine the impact of a new chronic disease diagnosis on substance use (i.e., smoking and drinking), utilization of preventive medical procedures, and physical activity among middle-aged and older adults. METHOD: Individual level data came from 1996 to 2010 waves of the U.S. Health and Retirement Study. Disease diagnosis was ascertained from self-reports of physician-diagnosed diseases. A case-control difference-in-differences approach estimated in logistic regression was applied to test study hypotheses. RESULTS: After a diagnosis of chronic disease, participants decreased substance use and increased utilization of preventive medical procedures. Physical activity declined after a diagnosis of lung disease, cancer, and stroke. DISCUSSION: Chronic disease diagnosis may be an important teachable moment that can motivate individuals to adopt multiple risk reducing health behaviors. Future research needs to elucidate the mechanisms through which disease diagnosis affects behaviors and test the modifying effect of time since diagnosis on intervention effectiveness. PMID- 26634996 TI - Central nervous system myeloid cells as drug targets: current status and translational challenges. AB - Myeloid cells of the central nervous system (CNS), which include parenchymal microglia, macrophages at CNS interfaces and monocytes recruited from the circulation during disease, are increasingly being recognized as targets for therapeutic intervention in neurological and psychiatric diseases. The origin of these cells in the immune system distinguishes them from ectodermal neurons and other glia and endows them with potential drug targets distinct from classical CNS target groups. However, despite the identification of several promising therapeutic approaches and molecular targets, no agents directly targeting these cells are currently available. Here, we assess strategies for targeting CNS myeloid cells and address key issues associated with their translation into the clinic. PMID- 26634999 TI - Arabidopsis CML38, a Calcium Sensor That Localizes to Ribonucleoprotein Complexes under Hypoxia Stress. AB - During waterlogging and the associated oxygen deprivation stress, plants respond by the induction of adaptive programs, including the redirected expression of gene networks toward the synthesis of core hypoxia-response proteins. Among these core response proteins in Arabidopsis (Arabidopsis thaliana) is the calcium sensor CML38, a protein related to regulator of gene silencing calmodulin-like proteins (rgsCaMs). CML38 transcripts are up-regulated more than 300-fold in roots within 6 h of hypoxia treatment. Transfer DNA insertional mutants of CML38 show an enhanced sensitivity to hypoxia stress, with lowered survival and more severe inhibition of root and shoot growth. By using yellow fluorescent protein (YFP) translational fusions, CML38 protein was found to be localized to cytosolic granule structures similar in morphology to hypoxia-induced stress granules. Immunoprecipitation of CML38 from the roots of hypoxia-challenged transgenic plants harboring CML38pro::CML38:YFP followed by liquid chromatography-tandem mass spectrometry analysis revealed the presence of protein targets associated with messenger RNA ribonucleoprotein (mRNP) complexes including stress granules, which are known to accumulate as messenger RNA storage and triage centers during hypoxia. This finding is further supported by the colocalization of CML38 with the mRNP stress granule marker RNA Binding Protein 47 (RBP47) upon cotransfection of Nicotiana benthamiana leaves. Ruthenium Red treatment results in the loss of CML38 signal in cytosolic granules, suggesting that calcium is necessary for stress granule association. These results confirm that CML38 is a core hypoxia response calcium sensor protein and suggest that it serves as a potential calcium signaling target within stress granules and other mRNPs that accumulate during flooding stress responses. PMID- 26635000 TI - SUMOylation of Syntaxin1A regulates presynaptic endocytosis. AB - Neurotransmitter release from the presynaptic terminal is under very precise spatial and temporal control. Following neurotransmitter release, synaptic vesicles are recycled by endocytosis and refilled with neurotransmitter. During the exocytosis event leading to release, SNARE proteins provide most of the mechanical force for membrane fusion. Here, we show one of these proteins, Syntaxin1A, is SUMOylated near its C-terminal transmembrane domain in an activity dependent manner. Preventing SUMOylation of Syntaxin1A reduces its interaction with other SNARE proteins and disrupts the balance of synaptic vesicle endo/exocytosis, resulting in an increase in endocytosis. These results indicate that SUMOylation regulates the emerging role of Syntaxin1A in vesicle endocytosis, which in turn, modulates neurotransmitter release and synaptic function. PMID- 26635002 TI - [A Case of Pneumococcal Pneumonia Early Diagnosed by Detection Kit RAPIRUN(r) in a Dialysis Patient]. AB - A 65-year-old woman developed fever and dyspnea and visited the emergency department of our hospital. On arrival she was hypoxic, and chest CT showed bilateral centrilobular nodules, infiltrative shadows and bronchial wall thickening. Gram staining wasn't performed on admission, and the urinary antigen detection test for Streptococcus pneumoniae couldn't be performed because the patient has suffered from anuria caused by renal failure. Therefore, we conducted S. pneumoniae antigen test (RAPIRUN(r) Streptococcus pneumoniae) using sputum sample, then rapidly diagnosed pneumococcal pneumonia due to the positive result of the rapid test. RAPIRUN(r) Streptococcus pneumoniae is considered to be useful in the differential diagnosis of pneumonia, especially for patients who are unable to urinate or on the facilities that Gram stain cannot be carried out timely. PMID- 26635003 TI - [Evaluating the Stability of Loop-Mediated Isothermal Amplification Reagents at Irregular Storage Temperatures for On-Site Diagnosis]. AB - Temperature-stability of loop-mediated isothermal amplification (LAMP) reagents was determined for their use in on-site diagnosis, such as in farms/pastures. Bst and Csa DNA polymerases and the reagents that were stored at different temperatures (4 or 25 degrees C) for 1, 2, or 4 days were used for the LAMP assay to detect orf virus DNA as a model. After storage at 4 and 25 degrees C for 2 days, the enzymes and reagents were found to retain sufficient activity to carry out successful DNA amplification. Visual diagnosis was also possible with the reagents (Loopamp Fluorescent Detection Reagent or hydroxy naphthol blue, as well as DNA amplification checker, D-Quick) that were stored for 2 days at different temperatures. Although the time taken to obtain the positive/negative results were delayed, the enzymes and reagents, stored at 25 degrees C for 4 days, were active and had the ability to efficiently amplify DNA in less than 50 min. These results indicate that LAMP assay can be successfully utilized for the diagnosis of infectious diseases under non-clinical settings such as for on-site diagnosis in farms/pastures, owing to the fact that the relevant enzymes and reagents does not require restricted temperature storage. PMID- 26635001 TI - The brown and brite adipocyte marker Cox7a1 is not required for non-shivering thermogenesis in mice. AB - The cytochrome c oxidase subunit isoform Cox7a1 is highly abundant in skeletal muscle and heart and influences enzyme activity in these tissues characterised by high oxidative capacity. We identified Cox7a1, well-known as brown adipocyte marker gene, as a cold-responsive protein of brown adipose tissue. We hypothesised a mechanistic relationship between cytochrome c oxidase activity and Cox7a1 protein levels affecting the oxidative capacity of brown adipose tissue and thus non-shivering thermogenesis. We subjected wildtype and Cox7a1 knockout mice to different temperature regimens and tested characteristics of brown adipose tissue activation. Cytochrome c oxidase activity, uncoupling protein 1 expression and maximal norepinephrine-induced heat production were gradually increased during cold-acclimation, but unaffected by Cox7a1 knockout. Moreover, the abundance of uncoupling protein 1 competent brite cells in white adipose tissue was not influenced by presence or absence of Cox7a1. Skin temperature in the interscapular region of neonates was lower in uncoupling protein 1 knockout pups employed as a positive control, but not in Cox7a1 knockout pups. Body mass gain and glucose tolerance did not differ between wildtype and Cox7a1 knockout mice fed with high fat or control diet. We conclude that brown adipose tissue function in mice does not require the presence of Cox7a1. PMID- 26635004 TI - [Rapid Identification Method Positive Blood Culture Bottles with MALDI Biotyper]. AB - Identification method positive blood culture bottles with MALDI Biotyper is the most important test on precisely and rapidly, for detamination the bacterial name in sepsis and bacteremia is very significant for decision a cure. This time, we devised a new method "blend" to identify the mixture hypostasis that were come into being by centrifuging blood culture broths and 70% formic acid with MALDI Biotyper (Bruker). This time, we identified 65 samples rapidly with MALDI biotyper by "on plate" and "blend," and verified their effectivity. As a result of six ways (on plate, blend-3, blend-6, blend-9, blend-12, blend-15), the highest detection rate was Gram negative rods: blend-15 (74.1%), Gram positive cocci: blend-9 (56.3%), total: blend-9 (55.4%). Moreover, we confirmed that the detection rate raised to 85.2% (GNR), 71.0% (GPC) and 77.6% (total), and the usefully was suggested. Our invented method is more excellently than recommended on Gram negative rods, especially Enterobacteriaceae, Staphylococcus aureus, and Enterococcus spp. PMID- 26635005 TI - The Qatar Biobank: background and methods. AB - BACKGROUND: The Qatar Biobank aims to collect extensive lifestyle, clinical, and biological information from up to 60,000 men and women Qatari nationals and long term residents (individuals living in the country for >=15 years) aged >=18 years (approximately one-fifth of all Qatari citizens), to follow up these same individuals over the long term to record any subsequent disease, and hence to study the causes and progression of disease, and disease burden, in the Qatari population. METHODS: Between the 11(th)-December-2012 and 20(th)-February-2014, 1209 participants were recruited into the pilot study of the Qatar Biobank. At recruitment, extensive phenotype information was collected from each participant, including information/measurements of socio-demographic factors, prevalent health conditions, diet, lifestyle, anthropometry, body composition, bone health, cognitive function, grip strength, retinal imaging, total body dual energy X-ray absorptiometry, and measurements of cardiovascular and respiratory function. Blood, urine, and saliva were collected and stored for future research use. A panel of 66 clinical biomarkers was routinely measured on fresh blood samples in all participants. Rates of recruitment are to be progressively increased in the coming period and the recruitment base widened to achieve a cohort of consented individuals broadly representative of the eligible Qatari population. In addition, it is planned to add additional measures in sub-samples of the cohort, including Magnetic Resonance Imaging (MRI) of the brain, heart and abdomen. RESULTS: The mean time for collection of the extensive phenotypic information and biological samples from each participant at the baseline recruitment visit was 179 min. The 1209 pilot study participants (506 men and 703 women) were aged between 28-80 years (median 39 years); 899 (74.4%) were Qatari nationals and 310 (25.6%) were long-term residents. Approximately two-thirds of pilot participants were educated to graduate level or above. CONCLUSIONS: The pilot has proven that recruitment of volunteers into the Qatar Biobank project with intensive baseline measurements of behavioural, physical, and clinical characteristics is well accepted and logistically feasible. Qatar Biobank will provide a powerful resource to investigate the major determinants of ill-health and well-being in Qatar, providing valuable insights into the current and future public health burden that faces the country. PMID- 26635006 TI - Adding physical therapy services in the emergency department to prevent immobilization syndrome - a feasibility study in a university hospital. AB - BACKGROUND: The association between the functional decline occurring with bedrest and hospitalization in older persons is well-known. A long wait in the emergency department (ED), where patients can be bedridden, is a risk factor for the development of an immobilization syndrome (IS). IS is one of the unwanted consequences of inactivity, which causes pathological changes in most organs and systems. Early mobility interventions, such as physical therapy (PT) delivered in the ED, may prevent its development. To our knowledge, no prior studies have reported on this topic. The goal of this study was to (i) assess the feasibility and (ii) explore the potential clinical value of adding PT services to the ED, in collaboration with nursing staff, to prevent IS. METHODS: For 12 weeks, PT services were delivered in the ED to older persons (>65 years old) presenting with >=1 clinical signs associated with the development of IS. Patients were screened by ED nurses and then seen by the physiotherapist. In order to assess feasibility, access to patients, percentage of patients who met eligibility criteria, acceptability of the intervention, and barriers/facilitators to the implementation were measured. To describe the clinical benefits of early PT services, we counted the number of new IS cases among patients after their admission to the ward. RESULTS: After 12 weeks, the ED nurses screened 187 potential patients and 20 received PT services in the ED (before their admission to the ward). Accessibility was not an issue and we observed good acceptability from the milieu. We did not find majors problems or insurmountable obstacles to implementation of the intervention. Clinical outcomes showed that nine patients received PT treatments in the ED and on the ward (after their admission). For the 11 other patients, no PT interventions were done in the ED following the assessment. Follow-up of these 11 patients showed that two of them developed IS during their hospital stay. As for the nine patients who began PT treatments in the ED, none of them developed IS. CONCLUSION: Based on the results of this feasibility study, it would be likely and potentially beneficial to implement PT services in the ED, which could have a positive impact on preventing the development of IS in older persons presenting risk factors. While only a small proportion of patients (11 %) received PT services, better screening tools/methods should be developed. PMID- 26635008 TI - Montreal Cognitive Assessment Performance in HIV/AIDS: Impact of Systemic Factors. AB - BACKGROUND: A large proportion of people living with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) suffer from neurocognitive impairment (NCI). The causes of the NCI are multifold in HIV infection although a subset of HIV/AIDS patients are affected by the spectrum syndrome, HIV-associated neurocognitive disorder (HAND). We investigated the Montreal Cognitive Assessment (MoCA) in relation to clinical, demographic and laboratory findings as well as its ability to predict symptomatic HAND (sHAND) among patients with HIV/AIDS. METHODS: All subjects were receiving regular HIV care including CD4+ T cell counts, plasma viral load measurements, clinical evaluations and antiretroviral therapy. The diagnosis of sHAND was based upon clinical, neuroimaging, and neuropsychological assessments. RESULTS: Among HIV-1 seropositive subjects (n=125), ethnicity, education and employment were positively correlated with their MoCA scores (p<0.05). In contrast, polypharmacy, central nervous system penetration-effectiveness (CPE) score, antiretroviral drug exposure, substance use and nucleoside/nucleotide reverse transcriptase inhibitor side effects were negatively correlated with MoCA scores (p<0.05). Of note, MoCA scores were not associated with CD4 T cell nadir levels, age, peak viral load, or veterans aging cohort study index. In subjects with or without sHAND, mean MoCA scores differed (sHAND, 22.8+/-3.51; non-HAND 25.2+/-2.64) (p<0.05) with a receiver operating characteristic curve showing an area under curve of 0.71 and an optimal MoCA cut off value of 23.5 when compared to the established diagnostic paradigm. CONCLUSIONS: MoCA scores were generally lower in this HIV/AIDS population compared to reported scores in the general population. MoCA performance was associated with multiple clinical variables but displayed limited predictive utility in detecting sHAND. PMID- 26635007 TI - Health worker migration from South Africa: causes, consequences and policy responses. AB - BACKGROUND: This paper arises from a four-country study that sought to better understand the drivers of skilled health worker migration, its consequences, and the strategies countries have employed to mitigate negative impacts. The four countries-Jamaica, India, the Philippines, and South Africa-have historically been "sources" of skilled health workers (SHWs) migrating to other countries. This paper presents the findings from South Africa. METHODS: The study began with a scoping review of the literature on health worker migration from South Africa, followed by empirical data collected from skilled health workers and stakeholders. Surveys were conducted with physicians, nurses, pharmacists, and dentists. Interviews were conducted with key informants representing educators, regulators, national and local governments, private and public sector health facilities, recruitment agencies, and professional associations and councils. Survey data were analyzed using descriptive statistics and regression models. Interview data were analyzed thematically. RESULTS: There has been an overall decrease in out-migration of skilled health workers from South Africa since the early 2000s largely attributed to a reduced need for foreign-trained skilled health workers in destination countries, limitations on recruitment, and tighter migration rules. Low levels of worker satisfaction persist, although the Occupation Specific Dispensation (OSD) policy (2007), which increased wages for health workers, has been described as critical in retaining South African nurses. Return migration was reportedly a common occurrence. The consequences attributed to SHW migration are mixed, but shortages appear to have declined. Most promising initiatives are those designed to reinforce the South African health system and undertaken within South Africa itself. CONCLUSIONS: In the near past, South Africa's health worker shortages as a result of emigration were viewed as significant and harmful. Currently, domestic policies to improve health care and the health workforce including innovations such as new skilled health worker cadres and OSD policies appear to have served to decrease SHW shortages to some extent. Decreased global demand for health workers and indications that South African SHWs primarily use migratory routes for professional development suggest that health worker shortages as a result of permanent migration no longer pertains to South Africa. PMID- 26635009 TI - Tracing regulatory routes in metabolism using generalised supply-demand analysis. AB - BACKGROUND: Generalised supply-demand analysis is a conceptual framework that views metabolism as a molecular economy. Metabolic pathways are partitioned into so-called supply and demand blocks that produce and consume a particular intermediate metabolite. By studying the response of these reaction blocks to perturbations in the concentration of the linking metabolite, different regulatory routes of interaction between the metabolite and its supply and demand blocks can be identified and their contribution quantified. These responses are mediated not only through direct substrate/product interactions, but also through allosteric effects. Here we subject previously published kinetic models of pyruvate metabolism in Lactococcus lactis and aspartate-derived amino acid synthesis in Arabidopsis thaliana to generalised supply-demand analysis. RESULTS: Multiple routes of regulation are brought about by different mechanisms in each model, leading to behavioural and regulatory patterns that are generally difficult to predict from simple inspection of the reaction networks depicting the models. In the pyruvate model the moiety-conserved cycles of ATP/ADP and NADH/NAD(+) allow otherwise independent metabolic branches to communicate. This causes the flux of one ATP-producing reaction block to increase in response to an increasing ATP/ADP ratio, while an NADH-consuming block flux decreases in response to an increasing NADH/NAD(+) ratio for certain ratio value ranges. In the aspartate model, aspartate semialdehyde can inhibit its supply block directly or by increasing the concentration of two amino acids (Lys and Thr) that occur as intermediates in demand blocks and act as allosteric inhibitors of isoenzymes in the supply block. These different routes of interaction from aspartate semialdehyde are each seen to contribute differently to the regulation of the aspartate semialdehyde supply block. CONCLUSIONS: Indirect routes of regulation between a metabolic intermediate and a reaction block that either produces or consumes this intermediate can play a much larger regulatory role than routes mediated through direct interactions. These indirect routes of regulation can also result in counter-intuitive metabolic behaviour. Performing generalised supply-demand analysis on two previously published models demonstrated the utility of this method as an entry point in the analysis of metabolic behaviour and the potential for obtaining novel results from previously analysed models by using new approaches. PMID- 26635010 TI - The chromosomal constitution of fish hybrid lineage revealed by 5S rDNA FISH. AB - BACKGROUND: The establishment of the bisexual fertile fish hybrid lineage including the allodiploid and allotetraploid hybrids, from interspecific hybridization of red crucian carp (Carassius auratus red var. 2n = 100, 2n = AA) (?) * common carp (Cyprinus carpio L. 2n = 100, 2n = BB) (?), provided a good platform to investigate genetic relationship between the parents and their hybrid progenies. RESULTS: The chromosomal inheritance of diploid and allotetraploid hybrid progenies in successive generations, was studied by applying 5S rDNA fluorescence in situ hybridization. Signals of 5S rDNA distinguished the chromosomal constitution of common carp (B-genome) from red crucian carp (A genome), in which two strong signals were observed on the first submetacentric chromosome, while no major signal was found in common carp. After fish hybridization, one strong signal of 5S rDNA was detected in the same locus on the chromosome of diploid hybrids. As expected, two strong signals were observed in 4nF3 tetraploid hybrids offspring and it is worth mentioning that two strong signals were detected in a separating bivalent of a primary spermatocyte in 4nF3. Furthermore, the mitosis of heterozygous chromosomes was shown normal and stable with blastular tissue histological studies. CONCLUSIONS: We revealed that 5S rDNA signal can be applied to discern A-genome from B-genome, and that 5S rDNA bearing chromosomes can be stably passed down in successive generations. Our work provided a significant method in fish breeding and this is important for studies in fish evolutionary biology. PMID- 26635011 TI - Evaluation of the effectiveness of photodynamic therapy for the endodontic treatment of primary teeth: study protocol for a randomized controlled clinical trial. AB - BACKGROUND: The elimination of pathogenic microorganisms from the root canal system is one of the major steps required for successful endodontic treatment. The aim of the proposed study is to conduct a randomized, controlled, clinical trial for the clinical and radiographic evaluation of the effectiveness of photodynamic therapy during the endodontic treatment of primary teeth. METHODS: Thirty primary anterior teeth in children aged 3 to 6 years old will be randomly divided into 2 groups: a control group, which will receive conventional treatment, and an experimental group, which will be subjected to photodynamic therapy. Microbiological evaluations will be performed before and after endodontic treatment. Moreover, clinical and radiographic evaluations will be performed on the day of treatment as well as 1, 3 and 6 months after treatment. Comparisons will be made of the two study groups. The data will be tabulated and presented in a descriptive, analytical fashion. Depending on the distribution (normal or non-normal), either the t test, ANOVA or the Mann-Whitney test will be used for analysis of the variables. The Wilcoxon test will be used for comparisons before and after treatment. P values<0.05 (95% significance level) will be considered indicative of statistically significant differences. DISCUSSION: As successful endodontic treatment is directly related to intra-canal bacterial disinfection and considering the difficult task of endodontic treatment in primary teeth, often due to difficulties in controlling young children, the internal anatomy of root canals and root resorption, the alternative of using PDT is a painless,easy-to-administer method that does not lead to microbial resistance and can assist in the achievement of successful endodontic treatment in primary teeth by eliminating the pain children can experience due to retreatment as well as premature tooth loss. TRIAL REGISTRATION: The protocol for this study was registered with Clinical Trials number NCT02485210 on 30 july 2015. PMID- 26635012 TI - Life-course social position, obesity and diabetes risk in the EPIC-Spain Cohort. AB - BACKGROUND: The literature has consistently shown that extreme social-economic groups predicted type 2 diabetes mellitus (T2D), rather than summarising the social gradient throughout all society stratification. Body mass index (BMI) was established as the principal mediator, with little support for other anthropometries. Our aim was to investigate an individual life-course social position (LiSoP) gradient and its mediators with T2D risk in the EPIC-Spain cohort. METHODS: 36 296 participants (62% women), mostly aged 30-65 years, and free of T2D at baseline (1992-1996) were followed up for a mean of 12.1 years. A combined score of paternal occupation in childhood and own adult education assessed individual life-course social risk accumulation. Hazard ratios of T2D were estimated using Cox regression, stratifying by centre and age, and adjusting for different explanatory models, including anthropometric indices; dietary history; smoking and physical activity lifestyles; and clinical information. RESULTS: Final models evidenced significant risks in excess of 63% for middle and 90% for lower classes of LiSoP in men; and of 104 and 126%, respectively, in women. Concurrently, LiSoP presented significant social gradients for T2D risk (P < 0.01) in both sexes. Waist circumference (WC) accounted for most of the risk excess in women, and BMI and WC in men. CONCLUSIONS: LiSoP gradient was related to T2D risk in Spanish men and women. WC mostly explained the relationship in both genders, together with BMI in men, yet LiSoP retained an independent effect in final models. PMID- 26635013 TI - Mortality in Italian veterans deployed in Bosnia-Herzegovina and Kosovo. AB - BACKGROUND AND AIMS: The possible increase of cancer risk in military personnel deployed in Balkans during and after the 1992-1999 wars, mainly related to the depleted uranium, was addressed by several studies on European veterans of those war theatres. This article reports on the results of the mortality study on the Italian cohort of Bosnia and Kosovo veterans (Balkan cohort). METHODS: Mortality rates for the Balkan cohort (71 144 persons) were compared with those of the Italian general population as well as to those of a comparable and unselected control cohort of not deployed military personnel (114 269 persons). Ascertainment of vital status during the period 1995-2008 of all the persons in the two cohorts has been carried out through deterministic record linkage with the national death records database, from information provided by the respective Armed Force General Staff, and through the civil registry offices of the veterans' residence or birth municipalities. RESULTS: The Balkan cohort experienced a mortality rates lower than both the general population (SMR = 0.56; 95% CI 0.51-0.62) and the control group (SMR = 0.88; 95% CI 0.79-0.97). Cancer mortality in the deployed cohort group was half of that from the general population mortality rates (SMR = 0.50; 95% CI 0.40-0.62) and slightly lower if compared with the control group cancer mortality rates (SMR = 0.95; 95% CI 0.77 1.18). CONCLUSION: Balkan veteran cohort did not show any increase in general mortality or in cancer mortality. PMID- 26635014 TI - Definitive radiotherapy alone over 60 Gy for patients unfit for combined treatment to stage II-III non-small cell lung cancer: retrospective analysis. AB - BACKGROUND: Elderly patients with non-small cell lung cancer (NSCLC) are frequently treated with radiation therapy (RT) alone, due to poor performance status or underlying disease. We investigated the effectiveness of RT over 60 Gy administered alone to NSCLC patients who were unfit or rejecting for combination treatment. METHODS AND MATERIALS: From April 2002 to July 2010, 83 patients with stage II-III NSCLC, aged over 60 years, treated by RT alone with a curative aim were analyzed. Radiation was targeted to the primary tumor and clinically involved lymph nodes. A total dose of 66 Gy in 30 fractions (2.2 Gy/fraction) was delivered once daily (5 fractions weekly). One month after completing RT, initial tumor responses were evaluated. RESULTS: Median age of patients was 73 years (range, 60 - 82 years). The median survival time was 18.6 months (range, 2-135). The actuarial overall survival rates at 2 and 3 years were 39 % and 23 %, and cause-specific survival rate at 2 and 3 years were 57 % and 47 %, respectively. When primary tumor was controlled, the 2- and 3-year CSS were 56 % and 45 %, but 32 % and 23 % in those patients with local failure, respectively (P = 0.017). Additionally, the local control rate was associated with the initial tumor response (P = 0.01). No patient experienced grade 4+ toxicity. CONCLUSIONS: For stage II-III NSCLC patients aged over 60 years and unfit or rejecting for combination treatment, RT alone showed promising result. Long-term disease control can be expected if an early tumor response to radiation is achieved, which could result in improved overall survival rates. PMID- 26635015 TI - Back pain was less explained than leg pain: a cross-sectional study using magnetic resonance imaging in low back pain patients with and without radiculopathy. AB - BACKGROUND: Cross-sectional studies have shown associations between lumbar degenerative manifestations on magnetic resonance imaging (MRI) and low back pain (LBP). Disc herniations and other degenerative manifestations, however, frequently occur in asymptomatic individuals. The purpose of this cross-sectional study was to analyze for associations between pain intensity and degenerative manifestations and other pain variables in patients for whom prognostic factors have been published previously. METHODS: Included were 141 consecutive patients with and without radiculopathy, all sick-listed 1-4 months due to low back pain and subsequently examined by MRI of the lumbar spine. Using different methods of grouping the degenerative manifestations, linear regression analyses were performed with the intensity of back + leg pain, back pain and leg pain as dependent variables covering actual pain and pain the preceding 2 weeks. The clinical classification into +/- radiculopathy was established before and independently of the standardised description of MRI findings. RESULTS: Radiculopathy was present in 43 % of the patients. Pain was best explained using rank-ordered degenerative manifestations on MRI. Back pain and leg pain were differently associated, and back pain was less explained than leg pain in the multivariate analyses (15 % vs. 31 % of the variation). Back pain intensity was higher in patients with type 1 Modic changes and in some patients with nerve root touch, but was not associated with disc herniations. Leg pain intensity was well explained by disc herniations causing MRI nerve root compromise and radiculopathy. In patients with radiculopathy, nerve root touch caused as much leg pain as nerve root displacement or compression. High intensity zones and osteophytes were not associated with back pain, but only associated with leg pain in patients with radiculopathy. Tender points explained some of the back pain, and widespread pain explained leg pain in some of the patients without radiculopathy. CONCLUSIONS: Back pain was associated with type 1 Modic changes, nerve root touch and tender points, whereas leg pain was associated with osteophytes, HIZ, disc herniation, all sorts of MRI nerve root compromise, radiculopathy and widespread pain. PMID- 26635016 TI - Timing of tracheotomy in ICU patients: a systematic review of randomized controlled trials. AB - INTRODUCTION: The optimal timing of tracheotomy in critically ill patients remains a topic of debate. We performed a systematic review to clarify the potential benefits of early versus late tracheotomy. METHODS: We searched PubMed and CENTRAL for randomized controlled trials that compared outcomes in patients managed with early and late tracheotomy. A random-effects meta-analysis, combining data from three a priori-defined categories of timing of tracheotomy (within 4 versus after 10 days, within 4 versus after 5 days, within 10 versus after 10 days), was performed to estimate the weighted mean difference (WMD) or odds ratio (OR). RESULTS: Of the 142 studies identified in the search, 12, including a total of 2,689 patients, met the inclusion criteria. The tracheotomy rate was significantly higher with early than with late tracheotomy (87 % versus 53 %, OR 16.1 (5.7-45.7); p <0.01). Early tracheotomy was associated with more ventilator-free days (WMD 2.12 (0.94, 3.30), p <0.01), a shorter ICU stay (WMD 5.14 (-9.99, -0.28), p = 0.04), a shorter duration of sedation (WMD -5.07 ( 10.03, -0.10), p <0.05) and reduced long-term mortality (OR 0.83 (0.69-0.99), p = 0.04) than late tracheotomy. CONCLUSIONS: This updated meta-analysis reveals that early tracheotomy is associated with higher tracheotomy rates and better outcomes, including more ventilator-free days, shorter ICU stays, less sedation, and reduced long-term mortality, compared to late tracheotomy. PMID- 26635018 TI - Can we use high precision metal isotope analysis to improve our understanding of cancer? AB - High precision natural isotope analyses are widely used in geosciences to trace elemental transport pathways. The use of this analytical tool is increasing in nutritional and disease-related research. In recent months, a number of groups have shown the potential this technique has in providing new observations for various cancers when applied to trace metal metabolism. The deconvolution of isotopic signatures, however, relies on mathematical models and geochemical data, which are not representative of the system under investigation. In addition to relevant biochemical studies of protein-metal isotopic interactions, technological development both in terms of sample throughput and detection sensitivity of these elements is now needed to translate this novel approach into a mainstream analytical tool. Following this, essential background healthy population studies must be performed, alongside observational, cross-sectional disease-based studies. Only then can the sensitivity and specificity of isotopic analyses be tested alongside currently employed methods, and important questions such as the influence of cancer heterogeneity and disease stage on isotopic signatures be addressed. PMID- 26635019 TI - Troubleshooting of the determination of bisphenol A at ultra-trace levels by liquid chromatography and tandem mass spectrometry. AB - Determination of trace amounts of bisphenol A (BPA) may cause problems mainly related to the presence of BPA in solvents (even in LC-MS grade), laboratory vessels, and plastic equipment used for sample preparation. Variable and sometimes significant amounts of BPA present in the background cause problems in obtaining good repeatability of measurements at the ultra-trace levels. Such observations (i.e., poor repeatability of results) were made during development of the LC-MS/MS method for determination of BPA in human serum samples. The method included gradient separation of the sample's constituents. The BPA peak was present in the chromatograms not only when procedural blanks were injected but also when void injections were made. One of the possible ways to eliminate background contamination is to change the source of solvents, use a different water purification system, and introduce rigorous equipment cleaning procedures. However, despite the use of these recommended guidelines, the peak of BPA was still present in the system blank. It was observed that the intensity of the BPA peak was proportional to the time of column conditioning. It was concluded that BPA, present in the components of the mobile phase, is being enriched in the front of the separation column during its conditioning (i.e., when mobile phase elution strength was low). This paper describes effects of gradient and isocratic elution conditions on LC-MS/MS system blank. The problem of spurious BPA peak, originating from the mobile phase, was solved by replacing gradient with isocratic elution mode. The use of isocratic elution conditions with the mobile phase of relatively high elution strength (50% of acetonitrile) allowed elimination of the peak of BPA coming from the mobile phase and significantly improved the precision of determination of BPA at low concentration levels. PMID- 26635020 TI - Identification of sirtuin 5 inhibitors by ultrafast microchip electrophoresis using nanoliter volume samples. AB - Sirtuin 5 (SIRT5) is a member of the sirtuin family of protein deacylases that catalyzes removal of post-translational modifications, such as succinyl and malonyl moieties, on lysine residues. In light of SIRT5's roles in regulating metabolism, and its reported oncogenic functions, SIRT5 modulators would be valuable tools for basic biological research and perhaps clinically. Several fluorescence assays for sirtuin modulators have been developed; however, the use of fluorogenic substrates has the potential to cause false positive results due to interactions of engineered substrates with enzyme or test compounds. Therefore, development of high-throughput screening (HTS) assays based on other methods is valuable. In this study, we report the development of a SIRT5 assay using microchip electrophoresis (MCE) for identification of SIRT5 modulators. A novel SIRT5 substrate based on succinate dehydrogenase (SDH) was developed to allow rapid and efficient separation of substrate and product peptide. To achieve high throughput, samples were injected onto the microchip using a droplet-based scheme. By coupling this approach to existing HTS sample preparation workflows, 1408 samples were analyzed at 0.5 Hz in 46 min. Using a 250 ms separation time, eight MCE injections could be made from each sample generating >11,000 electropherograms during analysis. Of the 1280 chemicals tested, eight were identified as inhibiting SIRT5 activity by at least 70% and verified by dose response analysis. PMID- 26635021 TI - Health risk assessment of hazardous metals for population via consumption of seafood from Ogoniland, Rivers State, Nigeria; a case study of Kaa, B-Dere, and Bodo City. AB - This study was designed to investigate the human health risk through consumption of seafood from contaminated sites in Kaa, B-Dere, and Bodo City all in Ogoniland. The potential non-carcinogenic health risk for consumers were investigated by assessing the estimated daily intake and target hazard quotients for Cr, Cd, Zn, Pb, Mn, and Fe while carcinogenic health effect from Cr, Cd, and Pb was also estimated. The estimated daily intake from seafood consumption was below the threshold values for Cr, Mn, and Zn while they exceeded the threshold for Cd, Pb, and Fe. The target hazard quotients for Zn and Cr were below 1. Target hazard quotients values for Cd, Pb, Mn, and Fe were greater than 1 except for Fe level in Liza falcipinis from Kaa. Furthermore, estimation of carcinogenic risk for Cr in all samples under study exceeded the accepted risk level of 10E-4. Also, Cd carcinogenic risk level for L. falcipinis and Callinectes pallidus collected from B-Dere and C. pallidus collected from Bodo City was 1.1E-3 which also exceeded the accepted risk level of 10E-4 for Cd. Estimation of carcinogenic risk for Pb was within the acceptable range of 10E-4. Consumers of seafood from these sites in Ogoniland may be exposed to metal pollution. PMID- 26635022 TI - Utilization of sewage sludge in the manufacture of lightweight aggregate. AB - This paper presents a comprehensive study on the possibility of sewage sludge management in a sintered ceramic material such as a lightweight aggregate. Made from clay and sludge lightweight aggregates were sintered at two temperatures: 1100 degrees C (name of sample LWA1) and 1150 degrees C (name of sample LWA2). Physical and mechanical properties indicate that the resulting expanded clay aggregate containing sludge meets the basic requirements for lightweight aggregates. The presence of sludge supports the swelling of the raw material, thereby causing an increase in the porosity of aggregates. The LWA2 has a lower value of bulk particle density (0.414 g/cm(3)), apparent particle density (0.87 g/cm(3)), and dry particle density (2.59 g/cm(3)) than it is in the case of LWA1 where these parameters were as follows: bulk particle density 0.685 g/cm(3), apparent particle density 1.05 g/cm(3), and dry particle density 2.69 g/cm(3). Water absorption and porosity of LWA1 (WA = 14.4 %, P = 60 %) are lower than the LWA2 (WA = 16.2 % and P = 66 %). This is due to the higher heating temperature of granules which make the waste gases, liberating them from the decomposition of organic sewage sludge. The compressive strength of LWA2 aggregate is 4.64 MPa and for LWA1 is 0.79 MPa. Results of leaching tests of heavy metals from examined aggregates have shown that insoluble metal compounds are placed in silicate and aluminosilicate structure of the starting materials (clays and sludges), whereas soluble substances formed crystalline skeleton of the aggregates. The thermal synthesis of lightweight aggregates from clay and sludge mixture is a waste-free method of their development. PMID- 26635023 TI - Torticollis in children: an alert symptom not to be turned away. PMID- 26635024 TI - Fasudil, a Rho-Associated Protein Kinase Inhibitor, Attenuates Traumatic Retinal Nerve Injury in Rabbits. AB - Inhibition of RhoA/Rock could promote axon growth and alleviate optic nerve injury. However, the role of RhoA/Rock in the traumatic retinal nerve in vivo was not completely clear. In this study, we established a rabbit model of traumatic retinal nerve injury, and primary retinal ganglion cells (RGCs) were isolated and cultured under hypoxia-hypoglycemia condition that was mock to the microenvironment in the injured retinas in vivo. The Rock inhibitor fasudil was used to treat primary RGCs and ear vein injected into the model rabbits in vivo. RhoA/Rock signaling was activated in the injured optic nerve in rabbits. Western blotting analysis showed that RhoA/Rock signaling in the retina was activated during the traumatic optic neuropathy. Data on gene expression examination and Annexin V/PI dual staining combined with flow cytometry analysis displayed that fasudil injection reduced expression of Rho/Rock and apoptotic genes, as well as the apoptosis of RGCs in traumatic retinal nerve injury in vitro and in vivo. Moreover, fasudil injection reduced expression of Rho/Rock and apoptotic genes, as well as the apoptosis of RGCs in the rabbits with traumatic retinal nerve injury in vivo. In conclusion, fasudil treatment could significantly reduce the apoptosis of RGCs and relieved retinal nerve injury in vitro and in vivo. PMID- 26635025 TI - Serotonin Receptor 2B Mediates Mechanical Hyperalgesia by Regulating Transient Receptor Potential Vanilloid 1. AB - Serotonin [5-hydroxytryptamine (5-HT)], an inflammatory mediator, contributes to inflammatory pain. The presence of multiple 5-HT subtype receptors on peripheral and central nociceptors complicates the role of 5-HT in pain. Previously, we found that 5-HT2B/2C antagonist could block 5-HT-induced mechanical hyperalgesia. However, the types of neurons or circuits underlying this effect remained unsolved. Here, we demonstrate that the Gq/11-phospholipase Cbeta-protein kinase Cepsilon (PKCepsilon) pathway mediated by 5-HT2B is involved in 5-HT-induced mechanical hyperalgesia in mice. Administration of a transient receptor potential vanilloid 1 (TRPV1) antagonist inhibited the 5-HT-induced mechanical hyperalgesia. 5-HT injection enhanced 5-HT- and capsaicin-evoked calcium signals specifically in isolectin B4 (IB4)-negative neurons; signals were inhibited by a 5-HT2B/2C antagonist and PKCepsilon blocker. Thus, 5-HT2B mediates 5-HT-induced mechanical hyperalgesia by regulating TRPV1 function. PMID- 26635026 TI - NPAS4 Facilitates the Autophagic Clearance of Endogenous Tau in Rat Cortical Neurons. AB - Tau, a microtubule-binding phosphoprotein, plays a critical role in the stabilisation of microtubules and neuronal function. However, hyperphosphorylated tau is involved in the pathogenesis of Alzheimer's disease (AD) and other tauopathies. The facilitation of tau clearance is now regarded as a valid therapeutic strategy for these neurodegenerative tauopathies. Here, we provide the first demonstration that the over-expression of neuronal PAS domain protein 4 (NPAS4)-induced autophagy and effectively facilitated the clearance of endogenous total and phosphorylated tau in rat primary cortical neurons. Moreover, the activation of autophagy by serum depletion significantly decreased endogenous total and phosphorylated tau levels. Autophagy inhibitors, such as 3 methyladenine (3-MA) and chloroquine (CQ), induced tau aggregation. However, NPAS4 over-expression reversed the aggregation of tau that was induced by the inhibition of autophagy. Interestingly, proteasome inhibition by MG132, had no effect on autophagy, but did reduce tau levels, indicating that NPAS4 may also degrade tau proteins through an unknown proteasome-mediated mechanism. Furthermore, NPAS4 did not alter the activity of two major tau kinases, glycogen synthase kinase 3beta (GSK3beta) and cyclin-dependent kinase 5 (CDK5). Taken together, the results indicate that targeting NPAS4 could provide a therapeutic approach for the treatment of AD and other tauopathies. PMID- 26635028 TI - Ventricular arrhythmia originating from scar border tissue during dobutamine myocardial perfusion gated SPECT on CZT camera. PMID- 26635027 TI - HTLV-1 subgroups associated with the risk of HAM/TSP are related to viral and host gene expression in peripheral blood mononuclear cells, independent of the transactivation functions of the viral factors. AB - Among human T cell leukemia virus type 1 (HTLV-1)-infected individuals, the risk of developing HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) across lifetime differs between ethnic groups. There is an association between HTLV-1 tax gene subgroups (subgroup-A or subgroup-B) and the risk of HAM/TSP in the Japanese population. In this study, we investigated the full-length proviral genome sequences of various HTLV-1-infected cell lines and patient samples. The functional differences in the viral transcriptional regulators Tax and HTLV-1 bZIP factor (HBZ) between each subgroup and the relationships between subgroups and the clinical and laboratory characteristics of HAM/TSP patients were evaluated. The results of these analyses indicated the following: (1) distinct nucleotide substitutions corresponding to each subgroup were associated with nucleotide substitutions in viral structural, regulatory, and accessory genes; (2) the HBZ messenger RNA (mRNA) expression in HTLV-1-infected cells was significantly higher in HAM/TSP patients with subgroup-B than in those with subgroup-A; (3) a positive correlation was observed between the expression of HBZ mRNA and its target Foxp3 mRNA in HAM/TSP patients with subgroup-B, but not in patients with subgroup-A; (4) no clear differences were noted in clinical and laboratory characteristics between HAM/TSP patients with subgroup-A and subgroup B; and (5) no functional differences were observed in Tax and HBZ between each subgroup based on reporter gene assays. Our results indicate that although different HTLV-1 subgroups are characterized by different patterns of viral and host gene expression in HAM/TSP patients via independent mechanisms of direct transcriptional regulation, these differences do not significantly affect the clinical and laboratory characteristics of HAM/TSP patients. PMID- 26635029 TI - Role of the MHC restriction during maturation of antigen-specific human T cells in the thymus. AB - In the thymus, a T-cell repertoire able to confer protection against infectious and noninfectious agents in a peptide-dependent, self-MHC-restricted manner is selected. Direct detection of Ag-specific thymocytes, and analysis of the impact of the expression of the MHC-restricting allele on their frequency or function has never been studied in humans because of the extremely low precursor frequency. Here, we used a tetramer-based enrichment protocol to analyze the ex vivo frequency and activation-phenotype of human thymocytes specific for self, viral and tumor-antigens presented by HLA-A*0201 (A2) in individuals expressing or not this allele. Ag-specific thymocytes were quantified within both CD4CD8 double or single-positive compartments in every donor. Our data indicate that the maturation efficiency of Ag-specific thymocytes is poorly affected by HLA-A2 expression, in terms of frequencies. Nevertheless, A2-restricted T-cell lines from A2(+) donors reacted to A2(+) cell lines in a highly peptide-specific fashion, whereas their alloreactive counterparts showed off-target activity. This first ex vivo analysis of human antigen-specific thymocytes at different stages of human T-cell development should open new perspectives in the understanding of the human thymic selection process. PMID- 26635031 TI - Thirdhand smoke contamination in hospital settings: assessing exposure risk for vulnerable paediatric patients. AB - BACKGROUND: Tobacco has regained the status of the world's number two killer behind heart/vascular disease. Thirdhand smoke (THS) residue and particles from secondhand smoke (SHS) are suspected health hazards (eg, DNA damage) that are likely to contribute to morbidity and mortality, especially in vulnerable children. THS is easily transported and deposited indoors, where it persists and exposes individuals for months, creating potential health consequences in seemingly nicotine-free environments, particularly for vulnerable patients. We collected THS data to estimate infant exposure in the neonatal ICU (NICU) after visits from household smokers. Infant exposure to nicotine, potentially from THS, was assessed via assays of infant urine. METHODS: Participants were mothers who smoked and had an infant in the NICU (N=5). Participants provided surface nicotine samples from their fingers, infants' crib/incubator and hospital provided furniture. Infant urine was analysed for cotinine, cotinine's major metabolite: trans-3'-hydroxycotinine (3HC) and 4-(methylnitrosamino)-1-(3 pyridyl)-1-butanol (NNAL), a metabolite of the nicotine-derived and tobacco specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). RESULTS: Incubators/cribs and other furniture had detectable surface nicotine. Detectable levels of cotinine, 3HC and NNAL were found in the infants' urine. DISCUSSION: THS appears to be ubiquitous, even in closely guarded healthcare settings. Future research will address potential health consequences and THS reduction policies. Ultimately, hospital policies and interventions to reduce THS transport and exposure may prove necessary, especially for immunocompromised children. PMID- 26635032 TI - Comparison of serum free light chain and urine electrophoresis for the detection of the light chain component of monoclonal immunoglobulins in light chain and intact immunoglobulin multiple myeloma. AB - Response criteria for multiple myeloma are based upon changes in monoclonal protein levels quantified using serum and/or urine protein electrophoresis. The latter lacks sensitivity at low monoclonal protein levels and since 2001, the serum free light chain test has been available and its clinical utility proven, yet guidelines have not recommended it as a replacement for urine assessment. Herein we evaluated responses using serum free light chain measurements and serum and urine electrophoresis after 2 and 4 cycles of therapy and after stem cell transplantation in 25 light chain and 157 intact immunoglobulin myeloma patients enrolled in the IFM 2007-02 MM trial. All 25 light chain patients had measurable disease by serum free light chain and urine methods at presentation. By contrast 98 out of 157 intact immunoglobulin patients had measurable disease by serum free light chain compared to 55 out of 157 by urine electrophoresis. In all patients there was substantial agreement between predicate (serum/urine protein electrophoresis) and test (serum protein electrophoresis and serum free light chain) methods for response assessment (Weighted Kappa=0.83). Urine immunofixation became negative in 47% light chain and 43% intact immunoglobulin patients after 2 cycles of therapy. At this time the serum free light chain ratio normalised in only 11% and 27% patients, respectively. In summary we found good agreement between methods for response assessment, but the serum free light chain test provided greater sensitivity than urine electrophoresis for monitoring. To our knowledge this is the first report comparing both methods for response assignment based on the International Myeloma Working Group guidelines. (Clinical Trials Register.eu identifier: 2007-005204-40). PMID- 26635033 TI - Ibrutinib and idelalisib target B cell receptor- but not CXCL12/CXCR4-controlled integrin-mediated adhesion in Waldenstrom macroglobulinemia. PMID- 26635034 TI - Hyperhomocysteinemia and high doses of nilotinib favor cardiovascular events in chronic phase Chronic Myelogenous Leukemia patients. PMID- 26635035 TI - von Willebrand factor binds to the surface of dendritic cells and modulates peptide presentation of factor VIII. AB - It has been proposed that von Willebrand factor might affect factor VIII immunogenicity by reducing factor VIII uptake by antigen presenting cells. Here we investigate the interaction of recombinant von Willebrand factor with immature monocyte-derived dendritic cells using flow cytometry and confocal microscopy. Surprisingly, von Willebrand factor was not internalized by immature dendritic cells, but remained bound to the cell surface. As von Willebrand factor reduces the uptake of factor VIII, we investigated the repertoire of factor VIII presented peptides when in complex with von Willebrand factor. Interestingly, factor VIII-derived peptides were still abundantly presented on major histocompatibility complex class II molecules, even though a reduction of factor VIII uptake by immature dendritic cells was observed. Inspection of peptide profiles from 5 different donors showed that different core factor VIII peptide sequences were presented upon incubation with factor VIII/von Willebrand factor complex when compared to factor VIII alone. No von Willebrand factor peptides were detected when immature dendritic cells were pulsed with different concentrations of von Willebrand factor, confirming lack of von Willebrand factor endocytosis. Several von Willebrand factor derived peptides were recovered when cells were pulsed with von Willebrand factor/factor VIII complex, suggesting that factor VIII promotes endocytosis of small amounts of von Willebrand factor by immature dendritic cells. Taken together, our results establish that von Willebrand factor is poorly internalized by immature dendritic cells. We also show that von Willebrand factor modulates the internalization and presentation of factor VIII-derived peptides on major histocompatibility complex class II. PMID- 26635036 TI - Twenty years of the Italian Fanconi Anemia Registry: where we stand and what remains to be learned. AB - The natural history of Fanconi anemia remains hard to establish because of its rarity and its heterogeneous clinical presentation; since 1994, the Italian Fanconi Anemia Registry has collected clinical, epidemiological and genetic data of Italian Fanconi Anemia patients. This registry includes 180 patients with a confirmed diagnosis of Fanconi anemia who have either been enrolled prospectively, at diagnosis, or later on. After enrollment, follow-up data were periodically collected to assess the clinical course, possible complications and long-term survival; the median follow up was 15.6 years. The main goal of the study was to describe the natural history of Fanconi anemia, focusing on the following variables: family history, disease presentation, development of hematological manifestations, development of malignancies, occurrence of hematopoietic stem cell transplantation and survival. Typical morphological and/or hematological abnormalities and/or growth retardation were the most common manifestations at diagnosis; the majority of patients (77%) exhibited hematological abnormalities at the initial presentation, and almost all (96%) eventually developed hematological manifestations. More than half of the patients (57%) underwent a bone-marrow transplant. The occurrence of cancer was quite rare at diagnosis, whereas the cumulative incidence of malignancies at 10, 20 and 30 years was 5%, 8% and 22%, respectively, for hematological cancers and 1%, 15% and 32%, respectively, for solid tumors. Overall survival at 10, 20 and 30 years were 88%, 56% and 37%, respectively; the main causes of death were cancer, complications of the hematological presentation and complications of transplantation. These data clearly confirm the detrimental outcome of Fanconi anemia, with no major improvement in the past decades. PMID- 26635038 TI - STAT1 activation in association with JAK2 exon 12 mutations. PMID- 26635037 TI - Increased hepcidin in transferrin-treated thalassemic mice correlates with increased liver BMP2 expression and decreased hepatocyte ERK activation. AB - Iron overload results in significant morbidity and mortality in beta-thalassemic patients. Insufficient hepcidin is implicated in parenchymal iron overload in beta-thalassemia and approaches to increase hepcidin have therapeutic potential. We have previously shown that exogenous apo-transferrin markedly ameliorates ineffective erythropoiesis and increases hepcidin expression in Hbb(th1/th1) (thalassemic) mice. We utilize in vivo and in vitro systems to investigate effects of exogenous apo-transferrin on Smad and ERK1/2 signaling, pathways that participate in hepcidin regulation. Our results demonstrate that apo-transferrin increases hepcidin expression in vivo despite decreased circulating and parenchymal iron concentrations and unchanged liver Bmp6 mRNA expression in thalassemic mice. Hepatocytes from apo-transferrin-treated mice demonstrate decreased ERK1/2 pathway and increased serum BMP2 concentration and hepatocyte BMP2 expression. Furthermore, hepatocyte ERK1/2 phosphorylation is enhanced by neutralizing anti-BMP2/4 antibodies and suppressed in vitro in a dose-dependent manner by BMP2, resulting in converse effects on hepcidin expression, and hepatocytes treated with MEK/ERK1/2 inhibitor U0126 in combination with BMP2 exhibit an additive increase in hepcidin expression. Lastly, bone marrow erythroferrone expression is normalized in apo-transferrin treated thalassemic mice but increased in apo-transferrin injected wild-type mice. These findings suggest that increased hepcidin expression after exogenous apo-transferrin is in part independent of erythroferrone and support a model in which apo-transferrin treatment in thalassemic mice increases BMP2 expression in the liver and other organs, decreases hepatocellular ERK1/2 activation, and increases nuclear Smad to increase hepcidin expression in hepatocytes. PMID- 26635039 TI - Prospective long-term minimal residual disease monitoring using RQ-PCR in RUNX1 RUNX1T1-positive acute myeloid leukemia: results of the French CBF-2006 trial. AB - In t(8;21)(q22;q22) acute myeloid leukemia, the prognostic value of early minimal residual disease assessed with real-time quantitative polymerase chain reaction is the most important prognostic factor, but how long-term minimal residual disease monitoring may contribute to drive individual patient decisions remains poorly investigated. In the multicenter CBF-2006 study, a prospective monitoring of peripheral blood and bone marrow samples was performed every 3 months and every year, respectively, for 2 years following intensive chemotherapy in 94 patients in first complete remission. A complete molecular remission was defined as a (RUNX1-RUNX1T1/ABL1)*100 <= 0.001%. After the completion of consolidation therapy, a bone marrow complete molecular remission was observed in 30% of the patients, but was not predictive of subsequent relapse. Indeed, 8 patients (9%) presented a positive bone marrow minimal residual disease for up to 2 years of follow-up while still remaining in complete remission. Conversely, a peripheral blood complete molecular remission was statistically associated with a lower risk of relapse whatever the time-point considered after the completion of consolidation therapy. During the 2-year follow-up, the persistence of peripheral blood complete molecular remission was associated with a lower risk of relapse (4 year cumulative incidence, 8.2%), while molecular relapse confirmed on a subsequent peripheral blood sample predicted hematological relapse (4-year cumulative incidence, 86.9%) within a median time interval of 3.9 months. In t(8;21)(q22;q22) acute myeloid leukemia, minimal residual disease monitoring on peripheral blood every 3 months allows for the prediction of hematological relapse, and to identify patients who could potentially benefit from intervention therapy. (ClinicalTrials.gov ID #NCT00428558). PMID- 26635042 TI - Welcoming carers on to the wards: too much pressure for some carers? PMID- 26635041 TI - Short-Term and Long-Term Survival After Revascularization with or without Mitral Valve Surgery of Patients with Ischemic Mitral Valve Regurgitation: A Meta Analysis. AB - BACKGROUND There is no consensus on whether mitral valve repair or replacement (MVRR) must be performed to treat ischemic mitral regurgitation (MVR) after myocardial infarction. Our objective in this study was to investigate the efficacy of coronary artery bypass grafting (CABG) combined with or without MVRR for the ischemic MVR. MATERIAL AND METHODS An article search was performed in OvidSP, PubMed, Cochrane Library, and Embase. In these articles, researchers compared the efficacy of CABG with or without MVRR in treating patients with ischemic MVR after acute coronary syndrome (ACS). We performed a meta-analysis to compare the differences in the short-term and long-term survival rates of patients treated with CABG only and those treated with both CABG and MVRR. Secondary outcomes were compared with the preoperative and postoperative degree of MVR, left ventricular end-systolic volume (LVESV), left ventricular ejection fraction (LVEF), and New York Heart Association (NYHA) class. RESULTS Out of the 1183 studies, we selected only 5 articles. A total of 3120 patients were enrolled; the CABG and MVRR group included 575 patients, while the CABG only group included 2545 patients. Long-term survival was higher in the CABG only group (hazard ratio [HR], 1.34; 95% confidence interval [CI] 1.15-1.58, P=0.003). Hospital mortality was similar in both the groups (odds ratio [OR], 2.54; 95% CI, 0.65-9.95; P=0.18). No differences were found in the degree of residual MVR, the mean of LVESV, LVEF, or NYHA class. CONCLUSIONS In patients with ischemic MVR, the short-term survival rate was similar in both groups. Moreover, there was no significant improvement in the long-term survival rates of patients treated with both CAG and MVRR. PMID- 26635040 TI - The anti-inflammatory effects of platelet-derived microparticles in human plasmacytoid dendritic cells involve liver X receptor activation. PMID- 26635043 TI - Ten Years of Routine alpha- and beta-Globin Gene Sequencing in UK Hemoglobinopathy Referrals Reveals 60 Novel Mutations. AB - We review and report here the genotypes and phenotypes of 60 novel thalassemia and abnormal hemoglobin (Hb) mutations discovered following the adoption of routine DNA sequencing of both alpha- and beta-globin genes for all UK hemoglobinopathy samples referred for molecular investigation. This screening strategy over the last 10 years has revealed a total of 11 new beta chain variants, 15 alpha chain variants, 19 beta-thalassemia (beta-thal) mutations and 15 alpha(+)-thalassemia (alpha(+)-thal) mutations. The large number of new thalassemia alleles confirms the wide racial heterogeneity of mutations in the UK immigrant population. Eleven of the new variants ran with Hb A on high performance liquid chromatography (HPLC), demonstrating the value of routine sequencing of both alpha- and beta-globin genes for all hemoglobinopathy investigations. The new beta chain variants are: Hb Bury [beta22(B4)Glu -> Asp (HBB: c.69A > T)], Hb Fulwood [beta35(C1)Tyr -> His (HBB: c.106T > C)], Hb Little Venice [beta42(CD1)Phe -> Cys (HBB: c.128T > G)], Hb Cork [beta57(E1)Asn -> Ser (HBB: c.173A > G), Hb Basingstoke [beta118(GH1)Phe -> Ser (HBB: c.356T > C)], Hb Howden [beta20(B2)Val -> Ala (HBB: c.62T > C)], Hb Wilton [beta41(C7)Phe -> Leu (HBB: c.126C > A)], Hb Belsize Park [beta120(GH3)Lys -> Asn (HBB: c.363A > T)], Hb Hampstead Heath [beta2(NA2)His -> Gln;beta26(B8)Glu -> Lys (HBB: c.[6C > G;79G > A])], Hb Grantham [beta85(F1)Phe -> Cys (HBB: c.257T > G)] and Hb Calgary [beta64(E8)Gly -> Val (HBB: c.194G > T). The new alpha chain variants are: Hb Edinburgh [alpha70(E19)Val -> Gly (HBA2: c.212T > G)], Hb Walsgrave [alpha116(GH4)Glu -> Val (HBA2: c.350A > T)], Hb Wexham [alpha117(GH5) and 118(H1) insertion Ser (HBA1: c.354-355insTCA)], Hb Coombe Park [alpha127(H10)Lys > Glu (HBA2: c.382A > G)], Hb Oxford [alpha17(A15)Val -> Asp (HBA2: c.53T > A)], Hb Bridlington [alpha32(B13)Met -> Thr (HBA1: c.98T > C), Hb Wolverhampton [alpha81(F2)Ser -> Tyr (HBA2: c.9245C > A)], Hb Little Waltham [alpha13(A11)Ala > Asp (HBA2: c.41C > A)], Hb Derby [alpha61(E10)Lys -> Arg (HBA1: c.185A > G)], Hb Uttoxter [alpha74(EF3)Tyr -> Asp (HBA2: c.223G > T)], Hb Harehills [alpha124(H7)Ser -> Cys (HBA1: c.374C > G)], Hb Hekinan II [alpha27(B8)Glu -> Asp (HBA1: c.84G > T)], Hb Manitoba IV [alpha102(G9)Ser -> Arg (HBA1: c.307A > C), Hb Witham [alpha139(HC1)Lys -> Arg (HBA2: c.419A > G) and Hb Farnborough [alpha9(A7)Asn -> Asp (HBA1: c.28A > G). In addition, 10 more paralogous alpha globin chain variants have been discovered. The novel beta-thal alleles are: HBB: c.-138C > G, HBB: c.-121C > T, HBB: c.-80T > G, HBB: c.18_19delTG, HBB: c.219_220insT, HBB: c.315 + 2_315 + 13delTGAGTCTATGGG, HBB: c.316-70C > G, HBB: c.345_346insTGTGCTG, HBB: c.354delC, HBB: c.376-381delCCAGTG, HBB: c.393T > A, HBB: c.394_395insA, HBB: c.375_376insA, HBB: c.*+95_*+107delTGGATTCTinsC, HBB: c.* + 111_*+112delAA, HBB: c.*+112A > T, HBB: c.394C > T, HBB: c.271delG and HBB: c.316-3C > T. The novel alpha (+ )-thal alleles are: HBA1: c.95+1G > C, HBA1: c.315C > G [Hb Donnington, alpha104(G11)Cys -> Trp], HBA1: c.327delC, HBA1: c.333_345del, HBA1: c.*+96G > A, HBA2: c.2T > G, HBA2: c.112delC, HBA2: c.143delA, HBA2: c.143_146delACCT, HBA2: c.156_157insG, HBA2: c.220_223delGTGG, HBA2: c.305T > C [Hb Bishopstown, alpha101(G8)Leu -> His], HBA2: c.169_170delAA, HBA2: c.1A > T and HBA2: c.-3delA. PMID- 26635044 TI - [The maze of the clinical evaluation reports]. PMID- 26635045 TI - [Iron deficiency in elderly patients: use of biomarkers]. AB - Iron deficiency, due to blood loss or malabsorption, is commonly observed in geriatric practice. In elderly people, association of inflammatory diseases to iron loss makes diagnosis of absolute iron deficiency sometimes difficult. In case of inflammation, the interpretation of usual biomarkers of iron deficiency (serum ferritin, transferrin saturation, serum iron) may be difficult. The recent discovery of the role of hepcidine in the iron homeostasis, in physiological and pathological situation, contributes to better understanding of the iron regulation. The aim of this short paper is to underline some specificities of elderly iron physiology, to explain hepcidine's role in physiological and pathological situations and to propose a diagnostic approach for a better interpretation of usual biomarkers, in order to differentiate absolute iron deficiency and functional iron deficiency. PMID- 26635046 TI - [Myelodysplastic syndromes: pathophysiology, clinical and biological features]. AB - Myelodysplastic syndromes (MDS) are hemopathies very common in geriatric practice. They are characterized by qualitative morphological abnormalities of one or more myeloid lineages responsible for an ineffective hematopoiesis, and therefore cytopenias of central origin contrasting with a usually rich bone marrow wealth. The MDS are asymptomatic in half of the cases and their discovery is a result of systematic blood analysis or tests to explore another disease. The evolution is marked by worsening cytopenias, and the risk of acute myeloid leukemia transformation with poor prognosis because frequently chemoresistant. The diagnosis of MDS is pronounced after a clinico-biological confrontation to discuss the differential diagnosis taking into account all clinical and cytological data, results of conventional cytogenetics and evolution after vitamin therapy. Knowledge more depth on MDS refine MDS classification criteria by developing successive classifications (FAB 1982, WHO 2001 and 2008) which aim the identification of MDS groups with clinical, biological and common prognostic. The treatment of MDS is essentially symptomatic. The development of new targeted therapeutic strategies enables high hopes in a context where treatment options are a difficult choice, because the advanced age of most patients. Finally, detailed knowledge of risk factors and prognostic scores are very useful to make the best treatment decisions. PMID- 26635047 TI - [Analysis of MGMT methylation with the therascreen((r)) MGMT Pyro((r)) Kit (Qiagen). A method verification]. AB - Promoter methylation of the MGMT gene, encoding the enzyme O6-methylguanine ubiquitous methyltransferase, is a theranostic good prognosis marker of glioblastomas treated with alkylating chemotherapy (temozolomide, Temodal((r))). Among the methylation analysis techniques, pyrosequencing is a reproducible and sensitive quantitative method. As part of the accreditation of the hospital platform of molecular genetics of cancer, Besancon, our objective was to verify the performance of the pyrosequencing commercial kit therascreen((r)) MGMT Pyro((r)) (Qiagen) in terms of repeatability, reproducibility, limit of blank (LOB), limit of detection (LOD), linearity and contamination by the guide SH GTA 04 delivered by the Cofrac. The repeatability tests show an average methylation of 3.22% [standard deviation (SD) = 0.41, coefficient of variation (CV) = 12.75%] for the unmethylated control and 70.16% (SD = 2.20, CV = 3.14%) for the methylated control. Reproducibility demontrates an average methylation of 1.39% (SD = 0.25, CV = 18.25%) for the unmethylated control and of 94.03% (SD = 2.56, CV = 2.73%) for the methylated control. The percentages of LOB and LOD are respectively 3.43% and 6.22% methylation. The regression coefficient of 0,983 confirms the linearity of the assay from 0% to 100% methylation. No contamination has been observed. Over 40% of glioblastomas studied in 2013 in our laboratory have shown a methylated MGMT gene. Our results confirms that the theraScreen((r)) MGMT Pyro((r)) kit (Qiagen) is performant in compliance with the quality requirements of the NF EN ISO 15189 for the routine analysis of methylation status of MGMT in glioblastomas. PMID- 26635048 TI - [Lipemia and bilirubin influences for twenty-four biochemical parameters measurement]. AB - The study of the influence of the lipemia and icterus was performed experimentally for twenty-four biochemistry parameters on the Roche Cobas 6000 CE analyzer. Overloads in Intralipid((r)) or ditaurate of bilirubin were performed on several plasma pools. The limit of 10% was chosen to define interference on the measurement. The parameters studied were classified into different categories depending on their measurement is affected or not. Knowledge of these data allows the biologist to adapt its reporting procedures in the case of lactescent and/or icteric samples. PMID- 26635049 TI - [Immunoproteomics of non water-soluble allergens from 4 legumes flours: peanut, soybean, sesame and lentil]. AB - Peanut, soybean, sesame and lentil are members of legumes worldwide consumed by human that can induce food allergy in genetically predisposed individuals. Several protein allergens, mainly water-soluble, have been described. We studied the non water-soluble fraction from these 4 food sources using immunoproteomics tools and techniques. Flour extracts were solubilized in detergent and chaotropes and analysed in 1 and 2 dimensional gel electrophoresis (2D). Results showed numerous proteins exhibiting wide ranges of isoelectric points and relative molecular masses. When IgE immunoreactivities of 18 food allergy patients were individually tested in 1 and 2D western-blots, a very diversified IgE repertoire was observed, reflecting extensive cross-reactivities but also co-sensitizations. Besides already well known and characterized allergens, mass spectrometry analysis allowed the identification of 22 allergens undescribed until now: 10 in peanut, 2 in soybean, 3 in sesame and 7 in lentil. Three allergens are legume storage proteins and the others belong to transport proteins, nucleotide binding proteins and proteins involved in the regulation of metabolism. Seven proteins are potentially similar to allergens described in plants and fungi and 11 are not related to any known allergen. Our results contribute to increase the repertoire of legume allergens that may improve the diagnosis, categorize patients and thus provide a better treatment of patients. PMID- 26635050 TI - [Hemolysis interferences on frequently required stat analysis: a French multicentric study]. AB - Hemolysis should lead to changes in test results. Our study evaluated the impact of hemolysis on 26 blood measurements of stat biochemistry markers (sodium, potassium, chloride, urea, creatinine, glucose, total protein, calcium, magnesium, inorganic phosphorus, uric acid, C-reactive protein, total bilirubin, ASAT, ALAT, LDH, creatine kinase, alkaline phosphatase, gamma glutamyl transferase, lipase, alcohol, iron, beta hCG, troponins, natriuretic peptides) determined with 13 different types of instruments in 17 hospital laboratories. Four pools of samples (collected from lithium heparin or EDTA or sodium fluoride tubes, according to the measured parameters) were overloaded with five increasing concentrations of whole blood lysate (final concentration from 0 to 2.000 mg/dL). Replication was performed for each assay, average values were calculated and differences between results with and without lysate were analyzed. A difference exceeding the square root of the sum of both squared analytic and biologic imprecisions for each analyte, was judged to be significant. Except homogeneous and expected impact of hemolysis on certain parameters like potassium, LDH... (due to their intra-erythrocyte concentration) a heterogeneous effect was found for other parameters, according to the analyzer and/or to the methodology. In summary, this study confirms the importance of mastering the measurement of the hemolysis and leads to several recommendations: (i) biologists should have a good knowledge of the impact of hemolysis on the measurements they perform, depending on their chosen analyzers; (ii) if an interference is noticed, it is recommended to add to the result a relevant comment and to check that the comment is properly edited in the laboratory computer software and appears on printed and transmitted results. PMID- 26635051 TI - [Comparative study of two techniques of ciclosporine monitoring]. AB - Ciclosporine (CsA) is an immunosuppressant drug used in bone marrow transplantation in order to extend allograft survival. Despite its efficiency, CsA can expose to therapeutic failure or to toxicity because of underdosing or overdosage. So, many techniques of monitoring CsA in blood were used, the referance one is the chromatographic technique then, the automated techniques: fluorescence polarization immunoassay (FPIA) and chimiluminescent microparticle immunoassay (CMIA). In this study, we aimed to compare the results of CsA concentrations measured by the two automised techniques. Statistical studies showed that the two techniques were repeatable and reproductible. Results obtained by FPIA were slightly higher than those obtained by CMIA but without a significative difference. In conclusion, FPIA technique could be used to measure CsA blood concentration in replacement of CMIA in case of technical problems. PMID- 26635052 TI - [Bacterial contamination of stethoscopes in hospital]. AB - Although many publications on the subject are available, only few campaigns for stethoscopes cleaning and disinfection are conducted. Stethoscope is a "not critical" reusable medical device and should benefit from a cleaning disinfection "low level" after each use. We studied the bacterial contamination of stethoscopes in our hospital and measured the role of bacterial reservoir and/or vector stethoscope could play. Mean microbial load was estimated at 1.550 CFU per stethoscope. Results obtained in our hospital and those of the literature, led us to propose a simple and efficient cleaning method. We believe motivate everyone to change their habits and carry out disinfection more frequent their very handling stethoscope. PMID- 26635053 TI - [Erythrocytic parameters Sysmex in a case of severe haemolysis]. AB - We are reporting a case of severe haemolytic anemia with cold agglutinins which combines several spurious determinations. It shows the usefulness of the new erythrocytic parameters of the XE 5000 Sysmex, specially: red blood cells with optical count (RBC-O), GR-He (intra-erythocytic hemoglobin) and R-MFV (most frequent volume). Optical red blood cells act as a substitute for red cells count instead of impedance red cells and R-MFV as a substitute for MCV (mean cell volume). The hematocrit (HCT) is corrected thanks to the following formula: HCT=(RBC-O X R- MFV)/1000. Free plasmatic hemoglobin is included in the measure of hemoglobin by the analyzer but is not available for tissue oxygenation. So, hemoglobin (HGB) has to be corrected by the means of GR- He thanks to the following formula: HGB=(GR He x RBC-O)/10. PMID- 26635054 TI - [Bernard-Soulier syndrome and pregnancy: a case report]. AB - Bernard-Soulier syndrome is an inherited bleeding disorder. Due to the rarity of the combination of this syndrome and pregnancy, data on the clinical course and outcome of pregnancy in women with Bernard-Soulier syndrome is scattered in individual case reports and there is no consensus in the management of SBS. In some patients, the pregnancy course was uneventful while in others post partum hemorrhage was the most common complication. We report our experience about the perioperative management of a pregnant woman with Bernard-Soulier syndrome. PMID- 26635055 TI - [Reply to the article Non-VKA oral anticoagulants: an update for the clinical biologists]. PMID- 26635056 TI - [Which method of renal function evaluation is best appropriate in patients with direct oral anticoagulants?]. PMID- 26635057 TI - Antibioresistance of Moroccan strains of Salmonella typhi: a need for updating the standardized treatment of typhoid fever set on 1994. PMID- 26635058 TI - Methods of ex vivo expansion of human cord blood cells: challenges, successes and clinical implications. AB - More than 40,000 unrelated cord blood transplantations (UCBT) have been performed worldwide as treatment for patients with malignant or non-malignant life threatening hematologic disorders. However, low absolute numbers of hematopoietic stem and progenitor cells (HSPCs) within a single cord blood unit has remained a limiting factor for this transplantation modality, particularly in adult recipients. Further, because UCB contains low numbers of mostly naive T cells, immune recovery after UCBT is slow, predisposing patients to severe infections. Other causes of UCBT failure has included graft-versus-host disease (GVHD) and relapse of the underlying disease. In this article, we first review the current landscape of cord blood engineering aimed at improving engraftment. This includes approaches of UCB-HSPCs expansion and methods aimed at improving UCB-HSCPs homing. We then discuss recent approaches of cord blood engineering developed to prevent infection [generation of multivirus-specific cytotoxic T cells (VSTs) from UCB], relapse [transduction of UCB-T cells with tumor-specific chimeric receptor antigens (CARs)] and GVHD (expansion of regulatory T cells from UCB). Although many of these techniques of UCB engineering remain currently technically challenging and expensive, they are likely to revolutionize the field of UCBT in the next decades. PMID- 26635060 TI - Laparoscopic gastro-jejunal anastomosis using novel r2 deflectable instruments in an ex vivo model. AB - OBJECTIVE: A novel 5 mm steerable instrument system (r2-DRIVE) was developed with active tip deflection and tip and shaft rotation. The feasibility and training effect of the r2 instruments were determined in a phantom model. MATERIAL AND METHODS: Experienced laparoscopic surgeons and untrained novices performed laparoscopic gastro-jejunal anastomoses using porcine tissue and r2 DRIVE instruments. Mean anastomosis time, anastomosis width and burst pressure were measured. Number of stitches, skipped stitches and dropped needles were counted. Results of trained and untrained subjects were compared. RESULTS: Mean time for suturing decreased rapidly for all participants, but was more evident for untrained persons. After five anastomoses no relevant improvement in anastomotic time was seen for the skilled group. The ease of use, efficacy of manipulation and swift training effect with the novel r2 instruments for both experienced laparoscopic surgeons and untrained non-surgeons could be demonstrated and after few cases stable anastomosis times and a fast learning curve were obtained. CONCLUSIONS: This study demonstrates the ease of use, efficacy of manipulation and swift training effect with the novel r2 instruments for both experienced laparoscopic surgeons and untrained non-surgeons. After few cases stable anastomosis times and a fast learning curve were obtained. PMID- 26635059 TI - Pharmacological treatment of schizophrenia with comorbid substance use disorder. AB - INTRODUCTION: While antipsychotics remain the cornerstone of treatment for schizophrenic patients with comorbid substance use disorder (SUD), such treatment is nonetheless complicated by frequent medical comorbidity and poor adherence to medication. AREAS COVERED: Randomised controlled trials (RCTs) on the efficacy of antipsychotics for the treatment of schizophrenic patients with comorbid SUD are reviewed and analysed on the basis of a systematic literature search (PubMed) ranging from 1985 to 2015. On the same basis, findings from RCTs on the efficacy of psychotropic and other medications used for primary SUD are summarised, and the main issues liable to influence treatment choice are discussed, including pharmacodynamic as well as pharmacokinetic interactions, adherence, medical comorbidity and the impact on brain structure. EXPERT OPINION: As far as the treatment of schizophrenic patients with SUD is concerned, direct and indirect evidence tends to stand in favour of the use of second-generation antipsychotics (SGAs), and particularly those with lower metabolic, cardiovascular and extrapyramidal side effects, as well as those with a depot formulation. A few of the usual medications for the treatment of primary SUD, such as naltrexone and disulfiram for alcohol use and bupropion for tobacco cessation, can also be safely and efficiently administered to schizophrenic patients with SUD. PMID- 26635061 TI - Effect of borneol on the transdermal permeation of drugs with differing lipophilicity and molecular organization of stratum corneum lipids. AB - The aim of the present paper was to investigate the promoting activity of borneol on the transdermal permeation of drugs with differing lipophilicity, and probe its alterations in molecular organization of stratum corneum (SC) lipids. The toxicity of borneol was evaluated in epidermal keratinocyte HaCaT and dermal fibroblast CCC-HSF-1 cell cultures and compared to known enhancers, and its irritant profile was also assessed by transepidermal water loss (TEWL) evaluation. The promoting effect of borneol on the transdermal permeation of five model drugs, namely 5-fluorouracil, antipyrine, aspirin, salicylic acid and ibuprofen, which were selected based on their lipophilicity denoted by logp value, were performed using in vitro skin permeation studies. Attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR) was employed to monitor the borneol-induced alteration in molecular organization of SC lipids. The enhancer borneol displayed lower cytotoxicity or irritation in comparison to the well-established and standard enhancer Azone. Borneol could effectively promote the transdermal permeation of five model drugs, and its enhancement ratios were found to be parabolic curve with the logp values of drugs, which exhibited the optimum permeation activity for relatively hydrophilic drugs (an estimated logp value of -0.5 ~0.5). The molecular mechanism studies suggested that borneol could perturb the structure of SC lipid alkyl chains, and extract part of SC lipids, resulting in the alteration in the skin permeability barrier. PMID- 26635062 TI - Direct saliva transcript analysis as a novel non-invasive method for oestrus marker detection in buffaloes. AB - Salivary RNA-based biomarkers are not available for any physiological condition in farm animals. Hence, an objective of this study was to perform salivary transcript analysis in buffaloes. Saliva, after removal of the cells and particulate matter, was directly used for RT-PCR without RNA isolation. Direct saliva transcript analysis (DSTA) showed a suggestively significant higher expression of the Heat shock protein 70 (HSP70) and Toll-like receptor 4 (TLR4) at oestrus than the diestrous period in buffaloes by a non-parametric Mann Whitney U test. Therefore, DSTA without RNA isolation is an easy method to identify salivary RNA markers for oestrus detection in buffaloes. PMID- 26635063 TI - Adverse drug reactions due to drug-drug interactions with proton pump inhibitors: assessment of systematic reviews with AMSTAR method. AB - INTRODUCTION: Many systematic reviews resulted in claims on drug-drug interactions (DDIs) with proton pump inhibitors (PPIs). Such a large number begs for consensus on the clinical significance of findings. AREAS COVERED: We critically evaluated the safety of PPI use with respect to DDIs with a meta review of systematic reviews published between 1978 and 2015. We assessed the evidence by their reliability, repeatability, transparency, and objectivity according to the Assessment of Multiple Systematic Reviews (AMSTAR) criteria. EXPERT OPINION: Clinicians must assess risks for each PPI for certain comorbid conditions. DDIs don't substantiate class effect for PPIs; each PPI could induce unique DDIs. Concomitant use of PPIs with thienopyridines (e.g. clopidogrel) could be justified in patients without strong affinity to cytochrome CYP2C19 and with high risk of bleeding (e.g. patients with prior upper gastrointestinal bleeding, Helicobacter pylori infection, advanced age, steroid treatment, and nonsteroidal anti-inflammatory drug use). DDIs could occur in an AIDS subpopulation treated with highly active antiretroviral therapy (HAART). DDIs exist for cancer patients undergoing targeted therapy. Hypomagnesemia could increase in the setting of advanced age and polypharmacy. Omeprazole poses high risks owing to its pharmacokinetic DDI profile. Future systematic reviews should incorporate these additional risks for better clinical guidance. PMID- 26635064 TI - High level of patient satisfaction and comfort during diagnostic urological procedures performed by urologists and residents. AB - OBJECTIVE: The aim of this study was to investigate how patients experience diagnostic urological procedures performed by urologists, junior residents and senior residents, and to assess the influence of procedure-related factors on patient experiences. METHODS: Data were collected during 222 procedures: 84 transrectal ultrasound-guided prostate biopsies (TRUSP; urologists n = 39, residents n = 45) and 138 urethrocystoscopies (UCS; urologists n = 44, residents n = 94) in six hospitals. Patient experiences were assessed using a questionnaire focusing on pain, comfort and satisfaction (visual analogue scale, 0-10) and communication aspects on a four-point Likert scale. Clinical observations were made to identify influencing factors. RESULTS: Median values for patient experiences across procedures were 10 (range 5-10) for patient satisfaction, 2 (0 9) for pain and 8 (0-10) for comfort. Generalized estimating equations revealed no significant differences between urologists, senior residents and junior residents in terms of experienced patient comfort, satisfaction or pain. Procedural time was longer for residents, but this did not correlate significantly with patient-experienced comfort (p = 0.3). In UCS, patient comfort and satisfaction were higher in the supine position for male and female patients, respectively (p < 0.01). In TRUSP, local anaesthesia resulted in a significant decrease in pain (p = 0.002) and an increase in comfort (p = 0.03). Finally, older patients experienced less pain and gave higher comfort and satisfaction responses than younger patients. CONCLUSIONS: Patients expressed high levels of satisfaction and comfort during diagnostic urological procedures. Experiences were not affected by the level of training, suggesting highly developed interpersonal and communication skills for residents in an early stage of residency training. Patients demonstrated significant preferences for local anaesthesia in TRUSP and performance of UCS in the supine position over the lithotomy position. PMID- 26635065 TI - EBV and not HPV sensitizes tobacco-associated head and neck cancer cell line FaDu to radiotherapy. AB - Conclusion EBV radiosensitized the p53 mutant tobacco associated head and neck cell line, FaDu. Objectives In the head and neck, HPV is a major risk factor associated with tonsil and base of tongue cancers, while a majority of undifferentiated nasopharyngeal cancers are positive for EBV. Clinically, head and neck tumors positive for HPV or EBV are more radiosensitive than tumors associated with tobacco and alcohol. This study aimed to evaluate whether viral infections can sensitize tobacco-associated head and neck squamous cell carcinoma cell line that harbors multiple mutations, especially TP53, to radiotherapy. Method Four FaDu cell lines (vector control - FaDu-DN; FaDu expressing HPV16 E6/E7 - FaDu-HPV; FaDu infected with EBV - FaDu-EBV; and FaDu-HPV infected with EBV - FaDu-HE) were evaluated for their radiation sensitivity using clonogenic assay. Cell cycle, protein expression, apoptosis, and cellular senescence were analyzed. Results FaDu-EBV and FaDu-HE exhibited significantly increased radiosensitivity in comparison with the control cell line. Radiation-induced cell cycle arrest was altered in all cell lines expressing viral genes. The observed distribution of cells at G1 and S phases was associated with a significant increase in expression of p21 protein along with decreased levels of pAKT/AKT and pERK/ERK ratio (p < 0.05) and increased cellular senescence (p < 0.05). PMID- 26635066 TI - Mesenchymal stem cell-conditioned medium accelerates wound healing with fewer scars. AB - Mesenchymal stem cells (MSCs) derived from umbilical cords (UC-MSCs) have been shown to enhance cutaneous wound healing by means of the paracrine activity. Fibroblasts are the primary cells involved in wound repair. The paracrine effects of UC-MSCs on dermal fibroblasts have not been fully explored in vitro or in vivo. Dermal fibroblasts were treated with conditioned media from UC-MSCs (UC-MSC CM). In this model, UC-MSC-CM increased the proliferation and migration of dermal fibroblasts. Moreover, adult dermal fibroblasts transitioned into a phenotype with a low myofibroblast formation capacity, a decreased ratio of transforming growth factor-beta1,3 (TGF-beta1/3) and an increased ratio of matrix metalloproteinase/tissue inhibitor of metalloproteinases (MMP/TIMP). Additionally, UC-MSC-CM-treated wounds showed accelerated healing with fewer scars compared with control groups. These observations suggest that UC-MSC-CM may be a feasible strategy to promote cutaneous repair and a potential means to realise scarless healing. PMID- 26635067 TI - Secondary bacteremia following adenovirus infection. AB - Adenovirus is a common pediatric pathogen responsible for a wide variety of infections. Despite this, secondary bacteremia following an adenovirus infection has not been previously systematically described. Herein, we describe seven cases of secondary bacteremia following an adenovirus infection in hospitalized children during an 8-year period. Pediatricians should be informed of this serious complication. PMID- 26635068 TI - Levorphanol use: past, present and future. AB - Levorphanol is a potent opioid analgesic that was first approved for use in the United States in 1953. Levorphanol is approved for use in moderate to severe pain where an opioid analgesic is appropriate. Levorphanol has a wide range of activities including mu opioid agonism, delta agonism, kappa1 and kappa3 receptor agonism, N-methyl-d-aspartate receptor antagonism and reuptake inhibition of both norepinephrine and serotonin. This multimodal profile might prove effective for pain syndromes that are refractory to other opioid analgesics, such as central and neuropathic pain and opioid-induced hyperalgesia. Levorphanol is well suited as a first-line opioid and can also be used during opioid rotation. It has no known effect on the cardiac QT interval or drug-drug interactions involving hepatic cytochrome P450s enzymes. In these regards, levorphanol may offer a superior safety profile over methadone and other long-acting opioids. Despite its prospective value of multiple mechanisms of action and the potential for treating various types of pain, levorphanol use has been largely supplanted by other recently approved opioids. Its waning use over the years has caused it to be referred to as the "Forgotten Opioid" and resulted in what some consider its underutilization. In fact, levorphanol is relatively unfamiliar to most prescribers. The purpose of this review is to inform practitioners about the attributes of this opioid and reintroduce it to clinicians as an option for treating moderate to severe pain when alternative treatment options are inadequate, not indicated or contraindicated. PMID- 26635069 TI - Increased post-operative cardiopulmonary fitness in gastric bypass patients is explained by weight loss. AB - Roux-en-Y gastric bypass (RYGB) leads to a major weight loss in obese patients. However, given that most patients remain obese after the weight loss, regular exercise should be part of a healthier lifestyle. The primary aim of this study was to investigate the cardiopulmonary fitness in obese patients before and after RYGB. Thirty-four patients had body composition and cardiopulmonary fitness (VO2max ) assessed and completed questionnaires regarding physical activity and function twice before RYGB (time points A and B) and 4 and 18 months after surgery (time points C and D). Weight loss was 37 +/- 2 kg during the study period. VO2max increased (A: 21 +/- 1 vs D: 29 mL/min/kg, P < 0.001), but absolute VO2max decreased (A: 2713 +/- 126 vs 2609 +/- 187 mL/min, P = 0.02) and VO2max per kilogram fat free mass did not change. Self-perceived limitations to perform exercise decreased and self-perceived physical fitness increased after RYGB. Self-reported low- and high-intensity physical activity did not change. With weight loss, self-rated fitness level increased and the limitations to perform exercise decreased in RYGB patients. Nevertheless, as shown by the lower absolute VO2max , RYGB patients do not adopt new exercise habits following surgery. PMID- 26635070 TI - N-acetyl cysteine-mediated effective attenuation of methoxychlor-induced granulosa cell apoptosis by counteracting reactive oxygen species generation in caprine ovary. AB - Methoxychlor (MXC), an organochloride insecticide, is a potent toxicant-targeting female reproductive system and known to cause follicular atresia by inducing apoptosis within granulosa cells. Oxidative stress plays a pivotal role in apoptosis; thus, this study focuses on the ameliorative action of N-acetyl cysteine (NAC) on MXC-induced oxidative stress and apoptosis within granulosa cell of caprine ovary. Classic histology, fluorescence assay, and biochemical parameters were employed to evaluate the effect of varied concentration of NAC (1, 5, and 10 mM) on granulosa cell apoptosis after 24, 48, and 72 h exposure duration. Histomorphological studies revealed that NAC diminished the incidence of apoptotic attributes like condensed or marginated chromatin, pyknosis, crescent-shaped nucleus, empty cell spaces, and degenerated cellular structure along with the presence of cytoplasmic processes within granulosa cells in dose- and time-dependent manner. NAC significantly downregulated the percentage of MXC induced granulosa cell apoptosis within healthy ovarian follicle with its increasing dose, maximum at 10 mM concentration. It also significantly (p < 0.05) upregulated the activity of antioxidant enzymes, namely catalase, superoxide dismutase, and glutathione-s-transferase, along with ferric reducing antioxidant power further declining lipid peroxidation in the MXC-treated caprine ovary. The results revealed a negative correlation between apoptosis frequency and antioxidant enzymes' activity (rCAT = -0.67, rSOD = -0.56, rGST = -0.31; p < 0.05) while a positive correlation was observed with lipid peroxidation (r = 0.63; p < 0.05) after NAC supplementation. Thus, NAC supplementation reduces the MXC-generated oxidative stress that perhaps declines the ROS generating signal transduction pathway of apoptosis, thereby preventing MXC-induced granulosa cell apoptosis and follicular atresia. (c) 2015 Wiley Periodicals, Inc. Environ Toxicol 32: 156-166, 2017. PMID- 26635071 TI - Engineering Promoter Architecture in Oleaginous Yeast Yarrowia lipolytica. AB - Eukaryotic promoters have a complex architecture to control both the strength and timing of gene transcription spanning up to thousands of bases from the initiation site. This complexity makes rational fine-tuning of promoters in fungi difficult to predict; however, this very same complexity enables multiple possible strategies for engineering promoter strength. Here, we studied promoter architecture in the oleaginous yeast, Yarrowia lipolytica. While recent studies have focused on upstream activating sequences, we systematically examined various components common in fungal promoters. Here, we examine several promoter components including upstream activating sequences, proximal promoter sequences, core promoters, and the TATA box in autonomously replicating expression plasmids and integrated into the genome. Our findings show that promoter strength can be fine-tuned through the engineering of the TATA box sequence, core promoter, and upstream activating sequences. Additionally, we identified a previously unreported oleic acid responsive transcription enhancement in the XPR2 upstream activating sequences, which illustrates the complexity of fungal promoters. The promoters engineered here provide new genetic tools for metabolic engineering in Y. lipolytica and provide promoter engineering strategies that may be useful in engineering other non-model fungal systems. PMID- 26635072 TI - Copper(I)-Catalyzed Intramolecular Trifluoromethylation of Methylenecyclopropanes. AB - Copper(I)-catalyzed intramolecular trifluoromethylation of methylenecyclopropanes has been developed to produce a variety of CF3-substituted dihydronaphthalenes in moderate to good yields, relying on the construction of C(sp(2))-CF3 bonds under mild conditions. The reactions proceed through a radical process under copper(I) catalysis with a good compatibility for the functional group. PMID- 26635073 TI - Recombinant human prothrombin (MEDI8111) prevents bleeding in haemophilia A and B mice. AB - BACKGROUND: Haemophilia A and B are treated with FVIII and FIX replacement therapy. Treatment may be complicated by inhibitory antibodies that require bypass therapy such as FEIBA((r)) in which prothrombin (FII) is suggested to be the main active component. METHODS: To evaluate the effect of FII on haemophilia recombinant human (rh) FII (MEDI8111) or plasma-derived human FII (pdhFII) was given as single doses to anaesthetized haemophilia A and B mice 3 min before tail transection and rhFVIII or rhFIX was used for comparison. After tail transection, automatic bleeding registration was used to continuously measure blood loss (BL) and bleeding time (BT). Thrombin generation and plasma concentrations of human FVIII, FIX, FII and thrombin-antithrombin complex (TAT) were measured. RESULTS: Blood loss and BT were dose-dependently decreased by rhFVIII or rhFIX. The concentrations that decreased BL and BT for rhFVIII by 50% (EC50) were 0.06 and 0.01 IU mL(-1) and for rhFIX 0.07 and 0.07 IU mL(-1) , respectively. Administration of rhFVIII and rhFIX dose-dependently increased thrombin generation potential but did not affect TAT. MEDI8111 and pdhFII dose-dependently decreased BL and BT in haemophilia A mice, EC50 37 and 87 and 100 and 155 mg L( 1) respectively. In haemophilia B mice given MEDI8111 EC50 was for BL 56 mg L(-1) and for BT 67 mg L(-1) . TAT and thrombin generation increased dose-dependently for MEDI8111 and pdhFII. CONCLUSION: MEDI8111 dose-dependently decreased bleeding and increased procoagulant activity in haemophilia A and B mice and suggest that MEDI8111 may be useful for preventing bleeding in patients with haemophilia A and B. PMID- 26635074 TI - Screening performance of different methods defining fetal nasal bone hypoplasia as a single and combined marker for the detection of trisomy 21 in the second trimester. AB - OBJECTIVE: To evaluate different methods of defining fetal nasal bone hypoplasia in the second trimester for the detection of trisomy 21. METHODS: Prospective study in Greek women undergoing anomaly scan between 18 + 0 and 23 + 6 weeks. The following methods of defining nasal bone hypoplasia were evaluated, either as a single marker or in combination with others: (1) BPD to nasal bone length (NBL) ratio; (2) multiples of the median (MoM) of NBL, according to normal curves from a Greek population; (3-4) NBL < 2.5 percentile according to normal curves (3) commonly used internationally curves and (4) curves from a Greek population. RESULTS: In total, 1301 singleton fetuses were evaluated - 10 with trisomy 21. The best detection rate of trisomy 21 was achieved when the applied method was nasal bone percentiles adjusted to maternal ethnicity, in combination with other markers (<2.5 percentile according to normal curves from a Greek population; p < 0.001; sensitivity 50%; specificity 94.8%; false-positive rate 5.2%; positive likelihood ratio 9.6). CONCLUSION: Screening performance of fetal nasal bone hypoplasia in detecting trisomy 21 varies according to the method applied. The best screening performance is achieved by using percentiles adjusted to maternal ethnicity in combination with other markers of aneuploidy. PMID- 26635075 TI - Validity of histology for the diagnosis of paediatric coeliac disease: a Swedish multicentre study. AB - OBJECTIVE Histological evaluation of intestinal biopsies for the diagnosis of coeliac disease can be challenging and compatible with risk of misdiagnosis. The aim was to evaluate the agreement of pathological diagnosis for coeliac disease in children investigated at four major paediatric university hospitals in Sweden. MATERIALS AND METHODS Intestinal duodenal biopsies were collected from 402 children at median 9.7 years (1.4-18.3 years). A pathologist at each hospital performed the primary evaluation. A designated pathologist, blinded to the primary evaluation, performed a second Marsh classification of biopsies (M0 to M3c) taken from the bulb and duodenum separately. Kappa (kappa) scores between first and second evaluation determined the agreement. Plasma samples were collected at the day of intestinal biopsy and analysed for tissue transglutaminase autoantibodies (tTGA) using radioligand-binding assays. RESULTS Marsh scores were concordant in 229/356 biopsies (64%, kappa = 0.52, p < 0.0001). Among discordant results, 15/127 (12%) showed M0 in distal duodenum but >= M2 in the bulb, whereas the opposite was true for 8/127 (6%) of the biopsies. There were fewer collected duodenal biopsies, more missing bulb biopsies and missing CD3 staining among discordant evaluations. The second evaluation revealed a Marsh score compliant with coeliac disease in 22 children of whom seven children were tTGA positive. CONCLUSIONS The variation between university hospitals on the pathological evaluation of biopsies may lead to misdiagnosis of coeliac disease in paediatric patients. Access to clinical and endoscopic information as well as tTGA levels may be useful for the pathologist to complement the evaluation in dubious cases. PMID- 26635077 TI - Distant Influence of Kuroshio Eddies on North Pacific Weather Patterns? AB - High-resolution satellite measurements of surface winds and sea-surface temperature (SST) reveal strong coupling between meso-scale ocean eddies and near surface atmospheric flow over eddy-rich oceanic regions, such as the Kuroshio and Gulf Stream, highlighting the importance of meso-scale oceanic features in forcing the atmospheric planetary boundary layer (PBL). Here, we present high resolution regional climate modeling results, supported by observational analyses, demonstrating that meso-scale SST variability, largely confined in the Kuroshio-Oyashio confluence region (KOCR), can further exert a significant distant influence on winter rainfall variability along the U.S. Northern Pacific coast. The presence of meso-scale SST anomalies enhances the diabatic conversion of latent heat energy to transient eddy energy, intensifying winter cyclogenesis via moist baroclinic instability, which in turn leads to an equivalent barotropic downstream anticyclone anomaly with reduced rainfall. The finding points to the potential of improving forecasts of extratropical winter cyclones and storm systems and projections of their response to future climate change, which are known to have major social and economic impacts, by improving the representation of ocean eddy-atmosphere interaction in forecast and climate models. PMID- 26635076 TI - Association of chronic kidney disease with abnormal cardiac mechanics and adverse outcomes in patients with heart failure and preserved ejection fraction. AB - AIMS: Chronic kidney disease (CKD) is associated with worse outcomes in heart failure with preserved ejection fraction (HFpEF). Whether this association is due the effect of CKD on intrinsic abnormalities in cardiac function is unknown. We hypothesized that CKD is independently associated with worse cardiac mechanics in HFpEF. METHODS AND RESULTS: We prospectively studied 299 patients enrolled in the Northwestern University HFpEF Program. Using the creatinine-based CKD-Epi equation to calculate estimated glomerular filtration rate (eGFR), study participants were analysed by CKD status (using eGFR <60 mL/min/1.73 m(2) to denote CKD). Indices of cardiac mechanics (longitudinal strain parameters) were measured using speckle-tracking echocardiography. Using multivariable-adjusted linear and Cox regression analyses, we determined the association between CKD and echocardiographic parameters and clinical outcomes (cardiovascular hospitalization or death). Of 299 study participants, 48% had CKD. CKD (dichotomous variable) and reduced eGFR (continuous variable) were both associated with worse cardiac mechanics indices including left atrial (LA) reservoir strain, LV longitudinal strain, and right ventricular free wall strain even after adjusting for potential confounders, including co-morbidities, EF, and volume status. For example, for each 1-SD decrease in eGFR, LA reservoir strain was 3.52% units lower (P < 0.0001) after multivariable adjustment. Reduced eGFR was also associated with worse outcomes [adjusted hazard ratio (HR) 1.28, 95% confidence interval (CI) 1.01-1.61 per 1-SD decrease in eGFR; P = 0.039]. The association was attenuated after adjustment for indices of cardiac mechanics (P = 0.064). CONCLUSION: In HFpEF, CKD is independently associated with worse cardiac mechanics, which may explain why HFpEF patients with CKD have worse outcomes. TRIAL REGISTRATION: NCT01030991. PMID- 26635078 TI - Suppression of Radiative Damping and Enhancement of Second Harmonic Generation in Bull's Eye Nanoresonators. AB - We report a drastic increase of the damping time of plasmonic eigenmodes in resonant bull's eye (BE) nanoresonators to more than 35 fs. This is achieved by tailoring the groove depth of the resonator and by coupling the confined plasmonic field in the aperture to an extended resonator mode such that spatial coherence is preserved over distances of more than 10 MUm. Experimentally, this is demonstrated by probing the plasmon dynamics at the field level using broadband spectral interferometry. The nanoresonator allows us to efficiently concentrate the incident field inside the central aperture of the BE and to tailor its local optical nonlinearity by varying the aperture geometry. By replacing the central circular hole with an annular ring structure, we obtain 50 times higher second harmonic generation efficiency, allowing us to demonstrate the efficient concentration of long-lived plasmonic modes inside nanoapertures by interferometric frequency-resolved autocorrelation. Such a light concentration in a nanoresonator with high quality factor has high potential for sensing and coherent control of light-matter interactions on the nanoscale. PMID- 26635080 TI - Variance-corrected Michaelis-Menten equation predicts transient rates of single enzyme reactions and response times in bacterial gene-regulation. AB - Many chemical reactions in biological cells occur at very low concentrations of constituent molecules. Thus, transcriptional gene-regulation is often controlled by poorly expressed transcription-factors, such as E.coli lac repressor with few tens of copies. Here we study the effects of inherent concentration fluctuations of substrate-molecules on the seminal Michaelis-Menten scheme of biochemical reactions. We present a universal correction to the Michaelis-Menten equation for the reaction-rates. The relevance and validity of this correction for enzymatic reactions and intracellular gene-regulation is demonstrated. Our analytical theory and simulation results confirm that the proposed variance-corrected Michaelis-Menten equation predicts the rate of reactions with remarkable accuracy even in the presence of large non-equilibrium concentration fluctuations. The major advantage of our approach is that it involves only the mean and variance of the substrate-molecule concentration. Our theory is therefore accessible to experiments and not specific to the exact source of the concentration fluctuations. PMID- 26635079 TI - Gut microbiota manipulation with prebiotics in patients with non-alcoholic fatty liver disease: a randomized controlled trial protocol. AB - BACKGROUND: Evidence for the role of the gut microbiome in the pathogenesis of non-alcoholic fatty liver disease (NAFLD) is emerging. Strategies to manipulate the gut microbiota towards a healthier community structure are actively being investigated. Based on their ability to favorably modulate the gut microbiota, prebiotics may provide an inexpensive yet effective dietary treatment for NAFLD. Additionally, prebiotics have established benefits for glucose control and potentially weight control, both advantageous in managing fatty liver disease. Our objective is to evaluate the effects of prebiotic supplementation, adjunct to those achieved with diet-induced weight loss, on heptic injury and liver fat, the gut microbiota, inflammation, glucose tolerance, and satiety in patients with NAFLD. METHODS/DESIGN: In a double blind, placebo controlled, parallel group study, adults (BMI >=25) with confirmed NAFLD will be randomized to either a 16 g/d prebiotic supplemented group or isocaloric placebo group for 24 weeks (n = 30/group). All participants will receive individualized dietary counseling sessions with a registered dietitian to achieve 10 % weight loss. Primary outcome measures include change in hepatic injury (fibrosis and inflammation) and liver fat. Secondary outcomes include change in body composition, appetite and dietary adherence, glycemic and insulinemic responses and inflammatory cytokines. Mechanisms related to prebiotic-induced changes in gut microbiota (shot-gun sequencing) and their metabolic by-products (volatile organic compounds) and de novo lipogenesis (using deuterium incorporation) will also be investigated. DISCUSSION: There are currently no medications or surgical procedures approved for the treatment of NAFLD and weight loss via lifestyle modification remains the cornerstone of current care recommendations. Given that prebiotics target multiple metabolic impairments associated with NAFLD, investigating their ability to modulate the gut microbiota and hepatic health in patients with NAFLD is warranted. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02568605) Registered 30 September 2015. PMID- 26635081 TI - Circulating Microparticles Alter Formation, Structure, and Properties of Fibrin Clots. AB - Despite the importance of circulating microparticles in haemostasis and thrombosis, there is limited evidence for potential causative effects of naturally produced cell-derived microparticles on fibrin clot formation and its properties. We studied the significance of blood microparticles for fibrin formation, structure, and susceptibility to fibrinolysis by removing them from platelet-free plasma using filtration. Clots made in platelet-free and microparticle-depleted plasma samples from the same healthy donors were analyzed in parallel. Microparticles accelerate fibrin polymerisation and support formation of more compact clots that resist internal and external fibrinolysis. These variations correlate with faster thrombin generation, suggesting thrombin mediated kinetic effects of microparticles on fibrin formation, structure, and properties. In addition, clots formed in the presence of microparticles, unlike clots from the microparticle-depleted plasma, contain 0.1-0.5-MUm size granular and CD61-positive material on fibres, suggesting that platelet-derived microparticles attach to fibrin. Therefore, the blood of healthy individuals contains functional microparticles at the levels that have a procoagulant potential. They affect the structure and stability of fibrin clots indirectly through acceleration of thrombin generation and through direct physical incorporation into the fibrin network. Both mechanisms underlie a potential role of microparticles in haemostasis and thrombosis as modulators of fibrin formation, structure, and resistance to fibrinolysis. PMID- 26635083 TI - Effects of histamine H1 receptor signaling on glucocorticoid receptor activity. Role of canonical and non-canonical pathways. AB - Histamine H1 receptor (H1R) antagonists and glucocorticoid receptor (GR) agonists are used to treat inflammatory conditions such as allergic rhinitis, atopic dermatitis and asthma. Consistent with the high morbidity levels of such inflammatory conditions, these receptors are the targets of a vast number of approved drugs, and in many situations their ligands are co-administered. However, this drug association has no clear rationale and has arisen from clinical practice. We hypothesized that H1R signaling could affect GR-mediated activity, impacting on its transcriptional outcome. Indeed, our results show a dual regulation of GR activity by the H1R: a potentiation mediated by G-protein betagamma subunits and a parallel inhibitory effect mediated by Galphaq-PLC pathway. Activation of the H1R by its full agonists resulted in a composite potentiating effect. Intriguingly, inactivation of the Galphaq-PLC pathway by H1R inverse agonists resulted also in a potentiation of GR activity. Moreover, histamine and clinically relevant antihistamines synergized with the GR agonist dexamethasone to induce gene transactivation and transrepression in a gene specific manner. Our work provides a delineation of molecular mechanisms underlying the widespread clinical association of antihistamines and GR agonists, which may contribute to future dosage optimization and reduction of well described side effects associated with glucocorticoid administration. PMID- 26635084 TI - Urinary podocalyxin levels were associated with urinary albumin levels among patients with diabetes. AB - Diabetic nephropathy has dramatically increased worldwide. In this study, we measured urinary podocalyxin in 240 patients with diabetes. The relationship between urinary podocalyxin and clinical parameters and the effects of dipeptidyl peptidase-4 inhibitors (DPP4i) and alpha-glucosidase inhibitor (a-GI) on urinary podocalyxin levels were examined. Urinary podocalyxin levels were significantly higher in patients with microalbuminuria than in those with normoalbuminuria. Urinary podocalyxin levels were also significantly related to albumin-to creatinine ratio. Neither DPP4i nor alpha-GI ameliorated the increase in urinary podocalyxin levels. Our results indicated that urinary podocalyxin will be not only an early marker but also a treatment target for DN. PMID- 26635085 TI - Zebrafish diras1 Promoted Neurite Outgrowth in Neuro-2a Cells and Maintained Trigeminal Ganglion Neurons In Vivo via Rac1-Dependent Pathway. AB - The small GTPase Ras superfamily regulates several neuronal functions including neurite outgrowth and neuron proliferation. In this study, zebrafish diras1a and diras1b were identified and were found to be mainly expressed in the central nervous system and dorsal neuron ganglion. Overexpression of green fluorescent protein (GFP)-diras1a or GFP-diras1b triggered neurite outgrowth of Neuro-2a cells. The wild types, but not the C terminus truncated forms, of diras1a and diras1b elevated the protein level of Ras-related C3 botulinum toxin substrate 1 (Rac1) and downregulated Ras homologous member A (RhoA) expression. Glutathione S transferase (GST) pull-down assay also revealed that diras1a and diras1b enhanced Rac1 activity. Interfering with Rac1, Pak1, or cyclin-dependent kinase 5 (CDK5) activity or with the Arp2/3 inhibitor prevented diras1a and diras1b from mediating the neurite outgrowth effects. In the zebrafish model, knockdown of diras1a and/or diras1b by morpholino antisense oligonucleotides not only reduced axon guidance but also caused the loss of trigeminal ganglion without affecting the precursor markers, such as ngn1 and neuroD. Co-injection with messenger RNA (mRNA) derived from mouse diras1 or constitutively active human Rac1 restored the population of trigeminal ganglion. In conclusion, we provided preliminary evidence that diras1 is involved in neurite outgrowth and maintains the number of trigeminal ganglions through the Rac1-dependent pathway. PMID- 26635087 TI - Advance of the application of nano-controlled release system in ophthalmic drug delivery. AB - The ocular prescription application of nanometer materials are mainly concentrated in controlled release systems. Due to the unique properties of nanometer materials such as higher bioavailability and less side effects, it has great advantages in carrying ocular drugs of eye diseases compared with the traditional dosing method. As a result, nano-controlled release system has good application prospect in eye diseases. At present, a variety of different types of nano-controlled release systems have been used to enhance the efficiency of the ocular drugs including nanomicelles, nanoparticles, nanosuspensions, liposomes and dendrimers. In this article, the research progress and the application of nano-controlled release system in ophthalmic drug delivery are reviewed. PMID- 26635086 TI - Topological Reorganization of the Default Mode Network in Irritable Bowel Syndrome. AB - The aim of this study was to investigate the topological reorganization of the brain default mode network (DMN) in patients with irritable bowel syndrome (IBS) using resting-state functional magnetic resonance imaging (rs-fMRI). With approval by our ethics committee, rs-fMRI was prospectively performed in 31 IBS patients (25 male, 27 +/- 8 years) and 32 healthy controls (25 male, 29 +/- 9 years). The DMN was determined by unbiased seed-based functional connectivity (FC) analysis and then parcellated into several subregions. FC across all pairs of DMN subregions was computed to construct the DMN architecture, for which topological properties were characterized by graph theoretical approaches. Pearson correlation was performed between abnormal DMN inter-regional FC and network measures and clinical indices in IBS patients. Compared to healthy controls, IBS patients showed decreased DMN inter-regional FC between the anterior cingulate cortex and precuneus, the medial orbital of the superior frontal gyrus (ORBsupmed) and precuneus, and the middle temporal gyrus and precuneus. IBS patients also showed decreased DMN global efficiency (E glob). Inclusion of anxiety and depression as covariates abolished FC between ORBsupmed and precuneus and some E glob differences. The average DMN FC was positively correlated with average E glob (r = 0.47, P = 0.008) and negatively correlated with symptom severity score (r = -0.37, P = 0.04) in IBS patients. In conclusion, IBS patients showed topological reorganization of the DMN to a non-optimized regularity configuration, which may partly be ascribed to high levels of anxiety and depression. PMID- 26635082 TI - Sixteen new lung function signals identified through 1000 Genomes Project reference panel imputation. AB - Lung function measures are used in the diagnosis of chronic obstructive pulmonary disease. In 38,199 European ancestry individuals, we studied genome-wide association of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC with 1000 Genomes Project (phase 1)-imputed genotypes and followed up top associations in 54,550 Europeans. We identify 14 novel loci (P<5 * 10(-8)) in or near ENSA, RNU5F-1, KCNS3, AK097794, ASTN2, LHX3, CCDC91, TBX3, TRIP11, RIN3, TEKT5, LTBP4, MN1 and AP1S2, and two novel signals at known loci NPNT and GPR126, providing a basis for new understanding of the genetic determinants of these traits and pulmonary diseases in which they are altered. PMID- 26635089 TI - Predicting Electrocatalytic Properties: Modeling Structure-Activity Relationships of Nitroxyl Radicals. AB - Stable nitroxyl radical-containing compounds, such as 2,2,6,6 tetramethylpiperidine-N-oxyl (TEMPO) and its derivatives, are capable of electrocatalytically oxidizing a wide range of alcohols under mild and environmentally friendly conditions. Herein, we examine the structure-function relationships that determine the catalytic activity of a diverse range of water soluble nitroxyl radical compounds. A strong correlation is described between the difference in the electrochemical oxidation potentials of a compound and its electrocatalytic activity. Additionally, we construct a simple computational model that is able to accurately predict the electrochemical potential and catalytic activity of a wide range of nitroxyl radical derivatives. PMID- 26635088 TI - Discovery of a novel genetic susceptibility locus on X chromosome for systemic lupus erythematosus. AB - INTRODUCTION: Systemic lupus erythematosus (SLE) is an autoimmune connective tissue disease affecting predominantly females. To discover additional genetic risk variants for SLE on the X chromosome, we performed a follow-up study of our previously published genome-wide association study (GWAS) data set in this study. METHODS: Twelve single nucleotide polymorphisms (SNPs) within novel or unpublished loci with P-value < 1.00 * 10(-02) were selected for genotype with a total of 2,442 cases and 2,798 controls(including 1,156 cases and 2,330 controls from central China, 1,012 cases and 335 controls from southern China and 274 cases and 133 controls from northern China) using Sequenom Massarry system. Associaton analyses were performed using logistic regression with sample region as a covariate through PLINK 1.07 software. RESULTS: Combined analysis in discovery and central validation dataset discovered a novel locus rs5914778 within LINC01420 associated with SLE at genome-wide significance (P = 1.00 * 10( 08); odds ratio (OR) = 1.32). We also confirmed rs5914778 in the southern Chinese sample cohort (P = 5.31 * 10(-05); OR = 1.51), and meta-analysis of the samples from the discovery, central and southern validations regions provided robust evidence for the association of rs5914778 (P = 5.26 * 10(-12); OR = 1.35). However, this SNP did not show association with SLE in the northern sample (P = 0.33). Further analysis represent the association of northern was significantly heterogeneous compared to central and southern respectively. CONCLUSIONS: Our study increases the number of established susceptibility loci for SLE in Han Chinese population and has further demonstrated the important role of X-linked genetic risk variants in the pathogenesis of SLE in Chinese Han population. PMID- 26635090 TI - Supplementation of standard antibiotic therapy with oral probiotics for bacterial vaginosis and aerobic vaginitis: a randomised, double-blind, placebo-controlled trial. AB - BACKGROUND: This multicentre, randomised, double-blind, placebo-controlled trial was performed to determine whether the use of oral probiotic preparation (prOVag(r)) containing three Lactobacillus strains together with standard metronidazole treatment and also targeted antibiotic treatment (following the failure of metronidazole therapy) could reduce the recurrence rates of bacterial vaginosis (BV) and aerobic vaginitis (AV). METHODS: Patients at private gynaecological clinics in Poland with histories of recurrent BV/AV and current symptoms were randomly allocated to receive metronidazole and probiotic or placebo, and assessed monthly on visits II and III-V. The total number of study visits was 5-6 (I, II, II bis - if applicable, III, IV, V). One probiotic or placebo capsule was administered with metronidazole/targeted antibiotic twice daily for 10 days; during follow up, patients took one capsule daily for 10 days perimenstrually. Clinical examination and vaginal swabbing were performed at each visit. Primary outcomes were clinical or microbiological BV/AV recurrence and probiotic safety. Secondary outcomes were vaginal pH, Nugent score, and Lactobacillus counts in the vaginal microbiota. Safety analysis was performed in 578 (probiotic, n = 285; placebo, n = 293) 18-50-year-old women who were randomised. RESULTS: BV/AV was confirmed microbiologically in 241 (probiotic, n = 118; placebo, n = 123) participants, who continued the trial. Data from 154 (probiotic, n = 73; placebo, n = 81) participants who completed the study were analysed to determine the efficacy of prOVag. Additional analyses included 37 (probiotic, n = 22; placebo, n = 15) participants who received targeted antibiotics and probiotics or placebo. prOVag lengthened the time to clinical relapse of BV/AV symptoms up to 51 % (p < 0.05) compared with placebo; AV relapse was delayed by up to 76 % (p < 0.05). Probiotic use also reduced and maintained low vaginal pH and Nugent score, and increased vaginal Lactobacillus counts following standard treatment. CONCLUSION: This study demonstrated that oral probiotics lengthened remission in patients with recurrent BV/AV and improved clinical and microbiological parameters. TRIAL REGISTRATION: NCT01993524 ; 20 November 2013. PMID- 26635093 TI - Experimental and Theoretical Studies on Corvol Ether Biosynthesis. AB - The biosynthesis of corvol ethers A and B, two sesquiterpenes from Kitasatospora setae, proceeds with involvement of either one 1,3- or two sequential 1,2-hydride shifts. Quantum chemical calculations revealed that the sequence of two 1,2 hydride shifts is energetically favoured. Labelling experiments were in agreement with this finding. In addition, the stereochemical course of a reprotonation step was investigated by incubation of (13)C-labelled isotopomers of farnesyl diphosphate in water and in deuterium oxide. PMID- 26635092 TI - A genome-wide association study of asthma symptoms in Latin American children. AB - BACKGROUND: Asthma is a chronic disease of the airways and, despite the advances in the knowledge of associated genetic regions in recent years, their mechanisms have yet to be explored. Several genome-wide association studies have been carried out in recent years, but none of these have involved Latin American populations with a high level of miscegenation, as is seen in the Brazilian population. METHODS: 1246 children were recruited from a longitudinal cohort study in Salvador, Brazil. Asthma symptoms were identified in accordance with an International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire. Following quality control, 1,877,526 autosomal SNPs were tested for association with childhood asthma symptoms by logistic regression using an additive genetic model. We complemented the analysis with an estimate of the phenotypic variance explained by common genetic variants. Replications were investigated in independent Mexican and US Latino samples. RESULTS: Two chromosomal regions reached genome-wide significance level for childhood asthma symptoms: the 14q11 region flanking the DAD1 and OXA1L genes (rs1999071, MAF 0.32, OR 1.78, 95% CI 1.45-2.18, p-value 2.83 * 10(-8)) and 15q22 region flanking the FOXB1 gene (rs10519031, MAF 0.04, OR 3.0, 95% CI 2.02-4.49, p-value 6.68 * 10(-8) and rs8029377, MAF 0.03, OR 2.49, 95% CI 1.76-3.53, p-value 2.45 * 10(-7)). eQTL analysis suggests that rs1999071 regulates the expression of OXA1L gene. However, the original findings were not replicated in the Mexican or US Latino samples. CONCLUSIONS: We conclude that the 14q11 and 15q22 regions may be associated with asthma symptoms in childhood. PMID- 26635091 TI - Mechanistic and therapeutic overview of glycosaminoglycans: the unsung heroes of biomolecular signaling. AB - Immune regulation is a complex biological signaling pathway in which several classes of biomolecules and small molecules play a complacent role to mediate this process. Glycoimmunology is a rapidly evolving research area that deals with the structure, binding interactions and immunological functions of glycans. Great deal of information regarding proteins and nucleic acids in molecular recognition events have been established owing to their well-established structural features and straight forward replication, transcription and translation principles. However considering the complexities of template free synthesis and structural heterogeneity, role of carbohydrates in immune regulation are still unsung to a large extent. In the current review, we illuminate the canonical structural features, emerging and significant pathophysiological functions of glycosaminoglycans (GAGs), the negatively charged linear carbohydrate molecules that are primarily present on all types of cell surfaces and extra cellular matrix. A snap shot of their association with protein counterparts of diversified protein families has been updated exclusively to provide mechanistic insights into their cellular signaling functions. Eventually, this review throws light on the recent biomedical/biotechnological advances of GAG based biomarkers, nutraceuticals, therapeutics, and nanocomposites for inflammatory, immune disorders and their invaluable contribution in tissue engineering. PMID- 26635094 TI - Fatty acid composition and biogenic amines in acidified and fermented fish silage: a comparison study. AB - In the presented study, ensiling of discard fish by acidification or fermentation was evaluated. Klunzinger's ponyfish which is a discard fish was used for the production of fish silage by acidification (3% formic acid for Method FA; 1.5% formic and 1.5% sulphuric acid for Method FASA) and fermentation (Lactobacillus plantarum for Method LP and Streptococcus thermophilus for Method ST). The chemical, microbiological and nutritional properties of the differently preserved fish silages were estimated during a storage period of 60 d at ambient temperature. Compared to the raw material, a slight increase in saturated fatty acids and a slight decrease in polyunsaturated fatty acids were observed in all silages. At the end of the storage period, the aerobic bacteria counts after applying Methods FA, FASA, LP and ST amounted to 2.35, 2.39, 5.77 and 5.43 log cfu/g, respectively. The analysis of thiobarbituric acid revealed that acidification of silages accelerated the lipid oxidation. Nine biogenic amines were found in raw fish and different silages. The initial histamine concentration in raw fish was 0.17 mg/100 g and in all silages it remained at low levels during the storage period. The initial tyramine content was found to be 1.56 mg/100 g in raw fish and increased significantly in all silages. The increase of the tyramine content in fermented silages was considerably higher than in acidified silages (23-48 mg/100 g and 5-10 mg/100 g, respectively). It can be concluded that acidified or fermented fish silage should be considered as potential feed component for animals because of its high nutritional value and appropriate microbiological and chemical quality. PMID- 26635095 TI - The impact of malocclusions on oral health-related quality of life in children-a systematic review and meta-analysis. AB - INTRODUCTION: A limited amount of systematic literature reviews on the association between malocclusions and oral health-related quality of life (OHRQOL) summarize inconclusive results. Therefore, we conduct a systematic review and meta-analysis on the association of malocclusions with OHRQOL in children. METHODS: Relevant studies were identified in Pubmed, Embase, Cochrane, Google Scholar and other databases. All studies with data on malocclusions or orthodontic treatment need and OHRQOL in children were included. Methodological quality of the studies was assessed with the Newcastle-Ottawa Scale (NOS). Random effects models were used to estimate summary effect measures for the association between malocclusion and OHRQOL in a continuous and a categorical data analysis. Tests for heterogeneity, publication bias and sensitivity of results were performed. RESULTS: In total, 40 cross-sectional studies were included in the meta-analyses. Summary measures of the continuous data show that OHRQOL was significantly lowered in children with malocclusions (standardized mean difference (95 % CI] = 0.29 (0.19-0.38)). The summary odds ratio for having an impact on OHRQOL was 1.74 times higher in children with malocclusion than in children without malocclusions. Heterogeneity among studies was partly explained by malocclusion assessment, age of the children and country of study conduction. CONCLUSION: Our results provide evidence for a clear inverse association of malocclusion with OHRQOL. We also showed that the strength of the association differed depending on the age of the children and their cultural environment. CLINICAL RELEVANCE: Dentists benefit from understanding the patient differences regarding the impact of malocclusions. PMID- 26635096 TI - Clinically used adhesive ceramic bonding methods: a survey in 2007, 2011, and in 2015. AB - OBJECTIVES: The objective of the study is to evaluate practices of dentists regarding adhesive cementation of all-ceramic restorations over a period of 8 years. MATERIALS AND METHODS: The authors developed a questionnaire regarding adhesive cementation procedures for all-ceramic restorations. Restorations were distinguished between made out of silicate ceramic or oxide ceramic. The questionnaire was handed out to all dentists participating in a local annual dental meeting in Northern Germany. The returned questionnaires were analyzed to identify incorrect cementation procedures based upon current evidence-based technique from the scientific dental literature. The survey was conducted three times in 2007, 2011, and 2015 and their results were compared. RESULTS: For silicate ceramic restorations, 38-69 % of the participants used evidence-based bonding procedures; most of the incorrect bonding methods did not use a silane containing primer. In case of oxide ceramic restorations, most participants did not use air-abrasion prior to bonding. Only a relatively low rate (7-14 %) of dentists used evidence-based dental techniques for bonding oxide ceramics. CONCLUSION: In adhesive cementation of all-ceramic restorations, the practices of surveyed dentists in Northern Germany revealed high rates of incorrect bonding. During the observation period, the values of evidence-based bonding procedures for oxide ceramics improved while the values for silicate ceramics declined. Based on these results, some survey participants need additional education for adhesive techniques. CLINICAL RELEVANCE: Neglecting scientifically accepted methods for adhesive cementation of all-ceramic restorations may result in reduced longevity of all-ceramic restorations. PMID- 26635097 TI - Serial vs. parallel models of attention in visual search: accounting for benchmark RT-distributions. AB - Visual search is central to the investigation of selective visual attention. Classical theories propose that items are identified by serially deploying focal attention to their locations. While this accounts for set-size effects over a continuum of task difficulties, it has been suggested that parallel models can account for such effects equally well. We compared the serial Competitive Guided Search model with a parallel model in their ability to account for RT distributions and error rates from a large visual search data-set featuring three classical search tasks: 1) a spatial configuration search (2 vs. 5); 2) a feature conjunction search; and 3) a unique feature search (Wolfe, Palmer & Horowitz Vision Research, 50(14), 1304-1311, 2010). In the parallel model, each item is represented by a diffusion to two boundaries (target-present/absent); the search corresponds to a parallel race between these diffusors. The parallel model was highly flexible in that it allowed both for a parametric range of capacity limitation and for set-size adjustments of identification boundaries. Furthermore, a quit unit allowed for a continuum of search-quitting policies when the target is not found, with "single-item inspection" and exhaustive searches comprising its extremes. The serial model was found to be superior to the parallel model, even before penalizing the parallel model for its increased complexity. We discuss the implications of the results and the need for future studies to resolve the debate. PMID- 26635100 TI - Preface to The Journal of Organic Chemistry's Special Issue "50 Years and Counting: The Woodward-Hoffmann Rules in the 21st Century". PMID- 26635098 TI - Endothelial Rictor is crucial for midgestational development and sustained and extensive FGF2-induced neovascularization in the adult. AB - To explore the general requirement of endothelial mTORC2 during embryonic and adolescent development, we knocked out the essential mTORC2 component Rictor in the mouse endothelium in the embryo, during adolescence and in endothelial cells in vitro. During embryonic development, Rictor knockout resulted in growth retardation and lethality around embryonic day 12. We detected reduced peripheral vascularization and delayed ossification of developing fingers, toes and vertebrae during this confined midgestational period. Rictor knockout did not affect viability, weight gain, and vascular development during further adolescence. However during this period, Rictor knockout prevented skin capillaries to gain larger and heterogeneously sized diameters and remodeling into tortuous vessels in response to FGF2. Rictor knockout strongly reduced extensive FGF2-induced neovascularization and prevented hemorrhage in FGF2-loaded matrigel plugs. Rictor knockout also disabled the formation of capillary-like networks by FGF2-stimulated mouse aortic endothelial cells in vitro. Low RICTOR expression was detected in quiescent, confluent mouse aortic endothelial cells, whereas high doses of FGF2 induced high RICTOR expression that was associated with strong mTORC2-specific protein kinase Calpha and AKT phosphorylation. We demonstrate that the endothelial FGF-RICTOR axis is not required during endothelial quiescence, but crucial for midgestational development and sustained and extensive neovascularization in the adult. PMID- 26635099 TI - Treatment-resistant panic disorder: a systematic review. AB - INTRODUCTION: The prevalence of panic disorder (PD) in the population is high and these patients have work impairment, high unemployment rates, seek medical treatment more frequently and have more hospitalizations than people without panic symptoms. Despite the availability of pharmacological, psychological and combined treatments, approximately one-third of all PD patients have persistent panic attacks and other PD symptoms after treatment. AREAS COVERED: MEDLINE/Pubmed, CENTRAL, PsycINFO and Web of Science databases were searched for clinical trials in treatment-resistant PD. Only studies published between 1980 and 2015, in English, with human subjects, considered "journal articles" and clinical trial were included. We included trials recruiting only adult subjects with treatment-resistant PD, consistent with criteria from DSM-III to DSM5. We included all prospective experimental studies. Case, case series, retrospective studies or studies with <10 PD subjects were not included. EXPERT OPINION: Only 11 articles were included in this review. There were few quality studies, only two were randomized, controlled and double blind. Augmentation of the pharmacological treatment with cognitive-behavioral therapy demonstrated some short-term efficacy in treatment-resistant PD. There were also preliminary evidences of efficacy for monotherapy with reboxetine and olanzapine, and augmentation with pindolol, divalproex sodium, aripiprazole and olanzapine in short-term treatment. PMID- 26635101 TI - Beauty in Simplicity: Celebrating 50 Years of the Woodward-Hoffmann Rules. PMID- 26635107 TI - Evaluation of goat milk as storage media to preserve viability of human periodontal ligament cells in vitro. AB - BACKGROUND AND AIM: The purpose of this study was to evaluate the effectiveness of goat milk as a storage media for maintenance of periodontal ligament (PDL) cell viability of avulsed teeth and compare it with commonly used and/or investigated storage media. MATERIALS AND METHODS: PDL cells were obtained from the root surface of healthy premolars and were cultured in Eagle's maintenance medium (EMM). Cell cultures were treated with the following storage media: tap water (negative control); EMM (positive control); Hank's balanced salt solution; ultra high temperature (UHT) long-shelf-life lactose-free cow milk; UHT long shelf-life whole cow milk; UHT long-shelf-life skimmed cow milk; UHT long-shelf life soy milk; UHT long-shelf-life goat milk, UHT long-shelf-life follow on milk with probiotic, 20% propolis, and egg white. Culture plates were incubated with experimental media at 20 degrees C for 1, 3, 6, 12, and 24 h. PDL cell viability was assessed by tetrazolium salt-based colorimetric (MTT) assay at each test period. One-way anova was used to evaluate the effects of storage solutions at each time point, followed by post hoc Duncan's multiple comparison test (P = 0.05). A dendrogram was constructed to show the arrangement of hierarchical clustering. RESULTS: Goat milk displayed the highest capacity to maintain cell viability at all test intervals (P < 0.001). Between 3 and 24 h, milk with the probiotic showed the lowest time-dependent PDL cell viability among all test media (P < 0.001). Compared with all milks, HBSS performed significantly less effectively in maintaining PDL cell viability during the entire test period (P < 0.001). CONCLUSION: Based on PDL viability, goat milk can be recommended as a suitable storage medium for avulsed teeth. PMID- 26635103 TI - Invasive pneumococcal disease in patients with haematological malignancies before routine use of conjugate vaccines in Finland. AB - The baseline national invasive pneumococcal disease (IPD) incidence rate, serotype distribution and serotype coverage of pneumococcal vaccines were evaluated in patients with Hodgkin's and non-Hodgkin's lymphomas, myeloma and leukaemia within 1 year after haematological diagnosis during 1995-2002, before introduction of pneumococcal conjugate vaccines. Pneumococcal serotype distribution among these patients was different from serotypes causing IPD in the general population. The serotype coverages of PCV13 and PPSV23 were 57% and 64%, respectively, lower than in the general population. This reflects a higher predisposition to IPD in vaccinated patients with haematological malignancies and possibly less benefit of herd immunity gained with the wide use of pneumococcal conjugate vaccines in the general population. This data will be useful as a baseline for determining the future role of adult PCV vaccination in these patient groups. PMID- 26635102 TI - Comparison of 10-day sequential therapy with 7-day standard triple therapy for Helicobacter pylori eradication in inactive peptic ulcer disease and the efficiency of sequential therapy in inactive peptic ulcer disease and non-ulcer dyspepsia. AB - BACKGROUND: Eradication rates of standard triple therapy for Helicobacter pylori infections have decreased in recent years due to a worldwide increase in bacterial resistance. Sequential therapy has the advantage of a two-phase treatment regimen and achieves a superior result for H. pylori eradication in peptic ulcer disease. However, no study has yet compared the efficacy of sequential therapy for H. pylori eradication exclusively in inactive duodenal ulcer (iDU) or non-ulcer dyspepsia (NUD). METHOD: We retrospectively recruited 408 patients with endoscopic proven iDU (170 patients) or NUD (238 patients) infected with H. pylori. Patients with iDU were assigned into two groups: iDU triple therapy group, 44 patients treated with 40 mg pantoprazole, 1000 mg amoxicillin and 500 mg clarithromycin, twice daily for 7 days; iDU sequential therapy group, 126 patients treated with 40 mg pantoprazole and 1000 mg amoxicillin, twice daily for the first 5 days, followed by 40 mg pantoprazole, 500 mg clarithromycin and 500 mg tinidazole, twice daily for the next 5 days. All patients with NUD were treated with sequential therapy and assigned as the NUD sequential group. Post-treatment H. pylori status was confirmed by a (13)C-urea breath test. RESULT: The eradication rates of intention-to-treat (ITT) and per protocol (PP) analysis were 77.3 % (95 % CI 64.9-89.7 %) and 85.0 % (95 % CI 73.9 96.1 %) in the iDU triple therapy group and 87.3 % (95 % CI 81.5-93.1 %) and 92.4 % (95 % CI 87.6-97.2 %) in the iDU sequential therapy group. The overall eradication efficacy was superior in the sequential group than in the triple group, both with ITT analysis (83.5 % vs. 77.3 %, P = 0.29) and PP analysis (88.1 % vs. 85.0 %, P = 0.57). Eradication rates for ITT and PP analysis were 81.5 % (95 % CI 76.6-86.4 %) and 85.8 % (95 % CI 83.5-88.2 %) in the NUD sequential therapy group. Eradication rate was statistically better in the iDU sequential therapy group than the NUD sequential therapy group according to per protocol analysis (P = 0.04). Eradication rate was not significantly different between the iDU sequential- and iDU triple therapy groups according to protocol analysis (P = 0.14). CONCLUSION: The sequential regimen has a better eradiation rate in the iDU group than in the NUD group. There is no statistically difference between 10-day sequential therapy and 7-day standard triple in iDU group. PMID- 26635108 TI - Identifying potential indicators to measure the outcome of translational cancer research: a mixed methods approach. AB - BACKGROUND: In a context where there is an increasing demand to evaluate the outcome of bio-medical research, our work aims to develop a set of indicators to measure the impact of translational cancer research. The objective of our study was to explore the scope and issues of translational research relevant to evaluation, explore the views of researchers on the evaluation of oncological translational research, and select indicators measuring the outcomes and outputs of translational research in oncology by consensus. METHODS: Semi-structured interviews amongst 23 researchers involved in translational cancer research were conducted and analysed using thematic analysis. A two-round modified Delphi survey of 35 participants with similar characteristics was then performed followed by a physical meeting. Participants rated the feasibility and validity of 60 indicators. The physical meeting was held to discuss the methodology of the new indicators. RESULTS: The main themes emerging from the interviews included a common definition for translational research but disagreements about the exact scope and limits of this research, the importance of multidisciplinarity and collaboration for the success of translational research, the disadvantages that translational research faces in current evaluation systems, the relative lack of pertinence of existing indicators, and propositions to measure translational cancer research in terms of clinical applications and patient outcomes. A total of 35 participants took part in the first round survey and 12 in the second round. The two-round survey helped us select a set of 18 indicators, including four that seemed to be particularly adapted to measure translational cancer research impact on health service research (number of biomarkers identified, generation of clinical guidelines, citation of research in clinical guidelines, and citation of research in public health guidelines). The feedback from participants helped refine the methodology and definition of indicators not commonly used. CONCLUSION: Indicators need to be accepted by stakeholders under evaluation. This study helped the selection and refinement of indicators considered as the most relevant by researchers in translational cancer research. The feasibility and validity of those indicators will be tested in a scientometric study. PMID- 26635109 TI - Bone: Autophagy regulates bone growth in mice. PMID- 26635110 TI - Sleep: Late to bed, late to rise, could be cardiometabolically unwise. PMID- 26635111 TI - Gut microbiota: Proteins released by E. coli in the gut influence host appetite control. PMID- 26635112 TI - Pregnancy: Maternal thyroid function in pregnancy - a tale of two tails. PMID- 26635113 TI - The Comparative Studies of Binding Activity of Curcumin and Didemethylated Curcumin with Selenite: Hydrogen Bonding vs Acid-Base Interactions. AB - In this report, the in vitro relative capabilities of curcumin (CCM) and didemethylated curcumin (DCCM) in preventing the selenite-induced crystallin aggregation were investigated by turbidity tests and isothermal titration calorimetry (ITC). DCCM showed better activity than CCM. The conformers of CCM/SeO3(2-) and DCCM/SeO3(2-) complexes were optimized by molecular orbital calculations. Results reveal that the selenite anion surrounded by CCM through the H-bonding between CCM and selenite, which is also observed via IR and NMR studied. For DCCM, the primary driving force is the formation of an acid-base adduct with selenite showing that the phenolic OH group of DCCM was responsible for forming major conformer of DCCM. The formation mechanisms of selenite complexes with CCM or DCCM explain why DCCM has greater activity than CCM in extenuating the toxicity of selenite as to prevent selenite-induced lens protein aggregation. PMID- 26635114 TI - Aspirin Inhibits LPS-Induced Expression of PI3K/Akt, ERK, NF-kappaB, CX3CL1, and MMPs in Human Bronchial Epithelial Cells. AB - This study focused on the effects of aspirin on lipopolysaccharide (LPS)-induced expression of phosphoinositide 3 kinase (PI3K)/protein kinase B (Akt), extracellular signal-regulated protein kinase (ERK), nuclear factor-kappaB (NF kappaB), CX3CL1, and MMPs in human bronchial epithelial cells. Human bronchial epithelial cells were seeded in six-well plates. After 24 h, the cells were classified into six groups: control blank (CK) group; LPS group; PD98059 (ERK inhibitor) (PD) group, treated with LPS + ERK inhibitor; LY294002(PI3K/Akt inhibitor) (LY) group, treated with LPS + PI3K/Akt inhibitor; Aspirin (Asp) group, treated with LPS + aspirin; and Pyrrolidinedithiocarbamic acid (PDTC) group, treated with LPS + NF-kappaB inhibitor. After 4-h treatment, the cells were harvested. Western blot analysis was performed to detect the expression of PI3K/Akt, ERK, NF-kappaB, and CX3CL1. Real-time quantitative PCR (RT-qPCR) was used to determine the gene expression of MMP-7, MMP-9, and MMP-12. Compared to the CK group, expression of PI3K/Akt, ERK, NF-kappaB, and CX3CL1 was significantly increased in the LPS group (P < 0.05). When compared to the LPS group, expression of PI3K/Akt, ERK, NF-kappaB, and CX3CL1 was significantly decreased in the PD group, PDTC group, and Asp group (P < 0.05). In addition, expression of NF-kappaB in the LY group was significantly reduced by comparison with the LPS group (P < 0.05). RT-qPCR: When compared to the LPS group, expression of MMP-7 and MMP-12 was significantly decreased in Asp group (P < 0.05). Expression of MMP-12 was significantly reduced in LY group (P < 0.05). LPS ERK, NF-kappaB-PI3K/Akt, and CX3CL1 signal pathways exist in human bronchial epithelial cells. The PI3K/Akt inhibitor repressed expression of MMP-12. Aspirin inhibited LPS-induced expression of PI3K, Akt, ERK, NF-kappaB, CX3CL1, MMP-7, and MMP-12 in human bronchial epithelial cells. PMID- 26635115 TI - Uncoupling of Vascular Endothelial Growth Factor (VEGF) and Inducible Nitric Oxide Synthase (iNOS) in Gingival Tissue of Type 2 Diabetic Patients. AB - In this study, we investigate the relation between vascular endothelial growth factor (VEGF) and inducible nitric oxide synthase (iNOS) in periodontal disease of diabetic and non-diabetic individuals. We evaluated immunohistochemical VEGF and iNOS expressions in gingival biopsies from healthy individuals (no chronic periodontitis (CP)), patients with periodontitis alone (CP), patients with diabetes alone (DM) and diabetic patients with chronic periodontitis (DM + CP). We found a significant positive correlation between VEGF and iNOS expression in non-diabetic groups, but not in diabetic ones. Periodontal clinical parameters were not found to be significantly correlated with the inflammatory markers in no CP, CP, and DM groups, whereas in DM + CP, positive and significant correlations were found between all the considered periodontal parameters and epithelial VEGF and endothelial iNOS. The uncoupling of VEGF and iNOS expression in diabetic individuals could allow a greater involvement of the markers in the inflammatory process of periodontitis. PMID- 26635116 TI - Induction of the Matrix Metalloproteinase 13 Gene in Bronchial Epithelial Cells by Interferon and Identification of its Novel Functional Polymorphism. AB - Matrix metalloproteinases (MMPs) are a class of extra-cellular and membrane-bound proteases involved in a wide array of physiological and pathological processes including tissue remodeling, inflammation, and cytokine secretion and activation. MMP-13 has been shown to be involved in lung diseases such as acute lung injury, viral infections, and chronic obstructive pulmonary disease; however, the molecular pathogenesis of MMP-13 in these conditions is not well understood. In this study, we investigated the mechanisms and roles of MMP-13 secretion in human small airway epithelial cells (SAECs) and functional polymorphisms of the MMP13 gene. Polyinosinic-polycytidylic acid (poly(I:C)) and interferon beta (IFN-beta) stimulated the secretion of MMP-13 from SAECs by more than several hundred-fold. Stimulation of the secretion by poly(I:C) was abolished by SB304680 (p38 inhibitor), LY294002 (PI3K inhibitor), Janus kinase (JAK) inhibitor I, RNA activated protein kinase (PKR) inhibitor, and Bay 11-7082 (NF-kappaB inhibitor), while stimulation by IFN-beta was inhibited by all except Bay 11-7082. These data suggested that the secretion of MMP-13 was mediated through IFN receptor pathways independently of nuclear factor kappa B (NF-kappaB) and that poly(I:C) stimulated IFN secretion in an NF-kappaB-dependent manner from SAECs, leading to IFN stimulated MMP-13 secretion. Chemical MMP-13 inhibitors and MMP-13 small interfering RNA (siRNA) inhibited IFN-stimulated secretion of interferon gamma inducible protein 10 (IP-10) and regulated on activation, normal T-cell expressed and secreted (RANTES), suggesting that MMP-13 is involved in the secretion of these virus-induced proinflammatory chemokines. We identified a novel functional polymorphism in the promoter region of the MMP13 gene. The MMP13 gene may play important roles in defense mechanisms of airway epithelial cells. PMID- 26635117 TI - Resveratrol overcomes gefitinib resistance by increasing the intracellular gefitinib concentration and triggering apoptosis, autophagy and senescence in PC9/G NSCLC cells. AB - Gefitinib (Gef) provides clinical benefits to non-small cell lung cancer (NSCLC) patients with activating EGFR mutations. However, acquired resistance (AR) is a major obstacle to effective Gef therapy. This study demonstrated that resveratrol (Res) could synergize with Gef to inhibit the proliferation of Gef-resistant NSCLC cells. The underlying mechanisms of synergism were investigated, and the results showed that cotreatment with Gef and Res could inhibit EGFR phosphorylation by increasing intracellular Gef accumulation through the impairment of Gef elimination from PC9/G cells. Consistently, CYP1A1 and ABCG2 expression were inhibited. Meanwhile, the cotreatment significantly induced cell apoptosis, autophagy, cell cycle arrest and senescence accompanied by increased expression of cleaved caspase-3, LC3B-II, p53 and p21. Further studies revealed that autophagy inhibition enhanced apoptosis and abrogated senescence while apoptosis inhibition had no notable effect on cell autophagy and senescence during cotreatment with Gef and Res. These results indicated that in addition to apoptosis, senescence promoted by autophagy contributes to the antiproliferation effect of combined Gef and Res on PC9/G cells. In conclusion, combined treatment with Gef and Res may represent a rational strategy to overcome AR in NSCLC cells. PMID- 26635118 TI - Deep sequencing analysis of the heterogeneity of seed and commercial lots of the bacillus Calmette-Guerin (BCG) tuberculosis vaccine substrain Tokyo-172. AB - BCG, only vaccine available to prevent tuberculosis, was established in the early 20th century by prolonged passaging of a virulent clinical strain of Mycobacterium bovis. BCG Tokyo-172, originally distributed within Japan in 1924, is one of the currently used reference substrains for the vaccine. Recently, this substrain was reported to contain two spontaneously arising, heterogeneous subpopulations (Types I and II). The proportions of the subpopulations changed over time in both distributed seed lots and commercial lots. To maintain the homogeneity of live vaccines, such variations and subpopulational mutations in lots should be restrained and monitored. We incorporated deep sequencing techniques to validate such heterogeneity in lots of the BCG Tokyo-172 substrain without cloning. By bioinformatics analysis, we not only detected the two subpopulations but also detected two intrinsic variations within these populations. The intrinsic variants could be isolated from respective lots as colonies cultured on plate media, suggesting analyses incorporating deep sequencing techniques are powerful, valid tools to detect mutations in live bacterial vaccine lots. Our data showed that spontaneous mutations in BCG vaccines could be easily monitored by deep sequencing without direct isolation of variants, revealing the complex heterogeneity of BCG Tokyo-172 and its daughter lots currently in use. PMID- 26635119 TI - Mother's postnatal stress: an investigation of links to various factors during pregnancy and post-partum. AB - BACKGROUND: Higher levels of parental stress have long-term effects on children's health and could lead to dysfunction in the parent-child interaction. Different background factors can be predictors of high parental stress. AIM: The aim of this study was to examine parental stress among Swedish women and identify different factors linked to women's parental stress. METHOD: About 702 women were recruited to a clinical study and followed up six months after birth. Data were collected by two questionnaires, and 279 women completed the Swedish Parental Stress Questionnaire (SPSQ). FINDINGS: Less than very good mental health and depressive symptoms after birth were strongly associated with parental stress, and the strongest association was found between post-partum depressive symptoms and high levels of stress in the subscale Incompetence. Multiparity was associated with high stress in two subscales, and lower level of education was a protective factor for stress in nearly all subscales. CONCLUSIONS: Depressive symptoms and perceived poor mental health post-partum are the most important factors related to high parental stress. The results point to the importance of identifying and supporting mothers with depressive symptoms, since these women have both mental illness and increased stress. PMID- 26635121 TI - Ultrafast Synthesis of Multifunctional N-Doped Graphene Foam in an Ethanol Flame. AB - A hard template method to prepare N-doped graphene foams (NGF) with superfast template removal was developed through a pyrolyzing commercial polyurethane (PU) sponge coated with graphene oxide (GO) sheets in an ethanol flame. The removal of the template was fast and facile, and could be completed in less than 60 s in an open environment. The synthesized graphene foams consisted of a unique structure of 3D interconnected hollow struts with highly wrinkled surfaces, and the morphology of the hollow struts could be tuned by controlling the GO dispersion concentration. The foams showed high hydrophobicity and were used as absorbents for a variety of organic solvents and oils. The unique NGF structure afforded a high absorption rate and capacity, and a remarkable 98.7% pore volume of the foam could be utilized for absorption of hexane, exhibiting one of the highest capacity values among existing absorptive counterparts. The N-doping brought higher capacitive performance than conventional graphene foams prepared by chemical vapor deposition on nickel foam templates. The NGFs also displayed high elasticity and could recover completely after 50% compressive strain. Owing to easy availability and reduction environment of the flame, complete thermal decomposition of the PU sponge and highly porous open-cell structure, and flame resistance of the graphene foam, the present flame method was demonstrated to be a simple, effective, and ultrafast approach to fabricate ultra-low-density NGFs with good electromechanical response, excellent organic liquid absorption, and high-energy dissipation capabilities. PMID- 26635120 TI - Freeze-thaw Caenorhabditis elegans freeze-thaw stress response is regulated by the insulin/IGF-1 receptor daf-2. AB - BACKGROUND: Adaption to cold temperatures, especially those below freezing, is essential for animal survival in cold environments. Freezing is also used for many medical, scientific, and industrial purposes. Natural freezing survival in animals has been extensively studied. However, the underlying mechanisms remain unclear. Previous studies demonstrated that animals survive in extremely cold weather by avoiding freezing or controlling the rate of ice-crystal formation in their bodies, which indicates that freezing survival is a passive thermodynamic process. RESULTS: Here, we showed that genetic programming actively promotes freezing survival in Caenorhabditis elegans. We found that daf-2, an insulin/IGF 1 receptor homologue, and loss-of-function enhanced survival during freeze-thaw stress, which required the transcription factor daf-16/FOXO and age-independent target genes. In particular, the freeze-thaw resistance of daf-2(rf) is highly allele-specific and has no correlation with lifespan, dauer formation, or hypoxia stress resistance. CONCLUSIONS: Our results reveal a new function for daf-2 signaling, and, most importantly, demonstrate that genetic programming contributes to freezing survival. PMID- 26635122 TI - Management of prosthetic patch infection after CEA. AB - It has been reported that 0.5-1% of patients undergoing carotid endarterectomy with prosthetic patch closure of the arteriotomy will develop patch infection. One third occur within the first 2 months after surgery, while two-thirds occur after >6 months have elapsed. Wound infection and abscess formation is the commonest mode of presentation in early cases, while chronic sinus discharge and false aneurysm formation are the commonest presentations in late cases. The commonest infecting organisms are Staphylococci/Streptococci (90%) and this should be borne in mind when planning antibiotic therapy before cultures are available. Most patch infections present (semi)-electively and patch rupture is relatively rare (10%), thereby enabling the surgeon to undertake careful evaluation of the patients overall clinical and anatomical status, whilst planning the optimal treatment strategy. If necessary, the patient should be transferred to a tertiary center for treatment. This is not an operation to be undertaken by an inexperienced surgeon. Operative planning should involve checking the original operation note (did the patient tolerate carotid clamping under locoregional anesthesia and therefore might tolerate carotid ligation), is there evidence of contralateral cranial nerve lesions (a contraindication to major open surgery) and has the surgeon planned for adequate distal exposure of the internal carotid artery. Patch excision and autologous reconstruction (usually vein) is the current 'gold standard' treatment, but highly selected patients can be successfully treated by less invasive surgery (including insertion of a covered stent). Patch excision and prosthetic reconstruction should be avoided. PMID- 26635123 TI - Gastrointestinal symptoms related to the irritable bowel syndrome - a longitudinal population-based register study. AB - OBJECTIVE: Functional gastrointestinal (GI) symptoms can develop into persistent states often categorised as the irritable bowel syndrome (IBS). In the severe end of the GI symptom continuum, other coexisting symptoms are common. We aimed to investigate the GI symptom continuum in relation to mortality and development of GI diseases, and to examine if coexisting symptoms had an influence on the outcomes. MATERIAL AND METHODS: A longitudinal population-based study comprising two 5-year follow-up studies: Dan-Monica1 (1982-1987) and Inter99 (1999-2004). IBS was defined according to a population-based IBS definition. The pooled cohort (n = 7278) was followed until December 2013 in Central Registries. RESULTS: Fifty one percent had no GI symptoms, 39% had GI symptoms but never fulfilled the IBS definition, 8% had fluctuating IBS and 2% had persisting IBS. There was no significant association between symptom groups and mortality (p = 0.47). IBS and GI symptoms with abdominal pain were significantly associated with development of GI diseases. Only GI symptoms with abdominal pain were associated with development of severe GI diseases (HR: 1.38; 95% CI: [1.06-1.79]). There were no statistically significant interactions between symptom groups and coexisting symptoms in relation to the two outcomes. CONCLUSIONS: GI diseases were seen more frequently, but IBS was not associated with severe GI diseases or increased mortality. Clinicians should be more aware when patients do not fulfil the IBS definition, but continue to report frequent abdominal pain. Coexisting symptoms did not influence mortality and development of GI diseases. PMID- 26635124 TI - Unrecognized indication for robot-assisted cardiac surgery: Patients with acute psychotic disorders. AB - Patients with acute psychotic disorders are often considered as inappropriate candidates for cardiac surgery as well as for other surgical interventions. Post operative care and patient compliance, which are the main problems associated with such patients, are the most important issues for conventional cardiac surgery. Robot-assisted cardiac surgery may be a new solution in this respect. In this report we aimed to present our acute psychotic patient with serious mitral insufficiency secondary to huge atrial myxoma, treated with robotic cardiac surgery. PMID- 26635125 TI - Erratum to: Shenmai injection as an adjuvant treatment for chronic cor pulmonale heart failure: a systematic review and meta-analysis of randomized controlled trials. PMID- 26635126 TI - Exposure to second hand tobacco smoke at home and child smoking at age 11 among British children with and without intellectual disability. AB - BACKGROUND: The exposure of children to second hand tobacco smoke (SHS) is a well established risk factor for a range of adverse health conditions in childhood and later life. Little is known about the extent to which children with intellectual disability (ID) may be exposed to SHS. Our aim in this study was to estimate the risk of childhood exposure to SHS and early experience of smoking among children with and without ID in a nationally representative cohort of British children. METHOD: Secondary analysis of data extracted from the UK's Millennium Cohort Study, a nationally representative sample of over 18,000 UK children born 2000 2002. RESULTS: Children with ID are significantly more likely than their peers to be exposed to SHS and to have themselves experimented with smoking by age 11. Controlling for between-group differences in socio-economic position eliminated the increased risk of exposure to SHS and significantly attenuated, but did not eliminate, increased risk of experimenting with smoking by age 11. CONCLUSIONS: Levels of exposure to SHS among children with ID are typical of those of families of children without ID living in similar socio-economic circumstances. The results lend no support to the hypothesis that increased rates of parental smoking may be associated with any additional 'burden of care' experienced by parents of children with ID. Nevertheless, it will be important to ensure that evidence-based interventions to reduce exposure to SHS are tailored to the specific needs of families supporting children with ID (e.g. through the provision of disability-friendly child care arrangements). PMID- 26635127 TI - Management of acute agitation in Hong Kong and comparisons with Australasia. AB - BACKGROUND: Little is known about the use of sedation drugs for the management of acute agitation in Hong Kong's Accident and Emergency Departments (AEDs) and how it compares with Australasian practice. OBJECTIVE: The aim of this study was to determine drug preferences, clinicians' perceived confidence in management, barriers/gaps in training and perceived usefulness of existing clinical practice guidelines (CPGs) in Hong Kong. METHOD: A validated questionnaire was used, with case vignettes typical of patients presenting to AEDs with acute agitation. The questionnaire was distributed by hand to all trainees and fellows of the Hong Kong College of Emergency Medicine (HKCEM). Two reminders were sent. RESULTS: Of 483 HKCEM members, 280 (58.0% [95% CI 53.5-62.3]) responded. For monotherapy, 46.8% (95% CI 41.0-52.6) of respondents chose haloperidol to manage the undifferentiated patient, followed by midazolam (33.9%, 95% CI 28.6-39.7) and diazepam (13.9%, 95% CI 10.4-18.5). Most respondents (83.6%, 95% CI 78.8-87.5) would not administer combination therapy. Respondents were confident in managing agitation overall. The lack of local/institutional CPGs (55.7%, 95% CI 49.9-61.4) was perceived as an important barrier. Institutional guidelines were considered the most useful CPGs (66.4%, 95% CI 60.7-71.7). Most respondents (72.9%, 95% CI 67.4-77.7) perceived a HKCEM endorsed CPG would be useful. CONCLUSION: Haloperidol and benzodiazepines are frequently used as monotherapy for the management of acute agitation in Hong Kong's AEDs. Management in Hong Kong differs from Australasian practice in that combination therapy is less common and clinicians' choice of sedation drugs are less variable overall. Results suggest that future work on CPG development and training regarding the safe use of combination therapy would be well received. PMID- 26635128 TI - Familial idiopathic basal ganglia calcification: Histopathologic features of an autopsied patient with an SLC20A2 mutation. AB - Idiopathic basal ganglia calcification (IBGC), or Fahr's disease, is a neurological disorder characterized by widespread calcification in the brain. Recently, several causative genes have been identified, but the histopathologic features of the brain lesions and expression of the gene products remain unclear. Here, we report the clinical and autopsy features of a 62-year-old Japanese man with familial IBGC, in whom an SLC20A2 mutation was identified. The patient developed mild cognitive impairment and parkinsonism. A brain CT scan demonstrated abnormal calcification in the bilateral basal ganglia, thalami and cerebellum. An MRI study at this point revealed glioblastoma, and the patient died 6 months later. At autopsy, symmetric calcification in the basal ganglia, thalami, cerebellar white matter and deeper layers of the cerebral cortex was evident. The calcification was observed in the tunica media of small arteries, arterioles and capillaries, but not in veins. Immunohistochemistry using an antibody against type III sodium-dependent phosphate transporter 2 (PiT-2), the SLC20A2 product, demonstrated that astrocytic processes were labeled in several regions in control brains, whereas in the patient, reactivity in astrocytes was apparently weak. Immunoblotting demonstrated a marked decrease of PiT-2 in the patient. There are few autopsy reports of IBGC patients with confirmation of the genetic background. The autopsy features seem informative for better understanding the histogenesis of IBGC lesions. PMID- 26635129 TI - Ventriculo-Bronchial Fistula: An Unusual Cause of Hemoptysis. PMID- 26635130 TI - Identifying delayed left ventricular lateral wall activation in patients with non specific intraventricular conduction delay using coronary venous electroanatomical mapping. AB - BACKGROUND: Delayed left ventricular (LV) lateral wall activation is considered the electrical substrate that characterises patients suitable for cardiac resynchronisation therapy (CRT). Although typically associated with left bundle branch block, delayed LV lateral wall activation may also be present in patients with non-specific intraventricular conduction delay (IVCD). We assessed LV lateral wall activation in a cohort of CRT candidates with IVCD using coronary venous electroanatomical mapping, and investigated whether baseline QRS characteristics on the ECG can identify delayed LV lateral wall activation in this group of patients. METHODS: Twenty-three consecutive CRT candidates with IVCD underwent intra-procedural coronary venous electroanatomical mapping using EnSite NavX. Electrical activation time was measured in milliseconds from QRS onset and expressed as percentage of QRS duration. LV lateral wall activation was considered delayed if maximal activation time measured at the LV lateral wall (LVLW-AT) exceeded 75 % of the QRS duration. QRS morphology, duration, fragmentation, axis deviation, and left anterior/posterior fascicular block were assessed on baseline ECGs. RESULTS: Delayed LV lateral wall activation occurred in 12/23 patients (maximal LVLW-AT = 133 +/- 20 ms [83 +/- 5 % of QRS duration]). In these patients, the latest activated region was consistently located on the basal lateral wall. QRS duration, and prevalence of QRS fragmentation and left/right axis deviation, and left anterior/posterior fascicular block did not differ between patients with and without delayed LV lateral wall activation. CONCLUSION: Coronary venous electroanatomical mapping can be used at the time of CRT implantation to determine the presence of delayed LV lateral wall activation in patients with IVCD. QRS characteristics on the ECG seem unable to identify delayed LV lateral wall activation in this subgroup of patients. PMID- 26635131 TI - Lymph node status of lateral neck compartment in patients with N1b papillary thyroid carcinoma. AB - Conclusion Loco-regional recurrence-free survival was significantly decreased in the papillary thyroid cancer patients with > 6 metastatic lymph nodes and a lymph node ratio > 0.22. Also, the risk of lung metastasis was significantly increased in cases with bilateral neck node metastases. Objective This study focused on the metastatic lymph node status of the lateral neck compartment to understand its prognostic significance for loco-regional recurrence and distant metastasis. Methods Between January 2004 and December 2009, 1040 patients were diagnosed with papillary thyroid cancer and underwent treatment. Results In a multivariate analysis, sex, the number of metastatic lymph nodes, and the lymph node ratio was significantly associated with loco-regional recurrence. The sensitivity/specificity of > 6 metastatic lymph nodes for predicting recurrence was 64.0%/69.7%. The 5-year loco-regional recurrence-free survival of patients with 0-6 metastatic lymph nodes and > 6 metastatic lymph nodes were 93.4% and 79.2%, respectively. The 5-year loco-regional recurrence-free survival of patients with a lymph node ratio <= 0.22 and a lymph node ratio > 0.22 were 97.1% and 78.8%, respectively. In the multivariate analysis, only bilateral neck node metastases were significantly associated with lung metastasis. PMID- 26635132 TI - Determinants of patient preferences for total knee replacement: African-Americans and whites. AB - INTRODUCTION: Patient preferences contribute to marked racial disparities in the utilization of total knee replacement (TKR). The objectives of this study were to identify the determinants of knee osteoarthritis (OA) patients' preferences regarding TKR by race and to identify the variables that may mediate racial differences in willingness to undergo TKR. METHODS: Five hundred fourteen White (WH) and 285 African-American (AA) patients with chronic knee pain and radiographic evidence of OA participated in the study. Participants were recruited from the community, an academic medical center, and a Veterans Affairs hospital. Structured interviews were conducted to collect socio-demographics, disease severity, socio-cultural determinants, and treatment preferences. Logistic regression was performed, stratified by race, to identify determinants of preferences. Clinical and socio-cultural factors were entered simultaneously into the models. Stepwise selection identified factors for inclusion in the final models (p < 0.20). RESULTS: Compared to WHs, AAs were less willing to undergo TKR (80 % vs. 62 %, respectively). Better expectations regarding TKR surgery outcomes determined willingness to undergo surgery in both AAs (odds ratio (OR) 2.08, 95 % confidence interval (CI) 0.91-4.79 for 4(th) vs. 1(st) quartile) and WHs (OR 5.11, 95 % CI 2.31-11.30 for 4(th) vs. 1(st) quartile). Among AAs, better understanding of the procedure (OR 1.80, 95 % CI 0.97-3.35), perceiving a short hospital course (OR 0.81, 95 % CI 0.58-1.13), and believing in less post-surgical pain (OR 0.73, 95 % CI 0.39-1.35) and walking difficulties (OR 0.66, 95 % CI 0.37 1.16) also determined willingness. Among WHs, having surgical discussion with a physician (OR 1.96, 95 % CI 1.05-3.68), not ever receiving surgical referral (OR 0.56, 95 % CI 0.32-0.99), and higher trust in the healthcare system (OR 1.58, 95 % CI 0.75-3.31 for 4(th) vs. 1(st) quartile) additionally determined willingness. Among the variables considered, only knowledge-related matters pertaining to TKR attenuated the racial difference in knee OA patients' treatment preference. CONCLUSIONS: Expectations of surgical outcomes influence preference for TKR in all patients, but clinical and socio-cultural factors exist that shape marked racial differences in preferences for TKR. Interventions to reduce or eliminate racial disparities in the utilization of TKR should consider and target these factors. PMID- 26635133 TI - Separation and identification of a novel tadalafil analogue adulterant in a dietary supplement. AB - A novel tadalafil analogue found in a dietary supplement by routine drug adulteration screening was isolated by column chromatography and HPLC. On the basis of extensive 1D- and 2D-nuclear magnetic resonance (NMR), infrared (IR) and mass spectral analyses, the structure of the new compound YJ-02 was established as 6-(benzo[d][1,3]dioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-(1E,2E)-3 phenylallylidene)amino)pyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione. Its common name is N-phenylpropenyltadalafil. PMID- 26635134 TI - A novel strategy for forensic age prediction by DNA methylation and support vector regression model. AB - High deviations resulting from prediction model, gender and population difference have limited age estimation application of DNA methylation markers. Here we identified 2,957 novel age-associated DNA methylation sites (P < 0.01 and R(2) > 0.5) in blood of eight pairs of Chinese Han female monozygotic twins. Among them, nine novel sites (false discovery rate < 0.01), along with three other reported sites, were further validated in 49 unrelated female volunteers with ages of 20 80 years by Sequenom Massarray. A total of 95 CpGs were covered in the PCR products and 11 of them were built the age prediction models. After comparing four different models including, multivariate linear regression, multivariate nonlinear regression, back propagation neural network and support vector regression, SVR was identified as the most robust model with the least mean absolute deviation from real chronological age (2.8 years) and an average accuracy of 4.7 years predicted by only six loci from the 11 loci, as well as an less cross-validated error compared with linear regression model. Our novel strategy provides an accurate measurement that is highly useful in estimating the individual age in forensic practice as well as in tracking the aging process in other related applications. PMID- 26635135 TI - Community Stroke Rehabilitation: How Do Rural Residents Fare Compared With Their Urban Counterparts? AB - BACKGROUND: Rural living has been demonstrated to have an effect on a person's overall health status, and rural residing individuals often have decreased access to health and specialized rehabilitation services. AIM: The aim of this study was to determine if there are differences in recovery from stroke between urban and rural-dwelling stroke survivors accessing an in-home, community-based, interdisciplinary, stroke rehabilitation program. METHODS: Data from a cohort of 1222 stroke survivors receiving care from the Community Stroke Rehabilitation Teams between January 2009 and June 2013 was analyzed. This program delivers stroke rehabilitation care directly in a person's home and community. Functional and psychosocial outcomes were evaluated at baseline, discharge, and six -month follow-up. A series of multiple linear regression analyses was performed to determine if rural versus urban status was a significant predictor of discharge and 6-month health outcomes. RESULTS: The mean age of the rural cohort was 68.8 (+/-13.1) years (53.6% male), and the urban cohort was 68.4 (+/-13.0) years (44.8% male). A total of 278 (35.4%) individuals were classified as living in a rural area using the Rurality Index for Ontario. In multivariate linear regression analysis, no significant differences on the Functional Independence Measure, the Stroke Impact Scale, the Hospital Anxiety and Depression Scale, or the Reintegration to Normal Living Index were found between urban and rural cohorts. CONCLUSIONS: When provided with access to a home-based, specialized stroke rehabilitation program, rural dwelling stroke survivors make and maintain functional gains comparable to their urban-living counterparts. PMID- 26635137 TI - Why oral opioids may not be effective in a subset of chronic pain patients. AB - OBJECTIVE: To identify possible underlying causes of poor oral opioid effectiveness. METHODS: Ninety-five (95) adults who were referred for evaluation and medical management of their intractable pain were screened to determine if oral opioids provided enough pain relief to physically and mentally function and carry out activities of daily living. A clinical evaluation included history, physical examination, cytochrome P450 enzyme testing and a hydromorphone injection to help confirm lack of oral opioid effectiveness. RESULTS: Twenty (20; 21.1%) of the 95 patients reported that three or more oral opioids had not provided enough pain relief to allow them to mentally and physically function and carry out activities of daily living. Patients all reported some typical symptoms of malabsorption including nausea and steatorrhea, and 14 (70.0%) reported that they had observed undigested medication in their stools. Fifteen (15; 75.0%) had experienced pain relief with an injectable opioid. Two major causes for lack of oral opioid effectiveness were apparent: (1) gastrointestinal disorder (11; 55.0%) and (2) cytochrome P450 enzymatic defects (9; 45.0%). In addition to these basic causes, a number of other possible contributing factors were identified which included abdominal, pelvic and spine surgeries, traumatic brain and neck injury, and autoimmune disorders. CONCLUSIONS: There is a group of intractable pain patients who do not effectively metabolize oral opioids. Although gastrointestinal disease and cytochrome P450 enzymatic defects appeared to be dominant causes of oral opioid ineffectiveness, there were other possible contributing factors such as abdominal, pelvic and spine surgeries, head and neck trauma, and autoimmune disease. Pain patients who report poor oral opioid effectiveness should be evaluated for the presence of underlying pathologic conditions which may interfere with oral opioid metabolism and, if found, be considered for nonoral opioid treatment. PMID- 26635136 TI - Surgical Ventricular Entry is a Key Risk Factor for Leptomeningeal Metastasis of High Grade Gliomas. AB - Leptomeningeal metastasis (LM) of high grade gliomas (HGG) can lead to devastating disease courses. Understanding of risk factors for LM is important to identify patients at risk. We reviewed patient records and magnetic resonance imaging (MRI) of all patients with a first diagnosis of HGG who underwent surgery in our institution between 2008 and 2012. To assess the influence of potential risk factors for LM and the impact of LM on survival multivariate statistics were performed. 239 patients with a diagnosis of HGG and at least 6 months of MRI and clinical follow-up were included. LM occurred in 27 (11%) patients and was symptomatic in 17 (65%). A strong correlation of surgical entry to the ventricle and LM was found (HR: 8.1). Ventricular entry was documented in 137 patients (57%) and LM ensued in 25 (18%) of these. Only two (2%) of 102 patients without ventricular entry developed LM. Median overall survival of patients after diagnosis of LM (239 days) was significantly shorter compared to patients without LM (626 days). LM is a frequent complication in the course of disease of HGG and is associated with poor survival. Surgical entry to the ventricle is a key risk factor for LM. PMID- 26635138 TI - Data on trial of anticoagulant is to be reanalyzed after discovery that investigators used faulty device. PMID- 26635140 TI - qsubsec: a lightweight template system for defining sun grid engine workflows. AB - The Sun Grid Engine (SGE) high-performance computing batch queueing system is commonly used in bioinformatics analysis. Creating re-usable scripts for the SGE is a common challenge. The qsubsec template language and interpreter described here allow researchers to easily create generic template definitions that encapsulate a particular computational job, effectively separating the process logic from the specific run details. At submission time, the generic template is filled in with specific values. This system provides an intermediate level between simple scripting and complete workflow management tools. AVAILABILITY AND IMPLEMENTATION: Qsubsec is open-source and is available at https://github.com/alastair-droop/qsubsec CONTACT: a.p.droop@leeds.ac.uk SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26635139 TI - An integrative somatic mutation analysis to identify pathways linked with survival outcomes across 19 cancer types. AB - MOTIVATION: Identification of altered pathways that are clinically relevant across human cancers is a key challenge in cancer genomics. Precise identification and understanding of these altered pathways may provide novel insights into patient stratification, therapeutic strategies and the development of new drugs. However, a challenge remains in accurately identifying pathways altered by somatic mutations across human cancers, due to the diverse mutation spectrum. We developed an innovative approach to integrate somatic mutation data with gene networks and pathways, in order to identify pathways altered by somatic mutations across cancers. RESULTS: We applied our approach to The Cancer Genome Atlas (TCGA) dataset of somatic mutations in 4790 cancer patients with 19 different types of tumors. Our analysis identified cancer-type-specific altered pathways enriched with known cancer-relevant genes and targets of currently available drugs. To investigate the clinical significance of these altered pathways, we performed consensus clustering for patient stratification using member genes in the altered pathways coupled with gene expression datasets from 4870 patients from TCGA, and multiple independent cohorts confirmed that the altered pathways could be used to stratify patients into subgroups with significantly different clinical outcomes. Of particular significance, certain patient subpopulations with poor prognosis were identified because they had specific altered pathways for which there are available targeted therapies. These findings could be used to tailor and intensify therapy in these patients, for whom current therapy is suboptimal. AVAILABILITY AND IMPLEMENTATION: The code is available at: http://www.taehyunlab.org CONTACT: jhcheong@yuhs.ac or taehyun.hwang@utsouthwestern.edu or taehyun.cs@gmail.com SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26635141 TI - rcellminer: exploring molecular profiles and drug response of the NCI-60 cell lines in R. AB - PURPOSE: The rcellminer R package provides a wide range of functionality to help R users access and explore molecular profiling and drug response data for the NCI 60. The package enables flexible programmatic access to CellMiner's unparalleled breadth of NCI-60 data, including gene and protein expression, copy number, whole exome mutations, as well as activity data for ~21K compounds, with information on their structure, mechanism of action and repeat screens. Functions are available to easily visualize compound structures, activity patterns and molecular feature profiles. Additionally, embedded R Shiny applications allow interactive data exploration. AVAILABILITY AND IMPLEMENTATION: rcellminer is compatible with R 3.2 and above on Windows, Mac OS X and Linux. The package, documentation, tutorials and Shiny-based applications are available through Bioconductor (http://www.bioconductor.org/packages/rcellminer); ongoing updates will occur according to the Bioconductor release schedule with new CellMiner data. The package is free and open-source (LGPL 3). CONTACT: lunaa@cbio.mskcc.org or vinodh.rajapakse@nih.gov. PMID- 26635142 TI - Efficacy of beta-mannanase supplementation to corn-soya bean meal-based diets on growth performance, nutrient digestibility, blood urea nitrogen, faecal coliform and lactic acid bacteria and faecal noxious gas emission in growing pigs. AB - A study was conducted to determine the efficacy of beta-mannanase supplementation to a diet based on corn and soya bean meal (SBM) on growth performance, nutrient digestibility, blood urea nitrogen (BUN), faecal coliforms and lactic acid bacteria, and noxious gas emission in growing pigs. A total of 140 pigs [(Landrace * Yorkshire) * Duroc; average body weight 25 +/- 3 kg] were randomly allotted to a 2 * 2 factorial arrangement with dietary treatments consisting of hulled or dehulled SBM without or with supplementation of 400 U beta mannanase/kg. During the 6 weeks of experimental feeding, beta-mannanase supplementation had no effect on body weight gain, feed intake and gain:feed (G:F) ratio. Compared with dehulled SBM, feeding hulled SBM caused an increased feed intake of pigs in the entire trial (p = 0.05). The G:F ratio was improved in pigs receiving dehulled SBM (p < 0.05). Dietary treatments did not influence the total tract digestibility of dry matter, nitrogen and gross energy. Enzyme supplementation reduced (p < 0.05) the population of faecal coliforms and tended to reduce the NH3 concentration after 24 h of fermentation in a closed box containing faecal slurry. Feeding hulled SBM tended to reduce NH3 emission on days 3 and 5 of fermentation. In conclusion, mannanase supplementation had no influence on growth performance and nutrient digestibility but showed a positive effect on reducing coliform population and tended to reduce NH3 emission. Dehulled SBM increased G:F ratio and hulled SBM tended to reduce NH3 emission. PMID- 26635143 TI - Dyotropic rearrangement of bridgehead substituents in closed dithienylethenes; conjugated verses non-conjugated analogues. AB - Type I dyotropic rearrangement reactions of halogen and methyl substituents at the bridgehead position of diarylethenes and dihydroarylethenes have been studied through density functional theory at B3LYP/6-31+G(d) level. The calculations have been performed to explore the dyotropic rearrangement as a possible factor for the elusive nature of halogenated dithienylethenes (closed). The dyotropic rearrangement process in closed dithienylethenes is then compared with the dihydro analogues. Moreover, the effect of hetero atom and conjugation is also explored through quantum mechanical calculations. PMID- 26635144 TI - De novo and comparative transcriptome analysis of cultivated and wild spinach. AB - Spinach (Spinacia oleracea L.) is an economically important green leafy vegetable crop. In this study, we performed deep transcriptome sequencing for nine spinach accessions: three from cultivated S. oleracea, three from wild S. turkestanica and three from wild S. tetrandra. A total of approximately 100 million high quality reads were generated, which were de novo assembled into 72,151 unigenes with a total length of 46.5 Mb. By comparing sequences of these unigenes against different protein databases, nearly 60% of them were annotated and 50% could be assigned with Gene Ontology terms. A total of 387 metabolic pathways were predicted from the assembled spinach unigenes. From the transcriptome sequencing data, we were able to identify a total of ~320,000 high-quality single nucleotide polymorphisms (SNPs). Phylogenetic analyses using SNPs as well as gene expression profiles indicated that S. turkestanica was more closely related to the cultivated S. oleracea than S. tetrandra. A large number of genes involved in responses to biotic and abiotic stresses were found to be differentially expressed between the cultivated and wild spinach. Finally, an interactive online database (http://www.spinachbase.org) was developed to allow the research community to efficiently retrieve, query, mine and analyze our transcriptome dataset. PMID- 26635145 TI - Busulfan and cyclosphamide induce liver inflammation through NLRP3 activation in mice after hematopoietic stem cell transplantation. AB - The aim of this study was to evaluate the role of NLRP3 inflammasome on BU/CY induced liver inflammation in mice after HSCT. HSCT mice model was established through infusion of 5 * 10(6) bone marrow mononuclear cells after conditioned with BU/CY. On day 7, 14, 21 and 28 after HSCT, mice were sacrificed for analysis of liver inflammation, cytokine secretion, NLRP3 expression and caspase-1 activation as well as release of ATP and high-mobility group protein B1 (HMGB1). Furthermore, NLRP3 selective inhibitor (BAY 11-7082) was administrated into mice after HSCT to evaluate its effects on liver inflammation. Severe liver inflammation and damage with elevated secretion of IL-1beta and IL-18 were found in mice after HSCT. Meanwhile, elevated expressions of NLRP3 and caspase-1 activation in liver were found. In addition, increased release of ATP and HMGB1 were observed. Selective inhibition of NLRP3 decreased caspase-1 activation and secretion of IL-1beta and IL-18. Furthermore, NLRP3 inhibition also reduced infiltration of macrophages and neutrophils and improved liver function. In conclusion, NLRP3 was involved in BU/CY-induced liver inflammation after HSCT and selectively inhibited it ameliorated liver inflammation and improved liver function, suggesting targeting NLRP3 might be a new approach in the prophylaxis of liver inflammation after HSCT. PMID- 26635147 TI - The Relationship Between Concussion Knowledge and the High School Athlete's Intention to Report Traumatic Brain Injury Symptoms. AB - Sports-related concussion or traumatic brain injury (TBI) is a frequent occurrence among high school athletes. Long-term and short-term effects of TBI on the athlete's developing brain can be minimized if the athlete reports and is effectively treated for TBI symptoms. Knowledge of concussion symptoms and a school culture of support are critical in order to promote the student's intention to report TBI symptoms. The purpose of this systematic review is to examine the relationship between the high school athlete's concussion knowledge and an intention to report TBI symptoms. One hundred eleven articles were retrieved and four articles met established criteria and were included in this systematic review. A link appears to exist between high school athlete concussion knowledge and an intention to report TBI symptoms. School nurses can provide a supportive environment and concussion knowledge to the high school athlete in order to ultimately facilitate TBI symptom reporting. PMID- 26635148 TI - Cardiovascular dynamics after acute and long-term alpha- and beta- adrenoceptor blockade at rest, supine and standing, and during exercise. AB - 1 After acute intravenous administration labetalol reduced mean values for BP, total peripheral resistance, heart rate and cardiac output. All changes were more pronounced during bicycle exercise. 2 After a mean duration of 20 months' treatment with oral labetalol the haemodynamic findings were broadly similar except for a more marked reduction in the total peripheral resistance and cardiac output had returned to pretreatment level due to an increased stroke volume which had counter balanced the reduction in heart rate. These changes occurred at rest, in the erect position and during exercise but the reductions in BP and peripheral resistance were most marked during exercise. 3 Left ventricular filling pressures and stroke volume/filling pressure ratios were not significantly altered after intravenous labetalol compared with pretreatment values. 4 Systolic BP x heart rate product was lowered particularly during exercise after both intravenous and oral labetalol. 5 After long-term oral labetalol, the most striking haemodynamic change was in the elevated resting stroke volume supine and standing. PMID- 26635146 TI - Optimal heating condition of ethylene-vinyl acetate co-polymer mouthguard sheet in vacuum-pressure formation. AB - BACKGROUND: The goal of the present study was to examine the thickness of mouthguards molded under a variety of heating conditions to clarify suitable conditions during vacuum-pressure forming of ethylene vinyl acetate sheets. MATERIALS AND METHODS: Mouthguards were fabricated using ethylene vinyl acetate (EVA) sheets (thickness: 4.0 mm) using a vacuum-pressure forming machine. The sheet was pressed against the working model, followed by vacuum forming for 10 s and compression molding for 2 min. Three heating conditions were investigated in which the sheet was molded when the center of the softened sheet sagged 10 mm, 15 mm, or 20 mm below the clamp (H-10, H-15, or H-20 respectively). The temperature of the sheet surface was measured using a radiation thermometer under each heating condition. The thickness of the mouthguard sheets after fabrication was determined for the incisal portion (incisal edge and labial surface) and molar portion (cusp and buccal surface), and dimensional measurements were obtained using a measuring device. Differences in thickness due to the heating condition of the sheets were analyzed by one-way analysis of variance and Bonferroni's multiple comparison tests. RESULTS: The temperature difference between the heated and non-heated surfaces was lowest under H-15. The thickness differences at incisal edge, labial surface, and cusp were determined. The thicknesses for H-10 and H-15 were greater than that for H-20, and the thicknesses for H-10 and H-15 were equivalent at all measurement points. No differences in thickness at the buccal surface were observed for the various heating conditions. CONCLUSION: The present study demonstrated that a sagging distance of 15 mm provided the most suitable forming process. The results of the present study provide a standard heating condition for EVA sheet forming. PMID- 26635149 TI - Comparative haemodynamic effects of labetalol, timolol, prazosin and the combination of tolamolol and prazosin. PMID- 26635150 TI - Effect of an alpha- and beta-adrenoceptor-blocking agent (labetalol) on haemodynamics in hypertension. AB - 1 The effect of an intravenous bolus of labetalol (0.6-1.6 mg/kg body weight) on central and peripheral haemodynamics was studied in nine subjects with essential hypertension and in eleven subjects with chronic renal disease and hypertension. 2 The BP reduction amounting to 20/13 mmHg was entirely due to the lowering of the total peripheral vascular resistance. This also included the vascular resistance in the muscles. 3 This peripheral vasodilatation was not counteracted by a reflex increase of the cardiac output. 4 The reflex tachycardia and overshoot of BP in Valsalva's manoeuvre were largely abolished. 5 Central and peripheral venous BPs, vascular volume of the forearm and venous distensibility did not show any significant change after treatment with labetalol. 6 In spite of the lowering of the vascular resistance of the forearm by labetalol, forearm blood flow was not significantly affected due to the parallel decrease in the perfusion pressure. 7 Plasma renin activity fell after labetalol in all instances. PMID- 26635151 TI - Effect of labetalol on continuous ambulatory blood pressure. AB - 1 The hypotensive action of labetalol was evaluated during 24 h by continuous intra-arterial ambulatory monitoring in 14 patients. The dose used ranged from 300-1800 mg daily. 2 The drug caused a significant reduction of systolic BP in 19 and diastolic BP in 20 of the 24 h of monitoring. Heart rate was also reduced but less markedly than BP. 3 The rapid early morning increase in BP was also effectively controlled. 4 The mild pre-waking increase in BP was not significantly reduced. 5 Labetalol treatment reduced the variation in systolic BP from the lowest observed quarter-hourly mean as compared with pre- treatment values. 6 The quarter hourly mean values were consistently smooth and revealed no sudden variations which might have resulted from postural hypotension. PMID- 26635152 TI - Interdose control of beta-blockade and arterial blood pressure during chronic oral labetalol treatment. AB - 1 The pharmacological and therapeutic effects of labetalol were investigated during an 8 h interdose period of chronic oral therapy in six patients with essential hypertension. 2 Peak plasma labetalol concentrations were observed 2 h after the morning oral dose, and subsequent decline was mono exponential. 3 Beta adrenoceptor blockade paralleled the changes in labetalol concentration and was maximal 2 and 4 h after the oral dose. 4 Resting supine systolic BP rose significantly during the interdose period, but no change occurred in diastolic BP. 5 Ambulatory intra-arterial BP studies in a further six patients with essential hypertension controlled with labetalol did not confirm the increase in BP during an 8 h interdose period. PMID- 26635153 TI - Monotherapy with labetalol for hypertensive patients with normal and impaired renal function. AB - 1 Labetalol was given to 41 hypertensive patients in a divided dosage of 150 2,400 mg daily for periods ranging from 1-64 months. 2 Monotherapy with labetalol was adequate in 12 out of 19 patients with essential hypertension and in 15 out of the 22 with renal hypertension. 3 Following a single dose of labetalol 200 mg orally a hypotensive response was seen between 1.5 and 2 hours. 4 In the doses used there was no exercise or postural hypotension. 5 No reduction in overall renal function attributable to labetalol was seen. PMID- 26635154 TI - Labetalol in the treatment of patients with hypertension and renal function impairment. PMID- 26635155 TI - Labetalol in the treatment of a patient with phaechromocytoma: a case report. PMID- 26635156 TI - Labetalol in severe and resistant hypertension. AB - 1 The efficacy of labetalol in the treatment of severe hypertension (diastolic greater than or equal to 115 mm Hg) was studied retrospectively. Ten patients were followed for more than 6 months. At 6 months, eight were well controlled and the mean dose in those was 975 mg daily. Four of these were receiving labetalol alone; two were on labetalol and diuretic only. 2 Three patients were resistant to doses of 1600, 1800 and 2400 mg daily respectively; two of these were controlled with increased doses of vasodilator drugs. In two cases labetalol had produced large falls in the standing BP while not influencing the supine BP. 3 Three other resistant patients were seen, of whom one merely required an increase in dose to 2200 mg daily and the addition of a diuretic. Both the others were elderly, had severe vascular disease, and suffered disabling postural hypotension on a dose of labetalol which did not influence the supine BP. 4 Labetalol can control severe hypertension. There remain patients whose supine BP is not influenced by a dose of labetalol which produces marked postural hypotension. PMID- 26635157 TI - A comparative study of methyldopa and labetalol in the treatment of hypertension. AB - 1 Twenty patients with essential hypertension completed a double-blind, dose tritrated, cross-over comparison of methyldopa and labetalol. 2 Average lying BPs (systolic/diastolic) were reduced by 28/15 mmHg with methyldopa and by 23/15 mmHg with labetalol. 3 Average standing BPs (systolic/diastolic) were reduced by 29/14 mmHg with methyldopa and by 29/15 mmHg with labetalol. 4 Both lying and standing heart rates were reduced with labetalol. 5 It is concluded that the antihypertensive properties of labetalol and methyldopa are similar but that larger patient populations are needed to study the relative incidence of subjective adverse effects. PMID- 26635158 TI - Mean steady-state plasma concentrations of labetalol in patients undergoing antihypertensive therapy. AB - 1 Mean steady-state plasma concentrations of labetalol (labetalol Css) in 17 hypertensive patients undergoing chronic treatment with this drug, have been examined in relation to dose, fall in BP, and beta- blockade. 2 A significant relationship (rs = 0.81, P less than 0.001) was observed between labetalol Css and daily dose. 3 No correlation was found between labetalol Css and antihypertensive response. 4 In thirteen patients, there seemed to be significant relationship between labetalol Css and beta-blockade (rs = 0.72, P less than 0.005). In three patients, the degree of beta-blockade was disproportionate to the drug concentration. PMID- 26635159 TI - Pharmacokinetics and pharmacodynamic studies of labetalol in hypertensive subjects. AB - 1 The pharmacokinetics of labetalol were studied in twelve hypertensive patients, ten of whom were not receiving other therapy. 2 Following intravenous administration there was a three- to fourfold variation in terminal elimination half-life, volume of distribution and total plasma clearance. The mean elimination half-life was 3.25 hours. 3 Following oral administration the drug was absorbed rapidly. Systemic availability varied from 11-86% (mean 33%). 4 Plasma levels correlated poorly with the acute effect on BP, raising the possibility of labetalol acting in a deep tissue compartment or alternatively an active metabolite contributing to its effect. PMID- 26635160 TI - A double-blind crossover comparison of pindolol, metoprolol, atenolol and labetalol in mild to moderate hypertension. AB - 1 This study was designed to compare in a double-blind randomized crossover trial, atenolol, labetalol, metoprolol and pindolol. Considerable differences in dose (atenolol 138 +/- 13 mg daily; labetalol 308 +/- 34 mg daily; metoprolol 234 +/- 22 mg daily; and pindolol 24 +/-2 mg daily were required to produce similar antihypertensive effects. 3 The overall incidence of side-effects was similar with atenolol, metoprolol and pindolol but was slightly less with labetalol. Sleep disturbances and abnormal dreaming patterns were most frequent with pindolol. 4 There was a significantly greater fall in pulse rate during atenolol and metoprolol treatment periods. PMID- 26635161 TI - A long-term study of labetalol in general practice. AB - 1 Forty-one patients with mild to moderate hypertension have been treated with labetalol for up to 5 years. 2 Mean BP before treatment was 180/107 mm Hg, after 2-3 yr treatment was 136/81 mmHg and after 5 yr was 136/74 mmHg. 3 One patient developed a licheniform rash and two patients have died of myocardial infarction. No other side-effects, not already observed in a previously reported double-blind trial, have emerged. PMID- 26635162 TI - Long-term treatment of hypertension with labetalol. AB - 1 Thirty-two hypertensive patients have been treated with labetalol for periods of up to 7 years. 2 Ten patients observed for 6 years from time of stabilization of dosage, did not show any tolerance to labetalol. 3 Postural and exercise hypotension were not seen in these patients over this prolonged follow-up, although they were seen in other patients given over 2 g labetalol daily. PMID- 26635163 TI - A multicentre open trial of labetalol in New Zealand. AB - 1 In a multicentre open trial, labetalol was given to 128 patients in ten centres. Forty-three patients had not previously received antihypertensive therapy; the remainder (85 patients) had been on antihypertensive therapy with either unsatisfactory BP control or troublesome side-effects. 2 Thirty-two patients were withdrawn from the trial in the first 6 months of therapy, 24 (19% of the total) because of side-effects. 3 Control of BP was generally satisfactory or considerably improved. Other drugs (usually a diuretic) had to be added in 23 patients. 4 There was an abnormality of liver function in one patient; otherwise there were no biochemical or haematological problems. PMID- 26635164 TI - A comparison and an investigation of a potential synergistic effect of labetalol and bethanidine in patients with mild hypertension. AB - 1 The effects of labetalol, bethanidine and combined treatment with both drugs were compared in a within-patient randomized cross-over study in mild essential hypertension. Attention was directed to whether or not labetalol and bethanidine differed in their pattern of effect on arterial BP and whether evidence of synergism was apparent. 2 At the doses used labetalol significantly lowered systolic and diastolic BPs and heart rate lying, sitting, standing and after exercise. The dose of bethanidine used did not affect heart rate significantly while lowering systolic and diastolic BPs only after exercise and less clearly on standing. Combined treatment lowered BPs on standing and after exercise and heart rate after exercise. 3 The type and frequency of side-effects were similar with bethanidine and labetalol but were much less with combined treatment. 4 No evidence of synergism was observed. PMID- 26635165 TI - Acute management of severe hypertension with oral labetalol. AB - 1 Six previously untreated emergency admissions to hospital with severe hypertension were given oral treatment with labetalol. 2 Pre-treatment diastolic BP exceeded 130 mmHg, and clinical evidence of either accelerated hypertension or encephalopathy was present. 3 Hypotensive response after treatment followed two patterns. 4 Quick-responders (n = 3) showed a sharp fall in BP to normal levels within 2 h, which was subsequently sustained for 10 or more hours. The daily dose of labetalol eventually required to achieve good BP control in this group was relatively low: 600-1200 mg. 5 Slow-responders (n = 3) showed a gradual, less marked fall in BP, which was sustained for many hours. These patients required further doses of labetalol to reduce BP to normal. The eventual daily dose of labetalol that ensured good BP control was high: 1200-2400 mg. 6 Heart rate was little changed by treatment. 7 Complications or side-effects were not observed. PMID- 26635166 TI - Comparison of effects on cerebral blood flow of rapid reduction in systemic arterial pressure by diazoxide and labetalol in hypertensive patients: preliminary findings. AB - 1 Diazoxide 300 mg and labetalol 150 mg were each injected intravenously on separate occasions into five patients with essentail hypertension. The reduction in BP caused by labetalol was slightly greater than that produced by diazoxide. 2 In contrast the reduction in cerebral blood flow (CBF) by labetalol was not statistically significant, whereas diazoxide gave a greater and statistically significant reduction in CBF. 3 These observations suggest that labetalol may have an advantage over diazoxide for the rapid reduction in BP. PMID- 26635167 TI - Treatment of severe hypertension by repeated bolus injections of labetalol. PMID- 26635168 TI - Open evaluation of labetalol in the treatment of angina pectoris occurring in hypertensive patients. AB - 1 In nine hypertensive subjects with angina pectoris, labetalol diminished the incidence of chest pain occurring spontaneously or induced by exercise. 2 Labetalol lowered BP in all subjects. 3 Exercise tolerance at maximum levels was increased by labetalol. 4 Improved cardiac function by labetalol may be related to decreased afterload on the left ventricle, and diminished oxygen utilization by the myocardium. PMID- 26635169 TI - Use of labetalol in the treatment of severe hypertension during pregnancy. AB - 1 Labetalol, a hypotensive agent combining alpha- and beta-adrenoceptor antagonist properties, was used to treat severe hypertensive disease complicating pregnancy. 2 Effective reduction in BP was achieved in all but 3 of the 25 patients treated. Careful monitoring of feto-placental function was undertaken to ensure the maintenance of fetal well-being. Maternal and fetal side-effects were minimal and it was not necessary to discontinue the drug in any patient. 3 Labetalol was estimated in the cord blood of the fetus at delivery as well as in the breast milk of mothers on day 3 post partum. There were no adverse effects of the drug on the infants and significant hypotension did not occur. 4 The reults suggest that labetalol has a direct action on fetal lung maturation and this, together with its effective hypotensive effect, contributes to the low perinatal mortality (3.5%) observed. 5 Oculotoxicity due to the labetalol was not observed in the infants delivered. 6 It is concluded that the efficient hypotensive action of labetalol, together with apparent freedom from maternal and fetal side- effects, and consequent improved perinatal mortality, suggest that it is a suitable drug for use in pregnancy complicated by hypertension. PMID- 26635171 TI - Use of labetalol during halothane anaesthesia. PMID- 26635170 TI - Use of labetalol and methyldopa in pregnancy-induced hypertension. AB - 1 Nineteen pregnant patients whose mean arterial pressure (MAP) was persistently greater than or equal to 103.3 mmHg were given labetalol or methyldopa. 2 Singificant falls (P less than 0.001) in BP only occurred in the group treated with labetalol, and daily BP control was better in this group. 3 Two severely hypertensive patients were successfully treated with intravenous labetalol. 4 There was a higher incidence of spontaneous labour in the labetalol group and a significant difference (P less than 0.05) in the Bishop score of the cervix between the two groups. 5 There were no apparent detrimental effects on the foetus antenatally, during labour or post partum. 6 Slight breathlessness in one patient treated with labetalol was the only side-effect observed but drowsiness, headache and postural hypotension were reported in patients receiving methyldopa. PMID- 26635172 TI - Use of labetalol during hypotensive anaesthesia and in the management of phaeochromocytoma. AB - 1 The circulatory effects of labetalol have been studied in 88 patients undergoing plastic surgery, 8 patients with carcinoma of the breast, 10 with carcinoma in the head and neck, and in 2 patients with phaeochromocytoma, each anaesthetized twice. 2 The use of labetalol intravenously produced hypotension and a bloodless operating field in patients undergoing plastic surgery and in those undergoing radical surgery for the removal of carcinoma. 3 Two patients with phaeochromocytoma pre-treated with oral labetalol before anaesthesia, had well controlled BPs and heart rates during surgery, although in one instance additional intravenous labetalol was required. 4 Pre-operative preparation of patients with phaeochromocytoma with labetalol seems to be simpler and safer than previous techniques involving drugs with separate alpha- and beta-adrenoceptor blocking effects. PMID- 26635173 TI - Labetalol infusion in acute myocardial infarction with systemic hypertension. AB - 1 Fifteen patients with suspected acute myocardial infarction and systemic BP of greater than 160/110 mmHg were treated with an incremental infusion of labetalol. 2 Systemic BPs were safely and effectively lowered to less than 130 mm Hg systolic or 90 mmHg diastolic in all pateints. 3 Heart rate, mean pulmonary artery wedge pressure cardiac index and stroke work index were significantly reduced. 4 The dose of labetalol varied from 30 mg-440 mg and was significantly higher (mean 295 mg) in those patients with pre-existing systemic hypertension compared with others (mean 133 mg). 5 No side- effects occurred and all patients survived to leave hospital. PMID- 26635174 TI - Labetalol, an alpha- and beta-adrenoceptor-blocking agent: its use in therapeutics. A summary of the symposium. PMID- 26635175 TI - Proceedings of the Second Symposium on Labetalol, London, March 1979. PMID- 26635176 TI - Effect of labetalol in hypertension during exercise and postural changes. AB - 1 Fourteen hypertensive patients were studied by intra-arterial BP monitoring to quantify the effects of standardized physiological stresses: Valsalva manoeuvre, isometric, treadmill and bicycle exercise, and 60 degree tilting before and after labetalol treatment. 2 The dose of labetalol ranged from 100-600 mg three times daily and the response was judged on outpatient clinic recordings. 3 The drug produced a sustained reduction of BP and heart rate responses during dynamic exercise and the Valsalva manoeuvre, but the degree of change from the lowered baseline were not changed by labetalol. The fall in BP on cessation of exercise was decreased rather than increased. 4 The response to controlled isometric muscle contraction was affected in a similar fashion. 5 Tilting produced a fall in BP after treatment, and this was most marked in those patients on the highest doses. However, compensatory increases in diastolic BP were observed. PMID- 26635177 TI - Lanreotide for the treatment of gastroenteropancreatic neuroendocrine tumors. AB - INTRODUCTION: The prevalence of gastropancreatic neuroendocrine tumors (GEP NETs), a largely sporadically occurring group of neoplasms, has rapidly increased. NET diagnoses often occur late and entail treatment challenges; treatment beyond surgical resection is typically required. Somatostatin analogs (SSAs), the cornerstone of GEP-NET therapy, target somatostatin receptors on NET cell surfaces and can ameliorate NET-related symptoms and prevent tumor progression. AREAS COVERED: This expert review summarizes the development of the SSA lanreotide and its role in treating NETs. Key lanreotide preclinical and clinical findings in acromegaly, carcinoid syndrome, and NETs are discussed, along with future treatment goals and therapeutic prospects. EXPERT OPINION: The role of SSAs in NET treatment was historically one of symptom management. Although this is a critical therapeutic component, ideal treatment would include prevention of tumor progression. As GEP-NETs are biologically diverse, progression prevention can be difficult, depending on primary tumor site and functional status. Recent data indicate that lanreotide significantly prolonged progression-free survival in metastatic GEP-NET patients. Practice patterns seem to be shifting toward using SSAs as first-line therapy. Response to SSAs has typically been categorized as either symptomatic or biochemical. However, SSA use to prevent tumor progression will lead to a new, objective response category based on tumor growth. PMID- 26635178 TI - Extreme sensitivity of the electric-field-induced band gap to the electronic topological transition in sliding bilayer graphene. AB - We have investigated the effect of electronic topological transition on the electric field-induced band gap in sliding bilayer graphene by using the density functional theory calculations. The electric field-induced band gap was found to be extremely sensitive to the electronic topological transition. At the electronic topological transition induced by layer sliding, four Dirac cones in the Bernal-stacked bilayer graphene reduces to two Dirac cones with equal or unequal Dirac energies depending on the sliding direction. While the critical electric field required for the band gap opening increases with increasing lateral shift for the two Dirac cones with unequal Dirac energies, the critical field is essentially zero with or without a lateral shift for the two Dirac cones with equal Dirac energies. The critical field is determined by the Dirac energy difference and the electronic screening effect. The electronic screening effect was also found to be enhanced with increasing lateral shift, apparently indicating that the massless helical and massive chiral fermions are responsible for the perfect and imperfect electronic screening, respectively. PMID- 26635180 TI - Isolation and characterization of a cold-resistant PCB209-degrading bacterial strain from river sediment and its application in bioremediation of contaminated soil. AB - A cold-resistant bacterium (strain QL) that can degrade 2,2',3,3',4,4',5,5',6,6' decachlorobiphenyl (PCB209) was isolated from Wei-he River sediment. Strain QL was identified as a rod-shaped gram-negative bacterial strain, which was further identified as Comamonas testosteroni. C. testosteroni has never been reported to be capable of degrading PCB209 at low temperatures. In this study, the degradation characteristics showed that strain QL could grow with PCB209 as the sole carbon source at low temperatures (10 +/- 0.5 degrees C). More significantly, strain QL of 40% inoculation volume was able to completely degrade PCB209 in 140 h (initial concentration of PCB209 was 100-500 ug L(-1) at 10 +/- 0.5 degrees C and pH 7-8). The degradation process proceeded with zero-order reaction kinetics. Moreover, both laboratory simulation and real-world field experiments demonstrated that strain QL was effective in practical applications of PCB209 biodegradation in contaminated soil. PMID- 26635179 TI - Nationwide surveillance of resistance rates of Staphylococcus aureus clinical isolates from Greek hospitals, 2012-2013. AB - Purpose To evaluate the in vitro efficacy of several anti-staphylococcal agents against a nationwide collection of contemporary Staphylococcus aureus clinical isolates from several healthcare centres in Greece. Methods Thirty hospitals throughout Greece (18 in Attica) provided all clinical isolates of S.aureus from April 2012 to May 2013 to a central lab to be re-submitted to susceptibility testing. The MICs were evaluated by Vitek(r) 2 with the exception of ceftaroline (OXOID M.I.C. EvaluatorTM). Vancomycin and daptomycin MICs were also evaluated by Etest(r). Heterogeneously vancomycin-intermediate strains (hVISA) were detected by the Etest(r) GRD. VISA phenotype was confirmed by PAP-AUC. Results A total of 1005 isolates (39% MRSA) were studied. Susceptibility rates were: erythromycin 66.5%, clindamycin 79.2%, SXT 98.9%, rifampicin 97.3%, fusidic acid 67%, moxifloxacin 78.8%, vancomycin 99.9%, ceftaroline 92.9% and linezolid, tigecycline and daptomycin 100%. For mupirocin, high level resistance could be excluded for 98.9% of isolates. Vancomycin Etest(r) MIC50/90 were 1.5/1.5 mg/L, 58.5% of isolates exhibited a MIC > 1 and 8.7% a MIC of 2 mg/L, while Vitek(r) MIC50/90 were 1/1 and 3.1% showed MIC > 1 mg/L. One VISA strain was detected. Among the selected 175 isolates that were screened for hVISA phenotype, six (3.4%) were positive. In 315 bloodstream isolates, 64.1% had a vancomycin Etest(r) MIC > 1 mg/L. Conclusions This multi-centre surveillance study revealed that a significant percentage of contemporary S.aureus isolates from Greek patients have a vancomycin MIC (> 1 mg/L) that may compromise the clinical efficacy of the drug for the treatment of serious infections. The in vitro activity of SXT, rifampicin, mupirocin, linezolid, tigecycline, daptomycin and ceftaroline remains excellent. PMID- 26635181 TI - Health effects of carbon-containing particulate matter: focus on sources and recent research program results. AB - Air pollution is a complex mixture of gas-, vapor-, and particulate-phase materials comprised of inorganic and organic species. Many of these components have been associated with adverse health effects in epidemiological and toxicological studies, including a broad spectrum of carbonaceous atmospheric components. This paper reviews recent literature on the health impacts of organic aerosols, with a focus on specific sources of organic material; it is not intended to be a comprehensive review of all the available literature. Specific emission sources reviewed include engine emissions, wood/biomass combustion emissions, biogenic emissions and secondary organic aerosol (SOA), resuspended road dust, tire and brake wear, and cooking emissions. In addition, recent findings from large toxicological and epidemiological research programs are reviewed in the context of organic PM, including SPHERES, NPACT, NERC, ACES, and TERESA. A review of the extant literature suggests that there are clear health impacts from emissions containing carbon-containing PM, but difficulty remains in apportioning responses to certain groupings of carbonaceous materials, such as organic and elemental carbon, condensed and gas phases, and primary and secondary material. More focused epidemiological and toxicological studies, including increased characterization of organic materials, would increase understanding of this issue. PMID- 26635182 TI - A recombinant, chimeric tetravalent dengue vaccine candidate based on a dengue virus serotype 2 backbone. AB - Dengue fever is caused by infection with one of four dengue virus (DENV) serotypes (DENV-1-4), necessitating tetravalent dengue vaccines that can induce protection against all four DENV. Takeda's live attenuated tetravalent dengue vaccine candidate (TDV) comprises an attenuated DENV-2 strain plus chimeric viruses containing the prM and E genes of DENV-1, -3 and -4 cloned into the attenuated DENV-2 'backbone'. In Phase 1 and 2 studies, TDV was well tolerated by children and adults aged 1.5-45 years, irrespective of prior dengue exposure; mild injection-site symptoms were the most common adverse events. TDV induced neutralizing antibody responses and seroconversion to all four DENV as well as cross-reactive T cell-mediated responses that may be necessary for broad protection against dengue fever. PMID- 26635183 TI - Postmarketing surveillance of the safety and effectiveness of abatacept in Japanese patients with rheumatoid arthritis. AB - OBJECTIVE: To perform a postmarketing surveillance study evaluating the safety and effectiveness of abatacept in Japanese patients with rheumatoid arthritis (RA). METHODS: Safety and effectiveness data were collected for all RA patients (at 772 sites) treated with intravenous abatacept between September 2010 and June 2011. Patients were treated by the approved dosing regimen according to the package insert. Treatment effectiveness was evaluated at baseline and at weeks 4, 12, and 24 using Disease Activity Score 28 (DAS28) according to erythrocyte sedimentation rate or serum C-reactive protein concentrations. RESULTS: Overall, 3882 and 3016 abatacept-naive RA patients were included in safety and effectiveness analyses, respectively. Adverse drug reactions (ADRs) were reported for 15.66% of patients and serious ADRs were detected for 2.52% of patients. The incidence of serious infections was 1.03% and these were mainly attributed to different types of bacterial pneumonia. Disease activity improved significantly over 6 months. Separate multivariate analysis identified predictors of severe ADR, and severe infections and factors predictive of clinically meaningful DAS28 improvement after 6 months of treatment with abatacept. CONCLUSIONS: Abatacept was efficacious and well tolerated in a clinical setting. No new safety concerns were detected. PMID- 26635185 TI - Oleic acid derivative of polyethylenimine-functionalized proliposomes for enhancing oral bioavailability of extract of Ginkgo biloba. AB - The present systematic study focused to investigate the oleic acid derivative of branched polyethylenimine (bPEI-OA)-functionalized proliposomes for improving the oral delivery of extract of Ginkgo biloba (GbE). The GbE proliposomes were prepared by a spray drying method at varying ratios of egg yolk phosphatidylcholine and cholesterol, and the optimized formulation was tailored with bPEI-OA to obtain bPEI-OA-functionalized proliposomes. The formulations were characterized for particle size, zeta potential, and entrapment efficiency. The release of GbE from proliposomes exhibited a sustained release. And the release rate was regulated by changing the amount of bPEI-OA on the proliposomes. The physical state characterization studies showed some interactions between GbE and other materials, such as hydrogen bonds and van der Waals forces during the process of preparation of proliposomes. The in situ single-pass perfusion and oral bioavailability studies were performed in rats. The significant increase in absorption constant (Ka) and apparent permeability coefficient (Papp) from bPEI OA-functionalized proliposomes indicated the importance of positive charge for effective uptake across the gastrointestinal tract. The oral bioavailability of bPEI-OA-functionalized proliposomes was remarkable enhanced in comparison with control and conventional proliposomes. The bPEI-OA-functionalized proliposomes showed great potential of improving oral absorption of GbE as a suitable carrier. PMID- 26635184 TI - Fibrocyte-like cells mediate acquired resistance to anti-angiogenic therapy with bevacizumab. AB - Bevacizumab exerts anti-angiogenic effects in cancer patients by inhibiting vascular endothelial growth factor (VEGF). However, its use is still limited due to the development of resistance to the treatment. Such resistance can be regulated by various factors, although the underlying mechanisms remain incompletely understood. Here we show that bone marrow-derived fibrocyte-like cells, defined as alpha-1 type I collagen-positive and CXCR4-positive cells, contribute to the acquired resistance to bevacizumab. In mouse models of malignant pleural mesothelioma and lung cancer, fibrocyte-like cells mediate the resistance to bevacizumab as the main producer of fibroblast growth factor 2. In clinical specimens of lung cancer, the number of fibrocyte-like cells is significantly increased in bevacizumab-treated tumours, and correlates with the number of treatment cycles, as well as CD31-positive vessels. Our results identify fibrocyte-like cells as a promising cell biomarker and a potential therapeutic target to overcome resistance to anti-VEGF therapy. PMID- 26635186 TI - Direct cellular reprogramming for cardiac repair and regeneration. AB - Heart failure is a major cause of morbidity and mortality, characterized by depletion of functioning cardiomyocytes, myocardial remodelling, and impaired contractile function. As the heart has a limited capacity for repair, and current treatments do not reverse myocardial attrition, novel regenerative strategies are imperative. Although cell delivery-based approaches remain promising, in situ reprogramming of endogenous cardiac fibroblasts (which are pathophysiologically implicated in cardiac remodelling) into functional cardiomyocytes may represent an advantageous approach. Several groups report successful in vitro and in vivo reprogramming of murine fibroblasts, using critical transcription factors, microRNA mimics, and small molecules, to cells demonstrating cardiomyocyte-like morphology, gene expression, and spontaneous contraction, which improve cardiac function in post-infarct models. Although proof-of-concept studies demonstrate reprogramming in human fibroblasts, significant barriers to therapeutic reprogramming remain. In this review, we evaluate the current status of reprogramming strategies for cardiac repair, and explore future perspectives within the context of clinical translation. PMID- 26635187 TI - Arsenic stress after the Proterozoic glaciations. AB - Protection against arsenic damage in organisms positioned deep in the tree of life points to early evolutionary sensitization. Here, marine sedimentary records reveal a Proterozoic arsenic concentration patterned to glacial-interglacial ages. The low glacial and high interglacial sedimentary arsenic concentrations, suggest deteriorating habitable marine conditions may have coincided with atmospheric oxygen decline after ~2.1 billion years ago. A similar intensification of near continental margin sedimentary arsenic levels after the Cryogenian glaciations is also associated with amplified continental weathering. However, interpreted atmospheric oxygen increase at this time, suggests that the marine biosphere had widely adapted to the reorganization of global marine elemental cycles by glaciations. Such a glacially induced biogeochemical bridge would have produced physiologically robust communities that enabled increased oxygenation of the ocean-atmosphere system and the radiation of the complex Ediacaran-Cambrian life. PMID- 26635188 TI - beta-C(sp(3))-H Arylation of alpha-Hydroxy Acid Derivatives Utilizing Amino Acid as a Directing Group. AB - The Pd(II)-catalyzed arylation of unactivated beta-C(sp(3))-H bonds in alpha hydroxy aliphatic acid with a variety of aryl iodides was developed utilizing an amino acid auxiliary as a directing group. This protocol provides access to biologically active beta-arylated-alpha-hydroxy acid derivatives. PMID- 26635189 TI - Patients' perceptions of quality of care and follow-up in inflammatory bowel disease. AB - BACKGROUND AND AIMS: Quality of care (QoC) has gained increased attention in IBD. A better QoC has, historically, been linked to improved treatment outcomes. Even so, factors of equal importance to patients may be quality of life (QoL), patient physician communication and access to care. Recent surveys suggest that IBD care in Europe is suboptimal. METHODS: Patients were recruited from nine hospitals in the south-eastern and western part of Norway as a part of an observational, multicenter study In addition to clinical and socio-demographic factors; a purposely designed 26 item questionnaire was used to quantify aspects related to IBD care, including QoC. Moreover, the Fatigue Questionnaire (FQ) was used to investigate fatigue. RESULTS: In total, 411 patients were included. Of these, 231 were diagnosed with CD and 180 with UC. Furthermore, 86.1% (354/411) were satisfied with the quality of IBD follow-up and only 4.1% (17/411) were dissatisfied. Most dissatisfaction was related to: lack of focus on personal relations (18.2%), HRQoL (15.1%), general practitioner knowledge of IBD (13.9%), ability to talk about important topics (7.8%), and hospital discharge communication (9.4%). Higher age and longer disease duration was associated with improved QoC scores in both UC and CD. Fatigue was associated with decreased QoC scores in both diagnoses. CONCLUSIONS: Patients are satisfied with quality of care in IBD. However, communication seems to be an important area of improvement not only related to patient-physician communication, but also to transitional communication between different health-care levels. PMID- 26635190 TI - Ablative neurosurgery for movement disorders related to cerebral palsy. AB - This article aims to describe the roles, operative strategies and outcomes of neuroablative procedures in treatment of movement disorders related to cerebral palsy (CP). The authors reviewed relevant medical literatures concerning ablative neurosurgical procedures for CP. Neurosurgery is an appropriate option for treatment of intractable movement disorders in CP. Destructive therapies can be selectively operated upon, on the brain, spinal cord, nerve root and peripheral nerve. Because all of them carry irreversible properties, presurgical evaluation and decision making for the surgery are critical. Selection of the procedures should be tailored for individual cases. Selective dorsal rhizotomy (SDR) is mostly suitable for CP children with spastic diplegia who are potential ambulators. Selective peripheral neurotomy (SPN) aims to diminish localized hypertonia. Intractable painful spasticity in an entire useless limb can be effectively treated by dorsal root entry zone lesion (DREZotomy). Stereotactic coagulation of specific targets in the brain is appropriate for more diffuse movement disorders or hyperkinesias confined to one side of the body. Combined surgery should be employed in management of more complicated abnormalities or coexisting neurologic and orthopedic disorders. Neuroablation remains an alternative to neuromodulation therapy, especially in circumstances when the latter is unavailable. PMID- 26635191 TI - The COFU3 Study. Improvement in cognitive function, attention, mental performance with Pycnogenol(r) in healthy subjects (55-70) with high oxidative stress. AB - AIM: This 12-month product registry study evaluated the effects of supplementation with French pine bark extract (Pycnogenol((r))) on cognitive function, attention, and mental performance in healthy subjects with high oxidative stress. METHODS: Healthy subjects (age range 55-70) were screened - within a cardiovascular screening program - for oxidative stress. Out of 150 subjects, high oxidative stress was present in 44; the use of the supplement Pycnogenol((r)) was suggested (100 mg/day). These subjects decided to use Pycnogenol((r)) and accepted to be evaluated by assessing cognitive functions. A group of subjects with comparable oxidative stress was followed as a reference. IQ Code (Informant Questionnaire on Cognitive Decline in the Elderly), daily tasks, cognitive function, oxidative stress and the short Blessed tests (SBT) were used (in defined scales) to evaluate cognitive functions (COFU). RESULTS: As for the IQ Code, at 12 months there was a significantlty total lower score in Pycnogenol((r)) patients and also a lower value (P<0.05) for 14 out of 16 items in the questionnaire. Daily tasks: all items were improved (P<0.05) with supplementation in comparison with controls. The improvement was seen for all 12 items (P<0.05) with the supplement. Cognitive function values (visual scale line) indicated a significant improvement (P<0.05) in all elements present in the questionnaire with the 12-month supplementation (no significant variations in controls). Oxidative stress was comparable in both groups at inclusion. It was significantly decreased with Pycnogenol((r)) (-28.07%; P<0.05) at 12 months; there was no decrease in controls. The short blessed test (SBT) value was significantly increased in controls (P<0.05); but significantly decreased in the Pycnogenol((r)) group (P<0.05). Values for supplemented patients at 12 months were almost within the normal range (21 out or 38 were below the normal value of 4). Tolerability and compliance for Pycnogenol((r)) were optimal with >97% of the doses of the supplement correctly used. No side effects were observed, recorded or described. CONCLUSION: Pycnogenol((r)) supplementation for 12 months appears to improve cognitive function and oxidative stress in normal subjects between 55 and 70 years of age. PMID- 26635192 TI - Hypofractionated irradiation for gliomas with 45.5Gy in 13 fractions: a retrospective study. AB - AIM: The aim of the present retrospective study was to evaluate the efficacy and toxicity of a hypofractionated radiotherapy (HFRT) schedule for grade IV glioblastoma multiforme (GBM). METHODS: Fourteen elderly patients with KPS less than 70, received 13 fractions of 350cGy with 3D-conformal technique (3DCRT) and non-coplanar fields. Acute and late skin and CNS toxicity was graded according to EORTC/RTOG criteria. RESULTS: The median follow-up was 9 months. All patients completed the irradiation without interruptions due to toxicity and received temozolomide (TMZ) after the completion of 3DCRT. The KPS during RT and at follow up was not significantly changed (P=0.108). The median overall survival was 7 months. No severe skin acute or late toxicity was noted. In terms of CNS toxicity, only one patient presented grade III toxicity requiring hospitalization for two days. The irradiation schedule of 45.5Gy in 13 fractions seems effective and without moderate or severe toxicity. CONCLUSION: The suggested HFRT schedule might be an alternative one, for elderly patients with dismal prognosis, unfit for six weeks of daily irradiation. Prospective studies are needed for further validation of our results, especially with the use of TMZ. PMID- 26635193 TI - Burr hole-less ultrasonic craniotomy: technical note and initial experience. PMID- 26635194 TI - Freezing of Gait in Parkinsonism and its Potential Drug Treatment. AB - Freezing of gait (FOG) is a heterogeneous symptom. Studies of treatment for FOG are scarce. Levodopa and monoamine oxidase inhibitors (rasagiline and selegiline) have shown effective improvement for FOG. Other drugs, such as L-threo-3, 4 dihydroxyphenylserine, amantadine, and botulinum toxin have exhibited some beneficial effects. The present review summarizes the potential drug treatment for FOG in Parkinsonism. PMID- 26635198 TI - Environmental Behavior of Chlorpyrifos and Endosulfan in a Tropical Soil in Central Brazil. AB - The environmental behavior of chlorpyrifos and endosulfan in soil was studied in the central-western region of Brazil by means of a field experiment. Sorption was evaluated in laboratory batch experiments. Chlorpyrifos and endosulfan were applied to experimental plots on uncultivated soil and the following processes were studied: leaching, runoff, and dissipation in top soil. Field dissipation of chlorpyrifos and endosulfan was more rapid than reported in temperate climates. Despite the high Koc of the studied pesticides, the two endosulfan isomers and endosulfan sulfate as well as chlorpyrifos were detected in percolated water. In runoff water and sediment, both endosulfan isomers and endosulfan sulfate were detected throughout the period of study. Observed losses of endosulfan by leaching (below a depth of 50 cm) and runoff were 0.0013 and 1.04% of the applied amount, whereas chlorpyrifos losses were 0.003 and 0.032%, respectively. Leaching of these highly adsorbed pesticides was attributed to preferential flow. PMID- 26635197 TI - The contributions of cardiac myosin binding protein C and troponin I phosphorylation to beta-adrenergic enhancement of in vivo cardiac function. AB - KEY POINTS: beta-adrenergic stimulation increases cardiac myosin binding protein C (MyBP-C) and troponin I phosphorylation to accelerate pressure development and relaxation in vivo, although their relative contributions remain unknown. Using a novel mouse model lacking protein kinase A-phosphorylatable troponin I (TnI) and MyBP-C, we examined in vivo haemodynamic function before and after infusion of the beta-agonist dobutamine. Mice expressing phospho-ablated MyBP-C displayed cardiac hypertrophy and prevented full acceleration of pressure development and relaxation in response to dobutamine, whereas expression of phosphor-ablated TnI alone had little effect on the acceleration of contractile function in response to dobutamine. Our data demonstrate that MyBP-C phosphorylation is the principal mediator of the contractile response to increased beta-agonist stimulation in vivo. These results help us understand why MyBP-C dephosphorylation in the failing heart contributes to contractile dysfunction and decreased adrenergic reserve in response to acute stress. beta-adrenergic stimulation plays a critical role in accelerating ventricular contraction and speeding relaxation to match cardiac output to changing circulatory demands. Two key myofilaments proteins, troponin I (TnI) and myosin binding protein-C (MyBP-C), are phosphorylated following beta-adrenergic stimulation; however, their relative contributions to the enhancement of in vivo cardiac contractility are unknown. To examine the roles of TnI and MyBP-C phosphorylation in beta-adrenergic-mediated enhancement of cardiac function, transgenic (TG) mice expressing non-phosphorylatable TnI protein kinase A (PKA) residues (i.e. serine to alanine substitution at Ser23/24; TnI(PKA-)) were bred with mice expressing non-phosphorylatable MyBP-C PKA residues (i.e. serine to alanine substitution at Ser273, Ser282 and Ser302; MyBPC(PKA-)) to generate a novel mouse model expressing non-phosphorylatable PKA residues in TnI and MyBP-C (DBL(PKA-)). MyBP-C dephosphorylation produced cardiac hypertrophy and increased wall thickness in MyBPC(PKA-) and DBL(PKA-) mice, and in vivo echocardiography and pressure-volume catheterization studies revealed impaired systolic function and prolonged diastolic relaxation compared to wild type and TnI(PKA-) mice. Infusion of the beta-agonist dobutamine resulted in accelerated rates of pressure development and relaxation in all mice; however, MyBPC(PKA-) and DBL(PKA-) mice displayed a blunted contractile response compared to wild-type and TnI(PKA-) mice. Furthermore, unanaesthesized MyBPC(PKA-) and DBL(PKA-) mice displayed depressed maximum systolic pressure in response to dobutamine as measured using implantable telemetry devices. Taken together, our data show that MyBP-C phosphorylation is a critical modulator of the in vivo acceleration of pressure development and relaxation as a result of enhanced beta adrenergic stimulation, and reduced MyBP-C phosphorylation may underlie depressed adrenergic reserve in heart failure. PMID- 26635199 TI - Further evidence of the involvement of the Wnt signaling pathway in Dupuytren's disease. AB - Genetic background plays an important role in the development of Dupuytren's disease. A genome-wide association study (GWAS) showed that nine loci are associated with the disease, six of which contain genes that are involved in Wnt signaling (WNT2, WNT4, WNT7B, RSPO2, SFRP4, SULF1). To obtain insight in the role of these genes, we performed expression studies on affected and unaffected patient's tissues. Surgically obtained nodules and cords from eight Dupuytren's patients were compared to patient-matched control tissue (unaffected transverse palmar fascia). The Wnt-related genes found in the GWAS, the classical Wnt downstream protein beta-catenin, as well as (myo)fibroblast markers were analyzed using real-time qPCR and immunohistochemical stainings for mRNA levels and protein levels, respectively. The collagen-coding genes COL1A1 and COL3A1 were highly upregulated on mRNA level, both in cords and nodules. Three Wnt-related genes were found to be differently regulated compared to control tissue: WNT2 was downregulated in nodules, WNT7B was upregulated in nodules, and SFRP4 was upregulated in nodules and cords. Immunohistochemistry revealed significantly less staining of Wnt2 in cords, but significantly more staining for Wnt7b in nodules. There was significantly more staining of alpha-SMA in nodules and cord and beta-catenin in nodules than in control tissue. We found differences in expression, both at mRNA and protein level, in several Wnt-related genes found earlier to be associated with Dupuytren's disease. Of these, Wnt7b was upregulated and found in close association with both alpha-SMA and beta-catenin expressing cells, making it a candidate pro-fibrotic mediator in Dupuytren's disease. PMID- 26635200 TI - A pathway map of glutamate metabolism. AB - Glutamate metabolism plays a vital role in biosynthesis of nucleic acids and proteins. It is also associated with a number of different stress responses. Deficiency of enzymes involved in glutamate metabolism is associated with various disorders including gyrate atrophy, hyperammonemia, hemolytic anemia, gamma hydoxybutyric aciduria and 5-oxoprolinuria. Here, we present a pathway map of glutamate metabolism representing metabolic intermediates in the pathway, 107 regulator molecules, 9 interactors and 3 types of post-translational modifications. This pathway map provides detailed information about enzyme regulation, protein-enzyme interactions, post-translational modifications of enzymes and disorders due to enzyme deficiency. The information included in the map was based on published experimental evidence reported from mammalian systems. PMID- 26635201 TI - The Three Possible 2-(Pyrenylethynyl) Adenosines: Rotameric Energy Barriers Govern the Photodynamics of These Structural Isomers. AB - This article presents a comprehensive study of the photophysics of 2-(2 pyrenylethynyl) adenosine and 2-(4-pyrenylethynyl) adenosine, which are structural isomers of the well-established fluorescent RNA label 2-(1 pyrenylethynyl) adenosine. We performed steady-state and ultrafast transient absorption spectroscopy studies along with time-resolved fluorescence emission experiments in different solvents to work out the interplay of locally excited and charge-transfer states. We found the ultrafast photodynamics to be crucial for the fluorescence decay behavior, which extends up to tens of nanoseconds and is partially multi-exponential. These features in the ultrafast dynamics are indicative of the rotational energy barriers in the first excited state. PMID- 26635202 TI - Mechanics, degradability, bioactivity, in vitro, and in vivo biocompatibility evaluation of poly(amino acid)/hydroxyapatite/calcium sulfate composite for potential load-bearing bone repair. AB - A ternary composite of poly(amino acid), hydroxyapatite, and calcium sulfate (PAA/HA/CS) was prepared using in situ melting polycondensation method and evaluated in terms of mechanical strengths, in vitro degradability, bioactivity, as well as in vitro and in vivo biocompatibility. The results showed that the ternary composite exhibited a compressive strength of 147 MPa, a bending strength of 121 MPa, a tensile strength of 122 MPa, and a tensile modulus of 4.6 GPa. After immersion in simulated body fluid, the compressive strength of the composite decreased from 147 to 98 MPa for six weeks and the bending strength decreased from 121 to 75 MPa for eight weeks, and both of them kept stable in the following soaking period. The composite could be slowly degraded with 7.27 wt% loss of initial weight after soaking in phosphate buffered solution for three weeks when started to keep stable weight in the following days. The composite was soaked in simulated body fluid solution and the hydroxyapatite layer, as flower like granules, formed on the surface of the composite samples, showing good bioactivity. Moreover, it was found that the composite could promote proliferation of MG-63 cells, and the cells with normal phenotype extended and spread well on the composite surface. The implantation of the composite into the ulna of sheep confirmed that the composite was biocompatible and osteoconductive in vivo, and offered the PAA/HA/CS composite promising material for load-bearing bone substitutes for clinical application. PMID- 26635204 TI - Antisecretory therapy with no improvement in functional level in Meniere's disease. AB - Conclusion Antisecretory factor-inducing (AF) specially processed cereals (SPC) were not shown to significantly improve the functional level in patients with MD. Objectives The aim of this study was to evaluate the effect of AF-inducing SPC in patients suffering from Meniere's disease (MD). Methods A randomized double blinded, placebo-controlled cross-over study was conducted. All patients had a 2 months intake of SPC and control cereal with a 2 months washout period in between. The severity of MD was classified according to the American Academy of Otolaryngology-Head and Neck Surgery (AOO-HNS) functional scale, and the frequency of attacks was registered. Results Thirty-two patients completed the study. No carryover effect was found. In both functional level and frequency of attacks no significant effect of SPC was found. Seventeen patients showed improvement in functional level when treated with SPC (mean improvement = 0.9 points) and 14 when treated with placebo (mean improvements = 0.7 points). No patients showed worsening in functional level during treatment with SPC, but three showed worsening when treated with placebo. Seventeen patients reported fewer attacks when treated with SPC, and 22 when treated with placebo. Three patients reported more frequent attacks when treated with SPC, and three when treated with placebo. A non-parametric comparison and a parametric analysis supported the findings. PMID- 26635205 TI - Massive Thrombosis of the Transplanted Heart in the Early Postoperative Period. AB - We experienced a case with the left atrium almost completely filled with a thrombus after orthotopic heart transplantation while the patient was supported on extracorporeal membrane oxygenation for primary graft failure. The patient had recurrent thrombosis even after successful surgical thrombectomy and appropriate anticoagulation. The cardiac thrombosis resolved only after starting plasmapheresis. PMID- 26635203 TI - MLLT1 YEATS domain mutations in clinically distinctive Favourable Histology Wilms tumours. AB - Wilms tumour is an embryonal tumour of childhood that closely resembles the developing kidney. Genomic changes responsible for the development of the majority of Wilms tumours remain largely unknown. Here we identify recurrent mutations within Wilms tumours that involve the highly conserved YEATS domain of MLLT1 (ENL), a gene known to be involved in transcriptional elongation during early development. The mutant MLLT1 protein shows altered binding to acetylated histone tails. Moreover, MLLT1-mutant tumours show an increase in MYC gene expression and HOX dysregulation. Patients with MLLT1-mutant tumours present at a younger age and have a high prevalence of precursor intralobar nephrogenic rests. These data support a model whereby activating MLLT1 mutations early in renal development result in the development of Wilms tumour. PMID- 26635206 TI - Unexpected Fascicle Length Changes In Denervated Feline Soleus Muscle During Stance Phase Of Walking. AB - After surgical repair of traumatically severed peripheral nerves, associated muscles are paralyzed for weeks. Little is known about fascicle length changes in paralyzed muscles during locomotion. The aim of this study was to investigate to what extent, if any, muscle fascicles of denervated feline soleus (SO) change length during stance of walking when intact SO synergists are actively contracting. Hindlimb kinematics, SO fascicle and muscle-tendon unit (MTU) length, and EMG activity of SO, lateral gastrocnemius (LG) and medial gastrocnemius (MG) were measured during level and slope walking in adult cats. Measurements were taken before and 1-2 weeks following SO-LG denervation. Unexpectedly, SO fascicle lengthening and shortening during stance in all walking conditions were evident after denervation. The greatest SO fascicle shortening (17.3 +/- 2.2% of a reference length) and least fascicle lengthening (1.5 +/- 0.8%) after denervation were found during upslope walking, where MG EMG activity was greatest across slopes (P < 0.05) and greatest discrepancies between post denervation SO fascicle and MTU length changes occurred. These findings suggest that myofascial linkages between denervated SO and its active synergists might affect its fascicle length changes. Further studies are needed to directly test this suggestion. PMID- 26635207 TI - Flibanserin-Stimulated Partner Grooming Reflects Brain Metabolism Changes in Female Marmosets. AB - INTRODUCTION: Female sexual interest and arousal disorder is personally distressing for women. To better understand the mechanism of the candidate therapeutic, flibanserin, we determined its effects on an index of brain glucose metabolism. AIM: We hypothesized that chronic treatment with flibanserin would alter metabolism in brain regions associated with serotonergic function and female sexual behavior. METHODS: In a crossover design, eight adult female common marmosets (Calithrix jacchus) received daily flibanserin or vehicle. After 7-12 weeks of treatment, the glucose metabolism radiotracer [(18) F]fluorodeoxyglucose (FDG) was administered to each female immediately prior to 30 minutes of interaction with her male pairmate, after which females were anesthetized and imaged by positron emission tomography. Whole-brain normalized images were analyzed with anatomically defined regions of interest. Whole-brain voxelwise mapping was used to explore treatment effects. Correlations were examined between alterations in metabolism and pairmate social grooming. MAIN OUTCOME MEASURES: Changes in metabolism associated with flibanserin were determined for dorsal raphe, medial prefrontal cortex (mPFC), medial preoptic area of hypothalamus (mPOA), ventromedial nucleus of hypothalamus, and field cornu ammonis 1 (CA1) of the hippocampus. RESULTS: In response to chronic flibanserin, metabolism in mPOA declined, and this reduction correlated with increases in pairmate grooming. A cluster of voxels in frontal cortico-limbic regions exhibited reduced metabolism in response to flibanserin and overlapped with a voxel cluster in which reductions in metabolism correlated with increases in pairmate grooming. Finally, reductions in mPOA metabolism correlated with increases in metabolism in a cluster of voxels in somatosensory cortex. CONCLUSIONS: Taken together, these results suggest that flibanserin-induced reductions in female mPOA neural activity increase intimate affiliative behavior with male pairmates. PMID- 26635208 TI - Tuberculosis in pediatric patients treated with anti-TNFalpha drugs: a cohort study. AB - BACKGROUND: Adult patients receiving anti-TNFalpha drugs are at increased risk of tuberculosis (TB), but studies in pediatric populations are limited, and the best strategy for latent tuberculosis infection (LTBI) screening in this population remains controversial. We describe the prevalence of LTBI prior to anti-TNFalpha therapy and the long-term follow-up after biological treatment initiation in a cohort of children and adolescents. METHODS: Cohort observational study in children and adolescents receiving anti-TNFalpha agents in a tertiary-care pediatric hospital. LTBI was ruled out prior to the implementation of anti TNFalpha drugs by tuberculin skin test (TST), and, from March 2012 on, QuantiFERON Gold-In Tube test (QTF-G). During anti-TNFalpha treatment, patients were evaluated every 6 months for TB with history and physical examination. TST/QTF-G were not repeated unless signs or symptoms consistent with TB arose or there was proven TB contact. RESULTS: The final cohort consisted of 221 patients (56.1% female; 261 treatments), of whom 51.7%/30.0%/17.3% were treated with etanercept/adalimumab/infliximab, respectively, for a variety of rheumatic diseases (75.6%), inflammatory bowel disease (20.8%), and inflammatory eye diseases (3.6%). The median (IQR) age at diagnosis of the primary condition was 6.8 years (2.7-11.0) and the duration of the disease before implementing the anti TNFalpha agent was 1.8 years (0.6-4.2). LTBI was diagnosed in 3 adolescent girls (prevalence rate: 1.4%; 95% CI: 0.4-4.2) affected with juvenile idiopathic arthritis: TST tested positive in only 1, while QTF-G was positive in all cases (including 2 patients already on etanercept). They all received antiTB chemoprophylaxis and were later (re)treated with etanercept for 24-29 months, without incidences. No incident cases of TB disease were observed during the follow-up period under anti-TNFalpha treatment of 641 patients-year, with a median (IQR) time per patient of 2.3 years (1.4-4.3). CONCLUSIONS: In our study, the prevalence of LTBI (1.4%) was similar to that reported in population screening studies in Spain; no incident cases of TB disease were observed. In low burden TB settings, initial screening for TB in children prior to anti-TNFalpha treatment should include both TST and an IGRA test, but systematic repetition of LTBI immunodiagnostic tests seems unnecessary in the absence of symptoms or known TB contact. PMID- 26635209 TI - Defining the Schistosoma haematobium kinome enables the prediction of essential kinases as anti-schistosome drug targets. AB - The blood fluke Schistosoma haematobium causes urogenital schistosomiasis, a neglected tropical disease (NTD) that affects more than 110 million people. Treating this disease by targeted or mass administration with a single chemical, praziquantel, carries the risk that drug resistance will develop in this pathogen. Therefore, there is an imperative to search for new drug targets in S. haematobium and other schistosomes. In this regard, protein kinases have potential, given their essential roles in biological processes and as targets for drugs already approved by the US Food and Drug Administration (FDA) for use in humans. In this context, we defined here the kinome of S. haematobium using a refined bioinformatic pipeline. We classified, curated and annotated predicted kinases, and assessed the developmental transcription profiles of kinase genes. Then, we prioritised a panel of kinases as potential drug targets and inferred chemicals that bind to them using an integrated bioinformatic pipeline. Most kinases of S. haematobium are very similar to those of its congener, S. mansoni, offering the prospect of designing chemicals that kill both species. Overall, this study provides a global insight into the kinome of S. haematobium and should assist the repurposing or discovery of drugs against schistosomiasis. PMID- 26635211 TI - Multiple sclerosis. Generic glatiramer acetate--a step toward cheaper MS drugs? AB - A randomized, double-blind, phase III trial of generic glatiramer acetate has shown equivalent efficacy and safety compared with the approved formulation, Copaxone. The impact of approval of generic glatiramer acetate, however, will mainly depend on the pricing of the drug. PMID- 26635212 TI - Parkinson disease. Sleep disorder deficits suggest signature for early Parkinson disease. PMID- 26635210 TI - The global burden of injury: incidence, mortality, disability-adjusted life years and time trends from the Global Burden of Disease study 2013. AB - BACKGROUND: The Global Burden of Diseases (GBD), Injuries, and Risk Factors study used the disability-adjusted life year (DALY) to quantify the burden of diseases, injuries, and risk factors. This paper provides an overview of injury estimates from the 2013 update of GBD, with detailed information on incidence, mortality, DALYs and rates of change from 1990 to 2013 for 26 causes of injury, globally, by region and by country. METHODS: Injury mortality was estimated using the extensive GBD mortality database, corrections for ill-defined cause of death and the cause of death ensemble modelling tool. Morbidity estimation was based on inpatient and outpatient data sets, 26 cause-of-injury and 47 nature-of-injury categories, and seven follow-up studies with patient-reported long-term outcome measures. RESULTS: In 2013, 973 million (uncertainty interval (UI) 942 to 993) people sustained injuries that warranted some type of healthcare and 4.8 million (UI 4.5 to 5.1) people died from injuries. Between 1990 and 2013 the global age standardised injury DALY rate decreased by 31% (UI 26% to 35%). The rate of decline in DALY rates was significant for 22 cause-of-injury categories, including all the major injuries. CONCLUSIONS: Injuries continue to be an important cause of morbidity and mortality in the developed and developing world. The decline in rates for almost all injuries is so prominent that it warrants a general statement that the world is becoming a safer place to live in. However, the patterns vary widely by cause, age, sex, region and time and there are still large improvements that need to be made. PMID- 26635214 TI - Long-Term Sustained Ciprofloxacin Release from PMMA and Hydrophilic Polymer Blended Nanofibers. AB - Nanofibers represent an attractive novel drug delivery system for prolonged and controlled release. However, sustained release of hydrophilic drugs, like ciprofloxacin hydrochloride (CIP), from polymeric nanofibers is not an easy task. The present study investigates the effect of different hydrophobic polymers (PCL and PMMA) alone in monolithic nanofibers or with hydrophilic polymers (PVA, PEO, and chitosan) in blended nanofibers aiming to achieve sustained CIP release. CIP release from PCL nanofibers was 46% and from PMMA just 1.5% over 40 day period. Thus, PMMA holds great promise for modification of CIP release from blended nanofibers. PMMA blends with 10% PEO, PVA, or chitosan were used to electrospin nanofibers from solution in the mixture of acetic and formic acid. These nanofibers exhibited different drug-release profiles: PEO containing nanofiber mats demonstrated high burst effect, chitosan containing mats revealed very slow gradual release, and PVA containing mats yielded smaller burst effect with favorable sustained release. We have also shown that gradual sustain release of antibiotic like CIP can be additionally tuned over 18 days with various blend ratios of PMMA with PVA or chitosan reaching almost 100%. A mathematical model in agreement with the experimental observation revealed that the sustained CIP release from the blended nanofibers corresponded to the two-stage desorption process. PMID- 26635215 TI - Swedish emergency medical services' identification of potential candidates for primary healthcare: Retrospective patient record study. AB - OBJECTIVE: To investigate patients who called the emergency medical services (EMS) for primary healthcare (PHC) problems. DESIGN: A retrospective and exploratory patient record study from an EMS perspective, comparing two groups: those who were potential candidates for PHC and those who were not. All data were gathered from EMS and hospital records. SETTINGS: The study was completed at the EMS and five hospital areas in the western region of Sweden. SUBJECTS: The patients (n = 3001) who called the EMS in 2011. Data were missing for 10%. MAIN OUTCOME MEASURES: The frequency and the clinical characteristics of the patients who called the EMS and were actually potential candidates for PHC. RESULTS: Of a total of 2703 patients, a group of 426 (16%) were assessed as potential candidates for PHC and could thus be treated at a level of care other than the emergency department. Patients who were classified as suitable for PHC were found at all priority levels and within all symptom groups, but were younger and healthier than the other group. CONCLUSION: Numerous patients seeking help from the EMS do not end up at the most appropriate level in the healthcare system. IMPLICATIONS: In the EMS, guidelines are needed to enable pre-hospital emergency nurses to assess and triage patients to the most appropriate level of healthcare. Key points Patients calling the emergency medical services do not always end up at an appropriate level of healthcare. In total, 16% of patients were identified by the Swedish emergency medical services as potential candidates for primary healthcare. These patients were younger and healthier than those needing care at the emergency department. They were found at all priority levels and within all symptom groups. PMID- 26635213 TI - Tau and neurodegenerative disease: the story so far. AB - In 1975, tau protein was isolated as a microtubule-associated factor from the porcine brain. In the previous year, a paired helical filament (PHF) protein had been identified in neurofibrillary tangles in the brains of individuals with Alzheimer disease (AD), but it was not until 1986 that the PHF protein and tau were discovered to be one and the same. In the AD brain, tau was found to be abnormally hyperphosphorylated, and it inhibited rather than promoted in vitro microtubule assembly. Almost 80 disease-causing exonic missense and intronic silent mutations in the tau gene have been found in familial cases of frontotemporal dementia but, to date, no such mutation has been found in AD. The first phase I clinical trial of an active tau immunization vaccine in patients with AD was recently completed. Assays for tau levels in cerebrospinal fluid and plasma are now available, and tau radiotracers for PET are under development. In this article, we provide an overview of the pivotal discoveries in the tau research field over the past 40 years. We also review the current status of the field, including disease mechanisms and therapeutic approaches. PMID- 26635216 TI - Occurrence and controls on transport and transformation of nitrogen in riparian zones of Dongting Lake, China. AB - Dongting Lake is the second largest freshwater lake in China. It is suffering from significant eutrophication as a result of excessive nutrients inputs, among which nitrogen (N) is becoming a major contributor. The objective of this study is to document the occurrence and controls on N transport and transformation in riparian zones of Dongting Lake wetland. Field experiments were conducted in the cultivated Li River (LR) and uncultivated Yuan River (YR) regions of the wetlands from June to November, 2014. Groundwater depth, redox potential (Eh), pH, and temperature were measured in situ. Groundwater and surface water samples were collected to determine concentrations of nitrate nitrogen (NO3 (-)-N), nitrite nitrogen (NO2 (-)-N), and ammonia nitrogen (NH4 (+)-N). The results showed that NH4 (+)-N was the dominant N pollutant with maximum average value of 2.7760 mg L( 1). All the groundwater samples were rated to Class V based on NH4 (+)-N content according to the groundwater quality standard, indicating the load of N in riparian zones had exceeded their capacity for assimilation and purification. Internal controls (including Eh and pH, temperature, and groundwater depth) and external controls (including surface water, land use, and rainfall) were analyzed in detail. The results suggested that Eh and pH were more significant in controlling N transport and transformation than temperature and groundwater depth; external controls influenced N fates through imposing an effect on internal controls. This study will provide important insights and a scientific basis for N pollution treatment and better protection of the Dongting Lake wetlands. PMID- 26635217 TI - Sensitivity of the deep-sea amphipod Eurythenes gryllus to chemically dispersed oil. AB - In the context of an oil spill accident and the following oil spill response, much attention is given to the use of dispersants. Dispersants are used to disperse an oil slick from the sea surface into the water column generating a cloud of dispersed oil droplets. The main consequence is an increasing of the sea water-oil interface which induces an increase of the oil biodegradation. Hence, the use of dispersants can be effective in preventing oiling of sensitive coastal environments. Also, in case of an oil blowout from the seabed, subsea injection of dispersants may offer some benefits compared to containment and recovery of the oil or in situ burning operation at the sea surface. However, biological effects of dispersed oil are poorly understood for deep-sea species. Most effects studies on dispersed oil and also other oil-related compounds have been focusing on more shallow water species. This is the first approach to assess the sensitivity of a macro-benthic deep-sea organism to dispersed oil. This paper describes a toxicity test which was performed on the macro-benthic deep-sea amphipod (Eurythenes gryllus) to determine the concentration causing lethality to 50% of test individuals (LC50) after an exposure to dispersed Brut Arabian Light (BAL) oil. The LC50 (24 h) was 101 and 24 mg L(-1) after 72 h and 12 mg L(-1) at 96 h. Based on EPA scale of toxicity categories to aquatic organisms, an LC50 (96 h) of 12 mg L(-1) indicates that the dispersed oil was slightly to moderately toxic to E. gryllus. As an attempt to compare our results to others, a literature study was performed. Due to limited amount of data available for dispersed oil and amphipods, information on other crustacean species and other oil-related compounds was also collected. Only one study on dispersed oil and amphipods was found, the LC50 value in this study was similar to the LC50 value of E. gryllus in our study. Since toxicity data are important input to risk assessment and net environmental benefit analyses, and since such data are generally lacking on deep sea species, the data set produced in this study is of interest to the industry, stakeholders, environmental management, and ecotoxicologists. However, studies including more deep-sea species covering different functional groups are needed to evaluate the sensitivity of the deep-sea compartments to dispersed oil relative to other environmental compartments. PMID- 26635218 TI - The effect of dispersed Petrobaltic oil droplet size on photosynthetically active radiation in marine environment. AB - Oil pollution in seawater, primarily visible on sea surface, becomes dispersed as an effect of wave mixing as well as chemical dispersant treatment, and forms spherical oil droplets. In this study, we examined the influence of oil droplet size of highly dispersed Petrobaltic crude on the underwater visible light flux and the inherent optical properties (IOPs) of seawater, including absorption, scattering, backscattering and attenuation coefficients. On the basis of measured data and Mie theory, we calculated the IOPs of dispersed Petrobaltic crude oil in constant concentration, but different log-normal size distributions. We also performed a radiative transfer analysis, in order to evaluate the influence on the downwelling irradiance Ed, remote sensing reflectance Rrs and diffuse reflectance R, using in situ data from the Baltic Sea. We found that during dispersion, there occurs a boundary size distribution characterized by a peak diameter d0 = 0.3 MUm causing a maximum E d increase of 40% within 0.5-m depth, and the maximum Ed decrease of 100% at depths below 5 m. Moreover, we showed that the impact of size distribution on the "blue to green" ratios of Rrs and R varies from 24% increase to 27% decrease at the same crude oil concentration. PMID- 26635219 TI - Moisture content-affected electrokinetic remediation of Cr(VI)-contaminated clay by a hydrocalumite barrier. AB - An electrokinetic-permeable reaction barrier (EK-PRB) system was introduced in this study with hydrocalumite as the barrier material. The combined system effectively remediated the Cr(VI)-contaminated clay after a 72-h treatment, and the Cr(VI) removal efficiency increased with the initial soil moisture content. Further evidence was found that the changing soil pH value and current density were highly associated with the initial moisture content, showing its important roles in the Cr(VI) removal process. Additionally, the total Cr removal efficiency was much lower than that of Cr(VI) owing to the partial conversion of Cr(VI) to Cr(III) in the electrokinetic remediation process. Under high soil moisture conditions (40%), the removal efficiency of Cr(VI) and total Cr was 96.6 and 67.3%, respectively. Further analysis also revealed the new mineral phase, chromate hydrocalumite, for Cr fixation in the hydrocalumite barrier, which was significantly affected by the initial soil moisture content. Our results showed that the EK-PRB system with a hydrocalumite barrier is highly promising with great potential for the effective remediation of Cr(VI)-contaminated clay and engineering implementation. PMID- 26635220 TI - The accumulation of elements in plants growing spontaneously on small heaps left by the historical Zn-Pb ore mining. AB - The study evaluated the levels of nine metals, namely Ca, Cd, Fe, K, Mg, Mn, Pb, Tl, and Zn, in soils and tissues of ten plant species growing spontaneously on heaps left by historical mining for Zn-Pb ores. The concentrations of Cd, Pb, Tl, and Zn in heap soils were much higher than in control soils. Plants growing on heaps accumulated excessive amounts of these elements in tissues, on average 1.3 52 mg Cd kg(-1), 9.4-254 mg Pb kg(-1), 0.06-23 mg Tl kg(-1) and 134-1479 mg Zn kg(-1) in comparison to 0.5-1.1 mg Cd kg(-1), 2.1-11 mg Pb kg(-1), 0.02-0.06 mg Tl kg(-1), and 23-124 mg Zn kg(-1) in control plants. The highest concentrations of Cd, Pb, and Zn were found in the roots of Euphorbia cyparissias, Fragaria vesca, and Potentilla arenaria, and Tl in Plantago lanceolata. Many species growing on heaps were enriched in K and Mg, and depleted in Ca, Fe, and Mn. The concentrations of all elements in plant tissues were dependent on species, organ (root vs. shoot), and species-organ interactions. Average concentrations of Ca, K, and Mg were generally higher in shoots than in roots or similar in the two organs, whereas Cd, Fe, Pb, Tl, and Zn were accumulated predominantly in the roots. Our results imply that heaps left by historical mining for Zn-Pb ores may pose a potential threat to the environment and human health. PMID- 26635221 TI - Modification, adsorption, and geochemistry processes on altered minerals and amorphous phases on the nanometer scale: examples from copper mining refuse, Touro, Spain. AB - The sulfide oxidation and precipitation of Al-Fe-secondary minerals associated with abandoned acid mine drainage (AMD) from the abandoned copper mine waste pile at Touro, Spain, has been studied by sequential extraction (SE) combined with several techniques with the intent of understanding the role of these processes play in the natural attenuation of hazardous element contaminants in the AMD. In addition, the fragile nature of nanominerals and ultrafine particle (UFP) assemblages from contaminated sediment systems from the abandoned copper mine required novel techniques and experimental approaches. The investigation of the geochemistry of complex nanominerals and UFP assemblages was a prerequisite to accurately assess the environmental and human health risks of contaminants and cost-effective chemical and biogeological remediation strategies. Particular emphasis was placed on the study and characterization of the complex mixed nanominerals and UFP containing potentially toxic elements. Nanometer-sized phases in sediments were characterized using energy-dispersive X-ray spectrometer (EDS), field-emission scanning electron microscope (FE-SEM), and high-resolution transmission electron microscopy (HR-TEM) images. The identification of the geochemical and mineralogical composition of AMD in Touro, as well as the different formation mechanisms proposed, complement the existing literature on secondary mineral assemblages and provide new emphasis to increase the understanding of extreme environments. The results also demonstrated that variations in the geochemical fractionation of hazardous elements in AMD were more influenced by the secondary mineral proportion and by AMD pH. PMID- 26635222 TI - Aerosol composition and properties variation at the ground and over the column under different air masses advection in South Italy. AB - Aerosol composition and properties variation under the advection of different air masses were investigated, as case studies, by contemporary measurements over the atmospheric column and at the ground in a semi-rural site in South Italy. The absence of local strong sources in this area allowed to characterize background aerosol and to compare particle mixing effects under various atmospheric circulation conditions. Aerosol optical depth (AOD) and Angstrom parameters from radiometric measurements allowed the detection and identification of polluted, dust, and volcanic atmospheric conditions. AODs were the input for a suitable model to evaluate the columnar aerosol composition, according to six main atmospheric components (water-soluble, soot, sea salt accumulation, sea salt coarse, mineral dus,t and biological). Scanning electron microscope (SEM) analysis of particulate sampled with a 13-stage impactor at the ground showed not only fingerprints typical of the different air masses but also the effects of transport and aging on atmospheric particles, suggesting processes that changed their chemical and optical properties. Background columnar aerosol was characterized by 72% of water-soluble and soot, in agreement with ground-based findings that highlighted 60% of contribution from anthropogenic carbonate particles and soot. In general, a good agreement between ground-based and columnar results was observed. Under the advection of trans-boundary air masses, water-soluble and soot were always present in columnar aerosol, whereas, in variable percentages, sea salt and mineral particles characterized both dust and volcanic conditions. At the ground, sulfates characterized the amorphous matrix produced in finer stages by the evaporation of solutions of organic and inorganic aerosols. Sulfates were also one of the key players involved in heterogeneous chemical reactions, producing complex secondary aerosol, as such clay-sulfate internally mixed particle externally mixed with soot chains. PMID- 26635223 TI - Impact of anti-inflammatories, beta-blockers and antibiotics on leaf litter breakdown in freshwaters. AB - Pharmaceuticals are now recognised as important pollutants in freshwater systems, but a shortcoming of effects studies is that they have focused on structural endpoints and impacts on ecosystem functioning are poorly understood. The decomposition of organic matter is an important functional process in aquatic systems, and it is known that this can be impacted by the presence of pollutants. Previous studies on leaf litter breakdown have only considered the effects of antibiotics and not other groups of drugs though. The current study investigated the effects of anti-inflammatories, a beta-blocker and an antibiotic on microbially mediated breakdown of leaf litter in the laboratory; colonisation of leaf packs by benthic macroinvertebrates when placed in a stream; and shredding of leaf litter by these organisms. Furthermore, the effects of single compounds relative to their mixture were assessed. It was found that exposure of leaf litter to the study compounds did not influence its breakdown by microbes in the laboratory or macroinvertebrates in a stream. Exposure of leaf litter to pharmaceuticals also had no effect on its colonisation by macroinvertebrates in this study. Many unknowns remain, however, and further studies of the effects of pharmaceuticals on structural and functional endpoints are needed to aid aquatic conservation. PMID- 26635224 TI - Testing the relationships between energy consumption, CO2 emissions, and economic growth in 24 African countries: a panel ARDL approach. AB - This study complements existing literature by examining the nexus between energy consumption (EC), CO2 emissions (CE), and economic growth (GDP; gross domestic product) in 24 African countries using a panel autoregressive distributed lag (ARDL) approach. The following findings are established. First, there is a long run relationship between EC, CE, and GDP. Second, a long-term effect from CE to GDP and EC is apparent, with reciprocal paths. Third, the error correction mechanisms are consistently stable. However, in cases of disequilibrium, only EC can be significantly adjusted to its long-run relationship. Fourth, there is a long-run causality running from GDP and CE to EC. Fifth, we find causality running from either CE or both CE and EC to GDP, and inverse causal paths are observable. Causality from EC to GDP is not strong, which supports the conservative hypothesis. Sixth, the causal direction from EC to GDP remains unobservable in the short term. By contrast, the opposite path is observable. There are also no short-run causalities from GDP, or EC, or EC, and GDP to EC. Policy implications are discussed. PMID- 26635225 TI - Heavy metal and polycyclic aromatic hydrocarbon concentrations in Quercus ilex L. leaves fit an a priori subdivision in site typologies based on human management. AB - Concentrations of four heavy metals (HMs) (Cd, Cr, Fe, Pb) and four polycyclic aromatic hydrocarbons (PAHs) (fluoranthene, phenanthrene, chrysene, benzo[a]pyrene) in Quercus ilex L. leaves collected at the Campania Region (Southern Italy) in previous air biomonitoring studies were employed to (1) test the correspondence with an a priori site subdivision (remote, periurban, and urban) and (2) evaluate long temporal trends of HM (approximately 20 years) and PAH (approximately 10 years) air contaminations. Overall, Q. ilex leaf HM and PAH concentrations resulted along the gradient: remote < periurban < urban sites, reflecting the a priori subdivision based on human management. Over a long time, although a clear decrease of leaf Pb, chrysene, fluoranthene, and phenanthrene concentrations occurred at the urban sites, a high contamination level persists. PMID- 26635226 TI - Health-related quality of life is inversely correlated with C-reactive protein and age in Mycobacterium avium complex lung disease: a cross-sectional analysis of 235 patients. AB - BACKGROUND: Mycobacterium avium complex (MAC) lung diseases generally cause chronic disease in immunocompetent hosts. Although a few studies have examined health-related quality of life (HRQL) in patients with MAC lung disease, there have been no large studies. This study aimed to evaluate HRQL and its correlation with clinical outcomes in MAC lung disease. METHODS: A cross-sectional study was conducted at Keio University Hospital to investigate the factors associated with HRQL in pulmonary nontuberculous mycobacterial diseases. MAC lung diseases were diagnosed according to the 2007 ATS/IDSA guidelines for nontuberculous mycobacterial diseases. The 36-item short form health survey (SF-36) was administered to assess clinical outcomes. Clinical variables included treatment status, latest haematological data, and bacterial smear and culture results. RESULTS: The SF-36 scores for the 235 patients (median age, 69 years; 45 men and 190 women) with MAC lung disease, except for the bodily pain and mental health subscale scores, were significantly lower than the Japanese population norms. In the multivariable analyses, current treatment for MAC and a positive sputum smear or culture within the past year were significantly associated with lower SF-36 scores. C-reactive protein (CRP) and age showed stronger inverse correlations with SF-36 scores. CONCLUSIONS: HRQL, especially the physical component, was impaired in patients with MAC lung diseases; this appears to be related with current treatment status, positive sputum smear or culture within the previous year, and particularly CRP and age. Further studies including qualitative assessments are needed to investigate the efficacy of CRP as a marker for progression or treatment response in MAC lung disease. TRIAL REGISTRATION: Clinical trial registered with UMIN ( UMIN000007964 ). PMID- 26635227 TI - Radiation dosimetry and biodistribution in non-human primates of the sodium/iodide PET ligand [(18)F]-tetrafluoroborate. AB - BACKGROUND: [(18)F]-tetrafluoroborate is a PET radiotracer taken up by the sodium/iodide symporter (NIS). Albeit the in vivo behavior in rodents is similar to the (99m)Tc-pertechnetate, no studies exist in primates or in humans. The aims of this study were to evaluate the biodistribution of [(18)F]-tetrafluoroborate in non-human primates with PET and to estimate the absorbed dose in organs. METHODS: Whole-body PET imaging was done in a Siemens ECAT HR+ scanner in two male Macaca fascicularis monkeys. After an i.v. injection of 24.93 +/- 0.05 MBq/kg of [(18)F]-tetrafluoroborate, prepared by isotopic exchange of sodium tetrafluoroborate with [(18)F]-fluoride under acidic conditions, eight sequential images from the head to the thigh (five beds) were collected for a total duration of 132 min. The whole-body emission scan was reconstructed applying attenuation and scatter corrections. After image reconstruction, three-dimensional volumes of interest (VOIs) were hand-drawn on the PET transaxial or coronal slices of the frame where the organ was most conspicuous. Time-activity curves for each VOI were obtained, and the organ residence times were calculated by integration of the time-activity curves. Human absorbed doses were estimated using the OLINDA/EXM software and the standard human model. RESULTS: [(18)F] tetrafluoroborate was able to discriminate clearly the thyroid gland with an excellent signal-to-noise ratio. Most of the radiotracers (residence time) are localised in the organs that express NIS (stomach wall, salivary glands, thyroid, olfactory mucosa), are involved in excretion (kidneys and bladder), or reflect the vascular phase (heart and lungs). Considering the OLINDA source organs, the critical organs were the stomach wall, thyroid and bladder wall, with absorbed doses lower than 0.078 mGy/MBq. The effective dose was 0.025 mSv/MBq. CONCLUSIONS: [(18)F]-tetrafluoroborate is a very useful radiotracer for PET thyroid imaging in primates, with a characteristic biodistribution in organs expressing NIS. It delivers an effective dose slightly higher than the dose produced by (99m)Tc-pertechnetate but much lower than that produced by radioiodine in the form of (131)INa, (123)INa, or (124)INa. PMID- 26635228 TI - Quasi-continuous metasurface for ultra-broadband and polarization-controlled electromagnetic beam deflection. AB - Two-dimensional metasurface has attracted growing interest in recent years, owing to its ability in manipulating the phase, amplitude and polarization state of electromagnetic wave within a single interface. However, most existing metasurfaces rely on the collective responses of a set of discrete meta-atoms to perform various functionalities. In this paper, we presented a quasi-continuous metasurface for high-efficiency and broadband beam steering in the microwave regime. It is demonstrated both in simulation and experiment that the incident beam deviates from the normal direction after transmitting through the ultrathin metasurface. The efficiency of the proposed metasurface approximates to the theoretical limit of the single-layer metasurface in a broad frequency range, owing to the elimination of the circuit resonance in traditional discrete structures. The proposed scheme promises potential applications in broadband electromagnetic modulation and communication systems, etc. PMID- 26635229 TI - Evaluation of a comprehensive intervention with a behavioural modification strategy for childhood obesity prevention: a nonrandomized cluster controlled trial. AB - BACKGROUND: With regard to the global childhood obesity epidemic, it is imperative that effective lifestyle interventions are devised to combat childhood obesity. This paper describes the development and implementation of a comprehensive (a combination of diet and physical activity (PA)), social cognitive behaviour modification intervention using accelerometry and a dietary diary to tackle child overweight and obesity. The comprehensive intervention effect was evaluated in a comparison with diet only, PA only and a no-treatment control group. METHODS: A pilot study was conducted with a non-randomized cluster design. Four hundred thirty-eight overweight and obese children aged 7-12 years from ten primary schools in Beijing were recruited to receive a one-year intervention. Participants were allocated into one of four groups: the comprehensive intervention group; the PA only group (Happy 10 program); the diet only group (nutrition education program); and a control group. The effects of intervention on adiposity, blood pressure, and biochemical indicators were assessed by examining 2-way interactions (time * intervention) in linear mixed models. Means and 95 % confidence intervals (CI) for the adjusted changes between post-intervention and baseline relative to changes in the control group were calculated and reported as effect sizes. RESULTS: The percentage of body fat in the comprehensive intervention group showed a significant relative decrease (adjusted change: -1.01 %, 95 % CI: (-1.81, -0.20) %) compared with the PA only, diet only or control groups (P < 0.001). Systolic blood pressure significantly decreased in the comprehensive intervention group (adjusted change: -4.37 mmHg, 95 % CI: (-8.42, -0.33) mmHg), as did diastolic blood pressure (adjusted change: 5.50 mmHg, 95 % CI (-8.81, -2.19) mmHg) (P < 0.05). Compared with the other two intervention groups and the control group, positive adjusted changes in fasting glucose in the comprehensive group were found, although not for the biochemical lipid metabolism indicators. Positive but non-significant adjusted changes in body mass index and waist circumference were observed. CONCLUSIONS: Compared with the diet or PA only intervention groups, the current comprehensive program had superior positive effects on body fat percentage and blood pressure but not on the biochemical lipid metabolism indicators in Chinese overweight and obese children. Future randomized controlled trials and long-term follow-up studies are required to elaborate the findings of the current intervention. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02228434. PMID- 26635231 TI - Reply to Albers: Acceptance of empirical evidence for gender disparities in Dutch research funding. PMID- 26635230 TI - Impact of CYP3A5 polymorphism on trough concentrations and outcomes of tacrolimus minimization during the early period after kidney transplantation. AB - PURPOSE: The purpose of this study is to determine the impacts of CYP3A5 polymorphism on tacrolimus concentration and the proportion of patients within a target therapeutic range during the first week after transplantation together with the 3-month acute rejection rate in kidney transplant patients receiving a minimized tacrolimus regimen. METHODS: A total of 164 patients participated in the study. All received oral tacrolimus twice daily starting on the day of surgery with the target pre-dose (trough) concentration of 4-8 ng/ml for prevention of allograft rejection. Cytochrome P450 (CYP) 3A5 genotypes were determined. The patients were divided into CYP3A5 expressers (CYP3A5*1 allele carriers) and CYP3A5 nonexpressers (homozygous CYP3A5*3). Whole blood tacrolimus concentrations on days 3 and 7 posttransplantation and the incidence of biopsy proven acute rejection (BPAR) at 3-month posttransplantation were compared between groups. RESULTS: On day 3, the median (IQR) dose-and-weight-normalized trough concentration in expressers and nonexpressers were 54.61 (31.98, 78.87) and 91.80 (57.60, 130.20) ng/ml per mg/kg/day, respectively (p < 0.001). Although only 47 and 42% of expressers and nonexpressers were within the target range on day 3, approximately 60% of both groups were within the target range on day 7. Proportions of BPAR among expressers and nonexpressers were 6.0 and 7.4 %, respectively (p = 0.723). The median (IQR) times to the first rejection in CYP3A5 expressers and nonexpressers were 32 (12, 68) and 15 (12, 37) days, respectively (p = 0.410). CONCLUSIONS: Although CYP3A5 polymorphism significantly influenced the tacrolimus dose required to achieve the target concentration, the impact of CYP3A5 polymorphism on BPAR was not observed in this study. PMID- 26635232 TI - Dutch research funding, gender bias, and Simpson's paradox. PMID- 26635233 TI - Content and activity of human liver microsomal protein and prediction of individual hepatic clearance in vivo. AB - The lack of information concerning individual variation in content and activity of human liver microsomal protein is one of the most important obstacles for designing personalized medicines. We demonstrated that the mean value of microsomal protein per gram of liver (MPPGL) was 39.46 mg/g in 128 human livers and up to 19-fold individual variations existed. Meanwhile, the metabolic activities of 10 cytochrome P450 (CYPs) were detected in microsomes and liver tissues, respectively, which showed huge individual variations (200-fold). Compared with microsomes, the activities of liver tissues were much suitable to express the individual variations of CYP activities. Furthermore, individual variations in the in vivo clearance of tolbutamide were successfully predicted with the individual parameter values. In conclusion, we offer the values for MPPGL contents in normal liver tissues and build a new method to assess the in vitro CYP activities. In addition, large individual variations exist in predicted hepatic clearance of tolbutamide. These findings provide important physiological parameters for physiologically-based pharmacokinetics models and thus, establish a solid foundation for future development of personalized medicines. PMID- 26635234 TI - Von Willebrand factor activity assay errors. PMID- 26635235 TI - Porous Cu Nanowire Aerosponges from One-Step Assembly and their Applications in Heat Dissipation. AB - Highly porous metal nanowire aerosponges are produced by direct assembly of the Cu nanowire in situ during their synthesis. Such a method offers not only great simplicity, but also excellent properties such as extremely low densities, high electrical conductivities, and remarkable mechanical properties. Furthermore, these Cu aerosponges exhibit excellent wicking behavior, suggesting their potential for heat-exchange applications in heat pipes. PMID- 26635236 TI - What IAPT services can learn from those who do not attend. AB - BACKGROUND: Rates of non-attendance within IAPT are 45-48%. Non-attendance has negative implications for patients, staff and services. AIMS: This research aimed to identify service-related factors that contribute to non-attendance. METHOD: Qualitative interviews with 14 patients recruited from six IAPT services in the South West. These were individuals who, having been referred to IAPT, never attended, or only attended one treatment contact. They were interviewed face-to face or by telephone using semi-structured interview schedules. The resulting data were analysed thematically through an iterative qualitative analysis using data mapping sheets. RESULTS: Five themes emerged from an analysis of the data including: the waiting process, the relationship between IAPT services and GPs, expectations of assessment and treatment, rigidity of service and practitioner contributions to the relationship. CONCLUSIONS: The analysis identifies ways in which IAPT services could reduce non-attendance. It also highlights areas of interest for future non-attendance in healthcare research, particularly collaborative care and protocolisation of treatment. PMID- 26635237 TI - A fully roll-to-roll gravure-printed carbon nanotube-based active matrix for multi-touch sensors. AB - Roll-to-roll (R2R) printing has been pursued as a commercially viable high throughput technology to manufacture flexible, disposable, and inexpensive printed electronic devices. However, in recent years, pessimism has prevailed because of the barriers faced when attempting to fabricate and integrate thin film transistors (TFTs) using an R2R printing method. In this paper, we report 20 * 20 active matrices (AMs) based on single-walled carbon nanotubes (SWCNTs) with a resolution of 9.3 points per inch (ppi) resolution, obtained using a fully R2R gravure printing process. By using SWCNTs as the semiconducting layer and poly(ethylene terephthalate) (PET) as the substrate, we have obtained a device yield above 98%, and extracted the key scalability factors required for a feasible R2R gravure manufacturing process. Multi-touch sensor arrays were achieved by laminating a pressure sensitive rubber onto the SWCNT-TFT AM. This R2R gravure printing system overcomes the barriers associated with the registration accuracy of printing each layer and the variation of the threshold voltage (Vth). By overcoming these barriers, the R2R gravure printing method can be viable as an advanced manufacturing technology, thus enabling the high throughput production of flexible, disposable, and human-interactive cutting-edge electronic devices based on SWCNT-TFT AMs. PMID- 26635239 TI - Hepatitis C drug maker puts profit ahead of patients, US Senate report charges. PMID- 26635240 TI - Reciprocal immune benefit based on complementary production of antibiotics by the leech Hirudo verbana and its gut symbiont Aeromonas veronii. AB - The medicinal leech has established a long-term mutualistic association with Aeromonas veronii, a versatile bacterium which can also display free-living waterborne and fish- or human-pathogenic lifestyles. Here, we investigated the role of antibiotics in the dynamics of interaction between the leech and its gut symbiont Aeromonas. By combining biochemical and molecular approaches, we isolated and identified for the first time the antimicrobial peptides (AMPs) produced by the leech digestive tract and by its symbiont Aeromonas. Immunohistochemistry data and PCR analyses evidenced that leech AMP genes are induced in the gut epithelial cells when Aeromonas load is low (starved animals), while repressed when Aeromonas abundance is the highest (post blood feeding). The asynchronous production of AMPs by both partners suggests that these antibiotic substances (i) provide them with reciprocal protection against invasive bacteria and (ii) contribute to the unusual simplicity of the gut microflora of the leech. This immune benefit substantially reinforces the evidence of an evolutionarily stable association between H. verbana and A. veronii. Altogether these data may provide insights into the processes making the association with an Aeromonas species in the digestive tract either deleterious or beneficial. PMID- 26635241 TI - Hip pain and radiographic signs of osteoarthritis. PMID- 26635242 TI - HCV genotype 3: a wolf in sheep's clothing. PMID- 26635245 TI - Understanding remission in real-world lupus patients across five European countries. AB - Systemic lupus erythematosus (SLE) is a chronic autoimmune disease associated with increased mortality and significant personal, psychological and socioeconomic consequences. An agreed definition of remission is needed and lacking. We sought to visualize 'remission in SLE' in European patients considered by their physicians to be 'in remission' by comparing the reported symptom burden as reported by treating physicians for patients considered to be 'in remission' and those not considered to be 'in remission'. Data for 1227 patients drawn from a multinational, real-world survey of patients with SLE consulting practising rheumatologists and nephrologists in France, Germany, Italy, Spain, and the UK show that physicians classed their patients as 'in remission' despite a considerable ongoing symptom burden and intensive immunosuppressive medication. Patients considered to be 'in remission' still had a mean of 2.68 current symptoms vs 5.48 for those considered to be not 'in remission' (p < 0.0001). The most common symptoms among those seen to be 'in remission' were joint symptoms, fatigue, pain, mucocutaneous involvement, haematological manifestations and kidney abnormalities. The current analysis highlights important ongoing disease activity, symptom burden and immunosuppressive medication in European patients with SLE considered by their treating physician to be 'in remission'. For a further improvement of outcome, there is an urgent need for an international consensus on the definitions for remission among patients with SLE. PMID- 26635246 TI - VRAC: molecular identification as LRRC8 heteromers with differential functions. AB - A major player of vertebrate cell volume regulation is the volume-regulated anion channel (VRAC), which conducts halide ions and organic osmolytes to counteract osmotic imbalances. The molecular entity of this channel was unknown until very recently, although its biophysical characteristics and diverse physiological roles have been extensively studied over the last 30 years. On the road to the molecular identification of VRAC, experimental difficulties led to the proposal of a variety of false candidates. In 2014, in a final breakthrough, two groups independently identified LRRC8A as indispensable component of VRAC. LRRC8A is part of the leucine-rich repeat containing 8 family, which is comprised of five members (LRRC8A-E). Of those, LRRC8A is an obligatory subunit of VRAC but it needs at least one of the other family members to mediate the swelling-induced Cl(-) current ICl,vol. This review discusses the remarkable journey which led to the molecular identification of VRAC, evidence for LRRC8 proteins forming the VRAC pore and their heteromeric assembly. Furthermore, first major insights on the role of LRRC8 proteins in cancer drug resistance and apoptosis and the role of LRRC8D in cisplatin and taurine transport will be summarized. PMID- 26635247 TI - 2015 White Paper on recent issues in bioanalysis: focus on new technologies and biomarkers (Part 3--LBA, biomarkers and immunogenicity). AB - The 2015 9th Workshop on Recent Issues in Bioanalysis (9th WRIB) took place in Miami, Florida with participation of 600 professionals from pharmaceutical and biopharmaceutical companies, biotechnology companies, contract research organizations and regulatory agencies worldwide. WRIB was once again a 5 day, week-long event - A Full Immersion Bioanalytical Week - specifically designed to facilitate sharing, reviewing, discussing and agreeing on approaches to address the most current issues of interest in bioanalysis. The topics covered included both small and large molecules, and involved LCMS, hybrid LBA/LCMS and LBA approaches, including the focus on biomarkers and immunogenicity. This 2015 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop, and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2015 edition of this comprehensive White Paper has been divided into three parts. Part 3 discusses the recommendations for large molecule bioanalysis using LBA, biomarkers and immunogenicity. Part 1 (small molecule bioanalysis using LCMS) and Part 2 (hybrid LBA/LCMS and regulatory inputs from major global health authorities) have been published in volume 7, issues 22 and 23 of Bioanalysis, respectively. PMID- 26635248 TI - Serotonin transporter variants play a role in anxiety sensitivity in South African adolescents. AB - OBJECTIVES: Anxiety sensitivity (AS) has predictive potential for the development of anxiety disorders. We investigated the role that gene-environment (G * E) interactions, focussing on childhood trauma (CT) and selected SLC6A4 variants, play in modulating levels of AS in a South African adolescent population. METHODS: All adolescents (n = 951) completed measures for AS and CT. Six SLC6A4 polymorphisms were genotyped. G * E influences on AS levels were assessed using multiple linear regression models. Relevant confounders were included in all analyses. RESULTS: Xhosa (n = 634) and Coloured (n = 317) participants were analysed independently of one another. The 5-HTTLPR-rs25531 L-G haplotype associated with reduced AS among Xhosa adolescents (P = 0.010). In addition, the rs1042173 CC-genotype protected against increased levels of AS in Xhosa participants who had experienced increased levels of CT (P = 0.038). Coloured males homozygous for the S-allele had significantly increased levels of AS compared to Coloured males with at least one L-allele (P = 0.016). CONCLUSIONS: This is the first study to be conducted on AS in adolescents from two ethnically diverse populations. Results indicate that the L-G haplotype confers protection against high AS levels in a Xhosa population. Furthermore, increased CT was found to protect against high levels of AS in Xhosa rs1042173 CC-carriers. PMID- 26635250 TI - Early right ventricular response to cardiac resynchronization therapy: impact on clinical outcomes. AB - AIMS: Right ventricular (RV) dysfunction has been associated with a worse outcome in heart failure patients undergoing CRT. However, evidence on the RV response to CRT is controversial and there are no data regarding the early effects of CRT on RV function (RVF). We sought to investigate whether a CRT device favourably influences the RVF acutely after implantation, impacting on long-term outcomes. METHODS AND RESULTS: Patients who successfully underwent CRT device implantation from January 2005 to January 2014 were retrospectively analysed. RV dysfunction was defined by an RV fractional area change <35%. Post-procedural echocardiographic evaluation was performed at a median time of 2 days (interquartile range 1-6 days). The primary endpoint was a composite of all-cause mortality and urgent heart transplantation. A total of 194 patients with available pre- and post-procedural RVF assessment were included. Sixty-two (32%) presented an impaired RVF before the procedure. Of them, 32% showed prompt normalization of RVF following CRT. This occurred in parallel with a large improvement in pulmonary arterial pressure, mitral regurgitation, E/E' ratio, and diastolic function. Pre-implantation independent predictors of early RVF normalization were LBBB (P = 0.034) and higher systolic blood pressure (P = 0.026). Improvement in RVF was independently associated with a better long-term prognosis at multivariable analysis [hazard ratio 0.124; 95% confidence interval 0.016-0.966, P = 0.04). CONCLUSIONS: Acute normalization of RVF can be observed after CRT along with haemodynamic improvement, and therefore can be used as an independent predictor of transplant-free survival. PMID- 26635249 TI - Comprehensive analysis of antibody recognition in convalescent humans from highly pathogenic avian influenza H5N1 infection. AB - Understanding the mechanism of protective antibody recognition against highly pathogenic avian influenza A virus H5N1 in humans is critical for the development of effective therapies and vaccines. Here we report the crystal structure of three H5-specific human monoclonal antibodies bound to the globular head of hemagglutinin (HA) with distinct epitope specificities, neutralization potencies and breadth. A structural and functional analysis of these epitopes combined with those reported elsewhere identifies four major vulnerable sites on the globular head of H5N1 HA. Chimeric and vulnerable site-specific mutant pseudoviruses are generated to delineate broad neutralization specificities of convalescent sera from two individuals who recovered from the infection with H5N1 virus. Our results show that the four vulnerable sites on the globular head rather than the stem region are the major neutralizing targets, suggesting that during natural H5N1 infection neutralizing antibodies against the globular head work in concert to provide protective antibody-mediated immunity. PMID- 26635252 TI - Coronary Sinus Flow Is Reduced and Recovered With Time in Viral Myocarditis Mimicking Acute Coronary Syndrome: A Transthoracic Doppler Echocardiographic Study. AB - OBJECTIVES: The clinical presentation of myocarditis often mimics acute coronary syndrome. Coronary sinus flow has been used for detection of the presence of myocardial ischemia. Whether myocarditis is associated with changes in coronary sinus flow remains unknown. The aim of this study was to assess coronary sinus flow at the onset and follow-up of myocarditis mimicking acute coronary syndrome using transthoracic Doppler echocardiography (TTE). METHODS: Sixty-four patients with clinically diagnosed viral myocarditis mimicking acute coronary syndrome underwent TTE on days 3, 7, 30, 90, 180, and 360 after onset. Coronary sinus flow was compared among different points in time. RESULTS: Compared to healthy participants, all patients with myocarditis had a larger cardiac size, reduced cardiac function, and electrocardiographic and myocardial enzyme abnormalities on days 3 and 7 days (P< .01; P< .05). They later had gradual restoration to normal levels. On days 3 and 7, the coronary sinus flow in patients with myocarditis was extremely lower than that in healthy participants (about one-tenth), although coronary angiography revealed unobstructed arteries. On days 30, 90, 180, and 360, the coronary sinus flow had been increasing; however, it was still far less than that in healthy participants (P < .01). CONCLUSIONS: Coronary sinus flow depicted by TTE is reduced but recovers with time in viral myocarditis mimicking acute coronary syndrome, which is a useful indicator in the follow-up of this type of myocarditis. PMID- 26635251 TI - Copper-Catalyzed Cyclopropanol Ring Opening Csp(3)-Csp(3) Cross-Couplings with (Fluoro)Alkyl Halides. AB - Novel and general copper-catalyzed cyclopropanol ring opening cross-coupling reactions with difluoroalkyl bromides, perfluoroalkyl iodides, monofluoroalkyl bromides, and 2-bromo-2-alkylesters to synthesize various beta-(fluoro)alkylated ketones are reported. The reactions feature mild conditions and excellent functional group compatibility and can be scaled up to gram scale. Preliminary mechanistic studies suggest the involvement of radical intermediates. The difluoroalkyl-alkyl cross-coupling products can also be readily converted to more valuable and diverse gem-difluoro-containing compounds by taking advantage of the carbonyl group resulting from cyclopropanol ring opening. PMID- 26635253 TI - Choice of Formula and Accuracy of Fetal Weight Estimation in Small-for Gestational-Age Fetuses. AB - OBJECTIVES: The purpose of this study was to identify the most accurate sonographic models for fetal weight estimation in specific subgroups of small-for gestational-age (SGA) fetuses. METHODS: We conducted a retrospective study of women who delivered an SGA neonate and underwent a sonographic estimation of fetal weight within 7 days of delivery in a single tertiary center (n = 370). The accuracy of fetal weight estimation was compared for 33 sonographic models (27 nontargeted and 6 targeted SGA- or low-birth-weight-specific models) in specific subgroups of SGA fetuses: early versus late SGA, asymmetric versus symmetric, and presence of Doppler abnormalities. RESULTS: A wide variation in the accuracy of the different models was found (systematic error, -12.5% to 15.1%; random error, 7.8% to 15.5%). Most nontargeted models tended to systematically overestimate the weight of SGA fetuses. The best performing model in the overall SGA group was the targeted model of Scott et al (J Ultrasound Med 1996; 15:669-672; systematic error +/- random error, -2.8% +/- 8.3%). However, the optimal models varied for different subgroups of SGA fetuses, and in most cases the targeted models were the most accurate. An approach that used the optimal model for each subgroup of SGA fetuses compared with the uniform use of the model of Scott et al for all SGA fetuses was associated with a lower systematic error (-0.38% versus -2.8%; P < .001) and a higher proportion of weight estimations within 5%, 10%, and 15% of birth weight (48.4% versus 40.8%; P= .038; 78.6% versus 71.4%; P= .022; 95.1% versus 89.2%; P = .003, respectively). CONCLUSIONS: Sonographic models in current use for fetal weight estimation in SGA fetuses have significant errors, and their performance varies for specific subgroups of SGA fetuses. An approach that uses subgroup-specific models may improve the accuracy of weight estimation among SGA fetuses. PMID- 26635254 TI - Color Doppler Sonography of Cutaneous Juvenile Xanthogranuloma With Clinical and Histologic Correlations. PMID- 26635255 TI - Polycystic Thyroid Disease in Pediatric Patients: An Uncommon Cause of Hypothyroidism. AB - Polycystic thyroid disease has been described as a rare cause of hypothyroidism. This uncommon entity has been reported in adults within areas with high iodine intake. Sonographic findings of multiple small thin-walled simple thyroid cysts in the context of hypothyroidism without thyroid autoantibodies are highly suggestive of this diagnosis. To our knowledge, we report the first 2 cases of polycystic thyroid disease in pediatric patients in Europe. PMID- 26635256 TI - Intrahepatic Persistent Right Umbilical Vein and Associated Outcomes: A Systematic Review of the Literature. AB - The aim of this study was to provide a comprehensive review of the current data surrounding an intrahepatic persistent right umbilical vein in the fetus, including associated anomalies and outcomes, and to assist practitioners in counseling and management of affected pregnancies. We performed a MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and Northern Light database search for articles reporting outcomes on prenatally diagnosed cases of a persistent right umbilical vein. Each article was independently reviewed for eligibility by the investigators. Thereafter, the data were extracted and validated independently by 3 investigators. A total of 322 articles were retrieved, and 16 were included in this systematic review. The overall prevalence of an intrahepatic persistent right umbilical vein was found to be 212 per 166,548 (0.13%). Of the 240 cases of an intrahepatic persistent right umbilical vein identified, 183 (76.3%) were isolated. The remaining cases had a coexisting abnormality, including 19 (7.9%) cardiac, 9 (3.8%) central nervous system, 15 (6.3%) genitourinary, 3 (1.3%) genetic, and 17 (7%) placental/cord (predominantly a single umbilical artery). In summary, a persistent right umbilical vein is commonly an isolated finding but may be associated with a coexisting cardiac defect in 8% of cases. Therefore, consideration should be given to fetal echocardiography in cases of a persistent right umbilical vein. PMID- 26635257 TI - Trends in caries experience and associated contextual factors among indigenous children. AB - OBJECTIVE: To assess dental caries trends in indigenous children in South Australia, 2001-2010; and contribution by area-level socioeconomic status (SES), remoteness and water fluoridation status. METHODS: This study is a part of the Child Dental Health Survey (CDHS) is an ongoing national surveillance survey in Australia including children enrolled in the School Dental Services (SDS). Postcode-level adjusted mean deciduous and permanent caries experience was estimated at each year. Time trend of dental caries experience was estimated using mixed effect models. Area-level socioeconomic status, remoteness, water fluoridation status were independent variables in the models. RESULTS: There was a significant upward trend of dental caries experience over the 10 years. Dental caries experience of indigenous children living in low SES areas had nearly one more deciduous tooth and a half permanent tooth with caries than indigenous children living in higher SES areas. The remote postcodes showed higher levels of decay in deciduous dentition (+1.25 teeth) compared with others regions. CONCLUSIONS: The dental caries trend increased in South Australian indigenous children over the study period, and was associated with area-level SES and remoteness. IMPLICATION: The increasing trend in dental caries in indigenous children is important evidence to inform policies to improve oral health. PMID- 26635258 TI - Intersocietal Accreditation Commission. PMID- 26635261 TI - The Importance of Giving Feedback. PMID- 26635262 TI - Collaboration and Relationship Building. PMID- 26635263 TI - Effectiveness of pacemaker tele-monitoring on quality of life, functional capacity, event detection and workload: The PONIENTE trial. AB - AIMS: The purpose of the present study was to assess the effectiveness of the remote monitoring (RM) of older adults with pacemakers on health-related quality of life, functional capacity, feasibility, reliability and safety. METHODS: The PONIENTE study is a controlled, non-randomized, non-blinded clinical trial, with data collection carried out during the pre-implant stage and after 12 months. Between October of 2012 and November of 2013, 82 patients were assigned to either a remote monitoring group (n = 30) or a conventional hospital monitoring (HM) group (n = 52). The EuroQol-5D (EQ-5D) and the Duke Activity Status Index were used to measure health-related quality of life and functional capacity, respectively. Baseline characteristics and number of hospital visits were also analyzed. RESULTS: The baseline characteristics of the two study groups were similar for both the EQ-5D (RM 0.74, HM 0.67; P = 0.404) and the Duke Activity Status Index (RM 21.42, HM 19.95; P = 0.272). At the 12-month follow up, the EQ 5D utility score was improved for both groups (RM 0.91, HM 0.81; P = 0.154), unlike the EQ-5D Visual Analog Scale (P = 0.043). The Duke Activity Status Index score was similar to the baseline score. The number of in-hospital visits was 27% lower (3 vs 4; P < 0.001) in the remote group as compared with the hospital group. CONCLUSIONS: The PONIENTE trial suggests that the remote monitoring of pacemakers in older adults is an equivalent option to hospital monitoring, in terms of health-related quality of life and functional capacity. Furthermore, it allows for the early detection of clinical and pacemaker-related adverse events, and significantly reduces the number of in-hospital visits. Geriatr Gerontol Int 2016; 16: 1188-1195. PMID- 26635264 TI - The Yin and Yang of Antiviral Innate Immunity in Central Nervous System. AB - The innate immune system provides protection against invading neurotropic viruses. It acts as the first line of defense against invading viruses and plays an elementary role in their pathogenesis. The list of viruses capable of infecting human central nervous system (CNS) is quite long, most important of them are Japanese Encephalitis virus (JEV), rabies virus, West Nile virus (WNV), herpes simplex virus (HSV), St. Louis encephalitis virus (SLEV), La Crosse virus, tick borne encephalitis virus (TEBE) and polio virus. Germ line pattern recognition receptors (PRRs) such as Toll like receptors (TLRs), nucleotide binding oligomerization domain (NOD) - like receptors (NLRs), retinoic acid inducible gene I (RIG-I) -like helicases or RIG-I-like receptors (RLRs) and cytosolic DNA sensors recognize the pathogen associated molecular patterns (PAMPs) and initiate an immune response against invading pathogen. Although PRRs were originally characterized in peripheral immune cells but accumulating evidence also suggest their crucial roles in CNS to combat against neurotropic viruses. In this review, we will highlight the recent developments in our understating of the mechanisms by which PRRs in resident brain cells provide protection against invading neurotropic viruses. PMID- 26635265 TI - The Role of Chinese Herbs and Acupuncture on the Inflammation Reaction After Cerebral Ischemia. AB - As a complex pathological process, immune inflammatory reaction plays an important role in the injury by cerebral ischemia. Inflammatory mediators can promote each other to coregulate the immune inflammatory reaction. Inflammatory cytokines play a pivotal role in regulating the immune inflammatory reaction process. Chinese herbs and acupuncture can exert a protective effect against neuronal damage by cerebral ischemia by inhibiting the production and expression of inflammatory cytokines and adhesion molecules, effectively blocking the inflammatory reaction and reducing the apoptosis of nerve cells. PMID- 26635266 TI - Evolving Insights into the Pathophysiology of Diabetic Neuropathy: Implications of Malfunctioning Glia and Discovery of Novel Therapeutic Targets. AB - Diabetic neuropathy subsequent to chronic high blood glucose-induced nerve damage is one of the most frustrating and debilitating complications of diabetes, which affects the quality of life in patients with diabetes. Approximately 60-70% of patients with diabetes suffer from a distal symmetrical form of mild to severe neuropathy that progresses in a fiber-length-dependent pattern, with sensory and autonomic manifestations predominating. High glucose and oxidative stress mediated damage in neurons and glial cells, as well as neuroinflammation and crosstalk between these disease processes, have garnered immense attention as the essential mechanisms underlying the development and progression of diabetic neuropathy. Although the metabolic causes of diabetic neuropathy are well understood and documented, treatment options for this disorder are still limited, highlighting the need for further studies to identify new molecular and therapeutic targets. This review covers recent advances in our knowledge of the pathophysiology of diabetic neuropathy, discusses how persistent hyperglycemic conditions and malfunctioning glia drive disease progression, and finally explores the possibilities and challenges offered by several potential novel therapeutic targets for both preventing and reversing diabetic neuropathy. PMID- 26635267 TI - Non Pharmacological Strategies to Promote Spinal Cord Regeneration: A View on Some Individual or Combined Approaches. AB - Spinal cord injury (SCI) is a complex condition that can result in functional impairment and paralysis, and occurs more frequently in young men. Several studies tested diverse treatments; however none achieved effective neuronal regeneration or improvement in neural function. Current research is being performed in areas such as cellular therapy (Schwann cells, embryonic stem cells, pluripotent stem cells, mesenchymal stem cells and olfactory cells), growth factors (BDNF), inhibitory molecules, fibroglial scar, gene therapies, etc. Some strategies have provided encouraging results by themselves, others have been tested as a combination, showing an improved outcome after SCI. Combined strategies could be more effective than individual therapies; for instance, cotransplantation of cells at the injury site to maximize their effect has been used, and it has demonstrated a greater efficacy in comparison to grafts of stem cells or of a particular cell type. The combination of neurotrophic factors such as BDNF and NT- 3 enhances axonal regeneration and myelination; other therapies include the use of biological matrices in combination with inhibitors of glial scar formation. Chondroitinase ABC (ChABC) has shown synergistic effects with other strategies, specifically to improve regeneration and functional recovery after SCI. Experimental evidence suggests that it is possible to obtain better results with a combination of strategies, which justifies further research for therapeutic approaches. This review intends to compile the most relevant information about available up-to-date therapeutic strategies that are administered alone or in combination with others, and have offered the best results in neural regeneration after spinal cord injury. PMID- 26635268 TI - Role of Immune Cells in the Course of Central Nervous System Injury: Modulation with Natural Products. AB - Immune cells actively participate to the central nervous system (CNS) injury either damaging or protecting neural tissue with release of various mediators. Residential microglia and monocyte-derived macrophages play a fundamental role within the injured CNS and, here, special emphasis will be placed on M1 and M2 macrophages for their different functional activities. On the other hand, peripheral T regulatory (Treg) cells exert antiinflammatory activities in the diseased host. In this respect, activation of Treg cells by nutraceuticals may represent a novel approach to treat neuroinflammation. Omega-3 fatty acids and polyphenols will be described as substances endowed with antioxidant and anti inflammatory activities. However, taking into account that Treg cells act in the later phase of CNS injury, favoring immune suppression, manipulation of host immune system with both substances requires caution to avoid undesired side effects. PMID- 26635269 TI - Experimental and Clinical Advances in Immunotherapy Strategies for Spinal Cord Injury Target on MAIs and Their Receptors. AB - In the injured adult mammalian central nervous system (CNS), the failure of axonal regeneration is thought to be attributed, at least in part, to various myelin-associated inhibitors (MAIs), such as Nogo, myelinassociated glycoprotein (MAG), and oligodendrocyte-myelin glycoprotein (OMgp) around the damaged site. Interestingly, these three structurally different inhibitors share two common receptors, Nogo-66 receptor (NgR) and paired immunoglobulin-like receptor B (PirB), and transduce the inhibitory signal into neurons via their complex combinant and co-receptors, such as p75 neurotrophin receptor (p75NTR), Nogo receptor-interacting protein 1 (LINGO-1), and TROY. Accordingly, targeting of the whole myelin or just portions by immunization has been proved to be neuroprotective and is able to promote regeneration in the injured spinal cords. In the past few years, vaccine approaches were initially achieved and could induce the production of antibodies against inhibitors in myelin to block the inhibitory effects and promote functional recovery in spinal cord injury (SCI) models by immunizing with MAIs, such as purified myelin, spinal cord homogenates, or their receptors with the concept of protective autoimmunity formulated. However, for safety consideration, further work is necessary before the immunotherapy strategies can be adopted to treat human injured spinal cords. PMID- 26635270 TI - Dietary Approaches and Supplements in the Prevention of Cognitive Decline and Alzheimer's Disease. AB - Age-associated cognitive decline and dementia are conditions in which there is deterioration in memory, thinking, and behavior, with profound effects on the ability to perform everyday activities and well-being. Even if dementia mainly affects older persons, it is not a normal part of aging. Alzheimer's disease accounts for 60-75% of dementia cases. The number of persons affected will increase in the next decades in parallel with aging of the world population. Hence, unless some approach is found to reduce age-related deterioration of cognitive functions, health care costs will continue to rise exponentially. There is a wealth of epidemiological evidence supporting a relationship between diet and Alzheimer's disease, and suggesting that the risk of cognitive decline may be reduced by dietary interventions. It has been proposed that adopting a healthy diet and lifestyle that improves cardiovascular function may help delaying the onset of Alzheimer's disease due to its potential association with vascular disease. Several nutrients, dietary components, supplements and dietary patterns have been reported in relation to their association with cognition and with the development of cognitive decline and Alzheimer's disease. The possible effect of diet on the prevention of dementia is of tremendous scientific and general interest, because hitherto there is no definitive evidence of any effective pharmacological treatment for dementia. The aim of this review is to evaluate the evidence for the effects of some dietary components, supplements, and dietary patterns as neuroprotective, with potential to delay cognitive decline and the onset of dementia. PMID- 26635271 TI - Oligodendrocyte Development and Myelination in Neurodevelopment: Molecular Mechanisms in Health and Disease. AB - Oligodendrocytes are the myelinating cells of the central nervous system that constitute about 5 to 10% of the total glial population. These cells are responsible for myelin sheath production, which is essential not only for the rapid and efficient conduction of the electrical impulses along the axons, but also for preserving axonal integrity. Oligodendrocytes arise from oligodendrocyte progenitor cells that proliferate and differentiate just before and after birth, under a highly-regulated program. Both oligodendrocytes and their precursors are very susceptible to injury by several mechanisms, including excitotoxic damage, oxidative stress and inflammatory events. In this review, we will cover not only several important aspects of oligodendrocyte development and regulatory mechanisms involved in this process, but also some of the most important pathways of injury associated to oligodendrogenesis. Moreover, we will also address some neurological disorders along life journey that present impairment in oligodendrocyte function and in myelination during neurodevelopment, such as periventricular leukomalacia, hypoxia/ischemia and hyperbilirubinemia that in turn can potentiate the emergence of neurological and neurodegenerative diseases like schizophrenia, multiple sclerosis and Alzheimer's disease. PMID- 26635272 TI - Biomarkers in Silent Traumatic Brain Injury. AB - Traumatic brain injury (TBI) has been recognized among the leading causes of mortality and morbidity in young adults. Traditionally, the diagnosis of TBI has been based on neuroimaging. However, a significant portion of insulted patients appear to be apparently asymptomatic. As a result, more elaborate indices of silent TBI are required in order to immediately detect focal and diffuse asymptomatic TBI. Such valid indices will potentially increase the efficacy of therapeutic strategies in TBI patients. In this review of the literature, we present novel circulating biomolecules, as potential biomarkers of silent TBI, like neurofilaments, Cleaved-Tau (C-Tau), Microtubule-Associated Protein 2 (MAP2), Neuron-Specific Enolase, S100B and ferritin. In addition to this, assessment of white matter abnormalities and white matter integrity by diffusion tensor imaging (DTI) have emerged as promising sensitive neuroimaging methods of silent TBI. An integrated research is needed to fully understand the interplay between all the aforementioned indices and DTI. The potential diagnostic, therapeutic and prognostic values of the all aforementioned indices will be analyzed in the proposed review. PMID- 26635273 TI - Dynamic labelling of neural connections in multiple colours by trans-synaptic fluorescence complementation. AB - Determining the pattern of activity of individual connections within a neural circuit could provide insights into the computational processes that underlie brain function. Here, we develop new strategies to label active synapses by trans synaptic fluorescence complementation in Drosophila. First, we demonstrate that a synaptobrevin-GRASP chimera functions as a powerful activity-dependent marker for synapses in vivo. Next, we create cyan and yellow variants, achieving activity dependent, multi-colour fluorescence reconstitution across synapses (X-RASP). Our system allows for the first time retrospective labelling of synapses (rather than whole neurons) based on their activity, in multiple colours, in the same animal. As individual synapses often act as computational units in the brain, our method will promote the design of experiments that are not possible using existing techniques. Moreover, our strategies are easily adaptable to circuit mapping in any genetic system. PMID- 26635274 TI - Respiratory effects of sulfur mustard exposure, similarities and differences with asthma and COPD. AB - CONTEXT: Previous research has found relationships between sulfur mustard (SM) toxicity and its adverse effects. OBJECTIVE: SM is highly toxic to the respiratory system, leading to hacking cough, rhinorrheachest tightness, acute pharyngitis and laryngitis, chronic bronchitis and lung fibrosis. In this review, based on the scientific literature, we provide an updated summary of information on SM exposures and their differences with asthma and COPD. METHOD: Information of this review was obtained by searching Medline/PubMed, ScienceDirect, Scopus, Google Scholar, ISI Web of Knowledge and Chemical Abstracts. RESULTS: SM exposure can decrease pulmonary function tests (PFTs) values. In addition, inflammatory cell accumulation in the respiratory tract and increased expression of some pro inflammatory cytokines including tumor necrosis factor-alpha (TNFalpha), IL-1a, IL-1beta, and reactive oxygen radicals due to SM exposure have been shown. Matrix metalloproteinase (MMP) which degrade extracellular matrix proteins, contributing to inflammatory cell recruitment, tissue injury and fibrosis are also up regulated in the lung after SM exposure. In the lung, SM exposure also can cause serious pathological changes including airway inflammation, parenchymal tissue destruction and airway obstruction which can lead to asthma or chronic obstructive pulmonary disease (COPD). Following SM poisoning, DNA damage, apoptosis and autophagy are observed in the lung along with the increased expression of activated caspases and DNA repair enzymes. CONCLUSION: In the present article, respiratory symptoms, changes in PFTs, lung pathology and lung inflammation due to SM exposure and the similarities and differences between them and those observed in asthma and COPD were reviewed. PMID- 26635275 TI - Challenges in the characterization of neutrophil extracellular traps: The truth is in the details. AB - Neutrophil extracellular traps play a key role in defense against extracellular pathogens. The release of these chromatin structures, that contain a combination of cytoplasmic and granule proteins, is known as NETosis, a regulated cell death modality typical of neutrophils. NETosis is induced by pathogens as well as other stimuli such as activated platelets. Our understanding of the molecular events underlying this phenomenon remains incomplete. The currently used experimental approaches to study NETs are semi-quantitative, subjective in nature, and low throughput, rendering it difficult to compare results between laboratories. This is highlighted in two articles published in this issue of the European Journal of Immunology which present what appear to be contradicting results on NET formation. Considering the extensive research on NETosis and the importance of this phenomenon in the immune response, we find it timely to briefly review the lacunae in the most commonly used methods to investigate NETosis. The impact these technical difficulties have on the advancement of our knowledge in this field as well as potential solutions are also discussed. PMID- 26635277 TI - Citrate anticoagulation for CRRT: don't always trust the postfilter iCa results! AB - Citrate has been recommended as the first-line anticoagulant for continuous renal replacement therapy (CRRT) in critically ill patients. Compared with heparin, citrate anticoagulation is safer and more efficacious. Citrate inhibits the coagulation cascade by lowering the ionized calcium (iCa) concentration in the filter. Monitoring of systemic iCa concentrations is inherent to the protocol, and monitoring of postfilter iCa is recommended to adjust citrate flow and optimize anticoagulation. While systemic iCa targets are in the physiological range, postfilter iCa concentrations are targeted between 0.20 and 0.35 mmol/l. In a previous issue of Critical Care, Schwarzer et al. compared systemic and postfilter iCa measurements of patients receiving citrate-based CRRT between six devices. They highlight the unreliability of iCa concentrations in the postfilter range, because the instruments cannot be validated in the low iCa range. The maximum mean difference between two instruments was as high as 0.33 mmol/l (range 0.21-0.50 mmol/l). The authors call for dialysis companies to revise their protocols. However, the first implication of their study is that the accuracy of blood gas analyzers to measure iCa in the low range needs to improve; and, secondly, clinicians using citrate anticoagulation need to be aware that the postfilter iCa result may be falsely high or low. This is particularly relevant when frequent premature filter clotting is observed despite postfilter iCa results in the seemingly target range. In these situations, citrate flow can be safely increased up to 4 mmol/l blood flow under monitoring of signs of citrate accumulation. PMID- 26635276 TI - Pregnancy outcomes following exposure to onabotulinumtoxinA. AB - PURPOSE: To evaluate pregnancy outcomes following onabotulinumtoxinA (US Food and Drug Administration pregnancy category C product) exposure using the Allergan safety database. METHODS: The Allergan Global Safety Database contains reports of onabotulinumtoxinA administration before/during pregnancy, including both prospective (reported before outcome) and retrospective (outcome already known) cases. The database was searched from 1/1/90 to 12/31/13 for eligible cases where treatment occurred during pregnancy or <=3 months before conception. To minimize reporting bias, prevalence rates were focused on prospective cases. RESULTS: Of 574 pregnancies with maternal onabotulinumtoxinA exposure, 232 were eligible with known outcomes. Patients received onabotulinumtoxinA most frequently for cosmetic indications (50.5%), movement disorders (16.8%), and pain disorders (14.2%). Of the 137 with dose information, 40.1% received <50U, 14.6% 50U to <100U, 27.7% 100U to <200U, and 17.5% >=200U. Among 146 cases with known maternal age, 47.9% were >=35 years. Most (96.0%) fetal exposures occurred during/before the first trimester. Of the 137 prospective cases (139 fetuses), 110 (79.1%) were live births; 29 (20.9%; 95% CI, 14.0-30.0%) ended in fetal loss (21 spontaneous, 8 induced abortions). Among live births, 106 (96.4%) were normal, with four abnormal birth outcomes (1 major fetal defect, 2 minor fetal malformations, 1 birth complication), giving a 2.7% (3/110; 95% CI, 0.6-8.0%) prevalence rate for overall fetal defects. CONCLUSIONS: A 24-year retrospective review of the Allergan safety database shows that the prevalence of fetal defects in onabotulinumtoxinA-exposed mothers before/during pregnancy (2.7%) is comparable with background rates in the general population. Pregnancy outcome monitoring in onabotulinumtoxinA-exposed women continues. PMID- 26635278 TI - Observation of uniaxial anisotropy along the [100] direction in crystalline Fe film. AB - We report an observation of uniaxial magnetic anisotropy along the [100] crystallographic direction in crystalline Fe film grown on Ge buffers deposited on a (001) GaAs substrate. As expected, planar Hall resistance (PHR) measurements reveal the presence of four in-plane magnetic easy axes, indicating the dominance of the cubic anisotropy in the film. However, systematic mapping of the PHR hysteresis loops observed during magnetization reversal at different field orientations shows that the easy axes along the and are not equivalent. Such breaking of the cubic symmetry can only be ascribed to the presence of uniaxial anisotropy along the direction of the Fe film. Analysis of the PHR data measured as a function of orientation of the applied magnetic field allowed us to quantify the magnitude of this uniaxial anisotropy field as Oe. Although this value is only 1.5% of cubic anisotropy field, its presence significantly changes the process of magnetization reversal, revealing the important role of the uniaxial anisotropy in Fe films. Breaking of the cubic symmetry in the Fe film deposited on a Ge buffer is surprising, and we discuss possible reason for this unexpected behavior. PMID- 26635280 TI - RhoA-JNK Regulates the E-Cadherin Junctions of Human Gingival Epithelial Cells. AB - The junctional epithelium (JE) is unique with regard to its wide intercellular spaces and sparsely developed intercellular junctions. Thus, knowledge of the molecular mechanisms that regulate the formation of the intercellular junctions of the junctional epithelium may be essential to understand the pathophysiology of the JE. HOK-16B cells, a normal human gingival epithelial cell line, were used to identify the molecules involved in the regulation of the formation of intercellular E-cadherin junctions between human gingival epithelial cells. Activation of c-Jun N-terminal kinase (JNK) disrupted the intercellular junctions through the dissociation of E-cadherin. The role of JNK in the formation of these E-cadherin junctions was further confirmed by demonstrating that JNK inhibition induced the formation of intercellular E-cadherin junctions. The upstream signaling of JNK was also examined. Activation of the small GTPase RhoA disrupted the formation of E-cadherin junctions between HOK-16B cells, which was accompanied by JNK activation. Disruption of these intercellular junctions upon RhoA activation was prevented when JNK activity was inhibited. In contrast, RhoA inactivation led to HOK-16B cell aggregation and the formation of intercellular junctions, even under conditions in which the cellular junctions were naturally disrupted by growth on a strongly adhesive surface. Furthermore, the JE of mouse molars had high JNK activity associated with low E-cadherin expression, which was reversed in the other gingival epithelia, including the sulcular epithelium. Interestingly, JNK activity was increased in cells grown on a solid surface, where cells showed higher RhoA activity than those grown on soft surfaces. Together, these results indicate that the decreased formation of intercellular E cadherin junctions within the JE may be coupled to high JNK activity, which is activated by the upregulation of RhoA on solid tooth surfaces. PMID- 26635279 TI - Light-Cured Self-Etch Adhesives Undergo Hydroxyapatite-Triggered Self-Cure. AB - Light cure is a popular mode of curing for dental adhesives. However, it suffers from inadequate light delivery when the restoration site is less accessible, in which case a self-cure mechanism is desirable to salvage any compromised polymerization. We previously reported a novel self-cure system mediated by ethyl 4-(dimethylamino)-benzoate (4E) and hydroxyapatite (HAp). The present work aims to investigate if such self-cure phenomenon takes place in adhesives that underwent prior inadequate light cure and to elucidate if HAp released from the dental etching process is sufficient to trigger it. Model self-etch adhesives were formulated with various components, including bis[2-methacryloyloxy)ethyl] phosphate (2MP) as acidic monomer and trimethylbenzoyl-diphenylphosphine oxide (TPO) as photoinitiator. In vitro evolution of degree of conversion (DC) of HAp incorporated adhesives was monitored by infrared spectroscopy during light irradiation and dark storage. Selected adhesives were allowed to etch and extract HAp from enamel, light-cured in situ, and stored in the dark, after which Raman line mapping was used to obtain spatially resolved DC across the enamel-resin interface. Results showed that TPO+4E adhesives reached DC similar to TPO-only counterparts upon completion of light irradiation but underwent another round of initiation that boosted DC to ~100% regardless of HAp level or prior light exposure. When applied to enamel, TPO-only adhesives had ~80% DC in resin, which gradually descended to ~50% in enamel, whereas TPO+4E adhesives consistently scored ~80% DC across the enamel-resin interface. These observations suggest that polymerization of adhesives that underwent insufficient light cure is salvaged by the novel self-cure mechanism, and such salvaging effect can be triggered by HAp released from dental substrate during the etching process. PMID- 26635281 TI - REPLY. PMID- 26635282 TI - Low Signals on T2* and SWI Sequences in Patients with MS with Progressive Multifocal Leukoencephalopathy. PMID- 26635283 TI - Asymptomatic Interhypothalamic Adhesions in Children. AB - With the use of high-resolution MR imaging techniques, we have increasingly observed anomalies of the hypothalamus characterized by a band of tissue spanning the third ventricle between the hypothalami, often without associated clinical sequelae. Historically, hypothalamic anomalies are highly associated with symptoms referable to a hypothalamic hamartoma, midline congenital disorder, hypothalamic-pituitary dysfunction, or seizures, with very few asymptomatic patients reported. The interhypothalamic tissue described in our cohort was observed incidentally through the routine acquisition of high-resolution T1WI. No referable symptoms were identified in most of the study group. In the appropriate patient population in which associated symptoms are absent, the described hypothalamic anomalies may be incidental and should not be misdiagnosed as hypothalamic hamartomas. PMID- 26635284 TI - Prevalence of Brain Microbleeds in Alzheimer Disease: A Systematic Review and Meta-Analysis on the Influence of Neuroimaging Techniques. AB - BACKGROUND AND PURPOSE: The literature on the prevalence of Alzheimer disease associated cerebral microbleeds assessed with MR imaging shows considerable heterogeneity in terms of imaging techniques and parameters. Our aim was to perform a meta-analysis of the role of imaging techniques, including image acquisition, field strength and scanner type, and clinical and demographic factors on the reported prevalence of microbleeds in Alzheimer disease. MATERIALS AND METHODS: The prevalence of microbleeds was examined with respect to a priori selected moderating variables via meta-analytic tools of literature reports. RESULTS: Fourteen unique studies providing 15 microbleed prevalence rates met the selection criteria for inclusion. The aggregate prevalence of microbleeds was 24% (95% CI, 19%-28%). Scan (SWI = 40%, gradient echo = 18%, EPI = 19%) and field strength (slope = 0.39; standard error = 15, P < .01) influenced the prevalence of microbleeds. The associations between microbleeds and age, sex, and global cognitive status were not significant. After updating the literature, the aggregate prevalence remained in the 95% CI range. CONCLUSIONS: Imaging technique and field strength are strongly associated with the prevalence of microbleeds over the global aggregate. Standardized imaging protocols for identification of microbleeds are recommended to minimize confounds. PMID- 26635285 TI - Age- and Level-Dependence of Fatty Infiltration in Lumbar Paravertebral Muscles of Healthy Volunteers. AB - BACKGROUND AND PURPOSE: Normative age-related decline in paravertebral muscle quality is important for reference to disease and risk identification in patients. We aimed to establish age- and vertebral level-dependence of paravertebral (multifidus and erector spinae) muscle volume and fat content in healthy adult volunteers. MATERIALS AND METHODS: In this prospective study multifidus and erector spinae fat signal fraction and volume at lumbar levels L1 L5 were measured in 80 healthy volunteers (10 women and men per decade, 20-62 years of age) by 2-point Dixon 3T MR imaging. ANOVA with post hoc Bonferroni correction compared fat signal fraction and volume among subgroups. Pearson and Spearman analysis were used for correlations (P < .05). RESULTS: Fat signal fraction was higher in women (17.8% +/- 10.7%) than men (14.7% +/- 7.8%; P < .001) and increased with age. Multifidus and erector spinae volume was lower in women (565.4 +/- 83.8 cm(3)) than in men (811.6 +/- 98.9 cm(3); P < .001) and was age-independent. No differences in fat signal fraction were shown between the right and left paravertebral muscles or among the L1, L2, and L3 lumbar levels. The fat signal fraction was highest at L5 (women, 31.9% +/- 9.3%; men, 25.7% +/- 8.0%; P < .001). The fat signal fraction at L4 correlated best with total lumbar fat signal fraction (women, r = 0.95; men, r = 0.92, P < .001). Total fat signal fraction was higher in the multifidus compared with erector spinae muscles at L1 L4 for both sexes (P < .001). CONCLUSIONS: Lumbar paravertebral muscle fat content increases with aging, independent of volume, in healthy volunteers 20-62 years of age. Women, low lumbar levels, and the multifidus muscle are most affected. Further study examining younger and older subjects and the functional impact of fatty infiltrated paravertebral muscles are warranted. PMID- 26635286 TI - Radiographic Local Control of Spinal Metastases with Percutaneous Radiofrequency Ablation and Vertebral Augmentation. AB - BACKGROUND AND PURPOSE: Combination radiofrequency ablation and vertebral augmentation is an emerging minimally invasive therapy for patients with metastatic spine disease who have not responded to or have contraindications to radiation therapy. The purpose of this study was to evaluate the rate of radiographic local control of spinal metastases treated with combination radiofrequency ablation and vertebral augmentation. MATERIALS AND METHODS: We retrospectively reviewed our tumor ablation database for all patients who underwent radiofrequency ablation and vertebral augmentation of spinal metastases between April 2012 and July 2014. Tumors treated in conjunction with radiation therapy were excluded. Tumor characteristics, procedural details, and complications were recorded. Posttreatment imaging was reviewed for radiographic evidence of tumor progression. RESULTS: Fifty-five tumors met study inclusion criteria. Radiographic local tumor control rates were 89% (41/46) at 3 months, 74% (26/35) at 6 months, and 70% (21/30) at 1 year after treatment. Clinical follow-up was available in 93% (51/55) of cases. The median duration of clinical follow-up was 34 weeks (interquartile range, 15-89 weeks), during which no complications were reported and no patients had clinical evidence of metastatic spinal cord compression at the treated levels. CONCLUSIONS: Combination radiofrequency ablation and vertebral augmentation appears to be an effective treatment for achieving local control of spinal metastases. A prospective clinical trial is now needed to replicate these results. PMID- 26635287 TI - A Systematic Review and Meta-Analysis of Treatment and Outcome of Blister-Like Aneurysms. AB - BACKGROUND AND PURPOSE: Blister-like aneurysms are uncommon but challenging lesions. Their small size and atypical location often make the diagnosis difficult. Microsurgery and endovascular procedures have been used for their treatment, but there is no consensus on the best treatment technique. We conducted a systematic review and meta-analysis of treatments and outcomes of these vascular lesions. MATERIALS AND METHODS: We reviewed English-language articles on "blood blister-like aneurysms" published between January 1997 and November 2014. All studies reporting patients with these aneurysms treated with surgery, endovascular procedures, or combined therapy with data on treatment modalities and clinical and/or angiographic outcomes were selected, including case reports and series. We performed a meta-analysis on the 2 largest treatment groups (surgery and endovascular management). RESULTS: Sixty studies with 334 patients met our inclusion criteria. Surgery was performed in 114 patients (34.2%), and endovascular treatment, in 199 patients (59.5%). A combined treatment was used in 19 patients (5.7%). A favorable outcome (mRS 0-2) was reported in 67.4% and 78.9% of patients treated with surgery and with endovascular therapy, respectively (P = .034). CONCLUSIONS: Blister-like aneurysms are challenging vascular lesions. The choice of treatment method must be based on the initial clinical presentation and an analysis of the radiologic features of the lesion to select the best technique. Endovascular treatment seems to have lower morbidity and mortality and provides a better outcome compared with surgical approaches. Further prospective studies must be performed to confirm such interesting results. PMID- 26635288 TI - Pathway, in silico and tissue-specific expression quantitative analyses of oesophageal squamous cell carcinoma genome-wide association studies data. AB - BACKGROUND: Oesophageal cancer is the fourth leading cause of cancer death in China where essentially all cases are histologically oesophageal squamous cell carcinoma (ESCC). Agnostic pathway-based analyses of genome-wide association study (GWAS) data combined with tissue-specific expression quantitative trait loci (eQTL) analysis and publicly available functional data can identify biological pathways and/or genes enriched with functionally-relevant disease associated variants. METHOD: We used the adaptive multilocus joint test to analyse 1827 pathways containing 6060 genes using GWAS data from 1942 ESCC cases and 2111 controls with Chinese ancestry. We examined the function of risk alleles using in silico and eQTL analyses in oesophageal tissues. RESULTS: Associations with ESCC risk were observed for 36 pathways predominantly involved in apoptosis, cell cycle regulation and DNA repair and containing known GWAS-associated genes. After excluding genes with previous GWAS signals, candidate pathways (and genes) for ESCC risk included taste transduction (KEGG_hsa04742; TAS2R13, TAS2R42, TAS2R14, TAS2R46,TAS2R50), long-patch base excision repair (Reactome_pid; POLD2) and the metabolics pathway (KEGG_hsa01100; MTAP, GAPDH, DCTD, POLD2, AMDHD1). We identified and validated CASP8 rs13016963 and IDH2 rs11630814 as eQTLs, and CASP8 rs3769823 and IDH2 rs4561444 as the potential functional variants in high-linkage disequilibrium with these single nucleotide polymorphisms (SNPs), respectively. Further, IDH2 mRNA levels were down-regulated in ESCC (tumour:normal-fold change = 0.69, P = .75E-14). CONCLUSION: Agnostic pathway-based analyses and integration of multiple types of functional data provide new evidence for the contribution of genes in taste transduction and metabolism to ESCC susceptibility, and for the functionality of both established and new ESCC risk related SNPs. PMID- 26635289 TI - Lipidomics comparing DCD and DBD liver allografts uncovers lysophospholipids elevated in recipients undergoing early allograft dysfunction. AB - Finding specific biomarkers of liver damage in clinical evaluations could increase the pool of available organs for transplantation. Lipids are key regulators in cell necrosis and hence this study hypothesised that lipid levels could be altered in organs suffering severe ischemia. Matched pre- and post transplant biopsies from donation after circulatory death (DCD, n = 36, mean warm ischemia time = 2 min) and donation after brain death (DBD, n = 76, warm ischemia time = none) were collected. Lipidomic discovery and multivariate analysis (MVA) were applied. Afterwards, univariate analysis and clinical associations were conducted for selected lipids differentiating between these two groups. MVA grouped DCD vs. DBD (p = 6.20 * 10(-12)) and 12 phospholipids were selected for intact lipid measurements. Two lysophosphatidylcholines, LysoPC (16:0) and LysoPC (18:0), showed higher levels in DCD at pre-transplantation (q < 0.01). Lysophosphatidylcholines were associated with aspartate aminotransferase (AST) 14 day post-transplantation (q < 0.05) and were more abundant in recipients undergoing early allograft dysfunction (EAD) (p < 0.05). A receiver-operating characteristics (ROC) curve combining both lipid levels predicted EAD with 82% accuracy. These findings suggest that LysoPC (16:0) and LysoPC (18:0) might have a role in signalling liver tissue damage due to warm ischemia before transplantation. PMID- 26635295 TI - Alteration of long-distance functional connectivity and network topology in patients with supratentorial gliomas. AB - INTRODUCTION: The need for information regarding functional alterations in patients with brain gliomas is increasing, but little is known about the functional consequences of focal brain tumors throughout the entire brain. Using resting-state functional MR imaging (rs-fMRI), this study assessed functional connectivity in patients with supratentorial brain gliomas with possible alterations in long-distance connectivity and network topology. METHODS: Data from 36 patients with supratentorial brain gliomas and 12 healthy subjects were acquired using rs-fMRI. The functional connectivity matrix (FCM) was created using 32 pairs of cortical seeds on Talairach coordinates in each individual subject. Local and distant connectivity were calculated using z-scores in the individual patient's FCM, and the averaged FCM of patients was compared with that of healthy subjects. Weighted network analysis was performed by calculating local efficiency, global efficiency, clustering coefficient, and small-world topology, and compared between patients and healthy controls. RESULTS: When comparing the averaged FCM of patients with that of healthy controls, the patients showed decreased long-distance, inter-hemispheric connectivity (0.32 +/- 0.16 in patients vs. 0. 42 +/- 0.15 in healthy controls, p = 0.04). In network analysis, patients showed increased local efficiency (p < 0.05), but global efficiency, clustering coefficient, and small-world topology were relatively preserved compared to healthy subjects. CONCLUSION: Patients with supratentorial brain gliomas showed decreased long-distance connectivity while increased local efficiency and preserved small-world topology. The results of this small case series may provide a better understanding of the alterations of functional connectivity in patients with brain gliomas across the whole brain scale. PMID- 26635296 TI - Highlighting consensus among medical scientists increases public support for vaccines: evidence from a randomized experiment. AB - BACKGROUND: A substantial minority of American adults continue to hold influential misperceptions about childhood vaccine safety. Growing public concern and refusal to vaccinate poses a serious public health risk. Evaluations of recent pro-vaccine health communication interventions have revealed mixed results (at best). This study investigated whether highlighting consensus among medical scientists about childhood vaccine safety can lower public concern, reduce key misperceptions about the discredited autism-vaccine link and promote overall support for vaccines. METHODS: American adults (N = 206) were invited participate in an online survey experiment. Participants were randomly assigned to either a control group or to one of three treatment interventions. The treatment messages were based on expert-consensus estimates and either normatively described or prescribed the extant medical consensus: "90 % of medical scientists agree that vaccines are safe and that all parents should be required to vaccinate their children". RESULTS: Compared to the control group, the consensus-messages significantly reduced vaccine concern (M = 3.51 vs. M = 2.93, p < 0.01) and belief in the vaccine-autism-link (M = 3.07 vs M = 2.15, p < 0.01) while increasing perceived consensus about vaccine safety (M = 83.93 vs M = 89.80, p < 0.01) and public support for vaccines (M = 5.66 vs M = 6.22, p < 0.01). Mediation analysis further revealed that the public's understanding of the level of scientific agreement acts as an important "gateway" belief by promoting public attitudes and policy support for vaccines directly as well as indirectly by reducing endorsement of the discredited autism-vaccine link. CONCLUSION: These findings suggest that emphasizing the medical consensus about (childhood) vaccine safety is likely to be an effective pro-vaccine message that could help prevent current immunization rates from declining. We recommend that clinicians and public health officials highlight and communicate the high degree of medical consensus on (childhood) vaccine safety when possible. PMID- 26635297 TI - Lung transplantation in IIP: A review. AB - The idiopathic interstitial pneumonias (IIP) encompass a large and diverse subtype of interstitial lung disease (ILD) with idiopathic pulmonary fibrosis (IPF) and non-specific interstitial pneumonia (NSIP) being the most common types. Although pharmacologic treatments are available for most types of IIP, many patients progress to advanced lung disease and require lung transplantation. Close monitoring with serial functional and radiographic tests for disease progression coupled with early referral for lung transplantation are of great importance in the management of patients with IIP. Both single and bilateral lung transplantation are acceptable procedures for IIP. Procedure selection is a complex decision influenced by multiple factors related to patient, donor and transplant centre. While single lung transplant may reduce waitlist time and mortality, the long-term outcomes after bilateral lung transplantation may be slightly superior. There are numerous complications following lung transplantation including primary graft dysfunction, chronic lung allograft dysfunction (CLAD), infections, gastroesophageal reflux disease (GERD) and airway disease that limit post-transplant longevity. The median survival after lung transplantation is 4.7 years in patients with ILD, which is less than in patients with other underlying lung diseases. Although long-term survival is limited, this intervention still conveys a survival benefit and improved quality of life in suitable IIP patients with advanced lung disease and chronic hypoxemic respiratory failure. PMID- 26635300 TI - Coronary artery bypass surgery in a patient with Haemophilia A: a case report. PMID- 26635299 TI - Tracing the Flow of Perceptual Features in an Algorithmic Brain Network. AB - The model of the brain as an information processing machine is a profound hypothesis in which neuroscience, psychology and theory of computation are now deeply rooted. Modern neuroscience aims to model the brain as a network of densely interconnected functional nodes. However, to model the dynamic information processing mechanisms of perception and cognition, it is imperative to understand brain networks at an algorithmic level--i.e. as the information flow that network nodes code and communicate. Here, using innovative methods (Directed Feature Information), we reconstructed examples of possible algorithmic brain networks that code and communicate the specific features underlying two distinct perceptions of the same ambiguous picture. In each observer, we identified a network architecture comprising one occipito-temporal hub where the features underlying both perceptual decisions dynamically converge. Our focus on detailed information flow represents an important step towards a new brain algorithmics to model the mechanisms of perception and cognition. PMID- 26635301 TI - Spatially Selective Nucleation and Growth of Water Droplets on Hierarchically Patterned Polymer Surfaces. AB - On a hierarchical polymer surface consisting of microposts and nanopillar arrays, water droplets are nucleated and grown selectively in the grooves between the microposts as the vapor pressure increases, whereas water droplets are randomly nucleated on a flat surface and surfaces consisting of microposts or nanopillars only. PMID- 26635302 TI - Beliefs about emotions mediate the relationship between emotional suppression and quality of life in irritable bowel syndrome. AB - BACKGROUND: Cross-sectional and experimental research has demonstrated an association between emotional suppression and IBS. However, the relationship is not well understood. AIM: To examine the relationships between emotional suppression, we compare the measures of beliefs about emotions and quality of life in irritable bowel syndrome (IBS) with healthy controls. METHOD: Online questionnaires measured beliefs about emotions, emotional suppression and IBS related quality of life in participants with (n = 87) and without (n = 37) IBS. Mediation analyses and group comparisons were used to explore the role of emotional suppression and beliefs about emotions in this sample. RESULTS: IBS participants held significantly more beliefs about the unacceptability of emotions compared to healthy controls despite no differences in emotional suppression. The relationship between beliefs about emotions and quality of life was not mediated by emotional suppression. However, the relationship between emotional suppression and quality of life was mediated by beliefs about emotions. CONCLUSION: The findings suggest a role of beliefs about emotions and emotional suppression in IBS, where emotional suppression may relate to changes in beliefs about emotions and consequently quality of life. This is discussed in relation to the cognitive-behavioural model of medically unexplained symptoms. PMID- 26635303 TI - Nausea and vomiting in palliative care. PMID- 26635304 TI - Characterization and phylogenetic analysis of fifteen NtabSPL genes in Nicotiana tabacum L. cv. Qinyan95. AB - Fifteen SPL (SQUAMOSA PROMOTER BINDING PROTEIN-LIKE) genes were identified and characterized in Nicotiana tabacum L. cv. Qinyan95. The exon-intron structures of these genes were determined according to the coding sequences confirmed by RT-PCR and the genomic DNA sequences downloaded from the databases in Sol Genomics Network, and thirteen of them were found to carry the response element of miR156. To elucidate the origin of the validated NtabSPL genes, multiple alignments of the nucleotide sequences encompassing the open reading frames were conducted by using the orthologs in N. tabacum, Nicotiana sylvestris, Nicotiana tomentosiformis, and Nicotiana otophora. The results showed that six NtabSPL genes were derived from a progenitor of N. sylvestris, and nine NtabSPL genes were derived from a progenitor of N. tomentosiformis, further corroborating that N. tabacum came from the interspecific hybridization between the ancestors of N. sylvestris and N. tomentosiformis. In contrast to previous statements about highly repetitive sequences, the genome of N. tabacum mainly retained the paternal-derived SPL genes in diploidization process. Phylogenetic analyses based on the highly conserved SBP (SQUAMOSA PROMOTER BINDING PROTEIN) domains and the full-length amino acid sequences reveal that the SPL proteins of tobacco, tomato, and Arabidopsis can be categorized into eight groups. It is worth noting that N. tabacum contains seven NtabSPL6 genes originated from two parental genomes and NtabSPL6-2 possesses a GC-AG intron. In addition, transgenic tobacco plants harboring Arabidopsis Pri-miR156A were generated by Agrobacterium-mediated transformation method, and the constitutive expression of miR156 could obviously inhibit the activity of the NtabSPL genes containing its target site, suggesting the function of miR156 is conservative in tobacco and Arabidopsis. PMID- 26635305 TI - Protein Requirements in the Critically Ill: A Randomized Controlled Trial Using Parenteral Nutrition. AB - BACKGROUND: Current recommendations for higher protein/amino acid provision in the critically ill are based on weak evidence. This double-blinded randomized controlled trial aimed to compare standard amino acid intake with the higher level recommended as the minimum for critically ill patients. METHODS: In total, 119 patients requiring parenteral nutrition (PN) in an intensive care unit (ICU) were randomized to receive blinded PN solutions containing amino acids at either 0.8 g/kg or 1.2 g/kg. Primary outcome was handgrip strength at ICU discharge. Secondary outcomes measured at study day 7 included handgrip strength, fatigue score (using the Chalder scale), and ultrasound measurements of muscle thickness at defined body sites. Analysis of covariance was used to control for age, sex, nutrition status (Subjective Global Assessment), Acute Physiology and Chronic Health Evaluation II (APACHE II) score, and baseline measurement. RESULTS: Actual amino acid delivery to the 2 groups was 0.9 and 1.1 g/kg respectively, averaged over the first 7 days. Grip strength at ICU discharge was not significantly different between groups (P =054) despite being improved at study day 7 in the group receiving the higher level of amino acids (mean [SD], 22.1 [10.1] vs 18.5 [11.8] kg, P =025). These patients also had less fatigue (Chalder score, mean [SD], 5.4 [2.2] vs 6.2 [2.2], P = .045) and greater forearm muscle thickness on ultrasound (mean [SD], 3.2 [0.4] vs 2.8 [0.4] cm, P < .0001). Nitrogen balance was significantly better at study day 3 but not at day 7. There was no difference between groups in mortality or length-of-stay measures. CONCLUSION: The higher level of amino acids was associated with small improvements in a number of different measures, supporting guideline recommendations for ICU patients. This trial was registered at Australian New Zealand Clinical Trials Registry (www.anzctr.org.au) as ACTRN12609000366257. PMID- 26635306 TI - Impact of skeletal-related events on survival in patients with metastatic prostate cancer prescribed androgen deprivation therapy. AB - OBJECTIVE: To investigate the impact of skeletal-related events on survival in patients with metastatic prostate cancer prescribed long-term androgen deprivation therapy. METHODS: This historical cohort study was conducted in two hospitals in Hong Kong. Patients who were diagnosed with metastatic prostate cancer and prescribed androgen deprivation therapy between January 2006 and December 2011 were included. Details of skeletal-related events and mortality were examined. RESULTS: The median follow-up was 28 (range, 1-97) months. Of 119 patients, 52 (43.7%) developed skeletal-related events throughout the study, and the majority received bone irradiation for pain control. The median actuarial overall survival and cancer-specific survival for patients with skeletal-related events were significantly shorter than those without skeletal-related events (23 vs 48 months, P=0.003 and 26 vs 97 months, P<0.001, respectively). Multivariate analysis revealed that the adjusted hazard ratio of presence of skeletal-related events on overall and cancer-specific survival was 2.73 (95% confidence interval, 1.46-5.10; P=0.002) and 3.92 (95% confidence interval, 1.87-8.23; P<0.001), respectively. A prostate-specific antigen nadir of >4 ng/mL was an independent poor prognostic factor for overall and cancer-specific survival after development of skeletal-related events (hazard ratio=10.42; 95% confidence interval, 2.10 51.66 and hazard ratio=10.54; 95% confidence interval, 1.94-57.28, respectively). CONCLUSIONS: Skeletal-related events were common in men with metastatic prostate cancer. This is the first reported study to show that a skeletal-related event is an independent prognostic factor in overall and cancer-specific survival in patients with metastatic prostate cancer prescribed androgen deprivation therapy. A prostate-specific antigen nadir of >4 ng/mL is an independent poor prognostic factor for overall and cancer-specific survival following development of skeletal related events. PMID- 26635307 TI - Blood transfusions and pulmonary complications after hematopoietic cell transplantation. AB - BACKGROUND: Transfusion of blood products is an essential component of the hematopoietic cell transplantation (HCT) process. Blood transfusion carries several risks including, but not limited to, lung injury. The effect of transfusions on lung complications after HCT has not been previously investigated. STUDY DESIGN AND METHODS: We retrospectively studied 215 adult allogeneic HCT recipients at the University of Minnesota and examined the association between transfusion of blood components and development of lung complications after HCT. Patients without lung complications were used as the control group. RESULTS: A total of 113 (58%) of the patients developed lung injury events before Day 180 after HCT. Six-month survival was significantly lower in the lung event group (52%) versus the controls (78%; p = 0.01). Patients who eventually developed lung events received more transfusion episodes per week in the first month after HCT (median, 4.3 vs. 2.7 for controls), platelet units per week (3.5 vs. 2.0), and RBC units per week (1.8 vs. 1.4; p < 0.01) for all. In a multivariable analysis, each additional transfusion before Day +30 was associated with a 2.7% higher risk of lung complication (95% confidence interval, 0.8-4.8; p = 0.01), adjusting for time to engraftment, conditioning intensity, and donor type. Blood utilization increased after the lung event and remained high for several months relative to controls. CONCLUSION: Our data suggest that transfusion of blood products is associated with and may further complicate lung complications after HCT. Cautious use of blood components in the post HCT period is recommended. PMID- 26635308 TI - Acute effects of acrolein in human volunteers during controlled exposure. AB - CONTEXT: Acrolein is a reactive aldehyde mainly formed by combustion. The critical effect is considered to be irritation of the eyes and airways; however, the scarce data available make it difficult to assess effect levels. OBJECTIVE: The aim of the study was to determine thresholds for acute irritation for acrolein. METHODS: Nine healthy volunteers of each sex were exposed at six occasions for 2 h at rest to: clean air, 15 ppm ethyl acetate (EA), and 0.05 ppm and 0.1 ppm acrolein with and without EA (15 ppm) to mask the potential influence of odor. Symptoms related to irritation and central nervous system effects were rated on 100-mm Visual Analogue Scales. RESULTS: The ratings of eye irritation were slightly but significantly increased during exposure to acrolein in a dose dependent manner (p < 0.001, Friedman test) with a median rating of 8 mm (corresponding to "hardly at all") at the 0.1 ppm condition and with no influence from EA. No significant exposure-related effects were found for pulmonary function, or nasal swelling, nor for markers of inflammation and coagulation in blood (IL-6, C-reactive protein, serum amyloid A, fibrinogen, factor VIII, von Willebrand factor, and Clara cell protein) or induced sputum (cell count, differential cell count, IL-6 and IL-8). Blink frequency recorded by electromyography was increased during exposure to 0.1 ppm acrolein alone but not during any of the other five exposure conditions. CONCLUSION: Based on subjective ratings, the present study showed minor eye irritation by exposure to 0.1 ppm acrolein. PMID- 26635309 TI - Reduced genetic diversity and increased reproductive isolation follow population level loss of larval dispersal in a marine gastropod. AB - Population-level consequences of dispersal ability remain poorly understood, especially for marine animals in which dispersal is typically considered a species-level trait governed by oceanographic transport of microscopic larvae. Transitions from dispersive (planktotrophic) to nondispersive, aplanktonic larvae are predicted to reduce connectivity, genetic diversity within populations, and the spatial scale at which reproductive isolation evolves. However, larval dimorphism within a species is rare, precluding population-level tests. We show the sea slug Costasiella ocellifera expresses both larval morphs in Florida and the Caribbean, regions with divergent mitochondrial lineages. Planktotrophy predominated at 11 sites, 10 of which formed a highly connected and genetically diverse Caribbean metapopulation. Four populations expressed mainly aplanktonic development and had markedly reduced connectivity, and lower genetic diversity at one mitochondrial and six nuclear loci. Aplanktonic dams showed partial postzygotic isolation in most interpopulation crosses, regardless of genetic or geographic distance to the sire's source, suggesting that outbreeding depression affects fragmented populations. Dams from genetically isolated and neighboring populations also exhibited premating isolation, consistent with reinforcement contingent on historical interaction. By increasing self-recruitment and genetic drift, the loss of dispersal may thus initiate a feedback loop resulting in the evolution of reproductive isolation over small spatial scales in the sea. PMID- 26635310 TI - Performance differences when using 26- and 29-inch-wheel bikes in Swiss National Team cross-country mountain bikers. AB - The purpose of this study was to analyse the effect of bike type - the 26-inch wheel bike (26" bike) and the 29-inch-wheel bike (29" bike) - on performance in elite mountain bikers. Ten Swiss National Team athletes (seven males, three females) completed six trials with individual start on a simulated cross-country course with 35 min of active recovery between trials (three trials on a 26" bike and three trials on a 29" bike, alternate order, randomised start-bike). The course consisted of two separate sections expected to favour either the 29" bike (section A) or the 26" bike (section B). For each trial performance, power output, cadence and heart rate were recorded and athletes' experiences were documented. Mean overall performance (time: 304 +/- 27 s vs. 311 +/- 29 s; P < 0.01) and performance in sections A (P < 0.001) and B (P < 0.05) were better when using the 29" bike. No significant differences were observed for power output, cadence or heart rate. Athletes rated the 29" bike as better for performance in general, passing obstacles and traction. The 29" bike supports superior performance for elite mountain bikers, even on sections supposed to favour the 26" bike. PMID- 26635311 TI - Midwives' Experiences, Education, and Support Needs Regarding Basic Newborn Resuscitation in Jordan. AB - Newborns who are compromised at birth require rapid attention to stabilize their respiration attempts. Lack of knowledge regarding basic newborn resuscitation is a contributing factor to poor newborn health outcomes and increased mortality. The purpose of this study was to explore Jordanian midwives' experiences, education, and support needs to competently perform basic newborn resuscitation. Qualitative descriptive methodology was used to analyze a convenience sample of 20 midwives. A thematic approach was used to analyze the data. Participants discussed their experiences of basic newborn resuscitation including knowledge, skills, and barriers and suggested solutions to improve practice. Four themes were revealed: lack of knowledge and skills in newborn resuscitation, organizational constraints, inadequate teamwork, and educational needs. The midwives perceived that their ability to perform newborn resuscitation was hindered by lack of knowledge and skills in newborn resuscitation, organizational constraints (such as lack of equipment), and poor co-ordination and communication among team members. PMID- 26635312 TI - Erratum to: Deep sequencing and de novo assembly of the mouse occyte transcriptome define the contribution of transcription to the DNA methylation landscape. PMID- 26635313 TI - "Doctors Shouldn't Underestimate the Power that they Have": NZ Doctors on the Care of the Dying Patient. AB - Rapidly aging populations and increased prevalence of chronic rather than acute illnesses have seen growing public and professional interest in medical decision making at the end of life and greater attention being paid to the factors that influence how individuals make such decisions. This study comprised 2 components: The first, a postal survey, based on the Remmelink questionnaire was sent in May 2013 to 3420 general practitioners (GPs) in New Zealand. Results from this component are reported elsewhere. The second component (reported here) sought information by inviting GPs to ring a free-phone number to be interviewed about their experiences caring for their dying patients. Interviews were recorded then transcribed with identifying information deleted to preserve anonymity. With an aging population, the provision of end-of-life care will increase in general practice. There is no doubt that hospice and specialist palliative care have transformed the quality of care for the dying and their families in New Zealand. However, while respondents in this study seemed realistic about what palliative care can and cannot achieve, patients and their families may have unrealistic expectations of both hospice and palliative medicine. Many GPs appear confused over the legality of the assistance they provide to the terminally ill, concerned that actions such as increasing medication to address refractory symptoms, or stopping food and fluids may put them at risk of legal censure when they foresee that their actions may hasten death. PMID- 26635314 TI - Design simplicity influences patient portal use: the role of aesthetic evaluations for technology acceptance. AB - OBJECTIVE: This study focused on patient portal use and investigated whether aesthetic evaluations of patient portals function are antecedent variables to variables in the Technology Acceptance Model. METHODS: A cross-sectional survey of current patient portals users (N = 333) was conducted online. Participants completed the Visual Aesthetics of Website Inventory, along with items measuring perceived ease of use (PEU), perceived usefulness (PU), and behavioral intentions (BIs) to use the patient portal. RESULTS: The hypothesized model accounted for 29% of the variance in BIs to use the portal, 46% of the variance in the PU of the portal, and 29% of the variance in the portal's PEU. Additionally, one dimension of the aesthetic evaluations functions as a predictor in the model - simplicity evaluations had a significant positive effect on PEU. CONCLUSION: This study provides evidence that aesthetic evaluations - specifically regarding simplicity - function as a significant antecedent variable to patients' use of patient portals and should influence patient portal design strategies. PMID- 26635315 TI - Nosocomial Acinetobacter pneumonia: Treatment and prognostic factors in 356 cases. AB - BACKGROUND AND OBJECTIVE: Acinetobacter baumannii and A. baumannii/calcoaceticus complex are commonly encountered pathogens in nosocomial infections. This study aimed to evaluate the treatment and prognostic risk factors in nosocomial pneumonia caused by these microorganisms. METHODS: The study was conducted retrospectively in Uludag University Hospital and included 356 adult non neutropenic patients with nosocomial pneumonia. RESULTS: Of the subjects, 94.9% (n = 338) had ventilator-associated pneumonia. The clinical response rate was 57.2%, the 14-day mortality 39.6% and the 30-day mortality 53.1%. The significant independent risk factors for the 30-day mortality were severe sepsis (OR, 2.60; 95% CI: 1.49-4.56; P = 0.001), septic shock (OR, 6.12; 95% CI: 2.75-13.64; P < 0.001), APACHE II score >= 20 (OR, 2.12; 95% CI: 1.28-3.50; P = 0.003) and empiric monotherapy (OR, 1.63; 95% CI: 1.00-2.64; P = 0.048). Multi-trauma (OR, 2.50; 95% CI: 1.11-5.68; P = 0.028) was found to be a protective factor. In patients with a clinical pulmonary infection score (CPIS) > 6 on the third day of treatment, both the 14- and 30-day mortality rates were high (P < 0.001, P < 0.001). Also, the 14- and 30-day mortality rates were significantly higher in the patients treated with empiric monotherapy compared with combination therapy (48/93 (51.6%)-46/123 (37.4%), P = 0.037 and 62/93 (66.7%)-65/123 (52.8%), P = 0.041, respectively) in pneumonia caused by imipenem-resistant strains. CONCLUSION: Mortality rates were high in pneumonia caused by imipenem-resistant A. baumannii or A. baumannii/calcoaceticus complex. In the units with a high level of carbapenem resistance, antibiotic combinations should be considered for empiric therapy. PMID- 26635316 TI - Programmable thermal emissivity structures based on bioinspired self-shape materials. AB - Programmable thermal emissivity structures based on the bioinspired self-shape anisotropic materials were developed at macro-scale, and further studied theoretically at smaller scale. We study a novel concept, incorporating materials that are capable of transforming their shape via microstructural rearrangements under temperature stimuli, while avoiding the use of exotic shape memory materials or complex micro-mechanisms. Thus, programmed thermal emissivity behaviour of a surface is achievable. The self-shape structure reacts according to the temperature of the surrounding environment or the radiative heat flux. A surface which incorporates self-shape structures can be designed to quickly absorb radiative heat energy at low temperature levels, but is simultaneously capable of passively controlling its maximum temperature in order to prevent overheating. It resembles a "game" of colours, where two or more materials coexist with different values of thermal emissivity/ absorptivity/ reflectivity. The transformation of the structure conceals or reveals one of the materials, creating a surface with programmable - and therefore, variable- effective thermal emissivity. Variable thermal emissivity surfaces may be developed with a total hemispherical emissivity ratio (epsilonEff_H/epsilonEff_L) equal to 28. PMID- 26635317 TI - Hierarchical Plasmonic Nanorods and Upconversion Core-Satellite Nanoassemblies for Multimodal Imaging-Guided Combination Phototherapy. AB - DNA-driven hierarchical core-satellite nanostructures with plasmonic gold nanorod dimers and upconversion nanoparticles are fabricated. Once the core-satellite structure is activated, combined photothermal therapy and photodynamic therapy are carried out under the guidance of upconversion luminesce, T1 -weighted magnetic resonance, photoacoustics, and computed tomography imaging of tumors in vivo, which exhibit the multifunctional biological applications of the DNA-based self-assemblies. PMID- 26635318 TI - Haustral boundary contractions in the proximal 3-taeniated rabbit colon. AB - The rabbit proximal colon is similar in structure to the human colon. Our objective was to study interactions of different rhythmic motor patterns focusing on haustral boundary contractions, which create the haustra, using spatiotemporal mapping of video recordings. Haustral boundary contractions were seen as highly rhythmic circumferential ring contractions that propagated slowly across the proximal colon, preferentially but not exclusively in the anal direction, at ~0.5 cycles per minute; they were abolished by nerve conduction blockers. When multiple haustral boundary contractions propagated in the opposite direction, they annihilated each other upon encounter. Ripples, myogenic propagating ring contractions at ~9 cycles per min, induced folding and unfolding of haustral muscle folds, creating an anarchic appearance of contractile activity, with different patterns in the three intertaenial regions. Two features of ripple activity were prominent: frequent changes in propagation direction and the occurrence of dislocations showing a frequency gradient with the highest intrinsic frequency in the distal colon. The haustral boundary contractions showed an on/off/on/off pattern at the ripple frequency, and the contraction amplitude at any point of the colon showed waxing and waning. The haustral boundary contractions are therefore shaped by interaction of two pacemaker activities hypothesized to occur through phase-amplitude coupling of pacemaker activities from interstitial cells of Cajal of the myenteric plexus and of the submuscular plexus. Video evidence shows the unique role haustral folds play in shaping contractile activity within the haustra. Muscarinic agents not only enhance the force of contraction, they can eliminate one and at the same time induce another neurally dependent motor pattern. PMID- 26635319 TI - Hyperammonemia results in reduced muscle function independent of muscle mass. AB - The mechanism of the nearly universal decreased muscle strength in cirrhosis is not known. We evaluated whether hyperammonemia in cirrhosis causes contractile dysfunction independent of reduced skeletal muscle mass. Maximum grip strength and muscle fatigue response were determined in cirrhotic patients and controls. Blood and muscle ammonia concentrations and grip strength normalized to lean body mass were measured in the portacaval anastomosis (PCA) and sham-operated pair-fed control rats (n = 5 each). Ex vivo contractile studies in the soleus muscle from a separate group of Sprague-Dawley rats (n = 7) were performed. Skeletal muscle force of contraction, rate of force development, and rate of relaxation were measured. Muscles were also subjected to a series of pulse trains at a range of stimulation frequencies from 20 to 110 Hz. Cirrhotic patients had lower maximum grip strength and greater muscle fatigue than control subjects. PCA rats had a 52.7 +/- 13% lower normalized grip strength compared with control rats, and grip strength correlated with the blood and muscle ammonia concentrations (r(2) = 0.82). In ex vivo muscle preparations following a single pulse, the maximal force, rate of force development, and rate of relaxation were 12.1 +/- 3.5 g vs. 6.2 +/- 2.1 g; 398.2 +/- 100.4 g/s vs. 163.8 +/- 97.4 g/s; -101.2 +/- 22.2 g/s vs. -33.6 +/- 22.3 g/s in ammonia-treated compared with control muscle preparation, respectively (P < 0.001 for all comparisons). Tetanic force, rate of force development, and rate of relaxation were depressed across a range of stimulation from 20 to 110 Hz. These data provide the first direct evidence that hyperammonemia impairs skeletal muscle strength and increased muscle fatigue and identifies a potential therapeutic target in cirrhotic patients. PMID- 26635321 TI - Mobile devices in the operating room: Intended and unintended consequences for nurses' work. AB - This article reports the results of a case study of the consequences of mobile device use for the work practices of operating room nurses. The study identifies different patterns of mobile technology use by operating room nurses, including both work-related and non-work-related use. These patterns have multiple consequences for nurses, such as improvements in information access, e-learning and work-related communication, as well as a perceived increase in distractions from the collaborative work. We conceptualize these consequences in terms of three level effects and explain how we find both positive and negative consequences on the third level. On the positive side, improvements were found in how nurses spent their unoccupied time during the stable parts of operations, contributing to their well-being and job satisfaction. A negative consequence was the perceived increase in distraction from the collaborative operating room work practices. PMID- 26635320 TI - Homeostasis alteration within small intestinal mucosa after acute enteral refeeding in total parenteral nutrition mouse model. AB - Feeding strategies to care for patients who transition from enteral nutrient deprivation while on total parenteral nutrition (TPN) to enteral feedings generally proceed to full enteral nutrition once the gastrointestinal tract recovers; however, an increasing body of literature suggests that a subgroup of patients may actually develop an increased incidence of adverse events, including death. To examine this further, we studied the effects of acute refeeding in a mouse model of TPN. Interestingly, refeeding led to some beneficial effects, including prevention in the decline in intestinal epithelial cell (IEC) proliferation. However, refeeding led to a significant increase in mucosal expression of proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-alpha), as well as an upregulation in Toll-like receptor 4 (TLR-4). Refeeding also failed to prevent TPN-associated increases in IEC apoptosis, loss of epithelial barrier function, and failure of the leucine-rich repeat-containing G protein-coupled receptor 5-positive stem cell expression. Transitioning from TPN to enteral feedings led to a partial restoration of the small bowel microbial population. In conclusion, while acute refeeding led to some restoration of normal gastrointestinal physiology, enteral refeeding led to a significant increase in mucosal inflammatory markers and may suggest alternative strategies to enteral refeeding should be considered. PMID- 26635322 TI - Syntactic and semantic errors in radiology reports associated with speech recognition software. AB - Speech recognition software can increase the frequency of errors in radiology reports, which may affect patient care. We retrieved 213,977 speech recognition software-generated reports from 147 different radiologists and proofread them for errors. Errors were classified as "material" if they were believed to alter interpretation of the report. "Immaterial" errors were subclassified as intrusion/omission or spelling errors. The proportion of errors and error type were compared among individual radiologists, imaging subspecialty, and time periods. In all, 20,759 reports (9.7%) contained errors, of which 3992 (1.9%) were material errors. Among immaterial errors, spelling errors were more common than intrusion/omission errors ( p < .001). Proportion of errors and fraction of material errors varied significantly among radiologists and between imaging subspecialties ( p < .001). Errors were more common in cross-sectional reports, reports reinterpreting results of outside examinations, and procedural studies (all p < .001). Error rate decreased over time ( p < .001), which suggests that a quality control program with regular feedback may reduce errors. PMID- 26635323 TI - Identifying an appropriate Content Management System to develop Clinical Practice Guidelines: A perspective. AB - Clinical Practice Guidelines are widely used to inform and improve the quality and consistency of clinical practice. Developing and publishing Clinical Practice Guidelines is a complex task involving multiple components. Electronic Content Management Systems are increasingly employed to make this task more manageable. The Content Management System market offers a variety of options for publishing content on the Internet. However, there are limited products that comprehensively address the requirements of publishing Clinical Practice Guidelines. The authors are involved in publishing guidelines for remote clinical practitioners in Australia and present their perspective about identifying an appropriate Content Management System. Several elements essential to addressing their unique editing needs are defined in this article. Unfortunately, customisation is very expensive and laborious: few Content Management System providers can comprehensively meet the needs of Clinical Practice Guidelines publishing. Being pragmatic about the level of functionality a product can offer to support publication is essential. PMID- 26635325 TI - Development and validation of a micellar electrokinetic capillary chromatography method for the determination of goserelin and related substances. AB - An MEKC method for the analysis of goserelin and related substances has been developed using a combination of additives including CTAB, beta-CD, and sodium hexanesulfonate. For this assay, the running buffer (pH and additives) and separation conditions (voltage and temperature) were optimized. The optimized system was the following: 200 mM 6-aminocaproic acid buffer (pH 4.2) supplemented with 175 mM CTAB, 3.0% w/v beta-CD, and 20 mM sodium hexanesulfonate; the voltage was 10 kV in reverse polarity mode, the temperature was 20 degrees C, and UV detection was measured at 220 nm. The method was qualified by evaluating the specificity, precision, linearity, accuracy, LOD, and LOQ. According to validation experiments, the optimized method was specific, accurate, and repeatable and satisfied the requirements for the analysis of goserelin and related substances. Compared with the RP-HPLC method, the MEKC method better solved the problem of overlapping impurity signals, and the migration time required was shorter. This method can be used for quality control and for the analysis of goserelin and its related substances. PMID- 26635324 TI - mHealth applications for diabetes: User preference and implications for app development. AB - Increasing diabetes prevalence has led to the need for more sustainable and person-centred services. The diabetes self-care mHealth marketplace is growing, but most effective/valued features are unknown. This study gauges diabetes app user opinion to inform development work. An analysis of diabetes mHealth apps informed design of a questionnaire sent to a random sample of 400 patients stratified by diabetes type and age. Responses were analysed by sub-group, and preferences were compared with current diabetes apps. App features included data storage/graphics, exercise tracking, health/diet, reminders/alarms, education. Questionnaire response rate was 59 per cent (234/400); 144/233 (62%) owned smartphones. Smartphone users expressed preference towards mHealth (101/142 (71%)), although diabetes use was low (12/163 (7%)). Respondents favoured many potential features, with similar preferences between diabetes types. This study demonstrates that while mHealth acceptance is high, current engagement is low. Engagement and functionality could be improved by including stakeholders in future development, driven by clinical/user need. PMID- 26635326 TI - Negative symptoms and longitudinal grey matter tissue loss in adolescents at risk of psychosis: preliminary findings from a 6-year follow-up study. AB - BACKGROUND: Negative symptoms are perhaps the most disabling feature of schizophrenia. Their pathogenesis remains poorly understood and it has been difficult to assess their development over time with imaging techniques. AIMS: To examine, using tensor-based structural imaging techniques, whether there are regions of progressive grey matter volume change associated with the development of negative symptoms. METHOD: A total of 43 adolescents at risk of psychosis were examined using magnetic resonance imaging and whole brain tensor-based morphometry at two time points, 6 years apart. RESULTS: When comparing the individuals with significant negative symptoms with the remaining participants, we identified five regions of significant grey matter tissue loss over the 6-year period. These regions included the left temporal lobe, the left cerebellum, the left posterior cingulate and the left inferior parietal sulcus. CONCLUSIONS: Negative symptoms are associated with longitudinal grey matter tissue loss. The regions identified include areas associated with psychotic symptoms more generally but also include regions uniquely associated with negative symptoms. PMID- 26635327 TI - Calibrating well-being, quality of life and common mental disorder items: psychometric epidemiology in public mental health research. AB - BACKGROUND: The assessment of 'general health and well-being' in public mental health research stimulates debates around relative merits of questionnaire instruments and their items. Little evidence regarding alignment or differential advantages of instruments or items has appeared to date. AIMS: Population-based psychometric study of items employed in public mental health narratives. METHOD: Multidimensional item response theory was applied to General Health Questionnaire (GHQ-12), Warwick-Edinburgh Mental Well-being Scale (WEMWBS) and EQ-5D items (Health Survey for England, 2010-2012; n = 19 290). RESULTS: A bifactor model provided the best account of the data and showed that the GHQ-12 and WEMWBS items assess mainly the same construct. Only one item of the EQ-5D showed relevant overlap with this dimension (anxiety/depression). Findings were corroborated by comparisons with alternative models and cross-validation analyses. CONCLUSIONS: The consequences of this lack of differentiation (GHQ-12 v. WEMWBS) for mental health and well-being narratives deserves discussion to enrich debates on priorities in public mental health and its assessment. PMID- 26635328 TI - Comparison of antidepressant classes and the risk and time course of suicide attempts in adults: propensity matched, retrospective cohort study. AB - BACKGROUND: Placebo-controlled clinical trials have led to concern over possible increased risk of suicide-related events in some populations exposed to antidepressants. AIMS: To evaluate the risk of suicide attempts by antidepressant drug class and the presence or absence of depression. METHOD: A retrospective propensity-matched new-user cohort study was used to compare participants with incident depression classified by antidepressant treatment with each other and with the general population. RESULTS: Among the treated group, the suicide attempt rate peaked in the month prior to diagnosis then decreased steadily over the next 6 months. Among the pharmacologically untreated group, the highest rate was seen in the second month after diagnosis. Cohorts with depression had significantly higher suicide attempt risk than the general population, but the treated group did not differ significantly from the untreated group. CONCLUSIONS: Patients on antidepressants did not have significantly higher risk compared with untreated patients. No significant differences were observed for patients treated with individual serotonin-noradrenaline reuptake inhibitors (SNRIs) or selective serotonin reuptake inhibitors (SSRIs) or by class (SSRI v. SNRI cohorts). PMID- 26635329 TI - Sleep in octogenarians during the postoperative phase after transcatheter or surgical aortic valve replacement. AB - BACKGROUND: Octogenarians with aortic stenosis are an increasing population of patients admitted for surgical aortic valve replacement (SAVR) or transcatheter aortic valve implantation (TAVI). Although adequate sleep is important after illness and surgery, it has scarcely been studied in the immediate postoperative phase. AIMS: To determine and compare the nature of self-reported sleep and insomnia, and recorded sleep-wake patterns in octogenarians during the in hospital postoperative phase after SAVR or TAVI. METHODS: A prospective cohort design was used that included octogenarian patients undergoing SAVR or TAVI at a regional university hospital. Self-reports were used to document sleep and insomnia, and actigraphy was used to record sleep-wake patterns. Data were collected at baseline preoperatively, and then daily for the first five postoperative days. RESULTS: SAVR patients experienced the most insomnia on postoperative nights later in recovery, while TAVI patients experienced the most insomnia on postoperative nights early in recovery. The median total sleep time, as measured by actigraphy, was 6.4 h, and the median sleep efficiency was 79% for the five postoperative nights, but no differences were found between SAVR and TAVI patients on this parameter. All patients slept more during daytime than at night, with SAVR patients having significantly more total sleep hours for all five days than TAVI patients (p < 0.01). CONCLUSION: Octogenarians with aortic stenosis had disturbed self-reported sleep, increased insomnia, and disturbed sleep-wake patterns postoperatively, resulting in more daytime sleep and inactivity. In patients undergoing SAVR or TAVI, sleep evolves differently during the in-hospital postoperative phase. PMID- 26635330 TI - No Variation in Patient Care Outcomes After Implementation of Resident Shift Work Duty Hour Limitations and a Hospitalist Model System. AB - This study examines whether implementing a resident shift work schedule (RSWS) alone or combined with a hospitalist-led model system (HMS/RSWS) affects patient care outcomes or costs at a pediatric tertiary care teaching hospital. A retrospective sample compared pre- and postintervention groups for the most common primary discharge diagnoses, including asthma and cellulitis (RSWS intervention) and inflammatory bowel disease and diabetic ketoacidosis (HMS/RSWS intervention). Outcome variables included length of stay, number of subspecialty consultations, and hospitalization charges. For the RSWS intervention, the preintervention (n = 107) and postintervention (n = 92) groups showed no difference in any of the outcome variables. For the HMS/RSWS intervention, the preintervention (n = 98) and postintervention (n = 69) groups did not differ in demographics or length of stay. However, subspecialty consultations increased significantly during postintervention from 0.83 to 1.52 consults/hospitalization ( P < .01) without significantly increasing hospitalization charges. Neither the RSWS nor HMS/RSWS intervention affected patient care outcomes at a pediatric tertiary care teaching hospital. PMID- 26635331 TI - Effect of insulin-like growth factor-I during the early postnatal period in intrauterine growth-restricted rats. AB - BACKGROUND: Insulin-like growth factor-I (IGF-I) is essential for perinatal growth and development; low serum IGF-I has been observed during intrauterine growth restriction (IUGR). We investigated the effects of recombinant human (rh) IGF-I in IUGR rats during the early postnatal period. METHODS: Intrauterine growth restriction was induced by bilateral uterine artery ligation in pregnant rats. IUGR pups were divided into two groups injected daily with rhIGF-I (2 mg/kg; IUGR/IGF-I, n = 16) or saline (IUGR/physiologic saline solution (PSS), n = 16) from postnatal day (PND) 7 to 13. Maternal sham-operated pups injected with saline were used as controls (control, n = 16). Serum IGF-I and IGF binding proteins (IGFBP) 3 and 5 were measured on PND25. The expression of Igf-i, IGF-I receptor (Igf-ir), Igfbp3, and 5 mRNA in the liver and brain was measured using real-time polymerase chain reaction on PND25. Immunohistochemical staining of the liver for IGF expression was performed. RESULTS: Mean bodyweight on PND3 and PND25 in the IUGR pups (IUGR/IGF-I and IUGR/PSS) was significantly lower than that of the control pups. Serum IGF-I and hepatic Igf-ir mRNA in the IUGR pups were significantly lower than those in the control pups. In the IUGR/IGF-I group, hepatic Igfbp3 mRNA and liver immunohistochemical staining were increased. In the IUGR/PSS and control pups, there were no significant differences between these two groups in serum IGFBP3 and IGFBP5, hepatic Igf-i and Igfbp-5 mRNA, or brain Igf mRNA. CONCLUSIONS: No benefits on body and brain weight gain but an effective increase in hepatic IGFBP-3 was observed after treatment with 2 mg/kg rhIGF-I during the early postnatal period. PMID- 26635333 TI - Will the Current Crisis in Police Legitimacy Increase Crime? Research Offers a Way Forward. PMID- 26635334 TI - The Impact of Psychological Science on Policing in the United States: Procedural Justice, Legitimacy, and Effective Law Enforcement. AB - The May 2015 release of the report of the President's Task Force on 21st Century Policing highlighted a fundamental change in the issues dominating discussions about policing in America. That change has moved discussions away from a focus on what is legal or effective in crime control and toward a concern for how the actions of the police influence public trust and confidence in the police. This shift in discourse has been motivated by two factors-first, the recognition by public officials that increases in the professionalism of the police and dramatic declines in the rate of crime have not led to increases in police legitimacy, and second, greater awareness of the limits of the dominant coercive model of policing and of the benefits of an alternative and more consensual model based on public trust and confidence in the police and legal system. Psychological research has played an important role in legitimating this change in the way policymakers think about policing by demonstrating that perceived legitimacy shapes a set of law-related behaviors as well as or better than concerns about the risk of punishment. Those behaviors include compliance with the law and cooperation with legal authorities. These findings demonstrate that legal authorities gain by a focus on legitimacy. Psychological research has further contributed by articulating and demonstrating empirical support for a central role of procedural justice in shaping legitimacy, providing legal authorities with a clear road map of strategies for creating and maintaining public trust. Given evidence of the benefits of legitimacy and a set of guidelines concerning its antecedents, policymakers have increasingly focused on the question of public trust when considering issues in policing. The acceptance of a legitimacy-based consensual model of police authority building on theories and research studies originating within psychology illustrates how psychology can contribute to the development of evidence-based policies in the field of criminal law. PMID- 26635335 TI - Structured Home-Based Exercise Versus Invasive Treatment: A Mission Impossible? A Pilot Randomized Study in Elderly Patients With Intermittent Claudication. AB - We compared the effects of an original structured home-based exercise program and revascularization in elderly patients with peripheral arterial disease over a 4 month period. Twenty-seven participants (n = 21; age = 68 +/- 7 years) with moderate to severe claudication were randomized into (1) a test in-train out group (Ti-To; n = 18) that performed a home-based walking program prescribed and controlled at the hospital or (2) a revascularization group (Rev; n = 9) that underwent an endovascular and/or surgical procedure. The primary end point was quality of life as evaluated by the physical component summary (PCS) score of the Medical Outcomes Study Short Form 36 questionnaire. Secondary outcome measures included initial claudication distance (ICD) and absolute claudication distance (ACD), 6-minute walk distance (6MWD) and pain-free walk distance (PFWD), ankle brachial index (ABI), and cost per walking meter gained. The PCS score significantly increased for both treatments at follow-up without a significant intergroup difference, as did ICD, ACD, and PFWD. The 6MWD and ABI significantly improved in the Rev group, and the Ti-To group exhibited a markedly lower cost per meter gained. The comparable effects of the 2 treatments need to be confirmed in a larger, randomized controlled trial. PMID- 26635336 TI - Overview of ICRP Committee 1: radiation effects. AB - This paper does not necessarily reflect the views of the International Commission on Radiological Protection. The author passed away on 13 November 2015.Committee 1 of the International Commission on Radiological Protection (ICRP) addresses issues pertinent to tissue reactions, risks of cancer and heritable diseases, radiation dose responses, effects of dose rate, and radiation quality. In addition, it reviews data on the effects of radiation on the embryo/fetus, genetic factors in radiation response, and uncertainties in providing judgements on radiation-induced health effects. Committee 1 advises the Main Commission on the biological basis of radiation-induced health effects, and how epidemiological, experimental, and theoretical data can be combined to make quantitative judgements on health risks to humans. The emphasis is on low radiation doses, in the form of detriment-adjusted nominal risk coefficients, where there are considerable uncertainties in terms of the biology and the epidemiology. Furthermore, Committee 1 reviews data from radiation epidemiology studies and publications on the molecular and cellular effects of ionising radiation relevant to updating the basis of the 2007 Recommendations published in ICRP Publication 103 This paper will provide an overview of the activities of Committee 1, the updated work of the Task Groups and Working Parties, and the future activities being pursued. PMID- 26635337 TI - Positron Emission Mammography Image Interpretation for Reduced Image Count Levels. AB - We studied the effects of reduced (18)F-FDG injection activity on interpretation of positron emission mammography (PEM) images and compared image interpretation between 2 postinjection imaging times. METHODS: We performed a receiver-operating characteristic (ROC) study using PEM images reconstructed with different count levels expected from injected activities between 23 and 185 MBq. Thirty patients received 2 PEM scans at postinjection times of 60 and 120 min. Half of the patients were scanned with a standard protocol; the others received one-half of the standard activity. Images were reconstructed using 100%, 50%, and 25% of the total counts acquired. Eight radiologists used a 5-point confidence scale to score 232 PEM images for the presence of up to 3 malignant lesions. Paired images were analyzed with conditional logistic regression and ROC analysis to investigate changes in interpretation. RESULTS: There was a trend for increasing lesion detection sensitivity with increased image counts: odds ratios were 2.2 (P = 0.01) and 1.9 (P = 0.04) per doubling of image counts for 60- and 120-min uptake images, respectively, without significant difference between time points (P = 0.7). The area under the ROC curve (AUC) was highest for the 100%-count, 60 min images (0.83 vs. 0.75 for 50%-counts, P = 0.02). The 120-min images had a similar trend but did not reach statistical significance (AUC = 0.79 vs. 0.73, P = 0.1). Our data did not yield significant trends between specificity and image counts. Lesion-to-background ratios increased between 60- and 120-min scans (P < 0.001). CONCLUSION: Reducing the image counts relative to the standard protocol decreased diagnostic accuracy. The increase in lesion-to-background ratio between 60- and 120-min uptake times was not enough to improve detection sensitivity in this study, perhaps in part due to fewer counts in the later scan. PMID- 26635338 TI - Complementary, Selective PET Imaging of Integrin Subtypes alpha5beta1 and alphavbeta3 Using 68Ga-Aquibeprin and 68Ga-Avebetrin. AB - Despite in vivo mapping of integrin alphavbeta3 expression being thoroughly investigated in recent years, its clinical value is still not well defined. For imaging of angiogenesis, the integrin subtype alpha5beta1 appears to be a promising target, for which purpose we designed the PET radiopharmaceutical (68)Ga-aquibeprin. METHODS: (68)Ga-aquibeprin was obtained by click-chemistry (CuAAC) trimerization of a alpha5beta1 integrin-binding pseudopeptide on the triazacyclononane-triphosphinate (TRAP) chelator, followed by automated (68)Ga labeling. Integrin alpha5beta1 and alphavbeta3 affinities were determined in enzyme linked immune sorbent assay on immobilized integrins, using fibronectin and vitronectin, respectively, as competitors. M21 (human melanoma)-bearing severe combined immunodeficient mice were used for biodistribution, PET imaging, and determination of in vivo metabolization. The expression of alpha5 and beta3 subunits was determined by immunohistochemistry on paraffin sections of M21 tumors. RESULTS: (68)Ga-aquibeprin shows high selectivity for integrin alpha5beta1 (50% inhibition concentration [IC50] = 0.088 nM) over alphavbeta3 (IC50 = 620 nM) and a pronounced hydrophilicity (log D = -4.2). Severe combined immunodeficient mice xenografted with M21 human melanoma were found suitable for in vivo evaluation, as M21 immunohistochemistry showed not only an endothelial and strong cytoplasmatic expression of the beta3 integrin subunit but also an intense expression of the alpha5 integrin subunit particularly in the endothelial cells of intratumoral small vessels. Ex vivo biodistribution (90 min after injection) showed high uptake in M21 tumor (2.42 +/- 0.21 percentage injected dose per gram), fast renal excretion, and low background; tumor-to-blood and tumor-to-muscle ratios were 10.6 +/- 2.5 and 20.9 +/- 2.4, respectively. (68)Ga aquibeprin is stable in vivo; no metabolites were detected in mouse urine, blood serum, kidney, and liver homogenates 30 min after injection. PET imaging was performed for (68)Ga-aquibeprin and the previously described, structurally related c(RGDfK) trimer (68)Ga-avebetrin, which shows an inverse selectivity for integrin alphavbeta3 (IC50 = 0.22 nM) over alpha5beta1 (IC50 = 39 nM). In vivo target specificity was proven by cross-competition studies; tumor uptake of either tracer was not affected by the coadministration of 40 nmol (~5 mg/kg) of the respective other compound. CONCLUSION: (68)Ga-aquibeprin and (68)Ga-avebetrin are recommendable for complementary mapping of integrins alpha5beta1 and alphavbeta3 by PET, allowing for future studies on the role of these integrins in angiogenesis, tumor progression, metastasis, and myocardial infarct healing. PMID- 26635339 TI - Reduction of Respiratory Motion During PET/CT by Pulsatile-Flow Ventilation: A First Clinical Evaluation. AB - Respiratory motion negatively affects PET/CT image quality and quantitation. A novel Pulsatile-Flow Ventilation (PFV) system reducing respiratory motion was applied in spontaneously breathing patients to induce sustained apnea during PET/CT. METHODS: Four patients (aged 65 +/- 14 y) underwent PET/CT for pulmonary nodule staging (mean, 11 +/- 7 mm; range, 5-18 mm) at 63 +/- 3 min after (18)F FDG injection and then at 47 +/- 7 min afterward, during PFV-induced apnea (with imaging lasting >=8.5 min). Anterior-posterior thoracic amplitude, SUVmax, and SUVpeak (SUVmean in a 1-cm-diameter sphere) were compared. RESULTS: PFV PET/CT reduced thoracic amplitude (80%), increased mean lesion SUVmax (29%) and SUVpeak (11%), decreased lung background SUVpeak (25%), improved lesion detectability, and increased SUVpeak lesion-to-background ratio (54%). On linear regressions, SUVmax and SUVpeak significantly improved (by 35% and 23%, respectively; P <= 0.02). CONCLUSION: PFV-induced apnea reduces thoracic organ motion and increases lesion SUV, detectability, and delineation, thus potentially affecting patient management by improving diagnosis, prognostication, monitoring, and external radiation therapy planning. PMID- 26635340 TI - 90Y Radioembolization of Colorectal Hepatic Metastases Using Glass Microspheres: Safety and Survival Outcomes from a 531-Patient Multicenter Study. AB - Hepatic metastases of colorectal carcinoma are a leading cause of cancer-related mortality. Most colorectal liver metastases become refractory to chemotherapy and biologic agents, at which point the median overall survival declines to 4-5 mo. Radioembolization with (90)Y has been used in the salvage setting with favorable outcomes. This study reports the survival and safety outcomes of 531 patients treated with glass-based (90)Y microspheres at 8 institutions, making it the largest (90)Y study for patients with colorectal liver metastases. METHODS: Data were retrospectively compiled from 8 institutions for all (90)Y glass microsphere treatments for colorectal liver metastases. Exposure to chemotherapeutic or biologic agents, prior liver therapies, biochemical parameters before and after treatment, radiation dosimetry, and complications were recorded. Uni- and multivariate analyses for predictors of survival were performed. Survival outcomes and clinical or biochemical adverse events were recorded. RESULTS: In total, 531 patients received (90)Y radioembolization for colorectal liver metastases. The most common clinical adverse events were fatigue (55%), abdominal pain (34%), and nausea (19%). Grade 3 or 4 hyperbilirubinemia occurred in 13% of patients at any time. The median overall survival from the first (90)Y treatment was 10.6 mo (95% confidence interval, 8.8-12.4). Performance status, no more than 25% tumor burden, no extrahepatic metastases, albumin greater than 3 g/dL, and receipt of no more than 2 chemotherapeutic agents independently predicted better survival outcomes. CONCLUSION: This multiinstitutional review of a large cohort of patients with colorectal liver metastases treated with (90)Y radioembolization using glass microspheres has demonstrated promising survival outcomes with low toxicity and low side effects. The outcomes were reproducible and consistent with prior reports of radioembolization. PMID- 26635341 TI - Optimizing Evaluation of Patients with Low-to-Intermediate-Risk Acute Chest Pain: A Randomized Study Comparing Stress Myocardial Perfusion Tomography Incorporating Stress-Only Imaging Versus Cardiac CT. AB - The purpose of this study was to determine whether stress myocardial perfusion (SPECT) optimized with stress-only (SO) imaging is comparable to cardiac CT angiography (CTA) for evaluating patients with acute chest pain (ACP). METHODS: This was a prospective randomized observational study in 598 ACP patients who underwent CTA versus SPECT. The primary endpoint was length of hospital stay, and secondary endpoints were test feasibility, time to diagnosis, diagnostic accuracy, radiation exposure, and overall cost. Median follow-up was 6.5 mo, with a 3.8% cardiac event rate defined as death or an acute coronary syndrome. RESULTS: Of 2,994 patients screened, 1,703 (56.9%) were not candidates for CTA because of prior cardiac disease (41%) or imaging contraindications (16%). Time to diagnosis (8.1 +/- 8.5 vs. 9.4 +/- 7.4 h) and length of hospital stay (19.7 +/ 27.8 vs. 23.5 +/- 34.4 h) were significantly shorter with CTA than with SPECT (P = 0.002). However, time to diagnosis (7.0 +/- 6.2 vs. 6.8 +/- 5.9 h, P = 0.20), length of stay (15.5 +/- 17.2 vs. 16.7 +/- 15.3 h, P = 0.36), and hospital costs ($4,242 +/- $3,871 vs. $4,364 +/- 1781, P = 0.86) were comparable with CTA versus SO SPECT, respectively. SO was also superior to conventional SPECT regarding all of the above metrics and significantly reduced radiation exposure (5.5 +/- 4.4 vs. 12.5 +/- 2.7 mSv, P < 0.0001). CONCLUSION: Stress SPECT when optimized with SO imaging is similar to CTA in time to diagnosis, length of hospital stay, and cost, with improved prognostic accuracy and less radiation exposure. Our results emphasize the importance of SO imaging, particularly in low-intermediate-risk emergency room patients who are a population likely to have a normal test result. PMID- 26635342 TI - c-Met PET Imaging Detects Early-Stage Locoregional Recurrence of Basal-Like Breast Cancer. AB - Locoregional recurrence of breast cancer poses significant clinical problems because of frequent inoperability once the chest wall is involved. Early detection of recurrence by molecular imaging agents against therapeutically targetable receptors, such as c-Met, would be of potential benefit. The aim of this study was to assess (18)F-AH113804, a peptide-based molecular imaging agent with high affinity for human c-Met, for the detection of early-stage locoregional recurrence in a human basal-like breast cancer model, HCC1954. METHODS: HCC1954 tumor-bearing xenograft models were established, and (18)F-AH113804 was administered. Distribution of radioactivity was determined via PET at 60 min after radiotracer injection. PET and CT images were acquired 10 d after tumor inoculation, to establish baseline distribution and uptake, and then on selected days after surgical tumor resection. CT images and caliper were used to determine the tumor volume. Radiotracer uptake was assessed by (18)F-AH113804 PET imaging. c-Met expression was assessed by immunofluorescence imaging of tumor samples and correlated with (18)F-AH113804 PET imaging results. RESULTS: Baseline uptake of (18)F-AH113804, determined in tumor-bearing animals after 10 d, was approximately 2-fold higher in the tumor than in muscle tissue or the contralateral mammary fat pad. The tumor growth rate, determined from CT images, was comparable between the animals with recurrent tumors, with detection of tumors of low volume (<10 mm(3)) only possible by day 20 after tumor resection. (18)F-AH113804 PET detected local tumor recurrence as early as 6 d after surgery in the recurrent tumor-bearing animals and exhibited significantly higher (18)F-AH113804 uptake (in comparison to mammary fatty tissue), with a target-to-background (muscle) ratio of approximately 3:1 (P < 0.01). The c-Met expression of individual resected tumor samples, determined by immunofluorescence, correlated with the respective (18)F AH113804 imaging signals (r = 0.82, P < 0.05). CONCLUSION: (18)F-AH113804 PET provides a new diagnostic tool for the detection of c-Met-expressing primary tumor and has potential utility for the detection of locoregional recurrence from an early stage. PMID- 26635343 TI - Utilizing High-Energy gamma-Photons for High-Resolution 213Bi SPECT in Mice. AB - The combined alpha-, gamma-, and x-ray emitter (213)Bi (half-life, 46 min) is promising for radionuclide therapy. SPECT imaging of (213)Bi is challenging, because most emitted photons have a much higher energy (440 keV) than common in SPECT. We assessed (213)Bi imaging capabilities of the Versatile Emission Computed Tomograph (VECTor) dedicated to (simultaneous) preclinical imaging of both SPECT and PET isotopes over a wide photon energy range of 25-600 keV. METHODS: VECTor was equipped with a dedicated clustered pinhole collimator. Both the 79 keV x-rays and the 440 keV gamma-rays emitted by (213)Bi could be imaged. Phantom experiments were performed to determine the maximum resolution, contrast to-noise ratio, and activity recovery coefficient for different energy window settings. Additionally, imaging of [(213)Bi-DOTA,Tyr(3)]octreotate and (213)Bi diethylene triamine pentaacetic acid (DTPA) in mouse models was performed. RESULTS: Using 440 keV gamma-rays instead of 79 keV x-rays in image reconstruction strongly improved the resolution (0.75 mm) and contrast-to-noise characteristics. Results obtained with a single 440 keV energy window setting were close to those with a combined 79 keV/440 keV window. We found a reliable activity recovery coefficient down to 0.240 MBq/mL with 30-min imaging time. In a tumor-bearing mouse injected with 3 MBq of [(213)Bi-DOTA,Tyr(3)]octreotate, tumor uptake could be visualized with a 1-h postmortem scan. Imaging a nontumor mouse at 5-min frames after injection of 7.4 MBq of (213)Bi-DTPA showed renal uptake and urinary clearance, visualizing the renal excretion pathway from cortex to ureter. Quantification of the uptake data allowed kinetic modeling and estimation of the absorbed dose to the kidneys. CONCLUSION: It is feasible to image (213)Bi down to a 0.75-mm resolution using a SPECT system equipped with a dedicated collimator. PMID- 26635344 TI - Monitoring Therapy Response of Experimental Arthritis with Radiolabeled Tracers Targeting Fibroblasts, Macrophages, or Integrin alphavbeta3. AB - Rheumatoid arthritis is an autoimmune disease resulting in chronic synovial inflammation. Molecular imaging could be used to monitor therapy response, thus enabling tailored therapy regimens and enhancing therapeutic outcome. Here, we hypothesized that response to etanercept could be monitored by radionuclide imaging in arthritic mice. We tested 3 different targets, namely fibroblast activation protein (FAP), macrophages, and integrin alphavbeta3. METHODS: Male DBA/1J mice with collagen-induced arthritis were treated with etanercept. SPECT/CT scans were acquired at 1, 24, and 48 h after injection of (111)In-RGD2 (integrin alphavbeta3), (111)In-anti-F4/80-A3-1 (antimurine macrophage antibody), or (111)In-28H1 (anti-FAP antibody), respectively, with nonspecific controls included. Mice were dissected after the last scan, and scans were analyzed quantitatively and were correlated with macroscopic scoring. RESULTS: Experimental arthritis was imaged with (111)In-28H1 (anti-FAP), (111)In-anti F4/80-A3-1, and (111)In-RGD2. Tracer uptake in joints correlated with arthritis score. Treatment decreased joint uptake of tracers from 23 +/- 15, 8 +/- 4, and 2 +/- 1 percentage injected dose per gram (%ID/g) to 11 +/- 11 (P < 0.001), 4 +/- 4 (P < 0.001), and 1 +/- 0.2 %ID/g (P < 0.01) for (111)In-28H1, (111)In-anti-F4/80 A3-1, and (111)In-RGD2, respectively. Arthritis-to-blood ratios (in mice with arthritis score 2 per joint) were higher for (111)In-28H1 (5.5 +/- 1; excluding values > 25), (111)In-anti-F4/80-A3-1 (10.4 +/- 4), and (111)In-RGD2 (7.2 +/- 1) than for control (111)In-DP47GS (0.7 +/- 0.5; P = 0.002), (111)In-rat IgG2b (0.5 +/- 0.2; P = 0.002), or coinjection of excess RGD2 (3.5), indicating specific uptake of all tracers in arthritic joints. CONCLUSION: (111)In-28H1, (111)In-anti F4/80-A3-1, and (111)In-RGD2 can be used to specifically monitor the response to therapy in experimental arthritis at the molecular level. Further studies, however, still need to be performed. PMID- 26635345 TI - Prognostic Value of Myocardial Perfusion SPECT After Intravenous Bolus Administration of Nicorandil in Patients with Acute Ischemic Heart Failure. AB - Nicorandil, a hybrid adenosine triphosphate (ATP)-sensitive potassium channel opener and nitrate, is commonly used for the management of acute ischemic heart failure (AIHF). The aims of this study were to predict the effect of nicorandil by calculating myocardium-to-background ratio increasing rate (MBR-IR) using nicorandil stress myocardial perfusion SPECT and to evaluate the prognostic value of MBR-IR in patients with AIHF. METHODS: Twenty-two patients (age, 70 +/- 12 y) admitted to the coronary care unit with AIHF underwent nicorandil-stress and rest myocardial perfusion SPECT. Using these images, MBR-IR was calculated by dividing stress MBR by rest MBR (MBR = peak value of left ventricular myocardial segments/mean value of upper mediastinum). In order to evaluate the clinical importance of MBR-IR derived from the nicorandil-stress test, all patients were divided into 2 groups, based on the value of MBR-IR. All patients were observed over 5 y from the onset of AIHF for the occurrence of major adverse cardiac events (MACE). RESULTS: Both high- and low-MBR-IR groups contained 11 participants. Median MBR-IR was 1.55 (1.34-1.61) in the high-MBR-IR group and 1.08 (1.02-1.10) in the low-MBR-IR group. The proportion of patients who experienced MACE was significantly higher in the low-MBR-IR group than in the high-MBR-IR group (91% vs. 18%, P < 0.001). CONCLUSION: This study demonstrated that the MBR-IR calculated using nicorandil-stress myocardial perfusion SPECT may have a high prognostic value for MACE in patients with AIHF. PMID- 26635347 TI - Sampling frequency affects the processing of Actigraph raw acceleration data to activity counts. AB - ActiGraph acceleration data are processed through several steps (including band pass filtering to attenuate unwanted signal frequencies) to generate the activity counts commonly used in physical activity research. We performed three experiments to investigate the effect of sampling frequency on the generation of activity counts. Ideal acceleration signals were produced in the MATLAB software. Thereafter, ActiGraph GT3X+ monitors were spun in a mechanical setup. Finally, 20 subjects performed walking and running wearing GT3X+ monitors. Acceleration data from all experiments were collected with different sampling frequencies, and activity counts were generated with the ActiLife software. With the default 30-Hz (or 60-Hz, 90-Hz) sampling frequency, the generation of activity counts was performed as intended with 50% attenuation of acceleration signals with a frequency of 2.5 Hz by the signal frequency band-pass filter. Frequencies above 5 Hz were eliminated totally. However, with other sampling frequencies, acceleration signals above 5 Hz escaped the band-pass filter to a varied degree and contributed to additional activity counts. Similar results were found for the spinning of the GT3X+ monitors, although the amount of activity counts generated was less, indicating that raw data stored in the GT3X+ monitor is processed. Between 600 and 1,600 more counts per minute were generated with the sampling frequencies 40 and 100 Hz compared with 30 Hz during running. Sampling frequency affects the processing of ActiGraph acceleration data to activity counts. Researchers need to be aware of this error when selecting sampling frequencies other than the default 30 Hz. PMID- 26635346 TI - Redistribution of inhaled hyperpolarized 3He gas during breath-hold differs by asthma severity. AB - The purpose of this work was to quantify the redistribution of ventilation weighted signal in the lungs of asthmatic subjects during a breath-hold using high temporal-spatial resolution hyperpolarized (HP) He-3 MRI. HP He-3 MRI was used to obtain time-resolved, volumetric images of lung ventilation during breath hold in 39 human subjects classified as either healthy/nondiseased (n = 14), mild to-moderate asthmatic (n = 17), or severely asthmatic (n = 8). Signals were normalized to a standard lung volume, so that voxels within the lung from all 39 subjects could be analyzed as a group to increase statistical power and enable semiautomated classification of voxels into 1 of 5 ventilation level categories (ranging from defect to hyperintense). End-inspiratory ventilation distribution and temporal rates of mean signal change for each of the five ventilation categories were compared using ANOVA. Time rates of signal change were hypothesized to represent underlying gas redistribution processes, potentially influenced by disease. We found that mild-to-moderate asthmatic subjects showed the greatest rate of signal change, even though those with severe asthma had the greatest end-inspiration ventilation heterogeneity. The observed results support the existence of local differences in airway resistances associated with the different obstructive patterns in the lungs for severe vs. mild-to-moderate asthmatic subjects. PMID- 26635348 TI - No effect of acute beetroot juice ingestion on oxygen consumption, glucose kinetics, or skeletal muscle metabolism during submaximal exercise in males. AB - Beetroot juice, which is rich in nitrate (NO3 (-)), has been shown in some studies to decrease oxygen consumption (Vo2) for a given exercise workload, i.e., increasing efficiency and exercise tolerance. Few studies have examined the effect of beetroot juice or nitrate supplementation on exercise metabolism. Eight healthy recreationally active males participated in three trials involving ingestion of either beetroot juice (Beet; ~8 mmol NO3 (-)), Placebo (nitrate depleted Beet), or Beet + mouthwash (Beet+MW), all of which were performed in a randomized single-blind crossover design. Two-and-a-half hours later, participants cycled for 60 min on an ergometer at 65% of Vo2 peak. [6,6 (2)H]glucose was infused to determine glucose kinetics, blood samples obtained throughout exercise, and skeletal muscle biopsies that were obtained pre- and postexercise. Plasma nitrite [NO2 (-)] increased significantly (~130%) with Beet, and this was attenuated in MW+Beet. Beet and Beet+MW had no significant effect on oxygen consumption, blood glucose, blood lactate, plasma nonesterified fatty acids, or plasma insulin during exercise. Beet and Beet+MW also had no significant effect on the increase in glucose disposal during exercise. In addition, Beet and Beet+MW had no significant effect on the decrease in muscle glycogen and phosphocreatine and the increase in muscle creatine, lactate, and phosphorylated acetyl CoA carboxylase during exercise. In conclusion, at the dose used, acute ingestion of beetroot juice had little effect on skeletal muscle metabolism during exercise. PMID- 26635349 TI - Retrograde lower body arterial reservoir discharge underlies rapid reversal of ductus arteriosus shunting after early cord clamping at birth in preterm lambs. AB - Arterial reservoir ("windkessel") function, whereby a part of left ventricular (LV) output is stored in elastic arteries during systole and discharged in diastole, is a well-established physiological phenomenon. However, its role in rapid reversal (to left-to-right) and a systolic-to-diastolic shift of shunting across the ductus arteriosus after birth is unknown. To address this question, ductal and aortic isthmus flows were measured with high-fidelity transit-time probes in six anesthetized preterm fetal lambs before and after cord clamping and subsequent early mechanical ventilation and for 30 min postbirth. Descending aortic flow was calculated as the sum of isthmus and ductal flows. Left-to-right ductal flow profiles were related to those of the isthmus and descending aorta, with upper body arterial reservoir discharge indicated by forward diastolic isthmus flow, and retrograde lower body arterial reservoir discharge by negative diastolic descending aortic flow. Left-to-right ductal shunting appeared immediately after cord clamping (P < 0.001), due entirely to newly emergent retrograde lower body reservoir discharge, and rose with ventilation via increased lower body reservoir discharge (P < 0.005), supplemented by upper body reservoir discharge after 45 s (P < 0.025) and LV systolic flow after 3 min (P = 0.025). The contribution of lower body reservoir discharge to left-to-right ductal shunting fell to 55 +/- 8% at >=15 min (P < 0.001) but remained higher (P < 0.002) than LV systolic flow (33 +/- 8%) or upper body reservoir discharge (12 +/- 5%). These results suggest that retrograde lower body arterial reservoir discharge plays a key role in rapid reversal and a systolic-to-diastolic shift of ductal shunting after cord clamping and early ventilation at birth. PMID- 26635350 TI - Hopping locomotion at different gravity: metabolism and mechanics in humans. AB - Previous literature on the effects of low gravity on the mechanics and energetics of human locomotion already dealt with walking, running, and skipping. The aim of the present study is to obtain a comprehensive view on that subject by including measurements of human hopping in simulated low gravity, a gait often adopted in many Apollo Missions and documented in NASA footage. Six subjects hopped at different speeds at terrestrial, Martian, and Lunar gravity on a treadmill while oxygen consumption and 3D body kinematic were sampled. Results clearly indicate that hopping is too metabolically expensive to be a sustainable locomotion on Earth but, similarly to skipping (and running), its economy greatly (more than *10) increases at lower gravity. On the Moon, the metabolic cost of hopping becomes even lower than that of walking, skipping, and running, but the general finding is that gaits with very different economy on Earth share almost the same economy on the Moon. The mechanical reasons for such a decrease in cost are discussed in the paper. The present data, together with previous findings, will allow also to predict the aerobic traverse range/duration of astronauts when getting far from their base station on low gravity planets. PMID- 26635351 TI - Probing the enzyme kinetics, allosteric modulation and activation of alpha1- and alpha2-subunit-containing AMP-activated protein kinase (AMPK) heterotrimeric complexes by pharmacological and physiological activators. AB - AMP-activated protein kinase (AMPK) is a serine/threonine protein kinase that serves as a pleotropic regulator of whole body energy homoeostasis. AMPK exists as a heterotrimeric complex, composed of a catalytic subunit (alpha) and two regulatory subunits (beta and gamma), each present as multiple isoforms. In the present study, we compared the enzyme kinetics and allosteric modulation of six recombinant AMPK isoforms, alpha1beta1gamma1, alpha1beta2gamma1, alpha1beta2gamma3, alpha2beta1gamma1, alpha2beta2gamma1 and alpha2beta2gamma3 using known activators, A769662 and AMP. The alpha1-containing complexes exhibited higher specific activities and lower Km values for a widely used peptide substrate (SAMS) compared with alpha2-complexes. Surface plasmon resonance (SPR)-based direct binding measurements revealed biphasic binding modes with two distinct equilibrium binding constants for AMP, ADP and ATP across all isoforms tested. The alpha2-complexes were ~25-fold more sensitive than alpha1 complexes to dephosphorylation of a critical threonine on their activation loop (pThr(172/174)). However, alpha2-complexes were more readily activated by AMP than alpha1-complexes. Compared with beta1-containing heterotrimers, beta2 containing AMPK isoforms are less sensitive to activation by A769662, a synthetic activator. These data demonstrate that ligand induced activation of AMPK isoforms may vary significantly based on their AMPK subunit composition. Our studies provide insights for the design of isoform-selective AMPK activators for the treatment of metabolic diseases. PMID- 26635352 TI - Protein kinase Czeta exhibits constitutive phosphorylation and phosphatidylinositol-3,4,5-triphosphate-independent regulation. AB - Atypical protein kinase C (aPKC) isoenzymes are key modulators of insulin signalling, and their dysfunction correlates with insulin-resistant states in both mice and humans. Despite the engaged interest in the importance of aPKCs to type 2 diabetes, much less is known about the molecular mechanisms that govern their cellular functions than for the conventional and novel PKC isoenzymes and the functionally-related protein kinase B (Akt) family of kinases. Here we show that aPKC is constitutively phosphorylated and, using a genetically-encoded reporter for PKC activity, basally active in cells. Specifically, we show that phosphorylation at two key regulatory sites, the activation loop and turn motif, of the aPKC PKCzeta in multiple cultured cell types is constitutive and independently regulated by separate kinases: ribosome-associated mammalian target of rapamycin complex 2 (mTORC2) mediates co-translational phosphorylation of the turn motif, followed by phosphorylation at the activation loop by phosphoinositide-dependent kinase-1 (PDK1). Live cell imaging reveals that global aPKC activity is constitutive and insulin unresponsive, in marked contrast to the insulin-dependent activation of Akt monitored by an Akt-specific reporter. Nor does forced recruitment to phosphoinositides by fusing the pleckstrin homology (PH) domain of Akt to the kinase domain of PKCzeta alter either the phosphorylation or activity of PKCzeta. Thus, insulin stimulation does not activate PKCzeta through the canonical phosphatidylinositol-3,4,5-triphosphate mediated pathway that activates Akt, contrasting with previous literature on PKCzeta activation. These studies support a model wherein an alternative mechanism regulates PKCzeta-mediated insulin signalling that does not utilize conventional activation via agonist-evoked phosphorylation at the activation loop. Rather, we propose that scaffolding near substrates drives the function of PKCzeta. PMID- 26635354 TI - The STAS domain of mammalian SLC26A5 prestin harbours an anion-binding site. AB - Prestin is a unique ATP- and Ca(2+)-independent molecular motor with piezoelectric characteristics responsible for the electromotile properties of mammalian cochlear outer hair cells, i.e. the capacity of these cells to modify their length in response to electric stimuli. This 'electromotility' is at the basis of the exceptional sensitivity and frequency selectivity distinctive of mammals. Prestin belongs to the SLC26 (solute carrier 26) family of anion transporters and needs anions to function properly, particularly Cl(-). In the present study, using X-ray crystallography we reveal that the STAS (sulfate transporter and anti-sigma factor antagonist) domain of mammalian prestin, considered an 'incomplete' transporter, harbours an unanticipated anion-binding site. In parallel, we present the first crystal structure of a prestin STAS domain from a non-mammalian vertebrate prestin (chicken) that behaves as a 'full' transporter. Notably, in chicken STAS, the anion-binding site is lacking because of a local structural rearrangement, indicating that the presence of the STAS anion-binding site is exclusive to mammalian prestin. PMID- 26635353 TI - Determination of sites of U50,488H-promoted phosphorylation of the mouse kappa opioid receptor (KOPR): disconnect between KOPR phosphorylation and internalization. AB - Phosphorylation sites of KOPR (kappa opioid receptor) following treatment with the selective agonist U50,488H {(-)(trans)-3,4-dichloro-N-methyl-N-[2-(1 pyrrolidiny)cyclo-hexyl]benzeneacetamide} were identified after affinity purification, SDS/PAGE, in-gel digestion with Glu-C and HPLC-MS/MS. Single- and double-phosphorylated peptides were identified containing phosphorylated Ser(356), Thr(357), Thr(363) and Ser(369) in the C-terminal domain. Antibodies were generated against three phosphopeptides containing pSer(356)/pThr(357), pThr(363) and pSer(369) respectively, and affinity-purified antibodies were found to be highly specific for phospho-KOPR. U50,488H markedly enhanced staining of the KOPR by pThr(363)-, pSer(369)- and pSer(356)/pThr(357)-specific antibodies in immunoblotting, which was blocked by the selective KOPR antagonist norbinaltorphimine. Ser(369) phosphorylation affected Thr(363) phosphorylation and vice versa, and Thr(363) or Ser(369) phosphorylation was important for Ser(356)/Thr(357) phosphorylation, revealing a phosphorylation hierarchy. U50,488H, but not etorphine, promoted robust KOPR internalization, although both were full agonists. U50,488H induced higher degrees of phosphorylation than etorphine at Ser(356)/Thr(357), Thr(363) and Ser(369) as determined by immunoblotting. Using SILAC (stable isotope labelling by amino acids in cell culture) and HPLC-MS/MS, we found that, compared with control (C), U50,488H (U) and etorphine (E) KOPR promoted single phosphorylation primarily at Thr(363) and Ser(369) with U/E ratios of 2.5 and 2 respectively. Both induced double phosphorylation at Thr(363)+Ser(369) and Thr(357)+Ser(369) with U/E ratios of 3.3 and 3.4 respectively. Only U50,488H induced triple phosphorylation at Ser(356)+Thr(357)+Ser(369). An unphosphorylated KOPR-(354-372) fragment containing all of the phosphorylation sites was detected with a C/E/U ratio of 1/0.7/0.4, indicating that ~60% and ~30% of the mouse KOPR are phosphorylated following U50,488H and etorphine respectively. Thus KOPR internalization requires receptor phosphorylation above a certain threshold, and higher-order KOPR phosphorylation may be disproportionally important. PMID- 26635355 TI - Effect of SLC26 anion transporter disease-causing mutations on the stability of the homologous STAS domain of E. coli DauA (YchM). AB - The human solute carrier 26 (SLC26) family of anion transporters consists of ten members that are found in various organs in the body including the stomach, intestine, kidney, thyroid and ear where they transport anions including bicarbonate, chloride and sulfate, typically in an exchange mode. Mutations in these genes cause a plethora of diseases such as diastrophic dysplasia affecting sulfate uptake into chondrocytes (SLC26A2), congenital chloride-losing diarrhoea (SLC26A3) affecting chloride secretion in the intestine and Pendred's syndrome (SLC26A4) resulting in hearing loss. To understand how these mutations affect the structures of the SLC26 membrane proteins and their ability to function properly, 12 human disease-causing mutants from SLC26A2, SLC26A3 and SLC26A4 were introduced into the equivalent sites of the sulfate transporter anti-sigma factor antagonist (STAS) domain of a bacterial homologue SLC26 protein DauA (YchM). Biophysical analyses including size-exclusion chromatography, circular dichroism (CD), differential scanning fluorimetry (DSF) and tryptophan fluorescence revealed that most mutations caused protein instability and aggregation. The mutation A463K, equivalent to N558K in human SLC26A4, which is located within alpha-helix 1 of the DauA STAS domain, stabilized the protein. CD measurements showed that most disease-related mutants had a mildly reduced helix content, but were more sensitive to thermal denaturation. Fluorescence spectroscopy showed that the mutants had more open structures and were more readily denatured by urea, whereas DSF indicated more labile folds. Overall, we conclude that the disease-associated mutations destabilized the STAS domain resulting in an increased propensity to misfold and aggregate. PMID- 26635356 TI - Circulating FGF21 proteolytic processing mediated by fibroblast activation protein. AB - Fibroblast growth factor 21 (FGF21), a hormone implicated in the regulation of glucose homoeostasis, insulin sensitivity, lipid metabolism and body weight, is considered to be a promising therapeutic target for the treatment of metabolic disorders. Despite observations that FGF21 is rapidly proteolysed in circulation rending it potentially inactive, little is known regarding mechanisms by which FGF21 protein levels are regulated. We systematically investigated human FGF21 protein processing using mass spectrometry. In agreement with previous reports, circulating human FGF21 was found to be cleaved primarily after three proline residues at positions 2, 4 and 171. The extent of FGF21 processing was quantified in a small cohort of healthy human volunteers. Relative abundance of FGF21 proteins cleaved after Pro-2, Pro-4 and Pro-171 ranged from 16 to 30%, 10 to 25% and 10 to 34%, respectively. Dipeptidyl peptidase IV (DPP-IV) was found to be the primary protease responsible for N-terminal cleavages after residues Pro-2 and Pro-4. Importantly, fibroblast activation protein (FAP) was implicated as the protease responsible for C-terminal cleavage after Pro-171, rendering the protein inactive. The requirement of FAP for FGF21 proteolysis at the C-terminus was independently demonstrated by in vitro digestion, immunodepletion of FAP in human plasma, administration of an FAP-specific inhibitor and by human FGF21 protein processing patterns in FAP knockout mouse plasma. The discovery that FAP is responsible for FGF21 inactivation extends the FGF21 signalling pathway and may enable novel approaches to augment FGF21 actions for therapeutic applications. PMID- 26635357 TI - Substrate specificity, kinetic properties and inhibition by fumonisin B1 of ceramide synthase isoforms from Arabidopsis. AB - Ceramide makes up the acyl-backbone of sphingolipids and plays a central role in determining the function of these essential membrane lipids. In Arabidopsis, the varied chemical composition of ceramide is determined by the specificity of three different isoforms of ceramide synthase, denoted LAG one homologue 1, -2 and -3 (LOH1, LOH2 and LOH3), for a range of long-chain base (LCB) and acyl-CoA substrates. The contribution of each of these isoforms to the synthesis of ceramide was investigated by in vitro ceramide synthase assays. The plant LCB phytosphingosine was efficiently used by the LOH1 and LOH3 isoforms, with LOH1 having the lowest Km for the LCB substrate of the three isoforms. In contrast, sphinganine was used efficiently only by the LOH2 isoform. Acyl-CoA specificity was also distinguished between the three isoforms with LOH2 almost completely specific for palmitoyl-CoA whereas the LOH1 isoform showed greatest activity with lignoceroyl- and hexacosanoyl-CoAs. Interestingly, unsaturated acyl-CoAs were not used efficiently by any isoform whereas unsaturated LCB substrates were preferred by LOH2 and 3. Fumonisin B1 (FB1) is a general inhibitor of ceramide synthases but LOH1 was found to have a much lower Ki than the other isoforms pointing towards the origin of FB1 sensitivity in plants. Overall, the data suggest distinct roles and modes of regulation for each of the ceramide synthases in Arabidopsis sphingolipid metabolism. PMID- 26635358 TI - Isotemporal substitution of sedentary time by physical activity of different intensities and bout lengths, and its associations with metabolic risk. AB - BACKGROUND: Time spent being sedentary, regardless of time in exercise, has been associated with metabolic risk using regression modelling. By using isotemporal substitution modelling, the effect of replacing sedentary time with an equal amount of time in physical activity (PA) of different intensities can be considered. The present study aims to investigate the effect of replacing sedentary time with time in light, moderate and vigorous PA to the prevalence of the metabolic syndrome (MetS). Also, replacement of sedentary time by PA of different bout lengths was studied. METHODS: In total, 836 participants (52% women), aged 50-64 years, from the SCAPIS pilot study were included. Daily time spent sedentary and in PA of different intensities was assessed using hip-worn accelerometers. RESULTS: In this cross-sectional study, replacing 10 minutes of sedentary time with the same amount of light PA was associated with significant lower MetS prevalence, odds ratio (OR) 0.96 (95% confidence interval 0.93-0.98). Replacement with moderate PA resulted in even lower OR, 0.89 (0.82-0.97), with the lowest OR for vigorous PA, 0.41 (0.26-0.66). Participants with high energy intake and high daily sedentary time benefitted more from the replacement of sedentary time with light PA. Significant associations were seen for all bout lengths of light, moderate and vigorous PA in a stepwise-like fashion from one minute to up to 120 minute bouts. CONCLUSION: Theoretical substitutions of sedentary time with PA of any intensity and of as little as one minute were associated with significantly lower ORs for MetS. This may be an easily communicable message in clinical practice and for public health purposes. PMID- 26635359 TI - SERVE-HF: What does it mean for cardiac rehabilitation? PMID- 26635360 TI - Work and leisure time sitting and inactivity: Effects on cardiorespiratory and metabolic health. AB - BACKGROUND: Prospective relationships between sedentary behaviour and cardiorespiratory and metabolic markers need to be better delineated in adults with different physical activity levels. We examined the separate and combined relationships of work and leisure time sitting and moderate to vigorous physical activity (MVPA) with cardiorespiratory fitness and cardiometabolic risk factors. METHODS: A total of 2308 adults from the Health2006 cohort were followed for five years. Work sitting, leisure time sitting and MVPA were self-reported and cardiorespiratory fitness (Vo2max) was estimated by a submaximal step test. Cardiometabolic risk factors included body mass index, waist circumference, systolic and diastolic blood pressure, triglycerides, high-density lipoprotein cholesterol and insulin levels. Prospective associations with each sitting domain alone and in combination with MVPA level were investigated by multiple linear regression analyses, as were the reverse associations with weight status (body mass index and waist circumference). RESULTS: Baseline leisure time sitting predicted increased insulin (p < 0.05) and decreased estimated Vo2max (p < 0.05), whereas work sitting predicted decreased waist circumference (p < 0.05) and increased estimated Vo2max (p < 0.01) over the five-year study. Low baseline leisure time sitting, but not work sitting, predicted increased estimated Vo2max regardless of the MVPA level. Weight status predicted increased leisure time sitting (p < 0.01), but leisure time sitting did not predict weight. CONCLUSIONS: These findings emphasize sedentary behaviour during leisure time, rather than at work, as a risk behaviour in relation to cardiorespiratory and metabolic health. For cardiorespiratory fitness, it may be important not only to promote MVPA, but also to discourage sedentary behaviour during leisure time. PMID- 26635361 TI - Long-term prognostic utility of pentraxin 3 and D-dimer as compared to high sensitivity C-reactive protein and B-type natriuretic peptide in suspected acute coronary syndrome. AB - BACKGROUND: Vascular inflammation plays a key role in the development of atherosclerosis and acute coronary syndrome (ACS), and pentraxin 3 (PTX3) is one of several novel, promising markers of inflammation. In addition, D-dimer might serve as a marker of thrombogenesis and a hypercoagulable state following plaque rupture. The present study assesses the prognostic utility of these two biomarkers as compared to high-sensitivity C-reactive protein (hsCRP) and B-type natriuretic peptide (BNP), in addition to conventional clinical risk factors for coronary heart disease in patients with suspected ACS. METHODS: Chest pain patients with suspected ACS (n = 871) were consecutively included in a prospective, observational study with a follow-up time of 84 months. RESULTS: At 7-year follow-up, 332 patients had died and 203 had suffered an adverse troponin T-positive, non-fatal cardiac event. In the multivariate analysis, levels of PTX3 above 5.88 ng/mL (median) and D-dimer above 436 ug/L (lower limit upper quartile) independently predicted mortality (HR 1.60 [95% CI 1.10-2.33]; p = 0.014 and HR 1.83 [95% CI 1.20-2.78]; p = 0.005, respectively). Also, BNP levels above 310.75 pg/mL (lower limit upper quartile) (HR 2.16 [95% CI 1.37-3.42]; p = 0.001), but not hsCRP, independently predicted mortality. Only hsCRP and BNP also predicted future myocardial infarction (HR 1.59 [95% CI 1.05-2.40]; p = 0.029 and HR 1.91 [95% CI 1.10-3.31]; p = 0.021, respectively). CONCLUSION: High levels of PTX3, D dimer and BNP were found to be independent, long-term predictors of all-cause mortality in chest pain patients with a suspected ACS. hsCRP and BNP also predicted future myocardial infarction. PMID- 26635362 TI - Linezolid Dosing in a Morbidly Obese Patient With MRSA Pneumonia. PMID- 26635364 TI - Wasabi: An Integrated Platform for Evolutionary Sequence Analysis and Data Visualization. AB - Wasabi is an open source, web-based environment for evolutionary sequence analysis. Wasabi visualizes sequence data together with a phylogenetic tree within a modern, user-friendly interface: The interface hides extraneous options, supports context sensitive menus, drag-and-drop editing, and displays additional information, such as ancestral sequences, associated with specific tree nodes. The Wasabi environment supports reproducibility by automatically storing intermediate analysis steps and includes built-in functions to share data between users and publish analysis results. For computational analysis, Wasabi supports PRANK and PAGAN for phylogeny-aware alignment and alignment extension, and it can be easily extended with other tools. Along with drag-and-drop import of local files, Wasabi can access remote data through URL and import sequence data, GeneTrees and EPO alignments directly from Ensembl. To demonstrate a typical workflow using Wasabi, we reproduce key findings from recent comparative genomics studies, including a reanalysis of the EGLN1 gene from the tiger genome study: These case studies can be browsed within Wasabi at http://wasabiapp.org:8000?id=usecases. Wasabi runs inside a web browser and does not require any installation. One can start using it at http://wasabiapp.org. All source code is licensed under the AGPLv3. PMID- 26635363 TI - Quantitative Profiling of Post-translational Modifications by Immunoaffinity Enrichment and LC-MS/MS in Cancer Serum without Immunodepletion. AB - A robust method was developed and optimized for enrichment and quantitative analysis of posttranslational modifications (PTMs) in serum/plasma samples by combining immunoaffinity purification and LC-MS/MS without depletion of abundant proteins. The method was used to survey serum samples of patients with acute myeloid leukemia (AML), breast cancer (BC), and nonsmall cell lung cancer (NSCLC). Peptides were identified from serum samples containing phosphorylation, acetylation, lysine methylation, and arginine methylation. Of the PTMs identified, lysine acetylation (AcK) and arginine mono-methylation (Rme) were more prevalent than other PTMs. Label-free quantitative analysis of AcK and Rme peptides was performed for sera from AML, BC, and NSCLC patients. Several AcK and Rme sites showed distinct abundance distribution patterns across the three cancer types. The identification and quantification of posttranslationally modified peptides in serum samples reported here can be used for patient profiling and biomarker discovery research. PMID- 26635365 TI - Recycling and Endosomal Sorting of Protease-activated Receptor-1 Is Distinctly Regulated by Rab11A and Rab11B Proteins. AB - Protease-activated receptor-1 (PAR1) is a G protein-coupled receptor that undergoes proteolytic irreversible activation by coagulant and anti-coagulant proteases. Given the irreversible activation of PAR1, signaling by the receptor is tightly regulated through desensitization and intracellular trafficking. PAR1 displays both constitutive and agonist-induced internalization. Constitutive internalization of PAR1 is important for generating an internal pool of naive receptors that replenish the cell surface and facilitate resensitization, whereas agonist-induced internalization of PAR1 is critical for terminating G protein signaling. We showed that PAR1 constitutive internalization is mediated by the adaptor protein complex-2 (AP-2), whereas AP-2 and epsin control agonist-induced PAR1 internalization. However, the mechanisms that regulate PAR1 recycling are not known. In the present study we screened a siRNA library of 140 different membrane trafficking proteins to identify key regulators of PAR1 intracellular trafficking. In addition to known mediators of PAR1 endocytosis, we identified Rab11B as a critical regulator of PAR1 trafficking. We found that siRNA-mediated depletion of Rab11B and not Rab11A blocks PAR1 recycling, which enhanced receptor lysosomal degradation. Although Rab11A is not required for PAR1 recycling, depletion of Rab11A resulted in intracellular accumulation of PAR1 through disruption of basal lysosomal degradation of the receptor. Moreover, enhanced degradation of PAR1 observed in Rab11B-deficient cells is blocked by depletion of Rab11A and the autophagy related-5 protein, suggesting that PAR1 is shuttled to an autophagic degradation pathway in the absence of Rab11B recycling. Together these findings suggest that Rab11A and Rab11B differentially regulate intracellular trafficking of PAR1 through distinct endosomal sorting mechanisms. PMID- 26635366 TI - Biochemical and Structural Characterization of the Interaction between the Siderocalin NGAL/LCN2 (Neutrophil Gelatinase-associated Lipocalin/Lipocalin 2) and the N-terminal Domain of Its Endocytic Receptor SLC22A17. AB - The neutrophil gelatinase-associated lipocalin (NGAL, also known as LCN2) and its cellular receptor (LCN2-R, SLC22A17) are involved in many physiological and pathological processes such as cell differentiation, apoptosis, and inflammation. These pleiotropic functions mainly rely on NGAL's siderophore-mediated iron transport properties. However, the molecular determinants underlying the interaction between NGAL and its cellular receptor remain largely unknown. Here, using solution-state biomolecular NMR in conjunction with other biophysical methods, we show that the N-terminal domain of LCN2-R is a soluble extracellular domain that is intrinsically disordered and interacts with NGAL preferentially in its apo state to form a fuzzy complex. The relatively weak affinity (~10 MUm) between human LCN2-R-NTD and apoNGAL suggests that the N terminus on its own cannot account for the internalization of NGAL by LCN2-R. However, human LCN2-R NTD could be involved in the fine-tuning of the interaction between NGAL and its cellular receptor or in a biochemical mechanism allowing the receptor to discriminate between apo- and holo-NGAL. PMID- 26635367 TI - Interaction of the RcsB Response Regulator with Auxiliary Transcription Regulators in Escherichia coli. AB - The Rcs phosphorelay is a two-component signal transduction system that is induced by cell envelope stress. RcsB, the response regulator of this signaling system, is a pleiotropic transcription regulator, which is involved in the control of various stress responses, cell division, motility, and biofilm formation. RcsB regulates transcription either as a homodimer or together with auxiliary regulators, such as RcsA, BglJ, and GadE in Escherichia coli. In this study, we show that RcsB in addition forms heterodimers with MatA (also known as EcpR) and with DctR. Our data suggest that the MatA-dependent transcription regulation is mediated by the MatA-RcsB heterodimer and is independent of RcsB phosphorylation. Furthermore, we analyzed the relevance of amino acid residues of the active quintet of conserved residues, and of surface-exposed residues for activity of RcsB. The data suggest that the activity of the phosphorylation dependent dimers, such as RcsA-RcsB and RcsB-RcsB, is affected by mutation of residues in the vicinity of the phosphorylation site, suggesting that a phosphorylation-induced structural change modulates their activity. In contrast, the phosphorylation-independent heterodimers BglJ-RcsB and MatA-RcsB are affected by only very few mutations. Heterodimerization of RcsB with various auxiliary regulators and their differential dependence on phosphorylation add an additional level of control to the Rcs system that is operating at the output level. PMID- 26635368 TI - Interaction between a Domain of the Negative Regulator of the Ras-ERK Pathway, SPRED1 Protein, and the GTPase-activating Protein-related Domain of Neurofibromin Is Implicated in Legius Syndrome and Neurofibromatosis Type 1. AB - Constitutional heterozygous loss-of-function mutations in the SPRED1 gene cause a phenotype known as Legius syndrome, which consists of symptoms of multiple cafe au-lait macules, axillary freckling, learning disabilities, and macrocephaly. Legius syndrome resembles a mild neurofibromatosis type 1 (NF1) phenotype. It has been demonstrated that SPRED1 functions as a negative regulator of the Ras-ERK pathway and interacts with neurofibromin, the NF1 gene product. However, the molecular details of this interaction and the effects of the mutations identified in Legius syndrome and NF1 on this interaction have not yet been investigated. In this study, using a yeast two-hybrid system and an immunoprecipitation assay in HEK293 cells, we found that the SPRED1 EVH1 domain interacts with the N-terminal 16 amino acids and the C-terminal 20 amino acids of the GTPase-activating protein (GAP)-related domain (GRD) of neurofibromin, which form two crossing alpha-helix coils outside the GAP domain. These regions have been shown to be dispensable for GAP activity and are not present in p120(GAP). Several mutations in these N- and C-terminal regions of the GRD in NF1 patients and pathogenic missense mutations in the EVH1 domain of SPRED1 in Legius syndrome reduced the binding affinity between the EVH1 domain and the GRD. EVH1 domain mutations with reduced binding to the GRD also disrupted the ERK suppression activity of SPRED1. These data clearly demonstrate that SPRED1 inhibits the Ras-ERK pathway by recruiting neurofibromin to Ras through the EVH1-GRD interaction, and this study also provides molecular basis for the pathogenic mutations of NF1 and Legius syndrome. PMID- 26635370 TI - The ageing practitioner: ANZCA's recommendations. AB - OBJECTIVES: The aim is to present recommendations of the Australian and New Zealand College of Anaesthetists (ANZCA) with respect to practice implications for ageing specialists, together with brief discussion of effects of ageing on professional medical capabilities and recommendations on preparing to retire from medical practice. CONCLUSIONS: Practitioners should recognise that planning for retirement is part of good management of a medical career, and that the ageing process will inevitably compromise their ability to treat patients safely unless they retire at the appropriate time. Planning should include adequate financial preparation, and cultivation of interests and friends outside medicine. Practitioners should also realise that insight is likely to be compromised, so that they should seek colleagues who are trusted to advise them if/when they begin to lose competency. Lastly all practitioners should ensure that they consult a General Practitioner frequently, and that they have arranged all the proper legal instructions such as a Will, a Power of Attorney and an Advanced Health Directive.The ANZCA recommendations concerning ageing specialists have wide application to all medical specialties, not just for anaesthetists, and therefore all Medical Colleges should generate their own specific recommendations for ageing practitioners and the general effects of fatigue particularly for aged practitioners. PMID- 26635371 TI - Quetiapine-induced cervical dystonia. AB - OBJECTIVE: Our objective was to report and describe a case of quetiapine-induced dystonia in an older lady with psychosis. Quetiapine is a second-generation antipsychotic and known to be rare in causing extrapyramidal side effects with rates similar to placebo. CONCLUSIONS: There have been few documented cases of quetiapine-induced dystonia. It is important to be vigilant and consider the development of dystonia in patients who may not fit the typical risk profile. PMID- 26635369 TI - The Molecular Basis of TnrA Control by Glutamine Synthetase in Bacillus subtilis. AB - TnrA is a master regulator of nitrogen assimilation in Bacillus subtilis. This study focuses on the mechanism of how glutamine synthetase (GS) inhibits TnrA function in response to key metabolites ATP, AMP, glutamine, and glutamate. We suggest a model of two mutually exclusive GS conformations governing the interaction with TnrA. In the ATP-bound state (A-state), GS is catalytically active but unable to interact with TnrA. This conformation was stabilized by phosphorylated L-methionine sulfoximine (MSX), fixing the enzyme in the transition state. When occupied by glutamine (or its analogue MSX), GS resides in a conformation that has high affinity for TnrA (Q-state). The A- and Q-state are mutually exclusive, and in agreement, ATP and glutamine bind to GS in a competitive manner. At elevated concentrations of glutamine, ATP is no longer able to bind GS and to bring it into the A-state. AMP efficiently competes with ATP and prevents formation of the A-state, thereby favoring GS-TnrA interaction. Surface plasmon resonance analysis shows that TnrA bound to a positively regulated promoter fragment binds GS in the Q-state, whereas it rapidly dissociates from a negatively regulated promoter fragment. These data imply that GS controls TnrA activity at positively controlled promoters by shielding the transcription factor in the DNA-bound state. According to size exclusion and multiangle light scattering analysis, the dodecameric GS can bind three TnrA dimers. The highly interdependent ligand binding properties of GS reveal this enzyme as a sophisticated sensor of the nitrogen and energy state of the cell to control the activity of DNA-bound TnrA. PMID- 26635372 TI - A personal perspective from the UK: ageing and psychiatrists. AB - OBJECTIVE: Psychiatrists appointed to National Health Service (NHS) consultant posts in the United Kingdom before a specific date in 1995 qualified for early retirement and this has implications for workforce planning. METHODS: The author reflects on the implications this has for ageing psychiatrists and for relationships between psychiatrists and patients and families using mental health services, from the perspective of a psychiatrist who took advantage of the opportunity to retire early from a consultant post in the NHS and to develop a new career. RESULTS: Older psychiatrists continuing to practise after retirement from consultant roles may bring disadvantages and advantages. CONCLUSIONS: Older psychiatrists may be a valuable resource for future mental health services, and they may be in a position to try out new ways of working which might be relevant to their younger colleagues in the uncertain future faced by mental health services at a time of austerity. PMID- 26635373 TI - Successful ageing for psychiatrists. AB - OBJECTIVE: This paper aims to explore the concept and determinants of successful ageing as they apply to psychiatrists as a group, and as they can be applied specifically to individuals. CONCLUSIONS: Successful ageing is a heterogeneous, inclusive concept that is subjectively defined. No longer constrained by the notion of "super-ageing", successful ageing can still be achieved in the face of physical and/or mental illness. Accordingly, it remains within the reach of most of us. It can, and should be, person-specific and individually defined, specific to one's bio-psycho-social and occupational circumstances, and importantly, reserves. Successful professional ageing is predicated upon insight into signature strengths, with selection of realistic goal setting and substitution of new goals, given the dynamic nature of these constructs as we age. Other essential elements are generativity and self-care. Given that insight is key, taking a regular stock or inventory of our reserves across bio-psycho-social domains might be helpful. Importantly, for successful ageing, this needs to be suitably matched to the professional task and load. This lends itself to a renewable personal ageing plan, which should be systemically adopted with routine expectations of self-care and professional responsibility. PMID- 26635374 TI - Neuroimaging in psychiatry: an update on neuroimaging in the clinical setting. AB - OBJECTIVE: We offered guidance on the role of structural and functional neuroimaging modalities for the general psychiatrist and for trainees in the clinical setting. METHODS: We outlined the utility of neuroimaging modalities in the clinical setting, specifically with a view to understanding the pathophysiology of manifestations of disease. RESULTS: Both structural and functional neuroimaging modalities have a clear role in diagnostic evaluation in the spectrum of neurodegenerative disorders. CONCLUSIONS: Whilst the role of neuroimaging in patients with mood, anxiety and psychotic disorders is less clear, structural and functional imaging modalities have utility in the clinical setting in the form of diagnostic refinement and in understanding the pathophysiology of disorders, towards explaining manifestations and planning treatment. PMID- 26635375 TI - Thyroid function testing in an inpatient mental health unit. AB - OBJECTIVE: Thyroid function tests are a common screening investigation for patients admitted to a psychiatric inpatient unit. METHOD: This study aimed to retrospectively assess the clinical utility of routine thyroid function testing performed on newly admitted psychiatric patients over a 4-year period in Victoria, Australia via chart review of all abnormal results identified. RESULTS: Our retrospective audit revealed only two cases where identification of thyroid dysfunction informed patient management. In each case, the patient had a known history of thyroid disease. In this audit period, 893 patients required screening to yield one clinically relevant abnormal result, costing AU$24,975.57. CONCLUSION: Such low clinical utility does not support routine admission thyroid function tests for psychiatric inpatients. We conclude that thyroid function tests should only be performed where the history and clinical signs suggest a likely contribution of thyroid dysfunction to the psychiatric presentation. PMID- 26635376 TI - Preliminary evaluation of a brief mindfulness-based stress reduction intervention for mental health professionals. AB - OBJECTIVES: Mental health professionals are particularly susceptible to occupational stress; however, there are limited formal programmes to address the problem. This paper discusses the preliminary results of a brief mindfulness based stress reduction (MBSR) programme for practising professionals in a public hospital mental health unit. METHOD: A mixed-group of nine mental health professionals participated in eight weeks of daily 15-minute MBSR training interspersed with three 30-minute education sessions developed by the authors (AD and AT). Levels of psychological distress and mindfulness skill were measured before and immediately after participation. RESULTS: Following the brief MBSR programme, quantitative and qualitative participant feedback revealed a perceived reduction in psychological distress. CONCLUSIONS: A brief MBSR programme can be incorporated into the full-time workloads of practicing mental health professionals, potentially addressing a significant unmet workplace need. PMID- 26635377 TI - Screening for the metabolic syndrome in Australia: a national survey of psychiatrists' attitudes and reported practice in patients prescribed antipsychotic drugs. AB - OBJECTIVE: To investigate current reported psychiatric practice in relation to screening for the metabolic syndrome in patients prescribed antipsychotic drugs within Australia. METHOD: A postal survey of all Fellows of the Royal Australian and New Zealand College of Psychiatrists. A 28-item questionnaire inquired into different aspects of screening and monitoring for metabolic syndrome in patients on antipsychotic medication. RESULTS: Of 3123 questionnaires sent, 955 were returned. Of respondents, 55% had no established metabolic monitoring protocol or guidelines in their work place, with 13% saying they did not know what to monitor to detect metabolic syndrome. Altogether, 76% reported there was no reliable system in place to remind them when to monitor. Fewer than 50% of respondents routinely check weight, fasting glucose or lipids in their patients on antipsychotics and under than 30% checked blood pressure. Waist circumference was routinely checked in fewer than 7% of patients. Basic monitoring equipment was reported unavailable in more than 50% of clinical settings. However, more than 80% of respondents considered monitoring for metabolic syndrome to be their responsibility and 83% felt they had a medicolegal obligation in this respect. CONCLUSIONS: Routine screening for metabolic syndrome in patients on antipsychotic agents, by Australian psychiatrists, is inadequate. Interventions to improve screening rates need to be developed, implemented and evaluated. PMID- 26635378 TI - The Nervous Heart: Role of Sympathetic Reinnervation in Cardiac Regeneration. PMID- 26635379 TI - Go to the Mattresses: A New Method for Human-Induced Pluripotent Stem Cell Derived Cardiomyocyte Maturation. PMID- 26635380 TI - Role of Subplasmalemmal Mitochondria in Angiotensin II-Mediated Contraction. PMID- 26635382 TI - Correction. PMID- 26635383 TI - Correction. PMID- 26635381 TI - Bringing It All Together: Bedside to Bench and Back Again. PMID- 26635384 TI - Correction. PMID- 26635385 TI - Correction. PMID- 26635386 TI - Correction. PMID- 26635387 TI - Correction. PMID- 26635389 TI - Endocardial Notch Signaling in Cardiac Development and Disease. AB - The Notch signaling pathway is an ancient and highly conserved signaling pathway that controls cell fate specification and tissue patterning in the embryo and in the adult. Region-specific endocardial Notch activity regulates heart morphogenesis through the interaction with multiple myocardial-, epicardial-, and neural crest-derived signals. Mutations in NOTCH signaling elements cause congenital heart disease in humans and mice, demonstrating its essential role in cardiac development. Studies in model systems have provided mechanistic understanding of Notch function in cardiac development, congenital heart disease, and heart regeneration. Notch patterns the embryonic endocardium into prospective territories for valve and chamber formation, and later regulates the signaling processes leading to outflow tract and valve morphogenesis and ventricular trabeculae compaction. Alterations in NOTCH signaling in the endocardium result in congenital structural malformations that can lead to disease in the neonate and adult heart. PMID- 26635391 TI - DriverDBv2: a database for human cancer driver gene research. AB - We previously presented DriverDB, a database that incorporates ~ 6000 cases of exome-seq data, in addition to annotation databases and published bioinformatics algorithms dedicated to driver gene/mutation identification. The database provides two points of view, 'Cancer' and 'Gene', to help researchers visualize the relationships between cancers and driver genes/mutations. In the updated DriverDBv2 database (http://ngs.ym.edu.tw/driverdb) presented herein, we incorporated >9500 cancer-related RNA-seq datasets and >7000 more exome-seq datasets from The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC), and published papers. Seven additional computational algorithms (meaning that the updated database contains 15 in total), which were developed for driver gene identification, are incorporated into our analysis pipeline, and the results are provided in the 'Cancer' section. Furthermore, there are two main new features, 'Expression' and 'Hotspot', in the 'Gene' section. 'Expression' displays two expression profiles of a gene in terms of sample types and mutation types, respectively. 'Hotspot' indicates the hotspot mutation regions of a gene according to the results provided by four bioinformatics tools. A new function, 'Gene Set', allows users to investigate the relationships among mutations, expression levels and clinical data for a set of genes, a specific dataset and clinical features. PMID- 26635390 TI - Revisiting Cardiac Cellular Composition. AB - RATIONALE: Accurate knowledge of the cellular composition of the heart is essential to fully understand the changes that occur during pathogenesis and to devise strategies for tissue engineering and regeneration. OBJECTIVE: To examine the relative frequency of cardiac endothelial cells, hematopoietic-derived cells, and fibroblasts in the mouse and human heart. METHODS AND RESULTS: Using a combination of genetic tools and cellular markers, we examined the occurrence of the most prominent cell types in the adult mouse heart. Immunohistochemistry revealed that endothelial cells constitute >60%, hematopoietic-derived cells 5% to 10%, and fibroblasts <20% of the nonmyocytes in the heart. A refined cell isolation protocol and an improved flow cytometry approach provided an independent means of determining the relative abundance of nonmyocytes. High dimensional analysis and unsupervised clustering of cell populations confirmed that endothelial cells are the most abundant cell population. Interestingly, fibroblast numbers are smaller than previously estimated, and 2 commonly assigned fibroblast markers, Sca-1 and CD90, under-represent fibroblast numbers. We also describe an alternative fibroblast surface marker that more accurately identifies the resident cardiac fibroblast population. CONCLUSIONS: This new perspective on the abundance of different cell types in the heart demonstrates that fibroblasts comprise a relatively minor population. By contrast, endothelial cells constitute the majority of noncardiomyocytes and are likely to play a greater role in physiological function and response to injury than previously appreciated. PMID- 26635392 TI - COMBREX-DB: an experiment centered database of protein function: knowledge, predictions and knowledge gaps. AB - The COMBREX database (COMBREX-DB; combrex.bu.edu) is an online repository of information related to (i) experimentally determined protein function, (ii) predicted protein function, (iii) relationships among proteins of unknown function and various types of experimental data, including molecular function, protein structure, and associated phenotypes. The database was created as part of the novel COMBREX (COMputational BRidges to EXperiments) effort aimed at accelerating the rate of gene function validation. It currently holds information on ~ 3.3 million known and predicted proteins from over 1000 completely sequenced bacterial and archaeal genomes. The database also contains a prototype recommendation system for helping users identify those proteins whose experimental determination of function would be most informative for predicting function for other proteins within protein families. The emphasis on documenting experimental evidence for function predictions, and the prioritization of uncharacterized proteins for experimental testing distinguish COMBREX from other publicly available microbial genomics resources. This article describes updates to COMBREX-DB since an initial description in the 2011 NAR Database Issue. PMID- 26635393 TI - Integrated microfluidic approach for quantitative high-throughput measurements of transcription factor binding affinities. AB - Protein binding to DNA is a fundamental process in gene regulation. Methodologies such as ChIP-Seq and mapping of DNase I hypersensitive sites provide global information on this regulation in vivo In vitro methodologies provide valuable complementary information on protein-DNA specificities. However, current methods still do not measure absolute binding affinities. There is a real need for large scale quantitative protein-DNA affinity measurements. We developed QPID, a microfluidic application for measuring protein-DNA affinities. A single run is equivalent to 4096 gel-shift experiments. Using QPID, we characterized the different affinities of ATF1, c-Jun, c-Fos and AP-1 to the CRE consensus motif and CRE half-site in two different genomic sequences on a single device. We discovered that binding of ATF1, but not of AP-1, to the CRE half-site is highly affected by its genomic context. This effect was highly correlated with ATF1 ChIP seq and PBM experiments. Next, we characterized the affinities of ATF1 and ATF3 to 128 genomic CRE and CRE half-site sequences. Our affinity measurements explained that in vivo binding differences between ATF1 and ATF3 to CRE and CRE half-sites are partially mediated by differences in the minor groove width. We believe that QPID would become a central tool for quantitative characterization of biophysical aspects affecting protein-DNA binding. PMID- 26635394 TI - RBP-Var: a database of functional variants involved in regulation mediated by RNA binding proteins. AB - Transcription factors bind to the genome by forming specific contacts with the primary DNA sequence; however, RNA-binding proteins (RBPs) have greater scope to achieve binding specificity through the RNA secondary structure. It has been revealed that single nucleotide variants (SNVs) that alter RNA structure, also known as RiboSNitches, exhibit 3-fold greater local structure changes than replicates of the same DNA sequence, demonstrated by the fact that depletion of RiboSNitches could result in the alteration of specific RNA shapes at thousands of sites, including 3' UTRs, binding sites of microRNAs and RBPs. However, the network between SNVs and post-transcriptional regulation remains unclear. Here, we developed RBP-Var, a database freely available at http://www.rbp var.biols.ac.cn/, which provides annotation of functional variants involved in post-transcriptional interaction and regulation. RBP-Var provides an easy-to-use web interface that allows users to rapidly find whether SNVs of interest can transform the secondary structure of RNA and identify RBPs whose binding may be subsequently disrupted. RBP-Var integrates DNA and RNA biology to understand how various genetic variants and post-transcriptional mechanisms cooperate to orchestrate gene expression. In summary, RBP-Var is useful in selecting candidate SNVs for further functional studies and exploring causal SNVs underlying human diseases. PMID- 26635395 TI - Prioritizing and selecting likely novel miRNAs from NGS data. AB - Small non-coding RNAs play a key role in many physiological and pathological processes. Since 2004, miRNA sequences have been catalogued in miRBase, which is currently in its 21st version. We investigated sequence and structural features of miRNAs annotated in the miRBase and compared them between different versions of this reference database. We have identified that the two most recent releases (v20 and v21) are influenced by next-generation sequencing based miRNA predictions and show significant deviation from miRNAs discovered prior to the high-throughput profiling period. From the analysis of miRBase, we derived a set of key characteristics to predict new miRNAs and applied the implemented algorithm to evaluate novel blood-borne miRNA candidates. We carried out 705 individual whole miRNA sequencings of blood cells and collected a total of 9.7 billion reads. Using miRDeep2 we initially predicted 1452 potentially novel miRNAs. After excluding false positives, 518 candidates remained. These novel candidates were ranked according to their distance to the features in the early miRBase versions allowing for an easier selection of a subset of putative miRNAs for validation. Selected candidates were successfully validated by qRT-PCR and northern blotting. In addition, we implemented a web-server for ranking potential miRNA candidates, which is available at:www.ccb.uni-saarland.de/novomirank. PMID- 26635397 TI - On the role of steric clashes in methylation control of restriction endonuclease activity. AB - Restriction-modification systems digest non-methylated invading DNA, while protecting host DNA against the endonuclease activity by methylation. It is widely believed that the methylated DNA would not 'fit' into the binding site of the endonuclease in the productive orientation, and thus steric clashes should account for most of the protection. We test this concept statistically by grafting methyl groups in silico onto non-methylated DNA in co-crystal structures with restriction endonucleases. Clash scores are significantly higher for protective than non-protective methylation (P < 0.05% according to the Wilcoxon rank sum test). Structural data alone are sufficient to distinguish between protective and non-protective DNA methylation with 90% confidence and decision thresholds of 1.1 A and 48 A(3) for the most severe distance-based and cumulative volume-based clash with the protein, respectively (0.1 A was deducted from each interatomic distance to allow for coordinate errors). The most severe clashes are more pronounced for protective methyl groups attached to the nitrogen atoms (N6 methyladenines and N4-methylcytosines) than for C5-methyl groups on cytosines. Cumulative clashes are comparable for all three types of protective methylation. PMID- 26635398 TI - ATP dependent NS3 helicase interaction with RNA: insights from molecular simulations. PMID- 26635396 TI - Systematic identification and annotation of human methylation marks based on bisulfite sequencing methylomes reveals distinct roles of cell type-specific hypomethylation in the regulation of cell identity genes. AB - DNA methylation is a key epigenetic mark that is critical for gene regulation in multicellular eukaryotes. Although various human cell types may have the same genome, these cells have different methylomes. The systematic identification and characterization of methylation marks across cell types are crucial to understand the complex regulatory network for cell fate determination. In this study, we proposed an entropy-based framework termed SMART to integrate the whole genome bisulfite sequencing methylomes across 42 human tissues/cells and identified 757 887 genome segments. Nearly 75% of the segments showed uniform methylation across all cell types. From the remaining 25% of the segments, we identified cell type specific hypo/hypermethylation marks that were specifically hypo/hypermethylated in a minority of cell types using a statistical approach and presented an atlas of the human methylation marks. Further analysis revealed that the cell type specific hypomethylation marks were enriched through H3K27ac and transcription factor binding sites in cell type-specific manner. In particular, we observed that the cell type-specific hypomethylation marks are associated with the cell type-specific super-enhancers that drive the expression of cell identity genes. This framework provides a complementary, functional annotation of the human genome and helps to elucidate the critical features and functions of cell type specific hypomethylation. PMID- 26635399 TI - The expression of a viral microRNA is regulated by clustering to allow optimal B cell transformation. AB - The Epstein-Barr virus (EBV) transforms B cells by expressing latent proteins and the BHRF1 microRNA cluster. MiR-BHRF1-3, its most transforming member, belongs to the recently identified group of weakly expressed microRNAs. We show here that miR-BHRF1-3 displays an unusually low propensity to form a stem-loop structure, an effect potentiated by miR-BHRF1-3's proximity to the BHRF1 polyA site. Cloning miR-BHRF1-2 or a cellular microRNA, but not a ribozyme, 5' of miR-BHRF1-3 markedly enhanced its expression. However, a virus carrying mutated miR-BHRF1-2 seed regions expressed miR-BHRF1-3 at normal levels and was fully transforming. Therefore, miR-BHRF1-2's role during transformation is independent of its seed regions, revealing a new microRNA function. Increasing the distance between miR BHRF1-2 and miR-BHRF1-3 in EBV enhanced miR-BHRF1-3's expression but decreased its transforming potential. Thus, the expression of some microRNAs must be restricted to a narrow range, as achieved by placing miR-BHRF1-3 under the control of miR-BHRF1-2. PMID- 26635400 TI - National Trends in the Use of Cardiac Resynchronization Therapy With or Without Implantable Cardioverter-Defibrillator. AB - BACKGROUND: Candidates for cardiac resynchronization therapy (CRT) receive either a biventricular pacemaker or a biventricular pacemaker with an implantable cardioverter-defibrillator (CRT-D). Optimal device selection remains challenging because the benefit of implantable cardioverter-defibrillator therapy may not be uniform, particularly in patients at competing risk of nonsudden death. METHODS AND RESULTS: In this serial cross-sectional study using the National Inpatient Sample database, we identified 311,086 admissions associated with CRT implant between 2006 to 2012. CRT-D was the most common device type (86.1%), including in patients >= 75 years of age with >= 5 Elixhauser comorbidities (75.5%). Multivariate predictors of CRT-D implant included demographic, clinical, and geographic factors: prior ventricular arrhythmia (rate ratio [RR], 1.14; 95% CI, 1.13-1.14), ischemic heart disease (RR, 1.11; 95% CI, 1.10-1.11), male sex (RR, 1.10; 95% CI, 1.09-1.10), black race (RR, 1.06; 95% CI: 1.04-1.07), and Northeast geographic region (RR, 1.06; 95% CI, 1.04-1.09). There was significant interhospital variation in the use of CRT-D (10-90 percentile range, 72.9%-98.0% CRT-D). CONCLUSIONS: The majority of patients in this contemporary US cohort underwent implantation of CRT-D. Predictors of CRT-D implant included demographic, clinical, and geographic factors. In patient subgroups predicted to have an attenuated benefit from implantable cardioverter-defibrillator therapy (older adults with multiple comorbidities), CRT-D remained the dominant device type. An improved understanding of the determinants of device selection may aid in decision making and ultimately better align patient risk with device benefit at the time of CRT implantation. PMID- 26635401 TI - Quadricuspid Aortic Valve: Characteristics, Associated Structural Cardiovascular Abnormalities, and Clinical Outcomes. AB - BACKGROUND: Quadricuspid aortic valve (QAV) is a rare congenital cardiac defect. This study sought to determine QAV frequency in a large echocardiography database, to characterize associated cardiovascular abnormalities, and to describe long-term outcomes. METHODS AND RESULTS: Fifty patients (mean +/- SD age, 43.5 +/- 21.8 years at the time of the index diagnosis; female sex, 52%) received a diagnosis of QAV between January 1, 1975, and March 14, 2014 (frequency, 0.006%). The QAV was type A in 32% and type B in 32% (Hurwitz and Roberts classification). Aortic dilatation was present in 29% of the patients, and 26% had moderate or severe aortic valve regurgitation at the index diagnosis. Stenosis affected only 8% of the valves and was mild. Other findings, including abnormalities of other cardiac valves, septal defects, persistent left superior vena cava, and patent ductus arteriosus, were present in 32% of patients. During a mean +/- SD follow-up of 4.8 +/- 5.6 years, 8 patients underwent aortic valve surgery, with severe aortic valve regurgitation being the surgical indication in 7 patients. One patient with mild to moderate aortic valve regurgitation underwent aortic valve repair for obstruction of the left coronary ostium by the accessory cusp of QAV. No infective endocarditis or aortic dissection was found. Overall survival was 91.5% and 87.7% at 5 and 10 years. CONCLUSIONS: Aortic dilatation and other structural cardiac abnormalities were relatively common among patients with QAV. Aortic valve regurgitation was the predominant hemodynamic abnormality and the indication for aortic valve surgery in most patients who received surgery. Long-term survival was excellent. PMID- 26635403 TI - Blood's 70th anniversary: a rich history. PMID- 26635402 TI - Extracorporeal Cardiopulmonary Resuscitation (E-CPR) During Pediatric In-Hospital Cardiopulmonary Arrest Is Associated With Improved Survival to Discharge: A Report from the American Heart Association's Get With The Guidelines Resuscitation (GWTG-R) Registry. AB - BACKGROUND: Although extracorporeal cardiopulmonary resuscitation (E-CPR) can result in survival after failed conventional CPR (C-CPR), no large, systematic comparison of pediatric E-CPR and continued C-CPR has been reported. METHODS AND RESULTS: Consecutive patients <18 years old with CPR events >=10 minutes in duration reported to the Get With the Guidelines-Resuscitation registry between January 2000 and December 2011 were identified. Hospitals were grouped by teaching status and location. Primary outcome was survival to discharge. Regression modeling was performed, conditioning on hospital groups. A secondary analysis was performed with the use of propensity score matching. Of 3756 evaluable patients, 591 (16%) received E-CPR and 3165 (84%) received C-CPR only. Survival to hospital discharge and survival with favorable neurological outcome (Pediatric Cerebral Performance Category score of 1-3 or unchanged from admission) were greater for E-CPR (40% [237 of 591] and 27% [133 of 496]) versus C-CPR patients (27% [862 of 3165] and 18% [512 of 2840]). Odds ratios (ORs) for survival to hospital discharge and survival with favorable neurological outcome were greater for E-CPR versus C-CPR. After adjustment for covariates, patients receiving E-CPR had higher odds of survival to discharge (OR, 2.80; 95% confidence interval, 2.13-3.69; P<0.001) and survival with favorable neurological outcome (OR, 2.64; 95% confidence interval, 1.91-3.64; P<0.001) than patients who received C-CPR. This association persisted when analyzed by propensity score matched cohorts (OR, 1.70; 95% confidence interval, 1.33-2.18; P<0.001; and OR, 1.78; 95% confidence interval, 1.31-2.41; P<0.001, respectively]. CONCLUSION: For children with in-hospital CPR of >=10 minutes duration, E-CPR was associated with improved survival to hospital discharge and survival with favorable neurological outcome compared with C-CPR. PMID- 26635404 TI - Blood: a brief survey of its chemical components and of their natural functions and clinical uses. PMID- 26635405 TI - ATL treatment: is it time to change? PMID- 26635406 TI - A little bit of kindlin goes a long way. PMID- 26635407 TI - A slan-based nomenclature for monocytes? PMID- 26635408 TI - The stop clock of platelet activation. PMID- 26635409 TI - Can selective migration explain why health is worse in regions with population decline?: A study on migration and self-rated health in the Netherlands. AB - BACKGROUND: Health disparities between population declining and non-declining areas have received little attention, even though population decline is an established phenomenon in Europe. Selective migration, in which healthier people move out of deprived areas, can possibly explain worse health in declining regions. We assessed whether selective migration can explain the observed worse average health in declining regions as compared with non-declining regions in the Netherlands. METHODS: Combining data from the Dutch Housing and Living Survey held in 2002 and 2006 with Dutch registry data, we studied the relation between health status and migration in a 5-year period at the individual level by applying logistic regression. In our sample of 130,600 participants, we compared health status, demographic and socioeconomic factors of movers and stayers from declining and non-declining regions. RESULTS: People in the Netherlands who migrated are healthier than those staying behind [odds ratio (OR): 1.80]. This effect is larger for persons moving out of declining regions (OR: 1.76) than those moving into declining regions (OR: 1.47). When controlled for demographic and socioeconomic characteristics, these effects are not significant. Moreover, only a small part of the population migrates out of (0.29%) or into (0.25%) declining regions in the course of 5 years. CONCLUSION: Despite the relation between health and migration, the effect of selective migration on health differences between declining and non-declining regions in the Netherlands is small. Both health and migration are complexly linked with socioeconomic and demographic factors. PMID- 26635410 TI - President's column. PMID- 26635411 TI - Soil bacterial community responses to warming and grazing in a Tibetan alpine meadow. AB - Warming and grazing significantly affect the structure and function of an alpine meadow ecosystem. Yet, the responses of soil microbes to these disturbances are not well understood. Controlled asymmetrical warming (+1.2/1.7 degrees C during daytime/nighttime) with grazing experiments were conducted to study microbial response to warming, grazing and their interactions. Significant interactive effects of warming and grazing were observed on soil bacterial alpha-diversity and composition. Warming only caused significant increase in bacterial alpha diversity under no-grazing conditions. Grazing induced no substantial differences in bacterial alpha-diversity and composition irrespective of warming. Warming, regardless of grazing, caused a significant increase in soil bacterial community similarity across space, but grazing only induced significant increases under no warming conditions. The positive effects of warming on bacterial alpha-diversity and grazing on community similarity were weakened by grazing and warming, respectively. Soil and plant variables explained well the variations in microbial communities, indicating that changes in soil and plant properties may primarily regulate soil microbial responses to warming in this alpine meadow. The results suggest that bacterial communities may become more similar across space in a future, warmed climate and moderate grazing may potentially offset, at least partially, the effects of global warming on the soil microbial diversity. PMID- 26635413 TI - Biomechanical Evaluation of Strength and Stiffness of Subtalar Joint Arthrodesis Screw Constructs. AB - BACKGROUND: Subtalar arthrodesis is a common treatment for end-stage subtalar joint arthritis as well as many other clinical problems. The best method of subtalar arthrodesis fixation is unknown. The purpose of this study was to compare the strength of subtalar arthrodesis fixation methods including a single posterior screw (SP), 2 posterior minimally divergent screws (MD) and a 2 screw highly divergent screw (HD) construct for subtalar arthrodesis. METHODS: A biomechanical study was performed including the three different screw configurations (SP, MD, HD). These surrogate bone specimens were subjected to applied inversion and eversion torques about the subtalar joint axis on a servo hydraulic load frame. Torsional stiffness of the construct and the maximum torque for each configuration were measured. Additionally, a cadaver study was performed using 5 fresh-frozen cadaver specimens. The perpendicular distance from the divergent screw guide-wire placement was measured from anatomic structures. RESULTS: The HD screw configuration was found to have the highest torsional stiffness in both inversion and eversion, followed by the MD construct and then the SP construct. Similarly, the HD construct had the highest maximum torque versus the MD and SP constructs. All between-group differences were statistically significant (P < .05). The mean distance from key structures to the divergent screw included the sural nerve (13 mm), peroneus brevis tendon (18 mm), tibialis anterior tendon (8 mm), and tibialis posterior tendon (21 mm). CONCLUSION: This biomechanical and cadaver study supports the use of 2 screws for fixation of subtalar arthrodesis over a single posterior screw. Additionally, we describe a biomechanically superior and potentially safe, alternative 2-screw divergent construct. CLINICAL RELEVANCE: This study gives biomechanical support for 2 screw, divergent fixation of subtalar arthrodesis or a single over a single screw or two screw minimally divergent construct. PMID- 26635414 TI - Placement of Plantar Plates for Lapidus Arthrodesis: Anatomical Considerations. AB - BACKGROUND: The modified Lapidus procedure is an accepted treatment option for patients with moderate to severe hallux valgus. Placing a plate plantar on the tension side of the arthrodesis has been shown to be biomechanically superior and has provided good clinical results. There is some concern about interference of the plantar placed plates on the tendon insertions. The purpose of this study was to determine a "safe zone" for plantar plate placement without irritation of the tendons. METHODS: Twenty-nine embalmed right feet were used for this study. The anatomy of the insertion of the peroneus longus (PL) tendon and tibialis anterior (TA) tendon on the medial cuneiform and first metatarsal were analyzed. Six different plate designs for plantar plating of the first tarsometatarsal fusion were included. The fit to the bone and contact to tendon insertion were analyzed. RESULTS: The PL showed a main insertion to the first metatarsal and a lesser insertion to the medial cuneiform. The TA inserted onto the medial cuneiform and first metatarsal in all cases in our series. There was a "safe zone" between the TA and PL insertion areas for plate placement. Straight, Y- and U-shaped plates could be placed without compromising the tendon insertion. Depending on the design, even preshaped plates may have to be bent to allow a good fit to the plantar side of the first tarsometatarsal joint. CONCLUSION: Plantar plating for modified Lapidus arthrodesis can be safely performed, without damaging the plantar tendon insertion area of the PL and TA. CLINICAL RELEVANCE: The exact knowledge of the anatomy of the plantar region of the tarsometatarsal joint can help to improve plate placement. PMID- 26635412 TI - Diversification of broad host range plasmids correlates with the presence of antibiotic resistance genes. AB - The IncP-1epsilon subgroup is a recently identified phylogenetic clade within IncP-1 plasmids, which plays an important role in the spread of antibiotic resistance and degradation of xenobiotic pollutants. Here, four IncP-1epsilon plasmids were exogenously captured from a petroleum-contaminated habitat in China and compared phylogenetically and genomically with previously reported IncP 1epsilon and other IncP-1 plasmids. The IncP-1epsilon plasmids can be clearly subdivided into two subclades, designated as epsilon-I and epsilon-II, based on phylogenetic analysis of backbone proteins TraI and TrfA. This was further supported by comparison of concatenated backbone genes. Moreover, the two subclades differed in the transposon types, phenotypes and insertion locations of the accessory elements. The accessory genes on epsilon-I plasmids were inserted between parA and traC, and harbored ISPa17 and Tn402-like transposon modules, typically carrying antibiotic resistance genes. In contrast, the accessory elements on epsilon-II plasmids were typically located between trfA and oriV, and contained IS1071, which was commonly inserted within the Tn501-like transposon, typically harboring a cluster of genes encoding mercury resistance and/or catabolic pathways. Our study is one of the first to compare IncP-1 plasmid genomes from China, expands the available collection of IncP-1epsilon plasmids and enhances our understanding of their diversity, biogeography and evolutionary history. PMID- 26635415 TI - Restraining of reactive oxygen species promotes invasion of Listeria monocytogenes into glia cells. AB - Listeria monocytogenes is a foodborne pathogen that could cause severe infection in the central nervous system of humans and animals. However, the molecular mechanism of the pathogenesis is not fundamentally assessed. This study aimed to analyze the role of reactive oxygen species (ROS) in L. monocytogenes during its invasion into glia cells. The ROS level in L. monocytogenes was manipulated using NAD(P)H oxidase inhibitor diphenyleneiodonium chloride (DPI) and ROS scavenger N acetyl cysteine (NAC). Results showed that the invasiveness of L. monocytogenes was elevated when ROS was downregulated by DPI and NAC treatment. Expression profiles of proinflammatory factors in glia cells were also examined because they play important roles in the functions of glia cells in the brain immune system. The expression levels of proinflammatory factors (tumor necrosis factor alpha and interleukin-1beta) in host glia cells were downregulated when invaded by L. monocytogenes with lower ROS level. This finding indicates that ROS may function as negative regulator during the invasion of L. monocytogenes in brain infection. PMID- 26635416 TI - Evaluation of antimicrobial properties of cork. AB - Cork presents a range of diverse and versatile properties making this material suitable for several and extremely diverse industrial applications. Despite the wide uses of cork, its antimicrobial properties and potential applications have deserved little attention from industry and the scientific community. Thus, the main purpose of this work was the evaluation of the antibacterial properties of cork, by comparison with commercially available antimicrobial materials (Ethylene Vinyl Acetate copolymer and a currently used antimicrobial commercial additive (ACA)), following the previous development and optimization of a method for such antimicrobial assay. The AATCC 100-2004 standard method, a quantitative procedure developed for the assessment of antimicrobial properties in textile materials, was used as reference and optimized to assess cork antibacterial activity. Cork displayed high antibacterial activity against Staphylococcus aureus, with a bacterial reduction of almost 100% (96.93%) after 90 minutes of incubation, similar to the one obtained with ACA. A more reduced but time-constant antibacterial action was observed against Escherichia coli (36% reduction of the initial number of bacterial colonies). To complement this study, antibacterial activity was further evaluated for a water extract of cork and an MIC of 6 mg mL( 1) was obtained against the reference strain S. aureus. PMID- 26635417 TI - Two Photon Induced Luminescence of BSA Protected Gold Clusters. AB - In this short letter, we have synthesized the BSA protected Au25 nanoclusters and studied their two photon luminescence behavior. We demonstrate that BSA Au25 nanoclusters can be used as a probe with two photon excitation capability. Our results show a quadratic relation between excitation power and emission intensity whereas with one photon excitation shows a linear dependence. The emission spectrum of BSA Au25 nanoclusters with one photon and two photon excitation shows no appreciable change. Due to its long wavelength emission (650 nm) and two photon excitation, BSA Au25 can be potentially used as a probe for deep tissue imaging. PMID- 26635418 TI - Making Heat Visible: Promoting Energy Conservation Behaviors Through Thermal Imaging. AB - Householders play a role in energy conservation through the decisions they make about purchases and installations such as insulation, and through their habitual behavior. The present U.K. study investigated the effect of thermal imaging technology on energy conservation, by measuring the behavioral effect after householders viewed images of heat escaping from or cold air entering their homes. In Study 1 (n = 43), householders who received a thermal image reduced their energy use at a 1-year follow-up, whereas householders who received a carbon footprint audit and a non-intervention control demonstrated no change. In Study 2 (n = 87), householders were nearly 5 times more likely to install draught proofing measures after seeing a thermal image. The effect was especially pronounced for actions that addressed an issue visible in the images. Findings indicate that using thermal imaging to make heat loss visible can promote energy conservation. PMID- 26635419 TI - Reduction and Accumulation of Gold(III) by Medicago sativa Alfalfa Biomass: X-ray Absorption Spectroscopy, pH, and Temperature Dependence. AB - We report herein the use of Medicago sativa alfalfa shoot biomass for the removal of gold from aqueous solutions. The accumulation process involves the reduction of Au(III) to colloidal Au(0) and is shown to increase at elevated temperatures and at lower pH. X-ray absorption spectroscopy (XAS) was used to determine that gold(III) was reduced to form gold(0) colloids, which varied in size depending on the pH of the initial solution. The gold cluster radius was 6.2 +/- 1 A at pH 5 and 9.0 +/- 1 A at pH 2. Our findings indicate that essentially another layer of gold atoms was deposited onto the colloid surface at pH 2. Possible mechanisms of bioreduction and accumulation are discussed. PMID- 26635420 TI - Engineering soil organic matter quality: Biodiesel Co-Product (BCP) stimulates exudation of nitrogenous microbial biopolymers. AB - Biodiesel Co-Product (BCP) is a complex organic material formed during the transesterification of lipids. We investigated the effect of BCP on the extracellular microbial matrix or 'extracellular polymeric substance' (EPS) in soil which is suspected to be a highly influential fraction of soil organic matter (SOM). It was hypothesised that more N would be transferred to EPS in soil given BCP compared to soil given glycerol. An arable soil was amended with BCP produced from either 1) waste vegetable oils or 2) pure oilseed rape oil, and compared with soil amended with 99% pure glycerol; all were provided with 15N labelled KNO3. We compared transfer of microbially assimilated 15N into the extracellular amino acid pool, and measured concomitant production of exopolysaccharide. Following incubation, the 15N enrichment of total hydrolysable amino acids (THAAs) indicated that intracellular anabolic products had incorporated the labelled N primarily as glutamine and glutamate. A greater proportion of the amino acids in EPS were found to contain 15N than those in the THAA pool, indicating that the increase in EPS was comprised of bioproducts synthesised de novo. Moreover, BCP had increased the EPS production efficiency of the soil microbial community (MUg EPS per unit ATP) up to approximately double that of glycerol, and caused transfer of 21% more 15N from soil solution into EPS amino acids. Given the suspected value of EPS in agricultural soils, the use of BCP to stimulate exudation is an interesting tool to consider in the theme of delivering sustainable intensification. PMID- 26635421 TI - A Marginalized Zero-inflated Poisson Regression Model with Random Effects. AB - Public health research often concerns relationships between exposures and correlated count outcomes. When counts exhibit more zeros than expected under Poisson sampling, the zero-inflated Poisson (ZIP) model with random effects may be used. However, the latent class formulation of the ZIP model can make marginal inference on the sampled population challenging. This article presents a marginalized ZIP model with random effects to directly model the mean of the mixture distribution consisting of 'susceptible' individuals and excess zeroes, providing straightforward inference for overall exposure effects. Simulations evaluate finite sample properties, and the new methods are applied to a motivational interviewing-based safer sex intervention trial, designed to reduce the number of unprotected sexual acts. PMID- 26635422 TI - Social Investment after Neoliberalism: Policy Paradigms and Political Platforms. AB - The concept of the 'social investment state' refocuses attention on the productive function of social policy eclipsed for some time by the emphasis on its social protection or compensation roles. Here we distinguish between different social investment strategies, the Nordic 'heavy' and the Liberal 'light', with particular reference to the inclusive growth approach adopted in Australia. In 2007, social democrats in Australia returned to government with a clear mandate to reject the labour market deregulation and other neoliberal policies of its predecessor, and to tackle entrenched social and economic disadvantage in Australian society. For the last five years, social investment and inclusive growth has been at the centre of the Australian social policy agenda. Against this background, the article examines and critically assesses the (re)turn to 'social investment' thinking in Australia during Labor's term in office (2007-13). Analysis focuses not just on what was actually achieved, but also on the constraining role of prevailing economic and political circumstances and on the processes that were used to drive social investment reform. In many ways, the article goes some way to exposing ongoing tensions surrounding the distinctiveness of 'social investment' strategies pursued by leftist parties within the (neo)liberal state. PMID- 26635423 TI - Filipino Mothers' Self-Efficacy in Managing Anger and in Parenting, and Parental Rejection as Predictors of Child Delinquency. AB - The authors tested a model in which Filipino mothers' self-efficacy in managing anger/irritation influenced child delinquency via two parenting variables: parental self-efficacy and parental rejection. Structured interviews were conducted with 99 mothers twice with an interval of one year with efficacy beliefs and rejection measured in the first year and child delinquency data collected in the following year. Path analyses showed that self-efficacy in managing anger/irritation negatively predicted child delinquency indirectly through the sequential mediation of parental self-efficacy and parental rejection. Results provided further evidence for the importance of efficacy beliefs, particularly self-efficacy in managing anger/irritation and parental self-efficacy, in the domain of child development. PMID- 26635424 TI - An examination of the vibration transmissibility of the hand-arm system in three orthogonal directions. AB - : The objective of this study is to enhance the understanding of the vibration transmission in the hand-arm system in three orthogonal directions (X, Y, and Z). For the first time, the transmitted vibrations distributed on the entire hand-arm system exposed in the three orthogonal directions via a 3-D vibration test system were measured using a 3-D laser vibrometer. Seven adult male subjects participated in the experiment. This study confirms that the vibration transmissibility generally decreased with the increase in distance from the hand and it varied with the vibration direction. Specifically, to the upper arm and shoulder, only moderate vibration transmission was measured in the test frequency range (16 to 500 Hz), and virtually no transmission was measured in the frequency range higher than 50 Hz. The resonance vibration on the forearm was primarily in the range of 16-30 Hz with the peak amplitude of approximately 1.5 times of the input vibration amplitude. The major resonance on the dorsal surfaces of the hand and wrist occurred at around 30-40 Hz and, in the Y direction, with peak amplitude of more than 2.5 times of the input amplitude. At higher than 50 Hz, vibration transmission was effectively limited to the hand and fingers. A major finger resonance was observed at around 100 Hz in the X and Y directions and around 200 Hz in the Z direction. In the fingers, the resonance magnitude in the Z direction was generally the lowest, and the resonance magnitude in the Y direction was generally the highest with the resonance amplitude of 3 times the input vibration, which was similar to the transmissibility at the wrist and hand dorsum. The implications of the results are discussed. RELEVANCE TO INDUSTRY: Prolonged, intensive exposure to hand-transmitted vibration could result in hand arm vibration syndrome. While the syndrome's precise mechanisms remain unclear, the characterization of the vibration transmissibility of the system in the three orthogonal dimensions performed in this study can help understand the syndrome and help develop improved frequency weightings for assessing the risk of the exposure for developing various components of the syndrome. PMID- 26635425 TI - Phobic Anxiety and Plasma Levels of Global Oxidative Stress in Women. AB - BACKGROUND AND OBJECTIVES: Psychological distress has been hypothesized to be associated with adverse biologic states such as higher oxidative stress and inflammation. Yet, little is known about associations between a common form of distress - phobic anxiety - and global oxidative stress. Thus, we related phobic anxiety to plasma fluorescent oxidation products (FlOPs), a global oxidative stress marker. METHODS: We conducted a cross-sectional analysis among 1,325 women (aged 43-70 years) from the Nurses' Health Study. Phobic anxiety was measured using the Crown-Crisp Index (CCI). Adjusted least-squares mean log-transformed FlOPs were calculated across phobic categories. Logistic regression models were used to calculate odds ratios (OR) comparing the highest CCI category (>=6 points) vs. lower scores, across FlOPs quartiles. RESULTS: No association was found between phobic anxiety categories and mean FlOP levels in multivariable adjusted linear models. Similarly, in multivariable logistic regression models there were no associations between FlOPs quartiles and likelihood of being in the highest phobic category. Comparing women in the highest vs. lowest FlOPs quartiles: FlOP_360: OR=0.68 (95% CI: 0.40-1.15); FlOP_320: OR=0.99 (95% CI: 0.61 1.61); FlOP_400: OR=0.92 (95% CI: 0.52, 1.63). CONCLUSIONS: No cross-sectional association was found between phobic anxiety and a plasma measure of global oxidative stress in this sample of middle-aged and older women. PMID- 26635426 TI - Narrative Interaction in Family Dinnertime Conversations. AB - Reminiscing has been shown to be a critical conversational context for the development of autobiographical memory, self-concept, and emotional regulation (for a review, see Fivush, Haden, & Reese, 2006). Although much past research has examined reminiscing between mothers and their preschool children, very little attention has been given to family narrative interaction with older children. In the present study, we examined family reminiscing in spontaneous narratives that emerged during family dinnertime conversations. The results revealed that mothers contributed more to the narratives than did fathers in that they provided, confirmed, and negated more information, although fathers requested more information than mothers. In exploratory analyses, mothers' contributions to shared family narratives were found to be related to fewer internalizing and externalizing behaviors in their children, while fathers' contributions to individual narratives of day-today experiences were related to fewer internalizing and externalizing behaviors in their children. These results indicate that mothers and fathers may play different roles in narrative construction with their children, and there is some suggestion that these differences may also be related to children's behavioral adjustment. PMID- 26635428 TI - Characterization of a Vortex Shaking Method for Aerosolizing Fibers. AB - Generation of well-dispersed, well-characterized fibers is important in toxicology studies. A vortex-tube shaking method is investigated using glass fibers to characterize the generated aerosol. Controlling parameters that were studied included initial batch amounts of glass fibers, preparation of the powder (e.g., preshaking), humidity, and airflow rate. Total fiber number concentrations and aerodynamic size distributions were typically measured. The aerosol concentration is only stable for short times (t < 10 min) and then falls precipitously, with concomitant changes in the aerosol aerodynamic size distribution; the plateau concentration and its duration both increase with batch size. Preshaking enhances the initial aerosol concentration and enables the aerosolization of longer fibers. Higher humidity strongly affects the particle size distribution and the number concentration, resulting in a smaller modal diameter and a higher number concentration. Running the vortex shaker at higher flow rates (Q > 0.3 lpm), yields an aerosol with a particle size distribution representative of the batch powder; running the vortex shaker at a lower aerosol flow rate (Q ~ 0.1 lpm) only aerosolizes the shorter fibers. These results have implications for the use of the vortex shaker as a standard aerosol generator. PMID- 26635427 TI - Procalcitonin, MR-Proadrenomedullin, and Cytokines Measurement in Sepsis Diagnosis: Advantages from Test Combination. AB - BACKGROUND: Elevated cytokines levels correlate with sepsis severity and mortality but their role in the diagnosis is controversial, whereas Procalcitonin (PCT) has been largely used. Recently, the mid-regional proadrenomedullin (MR proADM) has been combined with PCT for diagnosis optimization. In this study the combined measurement of PCT, MR-proADM, and cytokines in patients with sepsis was evaluated. METHODS: One hundred and four septic patients and 101 controls were enrolled. Receiver operating characteristic (ROC) analysis and multiple logistic regression were used to evaluate applicant markers for sepsis diagnosis. Markers with best Odds Ratio (OR) were combined, and the posttest probability and a composite score were computed. RESULTS: Based upon ROC curves analysis, PCT, MR proADM, IL-6, IL-10, TNF-alpha, and MCP-1 were considered applicant for sepsis diagnosis. Among these PCT, MR-proADM , IL-6, and TNF-alpha showed the best OR. A better posttest probability was found with the combination of PCT with MR-proADM and PCT with IL-6 or TNF-alpha compared to the single marker. A composite score of PCT, MR-proADM, and TNF-alpha showed the best ROC curve in the early diagnosis of sepsis. CONCLUSION: The combination of PCT with other markers should expedite diagnosis and treatment of sepsis optimizing clinical management. PMID- 26635430 TI - Compliance monitoring in business processes: Functionalities, application, and tool-support. AB - In recent years, monitoring the compliance of business processes with relevant regulations, constraints, and rules during runtime has evolved as major concern in literature and practice. Monitoring not only refers to continuously observing possible compliance violations, but also includes the ability to provide fine grained feedback and to predict possible compliance violations in the future. The body of literature on business process compliance is large and approaches specifically addressing process monitoring are hard to identify. Moreover, proper means for the systematic comparison of these approaches are missing. Hence, it is unclear which approaches are suitable for particular scenarios. The goal of this paper is to define a framework for Compliance Monitoring Functionalities (CMF) that enables the systematic comparison of existing and new approaches for monitoring compliance rules over business processes during runtime. To define the scope of the framework, at first, related areas are identified and discussed. The CMFs are harvested based on a systematic literature review and five selected case studies. The appropriateness of the selection of CMFs is demonstrated in two ways: (a) a systematic comparison with pattern-based compliance approaches and (b) a classification of existing compliance monitoring approaches using the CMFs. Moreover, the application of the CMFs is showcased using three existing tools that are applied to two realistic data sets. Overall, the CMF framework provides powerful means to position existing and future compliance monitoring approaches. PMID- 26635429 TI - Aerosol Generation by Modern Flush Toilets. AB - A microbe-contaminated toilet will produce bioaerosols when flushed. We assessed toilet plume aerosol from high efficiency (HET), pressure-assisted high efficiency (PAT), and flushometer (FOM) toilets with similar bowl water and flush volumes. Total and droplet nuclei "bioaerosols" were assessed. Monodisperse 0.25 1.9- MU m fluorescent microspheres served as microbe surrogates in separate trials in a mockup 5 m3 water closet (WC). Bowl water seeding was approximately 1012 particles/mL. Droplet nuclei were sampled onto 0.2- MU m pore size mixed cellulose ester filters beginning 15 min after the flush using open-face cassettes mounted on the WC walls. Pre- and postflush bowl water concentrations were measured. Filter particle counts were analyzed via fluorescent microscopy. Bowl headspace droplet count size distributions were bimodal and similar for all toilet types and flush conditions, with 95% of droplets <2MUm diameter and>99%<5MU m. Up to 145,000 droplets were produced per flush, with the high energy flushometer producing over three times as many as the lower energy PAT and over 12 times as many as the lowest energy HET despite similar flush volumes. The mean numbers of fluorescent droplet nuclei particles aerosolized and remaining airborne also increased with flush energy. Fluorescent droplet nuclei per flush decreased with increasing particle size. These findings suggest two concurrent aerosolization mechanisms-splashing for large droplets and bubble bursting for the fine droplets that form droplet nuclei. PMID- 26635431 TI - Influence of the Inherited Glucose-6-phosphate Dehydrogenase Deficiency on the Appearance of Neonatal Hyperbilirubinemia in Southern Croatia. AB - BACKGROUND: Neonatal hyperbilirubinemia is a common clinical manifestation of the inherited glucose-6-phosphate dehydrogenase (G6PD) deficiency. AIM OF THE STUDY: The aim of this study was to investigate the influence of the inherited G6PD deficiency on the appearance of neonatal hyperbilirubinemia in southern Croatia. METHODS: The fluorescent spot test (FST) was used in a retrospective study to screen blood samples of 513 male children who had neonatal hyperbilirubinemia, of unknown cause, higher than 240 MUmol/L. Fluorescence readings were performed at the beginning and at the fifth and tenth minute of incubation and were classified into three groups bright fluorescence (BF), weak fluorescence (WF) and no fluorescence (NF). Normal samples show bright fluorescence. All NF and WF samples at the fifth minute were quantitatively measured using the spectrophotometric method. RESULTS: Bright fluorescence was present in 461 patients (89.9%) at the fifth minute. The remaining 52 (10.1%) were quantitatively estimated using the spectrophotometric method. G6PD deficiency was observed in 38 patients (7.4%). CONCLUSIONS: Prevalence rate of G6PD deficiency among male newborns with hyperbilirubinemia in southern Croatia is significantly higher (p < 0.01) compared with the previously reported prevalence rate among male in general population of southern Croatia (0.75%). We recommend FST to be performed in hyperbilirubinemic newborns in southern Croatia. PMID- 26635432 TI - Significance of Sonographically Demonstrated Ureteral Dilatation in Evaluation of Vesicoureteral Reflux Verified with Voiding Urosonography in Children with Urinary Tract Infection. AB - OBJECTIVES: The aim of this study was to determine sensitivity, specificity, and predictive values of sonographically demonstrated ureteral dilatation in detecting vesicoureteral reflux (VUR). METHODS: Ethical approval from the Ethical Committee of Clinical Center University of Sarajevo and parental consent were obtained for this prospective study involving 120 children with history of urinary tract infections (UTIs). Ultrasound examination included the evaluation of the urinary tract, with a special emphasis on evaluation of ureteral dilatation. Voiding urosonography (VUS) was carried out according to a standard protocol with the use of ultrasound contrast agent Sono Vue of second generation. Ureteral diameter greater than 3 mm was considered pathological. Proven VUR was graded into one of three stages. RESULTS: Infectio tracti urinarii recidivans was referral diagnosis in the majority of patients. The average age of patients was 4.33 +/- 3.88 years (from 2 months to 16 years of age). VUS findings were normal in 59 (49.2%), and pathological in 61 (50.8%) patients. Statistical analysis showed significant correlation between type and grade of VUR. Our data confirmed predominance of VUR in females and in children under the age of 5. Statistically significant correlation between ureteral dilatation and the existence of VUR was found, with relatively high sensitivity (67.2%), specificity (81.4%), and high positive (78.8%) and negative predictive value (70.6%), total diagnostic accuracy of 74.2% in detecting VUR, and significantly increased probability (20 - 25%) of detecting VUR in patients with sonographically confirmed ureteral dilatation. CONCLUSION: Sonographically confirmed ureteral dilatation can be used as a predictor of VUR in children with UTIs, and in combination with other predictors, might find a place in an evidence-based selective strategy in children with suspected VUR. PMID- 26635433 TI - Contrast Media Injector Technology - Renal Safety During Coronarography. AB - AIM: This study sought to assess whether the volume and osmolarity of contrast media (CM) influences the occurrence of contrast induced nephropathy (CIN) following coronarography procedure. CIN can be defined as an increase in the serum concentration of creatinine greater than a 25% from baseline during the period of 12 to 48 hours after the administration of radiocontrast media. MATERIAL AND METHODS: We examined 100 patients without diabetes with serum creatinine concentration from 45 mmol/l to 141 mmol/l and 100 patients with diabetes with serum creatinine concentration from 46 mmol/l to 161 mmol/l who underwent coronary angiography. During procedure they received iso-osmolar contrast medium, Visipaque 320 (iodixanol-320), for group without diabetes from 40 to 340 ml and for group with diabetes from 49 to 310 ml. RESULTS: CIN occurred in 27 (13,5%) of the 200 study patients. There was a trend toward higher prevalence of CIN (16% vs.11%, p = 0.086) in the diabetic group compared with the non-diabetic group. Patient with diabetes received less contrast media, they are younger but number patients with CIN are higher. CONCLUSION: Increasing contrast media dose is associated with the occurrence of CIN following coronarography. But, another risk factors like diabetes mellitus, old age, male sex and preexisting kidney disease have influence of developing CIN after coronarography. PMID- 26635434 TI - Echocardiography Differences Between Athlete's Heart Hearth and Hypertrophic Cardiomyopathy. AB - INTRODUCTION: Among long term athletes there is always present hypertrophy of the left ventricle walls as well as increased cardiac mass. These changes are the result of the heart muscle adaptation to load during the years of training, which should not be considered as pathology. In people suffering from hypertrophic cardiomyopathy (HCM), there is also present hypertrophy of the left ventricle walls and increased mass of the heart, but these changes are the result of pathological changes in the heart caused by a genetic predisposition for the development HCM of. Differences between myocardial hypertrophy in athletes and HCM are not clearly differentiated and there are always dilemmas between pathological and physiological hypertrophy. The goal of the study is to determine and compare the echocardiographic cardiac parameters of longtime athletes to patients with hypertrophic cardiomyopathy. MATERIAL AND METHODS: The study included 60 subjects divided into two groups: active athletes and people with hypertrophic cardiomyopathy. RESULTS: Mean values of IVSd recorded in GB is IVSd=17.5 mm (n=20, 95% CI, 16.00-19.00 mm), while a significantly smaller mean value is recorded in GA, IVSd=10.0 mm (n=40, 95% CI, 9.00-11.00 mm). The mean value of the left ventricle in diastole (LVDd) recorded in the GA is LVDd=51 mm (n=40; 95% CI, 48.00 to 52.00 mm), while in the group with hypertrophic cardiomyopathy (GB) mean LVDd value is 42 mm (n=20; 95% CI, 40.00 to 48.00 mm). The mean value of the rear wall of the left ventricle (LVPWd) recorded in the GA is LVDd=10 mm (n=40; 95% CI, 9.00-10.00 mm) while in the group with hypertrophic cardiomyopathy (GB) mean LVDd is 14 mm (n=20; 95% CI, 12.00 to 16.00 mm). The mean of the left ventricle during systole (LVSD) observed in GA is LVSD=34 mm (n=40; 95% CI, 32.00 to 36.00 mm), while in the group with hypertrophic cardiomyopathy (GB) mean LVSD is 28 mm (n=20; 95% CI, 24.00 to 28.83 mm). The mean ejection fraction (EF%) observed in GA is EF=60% (n=40; 95% CI, 56.41 to 63.00%), while in the group with hypertrophic cardiomyopathy (GB) mean EF value is 69% (n=20; 95% CI, 62.00 to 70.83 mm). Somewhat higher mean diastolic left ventricular function (E/A) was observed in GA, E/A=1.76+/-0.15, and lower average values in the group with hypertrophic cardiomyopathy: (GB) E/A=0.78+/-0.02. CONCLUSION: Mean values of parameters intraventricular septum thickness in diastole (IVSd), the thickness of the rear wall of the left ventricle (LVPWd), the diameter of the left ventricle during systole (LVSD) were statistically different between groups of athletes (GA) compared to the group of patients with hypertrophic cardiomyopathy (GB). PMID- 26635435 TI - Evaluation of the Hemodynamic Response to Endotracheal Intubation Comparing the Airtraq((r)) with Macintosh Laryngoscopes in Cardiac Surgical Patients. AB - INTRODUCTION: Cardiac patients are more prone to develop hemodynamic instability on induction of anesthesia and endotracheal intubation. The Airtraq((r)) optical laryngoscope is a single-use rigid video laryngoscope that has been developed to facilitate tracheal intubation. There are limited studies comparing differences in the circulatory responses to Airtraq((r)) and direct Macintosh larynngoscopy in cardiac patients. AIM: The purpose of our study was to evaluate whether there was clinically significant difference between the hemodynamic response to orotracheal intubation guided by either of the two devices (Airtraq((r)) and Macintosh laryngoscopes) in patients who underwent coronary artery bypass grafting surgery. MATERIAL AND METHODS: In this clinical study we analyzed the hemodynamic response to endotracheal intubation performed with Airtraq((r)) or Macintosh laryngoscopes in patients who underwent elective coronary artery bypass graft surgery under general anesthesia. RESULTS: We analyzed: blood pressure (systolic, diastolic, mean), heart rate and peripheral oxygen saturation (all notified before induction in anesthesia, immediately after induction, at the time of intubation and thereafter one and five minutes after intubation). We also recorded the maximal values of blood pressure and heart rate, as well as calculated the product of heart rate and systolic blood pressure. There were statistically significant differences in the hemodynamic response between the groups. At the time of intubation, there was significant inter-group difference in heart rate, systolic, diastolic and mean blood pressure. Endotracheal intubation with Macintosh laryngoscope was accompanied by significant increase in blood pressure and heart rate compared to Airtraq((r)) group. CONCLUSION: The Airtraq((r)) laryngoscope performed better than the Macintosh laryngoscope in terms of hemodynamic to the patient undergoing routine coronary artery bypass graft surgery. PMID- 26635436 TI - Evaluation of Pharyngeal Space in Different Combinations of Class II Skeletal Malocclusion. AB - OBJECTIVES: The study was aimed to evaluate the pharyngeal airway linear measurements of untreated skeletal class II subjects with normal facial vertical pattern in prognathic maxilla with orthognathic mandible and orthognathic maxilla with retrognathic mandible. MATERIALS AND METHOD: the sample comprised of lateral Cephalograms of two groups (30 each) of class II malocclusion variants. Group 1 comprised of class II malocclusion with prognathic maxilla and orthognathic mandible, whereas group 2 comprised of class II malocclusion with orthognathic maxilla and retrognathic mandible. Each group was traced for the linear measurements of the pharyngeal airway like the oropharynx, nasopharynx and soft palate. The obtained data was subjected to independent t test and the Mann Whitney test to check the difference between the two groups and within the groups respectively. RESULTS: there was significant difference between all the linear measurements at the soft palate region and the distance between the tip of soft palate to its counter point on the pharyngeal wall in oropharynx region (p-ppm). CONCLUSION: the pharyngeal airway for class II malocclusion with various combination in an average growth pattern adult showed significant difference. The present results suggested, that the pharyngeal airway space might be the etiological factor for different sagittal growth pattern of the jaws and probable usage of different growth modification appliance can influence the pharyngeal airway. PMID- 26635437 TI - The Use of an Adapted Health IT Usability Evaluation Model (Health-ITUEM) for Evaluating Consumer Reported Ratings of Diabetes mHealth Applications: Implications for Diabetes Care and Management. AB - BACKGROUND: The aim of this paper is to present a usability analysis of the consumer ratings of key diabetes mHealth applications using an adapted Health IT Usability Evaluation Model (Health-ITUEM). METHODS: A qualitative content analysis method was used to analyze publicly available consumer reported data posted on the Android Market and Google Play for four leading diabetes mHealth applications. Health-ITUEM concepts including information needs, flexibility/customizability, learnability, performance speed, and competency guided the categorization and analysis of the data. Health impact was an additional category that was included in the study. A total of 405 consumers' ratings collected from January 9, 2014 to February 17, 2014 were included in the study. RESULTS: Overall, the consumers' ratings of the leading diabetes mHealth applications for both usability and health impacts were positive. The performance speed of the mHealth application and the information needs of the consumers were the primary usability factors impacting the use of the diabetes mHealth applications. There was also evidence on the positive health impacts of such applications. CONCLUSIONS: Consumers are more likely to use diabetes related mHealth applications that perform well and meet their information needs. Furthermore, there is preliminary evidence that diabetes mHealth applications can have positive impact on the health of patients. PMID- 26635438 TI - A Comparison of Logistic Regression Model and Artificial Neural Networks in Predicting of Student's Academic Failure. AB - BACKGROUND AND OBJECTIVE: Artificial Neural Networks (ANNs) have recently been applied in situations where an analysis based on the logistic regression (LR) is a standard statistical approach; direct comparisons of the results, however, are seldom attempted. In this study, we compared both logistic regression models and feed-forward neural networks on the academic failure data set. METHODS: The data for this study included 18 questions about study situation of 275 undergraduate students selected randomly from among nursing and midwifery and paramedic schools of Hormozgan University of Medical Sciences in 2013. Logistic regression with forward method and feed forward Artificial Neural Network with 15 neurons in hidden layer were fitted to the dataset. The accuracy of the models in predicting academic failure was compared by using ROC (Receiver Operating Characteristic) and classification accuracy. RESULTS: Among nine ANNs, the ANN with 15 neurons in hidden layer was a better ANN compared with LR. The Area Under Receiver Operating Characteristics (AUROC) of the LR model and ANN with 15 neurons in hidden layers, were estimated as 0.55 and 0.89, respectively and ANN was significantly greater than the LR. The LR and ANN models respectively classified 77.5% and 84.3% of the students correctly. CONCLUSION: Based on this dataset, it seems the classification of the students in two groups with and without academic failure by using ANN with 15 neurons in the hidden layer is better than the LR model. PMID- 26635439 TI - Quantitative and Qualitative Evaluation of Iranian Researchers' Scientific Production in Dentistry Subfields. AB - BACKGROUND: As in other fields of medicine, scientific production in the field of dentistry has significant placement. This study aimed at quantitatively and qualitatively evaluating Iranian researchers' scientific output in the field of dentistry and determining their contribution in each of dentistry subfields and branches. METHODS: This research was a scientometric study that applied quantitative and qualitative indices of Web of Science (WoS). Research population consisted of927indexed documents published under the name of Iran in the time span of 1993-2012 which were extracted from WoS on 10 March 2013. The Mann Whitney test and Pearson correlation coefficient were used to data analyses in SPSS 19. RESULTS: 777 (83. 73%) of indexed items of all scientific output in WoS were scientific articles. The highest growth rate of scientific productionwith90% belonged to endodontic sub field. The correlation coefficient test showed that there was a significant positive relationship between the number of documents and their publication age (P < 0. 0001). There was a significant difference between the mean number of published articles in the first ten- year (1993-2003) and that of the second one (2004-2013), in favor of the latter (P = 0. 001). CONCLUSIONS: The distribution frequencies of scientific production in various subfields of dentistry were very different. It needs to reinforce the infrastructure for more balanced scientific production in the field and its related subfields. PMID- 26635440 TI - Quantitative and Qualitative Evaluation of The Structural Designing of Medical Informatics Dynamic Encyclopedia. AB - INTRODUCTION: Encyclopedias and their compilation have become so prevalent as a valid cultural medium in the world. The daily development of computer industry and the expansion of various sciences have made indispensable the compilation of electronic, specialized encyclopedias, especially the web-based ones. MATERIALS AND METHODS: This is an applied-developmental study conducted in 2014. First, the main terms in the field of medical informatics were gathered using MeSH Online 2014 and the supplementary terms of each were determined, and then the tree diagram of the terms was drawn based on their relationship in MeSH. Based on the studies done by the researchers, the tree diagram of the encyclopedia was drawn with respect to the existing areas in this field, and the terms gathered were put in related domains. FINDINGS: In MeSH, 75 preferred terms together with 249 supplementary ones were indexed. One of the informatics' sub-branches is biomedical informatics and health which itself consists of three sub-divisions of bioinformatics, clinical informatics, and health informatics. Medical informatics which is a subdivision of clinical informatics has developed from the three fields of medical sciences, management and social sciences, and computational sciences and mathematics. RESULTS AND DISCUSSION: Medical Informatics is created of confluence and fusion and applications of the three major scientific branches include health and biological sciences, social sciences and management sciences, computing and mathematical sciences, and according to that the structure of MeSH is weak for future development of Encyclopedia of Medical Informatics. PMID- 26635441 TI - Designing of Intelligent Multilingual Patient Reported Outcome System (IMPROS). AB - BACKGROUND: By self-reporting outcome procedure the patients themselves record disease symptoms outside medical centers and then report them to medical staff in specific periods of time. One of the self-reporting methods is the application of interactive voice response (IVR), in which some pre-designed questions in the form of voice tracks would be played and then the caller responses the questions by pressing phone's keypad bottoms. AIM: The present research explains the main framework of such system designing according to IVR technology that is for the first time designed and administered in Iran. METHODS: Interactive Voice Response system was composed by two main parts of hardware and software. Hardware section includes one or several digital phone lines, a modem card with voice playing capability and a PC. IVR software on the other hand, acts as an intelligent control center, records call information and controls incoming data. RESULTS: One of the main features of the system is its capability to be administered in common PCs, utilizing simple and cheap modems, high speed to take responses and it's appropriateness to low literate patients. The system is applicable for monitoring chronic diseases, cancer and also in psychological diseases and can be suitable for taking care of elders and Children who require long term cares. Other features include user-friendly, decrease in direct and indirect costs of disease treatment and enjoying from high level of security to access patients' profiles. CONCLUSIONS: Intelligent multilingual patient reported outcome system (IMPROS) by controlling diseases gives the opportunity to patients to have more participation during treatment and it improves mutual interaction between patient and medical staff. Moreover it increases the quality of medical services, Additional to empowering patients and their followers. PMID- 26635442 TI - Development of Performance Dashboards in Healthcare Sector: Key Practical Issues. AB - BACKGROUND: Static nature of performance reporting systems in health care sector has resulted in inconsistent, incomparable, time consuming, and static performance reports that are not able to transparently reflect a round picture of performance and effectively support healthcare managers' decision makings. So, the healthcare sector needs interactive performance management tools such as performance dashboards to measure, monitor, and manage performance more effectively. The aim of this article was to identify key issues that need to be addressed for developing high-quality performance dashboards in healthcare sector. METHODS: A literature review was established to search electronic research databases, e-journals collections, and printed journals, books, dissertations, and theses for relevant articles. The search strategy interchangeably used the terms of "dashboard", "performance measurement system", and "executive information system" with the term of "design" combined with operator "AND". Search results (n=250) were adjusted for duplications, screened based on their abstract relevancy and full-text availability (n=147) and then assessed for eligibility (n=40). Eligible articles were included if they had explicitly focused on dashboards, performance measurement systems or executive information systems design. Finally, 28 relevant articles included in the study. RESULTS: Creating high-quality performance dashboards requires addressing both performance measurement and executive information systems design issues. Covering these two fields, identified contents were categorized to four main domains: KPIs development, Data Sources and data generation, Integration of dashboards to source systems, and Information presentation issues. CONCLUSION: This study implies the main steps to develop dashboards for the purpose of performance management. Performance dashboards developed on performance measurement and executive information systems principles and supported by proper back-end infrastructure will result in creation of dynamic reports that help healthcare managers to consistently measure the performance, continuously detect outliers, deeply analyze causes of poor performance, and effectively plan for the future. PMID- 26635443 TI - Chromatography as Method for Analytical Confirmation of Paracetamol in Postmortem Material Together with Psychoactive Substances. AB - INTRODUCTION: Paracetamol (Acetaminophen) in addition to aspirin is the most commonly used analgesic and antipyretic medication by millions of patients worldwide. It is an example that paracetamol as medicine that in the world is provided without a doctor's prescription, can lead to death. Today paracetamol became an integral part of a heroin mixture and is very popular at the street market. The main reason for this is that it can be obtained without a prescription, it is cheap, and by most people well tolerated without side effects. It is probably used for "cutting" the pure heroin, as it says in the jargon, and in that manner from small amount of pure drug is obtained greater amount, which is then sold on the street. The goal is to identify presence of paracetamol, by analytical method of gas chromatography mass spectrometer (GC-MS) in postmortem material together with psychoactive substances. MATERIAL AND METHODS: For chemical-toxicological analysis is used biological material collected trough autopsy of 20 deceased people, suspected to have died due to psychoactive substance overdose. All received samples are stored at -20 degrees C until analysis at our laboratory. From processed 47 samples that were analyzed in the period from 2014 to 2015, 19 are blood samples, urine 19, 3 samples of stomach contents, and 6 samples of bile content. Deceased were middle-aged, of which only 7 were female. The tested samples were processed according to two methods of extraction. Extraction by XAD-2 resin, and the extraction by the method of salting out with sodium tungstate. Extracts of the samples were then dissolved in chloroform and continued analysis at the analytical instrument. Identification of the paracetamol presence, in the test biological samples is demonstrated by the technique of gas chromatography with mass spectometry (hereinafter referred to as GC-MS). The technique of GC-MS is a selective, sensitive and reliable, and is therefore considered a "gold standard" for determining the drug, and the drug substance. Used GC-MS instrument was an Agilent 7890A with helium as the carrier gas. RESULTS: The analysis of blood samples, urine, bile and stomach contents, obtained after the autopsy of deceased persons, by using gas chromatography with mass spectrometry, in analytical manner confirmed the fact that paracetamol is a very common component of psychoactive substances poisoning. In our assay of samples we detected psychoactive substances (heroin, codeine, morphine, sertraline, diazepam), and almost all were found in the combination with paracetamol, indicating the poor quality of illicit drugs sold on the market. DISCUSSION: Paracetamol (Acetaminophen) is a very common component in mixtures of street drugs. Such mixtures almost anyone can afford, but the very quality of these drugs has become extremely low, because it does not sell the pure substance, but is mixed with various medications. According to research Pantazia et al. the heroin mixture proportion of the heroin is very small so a lot of that mixture has only 3% of heroin, a large number of cases can be only 1% of pure heroin. Most of the time it replaces caffeine and paracetamol. According to the Risser et al. reason why acetaminophen component is present in these mixtures is because it can be purchased without a prescription, it is cheap, well tolerated by most people and shows no side effects. CONCLUSION: When we talk about illegal drugs, we must emphasize the fact that there is no quality control, or the composition of the drug. The composition of the drug purchased on the black market is still unknown to potential user. While reaching the final drug users it pass through many hands, and at each step something is added to increase earnings. Most often present additives or impurities in narcotic drugs that are added are caffeine, ephedrine, acetaminophen, acetylsalicylic acid (aspirin) and additives such as powders, cement and chalk. PMID- 26635444 TI - The Most Influential Scientists in the Development of Medical Informatics (8): Jean Raoul Scherrer. PMID- 26635445 TI - Miku's mask: Fictional encounters in children's costume play. AB - Children's engagement with Japanese toys and fictional characters has taken on new significance in the age of YouTube. Drawing on ethnographic research on technology-mediated play among 8- and 9-year-olds in Norway, this article shows how boundaries between "real" humans and "fake" non-humans are blurred and undermined when children take on the perspective of a fictional pop star known as Miku. I argue that YouTube provides a platform for children's playful experimentation with posthuman subjectivities, where they orient themselves toward the future not in terms of becoming adult but in terms of multiple becomings. PMID- 26635446 TI - Porcine acellular dermis-based breast reconstruction: complications and outcomes following adjuvant radiotherapy. AB - BACKGROUND: Acellular dermal matrices (ADM) such as StratticeTM are increasingly used in UK during implant-based reconstruction. However, there are mixed opinions regarding the compatibility of radiotherapy treatment in pre- and post reconstructed breasts. The aims of this study are to audit the rates of radiation induced complications in patients who underwent breast reconstruction using StratticeTM and establish whether there is an association between timing of radiotherapy and complication rates. METHODS: Retrospective data collection was performed for all patients who underwent skin-sparing mastectomy and immediate or delayed StratticeTM-based reconstruction, and received pre- or post reconstruction radiotherapy from July 2010 to November 2014. RESULTS: The age ranged from 33 to 78 years (mean age 51 +/- 10.6) with a mean follow-up time of 21 months. There were 25 StratticeTM-based reconstructions performed. Sixteen had delayed reconstruction, and 9 had skin-sparing mastectomy and immediate reconstruction. There were 4 (16 %) abandoned procedures due to inability to stretch the mastectomy flap secondary to poor skin compliance. Two women (8 %) presented 4 and 9 months later with wound breakdown. One case (4 %) developed severe capsular contracture following radiotherapy post-reconstruction and 1 case (4 %) of implant rupture. There were no episodes of extrusion or implant infection. Overall complication rates were 32 %. The majority (75 %) of complications occurred in breasts reconstructed post-radiotherapy; however, this is not significant when analysed using chi-square (p = 0.43). CONCLUSIONS: Our evidence suggests that there is no difference in complication rates in pre- and post-radiation individuals; this would suggest that implant-based reconstruction using StratticeTM should not be an absolute contraindication in pre- or post radiotherapy patients. However, when planning these procedures, it is paramount that the increased risks are emphasised to patients in order to better manage patient expectation in cases where complications arise. Level of Evidence: Level III, risk / prognostic study. PMID- 26635447 TI - Cytokines as Mediators of Pain-Related Process in Breast Cancer. AB - Pain is a clinical sign of inflammation found in a wide variety of chronic pathologies, including cancer. The occurrence of pain in patients carrying breast tumors is reported and is associated with aspects concerning disease spreading, treatment, and surgical intervention. The persistence of pain in patients submitted to breast surgery is estimated in a range from 21% to 55% and may affect patients before and after surgery. Beyond the physical compression exerted by the metastatic mass expansion and tissue injury found in breast cancer, inflammatory components that are significantly produced by the host-tumor interaction can significantly contribute to the generation of pain. In this context, cytokines have been studied aiming to establish a cause-effect relationship in cancer pain-related syndromes, especially the proinflammatory ones. Few reports have investigated the relationship between pain and cytokines in women carrying advanced breast cancer. In this scenario, the present review analyzes the main cytokines produced in breast cancer and discusses the evidences from literature regarding its role in specific clinical features related with this pathology. PMID- 26635448 TI - Expression of Toll-Like Receptors 2 and 4 and Related Cytokines in Patients with Hepatic Cystic and Alveolar Echinococcosis. AB - Several studies have demonstrated the important role of Toll-like receptors in various parasitic infections. This study aims to explore expression of Toll-like receptors (TLRs) and related cytokines in patients with human cystic echinococcosis (CE) and alveolar echinococcosis (AE). 78 subjects including AE group (N = 28), CE group (N = 22), and healthy controls (HC, N = 28) were enrolled in this study. The mRNA expression levels of TLR2 and TLR4 in blood and hepatic tissue and plasma levels related cytokines were detected by using ELISA. Median levels of TLR2 mRNA in AE and CE groups were significantly elevated as compared with that in healthy control group. Median levels of TLR4 expression were increased in AE and CE. Plasma concentration levels of IL-5, IL-6, and IL-10 were slightly increased in AE and CE groups compared with those in HC group with no statistical differences (p > 0.05). The IL-23 concentration levels were significantly higher in AE and CE groups than that in HC subjects with statistical significance. The increased expression of TLR2 and IL-23 might play a potential role in modulating tissue infiltrative growth of the parasite and its persistence in the human host. PMID- 26635449 TI - Lipoxin Inhibits Fungal Uptake by Macrophages and Reduces the Severity of Acute Pulmonary Infection Caused by Paracoccidioides brasiliensis. AB - Cysteinyl leukotrienes (CysLTs) and lipoxins (LXs) are lipid mediators that control inflammation, with the former inducing and the latter inhibiting this process. Because the role played by these mediators in paracoccidioidomycosis was not investigated, we aimed to characterize the role of CysLT in the pulmonary infection developed by resistant (A/J) and susceptible (B10.A) mice. 48 h after infection, elevated levels of pulmonary LTC4 and LXA4 were produced by both mouse strains, but higher levels were found in the lungs of susceptible mice. Blocking the CysLTs receptor by MTL reduced fungal loads in B10.A, but not in A/J mice. In susceptible mice, MLT treatment led to reduced influx of PMN leukocytes, increased recruitment of monocytes, predominant synthesis of anti-inflammatory cytokines, and augmented expression of 5- and 15-lipoxygenase mRNA, suggesting a prevalent LXA4 activity. In agreement, MTL-treated macrophages showed reduced fungal burdens associated with decreased ingestion of fungal cells. Furthermore, the addition of exogenous LX reduced, and the specific blockade of the LX receptor increased the fungal loads of B10.A macrophages. This study showed for the first time that inhibition of CysLTs signaling results in less severe pulmonary paracoccidioidomycosis that occurs in parallel with elevated LX activity and reduced infection of macrophages. PMID- 26635450 TI - Constitutive Activation of the Nlrc4 Inflammasome Prevents Hepatic Fibrosis and Promotes Hepatic Regeneration after Partial Hepatectomy. AB - TThe molecular mechanisms responsible for the development of hepatic fibrosis are not fully understood. The Nlrc4 inflammasome detects cytosolic presence of bacterial components, activating inflammatory cytokines to facilitate clearance of pathogens and infected cells. We hypothesized that low-grade constitutive activation of the Nlrc4 inflammasome may lead to induced hepatocyte proliferation and prevent the development of hepatic fibrosis. The gene of Nlrc4 contains two single nucleotide polymorphisms (SNPs), one located within the Nlrc4 promoter and one contained within exon 5. These SNPs regulate Nlrc4 gene transcription and activation as measured through gene reporter assays and IL-1beta secretion. The 17C-6 mice have increased IL-1beta in plasma after chronic carbon tetrachloride (CCl4) administration compared to B6 mice. After two-thirds partial hepatectomy (2/3PH) 17C-6 mice have earlier restoration of liver mass with greater cyclin D1 protein and BrdU incorporation compared to B6 mice at several time points. These data reveal mild constitutive activation of the Nlrc4 inflammasome as the results of two SNPs, which leads to the stimulation of hepatocyte proliferation. The increased liver regeneration induces rapid liver mass recovery after hepatectomy and may prevent the development of hepatotoxin-induced liver fibrosis. PMID- 26635451 TI - An Overview of Ophthalmologic Survey Methodology in the 2008-2015 Korean National Health and Nutrition Examination Surveys. AB - The Korea National Health and Nutrition Examination Survey (KNHANES) is a national program designed to assess the health and nutritional status of the noninstitutionalized population of South Korea. The KNHANES was initiated in 1998 and has been conducted annually since 2007. Starting in the latter half of 2008, ophthalmologic examinations were included in the survey in order to investigate the prevalence and risk factors of common eye diseases such as visual impairment, refractive errors, strabismus, blepharoptosis, cataract, pterygium, diabetic retinopathy, age-related macular degeneration, glaucoma, dry eye disease, and color vision deficiency. The measurements included in the ophthalmic questionnaire and examination methods were modified in the KNHANES IV, V, and VI. In this article, we provide detailed information about the methodology of the ophthalmic examinations in KNHANES in order to aid in further investigations related to major eye diseases in South Korea. PMID- 26635452 TI - Surgical Outcomes of Canalicular Trephination Combined with Endoscopic Dacryocystorhinostomy in Patients with Distal or Common Canalicular Obstruction. AB - PURPOSE: This study investigated the surgical outcomes of canalicular trephination combined with endoscopic dacryocystorhinostomy (DCR) in patients with a distal or common canalicular obstruction. It also identified the factors affecting surgical success rates associated with this technique. METHODS: We retrospectively reviewed the medical records of 57 patients (59 eyes) in whom a canalicular obstruction was encountered during endoscopic DCR. All patients were treated with endoscopic DCR, followed by canalicular trephination and silicone tube placement. The surgical outcome was categorized as a functional success according to the patient's subjective assessment of symptoms, including epiphora, and as an anatomical success according to a postoperative nasolacrimal duct irrigation test. Surgical success rates were compared based on age, sex, location of the obstruction, number of silicone tubes, and experience of the surgeon. RESULTS: Functional success was achieved in 55 of 59 eyes (93%) at one month, 50 eyes (84%) at three months, and 46 eyes (78%) at six months. Anatomical success was achieved in 58 of 59 eyes (98%) at one month, 52 eyes (88%) at three months, and 50 eyes (84%) at six months. There was a statistically significant difference in surgical outcome according to the experience of the surgeon. The anatomical success rate at the six-month follow-up exam was 95.4% in the >5 years of experience group, and 53.3% in the <5 years of experience group (p = 0.008, Pearson chi-square test). CONCLUSIONS: The success rate of canalicular trephination combined with endoscopic DCR in patients with a distal or common canalicular obstruction decreased gradually during the six-month follow-up period. In particular, patients undergoing procedures with experienced surgeons tended to show excellent surgical outcomes at the six-month follow-up exam. PMID- 26635453 TI - A Comparative Study of Topical Mitomycin C, Cyclosporine, and Bevacizumab after Primary Pterygium Surgery. AB - PURPOSE: To compare the recurrence rates and complications associated with instillation of topical mitomycin C, cyclosporine, and bevacizumab after primary pterygium surgery. METHODS: Between July 2013 and June 2014, we performed surgery using the bare sclera method on 132 eyes (132 patients) with primary pterygium. We randomly selected 33 eyes (33 patients) and treated them with artificial tears four times a day for three months, 29 eyes (29 patients) were treated with topical 0.02% mitomycin C four times a day for five days, 34 eyes (34 patients) were treated with topical 0.05% cyclosporine four times a day for three months, and 36 eyes (36 patients) were treated with topical 2.5% bevacizumab four times a day for three months after surgery. We prospectively determined the recurrence rates of pterygium and complications at the six-month follow-up examination. RESULTS: At six months after surgery, the recurrence rates in each group were as follows: 45.5% (15 eyes) in the control group, 10.3% (three eyes) in the mitomycin C group, 20.6% (seven eyes) in the cyclosporine group, and 41.7% (15 eyes) in the bevacizumab group (p = 0.004). No serious complications, except subconjunctival hemorrhages, were observed in any group. CONCLUSIONS: Groups receiving topical 0.02% mitomycin C and 0.05% cyclosporine after surgery showed lower recurrence rates than the control group; however, no difference in recurrence rate was observed between the control group and the group receiving topical 2.5% bevacizumab after surgery. PMID- 26635454 TI - Comparison of Serum Cortisol and Testosterone Levels in Acute and Chronic Central Serous Chorioretinopathy. AB - PURPOSE: To compare the levels of serum cortisol and testosterone in acute and chronic central serous chorio-retinopathy (CSC). METHODS: Serum cortisol and testosterone levels in 30 patients with either acute or chronic CSC were evaluated using chemiluminescent immunoassay. RESULTS: The mean age was 42.43 +/- 6.37 years (range, 32 to 56 years). The mean 8:00 to 9.00 a.m. serum cortisol level was 12.61 +/- 4.74 ug/dL (range, 6.58 to 27.42 ug/dL). The mean serum testosterone level was 5.88 +/- 1.57 ng/dL (range, 2.81 to 9.94 ng/dL). The mean visual acuity was 20 / 65.07 +/- 40.56 (range, 20 / 25 to 20 / 200). There was no statistically significant difference in the mean levels of serum cortisol and testosterone between the acute and chronic cases (p > 0.05), but there was a statistically significant difference in the mean presenting visual acuity in the two groups (p < 0.05). CONCLUSIONS: All except one patient in the acute group had normal levels of serum cortisol. Testosterone levels were within the normal range in both the acute and chronic cases of CSC. There is unlikely to be any statistically significant difference in the mean levels of serum cortisol and testosterone between the acute and chronic cases, but there may be a statistically significant difference in the mean presenting visual acuity in these groups. PMID- 26635455 TI - Comparison of the Clinical Manifestations between Acute Vogt-Koyanagi-Harada Disease and Acute Bilateral Central Serous Chorioretinopathy. AB - PURPOSE: To compare clinical, angiographic, and optical coherence tomographic characteristics between eyes with acute Vogt-Koyanagi-Harada (VKH) disease and eyes with acute bilateral central serous chorioretinopathy (CSC), and to demonstrate distinguishing features between the two diseases in confusing cases. METHODS: The medical records of 35 patients with VKH disease and 25 patients with bilateral CSC were retrospectively reviewed. Characteristics according to slit lamp biomicroscopy, ophthalmoscopy, fundus photography, fluorescein angiography, indocyanine green angiography, and spectral-domain optical coherence tomography were compared between the two diseases. RESULTS: Five of 35 patients (10 of 70 eyes, 14.3%) with VKH disease were initially misdiagnosed as CSC patients, and six of 25 patients (12 of 50 eyes, 24%) with bilateral CSC were initially misdiagnosed as patients with VKH disease. Pigment epithelial detachment in CSC and optic disc hyperemia in VKH disease show the highest positive predictive values of 100% for each disease. CONCLUSIONS: Optic disc hyperemia in VKH disease and pigment epithelial detachment in bilateral CSC are the most specific clinical manifestations of each disease at initial patient presentation. PMID- 26635456 TI - Effects of Vitreomacular Traction on Ranibizumab Treatment Response in Eyes with Neovascular Age-related Macular Degeneration. AB - PURPOSE: To investigate the effects of vitreomacular traction (VMT) on ranibizumab treatment response for neovascular age-related macular degeneration (AMD). METHODS: A retrospective review of 85 eyes of 85 patients newly diagnosed with neovascular AMD was conducted. Patients were eligible if they had received more than three consecutive monthly ranibizumab (0.50 mg) treatments and ophthalmic evaluations. Patients were classified into a VMT (+) group or VMT (-) group according to optical coherence tomography imaging. Best corrected visual acuity and central retinal thickness (CRT) measurements were obtained at three and six months after initial injection. RESULTS: One month after the third injection, mean visual acuity (VA) increases of 6.36 and 9.87 letters were observed in the VMT (+) and VMT (-) groups, respectively. The corresponding mean CRT values decreased by 70.29 um and 121.68 um, respectively. A total 41 eyes were identified as eligible for a subsequent fourth injection; 71.1% of patients (27 eyes) in the VMT (+) group but only 29.8% of patients in the VMT (-) group needed a subsequent fourth injection. Follow-up was extended to six months for 42 of the 85 enrolled patients (49.4%). The trends in VA and optical coherence tomography were found to be maintained at six-month follow-up. CONCLUSIONS: VA and CRT appeared to be more improved after ranibizumab treatment in the VMT (-) group compared to the VMT (+) group. VMT might antagonize the effect of ranibizumab treatment in a subpopulation of AMD patients. PMID- 26635457 TI - Intravitreal Anti-vascular Endothelial Growth Factor for Newly Diagnosed Symptomatic Polypoidal Choroidal Vasculopathy with Extrafoveal Polyps. AB - PURPOSE: To evaluate the 12-month outcome of anti-vascular endothelial growth factor (VEGF) treatment for extrafoveal polypoidal choroidal vasculopathy (PCV). METHODS: This retrospective observational study included 32 eyes of 32 patients newly diagnosed with extrafoveal PCV (polyps located more than 500 um from the center of the fovea). Patients were treated with intravitreal ranibizumab, bevacizumab, or both. The best-corrected visual acuity (BCVA) and central foveal thickness (CFT) at diagnosis and at 12 months were compared. Eyes were divided into two groups according to the presence of submacular hemorrhage. The BCVA in each group was compared at baseline and at 12 months. RESULTS: During the 12 month study period, patients received an average of 4.0 +/- 1.1 anti-VEGF injections. The BCVA at baseline, three-month post-diagnosis, and 12-month post diagnosis was 0.59 +/- 0.40, 0.34 +/- 0.38, and 0.38 +/- 0.38, respectively. The BCVA at 12 months was significantly better than the baseline value (p = 0.002). The CFT at baseline, three-month, and 12-month post-diagnosis was 477.1 +/- 194.2 um, 214.5 +/- 108.8 um, and 229.8 +/- 106.1 um, respectively. The CFT at 12 months was significantly lower than the baseline value (p < 0.001). A significant improvement in BCVA was noted in eyes with and without submacular hemorrhage (n = 13, p = 0.032 and n = 19, p = 0.007, respectively). CONCLUSIONS: Anti-VEGF therapy was beneficial in extrafoveal PCV, regardless of the presence of submacular hemorrhage. PMID- 26635458 TI - Comparison of Surgical Outcomes with Unilateral Recession and Resection According to Angle of Deviation in Basic Intermittent Exotropia. AB - PURPOSE: The purpose of this study is to compare the surgical outcomes and near stereoacuities after unilateral medial rectus (MR) muscle resection and lateral rectus (LR) recession according to deviation angle in basic intermittent exotropia, X(T). METHODS: Ninety patients with basic type X(T) were included in this study. They underwent unilateral recession of the LR and resection of the MR and were followed postoperatively for at least 12 months. Patients were divided into three groups according to their preoperative deviation angle: group 1 <=20 prism diopter (PD), 20 PD< group 2 <40 PD, and group 3 >=40 PD. Surgical outcomes and near stereoacuities one year after surgery were evaluated. Surgical success was defined as having a deviation angle range within +/-10 PD for both near and distance fixation. RESULTS: Among 90 patients, groups 1, 2, and 3 included 30 patients each. The mean age in groups 1, 2, and 3 was 9.4 years, 9.4 years, and 11.0 years, respectively. The surgical success rates one year after surgery for groups 1, 2, and 3 were 80.0%, 73.3%, and 73.3% (chi-square test, p = 0.769), respectively. The undercorrection rates for groups 1, 2, and 3 were 16.7%, 23.3%, and 26.7%, and the overcorrection rates were 3.3%, 3.3%, and 0%, respectively. The mean preoperative near stereoacuities for groups 1, 2, and 3 were 224.3 arcsec, 302.0 arcsec, and 1,107.3 arcsec, and the mean postoperative near stereoacuities were 218.3 arcsec, 214.7 arcsec, and 743.0 arcsec (paired t-test; p = 0.858, p = 0.379, p = 0.083), respectively. CONCLUSIONS: In basic X(T) patients, the amount of angle deviation has no influence on surgical outcomes in unilateral LR recession and MR resection. The near stereoacuities by one year after LR recession and MR resection for intermittent X(T) were not different among patient groups separated by preoperative deviation angle. PMID- 26635459 TI - Differences between Non-arteritic Anterior Ischemic Optic Neuropathy and Open Angle Glaucoma with Altitudinal Visual Field Defect. AB - PURPOSE: To investigate the differences in retinal nerve fiber layer (RNFL) change and optic nerve head parameters between non-arteritic anterior ischemic optic neuropathy (NAION) and open angle glaucoma (OAG) with altitudinal visual field defect. METHODS: Seventeen NAION patients and 26 OAG patients were enrolled prospectively. The standard visual field indices (mean deviation, pattern standard deviation) were obtained from the Humphrey visual field test and differences between the two groups were analyzed. Cirrus HD-OCT parameters were used, including optic disc head analysis, average RNFL thickness, and RNFL thickness of each quadrant. RESULTS: The mean deviation and pattern standard deviation were not significantly different between the groups. In the affected eye, although the disc area was similar between the two groups (2.00 +/- 0.32 and 1.99 +/- 0.33 mm(2), p = 0.586), the rim area of the OAG group was smaller than that of the NAION group (1.26 +/- 0.56 and 0.61 +/- 0.15 mm(2), respectively, p < 0.001). RNFL asymmetry was not different between the two groups (p = 0.265), but the inferior RNFL thickness of both the affected and unaffected eyes were less in the OAG group than in the NAION group. In the analysis of optic disc morphology, both affected and unaffected eyes showed significant differences between two groups. CONCLUSIONS: To differentiate NAION from OAG in eyes with altitudinal visual field defects, optic disc head analysis of not only the affected eye, but also the unaffected eye, by using spectral domain optical coherence tomography may be helpful. PMID- 26635461 TI - Lacrimal Intrasaccal Cyst. PMID- 26635460 TI - Effects of Bevacizumab on Bcl-2 Expression and Apoptosis in Retinal Pigment Epithelial Cells under Oxidative Stress. AB - PURPOSE: To evaluate the effects of bevacizumab on expression of B-cell leukemia/lymphoma (Bcl)-2 and apoptosis in retinal pigment epithelial (RPE) cells under oxidative stress conditions. METHODS: RPE cells were treated with H(2)O(2) (0, 100, 200, 300, and 400 uM) and bevacizumab at or above the doses normally used in clinical practice (0, 0.33, 0.67, 1.33, and 2.67 mg/mL). Cell apoptosis was measured using flow cytometry with annexin V-fluorescein isothiocyanate. The expression of Bcl-2 mRNA was determined using reverse transcription polymerase chain reaction. RESULTS: Under low oxidative stress conditions (H(2)O(2) 100 uM), cell apoptosis was not significantly different at any concentration of bevacizumab, but Bcl-2 mRNA expression decreased with increasing concentration of bevacizumab (0.33, 0.67, 1.33, and 2.67 mg/mL). Under moderate oxidative stress conditions (H(2)O(2) 200 uM), Bcl-2 mRNA expression decreased with increasing concentration of bevacizumab (0.33, 0.67, 1.33, and 2.67 mg/mL), but cell apoptosis increased only at 2.67 mg/mL of bevacizumab. Under high oxidative stress (300 uM) conditions, cell apoptosis increased at high concentrations of bevacizumab (1.33 and 2.67 mg/mL), but it did not correlate with Bcl-2 expression. CONCLUSIONS: Withdrawal of vascular endothelial growth factor can lead to RPE cell apoptosis and influences the expression of anti-apoptotic genes such as Bcl-2 under oxidative stress conditions. Since oxidative stress levels of each patient are unknown, repeated injections of intravitreal bevacizumab, as in eyes with age-related macular degeneration, might influence RPE cell survival. PMID- 26635462 TI - Sympathetic Ophthalmia after Ocular Wasp Sting. PMID- 26635463 TI - Argon Green Laser for Valsalva Retinopathy Treatment and Long-term Follow-up of the Internal Limiting Membrane Changes in Optical Coherence Tomography. PMID- 26635464 TI - Choroidal Neovascularization Following Epiretinal Membrane Peeling. PMID- 26635465 TI - Saul: Towards Declarative Learning Based Programming. AB - We present Saul, a new probabilistic programming language designed to address some of the shortcomings of programming languages that aim at advancing and simplifying the development of AI systems. Such languages need to interact with messy, naturally occurring data, to allow a programmer to specify what needs to be done at an appropriate level of abstraction rather than at the data level, to be developed on a solid theory that supports moving to and reasoning at this level of abstraction and, finally, to support flexible integration of these learning and inference models within an application program. Saul is an object functional programming language written in Scala that facilitates these by (1) allowing a programmer to learn, name and manipulate named abstractions over relational data; (2) supporting seamless incorporation of trainable (probabilistic or discriminative) components into the program, and (3) providing a level of inference over trainable models to support composition and make decisions that respect domain and application constraints. Saul is developed over a declaratively defined relational data model, can use piecewise learned factor graphs with declaratively specified learning and inference objectives, and it supports inference over probabilistic models augmented with declarative knowledge based constraints. We describe the key constructs of Saul and exemplify its use in developing applications that require relational feature engineering and structured output prediction. PMID- 26635466 TI - Scleral buckling for primary rhegmatogenous retinal detachment using noncontact wide-angle viewing system with a cannula-based 25 G chandelier endoilluminator. AB - PURPOSE: The aim of this study is to report the result of scleral buckling (SB) using a combination of a noncontact wide-angle viewing system and a cannula-based 25 G chandelier endoilluminator. METHODS: Retrospective analyses of the medical records of 79 eyes of 79 patients with primary uncomplicated rhegmatogenous retinal detachments who had underwent SB using a combination of a noncontact wide angle viewing system and a chandelier endoilluminator were performed. RESULTS: There were 50 men and 29 women. The mean +/- standard deviation age was 43.7+/ 16.0 years. Their preoperative best-corrected visual acuity (BCVA) was 0.31+/ 0.65 logMAR units. The final BCVA was 0.10+/-0.31 logMAR units, which was significantly better than the preoperative BCVA (P<0.01). The initial and final anatomical success rates were 92.4% and 100%, respectively. Backward logistic multiple regression analysis revealed no relationship between explanatory variables and the primary anatomic success (P=0.104). CONCLUSION: SB using a combination of a noncontact wide-angle viewing system and a chandelier endoilluminator is a modified new technique and may be a valid option for the management of rhegmatogenous retinal detachments. PMID- 26635468 TI - The changes and factors associated with post-discharge self-care behaviors among Chinese patients with heart failure. AB - BACKGROUND: Self-care behavior is essential for achieving good outcomes among patients with heart failure. Understanding the factors associated with self-care over time is important for the provision of appropriate and targeted interventions. However, little is known regarding the changes and factors associated with post-discharge self-care behaviors among Chinese patients with heart failure. OBJECTIVE: To investigate the changes and factors of self-care behaviors during the first 3 months following discharge among patients with heart failure in the People's Republic of China. METHODS: A descriptive design with a convenience sample was utilized in this study. Patients (N=128) from two hospitals, West China Hospital and Angjin Hospital, in Chengdu, People's Republic of China, were recruited from June 2013 to June 2014. The instruments used in the study included the following: the Social Support Rating Scale, the Hospital Anxiety and Depression Scale, the Self-Efficacy for Managing Chronic Disease 6 Item Scale, and the European Heart Failure Self-Care Behaviour Scale. Multivariate linear regression analyses were used to identify the factors related to self-care behaviors at baseline, 1 month, and 3 months following discharge. RESULTS: Patients' self-care behaviors were poor and decreased significantly over time (F=4.09, P<0.05). The factors associated with self-care behaviors at baseline included the following: education level, comorbidities, and social support. The factors related to self-care behaviors at 1 and 3 months following discharge included the following: education level, comorbidities, social support, and self-efficacy. The variances in self-care behaviors attributed to these factors were 43%, 46%, and 42% at baseline, 1 month, and 3 months following discharge, respectively. CONCLUSION: Additional support should be provided to patients with heart failure with low educational levels and patients with multiple comorbidities. Follow-up, continuity of care, and family caregiver integration following discharge are necessary for the said patients to improve their self-care behaviors and obtain better outcomes. PMID- 26635467 TI - Current perspective of neuroprotection and glaucoma. AB - Glaucoma is the second leading cause of blindness worldwide and is most notably characterized by progressive optic nerve atrophy and advancing loss of retinal ganglion cells (RGCs). The main concomitant factor is the elevated intraocular pressure (IOP). Existing treatments are focused generally on lowering IOP. However, both RGC loss and optic nerve atrophy can independently occur with IOP at normal levels. In recent years, there has been substantial progress in the development of neuroprotective therapies for glaucoma in order to restore vital visual function. The present review intends to offer a brief insight into conventional glaucoma treatments and discuss exciting current developments of mostly preclinical data in novel neuroprotective strategies for glaucoma that include recent advances in noninvasive diagnostics going beyond IOP maintenance for an enhanced global view. Such strategies now target RGC loss and optic nerve damage, opening a critical therapeutic window for preventative monitoring and treatment. PMID- 26635469 TI - Physical activity in patients with heart failure: barriers and motivations with special focus on sex differences. AB - BACKGROUND: Adherence to recommendations for physical activity is low in both male and female patients with heart failure (HF). Men are more physically active than women. In order to successfully promote physical activity, it is therefore essential to explore how much and why HF patients are physically active and if this is related to sex. The aim of this study was therefore to evaluate physical activity in HF patients, to describe the factors related to physical activity, and to examine potential barriers and motivations to physical activity with special focus on sex differences. METHODS: The study had a cross-sectional survey design. HF patients living at home received a questionnaire during May-July 2014, with questions on physical activity (from the Short Form-International Physical Activity Questionnaire), and potential barriers and motivations to physical activity. RESULTS: A total of 154 HF patients, 27% women, with a mean age of 70+/ 10 were included. In total, 23% of the patients reported a high level of physical activity, 46% a moderate level, and 34% a low level. Higher education, self efficacy, and motivation were significantly associated with a higher amount of physical activity. Symptoms or severity of the disease were not related to physical activity. All the potential barriers to exercise were reported to be of importance. Psychological motivations were most frequently rated as being the most important motivation (41%) to be physically active. Physical motivations (33%) and social motivations were rated as the least important ones (22%). Women had significantly higher total motivation to be physically active. These differences were found in social, physical, and psychological motivations. DISCUSSION: One-third of the HF patients had a low level of physical activity in their daily life. Severity of the disease or symptoms were not related, whereas level of education, exercise self-efficacy, and motivation were important factors to take into account when advising a HF patient about physical activity. Women reported higher motivation to be physically active than men, but there was no difference in the reported level of physical activity. PMID- 26635470 TI - Evaluating preferences for profiles of GLP-1 receptor agonists among injection naive type 2 diabetes patients in the UK. AB - OBJECTIVE: To use a discrete choice experiment (DCE) to evaluate preferences for the actual treatment features and overall profiles of two injectable glucagon like peptide-1 receptor agonists (dulaglutide and liraglutide) among patients with type 2 diabetes mellitus (T2DM) in the UK. METHODS: In-person interviews were conducted in the UK to administer a DCE to patients with self-reported T2DM, naive to treatment with injectable medications. The DCE examined six attributes of T2DM treatment each described by two levels: "dosing frequency," "hemoglobin A1c change," "weight change," "type of delivery system," "frequency of nausea," and "frequency of hypoglycemia." Part-worth utilities were estimated using random effects logit models and were used to calculate relative importance (RI) values for each attribute. A chi-square test was used to determine differences in preferences for dulaglutide versus liraglutide profiles. RESULTS: A total of 243 participants [mean age: 60.5 (standard deviation 10.9) years; 76.1% male; mean body mass index: 29.8 (standard deviation 5.4) kg/m(2)] completed the study. RI values for the attributes in rank order were: "dosing frequency" (41.6%), "type of delivery system" (35.5%), "frequency of nausea" (10.4%), "weight change" (5.9%), "hemoglobin A1c change" (3.6%), and "frequency of hypoglycemia" (3.0%). Significantly more participants preferred the dulaglutide profile (83.1%) compared with the liraglutide profile (16.9%; P<0.0001). CONCLUSION: This study elicited patients' preferences for attributes and levels representing the actual characteristics of two specific glucagon-like peptide-1 medications. In this context, dosing frequency and type of delivery system were most important, accounting for over 75% of the RI. While previous studies have identified efficacy as highly important in T2DM medication decisions, this study suggests that when differences in efficacy between medications are small, other treatment features (eg, dosing frequency and delivery system) are of much greater importance to patients. PMID- 26635471 TI - Understanding patient preferences and willingness to pay for hemophilia therapies. AB - BACKGROUND: Despite clearly improved clinical outcomes for prophylaxis compared to on-demand therapy, on average only 56% of patients diagnosed with severe hemophilia receive prophylactic factor replacement therapy in the US. Prophylaxis rates generally drop as patients transition from childhood to adulthood, partly due to patients becoming less adherent when they reach adulthood. Assessment of patient preferences is important because these are likely to translate into increased treatment satisfaction and adherence. In this study, we assessed preferences and willingness to pay (WTP) for on-demand, prophylaxis, and longer acting prophylaxis therapies in a sample of US hemophilia patients. METHODS: Adult US hemophilia patients and caregivers (N=79) completed a discrete-choice survey that presented a series of trade-off questions, each including a pair of hypothetical treatment profiles. Using a mixed logit model for analysis, we compared the relative importance of five treatment characteristics: 1) out-of pocket treatment costs (paid by patients), 2) factor dose adjustment, 3) treatment side effects, 4) availability of premixed factor, and 5) treatment effectiveness and dosing frequency. Based on these attribute estimates, we calculated patients' WTP. RESULTS: Out-of-pocket treatment costs (P<0.001), side effects (P<0.001), and treatment effectiveness and dosing frequency (P<0.001) were found to be statistically significant in the model. Patients were willing to pay US $410 (95% confidence interval: $164-$656) out of pocket per month for thrice-weekly prophylaxis therapy compared to on-demand therapy and $360 (95% confidence interval: $145-$575) for a switch from thrice-weekly to once-weekly prophylaxis therapy. CONCLUSION: Improvements in treatment effectiveness and dosing frequency, treatment side effects, and out-of-pocket costs per month were the greatest determinants of hemophilia treatment choice and WTP. The positive preferences and WTP for longer acting prophylactic therapies suggest that the uptake is likely to increase adherence, improving treatment outcomes. These preferences should also inform the Food and Drug Administration's assessment of new longer acting hemophilia therapies. PMID- 26635472 TI - The effects of hierarchical micro/nanosurfaces decorated with TiO2 nanotubes on the bioactivity of titanium implants in vitro and in vivo. AB - In the present work, a hierarchical hybrid micro/nanostructured titanium surface was obtained by sandblasting with large grit and acid etching (SLA), and nanotubes of different diameters (30 nm, 50 nm, and 80 nm) were superimposed by anodization. The effect of each SLA-treated surface decorated with nanotubes (SLA + 30 nm, SLA + 50 nm, and SLA + 80 nm) on osteogenesis was studied in vitro and in vivo. The human MG63 osteosarcoma cell line was used for cytocompatibility evaluation, which showed that cell adhesion and proliferation were dramatically enhanced on SLA + 30 nm. In comparison with cells grown on the other tested surfaces, those grown on SLA + 80 nm showed an enhanced expression of osteogenesis-related genes. Cell spread was also enhanced on SLA + 80 nm. A canine model was used for in vivo evaluation of bone bonding. Histological examination demonstrated that new bone was formed more rapidly on SLA-treated surfaces with nanotubes (especially SLA + 80 nm) than on those without nanotubes. All of these results indicate that SLA + 80 nm is favorable for promoting the activity of osteoblasts and early bone bonding. PMID- 26635473 TI - Amyloids in solid-state nuclear magnetic resonance: potential causes of the usually low resolution. AB - Amyloids are non-crystalline and insoluble, which imply that the classical structural biology tools, ie, X-ray crystallography and solution nuclear magnetic resonance (NMR), are not suitable for their analysis. In the last years, solid state NMR (ssNMR) has emerged as an alternative tool to decrypt the structural signatures of amyloid fibrils, providing major contributions to our understanding of molecular structures of amyloids such as beta-amyloid peptide associated with Alzheimer's disease or fungal prions, among others. Despite this, the wide majority of amyloid fibrils display low resolution by ssNMR. Usually, this low resolution has been attributed to a high disorder or polymorphism of the fibrils, suggesting the existence of diverse elementary beta-sheet structures. Here, we propose that a single beta-sheet structure could be responsible for the broadening of the line widths in the ssNMR spectra. Although the fibrils and fibers consist of a single elementary structure, the angle of twist of each individual fibril in the mature fiber depends on the number of individual fibrils as well as the fibril arrangement in the final mature fiber. Thus, a wide range of angles of twist could be observed in the same amyloid sample. These twist variations involve changes in amino acid alignments that could be enough to limit the ssNMR resolution. PMID- 26635475 TI - The impact of nonmotor symptoms on quality of life in patients with Parkinson's disease in Taiwan. AB - PURPOSE: The nonmotor symptoms (NMS) of Parkinson's disease (PD) are important factors for quality of life (QoL). Few studies on NMS have been conducted in Asian PD patients. Additionally, effects of anti-PD drugs on risk of NMS are still controversial. We therefore conducted this hospital-based cross-sectional study to examine the clinical factors, including concomitant anti-PD medication use, on the occurrence of NMS and QoL in Taiwanese PD patients. PATIENTS AND METHODS: PD patients who received long-term follow-up in the movement disorders clinics were enrolled and received NMS questionnaire (NMSQuest) and the 39-item Parkinson's Disease Questionnaire (PDQ-39). Spearman's rank correlation coefficient was checked for the correlation between clinical factors and NMSQT/PDQSI. Multiple linear regressions were applied to assess the influence of clinical factors on NMSQT/PDQSI. RESULTS: A total of 210 PD patients (mean age 66.1+/-9.86 years, Hoehn and Yahr stage 2.2+/-0.9) were included in this study. Up to 98% of patients reported at least one symptom of NMS. The most prevalent symptom was urinary complaints (56%), followed by memory/apathy (30%) and depression/anxiety (28%). The correlation between NMSQT and PDQSI was strong (r s=0.667), especially the item of depression/anxiety (r s=0.607). The regression model for NMSQT indicated that disease duration and severity, but not pharmacological therapy, were major predictors of NMS. CONCLUSION: Our data indicated a high prevalence rate of NMS in PD patients. Among symptoms of NMS, depression and anxiety had the greatest impact on QoL. Concomitant anti-PD medication use did not affect the occurrence of NMS and QoL. PMID- 26635474 TI - Specific detection of CD133-positive tumor cells with iron oxide nanoparticles labeling using noninvasive molecular magnetic resonance imaging. AB - BACKGROUND: The use of ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles to visualize cells has been applied clinically, showing the potential for monitoring cells in vivo with magnetic resonance imaging (MRI). USPIO conjugated with anti-CD133 antibodies (USPIO-CD133 Ab) that recognize the CD133 molecule, a cancer stem cell marker in a variety of cancers, was studied as a novel and potent agent for MRI contrast enhancement of tumor cells. MATERIALS AND METHODS: Anti-CD133 antibodies were used to conjugate with USPIO via interaction of streptavidin and biotin for in vivo labeling of CD133-positive cells in xenografted tumors and N-ethyl-N-nitrosourea (ENU)-induced brain tumors. The specific binding of USPIO-CD133 Ab to CD133-positive tumor cells was subsequently detected by Prussian blue staining and MRI with T2-weighted, gradient echo and multiple echo recombined gradient echo images. In addition, the cellular toxicity of USPIO-CD133 Ab was determined by analyzing cell proliferation, apoptosis, and reactive oxygen species production. RESULTS: USPIO CD133 Ab specifically recognizes in vitro and labels CD133-positive cells, as validated using Prussian blue staining and MRI. The assays of cell proliferation, apoptosis, and reactive oxygen species production showed no significant differences in tumor cells with or without labeling of USPIO-CD133 Ab. In vivo imaging of CD133-positive cells was demonstrated by intravenous injection of USPIO-CD133 Ab in mice with HT29 xenografted tumors. The MRI of HT29 xenografts showed several clusters of hypotensive regions that correlated with CD133 expression and Prussian blue staining for iron. In rat, brain tumors induced by transplacental ENU mutagenesis, several clusters of hypointensive zones were observed in CD133-expressing brain tumors by MRI and intravenously administered USPIO-CD133 Ab. CONCLUSION: Combination of USPIO-CD133 Ab and MRI is valuable in recognizing CD133-expressing tumor cells in vitro, extracellularly labeling for cell tracking and detecting CD133-expressing tumors in xenografted tumors as well as ENU-induced rat brain tumors. PMID- 26635476 TI - The ability of early changes in motivation to predict later antidepressant treatment response. AB - INTRODUCTION: Baseline values and early changes of emotional reactivity, cognitive speed, psychomotor function, motivation, and sensory perception have not been studied to any extent in unipolar depression, although they could help to characterize different dimensions of illness that are harder to capture by clinicians, give new insights on how patients improve, and offer new early clinical markers for later treatment response. METHODS: About 1,565 adult outpatients with major depressive disorder receiving agomelatine completed the clinician-rated 16-item quick inventory of depressive symptoms, Clinical Global Impression, and Multidimensional Assessment of Thymic States (MAThyS) rating scales at inclusion, Week 2 and Week 6. The MAThyS includes a 20-item self-rated visual analog scale (from inhibition [0] to activation [10], with [5] representing the usual state) leading to five a priori dimensions (emotional reactivity, cognitive speed, psychomotor function, motivation, and sensory perception). RESULTS: All MAThyS dimension scores increased from inclusion to Week 2 and from inclusion to Week 6 (P<0.001). Improvement was around 2 points (out of 10) for motivation, 1.5 points for psychomotor function, and 0.5 points for other dimensions. Motivation showed a trend to being more severely impaired at inclusion in future nonresponders (t=1.25, df=1,563, P=0.10). Its improvement at Week 2 was the most discriminating MAThyS dimension between future responders and nonresponders, and represents the best predictor of future response, with the highest area under the receptor operating characteristic curve (area under curve =0.616, 95% confidence interval [0.588-0.643], P<0.001). Finally, improvements in motivation correlated the most strongly with clinician-rated 16-item quick inventory of depressive symptoms improvement (r=-0.491, df=1,563, P<0.001). CONCLUSION: Motivation had the most capacity for early improvement, the best predictive value for response, and the largest global margin of progress in depressed outpatients. Assessing the evolution of self-reported motivation over time in major depressive disorder could offer an interesting complementary approach to predict response. PMID- 26635478 TI - Systemic spread of tuberculosis after surgery for a splenic tuberculous abscess without postoperational antituberculosis treatment: a case report. AB - Solitary splenic tuberculosis (TB) is rare, with less than ten cases ever being reported. The diagnosis is established by the pathological analysis of a biopsy from a surgical operation or from a fine-needle aspiration sample. Manifestations of splenic TB include low-grade fever, weight loss, abdominal pain, and diarrhea. This case, however, has no obvious symptoms, and multiple splenic tubercles were discovered during a routine physical examination. Splenic abscesses from TB were diagnosed after the operation. Postoperative spread of TB lead to cerebral tuberculous abscesses and pulmonary TB. Resolution was achieved with anti-TB therapy. PMID- 26635479 TI - Increasing Patient Engagement in Pharmacovigilance Through Online Community Outreach and Mobile Reporting Applications: An Analysis of Adverse Event Reporting for the Essure Device in the US. AB - BACKGROUND: Preparing and submitting a voluntary adverse event (AE) report to the US Food and Drug Administration (FDA) for a medical device typically takes 40 min. User-friendly Web and mobile reporting apps may increase efficiency. Further, coupled with strategies for direct patient involvement, patient engagement in AE reporting may be improved. In 2012, the FDA Center for Devices and Radiologic Health (CDRH) launched a free, public mobile AE reporting app, MedWatcher, for patients and clinicians. During the same year, a patient community on Facebook adopted the app to submit reports involving a hysteroscopic sterilization device, brand name Essure(r). METHODS: Patient community outreach was conducted to administrators of the group "Essure Problems" (approximately 18,000 members as of June 2015) to gather individual case safety reports (ICSRs). After agreeing on key reporting principles, group administrators encouraged members to report via the app. Semi-structured forms in the app mirrored fields of the MedWatch 3500 form. ICSRs were transmitted to CDRH via an electronic gateway, and anonymized versions were posted in the app. Data collected from May 11, 2013 to December 7, 2014 were analyzed. Narrative texts were coded by trained and certified MedDRA coders (version 17). Descriptive statistics and metrics, including VigiGrade completeness scores, were analyzed. Various incentives and motivations to report in the Facebook group were observed. RESULTS: The average Essure AE report took 11.4 min (+/-10) to complete. Submissions from 1349 women, average age 34 years, were analyzed. Serious events, including hospitalization, disability, and permanent damage after implantation, were reported by 1047 women (77.6 %). A total of 13,135 product-event pairs were reported, comprising 327 unique preferred terms, most frequently fatigue (n = 491), back pain (468), and pelvic pain (459). Important medical events (IMEs), most frequently mental impairment (142), device dislocation (108), and salpingectomy (62), were reported by 598 women (44.3 %). Other events of interest included loss of libido (n = 115); allergy to metals (109), primarily nickel; and alopecia (252). VigiGrade completeness scores were high, averaging 0.80 (+/-0.15). Reports received via the mobile app were considered "well documented" 55.9 % of the time, compared with an international average of 13 % for all medical products. On average, there were 15 times more reports submitted per month via the app with patient community support versus traditional pharmacovigilance portals. CONCLUSIONS: Outreach via an online patient community, coupled with an easy-to-use app, allowed for rapid and detailed ICSRs to be submitted, with gains in efficiency. Two-way communication and public posting of narratives led to successful engagement within a Motivation Incentive-Activation-Behavior framework, a conceptual model for successful crowdsourcing. Reports submitted by patients were considerably more complete than those submitted by physicians in routine spontaneous reports. Further research is needed to understand how biases operate differently from those of traditional pharmacovigilance. PMID- 26635477 TI - Evidence-based treatments for cluster headache. AB - Cluster headache (CH), one of the most painful syndromes known to man, is managed with acute and preventive medications. The brief duration and severity of the attacks command the use of rapid-acting pain relievers. Inhalation of oxygen and subcutaneous sumatriptan are the two most effective acute therapeutic options for sufferers of CH. Several preventive medications are available, the most effective of which is verapamil. However, most of these agents are not backed by strong clinical evidence. In some patients, these options can be ineffective, especially in those who develop chronic CH. Surgical procedures for the chronic refractory form of the disorder should then be contemplated, the most promising of which is hypothalamic deep brain stimulation. We hereby review the pathogenesis of CH and the evidence behind the treatment options for this debilitating condition. PMID- 26635480 TI - O-GlcNAcylation enhances the invasion of thyroid anaplastic cancer cells partially by PI3K/Akt1 pathway. AB - BACKGROUND: The PI3K family participates in multiple signaling pathways to regulate cellular functions. PI3K/Akt signaling pathway plays an important role in tumorigenesis and development. O-GlcNAcylation, a posttranslational modification, is thought to modulate a wide range of biological processes, such as transcription, cell growth, signal transduction, and cell motility. O GlcNAcylation is catalyzed by the nucleocytoplasmic enzymes, OGT and OGA, which adds or removes O-GlcNAc moieties, respectively. Abnormal O-GlcNAcylation has been implicated in a variety of human diseases. However, the role of O GlcNAcylation in tumorigenesis and progression of cancer is still under investigated. Understanding the O-GlcNAc-associated molecular mechanism might be significant for diagnosis and therapy of cancer. METHODS: Human thyroid anaplastic cancer 8305C cells were used to evaluate the role of O-GlcNAcylation in tumorigenesis and progression of cancer. The global O-GlcNAc level of intracellular proteins was up-regulated by OGA inhibitor Thiamet-G treatment or OGT over-expression. Cell proliferation was assessed by MTT assay. Invasion in vitro was determined by Transwell assay, and phosphorylation of Akt1 at Ser473 was assessed by Western blot for activity of Akt1. PI3K-specific inhibitor LY294002 and RNA interference of Akt1 were used to investigate the impact of PI3K/Akt signaling on the regulation of O-GlcNAcylation during tumor progression. RESULTS: Cell models with remarkably up-regulated O-GlcNAcylation were constructed, and then cell proliferation and invasion were determined. The results indicated that the proliferation was not affected by OGA inhibition or OGT overexpression, while the invasion of 8305C cells with OGA inhibition or OGT overexpression was obviously increased. Akt1 activity was stimulated by elevated O-GlcNAcylation by mediating phosphorylation at Ser473. The enhanced invasion of thyroid cancer cells by Thiamet-G treatment or OGT overexpression was significantly depressed by PI3K inhibitor LY294002. Moreover, silence of Akt1 remarkably attenuated the increase of cell invasion induced by Thiamet-G treatment, but the invasion was still higher compared to Akt1-silenced only cells. In other words, Thiamet-G restored the invasion of Akt1-silenced thyroid cancer cells, but it was still lower relative to Thiamet-G-treated only cells. CONCLUSION: Taken together, our findings suggested that O-GlcNAcylation enhanced the invasion of thyroid anaplastic cancer cells partially by PI3K/Akt signaling, which might be a potential target for the diagnosis and treatment of thyroid anaplastic cancer. PMID- 26635481 TI - Concurrent radiotherapy with oral fluoropyrimidine versus gemcitabine in locally advanced pancreatic cancer: a systematic review and meta-analysis. AB - BACKGROUND: Gemcitabine (GEM) is the most widely utilized systemic agent in combination with radiation therapy (RT) for treating locally advanced pancreatic cancer (LAPC) in the concurrent setting. Despite recent interest in using two novel oral fluoropyrimidines (FUs), capecitabine and S-1, in this setting, there is a lack of randomized controlled trials (RCTs) to support this approach. METHODS: Trials published between 1994 and 2014 were identified by an electronic search of public databases (Medline, Embase, and the Cochrane Library). All prospective studies were independently identified by two authors for inclusion. Demographic data, treatment response, objective response rate (ORR), progression free and overall survival (PFS and OS, respectively), and toxicities were extracted and analyzed using comprehensive meta-analysis software (version 2.0). RESULTS: Twenty-three cohorts with 843 patients were included: 497 patients were treated with GEM and 346 patients were treated with oral FU. Pooled OS was significantly higher at 1 and 2 years for S-1 plus RT than for GEM plus RT (relative risk [RR] 1.27; 95% confidence interval [CI], 1.00-1.65; P=0.03; and RR 1.75; 95% CI, 1.18-2.60, P=0.002, respectively), while 1-year PFS and ORR were not significantly different between S-1 and GEM-based chemoradiotherapy (P=0.37 and P=0.06, respectively). Additionally, comparable efficacy was found between capecitabine and GEM-based chemoradiotherapy in terms of OS, PFS, and ORR. As for grade 3 and 4 acute toxicity, oral FU plus RT significantly reduced the risk of developing hematologic toxicities, nausea, and vomiting when compared to GEM plus RT (P<0.001). CONCLUSIONS: Oral FU plus RT may be a safe and feasible regimen for patients with LAPC, with similar efficacy and low rate of toxicities compared with GEM plus RT. Our findings support the need to compare S-1 with GEM in the concurrent setting in large prospective RCTs due to its potential survival benefits. PMID- 26635482 TI - Doctors commitment and long-term effectiveness for cost containment policies: lesson learned from biosimilar drugs. AB - BACKGROUND: Agency is a pervasive feature of the health care market, with doctors acting as agents for both patients and the health care system. In a context of scarce resources, doctors are required to take opportunity cost into account when prescribing treatments, while cost containment policies cannot overlook their active role in determining health care resource allocation. This paper addresses this issue, investigating the effects of cost containment measures in the market of biosimilar drugs that represent a viable and cost-saving strategy for the reduction of health care expenditure. The analysis focuses on a particular region in Italy, where several timely policies to incentivize biosimilar prescribing were launched. METHODS: Drugs were identified by the anatomical therapeutic chemical classification system. Information about biosimilar drugs and their originator biological products was extracted from the IMS Health regional database. Drug consumption was expressed in terms of counting units, while expenditure was evaluated in Euro (?). The market penetration of biosimilars was analyzed by year and quarterly. RESULTS: In the Campania region of Italy, the effects of cost containment policies, launched between 2009 and 2013, showed the prescription of biosimilars strongly increasing in 2010 until prescribing levels reached and exceeded the market share of the reference biological products in 2012. After a slight reduction, a plateau was observed at the beginning of 2013. At the same time, the use of the originator products had been decreasing until the first quarter of 2011. However, after a 1-year plateau, this trend was reversed, with a new increase in the consumption of the originators observed. CONCLUSION: Results show that the cost containment policies, applied to cut health expenditure "to cure and not to care", did not produce the cultural change necessary to make these policies effective in the long run. Therefore, top-down policies for cost containment are not successful; rather, a bottom-up approach based on consensus among professionals should become the preferred option. PMID- 26635483 TI - Effect of a perspective-taking intervention on the consideration of pain assessment and treatment decisions. AB - OBJECTIVES: Pain is often poorly managed, highlighting the need to better understand and treat patients' pain. Research suggests that pain is assessed and treated differently depending on patient sex, race, and/or age. Perspective taking, whereby one envisions the perspective of another, has been found to reduce racial disparities in pain management. This study used virtual human (VH) technology to examine whether a perspective-taking intervention impacts pain management decisions. METHODS: Ninety-six participants were randomized to an online treatment or control group and viewed 16 video clips of VHs with standardized levels of pain. Participants provided ratings on the VHs' pain intensity and their willingness to administer opioids to them. The intervention group received a brief perspective-taking intervention that consisted of having participants imagine how the patient's suffering could affect his/her life, whereas the control group was asked to wait for the next VH videos to load. A LENS model analysis was used to investigate both group level (nomothetic) and individual level (idiographic) decision policies. A LENS model of analysis is typically used as an analog method for capturing how groups of people and individuals use information in their environment to form judgments. RESULTS: Nomothetic results found that participants rated pain higher and were more likely to prescribe opioids to VHs postintervention, irrespective of group. Idiographic results, however, found that the use of cues to make pain management decisions was mitigated by the perspective-taking group. The participants in the perspective-taking group were more likely to think about pain and the patients' perspective during the intervention, while control participants were more likely to reflect on the VHs' sex, race, or age. CONCLUSION: A brief intervention may alter participants' pain management decisions. These results indicate that a brief intervention might be an initial step toward aligning observers' pain management ratings with those of the patient. Future research is needed to replicate findings in a health care population. PMID- 26635485 TI - Validation of International Classification of Diseases coding for bone metastases in electronic health records using technology-enabled abstraction. AB - OBJECTIVE: The accuracy of bone metastases diagnostic coding based on International Classification of Diseases, ninth revision (ICD-9) is unknown for most large databases used for epidemiologic research in the US. Electronic health records (EHR) are the preferred source of data, but often clinically relevant data occur only as unstructured free text. We examined the validity of bone metastases ICD-9 coding in structured EHR and administrative claims relative to the complete (structured and unstructured) patient chart obtained through technology-enabled chart abstraction. PATIENTS AND METHODS: Female patients with breast cancer with >=1 visit after November 2010 were identified from three community oncology practices in the US. We calculated sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of bone metastases ICD-9 code 198.5. The technology-enabled abstraction displays portions of the chart to clinically trained abstractors for targeted review, thereby maximizing efficiency. We evaluated effects of misclassification of patients developing skeletal complications or treated with bone-targeting agents (BTAs), and timing of BTA. RESULTS: Among 8,796 patients with breast cancer, 524 had confirmed bone metastases using chart abstraction. Sensitivity was 0.67 (95% confidence interval [CI] =0.63-0.71) based on structured EHR, and specificity was high at 0.98 (95% CI =0.98-0.99) with corresponding PPV of 0.71 (95% CI =0.67 0.75) and NPV of 0.98 (95% CI =0.98-0.98). From claims, sensitivity was 0.78 (95% CI =0.74-0.81), and specificity was 0.98 (95% CI =0.98-0.98) with PPV of 0.72 (95% CI =0.68-0.76) and NPV of 0.99 (95% CI =0.98-0.99). Structured data and claims missed 17% of bone metastases (89 of 524). False negatives were associated with measurable overestimation of the proportion treated with BTA or with a skeletal complication. Median date of diagnosis was delayed in structured data (32 days) and claims (43 days) compared with technology-assisted EHR. CONCLUSION: Technology-enabled chart abstraction of unstructured EHR greatly improves data quality, minimizing false negatives when identifying patients with bone metastases that may lead to inaccurate conclusions that can affect delivery of care. PMID- 26635484 TI - Rationale and development of image-guided intensity-modulated radiotherapy post prostatectomy: the present standard of care? AB - The indications for post-prostatectomy radiotherapy have evolved over the last decade, although the optimal timing, dose, and target volume remain to be well defined. The target volume is susceptible to anatomical variations with its borders interfacing with the rectum and bladder. Image-guided intensity-modulated radiotherapy has become the gold standard for radical prostate radiotherapy. Here we review the current evidence for image-guided techniques with intensity modulated radiotherapy to the prostate bed and describe current strategies to reduce or account for interfraction and intrafraction motion. PMID- 26635487 TI - Choroidal thickening and macular serous retinal detachment in pregnancy-induced hypertension. AB - OBJECTIVE: The purpose of this study was to report optical coherence tomography (OCT) and angiographic findings in a patient with pregnancy-induced hypertension (PIH). CASE REPORT: A 39-year-old woman, who was diagnosed with PIH, reported blurred and distorted vision at 5 days after an emergency cesarean delivery. OCT revealed a large serous retinal detachment (SRD) that included areas in the macula, along with an increased choroidal thickness noted in both eyes. Indocyanine green angiograms indicated delayed filling of the choroidal circulation in the early phase but choroidal hyperpermeability in the mid-phase. The SRD was gradually resolving without any treatment except for antihypertensive drugs. At 40 days after the initial examination, OCT revealed both the disappearance of the SRD and marked improvement of the choroidal thickening. CONCLUSION: Ophthalmologists need to be aware that PIH can cause choroidal ischemia, a breakdown of the outer blood-retinal barrier, and lead to the development of SRD. PMID- 26635486 TI - Piezosurgery in implant dentistry. AB - Piezosurgery, or the use of piezoelectric devices, is being applied increasingly in oral and maxillofacial surgery. The main advantages of this technique are precise and selective cuttings, the avoidance of thermal damage, and the preservation of soft-tissue structures. Through the application of piezoelectric surgery, implant-site preparation, bone grafting, sinus-floor elevation, edentulous ridge splitting or the lateralization of the inferior alveolar nerve are very technically feasible. This clinical overview gives a short summary of the current literature and outlines the advantages and disadvantages of piezoelectric bone surgery in implant dentistry. Overall, piezoelectric surgery is superior to other methods that utilize mechanical instruments. Handling of delicate or compromised hard- and soft-tissue conditions can be performed with less risk for the patient. With respect to current and future innovative surgical concepts, piezoelectric surgery offers a wide range of new possibilities to perform customized and minimally invasive osteotomies. PMID- 26635488 TI - Validation of pressure gradient and peripheral fractional flow reserve measured by a pressure wire for diagnosis of iliofemoral artery disease with intermediate stenosis. AB - OBJECTIVE: To examine the pressure gradient and peripheral fractional flow reserve (pFFR) measured by a pressure wire as indicators of hemodynamic significance in iliofemoral angiographic intermediate stenosis. BACKGROUND: The utility of pressure measurements using a pressure wire with vasodilators is unclear in cases with intermediate iliofemoral stenosis. METHODS: The mean pressure gradient (MPG) and mean pressure ratio (MPR) were measured at baseline and after injection of isosorbide dinitrate in 23 lesions with angiographically intermediate iliofemoral stenosis. Patients with complex lesions, infrapopliteal artery lesions, chronic total occlusion, and surgical bypass grafts were excluded. Hyperemic MPR was considered equivalent to pFFR. Changes in parameters in response to vasodilators were assessed and correlations of peak systolic velocity ratio (PSVR) with hyperemic MPG and pFFR were examined using duplex ultrasound. RESULTS: After injection of isosorbide dinitrate, hyperemic MPG increased significantly (from 9.0+/-5.7 to 16.3+/-6.2 mmHg; P<0.05) and hyperemic MPR (pFFR) decreased significantly (from 0.92+/-0.06 to 0.81+/-0.07; P<0.05). PSVR was significantly correlated with hyperemic MPG (R=0.52; P<0.05) and pFFR (R=-0.50; P<0.05). The optimal cut-off value of pFFR as an indicator of significant hemodynamic stenosis (PSVR >2.5) was 0.85 (area under the curve 0.72; sensitivity 94%; specificity 50%, P<0.05). CONCLUSION: pFFR measured using a pressure wire is reliable for prediction of hemodynamic significance in iliofemoral intermediate stenosis. PMID- 26635489 TI - Evaluation of the impact of viscosity, injection volume, and injection flow rate on subcutaneous injection tolerance. AB - AIM: The primary objective of this study was to evaluate the impact of fluid injection viscosity in combination with different injection volumes and flow rates on subcutaneous (SC) injection pain tolerance. METHODS: The study was a single-center, comparative, randomized, crossover, Phase I study in 24 healthy adults. Each participant received six injections in the abdomen area of either a 2 or 3 mL placebo solution, with three different fluid viscosities (1, 8-10, and 15-20 cP) combined with two different injection flow rates (0.02 and 0.3 mL/s). All injections were performed with 50 mL syringes and 27G, 6 mm needles. Perceived injection pain was assessed using a 100 mm visual analog scale (VAS) (0 mm/no pain, 100 mm/extreme pain). The location and depth of the injected fluid was assessed through 2D ultrasound echography images. RESULTS: Viscosity levels had significant impact on perceived injection pain (P=0.0003). Specifically, less pain was associated with high viscosity (VAS =12.6 mm) than medium (VAS =16.6 mm) or low (VAS =22.1 mm) viscosities, with a significant difference between high and low viscosities (P=0.0002). Target injection volume of 2 or 3 mL was demonstrated to have no significant impact on perceived injection pain (P=0.89). Slow (0.02 mL/s) or fast (0.30 mL/s) injection rates also showed no significant impact on perceived pain during SC injection (P=0.79). In 92% of injections, the injected fluid was located exclusively in SC tissue whereas the remaining injected fluids were found located in SC and/or intradermal layers. CONCLUSION: The results of this study suggest that solutions of up to 3 mL and up to 15-20 cP injected into the abdomen within 10 seconds are well tolerated without pain. High viscosity injections were shown to be the most tolerated, whereas injection volume and flow rates did not impact perceived pain. PMID- 26635491 TI - Subject preferences of first- and second-year medical students for their future specialization at Chitwan Medical College and Teaching Hospital, Chitwan, Nepal - a questionnaire-based study. AB - INTRODUCTION: The selection of a discipline for future specialization may be an important factor for the medical students' future career, and it is influenced by multiple factors. The interest of students in the early stages can be improved in subjects related to public health or of academic importance, as per need. METHODS: A questionnaire-based study was conducted among 265 first- and second year medical students of Chitwan Medical College, Nepal to find out their subject of preference for postgraduation and the factors affecting their selection along with their interesting basic science subject. Only the responses from 232 completely filled questionnaires were analyzed. RESULTS: The preference of the students for clinical surgical (50.9%), clinical medical (45.3%), and basic medical (3.9%) sciences for postgraduation were in descending order. The most preferred specialty among male students was clinical surgical sciences (56.3%), and among female students, it was clinical medical sciences (53.6%). Although all the students responded to their preferred specialty, only 178 students specified the subject of their interest. General surgery (23.4%), pediatrics (23.4%), and anatomy (2.4%) were the most favored subjects for postgraduation among clinical surgical, clinical medical, and basic medical sciences specialties, respectively. More common reasons for selection of specific subject for future career were found to be: personal interests, good income, intellectual challenge, and others. CONCLUSION: Many students preferred clinical surgical sciences for their future specialization. Among the reasons for the selection of the specialty for postgraduation, no significant reason could be elicited from the present study. PMID- 26635490 TI - Optimal management of ulnar collateral ligament injury in baseball pitchers. AB - The ulnar collateral ligament stabilizes the elbow joint from valgus stress associated with the throwing motion. During baseball pitching, this ligament is subjected to tremendous stress and injury if the force on the ulnar collateral ligament during pitching exceeds the physiological limits of the ligament. Injuries to the throwing elbow in baseball pitchers result in significant time loss and typically surgical intervention. The purpose of this paper is to provide a review of current information to sports medicine clinicians on injury epidemiology, injury mechanics, injury risk factors, injury prevention, surgical interventions, nonsurgical interventions, rehabilitation, and return to play outcomes in baseball pitchers of all levels. PMID- 26635492 TI - Gang membership and marijuana use among African American female adolescents in North Carolina. AB - The southeastern US sustains the highest high school dropout rates, and gangs persist in underserved communities. African American female adolescents who drop out of school and are gang members are at substantial risk of exposure to severe violence, physical abuse, and sexual exploitation. In this study of 237 female African American adolescents 16-19 years of age from North Carolina who dropped out or considered dropping out, 11% were current or past gang members. Adolescents who reported gang membership began smoking marijuana at a mean age of 13, whereas those who reported no gang membership began at a mean age of 15 years (P<0.001). The mean ages of first alcohol use were 14 years and 15 years for gang members and non-gang members, respectively (P=0.04). Problem alcohol use was high in both groups: 40% and 65% for non-gang and gang members, respectively (P=0.02). Controlling for frequent marijuana use and problem alcohol use, adolescents who reported gang membership were more likely than non-gang members to experience sexual abuse (odds ratio [OR] =2.60, 95% confidence interval [CI] [1.06, 6.40]), experience physical abuse (OR =7.33, 95% CI [2.90, 18.5]), report emotional abuse from their main partner (OR =3.55, 95% CI [1.44, 8.72]), run away from home (OR =4.65, 95% CI [1.90, 11.4]), get arrested (OR =2.61, 95% CI [1.05, 6.47]), and report violence in their neighborhood including murder (OR =3.27, 95% CI [1.35, 7.96]) and fights with weapons (OR =3.06, 95% CI [1.15, 8.11]). Gang members were less likely to receive emotional support (OR =0.89, 95% CI [0.81, 0.97]). These findings reinforce the urgent need to reach young African American women in disadvantaged communities affiliated with gangs to address the complexity of context and interconnected risk behaviors. PMID- 26635493 TI - Can developmental cognitive neuroscience inform intervention for social, emotional and behavioural difficulties (SEBD)? AB - An initial evaluation of the utility of designing an intervention to address neuroscience-based subtyping of children who have conduct problems was undertaken in this pilot study. Drawing on the literature on callous-unemotional traits, a novel intervention programme, 'Let's Get Smart', was implemented in a school for children with social emotional and behavioural difficulties. A mixed-methods design was used to investigate the perspectives of staff participant-observers in the change process, alongside standardised scores on measures of pupil performance and behaviour. Both qualitative and quantitative results showed reductions in externalising behaviour and improvements in measures of hypothesised underlying cognitive and affective processes. While externalising behaviour improved across subtypes, associated changes in underlying processes differed by subtype, supporting the potential value of neuroscience-informed contributions to intervention planning. PMID- 26635495 TI - Locating regional health policy: Institutions, politics, and practices. AB - Poverty reduction and health became central in the agendas of Southern regional organisations in the last two decades. Yet, little is known about how these organisations address poverty, inclusion and social inequality, and how Southern regional formations are engaging in power constellations, institutions, processes, interests and ideological positions within different spheres of governance. This article reviews academic literatures spanning global social policy, regional studies and diplomacy studies, and the state of knowledge and understanding of the 'place' of regional actors in health governance as a global political practice therein. It identifies theoretical and thematic points of connection between disparate literatures and how these can be bridged through research focusing on the social policies of regional organisations and regional integration processes. This framework hence locates the contributions of each of the research articles of this Special Issue of Global Social Policy on the regional dimension of health policy and diplomacy in relation to Southern Africa and South America. It also highlights the ways in which the articles bring new evidence about how social relations of welfare are being (re)made over larger scales and how regional actors may initiate new norms to improve health rights in international arenas engaging in new forms of 'regional' diplomacy. PMID- 26635494 TI - Assessing the first wave of epidemiological studies of nanomaterial workers. AB - The results of early animal studies of engineered nanomaterials (ENMs) and air pollution epidemiology suggest that it is important to assess the health of ENM workers. Initial epidemiological studies of workers' exposure to ENMs (<100 nm) are reviewed and characterized for their study designs, findings, and limitations. Of the 15 studies, 11 were cross-sectional, 4 were longitudinal (1 was both cross-sectional and longitudinal in design), and 1 was a descriptive pilot study. Generally, the studies used biologic markers as the dependent variables. All 11 cross-sectional studies showed a positive relationship between various biomarkers and ENM exposures. Three of the four longitudinal studies showed a negative relationship; the fourth showed positive findings after a 1 year follow-up. Each study considered exposure to ENMs as the independent variable. Exposure was assessed by mass concentration in 10 studies and by particle count in six studies. Six of them assessed both mass and particle concentrations. Some of the studies had limited exposure data because of inadequate exposure assessment. Generally, exposure levels were not very high in comparison to those in human inhalation chamber studies, but there were some exceptions. Most studies involved a small sample size, from 2 to 258 exposed workers. These studies represent the first wave of epidemiological studies of ENM workers. They are limited by small numbers of participants, inconsistent (and in some cases inadequate) exposure assessments, generally low exposures, and short intervals between exposure and effect. Still, these studies are a foundation for future work; they provide insight into where ENM workers are experiencing potentially adverse effects that might be related to ENM exposures. PMID- 26635496 TI - What's in a word? The framing of health at the regional level: ASEAN, EU, SADC and UNASUR. AB - The Association of Southeast Asian Nations, the European Union, the Southern African Development Community and the Union of South American Nations have increasingly been involved in health diplomacy in the past decade, yet little is known about how they frame health as a foreign policy issue and how this has an impact on their prioritisation of policies. For this, we conducted a review of existing grey and peer-reviewed literature that address regional integration and health, as well as a documentary review according to security, development, trade, human rights, moral/ethical reasonings and global public goods frames identified in the literature. The policy frames identified responded to the challenges these regions currently face. The Association of Southeast Asian Nation's struggle with re-emerging diseases has led to favouring a securitisation approach to health, the European Union approaches health as a cross-cutting policy issue, the Southern African Development Community presents health as a driver for development, and while the Union of South American Nations emphasises health as a human right and addresses the social determinants of health as an ethical imperative. Overall, these policy frames were useful in analysing the framing of health in foreign policy at the regional level. However, within our analysis, we identified a new frame that approaches health as an intersectoral issue. The impact of regional organisations' forward will depend on their ability to harness their convening power and speak in a coherent voice on health matters. PMID- 26635497 TI - UNASUR Health: A quiet revolution in health diplomacy in South America. AB - Since the creation of Union of South American Nations (UNASUR), health policies became a strategic factor in South America to collectively balance the legacy of neoliberal policies in the region. The aim of this article is first to describe the social, political, and economic processes that explain the emergence of UNASUR and its focus on social policy through healthcare. We then analyze how by virtue of UNASUR's Health Council, healthcare became the spearhead of cooperation giving way to novel forms of diplomacy. In so doing, this article contributes to a broader understanding of the regional health diplomacy and the process of unasurization of health policies as the process of building a new health framework. PMID- 26635498 TI - Regional health governance: A suggested agenda for Southern African health diplomacy. AB - Regional organisations can effectively promote regional health diplomacy and governance through engagement with regional social policy. Regional bodies make decisions about health challenges in the region, for example, the Union of South American Nations (UNASUR) and the World Health Organisation South East Asia Regional Office (WHO-SEARO). The Southern African Development Community (SADC) has a limited health presence as a regional organisation and diplomatic partner in health governance. This article identifies how SADC facilitates and coordinates health policy, arguing that SADC has the potential to promote regional health diplomacy and governance through engagement with regional social policy. The article identifies the role of global health diplomacy and niche diplomacy in health governance. The role of SADC as a regional organisation and the way it functions is then explained, focusing on how SADC engages with health issues in the region. Recommendations are made as to how SADC can play a more decisive role as a regional organisation to implement South-South management of the regional social policy, health governance and health diplomacy agenda. PMID- 26635499 TI - Regional and inter-regional economic rules and the enforcement of the right to health: The case of Colombia. AB - The regional policy level is often seen as a (potential) source of progressive policy-making in health (and in social policy more widely), complementing or substituting national policy levels, which are perceived as underperforming. While it can certainly be argued that there are important opportunities to adopt regional approaches to tackle border-crossing health issues, this article draws the attention to the fact that the linkage between (inter-)regional and national policy levels is not uni-directional. While in some instances the regional level may indeed take the lead in the promotion of (the right to) health, in other instances it may well be the other way round. This article focuses on the case of Colombia, where international economic rules have deeply permeated public policies in the health sector. On one hand, Colombia has been opening markets through the conclusion of regional integration arrangements (e.g. Andean Community and the Pacific Alliance) and the new generation of Free Trade Agreements. On the other hand, Colombia has been one of the most active emerging countries in promoting the right to health as a justiciable fundamental right, in line with the International Covenant on Economic, Social, and Cultural Rights of the United Nations mainly due to the judicial activism of the Colombian Constitutional Court with interesting implications for regional social governance. The article shows that national courts can play an important role in the protection of the right to health in a context of economic integration and the absence of regional balancing policies. PMID- 26635500 TI - Stretching health diplomacy beyond 'Global' problem solving: Bringing the regional normative dimension in. AB - The importance of the regional dimension of health diplomacy is only gaining slow and uneven recognition. This is in many ways surprising. As demonstrated in the work of Deacon on the 'globalization of social policy', global social policy has been animated and debated not only at the multilateral level but at the regional level as well. But at least in the diplomatic literature, the importance of this regional dynamic (with a focus on diverse sites and actors and the pursuit of democratic control) has been missed. The objective of this article is to explore whether health diplomacy is catching up to this larger debate re-shaping the conceptualization and practice of diplomacy more generally. In some ways, the results may be counter-productive in that this shift may encourage an increasingly fragmented process. Yet, it may also point to some breakthroughs, with diplomats, acting as 'go to' personnel on the front lines of operational activity, enabling actors to integrate with one another to produce effective governance. In doing so, the regional dimension is given greater recognition as a component of health diplomacy, albeit in an uneven and sometimes awkward manner. Whereas global diplomacy generally emphasizes problem solving, the regional dimension is animated by a normative orientation. PMID- 26635501 TI - Advancing regionalism and a social policy agenda for positive change: From rhetoric to action. PMID- 26635502 TI - Principles to guide a regional agenda on the right to health. PMID- 26635503 TI - The post-2015 development agenda and South-South and triangular cooperation - How the partnership model should be? PMID- 26635504 TI - Unasur Health Council: An emerging global actor in health policy and governance. PMID- 26635505 TI - Health governance in Sub-Saharan Africa. PMID- 26635506 TI - Why a renewed focus on regional governance is needed post-2015. PMID- 26635507 TI - Economic policy - Public health linkage and the importance of a regional platform: The case of tobacco control. PMID- 26635508 TI - Knowledge about dementia in South Korean nursing students: a cross-sectional survey. AB - BACKGROUND: The number of individuals with dementia is increasing substantially due to South Korea's rapidly aging society. Undergraduate nursing students need to have adequate knowledge about dementia to deliver appropriate nursing services. The purpose of this study was to assess the knowledge about dementia among undergraduate nursing students. METHODS: A total of 148 students ranging from freshmen to seniors at a nursing university participated in this study. Data were collected through self-reports using 12-item questionnaires with true/false responses. Knowledge levels about the general characteristics including demographic categories and dementia- related education and training were determined. Factors affecting the score of dementia knowledge were also investigated. RESULTS: The average score and standard deviation for knowledge about dementia were 10.26 and 1.24 out of 12 points. They had relatively low knowledge about the "prevention and treatment" and "causes" of dementia, with overall correct rate of 78.6 % and 85.4 %, respectively. Higher level of knowledge about dementia was associated with increase in grade level (p < 0.001), experience in education on dementia (p = 0.01), previous experience in caring for people with dementia during clinical practice (p < 0.001), and acquiring information on dementia (p = 0.02). Factors that influenced knowledge about dementia included grade level and experience in caring for dementia patients during clinical practice. CONCLUSIONS: This study showed that the level of knowledge about dementia among nursing students was reasonably good. Integrating dementia education and clinical experience into the curricula of undergraduates could improve knowledge about the causes, prevention, and treatment methods for dementia. PMID- 26635509 TI - Beyond cause to consequence: The road from possible to core self-revision. AB - Two studies addressed the ultimate consequences and pathways running from repeated possible self-revisions to gradual revisions in core selves over time. As hypothesized, greater prior experiences of downward possible self-revision ultimately predicted greater subsequent declines in core self-integrity (e.g., greater self-doubt, lower self-esteem). However, also as hypothesized, this effect was mediated by the relative use of defensive vs. remedial attributions for past downward self-revision experiences. In closing, we unpack how the present work extends prior work by situating possible selves and motivated self attributions as complementary systems that can slowly undermine as well as expand the integrity of core selves over time. PMID- 26635510 TI - Research that Helps Move Us Closer to a World where Each Child Thrives. AB - Schools are curtailing programs in arts, physical exercise, and play so more time and resources can be devoted to academic instruction. Yet indications are that the arts (e.g., music, dance, or theatre) and physical activity (e.g., sports, martial arts, or youth circus) are crucial for all aspects of children's development - including success in school. Thus in cutting those activities, schools may be impeding academic success, not aiding it. Correlational and retrospective studies have laid the groundwork, as have moving personal accounts, case studies, and theoretical arguments. The time is ripe for rigorous studies to investigate causality (Do arts and physical activities actually produce academic benefits or would kids in those activities have succeeded anyway?) and what characteristics of programs account for the benefits. Instead of simply claiming that the arts and/or physical activities can transform kids' lives, that needs to be demonstrated, and granting agencies need to be more open to funding rigorous research of real-world arts and physical-activity programs. PMID- 26635511 TI - Synthesis and Antiproliferative Activity of Steroidal Thiosemicarbazone Platinum (Pt(II)) Complexes. AB - Steroidal compounds exhibit particular physiological activities. In this paper, some steroidal thiosemicarbazones platinum (Pt(II)) complexes were synthesized by the condensation of steroidal ketones with thiosemicarbazide using estrone, chenodeoxycholic acid, and 7-deoxycholic acid as starting materials and complexation of steroidal thiosesemicarbazones with Pt(II). The complexes were characterized by IR, NMR, and MS, and their antiproliferative activities were evaluated. The results showed that some steroidal thiosemicarbazones platinum (Pt(II)) complexes displayed moderate cytotoxicity to HeLa and Bel-7404 cells. Thereinto, complex 6 showed an excellent inhibited selectivity to HeLa cells with an IC50 value of 9.2 MUM and SI value of 21.7. At the same time, all compounds were almost inactive to HEK293T (normal kidney epithelial cells). The information obtained from the studies may be useful for the design of novel chemotherapeutic drugs. PMID- 26635512 TI - Nesfatin-130-59 Injected Intracerebroventricularly Differentially Affects Food Intake Microstructure in Rats Under Normal Weight and Diet-Induced Obese Conditions. AB - Nesfatin-1 is well-established to induce an anorexigenic effect. Recently, nesfatin-130-59, was identified as active core of full length nesfatin-11-82 in mice, while its role in rats remains unclear. Therefore, we investigated the effects of nesfatin-130-59 injected intracerebroventricularly (icv) on the food intake microstructure in rats. To assess whether the effect was also mediated peripherally we injected nesfatin-130-59 intraperitoneally (ip). Since obesity affects the signaling of various food intake-regulatory peptides we investigated the effects of nesfatin-130-59 under conditions of diet-induced obesity (DIO). Male Sprague-Dawley rats fed ad libitum with standard diet were icv cannulated and injected with vehicle (5 MUl ddH2O) or nesfatin-130-59 at 0.37, 1.1, and 3.3 MUg (0.1, 0.3, 0.9 nmol/rat) and the food intake microstructure assessed using a food intake monitoring system. Next, naive rats were injected ip with vehicle (300 MUl saline) or nesfatin-130-59 (8.1, 24.3, 72.9 nmol/kg). Lastly, rats were fed a high fat diet for 10 weeks and those developing DIO were icv cannulated. Nesfatin-1 (0.9 nmol/rat) or vehicle (5 MUl ddH2O) was injected icv and the food intake microstructure assessed. In rats fed standard diet, nesfatin-130-59 caused a dose-dependent reduction of dark phase food intake reaching significance at 0.9 nmol/rat in the period of 4-8 h post injection (-29%) with the strongest reduction during the fifth hour (-75%), an effect detectable for 24 h (-12%, p < 0.05 vs. vehicle). The anorexigenic effect of nesfatin-130-59 was due to a reduction in meal size (-44%, p < 0.05), while meal frequency was not altered compared to vehicle. In contrast to icv injection, nesfatin-130-59 injected ip in up to 30-fold higher doses did not alter food intake. In DIO rats fed high fat diet, nesfatin-130-59 injected icv reduced food intake in the third hour post injection (-71%), an effect due to a reduced meal frequency (-27%, p < 0.05), while meal size was not altered. Taken together, nesfatin-130-59 is the active core of nesfatin-11-82 and acts centrally to reduce food intake in rats. The anorexigenic effect depends on the metabolic condition with increased satiation (reduction in meal size) under normal weight conditions, while in DIO rats satiety (reduction in meal frequency) is induced. PMID- 26635513 TI - Converting Static Image Datasets to Spiking Neuromorphic Datasets Using Saccades. AB - Creating datasets for Neuromorphic Vision is a challenging task. A lack of available recordings from Neuromorphic Vision sensors means that data must typically be recorded specifically for dataset creation rather than collecting and labeling existing data. The task is further complicated by a desire to simultaneously provide traditional frame-based recordings to allow for direct comparison with traditional Computer Vision algorithms. Here we propose a method for converting existing Computer Vision static image datasets into Neuromorphic Vision datasets using an actuated pan-tilt camera platform. Moving the sensor rather than the scene or image is a more biologically realistic approach to sensing and eliminates timing artifacts introduced by monitor updates when simulating motion on a computer monitor. We present conversion of two popular image datasets (MNIST and Caltech101) which have played important roles in the development of Computer Vision, and we provide performance metrics on these datasets using spike-based recognition algorithms. This work contributes datasets for future use in the field, as well as results from spike-based algorithms against which future works can compare. Furthermore, by converting datasets already popular in Computer Vision, we enable more direct comparison with frame based approaches. PMID- 26635514 TI - EEG Recorded from the Ear: Characterizing the Ear-EEG Method. AB - Highlights Auditory middle and late latency responses can be recorded reliably from ear-EEG.For sources close to the ear, ear-EEG has the same signal-to-noise ratio as scalp.Ear-EEG is an excellent match for power spectrum-based analysis. A method for measuring electroencephalograms (EEG) from the outer ear, so-called ear-EEG, has recently been proposed. The method could potentially enable robust recording of EEG in natural environments. The objective of this study was to substantiate the ear-EEG method by using a larger population of subjects and several paradigms. For rigor, we considered simultaneous scalp and ear-EEG recordings with common reference. More precisely, 32 conventional scalp electrodes and 12 ear electrodes allowed a thorough comparison between conventional and ear electrodes, testing several different placements of references. The paradigms probed auditory onset response, mismatch negativity, auditory steady-state response and alpha power attenuation. By comparing event related potential (ERP) waveforms from the mismatch response paradigm, the signal measured from the ear electrodes was found to reflect the same cortical activity as that from nearby scalp electrodes. It was also found that referencing the ear EEG electrodes to another within-ear electrode affects the time-domain recorded waveform (relative to scalp recordings), but not the timing of individual components. It was furthermore found that auditory steady-state responses and alpha-band modulation were measured reliably with the ear-EEG modality. Finally, our findings showed that the auditory mismatch response was difficult to monitor with the ear-EEG. We conclude that ear-EEG yields similar performance as conventional EEG for spectrogram-based analysis, similar timing of ERP components, and equal signal strength for sources close to the ear. Ear-EEG can reliably measure activity from regions of the cortex which are located close to the ears, especially in paradigms employing frequency-domain analyses. PMID- 26635515 TI - Extracting Social Information from Chemosensory Cues: Consideration of Several Scenarios and Their Functional Implications. AB - Across all sensory modalities, stimuli can vary along multiple dimensions. Efficient extraction of information requires sensitivity to those stimulus dimensions that provide behaviorally relevant information. To derive social information from chemosensory cues, sensory systems must embed information about the relationships between behaviorally relevant traits of individuals and the distributions of the chemical cues that are informative about these traits. In simple cases, the mere presence of one particular compound is sufficient to guide appropriate behavior. However, more generally, chemosensory information is conveyed via relative levels of multiple chemical cues, in non-trivial ways. The computations and networks needed to derive information from multi-molecule stimuli are distinct from those required by single molecule cues. Our current knowledge about how socially relevant information is encoded by chemical blends, and how it is extracted by chemosensory systems is very limited. This manuscript explores several scenarios and the neuronal computations required to identify them. PMID- 26635518 TI - Retraction: Benchmarking Neuromorphic Systems with Nengo. AB - [This retracts the article on p. 380 in vol. 9, PMID: 26539076.]. PMID- 26635517 TI - Metformin and Ara-a Effectively Suppress Brain Cancer by Targeting Cancer Stem/Progenitor Cells. AB - BACKGROUND: Gliomas and neuroblastomas pose a great health burden worldwide with a poor and moderate prognosis, respectively. Many studies have tried to find effective treatments for these primary malignant brain tumors. Of interest, the AMP-activated protein kinase (AMPK) pathway was found to be associated with tumorigenesis and tumor survival, leading to many studies on AMPK drugs, especially Metformin, and their potential role as anti-cancer treatments. Cancer stem cells (CSCs) are a small population of slowly-dividing, treatment-resistant, undifferentiated cancer cells that are being discovered in a multitude of cancers. They are thought to be responsible for replenishing the tumor with highly proliferative cells and increasing the risk of recurrence. METHODS: Metformin and 9-beta-d-Arabinofuranosyl Adenine (Ara-a) were used to study the role of the AMPK pathway in vitro on U251 (glioblastoma) and SH-SY5Y (neuroblastoma) cell lines. RESULTS: We found that both drugs are able to decrease the survival of U251 and SH-SY5Y cell lines in a 2D as well as a 3D culture model. Metformin and Ara-a significantly decreased the invasive ability of these cancer cell lines. Treatment with these drugs decreased the sphere forming units (SFU) of U251 cells, with Ara-a being more efficient, signifying the extinction of the CSC population. However, if treatment is withdrawn before all SFUs are extinguished, the CSCs regain some of their sphere-forming capabilities in the case of Metformin but not Ara-a treatment. CONCLUSION: Metformin and Ara-a have proved to be effective in the treatment of glioblastomas and neuroblastomas, in vitro, by targeting their cancer stem/progenitor cell population, which prevents recurrence. PMID- 26635516 TI - Non-invasive Central and Peripheral Stimulation: New Hope for Essential Tremor? AB - Essential tremor (ET) is among the most frequent movement disorders. It usually manifests as a postural and kinematic tremor of the arms, but may also involve the head, voice, lower limbs, and trunk. An oscillatory network has been proposed as a neural correlate of ET, and is mainly composed of the olivocerebellar system, thalamus, and motor cortex. Since pharmacological agents have limited benefits, surgical interventions like deep brain stimulation are the last-line treatment options for the most severe cases. Non-invasive brain stimulation techniques, particularly transcranial magnetic or direct current stimulation, are used to ameliorate ET. Their non-invasiveness, along with their side effects profile, makes them an appealing treatment option. In addition, peripheral stimulation has been applied in the same perspective. Hence, the aim of the present review is to shed light on the emergent use of non-invasive central and peripheral stimulation techniques in this interesting context. PMID- 26635519 TI - Analyzing the Effects of a G137V Mutation in the FXN Gene. AB - Reduced levels of frataxin, an essential mitochondrial protein involved in the regulation of iron-sulfur cluster biogenesis, are responsible for the recessive neurodegenerative Friedreich Ataxia (FRDA). Expansion of a GAA triplet in the first intron of the FRDA is essential for disease development which causes partial silencing of frataxin. In the vast majority of cases, patients are homozygotes for the expansion, but a small number of FRDA patients are heterozygotes for expansion and point mutations in the frataxin coding frame. In this study, we analyze the effects of a point mutation G137V. The patient P94-2, with a history of alcohol and drug abuse, showed a FRDA onset at the border between the classic and late onset phenotype. We applied a combination of biophysical and biochemical methods to characterize its effects on the structure, folding and activity of frataxin. Our study reveals no impairment of the structure or activity of the protein but a reduced folding stability. We suggest that the mutation causes misfolding of the native chain with consequent reduction of the protein concentration in the patient and discuss the possible mechanism of disease. PMID- 26635521 TI - Early Life Stress Effects on Glucocorticoid-BDNF Interplay in the Hippocampus. AB - Early life stress (ELS) is implicated in the etiology of multiple psychiatric disorders. Important biological effects of ELS are manifested in stress susceptible regions of the hippocampus and are partially mediated by long-term effects on glucocorticoid (GC) and/or neurotrophin signaling pathways. GC signaling mediates the regulation of stress response to maintain homeostasis, while neurotrophin signaling plays a key role in neuronal outgrowth and is crucial for axonal guidance and synaptic integrity. The neurotrophin and GC signaling pathways co-exist throughout the central nervous system (CNS), particularly in the hippocampus, which has high expression levels of glucocorticoid-receptors (GR) and mineralocorticoid-receptors (MR) as well as brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin-related kinase receptor B (TrkB). This review addresses the effects of ELS paradigms on GC- and BDNF-dependent mechanisms and their crosstalk in the hippocampus, including potential implications for the pathogenesis of common stress-related disorders. PMID- 26635520 TI - Protein and Signaling Networks in Vertebrate Photoreceptor Cells. AB - Vertebrate photoreceptor cells are exquisite light detectors operating under very dim and bright illumination. The photoexcitation and adaptation machinery in photoreceptor cells consists of protein complexes that can form highly ordered supramolecular structures and control the homeostasis and mutual dependence of the secondary messengers cyclic guanosine monophosphate (cGMP) and Ca(2+). The visual pigment in rod photoreceptors, the G protein-coupled receptor rhodopsin is organized in tracks of dimers thereby providing a signaling platform for the dynamic scaffolding of the G protein transducin. Illuminated rhodopsin is turned off by phosphorylation catalyzed by rhodopsin kinase (GRK1) under control of Ca(2+)-recoverin. The GRK1 protein complex partly assembles in lipid raft structures, where shutting off rhodopsin seems to be more effective. Re-synthesis of cGMP is another crucial step in the recovery of the photoresponse after illumination. It is catalyzed by membrane bound sensory guanylate cyclases (GCs) and is regulated by specific neuronal Ca(2+)-sensor proteins called guanylate cyclase-activating proteins (GCAPs). At least one GC (ROS-GC1) was shown to be part of a multiprotein complex having strong interactions with the cytoskeleton and being controlled in a multimodal Ca(2+)-dependent fashion. The final target of the cGMP signaling cascade is a cyclic nucleotide-gated (CNG) channel that is a hetero-oligomeric protein located in the plasma membrane and interacting with accessory proteins in highly organized microdomains. We summarize results and interpretations of findings related to the inhomogeneous organization of signaling units in photoreceptor outer segments. PMID- 26635522 TI - NF-KappaB in Long-Term Memory and Structural Plasticity in the Adult Mammalian Brain. AB - The transcription factor nuclear factor kappaB (NF-kappaB) is a well-known regulator of inflammation, stress, and immune responses as well as cell survival. In the nervous system, NF-kappaB is one of the crucial components in the molecular switch that converts short- to long-term memory-a process that requires de novo gene expression. Here, the researches published on NF-kappaB and downstream target genes in mammals will be reviewed, which are necessary for structural plasticity and long-term memory, both under normal and pathological conditions in the brain. Genetic evidence has revealed that NF-kappaB regulates neuroprotection, neuronal transmission, and long-term memory. In addition, after genetic ablation of all NF-kappaB subunits, a severe defect in hippocampal adult neurogenesis was observed during aging. Proliferation of neural precursors is increased; however, axon outgrowth, synaptogenesis, and tissue homeostasis of the dentate gyrus are hampered. In this process, the NF-kappaB target gene PKAcat and other downstream target genes such as Igf2 are critically involved. Therefore, NF kappaB activity seems to be crucial in regulating structural plasticity and replenishment of granule cells within the hippocampus throughout the life. In addition to the function of NF-kappaB in neurons, we will discuss on a neuroinflammatory role of the transcription factor in glia. Finally, a model for NF-kappaB homeostasis on the molecular level is presented, in order to explain seemingly the contradictory, the friend or foe, role of NF-kappaB in the nervous system. PMID- 26635523 TI - Morris Water Maze Training in Mice Elevates Hippocampal Levels of Transcription Factors Nuclear Factor (Erythroid-derived 2)-like 2 and Nuclear Factor Kappa B p65. AB - Research has identified several transcription factors that regulate activity dependent plasticity and memory, with cAMP-response element binding protein (CREB) being the most well-studied. In neurons, CREB activation is influenced by the transcription factor nuclear factor kappa B (NF-kappaB), considered central to immunity but more recently implicated in memory. The transcription factor early growth response-2 (Egr-2), an NF-kappaB gene target, is also associated with learning and memory. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2), an antioxidant transcription factor linked to NF-kappaB in pathological conditions, has not been studied in normal memory. Given that numerous transcription factors implicated in activity-dependent plasticity demonstrate connections to NF-kappaB, this study simultaneously evaluated protein levels of NF-kappaB, CREB, Egr-2, Nrf2, and actin in hippocampi from young (1 month-old) weanling CD1 mice after training in the Morris water maze, a hippocampal-dependent spatial memory task. After a 6-day acquisition period, time to locate the hidden platform decreased in the Morris water maze. Mice spent more time in the target vs. non-target quadrants of the maze, suggestive of recall of the platform location. Western blot data revealed a decrease in NF-kappaB p50 protein after training relative to controls, whereas NF-kappaB p65, Nrf2 and actin increased. Nrf2 levels were correlated with platform crosses in nearly all tested animals. These data demonstrate that training in a spatial memory task results in alterations in and associations with particular transcription factors in the hippocampus, including upregulation of NF-kappaB p65 and Nrf2. Training-induced increases in actin protein levels caution against its use as a loading control in immunoblot studies examining activity-dependent plasticity, learning, and memory. PMID- 26635524 TI - Orthosteric and Allosteric Ligands of Nicotinic Acetylcholine Receptors for Smoking Cessation. AB - Nicotine addiction, the result of tobacco use, leads to over six million premature deaths world-wide per year, a number that is expected to increase by a third within the next two decades. While more than half of smokers want and attempt to quit, only a small percentage of smokers are able to quit without pharmacological interventions. Therefore, over the past decades, researchers in academia and the pharmaceutical industry have focused their attention on the development of more effective smoking cessation therapies, which is now a growing 1.9 billion dollar market. Because the role of neuronal nicotinic acetylcholine receptors (nAChR) in nicotine addiction is well established, nAChR based therapeutics remain the leading strategy for smoking cessation. However, the development of neuronal nAChR drugs that are selective for a nAChR subpopulation is challenging, and only few neuronal nAChR drugs are clinically available. Among the many neuronal nAChR subtypes that have been identified in the brain, the alpha4beta2 subtype is the most abundant and plays a critical role in nicotine addiction. Here, we review the role of neuronal nAChRs, especially the alpha4beta2 subtype, in the development and treatment of nicotine addiction. We also compare available smoking cessation medications and other nAChR orthosteric and allosteric ligands that have been developed with emphasis on the difficulties faced in the development of clinically useful compounds with high nAChR subtype selectivity. PMID- 26635526 TI - Shift and Mean Algorithm for Functional Imaging with High Spatio-Temporal Resolution. AB - Understanding neuronal physiology requires to record electrical activity in many small and remote compartments such as dendrites, axon or dendritic spines. To do so, electrophysiology has long been the tool of choice, as it allows recording very subtle and fast changes in electrical activity. However, electrophysiological measurements are mostly limited to large neuronal compartments such as the neuronal soma. To overcome these limitations, optical methods have been developed, allowing the monitoring of changes in fluorescence of fluorescent reporter dyes inserted into the neuron, with a spatial resolution theoretically only limited by the dye wavelength and optical devices. However, the temporal and spatial resolutive power of functional fluorescence imaging of live neurons is often limited by a necessary trade-off between image resolution, signal to noise ratio (SNR) and speed of acquisition. Here, I propose to use a Super-Resolution Shift and Mean (S&M) algorithm previously used in image computing to improve the SNR, time sampling and spatial resolution of acquired fluorescent signals. I demonstrate the benefits of this methodology using two examples: voltage imaging of action potentials (APs) in soma and dendrites of CA3 pyramidal cells and calcium imaging in the dendritic shaft and spines of CA3 pyramidal cells. I show that this algorithm allows the recording of a broad area at low speed in order to achieve a high SNR, and then pick the signal in any small compartment and resample it at high speed. This method allows preserving both the SNR and the temporal resolution of the signal, while acquiring the original images at high spatial resolution. PMID- 26635525 TI - Are Microglial Cells the Regulators of Lymphocyte Responses in the CNS? AB - The infiltration of immune cells in the central nervous system is a common hallmark in different neuroinflammatory conditions. Accumulating evidence indicates that resident glial cells can establish a cross-talk with infiltrated immune cells, including T-cells, regulating their recruitment, activation and function within the CNS. Although the healthy CNS has been thought to be devoid of professional dendritic cells (DCs), numerous studies have reported the presence of a population of DCs in specific locations such as the meninges, choroid plexuses and the perivascular space. Moreover, the infiltration of DC precursors during neuroinflammatory situations has been proposed, suggesting a putative role of these cells in the regulation of lymphocyte activity within the CNS. On the other hand, under specific circumstances, microglial cells are able to acquire a phenotype of DC expressing a wide range of molecules that equip these cells with all the necessary machinery for communication with T-cells. In this review, we summarize the current knowledge on the expression of molecules involved in the cross-talk with T-cells in both microglial cells and DCs and discuss the potential contribution of each of these cell populations on the control of lymphocyte function within the CNS. PMID- 26635527 TI - Notch1 Regulates Hippocampal Plasticity Through Interaction with the Reelin Pathway, Glutamatergic Transmission and CREB Signaling. AB - Notch signaling plays a crucial role in adult brain function such as synaptic plasticity, memory and olfaction. Several reports suggest an involvement of this pathway in neurodegenerative dementia. Yet, to date, the mechanism underlying Notch activity in mature neurons remains unresolved. In this work, we investigate how Notch regulates synaptic potentiation and contributes to the establishment of memory in mice. We observe that Notch1 is a postsynaptic receptor with functional interactions with the Reelin receptor, apolipoprotein E receptor 2 (ApoER2) and the ionotropic receptor, N-methyl-D-aspartate receptor (NMDAR). Targeted loss of Notch1 in the hippocampal CA fields affects Reelin signaling by influencing Dab1 expression and impairs the synaptic potentiation achieved through Reelin stimulation. Further analysis indicates that loss of Notch1 affects the expression and composition of the NMDAR but not AMPAR. Glutamatergic signaling is further compromised through downregulation of CamKII and its secondary and tertiary messengers resulting in reduced cAMP response element-binding (CREB) signaling. Our results identify Notch1 as an important regulator of mechanisms involved in synaptic plasticity and memory formation. These findings emphasize the possible involvement of this signaling receptor in dementia. HIGHLIGHTS: In this paper, we propose a mechanism for Notch1-dependent plasticity that likely underlies the function of Notch1 in memory formation: Notch1 interacts with another important developmental pathway, the Reelin cascade.Notch1 regulates both NMDAR expression and composition.Notch1 influences a cascade of cellular events culminating in CREB activation. PMID- 26635529 TI - A Method for the Isolation and Culture of Adult Rat Retinal Pigment Epithelial (RPE) Cells to Study Retinal Diseases. AB - Diseases such as age-related macular degeneration (AMD) affect the retinal pigment epithelium (RPE) and lead to the death of the epithelial cells and ultimately blindness. RPE transplantation is currently a major focus of eye research and clinical trials using human stem cell-derived RPE cells are ongoing. However, it remains to be established to which extent the source of RPE cells for transplantation affects their therapeutic efficacy and this needs to be explored in animal models. Autotransplantation of RPE cells has attractions as a therapy, but existing protocols to isolate adult RPE cells from rodents are technically difficult, time-consuming, have a low yield and are not optimized for long-term cell culturing. Here, we report a newly devised protocol which facilitates reliable and simple isolation and culture of RPE cells from adult rats. Incubation of a whole rat eyeball in 20 U/ml papain solution for 50 min yielded 4 * 10(4) viable RPE cells. These cells were hexagonal and pigmented upon culture. Using immunostaining, we demonstrated that the cells expressed RPE cell-specific marker proteins including cytokeratin 18 and RPE65, similar to RPE cells in vivo. Additionally, the cells were able to produce and secrete Bruch's membrane matrix components similar to in vivo situation. Similarly, the cultured RPE cells adhered to isolated Bruch's membrane as has previously been reported. Therefore, the protocol described in this article provides an efficient method for the rapid and easy isolation of high quantities of adult rat RPE cells. This provides a reliable platform for studying the therapeutic targets, testing the effects of drugs in a preclinical setup and to perform in vitro and in vivo transplantation experiments to study retinal diseases. PMID- 26635530 TI - Norepinephrine Modulates Pyramidal Cell Synaptic Properties in the Anterior Piriform Cortex of Mice: Age-Dependent Effects of beta-adrenoceptors. AB - Early odor preference learning in rodents occurs within a sensitive period [<=postnatal day (P)10-12], during which pups show a heightened ability to form an odor preference when a novel odor is paired with a tactile stimulation (e.g., stroking). Norepinephrine (NE) release from the locus coeruleus during stroking mediates this learning. However, in older pups, stroking loses its ability to induce learning. The cellular and circuitry mechanisms underpinning the sensitive period for odor preference learning is not well understood. We first established the sensitive period learning model in mice - odor paired with stroking induced odor preference in P8 but not P14 mice. This learning was dependent on NE-beta adrenoceptors as it was prevented by propranolol injection prior to training. We then tested whether there are developmental changes in pyramidal cell excitability and NE responsiveness in the anterior piriform cortex (aPC) in mouse pups. Although significant differences of pyramidal cell intrinsic properties were found in two age groups (P8-11 and P14+), NE at two concentrations (0.1 and 10 MUM) did not alter intrinsic properties in either group. In contrast, in P8-11 pups, NE at 0.1 MUM presynaptically decreased miniature IPSC and increased miniature EPSC frequencies. These effects were reversed with a higher dose of NE (10 MUM), suggesting involvement of different adrenoceptor subtypes. In P14+ pups, NE at higher doses (1 and 10 MUM) acted both pre- and postsynaptically to promote inhibition. These results suggest that enhanced synaptic excitation and reduced inhibition by NE in the aPC network may underlie the sensitive period. PMID- 26635528 TI - ALS Patient Stem Cells for Unveiling Disease Signatures of Motoneuron Susceptibility: Perspectives on the Deadly Mitochondria, ER Stress and Calcium Triad. AB - Amyotrophic lateral sclerosis (ALS) is a largely sporadic progressive neurodegenerative disease affecting upper and lower motoneurons (MNs) whose specific etiology is incompletely understood. Mutations in superoxide dismutase-1 (SOD1), TAR DNA-binding protein 43 (TARDBP/TDP-43) and C9orf72, have been identified in subsets of familial and sporadic patients. Key associated molecular and neuropathological features include ubiquitinated TDP-43 inclusions, stress granules, aggregated dipeptide proteins from mutant C9orf72 transcripts, altered mitochondrial ultrastructure, dysregulated calcium homeostasis, oxidative and endoplasmic reticulum (ER) stress, and an unfolded protein response (UPR). Such impairments have been documented in ALS animal models; however, whether these mechanisms are initiating factors or later consequential events leading to MN vulnerability in ALS patients is debatable. Human induced pluripotent stem cells (iPSCs) are a valuable tool that could resolve this "chicken or egg" causality dilemma. Relevant systems for probing pathophysiologically affected cells from large numbers of ALS patients and discovering phenotypic disease signatures of early MN susceptibility are described. Performing unbiased 'OMICS and high throughput screening in relevant neural cells from a cohort of ALS patient iPSCs, and rescuing mitochondrial and ER stress impairments, can identify targeted therapeutics for increasing MN longevity in ALS. PMID- 26635532 TI - Dual Nitrergic/Cholinergic Control of Short-Term Plasticity of Corticostriatal Inputs to Striatal Projection Neurons. AB - The ability of nitric oxide and acetylcholine to modulate the short-term plasticity of corticostriatal inputs was investigated using current-clamp recordings in BAC mouse brain slices. Glutamatergic responses were evoked by stimulation of corpus callosum in D1 and D2 dopamine receptor-expressing medium spiny neurons (D1-MSNs and D2-MSN, respectively). Paired-pulse stimulation (50 ms intervals) evoked depressing or facilitating responses in subgroups of both D1 MSNs and D2 MSNs. In both neuronal types, glutamatergic responses of cells that displayed paired-pulse depression were not significantly affected by the nitric oxide donor S-nitroso-N-acetylpenicillamine (SNAP; 100 MUM). Conversely, in D1 MSNs and D2-MSNs that displayed paired-pulse facilitation, SNAP did not affect the first evoked response, but significantly reduced the amplitude of the second evoked EPSP, converting paired-pulse facilitation into paired-pulse depression. SNAP also strongly excited cholinergic interneurons and increased their cortical glutamatergic responses acting through a presynaptic mechanism. The effects of SNAP on glutamatergic response of D1-MSNs and D2-MSN were mediated by acetylcholine. The broad-spectrum muscarinic receptor antagonist atropine (25 MUM) did not affect paired-pulse ratios and did not prevent the effects of SNAP. Conversely, the broad-spectrum nicotinic receptor antagonist tubocurarine (10 MUM) fully mimicked and occluded the effects of SNAP. We concluded that phasic acetylcholine release mediates feedforward facilitation in MSNs through activation of nicotinic receptors on glutamatergic terminals and that nitric oxide, while increasing cholinergic interneurons' firing, functionally impairs their ability to modulate glutamatergic inputs of MSNs. These results show that nitrergic and cholinergic transmission control the short-term plasticity of glutamatergic inputs in the striatum and reveal a novel cellular mechanism underlying paired-pulse facilitation in this area. PMID- 26635531 TI - Gastrointestinal Parasites and the Neural Control of Gut Functions. AB - Gastrointestinal motility and transport of water and electrolytes play key roles in the pathophysiology of diarrhea upon exposure to enteric parasites. These processes are actively modulated by the enteric nervous system (ENS), which includes efferent, and afferent neurons, as well as interneurons. ENS integrity is essential to the maintenance of homeostatic gut responses. A number of gastrointestinal parasites are known to cause disease by altering the ENS. The mechanisms remain incompletely understood. Cryptosporidium parvum, Giardia duodenalis (syn. Giardia intestinalis, Giardia lamblia), Trypanosoma cruzi, Schistosoma species and others alter gastrointestinal motility, absorption, or secretion at least in part via effects on the ENS. Recent findings also implicate enteric parasites such as C. parvum and G. duodenalis in the development of post infectious complications such as irritable bowel syndrome, which further underscores their effects on the gut-brain axis. This article critically reviews recent advances and the current state of knowledge on the impact of enteric parasitism on the neural control of gut functions, and provides insights into mechanisms underlying these abnormalities. PMID- 26635533 TI - Schwann Cell Expressed Nogo-B Modulates Axonal Branching of Adult Sensory Neurons Through the Nogo-B Receptor NgBR. AB - In contrast to the central nervous system (CNS) nerve fibers do regenerate in the peripheral nervous system (PNS) although in a clinically unsatisfying manner. A major problem is excessive sprouting of regenerating axons which results in aberrant reinnervation of target tissue and impaired functional recovery. In the CNS, the reticulon protein Nogo-A has been identified as a prominent oligodendrocyte expressed inhibitor of long-distance growth of regenerating axons. We show here that the related isoform Nogo-B is abundantly expressed in Schwann cells in the PNS. Other than Nogo-A in oligodendrocytes, Nogo-B does not localize to the myelin sheath but is detected in the ER and the plasma membrane of Schwann cells. Adult sensory neurons that are cultured on nogo-a/b deficient Schwann cells form significantly fewer axonal branches vs. those on wildtype Schwann cells, while their maximal axonal extension is unaffected. We demonstrate that this effect of Nogo-B on neuronal morphology is restricted to undifferentiated Schwann cells and is mediated by direct physical contact between these two cell types. Moreover, we show that blocking the Nogo-B specific receptor NgBR, which we find expressed on sensory neurons and to interact with Schwann cell expressed Nogo-B, produces the same branching phenotype as observed after deletion of Nogo-B. These data provide evidence for a novel function of the nogo gene that is implemented by the Nogo-B isoform. The remarkably specific effects of Nogo-B/NgBR on axonal branching, while leaving axonal extension unaffected, are of potential clinical relevance in the context of excessive axonal sprouting after peripheral nerve injury. MAIN POINTS: Nogo-B is prominently expressed in Schwann cells and localizes to the ER and plasma membrane. It distributes to the external cytoplasmic compartment of Schwann cells in vivo, but is absent from the myelin sheath.Genetic deletion of Nogo-B in Schwann cells reduces axonal branching, but not long-distance growth, of co cultured adult sensory neurons.Schwann cell expressed Nogo-B interacts with neuronal NgBR. Blockade of NgBR mimics the loss-of-nogo branching phenotype. PMID- 26635535 TI - Heterogeneity of Intrinsic and Synaptic Properties of Neurons in the Ventral and Dorsal Parts of the Ventral Nucleus of the Lateral Lemniscus. AB - The ventral nucleus of the lateral lemniscus (VNLL) provides a major inhibitory projection to the inferior colliculus (IC). Neurons in the VNLL respond with various firing patterns and different temporal precision to acoustic stimulation. The present study investigates the underlying intrinsic and synaptic properties of various cell types in different regions of the VNLL, using in vitro electrophysiological recordings from acute brain slices of mice and immunohistochemistry. We show that the biophysical membrane properties and excitatory input characteristics differed between dorsal and ventral VNLL neurons. Neurons in the ventral VNLL displayed an onset-type firing pattern and little hyperpolarization-activated current (Ih). Stimulation of lemniscal inputs evoked a large all-or-none excitatory response similar to Calyx of Held synapses in neurons in the lateral part of the ventral VNLL. Neurons that were located within the fiber tract of the lateral lemniscus, received several and weak excitatory input fibers. In the dorsal VNLL onset-type and sustained firing neurons were intermingled. These neurons showed large Ih and were strongly immunopositive for the hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1) subunit. Both neuron types received several excitatory inputs that were weaker and slower compared to ventrolateral VNLL neurons. Using a mouse model that expresses channelrhodopsin under the promotor of the vesicular GABA transporter (VGAT) suggests that dorsal and ventral neurons were inhibitory since they were all depolarized by light stimulation. The diverse membrane and input properties in dorsal and ventral VNLL neurons suggest differential roles of these neurons for sound processing. PMID- 26635534 TI - Osteogenic and Neurogenic Stem Cells in Their Own Place: Unraveling Differences and Similarities Between Niches. AB - Although therapeutic use of stem cells (SCs) is already available in some tissues (cornea, blood, and skin), in most organs we are far from reaching the translational goal of regenerative medicine. In the nervous system, due to intrinsic features which make it refractory to regeneration/repair, it is very hard to obtain functionally integrated regenerative outcomes, even starting from its own SCs (the neural stem cells; NSCs). Besides NSCs, mesenchymal stem cells (MSCs) have also been proposed for therapeutic purposes in neurological diseases. Yet, direct (regenerative) and indirect (bystander) effects are often confused, as are MSCs and bone marrow-derived (stromal, osteogenic) stem cells (BMSCs), whose plasticity is actually overestimated (i.e., trans-differentiation along non mesodermal lineages, including neural fates). In order to better understand failure in the "regenerative" use of SCs for neurological disorders, it could be helpful to understand how NSCs and BMSCs have adapted to their respective organ niches. In this perspective, here the adult osteogenic and neurogenic niches are considered and compared within their in vivo environment. PMID- 26635536 TI - Pre-Synaptic Inhibition of Afferent Feedback in the Macaque Spinal Cord Does Not Modulate with Cycles of Peripheral Oscillations Around 10 Hz. AB - Spinal interneurons are partially phase-locked to physiological tremor around 10 Hz. The phase of spinal interneuron activity is approximately opposite to descending drive to motoneurons, leading to partial phase cancellation and tremor reduction. Pre-synaptic inhibition of afferent feedback modulates during voluntary movements, but it is not known whether it tracks more rapid fluctuations in motor output such as during tremor. In this study, dorsal root potentials (DRPs) were recorded from the C8 and T1 roots in two macaque monkeys following intra-spinal micro-stimulation (random inter-stimulus interval 1.5-2.5 s, 30-100 MUA), whilst the animals performed an index finger flexion task which elicited peripheral oscillations around 10 Hz. Forty one responses were identified with latency < 5 ms; these were narrow (mean width 0.59 ms), and likely resulted from antidromic activation of afferents following stimulation near terminals. Significant modulation during task performance occurred in 16/41 responses, reflecting terminal excitability changes generated by pre-synaptic inhibition (Wall's excitability test). Stimuli falling during large-amplitude 8 12 Hz oscillations in finger acceleration were extracted, and sub-averages of DRPs constructed for stimuli delivered at different oscillation phases. Although some apparent phase-dependent modulation was seen, this was not above the level expected by chance. We conclude that, although terminal excitability reflecting pre-synaptic inhibition of afferents modulates over the timescale of a voluntary movement, it does not follow more rapid changes in motor output. This suggests that pre-synaptic inhibition is not part of the spinal systems for tremor reduction described previously, and that it plays a role in overall-but not moment-by-moment-regulation of feedback gain. PMID- 26635537 TI - Effects of the Concomitant Activation of ON and OFF Retinal Ganglion Cells on the Visual Thalamus: Evidence for an Enhanced Recruitment of GABAergic Cells. AB - A fundamental question in vision neuroscience is how parallel processing of Retinal Ganglion Cell (RGC) signals is integrated at the level of the visual thalamus. It is well-known that parallel ON-OFF pathways generate output signals from the retina that are conveyed to the dorsal lateral geniculate nucleus (dLGN). However, it is unclear how these signals distribute onto thalamic cells and how these two pathways interact. Here, by electrophysiological recordings and c-Fos expression analysis, we characterized the effects of pharmacological manipulations of the retinal circuit aimed at inducing either a selective activation of a single pathway, OFF RGCs [intravitreal L-(+)-2-Amino-4 phosphonobutyric, L-AP4] or an unregulated activity of all classes of RGCs (intravitreal 4-Aminopyridine, 4-AP). In in vivo experiments, the analysis of c Fos expression in the dLGN showed that these two manipulations recruited active cells from the same area, the lateral edge of the dLGN. Despite this similarity, the unregulated co-activation of both ON and OFF pathways by 4-AP yielded a much stronger recruitment of GABAergic interneurons in the dLGN when compared to L-AP4 pure OFF activation. The increased activation of an inhibitory thalamic network by a high level of unregulated discharge of ON and OFF RGCs might suggest that cross-inhibitory pathways between opposing visual channels are presumably replicated at multiple levels in the visual pathway, thus increasing the filtering ability for non-informative or noisy visual signals. PMID- 26635540 TI - Corrigendum: Habitual Behavior and Dopamine Cell Vulnerability in Parkinson Disease. AB - [This corrects the article on p. 99 in vol. 9, PMID: 26300740.]. PMID- 26635538 TI - A 3D Searchable Database of Transgenic Zebrafish Gal4 and Cre Lines for Functional Neuroanatomy Studies. AB - Transgenic methods enable the selective manipulation of neurons for functional mapping of neuronal circuits. Using confocal microscopy, we have imaged the cellular-level expression of 109 transgenic lines in live 6 day post fertilization larvae, including 80 Gal4 enhancer trap lines, 9 Cre enhancer trap lines and 20 transgenic lines that express fluorescent proteins in defined gene specific patterns. Image stacks were acquired at single micron resolution, together with a broadly expressed neural marker, which we used to align enhancer trap reporter patterns into a common 3-dimensional reference space. To facilitate use of this resource, we have written software that enables searching for transgenic lines that label cells within a selectable 3-dimensional region of interest (ROI) or neuroanatomical area. This software also enables the intersectional expression of transgenes to be predicted, a feature which we validated by detecting cells with co-expression of Cre and Gal4. Many of the imaged enhancer trap lines show intrinsic brain-specific expression. However, to increase the utility of lines that also drive expression in non-neuronal tissue we have designed a novel UAS reporter, that suppresses expression in heart, muscle, and skin through the incorporation of microRNA binding sites in a synthetic 3' untranslated region. Finally, we mapped the site of transgene integration, thus providing molecular identification of the expression pattern for most lines. Cumulatively, this library of enhancer trap lines provides genetic access to 70% of the larval brain and is therefore a powerful and broadly accessible tool for the dissection of neural circuits in larval zebrafish. PMID- 26635541 TI - Characterization of Laminar Zones in the Mid-Gestation Primate Brain with Magnetic Resonance Imaging and Histological Methods. AB - Distinct populations of progenitor and postmitotic neural and glial cells are stratified in the fetal primate brain across developmentally transient tissue zones between the ventricular and pial surfaces. These zones were originally identified by light microscopy. However, it has subsequently been shown that various forms of magnetic resonance image (MRI) contrast can be used to distinguish layers of developing neural tissue in ex vivo, as well as in vivo (including in utero) conditions. Here we compare mid-gestation rhesus macaque tissue zones identified using histological techniques to ex vivo as well as in utero MRI performed on the same brains. These data are compared to mid-gestation fetal human brain MRI results, obtained in utero. We observe strong similarity between MRI contrast in vivo and post mortem, which facilitates interpretation of in utero images based on the histological characterization performed here. Additionally, we observe differential correspondence between the various forms of ex vivo MRI contrast and microscopy data, with maps of the water apparent diffusion coefficient providing the closest match to histologically-identified lamina of the nonhuman primate brain. Examination of histology and post mortem MRI helps to provide a better understanding of cytoarchitectrual characteristics that give rise to in utero MRI contrast. PMID- 26635539 TI - In Vivo Mapping of Cortical Columnar Networks in the Monkey with Focal Electrical and Optical Stimulation. AB - There are currently largescale efforts to understand the brain as a connection machine. However, there has been little emphasis on understanding connection patterns between functionally specific cortical columns. Here, we review development and application of focal electrical and optical stimulation methods combined with optical imaging and fMRI mapping in the non-human primate. These new approaches, when applied systematically on a large scale, will elucidate functionally specific intra-areal and inter-areal network connection patterns. Such functionally specific network data can provide accurate views of brain network topology. PMID- 26635542 TI - Commentary: Tractography-Activation Models Applied to Subcallosal Cingulate Deep Brain Stimulation. PMID- 26635543 TI - Meningeal Melanocytes in the Mouse: Distribution and Dependence on Mitf. AB - SUMMARY: Melanocytes are pigment producing cells derived from the neural crest. They are primarily found in the skin and hair follicles, but can also be found in other tissues including the eye, ear and heart. Here, we describe the distribution of pigmented cells in C57BL/6J mouse meninges, the membranes that envelope the brain. These cells contain melanosomes of all four stages of development and they depend on Microphthalmia associated transcription factor (MITF), the master regulator of melanocyte development, suggesting that they are bona-fide melanocytes. The location of these pigmented cells is consistent with the location of meningeal melanomas in humans and animal models. SIGNIFICANCE: Here, we document and define pigmented cells in the meninges of the mouse brain and confirm that they are melanocytes. This is important for understanding the role of this cell type and for understanding primary meningeal melanoma, a rare disease that likely arises from normal meningeal melanocytes. PMID- 26635544 TI - The Structural Connectivity Pattern of the Default Mode Network and Its Association with Memory and Anxiety. AB - The default mode network (DMN) is one of the most widely studied resting state functional networks. The structural basis for the DMN is of particular interest and has been studied by several researchers using diffusion tensor imaging (DTI). Most of these previous studies focused on a few regions or white matter tracts of the DMN so that the global structural connectivity pattern and network properties of the DMN remain unclear. Moreover, evidences indicate that the DMN is involved in both memory and emotion, but how the DMN regulates memory and anxiety from the perspective of the whole DMN structural network remains unknown. We used multimodal neuroimaging methods to investigate the structural connectivity pattern of the DMN and the association of its network properties with memory and anxiety in 205 young healthy subjects with age ranging from 18 to 29 years old. The Group ICA method was used to extract the DMN component from functional magnetic resonance imaging (fMRI) data and a probabilistic fiber tractography technique based on DTI data was applied to construct the global structural connectivity pattern of the DMN. Then we used the graph theory method to analyze the DMN structural network and found that memory quotient (MQ) score was significantly positively correlated with the global and local efficiency of the DMN whereas anxiety was found to be negatively correlated with the efficiency. The strong structural connectivity between multiple brain regions within DMN may reflect that the DMN has certain structural basis. Meanwhile, the results we found that the network efficiency of the DMN were related to memory and anxiety measures, indicated that the DMN may play a role in the memory and anxiety. PMID- 26635545 TI - Interactions between Inhibitory Interneurons and Excitatory Associational Circuitry in Determining Spatio-Temporal Dynamics of Hippocampal Dentate Granule Cells: A Large-Scale Computational Study. AB - This paper reports on findings from a million-cell granule cell model of the rat dentate gyrus that was used to explore the contributions of local interneuronal and associational circuits to network-level activity. The model contains experimentally derived morphological parameters for granule cells, which each contain approximately 200 compartments, and biophysical parameters for granule cells, basket cells, and mossy cells that were based both on electrophysiological data and previously published models. Synaptic input to cells in the model consisted of glutamatergic AMPA-like EPSPs and GABAergic-like IPSPs from excitatory and inhibitory neurons, respectively. The main source of input to the model was from layer II entorhinal cortical neurons. Network connectivity was constrained by the topography of the system, and was derived from axonal transport studies, which provided details about the spatial spread of axonal terminal fields, as well as how subregions of the medial and lateral entorhinal cortices project to subregions of the dentate gyrus. Results of this study show that strong feedback inhibition from the basket cell population can cause high frequency rhythmicity in granule cells, while the strength of feedforward inhibition serves to scale the total amount of granule cell activity. Results furthermore show that the topography of local interneuronal circuits can have just as strong an impact on the development of spatio-temporal clusters in the granule cell population as the perforant path topography does, both sharpening existing clusters and introducing new ones with a greater spatial extent. Finally, results show that the interactions between the inhibitory and associational loops can cause high frequency oscillations that are modulated by a low-frequency oscillatory signal. These results serve to further illustrate the importance of topographical constraints on a global signal processing feature of a neural network, while also illustrating how rich spatio-temporal and oscillatory dynamics can evolve from a relatively small number of interacting local circuits. PMID- 26635546 TI - Perception and Reality: Why a Wholly Empirical Paradigm is Needed to Understand Vision. AB - A central puzzle in vision science is how perceptions that are routinely at odds with physical measurements of real world properties can arise from neural responses that nonetheless lead to effective behaviors. Here we argue that the solution depends on: (1) rejecting the assumption that the goal of vision is to recover, however imperfectly, properties of the world; and (2) replacing it with a paradigm in which perceptions reflect biological utility based on past experience rather than objective features of the environment. Present evidence is consistent with the conclusion that conceiving vision in wholly empirical terms provides a plausible way to understand what we see and why. PMID- 26635547 TI - Prospects for Optogenetic Augmentation of Brain Function. AB - The ability to optically control neural activity opens up possibilities for the restoration of normal function following neurological disorders. The temporal precision, spatial resolution, and neuronal specificity that optogenetics offers is unequalled by other available methods, so will it be suitable for not only restoring but also extending brain function? As the first demonstrations of optically "implanted" novel memories emerge, we examine the suitability of optogenetics as a technique for extending neural function. While optogenetics is an effective tool for altering neural activity, the largest impediment for optogenetics in neural augmentation is our systems level understanding of brain function. Furthermore, a number of clinical limitations currently remain as substantial hurdles for the applications proposed. While neurotechnologies for treating brain disorders and interfacing with prosthetics have advanced rapidly in the past few years, partially addressing some of these critical problems, optogenetics is not yet suitable for use in humans. Instead we conclude that for the immediate future, optogenetics is the neurological equivalent of the 3D printer: its flexibility providing an ideal tool for testing and prototyping solutions for treating brain disorders and augmenting brain function. PMID- 26635548 TI - Impaired Processing in the Primary Auditory Cortex of an Animal Model of Autism. AB - Autism is a neurodevelopmental disorder clinically characterized by deficits in communication, lack of social interaction and repetitive behaviors with restricted interests. A number of studies have reported that sensory perception abnormalities are common in autistic individuals and might contribute to the complex behavioral symptoms of the disorder. In this context, hearing incongruence is particularly prevalent. Considering that some of this abnormal processing might stem from the unbalance of inhibitory and excitatory drives in brain circuitries, we used an animal model of autism induced by valproic acid (VPA) during pregnancy in order to investigate the tonotopic organization of the primary auditory cortex (AI) and its local inhibitory circuitry. Our results show that VPA rats have distorted primary auditory maps with over-representation of high frequencies, broadly tuned receptive fields and higher sound intensity thresholds as compared to controls. However, we did not detect differences in the number of parvalbumin-positive interneurons in AI of VPA and control rats. Altogether our findings show that neurophysiological impairments of hearing perception in this autism model occur independently of alterations in the number of parvalbumin-expressing interneurons. These data support the notion that fine circuit alterations, rather than gross cellular modification, could lead to neurophysiological changes in the autistic brain. PMID- 26635549 TI - Neural Networks for Beat Perception in Musical Rhythm. AB - Entrainment of cortical rhythms to acoustic rhythms has been hypothesized to be the neural correlate of pulse and meter perception in music. Dynamic attending theory first proposed synchronization of endogenous perceptual rhythms nearly 40 years ago, but only recently has the pivotal role of neural synchrony been demonstrated. Significant progress has since been made in understanding the role of neural oscillations and the neural structures that support synchronized responses to musical rhythm. Synchronized neural activity has been observed in auditory and motor networks, and has been linked with attentional allocation and movement coordination. Here we describe a neurodynamic model that shows how self organization of oscillations in interacting sensory and motor networks could be responsible for the formation of the pulse percept in complex rhythms. In a pulse synchronization study, we test the model's key prediction that pulse can be perceived at a frequency for which no spectral energy is present in the amplitude envelope of the acoustic rhythm. The result shows that participants perceive the pulse at the theoretically predicted frequency. This model is one of the few consistent with neurophysiological evidence on the role of neural oscillation, and it explains a phenomenon that other computational models fail to explain. Because it is based on a canonical model, the predictions hold for an entire family of dynamical systems, not only a specific one. Thus, this model provides a theoretical link between oscillatory neurodynamics and the induction of pulse and meter in musical rhythm. PMID- 26635550 TI - The Rise and Fall of Basic Science. PMID- 26635551 TI - Memory Formation Shaped by Astroglia. AB - Astrocytes, the most heterogeneous glial cells in the central nervous system (CNS), execute a multitude of homeostatic functions and contribute to memory formation. Consolidation of synaptic and systemic memory is a prolonged process and hours are required to form long-term memory. In the past, neurons or their parts have been considered to be the exclusive cellular sites of these processes, however, it has now become evident that astrocytes provide an important and essential contribution to memory formation. Astrocytes participate in the morphological remodeling associated with synaptic plasticity, an energy-demanding process that requires mobilization of glycogen, which, in the CNS, is almost exclusively stored in astrocytes. Synaptic remodeling also involves bidirectional astroglial-neuronal communication supported by astroglial receptors and release of gliosignaling molecules. Astroglia exhibit cytoplasmic excitability that engages second messengers, such as Ca(2+), for phasic, and cyclic adenosine monophosphate (cAMP), for tonic signal coordination with neuronal processes. The detection of signals by astrocytes and the release of gliosignaling molecules, in particular by vesicle-based mechanisms, occurs with a significant delay after stimulation, orders of magnitude longer than that present in stimulus-secretion coupling in neurons. These particular arrangements position astrocytes as integrators ideally tuned to support time-dependent memory formation. PMID- 26635552 TI - Delayed Visual Feedback of One's Own Action Promotes Sense of Control for Auditory Events. AB - Sense of control refers to one's feelings to control environmental events through one's own action. A prevailing view is that the sense of control is strong (or is not diminished) when predicted sensory signals, which are generated in motor control mechanisms, are consistent with afferent sensory signals. Such intact sense of control often leads to the misjudgment of temporal relation between timings of one's action and its effect (so-called, intentional binding). The present study showed that the intentional binding could be enhanced by the delayed visual feedback of an agent's action. We asked participants to press a button to produce a tone as action outcome. In some conditions, they were given the delayed visual feedback of their button press. Participants judged whether the onset of the auditory outcome was delayed from the timing of their button press. Consequently, delay detection thresholds were significantly higher when the feedback was given 0.2 and 0.4 s delays than when no feedback was displayed to the participants. The results indicate that action agents misjudge the timing of their action (button press) in the presence of the delayed visual feedback of their action. Interestingly, delay detection thresholds were strongly correlated with the subjective magnitude of the sense of control. Thus, the sense of control is possibly determined by cross-modal processing for action-related and outcome related sensory signals. PMID- 26635553 TI - Drosophila Bitter Taste(s). AB - Most animals possess taste receptors neurons detecting potentially noxious compounds. In humans, the ligands which activate these neurons define a sensory space called "bitter". By extension, this term has been used in animals and insects to define molecules which induce aversive responses. In this review, based on our observations carried out in Drosophila, we examine how bitter compounds are detected and if bitter-sensitive neurons respond only to molecules bitter to humans. Like most animals, flies detect bitter chemicals through a specific population of taste neurons, distinct from those responding to sugars or to other modalities. Activating bitter-sensitive taste neurons induces aversive reactions and inhibits feeding. Bitter molecules also contribute to the suppression of sugar-neuron responses and can lead to a complete inhibition of the responses to sugar at the periphery. Since some bitter molecules activate bitter-sensitive neurons and some inhibit sugar detection, bitter molecules are represented by two sensory spaces which are only partially congruent. In addition to molecules which impact feeding, we recently discovered that the activation of bitter-sensitive neurons also induces grooming. Bitter-sensitive neurons of the wings and of the legs can sense chemicals from the gram negative bacteria, Escherichia coli, thus adding another biological function to these receptors. Bitter-sensitive neurons of the proboscis also respond to the inhibitory pheromone, 7-tricosene. Activating these neurons by bitter molecules in the context of sexual encounter inhibits courting and sexual reproduction, while activating these neurons with 7-tricosene in a feeding context will inhibit feeding. The picture that emerges from these observations is that the taste system is composed of detectors which monitor different "categories" of ligands, which facilitate or inhibit behaviors depending on the context (feeding, sexual reproduction, hygienic behavior), thus considerably extending the initial definition of "bitter" tasting. PMID- 26635554 TI - Assessment of Cognitive Scales to Examine Memory, Executive Function and Language in Individuals with Down Syndrome: Implications of a 6-month Observational Study. AB - Down syndrome (DS) is the most commonly identifiable genetic form of intellectual disability. Individuals with DS have considerable deficits in intellectual functioning (i.e., low intellectual quotient, delayed learning and/or impaired language development) and adaptive behavior. Previous pharmacological studies in this population have been limited by a lack of appropriate endpoints that accurately measured change in cognitive and functional abilities. Therefore, the current longitudinal observational study assessed the suitability and reliability of existing cognitive scales to determine which tools would be the most effective in future interventional clinical studies. Subtests of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Cambridge Neuropsychological Test Automated Battery (CANTAB), and Clinical Evaluation of Language Fundamentals Preschool-2 (CELF-P-2), and the Observer Memory Questionnaire-Parent Form (OMQ PF), Behavior Rating Inventory of Executive Function(r)-Preschool Version (BRIEF P) and Leiter International Performance Scale-Revised were assessed. The results reported here have contributed to the optimization of trial design and endpoint selection for the Phase 2 study of a new selective negative allosteric modulator of the GABAA receptor alpha5-subtype (Basmisanil), and can be applied to other studies in the DS population. PMID- 26635555 TI - Semantic Verbal Fluency Pattern, Dementia Rating Scores and Adaptive Behavior Correlate With Plasma Abeta42 Concentrations in Down Syndrome Young Adults. AB - Down syndrome (DS) is an intellectual disability (ID) disorder in which language and specifically, verbal fluency are strongly impaired domains; nearly all adults show neuropathology of Alzheimer's disease (AD), including amyloid deposition by their fifth decade of life. In the general population, verbal fluency deficits are considered a strong AD predictor being the semantic verbal fluency task (SVFT) a useful tool for enhancing early diagnostic. However, there is a lack of information about the association between the semantic verbal fluency pattern (SVFP) and the biological amyloidosis markers in DS. In the current study, we used the SVFT in young adults with DS to characterize their SVFP, assessing total generated words, clustering, and switching. We then explored its association with early indicators of dementia, adaptive behavior and amyloidosis biomarkers, using the Dementia Questionnaire for Persons with Intellectual Disability (DMR), the Adaptive Behavior Assessment System-Second Edition (ABAS-II), and plasma levels of Abeta peptides (Abeta40 and Abeta42), as a potent biomarker of AD. In DS, worse performance in SVFT and poorer communication skills were associated with higher plasma Abeta42 concentrations, a higher DMR score and impaired communication skills (ABAS-II). The total word production and switching ability in SVFT were good indicators of plasma Abeta42 concentration. In conclusion, we propose the SVFT as a good screening test for early detection of dementia and amyloidosis in young adults with DS. PMID- 26635556 TI - Motivational Effects of Methylphenidate are Associated with GABRA2 Variants Conferring Addiction Risk. AB - BACKGROUND: Variations in the GABRA2 gene, encoding alpha2 subunits of GABAA receptors, have been associated with risk for addiction to several drugs, but the mechanisms by which variations in non-coding regions of GABRA2 increase risk for addictions are not understood. Mice with deletion of GABRA2 show deficits in the ability of psychostimulants to facilitate responding for conditioned reinforcers, offering a potential explanation. METHODS: We report human and mouse studies investigating a potential endophenotype underlying this association. Healthy human volunteers carrying either cocaine-addiction "risk" or "protective" GABRA2 single nucleotide polymorphism (SNPs) were tested for their subjective responses to methylphenidate, and methylphenidate's ability to facilitate conditioned reinforcement (CRf) for visual stimuli (CS+) associated with monetary reward. In parallel, methylphenidate's ability to facilitate responding for a visual CRf was studied in wildtype and alpha2 knockout (alpha2(-/-)) mice. RESULTS: Methylphenidate increased the number of CS+ presentations obtained by human subjects carrying protective, but not risk SNPs. In mice, methylphenidate increased responding for a CS+ in wildtype, but not alpha2(-/-) mice. Human subjects carrying protective SNPs felt stimulated, aroused and restless following methylphenidate, while individuals carrying risk SNPs did not. CONCLUSION: Human risk SNP carriers were insensitive to methylphenidate's effects on mood or in facilitating CRf. That mice with the gene deletion were also insensitive to methylphenidate's ability to increase responding for CRf, suggests a potential mechanism whereby low alpha2-subunit levels increase risk for addictions. Circuits employing GABAA-alpha2 subunit-containing receptors may protect against risk for addictions. PMID- 26635557 TI - Incidental Memory Encoding Assessed with Signal Detection Theory and Functional Magnetic Resonance Imaging (fMRI). AB - In functional magnetic resonance imaging (fMRI) studies that apply a "subsequent memory" approach, successful encoding is indicated by increased fMRI activity during the encoding phase for hits vs. misses, in areas underlying memory encoding such as the hippocampal formation. Signal-detection theory (SDT) can be used to analyze memory-related fMRI activity as a function of the participant's memory trace strength (d(')). The goal of the present study was to use SDT to examine the relationship between fMRI activity during incidental encoding and participants' recognition performance. To implement a new approach, post experimental group assignment into High- or Low Performers (HP or LP) was based on 29 healthy participants' recognition performance, assessed with SDT. The analyses focused on the interaction between the factors group (HP vs. LP) and recognition performance (hits vs. misses). A whole-brain analysis revealed increased activation for HP vs. LP during incidental encoding for remembered vs. forgotten items (hits > misses) in the insula/temporo-parietal junction (TPJ) and the fusiform gyrus (FFG). Parameter estimates in these regions exhibited a significant positive correlation with d('). As these brain regions are highly relevant for salience detection (insula), stimulus-driven attention (TPJ), and content-specific processing of mnemonic stimuli (FFG), we suggest that HPs' elevated memory performance was associated with enhanced attentional and content specific sensory processing during the encoding phase. We provide first correlative evidence that encoding-related activity in content-specific sensory areas and content-independent attention and salience detection areas influences memory performance in a task with incidental encoding of facial stimuli. Based on our findings, we discuss whether the aforementioned group differences in brain activity during incidental encoding might constitute the basis of general differences in memory performance between HP and LP. PMID- 26635558 TI - Evaluation of a Cognitive Rehabilitation Protocol in HIV Patients with Associated Neurocognitive Disorders: Efficacy and Stability Over Time. AB - The primary aim of the present study was to evaluate the efficacy and stability over time of a cognitive rehabilitation protocol (restorative and compensatory approach) in HIV/AIDS patients with HIV-associated Neurocognitive Disorder (HAND). At baseline, 32 HIV/AIDS patients (16 with and 16 without HAND) were assessed with a neuropsychological battery (i.e., pre-assessment) consisting of 22 tests covering eight cognitive domains. Then, the experimental group was administered over 4 months a cognitive rehabilitation protocol aimed at improving four cognitive domains by means of eight paper and pencil/computer-based exercises. The control group received guideline-adherent clinical care (i.e., standard of care). At the end of the cognitive treatment, both groups were re administered the neuropsychological battery (i.e., post-assessment). Additionally, 6 months after post-assessment, the experimental group was given the same neuropsychological battery (i.e., follow up-assessment). In order to test the efficacy of the cognitive rehabilitation protocol, we compared between groups the results of the neuropsychological battery at the pre- and post assessments. In order to evaluate the stability over time, the effects of the cognitive rehabilitation protocol was examined comparing within the experimental group the results of the neuropsychological battery at post- and follow up assessments. Our results show that the two groups did not differ at the pre assessment, but differed at post-assessment. Specifically, the experimental group showed a significant improvement in five domains (Learning and memory, Abstraction/executive functioning, Verbal fluency, Attention/working memory, and Functional), whereas the control group significantly worsened in the same domains. The improvement of the experimental group did not change in the follow up-assessment in two domains (Abstraction/executive functioning, Attention/working memory, and Functional). Overall, these findings support the efficacy and, to some extent, the stability over time of our cognitive rehabilitation protocol. PMID- 26635560 TI - Commentary: Noradrenaline and Dopamine Neurons in the Reward/Effort Trade-off: A Direct Electrophysiological Comparison in Behaving Monkeys. PMID- 26635559 TI - Roles of the Different Sub-Regions of the Insular Cortex in Various Phases of the Decision-Making Process. AB - This paper presents a coherent account of the role of the insular cortex (IC) in decision-making. We follow a conceptualization of decision-making that is very close to one previously proposed by Ernst and Paulus (2005): that the decision process is a progression of four phases: (1) re-focusing attention; (2) evaluation; (3) action; and (4) outcome processing, and we present evidence for the insula's role in all these phases. We review the existing work on insula's functional anatomy that subdivides the IC into posterior, dorsal anterior and ventral anterior regions. We re-map the results provided by the existing literature into these subdivisions wherever possible, to identify the components' role in each decision making phase. In addition, we identify a self-regulating quality of the IC focused on harm avoidance. PMID- 26635561 TI - Commentary: Oxytocin Enables Maternal Behavior by Balancing Cortical Inhibition. PMID- 26635562 TI - Administration of NaHS Attenuates Footshock-Induced Pathologies and Emotional and Cognitive Dysfunction in Triple Transgenic Alzheimer's Mice. AB - Alzheimer's disease (AD) is characterized by progressive cognitive decline and neuropsychiatric symptoms. Increasing evidence indicates that environmental risk factors in young adults may accelerate cognitive loss in AD and that Hydrogen Sulfide (H2S) may represent an innovative treatment to slow the progression of AD. Therefore, the aim of this study was to evaluate the effects of NaHS, an H2S donor, in a triple transgenic AD mouse model (3*Tg-AD) under footshock with situational reminders (SRs). Inescapable footshock with SRs induced anxiety and cognitive dysfunction as well as a decrease in the levels of plasma H2S and GSH and an increase in IL-6 levels in 3*Tg-AD mice. Under footshock with SR stimulus, amyloid deposition, tau protein hyperphosphorylation, and microgliosis were highly increased in the stress-responsive brain structures, including the hippocampus and amygdala, of the AD mice. Oxidative stress, inflammatory response, and beta-site APP cleaving enzyme 1 (BACE1) levels were also increased, and the level of inactivated glycogen synthase kinase-3beta (GSK3beta) (pSer9) was decreased in the hippocampi of AD mice subjected to footshock with SRs. Furthermore, the numbers of cholinergic neurons in the medial septum/diagonal band of Broca (MS/DB) and noradrenergic neurons in the locus coeruleus (LC) were also decreased in the 3*Tg-AD mice under footshock with SRs. These biochemical hallmarks and pathological presentations were all alleviated by the semi-acute administration of NaHS in the AD mice. Together, these findings suggest that footshock with SRs induces the impairment of spatial cognition and emotion, which involve pathological changes in the peripheral and central systems, including the hippocampus, MS/DB, LC, and BLA, and that the administration of NaHS may be a candidate strategy to ameliorate the progression of neurodegeneration. PMID- 26635563 TI - Impaired Contextual Fear Extinction Learning is Associated with Aberrant Regulation of CHD-Type Chromatin Remodeling Factors. AB - Successful attenuation of fearful memories is a cognitive process requiring initiation of highly coordinated transcription programs. Chromatin-modulating mechanisms such as DNA methylation and histone modifications, including acetylation, are key regulators of these processes. However, knowledge concerning the role of ATP-dependent chromatin remodeling factors (ChRFs) being required for successful fear extinction is lacking. Underscoring the potential importance of these factors that alter histone-DNA contacts within nucleosomes are recent genome-wide association studies linking several ChRFs to various human cognitive and psychiatric disorders. To better understand the role of ChRFs in the brain, and since to date little is known about ChRF expression in the brain, we performed a comprehensive survey of expression levels of 24 ATP-dependent remodelers across different brain areas, and we identified several distinct high molecular weight complexes by chromatographic methods. We next aimed to gain novel insight into the potential regulation of ChRFs in different brain regions in association with normal and impaired fear extinction learning. To this end, we established the 129S1/SvImJ (S1) laboratory mouse strain as a model for compromised contextual fear extinction learning that can be rescued by dietary zinc restriction (ZnR). Using this model along with genetically related but fear extinction-competent 129S6/SvEv (S6) mice as controls, we found that impaired fear extinction in S1 was associated with enhanced ventral hippocampal expression of CHD1 and reduced expression of CHD5 that was normalized following successful rescue of impaired fear extinction. Moreover, a select reduction in CHD3 expression was observed in the ventral hippocampus (vHC) following successful rescue of fear extinction in S1 mice. Taken together, these data provide novel insight into the regulation of specific ChRFs following an impaired cognitive process and its rescue, and they suggest that imbalance of CHD-type remodeler levels, which consequently may lead to changes of transcriptional programs, may be an underlying mechanism involved in impaired fear extinction learning and its therapeutic rescue. PMID- 26635564 TI - The Memory System Engaged During Acquisition Determines the Effectiveness of Different Extinction Protocols. AB - Previous research indicates that extinction of rodent maze behavior may occur without explicit performance of the previously acquired response. In latent extinction, confining an animal to a previously rewarded goal location without reinforcement is typically sufficient to produce extinction of maze learning. However, previous studies have not determined whether latent extinction may be successfully employed to extinguish all types of memory acquired in the maze, or whether only specific types of memory may be vulnerable to latent extinction. The present study examined whether latent extinction may be effective across two plus maze tasks that depend on anatomically distinct neural systems. Adult male Long Evans rats were trained in a hippocampus-dependent place learning task (Experiment 1), in which animals were trained to approach a consistent spatial location for food reward. A separate group of rats were trained in a dorsolateral striatum-dependent response learning task (Experiment 2), in which animals were trained to make a consistent egocentric body-turn response for food reward. Following training, animals received response extinction or latent extinction. For response extinction, animals were given the opportunity to execute the original running approach response toward the empty food cup. For latent extinction, animals were confined to the original goal locations with the empty food cup, thus preventing them from making the original running approach response. Results indicate that, relative to no extinction, latent extinction was effective at extinguishing memory in the place learning task, but remained ineffective in the response learning task. In contrast, typical response extinction remained very effective at extinguishing memory in both place and response learning tasks. The present findings confirm that extinction of maze learning may occur with or without overt performance of the previously acquired response, but that the effectiveness of latent extinction may depend on the type of memory being extinguished. The findings suggest that behavioral treatments modeled after response extinction protocols may be especially useful in alleviating human psychopathologies involving striatum-dependent memory processes (e.g., drug addiction and relapse). PMID- 26635565 TI - I Plan Therefore I Choose: Free-Choice Bias Due to Prior Action-Probability but Not Action-Value. AB - According to an emerging view, decision-making, and motor planning are tightly entangled at the level of neural processing. Choice is influenced not only by the values associated with different options, but also biased by other factors. Here we test the hypothesis that preliminary action planning can induce choice biases gradually and independently of objective value when planning overlaps with one of the potential action alternatives. Subjects performed center-out reaches obeying either a clockwise or counterclockwise cue-response rule in two tasks. In the probabilistic task, a pre-cue indicated the probability of each of the two potential rules to become valid. When the subsequent rule-cue unambiguously indicated which of the pre-cued rules was actually valid (instructed trials), subjects responded faster to rules pre-cued with higher probability. When subjects were allowed to choose freely between two equally rewarded rules (choice trials) they chose the originally more likely rule more often and faster, despite the lack of an objective advantage in selecting this target. In the amount task, the pre-cue indicated the amount of potential reward associated with each rule. Subjects responded faster to rules pre-cued with higher reward amount in instructed trials of the amount task, equivalent to the more likely rule in the probabilistic task. Yet, in contrast, subjects showed hardly any choice bias and no increase in response speed in favor of the original high-reward target in the choice trials of the amount task. We conclude that free-choice behavior is robustly biased when predictability encourages the planning of one of the potential responses, while prior reward expectations without action planning do not induce such strong bias. Our results provide behavioral evidence for distinct contributions of expected value and action planning in decision-making and a tight interdependence of motor planning and action selection, supporting the idea that the underlying neural mechanisms overlap. PMID- 26635566 TI - A Proteomic Study of Memory After Imprinting in the Domestic Chick. AB - The intermediate and medial mesopallium (IMM) of the domestic chick forebrain has previously been shown to be a memory system for visual imprinting. Learning related changes occur in certain plasma membrane and mitochondrial proteins in the IMM. Two-dimensional gel electrophoresis/mass spectrometry has been employed to identify more comprehensively learning-related expression of proteins in the membrane-mitochondrial fraction of the IMM 24 h after training. We inquired whether amounts of these proteins in the IMM and a control region (posterior pole of the nidopallium, PPN) are correlated with a behavioral estimate of memory for the imprinting stimulus. Learning-related increases in amounts of the following proteins were found in the left IMM, but not the right IMM or the left or right PPN: (i) membrane cognin; (ii) a protein resembling the P32 subunit of splicing factor SF2; (iii) voltage-dependent anionic channel-1; (iv) dynamin-1; (v) heterogeneous nuclear ribonucleoprotein A2/B1. Learning-related increases in some transcription factors involved in mitochondrial biogenesis were also found, without significant change in mitochondrial DNA copy number. The results indicate that the molecular processes involved in learning and memory underlying imprinting include protein stabilization, increased mRNA trafficking, synaptic vesicle recycling, and specific changes in the mitochondrial proteome. PMID- 26635568 TI - The Effects of Methylphenidate on Goal-directed Behavior in a Rat Model of ADHD. AB - Although attentional and motor alterations in Attention Deficit Hyperactivity Disorder (ADHD) have been well characterized, less is known about how this disorder impacts goal-directed behavior. To investigate whether there is a misbalance between goal-directed and habitual behaviors in an animal model of ADHD, we tested adult [P75-P105] Spontaneously Hypertensive Rats (SHR; ADHD rat model) and Wistar-Kyoto rats (WKY), the normotensive control strain, on an instrumental conditioning paradigm with two phases: a free-operant training phase in which rats separately acquired two distinct action-outcome contingencies, and a choice test conducted in extinction prior to which one of the food outcomes was devalued through specific satiety. To assess the effects of Methylphenidate (MPH), a commonly used ADHD medication, on goal-directed behavior, we injected rats with either MPH or saline prior to the choice test. Both rat strains acquired an instrumental response, with SHR responding at greater rates over the course of training. During the choice test WKY demonstrated goal-directed behavior, responding more frequently on the lever that delivered, during training, the still-valued outcome. In contrast, SHR showed no goal-directed behavior, responding equally on both levers. However, MPH administration prior to the choice test restored goal-directed behavior in SHR, and disrupted this behavior in WKY rats. This study provides the first experimental evidence for selective impairment in goal-directed behavior in rat models of ADHD, and how MPH acts differently on SHR and WKY animals to restore or impair this behavior, respectively. PMID- 26635567 TI - A Prefrontal-Hippocampal Comparator for Goal-Directed Behavior: The Intentional Self and Episodic Memory. AB - The hypothesis of this article is that the interactions between the prefrontal cortex and the hippocampus play a critical role in the modulation of goal directed self-action and the strengthening of episodic memories. We describe various theories that model a comparator function for the hippocampus, and then elaborate the empirical evidence that supports these theories. One theory which describes a prefrontal-hippocampal comparator for voluntary action is emphasized. Action plans are essential for successful goal-directed behavior, and are elaborated by the prefrontal cortex. When an action plan is initiated, the prefrontal cortex transmits an efference copy (or corollary discharge) to the hippocampus where it is stored as a working memory for the action plan (which includes the expected outcomes of the action plan). The hippocampus then serves as a response intention-response outcome working memory comparator. Hippocampal comparator function is enabled by the hippocampal theta rhythm allowing the hippocampus to compare expected action outcomes to actual action outcomes. If the expected and actual outcomes match, the hippocampus transmits a signal to prefrontal cortex which strengthens or consolidates the action plan. If a mismatch occurs, the hippocampus transmits an error signal to the prefrontal cortex which facilitates a reformulation of the action plan, fostering behavioral flexibility and memory updating. The corollary discharge provides the self referential component to the episodic memory, affording the personal and subjective experience of what behavior was carried out, when it was carried out, and in what context (where) it occurred. Such a perspective can be applied to episodic memory in humans, and episodic-like memory in non-human animal species. PMID- 26635569 TI - The Effects of Repeated Testing, Simulated Malingering, and Traumatic Brain Injury on Visual Choice Reaction Time. AB - Choice reaction time (CRT), the time required to discriminate and respond appropriately to different stimuli, is a basic measure of attention and processing speed. Here, we describe the reliability and clinical sensitivity of a new CRT test that presents lateralized visual stimuli and adaptively adjusts stimulus onset asynchronies using a staircase procedure. Experiment 1 investigated the test-retest reliability in three test sessions performed at weekly intervals. Performance in the first test session was accurately predicted from age and computer-use regression functions obtained in a previously studied normative cohort. Central processing time (CentPT), the difference between the CRTs and simple reaction time latencies measured in a separate experiment, accounted for 55% of CRT latency and more than 85% of CRT latency variance. Performance improved significantly across the three test sessions. High intraclass correlation coefficients were seen for CRTs (0.90), CentPTs (0.87), and an omnibus performance measure (0.81) that combined CRT and minimal SOA z scores. Experiment 2 investigated performance in the same participants when instructed to feign symptoms of traumatic brain injury (TBI): 87% produced abnormal omnibus z-scores. Simulated malingerers showed greater elevations in simple reaction times than CRTs, and hence reduced CentPTs. Latency-consistency z scores, based on the difference between the CRTs obtained and those predicted based on CentPT latencies, discriminated malingering participants from controls with high sensitivity and specificity. Experiment 3 investigated CRT test performance in military veterans who had suffered combat-related TBI and symptoms of post-traumatic stress disorder, and revealed small but significant deficits in performance in the TBI population. The results indicate that the new CRT test shows high test-retest reliability, can assist in detecting participants performing with suboptimal effort, and is sensitive to the effects of TBI on the speed and accuracy of visual processing. PMID- 26635570 TI - Neural Patterns of the Implicit Association Test. AB - The Implicit Association Test (IAT) is a reaction time based categorization task that measures the differential associative strength between bipolar targets and evaluative attribute concepts as an approach to indexing implicit beliefs or biases. An open question exists as to what exactly the IAT measures, and here EEG (Electroencephalography) has been used to investigate the time course of ERPs (Event-related Potential) indices and implicated brain regions in the IAT. IAT EEG research identifies a number of early (250-450 ms) negative ERPs indexing early-(pre-response) processing stages of the IAT. ERP activity in this time range is known to index processes related to cognitive control and semantic processing. A central focus of these efforts has been to use IAT-ERPs to delineate the implicit and explicit factors contributing to measured IAT effects. Increasing evidence indicates that cognitive control (and related top-down modulation of attention/perceptual processing) may be components in the effective measurement of IAT effects, as factors such as physical setting or task instruction can change an IAT measurement. In this study we further implicate the role of proactive cognitive control and top-down modulation of attention/perceptual processing in the IAT-EEG. We find statistically significant relationships between D-score (a reaction-time based measure of the IAT-effect) and early ERP-time windows, indicating where more rapid word categorizations driving the IAT effect are present, they are at least partly explainable by neural activity not significantly correlated with the IAT measurement itself. Using LORETA, we identify a number of brain regions driving these ERP-IAT relationships notably involving left-temporal, insular, cingulate, medial frontal and parietal cortex in time regions corresponding to the N2- and P3-related activity. The identified brain regions involved with reduced reaction times on congruent blocks coincide with those of previous studies. PMID- 26635571 TI - Visual Feedback of Tongue Movement for Novel Speech Sound Learning. AB - Pronunciation training studies have yielded important information concerning the processing of audiovisual (AV) information. Second language (L2) learners show increased reliance on bottom-up, multimodal input for speech perception (compared to monolingual individuals). However, little is known about the role of viewing one's own speech articulation processes during speech training. The current study investigated whether real-time, visual feedback for tongue movement can improve a speaker's learning of non-native speech sounds. An interactive 3D tongue visualization system based on electromagnetic articulography (EMA) was used in a speech training experiment. Native speakers of American English produced a novel speech sound (/d/; a voiced, coronal, palatal stop) before, during, and after trials in which they viewed their own speech movements using the 3D model. Talkers' productions were evaluated using kinematic (tongue-tip spatial positioning) and acoustic (burst spectra) measures. The results indicated a rapid gain in accuracy associated with visual feedback training. The findings are discussed with respect to neural models for multimodal speech processing. PMID- 26635572 TI - Dissociable Roles of Dorsolateral Prefrontal Cortex and Frontal Eye Fields During Saccadic Eye Movements. AB - The dorsolateral prefrontal cortex (DLPFC) and the frontal eye fields (FEF) have both been implicated in the executive control of saccades, yet possible dissociable roles of each region have not been established. Specifically, both establishing a "task set" as well as suppressing an inappropriate response have been linked to DLPFC and FEF activity, with behavioral outcome measures of these mechanisms mainly being the percentage of pro-saccade errors made on anti-saccade trials. We used continuous theta-burst stimulation (cTBS) to disrupt FEF or DLPFC function in humans during an anti-saccade task to assess the causal role of these regions in these executive control processes, and in programming saccades towards (pro-saccade) or away (anti-saccade) from visual targets. After right FEF cTBS, as compared to control cTBS to the right primary somatosensory cortex (rS1), anti saccade amplitude of the first saccade decreased and the number of anti-saccades to acquire final position increased; however direction errors to the visual target were not different. In contrast, after left DLPFC cTBS, as compared to left S1 cTBS, subjects displayed greater direction errors for contralateral anti saccades; however, there were no impairments on the number of saccades or the saccade amplitude. These results are consistent with the notion that DLPFC is necessary for executive control of saccades, whereas FEF is necessary for visuo motor aspects of anti-saccade programming. PMID- 26635573 TI - The Neural Correlates of Optimistic and Depressive Tendencies of Self-Evaluations and Resting-State Default Mode Network. AB - Unrealistic optimism is common among people making self-evaluations while reduced optimism has been linked to increased depressive symptoms. Given the importance of optimism for adaptive functioning, surprisingly little is known about resting brain states underlying optimistic and depressive tendencies. In the current study, two resting-state indices were used to examine neural correlates of the default mode network (DMN) associated with optimistic and depressive self evaluation tendencies in a non-clinical young adult sample (N = 49). The analysis was constrained due to the self-referential nature of the DMN. Across different indices, bilateral superior frontal gyri of the dorsolateral prefrontal cortex (DLPFC) and bilateral superior medial frontal gyri of the dorsal medial prefrontal cortex (DMPFC) played a key role in maintaining spontaneous optimistic self-evaluative tendencies. Conversely, decreased activity in the DLPFC and bilateral medial orbitofrontal cortices (OFC) were related to accentuated depressive symptoms. Together, results highlight the pivotal roles of the DLPFC and DMPFC in mediating valences of self-referential content. PMID- 26635575 TI - Electrophysiological Evidence of a Delay in the Visual Recognition Process in Young Children. AB - The present study analyzes the development of the visual recognition processing of the relevant stimulus in a Delayed Match-To-Sample (DMS) task during the matching phase. To do so, Electroencephalograms of 170 subjects between 6 and 26 years old were recorded. Behavioral responses and Event Related Potentials (ERPs) induced by the stimuli were obtained. Reaction times and errors, mainly omissions, were inversely related to age. The ERPs analysis showed a parietal negativity in the P7 and P8 electrodes when the relevant stimulus was presented in the contralateral site. This negativity resulting from the recognition and selection of the relevant stimulus was present in all age groups. However, the youngest children showed an extended latency in the recognition process. The results suggest that children and adults use similar processes to recognize the item maintained in visual short-term memory (VSTM), but children need more time to successfully recognize the memorized item. PMID- 26635576 TI - Commentary: The Embodied Brain: Towards a Radical Embodied Cognitive Neuroscience. PMID- 26635574 TI - Cerebral Hemodynamic Responses During Dynamic Posturography: Analysis with a Multichannel Near-Infrared Spectroscopy System. AB - To investigate cortical roles in standing balance, cortical hemodynamic activity was recorded from the right hemisphere using near-infrared spectroscopy (NIRS) while subjects underwent the sensory organization test (SOT) protocol that systematically disrupts sensory integration processes (i.e., somatosensory or visual inputs or both). Eleven healthy men underwent the SOT during NIRS recording. Group statistical analyses were performed based on changes in oxygenated hemoglobin concentration in 10 different cortical regions of interest and on a general linear analysis with NIRS statistical parametric mapping. The statistical analyses indicated significant activation in the right frontal operculum (f-Op), right parietal operculum (p-Op), and right superior temporal gyrus (STG), right posterior parietal cortex (PPC), right dorsal and ventral premotor cortex (PMC), and the supplementary motor area (SMA) under various conditions. The activation patterns in response to specific combinations of SOT conditions suggested that (1) f-Op, p-Op, and STG are essential for sensory integration when standing balance is perturbed; (2) the SMA is involved in the execution of volitional action and establishment of new motor programs to maintain postural balance; and (3) the PPC and PMC are involved in the updating and computation of spatial reference frames during instances of sensory conflict between vestibular and visual information. PMID- 26635577 TI - Automatic Sleep Spindle Detection and Genetic Influence Estimation Using Continuous Wavelet Transform. AB - Mounting evidence for the role of sleep spindles in neuroplasticity has led to an increased interest in these non-rapid eye movement (NREM) sleep oscillations. It has been hypothesized that fast and slow spindles might play a different role in memory processing. Here, we present a new sleep spindle detection algorithm utilizing a continuous wavelet transform (CWT) and individual adjustment of slow and fast spindle frequency ranges. Eighteen nap recordings of ten subjects were used for algorithm validation. Our method was compared with both a human scorer and a commercially available SIESTA spindle detector. For the validation set, mean agreement between our detector and human scorer measured during sleep stage 2 using kappa coefficient was 0.45, whereas mean agreement between our detector and SIESTA algorithm was 0.62. Our algorithm was also applied to sleep-related memory consolidation data previously analyzed with a SIESTA detector and confirmed previous findings of significant correlation between spindle density and declarative memory consolidation. We then applied our method to a study in monozygotic (MZ) and dizygotic (DZ) twins, examining the genetic component of slow and fast sleep spindle parameters. Our analysis revealed strong genetic influence on variance of all slow spindle parameters, weaker genetic effect on fast spindles, and no effects on fast spindle density and number during stage 2 sleep. PMID- 26635578 TI - Preservation of Person-Specific Semantic Knowledge in Semantic Dementia: Does Direct Personal Experience Have a Specific Role? AB - Semantic dementia patients seem to have better knowledge of information linked to the self. More specifically, despite having severe semantic impairment, these patients show that they have more general information about the people they know personally by direct experience than they do about other individuals they know indirectly. However, the role of direct personal experience remains debated because of confounding factors such as frequency, recency of exposure, and affective relevance. We performed an exploratory study comparing the performance of five semantic dementia patients with that of 10 matched healthy controls on the recognition (familiarity judgment) and identification (biographic information recall) of personally familiar names vs. famous names. As expected, intergroup comparisons indicated a semantic breakdown in semantic dementia patients as compared with healthy controls. Moreover, unlike healthy controls, the semantic dementia patients recognized and identified personally familiar names better than they did famous names. This pattern of results suggests that direct personal experience indeed plays a specific role in the relative preservation of person specific semantic meaning in semantic dementia. We discuss the role of direct personal experience on the preservation of semantic knowledge and the potential neurophysiological mechanisms underlying these processes. PMID- 26635579 TI - Your Brain on Art: Emergent Cortical Dynamics During Aesthetic Experiences. AB - The brain response to conceptual art was studied with mobile electroencephalography (EEG) to examine the neural basis of aesthetic experiences. In contrast to most studies of perceptual phenomena, participants were moving and thinking freely as they viewed the exhibit The Boundary of Life is Quietly Crossed by Dario Robleto at the Menil Collection-Houston. The brain activity of over 400 subjects was recorded using dry-electrode and one reference gel-based EEG systems over a period of 3 months. Here, we report initial findings based on the reference system. EEG segments corresponding to each art piece were grouped into one of three classes (complex, moderate, and baseline) based on analysis of a digital image of each piece. Time, frequency, and wavelet features extracted from EEG were used to classify patterns associated with viewing art, and ranked based on their relevance for classification. The maximum classification accuracy was 55% (chance = 33%) with delta and gamma features the most relevant for classification. Functional analysis revealed a significant increase in connection strength in localized brain networks while subjects viewed the most aesthetically pleasing art compared to viewing a blank wall. The direction of signal flow showed early recruitment of broad posterior areas followed by focal anterior activation. Significant differences in the strength of connections were also observed across age and gender. This work provides evidence that EEG, deployed on freely behaving subjects, can detect selective signal flow in neural networks, identify significant differences between subject groups, and report with greater-than-chance accuracy the complexity of a subject's visual percept of aesthetically pleasing art. Our approach, which allows acquisition of neural activity "in action and context," could lead to understanding of how the brain integrates sensory input and its ongoing internal state to produce the phenomenon which we term aesthetic experience. PMID- 26635580 TI - Intertemporal Choice Behavior in Emerging Adults and Adults: Effects of Age Interact with Alcohol Use and Family History Status. AB - Adults with alcohol use disorders (AUDs) show marked immediate reward selection (or "Now") bias in intertemporal choice tasks. This Now bias persists long into abstinence, suggesting an irreversible consequence of chronic alcohol abuse or a pre-existing AUD intermediate phenotype. However, some data show substantial Now bias among emerging adults (18-25), regardless of drinking behavior, suggesting age-dependent effects on Now bias. The objectives of the present study were to determine (1) whether Now bias is greater among emerging adults relative to adults, (2) whether any such age effect on Now bias is diminished in sub-clinical heavy alcohol users, and (3) whether having a problem drinking first degree relative is independently associated with elevated Now bias. To achieve these objectives, we used an intertemporal choice task to quantify Now bias in n = 237 healthy participants (ages 18-40; 50% female), and a wide range of non-zero alcohol use, based on the Alcohol Use Disorders Identification Test (AUDIT). We found that among non-heavy drinkers, Now bias inversely correlated with age; this relationship was not present among heavy drinkers. We found no significant relationship between AUDIT score and Now bias among emerging adults, but AUDIT scores and Now bias were positively correlated among 26-40 year olds. Additionally, non-heavy drinking adults who reported a problem drinking first degree relative showed greater Now bias compared to those not reporting familial problem drinking. While not definitive, these findings lend support for elevated Now bias in adulthood as an intermediate phenotype for AUDs. Moreover, non additive effects of age and heavy drinking on Now bias suggest perturbations in largely common neural circuits in both groups. PMID- 26635581 TI - The Role of the Human Entorhinal Cortex in a Representational Account of Memory. AB - Connectivity studies in animals form the basis for a representational view of medial temporal lobe (MTL) subregions. In this view, distinct subfields of the entorhinal cortex (EC) relay object-related and spatial information from the perirhinal and parahippocampal cortices (PRC, PHC) to the hippocampus (HC). Relatively recent advances in functional magnetic resonance imaging (fMRI) methodology allow examining properties of human EC subregions directly. Antero lateral and posterior-medial EC subfields show remarkable consistency to their putative rodent and nonhuman primate homologs with regard to intra- and extra-MTL functional connectivity. Accordingly, there is now evidence for a dissociation of object-related vs. spatial processing in human EC subfields. Here, variance in localization may be integrated in the antero-lateral vs. posterior-medial distinction, but may additionally reflect process differences. Functional results in rodents further suggest material-specific representations may be more integrated in EC compared to PRC/PHC. In humans, however, evidence for such a dissociation between EC and PRC/PHC is lacking. Future research may elucidate on the unique contributions of human EC to memory, especially in light of its high degree of intrinsic and extrinsic connectivity. A thorough characterization of EC subfield function may not only advance our understanding of human memory, but also have important clinical implications. PMID- 26635582 TI - Mental Schemas Hamper Memory Storage of Goal-Irrelevant Information. AB - Mental schemas exert top-down control on information processing, for instance by facilitating the storage of schema-related information. However, given capacity limits and competition in neural network processing, schemas may additionally exert their effects by suppressing information with low momentary relevance. In particular, when existing schemas suffice to guide goal-directed behavior, this may actually reduce encoding of the redundant sensory input, in favor of gaining efficiency in task performance. The present experiment set out to test this schema-induced shallow encoding hypothesis. Our approach involved a memory task in which faces had to be coupled to homes. For half of the faces the responses could be guided by a pre-learned schema, for the other half of the faces such a schema was not available. Memory storage was compared between schema-congruent and schema-incongruent items. To characterize putative schema effects, memory was assessed both with regard to visual details and contextual aspects of each item. The depth of encoding was also assessed through an objective neural measure: the parietal old/new ERP effect. This ERP effect, observed between 500-800 ms post stimulus onset, is thought to reflect the extent of recollection: the retrieval of a vivid memory, including various contextual details from the learning episode. We found that schema-congruency induced substantial impairments in item memory and even larger ones in context memory. Furthermore, the parietal old/new ERP effect indicated higher recollection for the schema-incongruent than the schema-congruent memories. The combined findings indicate that, when goals can be achieved using existing schemas, this can hinder the in-depth processing of novel input, impairing the formation of perceptually detailed and contextually rich memory traces. Taking into account both current and previous findings, we suggest that schemas can both positively and negatively bias the processing of sensory input. An important determinant in this matter is likely related to momentary goals, such that mental schemas facilitate memory processing of goal-relevant input, but suppress processing of goal-irrelevant information. HIGHLIGHTS: - Schema-congruent information suffers from shallow encoding.- Schema congruency induces poor item and context memory.- The parietal old/new effect is less pronounced for schema-congruent items.- Schemas exert different influences on memory formation depending on current goals. PMID- 26635583 TI - Altered Neuronal Firing Pattern of the Basal Ganglia Nucleus Plays a Role in Levodopa-Induced Dyskinesia in Patients with Parkinson's Disease. AB - BACKGROUND: Levodopa therapy alleviates the symptoms of Parkinson's disease (PD), but long-term treatment often leads to motor complications such as levodopa induced dyskinesia (LID). AIM: To explore the neuronal activity in the basal ganglia nuclei in patients with PD and LID. METHODS: Thirty patients with idiopathic PD (age, 55.1 +/- 11.0 years; disease duration, 8.7 +/- 5.6 years) were enrolled between August 2006 and August 2013 at the Xuanwu Hospital, Capital Medical University, China. Their Hoehn and Yahr (1967) scores ranged from 2-4 and their UPDRS III scores were 28.5 +/- 5.2. Fifteen of them had severe LID (UPDRS IV scores of 6.7 +/- 1.6). Microelectrode recording was performed in the globus pallidus internus (GPi) and subthalamic nucleus (STN) during pallidotomy (n = 12) or STN deep brain stimulation (DBS; bilateral, n = 12; unilateral, n = 6). The firing patterns and frequencies of various cell types were analyzed by assessing single cell interspike intervals (ISIs) and the corresponding coefficient of variation (CV). RESULTS: A total of 295 neurons were identified from the GPi (n = 12) and STN (n = 18). These included 26 (8.8%) highly grouped discharge, 30 (10.2%) low frequency firing, 78 (26.4%) rapid tonic discharge, 103 (34.9%) irregular activity, and 58 (19.7%) tremor-related activity. There were significant differences between the two groups (p < 0.05) for neurons with irregular firing, highly irregular cluster-like firing, and low-frequency firing. CONCLUSION: Altered neuronal activity was observed in the basal ganglia nucleus of GPi and STN, and may play important roles in the pathophysiology of PD and LID. PMID- 26635584 TI - Network-Level Connectivity Dynamics of Movie Watching in 6-Year-Old Children. AB - Better understanding of the developing brain's functional mechanisms is critical for improving diagnosis and treatment of different developmental disorders. Particularly, characterizing how the developing brain dynamically reorganizes during different cognitive states may offer novel insight into the neuronal mechanisms of cognitive deficits. Imaging the brain during naturalistic conditions, like movie watching, provides a highly practical way to study young children's developing functional brain systems. In this study we compared the network-level functional organization of 6-year-old children while they were at rest with their functional connectivity as they watched short video clips. We employed both a data-driven independent component analysis (ICA) approach and a hypothesis-driven seed-based analysis to identify changes in network-level functional interactions during the shift from resting to video watching. Our ICA results showed that naturally watching a movie elicits significant changes in the functional connectivity between the visual system and the dorsal attention network when compared to rest (t (32) = 5.02, p = 0.0001). More interestingly, children showed an immature, but qualitatively adult-like, pattern of reorganization among three of the brain's higher-order networks (frontal control, default-mode and dorsal attention). For both ICA and seed-based approaches, we observed a decrease in the frontal network's correlation with the dorsal attention network (ICA: t (32) = -2.46, p = 0.02; Seed-based: t (32) = -1.62, p =0.12) and an increase in its connectivity with the default mode network (ICA: t (32) = 2.84, p = 0.008; Seed-based: t (32) = 2.28, p =0.03), which is highly consistent with the pattern observed in adults. These results offer improved understanding of the developing brain's dynamic network-level interaction patterns during the transition between different brain states and call for further studies to examine potential alterations to such dynamic patterns in different developmental disorders. PMID- 26635586 TI - The Racer's Brain - How Domain Expertise is Reflected in the Neural Substrates of Driving. AB - A fundamental question in human brain plasticity is how sensory, motor, and cognitive functions adapt in the process of skill acquisition extended over a period of many years. Recently, there has emerged a growing interest in cognitive neuroscience on studying the functional and structural differences in the brains of elite athletes. Elite performance in sports, music, or the arts, allows us to observe sensorimotor and cognitive performance at the limits of human capability. In this mini-review, we look at driving expertise. The emerging brain imaging literature on the neural substrates of real and simulated driving is reviewed (for the first time), and used as the context for interpreting recent findings on the differences between racing drivers and non-athlete controls. Also the cognitive psychology and cognitive neuroscience of expertise are discussed. PMID- 26635585 TI - Detection of Motor Changes in Huntington's Disease Using Dynamic Causal Modeling. AB - Deficits in motor functioning are one of the hallmarks of Huntington's disease (HD), a genetically caused neurodegenerative disorder. We applied functional magnetic resonance imaging (fMRI) and dynamic causal modeling (DCM) to assess changes that occur with disease progression in the neural circuitry of key areas associated with executive and cognitive aspects of motor control. Seventy-seven healthy controls, 62 pre-symptomatic HD gene carriers (preHD), and 16 patients with manifest HD symptoms (earlyHD) performed a motor finger-tapping fMRI task with systematically varying speed and complexity. DCM was used to assess the causal interactions among seven pre-defined regions of interest, comprising primary motor cortex, supplementary motor area (SMA), dorsal premotor cortex, and superior parietal cortex. To capture heterogeneity among HD gene carriers, DCM parameters were entered into a hierarchical cluster analysis using Ward's method and squared Euclidian distance as a measure of similarity. After applying Bonferroni correction for the number of tests, DCM analysis revealed a group difference that was not present in the conventional fMRI analysis. We found an inhibitory effect of complexity on the connection from parietal to premotor areas in preHD, which became excitatory in earlyHD and correlated with putamen atrophy. While speed of finger movements did not modulate the connection from caudal to pre-SMA in controls and preHD, this connection became strongly negative in earlyHD. This second effect did not survive correction for multiple comparisons. Hierarchical clustering separated the gene mutation carriers into three clusters that also differed significantly between these two connections and thereby confirmed their relevance. DCM proved useful in identifying group differences that would have remained undetected by standard analyses and may aid in the investigation of between-subject heterogeneity. PMID- 26635587 TI - Perception and Cognition of Cues Used in Synchronous Brain-Computer Interfaces Modify Electroencephalographic Patterns of Control Tasks. AB - A motor imagery (MI)-based brain-computer interface (BCI) is a system that enables humans to interact with their environment by translating their brain signals into control commands for a target device. In particular, synchronous BCI systems make use of cues to trigger the motor activity of interest. So far, it has been shown that electroencephalographic (EEG) patterns before and after cue onset can reveal the user cognitive state and enhance the discrimination of MI related control tasks. However, there has been no detailed investigation of the nature of those EEG patterns. We, therefore, propose to study the cue effects on MI-related control tasks by selecting EEG patterns that best discriminate such control tasks, and analyzing where those patterns are coming from. The study was carried out using two methods: standard and all-embracing. The standard method was based on sources (recording sites, frequency bands, and time windows), where the modulation of EEG signals due to motor activity is typically detected. The all-embracing method included a wider variety of sources, where not only motor activity is reflected. The findings of this study showed that the classification accuracy (CA) of MI-related control tasks did not depend on the type of cue in use. However, EEG patterns that best differentiated those control tasks emerged from sources well defined by the perception and cognition of the cue in use. An implication of this study is the possibility of obtaining different control commands that could be detected with the same accuracy. Since different cues trigger control tasks that yield similar CAs, and those control tasks produce EEG patterns differentiated by the cue nature, this leads to accelerate the brain computer communication by having a wider variety of detectable control commands. This is an important issue for Neuroergonomics research because neural activity could not only be used to monitor the human mental state as is typically done, but this activity might be also employed to control the system of interest. PMID- 26635588 TI - An Event-related Potential Study on the Interaction between Lighting Level and Stimulus Spatial Location. AB - Due to heterogeneous photoreceptor distribution, spatial location of stimulation is crucial to study visual brain activity in different light environments. This unexplored issue was studied through occipital event-related potentials (ERPs) recorded from 40 participants in response to discrete visual stimuli presented at different locations and in two environmental light conditions, low mesopic (L, 0.03 lux) and high mesopic (H, 6.5 lux), characterized by a differential photoreceptor activity balance: rod > cone and rod < cone, respectively. Stimuli, which were exactly the same in L and H, consisted of squares presented at fixation, at the vertical periphery (above or below fixation) or at the horizontal periphery (left or right). Analyses showed that occipital ERPs presented important L vs. H differences in the 100 to 450 ms window, which were significantly modulated by spatial location of stimulation: differences were greater in response to peripheral stimuli than to stimuli presented at fixation. Moreover, in the former case, significance of L vs. H differences was even stronger in response to stimuli presented at the horizontal than at the vertical periphery. These low vs. high mesopic differences may be explained by photoreceptor activation and their retinal distribution, and confirm that ERPs discriminate between rod- and cone-originated visual processing. PMID- 26635589 TI - Functional Connectivity of EEG Signals Under Laser Stimulation in Migraine. AB - In previous studies, migraine patients showed abnormalities in pain-related evoked responses, as reduced habituation to repetitive stimulation. In this study, we aimed to apply a novel analysis of EEG bands synchronization and directed dynamical influences under painful stimuli in migraine patients compared to non-migraine healthy volunteers. Thirty-one migraine without aura outpatients (MIGR) were evaluated and compared to 19 controls (CONT). The right hand was stimulated by means of 30 consecutive CO2 laser stimuli. EEG signal was examined by means of Morlet wavelet, synchronization entropy (SE), and Granger causality (GC), and the statistically validated results were mapped on the corresponding scalp locations. The vertex complex of averaged laser-evoked responses (LEPs) showed reduced habituation compared to CONT. In the prestimulus phase, enhanced SE in the 0, 5-30 Hz range was present in MIGR and CONT between the bilateral temporal-parietal and the frontal regions around the midline. Migraine patients showed an anticipation of EEG changes preceding the painful stimulation compared to CONT. In the poststimulus phase, the same cortical areas were more connected in MIGR vs CONT. In both groups of patients and CONT, the habituation index was negatively correlated with the GC scores. A different pattern of cortical activation after painful stimulation was present in migraine. The increase in cortical connections during repetitive painful stimulation may subtend the phenomenon of LEPs reduced habituation. Brain network analysis may give an aid in understanding subtle changes of pain processing under laser stimuli in migraine patients. PMID- 26635590 TI - Regional Changes in Cerebral Oxygenation During Repeated Passive Movement Measured by Functional Near-infrared Spectroscopy. AB - The aim of this study is to investigate the influence of passive movement repetition frequency at 1.5-Hz and 1-Hz on changes in cerebral oxygenation and assess the temporal properties of these changes using functional near-infrared spectroscopy (fNIRS). No significant differences in systemic hemodynamics were observed between resting and passive movement phases for either 1.5-Hz or 1-Hz trial. Changes in cortical oxygenation as measured by fNIRS in bilateral supplementary motor cortex (SMC), left primary motor cortex (M1), left primary somatosensory cortex (S1), and left posterior association area (PAA) during passive movement of the right index finger revealed greater cortical activity at only 1.5-Hz movement frequency. However, there were no significant differences in the time for peak oxyhemoglobin (oxyHb) among regions (bilateral SMC, 206.4 +/- 14.4 s; left M1, 199.1 +/- 14.8 s; left S1, 207.3 +/- 9.4 s; left PAA, 219.1 +/- 10.2 s). Therefore, our results that passive movement above a specific frequency may be required to elicit a changed in cerebral oxygenation, and the times of peak DeltaoxyHb did not differ significantly among measured regions. PMID- 26635591 TI - Transfer in Motor Sequence Learning: Effects of Practice Schedule and Sequence Context. AB - Transfer (i.e., the application of a learned skill in a novel context) is an important and desirable outcome of motor skill learning. While much research has been devoted to understanding transfer of explicit skills the mechanisms of skill transfer after incidental learning remain poorly understood. The aim of this study was to (1) examine the effect of practice schedule on transfer and (2) investigate whether sequence-specific knowledge can transfer to an unfamiliar sequence context. We trained two groups of participants on an implicit serial response time task under a Constant (one sequence for 10 blocks) or Variable (alternating between two sequences for a total of 10 blocks) practice schedule. We evaluated response times for three types of transfer: task-general transfer to a structurally non-overlapping sequence, inter-manual transfer to a perceptually identical sequence, and sequence-specific transfer to a partially overlapping (three shared triplets) sequence. Results showed partial skill transfer to all three sequences and an advantage of Variable practice only for task-general transfer. Further, we found expression of sequence-specific knowledge for familiar sub-sequences in the overlapping sequence. These findings suggest that (1) constant practice may create interference for task-general transfer and (2) sequence-specific knowledge can transfer to a new sequential context. PMID- 26635592 TI - Modeling the Influence of Ion Channels on Neuron Dynamics in Drosophila. AB - Voltage gated ion channels play a major role in determining a neuron's firing behavior, resulting in the specific processing of synaptic input patterns. Drosophila and other invertebrates provide valuable model systems for investigating ion channel kinetics and their impact on firing properties. Despite the increasing importance of Drosophila as a model system, few computational models of its ion channel kinetics have been developed. In this study, experimentally observed biophysical properties of voltage gated ion channels from the fruitfly Drosophila melanogaster are used to develop a minimal, conductance based neuron model. We investigate the impact of the densities of these channels on the excitability of the model neuron. Changing the channel densities reproduces different in situ observed firing patterns and induces a switch from integrator to resonator properties. Further, we analyze the preference to input frequency and how it depends on the channel densities and the resulting bifurcation type the system undergoes. An extension to a three dimensional model demonstrates that the inactivation kinetics of the sodium channels play an important role, allowing for firing patterns with a delayed first spike and subsequent high frequency firing as often observed in invertebrates, without altering the kinetics of the delayed rectifier current. PMID- 26635593 TI - A Winding Road: Alzheimer's Disease Increases Circuitous Functional Connectivity Pathways. AB - Neuroimaging has been successful in characterizing the pattern of cerebral atrophy that accompanies the progression of Alzheimer's disease (AD). Examination of functional connectivity, the strength of signal synchronicity between brain regions, has gathered pace as another way of understanding changes to the brain that are associated with AD. It appears to have good sensitivity and detect effects that precede cognitive decline, and thus offers the possibility to understand the neurobiology of the disease in its earliest phases. However, functional connectivity analyzes to date generally consider only the strongest connections, with weaker links ignored. This proof-of-concept study compared patients with mild-to-moderate AD (N = 11) and matched control individuals (N = 12) based on functional connectivities derived from blood-oxygenation level dependent (BOLD) sensitive functional MRI acquired during resting wakefulness. All positive connectivities irrespective of their strength were included. Transitive closures of the resulting connectome were calculated that classified connections as either direct or indirect. Between-group differences in the proportion of indirect paths were observed. In AD, there was broadly increased indirect connectivity across greater spatial distances. Furthermore, the indirect pathways in AD had greater between-subject topological variance than controls. The prevailing characterization of AD as being a disconnection syndrome is refined by the observation that direct links between regions that are impaired are perhaps replaced by an increase in indirect functional pathways that is only detectable through inclusion of connections across the entire range of connection strengths. PMID- 26635595 TI - Editorial: Hierarchical Object Representations in the Visual Cortex and Computer Vision. PMID- 26635594 TI - H-Channels Affect Frequency, Power and Amplitude Fluctuations of Neuronal Network Oscillations. AB - Oscillations in network activity are ubiquitous in the brain and are involved in diverse cognitive functions. Oscillation characteristics, such as power, frequency, and temporal structure, depend on both network connectivity and intrinsic cellular properties, such as ion channel composition. An important class of channels, with key roles in regulating cell excitability, are h channels. The h-current (Ih) is a slow, hyperpolarization-activated, depolarizing current that contributes to neuronal resonance and membrane potential. The impact of Ih on network oscillations, however, remains poorly understood. To elucidate the network effects of Ih, we used a computational model of a generic oscillatory neuronal network consisting of inhibitory and excitatory cells that were externally driven by excitatory action potentials and sustained depolarizing currents. We found that Ih increased the oscillation frequency and, in combination with external action potentials, representing input from areas outside the network, strongly decreased the synchrony of firing. As a consequence, the oscillation power and the duration of episodes during which the network exhibited high-amplitude oscillations were greatly reduced in the presence of Ih. Our results suggest that modulation of Ih or impaired expression of h-channels, as observed in epilepsy, could, by affecting oscillation dynamics, markedly alter network-level activity and potentially influence oscillation dependent cognitive processes such as learning, memory and attention. PMID- 26635596 TI - Golgi: Interactive Online Brain Mapping. AB - Golgi (http://www.usegolgi.com) is a prototype interactive brain map of the rat brain that helps researchers intuitively interact with neuroanatomy, connectomics, and cellular and chemical architecture. The flood of "-omic" data urges new ways to help researchers connect discrete findings to the larger context of the nervous system. Here we explore Golgi's underlying reasoning and techniques and how our design decisions balance the constraints of building both a scientifically useful and usable tool. We demonstrate how Golgi can enhance connectomic literature searches with a case study investigating a thalamocortical circuit involving the Nucleus Accumbens and we explore Golgi's potential and future directions for growth in systems neuroscience and connectomics. PMID- 26635597 TI - TVB-EduPack-An Interactive Learning and Scripting Platform for The Virtual Brain. AB - The Virtual Brain (TVB; thevirtualbrain.org) is a neuroinformatics platform for full brain network simulation based on individual anatomical connectivity data. The framework addresses clinical and neuroscientific questions by simulating multi-scale neural dynamics that range from local population activity to large scale brain function and related macroscopic signals like electroencephalography and functional magnetic resonance imaging. TVB is equipped with a graphical and a command-line interface to create models that capture the characteristic biological variability to predict the brain activity of individual subjects. To enable researchers from various backgrounds a quick start into TVB and brain network modeling in general, we developed an educational module: TVB-EduPack. EduPack offers two educational functionalities that seamlessly integrate into TVB's graphical user interface (GUI): (i) interactive tutorials introduce GUI elements, guide through the basic mechanics of software usage and develop complex use-case scenarios; animations, videos and textual descriptions transport essential principles of computational neuroscience and brain modeling; (ii) an automatic script generator records model parameters and produces input files for TVB's Python programming interface; thereby, simulation configurations can be exported as scripts that allow flexible customization of the modeling process and self-defined batch- and post-processing applications while benefitting from the full power of the Python language and its toolboxes. This article covers the implementation of TVB-EduPack and its integration into TVB architecture. Like TVB, EduPack is an open source community project that lives from the participation and contribution of its users. TVB-EduPack can be obtained as part of TVB from thevirtualbrain.org. PMID- 26635598 TI - Cortical Spiking Network Interfaced with Virtual Musculoskeletal Arm and Robotic Arm. AB - Embedding computational models in the physical world is a critical step towards constraining their behavior and building practical applications. Here we aim to drive a realistic musculoskeletal arm model using a biomimetic cortical spiking model, and make a robot arm reproduce the same trajectories in real time. Our cortical model consisted of a 3-layered cortex, composed of several hundred spiking model-neurons, which display physiologically realistic dynamics. We interconnected the cortical model to a two-joint musculoskeletal model of a human arm, with realistic anatomical and biomechanical properties. The virtual arm received muscle excitations from the neuronal model, and fed back proprioceptive information, forming a closed-loop system. The cortical model was trained using spike timing-dependent reinforcement learning to drive the virtual arm in a 2D reaching task. Limb position was used to simultaneously control a robot arm using an improved network interface. Virtual arm muscle activations responded to motoneuron firing rates, with virtual arm muscles lengths encoded via population coding in the proprioceptive population. After training, the virtual arm performed reaching movements which were smoother and more realistic than those obtained using a simplistic arm model. This system provided access to both spiking network properties and to arm biophysical properties, including muscle forces. The use of a musculoskeletal virtual arm and the improved control system allowed the robot arm to perform movements which were smoother than those reported in our previous paper using a simplistic arm. This work provides a novel approach consisting of bidirectionally connecting a cortical model to a realistic virtual arm, and using the system output to drive a robotic arm in real time. Our techniques are applicable to the future development of brain neuroprosthetic control systems, and may enable enhanced brain-machine interfaces with the possibility for finer control of limb prosthetics. PMID- 26635599 TI - MicroRNAs 99b-5p/100-5p Regulated by Endoplasmic Reticulum Stress are Involved in Abeta-Induced Pathologies. AB - Alzheimer's disease (AD) is the most common cause of dementia. Amyloid beta (Abeta, Abeta) deposition and intracellular tangles are the pathological hallmarks of AD. MicroRNAs (miRNAs) are small non-coding RNAs, which have been found to play very important roles, and have the potential to serve as diagnostic markers during neuronal pathogenesis. In this study, we aimed to determine the roles of miR-99b-5p and miR-100-5p in Abeta-induced neuronal pathologies. We detected the expression levels of miR-99b-5p and miR-100-5p in the brains of APPswe/PS1DeltaE9 double-transgenic mice (APP/PS1 mice) at different age stages and found that both miRNAs were decreased at early stages while increased at late stages of APP/PS1 mice when compared with the age-matched wild type (WT) mice. Similar phenomenon was also observed in Abeta-treated cultured cells. We also confirmed that mammalian target of rapamycin (mTOR) is one of the targets of miR 99b-5p/100-5p, which is consistent with previous studies in cancer. MiR-99b 5p/100-5p has been found to promote cell apoptosis with the Abeta treatment. This effect may be induced via the mTOR pathway. In our study, we find both miR-99b-5p and miR-100-5p affect neuron survival by targeting mTOR. We also speculate that dynamic change of miR-99b-5p/100-5p levels during Abeta-associated pathologies might be attributed to Abeta-induced endoplasmic reticulum stress (ER stress), suggesting the potential role of the "ER stress-miRNAs-mTOR" axis in Abeta related AD pathogenesis. PMID- 26635600 TI - Perceived Risk of Mental Health Problems in Primary Care. AB - In the face of limited resources and an aging population with increasingly care needs, healthcare systems must identify community-dwelling older adults with mental health problems at higher risk of adverse outcomes such as institutionalization, hospitalization and death, in order to deliver timely and efficient care. The objectives of this study were to assess the prevalence of mental health concerns and the associated perceived risk of adverse outcomes in a large sample of older patients in primary care (PC). We trained general practitioners and nurses to use the Risk Instrument for Screening in the Community to rank perceived risk of mental health concerns (including neurocognitive and mood disorders) from 1 (mild) to 3 (severe). The mean age of the 4499 people assessed was 76.3 years (SD = 7.3) and 2645 (58.8%) were female. According to the PC team 1616 (35.9%) were perceived to have mental health concerns of whom 847 (52.4%) were mild, 559 (34.6%) were moderate and 210 (13%) were severe. Patients with mental health concerns had higher odds of perceived risk of adverse outcomes (OR = 2.22, 95% CI 1.83-2.69 for institutionalization; OR = 1.66, 95% CI 1.41-1.94 for hospitalization; OR = 1.69, 95% CI 1.42-2.01 for death). These results suggest a high prevalence of mental health concerns among older adults and supports the need for early identification of patients at high risk of adverse healthcare outcomes. PMID- 26635602 TI - Semaphorin 3A: A Potential Target for Low Back Pain. AB - Low back pain is a common disorder. Pathological innervation and intervertebral disc degeneration are two major factors associated with this disease. Semaphorin 3A, originally known for its potent inhibiting effect on axonal outgrowth, is recently found to correlate with disease activity and histological features in some skeletal disorders. Based on its effects on innervation and vascularization, as well as enzyme secretion, we presume that semaphorin 3A may act as a potential target for low back pain. PMID- 26635601 TI - Rapid Responsiveness to Practice Predicts Longer-Term Retention of Upper Extremity Motor Skill in Non-Demented Older Adults. AB - Skill acquisition is a form of motor learning that may provide key insights into the aging brain. Although previous work suggests that older adults learn novel motor tasks slower and to a lesser extent than younger adults, we have recently demonstrated no significant effect of chronological age on the rates and amounts of skill acquisition, nor on its long-term retention, in adults over the age of 65. To better understand predictors of skill acquisition in non-demented older adults, we now explore the relationship between early improvements in motor performance due to practice (i.e., rapid responsiveness) and longer-term retention of an upper extremity motor skill, and whether the extent of rapid responsiveness was associated with global cognitive status. Results showed significant improvements in motor performance within the first five (of 150) trials, and that this "rapid responsiveness" was predictive of skill retention 1 month later. Notably, the extent of rapid responsiveness was not dependent on global cognitive status, as measured by the Montreal Cognitive Assessment (MoCA). Thus, rapid responsiveness appears to be an important variable in longer-term neurorehabilitative efforts with older adults, regardless of their cognitive status. PMID- 26635603 TI - Perceiving Collision Impacts in Alzheimer's Disease: The Effect of Retinal Eccentricity on Optic Flow Deficits. AB - The present study explored whether the optic flow deficit in Alzheimer's disease (AD) reported in the literature transfers to different types of optic flow, in particular, one that specifies collision impacts with upcoming surfaces, with a special focus on the effect of retinal eccentricity. Displays simulated observer movement over a ground plane toward obstacles lying in the observer's path. Optical expansion was modulated by varying [Formula: see text]. The visual field was masked either centrally (peripheral vision) or peripherally (central vision) using masks ranging from 10 degrees to 30 degrees in diameter in steps of 10 degrees . Participants were asked to indicate whether their approach would result in "collision" or "no collision" with the obstacles. Results showed that AD patients' sensitivity to [Formula: see text] was severely compromised, not only for central vision but also for peripheral vision, compared to age- and education matched elderly controls. The results demonstrated that AD patients' optic flow deficit is not limited to radial optic flow but includes also the optical pattern engendered by [Formula: see text]. Further deterioration in the capacity to extract [Formula: see text] to determine potential collisions in conjunction with the inability to extract heading information from radial optic flow would exacerbate AD patients' difficulties in navigation and visuospatial orientation. PMID- 26635604 TI - Antimicrobial, Anthelmintic Activities and Characterisation of Functional Phenolic Acids of Achyranthes aspera Linn.: A Medicinal Plant Used for the Treatment of Wounds and Ringworm in East Africa. AB - Achyranthes aspera Linn. (Amaranthaceae) commonly known as Prickly Chaff flower (English) is traditionally used for treating a number of ailments. Different parts of the plant are used in treating wounds and ringworm in East Africa and elsewhere for a number of ailments. In this study, leaf extracts of A. aspera collected from two different geographical locations (Ciaat, Eritrea and Ukulinga, South Africa) were evaluated for antibacterial, antifungal, anthelmintic activities and the plant characterized for functional phenolic acids as well as protein binding capacity. The pathogens used in the tests were, two Gram-negative (Escherichia coli and Klebsiella pneumoniae), two Gram-positive bacteria (Bacillus subtilis and Staphylococcus aureus), a filamentus yeast-like fungus (Candida albicans) and a free-living nematode (Caenorhabditis elegans). The water and acetone extracts of the samples collected from Ciaat exhibited good antibacterial, antifungal and anthelmintic activity (MIC < 1 mg/ml) except the water extract against E. coli which showed moderate activity. In contrast, the extracts collected from Ukulinga exhibited moderate to weak activities except for the acetone (aq.) extracts which had good activity against some of the tested organisms. UHPLC-MS/MS revealed variation in the levels of some functional phenolic compounds, with rutin, chlorogenic acid and genistein not being detected in the extracts from Ukulinga. The variation was also observed in the protein binding capacity, which could offer a predictive wound healing model. All extracts from plant samples collected at Ciaat expressed significant dominant potency compared to similar extracts from Ukulinga. PMID- 26635605 TI - Drug Discovery Opportunities at the Endothelin B Receptor-Related Orphan G Protein-Coupled Receptors, GPR37 and GPR37L1. AB - Orphan G protein-coupled receptors (GPCRs) represent a largely untapped resource for the treatment of a variety of diseases, despite sophisticated advances in drug discovery. Two promising orphan GPCRs are the endothelin B receptor-like proteins, GPR37 [ET(B)R-LP, Pael-R] and GPR37L1 [ET(B)R-LP-2]. Originally identified through searches for homologs of endothelin and bombesin receptors, neither GPR37 nor GPR37L1 were found to bind endothelins or related peptides. Instead, GPR37 was proposed to be activated by head activator (HA) and both GPR37 and GPR37L1 have been linked to the neuropeptides prosaposin and prosaptide, although these pairings are yet to be universally acknowledged. Both orphan GPCRs are widely expressed in the brain, where GPR37 has received the most attention for its link to Parkinson's disease and parkinsonism, while GPR37L1 deletion leads to precocious cerebellar development and hypertension. In this review, the existing pharmacology and physiology of GPR37 and GPR37L1 is discussed and the potential therapeutic benefits of targeting these receptors are explored. PMID- 26635607 TI - Evaluation of Antioxidant, Free Radical Scavenging, and Antimicrobial Activity of Quercus incana Roxb. AB - Considering the indigenous utilization of Quercus incana Roxb., the present study deals with the investigation of antioxidant, free radical scavenging activity, total phenolic content, and antimicrobial activity of Q. incana Roxb. In vitro antioxidant activity of the plant fractions were determined by 1,1-diphenyl-2 picrylhydrazyl and nitric oxide scavenging method. Total phenolic contents were determined by gallic acid equivalent and antimicrobial activities were determined by agar well diffusion method. It was observed that Q. incana Roxb. showed significant antibacterial activity against Gram-positive and Gram-negative bacteria. n-Butanol fraction showed maximum activity against Micrococcus leuteus with 19 mm zone of inhibition. n-Butanol fraction of Q. incana Roxb. showed immense antifungal activity against Aspergillus niger (32 mm +/- 0.55) and A. flavus (28 mm +/- 0.45). Similarly n-butanol fraction showed relatively good antioxidant activity with IC50 value of 55.4 +/- 0.21 MUg/mL. The NO scavenging activity of ethyl acetate fraction (IC50 = 23.21 +/- 0.31 MUg/mL) was fairly good compared to other fractions. The current study of Q. incana Roxb. suggests the presences of synergetic action of some biological active compounds that may be present in the leaves of medicinal plant. Further studies are needed to better characterize the important active constituents responsible for the antimicrobial, antioxidant and free radical scavenging activity. PMID- 26635606 TI - The Function of Rho-Associated Kinases ROCK1 and ROCK2 in the Pathogenesis of Cardiovascular Disease. AB - Rho-associated kinases ROCK1 and ROCK2 are serine/threonine kinases that are downstream targets of the small GTPases RhoA, RhoB, and RhoC. ROCKs are involved in diverse cellular activities including actin cytoskeleton organization, cell adhesion and motility, proliferation and apoptosis, remodeling of the extracellular matrix and smooth muscle cell contraction. The role of ROCK1 and ROCK2 has long been considered to be similar; however, it is now clear that they do not always have the same functions. Moreover, depending on their subcellular localization, activation, and other environmental factors, ROCK signaling can have different effects on cellular function. With respect to the heart, findings in isoform-specific knockout mice argue for a role of ROCK1 and ROCK2 in the pathogenesis of cardiac fibrosis and cardiac hypertrophy, respectively. Increased ROCK activity could play a pivotal role in processes leading to cardiovascular diseases such as hypertension, pulmonary hypertension, angina pectoris, vasospastic angina, heart failure, and stroke, and thus ROCK activity is a potential new biomarker for heart disease. Pharmacological ROCK inhibition reduces the enhanced ROCK activity in patients, accompanied with a measurable improvement in medical condition. In this review, we focus on recent findings regarding ROCK signaling in the pathogenesis of cardiovascular disease, with a special focus on differences between ROCK1 and ROCK2 function. PMID- 26635608 TI - Importance of Apolipoprotein A-I in Multiple Sclerosis. AB - Jean-Martin Charcot has first described multiple sclerosis (MS) as a disease of the central nervous system (CNS) over a century ago. MS remains incurable today, and treatment options are limited to disease modifying drugs. Over the years, significant advances in understanding disease pathology have been made in autoimmune and neurodegenerative components. Despite the fact that brain is the most lipid rich organ in human body, the importance of lipid metabolism has not been extensively studied in this disorder. In MS, the CNS is under attack by a person's own immune system. Autoantigens and autoantibodies are known to cause devastation of myelin through up regulation of T-cells and cytokines, which penetrate through the blood-brain barrier to cause inflammation and myelin destruction. The anti-inflammatory role of high-density lipoproteins (HDLs) has been implicated in a plethora of biological processes: vasodilation, immunity to infection, oxidation, inflammation, and apoptosis. However, it is not known what role HDL plays in neurological function and myelin repair in MS. Understanding of lipid metabolism in the CNS and in the periphery might unveil new therapeutic targets and explain the partial success of some existing MS therapies. PMID- 26635610 TI - Effects of Topical Fucosyl-Lactose, a Milk Oligosaccharide, on Dry Eye Model: An Example of Nutraceutical Candidate. AB - PURPOSE: Colostrum has been proposed to treat severe dryness and problematic eye lesions showing a beneficial effect. The aim of the study was to investigate the effect of 2-fucosyl-lactose, a natural sugar present in the human colostrum, in an experimental dry eye. METHODS: Dry eye was induced in adult male New Zealand albino rabbits by topical administration of 1% atropine. Tear volume (Schirmer's test), tear film breakup time (TBUT), corneal staining and tear osmolarity were assessed. Fucosyl-lactose eye drops was instilled at different concentrations (0.01, 0.1, and, 1%). RESULTS: After 24 h from first atropine administration, tear volume and TBUT values were significantly improved in groups treated with 2 fucosyl-lactose in a dose-dependent manner. Tear volume increased from 5.25 to 10.75 mm and TBUT values from 8.75 to 34.5 s with 0.01% or 1% 2-fucosyl-lactose treatment, respectively. No changes were observed in terms of corneal staining among the all groups treated with 2-fucosyl-lactose. Atropine instillation caused an increase of tear osmolarity (428 mOsm/L), which was reversed by topical treatment with 2-fucosyl-lactose at all doses. CONCLUSION: The present study demonstrated that 2-fucosyl-lactose, a human milk oligosaccharide, has protective effect on tear film stability. PMID- 26635609 TI - beta1 Integrins as Therapeutic Targets to Disrupt Hallmarks of Cancer. AB - Integrins belong to a large family of alphabeta heterodimeric transmembrane proteins first recognized as adhesion molecules that bind to dedicated elements of the extracellular matrix and also to other surrounding cells. As important sensors of the cell microenvironment, they regulate numerous signaling pathways in response to structural variations of the extracellular matrix. Biochemical and biomechanical cues provided by this matrix and transmitted to cells via integrins are critically modified in tumoral settings. Integrins repertoire are subjected to expression level modifications, in tumor cells, and in surrounding cancer associated cells, implicated in tumor initiation and progression as well. As critical players in numerous cancer hallmarks, defined by Hanahan and Weinberg (2011), integrins represent pertinent therapeutic targets. We will briefly summarize here our current knowledge about integrin implications in those different hallmarks focusing primarily on beta1 integrins. PMID- 26635611 TI - Desert Hedgehog/Patch2 Axis Contributes to Vascular Permeability and Angiogenesis in Glioblastoma. AB - Glioblastoma multiforme (GBM) constitutes the most common and the most aggressive type of human tumors affecting the central nervous system. Prognosis remains dark due to the inefficiency of current treatments and the rapid relapse. Paralleling other human tumors, GBM contains a fraction of tumor initiating cells with the capacity to self-renew, initiate and maintain the tumor mass. These cells were found in close proximity to brain vasculature, suggesting functional interactions between brain tumor-initiating cells (BTICs) and endothelial cells within the so called vascular niche. However, the mechanisms by which these cells impact on the endothelium plasticity and function remain unclear. Using culture of BTICs isolated from a cohort of 14 GBM patients, we show that BTICs secretome promotes brain endothelial cell remodeling in a VEGF-independent manner. Gene array analysis unmasked that BTICs-released factors drove the expression of Ptch2 in endothelial cells. Interestingly, BTICs produce desert hedgehog (DHH) ligand, enabling a paracrine DHH/Ptch2 signaling cascade that conveys elevated permeability and angiogenesis. Finally, DHH silencing in BTICs dramatically reduced tumor growth, as well as vascularization and intra-tumor permeability. Collectively, our data unveil a role for DHH in exacerbated tumor angiogenesis and permeability, which may ultimately favor glioblastoma growth, and thus place the DHH/Ptch2 nexus as a molecular target for novel therapies. PMID- 26635612 TI - Role of ErbB Receptors in Cancer Cell Migration and Invasion. AB - Growth factors mediate their diverse biologic responses (regulation of cellular proliferation, differentiation, migration and survival) by binding to and activating cell-surface receptors with intrinsic protein kinase activity named receptor tyrosine kinases (RTKs). About 60 RTKs have been identified and can be classified into more than 16 different receptor families. Their activity is normally tightly controlled and regulated. Overexpression of RTK proteins or functional alterations caused by mutations in the corresponding genes or abnormal stimulation by autocrine growth factor loops contribute to constitutive RTK signaling, resulting in alterations in the physiological activities of cells. The ErbB receptor family of RTKs comprises four distinct receptors: the EGFR (also known as ErbB1/HER1), ErbB2 (neu, HER2), ErbB3 (HER3) and ErbB4 (HER4). ErbB family members are often overexpressed, amplified, or mutated in many forms of cancer, making them important therapeutic targets. EGFR has been found to be amplified in gliomas and non-small-cell lung carcinoma while ErbB2 amplifications are seen in breast, ovarian, bladder, non-small-cell lung carcinoma, as well as several other tumor types. Several data have shown that ErbB receptor family and its downstream pathway regulate epithelial-mesenchymal transition, migration, and tumor invasion by modulating extracellular matrix (ECM) components. Recent findings indicate that ECM components such as matrikines bind specifically to EGF receptor and promote cell invasion. In this review, we will present an in-depth overview of the structure, mechanisms, cell signaling, and functions of ErbB family receptors in cell adhesion and migration. Furthermore, we will describe in a last part the new strategies developed in anti-cancer therapy to inhibit ErbB family receptor activation. PMID- 26635613 TI - Heat Perception and Aversive Learning in Honey Bees: Putative Involvement of the Thermal/Chemical Sensor AmHsTRPA. AB - The recent development of the olfactory conditioning of the sting extension response (SER) has provided new insights into the mechanisms of aversive learning in honeybees. Until now, very little information has been gained concerning US detection and perception. In the initial version of SER conditioning, bees learned to associate an odor CS with an electric shock US. Recently, we proposed a modified version of SER conditioning, in which thermal stimulation with a heated probe is used as US. This procedure has the advantage of allowing topical US applications virtually everywhere on the honeybee body. In this study, we made use of this possibility and mapped thermal responsiveness on the honeybee body, by measuring workers' SER after applying heat on 41 different structures. We then show that bees can learn the CS-US association even when the heat US is applied on body structures that are not prominent sensory organs, here the vertex (back of the head) and the ventral abdomen. Next, we used a neuropharmalogical approach to evaluate the potential role of a recently described Transient Receptor Potential (TRP) channel, HsTRPA, on peripheral heat detection by bees. First, we applied HsTRPA activators to assess if such activation is sufficient for triggering SER. Second, we injected HsTRPA inhibitors to ask whether interfering with this TRP channel affects SER triggered by heat. These experiments suggest that HsTRPA may be involved in heat detection by bees, and represent a potential peripheral detection system in thermal SER conditioning. PMID- 26635614 TI - Hippocampal Transcriptomic and Proteomic Alterations in the BTBR Mouse Model of Autism Spectrum Disorder. AB - Autism spectrum disorders (ASD) are complex heterogeneous neurodevelopmental disorders of an unclear etiology, and no cure currently exists. Prior studies have demonstrated that the black and tan, brachyury (BTBR) T+ Itpr3tf/J mouse strain displays a behavioral phenotype with ASD-like features. BTBR T+ Itpr3tf/J mice (referred to simply as BTBR) display deficits in social functioning, lack of communication ability, and engagement in stereotyped behavior. Despite extensive behavioral phenotypic characterization, little is known about the genes and proteins responsible for the presentation of the ASD-like phenotype in the BTBR mouse model. In this study, we employed bioinformatics techniques to gain a wide scale understanding of the transcriptomic and proteomic changes associated with the ASD-like phenotype in BTBR mice. We found a number of genes and proteins to be significantly altered in BTBR mice compared to C57BL/6J (B6) control mice controls such as BDNF, Shank3, and ERK1, which are highly relevant to prior investigations of ASD. Furthermore, we identified distinct functional pathways altered in BTBR mice compared to B6 controls that have been previously shown to be altered in both mouse models of ASD, some human clinical populations, and have been suggested as a possible etiological mechanism of ASD, including "axon guidance" and "regulation of actin cytoskeleton." In addition, our wide-scale bioinformatics approach also discovered several previously unidentified genes and proteins associated with the ASD phenotype in BTBR mice, such as Caskin1, suggesting that bioinformatics could be an avenue by which novel therapeutic targets for ASD are uncovered. As a result, we believe that informed use of synergistic bioinformatics applications represents an invaluable tool for elucidating the etiology of complex disorders like ASD. PMID- 26635616 TI - Tendon Vasculature in Health and Disease. AB - Tendons represent a bradytrophic tissue which is poorly vascularized and, compared to bone or skin, heal poorly. Usually, a vascularized connective scar tissue with inferior functional properties forms at the injury site. Whether the increased vascularization is the root cause of tissue impairments such as loss of collagen fiber orientation, ectopic formation of bone, fat or cartilage, or is a consequence of these pathological changes remains unclear. This review provides an overview of the role of tendon vasculature in healthy and chronically diseased tendon tissue as well as its relevance for tendon repair. Further, the nature and the role of perivascular tendon stem/progenitor cells residing in the vascular niche will be discussed and compared to multipotent stromal cells in other tissues. PMID- 26635615 TI - Cortisol Regulates Acid Secretion of H(+)-ATPase-rich Ionocytes in Zebrafish (Danio rerio) Embryos. AB - Systemic acid-base regulation is vital for physiological processes in vertebrates. Freshwater (FW) fish live in an inconstant environment, and thus frequently face ambient acid stress. FW fish have to efficiently modulate their acid secretion processes for body fluid acid-base homeostasis during ambient acid challenge; hormonal control plays an important role in such physiological regulation. The hormone cortisol was previously proposed to be associated with acid base regulation in FW fish; however, the underlying mechanism has not been fully described. In the present study, mRNA expression of acid-secreting related transporters and cyp11b (encoding an enzyme involved in cortisol synthesis) in zebrafish embryos was stimulated by treatment with acidic FW (AFW, pH 4.0) for 3 d. Exogenous cortisol treatment (20 mg/L, 3 d) resulted in upregulated expression of transporters related to acid secretion and increased acid secretion function at the organism level in zebrafish embryos. Moreover, cortisol treatment also significantly increased the acid secretion capacity of H(+)-ATPase-rich cells (HRCs) at the cellular level. In loss-of-function experiments, microinjection of glucocorticoid receptor (GR) morpholino (MO) suppressed the expression of acid secreting related transporters, and decreased acid secretion function at both the organism and cellular levels; on the other hand, mineralocorticoid receptor (MR) MO did not induce any effects. Such evidence supports the hypothesized role of cortisol in fish acid-base regulation, and provides new insights into the roles of cortisol; cortisol-GR signaling stimulates zebrafish acid secretion function through transcriptional/translational regulation of the transporters and upregulation of acid secretion capacity in each acid-secreting ionocyte. PMID- 26635617 TI - Effect of Three Different Grip Angles on Physiological Parameters During Laboratory Handcycling Test in Able-Bodied Participants. AB - INTRODUCTION: Handcycling is a relatively new wheelchair sport that has gained increased popularity for people with lower limb disabilities. The aim of this study was to examine the effect of three different grip positions on physical parameters during handcycling in a laboratory setting. METHODS: Twenty one able bodied participants performed three maximum incremental handcycling tests until exhaustion, each with a different grip angle. The angle between the grip and the crank was randomly set at 90 degrees (horizontal), 0 degrees (vertical), or 10 degrees (diagonal). The initial load was 20 W and increased by 20 W each 5 min. In addition, participants performed a 20 s maximum effort. RESULTS: The relative peak functional performance (W/kg), peak heart rate (bpm), associated lactate concentrations (mmol/l) and peak oxygen uptake per kilogram body weight (ml.min( 1).kg(-1)) for the different grip positions during the stage test were: (a) Horizontal: 1.43 +/- 0.21 W/kg, 170.14 +/- 12.81 bpm, 9.54 +/- 1.93 mmol/l, 30.86 +/- 4.57 ml/kg; (b) Vertical: 1.38 +/- 0.20 W/kg, 171.81 +/- 13.87 bpm, 9.91 +/- 2.29 mmol/l, 29.75 +/- 5.13 ml/kg; (c) Diagonal: 1.40 +/- 0.22 W/kg, 169.19 +/- 13.31 bpm, 9.34 +/- 2.36 mmol/l, 29.39 +/- 4.70 ml/kg. Statistically significant (p < 0.05) differences could only be found for lactate concentration between the vertical grip position and the other grips during submaximal handcycling. CONCLUSION: The orientation of three different grip angles made no difference to the peak load achieved during an incremental handcycling test and a 20 s maximum effort. At submaximal load, higher lactate concentrations were found when the vertical grip position was used, suggesting that this position may be less efficient than the alternative diagonal or horizontal grip positions. PMID- 26635618 TI - Protein Kinase A Governs Oxidative Phosphorylation Kinetics and Oxidant Emitting Potential at Complex I. AB - The mitochondrial electron transport system (ETS) is responsible for setting and maintaining both the energy and redox charges throughout the cell. Reversible phosphorylation of mitochondrial proteins, particularly via the soluble adenylyl cyclase (sAC)/cyclic AMP (cAMP)/Protein kinase A (PKA) axis, has recently been revealed as a potential mechanism regulating the ETS. However, the governance of cAMP/PKA signaling and its implications on ETS function are incompletely understood. In contrast to prior reports using exogenous bicarbonate, we provide evidence that endogenous CO2 produced by increased tricarboxylic acid (TCA) cycle flux is insufficient to increase mitochondrial cAMP levels, and that exogenous addition of membrane permeant 8Br-cAMP does not enhance mitochondrial respiratory capacity. We also report important non-specific effects of commonly used inhibitors of sAC which preclude their use in studies of mitochondrial function. In isolated liver mitochondria, inhibition of PKA reduced complex I-, but not complex II-supported respiratory capacity. In permeabilized myofibers, inhibition of PKA lowered both the K m and V max for complex I-supported respiration as well as succinate-supported H2O2 emitting potential. In summary, the data provided here improve our understanding of how mitochondrial cAMP production is regulated, illustrate a need for better tools to examine the impact of sAC activity on mitochondrial biology, and suggest that cAMP/PKA signaling contributes to the governance of electron flow through complex I of the ETS. PMID- 26635619 TI - Salivary Hormones Response to Preparation and Pre-competitive Training of World class Level Athletes. AB - This study aimed to compare the response of salivary hormones of track and field athletes induced by preparation and pre-competitive training periods in an attempt to comment on the physiological effects consistent with the responses of each of the proteins measured. Salivary testosterone, cortisol, alpha-amylase, immunoglobulin A (IgA), chromogranin A, blood creatine kinase activity, and profile of mood state were assessed at rest in 24 world-class level athletes during preparation (3 times in 3 months) and pre-competitive (5 times in 5 weeks) training periods. Total mood disturbance and fatigue perception were reduced, while IgA (+61%) and creatine kinase activity (+43%) increased, and chromogranin A decreased (-27%) during pre-competitive compared to preparation period. A significant increase in salivary testosterone (+9 to +15%) and a decrease in testosterone/cortisol ratio were associated with a progressive reduction in training load during pre-competitive period (P < 0.05). None of the psycho physiological parameters were significantly correlated to training load during the pre-competitive period. Results showed a lower adrenocortical response and autonomic activity, and an improvement of immunity status, in response to the reduction in training load and fatigue, without significant correlations of salivary hormones with training load. Our findings suggest that saliva composition is sensitive to training contents (season period) but could not be related to workload resulting from track and field athletics training. PMID- 26635620 TI - Looking Beyond the Large Scale Effects of Global Change: Local Phenologies Can Result in Critical Heterogeneity in the Pine Processionary Moth. PMID- 26635621 TI - "Smooth Muscle Cell Stiffness Syndrome"-Revisiting the Structural Basis of Arterial Stiffness. AB - In recent decades, the pervasiveness of increased arterial stiffness in patients with cardiovascular disease has become increasingly apparent. Though, this phenomenon has been well documented in humans and animal models of disease for well over a century, there has been surprisingly limited development in a deeper mechanistic understanding of arterial stiffness. Much of the historical literature has focused on changes in extracellular matrix proteins-collagen and elastin. However, extracellular matrix changes alone appear insufficient to consistently account for observed changes in vascular stiffness, which we observed in our studies of aortic stiffness in aging monkeys. This led us to examine novel mechanisms operating at the level of the vascular smooth muscle cell (VSMC)-that include increased cell stiffness and adhesion to extracellular matrix-which that may be interrelated with other mechanisms contributing to arterial stiffness. We introduce these observations as a new concept-the Smooth Muscle Cell Stiffness Syndrome (SMCSS)-within the field of arterial stiffness and posit that stiffening of vascular cells impairs vascular function and may contribute stiffening to the vasculature with aging and cardiovascular disease. Importantly, this review article revisits the structural basis of arterial stiffness in light of these novel findings. Such classification of SMCSS and its contextualization into our current understanding of vascular mechanics may be useful in the development of strategic therapeutics to directly target arterial stiffness. PMID- 26635623 TI - Both Orai1 and TRPC1 are Involved in Excessive Store-Operated Calcium Entry in Striatal Neurons Expressing Mutant Huntingtin Exon 1. AB - It has been previously reported that N-terminus of mutant huntingtin (product of the 1st exon) is sufficient to cause a Huntington's disease (HD) pathological phenotype. In view of recent data suggesting that improper regulation of store operated calcium (SOC) channels is involved in neurodegenerative processes, we investigated influence of expression of the mutant huntingtin N-terminal fragment (Htt138Q-1exon) on SOC entry (SOCE) in mouse neuroblastoma cells (Neuro-2a) and in primary culture of medium spiny neurons (MSNs) isolated from mice. The results show that SOCE in these cells is enhanced upon lentiviral expression of the Htt138Q-1exon. Moreover, we demonstrated that RNAi-mediated knockdown of TRPC1, Orai1, or STIM1 proteins leads to dramatic reduction of abnormal SOCE in both Neuro-2a and MSNs, expressing Htt138Q-1exon. Thus, we concluded that abnormal SOCE in these cells is maintained by both TRPC1- and Orai1-containing channels and required STIM1 for its activation. Furthermore, EVP4593 compound previously tested as a potential anti-HD drug in a Drosophila screening system has proved to be capable of reducing SOCE to the normal level in MSNs expressing the Htt138Q 1exon. PMID- 26635622 TI - Mitochondrial Regulation of the Muscle Microenvironment in Critical Limb Ischemia. AB - Critical limb ischemia (CLI) is the most severe clinical presentation of peripheral arterial disease and manifests as chronic limb pain at rest and/or tissue necrosis. Current clinical interventions are largely ineffective and therapeutic angiogenesis based trials have shown little efficacy, highlighting the dire need for new ideas and novel therapeutic approaches. Despite a decade of research related to skeletal muscle as a determinant of morbidity and mortality outcomes in CLI, very little progress has been made toward an effective therapy aimed directly at the muscle myopathies of this disease. Within the muscle cell, mitochondria are well positioned to modulate the ischemic cellular response, as they are the principal sites of cellular energy production and the major regulators of cellular redox charge and cell death. In this mini review, we update the crucial importance of skeletal muscle to CLI pathology and examine the evolving influence of muscle and endothelial cell mitochondria in the complex ischemic microenvironment. Finally, we discuss the novelty of muscle mitochondria as a therapeutic target for ischemic pathology in the context of the complex co morbidities often associated with CLI. PMID- 26635624 TI - Redox Characterization of Functioning Skeletal Muscle. AB - Skeletal muscle physiology is influenced by the presence of chemically reactive molecules such as reactive oxygen species (ROS). These molecules regulate multiple redox-sensitive signaling pathways that play a critical role in cellular processes including gene expression and protein modification. While ROS have gained much attention for their harmful effects in muscle fatigue and dysfunction, research has also shown ROS to facilitate muscle adaptation after stressors such as physical exercise. This manuscript aims to provide a comprehensive review of the current understanding of redox signaling in skeletal muscle. ROS-induced oxidative stress and its role in the aging process are discussed. Mitochondria have been shown to generate large amounts of ROS during muscular contractions, and thus are susceptible to oxidative stress. ROS can modify proteins located in the mitochondrial membrane leading to cell death and osmotic swelling. ROS also contribute to the necrosis and inflammation of muscle fibers that is associated with muscular diseases including Duchenne muscular dystrophy. It is imperative that future research continues to investigate the exact role of ROS in normal skeletal muscle function as well as muscular dysfunction and disease. PMID- 26635625 TI - Cerium Dioxide Nanoparticle Exposure Improves Microvascular Dysfunction and Reduces Oxidative Stress in Spontaneously Hypertensive Rats. AB - The elevated production of reactive oxygen species (ROS) in the vascular wall is associated with cardiovascular diseases such as hypertension. This increase in oxidative stress contributes to various mechanisms of vascular dysfunction, such as decreased nitric oxide bioavailability. Therefore, anti-oxidants are being researched to decrease the high levels of ROS, which could improve the microvascular dysfunction associated with various cardiovascular diseases. From a therapeutic perspective, cerium dioxide nanoparticles (CeO2 NP) hold great anti oxidant potential, but their in vivo activity is unclear. Due to this potential anti-oxidant action, we hypothesize that injected CeO2 NP would decrease microvascular dysfunction and oxidative stress associated with hypertension. In order to simulate a therapeutic application, spontaneously hypertensive (SH) and Wistar-Kyoto (WKY) rats were intravenously injected with either saline or CeO2 NP (100 MUg suspended in saline). Twenty-four hours post-exposure mesenteric arteriolar reactivity was assessed via intravital microscopy. Endothelium dependent and -independent function was assessed via acetylcholine and sodium nitroprusside. Microvascular oxidative stress was analyzed using fluorescent staining in isolated mesenteric arterioles. Finally, systemic inflammation was examined using a multiplex analysis and venular leukocyte flux was counted. Endothelium-dependent dilation was significantly decreased in the SH rats (29.68 +/- 3.28%, maximal response) and this microvascular dysfunction was significantly improved following CeO2 NP exposure (43.76 +/- 4.33%, maximal response). There was also an increase in oxidative stress in the SH rats, which was abolished following CeO2 NP treatment. These results provided evidence that CeO2 NP act as an anti-oxidant in vivo. There were also changes in the inflammatory profile in the WKY and SH rats. In WKY rats, IL-10 and TNF-alpha were increased following CeO2 NP treatment. Finally, leukocyte flux was increased in the SH rats (34 +/- 4 vs. 17 +/- 3 cells/min in the normotensive controls), but this activation was decreased following exposure (15 +/- 2 vs. 34 +/- 4 cells/min). These results indicated that CeO2 NP may alter the inflammatory response in both SH and WKY rats. Taken together, these results provide evidence that CeO2 NP act as an anti oxidant in vivo and may improve microvascular reactivity in a model of hypertension. PMID- 26635626 TI - Age Differences of Salivary Alpha-Amylase Levels of Basal and Acute Responses to Citric Acid Stimulation Between Chinese Children and Adults. AB - It remains unclear how salivary alpha-amylase (sAA) levels respond to mechanical stimuli in different age groups. In addition, the role played by the sAA gene (AMY1) copy number and protein expression (glycosylated and non-glycosylated) in sAA activity has also been rarely reported. In this study, we analyzed saliva samples collected before and after citric acid stimulation from 47 child and 47 adult Chinese subjects. We observed that adults had higher sAA activity and sAA glycosylated levels (glycosylated sAA amount/total sAA amount) in basal and stimulated saliva when compared with children, while no differences were found in total or glycosylated sAA amount between them. Interestingly, adults showed attenuated sAA activity levels increase over those of children after stimulation. Correlation analysis showed that total sAA amount, glycosylated sAA amount, and AMY1 copy number * total sAA amount were all positively correlated with sAA activity before and after stimulation in both groups. Interestingly, correlation r between sAA levels (glycosylated sAA amount and total sAA amount) and sAA activity decreased after stimulation in children, while adults showed an increase in correlation r. In addition, the correlation r between AMY1 copy number * total sAA amount and sAA activity was higher than that between AMY1 copy number, total sAA amount, and sAA activity, respectively. Taken together, our results suggest that total sAA amount, glycosylated sAA amount, and the positive interaction between AMY1 copy number and total sAA amount are crucial in influencing sAA activity before and after stimulation in children and adults. PMID- 26635628 TI - Kinetic Studies to Elucidate Impaired Metabolism of Triglyceride-rich Lipoproteins in Humans. AB - To develop novel strategies for prevention and treatment of dyslipidemia, it is essential to understand the pathophysiology of dyslipoproteinemia in humans. Lipoprotein metabolism is a complex system in which abnormal concentrations of various lipoprotein particles can result from alterations in their rates of production, conversion, and/or catabolism. Traditional methods that measure plasma lipoprotein concentrations only provide static estimates of lipoprotein metabolism and hence limited mechanistic information. By contrast, the use of tracers labeled with stable isotopes and mathematical modeling, provides us with a powerful tool for probing lipid and lipoprotein kinetics in vivo and furthering our understanding of the pathogenesis of dyslipoproteinemia. PMID- 26635629 TI - Monitoring Fatigue Status with HRV Measures in Elite Athletes: An Avenue Beyond RMSSD? AB - Among the tools proposed to assess the athlete's "fatigue," the analysis of heart rate variability (HRV) provides an indirect evaluation of the settings of autonomic control of heart activity. HRV analysis is performed through assessment of time-domain indices, the square root of the mean of the sum of the squares of differences between adjacent normal R-R intervals (RMSSD) measured during short (5 min) recordings in supine position upon awakening in the morning and particularly the logarithm of RMSSD (LnRMSSD) has been proposed as the most useful resting HRV indicator. However, if RMSSD can help the practitioner to identify a global "fatigue" level, it does not allow discriminating different types of fatigue. Recent results using spectral HRV analysis highlighted firstly that HRV profiles assessed in supine and standing positions are independent and complementary; and secondly that using these postural profiles allows the clustering of distinct sub-categories of "fatigue." Since, cardiovascular control settings are different in standing and lying posture, using the HRV figures of both postures to cluster fatigue state embeds information on the dynamics of control responses. Such, HRV spectral analysis appears more sensitive and enlightening than time-domain HRV indices. The wealthier information provided by this spectral analysis should improve the monitoring of the adaptive training recovery process in athletes. PMID- 26635630 TI - Metabolome-Wide Analysis of Stable Isotope Labeling-Is It Worth the Effort? PMID- 26635627 TI - Obesity-Driven Gut Microbiota Inflammatory Pathways to Metabolic Syndrome. AB - The intimate interplay between immune system, metabolism, and gut microbiota plays an important role in controlling metabolic homeostasis and possible obesity development. Obesity involves impairment of immune response affecting both innate and adaptive immunity. The main factors involved in the relationship of obesity with inflammation have not been completely elucidated. On the other hand, gut microbiota, via innate immune receptors, has emerged as one of the key factors regulating events triggering acute inflammation associated with obesity and metabolic syndrome. Inflammatory disorders lead to several signaling transduction pathways activation, inflammatory cytokine, chemokine production and cell migration, which in turn cause metabolic dysfunction. Inflamed adipose tissue, with increased macrophages infiltration, is associated with impaired preadipocyte development and differentiation to mature adipose cells, leading to ectopic lipid accumulation and insulin resistance. This review focuses on the relationship between obesity and inflammation, which is essential to understand the pathological mechanisms governing metabolic syndrome. PMID- 26635631 TI - New Insights on the Maternal Diet Induced-Hypertension: Potential Role of the Phenotypic Plasticity and Sympathetic-Respiratory Overactivity. AB - Systemic arterial hypertension (SAH) is an important risk factor for cardiovascular disease and affects worldwide population. Current environment including life style coupled with genetic programming have been attributed to the rising incidence of hypertension. Besides, environmental conditions during perinatal development such as maternal malnutrition can program changes in the integration among renal, neural, and endocrine system leading to hypertension. This phenomenon is termed phenotypic plasticity and refers to the adjustment of a phenotype in response to environmental stimuli without genetic change, following a novel or unusual input during development. Human and animal studies indicate that fetal exposure to an adverse maternal environment may alter the renal morphology and physiology that contribute to the development of hypertension. Recently, it has been shown that the maternal protein restriction alter the central control of SAH by a mechanism that include respiratory dysfunction and enhanced sympathetic-respiratory coupling at early life, which may contribute to adult hypertension. This review will address the new insights on the maternal diet induced-hypertension that include the potential role of the phenotypic plasticity, specifically the perinatal protein malnutrition, and sympathetic respiratory overactivity. PMID- 26635633 TI - Methylprednisolone Protects Cardiac Pumping Mechanics from Deteriorating in Lipopolysaccharide-Treated Rats. AB - It has been shown that a prolonged low-dose corticosteroid treatment attenuates the severity of inflammation and the intensity and duration of organ system failure. In the present study, we determined whether low-dose methylprednisolone (a synthetic glucocorticoid) can protect male Wistar rats against cardiac pumping defects caused by lipopolysaccharide-induced chronic inflammation. For the induction of chronic inflammation, a slow-release ALZET osmotic pump was subcutaneously implanted to infuse lipopolysaccharide (1 mg kg(-1) d(-1)) for 2 weeks. The lipopolysaccharide-challenged rats were treated on a daily basis with intraperitoneal injection of methylprednisolone (5 mg kg(-1) d(-1)) for 2 weeks. Under conditions of anesthesia and open chest, we recorded left ventricular (LV) pressure and ascending aortic flow signals to calculate the maximal systolic elastance (E max) and the theoretical maximum flow (Q max), using the elastance resistance model. Physically, E max reflects the contractility of the myocardium as an intact heart, whereas Q max has an inverse relationship with the LV internal resistance. Compared with the sham rats, the cardiodynamic condition was characterized by a decline in E max associated with the increased Q max in the lipopolysaccharide-treated rats. Methylprednisolone therapy increased E max, which suggests that the drug may have protected the contractile status from deteriorating in the inflamed heart. By contrast, methylprednisolone therapy considerably reduced Q max, indicating that the drug may have normalized the LV internal resistance. In parallel, the benefits of methylprednisolone on the LV systolic pumping mechanics were associated with the reduced cardiac levels of negative inotropic molecules such as peroxynitrite, malondialdehyde, and high mobility group box 1 protein. Based on these data, we suggested that low-dose methylprednisolone might prevent lipopolysaccharide-induced decline in cardiac intrinsic contractility and LV internal resistance, possibly through its ability to reduce the aforementioned myocardial depressant substances. However, since our results were obtained in anesthetized open-chest rats, extrapolation to what may occur in conscious intact animals should be done with caution. PMID- 26635632 TI - The Measurement of Reversible Redox Dependent Post-translational Modifications and Their Regulation of Mitochondrial and Skeletal Muscle Function. AB - Mitochondrial oxidative stress is a common feature of skeletal myopathies across multiple conditions; however, the mechanism by which it contributes to skeletal muscle dysfunction remains controversial. Oxidative damage to proteins, lipids, and DNA has received the most attention, yet an important role for reversible redox post-translational modifications (PTMs) in pathophysiology is emerging. The possibility that these PTMs can exert dynamic control of muscle function implicates them as a mechanism contributing to skeletal muscle dysfunction in chronic disease. Herein, we discuss the significance of thiol-based redox dependent modifications to mitochondrial, myofibrillar, and excitation contraction (EC) coupling proteins with an emphasis on how these changes could alter skeletal muscle performance under chronically stressed conditions. A major barrier to a better mechanistic understanding of the role of reversible redox PTMs in muscle function is the technical challenges associated with accurately measuring the changes of site-specific redox PTMs. Here we will critically review current approaches with an emphasis on sample preparation artifacts, quantitation, and specificity. Despite these challenges, the ability to accurately quantify reversible redox PTMs is critical to understanding the mechanisms by which mitochondrial oxidative stress contributes to skeletal muscle dysfunction in chronic diseases. PMID- 26635634 TI - Thermal and Cardiovascular Strain Mitigate the Potential Benefit of Carbohydrate Mouth Rinse During Self-Paced Exercise in the Heat. AB - PURPOSE: To determine whether a carbohydrate mouth rinse can alter self-paced exercise performance independently of a high degree of thermal and cardiovascular strain. METHODS: Eight endurance-trained males performed two 40-km cycling time trials in 35 degrees C, 60% RH while swilling a 20-ml bolus of 6.5% maltodextrin (CHO) or a color- and taste-matched placebo (PLA) every 5 km. Heart rate, power output, rectal temperature (Tre), and mean skin temperature (Tsk) were recorded continuously; cardiac output, oxygen uptake (VO2), mean arterial pressure (MAP), and perceived exertion (RPE) were measured every 10 min. RESULTS: Performance time and mean power output were similar between treatments, averaging 63.9 +/- 3.2 and 64.3 +/- 2.8 min, and 251 +/- 23 and 242 +/- 18 W in CHO and PLA, respectively. Power output, stroke volume, cardiac output, MAP, and VO2 decreased during both trials, increasing slightly or remaining stable during a final 2-km end-spurt. Tre, Tsk, heart rate, and RPE increased throughout exercise similarly with both treatments. Changes in RPE correlated with those in Tre (P < 0.005) and heart rate (P < 0.001). CONCLUSIONS: These findings suggest that carbohydrate mouth rinsing does not improve ~1-h time trial performance in hot-humid conditions, possibly due to a failure in down-regulating RPE, which may be influenced more by severe thermal and cardiovascular strain. PMID- 26635635 TI - Replacement of Asymmetric Synaptic Profiles in the Molecular Layer of Dentate Gyrus Following Cycloheximide in the Pilocarpine Model in Rats. AB - Mossy fiber sprouting is among the best-studied forms of post-lesional synaptic plasticity and is regarded by many as contributory to seizures in both humans and animal models of epilepsy. It is not known whether mossy fiber sprouting increases the number of synapses in the molecular layer or merely replaces lost contacts. Using the pilocarpine (Pilo) model of status epilepticus to induce mossy fiber sprouting, and cycloheximide (CHX) to block this sprouting, we evaluated at the ultrastructural level the number and type of asymmetric synaptic contacts in the molecular layer of the dentate gyrus. As expected, whereas Pilo treated rats had dense silver grain deposits in the inner molecular layer (IML) (reflecting mossy fiber sprouting), pilocarpine + cycloheximide (CHX + Pilo) treated animals did not differ from controls. Both groups of treated rats (Pilo group and CHX + Pilo group) had reduced density of asymmetric synaptic profiles (putative excitatory synaptic contacts), which was greater for CHX-treated animals. For both treated groups, the loss of excitatory synaptic contacts was even greater in the outer molecular layer than in the best-studied IML (in which mossy fiber sprouting occurs). These results indicate that mossy fiber sprouting tends to replace lost synaptic contacts rather than increase the absolute number of contacts. We speculate that the overall result is more consistent with restored rather than with increased excitability. PMID- 26635637 TI - Preventing Compulsory Admission to Psychiatric Inpatient Care: Perceived Coercion, Empowerment, and Self-Reported Mental Health Functioning after 12 Months of Preventive Monitoring. AB - OBJECTIVE: To evaluate the effects of a preventive monitoring program targeted to reduce compulsory rehospitalization and perceived coercion in patients with severe mental disorder. We analyze patient outcomes in terms of perceived coercion, empowerment, and self-reported mental health functioning at 12 months. METHODS: The program consists of individualized psychoeducation, crisis cards and, after discharge from the psychiatric hospital, a 24-month preventive monitoring. In total, 238 psychiatric inpatients who had had compulsory admission(s) during the past 24 months were included in the trial. T1-assessment 12 months after baseline was achieved for 182 patients. RESULTS: Study participants reported lower levels of perceived coercion, negative pressures, and process exclusion, a higher level of optimism, and a lesser degree of distress due to symptoms, interpersonal relations, and social role functioning (significant time effects). However, improvements were not confined to the intervention group, but seen also in the treatment-as-usual group (no significant group or interaction effects). Altered perceptions were linked to older age, shorter illness duration, female sex, non-psychotic disorder, and compulsory hospitalization not due to risk of harm to others. CONCLUSION: Our findings suggest that changes in the subjective perspective were fueled primarily by participation in this study rather than by having received the specific intervention. The study contributes to a better understanding of the interaction between "objective" measures (compulsory readmissions) and patients' perceptions and highlights the need for treatment approaches promoting empowerment in individuals with a history of involuntary psychiatric hospitalizations. PMID- 26635638 TI - Neuropsychological Profiles Correlated with Clinical and Behavioral Impairments in a Sample of Brazilian Children with Attention-Deficit Hyperactivity Disorder. AB - Attention-deficit hyperactivity disorder (ADHD) is a complex neurodevelopmental disorder that implies several-step process, and there is no single test to diagnose both ADHD and associated comorbidities, such as oppositional-defiant disorder (ODD), anxiety disorder, depression, and certain types of learning disabilities. The purpose of the present study was to examine correlations between behavioral and clinical symptoms by administering an extensive neuropsychological battery to a sample of children and adolescents from a developing country. The sample was divided into three groups: non-ADHD, ADHD-non comorbid, and ADHD + comorbidity. A full neuropsychological battery and clinical assessment found that 105 children met DSM-5 criteria, of whom 46.6% had the predominantly inattentive presentation, 37.3% had combined presentation, and 16% were predominantly hyperactive/impulsive presentation. The internal correlation between neuropsychological tests did not reach statistical significance in the comparison between ADHD and non-ADHD cases (p < 0.17). Clinical ADHD cases, including both + comorbidity and non-comorbid groups, performed substantially worse on continuous performance test (CPT), working memory. Comparing ADHD-non comorbid and ADHD + comorbidity groups, the latter did significantly worse on inhibitory control, time processing, and the level of perseveration response on CPT indexes, as well as on working memory performance and child behavior checklist (CBCL) tests particularly the CBCL-deficient emotional self-regulation test in the ADHD + comorbidity group. Children diagnosed as ODD or with conduct disorder showed close correlations between clinical CBCL profiles and externalized symptoms. Our findings suggest that ADHD + comorbidity and ADHD non comorbid cases may be differentiated by a number of neuropsychological measures, such as processing speed, inhibitory control, and working memory, that may reflect different levels of involvement of the hot and cool executive domains, which are more impaired in cases of severe symptomatic-externalized behavior and emotional regulation problems. Therefore, profiles based on clinical and behavioral findings can help clinicians select better strategies for detecting neuropsychological impairment in Brazilian children with ADHD. PMID- 26635636 TI - Phospholipase C-beta1 Hypofunction in the Pathogenesis of Schizophrenia. AB - Schizophrenia is a mental disorder that is characterized by various abnormal symptoms. Previous studies indicate decreased expression of phospholipase C-beta1 (PLC-beta1) in the brains of patients with schizophrenia. PLC-beta1-null (PLC beta1(-/-)) mice exhibit multiple endophenotypes of schizophrenia. Furthermore, a study of PLC-beta1 knockdown in the medial prefrontal cortex of mice has shown a specific behavioral deficit, impaired working memory. These results support the notion that disruption of PLC-beta1-linked signaling in the brain is strongly involved in the pathogenesis of schizophrenia. In this review, we broadly investigate recent studies regarding schizophrenia-related behaviors as well as their various clinical and biological correlates in PLC-beta1(-/-) and knockdown mouse models. This will provide a better understanding of the pathological relevance of the altered expression of PLC-beta1 in the brains of patients with schizophrenia. Evidence accumulated will shed light on future in-depth studies, possibly in human subjects. PMID- 26635639 TI - Causality in Psychiatry: A Hybrid Symptom Network Construct Model. AB - Causality or etiology in psychiatry is marked by standard biomedical, reductionistic models (symptoms reflect the construct involved) that inform approaches to nosology, or classification, such as in the DSM-5 [Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition; (1)]. However, network approaches to symptom interaction [i.e., symptoms are formative of the construct; e.g., (2), for posttraumatic stress disorder (PTSD)] are being developed that speak to bottom-up processes in mental disorder, in contrast to the typical top down psychological construct approach. The present article presents a hybrid top down, bottom-up model of the relationship between symptoms and mental disorder, viewing symptom expression and their causal complex as a reciprocally dynamic system with multiple levels, from lower-order symptoms in interaction to higher order constructs affecting them. The hybrid model hinges on good understanding of systems theory in which it is embedded, so that the article reviews in depth non linear dynamical systems theory (NLDST). The article applies the concept of emergent circular causality (3) to symptom development, as well. Conclusions consider that symptoms vary over several dimensions, including: subjectivity; objectivity; conscious motivation effort; and unconscious influences, and the degree to which individual (e.g., meaning) and universal (e.g., causal) processes are involved. The opposition between science and skepticism is a complex one that the article addresses in final comments. PMID- 26635641 TI - Beyond Scientism and Skepticism: An Integrative Approach to Global Mental Health. AB - The global burden of disorders has shifted from infectious disease to non communicable diseases, including neuropsychiatric disorders. Whereas infectious disease can sometimes be combated by targeting single causal mechanisms, such as prevention of contact-spread illness by handwashing, in the case of mental disorders multiple causal mechanisms are typically relevant. The emergent field of global mental health has emphasized the magnitude of the treatment gap, particularly in the low- and middle-income world and has paid particular attention to upstream causal factors, for example, poverty, inequality, and gender discrimination in the pathogenesis of mental disorders. However, this field has also been criticized for relying erroneously on Western paradigms of mental illness, which may not be relevant or appropriate to the low- and middle income context. Here, it is important to steer a path between scientism and skepticism. Scientism regards mental disorders as essential categories, and takes a covering law approach to causality; skepticism regards mental disorders as merely social constructions and emphasizes the role of political power in causal relations. We propose an integrative model that emphasizes the contribution of a broad range of causal mechanisms operating at biological and societal levels to mental disorders and the consequent importance of broad spectrum and multipronged approaches to intervention. PMID- 26635642 TI - Use of Cognitive Behavioral Therapy and Token Economy to Alleviate Dysfunctional Behavior in Children with Attention-Deficit Hyperactivity Disorder. AB - Medication has proved highly efficacious as a means of alleviating general symptoms of attention-deficit hyperactivity disorder (ADHD). However, many patients remain functionally impaired by inappropriate behavior. The present study analyzed the use of cognitive behavioral therapy (CBT) with the Token Economy (TE) technique to alleviate problem behavior for 25 participants with ADHD, all children (19 boys, mean age 10.11) on long-term methylphenidate medication, who were given 20 CBT sessions with 10 weeks of TE introduced as of session 5. Their ten most acute problem behaviors were selected and written records kept. On weekdays, parents recorded each inappropriate behavior and provided a suitable model for their actions. At weekly sessions, problem behaviors were counted and incident-free participants rewarded with a token. To analyze improvement (less frequent problem behavior), a list of 11 behavioral categories was rated: inattention, impulsivity, hyperactivity, disorganization, disobeying rules and routines, poor self-care, verbal/physical aggression, low frustration tolerance, compulsive behavior, antisocial behavior, lacking in initiative and distraction. Two CBT specialists categorized behaviors and an ADHD specialist ruled on discrepancies. Statistical analyses used were Generalized Estimating Equations with Poisson distribution and autoregressive order correlation structure. In the course of the sessions, problematic behaviors decreased significantly in seven categories: impulsiveness, hyperactivity, disorganization, disobeying rules and routine, poor self-care, low frustration tolerance, compulsive behaviors, and antisocial behaviors. Caregiver attitudes to children's inappropriate behavior were discussed and reshaped. As functional improvement was observed on applying TE for 10 weeks, this type of intervention may be useful as an auxiliary strategy combined with medication. PMID- 26635640 TI - Sex Hormones Regulate Cytoskeletal Proteins Involved in Brain Plasticity. AB - In the brain of female mammals, including humans, a number of physiological and behavioral changes occur as a result of sex hormone exposure. Estradiol and progesterone regulate several brain functions, including learning and memory. Sex hormones contribute to shape the central nervous system by modulating the formation and turnover of the interconnections between neurons as well as controlling the function of glial cells. The dynamics of neuron and glial cells morphology depends on the cytoskeleton and its associated proteins. Cytoskeletal proteins are necessary to form neuronal dendrites and dendritic spines, as well as to regulate the diverse functions in astrocytes. The expression pattern of proteins, such as actin, microtubule-associated protein 2, Tau, and glial fibrillary acidic protein, changes in a tissue-specific manner in the brain, particularly when variations in sex hormone levels occur during the estrous or menstrual cycles or pregnancy. Here, we review the changes in structure and organization of neurons and glial cells that require the participation of cytoskeletal proteins whose expression and activity are regulated by estradiol and progesterone. PMID- 26635643 TI - Why the Diagnosis of Attention Deficit Hyperactivity Disorder Matters. AB - BACKGROUND: Attention Deficit Hyperactivity disorder (ADHD) is one of the most common and challenging childhood neurobehavioral disorders. ADHD is known to negatively impact children, their families, and their community. About one-third to one-half of patients with ADHD will have persistent symptoms into adulthood. The prevalence in the United States is estimated at 5-11%, representing 6.4 million children nationwide. The variability in the prevalence of ADHD worldwide and within the US may be due to the wide range of factors that affect accurate assessment of children and youth. Because of these obstacles to assessment, ADHD is under-diagnosed, misdiagnosed, and undertreated. OBJECTIVES: We examined factors associated with making and receiving the diagnosis of ADHD. We sought to review the consequences of a lack of diagnosis and treatment for ADHD on children's and adolescent's lives and how their families and the community may be involved in these consequences. METHODS: We reviewed scientific articles looking for factors that impact the identification and diagnosis of ADHD and articles that demonstrate naturalistic outcomes of diagnosis and treatment. The data bases PubMed and Google scholar were searched from the year 1995 to 2015 using the search terms "ADHD, diagnosis, outcomes." We then reviewed abstracts and reference lists within those articles to rule out or rule in these or other articles. RESULTS: Multiple factors have significant impact in the identification and diagnosis of ADHD including parents, healthcare providers, teachers, and aspects of the environment. Only a few studies detailed the impact of not diagnosing ADHD, with unclear consequences independent of treatment. A more significant number of studies have examined the impact of untreated ADHD. The experience around receiving a diagnosis described by individuals with ADHD provides some additional insights. CONCLUSION: ADHD diagnosis is influenced by perceptions of many different members of a child's community. A lack of clear understanding of ADHD and the importance of its diagnosis and treatment still exists among many members of the community including parents, teachers, and healthcare providers. More basic and clinical research will improve methods of diagnosis and information dissemination. Even before further advancements in science, strong partnerships between clinicians and patients with ADHD may be the best way to reduce the negative impacts of this disorder. PMID- 26635644 TI - Grammatical Class Effects Across Impaired Child and Adult Populations. AB - The aims of this study are to compare quantitative and qualitative differences for noun/verb retrieval across language-impaired groups, examine naming errors with reference to psycholinguistic models of word processing, and shed light on the nature of the naming deficit as well as determine relevant group commonalities and differences. This includes an attempt to establish whether error types differentiate language-impaired children from adults, to determine effects of psycholinguistic variables on naming accuracies, and to link the results to genetic mechanisms and/or neural circuitry in the brain. A total of 89 (language-)impaired participants took part in this report: 24 adults with acquired aphasia, 20 adults with schizophrenia-spectrum disorder, 31 adults with relapsing-remitting multiple sclerosis, and 14 children with specific language impairment. The results of simultaneous multiple regression analyses for the errors in verb naming compared to the psycholinguistic variables for all language impaired groups are reported and discussed in relation to models of lexical processing. This discussion will lead to considerations of genetic and/or neurobiological underpinnings: Presence of the noun-verb dissociation in focal and non-focal brain impairment make localization theories redundant, but support for wider neural network involvement.The patterns reported cannot be reduced to any one level of language processing, suggesting multiple interactions at different levels (e.g., receptive vs. expressive language abilities).Semantic conceptual properties constrain syntactic properties with implications for phonological word form retrieval.Competition needs to be resolved at both conceptual and phonological levels of representation. Moreover, this study may provide a cross-pathological baseline that can be probed further with respect to recent suggestions concerning a reconsideration of open- vs. closed-class items, according to which verbs may actually fall into the latter rather than the standardly received former class. PMID- 26635645 TI - The Relationship Between Specific Pavlovian Instrumental Transfer and Instrumental Reward Probability. AB - Goal-directed behavior is influenced by environmental cues: in particular, cues associated with a reward can bias action choice toward actions directed to that same reward. This effect is studied experimentally as specific Pavlovian instrumental transfer (specific PIT). We have investigated the hypothesis that cues associated to an outcome elicit specific PIT by rising the estimates of reward probability of actions associated to that same outcome. In other words, cues reduce the uncertainty on the efficacy of instrumental actions. We used a human PIT experimental paradigm to test the effects of two different instrumental contingencies: one group of participants had a 33% chance of being rewarded for each button press, while another had a 100% chance. The group trained with 33% reward probability showed a stronger PIT effect than the 100% group, in line with the hypothesis that Pavlovian cues linked to an outcome work by reducing the uncertainty of receiving it. The 100% group also showed a significant specific PIT effect, highlighting additional factors that could contribute to specific PIT beyond the instrumental training contingency. We hypothesize that the uncertainty about reward delivery due to testing in extinction might be one of these factors. These results add knowledge on how goal-directed behavior is influenced by the presence of environmental cues associated with a reward: such influence depends on the probability that we have to reach a reward, namely when there is less chance of getting a reward we are more influenced by cues associated with it, and vice versa. PMID- 26635646 TI - Attitudinal Change in Elderly Citizens Toward Social Robots: The Role of Personality Traits and Beliefs About Robot Functionality. AB - Attitudes toward robots influence the tendency to accept or reject robotic devices. Thus it is important to investigate whether and how attitudes toward robots can change. In this pilot study we investigate attitudinal changes in elderly citizens toward a tele-operated robot in relation to three parameters: (i) the information provided about robot functionality, (ii) the number of encounters, (iii) personality type. Fourteen elderly residents at a rehabilitation center participated. Pre-encounter attitudes toward robots, anthropomorphic thinking, and personality were assessed. Thereafter the participants interacted with a tele-operated robot (Telenoid) during their lunch (c. 30 min.) for up to 3 days. Half of the participants were informed that the robot was tele-operated (IC) whilst the other half were naive to its functioning (UC). Post-encounter assessments of attitudes toward robots and anthropomorphic thinking were undertaken to assess change. Attitudes toward robots were assessed with a new generic 35-items questionnaire (attitudes toward social robots scale: ASOR-5), offering a differentiated conceptualization of the conditions for social interaction. There was no significant difference between the IC and UC groups in attitude change toward robots though trends were observed. Personality was correlated with some tendencies for attitude changes; Extraversion correlated with positive attitude changes to intimate-personal relatedness with the robot (r = 0.619) and to psychological relatedness (r = 0.581) whilst Neuroticism correlated negatively (r = -0.582) with mental relatedness with the robot. The results tentatively suggest that neither information about functionality nor direct repeated encounters are pivotal in changing attitudes toward robots in elderly citizens. This may reflect a cognitive congruence bias where the robot is experienced in congruence with initial attitudes, or it may support action-based explanations of cognitive dissonance reductions, given that robots, unlike computers, are not yet perceived as action targets. Specific personality traits may be indicators of attitude change relating to specific domains of social interaction. Implications and future directions are discussed. PMID- 26635647 TI - Editorial: Using Noise to Characterize Vision. PMID- 26635648 TI - Why More Psychological Therapy Would Cost Nothing. PMID- 26635649 TI - New Structural Patterns in Moribund Grammar: Case Marking in Heritage German. AB - Research treats divergences between monolingual and heritage grammars in terms of performance-'L1 attrition,' e.g., lexical retrieval-or competence-'incomplete acquisition', e.g., lack of overt tense markers (e.g., Polinsky, 1995; Sorace, 2004; Montrul, 2008; Schmid, 2010). One classic difference between monolingual and Heritage German is reduction in morphological case in the latter, especially loss of dative marking. Our evidence from several Heritage German varieties suggests that speakers have not merely lost case, but rather developed innovative structures to mark it. More specifically, Heritage German speakers produce dative forms in line with established patterns of Differential Object Marking (Bossong, 1985, 1991; Aissen, 2003), suggesting a reallocated mapping of case. We take this as evidence for innovative reanalysis in heritage grammars (Putnam and Sanchez, 2013). Following Kamp and Reyle (1993) and Wechsler (2011, 2014), the dative adopts a more indexical discourse function, forging a tighter connection between morphosyntax and semantic properties. Moribund grammars deploy linguistic resources in novel ways, a finding which can help move us beyond simple narratives of 'attrition' and 'incomplete acquisition.' PMID- 26635650 TI - The Interaction of Morphological and Stereotypical Gender Information in Russian. AB - Previous research, for example in English, French, German, and Spanish, has investigated the interplay between grammatical gender information and stereotype gender information (e.g., that secretaries are usually female, in many cultures), in the interpretation of both singular noun phrases (the secretary) and plural nouns phrases, particularly so-called generic masculines-nouns that have masculine grammatical gender but that should be able to refer to both groups of men and mixed groups of men and women. Since the studies have been conducted in cultures with broadly similar stereotypes, the effects generally reflect differences in the grammatical systems of the languages. Russian has a more complex grammatical gender system than the languages previously studied, and, unlike those languages frequently presents examples in which grammatical gender is marked on the predicate (in an inflection on the verb). In this study we collected stereotype norms for 160 role names in Russian, providing a useful resource for further work in this language. We also conducted a reading time study examining the interaction of grammatical and stereotype gender information in the interpretation of both Russian singular noun phrases, and plurals that were (potentially) generic masculines. Our results show that, although both types of gender information are used, when available, the effects of grammatical marking on the predicate are not as strong as those of such marking on subject noun phrases. PMID- 26635651 TI - The Multilingual CID-5: A New Tool to Study the Perception of Communicative Interactions in Different Languages. AB - The investigation of the ability to perceive, recognize, and judge upon social intentions, such as communicative intentions, on the basis of body motion is a growing research area. Cross-cultural differences in ability to perceive and interpret biological motion, however, have been poorly investigated so far. Progress in this domain strongly depends on the availability of suitable stimulus material. In the present method paper, we describe the multilingual CID-5, an extension of the CID-5 database, allowing for the investigation of how non conventional communicative gestures are classified and identified by speakers of different languages. The CID-5 database contains 14 communicative interactions and 7 non-communicative actions performed by couples of agents and presented as point-light displays. For each action, the database provides movie files with the point-light animation, text files with the 3-D spatial coordinates of the point lights, and five different response alternatives. In the multilingual CID-5 the alternatives were translated into seven languages (Chinese, Dutch, English, French, German, Italian, and Polish). Preliminary data collected to assess the recognizability of the actions in the different languages suggest that, for most of the action stimuli, information presented in point-light displays is sufficient for the distinctive classification of the action as communicative vs. individual, as well as for identification of the specific communicative gesture performed by the actor in all the available languages. PMID- 26635652 TI - Information Use Differences in Hot and Cold Risk Processing: When Does Information About Probability Count in the Columbia Card Task? AB - OBJECTIVE: This paper aims to provide insight into information processing differences between hot and cold risk taking decision tasks within a single domain. Decision theory defines risky situations using at least three parameters: outcome one (often a gain) with its probability and outcome two (often a loss) with a complementary probability. Although a rational agent should consider all of the parameters, s/he could potentially narrow their focus to only some of them, particularly when explicit Type 2 processes do not have the resources to override implicit Type 1 processes. Here we investigate differences in risky situation parameters' influence on hot and cold decisions. Although previous studies show lower information use in hot than in cold processes, they do not provide decision weight changes and therefore do not explain whether this difference results from worse concentration on each parameter of a risky situation (probability, gain amount, and loss amount) or from ignoring some parameters. METHODS: Two studies were conducted, with participants performing the Columbia Card Task (CCT) in either its Cold or Hot version. In the first study, participants also performed the Cognitive Reflection Test (CRT) to monitor their ability to override Type 1 processing cues (implicit processes) with Type 2 explicit processes. Because hypothesis testing required comparison of the relative importance of risky situation decision weights (gain, loss, probability), we developed a novel way of measuring information use in the CCT by employing a conjoint analysis methodology. RESULTS: Across the two studies, results indicated that in the CCT Cold condition decision makers concentrate on each information type (gain, loss, probability), but in the CCT Hot condition they concentrate mostly on a single parameter: probability of gain/loss. We also show that an individual's CRT score correlates with information use propensity in cold but not hot tasks. Thus, the affective dimension of hot tasks inhibits correct information processing, probably because it is difficult to engage Type 2 processes in such circumstances. Individuals' Type 2 processing abilities (measured by the CRT) assist greater use of information in cold tasks but do not help in hot tasks. PMID- 26635653 TI - The Depression Schema: How Labels, Features, and Causal Explanations Affect Lay Conceptions of Depression. AB - Depression is a common clinical disorder characterized by a complex web of psychological, behavioral, and neurological causes and symptoms. Here we investigate everyday beliefs and attitudes about depression, as well as the factors that shape the depression schemas people hold. In each of three studies, participants read about a person experiencing several symptoms of depression and answered questions about their conception of the disorder. In some cases the symptoms were presented in isolation while in other cases the symptoms were presented with a diagnostic label and/or descriptions of its possible causes (e.g., genes versus personal experience). Results indicated that beliefs and attitudes toward depression were largely shaped by individual difference factors (e.g., personal experience, political ideology) and that the experimental manipulations primarily impacted attributions of responsibility and suggestions for a course of treatment. These findings represent an important advance in our understanding of the factors that influence the folk psychiatry of depression and help inform theories of schema formation for abstract and complex domains. PMID- 26635654 TI - People's Financial Choice Depends on their Previous Task Success or Failure. AB - Existing knowledge about the impact of the experience prior to financial choices has been limited almost exclusively to single risky choices. Moreover, the results obtained in these studies have not been entirely consistent. For example, some studies suggested that the experience of success makes people more willing to take a risk, while other studies led to the opposite conclusions. The results of the two experimental studies presented in this paper provide evidence for the hypothesis that the experience of success or failure influences people's financial choices, but the effect of the success or failure depends on the type of task (financial and non-financial) preceding a financial decision. The experience of success in financial tasks increased participants' tendency to invest and make risky investment choices, while it also made them less prone to save. On the other hand, the experience of failure heightened the amount of money that participants decided to save, and lowered their tendency to invest and make risky investment choices. However, the effects of the experience of success or failure in non-financial tasks were exactly the opposite. The presented studies indicated the role of the specific circumstances in which the individual gains the experience as a possible way to explain the discrepancies in the results of studies on the relationship between the experience prior to financial choice with a tendency to take risks. PMID- 26635656 TI - Being Mad in Early Modern England. AB - It has become almost a rule that the birth of scientific psychiatry and what we today term clinical psychology took place in the short period between the last decade of the XVIII century and the 1820s. Everything that happened before that period-every description, diagnosis, and therapy-has been considered "pre scientific," outdated, in a way worthless. In this paper, however, I am providing the argument that, first, the roots of contemporary psychiatry reach at least to England of the early modern period, and that, second, it may still turn out that in the field of mental health care historical continuities are more numerous and persistent than discontinuities. Thus, I briefly review the most important surviving documents about the treatment of mental disorders in England of Elizabethan and Jacobian period, organizing the argument around the well-known markers: diagnostics and etiology, therapy, organization of the asylum, the public image of the mentally ill. PMID- 26635655 TI - Filling Predictable and Unpredictable Gaps, with and without Similarity-Based Interference: Evidence for LIFG Effects of Dependency Processing. AB - One of the most replicated findings in neurolinguistic literature on syntax is the increase of hemodynamic activity in the left inferior frontal gyrus (LIFG) in response to object relative (OR) clauses compared to subject relative clauses. However, behavioral studies have shown that ORs are primarily only costly when similarity-based interference is involved and recently, Leiken and Pylkkanen (2014) showed with magnetoencephalography (MEG) that an LIFG increase at an OR gap is also dependent on such interference. However, since ORs always involve a cue indicating an upcoming dependency formation, OR dependencies could be processed already prior to the gap-site and thus show no sheer dependency effects at the gap itself. To investigate the role of gap predictability in LIFG dependency effects, this MEG study compared ORs to verb phrase ellipsis (VPE), which was used as an example of a non-predictable dependency. Additionally, we explored LIFG sensitivity to filler-gap order by including right node raising structures, in which the order of filler and gap is reverse to that of ORs and VPE. Half of the stimuli invoked similarity-based interference and half did not. Our results demonstrate that LIFG effects of dependency can be elicited regardless of whether the dependency is predictable, the stimulus materials evoke similarity-based interference, or the filler precedes the gap. Thus, contrary to our own prior data, the current findings suggest a highly general role for the LIFG in dependency interpretation that is not limited to environments involving similarity-based interference. Additionally, the millisecond time-resolution of MEG allowed for a detailed characterization of the temporal profiles of LIFG dependency effects across our three constructions, revealing that the timing of these effects is somewhat construction-specific. PMID- 26635657 TI - 'Forget me (not)?' - Remembering Forget-Items Versus Un-Cued Items in Directed Forgetting. AB - Humans need to be able to selectively control their memories. This capability is often investigated in directed forgetting (DF) paradigms. In item-method DF, individual items are presented and each is followed by either a forget- or remember-instruction. On a surprise test of all items, memory is then worse for to-be-forgotten items (TBF) compared to to-be-remembered items (TBR). This is thought to result mainly from selective rehearsal of TBR, although inhibitory mechanisms also appear to be recruited by this paradigm. Here, we investigate whether the mnemonic consequences of a forget instruction differ from the ones of incidental encoding, where items are presented without a specific memory instruction. Four experiments were conducted where un-cued items (UI) were interspersed and recognition performance was compared between TBR, TBF, and UI stimuli. Accuracy was encouraged via a performance-dependent monetary bonus. Experiments varied the number of items and their presentation speed and used either letter-cues or symbolic cues. Across all experiments, including perceptually fully counterbalanced variants, memory accuracy for TBF was reduced compared to TBR, but better than for UI. Moreover, participants made consistently fewer false alarms and used a very conservative response criterion when responding to TBF stimuli. Thus, the F-cue results in active processing and reduces false alarm rate, but this does not impair recognition memory beyond an un-cued baseline condition, where only incidental encoding occurs. Theoretical implications of these findings are discussed. PMID- 26635658 TI - Attaining Automaticity in the Visual Numerosity Task is Not Automatic. AB - This experiment is a replication of experiments reported by Lassaline and Logan (1993) using the visual numerosity task. The aim was to replicate the transition from controlled to automatic processing reported by Lassaline and Logan (1993), and to examine the extent to which this result, reported with average group results, can be observed in the results of individuals within a group. The group results in this experiment did replicate those reported by Lassaline and Logan (1993); however, one half of the sample did not attain automaticity with the task, and one-third did not exhibit a transition from controlled to automatic processing. These results raise questions about the pervasiveness of automaticity, and the interpretation of group means when examining cognitive processes. PMID- 26635660 TI - Backward- and Forward-Looking Potential of Anaphors. AB - Personal pronouns and demonstratives contribute differently to the encoding of information in the mental model and they serve distinct backward- and forward looking functions. While (unstressed) personal pronouns are the default means to indicate coreference with the most prominent discourse entity (backward-looking function) and typically mark the maintenance of the current topic, demonstratives are used to refer to a less prominent entity and serve the additional forward looking function of signaling a possible topic shift. In Experiment 1, we present an ERP study that examines the time course of processing personal and d-pronouns in German (er vs. der) and assesses the impact of two prominence features of the antecedent, thematic role and sentential position, as well as neurophysiological correlates of backward- and forward-looking functions of referential expressions. We tested the comprehension of personal and d-pronouns following context sentences containing two potential antecedents. In addition to the factor pronoun type (er vs. der), we varied the verb type (active accusative verbs vs. dative experiencer verbs) and the thematic role order (canonical vs. non-canonical) in the context sentences to vary the antecedent's prominence. Time-locked to pronoun onset, the ERPs revealed a general biphasic N400-Late Positivity for d-pronouns over personal pronouns with further subtle interactions of the prominence-lending cues in the early time window. The findings indicate that the calculation of the referential candidates' prominence (backward-looking function) is guided by thematic role and positional information. Thematic role information, in combination with initial position, thus represents a central predictor during referential processing. Coreference with a less prominent entity (assumed for d pronouns) results in processing costs (N400). The additional topic shift signaled by d-pronouns (forward-looking function) results in attentional reorienting (Late Positivity). This is further supported by Experiment 2, a story continuation study, which showed that personal pronouns trigger topic maintenance, while d pronouns yield topic shifts. PMID- 26635659 TI - Unexpected Acceptance? Patients with Social Anxiety Disorder Manifest their Social Expectancy in ERPs During Social Feedback Processing. AB - Previous studies on social anxiety have demonstrated negative-expectancy bias in social contexts. In this study, we used a paradigm that employed self-relevant positive or negative social feedback, in order to test whether this negative expectancy manifests in event-related potentials (ERPs) during social evaluation among socially anxious individuals. Behavioral data revealed that individuals with social anxiety disorder (SAD) showed more negative expectancy of peer acceptance both in the experiment and in daily life than did the healthy control participants. Regarding ERP results, we found a overally larger P2 for positive social feedback and also a group main effect, such that the P2 was smaller in SAD group. SAD participants demonstrated a larger feedback-related negativity (FRN) to positive feedback than to negative feedback. In addition, SAD participants showed a more positive DeltaFRN (DeltaFRN = negative - positive). Furthermore, acceptance expectancy in daily life correlated negatively with DeltaFRN amplitude, while the Interaction Anxiousness Scale (IAS) score correlated positively with the DeltaFRN amplitude. Finally, the acceptance expectancy in daily life fully mediated the relationship between the IAS and DeltaFRN. These results indicated that both groups could differentiate between positive and negative social feedback in the early stage of social feedback processing (reflected on the P2). However, the SAD group exhibited a larger FRN to positive social feedback than to negative social feedback, demonstrating their dysfunction in the late stage of social feedback processing. In our opinion, such dysfunction is due to their greater negative social feedback expectancy. PMID- 26635661 TI - The Future of Action Video Games in Psychological Research and Application. PMID- 26635662 TI - Adjustment to Subtle Time Constraints and Power Law Learning in Rapid Serial Visual Presentation. AB - We investigated whether attention could be modulated through the implicit learning of temporal information in a rapid serial visual presentation (RSVP) task. Participants identified two target letters among numeral distractors. The stimulus-onset asynchrony immediately following the first target (SOA1) varied at three levels (70, 98, and 126 ms) randomly between trials or fixed within blocks of trials. Practice over 3 consecutive days resulted in a continuous improvement in the identification rate for both targets and attenuation of the attentional blink (AB), a decrement in target (T2) identification when presented 200-400 ms after another target (T1). Blocked SOA1s led to a faster rate of improvement in RSVP performance and more target order reversals relative to random SOA1s, suggesting that the implicit learning of SOA1 positively affected performance. The results also reveal "power law" learning curves for individual target identification as well as the reduction in the AB decrement. These learning curves reflect the spontaneous emergence of skill through subtle attentional modulations rather than general attentional distribution. Together, the results indicate that implicit temporal learning could improve high level and rapid cognitive processing and highlights the sensitivity and adaptability of the attentional system to subtle constraints in stimulus timing. PMID- 26635664 TI - The Fractionalization and Anthropocentric View of Comparative Psychology. Commentary: A Crisis in Comparative Psychology: Where Have All the Undergraduates Gone? PMID- 26635663 TI - Those are Your Legs: The Effect of Visuo-Spatial Viewpoint on Visuo-Tactile Integration and Body Ownership. AB - Experiencing a body part as one's own, i.e., body ownership, depends on the integration of multisensory bodily signals (including visual, tactile, and proprioceptive information) with the visual top-down signals from peripersonal space. Although it has been shown that the visuo-spatial viewpoint from where the body is seen is an important visual top-down factor for body ownership, different studies have reported diverging results. Furthermore, the role of visuo-spatial viewpoint (sometime also called first-person perspective) has only been studied for hands or the whole body, but not for the lower limbs. We thus investigated whether and how leg visuo-tactile integration and leg ownership depended on the visuo-spatial viewpoint from which the legs were seen and the anatomical similarity of the visual leg stimuli. Using a virtual leg illusion, we tested the strength of visuo-tactile integration of leg stimuli using the crossmodal congruency effect (CCE) as well as the subjective sense of leg ownership (assessed by a questionnaire). Fifteen participants viewed virtual legs or non corporeal control objects, presented either from their habitual first-person viewpoint or from a viewpoint that was rotated by 90 degrees (third-person viewpoint), while applying visuo-tactile stroking between the participants legs and the virtual legs shown on a head-mounted display. The data show that the first-person visuo-spatial viewpoint significantly boosts the visuo-tactile integration as well as the sense of leg ownership. Moreover, the viewpoint dependent increment of the visuo-tactile integration was only found in the conditions when participants viewed the virtual legs (absent for control objects). These results confirm the importance of first person visuo-spatial viewpoint for the integration of visuo-tactile stimuli and extend findings from the upper extremity and the trunk to visuo-tactile integration and ownership for the legs. PMID- 26635665 TI - The Role of Affect Spin in the Relationships between Proactive Personality, Career Indecision, and Career Maturity. AB - This study attempted to investigate the influence of proactive personality on career indecision and career maturity, and to examine the moderating effects of affect spin. The author administered proactive personality, career indecision, and career maturity scales to 70 college students. Affect spin was calculated using the day reconstruction method, wherein participants evaluated their affective experiences by using 20 affective terms at the same time each day for 21 consecutive days. Hierarchical regression analyses showed that proactive personality significantly predicted career indecision and career maturity, even after controlling for valence and activation variability, neuroticism, age, and gender. Furthermore, affect spin moderated the associations of proactive personality with career indecision and maturity. The theoretical and practical implications of the moderating effects of affect spin are discussed. PMID- 26635666 TI - Appetitive Aggression and Adverse Childhood Experiences Shape Violent Behavior in Females Formerly Associated with Combat. AB - This study investigated the impact of violent experiences during childhood, posttraumatic stress disorder (PTSD) and appetitive aggression on everyday violent behavior in Burundian females with varying participation in war. Moreover, group differences in trauma-related and aggression variables were expected. Appetitive aggression describes the perception of violence perpetration as fascinating and appealing and is a common phenomenon in former combatants. Semi-structured interviews were conducted with 158 females, either former combatants, supporters of armed forces or civilians during the civil war in Burundi. The PTSD Symptom Scale Interview was used to assess PTSD symptom severity, the Appetitive Aggression Scale to measure appetitive aggression and the Domestic and Community Violence Checklist to assess both childhood maltreatment and recent aggressive behavior. Former combatants had experienced more traumatic events, perpetrated more violence and reported higher levels of appetitive aggression than supporters and civilians. They also suffered more severely from PTSD symptoms than civilians but not than supporters. The groups did not differ regarding childhood maltreatment. Both appetitive aggression and childhood violence predicted ongoing aggressive behavior, whereas the latter outperformed PTSD symptom severity. These findings support current research showing that adverse childhood experiences and a positive attitude toward aggression serve as the basis for aggressive behavior and promote an ongoing cycle of violence in post-conflict regions. Female members of armed groups are in need of demobilization procedures including trauma-related care and interventions addressing appetitive aggression. PMID- 26635667 TI - Editorial: Neuroimaging and Neuropsychology of Meditation States. PMID- 26635668 TI - Editorial: Inner Experiences: Theory, Measurement, Frequency, Content, and Functions. PMID- 26635669 TI - Enhanced Memory for both Threat and Neutral Information Under Conditions of Intergroup Threat. AB - Few studies have examined the effect of intergroup threat on cognitive outcomes such as memory. Different theoretical perspectives can inform how intergroup threat should affect memory for threat-relevant and neutral information, such as the mood-congruency approach, Yerkes-Dodson law, Easterbrook's theory, and also evolutionary perspectives. To test among these, we conducted two experiments to examine how exposure to intergroup threats affected memory compared to control conditions. In study 1, we manipulated symbolic threat and examined participants' memory for threat and neutral words. In study 2, memory performance was assessed following the induction of realistic threat. Across the studies, in the control condition participants showed better memory for threat-related than neutral information. However, participants under threat remembered neutral information as well as threat-related information. In addition, participants in the threat condition remembered threat-related information as well as participants in the control condition. The findings are discussed in terms of automatic vigilance processes but also the effects of threat on arousal and its effect on information processing. This latter perspective, suggests paradoxically, that under some circumstances involving an outgroup threat, non-threatening information about outgroups can be extensively processed. PMID- 26635670 TI - Perceived Parental Functioning, Self-Esteem, and Psychological Distress in Adults Whose Parents are Separated/Divorced. AB - OBJECTIVE: The objective of this research was to identify retrospectively the alienating behaviors and the parental bonding that occurred in an Italian sample of adults whose had parents separated or divorced and their associations with self-esteem and psychological distress. METHODS: Four hundred seventy adults in Chieti, Italy, completed an anonymous and confidential survey regarding their childhood exposure to parental alienating behaviors (using the Baker Strategy Questionnaire), quality of the parent-child relationship (using Parental Bonding Instruments), self-esteem (using Rosenberg Self-Esteem Scale), and global psychological distress (using Global Severity Index of Symptom Checklist-90 Revised). RESULTS: About 80% of the sample reported some exposure to parental alienating behaviors; about 65-70% of the sample has perceived non-optimal parenting by mother and by father; individuals who experienced affectionless control (low care and high overprotection) reported significantly higher exposure to parental loyalty conflict behaviors. Overall rates of reported exposure to low care, and overprotection and parental loyalty conflict behaviors were statistically significantly associated with self-esteem as well as the measure of current psychological distress. RESULTS revealed that exposure to parental loyalty conflict behaviors and self-esteem were associated with psychological distress over and above the effects of parental bonding and age. CONCLUSION: The pattern of findings supports the theory that children exposed to dysfunctional parenting, and with low self-esteem are at risk for their long-term psychological functioning. Implications for health policy changes and strengthening social services are discussed. PMID- 26635671 TI - Why does Existential Threat Promote Intergroup Violence? Examining the Role of Retributive Justice and Cost-Benefit Utility Motivations. AB - The current research examined the role of retributive justice and cost-benefit utility motivations in the process through which mortality salience increases support for violent responses to intergroup conflict. Specifically, previous research has shown that mortality salience often encourages political violence, especially when perceptions of retributive justice are activated. The current research examined whether mortality salience directly activates a justice mindset over a cost-benefit utility mindset, and whether this justice mindset is associated with support for political violence. In Study 1 (N = 209), mortality salience was manipulated among Israeli participants who then read about a Hamas attack on Israel with either no casualties or many casualties, after which justice and utility motivations for retribution were assessed. Study 2 (N = 112), examined whether the link between death primes and support for an Israeli preemptive strike on Iran's nuclear facilities is mediated by justice or cost benefit utility considerations. Results of both studies revealed that primes of death increased justice-related motivations, and these motives, rather than utility motives, were associated with support for violence. Findings suggest that existential concerns often fuel violent intergroup conflict because they increase desire for retributive justice, rather than increase belief that violence is an effective strategy. These findings expand our knowledge on the motivations for intergroup violence, and shed experimental light on real-life eruptions of violent conflict indicating that when existential concerns are salient, as they often are during violent conflict, the decision to engage in violence often disregards the utility of violence, and leads to the preference for violent solutions to political problems - even when these solutions make little practical sense. PMID- 26635672 TI - Rhythmic Effects of Syntax Processing in Music and Language. AB - Music and language are human cognitive and neural functions that share many structural similarities. Past theories posit a sharing of neural resources between syntax processing in music and language (Patel, 2003), and a dynamic attention network that governs general temporal processing (Large and Jones, 1999). Both make predictions about music and language processing over time. Experiment 1 of this study investigates the relationship between rhythmic expectancy and musical and linguistic syntax in a reading time paradigm. Stimuli (adapted from Slevc et al., 2009) were sentences broken down into segments; each sentence segment was paired with a musical chord and presented at a fixed inter onset interval. Linguistic syntax violations appeared in a garden-path design. During the critical region of the garden-path sentence, i.e., the particular segment in which the syntactic unexpectedness was processed, expectancy violations for language, music, and rhythm were each independently manipulated: musical expectation was manipulated by presenting out-of-key chords and rhythmic expectancy was manipulated by perturbing the fixed inter-onset interval such that the sentence segments and musical chords appeared either early or late. Reading times were recorded for each sentence segment and compared for linguistic, musical, and rhythmic expectancy. Results showed main effects of rhythmic expectancy and linguistic syntax expectancy on reading time. There was also an effect of rhythm on the interaction between musical and linguistic syntax: effects of violations in musical and linguistic syntax showed significant interaction only during rhythmically expected trials. To test the effects of our experimental design on rhythmic and linguistic expectancies, independently of musical syntax, Experiment 2 used the same experimental paradigm, but the musical factor was eliminated-linguistic stimuli were simply presented silently, and rhythmic expectancy was manipulated at the critical region. Experiment 2 replicated effects of rhythm and language, without an interaction. Together, results suggest that the interaction of music and language syntax processing depends on rhythmic expectancy, and support a merging of theories of music and language syntax processing with dynamic models of attentional entrainment. PMID- 26635673 TI - 'Right Now, Sophie (*)Swims in the Pool?!': Brain Potentials of Grammatical Aspect Processing. AB - We investigated whether brain potentials of grammatical aspect processing resemble semantic or morpho-syntactic processing, or whether they instead are characterized by an entirely distinct pattern in the same individuals. We studied aspect from the perspective of agreement between the temporal information in the context (temporal adverbials, e.g., Right now) and a morpho-syntactic marker of grammatical aspect (e.g., progressive is swimming). Participants read questions providing a temporal context that was progressive (What is Sophie doing in the pool right now?) or habitual (What does Sophie do in the pool every Monday?). Following a lead-in sentence context such as Right now, Sophie..., we measured event-related brain potentials (ERPs) time-locked to verb phrases in four different conditions, e.g., (a) is swimming (control); (b) (*)is cooking (semantic violation); (c) (*)are swimming (morpho-syntactic violation); or (d)?swims (aspect mismatch); ...in the pool." The collected ERPs show typical N400 and P600 effects for semantics and morpho-syntax, while aspect processing elicited an Early Negativity (250-350 ms). The aspect-related Negativity was short-lived and had a central scalp distribution with an anterior onset. This differentiates it not only from the semantic N400 effect, but also from the typical LAN (Left Anterior Negativity), that is frequently reported for various types of agreement processing. Moreover, aspect processing did not show a clear P600 modulation. We argue that the specific context for each item in this experiment provided a trigger for agreement checking with temporal information encoded on the verb, i.e., morphological aspect marking. The aspect-related Negativity obtained for aspect agreement mismatches reflects a violated expectation concerning verbal inflection (in the example above, the expected verb phrase was Sophie is X-ing rather than Sophie X-s in condition d). The absence of an additional P600 for aspect processing suggests that the mismatch did not require additional reintegration or processing costs. This is consistent with participants' post hoc grammaticality judgements of the same sentences, which overall show a high acceptability of aspect mismatch sentences. PMID- 26635674 TI - Commentary: Meditation Effects within the Hippocampal Complex Revealed by Voxel Based Morphometric and Cytoarchitectonic Probabilistic Mapping. PMID- 26635675 TI - Making Clear the Value of Basic Behavioral Research. Commentary: A Crisis in Comparative Psychology: Where Have All the Undergraduates Gone? PMID- 26635676 TI - Gender Differences in the Physical and Psychological Manifestation of Childhood Trauma and/or Adversity in People with Psychosis. AB - The link between childhood trauma and/or adversity and risk of psychosis is well known. Our aim was to determine the prevalence of childhood trauma and/or adversity in people who have psychotic disorders and to investigate the association between childhood trauma and/or adversity and a range of social and health measures. Participants (n = 391, 42% male) were specifically asked about any experience of childhood trauma and/or adversity. Respondents provided information about education, employment, physical health, and health service utilization. Univariate analyses revealed that childhood trauma and/or adversity was associated with poorer levels of self-reported physical health and social problems. This includes the experience of chronic pain, headaches, arthritis, asthma, and victimization/stigma in men. Participants with a childhood trauma and/or adversity history indicated higher rates of lifetime suicide attempts with women reporting more lifetime depressive symptoms. Multivariate analyses revealed differing profiles in relation to physical and psychological health variable between males and females. Males with the experience of childhood trauma and/or adversity were significantly more likely to report cardiovascular/stroke issues, migraines and anhedonia. Females with the experience of childhood trauma and/or adversity were more likely to report a lifetime history of elevated mood and to be married or in a de facto relationship. There has been very little research into the assessment and treatment of the effects of childhood trauma and/or adversity in adults with psychosis. Childhood trauma and/or adversity may contribute to higher rates of self-reported poor health in men and is associated with increased depression in women. Our findings suggest that interventions to address the effects of past trauma are urgently needed. PMID- 26635677 TI - Measuring Individual Differences in Decision Biases: Methodological Considerations. AB - Individual differences in people's susceptibility to heuristics and biases (HB) are often measured by multiple-bias questionnaires consisting of one or a few items for each bias. This research approach relies on the assumptions that (1) different versions of a decision bias task measure are interchangeable as they measure the same cognitive failure; and (2) that some combination of these tasks measures the same underlying construct. Based on these assumptions, in Study 1 we developed two versions of a new decision bias survey for which we modified 13 HB tasks to increase their comparability, construct validity, and the participants' motivation. The analysis of the responses (N = 1279) showed weak internal consistency within the surveys and a great level of discrepancy between the extracted patterns of the underlying factors. To explore these inconsistencies, in Study 2 we used three original examples of HB tasks for each of seven biases. We created three decision bias surveys by allocating one version of each HB task to each survey. The participants' responses (N = 527) showed a similar pattern as in Study 1, questioning the assumption that the different examples of the HB tasks are interchangeable and that they measure the same underlying construct. These results emphasize the need to understand the domain-specificity of cognitive biases as well as the effect of the wording of the cover story and the response mode on bias susceptibility before employing them in multiple-bias questionnaires. PMID- 26635678 TI - Psychotherapy and Social Change: Utilizing Principles of Cognitive-Behavioral Therapy to Help Develop New Prejudice-Reduction Interventions. AB - We propose that key concepts from clinical psychotherapy can inform science-based initiatives aimed at building tolerance and community cohesion. Commonalities in social and clinical psychology are identified regarding (1) distorted thinking (intergroup bias and cognitive bias), (2) stress and coping (at intergroup level and intrapersonal level), and (3) anxiety (intergroup anxiety and pathological anxiety). On this basis we introduce a new cognitive-behavioral model of social change. Mental imagery is the conceptual point of synthesis, and anxiety is at the core, through which new treatment-based approaches to reducing prejudice can be developed. More generally, we argue that this integration is illustrative of broader potential for cross-disciplinary integration in the social and clinical sciences, and has the potential to open up new possibilities and opportunities for both disciplines. PMID- 26635679 TI - A Prospective Longitudinal Study of Perceived Infant Outcomes at 18-24 Months: Neural and Psychological Correlates of Parental Thoughts and Actions Assessed during the First Month Postpartum. AB - The first postpartum months constitute a critical period for parents to establish an emotional bond with their infants. Neural responses to infant-related stimuli have been associated with parental sensitivity. However, the associations among these neural responses, parenting, and later infant outcomes for mothers and fathers are unknown. In the current longitudinal study, we investigated the relationships between parental thoughts/actions and neural activation in mothers and fathers in the neonatal period with infant outcomes at the toddler stage. At the first month postpartum, mothers (n = 21) and fathers (n = 19) underwent a neuroimaging session during which they listened to their own and unfamiliar baby's cry. Parenting-related thoughts/behaviors were assessed by interview twice at the first month and 3-4 months postpartum and infants' socioemotional outcomes were reported by mothers and fathers at 18-24 months postpartum. In mothers, higher levels of anxious thoughts/actions about parenting at the first month postpartum, but not at 3-4 months postpartum, were associated with infant's low socioemotional competencies at 18-24 months. Anxious thoughts/actions were also associated with heightened responses in the motor cortex and reduced responses in the substantia nigra to own infant cry sounds. On the other hand, in fathers, higher levels of positive perception of being a parent at the first month postpartum, but not at 3-4 months postpartum, were associated with higher infant socioemotional competencies at 18-24 months. Positive thoughts were associated with heightened responses in the auditory cortex and caudate to own infant cry sounds. The current study provides evidence that parental thoughts are related to concurrent neural responses to their infants at the first month postpartum as well as their infant's future socioemotional outcome at 18-24 months. Parent differences suggest that anxious thoughts in mothers and positive thoughts in fathers may be the targets for parenting-focused interventions very early postpartum. PMID- 26635680 TI - Explicit and Implicit Positive Alcohol Expectancies in Problem and Non-Problem Drinkers: Differences Across Age Groups from Young Adolescence to Adulthood. AB - AIMS: Recent studies with animal models showed that the stimulant and sedative effects of alcohol change during the adolescent period. In humans, the stimulant effects of ethanol are most often indirectly recorded through the measurement of explicit and implicit alcohol effect expectancies. However, it is unknown how such implicit and explicit expectancies evolve with age in humans during adolescence. METHODS: Adolescent (13-16 year old), young adult (17-18 year old), and adult (35-55 year old) participants were recruited. On the basis of their score on the Alcohol Use Disorder Identification Test (AUDIT), they were classified as non-problem (AUDIT <= 7) or problem (AUDIT >= 11) drinkers. The participants completed the Alcohol Expectancy Questionnaire (AEQ) and performed two unipolar Implicit Association Test (IAT) to assess implicit associations between alcohol and the concepts of "stimulation" and "sedation". RESULTS: Problem drinkers from the three age groups reported significantly higher positive alcohol expectancies than non-problem drinkers on all AEQ subscales. Positive alcohol explicit expectancies also gradually decreased with age, with adolescent problem drinkers reporting especially high positive expectancies. This effect was statistically significant for all positive expectancies, with the exception of relaxation expectancies that were only close to statistical significance. In contrast, stimulation and sedation alcohol implicit associations were not significantly different between problem and non-problem drinkers and did not change with age. CONCLUSION: These results indicate that explicit positive alcohol effect expectancies predict current alcohol consumption levels, especially in adolescents. Positive alcohol expectancies also gradually decrease with age in the three cross-sectional groups of adolescents, young adults, and adults. This effect might be related to changes in the physiological response to alcohol. PMID- 26635681 TI - High User Control in Game Design Elements Increases Compliance and In-game Performance in a Memory Training Game. AB - Computer games are increasingly being used for training cognitive functions like working memory and attention among the growing population of older adults. While cognitive training games often include elements like difficulty adaptation, rewards, and visual themes to make the games more enjoyable and effective, the effect of different degrees of afforded user control in manipulating these elements has not been systematically studied. To address this issue, two distinct implementations of the three aforementioned game elements were tested among healthy older adults (N = 21, 69.9 +/- 6.4 years old) playing a game-like version of the n-back task on a tablet at home for 3 weeks. Two modes were considered, differentiated by the afforded degree of user control of the three elements: user control of difficulty vs. automatic difficulty adaptation, difficulty-dependent rewards vs. automatic feedback messages, and user choice of visual theme vs. no choice. The two modes ("USER-CONTROL" and "AUTO") were compared for frequency of play, duration of play, and in-game performance. Participants were free to play the game whenever and for however long they wished. Participants in USER-CONTROL exhibited significantly higher frequency of playing, total play duration, and in game performance than participants in AUTO. The results of the present study demonstrate the efficacy of providing user control in the three game elements, while validating a home-based study design in which participants were not bound by any training regimen, and could play the game whenever they wished. The results have implications for designing cognitive training games that elicit higher compliance and better in-game performance, with an emphasis on home-based training. PMID- 26635682 TI - Relationships between Psychophysiological Responses to Cycling Exercise and Post Exercise Self-Efficacy. AB - Although self-efficacy (SE) is an important determinant of regular exercise, it is unclear how subjective and physiological states before, during, and after the exercise session affects post-exercise SE. The aim of this study was to clarify subjective and physiological factors affecting post-exercise SE assessed after a single exercise session at a physiologically equivalent level. Forty-three healthy volunteers (28 women, 15 men) completed an 82-min experimental session, comprising a 22-min pre-exercise rest, a 30-min steady-state cycling exercise at moderate intensity [40% of heart rate (HR) reserve], and a 30-min post-exercise rest. We measured physiological (HR) and subjective [Rating of Perceived Exertion (RPE), Feeling Scale (FS)] states during the experimental session. Autonomic states were assessed by power spectral analysis of heart rate variability (HRV) during pre- and post-exercise rest. Post-exercise SE, which was the participants' confidence in their ability to perform the 30-min exercise that they had just performed, was assessed at 30-min post-exercise. A stepwise multiple regression analysis, with post-exercise SE as the dependent variable and physiological and subjective measures of the exercise as candidate explanatory variables, showed that post-exercise SE was negatively correlated with RPE and positively correlated with FS at the end of the 30-min exercise. In addition, post-exercise SE was negatively correlated with high-frequency power of the post-exercise HRV, an index of parasympathetic function. These results indicate that post-exercise SE is related not only to subjective responses to the exercise but also to autonomic response after the exercise. PMID- 26635683 TI - Viewing Olfactory Affective Responses Through the Sniff Prism: Effect of Perceptual Dimensions and Age on Olfactomotor Responses to Odors. AB - Sniffing, which is the active sampling of olfactory information through the nasal cavity, is part of the olfactory percept. It is influenced by stimulus properties, affects how an odor is perceived, and is sufficient (without an odor being present) to activate the olfactory cortex. However, many aspects of the affective correlates of sniffing behavior remain unclear, in particular the modulation of volume and duration as a function of odor hedonics. The present study used a wide range of odorants with contrasted hedonic valence to test: (1) which psychophysical function best describes the relationship between sniffing characteristics and odor hedonics (e.g., linear, or polynomial); (2) whether sniffing characteristics are sensitive to more subtle variations in pleasantness than simple pleasant-unpleasant contrast; (3) how sensitive sniffing is to other perceptual dimensions of odors such as odor familiarity or edibility; and (4) whether the sniffing/hedonic valence relationship is valid in other populations than young adults, such as the elderly. Four experiments were conducted, using 16 48 odorants each, and recruiting a total of 102 participants, including a group of elderly people. Results of the four experiments were very consistent in showing that sniffing was sensitive to subtle variations in unpleasantness but not to subtle variations in pleasantness, and that, the more unpleasant the odor, the more limited the spontaneous sampling of olfactory information through the nasal cavity (smaller volume, shorter duration). This also applied, although to a lesser extent, to elderly participants. Relationships between sniffing and other perceptual dimensions (familiarity, edibility) were less clear. It was concluded that sniffing behavior might be involved in adaptive responses protecting the subject from possibly harmful substances. PMID- 26635684 TI - Increases in Perspective Embedding Increase Reading Time Even with Typical Text Presentation: Implications for the Reading of Literature. AB - Reading fiction is a major component of intellectual life, yet it has proven difficult to study experimentally. One aspect of literature that has recently come to light is perspective embedding ("she thought I left" embedding her perspective on "I left"), which seems to be a defining feature of fiction. Previous work (Whalen et al., 2012) has shown that increasing levels of embedment affects the time that it takes readers to read and understand short vignettes in a moving window paradigm. With increasing levels of embedment from 1 to 5, reading times in a moving window paradigm rose almost linearly. However, level 0 was as slow as 3-4. Accuracy on probe questions was relatively constant until dropping at the fifth level. Here, we assessed this effect in a more ecologically valid ("typical") reading paradigm, in which the entire vignette was visible at once, either for as long as desired (Experiment 1) or a fixed time (Experiment 2). In Experiment 1, reading times followed a pattern similar to that of the previous experiment, with some differences in absolute speed. Accuracy matched previous results: fairly consistent accuracy until a decline at level 5, indicating that both presentation methods allowed understanding. In Experiment 2, accuracy was somewhat reduced, perhaps because participants were less successful at allocating their attention than they were during the earlier experiment; however, the pattern was the same. It seems that literature does not, on average, use easiest reading level but rather uses a middle ground that challenges the reader, but not too much. PMID- 26635685 TI - Evoking Context with Contrastive Stress: Effects on Pragmatic Enrichment. AB - Although it is widely acknowledged that context influences a variety of pragmatic phenomena, it is not clear how best to articulate this notion of context and thereby explain the nature of its influence. In this paper, we target contextual alternatives that are evoked via focus placement and test how the same contextual manipulation can influence three different phenomena that involve pragmatic enrichment: scalar implicature, presupposition, and coreference. We argue that focus placement influences these three phenomena indirectly by providing the listener with information about the likely question under discussion (QUD) that a particular utterance answers (Roberts, 1996/2012). In three listening experiments, we find that the predicted interpretations are indeed made more available when focus placement is added to the final element (to the scalar adjective, to an entity embedded under the negated presupposition trigger, and to the predicate of a pronoun). These findings bring together several distinct strands of work on the effect of focus placement on interpretation all in the domain of pragmatic enrichment. Together they advance our empirical understanding of the relation between focus placement and QUD and highlight commonalities between implicature, presupposition, and coreference. PMID- 26635686 TI - Abstract "why" Thoughts About Success Lead to Greater Positive Generalization in Sport Participants. AB - Generalizing from a single failure or success to future performances and their self-concept could have an important impact on sport participants. This study examined the impact of the way sport participants think about success on positive generalization. Sport participants (N = 222) completed an online experimental study in which they were induced to think about meanings, causes and implications (i.e., abstract-"why"-thinking) or about more perceptual concrete aspects of their performance (i.e., concrete-"how"-thinking). We hypothesized that abstract "why"-thinking would lead to greater positive generalization and that this effect would be moderated by self-esteem. Our results supported our hypothesis that abstract thinking increased positive generalization, and this effect was more clearly visible in sport participants with higher self-esteem. These results suggest that retrospective thinking about the "why" of a good performance may benefit athletes in the long run because they generalize the outcome to future performances and their self-concept which may boost their motivation and consequently their performance. PMID- 26635687 TI - Chunks, Schemata, and Retrieval Structures: Past and Current Computational Models. PMID- 26635688 TI - Erratum: Voluntary Self-touch Increases Body Ownership. AB - [This corrects the article DOI: 10.3389/fpsyg.2015.01509.]. PMID- 26635689 TI - EEG can Track the Time Course of Successful Reference Resolution in Small Visual Worlds. AB - Previous research has shown that language comprehenders resolve reference quickly and incrementally, but not much is known about the neural processes and representations that are involved. Studies of visual short-term memory suggest that access to the representation of an item from a previously seen display is associated with a negative evoked potential at posterior electrodes contralateral to the spatial location of that item in the display. In this paper we demonstrate that resolving the reference of a noun phrase in a recently seen visual display is associated with an event-related potential that is analogous to this effect. Our design was adapted from the visual world paradigm: in each trial, participants saw a display containing three simple objects, followed by a question about the objects, such as Was the pink fish next to a boat?, presented word by word. Questions differed in whether the color adjective allowed the reader to identify the referent of the noun phrase or not (i.e., whether one or more objects of the named color were present). Consistent with our hypothesis, we observed that reference resolution by the adjective was associated with a negative evoked potential at posterior electrodes contralateral to spatial location of the referent, starting approximately 333 ms after the onset of the adjective. The fact that the laterality of the effect depended upon the location of the referent within the display suggests that reference resolution in visual domains involves, at some level, a modality-specific representation. In addition, the effect gives us an estimate of the time course of processing from perception of the written word to the point at which its meaning is brought into correspondence with the referential domain. PMID- 26635690 TI - Expressivism, Relativism, and the Analytic Equivalence Test. AB - The purpose of this paper is to show that, pace (Field, 2009), MacFarlane's assessment relativism and expressivism should be sharply distinguished. We do so by arguing that relativism and expressivism exemplify two very different approaches to context-dependence. Relativism, on the one hand, shares with other contemporary approaches a bottom-up, building block, model, while expressivism is part of a different tradition, one that might include Lewis' epistemic contextualism and Frege's content individuation, with which it shares an organic model to deal with context-dependence. The building-block model and the organic model, and thus relativism and expressivism, are set apart with the aid of a particular test: only the building-block model is compatible with the idea that there might be analytically equivalent, and yet different, propositions. PMID- 26635691 TI - Accountability Accentuates Interindividual-Intergroup Discontinuity by Enforcing Parochialism. AB - Interindividual-intergroup discontinuity is the tendency for relations between groups to be more competitive than relations between individuals. We examined whether the discontinuity effect arises in part because group members experience normative pressure to favor the ingroup (parochialism). Building on the notion that accountability enhances normative pressure, we hypothesized that the discontinuity effect would be larger when accountability is present (compared to absent). A prisoner's dilemma game experiment supported this prediction. Specifically, intergroup (compared to interindividual) interaction activated an injunctive ingroup-favoring norm, and accountability enhanced the influence of this norm on competitive behavior. PMID- 26635692 TI - Commentary: "Multimodal Theories of Recognition and Their Relation to Molyneux's Question". PMID- 26635694 TI - On the Evolving Biology of Language. PMID- 26635693 TI - Handedness for Unimanual Grasping in 564 Great Apes: The Effect on Grip Morphology and a Comparison with Hand Use for a Bimanual Coordinated Task. AB - A number of factors have been proposed to influence within and between species variation in handedness in non-human primates. In the initial study, we assessed the influence of grip morphology on hand use for simple reaching in a sample of 564 great apes including 49 orangutans Pongo pygmaeus, 66 gorillas Gorilla gorilla, 354 chimpanzees Pan troglodytes and 95 bonobos Pan paniscus. Overall, we found a significant right hand bias for reaching. We also found a significant effect of the grip morphology of hand use. Grasping with the thumb and index finger was more prevalent in the right compared to left hand in all four species. There was no significant sex effect on the patterns of handedness. In a subsample of apes, we also compared consistency in hand use for simple reaching with previously published data on a task that measures handedness for bimanual actions. We found that the ratio of subjects with consistent right compared to left hand use was more prevalent in bonobos, chimpanzees and gorillas but not orangutans. However, for all species, the proportion of subjects with inconsistent hand preferences between the tasks was relatively high suggesting some measures may be more sensitive in assessing handedness than others. PMID- 26635695 TI - Grammatical Encoding in Bilingual Language Production: A Focus on Code-switching. AB - In this study, I report three experiments that examined whether words from one language of bilinguals can use the syntactic features form the other language, and how such syntactic co-activation might influence syntactic processing. In other words, I examined whether there are any cases in which an inherent syntactic feature a lexical item is inhibited and the syntactic feature that belongs to the other language is used, instead. In the non-switch condition in Experiments 1 and 2, Persian-English bilinguals described pictures using an adjective-noun string from the same language requested. In the switch condition, they used a noun and an adjective from the other language. In the switch condition in Experiment 3, participants used only the adjective of a noun phrase from the other language. The results showed that bilinguals may inhibit the activation of a word's syntactic feature and use the syntactic property from the other language, instead [e.g., pirahane (shirt-N) black]. As the combinatorial node (the node that specifies different kinds of syntactic structures in which a word can be used) of a used adjective retains activation at least temporarily, bilinguals are more likely to use the same combinatorial node even with an adjective from the other language. Cross-language syntactic interference increased in the switch conditions. Moreover, more inappropriate responses were observed when switching from bilinguals' L2 to L1. The results also revealed that different experimental contexts may lead to different patterns of the control mechanism. The results will be interpreted in terms of Hartsuiker and Pickering's (2008) model of syntactic representation. PMID- 26635697 TI - Behavioral and Neurophysiological Signatures of Benzodiazepine-Related Driving Impairments. AB - Impaired driving due to drug use is a growing problem worldwide; estimates show that 18-23.5% of fatal accidents, and up to 34% of injury accidents may be caused by drivers under the influence of drugs (Drummer et al., 2003; Walsh et al., 2004; NHTSA, 2010). Furthermore, at any given time, up to 16% of drivers may be using drugs that can impair one's driving abilities (NHTSA, 2009). Currently, drug recognition experts (DREs; law enforcement officers with specialized training to identify drugged driving), have the most difficult time with identifying drivers potentially impaired on central nervous system (CNS) depressants (Smith et al., 2002). The fact that the use of benzodiazepines, a type of CNS depressant, is also associated with the greatest likelihood of causing accidents (Dassanayake et al., 2011), further emphasizes the need to improve research tools in this area which can facilitate the refinement of, or additions to, current assessments of impaired driving. Our laboratories collaborated to evaluate both the behavioral and neurophysiological effects of a benzodiazepine, alprazolam, in a driving simulation (miniSim(TM)). This drive was combined with a neurocognitive assessment utilizing time synched neurophysiology (electroencephalography, ECG). While the behavioral effects of benzodiazepines are well characterized (Rapoport et al., 2009), we hypothesized that, with the addition of real-time neurophysiology and the utilization of simulation and neurocognitive assessment, we could find objective assessments of drug impairment that could improve the detection capabilities of DREs. Our analyses revealed that (1) specific driving conditions were significantly more difficult for benzodiazepine impaired drivers and (2) the neurocognitive tasks' metrics were able to classify "impaired" vs. "unimpaired" with up to 80% accuracy based on lane position deviation and lane departures. While this work requires replication in larger studies, our results not only identified criteria that could potentially improve the identification of benzodiazepine intoxication by DREs, but also demonstrated the promise for future studies using this approach to improve upon current, real-world assessments of impaired driving. PMID- 26635696 TI - From Thought to Action: How the Interplay Between Neuroscience and Phenomenology Changed Our Understanding of Obsessive-Compulsive Disorder. AB - The understanding of obsessive-compulsive disorder (OCD) has evolved with the knowledge of behavior, the brain, and their relationship. Modern views of OCD as a neuropsychiatric disorder originated from early lesion studies, with more recent models incorporating detailed neuropsychological findings, such as perseveration in set-shifting tasks, and findings of altered brain structure and function, namely of orbitofrontal corticostriatal circuits and their limbic connections. Interestingly, as neurobiological models of OCD evolved from cortical and cognitive to sub-cortical and behavioral, the focus of OCD phenomenology also moved from thought control and contents to new concepts rooted in animal models of action control. Most recently, the proposed analogy between habitual action control and compulsive behavior has led to the hypothesis that individuals suffering from OCD may be predisposed to rely excessively on habitual rather than on goal-directed behavioral strategies. Alternatively, compulsions have been proposed to result either from hyper-valuation of certain actions and/or their outcomes, or from excessive uncertainty in the monitoring of action performance, both leading to perseveration in prepotent actions such as washing or checking. In short, the last decades have witnessed a formidable renovation in the pathophysiology, phenomenology, and even semantics, of OCD. Nevertheless, such progress is challenged by several caveats, not least psychopathological oversimplification and overgeneralization of animal to human extrapolations. Here we present an historical overview of the understanding of OCD, highlighting converging studies and trends in neuroscience, psychiatry and neuropsychology, and how they influenced current perspectives on the nosology and phenomenology of this disorder. PMID- 26635698 TI - Learning Styles and Vocabulary Acquisition in Second Language: How the Brain Learns. PMID- 26635699 TI - Syllable Structure Universals and Native Language Interference in Second Language Perception and Production: Positional Asymmetry and Perceptual Links to Accentedness. AB - The present study investigated how syllable structure differences between the first Language (L1) and the second language (L2) affect L2 consonant perception and production at syllable-initial and syllable-final positions. The participants were Mandarin-speaking college students who studied English as a second language. Monosyllabic English words were used in the perception test. Production was recorded from each Chinese subject and rated for accentedness by two native speakers of English. Consistent with previous studies, significant positional asymmetry effects were found across speech sound categories in terms of voicing, place of articulation, and manner of articulation. Furthermore, significant correlations between perception and accentedness ratings were found at the syllable onset position but not for the coda. Many exceptions were also found, which could not be solely accounted for by differences in L1-L2 syllabic structures. The results show a strong effect of language experience at the syllable level, which joins force with acoustic, phonetic, and phonemic properties of individual consonants in influencing positional asymmetry in both domains of L2 segmental perception and production. The complexities and exceptions call for further systematic studies on the interactions between syllable structure universals and native language interference with refined theoretical models to specify the links between perception and production in second language acquisition. PMID- 26635700 TI - Editorial: Nature and the Environment: The Psychology of Its Benefits and Its Protection. PMID- 26635702 TI - Mind-Reading Ability and Structural Connectivity Changes in Aging. AB - The Mind-Reading ability through the eyes is an important component of the affective Theory of Mind (ToM), which allows people to infer the other's mental state from the eye gaze. The aim of the present study was to investigate to which extent age-associated structural brain changes impact this ability and to determine if this association is related to executive functions in elderly subjects. For this purpose, Magnetic Resonance Imaging was used to determine both gray matter and white matter (WM) areas associated with aging. The resulting areas have been included in a subsequent correlation analysis to detect the brain regions whose structure was associated with the Mind-Reading ability through the eyes, assessed with the Italian version of the "Reading the Mind in the Eyes" (RME) test, in a sample of 36 healthy subjects ranging from 24 to 79 years of age. The analysis resulted in three important findings: (1) the performance to the RME test is relatively stable across the decades 20-70 (despite a slight decrease of this ability with aging) and independent from executive functions; (2) structural brain imaging demonstrated the involvement of a great number of cortical ToM areas for the execution of the RME test: the bilateral precentral gyrus, the bilateral posterior insula, the left superior temporal gyrus and the left inferior frontal gyrus, which also showed a significant volume decrease with age; (3) an age and task-related decline in WM connectivity on left fronto temporal portion of the brain. Our results confirm the age-related structural modifications of the brain and show that these changes have an influence on the Mind-Reading ability through the eyes. PMID- 26635704 TI - Find the Word! - But Where?: Maturana's 'Coordination' and Sartre's 'Reflection' around Naming. AB - 'Behavioral coordination' theory of language of Maturana (1928-) does not give a clear explanation for the questions of how naming takes place and where a word adequate for our experience comes from. This flaw may be alleviated by Sartre (1905-1980)s 'reflection' theory. According to Sartre's theory, we can make two types of sentences from the same data: for example, "I am conscious of this chair" and "There is consciousness of this chair." The difference between the two sentences is the existence of 'I' in the first or its lack in the second. Where did 'I' come from or how was it removed? There must be a field in which 'I' is brought forth, and it may also be a field where naming can take place. This essay concerns a naming process with special reference to Sartre's philosophy. At first, Maturana's biology and his linguistic theory are explained, and Sartre's fundamental ontology and in relation to this, his theory of reflection (two types of reflection) are introduced. Next, Sartre's notions of language (words and naming) are explained. Then, after operational correspondences between Maturana's 'coordination' and Sartre's 'reflection' are examined, our primary questions are answered. Finally, constraints burdened on our cognition with language and the possibility of liberation from them are discussed. Main arguments: (1) Maturana's 'coordination' and Sartre's 'reflection' are operationally equivalent concepts; (2) Sartre can complement Maturana's languaging theory of naming by providing both the domain for naming (the domain for the synthesis of identification, or for universalizing synthesis) and a mediator of naming (the cogito, namely the consciousness, of a languaging person). PMID- 26635703 TI - How Two Brains Make One Synchronized Mind in the Inferior Frontal Cortex: fNIRS Based Hyperscanning During Cooperative Singing. AB - One form of communication that is common in all cultures is people singing together. Singing together reflects an index of cognitive synchronization and cooperation of human brains. Little is known about the neural synchronization mechanism, however. Here, we examined how two brains make one synchronized behavior using cooperated singing/humming between two people and hyperscanning, a new brain scanning technique. Hyperscanning allowed us to observe dynamic cooperation between interacting participants. We used functional near-infrared spectroscopy (fNIRS) to simultaneously record the brain activity of two people while they cooperatively sang or hummed a song in face-to-face (FtF) or face-to wall (FtW) conditions. By calculating the inter-brain wavelet transform coherence between two interacting brains, we found a significant increase in the neural synchronization of the left inferior frontal cortex (IFC) for cooperative singing or humming regardless of FtF or FtW compared with singing or humming alone. On the other hand, the right IFC showed an increase in neural synchronization for humming only, possibly due to more dependence on musical processing. PMID- 26635701 TI - Prefrontal Cortex and Social Cognition in Mouse and Man. AB - Social cognition is a complex process that requires the integration of a wide variety of behaviors, including salience, reward-seeking, motivation, knowledge of self and others, and flexibly adjusting behavior in social groups. Not surprisingly, social cognition represents a sensitive domain commonly disrupted in the pathology of a variety of psychiatric disorders including Autism Spectrum Disorder (ASD) and Schizophrenia (SCZ). Here, we discuss convergent research from animal models to human disease that implicates the prefrontal cortex (PFC) as a key regulator in social cognition, suggesting that disruptions in prefrontal microcircuitry play an essential role in the pathophysiology of psychiatric disorders with shared social deficits. We take a translational perspective of social cognition, and review three key behaviors that are essential to normal social processing in rodents and humans, including social motivation, social recognition, and dominance hierarchy. A shared prefrontal circuitry may underlie these behaviors. Social cognition deficits in animal models of neurodevelopmental disorders like ASD and SCZ have been linked to an altered balance of excitation and inhibition (E/I ratio) within the cortex generally, and PFC specifically. A clear picture of the mechanisms by which altered E/I ratio in the PFC might lead to disruptions of social cognition across a variety of behaviors is not well understood. Future studies should explore how disrupted developmental trajectory of prefrontal microcircuitry could lead to altered E/I balance and subsequent deficits in the social domain. PMID- 26635705 TI - Observing Social Exclusion Leads to Dehumanizing the Victim. AB - We hypothesized that observing social exclusion would influence observers' judgments of the humanness of its victims and perpetrators. Specifically, we speculated that people would attribute victims and perpetrators to lower and higher mental capacities, respectively. Participants observed a simulated computer-based ball tossing game in which one of the players was either ostracized or not. They then rated the game players on traits associated with two dimensions of humanness, namely Human Nature (HN) and Human Uniqueness (HU). Overall, participants who witnessed an exclusion game judged the victim as less human on both domains compared to one of the perpetrators as well as to a player in the control condition. The perpetrator was attributed higher HN, but not significantly higher HU, compared to the control player. In addition, the less HN attributes a target was assigned, the more she was expected to be vulnerable to exploitation. On most of the other measures of target impression, however, the victim was rated more favorably than the perpetrator. The findings imply that social exclusion victims are often subtly derogated compared to the perpetrators, even while they are also more positively evaluated otherwise. PMID- 26635706 TI - Retinoic Acid Signaling: A New Piece in the Spoken Language Puzzle. AB - Speech requires precise motor control and rapid sequencing of highly complex vocal musculature. Despite its complexity, most people produce spoken language effortlessly. This is due to activity in distributed neuronal circuitry including cortico-striato-thalamic loops that control speech-motor output. Understanding the neuro-genetic mechanisms involved in the correct development and function of these pathways will shed light on how humans can effortlessly and innately use spoken language and help to elucidate what goes wrong in speech-language disorders. FOXP2 was the first single gene identified to cause speech and language disorder. Individuals with FOXP2 mutations display a severe speech deficit that includes receptive and expressive language impairments. The neuro molecular mechanisms controlled by FOXP2 will give insight into our capacity for speech-motor control, but are only beginning to be unraveled. Recently FOXP2 was found to regulate genes involved in retinoic acid (RA) signaling and to modify the cellular response to RA, a key regulator of brain development. Here we explore evidence that FOXP2 and RA function in overlapping pathways. We summate evidence at molecular, cellular, and behavioral levels that suggest an interplay between FOXP2 and RA that may be important for fine motor control and speech motor output. We propose RA signaling is an exciting new angle from which to investigate how neuro-genetic mechanisms can contribute to the (spoken) language ready brain. PMID- 26635707 TI - Environmental Design Shapes Perceptual-motor Exploration, Learning, and Transfer in Climbing. AB - This study investigated how environmental design shapes perceptual-motor exploration, when meta-stable regions of performance are created. Here, we examined how creating meta-stable regions of performance could destabilize pre existing skills, favoring greater exploration of performance environments, exemplified in this study by climbing surfaces. In this investigation we manipulated hold orientations on an indoor climbing wall to examine how nine climbers explored, learned, and transferred various trunk-rolling motion patterns and hand grasping movements. The learning protocol consisted of four sessions, in which climbers randomly ascended three different routes, as fluently as possible. All three routes were 10.3 m in height and composed of 20 hand-holds at the same locations on an artificial climbing wall; only hold orientations were altered: (i) a horizontal-edge route was designed to afford horizontal hold grasping, (ii) a vertical-edge route afforded vertical hold grasping, and (iii), a double-edge route was designed to afford both horizontal and vertical hold grasping. As a meta-stable condition of performance invite an individual to both exploit his pre existing behavioral repertoire (i.e., horizontal hold grasping pattern and trunk face to the wall) and explore new behaviors (i.e., vertical hold grasping and trunk side to the wall), it was hypothesized that the double-edge route characterized a meta-stable region of performance. Data were collected from inertial measurement units located on the neck and hip of each climber, allowing us to compute rolling motion referenced to the artificial climbing wall. Information on ascent duration, the number of exploratory and performatory movements for locating hand-holds, and hip path was also observed in video footage from a frontal camera worn by participants. Climbing fluency was assessed by calculating geometric index of entropy. Results showed that the meta-stable condition of performance may have afforded utilization of more adaptive climbing behaviors (expressed in higher values for range and variability of trunk rolling motion and greater number of exploratory movements). Findings indicated how climbers learn to explore and, subsequently, use effective exploratory search strategies that can facilitate transfer of learning to performance in novel climbing environments. PMID- 26635708 TI - How Facial Expressions of Emotion Affect Distance Perception. AB - Facial expressions of emotion are thought to convey expressers' behavioral intentions, thus priming observers' approach and avoidance tendencies appropriately. The present study examined whether detecting expressions of behavioral intent influences perceivers' estimation of the expresser's distance from them. Eighteen undergraduates (nine male and nine female) participated in the study. Six facial expressions were chosen on the basis of degree of threat anger, hate (threatening expressions), shame, surprise (neutral expressions), pleasure, and joy (safe expressions). Each facial expression was presented on a tablet PC held by an assistant covered by a black drape who stood 1, 2, or 3 m away from participants. Participants performed a visual matching task to report the perceived distance. Results showed that facial expression influenced distance estimation, with faces exhibiting threatening or safe expressions judged closer than those showing neutral expressions. Females' judgments were more likely to be influenced; but these influences largely disappeared beyond the 2 m distance. These results suggest that facial expressions of emotion (particularly threatening or safe emotions) influence others' (especially females') distance estimations but only within close proximity. PMID- 26635709 TI - Modality-specificity of Selective Attention Networks. AB - OBJECTIVE: To establish the modality specificity and generality of selective attention networks. METHOD: Forty-eight young adults completed a battery of four auditory and visual selective attention tests based upon the Attention Network framework: the visual and auditory Attention Network Tests (vANT, aANT), the Test of Everyday Attention (TEA), and the Test of Attention in Listening (TAiL). These provided independent measures for auditory and visual alerting, orienting, and conflict resolution networks. The measures were subjected to an exploratory factor analysis to assess underlying attention constructs. RESULTS: The analysis yielded a four-component solution. The first component comprised of a range of measures from the TEA and was labeled "general attention." The third component was labeled "auditory attention," as it only contained measures from the TAiL using pitch as the attended stimulus feature. The second and fourth components were labeled as "spatial orienting" and "spatial conflict," respectively-they were comprised of orienting and conflict resolution measures from the vANT, aANT, and TAiL attend-location task-all tasks based upon spatial judgments (e.g., the direction of a target arrow or sound location). CONCLUSIONS: These results do not support our a-priori hypothesis that attention networks are either modality specific or supramodal. Auditory attention separated into selectively attending to spatial and non-spatial features, with the auditory spatial attention loading onto the same factor as visual spatial attention, suggesting spatial attention is supramodal. However, since our study did not include a non-spatial measure of visual attention, further research will be required to ascertain whether non spatial attention is modality-specific. PMID- 26635710 TI - A Short Executive Function Training Program Improves Preschoolers' Working Memory. AB - Cognitive training has been shown to improve executive functions (EFs) in middle childhood and adulthood. However, fewer studies have targeted the preschool years a time when EFs undergo rapid development. The present study tested the effects of a short four session EF training program in 54 four-year-olds. The training group significantly improved their working memory from pre-training relative to an active control group. Notably, this effect extended to a task sharing few surface features with the trained tasks, and continued to be apparent 3 months later. In addition, the benefits of training extended to a measure of mathematical reasoning 3 months later, indicating that training EFs during the preschool years has the potential to convey benefits that are both long-lasting and wide-ranging. PMID- 26635711 TI - Comparative Psychology: A Perspective Rather than a Discipline. Commentary: A Crisis in Comparative Psychology: Where Have All the Undergraduates Gone? PMID- 26635712 TI - Commentary: Extensional Versus Intuitive Reasoning: The Conjunction Fallacy in Probability Judgment. PMID- 26635713 TI - Spatial Congruity Effects Reveal Metaphorical Thinking, not Polarity Correspondence. AB - Spatial congruity effects have often been interpreted as evidence for metaphorical thinking, but an alternative account based on polarity correspondence (a.k.a. markedness) has challenged this view. Here we compared metaphor- and polarity-correspondence-based explanations for spatial congruity effects, using musical pitch as a testbed. In one experiment, English speakers classified high- and low-frequency pitches as "high" and "low," or as "front" and "back," to determine whether space-pitch congruity effects could be elicited by any marked spatial continuum. Although both pairs of terms describe bipolar spatial continuums, we found congruity effects only for high/low judgments, indicating that markedness is not sufficient to produce space-pitch congruity effects. A second experiment confirmed that there were no space-pitch congruity effects for another pair of terms that have clear markedness (big/small), but which do not denote spatial height. By contrast, this experiment showed congruity effects for words that cued an appropriate vertical spatial schema (tall/short), even though these words are not used conventionally in English to describe pitches, ruling out explanations for the observed pattern of results based on verbal polysemy. Together, results suggest that space-pitch congruity effects reveal metaphorical uses of spatial schemas, not polarity correspondence effects. PMID- 26635714 TI - Alcohol Expectancies Mediate and Moderate the Associations between Big Five Personality Traits and Adolescent Alcohol Consumption and Alcohol-Related Problems. AB - Personality and expectancies are relevant psychological factors for the development of adolescent alcohol use and misuse. The present study examined their direct, mediated and moderated effects on different drinking behaviors in adolescence. Personality domains of the five-factor model, positive and negative alcohol expectancies (AEs), alcohol use during the week and the weekend, and alcohol-related problems were assessed in a sample of 361 adolescents. Different personality dimensions were directly associated with specific alcohol outcomes: Extraversion, low Conscientiousness and low Openness were associated with weekend alcohol use; low Agreeableness was related to weekday use; whereas low Agreeableness, low Conscientiousness and Extraversion were associated with alcohol-related problems. In addition, positive AEs mediated the relationship between Extraversion and alcohol use, whereas both positive and negative expectancies mediated the association between Neuroticism and alcohol consumption and alcohol-related problems. Finally, both types of expectancies interacted with Extraversion to predict alcohol problems. Our results highlight the importance of examining the complex interplay of comprehensive personality models and AEs to gain a better understanding of the development of different alcohol use and misuse patterns in adolescence. PMID- 26635715 TI - Motor Recovery After Subcortical Stroke Depends on Modulation of Extant Motor Networks. AB - INTRODUCTION: Stroke is the leading cause of long-term disability. Functional imaging studies report widespread changes in movement-related cortical networks after stroke. Whether these are a result of stroke-specific cognitive processes or reflect modulation of existing movement-related networks is unknown. Understanding this distinction is critical in establishing more effective restorative therapies after stroke. Using multivariate analysis (tensor independent component analysis - TICA), we map the neural networks involved during motor imagery (MI) and executed movement (EM) in subcortical stroke patients and age-matched controls. METHODS: Twenty subcortical stroke patients and 17 age-matched controls were recruited. They were screened for their ability to carry out MI (Chaotic MI Assessment). The fMRI task was a right-hand finger thumb opposition sequence (auditory-paced 1 Hz; 2, 3, 4, 5, 2...). Two separate runs were acquired (MI and rest and EM and rest; block design). There was no distinction between groups or tasks until the last stage of analysis, which allowed TICA to identify independent components (ICs) that were common or distinct to each group or task with no prior assumptions. RESULTS: TICA defined 28 ICs. ICs representing artifacts were excluded. ICs were only included if the subject scores were significant (for either EM or MI). Seven ICs remained that involved the primary and secondary motor networks. All ICs were shared between the stroke and age-matched controls. Five ICs were common to both tasks and three were exclusive to EM. Two ICs were related to motor recovery and one with time since stroke onset, but all were shared with age-matched controls. No IC was exclusive to stroke patients. CONCLUSION: We report that the cortical networks in stroke patients that relate to recovery of motor function represent modulation of existing cortical networks present in age-matched controls. The absence of cortical networks specific to stroke patients suggests that motor adaptation and other potential confounders (e.g., effort and additional muscle use) are not responsible for the changes in the cortical networks reported after stroke. This highlights that recovery of motor function after subcortical stroke involves preexisting cortical networks that could help identify more effective restorative therapies. PMID- 26635717 TI - Feasibility and Diagnostic Accuracy of Ischemic Stroke Territory Recognition Based on Two-Dimensional Projections of Three-Dimensional Diffusion MRI Data. AB - This study was conducted to assess the feasibility and diagnostic accuracy of brain artery territory recognition based on geoprojected two-dimensional maps of diffusion MRI data in stroke patients. In this retrospective study, multiplanar diffusion MRI data of ischemic stroke patients was used to create a two dimensional map of the entire brain. To guarantee correct representation of the stroke, a computer-aided brain artery territory diagnosis was developed and tested for its diagnostic accuracy. The test recognized the stroke-affected brain artery territory based on the position of the stroke in the map. The performance of the test was evaluated by comparing it to the reference standard of each patient's diagnosed stroke territory on record. This study was designed and conducted according to Standards for Reporting of Diagnostic Accuracy (STARD). The statistical analysis included diagnostic accuracy parameters, cross validation, and Youden Index optimization. After cross-validation on a cohort of 91 patients, the sensitivity of this territory diagnosis was 81% with a specificity of 87%. With this, the projection of strokes onto a two-dimensional map is accurate for representing the affected stroke territory and can be used to provide a static and printable overview of the diffusion MRI data. The projected map is compatible with other two-dimensional data such as EEG and will serve as a useful visualization tool. PMID- 26635716 TI - Blood-Based Proteomic Biomarkers of Alzheimer's Disease Pathology. AB - The complexity of Alzheimer's disease (AD) and its long prodromal phase poses challenges for early diagnosis and yet allows for the possibility of the development of disease modifying treatments for secondary prevention. It is, therefore, of importance to develop biomarkers, in particular, in the preclinical or early phases that reflect the pathological characteristics of the disease and, moreover, could be of utility in triaging subjects for preventative therapeutic clinical trials. Much research has sought biomarkers for diagnostic purposes by comparing affected people to unaffected controls. However, given that AD pathology precedes disease onset, a pathology endophenotype design for biomarker discovery creates the opportunity for detection of much earlier markers of disease. Blood-based biomarkers potentially provide a minimally invasive option for this purpose and research in the field has adopted various "omics" approaches in order to achieve this. This review will, therefore, examine the current literature regarding blood-based proteomic biomarkers of AD and its associated pathology. PMID- 26635718 TI - Sleep and Motor Learning: Implications for Physical Rehabilitation After Stroke. AB - Sleep is essential for healthy brain function and plasticity underlying learning and memory. In the context of physical impairment such as following a stroke, sleep may be particularly important for supporting critical recovery of motor function through similar processes of reorganization in the brain. Despite a link between stroke and poor sleep, current approaches to rehabilitative care often neglect the importance of sleep in clinical assessment and treatment. This review assimilates current evidence on the role of sleep in motor learning, with a focus on the implications for physical rehabilitation after stroke. We further outline practical considerations for integrating sleep assessment as a vital part of clinical care. PMID- 26635719 TI - High-Frequency Repetitive Sensory Stimulation as Intervention to Improve Sensory Loss in Patients with Complex Regional Pain Syndrome I. AB - Achieving perceptual gains in healthy individuals or facilitating rehabilitation in patients is generally considered to require intense training to engage neuronal plasticity mechanisms. Recent work, however, suggested that beneficial outcome similar to training can be effectively acquired by a complementary approach in which the learning occurs in response to mere exposure to repetitive sensory stimulation (rSS). For example, high-frequency repetitive sensory stimulation (HF-rSS) enhances tactile performance and induces cortical reorganization in healthy subjects and patients after stroke. Patients with complex regional pain syndrome (CRPS) show impaired tactile performance associated with shrinkage of cortical maps. We here investigated the feasibility and efficacy of HF-rSS, and low-frequency rSS (LF-rSS) to enhance tactile performance and reduce pain intensity in 20 patients with CRPS type I. Intermittent high- or low-frequency electrical stimuli were applied for 45 min/day to all fingertips of the affected hand for 5 days. Main outcome measures were spatial two-point-discrimination thresholds and mechanical detection thresholds measured on the tip of the index finger bilaterally. Secondary endpoint was current pain intensity. All measures were assessed before and on day 5 after the last stimulation session. HF-rSS applied in 16 patients improved tactile discrimination on the affected hand significantly without changes contralaterally. Current pain intensity remained unchanged on average, but decreased in four patients by >=30%. This limited pain relief might be due to the short stimulation period of 5 days only. In contrast, after LF-rSS, tactile discrimination was impaired in all four patients, while detection thresholds and pain were not affected. Our data suggest that HF-rSS could be used as a novel approach in CRPS treatment to improve sensory loss. Longer treatment periods might be required to induce consistent pain relief. PMID- 26635720 TI - Brain Network Activation as a Novel Biomarker for the Return-to-Play Pathway Following Sport-Related Brain Injury. AB - Children and adolescent athletes are at a higher risk for concussion than adults, and also experience longer recovery times and increased associated symptoms. It has also recently been demonstrated that multiple, seemingly mild concussions may result in exacerbated and prolonged neurological deficits. Objective assessments and return-to-play criteria are needed to reduce risk and morbidity associated with concussive events in these populations. Recent research has pushed to study the use of electroencephalography as an objective measure of brain injury. In the present case study, we present a novel approach that examines event-related potentials via a brain network activation (BNA) analysis as a biomarker of concussion and recovery. Specifically, changes in BNA scores, as indexed through this approach, offer a potential indicator of neurological health as the BNA assessment qualitatively and quantitatively indexes the network dynamics associated with brain injury. Objective tools, such as these support accurate and efficient assessment of brain injury and may offer a useful step in categorizing the temporal and spatial changes in brain activity following concussive blows, as well as the functional connectivity of brain networks, associated with concussion. PMID- 26635722 TI - A Systematic Review and Meta-Analysis of the Functional MRI Investigation of Motor Neuron Disease. AB - BACKGROUND: To assess the use of functional magnetic resonance imaging (fMRI) in motor neuron disease (MND), a systematic review and voxelwise meta-analysis of studies comparing brain activity in patients with MND and in healthy controls was conducted to identify common findings across studies. METHODS: A search for related papers published in English and Chinese was performed in Ovid Medline, Pubmed, and Embase database. Voxelwise meta-analysis was performed using signed differential mapping. RESULTS: The findings from 55 fMRI studies on MND were tabulated, and some common findings were discussed in further details. CONCLUSION: These findings are preliminary, sometimes even contradictory, and do not allow a complete understanding of the functional alterations in MND. However, we documented reliable findings that MND is not confined to the motor system, but is a multisystem disorder involving extra-motor cortex areas, causing cognitive dysfunction and deficits in socioemotional and sensory processing pathways. PMID- 26635721 TI - MicroRNAs: Not "Fine-Tuners" but Key Regulators of Neuronal Development and Function. AB - MicroRNAs (miRNAs) are a class of short non-coding RNAs that operate as prominent post-transcriptional regulators of eukaryotic gene expression. miRNAs are abundantly expressed in the brain of most animals and exert diverse roles. The anatomical and functional complexity of the brain requires the precise coordination of multilayered gene regulatory networks. The flexibility, speed, and reversibility of miRNA function provide precise temporal and spatial gene regulatory capabilities that are crucial for the correct functioning of the brain. Studies have shown that the underlying molecular mechanisms controlled by miRNAs in the nervous systems of invertebrate and vertebrate models are remarkably conserved in humans. We endeavor to provide insight into the roles of miRNAs in the nervous systems of these model organisms and discuss how such information may be used to inform regarding diseases of the human brain. PMID- 26635723 TI - Unlock the Thermogenic Potential of Adipose Tissue: Pharmacological Modulation and Implications for Treatment of Diabetes and Obesity. AB - Brown adipose tissue (BAT) is considered an interesting target organ for the treatment of metabolic disease due to its high metabolic capacity. Non-shivering thermogenesis, once activated, can lead to enhanced partitioning and oxidation of fuels in adipose tissues, and reduce the burden of glucose and lipids on other metabolic organs such as liver, pancreas, and skeletal muscle. Sustained long term activation of BAT may also lead to meaningful bodyweight loss. In this review, we discuss three different drug classes [the thiazolidinedione (TZD) class of PPARgamma agonists, beta3-adrenergic receptor agonists, and fibroblast growth factor 21 (FGF21) analogs] that have been proposed to regulate BAT and beige recruitment or activation, or both, and which have been tested in both rodent and human. The learnings from these classes suggest that restoration of functional BAT and beige mass as well as improved activation might be required to fully realize the metabolic potential of these tissues. Whether this can be achieved without the undesired cardiovascular side effects exhibited by the TZD PPARgamma agonists and beta3-adrenergic receptor agonists remains to be resolved. PMID- 26635724 TI - Recurrent Hypoglycemia Increases Anxiety and Amygdala Norepinephrine Release During Subsequent Hypoglycemia. AB - Recurrent hypoglycemia (RH) is a common and debilitating side effect of therapy in patients with both type 1 and, increasingly, type 2 diabetes. Previous studies in rats have shown marked effects of RH on subsequent hippocampal behavioral, metabolic, and synaptic processes. In addition to impaired memory, patients experiencing RH report alterations in cognitive processes that include mood and anxiety, suggesting that RH may also affect amygdala function. We tested the impact of RH on amygdala function using an elevated plus-maze test of anxiety together with in vivo amygdala microdialysis for norepinephrine (NEp), a widely used marker of basolateral amygdala cognitive processes. In contrast to findings in the hippocampus and prefrontal cortex, neither RH nor acute hypoglycemia alone significantly affected plus-maze performance or NEp release. However, animals tested when hypoglycemic who had previously experienced RH had elevated amygdala NEp during plus-maze testing, accompanied by increased anxiety (i.e., less time spent in the open arms of the plus-maze). The results show that RH has widespread effects on subsequent brain function, which vary by neural system. PMID- 26635727 TI - Editorial: Obesity and Diabetes: Energy Regulation by Free Fatty Acid Receptors. PMID- 26635725 TI - Molecular Targeted Therapies of Aggressive Thyroid Cancer. AB - Differentiated thyroid carcinomas (DTCs) that arise from follicular cells account >90% of thyroid cancer (TC) [papillary thyroid cancer (PTC) 90%, follicular thyroid cancer (FTC) 10%], while medullary thyroid cancer (MTC) accounts <5%. Complete total thyroidectomy is the treatment of choice for PTC, FTC, and MTC. Radioiodine is routinely recommended in high-risk patients and considered in intermediate risk DTC patients. DTC cancer cells, during tumor progression, may lose the iodide uptake ability, becoming resistant to radioiodine, with a significant worsening of the prognosis. The lack of specific and effective drugs for aggressive and metastatic DTC and MTC leads to additional efforts toward the development of new drugs. Several genetic alterations in different molecular pathways in TC have been shown in the past few decades, associated with TC development and progression. Rearranged during transfection (RET)/PTC gene rearrangements, RET mutations, BRAF mutations, RAS mutations, and vascular endothelial growth factor receptor 2 angiogenesis pathways are some of the known pathways determinant in the development of TC. Tyrosine kinase inhibitors (TKIs) are small organic compounds inhibiting tyrosine kinases auto-phosphorylation and activation, most of them are multikinase inhibitors. TKIs act on the aforementioned molecular pathways involved in growth, angiogenesis, local, and distant spread of TC. TKIs are emerging as new therapies of aggressive TC, including DTC, MTC, and anaplastic thyroid cancer, being capable of inducing clinical responses and stabilization of disease. Vandetanib and cabozantinib have been approved for the treatment of MTC, while sorafenib and lenvatinib for DTC refractory to radioiodine. These drugs prolong median progression-free survival, but until now no significant increase has been observed on overall survival; side effects are common. New efforts are made to find new more effective and safe compounds and to personalize the therapy in each TC patient. PMID- 26635726 TI - Homeostatic Control of the Thyroid-Pituitary Axis: Perspectives for Diagnosis and Treatment. AB - The long-held concept of a proportional negative feedback control between the thyroid and pituitary glands requires reconsideration in the light of more recent studies. Homeostatic equilibria depend on dynamic inter-relationships between thyroid hormones and pituitary thyrotropin (TSH). They display a high degree of individuality, thyroid-state-related hierarchy, and adaptive conditionality. Molecular mechanisms involve multiple feedback loops on several levels of organization, different time scales, and varying conditions of their optimum operation, including a proposed feedforward motif. This supports the concept of a dampened response and multistep regulation, making the interactions between TSH, FT4, and FT3 situational and mathematically more complex. As a homeostatically integrated parameter, TSH becomes neither normatively fixed nor a precise marker of euthyroidism. This is exemplified by the therapeutic situation with l thyroxine (l-T4) where TSH levels defined for optimum health may not apply equivalently during treatment. In particular, an FT3-FT4 dissociation, discernible FT3-TSH disjoint, and conversion inefficiency have been recognized in l-T4-treated athyreotic patients. In addition to regulating T4 production, TSH appears to play an essential role in maintaining T3 homeostasis by directly controlling deiodinase activity. While still allowing for tissue-specific variation, this questions the currently assumed independence of the local T3 supply. Rather it integrates peripheral and central elements into an overarching control system. On l-T4 treatment, altered equilibria have been shown to give rise to lower circulating FT3 concentrations in the presence of normal serum TSH. While data on T3 in tissues are largely lacking in humans, rodent models suggest that the disequilibria may reflect widespread T3 deficiencies at the tissue level in various organs. As a consequence, the use of TSH, valuable though it is in many situations, should be scaled back to a supporting role that is more representative of its conditional interplay with peripheral thyroid hormones. This reopens the debate on the measurement of free thyroid hormones and encourages the identification of suitable biomarkers. Homeostatic principles conjoin all thyroid parameters into an adaptive context, demanding a more flexible interpretation in the accurate diagnosis and treatment of thyroid dysfunction. PMID- 26635730 TI - Erratum: Structure Model Index Does Not Measure Rods and Plates in Trabecular Bone. AB - [This corrects the article on p. 162 in vol. 6, PMID: 26528241.]. PMID- 26635729 TI - Role of the Oxytocin Receptor Expressed in the Rostral Medullary Raphe in Thermoregulation During Cold Conditions. AB - Recent papers have reported that oxytocin (Oxt) and the oxytocin receptor (Oxtr) may be involved in the regulation of food intake in mammals. We therefore suspected the Oxt/Oxtr system to be involved in energy homeostasis. In previous studies, we found a tendency toward obesity in Oxtr-deficient (Oxtr (-/-)) mice, as well as impaired thermoregulation when these mice were exposed to cold conditions. In the present study, we observed the expression of Oxtr in the rostral medullary raphe (RMR), the brain region known to control thermogenesis in brown adipose tissue (BAT). Through immunohistochemistry, we detected neurons expressing Oxtr and c-Fos in the RMR of mice exposed to cold conditions. Up to 40% of Oxtr-positive neurons in RMR were classified as glutamatergic neurons, as shown by immunostaining using anti-VGLUT3 antibody. In addition, mice with exclusive expression of Oxtr in the RMR were generated by injecting an AAV-Oxtr vector into the RMR region of Oxtr (-/-) mice. We confirmed the recovery of thermoregulatory ability in the manipulated mice during exposure to cold conditions. Moreover, mice with RMR-specific expression of Oxtr lost the typical morphological change in BAT observed in Oxtr (-/-) mice. Additionally, increased expression of the beta3-adrenergic receptor gene, Adrb3, was observed in BAT. These results are the first to show the critical role of RMR Oxtr expression in thermoregulation during cold conditions. PMID- 26635728 TI - Contribution of GnIH Research to the Progress of Reproductive Neuroendocrinology. AB - Since the discovery of gonadotropin-releasing hormone (GnRH) in mammals at the beginning of the 1970s, it was generally accepted that GnRH is the only hypothalamic neuropeptide regulating gonadotropin release in mammals and other vertebrates. In 2000, however, gonadotropin-inhibitory hormone (GnIH), a novel hypothalamic neuropeptide that actively inhibits gonadotropin release, was discovered in quail. Numerous studies over the past decade and a half have demonstrated that GnIH serves as a key player regulating reproduction across vertebrates, acting on the brain and pituitary to modulate reproductive physiology and behavior. In the latter case, recent evidence indicates that GnIH can regulate reproductive behavior through changes in neurosteroid, such as neuroestrogen, biosynthesis in the brain. This review summarizes the discovery of GnIH, and the contributions to GnIH research focused on its mode of action, regulation of biosynthesis, and how these findings advance our understanding of reproductive neuroendocrinology. PMID- 26635731 TI - Sexual Dimorphism in Hepatic, Adipose Tissue, and Peripheral Tissue Insulin Sensitivity in Obese Humans. AB - Glucose and lipid metabolism differ between men and women, and women tend to have better whole-body or muscle insulin sensitivity. This may be explained, in part, by differences in sex hormones and adipose tissue distribution. Few studies have investigated gender differences in hepatic, adipose tissue, and whole-body insulin sensitivity between severely obese men and women. In this study, we aimed to determine the differences in glucose metabolism between severely obese men and women using tissue-specific measurements of insulin sensitivity. Insulin sensitivity was compared between age and body mass index (BMI)-matched obese men and women by a two-step euglycemic hyperinsulinemic clamp with infusion of [6,6 (2)H2]glucose. Basal endogenous glucose production (EGP) and insulin sensitivity of the liver, adipose tissue, and peripheral tissues were assessed. Liver fat content was assessed by proton magnetic resonance spectroscopy in a subset of included subjects. We included 46 obese men and women (age, 48 +/- 2 vs. 46 +/- 2 years, p = 0.591; BMI, 41 +/- 1 vs. 41 +/- 1 kg/m(2), p = 0.832). There was no difference in basal EGP (14.4 +/- 1.0 vs. 15.3 +/- 0.5 MUmol . kg fat-free mass( 1) . min(-1), p = 0.410), adipose tissue insulin sensitivity (insulin-mediated suppression of free fatty acids, 71.6 +/- 3.6 vs. 76.1 +/- 2.6%, p = 0.314), or peripheral insulin sensitivity (insulin-stimulated rate of disappearance of glucose, 26.2 +/- 2.1 vs. 22.7 +/- 1.7 MUmol . kg(-1) . min(-1), p = 0.211). Obese men were characterized by lower hepatic insulin sensitivity (insulin mediated suppression of EGP, 61.7 +/- 4.1 vs. 72.8 +/- 2.5% in men vs. women, respectively, p = 0.028). Finally, these observations could not be explained by differences in liver fat content (men vs. women, 16.5 +/- 3.1 vs. 16.0 +/- 2.5%, p = 0.913, n = 27). We conclude that obese men have lower hepatic, but comparable adipose tissue and peripheral tissue, insulin sensitivity compared to similarly obese women. Hepatic insulin resistance may contribute to the higher prevalence of diabetes in obese men. Further insight into the mechanisms underlying this gender difference may reveal novel targets for diabetes prevention and/or therapy. PMID- 26635733 TI - Different bacterial communities in heat and gamma irradiation treated replant disease soils revealed by 16S rRNA gene analysis - contribution to improved aboveground apple plant growth? AB - Replant disease (RD) severely affects apple production in propagation tree nurseries and in fruit orchards worldwide. This study aimed to investigate the effects of soil disinfection treatments on plant growth and health in a biotest in two different RD soil types under greenhouse conditions and to link the plant growth status with the bacterial community composition at the time of plant sampling. In the biotest performed we observed that the aboveground growth of apple rootstock M26 plants after 8 weeks was improved in the two RD soils either treated at 50 degrees C or with gamma irradiation compared to the untreated RD soils. Total community DNA was extracted from soil loosely adhering to the roots and quantitative real-time PCR revealed no pronounced differences in 16S rRNA gene copy numbers. 16S rRNA gene-based bacterial community analysis by denaturing gradient gel electrophoresis (DGGE) and 454-pyrosequencing revealed significant differences in the bacterial community composition even after 8 weeks of plant growth. In both soils, the treatments affected different phyla but only the relative abundance of Acidobacteria was reduced by both treatments. The genera Streptomyces, Bacillus, Paenibacillus, and Sphingomonas had a higher relative abundance in both heat treated soils, whereas the relative abundance of Mucilaginibacter, Devosia, and Rhodanobacter was increased in the gamma irradiated soils and only the genus Phenylobacterium was increased in both treatments. The increased abundance of genera with potentially beneficial bacteria, i.e., potential degraders of phenolic compounds might have contributed to the improved plant growth in both treatments. PMID- 26635734 TI - Environmental and Sanitary Conditions of Guanabara Bay, Rio de Janeiro. AB - Guanabara Bay is the second largest bay in the coast of Brazil, with an area of 384 km(2). In its surroundings live circa 16 million inhabitants, out of which 6 million live in Rio de Janeiro city, one of the largest cities of the country, and the host of the 2016 Olympic Games. Anthropogenic interference in Guanabara Bay area started early in the XVI century, but environmental impacts escalated from 1930, when this region underwent an industrialization process. Herein we present an overview of the current environmental and sanitary conditions of Guanabara Bay, a consequence of all these decades of impacts. We will focus on microbial communities, how they may affect higher trophic levels of the aquatic community and also human health. The anthropogenic impacts in the bay are flagged by heavy eutrophication and by the emergence of pathogenic microorganisms that are either carried by domestic and/or hospital waste (e.g., virus, KPC-producing bacteria, and fecal coliforms), or that proliferate in such conditions (e.g., vibrios). Antibiotic resistance genes are commonly found in metagenomes of Guanabara Bay planktonic microorganisms. Furthermore, eutrophication results in recurrent algal blooms, with signs of a shift toward flagellated, mixotrophic groups, including several potentially harmful species. A recent large-scale fish kill episode, and a long trend decrease in fish stocks also reflects the bay's degraded water quality. Although pollution of Guanabara Bay is not a recent problem, the hosting of the 2016 Olympic Games propelled the government to launch a series of plans to restore the bay's water quality. If all plans are fully implemented, the restoration of Guanabara Bay and its shores may be one of the best legacies of the Olympic Games in Rio de Janeiro. PMID- 26635732 TI - Drug Development Against the Major Diarrhea-Causing Parasites of the Small Intestine, Cryptosporidium and Giardia. AB - Diarrheal diseases are among the leading causes of morbidity and mortality in the world, particularly among young children. A limited number of infectious agents account for most of these illnesses, raising the hope that advances in the treatment and prevention of these infections can have global health impact. The two most important parasitic causes of diarrheal disease are Cryptosporidium and Giardia. Both parasites infect predominantly the small intestine and colonize the lumen and epithelial surface, but do not invade deeper mucosal layers. This review discusses the therapeutic challenges, current treatment options, and drug development efforts against cryptosporidiosis and giardiasis. The goals of drug development against Cryptosporidium and Giardia are different. For Cryptosporidium, only one moderately effective drug (nitazoxanide) is available, so novel classes of more effective drugs are a high priority. Furthermore, new genetic technology to identify potential drug targets and better assays for functional evaluation of these targets throughout the parasite life cycle are needed for advancing anticryptosporidial drug design. By comparison, for Giardia, several classes of drugs with good efficacy exist, but dosing regimens are suboptimal and emerging resistance begins to threaten clinical utility. Consequently, improvements in potency and dosing, and the ability to overcome existing and prevent new forms of drug resistance are priorities in antigiardial drug development. Current work on new drugs against both infections has revealed promising strategies and new drug leads. However, the primary challenge for further drug development is the underlying economics, as both parasitic infections are considered Neglected Diseases with low funding priority and limited commercial interest. If a new urgency in medical progress against these infections can be raised at national funding agencies or philanthropic organizations, meaningful and timely progress is possible in treating and possibly preventing cryptosporidiosis and giardiasis. PMID- 26635735 TI - Diversity and Activity of Lysobacter Species from Disease Suppressive Soils. AB - The genus Lysobacter includes several species that produce a range of extracellular enzymes and other metabolites with activity against bacteria, fungi, oomycetes, and nematodes. Lysobacter species were found to be more abundant in soil suppressive against the fungal root pathogen Rhizoctonia solani, but their actual role in disease suppression is still unclear. Here, the antifungal and plant growth-promoting activities of 18 Lysobacter strains, including 11 strains from Rhizoctonia-suppressive soils, were studied both in vitro and in vivo. Based on 16S rRNA sequencing, the Lysobacter strains from the Rhizoctonia-suppressive soil belonged to the four species Lysobacter antibioticus, Lysobacter capsici, Lysobacter enzymogenes, and Lysobacter gummosus. Most strains showed strong in vitro activity against R. solani and several other pathogens, including Pythium ultimum, Aspergillus niger, Fusarium oxysporum, and Xanthomonas campestris. When the Lysobacter strains were introduced into soil, however, no significant and consistent suppression of R. solani damping-off disease of sugar beet and cauliflower was observed. Subsequent bioassays further revealed that none of the Lysobacter strains was able to promote growth of sugar beet, cauliflower, onion, and Arabidopsis thaliana, either directly or via volatile compounds. The lack of in vivo activity is most likely attributed to poor colonization of the rhizosphere by the introduced Lysobacter strains. In conclusion, our results demonstrated that Lysobacter species have strong antagonistic activities against a range of pathogens, making them an important source for putative new enzymes and antimicrobial compounds. However, their potential role in R. solani disease suppressive soil could not be confirmed. In-depth omics'-based analyses will be needed to shed more light on the potential contribution of Lysobacter species to the collective activities of microbial consortia in disease suppressive soils. PMID- 26635736 TI - Development of a Laboratory Model of a Phototroph-Heterotroph Mixed-Species Biofilm at the Stone/Air Interface. AB - Recent scientific investigations have shed light on the ecological importance and physiological complexity of subaerial biofilms (SABs) inhabiting lithic surfaces. In the field of sustainable cultural heritage (CH) preservation, mechanistic approaches aimed at investigation of the spatiotemporal patterns of interactions between the biofilm, the stone, and the atmosphere are of outstanding importance. However, these interactions have proven difficult to explore with field experiments due to the inaccessibility of samples, the complexity of the ecosystem under investigation and the temporal resolution of the experiments. To overcome these limitations, we aimed at developing a unifying methodology to reproduce a fast-growing, phototroph-heterotroph mixed species biofilm at the stone/air interface. Our experiments underscore the ability of the dual-species SAB model to capture functional traits characteristic of biofilms inhabiting lithic substrate such as: (i) microcolonies of aggregated bacteria; (ii) network like structure following surface topography; (iii) cooperation between phototrophs and heterotrophs and cross feeding processes; (iv) ability to change the chemical parameters that characterize the microhabitats; (v) survival under desiccation and (vi) biocide tolerance. With its advantages in control, replication, range of different experimental scenarios and matches with the real ecosystem, the developed model system is a powerful tool to advance our mechanistic understanding of the stone-biofilm-atmosphere interplay in different environments. PMID- 26635738 TI - Niemeyer Virus: A New Mimivirus Group A Isolate Harboring a Set of Duplicated Aminoacyl-tRNA Synthetase Genes. AB - It is well recognized that gene duplication/acquisition is a key factor for molecular evolution, being directly related to the emergence of new genetic variants. The importance of such phenomena can also be expanded to the viral world, with impacts on viral fitness and environmental adaptations. In this work we describe the isolation and characterization of Niemeyer virus, a new mimivirus isolate obtained from water samples of an urban lake in Brazil. Genomic data showed that Niemeyer harbors duplicated copies of three of its four aminoacyl tRNA synthetase genes (cysteinyl, methionyl, and tyrosyl RS). Gene expression analysis showed that such duplications allowed significantly increased expression of methionyl and tyrosyl aaRS mRNA by Niemeyer in comparison to APMV. Remarkably, phylogenetic data revealed that Niemeyer duplicated gene pairs are different, each one clustering with a different group of mimivirus strains. Taken together, our results raise new questions about the origins and selective pressures involving events of aaRS gain and loss among mimiviruses. PMID- 26635739 TI - Hunting Down Frame Shifts: Ecological Analysis of Diverse Functional Gene Sequences. AB - Functional gene ecological analyses using amplicon sequencing can be challenging as translated sequences are often burdened with shifted reading frames. The aim of this work was to evaluate several bioinformatics tools designed to correct errors which arise during sequencing in an effort to reduce the number of frameshifts (FS). Genes encoding for alpha subunits of biphenyl (bphA) and benzoate (benA) dioxygenases were used as model sequences. FrameBot, a FS correction tool, was able to reduce the number of detected FS to zero. However, up to 44% of sequences were discarded by FrameBot as non-specific targets. Therefore, we proposed a de novo mode of FrameBot for FS correction, which works on a similar basis as common chimera identifying platforms and is not dependent on reference sequences. By nature of FrameBot de novo design, it is crucial to provide it with data as error free as possible. We tested the ability of several publicly available correction tools to decrease the number of errors in the data sets. The combination of maximum expected error filtering and single linkage pre clustering proved to be the most efficient read processing approach. Applying FrameBot de novo on the processed data enabled analysis of BphA sequences with minimal losses of potentially functional sequences not homologous to those previously known. This experiment also demonstrated the extensive diversity of dioxygenases in soil. A script which performs FrameBot de novo is presented in the supplementary material to the study or available at https://github.com/strejcem/FBdenovo. The tool was also implemented into FunGene Pipeline available at http://fungene.cme.msu.edu/FunGenePipeline/. PMID- 26635737 TI - Bloom Dynamics of Cyanobacteria and Their Toxins: Environmental Health Impacts and Mitigation Strategies. AB - Cyanobacteria are ecologically one of the most prolific groups of phototrophic prokaryotes in both marine and freshwater habitats. Both the beneficial and detrimental aspects of cyanobacteria are of considerable significance. They are important primary producers as well as an immense source of several secondary products, including an array of toxic compounds known as cyanotoxins. Abundant growth of cyanobacteria in freshwater, estuarine, and coastal ecosystems due to increased anthropogenic eutrophication and global climate change has created serious concern toward harmful bloom formation and surface water contamination all over the world. Cyanobacterial blooms and the accumulation of several cyanotoxins in water bodies pose severe ecological consequences with high risk to aquatic organisms and global public health. The proper management for mitigating the worldwide incidence of toxic cyanobacterial blooms is crucial for maintenance and sustainable development of functional ecosystems. Here, we emphasize the emerging information on the cyanobacterial bloom dynamics, toxicology of major groups of cyanotoxins, as well as a perspective and integrative approach to their management. PMID- 26635740 TI - Pseudomonads Rule Degradation of Polyaromatic Hydrocarbons in Aerated Sediment. AB - Given that the degradation of aromatic pollutants in anaerobic environments such as sediment is generally very slow, aeration could be an efficient bioremediation option. Using stable isotope probing (SIP) coupled with pyrosequencing analysis of 16S rRNA genes, we identified naphthalene-utilizing populations in aerated polyaromatic hydrocarbon (PAH)-polluted sediment. The results showed that naphthalene was metabolized at both 10 and 20 degrees C following oxygen delivery, with increased degradation at 20 degrees C as compared to 10 degrees C a temperature more similar to that found in situ. Naphthalene-derived (13)C was primarily assimilated by pseudomonads. Additionally, Stenotrophomonas, Acidovorax, Comamonas, and other minor taxa were determined to incorporate (13)C throughout the measured time course. The majority of SIP-detected bacteria were also isolated in pure cultures, which facilitated more reliable identification of naphthalene-utilizing populations as well as proper differentiation between primary consumers and cross-feeders. The pseudomonads acquiring the majority of carbon were identified as Pseudomonas veronii and Pseudomonas gessardii. Stenotrophomonads and Acidovorax defluvii, however, were identified as cross feeders unable to directly utilize naphthalene as a growth substrate. PAH degradation assays with the isolated bacteria revealed that all pseudomonads as well as Comamonas testosteroni degraded acenaphthene, fluorene, and phenanthrene in addition to naphthalene. Furthermore, P. veronii and C. testosteroni were capable of transforming anthracene, fluoranthene, and pyrene. Screening of isolates for naphthalene dioxygenase genes using a set of in-house designed primers for Gram-negative bacteria revealed the presence of such genes in pseudomonads and C. testosteroni. Overall, our results indicated an apparent dominance of pseudomonads in the sequestration of carbon from naphthalene and potential degradation of other PAHs upon aeration of the sediment at both 20 and 10 degrees C. PMID- 26635741 TI - Prokaryotes in Subsoil-Evidence for a Strong Spatial Separation of Different Phyla by Analysing Co-occurrence Networks. AB - Microbial communities in soil provide a wide range of ecosystem services. On the small scale, nutrient rich hotspots in soil developed from the activities of animals or plants are important drivers for the composition of microbial communities and their functional patterns. However, in subsoil, the spatial heterogeneity of microbes with differing lifestyles has been rarely considered so far. In this study, the phylogenetic composition of the bacterial and archaeal microbiome based on 16S rRNA gene pyrosequencing was investigated in the soil compartments bulk soil, drilosphere, and rhizosphere in top- and in the subsoil of an agricultural field. With co-occurrence network analysis, the spatial separation of typically oligotrophic and copiotrophic microbes was assessed. Four bacterial clusters were identified and attributed to bulk topsoil, bulk subsoil, drilosphere, and rhizosphere. The bacterial phyla Proteobacteria and Bacteroidetes, representing mostly copiotrophic bacteria, were affiliated mainly to the rhizosphere and drilosphere-both in topsoil and subsoil. Acidobacteria, Actinobacteria, Gemmatimonadetes, Planctomycetes, and Verrucomicrobia, bacterial phyla which harbor many oligotrophic bacteria, were the most abundant groups in bulk subsoil. The bacterial core microbiome in this soil was estimated to cover 7.6% of the bacterial sequencing reads including both oligotrophic and copiotrophic bacteria. In contrast the archaeal core microbiome includes 56% of the overall archaeal diversity. Thus, the spatial variability of nutrient quality and quantity strongly shapes the bacterial community composition and their interaction in subsoil, whereas archaea build a stable backbone of the soil prokaryotes due to their low variability in the different soil compartments. PMID- 26635742 TI - Degradation Network Reconstruction in Uric Acid and Ammonium Amendments in Oil Degrading Marine Microcosms Guided by Metagenomic Data. AB - Biostimulation with different nitrogen sources is often regarded as a strategy of choice in combating oil spills in marine environments. Such environments are typically depleted in nitrogen, therefore limiting the balanced microbial utilization of carbon-rich petroleum constituents. It is fundamental, yet only scarcely accounted for, to analyze the catabolic consequences of application of biostimulants. Here, we examined such alterations in enrichment microcosms using sediments from chronically crude oil-contaminated marine sediment at Ancona harbor (Italy) amended with natural fertilizer, uric acid (UA), or ammonium (AMM). We applied the web-based AromaDeg resource using as query Illumina HiSeq meta-sequences (UA: 27,893 open reading frames; AMM: 32,180) to identify potential catabolic differences. A total of 45 (for UA) and 65 (AMM) gene sequences encoding key catabolic enzymes matched AromaDeg, and their participation in aromatic degradation reactions could be unambiguously suggested. Genomic signatures for the degradation of aromatics such as 2-chlorobenzoate, indole-3-acetate, biphenyl, gentisate, quinoline and phenanthrene were common for both microcosms. However, those for the degradation of orcinol, ibuprofen, phenylpropionate, homoprotocatechuate and benzene (in UA) and 4-aminobenzene sulfonate, p-cumate, dibenzofuran and phthalate (in AMM), were selectively enriched. Experimental validation was conducted and good agreement with predictions was observed. This suggests certain discrepancies in action of these biostimulants on the genomic content of the initial microbial community for the catabolism of petroleum constituents or aromatics pollutants. In both cases, the emerging microbial communities were phylogenetically highly similar and were composed by very same proteobacterial families. However, examination of taxonomic assignments further revealed different catabolic pathway organization at the organismal level, which should be considered for designing oil spill mitigation strategies in the sea. PMID- 26635743 TI - Limits to Dihydrogen Incorporation into Electron Sinks Alternative to Methanogenesis in Ruminal Fermentation. AB - Research is being conducted with the objective of decreasing methane (CH4) production in the rumen, as methane emissions from ruminants are environmentally damaging and a loss of digestible energy to ruminants. Inhibiting ruminal methanogenesis generally results in accumulation of dihydrogen (H2), which is energetically inefficient and can inhibit fermentation. It would be nutritionally beneficial to incorporate accumulated H2 into propionate or butyrate production, or reductive acetogenesis. The objective of this analysis was to examine three possible physicochemical limitations to the incorporation of accumulated H2 into propionate and butyrate production, and reductive acetogenesis, in methanogenesis inhibited ruminal batch and continuous cultures: (i) Thermodynamics; (ii) Enzyme kinetics; (iii) Substrate kinetics. Batch (N = 109) and continuous (N = 43) culture databases of experiments with at least 50% inhibition in CH4 production were used in this meta-analysis. Incorporation of accumulated H2 into propionate production and reductive acetogenesis seemed to be thermodynamically feasible but quite close to equilibrium, whereas this was less clear for butyrate. With regard to enzyme kinetics, it was speculated that hydrogenases of ruminal microorganisms may have evolved toward high-affinity and low maximal velocity to compete for traces of H2, rather than for high pressure accumulated H2. Responses so far obtained to the addition of propionate production intermediates do not allow distinguishing between thermodynamic and substrate kinetics control. PMID- 26635744 TI - Pasteurella multocida Toxin Manipulates T Cell Differentiation. AB - Pasteurella multocida causes various diseases in a broad range of wild and domestic animals. Toxigenic strains of the serotypes A and D produce an AB protein toxin named Pasteurella multocida toxin (PMT). PMT constitutively activates the heterotrimeric G protein subunits Galphaq, Galpha13, and Galphai through deamidation of a glutamine residue, which results in cytoskeletal rearrangements as well as increased proliferation and survival of the host cell. In human monocytes, PMT alters the lipopolysaccharide (LPS)-induced activation toward a phenotype that suppresses T cell activation. Here we describe that the toxin also modulates CD4-positive T helper (Th) cells directly. PMT amplifies the expansion of Th cells through enhanced cell cycle progression and suppression of apoptosis and manipulates the differentiation of Th subclasses through activation of Signal Transducers and Activators of Transcription (STAT) family members and induction of subtype-specific master transcription factors. A large population of toxin-treated T cells is double-positive for Foxp3 and RORgammat, the transcription factors expressed by Treg and Th17 cells, respectively. This suggests that these cells could have the potential to turn into Th17 cells or suppressive Treg cells. However, in terms of function, the PMT-differentiated cells behave as inflammatory Th17 cells that produce IL-17 and trigger T cell proliferation. PMID- 26635745 TI - Diversity and Homogeneity among Small Plasmids of Aeromonas salmonicida subsp. salmonicida Linked with Geographical Origin. AB - Furunculosis, which is caused by Aeromonas salmonicida subsp. salmonicida, is a major salmonid disease in fish farms worldwide. Several plasmids found in this bacterium confer phenotypes such drug resistance and virulence. Small plasmids (pAsa1, pAsa2, pAsa3, and pAsal1) related to ColE1- and ColE2-type replicons are usually present in its normal plasmidome. In the present study, with the objective to investigate if these plasmids display particularities related to the origin of the isolates bearing them, a total of 153 isolates, including 78 new and 75 previously described, were analyzed for the presence of small plasmids by PCR and DNA restriction fragment profiling. A geographical dichotomy between Canadian and European isolates for their propensity to do not have pAsa3 or pAsal1 was found. In addition, the genotyping analysis led to the identification of two European isolates harboring an unusual pAsal1. An investigation by next generation sequencing (NGS) of these two isolates shed light on two pAsal1 variants (pAsal1C and pAsal1D). As with pAsal1B, another pAsal1 variant previously described, these two new variants bore a second insertion sequence (ISAS5) in addition to the usual ISAS11. The characterization of these variants suggested that they could predominate over the wild-type pAsal1 in stressful conditions such as growth at temperatures of 25 degrees C and above. To obtain a comprehensive portrait of the mutational pressure on small plasmids, 26 isolates whose DNA had been sequenced by NGS were investigated. pAsa3 and pAsal1 were more prone to mutations than pAsa1 and pAsa2, especially in the mobA gene, which encodes a relaxase and a primase. Lastly, the average copy number of each plasmid per cell was assessed using raw sequencing data. A clear trend with respect to the relative proportion per cell of each plasmid was identified. Our large-scale study revealed a geographical dichotomy in small plasmid repertoire in addition to a clear trend for pAsa3 and pAsal1 to be more frequently altered. Moreover, we present the discovery of two new variants of pAsal1: pAsal1C and pAsal1D. PMID- 26635747 TI - Differences in Intertidal Microbial Assemblages on Urban Structures and Natural Rocky Reef. AB - Global seascapes are increasingly modified to support high levels of human activity in the coastal zone. Modifications include the addition of defense structures and boating infrastructure, such as seawalls and marinas that replace natural habitats. Artificial structures support different macrofaunal communities to those found on natural rocky shores; however, little is known about differences in microbial community structure or function in urban seascapes. Understanding how artificial constructions in marine environments influence microbial communities is important as these assemblages contribute to many basic ecological processes. In this study, the bacterial communities of intertidal biofilms were compared between artificial structures (seawalls) and natural habitats (rocky shores) within Sydney Harbour. Plots were cleared on each type of habitat at eight locations. After 3 weeks the newly formed biofilm was sampled and the 16S rRNA gene sequenced using the Illumina Miseq platform. To account for differences in orientation and substrate material between seawalls and rocky shores that might have influenced our survey, we also deployed recruitment blocks next to the habitats at all locations for 3 weeks and then sampled and sequenced their microbial communities. Intertidal bacterial community structure sampled from plots differed between seawalls and rocky shores, but when substrate material, age and orientation were kept constant (with recruitment blocks) then bacterial communities were similar in composition and structure among habitats. This suggests that changes in bacterial communities on seawalls are not related to environmental differences between locations, but may be related to other intrinsic factors that differ between the habitats such as orientation, complexity, or predation. This is one of the first comparisons of intertidal microbial communities on natural and artificial surfaces and illustrates substantial ecological differences with potential consequences for biofilm function and the recruitment of macrofauna. PMID- 26635746 TI - Pathways and Bioenergetics of Anaerobic Carbon Monoxide Fermentation. AB - Carbon monoxide can act as a substrate for different modes of fermentative anaerobic metabolism. The trait of utilizing CO is spread among a diverse group of microorganisms, including members of bacteria as well as archaea. Over the last decade this metabolism has gained interest due to the potential of converting CO-rich gas, such as synthesis gas, into bio-based products. Three main types of fermentative CO metabolism can be distinguished: hydrogenogenesis, methanogenesis, and acetogenesis, generating hydrogen, methane and acetate, respectively. Here, we review the current knowledge on these three variants of microbial CO metabolism with an emphasis on the potential enzymatic routes and bio-energetics involved. PMID- 26635748 TI - Persistent Intra-Specific Variation in Genetic and Behavioral Traits in the Raphidophyte, Heterosigma akashiwo. AB - Motility is a key trait that phytoplankton utilize to navigate the heterogeneous marine environment. Quantifying both intra- and inter-specific variability in trait distributions is key to utilizing traits to distinguish groups of organisms and assess their ecological function. Because examinations of intra-specific variability are rare, here we measured three-dimensional movement behaviors and distribution patterns of seven genetically distinct strains of the ichthyotoxic raphidophyte, Heterosigma akashiwo. Strains were collected from different ocean basins but geographic distance between isolates was a poor predictor of genetic relatedness among strains. Observed behaviors were significantly different among all strains examined, with swimming speed and turning rate ranging from 33-115 MUm s(-1) and 41-110 degrees s(-1), respectively. Movement behaviors were consistent over at least 12 h, and in one case identical when measured several years apart. Movement behaviors were not associated with a specific cell size, carbon content, genetic relatedness, or geographic distance. These strain specific behaviors resulted in algal populations that had distinct vertical distributions in the experimental tank. This study demonstrates that the traits of genetic identity and motility can provide resolution to distinguish strains of species, where variations in size or biomass are insufficient characteristics. PMID- 26635749 TI - Comparative Analysis of Secretomes from Ectomycorrhizal Fungi with an Emphasis on Small-Secreted Proteins. AB - Fungi are major players in the carbon cycle in forest ecosystems due to the wide range of interactions they have with plants either through soil degradation processes by litter decayers or biotrophic interactions with pathogenic and ectomycorrhizal symbionts. Secretion of fungal proteins mediates these interactions by allowing the fungus to interact with its environment and/or host. Ectomycorrhizal (ECM) symbiosis independently appeared several times throughout evolution and involves approximately 80% of trees. Despite extensive physiological studies on ECM symbionts, little is known about the composition and specificities of their secretomes. In this study, we used a bioinformatics pipeline to predict and analyze the secretomes of 49 fungal species, including 11 ECM fungi, wood and soil decayers and pathogenic fungi to tackle the following questions: (1) Are there differences between the secretomes of saprophytic and ECM fungi? (2) Are small-secreted proteins (SSPs) more abundant in biotrophic fungi than in saprophytic fungi? and (3) Are there SSPs shared between ECM, saprotrophic and pathogenic fungi? We showed that the number of predicted secreted proteins is similar in the surveyed species, independently of their lifestyle. The secretome from ECM fungi is characterized by a restricted number of secreted CAZymes, but their repertoires of secreted proteases and lipases are similar to those of saprotrophic fungi. Focusing on SSPs, we showed that the secretome of ECM fungi is enriched in SSPs compared with other species. Most of the SSPs are coded by orphan genes with no known PFAM domain or similarities to known sequences in databases. Finally, based on the clustering analysis, we identified shared- and lifestyle-specific SSPs between saprotrophic and ECM fungi. The presence of SSPs is not limited to fungi interacting with living plants as the genome of saprotrophic fungi also code for numerous SSPs. ECM fungi shared lifestyle-specific SSPs likely involved in symbiosis that are good candidates for further functional analyses. PMID- 26635750 TI - Arbuscular Mycorrhizal Fungi for the Biocontrol of Plant-Parasitic Nematodes: A Review of the Mechanisms Involved. AB - Arbuscular mycorrhizal fungi (AMF) are obligate root symbionts that can protect their host plant against biotic stress factors such as plant-parasitic nematode (PPN) infection. PPN consist of a wide range of species with different life styles that can cause major damage in many important crops worldwide. Various mechanisms have been proposed to play a role in the biocontrol effect of AMF against PPN. This review presents an overview of the different mechanisms that have been proposed, and discusses into more detail the plausibility of their involvement in the biocontrol against PPN specifically. The proposed mechanisms include enhanced plant tolerance, direct competition for nutrients and space, induced systemic resistance (ISR) and altered rhizosphere interactions. Recent studies have emphasized the importance of ISR in biocontrol and are increasingly placing rhizosphere effects on the foreground as well, both of which will be the focal point of this review. Though AMF are not yet widely used in conventional agriculture, recent data help to develop a better insight into the modes of action, which will eventually lead toward future field applications of AMF against PPN. The scientific community has entered an exciting era that provides the tools to actually unravel the underlying molecular mechanisms, making this a timely opportunity for a review of our current knowledge and the challenges ahead. PMID- 26635752 TI - Host Innate Immune Responses of Ducks Infected with Newcastle Disease Viruses of Different Pathogenicities. AB - Though previous studies have identified two strains of duck-origin Newcastle disease virus (NDV) with varying levels of pathogenicity, the relationship between the early-phase host innate immune response, and pathogenesis of ducks infected with these strains in the lungs and thymuses remains unclear. In this study, we compared the viral distribution and mRNA expression of immune-related genes in ducks following infection with two NDV strains, Duck/CH/GD/SS/10 (SS-10) and Duck/CH/GD/NH/10 (NH-10). Both NDV strains replicated systemically in tested tissues (i.e., small intestine, cecal tonsils, brain, lung, bursa of Fabricius, thymus, and spleen) and exhibited different biological properties in duck pathogenicity. Real-time quantitative polymerase chain reaction showed that the expression of TLR3, TLR7, RIG-I, MDA5, IL-1beta, IL-2, IL-6, IL-8, IFN-alpha, IFN beta, IFN-gamma in the lungs was significantly greater than in the respective thymus genes during the early post infection stage. However, in the lungs, the expression of TLR3, TLR7, IL-1beta, IL-2, IL-8, IFN-alpha, IFN-gamma, and MHC II induced by SS-10 at 72 h post-inoculation (hpi) was less than with NH-10. Furthermore, the expression of IL-6 and IFN-beta in the lungs and thymuses following infection with SS-10 was greater than that with NH-10 at 24 and 48 hpi. These results highlight important differences in host innate immune responses, courses of infection, and pathogenesis following NDV infection. Further studies should work to expand understandings of the molecular mechanisms related to NDV infection. PMID- 26635753 TI - Molecular Players Involved in the Interaction Between Beneficial Bacteria and the Immune System. AB - The human gastrointestinal tract is a very complex ecosystem, in which there is a continuous interaction between nutrients, host cells, and microorganisms. The gut microbiota comprises trillions of microbes that have been selected during evolution on the basis of their functionality and capacity to survive in, and adapt to, the intestinal environment. Host bacteria and our immune system constantly sense and react to one another. In this regard, commensal microbes contribute to gut homeostasis, whereas the necessary responses are triggered against enteropathogens. Some representatives of our gut microbiota have beneficial effects on human health. Some of the most important roles of these microbes are to help to maintain the integrity of the mucosal barrier, to provide nutrients such as vitamins, or to protect against pathogens. In addition, the interaction between commensal microbiota and the mucosal immune system is crucial for proper immune function. This process is mainly performed via the pattern recognition receptors of epithelial cells, such as Toll-like or Nod-like receptors, which are able to recognize the molecular effectors that are produced by intestinal microbes. These effectors mediate processes that can ameliorate certain inflammatory gut disorders, discriminate between beneficial and pathogenic bacteria, or increase the number of immune cells or their pattern recognition receptors (PRRs). This review intends to summarize the molecular players produced by probiotic bacteria, notably Lactobacillus and Bifidobacterium strains, but also other very promising potential probiotics, which affect the human immune system. PMID- 26635754 TI - Root Associated Bacillus sp. Improves Growth, Yield and Zinc Translocation for Basmati Rice (Oryza sativa) Varieties. AB - Plant associated rhizobacteria prevailing in different agro-ecosystems exhibit multiple traits which could be utilized in various aspect of sustainable agriculture. Two hundred thirty four isolates were obtained from the roots of basmati-385 and basmati super rice varieties growing in clay loam and saline soil at different locations of Punjab (Pakistan). Out of 234 isolates, 27 were able to solubilize zinc (Zn) from different Zn ores like zinc phosphate [Zn3 (PO4)2], zinc carbonate (ZnCO3) and zinc oxide (ZnO). The strain SH-10 with maximum Zn solubilization zone of 24 mm on Zn3 (PO4)2ore and strain SH-17 with maximum Zn solubilization zone of 14-15 mm on ZnO and ZnCO3ores were selected for further studies. These two strains solubilized phosphorous (P) and potassium (K) in vitro with a solubilization zone of 38-46 mm and 47-55 mm respectively. The strains also suppressed economically important rice pathogens Pyricularia oryzae and Fusarium moniliforme by 22-29% and produced various biocontrol determinants in vitro. The strains enhanced Zn translocation toward grains and increased yield of basmati-385 and super basmati rice varieties by 22-49% and 18-47% respectively. The Zn solubilizing strains were identified as Bacillus sp. and Bacillus cereus by 16S rRNA gene analysis. PMID- 26635755 TI - Solute Concentrations Influence Microbial Methanogenesis in Coal-bearing Strata of the Cherokee Basin, USA. AB - Microorganisms have contributed significantly to subsurface energy resources by converting organic matter in hydrocarbon reservoirs into methane, the main component of natural gas. In this study, we consider environmental controls on microbial populations in coal-bearing strata of the Cherokee basin, an unconventional natural gas resource in southeast Kansas, USA. Pennsylvanian-age strata in the basin contain numerous thin (0.4-1.1 m) coalbeds with marginal thermal maturities (0.5-0.7% R o ) that are interbedded with shale and sandstone. We collected gas, water, and microbe samples from 16 commercial coalbed methane wells for geochemical and microbiological analysis. The water samples were Na-Cl type with total dissolved solids (TDS) content ranging from 34.9 to 91.3 g L(-1). Gas dryness values [C1/(C2 + C3)] averaged 2640 and carbon and hydrogen isotope ratios of methane differed from those of carbon dioxide and water, respectively, by an average of 65 and 1830/00. These values are thought to be consistent with gas that formed primarily by hydrogenotrophic methanogenesis. Results from cultivation assays and taxonomic analysis of 16S rRNA genes agree with the geochemical results. Cultivable methanogens were present in every sample tested, methanogen sequences dominate the archaeal community in each sample (avg 91%), and few archaeal sequences (avg 4.2%) were classified within Methanosarcinales, an order of methanogens known to contain methylotrophic methanogens. Although hydrogenotrophs appear dominant, geochemical and microbial analyses both indicate that the proportion of methane generated by acetoclastic methanogens increases with the solute content of formation water, a trend that is contrary to existing conceptual models. Consistent with this trend, beta diversity analyses show that archaeal diversity significantly correlates with formation water solute content. In contrast, bacterial diversity more strongly correlates with location than solute content, possibly as a result of spatial variation in the thermal maturity of the coalbeds. PMID- 26635751 TI - Establishing a Role for Bacterial Cellulose in Environmental Interactions: Lessons Learned from Diverse Biofilm-Producing Proteobacteria. AB - Bacterial cellulose (BC) serves as a molecular glue to facilitate intra- and inter-domain interactions in nature. Biosynthesis of BC-containing biofilms occurs in a variety of Proteobacteria that inhabit diverse ecological niches. The enzymatic and regulatory systems responsible for the polymerization, exportation, and regulation of BC are equally as diverse. Though the magnitude and environmental consequences of BC production are species-specific, the common role of BC-containing biofilms is to establish close contact with a preferred host to facilitate efficient host-bacteria interactions. Universally, BC aids in attachment, adherence, and subsequent colonization of a substrate. Bi-directional interactions influence host physiology, bacterial physiology, and regulation of BC biosynthesis, primarily through modulation of intracellular bis-(3'->5') cyclic diguanylate (c-di-GMP) levels. Depending on the circumstance, BC producers exhibit a pathogenic or symbiotic relationship with plant, animal, or fungal hosts. Rhizobiaceae species colonize plant roots, Pseudomonadaceae inhabit the phyllosphere, Acetobacteriaceae associate with sugar-loving insects and inhabit the carposphere, Enterobacteriaceae use fresh produce as vehicles to infect animal hosts, and Vibrionaceae, particularly Aliivibrio fischeri, colonize the light organ of squid. This review will highlight the diversity of the biosynthesis and regulation of BC in nature by discussing various examples of Proteobacteria that use BC-containing biofilms to facilitate host-bacteria interactions. Through discussion of current data we will establish new directions for the elucidation of BC biosynthesis, its regulation and its ecophysiological roles. PMID- 26635756 TI - Combined Culture-Based and Culture-Independent Approaches Provide Insights into Diversity of Jakobids, an Extremely Plesiomorphic Eukaryotic Lineage. AB - We used culture-based and culture-independent approaches to discover diversity and ecology of anaerobic jakobids (Excavata: Jakobida), an overlooked, deep branching lineage of free-living nanoflagellates related to Euglenozoa. Jakobids are among a few lineages of nanoflagellates frequently detected in anoxic habitats by PCR-based studies, however only two strains of a single jakobid species have been isolated from those habitats. We recovered 712 environmental sequences and cultured 21 new isolates of anaerobic jakobids that collectively represent at least ten different species in total, from which four are uncultured. Two cultured species have never been detected by environmental, PCR based methods. Surprisingly, culture-based and culture-independent approaches were able to reveal a relatively high proportion of overall species diversity of anaerobic jakobids-60 or 80%, respectively. Our phylogenetic analyses based on SSU rDNA and six protein-coding genes showed that anaerobic jakobids constitute a clade of morphologically similar, but genetically and ecologically diverse protists-Stygiellidae fam. nov. Our investigation combines culture-based and environmental molecular-based approaches to capture a wider extent of species diversity and shows Stygiellidae as a group that ordinarily inhabits anoxic, sulfide- and ammonium-rich marine habitats worldwide. PMID- 26635757 TI - Network of Interactions Between Ciliates and Phytoplankton During Spring. AB - The annually recurrent spring phytoplankton blooms in freshwater lakes initiate pronounced successions of planktonic ciliate species. Although there is considerable knowledge on the taxonomic diversity of these ciliates, their species-specific interactions with other microorganisms are still not well understood. Here we present the succession patterns of 20 morphotypes of ciliates during spring in Lake Zurich, Switzerland, and we relate their abundances to phytoplankton genera, flagellates, heterotrophic bacteria, and abiotic parameters. Interspecific relationships were analyzed by contemporaneous correlations and time-lagged co-occurrence and visualized as association networks. The contemporaneous network pointed to the pivotal role of distinct ciliate species (e.g., Balanion planctonicum, Rimostrombidium humile) as primary consumers of cryptomonads, revealed a clear overclustering of mixotrophic/omnivorous species, and highlighted the role of Halteria/Pelagohalteria as important bacterivores. By contrast, time-lagged statistical approaches (like local similarity analyses, LSA) proved to be inadequate for the evaluation of high-frequency sampling data. LSA led to a conspicuous inflation of significant associations, making it difficult to establish ecologically plausible interactions between ciliates and other microorganisms. Nevertheless, if adequate statistical procedures are selected, association networks can be powerful tools to formulate testable hypotheses about the autecology of only recently described ciliate species. PMID- 26635758 TI - Microbial Communities and Organic Matter Composition in Surface and Subsurface Sediments of the Helgoland Mud Area, North Sea. AB - The role of microorganisms in the cycling of sedimentary organic carbon is a crucial one. To better understand relationships between molecular composition of a potentially bioavailable fraction of organic matter and microbial populations, bacterial and archaeal communities were characterized using pyrosequencing-based 16S rRNA gene analysis in surface (top 30 cm) and subsurface/deeper sediments (30 530 cm) of the Helgoland mud area, North Sea. Fourier Transform Ion Cyclotron Resonance Mass Spectrometry (FT-ICR MS) was used to characterize a potentially bioavailable organic matter fraction (hot-water extractable organic matter, WE OM). Algal polymer-associated microbial populations such as members of the Gammaproteobacteria, Bacteroidetes, and Verrucomicrobia were dominant in surface sediments while members of the Chloroflexi (Dehalococcoidales and candidate order GIF9) and Miscellaneous Crenarchaeota Groups (MCG), both of which are linked to degradation of more recalcitrant, aromatic compounds and detrital proteins, were dominant in subsurface sediments. Microbial populations dominant in subsurface sediments (Chloroflexi, members of MCG, and Thermoplasmata) showed strong correlations to total organic carbon (TOC) content. Changes of WE-OM with sediment depth reveal molecular transformations from oxygen-rich [high oxygen to carbon (O/C), low hydrogen to carbon (H/C) ratios] aromatic compounds and highly unsaturated compounds toward compounds with lower O/C and higher H/C ratios. The observed molecular changes were most pronounced in organic compounds containing only CHO atoms. Our data thus, highlights classes of sedimentary organic compounds that may serve as microbial energy sources in methanic marine subsurface environments. PMID- 26635759 TI - Metagenomics of an Alkaline Hot Spring in Galicia (Spain): Microbial Diversity Analysis and Screening for Novel Lipolytic Enzymes. AB - A fosmid library was constructed with the metagenomic DNA from the water of the Lobios hot spring (76 degrees C, pH = 8.2) located in Ourense (Spain). Metagenomic sequencing of the fosmid library allowed the assembly of 9722 contigs ranging in size from 500 to 56,677 bp and spanning ~18 Mbp. 23,207 ORFs (Open Reading Frames) were predicted from the assembly. Biodiversity was explored by taxonomic classification and it revealed that bacteria were predominant, while the archaea were less abundant. The six most abundant bacterial phyla were Deinococcus-Thermus, Proteobacteria, Firmicutes, Acidobacteria, Aquificae, and Chloroflexi. Within the archaeal superkingdom, the phylum Thaumarchaeota was predominant with the dominant species "Candidatus Caldiarchaeum subterraneum." Functional classification revealed the genes associated to one-carbon metabolism as the most abundant. Both taxonomic and functional classifications showed a mixture of different microbial metabolic patterns: aerobic and anaerobic, chemoorganotrophic and chemolithotrophic, autotrophic and heterotrophic. Remarkably, the presence of genes encoding enzymes with potential biotechnological interest, such as xylanases, galactosidases, proteases, and lipases, was also revealed in the metagenomic library. Functional screening of this library was subsequently done looking for genes encoding lipolytic enzymes. Six genes conferring lipolytic activity were identified and one was cloned and characterized. This gene was named LOB4Est and it was expressed in a yeast mesophilic host. LOB4Est codes for a novel esterase of family VIII, with sequence similarity to beta-lactamases, but with unusual wide substrate specificity. When the enzyme was purified from the mesophilic host it showed half-life of 1 h and 43 min at 50 degrees C, and maximal activity at 40 degrees C and pH 7.5 with p nitrophenyl-laurate as substrate. Interestingly, the enzyme retained more than 80% of maximal activity in a broad range of pH from 6.5 to 8. PMID- 26635760 TI - Important Role of a Putative Lytic Transglycosylase Cj0843c in beta-Lactam Resistance in Campylobacter jejuni. AB - Beta-lactam antibiotics are an important class of antibiotics for treating bacterial infections. Despite prevalent beta-lactam resistance in Campylobacter jejuni, the leading bacterial cause of human diarrhea in developed countries, molecular mechanism of beta-lactam resistance in C. jejuni is still largely unknown. In this study, C. jejuni 81-176 was used for random transposon mutagenesis. Screening of a 2,800-mutant library identified 22 mutants with increased susceptibility to ampicillin. Of these mutants, two mutants contains mutations in Cj0843c (a putative lytic transglycosylase gene) and in its upstream gene Cj0844c, respectively. Complementation experiment demonstrated that the Cj0843 contributes to beta-lactam resistance. The Cj0843c insertional mutation was subsequently introduced to diverse C. jejuni clinical strains for MIC test, showing that Cj0843c contributes to both intrinsic and acquired beta-lactam resistance of C. jejuni. Consistent with this finding, inactivation of Cj0843c also dramatically reduced beta-lactamase activity. Genomic examination and PCR analysis showed Cj0843c is widely distributed in C. jejuni. High purity recombinant Cj0843c was produced for generation of specific antiserum. The Cj0843 was localized in the periplasm, as demonstrated by immunoblotting using specific antibodies. Turbidimetric assay further demonstrated the capability of the purified Cj0843c to hydrolyze cell walls. Inactivation of Cj0843c also significantly reduced C. jejuni colonization in the intestine. Together, this study identifies a mechanism of beta-lactam resistance in C. jejuni and provides insights into the role of cell wall metabolism in regulating beta-lactamase activity. PMID- 26635761 TI - Weak Coherence in Abundance Patterns Between Bacterial Classes and Their Constituent OTUs Along a Regulated River. AB - Deductions about the ecology of high taxonomic bacterial ranks (i.e., phylum, class, order) are often based on their abundance patterns, yet few studies have quantified how accurately variations in abundance of these bacterial groups represent the dynamics of the taxa within them. Using 454-pyrosequencing of the 16S rRNA gene, we investigated whether the changes in abundance of six dominant bacterial classes (Actinobacteria, Beta-/Alpha-/Gamma-proteobacteria, Flavobacteria, and Sphingobacteria) along a large dam-regulated river are reflected by those of their constituent Operational Taxonomic Units (OTUs; 97% similarity level). The environmental impact generated by the reservoirs promoted clear compositional shifts in all bacterial classes that resulted from changes in the abundance of individual OTUs rather than from the appearance of new taxa along the river. Abundance patterns at the class level represented the dynamics of only a small but variable proportion of their constituting OTUs, which were not necessarily the most abundant ones. Within most classes, we detected sub groups of OTUs showing contrasting responses to reservoir-induced environmental changes. Overall, we show that the patterns observed at the class level fail to capture the dynamics of a significant fraction of their constituent members, calling for caution when the ecological attributes of high-ranks are to be interpreted. PMID- 26635762 TI - The Structure of a Novel Thermophilic Esterase from the Planctomycetes Species, Thermogutta terrifontis Reveals an Open Active Site Due to a Minimal 'Cap' Domain. AB - A carboxyl esterase (TtEst2) has been identified in a novel thermophilic bacterium, Thermogutta terrifontis from the phylum Planctomycetes and has been cloned and over-expressed in Escherichia coli. The enzyme has been characterized biochemically and shown to have activity toward small p-nitrophenyl (pNP) carboxylic esters with optimal activity for pNP-acetate. The enzyme shows moderate thermostability retaining 75% activity after incubation for 30 min at 70 degrees C. The crystal structures have been determined for the native TtEst2 and its complexes with the carboxylic acid products propionate, butyrate, and valerate. TtEst2 differs from most enzymes of the alpha/beta-hydrolase family 3 as it lacks the majority of the 'cap' domain and its active site cavity is exposed to the solvent. The bound ligands have allowed the identification of the carboxyl pocket in the enzyme active site. Comparison of TtEst2 with structurally related enzymes has given insight into how differences in their substrate preference can be rationalized based upon the properties of their active site pockets. PMID- 26635763 TI - Volatile Organic Compounds from Native Potato-associated Pseudomonas as Potential Anti-oomycete Agents. AB - The plant kingdom represents a prominent biodiversity island for microbes that associate with the below- or aboveground organs of vegetal species. Both the root and the leaf represent interfaces where dynamic biological interactions influence plant life. Beside well-studied communication strategies based on soluble compounds and protein effectors, bacteria were recently shown to interact both with host plants and other microbial species through the emissions of volatile organic compounds (VOCs). Focusing on the potato late blight-causing agent Phytophthora infestans, this work addresses the potential role of the bacterial volatilome in suppressing plant diseases. In a previous study, we isolated and identified a large collection of strains with anti-Phytophthora potential from both the phyllosphere and the rhizosphere of potato. Here we report the characterization and quantification of their emissions of biogenic volatiles, comparing 16 Pseudomonas strains differing in (i) origin of isolation (phyllosphere vs. rhizosphere), (ii) in vitro inhibition of P. infestans growth and sporulation behavior, and (iii) protective effects against late blight on potato leaf disks. We systematically tested the pharmacological inhibitory activity of core and strain-specific single compounds against P. infestans mycelial growth and sporangial behavior in order to identify key effective candidate molecules present in the complex natural VOCs blends. We envisage the plant bacterial microbiome as a reservoir for functional VOCs and establish the basis for finding the primary enzymatic toolset that enables the production of active components of the volatile bouquet in plant-associated bacteria. Comprehension of these functional interspecies interactions will open perspectives for the sustainable control of plant diseases in forthcoming agriculture. PMID- 26635764 TI - Phytic Acid Enhances Biocontrol Activity of Rhodotorula mucilaginosa against Penicillium expansum Contamination and Patulin Production in Apples. AB - The effect of Rhodotorula mucilaginosa in combination with phytic acid (PA) on blue mold decay and patulin contamination of apples was investigated. Results from this study show that different concentrations of PA were effective in reducing the disease incidence of apples and that PA at concentration of 4 MUmol/mL, decreased the incidence of blue mold decay in apples from 86.1 to 62.5%, and showed higher control efficacy compared to untreated, control fruit during storage at 20 degrees C. However, R. mucilaginosa combined with PA (4 MUmol/mL) showed better control efficacy of blue mold decay than R. mucilaginosa used as single treatment, the disease incidence was reduced to 62.5% and lesion diameter on apples was reduced to 16.59 cm. In in vitro experiments, the addition of PA enhanced the biocontrol effect of R. mucilaginosa against the growth of Penicillium expansum and reduced patulin level when compared with either R. mucilaginosa or PA used separately. R. mucilaginosa together with PA, improved the inhibition of patulin production in wounded apples, decreasing the content of patulin by 89.6% compared to the control, under experimental conditions. Both R. mucilaginosa and R. mucilaginosa in combination with PA degraded patulin in vitro. In conclusion, the appropriate combination of R. mucilaginosa and PA may provide an effective biocontrol method for reducing postharvest decay of apples. PMID- 26635765 TI - Antibacterial Activity of Stenotrophomonas maltophilia Endolysin P28 against both Gram-positive and Gram-negative Bacteria. AB - Maltocin P28 is a phage-tail like bacteriocin produced by Stenotrophomonas maltophilia P28. The ORF8 of maltocin P28 gene cluster is predicted to encode an endolysin and we name it endolysin P28. Sequence analysis revealed that it contains the lysozyme_like superfamily conserved domain. Endolysin P28 has the four consensus motifs as that of Escherichia coli phage lambda gpR. In this study, endolysin P28 was expressed in E. coli BL21 (DE3) and purified with a C terminal oligo-histidine tag. The antibacterial activity of endolysin P28 increased as the temperature rose from 25 to 45 degrees C. Thermostability assays showed that endolysin P28 was stable up to 50 degrees C, while its residual activity was reduced by 55% after treatment at 70 degrees C for 30 min. Acidity and high salinity could enhance its antibacterial activity. Endolysin P28 exhibited a broad antibacterial activity against 14 out of 16 tested Gram positive and Gram-negative bacteria besides S. maltophilia. Moreover, it could effectively lyse intact Gram-negative bacteria in the absence of ethylenediaminetetraacetic acid as an outer membrane permeabilizer. Therefore, the characteristics of endolysin P28 make it a potential therapeutic agent against multi-drug-resistant pathogens. PMID- 26635766 TI - Forest Management Type Influences Diversity and Community Composition of Soil Fungi across Temperate Forest Ecosystems. AB - Fungal communities have been shown to be highly sensitive toward shifts in plant diversity and species composition in forest ecosystems. However, little is known about the impact of forest management on fungal diversity and community composition of geographically separated sites. This study examined the effects of four different forest management types on soil fungal communities. These forest management types include age class forests of young managed beech (Fagus sylvatica L.), with beech stands age of approximately 30 years, age class beech stands with an age of approximately 70 years, unmanaged beech stands, and coniferous stands dominated by either pine (Pinus sylvestris L.) or spruce (Picea abies Karst.) which are located in three study sites across Germany. Soil were sampled from 48 study plots and we employed fungal ITS rDNA pyrotag sequencing to assess the soil fungal diversity and community structure. We found that forest management type significantly affects the Shannon diversity of soil fungi and a significant interaction effect of study site and forest management on the fungal operational taxonomic units richness. Consequently distinct fungal communities were detected in the three study sites and within the four forest management types, which were mainly related to the main tree species. Further analysis of the contribution of soil properties revealed that C/N ratio being the most important factor in all the three study sites whereas soil pH was significantly related to the fungal community in two study sites. Functional assignment of the fungal communities indicated that 38% of the observed communities were Ectomycorrhizal fungi (ECM) and their distribution is significantly influenced by the forest management. Soil pH and C/N ratio were found to be the main drivers of the ECM fungal community composition. Additional fungal community similarity analysis revealed the presence of study site and management type specific ECM genera. This study extends our knowledge on the impact of forest management type on general and ectomycorrhizal fungal diversity and community structure in temperate forests. High plasticity across management types but also study site specific spatial distribution revealed new insights in the ECM fungal distribution patterns. PMID- 26635767 TI - Toxins Secreted by Bacillus Isolated from Lung Adenocarcinomas Favor the Penetration of Toxic Substances. AB - The aim was to explore the eventual role of bacteria in the induction of lung cancer by smoking habits. Viable bacteria closely related to the genus Bacillus were detected at high frequencies in lung-cancer biopsies. Similar, if not identical, microbes were isolated from cigarettes and in smog. Bacteria present in cigarettes could be transferred to a physiological solution via a "smoker" device that mimicked their potential transfer during smoking those bacteria produce exotoxins able to open transmembrane pores. These channels can be used as a way to penetrate cells of benzopyrenes and other toxic substances present in tobacco products. We hypothesize that Bacillaceae present in tobacco play a key role in the development of lung cancer. PMID- 26635768 TI - RfpA, RfpB, and RfpC are the Master Control Elements of Far-Red Light Photoacclimation (FaRLiP). AB - Terrestrial cyanobacteria often occur in niches that are strongly enriched in far red light (FRL; lambda > 700 nm). Some cyanobacteria exhibit a complex and extensive photoacclimation response, known as FRL photoacclimation (FaRLiP). During the FaRLiP response, specialized paralogous proteins replace 17 core subunits of the three major photosynthetic complexes: Photosystem (PS) I, PS II, and the phycobilisome. Additionally, the cells synthesize both chlorophyll (Chl) f and Chl d. Using biparental mating from Escherichia coli, we constructed null mutants of three genes, rfpA, rfpB, and rfpC, in the cyanobacteria Chlorogloeopsis fritschii PCC 9212 and Chroococcidiopsis thermalis PCC 7203. The resulting mutants were no longer able to modify their photosynthetic apparatus to absorb FRL, were no longer able to synthesize Chl f, inappropriately synthesized Chl d in white light, and were unable to transcribe genes of the FaRLiP gene cluster. We conclude that RfpA, RfpB, and RfpC constitute a FRL-activated signal transduction cascade that is the master control switch for the FaRLiP response. FRL is proposed to activate (or inactivate) the histidine kinase activity of RfpA, which leads to formation of the active state of RfpB, the key response regulator and transcription activator. RfpC may act as a phosphate shuttle between RfpA and RfpB. Our results show that reverse genetics via conjugation will be a powerful approach in detailed studies of the FaRLiP response. PMID- 26635769 TI - Toxoplasma gondii - Prevalence and Risk Factors in HIV-infected Patients from Songklanagarind Hospital, Southern Thailand. AB - Toxoplasmosis is one of the most common opportunistic parasitic diseases in patients living with HIV/AIDS. This study aimed to determine the seroprevalence of Toxoplasma infection in HIV-infected patients and to identify associated risk factors in Toxoplasma seropositive patients. This study was conducted at a regional public hospital in Hat Yai, southern Thailand during October 2009 to June 2010. Blood samples were collected from 300 HIV-infected patients. Each subject also answered a socio-demographic and risk factors associated with Toxoplasma infection. The prevalence of anti-Toxoplasma IgG antibodies in HIV infected patients was 109 (36.3%), of which 83 (76.2%) had past infection and 26 (23.9%) had recently acquired Toxoplasma infection as indicated by their IgG avidity. Multivariate analysis using logistic regression showed that gender difference (adjusted OR = 1.69, 95% CI = 1.05-2.72) was the only factor associated with Toxoplasma infection. From the results obtained, these HIV infected patients could be at high risk of developing clinical evidence of severe toxoplasmosis. Therefore, it is necessary to introduce primary behavioral practices to prevent Toxoplasma infection among HIV-infected patients. PMID- 26635770 TI - CCp5A Protein from Toxoplasma gondii as a Serological Marker of Oocyst-driven Infections in Humans and Domestic Animals. AB - Considering that the current immunoassays are not able to distinguish the infective forms that cause Toxoplasma gondii infection, the present study was carried out to evaluate the reactivity of two recombinant proteins (CCp5A and OWP1) from oocyst/sporozoite, in order to differentiate infections occurring by ingestion of oocysts or tissue cysts. The reactivity of the recombinant proteins was assessed against panels of serum samples from animals (chickens, pigs, and mice) that were naturally or experimentally infected by different infective stages of the parasite. Also, we tested sera from humans who have been infected by oocysts during a well-characterized toxoplasmosis outbreak, as well as sera from pregnant women tested IgM(+)/IgG(+) for T. gondii, which source of infection was unknown. Only the sporozoite-specific CCp5A protein was able to differentiate the parasite stage that infected chickens, pigs and mice, with specific reactivity for oocyst-infected animals. Furthermore, the CCp5A showed preferential reactivity for recent infection by oocyst/sporozoite in pigs and mice. In humans, CCp5A showed higher reactivity with serum samples from the outbreak, compared with serum from pregnant women. Altogether, these findings demonstrate the usefulness of the CCp5A protein as a new tool to identify the parasite stage of T. gondii infection, allowing its application for diagnosis and epidemiological investigations in animals and humans. The identification of parasite infective stage can help to design effective strategies to minimize severe complications in immunocompromised people and, particularly, in pregnant women to prevent congenital infection. PMID- 26635771 TI - Metabolic Engineering of Pseudomonas putida KT2440 to Produce Anthranilate from Glucose. AB - The Pseudomonas putida KT2440 strain was engineered in order to produce anthranilate (oAB, ortho-aminobenzoate), a precursor of the aromatic amino acid tryptophan, from glucose as sole carbon source. To enable the production of the metabolic intermediate oAB, the trpDC operon encoding an anthranilate phosphoribosyltransferase (TrpD) and an indole-3-glycerol phosphate synthase (TrpC), were deleted. In addition, the chorismate mutase (pheA) responsible for the conversion of chorismate over prephenate to phenylpyruvate was deleted in the background of the deletion of trpDC to circumvent a potential drain of precursor. To further increase the oAB production, a feedback insensitive version of 3-deoxy D-arabino-heptulosonate-7-phosphate synthase encoded by the aroG (D146N) gene and an anthranilate synthase (trpE (S40F) G) were overexpressed separately and simultaneously in the deletion mutants. With optimized production conditions in a tryptophan-limited fed-batch process a maximum of 1.54 +/- 0.3 g L(-1) (11.23 mM) oAB was obtained with the best performing engineered P. putida KT2440 strain (P. putida DeltatrpDC pSEVA234_aroG (D146N) _trpE (S40F) G). PMID- 26635772 TI - Cross-Kingdom Similarities in Microbiome Ecology and Biocontrol of Pathogens. PMID- 26635773 TI - Elucidating Host-Pathogen Interactions Based on Post-Translational Modifications Using Proteomics Approaches. AB - Microbes with the capability to survive in the host tissue and efficiently subvert its innate immune responses can cause various health hazards. There is an inherent need to understand microbial infection patterns and mechanisms in order to develop efficient therapeutics. Microbial pathogens display host specificity through a complex network of molecular interactions that aid their survival and propagation. Co-infection states further lead to complications by increasing the microbial burden and risk factors. Quantitative proteomics based approaches and post-translational modification analysis can be efficiently applied to gain an insight into the molecular mechanisms involved. The measurement of the proteome and post-translationally modified proteome dynamics using mass spectrometry, results in a wide array of information, such as significant changes in protein expression, protein abundance, the modification status, the site occupancy level, interactors, functional significance of key players, potential drug targets, etc. This mini review discusses the potential of proteomics to investigate the involvement of post-translational modifications in bacterial pathogenesis and host-pathogen interactions. PMID- 26635775 TI - Identification of a Ligand Binding Pocket in LdtR from Liberibacter asiaticus. AB - LdtR is a transcriptional activator involved in the regulation of a putative L,D transpeptidase in Liberibacter asiaticus, an unculturable pathogen and one of the causative agents of Huanglongbing disease. Using small molecule screens we identified benzbromarone as an inhibitor of LdtR activity, which was confirmed using in vivo and in vitro assays. Based on these previous results, the objective of this work was to identify the LdtR ligand binding pocket and characterize its interactions with benzbromarone. A structural model of LdtR was constructed and the molecular interactions with the ligand were predicted using the SwissDock interface. Using site-directed mutagenesis, these residues were changed to alanine. Electrophoretic mobility shift assays, thermal denaturation, isothermal titration calorimetry experiments, and in vivo assays were used to identify residues T43, L61, and F64 in the Benz1 pocket of LdtR as the amino acids most likely involved in the binding to benzbromarone. These results provide new information on the binding mechanism of LdtR to a modulatory molecule and provide a blue print for the design of therapeutics for other members of the MarR family of transcriptional regulators involved in pathogenicity. PMID- 26635774 TI - The Role of Ciliate Protozoa in the Rumen. AB - First described in 1843, Rumen protozoa with their striking appearance were assumed to be important for the welfare of their host. However, despite contributing up to 50% of the bio-mass in the rumen, the role of protozoa in rumen microbial ecosystem remains unclear. Phylogenetic analysis of 18S rDNA libraries generated from the rumen of cattle, sheep, and goats has revealed an unexpected diversity of ciliated protozoa although variation in gene copy number between species makes it difficult to obtain absolute quantification. Despite repeated attempts it has proven impossible to maintain rumen protozoa in axenic culture. Thus it has been difficult to establish conclusively a role of ciliate protozoa in rumen fiber degradation. The development of techniques to clone and express ciliate genes in lambda phage, together with bioinformatic indices to confirm the ciliate origin of the genes has allowed the isolation and characterization of fibrolytic genes from rumen protozoa. Elimination of the ciliate protozoa increases microbial protein supply by up to 30% and reduces methane production by up to 11%. Our recent findings suggest that holotrich protozoa play a disproportionate role in supporting methanogenesis whilst the small Entodinium are responsible for much of the bacterial protein turnover. As yet no method to control protozoa in the rumen that is safe and practically applicable has been developed, however a range of plant extract capable of controlling if not completely eliminating rumen protozoa have been described. PMID- 26635776 TI - Role of the Pre-neck Appendage Protein (Dpo7) from Phage vB_SepiS-phiIPLA7 as an Anti-biofilm Agent in Staphylococcal Species. AB - Staphylococcus epidermidis and Staphylococcus aureus are important causative agents of hospital-acquired infections and bacteremia, likely due to their ability to form biofilms. The production of a dense exopolysaccharide (EPS) matrix enclosing the cells slows the penetration of antibiotic down, resulting in therapy failure. The EPS depolymerase (Dpo7) derived from bacteriophage vB_SepiS phiIPLA7, was overexpressed in Escherichia coli and characterized. A dose dependent but time independent response was observed after treatment of staphylococcal 24 h-biofilms with Dpo7. Maximum removal (>90%) of biofilm attached cells was obtained with 0.15 MUM of Dpo7 in all polysaccharide producer strains but Dpo7 failed to eliminate polysaccharide-independent biofilm formed by S. aureus V329. Moreover, the pre-treatment of polystyrene surfaces with Dpo7 reduced the biofilm biomass by 53-85% in the 67% of the tested strains. This study supports the use of phage-encoded EPS depolymerases to prevent and disperse staphylococcal biofilms, thereby making bacteria more susceptible to the action of antimicrobials. PMID- 26635777 TI - Investigation of Antioxidative and Anticancer Potentials of Streptomyces sp. MUM256 Isolated from Malaysia Mangrove Soil. AB - A Streptomyces strain, MUM256 was isolated from Tanjung Lumpur mangrove soil in Malaysia. Characterization of the strain showed that it has properties consistent with those of the members of the genus Streptomyces. In order to explore the potential bioactivities, extract of the fermented broth culture of MUM256 was prepared with organic solvent extraction method. DPPH and SOD activity were utilized to examine the antioxidant capacity and the results have revealed the potency of MUM256 in superoxide anion scavenging activity in dose-dependent manner. The cytotoxicity of MUM256 extract was determined using cell viability assay against 8 different panels of human cancer cell lines. Among all the tested cancer cells, HCT116 was the most sensitive toward the extract treatment. At the highest concentration of tested extract, the result showed 2.3-, 2.0-, and 1.8 folds higher inhibitory effect against HCT116, HT29, and Caco-2 respectively when compared to normal cell line. This result has demonstrated that MUM256 extract was selectively cytotoxic toward colon cancer cell lines. In order to determine the constituents responsible for its bioactivities, the extract was then subjected to chemical analysis using GC-MS. The analysis resulted in the identification of chemical constituents including phenolic and pyrrolopyrazine compounds which may responsible for antioxidant and anticancer activities observed. Based on the findings of this study, the presence of bioactive constituents in MUM256 extract could be a potential source for the development of antioxidative and chemopreventive agents. PMID- 26635778 TI - The Prophylactic Effect of Probiotic Enterococcus lactis IW5 against Different Human Cancer Cells. AB - Enterococcus lactis IW5 was obtained from human gut and the potential probiotic characteristics of this organism were then evaluated. Results showed that this strain was highly resistant to low pH and high bile salt and adhered strongly to Caco-2 human epithelial colorectal cell lines. The supernatant of E. lactis IW5 strongly inhibited the growth of several pathogenic bacteria and decreased the viability of different cancer cells, such as HeLa, MCF-7, AGS, HT-29, and Caco-2. Conversely, E. lactis IW5 did not inhibit the viability of normal FHs-74 cells. This strain did not generate toxic enzymes, including beta-glucosidase, beta glucuronidase, and N-acetyl-beta-glucosaminidase and was highly susceptible to ampicillin, gentamycin, penicillin, vancomycin, clindamycin, sulfamethoxazol, and chloramphenicol but resistant to erythromycin and tetracyclin. This study provided evidence for the effect of E. lactis IW5 on cancer cells. Therefore, E. lactis IW5, as a bioactive therapeutics, should be subjected to other relevant tests to verify the therapeutic suitability of this strain for clinical applications. PMID- 26635781 TI - Integrated 'Omics', Targeted Metabolite and Single-cell Analyses of Arctic Snow Algae Functionality and Adaptability. AB - Snow algae are poly-extremophilic microalgae and important primary colonizers and producers on glaciers and snow fields. Depending on their pigmentation they cause green or red mass blooms during the melt season. This decreases surface albedo and thus further enhances snow and ice melting. Although the phenomenon of snow algal blooms has been known for a long time, large aspects of their physiology and ecology sill remain cryptic. This study provides the first in-depth and multi omics investigation of two very striking adjacent green and red snow fields on a glacier in Svalbard. We have assessed the algal community composition of green and red snow including their associated microbiota, i.e., bacteria and archaea, their metabolic profiles (targeted and non-targeted metabolites) on the bulk and single-cell level, and assessed the feedbacks between the algae and their physico chemical environment including liquid water content, pH, albedo, and nutrient availability. We demonstrate that green and red snow clearly vary in their physico-chemical environment, their microbial community composition and their metabolic profiles. For the algae this likely reflects both different stages of their life cycles and their adaptation strategies. Green snow represents a wet, carbon and nutrient rich environment and is dominated by the algae Microglena sp. with a metabolic profile that is characterized by key metabolites involved in growth and proliferation. In contrast, the dry and nutrient poor red snow habitat is colonized by various Chloromonas species with a high abundance of storage and reserve metabolites likely to face upcoming severe conditions. Combining a multitude of techniques we demonstrate the power of such complementary approaches in elucidating the function and ecology of extremophiles such as green and red snow algal blooms, which play crucial roles in glacial ecosystems. PMID- 26635780 TI - Optimizing Outcomes in Immunocompromised Hosts: Understanding the Role of Immunotherapy in Invasive Fungal Diseases. AB - A major global concern is the emergence and spread of systemic life-threatening fungal infections in critically ill patients. The increase in invasive fungal infections, caused most commonly by Candida and Aspergillus species, occurs in patients with impaired defenses due to a number of reasons such as underlying disease, the use of chemotherapeutic and immunosuppressive agents, broad-spectrum antibiotics, prosthetic devices and grafts, burns, neutropenia and HIV infection. The high morbidity and mortality associated with these infections is compounded by the limited therapeutic options and the emergence of drug resistant fungi. Hence, creative approaches to bridge the significant gap in antifungal drug development needs to be explored. Here, we review the potential anti-fungal targets for patient-centered therapies and immune-enhancing strategies for the prevention and treatment of invasive fungal diseases. PMID- 26635783 TI - Erratum: Evaluation of Fungal Laccase Immobilized on Natural Nanostructured Bacterial Cellulose. AB - [This corrects the article DOI: 10.3389/fmicb.2015.01245.]. PMID- 26635782 TI - Sophorolipids Production by Candida bombicola ATCC 22214 and its Potential Application in Microbial Enhanced Oil Recovery. AB - Biosurfactant production using Candida bombicola ATCC 22214, its characterization and potential applications in enhancing oil recovery were studied at laboratory scale. The seed media and the production media were standardized for optimal growth and biosurfactant production. The production media were tested with different carbon sources: glucose (2%w/v) and corn oil (10%v/v) added separately or concurrently. The samples were collected at 24 h interval up to 120 h and checked for growth (OD660), and biosurfactant production [surface tension (ST) and interfacial tension (IFT)]. The medium with both glucose and corn oil gave better biosurfactant production and reduced both ST and IFT to 28.56 + 0.42mN/m and 2.13 + 0.09mN/m, respectively within 72 h. The produced biosurfactant was quite stable at 13-15% salinity, pH range of 2-12, and at temperature up to 100 degrees C. It also produced stable emulsions (%E24) with different hydrocarbons (pentane, hexane, heptane, tridecane, tetradecane, hexadecane, 1 methylnaphthalene, 2,2,4,4,6,8-heptamethylnonane, light and heavy crude oil). The produced biosurfactant was extracted using ethyl acetate and characterized as a mixture of sophorolipids (SPLs). The potential of SPLs in enhancing oil recovery was tested using core-flooding experiments under reservoir conditions, where additional 27.27% of residual oil (Sor) was recovered. This confirmed the potential of SPLs for applications in microbial enhanced oil recovery. PMID- 26635779 TI - Paracoccidioides-host Interaction: An Overview on Recent Advances in the Paracoccidioidomycosis. AB - Paracoccidioides brasiliensis and P. lutzii are etiologic agents of paracoccidioidomycosis (PCM), an important endemic mycosis in Latin America. During its evolution, these fungi have developed characteristics and mechanisms that allow their growth in adverse conditions within their host through which they efficiently cause disease. This process is multi-factorial and involves host pathogen interactions (adaptation, adhesion, and invasion), as well as fungal virulence and host immune response. In this review, we demonstrated the glycoproteins and polysaccharides network, which composes the cell wall of Paracoccidioides spp. These are important for the change of conidia or mycelial (26 degrees C) to parasitic yeast (37 degrees C). The morphological switch, a mechanism for the pathogen to adapt and thrive inside the host, is obligatory for the establishment of the infection and seems to be related to pathogenicity. For these fungi, one of the most important steps during the interaction with the host is the adhesion. Cell surface proteins called adhesins, responsible for the first contact with host cells, contribute to host colonization and invasion by mediating this process. These fungi also present the capacity to form biofilm and through which they may evade the host's immune system. During infection, Paracoccidioides spp. can interact with different host cell types and has the ability to modulate the host's adaptive and/or innate immune response. In addition, it participates and interferes in the coagulation system and phenomena like cytoskeletal rearrangement and apoptosis. In recent years, Paracoccidioides spp. have had their endemic areas expanding in correlation with the expansion of agriculture. In response, several studies were developed to understand the infection using in vitro and in vivo systems, including alternative non-mammal models. Moreover, new advances were made in treating these infections using both well-established and new antifungal agents. These included natural and/or derivate synthetic substances as well as vaccines, peptides, and anti-adhesins sera. Because of all the advances in the PCM study, this review has the objective to summarize all of the recent discoveries on Paracoccidioides-host interaction, with particular emphasis on fungi surface proteins (molecules that play a fundamental role in the adhesion and/or dissemination of the fungi to host cells), as well as advances in the treatment of PCM with new and well-established antifungal agents and approaches. PMID- 26635784 TI - Erratum: Parasitic diarrheal disease: drug development and targets. AB - [This corrects the article DOI: 10.3389/fmicb.2015.01183.]. PMID- 26635785 TI - Structures of Microbial Communities in Alpine Soils: Seasonal and Elevational Effects. AB - Microbial communities in alpine environments are exposed to several environmental factors related to elevation and local site conditions and to extreme seasonal variations. However, little is known on the combined impact of such factors on microbial community structure. We assessed the effects of seasonal variations on soil fungal and bacterial communities along an elevational gradient (from alpine meadows to a glacier forefield, 1930-2519 m a.s.l.) over 14 months. Samples were taken during all four seasons, even under the winter snowpack and at snowmelt. Microbial community structures and abundances were investigated using Terminal Restriction Fragment Length Polymorphism (T-RFLP) and quantitative PCR (qPCR) of the 16S and 18S rRNA genes. Illumina sequencing was performed to identify key bacterial groups in selected samples. We found that the soil properties varied significantly with the seasons and along the elevational gradient. For example, concentrations of soluble nutrients (e.g., [Formula: see text], [Formula: see text], [Formula: see text]) significantly increased in October but decreased drastically under the winter snowpack. At all times, the alpine meadows showed higher soluble nutrient concentrations than the glacier forefield. Microbial community structures at the different sites were strongly affected by seasonal variations. Under winter snowpack, bacterial communities were dominated by ubiquitous groups (i.e., beta-Proteobacteria, which made up to 25.7% of the total reads in the glacier forefield). In the snow-free seasons, other groups (i.e., Cyanobacteria) became more abundant (from 1% under winter snow in the glacier forefield samples to 8.1% in summer). In summary, elevation had a significant effect on soil properties, whereas season influenced soil properties as well as microbial community structure. Vegetation had a minor impact on microbial communities. At every elevation analyzed, bacterial, and fungal community structures exhibited a pronounced annual cycle. PMID- 26635786 TI - Exploring Amino Acid Auxotrophy in Bifidobacterium bifidum PRL2010. AB - The acquisition and assimilation strategies followed by members of the infant gut microbiota to retrieve nitrogen from the gut lumen are still largely unknown. In particular, no information on these metabolic processes is available regarding bifidobacteria, which are among the first microbial colonizers of the human intestine. Here, evaluation of amino acid auxotrophy and prototrophy of Bifidobacterium bifidum, with particular emphasis on B. bifidum strain PRL2010 (LMG S-28692), revealed a putative auxotrophy for cysteine. In addition, we hypothesized that cysteine plays a role in the oxidative stress response in B. bifidum. The use of glutathione as an alternative reduced sulfur compound did not alleviate cysteine auxotrophy of this strain, though it was shown to stimulate expression of the genes involved in cysteine biosynthesis, reminiscent of oxidative stress response. When PRL2010 was grown on a medium containing complex substrates, such as whey proteins or casein hydrolysate, we noticed a distinct growth-promoting effect of these compounds. Transcriptional analysis involving B. bifidum PRL2010 cultivated on whey proteins or casein hydrolysate revealed that the biosynthetic pathways for cysteine and methionine are modulated by the presence of casein hydrolysate. Such findings support the notion that certain complex substrates may act as potential prebiotics for bifidobacteria in their ecological niche. PMID- 26635788 TI - Advances in the Prevention of Infection-Related Preterm Birth. AB - Infection-related preterm birth (PTB) is more common at early gestational ages and is associated with major neonatal mortality and morbidity. Abnormal genital tract microflora in early pregnancy predicts late miscarriage and early PTB. Accordingly, it is logical to consider antibiotics as an intervention. Unfortunately, the conclusions of systematic reviews and meta-analyses (SR&MAs) carried out in an attempt to explain the confusion over the heterogeneity of individual studies are flawed by the fact that undue reliance was placed on studies which: (a) had a suboptimal choice of antibiotic (mainly metronidazole) or used antibiotics not recommended for the treatment of bacterial vaginosis (BV) or BV-related organisms; (b) used antibiotics too late in pregnancy to influence outcome (23-27 weeks); and (c) included women whose risk of PTB was not due to abnormal genital tract colonization and hence unlikely to respond to antibiotics. These risks included: (a) previous PTB of indeterminate etiology; (b) low weight/body mass index; or (c) detection of fetal fibronectin, ureaplasmas, Group B streptococcus or Trichomonas vaginalis). While individual studies have found benefit of antibiotic intervention for the prevention of PTB, in meta-analyses these effects have been negated by large methodologically flawed studies with negative results. As a result, many clinicians think that any antibiotic given at any time in pregnancy to any woman at risk of PTB will cause more harm than good. Recently, a more focused SR&MA has demonstrated that antibiotics active against BV-related organisms, used in women whose risk of PTB is due to abnormal microflora, and used early in pregnancy before irreversible inflammatory damage has occurred, can reduce the rate of PTB. This review presents those data, the background and attempts to explain the confusion using new information from culture-independent molecular-based techniques. It also gives guidance on the structure of putative future antibiotic intervention studies. PMID- 26635787 TI - Mechanisms of Microbe-Host Interaction in Crohn's Disease: Dysbiosis vs. Pathobiont Selection. AB - Crohn's disease (CD) is a systemic chronic inflammatory condition mainly characterized by discontinuous transmural pathology of the gastrointestinal tract and frequent extraintestinal manifestations with intermittent episodes of remission and relapse. Genome-wide association studies identified a number of risk loci that, catalyzed by environmental triggers, result in the loss of tolerance toward commensal bacteria based on dysregulated innate effector functions and antimicrobial defense, leading to exacerbated adaptive immune responses responsible for chronic immune-mediated tissue damage. In this review, we discuss the inter-related role of changes in the intestinal microbiota, epithelial barrier integrity, and immune cell functions on the pathogenesis of CD, describing the current approaches available to investigate the molecular mechanisms underlying the disease. Substantial effort has been dedicated to define disease-associated changes in the intestinal microbiota (dysbiosis) and to link pathobionts to the etiology of inflammatory bowel diseases. A cogent definition of dysbiosis is lacking, as well as an agreement of whether pathobionts or complex shifts in the microbiota trigger inflammation in the host. Among the rarely available animal models, SAMP/Yit and TNF(deltaARE) mice are the best known displaying a transmural CD-like phenotype. New hypothesis-driven mouse models, e.g., epithelial-specific Caspase8(-/-), ATG16L1(-/-), and XBP1(-/-) mice, validate pathway-focused function of specific CD-associated risk genes highlighting the role of Paneth cells in antimicrobial defense. To study the causal role of bacteria in initiating inflammation in the host, the use of germ free mouse models is indispensable. Unraveling the interactions of genes, immune cells and microbes constitute a criterion for the development of safe, reliable, and effective treatment options for CD. PMID- 26635789 TI - Estrogen Signaling Modulates Allergic Inflammation and Contributes to Sex Differences in Asthma. AB - Asthma is a chronic airway inflammatory disease that affects ~300 million people worldwide. It is characterized by airway constriction that leads to wheezing, coughing, and shortness of breath. The most common treatments are corticosteroids and beta2-adrenergic receptor antagonists, which target inflammation and airway smooth muscle constriction, respectively. The incidence and severity of asthma is greater in women than in men, and women are more prone to develop corticosteroid resistant or "hard-to-treat" asthma. Puberty, menstruation, pregnancy, menopause, and oral contraceptives are known to contribute to disease outcome in women, suggesting a role for estrogen and other hormones impacting allergic inflammation. Currently, the mechanisms underlying these sex differences are poorly understood, although the effect of sex hormones, such as estrogen, on allergic inflammation is gaining interest. Asthma presents as a heterogeneous disease. In typical Th2-type allergic asthma, interleukin (IL)-4 and IL-13 predominate, driving IgE production and recruitment of eosinophils into the lungs. Chronic Th2-inflammation in the lung results in structural changes and activation of multiple immune cell types, leading to a deterioration of lung function over time. Most immune cells express estrogen receptors (ERalpha, ERbeta, or the membrane-bound G-protein-coupled ER) to varying degrees and can respond to the hormone. Together these receptors have demonstrated the capacity to regulate a spectrum of immune functions, including adhesion, migration, survival, wound healing, and antibody and cytokine production. This review will cover the current understanding of estrogen signaling in allergic inflammation and discuss how this signaling may contribute to sex differences in asthma and allergy. PMID- 26635791 TI - 1,25-Dihydroxyvitamin D3-Conditioned CD11c+ Dendritic Cells are Effective Initiators of CNS Autoimmune Disease. AB - Dendritic cells (DC) play a crucial role in regulating T cell activation. Due to their capacity to shape the immune response, tolerogenic DC have been used to treat autoimmune diseases. In this study, we examined whether 1,25 dihydroxyvitamin D3-conditioned bone marrow-derived DC (VitD-BMDC) were able to limit the development of autoimmune pathology in experimental autoimmune encephalomyelitis (EAE). We found that VitD-BMDC had lower expression of MHC class II and co-stimulatory molecules and were less effective at priming autoreactive T cells in vitro. Using our recently described BMDC-driven model of EAE, we demonstrated that VitD-BMDC had a significantly reduced ability to initiate EAE. We found that the impaired ability of VitD-BMDC to initiate EAE was not due to T cell tolerization. Instead, we discovered that the addition of 1,25(OH)2D3 to BMDC cultures resulted in a significant reduction in the proportion of CD11c+ cells. Purified CD11c+ VitD-BMDC were significantly less effective at priming T cells in vitro yet were similarly capable of initiating EAE as vehicle-treated CD11c+ BMDC. This study demonstrates that in vitro assays of DC function can be a poor predictor of in vivo behavior and that CD11c+ VitD BMDC are highly effective initiators of an autopathogenic T cell response. PMID- 26635790 TI - The Interplay Between Monocytes/Macrophages and CD4(+) T Cell Subsets in Rheumatoid Arthritis. AB - Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by inflammation of the synovial lining (synovitis). The inflammation in the RA joint is associated with and driven by immune cell infiltration, synovial hyperproliferation, and excessive production of proinflammatory mediators, such as tumor necrosis factor alpha (TNFalpha), interferon gamma (IFNgamma), interleukin (IL)-1beta, IL-6, and IL-17, eventually resulting in damage to the cartilage and underlying bone. The RA joint harbors a wide range of immune cell types, including monocytes, macrophages, and CD4(+) T cells (both proinflammatory and regulatory). The interplay between CD14(+) myeloid cells and CD4(+) T cells can significantly influence CD4(+) T cell function, and conversely, effector vs. regulatory CD4(+) T cell subsets can exert profound effects on monocyte/macrophage function. In this review, we will discuss how the interplay between CD4(+) T cells and monocytes/macrophages may contribute to the immunopathology of RA. PMID- 26635794 TI - Anergic B Cells: Precarious On-Call Warriors at the Nexus of Autoimmunity and False-Flagged Pathogens. PMID- 26635792 TI - The Application of Natural Killer Cell Immunotherapy for the Treatment of Cancer. AB - Natural killer (NK) cells are essential components of the innate immune system and play a critical role in host immunity against cancer. Recent progress in our understanding of NK cell immunobiology has paved the way for novel NK cell-based therapeutic strategies for the treatment of cancer. In this review, we will focus on recent advances in the field of NK cell immunotherapy, including augmentation of antibody-dependent cellular cytotoxicity, manipulation of receptor-mediated activation, and adoptive immunotherapy with ex vivo-expanded, chimeric antigen receptor (CAR)-engineered, or engager-modified NK cells. In contrast to T lymphocytes, donor NK cells do not attack non-hematopoietic tissues, suggesting that an NK-mediated antitumor effect can be achieved in the absence of graft-vs. host disease. Despite reports of clinical efficacy, a number of factors limit the application of NK cell immunotherapy for the treatment of cancer, such as the failure of infused NK cells to expand and persist in vivo. Therefore, efforts to enhance the therapeutic benefit of NK cell-based immunotherapy by developing strategies to manipulate the NK cell product, host factors, and tumor targets are the subject of intense research. In the preclinical setting, genetic engineering of NK cells to express CARs to redirect their antitumor specificity has shown significant promise. Given the short lifespan and potent cytolytic function of mature NK cells, they are attractive candidate effector cells to express CARs for adoptive immunotherapies. Another innovative approach to redirect NK cytotoxicity towards tumor cells is to create either bispecific or trispecific antibodies, thus augmenting cytotoxicity against tumor-associated antigens. These are exciting times for the study of NK cells; with recent advances in the field of NK cell biology and translational research, it is likely that NK cell immunotherapy will move to the forefront of cancer immunotherapy over the next few years. PMID- 26635793 TI - Laminin-Mediated Interactions in Thymocyte Migration and Development. AB - Intrathymic T-cell differentiation is a key process for the development and maintenance of cell-mediated immunity, and occurs concomitantly to highly regulated migratory events. We have proposed a multivectorial model for describing intrathymic thymocyte migration. One of the individual vectors comprises interactions mediated by laminins (LMs), a heterotrimeric protein family of the extracellular matrix. Several LMs are expressed in the thymus, being produced by microenvironmental cells, particularly thymic epithelial cells (TECs). Also, thymocytes and epithelial cells express integrin-type LM receptors. Functionally, it has been reported that the dy/dy mutant mouse (lacking the LM isoform 211) exhibits defective thymocyte differentiation. Several data show haptotactic effects of LMs upon thymocytes, as well as their adhesion on TECs; both effects being prevented by anti-LM or anti-LM receptor antibodies. Interestingly, LM synergizes with chemokines to enhance thymocyte migration, whereas classe-3 semaphorins and B ephrins, which exhibit chemorepulsive effects in the thymus, downregulate LM-mediated migratory responses of thymocytes. More recently, we showed that knocking down the ITGA6 gene (which encodes the alpha6 integrin chain of LM receptors) in human TECs modulates a large number of cell migration-related genes and results in changes of adhesion pattern of thymocytes onto the thymic epithelium. Overall, LM-mediated interactions can be placed at the cross-road of the multivectorial process of thymocyte migration, with a direct influence per se, as well as by modulating other molecular interactions associated with the intrathymic-trafficking events. PMID- 26635795 TI - Streptolysin O Rapidly Impairs Neutrophil Oxidative Burst and Antibacterial Responses to Group A Streptococcus. AB - Group A Streptococcus (GAS) causes a wide range of human infections, ranging from simple pharyngitis to life-threatening necrotizing fasciitis and toxic shock syndrome. A globally disseminated clone of M1T1 GAS has been associated with an increase in severe, invasive GAS infections in recent decades. The secreted GAS pore-forming toxin streptolysin O (SLO), which induces eukaryotic cell lysis in a cholesterol-dependent manner, is highly upregulated in the GAS M1T1 clone during bloodstream dissemination. SLO is known to promote GAS resistance to phagocytic clearance by neutrophils, a critical first element of host defense against invasive bacterial infection. Here, we examine the role of SLO in modulating specific neutrophil functions during their early interaction with GAS. We find that SLO at subcytotoxic concentrations and early time points is necessary and sufficient to suppress neutrophil oxidative burst, in a manner reversed by free cholesterol and anti-SLO blocking antibodies. In addition, SLO at subcytotoxic concentrations blocked neutrophil degranulation, interleukin-8 secretion and responsiveness, and elaboration of DNA-based neutrophil extracellular traps, cumulatively supporting a key role for SLO in GAS resistance to immediate neutrophil killing. A non-toxic SLO derivate elicits protective immunity against lethal GAS challenge in a murine infection model. We conclude that SLO exerts a novel cytotoxic-independent function at early stages of invasive infections (<30 min), contributing to GAS escape from neutrophil clearance. PMID- 26635797 TI - NK Cell Subgroups, Phenotype, and Functions After Autologous Stem Cell Transplantation. AB - High-dose chemotherapy with consecutive autologous stem cell transplantation (autoSCT) is a well-established treatment option for patients suffering from malignant lymphoma or multiple myeloma. Natural killer (NK) cells are an important part of the immune surveillance, and their cell number after autoSCT is predictive for progression-free and overall survival. To improve knowledge about the role of NK cells after autoSCT, we investigated different NK cell subgroups, their phenotype, and their functions in patients treated with autoSCT. Directly after leukocyte regeneration (>1000 leukocytes/MUl) following autoSCT, CD56(++) NK cells were the major NK cell subset. Surprisingly, these cells showed unusually high surface expression levels of CD57 and killer Ig-like receptors (KIRs) compared to expression levels before or at later time points after autoSCT. Moreover, these NK cells strongly upregulated KIR2DL2/3/S2 and KIR3DL1, whereas KIR2DL1/S1 remained constant, indicating that this cell population arose from more immature NK cells instead of from activated mature ones. Remarkably, NK cells were already able to degranulate and produce IFN-gamma and MIP-1beta upon tumor interaction early after leukocyte regeneration. In conclusion, we describe an unusual upregulation of CD57 and KIRs on CD56(++) NK cells shortly after autoSCT. Importantly, these NK cells were functionally competent upon tumor interaction at this early time point. PMID- 26635798 TI - Monocyte-Derived Dendritic Cells Are Essential for CD8(+) T Cell Activation and Antitumor Responses After Local Immunotherapy. AB - Tumors harbor several populations of dendritic cells (DCs) with the ability to prime tumor-specific T cells. However, these T cells mostly fail to differentiate into armed effectors and are unable to control tumor growth. We have previously shown that treatment with immunostimulatory agents at the tumor site can activate antitumor immune responses and is associated with the appearance of a population of monocyte-derived DCs (moDCs) in the tumor and tumor-draining lymph node (dLN). Here, we use depletion of DCs or monocytes and monocyte transfer to show that these moDCs are critical to the activation of antitumor immune responses. Treatment with the immunostimulatory agents monosodium urate crystals and Mycobacterium smegmatis induced the accumulation of monocytes in the dLN, their upregulation of CD11c and MHCII, and expression of iNOS, TNFalpha, and IL12p40. Blocking monocyte entry into the lymph node and tumor through neutralization of the chemokine CCL2 or inhibition of colony-stimulating factor-1 receptor signaling prevented the generation of moDCs, the infiltration of tumor-specific T cells into the tumor, and antitumor responses. In a reciprocal fashion, monocytes transferred into mice depleted of CD11c(+) cells were sufficient to rescue CD8(+) T cell priming in lymph node and delay tumor growth. Thus, monocytes exposed to the appropriate conditions become powerful activators of tumor-specific CD8(+) T cells and antitumor immunity. PMID- 26635796 TI - Identifying Individual T Cell Receptors of Optimal Avidity for Tumor Antigens. AB - Cytotoxic T cells recognize, via their T cell receptors (TCRs), small antigenic peptides presented by the major histocompatibility complex (pMHC) on the surface of professional antigen-presenting cells and infected or malignant cells. The efficiency of T cell triggering critically depends on TCR binding to cognate pMHC, i.e., the TCR-pMHC structural avidity. The binding and kinetic attributes of this interaction are key parameters for protective T cell-mediated immunity, with stronger TCR-pMHC interactions conferring superior T cell activation and responsiveness than weaker ones. However, high-avidity TCRs are not always available, particularly among self/tumor antigen-specific T cells, most of which are eliminated by central and peripheral deletion mechanisms. Consequently, systematic assessment of T cell avidity can greatly help distinguishing protective from non-protective T cells. Here, we review novel strategies to assess TCR-pMHC interaction kinetics, enabling the identification of the functionally most-relevant T cells. We also discuss the significance of these technologies in determining which cells within a naturally occurring polyclonal tumor-specific T cell response would offer the best clinical benefit for use in adoptive therapies, with or without T cell engineering. PMID- 26635799 TI - Purinergic Receptors: Key Mediators of HIV-1 Infection and Inflammation. AB - Human immunodeficiency virus type 1 (HIV-1) causes a chronic infection that afflicts more than 30 million individuals worldwide. While the infection can be suppressed with potent antiretroviral therapies, individuals infected with HIV-1 have elevated levels of inflammation as indicated by increased T cell activation, soluble biomarkers, and associated morbidity and mortality. A single mechanism linking HIV-1 pathogenesis to this inflammation has yet to be identified. Purinergic receptors are known to mediate inflammation and have been shown to be required for HIV-1 infection at the level of HIV-1 membrane fusion. Here, we review the literature on the role of purinergic receptors in HIV-1 infection and associated inflammation and describe a role for these receptors as potential therapeutic targets. PMID- 26635801 TI - Cardiac Arrest Disrupts Caspase-1 and Patterns of Inflammatory Mediators Differently in Skin and Muscle Following Localized Tissue Injury in Rats: Insights from Data-Driven Modeling. AB - BACKGROUND: Trauma often cooccurs with cardiac arrest and hemorrhagic shock. Skin and muscle injuries often lead to significant inflammation in the affected tissue. The primary mechanism by which inflammation is initiated, sustained, and terminated is cytokine-mediated immune signaling, but this signaling can be altered by cardiac arrest. The complexity and context sensitivity of immune signaling in general has stymied a clear understanding of these signaling dynamics. METHODOLOGY/PRINCIPAL FINDINGS: We hypothesized that advanced numerical and biological function analysis methods would help elucidate the inflammatory response to skin and muscle wounds in rats, both with and without concomitant shock. Based on the multiplexed analysis of inflammatory mediators, we discerned a differential interleukin (IL)-1alpha and IL-18 signature in skin vs. muscle, which was suggestive of inflammasome activation in the skin. Immunoblotting revealed caspase-1 activation in skin but not muscle. Notably, IL-1alpha and IL 18, along with caspase-1, were greatly elevated in the skin following cardiac arrest, consistent with differential inflammasome activation. CONCLUSION/SIGNIFICANCE: Tissue-specific activation of caspase-1 and the NLRP3 inflammasome appear to be key factors in determining the type and severity of the inflammatory response to tissue injury, especially in the presence of severe shock, as suggested via data-driven modeling. PMID- 26635800 TI - T Lymphocyte Migration: An Action Movie Starring the Actin and Associated Actors. AB - The actin cytoskeleton is composed of a dynamic filament meshwork that builds the architecture of the cell to sustain its fundamental properties. This physical structure is characterized by a continuous remodeling, which allows cells to accomplish complex motility steps such as directed migration, crossing of biological barriers, and interaction with other cells. T lymphocytes excel in these motility steps to ensure their immune surveillance duties. In particular, actin cytoskeleton remodeling is a key to facilitate the journey of T lymphocytes through distinct tissue environments and to tune their stop and go behavior during the scanning of antigen-presenting cells. The molecular mechanisms controlling actin cytoskeleton remodeling during T lymphocyte motility have been only partially unraveled, since the function of many actin regulators has not yet been assessed in these cells. Our review aims to integrate the current knowledge into a comprehensive picture of how the actin cytoskeleton drives T lymphocyte migration. We will present the molecular actors that control actin cytoskeleton remodeling, as well as their role in the different T lymphocyte motile steps. We will also highlight which challenges remain to be addressed experimentally and which approaches appear promising to tackle them. PMID- 26635803 TI - A Comparison of Statistical Methods for the Discovery of Genetic Risk Factors Using Longitudinal Family Study Designs. AB - The etiology of immune-related diseases or traits is often complex, involving many genetic and environmental factors and their interactions. While methodological approaches focusing on an outcome measured at one time point have succeeded in identifying genetic factors involved in immune-related traits, they fail to capture complex disease mechanisms that fluctuate over time. It is increasingly recognized that longitudinal studies, where an outcome is measured at multiple time points, have great potential to shed light on complex disease mechanisms involving genetic factors. However, longitudinal data require specialized statistical methods, especially in family studies where multiple sources of correlation in the data must be modeled. Using simulated data with known genetic effects, we examined the performance of different analytical methods for investigating associations between genetic factors and longitudinal phenotypes in twin data. The simulations were modeled on data from the Quebec Newborn Twin Study, an ongoing population-based longitudinal study of twin births with multiple phenotypes, such as cortisol levels and body mass index, collected multiple times in infancy and early childhood and with sequencing data on immune related genes and pathways. We compared approaches that we classify as (1) family based methods applied to summaries of the observations over time, (2) longitudinal-based methods with simplifications of the familial correlation, and (3) Bayesian family-based method with simplifications of the temporal correlation. We found that for estimation of the genetic main and interaction effects, all methods gave estimates close to the true values and had similar power. If heritability estimation is desired, approaches of type (1) also provide heritability estimates close to the true value. Our work shows that the simpler approaches are likely adequate to detect genetic effects; however, interpretation of these effects is more challenging. PMID- 26635805 TI - High-Risk Cardiovascular Patients: Clinical Features, Comorbidities, and Interconnecting Mechanisms. AB - Cardiovascular disease is the leading cause of death in the Western world with an increase over the last few decades. Atherosclerosis with its different manifestations in the coronary artery tree, the cerebral, as well as peripheral arteries is the basis for cardiovascular events, such as myocardial infarction, stroke, and cardiovascular death. The pathophysiological understanding of the mechanisms that promote the development of vascular disease has changed over the last few decades, leading to the recognition that inflammation and inflammatory processes in the vessel wall are major contributors in atherogenesis. In addition, a subclinical inflammatory status, e.g., in patients with diabetes or the presence of a chronic inflammatory disease, such as rheumatoid arthritis, have been recognized as strong risk factors for cardiovascular disease. The present review will summarize the different inflammatory processes in the vessel wall leading to atherosclerosis and highlight the role of inflammation in diabetes and chronic inflammatory diseases for cardiovascular morbidity and mortality. PMID- 26635802 TI - Molecular and Translational Classifications of DAMPs in Immunogenic Cell Death. AB - The immunogenicity of malignant cells has recently been acknowledged as a critical determinant of efficacy in cancer therapy. Thus, besides developing direct immunostimulatory regimens, including dendritic cell-based vaccines, checkpoint-blocking therapies, and adoptive T-cell transfer, researchers have started to focus on the overall immunobiology of neoplastic cells. It is now clear that cancer cells can succumb to some anticancer therapies by undergoing a peculiar form of cell death that is characterized by an increased immunogenic potential, owing to the emission of the so-called "damage-associated molecular patterns" (DAMPs). The emission of DAMPs and other immunostimulatory factors by cells succumbing to immunogenic cell death (ICD) favors the establishment of a productive interface with the immune system. This results in the elicitation of tumor-targeting immune responses associated with the elimination of residual, treatment-resistant cancer cells, as well as with the establishment of immunological memory. Although ICD has been characterized with increased precision since its discovery, several questions remain to be addressed. Here, we summarize and tabulate the main molecular, immunological, preclinical, and clinical aspects of ICD, in an attempt to capture the essence of this phenomenon, and identify future challenges for this rapidly expanding field of investigation. PMID- 26635806 TI - Cbl-b Deficiency in Mice Results in Exacerbation of Acute and Chronic Stages of Allergic Asthma. AB - Mice sensitized to ovalbumin (OVA) develop allergic airway disease (AAD) with short-term daily OVA aerosol challenge; inflammation resolves with long-term OVA aerosol exposure, resulting in local inhalational tolerance (LIT). Cbl-b is an E3 ubiquitin ligase involved with CD28 signaling; Cbl-b(-/-) effector T cells are resistant to regulatory T cell-mediated suppression in vitro and in vivo. The present study utilized Cbl-b(-/-) mice to investigate the role of Cbl-b in the development of AAD and LIT. Cbl-b(-/-) mice exhibited increased airway inflammation during AAD, which failed to resolve with long-term OVA aerosol exposure. Exacerbation of inflammation in Cbl-b(-/-) mice correlated with increased proinflammatory cytokine levels and expansion of effector T cells in the BAL during AAD, but did not result in either a modulation of lymphocyte subsets in systemic tissues or in OVA-specific IgE in serum. These results implicate a role for Cbl-b in the resolution of allergic airway inflammation. PMID- 26635804 TI - The Neuromodulation of the Intestinal Immune System and Its Relevance in Inflammatory Bowel Disease. AB - One of the main tasks of the immune system is to discriminate and appropriately react to "danger" or "non-danger" signals. This is crucial in the gastrointestinal tract, where the immune system is confronted with a myriad of food antigens and symbiotic microflora that are in constant contact with the mucosa, in addition to any potential pathogens. This large number of antigens and commensal microflora, which are essential for providing vital nutrients, must be tolerated by the intestinal immune system to prevent aberrant inflammation. Hence, the balance between immune activation versus tolerance should be tightly regulated to maintain intestinal homeostasis and to prevent immune activation indiscriminately against all luminal antigens. Loss of this delicate equilibrium can lead to chronic activation of the intestinal immune response resulting in intestinal disorders, such as inflammatory bowel diseases (IBD). In order to maintain homeostasis, the immune system has evolved diverse regulatory strategies including additional non-immunological actors able to control the immune response. Accumulating evidence strongly indicates a bidirectional link between the two systems in which the brain modulates the immune response via the detection of circulating cytokines and via direct afferent input from sensory fibers and from enteric neurons. In the current review, we will highlight the most recent findings regarding the cross-talk between the nervous system and the mucosal immune system and will discuss the potential use of these neuronal circuits and neuromediators as novel therapeutic tools to reestablish immune tolerance and treat intestinal chronic inflammation. PMID- 26635807 TI - Clinical Outlook for Type-1 and FOXP3(+) T Regulatory Cell-Based Therapy. AB - T regulatory cells (Tregs) are subsets of T lymphocytes specialized in modulating antigen-specific immune responses in vivo. Hence, Tregs represent an ideal therapeutic tool to control detrimental immune reactions. Based on solid pre clinical results, investigators started testing the safety and efficacy of Treg based therapies in humans. Despite promising results, a number of issues remain to be solved. We will discuss the results obtained from clinical trials and the challenges and risks we are facing in the further development of Treg-based therapies. PMID- 26635808 TI - Interaction of Intestinal Microorganisms with the Human Host in the Framework of Autoimmune Diseases. AB - Autoimmune diseases, such as systemic lupus erythematosus (SLE), are caused by a complex interaction of environmental-, genetic-, and sex-related factors. Although SLE has traditionally been considered independent from the microbiota, recent work published during the last 5 years suggests a strong connection between SLE and the composition of our gut commensals as one of the main environmental factors linked to this disease. Preliminary data have evidenced that (i) interaction of certain microbial-derived molecules with specific cell receptors and (ii) the influence of certain commensal microorganisms over specific immune cell subsets plays an important role in the pathogenesis of SLE and SLE-like diseases. In addition, epigenetic changes driven by certain microbial groups have been recently proposed as an additional link between gut microbiota and SLE. As immune responses elicited against commensal bacteria are deeply dependent on the composition of the latter, and as microbial populations can be modified by dietary interventions, identifying the precise gut microorganisms responsible for worsening the SLE symptoms is of crucial importance for this and other SLE-related diseases, including antiphospholipid syndrome or lupus nephritis. In this minireview, the current knowledge on the relationships between microbes and SLE and SLE-related diseases is compiled and discussed. PMID- 26635809 TI - Structural Relationship of the Lipid A Acyl Groups to Activation of Murine Toll Like Receptor 4 by Lipopolysaccharides from Pathogenic Strains of Burkholderia mallei, Acinetobacter baumannii, and Pseudomonas aeruginosa. AB - Toll-like receptor 4 (TLR4) is required for activation of innate immunity upon recognition of lipopolysaccharide (LPS) of Gram-negative bacteria. The ability of TLR4 to respond to a particular LPS species is important since insufficient activation may not prevent bacterial growth while excessive immune reaction may lead to immunopathology associated with sepsis. Here, we investigated the biological activity of LPS from Burkholderia mallei that causes glanders, and from the two well-known opportunistic pathogens Acinetobacter baumannii and Pseudomonas aeruginosa (causative agents of nosocomial infections). For each bacterial strain, R-form LPS preparations were purified by hydrophobic chromatography and the chemical structure of lipid A, an LPS structural component, was elucidated by HR-MALDI-TOF mass spectrometry. The biological activity of LPS samples was evaluated by their ability to induce production of proinflammatory cytokines, such as IL-6 and TNF, by bone marrow-derived macrophages. Our results demonstrate direct correlation between the biological activity of LPS from these pathogenic bacteria and the extent of their lipid A acylation. PMID- 26635810 TI - Alloreactive Regulatory T Cells Allow the Generation of Mixed Chimerism and Transplant Tolerance. AB - The induction of donor-specific transplant tolerance is one of the main goals of modern immunology. Establishment of a mixed chimerism state in the transplant recipient has proven to be a suitable strategy for the induction of long-term allograft tolerance; however, current experimental recipient preconditioning protocols have many side effects, and are not feasible for use in future therapies. In order to improve the current mixed chimerism induction protocols, we developed a non-myeloablative bone-marrow transplant (NM-BMT) protocol using retinoic acid (RA)-induced alloantigen-specific Tregs, clinically available immunosuppressive drugs, and lower doses of irradiation. We demonstrate that RA induced alloantigen-specific Tregs in addition to a NM-BMT protocol generates stable mixed chimerism and induces tolerance to allogeneic secondary skin allografts in mice. Therefore, the establishment of mixed chimerism through the use of donor-specific Tregs rather than non-specific immunosuppression could have a potential use in organ transplantation. PMID- 26635812 TI - A Diverse Repertoire of CD4 T Cells Targets the Immediate-Early 1 Protein of Human Cytomegalovirus. AB - T-cell responses to the immediate-early 1 (IE-1) protein of human cytomegalovirus (HCMV) are associated with protection from viral disease. Thus, IE-1 is a promising target for immunotherapy. CD8 T-cell responses to IE-1 are generally strong. In contrast, CD4 T-cell responses to IE-1 were described to be comparatively infrequent or undetectable in HCMV carriers, and information on their target epitopes and their function has been limited. To analyze the repertoire of IE-1-specific CD4 T cells, we expanded them from healthy donors with autologous IE-1-expressing mini-Epstein-Barr virus-transformed B-cell lines and established IE-1-specific CD4 T-cell clones. Clones from seven out of seven HCMV-positive donors recognized endogenously processed IE-1 epitopes restricted through HLA-DR, DQ, or DP. Three to seven IE-1 epitopes were recognized per donor. Cumulatively, about 27 different HLA/peptide class II complexes were recognized by 117 IE-1-specific clones. Our results suggest that a highly diversified repertoire of IE-1-specific CD4 T cells targeting multiple epitopes is usually present in healthy HCMV carriers. Therefore, multiepitope approaches to immunomonitoring and immunotherapy will make optimal use of this potentially important class of HCMV-specific effector cells. PMID- 26635811 TI - Macrophage and Innate Lymphoid Cell Interplay in the Genesis of Fibrosis. AB - Fibrosis is a characteristic pathological feature of an array of chronic diseases, where development of fibrosis in tissue can lead to marked alterations in the architecture of the affected organs. As a result of this process of sustained attrition to organs, many diseases that involve fibrosis are often progressive conditions and have a poor long-term prognosis. Inflammation is often a prelude to fibrosis, with innate and adaptive immunity involved in both the initiation and regulation of the fibrotic process. In this review, we will focus on the emerging roles of the newly described innate lymphoid cells (ILCs) in the generation of fibrotic disease with an examination of the potential interplay between ILC and macrophages and the adaptive immune system. PMID- 26635813 TI - Editorial: Influenza Virus Vaccines and Immunotherapies. PMID- 26635814 TI - Macrophages During the Fibrotic Process: M2 as Friend and Foe. AB - Macrophages play essential activities in homeostasis maintenance during different organism's conditions. They may be polarized according to various stimuli, which subsequently subdivide them into distinct populations. Macrophages with inflammatory activity function mainly during pathological context, while those with regulatory activity control inflammation and also remodel the repairing process. Here, we propose to review and to present a concise discuss on the role of different components during tissue repair, including those related to innate immune receptors and metabolic modifications. The scar formation is directly related to the degree of inflammation, but also with the appearance of M2 macrophages. In spite of greater numbers of macrophages in the fibrotic phase, regulatory macrophages present some characteristics related to promotion of fibrosis but also with the control of scar formation. These regulatory macrophages present an oxidative metabolism, and differ from the initial inflammatory macrophages, which in turn, present a glycolytic characteristic, which allow regulatory ones to optimize the oxygen consumption and minimizing their ROS production. We will emphasize the difference in macrophage subpopulations and the origin and plasticity of these cells during fibrotic processes. PMID- 26635816 TI - Involvement of CD8(+) T Cells in Multiple Sclerosis. AB - Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system characterized by focal demyelination patches associated with inflammatory infiltrates containing T lymphocytes. For decades, CD4(+) T cells have been recognized as playing a major role in the disease, especially in animal models, which has led to the development of several therapies. However, interest has recently developed in the involvement of CD8(+) T cells in MS following the analysis of infiltrating T cells in human brain lesions. A broad range of evidence now suggests that the pathological role of this T cell subset in MS may have been underestimated. In this review, we summarize the literature implicating CD8(+) T cells in the pathophysiology of MS. We present data from studies in the fields of genetics, anatomopathology and immunology, mainly in humans but also in animal models of MS. Altogether, this strongly suggests that CD8(+) T cells may be major effectors in the disease process, and that the development of treatments specifically targeting this subset would be germane. PMID- 26635815 TI - T Lymphocyte-Endothelial Interactions: Emerging Understanding of Trafficking and Antigen-Specific Immunity. AB - Antigen-specific immunity requires regulated trafficking of T cells in and out of diverse tissues in order to orchestrate lymphocyte development, immune surveillance, responses, and memory. The endothelium serves as a unique barrier, as well as a sentinel, between the blood and the tissues, and as such it plays an essential locally tuned role in regulating T cell migration and information exchange. While it is well established that chemoattractants and adhesion molecules are major determinants of T cell trafficking, emerging studies have now enumerated a large number of molecular players as well as a range of discrete cellular remodeling activities (e.g., transmigratory cups and invadosome-like protrusions) that participate in directed migration and pathfinding by T cells. In addition to providing trafficking cues, intimate cell-cell interaction between lymphocytes and endothelial cells provide instruction to T cells that influence their activation and differentiation states. Perhaps the most intriguing and underappreciated of these "sentinel" roles is the ability of the endothelium to act as a non-hematopoietic "semiprofessional" antigen-presenting cell. Close contacts between circulating T cells and antigen-presenting endothelium may play unique non-redundant roles in shaping adaptive immune responses within the periphery. A better understanding of the mechanisms directing T cell trafficking and the antigen-presenting role of the endothelium may not only increase our knowledge of the adaptive immune response but also empower the utility of emerging immunomodulatory therapeutics. PMID- 26635817 TI - Molecular Breeding Strategy and Challenges Towards Improvement of Blast Disease Resistance in Rice Crop. AB - Rice is a staple and most important security food crop consumed by almost half of the world's population. More rice production is needed due to the rapid population growth in the world. Rice blast caused by the fungus, Magnaporthe oryzae is one of the most destructive diseases of this crop in different part of the world. Breakdown of blast resistance is the major cause of yield instability in several rice growing areas. There is a need to develop strategies providing long-lasting disease resistance against a broad spectrum of pathogens, giving protection for a long time over a broad geographic area, promising for sustainable rice production in the future. So far, molecular breeding approaches involving DNA markers, such as QTL mapping, marker-aided selection, gene pyramiding, allele mining and genetic transformation have been used to develop new resistant rice cultivars. Such techniques now are used as a low-cost, high throughput alternative to conventional methods allowing rapid introgression of disease resistance genes into susceptible varieties as well as the incorporation of multiple genes into individual lines for more durable blast resistance. The paper briefly reviewed the progress of studies on this aspect to provide the interest information for rice disease resistance breeding. This review includes examples of how advanced molecular method have been used in breeding programs for improving blast resistance. New information and knowledge gained from previous research on the recent strategy and challenges towards improvement of blast disease such as pyramiding disease resistance gene for creating new rice varieties with high resistance against multiple diseases will undoubtedly provide new insights into the rice disease control. PMID- 26635819 TI - Genomic Prediction in Pea: Effect of Marker Density and Training Population Size and Composition on Prediction Accuracy. AB - Pea is an important food and feed crop and a valuable component of low-input farming systems. Improving resistance to biotic and abiotic stresses is a major breeding target to enhance yield potential and regularity. Genomic selection (GS) has lately emerged as a promising technique to increase the accuracy and gain of marker-based selection. It uses genome-wide molecular marker data to predict the breeding values of candidate lines to selection. A collection of 339 genetic resource accessions (CRB339) was subjected to high-density genotyping using the GenoPea 13.2K SNP Array. Genomic prediction accuracy was evaluated for thousand seed weight (TSW), the number of seeds per plant (NSeed), and the date of flowering (BegFlo). Mean cross-environment prediction accuracies reached 0.83 for TSW, 0.68 for NSeed, and 0.65 for BegFlo. For each trait, the statistical method, the marker density, and/or the training population size and composition used for prediction were varied to investigate their effects on prediction accuracy: the effect was large for the size and composition of the training population but limited for the statistical method and marker density. Maximizing the relatedness between individuals in the training and test sets, through the CDmean-based method, significantly improved prediction accuracies. A cross-population cross validation experiment was further conducted using the CRB339 collection as a training population set and nine recombinant inbred lines populations as test set. Prediction quality was high with mean Q (2) of 0.44 for TSW and 0.59 for BegFlo. Results are discussed in the light of current efforts to develop GS strategies in pea. PMID- 26635818 TI - Global analysis of WRKY transcription factor superfamily in Setaria identifies potential candidates involved in abiotic stress signaling. AB - Transcription factors (TFs) are major players in stress signaling and constitute an integral part of signaling networks. Among the major TFs, WRKY proteins play pivotal roles in regulation of transcriptional reprogramming associated with stress responses. In view of this, genome- and transcriptome-wide identification of WRKY TF family was performed in the C4model plants, Setaria italica (SiWRKY) and S. viridis (SvWRKY), respectively. The study identified 105 SiWRKY and 44 SvWRKY proteins that were computationally analyzed for their physicochemical properties. Sequence alignment and phylogenetic analysis classified these proteins into three major groups, namely I, II, and III with majority of WRKY proteins belonging to group II (53 SiWRKY and 23 SvWRKY), followed by group III (39 SiWRKY and 11 SvWRKY) and group I (10 SiWRKY and 6 SvWRKY). Group II proteins were further classified into 5 subgroups (IIa to IIe) based on their phylogeny. Domain analysis showed the presence of WRKY motif and zinc finger-like structures in these proteins along with additional domains in a few proteins. All SiWRKY genes were physically mapped on the S. italica genome and their duplication analysis revealed that 10 and 8 gene pairs underwent tandem and segmental duplications, respectively. Comparative mapping of SiWRKY and SvWRKY genes in related C4 panicoid genomes demonstrated the orthologous relationships between these genomes. In silico expression analysis of SiWRKY and SvWRKY genes showed their differential expression patterns in different tissues and stress conditions. Expression profiling of candidate SiWRKY genes in response to stress (dehydration and salinity) and hormone treatments (abscisic acid, salicylic acid, and methyl jasmonate) suggested the putative involvement of SiWRKY066 and SiWRKY082 in stress and hormone signaling. These genes could be potential candidates for further characterization to delineate their functional roles in abiotic stress signaling. PMID- 26635820 TI - Extracellular peptidases of the cereal pathogen Fusarium graminearum. AB - The plant pathogenic fungus Fusarium graminearum (Fgr) creates economic and health risks in cereals agriculture. Fgr causes head blight (or scab) of wheat and stalk rot of corn, reducing yield, degrading grain quality, and polluting downstream food products with mycotoxins. Fungal plant pathogens must secrete proteases to access nutrition and to breakdown the structural protein component of the plant cell wall. Research into the proteolytic activity of Fgr is hindered by the complex nature of the suite of proteases secreted. We used a systems biology approach comprising genome analysis, transcriptomics and label-free quantitative proteomics to characterize the peptidases deployed by Fgr during growth. A combined analysis of published microarray transcriptome datasets revealed seven transcriptional groupings of peptidases based on in vitro growth, in planta growth, and sporulation behaviors. A high resolution mass spectrometry based proteomics analysis defined the extracellular proteases secreted by F. graminearum. A meta-classification based on sequence characters and transcriptional/translational activity in planta and in vitro provides a platform to develop control strategies that target Fgr peptidases. PMID- 26635821 TI - Influence of light and shoot development stage on leaf photosynthesis and carbohydrate status during the adventitious root formation in cuttings of Corylus avellana L. AB - Adventitious root formation in plant cuttings is influenced by many endogenous and environmental factors. Leaf photosynthesis during rooting of leafy cuttings in hard to root species can contribute to supply carbohydrates to the intensive metabolic processes related to adventious root formation. Light intensity during rooting is artificially kept low to decrease potential cutting desiccation, but can be limiting for photosynthetic activity. Furthermore, leafy cuttings collected from different part of the shoot can have a different ability to fuel adventitious root formation in cutting stem. The aim of this work was to determine the role of leaf photosynthesis on adventitious root formation in hazelnut (Corylus avellana L) (a hard-to-root specie) leafy cuttings and to investigate the possible influence of the shoot developmental stage on cutting rooting and survival in the post-rooting phase. Cutting rooting was closely related to carbohydrate content in cutting stems during the rooting process. Cutting carbohydrate status was positively influenced by leaf photosynthesis during rooting. Non-saturating light exposure of leafy cuttings can contribute to improve photosynthetic activity of leafy cuttings. Collection of cuttings from different part of the mother shoots influenced rooting percentage and this appear related to the different capability to concentrate soluble sugars in the cutting stem during rooting. Adventitious root formation depend on the carbohydrate accumulation at the base of the cutting. Mother shoot developmental stage and leaf photosynthesis appear pivotal factors for adventitious roots formation. PMID- 26635824 TI - Yield and Production Gaps in Rainfed Wheat, Barley, and Canola in Alberta. AB - Improving crop yields are essential to meet the increasing pressure of global food demands. The loss of high quality land, the slowing in annual yield increases of major cereals, increasing fertilizer use, and the effect of this on the environment all indicate that we need to develop new strategies to increase grain yields with less impact on the environment. One strategy that could help address this concern is by narrowing the yield gaps of major crops using improved genetics and management. The objective of this study was to determine wheat (Triticum spp. L.), barley (Hordeum vulgare L.), and canola (Brassica napus L.) yields and production gaps in Alberta. We used 10 years of data (2005-2014) to understand yield variability and input efficiency at a farmers' specified level of management, and the yield potential under optimal management to suggest appropriate pathways for closing yield gaps. Significant management gaps were observed between attainable and actual yields of rainfed wheat (24%), barley (25%), and canola (30%). In addition, genetic gaps (i.e., gaps due to genetic selection) in wheat, barley, and canola were 18, 12, and 5%, respectively. Genetic selection with optimal crop management could increase yields of wheat, barley, and canola significantly, with estimated yield gains of 3.42, 1.92, and 1.65 million tons, respectively, each year under rainfed conditions in Alberta. This paper identifies yield gaps and offers suggestions to improve efficiency in crop production. PMID- 26635823 TI - A Large Family of AvrLm6-like Genes in the Apple and Pear Scab Pathogens, Venturia inaequalis and Venturia pirina. AB - Venturia inaequalis and V. pirina are Dothideomycete fungi that cause apple scab and pear scab disease, respectively. Whole genome sequencing of V. inaequalis and V. pirina isolates has revealed predicted proteins with sequence similarity to AvrLm6, a Leptosphaeria maculans effector that triggers a resistance response in Brassica napus and B. juncea carrying the resistance gene, Rlm6. AvrLm6-like genes are present as large families (>15 members) in all sequenced strains of V. inaequalis and V. pirina, while in L. maculans, only AvrLm6 and a single paralog have been identified. The Venturia AvrLm6-like genes are located in gene-poor regions of the genomes, and mostly in close proximity to transposable elements, which may explain the expansion of these gene families. An AvrLm6-like gene from V. inaequalis with the highest sequence identity to AvrLm6 was unable to trigger a resistance response in Rlm6-carrying B. juncea. RNA-seq and qRT-PCR gene expression analyses, of in planta- and in vitro-grown V. inaequalis, has revealed that many of the AvrLm6-like genes are expressed during infection. An AvrLm6 homolog from V. inaequalis that is up-regulated during infection was shown (using an eYFP-fusion protein construct) to be localized to the sub-cuticular stroma during biotrophic infection of apple hypocotyls. PMID- 26635822 TI - A Genome-wide Combinatorial Strategy Dissects Complex Genetic Architecture of Seed Coat Color in Chickpea. AB - The study identified 9045 high-quality SNPs employing both genome-wide GBS- and candidate gene-based SNP genotyping assays in 172, including 93 cultivated (desi and kabuli) and 79 wild chickpea accessions. The GWAS in a structured population of 93 sequenced accessions detected 15 major genomic loci exhibiting significant association with seed coat color. Five seed color-associated major genomic loci underlying robust QTLs mapped on a high-density intra-specific genetic linkage map were validated by QTL mapping. The integration of association and QTL mapping with gene haplotype-specific LD mapping and transcript profiling identified novel allelic variants (non-synonymous SNPs) and haplotypes in a MATE secondary transporter gene regulating light/yellow brown and beige seed coat color differentiation in chickpea. The down-regulation and decreased transcript expression of beige seed coat color-associated MATE gene haplotype was correlated with reduced proanthocyanidins accumulation in the mature seed coats of beige than light/yellow brown seed colored desi and kabuli accessions for their coloration/pigmentation. This seed color-regulating MATE gene revealed strong purifying selection pressure primarily in LB/YB seed colored desi and wild Cicer reticulatum accessions compared with the BE seed colored kabuli accessions. The functionally relevant molecular tags identified have potential to decipher the complex transcriptional regulatory gene function of seed coat coloration and for understanding the selective sweep-based seed color trait evolutionary pattern in cultivated and wild accessions during chickpea domestication. The genome-wide integrated approach employed will expedite marker-assisted genetic enhancement for developing cultivars with desirable seed coat color types in chickpea. PMID- 26635825 TI - SuMoToRI, an Ecophysiological Model to Predict Growth and Sulfur Allocation and Partitioning in Oilseed Rape (Brassica napus L.) Until the Onset of Pod Formation. AB - Sulfur (S) nutrition in rapeseed (Brassica napus L.) is a major concern for this high S-demanding crop, especially in the context of soil S oligotrophy. Therefore, predicting plant growth, S plant allocation (between the plant's compartments) and S pool partitioning (repartition of the mobile-S vs. non-mobile S fractions) until the onset of reproductive phase could help in the diagnosis of S deficiencies during the early stages. For this purpose, a process-based model, SuMoToRI (Sulfur Model Toward Rapeseed Improvement), was developed up to the onset of pod formation. The key features rely on (i) the determination of the S requirements used for growth (structural and metabolic functions) through critical S dilution curves and (ii) the estimation of a mobile pool of S that is regenerated by daily S uptake and remobilization from senescing leaves. This study describes the functioning of the model and presents the model's calibration and evaluation. SuMoToRI was calibrated and evaluated with independent datasets from greenhouse experiments under contrasting S supply conditions. It is run with a small number of parameters with generic values, except in the case of the radiation use efficiency, which was shown to be modulated by S supply. The model gave satisfying predictions of the dynamics of growth, S allocation between compartments and S partitioning, such as the mobile-S fraction in the leaves, which is an indicator of the remobilization potential toward growing sinks. The mechanistic features of SuMoToRI provide a process-based framework that has enabled the description of the S remobilizing process in a species characterized by senescence during the vegetative phase. We believe that this model structure could be useful for modeling S dynamics in other arable crops that have similar senescence-related characteristics. PMID- 26635826 TI - Water Stress Responses of Tomato Mutants Impaired in Hormone Biosynthesis Reveal Abscisic Acid, Jasmonic Acid and Salicylic Acid Interactions. AB - To investigate the putative crosstalk between JA and ABA in Solanum lycopersicum plants in response to drought, suppressor of prosystemin-mediated responses2 (spr2, JA-deficient) and flacca (flc, ABA-deficient) mutants together with the naphthalene/salicylate hydroxylase (NahG) transgenic (SA-deficient) line were used. Hormone profiling and gene expression of key enzymes in ABA, JA and SA biosynthesis were analyzed during early stages of drought. ABA accumulation was comparable in spr2 and wild type (WT) plants whereas expression of 9-cis epoxycarotenoid dioxygenase 1 (NCED1) and NCED2 was different, implying a compensation mechanism between NCED genes and an organ-specific regulation of NCED1 expression. JA levels and 12-oxo-phytodienoic acid reductase 3 (OPR3) expression in flc plants suggest that ABA regulates the induction of the OPR3 gene in roots. By contrast, ABA treatment to flc plants leads to a reduction of JA and SA contents. Furthermore, different pattern of SA accumulation (and expression of isochorismate synthase and phenylalanine ammonia lyase 1) was observed between WT seedlings and mutants, suggesting that SA plays an important role on the early response of tomato plants to drought and also that JA and ABA modulate its biosynthesis. Finally, hormone profiling in spr2 and NahG plants indicate a crosstalk between JA and SA that could enhance tolerance of tomato to water stress. PMID- 26635827 TI - Multi-Level Interactions Between Heat Shock Factors, Heat Shock Proteins, and the Redox System Regulate Acclimation to Heat. AB - High temperature has become a global concern because it seriously affects the growth and reproduction of plants. Exposure of plant cells to high temperatures result in cellular damage and can even lead to cell death. Part of the damage can be ascribed to the action of reactive oxygen species (ROS), which accumulate during abiotic stresses such as heat stress. ROS are toxic and can modify other biomacromolecules including membrane lipids, DNA, and proteins. In order to protect the cells, ROS scavenging is essential. In contrast with their inherent harms, ROS also function as signaling molecules, inducing stress tolerance mechanisms. This review examines the evidence for crosstalk between the classical heat stress response, which consists of heat shock factors (HSFs) and heat shock proteins (HSPs), with the ROS network at multiple levels in the heat response process. Heat stimulates HSF activity directly, but also indirectly via ROS. HSFs in turn stimulate the expression of HSP chaperones and also affect ROS scavenger gene expression. In the short term, HSFs repress expression of superoxide dismutase scavenger genes via induction of miRNA398, while they also activate scavenger gene expression and stabilize scavenger protein activity via HSP induction. We propose that these contrasting effects allow for the boosting of the heat stress response at the very onset of the stress, while preventing subsequent oxidative damage. The described model on HSFs, HSPs, ROS, and ROS scavenger interactions seems applicable to responses to stresses other than heat and may explain the phenomenon of crossacclimation. PMID- 26635828 TI - G-protein Signaling Components GCR1 and GPA1 Mediate Responses to Multiple Abiotic Stresses in Arabidopsis. AB - G-protein signaling components have been implicated in some individual stress responses in Arabidopsis, but have not been comprehensively evaluated at the genetic and biochemical level. Stress emerged as the largest functional category in our whole transcriptome analyses of knock-out mutants of GCR1 and/or GPA1 in Arabidopsis (Chakraborty et al., 2015a,b). This led us to ask whether G-protein signaling components offer converging points in the plant's response to multiple abiotic stresses. In order to test this hypothesis, we carried out detailed analysis of the abiotic stress category in the present study, which revealed 144 differentially expressed genes (DEGs), spanning a wide range of abiotic stresses, including heat, cold, salt, light stress etc. Only 10 of these DEGs are shared by all the three mutants, while the single mutants (GCR1/GPA1) shared more DEGs between themselves than with the double mutant (GCR1-GPA1). RT-qPCR validation of 28 of these genes spanning different stresses revealed identical regulation of the DEGs shared between the mutants. We also validated the effects of cold, heat and salt stresses in all the 3 mutants and WT on % germination, root and shoot length, relative water content, proline content, lipid peroxidation and activities of catalase, ascorbate peroxidase and superoxide dismutase. All the 3 mutants showed evidence of stress tolerance, especially to cold, followed by heat and salt, in terms of all the above parameters. This clearly shows the role of GCR1 and GPA1 in mediating the plant's response to multiple abiotic stresses for the first time, especially cold, heat and salt stresses. This also implies a role for classical G-protein signaling pathways in stress sensitivity in the normal plants of Arabidopsis. This is also the first genetic and biochemical evidence of abiotic stress tolerance rendered by knock-out mutation of GCR1 and/or GPA1. This suggests that G-protein signaling pathway could offer novel common targets for the development of tolerance/resistance to multiple abiotic stresses. PMID- 26635829 TI - Targeting Non-Coding RNAs in Plants with the CRISPR-Cas Technology is a Challenge yet Worth Accepting. AB - Non-coding RNAs (ncRNAs) have emerged as versatile master regulator of biological functions in recent years. MicroRNAs (miRNAs) are small endogenous ncRNAs of 18 24 nucleotides in length that originates from long self-complementary precursors. Besides their direct involvement in developmental processes, plant miRNAs play key roles in gene regulatory networks and varied biological processes. Alternatively, long ncRNAs (lncRNAs) are a large and diverse class of transcribed ncRNAs whose length exceed that of 200 nucleotides. Plant lncRNAs are transcribed by different RNA polymerases, showing diverse structural features. Plant lncRNAs also are important regulators of gene expression in diverse biological processes. There has been a breakthrough in the technology of genome editing, the CRISPR Cas9 (clustered regulatory interspaced short palindromic repeats/CRISPR associated protein 9) technology, in the last decade. CRISPR loci are transcribed into ncRNA and eventually form a functional complex with Cas9 and further guide the complex to cleave complementary invading DNA. The CRISPR-Cas technology has been successfully applied in model plants such as Arabidopsis and tobacco and important crops like wheat, maize, and rice. However, all these studies are focused on protein coding genes. Information about targeting non-coding genes is scarce. Hitherto, the CRISPR-Cas technology has been exclusively used in vertebrate systems to engineer miRNA/lncRNAs, but it is still relatively unexplored in plants. While briefing miRNAs, lncRNAs and applications of the CRISPR-Cas technology in human and animals, this review essentially elaborates several strategies to overcome the challenges of applying the CRISPR-Cas technology in editing ncRNAs in plants and the future perspective of this field. PMID- 26635830 TI - The IDA Peptide Controls Abscission in Arabidopsis and Citrus. AB - Organ abscission is an important process in plant development and reproduction. During abscission, changes in cellular adhesion of specialized abscission zone cells ensure the detachment of infected organs or those no longer serving a function to the plant. In addition, abscission also plays an important role in the release of ripe fruits. Different plant species display distinct patterns and timing of organ shedding, most likely adapted during evolution to their diverse life styles. However, it appears that key regulators of cell separation may have conserved function in different plant species. Here, we investigate the functional conservation of the citrus ortholog of the Arabidopsis peptide ligand INFLORESCENCE DEFICIENT IN ABSCISSION (AtIDA), controlling floral organ abscission. We discuss the possible implications of modifying the citrus IDA ortholog for citrus fruit production. PMID- 26635832 TI - Plastids: The Green Frontiers for Vaccine Production. AB - Infectious diseases pose an increasing risk to health, especially in developing countries. Vaccines are available to either cure or prevent many of these diseases. However, there are certain limitations related to these vaccines, mainly the costs, which make these vaccines mostly unaffordable for people in resource poor countries. These costs are mainly related to production and purification of the products manufactured from fermenter-based systems. Plastid biotechnology has become an attractive platform to produce biopharmaceuticals in large amounts and cost-effectively. This is mainly due to high copy number of plastids DNA in mature chloroplasts, a characteristic particularly important for vaccine production in large amounts. An additional advantage lies in the maternal inheritance of plastids in most plant species, which addresses the regulatory concerns related to transgenic plants. These and many other aspects of plastids will be discussed in the present review, especially those that particularly make these green biofactories an attractive platform for vaccine production. A summary of recent vaccine antigens against different human diseases expressed in plastids will also be presented. PMID- 26635831 TI - Endogenous Cytokinin Overproduction Modulates ROS Homeostasis and Decreases Salt Stress Resistance in Arabidopsis Thaliana. AB - Cytokinins in plants are crucial for numerous biological processes, including seed germination, cell division and differentiation, floral initiation and adaptation to abiotic stresses. The salt stress can promote reactive oxygen species (ROS) production in plants which are highly toxic and ultimately results in oxidative stress. However, the correlation between endogenous cytokinin production and ROS homeostasis in responding to salt stress is poorly understood. In this study, we analyzed the correlation of overexpressing the cytokinin biosynthetic gene AtIPT8 (adenosine phosphate-isopentenyl transferase 8) and the response of salt stress in Arabidopsis. Overproduction of cytokinins, which was resulted by the inducible overexpression of AtIPT8, significantly inhibited the primary root growth and true leaf emergence, especially under the conditions of exogenous salt, glucose and mannitol treatments. Upon cytokinin overproduction, the salt stress resistance was declined, and resulted in less survival rates and chlorophyll content. Interestingly, ROS production was obviously increased with the salt treatment, accompanied by endogenously overproduced cytokinins. The activities of catalase (CAT) and superoxide dismutase (SOD), which are responsible for scavenging ROS, were also affected. Transcription profiling revealed that the differential expressions of ROS-producing and scavenging related genes, the photosynthesis-related genes and stress responsive genes were existed in transgenic plants of overproducing cytokinins. Our results suggested that broken in the homeostasis of cytokinins in plant cells could modulate the salt stress responses through a ROS-mediated regulation in Arabidopsis. PMID- 26635833 TI - The First Attested Extraction of Ancient DNA in Legumes (Fabaceae). AB - Ancient DNA (aDNA) is any DNA extracted from ancient specimens, important for diverse evolutionary researches. The major obstacles in aDNA studies are mutations, contamination and fragmentation. Its studies may be crucial for crop history if integrated with human aDNA research and historical linguistics, both general and relating to agriculture. Legumes (Fabaceae) are one of the richest end economically most important plant families, not only from Neolithic onwards, since they were used as food by Neanderthals and Paleolithic modern man. The idea of extracting and analyzing legume aDNA was considered beneficial for both basic science and applied research, with an emphasis on genetic resources and plant breeding. The first reported successful and attested extraction of the legume aDNA was done from the sample of charred seeds of pea (Pisum sativum) and bitter vetch (Vicia ervilia) from Hissar, southeast Serbia, dated to 1,350-1,000 Before Christ. A modified version of cetyltrimethylammonium bromide (CTAB) method and the commercial kit for DNA extraction QIAGEN DNAesy yielded several ng MUl(-1) of aDNA of both species and, after the whole genome amplification and with a fragment of nuclear ribosomal DNA gene 26S rDNA, resulted in the detection of the aDNA among the PCR products. A comparative analysis of four informative chloroplast DNA regions (trnSG, trnK, matK, and rbcL) among the modern wild and cultivated pea taxa demonstrated not only that the extracted aDNA was genuine, on the basis of mutation rate, but also that the ancient Hissar pea was most likely an early domesticated crop, related to the modern wild pea of a neighboring region. It is anticipated that this premier extraction of legume aDNA may provide taxonomists with the answers to diverse questions, such as leaf development in legumes, as well as with novel data on the single steps in domesticating legume crops worldwide. PMID- 26635834 TI - The Urease Inhibitor NBPT Negatively Affects DUR3-mediated Uptake and Assimilation of Urea in Maize Roots. AB - Despite the widespread use of urease inhibitors in agriculture, little information is available on their effect on nitrogen (N) uptake and assimilation. Aim of this work was to study, at physiological and transcriptional level, the effects of N-(n-butyl) thiophosphoric triamide (NBPT) on urea nutrition in hydroponically grown maize plants. Presence of NBPT in the nutrient solution limited the capacity of plants to utilize urea as a N-source; this was shown by a decrease in urea uptake rate and (15)N accumulation. Noteworthy, these negative effects were evident only when plants were fed with urea, as NBPT did not alter (15)N accumulation in nitrate-fed plants. NBPT also impaired the growth of Arabidopsis plants when urea was used as N-source, while having no effect on plants grown with nitrate or ammonium. This response was related, at least in part, to a direct effect of NBPT on the high affinity urea transport system. Impact of NBPT on urea uptake was further evaluated using lines of Arabidopsis overexpressing ZmDUR3 and dur3-knockout; results suggest that not only transport but also urea assimilation could be compromised by the inhibitor. This hypothesis was reinforced by an over-accumulation of urea and a decrease in ammonium concentration in NBPT-treated plants. Furthermore, transcriptional analyses showed that in maize roots NBPT treatment severely impaired the expression of genes involved in the cytosolic pathway of ureic-N assimilation and ammonium transport. NBPT also limited the expression of a gene coding for a transcription factor highly induced by urea and possibly playing a crucial role in the regulation of its acquisition. This work provides evidence that NBPT can heavily interfere with urea nutrition in maize plants, limiting influx as well as the following assimilation pathway. PMID- 26635835 TI - Qualitative Distinction of Autotrophic and Heterotrophic Processes at the Leaf Level by Means of Triple Stable Isotope (C-O-H) Patterns. AB - Foliar samples were harvested from two oaks, a beech, and a yew at the same site in order to trace the development of the leaves over an entire vegetation season. Cellulose yield and stable isotopic compositions (delta(13)C, delta(18)O, and deltaD) were analyzed on leaf cellulose. All parameters unequivocally define a juvenile and a mature period in the foliar expansion of each species. The accompanying shifts of the delta(13)C-values are in agreement with the transition from remobilized carbohydrates (juvenile period), to current photosynthates (mature phase). While the opponent seasonal trends of delta(18)O of blade and vein cellulose are in perfect agreement with the state-of-art mechanistic understanding, the lack of this discrepancy for deltaD, documented for the first time, is unexpected. For example, the offset range of 18 permil (oak veins) to 57 permil (oak blades) in deltaD may represent a process driven shift from autotrophic to heterotrophic processes. The shared pattern between blade and vein found for both oak and beech suggests an overwhelming metabolic isotope effect on deltaD that might be accompanied by proton transfer linked to the Calvin-cycle. These results provide strong evidence that hydrogen and oxygen are under different biochemical controls even at the leaf level. PMID- 26635836 TI - The Two-Faced Potato Virus X: From Plant Pathogen to Smart Nanoparticle. AB - Potato virus X (PVX) is a single-stranded RNA plant virus, historically investigated in light of the detrimental effects on potato, the world's fourth most important food commodity. The study of the interactions with cells, and more generally with the plant, both locally and systemically, significantly contributed to unveil the mechanisms underlying gene silencing, fundamental not only in plant virology but also in the study of gene expression regulation. Unraveling the molecular events of PVX infection paved the way for the development of different viral expression vectors and consequential applications in functional genomics and in the biosynthesis of heterologous proteins in plants. Apart from that, the ease of manipulation and the knowledge of the virus structure (particle dimensions, shape and physicochemical features) are inspiring novel applications, mainly focused on nanobiotechnology. This review will lead the reader in this area, spanning from fundamental to applied research, embracing fields from plant pathology to vaccine and drug-targeted delivery, imaging and material sciences. Due to the versatile moods, PVX holds promise to become an interesting nanomaterial, in view to create the widest possible arsenal of new "bio-inspired" devices to face evolving issues in biomedicine and beyond. PMID- 26635837 TI - Elevated CO 2 Reduced Floret Death in Wheat Under Warmer Average Temperatures and Terminal Drought. AB - Elevated CO2 often increases grain yield in wheat by enhancing grain number per ear, which can result from an increase in the potential number of florets or a reduction in the death of developed florets. The hypotheses that elevated CO2 reduces floret death rather than increases floret development, and that grain size in a genotype with more grains per unit area is limited by the rate of grain filling, were tested in a pair of sister lines contrasting in tillering capacity (restricted- vs. free-tillering). The hypotheses were tested under elevated CO2, combined with +3 degrees C above ambient temperature and terminal drought, using specialized field tunnel houses. Elevated CO2 increased net leaf photosynthetic rates and likely the availability of carbon assimilates, which significantly reduced the rates of floret death and increased the potential number of grains at anthesis in both sister lines by an average of 42%. The restricted-tillering line had faster grain-filling rates than the free-tillering line because the free tillering line had more grains to fill. Furthermore, grain-filling rates were faster under elevated CO2 and +3 degrees C above ambient. Terminal drought reduced grain yield in both lines by 19%. Elevated CO2 alone increased the potential number of grains, but a trade-off in yield components limited grain yield in the free-tillering line. This emphasizes the need for breeding cultivars with a greater potential number of florets, since this was not affected by the predicted future climate variables. PMID- 26635838 TI - From Genetics to Functional Genomics: Improvement in Drought Signaling and Tolerance in Wheat. AB - Drought being a yield limiting factor has become a major threat to international food security. It is a complex trait and drought tolerance response is carried out by various genes, transcription factors (TFs), microRNAs (miRNAs), hormones, proteins, co-factors, ions, and metabolites. This complexity has limited the development of wheat cultivars for drought tolerance by classical breeding. However, attempts have been made to fill the lost genetic diversity by crossing wheat with wild wheat relatives. In recent years, several molecular markers including single nucleotide polymorphisms (SNPs) and quantitative trait loci (QTLs) associated with genes for drought signaling pathways have been reported. Screening of large wheat collections by marker assisted selection (MAS) and transformation of wheat with different genes/TFs has improved drought signaling pathways and tolerance. Several miRNAs also provide drought tolerance to wheat by regulating various TFs/genes. Emergence of OMICS techniques including transcriptomics, proteomics, metabolomics, and ionomics has helped to identify and characterize the genes, proteins, metabolites, and ions involved in drought signaling pathways. Together, all these efforts helped in understanding the complex drought tolerance mechanism. Here, we have reviewed the advances in wide hybridization, MAS, QTL mapping, miRNAs, transgenic technique, genome editing system, and above mentioned functional genomics tools for identification and utility of signaling molecules for improvement in wheat drought tolerance. PMID- 26635839 TI - Identification and Phylogenetic Analysis of a Novel Starch Synthase in Maize. AB - Starch is an important reserve of carbon and energy in plants, providing the majority of calories in the human diet and animal feed. Its synthesis is orchestrated by several key enzymes, and the amount and structure of starch, affecting crop yield and quality, are determined mainly by starch synthase (SS) activity. To date, five SS isoforms, including SSI-IV and Granule Bound Starch Synthase (GBSS) have been identified and their physiological functions have been well characterized. Here, we report the identification of a new SS isoform in maize, designated SSV. By searching sequenced genomes, SSV has been found in all green plants with conserved sequences and gene structures. Our phylogenetic analysis based on 780 base pairs has suggested that SSIV and SSV resulted from a gene duplication event, which may have occurred before the algae formation. An expression profile analysis of SSV in maize has indicated that ZmSSV is mainly transcribed in the kernel and ear leaf during the grain filling stage, which is partly similar to other SS isoforms. Therefore, it is likely that SSV may play an important role in starch biosynthesis. Subsequent analysis of SSV function may facilitate understanding the mechanism of starch granules formation, number and structure. PMID- 26635840 TI - Metabolic Adaptations of White Lupin Roots and Shoots under Phosphorus Deficiency. AB - White lupin (Lupinus albus L.) is highly adapted to phosphorus-diminished soils. P-deficient white lupin plants modify their root architecture and physiology to acquire sparingly available soil phosphorus. We employed gas chromatography-mass spectrometry (GC-MS) for metabolic profiling of P-deficient white lupins, to investigate biochemical pathways involved in the P-acquiring strategy. After 14 days of P-deficiency, plants showed reduced levels of fructose, glucose, and sucrose in shoots. Phosphorylated metabolites such as glucose-6-phosphate, fructose-6-phosphate, myo-inositol-phosphate and glycerol-3-phosphate were reduced in both shoots and roots. After 22 days of P-deficiency, no effect on shoot or root sugar metabolite levels was found, but the levels of phosphorylated metabolites were further reduced. Organic acids, amino acids and several shikimate pathway products showed enhanced levels in 22-day-old P-deficient roots and shoots. These results indicate that P-deficient white lupins adapt their carbohydrate partitioning between shoot and root in order to supply their growing root system as an early response to P-deficiency. Organic acids are released into the rhizosphere to mobilize phosphorus from soil particles. A longer period of P deficiency leads to scavenging of Pi from P-containing metabolites and reduced protein anabolism, but enhanced formation of secondary metabolites. The latter can serve as stress protection molecules or actively acquire phosphorus from the soil. PMID- 26635841 TI - Wrinkled1 Accelerates Flowering and Regulates Lipid Homeostasis between Oil Accumulation and Membrane Lipid Anabolism in Brassica napus. AB - Wrinkled1 (WRI1) belongs to the APETALA2 transcription factor family; it is unique to plants and is a central regulator of oil synthesis in Arabidopsis. The effects of WRI1 on comprehensive lipid metabolism and plant development were unknown, especially in crop plants. This study found that BnWRI1 in Brassica napus accelerated flowering and enhanced oil accumulation in both seeds and leaves without leading to a visible growth inhibition. BnWRI1 decreased storage carbohydrates and increased soluble sugars to facilitate the carbon flux to lipid anabolism. BnWRI1 is localized to the nucleus and directly binds to the AW-box at proximal upstream regions of genes involved in fatty acid (FA) synthesis and lipid assembly. The overexpression (OE) of BnWRI1 resulted in the up-regulation of genes involved in glycolysis, FA synthesis, lipid assembly, and flowering. Lipid profiling revealed increased galactolipids monogalactosyldiacylglycerol (MGDG), digalactosyldiacylglycerol (DGDG), and phosphatidylcholine (PC) in the leaves of OE plants, whereas it exhibited a reduced level of the galactolipids DGDG and MGDG and increased levels of PC, phosphatidylethanolamide, and oil [triacylglycerol (TAG)] in the siliques of OE plants during the early seed development stage. These results suggest that BnWRI1 is important for homeostasis among TAG, membrane lipids and sugars, and thus facilitates flowering and oil accumulation in B. napus. PMID- 26635842 TI - Assessing Conifer Ray Parenchyma for Ecological Studies: Pitfalls and Guidelines. AB - Ray parenchyma is an essential tissue for tree functioning and survival. This living tissue plays a major role for storage and transport of water, nutrients, and non-structural carbohydrates (NSC), thus regulating xylem hydraulics and growth. However, despite the importance of rays for tree carbon and water relations, methodological challenges hamper knowledge about ray intra- and inter tree variability and its ecological meaning. In this study we provide a methodological toolbox for soundly quantifying spatial and temporal variability of different ray features. Anatomical ray features were surveyed in different cutting planes (cross-sectional, tangential, and radial) using quantitative image analysis on stem-wood micro-sections sampled from 41 mature Scots pines (Pinus sylvestris). The percentage of ray surface (PERPAR), a proxy for ray volume, was compared among cutting planes and between early- and latewood to assess measurement-induced variability. Different tangential ray metrics were correlated to assess their similarities. The accuracy of cross-sectional and tangential measurements for PERPAR estimates as a function of number of samples and the measured wood surface was assessed using bootstrapping statistical technique. Tangential sections offered the best 3D insight of ray integration into the xylem and provided the most accurate estimates of PERPAR, with 10 samples of 4 mm(2) showing an estimate within +/-6.0% of the true mean PERPAR (relative 95% confidence interval, CI95), and 20 samples of 4 mm(2) showing a CI95 of +/-4.3%. Cross-sections were most efficient for establishment of time series, and facilitated comparisons with other widely used xylem anatomical features. Earlywood had significantly lower PERPAR (5.77 vs. 6.18%) and marginally fewer initiating rays than latewood. In comparison to tangential sections, PERPAR was systematically overestimated (6.50 vs. 4.92%) and required approximately twice the sample area for similar accuracy. Radial cuttings provided the least accurate PERPAR estimates. This evaluation of ray parenchyma in conifers and the presented guidelines regarding data accuracy as a function of measured wood surface and number of samples represent an important methodological reference for ray quantification, which will ultimately improve the understanding of the fundamental role of ray parenchyma tissue for the performance and survival of trees growing in stressed environments. PMID- 26635843 TI - Proteomic Analysis Reveals Key Proteins and Phosphoproteins upon Seed Germination of Wheat (Triticum aestivum L.). AB - Wheat (Triticum aestivum L.) is one of the oldest cultivated crops and the second most important food crop in the world. Seed germination is the key developmental process in plant growth and development, and poor germination directly affects plant growth and subsequent grain yield. In this study, we performed the first dynamic proteome analysis of wheat seed germination using a two-dimensional differential gel electrophoresis (2D-DIGE)-based proteomic approach. A total of 166 differentially expressed protein (DEP) spots representing 73 unique proteins were identified, which are mainly involved in storage, stress/defense/detoxification, carbohydrate metabolism, photosynthesis, cell metabolism, and transcription/translation/transposition. The identified DEPs and their dynamic expression profiles generally correspond to three distinct seed germination phases after imbibition: storage degradation, physiological processes/morphogenesis, and photosynthesis. Some key DEPs involved in storage substance degradation and plant defense mechanisms, such as globulin 3, sucrose synthase type I, serpin, beta-amylase, and plastid ADP-glucose pyrophosphorylase (AGPase) small subunit, were found to be phosphorylated during seed germination. Particularly, the phosphorylation site Ser(355) was found to be located in the enzyme active region of beta-amylase, which promotes substrate binding. Phosphorylated modification of several proteins could promote storage substance degradation and environmental stress defense during seed germination. The central metabolic pathways involved in wheat seed germination are proposed herein, providing new insights into the molecular mechanisms of cereal seed germination. PMID- 26635844 TI - Induction of Embryogenesis in Brassica Napus Microspores Produces a Callosic Subintinal Layer and Abnormal Cell Walls with Altered Levels of Callose and Cellulose. AB - The induction of microspore embryogenesis produces dramatic changes in different aspects of the cell physiology and structure. Changes at the cell wall level are among the most intriguing and poorly understood. In this work, we used high pressure freezing and freeze substitution, immunolocalization, confocal, and electron microscopy to analyze the structure and composition of the first cell walls formed during conventional Brassica napus microspore embryogenesis, and in cultures treated to alter the intracellular Ca(2+) levels. Our results revealed that one of the first signs of embryogenic commitment is the formation of a callose-rich, cellulose-deficient layer beneath the intine (the subintinal layer), and of irregular, incomplete cell walls. In these events, Ca(2+) may have a role. We propose that abnormal cell walls are due to a massive callose synthesis and deposition of excreted cytoplasmic material, and the parallel inhibition of cellulose synthesis. These features were absent in pollen-like structures and in microspore-derived embryos, few days after the end of the heat shock, where abnormal cell walls were no longer produced. Together, our results provide an explanation to a series of relevant aspects of microspore embryogenesis including the role of Ca(2+) and the occurrence of abnormal cell walls. In addition, our discovery may be the explanation to why nuclear fusions take place during microspore embryogenesis. PMID- 26635845 TI - Research Progress on the use of Plant Allelopathy in Agriculture and the Physiological and Ecological Mechanisms of Allelopathy. AB - Allelopathy is a common biological phenomenon by which one organism produces biochemicals that influence the growth, survival, development, and reproduction of other organisms. These biochemicals are known as allelochemicals and have beneficial or detrimental effects on target organisms. Plant allelopathy is one of the modes of interaction between receptor and donor plants and may exert either positive effects (e.g., for agricultural management, such as weed control, crop protection, or crop re-establishment) or negative effects (e.g., autotoxicity, soil sickness, or biological invasion). To ensure sustainable agricultural development, it is important to exploit cultivation systems that take advantage of the stimulatory/inhibitory influence of allelopathic plants to regulate plant growth and development and to avoid allelopathic autotoxicity. Allelochemicals can potentially be used as growth regulators, herbicides, insecticides, and antimicrobial crop protection products. Here, we reviewed the plant allelopathy management practices applied in agriculture and the underlying allelopathic mechanisms described in the literature. The major points addressed are as follows: (1) Description of management practices related to allelopathy and allelochemicals in agriculture. (2) Discussion of the progress regarding the mode of action of allelochemicals and the physiological mechanisms of allelopathy, consisting of the influence on cell micro- and ultra-structure, cell division and elongation, membrane permeability, oxidative and antioxidant systems, growth regulation systems, respiration, enzyme synthesis and metabolism, photosynthesis, mineral ion uptake, protein and nucleic acid synthesis. (3) Evaluation of the effect of ecological mechanisms exerted by allelopathy on microorganisms and the ecological environment. (4) Discussion of existing problems and proposal for future research directions in this field to provide a useful reference for future studies on plant allelopathy. PMID- 26635846 TI - Expanding Omics Resources for Improvement of Soybean Seed Composition Traits. AB - Food resources of the modern world are strained due to the increasing population. There is an urgent need for innovative methods and approaches to augment food production. Legume seeds are major resources of human food and animal feed with their unique nutrient compositions including oil, protein, carbohydrates, and other beneficial nutrients. Recent advances in next-generation sequencing (NGS) together with "omics" technologies have considerably strengthened soybean research. The availability of well annotated soybean genome sequence along with hundreds of identified quantitative trait loci (QTL) associated with different seed traits can be used for gene discovery and molecular marker development for breeding applications. Despite the remarkable progress in these technologies, the analysis and mining of existing seed genomics data are still challenging due to the complexity of genetic inheritance, metabolic partitioning, and developmental regulations. Integration of "omics tools" is an effective strategy to discover key regulators of various seed traits. In this review, recent advances in "omics" approaches and their use in soybean seed trait investigations are presented along with the available databases and technological platforms and their applicability in the improvement of soybean. This article also highlights the use of modern breeding approaches, such as genome-wide association studies (GWAS), genomic selection (GS), and marker-assisted recurrent selection (MARS) for developing superior cultivars. A catalog of available important resources for major seed composition traits, such as seed oil, protein, carbohydrates, and yield traits are provided to improve the knowledge base and future utilization of this information in the soybean crop improvement programs. PMID- 26635849 TI - A High-Throughput Regeneration and Transformation Platform for Production of Genetically Modified Banana. AB - Banana (Musa spp.) is an important staple food as well as cash crop in tropical and subtropical countries. Various bacterial, fungal, and viral diseases and pests such as nematodes are major constraints in its production and are currently destabilizing the banana production in sub-Saharan Africa. Genetic engineering is a complementary option used for incorporating useful traits in banana to bypass the long generation time, polyploidy, and sterility of most of the cultivated varieties. A robust transformation protocol for farmer preferred varieties is crucial for banana genomics and improvement. A robust and reproducible system for genetic transformation of banana using embryogenic cell suspensions (ECS) has been developed in this study. Two different types of explants (immature male flowers and multiple buds) were tested for their ability to develop ECS in several varieties of banana locally grown in Africa. ECS of banana varieties "Cavendish Williams" and "Gros Michel" were developed using multiple buds, whereas ECS of "Sukali Ndiizi" was developed using immature male flowers. Regeneration efficiency of ECS was about 20,000-50,000 plantlets per ml of settled cell volume (SCV) depending on variety. ECS of three different varieties were transformed through Agrobacterium-mediated transformation using gusA reporter gene and 20-70 independent transgenic events per ml SCV of ECS were regenerated on selective medium. The presence and integration of gusA gene in transgenic plants was confirmed by PCR, dot blot, and Southern blot analysis and expression by histochemical GUS assays. The robust transformation platform was successfully used to generate hundreds of transgenic lines with disease resistance. Such a platform will facilitate the transfer of technologies to national agricultural research systems (NARS) in Africa. PMID- 26635848 TI - Overexpression of Soybean Isoflavone Reductase (GmIFR) Enhances Resistance to Phytophthora sojae in Soybean. AB - Isoflavone reductase (IFR) is an enzyme involved in the biosynthetic pathway of isoflavonoid phytoalexin in plants. IFRs are unique to the plant kingdom and are considered to have crucial roles in plant response to various biotic and abiotic environmental stresses. Here, we report the characterization of a novel member of the soybean isoflavone reductase gene family GmIFR. Overexpression of GmIFR transgenic soybean exhibited enhanced resistance to Phytophthora sojae. Following stress treatments, GmIFR was significantly induced by P. sojae, ethephon (ET), abscisic acid (placeCityABA), salicylic acid (SA). It is located in the cytoplasm when transiently expressed in soybean protoplasts. The daidzein levels reduced greatly for the seeds of transgenic plants, while the relative content of glyceollins in transgenic plants was significantly higher than that of non transgenic plants. Furthermore, we found that the relative expression levels of reactive oxygen species (ROS) of transgenic soybean plants were significantly lower than those of non-transgenic plants after incubation with P. sojae, suggesting an important role of GmIFR might function as an antioxidant to reduce ROS in soybean. The enzyme activity assay suggested that GmIFR has isoflavone reductase activity. PMID- 26635847 TI - Control of Seed Germination and Plant Development by Carbon and Nitrogen Availability. AB - Little is known about the molecular basis of the influence of external carbon/nitrogen (C/N) ratio and other abiotic factors on phytohormones regulation during seed germination and plant developmental processes, and the identification of elements that participate in this response is essential to understand plant nutrient perception and signaling. Sugars (sucrose, glucose) and nitrate not only act as nutrients but also as signaling molecules in plant development. A connection between changes in auxin transport and nitrate signal transduction has been reported in Arabidopsis thaliana through the NRT1.1, a nitrate sensor and transporter that also functions as a repressor of lateral root growth under low concentrations of nitrate by promoting auxin transport. Nitrate inhibits the elongation of lateral roots, but this effect is significantly reduced in abscisic acid (ABA)-insensitive mutants, what suggests that ABA might mediate the inhibition of lateral root elongation by nitrate. Gibberellin (GA) biosynthesis has been also related to nitrate level in seed germination and its requirement is determined by embryonic ABA. These mechanisms connect nutrients and hormones signaling during seed germination and plant development. Thus, the genetic identification of the molecular components involved in nutrients-dependent pathways would help to elucidate the potential crosstalk between nutrients, nitric oxide (NO) and phytohormones (ABA, auxins and GAs) in seed germination and plant development. In this review we focus on changes in C and N levels and how they control seed germination and plant developmental processes through the interaction with other plant growth regulators, such as phytohormones. PMID- 26635850 TI - Micropropagation of Agave salmiana: Means to Production of Antioxidant and Bioactive Principles. AB - Maguey, Agave salmiana, is an important plant for the "pulque" beverage and functional food industries; however, it has several constraints for elite and homogeneous plant production. In this study, a micropropagation process was established to generate in vitro plants. The effect of the method on metabolite content and antioxidant (AOX) activity in regenerated plants was evaluated. Young germinated plantlets were micropropagated from axillary shoots using Murashige and Skoog medium supplemented with L2 vitamins, 0.04 mg/L 2,4 dichlorophenoxyacetic acid and 10 mg/L 6-benzylaminopurine. Total soluble sugars from the aqueous fraction and total phenolic acids, total saponins, and AOX activity of the methanol fraction were determined in wild-type (WT) plants, in in vitro (IN) plants, and ex vitro acclimated plants (EN). The results showed that IN plants have a 50% lower soluble sugar content compared to WT, and EN. The total phenolic acids content was at least 30% higher in micropropagated (IN) and regenerated (EN) plants compared to WT. The total saponin content in IN, and EN plants was 36 and 25 times higher compared to WT. The AOX capacity of IN plants was on average three times higher compared to other treatments. However, no correlation was found between the AOX activity and total phenolic acids or total saponins. A negative and significant correlation (r = -0.927; p = 0.003) was found between the AOX activity and the total soluble sugars content. Micropropagated plants of A. salmiana have a different phytochemical content and bioactivity after the in vitro process compared to WT plants. The micropropagation process could be used as a platform for phytochemical enhancement of Agave plants. PMID- 26635851 TI - Involvement of Plant Stem Cells or Stem Cell-Like Cells in Dedifferentiation. AB - Dedifferentiation is the transformation of cells from a given differentiated state to a less differentiated or stem cell-like state. Stem cell-related genes play important roles in dedifferentiation, which exhibits similar histone modification and DNA methylation features to stem cell maintenance. Hence, stem cell-related factors possibly synergistically function to provide a specific niche beneficial to dedifferentiation. During callus formation in Arabidopsis petioles, cells adjacent to procambium cells (stem cell-like cells) are dedifferentiated and survive more easily than other cell types. This finding indicates that stem cells or stem cell-like cells may influence the dedifferentiating niche. In this paper, we provide a brief overview of stem cell maintenance and dedifferentiation regulation. We also summarize current knowledge of genetic and epigenetic mechanisms underlying the balance between differentiation and dedifferentiation. Furthermore, we discuss the correlation of stem cells or stem cell-like cells with dedifferentiation. PMID- 26635852 TI - Association Analysis of Grain-setting Rates in Apical and Basal Spikelets in Bread Wheat (Triticum aestivum L.). AB - The rates of grain-setting in apical and basal spikelets in wheat directly affect the kernel number per spike (KNPS). In this study, 220 wheat lines from 18 Chinese provinces and five foreign countries were used as a natural population. Phenotypic analysis showed differences in grain-setting rates between apical and basal spikelets. The broad-sense heritability of grain-setting rate in apical spikelets (18.7-21.0%) was higher than that for basal spikelets (9.4-16.4%). Significant correlations were found between KNPS and grain numbers in apical (R (2) = 0.40-0.45, P < 0.01) and basal (R (2) = 0.41-0.56, P < 0.01) spikelets. Seventy two of 106 SSR markers were associated with grain setting, 32 for apical spikelets, and 34 for basal spikelets. The SSR loci were located on 17 chromosomes, except 3A, 3D, 4A, and 7D, and explained 3.7-22.9% of the phenotypic variance. Four markers, Xcfa2153-1A 202 , Xgwm186-5A 118 , Xgwm156-3B 319 , and Xgwm537-7B 210 , showed the largest effects on grain numbers in apical and basal spikelets. High grain numbers in apical and basal spikelets were associated with elite alleles. Ningmai 9, Ning 0569, and Yangmai 18 with high grain-setting rates carried larger numbers of favorable alleles. Comparison of grain numbers in basal and apical spikelets of 35 Yangmai and Ningmai lines indicated that the Ningmai lines had better grain-setting rates (mean 21.4) than the Yangmai lines (16.5). PMID- 26635853 TI - Bioconversion to Raspberry Ketone is Achieved by Several Non-related Plant Cell Cultures. AB - Bioconversion, i.e., the use of biological systems to perform chemical changes in synthetic or natural compounds in mild conditions, is an attractive tool for the production of novel active or high-value compounds. Plant cells exhibit a vast biochemical potential, being able to transform a range of substances, including pharmaceutical ingredients and industrial by-products, via enzymatic processes. The use of plant cell cultures offers possibilities for contained and optimized production processes which can be applied in industrial scale. Raspberry ketone [4-(4-hydroxyphenyl)butan-2-one] is among the most interesting natural flavor compounds, due to its high demand and significant market value. The biosynthesis of this industrially relevant flavor compound is relatively well characterized, involving the condensation of 4-coumaryl-CoA and malonyl-CoA by Type III polyketide synthase to form a diketide, and the subsequent reduction catalyzed by an NADPH-dependent reductase. Raspberry ketone has been successfully produced by bioconversion using different hosts and precursors to establish more efficient and economical processes. In this work, we studied the effect of overexpressed RiZS1 in tobacco on precursor bioconversion to raspberry ketone. In addition, various wild type plant cell cultures were studied for their capacity to carry out the bioconversion to raspberry ketone using either 4-hydroxybenzalacetone or betuligenol as a substrate. Apparently plant cells possess rather widely distributed reductase activity capable of performing the bioconversion to raspberry ketone using cheap and readily available precursors. PMID- 26635854 TI - Corrigendum: Eocene Podocarpium (Leguminosae) from South China and its biogeographic implications. AB - [This corrects the article DOI: 10.3389/fpls.2015.00938.]. PMID- 26635855 TI - Mechanically, the Shoot Apical Meristem of Arabidopsis Behaves like a Shell Inflated by a Pressure of About 1 MPa. AB - In plants, the shoot apical meristem contains the stem cells and is responsible for the generation of all aerial organs. Mechanistically, organogenesis is associated with an auxin-dependent local softening of the epidermis. This has been proposed to be sufficient to trigger outgrowth, because the epidermis is thought to be under tension and stiffer than internal tissues in all the aerial part of the plant. However, this has not been directly demonstrated in the shoot apical meristem. Here we tested this hypothesis in Arabidopsis using indentation methods and modeling. We considered two possible scenarios: either the epidermis does not have unique properties and the meristem behaves as a homogeneous linearly-elastic tissue, or the epidermis is under tension and the meristem exhibits the response of a shell under pressure. Large indentation depths measurements with a large tip (~size of the meristem) were consistent with a shell-like behavior. This also allowed us to deduce a value of turgor pressure, estimated at 0.82+/-0.16 MPa. Indentation with atomic force microscopy provided local measurements of pressure in the epidermis, further confirming the range of values obtained from large deformations. Altogether, our data demonstrate that the Arabidopsis shoot apical meristem behaves like a shell under a MPa range pressure and support a key role for the epidermis in shaping the shoot apex. PMID- 26635856 TI - Comparative Transcriptomic Analyses of Vegetable and Grain Pea (Pisum sativum L.) Seed Development. AB - Understanding the molecular mechanisms regulating pea seed developmental process is extremely important for pea breeding. In this study, we used high-throughput RNA-Seq and bioinformatics analyses to examine the changes in gene expression during seed development in vegetable pea and grain pea, and compare the gene expression profiles of these two pea types. RNA-Seq generated 18.7 G of raw data, which were then de novo assembled into 77,273 unigenes with a mean length of 930 bp. Our results illustrate that transcriptional control during pea seed development is a highly coordinated process. There were 459 and 801 genes differentially expressed at early and late seed maturation stages between vegetable pea and grain pea, respectively. Soluble sugar and starch metabolism related genes were significantly activated during the development of pea seeds coinciding with the onset of accumulation of sugar and starch in the seeds. A comparative analysis of genes involved in sugar and starch biosynthesis in vegetable pea (high seed soluble sugar and low starch) and grain pea (high seed starch and low soluble sugar) revealed that differential expression of related genes at late development stages results in a negative correlation between soluble sugar and starch biosynthetic flux in vegetable and grain pea seeds. RNA Seq data was validated by using real-time quantitative RT-PCR analysis for 30 randomly selected genes. To our knowledge, this work represents the first report of seed development transcriptomics in pea. The obtained results provide a foundation to support future efforts to unravel the underlying mechanisms that control the developmental biology of pea seeds, and serve as a valuable resource for improving pea breeding. PMID- 26635857 TI - Modulation of Chloride Channel Functions by the Plant Lignan Compounds Kobusin and Eudesmin. AB - Plant lignans are diphenolic compounds widely present in vegetables, fruits, and grains. These compounds have been demonstrated to have protective effect against cancer, hypertension and diabetes. In the present study, we showed that two lignan compounds, kobusin and eudesmin, isolated from Magnoliae Flos, could modulate intestinal chloride transport mediated by cystic fibrosis transmembrane conductance regulator (CFTR) and calcium-activated chloride channels (CaCCs). The compounds activated CFTR channel function in both FRT cells and in HT-29 cells. The modulating effects of kobusin and eudesmin on the activity of CaCCgie (CaCC expressed in gastrointestinal epithelial cells) were also investigated, and the result showed that both compounds could stimulate CaCCgie-mediated short-circuit currents and the stimulation was synergistic with ATP. In ex vivo studies, both compounds activated CFTR and CaCCgie chloride channel activities in mouse colonic epithelia. Remarkably, the compounds showed inhibitory effects toward ANO1/CaCC mediated short-circuit currents in ANO1/CaCC-expressing FRT cells, with IC50 values of 100 MUM for kobusin and 200 MUM for eudesmin. In charcoal transit study, both compounds mildly reduced gastrointestinal motility in mice. Taken together, these results revealed a new kind of activity displayed by the lignan compounds, one that is concerned with the modulation of chloride channel function. PMID- 26635858 TI - Evidence of Phytotoxicity and Genotoxicity in Hordeum vulgare L. Exposed to CeO2 and TiO2 Nanoparticles. AB - Engineered nanoscale materials (ENMs) are considered emerging contaminants since they are perceived as a potential threat to the environment and the human health. The reactions of living organisms when exposed to metal nanoparticles (NPs) or NPs of different size are not well known. Very few studies on NPs-plant interactions have been published, so far. For this reason there is also great concern regarding the potential NPs impact to food safety. Early genotoxic and phytotoxic effects of cerium oxide NPs (nCeO2) and titanium dioxide NPs (nTiO2) were investigated in seedlings of Hordeum vulgare L. Caryopses were exposed to an aqueous dispersion of nCeO2 and nTiO2 at, respectively 0, 500, 1000, and 2000 mg l(-1) for 7 days. Genotoxicity was studied by Randomly Amplified Polymorphism DNA (RAPDs) and mitotic index on root tip cells. Differences between treated and control plants were observed in RAPD banding patterns as well as at the chromosomal level with a reduction of cell divisions. At cellular level we monitored the oxidative stress of treated plants in terms of reactive oxygen species (ROS) generation and ATP content. Again nCeO2 influenced clearly these two physiological parameters, while nTiO2 were ineffective. In particular, the dose 500 mg l(-1) showed the highest increase regarding both ROS generation and ATP content; the phenomenon were detectable, at different extent, both at root and shoot level. Total Ce and Ti concentration in seedlings was detected by ICP OES. TEM EDSX microanalysis demonstrated the presence of aggregates of nCeO2 and nTiO2 within root cells of barley. nCeO2 induced modifications in the chromatin aggregation mode in the nuclei of both root and shoot cells. PMID- 26635859 TI - Association Mapping in Scandinavian Winter Wheat for Yield, Plant Height, and Traits Important for Second-Generation Bioethanol Production. AB - A collection of 100 wheat varieties representing more than 100 years of wheat breeding history in Scandinavia was established in order to identify marker-trait associations for plant height (PH), grain yield (GY), and biomass potential for bioethanol production. The field-grown material showed variations in PH from 54 to 122 cm and in GY from 2 to 6.61 t ha(-1). The release of monomeric sugars was determined by high-throughput enzymatic treatment of ligno-cellulosic material and varied between 0.169 and 0.312 g/g dm for glucose (GLU) and 0.146 and 0.283 g/g dm for xylose (XYL). As expected, PH and GY showed to be highly influenced by genetic factors with repeatability (R) equal to 0.75 and 0.53, respectively, while this was reduced for GLU and XYL (R = 0.09 for both). The study of trait correlations showed how old, low-yielding, tall varieties released higher amounts of monomeric sugars after straw enzymatic hydrolysis, showing reduced recalcitrance to bioconversion compared to modern varieties. Ninety-three lines from the collection were genotyped with the DArTseq((r)) genotypic platform and 5525 markers were used for genome-wide association mapping. Six quantitative trait loci (QTLs) for GY, PH, and GLU released from straw were mapped. One QTL for PH was previously reported, while the remaining QTLs constituted new genomic regions linked to trait variation. This paper is one of the first studies in wheat to identify QTLs that are important for bioethanol production based on a genome-wide association approach. PMID- 26635860 TI - A Role of TDIF Peptide Signaling in Vascular Cell Differentiation is Conserved Among Euphyllophytes. AB - Peptide signals mediate a variety of cell-to-cell communication crucial for plant growth and development. During Arabidopsis thaliana vascular development, a CLE (CLAVATA3/EMBRYO SURROUNDING REGION-related) family peptide hormone, TDIF (tracheary element differentiation inhibitory factor), regulates procambial cell fate by its inhibitory activity on xylem differentiation. To address if this activity is conserved among vascular plants, we performed comparative analyses of TDIF signaling in non-flowering vascular plants (gymnosperms, ferns and lycophytes). We identified orthologs of TDIF/CLE as well as its receptor TDR/PXY (TDIF RECEPTOR/PHLOEM INTERCALATED WITH XYLEM) in Ginkgo biloba, Adiantum aethiopicum, and Selaginella kraussiana by RACE-PCR. The predicted TDIF peptide sequences in seed plants and ferns were identical to that of A. thaliana TDIF. We examined the effects of exogenous CLE peptide-motif sequences of TDIF in these species. We found that liquid culturing of dissected leaves or shoots was useful for examining TDIF activity during vascular development. TDIF treatment suppressed xylem/tracheary element differentiation of procambial cells in G. biloba and A. aethiopicum leaves. In contrast, neither TDIF nor putative endogenous TDIF inhibited xylem differentiation in developing shoots and rhizophores of S. kraussiana. These data suggest that activity of TDIF in vascular development is conserved among extant euphyllophytes. In addition to the conserved function, via liquid culturing of its bulbils, we found a novel inhibitory activity on root growth in the fern Asplenium * lucrosum suggesting lineage-specific co-option of peptide signaling occurred during the evolution of vascular plant organs. PMID- 26635861 TI - Phylogeny of Algal Sequences Encoding Carbohydrate Sulfotransferases, Formylglycine-Dependent Sulfatases, and Putative Sulfatase Modifying Factors. AB - Many algae are rich sources of sulfated polysaccharides with biological activities. The physicochemical/rheological properties and biological activities of sulfated polysaccharides are affected by the pattern and number of sulfate moieties. Sulfation of carbohydrates is catalyzed by carbohydrate sulfotransferases (CHSTs) while modification of sulfate moieties on sulfated polysaccharides was presumably catalyzed by sulfatases including formylglycine dependent sulfatases (FGly-SULFs). Post-translationally modification of Cys to FGly in FGly-SULFs by sulfatase modifiying factors (SUMFs) is necessary for the activity of this enzyme. The aims of this study are to mine for sequences encoding algal CHSTs, FGly-SULFs and putative SUMFs from the fully sequenced algal genomes and to infer their phylogenetic relationships to their well characterized counterparts from other organisms. Algal sequences encoding CHSTs, FGly-SULFs, SUMFs, and SUMF-like proteins were successfully identified from green and brown algae. However, red algal FGly-SULFs and SUMFs were not identified. In addition, a group of SUMF-like sequences with different gene structure and possibly different functions were identified for green, brown and red algae. The phylogeny of these putative genes contributes to the corpus of knowledge of an unexplored area. The analyses of these putative genes contribute toward future production of existing and new sulfated carbohydrate polymers through enzymatic synthesis and metabolic engineering. PMID- 26635862 TI - The Small Ethylene Response Factor ERF96 is Involved in the Regulation of the Abscisic Acid Response in Arabidopsis. AB - Ethylene regulates many aspects of plant growth and development including seed germination, leaf senescence, and fruit ripening, and of plant responses to environmental stimuli including both biotic and abiotic stresses. Ethylene response factors (ERFs) are plant-specific transcription factors and are a subfamily of the AP2 (APETALA2)/ERF transcription factor family. The function of many members in this large gene family remains largely unknown. ERF96, a member of the Group IX ERF family transcription factors, has recently been shown to be a transcriptional activator that is involved in plant defense response in Arabidopsis. Here we provide evidence that ERF96 is a positive regulator of abscisic acid (ABA) responses. Bioinformatics analysis indicated that there are a total four small ERFs in Arabidopsis including ERF95, ERF96, ERF97, and ERF98, and that ERF96 forms a cluster with ERF95 and ERF97. By using quantitative RT PCR, we found that ERF96 is expressed in all tissues and organs examined except roots, with relatively high expression in flowers and seeds. Results from the protoplast transfection assay indicated that the EDLL motif-containing C-terminal domain is responsible for ERF96's transcriptional activity. Although loss-of function mutant of ERF96 was morphologically similar to wild type plants, transgenic plants overexpressing ERF96 had smaller rosette size and were delayed in flowering time. In ABA sensitivity assays, we found that ERF96 overexpression plants were hypersensitive to ABA in terms of ABA inhibition of seed germination, early seedling development and root elongation. Consistent with these observations, elevated transcript levels of some ABA-responsive genes including RD29A, ABI5, ABF3, ABF4, P5CS, and COR15A were observed in the transgenic plants in the presence of ABA. However, in the absence of ABA treatment, the transcript levels of these ABA-responsive genes remained largely unchanged. Our experiments also showed that water loss in ERF96 overexpression plants was slower than that in Col wild type plants. Stomatal closure assays indicated that ERF96 overexpression plants had reduced stomatal aperture in the presence of ABA. Taken together, our results suggest that ERF96 positively regulates ABA responses in Arabidopsis. PMID- 26635863 TI - Understanding the Physiology of Postharvest Needle Abscission in Balsam Fir. AB - Balsam fir (Abies balsamea) trees are commonly used as a specialty horticultural species for Christmas trees and associated greenery in eastern Canada and United States. Postharvest needle abscission has always been a problem, but is becoming an even bigger challenge in recent years presumably due to increased autumn temperatures and earlier harvesting practices. An increased understanding of postharvest abscission physiology in balsam fir may benefit the Christmas tree industry while simultaneously advancing our knowledge in senescence and abscission of conifers in general. Our paper describes the dynamics of needle abscission in balsam fir while identifying key factors that modify abscission patterns. Concepts such as genotypic abscission resistance, nutrition, environmental factors, and postharvest changes in water conductance and hormone evolution are discussed as they relate to our understanding of the balsam fir abscission physiology. Our paper ultimately proposes a pathway for needle abscission via ethylene and also suggests other potential alternative pathways based on our current understanding. PMID- 26635865 TI - riboFrame: An Improved Method for Microbial Taxonomy Profiling from Non-Targeted Metagenomics. AB - Non-targeted metagenomics offers the unprecedented possibility of simultaneously investigate the microbial profile and the genetic capabilities of a sample by a direct analysis of its entire DNA content. The assessment of the microbial taxonomic composition is frequently obtained by mapping reads to genomic databases that, although growing, are still limited and biased. Here we present riboFrame, a novel procedure for microbial profiling based on the identification and classification of 16S rDNA sequences in non-targeted metagenomics datasets. Reads overlapping the 16S rDNA genes are identified using Hidden Markov Models and a taxonomic assignment is obtained by naive Bayesian classification. All reads identified as ribosomal are coherently positioned in the 16S rDNA gene, allowing the use of the topology of the gene (i.e., the secondary structure and the location of variable regions) to guide the abundance analysis. We tested and verified the effectiveness of our method on simulated ribosomal data, on simulated metagenomes and on a real dataset. riboFrame exploits the taxonomic potentialities of the 16S rDNA gene in the context of non-targeted metagenomics, giving an accurate perspective on the microbial profile in metagenomic samples. PMID- 26635866 TI - AnGeLi: A Tool for the Analysis of Gene Lists from Fission Yeast. AB - Genome-wide assays and screens typically result in large lists of genes or proteins. Enrichments of functional or other biological properties within such lists can provide valuable insights and testable hypotheses. To systematically detect these enrichments can be challenging and time-consuming, because relevant data to compare against query gene lists are spread over many different sources. We have developed AnGeLi (Analysis of Gene Lists), an intuitive, integrated web tool for comprehensive and customized interrogation of gene lists from the fission yeast, Schizosaccharomyces pombe. AnGeLi searches for significant enrichments among multiple qualitative and quantitative information sources, including gene and phenotype ontologies, genetic and protein interactions, numerous features of genes, transcripts, translation, and proteins such as copy numbers, chromosomal positions, genetic diversity, RNA polymerase II and ribosome occupancy, localization, conservation, half-lives, domains, and molecular weight among others, as well as diverse sets of genes that are co-regulated or lead to the same phenotypes when mutated. AnGeLi uses robust statistics which can be tailored to specific needs. It also provides the option to upload user-defined gene sets to compare against the query list. Through an integrated data submission form, AnGeLi encourages the community to contribute additional curated gene lists to further increase the usefulness of this resource and to get the most from the ever increasing large-scale experiments. AnGeLi offers a rigorous yet flexible statistical analysis platform for rich insights into functional enrichments and biological context for query gene lists, thus providing a powerful exploratory tool through which S. pombe researchers can uncover fresh perspectives and unexpected connections from genomic data. AnGeLi is freely available at: www.bahlerlab.info/AnGeLi. PMID- 26635864 TI - MicroRNA Mechanisms of Action: What have We Learned from Mice? PMID- 26635868 TI - Myeloid Leukemias and Virally Induced Lymphomas in Miniature Inbred Swine: Development of a Large Animal Tumor Model. AB - The lack of a large animal transplantable tumor model has limited the study of novel therapeutic strategies for the treatment of liquid cancers. Swine as a species provide a natural option based on their similarities with humans and their already extensive use in biomedical research. Specifically, the Massachusetts General Hospital miniature swine herd retains unique genetic characteristics that facilitate the study of hematopoietic cell and solid organ transplantation. Spontaneously arising liquid cancers in these swine, specifically myeloid leukemias and B cell lymphomas, closely resemble human malignancies. The ability to establish aggressive tumor cell lines in vitro from these naturally occurring malignancies makes a transplantable tumor model a close reality. Here, we discuss our experience with myeloid and lymphoid tumors in major histocompatibility characterized miniature swine and future approaches regarding the development of a large animal transplantable tumor model. PMID- 26635867 TI - Mapping Mammalian Cell-type-specific Transcriptional Regulatory Networks Using KD CAGE and ChIP-seq Data in the TC-YIK Cell Line. AB - Mammals are composed of hundreds of different cell types with specialized functions. Each of these cellular phenotypes are controlled by different combinations of transcription factors. Using a human non islet cell insulinoma cell line (TC-YIK) which expresses insulin and the majority of known pancreatic beta cell specific genes as an example, we describe a general approach to identify key cell-type-specific transcription factors (TFs) and their direct and indirect targets. By ranking all human TFs by their level of enriched expression in TC-YIK relative to a broad collection of samples (FANTOM5), we confirmed known key regulators of pancreatic function and development. Systematic siRNA mediated perturbation of these TFs followed by qRT-PCR revealed their interconnections with NEUROD1 at the top of the regulation hierarchy and its depletion drastically reducing insulin levels. For 15 of the TF knock-downs (KD), we then used Cap Analysis of Gene Expression (CAGE) to identify thousands of their targets genome wide (KD-CAGE). The data confirm NEUROD1 as a key positive regulator in the transcriptional regulatory network (TRN), and ISL1, and PROX1 as antagonists. As a complimentary approach we used ChIP-seq on four of these factors to identify NEUROD1, LMX1A, PAX6, and RFX6 binding sites in the human genome. Examining the overlap between genes perturbed in the KD-CAGE experiments and genes with a ChIP seq peak within 50 kb of their promoter, we identified direct transcriptional targets of these TFs. Integration of KD-CAGE and ChIP-seq data shows that both NEUROD1 and LMX1A work as the main transcriptional activators. In the core TRN (i.e., TF-TF only), NEUROD1 directly transcriptionally activates the pancreatic TFs HSF4, INSM1, MLXIPL, MYT1, NKX6-3, ONECUT2, PAX4, PROX1, RFX6, ST18, DACH1, and SHOX2, while LMX1A directly transcriptionally activates DACH1, SHOX2, PAX6, and PDX1. Analysis of these complementary datasets suggests the need for caution in interpreting ChIP-seq datasets. (1) A large fraction of binding sites are at distal enhancer sites and cannot be directly associated to their targets, without chromatin conformation data. (2) Many peaks may be non-functional: even when there is a peak at a promoter, the expression of the gene may not be affected in the matching perturbation experiment. PMID- 26635869 TI - Editorial: Advances in Farm Animal Genomic Resources. PMID- 26635870 TI - Genome-Wide Screening of mRNA Expression in Leprosy Patients. AB - Leprosy, an infectious disease caused by Mycobacterium leprae, affects millions of people worldwide. However, little is known regarding its molecular pathophysiological mechanisms. In this study, a comprehensive assessment of human mRNA was performed on leprosy skin lesions by using DNA chip microarrays, which included the entire spectrum of the disease along with its reactional states. Sixty-six samples from leprotic lesions (10TT, 10BT, 10BB, 10BL, 4LL, 14R1, and 10R2) and nine skin biopsies from healthy individuals were used as controls (CC) (ages ranged from 06 to 83 years, 48 were male and 29 female). The evaluation identified 1580 differentially expressed mRNAs [Fold Change (FC) >= 2.0, p <= 0.05] in diseased lesions vs. healthy controls. Some of these genes were observed in all forms of the disease (CD2, CD27, chit1, FA2H, FAM26F, GZMB, MMP9, SLAMF7, UBD) and others were exclusive to reactional forms (Type "1" reaction: GPNMB, IL1B, MICAL2, FOXQ1; Type "2" reaction: AKR1B10, FAM180B, FOXQ1, NNMT, NR1D1, PTX3, TNFRSF25). In literature, these mRNAs have been associated with numerous pathophysiological processes and signaling pathways and are present in a large number of diseases. The role of these mRNAs maybe studied in the context of developing new diagnostic markers and therapeutic targets for leprosy. PMID- 26635872 TI - An Individual-Based Diploid Model Predicts Limited Conditions Under Which Stochastic Gene Expression Becomes Advantageous. AB - Recent studies suggest the existence of a stochasticity in gene expression (SGE) in many organisms, and its non-negligible effect on their phenotype and fitness. To date, however, how SGE affects the key parameters of population genetics are not well understood. SGE can increase the phenotypic variation and act as a load for individuals, if they are at the adaptive optimum in a stable environment. On the other hand, part of the phenotypic variation caused by SGE might become advantageous if individuals at the adaptive optimum become genetically less adaptive, for example due to an environmental change. Furthermore, SGE of unimportant genes might have little or no fitness consequences. Thus, SGE can be advantageous, disadvantageous, or selectively neutral depending on its context. In addition, there might be a genetic basis that regulates magnitude of SGE, which is often referred to as "modifier genes," but little is known about the conditions under which such an SGE-modifier gene evolves. In the present study, we conducted individual-based computer simulations to examine these conditions in a diploid model. In the simulations, we considered a single locus that determines organismal fitness for simplicity, and that SGE on the locus creates fitness variation in a stochastic manner. We also considered another locus that modifies the magnitude of SGE. Our results suggested that SGE was always deleterious in stable environments and increased the fixation probability of deleterious mutations in this model. Even under frequently changing environmental conditions, only very strong natural selection made SGE adaptive. These results suggest that the evolution of SGE-modifier genes requires strict balance among the strength of natural selection, magnitude of SGE, and frequency of environmental changes. However, the degree of dominance affected the condition under which SGE becomes advantageous, indicating a better opportunity for the evolution of SGE in different genetic models. PMID- 26635871 TI - Evaluation of Genome Wide Association Study Associated Type 2 Diabetes Susceptibility Loci in Sub Saharan Africans. AB - Genome wide association studies (GWAS) for type 2 diabetes (T2D) undertaken in European and Asian ancestry populations have yielded dozens of robustly associated loci. However, the genomics of T2D remains largely understudied in sub Saharan Africa (SSA), where rates of T2D are increasing dramatically and where the environmental background is quite different than in these previous studies. Here, we evaluate 106 reported T2D GWAS loci in continental Africans. We tested each of these SNPs, and SNPs in linkage disequilibrium (LD) with these index SNPs, for an association with T2D in order to assess transferability and to fine map the loci leveraging the generally reduced LD of African genomes. The study included 1775 unrelated Africans (1035 T2D cases, 740 controls; mean age 54 years; 59% female) enrolled in Nigeria, Ghana, and Kenya as part of the Africa America Diabetes Mellitus (AADM) study. All samples were genotyped on the Affymetrix Axiom PanAFR SNP array. Forty-one of the tested loci showed transferability to this African sample (p < 0.05, same direction of effect), 11 at the exact reported SNP and 30 others at SNPs in LD with the reported SNP (after adjustment for the number of tested SNPs). TCF7L2 SNP rs7903146 was the most significant locus in this study (p = 1.61 * 10(-8)). Most of the loci that showed transferability were successfully fine-mapped, i.e., localized to smaller haplotypes than in the original reports. The findings indicate that the genetic architecture of T2D in SSA is characterized by several risk loci shared with non African ancestral populations and that data from African populations may facilitate fine mapping of risk loci. The study provides an important resource for meta-analysis of African ancestry populations and transferability of novel loci. PMID- 26635873 TI - Synergic effects between ocellatin-F1 and bufotenine on the inhibition of BHK-21 cellular infection by the rabies virus. AB - BACKGROUND: Rabies is an incurable neglected zoonosis with worldwide distribution characterized as a lethal progressive acute encephalitis caused by a lyssavirus. Animal venoms and secretions have long been studied as new bioactive molecular sources, presenting a wide spectrum of biological effects, including new antiviral agents. Bufotenine, for instance, is an alkaloid isolated from the skin secretion of the anuran Rhinella jimi that inhibits cellular penetration by the rabies virus. Antimicrobial peptides, such as ocellatin-P1 and ocellatin-F1, are present in the skin secretion of anurans from the genus Leptodactylus and provide chemical defense against predators and microorganisms. METHODS: Skin secretion from captive Leptodactylus labyrinthicus was collected by mechanical stimulation, analyzed by liquid chromatography and mass spectrometry, and assayed for antiviral and cytotoxic activities. Synthetic peptides were obtained using solid phase peptide synthesis, purified by liquid chromatography and structurally characterized by mass spectrometry, and assayed in the same models. Cytotoxicity assays based on changes in cellular morphology were performed using baby hamster kidney (BHK-21) cells. Fixed Rabies virus (Pasteur Virus - PV) strain was used for virological assays based on rapid fluorescent focus inhibition test. RESULTS: Herein, we describe a synergic effect between ocellatin-F1 and bufotenine. This synergism was observed when screening the L. labyrinthicus skin secretion for antiviral activities. The active fraction major component was the antimicrobial peptide ocellatin-F1. Nevertheless, when the pure synthetic peptide was assayed, little antiviral activity was detectable. In-depth analyses of the active fraction revealed the presence of residual alkaloids together with ocellatin-F1. By adding sub-effective doses (e.g. < IC50) of pure bufotenine to synthetic ocellatin-F1, the antiviral effect was regained. Moreover, a tetrapetide derived from ocellatin-F1, based on alignment with the virus's glycoprotein region inferred as a possible cell ligand, was able to maintain the synergic antiviral activity displayed by the full peptide. CONCLUSIONS: This novel antiviral synergic effect between a peptide and an alkaloid may present an innovative lead for the study of new antiviral drugs. PMID- 26635874 TI - Relationship between Vitamin D Status and Striae Distensae: A Case-Referent Study. AB - Vitamin D (VD) plays a role in the skin regulation. Striae Distensae (SD) are manifestations of epidermal atrophy that occurs after tissue tearing due to overstretching or rapid growth. The objective of this study was to investigate the relation between serum VD and occurrence of SD in women who had undergone mammaplasty with silicone implants. A case-referent study was conducted. The blood values of 25-hydroxyvitamin D (25OHD) were measured before the surgery. For each patient postoperatively diagnosed with SD, four other participants submitted to the same surgery, without the development of SD, were enrolled as the healthy controls. 67 women with SD after the surgery entered the study. 268 formed the control group. In the serum of healthy controls 25OHD mean was 27 ng/mL, and SD cases presented 20 ng/mL (P = 0.01). Scarce values of VD have been observed in 56.71% of the cases presenting SD and in 39.91% without SD (P = 0.002). Chance of having VD values lower than 20 ng/mL amongst cases with SD is 2.38 (P = 0.0001). Lower serum levels of VD are linked to a higher occurrence of SD. PMID- 26635875 TI - The Prevalence of Gastric Intestinal Metaplasia and Distribution of Helicobacter pylori Infection, Atrophy, Dysplasia, and Cancer in Its Subtypes. AB - Objectives. Gastric intestinal metaplasia (IM) is frequently encountered and is considered a precursor of gastric adenocarcinoma. In the Van region of Turkey, gastric adenocarcinoma incidence is high but the prevalence of gastric IM is not known. Helicobacter pylori (H. pylori) infection is a main factor leading to atrophy, IM, and cancer development in the stomach. The aim of the current study was to investigate the prevalence of IM and its subtypes and the prevalence of H. pylori infection, atrophy, dysplasia, and cancer in gastric IM subtypes. Materials and Methods. This retrospective study was conducted on 560 IM among the 4050 consecutive patients who were undergoing esophagogastroduodenoscopy (EGD) with biopsy between June 2010 and October 2014. Clinical records and endoscopic and histopathologic reports of patients with IM were analyzed. Results. The prevalence of gastric IM was 13.8%. The prevalence of incomplete IM was statistically significantly higher than complete IM. Type III IM was the most frequent subtype. Conclusions. Gastric IM is a common finding in patients undergoing EGD with biopsy in this region. High prevalence of incomplete type IM, especially type III, can be associated with the high prevalence of gastric cancer in our region. PMID- 26635876 TI - Bipolar Transurethral Incision of Bladder Neck Stenoses with Mitomycin C Injection. AB - Introduction. To determine the efficacy of bipolar transurethral incision with mitomycin C (MMC) injection for the treatment of refractory bladder neck stenosis (BNS). Materials and Methods. Patients who underwent bipolar transurethral incision of BNS (TUIBNS) with MMC injection at our institution from 2013 to 2014 were retrospectively reviewed. A total of 2 mg of 40% mitomycin C solution was injected in four quadrants of the treated BNS. Treatment failure was defined as the need for subsequent intervention. Results. Thirteen patients underwent 17 bipolar TUIBNS with MMC injection. Twelve (92%) patients had failed a mean of 2.2 +/- 1.1 prior endoscopic procedures. Median follow-up was 16.5 months (IQR: 14 18.4 months). Initial success was 62%; five (38%) patients had a recurrence with a median time to recurrence of 7.3 months. Four patients underwent a repeat procedure, 2 (50%) of which failed. Overall success was achieved in 77% (10/13) of patients after a mean of 1.3 +/- 0.5 procedures. BNS recurrence was not significantly associated with history of pelvic radiation (33% versus 43%, p = 0.9). There were no serious adverse events. Conclusions. Bipolar TUIBNS with MMC injection was comparable in efficacy to previously reported techniques and did not result in any serious adverse events. PMID- 26635877 TI - Alteration of Blood Parameters and Histoarchitecture of Liver and Kidney of Silver Barb after Chronic Exposure to Quinalphos. AB - Quinalphos (QP) is commonly used for pest control in the agricultural fields surrounding freshwater reservoirs. This study was conducted to evaluate the chronic toxicity of this pesticide on blood parameters and some organs of silver barb, Barbonymus gonionotus. Fish were exposed to two sublethal concentrations, 0.47 ppm and 0.94 ppm, of QP for a period of 28 days. All the blood parameters (red blood cell, hematocrit, and hemoglobin) and blood glucose except for white blood cells decreased with increasing concentration of toxicant and become significantly lower (p < 0.05) at higher concentration when compared with control. The derived hematological indices of mean corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration were equally altered compared to control. Histoarchitectural changes of liver and kidney were observed after exposure to the QP. Hypertrophy of hepatocytes, mild to severe necrosis, ruptured central vein, and vacuolation were observed in the liver of treated groups. Highly degenerated kidney tubules and hematopoietic tissue, degeneration of renal corpuscle, vacuolization, and necrosis were evident in the kidney of treated groups. In conclusion, chronic exposure to QP at sublethal concentrations induced hematological and histological alterations in silver barb and offers a simple tool to evaluate toxicity derived alterations. PMID- 26635878 TI - Real-World Assessment of Clinical Outcomes in Patients with Lower-Risk Myelofibrosis Receiving Treatment with Ruxolitinib. AB - Few trial-based assessments of ruxolitinib in patients with lower-risk myelofibrosis (MF) have been conducted, and no studies have made such assessments in a real-world population. We assessed changes in spleen size and constitutional symptoms during ruxolitinib treatment using a retrospective, observational review of anonymized US medical record data of patients diagnosed with IPSS low-risk (n = 25) or intermediate-1-risk (n = 83) MF. The majority of patients were male (low risk, 60%; intermediate-1 risk, 69%). Most patients (92% and 77%) were still receiving ruxolitinib at the medical record abstraction date (median observation/exposure time, 8 months). The proportion of patients with moderate or severe palpable splenomegaly (>=10 cm) decreased from diagnosis (56%) to best response (12%). Fatigue was reported in 47% of patients and was the most common constitutional symptom. For most symptoms in both risk groups, shifts in the distribution of severity from more to less severe from diagnosis to best response were observed. Both patients with low-risk and intermediate-1-risk MF experienced a substantial decrease in spleen size with ruxolitinib treatment in real-world settings. For most symptoms examined, there were distinct improvements in the distribution of severity during ruxolitinib treatment. These findings suggest that patients with lower-risk MF may benefit clinically from ruxolitinib treatment. PMID- 26635879 TI - Systemic Levamisole-Induced Vasculitis in a Cocaine User without Cutaneous Findings: A Consideration in Diagnosis. AB - Levamisole is a known immunomodulating agent frequently used as a cutting agent in cocaine consumed in the United States today. Numerous cases of anti-neutrophil cytoplasmic antibody (ANCA) vasculitis connected with the use of levamisole adulterated cocaine have previously been reported in the literature, classically characterized by a retiform purpuric rash. We report a case of a crack-cocaine user without cutaneous abnormalities who developed ANCA-associated glomerulonephritis that progressed to renal failure. This case demonstrates the difficulties in solidifying the diagnosis of levamisole-induced vasculitis in the absence of cutaneous findings and the need to pursue more testing to establish causality in ANCA-associated vasculitis that has potential for severe end-organ damage in patients who continue to use cocaine. PMID- 26635880 TI - Primordial Germ Cells: Current Knowledge and Perspectives. AB - Infertility is a condition that occurs very frequently and understanding what defines normal fertility is crucial to helping patients. Causes of infertility are numerous and the treatment often does not lead to desired pregnancy especially when there is a lack of functional gametes. In humans, the primordial germ cell (PGC) is the primary undifferentiated stem cell type that will differentiate towards gametes: spermatozoa or oocytes. With the development of stem cell biology and differentiation protocols, PGC can be obtained from pluripotent stem cells providing a new therapeutic possibility to treat infertile couples. Recent studies demonstrated that viable mouse pups could be obtained from in vitro differentiated stem cells suggesting that translation of these results to human is closer. Therefore, the aim of this review is to summarize current knowledge about PGC indicating the perspective of their use in both research and medical application for the treatment of infertility. PMID- 26635881 TI - Parthenogenesis and Human Assisted Reproduction. AB - Parthenogenetic activation of human oocytes obtained from infertility treatments has gained new interest in recent years as an alternative approach to create embryos with no reproductive purpose for research in areas such as assisted reproduction technologies itself, somatic cell, and nuclear transfer experiments and for derivation of clinical grade pluripotent embryonic stem cells for regenerative medicine. Different activating methods have been tested on human and nonhuman oocytes, with varying degrees of success in terms of parthenote generation rates, embryo development stem cell derivation rates. Success in achieving a standardized artificial activation methodology for human oocytes and the subsequent potential therapeutic gain obtained from these embryos depends mainly on the availability of gametes donated from infertility treatments. This review will focus on the creation of parthenotes from clinically unusable oocytes for derivation and establishment of human parthenogenetic stem cell lines and their potential applications in regenerative medicine. PMID- 26635882 TI - Improvement in Isolation and Identification of Mouse Oogonial Stem Cells. AB - Female germline stem cells (FGSCs) or oogonial stem cells (OSCs) have the capacity to generate newborn oocytes and thus open a new door to fight ovarian aging and female infertility. However, the production and identification of OSCs are difficult for investigators. Rare amount of these cells in the ovary results in the failure of the acquisition of OSCs. Furthermore, the oocyte formation by OSCs in vivo was usually confirmed using tissue sections by immunofluorescence or immunohistochemistry in previous studies. STO or MEF feeder cells are derived from mouse, not human. In our study, we modified the protocol. The cells were digested from ovaries and cultured for 2-3 days and then were purified by magnetic-activated cell sorting (MACS). The ovaries and fetus of mice injected with EGFP-positive OSCs were prepared and put on the slides to directly visualize oocyte and progeny formation under microscope. Additionally, the human umbilical cord mesenchymal stem cells (hUC-MSCs) were also used as feeder cells to support the proliferation of OSCs. The results showed that all the modified procedures can significantly improve and facilitate the generation and characterization of OSCs, and hUC-MSCs as feeder will be useful for isolation and proliferation of human OSCs avoiding contamination from mouse. PMID- 26635883 TI - Challenges in Translating Germinal Stem Cell Research and Therapy. PMID- 26635884 TI - Novel Action of FSH on Stem Cells in Adult Mammalian Ovary Induces Postnatal Oogenesis and Primordial Follicle Assembly. AB - Adult mammalian ovary has been under the scanner for more than a decade now since it was proposed to harbor stem cells that undergo postnatal oogenesis during reproductive period like spermatogenesis in testis. Stem cells are located in the ovary surface epithelium and exist in adult and menopausal ovary as well as in ovary with premature failure. Stem cells comprise two distinct populations including spherical, very small embryonic-like stem cells (VSELs which express nuclear OCT-4 and other pluripotent and primordial germ cells specific markers) and slightly bigger ovarian germ stem cells (OGSCs with cytoplasmic OCT-4 which are equivalent to spermatogonial stem cells in the testes). These stem cells have the ability to spontaneously differentiate into oocyte-like structures in vitro and on exposure to a younger healthy niche. Bone marrow may be an alternative source of these stem cells. The stem cells express FSHR and respond to FSH by undergoing self-renewal, clonal expansion, and initiating neo-oogenesis and primordial follicle assembly. VSELs are relatively quiescent and were recently reported to survive chemotherapy and initiate oogenesis in mice when exposed to FSH. This emerging understanding and further research in the field will help evolving novel strategies to manage ovarian pathologies and also towards oncofertility. PMID- 26635885 TI - Effective Mobilization of Very Small Embryonic-Like Stem Cells and Hematopoietic Stem/Progenitor Cells but Not Endothelial Progenitor Cells by Follicle Stimulating Hormone Therapy. AB - Recently, murine hematopoietic progenitor stem cells (HSCs) and very small embryonic-like stem cells (VSELs) were demonstrated to express receptors for sex hormones including follicle-stimulating hormone (FSH). This raised the question of whether FSH therapy at clinically applied doses can mobilize stem/progenitor cells in humans. Here we assessed frequencies of VSELs (referred to as Lin( )CD235a(-)CD45(-)CD133(+) cells), HSPCs (referred to as Lin(-)CD235a( )CD45(+)CD133(+) cells), and endothelial progenitor cells (EPCs, identified as CD34(+)CD144(+), CD34(+)CD133(+), and CD34(+)CD309(+)CD133(+) cells) in fifteen female patients subjected to the FSH therapy. We demonstrated that FSH therapy resulted in statistically significant enhancement in peripheral blood (PB) number of both VSELs and HSPCs. In contrast, the pattern of responses of EPCs delineated by different cell phenotypes was not uniform and we did not observe any significant changes in EPC numbers following hormone therapy. Our data indicate that FSH therapy mobilizes VSELs and HSPCs into peripheral blood that on one hand supports their developmental origin from germ lineage, and on the other hand FSH can become a promising candidate tool for mobilizing HSCs and stem cells with VSEL phenotype in clinical settings. PMID- 26635886 TI - Computational Models for Predictive Cardiac Ion Channel Pharmacology. AB - A wealth of experimental data exists describing the elementary building blocks of complex physiological systems. However, it is increasingly apparent in the biomedical sciences that mechanisms of biological function cannot be observed or readily predicted via study of constituent elements alone. This is especially clear in the longstanding failures in prediction of effects of drug treatment for heart rhythm disturbances. These failures stem in part from classical assumptions that have been made in cardiac antiarrhythmic drug development - that a drug operates by one mechanism via one target receptor that arises from one gene. PMID- 26635887 TI - Clinician Perspectives on Using Pharmacogenomics in Clinical Practice. AB - AIM: To describe the knowledge and attitudes of clinicians participating in a large pharmacogenomics implementation program. MATERIALS & METHODS: Semi structured interviews with 15 physicians and nurse practitioners were conducted. RESULTS: Three categories of themes were identified: preparation and knowledge, pharmacogenomics usage in practice, and future management of genomic variants. Providers expressed an inability to keep up with the rapid pace of evidence generation and indicated strong support for clinical decision support to assist with genotype-tailored therapies. Concerns raised by clinicians included effectively communicating results, long-term responsibility for actionable results and hand-offs with providers outside the implementation program. CONCLUSIONS: Clinicians identified their own knowledge deficits, workflow integration, and longitudinal responsibility as challenges to successful usage of pharmacogenomics in clinical practice. PMID- 26635888 TI - The Ameliorating Effect of Myrrh on Scopolamine-Induced Memory Impairments in Mice. AB - Myrrh has been used since ancient times for the treatment of various diseases such as inflammatory diseases, gynecological diseases, and hemiplegia. In the present study, we investigated the effects of aqueous extracts of myrrh resin (AEM) on scopolamine-induced memory impairments in mice. AEM was estimated with (2E,5E)-6-hydroxy-2,6-dimethylhepta-2,4-dienal as a representative constituent by HPLC. The oral administration of AEM for 7 days significantly reversed scopolamine-induced reduction of spontaneous alternation in the Y-maze test. In the passive avoidance task, AEM also restored the decreased latency time of the retention trial by scopolamine treatment. In addition, Western blot analysis and Immunohistochemistry revealed that AEM reversed scopolamine-decreased phosphorylation of Akt and extracellular signal-regulated kinase (ERK). Our study demonstrates for the first time that AEM ameliorates the scopolamine-induced memory impairments in mice and increases the phosphorylation of Akt and ERK in the hippocampus of mice brain. These results suggest that AEM has the therapeutic potential in memory impairments. PMID- 26635889 TI - Inferring muscular ground patterns in Bivalvia: Myogenesis in the scallop Nodipecten nodosus. AB - BACKGROUND: Myogenesis is currently investigated in a number of invertebrate taxa using combined techniques, including fluorescence labeling, confocal microscopy, and 3D imaging, in order to understand anatomical and functional issues and to contribute to evolutionary questions. Although developmental studies on the gross morphology of bivalves have been extensively pursued, organogenesis including muscle development has been scarcely investigated so far. RESULTS: The present study describes in detail myogenesis in the scallop Nodipecten nodosus (Linnaeus, 1758) during larval and postmetamorphic stages by means of light, electron, and confocal microscopy. The veliger muscle system consists of an anterior adductor muscle, as well as four branched pairs of striated velum retractors and two pairs of striated ventral larval retractors. The pediveliger stage exhibits a considerably elaborated musculature comprising the velum retractors, the future adult foot retractor, mantle (pallial) muscles, and the anterior and posterior adductors, both composed of smooth and striated portions. During metamorphosis, all larval retractors together with the anterior adductor degenerate, resulting in the adult monomyarian condition, whereby the posterior adductor retains both myofiber types. Three muscle groups, i.e., the posterior adductor, foot retractor, and pallial muscles, have their origin prior to metamorphosis and are subsequently remodeled. CONCLUSIONS: Our data suggest a dimyarian condition (i.e., the presence of an anterior and a posterior adductor in the adult) as the basal condition for pectinids. Comparative analysis of myogenesis across Bivalvia strongly argues for ontogenetic and evolutionary independence of larval retractors from the adult musculature, as well as a complex set of larval retractor muscles in the last common bivalve ancestor. PMID- 26635890 TI - Retraction Note: Relationship between bone density and bone metabolism in adolescent idiopathic scoliosis. AB - [This retracts the article DOI: 10.1186/s13013-015-0043-x.]. PMID- 26635891 TI - Cytomegalovirus reactivation and its clinical impact in patients with solid tumors. AB - Cytomegalovirus reactivation can be life threatening. However, little evidence on its incidence in solid cancers is available. Therefore our single center Cytomegalovirus polymerase chain reaction database with altogether 890 CMV positive blood serum samples of mainly hematological and oncological patients was retrospectively analyzed to examine the occurrence of Cytomegalovirus reactivation in patients with solid tumors, resulting in 107 patients tested positive for Cytomegalovirus reactivation. Seventeen patients with solid cancer and a positive CMV-PCR test were identified, of which eight patients had clinically relevant CMV disease and received prompt antiviral treatment. Five patients fully recovered, but despite prompt antiviral treatment three patients died. Among these three patients two had significant co-infections (in one case EBV and in the other case Aspergillus) indicating that that CMV reactivation was at least one factor contributing to sepsis. The patient with the EBV co-infection was treated in an adjuvant therapy setting for breast cancer and died due to Cytomegalovirus and Epstein-Barr virus associated pneumonia despite intensive therapy. The other two patients had progressive disease of an underlying pancreatic cancer at the time of CMV diagnosis. One patient died due to attendant uncontrollable Aspergillus pneumonia, the other patient most likely died independent from CMV disease because of massively progressive underlying disease. Cytomegalovirus reactivation and disease might be underestimated in routine clinical practice. In our retrospective analysis we show that approximately 50 % of our patients suffering from solid cancers with a positive Cytomegalovirus polymerase chain reaction also had clinically relevant Cytomegalovirus disease requiring antiviral therapy. PMID- 26635892 TI - PROPER: Performance visualization for optimizing and comparing ranking classifiers in MATLAB. AB - BACKGROUND: One of the recent challenges of computational biology is development of new algorithms, tools and software to facilitate predictive modeling of big data generated by high-throughput technologies in biomedical research. RESULTS: To meet these demands we developed PROPER - a package for visual evaluation of ranking classifiers for biological big data mining studies in the MATLAB environment. CONCLUSION: PROPER is an efficient tool for optimization and comparison of ranking classifiers, providing over 20 different two- and three dimensional performance curves. PMID- 26635893 TI - Nursing highlights from the 2015 European Cancer Congress (ECCO18-ESMO40), 25-29 September 2015, Vienna: reinforcing multidisciplinarity. AB - The 2015 European Cancer Congress (ECC2015) was the widest European platform for every professional involved in the struggle against cancer (17,656 participants, 2482 abstracts submitted). In this context, the nursing contribution was very relevant, involving high quality research and experience. The major nursing issues were: online information and support; innovations in cancer nursing roles; patient safety and the nursing workforce; managing older people with cancer and other co-morbidities; living with and beyond cancer; nutrition and body image changes; the changing face of cancer care for oncology nurses. Indeed, an important amount of research was presented during proffered papers and poster presentations by nurses from all over the world, concerning challenging issues, such as advanced nursing roles, end of life care, impact of cancer on patients and families, new developments, supportive and palliative care, survivorship and rehabilitation, symptom management and transitions in care. Nurses' presentations were mainly focused on understanding patients' needs and on sharing the best evidence-based approach to meet those needs. This is particularly significant in a field where innovation develops rapidly in every area of clinical practice, such as cancer care, bridging the weaknesses between different approaches and profiles, within the paradigm of multidisciplinarity. PMID- 26635894 TI - Myxoid mesenchymal neoplasm presenting as massive arm and chest wall oedema with pleural effusion. AB - Myxoid mesenchymal tumours are a heterogeneous group of neoplasms characterised histologically by their abundant mucoid and myxoid extracellular matrix (ECM). Encompassing a broad spectrum of clinical behaviour ranging from benign to malignant, there are more than 60 reactive and neoplastic entities currently classified under its domain. Its varied clinical and histopathologic features continue to pose a diagnostic challenge to clinicians and pathologists. Here, we describe a rare case of myxoid mesenchymal tumour presenting as oedema of the upper extremity with pleural metastasis and partial response to chemotherapy, which to the best of our knowledge has not yet been described in the literature. PMID- 26635895 TI - Experiencing brain cancer: what physicians should know about patients. AB - During the last 20 years, numerous studies have highlighted the need to consider Quality of Life (QoL) issues in the treatment of brain cancer. However, gaps in scientific knowledge are still present as we have poor data surrounding the whole experience in patients and regarding their needs. The present study was aimed at evaluating QoL in brain cancer patients and correlated aspects. In particular, we aimed to assess QoL, mood state, and emotional issues in order to describe the patients' experience to find out the critical aspects involved. METHODS: We obtained data from 85 patients during chemotherapy treatment at the National Neurological Institute 'C. Besta' of Milan, Italy. We used standardised questionnaires to assess different aspects of patients' QoL. In particular, the functional assessment of cancer therapy-brain (FACT-Br) and the Hamilton scale were used. We also performed a semi-structured ad hoc interview in order to collect -narrative data about patients' experience. RESULTS: Our data depict a difficult adjustment process to the illness, even though positive elements emerged. Indeed, patients reported a satisfying self-perceived QoL, although specific concerns are still present. Further, even if many patients report depressive symptoms, only a minority have a severe condition. CONCLUSION: Brain cancer may heavily affect patients' QoL and well being. However, some element of the context may improve the -adjustment to the disease. In particular, we found that most patients found psychosocial resources to cope with cancer and that spiritual well being also seems to play a key role. These issues deserve further studies in order to obtain significant clinical recommendations. PMID- 26635896 TI - Chronic lymphocytic leukaemia during pregnancy: management and thoughts. AB - Chronic lymphocytic leukaemia (CLL) is the most common leukaemia in the Western world. Despite this fact, its coexistence with pregnancy is extremely rare, with few cases reported in the literature. Given the rarity of this event, it is difficult to conduct large prospective trials to evaluate diagnostic, management, and outcome aspects. The existing evidence is limited to the few published cases and scarce data from reviews on haematological malignancies and pregnancy. Here, we report a case of a 36-year-old patient who had already finished treatment for CLL and was under surveillance when she got pregnant. We describe the evolution of the pregnancy and of the disease's behaviour as well as the oncological and obstetrical management. Being an indolent disease, CLL during pregnancy can be usually followed up without treatment, but infectious and autoimmune complications might have a significant impact on the pregnancy outcome. Therefore, pregnancy must be closely monitored in specialised centres. PMID- 26635897 TI - Infracentimetric HER-2 positive breast tumours-review of the literature. AB - Breast cancer is the most common malignant neoplasm in the world among women. As a result of the dissemination of population screening programmes, about half of non-metastatic breast cancers are now diagnosed at stage I. 10-15% of T1abN0 tumours over-express human epidermal growth factor (HER-2). These tumours have a globally excellent prognosis, however, treatment with chemotherapy and/or targeted therapy may further improve outcomes in selected cases. In this article, we will review studies with information on prognosis and benefit of adjuvant therapy for T1abN0 HER-2+ breast cancer. PMID- 26635898 TI - Spindle cell carcinoma of the head and neck region: treatment and outcomes of 15 patients. AB - INTRODUCTION: Spindle cell carcinoma of the head and neck is a rare entity and the evidence of optimal management is lacking. The objective of our study was to report the treatment and outcomes of 15 patients treated in a single institution over a seven year period. MATERIALS AND METHODS: A total of 15 patients (12 males and 3 females) with spindle cell carcinoma of the head and neck were treated between July 2007 to June 2014. In six patients the disease developed after previous radiotherapy. Of the 15 patients, five patients had their primary in the tongue, four in the paranasal sinuses, two in the hypopharynx, two in the vocal cords, and one each in the soft palate and the floor of mouth. Eleven patients were treated with radical intent (seven patients required surgery only and four were treated with combined modality). The remaining four patients were treated with palliative intent. RESULTS: Among 11 patients treated with radical intent eight are alive or died of non-oncological causes. The disease recurred locally in three patients and they died of the disease (two patients with locally advanced disease in the tongue and one patient with T1N0 tumour in the hypopharynx). Median overall survival (OS) was 18 months. CONCLUSION: Surgery or surgery combined with radiotherapy has a real impact on the natural cause of spindle cell carcinoma of the head and neck region. Even locally advanced tumours can be controlled with aggressive treatment. The worst outcome is seen with the tongue as the primary site because of a high local recurrence rate. PMID- 26635899 TI - Barriers to preventive therapy for breast and other major cancers and strategies to improve uptake. AB - The global cancer burden continues to rise and the war on cancer can only be won if improvements in treatment go hand in hand with therapeutic cancer prevention. Despite the availability of several efficacious agents, utilisation of preventive therapy has been poor due to various barriers, such as the lack of physician and patient awareness, fear of side effects, and licensing and indemnity issues. In this review, we discuss these barriers in detail and propose strategies to overcome them. These strategies include improving physician awareness and countering prejudices by highlighting the important differences between preventive therapy and cancer treatment. The importance of the agent-biomarker cohort (ABC) paradigm to improve effectiveness of preventive therapy cannot be overemphasised. Future research to improve therapeutic cancer prevention needs to include improvements in the prediction of benefits and harms, and improvements in the safety profile of existing agents by experimentation with dose. We also highlight the role of drug repurposing for providing new agents as well as to address the current imbalance between therapeutic and preventive research. In order to move the field of therapeutic cancer prevention forwards, engagement with policymakers to correct research imbalance as well as to remove practical obstacles to implementation is also urgently needed. PMID- 26635900 TI - Risk factors and biomarkers of life-threatening cancers. AB - There is growing evidence that risk factors for cancer occurrence and for cancer death are not necessarily the same. Knowledge of cancer aggressiveness risk factors (CARF) may help in identifying subjects at high risk of developing a potentially deadly cancer (and not just any cancer). The availability of CARFs may have positive consequences for health policies, medical practice, and the search for biomarkers. For instance, cancer chemoprevention and cancer screening of subjects with CARFs would probably be more ethical and cost-effective than recommending chemoprevention and screening to entire segments of the population. Also, the harmful consequences of chemoprevention and of screening would be reduced while effectiveness would be optimised. We present examples of CARF already in use (e.g. mutations of the breast cancer (BRCA) gene), of promising avenues for the discovery of biomarkers thanks to the investigation of CARFs (e.g. breast radiological density and systemic inflammation), and of biomarkers commonly used that are not real CARFs (e.g. certain mammography images, prostate specific antigen (PSA) concentration, nevus number). PMID- 26635901 TI - Chemoprevention studies within lung cancer screening programmes. AB - While aggressive tobacco control and help to stop smoking are essential weapons in the fight against lung cancer, screening with low-dose computed tomography (LDCT) in high-risk populations and chemoprevention may also contribute to reducing lung cancer deaths. Persons undergoing LDCT screening are an ideal population to be tested for agents potentially able to prevent the development of lung cancer by the regression of precancerous lesions, which are routinely monitored as part of the screening process. Peripheral subsolid nodules appear as particularly suitable targets, since many are adenocarcinoma precursors. A study on inhaled budesonide (a potential chemopreventive drug) for 1 year found that the mean size of non-solid lung nodules was significantly reduced over 5 years of follow-up, compared to inhaled placebo, in a population of high-risk individuals with indeterminate lung nodules not requiring immediate specific investigation for lung cancer and detected as part of a lung cancer screening program with LDCT. A new randomised placebo-controlled phase-II trial to test the ability of aspirin to induce the regression of non-solid and partially solid nodules detected by LDCT screening has been started. The effect of aspirin on a miRNA signature able to predict the presence of both cancer and precancerous lesions in high-risk asymptomatic individuals is also being monitored in the trial. This signature was previously shown to predict the presence of both lung cancer and non-solid lung nodules in asymptomatic individuals. PMID- 26635902 TI - Molecular profile of liquid biopsies: next generation biomarkers to improve lung cancer treatment. AB - Molecular profiling of liquid biopsies is now emerging as pivotal for cancer biomarker discovery. The low-invasive nature of the approach used for collecting biospecimens (i.e. blood, urine, saliva, etc.) may allow a widespread application of novel molecular diagnostics based on liquid biopsies. This is relevant, for example, in cancer screening programmes where it is essential to reduce costs and the complexity of screening tests in order to increase study compliance and effectiveness. Here, I discuss recent advances in biomarkers for the early cancer detection and prediction of chemotherapy response based on the molecular profiling of liquid biopsies. PMID- 26635903 TI - Biomarkers in phase I-II chemoprevention trials: lessons from the NCI experience. AB - Early phase clinical trials are an essential component of chemopreventive drug development to identify signals of drug efficacy that can subsequently be explored definitively in phase III trials. Whereas phase I trials focus on safety and identification of optimal dose and schedule for cancer prevention, phase II trials focus on intermediate endpoints that are variably related to cancer development. The United States National Cancer Institute supports a programme devoted to early phase cancer prevention clinical trials. The experience, along with the benefits and limitations of the range of biomarker endpoints used in these studies, are reviewed here. PMID- 26635904 TI - Biomarkers of cancer angioprevention for clinical studies. AB - With the great advances made in the treatment and prevention of infectious diseases over the last century, chronic degenerative diseases-cardiovascular, cerebrovascular, and cancer-represent the major causes of death in the developed world. Although massive efforts and investments have been made in cancer therapy, the progress made towards reducing mortality has been more successful for cardiovascular disease than for tumours. This can be attributable largely to an active prevention approach implemented for cardiovascular disease. Cardiologists treat their patients before the overt disease becomes life threatening, performing early interventions in phenotypically healthy patients, by using several markers that predict risk. If the concept of prevention could be applied to cancer in a more extensive way, a significant number of tumours could be avoided through preventive measures. Prevention approaches range from avoiding tobacco exposure to dietary strategies to active pharmacological approaches in higher risk groups. Host targets rather than the tumour cells themselves are attractive for chemoprevention, in particular endothelial and immune cells. Angioprevention i.e. preventing cancer angiogenesis is a key concept that we introduced; yet one of the major current challenges for anti-angiogenesis in therapy and prevention is finding the right biomarkers. Here we discuss the importance of angioprevention and the potential use of VEGF, PlGF, CD31, Ang and Tie, circulating vascular cell precursors, and microRNA as potential biomarkers. PMID- 26635905 TI - New concepts and challenges in the clinical translation of cancer preventive therapies: the role of pharmacodynamic biomarkers. AB - Implementation of therapeutic cancer prevention strategies has enormous potential for reducing cancer incidence and related mortality. Trials of drugs including tamoxifen and aspirin have led the way in demonstrating proof-of-principle that prevention of breast and colorectal cancer is feasible. Many other compounds ranging from drugs in widespread use for various indications, including metformin, bisphosphonates, and vitamin D, to dietary agents such as the phytochemicals resveratrol and curcumin, show preventive activity against several cancers in preclinical models. Notwithstanding the wealth of opportunities, major challenges have hindered the development process and only a handful of therapies are currently approved for cancer risk reduction. One of the major obstacles to successful clinical translation of promising preventive agents is a lack of pharmacodynamic biomarkers to provide an early read out of biological activity in humans and for optimising doses to take into large scale randomised clinical trials. A further confounding factor is a lack of consideration of clinical pharmacokinetics in the design of preclinical experiments, meaning results are frequently reported from studies that use irrelevant or unachievable concentrations. This article focuses on recent findings from investigations with dietary-derived agents to illustrate how a thorough understanding of the mechanisms of action, using models that mimic the clinical scenario, together with the development of compound-specific accompanying pharmacodynamic biomarkers could accelerate the developmental pipeline for preventive agents and maximise the chances of success in future clinical trials. Moreover, the concept of a bell shaped dose-response curve for therapeutic cancer prevention is discussed, along with the need to rethink the traditional 'more is better' approach for dose selection. PMID- 26635906 TI - CpG island methylation profile in non-invasive oral rinse samples is predictive of oral and pharyngeal carcinoma. AB - BACKGROUND: There are currently no screening tests in routine use for oral and pharyngeal cancer beyond visual inspection and palpation, which are provided on an opportunistic basis, indicating a need for development of novel methods for early detection, particularly in high-risk populations. We sought to address this need through comprehensive interrogation of CpG island methylation in oral rinse samples. METHODS: We used the Infinium HumanMethylation450 BeadArray to interrogate DNA methylation in oral rinse samples collected from 154 patients with incident oral or pharyngeal carcinoma prior to treatment and 72 cancer-free control subjects. Subjects were randomly allocated to either a training or a testing set. For each subject, average methylation was calculated for each CpG island represented on the array. We applied a semi-supervised recursively partitioned mixture model to the CpG island methylation data to identify a classifier for prediction of case status in the training set. We then applied the resultant classifier to the testing set for validation and to assess the predictive accuracy. RESULTS: We identified a methylation classifier comprised of 22 CpG islands, which predicted oral and pharyngeal carcinoma with a high degree of accuracy (AUC = 0.92, 95 % CI 0.86, 0.98). CONCLUSIONS: This novel methylation panel is a strong predictor of oral and pharyngeal carcinoma case status in oral rinse samples and may have utility in early detection and post-treatment follow up. PMID- 26635907 TI - Targeting the fatty acid transport proteins (FATP) to understand the mechanisms linking fatty acid transport to metabolism. AB - One principal process driving fatty acid transport is vectorial acylation, where fatty acids traverse the membrane concomitant with activation to CoA thioesters. Current evidence is consistent with the proposal that specific fatty acid transport (FATP) isoforms alone or in concert with specific long chain acyl CoA synthetase (Acsl) isoforms function to drive this energy-dependent process. Understanding the details of vectorial acylation is of particular importance as disturbances in lipid metabolism many times leads to elevated levels of circulating free fatty acids, which in turn increases fatty acid internalization and ectopic accumulation of triglycerides. This is associated with changes in fatty acid oxidation rates, accumulation of reactive oxygen species, the synthesis of ceramide and ER stress. The correlation between chronically elevated plasma free fatty acids and triglycerides with the development of obesity, insulin resistance and cardiovascular disease has led to the hypothesis that decreases in pancreatic insulin production, cardiac failure, arrhythmias, and hypertrophy are due to aberrant accumulation of lipids in these tissues. To this end, a detailed understanding of how fatty acids traverse the plasma membrane, become activated and trafficked into downstream metabolic pools and the precise roles provided by the different FATP and Acsl isoforms are especially important questions. We review our current understanding of vectorial acylation and the contributions by specific FATP and Acsl isoforms and the identification of small molecule inhibitors from high throughput screens that inhibit this process and thus provide new insights into the underlying mechanistic basis of this process. PMID- 26635908 TI - Risk multipliers for severe food anaphylaxis. AB - Anaphylaxis is a severe, life threatening allergic reaction. In most fatal cases of food anaphylaxis, the fatality is not due merely to a simple, linear relationship between the allergen and exposure in a sensitized individual. Compounding factors such as the allergic disease burden-particularly the presence of asthma; comprehension of the potential severity of an event, training in the appropriate use of epinephrine, and emerging metabolic factors should be considered when assessing risk and establishing management strategies. This paper reviews the factors that contribute to the risk of severe anaphylactic events and provides a framework for the ongoing management of patients at risk of severe food allergy. PMID- 26635909 TI - Nitric Oxide-Mediated Posttranslational Modifications: Impacts at the Synapse. AB - Nitric oxide (NO) is an important gasotransmitter molecule that is involved in numerous physiological processes throughout the nervous system. In addition to its involvement in physiological plasticity processes (long-term potentiation, LTP; long-term depression, LTD) which can include NMDAR-mediated calcium dependent activation of neuronal nitric oxide synthase (nNOS), new insights into physiological and pathological consequences of nitrergic signalling have recently emerged. In addition to the canonical cGMP-mediated signalling, NO is also implicated in numerous pathways involving posttranslational modifications. In this review we discuss the multiple effects of S-nitrosylation and 3 nitrotyrosination on proteins with potential modulation of function but limit the analyses to signalling involved in synaptic transmission and vesicular release. Here, crucial proteins which mediate synaptic transmission can undergo posttranslational modifications with either pre- or postsynaptic origin. During normal brain function, both pathways serve as important cellular signalling cascades that modulate a diverse array of physiological processes, including synaptic plasticity, transcriptional activity, and neuronal survival. In contrast, evidence suggests that aging and disease can induce nitrosative stress via excessive NO production. Consequently, uncontrolled S-nitrosylation/3 nitrotyrosination can occur and represent pathological features that contribute to the onset and progression of various neurodegenerative diseases, including Parkinson's, Alzheimer's, and Huntington's. PMID- 26635910 TI - Higher Urinary Levels of 8-Hydroxy-2'-deoxyguanosine Are Associated with a Worse RANKL/OPG Ratio in Postmenopausal Women with Osteopenia. AB - Postmenopausal osteoporosis (PO) is a major public health issue which affects a large fraction of elderly women. Emerging in vitro evidence suggests a central role of oxidative stress (OxS) in postmenopausal osteoporosis (PO) development. Contrariwise, the human studies on this topic are still scarce and inconclusive. In the attempt to address this issue, we sought to determine if OxS, as assessed by 8-hydroxy-2-deoxyguanosine (8-OHdG), may influence the level of receptor activator of nuclear factor-kappab ligand (RANKL)/osteoprotegerin (OPG) ratio (a central regulator of bone metabolism) in a sample (n = 124), including postmenopausal women with osteoporosis, osteopenia and normal bone mass density (BMD). The most striking result that emerged in our study was the independent and positive (beta = 0.449, p = 0.004, and R(2) = 0.185) association between the OxS marker and RANKL/OPG ratio which was found in osteopenic but not in the other 2 sample groups. If confirmed by longitudinal studies, our findings would suggest that OxS is implicated in the derangement of bone homeostasis which precedes PO development. In line with these considerations, antioxidant treatment of postmenopausal women with moderately low BMD might contribute to preventing PO and related complications. PMID- 26635911 TI - Vasorelaxant Effect of a New Hydrogen Sulfide-Nitric Oxide Conjugated Donor in Isolated Rat Aortic Rings through cGMP Pathway. AB - Endothelium-dependent vasorelaxant injury leads to a lot of cardiovascular diseases. Both hydrogen sulfide (H2S) and nitric oxide (NO) are gasotransmitters, which play a critical role in regulating vascular tone. However, the interaction between H2S and NO in vasorelaxation is still unclear. ZYZ-803 was a novel H2S and NO conjugated donor developed by H2S-releasing moiety (S-propyl-L-cysteine (SPRC)) and NO-releasing moiety (furoxan). ZYZ-803 could time- and dose dependently relax the sustained contraction induced by PE in rat aortic rings, with potencies of 1.5- to 100-fold greater than that of furoxan and SPRC. Inhibition of the generations of H2S and NO with respective inhibitors abolished the vasorelaxant effect of ZYZ-803. ZYZ-803 increased cGMP level and the activity of vasodilator stimulated phosphoprotein (VASP) in aortic rings, and those effects could be suppressed by the inhibitory generation of H2S and NO. Both the inhibitor of protein kinase G (KT5823) and the inhibitor of KATP channel (glibenclamide) suppressed the vasorelaxant effect of ZYZ-803. Our results demonstrated that H2S and NO generation from ZYZ-803 cooperatively regulated vascular tone through cGMP pathway, which indicated that ZYZ-803 had therapeutic potential in cardiovascular diseases. PMID- 26635912 TI - Correlation between Mitochondrial Reactive Oxygen and Severity of Atherosclerosis. AB - Atherosclerosis has been associated with mitochondria dysfunction and damage. Our group demonstrated previously that hypercholesterolemic mice present increased mitochondrial reactive oxygen (mtROS) generation in several tissues and low NADPH/NADP+ ratio. Here, we investigated whether spontaneous atherosclerosis in these mice could be modulated by treatments that replenish or spare mitochondrial NADPH, named citrate supplementation, cholesterol synthesis inhibition, or both treatments simultaneously. Robust statistical analyses in pooled group data were performed in order to explain the variation of atherosclerosis lesion areas as related to the classic atherosclerosis risk factors such as plasma lipids, obesity, and oxidative stress, including liver mtROS. Using three distinct statistical tools (univariate correlation, adjusted correlation, and multiple regression) with increasing levels of stringency, we identified a novel significant association and a model that reliably predicts the extent of atherosclerosis due to variations in mtROS. Thus, results show that atherosclerosis lesion area is positively and independently correlated with liver mtROS production rates. Based on these findings, we propose that modulation of mitochondrial redox state influences the atherosclerosis extent. PMID- 26635913 TI - Serum Superoxide Dismutase Is Associated with Vascular Structure and Function in Hypertensive and Diabetic Patients. AB - Oxidative stress is associated with cardiac and vascular defects leading to hypertension and atherosclerosis, being superoxide dismutase (SOD) one of the main intracellular antioxidant defence mechanisms. Although several parameters of vascular function and structure have a predictive value for cardiovascular morbidity-mortality in hypertensive patients, there are no studies on the involvement of SOD serum levels with these vascular parameters. Thus, we assessed if SOD serum levels are correlated with parameters of vascular function and structure and with cardiovascular risk in hypertensive and type 2 diabetic patients. We enrolled 255 consecutive hypertensive and diabetic patients and 52 nondiabetic and nonhypertensive controls. SOD levels were measured with an enzyme linked immunosorbent assay kit. Vascular function and structure were evaluated by pulse wave velocity, augmentation index, ambulatory arterial stiffness index, and carotid intima-media thickness. We detected negative correlations between SOD and pressure wave velocity, peripheral and central augmentation index and ambulatory arterial stiffness index, pulse pressure, and plasma HDL-cholesterol, as well as positive correlations between SOD and plasma uric acid and triglycerides. Our study shows that SOD is a marker of cardiovascular alterations in hypertensive and diabetic patients, since changes in its serum levels are correlated with alterations in vascular structure and function. PMID- 26635915 TI - From Catheters To Ventricular Assist Devices: 60 Years of Cardiovascular Experiences With William L. Winters, JR., M.D. AB - Automatic typewriters, transistor radios, microfiche, black and white television...while considered high-tech in the 1950s, these technologies seem limited when viewed from the 21st century. The same is true for cardiovascular medicine, which back then relied on electrocardiograms and X-rays for most diagnoses. In the 60 years since, advances in medical capabilities have progressed at a staggering pace. Patient research that once required months poring over paper charts is now reduced to hours using electronic medical record databases. Diagnostic images that once took days to process can now be accessed instantly through ultrasound and magnetic resonance imaging. While a half-century ago no one would have imagined accessing any and all information with a 5-second Google search, so too would noninvasive heart surgery been considered unimaginable. Since the 1950s when he graduated from medical school, William L. Winters, Jr., has been a first-hand witness to breathtaking innovations in cardiovascular medicine-both globally and in Houston. Author of Houston Hearts: A History of Cardiovascular Surgery and Medicine at Houston Methodist DeBakey Heart & Vascular Center and long-time medical editor of the Methodist DeBakey Cardiovascular Journal, Dr. Winters sat down with the journal editors this past April to share his insights from the last half-century of medical practice. PMID- 26635914 TI - Intermittent Hypoxia Affects the Spontaneous Differentiation In Vitro of Human Neutrophils into Long-Lived Giant Phagocytes. AB - Previously we identified, for the first time, a new small-size subset of neutrophil-derived giant phagocytes (Gphi) which spontaneously develop in vitro without additional growth factors or cytokines. Gphi are CD66b(+)/CD63(+)/MPO(+)/LC3B(+) and are characterized by extended lifespan, large phagolysosomes, active phagocytosis, and reactive oxygen species (ROS) production, and autophagy largely controls their formation. Hypoxia, and particularly hypoxia/reoxygenation, is a prominent feature of many pathological processes. Herein we investigated Gphi formation by applying various hypoxic conditions. Chronic intermittent hypoxia (IH) (29 cycles/day for 5 days) completely abolished Gphi formation, while acute IH had dose-dependent effects. Exposure to 24 h (56 IH cycles) decreased their size, yield, phagocytic ability, autophagy, mitophagy, and gp91-phox/p22-phox expression, whereas under 24 h sustained hypoxia (SH) the size and expression of LC3B and gp91-phox/p22-phox resembled Gphi formed in normoxia. Diphenyl iodide (DPI), a NADPH oxidase inhibitor, as well as the PI3K/Akt and autophagy inhibitor LY294002 abolished Gphi formation at all oxygen conditions. However, the potent antioxidant, N acetylcysteine (NAC) abrogated the effects of IH by inducing large CD66b(+)/LC3B(+) Gphi and increased both NADPH oxidase expression and phagocytosis. These findings suggest that NADPH oxidase, autophagy, and the PI3K/Akt pathway are involved in Gphi development. PMID- 26635916 TI - Houston Hearts: A History of Cardiovascular Surgery and Medicine At Houston Methodist Debakey Heart & Vascular Center: From the Michael E. DeBakey, M.D., Distinguished Lectureship Series, presented by William L. Winters, Jr., M.D., Editor, Methodist DeBakey Cardiovascular Journal, on January 19, 2015. PMID- 26635917 TI - Ultrasound Strain Measurements for Evaluating Local Pulmonary Ventilation. AB - Local lung function is difficult to evaluate, because most lung function estimates are either global in nature, e.g. pulmonary function tests, or require equipment that cannot be used at a patient's bedside, such as computed tomograms. Yet, local function measurements would be highly desirable for many reasons. In a recent publication [1], we were able to track displacements of the lung surface during breathing. We have now extended these results to measuring lung strains during respiration as a means of assessing local lung ventilation. We studied two normal human volunteers and 12 mice with either normal lung function or experimentally induced pulmonary fibrosis. The difference in strains between the control, normal mice and those with pulmonary fibrosis was significant (p < 0.02), while the strains measured in the human volunteers closely matched linear strains predicted from the literature. Ultrasonography may be able to assess local lung ventilation. PMID- 26635918 TI - Phase 1 Dose-Escalation Study with LEC/chTNT-3 and Toceranib Phosphate (Palladia(r)) in Dogs with Spontaneous Malignancies. AB - OBJECTIVES: LEC chemokine promotes TH1 responses and recruits immune cells to inflammatory sites. By linking LEC to an antibody targeting tumor necrosis, LEC/chTNT-3 can be used for the immunotherapeutic treatment of tumors. The primary objective of this study was to determine the safety profile of LEC/chTNT 3 and toceranib phosphate (Palladia(r)) combination therapy in dogs with spontaneous malignancies. Secondary purpose was to determine objective responses to treatment. METHODS: Twenty-three dogs with cancer were enrolled, covering nine different malignancies. In this dose escalation study, dogs received LEC/chTNT-3 for five days, and toceranib every 48 hours for the remainder of the study. Dogs received physical exams, chemistry panel, urinalysis, and complete blood counts on days 0, 10, 28 of the study, and every 6-8 weeks thereafter. RESULTS: Lethargy was noted in 13% dogs. There were no statistical differences in the prevalence of anorexia, diarrhea, thrombocytopenia, renal toxicity, or hepatic toxicity before or during the study. There were trends in increases in the prevalence of vomiting, lymphopenia, and neutropenia (all grade 2 or lower, p=0.07) over the initial 28 days of the study. By day 28, 10% of dogs had partial responses, 58% had stable disease, and 32% had progressive disease. CONCLUSIONS: LEC/chTNT-3 and toceranib were well tolerated. This combination therapy showed some biological activity against a variety of cancers at a low dose and short duration of LEC/chTNT-3 administration. PMID- 26635919 TI - Social Relationships of Dually Diagnosed Homeless Adults Following Enrollment in Housing First or Traditional Treatment Services. AB - OBJECTIVE: Strong and effective social support is a critical element of mental health recovery, yet social support is often lacking for adults experiencing homelessness. This study examines differences in the social networks of participants newly enrolled in programs that use either a Housing First (HF) approach (i.e., provides immediate access to permanent housing with ongoing consumer-driven support services) or a treatment first (TF) approach (i.e., traditional clinician-driven staircse model that requires temporary or transitional housing and treatment placements before accessing permanent housing). METHOD: We use a mixed-methods social network analysis approach to assess group differences of 75 individuals based on program type (HF or TF) and program retention. RESULTS: Quantitative results show that compared with TF, HF participants have a greater proportion of staff members in their network. TF participants are more likely than HF participants to maintain mixed-quality relationships (i.e., relationships with elements of support and conflict). As compared with participants who remain in a program, those who disengage from programs have a greater proportion of mixed relationships and relationships that grow distant. Qualitative analyses suggest that HF participants regard housing as providing a stable foundation from which to reconnect or restore broken relationships. However, HF participants are guarded about close relationships for fear of being exploited due to their newly acquired apartments. TF participants report that they are less inclined to develop new relationships with peers or staff members due to the time-limited nature of the TF programs. CONCLUSIONS: These findings suggest that HF participants are not more socially isolated than those in traditional care. Implications for practice, policy and future research are discussed. PMID- 26635920 TI - Translational research of adult stem cell therapy. AB - Congestive heart failure (CHF) secondary to chronic coronary artery disease is a major cause of morbidity and mortality world-wide. Its prevalence is increasing despite advances in medical and device therapies. Cell based therapies generating new cardiomyocytes and vessels have emerged as a promising treatment to reverse functional deterioration and prevent the progression to CHF. Functional efficacy of progenitor cells isolated from the bone marrow and the heart have been evaluated in preclinical large animal models. Furthermore, several clinical trials using autologous and allogeneic stem cells and progenitor cells have demonstrated their safety in humans yet their clinical relevance is inconclusive. This review will discuss the clinical therapeutic applications of three specific adult stem cells that have shown particularly promising regenerative effects in preclinical studies, bone marrow derived mesenchymal stem cell, heart derived cardiosphere-derived cell and cardiac stem cell. We will also discuss future therapeutic approaches. PMID- 26635923 TI - Visualization of catheter ablation for atrial fibrillation: Impact of devices and anatomy. AB - Endocardial access to the left atrium is commonly achieved to treat patients with atrial fibrillation, using different device delivery systems for cardiac ablation. But the large variation in human anatomy presses the limits of existing medical devices. In this unique study, we directly visualized the device-tissue interface in fresh reanimated human hearts using Visible Heart((r)) methodologies. Our goal was to better understand any opportunities to improve therapeutic approaches. The visual images obtained in this study (also featured in this article) allow a more intimate grasp of the key steps required in various ablation procedures, as well as some limitations of current device designs. These images show the potential risks of conducting transseptal punctures and the difficulties of placing catheter tips in certain scenarios (e.g., when creating circumferential lesions); they also demonstrate potential problems that could occur while attempting to place catheter tips on such anatomies like the mitral isthmus. In our analysis of these images, we focus on where enhancements are needed to refine device functionality. PMID- 26635922 TI - Therapeutic modification of arterial stiffness: An update and comprehensive review. AB - Arterial stiffness has been recognized as a marker of cardiovascular disease and associated with long-term worse clinical outcomes in several populations. Age, hypertension, smoking, and dyslipidemia, known as traditional vascular risk factors, as well as diabetes, obesity, and systemic inflammation lead to both atherosclerosis and arterial stiffness. Targeting multiple modifiable risk factors has become the main therapeutic strategy to improve arterial stiffness in patients at high cardiovascular risk. Additionally to life style modifications, long-term omega-3 fatty acids (fish oil) supplementation in diet may improve arterial stiffness in the population with hypertension or metabolic syndrome. Pharmacological treatment such as renin-angiotensin-aldosterone system antagonists, metformin, and 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors were useful in individuals with hypertension and diabetes. In obese population with obstructive sleep apnea, weight reduction, aerobic exercise, and continuous positive airway pressure treatment may also improve arterial stiffness. In the populations with chronic inflammatory disease such as rheumatoid arthritis, a use of antibodies against tumor necrosis factor-alpha could work effectively. Other therapeutic options such as renal sympathetic nerve denervation for patients with resistant hypertension are investigated in many ongoing clinical trials. Therefore our comprehensive review provides knowledge in detail regarding many aspects of pathogenesis, measurement, and management of arterial stiffness in several populations, which would be helpful for physicians to make clinical decision. PMID- 26635924 TI - Coarctation of the aorta: Management from infancy to adulthood. AB - Coarctation of the aorta is a relatively common form of congenital heart disease, with an estimated incidence of approximately 3 cases per 10000 births. Coarctation is a heterogeneous lesion which may present across all age ranges, with varying clinical symptoms, in isolation, or in association with other cardiac defects. The first surgical repair of aortic coarctation was described in 1944, and since that time, several other surgical techniques have been developed and modified. Additionally, transcatheter balloon angioplasty and endovascular stent placement offer less invasive approaches for the treatment of coarctation of the aorta for some patients. While overall morbidity and mortality rates are low for patients undergoing intervention for coarctation, both surgical and transcatheter interventions are not free from adverse outcomes. Therefore, patients must be followed closely over their lifetime for complications such as recoarctation, aortic aneurysm, persistent hypertension, and changes in any associated cardiac defects. Considerable effort has been expended investigating the utility and outcomes of various treatment approaches for aortic coarctation, which are heavily influenced by a patient's anatomy, size, age, and clinical course. Here we review indications for intervention, describe and compare surgical and transcatheter techniques for management of coarctation, and explore the associated outcomes in both children and adults. PMID- 26635921 TI - Vascular endothelial dysfunction and pharmacological treatment. AB - The endothelium exerts multiple actions involving regulation of vascular permeability and tone, coagulation and fibrinolysis, inflammatory and immunological reactions and cell growth. Alterations of one or more such actions may cause vascular endothelial dysfunction. Different risk factors such as hypercholesterolemia, homocystinemia, hyperglycemia, hypertension, smoking, inflammation, and aging contribute to the development of endothelial dysfunction. Mechanisms underlying endothelial dysfunction are multiple, including impaired endothelium-derived vasodilators, enhanced endothelium-derived vasoconstrictors, over production of reactive oxygen species and reactive nitrogen species, activation of inflammatory and immune reactions, and imbalance of coagulation and fibrinolysis. Endothelial dysfunction occurs in many cardiovascular diseases, which involves different mechanisms, depending on specific risk factors affecting the disease. Among these mechanisms, a reduction in nitric oxide (NO) bioavailability plays a central role in the development of endothelial dysfunction because NO exerts diverse physiological actions, including vasodilation, anti-inflammation, antiplatelet, antiproliferation and antimigration. Experimental and clinical studies have demonstrated that a variety of currently used or investigational drugs, such as angiotensin-converting enzyme inhibitors, angiotensin AT1 receptors blockers, angiotensin-(1-7), antioxidants, beta-blockers, calcium channel blockers, endothelial NO synthase enhancers, phosphodiesterase 5 inhibitors, sphingosine-1-phosphate and statins, exert endothelial protective effects. Due to the difference in mechanisms of action, these drugs need to be used according to specific mechanisms underlying endothelial dysfunction of the disease. PMID- 26635925 TI - Neoatherosclerosis: Coronary stents seal atherosclerotic lesions but result in making a new problem of atherosclerosis. AB - Chronic inflammation of the native vessel wall with infiltration of lipid-laden foamy macrophages through impaired endothelium results in atherosclerosis. Percutaneous coronary intervention, including metallic stent implantation, is now widely utilized for the treatment of atherosclerotic lesions of the coronary artery. Bare-metal stents and the subsequently developed drug-eluting stents seal the atherosclerosis and resolve lumen stenosis or obstruction of the epicardial coronary artery and myocardial ischemia. After stent implantation, neointima proliferates within the stented segment. Chronic inflammation caused by a foreign body reaction to the implanted stent and subsequent neovascularization, which is characterized by the continuous recruitment of macrophages into the vessel, result in the transformation of the usual neointima into an atheromatous neointima. Neointima with an atherosclerotic appearance, such as that caused by thin-cap fibroatheromas, is now recognized as neoatherosclerosis, which can sometimes cause in-stent restenosis and acute thrombotic occlusion originating from the stent segment following disruption of the atheroma. Neoatherosclerosis is emerging as a new coronary stent-associated problem that has not yet been resolved. In this review article, we will discuss possible mechanisms, clinical challenges, and the future outlook of neoatherosclerosis. PMID- 26635927 TI - Short and long term outcomes of 200 patients supported by continuous-flow left ventricular assist devices. AB - AIM: To study the institutional experience over 8 years with 200 continuous-flow (CF) - left ventricular assist devices (LVAD). METHODS: We evaluated our institution's LVAD database and analyzed all patients who received a CF LVAD as a bridge to transplant (BTT) or destination therapy from March 2006 until June 2014. We identified 200 patients, of which 179 were implanted with a HeartMate II device (Thoratec Corp., Pleasanton, CA) and 21 received a Heartware HVAD (HeartWare Inc., Framingham, MA). RESULTS: The mean age of our LVAD recipients was 59.3 years (range 17-81), 76% (152/200) were males, and 49% were implanted for the indication of BTT. The survival rate for our LVAD patients at 30 d, 6 mo, 12 mo, 2 years, 3 years, and 4 years was 94%, 86%, 78%, 71%, 62% and 45% respectively. The mean duration of LVAD support was 581 d (range 2-2595 d). Gastrointestinal bleeding (was the most common adverse event (43/200, 21%), followed by right ventricular failure (38/200, 19%), stroke (31/200, 15%), re exploration for bleeding (31/200, 15%), ventilator dependent respiratory failure (19/200, 9%) and pneumonia (15/200, 7%). Our driveline infection rate was 7%. Pump thrombosis occurred in 6% of patients. Device exchanged was needed in 6% of patients. On multivariate analysis, preoperative liver dysfunction, ventilator dependent respiratory failure, tracheostomy and right ventricular failure requiring right ventricular assist device support were significant predictors of post LVAD survival. CONCLUSION: Short and long term survival for patients on LVAD support are excellent, although outcomes still remain inferior compared to heart transplantation. The incidence of driveline infections, pump thrombosis and pump exchange have declined significantly in recent years. PMID- 26635926 TI - Epigenetic regulation in cardiac fibrosis. AB - Cardiac fibrosis represents an adoptive response in the heart exposed to various stress cues. While resolution of the fibrogenic response heralds normalization of heart function, persistent fibrogenesis is usually associated with progressive loss of heart function and eventually heart failure. Cardiac fibrosis is regulated by a myriad of factors that converge on the transcription of genes encoding extracellular matrix proteins, a process the epigenetic machinery plays a pivotal role. In this mini-review, we summarize recent advances regarding the epigenetic regulation of cardiac fibrosis focusing on the role of histone and DNA modifications and non-coding RNAs. PMID- 26635928 TI - Comparison of echocardiography and device based algorithm for atrio-ventricular delay optimization in heart block patients. AB - AIM: To compare the atrio-ventricular (AV/PV) delay optimization by echocardiography and intra-cardiac electrocardiogram (IEGM) based QuickOpt algorithm in complete heart block (CHB) patients, implanted with a dual chamber pacemaker. METHODS: We prospectively enrolled 20 patients (age 59.45 +/- 18.1 years; male: 65%) with CHB, who were implanted with a dual chamber pacemaker. The left ventricular outflow tract velocity time-integral was measured after AV/PV delay optimization by both echocardiography and QuickOpt algorithm method. Bland Altman analysis was used for agreement between the two techniques. RESULTS: The optimal AV and PV delay determined by echocardiography was 155.5 +/- 14.68 ms and 122.5 +/- 17.73 ms (P < 0.0001), respectively and by QuickOpt method was 167.5 +/ 16.73 and 117.5 ms +/- 9.10 ms (P < 0.0001), respectively. A good agreement was observed between optimal AV and PV delay as measured by two methods. However, the correlation of the optimal AV (r = 0.0689, P = 0.77) and PV (r = 0.2689, P = 0.25) intervals measured by the two techniques was poor. The time required for AV/PV optimization was 45.26 +/- 1.73 min by echocardiography and 0.44 +/- 0.08 min by QuickOpt method (P < 0.0001). CONCLUSION: The programmer based IEGM method is an automated, quick, easier and reliable alternative to echocardiography for the optimization of AV/PV delay in CHB patients, implanted with a dual chamber pacemaker. PMID- 26635929 TI - Digoxin: A systematic review in atrial fibrillation, congestive heart failure and post myocardial infarction. AB - AIM: To review digoxin use in systolic congestive heart failure, atrial fibrillation, and after myocardial infarction. METHODS: A comprehensive PubMed search was performed using the key words "digoxin and congestive heart failure", "digoxin and atrial fibrillation", "digoxin, atrial fibrillation and systolic congestive heart failure", and "digoxin and myocardial infarction". Only articles written in English were included in this study. We retained studies originating from randomized controlled trials, registries and included at least 500 patients. The studies included patients with atrial fibrillation or heart failure or myocardial infarction and had a significant proportion of patients (at least 5%) on digoxin. A table reviewing the different hazard ratios was developed based on the articles selected. Our primary endpoint was the overall mortality in the patients on digoxin vs those without digoxin, among patients with atrial fibrillation and also among patients with atrial fibrillation and systolic heart failure. We reviewed the most recent international guidelines to discuss current recommendations. RESULTS: A total of 18 studies were found that evaluated digoxin and overall mortality in different clinical settings including systolic congestive heart failure and normal sinus rhythm (n = 5), atrial fibrillation with and without systolic congestive heart failure (n = 9), and myocardial infarction (n = 4). Overall, patients with systolic congestive heart failure with normal sinus rhythm, digoxin appears to have a neutral effect on mortality especially if close digoxin level monitoring is employed. However, most of the observational studies evaluating digoxin use in atrial fibrillation without systolic congestive heart failure showed an increase in overall mortality when taking digoxin. In the studies evaluated in this systematic review, the data among patients with atrial fibrillation and systolic congestive heart failure, as well as post myocardial infarction were more controversial. The extent to which discrepancies among studies are based on statistical methods is currently unclear, as these studies' findings are generated by retrospective analyses that employed different techniques to address confounding. CONCLUSION: Based on the potential risks and benefits, as well as the presence of alternative drugs, there is a limited role for digoxin in the management of patients with normal sinus rhythm and congestive heart failure. Based on the retrospective studies reviewed there is a growing volume of data showing increased mortality in those with only atrial fibrillation. The proper role of digoxin is, however, less certain in other subgroups of patients, such as those with both atrial fibrillation and systolic congestive heart failure or after a myocardial infarction. Further studies may provide helpful information for such subgroups of patients. PMID- 26635930 TI - Catheter-based intervention for symptomatic patient with severe mitral regurgitation and very poor left ventricular systolic function - Safe but no room for complacency. AB - Many patients with left ventricular systolic dysfunction have concomitant mitral regurgitation (MR). Their symptoms and prognosis worsen with increasing severity of MR. Percutaneous MitraClip((r)) can be used safely to reduce the severity of MR even in patients with advanced heart failure and is associated with improved symptoms, quality of life and exercise tolerance. However, a few patients with very poor left ventricular systolic function may experience significant haemodynamic disturbance in the peri-procedural period. We present three such patients, highlighting some of the potential problems encountered and discuss their possible pathophysiological mechanisms and safety measures. PMID- 26635931 TI - Imaging of pannus formation in patients with mechanical heart valves. AB - Patient-prosthesis mismatch (PPM) should be recognized in patients with elevated transprosthetic gradients but without leaflet immobility, since the treatment strategy may differ in either etiology. However, thrombus and/or pannus formation should be excluded before a diagnosis of PPM is made. Particularly, pannus formation may not be diagnosed with 2-dimensional transesophageal echocardiography. Electrocardiographically gated 64-section multidetector computed tomography (MDCT) may be a promising tool in diagnosing or excluding pannus formation. Our report underlines the utility of MDCT in this regard and also emphasizes the importance of recognition of PPM as a differential diagnosis in such patients. PMID- 26635933 TI - A Case of Acute Rheumatic Fever With Henoch Schonlein Purpura. PMID- 26635932 TI - The Use of Quaternary Ammonium to Combat Dental Caries. AB - Resin composites and adhesives are increasingly popular in dental restorations, but secondary caries is one of the main reasons for restoration failure. Quaternary ammonium monomers (QAMs) have an anti-microbial effect and are widely used in many fields. Since the concept of the immobilized antibacterial effect was put forward, dental restorations containing QAMs have been studied to reduce secondary caries. Previous studies have been struggling to develop novel anti caries materials which might have triple benefits: good mechanical properties, antibacterial effects and remineralization potentials. Different kinds of QAMs have been proven to be effective in inhibiting the growth and metabolism of biofilms. Combination of QAMs and other nanoparticles in resin composites and adhesives could enhance their anti-caries capability. Therefore, QAMs are promising to show significant impact on the future of restorative and preventive dentistry. PMID- 26635934 TI - Oral Zinc Sulfate as Adjuvant Treatment in Children With Nephrolithiasis: a Randomized, Double-Blind, Placebo-Controlled Clinical Trial. AB - BACKGROUND: Nephrolithiasis in children is associated with a high rate of complications and recurrence. OBJECTIVES: Since some evidences reported that zinc has an important place amongst inhibitors of crystallization and crystal growth, we decided to assess the effectiveness of oral zinc sulfate as adjuvant treatment in children with nephrolithiasis. PATIENTS AND METHODS: This was a randomized, double-blind, placebo-controlled clinical trial. 102 children in the age range 1 month to 11 years with first nephrolithiasis were recruited. Patients were randomly divided into two equal groups (intervention and control groups). Intervention group received conservative measures for stones and 1 mg/kg/day (maximum 20 mg/day) oral zinc sulfate syrup for 3 months. Control group received placebo in addition to conservative measures, also for 3 months. Patients were followed up by ultrasonography for 9 months, in 5 steps (at the end of 1st, 2nd, 3rd, 6th and 9th month after treatment) assessing size and number of stones in the kidneys. RESULTS: Only at the end of the first month, the average number (intervention: 1.15 +/- 3.78, control: 1.3 +/- 2.84) (P = 0.001) and size (cm) (intervention: 0.51 +/- 1.76, control: 0.62 +/- 1.39) (P = 0.001) of stones was significantly lower in the intervention group, and in other points there was no significant therapeutic efficacy in oral zinc adjuvant treatment compared to conservative treatment alone. Also, during the 9-month follow-up, the number and size of stones in both groups decreased significantly (both: P < 0.0001) in a way that the decrease in the intervention group showed no difference with the control group. CONCLUSIONS: Adjuvant treatment with zinc is not more effective than consecutive treatment in children with nephrolithiasis. However, further studies are recommended due to the lack of clinical evidence in this field. PMID- 26635935 TI - The Role of Epstein-Barr Virus LMP-1 Immunohistochemical Staining in Childhood Hodgkin Lymphoma. AB - BACKGROUND: There are a few published studies about prognostic markers of Epstein B virus (EBV) related to outcomes in pediatric Hodgkin Lymphoma (HL). OBJECTIVES: We aimed to investigate the prognostic value and effect of EBV on survival by using biopsy materials in children and adolescents diagnosed with HL. PATIENTS AND METHODS: EBV LMP-1 expression was examined using immunohistochemical methods in 58 tumor samples. Clinical features, overall survival (OS) and failure free survival time (FFS) were compared between EBV LMP-1 positive and negative patients. RESULTS: In 20 (35%) patients tumors were LMP-1 positive. When compared with patients above 10 years old, EBV LMP-1 was often positive in patients under 10 years old (30% vs. 70%, P = 0.02). In our most cases having B symptoms and advanced stage, EBV positiveness in Hodgkin Reed-Stenberg cells (H-RS) was not a significant determinant for survival (P = 0.78). Half of the past clinical trials in childhood HL reported longer survival rates in EBV LMP-1 positive patients. In some trials similar to our results there was no significant relationship between EBV and prognosis. CONCLUSIONS: The reason of diminished EBV positiviness may be related to technical methods such as not using immunohistochemical and in situ hybridization for EBER antigen but in laboratory conditions painting of control tissues with EBV impair this probability. In addition, cases enrolled to our study were living in Istanbul where social and economical factors are improved rather than generally. PMID- 26635936 TI - Eradication of Helicobacter pylori in Children by Triple Therapy Regimens of Amoxicillin, Omeprazole, and Clarithromycin or Azithromycin. AB - BACKGROUND AND OBJECTIVES: The present study aimed to evaluate the effect of classical and azithromycin-containing triple therapy eradication regimen against H. Pylori in children, and to determine the level of patients' tolerance. PATIENTS AND METHODS: This single clinical trial was performed in 2014 on 2 to 15 years old children. All children, in whom H. Pylori infection was confirmed through multiple biopsies of the stomach and required treatment, were enrolled in the study. H. Pylori-positive patients were treated alternately with two different drug regimens; Group OCA received clarithromycin 7.5 mg/kg/day every 12 hours for 10 days, amoxicillin 50 mg/kg/day every 12 hours for 10 days, and omeprazole 1 mg/kg/day every 12 hours for two weeks, and Group OAA received azithromycin 10 mg/kg/day once a day (before meal) for 6 days along with amoxicillin and omeprazole. Four to six weeks after completion of treatment, patients' stool was tested for H. Pylori through the monoclonal method using the Helicobacter antigen quick kit. RESULTS: There were no significant differences between the two groups regarding gender and age of patients. Based on ITT analysis, the therapeutic response in the OAA and OCA groups were 56.2% and 62.5%, respectively (P = 0.40). Drug adverse effects were 15.6% in the OCA and 3.1% in the OAA group (P = 0.19). CONCLUSIONS: The therapeutic response was seen in more than half of the patients treated with triple therapy of H. Pylori eradication regimen including azithromycin or clarithromycin, and there was no significant difference between the two treatment groups. PMID- 26635937 TI - A Randomized Double-Blind Placebo-Controlled Trial of Lactobacillus reuteri for Chronic Functional Abdominal Pain in Children. AB - BACKGROUND: Functional abdominal pain (FAP) is one of the most common diseases, and large percentages of children suffer from it. OBJECTIVES: The purpose of the study was to evaluate the effect of Lactobacillus reuteri in treatment of children with functional abdominal pain. PATIENTS AND METHODS: This study was a randomized double-blind placebo-controlled trial. Children aged 4 to 16 years with chronic functional abdominal pain (based on Rome III criteria) were enrolled in the study. They were randomly divided into two groups, one receiving probiotic and the other placebo. RESULTS: Forty children received probiotic and forty others placebo. There were no significant differences in age, weight, sex, location of pain, associated symptoms, frequency and intensity of pain between the groups. The severity and frequency of abdominal pain in the first month compared to baseline was significantly less and at the end of the second month, there was no significant difference between both groups compared to the end of the first month. CONCLUSIONS: This study showed that the severity of pain was significantly reduced in both groups. There was no significant difference in pain scores between them. The effect of probiotic and placebo can probably be attributed to psychological effect of the drugs. PMID- 26635938 TI - Primary Antibiotic Resistance to Helicobacter pylori Strains Isolated From Children in Northern Iran: A Single Center Study. AB - BACKGROUND: Initial resistance to antibiotics is the main reason for the failure of Helicobacter pylori (H. pylori) eradication in children. OBJECTIVES: As we commonly face high antibiotic resistance rates in children, we aimed to determine the susceptibility of H. pylori to common antibiotics. PATIENTS AND METHODS: In this cross-sectional in vitro study, 169 children younger than 14 years with clinical diagnosis of peptic ulcer underwent upper gastrointestinal endoscopy. Biopsy specimens from stomach and duodenum were cultured. In isolated colonies, tests of catalase, urease, and oxidase as well as gram staining were performed. After confirming the colonies as H. pylori, the antibiogram was obtained using disk diffusion method. RESULTS: Culture for H. pylori was positive in 12.3% of the specimens, urease test in 21.3%, serological test in 18.9% and stool antigen test was positive in 21.9%. We could show high specificity but moderate sensitivity of both histological and H. pylori stool antigen tests to detect H. pylori. The overall susceptibility to metronidazole was 42.9%, amoxicillin 95.2%, clarithromycin 85.7%, furazolidone 61.9%, azithromycin 81.0%, and tetracycline 76.2% with the highest resistance to metronidazole and the lowest to clarithromycin. CONCLUSIONS: In our region, there is high resistance of H. pylori to some antibiotics including metronidazole and furazolidone among affected children. To reduce the prevalence of this antibiotic resistance, more controlled use of antibiotics should be considered in children. PMID- 26635940 TI - Exogenous Lipoid Pneumonia: Dramatic Clinical and Radiological Improvement After Multiple Segmental Bronchoalveolar Lavages. PMID- 26635939 TI - Intellectual and Developmental Status in Children With Hyperphenylalaninemia and PKU Who Were Screened in a National Program. AB - BACKGROUND: Hyperphenylalaninemia (HPA) and Phenylkeonuria (PKU) are metabolic errors caused by deficiency of phenylalanine hydroxylase enzyme, which results in increased level of phenylalanine. This increase is toxic to the growing brain. OBJECTIVES: The purpose of this study was to compare the intellectual and developmental status in HPA and PKU children with normal population in national screening program. PATIENTS AND METHODS: In a historical cohort study, 41 PKU patients who had the inclusion criteria and 41 healthy children were evaluated. Wechsler preschool and primary scale of intelligence-3rd edition (WPPI-3) was used in order to assess the intellectual status of children 4 years and older and Ages and stages questionnaire (ASQ) was used to assess the developmental status of children 5 years and younger. RESULTS: In intellectual test comparison, the two groups showed significant difference in Wechsler's performance intelligence score and some performance subscales (P-value < 0.01). In comparison of developmental status, no significant difference was observed between the two groups (P-value > 0.05). CONCLUSIONS: Even with early diagnosis and treatment of PKU patients, these children show some deficiencies intellectually compared to normal children. This study emphasizes on necessity for screening intellectual and developmental status of PKU patients so that effective medical or educational measures can taken in case of deficiencies. PMID- 26635941 TI - Kawasaki Disease and Peripheral Gangrene in Infancy. AB - INTRODUCTION: Early diagnosis and treatment of Kawasaki disease as the most common cause of acquired heart disease in childhood, may significantly improve the prognosis. Diagnosing infantile Kawasaki (younger than a year) is difficult because of obscure symptoms; at the same time they are at the higher risk of coronary abnormalities. CASE PRESENTATION: We report three infants with prolonged (more than 5 days) fever and peripheral gangrene without any other clinical manifestations of Kawasaki disease. Kawasaki was diagnosed due to dilation of coronary artery and other aortic branches, thrombocytosis, and rising of ESR and CRP. All patients were treated with high dose aspirin, IVIG and pulse therapy with methylprednisolone. Additionally, cytotoxic drugs or infliximab were used for two of them because of severe aneurysms in the aortic branches. All 3 patients received aspirin with anti-platelet aggregation dose and 2 patients heparin as an anti-coagulant agent for longtime. After adequate treatment, peripheral gangrene, arterial dilations and aneurysms improved, but during 12 months follow-up coronary aneurysms did not improve completely. CONCLUSIONS: Peripheral gangrene must be regarded as an important sign of infantile Kawasaki disease early treatment of which can prevent severe permanent coronary involvements and sequels. PMID- 26635942 TI - Frequency of Genotype With DeltaF508 Mutation in CFTR Gene Among Iranian Cystic Fibrosis Patients With Pancreatic Insufficiency. AB - BACKGROUND: Cystic fibrosis (CF) is the most prevalent lethal autosomal recessive disease with a broad spectrum of phenotypes. Mutation of DeltaF508 in the CFTR gene is the most important and lethal mutation in CF, which contains 70% of all predisposing mutations for CF worldwide. OBJECTIVES: Determining frequency of genotypes with DeltaF508 mutation in CFTR gene, and evaluation of correlation between genotype and phenotype of Iranian patients with CF. PATIENTS AND METHODS: Thirty six patients were included in this cross sectional study. DeltaF508 mutations in both alleles of the CFTR gene were checked. RESULTS: Among 36 pediatric patients, DeltaF508 mutation was detected in 9 (25%) patients; 2 patients were heterozygous, and 7 patients homozygous for this mutation. From overall 72 tracked alleles, 11 (15.2%) were found to have DeltaF508 mutations. Differences in prevalence of dyspnea and bronchiectasis were significant in homozygote group, compared with non-mutated group for DeltaF508. CONCLUSIONS: It seems that more DeltaF508 mutated alleles lead to more severe symptoms of CF. PMID- 26635943 TI - Congenital Ewing's Sarcoma/Primitive Neuroectodermal Tumor of the Upper Extremity. PMID- 26635944 TI - Oxidative Status in Epileptic Children Using Carbamazepine. AB - BACKGROUND: There is an increasing attention towards the relationship between oxidative stress and epilepsy. The effect of antiepileptic drugs on oxidant status is of major interest. Antiepileptic drugs can increase levels of free radicals, which consequently might lead to seizures. Carbamazepine (CBZ) is an antiepileptic drug commonly used in childhood and adolescence. OBJECTIVES: Therefore we aimed to investigate the effects of CBZ on total antioxidant status, total oxidant stress, and oxidative stress index. PATIENTS AND METHODS: The study included 40 epileptic patients and 31 healthy children between 4 and 12 years of age. Serum CBZ level, total antioxidant capacity and total oxidant status were measured. Oxidative stress index was also calculated both in controls and patients. RESULTS: In the epileptic group, decreased levels of total antioxidant capacity, increased total oxidative stress and oxidative stress index levels were found. Positive correlation between plasma CBZ levels and total oxidant status was observed. CONCLUSIONS: Antioxidant action could not be playing any role in antiepileptic effect of CBZ. Furthermore, increased oxidative stress induced by CBZ could be the cause of CBZ-induced seizures. Therefore combining CBZ with antioxidants could be beneficial. PMID- 26635945 TI - Transcatheter Closure of Atrial Septal Defects in a Center With Limited Resources: Outcomes and Short Term Follow-Up. AB - BACKGROUND: Transcatheter closure of atrial septal defects (ASD) has been accepted world-wide as an alternative to surgical closure with excellent results. This interventional, non-surgical technique plays an important role in the treatment of ASD mostly in the developing world where resources are limited. OBJECTIVES: To report the outcomes and short term follow-up of transcatheter closure of ASD over a 12-year period at our institution with limited resources. PATIENTS AND METHODS: This retrospective study included all patients with the diagnosis of secundum ASD and significant shunting (Qp/Qs > 1.5:1) as well as dilated right atrium and right ventricle who had transcatheter closure at Integrated Cardiovascular Center (PJT), Dr. Cipto Mangunkusumo Hospital between October 2002 and October 2014. One hundred fifty-two patients enrolled in this study were candidates for device closure. Right and left heart cardiac catheterization was performed before the procedure. All patients underwent physical examination, ECG, chest X-ray and transthoracal echocardiography (TTE) prior to device implantation. RESULTS: A total of 152 patients with significant ASD underwent device implantation. Subjects' age ranged from 0.63 to 69.6 years, with median 9.36 years and mean 16.30 years. They consisted of 33 (21.7%) males and 119 (78.3%) females, with mean body weight of 29.9 kg (range 8 to 75; SD 18.2). The device was successfully implanted in 150 patients where the majority of cases received the Amplatzer septal occluder (147/150; 98%) and the others received the Heart Lifetech ASD occluder (3/150, 2%), whereas two other cases were not suitable for device closure and we decided for surgical closure. The mean ASD size was 19.75 (range 14 - 25) mm. During the procedure, 5 (4.9%) patients had bradycardia and 3 (2.9%) patients had supraventricular tachycardia (SVT), all of which resolved. CONCLUSIONS: In our center with limited facilities and manpower, transcatheter closure of atrial septal defect was effective and safe as an alternative treatment to surgery. The outcome and short-term follow-up revealed excellent results, but long-term follow-up is needed. PMID- 26635946 TI - Amelia: A Case Report and Literature Review. PMID- 26635947 TI - Serum Aminotransferases in Thai Children With Dengue Infection. AB - BACKGROUND: Hepatic manifestations are one of the unusual manifestations of dengue infection. OBJECTIVES: We conducted this study in order to study the pattern of serum aminotransferases and sequential changes before and after shock in Thai children with dengue infection. PATIENTS AND METHODS: Children who were clinically and serologically diagnosed as dengue infection and were admitted to King Chulalongkorn Memorial Hospital during a peroid of one year were enrolled. They were clinically classified into a non-shock group and a shock group. The majority of serum aminotransferases including aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were obtained within a week after the onset of fever and until 3 days after shock in the shock group. Student t-test and median in boxplot form were used for statistical analysis. RESULTS: We enrolled 127 children with a mean age of 7.6 +/- 3.6 years. The incidence of abnormal AST and ALT levels was 97.4% and 50.0% in the shock group, and 91.8% and 44.9% in the non shock group respectively. 29% and 15.4% of the patients in shock group and only 10.2% and 4.1% in non-shock group had the respective AST and ALT levels > 200 U/L. Serum aminotransferase levels were significantly higher in the shock group when compared to the non-shock group. AST tended to increase starting from one day before shock and continued to increase within a few days whereas ALT was less likely to be affected. CONCLUSIONS: Elevated serum aminotransferases are a common finding in children with dengue infection and the levels of AST are higher than those of ALT. Patients with shock have significantly higher aminotransferase levels that increase up to 3 days after shock. PMID- 26635948 TI - Beyond the Mean: Sensitivities of the Variance of Population Growth. AB - Populations in variable environments are described by both a mean growth rate and a variance of stochastic population growth. Increasing variance will increase the width of confidence bounds around estimates of population size, growth, probability of and time to quasi-extinction. However, traditional sensitivity analyses of stochastic matrix models only consider the sensitivity of the mean growth rate. We derive an exact method for calculating the sensitivity of the variance in population growth to changes in demographic parameters. Sensitivities of the variance also allow a new sensitivity calculation for the cumulative probability of quasi-extinction. We apply this new analysis tool to an empirical dataset on at-risk polar bears to demonstrate its utility in conservation biology We find that in many cases a change in life history parameters will increase both the mean and variance of population growth of polar bears. This counterintuitive behaviour of the variance complicates predictions about overall population impacts of management interventions. Sensitivity calculations for cumulative extinction risk factor in changes to both mean and variance, providing a highly useful quantitative tool for conservation management. The mean stochastic growth rate and its sensitivities do not fully describe the dynamics of population growth. The use of variance sensitivities gives a more complete understanding of population dynamics and facilitates the calculation of new sensitivities for extinction processes. PMID- 26635949 TI - PAX7 is required for patterning the esophageal musculature. AB - BACKGROUND: The mammalian esophageal musculature is unique in that it makes a transition from smooth to skeletal muscle, with most of this process occurring after birth. In order to better understand the mechanisms that control esophageal musculature development, we investigated the roles in this process of the paired box transcription factor, PAX7, a principal regulator of skeletal myogenic progenitor cells. Previous studies showed that Pax7 is important for determining the esophageal muscle composition. RESULTS: We characterized the postnatal development of the esophageal musculature in Pax7 (-/-) mice by analyzing morphology, muscle composition, and the expression of markers of myogenesis, cell proliferation, and apoptosis. Pax7 (-/-) mice displayed megaesophagus with a severe defect in the postnatal developmental process whereby esophageal smooth muscle is replaced by skeletal muscle. Pax7 (-/-) esophagi have substantially reduced skeletal muscle, most likely due to diminished proliferation and premature differentiation of skeletal muscle precursor cells. This impaired the proximal-to-distal progression of skeletal myogenesis and indirectly affected the patterning of the smooth muscle-containing portion of the esophageal musculature. CONCLUSIONS: Postnatal patterning of the esophageal musculature appears to require robust, PAX7-dependent cell proliferation to drive the proximal-to-distal progression of skeletal myogenesis. This process in turn influences distal smooth muscle morphogenesis and development of the mature pattern of the esophageal musculature. PMID- 26635950 TI - Factors and processes in children's transitive deductions. AB - Transitive tasks are important for understanding how children develop socio cognitively. However, developmental research has been restricted largely to questions surrounding maturation. We asked 6-, 7- and 8-year-olds (N = 117) to solve a composite of five different transitive tasks. Tasks included conditions asking about item-C (associated with the marked relation) in addition to the usual case of asking only about item-A (associated with the unmarked relation). Here, children found resolving item-C much easier than resolving item-A, a finding running counter to long-standing assumptions about transitive reasoning. Considering gender perhaps for the first time, boys exhibited higher transitive scores than girls overall. Finally, analysing in the context of one recent and well-specified theory of spatial transitive reasoning, we generated the prediction that reporting the full series should be easier than deducing any one item from that series. This prediction was not upheld. We discuss amendments necessary to accommodate all our earlier findings. PMID- 26635952 TI - Impact of different diagnostic technologies for MRSA admission screening in hospitals - a decision tree analysis. AB - BACKGROUND: Hospital infections with multiresistant bacteria, e.g., Methicillin resistant Staphylococcus aureus (MRSA), cause heavy financial burden worldwide. Rapid and precise identification of MRSA carriage in combination with targeted hygienic management are proven to be effective but incur relevant extra costs. Therefore, health care providers have to decide which MRSA screening strategy and which diagnostic technology should be applied according to economic criteria. AIM: The aim of this study was to determine which MRSA admission screening and infection control management strategy causes the lowest expected cost for a hospital. Focus was set on the Point-of-Care Testing (PoC). METHODS: A decision tree analytic cost model was developed, primarily based on data from peer reviewed literature. In addition, univariate sensitivity analyses of the different input parameters were conducted to study the robustness of the results. FINDINGS: In the basic analysis, risk-based PoC screening showed the highest mean cost savings with 14.98 ? per admission in comparison to no screening. Rapid universal screening methods became favorable at high MRSA prevalence, while in situations with low MRSA transmission rates omission of screening may be favorable. CONCLUSION: Early detection of MRSA by rapid PoC or PCR technologies and consistent implementation of appropriate hygienic measures lead to high economic efficiency of MRSA management. Whether general or targeted screening is more efficient depends mainly on epidemiological and infrastructural parameters. PMID- 26635953 TI - No apparent transmission of transgenic alpha-synuclein into nigrostriatal dopaminergic neurons in multiple mouse models. AB - BACKGROUND: alpha-synuclein (alpha-syn) is the main component of intracytoplasmic inclusions deposited in the brains of patients with Parkinson's disease (PD) and certain other neurodegenerative disorders. Recent studies have explored the ability of alpha-syn to propagate between or across neighboring neurons and supposedly "infect" them with a prion-like mechanism. However, much of this research has used stereotaxic injections of heterologous alpha-syn fibrils to induce the spreading of inclusions in the rodent brains. Whether alpha-syn is able to transmit from the host cells to their neighboring cells in vivo is unclear. METHODS: Using immunestaining, we examined the potential propagation of alpha-syn into nigrostriatal dopaminergic (DA) neurons in three lines of transgenic mice that overexpress human wild-type alpha-syn (halpha-syn) in different neuron populations. RESULTS: After testing for three different routes by which halpha-syn propagation might occur, we were unable to find any evidence that halpha-syn behaved like a prion and could be transmitted overtime into the DA neurons initially lack of halpha-syn expression. CONCLUSIONS: In transgenic mice halpha-syn does not have the ability to propagate at pathologically significant levels between or across neurons. It must be noted that these observations do not disprove the studies that show its prion-like qualities, but rather that propagation is not detectable in transgenic models that do not use any injections of heterologous proteins or viral vectors to induce a spreading state. PMID- 26635954 TI - Cardiac complications after laparoscopic large hiatal hernia repair. Is it related with staple fixation of the mesh? -Report of three cases. AB - INTRODUCTION: Laparoscopic Nissen operation with mesh reinforcement remains being the most popular operation for large hiatal hernia repair. Complications related to mesh placement have been widely described. Cardiac complications are rare, but have a fatal outcome if they are misdiagnosed. PRESENTATION OF CASES: We sought to outline our institutional experience of three patients who developed cardiac complications following a laparoscopic Nissen operation for large hiatal hernia repair. DISCUSSION: Laparoscopic hiatoplasty and Nissen fundoplication are safe and effective procedures for the hiatal hernia repair, but they are not exempt from complications. Fixation technique and material used must be taken into account. We have conducted a review of the literature on complications related to these procedures. CONCLUSION: In the differential diagnosis of hemodynamic instability after laparoscopic hiatal hernia repair, cardiac tamponade and other cardiac complications should be considered. PMID- 26635955 TI - Large cell neuroendocrine - Adenocarcinona mixed tumour of colon: Collision tumour with peculiar behaviour. What do we know about these tumours? AB - INTRODUCTION: Mixed glandular-endocrine carcinomas are rare tumours of gastrointestinal tract (MANEC). They are more frequent in stomach and hardly one hundred cases have been described in colon. According to Lewis, they are classified into collision (side by side pattern), composite (intermingled) or amphicrine (neuroendocrine and glandular features inside a same cell). Collision tumours are related to biclonal theory: two simultaneous cancerogenic events. Conversely, multidirectional differentiation from a stem cell is accepted as origin of composite tumours. The aim of this paper is to analyse the behaviour of these tumours, with an especial concern about how these tumours metastasise, and the different theories about carcinogenesis. PRESENTATION OF CASE: We report a rare case of collision adenocarcinoma-large cell neuroendocrine tumour of colon that after a three-year period of follow-up has presented a retroperitoneal recurrence that features adenocarcinoma and large cell neuroendocrine components. DISCUSSION: After an exhaustive review of the English literature, we found that only two cases of collision tumour of colon with metastases showing glandular and endocrine components have been described up to date, so we report the third case, and the first happening in transverse colon. CONCLUSION: We conclude that not all collision tumours follow the biclonal theory and more studies are needed to clarify the origin of these neoplasms, and consequently, to reach an adequate treatment. PMID- 26635956 TI - Ankle arthroplasty in a patient with bleeding diathesis and the mid-term clinical outcome of the case. AB - PURPOSE: The purpose of this report was to present the case of a patient with bleeding diathesis on whom we performed ankle arthroplasty for the first time. MATERIALS AND METHODS: A 29-year old male patient with bleeding diathesis, who had been treated and followed up over a long period, underwent ankle arthroplasty because of osteoarthritis of the ankle. The patient was prepared for surgery by the haematology department in accordance with the guidelines for surgical preparation, diagnosis and management of haemophilia. After ankle arthroplasty was performed, the preoperative and two-year postoperative clinical outcomes were evaluated using a subjective foot score and Maryland foot score. RESULTS: Preoperative factor VIII levels were raised to the target level of haemostasis prior to the surgical procedure. The factor VIII levels were maintained within the normal range up to postoperative day 14. The subjective foot score of the patient was 40 preoperatively and 85 postoperatively, whereas their Maryland foot scores were 33 preoperatively and 90 postoperatively. Both scoring systems indicate an excellent clinical outcome. CONCLUSION: As observed, the early and mid-term functional outcomes are promising for patients with bleeding diathesis who undergo ankle arthroplasty. PMID- 26635957 TI - Swallowed dentures: Two cases and a review. AB - INTRODUCTION: Denture ingestion or aspiration is a problem requiring awareness of different specialists including dentists, surgeons, otolaryngologists, anesthesiologists etc. in terms of prevention, early diagnosis and adequate treatment. Complications of swallowed dentures include hollow viscus necrosis, perforation, penetration to neighbor organs leading to fistulae, bleeding and obstruction. PRESENTATION OF CASES: First case is a 54-year-old female who accidentally swallowed retractable one-tooth denture during fall about 22 h before admission and clinical manifestation of acute small bowel obstruction developed. The patient underwent laparotomy, enterotomy with retrieval of the foreign body. The second case is a 31-year-old male who accidentally ingested fixed one-tooth prosthesis while eating which impacted in the ileocaecal valve. During the preparation to colonoscopy the denture spontaneously passed out with stools. DISCUSSION: Denture ingestion is more common among patients with psychoneurologic deficit, alcohol and drug abusers. Among healthy and younger population denture ingestion is rare. Both reported patients are not elder. Thus dislodgement of removable or fixed dentures is another risk factor of denture ingestion. Most common site of denture impaction is esophagus; small bowel impaction is rare. Moreover, in most reported cases, small bowel impaction of ingested dentures leads to small bowel perforation. In our first case the complication of denture ingestion appeared to be bowel obstruction what is even rarer. CONCLUSION: Fixed dentures can be accidentally ingested as well as removable dentures. Denture loosening leads to accidental denture ingestion. Patients with denture loosening should be recommended to visit dentist as soon as possible. PMID- 26635958 TI - Response to an Escherichia coli K88 oral challenge and productivity of weanling pigs receiving a dietary nucleotides supplement. AB - BACKGROUND: Dietary nucleotides, considered as antibiotics alternative, were shown to have positive effects on intestinal hyperaemia, systemic immunity, small intestinal growth, and hepatic composition in pigs. However, there is no previous research on nucleotide supplementation in weanling pigs under an oral challenged E. coli K88. Therefore, 2 experiments were conducted to investigate the effects of dietary nucleotides on weanling pig growth performance, nutrient digestibility, fecal score, and blood profile after being orally challenged with E. coli K88. METHODS: In Exp. 1, a total of 140 weanling pigs [8.33 +/- 0.33 kg of body weight (BW), 28-d old] were used in this 42-d feeding trial. Pigs were distributed into 1 of 4 treatments, 5 pigs/pen (3 barrows and 2 gilts) and 7 pens/treatment. Treatments were a control basal diet (CON) or the CON supplemented with 150 (R150), 220 (R220), or 275 (R275) mg/kg to give the three treatment diets. In Exp. 2, 28 weanling pigs (BW = 8.40 +/- 0.22 kg, 28-d old) were distributed into 1 of 4 treatments to give 1 pig/pen and 7 pens/treatment in a 42-d feeding and challenge trial. Dietary treatments were the same as in Exp. 1. On d 14, all those pigs (BW = 13.3 +/- 0.15 kg, 42-d old) were orally dosed with 1.5 mL suspension containing 10(10) cfu/mL of E. coli K88. Twenty four hours after challenge, blood and excreta samples were collected from each pigs for analysis. Fecal scores were measured on d 7, 14, 21, and 28 of the study. RESULTS: In Exp. 1, overall BW, average daily gain (ADG), gain/feed (G/F) ratio, and nutrient digestibilities were lower (P < 0.05) in CON group compared with the nucleotides fed pigs. In Exp. 2, after challenge, IgA, IgM, and IGF-I were higher (P < 0.05) in the nucleotide groups compared with CON. However, the nucleotide groups had lower (P < 0.05) cortisol and TNF-alpha compared with CON. Fecal E. coli counts and fecal score for the nucleotide groups were lower (P < 0.05) than for CON. CONCLUSIONS: In conclusion, dietary nucleotides supplementation could improve growth performance, nutrient digestibility, immune status, microbial balance, reduce diarrhea, and provide protection against enterotoxigenic E. coli K88 infection in weanling pigs. PMID- 26635959 TI - Early pregnancy in the horse revisited - does exception prove the rule? AB - Early equine pregnancy shares many features with that of more intensively assessed domestic animals species, but there are also characteristic differences. Some of those are poorly understood. Descent of the equine conceptus into the uterine lumen occurs at day 5 to 6 after ovulation but is only possible when the embryo secretes prostaglandin E2. Although maintenance of equine pregnancy probably involves secretion of a conceptus derived anti-luteolytic factor, this agent has not been identified. Rapid growth, conceptus mobility and presence of an acellular capsule at the time of maternal recognition of pregnancy, i.e. between days 12 and 14, are prerequisites to avoid pregnancy loss. Progesterone together with 5alpha-pregnanes is secreted by the corpus luteum and induces the production of endometrial histotroph which is responsible for conceptus nutrition until placention. A stable contact between the outer trophoblast layer of the allantochorion and the luminal epithelium of the endometrium is not established before days 40 to 42 of pregnancy. PMID- 26635960 TI - Influence of dietary canola oil and palm oil blend and refrigerated storage on fatty acids, myofibrillar proteins, chemical composition, antioxidant profile and quality attributes of semimembranosus muscle in goats. AB - BACKGROUND: Improving the unsaturated fatty acid content of ruminant meat is essential due to the generally saturated nature of fatty acids in ruminant meat and the negative effects this can have on human health. Nonetheless, enhancing the unsaturated fatty acid content of ruminant meat can have adverse effects on the shelf life and quality attributes of the meat. This study assessed the effects of dietary 80 % canola oil and 20 % palm oil blend (CPOB) on fatty acid composition, antioxidants, oxidative spoilage, cholesterol and physicochemical properties of semimembranosus (SM) muscle from goats. Twenty four Boer bucks were randomly assigned to diets containing on dry matter basis 0, 4 and 8 % CPOB, fed for 100 d and slaughtered. The carcasses were subjected to a 7 d postmortem refrigerated storage. All analyses were conducted on the SM muscle. RESULTS: Diet had no effect (P > 0.05) on the concentration of free thiol and carbonyl and the band intensity of myosin heavy chain, actin and troponin T. The muscle glycogen, pH, water holding capacity, tenderness, glutathione peroxidase (GPX) activity, total carotenoid, delta-tocopherol, cholesterol and proximate composition did not differ (P > 0.05) between diets. The SM muscle from goats fed 4 and 8 % CPOB had lower (P < 0.05) concentration of C14:0 and C16:0 and higher (P < 0.05) concentration of C18:1 trans-11, C18:1omega-9, C18:3omega-3, C20:5omega-3 and C22:5omega-3 than the SM muscle from the control goats. Dietary CPOB increased (P < 0.05) the concentration of alpha and gamma tocopherol and meat redness (a*) on d 1 and 4 postmortem. Regardless of diet, antioxidant vitamins, and shear force decreased (P < 0.05) while drip loss, lipid and protein oxidation increased (P < 0.05) as postmortem storage progressed. CONCLUSION: Results evince that dietary CPOB can be used as a management tool to enhance the beneficial fatty acids and antioxidant contents of chevon without deleterious effects on its physicochemical properties and shelf life. PMID- 26635961 TI - In vitro BMP2 stimulation of osteoblast citrate production in concert with mineralized bone nodule formation. AB - BACKGROUND: That citrate is a major indispensible component of bone in humans and in all osteovertebrates has been known for about seventy-five years. Yet, its role and importance in the structure and function of bone and bone formation have remained unknown. However, recent studies have identified that citrate is a major and essential component of the apatite/collagen structure of bone; and that the biomechanical properties of bone (e.g., stability, strength, resistance to fracture) depend on the appropriate incorporation of citrate in the structure of bone. The osteoblasts have recently been identified as citrate-producing cells that provide the citrate that is incorporated in the apatite/collagen structure during osteogenesis. Little is known regarding the factors and mechanisms involved in the regulation of citrate that is incorporated along with mineralization during the process of bone formation. Because of the importance of BMP2 in the initiation of osteogenesis and the development of the osteoblasts, it is essential to determine its possible implication in the development of the citrate-producing capability of the osteoblasts (i.e., "citration") during the formation of mineralized bone nodules. METHODS: The goal of this study was to determine if BMP2 promotes the development of citrate-producing osteoblasts for increased citrate incorporation in the formation of mineralized bone nodules. The study employed MC3T3 mesenchyme stem cell osteogenic differentiation in the presence and absence of BMP2. RESULTS: The results showed that BMP2 treatment increased the osteogenic development of mineralized bone nodules. In addition, BMP2 increased osteoblast citrate production and incorporation in the mineralized bone nodule. This was accompanied by increased ZIP1 transporter, which is an essential genetic/metabolic event for citrate-producing cells. CONCLUSIONS: The results demonstrate, for the first time, that BMP2 facilitates the osteoblast "citration" process in concert with mineralization during bone formation; and provide confirmation of the important role of osteoblasts as specialized citrate producing cells in the process of bone formation. However, it is essential to determine if these in vitro effects will occur in vivo in BMP2-implant induction of bone formation. "Citration" is essential for osteoinductive bone to represent the chemical, structural, and biomechanical properties of "normal" bone. PMID- 26635962 TI - Perceived psychosocial impairment associated with eating disorder features: responses to a mental health literacy intervention. AB - BACKGROUND: Whether and to what extent young adults are aware of the adverse impact of eating disorder features (EDF) on psychosocial functioning is unclear, although such awareness may affect the experience and behavior of sufferers. The aim of the current study was to examine young adults' perceptions of psychosocial impairment associated with EDF, and the potential effect on these perceptions of an eating disorders "mental health literacy" (ED-MHL) intervention. METHODS: Undergraduate students (male: n = 35; female: n = 141) completed self-report questionnaires prior to, immediately following, and 3 months after completion of a 3-h ED-MHL intervention. Perceived psychosocial impairment associated with EDF binge eating, purging, extreme dietary restriction, overvaluation of weight/shape, and excessive exercise-was assessed at each time point. RESULTS: At all 3 time points, EDF were considered to have a 'slightly negative' to 'very negative' impact on psychosocial functioning. Prior to the intervention, binge eating, purging and extreme dietary restriction were generally considered to have a greater negative impact than excessive exercise and overvaluation of weight/shape. Three months after the ED-MHL intervention, participants reported greater perceived impairment associated with excessive exercise and overvaluation; while perceptions of psychosocial impairment associated with binge eating, purging and dietary restriction remained largely unchanged. Females perceived greater impairment associated with EDF than males did immediately after the intervention, but not at the 3-month follow-up. CONCLUSIONS: The adverse effects on psychosocial functioning of binge eating, purging and extreme dietary restriction appear to be readily recognized by young people. Awareness of the adverse effects of excessive exercise and overvaluation may be poorer, but amenable to improvement by means of a relatively simple intervention. These features may warrant particular attention in health promotion programs. PMID- 26635963 TI - Testosterone and gonadotropins but not SHBG vary with CKD stages in young and middle aged men. AB - BACKGROUND: The aim of this study was to assess the effects chronic kidney disease (CKD) had on sex hormones and lipids in a subgroup of men between 18 and 50 years old with CKD 1-5 stage without diabetes and not treated with hemodialysis. METHODS: Data were collected from 101 men with different CKD stages. RESULTS: Higher CKD stage (lower function) had a significant negative linear trend on total testosterone level (p < 0.01) and free testosterone level (p < 0.01), with a significant increase of luteinizing hormone (LH) (p < 0.01), and prolactin (p < 0.01), while SHBG remained unchanged between the CKD stages. Triglycerides but not total cholesterol, HDL -cholesterol or LDL-cholesterol increased with higher CKD stage. A negative correlation was observed between BMI, SHBG and free testosterone (p < 0.01 for both) but not with other sex hormones. Age per se was related to a significant decrease of total and free testosterone level (p < 0.01 for both) even after correction for BMI. Decreased levels of total testosterone and estimated free testosterone levels had a significant correlation with an increased level of triglyceride levels (p <0.01). CONCLUSIONS: Our results indicate that CKD stage per se is a factor affecting testosterone levels in combination with age in men between 18 and 50 years old with CKD 1-5 stage, not treated with hemodialysis. With increased CKD stage there was a significant increase in LH level and a pattern of hypergonadotropic hypogonadism. SHBG remained unchanged between the CKD stages. PMID- 26635964 TI - Perceived ethical acceptability of financial incentives to improve diabetic eye screening attendance. AB - OBJECTIVE: To test the ethical acceptability of using financial incentives to increase diabetic retinopathy screening attendance. BACKGROUND: Financial incentives could be an effective way to increase attendance at screening for diabetic retinopathy, although there can be ethical concerns about this approach. DESIGN: Survey of people with diabetes in North West London. Those who were due to attend a screening appointment were invited to complete a questionnaire. Key demographic variables included age, gender, and deprivation. SETTING AND PARTICIPANTS: A questionnaire was issued to those invited to attend screening in North West London and those who run the screening service. The questionnaire captured views on aspects of the ethical problem and different incentive types. MAIN VARIABLES STUDIED: It captured views on the different dimensions of the ethical problem and different types of incentive. In order to understand how views might vary within a population, demographic variables were used to analyze the results. RESULTS AND CONCLUSIONS: Vouchers were found to be the most acceptable form of incentive, significantly more so than cash payments. Most rejected the notion of targeting those who need incentivizing, preferring equality. Age was an important factor, with those aged between 40 and 64 the most optimistic about the potential benefits. Higher levels of deprivation were linked to increased acceptability scores. While some ethical concerns are strongly held among certain groups, there is also much support for the principle of incentivizing positive behaviors. This paves the way for future research into the effectiveness of incentivizing diabetic retinopathy screening attendance. PMID- 26635965 TI - The Obesity-Fertility Protocol: a randomized controlled trial assessing clinical outcomes and costs of a transferable interdisciplinary lifestyle intervention, before and during pregnancy, in obese infertile women. AB - BACKGROUND: Obesity in infertile women increases the costs of fertility treatments, reduces their effectiveness and increases significantly the risks of many complications of pregnancy and for the newborn. Studies suggest that even a modest loss of 5-10 % of body weight can restore ovulation. However, there are gaps in knowledge regarding the benefits and cost-effectiveness of a lifestyle modification program targeting obese infertile women and integrated into the fertility clinics. This study will evaluate clinical outcomes and costs of a transferable interdisciplinary lifestyle intervention, before and during pregnancy, in obese infertile women. We hypothesize that the intervention will: 1) improve fertility, efficacy of fertility treatments, and health of mothers and their children; and 2) reduce the cost per live birth, including costs of fertility treatments and pregnancy outcomes. METHODS/DESIGN: Obese infertile women (age: 18-40 years; BMI >=30 kg/m(2) or >=27 kg/m(2) with polycystic ovary syndrome) will be randomised to either a lifestyle intervention followed by standard fertility treatments after 6 months if no conception has been achieved (intervention group) or standard fertility treatments only (control group). The intervention and/or follow-up will last for a maximum of 18 months or up to the end of pregnancy. Evaluation visits will be planned every 6 months where different outcome measures will be assessed. The primary outcome will be live birth rates at 18 months. The secondary outcomes will be sub-divided into four categories: lifestyle and anthropometric, fertility, pregnancy complications, and neonatal outcomes. Outcomes and costs will be also compared to similar women seen in three fertility clinics across Canada. Qualitative data will also be collected from both professionals and obese infertile women. DISCUSSION: This study will generate new knowledge about the implementation, impacts and costs of a lifestyle management program in obese infertile women. This information will be relevant for decision-makers and health care professionals, and should be generalizable to North American fertility clinics. TRIAL REGISTRATION: ClinicalTrials.gov NCT01483612. Registered 25 November 2011. PMID- 26635966 TI - Syncope as a health risk for soldiers - influence of medical history and clinical findings on the sensitivity of head-up tilt table testing. AB - BACKGROUND: Syncope is a relevant health problem in military environments. Reliable diagnosis is challenging. Tilt table testing is an important tool for syncope diagnosis. The aim of this study was to determine whether signs such as prodromal symptoms, co-morbidity, frequency of syncopal events, body length, body mass index, and electrocardiography abnormalities can be used to predict the success of tilt table testing at diagnosing syncope. METHODS: Data from 100 patients with histories of syncope or pre-syncope, who were diagnosed using head up tilt table testing, were retrospectively analyzed in a cross-sectional analysis. The diagnostic procedure was based upon a modified version of the Westminster protocol without any pharmacological provocation. RESULTS: Patients showing pathological reaction patterns during tilt table testing suffered from prodromal symptoms, such as dizziness and sweating, significantly more often. The patients reported more injuries resulting from syncopal events and more previous syncopal events, and the prevalence of co-morbidity was greater among patients presenting negative findings during tilt testing. An asthenic-leptosomal physique was not confirmed as a risk factor for syncopal events as is the case for idiopathic arterial hypotension. However, patients with pathological reaction patterns during tilt table testing were significantly taller. This finding was detected for both females and males. No significant predictors were found in the electrocardiogram (ECG) patterns of patients showing syncope during tilt table testing. CONCLUSIONS: Frequency of prior syncope and prodromal symptoms, and increased body length with an otherwise good state of health influence the predictive value of tilt table testing for syncope diagnosis. In particular, if these factors are present, tilt table testing should be considered part of the diagnostic algorithm for soldiers with recurrent syncope. PMID- 26635967 TI - The metallurgical characteristics of non-precious alloys using Nd:YAG laser welding. AB - BACKGROUND: This study aimed to determine the effect of hardness change according to penetration depth in the laser fusing zone and observed the correlation of the microstructure as an Nd:YAG laser was irradiated to Ni-Cr alloy for dental use by setting the spot diameter size with respect to defocusing distances. In all groups, the hardness depth profiles in the laser fusing zone and heat-affecteded zone (HAZ) had larger values than those of the base metal. In addition, the hardness values in places beyond the fusing zone and the HAZ were measured as being quantitatively lower. METHODS: The alloys used in this study were Verabond 2 V, Noritake Super, and Bellabond Plus, which are commercially used non-precious dental alloys. The specimens were cut to have a plate shape with a size of 0.5 * 3.0 * 2.5 mm. This was followed by setting the Nd:YAG laser output, pulse duration, and frequency to 60 W, 10 ms, and 5 Hz, respectively. The laser was then irradiated as the spot diameter condition varied between 0.5 mm and 1.4 mm in accordance with defocusing distance from 0.0 mm to 2.0 mm. After the laser irradiation, a cross-section of the fusing zone in the specimens was observed in terms of laser melted depth, hardness depth profile, and the microstructure of each alloy. RESULTS: The observation result of the diffusion of the constituent elements and microstructure using field emission scanning electron microscopy, energy dispersive spectroscopy (EDS), and electron probe micro-analyzer showed that the fusing zone revealed a much finer dendritic form than the base metal due to the self-quenching effect after laser melting, while no change in constituent elements was found although some evaporation of the main elements was observed. CONCLUSIONS: These results suggest that each Mo and Si combined inter-metallic compounds were formed on the interdendritic area. Through this study, the laser fusing zone had better hardenability due to the inter-metallic compound and grain refinement effect. PMID- 26629334 TI - Individuality, phenotypic differentiation, dormancy and 'persistence' in culturable bacterial systems: commonalities shared by environmental, laboratory, and clinical microbiology. AB - For bacteria, replication mainly involves growth by binary fission. However, in a very great many natural environments there are examples of phenotypically dormant, non-growing cells that do not replicate immediately and that are phenotypically 'nonculturable' on media that normally admit their growth. They thereby evade detection by conventional culture-based methods. Such dormant cells may also be observed in laboratory cultures and in clinical microbiology. They are usually more tolerant to stresses such as antibiotics, and in clinical microbiology they are typically referred to as 'persisters'. Bacterial cultures necessarily share a great deal of relatedness, and inclusive fitness theory implies that there are conceptual evolutionary advantages in trading a variation in growth rate against its mean, equivalent to hedging one's bets. There is much evidence that bacteria exploit this strategy widely. We here bring together data that show the commonality of these phenomena across environmental, laboratory and clinical microbiology. Considerable evidence, using methods similar to those common in environmental microbiology, now suggests that many supposedly non communicable, chronic and inflammatory diseases are exacerbated (if not indeed largely caused) by the presence of dormant or persistent bacteria (the ability of whose components to cause inflammation is well known). This dormancy (and resuscitation therefrom) often reflects the extent of the availability of free iron. Together, these phenomena can provide a ready explanation for the continuing inflammation common to such chronic diseases and its correlation with iron dysregulation. This implies that measures designed to assess and to inhibit or remove such organisms (or their access to iron) might be of much therapeutic benefit. PMID- 26635968 TI - Tocilizumab is effective against polymyalgia rheumatica: experience in 13 intractable cases. AB - Polymyalgia rheumatica (PMR) affects older people, and although glucocorticoids are effective in treating PMR, they frequently result in side effects. Therefore, we conducted a retrospective study to assess the effectiveness and safety of tocilizumab as an alternative to glucocorticoids. We included 13 consecutive patients with PMR (11 women and 2 men; median age, 74 years) diagnosed according to Bird's criteria and the 2012 European League Against Rheumatism/American College of Rheumatology provisional classification criteria. All patients received tocilizumab infusion (8 mg/kg every 4 weeks) at our institutions, between 2008 and 2014, because of PMR relapses (n=12) or insufficient response to initial prednisolone treatment (n=1), without increasing prednisolone dosage. Seven patients were on methotrexate, and all had one or more glucocorticoid related comorbidities. Administration of tocilizumab significantly improved inflammation and PMR symptoms such as morning stiffness, as well as the Patient Pain and Patient-Global Assessment visual analogue scales (p<0.05). Proximal muscle pain disappeared within 8 weeks, on average, and the Health Assessment Questionnaire-Disability Index scores (p=0.098) and concomitant prednisolone doses (p<0.05) decreased at 12 weeks. Severe adverse events were not observed during the mean tocilizumab treatment period of 43.4 weeks. Our findings suggest that tocilizumab is effective and safe for PMR treatment. PMID- 26635969 TI - Predictive value of autoantibodies from anti-CCP2, anti-MCV and anti-human citrullinated fibrinogen tests, in early rheumatoid arthritis patients with rapid radiographic progression at 1 year: results from the ESPOIR cohort. AB - OBJECTIVES: We compared the ability of antibodies against cyclic citrullinated peptides (anti-CCP2), against mutated citrullinated vimentin (anti-MCV) and against citrullinated fibrinogen (AhFibA) to predict 1 year rapid radiographic progression (RRP; total Sharp score variation >=5 points), in early rheumatoid arthritis (RA). METHODS: We analysed 566 patients from the ESPOIR cohort with early RA fulfilling the 2010 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) criteria at year 1. We assayed the 3 anticitrullinated peptide antibodies (ACPA) tests on baseline sera. We compared the performance of these 3 ACPA tests to predict first-year RRP, by comparing areas under the receiver operating characteristic curves (ROCs). We assessed the 1 year RRP risk by ACPA titres. We used a logistic multivariate regression to analyse RRP risk in terms either of ACPA positivity or titre: high (>3 times the N cut-off) and low (1 to 3N). RESULTS: 145 patients displayed RRP. Areas under the ROCs were similar (0.60) for the 3 tests. High ACPA titres were associated with 1 year RRP, whatever the test was, and with similar ORs. Low+ anti-MCV titres were not associated with 1-year RRP, whereas low+ anti-CCP2 titres (p=0.0226) and low+ AhFibA titres (p=0.0332) were significantly associated. In multivariate analysis, 1 year RRP was associated with anti-CCP2 positivity (p<0.0001), AhFibA positivity (p<0.0001) and high anti-MCV titres (p<0.0001). CONCLUSIONS: Anti-CCP2 antibodies and AhFibA were predictive of 1 year RRP in early RA whatever their titre was, whereas only high anti-MCV antibody titres were predictive, potentially making them more discriminant to predict 1 year RRP risk. PMID- 26635970 TI - Personalized NanoMedicine: Towards new Theranostic Approach. PMID- 26635971 TI - Designing Novel Nanoformulations Targeting Glutamate Transporter Excitatory Amino Acid Transporter 2: Implications in Treating Drug Addiction. AB - Chronic drug abuse is associated with elevated extracellular glutamate concentration in the brain reward regions. Deficit of glutamate clearance has been identified as a contributing factor that leads to enhanced glutamate concentration following extended drug abuse. Importantly, normalization of glutamate level through induction of glutamate transporter 1 (GLT1)/ excitatory amino acid transporter 2 (EAAT2) expression has been described in several in vivo studies. GLT1 upregulators including ceftriaxone, a beta-lactam antibiotic, have been effective in attenuating drug-seeking and drug-consumption behavior in rodent models. However, potential obstacles toward clinical translation of GLT1 (EAAT2) upregulators as treatment for drug addiction might include poor gastrointestinal absorption, serious peripheral adverse effects, and/or suboptimal CNS concentrations. Given the growing success of nanotechnology in targeting CNS ailments, nanoformulating known GLT1 (EAAT2) upregulators for selective uptake across the blood brain barrier presents an ideal therapeutic approach for treating drug addiction. In this review, we summarize the results obtained with promising GLT1 (EAAT2) inducing compounds in animal models recapitulating drug addiction. Additionally, the various nanoformulations that can be employed for selectively increasing the CNS bioavailability of GLT1 (EAAT2) upregulators are discussed. Finally, the applicability of GLT1 (EAAT2) induction via central delivery of drug-loaded nanoformulations is described. PMID- 26635973 TI - Steroids in Central Retinal Vein Occlusion: Is There a Role in Current Treatment Practice? AB - With the current widespread use of anti-VEGFs in the treatment of central retinal vein occlusion (CRVO), the role for steroids has become greatly diminished. Recent large scale randomized control trials (RCTs) have established the efficacy and safety of anti-VEGFs in the treatment of CRVO. Steroids are known to cause elevations in intraocular pressure as well as increase the risk of cataract formation. With that in mind many ophthalmologists are injecting steroids less frequently. This paper aims to review some of the data pertaining to the use of steroids either as a first line monotherapy, adjunct therapy, or an alternative therapy to help answer the question: Is there currently any role for steroids in the management of CRVO? PMID- 26635972 TI - Development of NanoART for HIV Treatment: Minding the Cytochrome P450 (CYP) Enzymes. AB - Sustained suppression of HIV viral load is the primary objective for HIV treatment, which successfully achieved by the use of a wide array of antiretroviral therapies (ART). Despite this enormous success low level of virus persists in the anatomical and cellular reservoirs of the body causing a multitude of immunological and neurocognitive deficits. Towards this, nano formulations are gaining attention to solve these problems by delivering ART to the targeted locations such as brain, lymphoid tissues, and monocytes/macrophages. As cytochrome P450 (CYP) enzymes play a critical role in the metabolism of drugs and other xenobiotics, it is expected that the interaction of nanoparticles with CYP enzymes may result in adverse drug reactions, cellular toxicity, and alterations in CYP-mediated metabolism of other drug molecules. Considering these potential adverse outcomes it is imperative to design the nano-carriers that will have minimal impact on CYP enzymes. Therefore, developing a long-acting nanoART regimen with minimal side effects is an essential step to improve patient's adherence to the treatment paradigm, effective treatment strategy, and to combat the HIV infection & AIDS. PMID- 26635974 TI - Determining the IC 50 Values for Vorozole and Letrozole, on a Series of Human Liver Cytochrome P450s, to Help Determine the Binding Site of Vorozole in the Liver. AB - Vorozole and letrozole are third-generation aromatase (cytochrome P450 19A1) inhibitors. [(11)C]-Vorozole can be used as a radiotracer for aromatase in living animals but when administered by IV, it collects in the liver. Pretreatment with letrozole does not affect the binding of vorozole in the liver. In search of finding the protein responsible for the accumulation of vorozole in the liver, fluorometric high-throughput screening assays were used to test the inhibitory capability of vorozole and letrozole on a series of liver cytochrome P450s (CYP1A1, CYP1A2, CYP2A6, and CYP3A4). It was determined that vorozole is a potent inhibitor of CYP1A1 (IC50 = 0.469 MUM) and a moderate inhibitor of CYP2A6 and CYP3A4 (IC50 = 24.4 and 98.1 MUM, resp.). Letrozole is only a moderate inhibitor of CYP1A1 and CYP2A6 (IC50 = 69.8 and 106 MUM) and a very weak inhibitor of CYP3A4 (<10% inhibition at 1 mM). Since CYP3A4 makes up the majority of the CYP content found in the human liver, and vorozole inhibits it moderately well but letrozole does not, CYP3A4 is a good candidate for the protein that [(11)C] vorozole is binding to in the liver. PMID- 26635975 TI - Previous Education, Sociodemographic Characteristics, and Nursing Cumulative Grade Point Average as Predictors of Success in Nursing Licensure Examinations. AB - Introduction. Success in the licensure examination is the only legal prerequisite to practice as a nurse in Ghana. However, a large percentage of nursing students who sit fail this examination for the first time. This study sought to unravel whether prior education, sociodemographic characteristics, and nursing Cumulative Grade Point Average (CGPA) could predict performance in the licensure examinations. Methods. The study was a descriptive cross-sectional survey conducted from November 2014 to April 2015 in the Kumasi metropolis, Ghana on 176 past nursing students. Data was collected using questionnaires and analyzed using SPSS version 22. A logistic regression model was fitted to look at the influence of the explanatory variables on the odds of passing the licensure examinations. All statistical significances were tested at p value of <0.05. Results. Majority, 56.3%, were females and 86.4% were between the ages of 25 and 31 years. Most of the students (88.6%) entered the nursing training colleges with a WASSCE qualification and 38% read general science. 73.9% passed the licensure examinations and the mean CGPA of the students was 2.89 (SD = 0.37). Sociodemographic characteristics and previous education had no influence on performance in the licensure examinations. CGPA had strong positive relationship with performance in licensure examinations (AOR = 15.27; 95% CI = 6.28, 27.11). Conclusion. Students CGPA could be a good predictor of their performance in the licensure examinations. On the other hand, students' sociodemographic and previous educational characteristics might not be important factors to consider in admitting students into the nursing training programme. PMID- 26635977 TI - Correlation between Fine-Needle Aspiration Cytology and Histology for Palpable Breast Masses in a Nigerian Tertiary Health Institution. AB - Background. Management of breast lumps can be challenging in resource poor settings. Fine-needle aspiration cytology (FNAC) especially when used with cell block can help improve affordability for the patients. Objective. To determine the diagnostic accuracy of FNAC of palpable breast lesions within a 5-year period. Methods. The findings obtained from FNAC of palpable breast lumps seen at the FNAC clinic of our department from January 2007 to December 2011 were retrieved and correlated with findings on histology of excisional biopsies. Results. A total of 1790 patients had FNAC of breast lumps during the 5-year period; 436 of them subsequently had biopsies. Our results compare favourably with the measures of test performance of the UK NHS Breast Screening Programme shown in brackets: absolute sensitivity 95.4% (>70%), complete sensitivity 99.2% (>90%), full specificity 88.9% (>65%), positive predictive value 99.6% (>99%), false-negative rate 0.8% (<4%), false-positive rate 0.4% (<0.5%), inadequate rate 3.2% (<15%), and suspicious rate 10.2% (<15%). Conclusion. Breast FNACs compare very well with histology of excisional biopsies and in experienced hands are extremely useful in the management of breast lumps. Further studies assessing the diagnostic accuracy of FNAC and cell blocks in our setting are recommended. PMID- 26635976 TI - Anatomy of the Ophthalmic Artery: A Review concerning Its Modern Surgical and Clinical Applications. AB - Anatomy of ophthalmic artery has been thoroughly studied and reviewed in many anatomical and surgical textbooks and papers. Issues of interest are its intracranial and extracranial course, its branches, its importance for vision, and its interaction with various intracranial pathologies. Improvement of our understanding about pathophysiology of certain diseases like aneurysm formation, central retinal artery occlusion, and retinoblastoma and also invention of new therapeutic modalities like superselective catheterization, intra-arterial fibrinolysis, and intra-arterial chemotherapy necessitate a reappraisal of its anatomy from a clinical point of view. The aim of this review is to examine clinical anatomy of ophthalmic artery and correlate it with new diagnostic and therapeutic applications. PMID- 26635978 TI - Sagittal and Frontal Plane Evaluation of the Whole Spine and Clinical Outcomes after Vertebral Fractures. AB - Although it is known that a change in any level of the spine alters biomechanics, there are not many studies to evaluate the spine as a whole in both sagittal and frontal planes. This prospective cohort study evaluates the morphology and mobility of the entire spine in patients with vertebral fractures. The Treatment Group consisted of 43 patients who underwent percutaneous balloon kyphoplasty or percutaneous balloon kyphoplasty plus fixation. The Control Group consisted of 39 healthy subjects. Spinal Mouse was used for the assessment of the curvatures and the mobility of the spine. Clinical outcomes were evaluated by Visual Analogue Scale and Oswestry Disability Index. The measurements were recorded at 15 days and 3, 6, and 12 months postoperatively. Regarding the curvatures and mobility in sagittal plane, a statistically significant increase appeared early at 3 months, for lumbar curve, spinopelvic angulation, and overall trunk inclination. In the frontal plane, most of the improvements were recorded after 6 months. Patients with osteoporotic fracture showed statistically significant lower mean value than patients with traumatic fracture. Pain and disability index showed early improvements. This study provides a comprehensive and complete picture of the functionality of the spine in patients treated with percutaneous balloon kyphoplasty. PMID- 26635979 TI - Atypical Case of Three Dental Implants Displaced into the Maxillary Sinus. AB - Oral rehabilitation with dental implants has become a routine treatment in contemporary dentistry. The displacement of dental implants into the sinus membrane, a complication related to the maxillary sinus, is one of the most common accidents reported in the literature. The treatment for this complication is the surgical removal of the implant. A 60-year-old woman with three dental implants displaced into the maxillary sinus (one implant displaced into the left maxillary sinus and two implants displaced into the right maxillary sinus) underwent surgery for removal of the implants. The surgery to remove the implants was performed under local anesthesia through the Caldwell-Luc technique. The patient was subsequently administered antibiotic, anti-inflammatory, and analgesic drugs. The patient returned 7 days after the surgery for suture removal and is being regularly monitored to determine whether future rehabilitation of the edentulous area is necessary. In conclusion, surgical removal of the dental implant displaced into the maxillary sinus is the treatment of choice. This technique is appropriate because it allows the use of local anesthesia and provides direct visualization for the removal of the implants. PMID- 26635980 TI - Melanoma of the Right Foot Simulating Kaposi's Disease. AB - Melanoma is a malignant tumor rarely being described in sub-Saharan Africa. We reported an unusual and atypical clinical presentation. It was a 59-year-old patient who was hospitalized for a monomelic black tumor evolving for 10 years. Histopathological examination confirmed the melanocytic origin of this tumor. Paraclinical assessment did not find any visceral metastasis. A partial resection of the tumor was performed. The patient left the hospital against medical consent due to lack of technical facilities. The delay in the consultation and the lack of knowledge of melanoma by doctors and patients might contribute to the severity and the difficulties of its management. PMID- 26635981 TI - Pneumatosis Intestinalis in a Patient with Acute Promyelocytic Leukemia. AB - Pneumatosis Intestinalis is a rare condition characterized by the presence of gas within the intestinal wall. We describe a case of a 33-year-old woman with acute promyelocytic leukemia who developed nausea and nonbloody diarrhea. CT showed intramural air in transverse and descending colon. Patient clinically improved with conservative management. PMID- 26635982 TI - Lymphoma Presenting as Acute-Onset Dysphagia. AB - A 61-year-old man with recent Bell's palsy developed acute vocal cord paralysis causing severe dysphagia. CSF analysis showed elevated protein and a normal cell count; contrast-enhanced MRI of the brain was normal. He was treated with IVIG for a presumed bulbar-variant AIDP and gradually improved. Six months later, the patient developed rapidly progressive hearing loss and vestibular dysfunction. Repeat MRI revealed bilateral enhancement of the eighth cranial nerves and a hypercellular mass in the left temporal lobe. Biopsy of the mass confirmed the diagnosis of diffuse large B-cell lymphoma. Lymphomatous invasion of the cranial nerves should be considered in cases of relapsing cranial neuropathies. PMID- 26635983 TI - Multiple Bone Metastases as the First Manifestation of Hepatocellular Carcinoma in Patient with Noncirrhotic Liver. AB - Hepatocellular carcinoma (HCC) generally occurs on the background of chronic liver disease. Chronic hepatitides B and C and alcoholic liver disease are well known risk factors for HCC, and it is uncommon in noncirrhotic liver. Extrahepatic metastasis seldom occurs in patients with early stage intrahepatic HCC and isolated bone metastases as a first documented extrahepatic metastasis is unusual presentation. In this report, we present a rare case of small solitary HCC (<3 cm) in noncirrhotic liver, presenting isolated bone metastases as a sole manifestation in patient with no well-known risk factors. This case suggests that HCC should be considered as one of differential diagnoses in patient presenting with multiple bone metastases, even in the absence of liver cirrhosis. PMID- 26635984 TI - Craniofacial Microsomia: Goldenhar Syndrome in Association with Bilateral Congenital Cataract. AB - Craniofacial microsomia (CFM) includes a spectrum of malformations primarily involving structures derived from the first and second branchial arches. Patients with hemifacial microsomia and epibulbar dermoids are said to have Goldenhar syndrome (GHS). Four-month-old boy with whitish pupillary reflex presented with the features of GHS in pediatric ophthalmology clinic. The child had ocular and auricular manifestations. There were no vertebral anomalies, but he had bilateral congenital cataract. The peculiarity of this case is the presence of the bilateral total congenital cataract, in association with CFM. There is absence of epibulbar dermoid or lipodermoid in the eyes, although the child had features of GHS. In addition to it, anesthetic intubation was smooth in this case. Any case diagnosed with CFM and/or GHS needs treatment through multidisciplinary approach, consultation in ophthalmology department is one of them. PMID- 26635985 TI - Fellow Eye Macular Edema Improvement after Intravitreal Bevacizumab for Radiation Retinopathy. AB - Radiation retinopathy (RR) is a progressive, chronic condition directly related to the amount of radiation administered to the retina. We report a 37-year-old patient with medulloblastoma that was treated with external beam radiation and presented to us with bilateral cystoid macular edema. He was treated with monthly bevacizumab injections only in his worst seeing eye. There was a significant improvement in his fellow eye, with marked retinal thickness reduction. Therefore, we present clinical evidence of systemic absorption and fellow eye activity of the drug (bevacizumab). One must be aware of distant side effects after intravitreal injections. PMID- 26635986 TI - Melkersson-Rosenthal Syndrome with Orofacial Swelling and Recurrent Lower Motor Neuron Facial Nerve Palsy: A Case Report and Review of the Literature. AB - Melkersson-Rosenthal Syndrome (MRS) is a rare otoneurologic condition, which is poorly understood and often underdiagnosed. Etiology and incidence are unclear, although infectious, inflammatory, and genetic causes have been implicated. Recurrent facial nerve palsy, facial swelling, and fissured tongue are the symptoms and signs of this condition. However, this triad is not typical in all patients as patients may present with one or more of the symptoms, which makes management of this condition difficult. Steroids may prove to be useful especially in patients who have facial nerve palsy. In this case report, we have described a 46 year-old Caucasian male who presented to the clinic for the evaluation of orofacial swelling and left facial deviation with a history of multiple treatments for recurrent lower motor neuron type facial nerve palsy. PMID- 26635987 TI - Subcutaneous Fat Necrosis of the Newborn: A Case Report of a Term Infant Presenting with Malaise and Fever at Age of 9 Weeks. AB - Background. Subcutaneous fat necrosis (SFN) is a rare, temporary, self-limited pathology affecting adipose tissue of full-term or postmature neonates. It is a rare entity especially in Nigeria and usually occurs in the first weeks following a complicated delivery. Because it is not very common, diagnosis is easily missed. It may resolve spontaneously without sequelae but patients need to be followed up because of development of late complications especially hypercalcemia. We report a case of SFN of the newborn noted within one week of birth and highlight the need for proper prompt diagnosis and the need for follow up to assess possible complications. PMID- 26635988 TI - Eikenella corrodens Sepsis with Cerebrospinal Fluid Pleocytosis in a Very Low Birth Weight Neonate. AB - We report a case of Eikenella corrodens sepsis associated with CSF pleocytosis in a very low birth weight neonate. A 1000-gram male neonate was born at 27-week gestation due to preterm labor. The patient presented with signs and symptoms of sepsis and was treated for suspected meningitis with intravenous ampicillin and gentamicin for 7 days, with cefotaxime added for three weeks. He had a normal brain MRI at discharge and normal development at 6 months of life. To our knowledge, this is the first case of E. corrodens sepsis and associated meningitis in a very low birth weight neonate. PMID- 26635989 TI - A Large Pleural Effusion following Abdominal Aortic Surgery. AB - Chylous ascites and coexistent chylothorax is a rare but important complication following retroperitoneal abdominal surgery. We report a 70-year-old male who developed gradual abdominal distension, chest tightness, and dyspnea five months after having an uncomplicated aortobifemoral bypass performed. Physical examination was consistent with a large right sided effusion and ascites which were confirmed by computed tomography. Thoracentesis yielded an opaque milky fluid with analysis consistent with a chylothorax with a paracentesis revealing fluid that was similar in both appearance and biochemistry. The patient failed initial conservative management so a chest tube was placed followed by chemical pleurodesis. We review the literature of the pathophysiology and treatment approach to such a pleural effusion. PMID- 26635990 TI - Ancient Schwannoma of Ansa Cervicalis: A Rare Clinical Entity and Review of the Literature. AB - Ancient schwannoma is an uncommon variant of schwannoma, a benign tumor arising from the nerve sheath. It is reported to arise from any nerves except optic and olfactory. However, only six cases of ancient schwannomas arising from ansa cervicalis nerve have been reported to date in English literature. Proper preoperative evaluation is necessary to rule out other causes of neck mass such as thyroid lesions, lymphadenopathy, and carotid body tumor. We report a case of ancient schwannoma arising from the ansa cervicalis nerve. The origin of the lesion from ansa cervicalis was confirmed by intraoperative finding. Postoperative histopathological examination revealed degenerative changes including pleomorphism, cellular atypia, large nuclei with prominent nucleoli, and paucity of mitotic figures. Periphery of the mass showed nuclear palisading with characteristic verocay bodies. Immunohistochemical evaluation for S-100 showed diffuse positivity of the tumor cells, thereby confirming the diagnosis of schwannoma. We consider that schwannoma of cervical region can have origin from any nerve and should try to identify the origin pre- and intraoperatively. The postoperative complications depend on the nerve of origin and the precision of the surgery performed. PMID- 26635991 TI - Management of Delayed Onset Postoperative Hemorrhage after Anastomotic Urethroplasty. AB - Excision with primary anastomosis (EPA) urethroplasty is generally the preferred method for short strictures in the bulbar urethra, given its high success rate and low complication rate compared to other surgical interventions. Bleeding is a presumed risk factor for any surgical procedure but perioperative hemorrhage after an EPA requiring hospitalization and/or reintervention is unreported with no known consensus on the best course for management. Through our experience with three separate cases of significant postoperative urethral hemorrhage after EPA, we developed an algorithm for treatment beginning with conservative management and progressing through endoscopic and open techniques, as well as consideration of embolization by interventional radiology. All the three of these cases were managed successfully though they did require multiple interventions. We theorize that younger patients with more robust corpus spongiosum and more vigorous spontaneous erections, patients that have undergone fewer prior urethral procedures and therefore have more prominent vasculature, and those patients managed with a two-layer closure of the ventral urethra without ligation of the transected bulbar arteries are at a higher risk for this complication. PMID- 26635992 TI - Four Copies of SNCA Responsible for Autosomal Dominant Parkinson's Disease in Two Italian Siblings. AB - Background. Parkinson's disease (PD) is mostly characterized by alpha-synuclein (SNCA) aggregation and loss of nigrostriatal dopamine-containing neurons. In this study a novel SNCA multiplication is described in two siblings affected by severe parkinsonism featuring early onset dyskinesia, psychiatric symptoms, and cognitive deterioration. Methods. SNCA dosage was performed using High-Density Comparative Genomic Hybridization Array (CGH-Array), Multiple Ligation Dependent Probe Amplification (MLPA), and Quantitative PCR (qPCR). Genetic analysis was associated with clinical evaluation. Results. Genetic analysis of siblings showed for the first time a 351 Kb triplication containing SNCA gene along with 6 exons of MMRN1 gene in 4q22.1 and a duplication of 1,29 Mb of a genomic region flanking the triplication. Conclusions. The identification of this family indicates a novel mechanism of SNCA gene multiplication, which confirms the genomic instability in this region and provides data on the genotype-phenotype correlation in PD patients. PMID- 26635993 TI - Anthropometry of Iranian Guidance School Students with Different Ethnicities: A Comparative Study. AB - Objective. We measured some anthropometric dimensions of Iranian guidance school students selected from different ethnicities. Background. Anthropometric dimensions are used for design of equipment, furniture, and clothing. Furniture with inappropriate design not fulfilling the users' anthropometric dimensions may have a negative effect on health. Method. A total of 7400 Iranian guidance school students aged 12-14 years entered the study and their static anthropometric dimensions were measured. Descriptive statistics such as mean, standard deviation, and key percentiles were calculated. All dimensions were compared among different ethnicities and different genders. Results. This study showed significant differences in a set of 22 anthropometric dimensions regarding gender, age, and ethnicity. Conclusion. According to the results of this study, difference between genders and among different ethnicities should be taken into account by designers and manufacturers of guidance school furniture. Application. This study has prepared a data bank of anthropometric dimensions of 12-14-year old students which can be used as basic information to find appropriate dimensions of school furniture. PMID- 26635994 TI - Fatty acid, amino acid, mineral and antioxidant contents of acha (Digitaria exilis) grown on the Jos Plateau, Nigeria. AB - Digitaria exilis (Kippist) Stapf (also known as acha, hungry rice) has been cultivated for millennia in the dry savannahs of West Africa, but much remains to be learned about its nutritional properties. Acha was collected in four villages in Northern Nigeria and analyzed for fatty acids, minerals, amino acids and antioxidant content. Fatty acids accounted for 1.91% of the dry weight, with 47.4% linoleic acid and 30.5% oleic acid. The content of the essential minerals, copper, magnesium, molybdenum, zinc and calcium averaged 4.88, 1060, 0.23, 23.0 and 172 MUg/g, respectively. The protein content was 6.53% and the essential amino acid pattern, except for lysine, compared favorably to a World Health Organization (WHO) reference protein. The total polyphenolic content of methanolic extracts of acha matched that of common cereals (for example, maize, rice, wheat) and the extracts contained substantial amounts of free-radical scavenging substances. Thus, acha is a source of many nutrients critical to human health. PMID- 26635995 TI - Mass Casualty Decontamination in a Chemical or Radiological/Nuclear Incident with External Contamination: Guiding Principles and Research Needs. AB - Hazardous chemical, radiological, and nuclear materials threaten public health in scenarios of accidental or intentional release which can lead to external contamination of people. Without intervention, the contamination could cause severe adverse health effects, through systemic absorption by the contaminated casualties as well as spread of contamination to other people, medical equipment, and facilities. Timely decontamination can prevent or interrupt absorption into the body and minimize opportunities for spread of the contamination, thereby mitigating the health impact of the incident. Although the specific physicochemical characteristics of the hazardous material(s) will determine the nature of an incident and its risks, some decontamination and medical challenges and recommended response strategies are common among chemical and radioactive material incidents. Furthermore, the identity of the hazardous material released may not be known early in an incident. Therefore, it may be beneficial to compare the evidence and harmonize approaches between chemical and radioactive contamination incidents. Experts from the Global Health Security Initiative's Chemical and Radiological/Nuclear Working Groups present here a succinct summary of guiding principles for planning and response based on current best practices, as well as research needs, to address the challenges of managing contaminated casualties in a chemical or radiological/nuclear incident. PMID- 26635996 TI - Who Is Worst Off? Developing a Severity-scoring Model of Complex Emergency Affected Countries in Order to Ensure Needs Based Funding. AB - BACKGROUND: Disasters affect close to 400 million people each year. Complex Emergencies (CE) are a category of disaster that affects nearly half of the 400 million and often last for several years. To support the people affected by CE, humanitarian assistance is provided with the aim of saving lives and alleviating suffering. It is widely agreed that funding for this assistance should be needs based. However, to date, there is no model or set of indicators that quantify and compare needs from one CE to another. In an effort to support needs-based and transparent funding of humanitarian assistance, the aim of this study is to develop a model that distinguishes between levels of severity among countries affected by CE. METHODS: In this study, severity serves as a predictor for level of need. The study focuses on two components of severity: vulnerability and exposure. In a literature and Internet search we identified indicators that characterize vulnerability and exposure to CE. Among the more than 100 indicators identified, a core set of six was selected in an expert ratings exercise. Selection was made based on indicator availability and their ability to characterize preexisting or underlying vulnerabilities (four indicators) or to quantify exposure to a CE (two indicators). CE from 50 countries were then scored using a 3-tiered score (Low-Moderate, High, Critical). RESULTS: The developed model builds on the logic of the Utstein template. It scores severity based on the readily available value of four vulnerability and four exposure indicators. These are 1) GNI per capita, PPP, 2) Under-five mortality rate, per 1 000 live births, 3) Adult literacy rate, % of people ages 15 and above, 4) Underweight, % of population under 5 years, and 5) number of persons and proportion of population affected, and 6) number of uprooted persons and proportion of population uprooted. CONCLUSION: The model can be used to derive support for transparent, needs-based funding of humanitarian assistance. Further research is needed to determine its validity, the robustness of indicators and to what extent levels of scoring relate to CE outcome. PMID- 26635997 TI - The Asymptotic Noise Distribution in Karhunen-Loeve Transform Eigenmodes. AB - Karhunen-Loeve Transform (KLT) is widely used in signal processing. Yet the well accepted result is that, the noise is uniformly distributed in all eigenmodes is not accurate. We apply a result of the random matrix theory to understand the asymptotic noise distribution in KLT eigenmodes. Noise variances in noise-only eigenmodes follow the Marcenko-Pastur distribution, while noise variances in signal-dominated eigenmodes still follow the uniform distribution. Both the mathematical expectation of noise level in each eigenmode and an analytical formula of KLT filter noise reduction effect with a hard threshold were derived. Numerical simulations agree with our theoretical analysis. The noise variance of an eigenmode may deviate more than 60% from the uniform distribution. These results can be modified slightly, and generalized to non-IID (independently and identically-distributed) noise scenario. Magnetic resonance imaging experiments show that the generalized result is applicable and accurate. These generic results can help us understand the noise behavior in the KLT and related topics. PMID- 26635998 TI - Phenothiazine vs 5HT3 antagonist prophylactic regimens to prevent Post-Anesthesia Care Unit rescue antiemetic: an observational study. AB - PURPOSE: Our practitioners are asked to consider a patient's postoperative nausea and vomiting (PONV) risk profile when developing their prophylactic antiemetic strategy. There is wide variation in employed strategies, and we have yet to determine the most effective PONV prophylactic regimen. The objective of this study is to compare prophylactic antiemetic regimens containing: phenothiazines to 5HT3 antagonists for effectiveness at reducing the incidence of Post Anesthesia Care Unit (PACU) rescue antiemetic administration. METHODS: This is an observational study of 4,392 nonsmoking women who underwent general anesthesia for breast surgery from 1/1/2009 through 6/30/2012. Previous history of PONV or motion sickness (HxPONV/MS) and the use of PACU opioids were recorded. Prophylactic antiemetic therapy was left to the discretion of the anesthesia care team. We compared phenothiazines and 5HT3 antagonists alone and with a glucocorticoid to determine the most effective treatment regimen in our practice for the prevention of the administration of PACU rescue antiemetics. RESULTS: Patients who received a phenothiazine regimen compared to a 5HT3 antagonist regimen were less likely to have an antiemetic administered in the PACU (p=0.0100) and this significant difference in rates holds in a logistic regression model adjusted for HxPONV/MS and PACU Opioid use (p=0.0103). CONCLUSIONS: Based on our findings our clinicians are encouraged to administer a combination of a phenothiazine and a glucocorticoid in female, nonsmoking surgical breast patients for the prevention of PACU rescue antiemetic administration. PMID- 26635999 TI - New therapeutic targets in rare genetic skeletal diseases. AB - Introduction: Genetic skeletal diseases (GSDs) are a diverse and complex group of rare genetic conditions that affect the development and homeostasis of the skeleton. Although individually rare, as a group of related diseases, GSDs have an overall prevalence of at least 1 per 4,000 children. There are currently very few specific therapeutic interventions to prevent, halt or modify skeletal disease progression and therefore the generation of new and effective treatments requires novel and innovative research that can identify tractable therapeutic targets and biomarkers of these diseases. Areas covered: Remarkable progress has been made in identifying the genetic basis of the majority of GSDs and in developing relevant model systems that have delivered new knowledge on disease mechanisms and are now starting to identify novel therapeutic targets. This review will provide an overview of disease mechanisms that are shared amongst groups of different GSDs and describe potential therapeutic approaches that are under investigation. Expert opinion: The extensive clinical variability and genetic heterogeneity of GSDs renders this broad group of rare diseases a bench to bedside challenge. However, the evolving hypothesis that clinically different diseases might share common disease mechanisms is a powerful concept that will generate critical mass for the identification and validation of novel therapeutic targets and biomarkers. PMID- 26636000 TI - Two-Stage Experimental Design for Dose-Response Modeling in Toxicology Studies. AB - The efficient design of experiments (i.e., selection of experimental doses and allocation of animals) is important to establishing dose-response relationships in toxicology studies. The proposed procedure for design of experiments is distinct from those in the literature because it is able to adequately accommodate the special features of the dose-response data, which include non normality, variance heterogeneity, possibly nonlinearity of the dose-response curve, and data scarcity. The design procedure is built in a sequential two-stage paradigm that allows for a learning process. In the first stage, preliminary experiments are performed to gain information regarding the underlying dose response curve and variance structure. In the second stage, the prior information obtained from the previous stage is utilized to guide the second-stage experiments. An optimization algorithm is developed to search for the design of experiments that will lead to dose-response models of the highest quality. To evaluate model quality (or uncertainty), which is the basis of design optimization, a bootstrapping method is employed; unlike standard statistical methods, bootstrapping is not subject to restrictive assumptions such as normality or large sample sizes. The design procedure in this paper will help to reduce the experimental cost/time in toxicology studies and alleviate the sustainability concerns regarding the tremendous new materials and chemicals. PMID- 26636001 TI - Mechanical versus enzymatic isolation of stromal vascular fraction cells from adipose tissue. AB - Clinical use of adipose-derived stem cells (ASCs) for a variety of indications is rapidly expanding in medicine. Most commonly, ASCs are isolated at the point of care from lipoaspirate tissue as the stromal vascular fraction (SVF). The cells are immediately administered to the patient as an injection or used to enrich fat grafts. Isolation of ASCs from adipose tissue is a relatively simple process performed routinely in cell biology laboratories, but isolation at the point of care for immediate clinical administration requires special methodology to prevent contamination, ensure integrity of clinical research and comply with regulatory requirements. A lack of practical laboratory experience, regulatory uncertainty and a relative paucity of objective published data can make selection of the optimum separation method for specific indications a difficult task for the clinician and can discourage clinical adoption. In this paper, we discuss the processes which can be used to separate SVF cells from fat tissue. We compare the various mechanical and enzymatic methods. We discuss the practical considerations involved in selecting an appropriate method from a clinical perspective. Studies consistently show that breakdown of the extracellular matrix achieved with proteolytic enzymes affords significantly greater efficiency to the separation process. SVF isolated through mechanical methods is equally safe, less costly and less time consuming but the product contains a higher frequency of blood mononuclear cells and fewer progenitor cells. Mechanical methods can provide a low cost, rapid and simple alternative to enzymatic isolation methods, and are attractive when smaller quantities of ASCs are sufficient. PMID- 26636002 TI - Phenolic profile and antioxidant potential of wild watercress (Nasturtium officinale L.). AB - Phenolic profile, antioxidant potential and pigment contents of wild watercress (Nasturtium officinale L.) were studied to assess the potential for future studies and its applications in neutraceuticals and bioactive functional ingredients. Different extracts of watercress (roots, stem and leaves) were analysed for pigment composition, total phenolic contents, and radical scavenging activity. The phenolic profile of the leaves and roots was studied using reversed phase HPLC-DAD. Results showed that total phenolic compounds in all samples were higher in the methanolic extracts than its corresponding aqueous extracts. The RSA of methanolic extracts was higher than aqueous extracts. Fourteen phenolic compounds were identified in the leaves, where coumaric acid and its derivatives, caftaric acid and quercetin derivatives were present in higher amounts. In roots, a total of 20 compounds was tentatively identified, with coumaric acid and its derivatives, sinapic acid, caftaric acid and quercetin derivatives were the major phenolic compounds. In conclusion, watercress has significant antioxidant activity and contains important phenolic compounds, which could be of potential biological interest. PMID- 26636003 TI - Her2 positivity and race predict higher mastectomy rates: a SEER database analysis. AB - Given the difference in incidence of biologic subtype of breast cancer between black and white women, and the potential disparity in type of surgery in black and white women presenting with early stage breast cancer, this study aimed to examine the odds of mastectomy compared to lumpectomy by molecular subtype in black and white women with size T1 and T2 invasive breast cancer. Using the SEER database, breast operation choice for women over the age of 15 with T1 or T2 tumors between 2010 and 2012 were examined. Tumors were categorized according to the Breast Subtype variable in the SEER database and data were stratified by tumor size and race. Bivariate comparisons and logistic regression models adjusted for age were used. In women with T1 or T2 tumors, mastectomy rates were higher in women with Her2 positive tumors than in those with Her2 negative tumors. When Her2 results are the same among comparison groups, those women with HR positive tumors were less likely to undergo a mastectomy than those with HR negative tumors. In T1 tumors, the magnitude of the association was larger for white women than women of other races. Results suggest there are differences in surgical decision making based on breast cancer subtype in women with T1 or T2 tumors and that race may play a role for size T1 tumors. The strong association between Her2 positive tumors and higher mastectomy rates warrants further investigation. PMID- 26636004 TI - Pathological brain detection in MRI scanning by wavelet packet Tsallis entropy and fuzzy support vector machine. AB - An computer-aided diagnosis system of pathological brain detection (PBD) is important for help physicians interpret and analyze medical images. We proposed a novel automatic PBD to distinguish pathological brains from healthy brains in magnetic resonance imaging scanning in this paper. The proposed method simplified the PBD problem to a binary classification task. We extracted the wavelet packet Tsallis entropy (WPTE) from each brain image. The WPTE is the Tsallis entropy of the coefficients of the discrete wavelet packet transform. The, the features were submitted to the fuzzy support vector machine (FSVM). We tested the proposed diagnosis method on 3 benchmark datasets with different sizes. A ten runs of K fold stratified cross validation was carried out. The results demonstrated that the proposed WPTE + FSVM method excelled 17 state-of-the-art methods w.r.t. classification accuracy. The WPTE is superior to discrete wavelet transform. The Tsallis entropy performs better than Shannon entropy. The FSVM excels standard SVM. In closing, the proposed method "WPTE + FSVM" is effective in PBD. PMID- 26636005 TI - Impact evaluation and association with EuroQol 5D health-related utility values in Meniere's disease. AB - The study was aimed at evaluating the validity of impact measures among patients with Meniere's disease (MD) with outcome variables of EuroQol generic health related quality of life (HRQoL) measures (i.e., EQ-5D) by using Visual Analogue Scale (VAS) and EQ-5D index values. 183 members (out of 200 contacted) of the Finish Meniere Association returned the questionnaires that they had filled out. Various open-ended and structured questionnaires focusing on diagnostic aspects of symptoms and impairment caused by the disease were used. For activity limitation and participation restriction, standardized questionnaires were used. Open-ended questions on impact of the disease were asked, and subsequently classified based on the WHO-ICF classification. The general HRQoL was evaluated with EQ-5D index value and EQ VAS instruments. Correlation and linear regression analyses were used to explore the association between HRQoL and other aspects. Based on the explanatory power of different models the disease specific semeionic model provides the most accurate prediction in EQ-5D index calculations (38 % of the variance explained). In EQ VAS scores, HRQoL is most accurately determined by participation restriction (53 % of the variance explained), but the worst prediction was in ICF-based limitations (8 % of the variance explained). Interestingly, attitude and personal trait explained the reduction of HRQoL somewhat better than ICF-based variables. Activity limitation and participation restrictions are significant components of MD, but are less frequently recognized as significant factors in self-evaluating the effect of MD on the quality of life. The current study results suggest that MD patients seem to have problem identifying factors causing activity limitation and participation restrictions and hence use the semiotic description focusing on complaints. PMID- 26636006 TI - Clinical significance of SUVmax in (18)F-FDG PET/CT scan for detecting nodal metastases in patients with oral squamous cell carcinoma. AB - To retrospectively investigate the diagnostic accuracy of FDG-PET/CT relative to CT for detection of cervical node metastases in patients with oral squamous cell carcinoma (OSCC), using histologic evaluation of dissected cervical nodes as the reference standard. Thirty-six patients with OSCC who underwent neck dissection (4 bilateral, 32 unilateral; 250 nodal levels) after FDG-PET/CT. Two observers consensually determined the lesion size and SUVmax of visible cervical nodes and compared the results with pathologic findings at the nodal level. Histopathology revealed nodal metastases in 13 (36.1 %) of 36 patients and 28 (11.2 %) of 250 nodal levels. Using a best discriminative SUVmax cut-off of 3.5 for the node, the sensitivity, specificity and accuracy of FDG-PET/CT for identification of nodal metastases on a level-by-level basis were 67.9, 94.6, and 91.6 %, respectively. The corresponding figures for CT were 42.9, 96.8, and 90.8 %, respectively. The sensitivity of FDG-PET/CT was significantly better than CT (p = 0.023). Moreover, using the level-based modified SUVmax cut-off, the respective figures for FDG PET/CT were 71.4, 95.9, and 93.2 %, with significantly higher sensitivity (p = 0.013) and accuracy (p = 0.041) than CT. FDG PET/CT with SUVmax is a useful modality for preoperative evaluation of cervical neck lymph node metastases in patients with OSCC. PMID- 26636007 TI - Effects of dietary allspice, Pimenta dioica powder on physiological responses of Oreochromis mossambicus under low pH stress. AB - This study investigated the effects of the supplementation with allspice (0, 5, 10, 15, or 20 g kg(-1)) on the haemato-immunological and biochemical variables in tilapia, Oreochromis mossambicus under acidic stress condition. In a 60-day feeding trial, 15 aquariums (80-L) were stocked with 18 fish (20.05 +/- 0.10 g) each. Then, acidic stress was achieved by exposing the sampled fish to acidic water (pH 5.5) for 3 days. Allspice supplementation influenced the haematological indices, serum glucose, protein, globulin and innate immune parameters such as respiratory burst activity, lysozyme, and myeloperoxidase activities. In general, at acidic pH decreased circulating red blood cell numbers (RBC), increased mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH) and the innate immune parameters were observed. On the other hand, the inclusion of allspice prevented an increase in blood glucose MCV and MCH, decreases in albumin, RBC, lysozyme activity and respiratory burst avtivity. In conclusion, this study demonstrated that allspice supplementation at 10 g kg(-1) for 60 days, has adequate beneficial effects on improvement of haemato-immunological and biochemical status of O. mossambicus after stressful management. PMID- 26636008 TI - Production of biodiesel from coastal macroalgae (Chara vulgaris) and optimization of process parameters using Box-Behnken design. AB - Renewable biodiesels are needed as an alternative to petroleum-derived transport fuels, which contribute to global warming and are of limited availability. Algae biomass, are a potential source of renewable energy, and they can be converted into energy such as biofuels. This study introduces an integrated method for the production of biodiesel from Chara vulgaris algae collected from the coastal region of Bangladesh. The Box-Behnken design based on response surface methods (RSM) used as the statistical tool to optimize three variables for predicting the best performing conditions (calorific value and yield) of algae biodiesel. The three parameters for production condition were chloroform (X1), sodium chloride concentration (X2) and temperature (X3). Optimal conditions were estimated by the aid of statistical regression analysis and surface plot chart. The optimal condition of biodiesel production parameter for 12 g of dry algae biomass was observed to be 198 ml chloroform with 0.75 % sodium chloride at 65 degrees C temperature, where the calorific value of biodiesel is 9255.106 kcal/kg and yield 3.6 ml. PMID- 26636009 TI - Fungal annexins: a mini review. AB - The large family of annexins is composed of more than a thousand members which are typically phospholipid-binding proteins. Annexins act in a number of signalling networks and membrane trafficking events which are fundamental to cell physiology. Annexins exert their functions mainly through their calcium-dependent membrane binding abilities; however, some calcium-independent interactions have been documented in the literature. Although mammalian and plant annexins have been well characterized, little is known about this family in fungi. This mini review summarizes the available data on fungal annexins. PMID- 26636010 TI - Almost automorphic solutions for shunting inhibitory cellular neural networks with time-varying delays. AB - This paper is concerned with the shunting inhibitory cellular neural networks with time-varying delays. Under some suitable conditions, we establish some criteria on the existence and global exponential stability of the almost automorphic solutions of the networks. Numerical simulations are given to support the theoretical findings. PMID- 26636011 TI - Underestimation of prevalence of raised blood sugar from history compared to biochemical estimation: support for the WHO rule of halves in a population based survey in Eritrea of 2009. AB - To ascertain the prevalence of diabetes mellitus from history and biochemical estimation so as to attest the WHO Rule of halves in a lean population. A population based national survey on diabetes mellitus was carried out in 2009. History and fingerpicks blood analysis were examined according to recommended procedures of the WHO STEPwise approach and the WHO recommended automated machine to compare the two modalities of estimating diabetes prevalence. Over 6000 people with a response rate of 95 % and a prevalence of raised blood glucose of 5.0 %. The prevalence from history of raised blood sugar was 2.2 %. Less than half (47 %) of the persons with high blood glucose were aware of their status with less than half on treatment. Of those on treatment less than half (30 %) were well controlled. Prevalence of raised fasting blood glucose was more than double that estimated from history, with less than half of the people aware of their status and of those on treatment nearly half are under good control. The underestimation of the disease through history supports the WHO rule of halves and calls for the use of biochemical tests when estimating prevalence of diabetes in the general population or at least doubling the rate from history alone. PMID- 26636012 TI - Augmented monomials in terms of power sums. AB - The problem of base changes for the classical symmetric functions has been solved a long time ago and has been incorporated into most computer software packages for symmetric functions. In this paper, we develop a simple recursive formula for the expansion of the augmented monomial symmetric functions into power sum symmetric functions. As corollaries, we present two algorithms that can be used to expressing the augmented monomial symmetric functions in terms of the power sum symmetric functions. PMID- 26636013 TI - Do general practitioners prescribe more antimicrobials when the weekend comes? AB - Inappropriate antimicrobial prescribing contributes to the global spread of antimicrobial resistance. The pending weekend with changed availability of general practitioners (GP) and increased patient concern may increase the intention to prescribe antimicrobials. The aim of this study is to analyse variation in antimicrobial prescribing between weekdays and weekend in Irish general practice. All prescribing data over a 15 month period was obtained from the 30 practices participating in the Supporting the Improvement and Management of Prescribing for urinary tract infection (SIMPle) study. Antimicrobials were classified using anatomical therapeutic chemical classification code guidelines. Prescribing of antimicrobials per total number of prescriptions was compared between weekdays (Monday to Thursday) and the weekend (Friday to Sunday). Antimicrobials were generally more often prescribed during weekends; the antimicrobial prescribing rate was greater by 9.2 % on Friday compared to average prescribing on other weekdays (21.4 vs. 19.6 %). The chance of an antimicrobial prescription was 1.07 (95 % CI 1.04-1.10) higher on weekend days compared to weekdays. This was reflected in increased prescriptions for ampicillin, co amoxiclav, nitrofurantoin, quinolones and macrolides. However, if antimicrobials were prescribed, no significant differences were observed between weekdays and weekend among the different classes of antimicrobials. GPs prescribe relatively more antimicrobials during the weekend compared to weekdays. However, the patterns of antimicrobial prescribing did not differ according to the day of prescription. Trial Registration The intervention was registered with ClinicalTrials.gov on 26 July 2013, ID number NCT01913860. PMID- 26636014 TI - Studies on lipase-catalyzed asymmetric synthesis of (S)-(hydroxymethyl)glutamic acid (HMG). AB - (S)-(Hydroxymethyl)glutamic acid was successfully synthesized in total 12 % yield over eight steps from tris(hydroxymethyl)aminomethane hydrochloride (Tris.HCl), employing lipase TL-induced enantioselective acetylation of a prochiral 1,3-diol as the key step. PMID- 26636015 TI - Knowledge of carbohydrate counting and insulin dose calculations among hospital staff in a regional general paediatrics unit. AB - The aim of this study was to assess the carbohydrate and insulin knowledge of the staff at Children's Ark at the University Hospital, Limerick. Carbohydrate counting and insulin dose calculations based on carbohydrates and blood sugars are integral to intensive insulin management of type 1 diabetes mellitus (T1DM). The PedCarbQuiz, a validated questionnaire, was modified, and applied to the staff on our general paediatrics ward. 48/70 eligible staff responded (rate 68 %). Overall knowledge was good: 75.5 % was the average score for correctly identifying foods containing carbohydrate. However, poor scores were obtained for calculating multiple items and meal values (average score 29 %), and exact values of insulin required (average score 38 %). These results highlight the need for re education among staff on a general paediatrics ward, to empower ward staff to contribute effectively to the education and management of patients with T1DM. PMID- 26636016 TI - Operative versus non-operative treatment in complex proximal humeral fractures: a meta-analysis of randomized controlled trials. AB - Whether operative treatment for complex proximal humeral fractures (CPHFs) has a greater benefit over non-operative treatment remains controversial. There is no consensus on the optimal treatment in elderly patients with CPHFs. This updated meta-analysis of randomized controlled trials (RCTs) aims to investigate whether operative treatment is superior to non-operative treatment in CPHFs. The authors searched RCTs in the electronic databases (Cochrane Central Register of Controlled Trials, PubMed, EMBASE, Medline, Embase, Springer Link, Web of Knowledge, OVID and Google Scholar) from their establishment to July 2015. Researches on operative and non-operative treatment for CPHFs were selected in this meta-analysis. The quality of all studies was assessed and effective data was pooled for this meta-analysis. Outcome measurements were functional status include constant scores (CS scores) and disabilities of the arm, shoulder and hand scores (DASH scores), total complication rates and healthy-related quality of life. The meta-analysis was performed with software revman 5.3. Nine articles with a total 518 patients (average age 70.93) met inclusion criteria. Patients were followed up for at least 1 year in all the studies. No statistical differences were found between operative and non-operative treatment in CS scores at 12 mo (months) [MD 1.06 95 % CI (-3.51, 5.62)] and 24 mo [MD -0.61 95 % CI ( 5.87, 4.65)]. There are also no statistical differences between operative and non operative treatment in DASH scores at 12 mo [MD -4.51 95 % CI (-13.49, 4.47)] and 24 mo [MD -7.43 95 % CI (-16.14, 1.27)]. Statistical differences were found between operative and non-operative treatment in total complication rates [RR 1.55, 95 % CI (1.24, 1.94)]. Statistical differences in EQ-5D at 24 mo [MD 0.15, 95 % CI (0.05, 0.24)] were found between operative and non-operative treatment but no statistical differences were found in ED-5D at 12 mo [MD 0.08, 95 % CI ( 0.01, 0.17)], 15D at 12 mo [MD 0.02, 95 % CI (-0.68, 0.73)] and 15D at 24 mo [MD 0.02, 95 % CI (-0.07, 0.83)]. Operative treatments did not significantly improve the functional outcome and healthy-related quality of life in elderly patients. Instead, Operative treatment for CPHFs led to higher incidence of postoperative complications. PMID- 26636017 TI - A rare cause of infant facial paralysis: atypical teratoid rhabdoid tumour located in the cerebellopontine angle. AB - Atypical teratoid rhabdoid tumour (ATRT) is a rare malignant tumour of the central nervous system with embryonal roots. The majority are seen in early childhood and location is often in the posterior fossa. Surgery, radiotherapy and chemotherapy are used in treatment. Knowledge of the localisation of the mass preoperatively is necessary for direction of the chemoradiotherapy and sufficient resection in surgery. Differentiation from other brain tumours is important because of poor prognosis and differences in treatment. In this paper it was aimed to present the clinical and radiological findings of an ATRT located in the cerebellopontine angle, which occurred with facial paralysis. PMID- 26636018 TI - A new Otogelin ENU mouse model for autosomal-recessive nonsyndromic moderate hearing impairment. AB - Approximately 10 % of the population worldwide suffers from hearing loss (HL) and about 60 % of persons with early onset HL have hereditary hearing loss due to genetic mutations. Highly efficient mutagenesis in mice with the chemical mutagen, ethylnitrosourea (ENU), associated with relevant phenotypic tools represents a powerful approach in producing mouse models for hearing impairment. A benefit of this strategy is to generate alleles to form a series revealing the full spectrum of gene function in vivo. It can also mimic the range of human mutations and polymorphisms for HL. In the course of a genome ENU mutagenesis program, we selected a new mouse model for hearing defect based on a dysmorphological screen. We identified by gene mapping the mutation responsible for this phenotype and characterized it at the histological level of the inner ear and evaluated the vestibule by following the recommendations of the standard operating procedures, IMPReSS. We have identified and characterized a new recessive allele of the otogelin gene, Otog (vbd/vbd) , due to a homozygous one base pair substitution at the splice donor site of intron 29. This mutation leads to a frame-shift and a premature stop codon. We observed a decrease in the amount of sensory cells in the maculae of Otog (vbd/vbd) mice as well as an apparent drastically decreased density to almost absence of the otoconial membrane. Compared to Otog (tm1Prs) and twister, the two other existing otogelin alleles, the detailed analysis of Otog (vbd/vbd) revealed that these mice share some common behavioural characteristics either with Otog (tm1Prs) or twister whereas the fine vestibular phenotype and the hearing defect are different. Our results emphasize the importance of detecting and characterizing a new allele of a gene in order to get comprehensive information about the gene function. PMID- 26636019 TI - Effect of jute yarn on the mechanical behavior of concrete composites. AB - The objective of the study is to investigate the effect of introducing jute yarn on the mechanical properties of concrete. Jute fibre is produced abundantly in Bangladesh and hence, very cheap. The investigation on the enhancement of mechanical properties of concrete with jute yarn as reinforcement, if enhanced, will not only explore a way to improve the properties of concrete, it will also explore the use of jute and restrict the utilization of polymer which is environmentally detrimental. To accomplish the objective, an experimental investigation of the compressive, flexural and tensile strengths of Jute Yarn Reinforced Concrete composites (JYRCC) has been conducted. Cylinders, prisms and cubes of standard dimensions have been made to introducing jute yarn varying the mix ratio of the ingredients in concrete, water cement ratio, length and volume of yarn to know the effect of parameters as mentioned. Compressive, flexural and tensile strength tests had been conducted on the prepared samples by appropriate testing apparatus following Standards of tests. Mechanical properties of JYRCC were observed to be enhanced for a particular range of lengths of cut (10, 15, 20 and 25 mm) and volume content of jute yarn (0.1, 0.25, 0.5 and 0.75 %). The maximum increment of compressive, flexural and tensile strengths observed in the investigation are 33, 23 and 38 %, respectively with respect to concrete without jute yarn. PMID- 26636020 TI - Porous POSS-PANI nanofibre from interfacial polymerization and hydrothermal approach. AB - Nowadays, novel applications for polyaniline (PANI) make new demands on its morphology controlling, and designing novel PANI or PANI composite polymeric materials has been more and more attractive. In this work, octaaminophenyl polyhedral oligomeric silsesquioxane (POSS) was employed to prepare nanostructured PANI composites via controlled fabrication. By interfacial copolymerization, fibrous nanostructure was obtained. The size and morphology of this structure was adjusted by changing POSS to OAPS ratio: the size increased from about 20 to 200 nm when the molar ratio of POSS in the composites increased from 0.5 to 2.0 mol %. More importantly, further hydrothermal treatment for the samples with higher POSS concentration resulted in mesoporous structure on a more microscopic scale, which helps to improve the thermal stability. In the total synthesis, POSS played an important role in the morphology controlling of the composites. PMID- 26636021 TI - A compact very wideband amplifying filter based on RTD loaded composite right/left-handed transmission lines. AB - The composite right/left-handed (CRLH) transmission line (TL) is presented as a general TL possessing both left-handed (LH) and right-handed (RH) natures. RH materials have both positive permittivity and positive permeability, and LH materials have both negative permittivity and negative permeability. This paper aims to design and analyze nonlinear CRLH-TL transmission line loaded with resonant tunneling diode (RTD). The main application of this design is a very wideband and compact filter that amplifies the travelling signal. We used OrCAD and ADS software to analyze the proposed circuit. CRLH-TL consists of a microstrip line which is loaded with complementary split-rings resonators (CSRRs), series gaps, and shunt inductor connected parallel to the RTD. The designed structure possess a wide band that ranges from 5 to 10.5 GHz and amplifies signal up to 50 %. The proposed design is of interest to microwave compact component designers. PMID- 26636022 TI - Determination of a strength index for upper body local endurance strength in sedentary individuals: a cross sectional analysis. AB - A range of balance between flexor and extensor muscles is fundamental in order to prevent pathologies caused by bad postures or to ensure health of the joint as a measure of prevention of overtraining in specific muscle groups. Therefore, the aim of this study is to examine the ratio between "pulling" and "pushing" strength in sedentary individuals. 212 healthy participants, of both genders (139 male and 73 female; age 32 +/- 13.3 years, weight 70.2 +/- 14.1 kg, height 173 +/ 9 cm) were retained for investigation. Strength was assessed through a new methodology: Pulling through a lat-pulldown test while pushing strength through a chest-press test. Both tests were performed to exhaustion with an overload of 30 % of each participants bodyweight. Such method aims to prevent excessive overloads in sedentary individuals. Pearson's correlations and a t test to assess differences were analyzed. Subsequently, the ratio for both genders of pulling and pushing local endurance strength was assessed by means. A mean number of 57 repetitions was shown with the lat-pulldown while 34 repetition with the chest press. A correlation of 0.42 has been found between the number of repetitions of the two tests. A significant difference (p < 0.001) was found between such performances. No correlation was found between the strength measures and the anthropometric parameters of the participants. The lat machine to chest press ratio was 1.36:1 for male while 2.69:1 for female. The results indicate that sedentary participants have higher pulling rather than pushing local endurance strength. Such ratio should be considered as a normative value when starting to perform exercise protocols. Resistance training should be performed in order to improve strength measures of the weaker muscles and reduce such ratio. PMID- 26636023 TI - A novel bit-quad-based Euler number computing algorithm. AB - The Euler number of a binary image is an important topological property in computer vision and pattern recognition. This paper proposes a novel bit-quad based Euler number computing algorithm. Based on graph theory and analysis on bit quad patterns, our algorithm only needs to count two bit-quad patterns. Moreover, by use of the information obtained during processing the previous bit-quad, the average number of pixels to be checked for processing a bit-quad is only 1.75. Experimental results demonstrated that our method outperforms significantly conventional Euler number computing algorithms. PMID- 26636024 TI - Discussion of Identification, Estimation and Approximation of Risk under Interventions that Depend on the Natural Value of Treatment Using Observational Data, by Jessica Young, Miguel Hernan, and James Robins. AB - Young, Hernan, and Robins consider the mean outcome under a dynamic intervention that may rely on the natural value of treatment. They first identify this value with a statistical target parameter, and then show that this statistical target parameter can also be identified with a causal parameter which gives the mean outcome under a stochastic intervention. The authors then describe estimation strategies for these quantities. Here we augment the authors' insightful discussion by sharing our experiences in situations where two causal questions lead to the same statistical estimand, or the newer problem that arises in the study of data adaptive parameters, where two statistical estimands can lead to the same estimation problem. Given a statistical estimation problem, we encourage others to always use a robust estimation framework where the data generating distribution truly belongs to the statistical model. We close with a discussion of a framework which has these properties. PMID- 26636025 TI - Matched Child Savings Accounts in Low-Resource Communities: Who Saves? AB - This study examines variations in saving behavior among poor families enrolled in a Child Savings Account program for orphaned and vulnerable school-going children in Uganda. We employ multilevel analyses using longitudinal data from a cluster randomized experimental design. Our analyses reveal the following significant results: (1) given the average number of months during which the account was open (18 months), families saved on average, USD 54.72, which, after being matched by the program (2:1 match rate) comes to USD 164.16-enough to cover approximately five academic terms of post-primary education; (2) children's saving behavior was not associated with quality of family relations; it was, however, significantly associated with family financial socialization; (3) family demographics were significantly associated with children's saving behavior in the matched Child Savings Account program; and (4) children enrolled in some schools saved better compared to children enrolled in other schools within the same treatment group. PMID- 26636026 TI - Is Perceived Parental Monitoring Associated with Sexual Risk Behaviors of Young Black Males? AB - OBJECTIVE: This study determined whether perceived parental monitoring (PPM) is associated with any of twelve selected outcomes related to sexual risk behaviors of young Black males (YBM). METHODS: Recruitment occurred in clinics diagnosing and treating sexually transmitted infections. YBM living with a parent or guardian (N = 324) were administered a 9-item scale assessing level of PPM. The obtained range was 10 - 45, with higher scores representing more frequent monitoring. RESULTS: The mean was 29.3 (sd=7.0). Eight of the twelve outcomes had significant associations with PPM (all in a direction indicating a protective effect). Of these eight, five retained significance in age-adjusted models were ever causing a pregnancy, discussing pregnancy prevention, safer sex, and condom use with sex partners, and using a condom during the last act of penile-vaginal sex. CONCLUSION: Monitoring by a parent figure may be partly protective against conceiving a pregnancy for Black males 15-23 years of age. PMID- 26636027 TI - Association between Apolipoprotein E polymorphism and myocardial infarction risk: A systematic review and meta-analysis. AB - Published data regarding the association between Apolipoprotein E (ApoE) genetic variation and myocardial infarction (MI) risk were not always consistent. Therefore, the current meta-analysis was conducted to derive a more precise estimation of the association between ApoE polymorphism and MI risk. PubMed and Web of Science were searched to identify relevant studies. Summary odds ratio (ORs) and 95% confidence intervals (CIs) were calculated using random-effect or fixed-effect models based on the heterogeneity of included studies. All the tests were performed using Stata 11.0. A total of 22 eligible studies were identified in this meta-analysis. The results show that ApoE epsilon2 and epsilon4 alleles were associated with MI risk. The study suggests that there is close association between ApoE polymorphism and MI risk. It shows that ApoE epsilon2 allele is a protective factor of MI, while epsilon4 allele is a risk factor of MI, especially in Caucasian and Asian population. Nevertheless, well-designed, unbiased and larger sample size studies are required to confirm the results. PMID- 26636028 TI - Disperse Orange 3 as a resonance Raman probe for measuring membrane order. AB - Resonance Raman spectra of azobenzene derivatives were examined in the presence of lipid membranes to find a probe that can distinguish different membrane phases. The NO2 symmetric stretching band of 4-(4-nitrophenylazo)aniline, also known as Disperse Orange 3 (DO3), is downshifted by about 4 cm(-1) on the phase transition of phosphatidylcholine membranes from the liquid crystalline to the gel phase. A comparable downshift also occurs when DO3 is bound to cholesterol containing membranes in the liquid-ordered phase. Our results demonstrate that Raman spectrum of DO3 is a unique tool for measuring the molecular order of lipids in membranes. PMID- 26636030 TI - A simple flash sintering setup under applied mechanical stress and controlled atmosphere. AB - Most flash sintering experimental set-ups use dog bone-shaped specimen and DC current, which results in heterogeneously distributed densification and grain growth throughout the sample. This is the reason why only the sample's core characteristics after flash are taken into account. On the other hand, some recent procedures suggest the use of cylindrical pellets, which have some advantages compared to the traditional mode as the use of easily conformed samples and its final uniformity. Our new experimental set-up offers the possibility of atmosphere control and pressure application. Also the electrodes material change can be easily made when necessary. Shrinkage measurements and impedance spectroscopy are realized in situ and experimental parameters, as oven heating for example, can be varied to control microstructure changes. ADVANTAGES: *Sample can be entirely recovered at the end of the experiment and can be analyzed throughout its entire extension, including regions in contact with the electrodes that may present some differences from pellets inner part.*The use of AC current enables the study of different frequencies effects.*Experimental set up can be adapted to different kinds of electrolytes (samples), easily changing electrode's material and atmosphere. PMID- 26636029 TI - Homoiterons and expansion in ribosomal RNAs. AB - Ribosomal RNAs in both prokaryotes and eukaryotes feature numerous repeats of three or more nucleotides with the same nucleobase (homoiterons). In prokaryotes these repeats are much more frequent in thermophile compared to mesophile or psychrophile species, and have similar frequency in both large RNAs. These features point to use of prokaryotic homoiterons in stabilization of both ribosomal subunits. The two large RNAs of eukaryotic cytoplasmic ribosomes have expanded to a different degree across the evolutionary ladder. The big RNA of the larger subunit (60S LSU) evolved expansion segments of up to 2400 nucleotides, and the smaller subunit (40S SSU) RNA acquired expansion segments of not more than 700 nucleotides. In the examined eukaryotes abundance of rRNA homoiterons generally follows size and nucleotide bias of the expansion segments, and increases with GC content and especially with phylogenetic rank. Both the nucleotide bias and frequency of homoiterons are much larger in metazoan and angiosperm LSU compared to the respective SSU RNAs. This is especially pronounced in the tetrapod vertebrates and seems to culminate in the hominid mammals. The stability of secondary structure in polyribonucleotides would significantly connect to GC content, and should also relate to G and C homoiteron content. RNA modeling points to considerable presence of homoiteron-rich double-stranded segments especially in vertebrate LSU RNAs, and homoiterons with four or more nucleotides in the vertebrate and angiosperm LSU RNAs are largely confined to the expansion segments. These features could mainly relate to protein export function and attachment of LSU to endoplasmic reticulum and other subcellular networks. PMID- 26636031 TI - Integrated targeted and non-targeted analysis of water sample extracts with micro scale UHPLC-MS. AB - A sensitive method is introduced to detect selected pharmaceutical residues and polar pesticides with UHPLC-MS in water samples of different origin. Active or passive water sampling was combined with a laboratory solid-phase extraction cleanup and stable isotope dilution analysis. Recovery experiments demonstrated that the internal standard correction performed well for the compensation of matrix effects. Besides, the original targeted analysis approach was expanded by non-target analysis of the samples with only one more consecutive injection run needed. The key benefits of this multi-residue analysis are:*Targeted analysis and quantification combined with non-target analysis on a micro-scale UHPLC-MS system usually employed for qualitative analysis only.*The internal standards for targeted analysis were used in non-target runs to calculate the partition coefficient log P of unknown substances employing the retention time index (RTI).*The filtering of database hits for two criteria (exact mass and partition coefficient) significantly reduced the list of suspects and at the same time rendered it possible to perform non-target analysis with lower mass accuracy (no lock-spray) in the range of 20-500 ppm. PMID- 26636032 TI - Genomics in Public Health: Perspective from the Office of Public Health Genomics at the Centers for Disease Control and Prevention (CDC). AB - The national effort to use genomic knowledge to save lives is gaining momentum, as illustrated by the inclusion of genomics in key public health initiatives, including Healthy People 2020, and the recent launch of the precision medicine initiative. The Office of Public Health Genomics (OPHG) at the Centers for Disease Control and Prevention (CDC) partners with state public health departments and others to advance the translation of genome-based discoveries into disease prevention and population health. To do this, OPHG has adopted an "identify, inform, and integrate" model: identify evidence-based genomic applications ready for implementation, inform stakeholders about these applications, and integrate these applications into public health at the local, state, and national level. This paper addresses current and future work at OPHG for integrating genomics into public health programs. PMID- 26636034 TI - Editorial: Endoplasmic Reticulum and Its Role in Tumor Immunity. PMID- 26636033 TI - Current Challenges in Glioblastoma: Intratumour Heterogeneity, Residual Disease, and Models to Predict Disease Recurrence. AB - Glioblastoma (GB) is the most common primary malignant brain tumor, and despite the availability of chemotherapy and radiotherapy to combat the disease, overall survival remains low with a high incidence of tumor recurrence. Technological advances are continually improving our understanding of the disease, and in particular, our knowledge of clonal evolution, intratumor heterogeneity, and possible reservoirs of residual disease. These may inform how we approach clinical treatment and recurrence in GB. Mathematical modeling (including neural networks) and strategies such as multiple sampling during tumor resection and genetic analysis of circulating cancer cells, may be of great future benefit to help predict the nature of residual disease and resistance to standard and molecular therapies in GB. PMID- 26636035 TI - Editorial: Image-Guided Radiotherapy for Effective Radiotherapy Delivery. PMID- 26636037 TI - Corrigendum: Ionizing Particle Radiation as a Modulator of Endogenous Bone Marrow Cell Reprogramming: Implications for Hematological Cancers. AB - [This corrects the article on p. 231 in vol. 5, PMID: 26528440.]. PMID- 26636036 TI - Stromal Targets for Fluorescent-Guided Oncologic Surgery. AB - Pre-operative imaging techniques are essential for tumor detection and diagnosis, but offer limited help during surgery. Recently, the applicability of imaging during oncologic surgery has been recognized, using near-infrared fluorescent dyes conjugated to targeting antibodies, peptides, or other vehicles. Image guided oncologic surgery (IGOS) assists the surgeFon to distinguish tumor from normal tissue during operation, and can aid in recognizing vital structures. IGOS relies on an optimized combination of a dedicated fluorescent camera system and specific probes for targeting. IGOS probes for clinical use are not widely available yet, but numerous pre-clinical studies have been published and clinical trials are being established or prepared. Most of the investigated probes are based on antibodies or peptides against proteins on the membranes of malignant cells, whereas others are directed against stromal cells. Targeting stroma cells for IGOS has several advantages. Besides the high stromal content in more aggressive tumor types, the stroma is often primarily located at the periphery/invasive front of the tumor, which makes stromal targets particularly suited for imaging purposes. Moreover, because stroma up-regulation is a physiological reaction, most proteins to be targeted on these cells are "universal" and not derived from a specific genetic variation, as is the case with many upregulated proteins on malignant cancer cells. PMID- 26636038 TI - Increase in Tumor Control and Normal Tissue Complication Probabilities in Advanced Head-and-Neck Cancer for Dose-Escalated Intensity-Modulated Photon and Proton Therapy. AB - INTRODUCTION: Presently used radiochemotherapy regimens result in moderate local control rates for patients with advanced head-and-neck squamous cell carcinoma (HNSCC). Dose escalation (DE) may be an option to improve patient outcome, but may also increase the risk of toxicities in healthy tissue. The presented treatment planning study evaluated the feasibility of two DE levels for advanced HNSCC patients, planned with either intensity-modulated photon therapy (IMXT) or proton therapy (IMPT). MATERIALS AND METHODS: For 45 HNSCC patients, IMXT and IMPT treatment plans were created including DE via a simultaneous integrated boost (SIB) in the high-risk volume, while maintaining standard fractionation with 2 Gy per fraction in the remaining target volume. Two DE levels for the SIB were compared: 2.3 and 2.6 Gy. Treatment plan evaluation included assessment of tumor control probabilities (TCP) and normal tissue complication probabilities (NTCP). RESULTS: An increase of approximately 10% in TCP was estimated between the DE levels. A pronounced high-dose rim surrounding the SIB volume was identified in IMXT treatment. Compared to IMPT, this extra dose slightly increased the TCP values and to a larger extent the NTCP values. For both modalities, the higher DE level led only to a small increase in NTCP values (mean differences <2%) in all models, except for the risk of aspiration, which increased on average by 8 and 6% with IMXT and IMPT, respectively, but showed a considerable patient dependence. CONCLUSION: Both DE levels appear applicable to patients with IMXT and IMPT since all calculated NTCP values, except for one, increased only little for the higher DE level. The estimated TCP increase is of relevant magnitude. The higher DE schedule needs to be investigated carefully in the setting of a prospective clinical trial, especially regarding toxicities caused by high local doses that lack a sound dose-response description, e.g., ulcers. PMID- 26636039 TI - Telomeres and Telomerase in the Radiation Response: Implications for Instability, Reprograming, and Carcinogenesis. AB - Telomeres are nucleoprotein complexes comprised of tandem arrays of repetitive DNA sequence that serve to protect chromosomal termini from inappropriate degradation, as well as to prevent these natural DNA ends from being recognized as broken DNA (double-strand breaks) and triggering of inappropriate DNA damage responses. Preservation of telomere length requires telomerase, the specialized reverse transcriptase capable of maintaining telomere length via template mediated addition of telomeric repeats onto the ends of newly synthesized chromosomes. Loss of either end-capping function or telomere length maintenance has been associated with genomic instability or senescence in a variety of settings; therefore, telomeres and telomerase have well-established connections to cancer and aging. It has long been recognized that oxidative stress promotes shortening of telomeres, and that telomerase activity is a radiation-inducible function. However, the effects of ionizing radiation (IR) exposure on telomeres per se are much less well understood and appreciated. To gain a deeper understanding of the roles, telomeres and telomerase play in the response of human cells to IRs of different qualities, we tracked changes in telomeric end capping function, telomere length, and telomerase activity in panels of mammary epithelial and hematopoietic cell lines exposed to low linear energy transfer (LET) gamma(gamma)-rays or high LET, high charge, high energy (HZE) particles, delivered either acutely or at low dose rates. In addition to demonstrating that dysfunctional telomeres contribute to IR-induced mutation frequencies and genome instability, we reveal non-canonical roles for telomerase, in that telomerase activity was required for IR-induced enrichment of mammary epithelial putative stem/progenitor cell populations, a finding also suggestive of cellular reprograming. Taken together, the results reported here establish the critical importance of telomeres and telomerase in the radiation response and, as such, have compelling implications not only for accelerated tumor repopulation following radiation therapy but also for carcinogenic potential following low dose exposures as well, including those of relevance to spaceflight-associated galactic cosmic radiations. PMID- 26636040 TI - Secondary Malignancy Risk Following Proton Radiation Therapy. AB - Radiation-induced secondary malignancies are a significant, yet uncommon cause of morbidity and mortality among cancer survivors. Secondary malignancy risk is dependent upon multiple factors including patient age, the biological and genetic predisposition of the individual, the volume and location of tissue irradiated, and the dose of radiation received. Proton therapy (PRT) is an advanced particle therapy with unique dosimetric properties resulting in reduced entrance dose and minimal to no exit dose when compared with standard photon radiation therapy. Multiple dosimetric studies in varying cancer subtypes have demonstrated that PRT enables the delivery of adequate target volume coverage with reduced integral dose delivered to surrounding tissues, and modeling studies taking into account dosimetry and radiation cell biology have estimated a significantly reduced risk of radiation-induced secondary malignancy with PRT. Clinical data are emerging supporting the lower incidence of secondary malignancies after PRT compared with historical photon data, though longer follow-up in proton treated cohorts is awaited. This article reviews the current dosimetric and clinical literature evaluating the incidence of and risk factors associated with radiation-induced secondary malignancy following PRT. PMID- 26636041 TI - Could the eIF2alpha-Independent Translation Be the Achilles Heel of Cancer? AB - Eukaryotic initiation factor eIF2 is a key component of the ternary complex whose role is to deliver initiator tRNA into the ribosome. A variety of stimuli, both physiologic and pathophysiologic activate eIF2 kinases that phosphorylate the alpha subunit of eIF2, preventing it from forming the ternary complex, thus attenuating cellular protein synthesis. Paradoxically, in cancer cells, the phosphorylation of eIF2alpha is associated with activation of survival pathways. This review explores the recently emerged novel mechanism of eIF2alpha independent translation initiation. This mechanism, which appears to be shared by some RNA viruses and Internal Ribosome Entry Site-containing cellular mRNAs and utilizes auxiliary proteins, such as eIF5B, eIF2D, and MCT-1, is responsible for the selective translation of cancer-associated genes and could represent a weak point amenable to specific targeting for the treatment of cancer. PMID- 26636042 TI - Mechanisms of Disease: Host-Pathogen Interactions between Burkholderia Species and Lung Epithelial Cells. AB - Members of the Burkholderia species can cause a range of severe, often fatal, respiratory diseases. A variety of in vitro models of infection have been developed in an attempt to elucidate the mechanism by which Burkholderia spp. gain entry to and interact with the body. The majority of studies have tended to focus on the interaction of bacteria with phagocytic cells with a paucity of information available with regard to the lung epithelium. However, the lung epithelium is becoming more widely recognized as an important player in innate immunity and the early response to infections. Here we review the complex relationship between Burkholderia species and epithelial cells with an emphasis on the most pathogenic species, Burkholderia pseudomallei and Burkholderia mallei. The current gaps in knowledge in our understanding are highlighted along with the epithelial host-pathogen interactions that offer potential opportunities for therapeutic intervention. PMID- 26636043 TI - Genome-wide Screen of Pseudomonas aeruginosa in Saccharomyces cerevisiae Identifies New Virulence Factors. AB - Pseudomonas aeruginosa is a human opportunistic pathogen that causes mortality in cystic fibrosis and immunocompromised patients. While many virulence factors of this pathogen have already been identified, several remain to be discovered. In this respect we set an unprecedented genome-wide screen of a P. aeruginosa expression library based on a yeast growth phenotype. Fifty-one candidates were selected in athree-round screening process. The robustness of the screen was validated by the selection of three well known secreted proteins including one demonstrated virulence factor, the protease LepA. Further in silico sorting of the 51 candidates highlighted three potential new Pseudomonas effector candidates (Pec). By testing the cytotoxicity of wild type P. aeruginosa vs. pec mutants toward macrophages and the virulence in the Caenorhabditis elegans model, we demonstrated that the three selected Pecs are novel virulence factors of P. aeruginosa. Additional cellular localization experiments in the host revealed specific localization for Pec1 and Pec2 that could inform about their respective functions. PMID- 26636045 TI - Commentary: The icmF3 Locus is Involved in Multiple Adaptation- and Virulence related Characteristics in Pseudomonas aeruginosa PAO1. PMID- 26636044 TI - Identification of Novel Laminin- and Fibronectin-binding Proteins by Far-Western Blot: Capturing the Adhesins of Streptococcus suis Type 2. AB - Bacterial cell wall (CW) and extracellular (EC) proteins are often involved in interactions with extracellular matrix (ECM) proteins such as laminin (LN) and fibronectin (FN), which play important roles in adhesion and invasion. In this study, an efficient method combining proteomic analysis and Far-Western blotting assays was developed to screen directly for bacterial surface proteins with LN- and FN-binding capacity. With this approach, fifteen potential LN-binding proteins and five potential FN-binding proteins were identified from Streptococcus suis serotype 2 (SS2) CW and EC proteins. Nine newly identified proteins, including oligopeptide-binding protein OppA precursor (OppA), elongation factor Tu (EF-Tu), enolase, lactate dehydrogenase (LDH), fructose bisphosphate aldolase (FBA), 3-ketoacyl-ACP reductase (KAR), Gly ceraldehyde-3 phosphate dehydrogenase (GAPDH), Inosine 5'-monophosphate dehydrogenase (IMPDH), and amino acid ABC transporter permease (ABC) were cloned, expressed, purified and further confirmed by Far-Western blotting and ELISA. Five proteins (OppA, EF Tu, enolase, LDH, and FBA) exhibited specifically binding activity to both human LN and human FN. Furthermore, seven important recombinant proteins were selected and identified to have the ability to bind Hep-2 cells by the indirect immunofluorescent assay. In addition, four recombinant proteins, and their corresponding polyclonal antibodies, were observed to decrease SS2 adhesion to Hep-2 cells, which indicates that these proteins contribute to the adherence of SS2 to host cell surface. Collectively, these results show that the approach described here represents a useful tool for investigating the host-pathogen interactions. PMID- 26636046 TI - Insights into the Role of Erysipelotrichaceae in the Human Host. PMID- 26636047 TI - Staphylococcus aureus vs. Osteoblast: Relationship and Consequences in Osteomyelitis. AB - Bone cells, namely osteoblasts and osteoclasts work in concert and are responsible for bone extracellular matrix formation and resorption. This homeostasis is, in part, altered during infections by Staphylococcus aureus through the induction of various responses from the osteoblasts. This includes the over-production of chemokines, cytokines and growth factors, thus suggesting a role for these cells in both innate and adaptive immunity. S. aureus decreases the activity and viability of osteoblasts, by induction of apoptosis-dependent and independent mechanisms. The tight relationship between osteoclasts and osteoblasts is also modulated by S. aureus infection. The present review provides a survey of the relevant literature discussing the important aspects of S. aureus and osteoblast interaction as well as the ability for antimicrobial peptides to kill intra-osteoblastic S. aureus, hence emphasizing the necessity for new anti infectious therapeutics. PMID- 26636048 TI - Chlamydia pneumoniae Clinical Isolate from Gingival Crevicular Fluid: A Potential Atherogenic Strain. AB - Chlamydia pneumoniae has been associated to atherosclerotic cardiovascular diseases. The aim of our study was to characterize, for the first time, a C. pneumoniae strain isolated from the gingival crevicular fluid of a patient with chronic periodontitis, described as a risk factor for cardiovascular diseases. C. pneumoniae isolate was characterized and compared to the respiratory AR-39 strain by VD4-ompA genotyping and by investigating the intracellular growth in epithelial and macrophage cell lines and its ability to induce macrophage-derived foam cells. Inflammatory cytokine levels were determined in the gingival crevicular fluid sample. C. pneumoniae isolate showed a 99% similarity with the AR-39 strain in the VD4-ompA gene sequence and shared a comparable growth kinetic in epithelial cells and macrophages, as evidenced by the infectious progeny and by the number of chlamydial genomic copies. C. pneumoniae isolate significantly increased the number of foam cells as compared to uninfected and LDL-treated macrophages (45 vs. 6%, P = 0.0065) and to the AR-39 strain (45 vs. 30%, P = 0.0065). Significantly increased levels of interleukin 1-beta (2.1 +/- 0.3 pg/MUL) and interleukin 6 (0.6 +/- 0.08 pg/MUL) were found. Our results suggest that C. pneumoniae may harbor inside oral cavity and potentially be atherogenic, even though further studies will be needed to clarify the involvement of C. pneumoniae in chronic periodontitis as a risk factor for cardiovascular diseases. PMID- 26636049 TI - Emerging roles for telemedicine and smart technologies in dementia care. AB - Demographic aging of the world population contributes to an increase in the number of persons diagnosed with dementia (PWD), with corresponding increases in health care expenditures. In addition, fewer family members are available to care for these individuals. Most care for PWD occurs in the home, and family members caring for PWD frequently suffer negative outcomes related to the stress and burden of observing their loved one's progressive memory and functional decline. Decreases in cognition and self-care also necessitate that the caregiver takes on new roles and responsibilities in care provision. Smart technologies are being developed to support family caregivers of PWD in a variety of ways, including provision of information and support resources online, wayfinding technology to support independent mobility of the PWD, monitoring systems to alert caregivers to changes in the PWD and their environment, navigation devices to track PWD experiencing wandering, and telemedicine and e-health services linking caregivers and PWD with health care providers. This paper will review current uses of these advancing technologies to support care of PWD. Challenges unique to widespread acceptance of technology will be addressed and future directions explored. PMID- 26636050 TI - Genioplasty using a simple CAD/CAM (computer-aided design and computer-aided manufacturing) surgical guide. AB - BACKGROUND: The present study introduces the design and fabrication of a simple surgical guide with which to perform genioplasty. METHODS: A three-dimensional reconstruction of the patient's cranio-maxilla region was built, with a dentofacial skeletal model, then derived from CT DICOM data. A surgical simulation was performed on the maxilla and mandible, using three-dimensional cephalometry. We then simulated a full genioplasty, in silico, using the three dimensional (3D) model of the mandible, according to the final surgical treatment plan. The simulation allowed us to design a surgical guide for genioplasty, which was then computer-rendered and 3D-printed. The manufactured surgical device was ultimately used in an actual genioplasty to guide the osteotomy and to move the cut bone segment to the intended location. RESULTS: We successfully performed the osteotomy, as planned during a genioplasty, using the computer-aided design and computer-aided manufacturing (CAD/CAM) surgical guide that we initially designed and tested using simulated surgery. CONCLUSIONS: The surgical guide that we developed proved to be a simple and practical tool with which to assist the surgeon in accurately cutting and removing bone segments, during a genioplasty surgery, as preoperatively planned during 3D surgical simulations. PMID- 26636051 TI - Neonatal and Pediatric Organ Donation: Ethical Perspectives and Implications for Policy. AB - The lifesaving processes of organ donation and transplantation in neonatology and pediatrics carry important ethical considerations. The medical community must balance the principles of autonomy, non-maleficence, beneficence, and justice to ensure the best interest of the potential donor and to provide equitable benefit to society. Accordingly, the US Organ Procurement and Transplantation Network (OPTN) has established procedures for the ethical allocation of organs depending on several donor-specific and recipient-specific factors. To maximize the availability of transplantable organs and opportunities for dying patients and families to donate, the US government has mandated that hospitals refer potential donors in a timely manner. Expedient investigation and diagnosis of brain death where applicable are also crucial, especially in neonates. Empowering trained individuals from organ procurement organizations to discuss organ donation with families has also increased rates of consent. Other efforts to increase organ supply include recovery from donors who die by circulatory criteria (DCDD) in addition to donation after brain death (DBD), and from neonates born with immediately lethal conditions such as anencephaly. Ethical considerations in DCDD compared to DBD include a potential conflict of interest between the dying patient and others who may benefit from the organs, and the precision of the declaration of death of the donor. Most clinicians and ethicists believe in the appropriateness of the Dead Donor Rule, which states that vital organs should only be recovered from people who have died. The medical community can maximize the interests of organ donors and recipients by observing the Dead Donor Rule and acknowledging the ethical considerations in organ donation. PMID- 26636053 TI - Motivations, Barriers, and Behaviors Related to Obtaining and Discussing Family Health History: A Sex-Based Comparison Among Young Adults. AB - BACKGROUND: Genetic predisposition is a risk factor for many chronic diseases, yet little is known about the frequency in which college students seek out their family health history or with whom they communicate relevant information. PURPOSE: This study examines motivations and barriers associated with obtaining one's family health history and discussing it with others. METHODS: Data were analyzed from 625 college students using an internet-delivered questionnaire, which comprised of questions about intentions and motivations to obtain and share family health history as well as barriers encountered when obtaining family health history. Responses were bifurcated by participants' sex. Chi-squared and t statistics were used to identify response differences by sex. RESULTS: Females were significantly more likely than males to be motivated to obtain their family health history, and more likely to have shared their family health history with others; state that they would share their family health history with others; and express a preference for sharing their family health history with a wider range of people. DISCUSSION: Educational interventions and improved student health services could be effective mechanisms to increase college students' knowledge, awareness, and perceived importance of obtaining their family health history. PMID- 26636052 TI - Neonatal Seizures: Impact on Neurodevelopmental Outcomes. AB - Neonatal period is the most vulnerable time for the occurrence of seizures, and neonatal seizures often pose a clinical challenge both for their acute management and frequency of associated long-term co-morbidities. Etiologies of neonatal seizures are known to play a primary role in the anti-epileptic drug responsiveness and the long-term sequelae. Recent studies have suggested that burden of acute recurrent seizures in neonates may also impact chronic outcomes independent of the etiology. However, not many studies, either clinical or pre clinical, have addressed the long-term outcomes of neonatal seizures in an etiology-specific manner. In this review, we briefly review the available clinical and pre-clinical research for long-term outcomes following neonatal seizures. As the most frequent cause of acquired neonatal seizures, we focus on the studies evaluating long-term effects of HIE-seizures with the goal to evaluate (1) what parameters evaluated during acute stages of neonatal seizures can reliably be used to predict long-term outcomes? and (2) what available clinical and pre-clinical data are available help determine importance of etiology vs. seizure burdens in long-term sequelae. PMID- 26636054 TI - Psychological Interventions for the Management of Glycemic and Psychological Outcomes of Type 2 Diabetes Mellitus in China: A Systematic Review and Meta Analyses of Randomized Controlled Trials. AB - INTRODUCTION: China has the largest number of type 2 diabetes mellitus (T2DM) cases globally, and T2DM management has become a critical public health issue in China. Individuals with T2DM have an increased risk of developing mental health disorders, psychological disturbances, and functional problems associated with living with their condition. Previous systematic reviews have demonstrated that, generally, psychological interventions are effective in the management of T2DM related outcomes; however, these reviews have predominantly included studies conducted within English-speaking countries and have not determined the efficacy of the varying types of psychological interventions. As such, this paper aims to synthesize evidence and quantify the efficacy of psychological therapies for the management of glycemic and psychological outcomes of T2DM in China, relative to control conditions. METHODS: A systematic search (MEDLINE, PsycINFO, CINAHL, Cochrane Central Register of Controlled Trials, China National Knowledge Infrastructure, and Wangfang Data) for all years to December 2014 identified all available literature. Eligibility criteria included: peer-reviewed journal articles, randomized controlled trials (RCTs) assessing the efficacy of a psychological therapy for the management of T2DM, adult participants (>=18 years) diagnosed with T2DM or non-insulin-dependent diabetes mellitus, and Chinese speaking participants only (in mainland China). Outcome measures were glycated hemoglobin, blood glucose concentration, depression, anxiety, and quality of life. Effect sizes were pooled using a random effects model. Negative effect sizes corresponded to positive outcomes favoring the intervention. RESULTS: Forty five RCTs were eligible for the meta-analyses. Cognitive behavioral therapy (CBT) and motivational interviewing (MI) were more effective than the control condition in the reduction of glycated hemoglobin [CBT: -0.97 (95% CI -1.37 to -0.57); MI: 0.71 (95% CI -1.00 to -0.43)]. CBT and client-centered therapy (CCT) were also associated with reductions in depression and blood glucose concentration, and CBT was associated with reductions in anxiety. CONCLUSION: Psychological interventions, namely, CBT, MI, and CCT are effective in improving certain T2DM related outcomes in China. Considerable levels of heterogeneity and unclear risk of bias associated with most included RCTs suggest caution when interpreting results. In China, where the burden of T2DM is increasing significantly, psychological interventions may provide promising approaches to assist in the management of T2DM to delay the progression of T2DM related outcomes. PMID- 26636055 TI - A Review of Existing Studies Reporting the Negative Effects of Alcohol Access and Positive Effects of Alcohol Control Policies on Interpersonal Violence. AB - Alcohol consumption often leads to elevated rates of violence yet alcohol access policies continue to relax across the globe. Our review establishes the extent alcohol policy can moderate violent crime through alcohol availability restrictions. Results were informed from comprehensive selection of peer-reviewed journals from 1950 to October 2015. Our search identified 87 relevant studies on alcohol access and violence conducted across 12 countries. Seventeen studies included quasi-control design, and 23 conducted intervention analysis. Seventy one (82%) reported a significant relationship between alcohol access and violent offenses. Alcohol outlet studies reported the greatest percentage of significant results (93%), with trading hours (63%), and alcohol price following (58%). Results from baseline studies indicated the effectiveness of increasing the price of commonly consumed alcohol, restricting the hours of alcohol trading, and limiting the number of alcohol outlets per region to prevent violent offenses. Unclear are the effects of tax reductions, restriction of on-premises re-entry, and different outlet types on violent crime. Further, the generalization of statistics over broad areas and the low number of control/intervention studies poses some concern for confounding or correlated effects on study results, and amount of information for local-level prevention of interpersonal violence. Future studies should focus on gathering longitudinal data, validating models, limiting crime data to peak drinking days and times, and wherever possible collecting the joint distribution between violent crime, intoxication, and place. A greater uptake of local-level analysis will benefit studies comparing the influence of multiple alcohol establishment types by relating the location of a crime to establishment proximity. Despite, some uncertainties particular studies showed that even modest policy changes, such as 1% increases in alcohol price, 1 h changes to closing times, and limiting establishment densities to <25 outlets per postal code substantively reduce violent crime. PMID- 26636056 TI - Building Partnership to Improve Migrants' Access to Healthcare in Mumbai. AB - OBJECTIVES: An intervention to improve migrants' access to healthcare was piloted in Mumbai with purpose of informing health policy and planning. This paper aims to describe the process of building partnership for improving migrants' access to healthcare of the pilot intervention, including the role played by different stakeholders and the contextual factors affecting the intervention. METHODS: The process evaluation was based on Baranowski and Stables' framework. Observations in community and conversations with stakeholders as recorded in daily diaries, minutes of pre-intervention workshops, and stakeholder meetings served as data sources. Data were coded using the framework and descriptive summaries of evaluation components were prepared. RESULTS: Recruitment of stakeholders was easier than sustaining their interest. Community representatives led the intervention assisted by government officials. They planned community-level interventions to improve access to healthcare that involved predominantly information, education, and communication activities for which pre-existing formal and informal social networks and community events were used. Although the intervention reached migrants living with families, single male migrants neither participated nor did the intervention reach them consistently. Contextual factors such as culture differences between migrants and native population and illegality in the nature of the settlement, resulting in the exclusion from services, were the barriers. CONCLUSION: Inclusive multi-stakeholder partnership, including migrants themselves and using both formal and informal networks in community is a feasible strategy for health education and has potential to improve the migrants' access to healthcare. However, there are challenges to the partnership process and new strategies to overcome these challenges need to be tested such as peer led models for involvement of single male migrants. For sustaining such efforts and mainstreaming migrants, addressing contextual factors and having formal mechanisms for their inclusion are equally important. PMID- 26636057 TI - User Feedback on the MSF Tele-Expertise Service After a 4-Year Pilot Trial - A Comprehensive Analysis. AB - We surveyed all users of the Medecins Sans Frontieres (MSF) tele-expertise service, approximately four years after it began operation. The survey contained 50 questions and was sent to 294 referrers and 254 specialists. There were 163 responses (response rate 30%). There were no significant differences between the responses from French and English users, so the responses were combined for subsequent analysis. Most of the responders were doctors (133 of 157 who answered that question), and most had completed field missions for MSF, i.e., both specialists and referrers. The majority stated that the system was user friendly and that they found it self-explanatory (i.e., they did not need to be shown how to use it). Almost all the referrers found that the telemedicine advice that they received was helpful, changed diagnosis and management, and/or reassured the patient. Similar feedback came from the specialists, who also felt that there was educational value for the field doctor. Although there was general satisfaction with the service, the survey identified various problems. The main concerns of the referrers were the lack of promotion of the system at headquarters' level, and the main concerns of the specialists were the lack of feedback about patient follow-up. Nonetheless, both referrers and specialists recognized the benefits of telemedicine in improving patient management, providing education, and reducing isolation in the field. PMID- 26636058 TI - High Dose ESAs Are Associated with High iPTH Levels in Hemodialysis Patients with End-Stage Kidney Disease: A Retrospective Analysis. AB - OBJECTIVE: Anemia and secondary hyperparathyroidism are the two most common complications associated with chronic kidney disease. Erythropoiesis-stimulating agents (ESAs) are widely used in the management of anemia in hemodialysis patients. A reverse correlation has been established between hyperparathyroidism and hemoglobin levels. The aim of this retrospective study is to evaluate the relationship of high-dose ESAs and hyperparathyroidism in hemodialysis patients with anemia. METHODS: A total of 240 uremic patients maintained on regular hemodialysis were enrolled in this study. Among them, 142 patients were treated with Epiao((r)) (epoetin-alfa) and 98 patients were treated with Recormon((r)) (epoetin-beta). The target hemoglobin concentration was 110-130 g/L. Laboratory measurements including hemoglobin, calcium, phosphorus, albumin, intact parathyroid hormone (iPTH), serum ferritin, and transferrin saturation were collected. RESULTS: Hemoglobin concentration increased as iPTH level decreased by stratification. However, no significant association between anemia and calcium or phosphorus level was found. Patients with iPTH levels within 150-300 pg/mL had the highest levels of hemoglobin, serum ferritin, and transferrin saturation. Patients treated with Recormon and Epiao had similar hemoglobin concentrations. However, the dose of Recormon for anemia treatment was significantly less than that the dose of Epiao (P < 0.05). The level of iPTH in the Recormon group was significantly lower than in the Epiao group. In patients with hemoglobin levels between 110 and 130 g/L (P < 0.05), iPTH level was found to be significantly lower in patients treated with lower doses of ESAs than in patients treated with higher doses of ESAs, no matter which ESA was used (Recormon or Epiao, P < 0.05). CONCLUSION: The dose of ESAs might be positively associated with iPTH level, suggesting that a reasonable hemoglobin target can be achieved by using the lowest possible ESA dose. PMID- 26636059 TI - Psychosis, Socioeconomic Disadvantage, and Health Service Use in South Australia: Findings from the Second Australian National Survey of Psychosis. AB - The association between mental illness and poor physical health and socioeconomic outcomes has been well established. In the twenty-first century, the challenge of how mental illnesses, such as psychosis, are managed in the provision of public health services remains complex. Developing effective clinical mental health support and interventions for individuals requires a coordinated and robust mental health system supported by social as well as health policy that places a priority on addressing socioeconomic disadvantage in mental health cohorts. This paper, thus, examines the complex relationship between socioeconomic disadvantage, family/social supports, physical health, and health service utilization in a community sample of 402 participants diagnosed with psychosis. The paper utilizes quantitative data collected from the 2010 Survey of High Impact Psychosis research project conducted in a socioeconomically disadvantaged region of Adelaide, SA, Australia. Participants (42% female) provided information about socioeconomic status, education, employment, physical health, contact with family and friends, and health service utilization. The paper highlights that socioeconomic disadvantage is related to increased self-reported use of emergency departments, decreased use of general practitioners for mental health reasons, higher body mass index, less family contact, and less social support. In particular, the paper explores the multifaceted relationship between socioeconomic disadvantage and poor health confronting individuals with psychosis, highlighting the complex link between socioeconomic disadvantage and poor health. It emphasizes that mental health service usage for those with higher levels of socioeconomic disadvantage differs from those experiencing lower levels of socioeconomic disadvantage. The paper also stresses that the development of health policy and practice that seeks to redress the socioeconomic and health inequalities created by this disadvantage be an important focus for mental health services. Such health policy would provide accessible treatment programs and linked pathways to illness recovery and diminish the pressure on the delivery of health services. Consequently, the development of policy and practice that seeks to redress the socioeconomic and health inequalities created by disadvantage should be an important focus for the improvement of mental health services. PMID- 26636061 TI - Globalization, Global Health, and Disaster. PMID- 26636060 TI - Improving Detection of Prediabetes in Children and Adults: Using Combinations of Blood Glucose Tests. AB - HIGHLIGHTS: The combined use of fasting plasma glucose and hemoglobin A1c test is associated with significantly higher diagnostic rates of prediabetes across age, race/ethnicity, and BMI than using only one test.Combined use of fasting plasma glucose, hemoglobin A1c, and oral glucose tolerance test do not improve the overall and gender-specific prediabetes prevalence beyond what is observed using a combination fasting plasma glucose and hemoglobin A1c test.A redefined hemoglobin A1c test that incorporates racial/ethnic, gender, age, and BMI differences may provide a better way to use hemoglobin A1c test in population based and clinical settings. AIM: To determine combinations of blood glucose tests: oral glucose tolerance (OGT), fasting plasma glucose (FPG), and hemoglobin A1C (HbA1C) that are associated with highest diagnostic rates of prediabetes in non-diabetic American children and adults. METHODS: The 2007-2008 U.S. National Health and Nutrition Examination Surveys data were used for this study. Overall and specific prevalence of prediabetes (defined using OGT + FPG, OGT + HbA1C, HbA1C + FPG, and OGT + FPG + HbA1C tests) were determined across age, race/ethnicity, sex, and BMI categories. RESULTS: FPG + HbA1C test was associated with significantly higher diagnostic rates of prediabetes across age, race/ethnicity, and BMI. Estimates of overall prevalence of prediabetes using OGT + FPG, OGT + HbA1C, HbA1C + FPG, and OGT + FPG + HbA1C tests were 20.3, 24.2, 33, and 34.3%, respectively. Compared to OGT + FPG, the use of HbA1C + FPG test in screening was associated with 44.8, 135, 38.6, and 35.9% increased prevalence of prediabetes in non-Hispanic White, non-Hispanic Black, Mexican-American, and other racial/ethnic men, respectively. The corresponding values in women were 67.8, 140, 37.2, and 42.6%, respectively. Combined use of all blood glucose tests did not improve the overall and gender-specific prediabetes prevalence beyond what was observed using HbA1C + FPG test. CONCLUSION: HbA1C criteria were associated with higher diagnosis rates of prediabetes than FPG and OGT tests in non-diabetic American children and adults. Using a combination of HbA1C and FPG test in screening for prediabetes reduces intrinsic systematic bias in using just HbA1C testing and offers the benefits of each test. A well-defined HbA1C that takes into consideration race/ethnicity, gender, age, and body mass index may improve detection of prediabetes in population and clinical settings. PMID- 26636062 TI - Assessing the Potential and Limitations of Leveraging Food Sovereignty to Improve Human Health. AB - Food sovereignty has been defined as "the right of peoples to healthy and culturally appropriate food produced through ecologically sound and sustainable methods, and their right to define their own food and agriculture systems." Human health is an implied component of this definition through the principle of healthy food. In fact, improved human health is commonly cited as a benefit of transforming food production away from the dominant practices of industrial agriculture. Yet, does the use of "ecologically sound and sustainable methods" of food production necessarily translate into better human health outcomes? Does greater choice in defining an agricultural or food system create gains in health and well-being? We elucidate the conceptual linkages between food sovereignty and human health, critically examine the empirical evidence supporting or refuting these linkages, and identify research gaps and key priorities for the food sovereignty-human health research agenda. Five domains of food sovereignty are discussed including: (1) use of agroecological management practices for food production, (2) the localization of food production and consumption, (3) promotion of social justice and equity, (4) valuation of traditional knowledge, and (5) the transformation of economic and political institutions and structures to support self-determination. We find that although there are many plausible linkages between food sovereignty and human health, the empirical evidence in support of the hypothesis that increasing food sovereignty yields improvements to human health is weak. We propose that a concerted effort to generate new empirical evidence on the health implications of these domains of food sovereignty is urgently needed, and suggest areas of research that may be crucial for addressing the gaps in the evidence base. PMID- 26636063 TI - Predicting Self-Rated Health in Diabetes and Chronic Heart Failure - A Multiple Mediation Model. AB - PURPOSE: Self-rated health (SRH) is a powerful predictor of health-related outcomes such as morbidity and mortality. Aim of the current study was to examine the role of comorbidity, well-being, functional health, and physical limitations as possible predictors of SRH in diabetes and chronic heart failure (CHF). METHODS: Three large samples with persons suffering from diabetes (n = 974), CHF (n = 955), or both diseases combined (n = 934) were analyzed longitudinally over the course of 4 months. To test the mediating effect of comorbidity, well-being, functional health, and physical limitations in association with former and future SRH multiple mediator models were applied. RESULTS: Across all groups emotional well-being was a consistent and powerful determinant of SRH. The effects of functional health and physical limitations on SRH were also significant but varied between diagnostic groups. The number of comorbid diseases did not predict SRH. CONCLUSION: Emotional well-being and physical health appraisal were strong predictors of SRH. Thus, SRH may be improved by influencing well-being and physical health appraisal via targeted interventions. PMID- 26636064 TI - Spatiotemporal Discordance in Five Common Measures of Rurality for US Counties and Applications for Health Disparities Research in Older Adults. AB - INTRODUCTION: Rural populations face numerous barriers to health, including poorer health care infrastructure, access to care, and other sociodemographic factors largely associated with rurality. Multiple measures of rurality used in the biomedical and public health literature can help assess rural-urban health disparities and may impact the observed associations between rurality and health. Furthermore, understanding what makes a place truly "rural" versus "urban" may vary from region to region in the US. PURPOSE: The objectives of this study are to compare and contrast five common measures of rurality and determine how well correlated these measures are at the national, regional, and divisional level, as well as to assess patterns in the correlations between the prevalence of obesity in the population aged 60+ and each of the five measures of rurality at the regional and divisional level. METHODS: Five measures of rurality were abstracted from the US Census and US Department of Agriculture (USDA) to characterize US counties. Obesity data in the population aged 60+ were abstracted from the Behavioral Risk Factor Surveillance System (BRFSS). Spearman's rank correlations were used to quantify the associations among the five rurality measurements at the national, regional, and divisional level, as defined by the US Census Bureau. Geographic information systems were used to visually illustrate temporal, spatial, and regional variability. RESULTS: Overall, Spearman's rank correlations among the five measures ranged from 0.521 (percent urban-urban influence code) to 0.917 (rural-urban continuum code-urban influence code). Notable discrepancies existed in these associations by Census region and by division. The associations between measures of rurality and obesity in the 60+ population varied by rurality measure used and by region. CONCLUSION: This study is among the first to systematically assess the spatial, temporal, and regional differences and similarities among five commonly used measures of rurality in the US. There are important, quantifiable distinctions in defining what it means to be a rural county depending on both the geographic region and the measurement used. These findings highlight the importance of developing and selecting an appropriate rurality metric in health research. PMID- 26636065 TI - Editorial: Leading People - Managing Organizations: Contemporary Public Health Leadership. PMID- 26636066 TI - Vaccines Through Centuries: Major Cornerstones of Global Health. AB - Multiple cornerstones have shaped the history of vaccines, which may contain live attenuated viruses, inactivated organisms/viruses, inactivated toxins, or merely segments of the pathogen that could elicit an immune response. The story began with Hippocrates 400 B.C. with his description of mumps and diphtheria. No further discoveries were recorded until 1100 A.D. when the smallpox vaccine was described. During the eighteenth century, vaccines for cholera and yellow fever were reported and Edward Jenner, the father of vaccination and immunology, published his work on smallpox. The nineteenth century was a major landmark, with the "Germ Theory of disease" of Louis Pasteur, the discovery of the germ tubercle bacillus for tuberculosis by Robert Koch, and the isolation of pneumococcus organism by George Miller Sternberg. Another landmark was the discovery of diphtheria toxin by Emile Roux and its serological treatment by Emil Von Behring and Paul Ehrlih. In addition, Pasteur was able to generate the first live attenuated viral vaccine against rabies. Typhoid vaccines were then developed, followed by the plague vaccine of Yersin. At the beginning of World War I, the tetanus toxoid was introduced, followed in 1915 by the pertussis vaccine. In 1974, The Expanded Program of Immunization was established within the WHO for bacille Calmette-Guerin, Polio, DTP, measles, yellow fever, and hepatitis B. The year 1996 witnessed the launching of the International AIDS Vaccine Initiative. In 1988, the WHO passed a resolution to eradicate polio by the year 2000 and in 2006; the first vaccine to prevent cervical cancer was developed. In 2010, "The Decade of vaccines" was launched, and on April 1st 2012, the United Nations launched the "shot@Life" campaign. In brief, the armamentarium of vaccines continues to grow with more emphasis on safety, availability, and accessibility. This mini review highlights the major historical events and pioneers in the course of development of vaccines, which have eradicated so many life-threatening diseases, despite the vaccination attitudes and waves appearing through history. PMID- 26636067 TI - Building Infectious Disease Research Programs to Promote Security and Enhance Collaborations with Countries of the Former Soviet Union. AB - Addressing the threat of infectious diseases, whether natural, the results of a laboratory accident, or a deliberate act of bioterrorism, requires no corner of the world be ignored. The mobility of infectious agents and their rapid adaptability, whether to climate change or socioeconomic drivers or both, demand the science employed to understand these processes be advanced and tailored to a country or a region, but with a global vision. In many parts of the world, largely because of economic struggles, scientific capacity has not kept pace with the need to accomplish this goal and has left these regions and hence the world vulnerable to infectious disease outbreaks. To build scientific capability in a developing region requires cooperation and participation of experienced international scientists who understand the issues and are committed to educate the next generations of young investigators in the region. These efforts need to be coupled with the understanding and resolve of local governments and international agencies to promote an aggressive science agenda. International collaborative scientific investigation of infectious diseases not only adds significantly to scientific knowledge, but it promotes health security, international trust, and long-term economic benefit to the region involved. This premise is based on the observation that the most powerful human inspiration is that which brings peoples together to work on and solve important global challenges. The republics of the former Soviet Union provide a valuable case study for the need to rebuild scientific capacity as they are located at the crossroads where many of the world's great epidemics began. The scientific infrastructure and disease surveillance capabilities of the region suffered significant decline after the breakup of the Soviet Union. The U.S. Cooperative Threat Reduction (CTR) Program, a part of the U.S. Department of Defense, together with partner countries, have worked diligently to improve the capabilities in this region to guard against the potential future risk from especially dangerous pathogens. The dissolution of the Soviet Union left behind many scientists still working to study pathogens using antiquated protocols in unsafe laboratories. To address this situation, the CTR program began improving laboratory infrastructure, establishing biosafety and biosecurity programs, and training scientists in modern techniques, with emphasis on biosurveillance and safe containment of especially dangerous pathogens. In the Republic of Georgia, this effort culminated in the construction of a modern containment laboratory, the Richard G. Lugar Center for Public Health Research in Tbilisi to house both isolated especially dangerous pathogens as well as the research to be conducted on these agents. The need now is to utilize and sustain the investment made by CTR by establishing strong public and animal health science programs in these facilities tailored to the needs of the region and the goals for which this investment was made. A similar effort is ongoing in other former Soviet Republics. Here, we provide the analysis and recommendations of an international panel of expert scientists appointed by the Cooperative Biological Engagement Program of the Defense Threat Reduction Agency to provide advice to the stakeholders on the scientific path for the future. The emphasis is on an implementation strategy for decision makers and scientists to consider providing a sustainable biological science program in support of the One Health initiative. Opportunities, potential barriers, and lessons learned while meeting the needs of the Republic of Georgia and the Caucasus region are discussed. It is hoped that this effort will serve as a model for similar scientific needs in not only the former Soviet Union republics but also other regions challenged by infectious diseases where the CTR program operates. PMID- 26636068 TI - Nanopesticides and Nanofertilizers: Emerging Contaminants or Opportunities for Risk Mitigation? AB - Research into nanotechnology applications for use in agriculture has become increasingly popular over the past decade, with a particular interest in developing novel nanoagrochemicals in the form of so-called "nanopesticides" and "nanofertilizers." In view of the extensive body of scientific literature available on the topic, many authors have foreseen a revolution in current agricultural practices. This perspective integrates scientific, regulatory, public and commercial viewpoints, and aims at critically evaluating progress made over the last decade. A number of key (and sometimes controversial) questions are addressed with the aim of identifying the products that will soon emerge on the market and analyzing how they can fit into current regulatory and commercial frameworks. Issues related to the differences in definitions and perceptions within different sectors are discussed, as well as our current ability to assess new risks and benefits relative to conventional products. Many nanoagrochemicals resemble products used currently, which raises the question whether the effect of formulation has been sufficiently taken into account when evaluating agrochemicals. This analysis identifies directions for future research and regulatory needs in order to encourage intelligent design and promote the development of more sustainable agrochemicals. PMID- 26636069 TI - The Potential of Silk and Silk-Like Proteins as Natural Mucoadhesive Biopolymers for Controlled Drug Delivery. AB - Drug delivery across mucus membranes is a particularly effective route of administration due to the large surface area. However, the unique environment present at the mucosa necessitates altered drug formulations designed to (1) deliver sensitive biologic molecules, (2) promote intimate contact between the mucosa and the drug, and (3) prolong the drug's local residence time. Thus, the pharmaceutical industry has an interest in drug delivery systems formulated around the use of mucoadhesive polymers. Mucoadhesive polymers, both synthetic and biological, have a history of use in local drug delivery. Prominently featured in the literature are chitosan, alginate, and cellulose derivatives. More recently, silk and silk-like derivatives have been explored for their potential as mucoadhesive polymers. Both silkworms and spiders produce sticky silk-like glue substances, sericin and aggregate silk respectively, that may prove an effective, natural matrix for drug delivery to the mucosa. This mini review will explore the potential of silk and silk-like derivatives as a biocompatible mucoadhesive polymer matrix for local controlled drug delivery. PMID- 26636070 TI - Associations Between the Molecular and Optical Properties of Dissolved Organic Matter in the Florida Everglades, a Model Coastal Wetland System. AB - Optical properties are easy-to-measure proxies for dissolved organic matter (DOM) composition, source, and reactivity. However, the molecular signature of DOM associated with such optical parameters remains poorly defined. The Florida coastal Everglades is a subtropical wetland with diverse vegetation (e.g., sawgrass prairies, mangrove forests, seagrass meadows) and DOM sources (e.g., terrestrial, microbial, and marine). As such, the Everglades is an excellent model system from which to draw samples of diverse origin and composition to allow classically-defined optical properties to be linked to molecular properties of the DOM pool. We characterized a suite of seasonally- and spatially-collected DOM samples using optical measurements (EEM-PARAFAC, SUVA254, S275-295, S350-400, SR, FI, freshness index, and HIX) and ultrahigh resolution mass spectrometry (FTICR-MS). Spearman's rank correlations between FTICR-MS signal intensities of individual molecular formulae and optical properties determined which molecular formulae were associated with each PARAFAC component and optical index. The molecular families that tracked with the optical indices were generally in agreement with conventional biogeochemical interpretations. Therefore, although they represent only a small portion of the bulk DOM pool, absorbance, and fluorescence measurements appear to be appropriate proxies for the aquatic cycling of both optically-active and associated optically-inactive DOM in coastal wetlands. PMID- 26636071 TI - Gradient Matching Methods for Computational Inference in Mechanistic Models for Systems Biology: A Review and Comparative Analysis. AB - Parameter inference in mathematical models of biological pathways, expressed as coupled ordinary differential equations (ODEs), is a challenging problem in contemporary systems biology. Conventional methods involve repeatedly solving the ODEs by numerical integration, which is computationally onerous and does not scale up to complex systems. Aimed at reducing the computational costs, new concepts based on gradient matching have recently been proposed in the computational statistics and machine learning literature. In a preliminary smoothing step, the time series data are interpolated; then, in a second step, the parameters of the ODEs are optimized, so as to minimize some metric measuring the difference between the slopes of the tangents to the interpolants, and the time derivatives from the ODEs. In this way, the ODEs never have to be solved explicitly. This review provides a concise methodological overview of the current state-of-the-art methods for gradient matching in ODEs, followed by an empirical comparative evaluation based on a set of widely used and representative benchmark data. PMID- 26636072 TI - Potential for Genetic Improvement of Sugarcane as a Source of Biomass for Biofuels. AB - Sugarcane (Saccharum spp. hybrids) has great potential as a major feedstock for biofuel production worldwide. It is considered among the best options for producing biofuels today due to an exceptional biomass production capacity, high carbohydrate (sugar + fiber) content, and a favorable energy input/output ratio. To maximize the conversion of sugarcane biomass into biofuels, it is imperative to generate improved sugarcane varieties with better biomass degradability. However, unlike many diploid plants, where genetic tools are well developed, biotechnological improvement is hindered in sugarcane by our current limited understanding of the large and complex genome. Therefore, understanding the genetics of the key biofuel traits in sugarcane and optimization of sugarcane biomass composition will advance efficient conversion of sugarcane biomass into fermentable sugars for biofuel production. The large existing phenotypic variation in Saccharum germplasm and the availability of the current genomics technologies will allow biofuel traits to be characterized, the genetic basis of critical differences in biomass composition to be determined, and targets for improvement of sugarcane for biofuels to be established. Emerging options for genetic improvement of sugarcane for the use as a bioenergy crop are reviewed. This will better define the targets for potential genetic manipulation of sugarcane biomass composition for biofuels. PMID- 26636073 TI - Scapulothoracic and Glenohumeral Kinematics During Daily Tasks in Users of Manual Wheelchairs. AB - BACKGROUND: Rates of shoulder pain in individuals who use manual wheelchairs (MWCs) as their primary means of mobility have been reported to be as high as 70% during activities of daily living. Current prevailing thought is that mechanical impingement of the soft tissues that reside within the subacromial space between the humeral head and coracoacromial arch is a major contributor to the shoulder pain in users of MWCs. The subacromial space size is directly related to the kinematics at the shoulder joint. Yet to be answered are questions about which common daily tasks are characterized by the most potentially detrimental kinematics. OBJECTIVE: The purpose of this analysis was to quantify and compare potentially detrimental kinematics in three common tasks performed by individuals with spinal cord injury and shoulder pain. These data will add to the body of knowledge and test common assumptions about relative risk of tasks. DESIGN: A cross-sectional study of 15 MWC users with shoulder pain. METHODS: Electromagnetic surface sensor measures of mean and peak scapulothoracic (ST) internal and downward rotation, anterior tilt, and glenohumeral (GH) internal rotation were compared across propulsion, weight relief, and scapular plane abduction tasks using one-way repeated-measure ANOVA. RESULTS: Statistical differences were observed between the tasks for all rotations. Mean ST anterior tilt was greater in weight relief and propulsion than during scapular plane abduction (24 degrees , 23 degrees , and 13 degrees of anterior tilt, respectively). Mean GH axial rotation during weight relief was more internally rotated than during propulsion and scapular plane abduction (9 degrees , 26 degrees , and 51 degrees of external rotation, respectively). LIMITATIONS: Surface-based measures of kinematics are subject to skin motion artifact, especially in translation which was not addressed in this study. CONCLUSION: Each task presented with specific variables that might contribute to risk of developing shoulder "impingement" and pain. These data may assist therapists in their assessment of movement contributions to shoulder pain in this population, as well as in subsequent treatment planning. PMID- 26636074 TI - GroPBS: Fast Solver for Implicit Electrostatics of Biomolecules. AB - Knowledge about the electrostatic potential on the surface of biomolecules or biomembranes under physiological conditions is an important step in the attempt to characterize the physico-chemical properties of these molecules and, in particular, also their interactions with each other. Additionally, knowledge about solution electrostatics may also guide the design of molecules with specified properties. However, explicit water models come at a high computational cost, rendering them unsuitable for large design studies or for docking purposes. Implicit models with the water phase treated as a continuum require the numerical solution of the Poisson-Boltzmann equation (PBE). Here, we present a new flexible program for the numerical solution of the PBE, allowing for different geometries, and the explicit and implicit inclusion of membranes. It involves a discretization of space and the computation of the molecular surface. The PBE is solved using finite differences, the resulting set of equations is solved using a Gauss-Seidel method. It is shown for the example of the sucrose transporter ScrY that the implicit inclusion of a surrounding membrane has a strong effect also on the electrostatics within the pore region and, thus, needs to be carefully considered, e.g., in design studies on membrane proteins. PMID- 26636075 TI - Challenges of Inversely Estimating Jacobian from Metabolomics Data. AB - Inferring dynamics of metabolic networks directly from metabolomics data provides a promising way to elucidate the underlying mechanisms of biological systems, as reported in our previous studies (Weckwerth, 2011; Sun and Weckwerth, 2012; Nagele et al., 2014) by a differential Jacobian approach. The Jacobian is solved from an overdetermined system of equations as JC + CJ(T) = -2D, called Lyapunov Equation in its generic form, where J is the Jacobian, C is the covariance matrix of metabolomics data, and D is the fluctuation matrix. Lyapunov Equation can be further simplified as the linear form Ax = b. Frequently, this linear equation system is ill-conditioned, i.e., a small variation in the right side b results in a big change in the solution x, thus making the solution unstable and error prone. At the same time, inaccurate estimation of covariance matrix and uncertainties in the fluctuation matrix bring biases to the solution x. Here, we first reviewed common approaches to circumvent the ill-conditioned problems, including total least squares, Tikhonov regularization, and truncated singular value decomposition. Then, we benchmarked these methods on several in silico kinetic models with small to large perturbations on the covariance and fluctuation matrices. The results identified that the accuracy of the reverse Jacobian is mainly dependent on the condition number of A, the perturbation amplitude of C, and the stiffness of the kinetic models. Our research contributes a systematical comparison of methods to inversely solve Jacobian from metabolomics data. PMID- 26636076 TI - Production of Hybrid Chimeric PVX Particles Using a Combination of TMV and PVX Based Expression Vectors. AB - We have generated hybrid chimeric potato virus X (PVX) particles by coexpression of different PVX coat protein fusions utilizing tobacco mosaic virus (TMV) and PVX-based expression vectors. Coinfection was achieved with a modified PVX overcoat vector displaying a fluorescent protein and a TMV vector expressing another PVX fluorescent overcoat fusion protein. Coexpression of the PVX-CP fusions in the same cells was confirmed by epifluorescence microscopy. Labeling with specific antibodies and transmission electron microscopy revealed chimeric particles displaying green fluorescent protein and mCherry on the surface. These data were corroborated by bimolecular fluorescence complementation. We used split mCherry fragments as PVX coat fusions and confirmed an interaction between the split-mCherry fragments in coinfected cells. The presence of assembled split mCherry on the surface confirmed the hybrid character of the chimeric particles. PMID- 26636077 TI - Efficient Eucalypt Cell Wall Deconstruction and Conversion for Sustainable Lignocellulosic Biofuels. AB - In order to meet the world's growing energy demand and reduce the impact of greenhouse gas emissions resulting from fossil fuel combustion, renewable plant based feedstocks for biofuel production must be considered. The first-generation biofuels, derived from starches of edible feedstocks, such as corn, create competition between food and fuel resources, both for the crop itself and the land on which it is grown. As such, biofuel synthesized from non-edible plant biomass (lignocellulose) generated on marginal agricultural land will help to alleviate this competition. Eucalypts, the broadly defined taxa encompassing over 900 species of Eucalyptus, Corymbia, and Angophora are the most widely planted hardwood tree in the world, harvested mainly for timber, pulp and paper, and biomaterial products. More recently, due to their exceptional growth rate and amenability to grow under a wide range of environmental conditions, eucalypts are a leading option for the development of a sustainable lignocellulosic biofuels. However, efficient conversion of woody biomass into fermentable monomeric sugars is largely dependent on pretreatment of the cell wall, whose formation and complexity lend itself toward natural recalcitrance against its efficient deconstruction. A greater understanding of this complexity within the context of various pretreatments will allow the design of new and effective deconstruction processes for bioenergy production. In this review, we present the various pretreatment options for eucalypts, including research into understanding structure and formation of the eucalypt cell wall. PMID- 26636078 TI - Synthetic Protein Scaffolds Based on Peptide Motifs and Cognate Adaptor Domains for Improving Metabolic Productivity. AB - The efficiency of many cellular processes relies on the defined interaction among different proteins within the same metabolic or signaling pathway. Consequently, a spatial colocalization of functionally interacting proteins has frequently emerged during evolution. This concept has been adapted within the synthetic biology community for the purpose of creating artificial scaffolds. A recent advancement of this concept is the use of peptide motifs and their cognate adaptor domains. SH2, SH3, GBD, and PDZ domains have been used most often in research studies to date. The approach has been successfully applied to the synthesis of a variety of target molecules including catechin, D-glucaric acid, H2, hydrochinone, resveratrol, butyrate, gamma-aminobutyric acid, and mevalonate. Increased production levels of up to 77-fold have been observed compared to non scaffolded systems. A recent extension of this concept is the creation of a covalent linkage between peptide motifs and adaptor domains, which leads to a more stable association of the scaffolded systems and thus bears the potential to further enhance metabolic productivity. PMID- 26636079 TI - On the Origin of Muscle Synergies: Invariant Balance in the Co-activation of Agonist and Antagonist Muscle Pairs. AB - Investigation of neural representation of movement planning has attracted the attention of neuroscientists, as it may reveal the sensorimotor transformation essential to motor control. The analysis of muscle synergies based on the activity of agonist-antagonist (AA) muscle pairs may provide insight into such transformations, especially for a reference frame in the muscle space. In this study, we examined the AA concept using the following explanatory variables: the AA ratio, which is related to the equilibrium-joint angle, and the AA sum, which is associated with joint stiffness. We formulated muscle synergies as a function of AA sums, positing that muscle synergies are composite units of mechanical impedance. The AA concept can be regarded as another form of the equilibrium point (EP) hypothesis, and it can be extended to the concept of EP-based synergies. We introduce, here, a novel tool for analyzing the neurological and motor functions underlying human movements and review some initial insights from our results about the relationships between muscle synergies, endpoint stiffness, and virtual trajectories (time series of EP). Our results suggest that (1) muscle synergies reflect an invariant balance in the co-activation of AA muscle pairs; (2) each synergy represents the basis for the radial, tangential, and null movements of the virtual trajectory in the polar coordinates centered on the specific joint at the base of the body; and (3) the alteration of muscle synergies (for example, due to spasticity or rigidity following neurological injury) results in significant distortion of endpoint stiffness and concomitant virtual trajectories. These results indicate that muscle synergies (i.e., the balance of muscle mechanical impedance) are essential for motor control. PMID- 26636080 TI - Editorial: Current Challenges in Modeling Cellular Metabolism. PMID- 26636081 TI - Commentary: Rab GTPase: A New Mitotic Delivery Service. PMID- 26636082 TI - The Dawn of Aurora Kinase Research: From Fly Genetics to the Clinic. AB - Aurora kinases comprise a family of highly conserved serine-threonine protein kinases that play a pivotal role in the regulation of cell cycle. Aurora kinases are not only involved in the control of multiple processes during cell division but also coordinate chromosomal and cytoskeletal events, contributing to the regulation of checkpoints and ensuring the smooth progression of the cell cycle. Because of their fundamental contribution to cell cycle regulation, Aurora kinases were originally identified in independent genetic screens designed to find genes involved in the regulation of cell division. The first aurora mutant was part of a collection of mutants isolated in C. Nusslein-Volhard's laboratory. This collection was screened in D. M. Glover's laboratory in search for mutations disrupting the centrosome cycle in embryos derived from homozygous mutant mothers. The mutants identified were given names related to the "polar regions," and included not only aurora but also the equally famous polo. Ipl1, the only Aurora in yeast, was identified in a genetic screen looking for mutations that caused chromosome segregation defects. The discovery of a second Aurora-like kinase in mammals opened a new chapter in the research of Aurora kinases. The rat kinase AIM was found to be highly homologous to the fly and yeast proteins, but localized at the midzone and midbody and was proposed to have a role in cytokinesis. Homologs of the equatorial Aurora (Aurora B) were identified in metazoans ranging from flies to humans. Xenopus Aurora B was found to be in a complex with the chromosomal passenger INCENP, and both proteins were shown to be essential in flies for chromosome structure, segregation, central spindle formation and cytokinesis. Fifteen years on, Aurora kinase research is an active field of research. After the successful introduction of the first anti-mitotic agents in cancer therapy, both Auroras have become the focus of attention as targets for the development of new anti-cancer drugs. In this review we will aim to give a historical overview of the research on Aurora kinases, highlighting the most relevant milestones in the advance of the field. PMID- 26636084 TI - Pathogenic Actions of Cell Adhesion Molecule 1 in Pulmonary Emphysema and Atopic Dermatitis. AB - Cell adhesion mediated by adhesion molecules is of central importance in the maintenance of tissue homeostasis. Therefore, altered expression of adhesion molecules leads to the development of various tissue disorders involving cell activation, degeneration, and apoptosis. Nevertheless, it still remains unclear what initiates the altered expression of adhesion molecules and how the subsequent pathological cascades proceed. In this regard, cell adhesion molecule 1 (CADM1) is one of the candidates that is involved in the development of pathological lesions; it is an intercellular adhesion molecule that is expressed in various types of cells such as pulmonary cells, neurons, and mast cells. Recent studies have revealed that alterations in the transcriptional or post transcriptional expressions of CADM1 correlate with the pathogenesis of pulmonary diseases and allergic diseases. In this review, we specifically focus on how CADM1 is involved in the development of pathological lesions in pulmonary emphysema and atopic dermatitis. PMID- 26636085 TI - Development of a Comprehensive Approach for the Early Diagnosis of Geriatric Syndromes in General Practice. AB - According to demographic projections, a significant increase in the proportion of the elderly population is anticipated worldwide. This aging of the population will lead to an increase in the prevalence of chronic diseases and functional impairment. This expected increase will result in growing use of the health care system that societies are largely unprepared to address. General practitioners (GPs) are at the front line of this huge epidemiological challenge, but appropriate tools to diagnose and manage elderly patients in routine general practice are lacking. Indeed, while primary prevention and the management of common chronic diseases, such as hypertension, diabetes, or cardiac ischemic diseases, are routinely and mostly adequately performed in primary care, the management of geriatric syndromes is often incomplete. In order to address these shortcomings, this theoretical work aims to first develop, based on the best available evidence, a brief assessment tool (BAT) specifically designed for geriatric syndromes identification in general practice and, second, to propose a conceptual framework for the management of elderly patients in general practice that integrates the BAT instrument into the usual care of GPs. To avoid proposing unachievable goals for the care of elderly patients in general practice (for example, performing all the best screening tools for geriatric conditions identification and care), this work proposes an innovative way to combine geriatric assessment with the management of common chronic diseases. PMID- 26636086 TI - Peripartum Cardiomyopathy in Intensive Care Unit: An Update. AB - Peripartum cardiomyopathy (PPCM) is a systolic heart failure that occurs during the last month of pregnancy or within 5 months after delivery. It is an uncommon disease of unknown etiopathogenesis and has a very high rate of maternal mortality. Because of similarity between symptoms of PPCM and physiological discomforts during pregnancy, the early diagnosis of PPCM presents a major challenge. Since hemodynamic changes during PPCM can vitally jeopardize the mother and the fetus, patients with severe forms of PPCM require a multidisciplinary approach in intensive care units. This review summarizes the current state of knowledge about the diagnosis, monitoring, and the treatment of PPCM. Having reviewed the recent researches, it gives insight into the new treatment strategies of this rare disease. PMID- 26636083 TI - The Ran Pathway in Drosophila melanogaster Mitosis. AB - Over the last two decades, the small GTPase Ran has emerged as a central regulator of both mitosis and meiosis, particularly in the generation, maintenance, and regulation of the microtubule (MT)-based bipolar spindle. Ran regulated pathways in mitosis bear many similarities to the well-characterized functions of Ran in nuclear transport and, as with transport, the majority of these mitotic effects are mediated through affecting the physical interaction between karyopherins and Spindle Assembly Factors (SAFs)-a loose term describing proteins or protein complexes involved in spindle assembly through promoting nucleation, stabilization, and/or depolymerization of MTs, through anchoring MTs to specific structures such as centrosomes, chromatin or kinetochores, or through sliding MTs along each other to generate the force required to achieve bipolarity. As such, the Ran-mediated pathway represents a crucial functional module within the wider spindle assembly landscape. Research into mitosis using the model organism Drosophila melanogaster has contributed substantially to our understanding of centrosome and spindle function. However, in comparison to mammalian systems, very little is known about the contribution of Ran-mediated pathways in Drosophila mitosis. This article sets out to summarize our understanding of the roles of the Ran pathway components in Drosophila mitosis, focusing on the syncytial blastoderm embryo, arguing that it can provide important insights into the conserved functions on Ran during spindle formation. PMID- 26636087 TI - Improvement of the Targeting of Radiolabeled and Functionalized Liposomes with a Two-Step System Using a Bispecific Monoclonal Antibody (Anti-CEA * Anti-DTPA-In). AB - This study proposes liposomes as a new tool for pretargeted radioimmunotherapy (RIT) in solid tumors. Tumor pretargeting is obtained by using a bispecific monoclonal antibody [BsmAb, anti-CEA * anti-DTPA-indium complex (DTPA-In)] and pegylated radioactive liposomes containing a lipid-hapten conjugate (DSPE-PEG DTPA-In). In this work, the immunospecificity of tumor targeting is demonstrated both in vitro by fluorescence microscopy and in vivo by biodistribution studies. METHODS: Carcinoembryonic antigen (CEA)-expressing cells (LS174T) were used either in cell culture or as xenografts in nude mice. Doubly fluorescent liposomes or doubly radiolabeled liposomes were, respectively, used for in vitro and in vivo studies. In each case, a tracer of the lipid bilayer [rhodamine or indium-111 ((111)In)] and a tracer of the aqueous phase [fluorescein or iodine 125 ((125)I)] were present. The targeting of liposomes was assessed with BsmAb for active targeting or without for passive targeting. RESULTS: Data obtained with the lipid bilayer tracer showed a fluorescent signal on cell membranes two to three times higher for active than for passive targeting. This immunospecificity was confirmed in vivo with tumor uptake of 7.5 +/- 2.4% ID/g (percentage of injected dose per gram of tissue) for active targeting versus 4.5 +/- 0.45% ID/g for passive targeting (p = 0.03). Regarding the aqueous phase tracer, results are slightly more contrasted. In vitro, the fluorescent tracer seems to be released in the extracellular matrix, which can be correlated with the in vivo data. Indeed, the tumor uptake of (125)I is lower than that of (111)In: 5.1 +/- 2.5% ID/g for active targeting and 2.7 +/- 0.6% ID/g for passive targeting, but resulted in more favorable tumor/organs ratios. CONCLUSION: This work demonstrated the tumor targeting immunospecificity of DSPE-PEG-DTPA-In liposomes by two different methods. This original and new approach suggests the potential of immunospecific targeting liposomes for the RIT of solid tumors. PMID- 26636088 TI - The Natural History of Femoroacetabular Impingement. AB - Femoroacetabular impingement (FAI) is a clinical syndrome resulting from abnormal hip joint morphology and is a common cause of hip pain in young adults. FAI has been posited as a precursor to hip osteoarthritis (OA); however, conflicting evidence exists and the true natural history of the disease is unclear. The purpose of this article is to review the current understanding of how FAI damages the hip joint by highlighting its pathomechanics and etiology. We then review the current evidence relating FAI to OA. Lastly, we will discuss the potential of hip preservation surgery to alter the natural history of FAI, reduce the risk of developing OA and the need for future arthroplasty. PMID- 26636089 TI - Anal Sphincter Augmentation Using Biological Material. AB - INTRODUCTION: The aim of this review is to provide an overview of the use of biological materials in the augmentation of the anal sphincter either as part of an overlapping sphincter repair (OSR) or anal bulking procedure. METHODS: A systematic search of PubMed was conducted using the search terms "anal bulking agents," "anal sphincter repair," or "overlapping sphincter repair." Five studies using biological material as part of an overlapping sphincter repair (OSR) or as an anal bulking agent were identified. RESULTS: 122 patients underwent anal bulking with a biological material. Anorectal physiology was conducted in 27 patients and demonstrated deterioration in maximum resting pressure, and no significant change in maximum squeeze increment. Quality of life scores (QoLs) demonstrated improvements at 6 weeks and 6 months, but this had deteriorated at 12 months of follow up. Biological material was used in 23 patients to carry out an anal encirclement procedure. Improvements in QoLs were observed in patients undergoing OSR as well as anal encirclement using biological material. Incontinence episodes decreased to an average of one per week from 8 to 10 preoperatively. CONCLUSION: Sphincter encirclement with biological material has demonstrated improvements in continence and QoLs in the short term compared to traditional repair alone. Long-term studies are necessary to determine if this effect is sustained. As an anal bulking agent the benefits are short-term. PMID- 26636090 TI - Dynamic Knee Alignment and Collateral Knee Laxity and Its Variations in Normal Humans. AB - Alignment of normal, arthritic, and replaced human knees is a much debated subject as is the collateral ligamentous laxity. Traditional quantitative values have been challenged. Methods used to measure these are also not without flaws. Authors review the recent literature and a novel method of measurement of these values has been included. This method includes use of computer navigation technique in clinic setting for assessment of the normal or affected knee before the surgery. Computer navigation has been known for achievement of alignment accuracy during knee surgery. Now its use in clinic setting has added to the inventory of measurement methods. Authors dispel the common myth of straight mechanical axis in normal knees and also look at quantification of amount of collateral knee laxity. Based on the scientific studies, it has been shown that the mean alignment is in varus in normal knees. It changes from lying non-weight bearing position to standing weight-bearing position in both coronal and the sagittal planes. It also varies with gender and race. The collateral laxity is also different for males and females. Further studies are needed to define the ideal alignment and collateral laxity which the surgeon should aim for individual knees. PMID- 26636091 TI - Surface-water Interface Induces Conformational Changes Critical for Protein Adsorption: Implications for Monolayer Formation of EAS Hydrophobin. AB - The class I hydrophobin EAS is part of a family of small, amphiphilic fungal proteins best known for their ability to self-assemble into stable monolayers that modify the hydrophobicity of a surface to facilitate further microbial growth. These proteins have attracted increasing attention for industrial and biomedical applications, with the aim of designing surfaces that have the potential to maintain their clean state by resisting non-specific protein binding. To gain a better understanding of this process, we have employed all atom molecular dynamics to study initial stages of the spontaneous adsorption of monomeric EAS hydrophobin on fully hydroxylated silica, a commonly used industrial and biomedical substrate. Particular interest has been paid to the Cys3-Cys4 loop, which has been shown to exhibit disruptive behavior in solution, and the Cys7-Cys8 loop, which is believed to be involved in the aggregation of EAS hydrophobin at interfaces. Specific and water mediated interactions with the surface were also analyzed. We have identified two possible binding motifs, one which allows unfolding of the Cys7-Cys8 loop due to the surfactant-like behavior of the Cys3-Cys4 loop, and another which has limited unfolding due to the Cys3 Cys4 loop remaining disordered in solution. We have also identified intermittent interactions with water which mediate the protein adsorption to the surface, as well as longer lasting interactions which control the diffusion of water around the adsorption site. These results have shown that EAS behaves in a similar way at the air-water and surface-water interfaces, and have also highlighted the need for hydrophilic ligand functionalization of the silica surface in order to prevent the adsorption of EAS hydrophobin. PMID- 26636092 TI - Removal of Chromophore-Proximal Polar Atoms Decreases Water Content and Increases Fluorescence in a Near Infrared Phytofluor. AB - Genetically encoded fluorescent markers have revolutionized cell and molecular biology due to their biological compatibility, controllable spatiotemporal expression, and photostability. To achieve in vivo imaging in whole animals, longer excitation wavelength probes are needed due to the superior ability of near infrared light to penetrate tissues unimpeded by absorbance from biomolecules or autofluorescence of water. Derived from near infrared-absorbing bacteriophytochromes, phytofluors are engineered to fluoresce in this region of the electromagnetic spectrum, although high quantum yield remains an elusive goal. An invariant aspartate residue is of utmost importance for photoconversion in native phytochromes, presumably due to the proximity of its backbone carbonyl to the pyrrole ring nitrogens of the biliverdin (BV) chromophore as well as the size and charge of the side chain. We hypothesized that the polar interaction network formed by the charged side chain may contribute to the decay of the excited state via proton transfer. Thus, we chose to further probe the role of this amino acid by removing all possibility for polar interactions with its carboxylate side chain by incorporating leucine instead. The resultant fluorescent protein, WiPhy2, maintains BV binding, monomeric status, and long maximum excitation wavelength while minimizing undesirable protoporphyrin IXalpha binding in cells. A crystal structure and time-resolved fluorescence spectroscopy reveal that water near the BV chromophore is excluded and thus validate our hypothesis that removal of polar interactions leads to enhanced fluorescence by increasing the lifetime of the excited state. This new phytofluor maintains its fluorescent properties over a broad pH range and does not suffer from photobleaching. WiPhy2 achieves the best compromise to date between high fluorescence quantum yield and long illumination wavelength in this class of fluorescent proteins. PMID- 26636093 TI - Assembly of Influenza Hemagglutinin Fusion Peptides in a Phospholipid Bilayer by Coarse-grained Computer Simulations. AB - Membrane fusion is critical to eukaryotic cellular function and crucial to the entry of enveloped viruses such as influenza and human immunodeficiency virus. Influenza viral entry in the host cell is mediated by a 20-23 amino acid long sequence, called the fusion peptide (FP). Recently, possible structures for the fusion peptide (ranging from an inverted V shaped alpha-helical structure to an alpha-helical hairpin, or to a complete alpha-helix) and their implication in the membrane fusion initiation have been proposed. Despite the large number of studies devoted to the structure of the FP, the mechanism of action of this peptide remains unclear with several mechanisms having been suggested, including the induction of local disorder, promoting membrane curvature, and/or altering local membrane composition. In recent years, several research groups have employed atomistic and/or coarse-grained molecular dynamics (MD) simulations to investigate the matter. In all previous works, the behavior of a single FP monomer was studied, while in this manuscript, we use a simplified model of a tripeptide (TP) monomer of FP (TFP) instead of a single FP monomer because each Influenza Hemagglutinin contains three FP molecules in the biological system. In this manuscript we report findings targeted at understanding the fusogenic properties and the collective behavior of these trimers of FP peptides on a 1 palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine model membrane. Here we show how the TFP monomers self-assemble into differently sized oligomers in the presence of the membrane. We measure the perturbation to the structure of the phospholipid membrane caused by the presence of these TFP oligomers. Our work (i) shows how self-assembly of TFP in the presence of the membrane induces non negligible deformation to the membrane and (ii) could be a useful starting point to stimulate discussion and further work targeted to fusion pore formation. PMID- 26636094 TI - Measuring Early Communication in Spanish Speaking Children: The Communication Complexity Scale in Peru. AB - BACKGROUND: There is a great need in the United States to develop presymbolic evaluation tools that are widely available and accurate for individuals that come from a bilingual and/or multicultural setting. The Communication Complexity Scale (CCS) is a measure that evaluates expressive presymbolic communication including gestures, vocalizations and eye gaze. Studying the effectiveness of this tool in a Spanish speaking environment was undertaken to determine the applicability of the CCS with Spanish speaking children. Methods & Procedures: In 2011-2012, researchers from the University of Kansas and Centro Ann Sullivan del Peru (CASP) investigated communication in a cohort of 71 young Spanish speaking children with developmental disabilities and a documented history of self-injurious, stereotyped and aggressive behaviors. Communication was assessed first by parental report with translated versions of the Communication and Symbolic Behavior Scales (CSBS), a well-known assessment of early communication, and then eleven months later with the CCS. HYPOTHESIS: We hypothesized that the CCS and the CSBS measures would be significantly correlated in this population of Spanish speaking children. OUTCOMES & RESULTS: The CSBS scores from time 1 with a mean participant age of 41 months were determined to have a strong positive relationship to the CCS scores obtained at time 2 with a mean participant age of 52 months. CONCLUSIONS & IMPLICATIONS: The CCS is strongly correlated to a widely accepted measure of early communication. These findings support the validity of the Spanish version of the CCS and demonstrate its usefulness for children from another culture and for children in a Spanish speaking environment. PMID- 26636095 TI - Segmentation of Retinal Blood Vessels Based on Cake Filter. AB - Segmentation of retinal blood vessels is significant to diagnosis and evaluation of ocular diseases like glaucoma and systemic diseases such as diabetes and hypertension. The retinal blood vessel segmentation for small and low contrast vessels is still a challenging problem. To solve this problem, a new method based on cake filter is proposed. Firstly, a quadrature filter band called cake filter band is made up in Fourier field. Then the real component fusion is used to separate the blood vessel from the background. Finally, the blood vessel network is got by a self-adaption threshold. The experiments implemented on the STARE database indicate that the new method has a better performance than the traditional ones on the small vessels extraction, average accuracy rate, and true and false positive rate. PMID- 26636096 TI - Estimating Measurement Error of the Patient Activation Measure for Respondents with Partially Missing Data. AB - The patient activation measure (PAM) is an increasingly popular instrument used as the basis for interventions to improve patient engagement and as an outcome measure to assess intervention effect. However, a PAM score may be calculated when there are missing responses, which could lead to substantial measurement error. In this paper, measurement error is systematically estimated across the full possible range of missing items (one to twelve), using simulation in which populated items were randomly replaced with missing data for each of 1,138 complete surveys obtained in a randomized controlled trial. The PAM score was then calculated, followed by comparisons of overall simulated average mean, minimum, and maximum PAM scores to the true PAM score in order to assess the absolute percentage error (APE) for each comparison. With only one missing item, the average APE was 2.5% comparing the true PAM score to the simulated minimum score and 4.3% compared to the simulated maximum score. APEs increased with additional missing items, such that surveys with 12 missing items had average APEs of 29.7% (minimum) and 44.4% (maximum). Several suggestions and alternative approaches are offered that could be pursued to improve measurement accuracy when responses are missing. PMID- 26636097 TI - Dynamic Contrast-Enhanced CT Characterization of Xp11.2 Translocation/TFE3 Gene Fusions versus Papillary Renal Cell Carcinomas. AB - PURPOSE: To compare the differences of CT characteristics between renal cell carcinomas (RCCs) associated with Xp11.2 translocation/TFE3 gene fusions (Xp11.2 RCCs) and papillary cell renal cell carcinomas (PRCCs). METHODS: CT images and clinical records of 64 patients (25 Xp11.2 RCCs, 15 type 1 and 24 type 2 PRCCs) were analyzed and compared retrospectively. RESULTS: Xp11.2 RCC more frequently affected young (30.7 +/- 8.7 years) women (16/25, 64%) with gross hematuria (12/25, 48%), while PRCC more frequently involved middle-aged (54.8 +/- 11.1 years) men (28/39, 71.8%) asymptomatically. Xp11.2 RCC tended to be heterogeneous density with some showing circular calcification. Lesion sizes of Xp11.2 RCC (5.4 +/- 2.2 cm) and type 2 PRCC (5.7 +/- 2.5 cm) were significantly larger than that of type 1 PRCC (3.8 +/- 1.8 cm). Xp11.2 RCC contained more cystic components (22/25, 88%) than type 1 PRCC (all solid) and type 2 PRCC (9/24, 36.0%). Type 1 PRCC (13/15, 86.7%) and Xp11.2 RCC (21/25, 84.0%) showed more clear boundary than type 2 PRCC (12/24, 50.0%). CONCLUSION: CT features including diameter, boundary, attenuation, nature, and circular calcification of the tumor, combined with demographic information and symptoms, may be useful to differentiate Xp11.2 RCC from different subtypes of PRCC. PMID- 26636098 TI - Selection of Single-Stranded DNA Molecular Recognition Elements against Exotoxin A Using a Novel Decoy-SELEX Method and Sensitive Detection of Exotoxin A in Human Serum. AB - Exotoxin A is one of the virulence factors of Pseudomonas aeruginosa, a bacterium that can cause infections resulting in adverse health outcomes and increased burden to health care systems. Current methods of diagnosing P. aeruginosa infections are time consuming and can require significant preparation of patient samples. This study utilized a novel variation of the Systematic Evolution of Ligand by Exponential Enrichment, Decoy-SELEX, to identify an Exotoxin A specific single-stranded DNA (ssDNA) molecular recognition element (MRE). Its emphasis is on increasing stringency in directing binding toward free target of interest and at the same time decreasing binding toward negative targets. A ssDNA MRE with specificity and affinity was identified after fourteen rounds of Decoy-SELEX. Utilizing surface plasmon resonance measurements, the determined equilibrium dissociation constant (Kd ) of the MRE is between 4.2 uM and 4.5 uM, and is highly selective for Exotoxin A over negative targets. A ssDNA MRE modified sandwich enzyme-linked immunosorbent assay (ELISA) has been developed and achieved sensitive detection of Exotoxin A at nanomolar concentrations in human serum. This study has demonstrated the proof-of-principle of using a ssDNA MRE as a clinical diagnostic tool. PMID- 26636100 TI - Corrigendum to "Williams-Beuren Syndrome: A Clinical Study of 55 Brazilian Patients and the Diagnostic Use of MLPA". PMID- 26636099 TI - Recent Developments in Minimally Invasive Cardiac Surgery: Evolution or Revolution? AB - Intraluminal aortic clamping has been achieved until now by means of a sophisticated device consisting of a three-lumen catheter named Endoclamp, which allows at the same time occlusion of the aorta, antegrade delivering of cardioplegia, and venting through the aortic root. This tool has shown important advantages allowing aortic occlusion and perfusate delivering without a direct contact with ascending aorta reducing meanwhile the risk of traumatic and/or iatrogenic injuries. Recently, a new device (Intraclude catheter) with the same characteristics and properties has been proposed and introduced in clinical practice. The aim of this paper is to investigate the differences between Endoclamp and Intraclude catheters and to analyze the advantages advocated by this new device for intraluminal aortic occlusion since it is noticeable as these new technological tools are gaining more and more attractiveness due to their appraised clinical efficacy. PMID- 26636101 TI - Descemet's Stripping Automated Endothelial Keratoplasty versus Descemet's Membrane Endothelial Keratoplasty in the Fellow Eye for Fuchs Endothelial Dystrophy: A Retrospective Study. AB - AIM: To evaluate visual outcome and endothelial cell density (ECD) after Descemet's Membrane Endothelial Keratoplasty (DMEK) in comparison with Descemet's Stripping Automated Endothelial Keratoplasty (DSAEK) in the fellow eye for Fuchs endothelial dystrophy (FED). DESIGN: Single-centre, retrospective case series. METHODS: 30 eyes of 30 patients undergoing DMEK, who completed a 1-year follow up, were compared with 30 fellow eyes which underwent DSAEK for bilateral FED. Main outcome measures studied included Best Corrected Visual Acuity (BCVA) and ECD during a 1-year follow-up period. RESULTS: BCVA improved from 0.78 +/- 0.35 logMAR, and 0.73 +/- 0.31 logMAR before surgery to 0.22 +/- 0.1 logMAR and 0.35 +/- 0.12 logMAR 6 months after DMEK and DSEK, respectively (P < 0.001). At one year after surgery, the BCVA was maintained at 0.21 +/- 0.12 logMAR and 0.34 +/- 0.1 logMAR, respectively, after DMEK and DSAEK. A statistically better visual outcome was observed after DMEK compared to DSAEK (P < 0.05) in fellow eyes. CONCLUSIONS: DMEK provided better visual rehabilitation when compared to DSAEK. Nevertheless, there were no significant differences with regard to the ECD within a 1-year follow-up. PMID- 26636102 TI - Diagnostic Accuracy of Obstructive Airway Adult Test for Diagnosis of Obstructive Sleep Apnea. AB - RATIONALE: The gold standard for the diagnosis of Obstructive Sleep Apnea (OSA) is polysomnography, whose access is however reduced by costs and limited availability, so that additional diagnostic tests are needed. OBJECTIVES: To analyze the diagnostic accuracy of the Obstructive Airway Adult Test (OAAT) compared to polysomnography for the diagnosis of OSA in adult patients. METHODS: Ninety patients affected by OSA verified with polysomnography (AHI >= 5) and ten healthy patients, randomly selected, were included and all were interviewed by one blind examiner with OAAT questions. MEASUREMENTS AND MAIN RESULTS: The Spearman rho, evaluated to measure the correlation between OAAT and polysomnography, was 0.72 (p < 0.01). The area under the ROC curve (95% CI) was the parameter to evaluate the accuracy of the OAAT: it was 0.91 (0.81-1.00) for the diagnosis of OSA (AHI >= 5), 0.90 (0.82-0.98) for moderate OSA (AHI >= 15), and 0.84 (0.76-0.92) for severe OSA (AHI >= 30). CONCLUSIONS: The OAAT has shown a high correlation with polysomnography and also a high diagnostic accuracy for the diagnosis of OSA. It has also been shown to be able to discriminate among the different degrees of severity of OSA. Additional large studies aiming to validate this questionnaire as a screening or diagnostic test are needed. PMID- 26636103 TI - Transcriptome and Molecular Endocrinology Aspects of Epicardial Adipose Tissue in Cardiovascular Diseases: A Systematic Review and Meta-Analysis of Observational Studies. AB - The objective of this study was to perform a systematic review of published literature on differentially expressed genes (DEGs) in human epicardial adipose tissue (EAT) to identify molecules associated with CVDs. A systematic literature search was conducted in PubMed, SCOPUS, and ISI Web of Science literature databases for papers published before October 2014 that addressed EAT genes and cardiovascular diseases (CVDs). We included original papers that had performed gene expressions in EAT of patients undergoing open-heart surgery. The Reporting Recommendations for Tumor Marker Prognostic Studies (PRIMARK) assessment tool was also used for methodological quality assessment. From the 180 papers identified by our initial search strategy, 40 studies met the inclusion criteria and presented DEGs in EAT samples from patients with and without CVDs. The included studies reported 42 DEGs identified through comparison of EAT-specific gene expression in patients with and without CVDs. Among the 42 DEGs, genes involved in regulating apoptosis had higher enrichment scores. Notably, interleukin-6 (IL 6) and tumor protein p53 (TP53) were the main hub genes in the network. The results suggest that regulation of apoptosis in EAT is critical for CVD development. Moreover, IL-6 and TP53 as hub genes could serve as biomarkers and therapeutic targets for CVDs. PMID- 26636104 TI - Metabolomics and Type 2 Diabetes: Translating Basic Research into Clinical Application. AB - Type 2 diabetes (T2D) and its comorbidities have reached epidemic proportions, with more than half a billion cases expected by 2030. Metabolomics is a fairly new approach for studying metabolic changes connected to disease development and progression and for finding predictive biomarkers to enable early interventions, which are most effective against T2D and its comorbidities. In metabolomics, the abundance of a comprehensive set of small biomolecules (metabolites) is measured, thus giving insight into disease-related metabolic alterations. This review shall give an overview of basic metabolomics methods and will highlight current metabolomics research successes in the prediction and diagnosis of T2D. We summarized key metabolites changing in response to T2D. Despite large variations in predictive biomarkers, many studies have replicated elevated plasma levels of branched-chain amino acids and their derivatives, aromatic amino acids and alpha hydroxybutyrate ahead of T2D manifestation. In contrast, glycine levels and lysophosphatidylcholine C18:2 are depressed in both predictive studies and with overt disease. The use of metabolomics for predicting T2D comorbidities is gaining momentum, as are our approaches for translating basic metabolomics research into clinical applications. As a result, metabolomics has the potential to enable informed decision-making in the realm of personalized medicine. PMID- 26636105 TI - Molecular Structure, Membrane Interactions, and Toxicity of the Islet Amyloid Polypeptide in Type 2 Diabetes Mellitus. AB - Human islet amyloid polypeptide (hIAPP) is the major component of the amyloid deposits found in the pancreatic islets of patients with type 2 diabetes mellitus (T2DM). Mature hIAPP, a 37-aa peptide, is natively unfolded in its monomeric state but forms islet amyloid in T2DM. In common with other misfolded and aggregated proteins, amyloid formation involves aggregation of monomers of hIAPP into oligomers, fibrils, and ultimately mature amyloid deposits. hIAPP is coproduced and stored with insulin by the pancreatic islet beta-cells and is released in response to the stimuli that lead to insulin secretion. Accumulating evidence suggests that hIAPP amyloid deposits that accompany T2DM are not just an insignificant phenomenon derived from the disease progression but that hIAPP aggregation induces processes that impair the functionality and the viability of beta-cells. In this review, we particularly focus on hIAPP structure, hIAPP aggregation, and hIAPP-membrane interactions. We will also discuss recent findings on the mechanism of hIAPP-membrane damage and on hIAPP-induced cell death. Finally, the development of successful antiamyloidogenic agents that prevent hIAPP fibril formation will be examined. PMID- 26636106 TI - Cardiac Resynchronization Therapy Outcomes in Type 2 Diabetic Patients: Role of MicroRNA Changes. AB - Heart failure (HF) and type 2 diabetes mellitus (T2DM) are two growing and related diseases in general population and particularly in elderly people. In selected patients affected by HF and severe dysfunction of left ventricle ejection fraction (LVEF), with left bundle brunch block, the cardiac resynchronization therapy with a defibrillator (CRT) is the treatment of choice to improve symptoms, NYHA class, and quality of life. CRT effects are related to alterations in genes and microRNAs (miRs) expression, which regulate cardiac processes involved in cardiac apoptosis, cardiac fibrosis, cardiac hypertrophy and angiogenesis, and membrane channel ionic currents. Different studies have shown a different prognosis in T2DM patients and T2DM elderly patients treated by CRT-D. We reviewed the literature data on CRT-D effect on adult and elderly patients with T2DM as compared with nondiabetic patients. PMID- 26636107 TI - New Insights into the Function of the Immunoproteasome in Immune and Nonimmune Cells. AB - The immunoproteasome is a highly efficient proteolytic machinery derived from the constitutive proteasome and is abundantly expressed in immune cells. The immunoproteasome plays a critical role in the immune system because it degrades intracellular proteins, for example, those of viral origin, into small proteins. They are further digested into short peptides to be presented by major histocompatibility complex (MHC) class I molecules. In addition, the immunoproteasome influences inflammatory disease pathogenesis through its ability to regulate T cell polarization. The immunoproteasome is also expressed in nonimmune cell types during inflammation or neoplastic transformation, supporting a role in the pathogenesis of autoimmune diseases and neoplasms. Following the success of inhibitors of the constitutive proteasome, which is now an established treatment modality for multiple myeloma, compounds that selectively inhibit the immunoproteasome are currently under active investigation. This paper will review the functions of the immunoproteasome, highlighting areas where novel pharmacological treatments that regulate immunoproteasome activity could be developed. PMID- 26636108 TI - Computational Modelling Approaches on Epigenetic Factors in Neurodegenerative and Autoimmune Diseases and Their Mechanistic Analysis. AB - Neurodegenerative as well as autoimmune diseases have unclear aetiologies, but an increasing number of evidences report for a combination of genetic and epigenetic alterations that predispose for the development of disease. This review examines the major milestones in epigenetics research in the context of diseases and various computational approaches developed in the last decades to unravel new epigenetic modifications. However, there are limited studies that systematically link genetic and epigenetic alterations of DNA to the aetiology of diseases. In this work, we demonstrate how disease-related epigenetic knowledge can be systematically captured and integrated with heterogeneous information into a functional context using Biological Expression Language (BEL). This novel methodology, based on BEL, enables us to integrate epigenetic modifications such as DNA methylation or acetylation of histones into a specific disease network. As an example, we depict the integration of epigenetic and genetic factors in a functional context specific to Parkinson's disease (PD) and Multiple Sclerosis (MS). PMID- 26636109 TI - Maternal serum ischemia modified albumin as a marker for hypertensive disorders of pregnancy: a pilot study. AB - BACKGROUND: Hypoxia driven oxidative stress of the placenta contributes to the pathogenesis of preeclampsia. Serum Ischemia Modified Albumin (IMA) has recently emerged as an oxidative stress marker, used in diagnosis of cardiac ischemia. Aim: To determine the efficiency of serum IMA in differentiating hypertensive disorders of pregnancy (pregnancy induced hypertension, preeclampsia) from normal pregnancy. METHODS: It was a case control study. Pregnant women >=32 weeks of gestation. Study population were included 3 groups, 19 Normotensive Pregnant (NP) women as controls, 18 pregnant women with Pregnancy Induced Hypertension (PIH) and 19 with preeclampsia (PE). Serum IMA was estimated by Enzyme Linked Immune Sorbent Assay (ELISA). Results were analyzed by student 't'test. Critical values for serum IMA were obtained by Receiver Operation Characteristics (ROC) curves. RESULTS: Serum IMA levels were significantly elevated in PE (56.84 +/- 21.57 ng/ml) when compared with PIH (36.24 +/- 14.51 ng/ml) and NP (35.47 +/- 11.58 ng/ml) (P value <0.001). With a cutoff of 38.33 ng/ml, sensitivity and specificity for preeclampsia was 88.9% and 73.7% respectively. CONCLUSIONS: Our study demonstrated that serum IMA, an oxidative stress marker is elevated in PE & PIH. Hence serum IMA can undergo further evaluation as a marker of PE. PMID- 26636110 TI - Report of a Curriculum Used in a Peer-Delivered Intervention to Reduce Obesity of Adolescents in Southern Appalachia and its Relationship to the National Health Education Standards. PMID- 26636111 TI - Reflections from an Undergraduate Student Peer Facilitator in the Team Up for Healthy Living School-Based Obesity Prevention Project. AB - Team Up for Healthy Living was a cluster-randomized trial to evaluate a cross peer school-based obesity prevention program in Southern Appalachia. Undergraduate students from the disciplines of Kinesiology, Nutrition, and Public Health were trained as peer facilitators to deliver an 8-week curriculum in high school Lifetime Wellness classes. The focus of the curriculum was on improving diet and physical activity with an additional emphasis on enhancing leadership and communication skills. Control group participants received their regularly scheduled Lifetime Wellness curriculum. The current article is about the experiences of an undergraduate kinesiology student participating as a peer facilitator in the Team-Up for Healthy Living trial. A brief overview of the program and peer facilitator training is followed by this students reflections on both personal development and student outcomes. PMID- 26636112 TI - Transgene-host cell interactions mediate significant influences on the production, stability, and function of recombinant canine FVIII. AB - Recombinant FVIII manufacturing is characterized by poor product stability and low yields. Codon-optimization of transgenes accelerates translation by exploiting the synonymous codon usage bias of a species. However, this can alter the performance of the final product. Additionally, the effects of transgene design across diverse cell types are not well understood and are of interest for next-generation protein and gene therapies. To investigate the effects of transgene design across different host cells, B-domain-deleted (BDD) and modified codon-optimized (CO-N6) transgenes were inserted via lentiviral delivery into cBOECs, HEK293T, and MDCK cells. The CO-N6 cFVIII transgene produced threefold more protein per transgene in HEK293T cells, and sixfold more protein in the two canine cell lines. However, pharmacokinetic analysis in hemophilia A dogs demonstrated that cFVIII produced from cBOECs transduced with the CO-N6 transgene had significantly reduced in vivo recovery. Furthermore, this product showed reduced in vitro stability and activity on thrombin activation versus the BDD product. This trend was reversed in HEK293T lines. Overall, our results demonstrate the need for an integrated approach that not only assesses protein expression levels but also considers the influence that host-cells have on preserving the molecular and biochemical properties of the naturally occurring FVIII. PMID- 26636113 TI - Vaccinia virus as a subhelper for AAV replication and packaging. AB - Adeno-associated virus (AAV) has been widely used as a gene therapy vector to treat a variety of disorders. While these vectors are increasingly popular and successful in the clinic, there is still much to learn about the viruses. Understanding the biology of these viruses is essential in engineering better vectors and generating vectors more efficiently for large-scale use. AAV requires a helper for production and replication making this aspect of the viral life cycle crucial. Vaccinia virus (VV) has been widely cited as a helper virus for AAV. However, to date, there are no detailed analyses of its helper function. Here, the helper role of VV was studied in detail. In contrast to common belief, we demonstrated that VV was not a sufficient helper virus for AAV replication. Vaccinia failed to produce rAAV and activate AAV promoters. While this virus could not support rAAV production, Vaccinia could initiate AAV replication and packaging when AAV promoter activation is not necessary. This activity is due to the ability of Vaccinia-driven Rep78 to transcribe in the cytoplasm and subsequently translate in the nucleus and undergo typical functions in the AAV life cycle. As such, VV is subhelper for AAV compared to complete helper functions of adenovirus. PMID- 26636114 TI - Automated construction of arterial and venous trees in retinal images. AB - While many approaches exist to segment retinal vessels in fundus photographs, only a limited number focus on the construction and disambiguation of arterial and venous trees. Previous approaches are local and/or greedy in nature, making them susceptible to errors or limiting their applicability to large vessels. We propose a more global framework to generate arteriovenous trees in retinal images, given a vessel segmentation. In particular, our approach consists of three stages. The first stage is to generate an overconnected vessel network, named the vessel potential connectivity map (VPCM), consisting of vessel segments and the potential connectivity between them. The second stage is to disambiguate the VPCM into multiple anatomical trees, using a graph-based metaheuristic algorithm. The third stage is to classify these trees into arterial or venous (A/V) trees. We evaluated our approach with a ground truth built based on a public database, showing a pixel-wise classification accuracy of 88.15% using a manual vessel segmentation as input, and 86.11% using an automatic vessel segmentation as input. PMID- 26636115 TI - Dissecting the in vivo leukemogenic potency of BCLxl. AB - Overexpression of anti-apoptotic members of the BCL2 family has been found in all types of cancer. A member of the family, BCLxl (B-cell lymphoma extra-large), is known to be associated with the progression of leukemogenesis. In the present study, we focused on understanding the domains of BCLxl responsible for in vivo oncogenic potency. To this end, we utilized engineered BCLxl proteins with alternative transmembrane domains (TM) or chimeric BCLxl proteins containing domains from a less potent BCL2-like protein, BCLb. As expected, mice receiving MYC-only expressing bone marrow develop leukemia by 100 days, whereas co expression of MYC with wild-type BCLxl led to aggressive myeloid leukemia with an average latency of ~25 days. Interestingly, mice injected with bone marrow co expressing MYC and BCLxl targeted specifically to either mitochondria or ER also succumbed to leukemia with an average latency of ~25 days. Further, our study was extended to examine the role of the BH4 domain in driving potent leukemogenesis. Mice injected with bone marrow co-expressing MYC and BCLb succumb to leukemia in an average of ~55 days, but interestingly a BCLxl protein containing only the loop region of BCLb drove MYC-induced leukemogenesis with the same latency as wild-type BCLxl. These data suggest that the localization of exogenous BCLxl to either mitochondria or ER is not a steadfast dictator of in vivo oncogenic potency. Further, our findings suggest that the loop domain of BCLb and BCLxl is not responsible for dictating the in vivo leukemogeneic potency. This study provides further mechanistic details into the biochemical functions of BCLxl. PMID- 26636116 TI - The Effect of Aloe Vera, Pomegranate Peel, Grape Seed Extract, Green Tea, and Sodium Ascorbate as Antioxidants on the Shear Bond Strength of Composite Resin to Home-bleached Enamel. AB - STATEMENT OF THE PROBLEM: Immediate application of bonding agent to home- bleached enamel leads to significant reduction in the shear bond strength of composite resin due to the residual oxygen. Different antioxidant agents may overcome this problem. PURPOSE: This study aimed to assess the effect of different antioxidants on the shear bond strength of composite resin to home bleached. MATERIALS AND METHOD: Sixty extracted intact human incisors were embedded in cylindrical acrylic resin blocks (2.5*1.5 cm), with the coronal portion left out of the block. After bleaching the labial enamel surface with 15% carbamide peroxide, they were randomly divided into 6 groups (n=10). Before performing composite resin restoration by using a cylindrical Teflon mold (5*2 mm), each group was treated with one of the following antioxidants: 10% sodium ascorbate solution, 10% pomegranate peel solution, 10% grape seed extract, 5% green tea extract, and aloe vera leaf gel. One group was left untreated as the control. The shear bond strength of samples was tested under a universal testing machine (ZwickRoell Z020). The shear bond strength data were analyzed by one-way ANOVA and post hoc Tukey tests (p< 0.05). RESULTS: No significant difference existed between the control and experimental groups. Moreover, there was no statistically significant difference between the effects of different antioxidants on the shear bond strength of bleached enamel. CONCLUSION: Different antioxidants used in this study had the same effect on the shear bond strength of home-bleached enamel, and none of them caused a statistically significant increase in its value. PMID- 26636117 TI - The Effect of Ovariectomy and Orchiectomy on Orthodontic Tooth Movement and Root Resorption in Wistar Rats. AB - STATEMENT OF THE PROBLEM: Root resorption (RR) after orthodontic tooth movement (OTM) is known as a multifactorial complication of orthodontic treatments. Hormonal deficiencies and their effect on bone turnover are reported to have influences on the rate of tooth movement and root resorption. PURPOSE: This study was designed to evaluate the effect of female and male steroid sex hormones on tooth movement and root resorption. MATERIALS AND METHOD: Orthodontic appliances were placed on the right maxillary first molars of 10 ovariectomized female and 10 orchiectomized male Wistar rats as experimental groups and 10 female and 10 male healthy Wistar rats as control groups. NiTi closed-coil springs (9mm, Medium, 011"*.030", Ortho Technology((r)); Tampa, Florida) were placed between the right incisors and the first right maxillary molars to induce tipping movement in the first molars with the application of a 60g force. After 21 days, the rats were sacrificed and tooth movement was measured by using a digital caliper (Guanglu, China). Orthodontic induced root resorption (OIRR) was assessed by histomorphometric analysis after hematoxylin and eosin staining of sections of the mesial root. RESULTS: The rate of tooth movement was significantly higher in all female rats, with the root resorption being lower in the experimental group. The rate of tooth movement in experimental male rats was significantly higher than the control group (p= 0.001) and the rate of root resorption was significantly lower in the experimental group (p= 0.001). CONCLUSION: It seems that alterations in plasma levels of estrogen, progesterone, and testosterone hormones can influence the rate of OTM and RR. The acceleration in tooth movement increased OTM and decreased RR. PMID- 26636118 TI - The Effect of Gap Angle on Tensile Strength of Preceramic Base Metal Solder Joints. AB - STATEMENT OF THE PROBLEM: Soldering is a process commonly used in fabricating dental prosthesis. Since most soldered prosthesis fail at the solder joints; the joint strength is of utmost importance. PURPOSE: The purpose of this study was to evaluate the effect of gap angle on the tensile strength of base metal solder joints. MATERIALS AND METHOD: A total number of 40 Ni-Cr samples were fabricated according to ADA/ISO 9693 specifications for tensile test. Samples were cut at the midpoint of the bar, and were placed at the considered angles by employing an explicitly designed device. They were divided into 4 groups regarding the gap angle; Group C (control group) with parallel gap on steady distance of 0.2mm, Group 1: 10 degrees , Group 2: 20 degrees , and Group3: 30 degrees gap angles. When soldered, the specimens were all tested for tensile strength using a universal testing machine at a cross-head speed of 0.5 mm/min with a preload of 10N. Kruskal-Wallis H test was used to compare tensile strength among the groups (p< 0.05). RESULTS: The mean tensile strength values obtained from the study groups were respectively 307.84, 391.50, 365.18, and 368.86 MPa. The tensile strength was not statistically different among the four groups in general (p<= 0.490). CONCLUSION: Making the gap angular at the solder joints and the subsequent unsteady increase of the gap distance would not change the tensile strength of the joint. PMID- 26636119 TI - Evaluating Stress Distribution Pattern in Periodontal Ligament of Maxillary Incisors during Intrusion Assessed by the Finite Element Method. AB - STATEMENT OF THE PROBLEM: The use of miniscrews has expedited the true maxillary incisor intrusion and has minimized untoward side effects such as labial tipping. PURPOSE: The aim of this study was to assess the stress distribution in the periodontal ligament of maxillary incisors when addressed to different models of intrusion mechanics using miniscrews by employing finite element methods. The degree of relative and absolute intrusion of maxillary incisors in different conditions was also evaluated. MATERIALS AND METHOD: Finite element model of maxillary central incisor to first premolar was generated by assembling images obtained from a three-dimensional model of maxillary dentition. Four different conditions of intrusion mechanics were simulated with different placement sites of miniscrews as well as different points of force application. In each model, 25 g force was applied to maxillary incisors via miniscrews. RESULTS: In all four models, increased stress values were identified in the apical region of lateral incisor. Proclination of maxillary incisors was also reported in all the four models. The minimum absolute intrusion was observed when the miniscrew was placed between the lateral incisor and canine and the force was applied at right angles to the archwire, which is very common in clinical practice. CONCLUSION: From the results yield by this study, it seems that the apical region of lateral incisor is the most susceptible region to root resorption during anterior intrusion. When the minimum flaring of maxillary incisors is required in clinical situations, it is suggested to place the miniscrew halfway between the roots of lateral incisor and canine with the force applied to the archwire between central and lateral incisor. In order to achieve maximum absolute intrusion, it is advised to place miniscrew between the roots of central and lateral incisors with the force applied at a right angle to the archwire between these two teeth. PMID- 26636120 TI - P63 and Ki-67 Expression in Dentigerous Cyst and Ameloblastomas. AB - STATEMENT OF THE PROBLEM: P63 gene is a member of TP53 and its homologous gene family. Its expression was observed in some odontogenic lesions, more expression in aggressive lesions. PURPOSE: This study aimed to investigate the possible diagnostic impact of P63 protein on dentigerous cysts and various types of ameloblastoma. Its expression with Ki-67 proliferation marker was also compared. MATERIALS AND METHOD: This cross-sectional retrospective study was enrolled on 25 cases of dentigerous cyst including 21 unicystic ameloblastomas and 17 conventional ameloblastomas. The expression of P63 and Ki-67 was assessed by immunohistochemical (IHC) examinations. Data were analyzed by employing Mann Whitney and correlation coefficient tests. RESULTS: P63 expression was significantly higher in ameloblastoma than unicystic ameloblastoma and dentigerous cysts. There was no significant difference between unicystic ameloblastoma and dentigerous cyst in P63 expression. A 90% cut-off point was obtained for basal layer which gave 88% sensitivity and 78% specificity to distinguish more invasive lesions from others. There was not any correlation between P63 and Ki-67 immunostaining in the three study groups. CONCLUSION: More aggressiveness and more invasiveness of odontogenic lesions depicted higher rate and also more intensive expression of P63. Moreover, the expression of P63 protein had not any correlation with Ki-67 protein in dentigerous cysts and ameloblastomas. PMID- 26636121 TI - How Do Children Behave Regarding Their Birth Order in Dental Setting? AB - STATEMENT OF THE PROBLEM: Prediction of child cooperation level in dental setting is an important issue for a dentist to select the proper behavior management method. Many psychological studies have emphasized the effect of birth order on patient behavior and personality; however, only a few researches evaluated the effect of birth order on child's behavior in dental setting. PURPOSE: This study was designed to evaluate the influence of children ordinal position on their behavior in dental setting. MATERIALS AND METHOD: A total of 158 children with at least one primary mandibular molar needing class I restoration were selected. Children were classified based on the ordinal position; first, middle, or last child as well as single child. A blinded examiner recorded the pain perception of children during injection based on Visual Analogue Scale (VAS) and Sound, Eye and Movement (SEM) scale. To assess the child's anxiety, the questionnaire known as "Dental Subscale of the Children's Fear Survey Schedule" (CFSS-DS) was employed. RESULTS: The results showed that single children were significantly less cooperative and more anxious than the other children (p<0.001). The middle children were significantly more cooperative in comparison with the other child's position (p< 0.001). CONCLUSION: Single child may behave less cooperatively in dental setting. The order of child birth must also be considered in prediction of child's behavior for behavioral management. PMID- 26636122 TI - The Feasibility of Ultrasonography in Defining the Size of Jaw Osseous Lesions. AB - STATEMENT OF THE PROBLEM: Jaw bone lesions are common pathologic conditions. The role of ultrasonography in evaluation of the extra-osseous lesions is confirmed, however, this imaging modality is not the diagnostic routine for the intra osseous jaw lesions. PURPOSE: The purpose of this study was to evaluate the efficiency of ultrasonography in diagnosis of intra-osseous jaw lesions concerning their size and content and also to study its correlation with the histopathological findings. MATERIALS AND METHOD: For this study, 15 patients with intra-osseous jaw lesions in the maxilla and mandible were selected from those referred to the Department of Oral Surgery. Panoramic imaging, computed tomography (CT) or cone beam computed tomography (CBCT) and ultrasonography (USG) were performed for all the lesions. The size of the lesions was measured by USG and then compared with CT or CBCT. Moreover, the correlation amongst the echographic patterns and histopathologic results was evaluated. RESULTS: In 12 cases, size values were in complete agreement with CT or CBCT. The size of 3 lesions could not be measured by the radiologist due to the thickness of buccal cortical plate. CONCLUSION: Findings of this study suggested that USG might be feasible in estimating the size of intra-osseous jaw lesions with little underestimation. This study also confirmed that ultrasound imaging was a very useful imaging technique which could provide significant diagnostic information regarding the content of jaw bone lesions where the buccal bone thickness was thin enough. PMID- 26636123 TI - The Effects of Different Miniscrew Thread Designs and Force Directions on Stress Distribution by 3-dimensional Finite Element Analysis. AB - STATEMENT OF THE PROBLEM: The use of miniscrew as an absolute anchorage device in clinical orthodontics is growing increasingly. Many attempts have been made to reduce the size, to improve the design, and to increase the stability of miniscrew. PURPOSE: The purpose of this study was to determine the effects of different thread shapes and force directions of orthodontic miniscrew on stress distribution in the supporting bone structure. MATERIALS AND METHOD: A three dimensional finite element analysis was used. A 200-cN force in three angles (0 degrees , 45 degrees , and 90 degrees ) was applied on the head of the miniscrew. The stress distribution between twelve thread shapes was investigated as categorized in four main groups; buttress, reverse buttress, square, and V-shape. RESULTS: Stress distribution was not significantly different among different thread shapes. The maximum amount of bone stress at force angles 0 degrees , 45 degrees , and 90 degrees were 38.90, 30.57 and 6.62 MPa, respectively. Analyzing the von Mises stress values showed that in all models, the maximum stress was concentrated on the lowest diameter of the shank, especially the part that was in the soft tissue and cervical cortical bone regions. CONCLUSION: There was no relation between thread shapes and von Mises stress distribution in the bone; however, different force angles could affect the von Mises stress in the bone and miniscrew. PMID- 26636124 TI - Antibacterial and Toxic Effect of Hydrogen Peroxide Combined with Different Concentrations of Chlorhexidine in Comparison with Sodium Hypochlorite. AB - STATEMENT OF THE PROBLEM: Hydrogen peroxide (H2O2) has been suggested to be used in sequence or in combination with chlorhexidine (CHX) to enhance the antibacterial activity against Enterococcus faecalis, but there is no research in the literature on the safety and effectiveness of this irrigation protocol. PURPOSE: This study aimed to assess the cytocompatibility and antibacterial activity of different concentrations of CHX combined with H2O2in comparison with the activity of 5.25 and 2.5% sodium hypochlorite (NaOCl). MATERIALS AND METHOD: Different concentrations of H2O2 (10, 5, 3 and 1%) were exposed to the PDL cells. Then, the solution with minimal cytotoxicity was selected (3% H2O2). The cytocompatibility and antibacterial activity of 0.1, 0.2, 1 and 2% CHX combined with 3% H2O2 were evaluated and compared with 5.25 and 2.5% NaOCl. The differences in the mean viability of PDL cells were evaluated by one-way ANOVA. Kruskal-Wallis and post-hoc Dunn's tests were adopted to compare the antibacterial activity of the solutions against E.faecalis. RESULTS: The viability of PDL cells was lower when treated with 5.25 or 2.5% NaOCl than all combinations of CHX and H2O2.There was no significant difference in the antibacterial activity of the solutions against E.faecalis, except for the 0.1% CHX + 3% H2O2 combination, which had significantly lower efficacy than other groups. CONCLUSION: All combinations of CHX and H2O2 (used in this study)except 0.1% CHX + 3% H2O2 were efficient irrigants against planktonic E.faecalis and had a better cytocompatibility with PDL cells than 5.25 and 2.5% NaOCl. PMID- 26636125 TI - The Prevalence of Pulp stones in Adult Patients of Shiraz Dental School, a Radiographic Assessment. AB - STATEMENT OF THE PROBLEM: Pulp stones are calcifications found in the pulp chamber or pulp canals of the teeth. Its different prevalence in different population is a matter of concern. PURPOSE: This study aimed to assess the prevalence of pulp stones in a sample of Iranian population and to report its occurrence regarding gender, dental arch, tooth type and dental status. MATERIALS AND METHODS: Dental records of patients who attended Shiraz Dental School were selected randomly. Only bitewing and periapical radiographs of maxillary and mandibular permanent posterior teeth were studied. Teeth were classified in the case of presence or absence of pulp stones, and the prevalence was analyzed in different gender, tooth types, dental arch, and dental status (intact, carious, or restored) groups. Statistical analysis was performed using X(2) test. RESULTS: Of the 652examined subjects, 306 (46.9%) had one or more teeth with pulp stones. Of the 8244 posterior teeth examined, 928 (11.25%) had pulp stones in the pulp chamber. These pulp stones were detected in 76(37.6%) of males and 230 (51%) of females. The frequency of pulp stones among different teeth between maxillary and mandibular arches had almost a similar pattern. Among teeth demonstrating the condition, first molars were the most prevalent, followed by second molars. In maxillary molars the frequency of occurrence (26%) was higher than mandibular molars (18.7%). No Significant difference was found between dental status and pulp stones occurrence. CONCLUSION: The occurrence of pulp stones noted in this study was significantly higher in female, molar teeth than premolar and 1st maxillary molar than mandibular. There was no significant association between pulp stone and condition of the crown. PMID- 26636126 TI - The Prevalence of Early Childhood Caries among 24 to 36 Months Old Children of Iran: Using the Novel ICDAS-II Method. AB - STATEMENT OF THE PROBLEM: Early childhood caries is an important oral health issue. Finding its prevalence would predict the need for oral health promotion disciplines for specific age groups. PURPOSE: The aim of this study was to assess the caries experience of children living in Tehran, Iran. It also would evaluate the impact of gender, ethnicity, and socioeconomic status (SES) on this oral condition. MATERIALS AND METHOD: This epidemiological cross-sectional study was based upon stratified cluster random sampling. The samples consisted of 239 children (2- to 3- years old) registered in Tehran's public healthcare centers for "Healthy Child Program". Mothers of the recruited children were interviewed for the background data; then children were examined for the oral health status according to ICDAS-II (International Caries Detection and Assessment System) and WHO (World Health Organization) criteria. Statistical analyses were conducted using STATA.11 for SES classification considering six socioeconomic variables, and SPSS.21 for descriptive/analytical analyses. RESULTS: Primary Component Analysis (PCA) demonstrated five classes of SES ranging from the lowest to the highest. The distribution of caries-free (CF) children was 10.87%, non-cavitated enamel caries (codes 01-02) were 28.03%, and about 61.1% had cavitated caries (codes 03-06). There was no significant difference in caries experience between the two genders. Cavitated lesions were more prevalent among Kurdish, who also had the least CF children. Caries prevalence, especially code 02, was more among children from 3(rd) class SES (moderate level). Gender, ethnicity, or SES had no impact on the CF status of the children; however, ethnicity showed significant impact on the prevalence of extensive caries (codes 05-06). CONCLUSION: The result of the present study is indicative of high caries prevalence among 2 to 3 years old children residing in Tehran. It highlights the need for comprehensive oral health promotion disciplines for this age group. PMID- 26636127 TI - Root Canal Treatment of a Maxillary Second Molar with Two Palatal Canals: a Case Report. AB - Careful understanding of internal anatomy of root canal system is crucial for successful endodontic treatment. The presence of two palatal canals in maxillary second molar is unusual but noteworthy as an aid to appropriate diagnosis and treatment. This paper reported a case of a maxillary right second molar with two root canals in the palatal root. The root canal treatment and case management were also explained. PMID- 26636128 TI - Cone Beam Computed Tomography Findings in Calcifying Cystic Odontogenic Tumor Associated with Odontome: A Case Report. AB - The calcifying cystic odontogenic tumor (CCOT) is a rare cystic odontogenic neoplasm frequently found in association with odontome. This report documents a case of CCOT associated with an odontome arising in the anterior maxilla in a 28 year-old man. Conventional radiographs showed internal calcification within the lesion but were unable to visualize its relation with the adjacent structures and its accurate extent. In this case cone beam computed tomography (CBCT) could accurately reveal the extent and the internal structure of the lesion which aided the presumptive diagnosis of the lesion as CCOT. This advanced imaging technique proved to be extremely useful in the radiographic assessment and management of this neoplasm of the maxilla. PMID- 26636129 TI - Strain-guided mineralization in the bone-PDL-cementum complex of a rat periodontium. AB - OBJECTIVE: The objective of this study was to investigate the effect of mechanical strain by mapping physicochemical properties at periodontal ligament (PDL)-bone and PDL-cementum attachment sites and within the tissues per se. DESIGN: Accentuated mechanical strain was induced by applying a unidirectional force of 0.06N for 14 days on molars in a rat model. The associated changes in functional space between tooth and bone, mineral formation and resorbing events at the PDL-bone and PDL-cementum attachment sites were identified by using micro X-ray computed tomography (micro-XCT), atomic force microscopy (AFM), dynamic histomorphometry, Raman microspectroscopy, AFM-based nanoindentation technique, and were correlated with histochemical stains specific to low and high molecular weight GAGs, including biglycan, and osteoclast distribution through tartrate resistant acid phosphatase (TRAP) staining. RESULTS: Unique chemical and mechanical qualities including heterogenous bony fingers with hygroscopic Sharpey's fibers contributing to a higher organic (amide III - 1240 cm-1) to inorganic (phosphate - 960 cm-1) ratio, with lower average elastic modulus of 8 GPa versus 12 GPa in unadapted regions were identified. Furthermore, an increased presence of elemental Zn in cement lines and mineralizing fronts of PDL-bone was observed. Adapted regions containing bony fingers exhibited woven bone-like architecture and these regions rich in biglycan (BGN) and bone sialoprotein (BSP) also contained high-molecular weight polysaccharides predominantly at the site of polarized bone growth. CONCLUSIONS: From a fundamental science perspective the shift in local properties due to strain amplification at the soft-hard tissue attachment sites is governed by semiautonomous cellular events at the PDL-bone and PDL-cementum sites. Over time, these strain-mediated events can alter the physicochemical properties of tissues per se, and consequently the overall biomechanics of the bone-PDL-tooth complex. From a clinical perspective, the shifts in magnitude and duration of forces on the periodontal ligament can prompt a shift in physiologic mineral apposition in cementum and alveolar bone albeit of an adapted quality owing to the rapid mechanical translation of the tooth. PMID- 26636130 TI - Leakage after Surgery for Rectum Cancer: Inconsistency in Reporting to the Danish Colorectal Cancer Group. AB - Purpose. Anastomotic leakage accounts for up to 1/3 of all fatalities after rectal cancer surgery. Evidence suggests that anastomotic leakage has a negative prognostic impact on local cancer recurrence and long-term cancer specific survival. The reported leakage rate in 2011 in Denmark varied from 7 to 45 percent. The objective was to clarify if the reporting of anastomotic leakage to the Danish Colorectal Cancer Group was rigorous and unequivocal. Methods. An Internet-based questionnaire was e-mailed to all Danish surgical departments, who reported to Danish Colorectal Cancer Group (DCCG) in 2011. There were 23 questions. Four core questions were whether pelvic collection, fecal appearance in a pelvic drain, rectovaginal fistula, and "watchfull" waiting patients were reported as anastomotic leakage. Results. Fourteen out of 17 departments, who in 2011 according to DDCG performed rectal cancer surgery, answered the questionnaire. This gave a response rate of 82%. In three of four core questions there was disagreement in what should be reported as anastomotic leakage. Conclusion. The reporting of anastomotic leakage to the Danish Colorectal Cancer Group was not rigorous and unequivocal. The reported anastomotic leakage rate in Danish Colorectal Cancer Group should be interpreted with caution. PMID- 26636133 TI - Gram scale synthesis of magnetite nanoparticles optimized for single-core MPI tracers. PMID- 26636132 TI - Interaction of expanding abdominal aortic aneurysm with surrounding tissue: Retrospective CT image studies. AB - OBJECTIVES: Abdominal aortic aneurysms (AAA) that rupture have a high mortality rate. Rupture occurs when local mechanical stress exceeds the local mechanical strength of an AAA, so stress profiles such as those from finite element analysis (FEA) are useful. The role and effect of surrounding tissues, like the vertebral column, which have not been extensively studied, are examined in this paper. METHODS: Longitudinal CT scans from ten patients with AAAs were studied to see the effect of surrounding tissues on AAAs. Segmentation was performed to distinguish the AAA from other tissues and we studied how these surrounding tissues affected the shape and curvature of the AAA. Previously established methods by Veldenz et al. were used to split the AAA into 8 sections and examine the specific effects of surrounding tissues on these sections [1]. Three dimensional models were created to better examine these effects over time. Registration was done in order to compare AAAs longitudinally. RESULTS: The vertebral column and osteophytes were observed to have been affecting the shape and the curvature of the AAA. Interaction with the spine caused focal flattening in certain areas of the AAA. In 16 of the 41 CT scans, the right posterior dorsal section (section 5), had the highest radius of curvature, which was by far the section that had the maximum radius for a specified CT scan. Evolution of the growing AAA showed increased flattening in this section when comparing the last CT scan to the first scan. CONCLUSION: Surrounding tissues have a clear influence on the geometry of an AAA, which may in turn affect the stress profile of AAA. Incorporating these structures in FEA and G&R models will provide a better estimate of stress. CLINICAL RELEVANCE: Currently, size is the only variable considered when deciding whether to undergo elective surgery to repair AAA since it is an easy enough measure for clinicians to utilize. However, this may not be the best indicator of rupture risk because small aneurysms also contribute to a high mortality rate. AAA's wall stress is a superior indicator and may be better predicted with the inclusion of these surrounding tissues, which then could be used by clinicians in their decision-making process on whether to operate on an AAA. PMID- 26636131 TI - Evaluation of Oxidative Stress Response Related Genetic Variants, Pro-oxidants, Antioxidants and Prostate Cancer. AB - BACKGROUND: Oxidative stress and detoxification mechanisms have been commonly studied in Prostate Cancer (PCa) due to their function in the detoxification of potentially damaging reactive oxygen species (ROS) and carcinogens. However, findings have been either inconsistent or inconclusive. These mixed findings may, in part, relate to failure to consider interactions among oxidative stress response related genetic variants along with pro- and antioxidant factors. METHODS: We examined the effects of 33 genetic and 26 environmental oxidative stress and defense factors on PCa risk and disease aggressiveness among 2,286 men from the Cancer Genetic Markers of Susceptibility project (1,175 cases, 1,111 controls). Single and joint effects were analyzed using a comprehensive statistical approach involving logistic regression, multi-dimensionality reduction, and entropy graphs. RESULTS: Inheritance of one CYP2C8 rs7909236 T or two SOD2 rs2758331 A alleles was linked to a 1.3- and 1.4-fold increase in risk of developing PCa, respectively (p-value = 0.006-0.013). Carriers of CYP1B1 rs1800440GG, CYP2C8 rs1058932TC and, NAT2 (rs1208GG, rs1390358CC, rs7832071TT) genotypes were associated with a 1.3 to 2.2-fold increase in aggressive PCa [p value = 0.04-0.001, FDR 0.088-0.939]. We observed a 23% reduction in aggressive disease linked to inheritance of one or more NAT2 rs4646247 A alleles (p = 0.04, FDR = 0.405). Only three NAT2 sequence variants remained significant after adjusting for multiple hypotheses testing, namely NAT2 rs1208, rs1390358, and rs7832071. Lastly, there were no significant gene-environment or gene-gene interactions associated with PCa outcomes. CONCLUSIONS: Variations in genes involved in oxidative stress and defense pathways may modify PCa. Our findings do not firmly support the role of oxidative stress genetic variants combined with lifestyle/environmental factors as modifiers of PCa and disease progression. However, additional multi-center studies poised to pool genetic and environmental data are needed to make strong conclusions. PMID- 26636136 TI - A Sparse Bayesian Learning Algorithm for Longitudinal Image Data. AB - Longitudinal imaging studies, where serial (multiple) scans are collected on each individual, are becoming increasingly widespread. The field of machine learning has in general neglected the longitudinal design, since many algorithms are built on the assumption that each datapoint is an independent sample. Thus, the application of general purpose machine learning tools to longitudinal image data can be sub-optimal. Here, we present a novel machine learning algorithm designed to handle longitudinal image datasets. Our approach builds on a sparse Bayesian image-based prediction algorithm. Our empirical results demonstrate that the proposed method can offer a significant boost in prediction performance with longitudinal clinical data. PMID- 26636134 TI - Deletion of SPARC Enhances Retinal Vaso-Obliteration in Mouse Model of Oxygen Induced Retinopathy. AB - BACKGROUND: Secreted Protein Acidic and Rich in Cysteine (SPARC) is a matricellular protein which is implicated in regulation of angiogenesis. PURPOSE: To characterize the changes in SPARC expression and effect of its deletion in a mouse model Oxygen Induced Retinopathy (OIR). MATERIALS AND METHODS: Wild type (wt) and SPARC-deficient mice were subjected to high oxygen (75%) for 5 days (p7 p12) before room air for additional 5 days (p12-p17). Retinas from both groups were flat mounted and retinal vessels were labeled with Isolectin-B4. Areas of Retinal Neovascularization (RNV) and vaso-obliteration were measured by Image-J and normalized to total retinal areas. SPARC expression was analyzed in both groups at p14 and p17 in retinal homogenates and sections by Western Blotting (WB) and immunofluorescence respectively. Human Retinal Endothelial Cells (HRECs) were exposed to hypoxia (1% O2) for 6 hours then SPARC was measured in cell lysate and condition medium by WB and ELISA. Moreover, HRECs were treated with VEGF or SPARC to study their mutual regulatory effect. RESULTS: SPARC-deficient mice demonstrated significant increase in the vaso-obliteration (p=0.03) and modest increase in RNV compared to the wt control. Retinal levels of SPARC was significantly decreased during OIR at p14 (p=0.01) and partially restored to normal level by p17. Moreover, hypoxia significantly reduced SPARC expression and secretion in HRECs (p=0.001). We noticed a mutual positive regulatory feedback between SPARC and VEGF. CONCLUSION: SPARC deletion enhances ischemic retinopathy, thus modulation of SPARC expression could be a novel therapeutic approach to prevent pathological RNV. PMID- 26636135 TI - GN-SCCA: GraphNet based Sparse Canonical Correlation Analysis for Brain Imaging Genetics. AB - Identifying associations between genetic variants and neuroimaging quantitative traits (QTs) is a popular research topic in brain imaging genetics. Sparse canonical correlation analysis (SCCA) has been widely used to reveal complex multi-SNP-multi-QT associations. Several SCCA methods explicitly incorporate prior knowledge into the model and intend to uncover the hidden structure informed by the prior knowledge. We propose a novel structured SCCA method using Graph constrained Elastic-Net (GraphNet) regularizer to not only discover important associations, but also induce smoothness between coefficients that are adjacent in the graph. In addition, the proposed method incorporates the covariance structure information usually ignored by most SCCA methods. Experiments on simulated and real imaging genetic data show that, the proposed method not only outperforms a widely used SCCA method but also yields an easy-to interpret biological findings. PMID- 26636137 TI - Surfaceome of pathogenic yeasts, Candida parapsilosis and Candida tropicalis, revealed with the use of cell surface shaving method and shotgun proteomic approach. AB - In the course of infections caused by pathogenic yeasts from the genus Candida, the fungal cell surface is the first line of contact with the human host. As the surface-exposed proteins are the key players in these interactions, their identification can significantly contribute to discovering the mechanisms of pathogenesis of two emerging pathogens from this genus, C. parapsilosis and C. tropicalis. Therefore, the aim of the present study was to identify the cell wall attached proteins of these two species with the use of cell surface shaving and a shotgun proteomic approach. Different morphological forms of C. parapsilosis and C. tropicalis cells obtained after growth under various conditions were subjected to this treatment. This allowed to indicate the most abundant cell surface proteins on the basis of the normalized spectral abundance factors. In case of yeast-like forms these were, among others, proteins similar to a chitinase, glyceraldehyde-3-phosphate dehydrogenase and an inducible acid phosphatase for C. parapsilosis, and a constitutive acid phosphatase, pyruvate decarboxylase and glyceraldehyde-3-phosphate dehydrogenase for C. tropicalis. In case of pseudohyphal forms, proteins similar to a cell surface mannoprotein Mp65, chitinase and glycosylphosphatidylinositol-anchored transglycosylase Crh11 were identified at the cell surface of C. parapsilosis. The Rbt1 cell wall protein, a hyphally regulated cell wall protein and proteins from agglutinin-like sequence protein family were found as the most abundant on C. tropicalis pseudohyphae. Apart from the abovementioned proteins, several additional covalently bound and atypical cell wall proteins were also identified. These results extend the current knowledge regarding the molecular basis of virulence of these two non albicans Candida species. PMID- 26636138 TI - The occurrence of killer activity in yeasts isolated from natural habitats. AB - Yeast's ability to restrict the growth and kill other yeasts, fungi and bacteria has been known for over 50 years. Killer activity was detected in yeasts deposited in the world collections or isolated from natural habitats. In this study, isolates from the forest environment, leaves of fruit trees, flower petals, cereals and frozen fruit have been screened in terms of their killer activities. Killer activity was tested on strains belonging to six yeast species: Candida, Rhodotorula, Pichia, Pachysolen, Yarrowia, Trichosporon. The reference strains were Kluyveromyces lactis Y-6682 and Kluyveromyces marxinanus Y-8281, well-known to be sensitive to yeast killer toxins. Among one hundred and two tested strains, 24 (23.5% of isolates) showed positive killer action, and 10 (9.8% of the isolates) a weak killer action against at least one sensitive reference strain. The highest killer activity was observed among isolates from forest soil and flowers. PMID- 26636139 TI - Kinetic and thermodynamic characterization of the interactions between the components of human plasma kinin-forming system and isolated and purified cell wall proteins of Candida albicans. AB - Cell wall proteins of Candida albicans, besides their best known role in the adhesion of this fungal pathogen to host's tissues, also bind some soluble proteins, present in body fluids and involved in maintaining the biochemical homeostasis of the human organism. In particular, three plasma factors - high molecular-mass kininogen (HK), factor XII (FXII) and prekallikrein (PPK) - have been shown to adhere to candidal cells. These proteins are involved in the surface-contact-catalyzed production of bradykinin-related peptides (kinins) that contribute to inflammatory states associated with microbial infections. We recently identified several proteins, associated with the candidal cell walls, and probably involved in the binding of HK. In our present study, a list of potential FXII- and PPK-binding proteins was proposed, using an affinity selection (on agarose-coupled FXII or PPK) from a whole mixture of beta-1,3 glucanase-extrated cell wall-associated proteins and the mass-spectrometry protein identification. Five of these fungal proteins, including agglutinin-like sequence protein 3 (Als3), triosephosphate isomerase 1 (Tpi1), enolase 1 (Eno1), phosphoglycerate mutase 1 (Gpm1) and glucose-6-phosphate isomerase 1 (Gpi1), were purified and characterized in terms of affinities to the human contact factors, using the surface plasmon resonance measurements. Except Gpm1 that bound only PPK, and Als3 that exhibited an affinity to HK and FXII, the other isolated proteins interacted with all three contact factors. The determined dissociation constants for the identified protein complexes were of 10(-7) M order, and the association rate constants were in a range of 10(4)-10(5) M(-1)s(-1). The identified fungal pathogen-host protein interactions are potential targets for novel anticandidal therapeutic approaches. PMID- 26636140 TI - Examination of cyp51A and cyp51B expression level of the first Polish azole resistant clinical Aspergillus fumigatus isolate. AB - Aspergillus fumigatus is one of the most prevalent airborne fungal pathogens causing infections worldwide. Most A. fumigatus strains are susceptible to azoles, which are administered as the first line therapeutics. However, during last decade the acquired resistance to triazoles by these species has been described. There is a number of publications concerning the examination of clinical A. fumigatus strains from different countries, however there has been no report from Poland. Here, we describe for the first time, an examination of cyp51A and cyp51B expression level of 11 clinical A. fumigatus strains isolated during 2007-2014 period from the collection of Medical University in Wroclaw. Their susceptibility to itraconazole, voriconazole and posaconazole has been examined. The MIC values of triazoles for one of the examined isolates were respectively: > 8 mg/L for itraconazole, 2 mg/L for voriconazole and 0.5 mg/L for posaconazole. The cyp51A gene with its promoter region of all isolates was sequenced. It was found that the resistant isolate harbors the TR34/L98H mutation in the cyp51A gene and when cultured on media supplemented with voriconazole exhibits overexpression of both, cyp51A and cyp51B genes. The level of cyp51A gene expression was about 50 times higher than cyp51B. PMID- 26636141 TI - Lipiodol versus diaphragm in 4D-CBCT-guided stereotactic radiotherapy of hepatocellular carcinomas. AB - PURPOSE: The purpose of this work was to investigate the potential of lipiodol as a direct tumor surrogate alternative to the diaphragm surrogate on four dimensional cone-beam computed tomography (4D-CBCT) image guidance for stereotactic radiotherapy of hepatocellular carcinomas. METHODS: A total of 29 hepatocellular carcinomas (HCC) patients treated by stereotactic radiotherapy following transarterial chemoembolization (TACE) with homogeneous or partial defective lipiodol retention were included. In all, 4-7 pretreatment 4D-CBCT scans were selected for each patient. For each scan, either lipiodol or the diaphragm was used for 4D registration. Resulting lipiodol/diaphragm motion ranges and position errors relative to the reconstructed midventilation images were analyzed to obtain the motion variations, and group mean (DeltaM), systematic (Sigma), and random (sigma) errors of the treatment setup. RESULTS: Of the lipiodolized tumors, 55 % qualified for direct localization on the 4D-CBCT. Significant correlations of lipiodol and diaphragm positions were found in the left-right (LR), craniocaudal (CC), and anteroposterior (AP) directions. DeltaM and sigma obtained with lipiodol and diaphragm were similar, agreed to within 0.5 mm in the LR and AP, and 0.3 mm in the CC directions, and Sigma differed by 1.4 (LR), 1.1 (CC), and 0.6 (AP) mm. Variations of diaphragm motion range > 5 mm were not observed with lipiodol and in one patient with diaphragm. The margin required for the tumor prediction error using the diaphragm surrogate was 6.7 (LR), 11.7 (CC), and 4.1 (AP) mm. CONCLUSION: Image-guidance combining lipiodol with 4D-CBCT enabled accurate localization of HCC and thus margin reduction. A major limitation was the degraded lipiodol contrast on 4D-CBCT. PMID- 26636142 TI - [Patient safety in anesthesiology : Multimodal strategies for perioperative care]. AB - The concept of patient safety is more of a presence in modern day medicine than ever before. All measures and processes aiming at preempting and preventing critical incidents and accidents in patient care are collectively grouped under this concept. With the Declaration of Helsinki in 2010 modern anesthesiology has undertaken a fundamental role in the clinical implementation and perioperative clinicians are confronted with a multitude of theories, models, methods and tools targeted at improving or facilitating optimized patient safety. One of the biggest challenges lies in their synergistic combination to create a functioning concept for perioperative risk management while also incorporating individual strengths and weaknesses. The aim of the present paper is to provide a structured overview of the various components presently available for increasing perioperative patient safety. PMID- 26636144 TI - Harold G Wolff. PMID- 26636143 TI - [Epidermal aging and anti-aging strategies]. AB - Epithelial senescence is a complex process depending on intrinsic as well as extrinsic factors (e.g., UV or IR light, tobacco smoke) and must be seen in the context of the aging process especially of the corium and the subcutis. Morphological alterations become apparent in the form of epithelial atrophy, structural changes within the basal membrane, and a decrease in cell count of melanocytes and Langerhans cells. Signs of cellular senescence are reduced proliferation of keratinocytes, cumulation of dysplastic keratinocytes, various mutations (e.g., c-Fos/c-Jun, STAT3, FoxO1), as well as multiple lipid or amino acid metabolic aberrations (e.g., production of advanced glycation endproducts). This causes functional changes within the physical (lipid deficiency, water distribution dysfunction, lack of hygroscopic substances), chemical (pH conditions, oxygen radicals), and immunological barrier. Prophylactically, barrier-protective care products, antioxidant substances (e.g., vitamin C, B3, E, polyphenols, flavonoids), sunscreen products/measurements, and retinoids are used. For correcting alterations in aged epidermis, chemical peelings (fruit acids, beta-hydroxy acid, trichloroacetic acid, phenolic compounds), non-ablative (IPL, PDL, Nd:YAG) as well as ablative (CO2, Erbium-YAG) light-assisted methods are used. PMID- 26636145 TI - Cystine crystals in bone marrow aspirate. PMID- 26636146 TI - Diagnosis of hantavirus cardiopulmonary syndrome with peripheral blood film. PMID- 26636147 TI - Data->information->knowledge->wisdom: when is South Africa going to get her act together? PMID- 26636148 TI - Zolpidem and restoration of consciousness--fact or fiction? PMID- 26636149 TI - Rendering a dangerous healthcare ocean safer. PMID- 26636150 TI - Euthanasia in SA--sacrificing one to render many vulnerable? PMID- 26636151 TI - Man impaled on crowbar saved by hospital trauma team. PMID- 26636152 TI - A variety of conditions. PMID- 26636153 TI - Bacillary angiomatosis: A rare finding in the setting of antiretroviral drugs. AB - An HIV-positive 39-year-old man presented with generalised nodular lesions. He was apyrexial and normotensive, with a normal respiratory rate. The rest of the examination was normal. He had been on antiretroviral therapy for >4 years; most importantly, he was on a second-line regimen (lopinavir/ritonavir (Aluvia) based). The appearance of the lesions, together with the history, led to the following possible diagnoses: bacillary angiomatosis, cutaneous cryptococcosis, nodular Kaposi sarcoma or cutaneous histoplasmosis. PMID- 26636154 TI - Basedow paraplegia: A possible misnomer. AB - Thyrotoxic myopathy frequently occurs in clinical practice; however, the association of hyperthyroidism with a flaccid, areflexic paraplegia, so-called Basedow paraplegia, appears to represent a controversial and doubtful entity. An 18-year-old female with undiagnosed and untreated Graves' disease presented with acute onset of global weakness predominantly in the lower limbs, but also affecting the upper limbs. The weakness was accompanied by hypotonia and areflexia. Clinically, the patient had a goitre and signs of thyroid ocular disease. Laboratory testing confirmed the presence of hyperthyroidism, and thyroid-stimulating hormone receptor antibodies were positive. The cerebrospinal fluid protein level was raised. The electroneuronographic and needle examinations were compatible with a clear denervation process, such as acute motor axonal neuropathy, a variant of Guillain-Barre syndrome. Intravenous immunoglobulin therapy, carbimazole and propranolol were administered. The occurrence of hyperthyroidism with a flaccid, areflexic paraplegia appears to represent more of a fortuitous than a causative association. It is important to consider and treat other causes, such as acute idiopathic polyneuritis. PMID- 26636155 TI - Cryptococcal laryngitis: An uncommon presentation of a common pathogen. AB - Cryptococcus neoformans is an ubiquitous encapsulated yeast found worldwide, especially in areas with pigeons. The fungus thrives in pigeon droppings and is responsible for primary pulmonary infection, but may disseminate and cause infection of the central nervous system, skin and bone. Most cases are reported in immunocompromised hosts, most commonly those infected with HIV. However, infection has been reported in immunocompetent hosts. Primary infection of the larynx is uncommon, and to date only 12 cases have been reported. We present the first South African report of a young woman with HIV who presented with hoarseness of uncertain aetiology, which was later confirmed to be cryptococcal laryngitis. PMID- 26636156 TI - Efavirenz as a cause of ataxia in children. AB - Acute ataxia in childhood is often caused by toxin ingestion. With the increasing number of paediatric patients on antiretroviral medication, we observe more side effects of these drugs. Acute ataxia is defined as unsteadiness of walking or fine motor movement of <72 hours. The most common causes are postinfectious acute cerebellar ataxia, toxin ingestion and Guillain-Barre syndrome. However, the possibility of a mass lesion must always be excluded. Reported neurological abnormalities in HIV-positive children range from 10% to 68%. A South African study found the prevalence of neurological complications to be 59%, the most common of which were HIV encephalopathy and long-tract motor signs; however, no cases of cerebellar dysfunction were documented. Ataxia rarely occurs in an HIV positive person, the chronic sequelae being neurocognitive impairment and polyneuropathy. Ataxia in the setting of HIV is generally secondary to an infectious, vascular or neoplastic cerebellar lesion. However, most infections are opportunistic and unlikely to occur when CD4 levels are adequate. The vascular or mass lesions are readily excluded with neuro-imaging. We report 2 cases of efavirenz toxicity that caused ataxia. We treated 2 children who presented in a 1-month period, which highlighted an important differential to consider in HIV-positive paediatric patients presenting with ataxia. PMID- 26636157 TI - The real value of endobronchial ultrasound. AB - Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has become a standard procedure worldwide, used in conjunction with bronchoscopy to obtain biopsies for mediastinal disorders. A 67-year-old man with a 40 pack-year smoking history presented with a 2-year history of hoarseness and weight loss. He also had a history of asbestos exposure. On examination under anaesthesia a lesion of the right false vocal fold was found and histology showed a moderately differentiated infiltrating keratinising squamous carcinoma. The question posed was whether this mass could be ascribed to metastatic supraglottic carcinoma or if it was indeed a metachronous primary bronchus carcinoma, as the treatment of these two malignancies differs significantly. Traditional bronchoscopy with TBNA is the least invasive procedure to obtain a cytological diagnosis, but the proximity of the aorta and pulmonary arteries and the mass being 14 mm from the bronchus would have made sampling by means of this procedure near impossible. We used EBUS to localise the mass and noted the position of the major vessels on Doppler ultrasound. Real-time ultrasound guidance allowed us to bridge the tissue plane between the mass and bronchial lumen using the longer EBUS needle and to obtain a fine-needle aspirate of the mass, which proved to be a keratinising squamous carcinoma. We describe this case in which EBUS-TBNA was pivotal in reducing the number of invasive procedures in a patient with metastatic supraglottic carcinoma. PMID- 26636158 TI - False-negative HIV-1 polymerase chain reaction in a 15-month-old boy with HIV-1 subtype C infection. AB - Polymerase chain reaction (PCR) testing is the gold standard for determining the HIV status in children <18 months of age. However, when clinical manifestations are not consistent with laboratory results, additional investigation is required. We report a 15-month-old HIV-exposed boy referred to our hospital after he had been admitted several times for infectious diseases. A rapid antibody test on the child was positive, while routine diagnostic HIV PCRs using the Roche COBAS Ampliprep/COBAS TaqMan HIV Qual Test were negative at 6 weeks, 6 months, 7 months and 15 months. In addition, the same PCR test performed on the HIV-infected mother was also negative. Alternative PCR and viral load assays using different primer sets detected HIV RNA or proviral DNA in both child and mother. Gag sequences from the child and his mother classified both infections as HIV-1 subtype C, with very rare mutations that may have resulted in PCR assay primer/probe mismatch. Consequently, the child was commenced on antiretroviral therapy and made a remarkable recovery. These findings indicate that more reliable PCR assays capable of detecting a wide range of HIV subtypes are desirable to circumvent the clinical problems created by false-negative PCR results. PMID- 26636159 TI - Delayed presentation and diagnosis of metastatic hepatocellular carcinoma in pregnancy. AB - Hepatocellular carcinoma (HCC) is rare in women of reproductive age. If diagnosed, the underlying cirrhosis is associated with infertility in the majority of cases. There is limited literature on HCC in pregnancy, even more so for cases of metastatic disease. We present a case of delayed presentation and diagnosis of metastatic HCC in pregnancy. A 30-year-old pregnant woman presented at 23 weeks' gestation and was diagnosed as HIV-infected, with anaemia. She was initiated on an efavirenz-based fixed-dose combination and oral haematinics. She subsequently presented at 32 weeks' gestation with dyspnoea, and was diagnosed with pre-eclampsia. She was also found to have hepatosplenomegaly and ascites. She went into spontaneous preterm labour at 32 weeks and 4 days. A diagnosis of metastatic HCC was made postpartum, based on the radiological findings and biochemistry. We discuss the challenges of diagnosing metastatic HCC in pregnancy. PMID- 26636160 TI - Kounis syndrome. AB - Kounis syndrome is characterised by a group of symptoms that manifest as unstable vasospastic or non-vasospastic angina secondary to a hypersensitivity reaction. It was first described by Kounis and Zavras in 1991 as the concurrence of an allergic response with an anaphylactoid or anaphylactic reaction and coronary artery spasm or even myocardial infarction. Since then, this condition has evolved to include a number of mast cell activation disorders associated with acute coronary syndrome. There are many triggering factors, including reactions to multiple medications, exposure to radiological contrast media, poison ivy, bee stings, shellfish and coronary stents. In addition to coronary arterial involvement, Kounis syndrome comprises other arterial systems with similar physiologies, such as mesenteric and cerebral circulation resulting in ischaemia/infarction of the vital organs. The incidence of this condition is difficult to establish owing to the number of potential instigating factors and its relatively infrequent documentation in the literature.We report the case of an HIV-negative 39-year-old man with no coronary risk factors or family history of premature coronary artery disease, who developed Kounis syndrome after the administration of fluoroquinolone for dysuria. However, to the best of our knowledge,no data on the incidence and prevalence of Kounis syndrome in South Africa have ever been reported in the literature. The recent understanding of Kounis syndrome has led to the condition being classified into three syndrome variants. PMID- 26636161 TI - Use of the Mentzer index will assist in early diagnosis of iron deficiency in South African children. PMID- 26636162 TI - HIV/AIDS stigma and discrimination in South Africa--still a problem. PMID- 26636163 TI - Contested PMB amendments--'funders the chief beneficiaries.'. PMID- 26636164 TI - Rural district hospitals--essential cogs in the district health system--and primary healthcare re-engineering. PMID- 26636165 TI - Inept drug supply management causing stock-outs. PMID- 26636166 TI - 'Populist politicians' take aim at 'soft-target' doctors. PMID- 26636167 TI - Chronic obstructive pulmonary disease in South Africa: under-recognized and undertreated. PMID- 26636168 TI - Chronic obstructive pulmonary disease--diagnosis and classification of severity. AB - Chronic obstructive pulmonary disease (COPD) is a common, progressive and preventable non-communicable respiratory disorder. It is often confused with asthma and poorly understood by many lay people. The primary cause of COPD is tobacco smoking, but in the South African (SA) context, biomass fuel exposure/household pollution, tuberculosis, HIV and mining exposure are additional important causes.There is a very high prevalence of COPD in SA and it is the third leading cause of mortality globally.The diagnosis of COPD is based predominantly on symptoms, i.e. progressive shortness of breath and cough in a patient with risk factors-usually smoking. Lung function testing is required to formally make the diagnosis, which places a significant hurdle in correctly identifying COPD in SA, given the limited access to spirometry in many areas. Spirometry is also required to grade the severity of lung function obstruction.Severity assessment, which is used to plan a management strategy (predominantly bronchodilators with inhaled steroids in severe cases), combines symptoms, lung function and exacerbations. Based on these 3 factors, a patient can be categorised into 1 of 4 groups and appropriate management instituted. Additional comorbidities, particularly cardiovascular and mental illness, should also be evaluated.Early identification of COPD, with further avoidance of an aetiological cause such as smoking, is key in preventing disease progression.Appropriate therapy, comprising non-pharmacological and pharmacological interventions and based on a comprehensive severity assessment, should result in symptom improvement and reduced risk for exacerbations. PMID- 26636169 TI - Pathogenesis of chronic obstructive pulmonary disease: An African perspective. AB - The importance of chronic obstructive pulmonary disease (COPD) as a global health problem cannot be overstated. According to the latest World Health Organization statistics (2005), 210 million people suffer from COPD worldwide, and 5% of all deaths globally are estimated to be caused by this disease. This corresponds to >3 million deaths annually, of which 90% are thought to occur in low- and middle income countries.While cigarette smoking remains the major risk factor, and much of the increase in COPD is associated with projected increases in tobacco use, epidemiological studies have demonstrated that in the majority of patients in developing countries the aetiology of COPD is multifactorial.This article summarises the epidemiology of and risk factors for COPD in Africa, including influences other than cigarette smoking that are important contributors to chronic irreversible airflow limitation in our setting. PMID- 26636170 TI - Non-pharmacological management of chronic obstructive pulmonary disease. AB - Chronic obstructive pulmonary disease (COPD) is the third leading cause of morbidity and mortality globally, contributing to a substantialuse of resources. According to World Health Organization estimates, 65 million people have moderate to severe COPD. The conditionis also recognised as a systemic disease with extrapulmonary manifestations, such as peripheral muscle dysfunction, malnutrition anddepression, which further contribute to disability, poor quality of life, exacerbations and mortality. Optimum management requires nonpharmacologicalinterventions combined with pharmacological treatment. However, the former is often neglected and not widely used indaily practice, with the focus mainly on the latter. PMID- 26636171 TI - Pharmacological management of chronic obstructive pulmonary disease. AB - There have been significant changes in the approach to the management of chronic obstructive pulmonary disease (COPD) over the pastdecade. The World Health Organization suggests four componentsto a COPD management plan: (i) assess and monitor disease; (ii) reducerisk factors; (iii) manage stable COPD; and (iv) manage exacerbations. Encouraging patients to limit their risk exposure is essential, whetherit be smoking cessation or removing exposure to biomass.The main objective of treatment is to relieve daily symptoms, improve quality of life and importantly decrease the risk of futureexacerbations. Current guidelines are based on grade A and B evidence. Pneumococcal and annual influenza vaccinations are encouraged.A holistic approach that augments pharmacological treatment includes good nutrition and pulmonary rehabilitation.Bronchodilators are the cornerstone of management. Depending on the patient's placement in the GOLD ABCD classification, treatmentis individualised. Short-acting bronchodilators are used as rescue medication, while long-acting bronchodilators or/and long actingmuscarinic agents are the treatment of choice for patients in groups B, C and D. Inhaled corticosteroids are only recommended for groups Cand D. Most patients respond well to combinations of the abovementioned medications. For patients who still have frequent exacerbations,alternative choices include long term macrolides and phosphodiesterase 4 inhibitors. PMID- 26636172 TI - Five tips for good office spirometry. PMID- 26636173 TI - Lung volume reduction in chronic obstructive pulmonary disease. AB - Pathognomonic features of advanced emphysema include a markedly reduced alveolar surface area due to the formation of blebs and bullae and significantly reduced elastic recoil. The aim of lung volume reduction, which can be achieved by either surgery or endoscopic techniques, is volume loss of the targeted, diseased region(s) and redirecting airflow to less affected regions.Lung volume reduction surgery (LVRS) entails reducing the lung volume by wedge excision of emphysematous tissue. LVRS carries significant morbidity and mortality, but can offer survival benefit and increased exercise capacity in selected patients with predominantly upper-lobe emphysema and low exercise capacity.Endoscopic lung volume reduction (ELVR) refers to bronchoscopically inducing volume loss to improve pulmonary mechanics and compliance, thereby reducing the work of breathing. Globally, this technique is increasingly used as treatment for advanced emphysema with the objective of obtaining similar functional advantages to surgical lung volume reduction, while decreasing risks and costs. Current evidence suggests that patients with either homogeneous or heterogeneous disease may benefit from ELVR.It remains paramount that a systematic approach is followed and selection criteria are met, given the high costs and potential complications related to both LVRS and ELVR. PMID- 26636174 TI - Metal-Organic Framework Thin Films as Platforms for Atomic Layer Deposition of Cobalt Ions To Enable Electrocatalytic Water Oxidation. AB - Thin films of the metal-organic framework (MOF) NU-1000 were grown on conducting glass substrates. The films uniformly cover the conducting glass substrates and are composed of free-standing sub-micrometer rods. Subsequently, atomic layer deposition (ALD) was utilized to deposit Co(2+) ions throughout the entire MOF film via self-limiting surface-mediated reaction chemistry. The Co ions bind at aqua and hydroxo sites lining the channels of NU-1000, resulting in three dimensional arrays of separated Co ions in the MOF thin film. The Co-modified MOF thin films demonstrate promising electrocatalytic activity for water oxidation. PMID- 26636175 TI - Interaction of Phenylalanine with DPPC Model Membranes: More Than a Hydrophobic Interaction. AB - The negative free energy previously reported is explained by the stabilization of a PC-Phe (phosphocholine-phenylalanine) complex in the presence of water shown by the decrease in the symmetric stretching frequency of the phosphate group of the lipid (PO2(-)). An entropic contribution due to the disruption of the water network around the phenyl and in the membrane defect may be invoked. The dipole potential decrease is explained by the orientation of the carboxylate opposing to the CO of the lipids with oxygen moiety toward the low hydrated hydrocarbon core. The symmetric bending frequency of NH3(+) group of Phe, decreases in 5.2 cm(-1) in relation to water congruent with zeta potential shift to positive values. The Phe to DPPC dissociation constant is Kd = 2.23 +/- 0.09 mM, from which the free energy change is about -4.54 kcal/mol at 25 degrees C. This may be due to hydrophobic contributions and two hydrogen bonds. PMID- 26636176 TI - Direct Observation of the Transition-State Region in the Photodissociation of CH3I by Femtosecond Extreme Ultraviolet Transient Absorption Spectroscopy. AB - Femtosecond extreme ultraviolet (XUV) pulses produced by high harmonic generation are used to probe the transition-state region in the 266 nm photodissociation of CH3I by the real-time evolution of core-to-valence transitions near the iodine N edge at 45-60 eV. During C-I bond breaking, new core-to-valence electronic states appear in the spectra, which decay concomitantly with the rise of the atomic iodine resonances of I((2)P3/2) and I*((2)P1/2). The short-lived features are assigned to repulsive valence-excited transition-state regions of (3)Q0 and (1)Q1, which can connect to transient core-excited states via promotion of 4d(I) core electrons. A simplified one-electron transition picture is described that accurately predicts the relative energies of the transient states observed. The transition-state resonances reach a maximum at ~40 fs and decay to complete C-I dissociation in ~90 fs, representing the shortest-lived chemical transition state observed by core-level, XUV, or X-ray spectroscopy. PMID- 26636178 TI - Prognostic and predictive biomarkers of abdominal aortic aneurysm growth rate. AB - OBJECTIVES: To test the utility of clinical and circulating biomarkers to predict abdominal aortic aneurysm (AAA) growth rate and response to doxycycline therapy. METHODS: Plasma samples were obtained in the Pharmaceutical Aneurysm Stabilization Trial that tested the effect of doxycycline (n = 44) vs. placebo (n = 49) in patients with a 35-50 mm AAA. Approximately 200 biomarkers were evaluated in a candidate approach that included markers of matrix turnover and cathepsin S activity and a broad-based approach of predominantly inflammation related and clinical biomarkers. RESULTS: In a recursive partitioning based analysis, total cholesterol, baseline AAA size, and apolipoprotein B were prognostic of AAA growth in the placebo group whereas elastin and biglycan degradation products were predictive of AAA growth with doxycycline treatment. Univariate analysis of these biomarkers showed that baseline total cholesterol (r = 0.38, unadjusted P = 0.011), apolipoprotein B (r = 0.41, unadjusted P = 0.005), and baseline AAA size (r = 0.35, unadjusted P = 0.013) correlated with AAA growth in the placebo but not the doxycycline group. Elastin fragments were associated with 18 month AAA growth (r = 0.33, unadjusted P = 0.031) in the doxycycline group. LIMITATIONS: Limitations of this study include small sample size, a retrospective growth analysis, and translatability of the method used to measure the analytes. CONCLUSIONS: This study implies that total cholesterol, baseline AAA size, and apolipoprotein B are predictors of AAA growth. Levels of elastin and biglycan fragments are predictive of doxycycline effects on AAA growth and provide a clue towards this unexpected negative effect. PMID- 26636177 TI - Increased Visceral Adipose Tissue Is an Independent Predictor for Future Development of Atherogenic Dyslipidemia. AB - CONTEXT: Atherogenic dyslipidemia is frequently observed in persons with a greater amount of visceral adipose tissue (VAT). However, it is still uncertain whether VAT is independently associated with the future development of atherogenic dyslipidemia. OBJECTIVES: The aim of this study was to determine whether baseline and changes in VAT and subcutaneous adipose tissue (SAT) are associated with future development of atherogenic dyslipidemia independent of baseline lipid levels and standard anthropometric indices. DESIGN AND SETTING: Community-based prospective cohort study with 5 years of follow-up. PARTICIPANTS: A total of 452 Japanese Americans (240 men, 212 women), aged 34-75 years were assessed at baseline and after 5 years of follow-up. MAIN OUTCOME MEASURES: Abdominal fat areas were measured by computed tomography. Atherogenic dyslipidemia was defined as one or more abnormalities in high-density lipoprotein (HDL) cholesterol, triglycerides, or non-HDL cholesterol levels. RESULTS: Baseline VAT and change in VAT over 5 years were independently associated with log-transformed HDL cholesterol, log-transformed triglyceride, and non-HDL cholesterol after 5 years (standardized beta = -0.126, 0.277, and 0.066 for baseline VAT, respectively, and -0.095, 0.223, and 0.090 for change in VAT, respectively). However, baseline and change in SAT were not associated with any future atherogenic lipid level. In multivariate logistic regression analysis, incremental change in VAT (odds ratio [95% confidence interval], 1.73 [1.20 2.48]; P = .003), triglycerides (4.01 [1.72-9.33]; P = .001), HDL cholesterol (0.32 [0.18-0.58]; P < .001), and non-HDL cholesterol (7.58 [4.43-12.95]; P < .001) were significantly associated with the future development of atherogenic dyslipidemia independent of age, sex, diastolic blood pressure, homeostasis model assessment insulin resistance, body mass index (BMI), change in BMI, SAT, and baseline atherogenic lipid levels. CONCLUSION: Baseline and change in VAT were independent predictors for future development of atherogenic dyslipidemia. However, BMI, waist circumference, and SAT were not associated with future development of atherogenic dyslipidemia. PMID- 26636179 TI - Contribution of the Antibiotic Chloramphenicol and Its Analogues as Precursors of Dichloroacetamide and Other Disinfection Byproducts in Drinking Water. AB - Dichloroacetamide (DCAcAm), a disinfection byproduct, has been detected in drinking water. Previous research showed that amino acids may be DCAcAm precursors. However, other precursors may be present. This study explored the contribution of the antibiotic chloramphenicol (CAP) and two of its analogues (thiamphenicol, TAP; florfenicol, FF) (referred to collectively as CAPs), which occur in wastewater-impacted source waters, to the formation of DCAcAm. Their formation yields were compared to free and combined amino acids, and they were investigated in filtered waters from drinking-water-treatment plants, heavily wastewater-impacted natural waters, and secondary effluents from wastewater treatment plants. CAPs had greater DCAcAm formation potential than two representative amino acid precursors. However, in drinking waters with ng/L levels of CAPs, they will not contribute as much to DCAcAm formation as the MUg/L levels of amino acids. Also, the effect of advanced oxidation processes (AOPs) on DCAcAm formation from CAPs in real water samples during subsequent chlorination was evaluated. Preoxidation of CAPs with AOPs reduced the formation of DCAcAm during postchlorination. The results of this study suggest that CAPs should be considered as possible precursors of DCAcAm, especially in heavily wastewater impacted waters. PMID- 26636180 TI - Serrulatane Diterpenoid from Eremophila neglecta Exhibits Bacterial Biofilm Dispersion and Inhibits Release of Pro-inflammatory Cytokines from Activated Macrophages. AB - The purpose of this study was to assess the biofilm-removing efficacy and inflammatory activity of a serrulatane diterpenoid, 8-hydroxyserrulat-14-en-19 oic acid (1), isolated from the Australian medicinal plant Eremophila neglecta. Biofilm breakup activity of compound 1 on established Staphylococcus epidermidis and Staphylococcus aureus biofilms was compared to the antiseptic chlorhexidine and antibiotic levofloxacin. In a time-course study, 1 was deposited onto polypropylene mesh to mimic a wound dressing and tested for biofilm removal. The ex-vivo cytotoxicity and effect on lipopolysaccharide-induced pro-inflammatory cytokine release were studied in mouse primary bone-marrow-derived macrophage (BMDM) cells. Compound 1 was effective in dispersing 12 h pre-established biofilms with a 7 log10 reduction of viable bacterial cell counts, but was less active against 24 h biofilms (approximately 2 log10 reduction). Compound-loaded mesh showed dosage-dependent biofilm-removing capability. In addition, compound 1 displayed a significant inhibitory effect on tumor necrosis factor alpha (TNF alpha) and interleukin-6 (IL-6) secretion from BMDM cells, but interleukin-1 beta (IL-1beta) secretion was not significant. The compound was not cytotoxic to BMDM cells at concentrations effective in removing biofilm and lowering cytokine release. These findings highlight the potential of this serrulatane diterpenoid to be further developed for applications in wound management. PMID- 26636182 TI - Cross-Coupling between Difluorocarbene and Carbene-Derived Intermediates Generated from Diazocompounds for the Synthesis of gem-Difluoroolefins. AB - Cross-coupling between difluorocarbene and carbene-derived intermediates generated from diazocompounds was developed to give gem-difluoroolefins, which constitutes a fast practical pathway to achieve hindered gem-difluoroolefins. The cross-coupling between difluorocarbene and aryl diazoacetates proceeded smoothly in the presence of a copper source, whereas its coupling with diaryl diazomethanes occurred well under metal-free conditions. A mechanism involving a copper-difluorocarbene complex was proposed. PMID- 26636183 TI - Mechanism of Charge Transfer and Recombination Dynamics in Organo Metal Halide Perovskites and Organic Electrodes, PCBM, and Spiro-OMeTAD: Role of Dark Carriers. AB - Despite the unprecedented interest in organic-inorganic metal halide perovskite solar cells, quantitative information on the charge transfer dynamics into selective electrodes is still lacking. In this paper, we report the time scales and mechanisms of electron and hole injection and recombination dynamics at organic PCBM and Spiro-OMeTAD electrode interfaces. On the one hand, hole transfer is complete on the subpicosecond time scale in MAPbI3/Spiro-OMeTAD, and its recombination rate is similar to that in neat MAPbI3. This was found to be due to a high concentration of dark charges, i.e., holes brought about by unintentional p-type doping of MAPbI3. Hence, the total concentration of holes in the perovskite is hardly affected by optical excitation, which manifested as similar decay kinetics. On the other hand, the decay of the photoinduced conductivity in MAPbI3/PCBM is on the time scale of hundreds of picoseconds to several nanoseconds, due to electron injection into PCBM and electron-hole recombination at the interface occurring at similar rates. These results highlight the importance of understanding the role of dark carriers in deconvoluting the complex photophysical processes in these materials. Moreover, optimizing the preparation processes wherein undesired doping is minimized could prompt the use of organic molecules as a more viable electrode substitute for perovskite solar cell devices. PMID- 26636181 TI - Pulsed Dipolar Spectroscopy Reveals That Tyrosyl Radicals Are Generated in Both Monomers of the Cyclooxygenase-2 Dimer. AB - Cyclooxygenases (COXs) are heme-containing sequence homodimers that utilize tyrosyl radical-based catalysis to oxygenate substrates. Tyrosyl radicals are formed from a single turnover of substrate in the peroxidase active site generating an oxy-ferryl porphyrin cation radical intermediate that subsequently gives rise to a Tyr-385 radical in the cyclooxygenase active site and a Tyr-504 radical nearby. We have utilized double-quantum coherence (DQC) spectroscopy to determine the distance distributions between Tyr-385 and Tyr-504 radicals in COX 2. The distances obtained with DQC confirm that Tyr-385 and Tyr-504 radicals were generated in each monomer and accurately match the distances measured in COX-2 crystal structures. PMID- 26636184 TI - Nonneural Androgen Receptors Affect Sexual Differentiation of Brain and Behavior. AB - Testosterone, acting via estrogenic and androgenic pathways, is the major endocrine mechanism promoting sexual differentiation of the mammalian nervous system and behavior, but we have an incomplete knowledge of which cells and tissues mediate these effects. To distinguish between neural and nonneural actions of androgens in sexual differentiation of brain and behavior, we generated a loxP-based transgenic mouse, which overexpresses androgen receptors (ARs) when activated by Cre. We used this transgene to overexpress AR globally in all tissues using a cytomegalovirus (CMV)-Cre driver (CMV-AR), and we used a Nestin-Cre driver to overexpress AR only in neural tissue (Nes-AR). We then examined whether neural or global AR overexpression can affect socio-sexual behaviors using a resident-intruder paradigm. We found that both neural and global AR overexpression resulted in decreased aggressive behaviors and increased thrusting during mounting of intruders, consistent with a neural site of action. Global, but not neural, AR overexpression in males led to an increase in same-sex anogenital investigation. Together, these results suggest novel roles for nonneural AR in sexual differentiation of mice, and indicate that excess AR can lead to a paradoxical reduction of male-typical behavior. PMID- 26636185 TI - Metformin Protects Kidney Cells From Insulin-Mediated Genotoxicity In Vitro and in Male Zucker Diabetic Fatty Rats. AB - Hyperinsulinemia is thought to enhance cancer risk. A possible mechanism is induction of oxidative stress and DNA damage by insulin, Here, the effect of a combination of metformin with insulin was investigated in vitro and in vivo. The rationales for this were the reported antioxidative properties of metformin and the aim to gain further insights into the mechanisms responsible for protecting the genome from insulin-mediated oxidative stress and damage. The comet assay, a micronucleus frequency test, and a mammalian gene mutation assay were used to evaluate the DNA damage produced by insulin alone or in combination with metformin. For analysis of antioxidant activity, oxidative stress, and mitochondrial disturbances, the cell-free ferric reducing antioxidant power assay, the superoxide-sensitive dye dihydroethidium, and the mitochondrial membrane potential-sensitive dye 5,5',6,6'tetrachloro-1,1',3,3' tetraethylbenzimidazol-carbocyanine iodide were applied. Accumulation of p53 and pAKT were analyzed. As an in vivo model, hyperinsulinemic Zucker diabetic fatty rats, additionally exposed to insulin during a hyperinsulinemic-euglycemic clamp, were treated with metformin. In the rat kidney samples, dihydroethidium staining, p53 and pAKT analysis, and quantification of the oxidized DNA base 8-oxo-7,8 dihydro-2'-deoxyguanosine were performed. Metformin did not show intrinsic antioxidant activity in the cell-free assay, but protected cultured cells from insulin-mediated oxidative stress, DNA damage, and mutation. Treatment of the rats with metformin protected their kidneys from oxidative stress and genomic damage induced by hyperinsulinemia. Metformin may protect patients from genomic damage induced by elevated insulin levels. This may support efforts to reduce the elevated cancer risk that is associated with hyperinsulinemia. PMID- 26636186 TI - Androgen Regulates Mafb Expression Through its 3'UTR During Mouse Urethral Masculinization. AB - External genitalia are prominent organs showing hormone-dependent sexual differentiation. Androgen is an essential regulator of masculinization of the genital tubercle, which is the anlage of external genitalia. We have previously shown that v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog B (MAFB) is an androgen-inducible regulator of embryonic urethral masculinization in mice. However, it remains unclear how androgen regulates Mafb expression. The current study suggests that the Mafb 3' untranslated region (UTR) is an essential region for its regulation by androgen. We identified 2 functional androgen response elements (AREs) in Mafb 3'UTR. Androgen receptor is bound to such AREs in 3'UTR during urethral masculinization. In addition to 3'UTR, Mafb 5'UTR also showed androgen responsiveness. Moreover, we also demonstrated that beta-catenin, one of genital tubercle masculinization factors, may be an additional regulator of Mafb expression during urethral masculinization. This study provides insights to elucidate mechanisms of gene regulation through AREs present in Mafb 3'UTR for a better understanding of the processes of urethral masculinization. PMID- 26636187 TI - Uncoupling Proteins and the Molecular Mechanisms of Thyroid Thermogenesis. PMID- 26636188 TI - Anion-Anion Bonding and Topology in Ternary Iridium Seleno-Stannides. AB - The synthesis and physical properties of two new and one known Ir-Sn-Se compound are reported. Their crystal structures are elucidated with transmission electron microscopy and powder X-ray diffraction. IrSn0.45Se1.55 is a pyrite phase which consists of tilted corner-sharing IrX6 octahedra with randomly distributed (Sn Se)(4-) and (Se-Se)(2-) dimers. Ir2Sn3Se3 is a known trigonally distorted skutterudite that consists of cooperatively tilted corner-sharing IrSn3Se3 octahedra with ordered (Sn-Se)2(4-) tetramers. Ir2SnSe5 is a layered, distorted beta-MnO2 (pyrolusite) structure consisting of a double IrSe6 octrahedral row, corner sharing in the a direction and edge sharing in the b direction. This distorted pyrolusite contains (Se-Se)(2-) dimers and Se(2-) anions, and each double row is "capped" with a (Sn-Se)n polymeric chain. Resistivity, specific heat, and magnetization measurements show that all three have insulating and diamagnetic behavior, indicative of low-spin 5d(6) Ir(3+). Electronic structure calculations on Ir2Sn3Se3 show a single, spherical, nonspin-orbit split valence band and suggest that Ir2Sn3Se3 is topologically nontrivial under tensile strain due to inversion of Ir-d and Se-p states. PMID- 26636189 TI - Three-terminal nanoelectromechanical switch based on tungsten nitride--an amorphous metallic material. AB - Nanoelectromechanical (NEM) switches inherently have zero off-state leakage current and nearly ideal sub-threshold swing due to their mechanical nature of operation, in contrast to semiconductor switches. A challenge for NEM switches to be practical for low-power digital logic application is their relatively large operation voltage which can result in higher dynamic power consumption. Herein we report a three-terminal laterally actuated NEM switch fabricated with an amorphous metallic material: tungsten nitride (WNx). As-deposited WN x thin films have high Young's modulus (300 GPa) and reasonably high hardness (3 GPa), which are advantageous for high wear resistance. The first prototype WN x switches are demonstrated to operate with relatively low control voltage, down to 0.8 V for an air gap thickness of 150 nm. PMID- 26636190 TI - Density Functional Model for Nondynamic and Strong Correlation. AB - A single-term density functional model for the left-right nondynamic/strong electron correlation is presented based on single-determinant Kohn-Sham density functional theory. It is derived from modeling the adiabatic connection for kinetic correlation energy based on physical arguments, with the correlation potential energy based on the Becke'13 model ( Becke, A.D. J. Chem. Phys . 2013 , 138 , 074109 ). This functional satisfies some known scaling relationships for correlation functionals. The fractional spin error is further reduced substantially with a new density-functional correction. Preliminary tests with self-consistent-field implementation show that the model, with only three empirical parameters, recovers the majority of left-right nondynamic/strong correlation upon bond dissociation and performs reasonably well for atomization energies and singlet-triplet energy splittings. This study also demonstrates the feasibility of developing DFT functionals for nondynamic and strong correlation within the single-determinant KS scheme. PMID- 26636191 TI - Four-Component Relativistic Density Functional Theory Calculations of EPR g- and Hyperfine-Coupling Tensors Using Hybrid Functionals: Validation on Transition Metal Complexes with Large Tensor Anisotropies and Higher-Order Spin-Orbit Effects. AB - The four-component matrix Dirac-Kohn-Sham (mDKS) implementation of EPR g- and hyperfine A-tensor calculations within a restricted kinetic balance framework in the ReSpect code has been extended to hybrid functionals. The methodology is validated for an extended set of small 4d(1) and 5d(1) [MEXn](q) systems, and for a series of larger Ir(II) and Pt(III) d(7) complexes (S = 1/2) with particularly large g-tensor anisotropies. Different density functionals (PBE, BP86, B3LYP-xHF, PBE0-xHF) with variable exact-exchange admixture x (ranging from 0% to 50%) have been evaluated, and the influence of structure and basis set has been examined. Notably, hybrid functionals with an exact-exchange admixture of about 40% provide the best agreement with experiment and clearly outperform the generalized gradient approximation (GGA) functionals, in particular for the hyperfine couplings. Comparison with computations at the one-component second-order perturbational level within the Douglas-Kroll-Hess framework (1c-DKH), and a scaling of the speed of light at the four-component mDKS level, provide insight into the importance of higher-order relativistic effects for both properties. In the more extreme cases of some iridium(II) and platinum(III) complexes, the widely used leading-order perturbational treatment of SO effects in EPR calculations fails to reproduce not only the magnitude but also the sign of certain g-shift components (with the contribution of higher-order SO effects amounting to several hundreds of ppt in 5d complexes). The four-component hybrid mDKS calculations perform very well, giving overall good agreement with the experimental data. PMID- 26636192 TI - Special Issue on Polarization. PMID- 26636193 TI - Derivation of Distributed Models of Atomic Polarizability for Molecular Simulations. AB - The main thrust of this investigation is the development of models of distributed atomic polarizabilities for the treatment of induction effects in molecular mechanics simulations. The models are obtained within the framework of the induced dipole theory by fitting the induction energies computed via a fast but accurate MP2/Sadlej-adjusted perturbational approach in a grid of points surrounding the molecule. Particular care is paid in the examination of the atomic quantities obtained from models of implicitly and explicitly interacting polarizabilities. Appropriateness and accuracy of the distributed models are assessed by comparing the molecular polarizabilities recovered from the models and those obtained experimentally and from MP2/Sadlej calculations. The behavior of the models is further explored by computing the polarization energy for aromatic compounds in the context of cation-pi interactions and for selected neutral compounds in a TIP3P aqueous environment. The present results suggest that the computational strategy described here constitutes a very effective tool for the development of distributed models of atomic polarizabilities and can be used in the generation of new polarizable force fields. PMID- 26636194 TI - Modeling Induction Phenomena in Intermolecular Interactions with an Ab Initio Force Field. AB - One possible road toward the development of a polarizable potential energy function relies on the use of distributed polarizabilities derived from the induction energy mapped around the molecule. Whereas such polarizable models are expected to reproduce the signature induction energy with an appreciable accuracy, it is far from clear whether they will perform equally well in the context of intermolecular interactions. To address this issue, while pursuing the ultimate goal of a "plug-and-play"-like approach, polarizability models determined quantum mechanically and consisting of atomic isotropic dipole plus charge-flow polarizabilities were combined with the classical, nonpolarizable Charmm force field. Performance of the models was probed in the challenging test cases of cation-pi binding and the association of a divalent calcium ion with water, where induction effects are envisioned to be considerable. Since brute force comparison of the binding energies estimated from the polarizable and the classical Charmm potential energy functions is not justified, the individual electrostatic and induction contributions of the force field were confronted to the corresponding terms of a symmetry-adapted perturbation theory (SAPT) expansion carried out with the 6-311++G(d,p) basis set. While the quantum mechanical and the molecular-mechanical electrostatic and damped induction contributions agree reasonably well, overall reproduction of the binding energies is plagued by an underestimated repulsion that underlines the necessity of de novo parametrization of the classical 6-12 form of the van der Waals potential. Based on the SAPT expansion, new Lennard-Jones parameters were optimized, which, combined with the remainder of the polarizable force field, yield an improved reproduction of the target binding energies. PMID- 26636195 TI - Recipe of Polarized One-Electron Potential Optimization for Development of Polarizable Force Fields. AB - Polarized one-electron potential (POP) optimization is a powerful and practical method to determine multicenter dipole polarizabilities that can be used for constructing polarizable force fields. The POP optimization is similar to the widely used electrostatic potential (ESP) optimization to determine the partial charges of molecules. However, while the ESP optimization targets the electrostatic potentials on a molecular surface, the POP optimization targets the change of electrostatic potentials on molecular surfaces which are induced by the field of a test charge on the molecular surface. Since only additional one electron integrals for the test charge are required for the estimation of the surface potentials, the change of electrostatic potentials has been named "polarized one-electron potentials". We show that in the POP optimization, both an explicitly interacting polarizability model and an implicitly interacting polarizability model can be used for the determination of the multicenter polarizabilities. In the explicitly interacting model, intramolecular induced dipole-induced dipole interaction is mutually included in the process of the POP optimization, but the interaction is not included in the implicitly interacting model. In the implicitly interacting polarizability model, a combined model of isotropic atom polarization and anisotropic bond polarization is shown to provide the best fitting results for nucleic acid bases which show large polarization anisotropy. A simple scaling model to the chemical bond has been newly proposed for the explicitly interacting polarizability model. We show that the simple model can be applied to molecular simulations without any damping of exponential type in the intramolecular induced dipole interaction. A detailed procedure for determination of the multicenter dipole polarizability by the POP optimization is also presented. PMID- 26636196 TI - Many-Body Polarization, a Cause of Asymmetric Solvation of Ions and Quadrupoles. AB - Three models are used to study the effect of many-body polarization in the solvation of non-dipolar molecules and ions in water. Two of the models are very simplified and are used to show a number of basic principles of correlation of solvent degrees of freedom and asymmetric solvent structures. These principles are used to interpret results from the third model: an accurate simulation of para-benzoquinone (PBQ) in aqueous solution with a combined quantum chemical statistical mechanical solvent model with an explicit solvent. It is found that nonzero polarizability of PBQ introduces correlation in the solvent degrees of freedom through the many-body nature of the polarization. The fluctuating electric field from the solvent on the solute increases in magnitude with the correlation. Solvent effects are hence modified. This correlation is not described within the mean-field approximation. In practice, the correlation will show up as an increased probability for asymmetric solvation of the molecule. PMID- 26636197 TI - The Effect of Polarizability for Understanding the Molecular Structure of Aqueous Interfaces. AB - A review is presented on recent progress of the application of molecular dynamics simulation methods with the inclusion of polarizability for the understanding of aqueous interfaces. Comparisons among a variety of models, including those based on density functional theory of the neat air-water interface, are given. These results are used to describe the effect of polarizability on modeling the microscopic structure of the neat air-water interface, including comparisons with recent spectroscopic studies. Also, the understanding of the contribution of polarization to the electrostatic potential across the air-water interface is elucidated. Finally, the importance of polarizability for understanding anion transfer across an organic-water interface is shown. PMID- 26636198 TI - Self-Consistent Reaction Field Model for Aqueous and Nonaqueous Solutions Based on Accurate Polarized Partial Charges. AB - A new universal continuum solvation model (where "universal" denotes applicable to all solvents), called SM8, is presented. It is an implicit solvation model, also called a continuum solvation model, and it improves on earlier SMx universal solvation models by including free energies of solvation of ions in nonaqueous media in the parametrization. SM8 is applicable to any charged or uncharged solute composed of H, C, N, O, F, Si, P, S, Cl, and/or Br in any solvent or liquid medium for which a few key descriptors are known, in particular dielectric constant, refractive index, bulk surface tension, and acidity and basicity parameters. It does not require the user to assign molecular-mechanics types to an atom or group; all parameters are unique and continuous functions of geometry. It may be used with any level of electronic structure theory as long as accurate partial charges can be computed for that level of theory; we recommend using it with self-consistently polarized Charge Model 4 or other self-consistently polarized class IV charges, in which case analytic gradients are available. The model separates the observable solvation free energy into two components: the long-range bulk electrostatic contribution arising from a self-consistent reaction field treatment using the generalized Born approximation for electrostatics is augmented by the non-bulk-electrostatic contribution arising from short-range interactions between the solute and solvent molecules in the first solvation shell. The cavities for the bulk electrostatics calculation are defined by superpositions of nuclear-centered spheres whose sizes are determined by intrinsic atomic Coulomb radii. The radii used for aqueous solution are the same as parametrized previously for the SM6 aqueous solvation model, and the radii for nonaqueous solution are parametrized by a training set of 220 bare ions and 21 clustered ions in acetonitrile, methanol, and dimethyl sulfoxide. The non bulk-electrostatic terms are proportional to the solvent-accessible surface areas of the atoms of the solute and have been parametrized using solvation free energies for a training set of 2346 solvation free energies for 318 neutral solutes in 90 nonaqueous solvents and water and 143 transfer free energies for 93 neutral solutes between water and 15 organic solvents. The model is tested with three density functionals and with four basis sets: 6-31+G(d,p), 6-31+G(d), 6 31G(d), and MIDI!6D. The SM8 model achieves mean unsigned errors of 0.5-0.8 kcal/mol in the solvation free energies of tested neutrals and mean unsigned errors of 2.2-7.0 kcal/mol for ions. The model outperforms the earlier SM5.43R and SM7 universal solvation models as well as the default Polarizable Continuum Model (PCM) implemented in Gaussian 98/03, the Conductor-like PCM as implemented in GAMESS, Jaguar's continuum model based on numerical solution of the Poisson equation, and the GCOSMO model implemented in NWChem. PMID- 26636199 TI - Polarizable Force Fields: History, Test Cases, and Prospects. AB - A consistent treatment of electrostatic energies is arguably the most important requirement for the realistic modeling of biological systems. An important part of electrostatic modeling is the ability to account for the polarizability of the simulated system. This can be done both macroscopically and microscopically, but the use of macroscopic models may lead to conceptual traps, which do not exist in the microscopic treatments. The present work describes the development of microscopic polarizable force fields starting with the introduction of these powerful tools and following some of the subsequent developments in the field. Special effort has been made to review a wide range of applications and emphasize cases when the use of polarizable force fields is important. Finally, a brief perspective is given on the future of this rapidly growing field. PMID- 26636200 TI - Charge Model 4 and Intramolecular Charge Polarization. AB - Partial atomic charges provide the most widely used model for molecular charge polarization, and Charge Model 4 (CM4) is designed to provide partial atomic charges that correspond to an accurate charge distribution, even though they may be calculated with polarized double-zeta basis sets with any density functional. Here we extend CM4 to six additional basis sets, and we present a model (CM4M) that is individually optimized for the M06 suite of density functionals for ten basis sets. These charge models yield class IV partial atomic charges by mapping from those obtained with Lowdin or redistributed Lowdin population analyses of density functional electronic charge distributions. CM4M/M06-2X/6-31G(d)//M06 2X/6-31+G(d,p) partial atomic charges are calculated for ethylene, CHnCl4-n (n = 0-4), benzene, nitrobenzene, phenol, and fluoromethanol and used to discuss gas phase polarization effects. PMID- 26636201 TI - Polarization Effects in Aqueous and Nonaqueous Solutions. AB - Polarization effects in aqueous and nonaqueous solutions were analyzed for nine neutral and three charged organic solutes by the SM8 universal implicit solvation model and class IV partial atomic charges based on Charge Model 4M (CM4M) with the M06-2X density functional. The CM4M partial atomic charges in neutral and ionic solutes and in the corresponding clustered solutes (supersolutes), which included one solute molecule and one or two solvent molecules, were modeled in three solvents (benzene, methylene chloride, and water) and compared to those in the gas phase. The use of the supersolute approach (microsolvation) allows one to account for charge transfer from the solute to the solvent, and we find charge transfers as large as 0.06 atomic units for neutral solutes (pyridine in water) and 0.32 atomic units for ions (methoxide anion in water). Relaxation of the electronic structure of the solute in the presence of solvent increases the polarization free energy of the neutral solutes studied here, on average, by 16% in benzene, 30% in methylene chloride, and 43% in water. The increase for the ions in water averaged 43%. PMID- 26636202 TI - Polarizable Atomic Multipole Solutes in a Generalized Kirkwood Continuum. AB - The generalized Born (GB) model of continuum electrostatics is an analytic approximation to the Poisson equation useful for predicting the electrostatic component of the solvation free energy for solutes ranging in size from small organic molecules to large macromolecular complexes. This work presents a new continuum electrostatics model based on Kirkwood's analytic result for the electrostatic component of the solvation free energy for a solute with arbitrary charge distribution. Unlike GB, which is limited to monopoles, our generalized Kirkwood (GK) model can treat solute electrostatics represented by any combination of permanent and induced atomic multipole moments of arbitrary degree. Here we apply the GK model to the newly developed Atomic Multipole Optimized Energetics for Biomolecular Applications (AMOEBA) force field, which includes permanent atomic multipoles through the quadrupole and treats polarization via induced dipoles. A derivation of the GK gradient is presented, which enables energy minimization or molecular dynamics of an AMOEBA solute within a GK continuum. For a series of 55 proteins, GK electrostatic solvation free energies are compared to the Polarizable Multipole Poisson-Boltzmann (PMPB) model and yield a mean unsigned relative difference of 0.9%. Additionally, the reaction field of GK compares well to that of the PMPB model, as shown by a mean unsigned relative difference of 2.7% in predicting the total solvated dipole moment for each protein in this test set. The CPU time needed for GK relative to vacuum AMOEBA calculations is approximately a factor of 3, making it suitable for applications that require significant sampling of configuration space. PMID- 26636203 TI - Induced-Polarization Energy Map: A Helpful Tool for Predicting Geometric Features of Anion-pi Complexes. AB - In this manuscript we propose the use of a new tool that we have found useful to predict the geometries of ion-pi complexes. This tool is entitled the Induced Polarization Energy map (IPE map). The novelty of this representation is that in the map only the contribution of the ion-induced polarization term to the total interaction energy for a given noncovalent interaction is contoured in a 2D region. The IPE map has been found useful to predict and explain geometries of several complexes of a tetrahedral 2 anion (BF4(-)) with perfluoropyrazine, perfluoropyridazine, perfluoropyrimidine, the three isomers of perfluorotriazine, and the three isomers of perfluorotetrazine. PMID- 26636204 TI - Improved Methods for Side Chain and Loop Predictions via the Protein Local Optimization Program: Variable Dielectric Model for Implicitly Improving the Treatment of Polarization Effects. AB - This paper presents significant improvements in both accuracy and computational efficiency of protein side chain and loop predictions using the Protein Local Optimization Program (PLOP). We introduce a novel energy model in which the internal dielectric constant of the protein is allowed to vary as a function of the interacting residues and present a physical rationale for this model. Using this model, we achieve qualitative improvements in the accuracy of side chain predictions with respect to experimental crystal structure and substantially reduce the RMSDs for loop predictions, particularly those predictions involving charged side chains. For the single side chain prediction of lysine, 40% of the errors are eliminated, and the accuracy increases from 62.6% to 76.8%. The errors in glutamate and aspartate predictions are reduced by 19% and 24%, respectively. When applied to a set of 240 loop predictions with 6, 8, 10, and 13 residue of loop length, this new model yields unprecedented accuracies with average backbone root-mean-square deviations of 0.39 A, 0.68 A, 0.80 A, and 1.00 A for 6, 8, 10, and 13 residue loops, respectively. We also describe a series of technical improvements in the PLOP simulation algorithms, which lead to a speedup of a factor of 2-4 in loop predictions. PMID- 26636205 TI - Group Polarizability Model for Molecular Mechanics Energy Functions. AB - A polarization model for molecular mechanics energy functions is developed that is based on a local group paradigm, namely the polarizability of a rigid substructure of covalently connected atoms. Axes at a "diffuse" site within the group define an anisotropic local group polarizability as well as hyperpolarizability. The theoretical basis for this model is presented, and its performance is described through applications to water, alkanes, and N methylacetamide. The excellent agreement with quantum mechanical electric potentials and molecular polarizabilities indicates that this model must be considered an important candidate for the inclusion of polarization into such force fields. The ab initio-based spectroscopically determined force field (SDFF) protocol for the calculation of parameters assures that, in addition to structures and energies, forces will be accurately modeled. PMID- 26636206 TI - On the Calculation of Atomic Forces in Classical Simulation Using the Charge-on Spring Method To Explicitly Treat Electronic Polarization. AB - An expression for the atomic forces in simulations using the charge-on-spring (COS) polarizable model is rederived. In previous implementations of COS-based models, contributions arising from the dependence of the induced dipoles (i.e., the positions of the charges-on-spring) on the coordinates of the other sites in the system were not taken into account. However, from calculations on gas-phase dimers we found a significant contribution of these terms. Errors in the forces when neglecting these contributions in condensed-phase calculations can be significantly reduced by choosing an appropriately large value for the size of the charge-on-spring. PMID- 26636207 TI - Results from an Early Polarization Model Based on Maxwell's Invariant Multipole Form. AB - This paper reviews the cooperative water model of Campbell and Mezei based on the Maxwellian form of multipole interaction. The Maxwellian form is described, and the algorithms and software for their implementation in both disordered and ordered phases are presented, followed by the specifics of the model. The model has been used in a number of calculations on various water clusters, liquid, and crystal models. The results of these calculations are briefly summarized, and their implications, relevant to polarization model in general, are discussed. PMID- 26636208 TI - Coarse-Grained Protein Model Coupled with a Coarse-Grained Water Model: Molecular Dynamics Study of Polyalanine-Based Peptides. AB - The coupling of a coarse-grained (CG) protein model with the CG water model developed by Marrink et al. (J. Phys. Chem. B 2004, 108, 750) is presented. The model was used in the molecular dynamics studies of Ac-(Ala)6-Xaa-(Ala)7-NHMe, Xaa = Ala, Leu, Val, and Gly. A Gly mutation in the middle of polyalanine is found to destabilize the helix and stabilize the hairpin by favoring a type-II' turn and probably to speed up hairpin folding. The simulations allow us to derive thermodynamic parameters of, in particular, the helical propensities (s) of amino acids in these polyalanine-based peptides. The calculated s values are 1.18 (Ala), 0.84 (Leu), 0.30 (Val), and <0.02 (Gly) at 291 K, in excellent agreement with experimental values (R(2)=0.970). Analyses using a structural approach method show that the helical propensity difference of these amino acids mainly comes from solvation effect. Leu and Val have lower helical propensities than Ala mainly because the larger side chains shield the solvation of helical structures, while Gly has a much poorer helical propensity mainly due to the much better solvation for the coil structures than for the helical structures. Overall, the model is at least about 10(2) times faster than current all-atom MD methods with explicit solvent. PMID- 26636209 TI - Improving the Accuracy of the Linear Interaction Energy Method for Solvation Free Energies. AB - A linear response method for estimating the free energy of solvation is presented and validated using explicit solvent molecular dynamics, thermodynamic perturbation calculations, and experimental data. The electrostatic contribution to the solvation free energy is calculated using a linear response estimate, which is obtained by comparison to the free energy calculated using thermodynamic perturbation. Systematic deviations from the value of (1)/2 in the potential energy scaling factor are observed for some types of compounds, and these are taken into account by introducing specific coefficients for different chemical groups. The derived model reduces the rms error of the linear response estimate significantly from 1.6 to 0.3 kcal/mol on a training set of 221 molecules used to parametrize the model and from 3.7 to 1.3 kcal/mol on a test set of 355 molecules that were not used in the derivation of the model. The total solvation free energy is estimated by combining the derived model with an empirical size dependent term for predicting the nonpolar contribution. Using this model, the experimental hydration free energies for 192 molecules are reproduced with an rms error of 1.1 kcal/mol. The use of LIE in simplified binding free energy calculations to predict protein-ligand binding free energies is also discussed. PMID- 26636210 TI - Stability of N10C10H10 and N12C12H12 Cages and the Effects of Endohedral Atoms and Ions. AB - Cages of carbon and nitrogen have been studied by theoretical calculations to determine the potential of these molecules as high-energy density materials. Following previous theoretical studies of high-energy N6C6H6 and N8C8H8 cages, a series of calculations on several isomers of the larger N10C10H10 and N12C12H12 is carried out to determine relative stability among a variety of three coordinate cage isomers with four-membered, five-membered, and/or six-membered rings. Additionally, calculations are carried out on the same molecules with atoms or ions inside the cage. Calculations are carried out with the B3LYP and PBE1PBE density functional (DFT) methods, with MP2 and MP4 calculations carried out to evaluate the accuracy of the DFT results. Trends in stability with respect to cage geometry and arrangements of atoms are calculated and discussed. Stability effects caused by the endohedral atoms and ions are also calculated and discussed. PMID- 26636211 TI - Relativistic Effects on the Topology of the Electron Density. AB - The topological analysis of electron densities obtained either from X-ray diffraction experiments or from quantum chemical calculations provides detailed insight into the electronic structure of atoms and molecules. Of particular interest is the study of compounds containing (heavy) transition-metal elements, which is still a challenge for experiment as well as from a quantum-chemical point of view. Accurate calculations need to take relativistic effects into account explicitly. Regarding the valence electron density distribution, these effects are often only included indirectly through relativistic effective core potentials. But as different variants of relativistic Hamiltonians have been developed all-electron calculations of heavy elements in combination with various electronic structure methods are feasible. Yet, there exists no systematic study of the topology of the total electron density distribution calculated in different relativistic approximations. In this work we therefore compare relativistic Hamiltonians with respect to their effect on the electron density in terms of a topological analysis. The Hamiltonians chosen are the four-component Dirac-Coulomb, the quasi-relativistic two-component zeroth-order regular approximation, and the scalar-relativistic Douglas-Kroll-Hess operators. PMID- 26636212 TI - Theoretical Characterization of a Tridentate Photochromic Pt(II) Complex Using Density Functional Theory Methods. AB - Density functional theory methods have been used to characterize a tridentate photochromic Pt(II) complex [Pt(AAA)Cl], its acetonitrile complex [Pt(AAA)Cl.CH3CN], and the transition state in the complexation reaction. B3LYP/6 31G* (effective core potential for Pt) optimized geometries of Pt(AAA)Cl and Pt(AAA)Cl.CH3CN are found to be in reasonably good agreement with most of the applicable parameters for the available experimental crystal structures of Pt(AAA)Cl and a Pt(AAA)Cl-triphenylphoshine complex, with the exception of one of the dihedral angles, the deviation of which is determined to be due to a steric cis versus trans effect. Vibrational frequencies are calculated for Pt(AAA)Cl and cis-Pt(AAA)Cl.CH3CN, and the predicted shift in the benzaldehyde carbonyl frequency is found to be in line with that observed experimentally. Singlet vertical excitation energies are calculated for Pt(AAA)Cl and cis-Pt(AAA)Cl.CH3CN using time-dependent density-functional theory and are found to be in good agreement with the experimental transition energies, although for cis Pt(AAA)Cl.CH3CN, the calculations suggest a reassignment of the experimental S1 and S2 transitions. Single point energies are calculated at the B3LYP/6 311+G(2d,2p) level (effective core potential for Pt) and the calculations predict the complexation reaction (dark reaction) to be exothermic and, after a correction to the entropy, to be exoergic at 298 K and to proceed with a reasonable activation energy. Based on singlet and triplet vertical excitation energies, it is speculated that the photoreaction occurs via an intersystem crossing from S1 to T1 for cis-Pt(AAA)Cl.CH3CN followed by an adiabatic reaction along the T1 surface and then nonradiative intersystem crossing to the S0 state of Pt(AAA)Cl. PMID- 26636213 TI - Influence of the Side Chain in the Structure and Fragmentation of Amino Acids Radical Cations. AB - The conformational properties of ionized amino acids (Gly, Ala, Ser, Cys, Asp, Gln, Phe, Tyr, and His) have been theoretically analyzed using the hybrid B3LYP and the hybrid-meta MPWB1K functionals as well as with the post-Hartree Fock CCSD(T) level of theory. As a general trend, ionization is mainly localized at the -NH2 group, which becomes more planar and acidic, the intramolecular hydrogen bond in which -NH2 acts as proton donor being strengthened upon ionization. For this reason, the so-called conformer IV(+) becomes the most stable for nonaromatic amino acid radical cations. Aromatic amino acids do not follow this trend because ionization takes place mainly at the side chain. For these amino acids for which ionization of the side chain prevails over the -NH2 group, structures III(+) and II(+) become competitive. The Calpha-X fragmentations of the ionized systems have also been studied. Among the different decompositions considered, the one that leads to the loss of COOH(*) is the most favorable one. Nevertheless, for aromatic amino acids fragmentations leading to R(*) or R(+) start being competitive. In fact, for His and Tyr, results indicate that the fragmentation leading to R(+) is the most favorable process. PMID- 26636214 TI - Theoretical Study of Binding Site Preference in [2]Rotaxanes. AB - Rotaxanes that can be switched between co-conformations by some external stimulus are of interest because the switching mechanism might be used to create molecular devices capable of producing useful work. Probably the most common approach to create a switchable rotaxane is to start with a rotaxane where the ring interacts more strongly with one of two possible binding sites along the shaft and then apply an external stimulus that weakens the binding interaction between the ring and the shaft at this site, thereby changing the binding site preference. We have investigated binding site preference in two rotaxanes and two pseudorotaxanes with electronic structure calculations at several levels of theory. To gain insight into the origins of the intercomponent binding, empirical approximations were applied to estimate the electrostatic and dispersion contributions. Dispersion has been thought to make an important contribution to the intercomponent interaction in the presence of pi-pi stacking interactions between the components, but the role of dispersion interaction has been a controversial issue because many computational methods neglect this interaction. For example, AM1 semiempirical calculations neglect dispersion but often predict correct co conformational preferences. This suggests that inclusion of the dispersion interaction is required for correct quantitative, but not qualitative, description of the intercomponent binding, a result that is supported by the analytic partitioning of the binding interactions. The origins of this result are investigated. PMID- 26636215 TI - Geometries of Second-Row Transition-Metal Complexes from Density-Functional Theory. AB - A data set of 19 second-row transition-metal complexes has been collated from sufficiently precise gas-phase electron-diffraction experiments and used for evaluating errors in DFT optimized geometries. Equilibrium geometries have been computed using 15 different combinations of exchange-correlation functionals in conjunction with up to three different effective core potentials. Most DFT levels beyond the local density approximation can reproduce the 29 metal-ligand bond distances selected in this set with reasonable accuracy and precision, as assessed by the mean and standard deviations of optimized vs experimentally observed bond lengths. The pure GGAs tested in this study all have larger standard deviations than their corresponding hybrid variants. In contrast to previous findings for first-row transition-metal complexes, the TPSSh hybrid meta GGA is slightly inferior to the best hybrid GGAs. The ranking of some popular density functionals, for second-row transition-metal complexes, ordered according to decreasing standard deviation, is VSXC ~ LSDA > BLYP > BP86 > B3LYP ~ TPSSh > PBE hybrid ~ B3PW91 ~ B3P86. When zero-point vibrational corrections, computed at the BP86/SDD level, are added to equilibrium bond distances obtained from a number of density-functional/basis-set combinations, the overall performance in terms of mean and standard deviations from experiment is not improved. For a combined data set comprised of the first- and second-row transition-metal complexes the hybrid functionals B3P86, B3PW91, and the meta-GGA hybrid TPSSh afford the lowest standard deviations. PMID- 26636216 TI - Charge and Spin Currents in Open-Shell Molecules: A Unified Description of NMR and EPR Observables. AB - The theory of EPR hyperfine coupling tensors and NMR nuclear magnetic shielding tensors of open-shell molecules in the limit of vanishing spin-orbit coupling (e.g., for organic radicals) is analyzed in terms of spin and charge current density vector fields. The ab initio calculation of the spin and charge current density response has been implemented at the Restricted Open-Shell Hartree-Fock, Unrestricted Hartree-Fock, and unrestricted GGA-DFT level of theory. On the basis of this formalism, we introduce the definition of nuclear hyperfine coupling density, a scalar function of position providing a partition of the EPR observable over the molecular domain. Ab initio maps of spin and charge current density and hyperfine coupling density for small radicals are presented and discussed in order to illustrate the interpretative advantages of the newly introduced approach. Recent NMR experiments providing evidence for the existence of diatropic ring currents in the open-shell singlet pancake-bonded dimer of the neutral phenalenyl radical are directly assessed via the visualization of the induced current density. PMID- 26636217 TI - 7-Norbornyl Cation [Formula: see text] Fact or Fiction? A QTAIM-DI-VISAB Computational Study. AB - QTAIM-DI-VISAB analyses were used to characterize the bonding of the 'nonclassical' 7-norbornyl cation and its rearrangement transitions states. These analyses involved obtaining QTAIM molecular graphs and delocalization indexes (DIs) that were correlated with the proximities of atomic basins (VISAB). This study showed that the so-called 7-norbornyl cation actually exhibits the molecular graph of the bicyclo[3.2.0]heptyl cation at its equilibrium geometry. Dynamical aspects of its molecular graph/density were explored with QTAIM by analyzing the nuclear motions of the 206 cm(-)(1) normal mode. This study cements the QTAIM-DI-VISAB analysis as a method of choice for establishing the nature of the bonding in so-called nonclassical carbocations while obviating the need for dotted-line representations of bonding. PMID- 26636218 TI - Carbon-Hydrogen Bond Activation in Hydridotris(pyrazolyl)borate Platinum(IV) Complexes: Comparison of Density Functionals, Basis Sets, and Bonding Patterns. AB - The reaction mechanism for the cycle beginning with the reductive elimination (RE) of methane from kappa(3)-TpPt(IV)(CH3)2H (1) (Tp = hydridotris(pyrazolyl)borate) and subsequent oxidative addition (OA) of benzene to form finally kappa(3)-TpPt(IV)(Ph)2H (19) was investigated by density functional theory (DFT). Two mechanistic steps are of particular interest, namely the barrier to C-H coupling (barrier 1 - Ba1) and the barrier to methane release (barrier 2 - Ba2). For 31 density functionals, the calculated values for Ba1 and Ba2 were benchmarked against the experimentally reported values of 26 (Ba1) and 35 (Ba2) kcal.mol(-1), respectively. Specifically, the values for Ba1 and Ba2, calculated at the B3LYP/double-zeta plus polarization level of theory, are 24.6 and 34.3 kcal.mol(-1), respectively. Overall, the best performing functional was BPW91 where the mae associated with the calculated values of the two barriers is 0.68 kcal.mol(-1). The calculated B3LYP values of Ba1 ranged between 20 and 26 kcal.mol(-1) for 12 effective core potential basis sets for platinum and 29 all electron basis sets for the first row elements. Polarization functions for the first row elements were important for accurate values, but the addition of diffuse functions to non-hydrogen (+) and hydrogen atoms (++) had little effect on the calculated values. Basis set saturation was achieved with APNO basis sets utilized for first-row atoms. Bader's "Atoms in Molecules" was used to analyze the electron density of several complexes, and the electron density at the Pt-Nax bond critical point (trans to the active site for C-H coupling) varied over a wider range than any of the other Pt-N bonds. PMID- 26636219 TI - Mechanism of 5,5-Dimethylhydantoin Chlorination: Monochlorination through a Dichloro Intermediate. AB - The hydantoin moiety is an important pharmacore, and when halogenated, hydantoin derivatives act as excellent biocides. However, there have been no computational studies concerning the chlorination mechanism for the hydantoin moiety reported. Herein we describe a computational mechanistic study of the chlorination of 5,5 dimethylhydantoin (H) at the B3LYP/6-311+G(2d,p) level. Under a 1:1 molar ratio of hydantoin and a chlorinating agent (HOCl), conproportionation is calculated to be favorable to give the N1 monochloro derivative as the major predicted product, which is in agreement with experiment. Initial direct chlorination at the N1 position is prevented by a high kinetic barrier. The first step involves the deprotonation of the hydantoin moiety (at the N3 position) which is followed by a SN2 step transferring a chloronium ion (Cl(+)) from HOCl to the ionized hydantoin anion. A mechanism is proposed where the N3 nitrogen is chlorinated first followed by the N1 position to form the dichloro derivative. When CPCM solvation free energies (DeltaG(solv)) were added to the gas-phase free energies (DeltaG(gas)) along the SN2 reaction path, a sudden decrease in free energy was observed due to the incipient formation of the hydroxide ion. Explicit consideration of solvation within a box of 512 water molecules led to a much more gradual free energy change along the reaction path but a very similar free energy of activation. PMID- 26636220 TI - First Hybrid Embedding Scheme for Polar Covalent Materials Using an Extended Border Region To Minimize Boundary Effects on the Quantum Region. AB - We present an improved scheme for constructing the border region within a hybrid quantum mechanics/molecular mechanics (QM/MM) embedded cluster approach for zeolites and covalent oxides that ensures proper modeling of adsorption complexes with QM regions of moderate size. The procedure employs a flexible orbital basis set on monovalent oxygen pseudoatoms at the boundary of the QM cluster and introduces a pseudopotential description without explicit representation of valence electrons for their immediate Si neighbors in the MM region. This novel QM/MM border scheme, implemented in the elastic polarizable environment method for polar covalent materials (covEPE), provides an accurate description of the local structure of zeolites and other silica based materials. We assessed the performance of the novel border scheme by comparing calculated and experimental results for structures, vibrational frequencies, and binding energies of CO adsorption complexes at bridging OH groups in zeolites with FAU and MFI structures. In addition, when modeling zeolite-supported metal clusters, the new approach implies considerably reduced corrections due to the basis set superposition error, compared to our previous scheme for treating the border region of the QM partition [J. Phys. Chem. B 2003, 107, 2228]. PMID- 26636221 TI - Binding of Gold Nanoclusters with Size-Expanded DNA Bases: A Computational Study of Structural and Electronic Properties. AB - Binding of gold nanoclusters with size-expanded DNA bases, xA, xC, xG, and xT, is studied using quantum chemical methods. Geometries of the neutral xA-Au6, xC-Au6, xG-Au6, and xT-Au6 complexes were fully optimized using the B3LYP density functional method (DFT). The gold clusters around xA and xT adopt triangular geometries, whereas irregular structures are obtained in the case of gold clusters complexed around xC and xG. The lengths of the bonds between atoms in the x-bases increase on gold complexation. The aromatic character of the x-bases also increases on gold complexation except for the five-member rings. A significant charge transfer from the x-base to gold atoms is seen in these complexes. Second-order interactions are observed in addition to direct covalent bonds between gold atoms and x-bases. PMID- 26636222 TI - Clustering Molecular Dynamics Trajectories: 1. Characterizing the Performance of Different Clustering Algorithms. AB - Molecular dynamics simulation methods produce trajectories of atomic positions (and optionally velocities and energies) as a function of time and provide a representation of the sampling of a given molecule's energetically accessible conformational ensemble. As simulations on the 10-100 ns time scale become routine, with sampled configurations stored on the picosecond time scale, such trajectories contain large amounts of data. Data-mining techniques, like clustering, provide one means to group and make sense of the information in the trajectory. In this work, several clustering algorithms were implemented, compared, and utilized to understand MD trajectory data. The development of the algorithms into a freely available C code library, and their application to a simple test example of random (or systematically placed) points in a 2D plane (where the pairwise metric is the distance between points) provide a means to understand the relative performance. Eleven different clustering algorithms were developed, ranging from top-down splitting (hierarchical) and bottom-up aggregating (including single-linkage edge joining, centroid-linkage, average linkage, complete-linkage, centripetal, and centripetal-complete) to various refinement (means, Bayesian, and self-organizing maps) and tree (COBWEB) algorithms. Systematic testing in the context of MD simulation of various DNA systems (including DNA single strands and the interaction of a minor groove binding drug DB226 with a DNA hairpin) allows a more direct assessment of the relative merits of the distinct clustering algorithms. Additionally, means to assess the relative performance and differences between the algorithms, to dynamically select the initial cluster count, and to achieve faster data mining by "sieved clustering" were evaluated. Overall, it was found that there is no one perfect "one size fits all" algorithm for clustering MD trajectories and that the results strongly depend on the choice of atoms for the pairwise comparison. Some algorithms tend to produce homogeneously sized clusters, whereas others have a tendency to produce singleton clusters. Issues related to the choice of a pairwise metric, clustering metrics, which atom selection is used for the comparison, and about the relative performance are discussed. Overall, the best performance was observed with the average-linkage, means, and SOM algorithms. If the cluster count is not known in advance, the hierarchical or average-linkage clustering algorithms are recommended. Although these algorithms perform well, it is important to be aware of the limitations or weaknesses of each algorithm, specifically the high sensitivity to outliers with hierarchical, the tendency to generate homogenously sized clusters with means, and the tendency to produce small or singleton clusters with average-linkage. PMID- 26636223 TI - Folding Simulations of the Transmembrane Helix of Virus Protein U in an Implicit Membrane Model. AB - Vpu is an 81-amino-acid auxiliary membrane protein encoded by human immunodeficiency virus type 1 (HIV-1). One of its roles is to amplify viral release by self-assembling in homo-oligomers to form functional water-filled pores enabling the flux of ions across the membrane. Various NMR and CD studies have shown that the transmembrane domain of Vpu has a helical conformation. With a recently developed implicit membrane model and an efficient Monte Carlo (MC) algorithm using concerted backbone rotations, we simulate the folding of the transmembrane domain of Vpu at atomic resolution. The implicit membrane environment is based on the generalized Born theory and enables very long time scale events, such as folding to be observed using detailed all-atom representation of the protein. Such studies are currently computationally unfeasible with fully explicit lipid bilayer molecular dynamics simulations. The correct helical transmembrane structure of Vpu is predicted from extended conformations and remains stably inserted. Tilt and kink angles agree well with experimental estimates from NMR measurements. The experimentally observed change in tilt angle in membranes of varying hydrophobic width is accurately reproduced. The extensive simulation of a pentamer of the Vpu transmembrane domain in the implicit membrane gives results similar to the ones reported previously for fully explicit bilayer simulations. PMID- 26636224 TI - Prediction of the Structure of Complexes Comprised of Proteins and Glycosaminoglycans Using Docking Simulation and Cluster Analysis. AB - A typical docking simulation provides information on the structure of ligand receptor complexes and their binding affinity in terms of a docking energy. We have developed a potent method combining a docking simulation with cluster analysis to extract adequate docking structures from the many possible output structures of the simulation. First, we tried to predict the structure of basic fibroblast growth factor (bFGF) bound to heparin, using the docking simulation program AutoDock 3.0. Two X-ray crystal structures had already been obtained for bFGF. One was a complex of the protein and heparin, a kind of glycosaminoglycan, and the other, only the protein itself, hereafter called a simplex. We docked a heparin molecule onto the protein simplex and generated many trial structures for the bFGF-heparin complex. The structures of those docked complexes were optimized through energy minimization by AMBER8. Although neither the docking energy calculated by AMBER8 nor that calculated by AutoDock 3.0 could be used satisfactorily by themselves to select a proper heparin-binding complex from the output structures, the majority of the structures generated by AutoDock 3.0 were fairly close to each other in atom geometry, and the averaged geometry over these structures was also close to that of the crystal. Hence, we utilized only the atom geometry for evaluation and carried out cluster analysis with the collection of geometries. This procedure enabled selection of a structure considerably close to the crystal's. We applied this approach to two other heparin-binding proteins: antithrombin and annexin V. Two crystal structures, a complex and a simplex, had been elucidated for these proteins as well as for bFGF. Our trials gave an exact prediction of the heparin-binding structures of these proteins, showing the approach in this study is effective in studying the docking of ligands that have a variety of docking conformations due to the presence of multiple rotatable bonds and charged chemical groups. PMID- 26636228 TI - Interview With Barbara Brown, Founder and Editor Emerita of NAQ. PMID- 26636229 TI - Expanding the Parameters for Excellence in Patient Assignments: Is Leveraging an Evidence-Data-Based Acuity Methodology Realistic? AB - Finding the balance of equitable assignments continues to be a challenge for health care organizations seeking to leverage evidence-based leadership practices. Ratios and subjective acuity strategies for nurse-patient staffing continue to be the dominant approach in health care organizations. In addition to ratio-based assignments and acuity-based assignment models driven by financial targets, more emphasis on using evidence-based leadership strategies to manage and create science for effective staffing is needed. In particular, nurse leaders are challenged to increase the sophistication of management of patient turnover (admissions, discharges, and transfers) and integrate tools from Lean methodologies and quality management strategies to determine the effectiveness of nurse-patient staffing. PMID- 26636230 TI - Accountable Care Units: A Disruptive Innovation in Acute Care Delivery. AB - Accountable Care Units are a disruptive innovation that has moved care on acute care units from a traditional silo model, in which each discipline works separately from all others, to one in which multiple disciplines work together with patients and their families to move patients safely through their hospital stay. This article describes the "what," "how," and "why" of the Accountable Care Units model as it has evolved in different locations across a single health system and includes the lessons learned as different units and hospitals continue working to implement the model in their complex care environments. PMID- 26636231 TI - Promoting a Strategic Approach to Clinical Nurse Leader Practice Integration. AB - The Office of Nursing Services of the Department of Veterans Affairs (VA) piloted implementation of the clinical nurse leader (CNL) into the care delivery model and established a strategic goal in 2011 to implement the CNL role across the VA health care system. The VA Office of Nursing Services CNL Implementation and Evaluation (CNL I&E) Service was created as one mechanism to facilitate that goal in response to a need identified by facility nurse executives for consultative support for CNL practice integration. This article discusses strategies employed by the CNL I&E consultative team to help facility-level nursing leadership integrate CNLs into practice. Measures of success include steady growth in CNL practice capacity as well as positive feedback from nurse executives about the value of consultative engagement. Future steps to better integrate CNL practice into the VA include consolidation of lessons learned, collaboration to strengthen the evidence base for CNL practice, and further exploration of the transformational potential of CNL practice across the care continuum. PMID- 26636232 TI - Partnership Negotiations: Innovation for Nurse Contract Negotiations During Turbulent Times. AB - Health care delivery is undergoing rapid change, with frontline nurses at the epicenter. A mind-set requiring innovative collaboration, creativity, flexibility, and openness to new care delivery models is necessary. This article describes an innovative approach to modern world contract negotiations in a 371 bed university-affiliated hospital. The nurses' contract negotiations were scheduled to begin 6 months after a layoff affected nurses and other caregivers. Concurrently, a strike was underway at a hospital in the state with the same union. Contentious negotiations were anticipated. Strategies employed to prepare for negotiations included consultation with a nurse expert, and an agreement between the chief nursing officer and chairman of the Shared Governance Committee to conduct negotiations that would allow for more dialogue between the staff nurse and nursing leadership teams. Sessions opened with a video address by a major health care nurse thought leader who provided an overview of the current health care landscape and future direction of nursing. Joint presentations by staff nurses and nurse leaders on topics of interest were conducted. "Nurses for Nurses" round table sessions took place each day, and valuable work was completed at breakout sessions. Ultimately, the partnership negotiations resulted in a successfully negotiated contract. PMID- 26636233 TI - On the Scene: Developing a Nurse Care Coordinator Role at City of Hope. AB - We describe the development of an oncology solid tumor disease-focused care coordination model. Consistent with our strategic plan to provide patient- and family-centered care and to organize care around disease management teams, we developed the role of nurse care coordinator as an integral team member in our care delivery model. Managing a defined high-risk patient population across the care trajectory, these nurses provide stable points of contact and continuity for patients and families as they navigate the complex treatments and systems required to deliver cancer care. We describe role delineation and staffing models; role clarity between the role of the nurse care coordinator and the case manager; core curriculum development; the use of workflow management tools to support the touch points of the patient and members of the care team; and the incorporation of electronic medical records and data streams to inform the care delivery model. We identify measures that we will use to evaluate the success of our program. PMID- 26636234 TI - The HackensackUMC Value-Based Care Model: Building Essentials for Value-Based Purchasing. AB - The Affordable Care Act, 2010, and the subsequent shift from a quantity-focus to a value-centric reimbursement model led our organization to create the HackensackUMC Value-Based Care Model to improve our process capability and performance to meet and sustain the triple aims of value-based purchasing: higher quality, lower cost, and consumer perception. This article describes the basics of our model and illustrates how we used it to reduce the costs of our patient sitter program. PMID- 26636236 TI - Leading the Future We Envision: Nurturing a Culture of Innovation Across the Continuum of Care. AB - In the Fall of 2012, this large integrated health care system located in Northern California, comprising 21 hospitals and employing more than 25 000 nurses across all inpatient, outpatient, and continuum of care areas, embarked upon a comprehensive initiative to further engage the "hearts and minds" of its nursing workforce while establishing a foundation for innovation in an era of health care reform. This article will outline the strategy employed to ensure that professional nurses across the continuum of care were made aware of the impact of the Affordable Care Act. Major shifts to value-based care and improved performance expectations focus our attention on quality, service, and affordability, also known as the "Triple Aim." Transitioning from a volume focused model to a value-based care model requires measurable and sustainable improvements over current performance, reinforcing the importance of increased levels of engagement, shared accountability, and purposeful collaboration. Over a span of 18 months, the organization conducted 55 interactive educational forums for point-of-care care teams and leadership. These dynamic learning events helped recalibrate the working foundation for how leaders would nurture the process for innovation among care teams and transform care across the continuum of care. PMID- 26636235 TI - RN Diabetes Virtual Case Management: A New Model for Providing Chronic Care Management. AB - The U.S. chronic disease health care system has substantial gaps in delivery of services. New models of care change traditional delivery of care and explore new settings for care. This article describes a new model of diabetes chronic care delivery: nurse-delivered care that includes protocol-based insulin titration and patient education delivered solely in a virtual environment. In phase 1, the clinical outcome of time to achievement of glycated hemoglobin (A(1C)) goals (P < .001; 95% confidence interval, 1.68-2.24) was significantly improved by registered nurse (RN) standing order intervention (n = 24) as compared with historical controls (n = 28). In phase 2, patients who were referred to an RN managed insulin titration protocol with individualized A(1C) goals had a significant (P < .001; 95% confidence interval, 1.680-2.242) reduction in results from a mean of 9.6% at baseline to 7.7% at completion. Average patient age was 66 years, with a mean duration of 11 years diagnosed with diabetes. Safety was demonstrated by the absence of hypoglycemia related to RN protocol adjustment. There were no admissions or emergency room (ER) visits for hypoglycemia. This study demonstrates safety and efficacy of RN virtual chronic disease management for an older population of patients with long-standing diabetes. PMID- 26636237 TI - Impacting the Trajectory of Chronic Kidney Disease With ARPN-Led Renal Teams. AB - Health care reform demands improvements in population health and the patient experience while reducing costs. This demand is referred to as The Triple Aim of Improvement. A sense of urgency must be created for development of new models of care that impact outcomes earlier in the disease process. One new model of care addressing the triple aim is the Advanced Practice Registered Nurse (APRN)-Led Specialty Care Team. APRN-Led Specialty Care Team members engage patients and implement evidence at a point in the disease trajectory that is most likely to influence population outcomes, resources, and cost. In the pilot described in this article, a nurse practitioner, a registered nurse, a licensed practice nurse, a registered nurse certified diabetes educator, a registered dietitian, and a clinical pharmacist provided care to 20 patients with diabetes and chronic kidney disease, using the chronic disease trajectory model. The team was trained and supported through virtual technology and chronic kidney disease clinical decision-making tools. This APRN-Led Renal Specialty Care Team was embedded into primary care, using group appointments with nephrology support. Lessons learned regarding implementation, with a focus on the role of the nursing executive, are presented along with recommendations for future implementation. PMID- 26636238 TI - Leadership Transitions: What You Leverage for Success. PMID- 26636239 TI - The BSN Quest 50 Years After the 1965 Position Paper. PMID- 26636240 TI - Reply to Letter: "Robot-assisted Minimally Invasive Distal Pancreatectomy Is Superior to the Laparoscopic Technique". PMID- 26636241 TI - Reply to Letter: "Rationale for Heating Oxaliplatin for the Intraperitoneal Treatment of Peritoneal Carcinomatosis". PMID- 26636243 TI - Effect of Hospital Volume on Surgical Outcomes After Pancreaticoduodenectomy: A Systematic Review and Meta-analysis. AB - OBJECTIVE: The aim of the study was to evaluate the relationship between hospital volume and outcome after pancreaticoduodenectomy (PD). SUMMARY BACKGROUND DATA: Previous reviews for the hospital volume-outcome relationship after pancreatic resection were limited owing to clinical or methodological heterogeneity, resulting from differences in surgical procedures and high-volume hospital (HVH) definitions across studies. METHODS: We conducted a rigorous meta-analysis on the influence of hospital volume on various outcomes after PD using strict inclusion criteria and single cutoff values for HVHs. RESULTS: Thirteen studies based on nationwide databases from 11 countries, and including 58,023 patients in total, were included in this study. The overall pooled odds ratio (OR) for mortality favoring the HVH group was 2.37 [95% confidence interval (CI): 1.95-2.88] with high heterogeneity (I = 63%). We therefore classified all included studies into categories according to the cutoff values for HVH as defined in each individual study. The pooled OR for each category of 1 to 19, 20 to 29, and >=30 PDs per year was 1.94, 2.34, and 4.05, respectively. There were significant differences among these categories (I = 58.9%, P = 0.09). The 2 former categories showed no statistical interstudy heterogeneities. The data did not suggest publication bias. These trends persisted in all subgroup analyses. Postoperative length of stay in the HVH group was significantly shorter with mild interstudy heterogeneity. CONCLUSIONS: This meta-analysis included studies from different countries with disparate health care systems and provided strong evidence for an inverse association between higher hospital volume and lower mortality after PD. Variations in HVH cutoff values across studies majorly influenced the overall heterogeneity. PMID- 26636244 TI - A further consideration on long-acting injectable versus oral antipsychotics in the treatment of schizophrenia: a narrative review and critical appraisal. AB - INTRODUCTION: Many patients with schizophrenia exhibit difficulties in maintaining adherence to oral antipsychotics, calling for more reliable drug delivery systems. AREAS COVERED: While non-randomized studies have indicated consistent effectiveness of long-acting injectable antipsychotics (LAIs) over oral counterparts to prevent negative consequences such as relapse, hospitalization and all-cause discontinuation, efficacy results from randomized controlled comparative trials have not been that impressive. The results rely heavily on the study design and the population studied. Further, LAIs are frequently used as an adjunctive to ongoing other antipsychotics or psychotropics, but not solely, in the real world. EXPERT OPINION: To put LAI-oral comparisons into clinical context, the following information is urgently necessary: (1) How LAIs compare with each other in head-to-head comparisons? (2) How effective is it to switch among different LAIs? (3) How early in the treatment stage should LAIs be utilized? (4) How long the interval of LAI administration can be extended? (5) How LAIs compare with clozapine in head-to head comparisons? (6) How effective are LAIs when clozapine is ineffective? (7) How effective is clozapine when LAIs are ineffective? (8) How effective is it to combine clozapine and LAIs when neither is effective alone? This paper narratively discusses these critical perspectives. PMID- 26636245 TI - G1 checkpoint is compromised in mouse ESCs due to functional uncoupling of p53 p21Waf1 signaling. AB - Mouse embryonic stem cells (mESCs) lack of G1 checkpoint despite that irradiation (IR) activates ATM/ATR-mediated DDR signaling pathway. The IR-induced p53 localizes in the nuclei and up-regulates p21/Waf1 transcription but that does not lead to accumulation of p21/Waf1 protein. The negative control of the p21Waf1 expression appears to occur at 2 levels of regulation. First, both p21/Waf1 gene transcription and the p21/Waf1 protein content increase in mESCs treated with histone-deacetylase inhibitors, implying its epigenetic regulation. Second, proteasome inhibitors cause the p21/Waf1 accumulation, indicating that the protein is a subject of proteasome-dependent degradation in ESSs. Then, the dynamics of IR-induced p21Waf1 protein show its accumulation at long-term time points (3 and 5 days) that coincides with an increase in the proportion of G1 phase cells, down-regulation of Oct4 and Nanog pluripotent gene transcription and activation of endoderm-specific genes sox17 and afp. In addition, nutlin dependent stabilization of p53 in mESC was also accompanied by the accumulation of p21/Waf1 as well as restoration of G1 checkpoint and an onset of differentiation. Thus, the lack of functional p21/Waf1 is indispensable for maintaining self-renewal and pluripotency of mESCs. PMID- 26636246 TI - Quantitative Assessment of Knee Effusion-Synovitis in Older Adults: Association With Knee Structural Abnormalities. AB - OBJECTIVE: To describe the natural history of quantitatively measured knee effusion-synovitis and the longitudinal associations between effusion-synovitis and knee structural factors, including cartilage defects, cartilage volume, subchondral bone marrow lesions, and meniscal pathology, in older adults. METHODS: A total of 406 subjects (with a mean age of 63 years, 50% women) were randomly selected at baseline and followed up 2.7 years later. T2- or T1-weighted fat saturation magnetic resonance imaging was used to assess knee effusion synovitis maximal area, cartilage defects, cartilage volume, bone marrow lesions, and meniscal pathology at baseline and follow-up. Multivariable generalized linear regression was performed to analyze the associations between the maximal area of effusion-synovitis and other joint structural factors after adjustment for age, sex, body mass index, tibial bone area, and/or radiographic osteoarthritis (OA). RESULTS: Over 2.7 years of follow-up, the size of effusion synovitis increased in 29%, remained stable in 50%, and decreased in 22% of the participants. Baseline effusion-synovitis maximal area was significantly associated with changes in knee cartilage defects (beta = 0.18 [95% confidence interval (95% CI)] 0.07, 0.29), bone marrow lesions (beta = 0.17 [95% CI 0.05, 0.30]), and cartilage volume (beta = -0.40 [95% CI -0.71, -0.09]) but not with change in meniscal pathology. In contrast, baseline structural measures were not associated with change or increase in effusion-synovitis maximal area. CONCLUSION: Our findings indicate that knee effusion-synovitis is not static in older adults. It is predictive of, but not predicted by, other structural abnormalities, suggesting a potential role in early knee OA changes. PMID- 26636247 TI - Racial Disparities in Comorbidities, Complications, and Maternal and Fetal Outcomes in Women With Preeclampsia/eclampsia. AB - OBJECTIVE: The mechanisms leading to worse outcomes in African-American (AA) women with preeclampsia/eclampsia remain unclear. Our objective was to identify racial differences in maternal comorbidities, peripartum characteristics, and maternal and fetal outcomes. METHODS/RESULTS: When compared to white women with preeclampsia/eclampsia, AA women had an increased unadjusted risk of inpatient maternal mortality (OR 3.70, 95% CI: 2.19-6.24). After adjustment for covariates, in-hospital mortality for AA women remained higher than that for white women (OR 2.85, 95% CI: 1.38-5.53), while the adjusted risk of death among Hispanic women did not differ from that for white women. We also found an increased risk of intrauterine fetal death (IUFD) among AA women. When compared to white women with preeclampsia, AA women had an increased unadjusted odds of IUFD (OR 2.78, 95% CI: 2.49-3.11), which remained significant after adjustment for covariates (adjusted OR 2.45, 95% CI: 2.14-2.82). In contrast, IUFD among Hispanic women did not differ from that for white women after adjusting for covariates. CONCLUSIONS AND RELEVANCE: Our data suggest that African-American women are more likely to have risk factors for preeclampsia and more likely to suffer an adverse outcome during peripartum care. Future research should examine whether controlling co morbidities and other risk factors will help to alleviate racial disparities in outcomes in this cohort of women. PMID- 26636248 TI - Changes in mandibular incisor position and arch form resulting from Invisalign correction of the crowded dentition treated nonextraction. AB - OBJECTIVE: To investigate changes in mandibular incisor position resulting from Invisalign correction of the crowded dentition without extraction. MATERIALS AND METHODS: A retrospective chart review was completed on 61 adult White patients. Patients were categorized into three groups based on the value of pretreatment crowding of the lower dentition: 20 mild (2.0-3.9 mm), 22 moderate (4.0-5.9 mm), and 19 severe (>6.0 mm). Cephalometric radiographs were measured to determine lower incisor changes. Interproximal reduction and changes in arch width were also measured. Statistical evaluation of T0 and T1 values using paired t-tests and analysis of covariance were applied to evaluate mean value changes. RESULTS: Lower incisor position and angulation changes were statistically significant in the severe crowding group. There were no statistically significant differences in lower incisor position between the mild and moderate crowding groups. There was a statistically significant increase in buccal expansion in each of the three groups. CONCLUSIONS: Invisalign((r)) treatment can successfully resolve mandibular arch crowding using a combination of buccal arch expansion, interproximal reduction, and lower incisor proclination. When there is <6 mm of crowding, lower incisor position remained relatively stable. The lower incisors proclined and protruded in the more severely crowded dentitions (>6 mm). PMID- 26636249 TI - Sports participation with Chiari I malformation. AB - OBJECT There is currently no consensus on the safety of sports participation for patients with Chiari I malformation (CM-I). The authors' goal was to define the risk of sports participation for children with the imaging finding of CM-I. METHODS A prospective survey was administered to 503 CM-I patients at 2 sites over a 46-month period. Data were gathered on imaging characteristics, treatment, sports participation, and any sport-related injuries. Additionally, 81 patients completed at least 1 subsequent survey following their initial entry into the registry and were included in a prospective group, with a mean prospective follow up period of 11 months. RESULTS Of the 503 CM-I patients, 328 participated in sports for a cumulative duration of 4641 seasons; 205 of these patients participated in contact sports. There were no serious or catastrophic neurological injuries. One patient had temporary extremity paresthesias that resolved within hours, and this was not definitely considered to be related to the CM-I. In the prospective cohort, there were no permanent neurological injuries. CONCLUSIONS No permanent or catastrophic neurological injuries were observed in CM-I patients participating in athletic activities. The authors believe that the risk of such injuries is low and that, in most cases, sports participation by children with CM-I is safe. PMID- 26636250 TI - Adjuvant hypofractionated partial-brain radiation therapy for pediatric Ewing sarcoma brain metastases: case report. AB - This case report demonstrates that hypofractionated partial-brain radiation therapy with limited margins is a reasonable approach following gross tumor resection of Ewing sarcoma metastases to the brain. The patient presented with 2 intracranial metastases treated with gross-total resection followed by radiation therapy to 30 Gy in 5 fractions. The patient experienced symptomatic treatment related inflammatory changes with resolution after receiving dexamethasone. He remains alive at 21 months of follow-up with no evidence of disease. PMID- 26636251 TI - Risk factors for shunt malfunction in pediatric hydrocephalus: a multicenter prospective cohort study. AB - OBJECT The rate of CSF shunt failure remains unacceptably high. The Hydrocephalus Clinical Research Network (HCRN) conducted a comprehensive prospective observational study of hydrocephalus management, the aim of which was to isolate specific risk factors for shunt failure. METHODS The study followed all first time shunt insertions in children younger than 19 years at 6 HCRN centers. The HCRN Investigator Committee selected, a priori, 21 variables to be examined, including clinical, radiographic, and shunt design variables. Shunt failure was defined as shunt revision, subsequent endoscopic third ventriculostomy, or shunt infection. Important a priori-defined risk factors as well as those significant in univariate analyses were then tested for independence using multivariate Cox proportional hazard modeling. RESULTS A total of 1036 children underwent initial CSF shunt placement between April 2008 and December 2011. Of these, 344 patients experienced shunt failure, including 265 malfunctions and 79 infections. The mean and median length of follow-up for the entire cohort was 400 days and 264 days, respectively. The Cox model found that age younger than 6 months at first shunt placement (HR 1.6 [95% CI 1.1-2.1]), a cardiac comorbidity (HR 1.4 [95% CI 1.0 2.1]), and endoscopic placement (HR 1.9 [95% CI 1.2-2.9]) were independently associated with reduced shunt survival. The following had no independent associations with shunt survival: etiology, payer, center, valve design, valve programmability, the use of ultrasound or stereotactic guidance, and surgeon experience and volume. CONCLUSIONS This is the largest prospective study reported on children with CSF shunts for hydrocephalus. It confirms that a young age and the use of the endoscope are risk factors for first shunt failure and that valve type has no impact. A new risk factor-an existing cardiac comorbidity-was also associated with shunt failure. PMID- 26636252 TI - Growth patterns of craniopharyngiomas: clinical analysis of 226 patients. AB - OBJECT Craniopharyngiomas (CPs) are rare epithelial tumors that are often associated with an enigmatic and unpredictable growth pattern. Understanding the growth patterns of these tumors has a direct impact on surgical planning and may enhance the safety of radical tumor removal. The aim of this study was to analyze the growth patterns and surgical treatment of CPs with a focus on the involvement of the hypothalamopituitary axis and the relationship of the tumor to the arachnoid membrane and surrounding structures. METHODS Clinical data from 226 consecutive patients with primary CP were retrospectively reviewed. Tumor location and the relationship of the tumor to the third ventricle floor and the pituitary stalk were evaluated using preoperative MRI and intraoperative findings. A topographic classification scheme was proposed based on the site of tumor origin and tumor development. The clinical relevance of this classification on patient presentation and outcomes was also analyzed. RESULTS The growth of CPs can be broadly divided into 3 groups based on the site of tumor origin and on tumor-meningeal relationships: Group I, infrasellar/infradiaphragmatic CPs (Id CPs), which mainly occurred in children; Group II, suprasellar subarachnoid extraventricular CPs (Sa-CPs), which were mainly observed in adults and rarely occurred in children; and Group III, suprasellar subpial ventricular CPs (Sp CPs), which commonly occurred in both adults and children. Tumors in each group may develop complex growth patterns during vertical expansion along the pituitary stalk. Tumor growth patterns were closely related to both clinical presentation and outcomes. Patients with Sp-CPs had more prevalent weight gain than patients with Id-CPs or Sa-CPs; the rates of significant weight gain were 41.7% for children and 16.7% for adults with Sp-CPs, 2.2% and 7.1% for those with Id-CPs, and 12.5% and 2.6% for those with Sa-CPs (p < 0.001). Moreover, patients with Sp CPs had increased hypothalamic dysfunction after radical removal; 39% of patients with Sp-CPs, 14.5% with Id-CPs, and 17.4% with Sa-CPs had high-grade hypothalamic dysfunction in the first 2 postoperative years (p < 0.001). CONCLUSIONS The classification of CPs based on growth pattern may elucidate the best course of treatment for this formidable tumor. More tailored, individualized surgical strategies based on tumor growth patterns are mandatory to provide long-term tumor control and to minimize damage to hypothalamic structures. Differences in the distribution of growth patterns between children and adults imply that hierarchical comparison is necessary when investigating outcomes and survival across treatment paradigms in patients with CP. PMID- 26636253 TI - Editorial: Reducing the risk of shunt malfunction: beacons of light. PMID- 26636254 TI - Sports participation with arachnoid cysts. AB - OBJECT There is currently no consensus on the safety of sports participation for patients with an intracranial arachnoid cyst (AC). The authors' goal was to define the risk of sports participation for children with this imaging finding. METHODS A survey was prospectively administered to 185 patients with ACs during a 46-month period at a single institution. Cyst size and location, treatment, sports participation, and any injuries were recorded. Eighty patients completed at least 1 subsequent survey following their initial entry into the registry, and these patients were included in a prospective registry with a mean prospective follow-up interval of 15.9 +/- 8.8 months. RESULTS A total 112 patients with ACs participated in 261 sports for a cumulative duration of 4410 months or 1470 seasons. Of these, 94 patients participated in 190 contact sports for a cumulative duration of 2818 months or 939 seasons. There were no serious or catastrophic neurological injuries. Two patients presented with symptomatic subdural hygromas following minor sports injuries. In the prospective cohort, there were no neurological injuries CONCLUSIONS Permanent or catastrophic neurological injuries are very unusual in AC patients who participate in athletic activities. In most cases, sports participation by these patients is safe. PMID- 26636255 TI - Exploiting Transient Protein States for the Design of Small-Molecule Stabilizers of Mutant p53. AB - The destabilizing p53 cancer mutation Y220C creates an extended crevice on the surface of the protein that can be targeted by small-molecule stabilizers. Here, we identify different classes of small molecules that bind to this crevice and determine their binding modes by X-ray crystallography. These structures reveal two major conformational states of the pocket and a cryptic, transiently open hydrophobic subpocket that is modulated by Cys220. In one instance, specifically targeting this transient protein state by a pyrrole moiety resulted in a 40-fold increase in binding affinity. Molecular dynamics simulations showed that both open and closed states of this subsite were populated at comparable frequencies along the trajectories. Our data extend the framework for the design of high affinity Y220C mutant binders for use in personalized anticancer therapy and, more generally, highlight the importance of implementing protein dynamics and hydration patterns in the drug-discovery process. PMID- 26636257 TI - Detection and isolation of plant-associated bacteria scavenging atmospheric molecular hydrogen. AB - High-affinity hydrogen (H2 )-oxidizing bacteria possessing group 5 [NiFe] hydrogenase genes are important contributors to atmospheric H2 uptake in soil environments. Although previous studies reported the occurrence of a significant H2 uptake activity in vegetation, there has been no report on the identification and diversity of the responsible microorganisms. Here, we show the existence of plant-associated bacteria with the ability to consume atmospheric H2 that may be a potential energy source required for their persistence in plants. Detection of the gene hhyL - encoding the large subunit of group 5 [NiFe]-hydrogenase - in plant tissues showed that plant-associated high-affinity H2 -oxidizing bacteria are widely distributed in herbaceous plants. Among a collection of 145 endophytic isolates, seven Streptomyces strains were shown to possess hhyL gene and exhibit high- or intermediate-affinity H2 uptake activity. Inoculation of Arabidopsis thaliana (thale cress) and Oryza sativa (rice) seedlings with selected isolates resulted in an internalization of the bacteria in plant tissues. H2 uptake activity per bacterial cells was comparable between plant and soil, demonstrating that both environments are favourable for the H2 uptake activity of streptomycetes. This study first demonstrated the occurrence of plant-associated high-affinity H2 -oxidizing bacteria and proposed their potential contribution as atmospheric H2 sink. PMID- 26636256 TI - Structure of the Helicase Domain of DNA Polymerase Theta Reveals a Possible Role in the Microhomology-Mediated End-Joining Pathway. AB - DNA polymerase theta (Poltheta) has been identified as a crucial alternative non homologous end-joining factor in mammalian cells. Poltheta is upregulated in a range of cancer cell types defective in homologous recombination, and knockdown has been shown to inhibit cell survival in a subset of these, making it an attractive target for cancer treatment. We present crystal structures of the helicase domain of human Poltheta in the presence and absence of bound nucleotides, and a characterization of its DNA-binding and DNA-stimulated ATPase activities. Comparisons with related helicases from the Hel308 family identify several unique features. Poltheta exists as a tetramer both in the crystals and in solution. We propose a model for DNA binding to the Poltheta helicase domain in the context of the Poltheta tetramer, which suggests a role for the helicase domain in strand annealing of DNA templates for subsequent processing by the polymerase domain. PMID- 26636258 TI - CWD prions remain infectious after passage through the digestive system of coyotes (Canis latrans). AB - Chronic wasting disease (CWD) is a geographically expanding prion disease of wild and captive cervids in North America. Disease can be transmitted directly, animal to animal, or indirectly via the environment. CWD contamination can occur residually in the environment via soil, water, and forage following deposition of bodily fluids such as urine, saliva, and feces, or by the decomposition of carcasses. Recent work has indicated that plants may even take up prions into the stems and leaves. When a carcass or gut pile is present in the environment, a large number of avian and mammalian species visit and consume the carrion. Additionally, predators like coyotes, likely select for disease-compromised cervids. Natural cross-species CWD transmission has not been documented, however, passage of infectious prion material has been observed in the feces of crows. In this study we evaluated the ability of CWD-infected brain material to pass through the gastrointestinal tract of coyotes (Canis latrans) following oral ingestion, and be infectious in a cervidized transgenic mouse model. Results from this study indicate that coyotes can pass infectious prions via their feces for at least 3 days post ingestion, demonstrating that mammalian scavengers could contribute to the translocation and contamination of CWD in the environment. PMID- 26636259 TI - Workplace bullying, sleep problems and leisure-time physical activity: a prospective cohort study. AB - OBJECTIVES: Workplace bullying is a potent stressor that may increase sleep problems. Since physical fitness improves resilience to stress, it seems plausible that recreational physical activities may moderate the association between bullying and sleep. The study aimed to examine prospectively whether (i) bullying increases the risk of sleep problems, and (ii) the association between bullying and sleep problems is moderated by leisure-time physical activity (LTPA). METHODS: The study sample comprised a cohort of public and private sector employees, who were enrolled into the Work Bullying and Harassment (WBH) cohort (N=3278) or the Psychosocial Risk Factors for Stress and Mental Disease (PRISME) cohort (N=4455). We measured workplace bullying using one question that was preceded by a definition of bullying. We used the Karolinska sleep questionnaire to assess sleep problems. The number of hours per week spent on LTPA estimated the degree of physical activity. RESULTS: Workplace bullying at baseline (T1) was associated with awakening problems and lack of restful sleep at follow-up (T2) but not with overall sleep problems and disturbed sleep. T1-LTPA did not moderate the association between T1-workplace bullying and T2-sleep problems. CONCLUSION: We found support that workplace bullying is related to development of T2-sleep problems, but this association seems not to be modified by LTPA. PMID- 26636261 TI - Complementary Iron(II)-Catalyzed Oxidative Transformations of Allenes with Different Oxidants. AB - Substituent- and oxidant-dependent transformations of allenes are described. Given the profound influence of the substituent on the reactivity of allenes, the subtle differences in allene structures are manifested in the formation of diverse products when reacted with different electrophiles/oxidants. In general, reactions of nonsilylated allenes involve an allylic cation intermediate by forming a C-O bond, at the sp-hybridized C2, with either DDQ (2,3-dichloro-5,6 dicyano-p-benzoquinone) or TBHP (tert-butyl hydroperoxide), along with FeCl2?4 H2O (10 mol %). In contrast, silylated allenes favor the formation of propargylic cation intermediates by transferring the allenic hydride to the oxidant, thus generating 1,3-enynes (E1 product) or propargylic THBP ethers (S(N)1 product). The formation of these different putative cationic intermediates from nonsilylated and silylated allenes is strongly supported by DFT calculations. PMID- 26636260 TI - End Group Functionalization of PFpP Macromolecules Via Fp Migration Insertion Reactions. AB - PFpP macromolecules, synthesized via migration insertion polymerization of CpFe(CO)2 (CH2)3 PPh2 (FpP), exhibit reactive Fp end groups for further migration insertion reactions in the presence of phosphines. A number of alkyl diphenylphosphines with varied alkyl length, Ph2PCn (n = 6, 10, 18), have been prepared for the reaction, resulting in PFpP-PPh2Cn (n = 6, 10, 18) amphiphiles. The phosphines with longer alkyl chains impose steric hindrance for the reaction and therefore require longer reaction times and excess phosphines relative to PFpP. PMID- 26636262 TI - Characterization of (Glucurono)arabinoxylans from Oats Using Enzymatic Fingerprinting. AB - Cell wall material from whole oat grains was sequentially extracted to study the structural characteristics of individual arabinoxylan (AX) populations. Araf was singly substituted at both O-3 (mainly) and O-2 positions of Xylp, and no disubstitution of Xylp with Araf residues was found in oat AXs. Both highly substituted and sparsely substituted segments were found in AXs in Ba(OH)2 extracts, whereas AXs in 1 and 6 M NaOH extracts were rarely branched and easily aggregated. Both O-2-linked GlcA and 4-O-MeGlcA residues were present in oat AXs. A series of AX oligomers with galactose as a substituent was detected for the first time in oats. The present study suggested that the distribution of Araf was contiguous in oat AXs, different from the homogeneous distribution of Araf in wheat and barley AXs, which might result in different fermentation patterns in humans and animals. PMID- 26636263 TI - ACR Presidential Address: RethinkingRheumatology: A Brave New World. PMID- 26636264 TI - The Plasma Membrane as a Reservoir, Protective Shield, and Light-Triggered Launch Pad for Peptide Therapeutics. AB - Although peptide-based therapeutics are finding increasing application in the clinic, extensive structural modification is typically required to prevent their rapid degradation by proteases in the blood. We have evaluated the ability of erythrocytes to serve as reservoirs, protective shields (against proteases), and light-triggered launch pads for peptides. We designed lipidated peptides that are anchored to the surface of red blood cells, which furnishes a protease-resistant environment. A photocleavable moiety is inserted between the lipid anchor and the peptide backbone, thereby enabling light-triggered peptide release from erythrocytes. We have shown that a cell-permeable peptide, a hormone (melanocyte stimulating hormone), and a blood-clotting agent can be anchored to erythrocytes, protected from proteases, and photolytically released to create the desired biological effect. PMID- 26636266 TI - Impressions from the Frankfurt Book Fair. PMID- 26636267 TI - Reply by the Authors of the Original Article. PMID- 26636268 TI - Fast-growing tumor of the eyelid. PMID- 26636269 TI - Access to Versatile beta-Cyclodextrin Scaffolds through Guest-Mediated Monoacylation. AB - Herein, we report the selective mono-derivatization of heptakis[6-deoxy-6-(2 aminoethylsulfanyl)]-beta-CD (1) through a guest-mediated covalent capture strategy. The use of guests functionalized with cleavable linkers enables the installation of an amine-orthogonal thiol group on the primary rim of 1 as a handle for further transformations to the beta-CD scaffold. Applying this methodology, two novel monoderivatized beta-CDs were obtained in good yield and high purity. Both of these monoacylated CDs were amenable to facile linker cleavage and further modification at the resulting thiol group. This methodology can be applied towards the synthesis heterofunctionalized beta-CD constructs for analyte sensing, drug delivery, and other applications. PMID- 26636270 TI - Dynamic Inversion of Stereoselective Phosphate Binding to a Bisurea Receptor Controlled by Light and Heat. AB - A chiral bisurea anion receptor, derived from a first-generation molecular motor, can undergo photochemical and thermal isomerization operating as a reconfigurable system. The two possible cis configurations in the isomerization cycle are opposite in helicity, as is shown by CD spectroscopy. (1)H NMR titrations demonstrate that the P and M helical cis isomers hold opposite enantioselectivity in the binding of binol phosphate, while anion complexation by the intermediate trans isomer is not selective. The difference in the binding affinity of the enantiomers was rationalized by DFT calculations, revealing very distinct binding modes. Thus, the enantiopreferred substrate binding in this receptor can be inverted in a dynamic fashion using light and heat. PMID- 26636274 TI - Risk Adjustment for Determining Surgical Site Infection in Colon Surgery: Are All Models Created Equal? AB - BACKGROUND: Colon surgical site infections (SSIs) are being utilized increasingly as a quality measure for hospital reimbursement and public reporting. The Centers for Medicare and Medicaid Services (CMS) now require reporting of colon SSI, which is entered through the U.S. Centers for Disease Control and Prevention's National Healthcare Safety Network (NHSN). However, the CMS's model for determining expected SSIs uses different risk adjustment variables than does NHSN. We hypothesize that CMS's colon SSI model will predict lower expected infection rates than will NHSN. METHODS: Colon SSI data were reported prospectively to NHSN from 2012-2014 for the six Fairview Hospitals (1,789 colon procedures). We compared expected quarterly SSIs and standardized infection ratios (SIRs) generated by CMS's risk-adjustment model (age and American Society of Anesthesiologist [ASA] classification) vs. NHSN's (age, ASA classification, procedure duration, endoscope [including laparoscope] use, medical school affiliation, hospital bed number, and incision class). RESULTS: The patients with more complex colon SSIs were more likely to be male (60% vs. 44%; p = 0.011), to have contaminated/dirty incisions (21% vs. 10%; p = 0.005), and to have longer operations (235 min vs. 156 min; p < 0.001) and were more likely to be at a medical school-affiliated hospital (53% vs. 40%; p = 0.032). For Fairview Hospitals combined, CMS calculated a lower number of expected quarterly SSIs than did the NHSN (4.58 vs. 5.09 SSIs/quarter; p = 0.002). This difference persisted in a university hospital (727 procedures; 2.08 vs. 2.33; p = 0.002) and a smaller, community-based hospital (565 procedures; 1.31 vs. 1.42; p = 0.002). There were two quarters in which CMS identified Fairview's SIR as an outlier for complex colon SSIs (p = 0.05 and 0.04), whereas NHSN did not (p = 0.06 and 0.06). CONCLUSION: The CMS's current risk-adjustment model using age and ASA classification predicts lower rates of expected colon SSIs than does NHSN. This may lead to financial penalties because of the use of limited risk factors. Further efforts at elucidating appropriate risk adjustment measures without unnecessarily burdening hospitals with expensive data collection are necessary. PMID- 26636271 TI - Examining the Relationships Between Bone Tissue Composition, Compositional Heterogeneity, and Fragility Fracture: A Matched Case-Controlled FTIRI Study. AB - Fourier transform infrared imaging (FTIRI) provides information on spatial distribution of the chemical composition of thin tissue specimens at ~7 um spatial resolution. This study of 120 age- and bone mineral density (BMD)-matched patients was designed to investigate the association of FTIRI variables, measured in iliac crest biopsies, with fragility fractures at any site. An earlier study of 54 women found hip BMD to be a significant explanatory variable of fracture risk for cortical bone but not for cancellous bone. In the current study, where age and BMD were controlled through matching, no such association was observed, validating the pairing scheme. Our first study of unmatched iliac crest biopsies found increases in collagen maturity (cancellous and cortical bone) and mineral crystal size (cortical bone only) to be a significant explanatory variable of fracture when combined with other covariates. The ratio for collagen maturity has been correlated to the amount of enzymatic collagen cross-links. To assess the impact of other FTIRI variables (acid phosphate substitution, carbonate-to phosphate ratio, and the pixel distribution [heterogeneity] of all relevant FTIRI variables), we examined biopsies from a matched case-controlled study, in which 60 women with fractures were each paired with an age- and BMD-matched female control. With the matched data set of 120 women, conditional logistic regression analyses revealed that significant explanatory variables of fracture were decreased carbonate-to-phosphate ratio in both cancellous (odds ratio [OR] = 0.580, 95% confidence interval [CI] 0.37-0.909, p = 0.0176) and cortical bone (OR = 0.519, 95% CI 0.325-0.829, p = 0.0061), and increased heterogeneity (broadened pixel distribution) of collagen maturity for cancellous bone (OR = 1.549, 95% CI 1.002-2.396, p = 0.0491). The observation that collagen maturity was no longer linked to fracture in age- and BMD-matched samples suggests that age-dependent variation in collagen maturity may be a more important contributory factor to fragility fractures than previously thought. (c) 2015 American Society for Bone and Mineral Research. PMID- 26636275 TI - Effect of age and sex on jumping mechanography and other measures of muscle mass and function. AB - OBJECTIVES: Sarcopenia increases falls and fracture risk. Sarcopenia clinical trials require robust quantitative tools to evaluate muscle function; jumping mechanography (JM) is likely one such tool. However, US data comparing JM with traditional tests across the lifespan is limited. This study evaluated the effect of age and sex on JM compared with traditional function tests and lean mass. METHODS: US adults (213 women/119 men; mean age 65.4 years, range 27-96) performed functional tests including JM, Short Physical Performance Battery (SPPB) and grip strength (GS). Appendicular lean mass (ALM) was measured using DXA. RESULTS: Men had higher relative jump power [mean (SD) 28.5 (10.52) vs. 21.9 (7.11) W/kg], GS [35.5 (9.84) vs. 22.7 (6.98) kg] and ALM/ht(2) [8.25 (1.35) vs. 6.99 (1.38) kg/m2] (all p<0.0001); no difference was observed for SPPB components. JM parameters were more strongly correlated with age than traditional tests (R2=0.38-0.61 vs. R2=0.01-0.28) and weakly with GS and chair rise time (R2=0.30-0.36). CONCLUSION: JM parameters are correlated with GS and chair rise time and demonstrate stronger correlations with age. JM shows promise as a valuable tool to evaluate and monitor interventions for sarcopenia as it could potentially detect change in muscle function more precisely than existing tools. PMID- 26636276 TI - Traumatic brain injury and bone healing: radiographic and biomechanical analyses of bone formation and stability in a combined murine trauma model. AB - INTRODUCTION: The combination of traumatic brain injury (TBI) and long-bone fractures has previously been reported to lead to exuberant callus formation. The aim of this experimental study was to radiographically and biomechanically study the effect of TBI on bone healing in a mouse model. MATERIALS AND METHODS: 138 female C57/Black6N mice were assigned to four groups (fracture (Fx) / TBI / combined trauma (Fx/TBI) / controls). Femoral osteotomy and TBI served as variables: osteotomies were stabilized with external fixators, TBI was induced with controlled cortical impact injury. During an observation period of four weeks, in vivo micro-CT scans of femora were performed on a weekly basis. Biomechanical testing of femora was performed ex vivo. RESULTS: The combined trauma group showed increased bone volume, higher mineral density, and a higher rate of gap bridging compared to the fracture group. The combined-trauma group showed increased torsional strength at four weeks. DISCUSSION: TBI results in an increased formation of callus and mineral density compared to normal bone healing in mice. This fact combined with a tendency towards accelerated gap bridging leads to increased torsional strength. The present study underscores the empirical clinical evidence that TBI stimulates bone healing. Identification of underlying pathways could lead to new strategies for bone-stimulating approaches in fracture care. PMID- 26636277 TI - Differential effects of low-magnitude high-frequency vibration on reloading hind limb soleus and gastrocnemius medialis muscles in 28-day tail-suspended rats. AB - OBJECTIVES: Low-magnitude high-frequency vibration (LMHFV) was reported beneficial to muscle contractile functions in clinical and preclinical studies. This study aims to investigate the effects of LMHFV on myofibers, myogenic cells and functional properties of disused soleus (Sol) and gastrocnemius medialis (GM) during reloading. METHODS: Sprague Dawley rats were hind-limb unloaded for 28 days and assigned to reloading control (Ctrl) or LMHFV group (Vib). Sol and GM of both groups were harvested for fiber typing, proliferating myogenic cell counting and in vitro functional assessment. RESULTS: Myogenic cells proliferation was promoted by LMHFV in both Sol and GM (p<0.001 and p<0.05 respectively). Force generating capacity was not much affected (Vib=Ctrl, p>0.05) but fast-fiber favorable changes in fiber type switching (more type IIA but lower type I in Vib; p<0.05 and 0.01 respectively) and fiber hypertrophy (type I, Vib50 activities. Separate regression analyses for Cohorts A&B tested explanatory value of arm totBLI for DXA outcomes, accounting for gynecological age, height and whole body non-bone lean mass. RESULTS: In both cohorts, arm totBLI reflecting 3 years of peri-menarcheal activity exposure exhibited strong explanatory value for post-menarcheal radius and arm outcomes (squared semi-partial r =0.07-0.34, p<0.05), except Arm Area. For both cohorts and most outcomes, arm totBLI explained significant variance, even after adjusting for local muscle mass. CONCLUSIONS: In two independent cohorts, arm totBLI may consistently indicate osteogenic and sarcogenic properties of represented activities; additional research is necessary for further refinement and validation. PMID- 26636283 TI - A rare intramuscular myxoma of the hypothenar. PMID- 26636284 TI - Complex regional pain syndrome in a young female. PMID- 26636285 TI - Magnetocaloric Properties of Heterometallic 3d-Gd Complexes Based on the [Gd(oda)3 ](3-) Metalloligand. AB - A series of heterometallic 3d-Gd(3+) complexes based on a lanthanide metalloligand, [M(H2 O)6 ][Gd(oda)3 ]?3 H2 O [M=Cr(3+) (1-Cr)] (H2 oda=2,2' oxydiacetic acid), [M(H2 O)6 ][MGd(oda)3 ]2 ?3 H2 O [M=Mn(2+) (2-Mn), Fe(2+) (2 Fe) and Co(2+) (2-Co)], and [M3 Gd2 (oda)6 (H2 O)6 ]?12 H2 O [M=Ni(2+) (3-Ni), Cu(2+) (3-Cu), and Zn(2+) (3-Zn)], are reported. Magnetic and heat-capacity studies revealed a significant impact on the magnetocaloric effect depending on the anisotropy of the 3d transition metal ions, as confirmed by comparison of the observed maximum values of -DeltaSm between complexes 2-Co and 1-Cr. In these two complexes, the 3d metal ions have the same spin (S=3/2 for Co(2+) and Cr(3+) ions), and the theoretical calculation suggested a larger -DeltaSm value for 2-Co (47.8 J K(-1) kg(-1) ) than 1-Cr (37.5 J K(-1) kg(-1) ); however, the significant anisotropy of Co(2+) ions in 2-Co, which can result in smaller effective spins, gives a smaller value of -DeltaSm for 2-Co (32.2 J K(-1) kg(-1) ) than for 1-Cr (35.4 J K(-1) kg(-1) ) at DeltaH=9 T. PMID- 26636286 TI - Nonengraftment donor lymphocyte infusions for refractory acute myeloid leukemia. PMID- 26636287 TI - High-dose chemotherapy followed by autologous stem cell transplantation for relapsed/refractory primary mediastinal large B-cell lymphoma. PMID- 26636289 TI - The Lineage Specification of Mesenchymal Stem Cells Is Directed by the Rate of Fluid Shear Stress. AB - The effective regulation of fluid shear stress (FSS) on the lineage specification of mesenchymal stem cells (MSCs) remains to be addressed. We hypothesized that when MSCs are recruited to musculoskeletal system following stimulation, their differentiation into osteogenic or chondrogenic cells is directed by the rate of FSS (DeltaSS) through modulation of the mechanosensitive, cation-selective channels (MSCCs), intracellular calcium levels, and F-actin. To this end, MSCs were exposed to laminar FSS linearly increased from 0 to 10 dyn/cm(2) in 0, 2, or 20 min and maintained at 10 dyn/cm(2) for a total of 20 min (termed as DeltaSS 0 0', 0-2', and 0-20', respectively, representing more physiological (0-0') and non physiological (0-2' and 0-20') DeltaSS treatments). Our results showed 0-0' facilitated MSC differentiation towards chondrogenic and not osteogenic phenotype, by promoting moderate intracellular calcium concentration ([Ca(2+) ]i ) increase from the calcium channels with the exception of MSCCs or intracellular calcium stores, and F-actin organization. In contrast, 0-2' promoted MSCs towards osteogenic and not chondrogenic phenotype, by inducing significant [Ca(2+) ]i increase mainly from the MSCCs, and F-actin assembly. However, 0-20' elicited the modest osteogenic and chondrogenic phenotypes, as it induced the lowest [Ca(2+) ]i increase mainly from MSCCs, and F-actin assembly. Our results suggest that compared to the more physiological DeltaSS, the non-physiological DeltaSS favors [Ca(2+) ]i influx from MSCCs. An appropriate non-physiological DeltaSS (0-2') even elicits a large [Ca(2+) ]i influx from the MSCCs that reverses the lineage specification of MSCs, providing validation for the high mechanosensitivity of MSCs and guidance for training osteoporosis and osteoarthritis patients. J. Cell. Physiol. 231: 1752-1760, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26636288 TI - Lower expression of activating transcription factors 3 and 4 correlates with shorter progression-free survival in multiple myeloma patients receiving bortezomib plus dexamethasone therapy. AB - Bortezomib (BTZ), a proteasome inhibitor, is widely used in the treatment of multiple myeloma (MM), but a fraction of patients respond poorly to this agent. To identify factors predicting the duration of progression-free survival (PFS) of MM patients on BTZ treatment, the expression of proteasome and endoplasmic reticulum (ER) stress-related genes was quantified in primary samples from patients receiving a combination of BTZ and dexamethasone (BD). Fifty-six MM patients were stratified into a group with PFS<6 months (n=33) and a second group with PFS?6 months (n=23). Of the 15 genes analyzed, the expression of activating transcription factor 3 (ATF3) and ATF4 was significantly lower in patients with shorter PFS (P=0.0157 and P=0.0085, respectively). Chromatin immunoprecipitation analysis showed that these ATFs bind each other and transactivate genes encoding the pro-apoptotic transcription factors, CHOP and Noxa, which promote ER stress associated apoptosis. When either ATF3 or ATF4 expression was silenced, MM cells partially lost sensitivity to BTZ treatment. This was accompanied by lower levels of Noxa, CHOP and DR5. Thus low basal expression of ATF3 and ATF4 may attenuate BTZ-induced apoptosis. Hence, ATF3 and ATF4 could potentially be used as biomarkers to predict efficacy of BD therapy in patients with MM. PMID- 26636290 TI - Epstein-Barr and cytomegalovirus DNA salivary shedding correlate with long-term plasma HIV RNA detection in HIV-infected men who have sex with men. AB - The aim of the study was to evaluate cytomegalovirus (CMV) and Epstein-Barr virus (EBV) DNA salivary shedding in HIV-positive men who have sex with men (MSM) and to determine whether viro-immunological parameters and long-term (24 months) plasma HIV RNA (pHIV) detection may predict herpesviruses replication. A total of 193 HIV-positive MSM were consecutively recruited (mean CD4+ cell count 607 cells/mm(3) and mean nadir value 333 cells/mm(3) ); pHIV was analyzed for 24 months prior to saliva sampling: patients were categorized as successfully suppressed (SS) and not suppressed (NS). The EBV viral load was categorized as high viral load (HVL), intermediate (IVL), or low (LVL), CMV DNA as positive or negative. NS patients experienced both herpesviruses detectability more frequently respect to SS patients (P = 0.034); conversely, no salivary shedding was more frequent in SS patients (P = 0.014). HVL EBV was more frequent in NS patients than in SS subjects (P = 0.038 for isolated EBV detection and P = 0.001 when CMV shedding was associated). NS subjects with HVL EBV had a median pHIV of 43,820 copies/ml, significantly higher respect to IVL and LVL patients (P = 0.027 and P = 0.0005, respectively). CMV shedding was mostly associated to EBV shedding. NS patients showed a significantly higher frequency of saliva HVL EBV detection compared to SS patients; moreover, NS patients with HVL EBV had a higher pHIV respect to those with IVL and LVL shedding. Our results suggest that a successful pHIV suppression could reduce the burden of salivary EBV replication and likely the risk of herpesviruses-related cancers. PMID- 26636317 TI - Natural Attributes and Agricultural Implications of Somatic Genome Variation. AB - This article proposes the concept of genome network, describes different variations of the somatic genome network, and reviews the agricultural implications of such variations. All genetic materials in a cell constitute the genome network of the cell and can jointly influence the cell's function and fate. The somatic genome of a plant is the genome network of cells in somatic tissues and of nonreproductive cells in pollen and ovules. Somatic genome variation (SGV, approximately equivalent to somagenetic variation) occurs at multiple levels, including stoichiometric, ploidy, and sequence variations. For a multicellular organism, the term "somatic genome variation" covers both the variation in part of the organism and the generation of new genotype individuals through somatic means from a sexually produced original genotype. For unicellular organisms, genome variation in somatic nuclei occurs at the whole organism level because there is only a single cell per individual. Growth, development and evolution of living organisms require both stability and instability of their genomes. Somatic genome variation displays many more attributes than genetic mutation and has strong implications for agriculture. PMID- 26636319 TI - The Effects of Language Dominance in the Perception and Production of the Galician Mid Vowel Contrasts. AB - AIMS: This study investigates the perception and production of the Galician mid vowel contrasts by 54 early Spanish-Galician bilinguals in the cities of Vigo and Santiago (Galicia, Spain). Empirical data is provided to examine the role of language dominance in the perception and production of Galician mid vowel contrasts in order to determine whether the Galician vowel system is becoming more Spanish-like as a result of extensive contact with Spanish in urban areas. METHODS: Perception and production data for each mid vowel contrast were collected in (1) binary forced-choice identification tasks, (2) AX discrimination tasks and (3) a reading-aloud task. RESULTS: Results from binary forced-choice identification and AX discrimination tasks indicate that Spanish-dominant bilinguals have great difficulty in discriminating between these mid vowels while Galician-dominant subjects display a robust categorical identification of the two mid vowel categories. Acoustic analyses of their productions show that Galician dominant bilinguals implement a Galician-specific /e/-/x025B;/ contrast but Spanish-dominant ones produce a single, merged Spanish-like front mid vowel. However, both language dominance groups seem to maintain a more robust /o/ /x0254;/ contrast. This asymmetry between front and back mid vowels is found in the productions of both language dominance groups. CONCLUSION: These results show that language dominance is a strong predictor of the production and perception abilities of Spanish-Galician bilinguals, and that only Galician-dominant subjects in these urban areas possess two independent phonetic categories in the front and back mid vowel space. PMID- 26636318 TI - Early Hepatic Dysfunction Is Associated with a Worse Outcome in Patients Presenting with Acute Respiratory Distress Syndrome: A Post-Hoc Analysis of the ACURASYS and PROSEVA Studies. AB - INTRODUCTION: Bilirubin is well-recognized marker of hepatic dysfunction in intensive care unit (ICU) patients. Multiple organ failure often complicates acute respiratory distress syndrome (ARDS) evolution and is associated with high mortality. The effect of early hepatic dysfunction on ARDS mortality has been poorly investigated. We evaluated the incidence and the prognostic significance of increased serum bilirubin levels in the initial phase of ARDS. METHODS: The data of 805 patients with ARDS were retrospectively analysed. This population was extracted from two recent multicenter, prospective and randomised trials. Patients presenting with ARDS with a ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen < 150 mmHg measured with a PEEP >= 5 cm of water were included. The total serum bilirubin was measured at inclusion and at days 2, 4, 7 and 14. The primary objective was to analyse the bilirubin at inclusion according to the 90-day mortality rate. RESULTS: The 90-day mortality rate was 33.8% (n = 272). The non-survivors were older, had higher Sepsis-related Organ Failure Assessment (SOFA) score and were more likely to have a medical diagnosis on admission than the survivors. At inclusion, the SOFA score without the liver score (10.3+/-2.9 vs. 9.0+/-3.0, p<0.0001) and the serum bilirubin levels (36.1+/-57.0 vs. 20.5+/-31.5 MUmol/L, p<0.0001) were significantly higher in the non-survivors than in the survivors. Age, the hepatic SOFA score, the coagulation SOFA score, the arterial pH level, and the plateau pressure were independently associated with 90-day mortality in patients with ARDS. CONCLUSION: Bilirubin used as a surrogate marker of hepatic dysfunction and measured early in the course of ARDS was associated with the 90-day mortality rate. PMID- 26636320 TI - Decreased Risk of Colorectal Cancer after Colonoscopy in Patients 76-85 Years Old in the United States. AB - BACKGROUND/AIMS: The benefits of colonoscopy in reducing colorectal cancer (CRC) risk for patients over 75 years are controversial. We aimed to determine whether colonoscopy use is associated with a decreased risk of CRC in patients 76-85 years old in the United States (US). PATIENTS AND METHODS: All patients in the Medicare 5% random sample of the Surveillance, Epidemiology and End Results Medicare linked database 76-85 years old at outpatient colonoscopy between January 1, 1998 and December 31, 2002 were identified. Using the Kaplan-Meier method, we estimated the cumulative incidence of CRC in the above-mentioned colonoscopy group and compared with the control group of patients without colonoscopy. All patients were followed until diagnosis of CRC or carcinoma in situ, death or December 31, 2005. The multivariate Cox proportional hazards model was used in statistical analysis. CRC was separated by location into distal vs. proximal CRC in subgroup analysis. RESULTS: Of 5,701 patients in the colonoscopy group, 37 (0.65%) patients were diagnosed with CRC, compared to 379 (1.55%) out of 24,437 patients in the control group (p < 0.001). The cumulative incidences of distal and proximal CRC were lower in the colonoscopy group compared to those in the control group (5-year distal CRC: 0.26 vs. 0.77%; 5-year proximal CRC: 0.43 vs. 0.79%, both p < 0.05). In multivariate Cox regression, colonoscopy was associated with decreased risk of all CRC (hazard ratio ((HR) 0.42, 95% CI 0.28 0.65), distal CRC (HR 0.36, 95% CI 0.18-0.70), and proximal CRC (HR 0.53, 95% CI 0.30-0.92)). CONCLUSION: Among patients 76-85 years old in the United States, colonoscopy use was associated with decreased risks of both distal and proximal CRC, with a smaller risk reduction in distal colon. Due to inherent limitations associated with our retrospective design, future prospective studies are needed to validate these findings. PMID- 26636321 TI - Identification of Peptide Inhibitors of Enveloped Viruses Using Support Vector Machine. AB - The peptides derived from envelope proteins have been shown to inhibit the protein-protein interactions in the virus membrane fusion process and thus have a great potential to be developed into effective antiviral therapies. There are three types of envelope proteins each exhibiting distinct structure folds. Although the exact fusion mechanism remains elusive, it was suggested that the three classes of viral fusion proteins share a similar mechanism of membrane fusion. The common mechanism of action makes it possible to correlate the properties of self-derived peptide inhibitors with their activities. Here we developed a support vector machine model using sequence-based statistical scores of self-derived peptide inhibitors as input features to correlate with their activities. The model displayed 92% prediction accuracy with the Matthew's correlation coefficient of 0.84, obviously superior to those using physicochemical properties and amino acid decomposition as input. The predictive support vector machine model for self- derived peptides of envelope proteins would be useful in development of antiviral peptide inhibitors targeting the virus fusion process. PMID- 26636322 TI - Transcript Quantification by RNA-Seq Reveals Differentially Expressed Genes in the Red and Yellow Fruits of Fragaria vesca. AB - Fragaria vesca (2n = 2x = 14), the woodland strawberry, is a perennial herbaceous plant with a small sequenced genome (240 Mb). It is commonly used as a genetic model plant for the Fragaria genus and the Rosaceae family. Fruit skin color is one of the most important traits for both the commercial and esthetic value of strawberry. Anthocyanins are the most prominent pigments in strawberry that bring red, pink, white, and yellow hues to the fruits in which they accumulate. In this study, we conducted a de novo assembly of the fruit transcriptome of woodland strawberry and compared the gene expression profiles with yellow (Yellow Wonder, YW) and red (Ruegen, RG) fruits. De novo assembly yielded 75,426 unigenes, 21.3% of which were longer than 1,000 bp. Among the high-quality unique sequences, 45,387 (60.2%) had at least one significant match to an existing gene model. A total of 595 genes, representing 0.79% of total unigenes, were differentially expressed in YW and RG. Among them, 224 genes were up-regulated and 371 genes were down-regulated in the fruit of YW. Particularly, some flavonoid biosynthetic pathway genes, including C4H, CHS, CHI, F3H, DFR and ANS, as well as some transcription factors (TFs), including MYB (putative MYB86 and MYB39), WDR and MADS, were down-regulated in YW fruit, concurrent with a reduction in anthocyanin accumulation in the yellow pigment phenotype, whereas a putative transcription repressor MYB1R was up-regulated in YW fruit. The altered expression levels of the genes encoding flavonoid biosynthetic enzymes and TFs were confirmed by quantitative RT-PCR. Our study provides important insights into the molecular mechanisms underlying the yellow pigment phenotype in F. vesca. PMID- 26636323 TI - Time-Dependent Transcriptional Changes in Axenic Giardia duodenalis Trophozoites. AB - Giardia duodenalis is the most common gastrointestinal protozoan parasite of humans and a significant contributor to the global burden of both diarrheal disease and post-infectious chronic disorders. Although G. duodenalis can be cultured axenically, significant gaps exist in our understanding of the molecular biology and metabolism of this pathogen. The present study employed RNA sequencing to characterize the mRNA transcriptome of G. duodenalis trophozoites in axenic culture, at log (48 h of growth), stationary (60 h), and declining (96 h) growth phases. Using ~400-times coverage of the transcriptome, we identified 754 differentially transcribed genes (DTGs), mainly representing two large DTG groups: 438 that were down-regulated in the declining phase relative to log and stationary phases, and 281 that were up-regulated. Differential transcription of prominent antioxidant and glycolytic enzymes implicated oxygen tension as a key factor influencing the transcriptional program of axenic trophozoites. Systematic bioinformatic characterization of numerous DTGs encoding hypothetical proteins of unknown function was achieved using structural homology searching. This powerful approach greatly informed the differential transcription analysis and revealed putative novel antioxidant-coding genes, and the presence of a near-complete two component-like signaling system that may link cytosolic redox or metabolite sensing to the observed transcriptional changes. Motif searching applied to promoter regions of the two large DTG groups identified different putative transcription factor-binding motifs that may underpin global transcriptional regulation. This study provides new insights into the drivers and potential mediators of transcriptional variation in axenic G. duodenalis and provides context for static transcriptional studies. PMID- 26636324 TI - Quality and Cost of Diabetes Mellitus Care in Community Health Centers in the United States. AB - OBJECTIVE: To examine variations in the quality and cost of care provided to patients with diabetes mellitus by Community Health Centers (CHCs) compared to other primary care settings. RESEARCH DESIGN AND METHODS: We used data from the 2005-2008 Medical Expenditure Panel Survey (N = 2,108). We used two dependent variables: quality of care and ambulatory care expenditures. Our primary independent variable was whether the respondent received care in a Community Health Centers (CHCs) or not. We estimated logistic regression models to determine the probability of quality of care, and used generalized linear models with log link and gamma distribution to predict expenditures for CHC users compared to non-users of CHCs, conditional on patients with positive expenditures. RESULTS: Results showed that variations of quality between CHC users and non-CHC users were not statistically significant. Patients with diabetes mellitus who used CHCs saved payers and individuals approximately $1,656 in ambulatory care costs compared to non-users of CHCs. CONCLUSIONS: These findings suggest an opportunity for policymakers to control costs for diabetes mellitus patients without having a negative impact on quality of care. PMID- 26636325 TI - The importance of sensitive screening for abnormal glucose metabolism in patients with IgA nephropathy. AB - AIM: To investigate the prevalence of abnormal glucose metabolism, insulin resistance (IR) and the related risk factors in IgA nephropathy (IgAN) patients. METHODS: We analyzed oral glucose tolerance test (OGTT) and clinical data of 107 IgAN patients and 106 healthy controls. Glucose metabolism, homeostasis model assessment of insulin resistance (HOMA-IR) and the insulin sensitivity index (ISI) of both groups were evaluated. RESULTS: The prevalence of abnormal glucose metabolism was significantly higher in the IgAN group than in the control group (41.12% vs. 9.43%, p < 0.001), while the prevalence of IR between the two groups was not significantly different. IgAN patients have significantly higher fasting blood glucose, fasting insulin, OGTT 2-hour blood glucose, OGTT 2-hour insulin, HOMA-IR, and lower ISI than healthy controls. Triglyceride (OR = 2.55), 24-hour urine protein excretion (OR = 1.39), and age (OR = 1.06) were independent risk factors for abnormal glucose metabolism in IgAN patients. BMI, eGFR, 24-hour urine protein excretion, triglyceride, fasting blood glucose, fasting insulin, OGTT 2-hour blood glucose, and OGTT 2-hour insulin were significantly higher in IgAN patients with IR than in IgAN patients without IR, while HDL and ISI were significantly lower. BMI, serum albumin, and 24-hour urine protein excretion were correlated factors of IR in IgAN patients. CONCLUSIONS: Our study highlighted that abnormal glucose metabolism was common in IgAN patients. Triglyceride and 24 hour urine protein excretion were significant risk factors for abnormal glucose metabolism. Therefore, sensitive screening for glucose metabolism status and timely intervention should be carried out in clinical work. PMID- 26636326 TI - Meta-analysis of the efficacy and safety of nucleotide/nucleoside analog monotherapy for hepatitis B virus-associated glomerulonephritis. AB - BACKGROUND/AIMS: Antiviral monotherapy is recommended for hepatitis B virus associated glomerulonephritis (HBV-GN) treatment. Although considered superior to interferon-I+/- in several respects, nucleotide/nucleoside analog (NA) monotherapy has not been studied. This metaanalysis evaluates the efficacy and safety of NA monotherapy for treating HBV-GN. METHODS: We searched for controlled clinical trials of NA monotherapy for HBVGN in the MEDLINE, Embase, Cochrane Library, Chinese BioMedical Literature on disc, Chinese National Knowledge Infrastructure, and Wanfang databases. Primary outcome measures were proteinuria remission, HBV-DNA negative conversion rate, and hepatitis B e-antigen (HBeAg) clearance. Secondary outcome measures were variations in proteinuria, serum albumin, alanine aminotransferase (ALT), and serum creatinine (Scr). RESULTS: Ten trials involving 325 patients were included: four randomized controlled trials, two cohort clinical trials, and four self-controlled studies. Based on the fixed effects model, we found significant proteinuria remission rate improvement in the NA group (relative risk (RR): 3.60, 95% confidence interval (CI): 1.99 a?? 6.50), negative conversion rate of HBV-DNA (RR: 2.20, 95% CI: 1.55 a?? 3.13), and clearance of HBeAg (RR: 4.49, 95% CI: 1.29 a?? 15.67). Improvement in ALT (mean difference (MD): 56.60, 95% CI: 50.41 a?? 62.79) was found with the fixedeffects model, and a slight decrease in Scr (MD: 25.25, 95% CI: a??17.11 a?? 67.61, p = 0.24) was shown. CONCLUSIONS: HBV-GN proteinuria remission with elevated serum albumin, decreased HBV replication, and improved HBeAg clearance could be achieved using NA monotherapy. Furthermore, NA monotherapy may protect renal function in HBV-GN patients by preventing Scr elevation. PMID- 26636327 TI - Development, validation, and implementation of a medication adherence survey to seek a better understanding of the hemodialysis patient. AB - BACKGROUND: Factors contributing to non-adherence have become a priority for clinicians, healthcare policy makers, and healthcare payers alike. Patients who are non-adherent to their medication regimen appear to have poor health outcomes, with evidence of both high mortality rates and high morbidity in the form of more frequent emergency room admissions, recurrent exacerbations of disease, and poor overall well-being. The primary objective of this study was to identify and describe patient-identified factors associated with non-adherence in patients maintained on chronic hemodialysis. METHODS: A 23-item questionnaire was developed and validated for use in the hemodialysis population. This questionnaire was administered to patients undergoing chronic hemodialysis in a single center during the period of October to December 2013. RESULTS: A total of 156/183 eligible patients consented. Of these 156 patients, 36 (23%) patients reported being non-adherent. The most common non-adherent behaviors were changing the frequency of taking medications and skipping doses. Patients identified information gaps around medication interactions, the flexibility around drug timings, and how best to manage medications that needed to be taken apart from, with, or without food. CONCLUSIONS: Our study shows that, despite an intensive drug education program, almost one quarter of patients continue to have problems with taking medication and that traditional education around medications is insufficient. We propose that clinicians customize education to the patient driven gaps in knowledge, in particular focusing on the education needed to empower patients to recognize which aspects of their care they can and should modify and which aspects require further clinician input. PMID- 26636328 TI - Acute kidney injury (AKI) outcome, a predictor of long-term major adverse cardiovascular events (MACE). AB - BACKGROUND AND OBJECTIVES: The incidence of acute kidney injury (AKI) in hospitalized patients is increasing. Many of these patients survive the immediate post-AKI period and may be prone to developing long-term complications of AKI. This study aimed to determine whether complete recovery following an episode of AKI is associated with a lower risk of long-term major adverse cardiovascular events (MACE). DESIGN: Retrospective cohort study. SETTING AND PARTICIPANTS: Adults admitted to the University of Virginia Medical Center between January 1, 2002 and December 31, 2012 who developed hospital-acquired AKI. PREDICTOR: AKI was defined as an increase in serum creatinine (SCr) by a?Y 0.3 mg/dL from the baseline and or requirement for acute dialysis during index hospitalization. Complete recovery was defined as a return of SCr to less than 1.25 times the baseline value and not dialysis dependent. Outcome and measurement: MACE was defined as subsequent admission for myocardial infarction, stroke or transient ischemic attach and heart failure using ICD- 9-CM codes. RESULTS: Overall, 11,538 patients survived beyond 90 days of AKI and had data available for analysis. Of the 9,673 survivors of AKI in whom recovery could be assessed, 7170 (74.12%) had complete renal recovery. MACE occurred in 27.28% of our study population over a median follow-up period of 399 days. 28.19% of patients who completely recovered renal function developed MACE, while only 32.48% did in those who did not recover completely. Patients who had complete recovery had a lower risk of long-term MACE when compared with those without complete recovery (adjusted hazard ratio 95% confidence interval (CI): 0.774 (0.713, 0.842)). LIMITATION: Measurement of albuminuria was not available. CONCLUSION: Complete renal recovery after an episode of AKI in patients with normal baseline kidney function is associated with a lower risk of long-term MACE when compared with those who did not fully recover. PMID- 26636329 TI - Minimal change disease: an unusual presentation of marginal zone MALT lymphoma. AB - Minimal change disease (MCD) in association with low-grade extra-nodal marginal zone B-cell lymphoma (MZL) of mucosa-associated lymphoid tissue (MALT) (MALT lymphoma) is a rare clinicopathologic entity. We report a 68-year-old male who presented with nephrotic range proteinuria as the first manifestation of underlying MZL, confirmed with standard set of investigations. Being a steroid non-responder, he was treated with rituximab demonstrating a marked response with resolution of proteinuria. However, he relapsed after 3 months. Upon relapse, a combination of rituximab and bendamustine (R-Benda) was initiated achieving sustained resolution of proteinuria. No additional treatment was administered and the proteinuria has remained in remission for over a year. PMID- 26636330 TI - A case of mistaken identity: fibrillary glomerulonephritis masquerading as crescentic anti-glomerular basement membrane disease. AB - Fibrillary glomerulonephritis (FGN) is a rare cause of rapidly progressive glomerulonephritis (RPGN). We report a case of FGN in which the patient presented with a clinical pulmonary-renal syndrome and whose kidney biopsy showed > 90% crescents on light microscopy. Immunofluorescence microscopy showed pseudo-linear IgG and C3 staining of the glomerular capillary walls resulting in an initial diagnosis of crescentic glomerulonephritis of anti-glomerular basement membrane (anti-GBM) antibody etiology. Electron microscopy showed fibrillary deposits permeating the glomerular capillary walls, characteristic of FGN. Although dialysis dependent at presentation and anuric at discharge, the patient recovered adequate renal function and urine output to come off dialysis at 20 weeks. A follow up biopsy performed at this stage showed progression of the underlying chronic kidney disease. This is the third reported case of FGN with a clinical presentation and histologic and immunofluorescence microscopic findings that closely mimicked anti-GBM antibody mediated disease. These cases demonstrate that FGN is a rare but important consideration in the differential diagnosis of RPGN. PMID- 26636331 TI - Patient characteristics, disease burden, and medication use in stage 4 - 5 chronic kidney disease patients. AB - AIMS: We aimed to assess demographic characteristics, comorbidity and hospitalization burdens, laboratory abnormalities, and patterns of chronic kidney disease (CKD)-related medication use in a large cohort of patients with CKD stage 4 - 5. METHODS: In a retrospective cohort analysis, the Medicare 5% sample and Truven MarketScan employer group health plan databases were used to examine patients aged >= 65 and < 65 years, respectively. CKD was determined by >= 1 inpatient or >= 2 outpatient claims with relevant ICD-9-CM diagnosis codes during the 1-year baseline period. The follow-up period was 1 year from day 91 after the index date RESULTS: In the Medicare data, 12,930 (1.1%) CKD stage 4 - 5 patients were identified. Mean age was 79.2 +/- 7.4 years; 56.1% were women and 83.1% white; 46.8% had atherosclerotic heart disease, and 36.9% congestive heart failure; 37.9% were hospitalized within 1 year. In the MarketScan data, 6,010 (0.04%) patients were identified. Mean age was 55.2 +/- 8.8 years; 48.0% were women; 21.4% were hospitalized within 1 year. Heart failure was the leading cause of hospitalization for both groups. Parathyroid hormone levels were > 300 pg/mL for 39.1% of MarketScan patients, but only 20.9% received activated vitamin D. ESAs were administered to 28.2% of MarketScan patients with iron saturation < 30% and to 7.7% with hemoglobin > 11.5% and saturation >= 30%. CONCLUSIONS: Comorbidity burdens and hospitalization rates were high for patients with advanced, non-dialysis requiring CKD. While hyperparathyroidism and anemia were common, appropriate medication use was not optimal, suggesting opportunities for improved care. PMID- 26636332 TI - Prawn Shell Chitosan Has Anti-Obesogenic Properties, Influencing Both Nutrient Digestibility and Microbial Populations in a Pig Model. AB - The potential of natural products to prevent obesity have been investigated, with evidence to suggest that chitosan has anti-obesity effects. The current experiment investigated the anti-obesity potential of prawn shell derived chitosan on a range of variables relevant to obesity in a pig model. The two dietary treatment groups included in this 63 day study were: T1) basal diet and T2) basal diet plus 1000 ppm chitosan (n = 20 gilts per group (70 +/- 0.90 kg). The parameter categories which were assessed included: performance, nutrient digestibility, serum leptin concentrations, nutrient transporter and digestive enzyme gene expression and gut microbial populations. Pigs offered chitosan had reduced feed intake and final body weight (P< 0.001), lower ileal digestibility of dry matter (DM), gross energy (GE) (P< 0.05) and reduced coefficient of apparent total tract digestibility (CATTD) of gross energy and nitrogen (P<0.05) when compared to the basal group. Fatty acid binding protein 2 (FABP2) gene expression was down-regulated in pigs offered chitosan (P = 0.05) relative to the basal diet. Serum leptin concentrations increased (P< 0.05) in animals offered the chitosan diet compared to pigs offered the basal diet. Fatness traits, back fat depth (mm), fat content (kg), were significantly reduced while lean meat (%) was increased (P<0.05) in chitosan supplemented pigs. Pigs offered chitosan had decreased numbers of Firmicutes in the colon (P <0.05), and Lactobacillus spp. in both the caecum (P <0.05) and colon (P <0.001). Bifidobacteria populations were increased in the caecum of animals offered the chitosan diet (P <0.05). In conclusion, these findings suggest that prawn shell chitosan has potent anti obesity/body weight control effects which are mediated through multiple biological systems in vivo. PMID- 26636333 TI - The Role of Right Inferior Parietal Cortex in Auditory Spatial Attention: A Repetitive Transcranial Magnetic Stimulation Study. AB - Behavioral studies support the concept of an auditory spatial attention gradient by demonstrating that attentional benefits progressively diminish as distance increases from an attended location. Damage to the right inferior parietal cortex can induce a rightward attention bias, which implicates this region in the construction of attention gradients. This study used event-related potentials (ERPs) to define attention-related gradients before and after repetitive transcranial magnetic stimulation (rTMS) to the right inferior parietal cortex. Subjects (n = 16) listened to noise bursts at five azimuth locations (left to right: -90 degrees , -45 degrees , 0 degrees midline, +45 degrees , +90 degrees ) and responded to stimuli at one target location (-90 degrees , +90 degrees , separate blocks). ERPs as a function of non-target location were examined before (baseline) and after 0.9 Hz rTMS. Results showed that ERP attention gradients were observed in three time windows (frontal 230-340, parietal 400-460, frontal 550-750 ms). Significant transient rTMS effects were seen in the first and third windows. The first window had a voltage decrease at the farthest location when attending to either the left or right side. The third window had on overall increase in positivity, but only when attending to the left side. These findings suggest that rTMS induced a small contraction in spatial attention gradients within the first time window. The asymmetric effect of attended location on gradients in the third time window may relate to neglect of the left hemispace after right parietal injury. Together, these results highlight the role of the right inferior parietal cortex in modulating frontal lobe attention network activity. PMID- 26636334 TI - Compass Cells in the Brain of an Insect Are Sensitive to Novel Events in the Visual World. AB - The central complex of the insect brain comprises a group of neuropils involved in spatial orientation and memory. In fruit flies it mediates place learning based on visual landmarks and houses neurons that encode the orientation for goal directed locomotion, based on landmarks and self-motion cues for angular path integration. In desert locusts, the central complex holds a compass-like representation of head directions, based on the polarization pattern of skylight. Through intracellular recordings from immobilized locusts, we investigated whether sky compass neurons of the central complex also represent the position or any salient feature of possible landmarks, in analogy to the observations in flies. Neurons showed strongest responses to the novel appearance of a small moving square, but we found no evidence for a topographic representation of object positions. Responses to an individual square were independent of direction of motion and trajectory, but showed rapid adaptation to successive stimulation, unaffected by changing the direction of motion. Responses reappeared, however, if the moving object changed its trajectory or if it suddenly reversed moving direction against the movement of similar objects that make up a coherent background-flow as induced by ego-motion. Response amplitudes co-varied with the precedent state of dynamic background activity, a phenomenon that has been related to attention-dependent saliency coding in neurons of the mammalian primary visual cortex. The data show that neurons of the central complex of the locust brain are visually bimodal, signaling sky compass direction and the novelty character of moving objects. These response properties might serve to attune compass-aided locomotor control to unexpected events in the environment. The difference to data obtained in fruit flies might relate to differences in the lifestyle of landmark learners (fly) and compass navigators (locust), point to the existence of parallel networks for the two orientation strategies, or reflect differences in experimental conditions. PMID- 26636335 TI - Additive Anti-Tumor Effects of Lovastatin and Everolimus In Vitro through Simultaneous Inhibition of Signaling Pathways. AB - BACKGROUND: The mTORC1-inhibitor everolimus shows limited efficacy in treating patients with gastro-entero-pancreatic or pulmonary neuroendocrine tumors (NETs), and poor outcome in patients with malignant pheochromocytoma or hepatic carcinoma. We speculated that any effect may be enhanced by antogonising other signaling pathways. METHODS: Therefore, we tested the effect of lovastatin--known to inhibit both ERK and AKT signaling--and everolimus, separately and in combination, on cell viability and signaling pathways in human midgut (GOT), pancreatic (BON1), and pulmonary (H727) NET, hepatocellular carcinoma (HepG2, Huh7), and mouse pheochromocytoma (MPC, MTT) cell lines. RESULTS: Lovastatin and everolimus separately significantly reduced cell viability in H727, HepG2, Huh7, MPC and MTT cells at clinically relevant doses (P <= 0.05). However, high doses of lovastatin were necessary to affect GOT or BON1 cell viability. Clinically relevant doses of both drugs showed additive anti-tumor effects in H727, HepG2, Huh7, MPC and MTT cells (P <= 0.05), but not in BON1 or GOT cells. In all cell lines investigated, lovastatin inhibited EGFR and AKT signaling. Subsequently, combination treatment more strongly inhibited EGFR and AKT signaling than everolimus alone, or at least attenuated everolimus-induced EGFR or AKT activation. Vice versa, everolimus constantly decreased pp70S6K and combination treatment more strongly decreased pp70S6K than lovastatin alone, or attenuated lovastatin-induced p70S6K activation: in BON1 cells lovastatin-induced EGFR inhibition was least pronounced, possibly explaining the low efficacy and consequent absent additive effect. CONCLUSION: In summary, clinically relevant doses of lovastatin and everolimus were effective separately and showed additive effects in 5 out of 7 cell lines. Our findings emphasize the importance of targeting several interacting signaling pathways simultaneously when attempting to attenuate tumor growth. However, the variable reactions of the different cell lines highlight the necessity to understand the unique molecular aberrations in any tumor. Nevertheless, this combination seems worthy of being tested in vivo. PMID- 26636336 TI - The Role of H3K4me3 in Transcriptional Regulation Is Altered in Huntington's Disease. AB - Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder resulting from expansion of CAG repeats in the Huntingtin (HTT) gene. Previous studies have shown mutant HTT can alter expression of genes associated with dysregulated epigenetic modifications. One of the most widely studied chromatin modifications is trimethylated lysine 4 of histone 3 (H3K4me3). Here, we conducted the first comprehensive study of H3K4me3 ChIP-sequencing in neuronal chromatin from the prefrontal cortex of six HD cases and six non-neurologic controls, and its association with gene expression measured by RNA-sequencing. We detected 2,830 differentially enriched H3K4me3 peaks between HD and controls, with 55% of them down-regulated in HD. Although H3K4me3 signals are expected to be associated with mRNA levels, we found an unexpected discordance between altered H3K4me3 peaks and mRNA levels. Gene ontology (GO) term enrichment analysis of the genes with differential H3K4me3 peaks, revealed statistically significantly enriched GO terms only in the genes with down-regulated signals in HD. The most frequently implicated biological process terms are organ morphogenesis and positive regulation of gene expression. More than 9,000 H3K4me3 peaks were located not near any recognized transcription start sites and approximately 36% of these "distal" peaks co-localized to known enhancer sites. Six transcription factors and chromatin remodelers are differentially enriched in HD H3K4me3 distal peaks, including EZH2 and SUZ12, two core subunits of the polycomb repressive complex 2 (PRC2). Moreover, PRC2 repressive state was significantly depleted in HD-enriched peaks, suggesting the epigenetic role of PRC2 inhibition associated with up-regulated H3K4me3 in Huntington's disease. In summary, our study provides new insights into transcriptional dysregulation of Huntington's disease by analyzing the differentiation of H3K4me3 enrichment. PMID- 26636338 TI - Inhibition of Plasmodium berghei Development in Mosquitoes by Effector Proteins Secreted from Asaia sp. Bacteria Using a Novel Native Secretion Signal. AB - Novel interventions are needed to prevent the transmission of the Plasmodium parasites that cause malaria. One possible method is to supply mosquitoes with antiplasmodial effector proteins from bacteria by paratransgenesis. Mosquitoes have a diverse complement of midgut microbiota including the Gram-negative bacteria Asaia bogorensis. This study presents the first use of Asaia sp. bacteria for paratransgenesis against P. berghei. We identified putative secreted proteins from A. bogorensis by a genetic screen using alkaline phosphatase gene fusions. Two were secreted efficiently: a siderophore receptor protein and a YVTN beta-propeller repeat protein. The siderophore receptor gene was fused with antiplasmodial effector genes including the scorpine antimicrobial peptide and an anti-Pbs21 scFv-Shiva1 immunotoxin. Asaia SF2.1 secreting these fusion proteins were fed to mosquitoes and challenged with Plasmodium berghei-infected blood. With each of these effector constructs, significant inhibition of parasite development was observed. These results provide a novel and promising intervention against malaria transmission. PMID- 26636337 TI - Center-Related Determinants of VKA Anticoagulation Quality: A Prospective, Multicenter Evaluation. AB - BACKGROUND: Center-specific TTR (c-TTR) is a measure reporting the mean patient TTR within an anticoagulation clinic describing the quality of anticoagulant monitoring offered by that clinic. c-TTR has a considerable between-center variation, but its determinants are poorly understood. OBJECTIVES: We aimed at evaluating which clinical, procedural or laboratory factors could be associated with c-TTR variability in a multicenter, observational cross-sectional study over a five-year period. PATIENTS/METHODS: Data from 832,204 individual patients followed for VKA therapy in 292 Centers affiliated with the Italian Federation of Anticoagulation Clinics (FCSA) were analyzed. c-TTR was computed based on the TTR of patients followed at each Center, and a mixed linear regression model was used for a predefined set of explanatory variables. RESULTS: The Center next-visit interval ratio (the mean number of days after a visit with an INR outside the therapeutic range, divided by the days after a visit with an INR within the therapeutic range), the Center mean patient INR and the Center laboratory performance at EQA proficiency testing were the only variables that were independently associated with c-TTR (beta-coefficients -17.32, 9.67, and -0.11, respectively; r2 = 0.635). CONCLUSIONS: These findings suggest that c-TTR associates with proactive strategies aimed at keeping patients very close to their target INR with a prompt re-evaluation of those patients with under- or over-therapeutic INR. PMID- 26636339 TI - Increased Blood Levels of Growth Factors, Proinflammatory Cytokines, and Th17 Cytokines in Patients with Newly Diagnosed Type 1 Diabetes. AB - The production of several cytokines could be dysregulated in type 1 diabetes (T1D). In particular, the activation of T helper (Th) type 1 (Th1) cells has been proposed to underlie the autoimmune pathogenesis of the disease, although roles for inflammatory processes and the Th17 pathway have also been shown. Nevertheless, despite evidence for the role of cytokines before and at the onset of T1D, the corresponding findings are inconsistent across studies. Moreover, conflicting data exist regarding the blood cytokine levels in T1D patients. The current study was performed to investigate genetic and autoantibody markers in association with the peripheral blood cytokine profiles by xMap multiplex technology in newly diagnosed young T1D patients and age-matched healthy controls. The onset of young-age T1D was characterized by the upregulation of growth factors, including granulocyte macrophage-colony stimulating factor (GM CSF) and interleukin (IL)-7, the proinflammatory cytokine IL-1beta (but not IL-6 or tumor necrosis factor [TNF]-alpha), Th17 cytokines, and the regulatory cytokines IL-10 and IL-27. Ketoacidosis and autoantibodies (anti-IA-2 and -ZnT8), but not human leukocyte antigen (HLA) genotype, influenced the blood cytokine levels. These findings broaden the current understanding of the dysregulation of systemic levels of several key cytokines at the young-age onset of T1D and provide a further basis for the development of novel immunoregulatory treatments in this disease. PMID- 26636340 TI - Overexpression of Lin28 Decreases the Chemosensitivity of Gastric Cancer Cells to Oxaliplatin, Paclitaxel, Doxorubicin, and Fluorouracil in Part via microRNA-107. AB - Higher Lin28 expression is associated with worse pathologic tumor responses in locally advanced gastric cancer patients undergoing neoadjuvant chemotherapy. However, the characteristics of Lin28 and its mechanism of action in chemotherapy resistance is still unclear. In this study, we found that transfection of Lin28 into gastric cancer cells (MKN45 and MKN28) increased their resistance to the chemo-drugs oxaliplatin (OXA), paclitaxel (PTX), doxorubicin (ADM), and fluorouracil (5-Fu) compared with gastric cancer cells transfected with a control vector. When knockdown Lin28 expression by Lin28 small interfering RNA (siRNA) was evaluated in vitro, we found that the resistance to chemo-drugs was reduced. Furthermore, we found that Lin28 up-regulates C-myc and P-gp and down-regulates Cylin D1. Finally, we found that miR-107 is a target microRNA of Lin28 and that it participates in the mechanism of chemotherapy resistance. Our results suggest that the Lin28/miR-107 pathway could be one of many signaling pathways regulated by Lin28 and associated with gastric cancer chemo-resistance. PMID- 26636341 TI - The Majority of Resorptions in Old Mice Are Euploid. AB - Chromosomal abnormality is a leading cause of aging-related infertility, spontaneous abortion and congenital birth defects in humans. Karyotype analyses of spontaneously aborted human fetuses reveal high proportions (~50%) being chromosomal abnormal with the majority being trisomies of various chromosomes. As a model organism, mice are widely used for studies of reproduction and reproductive aging. Like older women, older mice exhibit high incidences of early embryo death. However, it is not known if aneuploidy is prevalent amongst resorptions in older mice. We have karyotyped 65 retarded/resorbed fetuses in 10 month-old C57BL/6 mice, and found that 55 (84.6%+/-8.8%, with 95% confidence) were euploid. Similarly, of 40 such fetuses from 17 month-old C57BL/6 mice, we found 38 (95+/-7%, with 95% confidence 95%) being euploid. Therefore, aneuploidy is not a leading cause of embryo death in older mice. PMID- 26636342 TI - Mechanics of aligned carbon nanotube polymer matrix nanocomposites simulated via stochastic three-dimensional morphology. AB - The promise of enhanced and tailored properties motivates the study of one dimensional nanomaterials, especially aligned carbon nanotubes (A-CNTs), for the reinforcement of polymeric materials. While CNTs have remarkable theoretical properties, previous work on aligned CNT polymer matrix nanocomposites (A-PNCs) reported mechanical properties that are orders of magnitude lower than those predicted by rule of mixtures. This large difference primarily originates from the morphology of the CNTs, because the CNTs that comprise the A-PNCs have significant local curvature commonly referred to as waviness. Here we present a simulation framework capable of analyzing 10(5) wavy CNTs with realistic three dimensional morphologies to quantify the impact of waviness on the effective elastic modulus contribution of wavy CNTs. The simulation results show that due to the low shear modulus of the reinforcing CNT 'fibers', and large ([Formula: see text]) compliance contribution of the shear deformation mode, waviness reduces the effective stiffness contribution of the A-CNTs by two to three orders of magnitude. Also, the mechanical property predictions resulting from the simulation framework outperform those previously reported using finite element analysis since representative descriptions of the morphology are required to accurately predict properties of the A-PNCs. Further work to quantify the morphology of A-PNCs in three-dimensions, simulate their full non-isotropic constitutive relations, and predict their failure mechanisms is planned. PMID- 26636343 TI - Organic-Inorganic Hybrid Ternary Bulk Heterojunction of Nanostructured Perovskite Low Bandgap Polymer-PCBM for Improved Efficiency of Organic Solar Cells. AB - A new organic-inorganic ternary bulk heterojunction (TBHJ) hybrid configuration comprised of nanostructured (CH3)3NHPbI3 (MAPbI3) perovskite-low bandgap PCPDTBT PCBM was investigated. Well-organized TBHJ films were readily prepared by sequential spin-casting of sparsely covered MAPbI3 nano dots and PCPDTBT-PCBM bulk heterojunction (BHJ) composites on ITO/PEDOT:PSS substrates. The TBHJ hybrid device configuration comprising diiooctane (DIO) treated MAPbI3 perovskite nano dots and a PCPDTBT-PCBM BHJ composite processed with DIO additive exhibited excellent performances. The DIO additive played a key role in developing perovskite structures of MAPbI3 nano dots and induced the (110) directional crystallinity growth of longitudinal constructive morphologies such as nano rods. The improved photocurrent and fill factor compared to those of conventional BHJ devices led to an increase in efficiency of ~28%. This improved photovoltaic performance originated from the higher quantum efficiencies contributed by the charge transfer from nanostructured MAPbI3 perovskite to PCBM. These TBHJs composed of nanostructured MAPbI3 perovskite, PCPDTBT, and PCBM also facilitated the exciton dissociation in the multi-BHJ system between MAPbI3 perovskite, PCPDTBT, and PCBM. PMID- 26636344 TI - Optical Behaviors of Cholesteric Liquid-Crystalline Polyester Composites with Various Chiral Photochromic Dopants. AB - New developments in the field of chiral nematic liquid crystals, such as color displays, are now being widely proposed. This article describes the tunable incident reflection band based on composite materials of low-molecular-weight chiroptical dopants and polymeric networks. These materials have advantages including easily manageable color according to a change in the helical pitch of the cholesteric liquid crystal upon exposure to light. A series of novel chiral dopants of isosorbide derivatives containing photochromic groups and three new main-chain liquid crystalline polyesters were synthesized and identified using nuclear magnetic resonance (NMR), Fourier transform infrared spectroscopy (FTIR), and elemental analyses. The phase-transition temperatures and the liquid-crystal phase determination of the synthesized polymers were estimated using DSC, WAXD, and POM analyses. The influence of the dopant concentrations and the solubility in a liquid crystalline polymer blend were also studied. The reflection band of the cholesteric liquid crystalline composites could be adjusted and tuned with a wide range of color variation across the entire visible region. A real image recording of the chiral photochromic liquid crystalline polymer blend was achieved by exposing it to UV light through a mask. PMID- 26636345 TI - Heterobimetallic Complexes That Bond Vanadium to Iron, Cobalt, and Nickel. AB - Zero-valent iron, cobalt, and nickel were installed into the metalloligand V[N(o (NCH2P((i)Pr)2)C6H4)3] (1, VL), generating the heterobimetallic trio FeVL (2), CoVL (3), and NiVL (4), respectively. In addition, the one-electron-oxidized analogues [FeVL]X ([2(ox)]X, where X(-) = BPh4 or PF6) and [CoVL]BPh4 ([3(ox)]BPh4) were prepared. The complexes were characterized by a host of physical methods, including cyclic voltammetry, X-ray crystallography, magnetic susceptibility, electronic absorption, NMR, electron paramagnetic resonance (EPR), and Mossbauer spectroscopies. The CoV and FeV heterobimetallic compounds have short M-V bond lengths that are consistent with M-M multiple bonding. As revealed by theoretical calculations, the M-V bond is triple in 2, 2(ox), and 3(ox), double in 3, and dative (Ni -> V) in 4. The (d-d)(10) species, 2 and 3(ox), are diamagnetic and exhibit large diamagnetic anisotropies of -4700 * 10( 36) m(3)/molecule. Complexes 2 and 3(ox) are also characterized by intense visible bands at 760 and 610 nm (epsilon > 1000 M(-1) cm(-1)), respectively, which correspond to an intermetal (M -> V) charge-transfer transition. Magnetic susceptibility measurements and EPR characterization establish S = (1)/2 ground states for (d-d)(9) 2(ox) and (d-d)(11) 3, while (d-d)(12) 4 is S = 1 based on Evans' method. PMID- 26636346 TI - Titanium and Zirconium Hydride-Catalyzed Regioselective Isomerization of 1,4 Dihydrofulvenes: Access to 1-Substituted 1,2-Dihydrofulvenes. AB - Zirconium hydride-catalyzed C?C double bond migration from nonconjugated to conjugated dienes is described. Applied to 1-substituted 1,4-dihydrofulvenes, the migration leads selectively to 1-substituted 1,2-dihydrofulvenes. The C?C double bond migration can also be catalyzed by titanium hydride, allowing a one-pot procedure to provide 1-substituted 1,2-dihydrofulvenes from pentafulvenes via two titanium-catalyzed steps. This sequence was proven to be temperature-dependent, allowing the selective access to a conjugated or nonconjugated adduct by a simple temperature tuning. The synthetic potential of the methodology was illustrated by the diastereoselective synthesis of a polyhydroxycyclopentane. PMID- 26636347 TI - Evolution of the Single-Nanocrystal Photoluminescence Linewidth with Size and Shell: Implications for Exciton-Phonon Coupling and the Optimization of Spectral Linewidths. AB - The optimization of photoluminescence spectral linewidths in semiconductor nanocrystal preparations involves minimizing both the homogeneous and inhomogeneous contributions to the ensemble spectrum. Although the inhomogeneous contribution can be controlled by eliminating interparticle inhomogeneities, far less is known about how to synthetically control the homogeneous, or single nanocrystal, spectral linewidth. Here, we use solution photon-correlation Fourier spectroscopy (S-PCFS) to measure how the sample-averaged single-nanocrystal emission linewidth of CdSe core and core/shell nanocrystals change with systematic changes in the size of the cores and the thickness and composition of the shells. We find that the single-nanocrystal linewidth at room temperature is heavily influenced by the nature of the CdSe surface and the epitaxial shell, which have a profound impact on the internal electric fields that affect exciton phonon coupling. Our results explain the wide variations, both experimental and theoretical, in the magnitude and size dependence in previous reports on exciton phonon coupling in CdSe nanocrystals. Moreover, our findings offer a general pathway for achieving the narrow spectral linewidths required for many applications of nanocrystals. PMID- 26636348 TI - Revealing Chemical Processes Involved in Electrochemical (De)Lithiation of Al with in Situ Neutron Depth Profiling and X-ray Diffraction. AB - Herein we report a direct measurement of Li transport in real-time during charge and discharge process within an Al matrix using neutron depth profiling (NDP). In situ NDP was used to reveal and quantify parasitic losses during the first 25 mAhr/g of lithiation, followed by the formation of LiAl protrusions from the surface of pristine Al. Evidence of Li entrapment is also reported during delithiation. Subsequent lithiation and delithiation showed electrochemical charge passed to be equivalent to the amount of lithium incorporated into the Al matrix with negligible difference, suggesting that the parasitic losses including the formation of the solid electrolyte layer may be confined to the first lithiation. Parallel in situ XRD measurements also confirm the transformation of beta-LiAl from a solid solution of alpha-LiAl, revealing solid solution-mediated crystallization of beta-LiAl. PMID- 26636349 TI - Correction to "Understanding the Excited State Behavior of Cyclometalated Bis(tridentate)ruthenium(II) Complexes: A Combined Experimental and Theoretical Study". PMID- 26636350 TI - Spectroscopic Evidence for Through-Space Arene-Sulfur-Arene Bonding Interaction in m-Terphenyl Thioether Radical Cations. AB - Electronic absorption spectra and quantum chemical calculations of the radical cations of m-terphenyl tert-butyl thioethers, where the S-t-Bu bond is forced to be perpendicular to the central phenyl ring, show the occurrence of through-space [pi...S...pi](+) bonding interactions which lead to a stabilization of the thioether radical cations. In the corresponding methyl derivatives there is a competition between delocalization of the hole that is centered on a p-AO of the S atom into the pi-system of the central phenyl ring or through space into the flanking phenyl groups, which leads to a mixture of planar and perpendicular conformations in the radical cation. Adding a second m-terphenyl tert-butyl thioether moiety does not lead to further delocalization; the spin and charge remain in one of the two halves of the radical cation. These findings have interesting implications with regard to the role of methionines as hopping stations in electron transfer through proteins. PMID- 26636351 TI - Computing Nonequilibrium Conformational Dynamics of Structured Nucleic Acid Assemblies. AB - Synthetic nucleic acids can be programmed to form precise three-dimensional structures on the nanometer-scale. These thermodynamically stable complexes can serve as structural scaffolds to spatially organize functional molecules including multiple enzymes, chromophores, and force-sensing elements with internal dynamics that include substrate reaction-diffusion, excitonic energy transfer, and force-displacement response that often depend critically on both the local and global conformational dynamics of the nucleic acid assembly. However, high molecular weight assemblies exhibit long time-scale and large length-scale motions that cannot easily be sampled using all-atom computational procedures such as molecular dynamics. As an alternative, here we present a computational framework to compute the overdamped conformational dynamics of structured nucleic acid assemblies and apply it to a DNA-based tweezer, a nine layer DNA origami ring, and a pointer-shaped DNA origami object, which consist of 204, 3,600, and over 7,000 basepairs, respectively. The framework employs a mechanical finite element model for the DNA nanostructure combined with an implicit solvent model to either simulate the Brownian dynamics of the assembly or alternatively compute its Brownian modes. Computational results are compared with an all-atom molecular dynamics simulation of the DNA-based tweezer. Several hundred microseconds of Brownian dynamics are simulated for the nine-layer ring origami object to reveal its long time-scale conformational dynamics, and the first ten Brownian modes of the pointer-shaped structure are predicted. PMID- 26636352 TI - Perfluoroalkyl Acids Inhibit Reductive Dechlorination of Trichloroethene by Repressing Dehalococcoides. AB - The subsurface recalcitrance of perfluoroalkyl acids (PFAAs) derived from aqueous film-forming foams could have adverse impacts on the microbiological processes used for the bioremediation of co-mingled chlorinated solvents such as trichloroethene (TCE). Here, we show that reductive dechlorination by a methanogenic, mixed culture was significantly inhibited when exposed to concentrations representative of PFAA source zones (>66 mg/L total of 11 PFAA analytes, 6 mg/L each). TCE dechlorination, cis-dichloroethene and vinyl chloride production and dechlorination, and ethene generation were all inhibited at these PFAA concentrations. Phylogenetic analysis revealed that the abundances of 65% of the operational taxonomic units (OTUs) changed significantly when grown in the presence of PFAAs, although repression or enhancement resulting from PFAA exposure did not correlate with putative function or phylogeny. Notably, there was significant repression of Dehalococcoides (8-fold decrease in abundance) coupled with a corresponding enhancement of methane-generating Archaea (a 9-fold increase). Growth and dechlorination by axenic cultures of Dehalococcoides mccartyi strain 195 were similarly repressed under these conditions, confirming an inhibitory response of this pivotal genus to PFAA presence. These results suggest that chlorinated solvent bioattenuation rates could be impeded in subsurface environments near PFAA source zones. PMID- 26636353 TI - Binding of DNA-Intercalating Agents to Oxidized and Reduced Quinone Reductase 2. AB - Quinone reductase 2 (NQO2) is an enzyme that might have intracellular signaling functions. NQO2 can exist in either an oxidized state or a reduced state, and binding of compounds to one or both of these states inhibits enzymatic activity and could also affect intracellular signaling. A wide range of planar aromatic compounds bind NQO2, and we have identified three DNA-intercalating agents [ethidium bromide, acridine orange (AO), and doxorubicin] as novel nanomolar inhibitors of NQO2. Ethidium and AO, which carry a positive charge in their aromatic ring systems, bound reduced NQO2 with an affinity 50-fold higher than that of oxidized NQO2, while doxorubicin bound only oxidized NQO2. Crystallographic analyses of oxidized NQO2 in complex with the inhibitors indicated that the inhibitors were situated deep in the active site. The aromatic faces were sandwiched between the isoalloxazine ring of FAD and the phenyl ring of F178, with their edges making direct contact with residues lining the active site. In reduced NQO2, ethidium and AO occupied a more peripheral position in the active site, allowing several water molecules to interact with the polar end of the negatively charged isoalloxazine ring. We also showed that AO inhibited NQO2 at a nontoxic concentration in cells while ethidium was less effective at inhibiting NQO2 in cells. Together, this study shows that reduced NQO2 has structural and electrostatic properties that yield a preference for binding of planar, aromatic, and positively charged molecules that can also function as DNA intercalating agents. PMID- 26636354 TI - Determination of Protein Surface Hydration by Systematic Charge Mutations. AB - Protein surface hydration is critical to its structural stability, flexibility, dynamics, and function. Recent observations of surface solvation on picosecond time scales have evoked debate on the origin of such relatively slow motions, from hydration water or protein charged side chains, especially with molecular dynamics simulations. Here we used a unique nuclease with a single tryptophan as a local probe and systematically mutated three neighboring charged residues to differentiate the contributions from hydration water and charged side chains. By various mutations of one, two, and all three charged residues, we observed slight increases in the total tryptophan Stokes shifts with fewer neighboring charged residue(s) and found insensitivity of charged side chains to the relaxation patterns. The dynamics is correlated with hydration water relaxation with the slowest time in a dense charged environment and the fastest time at a hydrophobic site. On such picosecond time scales, the protein surface motion is restricted. The total Stokes shifts are dominantly from hydration water relaxation and the slow dynamics is from water-driven relaxation, coupled to local protein fluctuations. PMID- 26636355 TI - Revised Basis Sets for the LANL Effective Core Potentials. AB - We suggest a new contraction of the basis sets associated with the Hay-Wadt relativistic effective core potentials (RECPs) for the main group and transition metal atoms. These bases are more suitable for density functional theory investigations than the previous 'double-zeta' contractions based upon Hartree Fock atomic results. The original Hay-Wadt primitives are now contracted [5s5p3d], [4s4p3d], and [4s4p3d] for the first, second, and third transition series, respectively, and denoted as LANL2TZ basis sets. For the main group atoms, we advocate using a completely uncontracted basis denoted LANL08. While modestly extending the size of the basis, the resulting sets should be suitable for both DFT and wave function based approaches. The valence bases for the transition metal atoms can be supplemented with the polarization functions determined by Frenking. PMID- 26636356 TI - Combined Electrostatically Embedded Multiconfiguration Molecular Mechanics and Molecular Mechanical Method: Application to Molecular Dynamics Simulation of a Chemical Reaction in Aqueous Solution with Hybrid Density Functional Theory. AB - We here combine the electrostatically embedded multiconfiguration molecular mechanics (EE-MCMM) method for generating global potential energy surfaces in the presence of an electrostatic potential with molecular mechanics (MM). The resulting EE-MCMM/MM method is illustrated by applying it to carry out a molecular dynamics simulation for the symmetric bimolecular reaction Cl(-) + CH3Cl' -> ClCH3 + Cl'(-) in aqueous solution with hybrid density functional theory as the quantum mechanical level. The potential of mean force is calculated, and the free energy barrier is found to be 25.3 kcal/mol, which is in good agreement with previous work. The advantage of the combined EE-MCMM and MM method is that the number of quantum mechanical calculations required for the active subsystem is very small compared to straight direct dynamics. PMID- 26636357 TI - Ab Initio Molecular Dynamics Study of a Highly Concentrated LiCl Aqueous Solution. AB - The properties of a highly concentrated aqueous lithium chloride solution (|LiCl| = 14 mol L(-1)) are investigated using Car-Parrinello molecular dynamics. The coordination spheres of lithium ions, chloride ions, and water molecules are described successively. On the whole, our simulation provides results-distances and coordination numbers-in very good agreement with experimental data. The lithium solvation shell is found to exhibit a tetrahedral configuration on average, with three stable clusters observed during the simulation: Li(+)-4H2O, Li(+)(H2O)3Cl(-), and Li(+)(H2O)2(Cl(-))2. The chloride coordination sphere is logically formed by strong Cl-H hydrogen bonds with neighboring water molecules, for a mean coordination number of 4.4. The structuring of water molecules is strongly affected by the high concentration in LiCl. The hydrogen bond network is globally broken down, but little variation is calculated on water dipoles (MU = 3.07 D) because of the strong polarization from Li(+) and Cl(-) ions. We also point out some of the characteristic features of such a highly concentrated solution: water bridging between Li(+) and Cl(-) hydration spheres, Li(+)-Cl(-) ion-pairing, and intermediate behavior between dilute solutions and molten salts. Finally, the reliability of our simulation to describe ion-pairing is discussed. PMID- 26636358 TI - First Principles Study of Alkali-Tyrosine Complexes: Alkali Solvation and Redox Properties. AB - The oxidation of alkali-tyrosinate to radical alkali-tyrosine in aqueous solution is studied using ab initio Car-Parrinello molecular dynamics (CPMD). The aim is to investigate the cation-pi interactions between alkali cations M and the aromatic ring of tyrosine, in gas phase and in aqueous solution, using the influence of the cation M on the reaction M(+)(Tyr(-)) -> M(+)(Tyr(*)) + e(-) as a probe. To this end, we calculate the redox potential and the reorganization free energy using a CPMD-based method derived from the Marcus theory of electron transfer. We discuss the redox properties of Tyr, Na(+)(Tyr), and K(+)(Tyr), in reduced and oxidized states, by analyzing selected interatomic distances, coordination numbers, and charge populations. Our results confirm the known inversion in the relative stabilities of Na(+)(Tyr) and K(+)(Tyr) in going from gas phase to solution and point to a stronger cation-pi affinity of K(+) in solution. PMID- 26636359 TI - Electronic Structure Calculation of MgO (001) Surface with Aggregated Oxygen Vacancies. AB - The electronic structure of an MgO (001) surface with aggregated oxygen vacancies at the surface was investigated by using a density-functional embedded-cluster method using Mg45Ox (x = 39-45) clusters and the B3LYP/CEP-121G level of calculation. The investigation found that the distribution of energy levels corresponding to oxygen-vacancy states strongly depends on the number and configuration of oxygen vacancies. Molecular orbitals of the oxygen vacancy states consist of orbitals at the vacancy sites and their neighboring magnesium ions. These orbitals can simply be modeled by orbitals formed from interacting pseudoatoms. A pseudoatom is an electronically neutral atom representing an oxygen vacancy and electrons of magnesium ions near the vacancy. With this model, an N-atom system having n vacancies can be modeled by n pseudoatoms. Interactions among oxygen vacancies in MgO were qualitatively reproduced by the interacting pseudoatoms model. PMID- 26636360 TI - Calculation of Fukui Functions Without Differentiating to the Number of Electrons. 3. Local Fukui Function and Dual Descriptor. AB - An alternative approach for the calculation of DFT-based reactivity descriptors involving derivatives of the energy with respect to the number of electrons and the external potential is further evaluated. Using functional derivatives with respect to the external potential, the finite difference approximation was avoided for the local calculation of the Fukui functions and the dual descriptor. A relevant set of molecules has been calculated after the optimization of computational parameters. It is shown that the new approach correctly predicts the nucleophilic attack on CH2O, the formation of CO metal complexes, the regioselectivity of monosubstituted benzenes, and the softest nucleophilic site in some ambident nucleophiles. PMID- 26636361 TI - Computational Studies on the Mechanisms and Dynamics of OH Reactions with CHF2CHFOCF3 and CHF2CH2OCF3. AB - The dual-level direct dynamics method has been employed to investigate the multichannel hydrogen abstraction reactions of CHF2CHFOCF3 + OH (R1) and CHF2CH2OCF3 + OH (R2) theoretically. The optimized geometries and frequencies of the stationary points and the minimum energy path are calculated at the B3LYP/6 311G(d,p) level, and the energetic information is further refined by the MC-QCISD method. There are two hydrogen abstraction channels for reaction R1 and three hydrogen abstraction channels for reaction R2. And four products, CF2CHFOCF3, CHF2CFOCF3, CF2CH2OCF3, and CHF2CHOCF3, are produced during these two reactions. The enthalpies of formation for the species involved in the two reactions (CHF2CHFOCF3, CF2CHFOCF3, CHF2CFOCF3, CHF2CH2OCF3, CF2CH2OCF3, and CHF2CHOCF3) are calculated via isodesmic reaction. Furthermore, the reaction mechanisms of subsequent reactions of product radicals (CF2CHFOCF3, CHF2CFOCF3, CF2CH2OCF3, and CHF2CHOCF3) with the OH radical are studied at the same level. The rate constants of reactions R1 and R2 are evaluated by means of canonical variational transition state theory including the small-curvature tunneling correction over a wide range of temperatures, from 250 to 1200 K. Our results show that the tunneling correction plays an important role in the rate constant calculation in the low temperature range. Agreement between the calculated and experimental data available at 298 K is good. It is found that the fluorine substitution decreases the reactivity of the C-H bond, and as a result, reaction R2 may proceed much easier than reaction R1. The Arrhenius expressions over a wide temperature range are obtained, and the kinetic isotope effects for reactions CHF2CHFOCF3/CDF2CDFOCF3 + OH and CHF2CH2OCF3/CDF2CD2OCF3 + OH are estimated so as to provide theoretical estimation for future laboratory investigation. PMID- 26636362 TI - Atomistic Simulation of Adiabatic Reactive Processes Based on Multi-State Potential Energy Surfaces. AB - The adiabatic reactive molecular dynamics (ARMD) method provides a framework to study chemical reactions using molecular dynamics simulations with minimal computational overhead. Here, ARMD is generalized to an arbitrary reactive process between two states in which reactants and products can be treated by an atomistic force field. The implementation is described, and the method is applied to two systems: the kinetics of NO rebinding to myoglobin (Mb) as a validation system and the conformational transition in neuroglobin (Ngb) which explores the full functionality of ARMD. For MbNO, the nonexponential kinetics observed both in experiment and earlier ARMD studies is reproduced. Furthermore, the sensitivity of the results with respect to the asymptotic separation between the two potential energy surfaces (NO bound and unbound) is studied. PMID- 26636363 TI - Calculation of One-Photon and Two-Photon Absorption Spectra of Porphyrins Using Time-Dependent Density Functional Theory. AB - Time-dependent density functional theory has been used to calculate the one photon and two-photon absorption spectra of free-base porphyrin, a substituted zinc porphyrin, and a zinc porphyrin dimer, in order to assess the validity of the method to reproduce the large increase in the two-photon absorption (TPA) cross-section for the dimer. Three hybrid functionals with varying amounts of exact exchange were tested, and the calculated one-photon absorption spectra for each of the molecular systems were shown to be in qualitative agreement with the measured spectra. All three functionals predict a large enhancement in the TPA cross-section for the dimer relative to the monomer, in agreement with experimental results. However, because of the sensitivity of the resonance enhancement factor to small differences in the relevant state energies, quantitative prediction of the TPA cross-section by this method is still a challenge. PMID- 26636364 TI - Computing the Heat of Adsorption using Molecular Simulations: The Effect of Strong Coulombic Interactions. AB - Molecular simulations are an important tool for the study of adsorption of hydrocarbons in nanoporous materials such as zeolites. The heat of adsorption is an important thermodynamic quantity that can be measured both in experiments and molecular simulations, and therefore it is often used to investigate the quality of a force field for a certain guest-host (g - h) system. In molecular simulations, the heat of adsorption in zeolites is often computed using either of the following methods: (1) using the Clausius-Clapeyron equation, which requires the partial derivative of the pressure with respect to temperature at constant loading, (2) using the energy difference between the host with and without a single guest molecule present, and (3) from energy/particle fluctuations in the grand-canonical ensemble. To calculate the heat of adsorption from experiments (besides direct calorimetry), only the first method is usually applicable. Although the computation of the heat of adsorption is straightforward for all silica zeolites, severe difficulties arise when applying the conventional methods to systems with nonframework cations present. The reason for this is that these nonframework cations have very strong Coulombic interactions with the zeolite. We will present an alternative method based on biased interactions of guest molecules that suffers less from these difficulties. This method requires only a single simulation of the host structure. In addition, we will review some of the other important issues concerning the handling of these strong Coulombic interactions in simulating the adsorption of guest molecules. It turns out that the recently proposed Wolf method ( J. Chem. Phys. 1999, 110 , 8254 ) performs poorly for zeolites as a large cutoff radius is needed for convergence. PMID- 26636365 TI - Ensuring Mixing Efficiency of Replica-Exchange Molecular Dynamics Simulations. AB - We address the question of constructing a protocol for replica-exchange molecular dynamics (REMD) simulations that make efficient use of the replica space, assess whether published applications are achieving such "mixing" efficiency, and provide a how-to guide to assist users to plan efficient REMD simulations. To address our first question, we introduce and discuss three metrics for assessing the number of replica-exchange attempts required to justify the use of a replica scheme and define a "transit number" as the lower bound for the length of an efficient simulation. Our literature survey of applications of REMD simulations of peptides in explicit solvent indicated that authors are not routinely reporting sufficient details of their simulation protocols to allow readers to make independent assessments of the impact of the method on their results, particularly whether mixing efficiency has been achieved. Necessary details include the expected or observed replica-exchange probability, together with the total number of exchange attempts, the exchange period, and estimates of the autocorrelation time of the potential energy. Our analysis of cases where the necessary information was reported suggests that in many of these simulations there are insufficient exchanges attempted or an insufficiently long period between them to provide confidence that the simulation length justifies the size of the replica scheme. We suggest guidelines for designing REMD simulation protocols to ensure mixing efficiency. Two key recommendations are that the exchange period should in general be larger than 1 ps and the number of exchange attempts should be chosen to significantly exceed the transit number for the replica scheme. PMID- 26636366 TI - Quantum Chemical Modeling of the Dehalogenation Reaction of Haloalcohol Dehalogenase. AB - The dehalogenation reaction of haloalcohol dehalogenase HheC from Agrobacterium radiobacter AD1 was investigated theoretically using hybrid density functional theory methods. HheC catalyzes the enantioselective conversion of halohydrins into their corresponding epoxides. The reaction is proposed to be mediated by a catalytic Ser132-Tyr145-Arg149 triad, and a distinct halide binding site is suggested to facilitate halide displacement by stabilizing the free ion. We investigated the HheC-mediated dehalogenation of (R)-2-chloro-1-phenylethanol using three quantum chemical models of various sizes. The calculated barriers and reaction energies give support to the suggested reaction mechanism. The dehalogenation occurs in a single concerted step, in which Tyr145 abstracts a proton from the halohydrin substrate and the substrate oxyanion displaces the chloride ion, forming the epoxide. Characterization of the involved stationary points is provided. Furthermore, by using three different models of the halide binding site, we are able to assess the adopted modeling methodology. PMID- 26636367 TI - A Potential Energy Function for Heterogeneous Proton-Wires. Ground and Photoactive States of the Proton-Wire in the Green Fluorescent Protein. AB - In this paper an EVB-based method to describe the energetics of operation of arbitrary-length heterogeneous proton-wires is described. The method keeps the number of fittable parameters low by exploiting the idea of "protonation states". The method is applied to describe the 3-proton proton-wire described in Green Fluorescent Protein (GFP), and two sets of parameters have been obtained, one for the electronic ground state and another for the photoactive excited electronic state, of a chemical model including the groups supporting the proton-wire and based on CASPT2//CASSCF quality reference energies. The fitted EVB functions are analyzed in static terms. In this way, it is seen that only a minimum exists in S0 while two exist in S1: one for the photoproduct and one for the reactant in the excited state, even though consideration of the Franck-Condon excitation energy predicts an effective barrier under 1 kcal mol(-1). Topological analysis of the transition state structure reveals a concerted but asynchronous motion of the protons, where the chromophore's proton lags behind, and the final proton of the wire that goes from Ser205 to Glu222 leads the process. Inclusion of nuclear dynamic efects causes this small effective barrier to vanish and predicts an essentially barrierless process in the excited state. PMID- 26636368 TI - The pDynamo Program for Molecular Simulations using Hybrid Quantum Chemical and Molecular Mechanical Potentials. AB - The pDynamo program has been developed for the simulation of molecular systems using hybrid quantum chemical (QC) and molecular mechanical (MM) potentials. pDynamo is written in a mixture of the computer languages Python and C and is a successor to the previous version of Dynamo, now denoted fDynamo, that was written in Fortran 90 (J. Comput. Chem. 2000, 21, 1088). The current version of Dynamo has a similar range of functionality to the older one but extends it in some significant ways, including the addition of a density functional theory QC capability. This paper gives a general description of pDynamo and outlines some of the advantages and disadvantages that have been encountered in switching computer languages. Some technical aspects of the implementation of pDynamo's algorithms are also discussed and illustrated with the results of example calculations. pDynamo is available on the Web at the address http://www.pdynamo.org and is released under the CeCILL license which is equivalent to the GNU general public license but conforms to the principles of French law. PMID- 26636369 TI - Solvent-Driven Structural Changes in Anion-pi Complexes. AB - Among the pi interactions, the anion-pi interaction has been a novel type of interaction. In the cases of halide-pi complexes, which are the most typical examples of the anion-pi interaction, the theoretically predicted and experimentally observed structures in the gas phase are quite different from the most frequently observed crystal structures. We here investigate the structural changes in complexation of the F(-)/Cl(-) ion with triazine (TAz) as the number of water/acetonitrile molecules increases from 1 to 4. Both the covalent bonding type for F(-)-TAz and the hydrogen-bonding type for Cl(-)-TAz, which are the lowest-energy structures in the gas phase, change to the solvent-mediated anion pi-type or displaced anion-pi-type complexes. This study explains why the (displaced) anion-pi-type complexes with some flexible orientations are most common in many crystal structures. PMID- 26636370 TI - Patients' understanding of blood tests and attitudes to HIV screening in the emergency department of a Swiss teaching hospital: a cross-sectional observational study. AB - BACKGROUND: In Switzerland, patients may undergo "blood tests" without being informed what these are screening for. Inadequate doctor-patient communication may result in patient misunderstanding. We examined what patients in the emergency department (ED) believed they had been screened for and explored their attitudes to routine (non-targeted) human immunodeficiency virus (HIV) screening. METHODS: Between 1st October 2012 and 28th February 2013, a questionnaire-based survey was conducted among patients aged 16-70 years old presenting to the ED of Lausanne University Hospital. Patients were asked: (1) if they believed they had been screened for HIV; (2) if they agreed in principle to routine HIV screening and (3) if they agreed to be HIV tested during their current ED visit. RESULTS: Of 466 eligible patients, 411 (88%) agreed to participate. Mean age was 46 +/- 16 years; 192 patients (47%) were women; 366 (89%) were Swiss or European; 113 (27%) believed they had been screened for HIV, the proportion increasing with age (p <= 0.01), 297 (72%) agreed in principle with routine HIV testing in the ED, and 138 patients (34%) agreed to be HIV tested during their current ED visit. CONCLUSION: In this ED population, 27% believed incorrectly they had been screened for HIV. Over 70% agreed in principle with routine HIV testing and 34% agreed to be tested during their current visit. These results demonstrate willingness among patients concerning routine HIV testing in the ED and highlight a need for improved doctor patient communication about what a blood test specifically screens for. PMID- 26636371 TI - Energy-Based Pharmacophore and Three-Dimensional Quantitative Structure--Activity Relationship (3D-QSAR) Modeling Combined with Virtual Screening To Identify Novel Small-Molecule Inhibitors of Silent Mating-Type Information Regulation 2 Homologue 1 (SIRT1). AB - Silent mating-type information regulation 2 homologue 1 (SIRT1), being the homologous enzyme of silent information regulator-2 gene in yeast, has multifaceted functions. It deacetylates a wide range of histone and nonhistone proteins; hence, it has good therapeutic importance. SIRT1 was believed to be overexpressed in many cancers (prostate, colon) and inflammatory disorders (rheumatoid arthritis). Hence, designing inhibitors against SIRT1 could be considered valuable. Both structure-based and ligand-based drug design strategies were employed to design novel inhibitors utilizing high-throughput virtual screening of chemical databases. An energy-based pharmacophore was generated using the crystal structure of SIRT1 bound with a small molecule inhibitor and compared with a ligand-based pharmacophore model that showed four similar features. A three-dimensional quantitative structure-activity relationship (3D QSAR) model was developed and validated to be employed in the virtual screening protocol. Among the designed compounds, Lead 17 emerged as a promising SIRT1 inhibitor with IC50 of 4.34 MUM and, at nanomolar concentration (360 nM), attenuated the proliferation of prostate cancer cells (LnCAP). In addition, Lead 17 significantly reduced production of reactive oxygen species, thereby reducing pro inflammatory cytokines such as IL6 and TNF-alpha. Furthermore, the anti inflammatory potential of the compound was ascertained using an animal paw inflammation model induced by carrageenan. Thus, the identified SIRT1 inhibitors could be considered as potent leads to treat both cancer and inflammation. PMID- 26636372 TI - Aberration of the Citation. AB - Multiple inherent biases related to different citation practices (for e.g., self citations, negative citations, wrong citations, multi-authorship-biased citations, honorary citations, circumstantial citations, discriminatory citations, selective and arbitrary citations, etc.) make citation-based bibliometrics strongly flawed and defective measures. A paper can be highly cited for a while (for e.g., under circumstantial or transitional knowledge), but years later it may appear that its findings, paradigms, or theories were untrue or invalid anymore. By contrast, a paper may remain shelved or overlooked for years or decades, but new studies or discoveries may actualize its subject at any moment. As citation-based metrics are transformed into "commercial activities," the "citation credit" should be considered on a commercial basis too, in the sense that "citation credit" should be shared out as a "citation dividend" by shareholders (coauthors) averagely or proportionally to their contributions but not fully appropriated by each of them. At equal numbers of citations, the greater number of authors, the lower "citation credit" should be and vice versa. Overlooking the presence of distorted and subjective citation practices makes many people and administrators "obsessed" with the number of citations to such an extent to run after "highly cited" authors and to create specialized citation databases for commercial purposes. Citation-based bibliometrics, however, are unreliable and unscientific measures; citation counts do not mean that a more cited work is of a higher quality or accuracy than a less cited work because citations do not measure the quality or accuracy. Citations do not mean that a highly cited author or journal is more commendable than a less cited author or journal. Citations are not more than countable numbers: no more, no less. PMID- 26636373 TI - Ischemia-Modified Albumin (IMA): A Novel Marker for Preeclampsia Independent of Uterine Artery Notching Identified by Doppler Ultrasound. AB - OBJECTIVE: To determine the predictive value of second trimester serum ischemia modified albumin (IMA) levels for preeclampsia (PE), small for gestational age (SGA) and gestational diabetes mellitus (GDM). METHODS: The study was conducted at a tertiary care hospital between May and August 2014. Healthy pregnant women (n = 88) who were screened for fetal anomalies with ultrasound at 20-24 weeks of gestation were included in the study. Doppler measurements of the bilateral uterine arteries were performed in all the patients. Serum samples were obtained for an IMA assay. The maternal serum IMA levels were compared in pregnant women who had normal and abnormal uterine artery Doppler findings, including notching, and also in pregnant women who subsequently developed PE, SGA, and GDM during the follow-up period. RESULTS: Uterine artery notching was not significantly predictive for PE, GDM or SGA (p > 0.05). There was no significant difference between notching of the uterine arteries and serum IMA levels (p > 0.05). Eight pregnant women (9.1%) subsequently developed PE. Serum IMA levels were significantly elevated in patients with PE compared with patients who did not subsequently develop PE (p = 0.002). However, serum IMA levels were not significantly different in patients who subsequently developed SGA and GDM compared with women who did not (p > 0.05). There was no correlation between serum IMA levels and maternal characteristics and laboratory findings. CONCLUSION: Maternal serum IMA levels at 20-24 weeks' gestation might be a predictive biomarker for PE, independent of notching of the uterine arteries, maternal characteristics and laboratory findings. PMID- 26636374 TI - Getting to the core of prion superstructural variability. AB - The phenomenon of protein superstructural polymorphism has become the subject of increased research activity. Besides the relevance to explain the existence of multiple prion strains, such activity is partly driven by the recent finding that in many age-related neurodegenerative diseases highly ordered self-associated forms of peptides and proteins might be the structural basis of prion-like processes and strains giving rise to different disease phenotypes. Biophysical studies of prion strains have been hindered by a lack of tools to characterize inherently noncrystalline, heterogeneous and insoluble proteins. A description of the pressure response of prion quaternary structures might change this picture. This is because applying pressure induces quaternary structural changes of PrP, such as misfolding and self-assembly. From the thermodynamics of these processes, structural features in terms of associated volume changes can then be deduced. We suggest that conformation-enciphered prion strains can be distinguished in terms of voids in the interfaces of the constituting PrP protomers and thus in their volumetric properties. PMID- 26636376 TI - A retrospective analysis of the long-term test-retest stability of pain descriptors of the painDETECT questionnaire. AB - OBJECTIVE: PainDETECT (PD-Q) is a patient reported screening questionnaire to identify patients with neuropathic pain based on questions regarding typically sensory symptoms of neuropathic pain. The aim of the present investigation was to assess the test-retest stability of pain descriptors of the PD-Q within a time window of 1-3 weeks. METHODS: Data sets of 74 chronic pain patients sampled in an open pain register at two visits were analyzed and compared. Patients with change of pain localization between visits were excluded from analysis. Beside conventional measures (Pearson correlation coefficient r, intraclass correlation coefficient ICC, kappa), also calculated measures known from method comparison were used. RESULTS: The mean duration between visits was 15 days. The measures were in the range of r = 0.72-0.86, ICC = 0.71-0.86, and kappa = 0.62-0.72 for PD Q pain descriptors (burning, prickling, mechanical allodynia, pain attacks, thermal hyperalgesia, numbness, pressure induced pain). CONCLUSION: The individual PD-Q pain descriptors showed accurate test-retest stability as a prerequisite for use in repeated measurements (e. g. post baseline or follow up data) in clinical trials. PMID- 26636375 TI - Tetraploidization or autophagy: The ultimate fate of senescent human endometrial stem cells under ATM or p53 inhibition. AB - Previously we demonstrated that endometrium-derived human mesenchymal stem cells (hMESCs) via activation of the ATM/p53/p21/Rb pathway enter the premature senescence in response to oxidative stress. Down regulation effects of the key components of this signaling pathway, particularly ATM and p53, on a fate of stressed hMESCs have not yet been investigated. In the present study by using the specific inhibitors Ku55933 and Pifithrin-alpha, we confirmed implication of both ATM and p53 in H(2)O(2)-induced senescence of hMESCs. ATM or p53 down regulation was shown to modulate differently the cellular fate of H(2)O(2)-treated hMESCs. ATM inhibition allowed H(2)O(2)-stimulated hMESCs to escape the permanent cell cycle arrest due to loss of the functional ATM/p53/p21/Rb pathway, and induced bypass of mitosis and re-entry into S phase, resulting in tetraploid cells. On the contrary, suppression of the p53 transcriptional activity caused a pronounced cell death of H(2)O(2)-treated hMESCs via autophagy induction. The obtained data clearly demonstrate that down regulation of ATM or p53 shifts senescence of human endometrial stem cells toward tetraploidization or autophagy. PMID- 26636377 TI - Prospective, multidisciplinary recording of perioperative errors in cerebrovascular surgery: is error in the eye of the beholder? AB - OBJECT Surgery requires careful coordination of multiple team members, each playing a vital role in mitigating errors. Previous studies have focused on eliciting errors from only the attending surgeon, likely missing events observed by other team members. METHODS Surveys were administered to the attending surgeon, resident surgeon, anesthesiologist, and nursing staff immediately following each of 31 cerebrovascular surgeries; participants were instructed to record any deviation from optimal course (DOC). DOCs were categorized and sorted by reporter and perioperative timing, then correlated with delays and outcome measures. RESULTS Errors were recorded in 93.5% of the 31 cases surveyed. The number of errors recorded per case ranged from 0 to 8, with an average of 3.1 +/- 2.1 errors (+/- SD). Overall, technical errors were most common (24.5%), followed by communication (22.4%), management/judgment (16.0%), and equipment (11.7%). The resident surgeon reported the most errors (52.1%), followed by the circulating nurse (31.9%), the attending surgeon (26.6%), and the anesthesiologist (14.9%). The attending and resident surgeons were most likely to report technical errors (52% and 30.6%, respectively), while anesthesiologists and circulating nurses mostly reported anesthesia errors (36%) and communication errors (50%), respectively. The overlap in reported errors was 20.3%. If this study had used only the surveys completed by the attending surgeon, as in prior studies, 72% of equipment errors, 90% of anesthesia and communication errors, and 100% of nursing errors would have been missed. In addition, it would have been concluded that errors occurred in only 45.2% of cases (rather than 93.5%) and that errors resulting in a delay occurred in 3.2% of cases instead of the 74.2% calculated using data from 4 team members. Compiled results from all team members yielded significant correlations between technical DOCs and prolonged hospital stays and reported and actual delays (p = 0.001 and p = 0.028, respectively). CONCLUSIONS This study is the only of its kind to elicit error reporting from multiple members of the operating team, and it demonstrates error is truly in the eye of the beholder-the types and timing of perioperative errors vary based on whom you ask. The authors estimate that previous studies surveying only the attending physician missed up to 75% of perioperative errors. By finding significant correlations between technical DOCs and prolonged hospital stays and reported and actual delays, this study shows that these surveys provide relevant and useful information for improving clinical practice. Overall, the results of this study emphasize that research on medical error must include input from all members of the operating team; it is only by understanding every perspective that surgical staff can begin to efficiently prevent errors, improve patient care and safety, and decrease delays. PMID- 26636378 TI - Letter to the Editor: Innovations in neurosurgery. PMID- 26636379 TI - Hemodynamic and morphological characteristics of unruptured posterior communicating artery aneurysms with oculomotor nerve palsy. AB - OBJECT Unruptured posterior communicating artery (PCoA) aneurysms with oculomotor nerve palsy (ONP) have a very high risk of rupture. This study investigated the hemodynamic and morphological characteristics of intracranial aneurysms with high rupture risk by analyzing PCoA aneurysms with ONP. METHODS Fourteen unruptured PCoA aneurysms with ONP, 33 ruptured PCoA aneurysms, and 21 asymptomatic unruptured PCoA aneurysms were included in this study. The clinical, morphological, and hemodynamic characteristics were compared among the different groups. RESULTS The clinical characteristics did not differ among the 3 groups (p > 0.05), whereas the morphological and hemodynamic analyses showed that size, aspect ratio, size ratio, undulation index, nonsphericity index, ellipticity index, normalized wall shear stress (WSS), and percentage of low WSS area differed significantly (p < 0.05) among the 3 groups. Furthermore, multiple comparisons revealed that these parameters differed significantly between the ONP group and the asymptomatic unruptured group and between the ruptured group and the asymptomatic unruptured group, except for size, which differed significantly only between the ONP group and the asymptomatic unruptured group (p = 0.0005). No morphological or hemodynamic parameters differed between the ONP group and the ruptured group. CONCLUSIONS Unruptured PCoA aneurysms with ONP demonstrated a distinctive morphological-hemodynamic pattern that was significantly different compared with asymptomatic unruptured PCoA aneurysms and was similar to ruptured PCoA aneurysms. The larger size, more irregular shape, and lower WSS might be related to the high rupture risk of PCoA aneurysms. PMID- 26636380 TI - Effects of intracranial meningioma location, size, and surgery on neurocognitive functions: a 3-year prospective study. AB - OBJECT Current recommendations stress the need for cognitive parameters to be integrated in the evaluation of outcomes for intracranial meningioma surgery. The aim of this prospective study was to examine neurocognitive function in meningioma patients pre- and postoperatively. METHODS Patients with skull base (anterior and middle fossa) and convexity (anterior and posterior) meningiomas (n = 54) underwent neuropsychological examination prior to and 1 year after surgery. A control group (n = 52) of healthy volunteers matched for age, sex, and education underwent the same examination. Assessments included executive, memory, and motor functions with standardized testing. Patients with convexity meningiomas were clinically assessed for parietal association cortex functions. RESULTS All patients performed significantly worse (p < 0.05) in most neurocognitive domains than controls. The skull base group showed more disturbances in memory than the convexity group (p < 0.05). The anterior convexity group showed more deficits in executive function than the posterior convexity group, which presented with parietal association cortex deficits. Verbal deficits were more pronounced in the left hemisphere than in the right hemisphere. Patients with a large tumor (> 4 cm) had more severe neurocognitive deficits than those with a small tumor (< 4 cm). Postoperatively, patients showed no deterioration in neurocognitive function. Instead, significant improvement (p < 0.05) was observed in some executive, motor, and parietal association cortex functions. CONCLUSIONS According to the authors' findings, intracranial meningiomas may cause neurocognitive deficits in patients. Surgery does not cause a deterioration in cognitive function; instead, it may lead to improvements in some functions. Permanent neuropsychological postoperative deficits should be interpreted as tumor-induced rather than due to surgery. PMID- 26636381 TI - Editorial: Seizures with meningioma. PMID- 26636382 TI - Tumors of the peripheral nervous system: analysis of prognostic factors in a series with long-term follow-up and review of the literature. AB - OBJECT Only a few published studies of the surgical treatment of benign peripheral nerve sheath tumors (BPNSTs), malignant peripheral nerve sheath tumors (MPNSTs), and peripheral non-neural sheath tumors (PNNSTs) have analyzed the results and possible prognostic factors using multivariate analysis. The authors report on their surgical series of cases of BPNSTs, MPNSTs, and PNNSTs with long term follow-up and analyze the role of selected factors with respect to the prognosis and risk of recurrence of these tumors using multivariate analysis. They also review the pertinent literature and discuss their results in its context. METHODS The authors retrospectively reviewed data from cases involving patients who underwent resection of a peripheral nerve tumor between January 1983 and December 2013 at their institution. Of a total of 200 patients, 150 patients (with 173 surgically treated tumors) had adequate follow-up data available for analysis. Pain was assessed using a visual analog scale (VAS), and motor and sensory function were assessed by means of the Louisiana State University grading system. They also analyzed the relationship between tumor recurrence and patient sex, patient age, diagnosis of neurofibromatosis (NF), tumor histopathology, tumor size, tumor location, and extent of resection (subtotal vs gross-total resection), using univariate and multivariate analyses. RESULTS There was a statistically significant improvement in the mean VAS pain score (preoperative 3.96 +/- 2.41 vs postoperative 0.95 +/- 1.6, p = 0.0001). Motor strength and sensory function were significantly improved after resection of tumors involving the brachial plexus (p = 0.0457 and p = 0.0043, respectively), tumors involving the upper limb (p = 0.0016 and p = 0.0016, respectively), BPNSTs (p = 0.0011 and p < 0.0001, respectively), and tumors with dimensions less than 5 cm (motor strength: p = 0.0187 and p = 0.0021 for <= 3 cm and 3-5 cm tumors, respectively; sensory function: p = 0.0003 and p = 0.0001 for <= 3 cm and 3-5 cm tumors, respectively). Sensory function showed a statistically significant improvement also in patients who had undergone resection of tumors involving the lower limb (p = 0.0118). Total resection was associated with statistically significant improvement of motor strength (p = 0.0251) and sensory function (p < 0.0001). In univariate analysis, a history of NF (p = 0.0034), a diagnosis of MPNST or PNNST (p < 0.0001), and subtotal resection (p = 0.0042) were associated with higher risk of tumor recurrence. In multivariate analysis (logistic regression analysis), a history of NF (OR 9.28%, 95% CI 1.62-52.94, p = 0.0121) and a diagnosis of MPNST (OR 0.03%, 95% CI 0.002-0.429, p = 0.0098) or PNNST (OR 0.081%, 95% CI 0.013-0.509, p = 0.0077) emerged as independent prognostic factors for tumor recurrence. CONCLUSIONS A total resection should be attempted in all cases of peripheral nervous system tumors (irrespective of the supposed diagnosis and tumor dimensions) because it is associated with better prognosis in term of functional outcome and overall survival. Moreover, a total resection predicts a lower risk of tumor recurrence. Patients with a history of NF and tumors with malignant histology remain a challenge both for neurosurgeons and oncologists due to higher recurrence rates and the lack of standardized adjuvant therapies. PMID- 26636383 TI - Comparison of computer-assisted planning and manual planning for depth electrode implantations in epilepsy. AB - OBJECT The objective of this study was to evaluate the clinical utility of multitrajectory computer-assisted planning software (CAP) to plan stereoelectroencephalography (SEEG) electrode arrangements. METHODS A cohort of 18 patients underwent SEEG for evaluation of epilepsy at a single center between August 2013 and August 2014. Planning of electrodes was performed manually and stored using EpiNav software. CAP was developed as a planning tool in EpiNav. The user preselects a set of cerebral targets and optimized trajectory constraints, and then runs an automated search of potential scalp entry points and associated trajectories. Each trajectory is associated with metrics for a safety profile, derived from the minimal distance to vascular structures, and an efficacy profile, derived from the proportion of depth electrodes that are within or adjacent to gray matter. CAP was applied to the cerebral targets used in the cohort of 18 previous manually planned implantations to generate new multitrajectory implantation plans. A comparison was then undertaken for trajectory safety and efficacy. RESULTS CAP was applied to 166 electrode targets in 18 patients. There were significant improvements in both the safety profile and efficacy profile of trajectories generated by CAP compared with manual planning (p < 0.05). Three independent neurosurgeons assessed the feasibility of the trajectories generated by CAP, with 131 (78.9%) of 166 trajectories deemed suitable for implementation in clinical practice. CAP was performed in real time, with a median duration of 8 minutes for each patient, although this does not include the time taken for data preparation. CONCLUSIONS CAP is a promising tool to plan SEEG implantations. CAP provides feasible depth electrode arrangements, with quantitatively greater safety and efficacy profiles, and with a substantial reduction in duration of planning within the 3D multimodality framework. PMID- 26636384 TI - Risk factors for worsened muscle strength after the surgical treatment of arteriovenous malformations of the eloquent motor area. AB - OBJECT Case selection for the surgical treatment of arteriovenous malformations (AVMs) of the eloquent motor area remains challenging. The aim of this study was to determine the risk factors for worsened muscle strength after surgery in patients with this disorder. METHODS At their hospital the authors retrospectively studied 48 consecutive patients with AVMs involving motor cortex and/or the descending pathway. All patients had undergone preoperative functional MRI (fMRI) and diffusion tensor imaging (DTI), followed by resection. Both functional and angioarchitectural factors were analyzed with respect to the change in muscle strength. Functional factors included lesion-to-corticospinal tract distance (LCD) on DTI and lesion-to-activation area distance (LAD) and cortical reorganization on fMRI. Based on preoperative muscle strength, the changes in muscle strength at 1 week and 6 months after surgery were defined as short-term and long-term surgical outcomes, respectively. Statistical analysis was performed using the statistical package SPSS (version 20.0.0, IBM Corp.). RESULTS Twenty-one patients (43.8%) had worsened muscle strength 1 week after surgery. However, only 10 patients (20.8%) suffered from muscle strength worsening 6 months after surgery. The LCD was significantly correlated with short term (p < 0.001) and long-term (p < 0.001) surgical outcomes. For long-term outcomes, patients in the 5 mm >= LCD > 0 mm (p = 0.009) and LCD > 5 mm (p < 0.001) categories were significantly associated with a lower risk of permanent motor worsening in comparison with patients in the LCD = 0 mm group. No significant difference was found between patients in the 5 mm >= LCD > 0 mm group and LCD > 5 mm group (p = 0.116). Nidus size was the other significant predictor of short-term (p = 0.021) and long-term (p = 0.016) outcomes. For long-term outcomes, the area under the ROC curve (AUC) was 0.728, and the cutoff point was 3.6 cm. Spetzler-Martin grade was not associated with short-term surgical outcomes (0.143), although it was correlated with long-term outcomes (0.038). CONCLUSIONS An AVM with a nidus in contact with tracked eloquent fibers (LCD = 0) and having a large size is more likely to be associated with worsened muscle strength after surgery in patients with eloquent motor area AVMs. Surgical treatment in these patients should be carefully considered. In patients with an LCD > 5 mm, radical resection may be considered to eliminate the risk of hemorrhage. PMID- 26636385 TI - Phase-contrast magnetic resonance imaging reveals net retrograde aqueductal flow in idiopathic normal pressure hydrocephalus. AB - OBJECT The objective of this study was to assess the net aqueductal stroke volume (ASV) and CSF aqueductal flow rate derived from phase-contrast MRI (PC-MRI) in patients with probable idiopathic normal pressure hydrocephalus (iNPH) before and after ventriculoperitoneal shunt surgery, and to compare observations with intracranial pressure (ICP) scores. METHODS PC-MRI at the level of the sylvian aqueduct was undertaken in patients undergoing assessment for probable iNPH. Aqueductal flow in the craniocaudal direction was defined as positive, or antegrade flow, and net ASV was calculated by subtracting retrograde from antegrade aqueductal flow. Aqueductal flow rate per minute was calculated by multiplying net ASV by heart rate. During the same hospital admission, clinical examination was performed using NPH score and overnight continuous ICP monitoring. Twelve patients were followed prospectively 12 months after shunt placement with clinical assessment and a second PC-MRI. The study also included 2 healthy controls. RESULTS Among 21 patients examined for iNPH, 17 (81%) received a shunt (shunt group), and 4 were treated conservatively (conservative group). Among the patients with shunts, a clinical improvement was observed in 16 (94%) of the 17. Net ASV was negative in 16 (76%) of 21 patients before shunt placement and in 5 (42%) of 12 patients after shunt placement, and increased from a median of -5 MUl (range -175 to 27 MUl) to a median of 1 MUl (range -61 to 30 MUl; p = 0.04). Among the 12 patients with PC-MRI after shunt placement, 11 were shunt responders, and in 9 of these 11 either a reduced magnitude of retrograde aqueductal flow, or a complete reversal from retrograde to antegrade flow, occurred. Net ASV was significantly lower in the shunt group than in the conservative group (p = 0.01). The aqueductal flow rate increased from -0.56 ml/min (range -12.78 to 0.58 ml/min) to 0.06 ml/min (range -4.51 to 1.93 ml/min; p = 0.04) after shunt placement. CONCLUSIONS In this cohort of patients with iNPH, retrograde net aqueductal flow was observed in 16 (76%) of 21 patients. It was reversed toward the antegrade direction after shunt placement either by magnitude or completely in 9 (75%) of 12 patients examined using PC-MRI both before and after shunt placement (p = 0.04); 11 of the 12 were shunt responders. The study results question previously established concepts with respect to both CSF circulation pathways and CSF formation rate. PMID- 26636387 TI - Metabolic approach for tumor delineation in glioma surgery: 3D MR spectroscopy image-guided resection. AB - OBJECT The extent of resection is one of the most essential factors that influence the outcomes of glioma resection. However, conventional structural imaging has failed to accurately delineate glioma margins because of tumor cell infiltration. Three-dimensional proton MR spectroscopy ((1)H-MRS) can provide metabolic information and has been used in preoperative tumor differentiation, grading, and radiotherapy planning. Resection based on glioma metabolism information may provide for a more extensive resection and yield better outcomes for glioma patients. In this study, the authors attempt to integrate 3D (1)H-MRS into neuronavigation and assess the feasibility and validity of metabolically based glioma resection. METHODS Choline (Cho)-N-acetylaspartate (NAA) index (CNI) maps were calculated and integrated into neuronavigation. The CNI thresholds were quantitatively analyzed and compared with structural MRI studies. Glioma resections were performed under 3D (1)H-MRS guidance. Volumetric analyses were performed for metabolic and structural images from a low-grade glioma (LGG) group and high-grade glioma (HGG) group. Magnetic resonance imaging and neurological assessments were performed immediately after surgery and 1 year after tumor resection. RESULTS Fifteen eligible patients with primary cerebral gliomas were included in this study. Three-dimensional (1)H-MRS maps were successfully coregistered with structural images and integrated into navigational system. Volumetric analyses showed that the differences between the metabolic volumes with different CNI thresholds were statistically significant (p < 0.05). For the LGG group, the differences between the structural and the metabolic volumes with CNI thresholds of 0.5 and 1.5 were statistically significant (p = 0.0005 and 0.0129, respectively). For the HGG group, the differences between the structural and metabolic volumes with CNI thresholds of 0.5 and 1.0 were statistically significant (p = 0.0027 and 0.0497, respectively). All patients showed no tumor progression at the 1-year follow-up. CONCLUSIONS This study integrated 3D MRS maps and intraoperative navigation for glioma margin delineation. Optimum CNI thresholds were applied for both LGGs and HGGs to achieve resection. The results indicated that 3D (1)H-MRS can be integrated with structural imaging to provide better outcomes for glioma resection. PMID- 26636386 TI - Seizures in supratentorial meningioma: a systematic review and meta-analysis. AB - OBJECT Meningioma is the most common benign intracranial tumor, and patients with supratentorial meningioma frequently suffer from seizures. The rates and predictors of seizures in patients with meningioma have been significantly under studied, even in comparison with other brain tumor types. Improved strategies for the prediction, treatment, and prevention of seizures in patients with meningioma is an important goal, because tumor-related epilepsy significantly impacts patient quality of life. METHODS The authors performed a systematic review of PubMed for manuscripts published between January 1980 and September 2014, examining rates of pre- and postoperative seizures in supratentorial meningioma, and evaluating potential predictors of seizures with separate meta-analyses. RESULTS The authors identified 39 observational case series for inclusion in the study, but no controlled trials. Preoperative seizures were observed in 29.2% of 4709 patients with supratentorial meningioma, and were significantly predicted by male sex (OR 1.74, 95% CI 1.30-2.34); an absence of headache (OR 1.77, 95% CI 1.04-3.25); peritumoral edema (OR 7.48, 95% CI 6.13-9.47); and non-skull base location (OR 1.77, 95% CI 1.04-3.25). After surgery, seizure freedom was achieved in 69.3% of 703 patients with preoperative epilepsy, and was more than twice as likely in those without peritumoral edema, although an insufficient number of studies were available for formal meta-analysis of this association. Of 1085 individuals without preoperative epilepsy who underwent resection, new postoperative seizures were seen in 12.3% of patients. No difference in the rate of new postoperative seizures was observed with or without perioperative prophylactic anticonvulsants. CONCLUSIONS Seizures are common in supratentorial meningioma, particularly in tumors associated with brain edema, and seizure freedom is a critical treatment goal. Favorable seizure control can be achieved with resection, but evidence does not support routine use of prophylactic anticonvulsants in patients without seizures. Limitations associated with systematic review and meta-analysis should be considered when interpreting these results. PMID- 26636388 TI - Growth hormone-secreting macroadenoma of the pituitary gland successfully treated with the radiolabeled somatostatin analog (90)Y-DOTATATE: case report. AB - Pituitary tumors causing acromegaly are usually macroadenomas at the time of diagnosis, and they can grow aggressively, infiltrating surrounding tissues. Difficulty in achieving complete tumor removal at surgery can lead toward a strong tendency for recurrence, making it necessary to consider a means of treatment other than those currently used such as somatostatin analogs (SSAs), growth hormone (GH) receptor antagonist, surgical removal, and radiotherapy. The purpose of this paper is to describe a patient diagnosed with an aggressive, giant GH-secreting tumor refractory to medical therapy but ultimately treated with the radiolabeled somatostatin analog (90)Y-DOTATATE. A 26-year-old male with an invasive macroadenoma of the pituitary gland (5.6 * 2.5 * 3.6 cm) and biochemically confirmed acromegaly underwent 2 partial tumor resections: the first used the transsphenoidal approach and the second used the transcranial method. The patient received SSAs pre- and postoperatively. Because of the progression in pituitary tumor size, he underwent classic irradiation of the tumor (50 Gy). One and a half years later, the patient presented with clinically and biochemically active disease, and the tumor size was still 52 mm in diameter (height). Two neurosurgeons disqualified him from further surgical procedures. After confirming the presence of somatostatin receptors in the pituitary tumor by using (68)Ga-DOTATATE PET/CT, we treated the patient 4 times with an SSA bound with (90)Y-DOTATATE. After this treatment, the patient attained partial biochemical remission and a reduction in the tumor mass for the first time. Treatment with an SSA bound with (90)Y-DOTATATE may be a promising option for some aggressive GH-secreting pituitary adenomas when other methods have failed. PMID- 26636389 TI - Synergistic antitumor effect with indoleamine 2,3-dioxygenase inhibition and temozolomide in a murine glioma model. AB - OBJECT Indoleamine 2,3-dioxygenase (IDO), a key enzyme of tryptophan (Trp) metabolism, is involved in tumor-derived immune suppression through depletion of Trp and accumulation of the metabolite kynurenine, resulting in inactivation of natural killer cells and generation of regulatory T cells (Tregs). It has been reported that high expression of IDO in cancer cells is associated with suppression of the antitumor immune response and is consistent with a poor prognosis. Thus, IDO may be a therapeutic target for malignant cancer. The authors have recently shown that IDO expression is markedly increased in human glioblastoma and secondary glioblastoma with malignant change, suggesting that IDO targeting may also have therapeutic potential for patients with glioma. The aim of this study was to investigate the antitumor effect of IDO inhibition and to examine the synergistic function of IDO inhibitor and temozolomide (TMZ) in a murine glioma model. METHODS Murine glioma GL261 cells and human glioma U87 cells were included in this study. The authors used 3 mouse models to study glioma cell growth: 1) a subcutaneous ectopic model, 2) a syngeneic intracranial orthotopic model, and 3) an allogenic intracranial orthotopic model. IDO inhibition was achieved via knockdown of IDO in GL261 cells using short hairpin RNA (shRNA) and through oral administration of the IDO inhibitor, 1-methyl-l-tryptophan (1-MT). Tumor volume in the subcutaneous model and survival time in the intracranial model were evaluated. RESULTS In the subcutaneous model, oral administration of 1 MT significantly suppressed tumor growth, and synergistic antitumor effects of 1 MT and TMZ were observed (p < 0.01). Mice containing intracranially inoculated IDO knockdown cells had a significantly longer survival period as compared with control mice (p < 0.01). CONCLUSIONS These results suggest that IDO expression is implicated in immunosuppression and tumor progression in glioma cells. Therefore, combining IDO inhibition with standard TMZ treatment could be an encouraging therapeutic strategy for patients with malignant glioma. PMID- 26636390 TI - Panventriculomegaly with a wide foramen of Magendie and large cisterna magna. AB - OBJECT The authors' goal in this paper is to provide the first clinical, radiological, and genetic studies of panventriculomegaly (PaVM) defined by a wide foramen of Magendie and large cisterna magna. METHODS Clinical and brain imaging data from 28 PaVM patients (including 10 patients from 5 families) were retrospectively studied. Five children were included. In adult patients, the age at onset was 56.0 +/- 16.7 years. Tetraventricular dilation, aqueductal opening with flow void on T2-weighted images, and a wide foramen of Magendie and large cisterna magna (wide cerebrospinal fluid space at the fourth ventricle outlet) were essential MRI findings for PaVM diagnosis. 3D fast asymmetrical spin echo sequences were used for visualization of cistern membranes. Time-spatial labeling inversion pulse examination was performed to analyze cerebrospinal fluid movement. Copy number variations were determined using high-resolution microarray and were validated by quantitative polymerase chain reaction with breakpoint sequencing. RESULTS Adult patients showed gait disturbance, urinary dysfunction, and cognitive dysfunction. Five infant patients exhibited macrocranium. Patients were divided into 2 subcategories, those with or without downward bulging third ventricular floors and membranous structures in the prepontine cistern. Patients with bulging floors were successfully treated with endoscopic third ventriculostomy. Genetic analysis revealed a deletion in DNAH14 that encodes a dynein heavy chain protein associated with motile cilia function, and which co segregated with patients in a family without a downward bulging third ventricular floor. CONCLUSIONS Panventriculomegaly with a wide foramen of Magendie and a large cisterna magna may belong to a subtype of congenital hydrocephalus with familial accumulation, younger age at onset, and symptoms of normal pressure hydrocephalus. In addition, a family with PaVM has a gene mutation associated with dysfunction of motile cilia. PMID- 26636391 TI - Stroke prevention by direct revascularization for patients with adult-onset moyamoya disease presenting with ischemia. AB - OBJECT Moyamoya disease (MMD) is a progressive disease that can cause recurrent stroke. The authors undertook this retrospective case-control study with a large sample size in an attempt to assess the efficacy of direct or combined revascularization surgery for ischemia in adults with MMD. METHODS The authors investigated cases involving patients with moyamoya disease presenting with ischemia who visited Seoul National University Bundang Hospital and Seoul National University Hospital between 2000 and 2014. Among 441 eligible patients, 301 underwent revascularization surgery and 140 were treated conservatively. Variables evaluated included age at diagnosis, sex, surgical record, Suzuki stage, and occurrence of stroke. Patients were stratified into 2 groups based on whether or not they had undergone revascularization surgery. Actuarial 1-, 5-, and 10-year stroke rates were calculated using the life table method. Risk factor analysis for 5-year stroke occurrence was conducted with multivariate regression. RESULTS Of the 441 patients, 301 had been surgically treated (revascularization group) and 140 had not (control group). The mean follow-up durations were 45 and 77 months, respectively. The actuarial 10-year cumulative incidence rate for any kind of stroke was significantly lower in the revascularization group (9.4%) than in the control group (19.6%) (p = 0.041); the relative risk reduction (RRR) was also superior (52.0%) in the revascularization group, and the number needed to treat was 10. The 10-year rate of ischemic stroke was greater (13.3%) in the control group than in the revascularization group (3.9%) (p = 0.019). The RRR for ischemic stroke in the revascularization group was 70.7%, and the number needed to treat was 11. However, the actuarial 1- and 5-year rates of ischemic stroke did not significantly differently between the groups. Overall, revascularization surgery was shown to be an independent protective factor, as revealed by multivariate analysis. CONCLUSIONS Direct or combined revascularization for patients with adult-onset moyamoya disease presenting with ischemia can prevent further stroke. PMID- 26636392 TI - Erratum to: Tricuspid Valve Surgery in Patients with Isolated Tricuspid Valve Endocarditis: Analysis of Perioperative Parameters and Long-Term Outcomes. Thorac Cardiovasc Surg 2015 [efirst ahead of print]. PMID- 26636393 TI - Renal Function and Urinary Biomarkers in Cardiac Bypass Surgery: A Prospective Randomized Trial Comparing Three Surgical Techniques. AB - Background Cardiopulmonary bypass procedure is associated with an increased risk of renal impairment. To which extent structural damage causes functional decline is unknown. We evaluated perioperative kidney injury and function in patients treated with conventional extracorporeal circulation (CECC), minimized extracorporeal circulation (MECC), and off-pump coronary artery bypass grafting (OPCAB). Methods Blood and urine samples, collected at baseline and up to 72 hours after surgery from patients of the HEPCON trial (DRKS00007580, 120 patients randomized for heparin management and for surgical technique), were analyzed for differences in renal injury and function. Neutrophil gelatinase-associated lipocalin, alpha glutathione S-transferase, liver fatty acid-binding protein, and kidney injury molecule-1 were measured as urinary protein markers of renal tubular injury. Serum creatinine, blood urea levels, and estimated glomerular filtration rate were determined to monitor renal function. Results Markers of tubular injury differed significantly between surgical technique groups early after surgery, indicating the most detrimental effect in CECC. Hemolysis and hemodilution correlated with these early changes. A late rise did not show intergroup differences. Time courses of renal function parameters, as well as the development of acute kidney injury in 15 patients (13.5%), were irrespective of surgical technique. Heparin management did not influence renal parameters. Conclusion During coronary artery bypass grafting, CECC temporarily induces more tubular injury than MECC or OPCAB. However, late changes of renal function parameters occur irrespective of extracorporeal perfusion mode and even in off pump surgery. PMID- 26636395 TI - Colorimetric Characterization of Mobile Devices for Vision Applications. AB - PURPOSE: Available applications for vision testing in mobile devices usually do not include detailed setup instructions, sacrificing rigor to obtain portability and ease of use. In particular, colorimetric characterization processes are generally obviated. We show that different mobile devices differ also in colorimetric profile and that those differences limit the range of applications for which they are most adequate. METHODS: The color reproduction characteristics of four mobile devices, two smartphones (Samsung Galaxy S4, iPhone 4s) and two tablets (Samsung Galaxy Tab 3, iPad 4), have been evaluated using two procedures: 3D LUT (Look Up Table) and a linear model assuming primary constancy and independence of the channels. The color reproduction errors have been computed with the CIEDE2000 color difference formula. RESULTS: There is good constancy of primaries but large deviations of additivity. The 3D LUT characterization yields smaller reproduction errors and dispersions for the Tab 3 and iPhone 4 devices, but for the iPad 4 and S4, both models are equally good. The smallest reproduction errors occur with both Apple devices, although the iPad 4 has the highest number of outliers of all devices with both colorimetric characterizations. CONCLUSIONS: Even though there is good constancy of primaries, the large deviations of additivity exhibited by the devices and the larger reproduction errors make any characterization based on channel independence not recommendable. The smartphone screens show, in average, the best color reproduction performance, particularly the iPhone 4, and therefore, they are more adequate for applications requiring precise color reproduction. PMID- 26636396 TI - The Future of Myopia Control Contact Lenses. AB - The growing incidence of pediatric myopia worldwide has generated strong scientific interest in understanding factors leading to myopia development and progression. Although contact lenses (CLs) are prescribed primarily for refractive correction, there is burgeoning use of particular modalities for slowing progression of myopia following reported success in the literature. Standard soft and rigid CLs have been shown to have minimal or no effect for myopia control. Overall, orthokeratology and soft multifocal CLs have shown the most consistent performance for myopia control with the least side effects. However, their acceptance in both clinical and academic spheres is influenced by data limitations, required off-label usage, and a lack of clear understanding of their mechanisms for myopia control. Myopia development and progression seem to be multifactorial, with a complex interaction between genetics and environment influencing myopigenesis. The optical characteristics of the individual also play a role through variations in relative peripheral refraction, binocular vision function, and inherent higher-order aberrations that have been linked to different refractive states. Contact lenses provide the most viable opportunity to beneficially modify these factors through their close alignment with the eye and consistent wearing time. Contact lenses also have potential to provide a pharmacological delivery device and a possible feedback mechanism for modification of a visual environmental risk. An examination of current patents on myopia control provides a window to the future development of an ideal myopia controlling CL, which would incorporate the broadest treatment of all currently understood myopigenic factors. This ideal lens must also satisfy safety and comfort aspects, along with overcoming practical issues around U.S. Food and Drug Administration approval, product supply, and availability to target populations. Translating the broad field of myopia research into clinical practice is a multidisciplinary challenge, but an analysis of the current literature provides a framework on how a future solution may take shape. PMID- 26636397 TI - Optometric Trajectory--Gerald Westheimer. AB - A narrative starting with the author's entering the Optometry program at the Sydney Technical College in 1940, taking him through his days as an optometry and science student, an optometrist in private practice, and participant in organized optometry in Sydney. It described his steps to become an optometric scientist and his service as faculty member in three optometry schools in the United States. Finally, it follows him into a long career in vision science and neurophysiology at Berkeley. PMID- 26636398 TI - Vision Impairment and Ocular Morbidity in a Refugee Population in Malawi. AB - PURPOSE: To provide screening services and obtain information on the eye health status and distribution of visual impairments in a refugee population of the sole refugee camp in Malawi. METHODS: A general eye screening at Dzaleka refugee settlement camp was organized in November 2012. Final-year optometry students conducted detailed optometry examinations, including visual acuity (VA) assessment for near and distance, retinoscopy, and subjective refraction in cases with distance VA less than 6/12 or near VA less than N8, anterior and posterior segment evaluation. Their findings were then verified by an optometrist. The World Health Organization definition of vision impairment was followed, and the cause of vision impairment was determined at the end of each examination. Where possible, participants requiring refractive correction were provided spectacles free of cost. RESULTS: Of a total 635 participants examined, around one-half were male with 61% in the 16 to 49 years age group. The overall prevalence of presenting blindness, severe vision impairment, and vision impairment were 1.3% (95% confidence interval [95% CI], 0.5 to 2.4), 0.5% (95% CI, 0.0 to 1.1), and 3.6% (95% CI, 2.3 to 5.2), respectively. Overall vision impairment (VA <6/18) was present in 5.4% (95% CI, 3.6 to 7.1) of the participants. The principal causes of blindness, severe vision impairment, and vision impairment were cataracts, refractive errors, and corneal opacities, respectively; and more than 90% of the overall vision impairment was avoidable. Refractive errors and presbyopia were the most common morbidity, present in more than two-thirds of the participants examined. Only 5% of all the participants ever had a previous eye examination. CONCLUSIONS: The prevalence and causes of blindness and vision impairment in a refugee population are comparable with those of the general population. Lack of basic eye care services in the health center for refugees is a major concern. The health care facility in the settlement camp needs to be upgraded to provide comprehensive eye care including refractive care services. PMID- 26636399 TI - Ethambutol/Linezolid Toxic Optic Neuropathy. AB - PURPOSE: To report a rare toxic optic neuropathy after long-term use of two medications: ethambutol and linezolid. CASE REPORT: A 65-year-old man presented to the Miami Veterans Affairs Medical Center in December 2014 for evaluation of progressive vision decrease in both eyes. The patient presented with best corrected visual acuities of 20/400 in the right eye and counting fingers at 5 feet in the left eye. Color vision was significantly reduced in both eyes. Visual fields revealed a cecocentral defect in both eyes. His fundus and optic nerve examination was unremarkable. Because vision continued to decline after discontinuation of ethambutol, linezolid was also discontinued, after which vision, color vision, and visual fields improved. Because of these findings, the final diagnosis was toxic optic neuropathy. Final visual outcome was 20/30 in the right eye and 20/40 in the left eye. CONCLUSIONS: Drug-associated toxic optic neuropathy is a rare but vision-threatening condition. Diagnosis is made based on an extensive case history and careful clinical examination. The examination findings include varying decrease in vision, normal pupils and extraocular muscles, and unremarkable fundoscopy, with the possibility of swollen optic discs in the acute stage of the optic neuropathy. Other important findings descriptive of toxic optic neuropathy include decreased color vision and cecocentral visual field defects. This case illustrates the importance of knowledge of all medications and/or substances a patient consumes that may cause a toxic reaction and discontinuing them immediately if the visual functions are worsening or not improving. PMID- 26636400 TI - Human Ocular Dirofilariasis in Hong Kong. AB - PURPOSE: Human dirofilariasis is a helminthic infestation caused by filarial nematodes of the genus Dirofilaria. We report two cases of subconjunctival dirofilariasis in adult Chinese patients. CASE REPORTS: Case 1: A 57-year-old woman presented to us with 1-day history of left eye redness and migratory foreign body sensation. Physical examination showed a temporal subconjunctival motile mass in her left eye. Immediate surgical exploration showed a live nonpigmented roundworm measuring 120 mm in length with morphology compatible with Dirofilaria. It was later identified to be Dirofilaria repens by sequence analysis. Case 2: A 69-year-old woman presented with left eye redness and foreign body sensation for 2 weeks. She was treated elsewhere initially with topical antibiotics without any improvement. On slitlamp examination, a mobile subconjunctival mass was noted. Immediate surgical removal was performed under local anesthesia, revealing a live 50-mm-long worm. It was identified as Dirofilaria hongkongensis. Both patients had normal systemic workup results and remained symptom-free after surgical removal of the nematode. Clinical findings, diagnosis, pathogenesis, and management are discussed. CONCLUSIONS: Ophthalmic dirofilariasis is a rare condition. Clinicians should be aware of this disease entity so that prompt diagnosis and treatment could be offered to the patients. PMID- 26636401 TI - Binocular Vision and the Stroop Test. AB - PURPOSE: Recent studies report a link between optometric results, learning disabilities, and problems in reading. This study examines the correlations between optometric tests of binocular vision, namely, of vergence and accommodation, reading speed, and cognitive executive functions as measured by the Stroop test. METHODS: Fifty-one students (mean age, 20.43 +/- 1.25 years) were given a complete eye examination. They then performed the reading test L'Alouette and the Stroop interference test at their usual reading distance. Criteria for selection were the absence of significant refractive uncorrected error, strabismus, amblyopia, color vision defects, and other neurologic findings. RESULTS: The results show a correlation between positive fusional vergences (PFVs) at near distance and the interference effect (IE) in the Stroop test: the higher the PFV value is, the less the IE. Furthermore, the subgroup of 11 students presenting convergence insufficiency, according to Scheiman and Wick criteria (2002), showed a significantly higher IE during the Stroop test than the other students (N = 18) who had normal binocular vision without symptoms at near. Importantly, there is no correlation between reading speed and PFV either for the entire sample or for the subgroups. CONCLUSIONS: These results suggest for the first time a link between convergence capacity and the interference score in the Stroop test. Such a link is attributable to the fact that vergence control and cognitive functions mobilize the same cortical areas, for example, parietofrontal areas. The results are in favor of our hypothesis that vergence is a vector of attentional and cognitive functions. PMID- 26636402 TI - Influence of Vision on Ocular Comfort Ratings. AB - PURPOSE: To evaluate the influence of blur on ocular comfort while systematically manipulating vision using habitual refractive correction, induced spatial blur, dioptric defocus, and under the absence of visual structure. METHODS: Twenty emmetropic subjects rated vision, ocular comfort, and other sensations (burning, itching, and warmth) under clear viewing condition, spatial blur, and dioptric defocus, each lasting for 5 min. During each condition, subjects viewed digital targets projected from a distance of 3 m, and vision and ocular sensations were rated using magnitude estimation. Dioptric defocus was induced using +6.00DS contact lens, and equivalent spatial blur was produced by spatially filtering the targets. In a separate study, 15 participants rated vision and comfort while viewing a ganzfeld and behind an occluding patch (each of which provided an absence of visual structure) in addition to the above experimental conditions. Repeated-measures analysis of variance was used to compare the ratings of vision and comfort under the different experimental conditions. RESULTS: Vision under blurred conditions (both spatial blur and dioptric defocus) was rated significantly different (p < 0.001) from clear viewing condition. Vision was significantly different when targets were dioptrically defocused than when they were spatially blurred (p < 0.001). Ratings of comfort showed significant differences between clear and blurred conditions (p < 0.001). However, there was no significant difference in comfort ratings between dioptric defocus and spatial blur (p value at least 0.28). There were also no differences in comfort (p value at least 0.99) between clear vision, ganzfeld viewing, and occlusion despite the lack of visual structure in the latter two conditions. CONCLUSIONS: There does seem to be an association between clarity of vision and ocular comfort. Although the pathways for ocular surface pain and vision are perhaps exclusive, complex psychological influences such as nocebo or Hawthorne effects can subtly influence the participants to anticipate a change in comfort when vision is blurred. PMID- 26636403 TI - Corneal Sensitivity and Inflammatory Biomarkers in Contact Lens Discomfort. AB - PURPOSE: The aim of this study was to analyze whether symptoms of discomfort in hydrogel contact lens (HCL) wearers were associated with changes in corneal sensitivity or levels of tear inflammatory mediators. METHODS: Sixty-six subjects were included: 47 HCL wearers, further divided into 24 symptomatic and 23 asymptomatic wearers by the Contact Lens Dry Eye Questionnaire short form and 19 non-contact lens wearers. At least 24 h after HCL removal, we obtained scores from the Ocular Surface Disease Index and mechanical, hot, and cold corneal thresholds using a Belmonte esthesiometer. We collected 4 MUl of tears with a capillary micropipette and measured levels of 12 inflammatory markers using a bead-based array: epidermal growth factor, fractalkine, interleukin-10 (IL-10), IL-1beta, IL-1 receptor antagonist, IL-2, IL-4, IL-6, IL-8, monocyte chemoattractant protein 1, tumor necrosis factor-alpha, and matrix metalloproteinase 9. RESULTS: There were no significant differences between groups in corneal sensitivity thresholds and levels of tear molecules. The following significant correlations were found in the total sample pooled: Ocular Surface Disease Index correlated with mechanical threshold (p < 0.01; rho = 0.324) and epidermal growth factor (p < 0.01, rho = -0.330), and mechanical threshold correlated with heat threshold (p < 0.01, rho = -0.321). CONCLUSIONS: Twenty-four hours after HCL removal, symptoms of discomfort in HCL wearers are not related to changes in corneal sensitivity or tear inflammatory mediator levels. This might indicate either that HCL wear has no effect on these parameters or that ocular surfaces recover from HCL-caused effects during the first hours after HCL removal. However, there were correlations for associations between symptoms, corneal sensitivity, and some molecules in tears. PMID- 26636404 TI - Association of nonalcoholic fatty liver disease with bone mineral density and serum osteocalcin levels in Korean men. AB - OBJECTIVE: Bone mineral density has been reported to negatively associate with nonalcoholic fatty liver disease. Osteocalcin, a bone formation marker and metabolic regulator, has been previously evaluated as the mediator between bone mineral density and nonalcoholic fatty liver disease. Herein, we aimed to investigate the correlations of nonalcoholic fatty liver disease with bone mineral density and serum osteocalcin levels in Korean men. METHODS: A total of 859 men (249 and 610 men with and without nonalcoholic fatty liver disease, respectively) were recruited for this retrospective cross-sectional study. All participants underwent hepatic ultrasonography and dual energy X-ray absorptiometry. Anthropometric and biochemical data, including the serum osteocalcin levels and homeostasis model assessment of insulin resistance (HOMA IR), were collected. RESULTS: Nonalcoholic fatty liver disease negatively associated with right-hip bone mineral density (odds ratio, 0.797; 95% confidence interval, 0.645-0.984; P=0.035) and serum osteocalcin (odds ratio, 0.948; 95% confidence interval, 0.910-0.988; P=0.011) after adjusting for BMI and HOMA-IR. The mean right-hip bone mineral density was lower in men with versus without nonalcoholic fatty liver disease after adjusting for serum osteocalcin, BMI and HOMA-IR (0.11+/-0.06 vs. 0.29+/-0.04; P=0.019). CONCLUSION: Nonalcoholic fatty liver disease negatively associated with right-hip bone mineral density and serum osteocalcin in Korean men. General population-based prospective studies evaluating the causal relationship between bone metabolism and nonalcoholic fatty liver disease are needed, and the mechanism linking nonalcoholic fatty liver disease to bone mineral density beyond insulin resistance and osteocalcin should be evaluated in the future. PMID- 26636405 TI - Evaluation of advanced fibrosis measured by transient elastography after hepatitis C virus protease inhibitor-based triple therapy. AB - AIM: Few studies have investigated the course of liver stiffness after treatment with protease inhibitors. We evaluated the impact of this therapy on liver fibrosis measured by transient elastography. METHODS: This multicenter observational, cohort, prospective study included 90 patients with hepatitis C genotype 1 treated with telaprevir or boceprevir who had advanced fibrosis evidenced by liver stiffness (>=9.5 kPa). Liver stiffness was measured at baseline and 24 weeks after treatment ended, and was compared with virological responses at week 12. RESULTS: Liver stiffness decreased in 89% of patients who achieved sustained virological response. The median intrapatient liver stiffness value at the end of follow-up decreased by 5.1 kPa (35%) from baseline compared with 0.1 kPa (0.5%) in those who did not achieve a sustained virological response (P<0.001). The liver stiffness level fell below 9.5 kPa in 58% of patients with sustained virological response, and 71% of those with sustained virological response and cirrhosis evidenced by liver stiffness at baseline achieved regression below 12.5 kPa by the end of follow-up. Sustained virological response was the only variable associated with improved liver stiffness in multivariate analysis (odds ratio: 17.3; 95% confidence interval: 4.4-67.6; P<0.001). CONCLUSION: In patients with advanced fibrosis measured by transient elastography at the beginning of protease inhibitor-based therapy with sustained virological response, liver stiffness was significantly reduced 24 weeks after treatment. This suggests the possibility of liver cirrhosis evidenced by liver stiffness regression after sustained virological response in a significant proportion of patients. PMID- 26636406 TI - Long-term outcomes in patients diagnosed with bile-acid diarrhoea. AB - OBJECTIVE: Bile-acid diarrhoea (BAD) is a recognized cause of chronic diarrhoea; however, its detection remains suboptimal. Currently, there is a paucity of follow-up studies evaluating BAD. This work evaluates the natural history of BAD by examining individuals diagnosed with BAD [7 days of Se-homocholic acid taurine (SeHCAT) retention<10%] and determining the use of and response to bile-acid sequestrants (BAS). MATERIALS AND METHODS: Of the 515 patients, 40% (207/515) who underwent an SeHCAT test at Sheffield Teaching Hospitals (2001-2012) for chronic diarrhoea had BAD. Of the 207 (51%) patients, 107 were diagnosed between 2001 and 2009. In accordance with the guidelines, all of these patients were commenced on BAS. In March 2013, these individuals were reassessed either in the clinic or over the telephone as part of a local service evaluation project. Comparisons were made of both pretreatment and post-treatment variables using a Wilcoxon rank test. RESULTS: Of the 107 patients, 54% (58/107) were followed up, with a median time since diagnosis of 6 years. Among them, 38% were still using BAS at follow up, with 28% using alternative antidiarrhoeals. The median stool frequency decreased from seven stools per day to three (P=0.0008) in those using BAS. The 34% of patients not receiving treatment had no change in their daily bowel frequency. The main reason for discontinuing treatment was poor tolerability of the BAS (colestyramine/colestipol). CONCLUSION: Our findings indicate that BAD is a chronic condition that best improves with BAS. Consideration should be given to therapeutic options that have a better tolerability profile. PMID- 26636407 TI - Primary sclerosing cholangitis associated with inflammatory bowel disease: an update. AB - Primary sclerosing cholangitis (PSC) is a chronic progressive disease, usually associated with underlying inflammatory bowel diseases (IBDs), with a prevalence of 60-80% in western countries. Herein, we review the current knowledge about the association between PSC and IBD in terms of clinical approach and long-term patient management. A PubMed search was conducted for English-language publications from 2000 through 2015 using the following keywords: primary sclerosing cholangitis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, diagnosis, therapy, follow-up, and epidemiology. In terms of diagnosis, liver function tests and histology are currently used. The medical treatment options for PSC associated with IBD do not differ from the cases of PSC alone, and include ursodeoxycholic acid and immunosuppressive agents. These treatments do not seem to improve survival, even if ursodeoxycholic acid given at low doses may be chemopreventive against colorectal cancer (CRC). Liver transplantation is the only potential curative therapy for PSC with reported survival rates of 85 and 70% at 5 and 10 years after transplant; however, there is a risk for PSC recurrence, worsening of IBD activity, and de-novo IBD occurrence after liver transplantation. PSC-IBD represents an important public health concern, especially in view of the increased risk for malignancy, including CRC. Long-life annual surveillance colonoscopy is usually recommended, although the exact timescale is still unclear. Further studies are required both to clarify whether annual colonoscopy is cost-effective, especially in younger patients, and to identify potential pharmaceutical agents and genetic targets that may retard disease progression and protect against CRC. PMID- 26636408 TI - Nonalcoholic fatty liver is not associated with incident chronic kidney disease: a large histology-based comparison with healthy individuals. AB - BACKGROUND: Nonalcoholic steatohepatitis or fibrosis is associated with the increased prevalence of impaired kidney function. It is not known whether nonalcoholic fatty liver (NAFL), which is steatosis without inflammation or fibrosis, is associated with renal impairment as these individuals are not candidates for liver biopsy. MATERIALS AND METHODS: The study group included all liver donors who underwent a preoperative liver biopsy for various reasons. NAFL was defined as more than 5% hepatocytes having steatosis and no changes of steatohepatitis and/or fibrosis. Individuals with NAFL were compared with individuals with normal liver histology. Estimated glomerular filtration rate was calculated with the Modification of Diet in Renal Disease and Chronic Kidney Disease Epidemiology Collaboration methods. RESULTS: The mean age of the study group was 35+/-10.3 years and the mean BMI was 26+/-3.2 kg/m. A total of 187 adults having NAFL (80 men) were compared with 186 (88 men) individuals with normal liver histology (controls). Individuals with steatosis had significantly higher BMI (26.8+/-3.5 vs. 25.5+/-3.8 kg/m, P<0.001) and serum alanine transaminase levels (33.8+/-13.3 vs. 27.2+/-9.8 IU/l, P<0.000). There was no significant difference in the estimated glomerular filtration rate between the normal histology group and the NAFL group with Modification of Diet in Renal Disease (115+/-21.8 vs. 114.4+/-23.2 ml/min, P=0.803) and Chronic Kidney Disease Epidemiology Collaboration methods (113.6+/-14.8 vs. 113+/-14.7 ml/min, P=0.668). There was no significant difference as regards serum creatinine (0.73+/-0.16 vs. 0.74+/-0.16 mg%, P=0.536), proteinuria (P=0.121), diabetes (1 vs. 4, P=0.372), and hypertension (2 vs. 6, P=0.174) in individuals of both groups. CONCLUSION: Presence of NAFL does not adversely affect renal function. PMID- 26636409 TI - The Effects of Viewing and Preferences for Online Cancer Information Among Patients' Loved Ones. AB - Emotional and psychological distress is common among loved ones of cancer patients, who sometimes report more severe mental health issues than the patients themselves. In addition, many loved ones feel as though their information needs are not being met, which can lead them to seek out additional information online. This survey research examined the experiences of cancer patients' loved ones in viewing online content about the disease and the emotional outcomes of such browsing sessions. Participants (N = 191) were recruited from cancer- and caregiver-related nonprofits and online discussion boards. Results indicated that patients' loved ones were active users of online cancer Web sites. They primarily viewed and expressed a desire for information-based, rather than support-based, content. Many individuals desired in-depth treatment information, and those who viewed it had significantly more hope. Interestingly, multiple regression analysis revealed that viewing user-generated content was associated only with negative emotions, illustrating the potential dangers of social media spaces. Overall, this study shows the need for supporting patients' loved ones during their almost inevitable viewings of online cancer information. More research is needed in order to determine the best methods of mitigating potential negative effects of cancer Web sites and developing a useful online resource for this population. PMID- 26636411 TI - Flavobacterium psychrophilum Infections in Salmonid Broodstock and Hatchery Propagated Stocks of the Great Lakes Basin. AB - Bacterial coldwater disease (BCWD), caused by Flavobacterium psychrophilum, threatens wild and propagated salmonids worldwide and leads to substantial economic losses. In addition to being horizontally transmitted, F. psychrophilum can be passed from infected parents to their progeny, furthering the negative impacts of this pathogen. In Michigan, both feral and captive salmonid broodstocks are the gamete sources used in fishery propagation efforts. A 5-year study was initiated to follow the prevalence of systemic F. psychrophilum infections in feral broodstocks of four species (steelhead Oncorhynchus mykiss [potadromous Rainbow Trout]; Coho Salmon O. kisutch; Chinook Salmon O. tshawytscha; and Atlantic Salmon Salmo salar) residing in three Great Lakes watersheds. Additionally, captive broodstocks of four species (Rainbow Trout, Brown Trout Salmo trutta, Lake Trout Salvelinus namaycush, and Brook Trout Salvelinus fontinalis) maintained at two facilities were assessed for the presence of F. psychrophilum. The resultant offspring from each broodstock population were sampled for F. psychrophilum infections multiple times throughout hatchery residency. Using selective flavobacterial culture and PCR confirmation, F. psychrophilum was detected in all broodstocks except the captive Lake Trout and Brook Trout. Logistic regression analysis demonstrated that among the infected feral broodstocks, Chinook Salmon from the Lake Michigan watershed had the highest prevalence of systemic F. psychrophilum infection (mean = 63.2%). Among the captive broodstocks, the Gilchrist Creek strain of Brown Trout had the highest infection prevalence (mean = 5%). Collectively, the captive broodstocks were found to have significantly lower infection prevalence than the feral broodstocks. Despite the high prevalence of systemic F. psychrophilum infections in many broodstock populations, the bacterium was rarely detected in their progeny during hatchery rearing. However, heavy losses associated with clinical BCWD outbreaks did occur. Collectively, our results reinforce that BCWD continues to threaten Great Lakes basin salmonids. PMID- 26636410 TI - Visualizing Impending Cerebral Circulatory Arrest Caused by Intracranial Hypertension Following Aneurysmal Subarachnoid Hemorrhage. PMID- 26636412 TI - Comprehensive Molecular Analyses in a Case of Masked Philadelphia Chronic Myeloid Leukemia. AB - Here, we report the case of an 80-year-old woman with masked Philadelphia chronic myeloid leukemia (Ph CML). At diagnosis, qualitative PCR demonstrated the presence of a typical e14a2 configuration, and chromosome analysis showed an apparently normal female karyotype. However, FISH with BCR-ABL1 dual fusion probes gave a positive signal in 152/200 analyzed nuclei, with the fusion signal detected on the long arm of a cytogenetically normal chromosome 9. Using locus specific probes for chromosome 9 and 22 telomeres, a third chromosome involvement was excluded. Furthermore, microarray analysis from the same specimens showed a normal result. Due to a high Charlson Comorbidity Index, the patient was treated with a reduced dose of imatinib, achieving a rapid hematological response after 1 month. However, after 6 months of imatinib therapy, she had to be considered as warning (Ph+ 26.5%, BCR-ABL1 >1%) according to the European LeukemiaNet 2013 recommendations. In conclusion, we confirmed the importance of a combination of cytogenetic and molecular techniques for the diagnosis and therapy monitoring of masked Ph CML, but, different from what has been reported in the literature so far, we cannot completely exclude the fact that the unusual cytogenetic pattern of this patient may have negatively influenced her response to tyrosine kinase inhibitor therapy. PMID- 26636413 TI - Ramipril inhibits high glucose-stimulated up-regulation of adhesion molecules via the ERK1/2 MAPK signaling pathway in human umbilical vein endothelial cells. AB - Ramipril has recently been shown to have anti-atherogenic properties. However, the specific mechanisms underlying these effects remain unclear. The purpose of this study was to determine the effects of ramipril on induction of adhesion molecules in human umbilical vein endothelial cells (HUVECs) using high-glucose (HG) conditions and to investigate possible underlying molecular mechanisms. The effects of ramipril on expression of intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1 production, and ERK phosphorylation were examined in HG-induced HUVECs with inhibitors targeting the mitogen-activated protein kinase (MAPK) signaling pathway. HG induced the expression of the adhesion molecules ICAM-1 and VCAM-1. Pretreatment with ramipril drastically inhibited ICAM-1 and VCAM-1 production in a time- and dose-dependent manner. Moreover, upon investigating the effects of ramipril on the MAPK/extracellular signal-regulated kinase (ERK) signaling pathway, we found that ramipril completely inhibited HG-induced phosphorylation of ERK1/2. ERK inhibitors completely prevented the inhibitory effect of HG. This study demonstrated that ramipril reduces HG-stimulated induction of ICAM-1 and VCAM-1 expression via MAPK signaling, which may be useful for inhibition of atherosclerosis. PMID- 26636414 TI - The effect of cultureware surfaces on functional and structural components of differentiated 3T3-L1 preadipocytes. AB - Experiments using cultured primary cells or cell lines are a routine in vitro approach used across multiple biological disciplines, However, the structural and functional influences of various cultureware materials on cultured cells is not clearly understood. Surface treatments of cultureware have proven to have profound effects on cell viability and proliferation. In this study, we investigated the impact of polystyrene and fluorocarbon cultureware dishes on the proteomic profile of differentiated 3T3-L1 preadipocytes. After expansion and differentiation of cells on appropriate cultureware dishes, cell lysates were separated using two-dimensional gel electrophoresis and proteins were visualized with Coomassie blue staining. Spots with the highest differential expression between the two culture conditions were subsequently analyzed using matrix assisted laser desorption/ionization mass spectrometry and the identified proteins were subjected to pathway analysis. We observed that 43% of all spots were differentially expressed depending on the cultureware. Pathway analysis revealed that glucose metabolism, mitochondrial structure and cell differentiation, represented by 14-3-3 protein-mediated signaling and the mitochondrial inner membrane organizing system (MINOS), were significantly affected by cultureware material. These results indicate that cultureware material can have a profound effect on key adipocyte functional pathways. These effects modifications of the cells should be reflected in the design of in vitro experiments and interpretation of their results. PMID- 26636415 TI - Effect of Smoothing in Generalized Linear Mixed Models on the Estimation of Covariance Parameters for Longitudinal Data. AB - Besides being mainly used for analyzing clustered or longitudinal data, generalized linear mixed models can also be used for smoothing via restricting changes in the fit at the knots in regression splines. The resulting models are usually called semiparametric mixed models (SPMMs). We investigate the effect of smoothing using SPMMs on the correlation and variance parameter estimates for serially correlated longitudinal normal, Poisson and binary data. Through simulations, we compare the performance of SPMMs to other simpler methods for estimating the nonlinear association such as fractional polynomials, and using a parametric nonlinear function. Simulation results suggest that, in general, the SPMMs recover the true curves very well and yield reasonable estimates of the correlation and variance parameters. However, for binary outcomes, SPMMs produce biased estimates of the variance parameters for high serially correlated data. We apply these methods to a dataset investigating the association between CD4 cell count and time since seroconversion for HIV infected men enrolled in the Multicenter AIDS Cohort Study. PMID- 26636416 TI - Immunolocalization of MMP 2, 9 and 13 in prednisolone induced osteoporosis in mice. AB - Long-term use of glucocorticoids (GC) causes rapid bone loss and increases the risk of osteoporotic fractures. Matrix metalloproteinase (MMPs), the most prominent kind of proteases implicated in the proteolytic degradation of the extracellular matrix (ECM), have been reported to be involved in pathological process of GC induced osteoporosis. However, the underlining mechanisms are still unclear. The aim of this study was to investigate the spatial expression and the potential function of MMP 2, 9 and 13 in osteoporosis induced by prednisolone in the tibiae of mice. In this experiment, mice were given prednisolone (15 mg/kg body weight) in PBS intragastrically every other day, or only PBS as control. Two weeks later, mice were fixed with transcardial perfusion of 4% paraformaldehyde in 0.1 M phosphate buffer (pH 7.4), and tibiae were extracted for histochemical analysis. Compared with control group, the number of TRAP-positive osteoclasts and the immunoreactivity of MMP 2, 9 and 13 were significantly increased in the trabecular bone of mice administered with prednisolone, leading to the decrease of trabecular bone volume. On the other hand, lighter eosin staining areas containing numerous empty lacunae of osteocytes and crevices were seen in the narrowing cortical bone. Furthermore, intense immunoreaction of MMP 2 and MMP 13 were found in the enlarged lacunae and the crevices, respectively. Taken together, we concluded that prednisolone administration induced the increase of MMP 2, 9 and 13 expressions, while MMP 2 and MMP 13 played essential roles in the osteocytic osteolysis and the early impaired areas in the cortical bone. Therefore, MMPs might be new potential therapeutic targets for prevention and treatment of glucocorticoid induced osteoporosis, especially osteocytic osteolysis. PMID- 26636417 TI - The association between urbanization and rheumatoid arthritis in Taiwan. AB - OBJECTIVES: To investigate the association between rheumatoid arthritis (RA) and urbanization and compare the medication selection for RA patients in urban vs. rural areas. METHODS: RA patients were identified among 1,000,000 random individuals from a 23-million-person nationwide health insurance database, and controls were matched at a 1 : 10 ratio. Taiwan's 359 townships were grouped into 7 urbanization levels. Geographic region and monthly income were also analyzed. Medication use in the most urbanized and less-urbanized areas were also compared. RESULTS: Rural dwellers had lower odds of having an RA diagnosis. The odds ratio (OR) for level 5 area residents of having an RA diagnosis was 0.62 (95% confidence interval (CI) 0.46 - 0.85; p = 0.002), and they were both 0.76 for level 6 - 7 area residents (95% CI, 0.61 - 0.95 for level 6; p = 0.017 and 0.60 - 0.96 for level 7; p = 0.021) compared to level 1 (the most urban dwellers). The ORs of having a new RA diagnosis were 0.57 (95% CI 0.41 - 0.79, p = 0.001) in eastern Taiwan and 0.33 (95% CI 0.15 - 0.69, p = 0.004) on offshore islands compared to northern Taiwan. No association was found between monthly income and RA. Urban-dwelling RA patients used more tumor necrosis factor-alpha antagonists (level 1 urbanization; n = 24; 2.3%) than RA patients in less-urbanized areas (level 2 - 7 urbanization n = 30; 1.3%; p = 0.038). CONCLUSION: Results of this study suggested that an RA diagnosis and treatment are associated with urbanization. PMID- 26636418 TI - Effects of a novel finasteride 0.25% topical solution on scalp and serum dihydrotestosterone in healthy men with androgenetic alopecia. AB - OBJECTIVE: The effects on scalp and serum dihydrotestosterone (DHT) of different doses of a novel topical solution of 0.25% finasteride (P-3074), a type 2 5alpha reductase, were investigated in men with androgenetic alopecia. METHODS: Two randomized, parallel-group studies were conducted. Study I: 18 men received 1 mL (2.275 mg) P-3074, applied to the scalp once a day (o.d.) or twice a day (b.i.d), or 1 mg oral tablet o.d. for 1 week. Study II: 32 men received P-3074 at the dose of 100 (0.2275 mg), 200 (0.455 mg), 300 (0.6285 mg), or 400 (0.91 mg) MUL or the vehicle o.d. for 1 week. Scalp and serum DHT and serum testosterone were evaluated at baseline and treatment end. RESULTS: Change from baseline in scalp DHT was -70% for P-3074 o.d. and approx. -50% for P-3074 b.i.d. and the tablet. Serum DHT decreased by 60 - 70%. The doses of 100 and 200 MUL P-3074 resulted in a -47/-52% scalp DHT reduction, similar to the 300 and 400 MUL doses (i.e., -37/ 54%). A -5.6% inhibition was observed for the vehicle. Serum DHT was reduced by only -24/-26% with 100 and 200 MUL P-3074 and by -44/-48% with 300 and 400 MUL P 3074. No relevant changes occurred for serum testosterone. CONCLUSIONS: The novel finasteride 0.25% solution applied o.d. at the doses of 100 and 200 MUL results in an appropriate inhibition of scalp DHT potentially minimizing the untoward sexual side-effects linked to a systemic DHT reduction. PMID- 26636419 TI - The use of unboosted darunavir in the setting of ritonavir intolerance: three case reports. AB - OBJECTIVE: To describe three patients with human immunodeficiency virus (HIV) who were successfully managed with unboosted darunavir (uDRV). CASE SUMMARIES: The three cases included one woman and two men aged 58, 54, and 51 years, respectively. All patients were HIV positive and unable to tolerate ritonavir boosted protease inhibitors secondary to significant gastrointestinal intolerance. Unboosted darunavir was tolerated without any further issues when prescribed with an optimized antiretroviral (ARV) background regimen. Despite low darunavir (DRV) concentrations, all three patients achieved a virologic response. DISCUSSION: Darunavir is a relatively well-tolerated ARV, but concurrent ritonavir administration has several disadvantages (e.g., dose-related hyperlipidemia, gastrointestinal intolerance, drug-drug interactions) which may decrease patient adherence. The use of uDRV may be particularly useful in patients with limited therapy options who are unable to tolerate ritonavir boosted protease inhibitors. Therapeutic drug monitoring (TDM) was performed as unboosted DRV has a bioavailability of 37% and the virologic and immunologic response has only been demonstrated with ritonavirboosted DRV. CONCLUSION: Successful use of uDRV may be an acceptable ARV option in carefully selected patients with limited treatment options, particularly when an optimized background regimen is included. Darunavir TDM should be strongly considered if uDRV is initiated. PMID- 26636420 TI - Large doses of uterotonic drugs caused type II second degree sinoatrial block during cesarean section. AB - In China, it is a routine procedure to inject 250 MUg of hemabate (sterile solution, an oxytocic, contains the tromethamine salt of the (I5S)-15 methyl analogue of naturally occurring prostaglandin F2alpha in a solution suitable for intramuscular injection) into the myometrium of patients experiencing uterine inertia after delivery, with an additional dose given in the event that the efficacy is not obvious. Although hemabate is prohibited from being used in patients with active liver disease, there are no restrictions regarding the application of hemabate in positive hepatitis B surface antigen (HbsAg)-positive subjects with normal liver function. Here we report adverse effects of hemabate in 1 HbsAg-positive subject with normal liver function. This subject experienced increased blood pressure, chest tightness, and type II second degree sinoatrial block 25 minutes after an additional injection of hemabate. Thus, special attention should be paid when applying hemabate in HbsAgpositive subjects with normal liver function. PMID- 26636421 TI - Hemocoagulase agkistrodon-induced anaphylactic shock: A case report and literature review. AB - Hemocoagulase agkistrodon for injection is the national first-class new drug of China with good hemostatic function and safety for capillary hemorrhage in abdominal incision of surgical patients. Adverse drug reactions (ADRs) to hemocoagulase agkistrodon are rarely reported. In this paper, we describe a case of a 41-year-old woman who developed anaphylactic shock attributed to hemocoagulase agkistrodon before colon cancer surgery. Based on the Naranjo ADR probability score, a "probable" cause and effect relationship existed for this case. Although the cause of anaphylactic reaction (hemocoagulase or excipient) and exact mechanism of hemocoagulase agkistrodon-induced anaphylactic reaction are unknown, attention should be drawn to potential ADRs in clinical use. PMID- 26636422 TI - Pharmacokinetics and tolerability of febuxostat after oral administration in healthy Chinese volunteers: a randomized, open-label, singleand multiple-dose three-way crossover study. AB - OBJECTIVE: Febuxostat is a novel non-purine selective inhibitor of xanthine oxidase indicated for the chronic management of hyperuricemia in patients with gout. The aim of the present study was to evaluate the pharmacokinetic properties and tolerability of single and multiple oral administrations of febuxostat capsules in healthy Chinese volunteers. METHODS: This openlabel, single- and multiple-dose three-way crossover study was conducted in healthy Chinese volunteers. Subjects were randomized to receive a single dose of febuxostat 40, 80, or 120 mg in separate trial periods, with a 1-week washout between periods. Those allocated to the 40 mg and 80 mg dose continued into the multiple-dose phase, in which they received 40 mg or 80 mg once daily for 6 consecutive days. During the course of the study, blood samples were collected and the concentrations of febuxostat were determined using LC-MS/MS. Pharmacokinetic parameters were estimated using a noncompartmental model. Tolerability was determined using clinical evaluation and monitoring of adverse events (AEs). RESULTS: 12 healthy Chinese volunteers were enrolled and completed 3 treatment periods. After oral administration of single doses of 40, 80, and 120 mg of febuxostat, the mean (SD) Cmax was 2,835.43 (1,136.41), 5,356.75 (1,711.33), and 7,718.21 (2,446.34) ng/mL, respectively; the AUC0-48h was 8,821.10 (3,018.35), 17,854.46 (5,113.28), and 30,832.05 (10,992.20) ng*h/ mL; the AUC0-infinity was 8,990.33 (3,046.14), 18,193.58 (5,160.80), and 31,466.93 (1,1074.74) ng*h/mL; the t1/2 was 5.95 (2.71), 9.41 (7.47), and 12.34 (10.34) hours; the Cl/F was 4.81 (1.18), 4.70 (1.21), and 4.18(1.19) L/h; and the Vz/F was 39.66 (16.69), 62.72 (51.41), and 73.41 (64.84) L. After administration of multiple doses of 40 and 80 mg febuxostat, the mean (SD) Cmax,ss was 2,762.38 (1,331.96) and 5,047.27 (1,456.57) ng/mL; the Cmin,ss was 124.10 (6.32) and 46.93 (15.86) ng/mL; the AUCss,0-tau was 8,525.49 (2,160.64) and 16,757.12 (4,223.17) ng*h /mL; the steadystate plasma concentration (Css) was 355.23 (90.03) and 698.21 (175.97) ng/mL; the t1/2 was 7.68 (3.30) and 11.33 (6.94) hours; the Cl/F was 4.99 (1.30) and 5.05 (1.22) L/h; and the Vz/F was 54.10 (24.10) and 85.51 (65.99) L. No serious AEs were reported, and there were no discontinuations due to AEs. CONCLUSION: The PK of febuxostat exhibited dose proportional kinetics from 40 to 120 mg dose. After multiple doses, the pharmacokinetic parameters of febuxostat were consistent with those after single doses. There was no accumulation in febuxostat exposure in healthy Chinese between multiple doses and single dose. At the doses studied, febuxostat appeared to be well tolerated in these healthy volunteers. PMID- 26636423 TI - Acute renal haemodynamic effects of glucagon-like peptide-1 receptor agonist exenatide in healthy overweight men. AB - AIMS: To determine the acute effect of glucagon-like peptide-1 (GLP-1) receptor agonist exenatide and the involvement of nitric oxide (NO) on renal haemodynamics and tubular function, in healthy overweight men. METHODS: Renal haemodynamics and tubular electrolyte handling were measured in 10 healthy overweight men (aged 20 27 years; BMI 26-31 kg/m(2)) during intravenous administration of placebo (saline 0.9%), exenatide, and exenatide combined with the NO-synthase inhibitor L-N(G) monomethyl arginine (L-NMMA). Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were determined by inulin and para-aminohippurate clearance techniques, respectively, based on timed urine sampling. Glomerular hydrostatic pressure and vascular resistance of afferent and efferent renal arterioles were calculated using the Gomez formulae. Urinary electrolytes, osmolality and pH were also measured. RESULTS: GFR increased by a mean of 18 +/- 20 (+20%; p = 0.021) and ERPF increased by a median (interquartile range) of 68 (26; 197) ml/min/1.73 m(2) (+14%; p = 0.015) during exenatide infusion versus placebo. During L-NMMA infusion, exenatide increased GFR by mean 8 +/- 12 ml/min/1.73 m(2) (+9%; p = 0.049). Exenatide increased estimated glomerular pressure by +6% (p = 0.015) and reduced afferent renal vascular resistance by 33% (p = 0.038), whereas these effects were blunted during L-NMMA infusion. Exenatide increased absolute and fractional sodium excretion, urinary osmolality and urinary pH. The tubular effects of exenatide were not altered by concomitant L-NMMA infusion. CONCLUSIONS: Exenatide infusion in healthy overweight men acutely increases GFR, ERPF and glomerular pressure, probably by reducing afferent renal vascular resistance, and at least partially in an NO-dependent manner. As baseline renal haemodynamics in patients with type 2 diabetes differ from those in healthy individuals, clinical studies on the renal effects of GLP-1 receptor agonists are warranted. PMID- 26636425 TI - Brief Report: Monoclonal Gammopathy and Risk of Lymphoma and Multiple Myeloma in Patients With Primary Sjogren's Syndrome. AB - OBJECTIVE: To assess the link between monoclonal gammopathy (MG), disease activity, and incidence of malignant hematologic disorders (MHDs), including lymphoma and multiple myeloma (MM), in patients with primary Sjogren's syndrome (SS). METHODS: Screening for the presence of MG was performed in 352 primary SS patients. Each patient with MG was paired with 2 age- and sex-matched primary SS controls without MG. Their characteristics were compared for the presence of risk factors for MG and for the relationship between MG and MHD. RESULTS: Twenty-six of the 352 primary SS patients (7.4%) had MG; 88% were women, with a median age of 62.7 years (interquartile range [IQR] 50.3-69.1 years) and a median disease duration of 7.8 years (IQR 3.6-12.8 years). The parameters associated with MG on multivariate analysis were higher disease activity, as measured by either the European League Against Rheumatism Sjogren's Syndrome Disease Activity Index (ESSDAI; adjusted odds ratio [OR] 9.7, P = 0.0002) or the Clinical ESSDAI (adjusted OR 6.7, P = 0.001), and low C4 level (adjusted OR 3.4, P = 0.04). After a median follow-up of 6.3 years (IQR 3.1-9.5 years), 10 patients with MG had developed an MHD (38.5%; 4 had lymphomas and 6 had MM), as compared with 4 patients in the control group (7.7%; all had lymphomas) (OR 7.5, P = 0.002). The only factor associated with the risk of MHDs was the presence of MG (adjusted OR 5.5, P = 0.02), which was principally associated with an increased risk of MM (23% versus 0%; P = 0.0009), but not lymphoma (15% versus 8%; P = 0.3). CONCLUSION: The presence of MG was associated with higher disease activity and an increased risk of MHD in primary SS. In the presence of MG, the risk of MM was even higher than the risk of lymphoma. These results suggest that regular monitoring of primary SS patients with MG for the emergence of both lymphoma and MM is necessary. PMID- 26636424 TI - Effects of Lowering Glycemic Index of Dietary Carbohydrate on Plasma Uric Acid Levels: The OmniCarb Randomized Clinical Trial. AB - OBJECTIVE: The effects of carbohydrates on plasma uric acid levels are a subject of controversy. We determined the individual and combined effects of carbohydrate quality (the glycemic index) and quantity (the proportion of total daily energy [percentage of carbohydrates]) on uric acid levels. METHODS: We conducted a randomized, crossover trial of 4 different diets in overweight or obese adults without cardiovascular disease (n = 163). Participants consumed each of 4 diets over a 5-week period, each of which was separated by a 2-week washout period. Body weight was kept constant. The 4 diets were high glycemic index (>=65) with high percentage of carbohydrates (58% kcal), low glycemic index (<=45) with low percentage of carbohydrates (40% kcal), low glycemic index with high percentage of carbohydrates, and high glycemic index with low percentage of carbohydrates. Plasma uric acid levels were measured at baseline and after completion of each 5 week period for comparison between the 4 diets. RESULTS: Of the 163 study participants, 52% were women and 50% were non-Hispanic African American subjects; their mean age was 52.6 years, and their mean +/- SD uric acid level was 4.7 +/- 1.2 mg/dl. Reducing the glycemic index lowered uric acid levels when the percentage of carbohydrates was low (-0.24 mg/dl; P < 0.001) or high (-0.17 mg/dl; P < 0.001). Reducing the percentage of carbohydrates marginally increased the uric acid level only when the glycemic index was high (P = 0.05). The combined effect of lowering the glycemic index and increasing the percentage of carbohydrates was -0.27 mg/dl (P < 0.001). This effect was observed even after adjustment for concurrent changes in kidney function, insulin sensitivity, and products of glycolysis. CONCLUSION: Reducing the glycemic index lowers uric acid levels. Future studies should examine whether reducing the glycemic index can prevent gout onset or flares. PMID- 26636426 TI - EVALUATING POTENTIAL IATROGENIC SUICIDE RISK IN TRAUMA-FOCUSED GROUP COGNITIVE BEHAVIORAL THERAPY FOR THE TREATMENT OF PTSD IN ACTIVE DUTY MILITARY PERSONNEL. AB - OBJECTIVE: To determine whether group cognitive processing therapy-cognitive only version (CPT-C) is associated with iatrogenic suicide risk in a sample of active duty US Army personnel diagnosed with posttraumatic stress disorder (PTSD). Possible iatrogenic effects considered include the incidence and severity of suicide ideation, worsening of preexisting suicide ideation, incidence of new onset suicide ideation, and incidence of suicide attempts among soldiers receiving group CPT-C. Comparison with group present-centered therapy (PCT) was made to contextualize findings. METHOD: One hundred eight soldiers (100 men, eight women) diagnosed with PTSD were randomized to receive either group CPT-C or group PCT. PTSD diagnosis was confirmed via structured clinician interview. Suicide ideation, depression severity, and PTSD severity were assessed at pretreatment, weekly during treatment, and 2 weeks, 6 months, and 12 months posttreatment. RESULTS: Rates of suicide ideation significantly decreased across both treatments. Among soldiers with pretreatment suicide ideation, severity of suicide ideation significantly decreased across both treatments and was maintained for up to 12 months posttreatment. Exacerbation of preexisting suicide ideation was uncommon in both treatments. New-onset suicide ideation was rare and similar across both treatments (<16%). There were no suicide attempts during treatment or follow-up in either group. Change in depression symptoms predicted change in suicide risk. CONCLUSIONS: Suicide-related outcomes were similar across both treatments and primarily associated with comorbid depression. Suicide related outcomes in group CPT-C were rare and comparable to patterns observed in an active, nontrauma-focused therapy, even among soldiers who entered treatment with suicide ideation. GOV IDENTIFIER: NCT01286415, https://clinicaltrials.gov/ct2/show/NCT01286415. PMID- 26636427 TI - Widespread papules and hyperkeratotic nodules. PMID- 26636428 TI - Novel Genetic Loci Control Calcium Absorption and Femur Bone Mass as Well as Their Response to Low Calcium Intake in Male BXD Recombinant Inbred Mice. AB - Low dietary calcium (Ca) intake during growth limits peak bone mass but physiological adaptation can prevent this adverse effect. To assess the genetic control on the physiologic response to dietary Ca restriction (RCR), we conducted a study in 51 BXD lines fed either 0.5% (basal) or 0.25% (low) Ca diets from ages 4 to 12 weeks (n = 8/line/diet). Ca absorption (CaAbs), femur bone mineral density (BMD), and bone mineral content (BMC) were examined. ANCOVA with body size as covariate was used to detect significant line and diet main effects, and line-by-diet interactions. Body size-corrected residuals were used for linkage mapping and to estimate heritability (h(2) ). Loci controlling the phenotypes were identified using composite interval mapping on each diet and for the RCR. h(2) of basal phenotypes (0.37-0.43) and their RCR (0.32-0.38) was moderate. For each phenotype, we identified multiple quantitative trait loci (QTL) on each diet and for the RCR. Several loci affected multiple traits: Chr 1 (88.3-90.6 cM, CaAbs, BMC), Chr 4 (45.8-49.2 cM, CaAbs, BMD, BMC), Chr 8 (28.6-31.6 cM, CaAbs, BMD, RCR), and Chr 15 (13.6-24 cM, BMD, BMC; 32.3-36 cM, CaAbs RCR, BMD). This suggests that gene clusters may regulate interdependent bone-related phenotypes. Using in silico expression QTL (eQTL) mapping and bioinformatic tools, we identified novel candidates for the regulation of bone under Ca stress (Ext1, Deptor), and for the first time, we report genes modulating Ca absorption (Inadl, Sc4mol, Sh3rf1, and Dennd3), and both Ca and bone metabolism (Tceanc2, Tll1, and Aadat). Our data reveal gene-by-diet interactions and the existence of novel relationships between bone and Ca metabolism during growth. (c) 2015 American Society for Bone and Mineral Research. PMID- 26636429 TI - Concentrations of polycyclic aromatic hydrocarbons in New York City community garden soils: Potential sources and influential factors. AB - A total of 69 soil samples from 20 community gardens in New York City (New York, USA) were collected and analyzed for 23 polycyclic aromatic hydrocarbons (PAHs) and black carbon. For each garden, samples were collected from nongrowing areas (non-bed) and from vegetable-growing beds, including beds with and without visible sources of PAHs. The sum of the US Environmental Protection Agency's 16 priority PAHs ranged up to 150 mg/kg, and the median (5.4 mg/kg) and mean (14.2 mg/kg) were similar to those previously reported for urban areas in the northeast United States. Isomer ratios indicated that the main sources of PAHs were petroleum, coal, and wood combustion. The PAH concentrations were significantly and positively associated with black carbon and with modeled air PAH concentrations, suggesting a consistent relationship between historical deposition of atmospheric carbon-adsorbed PAHs and current PAH soil concentrations. Median PAH soil concentration from non-bed areas was higher (7.4 mg/kg) than median concentration from beds in the same garden (4.0 mg/kg), and significantly higher than the median from beds without visible sources of PAHs (3.5 mg/kg). Median PAH concentration in beds from gardens with records of soil amendments was 58% lower compared with beds from gardens without those records. These results suggest that gardening practices in garden beds without visible sources of PAHs contribute to reduce PAH soil concentrations. PMID- 26636430 TI - Biocatalysis: Successfully Crossing Boundaries. AB - " ... The creation of robust biocatalysts with desired properties was previously challenging. Nowadays, knowledge of bioinformatics, protein engineering, molecular biology, high-throughput screening, as well as experience in biocatalysis and organic synthesis, are key skills to identify, develop, and implement novel synthetic routes ..." Read more in the Editorial by Uwe T. Bornscheuer. PMID- 26636431 TI - [4+3] Cycloaddition of Donor-Acceptor Cyclopropanes with Amphiphilic Benzodithioloimine as Surrogate for ortho-Bisthioquinone. AB - Donor-acceptor cyclopropanes were reacted with amphiphilic benzodithioloimine to give seven-membered heterocycles with two sulfur atoms. Formally, this transformation can be regarded as a [4+3] cycloaddition reaction of the three membered ring and ortho-bisthioquinone. The benzodithioloimine serves as a surrogate for this highly reactive diene. The structure of the products was confirmed by X-ray crystallography. Broad signals in (13) C NMR studies suggest that several conformers, slowly interconverting on the NMR timescale, are present at room temperature. PMID- 26636432 TI - Foscarnet, zidovudine and dolutegravir combination efficacy and tolerability for late stage HIV salvage therapy: A case-series experience. AB - Salvage therapy including foscarnet (PFA), zidovudine (ZDV) and an optimized background ART (OBT) has been shown to be effective in patients with advanced HIV infection, and no therapeutic options. Dolutegravir (DTG) may offer a more active combination. Objective was to describe efficacy and tolerability of PFA-ZDV-DTG containing regimen. In our cohort, we identified patients who: (i) had plasma HIV 1 RNA load (pVL) >50 c/ml (>100 for HIV-2) on combination ART (cART); (ii) had at least 1 PI/r, 1 NRTI, 1 NNRTI (for HIV-1), and at least 1 raltegravir resistance mutations; (iii) were naive to DTG; and (iv) initiated on a PFA-ZDV-DTG containing-regimen with 48 weeks (W48) of follow-up. Out of 5 patients, 2 were infected with HIV-2. At PFA-ZDV-DTG initiation, CD4 cell count was (/mm(3) ) of 64, 40, 10, in HIV-1, and 37, 199, in HIV-2 infected patients; and pVL (log10 c/ml) of 4.8, 5.1, 4.4, in HIV-1, and 3.6, 4.2, in HIV-2 infected patients, respectively. Median OBT genotypic sensitivity score was 1.5 [1-2]. PFA was discontinued in one patient, due to an acute renal failure. At W48, one HIV-1 infected patient had a pVL <50 c/ml and two <200 c/ml; the two HIV-2 infected patients had pVL >100 c/ml. No lack of treatment adherence was observed. In treatment experienced HIV-infected patients, failing cART and without other therapeutic options, a PFA-ZDV-DTG combination therapy could be effective. Renal adverse events should be monitored. PMID- 26636433 TI - Brief Report: Patients With Primary Sjogren's Syndrome Who Are Positive for Autoantibodies to Tripartite Motif-Containing Protein 38 Show Greater Disease Severity. AB - OBJECTIVE: Autoantibodies reactive with Ro52 (tripartite motif-containing protein 21 [TRIM21]) are detected in 70% of patients with primary Sjogren's syndrome (SS). TRIM21 belongs to a 34-member C-IV family of TRIM proteins. Although autoantibodies against other TRIM proteins within the C-IV family have been detected in the sera of patients with primary SS, their clinical relevance remains unclear. This study was undertaken to investigate the frequency of anti TRIM38 in patients with primary SS and evaluate its association with various clinical measures of the disease. METHODS: Serum samples from patients with primary SS (n = 235) and controls (n = 50) were analyzed for reactivity with in vitro-transcribed and -translated (35) S-methionine-labeled TRIM38 protein. The associations of anti-TRIM38 with various laboratory and clinical measures of primary SS were evaluated. Reactivity of anti-TRIM38 with different structural domains of TRIM38 was analyzed. Affinity-purified anti-TRIM38 antibodies were used to immunoprecipitate TRIM21. RESULTS: TRIM38-reactive autoantibodies were detected in the sera of 24 of the 235 patients with primary SS and 2 of the 50 controls. Anti-TRIM38 positivity was significantly associated with the presence of anti-Ro60, anti-Ro52, anti-La, rheumatoid factor, and hypergammaglobulinemia. Clinically, anti-TRIM38 was associated with significantly higher ocular surface staining scores, lower Schirmer's test scores, and minor labial salivary gland biopsy focus scores of >=3.0. Anti-TRIM38 antibodies mainly recognized the cortactin-binding protein 2 (CortBP-2; amino acids 128-238) and the B30.2/SPRY (amino acids 268-465) domains on TRIM38. Affinity-purified antibodies to TRIM38 CortBP-2 and TRIM38-B30.2/SPRY domains reacted with TRIM21. CONCLUSION: Our data demonstrate that anti-TRIM38 specificity arising in a subset of patients with primary SS is associated with increased severity of the disease. PMID- 26636435 TI - Amide-Substituted Titanocenes in Hydrogen-Atom Transfer Catalysis. AB - Two new catalytic systems for hydrogen-atom transfer (HAT) catalysis involving the N-H bonds of titanocene(III) complexes with pendant amide ligands are reported. In a monometallic system, a bifunctional catalyst for radical generation and reduction through HAT catalysis depending on the coordination of the amide ligand is employed. The pendant amide ligand is used to activate Crabtree's catalyst to yield an efficient bimetallic system for radical generation and HAT catalysis. PMID- 26636436 TI - Enantioselective Aza Michael-Type Addition to Alkenyl Benzimidazoles Catalyzed by a Chiral Phosphoric Acid. AB - Highly enantioselective Michael-type addition (MTA) reactions between N-protected alkenyl benzimidazoles and either pyrazoles or indazoles as nitrogen nucleophiles are accomplished for the first time using chiral phosphoric acid catalyst. Theoretical studies elucidated the reaction pathway and the origin of the stereochemical outcomes, where the catalyst substituent and the N-protecting group of benzimidazole contributed to the resulting high enantioselectivity. PMID- 26636434 TI - Osteoactivin Promotes Migration of Oral Squamous Cell Carcinomas. AB - Nearly 50% of patients with oral squamous cell carcinoma (OSCC) die of metastases or locoregional recurrence. Metastasis is mediated by cancer cell adhesion, migration, and invasion. Osteoactivin (OA) overexpression plays a role in metastases in several malignancies. The aims were to determine how integrin interactions modulate OA-induced OSCC cell migration; and to investigate OA effects on cell survival and proliferation. We confirmed OA mRNA and protein overexpression in OSCC cell lines. We assessed OA's interactions with integrins using adhesion inhibition assays, fluorescent immunocytochemistry and co immunoprecipitation. We investigated OA-mediated activation of mitogen-activated protein kinases (MAPKs) and cell survival. Integrin inhibition effects on OA mediated cell migration were determined. We assessed effects of OA knock-down on cell migration and proliferation. OA is overexpressed in OSCC cell lines, and serves as a migration-promoting adhesion molecule. OA co-localized with integrin subunits, and co-immunoprecipitated with the subunits. Integrin blocking antibodies, especially those directed against the beta1 subunit, inhibited cell adhesion (P = 0.03 for SCC15 cells). Adhesion to OA activated MAPKs in UMSCC14a cells and OA treatment promoted survival of SCC15 cells. Integrin-neutralizing antibodies enhanced cell migration with OA in the extracellular matrix. OA knock down resulted in decreased proliferation of SCC15 and SCC25 cells, but did not inhibit cell migration. OA in the extracellular matrix promotes OSCC cell adhesion and migration, and may be a novel target in the prevention of HNSCC spread. J. Cell. Physiol. 231: 1761-1770, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26636437 TI - Cyano-Functionalized Triarylamines on Coinage Metal Surfaces: Interplay of Intermolecular and Molecule-Substrate Interactions. AB - The self-assembly of cyano-functionalized triarylamine derivatives on Cu(111), Ag(111) and Au(111) was studied by means of scanning tunnelling microscopy, low energy electron diffraction, X-ray photoelectron spectroscopy and density functional theory calculations. Different bonding motifs, such as antiparallel dipolar coupling, hydrogen bonding and metal coordination, were observed. Whereas on Ag(111) only one hexagonally close-packed pattern stabilized by hydrogen bonding is observed, on Au(111) two different partially porous phases are present at submonolayer coverage, stabilized by dipolar coupling, hydrogen bonding and metal coordination. In contrast to the self-assembly on Ag(111) and Au(111), for which large islands are formed, on Cu(111), only small patches of hexagonally close-packed networks stabilized by metal coordination and areas of disordered molecules are found. The significant variety in the molecular self-assembly of the cyano-functionalized triarylamine derivatives on these coinage metal surfaces is explained by differences in molecular mobility and the subtle interplay between intermolecular and molecule-substrate interactions. PMID- 26636438 TI - Assembly of MOF Microcapsules with Size-Selective Permeability on Cell Walls. AB - The assembly of metal-organic frameworks (MOFs) into microcapsules has attracted great interest because of their unique properties. However, it remains a challenge to obtain MOF microcapsules with size selectivity at the molecular scale. In this report, we used cell walls from natural biomaterials as non-toxic, stable, and inexpensive support materials to assemble MOF/cell wall (CW) microcapsules with size-selective permeability. By making use of the hollow structure, small pores, and high density of heterogeneous nucleation sites of the cell walls, uniform and continuous MOF layers could be easily obtained by inside/outside interfacial crystallization. The prepared MOF/CW microcapsules have excellent stability and enable the steady, slow, and size-selective release of small molecules. Moreover, the size selectivity of the microcapsules can be adjusted by changing the type of deposited MOF. PMID- 26636439 TI - Structure versus properties in alpha-Fe2O3 nanowires and nanoblades. AB - We report structure/property relationships in bicrystalline alpha-Fe2O3 nanowires (NWs) and nanoblades (NBs), synthesized by thermal oxidation of iron foils with different surface roughness. The electrical properties of individual nanostructures were studied by in situ transmission electron microscopy. Current voltage (I-V) measurements using gold electrodes showed that a Schottky contact forms between alpha-Fe2O3 NWs whereas an ohmic contact forms between alpha-Fe2O3 NBs. The difference in transport properties is attributed to the existence of oxygen vacancies in the coincidence-site-lattice boundary region of alpha-Fe2O3 NBs. Magnetic measurements indicate that the temperature-dependent zero-field cooled magnetization rises more rapidly near the Morin transition temperature for alpha-Fe2O3 NBs than that for NWs. The distinct magnetic properties of the NBs are ascribed to the enhanced magnetic order induced by the structural order in the two-dimensional NBs. These alpha-Fe2O3 NBs are promising building blocks for electronic and magnetic devices since their 2D geometries facilitate integration into devices with realistic pathways to manufacturing. In addition, our study shows that boundary engineering is an effective approach for tailoring the physical properties of nanomaterials. PMID- 26636468 TI - Phenomenological Transition of an Aluminum Surface in an Ionic Liquid and Its Beneficial Implementation in Batteries. AB - Aluminum (Al) electrochemical dissolution in organic nonaqueous media and room temperature ionic liquids (RTILs) is partially hampered by the presence of a native oxide. In this work, Al activation in EMIm(HF)2.3F RTIL is reported. It was confirmed that as a result of the interaction of Al with the RTIL, a new film is formed instead of the pristine oxide layer. Aluminum surface modifications result in a transformation from a passive state to the active behavior of the metal. This was confirmed via the employment of electrochemical methods and characterization by XPS, AFM, and TEM. It was shown that the pristine oxide surface film dissolves in EMIm(HF)2.3F, allowing an Al-O-F layer to be formed instead. This newly built up layer dramatically restricts Al corrosion while enabling high rates of Al anodic dissolution. These beneficial features allow the implementation of Al as an anode in advanced portable power sources, such as aluminum-air batteries. PMID- 26636440 TI - Antibody-like Biorecognition Sites for Proteins from Surface Imprinting on Nanoparticles. AB - Natural antibodies are used widely for important applications such as biomedical analysis, cancer therapy, and directed drug delivery, but they are expensive and may have limited stability. This study describes synthesis of antibody-like binding sites by molecular imprinting on silica nanoparticles (SiNP) using a combination of four organosilane monomers with amino acid-like side chains providing hydrophobic, hydrophilic, and H-bonding interactions with target proteins. This approach provided artificial antibody (AA) nanoparticles with good selectivity and specificity to binding domains on target proteins in a relatively low-cost synthesis. The AAs were made by polymer grafting onto SiNPs for human serum albumin (HSA) and glucose oxidase (GOx). Binding affinity, selectivity, and specificity was compared to several other proteins using adsorption isotherms and surface plasmon resonance (SPR). The Langmuir-Freundlich adsorption model was used to obtain apparent binding constants (KLF) from binding isotherms of HSA (6.7 * 10(4)) and GOx (4.7 * 10(4)) to their respective AAs. These values were 4 300 fold larger compared to a series of nontemplate proteins. SPR binding studies of AAs with proteins attached to a gold surface confirmed good specificity and revealed faster binding for the target proteins compared to nontarget proteins. Target proteins retained their secondary structures upon binding. Binding capacity of AAHSA for HSA was 5.9 mg HSA/g compared to 1.4 mg/g for previously report imprinted silica beads imprinted with poly(aminophenyl)boronic acid. Also, 90% recovery for HSA spiked into 2% calf serum was found for AAHSA. PMID- 26636469 TI - Mitochondria Targetable Time-Gated Luminescence Probe for Singlet Oxygen Based on a beta-Diketonate-Europium Complex. AB - Singlet oxygen ((1)O2) plays a key role in the photodynamic therapy (PDT) technique of neoplastic diseases. In this work, by using a 9,10-dimethyl-2 anthryl-containing beta-diketone, 1,1,1,2,2-pentafluoro-5-(9',10'-dimethyl-2' anthryl)-3,5-pentanedione (Hpfdap), as a (1)O2-recognition ligand, a novel beta diketonate-europium(III) complex that can act as a luminescence probe for (1)O2, [Eu(pfdap)3(tpy)] (tpy = 2,2',2"-terpyridine), has been designed and synthesized for the time-gated luminescence detection of (1)O2 in living cells. The complex is weakly luminescent due to the quenching effect of 9,10-dimethyl-2-anthryl groups. After reaction with (1)O2, accompanied by the formation of endoperoxides of 9,10-dimethyl-2-anthryl groups, the luminescence quenching disappears, so that the long-lived luminescence of the europium(III) complex is switched on. The complex showed highly selective luminescence response to (1)O2 with a remarkable luminescence enhancement. Combined with the time-gated luminescence imaging technique, the complex was successfully used as a luminescent probe for the monitoring of the time-dependent generation of (1)O2 in 5-aminolevulinic acid (a PDT drug) loaded HepG2 cells during the photodynamic process. In addition, by coloading the complex and a mitochondrial indicator, Mito-Tracker Green, into HepG2 cells, the specific localization of [Eu(pfdap)3(tpy)] molecules in mitochondria of HepG2 cells was demonstrated by confocal fluorescence imaging measurements. PMID- 26636470 TI - Base-Induced Radical Carboamination of Nonactivated Alkenes with Aryldiazonium Salts. AB - A new transition-metal-free version of the Meerwein arylation has been developed. The key feature of this carboamination-type reaction is the slow base-controlled generation of aryl radicals from aryldiazonium tetrafluoroborates, so that a sufficient quantity of diazonium ions remains to enable efficient trapping of the alkyl radical adduct resulting from aryl radical addition to the alkene. Under strongly basic conditions, diazoanhydrides are likely to take over the role of the nitrogen-centered radical scavengers. PMID- 26636471 TI - Multicomponent Quantum Hall Ferromagnetism and Landau Level Crossing in Rhombohedral Trilayer Graphene. AB - Using transport measurements, we investigate multicomponent quantum Hall (QH) ferromagnetism in dual-gated rhombohedral trilayer graphene (r-TLG) in which the real spin, orbital pseudospin, and layer pseudospins of the lowest Landau level form spontaneous ordering. We observe intermediate QH plateaus, indicating a complete lifting of the degeneracy of the zeroth Landau level (LL) in the hole doped regime. In charge neutral r-TLG, the orbital degeneracy is broken first, and the layer degeneracy is broken last and only in the presence of an interlayer potential U?. In the phase space of U? and filling factor nu, we observe an intriguing "hexagon" pattern, which is accounted for by a model based on crossings between symmetry-broken LLs. PMID- 26636472 TI - The Interplay of Al and Mg Speciation in Advanced Mg Battery Electrolyte Solutions. AB - Mg batteries are an attractive alternative to Li-based energy storage due to the possibility of higher volumetric capacities with the added advantage of using sustainable materials. A promising emerging electrolyte for Mg batteries is the magnesium aluminum chloride complex (MACC) which shows high Mg electrodeposition and stripping efficiencies and relatively high anodic stabilities. As prepared, MACC is inactive with respect to Mg deposition; however, efficient Mg electrodeposition can be achieved following an electrolytic conditioning process. Through the use of Raman spectroscopy, surface enhanced Raman spectroscopy, (27)Al and (35)Cl nuclear magnetic resonance spectroscopy, and pair distribution function analysis, we explore the active vs inactive complexes in the MACC electrolyte and demonstrate the codependence of Al and Mg speciation. These techniques report on significant changes occurring in the bulk speciation of the conditioned electrolyte relative to the as-prepared solution. Analysis shows that the active Mg complex in conditioned MACC is very likely the [Mg2(MU Cl)3.6THF](+) complex that is observed in the solid state structure. Additionally, conditioning creates free Cl(-) in the electrolyte solution, and we suggest the free Cl(-) adsorbs at the electrode surface to enhance Mg electrodeposition. PMID- 26636473 TI - Electronic Structure of a Mixed-Metal Fluoride-Centered Triangle Complex: A Potential Qubit Component. AB - A novel fluoride-centered triangular-bridged carboxylate complex, [Ni2Cr(MU3 F)(O2C(t)Bu)6(HO2C(t)Bu)3] (1), is reported. Simple postsynthetic substitution of the terminal pivalic acids in 1 with pyridine and 4-methylpyridine led to the isolation of [Ni2Cr(MU3-F)(O2C(t)Bu)6(C5H5N)3] (2) and [Ni2Cr(MU3 F)(O2C(t)Bu)6((4-CH3)C5H4N)3] (3). Structural and magnetic characterizations carried out on the series reveal a dominating antiferromagnetic interaction between the nickel and chromium centers leading to an S = (1)/2 ground state with a very unusual value of geff = 2.48. PMID- 26636474 TI - Local Excitation Approximations to Time-Dependent Density Functional Theory for Excitation Energies in Solution. AB - We derive, implement, and test three different local excitation approximations (LEAs) to time-dependent density functional theory (TDDFT) that are designed to be extremely efficient for computing excitations that are localized on a single chromophore surrounded by explicit solvent molecules. One of these approximations is equivalent to the "TDDFT for molecular interactions" [TDDFT(MI)] method that we have introduced previously, which exploits non-orthogonal, absolutely localized molecular orbitals to approximate full TDDFT for systems consisting of multiple, weakly-coupled chromophores. Further approximations are possible when the excitation is localized on only a single subsystem and are introduced here to reduce the cost of LEA-TDDFT(MI) with respect even to TDDFT(MI). We apply these methods to compute solvatochromatic shifts for the n -> pi* excitations in aqueous acetone and pyridine. The LEA-TDDFT(MI) method accurately reproduces the solvent-induced blue shifts in these systems, at a significant reduction in cost as compared to conventional TDDFT. PMID- 26636475 TI - Visualizing Organophosphate Precipitation at the Calcite-Water Interface by in Situ Atomic-Force Microscopy. AB - Esters of phosphoric acid constitute a large fraction of the total organic phosphorus (OP) in the soil environment and, thus, play an important role in the global phosphorus cycle. These esters, such as glucose-6-phosphate (G6P), exhibit unusual reactivity toward various mineral particles in soils, especially those containing calcite. Many important processes of OP transformation, including adsorption, hydrolysis, and precipitation, occur primarily at mineral-fluid interfaces, which ultimately governs the fate of organophosphates in the environment. However, little is known about the kinetics of specific mineral surface-induced adsorption and precipitation of organophosphates. Here, by using in situ atomic-force microscopy (AFM) to visualize the dissolution of calcite (1014) faces, we show that the presence of G6P results in morphology changes of etch pits from the typical rhombohedral to a fan-shaped form. This can be explained by a site-selective mechanism of G6P-calcite surface interactions that stabilize the energetically unfavorable (0001) or (0112) faces through step specific adsorption of G6P. Continuous dissolution at calcite (1014)-water interfaces caused a boundary layer at the calcite-water interface to become supersaturated with respect to a G6P-Ca phase that then drives the nucleation and growth of a G6P-Ca precipitate. Furthermore, after the introduction of the enzyme alkaline phosphatase (AP), the precipitates were observed to contain a mixture of components associated with G6P-Ca, amorphous calcium phosphate (ACP) hydroxyapatite (HAP) and dicalcium phosphate dihydrate (DCPD). These direct dynamic observations of the transformation of adsorption- and complexation surface precipitation and enzyme-mediated pathways may improve the mechanistic understanding of the mineral-interface-induced organophosphate sequestration in the soil environment. PMID- 26636476 TI - Correction to Alternative and Legacy Perfluoroalkyl Substances: Differences between European and Chinese River/Estuary Systems. PMID- 26636477 TI - Predictive Sampling of Rare Conformational Events in Aqueous Solution: Designing a Generalized Orthogonal Space Tempering Method. AB - In aqueous solution, solute conformational transitions are governed by intimate interplays of the fluctuations of solute-solute, solute-water, and water-water interactions. To promote molecular fluctuations to enhance sampling of essential conformational changes, a common strategy is to construct an expanded Hamiltonian through a series of Hamiltonian perturbations and thereby broaden the distribution of certain interactions of focus. Due to a lack of active sampling of configuration response to Hamiltonian transitions, it is challenging for common expanded Hamiltonian methods to robustly explore solvent mediated rare conformational events. The orthogonal space sampling (OSS) scheme, as exemplified by the orthogonal space random walk and orthogonal space tempering methods, provides a general framework for synchronous acceleration of slow configuration responses. To more effectively sample conformational transitions in aqueous solution, in this work, we devised a generalized orthogonal space tempering (gOST) algorithm. Specifically, in the Hamiltonian perturbation part, a solvent accessible-surface-area-dependent term is introduced to implicitly perturb near solute water-water fluctuations; more importantly in the orthogonal space response part, the generalized force order parameter is generalized as a two dimension order parameter set, in which essential solute-solvent and solute solute components are separately treated. The gOST algorithm is evaluated through a molecular dynamics simulation study on the explicitly solvated deca-alanine (Ala10) peptide. On the basis of a fully automated sampling protocol, the gOST simulation enabled repetitive folding and unfolding of the solvated peptide within a single continuous trajectory and allowed for detailed constructions of Ala10 folding/unfolding free energy surfaces. The gOST result reveals that solvent cooperative fluctuations play a pivotal role in Ala10 folding/unfolding transitions. In addition, our assessment analysis suggests that because essential conformational events are mainly driven by the compensating fluctuations of essential solute-solvent and solute-solute interactions, commonly employed "predictive" sampling methods are unlikely to be effective on this seemingly "simple" system. The gOST development presented in this paper illustrates how to employ the OSS scheme for physics-based sampling method designs. PMID- 26636478 TI - Philanthropy and Advocacy-Led Development of Gene Therapies and Drugs for Alpha-1 Antitrypsin Deficiency. PMID- 26636479 TI - Use of inpatient rehabilitation for cancer patients in Switzerland: who undergoes cancer rehabilitation? AB - QUESTION UNDER STUDY: Rehabilitation for cancer patients aims to reduce physical disability and mental distress resulting from the disease and its treatment. However, little is known about the use of cancer inpatient rehabilitation in Switzerland in relation to sociodemographic and medical characteristics. The main purpose of this study was to evaluate whether there are differences in sociodemographic and medical characteristics between patients who underwent inpatient rehabilitation (users) and those who did not (nonusers). METHODS: A total of 238 cancer patients from the University Hospital Zurich were included. The sociodemographic and medical characteristics of inpatient rehabilitation users were assessed and compared with those of nonusers. We analysed the differences between inpatient rehabilitation users and nonusers. RESULTS: Of the patients included, 101 (42.4%) used inpatient rehabilitation. They were less likely to be employed (p = 0.029), stayed longer in hospital (p <0.001), and were more likely to have semiprivate or private supplementary health insurance (p = 0.030) than nonusers. There were differences in cancer site (p = 0.001). Patients with tumours of the digestive organs or of the thoracic organs were more likely to use rehabilitation, whereas breast cancer patients were less likely to use it. Stratified analyses showed that male patients with semiprivate or private supplementary health insurance (p = 0.037), lower education (p = 0.039), and lower likelihood of employment (p = 0.051) were more likely to use rehabilitation. Women with an advanced tumour stage used inpatient rehabilitation more often (p = 0.012). CONCLUSIONS: Findings show the influence of duration of hospitalisation, insurance type, cancer site, employment status, and gender on the use of inpatient cancer rehabilitation. The results indicate the need of structured standardised procedures for medical referral to be implemented based on screening. PMID- 26636480 TI - Maternal Serum Resistin Is Reduced in First Trimester Preeclampsia Pregnancies and Is a Marker of Clinical Severity. AB - OBJECTIVE: To examine whether resistin levels in first trimester maternal serum are associated with insulin resistance or preeclampsia (PE). METHODS: A case control study of maternal serum resistin concentration conducted using 285 normal pregnancies and 123 PE pregnancies matched for gestational age, parity and maternal age. Samples were taken in gestational weeks 10+0-13+6. RESULTS: There was a negative correlation between resistin and clinical severity of PE, but no correlation with IS, TNF-alpha, body mass index, birth weight and pregnancy length. CONCLUSIONS: Resistin is reduced in first trimester of PE pregnancies, particularly in severe PE. Inflammation and IS cannot explain this phenomenon. PMID- 26636481 TI - The Annual September Peak in Asthma Exacerbation Rates. Still a Reality? AB - RATIONALE: Recent research suggests that the asthma epidemic observed in the 1980s and 1990s has stabilized. Changing trends in asthma may have an impact on the well-reported global phenomenon of the "asthma September peak." The 38th week of the year has been identified as the peak time for asthma exacerbations among children. OBJECTIVES: The purposes of this study were to examine the longitudinal trend of the September peak and to see if it changed over time, differed by age groups, or varied across different geographical regions. METHODS: Monthly rates of asthma emergency department (ED) and physician outpatient visits were calculated using data provided by the Ontario Asthma Surveillance Information System from 2003 to 2013 for patients of all ages. The Ontario Asthma Surveillance Information System is a population-based surveillance system with over 2 million individuals with asthma. Age-specific rates were calculated using the prevalent asthma population-asthma individuals with at least one health service claim for asthma in the respective year-as the denominator. Rates were stratified by age group and region of residence. Spatial relationships within the province were tested to examine if the September peak was more prominent in certain regions of Ontario. MEASUREMENTS AND MAIN RESULTS: The highest September peak in ED visits was observed in 2005 for children aged 0-4 years and 5-9 years (18.35 and 8.11 per 1,000 asthma prevalence, respectively). The rate of asthma ED visits of all children was consistently highest in September; however, the spike became marginally less pronounced over time. Since 2005, there has been a 51.7% decrease in the September asthma ED visit rate for all age groups. Monthly physician visits for all age groups usually peaked in October, roughly 4 weeks following the peak in ED visits. Analysis by residence showed that rates throughout Ontario were higher in September than in other months, suggesting that the spike was widespread rather than localized. CONCLUSIONS: While the magnitude of the September peak has decreased over time, the asthma ED visit rate remains significantly higher in September than in other months. Physician visits are also highest in the fall. These findings stress the importance of empowering children and families to maintain good asthma control throughout the year, including hand washing, to minimize respiratory viral infections in September. PMID- 26636482 TI - Potential approaches for heterologous prion protein treatment of prion diseases. AB - Prion diseases, or transmissible spongiform encephalopathies (TSEs) are progressive, fatal neurodegenerative diseases with no effective treatment. The pathology of these diseases involves the conversion of a protease sensitive form of the cellular prion protein (PrP(C)) into a protease resistant infectious form (PrP(res)). The efficiency of this conversion is predicated upon a number of factors, most notably a strong homology between cellular PrP(C) and PrP(res). In our recently published study, we infected mice with the RML-Chandler strain of scrapie and treated them with heterologous hamster prion proteins. This treatment was seen to reduce clinical signs of prion disease, to delay the onset of clinical symptoms and to prolong survival. In this current article we discuss potential mechanisms of action of treatment with heterologous prion proteins. We also discuss potential extensions of these studies using a heterologous rabbit PrP-based treatment strategy or a peptide based strategy, and improvement of treatment delivery including a lentiviral-based system. PMID- 26636483 TI - Lactate promotes glutamine uptake and metabolism in oxidative cancer cells. AB - Oxygenated cancer cells have a high metabolic plasticity as they can use glucose, glutamine and lactate as main substrates to support their bioenergetic and biosynthetic activities. Metabolic optimization requires integration. While glycolysis and glutaminolysis can cooperate to support cellular proliferation, oxidative lactate metabolism opposes glycolysis in oxidative cancer cells engaged in a symbiotic relation with their hypoxic/glycolytic neighbors. However, little is known concerning the relationship between oxidative lactate metabolism and glutamine metabolism. Using SiHa and HeLa human cancer cells, this study reports that intracellular lactate signaling promotes glutamine uptake and metabolism in oxidative cancer cells. It depends on the uptake of extracellular lactate by monocarboxylate transporter 1 (MCT1). Lactate first stabilizes hypoxia-inducible factor-2alpha (HIF-2alpha), and HIF-2alpha then transactivates c-Myc in a pathway that mimics a response to hypoxia. Consequently, lactate-induced c-Myc activation triggers the expression of glutamine transporter ASCT2 and of glutaminase 1 (GLS1), resulting in improved glutamine uptake and catabolism. Elucidation of this metabolic dependence could be of therapeutic interest. First, inhibitors of lactate uptake targeting MCT1 are currently entering clinical trials. They have the potential to indirectly repress glutaminolysis. Second, in oxidative cancer cells, resistance to glutaminolysis inhibition could arise from compensation by oxidative lactate metabolism and increased lactate signaling. PMID- 26636484 TI - Diagnosis and treatment of small intestinal bacterial overgrowth. AB - A huge number of bacteria are hosted in the gastrointestinal tract, following a gradient increasing towards the colon. Gastric acid secretion and intestinal clearance provide the qualitative and quantitative partitioning of intestinal bacteria; small intestinal bacteria overgrowth (SIBO) occurs when these barrier mechanisms fail. Diagnosis of SIBO is challenging due to the low specificity of symptoms, the frequent association with other diseases of the gastrointestinal tract and the absence of optimal objective diagnostic tests. The therapeutic approach to SIBO is oriented towards resolving predisposing conditions, and is supported by antibiotic treatment to restore the normal small intestinal microflora and by modifications of dietary habits for symptomatic relief. In the near future, metagenomics and metabolomics will help to overcome the uncertainties of SIBO diagnosis and the pitfalls of therapeutic management, allowing the design of a personalized strategy based on the direct insight into the small intestinal microbial community. PMID- 26636485 TI - Policy Levers Key for Primary Health Care Organizations to Support Primary Care Practices in Meeting Medical Home Expectations: Comparing Leading States to the Australian Experience. AB - Several countries with highly ranked delivery systems have implemented locally based, publicly-funded primary health care organizations (PHCOs) as vehicles to strengthen their primary care foundations. In the United States, state governments have started down a similar pathway with models that share similarities with international PHCOs. The objective of this study was to determine if these kinds of organizations were working with primary care practices to improve their ability to provide comprehensive, coordinated, and accessible patient-centered care that met quality, safety, and efficiency outcomes-all core attributes of a medical home. This qualitative study looked at 4 different PHCO models-3 from the United States and 1 from Australia-with similar objectives and scope. Primary and secondary data included semi-structured interviews with 26 PHCOs and a review of government documents. The study found that the 4 PHCO models were engaging practices to meet a number of medical home expectations, but the US PHCOs were more uniform in efforts to work with practices and focused on arranging services to meet the needs of complex patients. There was significant variation in level of effort between the Australian PHCOs. These differences can be explained through the state governments' selection of payment models and use of data frameworks to support collaboration and incentivize performance of both PHCOs and practices. These findings offer policy lessons to inform health reform efforts under way to better capitalize on the potential of PHCOs to support a high-functioning primary health foundation as an essential component to a reformed health system. PMID- 26636487 TI - A Biomechanical Comparison of Isometric and Anatomic Medial Patellofemoral Ligament Reconstruction. AB - The purpose of this study was to compare two different methods of medial patellar femoral ligament (MPFL) reconstructions: isometric and anatomic. These were then compared with the native MPFL. Fourteen fresh frozen cadaveric knees were carefully dissected to expose the MPFL. The patella was laterally translated 10 mm using an Instron and values were recorded for the intact ligament and the reconstructions. Neither the anatomic nor the isometric reconstructions completely restored the biomechanical properties of the intact MPFL. There were fewer differences between the isometric reconstruction and the intact specimens. The higher forces and stiffer constructs that occurred with the anatomic reconstruction may suggest that this reconstruction technique could overconstrain the patellofemoral joint. PMID- 26636488 TI - Extensor Mechanism Disruption in Knee Dislocation. AB - Disruption of the knee extensor mechanism is a challenging injury with no clear consensus on optimal treatment. Although rare in the setting of knee dislocations, these injuries should not be overlooked. Acute, complete rupture of either the quadriceps or patellar tendon necessitates primary repair with or without augmentation. Surgical management may also be required in the setting of a partial tear if a significant extensor lag is present or nonoperative treatment has failed. Tendon augmentation is used during primary repair if the native tissue is inadequate or after a failed primary repair. The purpose of this study is to evaluate extensor mechanism disruption incidence, injury patterns, associated injuries, and surgical options, including a novel tendon augmentation technique. This procedure consists of primary patellar or quadriceps tendon repair with semitendinosus autograft augmentation utilizing a distal or proximal patellar socket. Advantages of repair with tendon augmentation include accelerated rehabilitation, decreased risk of patellar fracture from transverse or longitudinal bone tunnels, and less hardware complications. We recommend consideration of this technique for selected cases of acute extensor mechanism disruption in the setting of tibiofemoral dislocation. PMID- 26636486 TI - GADD45A inhibits autophagy by regulating the interaction between BECN1 and PIK3C3. AB - GADD45A is a TP53-regulated and DNA damage-inducible tumor suppressor protein, which regulates cell cycle arrest, apoptosis, and DNA repair, and inhibits tumor growth and angiogenesis. However, the function of GADD45A in autophagy remains unknown. In this report, we demonstrate that GADD45A plays an important role in regulating the process of autophagy. GADD45A is able to decrease LC3-II expression and numbers of autophagosomes in mouse tissues and different cancer cell lines. Using bafilomycin A1 treatment, we have observed that GADD45A regulates autophagosome initiation. Likely, GADD45A inhibition of autophagy is through its influence on the interaction between BECN1 and PIK3C3. Immunoprecipitation and GST affinity isolation assays exhibit that GADD45A directly interacts with BECN1, and in turn dissociates the BECN1-PIK3C3 complex. Furthermore, we have mapped the 71 to 81 amino acids of the GADD45A protein that are necessary for the GADD45A interaction with BECN1. Knockdown of BECN1 can abolish autophagy alterations induced by GADD45A. Taken together, these findings provide the novel evidence that GADD45A inhibits autophagy via impairing the BECN1-PIK3C3 complex formation. PMID- 26636489 TI - Clinician reported ease of use for a novel fibrin sealant patch for hemostasis: results from four randomized controlled trials. AB - BACKGROUND: In addition to rapid and sustained efficacy, ease of use is also an important characteristic of topical hemostats. OBJECTIVES: To evaluate clinician reported ease of use for the Evarrest fibrin sealant patch across various surgical bleeding situations. METHODS: An ease of use questionnaire (EUQ) was validated and administered in four randomized studies comparing the fibrin sealant patch to standard of care (SoC) in soft tissue and hepatic surgical bleeding. Three of these randomized studies have been previously published and all have been registered (NCT00658723; NCT00977925; NCT01166243; NCT01993888). The EUQ is a 19 item instrument evaluating clinician's preferences on five subscales: product ease of use, satisfaction with product properties and efficiency, confidence in product efficacy, global confidence, and global satisfaction. A pair-wise meta-analysis using a random effects model was conducted on EUQ scores for trials that reported data for both treatment arms. Individual scores are presented for each trial. RESULTS: The fibrin sealant patch demonstrated numerically greater scores than SoC in all EUQ subscales. The meta analysis demonstrated that fibrin sealant patch scores improved for all subscales compared with SoC: satisfaction with product properties (mean difference [MD] = 0.38, 95% CI: 0.04 to 0.73; P = 0.03), confidence in efficacy (MD = 1.10, 95% CI: 0.47 to 1.74; P = 0.0007), global confidence (MD = 0.57, 95% CI: 0.05 to 1.10, P = 0.03), global satisfaction (MD = 0.79, 95% CI: 0.32 to 1.26, P = 0.001), and ease of use (MD = 0.33, 95% CI: -0.29 to 0.94; P = 0.23). Fibrin sealant patch single arm trial results aligned with these findings. CONCLUSIONS: Physicians consistently reported high EUQ scores for the fibrin sealant patch across surgical bleeding populations. An important limitation of this study was that the composition of SoC varied across studies and EUQ data were only available for the SoC in two of four trials. Future studies should evaluate ease of use for other hemostats and across other surgical subspecialties, as data are currently limited. PMID- 26636490 TI - Women in Metabolism: Part 3. AB - The "Rosies" of Cell Metabolism are back for the third part of the "Women in Metabolism" 2015 series. We are closing our anniversary celebrations with 14 inspiring and engaging new stories from women scientists in the metabolism field. A round of applause to all who contributed and supported this project! PMID- 26636491 TI - SCFAs Take a Toll En Route to Metabolic Syndrome. AB - Gut dysbiosis is associated with development of metabolic syndrome in Tlr5(-/-) mice, but the underlying mechanism remains unclear. In this issue, Singh et al. (2015) report that augmented SCFA levels play a deleterious role in metabolic syndrome by promoting conversion of SFA to oleate in Tlr5(-/-) mice via increased liver SCD1expression. PMID- 26636492 TI - Metastasis and Oxidative Stress: Are Antioxidants a Metabolic Driver of Progression? AB - The role of reactive oxygen species (ROS) and antioxidants in cancer is controversial because of their context-dependent ability to promote or suppress tumorigenesis. Piskounova et al. (2015) now show that ROS limit distant metastasis: only cells with increased antioxidant capacity are able to succeed in their purpose to metastasize. PMID- 26636493 TI - Casein Kinase 2--A Kinase that Inhibits Brown Fat Formation. AB - In adipose tissue, there is a delicate balance between storing and expending energy. In this issue, Shinoda et al. (2015) use phosphoproteomics to identify casein kinase 2 (CK2) as a suppressor of brown adipocyte formation, providing insights into how adipose tissue regulates its composition of white versus brown adipocytes. PMID- 26636494 TI - Can Your Microbiome Tell You What to Eat? AB - Prospects for using the gut microbiome for personalized medicine are substantial since the gut microbiome is known to modulate metabolism and varies substantially among individuals. Zeevi et al. (2015) demonstrate that the gut microbiota can be used to predict individualized blood glucose responses to particular foods, which differ between individuals. PMID- 26636496 TI - Phosphatidylethanolamine N-methyltransferase gene rs7946 polymorphism plays a role in risk of nonalcoholic fatty liver disease: evidence from meta-analysis. AB - BACKGROUND: Phosphatidylethanolamine N-methyltransferase (PEMT) governs the secretion of hepatic triglycerides in the form of very low-density lipoprotein and has been implicated in nonalcoholic fatty liver disease (NAFLD). Studies on the role of the PEMT rs7946 polymorphism as a genetic modifier of NAFLD have reported inconsistent results. This meta-analysis was carried out to evaluate and summarize the association of PEMT rs7946 with susceptibility to NAFLD. METHODS: A comprehensive literature search in Scopus, PubMed, Embase, Science Direct and Google Scholar was performed up to 31 August 2015, followed by data extraction and examination of summary estimates. RESULTS: Six independent studies with a total of 792 NAFLD cases and 2722 controls fulfilled the inclusion criteria. Pooled results indicated that the rs7946 A-allele was associated significantly with an increased risk of NAFLD [odds ratio (OR) 1.55, 95% confidence interval (CI) 1.14-2.11, P=0.005]. A significant association was also found in alternative genetic models of inheritance: dominant, recessive and homozygote (OR 1.62, 95% CI 1.10-2.39, P=0.01; OR 1.42, 95% CI 1.12-1.81, P=0.003; and OR 1.64, 95% CI 1.18-2.29, P=0.004, respectively). Subgroup analysis by ethnicity indicated a significant association only in the East-Asians in the additive (OR=2.08, 95% CI 1.12-3.86, P=0.02), recessive (OR=2.94, 95% CI 1.60-5.37, P=0.0005) and homozygote (OR=1.86, 95% CI 1.15-3.01, P=0.01) models. CONCLUSION: This study provides evidence of a significant association between the PEMT rs7946 A-allele and a risk of NAFLD, with the effect being more prominent in East-Asians, but not in non-Asians. PMID- 26636497 TI - Virulence profile: Nathalie Pujol. PMID- 26636498 TI - Incidence of Pediatric Inflammatory Bowel Disease in Finland: An Environmental Study. AB - OBJECTIVES: The aim of this study was to explore possible environmental factors behind the regional differences in the incidence of pediatric inflammatory bowel disease (IBD). METHODS: All of the patients diagnosed with IBD who were aged 0 to 14 years in Finland between 1987 and 2003 were identified from the Social Insurance Institution database. Finland was divided into squares of 250 * 250 m, and spatial variations of incidence rates were evaluated accordingly. The role of the environmental determinants (pediatric population density, agricultural industry, chemical contaminants of tap water and proximity to the sea or paper mills) in the geographic variations of the incidence rates was evaluated. RESULTS: During the study period, the overall incidence of pediatric IBD was 6.5 of 100,000 (95% confidence interval [CI] 6.1-6.9). The incidence in very sparsely populated areas (<=10 person-years per 250 * 250 m) was 9.2 of 100,000 (95% CI 6.3-13.1) and 5.6 of 100,000 (95% CI 4.8-6.4) in the districts with the highest population density (>800 person-years per 250 * 250 m). A nonsignificant trend toward the same direction was also seen for ulcerative colitis (trend P = 0.09). Chemical contaminant concentrations of tap water, residence near the seaside, or proximity to paper mills were not associated with the incidence of pediatric IBD. CONCLUSIONS: Our findings suggest higher incidence rates of pediatric IBD in the districts with low compared with high density of child population, but the differences cannot be explained by variations in the environmental exposures evaluated here. PMID- 26636499 TI - Spongiosis Hepatis in a Wild Aquarium-Maintained Red Irish Lord. AB - An aquarium-maintained female Red Irish Lord Hemilepidotus hemilepidotus presented with severe coelomic distension. The fish was anesthetized for ultrasonographic examination, which highlighted multiple cyst-like lesions in the liver and a distended ovary that was filled with follicles and an inspissated egg mass. Multiple exploratory celiotomies were performed for egg mass removal, liver biopsy, ovariosalpingectomy, and body wall rupture repair. Fourteen weeks after original presentation, and subsequent to 2 weeks of anorexia, the fish died. At necropsy, the liver was severely enlarged and distorted by multiple, coalescing, cyst-like spaces with no grossly normal liver parenchyma. The spleen also contained a raised cyst-like structure. Microscopically, the liver had well demarcated foci of hepatocyte loss with retained meshworks of interconnected, perisinusoidal stellate cells. The fluid-filled spaces surrounded by stellate cells were not lined by epithelium or endothelium. The spleen had similar fluid filled spaces formed of stellate cells. The cyst-like lesions in the liver were consistent with spongiosis hepatis; however, the concurrent development of a morphologically comparable lesion in the spleen is not typical of spongiosis hepatis cases. This case may represent the first report of spontaneously occurring spongiosis hepatis in a fish maintained in a public aquarium, as well as the first report in a fish of spongiosis hepatis-like lesions in an organ other than the liver. PMID- 26636500 TI - Incidental finding of paternal UPD15 in a child with a deletion of 11q21-q22.3, presenting with developmental delay, coloboma and characteristic dysmorphic features. PMID- 26636501 TI - Severe constipation in a patient with Myhre syndrome: a case report. AB - Myhre syndrome is a rare autosomal dominant genetic condition characterized by short stature, distinctive facial dysmorphisms, generalized muscle hypertrophy, skeletal abnormalities, decreased joint motility, developmental delay, deafness and cardiac defects. Myhre syndrome and the allelic laryngeal stenosis, arthropathy, prognathism and short stature syndrome are caused by a missense mutation of SMAD4, resulting in altered expression of transforming growth factor beta and bone morphogenic protein, affecting cell growth and differentiation. Here, we report on the case of a 7-year-old girl showing symptoms of Myhre syndrome and with a known SMAD4 mutation presenting with the novel symptom of severe constipation. PMID- 26636502 TI - The expression of PD-L1 APE1 and P53 in hepatocellular carcinoma and its relationship to clinical pathology. PMID- 26636503 TI - What really happens after zinc phosphide ingestion? A debate against the current proposed mechanism of phosphine liberation in zinc phosphide poisoning. PMID- 26636504 TI - More appropriate study design needs to confirm the diagnostic utility of S100A4 protein. [corrected]. PMID- 26636505 TI - Mechanism of BMP and TG2 in mesenchymal stem cell osteogenesis. AB - OBJECTIVE: To study the interactive effects of Type II glutamine transaminase (TG2) and bone morphogenetic protein-9 (BMP-9) in the induction of osteogenesis in mice mesenchymal stem cells (MSCs) C3H10T1/2 model. MATERIALS AND METHODS: Batches of MSCs C3H10T1/2, divided into two groups, were treated with BMP-9 (control group) or BMP-9 and TG2 (experimental group) under oxygen deficient conditions. The secreted alkaline phosphatase (SEAP) chemiluminescence and the histochemical staining methods were used to detect the alkaline phosphatase (ALP) expression. The alizarin red S staining was used to detect the calcium salt precipitation and the caspase-3 protein expression was monitored using Western blot. Flow cytometry was employed to identify cell cycle, and trypan blue exclusion method to count the living cells and monitor cell proliferation. RESULTS: The levels of ALP expression in the experimental group were much higher than that of the control group. The level of expression of advanced caspase-3 protein was significantly lower (p < 0.05) in the experimental group than in the control group. The highest fraction of cells in the experimental group was in the phase M while cells in the control group were in the interphase. Moreover, cell number in the experimental group was significantly increased (p < 0.05) relatively to the control group. CONCLUSIONS: BMP-9 interacts with TG2 in osteogenesis of MSCs C3H10T1/2 cells. Further studies are needed to understand the exact mechanism of BMP9/PG2 interactions in osteogenesis. PMID- 26636506 TI - Minimally invasive manipulative reduction with poking k-wire fixation in the treatment of various types of calcaneal fractures. AB - OBJECTIVE: The aim of this study is to investigate the safety and clinical efficacy of minimally invasive manipulative reduction with poking k-wire fixation in the treatment of various types of calcaneal fractures. PATIENTS AND METHODS: Between July 2012 and July 2014, a prospective parallel controlled study was conducted on 96 patients with closed calcaneal fractures who were admitted to our institution. These patients were randomly divided into two groups, with 48 in each group. Patients in plate group were treated using open reduction and internal fixation, whereas those of manipulation group were treated with minimally invasive manipulative reduction with poking k-wire fixation. All patients were followed up for six months to assess the postoperative recovery and complications. Kerr's scale was adopted to evaluate the functional recovery of fractured calcaneus. RESULTS: A mean healing duration of 9.48 +/- 1.92 weeks was achieved in patients of plate group compared with a healing duration of 9.35 +/- 1.66 weeks in those of manipulation group, with no statistical significance (p > 0.05). Complications occurred in 20 cases in plate group versus in seven cases in manipulation group with significant difference (p < 0.05). As for Sanders type II fracture, among patients with compression fracture and tongue type fracture, > 70% of patients achieved with excellent and good outcomes in both groups with no significant difference in clinical efficacy (p > 0.05). The rate of excellent and good outcomes in Sanders type III compression fractures was lower in manipulation group than in plate group (p < 0.05). As for Sanders type II fractures, the Kerr's score of tongue type fractures in manipulation group was higher than that in plate group, and comparison within manipulation group showed that the score of tongue type fractures was significantly higher than that of compression fractures (p < 0.05). However, as for Sanders type III fractures, the score of tongue type fractures in manipulation group was significantly higher than that in plate group, and the score of compression fractures in plate group was significantly higher than that in manipulation group (p < 0.05). CONCLUSIONS: Minimally invasive manipulative reduction with poking k-wire fixation is suitable for the treatment of Sanders type II tongue type and compression calcaneal fractures, as well as the treatment of Sanders type III tongue type fractures with several advantages, including easy operation, lower cost, fewer complications and favorable recovery. PMID- 26636507 TI - Do urban and rural residents living in Poland differ in their ways of coping with chronic diseases? AB - OBJECTIVE: Chronic disease is a critical life event which demands significant psychological adjustment. Coping strategies and resources such as sense of coherence, self-efficacy, etc. remain factors affecting stress response. PATIENTS AND METHODS: The examined group included patients with ischemic heart disease (n = 134), type 1 diabetes mellitus (n = 109) or rheumatoid arthritis (n = 92). 159 patients came from urban area whereas 176 came from rural setting. All patients filled up inventories of life satisfaction, severity of depression, coping strategies, self-efficacy, social support and sense of coherence. RESULTS: The analysis showed that patients from rural areas had higher levels of well-being, i.e., were characterized by lower severity of depression. The predictors of satisfaction with life included two types of resources i.e. self-efficacy, social support and two coping strategies i.e. turning to religion and self-distraction (R2 = 0.39; F = 26.87**). Life satisfaction was determined by social support, sense of coherence and positive reappraisal (R2 = 0.36; F = 29.11**). CONCLUSIONS: Rural/urban differences in the use of coping strategies may be associated with environmental or lifestyle differences. Patients with IHD, T1D or RA in Polish rural areas are high risk for depression so they may need help in finding systematic contact with specialists of healthcare. PMID- 26636508 TI - Relationships between obesity, bipolar spectrum features, and personality traits: a case-control study. AB - OBJECTIVE: Recently there has been widening stream of research on the relationships between obesity and mental disorders. Patients with obesity seem to be prone to developing bipolar spectrum disorders and they present with specific personality traits. The aim of this study was to analyze the associations between obesity, bipolarity features, and personality traits. PATIENTS AND METHODS: A nested case-control study was performed. Patients with obesity constituted the sample of cases (N = 90), and healthy individuals were ascribed to the control group (N = 70). The lifetime presence of bipolarity features was analyzed with the Mood Disorder Questionnaire (MDQ), while personality traits were assessed with the NEO-Five Factor Inventory (NEO-FFI). RESULTS: Bipolarity features were more prevalent in the patients with obesity, as compared to healthy individuals. Patients with obesity had both higher mean value of MDQ score (p = 0.01) and a higher proportion of subjects with MDQ score >= 7 points (p = 0.012) as well as lower score on the NEO-FFI openness to experience (p > 0.001), compared to control subjects. Using multivariate model, in patients with obesity, a significant positive correlation between bipolarity and neuroticism, and negative with agreeableness and conscientiousness was established. Such relationship was not observed in control subjects. CONCLUSIONS: In the population of patients with obesity, there is a specific combination between bipolarity and personality traits (high-trait neuroticism, low-trait conscientiousness, and low-trait agreeableness). This may have some consequences for both pharmacological and psychological management of such patients. PMID- 26636509 TI - Creation of experimental aneurysms at a surgically created arterial confluence. AB - OBJECTIVE: Complex vertebral confluence aneurysms remain clinically challenging despite the rapid technological advances in endovascular technology. Therefore, animal confluence aneurysm models are urgently needed for the preclinical development of related medical devices and training clinicians. This study aimed to establish canine confluence aneurysm model and evaluate hemodynamics in this model. MATERIALS AND METHODS: According to the shape and regional blood flow of vertebrobasilar junction (VBJ) aneurysms, confluence aneurysm was introduced in 9 dogs by microsurgical technique. We partially anastomosed right common carotid artery (CCA) and left CCA (end to side anastomosis) to create inverted Y-junction of arteries and, then, sutured a harvested segment of external jugular vein to the notch of anastomosis to simulate confluence aneurysm. These animals were examined by 3D digital subtraction angiography (DSA) 4 weeks after surgery. Geometry parameters of the aneurysm, surrounding vasculature and specific double inlet profiles were analyzed by simulating computational fluid dynamics (CFD) in these animals. RESULTS: Aneurysms were successfully established in all animals, including 8 complete and 1 partially thrombosed aneurysms. No neurological defects or death were observed. Geometric and hemodynamic parameters in these surgically introduced confluence aneurysm animals are similar to those reported for human VBJ aneurysms. CONCLUSIONS: This study documents a protocol to successfully establish confluence aneurysm models in dogs. This model may be useful in preclinical studies targeting various complex vertebral confluence aneurysms. PMID- 26636510 TI - The electroclinical-semiology of generalized tonic-clonic seizures among different epilepsies. AB - OBJECTIVE: The study reported here discusses the duration of the generalized tonic-clonic seizures (GTCS) among frontal lobe epilepsy (FLE), medial temporal lobe epilepsy (MTLE) and idiopathic generalized epilepsy (IGE). PATIENTS AND METHODS: The study was done by analyzing the data from patients who had undergone video-EEG in 2009 and had GTCS during the monitoring. The patients were selected for the frontal lobe epilepsy (FLE), medial temporal lobe epilepsy (MTLE), and idiopathic generalized epilepsy (IGE). Once they met the criteria, the durations of all the phases were measured, then discussed if there were any difference in duration for different epilepsies. RESULTS: On comparison of the total duration of various types of seizures it was found that the duration of FLE (177 +/- 212.6 sec.) was significantly different from the duration of MTLE (104.6 +/- 51.8 sec.) and IGE (63.9 +/- 28.2 sec.). It can be found in the comparison of GTCS that the duration of phase 6,7 of FLE (63.5 +/- 30.9 sec.) was statistically significant compared with MTLE (37.3 +/- 13.8 sec.) and IGE (46.4 +/- 30.1 sec.). The duration of various types of epilepsy in the generalized tonic-clonic period was not statistically significant. CONCLUSIONS: Through this study, we found the differences of the duration of different types of epilepsies that provide the clinical basis for further studies of seizure mechanism and neural network conduction. PMID- 26636511 TI - Effects of end tidal CO2 and venous CO2 levels on postoperative nausea and vomiting in paediatric patients. AB - OBJECTIVE: Postoperative nausea and vomiting (PONV) is a common complaint of paediatric surgical patients. The aim of this prospective study was to compare the effects of end tidal CO2 (PeCO2) and venous CO2 (PvCO2) in laryngeal mask (LMA) and face mask (FM) ventilation on the occurrence of PONV in paediatric patients with surgical interventions in the inguinal region. To date, no data regarding these parameters on PONV are available. PATIENTS AND METHODS: Ninety children were randomized using the sealed-envelope method. Group 1 consisted of 45 patients whose airway was managed with LMA; Group 2 consisted of 45 patients whose airway was managed with FM. Induction of anaesthesia was performed via administration of 8% sevoflurane in a mixture of air/oxygen in all patients. In both groups, manually controlled ventilation was applied. Five (t1) and fifteen (t2) min after the start of surgery, venous blood samples were obtained and PeCO2 was determined. RESULTS: PeCO2 (t2) and PvCO2 (t2) levels and the occurrence of PONV were significantly increased in Group 2 compared to Group 1 (p < 0.005 for all). In both groups, the occurrence of PONV was positively correlated with BMI, PeCO2 (t2), and PvCO2 (t2) levels (p < 0.05 for all), whereas it was inversely correlated with SpO2 levels (p < 0.05 for all) in a bivariate analysis. We found that the PeCO2 (t2) and PvCO2 (t2) levels were independently associated with the occurrence of PONV in both groups. CONCLUSIONS: Our results showed that elevated levels of PeCO2 (t2) and PvCO2 (t2) are independent risk factors for PONV, and these parameters may be used as adjunctive tools to assess the occurrence of PONV. PMID- 26636512 TI - Postoperative Pain Surveys in Italy from 2006 and 2012: (POPSI and POPSI-2). AB - OBJECTIVE: Despite established standards, effective treatments, and evidence based guidelines, postoperative pain control in Italy and other parts of the world remains suboptimal. Pain control has been recognized as a fundamental human right. Effective treatments exist to control postsurgical pain. Inadequate postoperative analgesia may prolong the length of hospital stays and may adversely impact outcomes. MATERIALS AND METHODS: The same multiple-choice survey administered at the SIAARTI National Congress in Perugia in 2006 (n=588) was given at the SIAARTI National Congress in Naples, Italy in 2012 (n=635). The 2012 survey was analysed and compared to the 2006 results. RESULTS: Postoperative pain control in Italy was less than optimal in 2006 and showed no substantial improvements in 2012. Geographical distinctions were evident with certain parts of Italy offering better postoperative pain control than other. Fewer than half of hospitals represented had an active Acute Pain Service (APS) and only about 10% of postsurgical patients were managed according to evidence-based guidelines. For example, elastomeric pumps for continuous IV infusion are commonly used in Italy, although patient-controlled analgesia systems are recommended in the guidelines. The biggest obstacles to optimal postoperative pain control reported by respondents could be categorized as organizational, cultural, and economic. CONCLUSIONS: There is considerable room for improvement in postoperative pain control in Italy, specifically in the areas of clinical education, evidence-based treatments, better equipment, and implementation of active APS departments in more hospitals. Two surveys taken six years apart in Italy reveal, with striking similarity, that there are many unmet needs in postoperative pain control and that Italy still falls below European standards for postoperative pain control. PMID- 26636513 TI - The modified proteins in erythrocytes and regulation of erythrocytes volume in patients with chronic kidney disease. AB - OBJECTIVE: The role of oxidatively modified proteins in progression of chronic kidney disease has been discussed. We have got the results demonstrating the alteration of band 3 protein activity in erythrocytes of patients with chronic kidney disease. We presumed that it might be associated with oxidative damage of intracellular proteins. The purpose of the research was to study the modified proteins (protein reactive carbonyl derivatives, membrane-bounded hemoglobin) in erythrocytes, as well as the regulation of erythrocyte volume in patients with chronic kidney disease. PATIENTS AND METHODS: 132 patients with various stages of chronic kidney disease and degree of chronic renal failure were divided into four groups. We enrolled 32 healthy subjects. In erythrocytes modified proteins (protein reactive carbonyl derivatives, membrane-bounded hemoglobin) concentrations and activity of Cl-/HCO3--exchanger have been estimated. RESULTS: the results demonstrated the strong disorder of Cl-/HCO3--exchanger activity in erythrocytes of patients. These data suggested the existence of erythrocytes subpopulations with different activity of Cl-/HCO3--exchangers in bloodstream of patients with chronic kidney disease depending on initial clinical form of the disease. In erythrocytes of all patients, the membrane-bounded hemoglobin concentration and reactive carbonyl derivatives of proteins were significantly higher than in control samples. CONCLUSIONS: We have assumed that in erythrocytes oxidized hemoglobin interacts with band 3 protein present on erythrocyte membrane. The membrane-bounded hemoglobin increase leads to increased stiffness of the erythrocyte membranes and affects the volume of erythrocytes. We hypothesized that erythrocytes with changed ability to regulate their volume and high concentration of modified proteins contributed to chronic kidney disease progression. PMID- 26636514 TI - Bioinformatic analysis of potential candidates for therapy of inflammatory bowel disease. AB - OBJECTIVE: Inflammatory bowel diseases (IBDs) including ulcerative colitis (UC) and Crohn's disease (CD) increased the risk for developing colorectal cancer. However, there is no effective therapy for IBDs. The aim of this study was to identify potential therapeutic targets for inflammatory bowel disease (IBD) and explore the possible mechanism underlying this disease. MATERIALS AND METHODS: Gene expression profile GSE6731 was downloaded from Gene Expression Omnibus database, which included 9 UC samples and 19 CD samples. Differentially expressed genes (DEGs) between affected colon tissues and non-affected tissues were identified in UC and CD group. Then, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways analysis of DEGs were performed. Modules in the protein-protein interaction (PPI) network were identified, and significant node genes were selected. RESULTS: Total 619 DEGs including 285 up-regulated genes and 334 down-regulated genes were identified in UC group and total 1159 DEGs of CD including 585 up-regulated genes and 574 down-regulated genes were selected. Module was selected from PPI network. From the PPI network and module, DEGs of mitogen-activated protein kinase 3 (MAPK3), N-myc downstream regulated 1 (NDRG1) and major histocompatibility complex, class II, DR alpha (HLA-DRA) have high degree. CONCLUSIONS: MAPK3, NDRG1 and HLA-DRA may play key roles in the progression and development of IBD. They may be used as specific therapeutic targets in the treatment of IBD. However, further experiments are still needed to confirm our results. PMID- 26636515 TI - Nutritional profile of adult patients with celiac disease. AB - Celiac disease (CD) is a chronic immune-mediated gluten dependent enteropathy induced by ingestion of gluten, characterized by intestinal malabsorption and subtotals or total atrophy of intestinal villi. The predominant consequence of CD in untreated patients, is malnutrition as a result of malabsorption. Moreover, several and increasing extra-intestinal clinical manifestations have been described in the CD patients. Strict adherence to a gluten-free diet (GFD) improves nutritional status, inducing an increase in fat and bone compartments, but does not completely normalize body composition and nutritional deficiencies. An early and accurate evaluation of nutritional status can be of the pivotal step in the clinical management of the adult CD patients. The aim of this review is to present the most important and recent data on nutritional and metabolic features in the CD adult patients, the related implications and the effects of the GFD on these conditions. PMID- 26636516 TI - Expression data analysis to identify key target genes in visceral fat tissue associated with obstructive sleep apnea. AB - OBJECTIVE: The purpose of this study was to screen key genes related to mechanisms and consequences of obstructive sleep apnea (OSA)-induced perturbations in visceral fat tissue depots. MATERIALS AND METHODS: Microarray data of GSE38792, comprising 10 visceral fat samples from OSA patients and 8 visceral fat samples from control subjects, was obtained from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified in visceral fat samples from OSA patients compared with controls using Bioconductor package limma. Gene Ontology (GO) and pathway enrichment analyses were carried out to identify significantly altered biological functions. Furthermore, a protein-protein interaction (PPI) network was constructed with STRING database and visualized with Cytoscape software. Additionally, the transcriptional regulatory relationships were screened using UCSC ENCODE Genome Browser. RESULTS: A total of 380 DEGs were identified, of which 188 were up-regulated and 192 were down-regulated. The DEGs were involved in different GO terms and pathways, mainly associated with metabolism such as proteolysis. PPI network analysis revealed that Actin, Alpha 1, Skeletal Muscle (ACTA1), Histone Deacetylase 2 (HDAC2), and Small Ubiquitin-Like Modifier 1 (SUMO1) were hub proteins. In addition, HDAC2 was shown to encode a transcription factor (TF) and it could regulate 3 DEGs. CONCLUSIONS: Genes such as ACTA1, HDAC2, and SUMO1 were presumed to play critical roles in the mechanisms and consequences of OSA-induced perturbations in visceral fat tissue depots, which may be useful for deeply studying the mechanisms underlying OSA. PMID- 26636517 TI - Clinical significance of serum procalcitonin level monitoring on early diagnosis of severe pneumonia on children. AB - OBJECTIVE: To discuss the method for early diagnosis of severe pneumonia on children. PATIENTS AND METHODS: Fifty-six children with severe pneumonia were enrolled from Department of Pediatrics and Intensive Care Unit (ICU) of our hospital and divided into two groups according to parasitological detection: bacterial pneumonia group consisting of 34 children patients and non-bacterial pneumonia group of 32 children patients. In the meanwhile, 37 healthy children, who were confirmed without infection through physical examination, were also enrolled and grouped in into normal control group. Peripheral venous blood of all children was collected to detect their procalcitonin (PCT). RESULTS: PCT level of patients in bacterial pneumonia group was significantly higher than that in the non-bacterial pneumonia group and control group, and difference had statistical significance (p < 0.01); serum PCT level on patients in bacterial pneumonia group before and after treatment had statistical significance (p < 0.01); serum PCT level on patients in non-bacterial pneumonia group before and after treatment had no statistical significance (p > 0.05). CONCLUSIONS: PCT was a very important biomarker for the diagnosis of bacterial infection and also a sensitive indicator for the distinction of child bacterial pneumonia and non-bacterial pneumonia. It had significant clinical diagnosis and differential diagnosis value. PMID- 26636518 TI - Early use of non invasive ventilation in patients with amyotrophic lateral sclerosis: what benefits? AB - OBJECTIVE: The aim of this study was to analyze the efficacy of an early start of NIV in ALS patients, evaluating respiratory and ventilatory parameters. PATIENTS AND METHODS: Functional respiratory parameters and arterial blood gas analysis were evaluated in forty-six patients. All patients were informed about the benefits and possible adverse effects of therapeutic support with NIV and divided in two groups based on the compliance to early start therapy with NIV (Group A) or not (Group B). RESULTS: Among 46 ALS patients consecutively visited in our Unit, we included 20 patients in the Group A and 16 in the Group B. We have emphasized the importance of the early use of NIV stressing the difference between two groups analyzed, particularly in terms of pulmonary function tests and arterial blood gas analysis. Significant correlation was observed between Vital Capacity (VC), Forced Expiratory volume in one second (FEV1), and maximal inspiratory pressures (PImax). CONCLUSIONS: Our study highlights the importance of noninvasive mechanical ventilation as a treatment for ALS patients and also shows the early start of NIV as an important approach in order to postpone the functional decline and the decrease of respiratory muscle strength. PMID- 26636519 TI - High-dose glucocorticoids increases the expression of mineralocorticoid receptor in vascular endothelial cells. AB - OBJECTIVE: To explore the role of glucocorticoid new mechanism to observe the expression of glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) with lipopolysaccharide (LPS) and dexamethasone (Dex) in human umbilical vein endothelial cells (HUVEC). MATERIALS AND METHODS: LPS "injured" endothelial cells with Dex for "treatment", and then detected the expression of glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) in the endothelial cells by RT PCR and immunohistochemistry. RESULTS: With high dose (10-6 mol/L) of Dex to stimulate cell 3h, GRmRNA no significant changes in the expression, 6h began to decrease, 12h peak, 24h recovered nearly the level before stimulation. Using different concentrations of Dex and 100 ng/ml LPS stimulation, HUVEC MRmRNA expression was decreased, and high dose (10-6 mol/L) of Dex to stimulate cell 3h, MRmRNA no significant changes in expression, and GRmRNA The difference is that the expression began to increase 6h, 12h, peaked, 24h rebound near the level before stimulation. Immunohistochemistry results consistent with the RT-PCR. CONCLUSIONS: Large dose of DEX (10-6 mol/l) up-regulated the expression of MR and GR in the reduction of the contrast exactly. GC induced the expression of GR and MR in different changes of stress injury of the body may be a regulatory mechanism, and indicate one new mechanism of glucocorticoid exist. PMID- 26636520 TI - Is it possible a new definition of metabolic syndrome in childhood? AB - OBJECTIVE: To investigate whether a group of Italian children and adolescents who were diagnosed to have metabolic syndrome (MS) according to a new ethnic age and gender specific definition had, in comparison with a control group, other signs and metabolic risk factors which are commonly associated with MS. PATIENTS AND METHODS: The cross-sectional study population included 300 subjects (51% boys, age range 6-14 years), who were divided into 2 groups according to the presence of MS, diagnosed on the basis of 3/5 factors derived from the age and gender specific quantile distribution of MS components in a large regional Italian population survey (Calabrian Sierras Community Study, CSCS). In all subjects the following data were collected: anthropometric measures, blood pressure, liver function, C-reactive protein (hsCRP), uric acid blood levels, lipid and glucose profile. Triglycerides/HDL-cholesterol (TG/HDL-C) ratio was calculated. RESULTS: There were 38 subjects (13%) with MS, who had higher indices of growth and fat distribution and higher blood levels of uric acid, alanine aminotransferase and gamma-glutamyltransferase. TG/HDL ratio was higher (median 3.11 vs. 1.14, p = 0.00001) in MS subjects who had lower apolipoprotein A and higher apolipoprotein B and non-HDL-C levels. hsCRP was not different between groups. CONCLUSIONS: Our ethnic age and gender specific definition of MS in Italian children and adolescents was able to identify in a youth group different cardiometabolic risk factors related to insulin resistance, endothelial damage and nonalcoholic fatty liver disease, which are commonly associated with MS diagnosis. PMID- 26636521 TI - Interrelationship between bone turnover markers, calciotropic hormones and leptin in obese Saudi children. AB - OBJECTIVE: Fat-bone relationship involves the interaction among endocrine, inflammatory, immune processes and bone turnover. We tried to assess the association between Leptin and bone turnover markers (OCN, beta-CTx, ALP), calciotropic hormones PTH and 25(OH)D in obese Saudi children. PATIENTS AND METHODS: A cross-sectional study performed with 60 obese children and 36 lean children. For all subjects, OCN, ALP, beta-CTx, PTH, 25(OH)D, leptin, Ca and Pi were investigated. Levels of leptin were measured by [ELISA] method, and OCN, beta-CTx, PTH and 25-(OH)D by an electrochemiluminescence immunoassay. RESULTS: Sixty obese Saudi children had means weight (38.3 vs. 13.8 kg), height (121.0 vs. 91.8 cm) leptin (23.04 vs.16.88 ng/ml), PTH (31.5 vs. 14.7 pg/ml), Pi (1.67 vs. 1.54 mmol/l) were significantly higher and 25(OH)D (21.02 vs. 29.45 ng/ml) was significantly lower than controls. There was no difference in serum OCN, beta CTx, ALP and calcium between groups (p > 0.05). In the correlation study, OCN were significantly positively correlated with height, ALP, age, PTH, and beta-CTx (r = 0.347, 0.32, p < 0.05), (r = 0.35, 0.51, 0.66, p < 0.01 respectively), while serum 25(OH)D was negatively correlated with PTH, weight, height and BMI (r = 0.45, -0.55, -0.55, -0.47, p < 0.01 respectively). PTH was positively correlated with leptin and beta-CTx (r = 0.41, 0.44, p < 0.01), but not to ALP and BMI percentile. beta-CTx correlated significantly positive with Pi (r = 0.34 p < 0.05) and ALP with BMI percentile (r = 0.42, p < 0.05). Multiple regression analysis demonstrated that PTH was predicted by leptin and beta-CTx (R2 = 0.55); beta-CTx by leptin and OCN (R2 = 0.498); OCN by PTH and beta-CTx (R2 = 0.47); and 25(OH)D by PTH (R2 = 0.21). CONCLUSIONS: The obese children had increased levels of leptin and PTH with strong associated with bone turn over markers OCN, beta CTx and deficiency of 25(OH)D which may be playing an important role in the pathogenesis of obesity and related bone metabolic risk diseases as osteoporosis and fractures. PMID- 26636522 TI - MIR-150 promotes prostate cancer stem cell development via suppressing p27Kip1. AB - OBJECTIVE: Our previous study found that high miR-150 expression was positively correlated with prostate tumor recurrence or metastasis. In this work, we investigated the expression of miR-150 in prostate cancer stem cells (CSCs) and explored its regulation over p27 in the development of CSCs. MATERIALS AND METHODS: MiR-150 expression in CD144 or CD44 positive primary prostate cells and in DU145 cell line was measured. It regulation over CSCs was measured using tumor sphere assay and qRT-PCR analysis of CSC related Oct4, Nestin and Nanog genes. The direct binding between miR-150 and 3'UTR of p27 mRNA was verified using dual luciferase, qRT-PCR and western blot assay. The influence of miR-150-p27 axis on prostate CSC properties was further investigated. RESULTS: Findings of this study found miR-150 expression was significantly upregulated in CD44+ or CD133+ subgroups of prostate cancer cells. MiR-150 could directly target 3'UTR of p27 and decrease its expression, through which it increased the number and volume of tumor sphere formed by DU145 cells, as well as the expression of CSC related Oct4, Nestin and Nanog genes. CONCLUSIONS: Increased miR-150 expression might participate in the development and progression of human prostate CSC by suppressing p27. This supported our previous study which found miR-150 was positively correlated with prostate tumor recurrence or metastasis. PMID- 26636523 TI - Transmembrane 7 superfamily member 4 regulates cell cycle progression in breast cancer cells. AB - OBJECTIVE: TM7SF4 (transmembrane 7 superfamily member 4) gene encodes a seven pass transmembrane protein that is primarily expressed in dendritic cells called as dendritic cell-specific expressed seven transmembrane protein (DC-STAMP). This protein regulates immunological functions, osteoclastogenesis and myeloid differentiation. Although the roles of TM7SF4 have been currently studied on Paget's disease of bone and papillary thyroid cancers, it is unclear whether TM7SF4 plays a role in breast cancer. In current study, we investigated the expression of TM7SF4 in human breast cancer cell lines. MATERIALS AND METHODS: In this study, five breast cancer lines were cultured. Small hairpin RNA against TM7SF4 using a lentiviral vector was generated and transfected into MCF-7 breast cancer cells. Effects of down-regulating TM7SF4 in transfected cells were examined by Western blot, RT-PCR, apoptotic rate, colony formation, and cell cycle analyses. RESULTS: The results demonstrated that down-regulation of TM7SF4 led to a decrease in colony formation in MCF-7 cells compared to the control group. This is likely due to a decrease in proliferation and cell cycle and an increase in apoptosis. CONCLUSIONS: To our knowledge, our data demonstrate for the first time that TM7SF4 plays an essential role in regulating cell cycle progression in breast cancer. PMID- 26636524 TI - Effect and mechanism analysis of siRNA in inhibiting VEGF and its anti angiogenesis effects in human osteosarcoma bearing rats. AB - OBJECTIVE: To explore the effect of siRNA in inhibiting vascular endothelial growth factor (VEGF) expression in tumor cells from human osteosarcoma bearing rats and its anti-angiogenesis effect, to further study the reliability, effectiveness and safety of VEGF as a therapeutic target in treating osteosarcoma. MATERIALS AND METHODS: After treatment, the long diameter and short diameter of tumor lesion were detected by Vernier caliper, and the tumor volume and tumor inhibition rate were calculated. The whole-body fluorescence imaging was used to detect the general morphology and volume change of tumor lesion before and after treatment. The rats were killed after treatment, RT-PCR and Western blot were used to detect VEGF expression. MTT was used to detect the proliferative ability of tumor cells in vitro. RESULTS: Three chemotherapies could inhibit the growth of tumor lesion, the decrease of tumor volume was significant (p < 0.05), the therapeutic effect in Ad-VEGF-siRNA + neoadjuvant chemotherapy group was better than the other two groups, the differences were statistically significant (p < 0.05). Furthermore, the three chemotherapies could inhibit the invasiveness of tumor cells, which was most significant in Ad-VEGF siRNA + neoadjuvant chemotherapy group (p < 0.05). CONCLUSIONS: The growth of tumor tissue in osteosarcoma bearing rats is inhibited in Ad-VEGF-siRNA group, Ad VEGF-siRNA + neoadjuvant chemotherapy group and Ad-VEGF-siRNA + anti-angiogenesis chemotherapy group. The effect in Ad-VEGF-siRNA + neoadjuvant chemotherapy is more significant than simple biological therapy or Ad-VEGF-siRNA + anti angiogenesis chemotherapy. PMID- 26636525 TI - Activin A as a novel biomarker for colorectal adenocarcinoma in humans. AB - OBJECTIVE: Early diagnostics of colorectal cancer is complicated by the lack of reliable serum biomarkers. This study aimed to investigate if the serum level of activin A can be used for diagnostics of this disease. PATIENTS AND METHODS: In this study we measured the level of activin A in patients with colorectal adenocarcinoma, benign colorectal polyps, as well as in healthy subjects. RESULTS: We found that the level of activin A was significantly higher in patients with colorectal adenocarcinoma, as compared to patients with polyps and healthy controls. Furthermore, activin A levels correlated well with the stage of colorectal cancer. The level of activin A was substantially reduced in post operative patients. Immunohistochemical staining demonstrated that high levels of activin A were present in the adenocarcinoma tissue samples but not in the non cancerous samples. RT-PCR further confirmed that mRNA of betaA subunit of activin A is significantly over-expressed in the majority of cancerous samples. Western blotting results further demonstrated the elevated level of activin A in cancer samples. CONCLUSIONS: Taken together, the findings suggest that colorectal adenocarcinomas directly secret activin A into the blood stream. Measuring the serum level of activin A might be used as a reliable diagnostic and screening tool in clinical practice. PMID- 26636526 TI - Treatment of childhood leukemia with haploidentical hematopoietic stem cell transplantation using parent as donor: a single-center study of 111 case. AB - OBJECTIVE: In the present study, the outcomes of childhood leukemia treated with haplo-HSCT using parent as donor were evaluated and the risk factors for survival were identified. PATIENTS AND METHODS: 111 consecutive cases from March 2002 to March 2012 in our center were analyzed. The median age of patients was 10 (3-14) years old. All patients received unmanipulated combined marrow and peripheral blood stem cells for transplant after conditioning with busulfan and cyclophosphamide (Cy)/Cy and total body irradiation (TBI) plus antithymocyte globulin (ATG). RESULTS: Durable hematopoietic reconstitution was seen in 98% of recipients. Engraftment failure occurred in 3 cases including 2 cases of father to daughter transplants. One-hundred-day transplant-related mortality (TRM) was only 4.5%. The cumulative incidences of grade II to IV acute graft-versus-host disease (aGvHD) and chronic GvHD (cGvHD) were 47.6% and 28.3%, respectively. With the median follow-up of 32 (12-134) months, 2-year and 5-year overall survival (OS) rates for all patients were 82.1% and 79.2%, respectively. Five-year OS rates for patients in early, intermediate and advanced disease were 84.0%, 81.0%, and 57.1%, respectively (p = 0.08). Five-year OS of transplants in father to son, father to daughter, mother to son, and mother to daughter were was 88.1%, 57.1%, 70.6%, and 82.6%, respectively (p = 0.08). CONCLUSIONS: Under current protocol, children with leukemia tolerate haplo-HSCT from their parent very well with lower TRM, less cGvHD, and better OS compared with our published data. Pre-transplant disease status and donor- recipient relationship and the recipient age have significant impact on survival. PMID- 26636527 TI - Serum uric acid and inflammation in patients with immune thrombocytopenic purpura: preliminary results. AB - OBJECTIVE: The purpose of this study was to evaluate the uric acid (UA) and C reactive protein (CRP) levels in patients with immune thrombocytopenic purpura (ITP). PATIENTS AND METHODS: Forty patients with newly diagnosed ITP and 40 healthy individuals were enrolled in the study. The patients were divided into two groups; group 1 (n = 40) consisted of patients with ITP, and group 2 (n = 40) consisted of healthy subjects. UA and CRP levels were measured in the blood samples from them. RESULTS: There were no statistical differences in gender, age and body mass index between two groups (p > 0.05 for all). Compared to group 2, group 1 had significantly higher UA levels (p = 0.002), whereas CRP levels were not significantly different (p > 0.05). In ITP patients, serum UA and CRP levels significantly correlated with low platelet count (r = -0.362, p = 0.022; r = 0.383, p = 0.015, respectively); and UA levels significantly correlated with CRP levels (r = 0.436, p = 0.005). CONCLUSIONS: The present study showed that UA levels increased in patients with ITP and negatively correlated with platelet counts. UA levels might be a mediator of inflammation via enhanced production of inflammatory cytokines; they might also be a potential mediator of low platelet count, and could play a pathophysiological role in the development of ITP. PMID- 26636528 TI - In vitro application of RNA interference to silence livin gene expression to induce apoptosis in leukemia cells. AB - OBJECTIVE: To search for new targets and novel methods of anti-leukemia treatment and to discuss the mechanism of silencing the livin gene using small RNA interference technology to induce apoptosis in the K562 leukemia cell line. METHODS: We designed and synthesized livin-specific small interference RNA (siRNA). Transfected K562 cells were cultured. Reverse-transcription polymer chain reaction (RT-PCR) was used to detect livin mRNA expression. Protein expression for livin was detected using Western blotting. A non-transfected group was used as a control. Meanwhile, vectors carrying enhanced green fluorescent protein (EGFP) were transfected as a positive control and flow cytometry was used to determine the transfection efficiency by detecting green fluorescence. The rate of apoptosis was determined using the annexin V and propidium iodide double staining method. ELISA was used to determine the activity of Caspase-3. RESULTS: The transfection efficiency of electroporation was as high as 50%. The siRNA sequences could knockdown livin gene expression at both the mRNA and protein levels. Apoptosis rate of the cells was 27.41 +/- 2.30% 48 h after transfection with specific siRNA. This was significantly higher than that of the control group (9.63 +/- 0.89%, p < 0.05). The 48-h apoptosis rate of the combined effect group VP-16 (5 umol/L) and transfection rate was 45.1 +/- 4.40%, which was significantly elevated (p < 0.05) compared with the groups treated with only VP 16 or by transfection. CONCLUSIONS: Caspase-3 activity in cells transfected with siRNA was significantly elevated compared to the cells in the non-transfected groups (p < 0.05). PMID- 26636529 TI - Hypoxic adipose mesenchymal stem cells derived conditioned medium protects myocardial infarct in rat. AB - OBJECTIVE: The aim of this study was to explore the impact of normoxic and hypoxic cell-culture conditions on the expression and secretion of adipose mesenchymal stem cells (ADMSCs)-derived paracrine molecules, and to evaluate the cardioprotective role of hypoxic condition medium (hypoCM) in vivo. MATERIALS AND METHODS: Semi-quantitative reverse transcriptase polymerase chain reaction (RT PCR) and enzyme-linked immunosorbent assay (ELISA) analyses of normoxic and hypoxic ADMSCs and their conditioned medium fractions. Then, the effect of hypoCM on cardiomyocytes proliferation and migration was assessed. Moreover, a rat model of myocardial infarct (MI) was established to test the therapeutic effect of hypoCM in vivo. RESULTS: ADMSCs expressed and secreted significantly higher amounts of vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF) and stromal derived factor-1 (SDF-1 or CXCL12) under hypoxic conditions. Furthermore, compared with the vehicle control, hypoCM significantly enhanced the proliferation and migration of cardiomyocytes. Consistent with the in vitro data, hypoCM decreased the infarct size, apoptosis index and apoptosis related protein in the rat MI model. CONCLUSIONS: These findings suggest that ADMSCs promote rat MI via hypoxia-enhanced paracrine. PMID- 26636530 TI - Observation of Kawasaki disease-related indexes and the study of relationship between myocardial enzyme changes and coronary artery lesions. AB - OBJECTIVE: To discuss the significance of Kawasaki disease-related laboratory indicators and relationship between myocardial enzyme changes and myocardial enzyme changes in children with Kawasaki disease. PATIENTS AND METHODS: Make an observation of C-reactive proteins and immune globulin changes in children with Kawasaki disease, and also a comparison about the myocardial enzyme changes between the children with myocardial enzyme changes and others without lesions. RESULTS: Compare the study group before treatment with the control group of normal children, there are significant differences in the levels of CRP, IgG, and IgM, and the difference was statistically significant (p < 0.05); make a comparison about the levels of AST, LDH, CK, HB-DH, and CK-MB in the group with or without coronary artery lesions, the difference was not statistically significant (p > 0.05). CONCLUSIONS: Relevant laboratory indices play an important role in the early diagnosis of Kawasaki disease. Myocardial injury and coronary artery lesions in children with Kawasaki disease have no correlation between each other, and there has an inconsistency characteristic. PMID- 26636531 TI - Diagnostic accuracy of adenosine deaminase for tuberculous pericarditis: a meta analysis. AB - OBJECTIVE: Many studies suggest that adenosine deaminase is a marker for tuberculous pericarditis, while controversy exists as to its diagnostic utility. This study aims to summarize the overall diagnostic performance of adenosine deaminase for tuberculous pericarditis through a meta-analysis. MATERIALS AND METHODS: Literatures published before May 2015 were searched in PubMed and EMBASE. The data were retrieved and the sensitivity, specificity, positive/negative likelihood ratio (PLR/NLR), diagnostic odds ratio (DOR) of adenosine deaminase for diagnosing tuberculous pericarditis were pooled, and the summary receiver operating characteristic (SROC) curves were used to examine the overall performance of adenosine deaminase. RESULTS: In total, 11 studies with 938 subjects were included in the meta-analysis. The summary estimates of adenosine deaminase for diagnosing tuberculous pericarditis were listed as follows: sensitivity of 0.90 (95% CI: 0.86-0.93), specificity of 0.86 (95% CI: 0.83-0.89), PLR of 5.90 (95% CI: 4.46-7.82), NLR of 0.15 (95% CI: 0.09-0.26), and DOR of 42.55 (95% CI: 21.51-84.18). The area under the SROC curve was 0.92, and the Q value was 0.85. No publication bias was identified. CONCLUSIONS: Adenosine deaminase is a valuable marker with both high sensitivity and specificity in the diagnosis of tuberculous pericarditis. Nevertheless, the results of adenosine deaminase assays should be interpreted in combination with other test results and clinical characteristics of patients. PMID- 26636532 TI - An association of boswellia, betaine and myo-inositol (Eumastos) in the treatment of mammographic breast density: a randomized, double-blind study. AB - OBJECTIVE: Mammographic breast density is a recognized risk factor for breast cancer. The causes that lead to the proliferation of the glandular breast tissue and, therefore, to an increase of breast density are still unclear. However, a treatment strategy to reduce the mammary density may bring about very relevant clinical outcomes in breast cancer prevention. Myo-inositol is a six-fold alcohol of cyclohexane, has already been proved to modulate different pathways: inflammatory, metabolic, oxidative and endocrine processes, in a wide array of human diseases, including cancer and the genesis of mammary gland and breast diseases, like fibrosis, as well as metabolic and endocrine cues. Similarly, boswellic acid and betaine (three-methyl glycine) both inhibit inflammation and exert protective effects on breast physiology. Based on this scientific background, we hypothesized that a combination including, boswellic acid, betaine and myo-inositol would be able to reduce breast density working on different pathways. PATIENTS AND METHODS: In this study, seventy-six premenopausal women were randomly assigned to the placebo and the experimental drug arms (Eumastos) for six months. RESULTS: After 6 months of treatment, statistically significant difference between the two groups was recorded on the breast density reduction (60% vs. 9%), using mammographic as well as ultrasound examination. CONCLUSIONS: Preliminary data collected here with support the starting assumptions, that the association comprising boswellic acid, betaine and myo-inositol significantly reduces mammary density, providing the first evidence for a new and safe approach for the management of mammographic density treatment. PMID- 26636533 TI - Comparison of the effects of dexmedetomidine and remifentanil on potential extreme haemodynamic and respiratory response following mask ventilation and laryngoscopy in patients with mandibular fractures. AB - OBJECTIVE: The safety profile and efficacy were compared for remifentanil and dexmedetomidine with respect to haemodynamic and respiratory response during mask ventilation and laryngoscopy in patients with mandibular fractures. PATIENTS AND METHODS: Seventy patients undergoing elective mandibular fracture surgery were randomly assigned to the remifentanil group (Group R, n = 35) or the dexmedetomidine group (Group D, n = 35). The primary outcomes were preoperative pain scores caused by jaw movement; haemodynamic response; intubation score; and side effects, such as the incidence of oxygen desaturation and muscle rigidity. Other side effects, such as tachycardia, bradycardia, hypertension and hypotension, were also compared. RESULTS: Preoperative pain scores caused by jaw movement were significantly high for both groups, but there were no statistically significant differences between the groups. The incidence of oxygen desaturation and muscle rigidity was significantly lower in Group D than in Group R (p = 0.025). No significant differences existed between the groups in terms of intubation score, haemodynamics, and other side effects (p > 0.05). DISCUSSION: Dexmedetomidine and remifentanil had equal effectiveness on the control of haemodynamic response due to mask ventilation and intubation in patients with mandibular fractures. However, at the doses used in this study, dexmedetomidine had a significant advantage over remifentanil in terms of respiratory stability. PMID- 26636534 TI - Protective role of selenium-enriched supplement on spinal cord injury through the up-regulation of CNTF and CNTF-Ralpha. AB - OBJECTIVE: Spinal cord injury (SCI), as one of the common serious spine disorders, often leads to severe neurological dysfunction and even permanent disability, which will cause heavy economical burden for family and society. Currently, selenium-enriched products have an obvious role in the protection and recovery of SCI; however, its protective mechanism is still unclear. MATERIALS AND METHODS: In order to explore the protective effect of selenium-enriched supplement (SES) on SCI, the adult rats were randomly divided into sham operation control (SC) group, ischemia-reperfusion model (IM) group and SES pretreatment (ST) group to investigate the change of ciliary neurotrophic factor (CNTF) and its receptor-alpha (CNTF-Ralpha) during SCI in the presence of SES. The rats in IM and ST groups were subjected to the blockage of their abdominal aorta to establish the model of SCI; but the rats in SC group were subjected to sham operation without the blockage of abdominal aorta. The rats in ST group were fed with foods containing SES at the dose of equivalent 5 mg/L selenium in water before blocking their abdominal aorta. After 7 days, the rats were sacrificed to observe the structure of nerve cells through HE staining and the expression of CNTF and CNTF-Ralpha by Western blot, immunohistochemical, and RT-PCR methods, respectively. RESULTS: Both protein and mRNA of CNTF and CNTF-Ralpha were positively expressed in rats from SC group. The mRNA expression levels of CNTF and CNTF-Ralpha in ST group were much higher than SCI model group. CONCLUSIONS: SES can execute a protective role in SCI through up-regulating the expression of CNTF and CNTF-Ralpha. PMID- 26636535 TI - Rational selection of predictive pharmacogenomics test for the Fluoropyrimidine/Oxaliplatin based therapy. AB - OBJECTIVE: Both Fluoropyrimidine and Oxaliplatin (FluOx) are the most common anticancer drugs used to treat colorectal, ovarian, and gastrointestinal cancers. Nevertheless, the efficacy of FluOx-based therapy is often compromised by the severe risk of neurotoxicity, cardiotoxicity, and gastrointestinal toxicity. Stratification of patients for their individual response to drugs is a promising approach for cancer treatment and cost-effectiveness. Here we evaluate the most recent findings on the most appropriate gene variants related to the toxicity in patients receiving FluOx chemotherapy. MATERIALS AND METHODS: A systematic literature search of the MEDLINE, EMBASE, and Cochrane databases was conducted to identify all clinical studies of any association between DPYD and 5-FU correlated to allelic status of 6 validated polymorphisms in five genes Dihydropyrimidine Dehydrogenase (DPYD), Thymidylate Synthase (TYMS), Glutathione S-Transferase (GSTP1), and DNA-repair genes (ERCC2 and XRCC1). RESULTS: The stratification of the patients into three genotype profiles group, who are most likely responders to FluOx treatments, provide informations about toxicity and/or resistance before starting therapy. Also, early evaluation cost of panel testing proposed is averaged about ?100,00 per sample. The evaluation costs of genotyping before starting treatment could be a good cost-effectiveness strategy. CONCLUSIONS: Based on the individual genomic profile, the oncologists will have new possibilities, based on the individual genetic profile, to make treatment decisions for their patients and to redefine scheduling and dosage of FluOx-based therapy. PMID- 26636536 TI - Impact of Adhesiolysis on Outcome of Colorectal Surgery. AB - BACKGROUND/AIMS: Adhesiolysis is a frequent part of colorectal surgery, potentially impeding the operation and causing inadvertent bowel injury. Such difficulties might compromise convalescence and oncological quality of resection. The aim of this prospective cohort study was to assess the impact of adhesiolysis on clinical outcomes and histopathological results in colorectal surgery. METHODS: Colorectal procedures were selected from a prospective cohort study of adhesiolysis-related problems. We compared the incidence of bowel injury, morbidity, costs, and the histopathology between patients undergoing elective colorectal surgery with or without adhesiolysis. RESULTS: Two hundred and forty nine colorectal surgeries were analysed. Adhesiolysis was required in 59.0%. The mean adhesiolysis time was 28 min. In the adhesiolysis group, enterotomies occurred in 6.1% and seromuscular injuries in 27.2% compared to 0 and 6.9% respectively in the non-adhesiolysis group (p = 0.012 and p < 0.001). In patients requiring adhesiolysis, 29.9% had major surgery-related complications (MSRC) compared to 15.7% without adhesiolysis (p = 0.007). There were no statistically significant differences regarding inpatient costs and resection margin or number of harvested lymph nodes. CONCLUSIONS: Adhesiolysis during colorectal surgery is related to an increased incidence of iatrogenic bowel injuries and MSRC. Despite the technical challenges associated with adhesiolysis, good histopathological results were obtained in oncological resections. PMID- 26636537 TI - Dimeric peroxiredoxins are druggable targets in human Burkitt lymphoma. AB - Burkitt lymphoma is a fast-growing tumor derived from germinal center B cells. It is mainly treated with aggressive chemotherapy, therefore novel therapeutic approaches are needed due to treatment toxicity and developing resistance. Disturbance of red-ox homeostasis has recently emerged as an efficient antitumor strategy. Peroxiredoxins (PRDXs) are thioredoxin-family antioxidant enzymes that scavenge cellular peroxides and contribute to red-ox homeostasis. PRDXs are robustly expressed in various malignancies and critically involved in cell proliferation, differentiation and apoptosis. To elucidate potential role of PRDXs in lymphoma, we studied their expression level in B cell-derived primary lymphoma cells as well as in cell lines. We found that PRDX1 and PRDX2 are upregulated in tumor B cells as compared with normal counterparts. Concomitant knockdown of PRDX1 and PRDX2 significantly attenuated the growth rate of lymphoma cells. Furthermore, in human Burkitt lymphoma cell lines, we isolated dimeric 2 cysteine peroxiredoxins as targets for SK053, a novel thiol-specific small molecule peptidomimetic with antitumor activity. We observed that treatment of lymphoma cells with SK053 triggers formation of covalent PRDX dimers, accumulation of intracellular reactive oxygen species, phosphorylation of ERK1/2 and AKT and leads to cell cycle arrest and apoptosis. Based on site-directed mutagenesis and modeling studies, we propose a mechanism of SK053-mediated PRDX crosslinking, involving double thioalkylation of active site cysteine residues. Altogether, our results suggest that peroxiredoxins are novel therapeutic targets in Burkitt lymphoma and provide the basis for new approaches to the treatment of this disease. PMID- 26636538 TI - Serum cyclin-dependent kinase 9 is a potential biomarker of atherosclerotic inflammation. AB - Atherosclerotic coronary artery disease (CAD) is one of the most prevalent diseases worldwide. Atherosclerosis was considered to be the single most important contributor to CAD. In this study, a distinct serum protein expression pattern in CAD patients was demonstrated by proteomic analysis with two dimensional gel electrophoresis coupled with mass spectrometry. In particular, CDK9 was found to be highly elevated in serum, monocytes and artery plaque samples of CAD patients. Furthermore, there was high infiltration of CD14+ monocytes/macrophages within artery plaques correlated with the expression of CDK9. Moreover, Flavopiridol (CDK9 inhibitor) could inhibit THP-1 cell (monocytic acute leukemia cell line) proliferation by targeting CDK9. Altogether, These findings indicate that CDK9 represent an important role for inflammation in the pathogenesis of atherosclerosis. It may be a potential biomarker of atherosclerotic inflammation and offer insights into the pathophysiology and targeted therapy for atherosclerotic CAD. PMID- 26636539 TI - miR-382 targeting PTEN-Akt axis promotes liver regeneration. AB - Liver regeneration is a highly orchestrated process which can be regulated by microRNAs (miRNAs, miRs), though the mechanisms are largely unclear. This study was aimed to identify miRNAs responsible for hepatocyte proliferation during liver regeneration. Here we detected a marked elevation of miR-382 in the mouse liver at 48 hrs after partial hepatectomy (PH-48h) using microarray analysis and qRT-PCRs. miR-382 overexpression accelerated the proliferation and the G1 to S phase transition of the cell cycle both in mouse NCTC1469 and human HL7702 normal liver cells, while miR-382 downregulation had inverse effects. Moreover, miR-382 negatively regulated PTEN expression and increased Akt phosphorylation both in vitro and in vivo. Using PTEN siRNA and Akt activator/inhibitor, we further found that PTEN inhibition and Akt phosphorylation were essential for mediating the promotive effect of miR-382 in the proliferation and cell growth of hepatocytes. Collectively, our findings identify miR-382 as a promoter for hepatocyte proliferation and cell growth via targeting PTEN-Akt axis which might be a novel therapeutic target to enhance liver regeneration capability. PMID- 26636540 TI - ROR functions as a ceRNA to regulate Nanog expression by sponging miR-145 and predicts poor prognosis in pancreatic cancer. AB - lncRNAs have emerged as key regulators of tumor development and progression. ROR is a typical lncRNA that plays important regulatory roles in the pathogenesis and progression of tumors. Nevertheless, current understanding of the involvement of ROR in pancreatic adenocarcinoma tumorigenesis remains limited. In this study, we measured ROR in 61 paired cancerous and noncancerous tissue samples by qRT-PCR and investigated the biological role of ROR on the phenotypes of pancreatic cancer stem cells (PCSCs) in vitro and in vivo. The effects of ROR on PCSCs were studied by RNA interference approaches in vitro and in vivo. Insights of the mechanism of competitive endogenous RNAs (ceRNAs) were gained from bioinformatic analysis, luciferase assays and RNA binding protein immunoprecipitation. The positive ROR/Nanog interaction was identified and verified by immunohistochemistry assay. Compared with adjacent non-tumor tissues, ROR was up regulated in most tumor tissues. Knockdown of ROR by RNA interference in PCSCs inhibited proliferation, induced apoptosis and decreased migration. Moreover, ROR silencing resulted in significantly decreased tumourigenicity of PCSCs in nude mice than controls. In particular, ROR may act as a ceRNA, effectively becoming a sink for miR-145, thereby activating the derepression of core transcription factors Nanog. In conclusions, we demonstrated that decreased ROR expression could inhibit cell proliferation, invasion, and tumourigenicity by modulating Nanog. Therefore, ROR is a potential novel prognostic marker to predict the clinical outcome of pancreatic cancer patients after surgery and may be a rational target for therapy. PMID- 26636541 TI - Ginsenoside Rg3 inhibits epithelial-mesenchymal transition (EMT) and invasion of lung cancer by down-regulating FUT4. AB - The epithelial-mesenchymal transition (EMT) is an important factor in lung cancer metastasis, and targeting EMT is a potential therapeutic strategy. Fucosyltransferase IV (FUT4) and its synthetic cancer sugar antigen Lewis Y (LeY) was abnormally elevated in many cancers. In this study, a traditional Chinese medicine ginsenoside Rg3 was used to investigate whether its inhibition to EMT and invasion of lung cancer is by the glycobiology mechanism. We found that Rg3 treatment (25, 50, 100 MUg/ml) inhibited cell migration and invasion by wound healing and transwell assays. Rg3 could significantly alter EMT marker proteins with increased E-cadherin, but decreased Snail, N-cadherin and Vimentin expression. Rg3 also down-regulated FUT4 gene and protein expression in lung cancer cells by qPCR, Western blot and immunofluorescence. After FUT4 down regulated with shFUT4, EMT was obviously inhibited. Furthermore, the activation of EGFR through decreased LeY biosynthesis was inhibited, which blocked the downstream MAPK and NF-kappaB signal pathways. In addition, Rg3 reduced tumor volume and weight in xenograft mouse model, and significantly decreased tumor metastasis nodules in lung tissues by tail vein injection. In conclusion, Rg3 inhibits EMT and invasion of lung cancer by down-regulating FUT4 mediated EGFR inactivation and blocking MAPK and NF-kappaB signal pathways. Rg3 may be a potentially effective agent for the treatment of lung cancer. PMID- 26636542 TI - Antihypertensive treatments in adult autosomal dominant polycystic kidney disease: network meta-analysis of the randomized controlled trials. AB - BACKGROUND: Blood pressure (BP) control is one of the most important treatments of Autosomal dominant polycystic kidney disease (ADPKD). The comparative efficacy of antihypertensive treatments in ADPKD patients is inconclusive. METHODS: Network meta-analysis was used to evaluate randomized controlled trials (RCT) which investigated antihypertensive treatments in ADPKD. PubMed, Embase, Ovid, and Cochrane Collaboration were searched. The primary outcome was estimated glomerular filtration rate (eGFR). Secondary outcomes were serum creatinine (Scr), urinary albumin excretion (UAE), systolic BP (SBP), diastolic BP (DBP), mean artery pressure (MAP) and left ventricular mass index (LVMI). RESULTS: We included 10 RCTs with 1386 patients and six interventions: angiotensin-converting enzyme inhibitors (ACEI), Angiotensin II receptor blocker (ARB), combination of ACEI and ARB, calcium channel blockers (CCB), beta-blockers and dilazep. There was no difference of eGFR in all the treatments in both network and direct comparisons. No significant differences of Scr, SBP, DBP, MAP, and LVMI were found in network comparisons. However, ACEI significantly reduced SBP, DBP, MAP and LVMI when compared to CCB. Significantly increased UAE was observed in CCB compared with ACEI or ARB. Bayesian probability analysis found ARB ranked first in the surrogate measures of eGFR, UAE and SBP. CONCLUSIONS: There is little evidence to detect differences of antihypertensive treatments on kidney disease progression in ADPKD patients. More RCTs will be needed in the future. Use of ARB may be an optimal choice in clinical practice. PMID- 26636544 TI - Voice Register in Mon: Acoustics and Electroglottography. AB - Mon is spoken in villages in Thailand and Myanmar. The dialect of Ban Nakhonchum, Thailand, has 2 voice registers, modal and breathy; these phonation types, along with other phonetic properties, distinguish minimal pairs. Four native speakers of this dialect recorded repetitions of 14 randomized words (7 minimal pairs) for acoustic analysis. We used a subset of these pairs in a listening test to verify the perceptual robustness of the register distinction. Acoustic analysis found significant differences in noise component, spectral slope and fundamental frequency. In a subsequent session 4 speakers were also recorded using electroglottography, which showed systematic differences in the contact quotient. The salience of these properties in maintaining the register distinction is discussed in the context of possible tonogenesis for this language. PMID- 26636543 TI - mTOR kinase inhibitor pp242 causes mitophagy terminated by apoptotic cell death in E1A-Ras transformed cells. AB - mTOR is a critical target for controlling cell cycle progression, senescence and cell death in mammalian cancer cells. Here we studied the role of mTOR-dependent autophagy in implementating the antiprolifrative effect of mTORC1-specific inhibitor rapamycin and ATP-competitive mTOR kinase inhibitor pp242. We carried out a comprehensive analysis of pp242- and rapamycin-induced autophagy in ERas tumor cells. Rapamycin exerts cytostatic effect on ERas tumor cells, thus causing a temporary and reversible cell cycle arrest, activation of non-selective autophagy not accompanied by cell death. The rapamycin-treated cells are able to continue proliferation after drug removal. The ATP-competitive mTORC1/mTORC2 kinase inhibitor pp242 is highly cytotoxic by suppressing the function of mTORC1 4EBP1 axis and mTORC1-dependent phosphorylation of mTORC1 target--ULK1-Ser757 (Atg1). In contrast to rapamycin, pp242 activates the selective autophagy targeting mitochondria (mitophagy). The pp242-induced mitophagy is accompanied by accumulation of LC3 and conversion of LC3-I form to LC3-II. However reduced degradation of p62/SQSTM indicates abnormal flux of autophagic process. According to transmission electron microscopy data, short-term pp242-treated ERas cells exhibit numerous heavily damaged mitochondria, which are included in single membrane-bound autophagic/autolysophagic vacuoles (mitophagy). Despite the lack of typical for apoptosis features, ERas-treated cells with induced mitophagy revealed the activation of caspase 3, 9 and nucleosomal DNA fragmentation. Thus, pp242 activates autophagy with suppressed later stages, leading to impaired recycling and accumulation of dysfunctional mitochondria and cell death. Better understanding of how autophagy determines the fate of a cell--survival or cell death, can help to development of new strategy for cancer therapy. PMID- 26636545 TI - Combined Pulmonary Fibrosis and Emphysema in Scleroderma-Related Lung Disease Has a Major Confounding Effect on Lung Physiology and Screening for Pulmonary Hypertension. AB - OBJECTIVE: To assess the prevalence of combined pulmonary fibrosis and emphysema (CPFE) in systemic sclerosis (SSc) patients with interstitial lung disease (ILD) and the effect of CPFE on the pulmonary function tests used to evaluate the severity of SSc-related ILD and the likelihood of pulmonary hypertension (PH). METHODS: High-resolution computed tomography (HRCT) scans were obtained in 333 patients with SSc-related ILD and were evaluated for the presence of emphysema and the extent of ILD. The effects of emphysema on the associations between pulmonary function variables and the extent of SSc-related ILD as visualized on HRCT and echocardiographic evidence of PH were quantified. RESULTS: Emphysema was present in 41 (12.3%) of the 333 patients with SSc-related ILD, in 26 (19.7%) of 132 smokers, and in 15 (7.5%) of 201 lifelong nonsmokers. When the extent of fibrosis was taken into account, emphysema was associated with significant additional differences from the expected values for diffusing capacity for carbon monoxide (DLco) (average reduction of 24.1%; P < 0.0005), and the forced vital capacity (FVC)/DLco ratio (average increase of 34.8%; P < 0.0005) but not FVC. These effects were identical in smokers and nonsmokers. Multivariate analysis showed that the presence of emphysema had a greater effect than echocardiographically determined PH on the FVC/DLco ratio, regardless of whether it was analyzed as a continuous variable or using a threshold value of 1.6 or 2.0. CONCLUSION: Among patients with SSc-related ILD, emphysema is sporadically present in nonsmokers and is associated with a low pack-year history in smokers. The confounding effect of CPFE on measures of gas exchange has major implications for the construction of screening algorithms for PH in patients with SSc-related ILD. PMID- 26636546 TI - Two Fatal Cases of Accidental Intrathecal Vincristine Administration: Learning from Death Events. AB - We report 2 cases of accidental intrathecal vincristine administration. These injections were scheduled as intravenous injections of vincristine at the same time as other intrathecal drugs were scheduled. The mistakes were recognized immediately after administration, and a lumbar puncture was performed to lavage the cerebrospinal fluid (CSF) immediately after the incident. However, both cases developed progressive sensorimotor and radiculo-myelo-encephalopathy and the patients died 3 and 6 days after the incidents due to decerebration. A number of cases of accidental intrathecal vincristine administration have occurred in recent years in other settings, and we add our events to emphasize the need for a preventative and strictly followed protocol in oncology treatment units to prevent further unnecessary deaths. The best 'cure' for mistakenly administered vincristine via lumbar puncture is prevention, which can be improved by strict adherence to a comprehensive guideline. Oncologic treatment centers should be aware of this guideline and evaluate their protocol for vincristine administration to prevent future incidents. Based on our past experiences, we strongly recommend 'time-independent' procedures to prevent this type of incident. PMID- 26636547 TI - REDUCTIONS IN CANNABIS USE ARE ASSOCIATED WITH MOOD IMPROVEMENT IN FEMALE EMERGING ADULTS. AB - BACKGROUND: Cannabis use and the development of depression symptoms have been linked in prospective research. However, no research has examined how depression symptoms might change relative to reductions in cannabis use. One group at risk for comorbid cannabis-use disorders and clinical depression is female emerging adults (those aged 18-25 years old) as cannabis use peaks during this period, depression is the most common psychiatric disorder among emerging adults, and females are at increased risk for depression relative to males. This study examined the longitudinal association between reductions in cannabis use and existing depression symptoms. METHODS: Secondary analyses from a cannabis intervention trial for 332 female emerging adults were conducted. Changes in depression symptoms (categorized as minimal, mild, and moderate or more severe depression) were assessed in relation to changes in cannabis use at 3- and 6 months postbaseline assessment. RESULTS: After controlling for alcohol use, the association between change in cannabis-use frequency and change in depression (measured by Beck Depression Inventory-II) was significantly stronger for those with mild depression (b = -0.26; 95% CI: -0.44, -0.08; P = .004), and for those with moderate or more severe depression (b = -0.50; 95% CI: -0.68, -0.33; P < .001) relative to those with minimal depression. CONCLUSIONS: These results indicate a relationship between reductions in cannabis use and reductions in depression symptoms among female emerging adults who report at least mild depression symptoms. This represents a clinically meaningful effect for clinicians treating patients with co-occurring cannabis use and depressive disorders. PMID- 26636549 TI - Successful treatment of severe hypokalemia in a dog with acute kidney injury caused by leptospirosis. AB - OBJECTIVE: To report the case management of a patient with severe hypokalemia resulting in cardiopulmonary arrest caused by infection with leptospirosis. CASE SUMMARY: A 3-year-old intact female Dachshund presented for polyuria, polydipsia, and refractory hypokalemia, which progressed to flaccid paralysis and cardiorespiratory arrest. Following successful resuscitation, the dog was apneic and managed with mechanical ventilation while volume status and electrolytes were corrected. The dog showed rapid improvement allowing for weaning from the ventilator within the first day. The dog was identified as having leptospirosis causing severe kaliuresis (fractional excretion of potassium 31%). Following discharge from hospital, the dog was managed with doxycycline, oral potassium supplementation, and spironolactone and made a full clinical recovery. NEW OR UNIQUE INFORMATION PROVIDED: This report identifies an unusually severe presentation of leptospirosis in a dog from a region where the disease is not considered common, which was successfully treated despite cardiopulmonary arrest on initial presentation. PMID- 26636548 TI - Development of Th17-Associated Interstitial Kidney Inflammation in Lupus-Prone Mice Lacking the Gene Encoding STAT-1. AB - OBJECTIVE: Type I interferon (IFN) signaling is a central pathogenic pathway in systemic lupus erythematosus (SLE), and therapeutics targeting type I IFN signaling are in development. Multiple proteins with overlapping functions play a role in IFN signaling, but the signaling events downstream of receptor engagement are unclear. This study was undertaken to investigate the roles of the type I and type II IFN signaling components IFN-alpha/beta/omega receptor 2 (IFNAR-2), IFN regulatory factor 9 (IRF-9), and STAT-1 in a mouse model of SLE. METHODS: We used immunohistochemical staining and highly multiplexed assays to characterize pathologic changes in histology, autoantibody production, cytokine/chemokine profiles, and STAT phosphorylation in order to investigate the individual roles of IFNAR-2, IRF-9, and STAT-1 in MRL/lpr mice. RESULTS: We found that STAT-1(-/-) mice, but not IRF-9(-/-) or IFNAR-2(-/-) mice, developed interstitial nephritis characterized by infiltration with retinoic acid receptor-related orphan nuclear receptor gammat-positive lymphocytes, macrophages, and eosinophils. Despite pronounced interstitial kidney disease and abnormal kidney function, STAT-1(-/-) mice had decreased proteinuria, glomerulonephritis, and autoantibody production. Phosphospecific flow cytometry revealed shunting of STAT phosphorylation from STAT-1 to STAT-3/4. CONCLUSION: We describe unique contributions of STAT-1 to pathology in different kidney compartments in a mouse model, and provide potentially novel insight into tubulointerstitial nephritis, a poorly understood complication that predicts end-stage kidney disease in SLE patients. PMID- 26636550 TI - The allometry of the smallest: superlinear scaling of microbial metabolic rates in the Atlantic Ocean. AB - Prokaryotic planktonic organisms are small in size but largely relevant in marine biogeochemical cycles. Due to their reduced size range (0.2 to 1 MUm in diameter), the effects of cell size on their metabolism have been hardly considered and are usually not examined in field studies. Here, we show the results of size-fractionated experiments of marine microbial respiration rate along a latitudinal transect in the Atlantic Ocean. The scaling exponents obtained from the power relationship between respiration rate and size were significantly higher than one. This superlinearity was ubiquitous across the latitudinal transect but its value was not universal revealing a strong albeit heterogeneous effect of cell size on microbial metabolism. Our results suggest that the latitudinal differences observed are the combined result of changes in cell size and composition between functional groups within prokaryotes. Communities where the largest size fraction was dominated by prokaryotic cyanobacteria, especially Prochlorococcus, have lower allometric exponents. We hypothesize that these larger, more complex prokaryotes fall close to the evolutionary transition between prokaryotes and protists, in a range where surface area starts to constrain metabolism and, hence, are expected to follow a scaling closer to linearity. PMID- 26636551 TI - Anaerobic oxidation of methane associated with sulfate reduction in a natural freshwater gas source. AB - The occurrence of anaerobic oxidation of methane (AOM) and trace methane oxidation (TMO) was investigated in a freshwater natural gas source. Sediment samples were taken and analyzed for potential electron acceptors coupled to AOM. Long-term incubations with (13)C-labeled CH4 ((13)CH4) and different electron acceptors showed that both AOM and TMO occurred. In most conditions, (13)C labeled CO2 ((13)CO2) simultaneously increased with methane formation, which is typical for TMO. In the presence of nitrate, neither methane formation nor methane oxidation occurred. Net AOM was measured only with sulfate as electron acceptor. Here, sulfide production occurred simultaneously with (13)CO2 production and no methanogenesis occurred, excluding TMO as a possible source for (13)CO2 production from (13)CH4. Archaeal 16S rRNA gene analysis showed the highest presence of ANME-2a/b (ANaerobic MEthane oxidizing archaea) and AAA (AOM Associated Archaea) sequences in the incubations with methane and sulfate as compared with only methane addition. Higher abundance of ANME-2a/b in incubations with methane and sulfate as compared with only sulfate addition was shown by qPCR analysis. Bacterial 16S rRNA gene analysis showed the presence of sulfate reducing bacteria belonging to SEEP-SRB1. This is the first report that explicitly shows that AOM is associated with sulfate reduction in an enrichment culture of ANME-2a/b and AAA methanotrophs and SEEP-SRB1 sulfate reducers from a low-saline environment. PMID- 26636552 TI - Microbial communities reflect temporal changes in cyanobacterial composition in a shallow ephemeral freshwater lake. AB - The frequency of freshwater cyanobacterial blooms is at risk of increasing as a consequence of climate change and eutrophication of waterways. It is increasingly apparent that abiotic data are insufficient to explain variability within the cyanobacterial community, with biotic factors such as heterotrophic bacterioplankton, viruses and protists emerging as critical drivers. During the Australian summer of 2012-2013, a bloom that occurred in a shallow ephemeral lake over a 6-month period was comprised of 22 distinct cyanobacteria, including Microcystis, Dolichospermum, Oscillatoria and Sphaerospermopsis. Cyanobacterial cell densities, bacterial community composition and abiotic parameters were assessed over this period. Alpha-diversity indices and multivariate analysis were successful at differentiating three distinct bloom phases and the contribution of abiotic parameters to each. Network analysis, assessing correlations between biotic and abiotic variables, reproduced these phases and assessed the relative importance of both abiotic and biotic factors. Variables possessing elevated betweeness centrality included temperature, sodium and operational taxonomic units belonging to the phyla Verrucomicrobia, Planctomyces, Bacteroidetes and Actinobacteria. Species-specific associations between cyanobacteria and bacterioplankton, including the free-living Actinobacteria acI, Bacteroidetes, Betaproteobacteria and Verrucomicrobia, were also identified. We concluded that changes in the abundance and nature of freshwater cyanobacteria are associated with changes in the diversity and composition of lake bacterioplankton. Given this, an increase in the frequency of cyanobacteria blooms has the potential to alter nutrient cycling and contribute to long-term functional perturbation of freshwater systems. PMID- 26636553 TI - Temperature-induced behavioral switches in a bacterial coral pathogen. AB - Evidence to date indicates that elevated seawater temperatures increase the occurrence of coral disease, which is frequently microbial in origin. Microbial behaviors such as motility and chemotaxis are often implicated in coral colonization and infection, yet little is known about the effect of warming temperatures on these behaviors. Here we present data demonstrating that increasing water temperatures induce two behavioral switches in the coral pathogen Vibrio coralliilyticus that considerably augment the bacterium's performance in tracking the chemical signals of its coral host, Pocillopora damicornis. Coupling field-based heat-stress manipulations with laboratory-based observations in microfluidic devices, we recorded the swimming behavior of thousands of individual pathogen cells at different temperatures, associated with current and future climate scenarios. When temperature reached ?23 degrees C, we found that the pathogen's chemotactic ability toward coral mucus increased by >60%, denoting an enhanced capability to track host-derived chemical cues. Raising the temperature further, to 30 degrees C, increased the pathogen's chemokinetic ability by >57%, denoting an enhanced capability of cells to accelerate in favorable, mucus-rich chemical conditions. This work demonstrates that increasing temperature can have strong, multifarious effects that enhance the motile behaviors and host-seeking efficiency of a marine bacterial pathogen. PMID- 26636555 TI - Building Interdisciplinary Research Models Through Interactive Education. AB - BACKGROUND: Critical interdisciplinary research skills include effective communication with diverse disciplines and cultivating collaborative relationships. Acquiring these skills during graduate education may foster future interdisciplinary research quality and productivity. OBJECTIVE: The project aim was to develop and evaluate an interactive Toolbox workshop approach within an interprofessional graduate level course to enhance student learning and skill in interdisciplinary research. We sought to examine the student experience of integrating the Toolbox workshop in modular format over the duration of a 14-week course. METHODS: The Toolbox Health Sciences Instrument includes six modules that were introduced in a 110-minute dialogue session during the first class and then integrated into the course in a series of six individual workshops in three phases over the course of the semester. RESULTS: Seventeen students participated; the majority were nursing students. Three measures were used to assess project outcomes: pre-post intervention Toolbox survey, competency self-assessment, and a postcourse survey. All measures indicated the objectives were met by a change in survey responses, improved competencies, and favorable experience of the Toolbox modular intervention. CONCLUSION: Our experience indicates that incorporating this Toolbox modular approach into research curricula can enhance individual level scientific capacity, future interdisciplinary research project success, and ultimately impact on practice and policy. PMID- 26636554 TI - Transcription factor levels enable metabolic diversification of single cells of environmental bacteria. AB - Transcriptional noise is a necessary consequence of the molecular events that drive gene expression in prokaryotes. However, some environmental microorganisms that inhabit polluted sites, for example, the m-xylene degrading soil bacterium Pseudomonas putida mt-2 seem to have co-opted evolutionarily such a noise for deploying a metabolic diversification strategy that allows a cautious exploration of new chemical landscapes. We have examined this phenomenon under the light of deterministic and stochastic models for activation of the main promoter of the master m-xylene responsive promoter of the system (Pu) by its cognate transcriptional factor (XylR). These analyses consider the role of co-factors for Pu activation and determinants of xylR mRNA translation. The model traces the onset and eventual disappearance of the bimodal distribution of Pu activity along time to the growth-phase dependent abundance of XylR itself, that is, very low in exponentially growing cells and high in stationary. This tenet was validated by examining the behaviour of a Pu-GFP fusion in a P. putida strain in which xylR expression was engineered under the control of an IPTG-inducible system. This work shows how a relatively simple regulatory scenario (for example, growth-phase dependent expression of a limiting transcription factor) originates a regime of phenotypic diversity likely to be advantageous in competitive environmental settings. PMID- 26636556 TI - Neuroimaging correlates of blinking abnormalities in patients with progressive supranuclear palsy. AB - OBJECTIVE: We aimed to identify the possible relationship between blinking abnormalities and neuroimaging changes in patients with progressive supranuclear palsy. METHODS: We studied 18 patients with progressive supranuclear palsy and 13 healthy subjects. Voluntary and spontaneous blinking were recorded using kinematic techniques. Changes in brain structures were detected by T1-weighted magnetic resonance imaging and voxel-based morphometry. We then sought possible correlations between blinking and neuroimaging abnormalities in patients. RESULTS: Kinematic analysis indicated several abnormalities during voluntary blinking and a markedly reduced spontaneous blink rate in patients compared with healthy subjects. Neuroimaging showed gray matter loss in cortical and subcortical structures and lower white matter volume in the brainstem. Gray matter loss in subcortical structures correlated with the prolonged pause duration between the closing and opening phases, during voluntary blinking. CONCLUSIONS: This study provides a more specific insight into the pathophysiological mechanisms underlying blinking abnormalities in progressive supranuclear palsy. PMID- 26636557 TI - Net methylmercury production in 2 contrasting stream sediments and associated accumulation and toxicity to periphyton. AB - Periphyton uptake of bioaccumulative methylmercury (MeHg) may be an important entryway into the food web of many stream ecosystems where periphyton can be dominant primary producers. The net production of MeHg in stream sediment, its bioaccumulation in periphyton, and the potential toxicity of divalent Hg (Hg[II]) and MeHg in sediment to periphyton were investigated with a 67-d in situ incubation experiment using chemical exposure substrates containing either a fine grained, organic-rich or a sandy, low-organic sediment, each amended with varying concentrations of mercuric chloride. Methylmercury was produced in sediment, and concentrations increased with greater amounts of added Hg(II); however, the net production of MeHg was inhibited in the highest Hg(II) treatments of both sediments. The range of total Hg concentrations that inhibited MeHg production was between approximately 80 000 ng Hg and 350 000 ng Hg per gram of organic matter for both sediments. Periphyton colonizing substrates accumulated MeHg in proportion to the concentration in sediment, but periphyton exposed to the sandy sediment accumulated approximately 20-fold more than those exposed to the organic rich sediment relative to sediment MeHg concentrations. Toxicity of either Hg(II) or MeHg to periphyton was not observed with either periphyton organic content, net primary production, or respiration as endpoints. These results suggest that in situ production and bioaccumulation of MeHg in stream ecosystems can vary as a function of sediment characteristics and Hg(II) loadings to the sediment. Environ Toxicol Chem 2016;35:1759-1765. (c) 2015 SETAC. PMID- 26636558 TI - Lack of P-glycoprotein expression in melanoma brain metastases of different melanoma types. PMID- 26636559 TI - Strangers in the archaeal world: osmostress-responsive biosynthesis of ectoine and hydroxyectoine by the marine thaumarchaeon Nitrosopumilus maritimus. AB - Ectoine and hydroxyectoine are compatible solutes widely synthesized by members of the Bacteria to cope with high osmolarity surroundings. Inspection of 557 archaeal genomes revealed that only 12 strains affiliated with the Nitrosopumilus, Methanothrix or Methanobacterium genera harbour ectoine/hydroxyectoine gene clusters. Phylogenetic considerations suggest that these Archaea have acquired these genes through horizontal gene transfer events. Using the Thaumarchaeon 'Candidatus Nitrosopumilus maritimus' as an example, we demonstrate that the transcription of its ectABCD genes is osmotically induced and functional since it leads to the production of both ectoine and hydroxyectoine. The ectoine synthase and the ectoine hydroxylase were biochemically characterized, and their properties resemble those of their counterparts from Bacteria. Transcriptional analysis of osmotically stressed 'Ca. N. maritimus' cells demonstrated that they possess an ectoine/hydroxyectoine gene cluster (hyp-ectABCD-mscS) different from those recognized previously since it contains a gene for an MscS-type mechanosensitive channel. Complementation experiments with an Escherichia coli mutant lacking all known mechanosensitive channel proteins demonstrated that the (Nm)MscS protein is functional. Hence, 'Ca. N. maritimus' cells cope with high salinity not only through enhanced synthesis of osmostress-protective ectoines but they already prepare themselves simultaneously for an eventually occurring osmotic down-shock by enhancing the production of a safety-valve (NmMscS). PMID- 26636560 TI - Photoswitchable "Turn-on" Fluorescence Diarylethenes: Substituent Effects on Photochemical Properties and Electrochromism. AB - A series of "turn-on" fluorescence diarylethenes derived from 2,3-bis(2 methylbenzo[b]thiophen-3-yl)-5,6-dihydro-4H-thieno[2,3-b]thiopyran-4-one (1) with alkyl and acetyl substituents were synthesized. The photochemical and photophysical properties of these derivatives, including the photoreaction of crystalline 1, were thoroughly investigated to reveal substituent effects on their properties. The results indicated that alkyl substituents did not significantly affect the absorption and emission spectra of the diarylethenes. However, large absorption and emission wavelength shifts were observed for the diarylethene with an acetyl substituent due to extension of pi-pi conjugation. Significantly, all of the fluorescent ring-closed forms of the compounds isomerized to their ring-open forms in the presence of Cu(2+) in the dark. EPR results provide clear evidence for the formation of the compound 1 radical cation intermediate that might be generated in the reaction between c-1 and Cu(2+) . DFT calculations found that the ground-state activation energy for ring-opening of 1(.+) was approximately 9.2 kcal mol(-1) lower than that of 1 without Cu(2+) , such that a Cu(2+) -catalyzed oxidative cycloreversion reaction at room temperature might be possible. PMID- 26636561 TI - History of incomplete vaccination may associate with occurrence of hemorrhagic fever with renal syndrome with relieved clinical symptoms. AB - OBJECTIVE: This retrospective study is aimed to investigate the clinical features of the patients with history of incomplete vaccination against hemorrhagic fever with renal syndrome (HFRS). METHODS: Data of 140 cases of hospitalized patients with HFRS were collected. The patients were divided into incomplete vaccinated group (n = 10) and unvaccinated group (n = 130) according to vaccination status. Demographic, clinical, and laboratory characteristics of the two groups' patients were compared through t test, Pearson chi(2) test, and Mann-Whitney test. RESULTS: In comparison with the unvaccinated group, the incidence rate of vomiting and hypotensive-shock, the white blood cell (WBC) and platelet count, the level of blood urea nitrogen and albumin, total number of dialysis and hospitalization cost of patients in the incomplete vaccinated group have statistically significant differences. CONCLUSION: HFRS disease may still occur in individuals with a history of HFRS incomplete vaccination although the symptoms may be mild. Effective vaccination against HFRS needs sufficient doses and booster shot of the vaccine. PMID- 26636562 TI - Reply. PMID- 26636563 TI - An Integrative Psychotherapy Approach to Foster Community Engagement and Rehabilitation in Schizophrenia: A Case Study Illustration. AB - This case study illustrates the use of a long-term integrative psychotherapy approach with a middle- aged man with chronic schizophrenia and a mood disorder. The case of "Holst" describes a man with a history of insecure attachment and trauma who later went on to contract a serious chronic illness, precipitating the onset of psychotic symptoms, depression, and chronic suicidal ideation, resulting in multiple hospitalizations. Combining metacognition-oriented therapy with elements of cognitive behavioral therapy and psychiatric rehabilitation, this approach fostered significantly improved community functioning and attainment of personal goals over time. Through the journey of therapy, the patient also developed a more coherent narrative about his life, established a stable sense of self, and became an active agent in the world. This case illustration demonstrates that these three different approaches can be used in a sequential and complementary fashion to foster recovery in the midst of serious physical and mental illness. PMID- 26636564 TI - The Origin of the Reactivity of the Criegee Intermediate: Implications for Atmospheric Particle Growth. AB - The electronic structure of the simplest Criegee intermediate, H2COO, is practically that of a closed shell. On the biradical scale (beta), where 0 corresponds to the pure closed shell and 1 to a pure biradical, its beta value is only 0.10, suggesting that its ground electronic state is best described as a H2C=O(delta+)-O(delta-) zwitterion. However, this picture of a nearly inert closed shell contradicts its rich reactivity in the atmosphere. It is shown that the mixing of its ground state with the first triplet excited state, which is a pure biradical state of the type H2C-O-O, is responsible for the formation of strongly bound products during reactions inducing atmospheric particle growth. PMID- 26636565 TI - Spectra Library: An Assumption-Free In Situ Method to Access the Kinetics of Catechols Binding to Colloidal ZnO Quantum Dots. AB - Assumption-free and in situ resolving of the kinetics of ligand binding to colloidal nanoparticles (NPs) with high time resolution is still a challenge in NP research. A unique concept of using spectra library and stopped-flow together with a "search best-match" Matlab algorithm to access the kinetics of ligand binding in colloidal systems is reported. Instead of deconvoluting superimposed spectra using assumptions, species absorbance contributions (ligand@ZnO NPs and ligand in solution) are obtained by offline experiments. Therefrom, a library of well-defined targets with known ligand distribution between particle surface and solution is created. Finally, the evolution of bound ligand is derived by comparing in situ spectra recorded by stopped-flow and the library spectra with the algorithm. Our concept is a widely applicable strategy for kinetic studies of ligand adsorption to colloidal NPs and a big step towards deep understanding of surface functionalization kinetics. PMID- 26636566 TI - Shape-Memory Platinum(II) Complexes: Intelligent Vapor-History Sensor with ON-OFF Switching Function. AB - A novel platinum(II)-diimine complex, [Pt(CN)2 (H2 dcphen)] (1; H2 dcphen=4,7 dicarboxy-1,10- phenanthroline), was synthesized and its vapochromic shape-memory behavior was evaluated. The as-synthesized amorphous purple solid, [Pt(CN)2 (H2 dcphen)]?2 H2 O (1 P), exhibited vapochromic behavior in the presence of alcoholic vapors through transformation to a red, crystalline, porous, vapor adsorbed form, 1 R?vapor. The obtained 1 R?vapor complex released the adsorbed vapors upon heating without collapse of the porous structure. The vaporfree, porous 1 R?open could detect water or n-hexane vapor, although these vapors could not induce 1 P-to-1 R?vapor transformation, and 1 R?open could easily be converted to the initial 1 P by manual grinding. These results indicate that 1 is a new shape-memory material that functions through formation and collapse of the porous framework with an emission change upon vapor-adsorption and grinding; this enables it to exhibit vapor history and ON-OFF switching sensing functions. PMID- 26636567 TI - Microtubule-Binding R3 Fragment from Tau Self-Assembles into Giant Multistranded Amyloid Ribbons. AB - Tau protein and its fragments self-assemble into amyloid fibrils in the presence of polyanions, such as heparin. By combining microscopy, scattering, and spectroscopy techniques, we studied the aggregation of the 26-mer Tau-derived peptide alone, Tau(306-327), the third repeat fragment (R3) of the microtubule binding domain. We show that: i) the sole Tau(306-327) can self-assemble into amyloid fibrils without the need of aggregation-promoting polyanions; ii) the resulting structures consist of surprisingly large, well-ordered 2D laminated flat ribbons, with a log-normal distribution of the lateral width, reaching the unprecedented lateral size of 350 nm and/or 45 individual protofilaments, that is, the largest amyloid laminated structures ever observed for Tau or any other amyloidogenic sequence. Our results provide insight into the molecular determinants of Tau aggregation and open new perspectives in the understanding of the assembly of amyloid fibrils and beta-sheet-based biomaterials. PMID- 26636569 TI - Water-dispersed thermo-responsive boron nitride nanotubes: synthesis and properties. AB - In this study, water-dispersed thermo-responsive boron nitride nanotubes (BNNTs) were prepared in a simple two-step process, where on the first step oligoperoxide was grafted via the interaction of amino groups (defects) of BNNTs with pyromellitic chloroanhydride fragments in oligoperoxide molecules. The second step involves N-isopropylacrylamide (NIPAM) graft polymerization 'from the surface' of oligoperoxide-functionalized BNNTs resulting in poly(N isopropylacrylamide) (PNIPAM) coating. The pristine and functionalized BNNTs were characterized by thermogravimetric analysis, Fourier transform infrared spectroscopy, ultraviolet-visible spectrophotometry, dynamic light scattering, scanning electron microscopy and atomic force microscopy. PNIPAM-functionalized BNNTs exhibit excellent dispersibility in water and possess thermo-responsive properties. The water-dispersion of thermo-responsive PNIPAM-functionalized BNNTs can help their potential use in biomedical applications as 'smart' surfaces, nanotransducers and nanocarriers. PMID- 26636568 TI - An Epidemiological Model of the Effects of Insecticide-Treated Bed Nets on Malaria Transmission. AB - Insecticide-treated bed nets (ITNs) have become a central tool for malaria control because they provide personal and community-wide protection through their repellent and insecticidal properties. Here we propose a model that allows to assess the relative importance of those two effects in different epidemiological contexts and we show that these two levels of protection may oppose each other. On the one hand, repellency offers personal protection to the users of ITNs. The repellent action, however, is a two-edged sword, for it diverts infectious mosquitoes to non-users, thereby increasing their risk. Furthermore, with increasing ITN coverage, the personal protection effect of repellency decreases as mosquitoes are forced to perform multiple feeding attempts even on ITN users. On the other hand, the insecticidal property, which offers community-wide protection by killing mosquitoes, requires that mosquitoes contact the insecticide on the ITN and is thus counteracted by the repellency. Our model confirms that ITNs are an effective intervention method by reducing total malaria prevalence in the population, but that there is a conflict between personal protection, offered by repellency, and community-wide protection, which relies on the ITN's insecticidal properties. Crucially, the model suggests that weak repellency allows disease elimination at lower ITN coverage levels. PMID- 26636570 TI - The Pattern of Adipose Tissue Accumulation during Early Infancy Provides an Environment for the Development of Dengue Hemorrhagic Fever. AB - BACKGROUND: Dengue is the most prevalent arthropod-borne viral illness in humans with half of the world's population at risk. During early infancy, severe dengue can develop after a primary dengue virus infection. There has been a clinical observation that severe dengue during the first year of life is seen only in chubby infants. METHODOLOGY/PRINCIPAL FINDINGS: We examined the associations between the development of severe dengue and adipose tissue accumulation patterns during the first year of life in a prospective observational clinical study of infants and dengue virus infections. We found that adipose tissue contains two potential targets for dengue virus infection and production- adipocytes and adipose tissue macrophages. During the first year of life, total body adiposity and visceral adipose tissue stores were at their highest levels in early infancy. Early infancy was also characterized by a relative decrease in alternatively activated (anti-inflammatory) macrophages, and a relative increase in circulating pro-inflammatory cytokines. CONCLUSIONS/SIGNIFICANCE: The data has been used to propose a model where the adipose tissue accumulation pattern and pro inflammatory environment during early infancy provide the conditions for the potential development of severe dengue in immune-susceptible infants. PMID- 26636571 TI - Composition of the Spruce Budworm (Choristoneura fumiferana) Midgut Microbiota as Affected by Rearing Conditions. AB - The eastern spruce budworm (Choristoneura fumiferana) is one of the most destructive forest insect pests in Canada. Little is known about its intestinal microbiota, which could play a role in digestion, immune protection, communication and/or development. The present study was designed to provide a first characterization of the effects of rearing conditions on the taxonomic diversity and structure of the C. fumiferana midgut microbiota, using a culture independent approach. Three diets and insect sources were examined: larvae from a laboratory colony reared on a synthetic diet and field-collected larvae reared on balsam fir or black spruce foliage. Bacterial DNA from the larval midguts was extracted to amplify and sequence the V6-V8 region of the 16S rRNA gene, using the Roche 454 GS-FLX technology. Our results showed a dominance of Proteobacteria, mainly Pseudomonas spp., in the spruce budworm midgut, irrespective of treatment group. Taxonomic diversity of the midgut microbiota was greater for larvae reared on synthetic diet than for those collected and reared on host plants, a difference that is likely accounted for by several factors. A greater proportion of bacteria from the phylum Bacteroidetes in insects fed artificial diet constituted the main difference between this group and those reared on foliage; within the phylum Proteobacteria, the presence of the genus Bradyrhizobium was also unique to insects reared on artificial diet. Strikingly, a Bray-Curtis analysis showed important differences in microbial diversity among the treatment groups, pointing to the importance of diet and environment in defining the spruce budworm midgut microbiota. PMID- 26636572 TI - Exploring the Y Chromosomal Ancestry of Modern Panamanians. AB - Geologically, Panama belongs to the Central American land-bridge between North and South America crossed by Homo sapiens >14 ka ago. Archaeologically, it belongs to a wider Isthmo-Colombian Area. Today, seven indigenous ethnic groups account for 12.3% of Panama's population. Five speak Chibchan languages and are characterized by low genetic diversity and a high level of differentiation. In addition, no evidence of differential structuring between maternally and paternally inherited genes has been reported in isthmian Chibchan cultural groups. Recent data have shown that 83% of the Panamanian general population harbour mitochondrial DNAs (mtDNAs) of Native American ancestry. Considering differential male/female mortality at European contact and multiple degrees of geographical and genetic isolation over the subsequent five centuries, the Y chromosome Native American component is expected to vary across different geographic regions and communities in Panama. To address this issue, we investigated Y-chromosome variation in 408 modern males from the nine provinces of Panama and one indigenous territory (the comarca of Kuna Yala). In contrast to mtDNA data, the Y-chromosome Native American component (haplogroup Q) exceeds 50% only in three populations facing the Caribbean Sea: the comarca of Kuna Yala and Bocas del Toro province where Chibchan languages are spoken by the majority, and the province of Colon where many Kuna and people of mixed indigenous-African-and European descent live. Elsewhere the Old World component is dominant and mostly represented by western Eurasian haplogroups, which signal the strong male genetic impact of invaders. Sub-Saharan African input accounts for 5.9% of male haplotypes. This reflects the consequences of the colonial Atlantic slave trade and more recent influxes of West Indians of African heritage. Overall, our findings reveal a local evolution of the male Native American ancestral gene pool, and a strong but geographically differentiated unidirectional sex bias in the formation of local modern Panamanian populations. PMID- 26636573 TI - Plasma Proteome Biomarkers of Inflammation in School Aged Children in Nepal. AB - Inflammation is a condition stemming from complex host defense and tissue repair mechanisms, often simply characterized by plasma levels of a single acute reactant. We attempted to identify candidate biomarkers of systemic inflammation within the plasma proteome. We applied quantitative proteomics using isobaric mass tags (iTRAQ) tandem mass spectrometry to quantify proteins in plasma of 500 Nepalese children 6-8 years of age. We evaluated those that co-vary with inflammation, indexed by alpha-1-acid glycoprotein (AGP), a conventional biomarker of inflammation in population studies. Among 982 proteins quantified in >10% of samples, 99 were strongly associated with AGP at a family-wise error rate of 0.1%. Magnitude and significance of association varied more among proteins positively (n = 41) than negatively associated (n = 58) with AGP. The former included known positive acute phase proteins including C-reactive protein, serum amyloid A, complement components, protease inhibitors, transport proteins with anti-oxidative activity, and numerous unexpected intracellular signaling molecules. Negatively associated proteins exhibited distinct differences in abundance between secretory hepatic proteins involved in transporting or binding lipids, micronutrients (vitamin A and calcium), growth factors and sex hormones, and proteins of largely extra-hepatic origin involved in the formation and metabolic regulation of extracellular matrix. With the same analytical approach and the significance threshold, seventy-two out of the 99 proteins were commonly associated with CRP, an established biomarker of inflammation, suggesting the validity of the identified proteins. Our findings have revealed a vast plasma proteome within a free-living population of children that comprise functional biomarkers of homeostatic and induced host defense, nutrient metabolism and tissue repair, representing a set of plasma proteins that may be used to assess dynamics and extent of inflammation for future clinical and public health application. PMID- 26636574 TI - Feasibility of Elective Nodal Irradiation (ENI) and Involved Field Irradiation (IFI) in Radiotherapy for the Elderly Patients (Aged >= 70 Years) with Esophageal Squamous Cell Cancer: A Retrospective Analysis from a Single Institute. AB - PURPOSE: We conducted a retrospective analysis to assess the feasibility of involved field irradiation (IFI) in elderly patients with esophageal squamous cell cancer (ESCC). MATERIALS AND METHODS: We performed a retrospective review of the records of elderly patients (>= 70 years) with unresectable ESCC and no distant metastases who received treatment with radiotherapy between January 2009 and March 2013. According to the irradiation volume, patients were allocated into either the elective nodal irradiation (ENI) group or the IFI group. Overall survival (OS), progression-free survival (PFS) and treatment-related toxicities were compared between the two groups. RESULTS: A total of 137 patients were enrolled. Fifty-four patients (39.4%) were allocated to the ENI group and 83 patients (60.6%) to the IFI group, the median doses in the two groups were 60 Gy and 59.4 Gy, respectively. For the entire group, the median survival time (MST) and PFS were 16 months and 12 months, respectively. The median PFS and 3-year PFS rate in the ENI group were 13 months and 20.6%, compared to 11 months and 21.0% in the IFI groups (p = 0.61). The MST and 3-year OS rate in the ENI and IFI groups were 17 months and 26.4% and 15.5 months and 21.7%, respectively (p = 0.25). The rate of grade >= 3 acute irradiation esophagitis in the ENI group was significantly higher than that in the IFI group (18.5% vs. 6.0%; p = 0.027). Other grade >= 3 treatment-related toxicities did not significantly differ between the two groups. CONCLUSIONS: IFI resulted in decreased irradiation toxicities without sacrificing OS in elderly patients with ESCC. PMID- 26636575 TI - Preanalytical Conditions and DNA Isolation Methods Affect Telomere Length Quantification in Whole Blood. AB - Telomeres are located at chromosome ends and their length (TL) has been associated with aging and human diseases such as cancer. Whole blood DNA is frequently used for TL measurements but the influence of preanalytical conditions and DNA isolation methods on TL quantification has not been thoroughly investigated. To evaluate potential preanalytical as well as methodological bias on TL, anonymized leftover EDTA-whole blood samples were pooled according to leukocyte counts and were incubated with and without actinomycin D to induce apoptosis as a prototype of sample degradation. DNA was isolated from fresh blood pools and after freezing at -80 degrees C. Commercially available kits using beads (Invitrogen), spin columns (Qiagen, Macherey-Nagel and 5prime) or precipitation (Stratec/Invisorb) and a published isopropanol precipitation protocol (IPP) were used for DNA isolation. TL was assessed by qPCR, and normalized to the single copy reference gene 36B4 using two established single plex and a new multiplex protocol. We show that the method of DNA isolation significantly affected TL (e.g. 1.86-fold longer TL when comparing IPP vs. Invitrogen). Sample degradation led to an average TL decrease of 22% when using all except for one DNA isolation method (5prime). Preanalytical storage conditions did not affect TL with exception of samples that were isolated with the 5prime kit, where a 27% increase in TL was observed after freezing. Finally, performance of the multiplex qPCR protocol was comparable to the single-plex assays, but showed superior time- and cost-effectiveness and required > 80% less DNA. Findings of the current study highlight the need for standardization of whole blood processing and DNA isolation in clinical study settings to avoid preanalytical bias of TL quantification and show that multiplex assays may improve TL/SCG measurements. PMID- 26636576 TI - Road Accident Prevention with Instant Emergency Warning Message Dissemination in Vehicular Ad-Hoc Network. AB - A Road Accident Prevention (RAP) scheme based on Vehicular Backbone Network (VBN) structure is proposed in this paper for Vehicular Ad-hoc Network (VANET). The RAP scheme attempts to prevent vehicles from highway road traffic accidents and thereby reduces death and injury rates. Once the possibility of an emergency situation (i.e. an accident) is predicted in advance, instantly RAP initiates a highway road traffic accident prevention scheme. The RAP scheme constitutes the following activities: (i) the Road Side Unit (RSU) constructs a Prediction Report (PR) based on the status of the vehicles and traffic in the highway roads, (ii) the RSU generates an Emergency Warning Message (EWM) based on an abnormal PR, (iii) the RSU forms a VBN structure and (iv) the RSU disseminates the EWM to the vehicles that holds the high Risk Factor (RF) and travels in High Risk Zone (HRZ). These vehicles might reside either within the RSU's coverage area or outside RSU's coverage area (reached using VBN structure). The RAP scheme improves the performance of EWM dissemination in terms of increase in notification and decrease in end-to-end delay. The RAP scheme also reduces infrastructure cost (number of RSUs) by formulating and deploying the VBN structure. The RAP scheme with VBN structure improves notification by 19 percent and end-to-end delay by 14.38 percent for a vehicle density of 160 vehicles. It is also proved from the simulation experiment that the performance of RAP scheme is promising in 4-lane highway roads. PMID- 26636577 TI - Hydroxychloroquine Protects against Cardiac Ischaemia/Reperfusion Injury In Vivo via Enhancement of ERK1/2 Phosphorylation. AB - An increasing number of investigations including human studies demonstrate that pharmacological ischaemic preconditioning is a viable way to protect the heart from myocardial ischaemia/reperfusion (I/R) injury. This study investigated the role of hydroxychloroquine (HCQ) in the heart during I/R injury. In vitro and in vivo models of myocardial I/R injury were used to assess the effects of HCQ. It was found that HCQ was protective in neonatal rat cardiomyocytes through inhibition of apoptosis, measured by TUNEL and cleaved caspase-3. This protection in vitro was mediated through enhancement of ERK1/2 phosphorylation mediated by HCQ in a dose-dependent fashion. A decrease in infarct size was observed in an in vivo model of myocardial I/R injury in HCQ treated animals and furthermore this protection was blocked in the presence of the ERK1/2 inhibitor U0126. For the first time, we have shown that HCQ promotes a preconditioning like protection in an in vivo simulated rat myocardial I/R injury model. Moreover, it was shown that HCQ is protective via enhanced phosphorylation of the pro-survival kinase ERK1/2. PMID- 26636579 TI - RNA Sequence Analysis of Human Huntington Disease Brain Reveals an Extensive Increase in Inflammatory and Developmental Gene Expression. AB - Huntington's Disease (HD) is a devastating neurodegenerative disorder that is caused by an expanded CAG trinucleotide repeat in the Huntingtin (HTT) gene. Transcriptional dysregulation in the human HD brain has been documented but is incompletely understood. Here we present a genome-wide analysis of mRNA expression in human prefrontal cortex from 20 HD and 49 neuropathologically normal controls using next generation high-throughput sequencing. Surprisingly, 19% (5,480) of the 28,087 confidently detected genes are differentially expressed (FDR<0.05) and are predominantly up-regulated. A novel hypothesis-free geneset enrichment method that dissects large gene lists into functionally and transcriptionally related groups discovers that the differentially expressed genes are enriched for immune response, neuroinflammation, and developmental genes. Markers for all major brain cell types are observed, suggesting that HD invokes a systemic response in the brain area studied. Unexpectedly, the most strongly differentially expressed genes are a homeotic gene set (represented by Hox and other homeobox genes), that are almost exclusively expressed in HD, a profile not widely implicated in HD pathogenesis. The significance of transcriptional changes of developmental processes in the HD brain is poorly understood and warrants further investigation. The role of inflammation and the significance of non-neuronal involvement in HD pathogenesis suggest anti inflammatory therapeutics may offer important opportunities in treating HD. PMID- 26636580 TI - Effect of Contrast on Visual Spatial Summation in Different Cell Categories in Cat Primary Visual Cortex. AB - Multiple cell classes have been found in the primary visual cortex, but the relationship between cell types and spatial summation has seldom been studied. Parvalbumin-expressing inhibitory interneurons can be distinguished from pyramidal neurons based on their briefer action potential durations. In this study, we classified V1 cells into fast-spiking units (FSUs) and regular-spiking units (RSUs) and then examined spatial summation at high and low contrast. Our results revealed that the excitatory classical receptive field and the suppressive non-classical receptive field expanded at low contrast for both FSUs and RSUs, but the expansion was more marked for the RSUs than for the FSUs. For most V1 neurons, surround suppression varied as the contrast changed from high to low. However, FSUs exhibited no significant difference in the strength of suppression between high and low contrast, although the overall suppression decreased significantly at low contrast for the RSUs. Our results suggest that the modulation of spatial summation by stimulus contrast differs across populations of neurons in the cat primary visual cortex. PMID- 26636581 TI - Identification and Expression Analysis of a Novel HbCIPK2-Interacting Ferredoxin from Halophyte H. brevisubulatum. AB - Ferredoxin is a small iron-sulfer protein involved in various one-eletron transfer pathways. Little is known about how ferredoxin is regulated to distribute electron under abiotic stress. Our previous study has showed that HbCIPK2 conferred salinity and drought tolerance. Thus, we hypothesized that HbCIPK2 could mediate the activities of interacting partners as a signal transducer. In this report, we identified a novel HbCIPK2-interacting ferredoxin (HbFd1) from halophyte Hordeum brevisubulatum by yeast two-hybrid screens, confirmed this interaction by BiFC in vivo and CoIP in vitro, and presented the expression pattern of HbFd1. HbFd1 was down-regulated under salinity and cold stress but up-regulated under PEG stress, its expression showed tissue-specific, mainly in shoot chloroplast, belonging to leaf-type subgroup. Moreover, HbCIPK2 could recruit HbFd1 to the nucleus for their interaction. The C-terminal segment in HbFd1 protein was involved in the interaction with HbCIPK2. These results provided insight into the connection between CBL-CIPK signaling network and Fd dependent metabolic pathways. PMID- 26636583 TI - Correction: Uncovering Spatiotemporal Characteristics of Human Online Behaviors during Extreme Events. PMID- 26636582 TI - Effects of Carbon Nanotube Environmental Dispersion on an Aquatic Invertebrate, Hirudo medicinalis. AB - The recent widespread applications of nanomaterials, because of their properties, opens new scenarios that affect their dispersal in the environment. In particular multiwall carbon nanotubes (MWCNTs), despite their qualities, seem to be harmful for animals and humans. To evaluate possible toxic effects caused by carbon nanotube environmental dispersion, with regard to aquatic compartment, we proposed as experimental model a freshwater invertebrate: Hirudo medicinalis. In the present study we analyse acute and chronic immune responses over a short (1, 3, 6 and 12 hours) and long time (from 1 to 5 weeks) exposure to MWCNTs by optical, electron and immunohistochemical approaches. In the exposed leeches angiogenesis and fibroplasia accompanied by massive cellular migration occur. Immunocytochemical characterization using specific markers shows that in these inflammatory processes the monocyte-macrophages (CD45+, CD68+) are the most involved cells. These immunocompetent cells are characterized by sequence of events starting from the expression of pro-inflammatory cytokines (in particular IL-18), and amyloidogenensis. Our combined experimental approaches, basing on high sensitive inflammatory response can highlight adverse effects of nanomaterials on aquatic organisms and could be useful to assess the MWCNTs impact on aquatic, terrestrial animal and human health. PMID- 26636578 TI - Late Antiretroviral Therapy (ART) Initiation Is Associated with Long-Term Persistence of Systemic Inflammation and Metabolic Abnormalities. AB - OBJECTIVES: HIV-induced immunodeficiency is associated with metabolic abnormalities and systemic inflammation. We investigated the effect of antiretroviral therapy (ART) on restoration of insulin sensitivity, markers of immune activation and inflammation. METHODS: Immunological, metabolic and inflammatory status was assessed at antiretroviral therapy initiation and three years later in 208 patients from the ANRS-COPANA cohort. Patients were compared according to their pre-ART CD4+ cell count (group 1: <= 200/mm3, n = 66 vs. group 2: > 200/mm3, n = 142). RESULTS: Median CD4+ cell count increased in both groups after 3 years of successful ART but remained significantly lower in group 1 than in group 2 (404 vs 572 cells/mm3). Triglyceride and insulin levels were higher or tended to be higher in group 1 than in group 2 at ART initiation (median: 1.32 vs 0.97 mmol/l, p = 0.04 and 7.6 vs 6.8 IU, p = 0.09, respectively) and remained higher after three years of ART (1.42 vs 1.16 mmol/L, p = 0.0009 and 8.9 vs 7.2 IU, p = 0.01). After adjustment for individual characteristics and antiretroviral therapy regimens (protease inhibitor (PI), zidovudine), insulin levels remained significantly higher in patients with low baseline CD4+ cell count. Baseline IL 6, sCD14 and sTNFR2 levels were higher in group 1 than in group 2. Most biomarkers of immune activation/inflammation declined during ART, but IL-6 and hsCRP levels remained higher in patients with low baseline CD4+ cell count than in the other patients (median are respectively 1.4 vs 1.1 pg/ml, p = 0.03 and 2.1 vs 1.3 mg/ml, p = 0.07). CONCLUSION: After three years of successful ART, low pretreatment CD4+ T cell count remained associated with elevated insulin, triglyceride, IL-6 and hsCRP levels. These persistent metabolic and inflammatory abnormalities could contribute to an increased risk of cardiovascular and metabolic disease. PMID- 26636608 TI - On-Chip Pressure Generation for Driving Liquid Phase Separations in Nanochannels. AB - In this Article, we describe the generation of pressure gradients on-chip for driving liquid phase separations in submicrometer deep channels. The reported pressure-generation capability was realized by applying an electrical voltage across the interface of two glass channel segments with different depths. A mismatch in the electroosmotic flow rate at this junction led to the generation of pressure-driven flow in our device, a fraction of which was then directed to an analysis channel to carry out the desired separation. Experiments showed the reported strategy to be particularly conducive for miniaturization of pressure driven separations yielding flow velocities in the separation channel that were nearly unaffected upon scaling down the depth of the entire fluidic network. Moreover, the small dead volume in our system allowed for high dynamic control over this pressure gradient, which otherwise was challenging to accomplish during the sample injection process using external pumps. Pressure-driven velocities up to 3.1 mm/s were realized in separation ducts as shallow as 300 nm using our current design for a maximum applied voltage of 3 kV. The functionality of this integrated device was demonstrated by implementing a pressure-driven ion chromatographic analysis that relied on analyte interaction with the nanochannel surface charges to yield a nonuniform solute concentration across the channel depth. Upon coupling such analyte distribution to the parabolic pressure-driven flow profile in the separation duct, a mixture of amino acids could be resolved. The reported assay yielded a higher separation resolution compared to its electrically driven counterpart in which sample migration was realized using electroosmosis/electrophoresis. PMID- 26636609 TI - Dithio- and Diselenophosphinate Thorium(IV) and Uranium(IV) Complexes: Molecular and Electronic Structures, Spectroscopy, and Transmetalation Reactivity. AB - We report a comparison of the molecular and electronic structures of dithio- and diselenophosphinate, (E2PR2)(1-) (E = S, Se; R = (i)Pr, (t)Bu), with thorium(IV) and uranium(IV) complexes. For the thorium dithiophosphinate complexes, reaction of ThCl4(DME)2 with 4 equiv of KS2PR2 (R = (i)Pr, (t)Bu) produced the homoleptic complexes, Th(S2P(i)Pr2)4 (1S-Th-(i)Pr) and Th(S2P(t)Bu2)4 (2S-Th-(t)Bu). The diselenophosphinate complexes were synthesized in a similar manner using KSe2PR2 to produce Th(Se2P(i)Pr2)4 (1Se-Th-(i)Pr) and Th(Se2P(t)Bu2)4 (2Se-Th-(t)Bu). U(S2P(i)Pr2)4, 1S-U-(i)Pr, could be made directly from UCl4 and 4 equiv of KS2P(i)Pr2. With (Se2P(i)Pr2)(1-), using UCl4 and 3 or 4 equiv of KSe2P(i)Pr2 yielded the monochloride product U(Se2P(i)Pr2)3Cl (3Se-U(iPr)-Cl), but using UI4(1,4-dioxane)2 produced the homoleptic U(Se2P(i)Pr2)4 (1Se-U-(i)Pr). Similarly, the reaction of UCl4 with 4 equiv of KS2P(t)Bu2 yielded U(S2P(t)Bu2)4 (2S-U-(t)Bu), whereas the reaction with KSe2P(t)Bu2 resulted in the formation of U(Se2P(t)Bu2)3Cl (4Se-U(tBu)-Cl). Using UI4(1,4-dioxane)2 and 4 equiv of KSe2P(t)Bu2 with UCl4 in acetonitrile yielded U(Se2P(t)Bu2)4 (2Se-U-(t)Bu). Transmetalation reactions were investigated with complex 2Se-U-(t)Bu and various CuX (X = Br, I) salts to yield U(Se2P(t)Bu2)3X (6Se-U(tBu)-Br and 7Se-U(tBu)-I) and 0.25 equiv of [Cu(Se2P(t)Bu2)]4 (8Se-Cu-(t)Bu). Additionally, 2Se-U-(t)Bu underwent transmetalation reactions with Hg2F2 and ZnCl2 to yield U(Se2P(t)Bu2)3F (6) and U(Se2P(t)Bu2)3Cl (4Se-U(tBu)-Cl), respectively. The molecular structures were analyzed using (1)H, (13)C, (31)P, and (77)Se NMR and IR spectroscopy and structurally characterized using X-ray crystallography. Using the QTAIM approach, the electronic structure of all homoleptic complexes was probed, showing slightly more covalent bonding character in actinide-selenium bonds over actinide-sulfur bonds. PMID- 26636610 TI - Enantioselective Cyano-Alkoxycarbonylation of alpha-Oxoesters Promoted by Bronsted Acid-Lewis Base Cooperative Catalysts. AB - The highly enantioselective cyano-alkoxycarbonylation of alpha-oxoesters with alkyl cyanoformates is promoted by a new chiral Bronsted acid-Lewis base cooperative organocatalyst. The present catalysis can be performed at room temperature under nitrogen or air. PMID- 26636611 TI - Synthesis and Properties of Benzothieno[b]-Fused BODIPY Dyes. AB - Two benzothieno[b]-fused BODIPYs, BT-BODIPY and BBT-BODIPY, in which one parent BODIPY core is fused with one and two benzothieno rings, respectively, were synthesized from BODIPYs substituted with 2-(methylsulfinyl)phenyl at the beta position. The first H2SO4-induced cyclization and deborylation afforded benzothieno[b]-fused dipyrrin derivatives, which can easily complex with BF3.OEt2 to form the desired benzothieno[b]-fused BODIPYs. It was revealed that the fusion of the benzothieno ring is more effective at extending conjugation than simple attachment of the 2-(methylthio)phenyl substituent, which presumably results from conformational restriction. Compared with the corresponding unstrained SPh-BODIPY and BSPh-BODIPY, which contain one and two 2-(methylthio)phenyl groups at the beta-position, BT-BODIPY and BBT-BODIPY display red shifted absorption, increased absorptivity, and fluorescence efficiency. Furthermore, the ring fusion is also helpful to increase stability of the formed cation in BBT-BODIPY. Thus, BBT BODIPY exhibits very intriguing properties, such as intense absorption and emission in the red region, very sharp emission spectra, and reversible oxidation and reduction potentials. PMID- 26636612 TI - Stereoselective Synthesis of Z-alpha,beta-Unsaturated Sulfones Using Peterson Reagents. AB - New Peterson reagents were prepared by introducing alkyloxy groups on the silicon atom in order to fix the conformation of the sulfone anion. The reagents 1d and 1e reacted with a variety of aldehydes after the treatment with Li-base to give Z alpha,beta-unsaturated sulfones with up to >99:1 selectivity in good to excellent yields. For the reaction with aliphatic aldehydes, CPME (cyclopentyl methyl ether) is the choice of solvent, while DME (1,2-dimethoxyethane) gave higher selectivity for the reaction with aromatic aldehydes. PMID- 26636613 TI - Virginia Orange: A Versatile, Red-Shifted Fluorescein Scaffold for Single- and Dual-Input Fluorogenic Probes. AB - Fluorogenic molecules are important tools for biological and biochemical research. The majority of fluorogenic compounds have a simple input-output relationship, where a single chemical input yields a fluorescent output. Development of new systems where multiple inputs converge to yield an optical signal could refine and extend fluorogenic compounds by allowing greater spatiotemporal control over the fluorescent signal. Here, we introduce a new red shifted fluorescein derivative, Virginia Orange, as an exceptional scaffold for single- and dual-input fluorogenic molecules. Unlike fluorescein, installation of a single masking group on Virginia Orange is sufficient to fully suppress fluorescence, allowing preparation of fluorogenic enzyme substrates with rapid, single-hit kinetics. Virginia Orange can also be masked with two independent moieties; both of these masking groups must be removed to induce fluorescence. This allows facile construction of multi-input fluorogenic probes for sophisticated sensing regimes and genetic targeting of latent fluorophores to specific cellular populations. PMID- 26636614 TI - Structural Insights and the Surprisingly Low Mechanical Stability of the Au-S Bond in the Gold-Specific Protein GolB. AB - The coordination bond between gold and sulfur (Au-S) has been widely studied and utilized in many fields. However, detailed investigations on the basic nature of this bond are still lacking. A gold-specific binding protein, GolB, was recently identified, providing a unique opportunity for the study of the Au-S bond at the molecular level. We probed the mechanical strength of the gold-sulfur bond in GolB using single-molecule force spectroscopy. We measured the rupture force of the Au-S bond to be 165 pN, much lower than Au-S bonds measured on different gold surfaces (~1000 pN). We further solved the structures of apo-GolB and Au(I)-GolB complex using X-ray crystallography. These structures showed that the average Au S bond length in GolB is much longer than the reported average value of Au-S bonds. Our results highlight the dramatic influence of the unique biological environment on the stability and strength of metal coordination bonds in proteins. PMID- 26636615 TI - Computation of Second Harmonic Generation for Crystalline Urea and KDP. An ab Initio Approach through the Coupled Perturbed Hartree-Fock/Kohn-Sham Scheme. AB - The electronic second harmonic generation (SHG) tensor, d, of crystalline urea and potassium dihydrogen phosphate (KDP) is evaluated as a function of frequency using a Gaussian type basis set and the Coupled Perturbed Hartree-Fock (CPHF) and Kohn-Sham (CPKS) schemes as implemented in the CRYSTAL code. The results of various functionals, including LDA, GGA (PBE), and global and range-separated hybrids (B3LYP, PBE0, LC-BLYP), as well as Hartree-Fock, are compared. It is found that the calculated SHG intensity always decreases as the percentage of exact exchange increases. The hybrid functionals turn out to provide results that agree well with experiment. For urea and KDP the percentage of exact exchange determined by the inverse dielectric constant is too large. At 1064 nm the vibrational contribution for urea is found to be less than 5% of the total value. To the authors' knowledge, this is the first coupled (self-consistent) calculation of SHG for any periodic system. PMID- 26636616 TI - Composition and Structure of the Inorganic Core of Relaxed Intermediate X(Y122F) of Escherichia coli Ribonucleotide Reductase. AB - Activation of the diferrous center of the beta2 (R2) subunit of the class 1a Escherichia coli ribonucleotide reductases by reaction with O2 followed by one electron reduction yields a spin-coupled, paramagnetic Fe(III)/Fe(IV) intermediate, denoted X, whose identity has been sought by multiple investigators for over a quarter of a century. To determine the composition and structure of X, the present study has applied (57)Fe, (14,15)N, (17)O, and (1)H electron nuclear double resonance (ENDOR) measurements combined with quantitative measurements of (17)O and (1)H electron paramagnetic resonance line-broadening studies to wild type X, which is very short-lived, and to X prepared with the Y122F mutant, which has a lifetime of many seconds. Previous studies have established that over several seconds the as-formed X(Y122F) relaxes to an equilibrium structure. The present study focuses on the relaxed structure. It establishes that the inorganic core of relaxed X has the composition [(OH(-))Fe(III)-O-Fe(IV)]: there is no second inorganic oxygenic bridge, neither oxo nor hydroxo. Geometric analysis of the (14)N ENDOR data, together with recent extended X-ray absorption fine structure measurements of the Fe-Fe distance (Dassama, L. M.; et al. J. Am. Chem. Soc. 2013, 135, 16758), supports the view that X contains a "diamond-core" Fe(III)/Fe(IV) center, with the irons bridged by two ligands. One bridging ligand is the oxo bridge (OBr) derived from O2 gas. Given the absence of a second inorganic oxygenic bridge, the second bridging ligand must be protein derived, and is most plausibly assigned as a carboxyl oxygen from E238. PMID- 26636617 TI - Experimental and Computational Evidence for the Reduction Mechanisms of Aromatic N-oxides by Aqueous Fe(II)-Tiron Complex. AB - A combined experimental-theoretical approach was taken to elucidate the reduction mechanisms of five representative aromatic N-oxides (ANOs) by Fe(II)-tiron complex and to identify the rate-limiting step. Based on the possible types of complexes formed with the reductant, three groups of ANOs were studied: type I refers to those forming 5-membered ring complexes through the N and O atoms on the side chain; type II refers to those forming 6-membered ring complexes through the N-oxide O atom and the O atom on the side chain; and type III refers to complexation through the N-oxide O atom only. Density functional theory calculations suggested that the elementary reactions, including protonation, N-O bond cleavage, and the second electron transfer processes, are barrierless, indicating that the first electron transfer is rate-limiting. Consistent with the theoretical results, the experimental solvent isotope effect, KIEH, for the reduction of quinoline N-oxide (a type III ANO) was obtained to be 1.072 +/- 0.025, suggesting protonation was not involved in the rate-limiting step. The measured nitrogen kinetic isotope effect, KIEN, for the reduction of pyridine N oxide (a type III ANO) (1.022 +/- 0.006) is in good agreement with the calculated KIEN for its first electron transfer (1.011-1.028), confirming that the first electron transfer is rate-limiting. Electrochemical cell experiments demonstrated that the electron transfer process can be facilitated significantly by type I complexation with FeL2(6-) (1:2 Fe(II)-tiron complex), to some extent by type II complexation with free Fe(II), but not by weak type III complexation. PMID- 26636619 TI - Synthesis of Tridecaptin-Antibiotic Conjugates with in Vivo Activity against Gram Negative Bacteria. AB - A series of tridecaptin-antibiotic conjugates were synthesized and evaluated for in vitro and in vivo activity against Gram-negative bacteria. Covalently linking unacylated tridecaptin A1 (H-TriA1) to rifampicin, vancomycin, and erythromycin enhanced their activity in vitro but not by the same magnitude as coadministration of the peptide and these antibiotics. The antimicrobial activities of the conjugates were retained in vivo, with the H-TriA1-erythromycin conjugate proving a more effective treatment of Klebseilla pneumoniae infections in mice than erythromycin alone or in combination with H-TriA1. PMID- 26636618 TI - Tunable Keratin Hydrogels for Controlled Erosion and Growth Factor Delivery. AB - Tunable erosion of polymeric materials is an important aspect of tissue engineering for reasons that include cell infiltration, controlled release of therapeutic agents, and ultimately to tissue healing. In general, the biological response to proteinaceous polymeric hydrogels is favorable (e.g., minimal inflammatory response). However, unlike synthetic polymers, achieving tunable erosion with natural materials is a challenge. Keratins are a class of intermediate filament proteins that can be obtained from several sources, including human hair, and have gained increasing levels of use in tissue engineering applications. An important characteristic of keratin proteins is the presence of a large number of cysteine residues. Two classes of keratins with different chemical properties can be obtained by varying the extraction techniques: (1) keratose by oxidative extraction and (2) kerateine by reductive extraction. Cysteine residues of keratose are "capped" by sulfonic acid and are unable to form covalent cross-links upon hydration, whereas cysteine residues of kerateine remain as sulfhydryl groups and spontaneously form covalent disulfide cross-links. Here, we describe a straightforward approach to fabricate keratin hydrogels with tunable rates of erosion by mixing keratose and kerateine. SEM imaging and mechanical testing of freeze-dried materials showed similar pore diameters and compressive moduli, respectively, for each keratose-kerateine mixture formulation (~1200 kPa for freeze-dried materials and ~1.5 kPa for hydrogels). However, the elastic modulus (G') determined by rheology varied in proportion with the keratose-kerateine ratios, as did the rate of hydrogel erosion and the release rate of thiol from the hydrogels. The variation in keratose-kerateine ratios also led to tunable control over release rates of recombinant human insulin-like growth factor 1. PMID- 26636620 TI - Spatial Decomposition of Translational Water-Water Correlation Entropy in Binding Pockets. AB - A number of computational tools available today compute the thermodynamic properties of water at surfaces and in binding pockets by using inhomogeneous solvation theory (IST) to analyze explicit-solvent simulations. Such methods enable qualitative spatial mappings of both energy and entropy around a solute of interest and can also be applied quantitatively. However, the entropy estimates of existing methods have, to date, been almost entirely limited to the first order terms in the IST's entropy expansion. These first-order terms account for localization and orientation of water molecules in the field of the solute but not for the modification of water-water correlations by the solute. Here, we present an extension of the Grid Inhomogeneous Solvation Theory (GIST) approach which accounts for water-water translational correlations. The method involves rewriting the two-point density of water in terms of a conditional density and utilizes the efficient nearest-neighbor entropy estimation approach. Spatial maps of this second order term, for water in and around the synthetic host cucurbit[7]uril and in the binding pocket of the enzyme Factor Xa, reveal mainly negative contributions, indicating solute-induced water-water correlations relative to bulk water; particularly strong signals are obtained for sites at the entrances of cavities or pockets. This second-order term thus enters with the same, negative, sign as the first order translational and orientational terms. Numerical and convergence properties of the methodology are examined. PMID- 26636621 TI - Complex preimplantation genetic diagnosis for beta-thalassaemia, sideroblastic anaemia, and human leukocyte antigen (HLA)-typing. AB - Preimplantation genetic diagnosis (PGD) to select histocompatible siblings to facilitate curative haematopoeitic stem-cell transplantation (HSCT) is now an acceptable option in the absence of an available human leukocyte antigen (HLA) compatible donor. We describe a case where the couple who requested HLA-PGD, were both carriers of two serious haematological diseases, beta-thalassaemia and sideroblastic anaemia. Their daughter, affected with sideroblastic anaemia, was programmed to have HSCT. A multiplex-fluorescent-touchdown-PCR protocol was optimized for the simultaneous amplification of: the two HBB-gene mutated regions (c.118C> T, c.25-26delAA), four short tandem repeats (STRs) in chr11p15.5 linked to the HBB gene, the SLC25A38 gene mutation (c.726C > T), two STRs in chr3p22.1 linked to the SLC25A38 gene, plus eleven informative STRs for HLA-haplotyping (chr6p22.1-21.3). This was followed by real-time nested PCR and high-resolution melting analysis (HRMA) for the detection of HBB and SLC25A38 gene mutations, as well as the analysis of all STRs on an automatic genetic analyzer (sequencer). The couple completed four clinical in vitro fertilization (IVF)/PGD cycles. At least one matched unaffected embryo was identified and transferred in each cycle. A twin pregnancy was established in the fourth PGD cycle and genotyping results at all loci were confirmed by prenatal diagnosis. Two healthy baby girls were delivered at week 38 of pregnancy. The need to exclude two familial disorders for HLA-PGD is rarely encountered. The methodological approach described here is fast, accurate, clinically-validated, and of relatively low cost. PMID- 26636622 TI - [Diagnosis and treatment of polycythemia vera in the year 2015]. PMID- 26636623 TI - Reconstruction of large upper eyelid defects with a free tarsal plate graft and a myocutaneous pedicle flap plus a free skin graft. AB - PURPOSE: To review and present the results of a one-step method employing a free tarsal plate graft and a myocutaneous pedicle flap plus a free skin graft for reconstruction of large upper eyelid defects after tumour surgery. METHODS: This was a retrospective case-series of 8 patients who underwent reconstruction of the upper eyelid after tumour removal. The horizontal defect involved 50-75% of the lid (3 pts.), more than 75% (3 pts.), and more than 75% plus the lateral canthus (2 pts.). The posterior lamella was reconstructed with contralateral upper eyelid tarsal plate. The anterior lamella was reconstructed with a laterally based myocutaneous pedicle flap in 7 patients, leaving a raw surface under the brow which was covered with a free skin graft. In 1 patient with little skin left under the brow, the anterior lamella was reconstructed with a bi-pedicle orbicularis muscle flap together with a free skin graft. RESULTS: All patients healed without necrosis, did not suffer from lagophthalmos, achieved reasonable cosmesis, and did not need lubricants. In one patient, a contact lens was necessary for three weeks because of corneal erosion. One patient still needs a contact lens 3 months after excision to avoid eye discomfort. CONCLUSION: Large upper eyelid defects can be reconstructed with a free tarsal plate graft and a laterally based myocutaneous pedicle flap in combination with a free skin graft. Two-step procedures can probably be avoided in most cases. PMID- 26636624 TI - Determinants of Wake Pco2 and Increases in Wake Pco2 over Time in Patients with Obstructive Sleep Apnea. AB - RATIONALE: The progression from obesity and obstructive sleep apnea to obesity with hypoventilation and daytime hypercapnia may relate to features of sleep disordered breathing events that affect loading and unloading of carbon dioxide. OBJECTIVES: To determine whether the wake Pco2 increases over time in untreated obstructive sleep apnea, and whether that increase is explained by changes in sleep-disordered breathing event duration, interevent duration, or postevent ventilation amplitude. METHODS: We selected 14 adults who had two polysomnographic studies more than 1 year apart because of untreated or suboptimally treated moderate to severe obstructive sleep apnea. Demographic and polysomnographic data were reviewed for both sets of studies, including the evening wake end-tidal CO2, the ratio of mean event to mean interevent duration (subsuming apneas and hypopneas), and the ratio of mean post- to preevent breath amplitude. MEASUREMENT AND MAIN RESULTS: The mean (SD) wake end-tidal Pco2 increased between studies from 35.9 (4.2) to 39.5 (3.9) mm Hg (P < 0.005). The wake end-tidal CO2 correlated inversely with the post- to pre-event breath amplitude and positively with the ratio of mean event to mean interevent duration and with body mass index. However, those three variables were not significantly changed between the two studies. The wake end-tidal CO2 did not correlate with the apnea-hypopnea index or age. There was a significant increase in bicarbonate level between studies (median, 24.0-26.5 mmol/L; P = 0.01). CONCLUSIONS: In our study cohort, wake end-tidal CO2 correlated with body mass index and features of sleep apnea that influence the balance of loading and unloading of CO2. However, those features remained fixed over time, even as the wake Pco2 and bicarbonate levels increased with untreated sleep apnea. PMID- 26636625 TI - Function of MYB domain transcription factors in abiotic stress and epigenetic control of stress response in plant genome. AB - Plants have developed highly efficient and remarkable mechanisms to survive under frequent and extreme environmental stress conditions. Exposure of plants to various stress factors is associated with coordinated changes in gene expression at the transcriptional level and hence transcription factors, such as those belonging to the MYB family play a central role in triggering the right responses. MYB transcription factors have been extensively studied in regard of their involvement in the regulation of a number of such stress responses in plants. Genetic and molecular biological studies, primarily in Arabidopsis, have also begun to unravel the role of MYB transcription factors in the epigenetic regulation of stress responses in plants. This review focuses on the role of MYB transcription factors in the regulation of various stress responses in general, highlighting on recent advances in our understanding of the involvement of this class of transcription factors in epigenetic regulation of stress response in plant genome. PMID- 26636626 TI - H3 Thr3 phosphorylation is crucial for meiotic resumption and anaphase onset in oocyte meiosis. AB - Haspin-catalyzed histone H3 threonine 3 (Thr3) phosphorylation facilitates chromosomal passenger complex (CPC) docking at centromeres, regulating indirectly chromosome behavior during somatic mitosis. It is not fully known about the expression and function of H3 with phosphorylated Thr3 (H3T3-P) during meiosis in oocytes. In this study, we investigated the expression and sub-cellular distribution of H3T3-P, as well as its function in mouse oocytes during meiotic division. Western blot analysis revealed that H3T3-P expression was only detected after germinal vesicle breakdown (GVBD), and gradually increased to peak level at metaphase I (MI), but sharply decreased at metaphase II (MII). Immunofluorescence showed H3T3-P was only brightly labeled on chromosomes after GVBD, with relatively high concentration across the whole chromosome axis from pro-metaphase I (pro-MI) to MI. Specially, H3T3-P distribution was exclusively limited to the local space between sister centromeres at MII stage. Haspin inhibitor, 5 iodotubercidin (5-ITu), dose- and time-dependently blocked H3T3-P expression in mouse oocytes. H3T3-P inhibition delayed the resumption of meiosis (GVBD) and chromatin condensation. Moreover, the loss of H3T3-P speeded up the meiotic transition to MII of pro-MI oocytes in spite of the presence of non-aligned chromosomes, even reversed MI-arrest induced with Nocodazole. The inhibition of H3T3-P expression distinguishably damaged MAD1 recruitment on centromeres, which indicates the spindle assembly checkpoint was impaired in function, logically explaining the premature onset of anaphase I. Therefore, Haspin-catalyzed histone H3 phosphorylation is essential for chromatin condensation and the following timely transition from meiosis I to meiosis II in mouse oocytes during meiotic division. PMID- 26636630 TI - [Vulvovaginal candidiasis]. AB - Vulvovaginal candidiasis is the second most common vaginal infection after bacterial vaginosis. It is caused by yeasts, the vast majority of which belong to the genus Candida. Vulvovaginal candidiasis affects as many as 75 % of women during their childbearing years and 40 % of them experience recurrences. The most common etiological agent is Candida albicans, which is responsible for nearly 90 % of cases. Vulvovaginal candidiasis can be treated with topical and/or systemic antifungals while risk factors for the infection must be eliminated. PMID- 26636631 TI - [Potential use of mass spectrometry for subtyping of Campylobacter]. AB - OBJECTIVES: Molecular epidemiology is a field that uses results of typing techniques to obtain information on detailed characterization of bacterial strains for determining the identity, similarity or difference in bacteria of the same genus, species or serotype. Nowadays, the most commonly used methods are based on monitoring differences in bacterial genotypes. However, most of these techniques are time-consuming and costly. A method increasingly used in routine microbiological testing is matrix-assisted laser desorption/ionization time-of flight mass spectrometry (MALDI-TOF MS), which is based on analysis of the bacterial proteome. It is mainly used for rapid and accurate classification of bacteria into genera and species. The aims were to assess the potential use of this method for typing of Campylobacter below the species level and to apply these results in epidemiological investigations. MATERIAL AND METHODS: The study comprised 39 strains of Campylobacter jejuni isolated from food (16) and humans (23). Macrorestriction fragment profiling by pulsed-field gel electrophoresis (PFGE) and simultaneous protein profile analysis using MALDI-TOF MS were performed for all tested strains. RESULTS: Similar pulse profiles were found among isolates originating from the same outbreak or repeatedly collected from a single patient. The same pulse profiles were also detected in strains of unknown relationship but sharing the same place of origin and year of isolation. The comparison of dendrograms from both analyses showed that strains identified as identical by PFGE appeared in the same subgroups in dendrograms obtained by MALDI TOF MS, the only exception being isolates repeatedly collected from a single patient. CONCLUSION: The results suggest that confirmation of the identity or similarity of strains in accordance with the established epidemiological facts has not been clearly demonstrated using MALDI-TOF MS. PMID- 26636635 TI - Role of Magnetic Resonance Imaging in the Imaging of Central Nervous System Emergencies. PMID- 26636627 TI - Integration of molecular pathology, epidemiology and social science for global precision medicine. AB - The precision medicine concept and the unique disease principle imply that each patient has unique pathogenic processes resulting from heterogeneous cellular genetic and epigenetic alterations and interactions between cells (including immune cells) and exposures, including dietary, environmental, microbial and lifestyle factors. As a core method field in population health science and medicine, epidemiology is a growing scientific discipline that can analyze disease risk factors and develop statistical methodologies to maximize utilization of big data on populations and disease pathology. The evolving transdisciplinary field of molecular pathological epidemiology (MPE) can advance biomedical and health research by linking exposures to molecular pathologic signatures, enhancing causal inference and identifying potential biomarkers for clinical impact. The MPE approach can be applied to any diseases, although it has been most commonly used in neoplastic diseases (including breast, lung and colorectal cancers) because of availability of various molecular diagnostic tests. However, use of state-of-the-art genomic, epigenomic and other omic technologies and expensive drugs in modern healthcare systems increases racial, ethnic and socioeconomic disparities. To address this, we propose to integrate molecular pathology, epidemiology and social science. Social epidemiology integrates the latter two fields. The integrative social MPE model can embrace sociology, economics and precision medicine, address global health disparities and inequalities, and elucidate biological effects of social environments, behaviors and networks. We foresee advancements of molecular medicine, including molecular diagnostics, biomedical imaging and targeted therapeutics, which should benefit individuals in a global population, by means of an interdisciplinary approach of integrative MPE and social health science. PMID- 26636629 TI - Inhibitory leukocyte immunoglobulin-like receptors: Immune checkpoint proteins and tumor sustaining factors. AB - Inhibitory leukocyte immunoglobulin-like receptors (LILRBs 1-5) transduce signals via intracellular immunoreceptor tyrosine-based inhibitory motifs (ITIMs) that recruit protein tyrosine phosphatase non-receptor type 6 (PTPN6 or SHP-1), protein tyrosine phosphatase non-receptor type 11 (PTPN11 or SHP-2), or Src homology 2 domain-containing inositol phosphatase (SHIP), leading to negative regulation of immune cell activation. Certain of these receptors also play regulatory roles in neuronal activity and osteoclast development. The activation of LILRBs on immune cells by their ligands may contribute to immune evasion by tumors. Recent studies found that several members of LILRB family are expressed by tumor cells, notably hematopoietic cancer cells, and may directly regulate cancer development and relapse as well as the activity of cancer stem cells. LILRBs thus have dual concordant roles in tumor biology - as immune checkpoint molecules and as tumor-sustaining factors. Importantly, the study of knockout mice indicated that LILRBs do not affect hematopoiesis and normal development. Therefore LILRBs may represent ideal targets for tumor treatment. This review aims to summarize current knowledge on expression patterns, ligands, signaling, and functions of LILRB family members in the context of cancer development. PMID- 26636636 TI - Magnetic Resonance Imaging of Pediatric Neurologic Emergencies. AB - Although computed tomography is often the first line of imaging in the emergency setting, magnetic resonance imaging (MRI) is of increasing importance in the evaluation of central nervous system emergencies in the pediatric population. As such, it is necessary to understand the indications for which MRI may be necessary. This article reviews the unique pathophysiologic entities affecting the pediatric population and the associated MRI findings. Specifically, utility of emergent MRI and characteristic appearances of traumatic brain injury, traumatic spinal injury, nonaccidental trauma, arterial ischemic stroke, cerebral sinovenous thrombosis, stroke mimics, and central nervous system infections are described. PMID- 26636637 TI - MRI in the Evaluation of Acute Visual Syndromes. AB - Acute visual symptom emergencies occur commonly and present a challenge to both clinical and radiologic facets. Although most patients with visual complaints routinely require clinical evaluation with direct ophthalmologic evaluation, imaging is rarely necessary. However, there are highly morbid conditions where the prompt recognition and management of an acute visual syndrome (AVS) requires an astute physician to probe further. Suspicious symptomatology including abrupt visual loss, diplopia, ophthalmoplegia, and proptosis/exophthalmos require further investigation with advanced imaging modalities such as magnetic resonance imaging and magnetic resonance angiography. This review will discuss a variety of AVSs including orbital apex syndrome, cavernous sinus thrombosis, cavernous carotid fistula, acute hypertensive encephalopathy (posterior reversible encephalopathy syndrome), optic neuritis, pituitary apoplexy including hemorrhage into an existing adenoma, and idiopathic intracranial hypertension. A discussion of each entity will focus on the clinical presentation, management and prognosis when necessary and finally, neuroimaging with emphasis on magnetic resonance imaging. The primary purpose of this review is to provide an organized approach to the differential diagnosis and typical imaging patterns for AVSs. We have provided a template for radiologists and specialists to assist in early intervention in order to decrease morbidity and provide value-based patient care through imaging. PMID- 26636638 TI - Magnetic Resonance Imaging of Spinal Emergencies. AB - Like the brain, the spinal cord is subject to trauma, infection, ischemia, hemorrhage, and compression. Early diagnosis is the key to preventing significant morbidity in the form of permanent disability. MR imaging is the gold standard for assessing acute injury to the spinal cord, intervertebral discs, ligaments, and surrounding soft tissues. In this article we systematically review the MRI findings in spinal cord trauma, ligamentous injury, epidural hematoma, epidural abscess, and metastatic disease. PMID- 26636639 TI - Magnetic Resonance Imaging in Ischemic Stroke and Cerebral Venous Thrombosis. AB - Imaging is indispensable in the evaluation of patients presenting with central nervous system emergencies. Although computed tomography (CT) is the mainstay of initial assessment and triage, magnetic resonance imaging (MRI) has become vital in expanding diagnostic capabilities, refining management strategies, and developing our understanding of disease processes. Ischemic stroke and cerebral venous thrombosis are 2 areas wherein MRI is actively revolutionizing patient care. Familiarity with the imaging manifestations of these 2 disease processes is crucial for any radiologist reading brain MR studies. In this review, the fundamentals of image interpretation will be addressed in-depth. Furthermore, advanced imaging techniques which are redefining the role of emergency MRI will be outlined, with a focus on the pathophysiological mechanisms that underlie image interpretation. In particular, emerging data surrounding the use of MR perfusion imaging in acute stroke management portend dramatic shifts in neurointerventional management. To this end, a review of the recent stroke literature will hopefully enhance the radiologist's role in both meaningful reporting and multidisciplinary teamwork. PMID- 26636640 TI - Current Clinical Applications and Future Potential of Diffusion Tensor Imaging in Traumatic Brain Injury. AB - In the setting of acute central nervous system (CNS) emergencies, computed tomography (CT) and conventional magnetic resonance imaging (MRI) play an important role in the identification of life-threatening intracranial injury. However, the full extent or even presence of brain damage frequently escapes detection by conventional CT and MRI. Advanced MRI techniques such as diffusion tensor imaging (DTI) are emerging as important adjuncts in the diagnosis of microstructural white matter injury in the acute and postacute brain-injured patient. Although DTI aids in detection of brain injury pathology, which has been repeatedly associated with typical adverse clinical outcomes, the evolution of acute changes and their long-term prognostic implications are less clear and the subject of much active research. A major aim of current research is to identify imaging-based biomarkers that can identify the subset of TBI patients who are at risk for adverse outcome and can therefore most benefit from ongoing care and rehabilitation as well as future therapeutic interventions.The aim of this study is to introduce the current methods used to obtain DTI in the clinical setting, describe a set of common interpretation strategies with their associated advantages and pitfalls, as well as illustrate the clinical utility of DTI through a set of specific patient scenarios. We conclude with a discussion of future potential for the management of TBI. PMID- 26636644 TI - Oral direct thrombin inhibitors or oral factor Xa inhibitors for the treatment of pulmonary embolism. AB - BACKGROUND: Pulmonary embolism is a potentially life-threatening condition in which a clot can travel from the deep veins, most commonly in the leg, up to the lungs. Previously, a pulmonary embolism was treated with the anticoagulants heparin and vitamin K antagonists. Recently, however, two forms of direct oral anticoagulants (DOACs) have been developed: oral direct thrombin inhibitors (DTI) and oral factor Xa inhibitors. The new drugs have characteristics that may be favourable over conventional treatment, including oral administration, a predictable effect, lack of frequent monitoring or re-dosing and few known drug interactions. To date, no Cochrane review has measured the effectiveness and safety of these drugs in the long-term treatment (minimum duration of three months) of pulmonary embolism. OBJECTIVES: To assess the effectiveness of oral DTIs and oral factor Xa inhibitors for the long-term treatment of pulmonary embolism. SEARCH METHODS: The Cochrane Vascular Trials Search Co-ordinator searched the Specialised Register (last searched January 2015) and the Cochrane Register of Studies (last searched January 2015). Clinical trials databases were also searched for details of ongoing or unpublished studies. We searched the reference lists of relevant articles retrieved by electronic searches for additional citations. SELECTION CRITERIA: We included randomised controlled trials in which patients with a pulmonary embolism confirmed by standard imaging techniques were allocated to receive an oral DTI or an oral factor Xa inhibitor for the long-term (minimum duration three months) treatment of pulmonary embolism. DATA COLLECTION AND ANALYSIS: Two review authors (LR, JM) independently extracted the data and assessed the risk of bias in the trials. Any disagreements were resolved by discussion with the third author (PK). We used meta-analyses when we considered heterogeneity low. The two primary outcomes were recurrent venous thromboembolism and pulmonary embolism. Other outcomes included all-cause mortality and major bleeding. We calculated all outcomes using an odds ratio (OR) with a 95% confidence interval (CI). MAIN RESULTS: We included five randomised controlled trials with a total of 7897 participants. Two studies tested oral DTIs (dabigatran) and three studies tested oral factor Xa inhibitors (one rivaroxaban, one edoxaban and one apixaban).Analysis showed no difference in the effectiveness of oral DTIs and standard anticoagulation in preventing recurrent pulmonary embolism (OR 1.02, 95% CI 0.50 to 2.04; two studies; 1602 participants; high quality evidence), recurrent venous thromboembolism (OR 0.93, 95% CI 0.52 to 1.66; two studies; 1602 participants; high quality evidence), deep vein thrombosis (DVT) (OR 0.79, 95% CI 0.29 to 2.13; two studies; 1602 participants; high quality evidence) and major bleeding (OR 0.50, 95% CI 0.15 to 1.68; two studies; 1527 participants; high quality evidence).For oral factor Xa inhibitors, when we combined the three included studies together in meta-analyses, there was significant heterogeneity for recurrent pulmonary embolism (OR 1.08, 95% CI 0.46 to 2.56; two studies; 4509 participants; I(2) = 58%; moderate quality evidence). The oral factor Xa inhibitors were no more or less effective in the prevention of recurrent venous thromboembolism (OR 0.85, 95% CI 0.63 to 1.15; three studies; 6295 participants; high quality evidence), DVT (OR 0.72, 95% CI 0.39 to 1.32; two studies; 4509 participants; high quality evidence), all-cause mortality (OR 1.16, 95% CI 0.79 to 1.70; one study; 4817 participants; moderate quality evidence) or major bleeding (OR 0.97, 95% CI 0.59 to 1.62; two studies; 4507 participants; high quality evidence). None of the studies measured quality of life. AUTHORS' CONCLUSIONS: Moderate to high quality evidence suggests that there are no differences between DOACs and standard anticoagulation for the long-term treatment of pulmonary embolism, for the outcomes recurrent pulmonary embolism, recurrent venous thromboembolism, DVT, all-cause mortality and major bleeding. PMID- 26636645 TI - Protein phosphatase 1 suppresses androgen receptor ubiquitylation and degradation. AB - The phosphoprotein phosphatases are emerging as important androgen receptor (AR) regulators in prostate cancer (PCa). We reported previously that the protein phosphatase 1 catalytic subunit (PP1alpha) can enhance AR activity by dephosphorylating a site in the AR hinge region (Ser650) and thereby decrease AR nuclear export. In this study we show that PP1alpha increases the expression of wildtype as well as an S650A mutant AR, indicating that it is acting through one or more additional mechanisms. We next show that PP1alpha binds primarily to the AR ligand binding domain and decreases its ubiquitylation and degradation. Moreover, we find that the PP1alpha inhibitor tautomycin increases phosphorylation of AR ubiquitin ligases including SKP2 and MDM2 at sites that enhance their activity, providing a mechanism by which PP1alpha may suppress AR degradation. Significantly, the tautomycin mediated decrease in AR expression was most pronounced at low androgen levels or in the presence of the AR antagonist enzalutamide. Consistent with this finding, the sensitivity of LNCaP and C4-2 PCa cells to tautomycin, as assessed by PSA synthesis and proliferation, was enhanced at low androgen levels or by treatment with enzalutamide. Together these results indicate that PP1alpha may contribute to stabilizing AR protein after androgen deprivation therapies, and that targeting PP1alpha or the AR-PP1alpha interaction may be effective in castration-resistant prostate cancer (CRPC). PMID- 26636647 TI - Active transcription without histone modifications. PMID- 26636646 TI - Development of a ten-signature classifier using a support vector machine integrated approach to subdivide the M1 stage into M1a and M1b stages of nasopharyngeal carcinoma with synchronous metastases to better predict patients' survival. AB - The aim of this study was to develop a prognostic classifier and subdivided the M1 stage for nasopharyngeal carcinoma patients with synchronous metastases (mNPC). A retrospective cohort of 347 mNPC patients was recruited between January 2000 and December 2010. Thirty hematological markers and 11 clinical characteristics were collected, and the association of these factors with overall survival (OS) was evaluated. Advanced machine learning schemes of a support vector machine (SVM) were used to select a subset of highly informative factors and to construct a prognostic model (mNPC-SVM). The mNPC-SVM classifier identified ten informative variables, including three clinical indexes and seven hematological markers. The median survival time for low-risk patients (M1a) as identified by the mNPC-SVM classifier was 38.0 months, and survival time was dramatically reduced to 13.8 months for high-risk patients (M1b) (P < 0.001). Multivariate adjustment using prognostic factors revealed that the mNPC-SVM classifier remained a powerful predictor of OS (M1a vs. M1b, hazard ratio, 3.45; 95% CI, 2.59 to 4.60, P < 0.001). Moreover, combination treatment of systemic chemotherapy and loco-regional radiotherapy was associated with significantly better survival outcomes than chemotherapy alone (the 5-year OS, 47.0% vs. 10.0%, P < 0.001) in the M1a subgroup but not in the M1b subgroup (12.0% vs. 3.0%, P = 0.101). These findings were validated by a separate cohort. In conclusion, the newly developed mNPC-SVM classifier led to more precise risk definitions that offer a promising subdivision of the M1 stage and individualized selection for future therapeutic regimens in mNPC patients. PMID- 26636648 TI - ACSL4 promotes prostate cancer growth, invasion and hormonal resistance. AB - Increases in fatty acid metabolism have been demonstrated to promote the growth and survival of a variety of cancers, including prostate cancer (PCa). Here, we examine the expression and function of the fatty acid activating enzyme, long chain fatty acyl-CoA synthetase 4 (ACSL4), in PCa. Ectopic expression of ACSL4 in ACSL4-negative PCa cells increases proliferation, migration and invasion, while ablation of ACSL4 in PCa cells expressing endogenous ACSL4 reduces cell proliferation, migration and invasion. The cell proliferative effects were observed both in vitro, as well as in vivo. Immunohistochemical analysis of human PCa tissue samples indicated ACSL4 expression is increased in malignant cells compared with adjacent benign epithelial cells, and particularly increased in castration-resistant PCa (CRPC) when compared with hormone naive PCa. In cell lines co-expressing both ACSL4 and AR, proliferation was independent of exogenous androgens, suggesting that ACSL4 expression may lead to CRPC. In support for this hypothesis, ectopic ACSL4 expression induced resistance to treatment with Casodex, via decrease in apoptosis. Our studies further indicate that ACSL4 upregulates distinct pathway proteins including p-AKT, LSD1 and beta-catenin. These results suggest ACSL4 could serve as a biomarker and potential therapeutic target for CRPC. PMID- 26636649 TI - Combination of exercise training and erythropoietin prevents cancer-induced muscle alterations. AB - Cancer cachexia is a syndrome characterized by loss of skeletal muscle mass, inflammation, anorexia and anemia, contributing to patient fatigue and reduced quality of life. In addition to nutritional approaches, exercise training (EX) has been proposed as a suitable tool to manage cachexia. In the present work the effect of mild exercise training, coupled to erythropoietin (EPO) administration to prevent anemia, has been tested in tumor-bearing mice. In the C26 hosts, acute exercise does not prevent and even worsens muscle wasting. Such pattern is prevented by EPO co-administration or by the adoption of a chronic exercise protocol. EX and EPO co-treatment spares oxidative myofibers from atrophy and counteracts the oxidative to glycolytic shift, inducing PGC-1alpha. LLC hosts are responsive to exercise and their treatment with the EX-EPO combination prevents the loss of muscle strength and the onset of mitochondrial ultrastructural alterations, while increases muscle oxidative capacity and intracellular ATP content, likely depending on PGC-1alpha induction and mitophagy promotion. Consistently, muscle-specific PGC-1alpha overexpression prevents LLC-induced muscle atrophy and Atrogin-1 hyperexpression. Overall, the present data suggest that low intensisty exercise can be an effective tool to be included in combined therapeutic approaches against cancer cachexia, provided that anemia is coincidently treated in order to enhance the beneficial action of exercise. PMID- 26636652 TI - Ablation of Perlecan Domain 1 Heparan Sulfate Reduces Progressive Cartilage Degradation, Synovitis, and Osteophyte Size in a Preclinical Model of Posttraumatic Osteoarthritis. AB - OBJECTIVE: To investigate the role of the heparan sulfate (HS) proteoglycan perlecan (HSPG-2) in regulating fibroblast growth factor (FGF) activity, bone and joint growth, and the onset and progression of posttraumatic osteoarthritis (OA) in a mouse gene-knockout model. METHODS: Maturational changes were evaluated histologically in the knees of 3-, 6-, and 12-week-old wild-type (WT) mice and Hspg2(Delta3-/Delta3-) mice (Hspg2 lacking domain 1 HS, generated by ablation of exon 3 of perlecan). Cartilage damage, subchondral bone sclerosis, osteophytosis, and synovial inflammation were scored at 4 and 8 weeks after surgical induction of OA in WT and Hspg2(Delta3-/Delta3-) mice. Changes in cartilage expression of FGF-2, FGF-18, HSPG-2, FGF receptor 1 (FGFR-1), and FGFR-3 were examined immunohistochemically. Femoral head cartilage from both mouse genotypes was cultured in the presence or absence of interleukin-1alpha (IL-1alpha), FGF-2, and FGF-18, and the content and release of glycosaminoglycan (GAG) and expression of messenger RNA (mRNA) for key matrix molecules, enzymes, and inhibitors were quantified. RESULTS: No effect of perlecan HS ablation on growth plate or joint development was detected. After induction of OA, Hspg2(Delta3-/Delta3-) mice had significantly reduced cartilage erosion, osteophytosis, and synovitis. OA-induced loss of chondrocyte expression of FGF-2, FGF-18, and HSPG-2 occurred in both genotypes. Expression of FGFR-1 after OA induction was maintained in WT mice, while FGFR-3 loss after OA induction was significantly reduced in Hspg2(Delta3 /Delta3-) mice. There were no genotypic differences in GAG content or release between unstimulated control cartilage and IL-1alpha-stimulated cartilage. However, IL-1alpha-induced cartilage expression of Mmp3 mRNA was significantly reduced in Hspg2(Delta3-/Delta3-) mice. Cartilage GAG release in either the presence or absence of IL-1alpha was unaltered by FGF-2 in both genotypes. In cartilage cultures with FGF-18, IL-1alpha-stimulated GAG loss was significantly reduced only in Hspg2(Delta3-/Delta3-) mice, and this was associated with maintained expression of Fgfr3 mRNA and reduced expression of Mmp2/Mmp3 mRNA. CONCLUSION: Perlecan HS has significant roles in directing the development of posttraumatic OA, potentially via the alteration of FGF/HS/FGFR signaling. These data suggest that the chondroprotection conferred by perlecan HS ablation could be attributed, at least in part, to the preservation of FGFR-3 and increased FGF signaling. PMID- 26636651 TI - Metastasis-associated MCL1 and P16 copy number alterations dictate resistance to vemurafenib in a BRAFV600E patient-derived papillary thyroid carcinoma preclinical model. AB - BRAF(V600E) mutation exerts an essential oncogenic function in many tumors, including papillary thyroid carcinoma (PTC). Although BRAF(V600E) inhibitors are available, lack of response has been frequently observed. To study the mechanism underlying intrinsic resistance to the mutant BRAF(V600E) selective inhibitor vemurafenib, we established short-term primary cell cultures of human metastatic/recurrent BRAF(V600E)-PTC, intrathyroidal BRAF(V600E)-PTC, and normal thyroid (NT). We also generated an early intervention model of human BRAF(V600E) PTC orthotopic mouse. We find that metastatic BRAF(V600E)-PTC cells elicit paracrine-signaling which trigger migration of pericytes, blood endothelial cells and lymphatic endothelial cells as compared to BRAF(WT)-PTC cells, and show a higher rate of invasion. We further show that vemurafenib therapy significantly suppresses these aberrant functions in non-metastatic BRAF(V600E)-PTC cells but lesser in metastatic BRAF(V600E)-PTC cells as compared to vehicle treatment. These results concur with similar folds of down-regulation of tumor microenvironment-associated pro-metastatic molecules, with no effects in BRAF(WT) PTC and NT cells. Our early intervention preclinical trial shows that vemurafenib delays tumor growth in the orthotopic BRAF(WT/V600E)-PTC mice. Importantly, we identify high copy number gain of MCL1 (chromosome 1q) and loss of CDKN2A (P16, chromosome 9p) in metastatic BRAF(V600E)-PTC cells which are associated with resistance to vemurafenib treatment. Critically, we demonstrate that combined vemurafenib therapy with BCL2/MCL1 inhibitor increases metastatic BRAF(V600E)-PTC cell death and ameliorates response to vemurafenib treatment as compared to single agent treatment. In conclusion, short-term PTC and NT cultures offer a predictive model for evaluating therapeutic response in patients with PTC. Our PTC pre-clinical model suggests that combined targeted therapy might be an important therapeutic strategy for metastatic and refractory BRAF(V600E)-positive PTC. PMID- 26636653 TI - Time to recovery from haemodialysis : location, intensity and beyond. AB - INTRODUCTION: Prolonged recovery time (RT) affects patient's quality-of-life adversely. Shorter dialysis RT in home haemodialysis (HHD) noted in observational studies has been attributed to intensive dialysis regimens. Home patients adopt different haemodialysis (HD) schedules. There is insufficient literature on RT in HHD patients receiving different HD schedules. METHODS: Data was prospectively collected for BASIC-HHD study, a multicentre study of home and hospital HD across five tertiary centres in the UK. Two hundred and eighty-eight patients answered the question, 'how long does it take for you to recover from a haemodialysis session?' Ninety-one patients (31.8%) of study population performed HHD. Participants completed neuropsychometric tests and depression and anxiety screening inventories. RESULTS: Recovery time is longest amongst 'in-centre' HD recipients (Mean 193 min; SD 295.37) and significantly higher than the mean RT of home HD recipients (Mean 67.3 min; SD 86.8). Within the home setting, RT was not significantly different between the intensive HD and conventional HD (67.8 vs 66.5 min; P > 0.05) groups but higher residual urine volumes in the standard home group had significantly shorter RT. Location of HD, not intensity, remained significant (P = 0.001) in the unadjusted and adjusted multivariable analysis. Longer RT was associated with female gender, unemployed or retired 'work' status, 'non-white' ethnicity, lower predialysis systolic blood pressure and greater depression screening score. CONCLUSIONS: Home-based HD and higher residual urine volumes are significantly associated with shorter RT. This home advantage for RT may be sustained by preserving residual renal function (in early stages) and increasing HD intensity (in later stages) of dialysis therapy. PMID- 26636654 TI - Protracted bacterial bronchitis: The last decade and the road ahead. AB - Cough is the single most common reason for primary care physician visits and, when chronic, a frequent indication for specialist referrals. In children, a chronic cough (>4 weeks) is associated with increased morbidity and reduced quality of life. One common cause of childhood chronic cough is protracted bacterial bronchitis (PBB), especially in children aged <6 years. PBB is characterized by a chronic wet or productive cough without signs of an alternative cause and responds to 2 weeks of appropriate antibiotics, such as amoxicillin-clavulanate. Most children with PBB are unable to expectorate sputum. If bronchoscopy and bronchoalveolar lavage are performed, evidence of bronchitis and purulent endobronchial secretions are seen. Bronchoalveolar lavage specimens typically reveal marked neutrophil infiltration and culture large numbers of respiratory bacterial pathogens, especially Haemophilus influenzae. Although regarded as having a good prognosis, recurrences are common and if these are frequent or do not respond to antibiotic treatments of up to 4-weeks duration, the child should be investigated for other causes of chronic wet cough, such as bronchiectasis. The contribution of airway malacia and pathobiologic mechanisms of PBB remain uncertain and, other than reduced alveolar phagocytosis, evidence of systemic, or local immune deficiency is lacking. Instead, pulmonary defenses show activated innate immunity and increased gene expression of the interleukin 1beta signalling pathway. Whether these changes in local inflammatory responses are cause or effect remains to be determined. It is likely that PBB and bronchiectasis are at the opposite ends of the same disease spectrum, so children with chronic wet cough require close monitoring. PMID- 26636650 TI - A novel approach to the discovery of anti-tumor pharmaceuticals: searching for activators of liponecrosis. AB - A recently conducted chemical genetic screen for pharmaceuticals that can extend longevity of the yeast Saccharomyces cerevisiae has identified lithocholic acid as a potent anti-aging molecule. It was found that this hydrophobic bile acid is also a selective anti-tumor chemical compound; it kills different types of cultured cancer cells if used at concentrations that do not compromise the viability of non-cancerous cells. These studies have revealed that yeast can be successfully used as a model organism for high-throughput screens aimed at the discovery of selectively acting anti-tumor small molecules. Two metabolic traits of rapidly proliferating fermenting yeast, namely aerobic glycolysis and lipogenesis, are known to be similar to those of cancer cells. The mechanisms underlying these key metabolic features of cancer cells and fermenting yeast have been established; such mechanisms are discussed in this review. We also suggest how a yeast-based chemical genetic screen can be used for the high-throughput development of selective anti-tumor pharmaceuticals that kill only cancer cells. This screen consists of searching for chemical compounds capable of increasing the abundance of membrane lipids enriched in unsaturated fatty acids that would therefore be toxic only to rapidly proliferating cells, such as cancer cells and fermenting yeast. PMID- 26636655 TI - Multiple granular cell tumors and primitive neuroectodermal tumors (PNETs)--is there a syndromic relationship? PMID- 26636656 TI - Oceanic fronts: transition zones for bacterioplankton community composition. AB - Oceanic fronts are widespread mesoscale features that exist in the boundary between different water masses. Despite the recognized importance of bacterioplankton (including bacteria and archaea) on the marine biogeochemical cycles and the ubiquitousness of fronts, the effect of frontal zones on the distribution of bacterioplankton community remains unknown. Using 16S rRNA gene sequencing coupled with a high spatial resolution analysis of the physical properties of the water masses, we demonstrate strong shifts in bacterioplankton community composition (BCC) across the subtropical frontal zone off New Zealand. The transition between water masses resulted in a clear modification of the dominant taxa and a significant increase in community dissimilarity. Our results, linking physical oceanography and marine molecular ecology, support the strong role of oceanic frontal zones in delimiting the distribution of bacterioplankton in the ocean. PMID- 26636657 TI - Eosinopenia in Children following Traumatic Intracranial Hemorrhage Is Associated with Poor Prognosis and Prolonged Hospital Admission. AB - BACKGROUND: Neutrophilia is associated with brain injury and is frequently accompanied by eosinopenia. Although eosinopenia is a poor prognostic indicator for various diseases, its significance in intracranial events has not been investigated. METHODS: We retrospectively included 22 pediatric patients (<=18 years old) who experienced traumatic intracranial hemorrhage between 2002 and 2015. Patients were divided into two groups based on the presence or absence of eosinopenia on admission, i.e. the proportion of eosinophils to total white blood cells <1.0%. RESULTS: The mean Glasgow Coma Scale score was marginally lower in the eosinopenia group (14.1 vs. 12.0, p = 0.06). The mean Glasgow Outcome Scale Extended (GOSE) score was significantly lower in the eosinopenia group (7.5 vs. 5.7, p = 0.02), and the mean length of hospital stay tended to be longer in patients with eosinopenia (7.8 vs. 28.4, p = 0.10). In our multivariate logistic regression analysis, eosinopenia was the only significant risk factor for poor outcome (GOSE score 1-7, OR 29.7, p = 0.03) and prolonged hospital stay (>2 weeks, OR 7.1, p = 0.047). CONCLUSION: These results demonstrate the significance of eosinopenia as a novel prognostic factor in traumatic intracranial hemorrhage in children. PMID- 26636658 TI - Efficacy and Safety of Carboplatin and Etoposide Combination Chemotherapy for Extrapulmonary Neuroendocrine Carcinoma: A Retrospective Case Series. AB - BACKGROUND: Neuroendocrine carcinoma (NEC) is a rare tumor type, and a standard therapy for NEC has not yet been established. From 2008 to 2013, carboplatin etoposide combination therapy has been used to treat almost all NEC patients in our department, and the objective of the present study was to investigate the therapeutic effects of carboplatin-etoposide combination therapy in NEC. METHODS: This retrospective study was conducted based on medical records from 2008 to 2013. Eligible patients had been pathologically diagnosed with NEC and had received a carboplatin-etoposide combination as first-line chemotherapy. RESULTS: Nineteen patients were included in the study, and the overall response rate was 47.4%. The median overall survival was 12.7 months, and the median progression free survival was 7.0 months. The median survival times were 10.8 and 8.9 months in NEC patients with primary sites in the gastrointestinal tract and hepatobiliary-pancreatic system, respectively. Median progression-free survival times were 5.0 and 3.1 months, respectively. The major toxicities were grade 3 and 4 leukopenia (73.7%), neutropenia (78.9%), anemia (31.6%), and thrombocytopenia (26.3%). CONCLUSIONS: Carboplatin-etoposide combination therapy for NEC may have comparable effectiveness and milder adverse events than cisplatin-etoposide combination therapy. PMID- 26636659 TI - Separation of Enantiomers by Inclusion Gas Chromatography: On the Influence of Water in the Molecular Complexation of Methyl 2-Chloropropanoate Enantiomers and the Modified gamma-Cyclodextrin Lipodex-E. AB - A profound influence of water has previously been detected in the complexation of the enantiomers of methyl 2-chloropropanoate (MCP) and the chiral selector octakis(3-O-butanoyl-2,6-di-O-pentyl)-gamma-cyclodextrin (Lipodex-E) in NMR and sensor experiments. We therefore investigated the retention behavior of MCP enantiomers on Lipodex-E by gas chromatography (GC) under hydrous conditions. Addition of water to the N2 carrier gas modestly reduced the retention factors k of the enantiomers, notably for the second eluted enantiomer (S)-MCP. This resulted in an overall decrease of enantioselectivity -DeltaS,R (DeltaG) in the presence of water. The effect was fully reversible. Consequently, for a conditioned column in the absence of residual water, the determined thermodynamic data, i.e. DeltaS,R (DeltaH) = -12.64 +/- 0.08 kJ mol(-1) and DeltaS,R (DeltaS) = -28.18 +/- 0.23 J K(-1) mol(-1), refer to a true 1:1 complexation process devoid of hydrophobic hydration. PMID- 26636660 TI - Wheat bran promotes enrichment within the human colonic microbiota of butyrate producing bacteria that release ferulic acid. AB - Cereal fibres such as wheat bran are considered to offer human health benefits via their impact on the intestinal microbiota. We show here by 16S rRNA gene based community analysis that providing amylase-pretreated wheat bran as the sole added energy source to human intestinal microbial communities in anaerobic fermentors leads to the selective and progressive enrichment of a small number of bacterial species. In particular, OTUs corresponding to uncultured Lachnospiraceae (Firmicutes) related to Eubacterium xylanophilum and Butyrivibrio spp. were strongly enriched (by five to 160 fold) over 48 h in four independent experiments performed with different faecal inocula, while nine other Firmicutes OTUs showed > 5-fold enrichment in at least one experiment. Ferulic acid was released from the wheat bran during degradation but was rapidly converted to phenylpropionic acid derivatives via hydrogenation, demethylation and dehydroxylation to give metabolites that are detected in human faecal samples. Pure culture work using bacterial isolates related to the enriched OTUs, including several butyrate-producers, demonstrated that the strains caused substrate weight loss and released ferulic acid, but with limited further conversion. We conclude that breakdown of wheat bran involves specialist primary degraders while the conversion of released ferulic acid is likely to involve a multi-species pathway. PMID- 26636661 TI - The Hologenome Concept: Helpful or Hollow? AB - With the increasing appreciation for the crucial roles that microbial symbionts play in the development and fitness of plant and animal hosts, there has been a recent push to interpret evolution through the lens of the "hologenome"--the collective genomic content of a host and its microbiome. But how symbionts evolve and, particularly, whether they undergo natural selection to benefit hosts are complex issues that are associated with several misconceptions about evolutionary processes in host-associated microbial communities. Microorganisms can have intimate, ancient, and/or mutualistic associations with hosts without having undergone natural selection to benefit hosts. Likewise, observing host-specific microbial community composition or greater community similarity among more closely related hosts does not imply that symbionts have coevolved with hosts, let alone that they have evolved for the benefit of the host. Although selection at the level of the symbiotic community, or hologenome, occurs in some cases, it should not be accepted as the null hypothesis for explaining features of host symbiont associations. PMID- 26636662 TI - Multivariate Assessment of the Effect of Pump Design and Pump Gap Design Parameters on Blood Trauma. AB - Pump gaps are the most critical regions in a rotary blood pump when it comes to blood trauma in the form of hemolysis, protein destruction, and platelet activation. This study investigated six pump design parameters affecting the flow in a radial pump gap. A multivariate approach was employed to determine individual and quantitative parameter effects on blood trauma as well as parameter interactions. To consider the effect of shear stress and blood cell residence time, a validated numerical Lagrangian particle tracking approach was used. Based on the results, small-diameter pumps can be as blood compatible, if not more blood compatible, as large-diameter pumps as long as identical circumferential velocities and clearance gaps are maintained. Furthermore, the results indicate that an eccentric rotor position in the casing is not harmful and that a pressure difference generating washout flow and thereby reducing the cell residence time is of significant importance. PMID- 26636663 TI - Metacognitive Reflection and Insight Therapy (MERIT) With a Patient With Severe Symptoms of Disorganization. AB - One recent development within the realm of psychotherapeutic interventions for schizophrenia has been a shift in focus from symptom management to consideration of metacognition, or the processes by which people synthesize information about themselves and others in an integrated manner. One such approach, metacognitive reflection and insight therapy (MERIT); in particular, offers a description of 8 therapeutic activities that should occur in each session, resulting in the stimulation and growth of metacognitive capacity. In this report, we present a description of 12 sessions with a patient suffering from schizophrenia manifesting significantly disorganized symptoms. Each MERIT element is described along with observed clinical and metacognitive gains. As illustrated in this report, these procedures helped the patient move from a state of having no complex ideas about himself or others, to one in which he could begin to develop integrated and realistic ideas about himself and others and use that capacity to think about life challenges. PMID- 26636665 TI - Enantioselective Formal [4+2] Cycloadditions to 3-Nitroindoles by Trienamine Catalysis: Synthesis of Chiral Dihydrocarbazoles. AB - The first enantioselective formal [4+2] cycloadditions of 3-nitroindoles are presented. By using 3-nitroindoles in combination with an organocatalyst, chiral dihydrocarbazole scaffolds are formed in moderate to good yields (up to 87%) and enantioselectivities (up to 97% ee). The reaction was extended to include enantioselective [4+2] cycloadditions of 3-nitrobenzothiophene. The reaction proceeds through a [4+2] cycloaddition/elimination cascade under mild reaction conditions. Furthermore, a diastereoselective reduction of an enantioenriched cycloadduct is presented. The mechanism of the reaction is discussed based on experimental and computational studies. PMID- 26636666 TI - Light-Induced Reversible Self-Assembly of Gold Nanoparticles Surface-Immobilized with Coumarin Ligands. AB - A novel light-induced reversible self-assembly (LIRSA) system is based on the reversible photodimerization and photocleavage of coumarin groups on the surface of gold nanoparticles (AuNPs) in THF solution. Facilitated by coumarin groups, light irradiation at 365 nm triggers the stable assembly of monodisperse AuNPs; the resulting self-assembly system can be disassembled back to the disassembled state by a relatively short exposure to benign UV light. The reversible self assembly cycle can be repeated 4 times. A specific concentration range of coumarin ligand and the THF solvent were identified to be the two predominant factors that contribute to the LIRSA of AuNPs. This is the first successful application of reversible photodimerization based on a coumarin derivative in the field of AuNP LIRSA. This LIRSA system may provide unique opportunities for the photoregulated synthesis of many adjustable nanostructures and devices. PMID- 26636664 TI - Lupus Nephritis IgG Induction of Calcium/Calmodulin-Dependent Protein Kinase IV Expression in Podocytes and Alteration of Their Function. AB - OBJECTIVE: Kidney podocytes and their slit diaphragms prevent urinary protein loss. T cells from patients with systemic lupus erythematosus display increased expression of calcium/calmodulin-dependent protein kinase IV (CaMKIV). The present study was undertaken to investigate the role of CaMKIV in podocyte function in lupus nephritis (LN). METHODS: We treated kidney podocytes with IgG derived from healthy individuals or patients with LN and then analyzed gene expression using a DNA microarray. The localization of IgG in podocytes was analyzed by immunofluorescence staining, with or without silencing of neonatal Fc receptor (FcRn). In addition, we silenced CAMK4 in podocytes and analyzed the expression of selected genes. We also examined the expression of CD86 in kidney podocytes from MRL/lpr, MRL/lpr.camkiv(-/-), and MRL/MPJ mice by in situ hybridization. RESULTS: We found that exposure of podocytes to IgG resulted in entry of IgG into the cytoplasm. IgG entered podocytes via the FcRn because less IgG was found in the cytoplasm of podocytes treated with FcRn small interfering RNA. DNA microarray studies of podocytes exposed to LN-derived IgG revealed up regulation of genes related to the activation of immune cells or podocyte damage. Interestingly, CD86 expression decreased after silencing CAMK4 in podocytes. Also, in situ hybridization experiments showed that the expression of CD86 was reduced in podocytes from MRL/lpr.camkiv(-/-) mice. CONCLUSION: LN-derived IgG enters podocytes and up-regulates CAMK4, which is followed by increased expression of genes known to be linked to podocyte damage and T cell activation. Targeted inhibition of CAMK4 in podocytes may prove to be clinically useful in patients with LN. PMID- 26636667 TI - Dynamic Coupling at the Angstrom Scale. AB - While momentum transfer from active particles to their immediate surroundings has been studied for both synthetic and biological micron-scale systems, a similar phenomenon was presumed unlikely to exist at smaller length scales due to the dominance of viscosity in the ultralow Reynolds number regime. Using diffusion NMR spectroscopy, we studied the motion of two passive tracers--tetramethylsilane and benzene--dissolved in an organic solution of active Grubbs catalyst. Significant enhancements in diffusion were observed for both the tracers and the catalyst as a function of reaction rate. A similar behavior was also observed for the enzyme urease in aqueous solution. Surprisingly, momentum transfer at the molecular scale closely resembles that reported for microscale systems and appears to be independent of swimming mechanism. Our work provides new insight into the role of active particles on advection and mixing at the Angstrom scale. PMID- 26636668 TI - Pyridine intercalated Bi2Se3 heterostructures: controlling the topologically protected states. AB - We use ab initio simulations to investigate the incorporation of pyridine molecules (C5H5N) in the van der Waals (vdW) gaps of Bi2Se3. The intercalated pyridine molecules increase the separation distance between the Bi2Se3 quintuple layers (QLs), suppressing the parity inversion of the electronic states at the Gamma-point. We find that (i) the intercalated region becomes a trivial insulator. By combining the pristine Bi2Se3 region with the one intercalated by the molecules (py-Bi2Se3), we have a trivial/topological heterojunction (py Bi2Se3/Bi2Se3) characterized by the presence of topologically protected metallic states at the interfacial region. Next, (ii) we apply an external compressive pressure to the system, and the results are a decrease of the separation distance between the QLs intercalated by pyridine molecules, and the metallic states are shifted toward the bulk region, turning the system back to the insulator. Our findings indicate that, through the intercalation of pyridine molecules in Bi2Se3 [(i)], we may have a number of topologically protected metallic channels embedded in (py-Bi2Se3) m /(Bi2Se3) n heterostructures/superlattices, in addition, through suitable tuning of the external pressure [(ii)], we can control its topological properties, turning on and off the topologically protected metallic states in (py Bi2Se3)m /(Bi2Se3)n. PMID- 26636669 TI - Impact of Cardiovascular Risk Factors on Carotid Intima-Media Thickness and Degree of Severity: A Cross-Sectional Study. AB - OBJECTIVE: Age, hypertension, dyslipidemia and diabetes are common cardiovascular risk factors (CVRFs) that contribute to the development of atherosclerosis in cardiovascular system including carotid artery disease. However, the impact of these risk factors on the increased carotid intima-media thickness (cIMT) and degree of carotid severity remains to be further clarified. This study aims to evaluate the relationship between CVRFs and degree of carotid severity and cIMT in high-risk subjects. METHODS: Four thousand and three hundred ninety-four subjects with one or more risk factors were retrospectively reviewed in this study. Patients were divided into different groups based on age, the type and quantity of CVRFs. cIMT and degree of carotid artery stenosis were measured and analyzed based on carotid ultrasound imaging with findings compared to the CVRFs to determine the correlation between these variables. RESULTS: Aging was significantly associated with degree of severity (P < 0.05) and cIMT was significantly increased with age (P < 0.05). Individual CVRF analysis shows that hypertension was more related to the degree of severity than dyslipidemia and diabetes with corresponding abnormal cIMT rates being 79.39%, 72.98% and 32.37%, respectively. The prevalence of carotid atherosclerosis were 20.06%, 22.88% and 28.63%, respectively corresponding to patients with zero, one and more than one chronic diseases. The percentage of abnormal cIMT in hypertensive patient group with dyslipidemia is significantly higher than the other groups (P< 0.05). CONCLUSIONS: This study shows a direct correlation between the degree of carotid severity and cIMT and cardiovascular risk factors, especially with age and hypertension. Carotid atherosclerosis is closely related to the number of cardiovascular risk factors. PMID- 26636670 TI - Correction: Fine Mapping of the Interaction between C4b-Binding Protein and Outer Membrane Proteins LigA and LigB of Pathogenic Leptospira interrogans. PMID- 26636671 TI - Correction: Long Term Natural History Data in Ambulant Boys with Duchenne Muscular Dystrophy: 36-Month Changes. PMID- 26636672 TI - Preparation and Characterization of a Novel Decellularized Fibrocartilage "Book" Scaffold for Use in Tissue Engineering. AB - At the tendon-to-bone insertion, there is a unique transitional structure: tendon, non-calcified fibrocartilage, calcified fibrocartilage, and bone. The reconstruction of this special graded structure after defects or damage is an important but challenging task in orthopedics. In particular, reconstruction of the fibrocartilage zone has yet to be successfully achieved. In this study, the development of a novel book-shape scaffold derived from the extracellular matrix of fibrocartilage was reported. Specifically, fibrocartilage from the pubic symphysis was obtained from rabbits and sliced into the shape of a book (dimensions: 10 mm * 3 mm * 1 mm) with 10 layers, each layer (akin to a page of a book) with a thickness of 100-MUm. These fibrocartilage "book" scaffolds were decellularized using sequentially 3 freeze-thaw cycles, 0.1% Triton X-100 with 1.5 M KCl, 0.25% trypsin, and a nuclease. Histology and DNA quantification analysis confirmed substantial removal of cells from the fibrocartilage scaffolds. Furthermore, the quantities of DNA, collagen, and glycosaminoglycan in the fibrocartilage were markedly reduced following decellularization. Scanning electron microscopy confirmed that the intrinsic ultrastructure of the fibrocartilage tissue was well preserved. Therefore, the results of this study suggest that the novel "book" fibrocartilage scaffold could have potential applications in tissue engineering. PMID- 26636673 TI - Poly(ADP-Ribosyl)ation Affects Histone Acetylation and Transcription. AB - Poly(ADP-ribosyl)ation (PARylation) is a posttranslational protein modification catalyzed by members of the poly(ADP-ribose) polymerase (PARP) enzyme family. PARylation regulates a wide variety of biological processes in most eukaryotic cells including energy metabolism and cell death, maintenance of genomic stability, chromatin structure and transcription. Inside the nucleus, cross-talk between PARylation and other epigenetic modifications, such as DNA and histone methylation, was already described. In the present work, using PJ34 or ABT888 to inhibit PARP activity or over-expressing poly(ADP-ribose) glycohydrolase (PARG), we show decrease of global histone H3 and H4 acetylation. This effect is accompanied by a reduction of the steady state mRNA level of p300, Pcaf, and Tnfalpha, but not of Dnmt1. Chromatin immunoprecipitation (ChIP) analyses, performed at the level of the Transcription Start Site (TSS) of these four genes, reveal that changes in histone acetylation are specific for each promoter. Finally, we demonstrate an increase of global deacetylase activity in nuclear extracts from cells treated with PJ34, whereas global acetyltransferase activity is not affected, suggesting a role for PARP in the inhibition of histone deacetylases. Taken together, these results show an important link between PARylation and histone acetylation regulated transcription. PMID- 26636674 TI - A Kinetic and Factorial Approach to Study the Effects of Temperature and Salinity on Growth and Toxin Production by the Dinoflagellate Alexandrium ostenfeldii from the Baltic Sea. AB - Alexandrium ostenfeldii is present in a wide variety of environments in coastal areas worldwide and is the only dinoflagellate known species that produces paralytic shellfish poisoning (PSP) toxins and two types of cyclic imines, spirolides (SPXs) and gymnodimines (GYMs). The increasing frequency of A. ostenfeldii blooms in the Baltic Sea has been attributed to the warming water in this region. To learn more about the optimal environmental conditions favoring the proliferation of A. ostenfeldii and its complex toxicity, the effects of temperature and salinity on the kinetics of both the growth and the net toxin production of this species were examined using a factorial design and a response surface analysis (RSA). The results showed that the growth of Baltic A. ostenfeldii occurs over a wide range of temperatures and salinities (12.5-25.5 degrees C and 5-21, respectively), with optimal growth conditions achieved at a temperature of 25.5 degrees C and a salinity of 11.2. Together with the finding that a salinity > 21 was the only growth-limiting factor detected for this strain, this study provides important insights into the autecology and population distribution of this species in the Baltic Sea. The presence of PSP toxins, including gonyautoxin (GTX)-3, GTX-2, and saxitoxin (STX), and GYMs (GYM-A and GYM-B/-C analogues) was detected under all temperature and salinity conditions tested and in the majority of the cases was concomitant with both the exponential growth and stationary phases of the dinoflagellate's growth cycle. Toxin concentrations were maximal at temperatures and salinities of 20.9 degrees C and 17 for the GYM-A analogue and > 19 degrees C and 15 for PSP toxins, respectively. The ecological implications of the optimal conditions for growth and toxin production of A. ostenfeldii in the Baltic Sea are discussed. PMID- 26636675 TI - Endoplasmic Reticulum Stress in Heat- and Shake-Induced Injury in the Rat Small Intestine. AB - We investigated the mechanisms underlying damage to rat small intestine in heat- and shake-induced stress. Eighteen Sprague-Dawley rats were randomly divided into a control group and a 3-day stressed group treated 2 h daily for 3 days on a rotary platform at 35 degrees C and 60 r/min. Hematoxylin and eosin-stained paraffin sections of the jejunum following stress revealed shedding of the villus tip epithelial cells and lamina propria exposure. Apoptosis increased at the villus tip and extended to the basement membrane. Photomicrographs revealed that the microvilli were shorter and sparser; the nuclear envelope invaginated and gaps in the karyolemma increased; and the endoplasmic reticulum (ER) swelled significantly. Gene microarray analysis assessed 93 differentially expressed genes associated with apoptosis, ER stress, and autophagy. Relevant genes were compiled from the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. Forty-one genes were involved in the regulation of apoptosis, fifteen were related to autophagy, and eleven responded to ER stress. According to KEGG, the apoptosis pathways, mitogen-activated protein kinase(MAPK) signaling pathway, the mammalian target of rapamycin (mTOR) signaling pathway, and regulation of autophagy were involved. Caspase3 (Casp3), caspase12 (Casp12), and microtubule-associate proteins 1 light chain 3(LC3) increased significantly at the villus tip while mTOR decreased; phosphorylated-AKT (P-AKT) decreased. ER stress was involved and induced autophagy and apoptosis in rat intestinal damage following heat and shake stress. Bioinformatic analysis will help determine the underlying mechanisms in stress-induced damage in the small intestine. PMID- 26636676 TI - Research Data in Core Journals in Biology, Chemistry, Mathematics, and Physics. AB - This study takes a stratified random sample of articles published in 2014 from the top 10 journals in the disciplines of biology, chemistry, mathematics, and physics, as ranked by impact factor. Sampled articles were examined for their reporting of original data or reuse of prior data, and were coded for whether the data was publicly shared or otherwise made available to readers. Other characteristics such as the sharing of software code used for analysis and use of data citation and DOIs for data were examined. The study finds that data sharing practices are still relatively rare in these disciplines' top journals, but that the disciplines have markedly different practices. Biology top journals share original data at the highest rate, and physics top journals share at the lowest rate. Overall, the study finds that within the top journals, only 13% of articles with original data published in 2014 make the data available to others. PMID- 26636678 TI - Histone Deacetylase Inhibitors Antagonize Distinct Pathways to Suppress Tumorigenesis of Embryonal Rhabdomyosarcoma. AB - Embryonal rhabdomyosarcoma (ERMS) is the most common soft tissue cancer in children. The prognosis of patients with relapsed or metastatic disease remains poor. ERMS genomes show few recurrent mutations, suggesting that other molecular mechanisms such as epigenetic regulation might play a major role in driving ERMS tumor biology. In this study, we have demonstrated the diverse roles of histone deacetylases (HDACs) in the pathogenesis of ERMS by characterizing effects of HDAC inhibitors, trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA; also known as vorinostat) in vitro and in vivo. TSA and SAHA suppress ERMS tumor growth and progression by inducing myogenic differentiation as well as reducing the self-renewal and migratory capacity of ERMS cells. Differential expression profiling and pathway analysis revealed downregulation of key oncogenic pathways upon HDAC inhibitor treatment. By gain-of-function, loss-of-function, and chromatin immunoprecipitation (ChIP) studies, we show that Notch1- and EphrinB1 mediated pathways are regulated by HDACs to inhibit differentiation and enhance migratory capacity of ERMS cells, respectively. Our study demonstrates that aberrant HDAC activity plays a major role in ERMS pathogenesis. Druggable targets in the molecular pathways affected by HDAC inhibitors represent novel therapeutic options for ERMS patients. PMID- 26636679 TI - Occupational Exposure to Swine, Poultry, and Cattle and Antibody Biomarkers of Campylobacter jejuni Exposure and Autoimmune Peripheral Neuropathy. AB - INTRODUCTION: Foodborne Campylobacter jejuni infection has been associated with an increased risk of autoimmune peripheral neuropathy, but risks of occupational exposure to C. jejuni have received less attention. This study compared anti-C. jejuni IgA, IgG, and IgM antibody levels, as well as the likelihood of testing positive for any of five anti-ganglioside autoantibodies, between animal farmers and non-farmers. Anti-C. jejuni antibody levels were also compared between farmers with different animal herd or flock sizes. The relationship between anti C. jejuni antibody levels and detection of anti-ganglioside autoantibodies was also assessed. METHODS: Serum samples from 129 Agricultural Health Study swine farmers (some of whom also worked with other animals) and 46 non-farmers, all from Iowa, were analyzed for anti-C. jejuni antibodies and anti-ganglioside autoantibodies using ELISA. Information on animal exposures was assessed using questionnaire data. Anti-C. jejuni antibody levels were compared using Mann Whitney tests and linear regression on log-transformed outcomes. Fisher's Exact Tests and logistic regression were used to compare likelihood of positivity for anti-ganglioside autoantibodies. RESULTS: Farmers had significantly higher levels of anti-C. jejuni IgA (p < 0.0001) and IgG (p = 0.02) antibodies compared to non farmers. There was no consistent pattern of anti-C. jejuni antibody levels based on animal herd or flock size. A higher percentage of farmers (21%) tested positive for anti-ganglioside autoantibodies compared to non-farmers (9%), but this difference was not statistically significant (p = 0.11). There was no significant association between anti-C. jejuni antibody levels and anti ganglioside autoantibodies. CONCLUSIONS: The findings provide evidence that farmers who work with animals may be at increased risk of exposure to C. jejuni. Future research should include longitudinal studies of exposures and outcomes, as well as studies of interventions to reduce exposure. Policies to reduce occupational exposure to C. jejuni should be considered. PMID- 26636680 TI - Extending Ripley's K-Function to Quantify Aggregation in 2-D Grayscale Images. AB - In this work, we describe the extension of Ripley's K-function to allow for overlapping events at very high event densities. We show that problematic edge effects introduce significant bias to the function at very high densities and small radii, and propose a simple correction method that successfully restores the function's centralization. Using simulations of homogeneous Poisson distributions of events, as well as simulations of event clustering under different conditions, we investigate various aspects of the function, including its shape-dependence and correspondence between true cluster radius and radius at which the K-function is maximized. Furthermore, we validate the utility of the function in quantifying clustering in 2-D grayscale images using three modalities: (i) Simulations of particle clustering; (ii) Experimental co expression of soluble and diffuse protein at varying ratios; (iii) Quantifying chromatin clustering in the nuclei of wt and crwn1 crwn2 mutant Arabidopsis plant cells, using a previously-published image dataset. Overall, our work shows that Ripley's K-function is a valid abstract statistical measure whose utility extends beyond the quantification of clustering of non-overlapping events. Potential benefits of this work include the quantification of protein and chromatin aggregation in fluorescent microscopic images. Furthermore, this function has the potential to become one of various abstract texture descriptors that are utilized in computer-assisted diagnostics in anatomic pathology and diagnostic radiology. PMID- 26636681 TI - 25-Hydroxyvitamin D3 Deficiency Independently Predicts Cognitive Impairment in Patients with Systemic Lupus Erythematosus. AB - OBJECTIVES: Cognitive dysfunction has been reported in 20-80% of SLE patients. Converging evidence has indicated the importance of vitamin D as a neuroimmunomodulator for cognitive function. In this study, we evaluated the relationship between vitamin D and cognitive dysfunction. METHODS: Consecutive age- and gender-matched SLE patients and healthy controls (HCs) were administered Automated Neuropsychological Assessment Metrics in this cross-sectional study. The primary outcome was the total throughput score (TTS). Anxiety and depression were measured using the Hospital Anxiety and Depression Scale (HADS). Levels of 25-hydroxyvitamin D [25(OH)D3 and total 25(OH)D] were measured using Liquid Chromatography-Tandem Mass Spectrometry. RESULTS: In total, 61 SLE patients and 61 HCs were studied. SLE patients scored significantly lower than HCs in the TTS (p = 0.004). There were no statistically significant differences in 25(OH)D3 levels, total 25(OH)D levels and total 25(OH)D deficiency between SLE patients and HCs. However, more SLE patients had 25(OH)D3 deficiency compared to HCs [12 (19.7%) versus 2 (3.3%), p = 0.003]. Deficiency of 25(OH)D3 (beta = -63.667, SE = 27.456, p = 0.025), but not other vitamin D variables, independently predicted worse TTS after adjusting for age, education, gender, ethnicity, HADS-Total, duration of SLE, SELENA-SLEDAI, SLICC/ACR Damage Index and cumulative steroid dose in SLE patients. Age (beta = -4.261, SE = 0.866, p < 0.001) was the only predictor of TTS after adjusting for education, gender, ethnicity, HADS-Total, vitamin D levels or status in HCs. CONCLUSIONS: Deficiency of 25(OH)D3, a potentially modifiable risk factor, independently predicted cognitive impairment in SLE patients. PMID- 26636677 TI - Characterization of Visceral and Subcutaneous Adipose Tissue Transcriptome and Biological Pathways in Pregnant and Non-Pregnant Women: Evidence for Pregnancy Related Regional-Specific Differences in Adipose Tissue. AB - OBJECTIVE: The purpose of this study was to compare the transcriptome of visceral and subcutaneous adipose tissues between pregnant and non-pregnant women. STUDY DESIGN: The transcriptome of paired visceral and abdominal subcutaneous adipose tissues from pregnant women at term and matched non-pregnant women (n = 11) was profiled with the Affymetrix Human Exon 1.0 ST array. Differential expression of selected genes was validated with the use of quantitative reverse transcription polymerase chain reaction. RESULTS: Six hundred forty-four transcripts from 633 known genes were differentially expressed (false discovery rate (FDR) <0.1; fold change >1.5), while 42 exons from 36 genes showed differential usage (difference in FIRMA scores >2 and FDR<0.1) between the visceral and subcutaneous fat of pregnant women. Fifty-six known genes were differentially expressed between pregnant and non-pregnant subcutaneous fat and three genes in the visceral fat. Enriched biological processes in the subcutaneous adipose tissue of pregnant women were mostly related to inflammation. CONCLUSION: The transcriptome of visceral and subcutaneous fat depots reveals pregnancy-related gene expression and splicing differences in both visceral and subcutaneous adipose tissue. Furthermore, for the first time, alternative splicing in adipose tissue has been associated with regional differences and human parturition. PMID- 26636712 TI - Stochastic Mesocortical Dynamics and Robustness of Working Memory during Delay Period. AB - The role of prefronto-mesoprefrontal system in the dopaminergic modulation of working memory during delayed response tasks is well-known. Recently, a dynamical model of the closed-loop mesocortical circuit has been proposed which employs a deterministic framework to elucidate the system's behavior in a qualitative manner. Under natural conditions, noise emanating from various sources affects the circuit's functioning to a great extent. Accordingly in the present study, we reformulate the model into a stochastic framework and investigate its steady state properties in the presence of constant background noise during delay period. From the steady state distribution, global potential landscape and signal to-noise ratio are obtained which help in defining robustness of the circuit dynamics. This provides insight into the robustness of working memory during delay-period against its disruption due to background noise. The findings reveal that the global profile of circuit's robustness is predominantly governed by the level of D1 receptor activity and high D1 receptor stimulation favors the working memory-associated sustained-firing state over the spontaneous-activity state of the system. Moreover, the circuit's robustness is further fine-tuned by the levels of excitatory and inhibitory activities in a way such that the robustness of sustained-firing state exhibits an inverted-U shaped profile with respect to D1 receptor stimulation. It is predicted that the most robust working memory is formed possibly at a subtle ratio of the excitatory and inhibitory activities achieved at a critical level of D1 receptor stimulation. The study also paves a way to understand various cognitive deficits observed in old-age, acute stress and schizophrenia and suggests possible mechanistic routes to the working memory impairments based on the circuit's robustness profile. PMID- 26636713 TI - The Extraintestinal Pathogenic Escherichia coli Factor RqlI Constrains the Genotoxic Effects of the RecQ-Like Helicase RqlH. AB - Extraintestinal pathogenic Escherichia coli colonize the human gut and can spread to other body sites to induce diseases such as urinary tract infections, sepsis, and meningitis. A complete understanding of the infection process is hindered by both the inherent genetic diversity of E. coli and the large number of unstudied genes. Here, we focus on the uncharacterized gene rqlI, which our lab recently uncovered in a Tn-seq screen for bacterial genes required within a zebrafish model of infection. We demonstrate that the DeltarqlI mutant experiences a growth defect and increased DNA stress in low oxygen conditions. In a genetic screen for suppressor mutations in the Deltarql strain, we found that the shortcomings of the Deltarql mutant are attributable to the activity of RqlH, which is known in other bacteria to be a helicase of the RecQ family that contains a phosphoribosyltransferase (PRTase) domain. Disruption of rqlH rescues the DeltarqlI strain in both in vivo and in vitro assays, while the expression of RqlH alone activates the SOS response coincident with bacterial filamentation, heightened sensitivity to DNA damage, and an increased mutation rate. The analysis of truncation mutants indicates that, in the absence of RqlI, RqlH toxicity is due to its PRTase domain. Complementary studies demonstrate that the toxicity of RqlH is modulated in a context-dependent fashion by overlapping domains within RqlI. This regulation is seemingly direct, given that the two proteins physically interact and form an operon. Interestingly, RqlH and RqlI orthologs are encoded by a diverse group of bacteria, but in many of these microbes, and especially in Gram-positive organisms, rqlH is found in the absence of rqlI. In total, this work shows that RqlH and RqlI can act in a strain specific fashion akin to a toxin-antitoxin system in which toxicity is mediated by an atypical helicase-associated PRTase domain. PMID- 26636715 TI - Microfluidic Magnetic Bead Assay for Cell Detection. AB - We present a novel cell detection device based on a magnetic bead cell assay and microfluidic Coulter counting technology. The device cannot only accurately measure cells size distribution and concentration but also detect specific target cells. The device consists of two identical micro Coulter counters separated by a fluid chamber where an external magnetic field is applied. Antibody functionalized magnetic beads were bound to specific antigens expressed on the target cells. A high-gradient magnetic field was applied to the chamber closer to the second counter via an external cylindrical magnet. Because of the magnetic interaction between the magnetic beads and the magnetic field, target cells were retarded by the magnetic field; transit time of a target cell (bound with magnetic beads) passing through the second counter was longer than that through the first counter. In comparison, transit times of a nontarget cell remained nearly the same when it passed through both counters. Thus, from the transit time delay we can identify target cells and quantify their concentration in a cell suspension. The transit time and the size of each cell were accurately measured in terms of the width and amplitude of the resistive pulses generated from the two Coulter counters. Experiments demonstrated that for mixed cells with various target cell ratios, the transit time delay increased approximately linearly with the increasing target cell ratio. The limit of detection (LOD) of the assay was estimated to be 5.6% in terms of target cell ratio. Cell viability tests further demonstrated that most cells were viable after the detection. With the simple device configuration and easy sample preparation, this rapid and reliable method is expected to accurately detect target cells and could be applied to facilitate stem cell isolation and characterization. PMID- 26636714 TI - Combined Delivery of Let-7b MicroRNA and Paclitaxel via Biodegradable Nanoassemblies for the Treatment of KRAS Mutant Cancer. AB - In the present study, we synthesized a novel cationic copolymer composed of polyethylene glycol 5000 (PEG5K), vitamin E (VE), and diethylenetriamine (DET) at 1:4:20 molar ratio. The resulting PEG5K-VE4-DET20 copolymer formed nanoassemblies when mixed with the neutral PEG5K-VE4 copolymer at 1:8 weight ratio, which were investigated as the nanocarriers for combined delivery of paclitaxel and let-7b mimic. We found that the PEG5K-VE4-DET20 nanoassemblies could entrap paclitaxel for an extended period and burst release the drug in the presence of cathepsin B, demonstrating the biodegradability of the copolymers. At N/P ratio of 12:1, the PEG5K-VE4-DET20 nanoassemblies formed stable polyplexes with let-7b mimic, which were efficiently taken up by tumor cells and underwent endosomal escape. In non small cell lung cancer A549 cells that harbor mutant KRAS, paclitaxel and let-7b mimic-loaded nanoassemblies (N-PTX/let-7b) markedly potentiated the cytotoxicity of paclitaxel, induced apoptosis, and diminished the invasiveness of tumor cells. In mice bearing subcutaneous A549 xenografts, intravenous administration of N PTX/let-7b retarded tumor growth more efficaciously than Taxol. Our study demonstrates the promise of the PEG5K-VE4-DET20 nanoassemblies for concurrent delivery of hydrophobic drugs and miRNA mimics. PMID- 26636716 TI - Single Site Isomeric Ru WOCs with an Electron-Withdrawing Group: Synthesis, Electrochemical Characterization, and Reactivity. AB - The synthetic intermediate cis(out),cis-[Ru(Cl)2(HL)(DMSO)2], 1 (DMSO = dimethyl sulfoxide), and four new mononuclear ruthenium complexes with general formula out/in-[Ru(HL)(trpy)(X)](m+) (trpy = 4-tert-butylpyridine; X = Cl(-), m = 1, 2a(+) and 2b(+); X = H2O, m = 2, 3a(2+) and 3b(2+)) based on the ligand 1H pyrazole-3-carboxylic acid, 5-(2-pyridinil)-, ethyl ester (HL), are synthesized and characterized by analytical, spectroscopic, and electrochemical methods. A linkage isomerism is observed for a DMSO moiety of 1, and relevant thermodynamics and kinetics values are obtained through electrochemical experiments and compared to literature. Different synthetic routes are developed to obtain isomeric 2a(+) and 2b(+), with different relative yields. Water oxidation activity of 3a(2+) and 3b(2+) is analyzed by means of electrochemical methods, through foot of the wave analysis, yielding kobs values of 1.00 and 2.23 s(-1), respectively. Chemically driven water oxidation activity is tested using [(NH4)2Ce(NO3)6] as sacrificial electron acceptor, and turnover number (TON) and turnover frequency (TOF) values of TON = 10.8 and TOFi = 58.2 * 10(-3) s(-1) for 3a(2+) and TON = 4.2 and TOFi = 15.4 * 10(-3) s(-1) for 3b(2+) are obtained. PMID- 26636717 TI - Atropisomerization of 8-Membered Dibenzolactam: Experimental NMR and Theoretical DFT Study. AB - Detailed experimental and theoretical quantum mechanical analysis of the atropisomerization mechanism of a complex, bridged biaryl molecule with imbedded biphenyl, amine, and lactam moieties, 7,8-diallyl-5-benzyl-7,8 dihydrodibenzo[e,g][1,4]diazocin-6(5H)-one (1), was undertaken. Experimental Gibbs free activation energy, activation enthalpy, and activation entropy were established by temperature-dependent kinetic NMR experiments. Theoretical analysis utilized density functional theory (DFT) calculations at the B3LYP/6 31G(d) level of theory. Twelve energy minima and 17 transition states associated with five different atropisomer interconversion pathways were found by the combination of DFT calculated two-dimensional potential energy surfaces (2D PES) and the quadratic synchronous transit-guided (QST2) method. Among the five possible atropisomerization pathways, the lowest Gibbs free activation energy 25.8 kcal/mol was in close agreement with the experimentally determined value of 26.8 kcal/mol. Theoretical activation entropies and enthalpies were also consistent with experimental data. Geometrical and vibrational analysis of transition states and metastable intermediates suggested the mechanism of atropisomer interconversion of 1 as a rotation of the eclipsed endocyclic coordinate in a clockwise or counterclockwise direction along the ring. Puckering ability at least in one of the segments of the ring appears to be one of the most critical factors defining the height of atropisomerization barrier. PMID- 26636718 TI - Superelectrophilic Activation of Crotonic/Methacrylic Acids: Direct Access to Thiochroman-4-ones from Benzenethiols by Microwave-Assisted One-Pot Alkylation/Cyclic Acylation. AB - An efficient microwave-assisted protocol for the synthesis of 2-/3 methylthiochroman-4-ones by superacid-catalyzed alkylation followed by cyclic acylation (cyclization via intramolecular acylation) is described. Using easily accessible benzenethiols and crotonic acid/methacrylic acid with triflic acid (as catalyst of choice for needed optimal acidity), the reaction was tuned toward the formation of the cyclized products in good selectivity and yield. A mechanism involving the formation of carbenium-carboxonium superelectrophilic species is suggested. PMID- 26636719 TI - One-Pot Synthesis of (S)-Baclofen via Aldol Condensation of Acetaldehyde with Diphenylprolinol Silyl Ether Mediated Asymmetric Michael Reaction as a Key Step. AB - An efficient asymmetric total synthesis of (S)-baclofen was accomplished via a one-pot operation from commercially available materials using sequential reactions, such as aldol condensation of acetaldehyde, diphenylprolinol silyl ether mediated asymmetric Michael reaction of nitromethane, Kraus-Pinnick oxidation, and Raney Ni reduction. Highly enantioenriched baclofen was obtained in one pot with a good yield over four reactions. PMID- 26636720 TI - Palladium-Catalyzed Intramolecular Aminotrifluoromethoxylation of Alkenes. AB - The first catalytic trifluoromethoxylation of unactivated alkenes has been developed, in which Pd(CH3CN)2Cl2 was used as catalyst, AgOCF3 as trifluoromethoxide source, and Selectfluor-BF4 as oxidant. A variety of 3-OCF3 substituted piperidines were selectively obtained in good yields. Direct evidence was provided to address the facile reductive elimination of Pd(IV)-OCF3 complex to form sp(3) C-OCF3 bond. PMID- 26636721 TI - Binding of Disordered Peptides to Kelch: Insights from Enhanced Sampling Simulations. AB - Keap1 protein plays an essential role in regulating cellular oxidative stress response and is a crucial binding hub for multiple proteins, several of which are intrinsically disordered proteins (IDP). Among Kelch's IDP binding partners, NRF2 and PTMA are the two most interesting cases. They share a highly similar binding motif; however, NRF2 binds to Kelch with a binding affinity of approximately 100 fold higher than that of PTMA. In this study, we perform an exhaustive sampling composed of 6 MUs well-tempered metadynamics and 2 MUs unbiased molecular dynamics (MD) simulations aiming at characterizing the binding mechanisms and structural properties of these two peptides. Our results agree with previous experimental observations that PTMA is remarkably more disordered than NRF2 in both the free and bound states. This explains PTMA's lower binding affinity. Our extensive sampling also provides valuable insights into the vast conformational ensembles of both NRF2 and PTMA, supports the hypothesis of coupled folding binding, and confirms the essential role of linear motifs in IDP binding. PMID- 26636722 TI - Viruses at Solid-Water Interfaces: A Systematic Assessment of Interactions Driving Adsorption. AB - Adsorption to solid-water interfaces is a major process governing the fate of waterborne viruses in natural and engineered systems. The relative contributions of different interaction forces to adsorption and their dependence on the physicochemical properties of the viruses remain, however, only poorly understood. Herein, we systematically studied the adsorption of four bacteriophages (MS2, fr, GA, and Qbeta) to five model surfaces with varying surface chemistries and to three dissolved organic matter adlayers, as a function of solution pH and ionic strength, using quartz crystal microbalance with dissipation monitoring. The viruses were selected to have similar sizes and shapes but different surface charges, polarities, and topographies, as identified by modeling the distributions of amino acids in the virus capsids. Virus-sorbent interactions were governed by long-ranged electrostatics and favorable contributions from the hydrophobic effect, and shorter-ranged van der Waals interactions were of secondary importance. Steric effects depended on the topographic irregularities on both the virus and sorbent surfaces. Differences in the adsorption characteristics of the tested viruses were successfully linked to differences in their capsid surface properties. Besides identifying the major interaction forces, this work highlights the potential of computable virus surface charge and polarity descriptors to predict virus adsorption to solid water interfaces. PMID- 26636723 TI - Dual Stimuli-Responsive Vesicular Nanospheres Fabricated by Lipopolymer Hybrids for Tumor-Targeted Photodynamic Therapy. AB - Smart delivery system of photosensitizer chlorin e6 (Ce6) has been developed for targeted photodynamic therapy (PDT). Simple self-assemblies of the mixtures comprising soybean lecithin derived phosphatidylcholine (PC), phosphatidylethanolamine-poly(L-histidine)40 (PE-p(His)40), and folic acid (FA) conjugated phosphatidylethanolamine-poly(N-isopropylacrylamide)40 (PE-p(NIPAM)40 FA) in different ratios yield smart nanospheres characterized by (i) stable and uniform particle size (~100 nm), (ii) positive surface charge, (iii) high hydrophobic drug (Ce6) loading efficiency up to 45%, (iv) covalently linked targeting moiety, (v) low cytotoxicity, and (vi) smartness showing p(His) block oriented pH and p(NIPAM) oriented temperature responsiveness. The Ce6 encapsulated vesicular nanospheres (Ce6@VNS) were used to confirm the efficiency of cellular uptake, intracellular distribution, and phototoxicity against KB tumor cells compared to free Ce6 at different temperature and pH conditions. The Ce6@VNS system showed significant photodynamic therapeutic efficiency on KB cells than free Ce6. A receptor-mediated inhibition study proved the site-specific delivery of Ce6 in targeted tumor cells. PMID- 26636724 TI - Correction to Multiconfiguration Pair-Density Functional Theory Outperforms Kohn Sham Density Functional Theory and Multireference Perturbation Theory for Ground State and Excited-State Charge Transfer. PMID- 26636725 TI - Impact of supplementary royal jelly on in vitro maturation of sheep oocytes: genes involved in apoptosis and embryonic development. AB - Optimizing culture conditions lead to the improvement of oocyte developmental competence and additives with anti-oxidative activity in culture media improved embryonic development. Royal jelly (RJ) is a product from the cephalic glands of nurse bees that has considerable health effects. The aim of this study was to investigate the effect of different concentrations of RJ on the maturation, cleavage, and blastocyst rates and gene expression in the oocyte and cumulus cells during in vitro maturation (IVM) of sheep oocyte. IVM of oocyte was performed in the presence of control (RJ0), 2.5 (RJ2.5), 5 (RJ5), 10 (RJ10), 20 (RJ20), and 40 (RJ40) mg/mL of RJ. Following the maturation period, parthenogenetic activation was carried out in two treatment groups (RJ0 and RJ10) and embryonic development was examined three and eight days thereafter. Moreover, the relative expression of BCL2 and BAX in oocyte as well as BCL2, BAX, HAS2, PTGS2, and STAR in cumulus cells were assessed. The results indicated that the addition of 10 mg/mL of RJ (90 +/- 4.51%) to the maturation medium linearly increased the oocyte maturation rate compared to the control group (57 +/- 2.42%), then it remained constant to the RJ40 (93 +/- 3.10%) group. The higher RJ concentrations were associated with increased (p < 0.01) cleavage (53.3 +/- 1.55% to 82.3 +/- 2.82%) and blastocyst rate (15.5 +/- 1.16% to 33.8 +/- 3.09%) from the RJ0 to the RJ10 group. The relative mRNA expression of BCL2 and BAX in the oocyte was higher at RJ10. In cumulus cells, the expression of BCL2 was not affected, but that of BAX decreased, and expression of HAS2, PTGS2, and STAR were increased following the addition of RJ to the maturation media. In conclusion, the addition of 10 mg/mL of RJ to maturation medium improved blastocyst formation and decreased the apoptotic incidence in sheep cumulus cells and the oocyte during the in vitro development. PMID- 26636726 TI - Mesohepatectomy for Centrally Located Tumors in Children. AB - INTRODUCTION: Central hepatectomy or mesohepatectomy (MH) is a complex surgical technique rarely used in children. It is indicated in central tumors to preserve functioning liver mass avoiding an extended right hepatectomy. The purpose of this article is to analyze our experience with this technique. METHODS: We reviewed five patients who underwent MH in the period from 2008 to 2014. Diagnoses were hepatoblastoma PRETEXT III (two cases), hepatic embryonal sarcoma (one case), focal nodular hyperplasia (one case), and vascular tumor with rapid growth in a newborn causing an acute liver failure, compartment syndrome, and multiple organ failure (one case). In all cases, the tumor was centrally located, including the segment IVb, with large displacement of the hepatic pedicle in two cases. RESULTS: MH was standard in three cases and under total vascular exclusion in two cases. All children are alive with a mean follow-up of 38 (6-70) months. None of the children required reoperation because of bleeding. One child developed a biliary fistula in the cutting area that closed spontaneously. The newborn with the vascular tumor required the placement of a Gore-Tex patch (W. L. Gore & Associates, Inc, Flagstaff, Arizona, United States) to relieve the compartment syndrome. He subsequently underwent partial embolization of the tumor and MH under vascular exclusion. CONCLUSIONS: In selected patients, MH is an alternative to trisegmentectomy and should be available in advanced pediatric hepatobiliary units. PMID- 26636727 TI - Evaluation of a short-term topical interferon alpha-2b treatment for histologically proven melanoma and primary acquired melanosis with atypia. AB - OBJECTIVE: To evaluate the efficiency of series of 6-week treatments with brief intervals (6-week = 1 cycle) of topical Interferon alpha-2b (IFNalpha-2b) treatment in primary acquired melanosis (PAM) with atypia and melanoma of the conjunctiva. PATIENTS AND METHODS: Five patients with biopsy-proven PAM with atypia and seven patients with melanoma of the conjunctiva, treated with topical IFNalpha-2b (1 million units/ml, 5 times daily), were included in the study. All patients had colour photographs and the tumour area was measured manually for each patient before and after treatment. RESULTS: The median age of 12 patients at initiation of treatment was 61.5 years (range 39-75 years). The mean therapy duration was 2.4 cycles (range 1-6 cycle). Compared to pretreatment lesion dimension, the mean decrease in tumour size were after the first cycle 66% (range 18-98%; p = 0.004; n = 10 patients), after the second cycle 55% (range 10-100%; p = 0.016; n = 7 patients), and after the third cycle 74% (range 23-100%; n = 3 patients). In one patient 6 cycles of topical IFNalpha-2b were needed. The decrease in size was 22% after the 4(th) cycle, 34% after the 5(th) cycle, and 98% after the 6(th) cycle. CONCLUSION: Our clinical experience demonstrates promising results of topical IFNalpha-2b treatment for PAM with atypia and melanoma of the conjunctiva without any local or systemic side effects. However, future multicenter prospective studies are recommended to confirm the efficiency and safety of topical IFNalpha-2b treatment. PMID- 26636730 TI - Reliability of the Superimposed-Burst Technique in Patients With Patellofemoral Pain: A Technical Report. AB - CONTEXT: The superimposed-burst (SIB) technique is commonly used to quantify central activation failure after knee-joint injury, but its reliability has not been established in pathologic cohorts. OBJECTIVE: To assess within-session and between-sessions reliability of the SIB technique in patients with patellofemoral pain. DESIGN: Descriptive laboratory study. SETTING: University laboratory. PATIENTS OR OTHER PARTICIPANTS: A total of 10 patients with self-reported patellofemoral pain (1 man, 9 women; age = 24.1 +/- 3.8 years, height = 167.8 +/- 15.2 cm, mass = 71.6 +/- 17.5 kg) and 10 healthy control participants (3 men, 7 women; age = 27.4 +/- 5.0 years, height = 173.5 +/- 9.9 cm, mass = 78.2 +/- 16.5 kg) volunteered. INTERVENTION(S): Participants were assessed at 6 intervals spanning 21 days. Intraclass correlation coefficients (ICCs [3,3]) were used to assess reliability. MAIN OUTCOME MEASURE(S): Quadriceps central activation ratio, knee-extension maximal voluntary isometric contraction force, and SIB force. RESULTS: The quadriceps central activation ratio was highly reliable within session (ICC [3,3] = 0.97) and between sessions through day 21 (ICC [3,3] = 0.90 0.95). Acceptable reliability of knee extension (ICC [3,3] = 0.75-0.91) and SIB force (ICC [3,3] = 0.77-0.89) was observed through day 21. CONCLUSIONS: The SIB technique was reliable for clinical research up to 21 days in patients with patellofemoral pain. PMID- 26636731 TI - How legumes recognize rhizobia. AB - Legume plants have developed the capacity to establish symbiotic interactions with soil bacteria (known as rhizobia) that can convert N2 to molecular forms that are incorporated into the plant metabolism. The first step of this relationship is the recognition of bacteria by the plant, which allows to distinguish potentially harmful species from symbiotic partners. The main molecular determinant of this symbiotic interaction is the Nod Factor, a diffusible lipochitooligosaccharide molecule produced by rhizobia and perceived by LysM receptor kinases; however, other important molecules involved in the specific recognition have emerged over the years. Secreted exopolysaccharides and the lipopolysaccharides present in the bacterial cell wall have been proposed to act as signaling molecules, triggering the expression of specific genes related to the symbiotic process. In this review we will briefly discuss how transcriptomic analysis are helping to understand how multiple signaling pathways, triggered by the perception of different molecules produced by rhizobia, control the genetic programs of root nodule organogenesis and bacterial infection. This knowledge can help to understand how legumes have evolved to recognize and establish complex ecological relationships with particular species and strains of rhizobia, adjusting gene expression in response to identity determinants of bacteria. PMID- 26636733 TI - Regulatory role of rpL3 in cell response to nucleolar stress induced by Act D in tumor cells lacking functional p53. AB - Many chemotherapeutic drugs cause nucleolar stress and p53-independent pathways mediating the nucleolar stress response are emerging. Here, we demonstrate that ribosomal stress induced by Actinomycin D (Act D) is associated to the up regulation of ribosomal protein L3 (rpL3) and its accumulation as ribosome-free form in lung and colon cancer cell lines devoid of p53. Free rpL3 regulates p21 expression at transcriptional and post-translational levels through a molecular mechanism involving extracellular-signal-regulated kinases1/2 (ERK1/2) and mouse double minute-2 homolog (MDM2). Our data reveal that rpL3 participates to cell response acting as a critical regulator of apoptosis and cell migration. It is noteworthy that silencing of rpL3 abolishes the cytotoxic effects of Act D suggesting that the loss of rpL3 makes chemotherapy drugs ineffective while rpL3 overexpression associates to a strong increase of Act D-mediated inhibition of cell migration. Taking together our results show that the efficacy of Act D chemotherapy depends on rpL3 status revealing new specific targets involved in the molecular pathways activated by Act D in cancers lacking of p53. Hence, the development of treatments aimed at upregulating rpL3 may be beneficial for the treatment of these cancers. PMID- 26636734 TI - Temperature Observation Time and Type Influence Estimates of Heat-Related Mortality in Seven U.S. Cities. AB - BACKGROUND: Extreme heat is a leading weather-related cause of mortality in the United States, but little guidance is available regarding how temperature variable selection impacts heat-mortality relationships. OBJECTIVES: We examined how the strength of the relationship between daily heat-related mortality and temperature varies as a function of temperature observation time, lag, and calculation method. METHODS: Long time series of daily mortality counts and hourly temperature for seven U.S. cities with different climates were examined using a generalized additive model. The temperature effect was modeled separately for each hour of the day (with up to 3-day lags) along with different methods of calculating daily maximum, minimum, and mean temperature. We estimated the temperature effect on mortality for each variable by comparing the 99th versus 85th temperature percentiles, as determined from the annual time series. RESULTS: In three northern cities (Boston, MA; Philadelphia, PA; and Seattle, WA) that appeared to have the greatest sensitivity to heat, hourly estimates were consistent with a diurnal pattern in the heat-mortality response, with strongest associations for afternoon or maximum temperature at lag 0 (day of death) or afternoon and evening of lag 1 (day before death). In warmer, southern cities, stronger associations were found with morning temperatures, but overall the relationships were weaker. The strongest temperature-mortality relationships were associated with maximum temperature, although mean temperature results were comparable. CONCLUSIONS: There were systematic and substantial differences in the association between temperature and mortality based on the time and type of temperature observation. Because the strongest hourly temperature-mortality relationships were not always found at times typically associated with daily maximum temperatures, temperature variables should be selected independently for each study location. In general, heat-mortality was more closely coupled to afternoon and maximum temperatures in most cities we examined, particularly those typically prone to heat-related mortality. CITATION: Davis RE, Hondula DM, Patel AP. 2016. Temperature observation time and type influence estimates of heat related mortality in seven U.S. cities. Environ Health Perspect 124:795-804; http://dx.doi.org/10.1289/ehp.1509946. PMID- 26636735 TI - Residential Location and Kidney Transplant Outcomes in Indigenous Compared With Nonindigenous Australians. AB - BACKGROUND: Indigenous Australians experience significantly worse graft and patient outcomes after kidney transplantation compared with nonindigenous Australians. It is unclear whether rural versus urban residential location might contribute to this. METHODS: All adult patients from the Australia and New Zealand Dialysis and Transplant Registry who received a kidney transplant in Australia between January 1, 2000, and December 31, 2012, were investigated. Patients' residential location was classified as urban (major city + inner regional) or rural (outer regional - very remote) using the Australian Bureau of Statistics Remoteness Area Classification. RESULTS: Of 7826 kidney transplant recipients, 271 (3%) were indigenous. Sixty-three percent of indigenous Australians lived in rural locations compared with 10% of nonindigenous Australians (P < 0.001). In adjusted analyses, the hazards ratio for graft loss for Indigenous compared with non-Indigenous race was 1.59 (95% confidence interval [95% CI], 1.01-2.50; P = 0.046). Residential location was not associated with graft survival. Both indigenous race and residential location influenced patient survival, with an adjusted hazards ratio for death of 1.94 (95% CI, 1.23 3.05; P = 0.004) comparing indigenous with nonindigenous and 1.26 (95% CI, 1.01 1.58; P = 0.043) comparing rural with urban recipients. Five-year graft and patient survivals were 70% (95% CI, 60%-78%) and 69% (95% CI, 61%-76%) in rural indigenous recipients compared with 91% (95% CI, 90%-92%) and 92% (95% CI, 91% 93%) in urban nonindigenous recipients. CONCLUSIONS: Indigenous kidney transplant recipients experience worse patient and graft survival compared with nonindigenous recipients, whereas rural residential location is associated with patient but not graft survival. Of all groups, indigenous recipients residing in rural locations experienced the lowest 5-year graft and patient survivals. PMID- 26636736 TI - Conversion From Calcineurin to Mammalian Target of Rapamycin Inhibitors in Liver Transplantation: A Meta-Analysis of Randomized Controlled Trials. AB - BACKGROUND: Conversion to mammalian target of rapamycin inhibitors (mTORi) is often used in liver transplantation to overcome calcineurin inhibitor (CNI) nephrotoxicity but the evidence base for this approach is not well defined. To summarize the evidence, from randomized clinical trials (RCTs), for conversion from CNI to mTORi-based immunosuppression after liver transplantation. METHODS: Databases and conference abstracts were searched up to August 2015. The RCTs evaluating conversion from CNI to mTORi-based maintenance immunosuppression after adult liver transplantation. Descriptive and quantitative information was extracted; summary mean difference and risk ratio (RR) estimates were synthesized under a random-effects model. Heterogeneity was assessed using the Q statistic and I. RESULTS: Ten RCTs, with a total of 1927 patients, met the final inclusion criteria. Patients converted to mTORi had significantly better renal function at 1 year after randomization compared with patients remaining on CNI (mean difference, 7.48 mL/min per 1.73 m; 95% confidence interval [95% CI], 3.18-11.8). The risks of graft loss (RR, 0.77; 95% CI, 0.29-2.09; I, 31%) and patient death (RR, 1.05; 95% CI, 0.63-1.73; I, 0%) were similar for patients converted to mTORi and patients remaining on CNI. However, conversion to mTORi was associated with a higher risk of acute rejection (RR, 1.76; 95% CI, 1.33-2.34; I, 0%) and study discontinuation due to adverse events (RR, 2.17; 95% CI, 1.38-3.44; I, 63%) up to 1 year after randomization. CONCLUSIONS: Conversion from CNI to mTORi after liver transplantation is associated with improved renal function after 1 year but increases the risk of acute rejection and may be poorly tolerated. PMID- 26636737 TI - De Novo Anti-HLA DSA Characteristics and Subclinical Antibody-Mediated Kidney Allograft Injury. AB - BACKGROUND: It is unclear whether all donor-specific antibodies (DSA) can cause chronic antibody-mediated rejection (AMR). Subclinical stage before manifestation of renal dysfunction may be a critical period for reversing AMR. The aim of our study was to identify factors related to the development of subclinical AMR and to clarify the characteristics of de novo DSA. METHODS: Eight hundred ninety-nine renal transplants were screened for HLA antibody. De novo DSA were detected in 95 patients. Forty-three patients without renal dysfunction who underwent renal biopsies were enrolled in this study. Eighteen patients (41.9%) were diagnosed with biopsy-proven subclinical AMR and treated with plasmapheresis and rituximab based therapy, whereas 25 showed no findings of AMR. RESULTS: Significant subclinical AMR-related factors were younger recipients, history of acute T cell mediated rejection and DSA class II, especially DR-associated DSA. Mean fluorescence intensity (MFI) values of DR-DSA were significantly higher, whereas DQ-DSA was not different between subclinical AMR and no AMR. The DeltaMFI (>50%), DSA-MFI values greater than 3000, and C1q binding DSA were also significant subclinical AMR-related factors (P < 0.05). Among 18 patients treated for subclinical AMR, 8 patients (44.4%) obtained over 50% reduction of DSA-MFI and/or improvement or no deterioration of pathological findings. In contrast, 25 patients without subclinical AMR did not show renal dysfunction clinically. Moreover, all of the 8 patients with rebiopsy after 2 years continued to demonstrate no AMR. CONCLUSIONS: About 40% of patients with de novo DSA demonstrated biopsy-proven subclinical AMR, leading to progressive graft injury. To validate the intervention and treatment for de novo DSA-positive patients without renal dysfunction, further study is necessary. PMID- 26636738 TI - The Chauvet 2014 Meeting Report: Psychiatric and Psychosocial Evaluation and Outcomes of Upper Extremity Grafted Patients. AB - Under the auspices for the International Society on Hand and Composite Tissue Allotransplantation, a section of The Transplantation Society (IHCTAS), a meeting was convened on March 21-22, 2014 in Paris to review the following areas that were deemed significant in the understanding of the psychosocial evaluation and outcomes of upper extremity transplant recipients: required domains of the evaluation, screening instruments, clinical monitoring pretransplant, clinical monitoring posttransplant, patient and team expectations, body image, psychiatric complications, functional goals and quality of life, ethics and media relations. Experts in the fields of psychiatry and psychology, transplantation, social work, ethics, and transplant administration met and reviewed center experiences and literature. The attendees highlighted the importance and the complexity of the psychiatric assessment in this field of transplantation. Moreover, the necessity to develop common instruments and evaluation protocols to predict psychosocial outcomes as well as to understand whether we are transplanting the right patients and how the transplantation is affecting the patients were pointed out. Psychiatric complications in upper extremity transplanted patients have been reported by the majority of teams. Preexisting psychiatric difficulties, the initial trauma of amputation, or adjusting to the transplantation process itself (especially the medical follow-up and rehabilitation process) appeared to be important factors. Monitoring during the whole follow-up was recommended to detect psychiatric issues and to facilitate and ensure long-term adherence. The participants proposed an annual meeting format to build upon the findings of this inaugural meeting to be called the Chauvet Workgroup meeting. PMID- 26636739 TI - Skeletal Myoblast Cell Sheet Implantation Ameliorates Both Systolic and Diastolic Cardiac Performance in Canine Dilated Cardiomyopathy Model. AB - BACKGROUND: Improving both systolic and diastolic function may be the most important factor in treating heart failure. In this study, we hypothesized that cell-sheet transplantation could improve these function in the damaged heart. METHODS: We generated a dilated cardiomyopathy model in beagles by continuous ventricle pacing at 240 beats per minute. After 4 weeks, the beagles underwent skeletal myoblast cell sheet transplantation (SMCST) or a sham operation, and rapid ventricle pacing continued for an additional 4 weeks. Six of the e8 beagles treated by SMCST were still alive 4 weeks after the procedure. We evaluated SMCST's cardiotherapeutic effects by comparing beagles treated by SMCST with beagles that underwent a sham operation (control, n = 5). RESULTS: Diastolic function, as well as systolic function improved significantly in the SMCST group as compared with the sham group (control vs SMCST group, median [interquartile range]: E/E', 16 [0.9] vs 11 [1.0]; P < 0.001; tau, 47 [6.0] vs 36 [4.4] ms: P = 0.005. Ejection fraction, 22 (6.0) versus 46 (7.5) %, P < 0.001; end-systolic elastance, 2.5 (0.4) versus 8.2 (3.5) mm Hg/ml, P = 0.001). Histological examination revealed that the volume of collagen I and the collagen I/III ratio in the myocardium were significantly higher in the control than that in the SMCST group (collagen I, 6.0 [0.8] vs 2.6 [1.3]; P = 0.006; collagen I/III ratio, 4.8 [1.7] vs 1.2 [0.4]; P = 0.010). CONCLUSIONS: The potential of SMCST to ameliorate both systolic and diastolic performance was proven. The SMCST may be an alternative therapy of conventional medical treatment in the dilated cardiomyopathy heart. PMID- 26636740 TI - iChoose Life: Using Technology to Individualize Decisions to Pursue Renal Transplantation. PMID- 26636741 TI - HLA and Risk of Diffuse Large B cell Lymphoma After Solid Organ Transplantation. AB - BACKGROUND: Solid organ transplant recipients have heightened risk for diffuse large B cell lymphoma (DLBCL). The role of donor-recipient HLA mismatch and recipient HLA type on DLBCL risk are not well established. METHODS: We examined 172 231 kidney, heart, pancreas, and lung recipients transplanted in the United States between 1987 and 2010, including 902 with DLBCL. Incidence rate ratios (IRRs) were calculated using Poisson regression for DLBCL risk in relation to HLA mismatch, types, and zygosity, adjusting for sex, age, race/ethnicity, year, organ, and transplant number. RESULTS: Compared with recipients who had 2 HLA-DR mismatches, those with zero or 1 mismatch had reduced DLBCL risk, (zero: IRR, 0.76, 95% confidence interval [95% CI], 0.61-0.95; one: IRR, 0.83; 95% CI, 0.69 1.00). In stratified analyses, recipients matched at either HLA-A, -B, or -DR had a significantly reduced risk of late-onset (>2 years after transplantation), but not early-onset DLBCL, and there was a trend for decreasing risk with decreasing mismatch across all 3 loci (P = 0.0003). Several individual recipient HLA-A, -B, C, -DR, and -DQ antigens were also associated with DLBCL risk, including DR13 (IRR, 0.74; 95% CI, 0.57-0.93) and B38 (IRR, 1.48; 95% CI, 1.10-1.93), confirming prior findings that these 2 antigens are associated with risk of infection associated cancers. CONCLUSIONS: In conclusion, variation in HLA is related to susceptibility to DLBCL, perhaps reflecting intensity of immunosuppression, control of Epstein-Barr virus infection among transplant recipients or chronic immune stimulation. PMID- 26636742 TI - Persistence and Recurrence Following Femoral Derotational Osteotomy in Ambulatory Children With Cerebral Palsy. AB - BACKGROUND: Excessive hip internal rotation is frequently seen in children with cerebral palsy (CP). Femoral derotational osteotomy (FDO) is effective in the short term, but factors associated with long-term correction remain unclear. The purposes of this study were to define the incidence of persistence and recurrence of hip internal rotation following FDO in ambulatory children with CP and to evaluate factors that influence outcome. METHODS: Following IRB approval, kinematic and passive range of motion (PROM) variables were retrospectively evaluated in children with spastic CP who had FDO to correct hip internal rotation as part of clinical care at a children's specialty hospital. Children included had a preoperative evaluation (Vpre), a short-term postoperative evaluation (Vshort, 1 to 3 y post), and, in some cases, a long-term postoperative evaluation (Vlong, >=5 y post). Age at surgery, physical exam measures, and kinematics variables were evaluated as predictors for dynamic and static recurrence. RESULTS: Kinematic hip rotation improved from 14+/-12 degrees (Vpre; internal positive) to 4+/-13 degrees (Vshort) and relapsed to 9+/-15 degrees long term (P<0.05 Vpre/Vshort/Vlong; 99 limbs). Hip PROM midpoint improved from 23+/-9 degrees (Vpre) to 8+/-11 degrees (Vshort) and relapsed to 14+/-13 degrees (P<0.01 Vpre/Vshort/Vlong). Persistent hip internal rotation was noted in 41% (kinematics) and 18% (PROM) of limbs at Vshort (105 children, 178 limbs). Of limbs that showed initial improvement at Vshort (62 children, 95 limbs), recurrence was seen in 40% (kinematic hip rotation) and 39% (hip midpoint) at Vlong. Comparing children who had recurrent hip internal rotation and those who maintained long-term correction, we saw higher levels of spasticity and lower gait velocity in the recurrent group (P<0.05). CONCLUSIONS: Although FDO is an accepted treatment in children with CP, persistence and recurrence of hip internal rotation can occur. Recurrence is associated with spasticity and slower gait velocity. Predictor variables may be useful for surgeons during preoperative discussions of expected outcome with families of FDO candidates. LEVEL OF EVIDENCE: Level III. PMID- 26636743 TI - Mechanism of product inhibition for cellobiohydrolase Cel7A during hydrolysis of insoluble cellulose. AB - The cellobiohydrolase cellulase Cel7A is extensively utilized in industrial treatment of lignocellulosic biomass under conditions of high product concentrations, and better understanding of inhibition mechanisms appears central in attempts to improve the efficiency of this process. We have implemented an electrochemical biosensor assay for product inhibition studies of cellulases acting on their natural substrate, cellulose. Using this method we measured the hydrolytic rate of Cel7A as a function of both product (inhibitor) concentration and substrate load. This data enabled analyses along the lines of conventional enzyme kinetic theory. We found that the product cellobiose lowered the maximal rate without affecting the Michaelis constant, and this kinetic pattern could be rationalized by two fundamentally distinct molecular mechanisms. One was simple reversibility, that is, an increasing rate of the reverse reaction, lowering the net hydrolytic velocity as product concentrations increase. Strictly this is not a case of inhibition, as no catalytically inactive is formed. The other mechanism that matched the kinetic data was noncompetitive inhibition with an inhibition constant of 490 +/- 40 MUM. Noncompetitive inhibition implies that the inhibitor binds with comparable strength to either free enzyme or an enzymesubstrate complex, that is, that association between enzyme and substrate has no effect on the binding of the inhibitor. This mechanism is rarely observed, but we argue, that the special architecture of Cel7A with numerous subsites for binding of both substrate and product could give rise to a true noncompetitive inhibition mechanism. Biotechnol. Bioeng. 2016;113: 1178-1186. (c) 2015 Wiley Periodicals, Inc. PMID- 26636744 TI - Atomic layer deposition of Pd and Pt nanoparticles for catalysis: on the mechanisms of nanoparticle formation. AB - The deposition of Pd and Pt nanoparticles by atomic layer deposition (ALD) has been studied extensively in recent years for the synthesis of nanoparticles for catalysis. For these applications, it is essential to synthesize nanoparticles with well-defined sizes and a high density on large-surface-area supports. Although the potential of ALD for synthesizing active nanocatalysts for various chemical reactions has been demonstrated, insight into how to control the nanoparticle properties (i.e. size, composition) by choosing suitable processing conditions is lacking. Furthermore, there is little understanding of the reaction mechanisms during the nucleation stage of metal ALD. In this work, nanoparticles synthesized with four different ALD processes (two for Pd and two for Pt) were extensively studied by transmission electron spectroscopy. Using these datasets as a starting point, the growth characteristics and reaction mechanisms of Pd and Pt ALD relevant for the synthesis of nanoparticles are discussed. The results reveal that ALD allows for the preparation of particles with control of the particle size, although it is also shown that the particle size distribution is strongly dependent on the processing conditions. Moreover, this paper discusses the opportunities and limitations of the use of ALD in the synthesis of nanocatalysts. PMID- 26636745 TI - Prevalence of Psoriatic Arthritis in Primary Care Patients With Psoriasis. AB - OBJECTIVE: To estimate the prevalence of psoriatic arthritis (PsA) in primary care patients diagnosed as having psoriasis and to estimate the prevalence of musculoskeletal symptoms in psoriasis patients in primary care. METHODS: We conducted a cross-sectional study in adult primary care patients with psoriasis. Responding patients reporting pain in joints, entheses, or the lower back were interviewed by telephone to determine eligibility and, if eligible, were invited for clinical evaluation. During clinical evaluation, skin, nails, joints, and entheses were assessed. Additionally, ultrasound of the enthesis was performed by an independent trained examiner if a patient had at least 1 tender enthesis (determined by the Leeds Enthesitis Index and the Maastricht Ankylosing Spondylitis Enthesitis Score). Patients who fulfilled the Classification of Psoriatic Arthritis (CASPAR) Study Group criteria were classified as having PsA. RESULTS: We invited 2,564 psoriasis patients from databases of 97 participating general practitioners. Of 1,673 responders (65.2%), 841 (50.3%) were willing to participate. A total of 823 patients (32.1%) reported having musculoskeletal symptoms; 659 of these patients were determined to be eligible, 524 of whom were clinically evaluated. We identified 64 cases of established PsA and another 17 cases of newly diagnosed PsA, leading to a prevalence of 3.2% (95% confidence interval [95% CI] 2.5-3.9) among psoriasis patients in primary care. This prevalence would increase to 4.6% (95% CI 3.8-5.4) if PsA cases based on enthesitis were also taken into account. CONCLUSION: Among psoriasis patients in primary care, the prevalence of PsA is conservatively estimated to be 3.2%, increasing to 4.6% if enthesitis is taken into account. The prevalence of musculoskeletal symptoms among psoriasis patients is comparable with the prevalence of musculoskeletal symptoms in the general population. PMID- 26636746 TI - Comorbidity recording and predictive power of comorbidities in the Australia and New Zealand dialysis and transplant registry compared with administrative data: 2000-2010. AB - AIM: To compare comorbidity recording and predictive power of comorbidities for mortality between a clinical renal registry and a state-based hospitalisation dataset. METHODS: All patients that started renal replacement therapy (dialysis or transplant - RRT) in New South Wales between 1/07/2001 and 31/7/2010 were identified using the Australia and New Zealand Dialysis and Transplant Registry (ANZDATA) and linked to the State Admitted Patient Data Collection (APDC) and the Death Registry. Comorbidities (diabetes mellitus, coronary artery disease (CAD), chronic lung disease, peripheral vascular disease and cerebrovascular disease) were identified at the start of RRT in both datasets and compared using kappa statistics (kappa). Survival was calculated using cox proportional hazards models from the start of RRT to death date or end of study (31/07/2011). Four multivariable models were adjusted for age, gender and comorbidities to estimate the predictive power of the comorbidities as recorded in ANZDATA, APDC, either or both datasets RESULTS: We identified 6285 people (23,845 person-years follow-up). Diabetes recording had excellent agreement (94.5%, kappa = 0.88), CAD had fair to good agreement (80. 6, kappa = 0.56), with poor agreement between the two datasets for the other comorbidities. Deaths totalled 2594 (41.3%). Median follow up time was 3.3 years (IQR 1.7 to 5.4). All five comorbidities were powerful predictors of poor survival in all four models. All models had a similar predictive ability (Harrell's c = 0.71-0.72). CONCLUSION: Variable agreement exists in comorbidity recording between the ANZDATA and APDC. The comorbidities have a similar predictive ability, irrespective of dataset of origin in an End Stage Kidney Disease (ESKD) population. PMID- 26636747 TI - Effectiveness of palivizumab in children with childhood interstitial lung disease: The French experience. AB - INTRODUCTION: There is a lack of evidence concerning the effectiveness of immunoprophylaxis with palivizumab in children with childhood interstitial lung disease (chILD). In this retrospective study, we evaluated the effectiveness of palivizumab for decreasing the rate of RSV-related hospitalizations in children under the age of 24 months with chILD treated with corticosteroids. METHODS: A retrospective national study was conducted in France. Patients born between 2007 and 2013, diagnosed with chILD and on corticosteroid treatment were identified through the French online database for pediatric interstitial lung disease (Respirare((r)) ). Data were collected for the etiology and severity of chILD, risk factors and preventive measures for bronchiolitis, palivizumab immunoprophylaxis, and hospitalizations for bronchiolitis and RSV-bronchiolitis. RESULTS: We included and evaluated 24 children during their first two RSV seasons, corresponding to 36 patient-seasons. The observed rate of RSV-related hospitalization (305/1000 patient-seasons), and the median length of stay (7 days), were higher than those for the general population. RSV-related hospitalization rates did not differ significantly between children with and without palivizumab prophylaxis (5/16 vs. 4/18, respectively, P = 0.70). CONCLUSION: Children with chILD on corticosteroid treatment are at high risk of hospitalization for RSV-bronchiolitis, which tends to be more severe in these children than in the general population. The effectiveness of palivizumab prophylaxis in this population remains to be demonstrated. Pediatr Pulmonol. 2016;51:688-695. (c) 2015 Wiley Periodicals, Inc. PMID- 26636748 TI - Unclear ulcerations on the lower extremities in a 30-year-old man. PMID- 26636749 TI - Management of Anesthesia in a Child with a Large Neck Rhabdoid Tumor. AB - OBJECTIVE: The aim of this paper was to report the management of anesthesia of a child with a large neck rhabdoid tumor. CLINICAL PRESENTATION AND INTERVENTION: A 9-month- old female patient underwent urgent neck tumor excision due to intratumoral bleeding from a large tumor that compressed and dislocated the trachea; therefore, intubation was expected to be difficult. Sevoflurane inhalation induction was utilized to maintain spontaneous respiration. Oral laryngoscopy revealed Cormack-Lehane grade 3 laryngeal view. The trachea was intubated using a reinforced tube on the third attempt. Fiberoptic bronchoscope assisted intubation was planned as an alternative in case of conventional intubation failure. Anticipation of massive blood loss necessitated central venous catheterization. CONCLUSION: Establishing a safe airway, intubation during spontaneous breathing and invasive hemodynamic monitoring are crucial factors in the anesthetic management of pediatric patients with a large neck tumor. PMID- 26636750 TI - Transient Horizontal Gaze Palsy in a One-Month-Old Boy after a Fall. AB - A 1-month-old boy was evaluated after a fall from a height of 3 feet and found to have right parietal skull fracture as well as right and left frontal traumatic hemorrhage. Ten days after the injury, he represented with a persistent left gaze preference. Further workup including MRI and EEG determined that this finding was most likely due to a small, focal, left-frontal eye field lesion. We review the horizontal gaze pathway and demonstrate that this is present at this very young age, and that a very focal and relatively minor injury can cause gaze disturbance. PMID- 26636751 TI - Individual and Complementary Effects of Human Papillomavirus Oncogenes on Epithelial Cell Proliferation and Differentiation. AB - Previous studies on human papillomavirus (HPV) type 16 protein functions have established the oncogenic nature of three viral proteins: E5, E6 and E7. Here we have studied the functions of these proteins by functional deletion of the individual E5, E6 or E7, or both E6 and E7 oncogenes in the context of the whole viral genome. These mutants, or the intact wild-type genome, were expressed from the natural viral promoters along with differentiation of epithelial HaCaT cells in three-dimensional collagen raft cultures. High episomal viral copy numbers were obtained using a transfection-based loxp-HPV16-eGFP-N1 vector system. All epithelial equivalents carrying the different HPV type 16 genomes showed pronounced hyperplastic and dysplastic morphology. Particularly the E7 oncogene, with contribution of E6, was shown to enhance cell proliferation. Specifically, the crucial role of E7 in HPV-associated hyperproliferation was clearly manifested. Based on morphological characteristics, immunohistochemical staining for differentiation and proliferation markers, and low expression of E1^E4, we propose that our raft culture models produce cervical intraepithelial neoplasia (CIN)1 and CIN2-like tissue. Our experimental setting provides an alternative tool to study concerted functions of HPV proteins in the development of epithelial dysplasia. PMID- 26636752 TI - Mechanism of Na(+)-dependent citrate transport from the structure of an asymmetrical CitS dimer. AB - The common human pathogen Salmonella enterica takes up citrate as a nutrient via the sodium symporter SeCitS. Uniquely, our 2.5 A x-ray structure of the SeCitS dimer shows three different conformations of the active protomer. One protomer is in the outside-facing state. Two are in different inside-facing states. All three states resolve the substrates in their respective binding environments. Together with comprehensive functional studies on reconstituted proteoliposomes, the structures explain the transport mechanism in detail. Our results indicate a six step process, with a rigid-body 31 degrees rotation of a helix bundle that translocates the bound substrates by 16 A across the membrane. Similar transport mechanisms may apply to a wide variety of related and unrelated secondary transporters, including important drug targets. PMID- 26636753 TI - Gene Expression Switching of Receptor Subunits in Human Brain Development. AB - Synaptic receptors in the human brain consist of multiple protein subunits, many of which have multiple variants, coded by different genes, and are differentially expressed across brain regions and developmental stages. The brain can tune the electrophysiological properties of synapses to regulate plasticity and information processing by switching from one protein variant to another. Such condition-dependent variant switch during development has been demonstrated in several neurotransmitter systems including NMDA and GABA. Here we systematically detect pairs of receptor-subunit variants that switch during the lifetime of the human brain by analyzing postmortem expression data collected in a population of donors at various ages and brain regions measured using microarray and RNA-seq. To further detect variant pairs that co-vary across subjects, we present a method to quantify age-corrected expression correlation in face of strong temporal trends. This is achieved by computing the correlations in the residual expression beyond a cubic-spline model of the population temporal trend, and can be seen as a nonlinear version of partial correlations. Using these methods, we detect multiple new pairs of context dependent variants. For instance, we find a switch from GLRA2 to GLRA3 that differs from the known switch in the rat. We also detect an early switch from HTR1A to HTR5A whose trends are negatively correlated and find that their age-corrected expression is strongly positively correlated. Finally, we observe that GRIN2B switch to GRIN2A occurs mostly during embryonic development, presumably earlier than observed in rodents. These results provide a systematic map of developmental switching in the neurotransmitter systems of the human brain. PMID- 26636754 TI - Does endoscopic sphincterotomy reduce the risk of post-endoscopic retrograde cholangiopancreatography pancreatitis after biliary stenting? A systematic review and meta-analysis. AB - BACKGROUND AND AIM: Endoscopic biliary sphincterotomy (ES) is often carried out prior to placement of a biliary stent apparently to reduce the risk of post endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP). However, the protective effect of ES prior to biliary stenting is controversial. The objective of this meta-analysis is to compare the risk of PEP and other complications after the placement of biliary stent with or without ES in patients with biliary obstruction and bile leak. METHODS: We carried out a systematic search in several electronic databases for randomized controlled trials (RCT) and observational studies (OS) comparing the risk of PEP after biliary stenting with or without ES. The Mantel-Haenszel method was used to pool data of adverse outcomes into fixed or random effect model meta-analyses. RESULTS: Seventeen studies (five RCT and 12 OS) with a total of 2710 patients met the inclusion criteria. No significant difference was observed in the risk of PEP with biliary stenting with and without ES (RD -0.01; 95% confidence interval [CI] -0.03, 0.01). In a subgroup analysis of stenting for biliary obstruction, no difference in the risk of PEP was observed with or without ES. However, ES was associated with lower risk of PEP in patients undergoing biliary stenting for bile leak (RD 0.05; CI -0.10, -0.01). CONCLUSIONS: ES shows risk reduction in prevention of PEP in patients undergoing endoscopic stenting for bile leak. However, placement of biliary stent without ES is not associated with an increased risk of PEP in patients with distal bile duct obstruction with involvement of pancreatic duct. PMID- 26636755 TI - Metagenomic evidence for the presence of phototrophic Gemmatimonadetes bacteria in diverse environments. AB - Gemmatimonadetes represents a poorly understood bacterial phylum with only a handful of cultured species. Recently, one of its few representatives, Gemmatimonas phototrophica, was found to contain purple bacterial photosynthetic reaction centres. However, almost nothing is known about the environmental distribution of phototrophic Gemmatimonadetes bacteria. To fill this gap, we took advantage of fast-growing public metagenomic databases and performed an extensive survey of metagenomes deposited into the NCBI's WGS database, the JGI's IMG webserver and the MG-RAST webserver. By employing Mg protoporphyrin IX monomethyl ester oxidative cyclase (AcsF) as a marker gene, we identified 291 AcsF fragments (24-361 amino acids long) that are closely related to G. phototrophica from 161 metagenomes originating from various habitats, including air, river waters/sediment, estuarine waters, lake waters, biofilms, plant surfaces, intertidal sediment, soils, springs and wastewater treatment plants, but none from marine waters or sediment. Based on AcsF hit counts, phototrophic Gemmatimonadetes bacteria make up 0.4-11.9% of whole phototrophic microbial communities in these habitats. Unexpectedly, an almost complete 37.9 kb long photosynthesis gene cluster with identical gene composition and arrangement to those in G. phototrophica was reconstructed from the Odense wastewater metagenome, only differing in a 7.2 kb long non-photosynthesis-gene insert. These data suggest that phototrophic Gemmatimonadetes bacteria are much more widely distributed in the environment and exhibit a higher genetic diversity than previously thought. PMID- 26636758 TI - Correction: Influence of Schistosoma mansoni and Hookworm Infection Intensities on Anaemia in Ugandan Villages. PMID- 26636757 TI - Uptake of and Resistance to the Antibiotic Berberine by Individual Dormant, Germinating and Outgrowing Bacillus Spores as Monitored by Laser Tweezers Raman Spectroscopy. AB - Berberine, an alkaloid originally extracted from the plant Coptis chinensis and other herb plants, has been used as a pharmacological substance for many years. The therapeutic effect of berberine has been attributed to its interaction with nucleic acids and blocking cell division. However, levels of berberine entering individual microbial cells minimal for growth inhibition and its effects on bacterial spores have not been determined. In this work the kinetics and levels of berberine accumulation by individual dormant and germinated spores were measured by laser tweezers Raman spectroscopy and differential interference and fluorescence microscopy, and effects of berberine on spore germination and outgrowth and spore and growing cell viability were determined. The major conclusions from this work are that: (1) colony formation from B. subtilis spores was blocked ~ 99% by 25 MUg/mL berberine plus 20 MUg/mL INF55 (a multidrug resistance pump inhibitor); (2) 200 MUg/mL berberine had no effect on B. subtilis spore germination with L-valine, but spore outgrowth was completely blocked; (3) berberine levels accumulated in single spores germinating with >= 25 MUg/mL berberine were > 10 mg/mL; (4) fluorescence microscopy showed that germinated spores accumulated high-levels of berberine primarily in the spore core, while dormant spores accumulated very low berberine levels primarily in spore coats; and (5) during germination, uptake of berberine began at the time of commitment (T1) and reached a maximum after the completion of CaDPA release (Trelease) and spore cortex lysis (Tlysis). PMID- 26636759 TI - Characteristics of the Norwegian Coastal Current during Years with High Recruitment of Norwegian Spring Spawning Herring (Clupea harengus L.). AB - Norwegian Spring Spawning herring (NSSH) Clupea harengus L. spawn on coastal banks along the west coast of Norway. The larvae are generally transported northward in the Norwegian Coastal Current (NCC) with many individuals utilizing nursery grounds in the Barents Sea. The recruitment to this stock is highly variable with a few years having exceptionally good recruitment. The principal causes of recruitment variability of this herring population have been elusive. Here we undertake an event analysis using data between 1948 and 2010 to gain insight into the physical conditions in the NCC that coincide with years of high recruitment. In contrast to a typical year when northerly upwelling winds are prominent during spring, the years with high recruitment coincide with predominantly southwesterly winds and weak upwelling in spring and summer, which lead to an enhanced northward coastal current during the larval drift period. Also in most peak recruitment years, low-salinity anomalies are observed to propagate northward during the spring and summer. It is suggested that consistent southwesterly (downwelling) winds and propagating low-salinity anomalies, both leading to an enhanced northward transport of larvae, are important factors for elevated recruitment. At the same time, these conditions stabilize the coastal waters, possibly leading to enhanced production and improved feeding potential along the drift route to Barents Sea. Further studies on the drivers of early life history mortality can now be undertaken with a better understanding of the physical conditions that prevail during years when elevated recruitment occurs in this herring stock. PMID- 26636760 TI - Comparison of a New Miniaturized Extracorporeal Membrane Oxygenation System With Integrated Rotary Blood Pump to a Standard System in a Porcine Model of Acute Lung Injury. AB - Extracorporeal membrane oxygenation (ECMO) is used for severe acute respiratory distress syndrome. However, available ECMO systems are large and not well designed for fast delivery, emergency implantation, and interhospital transfer. Therefore, a new miniaturized oxygenator with integrated rotary blood pump (ILIAS) was developed and compared with a standard ECMO system in a large animal model. Acute lung injury was induced with repeated pulmonary saline lavage in 14 pigs until PaO2 /FiO2 -ratio was <100 mm Hg with a positive-end-expiratory pressure of 5 mbar. Pigs were assigned to the following three groups: group 1 (n = 4): control group with conventional ventilation; group 2 (n = 5): standard vv ECMO; group 3 (n = 5): vv-ILIAS. Gas exchange, hemodynamics, hemolysis, and coagulation activation were examined over a period of 8 h. No device failed during the observation period. PaCO2 decreased from 59.40 +/- 4.14 mm Hg to 48.62 +/- 4.50 mm Hg after 1 h in the ILIAS group compared with an improvement of PaCO2 from 48.86 +/- 7.45 to 40.10 +/- 6.02 in the conventional ECMO group (P = not significant [n.s.]). ARDS-induced respiratory acidosis was controlled promptly with a pH of 7.2 +/- 0.1 at baseline increasing to 7.4 +/- 0.1 in both study groups after 60 min of ECMO support. Mean carbon dioxide transfer was comparable between the conventional ECMO and ILIAS (211.36 +/- 78.39 mL/min vs. 219.99 +/- 76.72 mL/min, P = n.s.). PaO2 /FiO2 increased from 118.4 +/- 15.5 mm Hg to 179.1 +/- 72.4 mm Hg in the ILIAS group compared with an improvement of oxygenation from 107.1 +/- 24.9 mm Hg to 179.0 +/- 45.7 mm Hg in the standard ECMO group (P = n.s.). Mean oxygen transfer was calculated with 136.09 +/- 30.25 mL/min for the ILIAS and 129.05 +/- 36.28 mL/min for the standard ECMO. Hemodynamic instability or significant activation of the plasmatic coagulation was not observed. However, hemolysis was significantly higher in the ILIAS group compared with the conventional ECMO. As the ILIAS prototype provided excellent gas exchange with hemodynamic stability comparable with a standard ECMO system, we believe this study serves as a proof of concept. Further development and design modifications (optimized rotation speed and surface coating of rotor) are already done and another experiment is projected to reduce hemolysis and platelet consumption for clinical application. PMID- 26636761 TI - MicroRNA-122 Inhibits the Production of Inflammatory Cytokines by Targeting the PKR Activator PACT in Human Hepatic Stellate Cells. AB - MicroRNA-122 (miR-122) is one of the most abundant miRs in the liver. Previous studies have demonstrated that miR-122 plays a role in inflammation in the liver and functions in hepatic stellate cells (HSCs), which reside in the space of Disse. Here, we showed that the transient inhibition of PKR-activating protein (PACT) expression, by miR-122 or siRNA targeting of PACT, suppressed the production of proinflammatory cytokines, such as interleukin (IL)-6, monocyte chemoattractant protein-1 (MCP-1) and IL-1beta, in human HSC LX-2. Sequence and functional analyses confirmed that miR-122 directly targeted the 3'-untranslated region of PACT. Immunofluorescence analysis revealed that miR-122 blocked NF kappaB-nuclear translocation in LX-2 cells. We also showed that conditioned medium from miR-122-transfected LX-2 cells suppressed human monocyte-derived THP 1 cell migration. Taken together, our study indicates that miR-122 may downregulate cytokine production in HSCs and macrophage chemotaxis and that the targeting of miR-122 may have therapeutic potential for preventing the progression of liver diseases. PMID- 26636762 TI - Treatment Planning and Delivery of Whole Brain Irradiation with Hippocampal Avoidance in Rats. AB - BACKGROUND: Despite the clinical benefit of whole brain radiotherapy (WBRT), patients and physicians are concerned by the long-term impact on cognitive functioning. Many studies investigating the molecular and cellular impact of WBRT have used rodent models. However, there has not been a rodent protocol comparable to the recently reported Radiation Therapy Oncology Group (RTOG) protocol for WBRT with hippocampal avoidance (HA) which is intended to spare cognitive function. The aim of this study was to develop a hippocampal-sparing WBRT protocol in Wistar rats. METHODS: The technical and clinical challenges encountered in hippocampal sparing during rat WBRT are substantial. Three key challenges were identified: hippocampal localization, treatment planning, and treatment localization. Hippocampal localization was achieved with sophisticated imaging techniques requiring deformable registration of a rat MRI atlas with a high resolution MRI followed by fusion via rigid registration to a CBCT. Treatment planning employed a Monte Carlo dose calculation in SmART-Plan and creation of 0.5 cm thick lead blocks custom-shaped to match DRR projections. Treatment localization necessitated the on-board image-guidance capability of the XRAD C225Cx micro-CT/micro-irradiator (Precision X-Ray). Treatment was accomplished with opposed lateral fields with 225 KVp X-rays at a current of 13 mA filtered through 0.3 mm of copper using a 40x40 mm square collimator and the lead blocks. A single fraction of 4 Gy was delivered (2 Gy per lateral field) with a 41 second beam on time per field at a dose rate of 304.5 cGy/min. Dosimetric verification of hippocampal sparing was performed using radiochromic film. In vivo verification of HA was performed after delivery of a single 4 Gy fraction either with or without HA using gamma-H2Ax staining of tissue sections from the brain to quantify the amount of DNA damage in rats treated with HA, WBRT, or sham-irradiated (negative controls). RESULTS: The mean dose delivered to radiochromic film beneath the hippocampal block was 0.52 Gy compared to 3.93 Gy without the block, indicating an 87% reduction in the dose delivered to the hippocampus. This difference was consistent with doses predicted by Monte Carlo dose calculation. The Dose Volume Histogram (DVH) generated via Monte Carlo simulation showed an underdose of the target volume (brain minus hippocampus) with 50% of the target volume receiving 100% of the prescription isodose as a result of the lateral blocking techniques sparing some midline thalamic and subcortical tissue. Staining of brain sections with anti-phospho-Histone H2A.X (reflecting double-strand DNA breaks) demonstrated that this treatment protocol limited radiation dose to the hippocampus in vivo. The mean signal intensity from gamma-H2Ax staining in the cortex was not significantly different from the signal intensity in the cortex of rats treated with WBRT (5.40 v. 5.75, P = 0.32). In contrast, the signal intensity in the hippocampus of rats treated with HA was significantly lower than rats treated with WBRT (4.55 v. 6.93, P = 0.012). CONCLUSION: Despite the challenges of planning conformal treatments for small volumes in rodents, our dosimetric and in vivo data show that WBRT with HA is feasible in rats. This study provides a useful platform for further application and refinement of the technique. PMID- 26636763 TI - Cleaved thin-film probes for scanning tunneling microscopy. AB - We introduce an alternative type of probe for scanning tunneling microscopy (STM). Instead of using a needle-like tip made from a piece of metallic wire, a sharp-edged cleaved insulating substrate, which is initially covered by a thin conductive film, is used. The sharp tip is formed at the intersection of the two cleaved sides. Using this approach a variety of materials for STM probes can be used, and functionalization of STM probes is possible. The working principle of different probes made of metallic (Pt, Co, and CoB), indium-tin oxide, as well as Cu/Pt and Co/Pt multilayer films are demonstrated by STM imaging of clean Cu(001) and Cu(111) surfaces as well as the epitaxial Co clusters on Cu(111). PMID- 26636764 TI - Asymmetric Conjugate Alkynylation of Cyclic alpha,beta-Unsaturated Carbonyl Compounds with a Chiral Diene Rhodium Catalyst. AB - Asymmetric conjugate alkynylation of cyclic alpha,beta-unsaturated carbonyl compounds (ketones, esters, and amides) was realized by use of diphenyl[(triisopropylsilyl)ethynyl]methanol as an alkynylating reagent in the presence of a rhodium catalyst coordinated with a new chiral diene ligand (Fc bod; bod=bicyclo[2.2.2]octa-2,5-diene, Fc=ferrocenyl) to give high yields of the corresponding beta-alkynyl-substituted carbonyl compounds with 95-98% ee. PMID- 26636765 TI - Expression and Quorum Sensing Regulation of Type III Secretion System Genes of Vibrio harveyi during Infection of Gnotobiotic Brine Shrimp. AB - Type III secretion systems enable pathogens to inject their virulence factors directly into the cytoplasm of the host cells. The type III secretion system of Vibrio harveyi, a major pathogen of aquatic organisms and a model species in quorum sensing studies, is repressed by the quorum sensing master regulator LuxR. In this study, we found that during infection of gnotobiotic brine shrimp larvae, the expression levels of three type III secretion operons in V. harveyi increased within the first 12h after challenge and decreased again thereafter. The in vivo expression levels were highest in a mutant with a quorum sensing system that is locked in low cell density configuration (minimal LuxR levels) and lowest in a mutant with a quorum sensing system that is locked in the high cell density configuration (maximal LuxR levels), which is consistent with repression of type III secretion by LuxR. Remarkably, in vivo expression levels of the type III secretion system genes were much (> 1000 fold) higher than the in vitro expression levels, indicating that (currently unknown) host factors significantly induce the type III secretion system. Given the fact that type III secretion is energy-consuming, repression by the quorum sensing master regulators might be a mechanism to save energy under conditions where it does not provide an advantage to the cells. PMID- 26636766 TI - Extending the Paradigm of Osteoarthritis: Comment on the Editorial by McAlindon. PMID- 26636767 TI - Relationships between Chromosome 7 Gain, MET Gene Copy Number Increase and MET Protein Overexpression in Chinese Papillary Renal Cell Carcinoma Patients. AB - To investigate the relationships between Chromosome 7 gain, mesenchymal epithelial transition factor (MET) gene copy number increase and MET protein overexpression in Chinese patients with papillary renal cell carcinoma (PRCC), immunohistochemistry (IHC), immunofluorescence (IF) and fluorescence in situ hybridization (FISH) were performed on 98 formalin-fixed, paraffin-embedded (FFPE) PRCC samples. Correlations between MET gene copy number increase, Chromosome 7 gain and MET protein overexpression were analyzed statistically. A highly significant correlation was observed between the percentage of tumor cells with MET gene copy number >=3 and CEP7 copy number >=3 (R2 = 0.90, p<0.001) across two subtypes of PRCC. In addition, the percentage of tumor cells with MET gene copy number >=3 was found to increase along with increases in MET IHC score. This correlation was further confirmed in those PRCC tumor cells with average MET gene copy number >5 using combined IF and FISH methodology. Overall, this study provides evidence that Chromosome 7 gain drives MET gene copy number increase in PRCC tumors, and appears to subsequently lead to an increase in MET protein overexpression in these tumor cells. This supports MET activation as a potential therapeutic target in sporadic PRCC. PMID- 26636768 TI - The Analysis of Intracellular and Intercellular Calcium Signaling in Human Anterior Lens Capsule Epithelial Cells with Regard to Different Types and Stages of the Cataract. AB - In this work we investigated how modifications of the Ca2+ homeostasis in anterior lens epithelial cells (LECs) are associated with different types of cataract (cortical or nuclear) and how the progression of the cataract (mild or moderate) affects the Ca2+ signaling. We systematically analyzed different aspects of intra- and inter-cellular Ca2+ signaling in the human LECs, which are attached to surgically isolated lens capsule (LC), obtained during cataract surgery. We monitored the temporal and spatial changes in intracellular Ca2+ concentration after stimulation with acetylcholine by means of Fura-2 fluorescence captured with an inverted microscope. In our analysis we compared the features of Ca2+ signals in individual cells, synchronized activations, spatio-temporal grouping and the nature of intercellular communication between LECs. The latter was assessed by using the methodologies of the complex network theory. Our results point out that at the level of individual cells there are no significant differences when comparing the features of the signals with regard either to the type or the stage of the cataract. On the other hand, noticeable differences are observed at the multicellular level, despite inter-capsule variability. LCs associated with more developed cataracts were found to exhibit a slower collective response to stimulation, a less pronounced spatio-temporal clustering of LECs with similar signaling characteristics. The reconstructed intercellular networks were found to be sparser and more segregated than in LCs associated with mild cataracts. Moreover, we show that spontaneously active LECs often operate in localized groups with quite well aligned Ca2+ activity. The presence of spontaneous activity was also found to affect the stimulated Ca2+ responses of individual cells. Our findings indicate that the cataract progression entails the impairment of intercellular signaling thereby suggesting the functional importance of altered Ca2+ signaling of LECs in cataractogenesis. PMID- 26636769 TI - Upregulation of Bone Morphogenetic Protein-2 Synthesis and Consequent Collagen II Expression in Leptin-stimulated Human Chondrocytes. AB - Bone morphogenetic proteins (BMPs) play positive roles in cartilage development, but they can barely be detected in healthy articular cartilage. However, recent evidence has indicated that BMPs could be detected in osteoarthritic and damaged cartilage and their precise roles have not been well defined. Extremely high amounts of leptin have been reported in obese individuals, which can be associated with osteoarthritis (OA) development. The aim of this study was to investigate whether BMPs could be induced in human primary chondrocytes during leptin-stimulated OA development and the underlying mechanism. We found that expression of BMP-2 mRNA, but not BMP-4, BMP-6, or BMP-7 mRNA, could be increased in human primary chondrocytes under leptin stimulation. Moreover, this BMP-2 induction was mediated through transcription factor-signal transducer and activator of transcription (STAT) 3 activation via JAK2-ERK1/2-induced Ser727 phosphorylation. Of note, histone deacetylases (HDACs) 3 and 4 were both involved in modulating leptin-induced BMP-2 mRNA expression through different pathways: HDAC3, but not HDAC4, associated with STAT3 to form a complex. Our results further demonstrated that the role of BMP-2 induction under leptin stimulation is to increase collagen II expression. The findings in this study provide new insights into the regulatory mechanism of BMP-2 induction in leptin-stimulated chondrocytes and suggest that BMP-2 may play a reparative role in regulating leptin-induced OA development. PMID- 26636770 TI - Elucidation of the zinc-dependent regulation in Amycolatopsis japonicum enabled the identification of the ethylenediamine-disuccinate ([S,S]-EDDS) genes. AB - The actinomycete Amycolatopsis japonicum produces the complexing agent ethylenediamine-disuccinate ([S,S]-EDDS), which is an isomer of the widely industrially applied ethylenediamine-tetraacetate (EDTA). In contrast to EDTA, [S,S]-EDDS is readily biodegradable and is therefore an alternative with a favourable environmental profile. Biotechnological production of [S,S]-EDDS, however, is not currently possible because its biosynthesis is inhibited by low micromolar zinc concentrations. Here we illustrate the development of a new strategy for identifying a biosynthetic pathway that is based on the elucidation of transcriptional regulation and the screening for binding sites of the respective regulator that controls the [S,S]-EDDS biosynthesis genes. To achieve this, we identified the zinc uptake regulator Zur in A. japonicum and showed that it mediates the repression of the zinc uptake system ZnuABCAj . The Zur-binding motif, recognized by the zinc-bound Zur protein in the upstream region of znuABCAj , was used to screen the genome, leading to the identification of the aes genes. Transcriptional analysis and shift assays reveal specific zinc responsive regulation of the aes genes by Zur, and gene inactivation shows their involvement in [S,S]-EDDS biosynthesis. Zur-mediated zinc repression of the [S,S] EDDS biosynthesis genes is abolished in a Deltazur mutant, which offers now the opportunity to develop a biotechnological process. PMID- 26636771 TI - 'He is the one who is providing you with everything so whatever he says is what you do': A Qualitative Study on Factors Affecting Secondary Schoolgirls' Dropout in Rural Western Kenya. AB - Education is an effective way to improve girls' self-worth, health, and productivity; however there remains a gender gap between girls' and boys' completion of school. The literature around factors influencing girls' decision to stay in school is limited. Seven focus group discussions took place among 79 girls in forms 2 to 4 at secondary schools in rural western Kenya, to examine their views on why girls absent themselves or dropout from school. Data were analysed thematically. Lack of resources, sexual relationships with boyfriends, and menstrual care problems were reported to lead directly to dropout or school absence. These were tied to girls increased vulnerability to pregnancy, poor performance in school, and punishments, which further increase school absence and risk of dropout. Poverty, unmet essential needs, coercive sexual relationships, and an inequitable school environment collude to counter girls' resolve to complete their schooling. Lack of resources drive girls to have sex with boyfriends or men who provide them with essentials their family cannot afford, such as sanitary pads and transport to school. While these improve quality of their school life, this dynamic increases their exposure to sexual risk, pregnancy, punishment, and dropout. Evaluation of interventions to ameliorate these challenges is warranted, including provision of pocket money to address their needs. PMID- 26636772 TI - Hierarchical Metal-Organic Framework Hybrids: Perturbation-Assisted Nanofusion Synthesis. AB - Metal-organic frameworks (MOFs) represent a new family of microporous materials; however, microporous-mesoporous hierarchical MOF materials have been less investigated because of the lack of simple, reliable methods to introduce mesopores to the crystalline microporous particles. State-of-the-art MOF hierarchical materials have been prepared by ligand extension methods or by using a template, resulting in intrinsic mesopores of longer ligands or replicated pores from template agents, respectively. However, mesoporous MOF materials obtained through ligand extension often collapse in the absence of guest molecules, which dramatically reduces the size of the pore aperture. Although the template-directed strategy allows for the preparation of hierarchical materials with larger mesopores, the latter requires a template removal step, which may result in the collapse of the implemented mesopores. Recently, a general template free synthesis of hierarchical microporous crystalline frameworks, such as MOFs and Prussian blue analogues (PBAs), has been reported. This new method is based on the kinetically controlled precipitation (perturbation), with simultaneous condensation and redissolution of polymorphic nanocrystallites in the mother liquor. This method further eliminates the use of extended organic ligands and the micropores do not collapse upon removal of trapped guest solvent molecules, thus yielding hierarchical MOF materials with intriguing porosity in the gram scale. The hierarchical MOF materials prepared in this way exhibited exceptional properties when tested for the adsorption of large organic dyes over their corresponding microporous frameworks, due to the enhanced pore accessibility and electrolyte diffusion within the mesopores. As for PBAs, the pore size distribution of these materials can be tailored by changing the metals substituting Fe cations in the PB lattice. For these, the textural mesopores increased from approximately 10 nm for Cu analogue (mesoCuHCF), to 16 nm in Co substituted compound (mesoCoHCF), and to as large as 30 nm for the Ni derivative (mesoNiHCF). While bulk PB and analogues have a higher capacitance than hierarchical analogues for Na-batteries, the increased accessibility to the microporous channels of PBAs allow for faster intercalated ion exchange and diffusion than in bulk PBA crystals. Thus, hierarchical PBAs are promising candidates for electrodes in future electrochemical energy storage devices with faster charge-discharge rates than batteries, namely pseudocapacitors. Finally, this new synthetic method opens the possibility to prepare hierarchical materials having bimodal distribution of mesopores, and to tailor the structural properties of MOFs for different applications, including contrasting agents for MRI, and drug delivery. PMID- 26636773 TI - A General Method for Extracting Individual Coupling Constants from Crowded (1)H NMR Spectra. AB - Couplings between protons, whether scalar or dipolar, provide a wealth of structural information. Unfortunately, the high number of (1)H-(1)H couplings gives rise to complex multiplets and severe overlap in crowded spectra, greatly complicating their measurement. Many different methods exist for disentangling couplings, but none approaches optimum resolution. Here, we present a general new 2D J-resolved method, PSYCHEDELIC, in which all homonuclear couplings are suppressed in F2, and only the couplings to chosen spins appear, as simple doublets, in F1. This approaches the theoretical limit for resolving (1)H-(1)H couplings, with close to natural linewidths and with only chemical shifts in F2. With the same high sensitivity and spectral purity as the parent PSYCHE pure shift experiment, PSYCHEDELIC offers a robust method for chemists seeking to exploit couplings for structural, conformational, or stereochemical analyses. PMID- 26636774 TI - Chemical Synthesis of Proteins with Non-Strategically Placed Cysteines Using Selenazolidine and Selective Deselenization. AB - Although native chemical ligation has enabled the synthesis of hundreds of proteins, not all proteins are accessible through typical ligation conditions. The challenging protein, 125-residue human phosphohistidine phosphatase 1 (PHPT1), has three cysteines near the C-terminus, which are not strategically placed for ligation. Herein, we report the first sequential native chemical ligation/deselenization reaction. PHPT1 was prepared from three unprotected peptide segments using two ligation reactions at cysteine and alanine junctions. Selenazolidine was utilized as a masked precursor for N-terminal selenocysteine in the middle segment, and, following ligation, deselenization provided the native alanine residue. This approach was used to synthesize both the wild-type PHPT1 and an analogue in which the active-site histidine was substituted with the unnatural and isosteric amino acid beta-thienyl-l-alanine. The activity of both proteins was studied and compared, providing insights into the enzyme active site. PMID- 26636775 TI - Expanding the Chemistry of Molecular U(2+) Complexes: Synthesis, Characterization, and Reactivity of the {[C5 H3 (SiMe3 )2 ]3 U}(-) Anion. AB - The synthesis of new molecular complexes of U(2+) has been pursued to make comparisons in structure, physical properties, and reactivity with the first U(2+) complex, [K(2.2.2-cryptand)][Cp'3 U], 1 (Cp'=C5 H4 SiMe3 ). Reduction of Cp''3 U [Cp''=C5 H3 (SiMe3 )2 ] with KC8 in the presence of 2.2.2-cryptand or 18 crown-6 generates [K(2.2.2-cryptand)][Cp''3 U], 2-K(crypt), or [K(18-crown 6)(THF)2 ][Cp''3 U], 2-K(18c6), respectively. The UV/Vis spectra of 2-K and 1 are similar, and they are much more intense than those of U(3+) analogues. Variable temperature magnetic susceptibility data for 1 and 2-K(crypt) reveal lower room temperature chiM T values relative to the experimental values for the 5f(3) U(3+) precursors. Stability studies monitored by UV/Vis spectroscopy show that 2 K(crypt) and 2-K(18c6) have t1/2 values of 20 and 15 h at room temperature, respectively, vs. 1.5 h for 1. Complex 2-K(18c6) reacts with H2 or PhSiH3 to form the uranium hydride, [K(18-crown-6)(THF)2 ][Cp''3 UH], 3. Complexes 1 and 2 K(18c6) both reduce cyclooctatetraene to form uranocene, (C8 H8 )2 U, as well as the U(3+) byproducts [K(2.2.2-cryptand)][Cp'4 U], 4, and Cp''3 U, respectively. PMID- 26636822 TI - Evaluation of the Genetic Basis of Familial Aggregation of Pacemaker Implantation by a Large Next Generation Sequencing Panel. AB - BACKGROUND: The etiology of conduction disturbances necessitating permanent pacemaker (PPM) implantation is often unknown, although familial aggregation of PPM (faPPM) suggests a possible genetic basis. We developed a pan-cardiovascular next generation sequencing (NGS) panel to genetically characterize a selected cohort of faPPM. MATERIALS AND METHODS: We designed and validated a custom NGS panel targeting the coding and splicing regions of 246 genes with involvement in cardiac pathogenicity. We enrolled 112 PPM patients and selected nine (8%) with faPPM to be analyzed by NGS. RESULTS: Our NGS panel covers 95% of the intended target with an average of 229x read depth at a minimum of 15-fold depth, reaching a SNP true positive rate of 98%. The faPPM patients presented with isolated cardiac conduction disease (ICCD) or sick sinus syndrome (SSS) without overt structural heart disease or identifiable secondary etiology. Three patients (33.3%) had heterozygous deleterious variants previously reported in autosomal dominant cardiac diseases including CCD: LDB3 (p.D117N) and TRPM4 (p.G844D) variants in patient 4; TRPM4 (p.G844D) and ABCC9 (p.V734I) variants in patient 6; and SCN5A (p.T220I) and APOB (p.R3527Q) variants in patient 7. CONCLUSION: FaPPM occurred in 8% of our PPM clinic population. The employment of massive parallel sequencing for a large selected panel of cardiovascular genes identified a high percentage (33.3%) of the faPPM patients with deleterious variants previously reported in autosomal dominant cardiac diseases, suggesting that genetic variants may play a role in faPPM. PMID- 26636823 TI - Relationship between C-Reactive Protein Level and Diabetic Retinopathy: A Systematic Review and Meta-Analysis. AB - OBJECTIVES: To date, the relationship between C-reactive protein (CRP) level and diabetic retinopathy (DR) remains controversial. Therefore, a systematic review and meta-analysis was used to reveal the potential relationship between CRP level and DR. METHODS: A systematic search of PubMed, Embase.com, and Web of Science was performed to identify all comparative studies that compared the CRP level of two groups (case group and control group). We defined that diabetic patients without retinopathy and/or matched healthy persons constituted the control group, and patients with DR were the case group. RESULTS: Two cross sectional studies and twenty case control studies including a total of 3679 participants were identified. After pooling the data from all 22 studies, obvious heterogeneity existed between the studies, so a subgroup analysis and sensitivity analysis were performed. Removing the sensitivity studies, the blood CRP levels in the case group were observed to be higher than those in the control group [SMD = 0.22, 95% confidence interval (CI), 0.11-0.34], and the blood CRP levels in the proliferative diabetic retinopathy (PDR) group were also higher than those in the non-proliferative diabetic retinopathy (NPDR) group [SMD = 0.50, 95% CI, 0.30 0.70]. CONCLUSIONS: The results from this current meta-analysis indicate that the CRP level might be used as a biomarker to determine the severity of DR. PMID- 26636824 TI - Preoperative Prediction of Cervical Lymph Node Metastasis Using Primary Tumor SUVmax on 18F-FDG PET/CT in Patients with Papillary Thyroid Carcinoma. AB - OBJECTIVES: The aim of the current study was to evaluate the value of preoperative 18F-FDG (FDG) PET/CT in predicting cervical lymph node (LN) metastasis in patients with papillary thyroid carcinoma (PTC). METHODS: One hundred and ninety-three newly diagnosed PTC patients (M: F = 25:168, age = 46.8 +/- 12.2) who had undergone pretreatment FDG PET/CT and had neck node dissection were included in this study. The FDG avidity of the primary tumor and the SUVmax of the primary tumor (pSUVmax) were analyzed for prediction of LN metastasis. Detectability by ultrasonography (US) and FDG PET/CT for cervical LN metastasis were also assessed and compared with the pSUVmax. RESULTS: The FDG avidity of the primary tumor was identified in 118 patients (FDG avid group: 61.0%, M: F = 16:102, age 47.0 +/- 12.7 years) and pSUVmax ranged from 1.3 to 35.6 (median 4.6) in the FDG avid group. The tumor size in the FDG avid group was bigger and there was a higher incidence of LN metastasis compared to the FDG non-avid group (0.93 vs. 0.59 cm, p <0.001 and 49.2 vs. 33.3%, p <0.05). In the FDG avid group, patients with LN metastasis had higher pSUVmax than patients without LN metastasis (8.7 +/- 8.3 vs. 5.7 +/- 5.1, p <0.001). The incidence of central LN metastasis in patients with a pSUVmax >4.6 was 54%; however, the detectability of central LN metastasis by US and FDG PET/CT were 10.3% and 3.6%, respectively. CONCLUSION: A high FDG avidity of the primary tumor was related to LN metastasis in PTC patients. Therefore, patients with a high pSUVmax should be cautiously assessed for LN metastasis and might need a more comprehensive surgical approach. PMID- 26636825 TI - Getting to zero the biomedical way in Africa: outcomes of deliberation at the 2013 Biomedical HIV Prevention Forum in Abuja, Nigeria. AB - BACKGROUND: Over the last few decades, biomedical HIV prevention research had engaged multiple African stakeholders. There have however been few platforms to enable regional stakeholders to engage with one another. In partnership with the World AIDS Campaign International, the Institute of Public Health of Obafemi Awolowo University, and the National Agency for the Control of AIDS in Nigeria, the New HIV Vaccine and Microbicide Advocacy Society hosted a forum on biomedical HIV prevention research in Africa. Stakeholders' present explored evidences related to biomedical HIV prevention research and development in Africa, and made recommendations to inform policy, guidelines and future research agenda. DISCUSSION: The BHPF hosted 342 participants. Topics discussed included the use of antiretrovirals for HIV prevention, considerations for biomedical HIV prevention among key populations; HIV vaccine development; HIV cure; community and civil society engagement; and ethical considerations in implementation of biomedical HIV prevention research. Participants identified challenges for implementation of proven efficacious interventions and discovery of other new prevention options for Africa. Concerns raised included limited funding by African governments, lack of cohesive advocacy and policy agenda for biomedical HIV prevention research and development by Africa, varied ethical practices, and limited support to communities' capacity to actively engaged with clinical trial conducts. Participants recommended that the African Government implement the Abuja +12 declaration; the civil society build stronger partnerships with diverse stakeholders, and develop a coherent advocacy agenda that also enhances community research literacy; and researchers and sponsors of trials on the African continent establish a process for determining appropriate standards for trial conduct on the continent. CONCLUSION: By highlighting key considerations for biomedical HIV prevention research and development in Africa, the forum has helped identify key advocacy issues that Civil Society can expend efforts on so as to strengthen support for future biomedical HIV prevention research on the continent. PMID- 26636826 TI - UV Light-Induced Generation of Reactive Oxygen Species and Antimicrobial Properties of Cellulose Fabric Modified by 3,3',4,4'-Benzophenone Tetracarboxylic Acid. AB - 3,3',4,4'-Benzophenone tetracarboxylic acid (BPTCA) could directly react with hydroxyl groups on cellulose to form ester bonds. The modified cotton fabrics not only provided good wrinkle-free and ultraviolet (UV) protective functions, but also exhibited important photochemical properties such as producing reactive oxygen species (ROS) including hydroxyl radicals (HO(*)) and hydrogen peroxide (H2O2) under UV light exposure. The amounts of the produced hydroxyl radical and hydrogen peroxide were measured, and photochemical reactive mechanism of the BPTCA treated cellulose was discussed. The results reveal that the fabrics possess good washing durability in generation of hydroxyl radicals and hydrogen peroxide. The cotton fabrics modified with different concentrations of BPTCA and cured at an elevated temperature demonstrated excellent antimicrobial activities, which provided 99.99% antibacterial activities against both E. coli and S. aureus. The advanced materials have potential applications in medical textiles and biological material fields. PMID- 26636827 TI - Evaluation of Endarterectomy Recanalization under Ultrasound Guidance in Symptomatic Patients with Carotid Artery Occlusion. AB - Rigorous screening and good imaging would help perform surgery on carotid artery occlusion CAO safely and effectively. The purpose of this study was to retrospectively evaluate carotid endarterectomy (CEA) recanalization in patients with common carotid artery occlusion (CCAO) or internal carotid artery occlusion (ICAO) with color Doppler flow imaging (CDFI). A total of 59 patients undergoing CEA were enrolled. According to the results of CEA, the patients were divided into successful recanalization (group A) and unsuccessful recanalization (group B) groups. The original diameter, lesion length, proximal-to-distal diameter ratio and echo characteristics of the lesion within the lumen of the carotid artery were recorded before CEA and compared between the two groups. In regards to the achievement of repatency by CEA, the overall success rate was 74.6% (44/59), the success rate in CCAO patients was 75.9% (22/29) and the success rate in ICAO patients was 73.3% (22/30). There was no significant difference in the success rates between the CCAO and ICAO patients (chi2 = 0.050, P = 0.824). The overall rate of stroke and death within 30 postoperative days was 5.1% (3/59). For the CCAO patients, the lesion length in group A was shorter than that in group B (t = 3.221, P = 0.004). For the ICAO patients, the original diameter of the distal ICA was broader (t = 6.254, P = 0.000) and the proximal-to-distal ICA diameter ratio was smaller (t = 8.036, P = 0.000) in group A than in group B. The rate of recanalization for lumens with a homogeneous echo pattern (hypoecho or isoecho) was significantly higher than that for lumens with echo heterogeneity for both the CCAO and ICAO patients (chi2 = 14.477, P = 0.001; chi2 = 10.519, P = 0.003). However, for both the CCAO and ICAO patients, there was no difference in the rate of recanalization between patients with hypoecho and isoecho lesions (chi2 = 0.109, P = 0.742; chi2 = 0.836, P = 0.429). The original diameter, proximal-to-distal ICA diameter ratio, lesion length and echo characteristics may affect the success of CEA recanalization in patients with CCAO and ICAO. CDFI is helpful in screening patients with carotid artery occlusion and may improve the success rate of CEA. PMID- 26636828 TI - Molecular Dynamics of Multivalent Soluble Antigen Arrays Support a Two-Signal Co delivery Mechanism in the Treatment of Experimental Autoimmune Encephalomyelitis. AB - Many current therapies for autoimmune diseases such as multiple sclerosis (MS) result in global immunosuppression, rendering insufficient efficacy with increased risk of adverse side effects. Multivalent soluble antigen arrays, nanomaterials presenting both autoantigen and secondary inhibitory signals on a flexible polymer backbone, are hypothesized to shift the immune response toward selective autoantigenic tolerance to repress autoimmune disease. Two-signal co delivery of both autoantigen and secondary signal were deemed necessary for therapeutic efficacy against experimental autoimmune encephalomyelitis, a murine model of MS. Dynamic light scattering and in silico molecular dynamics simulations complemented these studies to illuminate the role of two-signal co delivery in determining therapeutic potential. Physicochemical characteristics such as particle size and molecular affinity for intermolecular interactions and chain entanglement likely facilitated cotransport of two signals to produce efficacy. These findings elucidate potential mechanisms whereby soluble antigen arrays enact their therapeutic effect and help to guide the development of future multivalent antigen-specific immunotherapies. PMID- 26636829 TI - Development of a Direct and Continuous Phospholipase D Assay Based on the Chelation-Enhanced Fluorescence Property of 8-Hydroxyquinoline. AB - Through its production of phosphatidic acid (PA), phospholipase D (PLD) is strongly involved in vesicular trafficking and cell signaling, making this enzyme an important therapeutic target. However, most PLD assays developed so far are either discontinuous or based on the indirect determination of choline released during PLD-catalyzed phosphatidylcholine hydrolysis, making its kinetic characterization difficult. We present here the development of a direct, specific, and continuous PLD assay that is based on the chelation-enhanced fluorescence property of 8-hydroxyquinoline (8HQ) following Ca(2+) complexation with PLD-generated PA. The real-time fluorescence intensity from 8HQ/Ca(2+)/PA complexes can be converted to concentrations of product using a calibration curve, with a detection limit of 1.2 MUM of PA on a microplate scale, thus allowing measurement of the PLD-catalyzed reaction rate parameters. Hence, this assay is well adapted for studying the substrate specificity of PLD, together with its kinetic parameters, using natural phospholipids with various headgroups. In addition, the assay was found to be effective in monitoring the competitive inhibition of PA formation in the production of phosphatidylalcohols following the addition of primary alcohols, such as ethanol, propan-1-ol, or butan-1-ol. Finally, this assay was validated using the purified recombinant Vigna unguiculata PLD, as well as the PLD from Streptomyces chromofuscus, cabbage, or peanuts, and no PA production could be detected using phospholipase A1, phospholipase A2, or phospholipase C, allowing for a reliable determination of PLD activity in crude protein extract samples. This easy to handle PLD assay constitutes, to our knowledge, the first direct and continuous PA determination method on a microplate scale. PMID- 26636830 TI - Molecular and Electronic Structures of Homoleptic Six-Coordinate Cobalt(I) Complexes of 2,2':6',2"-Terpyridine, 2,2'-Bipyridine, and 1,10-Phenanthroline. An Experimental and Computational Study. AB - The crystal structures of nine homoleptic, pseudooctahedral cobalt complexes, 1 9, containing either 2,2':6',2"-terpyridine (tpy), 4,4'-di-tert-butyl-2,2' bipyridine ((t)bpy), or 1,10-phenanthroline (phen) ligands have been determined in three oxidation levels, namely, cobalt(III), cobalt(II), and, for the first time, the corresponding presumed cobalt(I) species. The intraligand bond distances in the complexes [Co(I)(tpy(0))2](+), [Co(I)((t)bpy(0))3](+), and [Co(I)(phen(0))3](+) are identical, within experimental error, not only with those in the corresponding trications and dications but also with the uncoordinated neutral ligands tpy(0), bpy(0), and phen(0). On this basis, a cobalt(I) oxidation state assignment can be inferred for the monocationic complexes. The trications are clearly low-spin Co(III) (S = 0) species, and the dicationic species [Co(II)(tpy(0))2](2+), [Co(II)((t)bpy(0))3](2+), and [Co(II)(phen(0))3](2+) contain high-spin (S = (3)/2) Co(II). Notably, the cobalt(I) complexes do not display any structural indication of significant metal to-ligand (t2g -> pi*) pi-back-donation effects. Consistent with this proposal, the temperature-dependent molar magnetic susceptibilities of the three cobalt(I) species have been recorded (3-300 K) and a common S = 1 ground state confirmed. In contrast to the corresponding electronic spectra of isoelectronic (and isostructural) [Ni(II)(tpy(0))2](2+), [Ni(II)(bpy(0))3](2+), and [Ni(II)(phen(0))3](2+), which display d -> d bands with very small molar extinction coefficients (epsilon < 60 M(-1) cm(-1)), the spectra of the cobalt(I) species exhibit intense bands (epsilon > 10(3) M(-1) cm(-1)) in the visible and near-IR regions. Density functional theory (DFT) calculations using the B3LYP functional have validated the experimentally derived electronic structure assignments of the monocations as cobalt(I) complexes with minimal cobalt-to ligand pi-back-bonding. Similar calculations for the six-coordinate neutral complexes [Co(II)(tpy(*))2](0) and [Co(II)(bpy(*))2(bpy(0))](0) point to a common S = (3)/2 ground state, each possessing a central high-spin Co(II) ion and two pi radical anion ligands. In addition, the excited-states and ground state magnetic properties of [Co(I)(tpy(0))2][Co(I-)(CO)4] have been explored by variable temperature variable-magnetic-field magnetic circular dichroism (MCD) spectroscopy. A series of strong signals associated with the paramagnetic monocation exhibit pronounced C-term behavior indicative of the presence of metal to-ligand charge-transfer bands [in contrast to d-d transitions of the nickel(II) analogue]. Time-dependent DFT calculations have allowed assignment of these transitions as Co(3d) -> pi*(tpy) excitations. Metal-to-ligand charge-transfer states intermixing with the Co(d(8)) multiplets explain the remarkably large (and negative) zero-field-splitting parameter D obtained from SQUID and MCD measurements. Ground-state electron- and spin-density distributions of [Co(I)(tpy(0))2](+) have been investigated by multireference electronic structure methods: complete active-space self-consistent field (CASSCF) and N-electron perturbation theory to second order (NEVPT2). Both correlated CASSCF/NEVPT2 and spin-unrestricted B3LYP-based DFT calculations show a significant delocalization of the spin density from the Co(I) dxz,yz orbitals toward the empty pi* orbitals located on the two central pyridine fragments in the trans position. This spin density is of an alternating alpha,beta-spin polarization type (McConnel mechanism I) and is definitely not due to magnetic metal-to-radical coupling. A comparison of these results with those for [Ni(II)(tpy(0))2](2+) (S = 1) is presented. PMID- 26636831 TI - Total Synthesis of (-)-Hymenosetin. AB - The 3-decalinoyltetramic acid (-)-hymenosetin and its N-methyl analogue were prepared in 11 and 8 steps, respectively, from (+)-citronellal using an intramolecular Diels-Alder reaction as the key step. This method represents the first example for the synthesis of a 3-decalinoyltetramic acid with a free NH moiety. The stereochemistry of the title compound, an unnatural diastereomer, and of a decalin building block was studied in detail using circular dichroism spectroscopy in the IR and UV/VIS freqeuncy range. This allowed to determine the absolute configuration of the natural product and to plan the synthetic route. PMID- 26636832 TI - Hierarchy of Steering Criteria Based on Moments for All Bipartite Quantum Systems. AB - Einstein-Podolsky-Rosen steering is a manifestation of quantum correlations exhibited by quantum systems that allows for entanglement certification when one of the subsystems is not characterized. Detecting the steerability of quantum states is essential to assess their suitability for quantum information protocols with partially trusted devices. We provide a hierarchy of sufficient conditions for the steerability of bipartite quantum states of any dimension, including continuous variable states. Previously known steering criteria are recovered as special cases of our approach. The proposed method allows us to derive optimal steering witnesses for arbitrary families of quantum states and provides a systematic framework to analytically derive nonlinear steering criteria. We discuss relevant examples and, in particular, provide an optimal steering witness for a lossy single-photon Bell state; the witness can be implemented just by linear optics and homodyne detection and detects steering with a higher loss tolerance than any other known method. Our approach is readily applicable to multipartite steering detection and to the characterization of joint measurability. PMID- 26636833 TI - Quantum Speed Limits for Leakage and Decoherence. AB - We introduce state-independent, nonperturbative Hamiltonian quantum speed limits for population leakage and fidelity loss, for a gapped open system interacting with a reservoir. These results hold in the presence of initial correlations between the system and the reservoir, under the sole assumption that their interaction and its commutator with the reservoir Hamiltonian are norm bounded. The reservoir need not be thermal and can be time dependent. We study the significance of energy mismatch between the system and the local degrees of freedom of the reservoir that directly interact with the system. We demonstrate that, in general, by increasing the system gap we may reduce this energy mismatch, and, consequently, drive the system and the reservoir into resonance; this can accelerate fidelity loss, irrespective of the thermal properties or state of the reservoir. This implies that quantum error suppression strategies based on increasing the gap are not uniformly beneficial. Our speed limits also yield an elementary lower bound on the relaxation time of spin systems. PMID- 26636834 TI - Limitations on the Evolution of Quantum Coherences: Towards Fully Quantum Second Laws of Thermodynamics. AB - The second law of thermodynamics places a limitation into which states a system can evolve into. For systems in contact with a heat bath, it can be combined with the law of energy conservation, and it says that a system can only evolve into another if the free energy goes down. Recently, it's been shown that there are actually many second laws, and that it is only for large macroscopic systems that they all become equivalent to the ordinary one. These additional second laws also hold for quantum systems, and are, in fact, often more relevant in this regime. They place a restriction on how the probabilities of energy levels can evolve. Here, we consider additional restrictions on how the coherences between energy levels can evolve. Coherences can only go down, and we provide a set of restrictions which limit the extent to which they can be maintained. We find that coherences over energy levels must decay at rates that are suitably adapted to the transition rates between energy levels. We show that the limitations are matched in the case of a single qubit, in which case we obtain the full characterization of state-to-state transformations. For higher dimensions, we conjecture that more severe constraints exist. We also introduce a new class of thermodynamical operations which allow for greater manipulation of coherences and study its power with respect to a class of operations known as thermal operations. PMID- 26636835 TI - Maximum of a Fractional Brownian Motion: Analytic Results from Perturbation Theory. AB - Fractional Brownian motion is a non-Markovian Gaussian process X_{t}, indexed by the Hurst exponent H. It generalizes standard Brownian motion (corresponding to H=1/2). We study the probability distribution of the maximum m of the process and the time t_{max} at which the maximum is reached. They are encoded in a path integral, which we evaluate perturbatively around a Brownian, setting H=1/2+epsilon. This allows us to derive analytic results beyond the scaling exponents. Extensive numerical simulations for different values of H test these analytical predictions and show excellent agreement, even for large epsilon. PMID- 26636837 TI - Shadows of Kerr Black Holes with Scalar Hair. AB - Using backwards ray tracing, we study the shadows of Kerr black holes with scalar hair (KBHSH). KBHSH interpolate continuously between Kerr BHs and boson stars (BSs), so we start by investigating the lensing of light due to BSs. Moving from the weak to the strong gravity region, BSs-which by themselves have no shadows are classified, according to the lensing produced, as (i) noncompact, which yield not multiple images, (ii) compact, which produce an increasing number of Einstein rings and multiple images of the whole celestial sphere, and (iii) ultracompact, which possess light rings, yielding an infinite number of images with (we conjecture) a self-similar structure. The shadows of KBHSH, for Kerr-like horizons and noncompact BS-like hair, are analogous to, but distinguishable from, those of comparable Kerr BHs. But for non-Kerr-like horizons and ultracompact BS like hair, the shadows of KBHSH are drastically different: novel shapes arise, sizes are considerably smaller, and multiple shadows of a single BH become possible. Thus, KBHSH provide quantitatively and qualitatively new templates for ongoing (and future) very large baseline interferometry observations of BH shadows, such as those of the Event Horizon Telescope. PMID- 26636838 TI - Search for GeV gamma-Ray Pair Halos Around Low Redshift Blazars. AB - We report on the results of a search for gamma-ray pair halos with a stacking analysis of low redshift blazars using data from the Fermi Large Area Telescope. For this analysis we used a number of a priori selection criteria, including the spatial and spectral properties of the Fermi sources. The angular distribution of ~1 GeV photons around 24 stacked isolated high-synchrotron-peaked BL Lacs with redshift z<0.5 shows an excess over that of pointlike sources. A frequentist test yields a p value of p~0.01 for the extended emission against the point-source hypothesis. A Bayesian estimation provides Bayes factors log_{10}B_{10}>2, consistent with expectations for pair halos produced in the intergalactic magnetic fields with strength B_{IGMF}~10^{-17}-10^{-15} G. PMID- 26636839 TI - Enhancing the Bandwidth of Gravitational-Wave Detectors with Unstable Optomechanical Filters. AB - Advanced interferometric gravitational-wave detectors use optical cavities to resonantly enhance their shot-noise-limited sensitivity. Because of positive dispersion of these cavities-signals at different frequencies pick up different phases, there is a tradeoff between the detector bandwidth and peak sensitivity, which is a universal feature for quantum measurement devices having resonant cavities. We consider embedding an active unstable filter inside the interferometer to compensate the phase, and using feedback control to stabilize the entire system. We show that this scheme in principle can enhance the bandwidth without sacrificing the peak sensitivity. However, the unstable filter under our current consideration is a cavity-assisted optomechanical device operating in the instability regime, and the thermal fluctuation of the mechanical oscillator puts a very stringent requirement on the environmental temperature and the mechanical quality factor. PMID- 26636840 TI - Gravitation-Wave Emission in Shift-Symmetric Horndeski Theories. AB - Gravity theories beyond general relativity typically predict dipolar gravitational emission by compact-star binaries. This emission is sourced by "sensitivity" parameters depending on the stellar compactness. We introduce a general formalism to calculate these parameters, and show that in shift-symmetric Horndeski theories stellar sensitivities and dipolar radiation vanish, provided that the binary's dynamics is perturbative (i.e., the post-Newtonian formalism is applicable) and cosmological-expansion effects can be neglected. This allows one to reproduce the binary-pulsar-observed orbital decay. PMID- 26636841 TI - Evanescent Effects can Alter Ultraviolet Divergences in Quantum Gravity without Physical Consequences. AB - Evanescent operators such as the Gauss-Bonnet term have vanishing perturbative matrix elements in exactly D=4 dimensions. Similarly, evanescent fields do not propagate in D=4; a three-form field is in this class, since it is dual to a cosmological-constant contribution. In this Letter, we show that evanescent operators and fields modify the leading ultraviolet divergence in pure gravity. To analyze the divergence, we compute the two-loop identical-helicity four graviton amplitude and determine the coefficient of the associated (nonevanescent) R^{3} counterterm studied long ago by Goroff and Sagnotti. We compare two pairs of theories that are dual in D=4: gravity coupled to nothing or to three-form matter, and gravity coupled to zero-form or to two-form matter. Duff and van Nieuwenhuizen showed that, curiously, the one-loop trace anomaly-the coefficient of the Gauss-Bonnet operator-changes under p-form duality transformations. We concur and also find that the leading R^{3} divergence changes under duality transformations. Nevertheless, in both cases, the physical renormalized two-loop identical-helicity four-graviton amplitude can be chosen to respect duality. In particular, its renormalization-scale dependence is unaltered. PMID- 26636842 TI - Isocurvature Perturbation of Weakly Interacting Massive Particles and Small Scale Structure. AB - The adiabatic perturbation of dark matter is damped during the kinetic decoupling due to the collision with a relativistic component on subhorizon scales. However, the isocurvature part is free from damping and could be large enough to make a substantial contribution to the formation of small scale structure. We explicitly study the weakly interacting massive particles as dark matter with an early matter dominated period before radiation domination and show that the isocurvature perturbation is generated during the phase transition and leaves an imprint in the observable signatures for small scale structure. PMID- 26636843 TI - Local Operators in the Eternal Black Hole. AB - In the AdS/CFT correspondence, states obtained by Hamiltonian evolution of the thermofield doubled state are also dual to an eternal black-hole geometry, which is glued to the boundary with a time shift generated by a large diffeomorphism. We describe gauge-invariant relational observables that probe the black hole interior in these states and constrain their properties using effective field theory. By adapting recent versions of the information paradox we show that these observables are necessarily described by state-dependent bulk-boundary maps, which we construct explicitly. PMID- 26636836 TI - Precision Measurement of the Helium Flux in Primary Cosmic Rays of Rigidities 1.9 GV to 3 TV with the Alpha Magnetic Spectrometer on the International Space Station. AB - Knowledge of the precise rigidity dependence of the helium flux is important in understanding the origin, acceleration, and propagation of cosmic rays. A precise measurement of the helium flux in primary cosmic rays with rigidity (momentum/charge) from 1.9 GV to 3 TV based on 50 million events is presented and compared to the proton flux. The detailed variation with rigidity of the helium flux spectral index is presented for the first time. The spectral index progressively hardens at rigidities larger than 100 GV. The rigidity dependence of the helium flux spectral index is similar to that of the proton spectral index though the magnitudes are different. Remarkably, the spectral index of the proton to helium flux ratio increases with rigidity up to 45 GV and then becomes constant; the flux ratio above 45 GV is well described by a single power law. PMID- 26636844 TI - Probing the Charm Quark Yukawa Coupling in Higgs+Charm Production. AB - We propose a new method for determining the coupling of the Higgs boson to charm quarks, via Higgs production in association with a charm-tagged jet: pp->hc. As a first estimate, we find that at the LHC with 3000 fb^{-1}, it should be possible to derive a constraint of order one, relative to the standard model (SM) value of the charm Yukawa coupling. As a by-product of this analysis, we present an estimate of the exclusive pp->hD^{(*)} electroweak cross section. Within the SM, the latter turns out to be not accessible at the LHC even in the high-luminosity phase. PMID- 26636845 TI - W' Boson near 2 TeV: Predictions for Run 2 of the LHC. AB - We present a renormalizable theory that includes a W' boson of mass in the 1.8-2 TeV range, which may explain the excess events reported by the ATLAS Collaboration in a WZ final state, and by the CMS Collaboration in e(+)e(-)jj, Wh(0), and jj final states. The W' boson couples to right-handed quarks and leptons, including Dirac neutrinos with TeV-scale masses. This theory predicts a Z' boson of mass in the 3.4-4.5 TeV range. The cross section times branching fractions for the narrow Z' dijet and dilepton peaks at the 13 TeV LHC are 10 and 0.6 fb, respectively, for M_(Z')=3.4 TeV, and an order of magnitude smaller for M_(Z')=4.5 TeV. PMID- 26636846 TI - Standard Model Prediction for Direct CP Violation in K->pipi Decay. AB - We report the first lattice QCD calculation of the complex kaon decay amplitude A_{0} with physical kinematics, using a 323*64 lattice volume and a single lattice spacing a, with 1/a=1.3784(68) GeV. We find Re(A_{0})=4.66(1.00)(1.26)*10(-7) GeV and Im(A_{0})=-1.90(1.23)(1.08)*10(-11) GeV, where the first error is statistical and the second systematic. The first value is in approximate agreement with the experimental result: Re(A_{0})=3.3201(18)*10(-7) GeV, while the second can be used to compute the direct CP-violating ratio Re(epsilon^{'}/epsilon)=1.38(5.15)(4.59)*10^{-4}, which is 2.1sigma below the experimental value 16.6(2.3)*10(-4). The real part of A_{0} is CP conserving and serves as a test of our method while the result for Re(epsilon^{'}/epsilon) provides a new test of the standard model theory of CP violation, one which can be made more accurate with increasing computer capability. PMID- 26636847 TI - Neutron Electric Dipole Moment and Tensor Charges from Lattice QCD. AB - We present lattice QCD results on the neutron tensor charges including, for the first time, a simultaneous extrapolation in the lattice spacing, volume, and light quark masses to the physical point in the continuum limit. We find that the "disconnected" contribution is smaller than the statistical error in the "connected" contribution. Our estimates in the modified minimal subtraction scheme at 2 GeV, including all systematics, are g_{T}^{d-u}=1.020(76), g_{T}^{d}=0.774(66), g_{T}^{u}=-0.233(28), and g_{T}^{s}=0.008(9). The flavor diagonal charges determine the size of the neutron electric dipole moment (EDM) induced by quark EDMs that are generated in many new scenarios of CP violation beyond the standard model. We use our results to derive model-independent bounds on the EDMs of light quarks and update the EDM phenomenology in split supersymmetry with gaugino mass unification, finding a stringent upper bound of d_{n}<4*10^{-28} e cm for the neutron EDM in this scenario. PMID- 26636849 TI - Dynamic Isovector Reorientation of Deuteron as a Probe to Nuclear Symmetry Energy. AB - We present the calculations on a novel reorientation effect of deuteron attributed to isovector interaction in the nuclear field of heavy target nuclei. The correlation angle determined by the relative momentum vector of the proton and the neutron originating from the breakup deuteron, which is experimentally detectable, exhibits significant dependence on the isovector nuclear potential but is robust against the variation of the isoscaler sector. In terms of sensitivity and cleanness, the breakup reactions induced by the polarized deuteron beam at about 100 MeV/u provide a more stringent constraint to the symmetry energy at subsaturation densities. PMID- 26636850 TI - Sensing Atomic Motion from the Zero Point to Room Temperature with Ultrafast Atom Interferometry. AB - We sense the motion of a trapped atomic ion using a sequence of state-dependent ultrafast momentum kicks. We use this atom interferometer to characterize a nearly pure quantum state with n=1 phonon and accurately measure thermal states ranging from near the zero-point energy to n[over -]~10^{4}, with the possibility of extending at least 100 times higher in energy. The complete energy range of this method spans from the ground state to far outside of the Lamb-Dicke regime, where atomic motion is greater than the optical wavelength. Apart from thermometry, these interferometric techniques are useful for characterizing ultrafast entangling gates between multiple trapped ions. PMID- 26636851 TI - Blast Dynamics in a Dissipative Gas. AB - The blast caused by an intense explosion has been extensively studied in conservative fluids, where the Taylor-von Neumann-Sedov hydrodynamic solution is a prototypical example of self-similarity driven by conservation laws. In dissipative media, however, energy conservation is violated, yet a distinctive self-similar solution appears. It hinges on the decoupling of random and coherent motion permitted by a broad class of dissipative mechanisms. This enforces a peculiar layered structure in the shock, for which we derive the full hydrodynamic solution, validated by a microscopic approach based on molecular dynamics simulations. We predict and evidence a succession of temporal regimes, as well as a long-time corrugation instability, also self-similar, which disrupts the blast boundary. These generic results may apply from astrophysical systems to granular gases, and invite further cross-fertilization between microscopic and hydrodynamic approaches of shock waves. PMID- 26636852 TI - Multicolor High-Gain Free-Electron Laser Driven by Seeded Microbunching Instability. AB - Laser-heater systems are essential tools to control and optimize high-gain free electron lasers (FELs) working in the x-ray wavelength range. Indeed, these systems induce a controllable increase of the energy spread of the electron bunch. The heating suppresses longitudinal microbunching instability which otherwise would limit the FEL performance. Here, we demonstrate that, through the action of the microbunching instability, a long-wavelength modulation of the electron beam induced by the laser heater at low energy can persist until the beam entrance into the undulators. This coherent longitudinal modulation is exploited to control the FEL spectral properties, in particular, multicolor extreme-ultraviolet FEL pulses can be generated through a frequency mixing of the modulations produced by the laser heater and the seed laser in the electron beam. We present an experimental demonstration of this novel configuration carried out at the FERMI FEL. PMID- 26636848 TI - Cross Sections for the Exclusive Photon Electroproduction on the Proton and Generalized Parton Distributions. AB - Unpolarized and beam-polarized fourfold cross sections (d^{4}sigma/dQ^{2}dx_{B}dtdphi) for the ep->e^{'}p^{'}gamma reaction were measured using the CLAS detector and the 5.75-GeV polarized electron beam of the Jefferson Lab accelerator, for 110 (Q^{2},x_{B},t) bins over the widest phase space ever explored in the valence-quark region. Several models of generalized parton distributions (GPDs) describe the data well at most of our kinematics. This increases our confidence that we understand the GPD H, expected to be the dominant contributor to these observables. Through a leading-twist extraction of Compton form factors, these results support the model predictions of a larger nucleon size at lower quark-momentum fraction x_{B}. PMID- 26636853 TI - Increasing the Brightness of Cold Ion Beams by Suppressing Disorder-Induced Heating with Rydberg Blockade. AB - A model for the equilibrium coupling of an ion system with varying initial hard sphere Rydberg blockade correlations is used to quantify the suppression of disorder-induced heating in Coulomb-expanding cold ion bunches. We show that bunches with experimentally achievable blockade parameters have an emittance reduced by a factor of 2.6 and increased focusability and brightness compared to a disordered bunch. Demonstrating suppression of disorder-induced heating is an important step in the development of techniques for the creation of beam sources with sufficient phase-space density for ultrafast, single-shot coherent diffractive imaging. PMID- 26636854 TI - Self-Organized Stationary States of Tokamaks. AB - We demonstrate that in a 3D resistive magnetohydrodynamic simulation, for some parameters it is possible to form a stationary state in a tokamak where a saturated interchange mode in the center of the discharge drives a near helical flow pattern that acts to nonlinearly sustain the configuration by adjusting the central loop voltage through a dynamo action. This could explain the physical mechanism for maintaining stationary nonsawtoothing "hybrid" discharges, often referred to as "flux pumping." PMID- 26636855 TI - Experimental Validation of a Filament Transport Model in Turbulent Magnetized Plasmas. AB - In a wide variety of natural and laboratory magnetized plasmas, filaments appear as a result of interchange instability. These convective structures substantially enhance transport in the direction perpendicular to the magnetic field. According to filament models, their propagation may follow different regimes depending on the parallel closure of charge conservation. This is of paramount importance in magnetic fusion plasmas, as high collisionality in the scrape-off layer may trigger a regime transition leading to strongly enhanced perpendicular particle fluxes. This work reports for the first time on an experimental verification of this process, linking enhanced transport with a regime transition as predicted by models. Based on these results, a novel scaling for global perpendicular particle transport in reactor relevant tokamaks such as ASDEX-Upgrade and JET is found, leading to important implications for next generation fusion devices. PMID- 26636856 TI - Ultrafast Synchrotron-Enhanced Thermalization of Laser-Driven Colliding Pair Plasmas. AB - We report on the first self-consistent numerical study of the feasibility of laser-driven relativistic pair shocks of prime interest for high-energy astrophysics. Using a QED-particle-in-cell code, we simulate the collective interaction between two counterstreaming electron-positron jets driven from solid foils by short-pulse (~60 fs), high-energy (~100 kJ) lasers. We show that the dissipation caused by self-induced, ultrastrong (>10^{6} T) electromagnetic fluctuations is amplified by intense synchrotron emission, which enhances the magnetic confinement and compression of the colliding jets. PMID- 26636857 TI - Electron and Ion Heating Characteristics during Magnetic Reconnection in the MAST Spherical Tokamak. AB - Electron and ion heating characteristics during merging reconnection start-up on the MAST spherical tokamak have been revealed in detail using a 130 channel yttrium aluminum garnet (YAG) and a 300 channel Ruby-Thomson scattering system and a new 32 chord ion Doppler tomography diagnostic. Detailed 2D profile measurements of electron and ion temperature together with electron density have been achieved for the first time and it is found that electron temperature forms a highly localized hot spot at the X point and ion temperature globally increases downstream. For the push merging experiment when the guide field is more than 3 times the reconnecting field, a thick layer of a closed flux surface form by the reconnected field sustains the temperature profile for longer than the electron and ion energy relaxation time ~4-10 ms, both characteristic profiles finally forming a triple peak structure at the X point and downstream. An increase in the toroidal guide field results in a more peaked electron temperature profile at the X point, and also produces higher ion temperatures at this point, but the ion temperature profile in the downstream region is unaffected. PMID- 26636858 TI - Antiferromagnetic Heisenberg Spin Chain of a Few Cold Atoms in a One-Dimensional Trap. AB - We report on the deterministic preparation of antiferromagnetic Heisenberg spin chains consisting of up to four fermionic atoms in a one-dimensional trap. These chains are stabilized by strong repulsive interactions between the two spin components without the need for an external periodic potential. We independently characterize the spin configuration of the chains by measuring the spin orientation of the outermost particle in the trap and by projecting the spatial wave function of one spin component on single-particle trap levels. Our results are in good agreement with a spin-chain model for fermionized particles and with numerically exact diagonalizations of the full few-fermion system. PMID- 26636859 TI - Optical Metacages. AB - We suggest a novel strategy for spectrally selective optical shielding of arbitrary shaped volumes by arranging specifically designed two- or three-layer nanowires around an area that needs to be protected. We show that such nanowire shields preserve their functionality for almost arbitrary geometry, and we term such structures optical metacages. We analyze several designs of such optical metacages made from either metallic or dielectric materials with experimentally measured parameters. We employ a semianalytical approach and also verify our results by numerical simulations. We further study optical properties of the introduced metacages in both near- and far-field regions, as well as analyze their frequency selectivity and the vanishing backscattering regime. PMID- 26636860 TI - Origin of the Large Anisotropic g Factor of Holes in Bismuth. AB - The ratio of the Zeeman splitting to the cyclotron energy (M=DeltaE_{Z}/homega_{c}) for holelike carriers in bismuth has been quantified with great precision by many experiments performed during the past five decades. It exceeds 2 when the magnetic field is along the trigonal axis and vanishes in the perpendicular configuration. Theoretically, however, M is expected to be isotropic and equal to unity in a two-band Dirac model. We argue that a solution to this half-a-century-old puzzle can be found by extending the k.p theory to multiple bands. Our model not only gives a quantitative account of the magnitude and anisotropy of M for holelike carriers in bismuth, but also explains its contrasting evolution with antimony doping and pressure, both probed by new experiments reported here. The present results have important implications for the magnitude and anisotropy of M in other systems with strong spin-orbit coupling. PMID- 26636861 TI - Quantum Phase Transition and Protected Ideal Transport in a Kondo Chain. AB - We study the low energy physics of a Kondo chain where electrons from a one dimensional band interact with magnetic moments via an anisotropic exchange interaction. It is demonstrated that the anisotropy gives rise to two different phases which are separated by a quantum phase transition. In the phase with easy plane anisotropy, Z_{2} symmetry between sectors with different helicity of the electrons is broken. As a result, localization effects are suppressed and the dc transport acquires (partial) symmetry protection. This effect is similar to the protection of the edge transport in time-reversal invariant topological insulators. The phase with easy axis anisotropy corresponds to the Tomonaga Luttinger liquid with a pronounced spin-charge separation. The slow charge density wave modes have no protection against localization. PMID- 26636862 TI - Resonant and Inelastic Andreev Tunneling Observed on a Carbon Nanotube Quantum Dot. AB - We report the observation of two fundamental subgap transport processes through a quantum dot (QD) with a superconducting contact. The device consists of a carbon nanotube contacted by a Nb superconducting and a normal metal contact. First, we find a single resonance with position, shape, and amplitude consistent with the theoretically predicted resonant Andreev tunneling (AT) through a single QD level. Second, we observe a series of discrete replicas of resonant AT at a separation of ~145 MUeV, with a gate, bias, and temperature dependence characteristic for boson-assisted, inelastic AT, in which energy is exchanged between a bosonic bath and the electrons. The magnetic field dependence of the replica's amplitudes and energies suggest that two different bosons couple to the tunnel process. PMID- 26636863 TI - Interplay of Surface and Dirac Plasmons in Topological Insulators: The Case of Bi_{2}Se_{3}. AB - We have investigated plasmonic excitations at the surface of Bi_{2}Se_{3}(0001) via high-resolution electron energy loss spectroscopy. For low parallel momentum transfer q_{?}, the loss spectrum shows a distinctive feature peaked at 104 meV. This mode varies weakly with q_{?}. The behavior of its intensity as a function of primary energy and scattering angle indicates that it is a surface plasmon. At larger momenta (q_{?}~0.04 A^{-1}), an additional peak, attributed to the Dirac plasmon, becomes clearly defined in the loss spectrum. Momentum-resolved loss spectra provide evidence of the mutual interaction between the surface plasmon and the Dirac plasmon of Bi_{2}Se_{3}. The proposed theoretical model accounting for the coexistence of three-dimensional doping electrons and two-dimensional Dirac fermions accurately represents the experimental observations. The results reveal novel routes for engineering plasmonic devices based on topological insulators. PMID- 26636864 TI - Bistable Photon Emission from a Solid-State Single-Atom Laser. AB - We predict a bistability in the photon emission from a solid-state single-atom laser comprising a microwave cavity coupled to a voltage-biased double quantum dot. To demonstrate that the single-atom laser is bistable, we evaluate the photon emission statistics and show that the distribution takes the shape of a tilted ellipse. The switching rates of the bistability can be extracted from the electrical current and the shot noise in the quantum dots. This provides a means to control the photon emission statistics by modulating the electronic transport in the quantum dots. Our prediction is robust against moderate electronic decoherence and dephasing and is important for current efforts to realize single atom lasers with gate-defined quantum dots as the gain medium. PMID- 26636865 TI - Self-Assembled Wigner Crystals as Mediators of Spin Currents and Quantum Information. AB - Technological applications of many-body structures that emerge in gated devices under minimal control are largely unexplored. Here we show how emergent Wigner crystals in a semiconductor quantum wire can facilitate a pivotal requirement for a scalable quantum computer, namely, transmitting quantum information encoded in spins faithfully over a distance of micrometers. The fidelity of the transmission is remarkably high, faster than the relevant decohering effects, independent of the details of the spatial charge configuration in the wire, and realizable in dilution refrigerator temperatures. The transfer can evidence near unitary many body nonequilibrium dynamics hitherto unseen in a solid-state device. It could also be useful in spintronics as a method for pure spin current over a distance without charge movement. PMID- 26636866 TI - Topological Edge States with Zero Hall Conductivity in a Dimerized Hofstadter Model. AB - The Hofstadter model is a simple yet powerful Hamiltonian to study quantum Hall physics in a lattice system, manifesting its essential topological states. Lattice dimerization in the Hofstadter model opens an energy gap at half filling. Here we show that even if the ensuing insulator has a Chern number equal to zero, concomitantly a doublet of edge states appear that are pinned at specific momenta. We demonstrate that these states are topologically protected by inversion symmetry in specific one-dimensional cuts in momentum space, define and calculate the corresponding invariants, and identify a platform for the experimental detection of these novel topological states. PMID- 26636867 TI - Quantum Nonlinear Hall Effect Induced by Berry Curvature Dipole in Time-Reversal Invariant Materials. AB - It is well known that a nonvanishing Hall conductivity requires broken time reversal symmetry. However, in this work, we demonstrate that Hall-like currents can occur in second-order response to external electric fields in a wide class of time-reversal invariant and inversion breaking materials, at both zero and twice the driving frequency. This nonlinear Hall effect has a quantum origin arising from the dipole moment of the Berry curvature in momentum space, which generates a net anomalous velocity when the system is in a current-carrying state. The nonlinear Hall coefficient is a rank-two pseudotensor, whose form is determined by point group symmetry. We discus optimal conditions to observe this effect and propose candidate two- and three-dimensional materials, including topological crystalline insulators, transition metal dichalcogenides, and Weyl semimetals. PMID- 26636868 TI - Spin-Fluctuation Mechanism of Anomalous Temperature Dependence of Magnetocrystalline Anisotropy in Itinerant Magnets. AB - The origins of the anomalous temperature dependence of magnetocrystalline anisotropy in (Fe_{1-x}Co_{x})_{2}B alloys are elucidated using first-principles calculations within the disordered local moment model. Excellent agreement with experimental data is obtained. The anomalies are associated with the changes in band occupations due to Stoner-like band shifts and with the selective suppression of spin-orbit "hot spots" by thermal spin fluctuations. Under certain conditions, the anisotropy can increase, rather than decrease, with decreasing magnetization due to these peculiar electronic mechanisms, which contrast starkly with those assumed in existing models. PMID- 26636869 TI - Phase Diagram of an Extended Quantum Dimer Model on the Hexagonal Lattice. AB - We introduce a quantum dimer model on the hexagonal lattice that, in addition to the standard three-dimer kinetic and potential terms, includes a competing potential part counting dimer-free hexagons. The zero-temperature phase diagram is studied by means of quantum Monte Carlo simulations, supplemented by variational arguments. It reveals some new crystalline phases and a cascade of transitions with rapidly changing flux (tilt in the height language). We analyze perturbatively the vicinity of the Rokhsar-Kivelson point, showing that this model has the microscopic ingredients needed for the "devil's staircase" scenario [Eduardo Fradkin et al. Phys. Rev. B 69, 224415 (2004)], and is therefore expected to produce fractal variations of the ground-state flux. PMID- 26636870 TI - Minimal Model of Spin-Transfer Torque and Spin Pumping Caused by the Spin Hall Effect. AB - In the normal-metal-ferromagnetic-insulator bilayer (such as Pt/Y_{3}Fe_{5}O_{12}) and the normal-metal-ferromagnetic-metal-oxide trilayer (such as Pt/Co/AlO_{x}) where spin injection and ejection are achieved by the spin Hall effect in the normal metal, we propose a minimal model based on quantum tunneling of spins to explain the spin-transfer torque and spin pumping caused by the spin Hall effect. The ratio of their dampinglike to fieldlike component depends on the tunneling wave function that is strongly influenced by generic material properties such as interface s-d coupling, insulating gap, and layer thickness, yet the spin relaxation plays a minor role. The quantified result renders our minimal model an inexpensive tool for searching for appropriate materials. PMID- 26636871 TI - Many-Body Theory of Ultrafast Demagnetization and Angular Momentum Transfer in Ferromagnetic Transition Metals. AB - Exact calculated time evolutions in the framework of a many-electron model of itinerant magnetism provide new insights into the laser-induced ultrafast demagnetization observed in ferromagnetic (FM) transition metal thin films. The interplay between local spin-orbit interactions and interatomic hopping is shown to be at the origin of the observed postexcitation breakdown of FM correlations between highly stable local magnetic moments. The mechanism behind spin- and angular-momentum transfer is revealed from a microscopic perspective by rigorously complying with all fundamental conservation laws. An energy-resolved analysis of the time evolution shows that the efficiency of the demagnetization process reaches almost 100% in the excited states. PMID- 26636872 TI - Observation of Fermi-Arc Spin Texture in TaAs. AB - We have investigated the spin texture of surface Fermi arcs in the recently discovered Weyl semimetal TaAs using spin- and angle-resolved photoemission spectroscopy. The experimental results demonstrate that the Fermi arcs are spin polarized. The measured spin texture fulfills the requirement of mirror and time reversal symmetries and is well reproduced by our first-principles calculations, which gives strong evidence for the topologically nontrivial Weyl semimetal state in TaAs. The consistency between the experimental and calculated results further confirms the distribution of chirality of the Weyl nodes determined by first principles calculations. PMID- 26636873 TI - High-Resolution Faraday Rotation and Electron-Phonon Coupling in Surface States of the Bulk-Insulating Topological Insulator Cu_{0.02}Bi_{2}Se_{3}. AB - We have utilized time-domain magnetoterahertz spectroscopy to investigate the low frequency optical response of the topological insulator Cu_{0.02}Bi_{2}Se_{3} and Bi_{2}Se_{3} films. With both field and frequency dependence, such experiments give sufficient information to measure the mobility and carrier density of multiple conduction channels simultaneously. We observe sharp cyclotron resonances (CRs) in both materials. The small amount of Cu incorporated into the Cu_{0.02}Bi_{2}Se_{3} induces a true bulk insulator with only a single type of conduction with a total sheet carrier density of ~4.9*10^{12}/cm^{2} and mobility as high as 4000 cm^{2}/V.s. This is consistent with conduction from two virtually identical topological surface states (TSSs) on the top and bottom of the film with a chemical potential ~145 meV above the Dirac point and in the bulk gap. The CR broadens at high fields, an effect that we attribute to an electron-phonon interaction. This assignment is supported by an extended Drude model analysis of the zero-field Drude conductance. In contrast, in normal Bi_{2}Se_{3} films, two conduction channels were observed, and we developed a self-consistent analysis method to distinguish the dominant TSSs and coexisting trivial bulk or two dimensional electron gas states. Our high-resolution Faraday rotation spectroscopy on Cu_{0.02}Bi_{2}Se_{3} paves the way for the observation of quantized Faraday rotation under experimentally achievable conditions to push the chemical potential in the lowest Landau level. PMID- 26636874 TI - Reciprocity Between Robustness of Period and Plasticity of Phase in Biological Clocks. AB - Circadian clocks exhibit the robustness of period and plasticity of phase against environmental changes such as temperature and nutrient conditions. Thus far, however, it is unclear how both are simultaneously achieved. By investigating distinct models of circadian clocks, we demonstrate reciprocity between robustness and plasticity: higher robustness in the period implies higher plasticity in the phase, where changes in period and in phase follow a linear relationship with a negative coefficient. The robustness of period is achieved by the adaptation on the limit cycle via a concentration change of a buffer molecule, whose temporal change leads to a phase shift following a shift of the limit-cycle orbit in phase space. Generality of reciprocity in clocks with the adaptation mechanism is confirmed with theoretical analysis of simple models, while biological significance is discussed. PMID- 26636875 TI - Small Crowders Slow Down Kinesin-1 Stepping by Hindering Motor Domain Diffusion. AB - The dimeric motor protein kinesin-1 moves processively along microtubules against forces of up to 7 pN. However, the mechanism of force generation is still debated. Here, we point to the crucial importance of diffusion of the tethered motor domain for the stepping of kinesin-1: small crowders stop the motor at a viscosity of 5 mPa.s-corresponding to a hydrodynamic load in the sub-fN (~10^{-4} pN) range-whereas large crowders have no impact even at viscosities above 100 mPa.s. This indicates that the scale-dependent, effective viscosity experienced by the tethered motor domain is a key factor determining kinesin's functionality. Our results emphasize the role of diffusion in the kinesin-1 stepping mechanism and the general importance of the viscosity scaling paradigm in nanomechanics. PMID- 26636876 TI - Convective Cage Release in Model Colloidal Glasses. AB - The mechanism of flow in glassy materials is interrogated using mechanical spectroscopy applied to model nearly hard sphere colloidal glasses during flow. Superimposing a small amplitude oscillatory motion orthogonal onto steady shear flow makes it possible to directly evaluate the effect of a steady state flow on the out-of-cage (alpha) relaxation as well as the in-cage motions. To this end, the crossover frequency deduced from the viscoelastic spectra is used as a direct measure of the inverse microstructural relaxation time, during flow. The latter is found to scale linearly with the rate of deformation. The microscopic mechanism of flow can then be identified as a convective cage release. Further insights are provided when the viscoelastic spectra at different shear rates are shifted to scale the alpha relaxation and produce a strain rate-orthogonal frequency superposition, the colloidal analogue of time temperature superposition in polymers with the flow strength playing the role of temperature. Whereas the scaling works well for the alpha relaxation, deviations are observed both at low and high frequencies. Brownian dynamics simulations point to the origins of these deviations; at high frequencies these are due to the deformation of the cages which slows down the short-time diffusion, while at low frequency, deviations are most probably caused by some mild hydroclustering. PMID- 26636877 TI - Long Lifetime Hole Traps at Grain Boundaries in CdTe Thin-Film Photovoltaics. AB - A novel time-resolved cathodoluminescence method, where a pulsed electron beam is generated via the photoelectric effect, is used to probe individual CdTe grain boundaries. Excitons have a short lifetime (<=100 ps) within the grains and are rapidly quenched at the grain boundary. However, a ~47 meV shallow acceptor, believed to be due to oxygen, can act as a long lifetime hole trap, even at the grain boundaries where their concentration is higher. This provides direct evidence supporting recent observations of hopping conduction across grain boundaries in highly doped CdTe at low temperature. PMID- 26636878 TI - Kinetics of Social Contagion. AB - Diffusion of information, behavioral patterns or innovations follows diverse pathways depending on a number of conditions, including the structure of the underlying social network, the sensitivity to peer pressure and the influence of media. Here we study analytically and by simulations a general model that incorporates threshold mechanism capturing sensitivity to peer pressure, the effect of "immune" nodes who never adopt, and a perpetual flow of external information. While any constant, nonzero rate of dynamically introduced spontaneous adopters leads to global spreading, the kinetics by which the asymptotic state is approached shows rich behavior. In particular, we find that, as a function of the immune node density, there is a transition from fast to slow spreading governed by entirely different mechanisms. This transition happens below the percolation threshold of network fragmentation, and has its origin in the competition between cascading behavior induced by adopters and blocking due to immune nodes. This change is accompanied by a percolation transition of the induced clusters. PMID- 26636879 TI - Erratum: Neutral Atom Frequency Reference in the Deep Ultraviolet with Fractional Uncertainty=5.7*10^{-15} [Phys. Rev. Lett. 108, 183004 (2012)]. PMID- 26636880 TI - Publisher's Note: Dichotomy between the Hole and Electron Behavior in Multiband Superconductor FeSe Probed by Ultrahigh Magnetic Fields [Phys. Rev. Lett. 115, 027006 (2015)]. PMID- 26636881 TI - How Well Does BODIPY-Cholesteryl Ester Mimic Unlabeled Cholesteryl Esters in High Density Lipoprotein Particles? AB - We compare the behavior of unlabeled and BODIPY-labeled cholesteryl ester (CE) in high density lipoprotein by atomistic molecular dynamics simulations. We find through replica exchange umbrella sampling and unbiased molecular dynamics simulations that BODIPY labeling has no significant effect on the partitioning of CE between HDL and the water phase. However, BODIPY-CE was observed to diffuse more slowly and locate itself closer to the HDL-water interface than CE due to the BODIPY probe that is constrained to the surface region, and because the CE body in BODIPY-CE prefers to align itself away from the HDL surface. The implications as to the suitability of BODIPY to explore lipoprotein properties are discussed. PMID- 26636882 TI - Synthesis of Stable Shape-Controlled Catalytically Active beta-Palladium Hydride. AB - We have developed an efficient strategy for the production of stable beta palladium hydride (PdH0.43) nanocrystals with controllable shapes and remarkable stability. The as-synthesized PdH0.43 nanocrystals showed impressive stability in air at room temperature for over 10 months, which has enabled the investigation of their catalytic property for the first time. The prepared PdH0.43 nanocrystals served as highly efficient catalysts in the oxidation of methanol, showing higher activity than their Pd counterparts. These studies opened a door for further exploration of beta-palladium hydride-based nanomaterials as a new class of promising catalytic materials and beyond. PMID- 26636883 TI - Oscillatory Diffusion and Second-Order Cyclostationarity in Alanine Tripeptide from Molecular Dynamics Simulation. AB - Molecular dynamics (MD) simulation distinctly describes motions of biomolecules at high resolution and can potentially be used to explain allosteric mechanism in subcellular processes. Statistical methods are necessary to realize this potential because MD simulations generate a large volume of data and because the analysis is never efficient, objective, or thorough without using appropriate statistical approaches. Tracing the flow of information within a biomolecule requires not only a description of an overall mechanism but also a multiscale statistical description from atomic interactions to the overall mechanism. The foundation of this multiscale description, in general, is a measure of correlation between motions of atoms or residues, as reflected by dynamic cross correlation, Pearson correlation, or mutual information. However, these correlations can be inadequate because they assume wide sense stationarity, which means that the instantaneous average and correlation of a particular property are time-independent. Consequently, these measures of correlation cannot account for correlation between motions of different frequencies, since frequency implies oscillation and variation over time. Here, we characterize the nonstationarity in the form of pure oscillatory instantaneous variance in the signed dihedral angular accelerations (SDAA) along the main chain of alanine tripeptide in MD simulations by power spectrum, corrected squared envelope spectrum (CSES), and cross-CSES. This oscillation has a physical interpretation of an oscillatory diffusion. The fraction of this oscillation in all motions is as high as about 40% at some frequencies. This shows that oscillatory instantaneous variance exists in the SDAA and that significant correlation may not be accounted for in current correlation analysis. This oscillation is also found to transmit between dihedral angles. These results could have implications in the understanding of the dynamics of biomolecules. PMID- 26636884 TI - Folate Receptor Targeted Delivery of siRNA and Paclitaxel to Ovarian Cancer Cells via Folate Conjugated Triblock Copolymer to Overcome TLR4 Driven Chemotherapy Resistance. AB - This paper focuses on the ability of a folate-decorated triblock copolymer to deliver a targeted dose of siRNA in order to overcome chemotherapy resistance which can commonly cause complications in ovarian cancer patients. The micelleplexes that are formed upon electrostatic interaction with siRNA are used to deliver siRNA in a targeted manner to SKOV-3 ovarian cancer cells that overexpress folate receptor-alpha (FRalpha). The triblock copolymer consists of polyethylenimine-graft-polycaprolactone-block-poly(ethylene glycol) (PEI-g-PCL-b PEG-Fol). In this work, polymers of different molecular weights of PEG, as well as different grafting degrees of the (g-PCL-b-PEG-Fol) chains to PEI, were analyzed to optimize targeted siRNA delivery. The polymers, their micelleplexes, and the in vitro performance of the latter were characterized by nuclear magnetic resonance, dynamic light scattering, transmission electron microscopy, flow cytrometry, western blot, confocal microscopy, and in luciferase assays. The different PEI-g-PCL-b-PEG-Fol conjugates showed suitable sizes below 260 nm, especially at N/P 5, which also allowed for full siRNA condensation. Furthermore, flow cytometry and Western blot analysis demonstrated that our best polymer was able to effectively deliver siRNA and that siRNA delivery resulted in efficient protein knockdown of toll-like receptor 4 (TLR4). Consequently, TLR4 knock down within SKOV-3 cells resensitized them toward paclitaxel (PTX) treatment, and apoptotic events increased. This study demonstrates that PEI-g-PCL-b-PEG-Fol conjugates are a reliable delivery system for siRNA and are able to mediate therapeutic protein knockdown within ovarian cancer cells. Additionally, this study provides further evidence to link TLR4 levels to chemotherapy resistance. PMID- 26636886 TI - Palliative Reconstruction for the Management of Incurable Head and Neck Cancer. AB - BACKGROUND: Surgical management of head and neck cancer is resource intensive and physiologically demanding. In patients with incurable disease, although the indications for surgery are not well defined, palliative benefit can be significant. The goal of this investigation was to compare outcomes of patients who underwent resection and reconstruction of head and neck cancer with curative intent with those who underwent similar procedures with palliative intent. METHODS: A retrospective review of patients who underwent reconstruction for head and neck cancer between 2008 and 2014 was conducted. Patients were divided into curative and palliative groups. Outcomes assessed included postoperative complications and survival. RESULTS: A total of 147 patients who underwent 156 operations met inclusion criteria (27 palliative and 129 curative). In both cohorts, the most common histology was squamous cell carcinoma (SCC) and the most common primary tumor site was the oral cavity. There was no significant difference between the cohorts in the rates of systemic and reconstructive complications, postoperative hospital length of stay, 30-day mortality, and flap survival. Overall survival in palliative patients was significantly shorter compared with curative patients (median OS, 6.2 months vs. 56.1 months, respectively; p < 0.0001). Among patients undergoing palliative surgery, patients without carotid involvement and those with non-SCC were significantly more likely to have longer survival. CONCLUSION: Surgical resection with reconstruction is possible in head and neck oncologic patients undergoing palliative treatment. Palliative patients have similar short-term outcomes when compared with patients undergoing resection for curative intent. Quality-of-life and economic implications of these approaches deserve closer scrutiny. PMID- 26636885 TI - Patterns of substance use and correlates of lifetime and active injection drug use among women in Malaysia. AB - BACKGROUND: While drug use is associated with HIV risk in Southeast Asia, little is known about substance use behaviors among women, including drug injection. OBJECTIVES: To describe patterns of substance use among women using alcohol and drugs in Malaysia and identify correlates of lifetime and active drug injection, a risk factor for HIV transmission. METHODS: A survey of 103 women who used drugs in the last 12 months assessed drug use history and frequency, including drug injection and drug use during pregnancy, self-reported HIV-status, childhood and adulthood physical and sexual abuse, and access to and utilization of harm reduction services, including needle-syringe exchange programs (NSEP) and opioid agonist maintenance therapy (OAT). Principal component analyses (PCA) were conducted to assess drug use grouping. RESULTS: Amphetamine-type substances (ATS; 82.5%), alcohol (75.7%) and heroin (71.8%) were the most commonly used drugs across the lifetime. Drug injection was reported by 32.0% (n = 33) of participants with 21.4% (n = 22) having injected in the last 30 days. PCA identified two groups of drug users: opioids/benzodiazepines and club drugs. Lifetime drug injection was significantly associated with lower education, homelessness, prior criminal justice involvement, opioid use, polysubstance use, childhood physical and sexual abuse, and being HIV-infected, but not with prior OAT. CONCLUSION: Women who use drugs in Malaysia report high levels of polysubstance use and injection-related risk behaviors, including sharing of injection equipment and being injected by others. Low OAT utilization suggests the need for improved access to OAT services and other harm reduction measures that prioritize women. PMID- 26636887 TI - Early Axonal Area Measurement Predicts Early Nerve Regeneration Outcomes. AB - BACKGROUND: Study of peripheral nerve injury and regeneration in laboratory animals can be time consuming and expensive. This study determines if it is possible to reduce time and cost for a peripheral nerve regeneration study. PURPOSE: The purpose of this study was to determine if nerve axonal area (NXA) or nerve fiber counting (NFC) correlates with compound muscle action potential (CMAP) recovery which is known to predict functional muscular recovery in the early stage of nerve regeneration. METHODS: In this study, six rats had a crush injury of the sciatic nerve without treatment. These rats were evaluated at 4 weeks of recovery with the following assessments: CMAP readings from the extensor digitorum longus, NXA measurement, and NFC. RESULTS: NXA correlated with CMAP; NFC did not correlate with CMAP. CONCLUSION: NFC is not a reliable method for predicting muscular recovery in the early stages. NXA is a dependable assessment for muscular recovery in the early stages of nerve regeneration. Using NXA measurement can predict later electrophysiological and functional recovery. Using NXA with CMAP measurement for nerve injury, repair, and treatment in the animal study can save cost and time. PMID- 26636888 TI - Analysis of 10-Year Training Results of Medical Students Using the Microvascular Research Center Training Program. AB - Background In this article, we reviewed the training results of medical students using the Microvascular Research Center Training Program (MRCP), and proposed an ideal microsurgical training program for all individuals by analyzing the training results of medical students who did not have any surgical experience. Methods As of 2015, a total of 29 medical students completed the MRCP. In the most recent 12 medical students, the number of trials performed for each training stage and the number of rats needed to complete the training were recorded. Additionally, we measured the operating time upon finishing stage 5 for the recent six medical students after it became a current program. Results The average operating time upon finishing stage 5 for the recent six medical students was 120 minutes +/- 11 minutes (standard deviation [SD]). The average vascular anastomosis time (for the artery and vein) was 52 minutes +/- 2 minutes (SD). For the most recent 12 medical students, there was a negative correlation between the number of trials performed in the non-rat stages (stages 1-3) and the number of rats used in the rat stages (stages 4-5). Conclusion Analysis of the training results of medical students suggests that performing microsurgery first on silicon tubes and chicken wings saves animals' lives later during the training program. We believe that any person can learn the technique of microsurgery by performing 7 to 8 hours of training per day over a period of 15 days within this program setting. PMID- 26636889 TI - Team NHS: working as one. PMID- 26636890 TI - Critical thinking in community nursing: is this the 7th C? PMID- 26636891 TI - Developing a person-centred approach to carer assessment and support. AB - Community nurses play an important role in providing palliative care and support for patients and carers at home. The Carer Support Needs Assessment Tool (CSNAT) provides practitioners with an evidence-based comprehensive tool to use with carers in palliative home care. As a practice tool, the CSNAT uses a person centred approach-that is, the process of carer assessment and support is facilitated by practitioners but is carerled. In this paper, the CSNAT research team provides an overview of the development of the tool and the benefits for both carers and practitioners arising from using the CSNAT as a person-centred approach in practice. The authors outline the five stages of the CSNAT approach to assist practitioners wishing to implement the CSNAT in practice. PMID- 26636892 TI - Concept of successful ageing among the community-dwelling oldest old in Japan. AB - AIM: In Japan, increasing human longevity has forced society to rethink the notion of what constitutes 'successful ageing'. This study attempts to advocate a new concept of successful ageing that involves complete acceptance of the ageing process. METHOD: Research was based on semi-structured interviews with 15 community dwelling oldest-old (aged 85 years and above) participants. The analysis was completed using a grounded theory approach. FINDINGS: Successful ageing for the oldest old was grouped into six categories. Within these categories, we discovered the structure of successful ageing, which synthesises ideas from the adaptation process with those of physical and cognitive decreased function as well as spirituality. CONCLUSION: The oldest old in Japan work to arrive at a conclusion with their lives, all the while coping with the drawbacks of ageing, such as declining physical and cognitive functions. This resilient and flexible way of life makes their form of ageing an equally 'successful' one. PMID- 26636893 TI - Learning to deal with crisis in the home: Part 2 - preparing preregistration students. AB - The global shift of health care is from acute services to community and primary care. Therefore, registrants must be prepared to work effectively within diverse settings. This article is the second in a series discussing the preparation of nurses for contemporary health-care challenges in the community. In it, we outline the design, implementation, and evaluation of simulated emergency scenarios within an honours degree-level, pre-registration nursing curriculum in Scotland. Over 3 years, 99 final-year students participated in interactive sessions focusing on recognition and management of the deteriorating patient and emergency care. Clinical scenarios were designed and delivered collaboratively with community practitioners. Debriefing challenged the students to reflect on learning and transferability of skills of clinical reasoning and care management to the community context. Students considered the scenarios to be realistic and perceived that their confidence had increased. Development of such simulation exercises is worthy of further debate in education and practice. PMID- 26636894 TI - Implications of case managers' perceptions and attitude on safety of home delivered care. AB - Perceptions on safety in community care have been relatively unexplored. A project that sought to understand the multiple perspectives on safety in the NHS case-management programme was carried out in relation to the structure, process, and outcome of care. This article presents a component of the nursing perspective that highlights an important element in the structure of nursing care that could potentially impede the nurses' ability to be fully effective and safe. A single case study of the case-management programme was undertaken. Three primary care organisations from three strategic health authorities participated, and three focus groups were conducted (one within each organisation). In total, 17 case management nurses participated. Data were audiotaped and transcribed verbatim and subjected to framework analysis. Nursing staff attitudes were identified as a structure of care that influence safety outcomes, particularly their perceptions of the care setting and the implications it has on their role and patient behaviour. Greater understanding of the expected role of the community nurse is necessary, and relevant training is required for nurses to be successful in empowering patients to perform more safely. In addition, efforts need to be made to improve patients' trust in the health-care system to prevent harm and promote more effective utilisation of resources. PMID- 26636895 TI - Exploring the activity profile of health care assistants and nurses in home nursing. AB - Are home nurses (also known as community nurses) ready for their changing role in primary care? A quantitative study was performed in home nursing in Flanders, Belgium, to explore the activity profile of home nurses and health care assistants, using the 24-hour recall instrument for home nursing. Seven dates were determined, covering each day of the week and the weekend, on which data collection would take place. All the home nurses and health care assistants from the participating organisations across Flanders were invited to participate in the study. All data were measured at nominal level. A total of 2478 home nurses and 277 health care assistants registered 336 128 (47 977 patients) and 36 905 (4558 patients) activities, respectively. Home nurses and health care assistants mainly perform 'self-care facilitation' activities in combination with 'psychosocial care' activities. Health care assistants also support home nurses in the 'selfcare facilitation' of patients who do not have a specific nursing indication. PMID- 26636896 TI - Understanding the Code: use of medicines. AB - The revised Code of the Nursing and Midwifery Council (NMC), the statutory professional regulator for district nurses, makes clear that while district nurses can interpret the values and principles for medication use in community settings, the standards are not negotiable or discretionary. They must be applied or the district nurse's fitness to practice will be called into question. In the final article in the series analysing the legal implications of the NMC Code on district nurse practice, Richard Griffith considers standard 18 on medicines. PMID- 26636897 TI - Taking a closer look at partnership in palliative care. PMID- 26636898 TI - Helping people with rheumatoid arthritis to live well. PMID- 26636899 TI - Getting home care right. PMID- 26636900 TI - A high density of cis-information terminates RNA Polymerase III on a 2-rail track. AB - Transcription termination delineates the 3' ends of transcripts, prevents otherwise runaway RNA polymerase (RNAP) from intruding into downstream genes and regulatory elements, and enables release of the RNAP for recycling. While other eukaryotic RNAPs require complex cis-signals and/or accessory factors to achieve these activities, RNAP III does so autonomously with high efficiency and precision at a simple oligo(dT) stretch of 5-6 bp. A basis for this high density cis-information is that both template and nontemplate strands of the RNAP III terminator carry distinct signals for different stages of termination. High density cis-information is a feature of the RNAP III system that is also reflected by dual functionalities of the tRNA promoters as both DNA and RNA elements. We review emerging developments in RNAP III termination and single strand nontemplate DNA use by other RNAPs. Use of nontemplate signals by RNAPs and associated transcription factors may be prevalent in gene regulation. PMID- 26636902 TI - RSV vaccine use--the missing data. AB - Respiratory syncytial virus (RSV) infection is the most important cause of hospitalization in infants and is one of the leading global causes of infant mortality and as such its prevention through vaccination is a public health priority. While essential for the successful implementation of vaccine programs, there remains a paucity of data on the epidemiology of the virus in different settings and age groups and limited knowledge about virus transmission and the health-care costs of the disease. Such data are now needed to populate health economic models and to inform optimal approaches to disease control through vaccination. PMID- 26636901 TI - Key factors influencing ADME properties of therapeutic proteins: A need for ADME characterization in drug discovery and development. AB - Protein therapeutics represent a diverse array of biologics including antibodies, fusion proteins, and therapeutic replacement enzymes. Since their inception, they have revolutionized the treatment of a wide range of diseases including respiratory, vascular, autoimmune, inflammatory, infectious, and neurodegenerative diseases, as well as cancer. While in vivo pharmacokinetic, pharmacodynamic, and efficacy studies are routinely carried out for protein therapeutics, studies that identify key factors governing their absorption, distribution, metabolism, and excretion (ADME) properties have not been fully investigated. Thorough characterization and in-depth study of their ADME properties are critical in order to support drug discovery and development processes for the production of safer and more effective biotherapeutics. In this review, we discuss the main factors affecting the ADME characteristics of these large macromolecular therapies. We also give an overview of the current tools, technologies, and approaches available to investigate key factors that influence the ADME of recombinant biotherapeutic drugs, and demonstrate how ADME studies will facilitate their future development. PMID- 26636904 TI - Dissolution enhancement of a model poorly water-soluble drug, atorvastatin, with ordered mesoporous silica: comparison of MSF with SBA-15 as drug carriers. AB - OBJECTIVES: The purpose of this study was to develop mesoporous silica materials incorporated with poorly water-soluble drug atorvastatin calcium (AC) in order to improve drug dissolution, and intended to be orally administrated. A comparison between 2D-hexagonal silica nanostructured SBA-15 and mesocellular siliceous foam (MSF) with continuous 3D pore system on drug release rate was investigated. METHODS: AC-loaded mesoporous silicas were characterized thorough N2 adsorption desorption analysis, Fourier transform infrared (FT-IR) spectroscopy, powder X ray diffraction (PXRD), differential scanning calorimetry (DSC) and dynamic light scattering (DLS). RESULTS: Results demonstrated a successful incorporation of AC into the silica-based hosts. The results taken from the drug release tests were also analyzed using different parameters, namely similarity factor (f2), difference factor (f1), dissolution efficiency (DE%), mean dissolution rate (MDR) and dissolution time (tm%). It confirmed a significant enhancement in the release profile of atorvastatin calcium with SBA-15, and MSF as drug carrier. Moreover, in comparison with SBA-15, MSF showed faster release rate of AC in enzyme-free simulated gastric fluid (pH 1.2). CONCLUSION: We believed that our findings can help the use of mesoporous silica materials in improving bioavailability of poorly water-soluble drugs. PMID- 26636903 TI - Metabolic coupling in urothelial bladder cancer compartments and its correlation to tumor aggressiveness. AB - Monocarboxylate transporters (MCTs) are vital for intracellular pH homeostasis by extruding lactate from highly glycolytic cells. These molecules are key players of the metabolic reprogramming of cancer cells, and evidence indicates a potential contribution in urothelial bladder cancer (UBC) aggressiveness and chemoresistance. However, the specific role of MCTs in the metabolic compartmentalization within bladder tumors, namely their preponderance on the tumor stroma, remains to be elucidated. Thus, we evaluated the immunoexpression of MCTs in the different compartments of UBC tissue samples (n = 111), assessing the correlations among them and with the clinical and prognostic parameters. A significant decrease in positivity for MCT1 and MCT4 occurred from normoxic toward hypoxic regions. Significant associations were found between the expression of MCT4 in hypoxic tumor cells and in the tumor stroma. MCT1 staining in normoxic tumor areas, and MCT4 staining in hypoxic regions, in the tumor stroma and in the blood vessels were significantly associated with UBC aggressiveness. MCT4 concomitant positivity in hypoxic tumor cells and in the tumor stroma, as well as positivity in each of these regions concomitant with MCT1 positivity in normoxic tumor cells, was significantly associated with an unfavourable clinicopathological profile, and predicted lower overall survival rates among patients receiving platinum-based chemotherapy. Our results point to the existence of a multi-compartment metabolic model in UBC, providing evidence of a metabolic coupling between catabolic stromal and cancer cells' compartments, and the anabolic cancer cells. It is urgent to further explore the involvement of this metabolic coupling in UBC progression and chemoresistance. PMID- 26636905 TI - Spontaneous fractures of the mandible concept & treatment strategy. AB - BACKGROUND: Spontaneous fractures of the mandible dispose a surgical challenge in comparisons to fractures caused by trauma due to several complicating factors. Additionally: controversies exist concerning the terminology of the field. MATERIAL AND METHODS: We conducted a retrospective study of all patients with mandibular fractures, with exclusion of fractures of the coronoid process and the alveolar process, treated at the Department of Oral and Maxillofacial Surgery, Aalborg University Hospital, Denmark between February 2003 and February 2013. Data collected from the medical records included sex, age, cause of fracture, site of fracture, and treatment. RESULTS: We identified 517 patients with 684 mandible fractures. Twenty-five of these were spontaneous fractures and 659 fractures were of traumatic origin. Condylar fractures rarely occur spontaneously, but constitute the majority of the traumatic fractures. Excluding these fractures from the analysis, we found a non-surgical approach in 14 of 24 (58%) of the spontaneous fractures and 110 of 376 (29%) of the traumatic fractures. This was statistically significant. CONCLUSIONS: We found a statistical significant difference in favor of non-surgical approach in spontaneous fractures and we discussed the treatment challenges of these fractures. We addressed the terminological controversies regarding pathological fractures, and suggested the term spontaneous fractures denoting a fracture occurring during normal jaw function being either pathological or non pathological. PMID- 26636906 TI - Urinary Polycyclic Aromatic Hydrocarbon Metabolites and Altered Lung Function in Wuhan, China. AB - RATIONALE: Exposure to polycyclic aromatic hydrocarbons (PAHs) has been associated with adverse effects on the respiratory system. However, the association between internal levels of PAH metabolites and lung function levels remains unclear. OBJECTIVES: We investigated the relationships between urinary PAH metabolite concentrations and lung function levels in a general Chinese population. METHODS: Lung function and 12 urinary PAH metabolites were measured in 2,747 participants from the Wuhan-Zhuhai cohort in China. Associations between urinary PAH metabolites and lung function were analyzed by linear mixed models. We also investigated associations among urinary PAH metabolite concentrations, traffic exposure time, and dietary PAH exposure. MEASUREMENTS AND MAIN RESULTS: We found significant associations between increased levels of urinary PAH metabolites and reduced lung function. Each 1-U increase in log-transformed levels of 2-hydroxynaphthalene, 9-hydroxyfluorene, 2-hydroxyfluorene, 4 hydroxyphenanthrene, 9-hydroxyphenanthrene, 3-hydroxyphenanthrene, 1 hydroxyphenanthrene, 2-hydroxyphenanthrene, 1-hydroxypyrene, or total urinary PAH metabolites was associated with a 23.79-, 19.36-, 41.76-, 36.87-, 33.47-, 27.37-, 39.53-, 34.35-, 25.03-, or 37.13-ml reduction in FEV1, respectively (all P < 0.05). Each 1-U increase in 2-hydroxynaphthalene, 2-hydroxyfluorene, 4 hydroxyphenanthrene, 1-hydroxyphenanthrene, 2-hydroxyphenanthrene, or total urinary PAH metabolites was associated with a 24.39-, 33.90-, 27.15-, 28.56-, 27.46-, or 27.99-ml reduction in FVC, respectively (all P < 0.05). The total urinary PAH metabolites concentration was positively associated with both traffic exposure time and dietary PAH exposure among nonsmokers. CONCLUSIONS: Total and specific urinary PAH metabolites were associated with lung function reduction in a general Chinese population. Further studies are needed to investigate the potential mechanism by which PAHs induces lung function reduction. PMID- 26636907 TI - Periodic acid-Schiff-positive loops and networks as a prognostic factor in oral mucosal melanoma. AB - The prognostic factors of oral mucosal melanoma (OMM), a rare and aggressive neoplasm, remain to be determined. The aim of this study is to investigate the prognostic significance of vasculogenic mimicry in OMM. The clinical data of 62 patients with primary OMM treated in Shanghai Ninth People's Hospital from April 2007 to April 2012 were retrieved and analyzed retrospectively. Staining of periodic acid-Schiff (PAS) and CD31 immunohistochemistry were performed to evaluate the prognostic value of PAS-positive patterns, blood lakes, and microvascular density. PAS-positive loops and networks (P<0.001) as well as blood lakes (P=0.040) were found to be predictors of overall survival (OS). The presence of PAS-positive loops and networks was an independent prognostic factor of poor OS in multivariate analysis (P=0.002). Although the presence of PAS positive loops and networks was associated with hematogenous metastasis (P=0.041) and lymphogenous metastasis (P=0.041), it was not an independent predictor of both types of metastasis in multivariate analysis. Microvascular density was not associated with OS (P=0.627) and metastasis of OMM patients. PAS-positive loops and networks have a significant prognostic value in OMM. Detection of PAS positive patterns may lead to better staging and serve as a prognostic parameter of OMM. PMID- 26636908 TI - Ipilimumab in anti-PD1 refractory metastatic melanoma: a report of eight cases. AB - Targeted therapy and immunotherapy in metastatic melanoma have led to a marked improvement in patients' survival and their quality of life. Although there are data on anti-programmed-death-receptor-1 (anti-PD1) after ipilimumab, only few data are available on ipilimumab following anti-PD1 as the first-line treatment. The aim of our study was to evaluate tolerance and survival of patients treated with ipilimumab as the second-line immunotherapy among metastatic melanoma patients following anti-PD1 treatment. Retrospective and descriptive epidemiological studies were carried out at the Dermatology Department of the University Hospital of Lille. We describe a case series of patients treated with ipilimumab after anti-PD1 failure for metastatic melanomas. For each patient, we assessed disease extension since ipilimumab introduction using RECIST 1.1. The time between ipilimumab introduction and other systemic treatment and overall survival (between ipilimumab introduction and last patient visit) was assessed. The effect of ipilimumab after anti-PD1 treatment was evaluated in eight patients. Four patients responded to ipilimumab: three showed a complete response and one showed a partial response. For these patients, the time period between the first ipilimumab injection and another systemic treatment ranged from 209 to 391 days and the overall survival ranged from 314 to 581 days. One patient showed grade 3 chorioretinitis, an unusual toxicity with ipilimumab or anti-PD1 to our knowledge. We have described the efficacy of ipilimumab following anti-PD1 in metastatic melanoma in eight patients. Several comparative studies are still in progress, and their results will be important to develop an optimal therapeutic strategy for our patients. PMID- 26636909 TI - Applications for quantitative measurement of BRAF V600 mutant cell-free tumor DNA in the plasma of patients with metastatic melanoma. AB - Small fragments of cell-free DNA that are shed by normal and tumor cells can be detected in the plasma of patients with advanced melanoma. Quantitative measurement of BRAF V600 mutant DNA within the cell-free DNA holds promise as a tumor-specific biomarker for diagnosis and therapeutic monitoring in patients with BRAF V600 mutant melanoma. Allele-specific quantitative PCR analysis for BRAF V600 E/E2/D/K/R/M mutations on DNA extracted from 1 ml of plasma is currently under evaluation in a number of ongoing prospective clinical studies. We report five patient cases that indicate the potential applications and utility of quantitative measurements of BRAF V600 mutant cell-free tumor DNA as a diagnostic test and as a therapeutic monitoring tool in stage IV melanoma patients treated with BRAF-targeted therapy or immunotherapy. Finally, we offer novel insights into the dynamics of cell-free tumor DNA in melanoma. PMID- 26636910 TI - Determining Brain Death: Erratum. PMID- 26636911 TI - Management of Intracranial Pressure: Erratum. PMID- 26636915 TI - Investigators seek ways to involve more older adults in cancer research. PMID- 26636916 TI - Recurrence, poor survival more likely in patients with acute myeloid leukemia who have certain mutations. PMID- 26636917 TI - E-cigarettes could impact health in the developing world. PMID- 26636919 TI - Single and double valence configuration interactions for recovering the exponential decay law while tunneling through a molecular wire. AB - The exponential decay of the electronic transmission through a molecular wire with its length is calculated using a configuration interaction elastic scattering quantum chemistry (CI-ESQC) theory [1, 2]. In the HOMO-LUMO gap and in a one-electron approximation, this decay is exponential since the scattering matrix comes from a product of spatial propagators along the wire. In a valence SD-CI (single and double-configurations interaction) description, such a product does not exist. An effective one was numerically obtained from the CI-ESQC scattering matrix. Fluctuations over the effective CI-exponential decay come from the truncation of the full CI basis set and also from many-body exchange correlation effects along the molecular wire. PMID- 26636920 TI - Reply. PMID- 26636922 TI - Preclinical and clinical characterization of the cutaneous bioavailability of the hydrophilic phase of a water-in-oil emulsion. AB - BACKGROUND: Interactions between the stratum corneum and individual phases of an emulsion system depend on various factors, but primarily on the outer continuous phase of the system. While there is plenty of data on the lipophilic phase, only very little data exists on the actual penetration of the hydrophilic phase of water-in-oil emulsions into the stratum corneum. PATIENTS AND METHODS: Against this background, two comparable water-in-oil emulsions were preclinically and clinically investigated on healthy as well as on artificially damaged skin with regard to interactions of the hydrophilic phase. In preclinical studies, following epicutaneous application on ex vivo skin, the distribution of the hydrophilic phase was quantified using fluorescence tests and analyzed according to anatomic layers. Additionally, a randomized, controlled, investigator-blinded study investigated the effects of the preparations on the barrier function of healthy and artificially damaged skin over time. RESULTS: The results clearly show that water substitution using a water-in-oil emulsion can only partially be attained by the addition of hygroscopic substances (e. g. urea). These effects may primarily be explained by the occlusive properties of the lipophilic phase. CONCLUSIONS: This, the use of water-in-oil emulsions may in particular be recommended for chronic barrier impairment, as long-lasting effects are not to be expected in acutely damaged skin. PMID- 26636921 TI - Self-efficacy beliefs, locus of control, religiosity and non-adherence to immunosuppressive medications in kidney transplant patients. AB - AIM: Adherence to immunosuppressive medication is essential for favourable kidney transplant outcomes. The present study aims to investigate how self-efficacy beliefs, health locus of control and religiosity are associated with adherence to immunosuppressives in post kidney transplant recipients. METHODS: This is a cross sectional study with 88 recipients with more than 1 year after transplantation. Three methods were used to classify patients as adherent or non-adherent: Basel Assessment of Adherence Scale for Immunosuppressives - BAASIS, the collateral report and blood levels of immunosuppressive medications. Self-efficacy, health locus of control, and religiosity were evaluated applying General Perceived Self Efficacy Scale, Multidimensional Health Locus of Control Scale and Duke University Religion Index, respectively. Non-adherence was modelled by uni- and multivariated analysis. RESULTS: Sixty-three percent of the patients were male, age 47.2 +/- 12.9 years, and median post-transplant time 108.71 (49.0-266.0) months. We found 70.5% of patients were non-adherent through at least one method. Adherent patients presented higher self-efficacy scores (45.1 +/- 4.9 vs 38.3 +/- 8.6; P < 0.001) and higher intrinsic religiosity (14.0 +/- 1.6 vs. 12.8 +/- 2.5; P = 0.016) compared to the non-adherents. Organizational and non-organizational religiosity did not differ between these groups. By logistic regression, non adherence was associated with lower self-efficacy (OR 0.81, IC 0.70-0.92, P = 0.002), chance locus of control (OR 1.23, IC 1.04-1.45, P = 0.016) and lower intrinsic religiosity (OR 0.56, IC 0.38-0.84, P = 0.006). CONCLUSION: Our study showed that self-efficacy, chance locus of control, and intrinsic religiosity were associated with non-adherence to immunosuppressives. A broader perception of the kidney transplant patient's integrality can help health professionals to design strategies to promote adherence in this population. PMID- 26636923 TI - Steroids are a risk factor for Kaposi's sarcoma-immune reconstitution inflammatory syndrome and mortality in HIV infection. AB - OBJECTIVES: To investigate the association between Kaposi's sarcoma-associated immune reconstitution inflammatory syndrome (KS-IRIS) and mortality, with the use of glucocorticoids in HIV-infected individuals. DESIGN: Case-control study. METHODS: We reviewed the medical records of 145 individuals with HIV-associated Kaposi's sarcoma receiving antiretroviral therapy. The association of different variables with KS-IRIS and Kaposi's sarcoma-related mortality was explored by univariate and multivariate analyses. The main exposure of interest was the use of glucocorticoids. We also compared the time to KS-IRIS and the time to death of individuals treated with glucocorticoids vs. those nontreated with glucocorticoids, and the time to death of individuals with KS-IRIS vs. those without KS-IRIS by hazards regression. RESULTS: Sixty of 145 individuals received glucocorticoids (41.4%) for the management or suspicion of Pneumocystis jirovecii pneumonia. Fifty individuals had KS-IRIS (37%). The use of glucocorticoids was more frequent in individuals with KS-IRIS than in those without KS-IRIS (54.9 vs. 36.47%, P = 0.047). Kaposi's sarcoma-related mortality occurred in 17 cases (11.7%), and glucocorticoid use was more frequent in this group (76.47 vs. 36.7%, P = 0.003). Glucocorticoid use was a risk factor for mortality (adjusted odds ratio = 4.719, 95% confidence interval = 1.383-16.103, P = 0.0132), and was associated with shorter periods to KS-IRIS (P = 0.03) and death (P = 0.0073). KS IRIS was a risk factor for mortality (P = 0.049). CONCLUSION: In HIV-infected individuals, the use of glucocorticoids is a risk factor for KS-IRIS and Kaposi's sarcoma-associated mortality. In addition, KS-IRIS is a risk factor for mortality. Therefore, glucocorticoid administration in this population requires careful consideration based on individualized risk-benefit analysis. PMID- 26636924 TI - The population impact of eliminating homelessness on HIV viral suppression among people who use drugs. AB - OBJECTIVE: We sought to estimate the change in viral suppression prevalence if homelessness were eliminated from a population of HIV-infected people who use drugs. DESIGN: Community-recruited prospective cohort of HIV-infected people who use drugs in Vancouver, Canada. Behavioural information was collected at baseline and linked to a province-wide HIV/AIDS treatment database. The primary outcome was viral suppression (<50 copies/ml) measured during subsequent routine clinical care. METHODS: We employed an imputation-based marginal modelling approach. First, we used modified Poisson regression to estimate the relationship between homelessness and viral suppression (adjusting for sociodemographics, substance use, addiction treatment, and other confounders). Then, we imputed an outcome probability for each individual while manipulating the exposure (homelessness). Population viral suppression prevalence under realized and 'housed' scenarios were obtained by averaging these probabilities across the study population. Bootstrapping was conducted to calculate 95% confidence limits. RESULTS: Of 706 individuals interviewed between January 2005 and December 2013, the majority were men (66.0%), of white race/ethnicity (55.1%), and had a history of injection drug use (93.6%). At first study visit, 223 (31.6%) reported recent homelessness, and 37.8% were subsequently identified as virally suppressed. Adjusted marginal models estimated a 15.1% relative increase [95% confidence interval (CI) 9.0 21.7%) in viral suppression in the entire population - to 43.5% (95% CI 39.4 48.2%) - if all homeless individuals were housed. Among those homeless, eliminating this exposure would increase viral suppression from 22.0 to 40.1% (95% CI 35.1-46.1%), an 82.3% relative increase. CONCLUSION: Interventions to house homeless, HIV-positive individuals who use drugs could significantly increase population viral suppression. Such interventions should be implemented as a part of renewed HIV/AIDS prevention and treatment efforts. PMID- 26636925 TI - The impact of transient combination antiretroviral treatment in early HIV infection on viral suppression and immunologic response in later treatment. AB - OBJECTIVE: Effects of transient combination antiretroviral treatment (cART) initiated during early HIV infection (EHI) remain unclear. We investigate whether this intervention affects viral suppression and CD4 cell count increase following its reinitiation in chronic infection (CHI). DESIGN: Longitudinal observational study. METHODS: We identified adult patients from Concerted Action of Seroconversion to AIDS and Death in Europe who seroconverted after 1/1/2000, had a 12 months or less HIV test interval and initiated cART from naive. We classified individuals as 'pretreated in EHI' if treated within 6 months of seroconversion, interrupted for at least 12 weeks, and reinitiated during CHI. Statistical analysis was performed using survival analysis methods and mixed models. RESULTS: Pretreated and initiated in CHI groups comprised 202 and 4263 individuals, with median follow-up after CHI treatment 4.5 and 3 years, respectively. Both groups had similar virologic response and relapse rates (P = 0.585 and P = 0.206) but pretreated individuals restarted treatment with higher baseline CD4 cell count (~80 cells/MUl; P < 0.001) and retained significantly higher CD4 cell count for more than 3 years after treatment (re)initiation. Assuming common baseline CD4 cell count, differences in CD4 cell count slopes were nonsignificant. Immunovirologic response to CHI treatment was not associated with timing or duration of the transient treatment. CONCLUSION: Although treatment interruptions are not recommended, stopping cART initiated in EHI does not seem to reduce the chance of a successful outcome of treatment in CHI. PMID- 26636926 TI - HIV infection and arterial stiffness among older-adults taking antiretroviral therapy in rural Uganda. AB - HIV infection is associated with arterial stiffness, but no studies have assessed this relationship in sub-Saharan Africa. We enrolled 205 participants over 40 years old in Uganda: 105 on antiretroviral therapy for a median of 7 years, and a random sample of 100 age and sex-matched HIV-uninfected controls from the clinic catchment area. The prevalence of arterial stiffness (ankle brachial index > 1.2) was 33%, 18%, 19% and 2% in HIV+ men, HIV- men, HIV+ women, and HIV- women. In multivariable models adjusted for cardiovascular risk factors, HIV+ individuals had over double the prevalence of arterial stiffness (adjusted prevalence ratio 2.86, 95% confidence interval 1.41-5.79, P = 0.003). PMID- 26636927 TI - Factors associated with initiation of antiretroviral therapy among HIV-positive people who use injection drugs in a Canadian setting. AB - OBJECTIVE: To identify behavioral, social, and structural factors associated with time from HIV seroconversion to antiretroviral therapy (ART) initiation among people who use injection drugs (PWID). DESIGN: Two complementary prospective cohorts of PWID linked to comprehensive ART dispensation records in a setting of universal no-cost HIV/AIDS treatment and care. METHODS: Multivariable extended Cox models of time to ART initiation among baseline HIV-seronegative PWID who seroconverted after recruitment adjusted with a time-updated measure of clinical eligibility for ART. RESULTS: We included 133 individuals of whom 98 (74%) initiated ART during follow-up at a rate of 12.4 per 100 person-years. In a multivariable model adjusted for ART eligibility, methadone maintenance therapy [adjusted hazard ratio (AHR) = 2.37, 95% confidence interval (95% CI): 1.56-3.60] and a more recent calendar year of observation (AHR = 1.06, 95% CI: 1.00-1.12) were associated with more rapid ART initiation, whereas informal income generation (AHR = 0.51, 95% CI: 0.32-0.79) and incarceration (AHR = 0.52, 95% CI: 0.28-0.97) were negatively associated with ART initiation. CONCLUSION: In this sample of community-recruited HIV-positive PWID with well defined dates of HIV seroconversion, we found that two measures related to the criminalization of illicit drug use each independently delayed ART initiation regardless of clinical eligibility. Engagement in methadone promoted ART initiation. Programs to scale up HIV treatment among PWID should consider decreased criminalization of PWID and increased access to opioid substitution therapy to optimize the impact of ART on HIV/AIDS-associated morbidity, mortality, and HIV transmission. PMID- 26636928 TI - Tenofovir clearance is reduced in HIV-positive patients with subclinical tubular impairment. AB - OBJECTIVE: To assess if tenofovir (TFV) clearance is associated with urinary retinal-binding protein (RBP) in HIV-positive patients with normal estimated filtration rate. DESIGN: A cross-sectional diagnostic study. METHODS: HIV positive patients with estimated creatinine clearance above 60 ml/min, on tenofovir disoproxil fumarate (TDF)-containing combination since at least 6 months, taking TDF at night, and without significant comorbidities (diabetes, untreated hypertension, known renal malformations, recurrent nephrolithiasis) and nephrotoxic drugs were included. TFV plasma and urinary concentrations were measured 12 h after drug intake (C12). RBP was measured through enzyme immunoassay kit on spot urines and corrected per urinary creatinine (uRBP/uCr); normality ranges were below 130 MUg/g (in patients aged <50 years) and below 172 MUg/g (in patients aged >=50 years). RESULTS: Two hundred and eighty-nine patients were included (median age of 45.8 years, 71.6% male and 85.4% whites); patients were concomitantly treated with nonnucleoside reverse transcriptase inhibitors (155, 53.6%), protease inhibitors (118, 40.8%), or integrase inhibitors (16, 5.5%)-containing regimens. Estimated creatinine clearance was 89.4 ml/min (78.6-105.9). Urinary RBP (uRBP) and uRBP/uCr were 204.6 ng/ml (92 380) and 169.7 MUg/g (85.8-318.3), respectively; abnormally high uRBP/uCr was observed in 157 patients (54.3%). A multivariate binary logistic regression confirmed that both ethnicity (P = 0.004, beta 2.93, 95% confidence interval 1.41 6.10) and TFV urinary C12 less than 21 mg/ml (P = 0.006, beta 2.04, 95% confidence interval 1.12-3.41) were significantly associated with abnormal uRBP/uCr. CONCLUSION: HIV-positive TDF-treated patients showed a high prevalence of proximal tubular impairment: ethnicity (whites) and low urinary TFV concentrations were significantly associated with elevated uRBP. SDC VIDEO:: http://links.lww.com/QAD/A852. PMID- 26636929 TI - A 48-week randomized phase 2b study evaluating cenicriviroc versus efavirenz in treatment-naive HIV-infected adults with C-C chemokine receptor type 5-tropic virus. AB - OBJECTIVE: To compare the efficacy, safety, and anti-inflammatory effects of cenicriviroc (CVC), an oral, once-daily C-C chemokine receptor types 5 and 2 antagonist, with those of efavirenz (EFV) in treatment-naive, HIV-1-infected adults. DESIGN: A 48-week, randomized, double-blind, double-dummy phase 2b trial at 43 institutions (USA and Puerto Rico). METHODS: Study participants (HIV-1 RNA >=1000 copies/ml, CD4 cell count >=200 cells/MUl, C-C chemokine receptor type 5 tropic virus) were randomized 2 : 2 : 1 to CVC 100 mg (CVC100), CVC 200 mg (CVC200), or EFV 600 mg, each administered with emtricitabine/tenofovir disoproxil fumarate. Key end points were virologic success (HIV-1 RNA <50 copies/ml) at week 24 (primary) and week 48 (secondary), safety/tolerability at weeks 24 and 48. Study sites and patients remained blinded until week 48. RESULTS: A total of 143 patients were randomized (CVC100, n = 59; CVC200, n = 56; EFV, n = 28). Virologic success was obtained at week 24 in 76, 73, and 71% of study participants for CVC100, CVC200, and EFV, respectively (all P > 0.05 versus EFV), and at week 48 in 68, 64, and 50%, respectively (all P > 0.05 versus EFV). Resistance mutations emerged in five and zero CVC and EFV-treated study participants, respectively. Virologic nonresponse and nucleoside reverse transcriptase inhibitor resistance decreased when CVC minimum plasma concentration was at least 47.8 ng/ml. Treatment-related adverse events of at least grade 2 and discontinuations because of adverse events were less frequent in CVC-treated study participants. Total and low-density lipoprotein cholesterol decreased with CVC, but increased with EFV. C-C chemokine ligand type 2 (CCL2) (aka monocyte chemotactic protein-1) increased in a dose-dependent manner, whereas soluble CD14 levels decreased with CVC. CONCLUSION: CVC showed efficacy and favorable safety in treatment-naive HIV-1-infected study participants, supporting selection of CVC200 for phase 3 studies. TRIAL REGISTRATION: NCT01338883. PMID- 26636930 TI - sCD14 is not a bona-fide biomarker of microbial translocation in HIV-1-infected Africans living in Belgium. AB - OBJECTIVE: To compare microbial translocation and its biomarkers in HIV-1 infected African and White patients of the Liege AIDS Reference Center. DESIGN: The study is based on a cross-sectional dataset of HIV-infected patients treated at the Liege AIDS Reference Center. Groups of white and African patients have been randomly selected to be identical for sex, age and duration of treatment. METHODS: sCD14, lipopolysaccharide (LPS), lipopolysaccharide-binding protein (LBP) and routine HIV-follow-up parameters were measured on plasma samples. RESULTS: High values of LPS and LBP were observed in both groups of patients without significant difference between them. High values of sCD14 were observed in 53.1% of whites and only in 18.8% of African patients (P = 0.0042). A correlation between LPS and sCD14 was observed in whites but not African patients. CONCLUSION: Our observation suggests that factors not related to microbial translocation are responsible for lower sCD14 value in Africans. PMID- 26636931 TI - Trends and determinants of survival for over 200 000 patients on antiretroviral treatment in the Botswana National Program: 2002-2013. AB - OBJECTIVES: To determine the incidence and risk factors of mortality for all HIV infected patients receiving antiretroviral treatment at public and private healthcare facilities in the Botswana National HIV/AIDS Treatment Programme. DESIGN: We studied routinely collected data from 226 030 patients enrolled in the Botswana National HIV/AIDS Treatment Programme from 2002 to 2013. METHODS: A person-years (P-Y) approach was used to analyse all-cause mortality and follow-up rates for all HIV-infected individuals with documented antiretroviral therapy initiation dates. Marginal structural modelling was utilized to determine the effect of treatment on survival for those with documented drug regimens. Sensitivity analyses were performed to assess the robustness of our results. RESULTS: Median follow-up time was 37 months (interquartile range 11-75). Mortality was highest during the first 3 months after treatment initiation at 11.79 (95% confidence interval 11.49-12.11) deaths per 100 P-Y, but dropped to 1.01 (95% confidence interval 0.98-1.04) deaths per 100 P-Y after the first year of treatment. Twelve-month mortality declined from 7 to 2% of initiates during 2002-2012. Tenofovir was associated with lower mortality than stavudine and zidovudine. CONCLUSION: The observed mortality rates have been declining over time; however, mortality in the first year, particularly first 3 months of antiretroviral treatment, remains a distinct problem. This analysis showed lower mortality with regimens containing tenofovir compared with zidovudine and stavudine. CD4 cell count less than 100 cells/MUl, older age and being male were associated with higher odds of mortality. PMID- 26636932 TI - Tau-ism: The Yin and Yang of Microtubule Sliding, Detachment, and Rupture. PMID- 26636933 TI - Fractal Characterization of Chromatin Decompaction in Live Cells. AB - Chromatin organization has a fundamental impact on the whole spectrum of genomic functions. Quantitative characterization of the chromatin structure, particularly at submicron length scales where chromatin fractal globules are formed, is critical to understanding this structure-function relationship. Such analysis is currently challenging due to the diffraction-limited resolution of conventional light microscopy. We herein present an optical approach termed inverse spectroscopic optical coherence tomography to characterize the mass density fractality of chromatin, and we apply the technique to observe chromatin decompaction in live cells. The technique makes it possible for the first time, to our knowledge, to sense intracellular morphology with length-scale sensitivity from ~30 to 450 nm, thus primarily probing the higher-order chromatin structure, without resolving the actual structures. We used chromatin decompaction due to inhibition of histone deacytelases and measured the subsequent changes in the fractal dimension of the intracellular structure. The results were confirmed by transmission electron microscopy and confocal fluorescence microscopy. PMID- 26636934 TI - Redox State of Cytochromes in Frozen Yeast Cells Probed by Resonance Raman Spectroscopy. AB - Cryopreservation is a well-established technique used for the long-term storage of biological materials whose biological activity is effectively stopped under low temperatures (suspended animation). Since most biological methods do not work in a low-temperature frozen environment, the mechanism and details of the depression of cellular activity in the frozen state remain largely uncharacterized. In this work, we propose, to our knowledge, a new approach to study the downregulation of the redox activity of cytochromes b and c in freezing yeast cells in a contactless, label-free manner. Our approach is based on cytochrome photobleaching effects observed in the resonance Raman spectra of live cells. Photoinduced and native redox reactions that contributed to the photobleaching rate were studied over a wide temperature range (from -173 to +25 degrees C). We found that ice formation influences both the rate of cytochrome redox reactions and the balance between the reduced and oxidized cytochromes. We demonstrate that the temperature dependence of native redox reaction rates can be well described by the thermal activation law with an apparent energy of 32.5 kJ/mol, showing that the redox reaction rate is ~10(15) times slower at liquid nitrogen temperature than at room temperature. PMID- 26636935 TI - Modeling the Mechanosensitivity of Neutrophils Passing through a Narrow Channel. AB - Recent experiments have found that neutrophils may be activated after passing through microfluidic channels and filters. Mechanical deformation causes disassembly of the cytoskeleton and a sudden drop of the elastic modulus of the neutrophil. This fluidization is followed by either activation of the neutrophil with protrusion of pseudopods or a uniform recovery of the cytoskeleton network with no pseudopod. The former occurs if the neutrophil traverses the narrow channel at a slower rate. We propose a chemo-mechanical model for the fluidization and activation processes. Fluidization is treated as mechanical destruction of the cytoskeleton by sufficiently rapid bending. Loss of the cytoskeleton removes a pathway by which cortical tension inhibits the Rac protein. As a result, Rac rises and polarizes through a wave-pinning mechanism if the chemical reaction rate is fast enough. This leads to recovery and reinforcement of the cytoskeleton at the front of the neutrophil, and hence protrusion and activation. Otherwise the Rac signal returns to a uniform pre deformation state and no activation occurs. Thus, mechanically induced neutrophil activation is understood as the competition between two timescales: that of chemical reaction and that of mechanical deformation. The model captures the main features of the experimental observation. PMID- 26636936 TI - An Intermittent Model for Intracellular Motions of Gold Nanostars by k-Space Scattering Image Correlation. AB - Anisotropic metallic nanoparticles have been devised as powerful potential tools for in vivo imaging, photothermal therapy, and drug delivery thanks to plasmon enhanced absorption and scattering cross sections, ease in synthesis and functionalization, and controlled cytotoxicity. The rational design of all these applications requires the characterization of the nanoparticles intracellular trafficking pathways. In this work, we exploit live-cell time-lapse confocal reflectance microscopy and image correlation in both direct and reciprocal space to investigate the intracellular transport of branched gold nanostars (GNSs). Different transport mechanisms, spanning from pure Brownian diffusion to (sub )ballistic superdiffusion, are revealed by temporal and spatio-temporal image correlation spectroscopy on the tens-of-seconds timescale. According to these findings, combined with numerical simulations and with a Bayesian (hidden Markov model-based) analysis of single particle tracking data, we ascribe the superdiffusive, subballistic behavior characterizing the GNSs dynamics to a two state switching between Brownian diffusion in the cytoplasm and molecular motor mediated active transport. For the investigation of intermittent-type transport phenomena, we derive an analytical theoretical framework for Fourier-space image correlation spectroscopy (kICS). At first, we evaluate the influence of all the dynamic and kinetic parameters (the diffusion coefficient, the drift velocity, and the transition rates between the diffusive and the active transport regimes) on simulated kICS correlation functions. Then we outline a protocol for data analysis and employ it to derive whole-cell maps for each parameter underlying the GNSs intracellular dynamics. Capable of identifying even simpler transport phenomena, whether purely diffusive or ballistic, our intermittent kICS approach allows an exhaustive investigation of the dynamics of GNSs and biological macromolecules. PMID- 26636937 TI - Integrin Molecular Tension within Motile Focal Adhesions. AB - Forces transmitted by integrins regulate many important cellular functions. Previously, we developed tension gauge tether (TGT) as a molecular force sensor and determined the threshold tension across a single integrin-ligand bond, termed integrin tension, required for initial cell adhesion. Here, we used fluorescently labeled TGTs to study the magnitude and spatial distribution of integrin tension on the cell-substratum interface. We observed two distinct levels of integrin tension. A >54 pN molecular tension is transmitted by clustered integrins in motile focal adhesions (FAs) and such force is generated by actomyosin, whereas the previously reported ~40 pN integrin tension is transmitted by integrins before FA formation and is independent of actomyosin. We then studied FA motility using a TGT-coated surface as a fluorescent canvas, which records the history of integrin force activity. Our data suggest that the region of the strongest integrin force overlaps with the center of a motile FA within 0.2 MUm resolution. We also found that FAs move in pairs and that the asymmetry in the motility of an FA pair is dependent on the initial FA locations on the cell-substratum interface. PMID- 26636938 TI - Conformational Flip of Nonactivated HCN2 Channel Subunits Evoked by Cyclic Nucleotides. AB - Hyperpolarization-activated cyclic nucleotide-modulated (HCN) channels are tetrameric proteins that evoke electrical rhythmicity in specialized neurons and cardiomyocytes. The channels are activated by hyperpolarizing voltage but are also receptors for the intracellular ligand adenosine-3',5'-cyclic monophosphate (cAMP) that enhances activation but is unable to activate the channels alone. Using fcAMP, a fluorescent derivative of cAMP, we analyzed the effect of ligand binding on HCN2 channels not preactivated by voltage. We identified a conformational flip of the channel as an intermediate state following the ligand binding and quantified it kinetically. Globally fitting the time courses of ligand binding and unbinding revealed modest cooperativity among the subunits in the conformational flip. The intensity of this cooperativity, however, was only moderate compared to channels preactivated by hyperpolarizing voltage. These data provide kinetic information about conformational changes proceeding in nonactivated HCN2 channels when cAMP binds. Moreover, our approach bears potential for analyzing the function of any other membrane receptor if a potent fluorescent ligand is available. PMID- 26636939 TI - Important Role of Asparagines in Coupling the Pore and Votage-Sensor Domain in Voltage-Gated Sodium Channels. AB - Voltage-gated sodium (NaV) channels contain an alpha-subunit incorporating the channel's pore and gating machinery composed of four homologous domains (DI-DIV), with a pore domain formed by the S5 and S6 segments and a voltage-sensor domain formed by the S1-S4 segments. During a membrane depolarization movement, the S4s in the voltage-sensor domains exert downstream effects on the S6 segments to control ionic conductance through the pore domain. We used lidocaine, a local anesthetic and antiarrhythmic drug, to probe the role of conserved Asn residues in the S6s of DIII and DIV in NaV1.5 and NaV1.4. Previous studies have shown that lidocaine binding to the pore domain causes a decrease in the maximum gating (Qmax) charge of ~38%, and three-fourths of this decrease results from the complete stabilization of DIII-S4 (contributing a 30% reduction in Qmax) and one fourth is due to partial stabilization of DIV-S4 (a reduction of 8-10%). Even though substitutions for the Asn in DIV-S6 in NaV1.5, N1764A and N1764C, produce little ionic current in transfected mammalian cells, they both express robust gating currents. Anthopleurin-A toxin, which inhibits movement of DIV-S4, still reduced Qmax by nearly 30%, a value similar to that observed in wild-type channels, in both N1764A and N1764C. By applying lidocaine and measuring the gating currents, we demonstrated that Asn residues in the S6s of DIII and DIV are important for coupling their pore domains to their voltage-sensor domains, and that Ala and Cys substitutions for Asn in both S6s result in uncoupling of the pore domains from their voltage-sensor domains. Similar observations were made for NaV1.4, although substitutions for Asn in DIII-S6 showed somewhat less uncoupling. PMID- 26636940 TI - Stiffening of Red Blood Cells Induced by Cytoskeleton Disorders: A Joint Theory Experiment Study. AB - The functions and elasticities of the cell are largely related to the structures of the cytoskeletons underlying the lipid bilayer. Among various cell types, the red blood cell (RBC) possesses a relatively simple cytoskeletal structure. Underneath the membrane, the RBC cytoskeleton takes the form of a two-dimensional triangular network, consisting of nodes of actins (and other proteins) and edges of spectrins. Recent experiments focusing on the malaria-infected RBCs (iRBCs) show that there is a correlation between the elongation of spectrins in the cytoskeletal network and the stiffening of the iRBCs. Here we rationalize the correlation between these two observations by combining the wormlike chain model for single spectrins and the effective medium theory for the network elasticity. We specifically focus on how the disorders in the cytoskeletal network affect its macroscopic elasticity. Analytical and numerical solutions from our model reveal that the stiffness of the membrane increases with increasing end-to-end distances of spectrins, but has a nonmonotonic dependence on the variance of the end-to-end distance distributions. These predictions are verified quantitatively by our atomic force microscopy and micropipette aspiration measurements of iRBCs. The model may, from a molecular level, provide guidelines for future identification of new treatment methods for RBC-related diseases, such as malaria infection. PMID- 26636941 TI - Pneumocytes Assemble Lung Surfactant as Highly Packed/Dehydrated States with Optimal Surface Activity. AB - Pulmonary surfactant (PS) is an essential complex of lipids and specific proteins synthesized in alveolar type II pneumocytes, where it is assembled and stored intracellularly as multilayered organelles known as lamellar bodies (LBs). Once secreted upon physiological stimulation, LBs maintain a densely packed structure in the form of lamellar body-like particles (LBPs), which are efficiently transferred into the alveolar air-water interface, lowering surface tension to avoid lung collapse at end-expiration. In this work, the structural organization of membranes in LBs and LBPs freshly secreted by primary cultures of rat ATII cells has been compared with that of native lung surfactant membranes isolated from porcine bronchoalveolar lavage. PS assembles in LBs as crystalline-like highly ordered structures, with a highly packed and dehydrated state, which is maintained at supraphysiological temperatures. This relatively ordered/packed state is retained in secreted LBPs. The micro- and nanostructural examination of LBPs suggests the existence of high levels of structural complexity in comparison with the material purified from lavages, which may contain partially inactivated or spent structures. Additionally, freshly secreted surfactant LBPs exhibit superior activity when generating interfacial films and a higher intrinsic resistance to inactivating agents, such as serum proteins or meconium. We propose that LBs are assembled as an energy-activated structure competent to form very efficient interfacial films, and that the organization of lipids and proteins and the properties displayed by the films formed by LBPs are likely similar to those established at the alveolar interface and represent the actual functional structure of surfactant as it sustains respiration. PMID- 26636942 TI - Evaluating the Raftophilicity of Rhodopsin Photoreceptor in a Patterned Model Membrane. AB - Lipid rafts in the cell membrane are believed to affect various membrane functions, including the signaling by G-protein coupled receptors (GPCRs). However, the regulatory roles of lipid rafts on GPCRs' functions are still poorly understood, partially owing to the lack of the methods to quantitatively evaluate the affinity of membrane proteins to lipid raft (raftophilicity). Here, we describe a methodology to gauge the raftophilicity of a representative GPCR in vertebrate photoreceptor, i.e., rhodopsin (Rh), and its cognate G protein transducin (Gt) by using a patterned model membrane. We generated a substrate supported planar lipid bilayer that has patterned regions of liquid-ordered (Lo) and liquid-disordered (Ld) membrane domains. We reconstituted Rh and Gt into the patterned membrane and observed their lateral distribution and diffusion. Mobile and functional Rh molecules could be reconstituted through the rapid dilution of solubilized Rh, by optimizing the reconstitution conditions including the chamber design, protein/detergent concentrations, and solution mixing. We determined the partition and diffusion coefficients of Rh and Gt in the Lo-rich and Ld-rich regions. Both Rh and Gt were predominantly localized in the Ld phase, suggesting their low affinity to lipid rafts. Patterned model membrane offers a robust and scalable platform for systematically and quantitatively studying the functional roles of lipid rafts in biological membranes including retinal disk membranes. PMID- 26636943 TI - Transbilayer Colocalization of Lipid Domains Explained via Measurement of Strong Coupling Parameters. AB - When micron-scale compositional heterogeneity develops in membranes, the distribution of lipids on one face of the membrane strongly affects the distribution on the other. Specifically, when lipid membranes phase separate into coexisting liquid phases, domains in each monolayer leaflet of the membrane are colocalized with domains in the opposite leaflet. Colocalized domains have never been observed to spontaneously move out of registry. This result indicates that the lipid compositions in one leaflet are strongly coupled to compositions in the opposing leaflet. Predictions of the interleaflet coupling parameter, Lambda, vary by a factor of 50. We measure the value of Lambda by applying high shear forces to supported lipid bilayers. This causes the upper leaflet to slide over the lower leaflet, moving domains out of registry. We find that the threshold shear stress required to deregister domains in the upper and lower leaflets increases with the inverse length of domains. We derive a simple, closed-form expression relating the threshold shear to Lambda, and find Lambda = 0.016 +/- 0.004 kBT/nm2. PMID- 26636944 TI - Mechanical Effects of Dynamic Binding between Tau Proteins on Microtubules during Axonal Injury. AB - The viscoelastic nature of axons plays a key role in their selective vulnerability to damage in traumatic brain injury (TBI). Experimental studies have shown that although axons can tolerate 100% strain under slow loading rates, even strain as small as 5% can rupture microtubules (MTs) during the fast loading velocities relevant to TBI. Here, we developed a computational model to examine rate-dependent behavior related to dynamic interactions between MTs and the MT associated protein tau under varying strains and strain rates. In the model, inverted pairs of tau proteins can dynamically cross-link parallel MTs via the respective MT-binding domain of each tau. The model also incorporates realistic thermodynamic breaking and reformation of the bonds between the connected tau proteins as they respond to mechanical stretch. With simulated stretch of the axon, the model shows that despite the highly dynamic nature of binding and unbinding events, under fast loading rates relevant to TBI, large tensile forces can be transmitted to the MTs that can lead to mechanical rupture of the MT cylinder, in agreement with experimental observations and as inferred in human TBI. In contrast, at slow loading rates, the progressive breaking and reformation of the bonds between the tau proteins facilitate the extension of axons up to ~100% strain without any microstructural damage. The model also predicts that under fast loading rates, individual MTs detach from MT bundles via sequential breaking of the tau-tau bonds. Finally, the model demonstrates that longer MTs are more susceptible to mechanical rupture, whereas short MTs are more prone to detachment from the MT bundle, leading to disintegration of the axonal MT ultrastructure. Notably, the predictions from the model are in excellent agreement with the findings of the recent in vitro mechanical testing of micropatterned neuronal cultures. PMID- 26636945 TI - Revisiting the Anomalous Bending Elasticity of Sharply Bent DNA. AB - Several recent experiments suggest that sharply bent DNA has a surprisingly high bending flexibility, but the cause of this flexibility is poorly understood. Although excitation of flexible defects can explain these results, whether such excitation can occur with the level of DNA bending in these experiments remains unclear. Intriguingly, the DNA contained preexisting nicks in most of these experiments but whether nicks might play a role in flexibility has never been considered in the interpretation of experimental results. Here, using full-atom molecular dynamics simulations, we show that nicks promote DNA basepair disruption at the nicked sites, which drastically reduces DNA bending energy. In addition, lower temperatures suppress the nick-dependent basepair disruption. In the absence of nicks, basepair disruption can also occur but requires a higher level of DNA bending. Therefore, basepair disruption inside B-form DNA can be suppressed if the DNA contains preexisting nicks. Overall, our results suggest that the reported mechanical anomaly of sharply bent DNA is likely dependent on preexisting nicks, therefore the intrinsic mechanisms of sharply bent nick-free DNA remain an open question. PMID- 26636946 TI - Automated Analysis of Single-Molecule Photobleaching Data by Statistical Modeling of Spot Populations. AB - The number of fluorophores within a molecule complex can be revealed by single molecule photobleaching imaging. A widely applied strategy to analyze intensity traces over time is the quantification of photobleaching step counts. However, several factors can limit and bias the detection of photobleaching steps, including noise, high numbers of fluorophores, and the possibility that several photobleaching events occur almost simultaneously. In this study, we propose a new approach, to our knowledge, to determine the fluorophore number that correlates the intensity decay of a population of molecule complexes with the decay of the number of visible complexes. We validated our approach using single and fourfold Atto-labeled DNA strands. As an example we estimated the subunit stoichiometry of soluble CD95L using GFP fusion proteins. To assess the precision of our method we performed in silico experiments showing that the estimates are not biased for experimentally observed intensity fluctuations and that the relative precision remains constant with increasing number of fluorophores. In case of fractional fluorescent labeling, our simulations predicted that the fluorophore number estimate corresponds to the product of the true fluorophore number with the labeling fraction. Our method, denoted by spot number and intensity correlation (SONIC), is fully automated, robust to noise, and does not require the counting of photobleaching events. PMID- 26636947 TI - Oxidative Stress Alters the Morphology and Toxicity of Aortic Medial Amyloid. AB - The aggregation and fibril deposition of amyloid proteins have been implicated in a range of neurodegenerative and vascular diseases, and yet the underlying molecular mechanisms are poorly understood. Here, we use a combination of cell based assays, biophysical analysis, and atomic force microscopy to investigate the potential involvement of oxidative stress in aortic medial amyloid (AMA) pathogenesis and deposition. We show that medin, the main constituent of AMA, can induce an environment rich in oxidative species, increasing superoxide and reducing bioavailable nitric oxide in human cells. We investigate the role that this oxidative environment may play in altering the aggregation process of medin and identify potential posttranslational modification sites where site-specific modification and interaction can be unambiguously demonstrated. In an oxidizing environment, medin is nitrated at tyrosine and tryptophan residues, with resultant effects on morphology that lead to longer fibrils with increased toxicity. This provides further motivation to investigate the role of oxidative stress in AMA pathogenicity. PMID- 26636948 TI - Pressure and Temperature Effects on the Activity and Structure of the Catalytic Domain of Human MT1-MMP. AB - Membrane type 1-matrix metalloproteinase (MT1-MMP or MMP-14) is a zinc transmembrane metalloprotease involved in the degradation of extracellular matrix and tumor invasion. While changes in solvation of MT1-MMP have been recently studied, little is known about the structural and energetic changes associated with MT1-MMP while interacting with substrates. Steady-state kinetic and thermodynamic data (including activation energies and activation volumes) were measured over a wide range of temperatures and pressures by means of a stopped flow fluorescence technique. Complementary temperature- and pressure-dependent Fourier-transform infrared measurements provided corresponding structural information of the protein. MT1-MMP is stable and active over a wide range of temperatures (10-55 degrees C). A small conformational change was detected at 37 degrees C, which is responsible for the change in activity observed at the same temperature. Pressure decreases the enzymatic activity until complete inactivation occurs at 2 kbar. The inactivation is associated with changes in the rate-limiting step of the reaction caused by additional hydration of the active site upon compression and/or minor conformational changes in the active site region. Based on these data, an energy and volume diagram could be established for the various steps of the enzymatic reaction. PMID- 26636949 TI - Transient-State Kinetic Analysis of the RNA Polymerase I Nucleotide Incorporation Mechanism. AB - Eukaryotes express three or more multisubunit nuclear RNA polymerases (Pols) referred to as Pols I, II, and III, each of which synthesizes a specific subset of RNAs. Consistent with the diversity of their target genes, eukaryotic cells have evolved divergent cohorts of transcription factors and enzymatic properties for each RNA polymerase system. Over the years, many trans-acting factors that orchestrate transcription by the individual Pols have been described; however, little effort has been devoted to characterizing the molecular mechanisms of Pol I activity. To begin to address this gap in our understanding of eukaryotic gene expression, here we establish transient-state kinetic approaches to characterize the nucleotide incorporation mechanism of Pol I. We collected time courses for single turnover nucleotide incorporation reactions over a range of substrate ATP concentrations that provide information on both Pol I's nucleotide addition and nuclease activities. The data were analyzed by model-independent and model dependent approaches, resulting in, to our knowledge, the first minimal model for the nucleotide addition pathway for Pol I. Using a grid searching approach we provide rigorous bounds on estimated values of the individual elementary rate constants within the proposed model. This work reports the most detailed analysis of Pol I mechanism to date. Furthermore, in addition to their use in transient state kinetic analyses, the computational approaches applied here are broadly applicable to global optimization problems. PMID- 26636950 TI - The Influence of Crowding Conditions on the Thermodynamic Feasibility of Metabolic Pathways. AB - Intracellular reactions are carried out in a crowded medium where the macromolecules occupy ~40% of the total volume. This decrease in the available volume affects the activity of the reactants. Scaled particle theory is used for the estimation of the activity coefficients of the metabolites, and thereby for the assessment of the impact of the presence of background molecules, on the estimation of the Gibbs free energy change (DeltarG) of the reactions. The lactic acid pathway and the central carbon metabolism of Actinobacillus succinogenes for the production of succinic acid from glycerol have been used as illustrative case studies. Results suggest the importance of maintaining intracellular crowded regions to favor the feasibility of a pathway that in other circumstances would be infeasible. Moreover, the crowding conditions may change the directionality of reactions and can modify the feasible range of fluxes estimated for a metabolic system compared with those obtained at standard biological conditions. PMID- 26636951 TI - Remodeling Tissue Interfaces and the Thermodynamics of Zipping during Dorsal Closure in Drosophila. AB - Dorsal closure during Drosophila embryogenesis is an important model system for investigating the biomechanics of morphogenesis. During closure, two flanks of lateral epidermis (with actomyosin-rich purse strings near each leading edge) close an eye-shaped opening that is filled with amnioserosa. At each canthus (corner of the eye) a zipping process remodels the tissue interfaces between the leading edges of the lateral epidermis and the amnioserosa. We investigated zipping dynamics and found that apposing leading edge cells come together at their apical ends and then square off basally to form a lateral junction. Meanwhile, the purse strings act as contractile elastic rods bent toward the embryo interior near each canthus. We propose that a canthus-localized force contributes to both bending the ends of the purse strings and the formation of lateral junctions. We developed a thermodynamic model for zipping based on three dimensional remodeling of the tissue interfaces and the reaction dynamics of adhesion molecules in junctions and elsewhere, which we applied to zipping during unperturbed wild-type closure and to laser or genetically perturbed closure. We identified two processes that can contribute to the zipping mechanism, consistent with experiments, distinguished by whether amnioserosa dynamics do or do not augment canthus adhesion dynamics. PMID- 26636952 TI - Erroneous Silencing of the Mitotic Checkpoint by Aberrant Spindle Pole Kinetochore Coordination. AB - To segregate chromosomes during cell division, microtubules that form the bipolar spindle attach to and pull on paired chromosome kinetochores. The spindle assembly checkpoint (SAC) is activated at unattached and misattached kinetochores to prevent further mitotic progression. The SAC is silenced after all the kinetochores establish proper and stable attachment to the spindle. Robust timing of SAC silencing after the last kinetochore-spindle attachment herein dictates the fidelity of chromosome segregation. Chromosome missegregation is rare in typical somatic cell mitosis, but frequent in cancer cell mitosis and in meiosis I of mammalian oocytes. In the latter cases, SAC is normally activated in response to disruptions of kinetochore-spindle attachments, suggesting that frequent chromosome missegregation ensues from faulty SAC silencing. In-depth understanding of how SAC silencing malfunctions in these cases is yet missing, but is believed to hold promise for treatment of cancer and prevention of human miscarriage and birth defects. We previously established a spatiotemporal model that, to the best of our knowledge, explained the robustness of SAC silencing in normal mitosis for the first time. In this article, we take advantage of the whole-cell perspective of the spatiotemporal model to identify possible causes of chromosome missegregation out of the distinct features of spindle assembly exhibited by cancer cells and mammalian oocytes. The model results explain why multipolar spindle could inhibit SAC silencing and spindle pole clustering could promote it-albeit accompanied by more kinetochore attachment errors. The model also eliminates geometric factors as the cause for nonrobust SAC silencing in oocyte meiosis, and instead, suggests atypical kinetochore-spindle attachment in meiosis as a potential culprit. Overall, the model shows that abnormal spindle pole formation and its aberrant coordination with atypical kinetochore-spindle attachments could compromise the robustness of SAC silencing. Our model highlights systems-level coupling between kinetochore-spindle attachment and spindle-pole formation in SAC silencing. PMID- 26636953 TI - A Transport Model for Estimating the Time Course of ERK Activation in the C. elegans Germline. AB - The Caenorhabditis elegans germline is a well-studied model system for investigating the control of cell fate by signaling pathways. Cell signals at the distal tip of the germline promote cell proliferation; just before the loop, signals couple cell maturation to organism-level nutrient status; at the proximal end of the germline, signals coordinate oocyte maturation and fertilization in the presence of sperm. The latter two events require dual phosphorylation and activation of ERK, the effector molecule of the Ras/MAPK cascade. In C. elegans, ERK is known as MPK-1. At this point, none of today's methods for real-time monitoring of dually phosphorylated MPK-1 are working in the germline. Consequently, quantitative understanding of the MPK-1-dependent processes during germline development is limited. Here, we make a step toward advancing this understanding using a model-based framework that reconstructs the time course of MPK-1 activation from a snapshot of a fixed germline. Our approach builds on a number of recent studies for estimating temporal dynamics from fixed organisms, but takes advantage of the anatomy of the germline to simplify the analysis. Our model predicts that the MPK-1 signal turns on ~30 h into germ cell progression and peaks ~7 h later. PMID- 26636956 TI - Organic Bioelectronic Materials and Devices. PMID- 26636960 TI - Evidence for the biogenic origin of manganese-enriched layers in Lake Superior sediments. AB - Manganese (Mn) and iron (Fe)-enriched sediment layers were discovered in Lake Superior within, above and below the oxic-anoxic interface. While the role of bacteria in redox reactions with Mn is known to be significant, little information exists about indigenous microbial communities in many freshwater environments. This study examined the bacterial communities of Mn-enriched layers in Lake Superior to identify the potential Mn(II) oxidizers responsible for the formation of Mn oxides. Anaerobic Mn(II) oxidation occurring in the Mn-enriched layers at the oxic-anoxic interface was investigated using Mn(II)-enriched cultures. High-resolution microscopic and spectroscopic investigations provided evidence of the biogenic formation of Mn oxides on cell surfaces. Spectroscopic mapping confirmed high levels of Mn in structures resembling biogenic Mn oxides. These structures were observed in enrichment cultures and in Mn-enriched layer sediment samples, indicating the significance of biogenic Mn oxidation occurring in situ. 16S ribosomal DNA pyrosequencing was used to identify the bacteria potentially responsible for Mnoxide formation in the enrichment cultures and Mn enriched layers, revealing that the Mn-enriched layer contains classes with known Mn(II)-oxidizing members. Pyrosequencing of bacterial cultures suggested that these bacteria may be Bacillus strains, and that anaerobic microbial-mediated Mn(II) oxidation contributes to the formation of the layers. PMID- 26636961 TI - Novel Endoscopic Findings as Visualized by Magnifying Endoscopy with Narrow-Band Imaging: White Opaque Substance Is Present in Colorectal Hyperplastic Polyps. AB - BACKGROUND: Magnifying endoscopy (ME) with narrow-band imaging (NBI) can visualize a white opaque substance (WOS) in gastric epithelial neoplasms, gastric intestinal metaplasias, and colorectal epithelial neoplasms. Histological examination showed the WOS to be lipid droplets accumulated in the epithelium. The white appearance of colorectal hyperplastic polyps suggests that they may contain WOS, but this has not been investigated as yet. AIMS: The purpose of this study was to determine whether WOS is present in colorectal hyperplastic polyps. METHODS: We retrospectively evaluated endoscopic images of 26 consecutive lesions investigated by ME with NBI and subsequently endoscopically resected and confirmed to be hyperplastic polyps. RESULTS: WOS was present in 21 of the 26 colorectal hyperplastic polyps (80.8%) based on the findings of ME with NBI. Adipophilin was present in 24 of the 26 colorectal hyperplastic polyps (92.3%). CONCLUSIONS: This study is the first to demonstrate that WOS (i.e. lipid droplets) accumulates in the epithelium of colorectal hyperplastic polyps. PMID- 26636965 TI - Predictors of Acute Renal Failure During Extracorporeal Membrane Oxygenation in Pediatric Patients After Cardiac Surgery. AB - Acute renal failure (ARF) is associated with increased mortality in pediatric extracorporeal membrane oxygenation (ECMO). The aim of this study was to identify predictors of ARF during ECMO in pediatric patients after cardiac surgery. A retrospective study analyzed 42 children (<=15 years) after cardiac surgery requiring venous-arterial ECMO between December 2008 and December 2014 at Fuwai Hospital. ARF was defined as >=300% rise in serum creatinine (SCr) concentration from baseline or application of dialysis. Multivariate logistic regression was performed to identify the predictors of ARF during ECMO. A total of 42 children (age, interquartile range [IQR], 13.0 [7.2-29.8] months; weight, IQR, 8.5 [6.7 11.0] kg) after cardiac surgery requiring ECMO were included in this study. The total survival rate was 52.4%, and the incidence of ARF was 40.5%. As the result of univariate analysis, ECMO duration, cardiopulmonary resuscitation, maximum free hemoglobin (FHB) during ECMO, lactate level, and mean blood pressure before initiation of ECMO were entered in multiple logistic regression analysis. In multiple logistic regression analysis, FHB during ECMO (OR 1.136, 95% CI 1.023 1.261) and lactate level before initiation of ECMO (OR 1.602, 95% CI 1.025-2.502) were risk factors for ARF during ECMO after pediatric cardiac surgery. There was a linear correlation between maximum SCr and maximum FHB (Pearson's r = 0.535, P = 0.001). Maximum SCr during ECMO has also a linear correlation with lactate level before initiation of ECMO (Pearson's r = 0.342, P = 0.044). Increased FHB during ECMO and high lactate level before initiation of ECMO were risk factors for ARF during ECMO in pediatric patients after cardiac surgery. PMID- 26636962 TI - Genomic Insights into the Ancestry and Demographic History of South America. AB - South America has a complex demographic history shaped by multiple migration and admixture events in pre- and post-colonial times. Settled over 14,000 years ago by Native Americans, South America has experienced migrations of European and African individuals, similar to other regions in the Americas. However, the timing and magnitude of these events resulted in markedly different patterns of admixture throughout Latin America. We use genome-wide SNP data for 437 admixed individuals from 5 countries (Colombia, Ecuador, Peru, Chile, and Argentina) to explore the population structure and demographic history of South American Latinos. We combined these data with population reference panels from Africa, Asia, Europe and the Americas to perform global ancestry analysis and infer the subcontinental origin of the European and Native American ancestry components of the admixed individuals. By applying ancestry-specific PCA analyses we find that most of the European ancestry in South American Latinos is from the Iberian Peninsula; however, many individuals trace their ancestry back to Italy, especially within Argentina. We find a strong gradient in the Native American ancestry component of South American Latinos associated with country of origin and the geography of local indigenous populations. For example, Native American genomic segments in Peruvians show greater affinities with Andean indigenous peoples like Quechua and Aymara, whereas Native American haplotypes from Colombians tend to cluster with Amazonian and coastal tribes from northern South America. Using ancestry tract length analysis we modeled post-colonial South American migration history as the youngest in Latin America during European colonization (9-14 generations ago), with an additional strong pulse of European migration occurring between 3 and 9 generations ago. These genetic footprints can impact our understanding of population-level differences in biomedical traits and, thus, inform future medical genetic studies in the region. PMID- 26636966 TI - The Effect of Gaze Position on Reaching Movements in an Obstacle Avoidance Task. AB - Numerous studies have addressed the issue of where people look when they perform hand movements. Yet, very little is known about how visuomotor performance is affected by fixation location. Previous studies investigating the accuracy of actions performed in visual periphery have revealed inconsistent results. While movements performed under full visual-feedback (closed-loop) seem to remain surprisingly accurate, open-loop as well as memory-guided movements usually show a distinct bias (i.e. overestimation of target eccentricity) when executed in periphery. In this study, we aimed to investigate whether gaze position affects movements that are performed under full-vision but cannot be corrected based on a direct comparison between the hand and target position. To do so, we employed a classical visuomotor reaching task in which participants were required to move their hand through a gap between two obstacles into a target area. Participants performed the task in four gaze conditions: free-viewing (no restrictions on gaze), central fixation, or fixation on one of the two obstacles. Our findings show that obstacle avoidance behaviour is moderated by fixation position. Specifically, participants tended to select movement paths that veered away from the obstacle fixated indicating that perceptual errors persist in closed-loop vision conditions if they cannot be corrected effectively based on visual feedback. Moreover, measuring the eye-movement in a free-viewing task (Experiment 2), we confirmed that naturally participants' prefer to move their eyes and hand to the same spatial location. PMID- 26636967 TI - Correction: The Effect of Deworming on Growth in One-Year-Old Children Living in a Soil-Transmitted Helminth-Endemic Area of Peru: A Randomized Controlled Trial. PMID- 26636968 TI - Nonadherence to Medication Therapy in Haemodialysis Patients: A Systematic Review. AB - BACKGROUND: End-stage kidney disease (ESKD) patients are often prescribed multiple medications. Together with a demanding weekly schedule of dialysis sessions, increased number of medicines and associated regimen complexity pre dispose them at high risk of medication nonadherence. This review summarizes existing literature on nonadherence and identifies factors associated with nonadherence to medication therapy in patients undergoing haemodialysis. METHODS: A comprehensive search of PubMed, Embase, CINAHL, PsycInfo, and Cochrane Database of Systematic Reviews covering the period from 1970 through November 2014 was performed following a predefined inclusion and exclusion criteria. Reference lists from relevant materials were reviewed. Data on study characteristics, measures of nonadherence, prevalence rates and factors associated with nonadherence were collected. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines was followed in conducting this systematic review. RESULTS: Of 920 relevant publications, 44 were included. The prevalence of medication nonadherence varied from 12.5% to 98.6%, with widespread heterogeneity in measures and definitions employed. Most common patient-related factors significantly associated with nonadherence were younger age, non Caucasian ethnicity, illness interfering family life, being a smoker, and living single and being divorced or widowed. Similarly, disease-related factors include longevity of haemodialysis, recurrent hospitalization, depressive symptoms and having concomitant illness like diabetes and hypertension. Medication-related factors such as daily tablet count, total pill burden, number of phosphate binders prescribed and complexity of medication regimen were also associated with poor adherence. CONCLUSIONS: A number of patient-, disease-, and medication related factors are associated with medication nonadherence in haemodialysis patients. Clinicians should be aware of such factors so that adherence to medications can be optimised in haemodialysis patients. Future research should be directed towards well-designed prospective longitudinal studies developing standard definitions and validating available measurement tools, while focusing on the role of additional factors such as psychosocial and behavioural factors in predicting nonadherence to medications. PMID- 26636969 TI - The Synergistic Local Immunosuppressive Effects of Neural Stem Cells Expressing Indoleamine 2,3-Dioxygenase (IDO) in an Experimental Autoimmune Encephalomyelitis (EAE) Animal Model. AB - Neurodegenerative diseases provoke robust immunological reactions in the central nervous system (CNS), which further deteriorate the neural tissue damage. We hypothesized that the expression levels of indoleamine 2,3-dioxygenase (IDO), an enzyme that has potent immune suppressive activities, in neural stem cells (NSCs) would have synergistic therapeutic effects against neurodegenerative diseases, since NSCs themselves have low IDO expression. In this study, the synergistic immune suppressive effects of rat fetal NSCs expressing IDO (rfNSCs-IDO) were validated by mixed leukocyte reaction (MLR) in vitro and an experimental autoimmune encephalomyelitis (EAE) animal model in vivo. rfNSCs-IDO showed significantly more suppressive effects on T cell proliferation in the MLR compared to control rfNSCs (rfNSCs-Cont). Importantly, IDO inhibition using 1 methyl-DL-tryptophan (1-MT), an IDO inhibitor, reversed the synergistic effects, confirming IDO-specific effects in rfNSCs-IDO. In the EAE animal model, systemic rfNSCs-IDO injections resulted in significant local immune suppression in the cervical lymph nodes and CNS, evidenced by a reduction in the number of activated T lymphocytes and an increase in regulatory T cell numbers, which induced significantly fewer clinical symptoms and faster recovery. In contrast, rfNSCs Cont failed to reduce symptoms in the EAE animal models, although they showed local immune suppression, which was significantly less than that in rfNSCs-IDO. Taken together, IDO expression in NSCs synergistically potentiates the immune suppression activities of NSCs and could be applicable for the development of therapeutic modalities against various neurodegenerative diseases. PMID- 26636970 TI - Prevalence and Risk Factors of Overweight and Obesity among Children Aged 6-59 Months in Cameroon: A Multistage, Stratified Cluster Sampling Nationwide Survey. AB - BACKGROUND: Childhood obesity is one of the most serious public health challenges of the 21st century. The prevalence of overweight and obesity among children (<5 years) in Cameroon, based on weight-for-height index, has doubled between 1991 and 2006. This study aimed to determine the prevalence and risk factors of overweight and obesity among children aged 6 months to 5 years in Cameroon in 2011. METHODS: Four thousand five hundred and eighteen children (2205 boys and 2313 girls) aged between 6 to 59 months were sampled in the 2011 Demographic Health Survey (DHS) database. Body Mass Index (BMI) z-scores based on WHO 2006 reference population was chosen to estimate overweight (BMI z-score > 2) and obesity (BMI for age > 3). Regression analyses were performed to investigate risk factors of overweight/obesity. RESULTS: The prevalence of overweight and obesity was 8% (1.7% for obesity alone). Boys were more affected by overweight than girls with a prevalence of 9.7% and 6.4% respectively. The highest prevalence of overweight was observed in the Grassfield area (including people living in West and North-West regions) (15.3%). Factors that were independently associated with overweight and obesity included: having overweight mother (adjusted odds ratio (aOR) = 1.51; 95% CI 1.15 to 1.97) and obese mother (aOR = 2.19; 95% CI = 155 to 3.07), compared to having normal weight mother; high birth weight (aOR = 1.69; 95% CI 1.24 to 2.28) compared to normal birth weight; male gender (aOR = 1.56; 95% CI 1.24 to 1.95); low birth rank (aOR = 1.35; 95% CI 1.06 to 1.72); being aged between 13-24 months (aOR = 1.81; 95% CI = 1.21 to 2.66) and 25-36 months (aOR = 2.79; 95% CI 1.93 to 4.13) compared to being aged 45 to 49 months; living in the grassfield area (aOR = 2.65; 95% CI = 1.87 to 3.79) compared to living in Forest area. Muslim appeared as a protective factor (aOR = 0.67; 95% CI 0.46 to 0.95).compared to Christian religion. CONCLUSION: This study underlines a high prevalence of early childhood overweight with significant disparities between ecological areas of Cameroon. Risk factors of overweight included high maternal BMI, high birth weight, male gender, low birth rank, aged between 13-36 months, and living in the Grassfield area while being Muslim appeared as a protective factor. Preventive strategies should be strengthened especially in Grassfield areas and should focus on sensitization campaigns to reduce overweight and obesity in mothers and on reinforcement of measures such as surveillance of weight gain during antenatal consultation and clinical follow-up of children with high birth weight. Meanwhile, further studies including nutritional characteristics are of great interest to understand the association with religion, child age and ecological area in this age group, and will help in refining preventive strategies against childhood overweight and obesity in Cameroon. PMID- 26636972 TI - Synchronous thyroid metastasis from lung adenocarcinoma. AB - Metastases from other primary malignancies to the thyroid gland are clinically uncommon, far less frequent than any malignant primary neoplasm, mostly affecting elderly patients. Recent autopsy studies have shown that metastases to the tyroid is relatively common, with a prevalence of of 1,9-24%. We present a case of a man (72 years old) with lung cancer and synchronous metastasis to thyroid gland. Typically the interval between the diagnosis of the primary tumor and the detection of thyroid metastasis is from one month to 26 years. Clinical manifestation of thyroid metastases are rare KEY WORDS: Thyroid cancer, Thyroid metastases, Thyroidectomy. PMID- 26636973 TI - [3,3]-Sigmatropic Rearrangement/Allylboration/Cyclization Sequence: Enantioenriched Seven-Membered-Ring Carbamates and Ring Contraction to Pyrrolidines. AB - The combination of in situ generated alpha-isocyanato allylboronic esters and aldehydes afforded seven-membered-ring enecarbamates with high levels of diastereo- and enantiocontrol. They were easily converted into diversely substituted 1,3-oxazepan-2-ones. An unprecedented rearrangement of 5-acetoxy-7 aryl or styryl derivatives led to tetrasubstituted pyrrolidines. A computational study provides evidence on the feasibility of the proposed mechanism of this unusual ring contraction. PMID- 26636971 TI - Preserved Error-Monitoring in Borderline Personality Disorder Patients with and without Non-Suicidal Self-Injury Behaviors. AB - BACKGROUND: The presence of non-suicidal self-injury acts in Borderline Personality Disorder (BPD) is very prevalent. These behaviors are a public health concern and have become a poorly understood phenomenon in the community. It has been proposed that the commission of non-suicidal self-injury might be related to a failure in the brain network regulating executive functions. Previous studies have shown that BPD patients present an impairment in their capacity to monitor actions and conflicts associated with the performance of certain actions, which suppose an important aspect of cognitive control. METHOD: We used Event Related Potentials to examine the behavioral and electrophysiological indexes associated with the error monitoring in two BPD outpatients groups (17 patients each) differentiated according to the presence or absence of non-suicidal self-injury behaviors. We also examined 17 age- and intelligence- matched healthy control participants. RESULTS: The three groups did not show significant differences in event-related potentials associated with errors (Error-Related Negativity and Pe) nor in theta power increase following errors. CONCLUSIONS: This is the first study investigating the behavioral and electrophysiological error monitoring indexes in BPD patients characterized by their history of non-suicidal self injury behaviors. Our results show that error monitoring is preserved in BPD patients and suggest that non-suicidal self-injury acts are not related to a dysfunction in the cognitive control mechanisms. PMID- 26636974 TI - Integrating Sphere Finger-Photoplethysmography: Preliminary Investigation towards Practical Non-Invasive Measurement of Blood Constituents. AB - The aim of this study was to compare conventional photoplethysmography (PPG) in a finger with PPG using an integrating sphere (ISPPG) to enhance scattered light collection. Two representative wavelengths were used; 1160 nm, a window through the absorption spectra of water and alcohol, and 1600 nm around where water absorption is high and there is an absorption peak of blood glucose. Simultaneous transmission-type measurements were made with conventional PPG and with ISPPG for each wavelength in the tips of index fingers of both hands in a total of 10 healthy young male and female volunteers (21.7 +/- 1.6 years old). During a 5 min period in which subjects were in a relaxed state we determined the signal-to noise ratio, SNR, and the PPG detectability (or sensitivity) by the two techniques. SNR during the test period was significantly higher with ISPPG as compared with conventional PPG, especially for the 1600 nm wavelength. PPG signals with 1600 nm could scarcely be detected by conventional PPG, while they could be detected with good sensitively by ISPPG. We conclude that under controlled conditions ISPPG has better SNR and higher sensitivity than conventional transmission PPG, especially in wavelength regions where water absorption is high but where there is potential for practical measurement of blood constituents including glucose. PMID- 26636975 TI - From Wolves to Dogs, and Back: Genetic Composition of the Czechoslovakian Wolfdog. AB - The Czechoslovakian Wolfdog is a unique dog breed that originated from hybridization between German Shepherds and wild Carpathian wolves in the 1950s as a military experiment. This breed was used for guarding the Czechoslovakian borders during the cold war and is currently kept by civilian breeders all round the world. The aim of our study was to characterize, for the first time, the genetic composition of this breed in relation to its known source populations. We sequenced the hypervariable part of the mtDNA control region and genotyped the Amelogenin gene, four sex-linked microsatellites and 39 autosomal microsatellites in 79 Czechoslovakian Wolfdogs, 20 German Shepherds and 28 Carpathian wolves. We performed a range of population genetic analyses based on both empirical and simulated data. Only two mtDNA and two Y-linked haplotypes were found in Czechoslovakian Wolfdogs. Both mtDNA haplotypes were of domestic origin, while only one of the Y-haplotypes was shared with German Shepherds and the other was unique to Czechoslovakian Wolfdogs. The observed inbreeding coefficient was low despite the small effective population size of the breed, possibly due to heterozygote advantages determined by introgression of wolf alleles. Moreover, Czechoslovakian Wolfdog genotypes were distinct from both parental populations, indicating the role of founder effect, drift and/or genetic hitchhiking. The results revealed the peculiar genetic composition of the Czechoslovakian Wolfdog, showing a limited introgression of wolf alleles within a higher proportion of the dog genome, consistent with the reiterated backcrossing used in the pedigree. Artificial selection aiming to keep wolf-like phenotypes but dog-like behavior resulted in a distinctive genetic composition of Czechoslovakian Wolfdogs, which provides a unique example to study the interactions between dog and wolf genomes. PMID- 26636976 TI - Family Meal Frequency and Association with Household Food Availability in United States Multi-Person Households: National Health and Nutrition Examination Survey 2007-2010. AB - OBJECTIVE: Family meals are associated with a healthier diet among children and adolescents, but how family meal frequency varies in the U.S. population overall by household food availability and sociodemographic characteristics is not well characterized. DESIGN: The U.S. National Health and Nutrition Examination Survey 2007-2010 assessed the frequency of family meals eaten at home in the past week and the household availability of fruits, dark green vegetables, salty snacks, and sugar-sweetened beverages. SETTING: Computer-assisted face-to-face interviews with a selected adult (>=18 years) who owned or rented the home (i.e., the household reference person). SUBJECTS: We analyzed information on family meal frequency for 18,031 participants living in multi-person households in relation to sociodemographic characteristics and food availability. RESULTS: Among the U.S. population living in households of two or more individuals, the prevalence (95% confidence interval) of having 0-2, 3-6 and >=7 family meals/week was 18.0% (16.6-19.3), 32.4% (31.0-33.9), and 49.6% (47.8-51.4), respectively. Greater household availability of fruits and dark green vegetables and less availability of salty snacks and sugar-sweetened beverages was associated with more frequent family meals. Family meals were more prevalent in low-income households and those in which the reference person was >=65 years, married, or had less than high school education. CONCLUSIONS: About half of the US population living in households of 2 or more people shares meals frequently with their family at home. Family meal frequency was positively associated with a healthier pattern of household food availability. PMID- 26636978 TI - Reply. PMID- 26636977 TI - The First Mitogenome of the Cyprus Mouflon (Ovis gmelini ophion): New Insights into the Phylogeny of the Genus Ovis. AB - Sheep are thought to have been one of the first livestock to be domesticated in the Near East, thus playing an important role in human history. The current whole mitochondrial genome phylogeny for the genus Ovis is based on: the five main domestic haplogroups occurring among sheep (O. aries), along with molecular data from two wild European mouflons, three urials, and one argali. With the aim to shed some further light on the phylogenetic relationship within this genus, the first complete mitochondrial genome sequence of a Cypriot mouflon (O. gmelini ophion) is here reported. Phylogenetic analyses were performed using a dataset of whole Ovis mitogenomes as well as D-loop sequences. The concatenated sequence of 28 mitochondrial genes of one Cypriot mouflon, and the D-loop sequence of three Cypriot mouflons were compared to sequences obtained from samples representatives of the five domestic sheep haplogroups along with samples of the extant wild and feral sheep. The sample included also individuals from the Mediterranean islands of Sardinia and Corsica hosting remnants of the first wave of domestication that likely went then back to feral life. The divergence time between branches in the phylogenetic tree has been calculated using seven different calibration points by means of Bayesian and Maximum Likelihood inferences. Results suggest that urial (O. vignei) and argali (O. ammon) diverged from domestic sheep about 0.89 and 1.11 million years ago (MYA), respectively; and dates the earliest radiation of domestic sheep common ancestor at around 0.3 MYA. Additionally, our data suggest that the rise of the modern sheep haplogroups happened in the span of time between six and 32 thousand years ago (KYA). A close phylogenetic relationship between the Cypriot and the Anatolian mouflon carrying the X haplotype was detected. The genetic distance between this group and the other ovine haplogroups supports the hypothesis that it may be a new haplogroup never described before. Furthermore, the updated phylogenetic tree presented in this study determines a finer classification of ovine species and may help to classify more accurately new mitogenomes within the established haplogroups so far identified. PMID- 26636979 TI - DNA Data Visualization (DDV): Software for Generating Web-Based Interfaces Supporting Navigation and Analysis of DNA Sequence Data of Entire Genomes. AB - Data visualization methods are necessary during the exploration and analysis activities of an increasingly data-intensive scientific process. There are few existing visualization methods for raw nucleotide sequences of a whole genome or chromosome. Software for data visualization should allow the researchers to create accessible data visualization interfaces that can be exported and shared with others on the web. Herein, novel software developed for generating DNA data visualization interfaces is described. The software converts DNA data sets into images that are further processed as multi-scale images to be accessed through a web-based interface that supports zooming, panning and sequence fragment selection. Nucleotide composition frequencies and GC skew of a selected sequence segment can be obtained through the interface. The software was used to generate DNA data visualization of human and bacterial chromosomes. Examples of visually detectable features such as short and long direct repeats, long terminal repeats, mobile genetic elements, heterochromatic segments in microbial and human chromosomes, are presented. The software and its source code are available for download and further development. The visualization interfaces generated with the software allow for the immediate identification and observation of several types of sequence patterns in genomes of various sizes and origins. The visualization interfaces generated with the software are readily accessible through a web browser. This software is a useful research and teaching tool for genetics and structural genomics. PMID- 26636980 TI - Dress Nicer = Know More? Young Children's Knowledge Attribution and Selective Learning Based on How Others Dress. AB - This research explored whether children judge the knowledge state of others and selectively learn novel information from them based on how they dress. The results indicated that 4- and 6-year-olds identified a formally dressed individual as more knowledgeable about new things in general than a casually dressed one (Study 1). Moreover, children displayed an overall preference to seek help from a formally dressed individual rather than a casually dressed one when learning about novel objects and animals (Study 2). These findings are discussed in relation to the halo effect, and may have important implications for child educators regarding how instructor dress might influence young students' knowledge attribution and learning preferences. PMID- 26636981 TI - A Multifunctional Frontloading Approach for Repeated Recycling of a Pressure Controlled AFM Micropipette. AB - Fluid force microscopy combines the positional accuracy and force sensitivity of an atomic force microscope (AFM) with nanofluidics via a microchanneled cantilever. However, adequate loading and cleaning procedures for such AFM micropipettes are required for various application situations. Here, a new frontloading procedure is described for an AFM micropipette functioning as a force- and pressure-controlled microscale liquid dispenser. This frontloading procedure seems especially attractive when using target substances featuring high costs or low available amounts. Here, the AFM micropipette could be filled from the tip side with liquid from a previously applied droplet with a volume of only a few MUL using a short low-pressure pulse. The liquid-loaded AFM micropipettes could be then applied for experiments in air or liquid environments. AFM micropipette frontloading was evaluated with the well-known organic fluorescent dye rhodamine 6G and the AlexaFluor647-labeled antibody goat anti-rat IgG as an example of a larger biological compound. After micropipette usage, specific cleaning procedures were tested. Furthermore, a storage method is described, at which the AFM micropipettes could be stored for a few hours up to several days without drying out or clogging of the microchannel. In summary, the rapid, versatile and cost-efficient frontloading and cleaning procedure for the repeated usage of a single AFM micropipette is beneficial for various application situations from specific surface modifications through to local manipulation of living cells, and provides a simplified and faster handling for already known experiments with fluid force microscopy. PMID- 26636982 TI - Electroluminescence Dynamics across Grain Boundary Regions of Monolayer Tungsten Disulfide. AB - We study how grain boundaries (GB) in chemical vapor deposition (CVD) grown monolayer WS2 influence the electroluminescence (EL) behavior in lateral source drain devices under bias. Real time imaging of the WS2 EL shows arcing between the electrodes when probing across a GB, which then localizes at the GB region as it erodes under high bias conditions. In contrast, single crystal WS2 domains showed no signs of arcing or localized EL. Analysis of the eroded GB region shows the formation of micro- and nanoribbons across the monolayer WS2 domains. Comparison of the EL spectrum with the photoluminescence spectrum from the monolayer WS2 shows close agreement, indicating the EL emission comes from direct band gap excitonic recombination. These results provide important insights into EL devices that utilize CVD grown monolayer transition metal dichalcogenides when GBs are present in the active device region. PMID- 26636983 TI - Influence of zygomycete-derived D'orenone on IAA signalling in Tricholoma-spruce ectomycorrhiza. AB - Despite the rising interest in microbial communication, only few studies relate to mycorrhization and the pool of potential morphogenic substances produced by the surrounding soil community. Here, we investigated the effect exerted by the C18 - ketone beta-apo-13-carotenone, D'orenone, on the ectomycorrhizal basidiomycete Tricholoma vaccinum and its symbiosis with the economically important host tree, spruce (Picea abies). D'orenone is an early intermediate in the biosynthesis of morphogens in sexual development of mucoromycetes, the trisporoids. In the ectomycorrhizal fungus T. vaccinum, D'orenone increased the production and/or release of the phytohormone indole-3-acetic acid (IAA) which had been proposed to be involved in the mutual symbiosis. The induced expression of the fungal aldehyde dehydrogenase, Ald5 is associated with IAA synthesis and excretion. In the host tree, D'orenone modulated root architecture by increasing lateral root length and hypertrophy of root cortex cells, likely via changed IAA concentrations and flux. Thus, we report for the first time on carotenoid metabolites from soil fungi affecting both ectomycorrhizal partners. The data imply a complex network of functions for secondary metabolites which act in an inter-kingdom signalling in soil. PMID- 26636984 TI - Deciphering the Complex Chemistry of Deep-Ocean Particles Using Complementary Synchrotron X-ray Microscope and Microprobe Instruments. AB - The reactivity and mobility of natural particles in aquatic systems have wide ranging implications for the functioning of Earth surface systems. Particles in the ocean are biologically and chemically reactive, mobile, and complex in composition. The chemical composition of marine particles is thought to be central to understanding processes that convert globally relevant elements, such as C and Fe, among forms with varying bioavailability and mobility in the ocean. The analytical tools needed to measure the complex chemistry of natural particles are the subject of this Account. We describe how a suite of complementary synchrotron radiation instruments with nano- and micrometer focusing, and X-ray absorption spectroscopy (XAS) and X-ray diffraction (XRD) capabilities are changing our understanding of deep-ocean chemistry and life. Submarine venting along mid-ocean ridges creates hydrothermal plumes where dynamic particle-forming reactions occur as vent fluids mix with deep-ocean waters. Whether plumes are net sources or sinks of elements in ocean budgets depends in large part on particle formation, reactivity, and transport properties. Hydrothermal plume particles have been shown to host microbial communities and exhibit complex size distributions, aggregation behavior, and composition. X-ray microscope and microprobe instruments can address particle size and aggregation, but their true strength is in measuring chemical composition. Plume particles comprise a stunning array of inorganic and organic phases, from single-crystal sulfides to poorly ordered nanophases and polymeric organic matrices to microbial cells. X ray microscopes and X-ray microprobes with elemental imaging, XAS, and XRD capabilities are ideal for investigating these complex materials because they can (1) measure the chemistry of organic and inorganic constituents in complex matrices, usually within the same particle or aggregate, (2) provide strong signal-to-noise data with exceedingly small amounts of material, (3) simplify the chemical complexity of particles or sets of particles with a focused-beam, providing spatial resolution over 6 orders of magnitude (nanometer to millimeter), (4) provide elemental specificity for elements in the soft-, tender , and hard-X-ray energies, (5) switch rapidly among elements of interest, and (6) function in the presence of water and gases. Synchrotron derived data sets are discussed in the context of important advances in deep-ocean technology, sample handling and preservation, molecular microbiology, and coupled physical-chemical biological modeling. Particle chemistry, size, and morphology are all important in determining whether particles are reactive with dissolved constituents, provide substrates for microbial respiration and growth, and are delivered to marine sediments or dispersed by deep-ocean currents. PMID- 26636985 TI - Solvent-Enabled Radical Selectivities: Controlled Syntheses of Sulfoxides and Sulfides. AB - Controlling selectivity is of central importance to radical chemistry. However, the highly reactive and unstable radical intermediates make this task especially challenging. Herein, a strategy for taming radical redox reactions has been developed, in which solvent-bonding can alter the reactivity of the generated radical intermediates and thereby drastically alter the reaction selectivity at room temperature. Various beta-oxy sulfoxides and beta-hydroxy sulfides can be facilely obtained, some of which are difficult to synthesize by existing methods. Notably, neither a metal catalyst nor any further additives are necessary in these processes. PMID- 26636986 TI - Accounting for microsaccadic artifacts in the EEG using independent component analysis and beamforming. AB - Neuronal activity in the gamma-band range was long considered a marker of object representation. However, scalp-recorded EEG activity in this range is contaminated by a miniature saccade-related muscle artifact. Independent component analysis (ICA) has been proposed as a method of removal of such artifacts. Alternatively, beamforming, a source analysis method in which potential sources of activity across the whole brain are scanned independently through the use of adaptive spatial filters, offers a promising method of accounting for the artifact without relying on its explicit removal. We present here the application of ICA-based correction to a previously published dataset. Then, using beamforming, we examine the effect of ICA correction on the scalp recorded EEG signal and the extent to which genuine activity is recoverable before and after ICA correction. We find that beamforming attributes much of the scalp-recorded gamma-band signal before correction to deep frontal sources, likely the eye muscles, which generate the artifact related to each miniature saccade. Beamforming confirms that what is removed by ICA is predominantly this artifactual signal, and that what remains after correction plausibly originates in the visual cortex. Thus, beamforming allows researchers to confirm whether their removal procedures successfully removed the artifact. Our results demonstrate that ICA-based correction brings about general improvements in signal to-noise ratio suggesting it should be used along with, rather than be replaced by, beamforming. PMID- 26637009 TI - Surface Composition of Silver Nanocubes and Their Influence on Morphological Stabilization and Catalytic Performance in Ethylene Epoxidation. AB - Silver nanocubes with exposed (100) facets are reported to have improved selectivity with respect to their spherical counterparts for ethylene epoxidation. In the present study, we observe that the surface composition of the silver nanocubes also has a critical impact on activity. Detailed investigation of the surface composition of silver nanocubes has been carried out using HRTEM, SEM, EDS, EELS, and EFTEM. Surfaces of silver nanocubes are "passivated" by chloride, and its removal is essential to achieve any catalytic activity. However, the surface chloride is apparently essential for stabilizing the cubic morphology of the particles. Attempts were made to understand the competing effects of the surface species for retaining the morphology of the nanocubes and on their catalytic activity in ethylene epoxidation. PMID- 26637010 TI - pi-Electron Systems That Form Planar and Interlocked Anion Complexes and Their Ion-Pairing Assemblies. AB - Interactions between designed charged species are important for the ordered arrangements of pi-electron systems in assembled structures. As precursors of pi electron anion units, new arylethynyl-substituted dipyrrolyldiketone boron complexes, which showed anion-responsive behavior, were synthesized. They formed a variety of receptor-anion complexes ([1+1] and [2+1] types) in solution, and the stabilities of these complexes were discussed in terms of their thermodynamic parameters. Solid-state ion-pairing assemblies of [1+1]- and [2+1]-type complexes with countercations were also revealed by single-crystal X-ray analysis. In particular, a totally charge-segregated assembly was constructed based on negatively and positively charged layers fabricated from [2+1]-type receptor anion complexes and tetrabutylammonium cations, respectively. Furthermore, the [1+1]-type anion complex of the receptor possessing long alkyl chains exhibited mesophases based on columnar assembled structures with contributions from charge by-charge and charge-segregated arrangements, which exhibited charge-carrier transporting properties. PMID- 26637011 TI - Toward Merging Untargeted and Targeted Methods in Mass Spectrometry-Based Metabolomics and Lipidomics. PMID- 26637012 TI - Photoreversible [2] Catenane via the Host-Guest Interactions between a Palladium Metallacycle and beta-Cyclodextrin. AB - We report the efficient preparation of an A2D2 (A = acceptor and D = donor) metallacycle 2 = [(en)2Pd2(1)2](NO3)4, using the coordination driven self assembly of trans-azobenzene based bispyridyl ligand 1 and (en)Pd(NO3)2 (en = ethylenediamine). In the metallacycle, the trans-azobenzene units serve both as a structural element and as sites for subsequent host-guest chemistry with beta cyclodextrin, leading to the formation of a [2] catenane 3. This catenation process is reversible and can be switched off and on in a photocontrollable manner via the trans-cis isomerization of the azobenzene units. PMID- 26637013 TI - Trapped Hydronium Radical Produced by Ultraviolet Excitation of Substituted Aromatic Molecule. AB - The gas phase structure and excited state dynamics of o-aminophenol-H2O complex have been investigated using REMPI, IR-UV hole-burning spectroscopy, and pump probe experiments with picoseconds laser pulses. The IR-UV spectroscopy indicates that the isomer responsible for the excitation spectrum corresponds to an orientation of the OH bond away from the NH2 group. The water molecule acts as H bond acceptor of the OH group of the chromophore. The complexation of o aminophenol with one water molecule induced an enhancement in the excited state lifetime on the band origin. The variation of the excited state lifetime of the complex with the excess energy from 1.4 +/- 0.1 ns for the 0-0 band to 0.24 +/- 0.3 ns for the band at 0-0 + 120 cm(-1) is very similar to the variation observed in the phenol-NH3 system. This experimental result suggests that the excited state hydrogen transfer reaction is the dominant channel for the non radiative pathway. Indeed, excited state ab initio calculations demonstrate that H transfer leading to the formation of the H3O(*) radical within the complex is the main reactive pathway. PMID- 26637015 TI - Organocatalytic Asymmetric Nucleophilic Addition to o-Quinone Methides by Alcohols. AB - The first catalytic asymmetric intermolecular alcohol conjugate addition to o quinone methides (o-QMs) is disclosed. Due to reversible C-O bond formation and low nucleophilicity of alcohols, catalytic asymmetric oxa-Michael additions with simple alcohol nucleophiles to establish acyclic oxygenated carbon stereocenters remain scarce. The present reaction represents a rare example of this type. With a suitable chiral acid catalyst, the in situ formation of o-QMs and subsequent conjugate addition proceeded with high efficiency and enantioselectivity. The chiral ether products are versatile precursors to other chiral molecules. PMID- 26637014 TI - Identification and Phylogeny of the First T Cell Epitope Identified from a Human Gut Bacteroides Species. AB - Host T cell reactivity toward gut bacterial epitopes has been recognized as part of disease pathogenesis. However, the specificity of T cells that recognize this vast number of epitopes has not yet been well described. After colonizing a C57BL/6J germ-free mouse with the human gut symbiotic bacteria Bacteroides thetaiotaomicron, we isolated a T cell that recognized these bacteria in vitro. Using this T cell, we mapped the first known non-carbohydrate T cell epitope within the phylum Bacteroidetes. The T cell also reacted to two other additional Bacteroides species. We identified the peptide that stimulated the T cell by using a genetic approach. Genomic data from the epitope-positive and epitope negative bacteria explain the cross-reactivity of the T cell to multiple species. This epitope degeneracy should shape our understanding of the T cell repertoire stimulated by the complex microbiome residing in the gastrointestinal tract in both healthy and disease states. PMID- 26637017 TI - Structural Properties of Protein-Detergent Complexes from SAXS and MD Simulations. AB - In experimental studies of solubilized membrane proteins, the detergent corona influences the protein behavior and the resulting measurement. Thus, combinations of experimental techniques with atomistic modeling have been used to resolve corona structural parameters and distributions. Here, we used small-angle X-ray scattering (SAXS) data and molecular dynamics simulations to study a model protein-detergent complex (PDC) consisting of aquaporin-0 and dodecyl-beta maltoside molecules (betaDDM). The corona morphology of single snapshots was found to be rough, but it is smooth and compacted in 100-ns-scale ensemble averages. Individual snapshots therefore were unable to accurately represent the ensemble information as captured by experimental SAXS. Mimicking of annular lipids by detergent was also observed. SAXS prediction using different published methods was used to identify optimal betaDDM numbers. Explicit-solvent methods predicted best agreement using 290-betaDDM PDCs, but implicit-solvent methods gave unclear predictions due to overcompensation by free solvation-layer density parameters. Thus, ensemble-based approaches and physically motivated constraints will help to extract structural information from SAXS data. PMID- 26637016 TI - Tales of Dihydrofolate Binding to R67 Dihydrofolate Reductase. AB - Homotetrameric R67 dihydrofolate reductase possesses 222 symmetry and a single active site pore. This situation results in a promiscuous binding site that accommodates either the substrate, dihydrofolate (DHF), or the cofactor, NADPH. NADPH interacts more directly with the protein as it is larger than the substrate. In contrast, the p-aminobenzoyl-glutamate tail of DHF, as monitored by nuclear magnetic resonance and crystallography, is disordered when bound. To explore whether smaller active site volumes (which should decrease the level of tail disorder by confinement effects) alter steady state rates, asymmetric mutations that decreased the half-pore volume by ~35% were constructed. Only minor effects on k(cat) were observed. To continue exploring the role of tail disorder in catalysis, 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide-mediated cross-linking between R67 DHFR and folate was performed. A two-folate, one tetramer complex results in the loss of enzyme activity where two symmetry related K32 residues in the protein are cross-linked to the carboxylates of two bound folates. The tethered folate could be reduced, although with a <=30-fold decreased rate, suggesting decreased dynamics and/or suboptimal positioning of the cross-linked folate for catalysis. Computer simulations that restrain the dihydrofolate tail near K32 indicate that cross-linking still allows movement of the p-aminobenzoyl ring, which allows the reaction to occur. Finally, a bis ethylene-diamine-alpha,gamma-amide folate adduct was synthesized; both negatively charged carboxylates in the glutamate tail were replaced with positively charged amines. The K(i) for this adduct was ~9-fold higher than for folate. These various results indicate a balance between folate tail disorder, which helps the enzyme bind substrate while dynamics facilitates catalysis. PMID- 26637018 TI - Stability of Water/Poly(ethylene oxide)43-b-poly(epsilon caprolactone)14/Cyclohexanone Emulsions Involves Water Exchange between the Core and the Bulk. AB - The formation of emulsions upon reverse self-association of the monodisperse amphiphilic block copolymer poly(ethylene oxide)43-b-poly(epsilon-caprolactone)14 in cyclohexanone is reported. Such emulsions are not formed in toluene, chloroform, or dichloromethane. We demonstrate by magnetic resonance spectroscopy the active role of the solvent on the stabilization of the emulsions. Cyclohexanone shows high affinity for both blocks, as predicted by the Hansen solubility parameters, so that the copolymer chains are fully dissolved as monomeric chains. In addition, the solvent is able to produce hydrogen bonding with water molecules. Water undergoes molecular exchange between water molecules associated with the polymer and water molecules associated with the solvent, dynamics of major importance for the stabilization of the emulsions. Association of polymeric chains forming reverse aggregates is induced by water over a concentration threshold of 5 wt %. Reverse copolymer aggregates show submicron average hydrodynamic diameters, as seen by dynamic light scattering, depending on the polymer and water concentration. PMID- 26637019 TI - Diffusion-Limited Cargo Loading of an Engineered Protein Container. AB - The engineered bacterial nanocompartment AaLS-13 is a promising artificial encapsulation system that exploits electrostatic interactions for cargo loading. In order to study its ability to take up and retain guests, a pair of fluorescent proteins was developed which allows spectroscopic determination of the extent of encapsulation by Forster resonance energy transfer (FRET). The encapsulation process is generally complete within a second, suggesting low energetic barriers for proteins to cross the capsid shell. Formation of intermediate aggregates upon mixing host and guest in vitro complicates capsid loading at low ionic strength, but can be sidestepped by increasing salt concentrations or diluting the components. Encapsulation of guests is completely reversible, and the position of the equilibrium is easily tuned by varying the ionic strength. These results, which challenge the notion that AaLS-13 is a continuous rigid shell, provide valuable information about cargo loading that will guide ongoing efforts to engineer functional host-guest complexes. Moreover, it should be possible to adapt the protein FRET pair described in this report to characterize functional capsid-cargo complexes generated by other encapsulation systems. PMID- 26637020 TI - Impact of PES on MD Results of the Coalescence of M2 + M with M = Ir, Pt, Au, Ag. AB - The accuracy of the Sutton-Chen potential energy surface (PES) for describing atomic interactions in small metal clusters was investigated by comparison with density functional theory (DFT) calculation results. The binding energies calculated using the Sutton-Chen PES for the dimers, trimers, and 8- and 13-atom clusters of four transition metals, Ir, Pt, Au, and Ag, differ from those obtained with DFT calculations. As the DFT results agree well with the available experimental data, the above disagreement indicates that the original Sutton-Chen PES cannot accurately describe the interactions among atoms in the cluster for these metals. The parameters of the Sutton-Chen potential were therefore optimized to the DFT results for each of the metals. Molecular dynamics (MD) simulations were carried out on the coalescence of a dimer with a single atom for these metals. Both the original bulk and the cluster optimized Sutton-Chen PESs were tested with various incident angles and initial kinetic energies. The MD results show that the coalescence is highly dependent on the PES. This demonstrates that use of an accurate PES is critical, particularly at low-energy regime. The kinetic energy, incident angle, and choice of metal were examined for their role in the outcome of the coalescence process. PMID- 26637021 TI - Atom-Centered Density Matrix Propagation Calculations on the Methyl Transfer from CH3Cl to NH3: Gas-Phase and Continuum-Solvated Trajectories. AB - Atom-centered density matrix propagation (ADMP) calculations have been carried out to determine gas-phase and continuum-solvated (aqueous) trajectories for the Menshutkin reaction of methyl chloride with ammonia. The gas-phase trajectories reveal an exit channel that has not been previously reported. The aqueous trajectories give the expected results, indicating that solvated ADMP trajectories may be successfully computed using implicit solvation models. The solvated trajectories demonstrate the same stability and convergence qualities as the gas-phase trajectories. PMID- 26637022 TI - Frozen Gaussian Wavepacket Study of the Ground State of the He Atom. AB - The Rayleigh-Ritz functional is used in conjunction with an approximate time evolution to improve ab initio estimates of ground-state energies. The improvement is due in part to the introduction of a novel variational "normalization function" for the approximate propagator. An additional variational parameter was introduced in the form of a constant shift energy of the Hamiltonian. The approximate propagator used was the frozen Gaussian propagator; however, the trajectories evolved on the coherent-state averaged Hamiltonian (Q representation). For Coulombic forces, this removes the singularity, easing the computation. An additional variational parameter was the width parameter used for the coherent states appearing in the frozen Gaussian propagator. Using an initial combination of nine Gaussian functions for He, with an initial energy of -2.5115 au, the variational method, with a very short time interval of integration, led to an improved energy of -2.81 +/- 0.04 au. PMID- 26637023 TI - Monte Carlo Simulations of an Isolated n-Octadecane Chain Solvated in Water Acetonitrile Mixtures. AB - To investigate conformational properties of an isolated n-octadecane chain solvated in water-acetonitrile mixtures, configurational-bias Monte Carlo simulations in the isobaric-isothermal ensemble were performed at T = 323 K and p = 10 atm. The united-atom version of the transferable potentials for phase equilibria force field was used to represent n-octadecane and acetonitrile, and the TIP-4P model was used for water. In all four environments (neat water, 33 and 67 mole percent acetonitrile, and neat acetonitrile), similar conformational distributions are observed as in a previous study for water-methanol solvent mixtures; that is, the n-octadecane chain is found to predominantly adopt extended but not all-trans conformations, and only a small fraction of more collapsed conformations is observed for aqueous hydration, water-rich solvent environments. Analysis of the local solvation structures in the water acetonitrile mixtures shows an enrichment of the acetonitrile molecules near the methylene and methyl segments of the n-octadecane chain. However, upon increasing the concentration of acetonitrile, the enhancement of acetonitrile and the depletion of water is more pronounced than for water-methanol mixtures because of the weaker interactions between acetonitrile and water. PMID- 26637024 TI - Conceptual Density-Functional Theory for General Chemical Reactions, Including Those That Are Neither Charge- nor Frontier-Orbital-Controlled. 1. Theory and Derivation of a General-Purpose Reactivity Indicator. AB - A new general-purpose reactivity indicator is derived. Unlike existing indicators, this indicator can describe the reactivity of molecules that lie between the electrostatic (or charge) control and electron-transfer (or frontier orbital) control paradigms. Depending on the parameters in the indicator, it describes electrostatic control (where the electrostatic potential is the appropriate indicator), electron-transfer control (where the Fukui function's potential is the appropriate indicator), and intermediate cases (where linear combinations of the electrostatic potential and the Fukui function's potential are appropriate indicators). Our analysis gives some insight into the origins of the local hard/soft-acid/base principle. The "minimum Fukui function" rule for hard reagents also emerges naturally from our analysis: if (1) a reaction is strongly electrostatically controlled and (2) there are two sites that are equally favorable from an electrostatic standpoint, then the most reactive of the electrostatically equivalent sites is the site with the smallest Fukui function. An analogous electrostatic potential rule for soft reagents is also introduced: if (1) a reaction is strongly electron-transfer-controlled and (2) there are two sites where the Fukui function's potential are equivalent, then the most reactive of the Fukui-equivalent sites will be the one with greatest electrostatic potential (for electrophilic attack on a nucleophile) or smallest electrostatic potential (for nucleophilic attack on an electrophile). PMID- 26637025 TI - Conceptual Density-Functional Theory for General Chemical Reactions, Including Those That Are Neither Charge- nor Frontier-Orbital-Controlled. 2. Application to Molecules Where Frontier Molecular Orbital Theory Fails. AB - This paper examines cases where frontier molecular orbital theory is known to fail, specifically electrophilic aromatic substitution reactions on isoquinoline and borazarophenanthrenes. While we are able to explain the experimental regioselectivity preferences for isoquinoline without too much difficulty, describing the regioselectivity of the borazarophenanthrenes is much more challenging. This is attributed to the fact that these molecules lie between the electrostatic (or charge) control and electron-transfer (or frontier-orbital) control paradigms. These molecules can, however, be described using the general purpose reactivity indicator introduced in the first paper of this series. The variation of the general-purpose reactivity indicator with respect to the parameters is readily summed up using what we term "reactivity transition tables", which provide a compact summary of which products form under different reaction conditions. For the otherwise problematic molecules considered here, the new reactivity indicator performs better than either the Fukui function or the electrostatic potential alone. PMID- 26637026 TI - Calculation of the Term of Magnetic Circular Dichroism. A Time-Dependent Density Functional Theory Approach. AB - A method for calculating the B term of magnetic circular dichroism utilizing time dependent density functional theory is presented. The expression for the B term is formulated through the standard sum-over-states approach, and all necessary matrix elements and transition energies are provided by the time-dependent density functional theory calculation. Test calculations of the magnetic circular dichroism spectra of ethene, propene, furan and its heavier homologues, and pyrrole and two of its derivatives are presented. The discrepancy between theory and experiment previously observed for ethene is not resolved, but the experimental spectra of the aromatic compounds are very well reproduced by the theory. PMID- 26637027 TI - Bonding in Low-Coordinate Environments: Electronic Structure of Pseudotetrahedral Iron-Imido Complexes. AB - A detailed density functional theory study of pseudotetrahedral Fe(III/IV)-imido phosphine complexes has yielded a host of new insights. The calculations confirm dxy(2)dx(2)-y(2)(2)dz(2)(1) (or ddelta(2)ddelta'(2)dsigma(1)) electronic configurations for Fe(III)-imido complexes of this type, as previously proposed, where the z direction may be identified with the Fe-Nimido vector. However, geometry optimization of a sterically unencumbered model complex indicated a bent (162 degrees ) imido linkage, in sharp contrast to the linear imido groups present in the sterically hindered complexes that have been studied experimentally. Under C3v symmetry, the Fe(III)-imido molecular orbital (MO) energy-level diagram indicates the existence of near-degenerate (2)A1 and (2)E states, and accordingly, the bending of the imido group appears to be ascribable to a pseudo-Jahn-Teller distortion. For Fe(IV)-imido complexes, our calculations indicate a dxy(2)dx(2)-y(2)(1)dz(2)(1) (or ddelta(2)ddelta'(1)dsigma(1)) electronic configuration, which is somewhat different from the dxy(1)dx(2) y(2)(1)dz(2)(2) (or ddelta(1)ddelta'(1)dsigma(2)) configuration proposed in the literature. Not surprisingly, for a sterically unencumbered Fe(IV)-imido complex, the degenerate (3)E state (under C3v symmetry) results in a mild Jahn-Teller distortion and a slightly bent (173 degrees ) imido linkage (on relaxing the symmetry constraint). The calculations also shed light on the surprising stability of the dz(2)-based MO, which points directly at the imido nitrogen, relative to the dpi-based MOs. The low-coordinate nature of the complexes [Formula: see text] the absence of equatorial ligands and of a ligand trans with respect to the imido ligand [Formula: see text] plays a key role in stabilizing the dz(2) orbital as well as the complexes as a whole. The electronic configurations of Fe(IV)-imido porphyrins are radically different from that of the pseudotetrahedral complexes studied here, and we have speculated that these differences may well account for the nonobservation so far of Fe(IV)-imido porphyrins. PMID- 26637028 TI - Evaluation of the SCF Combination of KS-DFT and 3D-RISM-KH; Solvation Effect on Conformational Equilibria, Tautomerization Energies, and Activation Barriers. AB - The effect of solvation on conformational equilibria, tautomerization energies, and activation barriers in simple SN2 reactions is reproduced by using the self consistent field coupling of the Kohn-Sham density functional theory (KS-DFT) for electronic structure and the three-dimensional reference interaction site model with the closure approximation of Kovalenko and Hirata (3D-RISM-KH) for molecular solvation structure. These examples are used in order to validate the implementation of the 3D-RISM-KH method in the Amsterdam Density Functional package. The computations of the free energy difference in the trans/gauche conformational equilibrium for 1,2-dichloroethane in different solvents; the relative tautomerization free energy for cytosine, isocytosine, and guanine; and the free energy activation barrier for a CH3X-type (X = F, Cl, Br) SN2 reaction exhibit agreement with the experimental data. The method is also applied to the electronic and hydration structure of carbon single-wall nanotubes of different diameters, including the effect of water located in the inner space of the nanotubes. A comparison with continuum models of solvation (including COSMO) as well as with other more precise and computationally more expensive calculations is made to demonstrate the accuracy and predictive capability of the new KS DFT/3D-RISM-KH method. PMID- 26637029 TI - The Effect of the Basis-Set Superposition Error on the Calculation of Dispersion Interactions: A Test Study on the Neon Dimer. AB - The dispersion interactions of the Ne2 dimer were studied using both the long range perturbative and supramolecular approaches: for the long-range approach, full CI or string-truncated CI methods were used, while for the supramolecular treatments, the energy curves were computed by using configuration interaction with single and double excitation (CISD), coupled cluster with single and double excitation, and coupled-cluster with single and double (and perturbative) triple excitations. From the interatomic potential-energy curves obtained by the supramolecular approach, the C6 and C8 dispersion coefficients were computed via an interpolation scheme, and they were compared with the corresponding values obtained within the long-range perturbative treatment. We found that the lack of size consistency of the CISD approach makes this method completely useless to compute dispersion coefficients even when the effect of the basis-set superposition error on the dimer curves is considered. The largest full-CI space we were able to use contains more than 1 billion symmetry-adapted Slater determinants, and it is, to our knowledge, the largest calculation of second order properties ever done at the full-CI level so far. Finally, a new data format and libraries (Q5Cost) have been used in order to interface different codes used in the present study. PMID- 26637030 TI - Specific Reaction Parametrization of the AM1/d Hamiltonian for Phosphoryl Transfer Reactions: H, O, and P Atoms. AB - A semiempirical AM1/d Hamiltonian is developed to model phosphoryl transfer reactions catalyzed by enzymes and ribozymes for use in linear-scaling calculations and combined quantum mechanical/molecular mechanical simulations. The model, designated AM1/d-PhoT, is parametrized for H, O, and P atoms to reproduce high-level density-functional results from a recently constructed database of quantum calculations for RNA catalysis ( http://theory.chem.umn.edu/Database/QCRNA ), including geometries and relative energies of minima, transition states and reactive intermediates, dipole moments, proton affinities, and other relevant properties. The model is tested in the gas phase and in solution using a QM/MM potential. The results indicate that the method provides significantly higher accuracy than MNDO/d, AM1, and PM3 methods and, for the transphosphorylation reactions, is in close agreement with the density-functional calculations at the B3LYP/6-311++G(3df,2p) level with a reduction in computational cost of 3-4 orders of magnitude. The model is expected to have considerable impact on the application of semiempirical QM/MM methods to transphosphorylation reactions in solution, enzymes, and ribozymes and to ultimately facilitate the design of improved next-generation multiscale quantum models. PMID- 26637031 TI - Reaction Mechanism of 1,3,5-Trinitro-s-triazine (RDX) Deciphered by Density Functional Theory. AB - 1,3,5-Trinitro-s-triazine, or cyclotrimethylene trinitramine, or RDX, is a sensitive, secondary explosive, which has been the subject of a number of studies regarding the sensitivity and mechanism of decomposition in energetic materials. Several initial mechanistic steps have been proposed for RDX decomposition, with no conclusive agreement upon any one as the definitive pathway. Our research utilizes density functional theory (DFT)-based calculations and concepts, particularly the nuclear Fukui function, to analyze the effects of additive/depletive electronic perturbation upon vapor conformers and crystal RDX structures. Since the nuclear Fukui function is a measure of the physical stress that a nucleus encounters upon a change in the electron population, it may provide useful information regarding the role of each atom in unimolecular decomposition. The results illustrate that both homolytic cleavage of N-N bonds and elimination of HONO from RDX exhibit favorability as initial steps in the decomposition of RDX in either phase. The nuclear Fukui function proved a valuable tool for gaining insight into the initial steps of unimolecular reactions. PMID- 26637032 TI - Catalytic Carbon-Halogen Bond Activation: Trends in Reactivity, Selectivity, and Solvation. AB - We have theoretically studied the oxidative addition of all halomethanes CH3X (with X = F, Cl, Br, I, At) to Pd and PdCl(-), using both nonrelativistic and zeroth-order-regular-approximation-relativistic density functional theory at BLYP/QZ4P. Our study covers the gas phase as well as the condensed phase (water), where solvent effects are described with the conductor-like screening model. The activation of the C*-X bond may proceed via two stereochemically different pathways: (i) direct oxidative insertion (OxIn) which goes with retention of the configuration at C* and (ii) an alternative SN2 pathway which goes with inversion of the configuration at C*. In the gas phase, for Pd, the OxIn pathway has the lowest reaction barrier for all CH3X's. Anion assistance, that is, going from Pd to PdCl(-), changes the preference for all CH3X's from OxIn to the SN2 pathway. Gas-phase reaction barriers for both pathways to C-X activation generally decrease as X descends in group 17. Two striking solvent effects are (i) the shift in reactivity of Pd + CH3X from OxIn to SN2 in the case of the smaller halogens, F and Cl, and (ii) the shift in reactivity of PdCl(-) + CH3X in the opposite direction, that is, from SN2 to OxIn, in the case of the heavier halogens, I and At. We use the activation strain model to arrive at a qualitative understanding of how the competition between OxIn and SN2 pathways is determined by the halogen atom in the activated C-X bond, by anion assistance, and by solvation. PMID- 26637033 TI - Modeling Aromatic Liquids: Toluene, Phenol, and Pyridine. AB - Aromatic groups are now acknowledged to play an important role in many systems of interest. However, existing molecular mechanics methods provide a poor representation of these groups. In a previous paper, we have shown that the molecular mechanics treatment of benzene can be improved by the incorporation of an explicit representation of the aromatic pi electrons. Here, we develop this concept further, developing charge-separation models for toluene, phenol, and pyridine. Monte Carlo simulations are used to parametrize the models, via the reproduction of experimental thermodynamic data, and our models are shown to outperform an existing atom-centered model. The models are then used to make predictions about the structures of the liquids at the molecular level and are tested further through their application to the modeling of gas-phase dimers and cation-pi interactions. PMID- 26637034 TI - Spin-Spin Coupling Constants for Iminoboranes RBNH, HBNR, and RBNR and Comparisons with Corresponding Isoelectronic Acetylenes RCCH and RCCR, for R = H, CH3, NH2, OH, and F. AB - Ab initio equation-of-motion coupled-cluster singles and doubles method calculations have been performed on iminoboranes RBNH, HBNR, and RBNR, for R = H, CH3, NH2, OH, and F, to evaluate substituent effects on one- and two-bond (15)N (11)B, (11)B-(1)H, and (15)N-(1)H spin-spin coupling constants. For comparison purposes, (13)C-(13)C coupling constants were evaluated for corresponding isoelectronic molecules RCCH and RCCR. The absolute values of (1)J(N-B) and (1)J(C-C) increase in the series HBNR and RCCH as the sigma-electron-withdrawing ability of R increases. In contrast, NH2 substitution at B leads to a decrease in the absolute value of (1)J(N-B), but OH and F substitution increase (1)J(N-B). Disubstitution has dramatically different effects on coupling constants for RCCR and RBNR. In the former, (1)J(C-C) more than doubles relative to the corresponding RCCH and HCCH; in the latter, disubstitution of OH and F decreases (1)J(N-B) relative to the corresponding monosubstituted derivatives, while NH2 substitution increases (1)J(N-B). Changes in one- and two-bond B-H and N-H coupling constants upon substitution are similar to changes observed for (1)J(N B) in the corresponding monosubstituted derivatives RBNH and HBNR. PMID- 26637035 TI - Improving Convergence of Replica-Exchange Simulations through Coupling to a High Temperature Structure Reservoir. AB - Parallel tempering or replica-exchange molecular dynamics (REMD) significantly increases the efficiency of conformational sampling for complex molecular systems. However, obtaining converged data with REMD remains challenging, especially for large systems with complex topologies. We propose a new variant to REMD where the replicas are also permitted to exchange with an ensemble of structures that have been generated in advance using high-temperature MD simulations, similar in spirit to J-walking methods. We tested this approach on two non-trivial model systems, a beta-hairpin and a 3-stranded beta-sheet and compared the results to those obtained from very long (>100 ns) standard REMD simulations. The resulting ensembles were indistinguishable, including relative populations of different conformations on the unfolded state. The use of the reservoir is shown to significantly reduce the time required for convergence. PMID- 26637036 TI - Representative Benchmark Suites for Barrier Heights of Diverse Reaction Types and Assessment of Electronic Structure Methods for Thermochemical Kinetics. AB - We propose three small sets of barrier heights for heavy-atom transfer, nucleophilic substitution, and unimolecular and association reactions as benchmarks for comparing and developing theoretical methods. We chose the data sets to be statistically representative subsets of the NHTBH38/04 database. Each data set consists of 6 barrier heights; we call these small benchmark suites HATBH6, NSBH6, and UABH6. Benchmark values are tabulated for 205 combinations of theory level and basis set. The theory levels studied include single-level wave function theory like Hartree-Fock, Moller-Plesset perturbation theory, quadratic configuration interaction, and coupled cluster theory; they also include multicoefficient correlation methods, local and hybrid density functional theory, and semiempirical molecular orbital methods. The three new representative data sets are combined with a previous representative data set for hydrogen-transfer reactions to form a new compact but diverse and representative data set called DBH24. Comparison of a large number of methods for their performance on DBH24 leads us to recommend the following methods for barrier height calculations, in order of decreasing cost: G3SX, BMC-CCSD, PWB6K, BB1K, M06-L, MPW1K, HF/MIDI!, and PM3. PMID- 26637037 TI - The Use of Processor Groups in Molecular Dynamics Simulations to Sample Free Energy States. AB - Molecular dynamics calculations composed of many independent simulations are frequently encountered in free-energy calculations, as well as many other simulation approaches. In principle, the availability of a large number of independent tasks should make possible the development of highly scalable parallel code that executes these tasks concurrently. This paper discusses the use of processor groups to write simulation codes of this type and describes results for a code that evaluates the volume dependence of the Helmholtz free energy for clusters of an immiscible fluid in a solvent. The results show that very high levels of scalability can be achieved using processor groups with corresponding reductions in the time to completion. The main limitation to scaling appears to be a load imbalance due to variations in the execution times of the individual tasks. PMID- 26637038 TI - Computational Requirements for Simulating the Structures and Proton Activity of Silicaceous Materials. AB - Structures of disiloxane and silanol and the energetics of their protonation, deprotonation, and proton exchange reactions have been studied with 14 density functionals in combination with eight basis sets. The geometries optimized by these 112 density functional methods are compared to those obtained by the second order Moller-Plesset perturbation theory and the coupled cluster method, and the performance of all these methods on energetics is evaluated with benchmark Weizmann-1w results. The most accurate density functional for both geometries and energetics is M05-2X. Polarized augmented triple-zeta basis sets are found to be about a factor of 3-4 more accurate than polarized augmented double-zeta basis sets. PMID- 26637039 TI - Theoretical Studies on the Color-Tuning Mechanism in Retinal Proteins. AB - The excited states of the three retinal proteins, bovine rhodopsin (Rh), bacteriorhodopsin (bR), and sensory rhodopsin II (sRII) were studied using the symmetry-adapted cluster-configuration interaction (SAC-CI) and combined quantum mechanical and molecular mechanical (QM/MM) methods. The computed absorption energies are in good agreement with the experimental ones for all three proteins. The spectral tuning mechanism was analyzed in terms of three contributions: molecular structures of the chromophore in the binding pockets, electrostatic (ES) interaction of the chromophore with the surrounding protein environment, and quantum-mechanical effect between the chromophore and the counterion group. This analysis provided an insight into the mechanism of the large blue-shifts in the absorption peak position of Rh and sRII from that of bR. Protein ES effect is primarily important both in Rh and in sRII, and the structure effect is secondary important in Rh. The quantum-mechanical interaction between the chromophore and the counterion is very important for quantitative reproduction of the excitation energy. These results indicate that the present approach is useful for studying the absorption spectra and the mechanism of the color tuning in the retinal proteins. PMID- 26637040 TI - The B(OH)-NH Analog Is a Surrogate for the Amide Bond (CO-NH) in Peptides: An ab Initio Study. AB - The conformational preferences of N-methyl-methylboronamide (NMB), a B(OH)-NH analog of the amide CO-NH in natural peptides, have been investigated at the Hartree-Fock; Becke's three-parameter exchange functional and the gradient corrected functional of Lee, Yang, and Parr; and second-order Moller-Plesset levels of theory with the 6-31+G* basis set. The minima, saddle points, and rotation barriers on the potential energy surface of NMB have been located and the energy barriers estimated. Besides the global minimum, there are three local minima within 2.0 kcal mol(-)(1) of the global minimum characterized by specific omega and tau torsion values. The energy barriers for rotation about the "omega angle" are 16.4-18.8 kcal mol(-)(1) and are a consequence of the double-bond character of the B-N bond as revealed by natural bond orbitals calculations. The "omega angle" and the omega rotation barrier are nearly the same as those seen in natural peptides. The tau rotation barriers (B-O bond) are relatively low because of the single-bond character of the B-O bond. Ala-BON, the Ala-dipeptide derived from NMB, has been constructed as a model peptide to study the conformational preferences about the phi and psi torsion angles. The study reveals a strong preference for alpha-helix, type-II beta-turn, 2.27 ribbon, and antiparallel beta sheet conformations, and mirror images of both type-II beta-turn and 2.27 ribbon motifs whose phi and psi values fall in the "disfavored regions" of the Ramachandran map. Thus, the replacement of the carbonyl group by B-OH retains the geometry and barrier around the "omega angle" and induces a strong preference for regular secondary structure motifs and also structures with positive phi values. This makes the B(OH)-NH analog an important surrogate for the peptide bond, with the additional advantage of stability to proteolytic enzymes. PMID- 26637041 TI - Automated Parametrization of Biomolecular Force Fields from Quantum Mechanics/Molecular Mechanics (QM/MM) Simulations through Force Matching. AB - We introduce a novel procedure to parametrize biomolecular force fields. We perform finite-temperature quantum mechanics/molecular mechanics (QM/MM) molecular dynamics simulations, with the fragment or moiety that has to be parametrized being included in the QM region. By applying a force-matching algorithm, we derive a force field designed in order to reproduce the steric, electrostatic, and dynamic properties of the QM subsystem. The force field determined in this manner has an accuracy that is comparable to the one of the reference QM/MM calculation, but at a greatly reduced computational cost. This allows calculating quantities that would be prohibitive within a QM/MM approach, such as thermodynamic averages involving slow motions of a protein. The method is tested on three different systems in aqueous solution: dihydrogenphosphate, glycyl-alanine dipeptide, and a nitrosyl-dicarbonyl complex of technetium(I). Molecular dynamics simulations with the optimized force field show overall excellent performance in reproducing properties such as structures and dipole moments of the solutes as well as their solvation pattern. PMID- 26637042 TI - Multiscale Optimization of a Truncated Newton Minimization Algorithm and Application to Proteins and Protein-Ligand Complexes. AB - We optimize a truncated Newton (TN) minimization algorithm and computer package, TNPACK, developed for macromolecular minimizations by applying multiscale methods, analogous to those used in molecular dynamics (e.g., r-RESPA). The molecular mechanics forces are divided into short- and long-range components, with the long-range forces updated only intermittently in the iterative evaluations. This algorithm, which we refer to as MSTN, is implemented as a modification to the TNPACK package and is tested on energy minimizations of protein loops, entire proteins, and protein-ligand complexes and compared with the unmodified truncated Newton algorithm, a quasi-Newton algorithm (LBFGS), and a conjugate gradient algorithm (CG+). In vacuum minimizations, the speedup of MSTN relative to the unmodified TN algorithm (TNPACK) depends on system size and the distance cutoffs used for defining the short- and long-range interactions and the long-range force updating frequency, but it is 4 to 5 times greater in the work reported here. This algorithm works best for the minimization of small portions of a protein and shows some degradation (speedup factor of 2-3) for the minimization of entire proteins. The MSTN algorithm is faster than the quasi Newton and conjugate gradient algorithms by approximately 1 order of magnitude. We also present a modification of the algorithm which permits minimizations with a generalized Born implicit solvent model, using a self-consistent procedure that increases the computational expense, relative to a vacuum, by only a small factor (~3-4). PMID- 26637043 TI - Theoretical Study of the Photochemical Isomerization of Colchicine. AB - The photochemical reaction of colchicine to beta- and gamma-lumicolchicine, through a mechanism involving a disrotatory cyclization, is studied by theoretical methods. The energetics of the reaction, including one or two methanol solvent molecules, are studied at the DFT-B3LYP and multireference perturbation levels of theory using the 6-31G(d) basis set. The results show that, in agreement with experimental results, the first excited state of colchicine at ~3.6 eV can lead to both beta- and gamma-lumicolchicine, whose energy is about 15 kcal mol(-)(1) above the colchicine energy. Owing to the high steric tension of the condensed four- and five-atom rings arising from cyclization, the two trans-lumicolchicines are higher in energy (>60 kcal mol( )(1)), and their formation appears much less probable. A partial inclusion of the solvent effects through the addition of two solvent molecules does not alter the general conclusions based on the free energy in the gas phase. The photochemical reaction path is studied by choosing the distance between the two carbon atoms which form the new sigma bond as the leading coordinate of the minimum-energy path of both the ground and the first singlet excited states. The energies are computed by Multi Configurational self-consistent-field calculations on a model molecule, retaining those atoms that presumably play an active role in the reaction. A reasonable mechanism starting from colchicine in the first singlet excited state and leading to gamma-lumicolchicine is proposed. On the contrary, a high-energy transition state is found for trans-lumicolchicines, whose formation, although not strictly forbidden for energetic reasons, appears to be rather improbable. PMID- 26637044 TI - Structure and Stability of Small ZnCn Clusters. AB - A theoretical study of the small ZnCn (n = 1-8) clusters has been carried out at the B3LYP/6-311+G(d) level. Different molecular properties for open-chain and cyclic species have been calculated. The computed properties include electronic energies, vibrational frequencies, dipole moments, and rotational constants for individual species. In addition, the relative stability of the different clusters is also discussed in terms of the incremental binding energy. In the case of open chain clusters, the lowest-lying states correspond to triplet states with the exception of ZnC2, whereas the electronic ground state is found to be a singlet state for cyclic clusters. The incremental binding energy graph shows a smooth even-odd parity effect in the incremental binding energy, n-even species being, in general, more stable than the adjacent odd-numbered ones. It was also found that the first members in the series, excepting ZnC2, prefer open-chain structures, whereas when n >= 6 cyclic ground states are favored. PMID- 26637045 TI - Geometry Optimization of a Ru(IV) Allyl Dicationic Complex: A DFT Failure? AB - Five pure and four hybrid DFT functionals associated with VDZP, VTZP, and VQZP basis sets are tested (Gaussian 03) for their performance on the geometry optimization of [Ru(eta(5)-C5H5)(eta(3)-CH2CHCHC6H5)(CH3CN)2](2+). When the calculated geometries were compared with the X-ray structure determination for the analogous complex with permethylated cyclopentadienyl, it was found that in all cases the coordination mode of the eta(3)-allyl was very poorly described, despite the functional used. The Ru-C bond distance corresponding to the substituted allyl carbon was overestimated by 0.23-0.50 A, depending on the functional and the basis set used. These results were reproduced by further testing carried out with the ADF program and larger basis sets. MP2 leads to an acceptable value for the same Ru-C distance, with an underestimation of 0.07 A, suggesting that, at least in the case of the functionals tested, DFT does not provide an accurate description of a weak Ru-C interaction. PMID- 26637046 TI - Sampangine (a Copyrine Alkaloid) Exerts Biological Activities through Cellular Redox Cycling of Its Quinone and Semiquinone Intermediates. AB - The cananga tree alkaloid sampangine (1) has been extensively investigated for its antimicrobial and antitumor potential. Mechanistic studies have linked its biological activities to the reduction of cellular oxygen, the induction of reactive oxygen species (ROS), and alterations in heme biosynthesis. Based on the yeast gene deletion library screening results that indicated mitochondrial gene deletions enhanced the sensitivity to 1, the effects of 1 on cellular respiration were examined. Sampangine increased oxygen consumption rates in both yeast and human tumor cells. Mechanistic investigation indicated that 1 may have a modest uncoupling effect, but predominately acts by increasing oxygen consumption independent of mitochondrial complex IV. Sampangine thus appears to undergo redox cycling that may involve respiratory chain-dependent reduction to a semi iminoquinone followed by oxidation and consequent superoxide production. Relatively high concentrations of 1 showed significant neurotoxicity in studies conducted with rat cerebellar granule neurons, indicating that sampangine use may be associated with potential neurotoxicity. PMID- 26637047 TI - Imprint Desorption Electrospray Ionization Mass Spectrometry Imaging for Monitoring Secondary Metabolites Production during Antagonistic Interaction of Fungi. AB - Direct analysis of microbial cocultures grown on agar media by desorption electrospray ionization mass spectrometry (DESI-MS) is quite challenging. Due to the high gas pressure upon impact with the surface, the desorption mechanism does not allow direct imaging of soft or irregular surfaces. The divots in the agar, created by the high-pressure gas and spray, dramatically change the geometry of the system decreasing the intensity of the signal. In order to overcome this limitation, an imprinting step, in which the chemicals are initially transferred to flat hard surfaces, was coupled to DESI-MS and applied for the first time to fungal cocultures. Note that fungal cocultures are often disadvantageous in direct imaging mass spectrometry. Agar plates of fungi present a complex topography due to the simultaneous presence of dynamic mycelia and spores. One of the most devastating diseases of cocoa trees is caused by fungal phytopathogen Moniliophthora roreri. Strategies for pest management include the application of endophytic fungi, such as Trichoderma harzianum, that act as biocontrol agents by antagonizing M. roreri. However, the complex chemical communication underlying the basis for this phytopathogen-dependent biocontrol is still unknown. In this study, we investigated the metabolic exchange that takes place during the antagonistic interaction between M. roreri and T. harzianum. Using imprint-DESI MS imaging we annotated the secondary metabolites released when T. harzianum and M. roreri were cultured in isolation and compared these to those produced after 3 weeks of coculture. We identified and localized four phytopathogen-dependent secondary metabolites, including T39 butenolide, harzianolide, and sorbicillinol. In order to verify the reliability of the imprint-DESI-MS imaging data and evaluate the capability of tape imprints to extract fungal metabolites while maintaining their localization, six representative plugs along the entire M. roreri/T. harzianum coculture plate were removed, weighed, extracted, and analyzed by liquid chromatography-high-resolution mass spectrometry (LC-HRMS). Our results not only provide a better understanding of M. roreri-dependent metabolic induction in T. harzianum, but may seed novel directions for the advancement of phytopathogen-dependent biocontrol, including the generation of optimized Trichoderma strains against M. roreri, new biopesticides, and biofertilizers. PMID- 26637048 TI - Efficacy and tolerability of switching therapy to vortioxetine versus other antidepressants in patients with major depressive disorder. AB - OBJECTIVES: To assess the relative efficacy and tolerability of vortioxetine against different antidepressant monotherapies in patients with major depressive disorder (MDD) with inadequate response to selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI) therapy. METHODS: A systematic search was conducted for monotherapy studies in patients with MDD with inadequate response to first-line therapy. Treatments included SSRIs, SNRIs, and other antidepressants. Identified studies underwent a three-stage screening/data extraction process and critical appraisal. Adjusted indirect treatment comparisons (ITCs) on systematic literature review outputs were made using Bucher's method, comparing remission rates and withdrawal rates due to adverse events (AEs). RESULTS: Of 27 studies meeting the inclusion criteria, a few studies were of high quality according to the National Institute of Health and Care Excellence checklist. Three studies contributed to an evidence network for quantitative assessment comparing vortioxetine with agomelatine, sertraline, venlafaxine XR, and bupropion SR. Vortioxetine had a statistically significantly higher remission rate than agomelatine (risk difference [RD]: -11.0% [95% CI: 19.4; -2.6]), and numerically higher remission rates than sertraline (RD: -14.4% [95% CI: -29.9; 1.1]), venlafaxine (RD: -7.20% [95% CI: -24.3; 9.9]), and bupropion (RD: -10.70% [95% CI: -27.8; 6.4]). Withdrawal rates due to AEs were statistically significantly lower for vortioxetine than sertraline (RD: 12.1% [95% CI: 3.1; 21.1]), venlafaxine XR (RD: 12.3% [95% CI: 0.8; 23.8]), and bupropion SR (RD: 18.3% [95% CI: 6.4; 30.1]). CONCLUSIONS: The current systematic literature review found a few high quality switch studies assessing monotherapies in patients with MDD with inadequate response to SSRI/SNRIs. ITCs indicated that switching to vortioxetine leads to numerically higher remission rates compared with other antidepressants. Vortioxetine is a well tolerated treatment, showing statistically lower withdrawal rates due to AEs compared with other antidepressants. Vortioxetine is a relevant therapeutic alternative in patients experiencing inadequate response to prior SSRI or SNRI therapy. PMID- 26637049 TI - [New Pathogenetic Concepts and Pharmacological Studies on Adjuvant Therapy in Severe Pneumonia]. AB - Acute lung injury secondary to pneumonia results from inadequate activation of the innate immune system with hyperinflammation and alveolar-capillary barrier dysfunction. To date, effective strategies for prevention or treatment of acute lung injury in pneumonia besides antibiotics are lacking. In preclinical studies, promising therapeutic targets have been identified and novel strategies demonstrated to protect against lung failure in pneumonia. This review highlights some adjuvant therapeutic strategies for modulation of inflammation and stabilization of lung barrier function in pneumonia. PMID- 26637050 TI - Editorial. PMID- 26637052 TI - ERRATUM. PMID- 26637053 TI - Transcript RNA supports precise repair of its own DNA gene. AB - The transfer of genetic information from RNA to DNA is considered an extraordinary process in molecular biology. Despite the fact that cells transcribe abundant amount of RNA with a wide range of functions, it has been difficult to uncover whether RNA can serve as a template for DNA repair and recombination. An increasing number of experimental evidences suggest a direct role of RNA in DNA modification. Recently, we demonstrated that endogenous transcript RNA can serve as a template to repair a DNA double-strand break (DSB), the most harmful DNA lesion, not only indirectly via formation of a DNA copy (cDNA) intermediate, but also directly in a homology driven mechanism in budding yeast. These results point out that the transfer of genetic information from RNA to DNA is more general than previously thought. We found that transcript RNA is more efficient in repairing a DSB in its own DNA (in cis) than in a homologous but ectopic locus (in trans). Here, we summarize current knowledge about the process of RNA-driven DNA repair and recombination, and provide further data in support of our model of DSB repair by transcript RNA in cis. We show that a DSB is precisely repaired predominately by transcript RNA and not by residual cDNA in conditions in which formation of cDNA by reverse transcription is inhibited. Additionally, we demonstrate that defects in ribonuclease (RNase) H stimulate precise DSB repair by homologous RNA or cDNA sequence, and not by homologous DNA sequence carried on a plasmid. These results highlight an antagonistic role of RNase H in RNA-DNA recombination. Ultimately, we discuss several questions that should be addressed to better understand mechanisms and implications of RNA templated DNA repair and recombination. PMID- 26637054 TI - VH-VL orientation prediction for antibody humanization candidate selection: A case study. AB - Antibody humanization describes the procedure of grafting a non-human antibody's complementarity-determining regions, i.e., the variable loop regions that mediate specific interactions with the antigen, onto a beta-sheet framework that is representative of the human variable region germline repertoire, thus reducing the number of potentially antigenic epitopes that might trigger an anti-antibody response. The selection criterion for the so-called acceptor frameworks (one for the heavy and one for the light chain variable region) is traditionally based on sequence similarity. Here, we propose a novel approach that selects acceptor frameworks such that the relative orientation of the 2 variable domains in 3D space, and thereby the geometry of the antigen-binding site, is conserved throughout the process of humanization. The methodology relies on a machine learning-based predictor of antibody variable domain orientation that has recently been shown to improve the quality of antibody homology models. Using data from 3 humanization campaigns, we demonstrate that preselecting humanization variants based on the predicted difference in variable domain orientation with regard to the original antibody leads to subsets of variants with a significant improvement in binding affinity. PMID- 26637060 TI - Size-dependent nanoparticulate drug delivery in inflammatory bowel diseases. AB - INTRODUCTION: Inflammatory bowel disease (IBD) is a chronic autoimmune disease, whose main forms are Crohn's disease and ulcerative colitis. The main treatment of IBD includes oral administration of anti-inflammatory or immunosuppressive agents enclosed in traditional dosage forms, intended to release the active ingredient in the large intestine. However, most of them have been designed based on the physiology of healthy colon, which differs distinctly from conditions met in IBD patients risking adverse effects and patient intolerance. The use of nanoparticles as a drug carrier for treatment of IBD is a promising approach that is capable of solving this problem. Previous studies have shown a size-dependent behavior, where reducing the particle size, increases the targeting efficacy and the residence time compared to healthy controls. AREAS COVERED: This review covers the utilization of nanoparticles as drug delivery carriers for treating IBD. They can reach the inflamed colonic sites either by endothelial or epithelial delivery employing passive and active targeting strategies. The effect of particle size is analyzed in detail while elucidating other essential parameters such as the particle surface properties. EXPERT OPINION: One of the most important advantages of nanoparticles is their passive targeting to the inflamed colonic tissues due to their size. Recent findings underline that this size-dependent bioadhesion behavior can be further enhanced by selecting smart surface properties to help in penetrating the mucus and reach the inflamed sites. PMID- 26637059 TI - Overexpression of miR-26b-5p regulates the cell cycle by targeting CCND2 in GC-2 cells under exposure to extremely low frequency electromagnetic fields. AB - The increasing prevalence of extremely low frequency electromagnetic fields (ELF EMFs) exposure has raised considerable public concern regarding the potential hazardous effects of ELF-EMFs on male reproductive function. Increasing evidence indicates that miRNAs are necessary for spermatogenesis and male fertility. However, the regulation of miRNA expression and the roles of miRNAs in response to ELF-EMFs remain unclear. In our study, mouse spermatocyte-derived GC-2 cells were intermittently exposed to a 50 Hz ELF-EMF for 72 h (5 min on/10 min off) at magnetic field intensities of 1 mT, 2 mT and 3 mT. MiR-26b-5p was differentially expressed in response to different magnetic field intensities of ELF-EMFs. The host gene CTDSP1 showed an unmethylation status in GC-2 cells at different magnetic field intensities of ELF-EMF exposure. MiR-26b-5p had no significant, obvious influence on the cell viability, apoptosis or cell cycle of GC-2 cells. However, the overexpression of miR-26b-5p significantly decreased the percentage of G0/G1 phase cells and slightly increased the percentage of S phase cells compared to the sham group that was exposed to a 50 Hz ELF-EMF. Computational algorithms identified Cyclin D2 (CCND2) as a direct target of miR-26b-5p. MiR-26b 5p and a 50 Hz ELF-EMF altered the expression of CCND2 at both the mRNA and protein levels. Overexpressed miR-26b-5p in GC-2 cells can change the mRNA expression of CCND2 following 50 Hz ELF-EMF at 3 mT. These findings demonstrate that miR-26b-5p could serve as a potential biomarker following 50 Hz ELF-EMF exposure, and miR-26b-5p-CCND2-mediated cell cycle regulation might play a pivotal role in the biological effects of ELF-EMFs. PMID- 26637061 TI - Far caudally migrated extraforaminal lumbosacral disc herniation treated by a microsurgical lateral extraforaminal transmuscular approach: case report. AB - A 33-year-old man presented with moderate low-back pain and L-5 radiculopathy that progressed to severe paresis of L-5. On initial imaging, a corresponding spinal lesion was overlooked. Further CT and contrast-enhanced MRI demonstrated a presacral mass along the L-5 root far extraforaminally. A herniated disc was suspected, but with standard imaging a schwannoma could not be ruled out. The presacral L-5 root was explored via a microsurgical lateral extraforaminal transmuscular approach. To the best of the authors' knowledge, there have been no reports of sequestered extraforaminal lumbosacral disc herniations that herniated into the presacral region. PMID- 26637062 TI - Inferior vena cava injury caused by an anteriorly migrated cage resulting in ligation: case report. AB - Anterior dislodgement of the transforaminal lumbar interbody fusion (TLIF) cage is one of the severe complications seen in this procedure, which may cause an intraoperative major vessel injury. The objective of this report is to present a rare case of inferior vena cava (IVC) injury during revision surgery for removal of the anteriorly migrated cage. The authors describe a case of 74-year-old woman with lumbar spinal canal stenosis and degenerative scoliosis. During the TLIF surgery, an inserted titanium cage at the L4-5 level dislodged anteriorly to the retroperitoneal space without massive bleeding from the disc space. In the second surgery, which was performed via an anterior retroperitoneal approach to remove the migrated cage, massive torrential bleeding occurred because of IVC injury. The laceration in the posterior wall of the IVC necessitated ligation of this vessel and both common iliac veins by a vascular surgeon. Postoperative edema of the lower extremities after ligation of the vessels was well tolerated, and the patient showed almost full recovery. For removal surgery of an anteriorly migrated cage, the surgeon should be well prepared for the risk of IVC injury, including requesting the attendance of a vascular surgeon. Ligation of the infrarenal IVC is an acceptable solution in irreparable IVC injury. PMID- 26637063 TI - The unusual presentation of a vascular injury after lumbar microdiscectomy: case report. AB - Vascular injury during lumbar spine surgery is a relatively rare complication but can have devastating outcomes. The injury may not be apparent during surgery and can present acutely or late in various manners, and some injuries can be asymptomatic. This report discusses the unusual case of a 35-year-old woman who underwent a right L4-5 microdiscectomy for disc herniation and 4 days postoperatively presented with a pulmonary embolus. A subsequent CT scan revealed a pseudoaneurysm and arteriovenous fistula of the right common iliac vein and artery, which gave rise to the embolus. The patient received a right iliac artery stent, and at 4 months after surgery she continues to be symptom free. This report describes the atypical presentation of vascular injury after lumbar microdiscectomy and stresses the importance of cautiously using the pituitary rongeur when removing deeper disc fragments. PMID- 26637064 TI - Erratum: Isadore Max Tarlov (1905-1977) and the controversial Tarlov cyst: historical perspective. PMID- 26637065 TI - Effects of fusion and conservative treatment on disc degeneration and rates of subsequent surgery after thoracolumbar fracture. AB - OBJECT: The objective of this study was to compare the incidence of degeneration and need for subsequent fusion surgery between patients who were treated nonsurgically and patients treated with fusion after a diagnosis of thoracic-or lumbar-level fracture without degenerative disease. METHODS: The authors performed a retrospective study of Orthopedic United Healthcare patients diagnosed with thoracic or lumbar fracture. Patients were filtered into thoracic and lumbar fracture groups using diagnostic codes and then assigned to one of 2 treatment subgroups (fusion surgery or no surgery) on the basis of procedural codes. Disc degeneration and follow-up surgery were recorded. Chi-square statistical analysis was used. RESULTS: Of 3699 patients diagnosed with a thoracic fracture, 117 (3.2%) underwent thoracic fusion and 3215 (86.9%) were treated nonsurgically. Within 3 years, 147 (4.6%) patients from the nonsurgical subgroup and fewer than 11 (0.9%-8.5%) from the fusion subgroup were diagnosed with thoracic disc degeneration. From the nonsurgical subgroup, 11 (0.3%) patients underwent a thoracic surgery related to disc degeneration compared with zero from the fusion group (p > 0.05). Of 5016 patients diagnosed with lumbar fracture, 150 (3.0%) underwent fusion and 4371 (87.1%) had no surgery. Within 3 years, 503 patients (11.5%) from the nonsurgical subgroup and 35 (23.3%) from the fusion subgroup were diagnosed with lumbar disc degeneration (p < 0.05). From the nonsurgical subgroup, 42 (1.0%) went on to have surgery related to disc degeneration, compared with fewer than 11 (0.7%-6.7%) from the fusion subgroup (values not precise due to privacy limitations). CONCLUSIONS: Fusion surgery for thoracic fracture does not appear to increase the likelihood of undergoing future surgery. In the lumbar region, initial fusion surgery appears to increase the incidence of disc degeneration and could potentially necessitate future surgeries. PMID- 26637066 TI - Editorial: Vascular injury during spinal procedures. PMID- 26637067 TI - A biomechanical comparison of 3 different posterior fixation techniques for 2 level lumbar spinal disorders. AB - OBJECT: This study sought to make a biomechanical comparison of 3 different posterior fixation techniques for 2-level lumbar spinal disorders. METHODS: Eight fresh-frozen human cadaver lumbar spines (4 from L-1 to L-5, 4 from L-1 to S-1) were tested by applying pure moments of +/- 8 Nm. Each specimen was first tested intact, and then the left facetectomies of L3-4 and L4-5 were performed to establish an unstable condition without removal of discs. Three instrumentation systems were then tested randomly: unilateral pedicle screw (UPS), UPS with contralateral translaminar facet screw (UPSFS), and bilateral pedicle screw (BPS). The range of motion (ROM) and the neutral zone (NZ) of L3-5 were measured. RESULTS: All fixation types could reduce the ROM of L3-5 significantly in flexion, extension, and lateral bending, compared with the intact state. In axial torsion, only BPS reduced the ROM significantly, compared with the intact state. The UPSFS technique provided intermediate stability, which was superior to the UPS in flexion-extension and lateral bending, and inferior to the BPS in lateral bending. Compared with the intact state, the NZs decreased significantly for UPS, UPSFS, and BPS in flexion-extension, while not significantly in lateral bending and axial torsion. CONCLUSIONS: In this study, among the 3 fixation techniques, BPS offered the highest stability, UPSFS provided intermediate stability, and UPS was the least stable for 2-level lumbar spinal disorders. UPSFS appeared to be able to offer a less invasive choice than BPS in well-selected patients with 2 level lumbar spinal disorders. PMID- 26637068 TI - Hospitalization Risk Before and After Discontinuation of Long-Acting Injectable Antipsychotics. PMID- 26637069 TI - The High Multiplicity of Prenatal (Congenital Type) Nevi in Adolescents and Adults. AB - In the absence of work on prenatal nevogenesis, it has long been necessary to define congenital melanocytic nevi by clinical detection on neonatal skin examination. They are seen in approximately 1% of newborns, with multiplicity in approximately 3% of cases. Melan-A staining of grossly normal fetal skin recently demonstrated fetal nevi, whose features validated certain traditional histologic criteria for "congenital type" nevi that may not have been detectable at birth. This suggested that many clinically acquired nevi actually formed in utero, like congenital nevi. Prenatal nevi has been suggested as a preferred synonym for "congenital type" nevi. Prenatal nevi were detected in 6 of 25 fetuses (24%), a strikingly higher incidence than congenital nevi in newborns. In this series of 354 patients with prenatal (congenital type) nevi encountered in routine practice at a community hospital, over 30% of both adolescents and adults had multiple prenatal nevi; a strikingly higher rate of multiplicity than congenital nevi in newborns. This high multiplicity may reflect origin beneath the epidermis, with many prenatal nevi working their way up to the surface of the skin decades after birth. PMID- 26637071 TI - Applications of both time of flight and point spread function in brain PET image reconstruction. AB - AIM: To assess the effects of different high-resolution image reconstruction methods on the quality of images and quantitatively compare their accuracy in human brain PET images. MATERIALS AND METHODS: Brain images were reconstructed using six algorithms including back-projection (B), B+time of flight (TOF), ordered subsets expectation maximization (OSEM), OSEM+TOF, OSEM+point spread function (PSF), and OSEM+PSF+TOF. The qualities of images including the spatial resolution, contrast, and signal-to-noise ratio (SNR) were compared qualitatively and quantitatively, and the mean standardized uptake value (SUVmean) of different brain regions obtained by different reconstruction algorithms were also compared. RESULTS: The contrast of images obtained by the six reconstruction algorithms was not significantly different (P>0.05). PSF significantly improved the spatial resolution and SNR by 23.8%. Combined PSF significantly increased the SUVmean of all brain regions, except the mesial temporal lobe and part of the basal ganglia. Application of TOF did not obviously increase the resolution and contrast, but improved SNR by up to 11.9%. Compared with OSEM and OSEM+PSF, application of OSEM+TOF and OSEM+PSF+TOF evidently affected the SUVmean of some brain regions and resulted in differentiation phenomena. TOF obviously increased the SUVmean of the temporal lobe, but significantly reduced that of the cingulate and paracingulate gyri, mesial temporal lobe, and cerebellum. CONCLUSION: PSF was the most effective reconstruction algorithm to improve the quality of brain images. The combined PSF algorithm could increase the SUVmean and made it closer to the actual standardized uptake value. The combined TOF algorithm should be applied with caution in quantitative analysis. PMID- 26637070 TI - Temporal and Spatial Expression of Transforming Growth Factor-beta after Airway Remodeling to Tobacco Smoke in Rats. AB - Airway remodeling is strongly correlated with the progression of chronic obstructive pulmonary disease (COPD). In this study, our goal was to characterize progressive structural changes in site-specific airways, along with the temporal and spatial expression of transforming growth factor (TGF)-beta in the lungs of male spontaneously hypertensive rats exposed to tobacco smoke (TS). Our studies demonstrated that TS-induced changes of the airways is dependent on airway generation and exposure duration for proximal, midlevel, and distal airways. Stratified squamous epithelial cell metaplasia was evident in the most proximal airways after 4 and 12 weeks but with minimal levels of TGF-beta-positive epithelial cells after only 4 weeks of exposure. In contrast, epithelial cells in midlevel and distal airways were strongly TGF-beta positive at both 4 and 12 weeks of TS exposure. Airway smooth muscle volume increased significantly at 4 and 12 weeks in midlevel airways. Immunohistochemistry of TGF-beta was also found to be significantly increased at 4 and 12 weeks in lymphoid tissues and alveolar macrophages. ELISA of whole-lung homogenate demonstrated that TGF-beta2 was increased after 4 and 12 weeks of TS exposure, whereas TGF-beta1 was decreased at 12 weeks of TS exposure. Airway levels of messenger RNA for TGF-beta2, as well as platelet-derived growth factor-A, granulocyte-macrophage colony-stimulating factor, and vascular endothelial growth factor-alpha, growth factors regulated by TGF-beta, were significantly decreased in animals after 12 weeks of TS exposure. Our data indicate that TS increases TGF-beta in epithelial and inflammatory cells in connection with airway remodeling, although the specific role of each TGF-beta isoform remains to be defined in TS-induced airway injury and disease. PMID- 26637072 TI - The strange case of the [13N]NH3: validation of the production process for human use. AB - OBJECTIVE: PET radiopharmaceuticals are often injected in patients before all quality controls are performed and before sterility results are available. We propose a process validation to produce very safe and pure [N]NH3 for human use. METHODS: [N]NH3 was produced in the cyclotron target. Online purification was performed by anionic exchange resin. All the production steps were subjected to a sterility test. Some additional controls were added to those required by the monograph. RESULTS: The radiochemical yield of the syntheses was 26.3 and 61.5% corrected for decay, with a radiochemical purity of 100%. In addition to quality controls requested by the European Pharmacopeia monograph, we carefully analyzed the product for the presence of possible contaminants. Some elements, mainly metals, were found in very low amounts at concentrations in the range of ppb. The radionuclidic purity was verified. The achievement of the parameters of osmolality, by addition of saline solution to the preparation, made the analysis of chemical purity difficult and worsened the measurement of radiochemical purity by high performance liquid chromatography. Only pH control is necessary before administration to patients and therefore a safe production process was set up to prevent microbiological contamination. All phases were carefully standardized, starting from in-target production of [N]NH3, to final splitting in the syringes. Sterility tests showed no bacterial growth, indicating the safety of the production process. CONCLUSION: All our syntheses followed the monograph indications and were optimal to obtain PET imaging of a patient's myocardium. PMID- 26637073 TI - A risk prediction model for colorectal cancer using genome-wide association study identified polymorphisms and established risk factors among Japanese: results from two independent case-control studies. AB - Most genome-wide association studies of colorectal cancer (CRC) carried out to date have been in populations with European ancestry, and the extent to which the identified variants contribute as predictors of CRC among Japanese populations has not been clarified. We analyzed 23 genetic variants identified in previous genome-wide association studies in a derivation case-control study with 558 cases and 1116 age-matched and sex-matched controls. Six single nucleotide polymorphisms were selected for synthesis of the genetic risk score. A dose dependent association was observed between CRC risk and genetic risk score, which is the aggregate number of alleles in six selected variants: 8q24 - rs6983267, 15q13 - rs4779584 and rs1696961, 14q22 - rs444435, 16q22 - rs9929218, and 3q26.2 rs1093599. The c statistic for a model that included the genetic risk score and conventional risk factors was 0.7167, versus 0.7009 with the conventional risk factors only (P=0.0013). This model was evaluated in a replication study with 547 cases and 547 age-matched and sex-matched controls, and the corresponding c statistics were 0.6356 and 0.6391 with no statistical significance. When the two studies were combined, the corresponding c statistics were 0.6132 and 0.6198 (P=0.0126). We developed a risk model that incorporates a genetic risk score and established risk factors, but this model was not satisfactory in the replication study. The results in the combined study still encourage further attempts using a similar approach among individual countries. PMID- 26637074 TI - High-resolution microendoscopy: a point-of-care diagnostic for cervical dysplasia in low-resource settings. AB - Cervical cancer is the third leading cause of cancer-related death among women in low-to-middle income countries. Pap testing and pathological services are difficult to implement under these settings. Alternative techniques for the diagnosis of cervical precancer in these settings are needed to reduce the burden of the disease. The objective of this study was to evaluate the diagnostic accuracy of a low-cost, high-resolution microendoscope imaging system in identifying precancerous lesions of the cervix in vivo. A retrospective study of 59 patients undergoing colposcopy for an abnormal Pap test was performed at Hospital de Cancer de Barretos in Brazil. All patients underwent colposcopy as per standard of care, and acetowhite lesions were recorded. High-resolution microendoscopy (HRME) images were obtained from one colposcopically normal region and from all lesions observed on colposcopy. Biopsies of abnormal areas were obtained and reviewed by three independent, blinded pathologists and compared with HRME findings. The mean nuclear area and the median nuclear eccentricity were calculated from HRME images acquired from each site. A diagnostic algorithm to distinguish histopathologically diagnosed cervical intraepithelial neoplasias of grade 2 or more severe lesions (high grade) from less severe lesions (low grade) was developed using these parameters. A test of trend was used to analyze the relationship between HRME positivity and severity of histopathogical diagnosis. Fisher's exact test was used to analyze differences in HRME positivity between high-grade and low-grade lesions. Evaluable images were obtained from 108 of 143 discrete sites. Of these, 71 sites were colposcopically normal or low grade according to histopathology and 37 were diagnosed as high grade on the basis of histopathology. Using the mean nuclear area and the median nuclear eccentricity, HRME images from 59 colposcopically abnormal sites were classified as high grade or low grade with 92% sensitivity and 77% specificity compared with histopathological findings. Increasing HRME positivity showed a significant trend with increasing severity of diagnosis (Ptrend<0.001). We found a strong association (P<0.001) between HRME positivity and a histopathological diagnosis of cervical intraepithelial neoplasia of grade 2 or higher. HRME demonstrated an accurate in-situ diagnosis of high-grade dysplasia. In low-resource settings in which colposcopy and histopathology services are severely limited or unavailable, HRME may provide a low-cost, accurate method for diagnosis of cervical precancer without the need for biopsy, allowing for a single 'screen-and-treat' approach. PMID- 26637075 TI - An Unusual Ectopic Pregnancy. PMID- 26637076 TI - Something in the Air. PMID- 26637077 TI - Risk of Preterm Birth According to Maternal and Paternal Country of Birth: A Population-Based Study. AB - OBJECTIVE: To examine the co-contribution of maternal and paternal country of origin to preterm birth, and the differences in PTB rates between immigrants giving birth in Canada and those giving birth in their country of origin. METHODS: Using a population-based study for all of Ontario, we included 1 200 864 singleton and twin livebirths from 2002 to 2011. The risk of PTB in infants of immigrant parents from the same country was compared to those whose parents were both Canadian-born. Logistic regression analysis adjusted for maternal and paternal age, parity, marital status, income, infant sex, and twins. We also measured differences in the calculated rate of PTB among immigrants by parental country of birth minus the published PTB rate within their native country. The main outcome measures were PTB < 37 weeks, late PTB at 34 to 36 weeks, and very PTB < 32 weeks. RESULTS: Compared with infants of two Canadian-born parents, those of immigrant parents from the same country had a lower risk of PTB (aOR 0.94, 95% CI 0.92 to 0.96) and late PTB (aOR 0.92, 95% CI 0.89 to 0.94) but a higher risk of very PTB (aOR 1.09, 95% CI 1.04 to 1.16). Infants of couples from Guyana, Trinidad and Tobago, the Philippines, and Jamaica were at increased risk of PTB, late PTB, and very PTB. The rate of PTB was, on average, 3% lower for newborns of immigrant parents than the published rate of PTB in their native country. CONCLUSION: The rate of PTB is influenced by maternal and paternal country of birth. That rate is generally lower among immigrants than the rate in their native country of origin. PMID- 26637078 TI - Learning From Experience: Development of a Cognitive Task List to Perform a Caesarean Section in the Second Stage of Labour. AB - OBJECTIVE: Caesarean section at full cervical dilatation is a challenging procedure with a higher risk of fetal and maternal morbidity. We wished to elicit the essential clinical components of a CS at full dilatation performed skilfully and safely. METHODS: We conducted a prospective study with both qualitative (individual interviews) and quantitative (questionnaire) components. In the qualitative components, senior clinicians were interviewed using open-ended questions regarding techniques used for performance of CS at full cervical dilatation. Interviews were recorded and thematic analysis was performed until saturation was achieved. In the second (quantitative) component of the study, clinicians completed a questionnaire regarding tips and techniques to perform a CS at full cervical dilatation. RESULTS: For the qualitative component, 15 clinicians agreed to participate. There was a 90% (n = 27) response rate to the questionnaire. Common themes from both components of the study included the advice to routinely re-examine the patient (with abdominal and vaginal examinations) in the operating room after induction of anaesthesia to determine pelvic architecture, fetal size, and the station of the presenting part, and especially to assess for progress since the initial decision to perform a CS in the labour room. When the decision is made to proceed with CS, the following modifications to a standard CS technique were suggested: first, to make a more superior transverse uterine incision than usual, and second, to secure each uterine angle separately before uterine closure is commenced in order to identify and manage angle extension and thereby minimize blood loss. Other modifications, such as vaginal disimpaction of the fetal head before beginning the operation, were more controversial. Participants developed their own techniques by combining teaching from senior obstetricians, watching others operate, and learning from their own clinical experience. CONCLUSION: There is an increasing role for good quality clinical training programs on how best to perform complex deliveries such as CS at full cervical dilatation. After identifying the essential components of CS at full cervical dilatation reported by multiple skilled clinicians, these can then be translated into a useful educational tool. PMID- 26637079 TI - Is Any Press Good Press? The Impact of Media Portrayals of Infertility on Young Adults' Perceptions of Infertility. AB - OBJECTIVE: Infertility is an issue of current concern across North America. The Society of Obstetricians and Gynaecologists of Canada advocates for public education regarding infertility issues. Public education is supposed to be a fundamental objective of news media. However, it is uncertain whether the media are acting as good partners to the medical profession in this objective of educating the public, and young women in particular. Recent findings suggest that print news tends to present infertility using high-alarm framing strategies; however, the impact of this framing on news consumers is unknown. The purpose of this study was to understand the effects of high- versus low-alarm frames on consumers of infertility-related news. METHODS: In this experiment, 131 undergraduate students were randomly assigned to read infertility-focused news articles judged to employ either high- or low-alarm framing strategies in presenting infertility. Participants subsequently completed various psychological, emotional, and knowledge measures to gauge the impact of the news exposure. RESULTS: The participants exposed to the high-alarm framing showed higher levels of perceived personal susceptibility to infertility, marginally higher levels of worry about infertility, and significantly lower levels of infertility-related knowledge than those exposed to the low-alarm framing. CONCLUSION: The manner in which the news media report on infertility has repercussions on how individuals think and feel about infertility. The findings of this study can inform health care providers about how the media are shaping perceptions of infertility, and can assist professional bodies interested in undertaking public education initiatives. PMID- 26637080 TI - Early Versus Delayed Postoperative Feeding After Major Gynaecological Surgery and its Effects on Clinical Outcomes, Patient Satisfaction, and Length of Stay: A Randomized Controlled Trial. AB - OBJECTIVE: To compare early versus delayed postoperative feeding in women undergoing major gynaecological surgery with regard to clinical outcomes, duration of postoperative stay, and patient satisfaction. METHODS: We conducted a parallel-randomized controlled trial at a tertiary care centre in Montreal, Quebec, between June 2000 and July 2001. Patients undergoing major gynaecological surgery were randomized following a 1:1 allocation ratio to receive either early postoperative feeding in which oral clear fluids were begun up to six hours after surgery followed by solid foods as tolerated, or delayed postoperative feeding, in which clear fluids were begun on the first postoperative day and solid foods on the second or third day as tolerated. The primary outcomes analyzed were duration of postoperative stay and patient satisfaction. Secondary outcomes included mean time to appetite, passage of flatus, and bowel movement, as well as the presence of symptoms of paralytic ileus. RESULTS: A total of 119 patients were randomized; 61 patients were assigned to the early feeding group and 58 to the delayed feeding group. Demographic characteristics, including age, weight, smoking status, and prior surgical history were comparable between both groups. There was no difference in length of postoperative stay between the two groups (86.4 +/- 21.0 hours in the early feeding group vs. 85.6 +/- 26.2 hours in the delayed feeding group; P > 0.05). No significant difference was noted in patient satisfaction (P > 0.05). No difference was found in the frequency of postoperative ileus, mean time to appetite, passage of flatus, or first bowel movement. CONCLUSION: The introduction of early postoperative feeding appears to be safe and well tolerated by patients undergoing major gynaecological surgery. The duration of postoperative stay, patient satisfaction, and gastrointestinal symptoms are comparable between patients undergoing early or delayed postoperative feeding. PMID- 26637081 TI - The Cost of Unintended Pregnancies in Canada: Estimating Direct Cost, Role of Imperfect Adherence, and the Potential Impact of Increased Use of Long-Acting Reversible Contraceptives. AB - OBJECTIVE: Unintended pregnancies (UPs) are associated with a significant cost burden, but the full cost burden in Canada is not known. The objectives of this study were to quantify the direct cost of UPs in Canada, the proportion of cost attributable to UPs and imperfect contraceptive adherence and the potential cost savings with increased uptake of long-acting reversible contraceptives (LARCs). METHODS: A cost model was constructed to estimate the annual number and direct costs of UP in women aged 18 to 44 years. Adherence-associated UP rates were estimated using perfect- and typical-use contraceptive failure rates. Change in annual number of UPs and impact on cost burden were projected in three scenarios of increased LARC usage. One-way sensitivity analyses were conducted to assess the impact of key variables on scenarios of increased LARC use. RESULTS: There are more than 180 700 UPs annually in Canada. The associated direct cost was over $320 million. Fifty-eight percent (58%) of UPs occurred in women aged 20 to 29 years at an annual cost of $175 million; 82% of this cost ($143 million) was attributable to contraceptive non-adherence. Increased LARC uptake produced cost savings of over $34 million in all three switching scenarios; the largest savings ($35 million) occurred when 10% of oral contraceptive users switched to LARCs. The minimum duration of LARC usage required before cost savings was realized was 12 months. CONCLUSION: The cost of UPs in Canada is significant and much of it can be attributed to imperfect contraceptive adherence. Increased LARC uptake may reduce contraceptive non-adherence, thereby reducing rates of UP and generating significant cost savings, particularly in women aged 20 to 29. PMID- 26637082 TI - Vaginally Administered Danazol: An Overlooked Option in the Treatment of Rectovaginal Endometriosis? AB - Danazol has been used in the treatment of endometriosis and heavy menstrual bleeding for more than 40 years. This medication has both central antigonadotropic actions and direct atrophic effects on endometriotic tissue. Although it demonstrates a high-efficacy profile, the associated side effects have resulted in limited usage. Vaginal administration of the drug may prove favourable specifically in rectovaginal endometriosis. This targeted mode of delivery is associated with a significant reduction in both pain symptoms and nodule size. The relative persistence of these therapeutic benefits is likely related to the direct tissue effects after absorption through the vaginal mucosa. Vaginal administration would also limit systemic propagation of danazol and thus should minimize androgenic side effects. Use of vaginal danazol also improves heavy menstrual bleeding and may even restore fertility in some patients. In this review we provide a critical analysis of the existing literature on the use of vaginal danazol. PMID- 26637083 TI - Competency-Based Medical Education: Developing a Framework for Obstetrics and Gynaecology. AB - The development of a Canadian competency-based medical education (CBME) curriculum in obstetrics and gynaecology, slated to begin in 2017, must be rooted in, and aligned with, the principles of CanMEDS 2015 and Competence by Design. It must also reflect the unique realities of the practice of the specialty. The Dutch Society of Obstetrics and Gynaecology has been at the forefront of the movement to design and implement competency-based training for obstetrics and gynaecology. The Dutch curriculum represents a practical example of how such a program could be developed. Several CBME curricular initiatives have now also begun across Canada. PMID- 26637084 TI - Doctors Behaving Badly and the Tyranny of Peer Pressure. PMID- 26637085 TI - Preparedness for Emergency "Crash" Caesarean Section. PMID- 26637086 TI - Antepartum Screening for Maternal Infection and Immune Status: Is it Time to Broaden Our Routine? AB - Maternal infections with PVB19, HCV, CMV, and HIV during the antepartum period are important health problems for which the technological capacities for screening and diagnosis during the antepartum period are available. Each of these viruses requires individual consideration for inclusion in screening and for the method of screening during the antepartum period. The availability of efficacious treatments for HCV and CMV, with demonstrable benefits to the mother or fetus, is required before antepartum screening for these infections can be justified. Screening for parvovirus B19 presents a greater concern because it meets most of the features of a screening test (Wilson's criteria) endorsed by the WHO. There is insufficient evidence to argue strongly for implementation of antepartum PVB19 screening, but the available evidence indicates a need for large studies of potential effectiveness and costs of routine PVB19 screening, either for all pregnant woman or for those at high risk of exposure to PVB19. While the technology to screen for HCV, PVB19, and CMV certainly exists, there must be careful consideration of the downstream implications of routine screening at the level of the individual patient, the general population, and other health care resources, including laboratory infrastructure, before recommending that these infections be screened for routinely in the antepartum period. A strategy for national adoption of an opt-out screening strategy for HIV should be considered. PMID- 26637087 TI - Assisted Reproductive Technologies in Alberta: An Economic Analysis to Inform Policy Decision-Making. AB - OBJECTIVE: Regulation and public funding of assisted reproductive technologies (ARTs) vary across the Canadian provinces. In Alberta, neither of these exists. We conducted this study to evaluate the cost effectiveness and budget impact of providing ARTs in Alberta under three different policy scenarios (a "restrictive" policy, a policy based on Quebec's model, and a "permissive" policy) in comparison with the status quo. METHODS: To predict the cost effectiveness and budget impact of three policy options for publicly funded ARTs in Alberta, we developed an economic model by combining a state transition Markov model and a decision tree. The primary outcome was cost per healthy singleton. Probabilistic and one-way sensitivity analyses were conducted. RESULTS: The restrictive policy was the most cost effective option for two subgroups of age (< 35 years and 35 to 39 years), while the Quebec policy option was most cost-effective for the >= 40 years subgroup. Budget impact analysis extending up to the age of 18 years for the children in the model showed the cost savings of $8.33 million for the restrictive policy for the < 35 years subgroup. For the >= 40 years subgroup, the Quebec policy option resulted in total cost savings of $3.75 million. Sensitivity analyses showed that the model results were robust. CONCLUSION: This economic modelling study shows that publicly funded and scientifically regulated ARTs could provide treatment access and save health care expenditures for the province. PMID- 26637088 TI - Obstetrical Anal Sphincter Injuries (OASIS): Prevention, Recognition, and Repair. AB - OBJECTIVE: To review the evidence relating to obstetrical anal sphincter injuries (OASIS) with respect to diagnosis, repair techniques and outcomes. To formulate recommendations as to patient counselling regarding route of delivery for subsequent pregnancy after OASIS. OPTIONS: Obstetrical care providers caring for women with OASIS have the option of repairing the anal sphincter using end-to-end or overlapping techniques. They may also be involved in counselling women with prior OASIS regarding the route of delivery for future pregnancies. OUTCOMES: The outcome measured is anal continence following primary OASIS repair and after subsequent childbirth. EVIDENCE: Published literature was retrieved through searches of Medline, EMBASE, and The Cochrane Library in May 2011 using appropriate controlled vocabulary (e.g., anal canal, obstetrics, obstetric labour complication, pregnancy complication, treatment outcome, surgery, quality of life) and key words (obstetrical anal sphincter injur*, anus sphincter, anus injury, delivery, obstetrical care, surgery, suturing method, overlap, end-to end, feces incontinence). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational. There were no date or language restrictions. Searches were updated on a regular basis and incorporated in the guideline to September 2014. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. VALUES: The quality of evidence in this document was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table 1). BENEFITS, HARMS, AND COSTS: Benefits from implementation of these guidelines include: improved diagnosis of OASIS, optimal functional outcomes following repair, and evidence-based counselling of women for future childbirth. PMID- 26637089 TI - Benign prostatic hyperplasia - progress in pathophysiology and management. AB - Benign prostatic hyperplasia (BPH) is a common disease of the aging male population, in affected individuals often accompanied by metabolic syndrome. BPH is manifested by a complex range of symptoms originating from the lower urinary tract (LUTS - lower urinary tract symptoms), including disturbances resulting from impaired bladder compliance and bladder overactivity (e.g. frequency, nocturia, urinary incontinence, dysuria) and symptoms associated with the bladder outlet obstruction (e.g. the difficulty in voiding initiating, intermittency, involuntary interruption of voiding, weak urinary stream, straining to void). Despite numerous studies, the pathogenesis of BPH remains not completely understood, and the condition awaits a comprehensive description. The current pathophysiological view emphasizes the role of hormonal dysregulation, locally released in the prostate growth factors action and a complex inflammatory, BPH associated process with the release of a number of pro-proliferative mediators. The current BPH pharmacotherapy involves administration of alpha-1-blockers, 5 alpha-reductase inhibitors, antimuscarinic drugs (cholinolytics) and phosphodiesterase- 5-inhibitors. Progress in the BPH pathophysiology allows the disclosure of additional, potential targets of pharmacological intervention, such as beta-3 adrenoreceptor or CB1 cannabinoid receptor agonists, P2X1 purinergic or ETA endothelin receptors antagonists, RhoA/Rho kinase system inhibitors, nitric oxide donors, drugs indirectly (luteinizing hormone - releasing hormone antagonists) or directly (antiandrogens) abolishing the effect of testosterone and its derivatives or agents blocking the action of proinflammatory cytokines. The article briefly discusses the pathophysiology of the aforementioned issues and the current BPH management along with the future, potential opportunities for pharmacotherapy of the. PMID- 26637090 TI - [The effectiveness of RF ablation of ventricular ectopic beats made using selected mapping techniques]. AB - Only several world-leading centers have summarized outcomes of invasive therapy of ventricular arrhythmia. AIM: The aim of the work is to compare the effectiveness of RF ablation of ventricular arrhythmia. MATERIALS AND METHODS: 183 patients (111 males, mean age 50 +/- 17) underwent RF ablation of ventricular ecopic beats (VEB). Retrospective analysis of procedural protocols, in- and outpatient medical records was performed. RF ablation was done using electroanatomical CARTO system, Pacemapping or both methods (CARTO + Pacemapping). RESULTS: Long-term ablation effectiveness was as follows: CARTO - success rate assessed during the ablation procedure was 84,4%; during post operation period follow-up 70,3%, and in long term followup 71,1%; Pacemaping success rate assessed during the ablation procedure was 91,7%; during post operation period follow-up 83,3%, and in long term follow-up 75,0%; CARTO + Pacemaping - success rate assessed during the ablation procedure was 85,4%; during post operation period follow-up 70,8%, and in long term follow-up 77,1%. Mean amount of VEBs per day before ablation was 18750 +/- 12560 (2435 to 50000) and after ablation 575 +/- 428 (0 to 1550), p<0.001. Best results were achieved in cases where both mapping techniques were used in combination. Among clinical parameters affecting long-term ablation effectiveness, only hypertension was found to significantly decrease long-term effectiveness of VEB ablation. Only ablation temperature and energy affected long-term therapy effect significantly (p<0,0014; HR=0,84). After the ablation, there was improvement of the left ventricular end-diastolic diameter and ejection fraction. CONCLUSIONS: Long-term success of ventricular extrasystoly ablation in combined method (CARTO+Pacemapping) was slightly higher compared in CARTO technique and in Pacemapping technique. Classic RF ablation is effective and safe, therefore it can be considered as first-line therapy. In ablation, precise localization of arrhythmic focus is the most important factor. Ablation temperature and energy were significantly correlated to long-term ablation effectiveness. After ventricular extrasystoly ablation, left ventricle ejection fraction increased and left ventricle end-diastolic diameter decreased. Hypertension significantly decreased long-term effectiveness of ventricular extrasystoly ablation. PMID- 26637091 TI - Clinical usefulness of baroreflex sensitivity test in the detection of cardiovascular autonomic neuropathy in patients with type 2 diabetes mellitus. AB - Cardiovascular autonomic neuropathy (CAN) is one of the most common chronic complications of diabetes. It is defined as an impaired control of the cardiovascular system by the autonomic nervous system. The gold standard in detecting it is the Ewing test suite. The usefulness of other methods is still a subject of research. AIM: The aim of this study was to assess the clinical usefulness of baroreflex sensitivity (BRS) test in the detection of CAN in patients with type 2 diabetes mellitus. MATERIALS AND METHODS: The study included diabetic patients: 24 with CAN, diagnosed through the Ewing tests (the mean age 58 +/- 7 years, BMI 33.6 +/- 5 kg*m-2, HbA1c% 8.3 +/- 3, duration of diabetes 13.3 +/- 7 years), and 24 without CAN (56 +/- 8 years, BMI 32.2 +/- 5 kg*m-2, HbA1c% 9.1 +/- 2, 9.3 +/- 9 years, respectively). The control group consisted of 12 patients without diabetes, homogeneous regarding gender and age. BRS was assessed in the supine (L-BRS), and in the standing position (S-BRS). RESULTS: L BRS was lower in the group with CAN vs the non-CAN group (6.2 +/- 4 vs 9.6 +/- 4 ms/mmHg; p=0,009); S-BRS respectively (4.4 +/- 3 vs 6.9 +/- 4 ms/mmHg; p=0.02). BRS well differentiates patients with and without polyneuropathy. The highest sensitivity of L-BRS and SBRS for detecting CAN is by cutoff <= 7 ms/mmHg. CONCLUSIONS: The study confirms the value of baroreflex sensitivity in the early detection of CAN among patients with type 2 diabetes. We recommended cutoff points for BRS to detect CAN among patients with type 2 diabetes mellitus. PMID- 26637092 TI - [The level of superoxide dismutase expression in primary and metastatic colorectal cancer cells in hypoxia and tissue normoxia]. AB - Superoxide oxidase (SOD) is a key antioxidant enzyme protecting cells against oxidative stress, which might induce cancerogenesis. In tumor cells SOD influences the level of the reactive oxygen species (ROS) allowing for survival and proliferation. High rate of cells proliferation in tumor leads to their temporary hypoxia due to lower rate of angiogenesis. Therefore during tumor development, cancer cells function in conditions of hypoxia or tissue normoxia. AIM: The aim of study was to evaluate of SOD isoenzymes (SOD1 and SOD2) expression level in cell lines of primary (SW 480) and metastatic (SW 620) colorectal cancer, cultured in hypoxia (1% oxygen), tissue normoxia (10% oxygen), and atmospheric normoxia (21% oxygen). MATERIALS AND METHODS: Cells were cultured in MEM medium in different oxygen concentrations (1%, 10%, 21%) in hypoxic chamber with oxygenation regulator. The number of living cells in lines SW 480 and 620 was determined by trypan blue method. Expression of SOD1 and SOD2 at the mRNA level was determined by RT-PCR and PCR. RESULTS: In both studied cell lines (SW 480 and SW 620), the number of living cells (viability) was increased in hypoxia and atmospheric normoxia. The expression level of SOD1 and SOD2 in studied cell lines was different. The lowest level of expression of both SOD isoenzymes was observed in hypoxia. In conditions of atmospheric normoxia the expression level of SOD1 in SW480 cell line was increased, and similar in SW620 cell line comparing to tissue normoxia. Whereas the SOD2 expression level in atmospheric normoxia conditions in both cell lines was significantly increased. Observed differences were statistically significant (p <= 0,05). CONCLUSIONS: The profile of expression of SOD1 and SOD2 in cell lines SW480 and SW620 indicates differentiated response of tumor cells depending on access to oxygen. Low level of SOD isoenzymes expression in SW480 and SW620 cells in hypoxia indicates decreased production of ROS. Differences of SOD isoenzymes expression level in tissue normoxia indicate their compensatory action, allowing to maintain the balance between O2- removal and H2O2production in studied tumor cells. In atmospheric normoxia conditions increased expression level of SOD1 and SOD2 observed in studied cell lines points to oxidative stress. PMID- 26637093 TI - [Emotional and psychosomatic disorder among female patients undergoing breast cancer diagnosis]. AB - Basics of psychoneuroimmunology indicate factors such as emotions, behaviour, personality and cognitive functions to have impact on weakening of immunological system and worsening the risk to develop medical conditions, including breast cancer. AIM: The aim of research was to attempt a coping of emotional and psychosomatic disorders among women undergoing breast tumor diagnostic process. MATERIALS AND METHODS: 145 female patients were included in the the research, among which 99 belonged to the research group (RG) and 46 belonged to the control group (CG). The average age in GB 49, 67 (+/- 9,47) i GK 46,43 (+/- 11,2). The research group members were undergoing diagnosis process for suspected breast cancer. The subjects filled out a survey and Symptom Questionnaire S-II, and were subject to mammographic and ultrasound examination, as well as aspiration biopsy was performed on them. 99 individual subjects were positively diagnosed with breast cancer, and 46 were negatively diagnosed. RESULTS: One in three women belonging to RG displayed emotional disorders. In CG only one in ten displayed symptoms of such disorders. Anxiety was the most common disorder mentioned by both RG and CG. There is however statistically relevant difference in anxiety intensity between the two groups. A statistically relevant corelation has been observed among members of the research group between certain psychosomatic disorders and a number of sociodemographic and medical variables' levels. CONCLUSIONS: Stress-related and formed psychophysiological and psychosomatic reactions are likely to play the role of psychosomatic and emotional factors leading to breast cancer development. PMID- 26637094 TI - [The level of nutrition knowledge versus dietary habits of diabetes patients treated with insulin]. AB - Diabetes is one of the fastest spreading XXI century diseases. One of the most important element of diabetes therapy should constitute dietary treatment resulting from thorough nutritional knowledge. AIM: The aim of study was to investigate the connection between the level of knowledge and way of feeding among patients with type 1 and 2 diabetes treated with insulin. MATERIALS AND METHODS: The research was conducted among 105 patients with type 1 and 2 diabetes treated with insulin. Knowledge level was assessed in accordance with author's questionnaire, way of feeding in accordance with 24 hour nutritional interview. Diet 5 and Statistical 10 has been used to carry out data analysis. RESULTS: The largest correctness has been demonstrated in the question about the carbohydrate content in food (60%), the lowest correctness while carbohydrate exchanges knowledge has been checked (12%). Generally, patients demonstrated medium knowledge level (41% correct answers). Good level of knowledge (>50% corrects answers) has been represented by 26%, medium level of knowledge (30-50% corrects answers) by 49%, low level of knowledge (<30% correct answers) by 25% of responders. Knowledge assessment has shown too high percentage of energy from carbohydrates and saturated fatty acids and too high consumption of cholesterol and sodium. Moreover dietary fiber and polyunsaturated fatty acids shortage has been observed in analyzing diets. Interdependence between knowledge level and way of feeding has not been found (exception: lower percentage of energy from fat in patient's with medium level of knowledge diets). CONCLUSIONS: Improper way of feeding and low level of knowledge can constitute a obstacle to achieve optimal treatment results. PMID- 26637095 TI - [Horse riding as a form of recreation and professional sport taking into account the spine mobility of riders - a preliminary results]. AB - Horse riding becoming increasingly common and popular form of recreation and leisure activities. However, enforced, proper posture while riding a horse, may contribute to decrease mobility of spine and lead to occurrence back pain. AIM: The aim of this study was to assess the impact of the systematic training of horse riding on the global mobility of the spine and back pain prevalence in training horse riders professionally and recreational. MATERIALS AND METHODS: The study included 70 horse riders. The subjects were divided into two groups: 1) professional horse riders (n=50; 71.43%) or 2) a group of subjects who train for recreation (n=20; 28.57%). Performed functional tests to assess the range of motion of the spine. The study used an original survey about exercise intensity and occurrence pain complaints. RESULTS: It has been shown statistically significant difference in the measurement range of the global spine mobility between professional horse riders and recreational horse riders (p<0.007). Professional horse riders have often limited range of motion of the spine. It was also observed that every fifth (20%) professional horse rider and one in four (25%) subject which training recreational experience back pain during training and it is dependent upon the mobility of the spine (p <0.04). CONCLUSIONS: In professional horse riders more often seen limitation of global mobility of the spine compared with subjects who training recreational while the occurrence of back pain was related in both group - in professional and recreational horse riders. PMID- 26637096 TI - [Analysis of effectiveness of selected treatment methods in patients with chronic low back pain]. AB - Chronic low back pain (CLBP) are becoming more and more frequently met disorder in modern society. Appearance of these symptoms mainly contribute degenerative changes in spine joints. Preventive, noninvasive treatment constitutes an important factor in therapy of chronic pain, therefore effective treatment methods for inhibiting the disease progression, pain-reducing and retrieving patients the functional ability are still seeking. AIM: The aim of the study was to evaluate the efficacy of ultrasounds, exercise therapy and combination therapy of both methods in the treatment of CLBP and comparing their effectiveness. MATERIALS AND METHODS: The study included 90 patients in the age of 42-82 treated for CLBP as a result of degenerative changes. Patients were divided into three 30 members groups. The first group used treatment consisted of ultrasounds. The second one included only exercise therapy and the third one underwent the combination of both methods - exercise therapy and sonotherapy. Treatment was continued for 2 weeks and was performed daily with the weekend break. Assessment of the pain level of was done with a VAS scale and a Laitinen questionnaire. The level of functional disability was determined on the basis of a modified Oswestry questionnaire. The spine motion was measured according to the Zembaty's methodology. Patients were examined twice - before and after therapy. RESULTS: In all patients significant pain reduction was noticed. In addition, level of disability of patients became considerably less and the mobility of the spine for all tests increased significantly. There were no significant differences between groups after all therapies. CONCLUSIONS: Ultrasounds, exercise therapy and combination of these two methods had a similar effectiveness in treatment of CLBP. PMID- 26637097 TI - [Analysis of using assistive devices by patients suffering from cerebral palsy - preliminary report]. AB - Cerebral palsy (CP) is still significant health and social issue in the world. Adults who suffer from that illness have problem with mobility which make their functioning much harder. Common symptoms include spasticity, chronic pain of musculoskeletal system, disturbance of sensation, epilepsy or mental retardation. AIM: The aim of the study was analysis of assistive devices used by patients with CP through childhood and adulthood. The results were compared with the situation in this field of CP patients in other countries. MATERIALS AND METHODS: The study involved 30 patients with CP in age between 20-43 living in Poznan and under the care of Occupational Therapy Workshop and Enviromental Self-help Houses. The research method was questionnaire which was directed to caregivers of adults with CP. They were asked about diagnosis, accompanying symptoms as well as assistive devices used during childhood and adulthood. RESULTS: During childhood wheelchair and standing frame were used the most often while during adulthood the most common were also the first mentioned above as well as rehabilitation lift. Although unfavourable evaluation of fitting assistive devices, majority of caregivers of CP sufferer claimed that there was varying improvement in patients motor functionality. CONCLUSIONS: Comprehensive rehabilitation and assistive devices are necessary for patients with CP during adulthood not less than during childhood. Wheelchairs are even more essential for adults than for children. PMID- 26637098 TI - [Recurrent right atrial thrombus in a patient with atrial fibrillation and heart failure]. AB - Atrial fibrillation and heart failure are factors predisposing to locally formed intracardiac thrombosis, which is usually localized in left-sided chambers. A case report. The authors present a case of a 50-year-old male with permanent atrial fibrillation and dilated cardiomyopathy in whom recurrent right atrial thrombus was observed. Initially, the lesion was detected in echocardiography while he was hospitalized due to extensive right-sided pneumonia. The thrombus was successfully treated with heparin, followed by warfarin. Even though the patient continued warfarin use properly, there was recurrence of the thrombus two years later during a new episode of heart failure exacerbation. Because the thrombus was resistant to intensified anticoagulation, cardiac surgery was needed. A large (30 x 25 mm) pedunculated thrombus, as well as two smaller ones (each of 10 x 10 mm) attached closely to the atrial wall and previously not detected either by echocardiography or by magnetic resonance imaging, were excited. A partially organized pattern of the thrombi in histological examination can explain lack of anticoagulation effectiveness. PMID- 26637099 TI - [The extensive phlegmon of the neck leading to severe complications - a case report]. AB - Purulent infection of the neck is a serious condition, which can occur at any age and regardless of any factors. It often leads to the serious complications, including death. A case report. The authors present a case of a 56-year-old patient who reported to the emergency department because of the severe neck pain, fever and progressive weakness. Physical examination revealed an extensive inflammation involving skin and subcutaneous tissue surrounding suboccipital area and neck. Palpation of the thyroid gland showed tumor of the left lobe. Due to deteriorating condition, it was decided to admit the patient to the hospital, along with urgent surgery. It was necessary to perform a repeated removal of the necrotic tissues of the nuchal area. Diabetes mellitus type II was diagnosed during hospitalisation. Long and laborious extensive wound care enabled to perform a skin graft and full recovery. The patient was discharged in good general and local condition in the 11th week of the hospitalization. PMID- 26637100 TI - [A mistake in forensic psychiatric evaluation or abuse of psychiatry for non medical purposes - a case report]. AB - In this study we attempted to visualize certain irregularities that took place in the evaluation of a patient with personality disorders performed by psychiatrist expert witness, which resulted in an incorrect diagnosis, leading to wrong ruling of the court and a referral of the patient to clinical therapy lasting six years. The psychiatric and psychological expert opinions submitted to the court and first-hand psychiatric and psychological examination of the patient were analyzed. Efforts were made to show that the failure to comply with the diagnostic criteria in the process of diagnosis and not taking into account the previously issued five forensic psychiatric opinions issued by independent and experienced teams of psychiatrist expert witnesses, as well as not taking into account the nature of the offense committed have led to a number of irregularities in the assessment of the mental state of the patient. Above mentioned shortcomings have caused unjustified legal classification of the offense and six years long detention of the patient in closed psychiatric institutions, in our regard unnecessary. The described case could be regarded as an abuse of psychiatry for the non-medical purposes and thus should have be punish. Based on the presented case it has been demonstrated that insufficient experience in forensic psychiatry and failure to comply with diagnostic criteria of psychiatrists and psychologists expert witnesses had led to a series of blatant offense of civil rights and liberties, and thus unnecessary detention of the patient for six years. PMID- 26637101 TI - [Prophylaxis of sudden cardiac death in patients with chronic kidney disease]. AB - In everyday practice, more commonly can we meet patients suffering from chronic kidney disease at different stages. Such patients are more susceptible to new risk factors, that can impair their health, along with the development of the disease. Sudden cardiac death (SCD) is the most common cause of death, that occurs in such group of patients. This article reviews the most important risk factors of SCD. They can be divided into two groups: heart dependent risk factors, such as: ischemic heart disease, cardiomyopathy, electrophysiology disturbances and dializo-therapy dependent risk factors, such as: type of dialysis, composition of dialysate, ions and hormonal disturbances. Also, prophylactic options, decreasing the risk of SCD, will be introduced, such as: pharmacotherapy, type of dializo-therapy and implantation of cardioverter defibrillator. PMID- 26637102 TI - [Nutritional status of adults with cystic fibrosis - current methods of assessment]. AB - Cystic fibrosis (CF) is one of the most frequent monogenic disease in the Caucasian population, inherited in an autosomal recessive pattern. This is a multiple organ disease and its main manifestations include pulmonary and gastrointestinal dysfunction. The exocrine pancreatic deficiency results in impaired digestion and absorption what may lead to malnutrition and vitamins and minerals deficiencies. The life expectancy of cystic fibrosis patients has been increasing over the past years, so there is a need to verify usefulness of existing or create new methods of nutritional status assessment. The aim of this paper was presentation current data on the methods of assessment and monitoring of nutritional status. Particular attention has been paid to appropriate nutritional support in prevention and treatment of malnutrition patients with cystic fibrosis. On the basis of recent literature we can conclude that the advanced nutritional status assessment is recommended in patient with CF by using anthropometrical methods, body composition analysis and biochemical data. Good nutritional status is connected with pulmonary functions, quality and life length. PMID- 26637103 TI - [Novel strategies of ovarian cancer treatment]. AB - Ovarian cancer is the most lethal gynecological malignancy. Due to scarce specific symptoms, women usually seek medical help once the disease is highly advanced, with distant metastases. Currently no screening is available, making this particular cancer hard to detect in the early stage. Standard treatment is insufficient for many patients, especially in the recurrent disease. This fact explains the tremendous need to search for novel therapeutic approaches. Inhibition of angiogenesis and destruction of cancer stem cells are attempts that affect the tumor microenvironment. There is a lot of potential in inhibiting poly(ADP-rybose)polymerase (PARP) or I class histone deacetylase. Drug repositioning may also be beneficial, as it gives old drugs new purposes. Metformin, a well-known antidiabetic agent, is an example of this phenomenon. Constant progress in medicine and science makes us hope for positive outcomes while treating this highly dangerous disease. PMID- 26637104 TI - Comparison of the use of NiFe and CoFe as electrodes for metallic lateral spin valves. AB - Spin injection and detection in Co60Fe40-based all-metallic lateral spin valves have been studied at both room and low temperatures. The obtained spin signals amplitudes have been compared to those of identical Ni80Fe20-based devices. The replacement of Ni80Fe20 by CoFe allows increasing the spin signal amplitude by up to one order of magnitude, thus reaching 50 mOmega at room temperature. The spin signal dependence with the distance between the ferromagnetic electrodes has been analyzed using both a 1D spin-transport model and finite element method simulations. The enhancement of the spin signal amplitude when using CoFe electrodes can be explained by a higher effective polarization. PMID- 26637105 TI - Is it Appropriate to Conclude That Muscle Power Is an "Independent" Determinant of Pain and Quality of Life in Knee Osteoarthritis? Comment on the Article by Reid et al. PMID- 26637106 TI - Templated Chromophore Assembly by Dynamic Covalent Bonds. AB - Through the simultaneous use of three orthogonal dynamic covalent reactions, namely disulfide, boronate, and acyl hydrazone formation, we conceived a facile and versatile protocol to spatially organize tailored chromophores, which absorb in the blue, red, and yellow regions, on a preprogrammed alpha-helix peptide. This approach allowed the assembly of the dyes in the desired ratio and spacing, as dictated by both the relative positioning and distribution of the recognition units on the peptide scaffold. Steady-state UV/Vis absorption and emission studies suggest an energy transfer from the yellow and red donors to the blue acceptor. A molecular dynamics simulation supports the experimental findings that the helical structure is maintained after the assembly and the three dyes are confined in defined conformational spaces. PMID- 26637107 TI - Porokeratosis ptychotropica involving the glans penis: a unique case of this rare condition. PMID- 26637108 TI - Toward the Control of the Creation of Mixed Monolayers on Glassy Carbon Surfaces by Amine Oxidation. AB - A versatile and simple methodology for the creation of mixed monolayers on glassy carbon (GC) surfaces was developed, using an osmium-bipyridyl complex and anthraquinone as model redox probes. The work consisted in the electrochemical grafting on GC of a mixture of mono-protected diamine linkers in varying ratios which, after attachment to the surface, allowed orthogonal deprotection. After optimisation of the deprotection conditions, it was possible to remove one of the protecting groups selectively, couple a suitable osmium complex and cap the residual free amines. The removal of the second protecting group allowed the coupling of anthraquinone. The characterisation of the resulting surfaces by cyclic voltammetry showed the variation of the surface coverage of the two redox centres in relation to the initial ratio of the linking amine in solution. PMID- 26637109 TI - Thermal and geochemical influences on microbial biogeography in the hydrothermal sediments of Guaymas Basin, Gulf of California. AB - Extreme thermal gradients and compressed metabolic zones limit the depth range of microbial colonization in hydrothermally active sediments at Guaymas Basin. We investigated the physicochemical characteristics of this ecosystem and their influence on microbial community structure. Temperature-related trends of delta(13)C values of methane and dissolved inorganic carbon from 36 sediment cores suggest in situ thermal limits for microbial anaerobic methane oxidation and organic carbon re-mineralization near 80 degrees C and 100 degrees C respectively. Temperature logging probes deposited in hydrothermal sediments for 8 days demonstrate substantial thermal fluctuations of up to 25 degrees C. Putative anaerobic methanotroph (ANME) populations dominate the archaeal community, transitioning from ANME-1 archaea in warm surficial sediments towards ANME-1 Guaymas archaea as temperatures increase downcore. Since ANME archaea performing anaerobic oxidation of methane double on longer time scales (months) compared with relatively rapid in situ temperature fluctuations (hours to days), we conclude that ANME archaea possess a high tolerance for short-term shifts in the thermal regime. PMID- 26637110 TI - Safety and efficacy of antibiotic prophylaxis in patients undergoing elective laparoscopic cholecystectomy: A systematic review and meta-analysis. AB - BACKGROUND AND AIM: Owing to persistent controversy regarding the use of routine antibiotic prophylaxis in patients undergoing elective laparoscopic cholecystectomy and the availability of several new randomized controlled trials (RCTs), we conducted an up-to-date meta-analysis to provide the best current evidence. The aim of the article is to evaluate the safety and efficacy of routine antibiotic prophylaxis in low-risk patients undergoing elective laparoscopic cholecystectomy. METHODS: We conducted a comprehensive literature review of the PubMed, Embase, and Cochrane Library databases for RCTs that compared antibiotic prophylaxis versus placebo or no antibiotics in low-risk patients undergoing elective laparoscopic cholecystectomy. RESULTS: The meta analysis included 21 RCTs (5207 patients). Antibiotic prophylaxis reduced the incidence of surgical site infections (risk ratio [RR] 0.61, 95% confidence interval [CI] 0.45 to 0.82, P = 0.001) and global infections (RR 0.55, 95% CI 0.38 to 0.79, P = 0.001) during hospitalization or after discharge, and postoperative length of hospital stay (weighted mean difference -0.16, 95% CI 0.28 to -0.04, P = 0.008). No adverse events were reported. Subgroup analyses demonstrated that two doses of antibiotic and 3-10 doses of antibiotic significantly reduced the incidence of surgical site infections compared with placebo or no antibiotics (two doses: RR 0.16, 95% CI 0.06-0.47; 3-10 doses: RR 0.46, 95% CI 0.27-0.80), while a single dose of antibiotic administration did not. CONCLUSION: Antibiotic prophylaxis is safe and effective in reducing surgical site infections and global infections during hospitalization or after discharge, and postoperative length of hospital stay in low-risk patients undergoing elective laparoscopic cholecystectomy. PMID- 26637111 TI - Decellularization and Recellularization of Rat Livers With Hepatocytes and Endothelial Progenitor Cells. AB - Whole-organ decellularization has been identified as a promising choice for tissue engineering. The aim of the present study was to engineer intact whole rat liver scaffolds and repopulate them with hepatocytes and endothelial progenitor cells (EPCs) in a bioreactor. Decellularized liver scaffolds were obtained by perfusing Triton X-100 with ammonium hydroxide. The architecture and composition of the original extracellular matrix were preserved, as confirmed by morphologic, histological, and immunolabeling methods. To determine biocompatibility, the scaffold was embedded in the subcutaneous adipose layer of the back of a heterologous animal to observe the infiltration of inflammatory cells. Hepatocytes were reseeded using a parenchymal injection method and cultured by continuous perfusion. EPCs were reseeded using a portal vein infusion method. Morphologic and functional examination showed that the hepatocytes and EPCs grew well in the scaffold. The present study describes an effective method of decellularization and recellularization of rat livers, providing the foundation for liver engineering and the development of bioartificial livers. PMID- 26637112 TI - Choroidal Thickness Changes in the Acute Attack Period in Patients with Familial Mediterranean Fever. AB - PURPOSE: The aim of this study was to evaluate choroidal thickness changes during acute attacks of familial Mediterranean fever (FMF). METHODS: Fifty patients with FMF and 50 healthy controls were included. Choroidal thickness of each participant was measured at the foveola and horizontal nasal and temporal quadrants at 500-um intervals to 1,500 um from the foveola using spectral-domain optical coherence tomography. White blood cell count, erythrocyte sedimentation rate (ESR) and serum levels of fibrinogen and C-reactive protein (CRP) were evaluated. The clinical findings (peritonitis, arthritis and pleuritis) were noted. RESULTS: Choroidal thickness was significantly thicker at all measurement points in FMF patients compared to healthy controls during an acute attack (p < 0.05). There were positive correlations between the choroidal thickness and ESR, fibrinogen and, particularly, CRP levels. Clinical findings did not change the choroidal thickness significantly (p > 0.05). CONCLUSIONS: Increased choroidal thickness in the acute phase of FMF is possibly related to the inflammatory edematous changes in the choroid. PMID- 26637113 TI - Effect of Timing of Proton Pump Inhibitor Administration on Acid Suppression. AB - BACKGROUND: Esomeprazole has been reported to show a strong acid suppression following preprandial as compared to postprandial administration, though no known study has compared the acid suppressing effects of other proton pump inhibitors between those administrations. The aim of this study was to compare intragastric pH levels following pre- and postprandial administrations of rabeprazole and esomeprazole. METHODS: In 15 Helicobacter pylori-negative healthy volunteers, we measured intragastric pH after 7 days of pre- and postprandial administrations of rabeprazole (10 mg) or esomeprazole (20 mg) using a 5-way crossover design. RESULTS: Preprandial administration of esomeprazole showed stronger acid suppression than postprandial administration. The values for percent time at pH >4.0 over a 24-hour period increased from 45.3% with postprandial administration of esomeprazole to 54.4% with preprandial administration, while the percent time at pH >4.0 during daytime was increased to a greater extent from 51.4 to 66.5% with preprandial administration (p = 0.05). On the other hand, the acid suppressing effect of rabeprazole was not influenced by the timing of administration. CONCLUSIONS: The acid suppressing effect of esomeprazole is influenced by administration timing. In contrast, the acid suppressing effect of rabeprazole is not augmented by preprandial administration. PMID- 26637114 TI - Convergent Evolution of Hemoglobin Function in High-Altitude Andean Waterfowl Involves Limited Parallelism at the Molecular Sequence Level. AB - A fundamental question in evolutionary genetics concerns the extent to which adaptive phenotypic convergence is attributable to convergent or parallel changes at the molecular sequence level. Here we report a comparative analysis of hemoglobin (Hb) function in eight phylogenetically replicated pairs of high- and low-altitude waterfowl taxa to test for convergence in the oxygenation properties of Hb, and to assess the extent to which convergence in biochemical phenotype is attributable to repeated amino acid replacements. Functional experiments on native Hb variants and protein engineering experiments based on site-directed mutagenesis revealed the phenotypic effects of specific amino acid replacements that were responsible for convergent increases in Hb-O2 affinity in multiple high altitude taxa. In six of the eight taxon pairs, high-altitude taxa evolved derived increases in Hb-O2 affinity that were caused by a combination of unique replacements, parallel replacements (involving identical-by-state variants with independent mutational origins in different lineages), and collateral replacements (involving shared, identical-by-descent variants derived via introgressive hybridization). In genome scans of nucleotide differentiation involving high- and low-altitude populations of three separate species, function altering amino acid polymorphisms in the globin genes emerged as highly significant outliers, providing independent evidence for adaptive divergence in Hb function. The experimental results demonstrate that convergent changes in protein function can occur through multiple historical paths, and can involve multiple possible mutations. Most cases of convergence in Hb function did not involve parallel substitutions and most parallel substitutions did not affect Hb O2 affinity, indicating that the repeatability of phenotypic evolution does not require parallelism at the molecular level. PMID- 26637115 TI - Adaption to High Altitude: An Evaluation of the Storage Quality of Suspended Red Blood Cells Prepared from the Whole Blood of Tibetan Plateau Migrants. AB - Hypoxia has been reported to cause the significant enhancement of hemoglobin (Hb) and hematocrit (Hct), which stabilizes at relatively high levels after an individual ascends to a high altitude. However, the quality of the suspended red blood cells (SRBCs) obtained from individuals at high altitudes such as Tibetan plateau migrants after storage has not been studied. In this study, we compared the storage quality of SRBCs prepared from Tibetan plateau and Deyang lowland populations by adding a normal volume of mannitol-adenine-phosphate (MAP), which is a common additive solution used in blood storage in Asian countries. The storage cell characteristics were examined on days 1, 7, 14 and 35.We found higher Hct and Hb levels and viscosity in the high altitude samples. The metabolic rates, including those for electrolytes and lactate, were higher in plateau SRBCs than in lowland SRBCs; these findings were consistent with the higher osmotic fragility and hemolysis of plateau SRBCs throughout the entire storage period. In addition, the reduction rates of 2,3-diphosphoglycerate (2,3 DPG) and oxygen tension to attain 50% oxygen saturation of Hb (P50) in plateau SRBCs were higher than those in lowland SRBCs, and the oxygen delivering capacity in plateau SRBCs was weaker than that in lowland SRBCs. We concluded that the storage quality of plateau SRBCs was inferior to that of lowland SRBCs when using the same concentration of MAP. We suggested that the optimal formula, including the MAP concentration or even a new additive solution, to store the plateau SRBCs must be assessed and regulated. PMID- 26637116 TI - Sexual Size Dimorphism and Body Condition in the Australasian Gannet. AB - Sexual size dimorphism is widespread throughout seabird taxa and several drivers leading to its evolution have been hypothesised. While the Australasian Gannet (Morus serrator) has previously been considered nominally monomorphic, recent studies have documented sexual segregation in diet and foraging areas, traits often associated with size dimorphism. The present study investigated the sex differences in body mass and structural size of this species at two colonies (Pope's Eye, PE; Point Danger, PD) in northern Bass Strait, south-eastern Australia. Females were found to be 3.1% and 7.3% heavier (2.74 +/- 0.03, n = 92; 2.67 +/- 0.03 kg, n = 43) than males (2.66 +/- 0.03, n = 92; 2.48 +/- 0.03 kg, n = 43) at PE and PD, respectively. Females were also larger in wing ulna length (0.8% both colonies) but smaller in bill depth (PE: 2.2%; PD: 1.7%) than males. Despite this dimorphism, a discriminant function provided only mild accuracy in determining sex. A similar degree of dimorphism was also found within breeding pairs, however assortative mating was not apparent at either colony (R2 < 0.04). Using hydrogen isotope dilution, a body condition index was developed from morphometrics to estimate total body fat (TBF) stores, where TBF(%) = 24.43+1.94*(body mass/wing ulna length) - 0.58*tarsus length (r2 = 0.84, n = 15). This index was used to estimate body composition in all sampled individuals. There was no significant difference in TBF(%) between the sexes for any stage of breeding or in any year of the study at either colony suggesting that, despite a greater body mass, females were not in a better condition than males. While the driving mechanism for sexual dimorphism in this species is currently unknown, studies of other Sulids indicate segregation in foraging behaviour, habitat and diet may be a contributing factor. PMID- 26637117 TI - Total Synthesis and Biological Evaluation of Rakicidin A and Discovery of a Simplified Bioactive Analogue. AB - We report a concise asymmetric synthesis of rakicidin A, a macrocyclic depsipeptide that selectively inhibits the growth of hypoxic cancer cells and stem-like leukemia cells. Key transformations include a diastereoselective organocatalytic cross-aldol reaction to build the polyketide portion of the molecule, a highly hindered ester fragment coupling reaction, an efficient Helquist-type Horner-Wadsworth-Emmons (HWE) macrocyclization, and a new DSC mediated elimination reaction to construct the sensitive APD portion of rakicidin A. We further report the preparation of a simplified structural analogue (WY1) with dramatically enhanced hypoxia-selective activity. PMID- 26637118 TI - Improvement of Expressed Breast Milk in Mothers of Preterm Infants by Recording Breast Milk Pumping Diaries in a Neonatal Center in China. AB - OBJECTIVES: Because inadequate expression of human milk (EBM) in mothers of hospitalized infants were noticed in a neonatal center of our hospital, family education program was carried out to increase the EBM. METHODS: A breast milk pumping diary was introduced to the mothers with preterm infant(s) admitted in the NICU. The ratios of EBM (days of EBM to NICU/hospitalized days), breast milk feeding (BMF) (days of infants fed with exclusive human milk/hospitalized days), mixed feeding (MF) (days of infants fed with partial breast milk and partial formula/hospitalized days), and formula feeding (FF) (days of infants fed with preterm formula/hospitalized days) were evaluated. RESULTS: During January to April, 2014, the ratios of EBM to the NICU, BMF, MF and FF were 28.11%, 6.6%, 32.8% and 60.6%, respectively. After the introduction of breast milk pumping diary to the mothers from May 2014, the ratio of EBM to the NICU increased significantly to 53.3% (p<0.01) within the following eight months. Both the ratios of BMF and MF also rose to 23.8% and MF 55.3%, respectively. Consequently, the ratio of FF was reduced to 20.9%. Exclusive breast milk feeding also significantly reduce the duration of nil per oral (NPO) of the very low birth weight infants during hospital stay as compared to those fed with mixed feeding and formula feeding. CONCLUSION: The introduction of a breast milk pumping diary was associated with a significant increase in the intake of EBM of the hospitalized preterm newborns. PMID- 26637119 TI - Low Cloud Cover-Adjusted Ultraviolet B Irradiance Is Associated with High Incidence Rates of Leukemia: Study of 172 Countries. AB - There are 52,380 cases of leukemia and 24,090 deaths from it in the US annually. Its causes are unknown and no preventive strategies have been implemented. We hypothesized that leukemia is due mainly to vitamin D deficiency, which is due mainly to low solar ultraviolet B (UVB) irradiance. To test this hypothesis, we estimated age-standardized cloud-cover-adjusted winter UVB irradiance using cloud cover data from the International Satellite Cloud Climatology Project, latitudes of population centroids, and standard astronomical calculations. Incidence rates for 172 countries, available from the International Agency for Cancer Research, were plotted according to cloud-adjusted UVB irradiance. We used multiple regression to account for national differences in elevation and average life expectancy. Leukemia incidence rates were inversely associated with cloud adjusted UVB irradiance in males (p <= 0.01) and females (p <= 0.01) in both hemispheres. There were few departures from the trend line, which was parabolic when plotted with the equator at the center of the display, northern hemisphere countries on the right side and southern hemisphere countries on the left. The bivariate association displayed by the polynomial trend line indicated that populations at higher latitudes had at least two times the risk of leukemia compared to equatorial populations. The association persisted in males (p <= 0.05) and females (p <= 0.01) after controlling for elevation and life expectancy. Incidence rates of leukemia were inversely associated with solar UVB irradiance. It is plausible that the association is due to vitamin D deficiency. This would be consistent with laboratory studies and a previous epidemiological study. Consideration should be given to prudent use of vitamin D for prevention of leukemia. PMID- 26637120 TI - Breeding Bird Community Continues to Colonize Riparian Buffers Ten Years after Harvest. AB - Riparian ecosystems integrate aquatic and terrestrial communities and often contain unique assemblages of flora and fauna. Retention of forested buffers along riparian habitats is a commonly employed practice to reduce potential negative effects of land use on aquatic systems. However, very few studies have examined long-term population and community responses to buffers, leading to considerable uncertainty about effectiveness of this practice for achieving conservation and management outcomes. We examined short- (1-2 years) and long term (~10 years) avian community responses (occupancy and abundance) to riparian buffer prescriptions to clearcut logging silvicultural practices in the Pacific Northwest USA. We used a Before-After-Control-Impact experimental approach and temporally replicated point counts analyzed within a Bayesian framework. Our experimental design consisted of forested control sites with no harvest, sites with relatively narrow (~13 m) forested buffers on each side of the stream, and sites with wider (~30 m) and more variable width unharvested buffer. Buffer treatments exhibited a 31-44% increase in mean species richness in the post harvest years, a pattern most evident 10 years post-harvest. Post-harvest, species turnover was much higher on both treatments (63-74%) relative to the controls (29%). We did not find evidence of local extinction for any species but found strong evidence (no overlap in 95% credible intervals) for an increase in site occupancy on both Narrow (short-term: 7%; long-term 29%) and Wide buffers (short-term: 21%; long-term 93%) relative to controls after harvest. We did not find a treatment effect on total avian abundance. When assessing relationships between buffer width and site level abundance of four riparian specialists, we did not find strong evidence of reduced abundance in Narrow or Wide buffers. Silviculture regulations in this region dictate average buffer widths on small and large permanent streams that range from ~22-25 m. Guidelines for this region are within the range of buffers included in our study, in which we observed no evidence for avian species loss or for a decline in species abundance (including riparian associated species). PMID- 26637121 TI - Short-Term Summer Inundation as a Measure to Counteract Acidification in Rich Fens. AB - In regions with intensive agriculture, water level fluctuation in wetlands has generally become constricted within narrow limits. Water authorities are, however, considering the re-establishment of fluctuating water levels as a management tool in biodiverse, base-rich fens ('rich fens'). This includes temporary inundation with surface water from ditches, which may play an important role in counteracting acidification in order to conserve and restore biodiversity. Inundation may result in an increased acid neutralizing capacity (ANC) for two reasons: infiltration of base-rich inundation water into peat soils, and microbial alkalinity generation under anaerobic conditions. The main objectives of this study were to test whether short-term (2 weeks) summer inundation is more effective than short-term winter inundation to restore the ANC in the upper 10 cm of non-floating peat soils, and to explain potential differences. Large-scale field experiments were conducted for five years in base rich fens and Sphagnum-dominated poor fens. Winter inundation did not result in increased porewater ANC, because infiltration was inhibited in the waterlogged peat and evapotranspiration rates were relatively low. Also, low temperatures limit microbial alkalinity generation. In summer, however, when temperature and evapotranspiration rates are higher, inundation resulted in increased porewater Ca and HCO3- concentrations, but only in areas with characteristic rich fen bryophytes. This increase was not only due to stronger infiltration into the soil, but also to higher microbial alkalinity generation under anaerobic conditions. In contrast, porewater ANC did not increase in Sphagnum-plots as a result of the ability of Sphagnum spp. to acidify their environment. In both rich and poor fens, flooding-induced P-mobilization remained sufficiently low to safeguard P-limited vegetation. NO3(-) and NH4(+) dynamics showed no considerable changes either. In conclusion, short-term summer inundation with base-rich and nutrient-poor surface water is considered beneficial in the management of non floating rich fens, and much more effective than winter inundation. PMID- 26637122 TI - Treatment of Patients With Nonradiographic Axial Spondyloarthritis Who Have Negative Magnetic Resonance Imaging Results and Normal C-Reactive Protein Levels at Baseline: Comment on the Article by Ward et al. PMID- 26637124 TI - Self-Organization of Gold Nanoparticle Assemblies with 3D Spatial Order and Their External Stimuli Responsiveness. AB - Gold nanoparticles (AuNP) with pyridyl end-capped polystyrenes (PS-4VP) as "quasi monodentate" ligands self-assemble into ordered PS-4VP/AuNP nanostructures with 3D hexagonal spatial order in the dried solid state. The key for the formation of these ordered structures is the modulation of the ratio AuNP versus ligands, which proves the importance of ligand design and quantity for the preparation of novel ordered polymer/metal nanoparticle conjugates. Although the assemblies of PS-4VP/AuNP in dispersion lack in high dimensional order, strong plasmonic interactions are observed due to close contact of AuNP. Applying temperature as an external stimulus allows the reversible distortion of plasmonic interactions within the AuNP nanocomposite structures, which can be observed directly by naked eye. The modulation of the macroscopic optical properties accompanied by this structural distortion of plasmonic interaction opens up very interesting sensoric applications. PMID- 26637123 TI - Enhanced Phospholipase A2 Group 3 Expression by Oxidative Stress Decreases the Insulin-Degrading Enzyme. AB - Oxidative stress has a ubiquitous role in neurodegenerative diseases and oxidative damage in specific regions of the brain is associated with selective neurodegeneration. We previously reported that Alzheimer disease (AD) model mice showed decreased insulin-degrading enzyme (IDE) levels in the cerebrum and accelerated phenotypic features of AD when crossbred with alpha-tocopherol transfer protein knockout (Ttpa-/-) mice. To further investigate the role of chronic oxidative stress in AD pathophysiology, we performed DNA microarray analysis using young and aged wild-type mice and aged Ttpa-/- mice. Among the genes whose expression changed dramatically was Phospholipase A2 group 3 (Pla2g3); Pla2g3 was identified because of its expression profile of cerebral specific up-regulation by chronic oxidative stress in silico and in aged Ttpa-/- mice. Immunohistochemical studies also demonstrated that human astrocytic Pla2g3 expression was significantly increased in human AD brains compared with control brains. Moreover, transfection of HEK293 cells with human Pla2g3 decreased endogenous IDE expression in a dose-dependent manner. Our findings show a key role of Pla2g3 on the reduction of IDE, and suggest that cerebrum specific increase of Pla2g3 is involved in the initiation and/or progression of AD. PMID- 26637125 TI - A New Secondary Pollen Presentation Mechanism from a Wild Ginger (Zingiber densissimum) and Its Functional Roles in Pollination Process. AB - BACKGROUND AND AIMS: Secondary pollen presentation (SPP), a floral mechanism of reproductive adaptation, has been described for more than 200 years, with nine types SPP recorded. However, few studies have been done experimentally to link the floral mechanism of SPP to its functional roles in pollination process. This study aims to describe a new SPP mechanism from a wild ginger (Zingiber densissimum, Zingiberaceae) and explore how the pollen arrangement of SPP affects pollen removal during the interaction with different pollinators. METHODOLOGY/PRINCIPAL FINDINGS: Field observations and experiments revealed that flowers lasted for less than one day. The breeding system was partially self incompatible. Two bee species, Macropis hedini (which carried pollen dorsally) and Amegilla zonata (which carried pollen ventrally) were the primary pollinators. About a third of pollen grains were relocated from the anther to the labellum staminode of flowers through the adherence of aggregated pollen chains, while other grains were presented on the anther. In a single visit, each bee species removed pollen grains from both the labellum staminode and the anther. Macropis hedini was more effective than Amegilla zonata. CONCLUSIONS/SIGNIFICANCE: Our study describes a new SPP mechanism in angiosperms. The new SPP mode enables pollen grains presented on the anther and the labellum staminode simultaneously via the adherence of aggregated pollen chains, thus promoting pollen to be taken away by different pollinators. This SPP mechanism plays a key role during pollen removal and may have evolved under the pressure to improve male fitness. PMID- 26637127 TI - Diversity and Community Composition of Vertebrates in Desert River Habitats. AB - Animal species are seldom distributed evenly at either local or larger spatial scales, and instead tend to aggregate in sites that meet their resource requirements and maximise fitness. This tendency is likely to be especially marked in arid regions where species could be expected to concentrate at resource rich oases. In this study, we first test the hypothesis that productive riparian sites in arid Australia support higher vertebrate diversity than other desert habitats, and then elucidate the habitats selected by different species. We addressed the first aim by examining the diversity and composition of vertebrate assemblages inhabiting the Field River and adjacent sand dunes in the Simpson Desert, western Queensland, over a period of two and a half years. The second aim was addressed by examining species composition in riparian and sand dune habitats in dry and wet years. Vertebrate species richness was estimated to be highest (54 species) in the riverine habitats and lowest on the surrounding dune habitats (45 species). The riverine habitats had different species pools compared to the dune habitats. Several species, including the agamid Gowidon longirostris and tree frog Litoria rubella, inhabited the riverine habitats exclusively, while others such as the skinks Ctenotus ariadnae and C. dux were captured only in the dune habitats. The results suggest that, on a local scale, diversity is higher along riparian corridors and that riparian woodland is important for tree-dependent species. Further, the distribution of some species, such as Mus musculus, may be governed by environmental variables (e.g. soil moisture) associated with riparian corridors that are not available in the surrounding desert environment. We conclude that inland river systems may be often of high conservation value, and that management should be initiated where possible to alleviate threats to their continued functioning. PMID- 26637126 TI - Synapse Loss and Dendrite Remodeling in a Mouse Model of Glaucoma. AB - It has been hypothesized that synaptic pruning precedes retinal ganglion cell degeneration in glaucoma, causing early dysfunction to retinal ganglion cells. To begin to assess this, we studied the excitatory synaptic inputs to individual ganglion cells in normal mouse retinas and in retinas with ganglion cell degeneration from glaucoma (DBA/2J), or following an optic nerve crush. Excitatory synapses were labeled by AAV2-mediated transfection of ganglion cells with PSD-95-GFP. After both insults the linear density of synaptic inputs to ganglion cells decreased. In parallel, the dendritic arbors lost complexity. We did not observe any cells that had lost dendritic synaptic input while preserving a normal or near-normal morphology. Within the temporal limits of these observations, dendritic remodeling and synapse pruning thus appear to occur near simultaneously. PMID- 26637128 TI - The deep-sea glass sponge Lophophysema eversa harbours potential symbionts responsible for the nutrient conversions of carbon, nitrogen and sulfur. AB - Glass sponge (Hexactinellida, Porifera) is a special lineage because of its unique tissue organization and skeleton material. Structure and physiology of glass sponge have been extensively studied. However, our knowledge of the glass sponge-associated microbial community and of the interaction with the host is rather limited. Here, we performed genomic studies on the microbial community in the glass sponge Lophophysema eversa in seamount. The microbial community was dominated by an ammonia-oxidizing archaeum (AOA), a nitrite-oxidizing bacterium (NOB) and a sulfur-oxidizing bacterium (SOB), all of which were autotrophs. Genomic analysis on the AOA, NOB and SOB in the sponge revealed specific functional features of sponge-associated microorganisms in comparison with the closely related free-living relatives, including chemotaxis, phage defence, vitamin biosynthesis and nutrient uptake among others, which are related to ecological functions. The three autotrophs play essential roles in the cycles of carbon, nitrogen and sulfur in the microenvironment inside the sponge body, and they are considered to play symbiotic roles in the host as scavengers of toxic ammonia, nitrite and sulfide. Our study extends knowledge regarding the metabolism and the evolution of chemolithotrophs inside the invertebrate body. PMID- 26637129 TI - The Role of Cryptococcus in the Immune System of Pulmonary Cryptococcosis Patients. AB - OBJECTIVES: To investigate the role of Cryptococcus in the immune system of immunocompetent patients with pulmonary cryptococcosis (PC) by analysing the dynamic changes of patients' immune status before and after antifungal therapy. METHODS: The level of the serum interferon-gamma (IFN-gamma) and interleukin (IL) 2, -4, -10 and -12 was measured before and after 6-months of treatment. Peripheral blood samples were obtained from 30 immunocompetent PC patients and 30 age- and gender-matched healthy controls. Peripheral blood mononuclear cells (PBMCs) were isolated and incubated with recombinant human IL-12 (rhIL-12) for 48 h. Then the concentrations of IFN-gamma and IL-4 in the supernatant were analysed. RESULTS: Baseline serum IFN-gamma level was significantly lower in the PC patients as compared with the control group (P < 0.001). The serum IL-2 and IFN-gamma of PC patients were significantly increased after appropriate treatments (P < 0.05 and P < 0.001 when compared to their baseline levels). The productions of IFN-gamma in the culture supernatant of PBMCs showed no significant difference between the control and PC patients both before and after antifungal treatments. RhIL-12 is a potent stimulus for IFN-gamma production. Culture PBMCs collected from PC patients before treatments had a smaller increase of IFN-gamma production in the present of rhIL-12 than the control (P < 0.01); PBMCs from PC patients completing 6-months of treatment showed a comparable increase of IFN-gamma production by rhIL-12 stimulation to the control group. CONCLUSIONS: In apparently immunocompetent patients with PC, a normalization of serum IFN-gamma was achieved after recovery from infection. This suggests that Cryptococcus infection per se can suppress the immune system and its elimination contributes to the reestablishment of an immune equilibrium. PMID- 26637131 TI - Asymmetric Allylic Alkylation of beta-Ketoesters with Allylic Alcohols by a Nickel/Diphosphine Catalyst. AB - Asymmetric allylic alkylation of beta-ketoesters with allylic alcohols catalyzed by [Ni(cod)2]/(S)-H8-BINAP was found to be a superior synthetic protocol for constructing quaternary chiral centers at the alpha-position of beta-ketoesters. The reaction proceeded in high yield and with high enantioselectivity using various beta-ketoesters and allylic alcohols, without any additional activators. The versatility of this methodology for accessing useful and enantioenriched products was demonstrated. PMID- 26637130 TI - Psychiatric Comorbidity, Social Aspects and Quality of Life in a Population-Based Cohort of Expecting Fathers with Epilepsy. AB - OBJECTIVES: To investigate psychiatric disorders, adverse social aspects and quality of life in men with epilepsy during partner's pregnancy. METHOD: We used data from the Norwegian Mother and Child Cohort Study, including 76,335 men with pregnant partners. Men with epilepsy were compared to men without epilepsy, and to men with non-neurological chronic diseases. RESULTS: Expecting fathers in 658 pregnancies (mean age 31.8 years) reported a history of epilepsy, 36.9% using antiepileptic drugs (AEDs) at the onset of pregnancy. Symptoms of anxiety or depression were increased in epilepsy (7.0% and 3.9%, respectively) vs. non epilepsy (4.6% and 2.5%, respectively, p = 0.004 and 0.023), and so were new onset symptoms of depression (2.0% vs. 1.0%, p < 0.031) and anxiety (4.3% vs. 2.3%, p = 0.023). Low self-esteem (2.5%) and low satisfaction with life (1.7%) were more frequent among fathers with epilepsy compared to fathers without epilepsy (1.3% and 0.7%, respectively, p = 0.01 and 0.010). Adverse social aspects and life events were associated with epilepsy vs. both reference groups. Self-reported diagnoses of ADHD (2.2%) and bipolar disorder (1.8%) were more common in epilepsy vs. non-epilepsy (0.4% and 0.3%, respectively, p = 0.002 and 0.003) and non-neurological chronic disorders (0.5% and 0.5%, respectively, p = 0.004 and 0.018). A screening tool for ADHD symptoms revealed a higher rate compared to self-reported ADHD (9.5% vs. 2.2%, p < 0.001). CONCLUSION: Expecting fathers with epilepsy are at high risk of depression and anxiety, adverse socioeconomic aspects, low self-esteem, and low satisfaction with life. Focus on mental health in fathers with epilepsy during and after pregnancy is important. The use of screening tools can be particularly useful to identify those at risk. PMID- 26637132 TI - Controlling Posture and Vergence Eye Movements in Quiet Stance: Effects of Thin Plantar Inserts. AB - The purpose of this study was to assess properties of vergence and saccade eye movements as well as posture in quiet stance, and the effects of thin plantar inserts upon postural and oculomotor control. The performances of 36 young healthy subjects were recorded by a force platform and an eye tracker in three testing conditions: without plantar stimulation, with a 3 millimetre-thick plantar insert, either a Medial or a Lateral Arch Support (MAS/LAS). The results showed a decrease of the Surface and Variance of Speed and a more posterior position of the CoP with either stimulation compared with the control condition. The fractal analysis showed a decrease with MAS. Wavelet analysis in the time frequency domain revealed an increase in the Cancelling Time of the low frequency band with MAS. These results suggest a better stability for a lower energy cost. Concerning eye movements, the inserts influenced only vergence (not saccades): MAS caused an increase of the phasic amplitude of divergence, and conversely a decrease of the tonic amplitude. In contrast, LAS caused an increase of the tonic amplitude of convergence. Thus, MAS renders divergence less visually driven, while LAS renders convergence more visually driven. We conclude that the CNS uses the podal signal for both postural and vergence control via specific mechanisms. Plantar inserts have an influence upon posture and vergence movements in a different way according to the part of the foot sole being stimulated. These results can be useful to clinicians interested in foot or eye. PMID- 26637161 TI - UGT1A1 genotype-dependent dose adjustment of belinostat in patients with advanced cancers using population pharmacokinetic modeling and simulation. AB - Belinostat is a second-generation zinc-binding histone deacetylase inhibitor that is approved for peripheral T-cell lymphoma and is currently being studied in small cell lung cancer and other advanced carcinomas as a 48-hour continuous intravenous infusion. Belinostat is predominantly metabolized by UGT1A1, which is polymorphic. Preliminary analyses revealed a difference in belinostat clearance based on UGT1A1 genotype. A 2-compartment population pharmacokinetic (PK) model was developed and validated that incorporated the UGT1A1 genotype, albumin, and creatinine clearance on the clearance parameter; body weight was a significant covariate on volume. Simulated doses of 600 and 400 mg/m(2) /24 h given to patients considered extensive or impaired metabolizers, respectively, provided equivalent AUCs. This model and subsequent simulations supported additional PK/toxicity and pharmacogenomics/toxicity analyses to suggest a UGT1A1 genotype based dose adjustment to normalize belinostat exposure and allow for more tolerable therapy. In addition, global protein lysine acetylation was modeled with PK and demonstrated a reversible belinostat exposure/response relationship, consistent with previous reports. PMID- 26637162 TI - Exploring the Antibacterial and Antifungal Potential of Jellyfish-Associated Marine Fungi by Cultivation-Dependent Approaches. AB - Fungi isolated from marine invertebrates are of considerable importance as new promising sources of unique secondary metabolites with significant biomedical potential. However, the cultivable fungal community harbored in jellyfish was less investigated. In this work, we seek to recover symbiotic fungi from different tissues of jellyfish Nemopilema nomurai. A total of seven morphotypes were isolated, which were assigned into four genera (Aspergillus, Cladosporium, Purpureocillium, and Tilletiopsis) from two phyla (Ascomycota and Basidiomycota) by comparing the rDNA-ITS sequences with the reference sequences in GenBank. The most fungi were found in the inner tissues of subumbrella. Two of the cultivation independent procedures, changing media type and co-cultivation, were employed to maximize the complexity of metabolites. Thus, thirteen EtOAc gum were obtained and fingerprinted by High Performance Liquid Chromatography (HPLC) equipped with a photodiode array (PDA) detector. Antibacterial and antifungal activities of these complex mixtures were tested against a panel of bacterial and fungal pathogens. The antimicrobial results showed that all of the 13 EtOAc extracts displayed different levels of antibacterial activity, three of which exhibited strong to significant antibacterial activity to the bacterial pathogens Staphylococcus aureus and Salmonella entrica. Antifungal activity indicated that the EtOAc extracts from pure culture of Aspergillus versicolor and co-culture of A. versicolor and Tilletiopsis sp. in rice media were promising for searching new compounds, with the maximal mycelial growth inhibition of 82.32% +/- 0.61% for Rhizoctonia solani and 48.41% +/- 11.02% for Botrytis cinerea at 200 MUg/ml, respectively. This study is the first report on the antibacterial and antifungal activity of jellyfish-associated fungi and allows the first sight into cultivable fungal community residing in jellyfish. Induced metabolites by cultivation dependent approaches provides a new reservoir for drug discovery from jellyfish derived fungi. PMID- 26637163 TI - Collegium Ramazzini response to 'Asbestos, asbestosis, and cancer, the Helsinki criteria for diagnosis and attribution 2014: recommendations'. PMID- 26637164 TI - Identification of Top-ranked Proteins within a Directional Protein Interaction Network using the PageRank Algorithm: Applications in Humans and Plants. AB - Somatic mutation of signal transduction genes or key nodes of the cellular protein network can cause severe diseases in humans but can sometimes genetically improve plants, likely because growth is determinate in animals but indeterminate in plants. This article reviews protein networks; human protein ranking; the mitogen-activated protein kinase (MAPK) and insulin (phospho- inositide 3kinase [PI3K]/phosphatase and tensin homolog [PTEN]/protein kinase B [AKT]) signaling pathways; human diseases caused by somatic mutations to the PI3K/PTEN/ AKT pathway; use of the MAPK pathway in plant molecular breeding; and protein domain evolution. Casitas B-lineage lymphoma (CBL), PTEN, MAPK1 and PIK3CA are among PIK3CA the top-ranked proteins in directional rankings. Eight proteins (ACVR1, CDC42, RAC1, RAF1, RHOA, TGFBR1, TRAF2, and TRAF6) are ranked in the top 50 key players in both signal emission and signal reception and in interaction with many other proteins. Top-ranked proteins likely have major impacts on the network function. Such proteins are targets for drug discovery, because their mutations are implicated in various cancers and overgrowth syndromes. Appropriately managing food intake may help reduce the growth of tumors or malformation of tissues. The role of the protein kinase C/ fatty acid synthase pathway in fat deposition in PTEN/PI3K patients should be investigated. Both the MAPK and insulin signaling pathways exist in plants, and MAPK pathway engineering can improve plant tolerance to biotic and abiotic stresses such as salinity. PMID- 26637165 TI - Autologous Breast Reconstruction in Women Older Than 65 Years Versus Women Younger Than 65 Years: A Multi-Center Analysis. AB - BACKGROUND: Autologous breast reconstruction has been shown to have fewer complications and superior outcomes. In the elderly patient population, a paucity of literature on the subject may render the surgeon reluctant to recommend or perform such a procedure. The objective of this study was to compare complications and satisfaction after abdominally based breast reconstruction in patients older than versus younger than 65 years. METHODS: A retrospective study was performed with data from 5 North American centers from 2002 to 2012. Patients who underwent autologous reconstruction were identified retrospectively, and chart review was performed. The BREAST-Q questionnaire was sent to these patients via mail. Patient variables, operative outcomes and BREASTQ results were analyzed. The Pearson chi2 and analysis of variance tests were used. Given the number of analyses, a more conservative alpha of 0.01 was used for each comparison. RESULTS: A total of 1809 patients were included with 1751 patients younger than 65 years and 58 patients aged 65 years or older. Analysis of postoperative complications showed no significant differences between the age groups, though there was a trend toward higher seroma development (17.2% vs 8.1%; P = 0.013) and infection (19.0% vs 10.0%; P = 0.028) in the older group with statistical significance set at P less than 0.01 to account for multiple comparisons. A total of 1809 BREAST-Q surveys were sent with a response rate of 52.5%. Patient satisfaction results were equally high between the 2 age groups. CONCLUSIONS: This is the largest study to compare patients undergoing autologous breast reconstruction older than and younger than 65 years within the same cohort. Women older than 65 years represent a minority and constituted only 3% of patients in this multicenter 10-year review. We have shown that with careful patient selection, abdominally based autologous reconstruction should be considered in the elderly patient population because it is well tolerated and achieves high patient satisfaction. PMID- 26637166 TI - Intravitreal Aflibercept for Treatment-Resistant Neovascular Age-Related Macular Degeneration: 12-Month Safety and Efficacy Outcomes. AB - PURPOSE: To prospectively assess the safety and efficacy of intravitreal aflibercept for treatment-resistant neovascular age-related macular degeneration (nAMD). METHODS: This prospective, non-randomized clinical trial included 49 patients with treatment-resistant nAMD who received 2 mg intravitreal aflibercept as 3 monthly loading doses, followed by injections every 2 months over 12 months. Inclusion criteria included active nAMD on fluorescein angiography at baseline and persistent intra- or subretinal fluid on optical coherence tomography (OCT) for >= 6 months prior to baseline with a minimum of 4 injections of bevacizumab and/or ranibizumab. Patients were assessed monthly for best-corrected visual acuity (BCVA), central retinal thickness (CRT) measured with OCT and occurrence of adverse events. Retinal pigment epithelium atrophy (RPEA) was assessed at baseline and at 12 months. RESULTS: Mean BCVA improved by 4.7 letters (95% CI: 2.1-7.3, p < 0.001) and CRT decreased by 97.2 um (95% CI: 54.4-140.1, p < 0.001) at 12 months compared to baseline. Median RPEA area increased by 0.48 mm2 (range = -0.1 to 19.9, p < 0.001). There was 1 arterial thromboembolic event and 2 cases of submacular haemorrhage. CONCLUSION: In this cohort of treatment-resistant nAMD patients, intravitreal aflibercept was effective in improving vision and reducing exudation. Early visual and anatomic outcomes may predict longer-term response to treatment, but further assessment is required. PMID- 26637167 TI - Fmrp Interacts with Adar and Regulates RNA Editing, Synaptic Density and Locomotor Activity in Zebrafish. AB - Fragile X syndrome (FXS) is the most frequent inherited form of mental retardation. The cause for this X-linked disorder is the silencing of the fragile X mental retardation 1 (fmr1) gene and the absence of the fragile X mental retardation protein (Fmrp). The RNA-binding protein Fmrp represses protein translation, particularly in synapses. In Drosophila, Fmrp interacts with the adenosine deaminase acting on RNA (Adar) enzymes. Adar enzymes convert adenosine to inosine (A-to-I) and modify the sequence of RNA transcripts. Utilizing the fmr1 zebrafish mutant (fmr1-/-), we studied Fmrp-dependent neuronal circuit formation, behavior, and Adar-mediated RNA editing. By combining behavior analyses and live imaging of single axons and synapses, we showed hyperlocomotor activity, as well as increased axonal branching and synaptic density, in fmr1-/- larvae. We identified thousands of clustered RNA editing sites in the zebrafish transcriptome and showed that Fmrp biochemically interacts with the Adar2a protein. The expression levels of the adar genes and Adar2 protein increased in fmr1-/- zebrafish. Microfluidic-based multiplex PCR coupled with deep sequencing showed a mild increase in A-to-I RNA editing levels in evolutionarily conserved neuronal and synaptic Adar-targets in fmr1-/- larvae. These findings suggest that loss of Fmrp results in increased Adar-mediated RNA editing activity on target specific RNAs, which, in turn, might alter neuronal circuit formation and behavior in FXS. PMID- 26637168 TI - Effects of Mesenchymal Stem Cell Treatment on the Expression of Matrix Metalloproteinases and Angiogenesis during Ischemic Stroke Recovery. AB - BACKGROUND: The efficacy of mesenchymal stem cell (MSC) transplantation in ischemic stroke might depend on the timing of administration. We investigated the optimal time point of MSC transplantation. After MSC treatment, we also investigated the expression of matrix metalloproteinases (MMPs), which play a role in vascular and tissue remodeling. METHODS: Human bone marrow-derived MSCs (2 * 10(6), passage 5) were administrated intravenously after permanent middle cerebral artery occlusion (MCAO) was induced in male Sprague-Dawley rats. First, we determined the time point of MSC transplantation that led to maximal neurological recovery at 1 h, 1 day, and 3 days after MCAO. Next, we measured activity of MMP-2 and MMP-9, neurological recovery, infarction volume, and vascular density after transplanting MSCs at the time that led to maximal neurological recovery. RESULTS: Among the MSC-transplanted rats, those of the MSC 1-hour group showed maximal recovery in the rotarod test (P = 0.023) and the Longa score (P = 0.018). MMP-2 activity at 1 day after MCAO in the MSC 1-hour group was significantly higher than that in the control group (P = 0.002), but MMP-9 activity was not distinct. The MSC 1-hour group also showed smaller infarction volume and higher vascular density than did the control group. CONCLUSIONS: In a permanent model of rodent MCAO, very early transplantation of human MSCs (1 h after MCAO) produced greater neurological recovery and decreased infraction volume. The elevation of MMP-2 activity and the increase in vascular density after MSC treatment suggest that MSCs might help promote angiogenesis and lead to neurological improvement during the recovery phase after ischemic stroke. PMID- 26637169 TI - A Cluster-Randomized Trial of Two Strategies to Improve Antibiotic Use for Patients with a Complicated Urinary Tract Infection. AB - BACKGROUND: Up to 50% of hospital antibiotic use is inappropriate and therefore improvement strategies are urgently needed. We compared the effectiveness of two strategies to improve the quality of antibiotic use in patients with a complicated urinary tract infection (UTI). METHODS: In a multicentre, cluster randomized trial 19 Dutch hospitals (departments Internal Medicine and Urology) were allocated to either a multi-faceted strategy including feedback, educational sessions, reminders and additional/optional improvement actions, or a competitive feedback strategy, i.e. providing professionals with non-anonymous comparative feedback on the department's appropriateness of antibiotic use. Retrospective baseline- and post-intervention measurements were performed in 2009 and 2012 in 50 patients per department, resulting in 1,964 and 2,027 patients respectively. Principal outcome measures were nine validated guideline-based quality indicators (QIs) that define appropriate antibiotic use in patients with a complicated UTI, and a QI sumscore that summarizes for each patient the appropriateness of antibiotic use. RESULTS: Performance scores on several individual QIs showed improvement from baseline to post-intervention measurements, but no significant differences were found between both strategies. The mean patient's QI sum score improved significantly in both strategy groups (multi-faceted: 61.7% to 65.0%, P = 0.04 and competitive feedback: 62.8% to 66.7%, P = 0.01). Compliance with the strategies was suboptimal, but better compliance was associated with more improvement. CONCLUSION: The effectiveness of both strategies was comparable and better compliance with the strategies was associated with more improvement. To increase effectiveness, improvement activities should be rigorously applied, preferably by a locally initiated multidisciplinary team. TRIAL REGISTRATION: Nederlands Trial Register 1742. PMID- 26637170 TI - Genomic Epidemiology of an Endoscope-Associated Outbreak of Klebsiella pneumoniae Carbapenemase (KPC)-Producing K. pneumoniae. AB - Increased incidence of infections due to Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae (KPC-Kp) was noted among patients undergoing endoscopic retrograde cholangiopancreatography (ERCP) at a single hospital. An epidemiologic investigation identified KPC-Kp and non-KPC-producing, extended-spectrum beta-lactamase (ESBL)-producing Kp in cultures from 2 endoscopes. Genotyping was performed on patient and endoscope isolates to characterize the microbial genomics of the outbreak. Genetic similarity of 51 Kp isolates from 37 patients and 3 endoscopes was assessed by pulsed-field gel electrophoresis (PFGE) and multi-locus sequence typing (MLST). Five patient and 2 endoscope isolates underwent whole genome sequencing (WGS). Two KPC-encoding plasmids were characterized by single molecule, real-time sequencing. Plasmid diversity was assessed by endonuclease digestion. Genomic and epidemiologic data were used in conjunction to investigate the outbreak source. Two clusters of Kp patient isolates were genetically related to endoscope isolates by PFGE. A subset of patient isolates were collected post-ERCP, suggesting ERCP endoscopes as a possible source. A phylogeny of 7 Kp genomes from patient and endoscope isolates supported ERCP as a potential source of transmission. Differences in gene content defined 5 ST258 subclades and identified 2 of the subclades as outbreak associated. A novel KPC-encoding plasmid, pKp28 helped define and track one endoscope-associated ST258 subclade. WGS demonstrated high genetic relatedness of patient and ERCP endoscope isolates suggesting ERCP-associated transmission of ST258 KPC-Kp. Gene and plasmid content discriminated the outbreak from endemic ST258 populations and assisted with the molecular epidemiologic investigation of an extended KPC-Kp outbreak. PMID- 26637172 TI - Predicting Stroke Risk Based on Health Behaviours: Development of the Stroke Population Risk Tool (SPoRT). AB - BACKGROUND: Health behaviours, important factors in cardiovascular disease, are increasingly a focus of prevention. We appraised whether stroke risk can be accurately assessed using self-reported information focused on health behaviours. METHODS: Behavioural, sociodemographic and other risk factors were assessed in a population-based survey of 82,259 Ontarians who were followed for a median of 8.6 years (688,000 person-years follow-up) starting in 2001. Predictive algorithms for 5-year incident stroke resulting in hospitalization were created and then validated in a similar 2007 survey of 28,605 respondents (median 4.2 years follow up). RESULTS: We observed 3236 incident stroke events (1551 resulting in hospitalization; 1685 in the community setting without hospital admission). The final algorithms were discriminating (C-stat: 0.85, men; 0.87, women) and well calibrated (in 65 of 67 subgroups for men; 61 of 65 for women). An index was developed to summarize cumulative relative risk of incident stroke from health behaviours and stress. For men, each point on the index corresponded to a 12% relative risk increase (180% risk difference, lowest (0) to highest (9) scores). For women, each point corresponded to a 14% relative risk increase (340% difference, lowest (0) to highest (11) scores). Algorithms for secondary stroke outcomes (stroke resulting in death; classified as ischemic; excluding transient ischemic attack; and in the community setting) had similar health behaviour risk hazards. CONCLUSION: Incident stroke can be accurately predicted using self reported information focused on health behaviours. Risk assessment can be performed with population health surveys to support population health planning or outside of clinical settings to support patient-focused prevention. PMID- 26637171 TI - A Synthetic Lethality Screen Using a Focused siRNA Library to Identify Sensitizers to Dasatinib Therapy for the Treatment of Epithelial Ovarian Cancer. AB - Molecular targeted therapies have been the focus of recent clinical trials for the treatment of patients with recurrent epithelial ovarian cancer (EOC). The majority have not fared well as monotherapies for improving survival of these patients. Poor bioavailability, lack of predictive biomarkers, and the presence of multiple survival pathways can all diminish the success of a targeted agent. Dasatinib is a tyrosine kinase inhibitor of the Src-family kinases (SFK) and in preclinical studies shown to have substantial activity in EOC. However, when evaluated in a phase 2 clinical trial for patients with recurrent or persistent EOC, it was found to have minimal activity. We hypothesized that synthetic lethality screens performed using a cogently designed siRNA library would identify second-site molecular targets that could synergize with SFK inhibition and improve dasatinib efficacy. Using a systematic approach, we performed primary siRNA screening using a library focused on 638 genes corresponding to a network centered on EGFR, HER2, and the SFK-scaffolding proteins BCAR1, NEDD9, and EFS to screen EOC cells in combination with dasatinib. We followed up with validation studies including deconvolution screening, quantitative PCR to confirm effective gene silencing, correlation of gene expression with dasatinib sensitivity, and assessment of the clinical relevance of hits using TCGA ovarian cancer data. A refined list of five candidates (CSNK2A1, DAG1, GRB2, PRKCE, and VAV1) was identified as showing the greatest potential for improving sensitivity to dasatinib in EOC. Of these, CSNK2A1, which codes for the catalytic alpha subunit of protein kinase CK2, was selected for additional evaluation. Synergistic activity of the clinically relevant inhibitor of CK2, CX-4945, with dasatinib in reducing cell proliferation and increasing apoptosis was observed across multiple EOC cell lines. This overall approach to improving drug efficacy can be applied to other targeted agents that have similarly shown poor clinical activity. PMID- 26637173 TI - Effectiveness of Knee Injury and Anterior Cruciate Ligament Tear Prevention Programs: A Meta-Analysis. AB - OBJECTIVE: Individuals frequently involved in jumping, pivoting or cutting are at increased risk of knee injury, including anterior cruciate ligament (ACL) tears. We sought to use meta-analytic techniques to establish whether neuromuscular and proprioceptive training is efficacious in preventing knee and ACL injury and to identify factors related to greater efficacy of such programs. METHODS: We performed a systematic literature search of studies published in English between 1996 and 2014. Intervention efficacy was ascertained from incidence rate ratios (IRRs) weighted by their precision (1/variance) using a random effects model. Separate analyses were performed for knee and ACL injury. We examined whether year of publication, study quality, or specific components of the intervention were associated with efficacy of the intervention in a meta-regression analysis. RESULTS: Twenty-four studies met the inclusion criteria and were used in the meta analysis. The mean study sample was 1,093 subjects. Twenty studies reported data on knee injury in general terms and 16 on ACL injury. Maximum Jadad score was 3 (on a 0-5 scale). The summary incidence rate ratio was estimated at 0.731 (95% CI: 0.614, 0.871) for knee injury and 0.493 (95% CI: 0.285, 0.854) for ACL injury, indicating a protective effect of intervention. Meta-regression analysis did not identify specific intervention components associated with greater efficacy but established that later year of publication was associated with more conservative estimates of intervention efficacy. CONCLUSION: The current meta analysis provides evidence that neuromuscular and proprioceptive training reduces knee injury in general and ACL injury in particular. Later publication date was associated with higher quality studies and more conservative efficacy estimates. As study quality was generally low, these data suggest that higher quality studies should be implemented to confirm the preventive efficacy of such programs. PMID- 26637174 TI - Aloin Protects Skin Fibroblasts from Heat Stress-Induced Oxidative Stress Damage by Regulating the Oxidative Defense System. AB - Oxidative stress is commonly involved in the pathogenesis of skin damage induced by environmental factors, such as heat stress. Skin fibroblasts are responsible for the connective tissue regeneration and the skin recovery from injury. Aloin, a bioactive compound in Aloe vera, has been reported to have various pharmacological activities, such as anti-inflammatory effects. The aim of this study was to investigate the protective effect of aloin against heat stress mediated oxidative stress in human skin fibroblast Hs68 cells. Hs68 cells were first incubated at 43 degrees C for 30 min to mimic heat stress. The study was further examined if aloin has any effect on heat stress-induced oxidative stress. We found that aloin protected Hs68 cells against heat stress-induced damage, as assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and lactate dehydrogenase assay. Aloin protected Hs68 cells by regulating reactive oxygen species production and increasing the levels of glutathione, cytosolic and mitochondrial superoxide dismutase. Aloin also prevented the elevation of thiobarbituric acid reactive substances and the reduction of 8-OH-dG induced by heat stress. These results indicated that aloin protected human skin fibroblasts from heat stress-induced oxidative stress damage by regulating the oxidative defense system. PMID- 26637175 TI - Time to Integrate to Nest Test Evaluation in a Mouse DSS-Colitis Model. AB - Severity assessment in laboratory animals is an important issue regarding the implementation of the 3R concept into biomedical research and pivotal in current EU regulations. In mouse models of inflammatory bowel disease severity assessment is usually undertaken by clinical scoring, especially by monitoring reduction of body weight. This requires daily observance and handling of each mouse, which is time consuming, stressful for the animal and necessitates an experienced observer. The time to integrate to nest test (TINT) is an easily applicable test detecting disturbed welfare by measuring the time interval mice need to integrate nesting material to an existing nest. Here, TINT was utilized to assess severity in a mouse DSS-colitis model. TINT results depended on the group size of mice maintained per cage with most consistent time intervals measured when co-housing 4 to 5 mice. Colitis was induced with 1% or 1.5% DSS in group-housed WT and Cd14 deficient mice. Higher clinical scores and loss of body weight were detected in 1.5% compared to 1% DSS treated mice. TINT time intervals showed no dose dependent differences. However, increased clinical scores, body weight reductions, and increased TINT time intervals were detected in Cd14-/- compared to WT mice revealing mouse strain related differences. Therefore, TINT is an easily applicable method for severity assessment in a mouse colitis model detecting CD14 related differences, but not dose dependent differences. As TINT revealed most consistent results in group-housed mice, we recommend utilization as an additional method substituting clinical monitoring of the individual mouse. PMID- 26637176 TI - Glucocorticoid Metabolism in Hypertensive Disorders of Pregnancy: Analysis of Plasma and Urinary Cortisol and Cortisone. AB - OBJECTIVES: The aim of the study was to analyze the plasma and urinary cortisol (F) and cortisone (E) levels in normotensive and hypertensive pregnant women. The parameters known to reflect the function of 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) were calculated to verify the changes in glucocorticoid balance over the course of gestational hypertension (GH) and pre-eclampsia (PE). MATERIALS AND METHODS: This retrospective case-control study included women in the third trimester of pregnancy, diagnosed with: GH (n = 29), PE (n = 26), or chronic hypertension (CH; n = 22). Normotensive women in their third trimester of pregnancy were also included (controls; n = 43). The plasma and urinary F and E levels were measured with the HPLC-FLD method. The 11beta-HSD2 function was estimated by calculating the following ratios: plasma F/E and urinary free F to urinary free E (UFF/UFE). A statistical analysis was performed based on case control structure. RESULTS AND DISCUSSION: PE was characterized by lower plasma F levels (639.0 nmol/L), UFF/Cr levels (3.80 MUg/mmol) and F/E ratio (3.46) compared with that of the controls (811.7 nmol/L, 6.28 MUg/mmol and 5.19, respectively) with marked abnormalities observed in the changes of F/E and UFF/UFE ratios with advancing gestation. GH patients showed significant disparities in the urinary steroid profile with lower UFF/UFE ratio (0.330 vs. 0.401) compared with the normotensive controls and abnormal changes in the UFF/UFE throughout pregnancy. The observed tendency towards lower F/E and UFF/UFE ratios in PE and GH patients may reflect more intensive F metabolism over the course of those disorders. In the normal pregnancy group, the plasma F/E and UFF/UFE ratios tended to present inverse correlations with advancing gestation. This trend was much less marked in PE and GH patients, suggesting that the abnormalities in 11beta-HSD2 functions progressed with the GA. The birth weights of neonates born from pre-eclamptic pregnancies were lower than those from uncomplicated pregnancies, although only when the babies were born prematurely. Children born at term to normotensive mothers or mothers suffering from PE had comparable birth weights. PMID- 26637177 TI - Transient Intervals of Hyper-Gravity Enhance Endothelial Barrier Integrity: Impact of Mechanical and Gravitational Forces Measured Electrically. AB - BACKGROUND: Endothelial cells (EC) guard vascular functions by forming a dynamic barrier throughout the vascular system that sensitively adapts to 'classical' biomechanical forces, such as fluid shear stress and hydrostatic pressure. Alterations in gravitational forces might similarly affect EC integrity, but remain insufficiently studied. METHODS: In an unique approach, we utilized Electric Cell-substrate Impedance Sensing (ECIS) in the gravity-simulators at the European Space Agency (ESA) to study dynamic responses of human EC to simulated micro- and hyper-gravity as well as to classical forces. RESULTS: Short intervals of micro- or hyper-gravity evoked distinct endothelial responses. Stimulated micro-gravity led to decreased endothelial barrier integrity, whereas hyper gravity caused sustained barrier enhancement by rapid improvement of cell-cell integrity, evidenced by a significant junctional accumulation of VE-cadherin (p = 0.011), significant enforcement of peripheral F-actin (p = 0.008) and accompanied by a slower enhancement of cell-matrix interactions. The hyper-gravity triggered EC responses were force dependent and nitric-oxide (NO) mediated showing a maximal resistance increase of 29.2+/-4.8 ohms at 2g and 60.9+/-6.2 ohms at 4g vs. baseline values that was significantly suppressed by NO blockage (p = 0.011). CONCLUSION: In conclusion, short-term application of hyper-gravity caused a sustained improvement of endothelial barrier integrity, whereas simulated micro gravity weakened the endothelium. In clear contrast, classical forces of shear stress and hydrostatic pressure induced either short-lived or no changes to the EC barrier. Here, ECIS has proven a powerful tool to characterize subtle and distinct EC gravity-responses due to its high temporal resolution, wherefore ECIS has a great potential for the study of gravity-responses such as in real space flights providing quantitative assessment of a variety of cell biological characteristics of any adherent growing cell type in an automated and continuous fashion. PMID- 26637178 TI - Clinical Manifestation of Depression after Stroke: Is It Different from Depression in Other Patient Populations? AB - BACKGROUND: Despite ample research on depression after stroke, the debate continues regarding whether symptoms such as sleep disturbances, loss of energy, changes in appetite and diminished concentration should be considered to be consequences of stroke or general symptoms of depression. By comparing symptoms in depressed and non-depressed stroke patients with patients in general practice and patients with symptomatic atherosclerotic diseases, we aim to further clarify similarities and distinctions of depression after stroke and depression in other patient populations. Based on this, it is possible to determine if somatic symptoms should be evaluated in stroke patients in diagnosing depression after stroke. METHODS: An observational multicenter study is conducted in three hospitals and seven general practices including 382 stroke patients admitted to hospital with a clinical diagnosis of intracerebral hemorrhage or ischemic infarction, 1160 patients in general practice (PREDICT-NL), and 530 patients with symptomatic atherosclerotic diseases (SMART-Medea). RESULTS: The prevalence of major depressive disorder according to DSM-IV criteria was 14.1% (95% CI 11.0% 18.0%) in the stroke cohort, 5.4% (95% CI 3.8%-7.9%) in the symptomatic atherosclerotic diseases cohort and 12.9% (95% CI 11.1%-15.0%) in the general practice cohorts. Comparing depressed patients of the three cohorts demonstrated broadly similar symptom profiles, as well as comparable levels of individual symptom prevalence. However, the stroke patients suffered more severely from these symptoms than patients in the other populations. CONCLUSIONS: The findings suggest that depression after stroke is not a different type of depression. This finding indicates that all depressive symptoms should be evaluated in stroke patients, including somatic symptoms. PMID- 26637179 TI - Diel Vertical Dynamics of Gelatinous Zooplankton (Cnidaria, Ctenophora and Thaliacea) in a Subtropical Stratified Ecosystem (South Brazilian Bight). AB - The diel vertical dynamics of gelatinous zooplankton in physically stratified conditions over the 100-m isobath (~110 km offshore) in the South Brazilian Bight (26 degrees 45'S; 47 degrees 33'W) and the relationship to hydrography and food availability were analyzed by sampling every six hours over two consecutive days. Zooplankton samples were taken in three depth strata, following the vertical structure of the water column, with cold waters between 17 and 13.1 degrees C, influenced by the South Atlantic Central Water (SACW) in the lower layer (>70 m); warm (>20 degrees C) Tropical Water in the upper 40 m; and an intermediate thermocline with a deep chlorophyll-a maximum layer (0.3-0.6 mg m-3). Two distinct general patterns were observed, emphasizing the role of (i) physical and (ii) biological processes: (i) a strong influence of the vertical stratification, with most zooplankton absent or little abundant in the lower layer. The influence of the cold SACW on the bottom layer apparently restricted the vertical occupation of most species, which typically inhabit epipelagic warm waters. Even among migratory species, only a few (Aglaura hemistoma, Abylopsis tetragona eudoxids, Beroe sp., Thalia democratica, Salpa fusiformis) crossed the thermocline and reached the bottom layer. (ii) A general tendency of partial migrations, with variable intensity depending on the different species and developmental stages; populations tended to be more widely distributed through the water column during daylight, and to become more aggregated in the upper layer during the night, which can be explained based on the idea of the "hunger satiation hypothesis", maximizing feeding and minimizing the chances of being predated. PMID- 26637180 TI - Response by the organizers of the Helsinki criteria updates 2014: Criteria for asbestos-related diseases need periodic updates. PMID- 26637181 TI - Minor Role of Plasminogen in Complement Activation on Cell Surfaces. AB - Atypical hemolytic uremic syndrome (aHUS) is a rare, but severe thrombotic microangiopathy. In roughly two thirds of the patients, mutations in complement genes lead to uncontrolled activation of the complement system against self cells. Recently, aHUS patients were described with deficiency of the fibrinolytic protein plasminogen. This zymogen and its protease form plasmin have both been shown to interact with complement proteins in the fluid phase. In this work we studied the potential of plasminogen to restrict complement propagation. In hemolytic assays, plasminogen inhibited complement activation, but only when it had been exogenously activated to plasmin and when it was used at disproportionately high concentrations compared to serum. Addition of only the zymogen plasminogen into serum did not hinder complement-mediated lysis of erythrocytes. Plasminogen could not restrict deposition of complement activation products on endothelial cells either, as was shown with flow cytometry. With platelets, a very weak inhibitory effect on deposition of C3 fragments was observed, but it was considered too weak to be significant for disease pathogenesis. Thus it was concluded that plasminogen is not an important regulator of complement on self cells. Instead, addition of plasminogen was shown to clearly hinder platelet aggregation in serum. This was attributed to plasmin causing disintegration of formed platelet aggregates. We propose that reduced proteolytic activity of plasmin on structures of growing thrombi, rather than on complement activation fragments, explains the association of plasminogen deficiency with aHUS. This adds to the emerging view that factors unrelated to the complement system can also be central to aHUS pathogenesis and suggests that future research on the mechanism of the disease should expand beyond complement dysregulation. PMID- 26637182 TI - Impaired Visual Integration in Children with Traumatic Brain Injury: An Observational Study. AB - BACKGROUND: Axonal injury after traumatic brain injury (TBI) may cause impaired sensory integration. We aim to determine the effects of childhood TBI on visual integration in relation to general neurocognitive functioning. METHODS: We compared children aged 6-13 diagnosed with TBI (n = 103; M = 1.7 years post injury) to children with traumatic control (TC) injury (n = 44). Three TBI severity groups were distinguished: mild TBI without risk factors for complicated TBI (mildRF- TBI, n = 22), mild TBI with >=1 risk factor (mildRF+ TBI, n = 46) or moderate/severe TBI (n = 35). An experimental paradigm measured speed and accuracy of goal-directed behavior depending on: (1) visual identification; (2) visual localization; or (3) both, measuring visual integration. Group-differences on reaction time (RT) or accuracy were tracked down to task strategy, visual processing efficiency and extra-decisional processes (e.g. response execution) using diffusion model analysis. General neurocognitive functioning was measured by a Wechsler Intelligence Scale short form. RESULTS: The TBI group had poorer accuracy of visual identification and visual integration than the TC group (Ps <= .03; ds <= -0.40). Analyses differentiating TBI severity revealed that visual identification accuracy was impaired in the moderate/severe TBI group (P = .05, d = -0.50) and that visual integration accuracy was impaired in the mildRF+ TBI group and moderate/severe TBI group (Ps < .02, ds <= -0.56). Diffusion model analyses tracked impaired visual integration accuracy down to lower visual integration efficiency in the mildRF+ TBI group and moderate/severe TBI group (Ps < .001, ds <= -0.73). Importantly, intelligence impairments observed in the TBI group (P = .009, d = -0.48) were statistically explained by visual integration efficiency (P = .002). CONCLUSIONS: Children with mildRF+ TBI or moderate/severe TBI have impaired visual integration efficiency, which may contribute to poorer general neurocognitive functioning. PMID- 26637183 TI - Impact of the Implementation of Thrombectomy with Stent Retrievers on the Frequency of Hemicraniectomy in Patients with Acute Ischemic Stroke. AB - BACKGROUND: The increasing use of endovascular treatments has led to higher recanalization rates and better clinical outcomes compared with intravenous thrombolysis alone. Stent retrievers represent the latest development for recanalization of large vessel occlusions. Decompressive hemicraniectomy has proved beneficial in patients suffering from rising intracranial pressure after malignant stroke. AIMS AND/OR HYPOTHESIS: We investigated the effect of the implementation of stent retriever treatment on the frequency of hemicraniectomy as a surrogate marker for infarct size and thus for poor neurological outcome. METHODS: Patients with acute ischemic stroke were retrospectively studied. We compared the frequency of hemicraniectomy following proximal artery occlusion of the internal carotid artery and middle cerebral artery main stem in the years before (2009 and 2010) and after (2012 and 2013) introducing stent retrievers. RESULTS: Overall, 497 patients with proximal arterial occlusion were included in the study. Of 253 patients admitted in the years 2009 and 2010 44 (17.4 %) and of 244 patients admitted in 2012 and 2013, 20 (8.2 %) received a hemicraniectomy. This decrease in the proportion of hemicraniectomies was statistically significant (p < 0.01). CONCLUSIONS: The findings in this study illustrate a significantly reduced rate of hemicraniectomies in patients with proximal artery occlusions after implementation of thrombectomy with stent retriever. Hereby, we could show a significant reduction of malignant infarctions after thrombectomy with stent retriever. PMID- 26637185 TI - Psychosocial Vulnerability, Resilience Resources, and Coping with Infertility: A Longitudinal Model of Adjustment to Primary Ovarian Insufficiency. AB - BACKGROUND: The infertility associated with primary ovarian insufficiency (POI) presents significant emotional challenges requiring psychosocial adjustment. Few investigations have explored the longitudinal process of adaptation to POI. PURPOSE: This longitudinal investigation tests a model of adjustment to POI that includes separate psychosocial vulnerability and resilience resource factors. METHODS: Among 102 women with POI, personal attributes reflective of vulnerability and resilience were assessed at baseline. Coping strategies were assessed 4 months later and measures of distress and well-being 12 months later. RESULTS: As hypothesized, confirmatory factor analysis yielded separate, inversely correlated vulnerability and resilience resource factors at baseline, and distress and well-being factors at 12 months. Contrary to predictions, maladaptive and adaptive coping strategies were not bi-factorial. Moreover, a single stand-alone strategy, avoidance (i.e., refusing to acknowledge stress), mediated the association between baseline vulnerability and 12-month distress. CONCLUSIONS: For women with POI, interventional studies targeted to reduce avoidance are indicated. PMID- 26637184 TI - Differential expression of glucose-metabolizing enzymes in multiple sclerosis lesions. AB - INTRODUCTION: Demyelinated axons in multiple sclerosis (MS) lesions have an increased energy demand in order to maintain conduction. However, oxidative stress-induced mitochondrial dysfunction likely alters glucose metabolism and consequently impairs neuronal function in MS. Imaging and pathological studies indicate that glucose metabolism is altered in MS, although the underlying mechanisms and its role in neurodegeneration remain elusive. We investigated expression patterns of key enzymes involved in glycolysis, tricarboxylic acid (TCA) cycle and lactate metabolism in well-characterized MS tissue to establish which regulators of glucose metabolism are involved in MS and to identify underlying mechanisms. RESULTS: Expression levels of glycolytic enzymes were increased in active and inactive MS lesions, whereas expression levels of enzymes involved in the TCA cycle were upregulated in active MS lesions, but not in inactive MS lesions. We observed reduced expression and production capacity of mitochondrial alpha-ketoglutarate dehydrogenase (alphaKGDH) in demyelinated axons, which correlated with signs of axonal dysfunction. In inactive lesions, increased expression of lactate-producing enzymes was observed in astrocytes, whereas lactate-catabolising enzymes were mainly detected in axons. Our results demonstrate that the expression of various enzymes involved in glucose metabolism is increased in both astrocytes and axons in active MS lesions. In inactive MS lesions, we provide evidence that astrocytes undergo a glycolytic shift resulting in enhanced astrocyte-axon lactate shuttling, which may be pivotal for the survival of demyelinated axons. CONCLUSION: In conclusion, we show that key enzymes involved in energy metabolism are differentially expressed in active and inactive MS lesions. Our findings imply that, in addition to reduced oxidative phosphorylation activity, other bioenergetic pathways are affected as well, which may contribute to ongoing axonal degeneration in MS. PMID- 26637186 TI - Strengthening health system governance using health facility service charters: a mixed methods assessment of community experiences and perceptions in a district in Kenya. AB - BACKGROUND: Enhancing accountability in health systems is increasingly emphasised as crucial for improving the nature and quality of health service delivery worldwide and particularly in developing countries. Accountability mechanisms include, among others, health facilities committees, suggestion boxes, facility and patient charters. However, there is a dearth of information regarding the nature of and factors that influence the performance of accountability mechanisms, especially in developing countries. We examine community members' experiences of one such accountability mechanism, the health facility charter in Kericho District, Kenya. METHODS: A household survey was conducted in 2011 among 1,024 respondents (36% male, 64% female) aged 17 years and above stratified by health facility catchment area, situated in a division in Kericho District. In addition, sixteen focus group discussions were conducted with health facility users in the four health facility catchment areas. Quantitative data were analysed through frequency distributions and cross-tabulations. Qualitative data were transcribed and analysed using a thematic approach. RESULTS: The majority (65%) of household survey respondents had seen their local facility service charter, 84% of whom had read the information on the charter. Of these, 83% found the charter to be useful or very useful. According to the respondents, the charters provided useful information about the services offered and their costs, gave users a voice to curb potential overcharging and helped users plan their medical expenses before receiving the service. However, community members cited several challenges with using the charters: non-adherence to charter provisions by health workers; illegibility and language issues; lack of expenditure records; lack of time to read and understand them, often due to pressures around queuing; and socio-cultural limitations. CONCLUSION: Findings from this study suggest that improving the compliance of health facilities in districts across Kenya with regard to the implementation of the facility service charter is critical for accountability and community satisfaction with service delivery. To improve the compliance of health facilities, attention needs to be focused on mechanisms that help enforce official guidelines, address capacity gaps, and enhance public awareness of the charters and their use. PMID- 26637187 TI - Theoretical study of carbon dioxide activation by metals (Co, Cu, Ni) supported on activated carbon. AB - The activation of carbon dioxide (CO2) by catalytic systems comprising a transition metal (Co, Cu,Ni) on an activated carbon (AC) support was investigated using a combination of different theoretical calculation methods: Monte Carlo simulation, DFT and DFT-D, molecular dynamics (MD), and a climbing image nudged elastic band (CI-NEB) method. The results obtained indicate that CO2 is easily adsorbed by AC or MAC (M: Cu, Co, Ni). The results also showed that the process of adsorbing CO2 does not involve a transition state, and that NiAC and CoAC are the most effective of the MAC catalysts at adsorbing CO2. Adsorption on NiAC led to the strongest activation of the C-O bond, while adsorption on CuAC led to the weakest activation. Graphical Abstract Models of CO2 activation on: a)- activated carbon; b)- metal supported activated carbon (M-AC), where M: Co, Cu, Ni. PMID- 26637188 TI - Precision and cost considerations for two-stage sampling in a panelized forest inventory design. AB - Due to the relatively high cost of measuring sample plots in forest inventories, considerable attention is given to sampling and plot designs during the forest inventory planning phase. A two-stage design can be efficient from a field work perspective as spatially proximate plots are grouped into work zones. A comparison between subsampling with units of unequal size (SUUS) and a simple random sample (SRS) design in a panelized framework assessed the statistical and economic implications of using the SUUS design for a case study in the Northeastern USA. The sampling errors for estimates of forest land area and biomass were approximately 1.5-2.2 times larger with SUUS prior to completion of the inventory cycle. Considerable sampling error reductions were realized by using the zones within a post-stratified sampling paradigm; however, post stratification of plots in the SRS design always provided smaller sampling errors in comparison. Cost differences between the two designs indicated the SUUS design could reduce the field work expense by 2-7 %. The results also suggest the SUUS design may provide substantial economic advantage for tropical forest inventories, where remote areas, poor access, and lower wages are typically encountered. PMID- 26637189 TI - Bioaccumulation of mercury and polychlorinated dibenzo-p-dioxins and dibenzofurans in salty water organisms. AB - Mercury and polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) accumulate in organisms through food webs and exert potentially toxic effects on aquatic organisms and humans. This study examined the levels of mercury and PCDD/Fs in organisms and sediment samples collected from a saltwater pond at the An-Shun site, a chloralkali factory that shut down in Tainan City, Taiwan. It was also a pentachlorophenol production plant. After the factories were shut down in the 1980s, mercury and PCDD/Fs contamination remained, posing severe health hazards. The correlation between PCDD/Fs congener accumulation patterns in distinct fish organs and the sediment was evaluated. Mercury and PCDD/Fs levels in all the fish samples exceeded food safety limits, and the concentrations of mercury and PCDD/Fs in each species were closely correlated (n = 12, Spearman's rank correlation [R] = 0.811, p < 0.01). The mercury concentrations were positively but non-significantly correlated with the weight (n = 11, R = 0.741, p < 0.01) and length (n = 11, R = 0.618, p < 0.05) of the species. The fish likely accumulated the contaminants through ingestion of other organisms or the sediment. However, after the pollutants entered a fish, they exhibited distinct accumulation patterns because of their differing chemical properties. Specifically, the mercury concentration was correlated with organism weight and length, whereas the PCDD/Fs concentration was associated with organ lipid content. The study results are valuable for assessing the health risks associated with ingesting mercury- and PCFF/F-contaminated seafood from the study site. PMID- 26637190 TI - A longitudinal examination of the association between nurse staffing levels, the practice environment and nurse-sensitive patient outcomes in hospitals. AB - BACKGROUND: The level of patient safety and outcomes accomplished depends on the quality of care provided. Previous studies found that nurse-to-patient ratio, practice environment, and nursing education were significant predictors of patient outcomes. However, the outcomes measured in previous studies were mainly inpatient mortality and failure-to-rescue rates. Few nurse-sensitive patient outcomes have been measured that quantify nurses' contribution to patient care. Selecting appropriate outcomes that reflect the clinically relevant effect of nursing care is important. Moreover previous studies were largely cross-sectional and retrospective. These research designs are limited in their ability to explain the casual links between the variables examined. This study is aimed at determining the associations among staffing levels, skill mix of baccalaureate prepared registered nurses, and practice environment on nurse-sensitive outcomes for medical and surgical patients in public hospitals in Hong Kong. METHOD/DESIGNS: A multi-method research design will be adopted. The sample includes all medical and surgical wards of four major public hospitals that offer 24-h accident and emergency services. Multiple responses from registered nurses who work in the study wards will be collected over 12 months to examine their individual characteristics and perceptions of the practice environment. A 12 month prospective observational study will be performed to determine the association between nurse staffing levels, the practice environment, and nurse sensitive patient outcomes including pressure ulcers, falls and restraint prevalence, urinary catheter-associated urinary tract infections, and central line catheter-associated bloodstream infections. Multilevel Cox proportional hazards models will be employed to examine the association between these patient outcomes and the explanatory nursing factors of primary interest (nurse staffing levels, education composition, and practice environment), with adjustment for all patient-, ward- and hospital-level potential confounders (age, sex, diagnosis, comorbidities, level of surgical invasiveness, mortality, length of stay, and type of admission). DISCUSSION: It is anticipated that knowledge of the association between nurse staffing levels, the practice environment, and nurse sensitive outcomes will inform the provision of quality and timely patient care. This study will provide a landmark report that is of relevance and importance to patients and to hospital stakeholders and managers, health policy makers, nurses, and educators who advocate patient benefits. TRIAL REGISTRATION: Clinical Trials Registry CCTCTR CUHK_CCT00460 . Date of trial registration: 02 July 2015. PMID- 26637191 TI - [Peritonitis]. PMID- 26637192 TI - [Therapy concepts for diffuse peritonitis: When laparoscopic lavage and when open abdomen?]. AB - Secondary diffuse peritonitis still has a high morbidity and mortality even now; therefore, the various strategies and options for the different surgical therapies are undergoing an evidence-based review. Laparoscopic lavage without resection of the focus of sepsis for example is a profoundly different approach in the treatment of diffuse peritonitis from the damage control-based strategy of surgery with initial laparostomy and deferred anastomosis. The evidential data for minimally invasive therapy are comparatively well-reviewed for appendicitis, cholecystitis and ulcerated perforation of the stomach and duodenum. In contrast, the evidence for laparoscopy and minimally invasive surgery with lavage and deferred anastomosis or damage control in secondary peritonitis has improved but is still low and cannot yet be clearly recommended. This article presents an overview of the currently available therapeutic methods for diffuse peritonitis and a critical consideration of the evidence-based data. The key recommendation is that the decision to use a surgical procedure based on the currently available data depends more on the severity of the abdominal sepsis, the duration, the age of the patient and comorbidities than on the individual technique. PMID- 26637193 TI - NMDA receptor agonists reverse impaired psychomotor and cognitive functions associated with hippocampal Hbegf-deficiency in mice. AB - BACKGROUND: Structural and functional changes of the hippocampus are correlated with psychiatric disorders and cognitive dysfunctions. Genetic deletion of heparin-binding epidermal growth factor-like growth factor (HB-EGF), which is predominantly expressed in cortex and hippocampus, also causes similar psychiatric and cognitive dysfunctions, accompanying down-regulated NMDA receptor signaling. However, little is known of such dysfunctions in hippocampus-specific Hbegf cKO mice. RESULTS: We successfully developed hippocampus-specific cKO mice by crossbreeding floxed Hbegf and Gng7-Cre knock-in mice, as Gng7 promoter-driven Cre is highly expressed in hippocampal neurons as well as striatal medium spiny neurons. In mice lacking hippocampus Hbegf gene, there was a decreased neurogenesis in the subgranular zone (SGZ) of the dentate gyrus as well as down regulation of PSD-95/NMDA-receptor-NR1/NR2B subunits and related NMDA receptor signaling. Psychiatric, social-behavioral and cognitive abnormalities were also observed in hippocampal cKO mice. Interestingly, D-cycloserine and nefiracetam, positive allosteric modulators (PAMs) of NMDA receptor reversed the apparent reduction in NMDA receptor signaling and most behavioral abnormalities. Furthermore, decreased SGZ neurogenesis in hippocampal cKO mice was reversed by nefiracetam. CONCLUSIONS: The present study demonstrates that PAMs of NMDA receptor have pharmacotherapeutic potentials to reverse down-regulated NMDA receptor signaling, neuro-socio-cognitive abnormalities and decreased neurogenesis in hippocampal cKO mice. PMID- 26637194 TI - The care needs of patients with idiopathic pulmonary fibrosis and their carers (CaNoPy): results of a qualitative study. AB - BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic, fibrotic interstitial lung disease of unknown origin. It has a median survival of three years but a wide range in survival rate which is difficult to predict at the time of diagnosis. Specialist guidance promotes a patient centred approach emphasising regular assessment, information giving and supportive care coordinated by a multidisciplinary team (MDT). However understanding of patient and carer experience across the disease trajectory is limited and detailed guidance for MDTs on communication, assessment, and triggers for supportive and palliative interventions is lacking. This study addresses uncertainties relating to care needs of patients and carers at different stages of the IPF disease trajectory. METHODS: Following ethical approval a multi-centre mixed-methods study recruited participants with IPF at four stages of the disease trajectory. Qualitative analysis was used to analyse 48 semi-structured interviews with patients (27) and paired carers (21). RESULTS: Patients and carers outlined key elements of MDT activity capable of having significant impact on the care experience. These were structured around: Focus of clinical encounters. Timely identification of changes in health status and functional activity. Understanding of symptoms and medical interventions. Coping strategies and carer roles. CONCLUSIONS: Patients diagnosed with IPF have a clear understanding of their prognosis but little understanding of how their disease will progress and how it will be managed. In depth analysis of the experiences of patients and carers offers guidance for refining IPF clinical pathways. This will support patients and carers at key transition points in line with National Institute for Health and Care Excellence (NICE) guidance. PMID- 26637196 TI - The 2 degrees C global warming effect on summer European tourism through different indices. AB - Climate and weather patterns are an essential resource for outdoor tourism activities. The projected changes in climate and weather patterns are expected to affect the future state of tourism. The present study aims to quantify the positive or negative effect of a 2 degrees C global warming on summertime climate comfort in the sense of exercising activities that involve light body activity. The well-established Climate Index for Tourism (CIT) and three variants of the widely used Tourism Climatic Index (TCI) were analyzed. Additionally, a new index based on TCI and CIT was tested and compared against the precious indices. Past and future climate data of five high-resolution regional climate models (RCMs) from different Representative Concentration Pathways (RCP4.5 and RCP8.5) of the European Coordinated Regional Climate Downscaling Experiment (Euro CORDEX) for a +2 degrees C period were used. The results indicate improvement in the climate comfort for the majority of European areas for the May to October period. For the June to August period, central and northern European areas are projected to improve, while marginal improvement is found for Mediterranean countries. Furthermore, in specific cases of adjacent Mediterranean areas such as the southern Iberian Peninsula, the June to August climate favorability is projected to reduce as a result of the increase to daytime temperature. The use of a set of different indices and different RCMs and RCPs samples a large fraction of the uncertainty that is crucial for providing robust regional impact information due to climate change. The analysis revealed the similarities and the differences in the magnitude of change across the different indices. Moreover, discrepancies were found in the results of different concentration pathways to the +2 degrees C global warming, with the RCP8.5 projecting more significant changes for some of the analyzed indices. The estimation of the TCI using different timescale climate data did not change the results on tourism significantly. PMID- 26637195 TI - An integrative analysis of small molecule transcriptional responses in the human malaria parasite Plasmodium falciparum. AB - BACKGROUND: Transcriptional responses to small molecules can provide insights into drug mode of action (MOA). The capacity of the human malaria parasite, Plasmodium falciparum, to respond specifically to transcriptional perturbations has been unclear based on past approaches. Here, we present the most extensive profiling to date of the parasite's transcriptional responsiveness to thirty-one chemically and functionally diverse small molecules. METHODS: We exposed two laboratory strains of the human malaria parasite P. falciparum to brief treatments of thirty-one chemically and functionally diverse small molecules associated with biological effects across multiple pathways based on various levels of evidence. We investigated the impact of chemical composition and MOA on gene expression similarities that arise between perturbations by various compounds. To determine the target biological pathways for each small molecule, we developed a novel framework for encoding small molecule effects on a spectra of biological processes or GO functions that are enriched in the differentially expressed genes of a given small molecule perturbation. RESULTS: We find that small molecules associated with similar transcriptional responses contain similar chemical features, and/ or have a shared MOA. The approach also revealed complex relationships between drugs and biological pathways that are missed by most exisiting approaches. For example, the approach was able to partition small molecule responses into drug-specific effects versus non-specific effects. CONCLUSIONS: Our work provides a new framework for linking transcriptional responses to drug MOA in P. falciparum and can be generalized for the same purpose in other organisms. PMID- 26637197 TI - Microsatellite instability in pulmonary adenocarcinomas: a comprehensive study of 480 cases. AB - A major molecular pathway of genetic instability in cancer is DNA mismatch repair deficiency, leading to accumulation of numerous mutations at repetitive DNA sequence stretches (microsatellites), known as high-level microsatellite instability (MSI-H). In colorectal cancer, MSI-H tumors show a clinical behavior different from microsatellite-stable (MSS) tumors. Data about the prevalence of MSI among non-small cell lung cancer (NSCLC) are conflicting, and clinical relevance of MSI is largely unknown. We analyzed a series of 480 pulmonary adenocarcinomas (ADC) for MSI using a sensitive mononucleotide marker panel (BAT25, BAT26, and CAT25). Positive cases were further analyzed by immunohistochemical staining for DNA mismatch repair proteins. Results were correlated with clinicopathological variables. MSI-H was detected in 4/480 (0.8 %) cases. In none of these, a background of Lynch syndrome was found. Three of the patients developed a metachronous carcinoma (esophagus, pancreas, and kidney). All MSI-H cases were stage I and occurred in smokers/ex-smokers. Mutations were found in EGFR (n = 2), KRAS (n = 1), or BRAF (n = 1). MSI-H neoplasms had a higher proliferative activity (38.7 %) than MSS neoplasms (28.3 %). Mean overall survival for MSS and MSI-H cases was 64.8 (CI 60.4-69.1) and 47.1 (CI 21-73.2) months, respectively. When specific mononucleotide marker panels are applied, the MSI-H phenotype is rare and predominantly found in early stage ADC of smokers. However, the frequency of MSI-H is in the range of other relevant molecular alterations. In the era of precision therapy, associations with distinct clinicopathological variables merit further investigation. PMID- 26637198 TI - Prognostic value of pathological response to neoadjuvant chemotherapy in bulky stage Ib2 and IIa cervical squamous cell cancer patients. AB - Neoadjuvant chemotherapy (NAC) is widely used to treat patients with locally advanced cervical cancer. Optimal pathological response to neoadjuvant therapy has proven to be a good prognostic indicator for patient survival, but the prognostic significance of a partial response remains unclear. The aim of this study was to identify prognostic predictors for patients with partial response. We included in the study 190 patients with bulky stage Ib2 or IIa cervical squamous cell cancer, who underwent neoadjuvant chemotherapy followed by surgery. A novel pathological grading system, including optimal response (complete disappearance of tumor, grade 1), viable tumor cells occupying <(2)/3 (grade 2) or >(2)/3 (grade 3) of the tumor bed area and extra-cervical tumor deposits (grade 4), was developed and associations with disease-free survival and overall survival were studied. Survival analysis was conducted using log-rank testing and Cox regression analysis. We found statistically significant differences between 4 different pathological response groups both in terms of disease-free survival (p = 0.001) and overall survival (p = 0.003). Combining adjacent survival curves in the pathological grading system allowed us to identify response grade 2 patients with disease-free and overall survival similar to those of optimal response patients (p = 0.000, p = 0.002). Multivariate analyses showed that the pathological response grading system is the only independent predictor for progression-free survival and overall survival (p = 0.001 and p = 0.007). A response grading system based on pathological parameters may be useful to predict both progression-free and overall survival in bulky stage Ib2 and IIa cervical squamous cell cancer patients treated with NAC. PMID- 26637199 TI - Solitary, multiple, benign, atypical, or malignant: the "Granular Cell Tumor" puzzle. AB - The clinical evolution and biology of granular cell tumors (GCT) are poorly understood and treatment remains an issue of discussion. The majority of GCT are benign, although some display malignant behavior. The distinction between benign, atypical, and malignant GCT is controversial due to morphological and immunohistochemical overlap and lack of consistent histological and phenotypic criteria that predict behavior. Although histological criteria may indicate increased risk of malignant evolution, some GCT with evident benign appearance exceptionally progress towards metastatic disease. In this review, we discuss current knowledge on GCT, including histologic, immunophenotypic, and molecular characteristics and differential diagnosis. We focus on the following problematic items in GCT: (1) evolution of classification, (2) neural versus non-neural GCT, (3) neoplastic versus reactive disease, (4) malignant transformation of benign GCT, and (5) multiple versus metastatic GCT. We conclude that although a Ki-67 index >10 % and the presence of mitoses and/or of necrosis are frequently associated with malignant behavior, metastasis remains the only unequivocal sign of malignancy in GCT. An infiltrative growth pattern and vascular and/or perineural invasion are not indicative of malignancy. GCT with atypical/uncertain features almost never metastasize, and many of these tumors either behave in a benign fashion or only recur locally (similar to incompletely excised benign tumors). We therefore propose that classical and atypical histological variants form a single group of GCT. GCT with various unfavorable histological features might be labeled as "GCT with increased risk of metastasis" rather than malignant GCT. PMID- 26637200 TI - Six-years survival and predictors of mortality after CABG using cold vs. warm blood cardioplegia in elective and emergent settings. AB - BACKGROUND: The aim of this study was to determine whether intermittent warm blood cardioplegia (IWC) is associated with comparable myocardial protection compared to cold blood cardioplegia (ICC) in patients undergoing elective vs. emergent CABG procedures. METHODS: Out of 2292 consecutive patients who underwent isolated on-pump CABG surgery using cardioplegic arrest either with ICC or IWC between January 2008 and December 2010, 247 consecutive emergent patients were identified and consecutively matched 1:2 with elective patients based on gender, age (<50 years, 50-70 years, >70 years) and ejection fraction (<40 %, 40-50 %, >50 %). Perioperative outcomes and long-term mortality were compared between ICC and IWC strategies and predictors for 30-day mortality and perioperative myocardial injury were identified in both elective and emergent subgroups of patients. RESULTS: Preoperative demographics and baseline characteristics, logistic Euroscore, CPB-time, number of distal anastomoses and LIMA-use were comparable. Aortic cross clamp time was significantly longer in the IWC-group regardless of the urgency of the procedure (p = 0.05 and p = 0.015 for emergent and elective settings). There were no significant differences regarding ICU-stay, ventilation time, total blood loss and need for dialysis. The overall 30-day, 1-, 3- and 6-year survival of the entire patient cohort was 93.7, 91.8, 90.4 and 89.1 %, respectively, with significantly better outcomes when operated electively (p < 0.001) but no differences between ICC and IWC both in elective (p = 0.857) and emergent (p = 0.741) subgroups. Multivariate analysis did not identify the type of cardioplegia as a predictor for 30-day mortality and for perioperative myocardial injury. However, independent factors predictive of 30-day mortality were: EF < 40 % (OR 3.66; 95 % CI: 1.79-7.52; p < 0.001), atrial fibrillation (OR 3.33; 95 % CI: 1.49-7.47; p < 0.003), peripheral artery disease (OR 2.51; 95 % CI: 1.13-5.55; p < 0.023) and COPD (OR 0.26; 95 % CI: 1.05-6.21; p < 0.038); predictors for perioperative myocardial infarction were EF < 40 % (OR 2.04; 95 % CI: 1.32-3.15; p < 0.001), preoperative IABP support (OR 3.68; 95 % CI: 1.34 10.13; p < 0.012), and hemofiltration (OR 3.61; 95 % CI: 2.22-5.87; p < 0.001). CONCLUSION: Although the aortic cross clamp time was prolonged in the IWC group our results confirm effective myocardial protection under IWC, regardless of the urgency of the procedure. We suggest that intermittent warm cardioplegia in emergent CABG setting is a low-cost alternative and safe. It is associated with similar long-term outcomes both in elective and emergent settings compared to intermittent cold cardioplegia. PMID- 26637201 TI - Effect of injuries worldwide has fallen by almost a third since 1990. PMID- 26637202 TI - Elevated concentrations of serum matrix metalloproteinase-2 and -9 and their associations with circulating markers of cardiovascular diseases in chronic arsenic-exposed individuals. AB - BACKGROUND: Cardiovascular diseases (CVDs) and cancers are the major causes of chronic arsenic exposure-related morbidity and mortality. Matrix metalloproteinase-2 (MMP-2) and -9 (MMP-9) are deeply involved in the pathogenesis of CVDs and cancers. This study has been designed to evaluate the interactions of arsenic exposure with serum MMP-2 and MMP-9 concentrations especially in relation to the circulating biomarkers of CVDs. METHODS: A total of 373 human subjects, 265 from arsenic-endemic and 108 from non-endemic areas in Bangladesh were recruited for this study. Arsenic concentrations in the specimens were measured by inductively coupled plasma mass spectroscopy (ICP-MS) and serum MMPs were quantified by immunoassay kits. RESULTS: Serum MMP-2 and MMP-9 concentrations in arsenic-endemic population were significantly (p < 0.001) higher than those in non-endemic population. Both MMPs showed significant positive interactions with drinking water (r s = 0.208, p < 0.001 for MMP-2; r s = 0.163, p < 0.01 for MMP-9), hair (r s = 0.163, p < 0.01 for MMP-2; r s = 0.173, p < 0.01 for MMP-9) and nail (r s = 0.160, p < 0.01 for MMP-2; r s = 0.182, p < 0.001 for MMP-9) arsenic of the study subjects. MMP-2 concentrations were 1.02, 1.03 and 1.05 times, and MMP-9 concentrations were 1.03, 1.06 and 1.07 times greater for 1 unit increase in log-transformed water, hair and nail arsenic concentrations, respectively, after adjusting for covariates (age, sex, BMI, smoking habit and hypertension). Furthermore, both MMPs were increased dose dependently when the study subjects were split into three (<=10, 10.1-50 and > 50 MUg/L) groups based on the regulatory upper limit of water arsenic concentration set by WHO and Bangladesh Government. MMPs were also found to be significantly (p < 0.05) associated with each other. Finally, the concentrations of both MMPs were correlated with several circulating markers related to CVDs. CONCLUSIONS: This study showed the significant positive associations and dose-response relationships of arsenic exposure with serum MMP-2 and MMP-9 concentrations. This study also showed the interactions of MMP-2 and MMP-9 concentrations with the circulating markers of CVDs suggesting the MMP-2 and MMP-9 -mediated mechanism of arsenic-induced CVDs. PMID- 26637203 TI - Enhanced Recovery After Surgery (ERAS(r)) protocol in patients undergoing laparoscopic resection for stage IV colorectal cancer. AB - BACKGROUND: There is strong evidence for the use of Enhanced Recovery After Surgery (ERAS) protocol with colorectal surgery. However, in most studies on ERAS, patients with stage IV colorectal cancer (CRC) are commonly excluded. It is not certain if the ERAS protocol combined with laparoscopy improves outcomes in this group of patients as well. The aim of the study is to assess the feasibility of the ERAS protocol implementation in patients operated laparoscopically due to stage IV CRC. METHODS: A prospective analysis of patients undergoing laparoscopic colorectal surgery was performed. Group 1 included patients with stages I-III, and group 2 included patients with stage IV CRC. Demographic, surgical factors, length of stay (LOS), complications, readmissions, ERAS implementation and early postoperative recovery were compared between the groups. RESULTS: Group 1 included 168 patients, and group 2 included 20 patients. There was no difference in the age, sex, BMI, ASA, cancer localisation or surgical parameters. No statistically significant difference was noted in complications (26.8 vs 20 %, p = 0.51344), LOS (4.7 vs 5.7 days, p = 0.28228) or readmissions (6 vs 10 %, p = 0.48392). The ERAS protocol compliance was 86.3 and 83.0 %, respectively (p = 0.17158). CONCLUSIONS: Implementation of the ERAS protocol and laparoscopic surgery among patients with stage IV CRC is feasible and provides similar short term clinical outcomes and recovery as with patients with stages I-III. PMID- 26637204 TI - Prospective comparison of (68)Ga-DOTATATE and (18)F-FDOPA PET/CT in patients with various pheochromocytomas and paragangliomas with emphasis on sporadic cases. AB - PURPOSE: Pheochromocytomas/paragangliomas (PHEOs/PGLs) overexpress somatostatin receptors and recent studies have already shown excellent results in the localization of these tumors using (68)Ga-labeled somatostatin analogs ((68)Ga DOTA-SSA), especially in patients with germline succinate dehydrogenase subunit B gene (SDHB) mutations and head and neck PGLs (HNPGLs). The value of (68)Ga-DOTA SSA has to be established in sporadic cases, including PHEOs. Thus, the aim of this study was to compare (68)Ga-DOTATATE PET/CT, (18)F-FDOPA PET/CT, and conventional imaging in patients with various PHEOs/PGLs with a special emphasis on sporadic cases, including those located in the adrenal gland. DESIGN: (68)Ga DOTATATE, (18)F-FDOPA PET/CT, and conventional imaging (contrast-enhanced CT and MRI with MR angiography sequences) were prospectively performed in 30 patients (8 with SDHD mutations, 1 with a MAX mutation and 21 sporadic cases) with PHEO/PGL at initial diagnosis or relapse. RESULTS: The patient-based sensitivities were 93 % (28/30), 97 % (29/30), and 93 % (28/30) for (68)Ga-DOTATATE PET/CT, (18)F-FDOPA PET/CT, and conventional imaging, respectively. The lesion-based sensitivities were 93 % (43/46), 89 % (41/46), and 76 % (35/46) for (68)Ga-DOTATATE PET/CT, (18)F-FDOPA PET/CT, and conventional imaging respectively (p = 0.042). (68)Ga DOTATATE PET/CT detected a higher number of HNPGLs (30/30) than (18)F-FDOPA PET/CT (26/30; p = 0.112) and conventional imaging (24/30; p = 0.024). (68)Ga DOTATATE PET/CT missed two PHEOs of a few millimeters in size and a large recurrent PHEO. One lesion was considered false-positive on (68)Ga-DOTATATE PET/CT and corresponded to a typical focal lesion of fibrous dysplasia on MRI. Among the 11 lesions missed by conventional imaging, 7 were detected by conventional imaging with knowledge of the PET results (4 HNPGLs, 2 LNs, and 1 recurrent PHEO). CONCLUSION: (68)Ga-DOTATATE PET/CT is the most sensitive tool in the detection of HNPGLs, especially SDHD-related tumors, which may be very small and fail to concentrate sufficient (18)F-FDOPA. The present study further expands the use of (68)Ga-DOTATATE for all patients with HNPGLs, regardless of their genotype. (68)Ga-DOTATATE PET/CT may be inferior to (18)F-FDOPA PET/CT in the detection PHEOs. PMID- 26637205 TI - Rare variants analysis using penalization methods for whole genome sequence data. AB - BACKGROUND: Availability of affordable and accessible whole genome sequencing for biomedical applications poses a number of statistical challenges and opportunities, particularly related to the analysis of rare variants and sparseness of the data. Although efforts have been devoted to address these challenges, the performance of statistical methods for rare variants analysis still needs further consideration. RESULT: We introduce a new approach that applies restricted principal component analysis with convex penalization and then selects the best predictors of a phenotype by a concave penalized regression model, while estimating the impact of each genomic region on the phenotype. Using simulated data, we show that the proposed method maintains good power for association testing while keeping the false discovery rate low under a verity of genetic architectures. Illustrative data analyses reveal encouraging result of this method in comparison with other commonly applied methods for rare variants analysis. CONCLUSION: By taking into account linkage disequilibrium and sparseness of the data, the proposed method improves power and controls the false discovery rate compared to other commonly applied methods for rare variant analyses. PMID- 26637206 TI - Mycetismus: a review. AB - Although rare, death from amanitin exposure poses a significant health risk and a diagnostic challenge to the clinician due to its rarity. This is one of the few conditions to be voluntarily reported by healthcare professionals. No antidote exists for this poisoning and, perhaps due to its rarity or lack of attention, the United States has lagged behind Europe for almost three decades in treatment, diagnostics and experimentation. This regrettable fact warrants the formation of a centralized agency for education, the advancement of research and the collection of data, to provide better treatment for the population. PMID- 26637207 TI - Acquired Smell? Mature Females of the Common Green Bottle Fly Shift Semiochemical Preferences from Feces Feeding Sites to Carrion Oviposition Sites. AB - We investigated foraging decisions by adult females of the common green bottle fly, Lucilia sericata, in accordance with their physiological state. When we gave female flies a choice between visually occluded, fresh canine feces (feeding site) and a CO2-euthanized rat (carrion oviposition site), 3-d-old "protein starved" females responded equally well to feces and carrion, whereas protein-fed gravid females with mature oocytes responded only to carrion, indicating resource preferences based on a fly's physiological state. Dimethyl trisulfide (DMTS) is known to attract gravid L. sericata females to carrion. Therefore, we analyzed headspace from canine feces by gas chromatographic-electroantennographic detection (GC-EAD) and GC/mass spectrometry. In bioassays, of the 17 fecal odorants that elicited GC-EAD responses from fly antennae, a blend of indole and one or more of the alcohols phenol, m-/p-cresol and 1-octen-3-ol proved as attractive to flies as canine feces. Unlike young females, gravid females need to locate carrion for oviposition and distinguish between fresh and aging carrion, the latter possibly detrimental to offspring. Gravid female L. sericata accomplish this task, in part, by responding to trace amounts of DMTS emanating from fresh carrion and by discriminating against carrion as soon it begins to produce appreciable amounts of indole, which is also the second-most abundant semiochemical in fresh canine feces, and apparently serves as an indicator of food rather than oviposition resources. Our results emphasize the importance of studying foraging choices by flies in accordance with their physiological stage. PMID- 26637208 TI - Sigma-1 Agonist Binding in the Aging Rat Brain: a MicroPET Study with [(11)C]SA4503. AB - PURPOSE: Sigma-1 receptor ligands modulate the release of several neurotransmitters and intracellular calcium signaling. We examined the binding of a radiolabeled sigma-1 agonist in the aging rat brain with positron emission tomography (PET). PROCEDURES: Time-dependent uptake of [(11)C]SA4503 was measured in the brain of young (1.5 to 3 months) and aged (18 to 32 months) Wistar Hannover rats, and tracer-kinetic models were fitted to this data, using metabolite-corrected plasma radioactivity as input function. RESULTS: In aged animals, the injected probe was less rapidly metabolized and cleared. Logan graphical analysis and a 2-tissue compartment model (2-TCM) fit indicated changes of total distribution volume (V T) and binding potential (BP ND) of the tracer. BP ND was reduced particularly in the (hypo)thalamus, pons, and medulla. CONCLUSIONS: Some areas showed reductions of ligand binding with aging whereas binding in other areas (cortex) was not significantly affected. PMID- 26637209 TI - A C. elegans model of electronic cigarette use: Physiological effects of e liquids in nematodes. AB - BACKGROUND: Electronic cigarettes (e-cigs) have recently become very popular particularly among the younger generation. These nicotine delivery devices are viewed as a preferable alternative to more conventional forms of tobacco use and are thought to reduce the risk of chronic obstructive pulmonary disease, the third leading cause of death worldwide. However, there is very little data available on the consequences of e-cig use, though recently nicotine-independent inflammatory responses have been reported. The genetic model organism Caenorhabditis elegans is a soil nematode whose cell biology is remarkably well conserved with mammals. Here, we used C. elegans to test the physiologic effects of e-liquids used to refill e-cigs. METHODS: Larval worms were exposed from hatching onwards to low concentrations (0.2 %) of e-liquids, distilled e-liquid vapor, propylene glycol (PG), or M9 buffer as a negative control. E-liquids tested included grape, menthol, and V2 Red "classic tobacco" flavors. Nicotine (48 ppm) was tested as a second level variable. Stereotypical physiological outputs were then measured, including developmental rate, fecundity, locomotion, lifespan, and the induction of canonical stress signaling pathways. RESULTS: A small but significant impairment of developmental rate and brood size was observed for PG and V2 Red treated worms compared to the negative control. Worms treated with e-liquids containing nicotine fared significantly worse than those that did not, but vaporization did not increase toxicity. Finally, both PG and V2 Red e-liquid induced an oxidative stress response in the absence of nicotine. CONCLUSIONS: PG exposure is sufficient to induce an oxidative stress response in nematodes, while nicotine is not. Both PG and nicotine independently influence physiologic measures of health and viability. The e-liquid flavorings did not significantly impact outcomes and there was no evidence for vaporization altering toxicity. These data suggest that the major physiologically significant component of e-liquids besides nicotine is likely the common solvent PG. We conclude that C. elegans are an appropriate model to rapidly assess parameters that may contribute to the basic cell biological effects of e-cigs. PMID- 26637210 TI - Low dose of mycophenolate mofetil is enough in desensitized kidney transplantation using rituximab. AB - BACKGROUND: Rituximab is widely used in kidney transplantation. However, it is not clear whether the conventional doses of maintenance immunosuppressant in rituximab-treated kidney transplantation (KT) are appropriate. In our previous study, decreasing mycophenolate mofetil (MMF) dose due to infection did not increase the incidence of rejection or graft failure. Based on these experiences, we developed a new protocol with a lower dose of MMF and studied its clinical outcomes in rituximab-treated KT. METHODS: We enrolled all patients who underwent ABO-incompatible or human leukocyte antigen (HLA)-sensitized living donor KT with the new immunosuppressant protocol after preconditioning with rituximab, but without splenectomy from November 2011 to May 2013. Seventy-two patients (group 1) were consecutively enrolled in this study and followed until November 2013. Patients from our previous study served as control groups. Sixty-seven patients received KT using rituximab with a conventional dose of MMF (group 2), and 87 patients received ABO compatible KT without need for rituximab (group 3). Clinical outcomes, including rejection, infection, and graft survival, were compared between the groups. The chi (2) test and Fisher's exact test were used for categorical variables, the Student's t-test and Mann-Whitney U test were used for continuous variables, and a log-rank test was used for mortality analysis. RESULTS: Doses of postoperative MMF (g/day) were lower in group 1 than in the other groups (1.03 +/- 0.19, 1.48 +/- 0.34 and 1.48 +/- 0.32 g/day at 1 week, p < 0.001). Infectious complications occurred more often in groups with conventional MMF doses (group 2 and 3) than in group 1 (16.7 vs. 37.3 %, p = 0.007 and 16.7 vs. 34.5 %, p = 0.012, respectively). Notably, group 1 showed a lower incidence of cytomegalovirus infection than group 2. However, reduction in MMF dose did not increase the incidence of acute rejection (4.2, 4.5 and 10.3 %). Only one graft failure occurred in group 2 due to vessel kinking after operation. There were no significant differences in the incidence of malignancy and mortality between groups. CONCLUSIONS: A low MMF dose reduces infection without increasing rejection or graft loss and it may be appropriate to reduce the dose of MMF for rituximab-treated KT patients. PMID- 26637211 TI - The effects of an intentional transition from extrapleural pneumonectomy to extended pleurectomy/decortication. AB - OBJECTIVES: For many years, extrapleural pneumonectomy (EPP) was the operation of choice for the radical management of pleural mesothelioma in the UK. However, doubts surrounding the efficacy of EPP, and the change in demographics of the affected population, have prompted a transition in our practice towards extended pleurectomy/decortication (EPD). The aim of this study was to determine the effects an intentional transition from EPP to EPD has had on patient outcome. METHODS: Data from 362 patients undergoing radical surgery (229 EPD, 133 EPP) during 1999-2014 were included. Demographics and outcome were compared between the two groups; EPP versus EPD. RESULTS: The median age of patients undergoing EPD was significantly higher than those undergoing EPP [57 years (range 14-70 years) vs 65 years (range 42-81 years), P < 0.001]. There was a significantly higher proportion of patients with performance status >=1 in the EPD group (46.3 vs 35.4%, P = 0.047). There was no difference in the median length of hospital stay between the two groups [14 days (range 1-133 days) vs 13 days (range 0-93 days), P = 0.409]. There was also no difference between the groups in terms of in hospital mortality (EPP 5.3% and EPD 6.6%, P = 0.389), 30-day mortality [EPP 8 (6.0%) and EPD 8 (3.5%), P = 0.294] or 90-day mortality [EPP 18 (13.5%) and EPD 21 (9.2%), P = 0.220]. There was a significantly higher early reoperation rate in the EPP group (15.0 vs 6.2%, P = 0.008) but a significantly higher late reoperation rate in the EPD group (0.8 vs 5.3%, P = 0.037). There was no significant difference in overall survival or disease-free interval between the two groups (P = 0.899 and P = 0.399, respectively). However, overall survival was significantly greater in patients over the age of 65 undergoing EPD (12.5 vs 4.7 months, P = 0.001). CONCLUSION: The transition from EPP to EPD in our standard practice has enabled us to operate on more elderly, frail patients with no significant increase in use of hospital resources, and without detriment to overall survival. PMID- 26637212 TI - The use and impact of 12-lead electrocardiograms in acute stroke patients: A systematic review. AB - BACKGROUND: Stroke is a leading cause of mortality and disability across the globe. Emergency Medical Services assess and transport a large number of these patients in the prehospital setting. Guidelines for UK ambulance services recommend recording a 12-lead electrocardiogram in the prehospital environment, providing this does not add to significant delay in transporting the patient to hospital; however, this recommendation is not based on any evidence. METHODS: A systematic review was conducted to search and synthesise the literature surrounding the use of prehospital electrocardiograms in acute stroke patients, focusing on the prevalence of abnormalities and their association with prognosis and outcome. Online databases, references from selected articles and hand searches were made to identify eligible studies. Two authors independently reviewed the studies to ensure eligibility criteria were met. Main outcomes were presence of abnormality on electrocardiogram, mortality and disability. No studies set in the prehospital environment were found by the search; therefore the eligibility criteria were widened to include hospital-based studies. A total of 18 studies were subsequently included in the review. RESULTS: Although the prevalence of electrocardiogram abnormalities appears common in hospitalised patients, their prognostic impact on mortality, disability and other adverse outcomes is conflicting amongst the literature. There is a lack of research surrounding the use of prehospital electrocardiogram in acute stroke patients. CONCLUSION: Future studies should be based in the prehospital environment and should investigate whether undertaking an electrocardiogram in the prehospital setting affects clinical management decisions or has an association with mortality or morbidity. PMID- 26637213 TI - [Toxic anterior segment syndrome following cataract surgery]. PMID- 26637214 TI - Evaluation of performance reference compounds (PRCs) to monitor emerging polar contaminants by polar organic chemical integrative samplers (POCIS) in rivers. AB - In this work, a method combining polar organic chemical integrative samplers (POCIS) and ultraperformance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS) was assessed for the determination of two corrosion inhibitors (benzotriazole and methylbenzotriazole), seven pesticides (atrazine, diuron, isoproturon, linuron, metolachlor, penconazole, terbuthylazine), and four pharmaceuticals (carbamazepine, diclofenac, metformin, sulfamethoxazole) in river water. As a first step, two POCIS sorbents, hydrophilic-lipophilic balance (HLB) and Strata X-CW, were compared. The comparison of the uptake profiles of the studied compounds showed that the HLB sorbent provides better uptake (higher sampled amount and better linearity) than Strata X-CW except for the basic compound metformin. Since the sampling rate (R s) of POCIS depends on environmental factors, seven compounds were evaluated as potential performance reference compounds (PRCs) through kinetic experiments. Deisopropylatrazine-d5 (DIA-d5) and, as far as we know, for the first time 4-methylbenzotriazole-d3 showed suitable desorption. The efficiency of both compounds to correct for the effect of water velocity was shown using a channel system in which POCIS were exposed to 2 and 50 cm s(-1). Finally, POCIS were deployed upstream and downstream of agricultural wine-growing and tree-growing areas in the Lienne River and the Uvrier Canal (Switzerland). The impact of the studied areas on both streams could be demonstrated. PMID- 26637215 TI - Ultrasensitive electrospun fluorescent nanofibrous membrane for rapid visual colorimetric detection of H2O2. AB - We report herein a flexible fluorescent nanofibrous membrane (FNFM) prepared by decorating the gold nanocluster (AuNC) on electrospun polysulfone nanofibrous membrane for rapid visual colorimetric detection of H2O2. The provision of AuNC coupled to NFM has proven to be advantageous for facile and quick visualization of the obtained results, permitting instant, selective, and on-site detection. We strongly suggest that the fast response time is ascribed to the enhanced probabilities of interaction with AuNC located at the surface of NF. It has been observed that the color change from red to blue is dependent on the concentration, which is exclusively selective for hydrogen peroxide. The detection limit has been found to be 500 nM using confocal laser scanning microscope (CLSM), visually recognizable with good accuracy and stability. A systematic comparison was performed between the sensing performance of FNFM and AuNC solution. The underlying sensing mechanism is demonstrated using UV spectra, transmission electron microscopy (TEM), and X-ray photoelectron spectroscopy (XPS). The corresponding disappearance of the characteristic emissions of gold nanoclusters and the emergence of a localized surface plasmon resonance (LSPR) band, stressing this unique characteristic of gold nanoparticles. Hence, it is evident that the conversion of nanoparticles from nanoclusters has taken place in the presence of H2O2. Our work here has paved a new path for the detection of bioanalytes, highlighting the merits of rapid readout, sensitivity, and user friendliness. PMID- 26637216 TI - Morphology, chemical composition and nanostructure of single carbon-rich particles studied by transmission electron microscopy: source apportionment in workroom air of aluminium smelters. AB - Sources of C-rich particles at work places in two aluminium smelters in Norway were studied by transmission electron microscopy and energy-dispersive X-ray microanalysis. Based on morphology, nanostructure and chemistry, three different types of C-rich particles are distinguished: (a) chain-like agglomerates (70-100% by number, relative to the sum of C-rich particles) consisting of primary particles with typical onion-shell structure of graphene layers, (b) multi-walled carbon nanotube particles (~3%) and (c) spheres or agglomerates of amorphous C rich particles (0-30%). Chain-like agglomerates are interpreted as diesel soot in accordance with literature data on primary particle diameter, chemical composition and nanostructure of primary particles. The source of the observed multi-walled carbon nanotubes is not known. The amorphous C-rich particles most likely consist of organic carbon species which cannot be characterized further by X-ray microanalysis. Unaltered graphitic electrode material was not found among the C-rich particles. The high fraction of diesel soot particles indicates that elemental carbon is generally suited as proxy for diesel soot in aluminium smelters. However, due to the presence of carbon nanotubes and amorphous C-rich particles, detailed characterization of sources of carbon-rich particles by electron microscopy is recommended for accurate assessment of adverse health effects. PMID- 26637217 TI - Optimized efficiency of mapping a site contaminated with dioxins by immunoassay compared to gas chromatography-high resolution mass spectrometry. AB - The use of an enzyme-linked immunosorbent assay (ELISA) to screen for polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDD/F) has shown promise as a complementary tool to gas chromatography-high resolution mass spectrometry (GC-HRMS). This is especially true due to its low cost, ease of sample preparation and fast sample turnaround time. One problem that was unaddressed by other research is how to increase the efficiency of ELISA to a point that makes it practical for the analysis of large groups of samples that can have a wide range of unknown PCDD/F concentrations; one ELISA test is unable to screen for PCDD/F concentrations that can range anywhere from background levels to upwards of 10,000 picograms toxic equivalents per gram of soil (pgTEQ g(-1)). This paper resolves this problem by introducing a sample algorithm which enables the correct amount of dioxin to enter an ELISA tube from a sample (whose unknown PCDD/F concentration can range between 30 and 10,500 pgTEQ g(-1)) in only two ELISA runs. In doing so, the time and cost benefits of ELISA are preserved. ELISA results for soils and sediment samples processed using the algorithm were then plotted on two site maps alongside their GC-HRMS counterparts. A comparison of both analytical methods showed that areas of high and low PCDD/F concentrations were equally identifiable with either analytical tool; 29 of 32 sample locations on the site maps were placed into the same of three possible screening levels. Therefore, processing ELISA samples through the sample algorithm achieves the necessary level of efficiency while producing virtually equal screening results in comparison to GC-HRMS but at a fraction of the cost. The agreement between GC-HRMS and ELISA was 94% (R (2) = 0.99, n = 53). GC-HRMS and ELISA results were significantly correlated (Wilcoxon signed rank test p < 0.001). PMID- 26637218 TI - Novel behavior of the chromatographic separation of linear and cyclic polymers. AB - In various polymerization processes, the formation of a wide variety of chains, not only in length but also in chemical composition, broadly complicates comprehensive polymer characterization. In this communication, we compare different stationary and mobile phases for the analysis of complex polymer mixtures via size-exclusion chromatography-mass spectrometry (SEC-MS). To the best of our knowledge, we report novel chromatographic effects for the separation of linear and cyclic oligomers for polyesters (PE) and polyurethanes (PUR). A complete separation for the different structures was achieved for both polymer types with a single-solvent system (acetonitrile, ACN) and without extensive optimization. Additionally, cyclic species were found to show an inverse elution profile compared to their linear counterparts, suggesting distinct physical properties between species. PMID- 26637219 TI - Surface-imprinted magnetic particles for highly selective sulfonamides recognition prepared by reversible addition fragmentation chain transfer polymerization. AB - In this work, novel magnetic molecularly imprinted polymers (MMIPs) were prepared by reversible addition fragmentation chain transfer (RAFT) polymerization using sulfamerazine as the template. With the controlled/living property of RAFT polymerization, the resulting MMIPs showed high selectivity for sulfonamides recognition. The MMIPs were characterized by transmission electron microscopy, Fourier transform infrared, vibrating sample magnetometer, X-ray diffraction, X ray photoelectron spectroscopy, and thermogravimetric analysis. The static and selectivity binding experiments demonstrated the desirable adsorption capacity and high selectivity of the MMIPs. The developed MMIPs were used as the solid phase extraction sorbents to selectively extract four sulfonamides from aqueous solution. The recoveries of the spiked pond water ranged from 61.2 to 94.1% with RSD lower than 6.5%. This work demonstrated a versatile approach for the preparation of well-constructed MMIPs for application in the field of solid-phase extraction. PMID- 26637220 TI - Triamcinolone acetonide activates an anti-inflammatory and folate receptor positive macrophage that prevents osteophytosis in vivo. AB - INTRODUCTION: Triamcinolone acetonide (TA) is used for osteoarthritis management to reduce pain, and pre-clinical studies have shown that TA limits osteophyte formation. Osteophyte formation is known to be facilitated by synovial macrophage activation. TA injections might influence macrophage activation and subsequently reduce osteophytosis. Although widely applied in clinical care, the mechanism through which TA exerts this effect remains unknown. In this animal study, we investigated the in vivo effects of TA injections on macrophage activation, osteophyte development and joint degeneration. Furthermore, in vitro macrophage differentiation experiments were conducted to further explain working mechanisms of TA effects found in vivo. METHODS: Osteoarthritis was induced in rat knees using papain injections and a running protocol. Untreated and TA-treated animals were longitudinally monitored for 12 weeks with in vivo micro-computed tomography (MUCT) to measure subchondral bone changes. Synovial macrophage activation was measured in vivo using folate receptor beta (FRbeta)-targeted single-photon emission computed tomography/computed tomography. Articular cartilage was analyzed at 6 and 12 weeks with ex vivo contrast-enhanced MUCT and histology. To further explain the outcomes of our in vivo study, TA on macrophages was also studied in vitro. These cultured macrophages were either M1- or M2-activated, and they were analyzed using fluorescence-activated cell sorting for CD163 and FRbeta expression as well as for messenger RNA (mRNA) expression of interleukin (IL)-10. RESULTS: Our in vivo study showed that intra-articular injections with TA strongly enhanced FRbeta(+) macrophage activation. Despite stimulated macrophage activation, osteophyte formation was fully prevented. There was no beneficial effect of TA against cartilage degradation or subchondral bone sclerosis. In vitro macrophage cultures showed that TA strongly induced monocyte differentiation towards CD163(+) and FRbeta(+) macrophages. Furthermore, TA stimulated M2 macrophages showed enhanced IL-10 expression at the mRNA level. CONCLUSIONS: TA injections potently induce a CD163(+)- and FRbeta(+)-activated macrophage with anti-inflammatory characteristics such as reduced IL-10 production in vitro and lack of osteophytosis in vivo. PMID- 26637221 TI - Quantitative three-dimensional myocardial perfusion cardiovascular magnetic resonance with accurate two-dimensional arterial input function assessment. AB - BACKGROUND: Quantification of myocardial perfusion from first-pass cardiovascular magnetic resonance (CMR) images at high contrast agent (CA) dose requires separate acquisition of blood pool and myocardial tissue enhancement. In this study, a dual-sequence approach interleaving 2D imaging of the arterial input function with high-resolution 3D imaging for myocardial perfusion assessment is presented and validated for low and high CA dose. METHODS: A dual-sequence approach interleaving 2D imaging of the aortic root and 3D imaging of the whole left ventricle using highly accelerated k-t PCA was implemented. Rest perfusion imaging was performed in ten healthy volunteers after administration of a Gadolinium-based CA at low (0.025 mmol/kg b.w.) and high dose (0.1 mmol/kg b.w.). Arterial input functions extracted from the 2D and 3D images were analysed for both doses. Myocardial contrast-to-noise ratios (CNR) were compared across volunteers and doses. Variations of myocardial perfusion estimates between volunteers and across myocardial territories were studied. RESULTS: High CA dose imaging resulted in strong non-linearity of the arterial input function in the 3D images at peak CA concentration, which was avoided when the input function was derived from the 2D images. Myocardial CNR was significantly increased at high dose compared to low dose, with a 2.6-fold mean CNR gain. Most robust myocardial blood flow estimation was achieved using the arterial input function extracted from the 2D image at high CA dose. In this case, myocardial blood flow estimates varied by 24% between volunteers and by 20% between myocardial territories when analysed on a per-volunteer basis. CONCLUSION: Interleaving 2D imaging for arterial input function assessment enables robust quantitative 3D myocardial perfusion imaging at high CA dose. PMID- 26637222 TI - The long-term effect of being treated in a geriatric ward compared to an orthopaedic ward on six measures of free-living physical behavior 4 and 12 months after a hip fracture - a randomised controlled trial. AB - BACKGROUND: This study is part of the Trondheim Hip Fracture Trial, where we compared free-living physical behavior in daily life 4 and 12 months following hip surgery for patients managed with comprehensive geriatric care (CGC) in a geriatric ward with those managed with orthopedic care (OC) in an orthopedic ward. METHODS: This is a single centre, prospective, randomized controlled trial. 397 hip fracture patients were randomized to CGC (n = 199) or OC (n = 198) in the Emergency Department with follow-up assessments performed four and 12 months post surgery. Outcomes were mean upright time, number and length of upright events recorded continuously for four days at four and 12 months post-surgery by an accelerometer-based activity monitor. Missing data were handled by multiple imputation and group differences assessed by linear regression with adjustments for gender, age and fracture type. RESULTS: There were no group differences in participants' pre-fracture characteristics. Estimated group difference in favor of CGC in upright time at 4 months was 34.6 min (17.4 %, CI 9.6 to 59.6, p = .007) and at 12 months, 27.7 min (13.9 %, CI 3.5 to 51.8, p = .025). Average and maximum length of upright events was longer in the CGC (p's < .042). No group difference was found for number of upright events (p's > .452). CONCLUSION: Participants treated with CGC during the hospital stay improved free-living physical behavior more than those treated with OC both 4 and 12 months after surgery, with more time and longer periods spent in upright. Results support findings from the same study for functional outcomes, and demonstrate that CGC impacts daily life as long as one year after surgery. TRIALS REGISTRATION: ClinicalTrials.gov, NCT00667914 , April 18, 2008. PMID- 26637223 TI - Report calls for halt to "deeply flawed" emergency department closure programme. PMID- 26637224 TI - FAM172A is a tumor suppressor in colorectal carcinoma. AB - The present study was designed to elucidate the regulatory role of a novel protein FAM172A in carcinogenesis of colorectal carcinoma (CRC). Investigation of clinical samples using Western blotting showed that expression of FAM172A is significantly lower in cancerous tissues than in adjacent tissues. Furthermore, we constructed in vitro model for continuous overexpression and silencing of FAM172A with a retroviral vector system. FAM172A suppressed the proliferative and invasive potentials of LOVO cells as shown in MTT test, transwell migration assay, wound healing assay, 3D-culture morphologic study, and xenograft experiment. RT-PCR and Western blotting showed that FAM172A overexpression inhibited expressions of Cyclin D1, CDK2, MMP-2, MMP-9, PERK, elF2alpha, ATF6, XBP1, and GRP78, while FAM172A silencing induced their expressions. FAM172A might regulate ERS through PERK-elF2alpha, ATF6-XBP1-GRP78 signal pathway. The results implicated that FAM172A functioned as a tumor suppressor in colorectal carcinoma. PMID- 26637225 TI - In vitro and in vivo anti-melanoma effects of Daphne gnidium aqueous extract via activation of the immune system. AB - The purpose of this study was to assess the antitumor and immunomodulatory effects of the aqueous extract from Daphne gnidium in mice-bearing melanoma tumor. Balb/C mice were subcutaneously implanted with B16-F10 cells and treated intraperitoneally with the aqueous extract at 200 mg/Kg b.w for 21 days. After euthanization on day 22, the tumors were weighed; lymphocyte proliferation, cytotoxic T lymphocyte (CTL), and natural killer (NK) cell activities were evaluated using the MTT assay. Macrophage phagocytosis was studied by measuring the lysosomal activity. In addition to its potential to inhibit the growth of the transplantable tumor, the aqueous extract remarkably induced splenocyte proliferation and both NK and CTL activities in tumor-bearing mice. The aqueous extract was also seen to have promoted lysosomal activity of host macrophages. PMID- 26637226 TI - Roles of phosphatidylinositol 3-kinase regulatory subunit alpha, activator protein-1, and programmed cell death 4 in diagnosis of papillary thyroid carcinoma. AB - This study evaluated the diagnostic values of phosphatidylinositol 3-kinase regulatory subunit alpha (P85alpha), activator protein-1 (AP-1), and programmed cell death 4 (PDCD4) in papillary thyroid carcinoma (PTC). P85alpha, AP-1, and PDCD4 expressions were detected in PTC tissues (n = 116) and thyroid papillary hyperplasia (PTH) tissues (n = 90) by immunohistochemistry, western blot, and enzyme-linked immunosorbent assay (ELISA). Associations of P85alpha, AP-1, and PDCD4 expressions with clinicopathological features in PTC were analyzed. Diagnostic values of P85alpha, AP-1, and PDCD4 in PTC were evaluated by receiver operating characteristic (ROC) curve. P85alpha, AP-1, and PDCD4 expression levels in PTC tissues were statistically different from those in PTH tissues (all P < 0.05). In PTC tissues, AP-1 expression was positively associated with P85alpha expression (r = 0.841, P < 0.01), while negatively associated with PDCD4 expression (r = -0.755, P < 0.01). P85alpha expression was associated with lymph node metastasis (LNM) and the degree of differentiation (both P < 0.05); AP-1 and PDCD4 expressions were associated with the degree of differentiation (both P < 0.05). The diagnostic sensitivity and specificity of P85alpha were 92.2 and 91.1 %, respectively, with a cutoff value of 2.100 and an area under curve (AUC) of 0.966. The diagnostic sensitivity and specificity of AP-1 reached 94.4 and 93.3 % with a cutoff value of 1.655 and an AUC of 0.987. The diagnostic sensitivity and specificity of PDCD4 were 54.4 and 85.6 % with a cutoff value of 2.025 and an AUC of 0.754. P85alpha, AP-1, and PDCD4 proteins may be related to the tumorigenesis and progression of PTC. Moreover, P85alpha, AP-1, and PDCD4 proteins may serve as potential diagnostic markers to the biological behavior of PTC. PMID- 26637227 TI - Desacetyl nimbinene inhibits breast cancer growth and metastasis through reactive oxygen species mediated mechanisms. AB - Accumulation of reactive oxygen species (ROS) has been implicated in induction of apoptosis and regulation of key signaling molecules in cancer cells. Phytochemicals are potent source of anticancer drugs as wells as potential inducers of ROS. Neem (Azadirachta indica) is a medicinal plant used for the treatment of various diseases. The main objective of this study is to investigate the anticancer effect of desacetyl nimbinene (DAN; an active ingredient of neem) against breast cancer. Normal and breast cancer cell lines were used for the study. The effect of DAN on cell proliferation, apoptosis, ROS generation, migration, and invasion was analyzed. Antioxidant enzymes superoxide dismutase (SOD)1 and SOD2 were overexpressed to test the effect of DAN-induced ROS generation on breast cancer growth. Key survival and apoptotic protein markers were analyzed to validate the anticancer effect of DAN. Our data demonstrated that DAN inhibited the growth of breast cancer cells by inducing ROS generation. Further investigations revealed that DAN treatment lead to the loss of mitochondrial membrane potential resulting in mitochondria-dependent apoptotic cell death. Increased phosphorylation of c-Jun-N-terminal kinase (JNK) and reduced phosphorylation of p38 were also observed in response to DAN treatment. Inhibition of ROS production by overexpressing antioxidant enzymes SOD1 and SOD2 reduced the DAN-induced cytotoxicity. Additionally, DAN significantly inhibited migration and invasion of MDA-MB-231 breast cancer cells. Overall, our data suggest that DAN exerts its anticancer effect on breast cancer by induction of mitochondria-mediated apoptosis mediated by ROS accumulation. PMID- 26637228 TI - Combination of miR-125b and miR-27a enhances sensitivity and specificity of AFP based diagnosis of hepatocellular carcinoma. AB - Non-invasive biomarkers of early-stage hepatocellular carcinoma (HCC) could offer immense benefits. Currently available tumor markers for HCC are of not much clinical relevance. In this study, we investigated the potential for using a panel of serum microRNAs (miRNAs) as novel tumor markers in conjunction with serum alpha-fetoprotein (AFP) for diagnosis of HCC. Serum expression of four miRNAs was assessed in 150 subjects (90 cases of HCC and 60 cases without cancer) by quantitative real-time polymerase chain reaction (qRT-PCR). Logistic regression analysis was performed to assess the potential use of miRNAs for detection of HCC. Receiver operating characteristic curves were used to evaluate diagnostic accuracy. A panel of serum miRNAs (miR-125b, miR-223, miR-27a, and miR 26a) used in conjunction with AFP helped differentiate HCC patients from those in the non-cancer group after adjusting for age and gender, with the area under the curve of 0.870. In addition, the use of miR-125b/miR-27a panel differentiated HBV related early-stage HCC with a high sensitivity (80.0 %) and specificity (87.2 %) in AFP-negative (-) subjects. A combination of serum miR-125b, miR-223, miR-27a, and miR-26a as a second-line tests could help detect HCC in AFP (-) subjects. The panel of miR-125b/miR-27a/AFP had a higher sensitivity and specificity for diagnosis of early-stage HCC as compared to that of a single marker. PMID- 26637229 TI - Effect of Intravenous Infusion Solutions on Bioelectrical Impedance Spectroscopy. AB - BACKGROUND: Bioelectrical impedance (BIA) is often used to measure body fluid spaces and thereby body composition. However, in acute animal studies, we found that impedance was driven by the saline content of intravenous (IV) fluids and not by the volume. The aim of the study was to investigate the effect of 3 different fluids acutely administered on the change in impedance, specifically resistance (R). MATERIALS AND METHODS: Nine healthy adults participated in 3 treatment (0.9% saline, 5% dextrose, and a mixture of 0.3% saline + 3.3% dextrose) experiments on nonconsecutive days. They all received 1 L of one of the treatments intravenously over a 1-hour period. Repeated BIA measurements were performed prior to IV infusion and then every 5 minutes for the 1-hour infusion period, plus 3 more measurements up to 15 minutes after the completion of the infusion. RESULTS: The change in R in the 0.9% saline infusion experiment was significantly lower than that of the glucose and mixture treatment ( P < .001). CONCLUSION: Bioelectrical impedance spectroscopy and BIA measure salt rather than the volume changes over the infusion period. Hence, in patients receiving IV fluids, BIA of any kind (single frequency or multifrequency) cannot be used to measure body fluid spaces or body composition. PMID- 26637230 TI - Erratum to: Design and pilot validation of A-gear: a novel wearable dynamic arm support. AB - Unfortunately, the original version of this article [1] contained an error. Equation 6 was included incorrectly: in the original equation variable slinks3 was missing.The correct Equation 6 can be found below: PMID- 26637231 TI - Evaluation of Serum Interleukin-17 (IL-17) Levels as a Diagnostic Marker in Pancreatic Adenocarcinoma. AB - BACKGROUND: Inflammatory cytokines modulate immune responses in the tumor microenvironment during progression. The role of interleukin (IL-17) in cancer is currently under debate. This study was conducted to investigate the serum levels of IL-17 in patients with pancreatic adenocarcinoma (PA) and the relationship with tumor progression and known prognostic parameters. MATERIAL AND METHODS: Thirty-five patients with PA were investigated. Serum samples were obtained on first admission before treatment and follow-up. Both serum IL-17 levels were determined using enzyme-linked immunosorbent assay (ELISA). Age- and sex-matched 35 healthy controls were included in the analysis. RESULTS: The median age at diagnosis was 61 years, range 38-84 years; 21 (60%) patients were men. The tumor was located in the head of pancreas in 24 (69%) patients. The most common metastatic site was liver in 20 patients with metastasis (n = 18, 90%). The median follow-up time was 24.0 weeks (range 1.0-191.0 weeks). At the end of the observation period, 12 (34%) patients experienced disease progression and 23 patients (66%) were dead. Forty-four percent of 18 metastatic patients who received palliative chemotherapy (CTx) were CTx-responsive. Median progression free survival and overall survival of the whole group were 13.7 +/- 2.3 weeks [95% confidence interval (CI) = 9-18 weeks] and 48.0 +/- 12.8 weeks (95% CI = 23 73 weeks), respectively. The baseline serum IL-17 levels were significantly higher in patients with PA than in the control group (p = 0.001). Moreover, serum IL-17 levels were significantly higher in the patients with large pathologic tumor status and low albumin levels (p = 0.04 and p = 0.03, respectively). However, serum IL-17 assays had no prognostic roles on outcome. CONCLUSION: Although serum levels of IL-17 assays were found to be diagnostic value, no predictive and prognostic value was determined in PA patients. PMID- 26637232 TI - Use of Polyvinyl Alcohol as a Solubility-Enhancing Polymer for Poorly Water Soluble Drug Delivery (Part 1). AB - Polyvinyl alcohol (PVAL) has not been investigated in a binary formulation as a concentration-enhancing polymer owing to its high melting point/high viscosity and poor organic solubility. Due to the unique attributes of the KinetiSol(r) dispersing (KSD) technology, PVAL has been enabled for this application and it is the aim of this paper to investigate various grades for improvement of the solubility and bioavailability of poorly water soluble active pharmaceutical ingredients. Solid amorphous dispersions were created with the model drug, itraconazole (ITZ), at a selected drug loading of 20%. Polymer grades were chosen with variation in molecular weight and degree of hydroxylation to determine the effects on performance. Differential scanning calorimetry, powder X-ray diffraction, polarized light microscopy, size exclusion chromatography, and dissolution testing were used to characterize the amorphous dispersions. An in vivo pharmacokinetic study in rats was also conducted to compare the selected formulation to current market formulations of ITZ. The 4-88 grade of PVAL was determined to be effective at enhancing solubility and bioavailability of itraconazole. PMID- 26637233 TI - Lessons Learned About Motivation From a Pilot Physical Activity Intervention for African American Men. AB - African American men are less likely than White men to meet physical activity recommendations, and few physical activity interventions have focused on the unique needs of African American men. Because health is not more important to men than fulfilling the role of a provider or other socially important roles, one of the biggest challenges in creating interventions for African American men is helping them identify reasons that they should prioritize both health and life goals. In a recent pilot physical activity intervention for 30- to 70-year-old African American men, we used self-determination theory and motivational interviewing principles to create worksheets that helped men identify their core values and life goals and asked them to describe how their values and goals were related to health and physical activity. We used basic statistics and thematic analysis to identify and examine key sources of motivation for men to be healthier and more physically active. We found that being healthy, a good Christian, a good spouse/partner, disciplined, and successful were among men's most important life goals. This article highlights a strategy for identifying key sources of motivation in African American men's lives and key themes that can be used in to enhance future interventions. PMID- 26637234 TI - A tutorial on testing the race model inequality. AB - When participants respond in the same way to stimuli of two categories, responses are often observed to be faster when both stimuli are presented together (redundant signals) relative to the response time obtained when they are presented separately. This effect is known as the redundant signals effect. Several models have been proposed to explain this effect, including race models and coactivation models of information processing. In race models, the two stimulus components are processed in separate channels, and the faster channel determines the processing time. This mechanism leads, on average, to faster responses to redundant signals. In contrast, coactivation models assume integrated processing of the combined stimuli. To distinguish between these two accounts, Miller (Cognitive Psychology, 14, 247-279, 1982) derived the well-known race model inequality, which has become a routine test for behavioral data in experiments with redundant signals. In this tutorial, we review the basic properties of redundant signals experiments and current statistical procedures used to test the race model inequality during the period between 2011 and 2014. We highlight and discuss several issues concerning study design and the test of the race model inequality, such as inappropriate control of Type I error, insufficient statistical power, wrong treatment of omitted responses or anticipations, and the interpretation of violations of the race model inequality. We make detailed recommendations on the design of redundant signals experiments and on the statistical analysis of redundancy gains. We describe a number of coactivation models that may be considered when the race model has been shown to fail. PMID- 26637235 TI - Gradient cuts and extremal edges in relative depth and figure-ground perception. AB - Extremal edges (EEs) are borders consisting of luminance gradients along the projected edge of a partly self-occluding curved surface (e.g., a cylinder), with equiluminant contours (ELCs) that run approximately parallel to that edge. Gradient cuts (GCs) are similar luminance gradients with ELCs that intersect (are "cut" by) an edge that could be due to occlusion. EEs are strongly biased toward being seen as closer/figural surfaces (Palmer & Ghose, Psychological Science, 19(1), 77-83, 2008). Do GCs produce a complementary bias toward being seen as ground? Experiment 1 shows that, with EEs on the opposite side, GCs produce a ground bias that increases with increasing ELC angles between ELCs and the shared edge. Experiment 2 shows that, with flat surfaces on the opposite side, GCs do not produce a ground bias, suggesting that more than one factor may be operating. We suggest that two partially dissociable factors may operate for curved surfaces ELC angle and 3-D surface convexity-that reinforce each other in the figural cues of EEs but compete with each other in GCs. Moreover, this figural bias is modulated by the presence of EEs and GCs, as specified by the ELC angle between ELCs and the shared contour. PMID- 26637236 TI - The management of isolated positive syphilis enzyme immunoassay results in HIV negative patients attending a sexual health clinic. AB - An unconfirmed positive treponemal enzyme immunoassay (enzyme immunoassay positive, Treponema pallidum particle agglutination negative and rapid plasma reagin negative) presents a clinical challenge to distinguish early syphilis infection from false-positive results. These cases are referred for syphilis line assay (INNO-LIA) and recalled for repeat syphilis serology. We performed a retrospective audit to establish the proportion of HIV-negative cases with unconfirmed positive enzyme immunoassay results, the proportion of these cases that received an INNO-LIA test and repeat syphilis serology testing and reviewed the clinical outcomes; 0.35% (80/22687) cases had an unconfirmed positive treponemal enzyme immunoassay result. Repeat syphilis serology was performed in 80% (64/80) cases, but no additional cases of syphilis were identified. Eighty eight per cent (70/80) received an INNO-LIA test; 14% (5/37) unconfirmed enzyme immunoassay-positive cases with no prior history of syphilis were confirmed on INNO-LIA assay, supporting a diagnosis of latent syphilis. As a confirmatory treponemal test, the INNO-LIA assay may be more useful than repeat syphilis serological testing. PMID- 26637237 TI - Pathophysiological targets for non-pharmacological treatment of migraine. AB - Background Migraine is the most prevalent neurological disorder worldwide and ranked sixth among all diseases in years lived with disability. Overall preventive anti-migraine therapies have an effect in one patient out of two at the most, many of them being endowed with disabling adverse effects. No new disease-modifying drugs have come into clinical practice since the application to migraine of topiramate and botulinum toxin, the latter for its chronic form. There is thus clearly a need for more effective treatments that are devoid of, or have acceptable side effects. In recent years, scientific progress in migraine research has led to substantial changes in our understanding of the pathophysiology of migraine and paved the way for novel non-drug pathophysiological-targeted treatment strategies. Overview Several such non-drug therapies have been tested in migraine, such as oxidative phosphorylation enhancers, diets and non-invasive central or peripheral neurostimulation. All of them are promising for preventive migraine treatment and are quasi-devoid of side effects. Their advantage is that they can in theory be selected for individual patients according to their pathophysiological profile and they can (and probably should) be combined with the classical pharmacological armamentarium. Conclusion We will review here how knowledge of the functional anatomy and physiology of migraine mechanisms holds the key for more specific and effective non pharmacological treatments. PMID- 26637238 TI - Pain, depression and the postoperative stiff shoulder. AB - BACKGROUND: The surgical repair of shoulder pathologies, including rotator cuff disease and acromio-clavicular joint arthritis, have undergone many technical advances. However the debilitating postoperative stiff shoulder remains a common and significant complication of these surgeries, occurring in 4.9 to 23.2 % of patients undergoing rotator cuff repairs. The pathology of the pathological postoperative stiff shoulder and its associated condition "frozen shoulder" are poorly understood and both lack formal objective clinical diagnostic criteria. Additionally, although factors associated with the development of idiopathic frozen shoulder have been well described, multiple studies looking at predictors of postoperative stiff shoulder have produced conflicting results. It has been hypothesised that increased pain in the postoperative period, and depression may be predictors of the development of postoperative stiff shoulder. METHOD: A prospective cohort study involving 132 consecutive participants. Preoperatively, participants undergoing arthroscopic subacromial decompression and/or excision of the distal clavicle and/or rotator cuff repair will complete questionnaires about their levels of shoulder pain using a numerical rating scale from 0 to 10, and answer a Patient Health Questionnaire - 9 depression questionnaire. Postoperatively, the participants' pain levels will be self-assessed at two, five and seven days and weeks four, seven and ten. They will complete the depression questionnaire twice, at the time of their routine first and final postoperative appointments with the treating surgeon. At the final appointment, approximately three months postoperatively, the treating surgeon will clinically diagnose participants as having a postoperative stiff shoulder or not. Their shoulders' range of motion will be measured. The incidence of postoperative stiff shoulder will be determined, both pain and depression will be analysed as predictors for its development and incidences determined by different objective criteria will be compared. DISCUSSION: This trial will add to clinical understanding of the postoperative stiff shoulder by providing further insight into the incidence of this condition following shoulder surgery and assessing whether perioperative pain and depression can be used as clinical predictors of postoperative stiff shoulder or markers for possible early intervention. This study will also allow the comparison of incidences determined by different objective criteria in the same cohort. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR). ACTRN12613001271796. 17-11-2013. PMID- 26637239 TI - Pitch Discrimination in Musicians and Non-Musicians: Effects of Harmonic Resolvability and Processing Effort. AB - Musicians typically show enhanced pitch discrimination abilities compared to non musicians. The present study investigated this perceptual enhancement behaviorally and objectively for resolved and unresolved complex tones to clarify whether the enhanced performance in musicians can be ascribed to increased peripheral frequency selectivity and/or to a different processing effort in performing the task. In a first experiment, pitch discrimination thresholds were obtained for harmonic complex tones with fundamental frequencies (F0s) between 100 and 500 Hz, filtered in either a low- or a high-frequency region, leading to variations in the resolvability of audible harmonics. The results showed that pitch discrimination performance in musicians was enhanced for resolved and unresolved complexes to a similar extent. Additionally, the harmonics became resolved at a similar F0 in musicians and non-musicians, suggesting similar peripheral frequency selectivity in the two groups of listeners. In a follow-up experiment, listeners' pupil dilations were measured as an indicator of the required effort in performing the same pitch discrimination task for conditions of varying resolvability and task difficulty. Pupillometry responses indicated a lower processing effort in the musicians versus the non-musicians, although the processing demand imposed by the pitch discrimination task was individually adjusted according to the behavioral thresholds. Overall, these findings indicate that the enhanced pitch discrimination abilities in musicians are unlikely to be related to higher peripheral frequency selectivity and may suggest an enhanced pitch representation at more central stages of the auditory system in musically trained listeners. PMID- 26637240 TI - Medication Adherence With Diabetes Medication: A Systematic Review of the Literature. AB - PURPOSE: The primary purpose of this systematic review is to synthesize the evidence regarding risk factors associated with nonadherence to prescribed glucose-lowering agents, the impact of nonadherence on glycemic control and the economics of diabetes care, and the interventions designed to improve adherence. METHODS: Medline, EMBASE, the Cochrane Collaborative, BIOSIS, and the Health and Psychosocial Instruments databases were searched for studies of medication adherence for the period from May 2007 to December 2014. Inclusion criteria were study design and primary outcome measuring or characterizing adherence. Published evidence was graded according to the American Association of Clinical Endocrinologists protocol for standardized production of clinical practice guidelines. RESULTS: One hundred ninety-six published articles were reviewed; 98 met inclusion criteria. Factors including age, race, health beliefs, medication cost, co-pays, Medicare Part D coverage gap, insulin use, health literacy, primary nonadherence, and early nonpersistence significantly affect adherence. Higher adherence was associated with improved glycemic control, fewer emergency department visits, decreased hospitalizations, and lower medical costs. Adherence was lower when medications were not tolerated or were taken more than twice daily, with concomitant depression, and with skepticism about the importance of medication. Intervention trials show the use of phone interventions, integrative health coaching, case managers, pharmacists, education, and point-of-care testing improve adherence. CONCLUSION: Medication adherence remains an important consideration in diabetes care. Health professionals working with individuals with diabetes (eg, diabetes educators) are in a key position to assess risks for nonadherence, to develop strategies to facilitate medication taking, and to provide ongoing support and assessment of adherence at each visit. PMID- 26637241 TI - Endovascular treatment of distal middle cerebral artery aneurysms: Report of eight cases and literature review. AB - BACKGROUND: Endovascular treatment is an alternative choice for the treatment of distal middle cerebral artery (dMCA) aneurysm, in addition to open surgery; but is still seldom considered. We performed this retrospective study to evaluate the outcome of dMCA in patients. METHODS: During a period of 10 years, we were able to identify seven patients with a total of eight dMCA aneurysms that were treated endovascularly. They were five men and two women, with a mean age of 36.1 years. All of the aneurysms, including five infectious and three dissecting ones, were treated for the aneurysm and its parent artery's occlusion, using coils and/or glue. RESULTS: The clinical follow-up (9-96 m, mean 36.8 m) showed that they all improved over baseline; except for one patient in whom a mild right hemiparesis remained, after the hematoma evacuation. Angiographic follow-up (7-24 m; mean: 14.6 m) showed that all of them were stable and without the need for recanalization. CONCLUSIONS: Our data indicated that endovascular treatment is a safe and effective alternative for the treatment of dMCA aneurysms, and should be considered when treating these aneurysms. PMID- 26637242 TI - Comparison of Acoustic Structure Quantification (ASQ), shearwave elastography and histology in patients with diffuse hepatopathies. AB - BACKGROUND: Objective of the study was to evaluate the diagnostic value of novel ultrasonographic modalities in comparison with simultaneously performed liver biopsy. METHODS: The results of simultaneously performed examinations using Acoustic Structure Quantification (ASQ), Virtual Touch Imaging and Quantification (VTIQ) and Virtual Touch Tissue Quantification (VTTQ) were compared with the findings of liver biopsy in patients with a wide variety of diffuse hepatopathies (n = 51). The histologically determined fibrosis stage according to Desmet and Scheuer was compared with quantitative measurements returned by the ultrasonographic imaging modalities. RESULTS: No statistically significant correlation with histologically determined fibrosis stage could be identified for any measurements returned using ASQ. Increasing severity of hepatic steatosis, however, was associated with a reduction in the focal disturbance (FD) ratio (r = -0.55; p < 0.0001). The shearwave velocities measured using VTTQ satisfyingly correlated with fibrosis stage (r = 0.56; p > 0.0001). Fibrosis stages > F2 were associated with an area under the curve (AUC) of 0.94 (95%-CI:0.84-0.99). A cut off value for shearwave velocity of 1.66 m/s was determined with a sensitivity of 100% and a specificity of 84 %. VTIQ showed a less pronounced but acceptable correlation with fibrosis stage (r = 0.35; p = 0.0154). For fibrosis stages > F2 analysis showed an AUC of 0.84 (95%-CI:0.70-0.93). The cut-off value was 1.82 m/s with a sensitivity of 100% and a specificity of 58 %. CONCLUSION: While ASQ showed no diagnostic advantage in our patient collective, VTTQ showed high reliability for determining severe liver fibrosis in a group of patients with diffuse liver diseases of different etiology. PMID- 26637244 TI - Risk of cancer from occupational exposure to ionising radiation: retrospective cohort study of workers in France, the United Kingdom, and the United States (INWORKS). PMID- 26637243 TI - Antimicrobial Susceptibility Test with Plasmonic Imaging and Tracking of Single Bacterial Motions on Nanometer Scale. AB - Antimicrobial susceptibility tests (ASTs) are important for confirming susceptibility to empirical antibiotics and detecting resistance in bacterial isolates. Currently, most ASTs performed in clinical microbiology laboratories are based on bacterial culturing, which take days to complete for slowly growing microorganisms. A faster AST will reduce morbidity and mortality rates and help healthcare providers administer narrow spectrum antibiotics at the earliest possible treatment stage. We report the development of a nonculture-based AST using a plasmonic imaging and tracking (PIT) technology. We track the motion of individual bacterial cells tethered to a surface with nanometer (nm) precision and correlate the phenotypic motion with bacterial metabolism and antibiotic action. We show that antibiotic action significantly slows down bacterial motion, which can be quantified for development of a rapid phenotypic-based AST. PMID- 26637245 TI - Headache specialist is suspended for dishonesty. PMID- 26637246 TI - Second-hand smoke in Italy. AB - Second-hand smoke (SHS) has been classified as carcinogenic to humans by the International Agency for Research on Cancer (IARC) of the World Health Organization (WHO) [IARC, 2004]. Of the 5.7 million deaths attributable each year to tobacco smoking, more than 600,000 (i.e., around 1% of all deaths worldwide) refer to subjects who never smoked and that prematurely die due to their lifetime exposure to SHS [WHO, 2012]. Italy has been one of the pioneering countries - and the first large country worldwide - to enact a comprehensive smoke-free legislation in 2005. The law, introduced in order to reduce SHS exposure, banned smoking in indoor public places, including restaurants and bars, and in all workplaces [Gallus et al., 2006]. This legislation has had an undisputed success from a public health perspective: it was widely supported and strongly observed, restaurant and bar owners did not experience any dreaded decline in their business, and tobacco smoking (and its detrimental health effects) substantially decreased [Gallus et al., 2006; Gorini et al., 2007]. More importantly, the regulation has been effective in dramatically reducing SHS exposure [Gorini et al., 2007; Martinez-Sanchez et al., 2012]. Most high- income countries followed Italy in the adoption of similar comprehensive smoking ban legislations over the last decade [IARC, 2009]. These regulations and the information campaigns conducted for their enforcement had also the effect to increase the social unacceptability of SHS and consequently the adoption of voluntary home smoking bans [Ferketich et al., 2014; Martinez-Sanchez et al., 2014]. This notwithstanding, in 2010 specific Italian subpopulations were still frequently exposed to SHS, both in public and private places. In particular, 54% of the young (i.e., age 15-24 years) were still exposed to SHS in any settings, 27% in private houses, and 33% in private cars [Martinez-Sanchez et al., 2012]. The relatively high SHS exposure in private cars is of particular concerns. Inside vehicles, in fact, the smoke of one single cigarette causes concentrations of fine particulate matter three times higher than what is considered the threshold of hazard. According to surveys conducted by DOXA (an Italian statistical and opinion research company) in 2011-2012, two thirds of Italian smokers smoked in private cars [Martinez-Sanchez, Gallus et al., 2014]. Despite this, 80% of Italian adults (and 49% of current smokers) supported a smoking ban in private cars, and 93% (and 84% of current smokers) supported such a ban in cars carrying children [Martinez-Sanchez, Gallus et al., 2014]. We therefore welcome the incoming Minister's Decree banning tobacco smoking in private vehicles in presence of minors or pregnant women. The risk associated to SHS exposure is still largely underestimated. To give an idea of its harmful effect, we recommend viewing a video realised by colleagues at the National Cancer Institute of Milan, showing how the indoor air pollution generated by one single cigarette is 4 to 6 times higher than that produced by a diesel truck [Ruprecht et al., 2015]. There is a need to further inform the (Italian) population, including in particular smokers with young children, about the harmful effects of SHS, in order to increase the number of smoke-free homes and cars. In this sense, paediatricians or paediatric dentists have today the opportunity to give a major help. Their contribution can imply a minimum effort, e.g., providing informative leaflets, or making available, in the waiting rooms of their clinics, monitors showing informative videos, including the one previously described [Ruprecht et al., 2015]. PMID- 26637247 TI - Effects of soft-drinks and remineralising treatment on teeth assessed by morphological and quantitative X-ray investigations. AB - AIM: To morphologically and chemical-physically analyse both the surface and the subsurface of enamel undergoing soft- drink demineralisation and remineralisation treatment. MATERIALS AND METHODS: Fifteen human premolars were split and immersed in saline or three popular soft drinks, as demineralising agent, 15 minutes per day, for seven days at room temperature. Half of drink-processed teeth was then treated with casein phosphopeptide-amorphous calcium phosphate, as remineralising agent, for an additional seven days. The surface morphology was evaluated by stereomicroscope and scanning electron microscope (SEM). Teeth were then re embedded and sectioned, and analysed under SEM and X-ray microprobe. RESULTS: Drink-processed teeth showed root pigmentation, opacification and deterioration of the superficial enamel. The enamel surface resulted greatly furrowed after drink processing, and apparently restored after remineralising treatment. However, in tooth sections, SEM showed always a subsurface demineralisation of dentine and enamel, in particular at the cementoenamel junction, also after reminalising treatment. The remineralising agent produced a partial remineralisation of the subsurface enamel, sometimes statistically significant, but not in hydroxyapatite stoichiometry. CONCLUSION: Soft-drink erosion impaired not only the surface but also the subsurface enamel. The applied remineralising treatment, yielding some effects on surface and subsurface enamel reversing basically the decalcification process. PMID- 26637248 TI - The timing of extraction of non-restorable first permanent molars: a systematic review. AB - AIM: To identify the ideal timing of first permanent molar extraction to reduce the future need for orthodontic treatment. MATERIALS AND METHODS: A computerised database and subsequent manual search was performed using Medline database, Embase and Ovid, covering the period from January 1946 to February 2013. Two reviewers (JE and ME) extracted the data independently and evaluated if the studies matched the inclusion criteria. Inclusion criteria were specification of the follow-up with clinical examination or analysis of models, specification of the chronological age or dental developmental stage at the time of extraction, no treatment in between, classification of the treatment result into perfect, good, average and poor. The search was limited to human studies and no language limitations were set. RESULTS: The search strategy resulted in 18 full-text articles, of which 6 met the inclusion criteria. By pooling the data from maxillary sites, good to perfect clinical outcome was estimated in 72% (95% confidence interval 63%-82%). Extractions at the age of 8-10.5 years tended to show better spontaneous clinical outcomes compared to the other age groups. By pooling the data from mandibular sites, extractions performed at the age of 8 10.5 and 10.5-11.5 years showed significantly superior spontaneous clinical outcome with a probability of 50% and 59% likelihood, respectively, to achieve good to perfect clinical result (p<0.05) compared to the other age groups (<8 years of age: 34%, >11.5 years of age: 44%). CONCLUSION: Prevention of complications after first permanent molars extractions is an important issue. The overall success rate of spontaneous clinical outcome for maxillary extraction of first permanent molars was superior to mandibular extraction. Extractions of mandibular first permanent molars should be performed between 8 and 11.5 years of age in order to achieve a good spontaneous clinical outcome. For the extraction in the maxilla, no firm conclusions concerning the ideal extraction timing could be drawn. PMID- 26637249 TI - Preventive treatment of post-traumatic dental infraocclusion: study on the knowledge of dental decoronation in a sample of Italian dental students and dentists. AB - AIM: The aim of the present work is to investigate whether dental decoronation is a procedure known by a sample of dental students and Italian dentists. Dental decoronation technique is performed in order to mitigate the outcomes which may occur after a delayed tooth replantation. MATERIALS AND METHODS: A cognitive survey about the knowledge of the dental decoronation technique was carried on two groups: a sample of 120 dental students (5th year of dental school), from University of Cagliari, Sassari and of Chieti-Pescara (60 males and 60 females), and a group which involved 200 Italian dentists (age comprised between 25 and 45, 130 females and 70 males) enrolled at pedodontics and orthodontics Masters and CE courses (University of Roma Sapienza, Chieti- Pescara, Cagliari). The latter group's main field of work was paediatric dentistry and orthodontics, two dental specialties often involved in treating Traumatic dental injuries. RESULTS: Only 20 dentists out of the 200 interviewed answered that they knew this technique and only 5 of them proved to know it and were able to describe it correctly. No students interviewed knew this technique. CONCLUSION: It is apparent from the results of this survey that there is very little information about the dental decoronation technique both during the Degree Course in Dentistry and Post Graduate specialty programmes (Continuing Education Courses and Masters). PMID- 26637250 TI - Use of mini implants to replace a missing tooth in a growing patient: a six-year follow up case report. AB - BACKGROUND: Loss of anterior permanent teeth can have a detrimental effect on children's quality of life and the therapeutic approaches are always a challenge. From a physiologic and psychological standpoint, the use of dental implants has several advantages in replacing missing teeth. However, several studies have shown that conventional implants are not indicated in patients that are still growing, since they interfere with the sagittal and transversal growth of the maxilla. Recent literature has suggested that Mini Dental Implants (MDIs) can be successfully applied in growing patients, without interfering with the normal craniofacial growth process. CASE REPORT: This report describes the replacement of missing teeth in a 10-year-old patient by a mini implant of 1.8 mm diameter. After a six-year follow-up period, the mini implant did not follow the regular growth process of the maxilla, resulting in functional and aesthetic complications. Removal of the mini implant entailed some difficulties. PMID- 26637251 TI - Mineral trioxide aggregate in treatment of permanent teeth with open apex and endo-perio lesions. A case report. AB - BACKGROUND: Mineral trioxide aggregate (MTA), one of the latest materials applied in dentistry, has a variety of potential uses. Numerous studies emphasise its biocompatibility with periodontal and hard tissues, as well as excellent sealing and regeneration abilities. CASE REPORT This article describes the successful therapy of immature mandibular premolars with large open apex, resorption, and endo-perio lesions. In the presented case, the canal was filled with the MTA material. At present, the treated tooth is asymptomatic, and a three-year follow up radiographic examination demonstrated the dramatic regeneration of periradicular tissues and the new hard tissue formation in the area of the affected teeth. PMID- 26637252 TI - Post-traumatic rehabilitation of anterior teeth with laminates composite veneers in children. Report of two cases. AB - BACKGROUND: When treating children, a conservative and minimally invasive approach is mandatory. In dental traumas with partial coronal destruction, veneers represent the fastest and most effective method to rehabilitate front teeth of a young patient, since these no- or minimal-preparation restorations were proved to have predictable results without reducing the enamel layer. Indirect additive anterior composite restorations, besides being quick and minimally invasive, have to be considered a good treatment option for rehabilitating children, because they are inexpensive and repairable over time. Current laboratory techniques, associated with a strict clinical protocol, satisfy patients' restorative and aesthetic needs in few appointments and in a short time. CASE REPORT: The cases reported describe the minimally invasive treatment of two lateral incisors with nano-hybrid resin composite veneers after traumatic events. The patient satisfaction and good integration of indirect restorations confirmed the success of this rehabilitation. PMID- 26637253 TI - The effect of cavity disinfectants on microleakage of composite restorations in primary teeth. AB - AIM: The purpose of this study was to determine the effect of different cavity disinfectants on microleakage of Class V resin- based composite restorations in primary teeth. MATERIALS AND METHODS: Standard non-beveled Class V cavities were prepared on 50 human primary anterior teeth with the incisal and cervical margin placed on the enamel. The crowns were randomly divided into 6 groups. Four experimental groups of 10 teeth each, in which cavities were disinfected using the following solutions: 1) S. persica extract (Ethanol 1 mg/ml); 2) 1.3% sodium hypochlorite (NaOCl); 3) 0.2% chlorhexidine gluconate (CHX), and 4) No solution applied. Two control groups; 5 teeth each; 5) Negative control: filled cavity and entirely coated with nail varnish and 6) positive control: empty cavity and without nail varnish coating. Each cavity in groups 1-5 were filled with Filtek Z350 XT Universal Restorative (3M Espe, St. Paul, USA). All specimens were thermocycled for 500 cycles (5 degrees C/55 degrees C) and prepared for microleakage evaluation using a 2% methylene blue. RESULTS: For the experimental groups; there was no significant difference in dye penetration between the incisal and cervical walls in all groups (P=0.176). However comparing microleakage by location/walls showed a significant difference in dye penetration between the incisal walls (P=0.014) and cervical walls (P=.045). CONCLUSIONS: None of the disinfectant solutions in the experimental groups were able to prevent dye penetration. In comparison to chlorhexidine gluconate and sodium hypochlorite; application of S. persica did not increase microleakage and was not detrimental to enamel and dentin adhesion using the restorative technique and materials used in this study. PMID- 26637254 TI - A study on the chronology and sequence of eruption of primary teeth in Spanish children. AB - AIM: The aim of this study is to determine the timing of primary teeth eruption in Spanish children, and to distinguish gender and arch differences. MATERIALS AND METHODS: A cross-sectional study was performed on primary teeth eruption in a sample of 1,250 children (623 girls and 627 boys) from the Region of Madrid aged between 3 and 42 months. The clinical emergence of teeth was taken to estimate the mean ages of primary teeth eruption. The t test was used to analyse gender and arch differences. RESULTS: The process of primary dentition lasted 22.28 months, and statistically significant differences were found in the eruption of homologous contralateral teeth. The first molars and maxillary lateral incisors erupted earlier in girls than in boys, with no statistically significant chronological differences. The central incisors and second molars erupted first in the mandibular arch, while the lateral incisors, canines and first molars erupted first in the maxilla. A greater chronological difference was found between the lateral incisors, which erupted more than 8 months earlier in the maxilla than in the mandible. CONCLUSIONS: In the overall sample, the first tooth to erupt was the lower right central incisor at 10.96 +/- 1.88 months, and the last was the upper left second molar, at 33.24 +/- 4.35 months, symmetry was found in the eruption of the deciduous teeth. The greatest chronological difference was observed in the lateral incisors, with the upper ones erupting more than 8 months before the lower ones. Although statistically significant gender differences were found, they were considered clinically irrelevant. PMID- 26637255 TI - Analysis of pulp chamber of primary maxillary second molars using 3D micro-CT system: an in vitro study. AB - AIM: The aim of this study was to determine the positional relationship between the crown contour and the pulp chamber as well as the morphological characteristics of the pulp chamber using micro-CT in order to plan, in restorations of deciduous maxillary second molars, reconstructions with a volumetric rendering programme. MATERIALS AND METHODS: STUDY DESIGN: In total 16 deciduous maxillary second molar teeth (8 from boys, 8 from girls) were used. The positional relationship between crown contour and pulp chamber was three dimensionally observed by micro-CT. Differences in sex, dentin thickness and pulp volumes were evaluated using chi-square and paired t-tests. Differences were considered significant when P < 0.05. RESULTS: Dentin thickness was found to be 2.8 mm +/- 0.2, mesiobuccally 3.15 mm +/- 0.2 distobuccally 3.8 +/- 0.3, which was statistically significant (p <= 0.05). The pulp volume for boys was 77 mm3 +/ 4, for girls 64 mm3 +/- 5, with a statistical significance (p <= 0.05). CONCLUSIONS: General differences could play a role when planning a treatment for a child; however for both genders it should be noted that mesiobuccal pulp horn is most likely to get exposed during cavity preparation. PMID- 26637256 TI - Freeman-Sheldon syndrome: a case report. AB - BACKGROUND: Freeman-Sheldon syndrome is a rare hereditary disorder characterised by three basic abnormalities, namely microstomia, camptodactyly with ulnar deviation of the fingers, and clubfoot. The majority of these patients have microstomia and dental crowding, making oral hygiene difficult and increasing the risk of caries. Treatment of these patients requires a coordinated effort by a team of specialists, including a paediatrician, an anaesthesiologist, a plastic surgeon, a paediatric dentist, and an orthodontist. Herein, we describe dental problems of a child with Freeman-Sheldon syndrome and the treatment procedures performed. PMID- 26637257 TI - A fixed denture for a child with epidermolysis bullosa simplex. AB - AIM: To report the caries treatment and delivery of a fixed denture for a 3-year old girl with epidermolysis bullosa simplex (EBS). CASE REPORT: EBS is manifested on the skin or mucous membranes where skin separation is easily induced by trauma. Full- mouth rehabilitation under in-patient general anaesthesia was performed to the patient in conjunction with proper pre- and postoperative care. A fixed denture was fabricated and installed to replace the extracted teeth without later causing irritation on the mucosa. The prosthesis restored aesthetics and provided comfort without imposing the burden of compliance on the patient. CONCLUSION: Aided by meticulous pre- and postoperative care and oral hygiene reinforcement, comprehensive dental treatment coupled with fixed denture delivery can greatly improve the life quality and aesthetics for children with EBS. PMID- 26637258 TI - Investigation of periodontal status in type 1 diabetic adolescents. AB - AIM: The purpose of this study was to evaluate the effects of type 1 diabetes and the possible role of metabolic control on the periodontal status of diabetic adolescents. MATERIALS AND METHODS: Three groups of 40 patients each were examined: diabetic subjects with a good metabolic control (well controlled WC) (glycated haemoglobin HbA1c <= 7%) (20 males and 20 females; mean age: 14.1 +/- 1.5 years); diabetic subjects with poor metabolic control (poorly controlled PC) (glycated haemoglobin HbA1c> 7%) (20 males and 20 females; mean age: 14.5 +/- 1.3 years); and patients in good general health, which constituted the control group (20 males and 20 females; mean age: 14.1 +/- 1.2 years). For each subject, a periodontal evaluation was performed and the following parameters were assessed: Plaque Index (PI), Gingival Index (GI), Bleeding on probing (BOP), Probing Depth (PD), Clinical Attachment Level (CAL). Chi-square was used to compare categorical variables. Kruskal-Wallis one-way ANOVA by ranks was used to compare the quantitative variables (GBI, PD) among the 3 groups. Post-hoc comparison between pairs of groups was assessed by Wilcoxon's rank sum test, with a downward adjustment of the alpha level to compensate for multiple comparisons. RESULTS: The levels of PI in WC subjects (1.9 +/- 0.8) and in PC subjects (2.1 +/- 0.6) were significantly higher compared to healthy subjects in the control group (0.8 +/- 0.7) (p <0.0001). Similarly, the GI in both PC (1.9 +/- 0.8) and WC subjetcs (1.7 +/- 0.9) was significantly higher (p <0.05) compared to controls (0.9 +/- 0.8). GBI in the PC (60.2 +/- 23.6%) and the WC (57.4 +/- 22.5%) groups was significantly higher compared to healthy subjects (35.9 +/- 18.7%) (p <0.05). The PD parameter was found significantly higher (p <0.05) in the PC group (26.7 +/- 12.6) and WC group (23.5 +/- 11.3%) compared with controls (8.3 +/- 6.2%). Regarding the CAL, no significant differences were found between the groups (p> 0.05). In addition, the comparisons between groups PC and WC were not statistically significant (p> 0.05). CONCLUSIONS: Adolescents affected with type 1 diabetes show a higher level of bacterial plaque, gingival inflammation with bleeding on probing and probing depth, compared to healthy subjects. There were no significant changes with regard to the accumulation of plaque and periodontal status among diabetic patients both with good control and with poor metabolic control. PMID- 26637259 TI - Allgrove syndrome: a report of a unique case characterised by peculiar dental findings resembling those of ectodermal dysplasia. AB - BACKGROUND: Triple A or Allgrove Syndrome (OMIM#231550) is a rare, autosomal recessive genetic disorder in which patients typically suffer from chronic adrenal insufficiency due to resistance to ACTH (Addison's disease), esophageal achalasia, and defective tear formation (alacrima). The syndrome is caused by mutations in the AAAS gene on chromosome 12q13 encoding a 546 aminoacid protein named alacrimia-achalasia-adrenal insufficiency neurologic disorder (ALADIN), a constituent of eukaryotic nuclear pore complexes. CASE REPORT: We describe a case of Allgrove Syndrome presenting with anhidrosis and peculiar dental features resembling those of Ectodermal Dysplasia (ED). CONCLUSION: Given the clinical findings in this case we suggest the hypothesis that the pathogenetic mechanism in Allgrove syndrome is related to the ED. PMID- 26637260 TI - Dental anomalies associated with cleft lip and palate in Northern Finland. AB - AIM: Despite the reported occurrence of dental anomalies of cleft lip and palate, little is known about their prevalence in children from Northern Finland with cleft lip and palate. The aim was to investigate the prevalence of dental anomalies among patients with different types of clefts in Northern Finland. MATERIALS AND METHODS: Design and Statistics: patient records of 139 subjects aged three years and older (with clefts treated in Oulu University Hospital, Finland during the period 1996-2010 (total n. 183) were analysed for dental anomalies including the number of teeth, morphological and developmental anomalies and their association with the cleft type. The analyses were carried out using Chi-square test and Fisher's exact test. Differences between the groups were considered statistically significant at p values < 0.05. RESULTS: More than half of the patients had clefts of the hard palate, 18% of the lip and palate, and 13% of the lip. At least one dental anomaly was detected in 47% of the study population. Almost one in three (26.6%) subjects had at least one anomaly and 17.9% had two or three anomalies. The most common type of anomaly in permanent teeth were missing teeth followed by supernumerary teeth. Supernumerary teeth were significantly more apparent when the lip was involved in the cleft compared with palatal clefts. Missing teeth were less prevalent among those 5 years or younger. The prevalence of different anomalies was significantly associated with the cleft type in both age groups. CONCLUSIONS: Dental anomalies are more prevalent among cleft children than in the general population in Finland. The most prevalent anomalies associated with cleft were missing and supernumerary teeth. PMID- 26637261 TI - Semiconductor Nanocrystal Quantum Dot Synthesis Approaches Towards Large-Scale Industrial Production for Energy Applications. AB - This paper reviews the experimental synthesis and engineering developments that focused on various green approaches and large-scale process production routes for quantum dots. Fundamental process engineering principles were illustrated. In relation to the small-scale hot injection method, our discussions focus on the non-injection route that could be scaled up with engineering stir-tank reactors. In addition, applications that demand to utilize quantum dots as "commodity" chemicals are discussed, including solar cells and solid-state lightings. PMID- 26637262 TI - Quantum Oscillations of the Nanoscale Structural Inhomogeneities of the Domain Wall in Magnetic Bubble. AB - It is shown that at low temperatures, quantum oscillations of nanoscale structural inhomogeneities (the vertical Bloch line and the Bloch point) occur in the domain walls of cylindrical magnetic domains formed in a uniaxial magnetic film with strong magnetic anisotropy. The conditions for the excitation of these oscillations are determined. PMID- 26637263 TI - Initial Assessment of beta3-Adrenoceptor-Activated Brown Adipose Tissue in Streptozotocin-Induced Type 1 Diabetes Rodent Model Using [18F]Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography. AB - Metabolic activity of brown adipose tissue (BAT) is activated by beta3 adrenoceptor agonists and norepinephrine transporter (NET) blockers and is measurable using [(18)F]fluorodeoxyglucose ([(18)F]FDG) positron emission tomography/computed tomography (PET/CT) in rats. Using the streptozotocin (STZ) treated rat model of type 1 diabetes mellitus (T1DM), we investigated BAT activity in this rat model under fasting and nonfasting conditions using [(18)F]FDG PET/CT. Drugs that enhance BAT activity may have a potential for therapeutic development in lowering blood sugar in insulin-resistant diabetes. Rats were rendered diabetic by administration of STZ and confirmed by glucose measures. [(18)F]FDG was injected in the rats (fasted or nonfasted) pretreated with either saline or beta3-adrenoceptor agonist CL316,243 or the NET blocker atomoxetine for PET/CT scans. [(18)F]FDG metabolic activity was computed as standard uptake values (SUVs) in interscapular brown adipose tissue (IBAT) and compared across the different drug treatment conditions. Blood glucose levels > 500 mg/dL were established for the STZ-treated diabetic rats. Under fasting conditions, average uptake of [(18)F]FDG in the IBAT of STZ-treated diabetic rats was approximately 70% lower compared to that of normal rats. Both CL316,243 and atomoxetine activated IBAT in normal rats had an SUV > 5, whereas activation in STZ-treated rats was significantly lower. The agonist CL316,243 activated IBAT up to threefold compared to saline in the fasted STZ-treated rat. In the nonfasted rat, the IBAT activation was up by twofold by CL316243. Atomoxetine had a greater effect on lowering blood sugar levels compared to CL316,243 in the nonfasted rats. A significant reduction in metabolic activity was observed in the STZ treated diabetic rodent model. Increased IBAT activity in the STZ-treated diabetic rat under nonfasted conditions using the beta3-adrenoceptor agonist CL316,243 suggests a potential role of BAT in modulating blood sugar levels. Further studies are needed to evaluate the therapeutic role of beta3-adrenoceptor agonists in insulin-resistant T1DM. PMID- 26637264 TI - Antibiotic prophylaxis for surgical site infection in people undergoing liver transplantation. AB - BACKGROUND: Surgical site infection is more frequent in liver transplantation than in other types of solid organ transplantation with different antibiotics. Studies have shown that the rate of surgical site infection varies from 8.8% to 37.5% after liver transplantation. Therefore, antimicrobial prophylaxis is likely an essential tool for reducing these infections. However, the literature lacks evidence indicating the best prophylactic antibiotic regimen that can be used for liver transplantation. OBJECTIVES: To assess the benefits and harms of antibiotic prophylactic regimens for surgical site infection in people undergoing liver transplantation. SEARCH METHODS: We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Science Citation Index Expanded and Latin American Caribbean Health Sciences Literature (LILACS). The most recent search was performed on 11 September 2015. SELECTION CRITERIA: All eligible randomised clinical trials comparing any antibiotic regimen versus placebo, versus no intervention or versus another antibiotic regimen for surgical site infection in liver transplant recipients, regardless of age, sex and reason for transplantation. Quasi-randomised studies and other observational studies were considered for data on harm if retrieved with search results for randomised clinical trials. DATA COLLECTION AND ANALYSIS: Two review authors selected relevant trials, assessed risk of bias of studies and extracted data. MAIN RESULTS: The electronic search identified 786 publications after removal of duplicates. From this search, only one seemingly randomised clinical trial, published in abstract form, fulfilled the inclusion criteria of this review. This trial was conducted at Shiraz Transplant Centre, Shiraz, Iran, where investigators randomly assigned a total of 180 consecutive liver transplant recipients. We judged the overall risk of bias of the trial published in abstract form as high. Researchers reported no numerical data but mentioned that 163 participants met the inclusion criteria after randomisation, and hence were included in the analyses. Most probably, the 17 excluded participants were high risk liver transplant recipients. Trial authors concluded that they could find no differences between the two antibiotic regimens - ceftriaxone plus metronidazole versus ampicillin-sulbactam plus ceftizoxime - when given to liver transplant recipients. Review authors could not reconfirm the analyses because, as it has been mentioned, trial authors provided no trial data for analyses. AUTHORS' CONCLUSIONS: Benefits and harms of antibiotic prophylactic regimens for surgical site infection in liver transplantation remain unclear. Additional well-conducted randomised clinical trials adhering to SPIRIT (Spirit Protocol Items: Recommendations for Interventional Trials) and CONSORT (Consolidated Standards of Reporting Trials) guidelines are needed to determine the exact role of antibiotic prophylactic regimens in patients undergoing liver transplantation. PMID- 26637265 TI - Impact of Cardiogenic Vomiting in Patients with STEMI: A Study From China. AB - BACKGROUND Different patients with ST-elevation myocardial infarction (STEMI) have different symptoms. A third of them may have medical emergencies caused by symptoms such as vomiting and syncope. These concomitant symptoms may influence subsequent therapy and final outcomes. The aim of this study was to determine whether cardiogenic vomiting is a predictor of clinical outcomes in patients with STEMI. MATERIAL AND METHODS We classified 152 STEMI patients from different areas into 2 groups on the basis of vomiting: group A and group B. Their demographics and conditions of hospitalization were recorded. After follow-up, major adverse cardiac events (MACE) were regarded as study endpoints for the effect of cardiogenic vomiting in STEMI patients. RESULTS We found no significant difference in demographic and clinical characteristics of the 2 groups (P>0.05). The hospitalized conditions of group A were more serious than in group B. During a follow-up of 6 months, MACE rate was higher in vomiting patients (42; 67.7%) compared with group B (25; 27.8%). Multivariate Cox regression analysis revealed that cardiogenic vomiting was an independent predictor of clinical outcomes. CONCLUSIONS Cardiogenic vomiting is a useful predictor of major adverse cardiac events in STEMI patients for the hospitalization and after discharge. PMID- 26637268 TI - Quantifying the Role of Circulating Unconjugated Estradiol in Mediating the Body Mass Index-Breast Cancer Association. AB - BACKGROUND: Higher body mass index (BMI) and circulating estrogen levels each increase postmenopausal breast cancer risk, particularly estrogen receptor positive (ER(+)) tumors. Higher BMI also increases estrogen production. METHODS: We estimated the proportion of the BMI-ER(+) breast cancer association mediated through estrogen in a case-control study nested within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Participants included 143 women with invasive ER(+) breast cancer and 268 matched controls, all postmenopausal and never having used hormone therapy at baseline. We used liquid chromatography tandem mass spectrometry to measure 15 estrogens and estrogen metabolites in baseline serum. We calculated BMI from self-reported height and weight at baseline. We estimated the mediating effect of unconjugated estradiol on the BMI ER(+) breast cancer association using Aalen additive hazards and Cox regression models. RESULTS: All estrogens and estrogen metabolites were statistically significantly correlated with BMI, with unconjugated estradiol most strongly correlated [Pearson correlation (r) = 0.45]. Approximately 7% to 10% of the effect of overweight, 12% to 15% of the effect of obesity, and 19% to 20% of the effect of a 5 kg/m(2) BMI increase on ER(+) breast cancer risk was mediated through unconjugated estradiol. The BMI-breast cancer association, once adjusted for unconjugated estradiol, was not modified by further adjustment for two metabolic ratios statistically significantly associated with both breast cancer and BMI. CONCLUSION: Circulating unconjugated estradiol levels partially mediate the BMI-breast cancer association, but other potentially important estrogen mediators (e.g., bioavailable estradiol) were not evaluated. IMPACT: Further research is required to identify mechanisms underlying the BMI-breast cancer association. PMID- 26637267 TI - A Cross-Cancer Genetic Association Analysis of the DNA Repair and DNA Damage Signaling Pathways for Lung, Ovary, Prostate, Breast, and Colorectal Cancer. AB - BACKGROUND: DNA damage is an established mediator of carcinogenesis, although genome-wide association studies (GWAS) have identified few significant loci. This cross-cancer site, pooled analysis was performed to increase the power to detect common variants of DNA repair genes associated with cancer susceptibility. METHODS: We conducted a cross-cancer analysis of 60,297 single nucleotide polymorphisms, at 229 DNA repair gene regions, using data from the NCI Genetic Associations and Mechanisms in Oncology (GAME-ON) Network. Our analysis included data from 32 GWAS and 48,734 controls and 51,537 cases across five cancer sites (breast, colon, lung, ovary, and prostate). Because of the unavailability of individual data, data were analyzed at the aggregate level. Meta-analysis was performed using the Association analysis for SubSETs (ASSET) software. To test for genetic associations that might escape individual variant testing due to small effect sizes, pathway analysis of eight DNA repair pathways was performed using hierarchical modeling. RESULTS: We identified three susceptibility DNA repair genes, RAD51B (P < 5.09 * 10(-6)), MSH5 (P < 5.09 * 10(-6)), and BRCA2 (P = 5.70 * 10(-6)). Hierarchical modeling identified several pleiotropic associations with cancer risk in the base excision repair, nucleotide excision repair, mismatch repair, and homologous recombination pathways. CONCLUSIONS: Only three susceptibility loci were identified, which had all been previously reported. In contrast, hierarchical modeling identified several pleiotropic cancer risk associations in key DNA repair pathways. IMPACT: Results suggest that many common variants in DNA repair genes are likely associated with cancer susceptibility through small effect sizes that do not meet stringent significance testing criteria. PMID- 26637269 TI - Directed evolution of Tau class glutathione transferases reveals a site that regulates catalytic efficiency and masks co-operativity. AB - A library of Tau class GSTs (glutathione transferases) was constructed by DNA shuffling using the DNA encoding the Glycine max GSTs GmGSTU2-2, GmGSTU4-4 and GmGSTU10-10. The parental GSTs are >88% identical at the sequence level; however, their specificity varies towards different substrates. The DNA library contained chimaeric structures of alternated segments of the parental sequences and point mutations. Chimaeric GST sequences were expressed in Escherichia coli and their enzymatic activities towards CDNB (1-chloro-2,4-dinitrobenzene) and the herbicide fluorodifen (4-nitrophenyl alpha,alpha,alpha-trifluoro-2-nitro-p-tolyl ether) were determined. A chimaeric clone (Sh14) with enhanced CDNB- and fluorodifen detoxifying activities, and unusual co-operative kinetics towards CDNB and fluorodifen, but not towards GSH, was identified. The structure of Sh14 was determined at 1.75 A (1 A=0.1 nm) resolution in complex with S-(p-nitrobenzyl) glutathione. Analysis of the Sh14 structure showed that a W114C point mutation is responsible for the altered kinetic properties. This was confirmed by the kinetic properties of the Sh14 C114W mutant. It is suggested that the replacement of the bulky tryptophan residue by a smaller amino acid (cysteine) results in conformational changes of the active-site cavity, leading to enhanced catalytic activity of Sh14. Moreover, the structural changes allow the strengthening of the two salt bridges between Glu(66) and Lys(104) at the dimer interface that triggers an allosteric effect and the communication between the hydrophobic sites. PMID- 26637271 TI - Severe Childhood Anaemia and Blood Transfusion in a Nigerian Secondary Level Facility. AB - This study aimed to describe the pattern and immediate outcome of severe childhood anaemia requiring blood transfusion at a secondary level of care in Nigeria. A cross-sectional survey of children hospitalized in a secondary health facility in Ogun State, Nigeria, with packed cell volume <20% and who received blood transfusion was done. Of the 253 children admitted between March 2013 and June 2014, 79 (31.2%) had severe anaemia and were transfused with blood. Two thirds had multiple transfusions. Higher rates of blood transfusion were obtained among underweight children. Fever (98.7%), hypoglycaemia (65.8%) and tender liver (54.4%) were the leading co-morbidities. The case fatality rate was 21.5%. Respiratory distress, convulsions and altered sensorium were significantly associated with mortality. In conclusion, severe anaemia was associated with major morbidities and mortality at the secondary level of paediatric care in Nigeria. PMID- 26637272 TI - Malaria Parasite Density Estimation using Actual and Assumed White Blood Cells Count in Children in Eastern Sudan. AB - BACKGROUND: Estimating malaria parasite count is needed for estimating the severity of the disease and during the follow-up. OBJECTIVE: This study was conducted to determine the malaria parasite density among children using actual white blood cell (WBC) and the assumed WBC counts (8.0 * 10(9)/l). METHODS: A cross-sectional study was conducted at New Halfa Hospital, Sudan. WBC count and count of asexual malaria parasite were performed on blood films. RESULTS: One hundred and three children were enrolled. The mean (SD) WBCs was 6.2 (2.9) cells * 10(9)/l. The geometric mean (SD) of the parasite count using the assumed WBCs (8.0 * 10(9)/l cells/MUl) was significantly higher than that estimated using the actual WBC count [7345.76 (31,038.56) vs. 5965 (28,061.57) rings/MUl,p = 0.042]. CONCLUSION: Malaria parasitemia based on assumed (8.0 * 10(9)/) WBCs is higher than parasitemia based on actual WBCs. PMID- 26637270 TI - Role of Munc13-4 as a Ca2+-dependent tether during platelet secretion. AB - The Munc13 family of exocytosis regulators has multiple Ca(2+)-binding, C2 domains. Here, we probed the mechanism by which Munc13-4 regulates in vitro membrane fusion and platelet exocytosis. We show that Munc13-4 enhances in vitro soluble NSF attachment protein receptor (SNARE)-dependent, proteoliposome fusion in a Ca(2+)- and phosphatidylserine (PS)-dependent manner that was independent of SNARE concentrations. Munc13-4-SNARE interactions, under the conditions used, were minimal in the absence or presence of Ca(2+). However, Munc13-4 was able to bind and cluster liposomes harbouring PS in response to Ca(2+). Interestingly, Ca(2+)-dependent liposome binding/clustering and enhancement of proteoliposome fusion required both Munc13-4 C2 domains, but only the Ca(2+)-liganding aspartate residues of the C2B domain. Analytical ultracentrifugation (AUC) measurements indicated that, in solution, Munc13-4 was a monomeric prolate ellipsoid with dimensions consistent with a molecule that could bridge two fusing membranes. To address the potential role of Munc13-4 as a tethering protein in platelets, we examined mepacrine-stained, dense granule mobility and secretion in platelets from wild-type and Munc13-4 null (Unc13d(Jinx)) mice. In the absence of Munc13-4, dense granules were highly mobile in both resting and stimulated platelets, and stimulation-dependent granule release was absent. These observations suggest that dense granules are stably docked in resting platelets awaiting stimulation and that Munc13-4 plays a vesicle-stabilizing or tethering role in resting platelets and also in activated platelets in response to Ca(2+). In summary, we show that Munc13-4 conveys Ca(2+) sensitivity to platelet SNARE-mediated membrane fusion and reveal a potential mechanism by which Munc13-4 bridges and stabilizes apposing membranes destined for fusion. PMID- 26637273 TI - Plantaris Excision and Ventral Paratendinous Scraping for Achilles Tendinopathy in an Athletic Population. AB - BACKGROUND: Achilles tendinopathy is a frequent problem in high-level athletes. Recent research has proposed a combined etiologic role for the plantaris tendon and neovascularization. Both pathologies can be observed on ultrasound imaging.(1,13) However, little is known about the change in structure of the Achilles tendon following the surgical treatment of these issues. The purpose of the study was to assess if excising the plantaris and performing ventral paratendinous "scraping" of the neovascularization improved symptoms of Achilles tendinopathy and whether there was a change in the fibrillar structure of the tendon with ultrasound tissue characterization (UTC) following this operation. METHODS: This prospective consecutive case series included 15 professional/semiprofessional athletes (17 Achilles tendons) who underwent plantaris excision and paratendinous scraping to treat noninsertional Achilles tendinopathy. The plantaris tendon was excised if adherent to the Achilles tendon, and the area of neovascularization for scraping was demarcated on preoperative imaging. Preoperative and postoperative Victorian Institute of Sports Assessment-Achilles (VISA-A) scores were taken. UTC was performed on 11 of 17 tendons preoperatively and postoperatively. The mean follow-up was for 25 months. RESULTS: Fourteen of 15 patients had a successful outcome after the surgery. The mean VISA-A improved from 51 to 95 (p=.0001). There was a statistically significant (p=.04) improvement in the aligned fibrillar structure of the tendon confirmed with UTC scanning following surgery from 90% (+/-8) to 96% (+/-5). CONCLUSION: This group of high-level athletes derived an excellent clinical result from this operation. Furthermore, UTC scanning offered an objective method to evaluate the healing of Achilles tendons. LEVEL OF EVIDENCE: Level IV, case series. PMID- 26637274 TI - Biomechanical Comparison of Intramedullary Screw Versus Low-Profile Plate Fixation of a Jones Fracture. AB - BACKGROUND: Intramedullary screw fixation of fifth metatarsal Jones fractures often produces satisfactory results, however, nonunion and refracture rates are not negligible. The low-profile "hook" plate is an alternative fixation method that has been promoted to offer improved rotational control at the fracture site, but this remains to be proven. The purpose of this study was to document biomechanical performance differences between this type of plate and a contemporary solid, dual-pitch intramedullary screw in a cadaveric Jones fracture model. METHODS: Simulated Jones fractures were created in 8 matched pairs of fresh-frozen cadaveric fifth metatarsals. One bone from each pair was stabilized using an intramedullary TriMed Jones Screw and the other using a TriMed Jones Fracture Plate (TriMed, Inc, Santa Clarita, CA). Controlled bending and torsional loads were applied. Bending stiffness and fracture site angulation, as well as torsional stiffness, peak torque, and fracture site rotation were quantified and compared. RESULTS: Intramedullary screw fixation demonstrated greater bending stiffness and less fracture site angulation than plate fixation during plantar-to dorsal and lateral-to-medial bending. Torsional stiffness of screw-fixed metatarsals exceeded that of plate-fixed bones at initial loading; however, as rotation progressed, the plate resisted torque better than the screw. No difference in peak torque was demonstrable between fixation methods, but it was reached earlier in specimens fixed with screws and later in those fixed with plates as rotation progressed. CONCLUSION: In this cadaveric Jones fracture model, intramedullary screw fixation demonstrated bending stiffness and resistance to early torsional loading that was superior to that offered by plate fixation. CLINICAL RELEVANCE: Although low-profile "hook" plates offer an alternative for fixation of fifth metatarsal Jones fractures, intramedullary screw fixation may provide better resistance to bending and initiation of fracture site rotation. The influence of these mechanical characteristics on fracture healing is unknown, and further clinical investigation is warranted. PMID- 26637275 TI - Impact of Metformin on Advanced Pancreatic Cancer Survival: Too Little, Too Late? AB - Metformin offers no survival advantage in patients with metastatic pancreatic cancer. Despite promising experimental evidence suggesting an antitumor effect of metformin, its impact on the survival of advanced pancreatic cancer is likely very limited. Future studies may need to consider its role in early-stage pancreatic cancer. See related article by Reni et al., p. 1076. PMID- 26637276 TI - Comparing Patient-Derived Xenograft and Computational Response Prediction for Targeted Therapy in Patients of Early-Stage Large Cell Lung Cancer. AB - PURPOSE: Targeted therapy (TT) provides highly effective cancer treatment for appropriately selected individuals. A major challenge of TT is to select patients who would benefit most. EXPERIMENTAL DESIGN: The study uses cancer material from 25 patients primarily diagnosed with non-small cell lung cancer (NSCLC). Patient derived xenografts (PDXs) are treated with cetuximab and erlotinib. Treatment response is measured by tumor shrinkage comparing tumor volume at day 25 (V25) with tumor volume at baseline (V0). Shrinkage below 40% is considered as treatment response: V25/V0 < 0.4 (<40%). Furthermore, RNA-seq data from each tumor sample are used to predict tumor response to either treatment using an in silico molecular signaling map (MSM) approach. RESULTS: PDX response was 40% (10/25; 95% CI [21.13%, 61.34%]) under cetuximab and 20% (5/25; 95% CI [6.83%, 40.70%]) under erlotinib. MSM predicted response was 48% (12/25; 95% CI [27.8%, 68.7%]) under cetuximab and 40% (10/25; 95% CI [21.13%, 61.34%]) under erlotinib. Agreement between PDX and MSM response prediction is substantial under cetuximab and erlotinib: 84% (21/25, P = 0.001) and 80% (20/25, P = 0.003). A total of 5 from the 25 patients have been treated with cetuximab showing a clinical response identical to both predictions. CONCLUSIONS: For NSCLC patients, this proof-of concept study shows a considerable agreement in response prediction from MSM and PDX approaches, but MSM saves time and laboratory resources. Our result indicates the potential of MSM-based approach for clinical decision making when selecting cancer TTs. Clin Cancer Res; 22(9); 2167-76. (c)2015 AACR. PMID- 26637277 TI - Current therapies for lowering lipoprotein (a). AB - Lipoprotein (a) [Lp(a)] is a human plasma lipoprotein with unique structural and functional characteristics. Lp(a) is an assembly of two components: a central core with apoB and an additional glycoprotein, called apo(a). Ever since the strong association between elevated levels of Lp(a) and an increased risk for CVD was recognized, interest in the therapeutic modulation of Lp(a) levels has increased. Here, the past and present therapies aiming to lower Lp(a) levels will be reviewed, demonstrating that these agents have had varying degrees of success. The next challenge will be to prove that Lp(a) lowering also leads to cardiovascular benefit in patients with elevated Lp(a) levels. Therefore, highly specific and potent Lp(a)-lowering strategies are awaited urgently. PMID- 26637278 TI - Lipoprotein (a) measurements for clinical application. AB - The high degree of size heterogeneity of apo(a), the distinct protein component of lipoprotein (a) [Lp(a)], renders the development and selection of specific antibodies directed to apo(a) more difficult and poses significant challenges to the development of immunoassays to measure its concentration in plasma or serum samples. Apo(a) is extremely variable in size not only between but also within individuals because of the presence of two different, genetically determined apo(a) isoform sizes. Therefore, the antigenic determinants per particle available to interact with the antibodies will vary in the samples and the calibrators, thus contributing to apo(a) size-dependent inaccuracy of different methods. The lack of rigorous validation of the immunoassays and common means of expressing Lp(a) concentrations hinder the harmonization of results obtained by different studies and contribute to the lack of common cut points for identification of individuals at risk for coronary artery disease or for interventions aimed at reducing Lp(a) levels. The aim of our review is to present and critically evaluate the issues surrounding the measurements of Lp(a), their impact on the clinical interpretation of the data, and the obstacles we need to overcome to achieve the standardization of Lp(a) measurements. PMID- 26637280 TI - The large N-terminal region of the Brr2 RNA helicase guides productive spliceosome activation. AB - The Brr2 helicase provides the key remodeling activity for spliceosome catalytic activation, during which it disrupts the U4/U6 di-snRNP (small nuclear RNA protein), and its activity has to be tightly regulated. Brr2 exhibits an unusual architecture, including an ~ 500-residue N-terminal region, whose functions and molecular mechanisms are presently unknown, followed by a tandem array of structurally similar helicase units (cassettes), only the first of which is catalytically active. Here, we show by crystal structure analysis of full-length Brr2 in complex with a regulatory Jab1/MPN domain of the Prp8 protein and by cross-linking/mass spectrometry of isolated Brr2 that the Brr2 N-terminal region encompasses two folded domains and adjacent linear elements that clamp and interconnect the helicase cassettes. Stepwise N-terminal truncations led to yeast growth and splicing defects, reduced Brr2 association with U4/U6*U5 tri-snRNPs, and increased ATP-dependent disruption of the tri-snRNP, yielding U4/U6 di-snRNP and U5 snRNP. Trends in the RNA-binding, ATPase, and helicase activities of the Brr2 truncation variants are fully rationalized by the crystal structure, demonstrating that the N-terminal region autoinhibits Brr2 via substrate competition and conformational clamping. Our results reveal molecular mechanisms that prevent premature and unproductive tri-snRNP disruption and suggest novel principles of Brr2-dependent splicing regulation. PMID- 26637283 TI - Return to Training and Playing After Acute Lisfranc Injuries in Elite Professional Soccer and Rugby Players. AB - BACKGROUND: Lisfranc joint injuries are increasingly recognized in elite soccer and rugby players. Currently, no evidence-based guidelines exist on time frames for return to training and competition after surgical treatment. PURPOSE: To assess the time to return to training and playing after Lisfranc joint injuries. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: A consecutive series of 17 professional soccer and rugby players in the English Premier/Championship leagues was assessed using prospectively collected data. All were isolated injuries sustained during training or competitive matches. Each player had clinical and radiological evidence of an unstable Lisfranc injury and required surgical treatment. A standardized postoperative regimen was used. The minimum follow-up time was 2 years. RESULTS: Clinical and radiological follow-up was obtained in all 17 players. Seven players had primarily ligamentous injuries, and 10 had bony injuries. The time from injury to fixation ranged from 8 to 31 days, and hardware was removed at 16 weeks postoperatively. One athlete retired after a ligamentous injury; the remaining 16 players returned to training and full competition. Excluding the retired player, the mean time to return to training was 20.1 weeks (range, 18-24 weeks) and to full competition was 25.3 weeks (range, 21-31 weeks). There was a significant difference between the mean time to return to competition for rugby (27.8 weeks) and soccer players (24.1 weeks; P = .02) and for ligamentous (22.5 weeks) compared with bony injuries (26.9 weeks; P = .003). Three patients suffered deep peroneal nerve sensation loss, from which 1 patient did not fully recover. CONCLUSION: Return to competitive elite-level soccer and rugby is possible after surgically treated Lisfranc injuries. Return to training can take up to 24 weeks and return to playing up to 31 weeks, with bony injuries taking longer. PMID- 26637282 TI - FANCJ suppresses microsatellite instability and lymphomagenesis independent of the Fanconi anemia pathway. AB - Microsatellites are short tandem repeat sequences that are highly prone to expansion/contraction due to their propensity to form non-B-form DNA structures, which hinder DNA polymerases and provoke template slippage. Although error correction by mismatch repair plays a key role in preventing microsatellite instability (MSI), which is a hallmark of Lynch syndrome, activities must also exist that unwind secondary structures to facilitate replication fidelity. Here, we report that Fancj helicase-deficient mice, while phenotypically resembling Fanconi anemia (FA), are also hypersensitive to replication inhibitors and predisposed to lymphoma. Whereas metabolism of G4-DNA structures is largely unaffected in Fancj(-/-) mice, high levels of spontaneous MSI occur, which is exacerbated by replication inhibition. In contrast, MSI is not observed in Fancd2(-/-) mice but is prevalent in human FA-J patients. Together, these data implicate FANCJ as a key factor required to counteract MSI, which is functionally distinct from its role in the FA pathway. PMID- 26637284 TI - Age-Related Risk Factors for Revision Anterior Cruciate Ligament Reconstruction: A Cohort Study of 21,304 Patients From the Kaiser Permanente Anterior Cruciate Ligament Registry. AB - BACKGROUND: It is not clear whether risk factors for revision anterior cruciate ligament reconstruction (ACLR) are the same throughout patients' lives. PURPOSE: To assess (1) the risk of revision ACLR by age and (2) age-specific risk factors for revision ACLR. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: A cohort study using patients having undergone primary ACLR who were registered in the Kaiser Permanente ACLR Registry (February 2005 to June 2013) was conducted. Aseptic revision was the main endpoint. Age was evaluated as a risk factor for revision. The cohort was stratified into 4 age groups: <21, 21-30, 31-40, and >40 years. Graft type, sex, body mass index (BMI), and race were assessed as revision risk factors within each group. Survival analyses were conducted. RESULTS: Of the 21,304 patients evaluated, 7026 (33%) patients were aged <21 years, 5762 (27%) were 21-30 years, 4656 (22%) were 31-40 years, and 3860 (18%) were >40 years. Allografts were used in 8671 (41%) patients, hamstring autografts in 6823 (32%), and bone-patellar tendon-bone (BPTB) autografts in 5260 (25%). The 5-year revision probability was highest in patients <21 years old (9.0%; 95% CI, 8.0% 10.1%) and lowest in those >40 years old (1.9%; 95% CI, 1.3%-2.7%). Compared with patients aged >40 years, the adjusted revision risk for patients aged <21 years was 7.76 (95% CI, 5.52-10.90). In patients aged <21 years, a lower revision risk was seen in female patients (hazard ratio [HR], 0.76; 95% CI, 0.61-0.93) compared with male patients, patients with a BMI of 30-35 kg/m(2) (HR, 0.75; 95% CI, 0.59 0.95) and BMI >35 kg/m(2) (HR, 0.49; 95% CI, 0.34-0.70) compared with those with a BMI <30 kg/m(2), and black patients (HR, 0.55, 95% CI, 0.36-0.85) compared with white patients. Sex, BMI, and race were not associated with the risk of revision in older patients. In patients <=40 years old, those with allografts had a higher risk of revision than those with BPTB autografts (HR, 2.69, 2.35, and 3.04 for patients aged <21, 21-30, and 31-40 years, respectively). Patients <21 years old with hamstring autografts had a 1.61 times (95% CI, 1.20-2.17) higher risk of revision than did patients with BPTB autografts; these differences were not identified in older patients. CONCLUSION: Age at the time of ACLR surgery is a strong risk factor for revision ACLR. Other risk factors for revision ACLR, such as graft type, sex, race, and BMI, may vary in strength and significance over a patient's life. Understanding the age-related risk factors associated with revision ACLR may help with appropriate patient counseling and optimal graft choice when performing ACLR. PMID- 26637281 TI - Impaired PRC2 activity promotes transcriptional instability and favors breast tumorigenesis. AB - Alterations of chromatin modifiers are frequent in cancer, but their functional consequences often remain unclear. Focusing on the Polycomb protein EZH2 that deposits the H3K27me3 (trimethylation of Lys27 of histone H3) mark, we showed that its high expression in solid tumors is a consequence, not a cause, of tumorigenesis. In mouse and human models, EZH2 is dispensable for prostate cancer development and restrains breast tumorigenesis. High EZH2 expression in tumors results from a tight coupling to proliferation to ensure H3K27me3 homeostasis. However, this process malfunctions in breast cancer. Low EZH2 expression relative to proliferation and mutations in Polycomb genes actually indicate poor prognosis and occur in metastases. We show that while altered EZH2 activity consistently modulates a subset of its target genes, it promotes a wider transcriptional instability. Importantly, transcriptional changes that are consequences of EZH2 loss are predominantly irreversible. Our study provides an unexpected understanding of EZH2's contribution to solid tumors with important therapeutic implications. PMID- 26637279 TI - Lipoprotein (a): impact by ethnicity and environmental and medical conditions. AB - Levels of lipoprotein (a) [Lp(a)], a complex between an LDL-like lipid moiety containing one copy of apoB, and apo(a), a plasminogen-derived carbohydrate-rich hydrophilic protein, are primarily genetically regulated. Although stable intra individually, Lp(a) levels have a skewed distribution inter-individually and are strongly impacted by a size polymorphism of the LPA gene, resulting in a variable number of kringle IV (KIV) units, a key motif of apo(a). The variation in KIV units is a strong predictor of plasma Lp(a) levels resulting in stable plasma levels across the lifespan. Studies have demonstrated pronounced differences across ethnicities with regard to Lp(a) levels and some of this difference, but not all of it, can be explained by genetic variations across ethnic groups. Increasing evidence suggests that age, sex, and hormonal impact may have a modest modulatory influence on Lp(a) levels. Among clinical conditions, Lp(a) levels are reported to be affected by kidney and liver diseases. PMID- 26637285 TI - Rates and Determinants of Return to Play After Anterior Cruciate Ligament Reconstruction in National Collegiate Athletic Association Division I Soccer Athletes: A Study of the Southeastern Conference. AB - BACKGROUND: Factors and details regarding return to play in elite, collegiate female soccer athletes after an anterior cruciate ligament (ACL) injury and reconstruction have not been well studied. PURPOSE: To evaluate return to play among collegiate female soccer players, specifically examining the effect of surgical and individual athlete characteristics on the return-to-play rate. STUDY DESIGN: Descriptive epidemiology study. METHODS: Sports medicine and athletic training staff at institutions from the National Collegiate Athletic Association Southeastern Conference (SEC) were contacted to request participation in the study. All institutions were sent a standardized spreadsheet with response choices and instructions regarding athlete inclusion criteria. Athlete, injury, surgical technique, and return-to-play data were requested for ACL reconstructions performed on female soccer athletes at the participating institutions over the previous 8 years. chi(2) analyses were used to compare the return-to-play rate by year in school, scholarship status, position, depth chart status, procedure, graft type, graft fixation, concomitant procedures, and previous ACL injuries. RESULTS: All 14 of the SEC institutions chose to participate and provided data. A total of 80 ACL injuries were reported, with 79 surgical reconstructions and return-to-play data for 78 collegiate soccer athletes. The overall return-to-play rate was 85%. There was a statistical significance in return-to-play rates favoring athletes in earlier years of eligibility versus later years (P < .001). Athletes in eligibility years 4 and 5 combined had a return-to-play rate of only 40%. Scholarship status likewise showed significance (P < .001), demonstrating a higher return-to-play rate for scholarship athletes (91%) versus nonscholarship athletes (46%). No significant differences in return-to-play rates were observed based on surgical factors, including concomitant knee procedures, graft type, and graft fixation method. CONCLUSION: Collegiate female soccer athletes have a high initial return-to-play rate. Undergoing ACL reconstruction earlier in the college career as well as the presence of a scholarship had a positive effect on return to play. Surgical factors including graft type, fixation method, tunnel placement technique, concomitant knee surgeries, and revision status demonstrated no significant effect on the return-to-play rate. PMID- 26637286 TI - Control of Adult Neurogenesis by Short-Range Morphogenic-Signaling Molecules. AB - Adult neurogenesis is dynamically regulated by a tangled web of local signals emanating from the neural stem cell (NSC) microenvironment. Both soluble and membrane-bound niche factors have been identified as determinants of adult neurogenesis, including morphogens. Here, we review our current understanding of the role and mechanisms of short-range morphogen ligands from the Wnt, Notch, Sonic hedgehog, and bone morphogenetic protein (BMP) families in the regulation of adult neurogenesis. These morphogens are ideally suited to fine-tune stem-cell behavior, progenitor expansion, and differentiation, thereby influencing all stages of the neurogenesis process. We discuss cross talk between their signaling pathways and highlight findings of embryonic development that provide a relevant context for understanding neurogenesis in the adult brain. We also review emerging examples showing that the web of morphogens is in fact tightly linked to the regulation of neurogenesis by diverse physiologic processes. PMID- 26637287 TI - Working Memory: Maintenance, Updating, and the Realization of Intentions. AB - "Working memory" refers to a vast set of mnemonic processes and associated brain networks, relates to basic intellectual abilities, and underlies many real-world functions. Working-memory maintenance involves frontoparietal regions and distributed representational areas, and can be based on persistent activity in reentrant loops, synchronous oscillations, or changes in synaptic strength. Manipulation of content of working memory depends on the dorsofrontal cortex, and updating is realized by a frontostriatal '"gating" function. Goals and intentions are represented as cognitive and motivational contexts in the rostrofrontal cortex. Different working-memory networks are linked via associative reinforcement-learning mechanisms into a self-organizing system. Normal capacity variation, as well as working-memory deficits, can largely be accounted for by the effectiveness and integrity of the basal ganglia and dopaminergic neurotransmission. PMID- 26637288 TI - Maturation and Functional Integration of New Granule Cells into the Adult Hippocampus. AB - The adult hippocampus generates functional dentate granule cells (GCs) that release glutamate onto target cells in the hilus and cornus ammonis (CA)3 region, and receive glutamatergic and gamma-aminobutyric acid (GABA)ergic inputs that tightly control their spiking activity. The slow and sequential development of their excitatory and inhibitory inputs makes them particularly relevant for information processing. Although they are still immature, new neurons are recruited by afferent activity and display increased excitability, enhanced activity-dependent plasticity of their input and output connections, and a high rate of synaptogenesis. Once fully mature, new GCs show all the hallmarks of neurons generated during development. In this review, we focus on how developing neurons remodel the adult dentate gyrus and discuss key aspects that illustrate the potential of neurogenesis as a mechanism for circuit plasticity and function. PMID- 26637289 TI - Simple screening tool for assessing attention deficit in pediatric lupus. PMID- 26637291 TI - Outcome of lupus nephritis in childhood onset SLE in North and Central India: single-centre experience over 25 years. AB - INTRODUCTION: Childhood SLE (cSLE) has a higher prevalence of lupus nephritis (LN), and there are ethnic variations in response to treatment as well as outcome of LN. There are limited data on long-term outcome of LN in cSLE from the Indian subcontinent. METHODS: Retrospective analysis of case records of patients with cSLE (satisfying revised American College of Rheumatology (ACR) 1997 criteria for diagnosis) and age of onset <18 years was conducted from 1989 to 2013. Data on clinical features, renal involvement and biopsy findings, treatment, renal outcome, damage accrual and mortality were collected. End-stage renal disease (ESRD) was defined as the need for renal replacement therapy. Actuarial ESRD-free survival was studied as the primary outcome measure using Kaplan-Meier analysis. RESULTS: Among 205 children with cSLE, 134 (121 girls) had evidence of LN. The mean age at disease onset was 13.7 +/- 3.5 years and the mean disease duration at presentation was 1.9 +/- 2.5 years. Kidney biopsy was available for 92 patients, and histology included: 13 (14.2%) Class II, 24 (26%) Class III, 43 (46.7%) Class IV and 12 (13.1%) Class V LN. The mean follow-up period was 6.75 +/- 5.7 years. At last visit, 81 (60.4%) children were in complete remission, 28 (20.9%) were in partial remission, 15 (11.2%) still had active nephritis and 10 (7.4%) had progressed to ESRD. Almost two-thirds (62.9%) of patients experienced lupus flares, and mean flare rate was 0.09 flares/patient follow-up year. Fifty-six (43.8%) children accrued damage and the mean Systemic Lupus International Collaborating Clinics (SLICC)/ACR damage score was 0.79 +/- 1.13. Actuarial ESRD free survival at five, 10 and 15 years was 91.1%, 79% and 76.2%, and five-, 10- and 15-year renal survival was 93.8%, 87.1% and 84%, respectively. Although multiple factors individually predicted poor outcome (death/ESRD), only raised serum creatinine at onset (R square = 0.65, p <= 0.0001) and damage accrual (R square = 0.62, p <= 0.0001) remained significant on multivariate analysis. Eleven (8.2%) children died during the follow-up period, and infections were the leading cause of mortality. CONCLUSIONS: Long-term outcome of LN in cSLE in our cohort was better than previous reports from India. However, a high rate of major infection still remains the leading cause of mortality. PMID- 26637290 TI - GlycA, a novel marker of inflammation, is elevated in systemic lupus erythematosus. AB - BACKGROUND: GlycA is a novel marker of systemic inflammation detected by nuclear magnetic resonance (NMR) spectroscopy. In the general population, GlycA is correlated with inflammatory markers such as C-reactive protein (CRP) and associated with coronary heart disease and diabetes. The utility of GlycA in patients with systemic lupus erythematosus (SLE) has not been defined. Therefore, we tested the hypothesis that GlycA concentrations are elevated in patients with SLE and associated with other markers of inflammation and coronary atherosclerosis. METHODS: We compared concentrations of GlycA, detected by NMR, in 116 patients with SLE and 84 control subjects frequency-matched for age, sex, and race. SLE disease activity index (SLEDAI) and the SLE Collaborating Clinics damage index (SLICC) were calculated. Acute phase reactants, a panel of cytokines, and a lipid panel were measured. Electron beam computer tomography (EBCT) was used to quantify coronary artery calcification, a measure of coronary artery atherosclerosis. RESULTS: Patients with SLE had higher concentrations of GlycA (398 (350-445)) than control subjects (339 (299-391)) umol/L, p < 0.001. In patients with SLE, concentrations of GlycA were significantly associated with sedimentation rate (rho = 0.43), C-reactive protein (rho = 0.59), e-selectin (rho = 0.28), intracellular adhesion molecule-1 (rho = 0.30), triglycerides (rho = 0.45), all p < 0.0023 to account for multiple comparisons, but not with creatinine, SLEDAI, SLICC, or coronary calcium scores. CONCLUSIONS: Concentrations of GlycA are higher in patients with SLE than control subjects and associated with markers of inflammation but not with SLE disease activity or chronicity scores or coronary artery calcification. PMID- 26637292 TI - Maligner: a fast ordered restriction map aligner. AB - MOTIVATION: The Optical Mapping System discovers structural variants and potentiates sequence assembly of genomes via scaffolding and comparisons that globally validate or correct sequence assemblies. Despite its utility, there are few publicly available tools for aligning optical mapping datasets. RESULTS: Here we present software, named 'Maligner', for the alignment of both single molecule restriction maps (Rmaps) and in silico restriction maps of sequence contigs to a reference. Maligner provides two modes of alignment: an efficient, sensitive dynamic programming implementation that scales to large eukaryotic genomes, and a faster indexed based implementation for finding alignments with unmatched sites in the reference but not the query. We compare our software to other publicly available tools on Rmap datasets and show that Maligner finds more correct alignments in comparable runtime. Lastly, we introduce the M-Score statistic for normalizing alignment scores across restriction maps and demonstrate its utility for selecting high quality alignments. AVAILABILITY AND IMPLEMENTATION: The Maligner software is written in C ++ and is available at https://github.com/LeeMendelowitz/maligner under the GNU General Public License. CONTACT: mpop@umiacs.umd.edu. PMID- 26637293 TI - The defining pathology of the new clinical and histopathologic entity ACTA2 related cerebrovascular disease. AB - INTRODUCTION: Smooth muscle cell contraction is an essential function of arteries and relies on the integrity of the actin-myosin apparatus. The tissue-specific alpha2-smooth muscle actin, encoded by ACTA2, is predominantly expressed in vascular smooth muscle cells. ACTA2 mutations predispose to development of aortic aneurysms and early onset coronary and cerebrovascular disease. Based on arteriographic findings, a distinct cerebrovascular disease has been proposed for ACTA2 heterozygous patients carrying the R179H mutation. RESULTS: We present the first integrated analysis of a severely compromised patient with the R179H mutation and define the arterial pathology of ACTA2-related cerebrovascular disease. Histologically, striking morphological abnormalities were present in cerebral arteries of all sizes. Massive intimal smooth muscle cell proliferation, fragmentation of the elastic laminae and medial fibromuscular proliferation characterized large arteries whereas prominent vessel wall thickening, fibrosis and smooth muscle cell proliferation were unique changes in small arteries. The medial fibrosis and smooth muscle cell proliferation explain the characteristic radiologic appearance of "straight arteries" and suggest impaired function of mutant smooth muscle cells. Actin three-dimensional molecular modeling revealed critical positioning of R179 at the interface between the two strands of filamentous actin and destabilization of inter-strand bundling by the R179H mutation, explaining the severe associated phenotype. CONCLUSIONS: In conclusion, these characteristic clinical and pathologic findings confirm ACTA2-related cerebrovascular disease as a new cerebrovascular disorder for which new therapeutic strategies need to be designed. PMID- 26637294 TI - Metallothionein-3 modulates the amyloid beta endocytosis of astrocytes through its effects on actin polymerization. AB - BACKGROUND: Astrocytes may play important roles in the pathogenesis of Alzheimer's disease (AD) by clearing extracellular amyloid beta (Abeta) through endocytosis and degradation. We recently showed that metallothionein 3 (Mt3), a zinc-binding metallothionein that is enriched in the central nervous system, contributes to actin polymerization in astrocytes. Because actin is likely involved in the endocytosis of Abeta, we investigated the possible role of Mt3 in Abeta endocytosis by cortical astrocytes in this study. RESULTS: To assess the route of Abeta uptake, we exposed cultured astrocytes to fluorescently labeled Abeta1-40 or Abeta1-42 together with chloropromazine (CP) or methyl-beta cyclodextrin (MbetaCD), inhibitors of clathrin- and caveolin-dependent endocytosis, respectively. CP treatment almost completely blocked Abeta1-40 and Abeta1-42 endocytosis, whereas exposure to MbetaCD had no significant effect. Actin disruption with cytochalasin D (CytD) or latrunculin B also completely blocked Abeta1-40 and Abeta1-42 endocytosis. Because the absence of Mt3 also results in actin disruption, we examined Abeta1-40 and Abeta1-42 uptake and expression in Mt3 (-/-) astrocytes. Compared with wild-type (WT) cells, Mt3 (-/-) cells exhibited markedly reduced Abeta1-40 and Abeta1-42 endocytosis and expression of Abeta1-42 monomers and oligomers. A similar reduction was observed in CytD-treated WT cells. Finally, actin disruption and Mt3 knockout each increased the overall levels of clathrin and the associated protein phosphatidylinositol-binding clathrin assembly protein (PICALM) in astrocytes. CONCLUSIONS: Our results suggest that the absence of Mt3 reduces Abeta uptake in astrocytes through an abnormality in actin polymerization. In light of evidence that Mt3 is downregulated in AD, our findings indicate that this mechanism may contribute to the extracellular accumulation of Abeta in this disease. PMID- 26637295 TI - How online sexual health services could work; generating theory to support development. AB - BACKGROUND: Online sexual health services are an emerging area of service delivery. Theory of change critically analyses programmes by specifying planned inputs and articulating the causal pathways that link these to anticipated outcomes. It acknowledges the changing and contested nature of these relationships. METHODS: We developed two versions of a theory of change for an online sexual health service. The first articulated the theory presented in the original programme proposal and the second documented its development in the early stages of implementation through interviews with key programme stakeholders. RESULTS: The programme proposal described an autonomous and empowered user completing a sexual health check using a more convenient, accessible and discreet online service and a shift from clinic based to online care. The stakeholder interviews confirmed this and described new and more complex patterns of service use as the online service creates opportunities for providers to contact users outside of the traditional clinic visit and users move between online and clinic based care. They described new types of user/provider relationships which we categorised as: those influenced by an online retail culture; those influenced by health promotion outreach and surveillance and those acknowledging the need for supported access. CONCLUSIONS: This analysis of stakeholder views on the likely the impacts of online sexual health services suggests three areas for further thinking and research. 1. Co-development of clinic and online services to support complex patterns of service use. 2. Developing access to online services for those who could use them with support. 3. Understanding user experience of sexual health services as increasing user autonomy and choice in some situations; creating exclusion and a need for support in others and intrusiveness and a lack of control in still others. This work has influenced the evaluation of this programme which will focus on; mapping patterns of use to understand how users move between the online and clinic based services; barriers to use of online services among some populations and how to overcome these; understanding user perceptions of autonomy in relation to online services. PMID- 26637297 TI - Complementary effect of patient volume and quality of care on hospital cost efficiency. AB - This study explores the direct effect of an increase in patient volume in a hospital and the complementary effect of quality of care on the cost efficiency of U.S. hospitals in terms of patient volume. The simultaneous equation model with three-stage least squares is used to measure the direct effect of patient volume and the complementary effect of quality of care and volume. Cost efficiency is measured with a data envelopment analysis method. Patient volume has a U-shaped relationship with hospital cost efficiency and an inverted U shaped relationship with quality of care. Quality of care functions as a moderator for the relationship between patient volume and efficiency. This paper addresses the economically important question of the relationship of volume with quality of care and hospital cost efficiency. The three-stage least square simultaneous equation model captures the simultaneous effects of patient volume on hospital quality of care and cost efficiency. PMID- 26637296 TI - Dissecting seipin function: the localized accumulation of phosphatidic acid at ER/LD junctions in the absence of seipin is suppressed by Sei1p(DeltaNterm) only in combination with Ldb16p. AB - BACKGROUND: Seipin is required for the correct assembly of cytoplasmic lipid droplets. In the absence of the yeast seipin homolog Sei1p (formerly Fld1p), droplets are slow to bud from the endoplasmic reticulum, lack the normal component of proteins on their surface, are highly heterogeneous in size and shape, often bud into the nucleus, and promote local proliferation of the endoplasmic reticulum in which they become tangled. But the mechanism by which seipin catalyzes lipid droplet formation is still uncertain. RESULTS: Seipin prevents a localized accumulation of phosphatidic acid (PA puncta) at ER-droplet junctions. PA puncta were detected with three different probes: Opi1p, Spo20p(51 91) and Pah1p. A system of droplet induction was used to show that PA puncta were not present until droplets were formed; the puncta appeared regardless of whether droplets consisted of triacylglycerol or steryl ester. Deletion strains were used to demonstrate that a single phosphatidic acid-producing enzyme is not responsible for the generation of the puncta, and the puncta remain resistant to overexpression of enzymes that metabolize phosphatidic acid, suggesting that this lipid is trapped in a latent compartment. Suppression of PA puncta requires the first 14 amino acids of Sei1p (Nterm), a domain that is also important for initiation of droplet assembly. Consistent with recent evidence that Ldb16p and Sei1p form a functional unit, the PA puncta phenotype in the ldb16Delta sei1Delta strain was rescued by human seipin. Moreover, PA puncta in the sei1Delta strain expressing Sei1p(DeltaNterm) was suppressed by overexpression of Ldb16p, suggesting a functional interaction of Nterm with this protein. Overexpression of both Sei1p and Ldb16p, but not Sei1p alone, is sufficient to cause a large increase in droplet number. However, Ldb16p alone increases triacylglycerol accumulation in the ldb16Delta sei1Delta background. CONCLUSION: We hypothesize that seipin prevents formation of membranes with extreme curvature at endoplasmic reticulum/droplet junctions that would attract phosphatidic acid. While Ldb16p alone can affect triacylglycerol accumulation, proper droplet formation requires the collaboration of Sei1p and Ldb16. PMID- 26637298 TI - Arthroscopic popliteus bypass graft for posterolateral instabilities of the knee : A new surgical technique. AB - OBJECTIVE: An arthroscopic technique for the reconstruction of the posterolateral corner combined with posterior cruciate ligament (PCL) reconstruction was developed. INDICATIONS: Posterolateral rotational instabilities of the knee. Combined lesions of the PCL, the popliteus complex (PLT) and the posterolateral corner. Isolated PLT lesions lacking static stabilizing function. CONTRAINDICATIONS: Neuromuscular disorders; knee deformities or fractures; severe posterolateral soft tissue damage. SURGICAL TECHNIQUE: Six arthroscopic portals are necessary. Using the posteromedial portal, resect dorsal septum with a shaver. Visualize the PCL, the lateral femoral condyle and the posterolateral recessus with the PLT. Dissect the popliteomeniscal fibers; retract PLT until sulcus popliteus is visualized. Drill a 6-mm tunnel anteriorly into the distal third of the sulcus popliteus. Visualize femoral footprint of the PLT and place an anatomical drill tunnel. Pull the popliteus bypass graft into the knee and fix with bioscrews. Fix the reconstructed PCL. In cases of additional LCL injury, reconstruct LCL with autologous graft. POSTOPERATIVE MANAGEMENT: Partial weight bearing for 6 weeks, range of motion exercises, quadriceps-strengthening exercises on postoperative day 1. Full extension allowed immediately with flexion limited to 20 degrees for 2 weeks, to 45 degrees for up to week 4, and to 60 degrees up to week 6. Use a PCL brace for 3 months, running and squatting exercises allowed after 3 months. RESULTS: In the 35 patients treated, no technique-related complications. After 1 year, 12 patients had a mean Lysholm Score of 88.6 (+/- 8.7) points and a side-to-side difference in the posterior drawer test of 2.9 (+/- 2.2) mm (preoperative 13.3 [+/- 1.9] mm). CONCLUSION: Low complication risk and good and excellent clinical results after arthroscopic posterolateral corner reconstruction. PMID- 26637299 TI - Next Generation Sequencing in the Clinic: a Patterns of Care Study in a Retrospective Cohort of Subjects Referred to a Genetic Medicine Clinic for Suspected Lynch Syndrome. AB - Next generation sequencing (NGS) gene panels are increasingly used in medical genetics clinics for the evaluation of common inherited cancer syndromes, but the clinical efficacy of these tests, and the factors driving clinical providers to order them are unclear. We conducted a patterns-of-care study to compare patients evaluated with NGS gene panels with a reference group. We abstracted demographic, socioeconomic, and clinical information in a retrospective cohort of patients referred to a large medical genetics clinic for evaluation of inherited colorectal cancer and polyposis syndromes. Patients tested with NGS gene panels were more likely to be insured compared to the reference group (85.3 % vs. 69.2 %, p = 0.0068),less likely to have prior tumor tissue testing (29.4 % vs. 54.3 %, p = 0.0004), and less likely to have an abnormal tumor tissue test result (46.7 % vs. 74.5 %, p = 0.01). No significant differences were found between groups in age, gender, race, employment status, personal history of colorectal cancer, or proportion of patients fulfilling Lynch syndrome clinical criteria. Patients with NGS testing were less likely to have a pathogenic/likely pathogenic variant detected (13.7 % vs. 31.9 %, p = 0.002). Patients referred for NGS testing to evaluate inherited colorectal cancer/polyposis risk appear to undergo tumor tissue testing less frequently than non-NGS testing patients. Further studies are needed to assess the most effective and cost-effective approach to genomic diagnosis in this patient population. PMID- 26637300 TI - Measuring the Effectiveness of a Genetic Counseling Supervision Training Conference. AB - Genetic counselors who receive formal training report increased confidence and competence in their supervisory roles. The effectiveness of specific formal supervision training has not been assessed previously. A day-long GC supervision conference was designed based on published supervision competencies and was attended by 37 genetic counselors. Linear Mixed Model and post-hoc paired t-test was used to compare Psychotherapy Supervisor Development Scale (PSDS) scores among/between individuals pre and post conference. Generalized Estimating Equation (GEE) model and post-hoc McNemar's test was used to determine if the conference had an effect on GC supervision competencies. PSDS scores were significantly increased 1 week (p < 0.001) and 6 months (p < 0.001) following the conference. For three supervision competencies, attendees were more likely to agree they were able to perform them after the conference than before. These effects remained significant 6 months later. For the three remaining competencies, the majority of supervisors agreed they could perform these before the conference; therefore, no change was found. This exploratory study showed this conference increased the perceived confidence and competence of the supervisors who attended and increased their self-reported ability to perform certain supervision competencies. While still preliminary, this supports the idea that a one day conference on supervision has the potential to impact supervisor development. PMID- 26637301 TI - Trace elements deposition in the Tierra del Fuego region (south Patagonia) by using lichen transplants after the Puyehue-Cordon Caulle (north Patagonia) volcanic eruption in 2011. AB - Lichen Usnea barbata transplants were tested as a biomonitor of atmospheric deposition in an apparently pristine environment that is Tierra del Fuego region (Patagonia, Argentina). The present survey is connected with the volcanic eruption that started in north Patagonia on June 4, 2011 from the Puyehue-Cordon Caulle volcano, Chile (north Patagonia, at 1700 km of distance of our sampling sites). Lichens were collected in September 2011 (one month of exposure) and September 2012 (1 year of exposure) in 27 sites covering the northern region of the province where trees are not present. The atmospheric deposition of 27 elements by using Neutron Activation Analysis (NAA) was determined in the collected samples. The first aim of the study was to evaluate the influence of the volcanic eruption on the regional atmospheric deposition comparing our results with baseline data we determined in U. barbata in 2006 in the same sites. The second aim was to test possible patterns of bioaccumulation between the two sampling campaigns after the volcanic eruption. With respect to 2006 baseline levels, we found significant higher levels for As, Ba, Co, Cr, Cs, Na, Sb and U in lichens collected after 1 month of exposure (first sampling campaign--2011). Between the two sampling campaigns (2011-2012) after the eruption, lichens reflected the natural contamination by volcanic ashes with significantly higher median levels of Br, Cr, Fe, K, Na, Sc, and Se. Results confirmed the very good aptitude of U. barbata to reflect the levels of elements in the environment at global scale and to reflect the volcanic emissions at distant places. Volcanic eruptions cause the emission in the atmosphere of elevated levels of particulate matter. In this regard, our findings demonstrate the importance to evaluate the metal composition of the particles to avoid possible health effects. PMID- 26637302 TI - Stress tolerance and biocontrol performance of the yeast antagonist, Candida diversa, change with morphology transition. AB - As an eco-friendly management method, biological control of postharvest diseases, utilizing antagonistic yeasts, is a research topic receiving considerable attention. Detailed knowledge on the biology of yeast antagonists is crucial when considering their potential application and development as biocontrol products. Changes in the growth form, such as single-cell to pseudohyphae, have been associated with the mode of action in postharvest biocontrol yeasts. In this study, the antagonistic yeast, Candida diversa, reversibly shifted from a single cell morphology on yeast peptone dextrose (YPD) medium with 2 % agar to a pseudohyphal morphology on YPD with 0.3 % agar. The tolerance of the pseudohyphal form to heat and oxidative stresses, as well as the biocontrol efficacy against Botrytis cinerea on apple and kiwifruit stored at 25 and 4 degrees C, was significantly higher as compared to the single-cell form. This study provides new information on the ability of C. diversa to change its morphology and the impact of the morphology shift on stress tolerance and biocontrol performance. PMID- 26637303 TI - Fluorescence characteristics of human Barrett tissue specimens grafted on chick chorioallantoic membrane. AB - To improve (pre)malignant lesion identification in Barrett's esophagus (BE), recent research focuses on new developments in fluorescence imaging and spectroscopy to enhance tissue contrast. Our aim was to validate the chorioallantoic membrane (CAM) model as a preclinical tool to study the fluorescence characteristics such as autofluorescence and exogenously induced fluorescence of human Barrett's tissue. Therefore, esophageal biopsy specimens from Barrett's patients were freshly grafted onto the CAM of fertilized hen's eggs to simulate the in vivo situation. The BE biopsy specimens stayed between 1 and 9 days on the CAM to study the persistence of vitality. Fluorescence spectroscopy was performed using six excitation wavelengths (369, 395, 400, 405, 410, 416 nm). Obtained autofluorescence spectra were compared with in vivo spectra of an earlier study. Exogenous administration of 5-aminolevulinic-acid to the biopsy specimens was followed by fluorescence spectroscopy at several time points. Afterwards, the biopsy specimens were harvested and histologically evaluated. In total, 128 biopsy specimens obtained from 34 patients were grafted on the CAM. Biopsy specimens which stayed on average 1.7 days on the CAM were still vital. Autofluorescence spectra of the specimens correlated well with in vivo spectra. Administered 5-aminolevulinic-acid to the biopsy specimens showed conversion into protoporphyrin-IX. In conclusion, we showed that grafting freshly collected human BE biopsy specimens on the CAM is feasible. Our results suggest that the CAM model might be used to study the fluorescence behavior of human tissue specimens. Therefore, the CAM model might be a preclinical research tool for new photosensitizers. PMID- 26637304 TI - Local changes in arterial oxygen saturation induced by visible and near-infrared light radiation. AB - In this study, we investigate the efficiency of laser radiation on oxyhemoglobin (HbO2) rate in blood vessels and its wavelength dependence. The results of in vivo experimental measurements of the laser-induced photodissociation of HbO2 in cutaneous blood vessels in the visible and near-infrared (IR) spectral range are presented. Arterial oxygen saturation (SpO2) was measured by a method of fingertip pulse oximetry, which is based on the measurement of the modulated pulse wave of the blood. The light irradiating the finger was provided by corresponding light-emitting diodes (LED) at 15 wavelengths in the 400-940 nm spectrum range. Statistical results with a value of p < 0.05 were viewed as being significant for all volunteers. The results show that there is a decrease in SpO2 in the blood under the influence of the transcutaneous laser irradiation. Three maxima in the spectral range (530, 600, and 850 nm) are revealed, wherein decrease in the relative concentration of SpO2 reaches 5 % +/- 0.5 %. Near-IR radiation plays a dominant role in absorption of laser radiation by oxyhemoglobin in deeper layers of tissue blood vessels. The obtained data correlate with the processes of light propagation in biological tissue. The observed reduction in SpO2 indicates the process of photodissociation of HbO2 in vivo and may result in local increase in O2 in the tissue. Such laser-induced enrichment of tissue oxygenation can be used in phototherapy of pathologies, where the elimination of local tissue hypoxia is critical. PMID- 26637305 TI - The roles and training of primary care doctors: China, India, Brazil and South Africa. AB - China, India, Brazil and South Africa contain 40% of the global population and are key emerging economies. All these countries have a policy commitment to universal health coverage with an emphasis on primary health care. The primary care doctor is a key part of the health workforce, and this article, which is based on two workshops at the 2014 Towards Unity For Health Conference in Fortaleza, Brazil, compares and reflects on the roles and training of primary care doctors in these four countries. Key themes to emerge were the need for the primary care doctor to function in support of a primary care team that provides community-orientated and first-contact care. This necessitates task-shifting and an openness to adapt one's role in line with the needs of the team and community. Beyond clinical competence, the primary care doctor may need to be a change agent, critical thinker, capability builder, collaborator and community advocate. Postgraduate training is important as well as up-skilling the existing workforce. There is a tension between training doctors to be community-orientated versus filling the procedural skills gaps at the facility level. In training, there is a need to plan postgraduate education at scale and reform the system to provide suitable incentives for doctors to choose this as a career path. Exposure should start at the undergraduate level. Learning outcomes should be socially accountable to the needs of the country and local communities, and graduates should be person-centred comprehensive generalists. PMID- 26637307 TI - [Sarcopenia and strength]. PMID- 26637306 TI - Removal of redundant contigs from de novo RNA-Seq assemblies via homology search improves accurate detection of differentially expressed genes. AB - BACKGROUND: For plant species with unsequenced genomes, cDNA contigs created by de novo assembly of RNA-Seq reads are used as reference sequences for comparative analysis of RNA-Seq datasets and the detection of differentially expressed genes (DEGs). Redundancies in such contigs are evident in previous RNA-Seq studies, and such redundancies can lead to difficulties in subsequent analysis. Nevertheless, the effects of removing redundancy from contig assemblies on comparative RNA-Seq analysis have not been evaluated. RESULTS: Here we describe a method for removing redundancy from raw contigs that were primarily created by de novo assembly of Arabidopsis thaliana RNA-Seq reads. Specifically, the contigs with the highest bit scores were selected from raw contigs by a homology search against the gene dataset in the TAIR10 database. The two existing methods for removal of redundancy based on contig length or clustering analysis used to eliminate redundancies from raw contigs. Contig number was reduced most effectively with the method based on homology search. In a comparative analysis of RNA-Seq datasets, DEGs detected in contigs that underwent redundancy removal via the homology search method showed the highest identity to the DEGs detected when the TAIR10 gene dataset was used as an exact reference. Redundancy in raw contigs could also be removed by a homology search against integrated protein datasets from several plant species other than A. thaliana. DEGs detected using contigs that underwent such redundancy-removed also showed high homology to DEGs detected using the TAIR10 gene dataset. CONCLUSION: Here we describe a method for removing redundant contigs within raw contigs; this method involves a homology search against a gene or protein database. In principal, this method can be used with unsequenced plant genomes that lack a well-developed gene database. Redundant contigs were not removed adequately via either of two existing methods, but our method allowed for removal of all redundant contigs. To our knowledge, this is the first reported improvement in accurate detection of DEGs via comparative RNA Seq analysis that involved preparation of a non-redundant reference sequence. This method could be used to rapidly and cost-effectively detect useful genes in unsequenced plants. PMID- 26637308 TI - [Ambivalence--a key concept in gerontology? Elements of heuristics exemplified by identity formation in old age]. AB - Ambivalence is a widely used concept in gerontology, mostly used in the common sense meaning. We propose that an elaborated notion based on the historical and systematic analysis, reveals important theoretical, methodological and practical potentials of the idea of ambivalence for the study of aging. We exemplify this view by proposing a heuristic perspective for the analysis of processes to constitute and reconstitute identities in old age using a model based on a multidimensional understanding of ambivalence. Ambivalence is defined as referring to the experiences of vacillating between polar contradictions of feeling, thinking, wanting and social structures in the search for the sense and meaning of social relationships, facts and texts, which are important for unfolding and altering facets of the self and agency. PMID- 26637309 TI - The burden of hypertension in sub-Saharan Africa: a four-country cross sectional study. AB - BACKGROUND: Hypertension, the leading single cause of morbidity and mortality worldwide, is a growing public health problem in sub-Saharan Africa (SSA). Few studies have estimated and compared the burden of hypertension across different SSA populations. We conducted a cross-sectional analysis of blood pressure data collected through a cohort study in four SSA countries, to estimate the prevalence of pre-hypertension, the prevalence of hypertension, and to identify the factors associated with hypertension. METHODS: Participants were from five different population groups defined by occupation and degree of urbanization, including rural and peri-urban residents in Uganda, school teachers in South Africa and Tanzania, and nurses in Nigeria. We used a standardized questionnaire to collect data on demographic and behavioral characteristics, injuries, and history of diagnoses of chronic diseases and mental health. We also made physical measurements (weight, height and blood pressure), as well as biochemical measurements; which followed standardized protocols across the country sites. Modified Poison regression modelling was used to estimate prevalence ratios (PR) as measures of association between potential risk factors and hypertension. RESULTS: The overall age-standardized prevalence of hypertension among the 1216 participants was 25.9%. Prevalence was highest among nurses with an age standardized prevalence (ASP) of 25.8%, followed by school teachers (ASP = 23.2%), peri-urban residents (ASP = 20.5%) and lowest among rural residents (ASP = 8.7%). Only 50.0% of participants with hypertension were aware of their raised blood pressure. The overall age-standardized prevalence of pre-hypertension was 21.0%. Factors found to be associated with hypertension were: population group, older age, higher body mass index, higher fasting plasma glucose level, lower level of education, and tobacco use. CONCLUSIONS: The prevalence of hypertension and pre-hypertension are high, and differ by population group defined by occupation and degree of urbanization. Only half of the populations with hypertension are aware of their hypertension, indicating a high burden of undiagnosed and un-controlled high blood pressure in these populations. PMID- 26637310 TI - DDX5/p68 RNA helicase expression is essential for initiating adipogenesis. AB - BACKGROUND: DDX5/p68 RNA helicase is a member of the DEAD (Asp-Glu-Ala-Asp) box proteins. Apart from RNA unwinding, DDX5 is an important transcriptional factor and co-activator in cell proliferation and differentiation. FINDINGS: Here, we have characterised the role of DDX5 in adipogenesis in 3T3-L1 cells using siRNA mediated suppression. Transient inhibition of Ddx5 mRNA expression at the start of adipogenesis impairs the differentiation programme even when DDX5 expression is restored later in adipogenesis. However transient suppression of Ddx5 at the later stages of adipogenesis do not impair adipogenesis or triglyceride accumulation suggesting Ddx5 expression is dispensable in a mature adipocyte. CONCLUSION: These results implicate DDX5 as a crucial factor involved in the complex transcriptional cascade of events that regulate adipogenesis and essential to the initiation of adipogenesis. PMID- 26637311 TI - A mucin-like peptide from Fasciola hepatica induces parasite-specific Th1-type cell immunity. AB - Fasciolosis, caused by the liver fluke Fasciola hepatica, is a major parasitic disease of livestock that causes significant economic losses worldwide. Although drugs are effective against liver flukes, they do not prevent reinfection, and continuous treatment is costly. Moreover, resistant fluke strains are emerging. In this context, vaccination is a good alternative since it provides a cost effective long-term prevention strategy to control fasciolosis. In this paper, we evaluate the Fhmuc peptide as a potential vaccine against fasciolosis. This peptide derives from a mucin-like protein highly expressed in the infective stage of Fasciola hepatica. Mucin-like molecules expressed by parasites can contribute to several infection processes by protecting the parasite from host proteases and recognition by the immune system. We show that the Fhmuc peptide induces Th1-like immune responses specific for F. hepatica excretion-secretion products (FhESP) with a high production of IFNgamma. We also investigated whether this peptide could protect animals from infection, and present preliminary data indicating that animals treated with Fhmuc exhibited reduced liver damage compared to non immunised animals and that this protection was associated with a recruitment of B and T lymphocytes in the peritoneum, as well as eosinophils and mature dendritic cells. These results suggest that the mucin-like peptide Fhmuc could constitute a potential vaccine candidate against fasciolosis and pave the way towards the development of vaccines against parasites. PMID- 26637312 TI - First evidence of the European wildcat (Felis silvestris silvestris) as definitive host of Angiostrongylus chabaudi. AB - Angiostrongylus chabaudi (Strongylida, Angiostrongylidae) is a parasitic nematode described for the first time last century from the pulmonary arteries of six European wildcats (Felis silvestris silvestris) in central Italy. Since then, this parasite remained practically unknown until recently, when immature A. chabaudi have been reported from one wildcat in Germany and two domestic cats (Felis silvestris catus) in Italy. The present report describes the first record of A. chabaudi in Greece and, most importantly, the first known case of patent infection by A. chabaudi. The necropsy of a road-killed F. s. silvestris found near the lake Kerkini, in the municipality of Serres (Macedonia, Greece), revealed the presence of nematodes of both sexes in the right ventricle and the pulmonary artery of the heart. All parasites were mature adults and numerous eggs were present in the uteruses of females. The morphological characteristics of the parasites were consistent with those of A. chabaudi. Moreover, Angiostrongylus like first stage larvae (L1) were present in the faeces of the animal that was negative for any other cardio-pulmonary parasite. Genetic examination of adult parasites and L1 confirmed the morphological identification as A. chabaudi. Histopathological examination of the lungs showed severe, multifocal to coalescing, chronic, interstitial granulomatous pneumonia due to the presence of adult parasites, larvae and eggs. These findings demonstrate for the first unequivocal time that this nematode reproduces in the European wildcat which should be ultimately considered a definitive host of A. chabaudi. Finally, the L1 of A. chabaudi are described here for the first time, opening new prospects for further studies on this neglected parasite. PMID- 26637313 TI - Incidence of Ascaris suum-specific antibodies in Austrian patients with suspected larva migrans visceralis (VLM) syndrome. AB - The pig roundworm, Ascaris suum, is commonly found in domestic pigs all over the world. The transmission to humans takes place by ingestion of infective A. suum eggs present in soil because pig manure is widely used as fertilizer. The possible role of A. suum in the human visceral larva migrans (VLM) syndrome has been discussed controversially during past decades, even though various case reports, particularly from Japan document pulmonal, hepatic and even cerebral symptoms caused by migrating A. suum larvae after ingestion of infected row meat (liver) or contaminated vegetables. We examined 4481 sera by A. suum immunoblot (As-IB) and 5301 sera by Toxocara-ELISA from patients with symptoms associated with the VLM syndrome during three consecutive years (2012-2014). The incidence of A. suum-specific antibodies was 13.2 %, the incidence of T. canis specific antibodies 12.9 % and from a part of the As-IB positive sera (n = 417) additional Toxocara serology was performed to demonstrate the specificity of our tests. Only 56 out of the 417 (13.4 %) sera showed antibodies to both helminth species demonstrating that double infections exist. Interestingly the age distribution of the patients showed that 2.8 % of the Ascaris-positive patients were younger than 21 years, while in the Toxocara-positive group 13.4 % were <21 years. These results are in accordance with a Dutch study suspecting different ways of transmission as cause for this interesting age distribution. Due to the fact that large amounts of untreated pig manure are used as fertilizer and that the expulsion of adult A. suum worms causing intestinal ascariosis is extremely rare in Central European countries, the zoonotic potential of A. suum is considerably underestimated. We suggest that the performance of reliable immunoserological tests, in all industrialized countries where pigs are raised and their manure is used as fertilizer, could help to assess the actual potential of A. suum as causative agent of the VLM syndrome in humans. PMID- 26637314 TI - Ischemic heart disease among subjects with and without chronic obstructive pulmonary disease--ECG-findings in a population-based cohort study. AB - BACKGROUND: Cardiovascular comorbidity in COPD is common and contributes to increased mortality. A few population-based studies indicate that ischemic electrocardiogram (ECG)-changes are more prevalent in COPD, while others do not. The aim of the present study was to estimate the presence of ischemic heart disease (IHD) in a population-based COPD-cohort in comparison with subjects without COPD. METHODS: All subjects with obstructive lung function (COPD, n = 993) were identified together with age- and sex-matched controls (non-COPD, n = 993) from population-based cohorts examined in 2002-04. In 2005, data from structured interview, spirometry and ECG were collected from 1625 subjects. COPD was classified into GOLD 1-4 after post-bronchodilator spirometry. Ischemic ECG changes, based on Minnesota-coding, were classified according to the Whitehall criteria into probable and possible IHD. RESULTS: Self-reported IHD was equally common in COPD and non-COPD, and so were probable and possible ischemic ECG changes according to Whitehall. After excluding subjects with restrictive spirometric pattern from the non-COPD-group, similar comparison with regard to presence of IHD performed between those with COPD and those with normal lung function did neither show any differences. There was a significant association between self-reported IHD (p = 0.007) as well as probable ischemic ECG-changes (p = 0.042), and increasing GOLD stage. In COPD there was a significant association between level of FEV1 percent of predicted and self-reported as well as probable ischemic ECG-changes, and this association persisted for self-reported IHD also after adjustment for sex and age. CONCLUSION: In this population-based study, self-reported IHD and probable ischemic ECG-changes were associated with COPD disease severity assessed by spirometry. PMID- 26637315 TI - Infant bone age estimation based on fibular shaft length: model development and clinical validation. AB - BACKGROUND: Bone age in infants (<1 year old) is generally estimated using hand/wrist or knee radiographs, or by counting ossification centers. The accuracy and reproducibility of these techniques are largely unknown. OBJECTIVE: To develop and validate an infant bone age estimation technique using fibular shaft length and compare it to conventional methods. MATERIALS AND METHODS: We retrospectively reviewed negative skeletal surveys of 247 term-born low-risk-of abuse infants (no persistent child protection team concerns) from July 2005 to February 2013, and randomized them into two datasets: (1) model development (n = 123) and (2) model testing (n = 124). Three pediatric radiologists measured all fibular shaft lengths. An ordinary linear regression model was fitted to dataset 1, and the model was evaluated using dataset 2. Readers also estimated infant bone ages in dataset 2 using (1) the hemiskeleton method of Sontag, (2) the hemiskeleton method of Elgenmark, (3) the hand/wrist atlas of Greulich and Pyle, and (4) the knee atlas of Pyle and Hoerr. For validation, we selected lower extremity radiographs of 114 normal infants with no suspicion of abuse. Readers measured the fibulas and also estimated bone ages using the knee atlas. Bone age estimates from the proposed method were compared to the other methods. RESULTS: The proposed method outperformed all other methods in accuracy and reproducibility. Its accuracy was similar for the testing and validating datasets, with root-mean-square error of 36 days and 37 days; mean absolute error of 28 days and 31 days; and error variability of 22 days and 20 days, respectively. CONCLUSION: This study provides strong support for an infant bone age estimation technique based on fibular shaft length as a more accurate alternative to conventional methods. PMID- 26637316 TI - Erosion or normal variant? 4-year MRI follow-up of the wrists in healthy children. AB - BACKGROUND: A large proportion of healthy children have wrist changes on MRI, namely carpal depressions, findings that have been described as pathological in children with juvenile idiopathic arthritis. OBJECTIVE: We performed follow-up imaging in a cohort of healthy children to evaluate carpal surface depressions over time, focusing on the presence of overlying cartilage as a potential discriminator between normal variants and true erosions. MATERIALS AND METHODS: 74 of the initial cohort of 89 healthy children (83%) had a re-scan of their wrists using the same protocol, including coronal T1 and fat-saturated T2 sequences. A cartilage-selective sequence was added for this study. We registered number and location of bony depressions and presence of overlying cartilage. RESULTS: The total number of carpal depressions increased by age group and over time; their location was unchanged in 370 of 487 (76%) carpal sites and 91 of 117 (78%) metacarpal sites. In total, 426 of the 1,087 (39.2%) bony depressions were covered by cartilage, with a decreasing percentage by age (P = 0.001). CONCLUSION: Normal appearances during growth, such as bony depressions, should not be mistaken for pathology. There must be additional findings to support a diagnosis of disease. A cartilage sequence may add to the diagnostic image analysis. PMID- 26637317 TI - CT cystography for evaluation of bladder perforation--be safe and know the limitations--reply to Dr. Karmazyn. PMID- 26637318 TI - Interventional embolization of congenital intrahepatic shunts in children. AB - BACKGROUND: Congenital intrahepatic shunts in children are rare and precise treatment strategies have not been established. OBJECTIVE: The purpose of this study was to present our experience with transcatheter embolization in a descriptive case series of congenital intrahepatic shunts in children. MATERIALS AND METHODS: We retrospectively studied 10 children with symptomatic congenital intrahepatic shunts who were treated with embolization at our institute between January 2008 and December 2014. RESULTS: Seven children had arteriovenous shunts in association with hepatic hemangiomas, two had arterioportal shunts and one had portosystemic shunts. The major presentations were congestive heart failure and severe anemia in the groups with arteriovenous and arterioportal shunts, respectively. Following embolization, two children died in the arteriovenous group, one from progressive liver dysfunction and the other from abdominal compartment syndrome. One child in the arterioportal group required liver transplantation after initial embolization. With mean post-procedure follow-up of 15 months (range 4-54 months), all the remaining children were well, with resolution of the symptoms. CONCLUSION: Interventional embolization provides an alternative to surgical ligation or hepatic resection in children with clinically significant intrahepatic shunts. For lesions with complex morphology, embolization may be inadequate and liver transplantation might be the only therapeutic option. PMID- 26637319 TI - Radiographic signs of non-venous placement of intended central venous catheters in children. AB - BACKGROUND: Central venous catheters (CVCs) are commonly used in children, and inadvertent arterial or extravascular cannulation is rare but has potentially serious complications. OBJECTIVE: To identify the radiographic signs of arterial placement of CVCs. MATERIALS AND METHODS: We retrospectively reviewed seven cases of arterially malpositioned CVCs on chest radiograph. These cases were identified through departmental quality-assurance mechanisms and external consultation. Comparison of arterial cases was made with 127 age-matched chest radiographs with CVCs in normal, expected venous location. On each anteroposterior (AP) radiograph we measured the distance of the catheter tip from the right lateral border of the thoracic spine, and the angle of the vertical portion of the catheter relative to the midline. On each lateral radiograph we measured the angle of the vertical portion of each catheter relative to the anterior border of the thoracic spine. When bilateral subclavian catheters were present, the catheter tips were described as crossed, overlapping or uncrossed. RESULTS: On AP radiographs, arterially placed CVCs were more curved to the left, with catheter tip positions located farther to the left of midline than normal venous CVCs. When bilateral, properly placed venous catheters were present, all catheters crossed at the level of the superior vena cava (SVC). When one of the bilateral catheters was in arterial position, neither of the catheters crossed or the inter-catheter crossover distance was exaggerated. On lateral radiographs, there was a marked anterior angulation of the vertical portion of the catheter (mean angle 37 +/- 15 degrees standard deviation [SD] in arterial catheters versus 5.9 +/- 8.3 degrees SD in normally placed venous catheters). CONCLUSION: Useful radiographic signs suggestive of unintentional arterial misplacement of vascular catheters include leftward curvature of the vertical portion of the catheter, left-side catheter tip position, lack of catheter crossover on the frontal radiograph, as well as exaggerated anterior angulation of the catheter on the lateral chest radiograph. PMID- 26637320 TI - Use of cone-beam CT and live 3-D needle guidance to facilitate percutaneous nephrostomy and nephrolithotripsy access in children and adolescents. AB - BACKGROUND: Gaining access into non-dilated renal collecting systems for percutaneous nephrolithotripsy, particularly in patients with prohibitive body habitus and/or scoliosis, is often challenging using conventional techniques. OBJECTIVE: To evaluate the feasibility of cone-beam CT for percutaneous nephrostomy placement for subsequent percutaneous nephrolithotripsy in children and adolescents. MATERIALS AND METHODS: A retrospective review of percutaneous nephrostomy revealed use of cone-beam CT and 3-D guidance in 12 percutaneous nephrostomy procedures for 9 patients between 2006 and 2015. All cone-beam CT guided percutaneous nephrostomies were for pre-lithotripsy access and all 12 were placed in non-dilated collecting systems. RESULTS: Technical success was 100%. There were no complications. CONCLUSION: Cone-beam CT with 3-D guidance is a technically feasible technique for percutaneous nephrostomy in children and adolescents, specifically for nephrolithotripsy access in non-dilated collecting systems. PMID- 26637321 TI - Gastrointestinal symptoms and association with medication use patterns, adherence, treatment satisfaction, quality of life, and resource use in osteoporosis: baseline results of the MUSIC-OS study. AB - SUMMARY: The Medication Use Patterns, Treatment Satisfaction, and Inadequate Control of Osteoporosis Study (MUSIC-OS) is a prospective, observational study of women with osteoporosis in Europe and Canada. At baseline, patients with gastrointestinal symptoms reported lower adherence to osteoporosis treatment, treatment satisfaction, and health-related quality of life, than those without gastrointestinal symptoms. INTRODUCTION: The aim of the study was to examine gastrointestinal (GI) symptoms and the association between GI symptoms and treatment adherence, treatment satisfaction, and health-related quality of life (HRQoL) among osteoporotic women in Europe and Canada. METHODS: Baseline results are reported here for a prospective study which enrolled postmenopausal, osteoporotic women who were initiating (new users) or continuing (experienced users) osteoporosis treatment at study entry (baseline). A patient survey was administered at baseline and included the occurrence of GI symptoms during 6 month pre-enrolment, treatment adherence (adherence evaluation of osteoporosis (ADEOS), score 0-22), treatment satisfaction (Osteoporosis Treatment Satisfaction Questionnaire for Medications (OPSAT-Q), score 0-100) and HRQoL (EuroQol-5 dimension (EQ-5D) utility, score 0-1; OPAQ-SV, score 0-100). The association between GI symptoms and ADEOS (experienced users), OPSAT-Q (experienced users), and HRQoL (new and experienced users) was assessed by general linear models adjusted for patient characteristics. RESULTS: A total of 2959 patients (2275 experienced and 684 new users) were included. Overall, 68.1% of patients experienced GI symptoms in the past 6 months. Compared with patients without GI symptoms, patients with GI symptoms had lower mean baseline scores on most measures. The mean adjusted differences were ADEOS, -0.43; OPSAT-Q, -5.68; EQ-5D, -0.04 (new users) and -0.06 (experienced users), all P < 0.01. GI symptoms were also associated with lower OPAQ-SV domain scores: physical function, -4.17 (experienced users); emotional status, -4.28 (new users) and -5.68 (experienced users); back pain, -5.82 (new users) and -11.33 (experienced users), all P < 0.01. CONCLUSIONS: Patients with GI symptoms have lower treatment adherence and treatment satisfaction and worse HRQoL than patients without GI symptoms. PMID- 26637322 TI - Severely exacerbated neuromyelitis optica rat model with extensive astrocytopathy by high affinity anti-aquaporin-4 monoclonal antibody. AB - INTRODUCTION: Neuromyelitis optica (NMO), an autoimmune astrocytopathic disease associated with anti-aquaporin-4 (AQP4) antibody, is characterized by extensive necrotic lesions preferentially involving the optic nerves and spinal cord. However, previous in-vivo experimental models injecting human anti-AQP4 antibodies only resulted in mild spinal cord lesions compared to NMO autopsied cases. Here, we investigated whether the formation of severe NMO-like lesions occurs in Lewis rats in the context of experimental autoimmune encephalomyelitis (EAE), intraperitoneally injecting incremental doses of purified human immunoglobulin-G from a NMO patient (hIgGNMO) or a high affinity anti-AQP4 monoclonal antibody (E5415A), recognizing extracellular domain of AQP4 made by baculovirus display method. RESULTS: NMO-like lesions were observed in the spinal cord, brainstem, and optic chiasm of EAE-rats with injection of pathogenic IgG (hIgGNMO and E5415A), but not in control EAE. Only in higher dose E5415A rats, there were acute and significantly severer clinical exacerbations (tetraparesis or moribund) compared with controls, within half day after the injection of pathogenic IgG. Loss of AQP4 was observed both in EAE rats receiving hIgGNMO and E5415A in a dose dependent manner, but the ratio of AQP4 loss in spinal sections became significantly larger in those receiving high dose E5415A up to about 50 % than those receiving low-dose E5415A or hIgGNMO less than 3 %. These lesions were also characterized by extensive loss of glial fibrillary acidic protein but relatively preserved myelin sheaths with perivascular deposition of IgG and C5b 9, which is compatible with post mortem NMO pathology. In high dose E5415A rats, massive neutrophil infiltration was observed especially at the lesion edge, and such lesions were highly vacuolated with partial demyelination and axonal damage. In contrast, such changes were absent in EAE rats receiving low-dose E5415A and hIgGNMO. CONCLUSIONS: In the present study, we established a severe experimental NMO rat model with highly clinical exacerbation and extensive tissue destructive lesions typically observed in NMO patients, which has not adequately been realized in in-vivo rodent models. Our data suggest that the pathogenic antibodies could induce immune mediated astrocytopathy with mobilized neutrophils, resulted in early lesion expansion of NMO lesion with vacuolation and other tissue damages. (350/350). PMID- 26637323 TI - Nucleophilic Aromatic Substitution Between Halogenated Benzene Dopants and Nucleophiles in Atmospheric Pressure Photoionization. AB - In a preceding work with dopant assisted-atmospheric pressure photoionization (DA APPI), an abundant ion at [M + 77](+) was observed in the spectra of pyridine and quinoline with chlorobenzene dopant. This contribution aims to reveal the identity and route of formation of this species, and to systematically investigate structurally related analytes and dopants. Compounds containing N-, O , and S-lone pairs were investigated with APPI in the presence of fluoro-, chloro , bromo-, and iodobenzene dopants. Computational calculations on a density functional theory (DFT) level were carried out to study the reaction mechanism for pyridine and the different halobenzenes. The experimental and computational results indicated that the [M + 77](+) ion was formed by nucleophilic aromatic ipso-substitution between the halobenzene radical cation and nucleophilic analytes. The reaction was most efficient for N-heteroaromatic compounds, and it was weakened by sterical effects and enhanced by resonance stabilization. The reaction was most efficient with chloro-, bromo-, and iodobenzenes, whereas with fluorobenzene the reaction was scarcely observed. The calculated Gibbs free energies for the reaction between pyridine and the halobenzenes were shown to increase in the order I < Br < Cl < F. The reaction was found endergonic for fluorobenzene due to the strong C-F bonding, and exergonic for the other halobenzenes. For fluoro- and chlorobenzenes the reaction was shown to proceed through an intermediate state corresponding to [M + dopant](+), which was highly stable for fluorobenzene. For the bulkier bromine and iodine, this intermediate did not exist, but the halogens were shown to detach already during the approach by the nucleophile. PMID- 26637324 TI - [Cardiovascular risk patients under androgen deprivation therapy: Lower risk with GnRH antagonists compared to LHRH agonists?]. AB - BACKGROUND: Androgen deprivation therapy (ADT) with gonadotropin-releasing hormone (GnRH) agonists or GnRH antagonists is the mainstay of treatment for metastatic prostate cancer (mCaP). However, ADT is associated with serious cardiovascular events. Only a few studies that directly compare the cardiovascular risk of LHRH agonists versus GnRH antagonists have been published. OBJECTIVES: This review aims to compare the cardiovascular risk of LHRH agonists versus GnRH antagonists based on the literature. METHODS: A literature search that considered full publications and abstracts published before December 10, 2014 was performed. Due to their high evidence quality, only meta-analyses and pooled studies were included in this review. RESULTS: Four studies were included. These investigated the cardiovascular risk of patients receiving an ADT with LHRH agonists and/or GnRH antagonists. However, only one of these directly compared the cardiovascular risk of ADT with LHRH agonists versus GnRH antagonists. This meta-analysis showed a significant reduction in cardiovascular risk for patients receiving a GnRH antagonist compared to those patients receiving a LHRH agonist (HR: 0.597; 95 % CI: 0.380-0.938; P = 0.0253). Subgroup analyses showed that, in particular, patients with pre-existing cardiovascular diseases who were treated with a GnRH antagonist have a significantly lower risk of experiencing a cardiovascular event when compared with patients receiving a GnRH agonist (HR: 0.44; 95 % CI: 0.26-0.74; P = 0.002). CONCLUSION: In conclusion, GnRH antagonists are associated with a lower risk of cardiovascular events, compared with LHRH agonists, when administered as ADT in CaP patients, and particularly in patients with a history of cardiovascular disease. Thus, patients with a history of cardiovascular disease may benefit from ADT with a GnRH antagonist. PMID- 26637326 TI - ENC1 Modulates the Aggregation and Neurotoxicity of Mutant Huntingtin Through p62 Under ER Stress. AB - Huntington's disease (HD) is a devastating neurodegenerative disorder, which is caused by the expression and aggregation of polyQ-expanded mutant huntingtin protein (mtHTT). While toxic mtHTT aggregates are primarily eliminated through autophagy, autophagy dysfunction is often observed in HD pathogenesis. Here, we show that ectodermal-neural cortex 1 (ENC1), a novel binding partner of sequestosome 1 (p62), negatively regulates autophagy under endoplasmic reticulum (ER) stress. We found that ER stress significantly increases the expression of ENC1 via inositol-requiring enzyme 1 (IRE1)-TNF receptor-associated factor 2 (TRAF2)-c-Jun N-terminal kinase (JNK) pathway. Ectopic expression of ENC1 alone induces the accumulation of detergent-resistant mtHTT aggregates and downregulation of ENC1 alleviates ER stress-induced mtHTT aggregation. Simultaneously, ER stress-induced impairment of autophagy flux is ameliorated by downregulation of ENC1. From immunoprecipitation and immunocytochemical assays, we found that ENC1 binds to p62 through its BTB and C-terminal Kelch (BACK) domain and this interaction is enhanced under ER stress. In particular, ENC1 preferentially interacts with the phosphorylated p62 at Ser403 during ER stress. Interestingly, ENC1 colocalizes with mtHTT aggregates and its C-terminal Kelch domain is required for interfering with the access of p62 to ubiquitinated mtHTT aggregates, thus inhibiting cargo recognition of p62. Accordingly, knockdown of ENC1 expression enhances colocalization of p62 with mtHTT aggregates. Consequently, ENC1 knockdown relieves death of neuronal cells expressing mtHTT under ER stress. These results suggest that ENC1 interacts with the phosphorylated p62 to impair autophagic degradation of mtHTT aggregates and affects cargo recognition failure under ER stress, leading to the accumulation and neurotoxicity of mtHTT aggregates. PMID- 26637327 TI - The Role of Acetylcholine in the Inflammatory Response in Animals Surviving Sepsis Induced by Cecal Ligation and Puncture. AB - The cholinergic anti-inflammatory pathway controls the inflammatory response and nonreflexive consciousness through bidirectional communication between the brain and immune system. Moreover, brain acetylcholinesterase activity may have a role in regulating the vagus nerve in this pathway. Thus, we analyzed the role of acetylcholine (ACh) in the inflammatory response 15 days after induction of sepsis by cecal ligation and puncture (CLP). Balb/c mice were pretreated with or without donepezil (5 mg/kg/day, orally) 7 days before CLP, and mice homozygous for vesicular ACh transporter (VAChT) knockdown (KD) were subjected to CLP. All animals were sacrificed 15 days after CLP, and the plasma, spleen, and hippocampus were collected. Characterization of splenic lymphocytes and cytokine levels in the plasma, spleen, and hippocampus was determined. Our results showed a splenomegaly in group CLP. The numbers of cytotoxic T cells, helper T cells, regulatory T cells, B cells, and Th17 cells differed between mice subjected to CLP and to sham operation in both untreated and donepezil-treated groups. In VAChT-KD mice, CLP resulted in decreased cytotoxic and helper T cells and increased in Th17 cells compared with the sham. Additionally, in VAChT-KD mice, the levels of pro-inflammatory cytokines, such as IL-1beta, IL-6, and TNF-alpha, were increased following CLP. Thus, we concluded that ACh affected the inflammatory response at 15 days after CLP since stimulation of cholinergic transmission increased the proliferation of lymphocytes, including regulatory T cells, in association with a lower inflammatory profile and VAChT-KD decreased the number of lymphocytes and increased inflammation. PMID- 26637325 TI - Convergent Lines of Evidence Support LRP8 as a Susceptibility Gene for Psychosis. AB - Reelin (RELN) is identified as a risk gene for major psychiatric disorders such as schizophrenia (SCZ) and bipolar disorder (BPD). However, the role of its downstream signaling molecule, the low-density lipoprotein receptor-related protein 8 (LRP8) in these illnesses is still unclear. To detect whether LRP8 is a susceptibility gene for SCZ and BPD, we analyzed the associations of single nucleotide polymorphisms (SNPs) in LRP8 in a total of 47,187 subjects (including 9379 SCZ patients; 6990 BPD patients; and 12,556 controls in a screening sample, and 1397 SCZ families, 3947 BPD patients, and 8387 controls in independent replications), and identified a non-synonymous SNP rs5174 in LRP8 significantly associated with SCZ and BPD as well as the combined psychosis phenotype (P meta = 1.99 * 10-5, odds ratio (OR) = 1.066, 95 % confidence interval (CI) = 1.035 1.098). The risk SNP rs5174 was also associated with LRP8 messenger RNA (mRNA) expression in multiple brain tissues across independent samples (lowest P = 0.00005). Further exploratory analysis revealed that LRP8 was preferentially expressed in fetal brain tissues. Protein-protein interaction (PPI) analysis demonstrated that LRP8 significantly participated in a highly interconnected PPI network build by top risk genes for SCZ and BPD (P = 7.0 * 10-4). Collectively, we confirmed that LRP8 is a risk gene for psychosis, and our results provide useful information toward a better understanding of genetic mechanism involving LRP8 underlying risk of complex psychiatric disorders. PMID- 26637328 TI - LDOC1 inhibits proliferation and promotes apoptosis by repressing NF-kappaB activation in papillary thyroid carcinoma. AB - BACKGROUND: The incidence of thyroid cancer has progressively increased over the past few decades, and the most frequent types of this cancer are papillary thyroid carcinoma (PTC) and small primary tumors. In PTC, oncogene activation is known to occur at a high frequency. However, the potential roles of tumor suppressor genes in thyroid carcinogenesis remain unclear. LDOC1 was first identified as a gene encoding a leucine zipper protein whose expression was decreased in a series of pancreatic and gastric cancer cell lines. In this study, we aimed to determine the status of LDOC1 in PTC and identify its mechanistic role in PTC pathogenesis. METHODS: LDOC1 expression was evaluated in fresh samples and stored specimens of human PTC and contralateral normal tissues by performing quantitative reverse transcription-PCR and immunohistochemical staining. The correlation to nuclear p65 content in the stored specimens was analyzed. Moreover, the basal level of LDOC1 in two human PTC-derived cell lines (BCPAP and TPC-1) compared with normal thyroid tissue was determined. Human LDOC1 cDNA was inserted into a lentiviral vector and transduced into TPC-1 cells. TPC-1 cells overexpressing LDOC1/GFP (Lv-LDOC1) or negative control GFP (Lv-NC) were stimulated with TNFalpha or recombinant TGF-beta1, and then cell proliferation, cell cycle distribution, and apoptosis were assessed. Western blotting was used to examine the expression of p65, IkappaBalpha, c-Myc, Bax, and Bcl-xL, and a luciferase reporter assay was used to measure NF-kappaB activity stimulated by TNFalpha. Statistical significance was determined using Student's t tests or ANOVA and Newman-Keuls multiple comparison tests. Pearson chi-square test was used to analyze possible associations. RESULTS: LDOC1 expression was significantly downregulated in PTC specimens as compared with the expression in normal thyroid tissues, and this downregulation was associated with an increase in tumor size (P < 0.05). There is a correlation between LDOC1 and nuclear P65 expression in human PTC tissues (P < 0.01). Lentivirus-mediated restoration of LDOC1 expression in TPC-1 cells characterized by low level of LDOC1 expression suppressed proliferation and induced apoptosis by inhibiting NF-kappaB activation, and LDOC1-overexpressing TPC-1 cells recovered responsiveness to TGF beta1 antiproliferative signaling. CONCLUSIONS: LDOC1 might function as a tumor suppressor gene in PTC by inhibiting NF-kappaBeta signaling, and thus might represent a promising therapeutic target in patients with PTC. PMID- 26637329 TI - Radiologic assessment of third molar tooth and spheno-occipital synchondrosis for age estimation: a multiple regression analysis study. AB - For forensic age estimation, radiographic assessment of third molar mineralization is important between 14 and 21 years which coincides with the legal age in most countries. The spheno-occipital synchondrosis (SOS) is an important growth site during development, and its use for age estimation is beneficial when combined with other markers. In this study, we aimed to develop a regression model to estimate and narrow the age range based on the radiologic assessment of third molar and SOS in a Turkish subpopulation. Panoramic radiographs and cone beam CT scans of 349 subjects (182 males, 167 females) with age between 8 and 25 were evaluated. Four-stage system was used to evaluate the fusion degree of SOS, and Demirjian's eight stages of development for calcification for third molars. The Pearson correlation indicated a strong positive relationship between age and third molar calcification for both sexes (r = 0.850 for females, r = 0.839 for males, P < 0.001) and also between age and SOS fusion for females (r = 0.814), but a moderate relationship was found for males (r = 0.599), P < 0.001). Based on the results obtained, an age determination formula using these scores was established. PMID- 26637331 TI - Severe gastritis decreases success rate of Helicobacter pylori eradication. AB - BACKGROUND: In several studies, different risk factors other than antibiotic resistance have been documented with Helicobacter pylori eradication failure. We aimed in this study to investigate the relationship of gastric density of H. pylori, the occurrence/degree of gastric atrophy, and intestinal metaplasia (IM) with success rate of H. pylori eradication. METHODS: Two hundred consecutive treatment naive patients who received bismuth containing standart quadruple treatment due to H. pylori infection documented by histopathological examination of two antral or two corpal biopsies entered this retrospective study. The updated Sydney system was used to grade the activity of gastritis, density of H. pylori colonization, atrophy, and IM. Stages III and IV of operative link for gastritis assessment (OLGA) or the operative link on gastric intestinal metaplasia assessment (OLGIM) stages was considered as severe gastritis. H. pylori eradication was determined via stool H. pylori antigen test performed 4 weeks after the end of therapy. RESULTS: The presence of gastric atrophy and IM was significantly higher in patients with eradication failure (p = 0.001 and 0.01, respectively). Severe gastritis (OLGA III-IV and OLGIM III-IV) rates were higher in eradication failure group. A multiple linear regression analysis showed that OLGA and OLGIM stages were to be independent risk factors for eradication failure (p = 0.03 and 0.01, respectively). CONCLUSION: Our results suggested that histopathologically severe gastritis may cause H. pylori eradication failure. In addition, we found that H. pylori density was not a risk factor for treatment failure in patients who receive quadruple treatment. PMID- 26637330 TI - Lupus erythematosus revisited. AB - Lupus erythematosus (LE) is a multifactorial autoimmune disease with clinical manifestations of differing severity. The exact pathomechanisms and interactions resulting in the inflammatory and immunological processes of this heterogeneous disease remain elusive. Approaches in the understanding of the pathomechanisms revealed that the clinical expression of LE is predisposed by susceptibility genes and that various environmental factors are responsible for an abnormal immune response. Several studies demonstrated that ultraviolet (UV) light is one of the major factors in the pathogenesis of the disease. Standardized photoprovocation in patients with LE has been shown to be a safe and efficient model for evaluating the underlying pathomechanisms which lead to the production of autoantibodies and immune complexes. In particular, interferons were defined as important players in the early activation of the immune system and were observed to play a specific role in the immunological interface between the innate and the adaptive immune system. Abnormalities or disturbances in the different processes of cell death, such as apoptosis or necrosis, have also been recognized as crucial in the pathogenesis of LE. Although each process is different and characterized by unique features, the processes are interrelated and result in a complex disease. PMID- 26637333 TI - Protocol for a systematic review of psychological interventions for cancer related fatigue in post-treatment cancer survivors. AB - BACKGROUND: Fatigue is a common symptom in cancer patients that can persist beyond the curative treatment phase. Some evidence has been reported for interventions for fatigue during active treatment. However, to date, there is no systematic review on psychological interventions for fatigue after the completion of curative treatment for cancer. This is a protocol for a systematic review that aims to evaluate the effectiveness of psychological interventions for cancer related fatigue in post-treatment cancer survivors. This systematic review protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO) database. METHODS/DESIGN: We will search the Cochrane Central Register of Controlled Trials (CENTRAL; The Cochrane Library), PubMed, MEDLINE, EMBASE, CINAHL, PsycINFO, and relevant sources of grey literature. Randomised controlled trials (RCTs) which have evaluated psychological interventions in adult cancer patients after the completion of treatment, with fatigue as an outcome measure, will be included. Two review authors will independently extract data from the selected studies and assess the methodological quality using the Cochrane Collaboration Risk of Bias Tool. DISCUSSION: Most existing evidence on cancer-related fatigue is from those in active cancer treatment. This systematic review and meta-analysis will build upon previous evaluations of psychological interventions in people during and after cancer treatment. With the growing need for stage-specific research in cancer, this review seeks to highlight a gap in current practice and to strengthen the evidence base of randomised controlled trials in the area. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42014015219. PMID- 26637332 TI - NF-kappaB transcriptional activation by TNFalpha requires phospholipase C, extracellular signal-regulated kinase 2 and poly(ADP-ribose) polymerase-1. AB - BACKGROUND: The nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP-1) is required for pro-inflammatory effects of TNFalpha. Our previous studies demonstrated that PARP-1 mediates TNFalpha-induced NF-kappaB activation in glia. Here, we evaluated the mechanisms by which TNFalpha activates PARP-1 and PARP-1 mediates NF-kappaB activation. METHODS: Primary cultures of mouse cortical astrocytes and microglia were treated with TNFalpha and suitable signaling pathway modulators (pharmacological and molecular). Outcome measures included calcium imaging, PARP 1 activation status, NF-kappaB transcriptional activity, DNA damage assesment and cytokine relesease profiling. RESULTS: TNFalpha induces PARP-1 activation in the absence of detectable DNA strand breaks, as measured by the PANT assay. TNFalpha induced transcriptional activation of NF-kappaB requires PARP-1 enzymatic activity. Enzymatic activation of PARP-1 by TNFalpha was blocked in Ca(2+)-free medium, by Ca(2+) chelation with BAPTA-AM, and by D609, an inhibitor of phoshatidyl choline-specific phospholipase C (PC-PLC), but not by thapsigargin or by U73112, an inhibitor of phosphatidyl inisitol-specific PLC (PI -PLC). A TNFR1 blocking antibody reduced Ca(2+) influx and PARP-1 activation. TNFalpha-induced PARP-1 activation was also blocked by siRNA downregulation of ERK2 and by PD98059, an inhibitor of the MEK / ERK protein kinase cascade. Moreover, TNFalpha induced NF-kappaB (p65) transcriptional activation was absent in cells expressing PARP-1 that lacked ERK2 phosphorylation sites, while basal NF-kappaB transcriptional activation increased in cells expressing PARP-1 with a phosphomimetic substitution at an ERK2 phophorylation site. CONCLUSIONS: These results suggest that TNFalpha induces PARP-1 activation through a signaling pathway involving TNFR1, Ca(2+) influx, activation of PC-PLC, and activation of the MEK1 / ERK2 protein kinase cascade. TNFalpha-induced PARP-1 activation is not associated with DNA damage, but ERK2 mediated phosphorylation of PARP-1. PMID- 26637335 TI - The effectiveness of interventions to improve laboratory requesting patterns among primary care physicians: a systematic review. AB - BACKGROUND: Laboratory testing is an integral part of day-to-day primary care practice, with approximately 30 % of patient encounters resulting in a request. However, research suggests that a large proportion of requests does not benefit patient care and is avoidable. The aim of this systematic review was to comprehensively search the literature for studies evaluating the effectiveness of interventions to improve primary care physician use of laboratory tests. METHODS: A search of PubMed, Cochrane Library, Embase and Scopus (from inception to 09/02/14) was conducted. The following study designs were considered: systematic reviews, randomised controlled trials (RCTs), controlled clinical trials (CCTs), controlled before and after studies (CBAs) and interrupted time series analysis (ITSs). Studies were quality appraised using a modified version of the Effective Practice and Organisation of Care (EPOC) checklist. The population of interest was primary care physicians. Interventions were considered if they aimed to improve laboratory testing in primary care. The outcome of interest was a volume of laboratory tests. RESULTS: In total, 6,166 titles and abstracts were reviewed, followed by 87 full texts. Of these, 11 papers were eligible for inclusion in the systematic review. This included four RCTs, six CBAs and one ITS study. The types of interventions examined included education, feedback, guidelines, education with feedback, feedback with guidelines and changing order forms. The quality of included studies varied with seven studies deemed to have a low risk of bias, three with unclear risk of bias and one with high risk of bias. All but one study found significant reductions in the volume of tests following the intervention, with effect sizes ranging from 1.2 to 60 %. Due to heterogeneity, meta-analysis was not performed. CONCLUSIONS: Interventions such as educational strategies, feedback and changing test order forms may improve the efficient use of laboratory tests in primary care; however, the level of evidence is quite low and the quality is poor. The reproducibility of findings from different laboratories is also difficult to ascertain from the literature. Some standardisation of both interventions and outcome measures is required to enable formal meta-analysis. PMID- 26637334 TI - Longitudinal follow-up study on fear of falling during and after rehabilitation in skilled nursing facilities. AB - BACKGROUND: Fear of falling (FoF) is regarded as a major constraint for successful rehabilitation in older people. However, few studies have investigated FoF in vulnerable older people who rehabilitate in a skilled nursing facility (SNF). Therefore, this study measures the prevalence of FoF during and after rehabilitation and assesses differences between those with and without FoF. The relation between FoF and instrumental activities of daily living (IADL) after discharge was also assessed. METHODS: In this longitudinal follow-up study, patients who rehabilitated in a SNF were assessed at admission and at 4 weeks after discharge. A one-item instrument was used to measure FoF at admission; based on their answer, the patients were divided into groups with no FoF and with FoF. To study FoF after discharge, the one-item instrument and the short Falls Efficacy Scale-International (FES-I) were used. IADL after discharge was assessed with the Frenchay Activities Index (FAI). RESULTS: Of all participants, 62.5 % had FoF at admission. The participants with FoF were older, more often female, and had a higher average number of falls per week, more depressive symptoms and a lower level of self-efficacy. Four weeks after discharge, 82.1 % of the participants had FoF. IADL after discharge was considerably lower in patients with FoF (FAI of 27.3 vs. 34.8; p = 0.001). CONCLUSIONS: FoF is common among older persons who rehabilitate in SNF. FoF seems to be persistent and may even increase after rehabilitation, thereby hampering IADL after discharge. Interventions are needed to reduce FoF to ensure better outcomes in older patients rehabilitating in a SNF. PMID- 26637336 TI - Epidemiological study and variation analysis of the porcine kobuvirus 3D gene in Sichuan province, China. PMID- 26637337 TI - Rotating turbulence under "precession-like" perturbation. AB - The effects of changing the orientation of the rotation axis on homogeneous turbulence is considered. We perform direct numerical simulations on a periodic box of 1024(3) grid points, where the orientation of the rotation axis is changed (a) at a fixed time instant (b) regularly at time intervals commensurate with the rotation time scale. The former is characterized by a dominant inverse energy cascade whereas in the latter, the inverse cascade is stymied due to the recurrent changes in the rotation axis resulting in a strong forward energy transfer and large-scale structures that resemble those of isotropic turbulence. PMID- 26637338 TI - Overwriting and intrusion in short-term memory. AB - Studies of interference in working and short-term memory suggest that irrelevant information may overwrite the contents of memory or intrude into memory. While some previous studies have reported greater interference when irrelevant information is similar to the contents of memory than when it is dissimilar, other studies have reported greater interference for dissimilar distractors than for similar distractors. In the present study, we find the latter effect in a paradigm that uses auditory tones as stimuli. We suggest that the effects of distractor similarity to memory contents are mediated by the type of information held in memory, particularly the complexity or simplicity of information. PMID- 26637339 TI - Lexical factors in conceptual processes: The relationship between semantic representations and their corresponding phonological and orthographic lexical forms. AB - To examine phonological and orthographic effects on semantic processing, the present study utilized a semantic task with nonverbal stimuli. In Experiment 1, Hebrew speakers were asked to decide whether 2 pictorial targets are semantically related or not. In Experiment 2, Hebrew speakers and non-Hebrew speakers were asked to rate the semantic relatedness of the same targets on a 5-point scale. Experiment 3 was identical to the first experiment except that the 2 pictures were presented simultaneously rather than sequentially. In all experiments, we compared responses to semantically unrelated pairs in 2 conditions: In the ambiguous condition, each pair represented 2 distinct meanings of an ambiguous Hebrew word. In the unambiguous condition, the first picture was replaced with an unambiguous control. To disentangle phonological and orthographic effects, three types of Hebrew ambiguous words were used: homonyms, homophones, and homographs. Ambiguous pairs were more difficult to be judged as semantically unrelated in comparison to their unambiguous controls. Moreover, while non-Hebrew speakers did not distinguish between the 2 lexical conditions, Hebrew speakers rated ambiguous pairs as significantly more related than their unambiguous controls. Importantly, in general, the ambiguity effect was stronger for homonyms, where both lexical forms are shared, than for either homophones or homographs, which are only phonologically or orthographically related. Thus, consistent with interactive "triangle" models, the results suggest that (a) conceptual-semantic representations automatically activate both their corresponding phonological and orthographic lexical forms, and (b) these lexical forms, once activated, may in turn affect semantic-conceptual processes via feedback connections. PMID- 26637340 TI - FitForLife: study protocol for a randomized controlled trial. AB - BACKGROUND: Psychosis is a serious mental illness that typically emerges during early adulthood. The disorder is characterized by inactivity, cognitive deficits and the need for ongoing support. Regular exercise has mood enhancing and anxiolytic effects that could benefit this patient group. To date, few studies have examined the effects of prescribed exercise on autonomy, health and cognitive functioning in psychosis. METHODS/DESIGN: This is a single-center, randomized controlled trial (RCT) with a 3-month follow-up. Usual care plus a 12 week supervised exercise program will be compared to usual outpatient care alone. The primary outcome will be patient autonomy measured by the Camberwell Assessment of Need (CAN) schedule - clinician rated. Secondary outcomes include cardiovascular risk factors, cognitive functioning, substance abuse, body awareness, depression and mood state. Changes in inflammatory markers and microbiotica will be explored. The feasibility of using patients as exercise trainers will also be assessed. DISCUSSION: The treatment potential for exercise in psychosis is large because most individuals with the disorder are young and inactive. The study is one of the first to comprehensively assess the effects of regular exercise in young adults with psychosis. Sessions will be closely supervised and adjusted to meet patient needs. Both the feasibility and treatment effects of exercise interventions in psychosis will be discussed. TRIAL REGISTRATION: German Clinical Trials Register DRKS00008991 7 August 2015. PMID- 26637341 TI - Cancer drugs can be four times more costly in some wealthy countries than in others. PMID- 26637342 TI - Comparison of food and nutrient intakes between cohorts of the HAPIEE and Whitehall II studies. AB - BACKGROUND: Differences in dietary habits have been suggested as an important reason for the large health gap between Eastern and Western European populations. Few studies have compared individual-level nutritional data directly between the two regions. This study addresses this hypothesis by comparing food, drink and nutrient intakes in four large population samples. METHODS: Czech, Polish and Russian participants of the Health, Alcohol and Psychosocial Factors in Eastern Europe (HAPIEE) study, and British participants in the Whitehall II study, altogether 29 972 individuals aged 45-73 years, were surveyed in 2002-2005. Dietary data were collected by customised food frequency questionnaires. Reported food, drink and nutrient intake data were harmonised and compared between cohorts using multivariable adjusted quantile regression models. RESULTS: Median fruit and vegetable intakes were lower in the pooled Eastern European sample, but not in all country cohorts, compared with British subjects. Median daily consumption of fruits were 275, 213, 130 and 256 g in the Czech, Polish, Russian and Whitehall II cohort, respectively. The respective median daily intakes of vegetables were 185, 197, 292 and 246 g. Median intakes of animal fat foods and saturated fat, total fat and cholesterol nutrients were significantly higher in the Czech, Polish and Russian cohorts compared with the British; for example, median daily intakes of saturated fatty acids were 31.3, 32.5, 29.2 and 25.4 g, respectively. CONCLUSION: Our findings suggest that there are important differences in dietary habits between and within Eastern and Western European populations which may have contributed to the health gap between the two regions. PMID- 26637343 TI - Reflections on Native Ethnography by a Nurse Researcher. AB - There are benefits and challenges associated with conducting research in a familiar setting, especially when the researcher is more an insider than an outsider. The aim of this article is to explore the author's experience as a native scholar conducting ethnographic research among the Swahili peoples of Lamu, Kenya. This article focuses on methodological issues related to conducting ethnographic research among the author's own people, including examining the issues of anthropological reflexivity as a native ethnographer and highlighting the author's experiences embodying multiple identities. Native ethnographers must consider the challenges associated with negotiating multiple roles in the research setting, especially in the presence of sociocultural factors such as gender stratification, complex kinship networks, socioeconomic hierarchies, illiteracy, and poverty. Embracing rather than being confused by the multiple levels of understanding native researchers bring to studies of their communities opens up new avenues of research and possibilities. PMID- 26637344 TI - Effects of acceptance of disability on death or dialysis in chronic kidney disease patients: a 3-year prospective cohort study. AB - BACKGROUND: Acceptance of disability (AOD) is a useful construct that assesses the ability of a patient to psychologically cope with chronic diseases, but its effect on long-term outcomes of patients with chronic kidney disease (CKD) remains unclear. This study aimed to evaluate the relation between AOD level and clinical outcomes in a cohort of CKD patients in Taiwan. METHODS: 262 CKD patients without dialysis at a hospital in Taiwan were consecutively recruited, from 2010 to 2011, and followed up for 3 years. At enrollment, demographic and clinical data were obtained, including baseline level measurement of AOD, using the Acceptance of Disability Scale-Revised (AODS-R). During follow-up, the authors assessed the effect of AOD on progression to dialysis and all-cause mortality by using Cox proportional hazard regression analysis. RESULTS: Of the patients included in the analyses, 145 (55.3 %) whose total scores of AOD were below the median (86.00) were regarded as having low AOD at enrollment. At the end of 3-year follow-up, 25 have died and 57 initiated dialysis. Participants with low AOD were more likely to have the composite end-point of progression to dialysis or death (adjusted hazard ratios [AHR] = 1.89, 95 % confidence interval [CI]: 1.18-3.20). In addition, CKD stage at IV or above and hemoglobin level were found to be associated with the occurrence of the composite end-point. CONCLUSION: AOD was associated with an increased risk for poor clinical outcomes, thus suggesting that prompt awareness and management of the psychological reactions may improve clinical outcomes of patients with CKD. PMID- 26637345 TI - A Rare Cause of Lower Extremity Ulcers: Prolidase Deficiency. AB - Prolidase deficiency is an autosomal recessive disorder, which is associated with chronic skin ulcers, a characteristic facial appearance, mental retardation, and recurrent infections. This study describes 4 patients with recurrent leg ulcerations and abnormal facies who were first clinically suspected of prolidase deficiency and then biochemically confirmed. Two siblings and 2 other patients were admitted to our clinic at different times, and they had some common features such as chronic leg and foot ulcers recalcitrant to treatment, consanguineous parents, facial dysmorphism, mental retardation, and widespread telangiectasias. Physical examination and detection of low prolidase level in blood finally led us to the diagnose of ulcers secondary to prolidase deficiency. Prolidase deficiency is a rare genodermatosis and must be considered in the differential diagnosis of recurrent leg and foot ulcers that develop at an early age. PMID- 26637346 TI - ICRP Publication 131: Stem Cell Biology with Respect to Carcinogenesis Aspects of Radiological Protection. AB - This report provides a review of stem cells/progenitor cells and their responses to ionising radiation in relation to issues relevant to stochastic effects of radiation that form a major part of the International Commission on Radiological Protection's system of radiological protection. Current information on stem cell characteristics, maintenance and renewal, evolution with age, location in stem cell 'niches', and radiosensitivity to acute and protracted exposures is presented in a series of substantial reviews as annexes concerning haematopoietic tissue, mammary gland, thyroid, digestive tract, lung, skin, and bone. This foundation of knowledge of stem cells is used in the main text of the report to provide a biological insight into issues such as the linear-no-threshold (LNT) model, cancer risk among tissues, dose-rate effects, and changes in the risk of radiation carcinogenesis by age at exposure and attained age. Knowledge of the biology and associated radiation biology of stem cells and progenitor cells is more developed in tissues that renew fairly rapidly, such as haematopoietic tissue, intestinal mucosa, and epidermis, although all the tissues considered here possess stem cell populations. Important features of stem cell maintenance, renewal, and response are the microenvironmental signals operating in the niche residence, for which a well-defined spatial location has been identified in some tissues. The identity of the target cell for carcinogenesis continues to point to the more primitive stem cell population that is mostly quiescent, and hence able to accumulate the protracted sequence of mutations necessary to result in malignancy. In addition, there is some potential for daughter progenitor cells to be target cells in particular cases, such as in haematopoietic tissue and in skin. Several biological processes could contribute to protecting stem cells from mutation accumulation: (a) accurate DNA repair; (b) rapidly induced death of injured stem cells; (c) retention of the DNA parental template strand during divisions in some tissue systems, so that mutations are passed to the daughter differentiating cells and not retained in the parental cell; and (d) stem cell competition, whereby undamaged stem cells outcompete damaged stem cells for residence in the niche. DNA repair mainly occurs within a few days of irradiation, while stem cell competition requires weeks or many months depending on the tissue type. The aforementioned processes may contribute to the differences in carcinogenic radiation risk values between tissues, and may help to explain why a rapidly replicating tissue such as small intestine is less prone to such risk. The processes also provide a mechanistic insight relevant to the LNT model, and the relative and absolute risk models. The radiobiological knowledge also provides a scientific insight into discussions of the dose and dose-rate effectiveness factor currently used in radiological protection guidelines. In addition, the biological information contributes potential reasons for the age-dependent sensitivity to radiation carcinogenesis, including the effects of in-utero exposure. PMID- 26637347 TI - Airway reactivity and sphingolipids-implications for childhood asthma. AB - Asthma is a clinically heterogeneous disorder, whose onset and progression results from a complex interplay between genetic susceptibility, allergens, and viral triggers. Sphingolipids and altered sphingolipid metabolism have emerged as potential key contributors to the pathogenesis of asthma. Orosomucoid-like 3 gene (ORMDL3) and the asthma susceptibility locus 17q21 have been strongly and reproducibly linked to childhood asthma, but how this gene is functionally linked to asthma is incompletely understood. ORMDL proteins play an integral role in sphingolipid homeostasis and synthesis, and asthma-associated ORMDL3 polymorphisms have been associated with early viral respiratory infections and increased risk of asthma. ORMDL proteins act as inhibitors of serine palmitoyl CoA transferase (SPT), the rate-limiting enzyme for de novo sphingolipid synthesis, and decreased sphingolipid synthesis through SPT increases airway hyperreactivity, which is independent of allergy or inflammation. In allergic models of asthma, the sphingolipid mediators sphingosine-1-phosphate (S1P) and ceramide have been shown to be important signaling molecules for airway hyperreactivity, mast cell activation, and inflammation. This review will highlight how sphingolipids and altered sphingolipid metabolism may contribute towards the underlying mechanisms of childhood asthma. PMID- 26637349 TI - Flagship L800m contract collapses after just eight months. PMID- 26637350 TI - Another MSF clinic is bombed in Yemen. PMID- 26637348 TI - An association between liraglutide treatment and reduction in excessive daytime sleepiness in obese subjects with type 2 diabetes. AB - BACKGROUND: The main purpose of the present study is to evaluate whether treatment with long-acting human glucagon-like peptide-1 liraglutide was associated with an improvement of excessive daytime sleepiness (EDS) in obese subjects with type-2 diabetes. METHODS: This single-centre retrospective study included 158 obese (body mass index [BMI] >= 30 kg/m(2)) adult subjects with type 2 diabetes who were initiated with liraglutide treatment at least 3 months before study inclusion. Data of the Epworth Sleepiness Scale (ESS), anthropometric parameters, glucose-control and metabolic parameters were collected at liraglutide initiation (baseline) and at months 1 and 3 after liraglutide initiation. RESULTS: Significant reductions in ESS score were achieved at months 1 (-1.3 +/- 2.8, p < 0.001) and 3 (-1.5 +/- 3.0, p < 0.001) after liraglutide introduction. After 3 months of treatment with liraglutide, significant changes in body weight (p < 0.001), BMI (p < 0.001), waist (p < 0.001) and neck circumferences (p < 0.005), HbA1c (p < 0.001), mean blood glucose (p < 0.001), fasting plasma glucose (p < 0.001), triglycerides (p < 0.01) and total cholesterol (p < 0.001) were achieved. CONCLUSIONS: After 3 months of treatment with liraglutide a significant reduction in EDS was observed in obese subjects with type-2 diabetes. Besides this, significant changes in body weight and metabolic parameters of diabetes control were also accomplished. Further investigation is required to determine whether liraglutide could improve other abnormal sleep patterns and obstructive sleep apnoea. PMID- 26637351 TI - Transferrin Receptor 1 Facilitates Poliovirus Permeation of Mouse Brain Capillary Endothelial Cells. AB - As a possible route for invasion of the CNS, circulating poliovirus (PV) in the blood is believed to traverse the blood-brain barrier (BBB), resulting in paralytic poliomyelitis. However, the underlying mechanism is poorly understood. In this study, we demonstrated that mouse transferrin receptor 1 (mTfR1) is responsible for PV attachment to the cell surface, allowing invasion into the CNS via the BBB. PV interacts with the apical domain of mTfR1 on mouse brain capillary endothelial cells (MBEC4) in a dose-dependent manner via its capsid protein (VP1). We found that F-G, G-H, and H-I loops in VP1 are important for this binding. However, C-D, D-E, and E-F loops in VP1-fused Venus proteins efficiently penetrate MBEC4 cells. These results imply that the VP1 functional domain responsible for cell attachment is different from that involved in viral permeation of the brain capillary endothelium. We observed that co-treatment of MBEC4 cells with excess PV particles but not dextran resulted in blockage of transferrin transport into cells. Using the Transwell in vitro BBB model, transferrin co-treatment inhibited permeation of PV into MBEC4 cells and delayed further viral permeation via mTfR1 knockdown. With mTfR1 as a positive mediator of PV-host cell attachment and PV permeation of MBEC4 cells, our results indicate a novel role of TfR1 as a cellular receptor for human PV receptor/CD155 independent PV invasion of the CNS. PMID- 26637352 TI - Evidence for Dual Binding Sites for 1,1,1-Trichloro-2,2-bis(p-chlorophenyl)ethane (DDT) in Insect Sodium Channels. AB - 1,1,1-Trichloro-2,2-bis(p-chlorophenyl)ethane (DDT), the first organochlorine insecticide, and pyrethroid insecticides are sodium channel agonists. Although the use of DDT is banned in most of the world due to its detrimental impact on the ecosystem, indoor residual spraying of DDT is still recommended for malaria control in Africa. Development of resistance to DDT and pyrethroids is a serious global obstacle for managing disease vectors. Mapping DDT binding sites is necessary for understanding mechanisms of resistance and modulation of sodium channels by structurally different ligands. The pioneering model of the housefly sodium channel visualized the first receptor for pyrethroids, PyR1, in the II/III domain interface and suggested that DDT binds within PyR1. Previously, we proposed the second pyrethroid receptor, PyR2, at the I/II domain interface. However, whether DDT binds to both pyrethroid receptor sites remains unknown. Here, using computational docking of DDT into the Kv1.2-based mosquito sodium channel model, we predict that two DDT molecules can bind simultaneously within PyR1 and PyR2. The bulky trichloromethyl group of each DDT molecule fits snugly between four helices in the bent domain interface, whereas two p-chlorophenyl rings extend into two wings of the interface. Model-driven mutagenesis and electrophysiological analysis confirmed these propositions and revealed 10 previously unknown DDT-sensing residues within PyR1 and PyR2. Our study proposes a dual DDT-receptor model and provides a structural background for rational development of new insecticides. PMID- 26637353 TI - Mycobacterium tuberculosis WhiB3 Responds to Vacuolar pH-induced Changes in Mycothiol Redox Potential to Modulate Phagosomal Maturation and Virulence. AB - The ability of Mycobacterium tuberculosis to resist intraphagosomal stresses, such as oxygen radicals and low pH, is critical for its persistence. Here, we show that a cytoplasmic redox sensor, WhiB3, and the major M. tuberculosis thiol, mycothiol (MSH), are required to resist acidic stress during infection. WhiB3 regulates the expression of genes involved in lipid anabolism, secretion, and redox metabolism, in response to acidic pH. Furthermore, inactivation of the MSH pathway subverted the expression of whiB3 along with other pH-specific genes in M. tuberculosis. Using a genetic biosensor of mycothiol redox potential (EMSH), we demonstrated that a modest decrease in phagosomal pH is sufficient to generate redox heterogeneity in EMSH of the M. tuberculosis population in a WhiB3 dependent manner. Data indicate that M. tuberculosis needs low pH as a signal to alter cytoplasmic EMSH, which activates WhiB3-mediated gene expression and acid resistance. Importantly, WhiB3 regulates intraphagosomal pH by down-regulating the expression of innate immune genes and blocking phagosomal maturation. We show that this block in phagosomal maturation is in part due to WhiB3-dependent production of polyketide lipids. Consistent with these observations, MtbDeltawhiB3 displayed intramacrophage survival defect, which can be rescued bypharmacological inhibition of phagosomal acidification. Last, MtbDeltawhiB3 displayed marked attenuation in the lungs of guinea pigs. Altogether, our study revealed an intimate link between vacuolar acidification, redox physiology, and virulence in M. tuberculosis and discovered WhiB3 as crucial mediator of phagosomal maturation arrest and acid resistance in M. tuberculosis. PMID- 26637354 TI - Severe Hypomyelination and Developmental Defects Are Caused in Mice Lacking Protein Arginine Methyltransferase 1 (PRMT1) in the Central Nervous System. AB - Protein arginine methyltransferase 1 (PRMT1) is involved in cell proliferation, DNA damage response, and transcriptional regulation. Although PRMT1 is extensively expressed in the CNS at embryonic and perinatal stages, the physiological role of PRMT1 has been poorly understood. Here, to investigate the primary function of PRMT1 in the CNS, we generated CNS-specific PRMT1 knock-out mice by the Cre-loxP system. These mice exhibited postnatal growth retardation with tremors, and most of them died within 2 weeks after birth. Brain histological analyses revealed prominent cell reduction in the white matter tracts of the mutant mice. Furthermore, ultrastructural analysis demonstrated that myelin sheath was almost completely ablated in the CNS of these animals. In agreement with hypomyelination, we also observed that most major myelin proteins including myelin basic protein (MBP), 2',3'-cyclic-nucleotide 3' phosphodiesterase (CNPase), and myelin-associated glycoprotein (MAG) were dramatically decreased, although neuronal and astrocytic markers were preserved in the brain of CNS-specific PRMT1 knock-out mice. These animals had a reduced number of OLIG2(+) oligodendrocyte lineage cells in the white matter. We found that expressions of transcription factors essential for oligodendrocyte specification and further maturation were significantly suppressed in the brain of the mutant mice. Our findings provide evidence that PRMT1 is required for CNS development, especially for oligodendrocyte maturation processes. PMID- 26637355 TI - Structural Basis of Stereospecificity in the Bacterial Enzymatic Cleavage of beta Aryl Ether Bonds in Lignin. AB - Lignin is a combinatorial polymer comprising monoaromatic units that are linked via covalent bonds. Although lignin is a potential source of valuable aromatic chemicals, its recalcitrance to chemical or biological digestion presents major obstacles to both the production of second-generation biofuels and the generation of valuable coproducts from lignin's monoaromatic units. Degradation of lignin has been relatively well characterized in fungi, but it is less well understood in bacteria. A catabolic pathway for the enzymatic breakdown of aromatic oligomers linked via beta-aryl ether bonds typically found in lignin has been reported in the bacterium Sphingobium sp. SYK-6. Here, we present x-ray crystal structures and biochemical characterization of the glutathione-dependent beta etherases, LigE and LigF, from this pathway. The crystal structures show that both enzymes belong to the canonical two-domain fold and glutathione binding site architecture of the glutathione S-transferase family. Mutagenesis of the conserved active site serine in both LigE and LigF shows that, whereas the enzymatic activity is reduced, this amino acid side chain is not absolutely essential for catalysis. The results include descriptions of cofactor binding sites, substrate binding sites, and catalytic mechanisms. Because beta-aryl ether bonds account for 50-70% of all interunit linkages in lignin, understanding the mechanism of enzymatic beta-aryl ether cleavage has significant potential for informing ongoing studies on the valorization of lignin. PMID- 26637356 TI - Munc13-4 Is a Rab11-binding Protein That Regulates Rab11-positive Vesicle Trafficking and Docking at the Plasma Membrane. AB - The small GTPase Rab11 and its effectors control trafficking of recycling endosomes, receptor replenishment and the up-regulation of adhesion and adaptor molecules at the plasma membrane. Despite recent advances in the understanding of Rab11-regulated mechanisms, the final steps mediating docking and fusion of Rab11 positive vesicles at the plasma membrane are not fully understood. Munc13-4 is a docking factor proposed to regulate fusion through interactions with SNAREs. In hematopoietic cells, including neutrophils, Munc13-4 regulates exocytosis in a Rab27a-dependent manner, but its possible regulation of other GTPases has not been explored in detail. Here, we show that Munc13-4 binds to Rab11 and regulates the trafficking of Rab11-containing vesicles. Using a novel Time-resolved Fluorescence Resonance Energy Transfer (TR-FRET) assay, we demonstrate that Munc13-4 binds to Rab11a but not to dominant negative Rab11a. Immunoprecipitation analysis confirmed the specificity of the interaction between Munc13-4 and Rab11, and super-resolution microscopy studies support the interaction of endogenous Munc13-4 with Rab11 at the single molecule level in neutrophils. Vesicular dynamic analysis shows the common spatio-temporal distribution of Munc13-4 and Rab11, while expression of a calcium binding-deficient mutant of Munc13-4 significantly affected Rab11 trafficking. Munc13-4-deficient neutrophils showed normal endocytosis, but the trafficking, up-regulation, and retention of Rab11 positive vesicles at the plasma membrane was significantly impaired. This correlated with deficient NADPH oxidase activation at the plasma membrane in response to Rab11 interference. Our data demonstrate that Munc13-4 is a Rab11 binding partner that regulates the final steps of Rab11-positive vesicle docking at the plasma membrane. PMID- 26637357 TI - Vicarious Fear Learning Depends on Empathic Appraisals and Trait Empathy. AB - Empathy and vicarious learning of fear are increasingly understood as separate phenomena, but the interaction between the two remains poorly understood. We investigated how social (vicarious) fear learning is affected by empathic appraisals by asking participants to either enhance or decrease their empathic responses to another individual (the demonstrator), who received electric shocks paired with a predictive conditioned stimulus. A third group of participants received no appraisal instructions and responded naturally to the demonstrator. During a later test, participants who had enhanced their empathy evinced the strongest vicarious fear learning as measured by skin conductance responses to the conditioned stimulus in the absence of the demonstrator. Moreover, this effect was augmented in observers high in trait empathy. Our results suggest that a demonstrator's expression can serve as a "social" unconditioned stimulus (US), similar to a personally experienced US in Pavlovian fear conditioning, and that learning from a social US depends on both empathic appraisals and the observers' stable traits. PMID- 26637358 TI - Inferring Identity From Language: Linguistic Intergroup Bias Informs Social Categorization. AB - The present research examined whether a communicator's verbal, implicit message regarding a target is used as a cue for inferring that communicator's social identity. Previous research has found linguistic intergroup bias (LIB) in individuals' speech: They use abstract language to describe in-group targets' desirable behaviors and concrete language to describe their undesirable behaviors (favorable LIB), but use concrete language for out-group targets' desirable behaviors and abstract language for their undesirable behaviors (unfavorable LIB). Consequently, one can infer the type of language a communicator is likely to use to describe in-group and out-group targets. We hypothesized and found evidence for the reverse inference. Across four studies, individuals inferred a communicator's social identity on the basis of the communicator's use of an LIB. Specifically, participants more strongly believed that a communicator and target shared a social identity when the communicator used the favorable, rather than the unfavorable, LIB in describing that target. PMID- 26637359 TI - Energy Adaptations Persist 2 Years After Sleeve Gastrectomy and Gastric Bypass. AB - Non-surgical weight loss induces a greater than expected decrease in energy expenditure, a phenomenon known as 'metabolic adaptation'. The effects of different bariatric surgery procedures on metabolic adaptation are not yet known and may partially contribute to weight loss success. We compared resting energy expenditure (REE) in 35 subjects (nine males; age = 46 +/- 11 years; BMI = 42.1 +/- 6.5 kg/m(2)) undergoing gastric band, sleeve gastrectomy or Roux-en-Y gastric bypass (RYGB) up to 2 years after surgery. We found a greater than expected reduction of 130-300 kcal/day at 6 weeks after sleeve and bypass surgery which was not explained by changes in body composition; this change was not seen in the band group. The suppression in REE after sleeve and RYGB remained up to 2 years, even after weight loss had plateaued. Our findings suggest that energy adaptation is not a contributing mechanism to medium-term weight maintenance after sleeve and RYGB bariatric surgeries. PMID- 26637360 TI - LDL biochemical modifications: a link between atherosclerosis and aging. AB - Atherosclerosis is an aging disease in which increasing age is a risk factor. Modified low-density lipoprotein (LDL) is a well-known risk marker for cardiovascular disease. High-plasma LDL concentrations and modifications, such as oxidation, glycosylation, carbamylation and glycoxidation, have been shown to be proatherogenic experimentally in vitro and in vivo. Atherosclerosis results from alterations to LDL in the arterial wall by reactive oxygen species (ROS). Evidence suggests that common risk factors for atherosclerosis raise the likelihood that free ROS are produced from endothelial cells and other cells. Furthermore, oxidative stress is an important factor in the induction of endothelial senescence. Thus, endothelial damage and cellular senescence are well established markers for atherosclerosis. This review examines LDL modifications and discusses the mechanisms of the pathology of atherosclerosis due to aging, including endothelial damage and oxidative stress, and the link between aging and atherosclerosis. PMID- 26637361 TI - Integrated Optimization of the In Vivo Heme Biosynthesis Pathway and the In Vitro Iron Concentration for 5-Aminolevulinate Production. AB - 5-Aminolevulinic acid (ALA) is a nonprotein amino acid that has been widely used in many fields. In this study, we developed a new process for ALA production by optimizing the in vivo heme biosynthesis pathway and the iron concentration during cultivation. With the addition of iron, co-overexpression of the heme synthesis pathway genes hemA, hemL, hemF, and hemD significantly increased the accumulation of ALA and cell biomass. Further experiments demonstrated that the increased ALA accumulation resulted from moderate repression of ALA dehydratase (encoded by hemB), which was caused by hemF overexpression. After the addition of an optimized concentration (7.5 mg/L) of iron, ALA production by the recombinant Escherichia coli LADF-6 strain that overexpressed hemA, hemL, hemD, and hemF increased to 2840 mg/L in flask cultures. After applying a batch fermentation strategy, the ALA concentration increased to 4.05 g/L, with a productivity of 0.127 g/L.h. The results showed that the moderate repression of the in vivo heme pathway enzyme ALA dehydratase and the simultaneous optimization of the in vitro iron ion concentration served to increase the production of ALA and cell biomass. PMID- 26637362 TI - SSR Markers Associated with Proline in Drought Tolerant Wheat Germplasm. AB - Water stress causes major agricultural loss throughout the world as survival of the crops remained under stress and loss in yield. Plants respond to drought stress by means of different adaptive mechanisms such as accumulation of osmoprotectants to counteract the water stress. Amino acid proline is known to occur widely in higher plants and normally accumulates in large quantities as an osmolyte in response to environmental stresses. Biochemical estimation of proline was done in the drought-affected wheat genotypes by spectrophotometric method. Proline promoted a positive effect as root/shoot ratio was enhanced in wheat germplasm under drought stress. SSR primer pairs (45) were tested for polymorphism among selected wheat genotypes. The dendrogram results have shown the wheat genotype association with the levels of proline during induced drought stress. The relationship between pattern of drought responsive biochemical attributes and DNA markers in the selected wheat genotypes was recognized to select drought tolerant genotypes for sowing in drought affected areas of the country. PMID- 26637363 TI - Republican campaign against Planned Parenthood falters after clinic shooting. PMID- 26637364 TI - High XIST and Low 53BP1 Expression Predict Poor Outcome after High-Dose Alkylating Chemotherapy in Patients with a BRCA1-like Breast Cancer. AB - In previous studies, high expression of XIST and low expression of 53BP1 were respectively associated with poor systemic therapy outcome in patients and therapy resistance in BRCA1-deficient mouse tumor models, but have not been evaluated in BRCA1-deficient patients. Previously, we demonstrated that classifying breast cancer copy number profiles as BRCA1-like or non-BRCA1-like identified patients enriched for defects in BRCA1 that benefit from high-dose (HD) alkylating chemotherapy compared with a conventional standard regimen. We investigated whether XIST and 53BP1 expression predicted poor outcome of HD chemotherapy within 28 BRCA1-like patients from a trial randomizing between HD [4 cycles 5-fluorouracil, epirubicin, cyclophosphamide (FEC) followed by 1 cycle HD carboplatin, thiotepa, cyclophosphamide] or conventional chemotherapy (5 cycles FEC), for which both XIST and 53BP1 statuses were available. High RNA expression of XIST (n = 5) and low protein expression of 53BP1 (n = 3) expression did not coincide. Patients with either one had poor outcome after treatment with HD chemotherapy, whereas patients with low expression of XIST and high expression of 53BP1 derived substantial benefit of this regimen on recurrence-free survival, disease-free survival, and overall survival, corroborating preclinical findings. XIST and 53BP1 may be predictive biomarkers in BRCA1-like breast cancer. PMID- 26637365 TI - Specific Antileukemic Activity of PD0332991, a CDK4/6 Inhibitor, against Philadelphia Chromosome-Positive Lymphoid Leukemia. AB - S-phase progression of the cell cycle is accelerated in tumors through various genetic abnormalities, and, thus, pharmacologic inhibition of altered cell-cycle progression would be an effective strategy to control tumors. In the current study, we analyzed the antileukemic activity of three available small molecules targeting CDK4/CDK6 against lymphoid crisis of chronic myeloid leukemia (CML-LC) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL), and found that all three molecules showed specific activities against leukemic cell lines derived from CML-LC and Ph(+) ALL. In particular, PD0332991 exhibited extremely high antileukemic activity against CML-LC and Ph(+) ALL cell lines in the nanomolar range by the induction of G0-G1 arrest and partially cell death through dephosphorylation of pRb and downregulation of the genes that are involved in S-phase transition. As an underlying mechanism for favorable sensitivity to the small molecules targeting CDK4/CDK6, cell-cycle progression of Ph(+) lymphoid leukemia cells was regulated by transcriptional and posttranscriptional modulation of CDK4 as well as Cyclin D2 gene expression under the control of BCR-ABL probably through the PI3K pathway. Consistently, the gene expression level of Cyclin D2 in Ph(+) lymphoid leukemia cells was significantly higher than that in Ph(-) lymphoid leukemia cells. Of note, three Ph(+) ALL cell lines having the T315I mutation also showed sensitivity to PD0332991. In a xenograft model, PD0332991, but not imatinib, suppressed dissemination of Ph(+) ALL having the T315I mutation and prolonged survival, demonstrating that this reagent would be a new therapeutic modality for relapsed CML-LC and Ph(+) ALL patients after treatment with tyrosine kinase inhibitors. PMID- 26637366 TI - Synergistic Myeloma Cell Death via Novel Intracellular Activation of Caspase-10 Dependent Apoptosis by Carfilzomib and Selinexor. AB - Exportin1 (XPO1; also known as chromosome maintenance region 1, or CRM1) controls nucleo-cytoplasmic transport of most tumor suppressors and is overexpressed in many cancers, including multiple myeloma, functionally impairing tumor suppressive function via target mislocalization. Selective inhibitor of nuclear export (SINE) compounds block XPO1-mediated nuclear escape by disrupting cargo protein binding, leading to retention of tumor suppressors, induction of cancer cell death, and sensitization to other drugs. Combined treatment with the clinical stage SINE compound selinexor and the irreversible proteasome inhibitor (PI) carfilzomib induced synergistic cell death of myeloma cell lines and primary plasma cells derived from relapsing/refractory myeloma patients and completely impaired the growth of myeloma cell line-derived tumors in mice. Investigating the details of SINE/PI-induced cell death revealed (i) reduced Bcl-2 expression and cleavage and inactivation of Akt, two prosurvival regulators of apoptosis and autophagy; (ii) intracellular membrane-associated aggregation of active caspases, which depended on caspase-10 protease activity; and (iii) novel association of caspase-10 and autophagy-associated proteins p62 and LC3 II, which may prime activation of the caspase cascade. Overall, our findings provide novel mechanistic rationale behind the potent cell death induced by combining selinexor with carfilzomib and support their use in the treatment of relapsed/refractory myeloma and potentially other cancers. PMID- 26637367 TI - AT2R Gene Delivered by Condensed Polylysine Complexes Attenuates Lewis Lung Carcinoma after Intravenous Injection or Intratracheal Spray. AB - Transfection efficiency and toxicity concerns remain a challenge for gene therapy. Cell-penetrating peptides (CPP) have been broadly investigated to improve the transfection of genetic material (e.g., pDNA and siRNA). Here, a synthetic CPP (polylysine, K9 peptide) was complexed with angiotensin II type 2 receptor (AT2R) plasmid DNA (pAT2R) and complexes were condensed using calcium chloride. The resulting complexes were small (~150 nm) and showed high levels of gene expression in vitro and in vivo. This simple nonviral formulation approach showed negligible cytotoxicity in four different human cell lines (cervix, breast, kidney, and lung cell lines) and one mouse cell line (a lung cancer cell line). In addition, this K9-pDNA-Ca(2+) complex demonstrated cancer-targeted gene delivery when administered via intravenous injection or intratracheal spray. The transfection efficiency was evaluated in Lewis lung carcinoma (LLC) cell lines cultured in vitro and in orthotopic cancer grafts in syngeneic mice. Immunohistochemical analysis confirmed that the complex effectively delivered pAT2R to the cancer cells, where it was expressed mainly in cancer cells along with bronchial epithelial cells. A single administration of these complexes markedly attenuated lung cancer growth, offering preclinical proof-of-concept for a novel nonviral gene delivery method exhibiting effective lung tumor gene therapy via either intravenous or intratracheal administration. PMID- 26637368 TI - AKT Inhibition Promotes Nonautonomous Cancer Cell Survival. AB - Small molecule inhibitors of AKT (v-akt murine thymoma viral oncogene homolog) signaling are being evaluated in patients with various cancer types, but have so far proven therapeutically disappointing for reasons that remain unclear. Here, we treat cancer cells with subtherapeutic doses of Akti-1/2, an allosteric small molecule AKT inhibitor, in order to experimentally model pharmacologic inhibition of AKT signaling in vitro. We then apply a combined RNA, protein, and metabolite profiling approach to develop an integrated, multiscale, molecular snapshot of this "AKT(low)" cancer cell state. We find that AKT-inhibited cancer cells suppress thousands of mRNA transcripts, and proteins related to the cell cycle, ribosome, and protein translation. Surprisingly, however, these AKT-inhibited cells simultaneously upregulate a host of other proteins and metabolites posttranscriptionally, reflecting activation of their endo-vesiculo-membrane system, secretion of inflammatory proteins, and elaboration of extracellular microvesicles. Importantly, these microvesicles enable rapidly proliferating cancer cells of various types to better withstand different stress conditions, including serum deprivation, hypoxia, or cytotoxic chemotherapy in vitro and xenografting in vivo. These findings suggest a model whereby cancer cells experiencing a partial inhibition of AKT signaling may actually promote the survival of neighbors through non-cell autonomous communication. PMID- 26637369 TI - The DNA Repair Inhibitor DT01 as a Novel Therapeutic Strategy for Chemosensitization of Colorectal Liver Metastasis. AB - Metastatic liver disease from colorectal cancer is a significant clinical problem. This is mainly attributed to nonresectable metastases that frequently display low sensitivities to available chemotherapies and develop drug resistance partly via hyperactivation of some DNA repair functions. Combined therapies have shown some disease control; however, there is still a need for more efficient chemotherapies to achieve eradication of colorectal cancer liver metastasis. We investigated the tolerance and efficacy of a novel class of DNA repair inhibitors, Dbait, in association with conventional chemotherapy. Dbait mimics double-strand breaks and activates damage signaling, consequently inhibiting single- and double-stranded DNA repair enzyme recruitment. In vitro, Dbait treatment increases sensitivity of HT29 and HCT116 colorectal cancer cell lines. In vivo, the pharmacokinetics, biodistribution and the efficacy of the cholesterol-conjugated clinical form of Dbait, DT01, were assessed. The chemosensitizing abilities of DT01 were evaluated in association with oxaliplatin and 5-fluorouracil in intrahepatic HT29 xenografted mice used as a model for colorectal cancer liver metastasis. The high uptake of DT01 indicates that the liver is a specific target. We demonstrate significant antitumor efficacy in a liver metastasis model with DT01 treatment in combination with oxaliplatin and 5 fluorouracil (mean: 501 vs. 872 mm(2), P = 0.02) compared to chemotherapy alone. The decrease in tumor volume is further associated with significant histologic changes in necrosis, proliferation, angiogenesis and apoptosis. Repeated cycles of DT01 do not increase chemotherapy toxicity. Combining DT01 with conventional chemotherapy may prove to be a safe and effective therapeutic strategy in the treatment of metastatic liver cancer. PMID- 26637370 TI - 2-Deoxy-Glucose Downregulates Endothelial AKT and ERK via Interference with N Linked Glycosylation, Induction of Endoplasmic Reticulum Stress, and GSK3beta Activation. AB - Interference with endothelial cell metabolism is a promising, yet unexploited strategy for angiogenesis inhibition. We reported that the glucose analogue 2 deoxy-D-glucose (2-DG) inhibits angiogenesis at significantly lower concentrations than those required for tumor cytotoxicity. Here, we found that hypersensitivity to 2-DG in endothelial cells is not associated with enhanced drug uptake compared with tumor cells, but with time-dependent, endothelial selective inhibition of AKT and ERK phosphorylation. Downregulation of these critical survival pathways is shown to be due to 2-DG's interference with N linked glycosylation, leading to alterations in VEGFR2 (and downstream signaling) as well as induction of endoplasmic reticulum (ER) stress, GSK3beta activation, and apoptosis. In vivo, periocular administration of 2-DG in LHBETATAG mice was associated with significant reduction of newly formed (CD105(+)) tumor capillaries, ER stress (GRP 78 expression), and endothelial apoptosis (TUNEL). These findings uniquely link N-linked glycosylation inhibition, ER stress, and ERK/AKT downregulation in endothelial cells, and provide a novel drug development strategy to overcome resistance mechanisms to currently available antiangiogenic agents. PMID- 26637371 TI - The participation of insulin-like growth factor-binding protein 3 released by astrocytes in the pathology of Alzheimer's disease. AB - BACKGROUND: Alzheimer's disease (AD) is characterized by senile plaques, extracellular deposits composed primarily of amyloid-beta (Abeta), and neurofibrillary tangles, which are abnormal intracellular inclusions containing hyperphosphorylated tau. The amyloid cascade hypothesis posits that the deposition of Abeta in the brain parenchyma initiates a sequence of events that leads to dementia. However, the molecular process by which the extracellular accumulation of Abeta peptides promotes intracellular pathologic changes in tau filaments remains unclear. To elucidate this process, we presumed that astrocytes might trigger neuronal reactions, leading to tau phosphorylation. In this study, we examined AD pathology from the perspective of the astrocyte-neuron interaction. RESULTS: A cytokine-array analysis revealed that Abeta stimulates astrocytes to release several chemical mediators that are primarily related to inflammation and cell adhesion. Among those mediators, insulin-like growth factor (IGF)-binding protein 3 (IGFBP-3) was highly upregulated. In AD brains, the expression of IGFBP-3 was found to be increased by western blot analysis, and increased expression of IGFBP-3 was observed in astrocytes via fluorescence microscopy. In addition, we reproduced the increase in IGFBP-3 after treatment with Abeta using human astrocytoma cell lines and found that IGFBP-3 was expressed via calcineurin. In AD brains, the activated forms of calcineurin were found to be increased by western blot analysis, and increased expression of calcineurin was observed in astrocytes via fluorescence microscopy. When Ser9 of glycogen synthase kinase-3beta (GSK-3beta) is phosphorylated, GSK-3beta is controlled and tau phosphorylation is suppressed. Abeta suppresses the phosphorylation of GSK-3beta, leading to tau phosphorylation. In this study, we found that IGF-Iota suppressed tau phosphorylation induced by Abeta, although IGFBP-3 inhibited this property of IGF-Iota. As a result, IGFBP-3 contributed to tau phosphorylation and cell death induced by Abeta. CONCLUSIONS: Our study suggested that calcineurin in astrocytes was activated by Abeta, leading to IGFBP 3 release. We further demonstrated that IGFBP-3 produced by astrocytes induced tau phosphorylation in neurons. Our study provides novel insights into the role of astrocytes in the induction of tau phosphorylation and suggests that IGFBP-3 could be an important link between Abeta and tau pathology and an important therapeutic target. PMID- 26637372 TI - Phylogenomic methods outperform traditional multi-locus approaches in resolving deep evolutionary history: a case study of formicine ants. AB - BACKGROUND: Ultraconserved elements (UCEs) have been successfully used in phylogenomics for a variety of taxa, but their power in phylogenetic inference has yet to be extensively compared with that of traditional Sanger sequencing data sets. Moreover, UCE data on invertebrates, including insects, are sparse. We compared the phylogenetic informativeness of 959 UCE loci with a multi-locus data set of ten nuclear markers obtained via Sanger sequencing, testing the ability of these two types of data to resolve and date the evolutionary history of the second most species-rich subfamily of ants in the world, the Formicinae. RESULTS: Phylogenetic analyses show that UCEs are superior in resolving ancient and shallow relationships in formicine ants, demonstrated by increased node support and a more resolved phylogeny. Phylogenetic informativeness metrics indicate a twofold improvement relative to the 10-gene data matrix generated from the identical set of taxa. We were able to significantly improve formicine classification based on our comprehensive UCE phylogeny. Our divergence age estimations, using both UCE and Sanger data, indicate that crown-group Formicinae are older (104-117 Ma) than previously suggested. Biogeographic analyses infer that the diversification of the subfamily has occurred on all continents with no particular hub of cladogenesis. CONCLUSIONS: We found UCEs to be far superior to the multi-locus data set in estimating formicine relationships. The early history of the clade remains uncertain due to ancient rapid divergence events that are unresolvable even with our genomic-scale data, although this might be largely an effect of several problematic taxa subtended by long branches. Our comparison of divergence ages from both Sanger and UCE data demonstrates the effectiveness of UCEs for dating analyses. This comparative study highlights both the promise and limitations of UCEs for insect phylogenomics, and will prove useful to the growing number of evolutionary biologists considering the transition from Sanger to next-generation sequencing approaches. PMID- 26637374 TI - Influence of silver nanoparticles on metabolism and toxicity of moulds. AB - The unique antimicrobial features of silver nanoparticles (AgNPs) are commonly applied in innumerable products. The lack of published studies on the mechanisms of AgNPs action on fungi resulted in identification of the aim of this study, which was: the determination of the influence of AgNPs on the mould cytotoxicity for swine kidney cells (MTT test) and the production of selected mycotoxins, organic acids, extracellular enzymes by moulds. The conducted study had shown that silver nanoparticles can change the metabolism and toxicity of moulds. AgNPs decrease the mycotoxin production of Aspergillus sp. (81-96%) and reduce mould cytotoxicity (50-75%). AgNPs influence the organic acid production of A. niger and P. chrysogenum by decreasing their concentration (especially of the oxalic and citric acid). Also, a change in the extracellular enzyme profile of A. niger and P. chrysogenum was observed, however, the total enzymatic activity was increased. PMID- 26637373 TI - Acute hospital-based services used by adults during the last year of life in New South Wales, Australia: a population-based retrospective cohort study. AB - BACKGROUND: There is limited information about health care utilisation at the end of life for people in Australia. We describe acute hospital-based services utilisation during the last year of life for all adults (aged 18+ years) who died in a 12-month period in Australia's most populous state, New South Wales (NSW). METHODS: Linked administrative health data were analysed for all adults who died in NSW in 2007 (the most recent year for which cause of death information was available for linkage for this study). The data comprised linked death records (2007), hospital admissions and emergency department (ED) presentations (2006 2007) and cancer registrations (1994-2007). Measures of hospital-based service utilisation during the last year of life included: number and length of hospital episodes, ED presentations, admission to an intensive care unit (ICU), palliative related admissions and place of death. Factors associated with these measures were examined using multivariable logistic regression. RESULTS: Of the 45,749 adult decedents, 82% were admitted to hospital during their last year of life: 24% had >3 care episodes (median 2); 35% stayed a total of >30 days in hospital (median 17); 42% were admitted to 2 or more different hospitals. Twelve percent of decedents spent time in an ICU with median 3 days. In the metropolitan area, 80% of decedents presented to an ED and 18% had >3 presentations. Overall 55% died in a hospital or inpatient hospice. Although we could not quantify the extent and type of palliative care, 24% had mention of "palliative care" in their records. The very elderly and those dying from diseases of the circulatory system or living in the least disadvantaged areas generally had lower hospital service use. CONCLUSIONS: These population-wide health data collections give a highly informative description of NSWhospital-based end-of-life service utilisation. Use of hospital-based services during the last year of life was common, with substantial variation across sociodemographic groups, especially defined by age, cause of death and socioeconomic classification of the decedents' place of residence. Further research is now needed to identify the contributors to these findings. Gaps in data collection were identified - particularly for palliative care and patient-reported outcomes. Addressing these gaps should facilitate improved monitoring and assessment of service use and care. PMID- 26637375 TI - Comparison of antibiotic resistance and virulence between biofilm-producing and non-producing clinical isolates of Enterococcus faecium. AB - An increase in the antibiotic resistance among Enterococcus faecium strains has been observed worldwide. Moreover, this bacteria has the ability to produce several virulence factors and to form biofilm that plays an important role in human infections. This study was designed to compare the antibiotic resistance and the prevalence of genes encoding surface protein (esp), aggregation substance (as), surface adhesin (efaA), collagen adhesin (ace), gelatinase (gelE), and hialuronidase (hyl) between biofilm-producing and non-producing E. faecium strains. Therefore, ninety E. faecium clinical isolates were tested for biofilm forming ability, and then were assigned to two groups: biofilm-positive (BIO(+), n =70) and biofilm-negative (BIO(-), n = 20). Comparison of these groups showed that BIO(+) isolates were resistant to beta-lactams, whereas 10% of BIO(-) strains were susceptible to ampicillin (statistically significant difference, p = 0.007) and 5% to imipenem. Linezolid and tigecycline were the only antibiotics active against all tested isolates. Analysis of the virulence factors revealed that ace, efaA, and gelE genes occurred more frequently in BIO(-) strains (ace in 50% BIO(+) vs. 75% BIO(-); efaA 44.3% vs. 85%; gelE 2.9% vs. 15%, respectively), while hyl gene appeared more frequently in BIO(+) isolates (87.1% BIO(+) vs. 65% BIO(-)). These differences were significant (p < 0.05). We concluded that BIO(+) strains were more resistant to antibiotics than BIO(-) strains, but interestingly, BIO(-) isolates were characterized by possession of higher virulence capabilities. PMID- 26637376 TI - Klebsiella pneumoniae: characteristics of carbapenem resistance and virulence factors. AB - Klebsiella pneumoniae, known as a major threat to public health, is the most common factor of nosocomial and community acquired infections. In this study, 50 K. pneumoniae clinical specimens isolated from bronchial, urea, blood, catheter, rectal, bile, tracheal and wound cultures were collected. These isolates were identified and carbapenem resistance was determined via an automated system, CHROMagar Orientation and CHROMagar KPC. The carbapenemase gene regions (blaIMP, blaVIM, blaOXA, blaNDM and blaKPC) and presence of virulence factors (magA, k2A, rmpA, wabG, uge, allS, entB, ycfM, kpn, wcaG, fimH, mrkD, iutA, iroN, hly ve cnf 1) of these isolates were determined by using Multiplex-PCR. The OXA-48 carbapenemase gene regions were determined in 33 of 50 K. pneumoniae strains. In addition, NDM-1 resistance in one, OXA-48 and NDM-1 resistance in four unusual K. pneumoniae isolates were detected. Virulence gene regions that were encountered among K. pneumoniae isolates were 88% wabG, 86% uge, 80% ycfM and 72% entB, related with capsule, capsule lipoprotein and external membrane protein, responsible for enterobactin production, respectively. Even though there was no significant difference between resistant and sensitive strains due to the virulence gene regions (P>=0.05), virulence factors in carbapenem resistant isolates were found to be more diverse. This study is important for both, to prevent the spread of carbapenem resistant infections and to plan for developing effective treatments. Moreover, this study is the first detailed study of the carbapenem resistance and virulence factors in K. pneumoniae strains. PMID- 26637377 TI - Biological activity of surfactins - a case of a biosurfactant produced by Bacillus subtilis PCM 1949. AB - Biosurfactants are microbial surface active compounds which, contrary to synthetic surfactants, are natural in origin, biodegradable and less toxic to a human organism. For that reason, there is a great research potential in studies aimed at their purification, finding potential ways of their utilization and decreasing their production costs. This paper demonstrates the process of isolating and purifying a surfactin synthesized by Bacillus subtilis PCM 1949. Surfactin samples were prepared by a classical organic solvent extraction and were studied using mass spectrometry (MS). Analysis of the susceptibility profile of microorganisms utilized in the diffusion-plate tests demonstrated that their sensitivity to this surfactin is differentiated and depends on the microorganism species. In our studies, we found that the selected strains of bacteria and fungi were insensitive to this surfactin at a wide range of concentrations. PMID- 26637378 TI - Evaluation of the BYG Carba Test, a New Electrochemical Assay for Rapid Laboratory Detection of Carbapenemase-Producing Enterobacteriaceae. AB - Accurate detection of carbapenemase-producing Enterobacteriaceae (CPE) constitutes a major laboratory diagnostic challenge. We evaluated an electrochemical technique (the BYG Carba test) which allows detection of CPE in less than 35 min. The BYG Carba test was first validated in triplicate against 57 collection isolates with previously characterized beta-lactam resistance mechanisms (OXA-48, n = 12; KPC, n = 8; NDM, n = 8; VIM, n = 8; IMP, n = 3; GIM, n = 1; GES-6, n = 1; no carbapenemase, n = 16) and against a panel of 10 isolates obtained from the United Kingdom National External Quality Assessment Service (NEQAS). The test was then evaluated prospectively against 324 isolates referred to the national reference center for suspicion of CPE. The BYG Carba test results were compared with those obtained with the Carba NP test using multiplex PCR sequencing as the gold standard. Of the 57 collection and the 10 NEQAS isolates, all but one GES-6-producing isolate were correctly identified by the Carba BYG test. Among the 324 consecutive Enterobacteriaceae isolates tested prospectively, 146 were confirmed as noncarbapenemase producers by PCR while 178 harbored a carbapenemase gene (OXA-48, n = 117; KPC, n = 25; NDM, n = 23; and VIM, n = 13). Prospectively, in comparison with PCR results, the BYG Carba test displayed 95% sensitivity and 100% specificity versus 89% and 100%, respectively, for the Carba NP test. The BYG Carba test is a novel, rapid, and efficient assay based on an electro-active polymer biosensing technology discriminating between CPE and non CPE. The precise electrochemical signal (electrochemical impedance variations) allows the establishment of real-time objective measurement and interpretation criteria which should facilitate the accreditation process of this technology. PMID- 26637379 TI - Metagenomic Approach for Identification of the Pathogens Associated with Diarrhea in Stool Specimens. AB - The potential to rapidly capture the entire microbial community structure and/or gene content makes metagenomic sequencing an attractive tool for pathogen identification and the detection of resistance/virulence genes in clinical settings. Here, we assessed the consistency between PCR from a diagnostic laboratory, quantitative PCR (qPCR) from a research laboratory, 16S rRNA gene sequencing, and metagenomic shotgun sequencing (MSS) for Clostridium difficile identification in diarrhea stool samples. Twenty-two C. difficile-positive diarrhea samples identified by PCR and qPCR and five C. difficile-negative diarrhea controls were studied. C. difficile was detected in 90.9% of C. difficile-positive samples using 16S rRNA gene sequencing, and C. difficile was detected in 86.3% of C. difficile-positive samples using MSS. CFU inferred from qPCR analysis were positively correlated with the relative abundance of C. difficile from 16S rRNA gene sequencing (r(2) = -0.60) and MSS (r(2) = -0.55). C. difficile was codetected with Clostridium perfringens, norovirus, sapovirus, parechovirus, and anellovirus in 3.7% to 27.3% of the samples. A high load of Candida spp. was found in a symptomatic control sample in which no causative agents for diarrhea were identified in routine clinical testing. Beta-lactamase and tetracycline resistance genes were the most prevalent (25.9%) antibiotic resistance genes in these samples. In summary, the proof-of-concept study demonstrated that next-generation sequencing (NGS) in pathogen detection is moderately correlated with laboratory testing and is advantageous in detecting pathogens without a priori knowledge. PMID- 26637381 TI - Evaluation of Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry for Identification of Mycobacterium species, Nocardia species, and Other Aerobic Actinomycetes. AB - The value of matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) for the identification of bacteria and yeasts is well documented in the literature. Its utility for the identification of mycobacteria and Nocardia spp. has also been reported in a limited scope. In this work, we report the specificity of MALDI-TOF MS for the identification of 162 Mycobacterium species and subspecies, 53 Nocardia species, and 13 genera (totaling 43 species) of other aerobic actinomycetes using both the MALDI-TOF MS manufacturer's supplied database(s) and a custom database generated in our laboratory. The performance of a simplified processing and extraction procedure was also evaluated, and, similar to the results in an earlier literature report, our viability studies confirmed the ability of this process to inactivate Mycobacterium tuberculosis prior to analysis. Following library construction and the specificity study, the performance of MALDI-TOF MS was directly compared with that of 16S rRNA gene sequencing for the evaluation of 297 mycobacteria isolates, 148 Nocardia species isolates, and 61 other aerobic actinomycetes isolates under routine clinical laboratory working conditions over a 6-month period. MALDI-TOF MS is a valuable tool for the identification of these groups of organisms. Limitations in the databases and in the ability of MALDI-TOF MS to rapidly identify slowly growing mycobacteria are discussed. PMID- 26637380 TI - How Many Samples and How Many Culture Media To Diagnose a Prosthetic Joint Infection: a Clinical and Microbiological Prospective Multicenter Study. AB - Although numerous perioperative samples and culture media are required to diagnose prosthetic joint infection (PJI), their exact number and types have not yet been definitely determined with a high level of proof. We conducted a prospective multicenter study to determine the minimal number of samples and culture media required for accurate diagnosis of PJI. Over a 2-year period, consecutive patients with clinical signs suggesting PJI were included, with five perioperative samples per patient. The bacteriological and PJI diagnosis criteria were assessed using a random selection of two, three, or four samples and compared with those obtained using the recommended five samples (references guidelines). The results obtained with two or three culture media were then compared with those obtained with five culture media for both criteria. The times to-positivity of the different culture media were calculated. PJI was confirmed in 215/264 suspected cases, with a bacteriological criterion in 192 (89%). The PJI was monomicrobial (85%) or polymicrobial (15%). Percentages of agreement of 98.1% and 99.7%, respectively, for the bacteriological criterion and confirmed PJI diagnosis were obtained when four perioperative samples were considered. The highest percentages of agreement were obtained with the association of three culture media, a blood culture bottle, a chocolate agar plate, and Schaedler broth, incubated for 5, 7, and 14 days, respectively. This new procedure leads to significant cost saving. Our prospective multicenter study showed that four samples seeded on three culture media are sufficient for diagnosing PJI. PMID- 26637382 TI - An Improved One-Step Real-Time Reverse Transcription-PCR Assay for Detection of Norovirus. PMID- 26637383 TI - Comparative Evaluation of the Diagnostic Performance of the Prototype Cepheid GeneXpert Ebola Assay. AB - The Ebola virus disease (EVD) outbreak in West Africa has highlighted an urgent need for point-of-care (POC) assays for the diagnosis of this devastating disease in resource-limited African countries. The diagnostic performance characteristics of a prototype Cepheid GeneXpert Ebola POC used to detect Ebola virus (EBOV) in stored serum and plasma samples collected from suspected EVD cases in Sierra Leone in 2014 and 2015 was evaluated. The GeneXpert Ebola POC is a self-contained single-cartridge automated system that targets the glycoprotein (GP) and nucleoprotein (NP) genes of EBOV and yields results within 90 min. Results from 281 patient samples were compared to the results of a TaqMan real-time reverse transcription-PCR (RT-PCR) targeting the polymerase gene and performed on two real-time PCR machines. Agreement between the three platforms was 100% at cycle threshold (CT) values of <=34.99, but discordant results were noted between CT values of 35 and 45.The diagnostic sensitivity of the three platforms was 100% in 91 patient samples that were confirmed to be infectious by virus isolation. All three molecular platforms detected viral EBOV RNA in additional samples that did not contain viable EBOV. The analytical sensitivity of the GeneXpert Ebola POC for the detection of NP was higher, and comparable to that of polymerase gene detection, than that for the detection of GP when using a titrated laboratory stock of EBOV. There was no detectable cross-reactivity with other hemorrhagic fever viruses or arboviruses. The GeneXpert Ebola POC offers an easy to operate and sensitive diagnostic tool that can be used for the rapid screening of suspected EVD cases in treatment or in holding centers during EVD outbreaks. PMID- 26637385 TI - The Use of Microdispensers with Spatial Repellents for Personal Protection Against Mosquito Biting. AB - Mosquito-borne pathogens affect millions of people worldwide. This work describes a new method to deliver spatial repellents. Functional microdispensers (FMDs) were designed to deliver spatial repellents against mosquitoes. In vivo trials showed that FMDs protect human subjects against mosquitoes by reducing 70-90% of bites received, with a protection that lasted up to 4 weeks. FMDs can be cost effectively implemented as wearable or field-dispensed devices for local area protection, defined as a confined geographical region. PMID- 26637384 TI - Seed dormancy cycling and mortality differ between two locally adapted populations of Arabidopsis thaliana. AB - BACKGROUND AND AIMS: Intraspecific variation in seed bank dynamics should contribute to local adaptation, but is not well studied. The extent to which genetic and environmental factors affect dormancy cycling and seed mortality was investigated in the annual herb Arabidopsis thaliana by conducting a reciprocal seed burial experiment. METHODS: Seeds from two locally adapted populations (from Italy and Sweden) were buried at both of the sites of origin, and seed mortality and germinability were determined during the following 2 years for initially non dormant glasshouse-matured seeds and dormant field-matured seeds. KEY RESULTS: Mean soil temperature was higher at the Italian site compared with the Swedish site throughout the year, and the germination proportions were in general higher for seeds buried in Italy than in Sweden. The rate of secondary dormancy induction of the Italian genotype was faster than that of the Swedish genotype at both sites, while the opposite was true for the rate of dormancy release, at least at the Swedish site. The comparison of non-dormant glasshouse seeds with dormant field seeds demonstrated that A. thaliana seeds can adjust their dormancy levels to current environmental conditions, and suggests that maternal environmental conditions have only minor effects on dormancy cycles. At both sites, locally produced seeds had low germinability in the first year compared with the second year, suggesting that a considerable fraction of the seeds would enter the seed bank. In Italy, but not in Sweden, seed mortality increased rapidly during the second year of burial. CONCLUSIONS: This is the first demonstration of intraspecific genetic differentiation in the annual seed dormancy cycle of any species, and the documented difference is likely to contribute to local adaptation. The results suggest that the contribution of a seed bank to seedling recruitment should vary among environments due to differences in the rate of seed mortality. PMID- 26637386 TI - Behavioral and Toxicological Responses of Rhodnius prolixus (Hemiptera: Reduviidae) to the Insect Repellents DEET and IR3535. AB - ,N-diethyl-3-methylbenzamide (DEET) is a broad-spectrum insect repellent used by millions of people since the 1950s. Ethyl 3-[acetyl(butyl)amino]propanoate (IR3535) is a repellent developed more recently that is still not used as extensively. This study compares the behavioral and toxicological effects of both substances in fifth-instar nymphs of the blood-sucking bug Rhodnius prolixus Stal (Hemiptera: Reduviidae), one of the main vectors of American trypanosomiasis (Chagas disease). Repellency was quantified using filter paper discs as experimental arenas. Half the discs were treated with solution of repellent in acetone, and the other half with acetone alone. The lowest observed effect level was identical for both substances, 74 ug/cm2. Nymph age (between 1-3 h and 99 d from last ecdysis) had no influence on repellency. Topical application of 750 ug of DEET per nymph produced a mortality rate between 0% (24 h after application) and 40% (7 d later). The same dose of IR3535 produced no mortality during the same period of time. Simultaneous treatment with piperonylbutoxide (a mixed function microsomal oxidase inhibitor) synergized the lethal effect of DEET. Only DEET increased locomotor activity in nymphs exposed to a treated surface. Nymph antennectomy abolished DEET repellency but not its effect on locomotor activity. The concentrations of both these compounds required to produce either behavioral or toxicological effects are too high to have any practical applications in the control of R. prolixus. PMID- 26637387 TI - [Parental Social Status and other determinants of quality of life and behavioral problems: An analysis of German preterm births between 1987-2004]. AB - BACKGROUND: Knowledge of the factors affecting the development of preterm children in Germany is limited. We analysed the prevalence of preterm birth in Germany using the German Health Interview and Examination Survey for Children and Adolescents 2003-2006 and assessed factors associated with quality of life (QOL) and behavioural development in preterm children (< 37 weeks' gestational age). METHODS: Data were weighted and preterm prevalence was calculated by socioeconomic status (SES) and year of birth for 1,106 preterm children. Using linear regression models, the relationship between sociodemographic, pre- and perinatal, lifestyle, and contextual determinants on the one hand, and the QOL (KINDL(r) parent questionnaire) and behavioural problems (the total problem behaviour scale, the Strengths and Difficulties Questionnaire [SDQ]) on the other was calculated. RESULTS: Prevalence of preterm birth (mean 7.5 %) was higher in families with low compared with high SES (8.4 versus 7.0 %). In the final regression models, preterm children with high SES had higher QOL scores (+ 3.3 KINDL points, p = 0.024) compared with children with low SES, and adolescents (aged 14-17 years) had a higher QOL than children aged 7-13 years. All other variables (contextual, pre- and perinatal) were not related to QOL. In contrast, there were many determinants of behavioural development in preterms: the SDQ total score was lower in girls, children with older mothers, those from high SES and those with a high level of physical activity. However, both very low birth weight (< 1,500 g) and birth at > 34 weeks' gestation were associated with a higher SDQ total score. CONCLUSION: Given its high prevalence, preterm birth is a relevant public health issue in Germany. While SES may be the most important determinant of QOL in preterms, determinants of behavioural problems are the same as those in term children and also encompass perinatal factors. PMID- 26637388 TI - Reproductive biology and medicine 2015--the year in review. PMID- 26637389 TI - Meiotic and pedigree segregation analyses in carriers of t(4;8)(p16;p23.1) differing in localization of breakpoint positions at 4p subband 4p16.3 and 4p16.1. AB - PURPOSE: The purpose of this study was to compare meiotic segregation in sperm cells from two carriers with t(4;8)(p16;p23.1) reciprocal chromosome translocations (RCTs), differing in localization of the breakpoint positions at the 4p subband-namely, 4p16.3 (carrier 1) and 4p16.1 (carrier 2)-and to compare data of the pedigree analyses performed by direct method. METHODS: Three-color fluorescent in situ hybridization (FISH) on sperm cells and FISH mapping for the evaluation of the breakpoint positions, data from pedigrees, and direct segregation analysis of the pedigrees were performed. RESULTS: Similar proportions of normal/balanced and unbalanced sperm cells were found in both carriers. The most common was an alternate type of segregation (about 52 % and about 48 %, respectively). Unbalanced adjacent I and adjacent II karyotypes were found in similar proportions about 15 %. The direct segregation analysis (following Stengel-Rutkowski) of the pedigree of carriers of t(4;8)(p16.1;p23.1) was performed and results were compared with the data of the pedigree segregation analysis obtained earlier through the indirect method. The probability of live born progeny with unbalanced karyotype for carriers of t(4;8)(p16.1;p23.1) was moderately high at 18.8 %-comparable to the value obtained using the indirect method for the same carriership, which was 12 %. This was, however, markedly lower than the value of 41.2 % obtained through the pedigree segregation indirect analysis estimated for carriers of t(4;8)(p16.3;p23.1), perhaps due to the unique composition of genes present within the 4p16.1-4p 16.3 region. CONCLUSIONS: Revealed differences in pedigree segregation analysis did not correspond to the very similar profile of meiotic segregation patterns presented by carrier 1 and carrier 2. Most probably, such discordances may be due to differences in embryo survival rates arising from different genetic backgrounds. PMID- 26637390 TI - Morphokinetics of embryos developed from oocytes matured in vitro. AB - PURPOSE: In in vitro maturation (IVM) cycles primed with human chorionic gonadotropin (hCG), both immature and mature oocytes are retrieved from antral follicles sized 8-12 mm. Using time-lapse microscopy, we compared the morphokinetic behavior of embryos developed from oocytes matured in vivo and in vitro, testing the hypothesis that IVM affects preimplantation development. Furthermore, we extended the morphokinetic analysis of these embryos by a comparison with embryos obtained in stimulated assisted reproduction technology (ART) cycles. METHODS: In IVM cycles primed with follicle-stimulating hormone (FSH)/hCG, prior to sperm microinjection, oocytes surrounded by an expanded cumulus at retrieval and presumably mature (EC-MII) were incubated for 6 h, while immature oocytes enclosed in a compact cumulus (CC) were matured in vitro for 30 h. The morphokinetics of embryos selected for transfer or cryopreservation, derived from EC-MII and CC oocytes, were comparatively and retrospectively analyzed in terms of cleavage times (t2, t3, t4, t5, and t8) and intervals (cc2, cc3, s2, s3). For further comparison, the morphokinetics of embryos selected for transfer or cryopreservation (ICSI) or giving rise to ongoing pregnancies (model) in stimulated ART cycles was also assessed. RESULTS: The morphokinetic behavior of EC-MII and CC embryos was entirely comparable, as suggested by the absence of statistical differences in the averages of all cleavage times and intervals. Almost all cleavage and interval times were also similar between EC-MII, CC, ICSI, and model groups, with the exception of t4 and s2, which were delayed and longer, respectively, in embryos generated in IVM cycles (EC-MII and CC). CONCLUSIONS: These findings do not support the hypothesis that maturation in vitro affects embryo morphokinetics, while they suggest only marginal differences in the morphokinetics of embryos developed from oocytes matured in vivo and in vitro in IVM cycles and embryos developed from mature oocytes recovered in stimulated cycles. PMID- 26637391 TI - Characterization of gammadelta T-cells via flow cytometry. PMID- 26637392 TI - Validity of a multi-context sitting questionnaire across demographically diverse population groups: AusDiab3. AB - BACKGROUND: Sitting time questionnaires have largely been validated in small convenience samples. The validity of this multi-context sitting questionnaire against an accurate measure of sitting time is reported in a large demographically diverse sample allowing assessment of validity in varied demographic subgroups. METHODS: A subgroup of participants of the third wave of the Australian Diabetes, Obesity, and Lifestyle (AusDiab3) study wore activPAL3TM monitors (7 days, 24 hours/day protocol) and reported their sitting time for work, travel, television viewing, leisure computer use and "other" purposes, on weekdays and weekend days (n = 700, age 36-89 years, 45% men). Correlations (Pearson's r; Spearman's rho) of the self-report measures (the composite total, contextual measures and items) with monitor-assessed sitting time were assessed in the whole sample and separately in socio-demographic subgroups. Agreement was assessed using Bland-Altman plots. RESULTS: The composite total had a correlation with monitor-assessed sitting time of r = 0.46 (95% confidence interval [CI]: 0.40, 0.52); this correlation did not vary significantly between demographic subgroups (all >0.4). The contextual measure most strongly correlated with monitor-assessed sitting time was work (rho = 0.25, 95 % CI: 0.17, 0.31), followed by television viewing (rho = 0.16, 95 % CI: 0.09, 0.24). Agreement of the composite total with monitored sitting time was poor, with a positive bias (B = 0.53, SE 0.04, p < 0.001) and wide limits of agreement (+/-4.32 h). CONCLUSIONS: This multi-context questionnaire provides a total sitting time measure that ranks participants well for the purposes of assessing health associations but has limited accuracy relative to activPAL-assessed sitting time. Findings did not differ in demographic subgroups. PMID- 26637393 TI - High Fluorescence Anisotropy of Thioflavin T in Aqueous Solution Resulting from Its Molecular Rotor Nature. AB - Thioflavin T (ThT) is widely used to study amyloid fibrils while its properties are still debated in the literature. By steady-state and femtosecond time resolved fluorescence we showed that, unlike small sized rigid molecules, the fluorescence anisotropy value of the free ThT in aqueous solutions is very high, close to the limiting value. This is determined by the molecular rotor nature of ThT, where the direction of the ThT transition dipole moment S0 -> S1* is not changed either by the internal rotation of the ThT benzothiazole and aminobenzene rings relative to each other in the excited state, because the axis of this rotation coincides with the direction of the transition dipole moment, or by the rotation of the ThT molecule as a whole, because the rate of this process is 3 orders of magnitude smaller than the rate of the internal rotation which leads to the fluorescence quenching. Consequently, ThT fluorescence anisotropy cannot be directly used to study amyloid fibrils formation, as it was proposed by some authors. PMID- 26637394 TI - Outcomes and risk factors for cancer patients undergoing endoscopic intervention of malignant biliary obstruction. AB - BACKGROUND: Malignant bile duct obstruction is a common problem among cancer patients with hepatic or lymphatic metastases. Endoscopic retrograde cholangiography (ERC) with the placement of a stent is the method of choice to improve biliary flow. Only little data exist concerning the outcome of patients with malignant biliary obstruction in relationship to microbial isolates from bile. METHODS: Bile samples were taken during the ERC procedure in tumor patients with biliary obstruction. Clinical data including laboratory values, tumor specific treatment and outcome data were prospectively collected. RESULTS: 206 ERC interventions in 163 patients were recorded. In 43 % of the patients, systemic treatment was (re-) initiated after successful biliary drainage. A variety of bacteria and fungi was detected in the bile samples. One-year survival was significantly worse in patients from whom multiresistant pathogens were isolated than in patients, in whom other species were detected. Increased levels of inflammatory markers were associated with a poor one-year survival. The negative impact of these two factors was confirmed in multivariate analysis. In patients with pancreatic cancer, univariate analysis showed a negative impact on one-year survival in case of detection of Candida species in the bile. Multivariate analysis confirmed the negative prognostic impact of Candida in the bile in pancreatic cancer patients. CONCLUSION: Outcome in tumor patients with malignant bile obstruction is associated with the type of microbial biliary colonization. The proof of multiresistant pathogens or Candida, as well as the level of inflammation markers, have an impact on the prognosis of the underlying tumor disease. PMID- 26637395 TI - Role of Noncoding RNAs as Biomarker and Therapeutic Targets for Liver Fibrosis. AB - Noncoding RNAs (ncRNAs) including microRNAs (miRNAs) regulate gene expression at the posttranscriptional level, whereas long coding RNAs (lncRNAs) modulate gene expression both at transcriptional and posttranscriptional levels in mammals. Accumulated evidence demonstrates the widespread aberrations in ncRNA expression associated with almost all types of liver disease. However, the role of ncRNAs in liver fibrosis is poorly understood. Liver fibrosis is the process of excessive accumulation of extracellular matrix (ECM) proteins in the liver that lead to organ dysfunction and tumorigenesis. In this review, we summarize the current knowledge on the role of ncRNAs in promoting or repressing liver fibrosis caused by nonviral agents, potential use of circulating miRNAs as biomarkers of liver fibrosis, and therapeutic approaches to treat liver fibrosis by targeting the dysregulated miRNAs. PMID- 26637396 TI - GATA3 in Breast Cancer: Tumor Suppressor or Oncogene? AB - GATA3 is a highly conserved, essential transcription factor expressed in a number of tissues, including the mammary gland. GATA3 expression is required for normal development of the mammary gland where it is estimated to be the most abundant transcription factor in luminal epithelial cells. In breast cancer, GATA3 expression is highly correlated with the luminal transcriptional program. Recent genomic analysis of human breast cancers has revealed high-frequency mutation in GATA3 in luminal tumors, suggesting "driver" function(s). Here we discuss mutation of GATA3 in breast cancer and the potential mechanism(s) by which mutation may lead to a growth advantage in cancer. PMID- 26637397 TI - Cord Blood-Derived Quiescent CD34+ Cells Are More Transcriptionally Matched to AML Blasts Than Cytokine-Induced Normal Human Hematopoietic CD34+ Cells. AB - Acute myeloid leukemia (AML) is characterized by developmental arrest, which is thought to arise from transcriptional dysregulation of myeloid development programs. Hematopoietic stem and progenitor cells (HSPCs) isolated from human blood are frequently used as a normal comparator in AML studies. Previous studies have reported changes in the transcriptional program of genes involved in proliferation, differentiation, apoptosis, and homing when HSPCs were expanded ex vivo. The intrinsic functional differences between quiescent and dividing CD34+ HSPCs prompted us to determine whether fresh or cytokine-induced cord blood derived CD34+ HSPCs are a more appropriate normal control compared to AML blasts. Based on principal component analysis and gene expression profiling we demonstrate that CD34+ HSPCs that do not undergo ex vivo expansion are transcriptionally similar to minimally differentiated AML blasts. This was confirmed by comparing the cell cycle status of the AML blasts and the HSPCs. We suggest that freshly isolated CD34+ HSPCs that do not undergo ex vivo expansion would serve as a better control to identify novel transcriptional targets in the AML blast population. PMID- 26637398 TI - Association of Genetic Variants of SIRT1 With Type 2 Diabetes Mellitus. AB - SIRT1 has been demonstrated in nutrient-sensing and insulin-signaling pathways in in vivo and in vitro experiments, but there is minimal information concerning the association between gene polymorphisms of SIRT1 and type 2 diabetes mellitus (T2DM) in a Chinese Han population. Using case-control design, we recruited 310 unrelated T2DM patients from inpatients at Shanghai Jiao Tong University Affiliated Sixth People's Hospital, while 301 healthy controls were volunteers from the community for regular medical checkup. All participants were genotyped within the SIRT1 region. The following five SNPs rs10509291, rs12778366, rs10997870, rs10823112, and rs4746720 cover 100% of common genetic variations (minor allele frequency>=0.05) within the SIRT1 gene (r2>=0.8). The genotypes of SIRT1 gene polymorphisms were analyzed by the Snapshot assay and DNA sequencing. The resulting data show that there was significant genetic differentiation in rs10823112 [p=0.003; OR (95% CI)=1.515 (1.152-1.994) for genotype], rs4746720 [p=0.024; OR (95% CI)=1.37 (1.037-1.674) for genotype], and rs10509291 [p=0.002; OR (95% CI)=1.551 (1.179-2.04) for genotype] between T2DM and control subjects. However, the result of rs4746720 was no longer significant after correction for multiple testing (p after Bonferroni correction=0.12); the results of rs10509291and rs10823112 were still significantly different between the two groups (p after Bonferroni correction=0.01 and 0.015, respectively). Linear regression analyses adjusting for age, gender, and body mass index (BMI) showed that HbA1c and HOMA-IR in subjects with rs10509291 AA genotype were higher than those with TT genotype in T2DM group (p=0.045, p=0.035, respectively). Together, our data show that genetic variation of the SIRT1 gene is related to insulin resistance and increase risk of T2DM in Chinese Han population. The risk allele A at SIRT1 rs10509291 was closely associated with T2DM, and subjects who were homozygous of the A allele were more likely to develop T2DM. PMID- 26637399 TI - The Histone Acetyltransferase GCN5 Expression Is Elevated and Regulated by c-Myc and E2F1 Transcription Factors in Human Colon Cancer. AB - The histone acetyltransferase GCN5 has been suggested to be involved in promoting cancer cell growth. But its role in human colon cancer development remains unknown. Herein we discovered that GCN5 expression is significantly upregulated in human colon adenocarcinoma tissues. We further demonstrate that GCN5 is upregulated in human colon cancer at the mRNA level. Surprisingly, two transcription factors, the oncogenic c-Myc and the proapoptotic E2F1, are responsible for GCN5 mRNA transcription. Knockdown of c-Myc inhibited colon cancer cell proliferation largely through downregulating GCN5 transcription, which can be fully rescued by the ectopic GCN5 expression. In contrast, E2F1 expression induced human colon cancer cell death, and suppression of GCN5 expression in cells with E2F1 overexpression further facilitated cell apoptosis, suggesting that GCN5 expression is induced by E2F1 as a possible negative feedback in suppressing E2F1-mediated cell apoptosis. In addition, suppression of GCN5 with its specific inhibitor CPTH2 inhibited human colon cancer cell growth. Our studies reveal that GCN5 plays a positive role in human colon cancer development, and its suppression holds a great therapeutic potential in antitumor therapy. PMID- 26637400 TI - ELK3 Expression Correlates With Cell Migration, Invasion, and Membrane Type 1 Matrix Metalloproteinase Expression in MDA-MB-231 Breast Cancer Cells. AB - ELK3 is a member of the Ets family of transcription factors. Its expression is associated with angiogenesis, vasculogenesis, and chondrogenesis. ELK3 inhibits endothelial migration and tube formation through the regulation of MT1-MMP transcription. This study assessed the function of ELK3 in breast cancer (BC) cells by comparing its expression between basal and luminal cells in silico and in vitro. In silico analysis showed that ELK3 expression was higher in the more aggressive basal BC cells than in luminal BC cells. Similarly, in vitro analysis showed that ELK3 mRNA and protein expression was higher in basal BC cells than in normal cells and luminal BC cells. To investigate whether ELK3 regulates basal cell migration or invasion, knockdown was achieved by siRNA in the basal BC cell line MDA-MB-231. Inhibition of ELK3 expression decreased cell migration and invasion and downregulated MT1-MMP, the expression of which is positively correlated with tumor cell invasion. In silico analysis revealed that ELK3 expression was associated with that of MT1-MMP in several BC cell lines (0.98 Pearson correlation coefficient). Though MT1-MMP expression was upregulated upon ELK3 nuclear translocation, ELK3 did not directly bind to the 1.3-kb promoter region of the MT1-MMP gene. These results suggest that ELK3 plays a positive role in the metastasis of BC cells by indirectly regulating MT1-MMP expression. PMID- 26637402 TI - Poor Concordance Between Elevated Blood Pressures in the Preschool Years. AB - The 2013 US Preventive Services Task Force report found insufficient evidence for pediatric blood pressure screening. This retrospective study evaluated the reliability of successive annual blood pressure screening of children for hypertension at the 3-, 4-, and 5-year-old health maintenance visits (January 1, 2010 to June 18, 2014). Of 328 patients, 290 (88%) were normotensive at all 3 visits. All elevated blood pressures (>=95th percentile) were stage 1. No patient was hypertensive (3 elevated measures). The extended concordance correlation coefficient indicated poor agreement for systolic (0.19, 95% CI -0.49 to 0.72) and diastolic (0.11, 95% CI -0.39 to 0.56) measurements. Blood pressure at the 3 year (kappa -0.008, 95% CI -0.11 to 0.09), 4-year (kappa 0.09, 95% CI -0.06 to 0.24), or 5-year (kappa 0.08, 95% CI -0.05 to 0.20) visit was not associated with elevated blood pressures at the other 2 time points. In the preschool years, stage 1 elevated blood pressures do not correlate with hypertension and may be better managed by watchful waiting and parental reassurance. PMID- 26637401 TI - Dual-source CT in blunt trauma patients: elimination of diaphragmatic motion using high-pitch spiral technique. AB - The purpose of this study was to compare diaphragmatic motion on dual-source high pitch (DS-HP) and conventional single-source (SS) CT scans in trauma patients. Seventy-five consecutive trauma patients who presented to a level one trauma center over a 6-month period were scanned with a standardized whole body trauma CT protocol including both DS-HP chest (pitch = 2.1-2.5) and SS abdominal CT scans. Subjective analysis of diaphragmatic motion was performed by two readers using a four-point motion scale in seven regions of the diaphragm on coronal and axial slices. An overall confidence score to exclude a diaphragmatic tear was determined (1 to 10, 10: completely confident and 1: impossible to exclude). Wilcoxon rank sum tests were used for statistical analysis, and p < 0.05 was considered significant. Mean confidence score of 9.85 for DS-HP was significantly better than the mean score of 7.66 for SS images (p < 0.0001). Diaphragmatic motion scores and subjective diaphragmatic motion artifact on coronal and axial images were significantly better for DS-HP images in all areas when compared individually (p < 0.0001) and overall (p < 0.0001). Regions of DS-HP (99.2 %) were diagnostic, whereas only 87.0 % % regions on SS were. Complete agreement of motion scores was present in 92 % of cases, with moderate overall agreement for confidence to exclude a diaphragmatic tear (kappa = 0.45). Dual-source high-pitch CT scanning is advantageous as it allows for significantly better evaluation of diaphragmatic structures by minimizing motion artifacts on images of freely breathing trauma patients. PMID- 26637403 TI - Email Isn't Just for Old People: Teen Acceptability of Internet Communication With Medical Providers. PMID- 26637404 TI - Massachusetts Pediatricians' Views Toward Body Mass Index Screening in Schools: Continued Controversy. AB - Objective Evaluate Massachusetts pediatricians' views toward school-based body mass index screening since its implementation. Methods Survey of 286 members of the Massachusetts Chapter of the American Academy of Pediatrics on attitudes toward screening and perceived impact on clinical practice. Results Overall, 36.3% supported screening, with suburban or rural pediatricians significantly less likely (vs urban) to indicate support. Less than 10% of pediatricians agreed or strongly agreed that screening improved communication with schools (4.2%), communication with families (8.9%), or helped them care for patients (7.0%), with suburban or rural pediatricians significantly less likely to agree. Most pediatricians reported contact from patients regarding screening (59.4%) and identifying concerns from patients regarding screening during office visits (60.4%), including bullying and self-esteem. Suburban or rural pediatricians were significantly more likely to report patient contact and concerns related to screening. Conclusions Support for school-based body mass index screening is low among Massachusetts pediatricians, particularly among suburban and rural pediatricians. PMID- 26637406 TI - The regulation of function, growth and survival of GLP-1-producing L-cells. AB - Glucagon-like peptide-1 (GLP-1) is a peptide hormone, released from intestinal L cells in response to hormonal, neural and nutrient stimuli. In addition to potentiation of meal-stimulated insulin secretion, GLP-1 signalling exerts numerous pleiotropic effects on various tissues, regulating energy absorption and disposal, as well as cell proliferation and survival. In Type 2 Diabetes (T2D) reduced plasma levels of GLP-1 have been observed, and plasma levels of GLP-1, as well as reduced numbers of GLP-1 producing cells, have been correlated to obesity and insulin resistance. Increasing endogenous secretion of GLP-1 by selective targeting of the molecular mechanisms regulating secretion from the L-cell has been the focus of much recent research. An additional and promising strategy for enhancing endogenous secretion may be to increase the L-cell mass in the intestinal epithelium, but the mechanisms that regulate the growth, survival and function of these cells are largely unknown. We recently showed that prolonged exposure to high concentrations of the fatty acid palmitate induced lipotoxic effects, similar to those operative in insulin-producing cells, in an in vitro model of GLP-1-producing cells. The mechanisms inducing this lipototoxicity involved increased production of reactive oxygen species (ROS). In this review, regulation of GLP-1-secreting cells is discussed, with a focus on the mechanisms underlying GLP-1 secretion, long-term regulation of growth, differentiation and survival under normal as well as diabetic conditions of hypernutrition. PMID- 26637407 TI - Abiraterone-induced rhabdomyolysis: A case report. AB - Abiraterone is an inhibitor of androgen biosynthesis indicated for the treatment of metastatic castration-resistant prostate cancer. Common side effects include diarrhea, edema, hypokalemia, hypertension, and liver function test abnormalities. We report a case of rhabdomyolysis developing in association with the use of abiraterone. Following discontinuation of abiraterone, creatine kinase concentrations decreased gradually throughout the duration of the hospitalization. PMID- 26637408 TI - Reliability of chemotherapy preparation processes: Evaluating independent double checking and computer-assisted gravimetric control. AB - Background and objectives Centralized chemotherapy preparation units have established systematic strategies to avoid errors. Our work aimed to evaluate the accuracy of manual preparations associated with different control methods. Method A simulation study in an operational setting used phenylephrine and lidocaine as markers. Each operator prepared syringes that were controlled using a different method during each of three sessions (no control, visual double-checking, and gravimetric control). Eight reconstitutions and dilutions were prepared in each session, with variable doses and volumes, using different concentrations of stock solutions. Results were analyzed according to qualitative (choice of stock solution) and quantitative criteria (accurate, <5% deviation from the target concentration; weakly accurate, 5%-10%; inaccurate, 10%-30%; wrong, >30% deviation). Results Eleven operators carried out 19 sessions. No final preparation (n = 438) contained a wrong drug. The protocol involving no control failed to detect 1 of 3 dose errors made and double-checking failed to detect 3 of 7 dose errors. The gravimetric control method detected all 5 out of 5 dose errors. The accuracy of the doses measured was equivalent across the control methods ( p = 0.63 Kruskal-Wallis). The final preparations ranged from 58% to 60% accurate, 25% to 27% weakly accurate, 14% to 17% inaccurate and 0.9% wrong. A high variability was observed between operators. Discussion Gravimetric control was the only method able to detect all dose errors, but it did not improve dose accuracy. A dose accuracy with <5% deviation cannot always be guaranteed using manual production. Automation should be considered in the future. PMID- 26637405 TI - The natriuretic peptides system in the pathophysiology of heart failure: from molecular basis to treatment. AB - After its discovery in the early 1980s, the natriuretic peptide (NP) system has been extensively characterized and its potential influence in the development and progression of heart failure (HF) has been investigated. HF is a syndrome characterized by the activation of different neurohormonal systems, predominantly the renin-angiotensin (Ang)-aldosterone system (RAAS) and the sympathetic nervous system (SNS), but also the NP system. Pharmacological interventions have been developed to counteract the neuroendocrine dysregulation, through the down modulation of RAAS with ACE (Ang-converting enzyme) inhibitors, ARBs (Ang receptor blockers) and mineralcorticoid antagonists and of SNS with beta blockers. In the last years, growing attention has been paid to the NP system. In the present review, we have summarized the current knowledge on the NP system, focusing on its role in HF and we provide an overview of the pharmacological attempts to modulate NP in HF: from the negative results of the study with neprilysin (NEP) inhibitors, alone or associated with an ACE inhibitor and vasopeptidase inhibitors, to the most recently and extremely encouraging results obtained with the new pharmacological class of Ang receptor and NEP inhibitor, currently defined ARNI (Ang receptor NEP inhibitor). Indeed, this new class of drugs to manage HF, supported by the recent results and a vast clinical development programme, may prompt a conceptual shift in the treatment of HF, moving from the inhibition of RAAS and SNS to a more integrated target to rebalance neurohormonal dysregulation in HF. PMID- 26637409 TI - Establishing a birth cohort to investigate the course and aetiology of asthma and allergies across three generations - rationale, design, and methods of the ACROSSOLAR study. AB - BACKGROUND: Atopic diseases are a major burden of disease on a global scale. Regarding their aetiology, the early years of life are assumed to play a crucial role. In addition, there is growing evidence that elucidating the impact of cross generational effects and epigenetic mechanisms such as DNA methylation can substantially widen the scientific knowledge of the occurrence and progression of these diseases. We are thus aiming at following the course of asthma, allergies, and potential risk factors for their occurrence across three generations by establishing a birth cohort in the offspring of an existing population-based cohort. METHODS/DESIGN: 2051 young adults who have been recruited in 1995 for Phase II of the International Study of Asthma and Allergies in Childhood (ISAAC) and who have subsequently been followed-up by the Study on Occupational Allergy Risks (SOLAR) are asked bi-annually since 2009 if they conceived a child in the meantime. If parenthood is reported, parents are invited to enrol along with their children in the ACROSSOLAR cohort. Participation involves completing a questionnaire assessing general and health-related information about the course of the pregnancy and the first year of life of their children. Subsequently, the children are followed up until primary school age when asthma and allergies can be diagnosed reliably. In addition, DNA for epigenetic analysis will be collected and analysed. Longitudinal data analysis techniques will then be used to assess potential associations between early-life exposures and onset of childhood asthma and allergies taking into account epigenetics. DISCUSSION: Birth cohorts are especially suited to elucidate the impact of genetic predisposition, epigenetics, exposures during the first years of life, and gene-environment interactions on the occurrence and progression of asthma and allergies. By building upon an existing cohort, ACROSSOLAR offers a unique and cost-effective opportunity to investigate the aetiology of atopic disease in a prospective and cross generational way. PMID- 26637410 TI - Renal abnormalities in a cohort of HIV-infected children and adolescents. AB - BACKGROUND: This study aimed to identify the prevalence of renal abnormalities and the evolution of glomerular filtration rate (GFR) among human immunodeficiency virus (HIV)- infected children and adolescents followed up in an infectious disease outpatient pediatric clinic. METHODS: We performed a cohort study of 115 children and adolescents. Outcomes of two evaluations for urinalysis, microalbuminuria/urinary creatinine ratio, urinary retinol-binding protein (uRBP) concentration, and estimated GFR (eGFR) were obtained for each patient, with an average interval of 6 months between evaluations. These changes were correlated with gender, age, race, body mass index (BMI), height-for-age (H/A) percentile, clinical and immunological classification of HIV infection, use of antiretroviral therapy (ART), HIV viral load (VL), and CD4+ T-lymphocyte count. RESULTS: Mean patient age at the time of inclusion in the study was 12.6 +/- 3.2 years; 50.4 % were male, 81.7 % had acquired immune defeciency syndrome (AIDS), 80.9 % had CD4+ < 500 cells/mm(3), and 87.8 % were on ART. Urinary changes included hematuria (11.3 %), proteinuria (7 %), and microalbuminuria (11.6 %); uRBP was present in 3.8 %; and mean eGFR was 163 +/- 32 ml/min/1.73 m(2). CONCLUSIONS: The subclinical renal abnormalities found in this study may indicate early manifestations of a broad spectrum of renal dysfunction associated with HIV and involves the decision to initiate or modify ART. PMID- 26637411 TI - Is the routine use of a water-soluble contrast enema prior to closure of a loop ileostomy necessary? A review of a single institution experience. AB - BACKGROUND: The aims of the study were to determine the radiological leak rate in those patients who had undergone a resection for left-sided colorectal cancer and to see if the presence of a leak can be related with the postoperative clinical period. We also aimed to identify any common factors between patients with leak. METHODS: A retrospective analysis of prospectively collected data of all patients who underwent a left-sided colorectal cancer resection with formation of a defunctioning ileostomy was undertaken. Between 2005 and 2010, 418 such patients were identified. RESULTS: A water-soluble contrast enema was performed in 339 patients (81.1 %). Of these, 24 (7.1 %) were reported to show an anastomotic leak. Data for these 24 patients is presented in this study. Twenty-three (95.8 %) of the leaks occurred in patients who had undergone an anterior resection; 95.8 % of the patients with a leak were male. Fifteen (62.5 %) patients underwent neo-adjuvant radiation. The mean length of stay in those patients shown to have a subsequent radiological leak was 18.8 days (median), compared with the overall unit figures of 12 days. Only 29.2 % of the patients who had a leak identified had an uncomplicated postoperative period. Overall 87.5 % of the patients had a reversal of the ileostomy. CONCLUSIONS: Radiological leakage is not uncommon. The majority of patients, who were shown to have a radiological leak in this study, were male, had undergone an anterior resection, had received neo-adjuvant radiation, had a longer initial length of stay and had postoperative complications. Water-soluble contrast enemas could be selectively used in patients with these characteristics. PMID- 26637412 TI - Novel MR imaging method--MAVRIC--for metal artifact suppression after joint replacement in musculoskeletal tumor patients. AB - BACKGROUND: Standard imaging modality for the follow-up after prosthetic replacements for musculoskeletal tumor patients has been conventional radiography. This technique is effective in detecting subtle changes in bone adjacent to metal implants, but in many cases, radiographs do not lead to definitive diagnosis of postoperative adverse events such as acute infection, local recurrence of soft tissue tumor or soft tissue local recurrence of osseous sarcoma. Conventional MRI sequences have not been effective due to metal artifacts. In this study, we tried to elucidate the effectiveness of metal artifact suppression using novel sequence, multiacquisition variable-resonance image combination (MAVRIC), after musculoskeletal tumor surgeries. METHODS: We retrospectively analyzed 5 cases of malignant bone and soft tissue sarcoma patients who were reconstructed with metal prosthesis after wide resection of tumors. Images obtained using MAVRIC and short tau inversion recovery (STIR) were compared side by side. The paired MAVRIC and STIR images were qualitatively compared independently by two specialists for 4 parameters: visualization of bone - implant interface, visualization of surrounding soft tissues, image blurring, and overall image quality. Quantitatively, paired images were reviewed to identify the slice where the metal artifact was maximal, and a region of interest encompassing the implant and surrounding artifact was drawn using Advantage Workstation (GE Healthcare, Japan). RESULTS: There were no local recurrences that were detected. By utilizing MAVRIC, visualization of the bone - implant interface and visualization of the surrounding soft tissue were significantly improved in MAVRIC compared to STIR. Although blurring was worse on the MAVRIC acquisitions, the overall image quality was still better on MAVRIC. Quantitatively, the area of metal artifact measured using MAVRIC was markedly less compared to STIR (61.4 cm(2) vs 135.9 cm(2)). CONCLUSION: Despite the relatively small number of cases in the present study, our observation strongly suggests that MAVRIC is able to improve the quality of images by decreasing the artifact caused by endoprosthesis, frequently utilized in reconstruction of musculoskeletal tumor patients. Further installments of conventional imaging sequences with the addition of gadolinium - enhancement will enable increased accuracy in diagnosing local recurrences of sarcoma patients. PMID- 26637413 TI - The lost correlation between heat shock protein 70 (HSPA1A) and plasminogen activator inhibitor-1 in patients with type 2 diabetes and albuminuria. AB - We aimed to study the relation between plasma levels of stress-induced heat shock protein 70 (HSPA1A) with plasminogen activator inhibitor-1 (PAI-1) and high density lipoprotein cholesterol (HDL-C), apolipoprotein A1 (Apo-A1), and HDL C/Apo-A1 ratio. In a matched case-control study on patients with diabetes (40 patients with albuminuria and 40 without albuminuria matched for age, sex, and body mass index), we observed that plasma levels of HSPA1A and PAI-1 are increased in patients with albuminuria (0.55 +/- 0.02 vs. 0.77 +/- 0.04 ng/ml, p value <0.001 for HSPA1A; 25.9 +/- 2 vs. 31.8 +/- 2.4 ng/ml, p value <0.05 for PAI 1). There was a significant correlation between HSPA1A and PAI-1 in diabetic patients without albuminuria (r = 0.28; p value = 0.04), but not in those with albuminuria (r = 0.07; p value = 0.63). No association was found between HSPA1A and HDL-C, between HSPA1A and Apo-A1, or between HSPA1A and HDL-C/Apo-A1 ratio. We concluded that there is a direct correlation between plasma HSPA1A and PAI-1 levels in patients with diabetes, which is lost when they develop albuminuria. PMID- 26637414 TI - Characterization and function analysis of Hsp60 and Hsp10 under different acute stresses in black tiger shrimp, Penaeus monodon. AB - Heat shock proteins (Hsps) are a class of highly conserved proteins produced in virtually all living organisms from bacteria to humans. Hsp60 and Hsp10, the most important mitochondrial chaperones, participate in environmental stress responses. In this study, the full-length complementary DNAs (cDNAs) of Hsp60 (PmHsp60) and Hsp10 (PmHsp10) were cloned from Penaeus monodon. Sequence analysis showed that PmHsp60 and PmHsp10 encoded polypeptides of 578 and 102 amino acids, respectively. The expression profiles of PmHsp60 and PmHsp10 were detected in the gills and hepatopancreas of the shrimps under pH challenge, osmotic stress, and heavy metal exposure, and results suggested that PmHsp60 and PmHsp10 were involved in the responses to these stimuli. ATPase and chaperone activity assay indicated that PmHsp60 could slow down protein denaturation and that Hsp60/Hsp10 may be combined to produce a chaperone complex with effective chaperone and ATPase activities. Overall, this study provides useful information to help further understand the functional mechanisms of the environmental stress responses of Hsp60 and Hsp10 in shrimp. PMID- 26637416 TI - IOF Regionals - 3rd Middle East & Africa Osteoporosis Meeting : Oral Communication Abstracts. PMID- 26637415 TI - IOF Regionals - 3rd Middle East & Africa Osteoporosis Meeting : Plenary Lecture Abstracts. PMID- 26637417 TI - IOF Regionals - 3rd Middle East & Africa Osteoporosis Meeting : Poster Presentation Abstracts. PMID- 26637419 TI - The cystic fibrosis microbiome in an ecological perspective and its impact in antibiotic therapy. AB - The recent focus on the cystic fibrosis (CF) complex microbiome has led to the recognition that the microbes can interact between them and with the host immune system, affecting the disease progression and treatment routes. Although the main focus remains on the interactions between traditional pathogens, growing evidence supports the contribution and the role of emergent species. Understanding the mechanisms and the biological effects involved in polymicrobial interactions may be the key to improve effective therapies and also to define new strategies for disease control. This review focuses on the interactions between microbe-microbe and host-microbe, from an ecological point of view, discussing their impact on CF disease progression. There are increasing indications that these interactions impact the success of antimicrobial therapy. Consequently, a new approach where therapy is personalized to patients by taking into account their individual CF microbiome is suggested. PMID- 26637420 TI - Enhancement of sludge granulation in hydrolytic acidogenesis by denitrification. AB - Acidogenesis is an important pretreatment process for various industrial wastewater treatments. Granular sludge is an efficient form of a microbial community in anaerobic methanogenic reactors, such as upflow anaerobic sludge blanket (UASB), but it is hard to develop in the acidogenic process due to the short hydraulic retention times (HRTs) of acidogenesis. In this study, nitrate was added into an acidogenic reactor as an electron acceptor to enhance electron exchange between acidogenic and denitrifying bacteria to accelerate sludge growth in the acidogenesis process. The results showed that it developed solid and mature granular sludge with a mean size of 410 +/- 35 MUm over 84 days of operation. Comparatively, the sludge in a no-nitrate acidogenic reactor showed a flocculent appearance with a mean size of 110 +/- 18 MUm. Analysis of the microbial community indicated that denitrifying bacteria interwoven with propionate-oxidizing bacteria were distributed in the outer granule layer, which provided an ideal shield for susceptible microorganisms inside the granules. This microbial structure was favorable for the development of granular sludge and made the system possible to respond well to shocks in the operation. PMID- 26637421 TI - Two transcription factors, CabA and CabR, are independently involved in multilevel regulation of the biosynthetic gene cluster encoding the novel aminocoumarin, cacibiocin. AB - Aminocoumarins are potent antibiotics belonging to a relatively small group of secondary metabolites produced by actinomycetes. Genome mining of Catenulispora acidiphila has recently led to the discovery of a gene cluster responsible for biosynthesis of novel aminocoumarins, cacibiocins. However, regulation of the expression of this novel gene cluster has not yet been analyzed. In this study, we identify transcriptional regulators of the cacibiocin gene cluster. Using a heterologous expression system, we show that the CabA and CabR proteins encoded by cabA and cabR genes in the cacibiocin gene cluster control the expression of genes involved in the biosynthesis, modification, regulation, and potentially, efflux/resistance of cacibiocins. CabA positively regulates the expression of cabH (the first gene in the cabHIYJKL operon) and cabhal genes encoding key enzymes responsible for the biosynthesis and halogenation of the aminocoumarin moiety, respectively. We provide evidence that CabA is a direct inducer of cacibiocin production, whereas the second transcriptional factor, CabR, is involved in the negative regulation of its own gene and cabT-the latter of which encodes a putative cacibiocin transporter. We also demonstrate that CabR activity is negatively regulated in vitro by aminocoumarin compounds, suggesting the existence of analogous regulation in vivo. Finally, we propose a model of multilevel regulation of gene transcription in the cacibiocin gene cluster by CabA and CabR. PMID- 26637422 TI - Biotechnology and pharmacological evaluation of Indian vegetable crop Lagenaria siceraria: an overview. AB - Bottle gourd (Lagenaria siceraria) belongs to the family Cucurbitaceae, which comprises about 118 genera and 825 species. It is an important vegetable crop of India, and its production is influenced by a number of factors viz., environmental, nutritional, cultural operation and use of plant growth regulators. Since, bottle gourd belongs to a medicinal family, it plays a major role in the treatment of several diseases related to the skin and heart. There are several organic chemical compounds including vitamin B complex, pectin, dietary soluble fibres, ascorbic acid, beta-carotene, amino acids and minerals which have been isolated from this species. Therefore, the bottle gourd is considered to have a great impact on therapeutic health benefits. Due to drastic industrialization and urbanization, most of the human beings are facing several ill effects which may lead to death at extreme cases. Hence, the major research area was said to be nanotechnology. Taking into consideration, we have combined nanotechnology field with waste source in the name of green synthesis and planned to cure several diseases, as most of the researchers focused their work on this and succeeded too. The present study is a complete review of L. siceraria that covers the ethnomedical uses, chemical constituents, and pharmacological profile. This study is mainly focused on the antibacterial, hepatoprotective, diuretic and anthelminthic activities. PMID- 26637423 TI - Microbial analysis of in situ biofilm formation in drinking water distribution systems: implications for monitoring and control of drinking water quality. AB - Biofilm formation in drinking water distribution systems (DWDS) is influenced by the source water, the supply infrastructure and the operation of the system. A holistic approach was used to advance knowledge on the development of mixed species biofilms in situ, by using biofilm sampling devices installed in chlorinated networks. Key physico-chemical parameters and conventional microbial indicators for drinking water quality were analysed. Biofilm coverage on pipes was evaluated by scanning electron microscopy (SEM) and confocal laser scanning microscopy (CLSM). The microbial community structure, bacteria and fungi, of water and biofilms was assessed using pyrosequencing. Conventional wisdom leads to an expectation for less microbial diversity in groundwater supplied systems. However, the analysis of bulk water showed higher microbial diversity in groundwater site samples compared with the surface water site. Conversely, higher diversity and richness were detected in biofilms from the surface water site. The average biofilm coverage was similar among sites. Disinfection residual and other key variables were similar between the two sites, other than nitrates, alkalinity and the hydraulic conditions which were extremely low at the groundwater site. Thus, the unexpected result of an exceptionally low diversity with few dominant genera (Pseudomonas and Basidiobolus) in groundwater biofilm samples, despite the more diverse community in the bulk water, is attributed to the low-flow hydraulic conditions. This finding evidences that the local environmental conditions are shaping biofilm formation, composition and amount, and hence managing these is critical for the best operation of DWDS to safeguard water quality. PMID- 26637424 TI - Pilot-scale verification of maximum tolerable hydrodynamic stress for mammalian cell culture. AB - Although several scaling bioreactor models of mammalian cell cultures are suggested and described in the literature, they mostly lack a significant validation at pilot or manufacturing scale. The aim of this study is to validate an oscillating hydrodynamic stress loop system developed earlier by our group for the evaluation of the maximum operating range for stirring, based on a maximum tolerable hydrodynamic stress. A 300-L pilot-scale bioreactor for cultivation of a Sp2/0 cell line was used for this purpose. Prior to cultivations, a stress sensitive particulate system was applied to determine the stress values generated by stirring and sparging. Pilot-scale data, collected from 7- to 28-Pa maximum stress conditions, were compared with data from classical 3-L cultivations and cultivations from the oscillating stress loop system. Results for the growth behavior, analyzed metabolites, productivity, and product quality showed a dependency on the different environmental stress conditions but not on reactor size. Pilot-scale conditions were very similar to those generated in the oscillating stress loop model confirming its predictive capability, including conditions at the edge of failure. PMID- 26637425 TI - Key high molecular weight PAH-degrading bacteria in a soil consortium enriched using a sand-in-liquid microcosm system. AB - A novel biphasic system containing mineral medium and sand coated with a biologically weathered creosote-PAH mixture was developed to specifically enrich the high molecular weight polycyclic aromatic hydrocarbon (HMW PAH)-degrading community from a creosote-polluted soil. This consortium (UBHP) removed 70% of the total HMW PAHs and their alkyl-derivatives in 12 weeks. Based on a combined culture-dependent/independent approach, including clone library analysis, detection of catabolic genes, metabolomic profiles, and characterization of bacterial isolates, 10 phylotypes corresponding to five major genera (Sphingobium, Sphingomonas, Achromobacter, Pseudomonas, and Mycobacterium) were pointed out as key players within the community. In response to exposure to different single PAHs, members of sphingomonads were associated to the utilization of phenanthrene, fluoranthene, benzo[a]anthracene, and chrysene, while the degradation of pyrene was mainly associated to low-abundance mycobacteria. In addition to them, a number of uncultured phylotypes were detected, being of special relevance a group of Gammaproteobacteria closely related to a group previously associated with pyrene degradation that were here related to benzo(a)anthracene degradation. The overall environmental relevance of these phylotypes was confirmed by pyrosequencing analysis of the microbial community shift in the creosote-polluted soil during a lab-scale biostimulation. PMID- 26637426 TI - Identification and characterization of a unique role for EDB fibronectin in phagocytosis. AB - Plasma fibronectin is a circulating protein that facilitates phagocytosis by connecting bacteria to immune cells. A fibronectin isoform, which includes a sequence of 90 AA called extra-domain B (EDB), is synthesized de novo at the messenger RNA (mRNA) level in immune cells, but the reason for its expression remains elusive. We detected an 80-fold increase in EDB-containing fibronectin in the cerebrospinal fluid of patients with bacterial meningitis that was most pronounced in staphylococcal infections. A role for this isoform in phagocytosis was further suggested by enhanced EDB fibronectin release after internalization of Staphylococcus aureus in vitro. Using transgenic mouse models, we established that immune cell production of fibronectin contributes to phagocytosis, more so than circulating plasma fibronectin, and that accentuated release of EDB containing fibronectin by immune cells improved phagocytosis. In line with this, administration of EDB fibronectin enhanced in vitro phagocytosis to a larger extent than plasma fibronectin. This enhancement was mediated by alphavbeta3 integrin as shown using inhibitors or cells from beta3 integrin knockout mice. Thus, we identified both a novel function for EDB fibronectin in augmenting phagocytosis over circulating plasma fibronectin, as well as the mediating receptor. Our data also establish for the first time, a direct role for beta3 integrin in bacterial phagocytosis in mammals. KEY MESSAGES: * Fibronectin containing an extra domain called EDB is released in bacterial meningitis. * EDB containing fibronectin enhances phagocytosis more than plasma fibronectin. * The enhancement is mediated by activation of alphavbeta3 integrin in the presence of EDB. PMID- 26637427 TI - Autoimmune encephalitis in humans: how closely does it reflect multiple sclerosis ? AB - INTRODUCTION: Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system. Immunological studies suggest that it is a T-cell mediated autoimmune disease, although an MS-specific target antigen for autoimmunity has so far not been identified. Models of experimental autoimmune encephalomyelitis in part reproduce features of MS, but none of the models so far covers the entire spectrum of pathology and immunology. Autoimmune disease of the nervous system has occasionally been observed in humans after active sensitization with brain tissue or brain cells, giving rise to acute demyelinating polyradiculoneuritis, acute disseminated encephalomyelitis and in rare cases reflecting an inflammatory demyelinating condition similar to acute multiple sclerosis. In this study we analyzed in detail the immunopathology in archival autopsy tissue of a patient who died with an MS like disease after repeated exposure to subcutaneous injections of lyophilized brain cells. RESULTS: The pathology of this patient fulfilled all pathological diagnostic criteria of MS. Demyelination and tissue injury was associated with antibody (IgM) deposition at active lesion sites and complement activation. Major differences to classical EAE models were seen in the composition of inflammatory infiltrates, being dominated by B-cells, infiltration of IgM positive plasma cells, profound infiltration of the tissue by CD8(+) T-lymphocytes and a nearly complete absence of CD4(+) T-cells. CONCLUSIONS: Our study shows that auto-sensitization of humans with brain tissue can induce a disease, which closely reflects the pathology of MS, but that the mechanisms leading to demyelination and tissue injury differ from those, generally implicated in the pathophysiology of MS through studies in experimental autoimmune encephalomyelitis. PMID- 26637428 TI - Effects of corticosteroids and their combinations with hyaluronanon on the biochemical properties of porcine cartilage explants. AB - BACKGROUND: Intra-articular injection of corticosteroids is used to treat the inflammatory pain of arthritis and osteoarthritis (OA), but our previous study found a deleterious effect of these steroids on chondrocyte cells. Hyaluronic acid (HA) injection has been suggested as a means to counteract negative side effects through replenishment of synovial fluid that can decrease pain in affected joints. To better understand the effects of corticosteroids on these processes, dexamethasone (Dex) and prednisolone (Pred) were administered to porcine cartilage explants at several concentrations with and without HA. We examined corticoid effects by determining sulfate-glycosaminoglycan (s-GAG) and uronic acid (UA) content of the explant media, and safranin-O staining of the cells. Analysis of lactate dehydrogenase (LDH) activity was conducted to assess cell cytotoxicity. RESULTS: Dex treatment significantly reduced cellular cytotoxicity compared to the other treatment groups, especially with regards to the release of s-GAG, and protects against superficial proteoglycan damage. However, there was no difference between Pred and Dex, with and without HA, in the UA content remaining in porcine cartilage explants. CONCLUSIONS: The data suggest that combinations of Dex and Pred with HA did not have a significant effect on protection or enhancement of the articular cartilage matrix under the current conditions. PMID- 26637430 TI - Novel approaches to treating type 2 diabetes. PMID- 26637429 TI - Multilevel analysis of neuropathogenesis of neurocognitive impairment in HIV. AB - The neuropathogenesis of HIV-associated neurocognitive disorders (HAND) remains puzzling. We interrogated several levels of data (host genetic, histopathology, brain viral load, and neurocognitive) to identify histopathological changes most relevant to HAND. The design of the study is a clinicopathological study employing genetic association analyses. Data and brain tissue from 80 HIV infected adults were used. Markers in monocyte chemoattractant protein-1 (MCP-1), interleukin 1-alpha (IL1-alpha), macrophage inflammatory protein 1-alpha (MIP1 alpha), DRD3, DRD2, and apolipoprotein E (ApoE) were genotyped. Microtubule associated protein 2 (MAP2), synaptophysin (SYP), human leukocyte antigen-DR (HLA DR), glial fibrillary acidic protein (GFAP), amyloid beta (A-Beta), and ionized calcium-binding adaptor molecule-1 (Iba-1) immunoreactivity were quantified in the frontal cortex, putamen, and hippocampus. A composite score for each marker (mean of the three brain regions) was used. Neurocognitive functioning and other clinical variables were determined within 1 year of death. Brain HIV RNA viral load was available for a subset of cases. MAP2 and SYP proved most relevant to neurocognitive functioning. Immunoreactivity of these markers, as well as A-Beta and Iba-1, was correlated with brain HIV RNA viral load. Several genetic markers in combination with other factors predicted histopathology: HIV blood viral load, MIP1-alpha genotype, and DRD3 genotype predicted Iba-1 immunoreactivity; the duration of infection and IL1-alpha genotype predicted GFAP immunoreactivity; ApoE genotype and age at death predicted A-Beta immunoreactivity. These data indicate that HIV replication in the brain is the primary driving force leading to neuroinflammation and dysfunctional protein clearance, as reflected by A-Beta and Iba-1. Downstream to these changes are synaptodendritic degeneration, which is the immediate histopathological substrate of the neurocognitive impairment characteristic of HAND. These intermediate histopathological phenotypes are influenced by host genetic polymorphisms in genes encoding cytokines/chemokines, neuronal protein clearance pathways, and dopaminergic factors. PMID- 26637431 TI - The Extent of mRNA Editing Is Limited in Chicken Liver and Adipose, but Impacted by Tissular Context, Genotype, Age, and Feeding as Exemplified with a Conserved Edited Site in COG3. AB - RNA editing is a posttranscriptional process leading to differences between genomic DNA and transcript sequences, potentially enhancing transcriptome diversity. With recent advances in high-throughput sequencing, many efforts have been made to describe mRNA editing at the transcriptome scale, especially in mammals, yielding contradictory conclusions regarding the extent of this phenomenon. We show, by detailed description of the 25 studies focusing so far on mRNA editing at the whole-transcriptome scale, that systematic sequencing artifacts are considered in most studies whereas biological replication is often neglected and multi-alignment not properly evaluated, which ultimately impairs the legitimacy of results. We recently developed a rigorous strategy to identify mRNA editing using mRNA and genomic DNA sequencing, taking into account sequencing and mapping artifacts, and biological replicates. We applied this method to screen for mRNA editing in liver and white adipose tissue from eight chickens and confirm the small extent of mRNA recoding in this species. Among the 25 unique edited sites identified, three events were previously described in mammals, attesting that this phenomenon is conserved throughout evolution. Deeper investigations on five sites revealed the impact of tissular context, genotype, age, feeding conditions, and sex on mRNA editing levels. More specifically, this analysis highlighted that the editing level at the site located on COG3 was strongly regulated by four of these factors. By comprehensively characterizing the mRNA editing landscape in chickens, our results highlight how this phenomenon is limited and suggest regulation of editing levels by various genetic and environmental factors. PMID- 26637432 TI - Effects of DNA Methylation and Chromatin State on Rates of Molecular Evolution in Insects. AB - Epigenetic information is widely appreciated for its role in gene regulation in eukaryotic organisms. However, epigenetic information can also influence genome evolution. Here, we investigate the effects of epigenetic information on gene sequence evolution in two disparate insects: the fly Drosophila melanogaster, which lacks substantial DNA methylation, and the ant Camponotus floridanus, which possesses a functional DNA methylation system. We found that DNA methylation was positively correlated with the synonymous substitution rate in C. floridanus, suggesting a key effect of DNA methylation on patterns of gene evolution. However, our data suggest the link between DNA methylation and elevated rates of synonymous substitution was explained, in large part, by the targeting of DNA methylation to genes with signatures of transcriptionally active chromatin, rather than the mutational effect of DNA methylation itself. This phenomenon may be explained by an elevated mutation rate for genes residing in transcriptionally active chromatin, or by increased structural constraints on genes in inactive chromatin. This result highlights the importance of chromatin structure as the primary epigenetic driver of genome evolution in insects. Overall, our study demonstrates how different epigenetic systems contribute to variation in the rates of coding sequence evolution. PMID- 26637433 TI - Quantitative Trait Locus and Genetical Genomics Analysis Identifies Putatively Causal Genes for Fecundity and Brooding in the Chicken. AB - Life history traits such as fecundity are important to evolution because they make up components of lifetime fitness. Due to their polygenic architectures, such traits are difficult to investigate with genetic mapping. Therefore, little is known about their molecular basis. One possible way toward finding the underlying genes is to map intermediary molecular phenotypes, such as gene expression traits. We set out to map candidate quantitative trait genes for egg fecundity in the chicken by combining quantitative trait locus mapping in an advanced intercross of wild by domestic chickens with expression quantitative trait locus mapping in the same birds. We measured individual egg fecundity in 232 intercross chickens in two consecutive trials, the second one aimed at measuring brooding. We found 12 loci for different aspects of egg fecundity. We then combined the genomic confidence intervals of these loci with expression quantitative trait loci from bone and hypothalamus in the same intercross. Overlaps between egg loci and expression loci, and trait-gene expression correlations identify 29 candidates from bone and five from hypothalamus. The candidate quantitative trait genes include fibroblast growth factor 1, and mitochondrial ribosomal proteins L42 and L32. In summary, we found putative quantitative trait genes for egg traits in the chicken that may have been affected by regulatory variants under chicken domestication. These represent, to the best of our knowledge, some of the first candidate genes identified by genome wide mapping for life history traits in an avian species. PMID- 26637434 TI - Dynamics of Dark-Fly Genome Under Environmental Selections. AB - Environmental adaptation is one of the most fundamental features of organisms. Modern genome science has identified some genes associated with adaptive traits of organisms, and has provided insights into environmental adaptation and evolution. However, how genes contribute to adaptive traits and how traits are selected under an environment in the course of evolution remain mostly unclear. To approach these issues, we utilize "Dark-fly", a Drosophila melanogaster line maintained in constant dark conditions for more than 60 years. Our previous analysis identified 220,000 single nucleotide polymorphisms (SNPs) in the Dark fly genome, but did not clarify which SNPs of Dark-fly are truly adaptive for living in the dark. We found here that Dark-fly dominated over the wild-type fly in a mixed population under dark conditions, and based on this domination we designed an experiment for genome reselection to identify adaptive genes of Dark fly. For this experiment, large mixed populations of Dark-fly and the wild-type fly were maintained in light conditions or in dark conditions, and the frequencies of Dark-fly SNPs were compared between these populations across the whole genome. We thereby detected condition-dependent selections toward approximately 6% of the genome. In addition, we observed the time-course trajectory of SNP frequency in the mixed populations through generations 0, 22, and 49, which resulted in notable categorization of the selected SNPs into three types with different combinations of positive and negative selections. Our data provided a list of about 100 strong candidate genes associated with the adaptive traits of Dark-fly. PMID- 26637435 TI - Congenital Chloride Diarrhea - Novel Mutation in SLC26A3 Gene. AB - The authors report a case of congenital chloride diarrhea with molecular confirmation of diagnosis. A 10-mo-old boy presented with failure to thrive, voluminous diarrhea, dehydration, hyponatremia, hypokalemia, metabolic alkalosis and history of maternal polyhydramnios. The diagnosis of congenital chloride diarrhea was based on high fecal and low urinary chloride excretion, in addition to biochemical abnormalities. Genetic testing revealed a novel homozygous mutation in exon 4 of the SLC26A3 gene that encodes the protein regulating chloride bicarbonate absorption in distal ileum and colon. Therapy with oral fluids and electrolytes led to decrease in stool frequency and improvement in growth parameters. PMID- 26637436 TI - Editorial: Pediatric Rheumatology has Come of Age in India. PMID- 26637437 TI - Neonatal and Infantile Epilepsy: Acquired and Genetic Models. AB - The incidence of seizures and epilepsies is particularly high during the neonatal and infantile periods. We will review selected animal models of early-life epileptic encephalopathies that have addressed the dyscognitive features of frequent interictal spikes, the pathogenesis and treatments of infantile spasms (IS) or Dravet syndrome, disorders with mammalian target of rapamycin (mTOR) dysregulation, and selected early-life epilepsies with genetic defects. Potentially pathogenic mechanisms in these conditions include interneuronopathies in IS or Dravet syndrome and mTOR dysregulation in brain malformations, tuberous sclerosis, and related genetic disorders, or IS of acquired etiology. These models start to generate the first therapeutic drugs, which have been specifically developed in immature animals. However, there are challenges in translating preclinical discoveries into clinically relevant findings. The advances made so far hold promise that the new insights may potentially have curative or disease-modifying potential for many of these devastating conditions. PMID- 26637438 TI - p53 as an Effector or Inhibitor of Therapy Response. AB - Although integrity of the p53 signaling pathway in a given tumor was expected to be a critical determinant of response to therapies, most clinical studies failed to link p53 status and treatment outcome. Here, we present two opposite situations: one in which p53 is an essential effector of cure by targeted leukemia therapies and another one in advanced breast cancers in which p53 inactivation is required for the clinical efficacy of dose-dense chemotherapy. If p53 promotes or blocks therapy response, therapies must be tailored on its status in individual tumors. PMID- 26637439 TI - Dissecting the Mechanisms Underlying Unusually Successful Human Health Span and Life Span. AB - Humans age at different rates and families with exceptional survival provide the opportunity to understand why some people age slower than others. Unique features exhibited by centenarians include a family history of longevity, compression of morbidity with resultant extension of health span, and biomarkers such as low circulating insulin-like growth factor 1 (IGF-1) and elevated high-density lipoprotein (HDL) cholesterol levels. Given the rarity of the centenarian phenotype, it has not been surprising that the use of discovery methods that relied on common population single nucleotide polymorphisms (SNPs) to unlock the genetic determinants of exceptional longevity have not yielded significant results. Conversely, gene sequencing has resulted in discoveries of functional gene variants that support several of the centenarian phenotypes. These discoveries have led to the strategic developments of drugs that may delay aging and prolong health span. PMID- 26637441 TI - Overcoming physical constraints in bone engineering: 'the importance of being vascularized'. AB - Bone plays several physiological functions and is the second most commonly transplanted tissue after blood. Since the treatment of large bone defects is still unsatisfactory, researchers have endeavoured to obtain scaffolds able to release growth and differentiation factors for mesenchymal stem cells, osteoblasts and endothelial cells in order to obtain faster mineralization and prompt a reliable vascularization. Nowadays, the application of osteoblastic cultures spans from cell physiology and pharmacology to cytocompatibility measurement and osteogenic potential evaluation of novel biomaterials. To overcome the simple traditional monocultures in vitro, co-cultures of osteogenic and vasculogenic precursors were introduced with very interesting results. Increasingly complex culture systems have been developed, where cells are seeded on proper scaffolds and stimulated so as to mimic the physiological conditions more accurately. These bioreactors aim at enabling bone regeneration by incorporating different cells types into bio-inspired materials within a surveilled habitat. This review is focused on the most recent developments in the organomimetic cultures of osteoblasts and vascular endothelial cells for bone tissue engineering. PMID- 26637440 TI - Dual inhibition of Type I and Type III PI3 kinases increases tumor cell apoptosis in HER2+ breast cancers. AB - INTRODUCTION: Human epidermal growth factor receptor-2 (HER2) gene amplification (HER2+) drives tumor cell growth and survival in ~25% of breast cancers. HER2 signaling activates the type I phosphoinositide 3-kinase (PI3K), upon which these tumors rely. Consequently, inhibitors of HER2 and type I PI3K block growth and increase apoptosis in HER2+ breast cancers, especially when used in combination. However, the impact of type III PI3K inhibition, particularly in combination with HER2 blockade or type I PI3K inhibition, remains less clear. METHODS: We utilized small molecule kinase inhibitors, locked nucleic acid antisense oligonucleotides (LNA-ASOs), and siRNA to assess proliferation, autophagy, apoptosis, and protein expression in cell culture models of HER2+ breast cancers. RESULTS: Treatment of HER2+ breast cancer cells with HER2 inhibitors or type I PI3K kinase inhibitors, alone or in combination, blocked type I PI3K signaling, reduced tumor cell growth, and induced autophagy. Knockdown of the type I PI3K, p110alpha, using an LNA-ASO termed EZN4150 inhibited PI3K-mediated Akt phosphorylation. However, in contrast to catalytic inhibitors of type I PI3Ks, EZN4150 did not induce autophagy, and blocked autophagy in response to inhibitors of HER2 or type I PI3Ks in a dominant fashion. Sequence analysis of EZN4150 revealed significant homology to the gene encoding the type III PI3K, Vps34, a key component for autophagy induction. EZN4150 simultaneously reduced expression of both p110alpha and Vps34. Combined inhibition of PI3K signaling and autophagy using individual siRNAs against p110alpha and Vps34 or using pharmacological type I and type III PI3K inhibitors recapitulated what was seen with EZN4150, and robustly enhanced tumor cell killing. CONCLUSIONS: These studies highlight the important role of Vps34-mediated autophagy in limiting the anti-tumor response to inhibitors of HER2 or type I PI3K in HER2+ breast cancers. The type III PI3K Vps34 represents a potential therapeutic target to block treatment-induced autophagy and enhance tumor cell killing. PMID- 26637442 TI - Transdermal solid delivery of epigallocatechin-3-gallate using self-double emulsifying drug delivery system as vehicle: Formulation, evaluation and vesicle skin interaction. AB - The present study investigated a self-double-emulsifying drug delivery system loaded with epigallocatechin-3-gallate to improve epigallocatechin-3-gallate skin retention. The long chain solid lipids (cetostearyl alcohol) and macadamia oil were utilized as a carrier to deliver the bioactive ingredient. Response surface methodology was used to optimize the formulation, and the solid lipid to total lipid weight ratio, concentration of epigallocatechin-3-gallate and hydrophilic surfactant on skin retention were found to be the principal factors. The optimum formulation with high encapsulation efficiency (95.75%), self-double emulsification performance (99.58%) and skin retention (87.24%) were derived from the fitted models and experimentally examined, demonstrating a reasonable agreement between experimental and predicted values. Epigallocatechin-3-gallate self-double-emulsifying drug delivery system was found to be stable for 3 months. Transdermal studies could explain a higher skin diffusion of epigallocatechin-3 gallate from the self-double-emulsifying drug delivery system compared with EGCG aqueous solution. In vitro cytotoxicity showed that epigallocatechin-3-gallate self-double-emulsifying drug delivery system did not exert hazardous effect on L929 cells up to 1:10. PMID- 26637443 TI - Osteoblast functions in functionally graded Ti-6Al-4 V mesh structures. AB - We describe here the combined efforts of engineering and biological sciences as a systemic approach to fundamentally elucidate osteoblast functions in functionally graded Ti-6Al-4 V mesh structures in relation to uniform/monolithic mesh arrays. First, the interconnecting porous architecture of functionally graded mesh arrays was conducive to cellular functions including attachment, proliferation, and mineralization. The underlying reason is that the graded fabricated structure with cells seeded from the large pore size side provided a channel for efficient transfer of nutrients to other end of the structure (small pore size), leading to the generation of mineralized extracellular matrix by differentiating pre osteoblasts. Second, a comparative and parametric study indicated that gradient mesh structure had a pronounced effect on cell adhesion and mineralization, and strongly influenced the proliferation phase. High intensity and near-uniform distribution of proteins (actin and vinculin) on struts of the gradient mesh structure (cells seeded from large pore side) implied signal transduction during cell adhesion and was responsible for superior cellular activity, in comparison to the uniform mesh structure and non-porous titanium alloy. Cells adhered to the mesh struts by forming a sheet, bridging the pores through numerous cytoplasmic extensions, in the case of porous mesh structures. Intercellular interaction in porous structures provided a pathway for cells to communicate and mature to a differentiated phenotype. Furthermore, the capability of cells to migrate through the interconnecting porous architecture on mesh structures led to colonization of the entire structure. Cells were embedded layer-by-layer in the extracellular matrix as the matrix mineralized. The outcomes of the study are expected to address challenges associated with the treatment of segmental bone defects and bone-remodeling through favorable modulation of cellular response. Moreover, the study provides a foundation for a new branch of functionally graded materials with interconnected porous architecture. PMID- 26637444 TI - Modulation of osteoblast behavior on TiNxOy coatings by altering the N/O stoichiometry while maintaining a high thrombogenic potential. AB - INTRODUCTION: Titanium nitride oxide (TiNxOy) coatings are known to stimulate osteoblast proliferation and osseointegration when compared to microrough titanium implants. The objectives of the present study were to determine whether the beneficial effects of TiNxOy coatings observed with implant osseointegration are dependent on N/O stoichiometry, with the final goal of optimizing these benefits. MMS: TiNxOy coatings with various N/O compositions were deposited on microrough titanium plates (Ti-SLA, 11 * 11 mm). Human primary osteoblast (hOBs) proliferation and gene expression were analyzed for a time course of three weeks, with or without additional stimulation by 1.25 (OH)2 vitamin D3 100 nM. Platelet adhesion/activation and thrombin generation were also assessed. RESULTS: hOBs proliferation gradually increased with the amount of oxygen contained in the coatings. The effect was observed from day 7 to reach a maximum at day 10, with a 1.8 fold increase for the best coating as compared to Ti-SLA. SEM views indicated that cells adhered, spread and elongated faster on oxygen-rich TiNxOy films, while the differentiation process as well as the thombogenic potential was not affected. CONCLUSIONS: The effect of TiNxOy coatings on osteoblast is dependent on their chemical composition; it increases with the amount of oxygen. TiNxOy coatings may act as a catalyst for cell-adhesion and proliferation early after seeding. In contrast, thrombogenicity of Ti-SLA surface is not affected by TiNxOy application. PMID- 26637445 TI - Promoting spinal fusions by biomineralized silk fibroin films seeded with bone marrow stromal cells: An in vivo animal study. AB - OBJECTIVES: To prepare a biomineralized nano silk fibroin film seeded with bone marrow stromal cells (BMSCs), and to evaluate its performance in spinal fusion. METHODS: The silk fibroin film was mineralized in a modified, simulated body fluid, seeded with BMSCs, and evaluated in a rat model of posterolateral lumbar fusion, compared with pure silk fibroin, silk fibroin/bone marrow stromal cells, mineralized silk fibroin, mineralized silk fibroin/bone marrow stromal cells, iliac crest bone, and no graft. After 12 weeks, all rats were sacrificed and underwent manual palpation, micro-CT scanning, biomechanical testing, and histology. RESULTS: The infrared spectrum, X-ray diffraction, and scanning electron microscopy demonstrated deposition of mineral layers on the silk fibroin film surface. The fusion rate, bone volume, relative strength and stiffness, and histological score of the mineralized silk fibroin/bone marrow stromal cells were slightly lower than the autograft, but without any significant difference (p > 0.05). In addition, the mineralized silk fibroin was significantly greater in most parameters than the silk fibroin/bone marrow stromal cells (p < 0.05). CONCLUSION: The mineralized silk fibroin resembles natural bone structurally, and the cellular and mineral layers of silk fibroin are both critical to bone regeneration. The ability to promote spinal fusion is enhanced when the mineralized silk fibroin is seeded with bone marrow stromal cells. PMID- 26637446 TI - Peripheral corneal relaxing incisions based on anterior keratometry from Scheimpflug tomography versus Placido topography during standard cataract surgery. AB - AIM: To compare the outcomes of peripheral corneal relaxing incisions (PCRIs) based on standardized nomogram using keratometry from Scheimpflug and Placido machines during standard cataract surgery and to assess the astigmatism neutralization potential of PCRIs. METHODS: In this prospective, comparative case series of eyes with keratometric astigmatism between 0.75D to 2.5D, undergoing routine cataract surgery, PCRIs were performed using standardized nomogram and keratometric data from either Scheimpflug or Placido machines. A single eye of 42 consecutive patients was recruited in each group. Data on pre- and postoperative uncorrected distance visual acuity (UDVA), corrected DVA (CDVA), keratometry and refraction were assessed at 10 weeks postoperatively. Refractive and keratometric J0 J45 vectors were also analyzed. RESULTS: Data on 41 and 39 eyes were available in each group, respectively. There was a significant reduction in keratometric astigmatism in both groups. However, between Scheimpflug and Placido groups, there was no difference in postoperative logMAR UDVA [0.15 +/- 0.18 vs 0.14 +/- 0.16, p = 0.82] and CDVA [0.11 +/- 0.11 vs 0.09 +/- 0.10, p = 0.58], postoperative spherical equivalent [-0.34D +/- 0.40D vs -0.50D +/- 0.43D, p = 0.11], keratometric J0 [-0.03 +/- 0.39 vs 0.01 +/- 0.85, p = 0.67] and J45 [-0.03 +/- 0.41 vs 0.01 +/- 0.86, p = 0.65] and refractive J0 [0.05 +/- 0.46 vs -0.03 +/ 0.92, p = 0.47)] and J45 [-0.06 +/- 0.49 vs -0.03 +/- 0.99, p = 0.82] vectors, reduction of keratometric astigmatism [-0.40D +/- 0.55D vs -0.35D +/- 1.24D, p = 0.75] and the keratometric astigmatism neutralization potential [38.56 % +/- 29.71 % vs 52.66 % +/- 44.06 %, p = 0.12]. - CONCLUSIONS: Although PCRIs performed using Scheimpflug or Placido keratometry reduced the keratometric astigmatism significantly during standard cataract surgery. The astigmatic neutralization potentials of PCRIs comparing these two groups were not significantly different and remain low during the early postoperative period. PMID- 26637447 TI - Effects of diagnostic ultrasound-targeted microbubble destruction on the homing ability of bone marrow stromal cells to the kidney parenchyma. AB - OBJECTIVES: Bone marrow stromal cells (BMSC) transplantation proves successful in treating kidney disease and injury in many studies. However, their reparative capacity is limited by the poor homing ability in vivo, which is decided mainly by the local expression of chemoattractants. Our study explored the mechanical effects of ultrasound targeted microbubble destruction (UTMD) on BMSCs homing ability in treated kidney tissues. METHODS: Rats were injected with red fluorescent protein (RFP)-labelled BMSCs and sonicated with microbubble-mediated ultrasound. Then, we tested kidney micro-environment changes induced and their influence on stem cell homing ability. RESULTS: The results showed that the mechanical effects of UTMD would increase local and transient levels of chemoattractants (i.e. cytokines, integrins and growth factors) in targeted kidney tissues. Transmission electron microscopy showed that vascular endothelial cell was discontinuous in the UTMD group post-treatment, becoming smooth 72 h later. Confocal laser scanning microscopy and RT-PCR showed up to eight times more stem cells in the peritubular regions of experimental kidneys on days 1 and 3 post-treatment compared with the contralateral kidney. CONCLUSIONS: These results confirmed that renal micro-environment changes caused by appropriate UTMD may promote BMSC homing ability toward treated kidney tissues without renal toxicity and cell damage. KEY POINTS: * This experiment showed a feasible strategy in promoting stem cell homing ability. * The treatment uses diagnostic ultrasound during enhancement with IV microbubbles. * A suitable micro environment was important for targeted stem cell homing and retention. * The method is effective for stem cell homing to kidney diseases. * More work is required with larger animals before potential human trials. PMID- 26637448 TI - Evidence for Competition for Target Innervation in the Medial Prefrontal Cortex. AB - Inputs to sensory cortices are known to compete for target innervation through an activity-dependent mechanism during critical periods. To investigate whether this principle also applies to association cortices such as the medial prefrontal cortex (mPFC), we produced a bilateral lesion during early development to the ventral hippocampus (vHC), an input to the mPFC, and analyzed the intensity of the projection from another input, the basolateral amgydala (BLA). We found that axons from the BLA had a higher density of "en passant" boutons in the mPFC of lesioned animals. Furthermore, the density of neurons labeled with retrograde tracers was increased, and neurons projecting from the BLA to the mPFC showed increased expression of FosB. Since neonatal ventral hippocampal lesion has been used as an animal model of schizophrenia, we investigated its effects on behavior and found a negative correlation between the density of retrogradely labeled neurons in the BLA and the reduction of the startle response in the prepulse inhibition test. Our results not only indicate that the inputs from the BLA and the vHC compete for target innervation in the mPFC during postnatal development but also that subsequent abnormal rewiring might underlie the pathophysiology of neuropsychiatric disorders such as schizophrenia. PMID- 26637449 TI - Neocortical Layer 6B as a Remnant of the Subplate - A Morphological Comparison. AB - The fate of the subplate (SP) is still a matter of debate. The SP and layer 6 (which is ontogenetically the oldest and innermost neocortical lamina) develop coincidentally. Yet, the function of sublamina 6B is largely unknown. It has been suggested that it consists partly of neurons from the transient SP, however, experimental evidence for this hypothesis is still missing. To obtain first insights into the neuronal complement of layer 6B in the somatosensory rat barrel cortex, we used biocytin stainings of SP neurons (aged 0-4 postnatal days, PND) and layer 6B neurons (PND 11-35) obtained during in vitro whole-cell patch-clamp recordings. Neurons were reconstructed for a quantitative characterization of their axonal and dendritic morphology. An unsupervised cluster analysis revealed that the SP and layer 6B consist of heterogeneous but comparable neuronal cell populations. Both contain 5 distinct spine-bearing cell types whose relative fractions change with increasing age. Pyramidal cells were more prominent in layer 6B, whereas non-pyramidal neurons were less frequent. Because of the high morphological similarity of SP and layer 6B neurons, we suggest that layer 6B consists of persistent non-pyramidal neurons from the SP and cortical L6B pyramidal neurons. PMID- 26637450 TI - Anatomical and Functional Findings in Female-to-Male Transsexuals: Testing a New Hypothesis. AB - : Gender dysphoria (GD) is characterized by incongruence between ones gender assigned at birth and the gender that one identifies with. The biological mechanisms of GD are unclear, especially in female-to-male transsexuals (FtM-TR). Here, we investigate whether distinct structural and functional patterns along cerebral midline networks processing own-body perception may constitute a biological correlate. METHOD: MRI of functional connectivity, cortical thickness, surface area, and gray matter volume was carried out in 28 female-to-male transsexuals (FtM-TR) and 68 cis-sexual controls (34 male). FtM-TR displayed thicker mid-frontal, precuneal-parietal, and lingual cortex than both male and female controls, whereas, in regions with reported anatomical sex differences among the controls, FtM-TR followed patterns of the gender assigned at their birth. FtM-TR also displayed weaker functional connections from the pregenual anterior cingulate to the insular cortex, and the temporo parietal junction compared with both control groups. Distinct structural and functional pattern in the own-body image network may represent biological markers for the dysphoric own body perception in transgender individuals. PMID- 26637451 TI - Local GABA Concentration Predicts Perceptual Improvements After Repetitive Sensory Stimulation in Humans. AB - Learning mechanisms are based on synaptic plasticity processes. Numerous studies on synaptic plasticity suggest that the regulation of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) plays a central role maintaining the delicate balance of inhibition and excitation. However, in humans, a link between learning outcome and GABA levels has not been shown so far. Using magnetic resonance spectroscopy of GABA prior to and after repetitive tactile stimulation, we show here that baseline GABA+ levels predict changes in perceptual outcome. Although no net changes in GABA+ are observed, the GABA+ concentration prior to intervention explains almost 60% of the variance in learning outcome. Our data suggest that behavioral effects can be predicted by baseline GABA+ levels, which provide new insights into the role of inhibitory mechanisms during perceptual learning. PMID- 26637452 TI - Dimerization of the SP1 Region of HIV-1 Gag Induces a Helical Conformation and Association into Helical Bundles: Implications for Particle Assembly. AB - HIV-1 immature particle (virus-like particle [VLP]) assembly is mediated largely by interactions between the capsid (CA) domains of Gag molecules but is facilitated by binding of the nucleocapsid (NC) domain to nucleic acid. We previously investigated the role of SP1, a "spacer" between CA and NC, in VLP assembly. We found that small changes in SP1 drastically disrupt assembly and that a peptide representing the sequence around the CA-SP1 junction is helical at high but not low concentrations. We suggested that by virtue of such a concentration-dependent change, this region could act as a molecular switch to activate HIV-1 Gag for VLP assembly. A leucine zipper domain can replace NC in Gag and still lead to the efficient assembly of VLPs. We find that SP1 mutants also disrupt assembly by these Gag-Zip proteins and have now studied a small fragment of this Gag-Zip protein, i.e., the CA-SP1 junction region fused to a leucine zipper. Dimerization of the zipper places SP1 at a high local concentration, even at low total concentrations. In this context, the CA-SP1 junction region spontaneously adopts a helical conformation, and the proteins associate into tetramers. Tetramerization requires residues from both CA and SP1. The data suggest that once this region becomes helical, its propensity to self associate could contribute to Gag-Gag interactions and thus to particle assembly. There is complete congruence between CA/SP1 sequences that promote tetramerization when fused to zippers and those that permit the proper assembly of full-length Gag; thus, equivalent interactions apparently participate in VLP assembly and in SP1-Zip tetramerization. IMPORTANCE: Assembly of HIV-1 Gag into virus-like particles (VLPs) appears to require an interaction with nucleic acid, but replacement of its principal nucleic acid-binding domain with a dimerizing leucine zipper domain leads to the assembly of RNA-free VLPs. It has not been clear how dimerization triggers assembly. Results here show that the SP1 region spontaneously switches to a helical state when fused to a leucine zipper and that these helical molecules further associate into tetramers, mediated by interactions between hydrophobic faces of the helices. Thus, the correct juxtaposition of the SP1 region makes it "association competent." Residues from both capsid and SP1 contribute to tetramerization, while mutations disrupting proper assembly in Gag also prevent tetramerization. Thus, this region is part of an associating interface within Gag, and its intermolecular interactions evidently help stabilize the immature Gag lattice. These interactions are disrupted by proteolysis of the CA-SP1 junction during virus maturation. PMID- 26637453 TI - Influenza Virus Infection Induces Platelet-Endothelial Adhesion Which Contributes to Lung Injury. AB - Lung injury after influenza infection is characterized by increased permeability of the lung microvasculature, culminating in acute respiratory failure. Platelets interact with activated endothelial cells and have been implicated in the pathogenesis of some forms of acute lung injury. Autopsy studies have revealed pulmonary microthrombi after influenza infection, and epidemiological studies suggest that influenza vaccination is protective against pulmonary thromboembolism; however, the effect of influenza infection on platelet endothelial interactions is unclear. We demonstrate that endothelial infection with both laboratory and clinical strains of influenza virus increased the adhesion of human platelets to primary human lung microvascular endothelial cells. Platelets adhered to infected cells as well as to neighboring cells, suggesting a paracrine effect. Influenza infection caused the upregulation of von Willebrand factor and ICAM-1, but blocking these receptors did not prevent platelet-endothelial adhesion. Instead, platelet adhesion was inhibited by both RGDS peptide and a blocking antibody to platelet integrin alpha5beta1, implicating endothelial fibronectin. Concordantly, lung histology from infected mice revealed viral dose-dependent colocalization of viral nucleoprotein and the endothelial marker PECAM-1, while platelet adhesion and fibronectin deposition also were observed in the lungs of influenza-infected mice. Inhibition of platelets using acetylsalicylic acid significantly improved survival, a finding confirmed using a second antiplatelet agent. Thus, influenza infection induces platelet-lung endothelial adhesion via fibronectin, contributing to mortality from acute lung injury. The inhibition of platelets may constitute a practical adjunctive strategy to the treatment of severe infections with influenza.IMPORTANCE There is growing appreciation of the involvement of the lung endothelium in the pathogenesis of severe infections with influenza virus. We have recently shown that the virus can infect human lung endothelial cells, but the functional consequences of this infection are unknown (S. M. Armstrong, C. Wang, J. Tigdi, X. Si, C. Dumpit, S. Charles, A. Gamage, T. J. Moraes, and W. L. Lee, PLoS One 7:e47323, 2012, http://dx.doi.org/10.1371/journal.pone.0047323). Here, we show that this infection causes platelets to adhere to the lung endothelium. Importantly, blocking platelets using two distinct antiplatelet drugs improved survival in a mouse model of severe influenza infection. Thus, platelet inhibition may constitute a novel therapeutic strategy to improve the host response to severe infections with influenza. PMID- 26637454 TI - Episodic Diversifying Selection Shaped the Genomes of Gibbon Ape Leukemia Virus and Related Gammaretroviruses. AB - Gibbon ape leukemia viruses (GALVs) are part of a larger group of pathogenic gammaretroviruses present across phylogenetically diverse host species of Australasian mammals. Despite the biomedical utility of GALVs as viral vectors and in cancer gene therapy, full genome sequences have not been determined for all of the five identified GALV strains, nor has a comprehensive evolutionary analysis been performed. We therefore generated complete genomic sequences for each GALV strain using hybridization capture and high-throughput sequencing. The four strains of GALV isolated from gibbons formed a monophyletic clade that was closely related to the woolly monkey virus (WMV), which is a GALV strain that likely originated in a gibbon host. The GALV-WMV clade in turn formed a sister group to the koala retroviruses (KoRVs). Genomic signatures of episodic diversifying selection were detected among the gammaretroviruses with concentration in the env gene across the GALV strains that were particularly oncogenic and KoRV strains that were potentially exogenous, likely reflecting their adaptation to the host immune system. In vitro studies involving vectors chimeric between GALV and KoRV-B established that variable regions A and B of the surface unit of the envelope determine which receptor is used by a viral strain to enter host cells. IMPORTANCE: The gibbon ape leukemia viruses (GALVs) are among the most medically relevant retroviruses due to their use as viral vectors for gene transfer and in cancer gene therapy. Despite their importance, full genome sequences have not been determined for the majority of primate isolates, nor has comprehensive evolutionary analysis been performed, despite evidence that the viruses are facing complex selective pressures associated with cross-species transmission. Using hybridization capture and high-throughput sequencing, we report here the full genome sequences of all the GALV strains and demonstrate that diversifying selection is acting on them, particularly in the envelope gene in functionally important domains, suggesting that host immune pressure is shaping GALV evolution. PMID- 26637455 TI - ORF33 and ORF38 of Kaposi's Sarcoma-Associated Herpesvirus Interact and Are Required for Optimal Production of Infectious Progeny Viruses. AB - We recently showed that the interaction between Kaposi's sarcoma-associated herpesvirus (KSHV) tegument proteins ORF33 and ORF45 is crucial for progeny virion production, but the exact functions of KSHV ORF33 during lytic replication were unknown (J. Gillen, W. Li, Q. Liang, D. Avey, J. Wu, F. Wu, J. Myoung, and F. Zhu, J Virol 89:4918-4931, 2015, http://dx.doi.org/10.1128/JVI.02925-14). Therefore, here we investigated the relationship between ORF33 and ORF38, whose counterparts in both alpha- and betaherpesviruses interact with each other. Using specific monoclonal antibodies, we found that both proteins are expressed during the late lytic cycle with similar kinetics and that both are present in mature virions as components of the tegument. Furthermore, we confirmed that ORF33 interacts with ORF38. Interestingly, we observed that ORF33 tightly associates with the capsid, whereas ORF38 associates with the envelope. We generated ORF33 null, ORF38-null, and double-null mutants and found that these mutants apparently have identical phenotypes: the mutations caused no apparent effect on viral gene expression but reduced the yield of progeny virion by about 10-fold. The progeny virions also lack certain virion component proteins, including ORF45. During viral lytic replication, the virions associate with cytoplasmic vesicles. We also observed that ORF38 associates with the membranes of vesicles and colocalizes with the Golgi membrane or early endosome membrane. Further analyses of ORF33/ORF38 mutants revealed the reduced production of virion-containing vesicles, suggesting that ORF33 and ORF38 are involved in the transport of newly assembled viral particles into cytoplasmic vesicles, a process important for viral maturation and egress. IMPORTANCE: Herpesvirus assembly is an essential step in virus propagation that leads to the generation of progeny virions. It is a complicated process that depends on the delicate regulation of interactions among virion proteins. We previously revealed an essential role of ORF45-ORF33 binding for virus assembly. Here, we report that ORF33 and its binding partner, ORF38, are required for infectious virus production due to their important role in the tegumentation process. Moreover, we found that both ORF33 and ORF38 are involved in the transportation of virions through vesicles during maturation and egress. Our results provide new insights into the important roles of ORF33 and ORF38 during viral assembly, a process critical for virus propagation that is intimately linked to KSHV pathobiology. PMID- 26637456 TI - NP1 Protein of the Bocaparvovirus Minute Virus of Canines Controls Access to the Viral Capsid Genes via Its Role in RNA Processing. AB - Minute virus of canines (MVC) is an autonomous parvovirus in the genus Bocaparvovirus. It has a single promoter that generates a single pre-mRNA processed via alternative splicing and alternative polyadenylation to produce at least 8 mRNA transcripts. MVC contains two polyadenylation sites, one at the right-hand end of the genome, (pA)d, and another complex site, (pA)p, within the capsid-coding region. During viral infection, the mRNAs must extend through (pA)p and undergo additional splicing of the immediately upstream 3D/3A intron to access the capsid gene. MVC NP1 is a 22-kDa nuclear phosphoprotein unique to the genus Bocaparvovirus of the Parvovirinae which we have shown governs suppression of (pA)p independently of viral genome replication. We show here that in addition to suppression of (pA)p, NP1 is also required for the excision of the MVC 3D/3A intron, independently of its effect on alternative polyadenylation. Mutations of the arginine/serine (SR) di-repeats within the intrinsically disordered amino terminus of NP1 are required for splicing of the capsid transcript but not suppression of polyadenylation at (pA)p. 3'-end processing of MVC mRNAs at (pA)p is critical for viral genome replication and the optimal expression of NP1 and NS1. Thus, a finely tuned balance between (pA)p suppression and usage is necessary for efficient virus replication. NP1 is the first parvovirus protein implicated in RNA processing. Its characterization reveals another way that parvoviruses govern access to their capsid protein genes, namely, at the RNA level, by regulating the essential splicing of an intron and the suppression of an internal polyadenylation site. IMPORTANCE: The Parvovirinae are small nonenveloped icosahedral viruses that are important pathogens in many animal species, including humans. Although parvoviruses have only subtle early-to-late expression shifts, they all regulate access to their capsid genes. Minute virus of canines (MVC) is an autonomous parvovirus in the genus Bocaparvovirus. It has a single promoter generating a single pre-mRNA which is processed via alternative splicing and alternative polyadenylation to generate at least 8 mRNA transcripts. MVC contains two polyadenylation sites, one at the right-hand end of the genome, (pA)d, and another, (pA)p, within the capsid-coding region. It had not been clear how the potent internal polyadenylation motif is suppressed to allow processing, export, and accumulation of the spliced capsid protein-encoding mRNAs. We show here that MVC NP1, the first parvovirus protein to be implicated in RNA processing, governs access to the MVC capsid gene by facilitating splicing and suppressing internal polyadenylation of MVC pre-mRNAs. PMID- 26637457 TI - Hepatitis B Virus X Protein Induces Hepatic Steatosis by Enhancing the Expression of Liver Fatty Acid Binding Protein. AB - Hepatitis B virus (HBV) has been implicated as a potential trigger of hepatic steatosis although molecular mechanisms involved in the pathogenesis of HBV associated hepatic steatosis still remain elusive. Our prior work has revealed that the expression level of liver fatty acid binding protein 1 (FABP1), a key regulator of hepatic lipid metabolism, was elevated in HBV-producing hepatoma cells. In this study, the effects of HBV X protein (HBx) mediated FABP1 regulation on hepatic steatosis and the underlying mechanism were determined. mRNA and protein levels of FABP1 were measured by quantitative RT-PCR (qPCR) and Western blotting. HBx-mediated FABP1 regulation was evaluated by luciferase assay, coimmunoprecipitation, and chromatin immunoprecipitation. Hepatic lipid accumulation was measured by using Oil-Red-O staining and the triglyceride level. It was found that expression of FABP1 was increased in HBV-producing hepatoma cells, the sera of HBV-infected patients, and the sera and liver tissues of HBV transgenic mice. Ectopic overexpression of HBx resulted in upregulation of FABP1 in HBx-expressing hepatoma cells, whereas HBx abolishment reduced FABP1 expression. Mechanistically, HBx activated the FABP1 promoter in an HNF3beta-, C/EBPalpha-, and PPARalpha-dependent manner, in which HBx increased the gene expression of HNF3beta and physically interacted with C/EBPalpha and PPARalpha. On the other hand, knockdown of FABP1 remarkably blocked lipid accumulation both in long-chain free fatty acids treated HBx-expressing HepG2 cells and in a high fat diet-fed HBx-transgenic mice. Therefore, FABP1 is a key driver gene in HBx induced hepatic lipid accumulation via regulation of HNF3beta, C/EBPalpha, and PPARalpha. FABP1 may represent a novel target for treatment of HBV-associated hepatic steatosis. IMPORTANCE: Accumulating evidence from epidemiological and experimental studies has indicated that chronic HBV infection is associated with hepatic steatosis. However, the molecular mechanism underlying HBV-induced pathogenesis of hepatic steatosis still remains to be elucidated. In this study, we found that expression of liver fatty acid binding protein (FABP1) was dramatically increased in the sera of HBV-infected patients and in both sera and liver tissues of HBV-transgenic mice. Forced expression of HBx led to FABP1 upregulation, whereas knockdown of FABP1 remarkably diminished lipid accumulation in both in vitro and in vivo models. It is possible that HBx promotes hepatic lipid accumulation through upregulating FABP1 in the development of HBV-induced nonalcoholic fatty liver disease. Therefore, inhibition of FABP1 might have therapeutic value in steatosis-associated chronic HBV infection. PMID- 26637458 TI - Equine Infectious Anemia Virus Gag Assembly and Export Are Directed by Matrix Protein through trans-Golgi Networks and Cellular Vesicles. AB - Gag intracellular assembly and export are very important processes for lentiviruses replication. Previous studies have demonstrated that equine infectious anemia virus (EIAV) matrix (MA) possesses distinct phosphoinositide affinity compared with HIV-1 MA and that phosphoinositide-mediated targeting to peripheral and internal membranes is a critical factor in EIAV assembly and release. In this study, we compared the cellular assembly sites of EIAV and HIV 1. We observed that the assembly of EIAV particles occurred on interior cellular membranes, while HIV-1 was targeted to the plasma membrane (PM) for assembly. Then, we determined that W7 and K9 in the EIAV MA N terminus were essential for Gag assembly and release but did not affect the cellular distribution of Gag. The replacement of EIAV MA with HIV-1 MA directed chimeric Gag to the PM but severely impaired Gag release. MA structural analysis indicated that the EIAV and HIV-1 MAs had similar spatial structures but that helix 1 of the EIAV MA was closer to loop 2. Further investigation indicated that EIAV Gag accumulated in the trans Golgi network (TGN) but not the early and late endosomes. The 9 N-terminal amino acids of EIAV MA harbored the signal that directed Gag to the TGN membrane system. Additionally, we demonstrated that EIAV particles were transported to the extracellular space by the cellular vesicle system. This type of EIAV export was not associated with multivesicular bodies or microtubule depolymerization but could be inhibited by the actin-depolymerizing drug cytochalasin D, suggesting that dynamic actin depolymerization may be associated with EIAV production. IMPORTANCE: In previous studies, EIAV Gag was reported to localize to both the cell interior and the plasma membrane. Here, we demonstrate that EIAV likely uses the TGN as the assembly site in contrast to HIV-1, which is targeted to the PM for assembly. These distinct assembly features are determined by the MA domain. We also identified two sites in the N terminus of EIAV MA that were important for Gag assembly and release. Furthermore, the observation of EIAV transport by cellular vesicles but not by multivesicular bodies sheds light on the mechanisms underlying EIAV cellular replication. PMID- 26637459 TI - Acute Viral Escape Selectively Impairs Nef-Mediated Major Histocompatibility Complex Class I Downmodulation and Increases Susceptibility to Antiviral T Cells. AB - Nef-specific CD8(+) T lymphocytes (CD8TL) are associated with control of simian immunodeficiency virus (SIV) despite extensive nef variation between and within animals. Deep viral sequencing of the immunodominant Mamu-B*017:01-restricted Nef165-173IW9 epitope revealed highly restricted evolution. A common acute escape variant, T170I, unexpectedly and uniquely degraded Nef's major histocompatibility complex class I (MHC-I) downregulatory capacity, rendering the virus more vulnerable to CD8TL targeting other epitopes. These data aid in a mechanistic understanding of Nef functions and suggest means of immunity-mediated control of lentivirus replication. PMID- 26637460 TI - Influenza A Virus-Induced Expression of a GalNAc Transferase, GALNT3, via MicroRNAs Is Required for Enhanced Viral Replication. AB - Influenza A virus (IAV) affects the upper and lower respiratory tracts and rapidly induces the expression of mucins, which are common O-glycosylated proteins, on the epithelial surfaces of the respiratory tract. Although mucin production is associated with the inhibition of virus transmission as well as characteristic clinical symptoms, little is known regarding how mucins are produced on the surfaces of respiratory epithelial cells and how they affect IAV replication. In this study, we found that two microRNAs (miRNAs), miR-17-3p and miR-221, which target GalNAc transferase 3 (GALNT3) mRNA, are rapidly downregulated in human alveolar basal epithelial cells during the early stage of IAV infection. We demonstrated that the expression of GALNT3 mRNA is upregulated in an IAV replication-dependent fashion and leads to mucin production in bronchial epithelial cells. A lectin microarray analysis revealed that the stable expression of GALNT3 by human alveolar basal epithelial cells induces mucin-type O-glycosylation modifications similar to those present in IAV-infected cells, suggesting that GALNT3 promotes mucin-type O-linked glycosylation in IAV-infected cells. Notably, analyses using short interfering RNAs and miRNA mimics showed that GALNT3 knockdown significantly reduces IAV replication. Furthermore, IAV replication was markedly decreased in embryonic fibroblast cells obtained from galnt3-knockout mice. Interestingly, IAV-infected galnt3-knockout mice exhibited high mortality and severe pathological alterations in the lungs compared to those of wild-type mice. Our results demonstrate not only the molecular mechanism underlying rapid mucin production during IAV infection but also the contribution of O-linked glycosylation to the replication and propagation of IAV in lung cells. IMPORTANCE: Viral infections that affect the upper or lower respiratory tracts, such as IAV, rapidly induce mucin production on the epithelial surfaces of respiratory cells. However, the details of how mucin-type O-linked glycosylation is initiated by IAV infection and how mucin production affects viral replication have not yet been elucidated. In this study, we show that levels of two miRNAs that target the UDP-GalNAc transferase GALNT3 are markedly decreased during the early stage of IAV infection, resulting in the upregulation of GALNT3 mRNA. We also demonstrate that the expression of GALNT3 initiates mucin production and affects IAV replication in infected cells. This is the first report demonstrating the mechanism underlying the miRNA-mediated initiation of mucin-type O-glycosylation in IAV-infected cells and its role in viral replication. Our results have broad implications for understanding IAV replication and suggest a strategy for the development of novel anti-influenza approaches. PMID- 26637461 TI - Antibody Binding Modulates Conformational Exchange in Domain III of Dengue Virus E Protein. AB - Domain III of dengue virus E protein (DIII) participates in the recognition of cell receptors and in structural rearrangements required for membrane fusion and ultimately viral infection; furthermore, it contains epitopes for neutralizing antibodies and has been considered a potential vaccination agent. In this work, we addressed various structural aspects of DIII and their relevance for both the dengue virus infection mechanism and antibody recognition. We provided a dynamic description of DIII at physiological and endosomal pHs and in complex with the neutralizing human antibody DV32.6. We observed conformational exchange in the isolated DIII, in regions important for the packing of E protein dimers on the virus surface. This conformational diversity is likely to facilitate the partial detachment of DIII from the other E protein domains, which is required to achieve fusion to the host cellular membranes and to expose the epitopes of many anti DIII antibodies. A comparison of DIII of two dengue virus serotypes revealed many common features but also some possibly unexpected differences. Antibody binding to DIII of dengue virus serotype 4 attenuated the conformational exchange in the epitope region but, surprisingly, generated exchange in other parts of DIII through allosteric effects. IMPORTANCE: Many studies have provided extensive structural information on the E protein and particularly on DIII, also in complex with antibodies. However, there is very scarce information regarding the molecular dynamics of DIII, and almost nothing is available on the dynamic effect of antibody binding, especially at the quantitative level. This work provides one of the very rare descriptions of the effect of antibody binding on antigen dynamics. PMID- 26637462 TI - A Highly Conserved Residue of the HIV-1 gp120 Inner Domain Is Important for Antibody-Dependent Cellular Cytotoxicity Responses Mediated by Anti-cluster A Antibodies. AB - Previous studies have shown that sera from HIV-1-infected individuals contain antibodies able to mediate antibody-dependent cellular cytotoxicity (ADCC). These antibodies preferentially recognize envelope glycoprotein (Env) epitopes induced upon CD4 binding. Here, we show that a highly conserved tryptophan at position 69 of the gp120 inner domain is important for ADCC mediated by anti-cluster A antibodies and sera from HIV-1-infected individuals. PMID- 26637463 TI - Effect of gaseous ozone on Enterococcus faecalis biofilm-an in vitro study. AB - OBJECTIVES: The aim of this study was to evaluate the antimicrobial effect of gaseous ozone compared to conventional methods against Enterococcus faecalis. MATERIALS AND METHODS: One hundred twenty-five teeth were infected by E. faecalis and were incubated for 72 h to form biofilm. Teeth were distributed among five groups. In the first group, ozone was used; in the second group, teeth were rinsed with 20 % ethylenediaminetetraacetic acid (EDTA); in the third group, with 3 % sodium hypochlorite (NaOCl). Group 4 combined 20 % EDTA with ozone. NaOCl and ozone were combined in group 5. After treatment, the samples with paper points were taken, followed by dentin samples taken with K-file, and cultured for 24 h. Then bacterial colonies were counted. RESULTS: All treatments reduced significantly (p < 0.05) the bacteria. Paper points' samples showed 85.38 % reduction after ozone. The highest reduction was observed in NaOCl group (99.98 %). EDTA reduced bacteria by 80.64 %. Combination of NaOCl and ozone eradicated 99.95 % of the bacteria. Combination of EDTA and ozone reduced E. faecalis up to 91.33 %. The dentin chips showed the following: the highest CFU counts were observed in EDTA group, followed by ozone and NaOCl group. The lowest CFU counts were found in NaOCl-ozone group and EDTA-ozone group. CONCLUSIONS: Ozone reduced E. faecalis, even organised in a biofilm, however, lower than NaOCl. No treatment reduced totally the bacteria. CLINICAL RELEVANCE: Used as an adjuvant, ozone can increase the efficacy of conventional rinsing like EDTA and presents an alternative treatment when NaOCl cannot be used e.g. in teeth with a wide-open apical foramen. PMID- 26637464 TI - Assessment of the safety of antimalarial drug use during early pregnancy (ASAP): protocol for a multicenter prospective cohort study in Burkina Faso, Kenya and Mozambique. AB - BACKGROUND: A major unresolved safety concern for malaria case management is the use of artemisinin combination therapies (ACTs) in the first trimester of pregnancy. There is a need for human data to inform policy makers and treatment guidelines on the safety of artemisinin combination therapies (ACT) when used during early pregnancy. METHODS: The overall goal of this paper is to describe the methods and implementation of a study aimed at developing surveillance systems for identifying exposures to antimalarials during early pregnancy and for monitoring pregnancy outcomes using health and demographic surveillance platforms. This was a multi-center prospective observational cohort study involving women at health and demographic surveillance sites in three countries in Africa: Burkina Faso, Kenya and Mozambique [(ClinicalTrials.gov Identifier: NCT01232530)]. The study was designed to identify pregnant women with artemisinin exposure in the first trimester and compare them to: 1) pregnant women without malaria, 2) pregnant women treated for malaria, but exposed to other antimalarials, and 3) pregnant women with malaria and treated with artemisinins in the 2nd or 3rd trimesters from the same settings. Pregnant women were recruited through community-based surveys and attendance at health facilities, including antenatal care clinics and followed until delivery. Data from the three sites will be pooled for analysis at the end of the study. Results are forthcoming. DISCUSSION: Despite few limitations, the methods described here are relevant to the development of sustainable pharmacovigilance systems for drugs used by pregnant women in the tropics using health and demographic surveillance sites to prospectively ascertain drug safety in early pregnancy. TRIAL REGISTRATION: NCT01232530. PMID- 26637465 TI - Describe the outcomes of dysvascular partial foot amputation and how these compare to transtibial amputation: a systematic review protocol for the development of shared decision-making resources. AB - BACKGROUND: Helping people make well-informed decisions about dysvascular partial foot amputation is becoming increasingly important as improvements in diabetes care and vascular surgery make more distal amputations increasingly possible. The high rates of complications and reamputations associated with partial foot amputation are of concern, particularly given that transtibial amputation seems to result in similar outcomes (e.g., mobility and quality of life) with comparatively few complications and reamputations. The aim of this review is to describe the outcomes of dysvascular partial foot amputation and compare these to transtibial amputation. Results from the review are intended for use in the development of shared decision-making resources. METHODS/DESIGN: A comprehensive range of databases-MEDLINE, EMBASE, PsycINFO, AMED, Cumulative Index of Nursing and Allied Health Literature (CINAHL), ProQuest Nursing and Allied Health, and Web of Science-will be searched using National Library of Medicine, Medical Subject Headings (MeSH) terms as well as title, abstract, and keywords relating to different amputation levels and outcomes of interest; specifically: incidence, prevalence, and rate of amputation; rate of mortality, wound failure, dehiscence, and time between index and ipsilateral reamputations; and mobility, functional ability, activity and participation, quality of life, pain, and psychosocial outcomes including depression and anxiety. Articles that meet the inclusion criteria will be hand-searched for relevant citations. A forward citation search using Google Scholar will be used to identify articles not yet indexed. Original research published in the English language after 1 January 2000 will be included. The McMaster Critical Review Forms will be used to assess methodological quality and identify sources of bias. Included articles will be independently appraised by two reviewers. Data will be extracted using a spreadsheet based on the Cochrane Consumers and Communication Review Group's data extraction template by a primary reviewer and checked for accuracy and clarity by a second reviewer. Findings from the review will be reported as a narrative without meta-analysis given the anticipated heterogeneity of the literature. DISCUSSION: Results from the review can be used in the design of shared decision-making resources to help inform difficult decisions about partial foot amputation. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015029186. PMID- 26637466 TI - The correlation between pretreatment cytokine expression patterns in peripheral blood mononuclear cells with chronic hepatitis C outcome. AB - BACKGROUD: Cytokine response against hepatitis C virus (HCV) is likely to determine the natural course of infection as well as the outcome of antiviral treatment. However, the role of particular cytokines remains unclear. The current study analyzed activation of cytokine response in chronic hepatitis C patients undergoing standard antiviral treatment. METHODS: Twenty-two patients were treated with pegylated interferon and ribavirin. Twenty-six different cytokine transcripts were measured quantitatively in peripheral blood mononuclear cells (PBMC) before and after therapy and correlated with therapy outcome as well as with clinical and liver histological data. RESULTS: We found that patients who achieved sustained virological response (SVR) showed higher pretreatment cytokine response when compared to subjects in whom therapy was unsuccessful. The differentially expressed factors included IL-8, IL-16, TNF-alpha, GM-CSF, MCP-2, TGF-beta, and IP-10. Serum ALT activity and/or histological grading also positively correlated with the expression of IL-1alpha, IL-4, IL-6, IL-10, IL-12, IL-15, GM-CSF, M-CSF, MCP-2 and TGF-beta. CONCLUSION: Pretreatment activation of the immune system, as reflected by cytokines transcripts upregulation, positively correlates with treatment outcome and closely reflects liver inflammatory activity. PMID- 26637467 TI - Population Variation Reveals Independent Selection toward Small Body Size in Chinese Debao Pony. AB - Body size, one of the most important quantitative traits under evolutionary scrutiny, varies considerably among species and among populations within species. Revealing the genetic basis underlying this variation is very important, particularly in humans where there is a close relationship with diseases and in domestic animals as the selective patterns are associated with improvements in production traits. The Debao pony is a horse breed with small body size that is unique to China; however, it is unknown whether the size-related candidate genes identified in Western breeds also account for the small body size of the Debao pony. Here, we compared individual horses from the Debao population with other two Chinese horse populations using single nucleotide polymorphisms (SNPs) identified with the Equine SNP 65 Bead Chip. The previously reported size-related candidate gene HMGA2 showed a significant signature for selection, consistent with its role observed in human populations. More interestingly, we found a candidate gene TBX3, which had not been observed in previous studies on horse body size that displayed the highest differentiation and most significant association, and thus likely is the dominating factor for the small stature of the Debao pony. Further comparison between the Debao pony and other breeds of horses from around the world demonstrated that TBX3 was selected independently in the Debao pony, suggesting that there were multiple origins of small stature in the horse. PMID- 26637468 TI - Transcription, Signaling Receptor Activity, Oxidative Phosphorylation, and Fatty Acid Metabolism Mediate the Presence of Closely Related Species in Distinct Intertidal and Cold-Seep Habitats. AB - Bathyal cold seeps are isolated extreme deep-sea environments characterized by low species diversity while biomass can be high. The Hakon Mosby mud volcano (Barents Sea, 1,280 m) is a rather stable chemosynthetic driven habitat characterized by prominent surface bacterial mats with high sulfide concentrations and low oxygen levels. Here, the nematode Halomonhystera hermesi thrives in high abundances (11,000 individuals 10 cm(-2)). Halomonhystera hermesi is a member of the intertidal Halomonhystera disjuncta species complex that includes five cryptic species (GD1-5). GD1-5's common habitat is characterized by strong environmental fluctuations. Here, we compared the transcriptomes of H. hermesi and GD1, H. hermesi's closest relative. Genes encoding proteins involved in oxidative phosphorylation are more strongly expressed in H. hermesi than in GD1, and many genes were only observed in H. hermesi while being completely absent in GD1. Both observations could in part be attributed to high sulfide concentrations and low oxygen levels. Additionally, fatty acid elongation was also prominent in H. hermesi confirming the importance of highly unsaturated fatty acids in this species. Significant higher amounts of transcription factors and genes involved in signaling receptor activity were observed in GD1 (many of which were completely absent in H. hermesi), allowing fast signaling and transcriptional reprogramming which can mediate survival in dynamic intertidal environments. GC content was approximately 8% higher in H. hermesi coding unigenes resulting in differential codon usage between both species and a higher proportion of amino acids with GC-rich codons in H. hermesi. In general our results showed that most pathways were active in both environments and that only three genes are under natural selection. This indicates that also plasticity should be taken in consideration in the evolutionary history of Halomonhystera species. Such plasticity, as well as possible preadaptation to low oxygen and high sulfide levels might have played an important role in the establishment of a cold-seep Halomonhystera population. PMID- 26637469 TI - Genomic and Functional Characterization of the Unusual pLOCK 0919 Plasmid Harboring the spaCBA Pili Cluster in Lactobacillus casei LOCK 0919. AB - Here, we report the extensive bioinformatic and functional analyses of the unusual pLOCK 0919, a plasmid originating from the probiotic Lactobacillus casei LOCK 0919 strain. This plasmid is atypical because it harbors the spaCBA-srtC gene cluster encoding SpaCBA pili. We show that all other spaCBA-srtC sequences of the Lactobacillus genus that have been previously described and deposited in GenBank are present in the chromosomal DNA. Another important observation for pLOCK 0919 is that the spaCBA-srtC gene cluster and its surrounding genes are highly similar to the respective DNA region that is present in the most well known and active SpaCBA pili producer, the probiotic Lactobacillus rhamnosus GG strain. Our results demonstrate that the spaCBA-srtC clusters of pLOCK 0919 and L. rhamnosus GG are genealogically similar, located in DNA regions that are rich in transposase genes and are poorly conserved among the publicly available sequences of Lactobacillus sp. In contrast to chromosomally localized pilus gene clusters from L. casei and Lactobacillus paracasei, the plasmidic spaC of L. casei LOCK 0919 is expressed and undergoes a slight glucose-induced repression. Moreover, results of series of in vitro tests demonstrate that L. casei LOCK 0919 has an adhesion potential, which is largely determined by the presence of the pLOCK 0919 plasmid. In particular, the plasmid occurrence positively influenced the hydrophobicity and aggregation abilities of L. casei LOCK 0919. Moreover, in vivo studies indicate that among the three Lactobacillus strains used to colonize the gastrointestinal tract of germ-free mice, already after 2 days of colonization, L. casei LOCK 0919 became the dominant strain and persisted there for at least 48 days. PMID- 26637470 TI - Draft Genome Sequences of Two Closely Related Aflatoxigenic Aspergillus Species Obtained from the Ivory Coast. AB - Aspergillus ochraceoroseus and Aspergillus rambellii were isolated from soil detritus in Tai National Park, Ivory Coast, Africa. The Type strain for each species happens to be the only representative ever sampled. Both species secrete copious amounts of aflatoxin B1 and sterigmatocystin, because each of their genomes contains clustered genes for biosynthesis of these mycotoxins. We sequenced their genomes using a personal genome machine and found them to be smaller in size (A. ochraceoroseus = 23.9 Mb and A. rambellii = 26.1 Mb), as well as in numbers of predicted genes (7,837 and 7,807, respectively), compared to other sequenced Aspergilli. Our findings also showed that the A. ochraceoroseus Type strain contains a single MAT1-1 gene, while the Type strain of A. rambellii contains a single MAT1-2 gene, indicating that these species are heterothallic (self-infertile). These draft genomes will be useful for understanding the genes and pathways necessary for the cosynthesis of these two toxic secondary metabolites as well as the evolution of these pathways in aflatoxigenic fungi. PMID- 26637471 TI - Long term results of postoperative Intensity-Modulated Radiation Therapy (IMRT) in the treatment of Squamous Cell Carcinoma (SCC) located in the oropharynx or oral cavity. AB - BACKGROUND: To report our long-term results with postoperative intensity modulated radiation therapy (IMRT) in patients suffering from squamous-cell carcinoma (SCC) of the oral cavity or oropharynx. METHODS: Seventy five patients were retrospectively analyzed. Median age was 58 years and 84 % were male. 76 % of the primaries were located in the oropharynx. Surgery resulted in negative margins (R0) in 64 % of the patients while 36 % suffered from positive margins (R1). Postoperative stages were as follows: stage 1:4 %, stage 2:9 %, stage 3:17 %, stage 4a:69 % with positive nodes in 84 %. Perineural invasion (Pn+) and extracapsular extension (ECE) were present in 7 % and 29 %, respectively. All patients received IMRT using the step-and-shoot approach with a simultaneously integrated boost (SIB) in 84 %. Concurrent systemic therapy was applied to 53 patients, mainly cisplatin weekly. RESULTS: Median follow-up was 55 months (5 150). 13 patients showed locoregional failures (4 isolated local, 4 isolated neck, 5 combined) transferring into 5-year-LRC rates of 85 %. Number of positive lymph nodes (n > 2) and presence of ECE were significantly associated with decreased LRC in univariate analysis, but only the number of nodes remained significant in multivariate analysis. Overall treatment failures occurred in 20 patients (9 locoregional only, 7 distant only, 4 combined), transferring into 3 and 5-year-FFTF rates of 77 % and 75 %, respectively. The 3-and 5-year-OS rates were 80 % and 72 %, respectively. High clinical stage, high N stage, number of positive nodes (n > 2), ECE and Pn1 were significantly associated with worse FFTF and OS in univariate analysis, but only number of nodes remained significant for FFTF in multivariate analysis. Maximum acute toxicity was grade 3 in 64 % and grade 4 in 1 %, mainly hematological or mucositis/dysphagia. Maximum late toxicity was grade 3 in 23 % of the patients, mainly long-term tube feeding dependency. CONCLUSION: Postoperative IMRT achieved excellent LRC and good OS with acceptable acute and low late toxicity rates. The number of positive nodes (n > 2) was a strong prognostic factor for all endpoints in univariate and the only significant factor for LRC and FFTF in multivariate analysis. Patients with feeding tubes due to postoperative complications had an increased risk for long term feeding tube dependency. PMID- 26637472 TI - Georgia Primary Care Providers' Knowledge of Hereditary Breast and Ovarian Cancer Syndrome. AB - Hereditary breast and ovarian cancer syndrome (HBOC) is an inherited condition associated with mutations in the BRCA1 or BRCA2 (BRCA) genes. Identification of individuals with HBOC requires that primary care providers understand the genetic principles required to appropriately collect family history and refer individuals for genetic evaluation. A survey was developed and administered to primary care providers in Georgia to assess their existing knowledge of HBOC and direct targeted educational efforts.We found that Georgia providers demonstrate some knowledge of basic genetic principles but were unable to consistently identify individuals at risk for HBOC. Knowledge deficits included lack of understanding of inheritance patterns and failure to recognize the significance of ovarian cancer history. Strategies for improving identification of patients with HBOC include increasing provider knowledge and integrating HBOC risk assessment tools into practice. Identification of individuals at risk is the critical first step in the process of reducing incidence of breast and ovarian cancer associated with BRCA mutations. PMID- 26637473 TI - Assessing the Acceptability, Feasibility, and Effectiveness of a Tablet-Based Cervical Cancer Educational Intervention. AB - Cervical cancer is a common and deadly disease, especially in developing countries. We developed and implemented an interactive, tablet-based educational intervention to improve cervical cancer knowledge among women in rural Malawi. Chichewa-speaking adult women in six rural villages participated. Each woman took a pretest, participated in the lesson, and then took a posttest. The lesson included information on cervical cancer symptoms, causes, risk factors, prevention, and treatment. Over the 6-month study period, 243 women participated. Women ranged in age from 18 to 77 years. Only 15 % had education beyond primary school. Nearly half of participants (48 %) had heard of cervical cancer prior to viewing the lesson. For these women, the median number of correct responses on the pretest was 11 out of 20; after the lesson, they had a median of 18 correct responses (p < 0.001). After the intervention, 93 % of women indicated a desire for cervical cancer screening. Despite lack of familiarity with computers (96 %), most women (94 %) found the tablet easy to use. A tablet-based educational program was an effective, feasible, and acceptable strategy to disseminate cervical cancer information to women with low education in rural Malawi. This method may be appropriate to distribute health information about other health topics in low-resource settings. PMID- 26637474 TI - Prognostic impact of ICG-PDR in patients with hypoxic hepatitis. AB - BACKGROUND: Hepatic impairment is found in up to 20 % in critically ill patients. Hypoxic/ischemic hepatitis (HH) is a diffuse hepatic damage associated with high morbidity and mortality. Indocyanine green plasma disappearance rate (ICG-PDR) is an effective tool assessing liver function in acute and chronic hepatic diseases. Aim of this study was to evaluate the prognostic impact of ICG-PDR in comparison to established parameters for risk stratification. METHODS: Patients with HH were included in this prospective observational study and compared to cirrhosis, acute liver failure (ALF) and patients without underlying liver disease. ICG-PDR, measured non-invasively by finger pulse densitometry, was assessed on admission and in patients with HH serially and results were compared between groups. Diagnostic test accuracy of ICG-PDR predicting 28-day mortality was analyzed by receiver operating characteristics (ROC). RESULTS: ICG-PDR on admission was significantly lower in patients with liver diseases than in patients without hepatic impairment (median 5.7 %/min, IQR 3.8-7.9 vs. 20.7 %/min, IQR 14.1-25.4 %/min; p < 0.001). ICG-PDR predicted 28-day mortality independently of SOFA score and serum lactate in patients with underlying liver disease (HR 1.27, 95 % CI 1.10-1.45, p < 0.001). In patients with HH, ICG-PDR was identified as best predictor of 28-day mortality which performed significantly better than SOFA, lactate, INR and AST over course of time (p < 0.05). Best cut-off for identification of 28-day survivors was ICG-PDR >=9.0 %/min 48 h after admission. CONCLUSIONS: ICG-PDR is an independent predictor of mortality in patients with liver disease. Diagnostic test accuracy of ICG-PDR was superior to standard liver function parameters and established scoring systems in patients with HH. PMID- 26637475 TI - A man with a murmur and missing heart. PMID- 26637476 TI - Expression of Annexin A2 and Its Correlation With Drug Resistance and Recurrence of Bladder Cancer. AB - OBJECTIVE: To explore the expressions of annexin A2 in bladder cancer cell lines and bladder cancer tissues, we want to find the relationship among annexin A2, drug resistance, and recurrence of bladder cancer. METHODS: Our laboratory established the PUMC-91 bladder cancer cell line against gradient concentration of Adriamycin (0.3, 0.6, and 1.0 MUg/mL), and we also collected 60 cases of surgically resected bladder cancer recurrent tissue samples. The tissues were classified into 2 groups according to the frequency of recurrence (<6 months and >2 years) after initial surgery. The method of immunohistochemistry was used to examine the differences in the expression of annexin A2. RESULTS: There were statistical differences in annexin A2 among normal bladder epithelial cell line SV-HUC-1, PUMC-91, PUMC-91 against 0.3 MUg/mL Adriamycin, and PUMC-91 against 1.0 MUg/mL Adriamycin (P < .05). The expressions of Annexin A2 were found to be higher than those that recurred at >2 years (P = .002) in the bladder cancer tissues and that recurred at <6 months after initial surgery. It was also associated with invasion depth (stage) of bladder cancer, such as higher expression in T2 (invasive muscular) group than Tis (carcinoma in situ) and T1 (invasive mucosa lamina propria) groups (P = .003 and P = .000, respectively). But, it did not correlate with the differentiation (grade) of cancer cells in bladder cancer tissues (P = .593). CONCLUSION: Annexin A2 can act as a valuable biomarker for predicting the drug resistance and recurrence of bladder cancer. PMID- 26637477 TI - Cold adaptive traits revealed by comparative genomic analysis of the eurypsychrophile Rhodococcus sp. JG3 isolated from high elevation McMurdo Dry Valley permafrost, Antarctica. AB - The permafrost soils of the high elevation McMurdo Dry Valleys are the most cold, desiccating and oligotrophic on Earth. Rhodococcus sp. JG3 is one of very few bacterial isolates from Antarctic Dry Valley permafrost, and displays subzero growth down to -5 degrees C. To understand how Rhodococcus sp. JG3 is able to survive extreme permafrost conditions and be metabolically active at subzero temperatures, we sequenced its genome and compared it to the genomes of 14 mesophilic rhodococci. Rhodococcus sp. JG3 possessed a higher copy number of genes for general stress response, UV protection and protection from cold shock, osmotic stress and oxidative stress. We characterized genome wide molecular adaptations to cold, and identified genes that had amino acid compositions favourable for increased flexibility and functionality at low temperatures. Rhodococcus sp. JG3 possesses multiple complimentary strategies which may enable its survival in some of the harshest permafrost on Earth. PMID- 26637478 TI - Impact of Implementing Preanalytical Laboratory Standards on the Diagnosis of Gestational Diabetes Mellitus: A Prospective Observational Study. AB - BACKGROUND: Gestational diabetes mellitus (GDM) is associated with adverse pregnancy outcomes, but risk is reduced with identification and early treatment. Glucose measurements are affected by preanalytical sample handling, such as temperature of storage, phlebotomy-analysis interval, and use of a glycolysis inhibitor. We evaluated glucose concentrations and the incidence of GDM after strict implementation of the American Diabetes Association (ADA) preanalytical guidelines, compared with usual hospital conditions. METHODS: Women screened selectively for GDM at 24-32 weeks' gestation were recruited at their convenience before a 75-g oral glucose tolerance test. Paired samples were taken: the first sample followed ADA recommendations and was transferred to the laboratory on an iced slurry for immediate separation and analysis (research conditions), and the second sample was not placed on ice and was transferred according to hospital practice (usual conditions). RESULTS: Of samples from 155 women, the mean fasting, 1-h, and 2-h results were 90.0 (12.6) mg/dL [5.0 (0.7) mmol/L], 142.2 (43.2) mg/dL [7.9 (2.4) mmol/L], and 102.6 (32.4) mg/dL [5.7 (1.8) mmol/L], respectively, under research conditions, and 81 (12.6) mg/dL [4.5 (0.7) mmol/L], 133.2 (41.4) mg/dL [7.4 (2.3) mmol/L], and 99 (32.4) mg/dL [5.5 (1.8) mmol/L] under usual conditions (all P < 0.0001). GDM was diagnosed in 38.1% (n = 59) under research conditions and 14.2% (n = 22) under usual conditions (P < 0.0001). The phlebotomy-analysis interval for the fasting, 1-h, and 2-h samples was 20 (9), 17 (10), and 17 (9) min under research conditions and 162 (19), 95 (23), and 32 (19) min under usual conditions (all P < 0.0001). All cases of GDM were diagnosed on fasting or 1-h samples; the 2-h test diagnosed no additional cases. CONCLUSIONS: Implementation of ADA preanalytical glucose sample handling recommendations resulted in higher mean glucose concentrations and 2.7-fold increased detection of GDM compared with usual hospital practices. PMID- 26637479 TI - Functional Studies on Viable Circulating Tumor Cells. AB - BACKGROUND: Research on circulating tumor cells (CTCs) as new biomarkers has received great attention over the past decade. In particular, the capture and analysis of CTCs as "liquid biopsies" provides the possibility to avoid invasive tissue biopsies, with obvious implications in cancer diagnostics. CONTENT: The focus of this review is to describe and discuss how functional studies on viable CTCs can enlarge the spectrum of applications of liquid biopsies, with emphasis on breast, prostate, colon, and lung cancer as the major tumor entities in industrialized countries. The low number of CTCs in the peripheral blood of most cancer patients makes challenging the in vitro culture of CTCs. Epithelial tumor cells are difficult to culture, even when starting with millions of tumor cells. Recently, several groups have achieved important advances in the in vitro and in vivo expansion of CTCs from cancer patients at very advanced stages with higher amounts of CTCs. Here, we present current technologies to enrich and detect viable human CTCs, including positive and negative enrichment strategies that are based on antigen expression and physical properties of CTCs. We also discuss published data about functional studies on CTCs that use in vitro and in vivo models. SUMMARY: Functional analyses on CTCs offer the possibility to identify the biological properties of metastatic cells, including the identification of metastasis-initiating cells. Moreover, CTC-derived cell lines and xenografts might reveal new therapeutic targets and can be used for drug screening. PMID- 26637480 TI - Plasma Renin Activity: The Importance of Correct Sample Type. PMID- 26637481 TI - Analytical Performance of Multiplexed Screening Test for 10 Antibiotic Resistance Genes from Perianal Swab Samples. AB - BACKGROUND: Multiantibiotic-resistant bacteria pose a threat to patients and place an economic burden on health care systems. Carbapenem-resistant bacilli and extended-spectrum beta-lactamase (ESBL) producers drive the need to screen infected and colonized patients for patient management and infection control. METHODS: We describe a multiplex microfluidic PCR test for perianal swab samples (Acuitas((r)) MDRO Gene Test, OpGen) that detects the vancomycin-resistance gene vanA plus hundreds of gene subtypes from the carbapenemase and ESBL families Klebsiella pneumoniae carbapenemase (KPC), New Delhi metallo-beta-lactamase (NDM), Verona integron-mediated metallo-beta-lactamase (VIM), imipenemase metallo beta-lactamase (IMP), OXA-23, OXA-48, OXA-51, CTX-M-1, and CTX-M-2, regardless of the bacterial species harboring the antibiotic resistance. RESULTS: Analytical test sensitivity per perianal swab is 11-250 CFU of bacteria harboring the antibiotic resistance genes. Test throughput is 182 samples per test run (1820 antibiotic resistance gene family results). We demonstrate reproducible test performance and 100% gene specificity for 265 clinical bacterial organisms harboring a variety of antibiotic resistance genes. CONCLUSIONS: The Acuitas MDRO Gene Test is a sensitive, specific, and high-throughput test to screen colonized patients and diagnose infections for several antibiotic resistance genes directly from perianal swab samples, regardless of the bacterial species harboring the resistance genes. PMID- 26637482 TI - Comparison of tripterygium wilfordii multiglycosides and tacrolimus in the treatment of idiopathic membranous nephropathy: a prospective cohort study. AB - BACKGROUND: Idiopathic membranous nephropathy (IMN) is a major cause of nephrotic syndrome among adults. Considering the natural course of IMN, when to treat and with which immunosuppressive treatment need to be carefully considered in such patients. A combination of tripterygium wilfordii multiglycosides (TWG) and prednisone may be an effective option for treating patients with IMN. METHODS: In this prospective cohort study, we enrolled patients with biopsy-proven IMN at our kidney centre. One cohort received TWG combined with prednisone, whereas another cohort received tacrolimus (TAC) combined with prednisone, for 36 weeks. The primary outcome was the remission rate, whereas the secondary outcomes included the time to remission, relapse rate, changes in serum albumin levels and daily urinary protein levels, estimated glomerular filtration rate, and adverse events. RESULTS: A total of 53 patients with IMN met the criteria for enrollment, and all patients completed the therapy. At the end of the 36-week therapy, remission (either partial remission [PR] or complete remission [CR]) was observed in 20 patients (86.9 %) receiving TWG and in 27 patients (90.0 %) receiving TAC (p > 0.05), whereas CR was noted in 12 patients (52.2 %) receiving TWG and 14 patients (46.7 %) receiving TAC (p > 0.05). The probability of remission was similar for both the TWG and TAC groups (p > 0.05, by log-bank test). The mean time for achieving remission was 11.8 +/- 12.5 weeks in the TWG group and 8.5 +/- 9.1 weeks in the TAC group (p > 0.05). CONCLUSIONS: The combination of TWG and predisone is an effective and safe therapy for IMN. PMID- 26637484 TI - Australia's national youth mental health initiative: Is headspace underachieving? PMID- 26637483 TI - Downregulation of SMC1A inhibits growth and increases apoptosis and chemosensitivity of colorectal cancer cells. AB - OBJECTIVE: The structural maintenance of chromosomes (SMC) 1A protein is a component of the cohesin multiprotein complex that is essential for sister chromatid cohesion. SMC1A gene mutations have been reported in colorectal cancer. This study aimed to investigate the role of SMC1A gene expression in colorectal cancer in vitro. METHODS: SMC1A gene expression was silenced by lentivirus mediated infection with small interfering RNA (siRNA) in the human colorectal cancer cell line HT-29. Cell proliferation rates, SMC1A mRNA and protein levels, apoptosis and chemosensitivity to oxaliplatin were evaluated using routine in vitro assays, real-time polymerase chain reaction, Western blotting and flow cytometry. RESULTS: Knockdown of SMC1A protein and mRNA levels resulted in the inhibition of cell proliferation, an increased rate of apoptosis and enhanced chemosensitivity to oxaliplatin in HT-29 cells. CONCLUSIONS: The findings of this study suggest that SMC1A plays an oncogenic role in colorectal cancer and that it might be a promising target for colorectal cancer therapy. PMID- 26637485 TI - Study on health hazards through medicines purchased on the Internet: a cross sectional investigation of the quality of anti-obesity medicines containing crude drugs as active ingredients. AB - BACKGROUND: Weight-loss medicines, including crude drugs and herbal supplements disguised as diet-aid products, are readily obtainable and distributed widely, especially in Southeast Asia. Even if such products are unapproved or prescription-only medicines, consumers can purchase them through an agency or directly on the Internet. We evaluated the quality and safety of herbal products purchased on the Internet to reveal their influence on public health. METHODS: Diet-aid products containing Bukuryo (Poria sclerotium), Bakumondo (Ophiopogonis tuber), or Daio (rhubarb rhizome) were purchased through websites that did not provide physical addresses or which advertised misleading medicines (e.g., unapproved Cialis 100 mg tablets, Viagra 100 mg tablets) on websites. We carefully noted details in the descriptions on package inserts or accompanying product characteristics and analyzed the ingredients using qualitative and quantitative methods, namely high-performance liquid chromatography equipped with a photodiode array detector. We requested the respective manufacturers to authenticate their products through a structured questionnaire. RESULTS: We purchased 15 items from 15 Internet sites and imported all 15 items to Japan. One item stated to contain rhubarb rhizome was identified as a prescription medicine; the others were dietary supplements and not medicines. Even though we did not analyze the constituents of all crude drugs, we found some active ingredients in the items. Sibutramine was detected in items confirmed to be supplements, including those containing Poria sclerotium and Ophiopogonis tuber. Each capsule contained ~ 12 mg of sibutramine, which is the daily dose for anti-obesity medicines. Sibutramine is not approved for use in Japan and its sale has been suspended in Europe and the USA owing to serious adverse effects on the circulatory system. CONCLUSIONS: Our findings indicate that dietary supplements containing injurious ingredients are distributed to Japanese consumers and potentially to a broader international audience, and that purchasing them through unreliable websites bears potential health risks. To avoid potential adverse events, there should be adequate alerts about the risks of taking products without appropriate indications. PMID- 26637486 TI - Cyclotron production of (43)Sc for PET imaging. AB - BACKGROUND: Recently, significant interest in (44)Sc as a tracer for positron emission tomography (PET) imaging has been observed. Unfortunately, the co emission by (44)Sc of high-energy gamma rays (E gamma = 1157, 1499 keV) causes a dangerous increase of the radiation dose to the patients and clinical staff. However, it is possible to produce another radionuclide of scandium-(43)Sc-having properties similar to (44)Sc but is characterized by much lower energy of the concurrent gamma emissions. This work presents the production route of (43)Sc by alpha irradiation of natural calcium, its separation and purification processes, and the labeling of [DOTA,Tyr3] octreotate (DOTATATE) bioconjugate. METHODS: Natural CaCO3 and enriched [(40)Ca]CaCO3 were irradiated with alpha particles for 1 h in an energy range of 14.8-30 MeV at a beam current of 0.5 or 0.25 MUA. In order to find the optimum method for the separation of (43)Sc from irradiated calcium targets, three processes previously developed for (44)Sc were tested. Radiolabeling experiments were performed with DOTATATE radiobioconjugate, and the stability of the obtained (43)Sc-DOTATATE was tested in human serum. RESULTS: Studies of (nat)CaCO3 target irradiation by alpha particles show that the optimum alpha particle energies are in the range of 24-27 MeV, giving 102 MBq/MUA/h of (43)Sc radioactivity which creates the opportunity to produce several GBq of (43)Sc. The separation experiments performed indicate that, as with (44)Sc, due to the simplicity of the operations and because of the chemical purity of the (43)Sc obtained, the best separation process is when UTEVA resin is used. The DOTATATE conjugate was labeled by the obtained (43)Sc with a yield >98 % at elevated temperature. CONCLUSIONS: Tens of GBq activities of (43)Sc of high radionuclidic purity can be obtainable for clinical applications by irradiation of natural calcium with an alpha beam. PMID- 26637487 TI - Preservice and inservice teachers' knowledge of language constructs in Finland. AB - The aim of the study was to explore the Finnish preservice and inservice teachers' knowledge of language constructs relevant for literacy acquisition. A total of 150 preservice teachers and 74 inservice teachers participated in the study by filling out a questionnaire that assessed self-perceived expertise in reading instruction, knowledge of phonology and phonics, and knowledge of morphology. The inservice teachers outperformed the preservice teachers in knowledge of phonology and phonics, as well as morphology. Both groups' knowledge of morphology was markedly lower than their knowledge of phonology and phonics. Because early reading instruction does not focus on the morphological level of language but is phonics-based, this result was expected. However, the findings also revealed a lack of explicit knowledge of basic phonological constructs and less-than-optimal phonemic awareness skills in both groups. Problems in phonemic skills manifested mostly as responding to the phonological tasks based on orthographic knowledge, which reflects an overreliance on the one-to-one correspondence between graphemes and phonemes. The preservice teachers' perceptions of expertise were weakly related to their knowledge and skills. Among the inservice teachers, perceived expertise and knowledge of language constructs were completely unrelated. Although the study was exploratory, these findings suggest that within the Finnish teacher education there is a need to focus more on explicit content studies for language structures and the concepts relevant for literacy instruction, as well as phonological and phonemic skills. PMID- 26637489 TI - Margaret McCartney: Disrespecting confidentiality isn't the answer to FGM. PMID- 26637488 TI - Cortical atrophy patterns in multiple sclerosis are non-random and clinically relevant. AB - Grey matter atrophy is common in multiple sclerosis. However, in contrast with other neurodegenerative diseases, it is unclear whether grey matter atrophy in multiple sclerosis is a diffuse 'global' process or develops, instead, according to distinct anatomical patterns. Using source-based morphometry we searched for anatomical patterns of co-varying cortical thickness and assessed their relationships with white matter pathology, physical disability and cognitive functioning. Magnetic resonance imaging was performed at 3 T in 208 patients with long-standing multiple sclerosis (141 females; age = 53.7 +/- 9.6 years; disease duration = 20.2 +/- 7.1 years) and 60 age- and sex-matched healthy controls. Spatial independent component analysis was performed on cortical thickness maps derived from 3D T1-weighted images across all subjects to identify co-varying patterns. The loadings, which reflect the presence of each cortical thickness pattern in a subject, were compared between patients with multiple sclerosis and healthy controls with generalized linear models. Stepwise linear regression analyses were used to assess whether white matter pathology was associated with these loadings and to identify the cortical thickness patterns that predict measures of physical and cognitive dysfunction. Ten cortical thickness patterns were identified, of which six had significantly lower loadings in patients with multiple sclerosis than in controls: the largest loading differences corresponded to the pattern predominantly involving the bilateral temporal pole and entorhinal cortex, and the pattern involving the bilateral posterior cingulate cortex. In patients with multiple sclerosis, overall white matter lesion load was negatively associated with the loadings of these two patterns. The final model for physical dysfunction as measured with Expanded Disability Status Scale score (adjusted R(2) = 0.297; P < 0.001) included the predictors age, overall white matter lesion load, the loadings of two cortical thickness patterns (bilateral sensorimotor cortex and bilateral insula), and global cortical thickness. The final model predicting average cognition (adjusted R(2) = 0.469; P < 0.001) consisted of age, the loadings of two cortical thickness patterns (bilateral posterior cingulate cortex and bilateral temporal pole), overall white matter lesion load and normal appearing white matter integrity. Although white matter pathology measures were part of the final clinical regression models, they explained limited incremental variance (to a maximum of 4%). Several cortical atrophy patterns relevant for multiple sclerosis were found. This suggests that cortical atrophy in multiple sclerosis occurs largely in a non-random manner and develops (at least partly) according to distinct anatomical patterns. In addition, these cortical atrophy patterns showed stronger associations with clinical (especially cognitive) dysfunction than global cortical atrophy. PMID- 26637490 TI - It takes two to tango: information-sharing with offspring among heterosexual parents following identity-release sperm donation. AB - STUDY QUESTION: How do heterosexual parents reason about and experience information-sharing with offspring following identity-release sperm donation? SUMMARY ANSWER: Sharing information about using donor-conception with offspring is a complex process at several levels, with the parent's personal beliefs and the child's responses serving as driving or impeding forces for the information sharing process. WHAT IS KNOWN ALREADY: The overall view of disclosure in gamete donation has shifted from secrecy to openness, but there is still uncertainty among parents concerning how and when to tell the child about his/her genetic origin. Most research on donor-conceived families has focused on donation treatment under anonymous or known circumstances, and there is a lack of studies in settings with identity-release donations. STUDY DESIGN, SIZE, DURATION: A qualitative interview study among 30 parents following identity-release sperm donation treatment. Interviews were conducted from February 2014 to March 2015. PARTICIPANTS/MATERIALS, SETTING, METHODS: The present study is part of the prospective longitudinal Swedish Study on Gamete Donation (SSGD), including all fertility clinics performing gamete donation in Sweden. A sample of participants in the SSGD, consisting of heterosexual parents with children aged 7-8 years following identity-release sperm donation, participated in individual semi structured interviews. MAIN RESULTS AND THE ROLE OF CHANCE: The analysis revealed one main theme: information-sharing is a process, with three subthemes; (i) the parent as process manager, (ii) the child as force or friction and (iii) being in the process. The first two subthemes were viewed as being linked together and their content served as driving or impeding forces in the information-sharing process. LIMITATIONS, REASONS FOR CAUTION: The fact that the study was performed within the context of the Swedish legislation on identity-release donation must be taken into consideration as regards transferability to other populations, as this may affect parents' reasoning concerning their information-sharing with the child. WIDER IMPLICATIONS OF THE FINDINGS: The present findings highlight the role of the donor-conceived child in the information-sharing process and may contribute to develop counselling that increases parents' confidence in handling children's reactions to information about their genetic origin. STUDY FUNDING/COMPETING INTERESTS: Financial support from The Swedish Research Council, The Family Planning Fund in Uppsala and Ferring Pharmaceuticals. There are no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A. PMID- 26637491 TI - Timing of human preimplantation embryonic development is confounded by embryo origin. AB - STUDY QUESTION: To what extent do patient- and treatment-related factors explain the variation in morphokinetic parameters proposed as embryo viability markers? SUMMARY ANSWER: Up to 31% of the observed variation in timing of embryo development can be explained by embryo origin, but no single factor elicits a systematic influence. WHAT IS KNOWN ALREADY: Several studies report that culture conditions, patient characteristics and treatment influence timing of embryo development, which have promoted the perception that each clinic must develop individual models. Most of the studies have, however, treated embryos from one patient as independent observations, and only very few studies that evaluate the influence from patient- and treatment-related factors on timing of development or time-lapse parameters as predictors of viability have controlled for confounding, which implies a high risk of overestimating the statistical significance of potential correlations. STUDY DESIGN, SIZE, DURATION: Infertile patients were prospectively recruited to a cohort study at a hospital fertility clinic from February 2011 to May 2013. Patients aged <38 years without endometriosis were eligible if >=8 oocytes were retrieved. Patients were included only once. All embryos were monitored for 6 days in a time-lapse incubator. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 1507 embryos from 243 patients were included. The influence of fertilization method, BMI, maternal age, FSH dose and number of previous cycles on timing of t2-t5, duration of the 2- and 3-cell stage, and development of a blastocoel (tEB) and full blastocoel (tFB) was tested in multivariate, multilevel linear regression analysis. Predictive parameters for live birth were tested in a logistic regression analysis for 223 single transferred blastocysts, where time-lapse parameters were investigated along with patient and embryo characteristics. MAIN RESULTS AND THE ROLE OF CHANCE: Moderate intra-class correlation coefficients (0.16-0.31) were observed for all parameters except duration of the 3-cell stage, which demonstrates that embryos from one patient elicit clustering at a patient level. No single patient- and treatment-related factor was found to systematically influence the timing from cleavage to blastocyst stage, which indicates that no individual patient related factor can be identified that separately explains the clustering throughout the entire developmental stages. The blastocyst parameters were more affected by patient-related factors than cleavage stage parameters, as tEB occurred significantly later with older age (0.29 h/year (95% confidence interval: CI 0.03; 0.56)), while both tEB and tFB occurred significantly later with increasing dose of FSH (tEB: 0.12 h/100 IU FSH (95% CI 0.01;0.24); tFB 0.14 h/100 IU FSH (95% CI 0.03;0.27)) and with more previous attempts (tEB: 1.2 h/attempt (95% CI 0.01;2.5); tFB 1.4 h/attempt (0.10;2.7)). Fertilization method affected timing of the first division, with ICSI embryos cleaving significantly faster than IVF embryos (-3.6% (95% CI -6.4; -0.77)), whereas no difference was found in the subsequent divisions. The univariable regression analysis identified female age, cumulative FSH dose, degree of blastocyst expansion, score of the inner cell mass and timing of full blastocyst formation as predictors of live birth. The timing of full blastocyst formation (tFB) did not remain significant when adjusting for age, number of previous cycles and cumulative FSH dose, which were the parameters shown to influence tFB in the mixed regression model. LIMITATIONS, REASONS FOR CAUTION: Only good prognosis patients were enrolled, so these results may not be generalized to all infertile women. Not all patient related factors were investigated. WIDER IMPLICATIONS OF THE FINDINGS: Our findings underline the importance of treating embryos as dependent observations and suggest a high risk of patient-based confounding in retrospective studies. The impact of confounders and the embryo origin needs to be addressed in order to apply appropriate statistical models in observational studies. Furthermore, this observation emphasizes the need for RCTs for evaluating use of time-lapse parameters for embryo selection. STUDY FUNDING/COMPETING INTERESTS: Funding for the cohort study was provided by the Lippert Foundation, the Toyota Foundation, the Aase og Einar Danielsen foundation and NordicInfu Care research grant. Research at the Fertility Clinic, Aarhus University Hospital is supported by an unrestricted grant from MSD and Ferring. K.K. is funded by a grant from the Danish Council for Independent Research Medical Sciences. The authors declare no competing interest. PMID- 26637492 TI - Consistent and reproducible outcomes of blastocyst biopsy and aneuploidy screening across different biopsy practitioners: a multicentre study involving 2586 embryo biopsies. AB - STUDY QUESTION: Is blastocyst biopsy and quantitative real-time PCR based comprehensive chromosome screening a consistent and reproducible approach across different biopsy practitioners? SUMMARY ANSWER: The blastocyst biopsy approach provides highly consistent and reproducible laboratory and clinical outcomes across multiple practitioners from different IVF centres when all of the embryologists received identical training and use similar equipment. WHAT IS KNOWN ALREADY: Recently there has been a trend towards trophectoderm (TE) biopsy in preimplantation genetic screening (PGS)/preimplantation genetic diagnosis (PGD) programmes. However, there is still a lack of knowledge about the reproducibility that can be obtained from multiple biopsy practitioners in different IVF centres in relation also to blastocysts of different morphology. Although it has been demonstrated that biopsy at the blastocyst stage has no impact on embryo viability, it remains a possibility that less experienced individual biopsy practitioners or laboratories performing TE biopsy may affect certain outcomes. We investigated whether TE biopsy practitioners can have an impact on the quality of the genetic test and the subsequent clinical outcomes. STUDY DESIGN, SIZE, DURATION: This longitudinal cohort study, between April 2013 and December 2014, involved 2586 consecutive blastocyst biopsies performed at three different IVF centres and the analysis of 494 single frozen euploid embryo transfer cycles (FEET). PARTICIPANTS/MATERIALS, SETTING, METHODS: Seven biopsy practitioners performed the blastocyst biopsies in the study period and quantitative PCR was used for comprehensive chromosome screening (CCS). The same practitioner performed both the biopsy and tubing procedures for each blastocyst they biopsied. To investigate the quality of the biopsied samples, the diagnostic rate, sample-specific concurrence and the cell number retrieved in the biopsy were evaluated for each biopsy operator. Clinical outcomes following FEET cycles were stratified by biopsy operator and compared. Cellularity of the biopsy sample was also correlated with clinical outcomes. MAIN RESULTS AND THE ROLE OF CHANCE: The seven practitioners performed 2586 biopsies, five in centre IVF-1 and one in each of the other two IVF centres (IVF-2 and IVF-3). Overall, 2437 out of 2586 (94.2%) blastocyst biopsies resulted in a conclusive diagnosis, 119 (4.6%) showed a nonconcurrent result and 30 (1.2%) failed to amplify, suggesting the absence of TE cells in the test tube or presence of degenerated/lysed cells only. Among the samples producing a conclusive diagnosis, a mean concurrence value of 0.253 (95% CI = 0.250-0.257) was observed. Logistic regression analysis adjusted for confounding factors showed no differences in the diagnosis rate and in the concurrence of the genetic analysis between different biopsy practitioners. An overall mean number of 7.32 cells (95% CI = 6.82-7.81; range 2-15) were predicted from all biopsies. Higher cellularity was significantly associated with a better quality of the CCS diagnosis (P < 0.01) and with the conclusive diagnosis rate, with nonconcurrent samples showing significantly lower numbers of cells (2.1; 95% CI=1.5-2.7) compared with samples resulting in a conclusive diagnosis (mean cells number 7.5; 95% CI = 7.1-7.9, P < 0.01). However, no differences were recorded between different biopsy practitioners regarding cellularity of the biopsy. Finally, logistic analysis showed no impact of the biopsy practitioners on the observed ongoing rates of implantation, biochemical pregnancy loss and miscarriage after the FEET cycles. LIMITATIONS, REASONS FOR CAUTION: These data come from a restricted set of laboratories where all of the embryologists received identical training and use identical equipment. A single TE biopsy method and CCS technology was used and these data particularly apply to PGS programmes using blastocyst biopsy without zona opening at the cleavage stage and using qPCR-based CCS. To make firm conclusions on the potential impact of biopsy on biochemical pregnancy loss and miscarriages according to practitioner and biopsy cellularity, a larger sample size is needed. WIDER IMPLICATIONS OF THE FINDINGS: We reported a very high consistency and reproducibility of the blastocyst biopsy approach coupled with qPCR-based CSS for both genetic and clinical outcomes across different practitioners working in different IVF centres when appropriate training is provided and when the same laboratory setting is used. These data are important considering the trend towards the use of blastocyst biopsy worldwide for PGD/PGS applications. STUDY FUNDING/COMPETING INTERESTS: None. PMID- 26637493 TI - Dietary selenium increases the antioxidant levels and ATPase activity in the arteries and veins of poultry. AB - Selenium (Se) deficiency is associated with the pathogenesis of vascular diseases. It has been shown that oxidative levels and ATPase activity were involved in Se deficiency diseases in humans and mammals; however, the mechanism by how Se influences the oxidative levels and ATPase activity in the poultry vasculature is unclear. We assessed the effects of dietary Se deficiency on the oxidative stress parameters (superoxide dismutase, catalase, and hydroxyl radical) and ATPase (Na(+)K(+)-ATPase, Ca(++)-ATPase, Mg(++)-ATPase, and Ca(++)Mg(++)-ATPase) activity in broiler poultry. A total of 40 broilers (1-day old) were randomly divided into a Se-deficient group (L group, fed a Se-deficient diet containing 0.08 mg/kg Se) and a control group (C group, fed a diet containing sodium selenite at 0.20 mg/kg Se). Then, arteries and veins were collected following euthanasia when typical symptoms of Se deficiency appeared. Antioxidant indexes and ATPase activity were evaluated using standard assays in arteries and veins. The results indicated that superoxide dismutase activity in the artery according to dietary Se deficiency was significantly lower (p < 0.05) compared with the C group. The catalase activity in the veins and hydroxyl radical inhibition in the arteries and veins by dietary Se deficiency were significantly higher (p < 0.05) compared with the C group. The Se-deficient group showed a significantly lower (p < 0.05) tendency in Na(+)K(+)-ATPase activity, Ca(++)-ATPase activity, and Ca(++)Mg(++)-ATPase activity. There were strong correlations between antioxidant indexes and Ca(++)-ATPase activity. Thus, these results indicate that antioxidant indexes and ATPases may have special roles in broiler artery and vein injuries under Se deficiency. PMID- 26637494 TI - Effect of Zinc on Appetite Regulatory Peptides in the Hypothalamus of Salmonella Challenged Broiler Chickens. AB - The effects of dietary Zinc (Zn) supplementation on the gene expression of appetite regulatory peptides were investigated in Salmonella-infected broiler chickens. Broiler chickens (Arbor Acres, 1 day old) were allocated randomly into 24 pens of 10 birds. The chickens from 12 pens were fed with basal diet and the other with basal diet supplemented with Zn (ZnSO4.H2O, 120 mg/kg). At 5 days of age, the chickens were divided into 4 treatments with 6 pens: basal diet; basal diet and Salmonella challenge; Zn-supplemented diet; Zn-supplemented diet and Salmonella challenge. At 42 days of age, the hypothalamus from 6 chickens per treatment (1 chicken per pen) was individually collected for gene expression determination. Results showed that dietary supplementation of Zn reduced the gene expression of hypothalamic ghrelin and tumor necrosis factor alpha (TNF-alpha) (P < 0.05). Salmonella infection upregulated the messenger RNA (mRNA) levels of hypothalamic neuropeptide Y (NPY) and TNF-alpha. Zn supplementation and Salmonella inoculation were significantly correlated with the mRNA levels of toll like receptor 2-1 (P < 0.05). However, neither dietary Zn supplementation nor Salmonella inoculation had significant effect on hypothalamic agouti-related protein, cocaine- and amphetamine-regulated transcript, and pro-opiomelanocortin. This study shows that dietary Zn supplementation promoted orexigenic appetite regulatory peptides and reduced the expression of the inflammatory cytokine TNF alpha in the hypothalamus of Salmonella-challenged broilers. PMID- 26637495 TI - Bioaccumulation of Heavy Metals in Different Organs of Wallago attu from River Kabul Khyber Pakhtunkhwa, Pakistan. AB - The aim of the study was to quantify the accumulation of heavy metals like Zn, Ni, Cr, Cu, Cd, Mn, Fe, and Hg in various organs of Wallago attu. Samples were collected from polluted parts of River Kabul and compared with control fish netted from Warsak Dam. The data indicated that the sequence of metal bioaccumulation in the skin, gills, and muscle was Zn > Cr > Pb > Cu > Ni > Fe > Mn > Hg > Cd, in the intestine was Zn > Pb > Cr > Cu > Ni > Fe > Mn > Hg > Cd, and in the liver was Zn > Pb > Cr > Cu > Ni > Fe > Mn > Hg > Cd. The overall metal burden in different tissues of W. attu was in the sequence of skin > gills > intestine > muscle > liver. The skin being the prime target organ showed that the route of metal uptake was the direct result of fish to metal exposure. The liver accumulated the least level of metals than other organs of the same fish. PMID- 26637496 TI - Pushing the Limits of Laparoscopic Surgery: "How High Is the Sky?" or "When Conversion Is Not Needed". PMID- 26637497 TI - Resection of Sentinel Lymph Nodes by an Extraperitoneal Minilaparoscopic Approach Using Indocyanine Green for Uterine Malignancies: A Preclinical Comparative Study. AB - Background The sentinel lymph node (SLN) concept might minimize surgical aggressiveness in cervical and endometrial malignancies. The aim of the study was to test the feasibility and reliability of minilaparoscopic extraperitoneal SLN excision after indocyanine green (ICG) cervical injection using a high-definition near infrared (NIR) imaging system in an in vivo porcine model. The same procedure was performed using conventional laparoscopic instruments and both outcomes were compared. Methods Twenty-four animals were equally and randomly divided into a minilaparoscopic group (group A) and a 5-mm conventional laparoscopic group (group B). A high-definition NIR imaging system and a 30 degrees ICG endoscope were used. First, ICG (0.5 mL) was injected in the paracervical region. The SLN coloring time was recorded. An extraperitoneal approach to the SLN was executed with the same CO2 retropneumoperitoneum pressures (10 mm Hg). In both groups, the times for SLN localization and excision, as well as complications, were registered. Finally, a laparotomy was then done to evaluate whether any stained SLN still remained. The same surgical team performed all experiments. Results SLNs were identified and extraperitoneally excised in all animals without major complications. The SLN localization varied between animals from external iliac to preaortic regions. The surgical times were shorter with minilaparoscopy (39.3 +/- 13 minutes) than with conventional 5-mm instruments (51.3 +/- 14.17 minutes; P = .042). In group B, one stained SLN remained and was only detected by laparotomy. Conclusions We confirmed the feasibility and reliability of extraperitoneal minilaparoscopic approach for identification, dissection, and excision of SLN using an NIR imaging system and ICG. PMID- 26637498 TI - Coca-Cola funded group set up to promote "energy balance" is disbanded. PMID- 26637499 TI - In vitro and in vivo characterization of CYP inhibition by 1-aminobenzotriazole in rats. AB - 1-Aminobenzotriazole (ABT) is a non-isoform specific, time-dependent inhibitor of cytochrome P450 (CYP) enzymes used extensively in preclinical studies to determine the relative contribution of oxidative metabolism. Although ABT has been widely used, the extent and duration of its inhibitory effect is not well understood. The purpose of this study is to characterize ABT inhibition of CYP in rats at both the hepatic and intestinal levels. In vivo studies using midazolam (p.o. and i.v.), as a probe for CYP activity, demonstrated that CYP inhibition was not complete even at the highest dose (300 mg/kg). Additional in vivo studies demonstrated that even at 26 h following ABT administration, there was significant CYP inhibition remaining. In vitro studies, conducted in both rat liver microsomes and rat hepatocytes, confirm that ABT is a time-dependent inhibitor of rat CYP orthologs. However, in rat liver microsomes, there was more than 15% CYP activity remaining following a 60 min preincubation at 2 mm ABT and 5-10% of CYP activity was remaining in rat hepatocytes suspended in rat plasma following a 60 min preincubation at 2 mm ABT. 1-Aminobenzotriazole is a useful tool in elucidating the oxidative component of metabolism in preclinical species; however, conclusions made from the preclinical use of ABT should not operate under the assumption that CYP enzymatic activity is completely inhibited. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26637500 TI - Coronary arteriography in the diagnosis results and prognosis analysis of suspected coronary artery disease in patients with normal SPET myocardial perfusion imaging. AB - OBJECTIVE: Anatomic coronary artery disease (CAD) can be determined by coronary angiography (CAG) in patients with normal stress single photon emission tomography (SPET) myocardial perfusion imaging (MPI). Coronary angiography results of patients with negative exercise MPI and the prognosis of these patients (CAG-diagnosed CAD vs. non-CAD) were investigated in the current study. SUBJECTS AND METHODS: Suspected CAD patients who had SPET-MPI and subsequent CAG studies were retrospectively reviewed from May 2002 to November 2006. Siemens Diacam SPET and Siemens Ecam SPET gamma-cameras were used for the examination of rest/exercise technetium-99m methoxy isobutyl isonitrile ((99m)Tc-MIBI) myocardial imaging. Coronary angiography was performed with Philips arura angiography machine by the standard Judkins method. RESULTS: In all, 6598 patients underwent clinically indicated rest/exercise (99m)Tc-MIBI SPET-MPI, and 133 patients underwent CAG despite negative MPI. Thirty one patients were diagnosed with CAD by CAG. Most of these lesions (66%) were located in distal vessels and most of these patients (68%) had 1 vessel disease. Age (P<0.01), hypertension (P<0.01), typical angina pectoris (P<0.01), high pretest likelihood of CAD (P<0.001), exercise induced angina (P<0.05), positive exercise ECG (P<0.01), and transient enlargement of scintigraphic left ventricular size (P<0.05) were significantly different between non-CAD and CAD groups. After median follow-up time of 53 +/- 18 months, annualized cardiac event rate was 0.9% and 0.2% in CAD and non-CAD group, respectively (chi2 = 1.22, P=0.27). CONCLUSION: In all, 23% of 133 patients in our study we confirmed anatomic CAD by CAG, despite negative findings in SPET-MPI. Several clinical, stress, and MPI findings could be potential predictors. However, similar to non-CAD group, the CAG diagnosed CAD patients negative (99m)Tc-MIBI SPET-MPI exercise test had a good prognosis with annualized cardiac event rate less than 1.0%. PMID- 26637501 TI - Is vitamin D related to pathogenesis and treatment of Hashimoto's thyroiditis? AB - OBJECTIVE: The aim of this study was to investigate vitamin D status by measuring serum 25(OH)D levels in euthyroid patients with Hashimoto's thyroiditis (HT) who lived and worked on the sunny island of Crete, Greece, and to evaluate whether vitamin D3 supplementation is beneficial for the management of HT patients with vitamin D deficiency. SUBJECTS AND METHODS: We studied 218 HT patients, euthyroid Caucasian Cretan Greek citizens: 180 females and 38 males. Among these patients, 186 (85.3%) had vitamin D deficiency defined as serum 25(OH)D levels < 30 ng/mL. The mean age of all these 218 HT patients was 35.3 +/- 8.5 years. The mean age of the 186 vitamin D deficient HT patients (173 females and 13 males) was 37.3 +/- 5.6 years. The 186 vitamin D deficient HT patients received vitamin D3 (cholecalciferol, CF) orally, 1200-4000 IU, every day for 4 months aiming to maintain serum 25(OH)D levels >= 40 ng/mL. Anthropometric characteristics (height, weight, waist circumference), systolic and diastolic blood pressure, serum concentration of 25(OH)D, thyrotropin (TSH), free thyroxine (FT4), anti thyroid peroxidase (anti-TPO), antithyroglobulin (anti-TG), calcium and phosphorus levels and thyroid and kidney sonographic findings were recorded and measured before and after CF administration. RESULTS: There was a significant negative correlation only between serum 25(OH)D levels and anti-TPO levels among all 218 HT patients. Also, anti-TPO levels were significantly higher in 186/218 vitamin D deficient HT patients compared to 32/218 HT patients with no vitamin D deficiency (364 +/- 181IU/mL versus 115.8 +/- 37.1IU/mL, P<0.0001). Supplementation of CF in 186 vitamin D deficient HT patients caused a significant decrease (20.3%) in serum anti-TPO levels. Although at the end of the 4 months period of the study body mass index (BMI), serum anti-TG and TSH levels decreased by 2.2%, 5.3% and 4% respectively, these differences were not significant. No changes in the sonographic findings were observed. CONCLUSION: The majority (85.3%) of the Greek Caucasian patients with HT studied who lived and worked in Crete had low serum 25(OH)D levels inversely correlated with serum anti-TPO thyroid antibodies. After 4 months of CF supplementation in the 186 HT patients with vitamin D deficiency, a significant decrease (20.3%) of serum anti-TPO levels was found. These findings suggest that vitamin D deficiency may be related to pathogenesis of HT and that its supplementation could contribute to the treatment of patients with HT. PMID- 26637502 TI - Hypoxia-inducible factor-1alpha, adrenomedullin and Bcl-2 although expected are not related to increased uptake of fluorine-18-fluorodeoxyglucose in endometrial cancer. AB - OBJECTIVE: To study the relation between SUVmax, hypoxia inducible factor 1alpha (HIF-1alpha), angiogenetic factor adrenomedullin (AM) and antiapoptotic factor Bcl-2 in endometrial cancer. SUBJECTS AND METHODS: Thirthy eight patients who were diagnosed after a preoperative endometrial biopsy with endometrium cancer underwent pre-operative positron emission tomography/computed tomography (PET/CT) utilizing fluorine-18-fluorodeoxy glucose (18F-FDG). Maximum standardized uptake values (SUVmax) of the primary tumor were measured. After hysterectomy and bilateral salpingo-oophorectomy, microscopic slides of the 38 endometrial adenocarcinoma patients were evaluated by a surgical pathologist to confirm the diagnosis. Immunohistochemical staining for AM, Bcl-2 and HIF-1alpha was studied. RESULTS: In all patients, 18F-FDG uptake was detected. The mean SUVmax of the tumors was 11.8 +/- 5.9. Although SUVmax was higher in HIF-1alpha positive tumors, this finding was not statistically important. No correlation was found between SUVmax and HIF-1alpha positivity. Mean SUVmax was 6.4 +/- 3 and 12.3 +/- 1.4 in AM negative and AM positive patients, respectively. Mean SUVmax was 10.6 +/- 4.9 and 12.3 +/- 1.4 in Bcl-2 negative and Bcl-2 positive patients, respectively. We found no correlation between SUVmax, AM or Bcl-2 expression. Allred scores were not related with SUVmax in regression analysis. CONCLUSION: Our study in a small number of patients is the first to show that SUVmax, although expected is not associated with HIF-1alpha, AM or with Bcl-2 in endometrial cancer. Increased uptake of 18F-FDG in endometrial cancer seems to be independent of HIF-1alpha and its downstream factors. PMID- 26637503 TI - Sedation practice for paediatric nuclear medicine procedures in Denmark related to EANM guidelines. AB - OBJECTIVE: The objective of this study was to examine sedation practices for paediatric nuclear medicine examinations. METHODS: A questionnaire was sent to all nuclear medicine departments in Denmark about sedation practices during 2012. RESULTS: The response rate was 100% (18 departments). Three departments did not examine children at all. The total number of paediatric examinations among the remaining 15 sites varied from 20 to 1,583 (median 191). Sedation practice showed that approximately 50% of the sites regularly (>50% of the patients) used pharmacological sedation for renography in children aged 6-12 months and 1-3 years. A minority of centres (~15%) regularly used sedation in children aged 0-6 months, and no sites regularly used sedation in children aged and 4-6 years. Similar findings were found for renal scintigraphy. However, one large site used no sedation in children aged 1-3 years for renography but approximately 50% of patients used it in the same age group receiving renal scintigraphy with SPET. There was a trend for reduced use of sedation with increasing total number of paediatric medicine procedures. The most frequently used agents were benzodiazepines and barbiturates. The most common route of administration was rectal, oral, and intravenous. CONCLUSION: The sedation practices varied considerably among Danish nuclear medicine departments. The sedation of children in clinical practice seemed to be more prevalent than is recommended by guidelines. PMID- 26637504 TI - Description of the thyroid hormone resistance syndrome illustrated by such a case, which had two different carcinomas and was mistreated with iodine-131. AB - OBJECTIVE: Hyperthyroidism with increased serum thyroid hormones and also increased thyroid stimulating hormone (TSH) is described as the resistance thyroid hormone (RTH) syndrome. This syndrome may be due to various factors including tumors. We describe the different types of RTH syndrome and mention that this syndrome may be misdiagnosed and mistreated. To illustrate the RTH syndrome we describe such a case which also had two different carcinomas. This case was treated with anti-thyroid drugs, triiodothyroacetic acid and iodine-131 (131I). In the following 5.5 years after 131I treatment, TSH progressively increased and was not suppressed by normal doses of L-thyroxine (L-T4). A thyroid nodule was diagnosed as papillary thyroid carcinoma (PTC) and a small cell neuroendocrine carcinoma was diagnosed in the nasal septum. Under L-T4 replacement treatment and after ablation of both carcinomas, TSH returned to normal. Small cell neuroendocrine carcinomas accompanied with PTC, are extremely rare causes of RTH. CONCLUSION: A description of the resistance to thyroid hormone syndrome is presented and this syndrome is illustrated by a referring case which could be of a selective pituitary type or due to the neuroendocrine tumor. PMID- 26637505 TI - How a tertiary medical nuclear medicine department at the Himalayan area in India can be established and function in an exemplary manner. Basic rules revisited. AB - OBJECTIVE: We describe and discuss the various medical, social and financial aspects of setting up, and optimizing, working conditions of a tertiary Nuclear Medicine Department. This department was established in a North Indian state which comprises 93% of hilly area. During the first three years after establishment we have developed infrastructure, cooperation with other departments, improved radiation safety and cost effectiveness of our work and designed future perspectives. The facility was established in a cancer center of a tertiary care hospital where a medical college infrastructure was developed. National guidelines formulated by the Atomic Energy Regulatory Board (AERB) were followed. Our department served a population area of 10.08 million inhabitants. Over the first three years 2,400 patients underwent diagnostic scans and 106 patients underwent low dose radioiodine treatment for thyrotoxicosis. To optimize resources and at the same time, enhance their effectivity, we procured our (99)Mo/ (99m)Tc generator every other week and arranged our daily programme accordingly. Fractionation of cold kits allowed us to perform low cost in-vivo procedures on a daily basis and to save the department's running costs by 30% 50%. We run continuing education nuclear medicine programmes for referring physicians, medical students and paramedical workers which were included in routine practice which led to a consistent growth in patients referral. The need for a positron emission tomography/computed tomography (PET/CT) scan and high dose treatment department for thyroid cancer was strongly felt. CONCLUSION: Our nuclear medicine department in a peripheral region of a developing country applied better logistics by procuring new generator every fortnight, fractionating the cold kits and by organizing complete teaching programmes. PMID- 26637506 TI - The origin of the Hox/ParaHox genes, the Ghost Locus hypothesis and the complexity of the first animal. AB - A key aim in evolutionary biology is to deduce ancestral states to better understand the evolutionary origins of clades of interest and the diversification process(es) that has/have elaborated them. These ancestral deductions can hit difficulties when undetected loss events are misinterpreted as ancestral absences. With the ever-increasing amounts of animal genomic sequence data, we are gaining a much clearer view of the preponderance of differential gene losses across animal lineages. This has become particularly clear with recent progress in our understanding of the origins of the Hox/ParaHox developmental control genes relative to the earliest branching lineages of the animal kingdom: the sponges (Porifera), comb jellies (Ctenophora) and placozoans (Placozoa). These reassessments of the diversity and complexity of developmental control genes in the earliest animal ancestors need to go hand-in-hand with complementary advances in comparative morphology, phylogenetics and palaeontology to clarify our understanding of the complexity of the last common ancestor of all animals. The field is currently undergoing a shift from the traditional consensus of a sponge like animal ancestor from which morphological and molecular elaboration subsequently evolved, to a scenario of a more complex animal ancestor, with subsequent losses and simplifications in various lineages. PMID- 26637507 TI - Strength of the Lewis-Bronsted Superacids Containing In, Sn, and Sb and the Electron Binding Energies of Their Corresponding Superhalogen Anions. AB - The HInnF3n+1, HSnnF4n+1, and HSbnF5n+1 (n = 1-3) compounds and their corresponding InnF3n+1(-), SnnF4n+1(-), SbnF5n+1(-) (n = 1-3) anions were investigated by employing the B3LYP, QCISD, and OVGF quantum chemistry methods and the LANL2DZ/6-311++G(d,p) basis sets. Our calculations revealed very strong acidity of all examined neutral compounds and large electronic stabilities (in the range 9.9-13.3 eV) of their corresponding anions. The gas phase acidities (manifested by small Gibbs free energies of deprotonation, DeltaGacid) predicted for the HSn3F13 and HSb3F16 (DeltaGacid of 243.5 and 230.3 kcal/mol at T = 298.15 K, respectively) suggest that these systems should actually act as even stronger acids than the F(SO3)4H and HSbF6 compounds (recognized thus far as the strongest superacids). PMID- 26637509 TI - Mepolizumab approved as add-on long-term therapy for severe asthma. PMID- 26637510 TI - Advanced pharmacy services support multiple myeloma clinic. PMID- 26637511 TI - Palmetto weathers South Carolina flooding. PMID- 26637513 TI - Diabetic foot infection caused by Raoultella ornithinolytica. AB - PURPOSE: The case of a diabetic foot infection caused by Raoultella ornithinolytica is reported. SUMMARY: A 68-year-old Caucasian man arrived at the hospital with a fever (38.5 degrees C) and a foul-smelling pressure ulcer on his left foot and was admitted for treatment of a moderate diabetic foot infection. The patient's medical history included type II diabetes mellitus, hypertension, chronic kidney disease, dyslipidemia, cataract surgery, and total hip arthroplasty. A tissue biopsy of the diabetic foot lesion was performed, and a blood sample was cultured. Empirical antimicrobial treatment consisting of amoxicillin-clavulanate 1.2 g (of amoxicillin) i.v. every 12 hours and ciprofloxacin 200 mg i.v. every 12 hours was initiated to target aerobic gram positive and gram-negative and anaerobic microorganisms. After 48 hours, the results of the blood culture were negative, but the left ankle wound culture grew R. ornithinolytica. Although the isolated R. ornithinolytica was relatively sensitive, showing resistance only to cefazolin and ampicillin, the antibiotic regimen was not changed. The patient showed clinical and laboratory improvement during his 5-day hospitalization. Subsequently, i.v. antibiotics were discontinued, and the patient was discharged on oral amoxicillin-clavulanate 1 g (of amoxicillin) twice daily and oral ciprofloxacin 750 mg twice daily for an additional 9 days to complete a total duration of 14 days of treatment, after which the infection was completely resolved. CONCLUSION: A 68-year-old man diagnosed with a diabetic foot infection caused by R. ornithinolytica was successfully treated with amoxicillin-clavulanate and ciprofloxacin. PMID- 26637512 TI - Ceftolozane-tazobactam: A new-generation cephalosporin. AB - PURPOSE: The chemistry, pharmacokinetic and pharmacodynamic properties, efficacy, and safety of the recently introduced combination antimicrobial agent ceftolozane tazobactam are reviewed. SUMMARY: Ceftolozane-tazobactam (Zerbaxa, Cubist Pharmaceuticals) is a cephalosporin beta-lactam and beta-lactamase inhibitor marketed as a fixed-dose combination agent for the treatment of complicated urinary tract and intraabdominal infections. Its dosing and chemistry provide expansive antimicrobial coverage of gram-negative organisms, including Pseudomonas aeruginosa, and stable activity against many beta-lactamases, as well as coverage of most extended-spectrum beta-lactamase-producing organisms and some anaerobes. Ceftolozane-tazobactam is susceptible to hydrolysis by carbapenemase enzymes but is not affected by other resistance mechanisms such as efflux pumps and porin loss. Clinical trials demonstrated that combination treatment with ceftolozane-tazobactam plus metronidazole had efficacy comparable to that of levofloxacin in patients with complicated urinary tract infections, including pyelonephritis, and comparable to that of meropenem against complicated intraabdominal infections. A Phase III trial of ceftolozane-tazobactam versus meropenem for treatment of bacterial pneumonia, including ventilator-associated pneumonia, is underway. Adverse effects reported with ceftolozane-tazobactam use are comparable to those seen with other beta-lactams (e.g., hypersensitivity, nausea, diarrhea, headache). Initially, ceftolozane-tazobactam may be reserved for targeted therapy against multidrug-resistant pathogens. CONCLUSION: Ceftolozane-tazobactam is a new cephalosporin with enhanced activity against multidrug-resistant P. aeruginosa and other gram-negative pathogens. PMID- 26637514 TI - Safety and tolerability of eribulin mesylate in patients with pretreated metastatic breast cancer. AB - PURPOSE: The safety and tolerability of eribulin mesylate for the treatment of metastatic breast cancer (MBC) are examined. METHODS: This retrospective analysis used pooled safety and tolerability data from three Phase II trials and one Phase III trial of eribulin in patients with MBC. In these studies, patients with pretreated MBC received eribulin mesylate 1.4 mg/m(2) as a two- to five-minute i.v. infusion on days 1 and 8 of a 21-day cycle. Adverse events were assessed according to the Common Terminology Criteria for Adverse Events, version 3.0. RESULTS: Across the four trials, 908 patients received eribulin and were assessed for safety. Aside from anthracyclines and taxanes, the most common prior chemotherapy agents were capecitabine, vinorelbine, and gemcitabine. Patients had received a mean of 3.7 (range, 1-11) prior chemotherapeutic regimens. Dose delays, reductions, and interruptions due to treatment-emergent adverse events occurred in 35.0%, 17.3%, and 2.9% of patients, respectively. Treatment was discontinued in 12.3% of patients due to adverse events, regardless of whether the adverse event was considered treatment related. The most common grade 3 or 4 treatment-related adverse events were neutropenia (52.4%) and leukopenia (19.3%). Serious adverse events occurred in 26.1% of patients, with the most common being febrile neutropenia (3.6%) and pyrexia (2.3%). Peripheral neuropathy was seen in 30.6% of patients, with 6.6% experiencing grade 3 or 4 reactions. CONCLUSION: Despite heavy pretreatment with anthracyclines, taxanes, and capecitabine, eribulin was well tolerated in this pooled analysis of patients with MBC. PMID- 26637515 TI - An evaluation of acuity adjustment metrics to track medication expense over time. AB - PURPOSE: The acuity adjustment metric that correlates most closely with actual medication expense at a large, tertiary care academic medical center was investigated. METHODS: This evaluation was conducted at the Ohio State University Wexner Medical Center. All inpatient discharges between July 1, 2012, and March 31, 2013, were included in this study. Patient medical and financial records were used to obtain the diagnosis-related group (DRG) codes and total medication cost for each patient discharge. The primary DRG for each patient was then used to assign the corresponding relative weight (RW) and pharmacy intensity weight (PIW). The correlation between actual and predicted medication expenditure was determined for every DRG for both RW and PIW. Since this compares cost at the DRG level, RW and PIW were used as markers for case-mix index (CMI) and pharmacy intensity score (PIS), respectively. RESULTS: At this single institution, medication cost per discharge was more strongly correlated with PIW (as a marker for PIS) than with RW (as a marker for CMI). Extrapolating these data to hospital specific values, the results suggest that PIS is more strongly correlated with overall medication expense than CMI and therefore a better adjustment metric for monitoring medication expense over time. CONCLUSION: A single-institution study demonstrated that PIW was more strongly correlated than RW with actual medication expenditure. PIS may be a more accurate acuity metric than CMI for predicting changes in drug expense over time. PMID- 26637516 TI - Independent prescribing by hospital pharmacists: Patterns and practices in a Canadian province. AB - PURPOSE: Results of a survey to determine the frequency of prescribing by Canadian hospital pharmacists with independent prescribing authority are reported. METHODS: A Web-based questionnaire was used to collect data on the prescribing activities of a designated group of hospital-affiliated pharmacists in the province of Alberta who had been granted "additional prescribing authorization" (APA) through a peer-review process and were providing clinical pharmacy services in inpatient and/or outpatient settings at the time of the survey (January-March 2014). Descriptive statistics and logistic regression analysis were used to determine the median weekly frequency of prescribing, factors associated with increased use of APA, and perceived prescribing barriers and enablers. RESULTS: The survey response rate was about 50% (77 of 153 eligible pharmacists). The median self-reported number of prescriptions and medication orders written during an average week was 4.2 (interquartile range, 2.0-10.0) per 10 patients. Antibiotics and anticoagulants were the most commonly prescribed medications. Interdisciplinary care team dynamics was rated as a leading enabler of prescribing but also a leading barrier to the exercise of APA. The greatest motivators to apply for APA were the potential for increased efficiency and the potential for enhanced patient care. CONCLUSION: The survey results indicated that, in an average week, hospital pharmacists with APA prescribed for almost half of the patients they cared for as part of the interdisciplinary team. Prescribing most frequently occurred after team discussion and most often involved adjusting dosages based on organ function and clinical assessment. PMID- 26637517 TI - Comparison of antibiotic susceptibility of Escherichia coli in urinary isolates from an emergency department with other institutional susceptibility data. AB - PURPOSE: The antibiotic susceptibility of Escherichia coli in isolates from patients with uncomplicated urinary tract infection (UTI) in an emergency department (ED) was compared with susceptibility data from the associated hospital. METHODS: Patients eligible for study participation included women age 18-65 years with one or more symptoms consistent with a UTI for whom a urine dipstick, urinalysis, or urine culture was ordered. Clinical decision-making, including the decision to order a urine culture, was at the discretion of the individual healthcare provider; however, a deidentified urine culture and antimicrobial susceptibility testing were performed for those study participants for whom a urine culture was not ordered. We compared the E. coli-specific antibiogram for uncomplicated UTI to the antibiogram based on all urine cultures in the ED regardless of patient disposition, non-intensive care unit (ICU) hospital inpatients, and the hospitalwide antibiogram. RESULTS: Of the 578 ED patients screened for study eligibility, 119 met the inclusion criteria. E. coli, detected in 53 (74%) of the 72 pathogen-positive cultures, was the most common pathogen isolated. For E. coli, ciprofloxacin nonsusceptibility was significantly less common in isolates from ED patients with uncomplicated cystitis and pyelonephritis than in isolates from non-ICU inpatients or from the hospitalwide population. E. coli nonsusceptibility to ciprofloxacin was significantly less common in ED isolates from patients with uncomplicated UTI than in isolates from all ED patients with clinician-ordered urine cultures. CONCLUSION: Antibiotic susceptibility of E. coli in an ED and its associated hospital depended on factors such as whether patients were hospitalized and whether ED isolates were from patients with uncomplicated UTI. PMID- 26637519 TI - Navigating financial assistance options for patients receiving specialty medications. PMID- 26637518 TI - Stability of furosemide and chlorothiazide stored in syringes. AB - PURPOSE: The results of a study to determine the stability of solutions of furosemide and chlorothiazide over 96 hours are reported. METHODS: Chlorothiazide and furosemide were diluted in 5% dextrose USP to final concentrations of 10 and 1 mg/mL, respectively, and combined. In addition, sample solutions of chlorothiazide in dextrose, furosemide in dextrose, and dextrose alone were prepared for control purposes. The resulting solutions were analyzed immediately after preparation and 24, 48, 72, and 96 hours later using a liquid chromatography-tandem mass spectroscopy (LC-MS/MS) system with an electrospray ionization source. Mixtures and samples were diluted 10,000-fold prior to LC MS/MS analysis so that concentrations of both drugs would be within the assay's linear range of detection. RESULTS: LC-MS/MS analysis showed that chlorothiazide typically eluted at 2.6 minutes and furosemide at 4.8 minutes. Each compound was degraded by exposure to strong ultraviolet light in a time-dependent manner. Both unmixed and mixed solutions retained over 90% of the original concentrations of chlorothiazide and furosemide for up to 96 hours. Furosemide and chlorothiazide are commonly used concomitantly to maximize diuresis in pediatric patients; the study findings suggest that solutions of furosemide and chlorothiazide can be combined in the same syringe without loss of stability for up to 96 hours. CONCLUSION: Solutions of chlorothiazide (10 mg/mL) and furosemide (1 mg/mL) stored either separately or together in polypropylene syringes remained stable for up to 96 hours at room temperature and protected from light. PMID- 26637522 TI - Association between urticaria and virus infections: A systematic review. AB - BACKGROUND: The association between urticaria and virus infections has rarely been reported in the literature. The lack of reported cases is probably due to the difficulty in establishing a cause-and-effect relationship. It is not possible to challenge the patient with an etiologic agent. OBJECTIVE: The purpose of this work was to perform a systematic review on the association between urticaria and virus infections. METHODS: This systematic review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We searched for articles from January 1, 2008, through May 2015, by using two key terms related to urticaria and virus diseases, "urticaria" and one key term related to virus infections, "virus disease," then "urticaria" and the name of each virus family, and of the most representative virus serotypes. RESULTS: We reported cases of patients affected either by acute or chronic urticaria with a concurrent virus infection. Previous other causes of urticaria had to be excluded. Herpesviridae infections and urticaria were the most frequently reported associations in children. However, hepatitis virus infections would appear to be the most-frequent cause of urticaria in adults. CONCLUSIONS: Data obtained indicated viral infection as a potential trigger and sometimes as the main etiologic agent in causing acute or chronic urticaria. In every case, urticarial manifestation cleared up after either healing or controlling of the viral infection. However, prospective studies and well-structured research is needed to better clarify the role of viruses in the pathogenesis of urticaria and their relative prevalence. PMID- 26637523 TI - Transition of Thai HIV-infected adolescents to adult HIV care. PMID- 26637524 TI - To Bayes or not to Bayes .... PMID- 26637525 TI - Pre-training perceived wellness impacts training output in Australian football players. AB - The impact of perceived wellness on a range of external load parameters, rating of perceived exertion (RPE) and external load:RPE ratios, was explored during skill-based training in Australian footballers. Fifteen training sessions involving 36 participants were analysed. Each morning before any physical training, players completed a customised perceived wellness questionnaire (sleep quality, fatigue, stress, mood and muscle soreness). Microtechnology devices provided external load (average speed, high-speed running distance, player load and player load slow). Players provided RPE using the modified Borg category ratio 10 RPE scale. Mixed-effect linear models revealed significant effects of wellness Z-score on player load and player load slow. Effects are reported with 95% confidence limits. A wellness Z-score of -1 corresponded to a -4.9 +/- 3.1 and -8.6 +/- 3.9% reduction in player load and player load slow, respectively, compared to those without reduced wellness. Small significant effects were also seen in the average speed:RPE and player load slow:RPE models. A wellness Z-score of -1 corresponded to a 0.43 +/- 0.38 m.min(-1) and -0.02 +/- 0.01 au.min(-1) change in the average speed:RPE and player load slow:RPE ratios, respectively. Magnitude-based analysis revealed that the practical size of the effect of a pre training perceived wellness Z-score of -1 would have on player load slow was likely negative. The results of this study suggests that monitoring pre-training perceived wellness may provide coaches with information about the intensity of output that can be expected from individual players during a training session. PMID- 26637526 TI - Genome management and mismanagement--cell-level opportunities and challenges of whole-genome duplication. AB - Whole-genome duplication (WGD) doubles the DNA content in the nucleus and leads to polyploidy. In whole-organism polyploids, WGD has been implicated in adaptability and the evolution of increased genome complexity, but polyploidy can also arise in somatic cells of otherwise diploid plants and animals, where it plays important roles in development and likely environmental responses. As with whole organisms, WGD can also promote adaptability and diversity in proliferating cell lineages, although whether WGD is beneficial is clearly context-dependent. WGD is also sometimes associated with aging and disease and may be a facilitator of dangerous genetic and karyotypic diversity in tumorigenesis. Scaling changes can affect cell physiology, but problems associated with WGD in large part seem to arise from problems with chromosome segregation in polyploid cells. Here we discuss both the adaptive potential and problems associated with WGD, focusing primarily on cellular effects. We see value in recognizing polyploidy as a key player in generating diversity in development and cell lineage evolution, with intriguing parallels across kingdoms. PMID- 26637527 TI - FGF2 mediates hepatic progenitor cell formation during human pluripotent stem cell differentiation by inducing the WNT antagonist NKD1. AB - Fibroblast growth factors (FGFs) are required to specify hepatic fate within the definitive endoderm through activation of the FGF receptors (FGFRs). While the signaling pathways involved in hepatic specification are well understood, the mechanisms through which FGFs induce hepatic character within the endoderm are ill defined. Here we report the identification of genes whose expression is directly regulated by FGFR activity during the transition from endoderm to hepatic progenitor cell. The FGFR immediate early genes that were identified include those encoding transcription factors, growth factors, and signaling molecules. One of these immediate early genes encodes naked cuticle homolog 1 (NKD1), which is a repressor of canonical WNT (wingless-type MMTV integration site) signaling. We show that loss of NKD1 suppresses the formation of hepatic progenitor cells from human induced pluripotent stem cells and that this phenotype can be rescued by using a pharmacological antagonist of canonical WNT signaling. We conclude that FGF specifies hepatic fate at least in large part by inducing expression of NKD1 to transiently suppress the canonical WNT pathway. PMID- 26637529 TI - ONRLDB--manually curated database of experimentally validated ligands for orphan nuclear receptors: insights into new drug discovery. AB - Orphan nuclear receptors are potential therapeutic targets. The Orphan Nuclear Receptor Ligand Binding Database (ONRLDB) is an interactive, comprehensive and manually curated database of small molecule ligands targeting orphan nuclear receptors. Currently, ONRLDB consists of ~11,000 ligands, of which ~6500 are unique. All entries include information for the ligand, such as EC50 and IC50, number of aromatic rings and rotatable bonds, XlogP, hydrogen donor and acceptor count, molecular weight (MW) and structure. ONRLDB is a cross-platform database, where either the cognate small molecule modulators of a receptor or the cognate receptors to a ligand can be searched. The database can be searched using three methods: text search, advanced search or similarity search. Substructure search, cataloguing tools, and clustering tools can be used to perform advanced analysis of the ligand based on chemical similarity fingerprints, hierarchical clustering, binning partition and multidimensional scaling. These tools, together with the Tree function provided, deliver an interactive platform and a comprehensive resource for identification of common and unique scaffolds. As demonstrated, ONRLDB is designed to allow selection of ligands based on various properties and for designing novel ligands or to improve the existing ones. Database URL: http://www.onrldb.org/. PMID- 26637528 TI - SREBP and MDT-15 protect C. elegans from glucose-induced accelerated aging by preventing accumulation of saturated fat. AB - Glucose-rich diets shorten the life spans of various organisms. However, the metabolic processes involved in this phenomenon remain unknown. Here, we show that sterol regulatory element-binding protein (SREBP) and mediator-15 (MDT-15) prevent the life-shortening effects of a glucose-rich diet by regulating fat converting processes in Caenorhabditis elegans. Up-regulation of the SREBP/MDT-15 transcription factor complex was necessary and sufficient for alleviating the life-shortening effect of a glucose-rich diet. Glucose feeding induced key enzymes that convert saturated fatty acids (SFAs) to unsaturated fatty acids (UFAs), which are regulated by SREBP and MDT-15. Furthermore, SREBP/MDT-15 reduced the levels of SFAs and moderated glucose toxicity on life span. Our study may help to develop strategies against elevated blood glucose and free fatty acids, which cause glucolipotoxicity in diabetic patients. PMID- 26637530 TI - Surgery for Aortic Dilatation in Patients With Bicuspid Aortic Valves: A Statement of Clarification From the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. AB - Two guidelines from the American College of Cardiology (ACC), the American Heart Association (AHA), and collaborating societies address the risk of aortic dissection in patients with bicuspid aortic valves and severe aortic enlargement: the "2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM Guidelines for the Diagnosis and Management of Patients With Thoracic Aortic Disease" (Circulation. 2010;121:e266-e369) and the "2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease" (Circulation. 2014;129:e521-e643). However, the 2 guidelines differ with regard to the recommended threshold of aortic root or ascending aortic dilatation that would justify surgical intervention in patients with bicuspid aortic valves. The ACC and AHA therefore convened a subcommittee representing members of the 2 guideline writing committees to review the evidence, reach consensus, and draft a statement of clarification for both guidelines. This statement of clarification uses the ACC/AHA revised structure for delineating the Class of Recommendation and Level of Evidence to provide recommendations that replace those contained in Section 9.2.2.1 of the thoracic aortic disease guideline and Section 5.1.3 of the valvular heart disease guideline. PMID- 26637532 TI - Communicating the molecular basis of cancer cell-by-cell: an interview with Tatsushi Igaki. AB - Tatsushi Igaki is currently based at the Kyoto University Graduate School of Biostudies, where he leads a research group dedicated to using Drosophila genetics to build a picture of the cell-cell communications underlying the establishment and maintenance of multicellular systems. His work has provided insight into the molecular bases of cell competition in the context of development and tumorigenesis, including the landmark discovery that oncogenic cells communicate with normal cells in the tumor microenvironment to induce tumor progression in a non-autonomous fashion. In this interview, he describes his career path, highlighting the shift in his research focus from the basic principles of apoptosis to clonal evolution in cancer, and also explains why Drosophila provides a powerful model system for studying cancer biology. PMID- 26637533 TI - Evolution of Resistance by Helicoverpa zea (Lepidoptera: Noctuidae) Infesting Insecticidal Crops in the Southern United States. AB - We created a deterministic, frequency-based model of the evolution of resistance by corn earworm, Helicoverpa zea (Boddie) (Lepidoptera: Noctuidae), to insecticidal traits expressed in crops planted in the heterogeneous landscapes of the southern United States. The model accounts for four generations of selection by insecticidal traits each year. We used the model results to investigate the influence of three factors on insect resistance management (IRM): 1) how does adding a third insecticidal trait to both corn and cotton affect durability of the products, 2) how does unstructured corn refuge influence IRM, and 3) how do block refuges (50% compliance) and blended refuges compare with regard to IRM? When Bt cotton expresses the same number of insecticidal traits, Bt corn with three insecticidal traits provides longer durability than Bt corn with two pyramided traits. Blended refuge provides similar durability for corn products compared with the same level of required block refuge when the rate of refuge compliance by farmers is 50%. Results for Mississippi and Texas are similar, but durabilities for corn traits are surprisingly lower in Georgia, where unstructured corn refuge is the highest of the three states, but refuge for Bt cotton is the lowest of the three states. Thus, unstructured corn refuge can be valuable for IRM but its influence is determined by selection for resistance by Bt cotton. PMID- 26637534 TI - Evaluation of Alternatives to Carbamate and Organophosphate Insecticides Against Thrips and Tomato Spotted Wilt Virus in Peanut Production. AB - Thrips are important pests of peanut. They cause severe feeding injuries on peanut foliage in the early season. They also transmit Tomato spotted wilt virus (TSWV), which causes spotted wilt disease. At-plant insecticides and cultivars that exhibit field resistance to TSWV are often used to manage thrips and spotted wilt disease. Historically, peanut growers used the broad-spectrum insecticides aldicarb (IRAC class 1A; Temik) and phorate (IRAC class 1B; Thimet) for managing thrips and thereby reducing TSWV transmission. Aldicarb has not been produced since 2011 and its usage in peanut will be legally phased out in 2018; therefore, identification of alternative chemistries is critical for thrips and spotted wilt management. Here, eight alternative insecticides, with known thrips activity, were evaluated in field trials conducted from 2011 through 2013. In addition, different application methods of alternatives were also evaluated. Imidacloprid (Admire Pro), thiamethoxam (Actara), spinetoram (Radiant), and cyantraniliprole (Exirel) were as effective as aldicarb and phorate in suppressing thrips, but none of the insecticides significantly suppressed spotted wilt incidence. Nevertheless, greenhouse assays demonstrated that the same alternative insecticides were effective in suppressing thrips feeding and reducing TSWV transmission. Spotted wilt incidence in the greenhouse was more severe (~80%) than in the field (5-25%). In general, field resistance to TSWV in cultivars only marginally influenced spotted wilt incidence. Results suggest that effective management of thrips using alternative insecticides and subsequent feeding reduction could improve yields under low to moderate virus pressure. PMID- 26637535 TI - Effects of Various Interventions, Including Mass Trapping with Passive Pitfall Traps, on Low-Level Bed Bug Populations in Apartments. AB - Two experiments were conducted to evaluate the effects of various interventions on low-level bed bug, Cimex lectularius L., populations in occupied apartments. The first experiment was conducted in occupied apartments under three intervention conditions: never treated (Group I), recently treated with no further treatment (Group II), and recently treated with continued treatment (Group III). Each apartment was monitored with pitfall-style traps (interceptors) installed at beds and upholstered furniture (sleeping and resting areas) along with ~18 additional interceptors throughout the apartment. The traps were inspected every 2 wk. After 22 wk, bed bugs had been eliminated (zero trap catch for eight consecutive weeks and none detected in visual inspections) in 96, 87, and 100% of the apartments in Groups I, II, and III, respectively. The second experiment investigated the impact of interceptors as a control measure in apartments with low-level infestations. In the treatment group, interceptors were continuously installed at and away from sleeping and resting areas and were inspected every 2 wk for 16 wk. In the control group, interceptors were placed in a similar fashion as the treatment group but were only placed during 6-8 and 14 16 wk to obtain bed bug counts. Bed bug counts were significantly lower at 8 wk in the treatment group than in the control group. At 16 wk, bed bugs were eliminated in 50% of the apartments in the treatment group. The implications of our results in the development of bed bug management strategies and monitoring protocols are discussed. PMID- 26637536 TI - Disentangling Effects of Vector Birth Rate, Mortality Rate, and Abundance on Spread of Plant Pathogens. AB - Models on the spread of insect-transmitted plant pathogens often fix vector population size by assuming that deaths are offset by births. Although such mathematical simplifications are often justified, deemphasizing parameters that govern vector population size is problematic, as reproductive biology and mortality schedules of vectors of plant pathogens receive little empirical attention. Here, the importance of explicitly including parameters for vector birth and death rates was evaluated by comparing results from models with fixed vector population size with models with logistic vector population growth. In fixed vector population size models, increasing vector mortality decreased percentage of inoculative vectors, but had no effect on vector population size, as deaths were offset by births. In models with logistic vector population growth, increasing vector mortality decreased percentage of inoculative vectors and decreased vector population size. Consequently, vector mortality had a greater effect on pathogen spread in models with logistic vector population growth than in models with fixed vector population size. Further, in models with logistic vector population growth, magnitude of vector birth rate determined time required for vector populations to reach large size, thereby determining when pathogen spread occurred quickly. Assumptions regarding timing of vector mortality within a time step also affected model outcome. A greater emphasis of vector entomologists on studying reproductive biology and mortality schedules of insect species that transmit plant pathogens will facilitate identification of conditions associated with rapid growth of vector populations and could lead to development of novel control strategies. PMID- 26637537 TI - The DEAD-Box RNA Helicase AtRH7/PRH75 Participates in Pre-rRNA Processing, Plant Development and Cold Tolerance in Arabidopsis. AB - DEAD-box RNA helicases belong to an RNA helicase family that plays specific roles in various RNA metabolism processes, including ribosome biogenesis, mRNA splicing, RNA export, mRNA translation and RNA decay. This study investigated a DEAD-box RNA helicase, AtRH7/PRH75, in Arabidopsis. Expression of AtRH7/PRH75 was ubiquitous; however, the levels of mRNA accumulation were increased in cell division regions and were induced by cold stress. The phenotypes of two allelic AtRH7/PRH75-knockout mutants, atrh7-2 and atrh7-3, resembled auxin-related developmental defects that were exhibited in several ribosomal protein mutants, and were more severe under cold stress. Northern blot and circular reverse transcription-PCR (RT-PCR) analyses indicated that unprocessed 18S pre-rRNAs accumulated in the atrh7 mutants. The atrh7 mutants were hyposensitive to the antibiotic streptomycin, which targets ribosomal small subunits, suggesting that AtRH7 was also involved in ribosome assembly. In addition, the atrh7-2 and atrh7 3 mutants displayed cold hypersensitivity and decreased expression of CBF1, CBF2 and CBF3, which might be responsible for the cold intolerance. The present study indicated that AtRH7 participates in rRNA biogenesis and is also involved in plant development and cold tolerance in Arabidopsis. PMID- 26637538 TI - Staying Alive: Molecular Aspects of Seed Longevity. AB - Mature seeds are an ultimate physiological status that enables plants to endure extreme conditions such as high and low temperature, freezing and desiccation. Seed longevity, the period over which seed remains viable, is an important trait not only for plant adaptation to changing environments, but also, for example, for agriculture and conservation of biodiversity. Reduction of seed longevity is often associated with oxidation of cellular macromolecules such as nucleic acids, proteins and lipids. Seeds possess two main strategies to combat these stressful conditions: protection and repair. The protective mechanism includes the formation of glassy cytoplasm to reduce cellular metabolic activities and the production of antioxidants that prevent accumulation of oxidized macromolecules during seed storage. The repair system removes damage accumulated in DNA, RNA and proteins upon seed imbibition through enzymes such as DNA glycosylase and methionine sulfoxide reductase. In addition to longevity, dormancy is also an important adaptive trait that contributes to seed lifespan. Studies in Arabidopsis have shown that the seed-specific transcription factor ABSCISIC ACID INSENSITIVE3 (ABI3) plays a central role in ABA-mediated seed dormancy and longevity. Seed longevity largely relies on the viability of embryos. Nevertheless, characterization of mutants with altered seed coat structure and constituents has demonstrated that although the maternally derived cell layers surrounding the embryos are dead, they have a significant impact on longevity. PMID- 26637539 TI - Quantitative Proteomics of Gut-Derived Th1 and Th1/Th17 Clones Reveal the Presence of CD28+ NKG2D- Th1 Cytotoxic CD4+ T cells. AB - T-helper cells are differentiated from CD4+ T cells and are traditionally characterized by inflammatory or immunosuppressive responses in contrast to cytotoxic CD8+ T cells. Mass-spectrometry studies on T-helper cells are rare. In this study, we aimed to identify the proteomes of human Th1 and Th1/Th17 clones derived from intestinal biopsies of Crohn's disease patients and to identify differentially expressed proteins between the two phenotypes. Crohn's disease is an inflammatory bowel disease, with predominantly Th1- and Th17-mediated response where cells of the "mixed" phenotype Th1/Th17 have also been commonly found. High resolution mass spectrometry was used for protein identification and quantitation. In total, we identified 7401 proteins from Th1 and Th1/Th17 clones, where 334 proteins were differentially expressed. Major differences were observed in cytotoxic proteins that were overrepresented in the Th1 clones. The findings were validated by flow cytometry analyses using staining with anti-granzyme B and anti-perforin and by a degranulation assay, confirming higher cytotoxic features of Th1 compared with Th1/Th17 clones. By testing a larger panel of T-helper cell clones from seven different Crohn's disease patients, we concluded that only a subgroup of the Th1 cell clones had cytotoxic features, and these expressed the surface markers T-cell-specific surface glycoprotein CD28 and were negative for expression of natural killer group 2 member D. PMID- 26637540 TI - Comparative Secretome Analysis of Ralstonia solanacearum Type 3 Secretion Associated Mutants Reveals a Fine Control of Effector Delivery, Essential for Bacterial Pathogenicity. AB - Ralstonia solanacearum, the causal agent of bacterial wilt, exerts its pathogenicity through more than a hundred secreted proteins, many of them depending directly on the functionality of a type 3 secretion system. To date, only few type 3 effectors have been identified as required for bacterial pathogenicity, notably because of redundancy among the large R. solanacearum effector repertoire. In order to identify groups of effectors collectively promoting disease on susceptible hosts, we investigated the role of putative post translational regulators in the control of type 3 secretion. A shotgun secretome analysis with label-free quantification using tandem mass spectrometry was performed on the R. solanacearum GMI1000 strain. There were 228 proteins identified, among which a large proportion of type 3 effectors, called Rip (Ralstonia injected proteins). Thanks to this proteomic approach, RipBJ was identified as a new effector specifically secreted through type 3 secretion system and translocated into plant cells. A focused Rip secretome analysis using hpa (hypersensitive response and pathogenicity associated) mutants revealed a fine secretion regulation and specific subsets of Rips with different secretion patterns. We showed that a set of Rips (RipF1, RipW, RipX, RipAB, and RipAM) are secreted in an Hpa-independent manner. We hypothesize that these Rips could be preferentially involved in the first stages of type 3 secretion. In addition, the secretion of about thirty other Rips is controlled by HpaB and HpaG. HpaB, a candidate chaperone was shown to positively control secretion of numerous Rips, whereas HpaG was shown to act as a negative regulator of secretion. To evaluate the impact of altered type 3 effectors secretion on plant pathogenesis, the hpa mutants were assayed on several host plants. HpaB was required for bacterial pathogenicity on multiple hosts whereas HpaG was found to be specifically required for full R. solanacearum pathogenicity on the legume plant Medicago truncatula. PMID- 26637541 TI - Complex aortic arch repair in a patient with Takayasu's disease presenting with acute aortic dissection type Stanford A and complete collateral perfusion of the brain. AB - We describe a rare case of a 46-year old woman suffering from Takayasu's disease. She had undergone aorto-biaxillary bypass and aorto-cerebral bypass surgery in 1985 for occlusive arterial disease and developed a large ascending pseudoaneurysm of the aorto-biaxillary bypass. The aorto-cerebral bypass and right axillary bypass were occluded. Native supra-aortic arteries were found to be proximally occluded and arterial blood supply to the brain was maintained by a dense arterial collateral network. The patient did not show neurological deficits and was able to work using both arms without restrictions. She refused early surgery but suffered from acute aortic dissection type Stanford A shortly after. Supracommissural ascending aortic and aortic arch repair under deep hypothermic circulatory arrest with no additional bypass to the head vessels was performed. This case demonstrates the significance of aortic complications in Takayasu's disease and the effectiveness of collateral brain perfusion in selected patients. PMID- 26637543 TI - Can't stop, won't stop. PMID- 26637542 TI - An Equation to Predict the Accuracy of Genomic Values by Combining Data from Multiple Traits, Populations, or Environments. AB - Predicting the accuracy of estimated genomic values using genome-wide marker information is an important step in designing training populations. Currently, different deterministic equations are available to predict accuracy within populations, but not for multipopulation scenarios where data from multiple breeds, lines or environments are combined. Therefore, our objective was to develop and validate a deterministic equation to predict the accuracy of genomic values when different populations are combined in one training population. The input parameters of the derived prediction equation are the number of individuals and the heritability from each of the populations in the training population; the genetic correlations between the populations, i.e., the correlation between allele substitution effects of quantitative trait loci; the effective number of chromosome segments across predicted and training populations; and the proportion of the genetic variance in the predicted population captured by the markers in each of the training populations. Validation was performed based on real genotype information of 1033 Holstein-Friesian cows that were divided into three different populations by combining half-sib families in the same population. Phenotypes were simulated for multiple scenarios, differing in heritability within populations and in genetic correlations between the populations. Results showed that the derived equation can accurately predict the accuracy of estimating genomic values for different scenarios of multipopulation genomic prediction. Therefore, the derived equation can be used to investigate the potential accuracy of different multipopulation genomic prediction scenarios and to decide on the most optimal design of training populations. PMID- 26637544 TI - Investigating the Relationship between Transverse Relaxation Rate (R2) and Interecho Time in MagA-Expressing, Iron-Labeled Cells. AB - Reporter gene-based labeling of cells with iron is an emerging method of providing magnetic resonance imaging contrast for long-term cell tracking and monitoring cellular activities. This report investigates 9.4 T nuclear magnetic resonance properties of mammalian cells overexpressing MagA, a putative iron transport protein from magnetotactic bacteria. MagA-expressing MDA-MB-435 cells were cultured in the presence and absence of iron supplementation and compared to the untransfected control. The relationship between the transverse relaxation rate (R2) and interecho time was investigated using the Carr-Purcell-Meiboom-Gill sequence. This relationship was analyzed using a model based on water diffusion in weak magnetic field inhomogeneities (Jensen-Chandra model) as well as a fast exchange model (Luz-Meiboom model). Increases in R2 with increasing interecho time were larger in the iron-supplemented, MagA-expressing cells compared to other cells. The dependence of R2 on interecho time in these iron-supplemented, MagA-expressing cells was better represented by the Jensen-Chandra model compared to the Luz-Meiboom model, whereas the Luz-Meiboom model performed better for the remaining cell types. Our findings provide an estimate of the distance scale of microscopic magnetic field variations in MagA-expressing cells, which is thought to be related to the size of iron-containing vesicles. PMID- 26637546 TI - Host-Plant Specialization Mediates the Influence of Plant Abundance on Host Use by Flower Head-Feeding Insects. AB - Among-population variation in host use is a common phenomenon in herbivorous insects. The simplest and most trivial explanation for such variation in host use is the among-site variation in plant species composition. Another aspect that can influence spatial variation in host use is the relative abundance of each host plant species compared to all available hosts. Here, we used endophagous insects that develop in flower heads of Asteraceae species as a study system to investigate how plant abundance influences the pattern of host-plant use by herbivorous insects with distinct levels of host-range specialization. Only herbivores recorded on three or more host species were included in this study. In particular, we tested two related hypotheses: 1) plant abundance has a positive effect on the host-plant preference of herbivorous insects, and 2) the relative importance of plant abundance to host-plant preference is greater for herbivorous species that use a wider range of host-plant species. We analyzed 11 herbivore species in 20 remnants of Cerrado in Southeastern Brazil. For 8 out of 11 herbivore species, plant abundance had a positive influence on host use. In contrast to our expectation, both the most specialized and the most generalist herbivores showed a stronger positive effect of plant species abundance in host use. Thus, we found evidence that although the abundance of plant species is a major factor determining the preferential use of host plants, its relative importance is mediated by the host-range specialization of herbivores. PMID- 26637547 TI - Diversity and Abundance of House Fly Pupal Parasitoids in Israel, with First Records of Two Spalangia Species. AB - Filth flies (Diptera: Muscidae), particularly the house fly, Musca domestica L., are global pests of livestock production. In this study, we characterized the fauna of house fly pupal parasitoids in Israel and identified factors affecting their diversity and abundance. The study, which included one round of sampling during the fall of 2013 and another round of sampling in the spring of 2014, encompassed 26 locations of common fly-breeding habitats: dairy, egg-laying, and goat farms throughout Israel. Nine parasitoid species were found: Spalangia cameroni Perkins, Spalangia endius Walker, Spalangia drosophilae Ashmead, Spalangia gemina Boucek, Spalangia nigroaenea Curtis, Pachycrepoideus vindemmiae Rondani, Muscidifurax raptor Girault and Sanders, Muscidifurax zaraptor Kogan & Legner (all Hymenoptera: Pteromalidae), and Dirhinus giffardii Silvestri (Hymenoptera: Chalcididae). This is the first record of S. gemina from the Palearctic, as well as the first record of S. drosophilae from the Middle East. The composition and relative abundance of parasitoid species varied markedly among localities, climatic regions (Mediterranean vs. desert), habitat types (dairy vs. egg-laying vs. goat farm), and seasons. Overall, parasitoid richness in egg-laying farms was two- and sevenfold higher than in dairy and goat farms, respectively, and three times higher in Mediterranean than desert climate. The significance and implications of our results for inundative biological control programs of filth flies are discussed. PMID- 26637550 TI - Erratum: Flavocoxid Protects Against Cadmium-Induced Disruption of the Blood Testis Barrier and Improves Testicular Damage and Germ Cell Impairment in Mice. PMID- 26637548 TI - PHABULOSA Mediates an Auxin Signaling Loop to Regulate Vascular Patterning in Arabidopsis. AB - Plant vascular tissues, xylem and phloem, differentiate in distinct patterns from procambial cells as an integral transport system for water, sugars, and signaling molecules. Procambium formation is promoted by high auxin levels activating class III homeodomain leucine zipper (HD-ZIP III) transcription factors (TFs). In the root of Arabidopsis (Arabidopsis thaliana), HD-ZIP III TFs dose-dependently govern the patterning of the xylem axis, with higher levels promoting metaxylem cell identity in the central axis and lower levels promoting protoxylem at its flanks. It is unclear, however, by what mechanisms the HD-ZIP III TFs control xylem axis patterning. Here, we present data suggesting that an important mechanism is their ability to moderate the auxin response. We found that changes in HD-ZIP III TF levels affect the expression of genes encoding core auxin response molecules. We show that one of the HD-ZIP III TFs, PHABULOSA, directly binds the promoter of both MONOPTEROS (MP)/AUXIN RESPONSE FACTOR5, a key factor in vascular formation, and IAA20, encoding an auxin/indole acetic acid protein that is stable in the presence of auxin and able to interact with and repress MP activity. The double mutant of IAA20 and its closest homolog IAA30 forms ectopic protoxylem, while overexpression of IAA30 causes discontinuous protoxylem and occasional ectopic metaxylem, similar to a weak loss-of-function mp mutant. Our results provide evidence that HD-ZIP III TFs directly affect the auxin response and mediate a feed-forward loop formed by MP and IAA20 that may focus and stabilize the auxin response during vascular patterning and the differentiation of xylem cell types. PMID- 26637551 TI - A KNIME-Based Analysis of the Zebrafish Photomotor Response Clusters the Phenotypes of 14 Classes of Neuroactive Molecules. AB - Recently, the photomotor response (PMR) of zebrafish embryos was reported as a robust behavior that is useful for high-throughput neuroactive drug discovery and mechanism prediction. Given the complexity of the PMR, there is a need for rapid and easy analysis of the behavioral data. In this study, we developed an automated analysis workflow using the KNIME Analytics Platform and made it freely accessible. This workflow allows us to simultaneously calculate a behavioral fingerprint for all analyzed compounds and to further process the data. Furthermore, to further characterize the potential of PMR for mechanism prediction, we performed PMR analysis of 767 neuroactive compounds covering 14 different receptor classes using the KNIME workflow. We observed a true positive rate of 25% and a false negative rate of 75% in our screening conditions. Among the true positives, all receptor classes were represented, thereby confirming the utility of the PMR assay to identify a broad range of neuroactive molecules. By hierarchical clustering of the behavioral fingerprints, different phenotypical clusters were observed that suggest the utility of PMR for mechanism prediction for adrenergics, dopaminergics, serotonergics, metabotropic glutamatergics, opioids, and ion channel ligands. PMID- 26637549 TI - MdMYB1 Regulates Anthocyanin and Malate Accumulation by Directly Facilitating Their Transport into Vacuoles in Apples. AB - Tonoplast transporters, including proton pumps and secondary transporters, are essential for plant cell function and for quality formation of fleshy fruits and ornamentals. Vacuolar transport of anthocyanins, malate, and other metabolites is directly or indirectly dependent on the H(+)-pumping activities of vacuolar H(+) ATPase (VHA) and/or vacuolar H(+)-pyrophosphatase, but how these proton pumps are regulated in modulating vacuolar transport is largely unknown. Here, we report a transcription factor, MdMYB1, in apples that binds to the promoters of two genes encoding the B subunits of VHA, MdVHA-B1 and MdVHA-B2, to transcriptionally activate its expression, thereby enhancing VHA activity. A series of transgenic analyses in apples demonstrates that MdMYB1/10 controls cell pH and anthocyanin accumulation partially by regulating MdVHA-B1 and MdVHA-B2. Furthermore, several other direct target genes of MdMYB10 are identified, including MdVHA-E2, MdVHP1, MdMATE-LIKE1, and MdtDT, which are involved in H(+)-pumping or in the transport of anthocyanins and malates into vacuoles. Finally, we show that the mechanism by which MYB controls malate and anthocyanin accumulation in apples also operates in Arabidopsis (Arabidopsis thaliana). These findings provide novel insights into how MYB transcription factors directly modulate the vacuolar transport system in addition to anthocyanin biosynthesis, consequently controlling organ coloration and cell pH in plants. PMID- 26637552 TI - Activation of Yap-Directed Transcription by Knockdown of Conserved Cellular Functions. AB - The Yap-Hippo pathway has a significant role in regulating cell proliferation and growth, thus controlling organ size and regeneration. The Hippo pathway regulates two highly conserved, transcription coactivators, YAP and TAZ. The upstream regulators of the Yap-Hippo pathway have not been fully characterized. The aim of this study was to use a siRNA screen, in a liver biliary cell line, to identify regulators of the Yap-Hippo pathway that allow activation of the YAP transcription coactivator at high cell density. Activation of the YAP transcription coactivator was monitored using a high-content, image-based assay that measured the intracellular localization of native YAP protein. Active siRNAs were identified and further validated by quantification of CYR61 mRNA levels (a known YAP target gene). The effect of compounds targeting the putative gene targets identified as hits was also used for further validation. A number of validated hits reveal basic aspects of Yap-Hippo biology, such as components of the nuclear pore, by which YAP cytoplasmic-nuclear shuttling occurs, or how proteasomal degradation regulates intracellular YAP concentrations, which then alter YAP localization and transcription. Such results highlight how targeting conserved cellular functions can lead to validated activity in phenotypic assays. PMID- 26637553 TI - An Automated Microscale Thermophoresis Screening Approach for Fragment-Based Lead Discovery. AB - Fragment-based lead discovery has proved to be an effective alternative to high throughput screenings in identifying chemical matter that can be developed into robust lead compounds. The search for optimal combinations of biophysical techniques that can correctly and efficiently identify and quantify binding can be challenging due to the physicochemical properties of fragments. In order to minimize the time and costs of screening, optimal combinations of biophysical techniques with maximal information content, sensitivity, and robustness are needed. Here we describe an approach utilizing automated microscale thermophoresis (MST) affinity screening to identify fragments active against MEK1 kinase. MST identified multiple hits that were confirmed by X-ray crystallography but not detected by orthogonal methods. Furthermore, MST also provided information about ligand-induced aggregation and protein denaturation. The technique delivered a large number of binders while reducing experimentation time and sample consumption, demonstrating the potential of MST to execute and maximize the efficacy of fragment screening campaigns. PMID- 26637554 TI - A High-Throughput Assay for the Detection of alpha-Dystroglycan N-Terminus in Human Uterine Fluid to Determine Uterine Receptivity. AB - Embryo implantation requires a healthy embryo and a receptive uterus. In women, the uterus remains a hostile environment and must undergo functional changes to convert to a receptive state for embryo implantation. Determining uterine receptivity is vital in IVF treatment, as the timing of embryo transfer needs to be synchronized with uterine receptivity. However, to date, no reliable biochemical tests are available to determine uterine receptivity. We recently established that removal of alpha-dystroglycan N-terminus (alpha-DG-N) from the uterine surface plays an important role in the establishment of uterine receptivity. Importantly, the alpha-DG-N removed from the uterine tissue enters into the uterine fluid, and the levels correlate with the tissue status of receptivity. Detection of alpha-DG-N in uterine fluid may therefore provide a nonsurgical approach to assess uterine receptivity. In this study, we first validated three monoclonal antibodies raised against alpha-DG-N in our system, and then established a sandwich ELISA suitable for the detection of alpha-DG-N in human uterine fluid. This ELISA detected significantly higher concentrations of alpha-DG-N in uterine fluid of women in the receptive phase. We believe this newly established alpha-DG-N ELISA may provide an important tool in the development of noninvasive strategies to detect uterine receptivity in women. PMID- 26637555 TI - Long-Distance Dispersal Shaped Patterns of Human Genetic Diversity in Eurasia. AB - Most previous attempts at reconstructing the past history of human populations did not explicitly take geography into account or considered very simple scenarios of migration and ignored environmental information. However, it is likely that the last glacial maximum (LGM) affected the demography and the range of many species, including our own. Moreover, long-distance dispersal (LDD) may have been an important component of human migrations, allowing fast colonization of new territories and preserving high levels of genetic diversity. Here, we use a high-quality microsatellite data set genotyped in 22 populations to estimate the posterior probabilities of several scenarios for the settlement of the Old World by modern humans. We considered models ranging from a simple spatial expansion to others including LDD and a LGM-induced range contraction, as well as Neolithic demographic expansions. We find that scenarios with LDD are much better supported by data than models without LDD. Nevertheless, we show evidence that LDD events to empty habitats were strongly prevented during the settlement of Eurasia. This unexpected absence of LDD ahead of the colonization wave front could have been caused by an Allee effect, either due to intrinsic causes such as an inbreeding depression built during the expansion or due to extrinsic causes such as direct competition with archaic humans. Overall, our results suggest only a relatively limited effect of the LGM contraction on current patterns of human diversity. This is in clear contrast with the major role of LDD migrations, which have potentially contributed to the intermingled genetic structure of Eurasian populations. PMID- 26637557 TI - Contribution of the late sodium current to intracellular sodium and calcium overload in rabbit ventricular myocytes treated by anemone toxin. AB - Pathological enhancement of late Na(+) current (INa) can potentially modify intracellular ion homeostasis and contribute to cardiac dysfunction. We tested the hypothesis that modulation of late INa can be a source of intracellular Na(+) ([Na(+)]i) overload. Late INa was enhanced by exposing rabbit ventricular myocytes to Anemonia sulcata toxin II (ATX-II) and measured using whole cell patch-clamp technique. [Na(+)]i was determined with fluorescent dye Asante NaTRIUM Green-2 AM. Pacing-induced changes in the dye fluorescence measured at 37 degrees C were more pronounced in ATX-II-treated cells than in control (dye washout prevented calibration). At 22-24 degrees C, resting [Na(+)]i was 6.6 +/- 0.8 mM. Treatment with 5 nM ATX-II increased late INa 8.7-fold. [Na(+)]i measured after 2 min of electrical stimulation (1 Hz) was 10.8 +/- 1.5 mM and 22.1 +/- 1.6 mM (P < 0.001) in the absence and presence of 5 nM ATX-II, respectively. Inhibition of late INa with GS-967 (1 MUM) prevented Na(+) i accumulation. A strong positive correlation was observed between the late INa and the pacing induced increase of [Na(+)]i (R(2) = 0.88) and between the rise in [Na(+)]i and the increases in cytosolic Ca(2+) (R(2) = 0.96). ATX-II, tetrodotoxin, or GS-967 did not affect [Na(+)]i in quiescent myocytes suggesting that late INa was solely responsible for triggering the ATX-II effect on [Na(+)]i. Experiments with pinacidil and E4031 indicate that prolongation of the action potential contributes to as much as 50% of the [Na(+)]i overload associated with the increase in late INa caused by ATX-II. Enhancement of late INa can cause intracellular Na(+) overload in ventricular myocytes. PMID- 26637556 TI - Cross talk between AT1 receptors and Toll-like receptor 4 in microglia contributes to angiotensin II-derived ROS production in the hypothalamic paraventricular nucleus. AB - ANG II is thought to increase sympathetic outflow by increasing oxidative stress and promoting local inflammation in the paraventricular nucleus (PVN) of the hypothalamus. However, the relative contributions of inflammation and oxidative stress to sympathetic drive remain poorly understood, and the underlying cellular and molecular targets have yet to be examined. ANG II has been shown to enhance Toll-like receptor (TLR)4-mediated signaling on microglia. Thus, in the present study, we aimed to determine whether ANG II-mediated activation of microglial TLR4 signaling is a key molecular target initiating local oxidative stress in the PVN. We found TLR4 and ANG II type 1 (AT1) receptor mRNA expression in hypothalamic microglia, providing molecular evidence for the potential interaction between these two receptors. In hypothalamic slices, ANG II induced microglial activation within the PVN (~65% increase, P < 0.001), an effect that was blunted in the absence of functional TLR4. ANG II increased ROS production, as indicated by dihydroethidium fluorescence, within the PVN of rats and mice (P < 0.0001 in both cases), effects that were also dependent on the presence of functional TLR4. The microglial inhibitor minocycline attenuated ANG II-mediated ROS production, yet ANG II effects persisted in PVN single-minded 1-AT1a knockout mice, supporting the contribution of a non-neuronal source (likely microglia) to ANG II-driven ROS production in the PVN. Taken together, these results support functional interactions between AT1 receptors and TLR4 in mediating ANG II dependent microglial activation and oxidative stress within the PVN. More broadly, our results support a functional interaction between the central renin angiotensin system and innate immunity in the regulation of neurohumoral outflows from the PVN. PMID- 26637558 TI - Aging is associated with changes to the biomechanical properties of the posterior cerebral artery and parenchymal arterioles. AB - Artery remodeling, described as a change in artery structure, may be responsible for the increased risk of cardiovascular disease with aging. Although the risk for stroke is known to increase with age, relatively young animals have been used in most stroke studies. Therefore, more information is needed on how aging alters the biomechanical properties of cerebral arteries. Posterior cerebral arteries (PCAs) and parenchymal arterioles (PAs) are important in controlling brain perfusion. We hypothesized that aged (22-24 mo old) C57bl/6 mice would have stiffer PCAs and PAs than young (3-5 mo old) mice. The biomechanical properties of the PCAs and PAs were assessed by pressure myography. Data are presented as means +/- SE of young vs. old. In the PCA, older mice had increased outer (155.6 +/- 3.2 vs. 169.9 +/- 3.2 MUm) and lumen (116.4 +/- 3.6 vs. 137.1 +/- 4.7 MUm) diameters. Wall stress (375.6 +/- 35.4 vs. 504.7 +/- 60.0 dyn/cm(2)) and artery stiffness (beta-coefficient: 5.2 +/- 0.3 vs. 7.6 +/- 0.9) were also increased. However, wall strain (0.8 +/- 0.1 vs. 0.6 +/- 0.1) was reduced with age. In the PAs from old mice, wall thickness (3.9 +/- 0.3 vs. 5.1 +/- 0.2 MUm) and area (591.1 +/- 95.4 vs. 852.8 +/- 100 MUm(2)) were increased while stress (758.1 +/- 100.0 vs. 587.2 +/- 35.1 dyn/cm(2)) was reduced. Aging also increased mean arterial and pulse pressures. We conclude that age-associated remodeling occurs in large cerebral arteries and arterioles and may increase the risk of cerebrovascular disease. PMID- 26637559 TI - The NRF2 knockout rat: a new animal model to study endothelial dysfunction, oxidant stress, and microvascular rarefaction. AB - Nuclear factor (erythroid-derived 2)-like-2 (NRF2) is a master antioxidant and cell protective transcription factor that upregulates antioxidant defenses. In this study we developed a strain of Nrf2 null mutant rats to evaluate the role of reduced NRF2-regulated antioxidant defenses in contributing to endothelial dysfunction and impaired angiogenic responses during salt-induced ANG II suppression. Nrf2(-/-) mutant rats were developed using transcription activator like effector nuclease technology in the Sprague-Dawley genetic background, and exhibited a 41-bp deletion that included the start codon for Nrf2 and an absence of immunohistochemically detectable NRF2 protein. Expression of mRNA for the NRF2 regulated indicator enzymes heme oxygenase-1, catalase, superoxide dismutase 1, superoxide dismutase 2, and glutathione reductase was significantly lower in livers of Nrf2(-/-) mutant rats fed high salt (HS; 4% NaCl) for 2 wk compared with wild-type controls. Endothelium-dependent dilation to acetylcholine was similar in isolated middle cerebral arteries (MCA) of Nrf2(-/-) mutant rats and wild-type littermates fed low-salt (0.4% NaCl) diet, and was eliminated by short term (3 days) HS diet in both strains. Low-dose ANG II infusion (100 ng/kg sc) reversed salt-induced endothelial dysfunction in MCA and prevented microvessel rarefaction in wild-type rats fed HS diet, but not in Nrf2(-/-) mutant rats. The results of this study indicate that suppression of NRF2 antioxidant defenses plays an essential role in the development of salt-induced oxidant stress, endothelial dysfunction, and microvessel rarefaction in normotensive rats and emphasize the potential therapeutic benefits of directly upregulating NRF2 mediated antioxidant defenses to ameliorate vascular oxidant stress in humans. PMID- 26637560 TI - Blunted flow-mediated responses and diminished nitric oxide synthase expression in lymphatic thoracic ducts of a rat model of metabolic syndrome. AB - Shear-dependent inhibition of lymphatic thoracic duct (TD) contractility is principally mediated by nitric oxide (NO). Endothelial dysfunction and poor NO bioavailability are hallmarks of vasculature dysfunction in states of insulin resistance and metabolic syndrome (MetSyn). We tested the hypothesis that flow dependent regulation of lymphatic contractility is impaired under conditions of MetSyn. We utilized a 7-wk high-fructose-fed male Sprague-Dawley rat model of MetSyn and determined the stretch- and flow-dependent contractile responses in an isobaric ex vivo TD preparation. TD diameters were tracked and contractile parameters were determined in response to different transmural pressures, imposed flow, exogenous NO stimulation by S-nitro-N-acetylpenicillamine (SNAP), and inhibition of NO synthase (NOS) by l-nitro-arginine methyl ester (l-NAME) and the reactive oxygen species (ROS) scavenging molecule 4-hydroxy-tempo (tempol). Expression of endothelial NO synthase (eNOS) in TD was determined using Western blot. Approximately 25% of the normal flow-mediated inhibition of contraction frequency was lost in TDs isolated from MetSyn rats despite a comparable SNAP response. Inhibition of NOS with l-NAME abolished the differences in the shear dependent contraction frequency regulation between control and MetSyn TDs, whereas tempol did not restore the flow responses in MetSyn TDs. We found a significant reduction in eNOS expression in MetSyn TDs suggesting that diminished NO production is partially responsible for impaired flow response. Thus our data provide the first evidence that MetSyn conditions diminish eNOS expression in TD endothelium, thereby affecting the flow-mediated changes in TD lymphatic function. PMID- 26637562 TI - Association of body mass index and other factors with histamine skin reactivity in adults with allergic nasal symptoms. AB - BACKGROUND: The skin-prick test is the most commonly used method to diagnose allergy. In addition, histamine skin reactivity is used as a positive control for the skin-prick test. However, there is individual variation in histamine skin reactivity. The factors that influence individual variation in histamine skin reactivity remain unknown. OBJECTIVES: We aimed to investigate the factors associated with histamine skin reaction. METHODS: Ninety-seven subjects who underwent a skin-prick test to diagnose allergic rhinitis were enrolled in this study. The skin-prick test was performed with six common allergens. The wheal size of the histamine skin reaction was analyzed; other variables included age, sex, body mass index (BMI), atopy, smoking history, and the testing season. RESULTS: The wheal size in the histamine skin test was significantly associated with age and BMI. The association between histamine skin reactivity and BMI was also present in multivariate analysis, adjusted for age, sex, atopy, smoking history, and season. CONCLUSION: Histamine skin reactivity increased with BMI (degree of obesity). This association should be considered for better interpretation of the skin-prick test. Further studies regarding the mechanism for this association are needed. PMID- 26637561 TI - Activation of mitochondrial calpain and increased cardiac injury: beyond AIF release. AB - Calpain 1 (CPN1) is a ubiquitous cysteine protease that exists in both cytosol and cardiac mitochondria. Mitochondrial CPN1 (mit-CPN1) is located in the intermembrane space and matrix. Activation of mit-CPN1 within the intermembrane space increases cardiac injury by releasing apoptosis-inducing factor from mitochondria during ischemia-reperfusion (IR). We asked if activation of mit-CPN1 is involved in mitochondrial injury during IR. MDL-28170 (MDL) was used to inhibit CPN1 in buffer-perfused hearts following 25-min ischemia and 30-min reperfusion. MDL treatment decreased the release of lactate dehydrogenase into coronary effluent compared with untreated hearts, indicating that inhibition of CPN1 decreases cardiac injury. MDL also prevented the cleavage of spectrin (a substrate of CPN1) in cytosol during IR, supporting that MDL treatment decreased cytosolic calpain activation. In addition, MDL markedly improved calcium retention capacity compared with untreated heart, suggesting that MDL treatment decreases mitochondrial permeability transition pore opening. In addition, we found that IR led to decreased complex I activity, whereas inhibition of mit-CPN1 using MDL protected complex I. Pyruvate dehydrogenase content was decreased following IR. However, pyruvate dehydrogenase content was preserved in MDL treated mitochondria. Taken together, MDL treatment decreased cardiac injury during IR by inhibiting both cytosolic and mit-CPN1. Activation of mit-CPN1 increases cardiac injury during IR by sensitizing mitochondrial permeability transition pore opening and impairing mitochondrial metabolism through damage of complex I. PMID- 26637563 TI - Acute invasive fungal rhinosinusitis: Survival analysis and the prognostic indicators. AB - BACKGROUND: Acute invasive fungal rhinosinusitis (AIFR) is a highly mortal, progressive fungal infection of the paranasal sinuses and surrounding structures that is almost always seen in patients who are immunocompromised. Despite the use of newer antifungal treatments and early diagnosis, the prognosis of AIFR does not improve significantly. Due to the higher incidence of patients who are immunocompromised and have more complex disease, AIFR is a growing medical issue in tertiary medical centers. OBJECTIVE: The aim of this study was to present the outcomes and analyze the prognostic indicators of patients with AIFR who underwent surgery. METHODS: Between October 2009 and November 2014, 37 patients who underwent surgery for AIFR at a tertiary care university hospital were included in the study. Overall survival and disease-specific mortality and survival rates were calculated to estimate survival function. The impact of age, sex, underlying disease, extent of AIFR, applied medical treatment, and causative species (mucormycosis, aspergillosis) were also taken into consideration. Also, the effect of a variety of laboratory parameters, such as hemoglobin, leukocyte, neutrophil, lymphocyte, platelet, and C-reactive protein (CRP) levels, to survival were evaluated. RESULTS: The median follow-up time was 58 days (interquartile range = 304). Overall and disease-specific mortality rates were 64.9 and 51.4%, respectively. Fever was the most common symptom (86.5%), along with nasal obstruction and/or fullness (48.6%) and epistaxis (48.6%). Age and sex did not have a significant impact on survival (p > 0.05). Palate involvement was significantly associated with mortality (p < 0.05). According to the results of Cox, regression analysis for disease-specific mortality rate, leukocyte and neutrophil counts as well as CRP levels had a significant effect on survival function (p < 0.05). CONCLUSIONS: Palatal involvement was associated with a higher mortality in our study. Also, leukocyte counts, neutrophile counts, and CRP values had a significant impact on survival function. The reversal of the underlying disease and immunosuppression is as important as the medical and surgical treatment. PMID- 26637564 TI - Dietary modifications for refractory chronic rhinosinusitis? Manipulating diet for the modulation of inflammation. AB - BACKGROUND: An endotype of chronic rhinosinusitis (CRS) refractory to medical and surgical management is characterized by persistent T-helper 1/T-helper 17 inflammation of the sinus mucosa, which potentially facilitates colonization with dysbiotic microbial flora. Dietary interventions that target reduction of systemic inflammation are increasingly recommended as adjuncts to ongoing medical therapy in chronic disorders with a strong inflammatory component, such as cardiac disease, diabetes, and metabolic syndrome. Inflammation-reducing dietary modifications may thus be of benefit in patients with refractory CRS (RCRS). OBJECTIVE: To identify nonpharmacologic approaches that implicate modification of dietary factors, potentially reducing systemic level of inflammation in RCRS. METHODS: A systematic review of the literature was undertaken to identify dietary strategies for reducing inflammation in metabolic syndrome, diabetes, and cardiac disease. Mechanistic-based strategies for reducing systemic inflammation were identified and categorized to identify potential therapeutic avenues, which would be applicable to RCRS. RESULTS: Principal mechanisms for altering inflammation at the systemic level via dietary manipulation center around (1) increased consumption of foods with anti-inflammatory properties, and (2) modulation of the gut microbiome to reduce short-chain fatty acid secretion by dysbiotic gut flora. Recommended dietary modifications to reduce systemic markers of inflammation or to improve RCRS include alteration of macronutrient intake, alterations in consumption of meat and fats, consumption of prebiotics and probiotics, and a low salicylate diet in the context of aspirin-exacerbated respiratory disease. CONCLUSION: Dietary modifications may offer a potential nonpharmacologic means of reducing inflammation in patients with RCRS and hence may represent a complementary adjunct to existing medical therapies. Additional prospective studies are required to further validate the concept of dietary modifications in patients with RCRS to support the findings. PMID- 26637565 TI - Influence of air temperature variations on incidence of epistaxis. AB - OBJECTIVE: Epistaxis is the most common ear, nose, and throat emergency observed in the emergency department (ED). An increased frequency of this condition has been observed during cooler months, but the results of available studies are controversial. The aim of this study was to investigate the seasonality and association of epistaxis presentations to a large urban ED with variations of air temperature and humidity. METHODS: This study was a retrospective case series. Information on all the patients who presented for epistaxis in the ED of the Academic Hospital of Parma during the years 2003-2012 and ages >= 14 years were retrieved from the hospital data base, excluding those attributable to trauma. The chronologic data of all visits were associated with climate data (air temperature and humidity) by univariate linear regression analysis. RESULTS: Among the 819,596 ED patients seen throughout the observational period, 5404 were admitted for epistaxis. Of these, 5220 were discharged from the ED, whereas 184 (3.4%) needed hospital admission. A strong seasonality of epistaxis was observed, with a peak during winter. A strong negative correlation was also found between the daily number of epistaxes and the mean daily temperature in the whole population as well as in patient subgroups (those undergoing anticoagulant or antiplatelet therapy, or those with hypertension, inherited bleeding disorders, liver cirrhosis, or advanced malignancy). A weaker correlation was also found between air humidity and epistaxis but only in certain subgroups. CONCLUSIONS: The results of this study provided a contribution to improve our understanding of the epidemiology of epistaxis and for specific health policies that should also be planned by considering the seasonality of nosebleed. PMID- 26637566 TI - Endonasal extended columellar strut in Asian rhinoplasty. AB - BACKGROUND: Recently, sculpturing of projected and sharp nasal tips, as is usual in the white population, has been of great concern in Asian rhinoplasty. However, tip surgery in Asians should be performed in a different way due to anatomic differences. The authors used an endonasal rhinoplasty to correct the position of lower lateral cartilage by adopting a modified columellar strut. This novel technique of an endonasal extended columellar strut (EECS) could project the nasal tip significantly while avoiding hard fixation. This study aimed to evaluate the usefulness of the EECS in Asians. MATERIALS AND METHODS: A retrospective study was performed with 40 patients who underwent EECS from March 2012 to August 2014. Photographs taken preoperatively and postoperatively were analyzed. The tip projection, the ratio of the length of the infratip lobule to the total length of the tip, and a columellar labial angle change were measured. Overall, surgical outcomes were rated into three grades (excellent, good, and fair) by two experienced rhinoplasty surgeons (J.Y.K., M.S.C.). All the patients were asked to rate their cosmetic satisfaction by using a visual analog scale (10 points). RESULTS: Postoperative nasal tip projection significantly increased, from 24.2 to 26.7 mm (p < 0.01). The ratio of the length of the infratip lobule to the total length of the tip mildly increased, from 0.45 to 046 in men, and remained unchanged, at 0.48, in women. The columellar labial angle significantly increased, from 86.9 degrees to 93.7 degrees (p < 0.01). Surgical outcomes were rated by two experienced surgeons as excellent (40%), good (42%), and fair (18%). Subjectively, patients graded their satisfaction at ~ 8.7 on the visual analog scale. CONCLUSION: This novel EECS technique enabled satisfactory tip projection in Asians while maintaining a natural ratio of infratip lobule to total length of tip and leaving no external scar. PMID- 26637567 TI - Nasal nitric oxide in relation to quality-of-life improvements after endoscopic sinus surgery. AB - BACKGROUND: The level of nasal nitric oxide (nNO) in patients with chronic rhinosinusitis (CRS) has been proven to increase after surgical treatment. The relationship between nNO and treatment outcome has not been documented to date. OBJECTIVE: To evaluate the levels of and changes in nNO after sinus surgery and its effects on quality-of-life improvements for patients with CRS after surgical treatment. METHODS: By using a clinical cohort study design, we identified patients who were receiving bilateral endoscopic sinus surgery for CRS with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP) with a 1-year follow-up. We assessed the demographics, preoperative prognostic predictors, pre- and postoperative nNO levels, and disease-related quality of life via a questionnaire. RESULTS: Sixty-nine patients were enrolled, including 53 with CRSwNP and 16 with CRSsNP. The CRSwNP group had lower initial nNO levels and higher endoscopic and image scores but similar demographics and questionnaire scores. In the patients with CRSwNP, nNO levels recovered and reached a plateau at the third month after surgery. However, nNO levels in the CRSsNP group continued to increase until 6 months after surgery before reaching a steady level. Higher preoperative nNO levels were significantly related to better quality-of-life improvements at 3 months after surgery in both groups. CONCLUSION: The nNO levels in patients with CRS increased and reached a plateau after sinus surgery for both groups. Under similar subjective disease severity, the CRSsNP group had higher preoperative nNO levels and maintained a continuously longer rise before reaching a steady level after surgery. For both CRS groups, a higher initial nNO level brought better quality-of-life improvements and could be provided as a preoperative prognostic indicator. PMID- 26637568 TI - The effect of compound nasal surgery on obstructive sleep apnea syndrome. AB - BACKGROUND: Nasal surgery often fails to ameliorate the symptoms of obstructive sleep apnea syndrome (OSAS). We developed a compound nasal surgery (CNS) method that consists of septoplasty combined with submucosal inferior turbinectomy and posterior nasal neurectomy to ensure low nasal resistance during sleep. OBJECTIVE: To clarify the effect of CNS on OSAS, pre- and postoperative changes in sleep-related events were studied by using polysomnography, the Epworth sleepiness scale (ESS), the visual analog scale for snoring, and health-related quality of life (QOL). METHODS: Forty-five consecutive patients with OSAS and with nasal problems underwent CNS. Three months later, the postoperative effect on OSAS was assessed by using polysomnography findings, daytime sleepiness by the ESS, nasal allergy symptoms, and health-related QOL. Snoring was assessed by the family by using a visual analog scale. RESULTS: The indices of apnea, apnea hypopnea, oxygen desaturation, and arousal; the ESS; allergic symptom score; health-related QOL; and snoring on a visual analog scale were all significantly improved. CONCLUSIONS: CNS improves OSAS events without any pharyngeal surgical procedure in selected patients. If high nasal resistance associated with OSAS is present, then CNS should thus be considered. PMID- 26637569 TI - The role of viruses in the clinical presentation of chronic rhinosinusitis. AB - BACKGROUND: The role of viruses in chronic rhinosinusitis (CRS) is poorly understood. In part, this is secondary to difficulty in isolating viruses. Although traditional detection methods for respiratory viruses have had little clinical utility, modern viral screening techniques that use molecular sequencing are now both rapid and feasible, which makes analysis of the paranasal sinus microbiome more accessible. OBJECTIVE: To detect respiratory viruses in the paranasal sinuses of patients with CRS and of healthy controls as well as to correlate clinical and radiographic measures of CRS with viral presence. METHODS: In this prospective study, 13 patients with CRS with nasal polyposis (CRSwNP) and 8 patients without nasal polyposis (CRSsNP) were enrolled and compared with 14 healthy controls. Samples were obtained from the paranasal sinuses and were screened for viral DNA with polymerase chain reaction--based sequencing techniques. Typical symptoms of CRS, the Sinonasal Questionnaire, and objective measures, including the modified Lund-Mackay and modified Lund-Kennedy scores were obtained. RESULTS: Eighty percent of the positive screens (4/5) were found in patients with CRSsNP, whereas 20% of the positive tests (1/5) were in the CRSwNP group, and none of the controls tested positive (p = 0.0029). Coronavirus was the most common virus detected. Sinonasal Questionnaire scores of the patients with CRS who tested positive for viruses were higher but not statistically different than those without a positive screen (p = 0.31). Radiographic and endoscopic measures of disease were not significantly different in the setting of a positive viral screen (p = 0.12 and 0.11 respectively). CONCLUSION: Although traditionally difficult, advances in molecular sequencing enhance detection of viruses in the sinonasal tract. In this study, respiratory viruses were more commonly isolated from patients with CRS compared with healthy controls. Moreover, viral infection may play a greater role in symptom exacerbation in CRSsNP than in CRSwNP. These findings warrant further investigation into the role of the viral microbiome in CRS. PMID- 26637570 TI - The radiologic evaluation of osteitis type and formation in chronic rhinosinusitis with and without nasal polyposis. AB - OBJECTIVE: To evaluate the amount and type of osteitis observed in chronic rhinosinusitis with nasal polyposis (CRSwNP) and compare it with that of chronic rhinosinusitis without nasal polyposis (CRSnNP). SETTING: Sisli Etfal Research and Education Hospital, Istanbul, Turkey. STUDY DESIGN: Prospective, single blind, cohort study. METHODS: Three different patient groups, designated as the CRSwNP, CRSnNP, and control groups, were included in the study. Forty patients who had CRSnNP and/or CRSwNP confirmed with a paranasal sinus computerized tomography (CT) study were included for the study group, and 20 individuals were included in the control group. Paranasal sinus CTs were evaluated and compared for osteitis. RESULTS: Hounsfield units obtained from the right and left agger nasi walls and the medial maxillary sinus wall in the control group were significantly different from the entire group. Similarly, values for the anterior ethmoid wall were statistically significant for the CRSwNP group compared with all the subjects. When the groups were compared to one another, there were significant differences in both the right and left agger nasi walls and the frontal sinus wall. CONCLUSION: Differentiating and acknowledging osteitis induced by CRSwNP rather than CRSnNP may aid in preoperative planning and indicate where to be more aggressive when excising bony structures. This may help in reducing recurrence and in increasing quality of life. PMID- 26637571 TI - Nasal tip sutures: Techniques and indications. AB - OBJECTIVES: The surgical anatomy of the nasal tip is determined by intrinsic factors, such as the nasal tip volume, shape, definition, and symmetry. These factors are intimately related to the morphology of the lower lateral cartilages. Tip sutures reduce the need for grafts and allow the surgeon to manipulate the tip with a high degree of precision and better long-term clinical outcomes. In this review, we evaluated common nasal tip suture techniques to clarify the similarities and differences among them. METHODS: The following nasal tip suture techniques were investigated: medial crural fixation suture, middle crura suture, transdomal (dome creating, dome binding, domal definition) suture, interdomal suture, lateral crural mattress suture, columella septal suture, intercrural suture, tip rotation suture, craniocaudal transdomal suture, lateral crural spanning suture, suspension suture, tongue-in-groove technique, and lateral crural steal. RESULTS: Tip sutures increase tip projection, narrow the tip, provide stabilization, and provide tip rotation. The sutures may be used separately or together. CONCLUSION: Nasal tip sutures have long been used as noninvasive suture techniques. Each suture technique has unique benefits, and various key points must be considered when using these techniques. PMID- 26637572 TI - Development of a questionnaire for measuring health-related quality of life among children and adolescents with mouth breathing. AB - BACKGROUND: Mouth breathing can exert an influence on quality of life and should be evaluated within a multidimensional context. However, there is no specific questionnaire to measure the impact of mouth breathing on quality of life. OBJECTIVE: To develop and validate a questionnaire for measuring the impact of mouth breathing on quality of life among children and adolescents. METHODS: Thirty-six items were evaluated by six health care professionals, one parent and one child with mouth breathing. After a qualitative evaluation, a modified set of 32 items was developed. The modified Mouth Breather Quality of Life (MBQoL) questionnaire was submitted to a pretest with a sample of 30 children and adolescents diagnosed with mouth breathing to evaluate comprehension, the order of the items, and the form of administration. The MBQoL questionnaire was then administered to 60 children and adolescents (30 mouth breathers and 30 nose breathers) for the evaluation of construct validity, internal consistency, and reproducibility. All the participants answered the questionnaire, and 50% of each group answered the questionnaire a second time after a 1-week interval (test retest). RESULTS: Higher MBQoL scores (which indicated poorer quality of life) were significantly associated with mouth breathing. The Cronbach alpha coefficient for the items of the questionnaire was 0.88, and the Spearman correlation coefficient for test-retest reliability demonstrated that the questionnaire was reproducible (r = 0.993; p < 0.01). CONCLUSION: Through this validation study, the MBQoL questionnaire demonstrated a good performance in the evaluation of the quality of life of children and adolescents with mouth breathing and may be a useful tool in clinical studies as well as public health programs. However, further studies are needed to establish its applicability in other populations with respiration disorders. PMID- 26637573 TI - The orbital floor is a surgical landmark for the Asian anterior skull base. AB - BACKGROUND: Surgical landmarks for defining the level of the skull base during endoscopic sinus and skull base surgery (ESBS), e.g., the middle turbinate, may be distorted by tumor or previous surgery. The orbital floor is a valid fixed anatomic landmark for the white population, but it is not known if its use is useful for an Asian population. OBJECTIVES: To define fixed anatomic landmarks for ESBS in an Asian population and to compare the level of the skull base and its relation with anatomic landmarks between Asian and white populations. METHODS: Computed tomographies performed on paranasal sinuses of Thai patients were retrospectively assessed. The distance between the nasal floor to four structures, the orbital floor, sphenoid planum, cribriform, and ethmoid roof, were measured. The level of skull base related to the orbital floor of an Asian population was compared with data of a white population from a previously published study. RESULTS: A total of 150 Thai patients (300 paranasal sinus systems) were assessed and compared with 150 white patients. The orbital floor was always below the skull base (600 sides [100%]). When compared with white patients, the Asian patients had significantly higher mean (standard deviation [SD]) values: orbital floor (35.2 +/- 3.4 mm versus 33.9 +/- 3.0 mm; p < 0.001), ethmoid roof (49.3 +/- 3.8 mm versus 48.4 +/- 4.5 mm; p = 0.01), cribriform (46.4 +/- 3.6 mm versus 44.0 +/- 3.7 mm; p < 0.001), and sphenoid roof (45.7 +/- 3.7 mm versus 44.9 +/- 3.7 mm; p = 0.01). The Asian population had a mean (SD) longer distance from the orbital floor to the cribiform (11.2 +/- 2.5 mm versus 10.1 +/- 2.7 mm; p < 0.001), a shorter distance to the sphenoid roof (10.5 +/- 3.3 mm versus 11.0 +/- 2.9 mm; p = 0.03), and a similar distance to the ethmoid roof (14.1 +/- 3.1 mm versus 14.5 +/- 3.5 mm; p = 0.09). CONCLUSION: Although a statistical difference exists between racial groups, clinically, the orbital floor is a useful fixed anatomic landmark for ESBS for both Asian and white populations. PMID- 26637574 TI - Recurrent asystole as an electrocardiographic artifact during microdebrider use in functional endoscopic sinus surgery. AB - INTRODUCTION: Electrocardiographic (EKG) artifacts can lead to unnecessary treatment and costly diagnostic workup. Two previous studies reported a ventricular tachycardia artifact as a result of microdebrider malfunction. In this study, we report the first case of EKG artifacts that mimick asystole from microdebrider use during functional endoscopic sinus surgery (FESS). CASE: A healthy 19-year-old woman presented with chronic rhinosinusitis, nasal polyposis, and a deviated nasal septum. She was scheduled for a bilateral FESS and septoplasty. During surgery, the microdebrider was changed after 1 hour. While using the second microdebrider, the EKG monitor showed three distinct asystolic events, all lasted approximately 3 seconds. The EKG tracing returned to normal sinus rhythm every time the microdebrider was stopped. The patient's oxygen saturation remained at 100%, and blood pressure remained stable during the episodes. The procedure was aborted, and an extensive cardiology workup was performed, which returned negative results. Biomedical engineering investigated the microdebrider and found a far greater than expected chassis leak, which likely caused electrical interference. Six months later, the patient underwent a right-sided FESS and revision left frontal FESS. There were no EKG abnormalities during the second surgery. DISCUSSION: Although other EKG artifacts have been reported in the literature, this is the first case report of an artifact that mimicked asystole that stemmed from microdebrider use. Improved awareness of this potential EKG artifact for both the surgeon and the anesthesiologist may prevent an unnecessary costly workup. PMID- 26637575 TI - Probiotics in prevention and treatment of allergic rhinitis. PMID- 26637576 TI - Chronic rhinosinusitis in gastroesophageal reflux disease. PMID- 26637577 TI - Understanding the basic science and augmenting the clinical knowledge base of rhinologic disorders. PMID- 26637578 TI - Pirfenidone inhibits transforming growth factor beta1-induced extracellular matrix production in nasal polyp-derived fibroblasts. AB - PURPOSE: Pirfenidone has been shown to have antifibrotic and anti-inflammatory effects in the lungs. The purpose of this study was to evaluate the inhibitory effects of pirfenidone on transforming growth factor (TGF)-beta1-induced myofibroblast differentiation and extracellular matrix accumulation. We also determined the molecular mechanisms of pirfenidone in nasal polyp-derived fibroblasts (NPDF). METHODS: NPDFs were isolated from nasal polyps from eight patients who had chronic rhinosinusitis with nasal polyp. Pirfenidone was used to treat TGF-beta1-induced NPDFs. Cytotoxicity was evaluated by using a 3-(4,5 dimethylthiazol-2yl)-2,5-diphenyl-tetrazolium bromide assay. Fibroblast migration was evaluated with scratch assays. Expression levels of alpha-smooth muscle actin (SMA), fibronectin, and phosphorylated Smad2/3 were determined by Western blot and/or reverse transcription-polymerase chain reaction and immunofluorescent staining. Total collagen production was analyzed with the Sircol collagen assay and contractile activity was measured by a collagen gel contraction assay. RESULTS: Pirfenidone (0-2 mg/mL) has no significant cytotoxic effects in TGF beta1-induced NPDFs. Migration of NPDFs was significantly inhibited by pirfenidone treatment. The expression levels of alpha-SMA and fibronectin were significantly reduced in pirfenidone-treated NPDFs. Collagen contraction and production were also significantly decreased by pirfenidone treatment. Finally, pirfenidone significantly inhibited phosphorylation of the Smad2/3 pathway in TGF beta1-induced NPDFs. CONCLUSIONS: Pirfenidone has an inhibitory effect on TGF beta1-induced migration, myofibroblast differentiation (alpha-SMA), extracellular matrix accumulation, and collagen contraction by blocking the phosphorylation of Smad2/3 pathways in NPDFs. Thus, pirfenidone may inhibit TGF-beta1-induced extracellular matrix by regulating Smad2/3. PMID- 26637579 TI - Pediatric chronic rhinosinusitis. AB - The goal of this review is to elucidate the pathogenic factors, histopathologic features, and special considerations that relate to pediatric versus adult chronic rhinosinusitis (CRS) and to emphasize differences and similarities between the adult and pediatric conditions. Emphasis is placed on understanding of the differences in pathogenic mechanisms, host-microbial interactions, potential defects in innate antimicrobial immunity, and the role of biofilm formation in pediatric versus adult CRS and how these translate to different approaches toward both medical and surgical management. Pediatric CRS can be viewed as evolving from acute bacterial rhinosinusitis into an uncomplicated "early" stage of CRS, later evolving into a persistent stage and, in some cases, evolving into a late "maladaptive-eosinophilic" stage disease. Given this potential evolution toward more irreversible disease, a plea can be made for improved recognition of and more aggressive early intervention for pediatric CRS, it is hoped, to prevent these long-term consequences. For the primary care physician, this may necessitate enlisting the support of a sinus specialist before the symptoms of CRS have persisted for months or years. It may also necessitate, in some cases, the use of sinus computed tomography imaging to demonstrate that sinus abnormalities have resolved. Other arguments can be made for prompt and comprehensive management of pediatric CRS, including the need to reduce the burden of illness, reduce health care costs, avoid unnecessary antibiotic use and its attendant effects toward promoting antibiotic resistant infections and, potentially, to reduce the development of important comorbidities, e.g., asthma. PMID- 26637580 TI - Long-term postoperative azithromycin in patients with chronic rhinosinusitis: A randomized clinical trial. AB - BACKGROUND: Chronic rhinosinusitis (CRS) is recognized as a common disease that imposes a big burden on the health system worldwide. There is ongoing evidence of the anti-inflammatory effect of long-term macrolide in the management of patients with CRS. OBJECTIVE: The aim of this randomized clinical trial was to evaluate the efficacy of long-term consumption of low-dose azithromycin after functional endoscopic sinus surgery. METHODS: Sixty-six patients who fulfilled the inclusion criteria were randomly divided into intervention and control groups. The subjects received the standard conventional treatment (fluticasone nasal spray plus normal saline solution irrigation) or the conventional treatment plus 250 mg of azithromycin on a daily basis for 3 months. Evaluation was made based on the 22 item Sino-Nasal Outcome Test (SNOT-22) immediately before surgery and 3 months after surgery. RESULTS: The intervention group showed a statistically significant improvement in SNOT-22 scores after the treatment and a higher percentage change after 3 months of therapy compared with the control group. A significant correlation was found between the percentage change of SNOT-22 scores and smoking in the placebo group. Lund-Mackay scores, patient age, and the duration of symptoms had no significant correlation with the percentage change. CONCLUSION: Treatment with long-term low-dose azithromycin in combination with the conventional therapy could statistically reduce the recurrence rate of CRS symptoms after functional endoscopic sinus surgery, but there was not sufficient evidence to support clinical significance of azithromycin at the investigated dose. Further larger scale trials, along with a longer follow-up period, is needed to evaluate the effectiveness of the therapy. PMID- 26637581 TI - Computed tomographic analysis of frontal recess cells in pediatric patients. AB - OBJECTIVE: To describe the prevalence of frontoethmoid cells and superior uncinate process attachment in pediatric patients with sinonasal symptoms. METHOD: Fifty high-resolution computed tomographies of the paranasal sinuses for pediatric patients were evaluated for the presence of frontoethmoid cells and uncinate process insertion. The computed tomographies were randomly collected for patients with sinonasal symptoms (age range, 4-15 years) at our clinic. The prevalence of these cells was compared against age group and type of uncinate process. RESULTS: The prevalence of each structure was agger nasi cell (97%), type 1 frontal cell (39%), type 2 frontal cell (27%), type 3 frontal cell (11%), type 4 frontal cell (1%), supraorbital ethmoid cell (38%), suprabullar cell (57%), frontal bullar cell (9%), and interfrontal septal cell (16%). When excluding the agger nasi cell, 48 patients (96%) had at least one type of frontoethmoid cell and 43 (86%) had at least one frontal cell. The frequency of these cells did not significantly differ based on sex or uncinate process insertion, but it did with age. Lamina papyracea was the most common site of superior uncinate process attachment. CONCLUSION: Our results indicated a high frequency of frontoethmoid cells in the pediatric age group. The prevalence of these variations changes during childhood development. As in adults, lamina papyracea is the most common site of superior uncinate process attachment. Recognition of these variations in the frontal recess can provide useful information for safe and efficient endoscopic dissection in the frontal recess region. PMID- 26637582 TI - Reduction of adhesions and antrostomy stenosis with topical vitamin A after endoscopic sinus surgery. AB - BACKGROUND: Prevention of adhesion formation and restoration of mucociliary mucosa are major determinants of the success of endoscopic sinus surgery (ESS). Vitamin A (VA) can promote mucociliary differentiation of respiratory epithelium. However, whether topical VA can promote sinonasal wound healing or reduce adhesion formation after ESS in humans remains unexplored. OBJECTIVE: To investigate the effect of topical VA on sinonasal wound healing and adhesion formation after ESS. METHODS: This is a within-subject control study. Patients with chronic rhinosinusitis were included. Each patient underwent ESS, and topical VA was applied over the sinonasal wound. Postoperative outcomes were assessed by using the Lund-Kennedy score, and the antrostomy size was measured. In vitro wound healing assay of fibroblasts with or without VA was evaluated. Restoration of ciliated epithelium was examined by using scanning electron microscopy. RESULTS: Thirty patients were enrolled. The mean (standard deviation {SD}) scores for scarring/adhesion in the VA-treated side at 3 and 12 months after surgery (0.20 +/- 0.40 and 0.23 +/- 0.42, respectively) were significantly lower than those in the controls (0.47 +/- 0.50 and 0.53 +/- 0.62, respectively). The mean (SD) antrostomy size in the VA treated side at 1, 3, and 12 months after surgery (0.85 +/- 0.30 cm(2), 0.7 +/- 0.30 cm(2), and 0.70 +/- 0.27 cm(2), respectively) were significantly larger than those in the controls (0.79 +/- 0.26 cm(2), 0.60 +/- 0.25 cm(2), and 0.57 +/- 0.24 cm(2), respectively). Wound healing assay revealed that VA significantly inhibited the proliferation and migration of fibroblasts. Scanning electron microscopy showed mature ciliated cells in the VA treated side. CONCLUSION: Topical VA is a promising agent for sinonasal wound healing after ESS because it can promote mucociliary reepithelization, reduce adhesion, and prevent antrostomy stenosis. PMID- 26637583 TI - Amphotericin B nasal irrigation as an adjuvant therapy after functional endoscopic sinus surgery. AB - BACKGROUND: Fungus-driven inflammation is proposed to play an important role in the pathogenesis of chronic rhinosinusitis (CRS). Previous studies evaluated the efficacy of intranasal amphotericin B (AMB) in the treatment of patients with CRS, but the results were controversial. The purpose of this study was to evaluate the efficacy of 100 MUg/mL of AMB nasal irrigation as postoperative care after functional endoscopic sinus surgery (FESS). METHODS: Patients with CRS who received FESS for treatment were recruited and randomly assigned to two groups at 1 month after surgery. Patients in the AMB group received 100 MUg/mL of AMB nasal irrigation daily for 2 months, and those in the normal saline (NS) group received NS solution nasal irrigation daily for 2 months. Pre-FESS, pre-irrigation, and postirrigation sinonasal symptoms were assessed by questionnaires, and the patients received endoscopic examination, acoustic rhinometry, smell test, and saccharine transit test. RESULTS: Seventy-seven patients were enrolled between June 2012 and December 2014. Among the patients who completed the study, 38 received AMB irrigation, and 39 received NS solution irrigation. Although all the patients reported improvement after irrigation, there was no difference in outcome between patients who received AMB and those who received NS solution. CONCLUSION: Our study showed that nasal irrigation with 100 MUg/mL of AMB did not confer a greater benefit than that of NS solution nasal irrigation in post-FESS care. PMID- 26637584 TI - Inverted papilloma of the maxillary sinus: Surgical approach and long-term results. AB - BACKGROUND: Inverted papillomas (IP) commonly develop in the maxillary sinus (MS). However, the MS is a complex structure, and all areas in the MS are not easily approachable. OBJECTIVE: This study reviewed our surgical outcome of patients with IPs that originated from the MS in long-term follow-up and suggests appropriate approaches according to the tumor origin. METHODS: Thirty-one patients who were diagnosed with IP that originated from the MS, underwent surgery by a single operator between 1999 and 2011, and had postoperative follow up of >3 years were enrolled. RESULTS: In all the cases, the endoscopic endonasal approach (EEA) was attempted at first and then canine fossa puncture (CP), canine fossa opening via the Caldwell-Luc approach (CO), and Caldwell-Luc operation (CLO) were added in consecutive order as the occasion demands. Six patients (19.4%) were treated only with EEA, and they had IPs from the superior, posterior, or medial wall. Five (16.1%) were treated with EEA plus CP, which was added for removal of IPs that originated from the lateral wall. Sixteen (51.6%) were treated with EEA plus CO, which was for removal of tumors from the medial, anterior, or inferior wall. Four patients (12.5%) whose IP attached to the whole MS mucosa underwent CLO. Three (9.7%) experienced recurrences, and the mean period to recurrence was 20.7 months. CONCLUSION: The overall recurrence rate was 9.7%. IPs that originated from the lateral wall of the MS can be removed by using CP. When IPs originate from the anterior, inferior, or medial wall of the MS, CO may be needed for the thorough removal of them. PMID- 26637585 TI - Endoscopic transantral and transnasal repair of orbital floor fracture with the ballooning technique, and classification and characterization of orbital floor fractures. AB - BACKGROUND: The level of difficulty during an endoscopic approach for an inferior orbital fracture depends on the fracture pattern and the presence of a ruptured membrane (orbital periosteum and sinus mucosa). The purpose of our study was to examine fracture patterns according to age group and to determine the relationship between the type of fracture and the type of membrane injury. METHODS: We reviewed the records of 30 patients who, from 2006 to 2010, underwent endoscopic transantral and transnasal approach with a balloon catheter technique to repair orbital floor fracture. The procedure was done through middle or inferior meatal antrostomy and two small antrostomies made in the anterior wall of the maxillary sinus by using an endoscope and specially designed curved dissectors. RESULTS: There were 3 linear, 20 trapdoor-type and 7 blowout fractures. There was a tendency toward a higher incidence of linear fractures at younger ages and of blowout fractures in older patients. All linear fractures had rupture of both membranes, whereas both membranes were intact in 15 of the 20 patients with trapdoor fractures. Among blowout fractures, there was no membrane rupture in five and both membranes were ruptured in two patients. No patient reported diplopia after fracture repair. CONCLUSIONS: Rupture of the periosteum, which makes visualization and reduction of orbital tissue difficult for the surgeon during endoscopic repair of the orbital floor fracture, was observed in 3 of 3 linear fractures and 5 of 20 trapdoor fractures. We found that linear fractures were more common in pediatric patients. Care of pediatric orbital floor fracture requires particular caution. PMID- 26637586 TI - Endoscopic endonasal orbital transposition to expand the frontal sinus approaches. AB - BACKGROUND: The management of frontal sinus disease still remains a challenging issue for rhinologists. Although endoscopic frontal sinus surgery has significantly advanced over the past years, there are some conditions in which the external approaches are still necessary. Recently, the increasing experience in endoscopic sinus surgery together with important technologic advancements have allowed expansion of the indications for selected lesions localized more and more lateral into the frontal sinus. OBJECTIVE: The aim of this study was to describe the endoscopic endonasal approach to the far lateral portion of the frontal sinus and to evaluate the outcomes of this technique. METHODS: A retrospective evaluation was carried out with patients at a single institution, who, from 2004 to 2012, underwent an exclusive endoscopic transnasal approach to the far lateral portion of the frontal sinus at a single institution. The surgical technique included the Draf IIb procedure, a modified Lothrop procedure (Draf III), and endoscopic lateralization of the orbit, differently associated according to the needs of each case. RESULTS: Twenty-four patients were eligible for the present study. The lesions included were mucoceles in 9 cases, fibro-osseous lesions in 10 cases, and inverted papillomas in 5 cases. The overall follow-up ranged from 12 to 120 months (mean, 40.6 months). At the time of the last follow-up, no recurrence of disease was observed in the patients treated; in one case of osteoma, a small and stable in size (1 mm) persistent lesion was observed in an asymptomatic patient. One scheduled and one accidental cerebrospinal fluid leak with immediate skull base reconstruction occurred. No intraoperative or postoperative early or late orbital complication was observed in any case. CONCLUSION: The endoscopic endonasal orbital transposition seems to facilitate the endoscopic management of selected far-lateral frontal sinus lesions. However, it is a demanding procedure that requires experience and skill to avoid intraoperative skull base and orbital complications. PMID- 26637587 TI - How I Do It: The Sphenoethmoidectomy. AB - BACKGROUND: Several techniques for performing the sphenoethmoidectomy have been described. We present a safe, effective, and efficient technique. OBJECTIVE: We present text, images, and video to demonstrate our preferred technique for performing a sphenoethmoidectomy. METHODS: A description of the technique without prospective or retrospective data, whereby a Kerrison rongeur and microdebrider were used to perform a total sphenoethmoidectomy by skeletonizing the skull base and lamina papyracea. RESULTS: In our hands, the Kerrison rongeur and microdebrider allowed for a reliably safe and efficient sphenoethmoidectomy for chronic sinusitis with or without polyposis or skull base approaches. CONCLUSION: The technique described can be added to the armamentarium of the endoscopic sinus surgeon. PMID- 26637589 TI - "I Don't Care About What You Want!" The Relation Between Juvenile Delinquents' Responses to Social Problem Situations and Empathy in Secure Juvenile Institutions. AB - The present study examined the relation between juvenile delinquents' responses to social problem situations and empathy in secure juvenile institutions. The sample consisted of 79 delinquent boys (62%) and 49 delinquent girls (38%), aged 12 to 19 years. Results showed problems with accepting authority to be negatively related to both affective and cognitive empathy. Inadequate coping with competition was negatively related to cognitive empathy, whereas problems with receiving or giving help were negatively related to affective empathy. The central role of authority problems suggests that group workers could influence adolescents' empathy development by helping them to learn to cope with social problem situations. PMID- 26637590 TI - Facets of Male Violence Against Women With Substance Abuse Problems: Women With a Residence and Homeless Women. AB - The aims of this study were to investigate the type and extent to which women with substance abuse problems have been exposed to male violence during their lifetime, and to examine possible differences between women with a residence (WR) and homeless women (HW). The total sample included 79 women (WR, n = 35; HW, n = 44; M age = 47.8 years). Of the total sample, 72 women (91%) had experienced different kinds of male violence, 88% from former partners, and 26% from male friends or acquaintances. Of the 72 women, 71% further reported "Countless occasions of violent events," and 36% had been forced to commit criminal acts. Abused women who had been forced to commit criminal acts were significantly more frequently found to be homeless, have reported parental alcohol and/or drug problems, have witnessed domestic violence in childhood, have been victims of sexual violence, have used illicit drugs as a dominant preparation, and have injected illicit drugs. Almost half of the abused women (46%) met criteria for posttraumatic stress disorder (PTSD), where HW showed an almost 4-time higher risk (RR 3.78) than WR. In conclusion there is a particular vulnerability in women with substance abuse to male violence, which has an important impact on their health status. Thus, from a public health perspective, it is suggested that for those women who have experienced male violence, treatment protocols need to include both assessing and addressing the impact of such experience in relation to substance abuse as well as concomitant health concerns. PMID- 26637592 TI - Direct Image-Based Enumeration of Clostridium phytofermentans Cells on Insoluble Plant Biomass Growth Substrates. AB - A dual-fluorescent-dye protocol to visualize and quantify Clostridium phytofermentans ISDg (ATCC 700394) cells growing on insoluble cellulosic substrates was developed by combining calcofluor white staining of the growth substrate with cell staining using the nucleic acid dye Syto 9. Cell growth, cell substrate attachment, and fermentation product formation were investigated in cultures containing either Whatman no. 1 filter paper, wild-type Sorghum bicolor, or a reduced-lignin S. bicolor double mutant (bmr-6 bmr-12 double mutant) as the growth substrate. After 3 days of growth, cell numbers in cultures grown on filter paper as the substrate were 6.0- and 2.2-fold higher than cell numbers in cultures with wild-type sorghum and double mutant sorghum, respectively. However, cells produced more ethanol per cell when grown with either sorghum substrate than with filter paper as the substrate. Ethanol yields of cultures were significantly higher with double mutant sorghum than with wild-type sorghum or filter paper as the substrate. Moreover, ethanol production correlated with cell attachment in sorghum cultures: 90% of cells were directly attached to the double mutant sorghum substrate, while only 76% of cells were attached to wild-type sorghum substrate. With filter paper as the growth substrate, ethanol production was correlated with cell number; however, with either wild-type or mutant sorghum, ethanol production did not correlate with cell number, suggesting that only a portion of the microbial cell population was active during growth on sorghum. The dual-staining procedure described here may be used to visualize and enumerate cells directly on insoluble cellulosic substrates, enabling in-depth studies of interactions of microbes with plant biomass. PMID- 26637591 TI - Secreted Acb1 Contributes to the Yeast-to-Hypha Transition in Cryptococcus neoformans. AB - Adaptation to stress by eukaryotic pathogens is often accompanied by a transition in cellular morphology. The human fungal pathogen Cryptococcus neoformans is known to switch between the yeast and the filamentous form in response to amoebic predation or during mating. As in the classic dimorphic fungal pathogens, the morphotype is associated with the ability of cryptococci to infect various hosts. Many cryptococcal factors and environmental stimuli, including pheromones (small peptides) and nutrient limitation, are known to induce the yeast-to-hypha transition. We recently discovered that secreted matricellular proteins could also act as intercellular signals to promote the yeast-to-hypha transition. Here we show that the secreted acyl coenzyme A (acyl-CoA)-binding protein Acb1 plays an important role in enhancing this morphotype transition. Acb1 does not possess a signal peptide. Its extracellular secretion and, consequently, its function in filamentation are dependent on an unconventional GRASP (Golgi reassembly stacking protein)-dependent secretion pathway. Surprisingly, intracellular recruitment of Acb1 to the secretory vesicles is independent of Grasp. In addition to Acb1, Grasp possibly controls the secretion of other cargos, because the graspDelta mutant, but not the acb1Delta mutant, is defective in capsule production and macrophage phagocytosis. Nonetheless, Acb1 is likely the major or the sole effector of Grasp in terms of filamentation. Furthermore, we found that the key residue of Acb1 for acyl binding, Y80, is critical for the proper subcellular localization and secretion of Acb1 and for cryptococcal morphogenesis. PMID- 26637593 TI - Field-Evolved Mode 1 Resistance of the Fall Armyworm to Transgenic Cry1Fa Expressing Corn Associated with Reduced Cry1Fa Toxin Binding and Midgut Alkaline Phosphatase Expression. AB - Insecticidal protein genes from the bacterium Bacillus thuringiensis (Bt) are expressed by transgenic Bt crops (Bt crops) for effective and environmentally safe pest control. The development of resistance to these insecticidal proteins is considered the most serious threat to the sustainability of Bt crops. Resistance in fall armyworm (Spodoptera frugiperda) populations from Puerto Rico to transgenic corn producing the Cry1Fa insecticidal protein resulted, for the first time in the United States, in practical resistance, and Bt corn was withdrawn from the local market. In this study, we used a field-collected Cry1Fa corn-resistant strain (456) of S. frugiperda to identify the mechanism responsible for field-evolved resistance. Binding assays detected reduced Cry1Fa, Cry1Ab, and Cry1Ac but not Cry1Ca toxin binding to midgut brush border membrane vesicles (BBMV) from the larvae of strain 456 compared to that from the larvae of a susceptible (Ben) strain. This binding phenotype is descriptive of the mode 1 type of resistance to Bt toxins. A comparison of the transcript levels for putative Cry1 toxin receptor genes identified a significant downregulation (>90%) of a membrane-bound alkaline phosphatase (ALP), which translated to reduced ALP protein levels and a 75% reduction in ALP activity in BBMV from 456 compared to that of Ben larvae. We cloned and heterologously expressed this ALP from susceptible S. frugiperda larvae and demonstrated that it specifically binds with Cry1Fa toxin. This study provides a thorough mechanistic description of field evolved resistance to a transgenic Bt crop and supports an association between resistance and reduced Cry1Fa toxin binding and levels of a putative Cry1Fa toxin receptor, ALP, in the midguts of S. frugiperda larvae. PMID- 26637594 TI - To Modulate Survival under Secondary Stress Conditions, Listeria monocytogenes 10403S Employs RsbX To Downregulate sigmaB Activity in the Poststress Recovery Stage or Stationary Phase. AB - Listeria monocytogenes is a saprophytic bacterium that thrives in diverse environments and causes listeriosis via ingestion of contaminated food. RsbX, a putative sigma B (sigma(B)) regulator, is thought to maintain the ready state in the absence of stress and reset the bacterium to the initial state in the poststress stage in Bacillus subtilis. We wondered whether RsbX is functional in L. monocytogenes under different stress scenarios. Genetic deletion and complementation of the rsbX gene were combined with survival tests and transcriptional and translational analyses of sigma(B) expression in response to stresses. We found that deletion of rsbX increased survival under secondary stress following recovery of growth after primary stress or following stationary phase culturing. The DeltarsbX mutant had higher expression of sigma(B) than its parent strain in the recovery stage following primary sodium stress and in stationary-phase cultures. Apparently, increased sigma(B) expression had contributed to improved survival in the absence of RsbX. There were no significant differences in survival rates or sigma(B) expression levels in response to primary stresses between the rsbX mutant and its parent strain during the exponential phase. Therefore, we provide clear evidence that RsbX is a negative regulator of L. monocytogenes sigma(B) during the recovery period after a primary stress or in the stationary phase, thus affecting its survival under secondary stress. PMID- 26637595 TI - Mechanism of Sporicidal Activity for the Synergistic Combination of Peracetic Acid and Hydrogen Peroxide. AB - There is still great interest in controlling bacterial endospores. The use of chemical disinfectants and, notably, oxidizing agents to sterilize medical devices is increasing. With this in mind, hydrogen peroxide (H2O2) and peracetic acid (PAA) have been used in combination, but until now there has been no explanation for the observed increase in sporicidal activity. This study provides information on the mechanism of synergistic interaction of PAA and H2O2 against bacterial spores. We performed investigations of the efficacies of different combinations, including pretreatments with the two oxidizers, against wild-type spores and a range of spore mutants deficient in the spore coat or small acid soluble spore proteins. The concentrations of the two biocides were also measured in the reaction vessels, enabling the assessment of any shift from H2O2 to PAA formation. This study confirmed the synergistic activity of the combination of H2O2 and PAA. However, we observed that the sporicidal activity of the combination is largely due to PAA and not H2O2. Furthermore, we observed that the synergistic combination was based on H2O2 compromising the spore coat, which was the main spore resistance factor, likely allowing better penetration of PAA and resulting in the increased sporicidal activity. PMID- 26637596 TI - Mapping the Distribution of Cysts from the Toxic Dinoflagellate Cochlodinium polykrikoides in Bloom-Prone Estuaries by a Novel Fluorescence In Situ Hybridization Assay. AB - Cochlodinium polykrikoides is a cosmopolitan dinoflagellate that is notorious for causing fish-killing harmful algal blooms (HABs) across North America and Asia. While recent laboratory and ecosystem studies have definitively demonstrated that Cochlodinium forms resting cysts that may play a key role in the dynamics of its HABs, uncertainties regarding cyst morphology and detection have prohibited even a rudimentary understanding of the distribution of C. polykrikoides cysts in coastal ecosystems. Here, we report on the development of a fluorescence in situ hybridization (FISH) assay using oligonucleotide probes specific for the large subunit (LSU) ribosomal DNA (rDNA) of C. polykrikoides. The LSU rDNA-targeted FISH assay was used with epifluorescence microscopy and was iteratively refined to maximize the fluorescent reaction with C. polykrikoides and minimize cross reactivity. The final LSU rDNA-targeted FISH assay was found to quantitatively recover cysts made by North American isolates of C. polykrikoides but not cysts formed by other common cyst-forming dinoflagellates. The method was then applied to identify and map C. polykrikoides cysts across bloom-prone estuaries. Annual cyst and vegetative cell surveys revealed that elevated densities of C. polykrikoides cysts (>100 cm(-3)) during the spring of a given year were spatially consistent with regions of dense blooms the prior summer. The identity of cysts in sediments was confirmed via independent amplification of C. polykrikoides rDNA. This study mapped C. polykrikoides cysts in a natural marine setting and indicates that the excystment of cysts formed by this harmful alga may play a key role in the development of HABs of this species. PMID- 26637597 TI - An Environmental Shiga Toxin-Producing Escherichia coli O145 Clonal Population Exhibits High-Level Phenotypic Variation That Includes Virulence Traits. AB - Shiga toxin-producing Escherichia coli (STEC) serotype O145 is one of the major non-O157 serotypes associated with severe human disease. Here we examined the genetic diversity, population structure, virulence potential, and antimicrobial resistance profiles of environmental O145 strains recovered from a major produce production region in California. Multilocus sequence typing analyses revealed that sequence type 78 (ST-78), a common ST in clinical strains, was the predominant genotype among the environmental strains. Similarly, all California environmental strains belonged to H28, a common H serotype in clinical strains. Although most environmental strains carried an intact fliC gene, only one strain retained swimming motility. Diverse stx subtypes were identified, including stx1a, stx2a, stx2c, and stx2e. Although no correlation was detected between the stx genotype and Stx1 production, high Stx2 production was detected mainly in strains carrying stx2a only and was correlated positively with the cytotoxicity of Shiga toxin. All environmental strains were capable of producing enterohemolysin, whereas only 10 strains were positive for anaerobic hemolytic activity. Multidrug resistance appeared to be common, as nearly half of the tested O145 strains displayed resistance to at least two different classes of antibiotics. The core virulence determinants of enterohemorrhagic E. coli were conserved in the environmental STEC O145 strains; however, there was large variation in the expression of virulence traits among the strains that were highly related genotypically, implying a trend of clonal divergence. Several cattle isolates exhibited key virulence traits comparable to those of the STEC O145 outbreak strains, emphasizing the emergence of hypervirulent strains in agricultural environments. PMID- 26637598 TI - Single-Cell-Genomics-Facilitated Read Binning of Candidate Phylum EM19 Genomes from Geothermal Spring Metagenomes. AB - The vast majority of microbial life remains uncatalogued due to the inability to cultivate these organisms in the laboratory. This "microbial dark matter" represents a substantial portion of the tree of life and of the populations that contribute to chemical cycling in many ecosystems. In this work, we leveraged an existing single-cell genomic data set representing the candidate bacterial phylum "Calescamantes" (EM19) to calibrate machine learning algorithms and define metagenomic bins directly from pyrosequencing reads derived from Great Boiling Spring in the U.S. Great Basin. Compared to other assembly-based methods, taxonomic binning with a read-based machine learning approach yielded final assemblies with the highest predicted genome completeness of any method tested. Read-first binning subsequently was used to extract Calescamantes bins from all metagenomes with abundant Calescamantes populations, including metagenomes from Octopus Spring and Bison Pool in Yellowstone National Park and Gongxiaoshe Spring in Yunnan Province, China. Metabolic reconstruction suggests that Calescamantes are heterotrophic, facultative anaerobes, which can utilize oxidized nitrogen sources as terminal electron acceptors for respiration in the absence of oxygen and use proteins as their primary carbon source. Despite their phylogenetic divergence, the geographically separate Calescamantes populations were highly similar in their predicted metabolic capabilities and core gene content, respiring O2, or oxidized nitrogen species for energy conservation in distant but chemically similar hot springs. PMID- 26637599 TI - Cytoplasmic CopZ-Like Protein and Periplasmic Rusticyanin and AcoP Proteins as Possible Copper Resistance Determinants in Acidithiobacillus ferrooxidans ATCC 23270. AB - Acidophilic organisms, such as Acidithiobacillus ferrooxidans, possess high-level resistance to copper and other metals. A. ferrooxidans contains canonical copper resistance determinants present in other bacteria, such as CopA ATPases and RND efflux pumps, but these components do not entirely explain its high metal tolerance. The aim of this study was to find other possible copper resistance determinants in this bacterium. Transcriptional expression of A. ferrooxidans genes coding for a cytoplasmic CopZ-like copper-binding chaperone and the periplasmic copper-binding proteins rusticyanin and AcoP, which form part of an iron-oxidizing supercomplex, was found to increase when the microorganism was grown in the presence of copper. All of these proteins conferred more resistance to copper when expressed heterologously in a copper-sensitive Escherichia coli strain. This effect was absent when site-directed-mutation mutants of these proteins with altered copper-binding sites were used in this metal sensitivity assay. These results strongly suggest that the three copper-binding proteins analyzed here are copper resistance determinants in this extremophile and contribute to the high-level metal resistance of this industrially important biomining bacterium. PMID- 26637600 TI - Phytic Acid and Sodium Chloride Show Marked Synergistic Bactericidal Effects against Nonadapted and Acid-Adapted Escherichia coli O157:H7 Strains. AB - The synergistic antimicrobial effects of phytic acid (PA), a natural extract from rice bran, plus sodium chloride against Escherichia coli O157:H7 were examined. Exposure to NaCl alone at concentrations up to 36% (wt/wt) for 5 min did not reduce bacterial populations. The bactericidal effects of PA alone were much greater than those of other organic acids (acetic, citric, lactic, and malic acids) under the same experimental conditions (P < 0.05). Combining PA and NaCl under conditions that yielded negligible effects when each was used alone led to marked synergistic effects. For example, whereas 0.4% PA or 3 or 4% NaCl alone had little or no effect on cell viability, combining the two completely inactivated both nonadapted and acid-adapted cells, reducing their numbers to unrecoverable levels (>7-log CFU/ml reduction). Flow cytometry confirmed that PA disrupted the cell membrane to a greater extent than did other organic acids, although the cells remained viable. The combination of PA and NaCl induced complete disintegration of the cell membrane. By comparison, none of the other organic acids acted synergistically with NaCl, and neither did NaCl-HCl solutions at the same pH values as the test solutions of PA plus NaCl. These results suggest that PA has great potential as an effective bacterial membrane permeabilizing agent, and we show that the combination is a promising alternative to conventional chemical disinfectants. These findings provide new insight into the utility of natural compounds as novel antimicrobial agents and increase our understanding of the mechanisms underlying the antibacterial activity of PA. PMID- 26637601 TI - N-Glycosylation Improves the Pepsin Resistance of Histidine Acid Phosphatase Phytases by Enhancing Their Stability at Acidic pHs and Reducing Pepsin's Accessibility to Its Cleavage Sites. AB - N-Glycosylation can modulate enzyme structure and function. In this study, we identified two pepsin-resistant histidine acid phosphatase (HAP) phytases from Yersinia kristensenii (YkAPPA) and Yersinia rohdei (YrAPPA), each having an N glycosylation motif, and one pepsin-sensitive HAP phytase from Yersinia enterocolitica (YeAPPA) that lacked an N-glycosylation site. Site-directed mutagenesis was employed to construct mutants by altering the N-glycosylation status of each enzyme, and the mutant and wild-type enzymes were expressed in Pichia pastoris for biochemical characterization. Compared with those of the N glycosylation site deletion mutants and N-deglycosylated enzymes, all N glycosylated counterparts exhibited enhanced pepsin resistance. Introduction of the N-glycosylation site into YeAPPA as YkAPPA and YrAPPA conferred pepsin resistance, shifted the pH optimum (0.5 and 1.5 pH units downward, respectively) and improved stability at acidic pH (83.2 and 98.8% residual activities at pH 2.0 for 1 h). Replacing the pepsin cleavage sites L197 and L396 in the immediate vicinity of the N-glycosylation motifs of YkAPPA and YrAPPA with V promoted their resistance to pepsin digestion when produced in Escherichia coli but had no effect on the pepsin resistance of N-glycosylated enzymes produced in P. pastoris. Thus, N-glycosylation may improve pepsin resistance by enhancing the stability at acidic pH and reducing pepsin's accessibility to peptic cleavage sites. This study provides a strategy, namely, the manipulation of N glycosylation, for improvement of phytase properties for use in animal feed. PMID- 26637602 TI - Novel Rhizosphere Soil Alleles for the Enzyme 1-Aminocyclopropane-1-Carboxylate Deaminase Queried for Function with an In Vivo Competition Assay. AB - Metagenomes derived from environmental microbiota encode a vast diversity of protein homologs. How this diversity impacts protein function can be explored through selection assays aimed to optimize function. While artificially generated gene sequence pools are typically used in selection assays, their usage may be limited because of technical or ethical reasons. Here, we investigate an alternative strategy, the use of soil microbial DNA as a starting point. We demonstrate this approach by optimizing the function of a widely occurring soil bacterial enzyme, 1-aminocyclopropane-1-carboxylate (ACC) deaminase. We identified a specific ACC deaminase domain region (ACCD-DR) that, when PCR amplified from the soil, produced a variant pool that we could swap into functional plasmids carrying ACC deaminase-encoding genes. Functional clones of ACC deaminase were selected for in a competition assay based on their capacity to provide nitrogen to Escherichia coli in vitro. The most successful ACCD-DR variants were identified after multiple rounds of selection by sequence analysis. We observed that previously identified essential active-site residues were fixed in the original unselected library and that additional residues went to fixation after selection. We identified a divergent essential residue whose presence hints at the possible use of alternative substrates and a cluster of neutral residues that did not influence ACCD performance. Using an artificial ACCD-DR variant library generated by DNA oligomer synthesis, we validated the same fixation patterns. Our study demonstrates that soil metagenomes are useful starting pools of protein-coding-gene diversity that can be utilized for protein optimization and functional characterization when synthetic libraries are not appropriate. PMID- 26637603 TI - Involvement of Agrobacterium tumefaciens Galacturonate Tripartite ATP-Independent Periplasmic (TRAP) Transporter GaaPQM in Virulence Gene Expression. AB - Monosaccharides capable of serving as nutrients for the soil bacterium Agrobacterium tumefaciens are also inducers of the vir regulon present in the tumor-inducing (Ti) plasmid of this plant pathogen. One such monosaccharide is galacturonate, the predominant monomer of pectin found in plant cell walls. This ligand is recognized by the periplasmic sugar binding protein ChvE, which interacts with the VirA histidine kinase that controls vir gene expression. Although ChvE is also a member of the ChvE-MmsAB ABC transporter involved in the utilization of many neutral sugars, it is not involved in galacturonate utilization. In this study, a putative tripartite ATP-independent periplasmic (TRAP) transporter, GaaPQM, is shown to be essential for the utilization of galacturonic acid; we show that residue R169 in the predicted sugar binding site of the GaaP is required for activity. The gene upstream of gaaPQM (gaaR) encodes a member of the GntR family of regulators. GaaR is shown to repress the expression of gaaPQM, and the repression is relieved in the presence of the substrate for GaaPQM. Moreover, GaaR is shown to bind putative promoter regions in the sequences required for galacturonic acid utilization. Finally, A. tumefaciens strains carrying a deletion of gaaPQM are more sensitive to galacturonate as an inducer of vir gene expression, while the overexpression of gaaPQM results in strains being less sensitive to this vir inducer. This supports a model in which transporter activity is crucial in ensuring that vir gene expression occurs only at sites of high ligand concentration, such as those at a plant wound site. PMID- 26637604 TI - Oxygen Affects Gut Bacterial Colonization and Metabolic Activities in a Gnotobiotic Cockroach Model. AB - The gut microbiota of termites and cockroaches represents complex metabolic networks of many diverse microbial populations. The distinct microenvironmental conditions within the gut and possible interactions among the microorganisms make it essential to investigate how far the metabolic properties of pure cultures reflect their activities in their natural environment. We established the cockroach Shelfordella lateralis as a gnotobiotic model and inoculated germfree nymphs with two bacterial strains isolated from the guts of conventional cockroaches. Fluorescence microscopy revealed that both strains specifically colonized the germfree hindgut. In diassociated cockroaches, the facultatively anaerobic strain EbSL (a new species of Enterobacteriaceae) always outnumbered the obligately anaerobic strain FuSL (a close relative of Fusobacterium varium), irrespective of the sequence of inoculation, which showed that precolonization by facultatively anaerobic bacteria does not necessarily favor colonization by obligate anaerobes. Comparison of the fermentation products of the cultures formed in vitro with those accumulated in situ indicated that the gut environment strongly affected the metabolic activities of both strains. The pure cultures formed the typical products of mixed-acid or butyrate fermentation, whereas the guts of gnotobiotic cockroaches accumulated mostly lactate and acetate. Similar shifts toward more-oxidized products were observed when the pure cultures were exposed to oxygen, which corroborated the strong effects of oxygen on the metabolic fluxes previously observed in termite guts. Oxygen microsensor profiles of the guts of germfree, gnotobiotic, and conventional cockroaches indicated that both gut tissue and microbiota contribute to oxygen consumption and suggest that the oxygen status influences the colonization success. PMID- 26637605 TI - Optical Sensing of Microbial Life on Surfaces. AB - The label-free detection of microbial cells attached to a surface is an active field of research. The field is driven by the need to understand and control the growth of biofilms in a number of applications, including basic research in natural environments, industrial facilities, and clinical devices, to name a few. Despite significant progress in the ability to monitor the growth of biofilms and related living cells, the sensitivity and selectivity of such sensors are still a challenge. We believe that among the many different technologies available for monitoring biofilm growth, optical techniques are the most promising, as they afford direct imaging and offer high sensitivity and specificity. Furthermore, as each technique offers different insights into the biofilm growth mechanism, our analysis allows us to provide an overview of the biological processes at play. In addition, we use a set of key parameters to compare state-of-the-art techniques in the field, including a critical assessment of each method, to identify the most promising types of sensors. We highlight the challenges that need to be overcome to improve the characteristics of current biofilm sensor technologies and indicate where further developments are required. In addition, we provide guidelines for selecting a suitable sensor for detecting microbial cells on a surface. PMID- 26637606 TI - Alterations in the Quinolone Resistance-Determining Regions and Fluoroquinolone Resistance in Clinical Isolates and Laboratory-Derived Mutants of Mycoplasma bovis: Not All Genotypes May Be Equal. AB - Mycoplasma bovis is considered a major contributor to respiratory diseases in young cattle. Resistant M. bovis isolates have increasingly been reported worldwide due to extensive use of antimicrobials to treat bovine pneumonia. The frequency of isolates resistant to fluoroquinolones varies considerably from one country to another. The MICs of isolates collected in France have only increased from "very low" to "low." The present study was conducted to investigate whether alterations in the quinolone resistance-determining regions (QRDRs) could account for this slight modification in susceptibility. No correlation between QRDR alterations and increased MICs was evidenced in clinical isolates. In addition, all clinical isolates were subtyped, and the tendencies of the different sequence types to develop resistance through mutations in QRDRs under selective pressure in vitro were examined. In vitro, 3 hot spots for mutations in QRDRs (position 83 in GyrA and positions 80 and 84 in ParC) were associated with a high level of resistance when cumulated. We showed that the point mutations in the QRDRs observed in vitro were different (in location and selection rapidity) between the different subtypes. Our in vitro observations were corroborated by the recent detection of a clinical isolate highly resistant to fluoroquinolones (MIC >= 16 MUg/ml) and belonging to the subtype which easily accumulates QRDR alterations in vitro. The current increased prevalence of this subtype in clinical isolates highlights the urgent need to control fluoroquinolone usage in veterinary medicine. PMID- 26637608 TI - Spending cuts: Defra outlines its plans for the future. PMID- 26637609 TI - Badger vaccination project to be suspended in Wales. PMID- 26637607 TI - Genomic Features of Environmental and Clinical Vibrio parahaemolyticus Isolates Lacking Recognized Virulence Factors Are Dissimilar. AB - Vibrio parahaemolyticus is a bacterial pathogen that can cause illness after the consumption or handling of contaminated seafood. The primary virulence factors associated with V. parahaemolyticus illness are thermostable direct hemolysin (TDH) and Tdh-related hemolysin (TRH). However, clinical strains lacking tdh and trh have recently been isolated, and these clinical isolates are poorly understood. To help understand the emergence of clinical tdh- and trh-negative isolates, a genomic approach was used to comprehensively compare 4 clinical tdh- and trh-negative isolates with 16 environmental tdh- and trh-negative isolates and 34 clinical isolates positive for tdh or trh, or both, with the objective of identifying genomic features that are unique to clinical tdh- and trh-negative isolates. The prevalence of pathogenicity islands (PAIs) common to clinical isolates was thoroughly examined in each of the clinical tdh- and trh-negative isolates. The tdh PAI was not present in any clinical or environmental tdh- and trh-negative isolates. The trh PAI was not present in any environmental isolates; however, in clinical tdh- and trh-negative isolate 10-4238, the majority of the trh PAI including a partial trh1 gene was present, which resulted in reclassification of this isolate as a tdh-negative and trh-positive isolate. In the other clinical tdh- and trh-negative isolates, neither the trh gene nor the trh PAI was present. We identified 862 genes in clinical tdh- and trh-negative isolates but not in environmental tdh- and trh-negative isolates. Many of these genes are highly homologous to genes found in common enteric bacteria and included genes encoding a number of chemotaxis proteins and a novel putative type VI secretion system (T6SS) effector and immunity protein (T6SS1). The availability of genome sequences from clinical V. parahaemolyticus tdh- and trh negative isolates and the comparative analysis may help provide an understanding of how this pathotype is able to survive in vivo during clinical illness. PMID- 26637610 TI - Disciplinary Committee dismisses application for restoration to the Register. PMID- 26637611 TI - RUMA expresses concern about new resistance finding. PMID- 26637612 TI - 'Many unknowns' in French HPAI case. PMID- 26637613 TI - All take and no give? AB - Benefits of the human-animal bond are often highlighted, but how equal is the relationship? Delegates at the BVA Congress at the London Vet Show heard that, while animals can bring benefits to people, people do not always fulfil their side of the bargain. Laura Honey reports. PMID- 26637614 TI - Meeting the challenge of disease threats to the U.K. AB - Official Veterinarians (OVs) from across the U.K. came together recently at conference organised to provide targeted CPD for their particular roles. With the theme of 'Reducing the impact of notifiable diseases in the UK', the meeting considered a wide range of topics, spanning large animal, small animal and equine issues. Georgina Mills reports on some of the sessions. PMID- 26637615 TI - Veterinary medicines update. AB - The following information has been produced for Veterinary Record by the Veterinary Medicines Directorate (VMD) to provide an update for veterinary surgeons on recent changes to marketing authorisations for veterinary medicines in the UK and on other relevant issues. PMID- 26637616 TI - Extending the role of veterinary nurses in anaesthesia. AB - Allowing registered veterinary nurses to assist with all aspects of anaesthesia. Update on the alternative dispute resolution trial. Potential implications of a British exit from the EU. English language requirement to be included in the Code of Professional Conduct. Providing a line to the RCVS for 'whistle-blowers'. An ethical review panel for practice-based research. These were among matters discussed by the RCVS Council at its meeting on November 5. The RCVS President, Bradley Viner, chaired the meeting, which was held at Belgravia House, London SW1P. PMID- 26637618 TI - Alveolar echinococcosis in dogs: an emerging issue? PMID- 26637619 TI - Extension of Cymorth TB. PMID- 26637620 TI - Vet Futures' ambition for business. PMID- 26637621 TI - Responsibility to prevent mental suffering in animals. PMID- 26637622 TI - Suitability of species kept as pets. PMID- 26637630 TI - Vets drive CPD in Scotland. AB - The CPD provider, VET Trust, was set up by a group of vets nearly 25 years ago with the aim of making CPD accessible to vets and veterinary nurses in Scotland. Kathleen Robertson reports on the Trust's aims and its newest CPD prize. PMID- 26637631 TI - Diary of a parliamentary intern. AB - Anthony Ridge, the new parliamentary intern to Lord Trees, reflects on his first month in Parliament. PMID- 26637632 TI - TRIM72 modulates caveolar endocytosis in repair of lung cells. AB - Alveolar epithelial and endothelial cell injury is a major feature of the acute respiratory distress syndrome, in particular when in conjunction with ventilation therapies. Previously we showed [Kim SC, Kellett T, Wang S, Nishi M, Nagre N, Zhou B, Flodby P, Shilo K, Ghadiali SN, Takeshima H, Hubmayr RD, Zhao X. Am J Physiol Lung Cell Mol Physiol 307: L449-L459, 2014.] that tripartite motif protein 72 (TRIM72) is essential for amending alveolar epithelial cell injury. Here, we posit that TRIM72 improves cellular integrity through its interaction with caveolin 1 (Cav1). Our data show that, in primary type I alveolar epithelial cells, lack of TRIM72 led to significant reduction of Cav1 at the plasma membrane, accompanied by marked attenuation of caveolar endocytosis. Meanwhile, lentivirus-mediated overexpression of TRIM72 selectively increases caveolar endocytosis in rat lung epithelial cells, suggesting a functional association between these two. Further coimmunoprecipitation assays show that deletion of either functional domain of TRIM72, i.e., RING, B-box, coiled-coil, or PRY-SPRY, abolishes the physical interaction between TRIM72 and Cav1, suggesting that all theoretical domains of TRIM72 are required to forge a strong interaction between these two molecules. Moreover, in vivo studies showed that injurious ventilation induced lung cell death was significantly increased in knockout (KO) TRIM72(KO) and Cav1(KO) lungs compared with wild-type controls and was particularly pronounced in double KO mutants. Apoptosis was accompanied by accentuation of gross lung injury manifestations in the TRIM72(KO) and Cav1(KO) mice. Our data show that TRIM72 directly and indirectly modulates caveolar endocytosis, an essential process involved in repair of lung epithelial cells through removal of plasma membrane wounds. Given TRIM72's role in endomembrane trafficking and cell repair, we consider this molecule an attractive therapeutic target for patients with injured lungs. PMID- 26637634 TI - Increased TGF-beta: a drawback of tracheal occlusion in human and experimental congenital diaphragmatic hernia? AB - Survivors of severe congenital diaphragmatic hernia (CDH) present significant respiratory morbidity despite lung growth induced by fetal tracheal occlusion (TO). We hypothesized that the underlying mechanisms would involve changes in lung extracellular matrix and dysregulated transforming growth factor (TGF)-beta pathway, a key player in lung development and repair. Pulmonary expression of TGF beta signaling components, downstream effectors, and extracellular matrix targets were evaluated in CDH neonates who died between birth and the first few weeks of life after prenatal conservative management or TO, and in rabbit pups that were prenatally randomized for surgical CDH and TO vs. sham operation. Before tissue harvesting, lung tissue mechanics in rabbits was measured using the constant phase model during the first 30 min of life. Human CDH and control fetal lungs were also collected from midterm onwards. Human and experimental CDH did not affect TGF-beta/Smad2/3 expression and activity. In human and rabbit CDH lungs, TO upregulated TGF-beta transcripts. Analysis of downstream pathways indicated increased Rho-associated kinases to the detriment of Smad2/3 activation. After TO, subtle accumulation of collagen and alpha-smooth muscle actin within alveolar walls was detected in rabbit pups and human CDH lungs with short-term mechanical ventilation. Despite TO-induced lung growth, mediocre lung tissue mechanics in the rabbit model was associated with increased transcription of extracellular matrix components. These results suggest that prenatal TO increases TGF-beta/Rho kinase pathway, myofibroblast differentiation, and matrix deposition in neonatal rabbit and human CDH lungs. Whether this might influence postnatal development of sustainably ventilated lungs remains to be determined. PMID- 26637633 TI - Pseudomonas aeruginosa exoenzymes U and Y induce a transmissible endothelial proteinopathy. AB - We tested the hypothesis that Pseudomonas aeruginosa type 3 secretion system effectors exoenzymes Y and U (ExoY and ExoU) induce release of a high-molecular weight endothelial tau, causing transmissible cell injury characteristic of an infectious proteinopathy. Both the bacterial delivery of ExoY and ExoU and the conditional expression of an activity-attenuated ExoU induced time-dependent pulmonary microvascular endothelial cell gap formation that was paralleled by the loss of intracellular tau and the concomitant appearance of high-molecular-weight extracellular tau. Transfer of the high-molecular-weight tau in filtered supernatant to naive endothelial cells resulted in intracellular accumulation of tau clusters, which was accompanied by cell injury, interendothelial gap formation, decreased endothelial network stability in Matrigel, and increased lung permeability. Tau oligomer monoclonal antibodies captured monomeric tau from filtered supernatant but did not retrieve higher-molecular-weight endothelial tau and did not rescue the injurious effects of tau. Enrichment and transfer of high molecular-weight tau to naive cells was sufficient to cause injury. Thus we provide the first evidence for a pathophysiological stimulus that induces release and transmissibility of high-molecular-weight endothelial tau characteristic of an endothelial proteinopathy. PMID- 26637635 TI - Angiotensin-(1-7)/mas inhibits apoptosis in alveolar epithelial cells through upregulation of MAP kinase phosphatase-2. AB - Earlier work from this laboratory showed that autocrine generation of angiotensin II and c-Jun-NH2-terminal kinase phosphorylation (p-JNK) are both required events in alveolar epithelial cell (AEC) apoptosis. Although earlier data showed that angiotensin-(1-7) [ANG-(1-7)] protects against AEC apoptosis, the pathways by which ANG-(1-7)/mas activation prevent JNK phosphorylation and apoptosis are poorly understood. Therefore, in the current study, it was theorized that ANG-(1 7) activates a mitogen-activated protein kinase phosphatase (MKP) and thereby reduces JNK phosphorylation to inhibit apoptosis and promote cell survival. This hypothesis was evaluated in the human A549 and mouse MLE12 AEC lines and primary cultures of human AECs. Cells were transfected with small-interfering RNAs, antisense oligonucleotides, or inhibitors specific for MKP-2 or mas, and were then assayed for phospho-JNK, caspase-9, loss of mitochondrial membrane potential, and nuclear fragmentation. Silencing of MKP-2 significantly prevented the blockade of all apoptotic markers by ANG-(1-7). Knockdown or blockade of mas receptor by antisense oligonucleotides or by the receptor antagonist A779, respectively, caused significant decreases in MKP-2, and simultaneously increased the apoptotic markers of caspase-9 activation and nuclear fragmentation. These data show that the ANG-(1-7)/mas pathway constitutively prevents JNK phosphorylation and apoptosis of AECs by maintaining activation of the JNK selective phosphatase MKP-2, and further demonstrate the critical role of the ANG (1-7) receptor mas in AEC survival. PMID- 26637636 TI - Endothelial HIF signaling regulates pulmonary fibrosis-associated pulmonary hypertension. AB - Pulmonary hypertension (PH) complicating chronic parenchymal lung disease, such as idiopathic pulmonary fibrosis, results in significant morbidity and mortality. Since the hypoxia-inducible factor (HIF) signaling pathway is important for development of pulmonary hypertension in chronic hypoxia, we investigated whether HIF signaling in vascular endothelium regulates development of PH related to pulmonary fibrosis. We generated a transgenic model in which HIF is deleted within vascular endothelial cells and then exposed these mice to chronic intraperitoneal bleomycin to induce PH associated with lung fibrosis. Although no differences in the degree of fibrotic remodeling were observed, we found that endothelial HIF-deficient mice were protected against development of PH, including right ventricle and pulmonary vessel remodeling. Similarly, endothelial HIF-deficient mice were protected from PH after a 4-wk exposure to normobaric hypoxia. In vitro studies of pulmonary vascular endothelial cells isolated from the HIF-targeted mice and controls revealed that endothelial HIF signaling increases endothelial cell expression of connective tissue growth factor, enhances vascular permeability, and promotes pulmonary artery smooth muscle cell proliferation and wound healing ability, all of which have the potential to impact the development of PH in vivo. Taken together, these studies demonstrate that vascular endothelial cell HIF signaling is necessary for development of hypoxia and pulmonary fibrosis associated PH. As such, HIF and HIF-regulated targets represent a therapeutic target in these conditions. PMID- 26637637 TI - Augmentation of CFTR maturation by S-nitrosoglutathione reductase. AB - S-nitrosoglutathione (GSNO) reductase regulates novel endogenous S-nitrosothiol signaling pathways, and mice deficient in GSNO reductase are protected from airways hyperreactivity. S-nitrosothiols are present in the airway, and patients with cystic fibrosis (CF) tend to have low S-nitrosothiol levels that may be attributed to upregulation of GSNO reductase activity. The present study demonstrates that 1) GSNO reductase activity is increased in the cystic fibrosis bronchial epithelial (CFBE41o(-)) cells expressing mutant F508del-cystic fibrosis transmembrane regulator (CFTR) compared with the wild-type CFBE41o(-) cells, 2) GSNO reductase expression level is increased in the primary human bronchial epithelial cells expressing mutant F508del-CFTR compared with the wild-type cells, 3) GSNO reductase colocalizes with cochaperone Hsp70/Hsp90 organizing protein (Hop; Stip1) in human airway epithelial cells, 4) GSNO reductase knockdown with siRNA increases the expression and maturation of CFTR and decreases Stip1 expression in human airway epithelial cells, 5) increased levels of GSNO reductase cause a decrease in maturation of CFTR, and 6) a GSNO reductase inhibitor effectively reverses the effects of GSNO reductase on CFTR maturation. These studies provide a novel approach to define the subcellular location of the interactions between Stip1 and GSNO reductase and the role of S-nitrosothiols in these interactions. PMID- 26637639 TI - Use of CT Angiogram in Interventions Involving Coronary Artery Anomalies: A Case Series. AB - BACKGROUND: Coronary artery anomalies are rare, accounting for about 0.3-1.3% of patients undergoing diagnostic coronary angiography. Interventions in these cases are still rare, and therefore pose technical challenges during intervention. CT Angiography provides a non-invasive means of assessment of coronary artery disease and also shows the anatomy of the coronary tree. This helps in knowing the origin of the coronaries and also to plan selection of hardware. There are no specific guidelines for use of guiding catheters and guide wires in anomalous coronary artery intervention. CASE REPORT: We report a series of 5 patients presenting with effort angina who had anomalous coronary arteries with coronary stenosis diagnosed by CT angiography. Three patients received percutaneous intervention, 1 patient underwent CABG, and 1 patient received medical management. CONCLUSIONS: CT Angiography provides a useful tool for showing the coronary anatomy and for selecting the guiding catheter and the guide wire that remain the mainstay of interventions in coronary artery anomalies. PMID- 26637638 TI - Developmental acceleration of bradykinin-dependent relaxation by prenatal chronic hypoxia impedes normal development after birth. AB - Bradykinin-induced activation of the pulmonary endothelium triggers nitric oxide production and other signals that cause vasorelaxation, including stimulation of large-conductance Ca(2+)-activated K(+) (BKCa) channels in myocytes that hyperpolarize the plasma membrane and decrease intracellular Ca(2+). Intrauterine chronic hypoxia (CH) may reduce vasorelaxation in the fetal-to-newborn transition and contribute to pulmonary hypertension of the newborn. Thus we examined the effects of maturation and CH on the role of BKCa channels during bradykinin induced vasorelaxation by examining endothelial Ca(2+) signals, wire myography, and Western immunoblots on pulmonary arteries isolated from near-term fetal (~ 140 days gestation) and newborn, 10- to 20-day-old, sheep that lived in normoxia at 700 m or in CH at high altitude (3,801 m) for >100 days. CH enhanced bradykinin-induced relaxation of fetal vessels but decreased relaxation in newborns. Endothelial Ca(2+) responses decreased with maturation but increased with CH. Bradykinin-dependent relaxation was sensitive to 100 MUM nitro-L arginine methyl ester or 10 MUM 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, supporting roles for endothelial nitric oxide synthase and soluble guanylate cyclase activation. Indomethacin blocked relaxation in CH vessels, suggesting upregulation of PLA2 pathways. BKCa channel inhibition with 1 mM tetraethylammonium reduced bradykinin-induced vasorelaxation in the normoxic newborn and fetal CH vessels. Maturation reduced whole cell BKCa channel alpha1 subunit expression but increased beta1-subunit expression. These results suggest that CH amplifies the contribution of BKCa channels to bradykinin-induced vasorelaxation in fetal sheep but stunts further development of this vasodilatory pathway in newborns. This involves complex changes in multiple components of the bradykinin-signaling axes. PMID- 26637640 TI - Physical Therapists' Ways of Talking About Overweight and Obesity: Clinical Implications. AB - BACKGROUND: How people think and talk about weight is important because it can influence their behavior toward people who are overweight. One study has shown that physical therapists have negative attitudes toward people who are overweight. However, how this finding translates into clinical practice is not well understood. Investigating physical therapists' ways of thinking and speaking about overweight and obesity in the context of their work can provide insight into this underresearched area. OBJECTIVES: The purpose of this study was to investigate physical therapists' ways of talking about overweight individuals and discuss clinical implications. DESIGN: An interpretive qualitative design was used. METHODS: The research team used discourse analysis, a type of inductive qualitative methodology, to guide data collection and analysis. The data came from 6 focus groups of 4 to 6 physical therapists in Queensland, Australia, who discussed weight in a physical therapy environment. Participants (N=27) represented a variety of physical therapy subdisciplines. RESULTS: Data analysis identified 4 main weight discourses (ways of thinking and speaking about weight). Participants described patients who are overweight as little affected by stigma and difficult to treat. Furthermore, participants portrayed weight as having simple causes and being important in physical therapy. Alternate weight discourses were less frequent in these data. CONCLUSIONS: The results indicated that some physical therapists' understandings of weight might lead to negative interactions with patients who are overweight. The findings suggest physical therapists require more nuanced understandings of: how patients who are overweight might feel in a physical therapy setting, the complexity of causes of weight, and possible benefits and disadvantages of introducing weight-management discussions with patients. Therefore, education should encourage complex understandings of working with patients of all sizes, including knowledge of weight stigma. PMID- 26637641 TI - Physical Therapy as Treatment for Childhood Obesity in Primary Health Care: Clinical Recommendation From AXXON (Belgian Physical Therapy Association). PMID- 26637642 TI - Improving Shoulder Kinematics in Individuals With Paraplegia: Comparison Across Circuit Resistance Training Exercises and Modifications in Hand Position. AB - BACKGROUND: Circuit resistance training (CRT) should promote favorable kinematics (scapular posterior tilt, upward rotation, glenohumeral or scapular external rotation) to protect the shoulder from mechanical impingement following paraplegia. Understanding kinematics during CRT may provide a biomechanical rationale for exercise positions and exercise selection promoting healthy shoulders. OBJECTIVE: The purposes of this study were: (1) to determine whether altering hand position during CRT favorably modifies glenohumeral and scapular kinematics and (2) to compare 3-dimensional glenohumeral and scapular kinematics during CRT exercises. HYPOTHESES: The hypotheses that were tested were: (1) modified versus traditional hand positions during exercises improve kinematics over comparable humerothoracic elevation angles, and (2) the downward press demonstrates the least favorable kinematics. DESIGN: This was a cross-sectional observational study. METHODS: The participants were 18 individuals (14 men, 4 women; 25-76 years of age) with paraplegia. An electromagnetic tracking system acquired 3-dimensional position and orientation data from the trunk, scapula, and humerus during overhead press, chest press, overhead pulldown, row, and downward press exercises. Participants performed exercises in traditional and modified hand positions. Descriptive statistics and 2-way repeated-measures analysis of variance were used to evaluate the effect of modifications and exercises on kinematics. RESULTS: The modified position improved kinematics for downward press (glenohumeral external rotation increased 4.5 degrees [P=.016; 95% CI=0.7, 8.3] and scapular external rotation increased 4.4 degrees [P<.001; 95% CI=2.5, 6.3]), row (scapular upward rotation increased 4.6 degrees [P<.001; 95% CI=2.3, 6.9]), and overhead pulldown (glenohumeral external rotation increased 18.2 degrees [P<.001, 95% CI=16, 21.4]). The traditional position improved kinematics for overhead press (glenohumeral external rotation increased 9.1 degrees [P=.001; 95% CI=4.1, 14.1], and scapular external rotation increased 5.5 degrees [P=.004; 95% CI=1.8, 9.2]). No difference existed between chest press positions. Downward press (traditional or modified) demonstrated the least favorable kinematics. LIMITATIONS: It is unknown whether faulty kinematics causes impingement or whether pre-existing impingement causes altered kinematics. Three-dimensional modeling is needed to verify whether "favorable" kinematics increase the subacromial space. CONCLUSIONS: Hand position alters kinematics during CRT and should be selected to emphasize healthy shoulder mechanics. PMID- 26637644 TI - Disability Trajectories in Patients With Complaints of Arm, Neck, and Shoulder (CANS) in Primary Care: Prospective Cohort Study. AB - BACKGROUND: Nontraumatic complaints of arm, neck, and shoulder (CANS) represent an important health issue, with a high prevalence in the general working age population and huge economic impact. Nevertheless, only few prospective cohort studies for the outcome of CANS are available. OBJECTIVES: The purpose of this study was to identify disability trajectories and associated prognostic factors during a 2-year follow-up of patients with a new episode of CANS in primary care. DESIGN: This was a prospective cohort study. METHODS: Data of 682 participants were collected through questionnaires at baseline and every 6 months thereafter. Disability was measured with the Disabilities of the Arm, Shoulder and Hand questionnaire (DASH). Latent class growth mixture (LCGM) modeling was used to identify clinically meaningful groups of patients who were similar in their disability trajectory during follow-up. Multivariate multinomial regression analysis was used to evaluate associations between sociodemographic, complaint related, physical, and psychosocial variables and the identified disability trajectories. RESULTS: Three disability trajectories were identified: fast recovery (67.6%), modest recovery (23.6%), and continuous high disability (8.8%). A high level of somatization was the most important baseline predictor of continuous high disability. Furthermore, poor general health, widespread complaints, and medium level of somatization were associated with this trajectory and >3 months complaint duration, musculoskeletal comorbidity, female sex, history of trauma, low educational level, low social support, and high complaint severity were associated with both continuous high disability and modest recovery. Age, kinesiophobia, and catastrophizing showed significant associations only with modest recovery. LIMITATIONS: Loss to follow-up ranged from 10% to 22% at each follow-up measurement. Disabilities were assessed only with the DASH and not with physical tests. Misclassification by general practitioners regarding specific or nonspecific diagnostic category might have occurred. The decision for optimal LCGM model, resulting in the disability trajectories, remains arbitrary to some extent. CONCLUSIONS: Three trajectories described the course of disabilities due to CANS. Several prognostic indicators were identified that can easily be recognized in primary care. As some of these prognostic indicators may be amenable for change, their presence in the early stages of CANS may lead to more intensive or additional interventions (eg, psychological or multidisciplinary therapy). Further research focusing on the use of these prognostic indicators in treatment decisions is needed to further substantiate their predictive value. PMID- 26637643 TI - Understanding Mechanobiology: Physical Therapists as a Force in Mechanotherapy and Musculoskeletal Regenerative Rehabilitation. AB - Achieving functional restoration of diseased or injured tissues is the ultimate goal of both regenerative medicine approaches and physical therapy interventions. Proper integration and healing of the surrogate cells, tissues, or organs introduced using regenerative medicine techniques are often dependent on the co introduction of therapeutic physical stimuli. Thus, regenerative rehabilitation represents a collaborative approach whereby rehabilitation specialists, basic scientists, physicians, and surgeons work closely to enhance tissue restoration by creating tailored rehabilitation treatments. One of the primary treatment regimens that physical therapists use to promote tissue healing is the introduction of mechanical forces, or mechanotherapies. These mechanotherapies in regenerative rehabilitation activate specific biological responses in musculoskeletal tissues to enhance the integration, healing, and restorative capacity of implanted cells, tissues, or synthetic scaffolds. To become future leaders in the field of regenerative rehabilitation, physical therapists must understand the principles of mechanobiology and how mechanotherapies augment tissue responses. This perspective article provides an overview of mechanotherapy and discusses how mechanical signals are transmitted at the tissue, cellular, and molecular levels. The synergistic effects of physical interventions and pharmacological agents also are discussed. The goals are to highlight the critical importance of mechanical signals on biological tissue healing and to emphasize the need for collaboration within the field of regenerative rehabilitation. As this field continues to emerge, physical therapists are poised to provide a critical contribution by integrating mechanotherapies with regenerative medicine to restore musculoskeletal function. PMID- 26637645 TI - Effect of Contralateral Strength Training on Muscle Weakness in People With Multiple Sclerosis: Proof-of-Concept Case Series. AB - BACKGROUND: The contralateral strength training (CST) effect is a transfer of muscle performance to the untrained limb following training of the contralateral side. OBJECTIVE: The aim of this study was to explore, in individuals with multiple sclerosis (MS) presenting marked lower limb strength asymmetry, the effectiveness of CST on management of muscle weakness of the more-affected limb following training of the less-affected limb. DESIGN: A single-subject research design was used. METHODS: Eight individuals with MS underwent 16 to 18 high intensity training sessions of the less-affected ankle dorsiflexor muscles. The primary outcome measure of this single-system case series was maximal strength expressed as peak moment and maximal work. Secondary outcome measures were: Six Minute-Walk Test, Timed "Up & Go" Test, 10-Meter Timed Walk Test, and Multiple Sclerosis Quality of Life-54 questionnaire. RESULTS: After the 6-week intervention, the contralateral more affected (untrained) limb showed a 22% to 24% increase in maximal strength. From pretest-posttest measurements, participants also performed significantly better on the clinical and functional secondary outcome measures. At the 12-week follow-up, the strength levels of the weaker untrained limb remained significantly superior to baseline levels in the majority (5 out of 8) of the outcome parameters. LIMITATIONS: Considering the design used, the absence of a control group, and the sample size, these findings should be cautiously generalized and will need confirmation in a properly planned randomized controlled trial. CONCLUSIONS: The present proof-of-concept study shows, for the first time, the occurrence of the CST effect on muscle performance of ankle dorsiflexor muscles in people with MS. These preliminary findings reveal new potential implications for CST as a promising rehabilitation approach to those conditions where unilateral muscle weakness does not allow or makes difficult performing conventional strength training of the weaker limb. PMID- 26637646 TI - Criterion Validity of the activPAL Activity Monitor for Sedentary and Physical Activity Patterns in People Who Have Rheumatoid Arthritis. AB - BACKGROUND: Accurate measurement of physical activity and sedentary behavior is an important consideration for health care professionals. The activPAL activity monitor has not been validated against a criterion measure for people with rheumatoid arthritis (RA). OBJECTIVE: The objective of this study was to determine the criterion validity of the activPAL activity monitor for measuring step counts, transition counts, and time spent in sedentary, standing, and walking behaviors in people with RA. DESIGN: A laboratory-based criterion validation study was conducted. METHODS: Participants with a confirmed medical diagnosis of RA were recruited from 2 outpatient rheumatology clinics. The testing procedure consisted of standardized testing components and tasks related to activities of daily living. Participants wore an activPAL activity monitor and were video recorded throughout the testing procedure. Direct observation was used as the criterion measure. Data analysis consisted of validation analysis of the activPAL activity monitor data and the criterion measure data. RESULTS: Twenty four people participated in the study. Data from 20 participants were included in the final analysis. The activPAL significantly underestimated step counts by 26% and transition counts by 36%. There was no significant difference between the activPAL activity monitor and the criterion measure for time spent in sedentary, standing or light activity, and walking behaviors. LIMITATIONS: Validation of activities of daily living in a laboratory environment is a limitation of this study. CONCLUSIONS: The activPAL activity monitor underestimated step and transition counts and, therefore, is not valid for measuring these outcomes in people with RA. Relative to direct observation, the activPAL activity monitor is valid for measuring time spent in sedentary, standing, and walking behaviors in people with RA. PMID- 26637647 TI - Translating Genomic Advances to Physical Therapist Practice: A Closer Look at the Nature and Nurture of Common Diseases. AB - The Human Genome Project and the International HapMap Project have yielded new understanding of the influence of the human genome on health and disease, advancing health care in significant ways. In personalized medicine, genetic factors are used to identify disease risk and tailor preventive and therapeutic regimens. Insight into the genetic bases of cellular processes is revealing the causes of disease and effects of exercise. Many diseases known to have a major lifestyle contribution are highly influenced by common genetic variants. Genetic variants are associated with increased risk for common diseases such as cardiovascular disease and osteoarthritis. Exercise response also is influenced by genetic factors. Knowledge of genetic factors can help clinicians better understand interindividual differences in disease presentation, pain experience, and exercise response. Family health history is an important genetic tool and encourages clinicians to consider the wider client-family unit. Clinicians in this new era need to be prepared to guide patients and their families on a variety of genomics-related concerns, including genetic testing and other ethical, legal, or social issues. Thus, it is essential that clinicians reconsider the role of genetics in the preservation of wellness and risk for disease to identify ways to best optimize fitness, health, or recovery. Clinicians with knowledge of the influence of genetic variants on health and disease will be uniquely positioned to institute individualized lifestyle interventions, thereby fulfilling roles in prevention and wellness. This article describes how discoveries in genomics are rapidly evolving the understanding of health and disease by highlighting 2 conditions: cardiovascular disease and osteoarthritis. Genetic factors related to exercise effects also are considered. PMID- 26637648 TI - Prognostic Models in Adults Undergoing Physical Therapy for Rotator Cuff Disorders: Systematic Review. AB - BACKGROUND: Rotator cuff-related disorders represent the largest subgroup of shoulder complaints. Despite the availability of various conservative and surgical treatment options, the precise indications for these options remain unclear. PURPOSE: The purpose of this systematic review was to synthesize the available research on prognostic models for predicting outcomes in adults undergoing physical therapy for painful rotator cuff disorders. DATA SOURCES: The MEDLINE, EMBASE, CINAHL, Cochrane CENTRAL, and PEDro databases and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) up to October 2015 were searched. STUDY SELECTION: The review included primary studies exploring prognostic models in adults undergoing physical therapy, with or without other conservative measures, for painful rotator cuff disorders. Primary outcomes were pain, disability, and adverse events. Inclusion was limited to prospective investigations of prognostic factors elicited at the baseline assessment. Study selection was independently performed by 2 reviewers. DATA EXTRACTION: A pilot-tested form was used to extract data on key aspects of study design, characteristics, analyses, and results. Risk of bias and applicability were independently assessed by 2 reviewers using the Prediction Study Risk of Bias Assessment tool (PROBAST). DATA SYNTHESIS: Five studies were included in the review. These studies were extremely heterogeneous in many aspects of design, conduct, and analysis. The findings were analyzed narratively. LIMITATIONS: All included studies were rated as at high risk of bias, and none of the resulting prognostic models was found to be usable in clinical practice. CONCLUSIONS: There are no prognostic models ready to inform clinical practice in the context of the review question, highlighting the need for further research on prognostic models for predicting outcomes in adults who undergo physical therapy for painful rotator cuff disorders. The design and conduct of future studies should be receptive to developing methods. PMID- 26637649 TI - Multidisciplinary Biopsychosocial Rehabilitation for Nonspecific Chronic Low Back Pain. PMID- 26637650 TI - Hospital Readmission Following Discharge From Inpatient Rehabilitation for Older Adults With Debility. AB - BACKGROUND: Debility accounts for 10% of inpatient rehabilitation cases among Medicare beneficiaries. Debility has the highest 30-day readmission rate among 6 impairment groups most commonly admitted to inpatient rehabilitation. OBJECTIVE: The purpose of this study was to examine rates, temporal distribution, and factors associated with hospital readmission for patients with debility up to 90 days following discharge from inpatient rehabilitation. DESIGN: A retrospective cohort study was conducted using records for 45,424 Medicare fee-for-service beneficiaries with debility discharged to community from 1,199 facilities during 2006-2009. METHODS: Cox proportional hazard regression models were used to estimate hazard ratios for readmission. Schoenfeld residuals were examined to identify covariate-time interactions. Factor-time interactions were included in the full model for Functional Independence Measure (FIM) discharge motor functional status, comorbidity tier, and chronic pulmonary disease. Most prevalent reasons for readmission were summarized by Medicare severity diagnosis related groups. RESULTS: Hospital readmission rates for patients with debility were 19% for 30 days and 34% for 90 days. The highest readmission count occurred on day 3 after discharge, and 56% of readmissions occurred within 30 days. A higher FIM discharge motor rating was associated with lower hazard for readmissions prior to 60 days (30-day hazard ratio=0.987; 95% confidence interval=0.986, 0.989). Comorbidities with hazard ratios >1.0 included comorbidity tier and 11 Elixhauser conditions, 3 of which (heart failure, renal failure, and chronic pulmonary disease) were among the most prevalent reasons for readmission. LIMITATIONS: Analysis of Medicare data permitted only use of variables reported for administrative purposes. Comorbidity data were analyzed only for inpatient diagnoses. CONCLUSIONS: One-third of patients were readmitted to acute hospitals within 90 days following rehabilitation for debility. Protective effect of greater motor function was diminished by 60 days after discharge from inpatient rehabilitation. PMID- 26637651 TI - Alberta Infant Motor Scale (AIMS) Performance of Greek Preterm Infants: Comparisons With Full-Term Infants of the Same Nationality and Impact of Prematurity-Related Morbidity Factors. AB - BACKGROUND: Only a few studies have been conducted with the objective of creating norms of the Alberta Infant Motor Scale (AIMS) for the assessment of gross motor development of preterm infants. The AIMS performance of preterm infants has been compared with that of the Canadian norms of full-term infants, but not with that of full-term infants of the same nationality. Moreover, the possible impact of prematurity-related morbidity factors on AIMS performance is unknown. OBJECTIVES: The aims of this study were: (1) to evaluate AIMS trajectory in a large population of Greek preterm infants and create norms, (2) to compare it with the AIMS trajectory of Greek full-term infants, and (3) to examine the possible influence of neonatal morbidity on AIMS scores in the preterm sample. DESIGN: This was a cross-sectional study. METHODS: Mean AIMS scores were compared, per month (1-19), between 403 preterm infants (<=32 weeks of age, corrected for prematurity) and 1,038 full-term infants. In preterm infants, the association of AIMS scores with respiratory distress syndrome (RDS), intraventricular hemorrhage (IVH) of grade <=III, bronchopulmonary dysplasia (BPD), retinopathy of prematurity (ROP), and sepsis was assessed by hierarchical regression analysis. RESULTS: Alberta Infant Motor Scale scores were significantly lower in preterm infants than in full-term infants. Mean AIMS scores in preterm infants were significantly associated with RDS (b=-1.93; 95% CI=-2.70, -1.16), IVH (b=-0.97; 95% CI=-1.69, -0.25), and ROP (b=-1.12; 95% CI=-1.99, -0.24) but not with BPD or sepsis in hierarchical regression analysis. CONCLUSIONS: Alberta Infant Motor Scale norms were created for Greek preterm infants. This study confirms that AIMS trajectories of preterm infants are below those of full-term infants of the same nationality. The influence of morbidity factors, including RDS, IVH, and ROP, should be taken into account when administering the AIMS in preterm infants. PMID- 26637652 TI - Locomotor Performance During Rehabilitation of People With Lower Limb Amputation and Prosthetic Nonuse 12 Months After Discharge. AB - BACKGROUND: It is recognized that multifactorial assessments are needed to evaluate balance and locomotor function in people with lower limb amputation. There is no consensus on whether a single screening tool could be used to identify future issues with locomotion or prosthetic use. OBJECTIVE: The purpose of this study was to determine whether different tests of locomotor performance during rehabilitation were associated with significantly greater risk of prosthetic abandonment at 12 months postdischarge. DESIGN: This was a retrospective cohort study. METHOD: Data for descriptive variables and locomotor tests (ie, 10-Meter Walk Test [10MWT], Timed "Up & Go" Test [TUGT], Six-Minute Walk Test [6MWT], and Four Square Step Test [FSST]) were abstracted from the medical records of 201 consecutive participants with lower limb amputation. Participants were interviewed and classified as prosthetic users or nonusers at 12 months postdischarge. The Mann-Whitney U test was used to analyze whether there were differences in locomotor performance. Receiver operating characteristic curves were generated to determine performance thresholds, and relative risk (RR) was calculated for nonuse. RESULTS: At 12 months postdischarge, 18% (n=36) of the participants had become prosthetic nonusers. Performance thresholds, area under the curve (AUC), and RR of nonuse (95% confidence intervals [CI]) were: for the 10MWT, if walking speed was <=0.44 ms( 1) (AUC=0.743), RR of nonuse=2.76 (95% CI=1.83, 3.79; P<.0001); for the TUGT, if time was >=21.4 seconds (AUC=0.796), RR of nonuse=3.17 (95% CI=2.17, 4.14; P<.0001); for the 6MWT, if distance was <=191 m (AUC=0.788), RR of nonuse=2.84, (95% CI=2.05, 3.48; P<.0001); and for the FSST, if time was >=36.6 seconds (AUC=0.762), RR of nonuse=2.76 (95% CI=1.99, 3.39; P<.0001). LIMITATIONS: Missing data, potential recall bias, and assessment times that varied were limitations of the study. CONCLUSIONS: Locomotor performance during rehabilitation may predict future risk of prosthetic nonuse. It may be implied that the 10MWT has the greatest clinical utility as a single screening tool for prosthetic nonuse, given the highest proportion of participants were able to perform this test early in rehabilitation. However, as locomotor skills improve, other tests (in particular, the 6MWT) have specific clinical utility. To fully enable implementation of these locomotor criteria for prosthetic nonuse into clinical practice, validation is warranted. PMID- 26637653 TI - Treatment-Based Classification System for Low Back Pain: Revision and Update. AB - The treatment-based classification (TBC) system for the treatment of patients with low back pain (LBP) has been in use by clinicians since 1995. This perspective article describes how the TBC was updated by maintaining its strengths, addressing its limitations, and incorporating recent research developments. The current update of the TBC has 2 levels of triage: (1) the level of the first-contact health care provider and (2) the level of the rehabilitation provider. At the level of first-contact health care provider, the purpose of the triage is to determine whether the patient is an appropriate candidate for rehabilitation, either by ruling out serious pathologies and serious comorbidities or by determining whether the patient is appropriate for self-care management. At the level of the rehabilitation provider, the purpose of the triage is to determine the most appropriate rehabilitation approach given the patient's clinical presentation. Three rehabilitation approaches are described. A symptom modulation approach is described for patients with a recent-new or recurrent-LBP episode that has caused significant symptomatic features. A movement control approach is described for patients with moderate pain and disability status. A function optimization approach is described for patients with low pain and disability status. This perspective article emphasizes that psychological and comorbid status should be assessed and addressed in each patient. This updated TBC is linked to the American Physical Therapy Association's clinical practice guidelines for low back pain. PMID- 26637654 TI - Concussion Attitudes and Beliefs, Knowledge, and Clinical Practice: Survey of Physical Therapists. AB - BACKGROUND: A concussion is considered a mild traumatic brain injury that may cause physical, cognitive, affective, and sleep dysfunction. Physical therapists have been identified as health care providers involved in the multidisciplinary care of a patient with concussion. OBJECTIVE: The purpose of this study was to describe the current attitudes and beliefs, knowledge, and practice of physical therapists in the treatment of patients with concussion. METHODS: A 55-question electronic survey divided into 6 sections-(1) demographics, (2) current practice in concussion, (3) youth concussion legislation, (4) attitudes and beliefs toward concussion management, (5) concussion knowledge, and (6) clinical decision making was developed and distributed online through selected American Physical Therapy Association sections. RESULTS: A total of 1,272 physical therapists completed the survey. Seventy percent of the respondents (n=894) reported having concussion training. Although supportive of the role of the physical therapist in the treatment of a person with concussion, the respondents demonstrated less confidence when making return-to-play decisions. Respondents correctly answered, on average, 13 (out of 15) concussion knowledge questions, with gaps exhibited in understanding the clinical utilization of concussion severity scales, the conservative treatment of youth who sustain a concussion, and anticipated normal computed tomography and magnetic resonance imaging after a concussion. When provided with clinical scenarios, respondents were able to recognize when a referral to a physician was indicated; however, they demonstrated variability in identifying a need for vestibular or manual physical therapy. LIMITATIONS: Convenience sampling was utilized, limiting generalizability of the results of the study to the physical therapy profession as a whole. CONCLUSION: Physical therapists demonstrated a solid foundation of concussion knowledge, but gaps still existed. Future professional development opportunities should be developed to target identified gaps in knowledge and current practice patterns. PMID- 26637657 TI - Overcoming Antigen Escape with CAR T-cell Therapy. AB - Sotillo and colleagues describe the molecular events associated with apparent loss of target antigen expression following CAR T-cell therapy. We propose that broader immune activation is required to prevent outgrowth of tumor antigen escape variants following targeted therapies. PMID- 26637659 TI - Infection and the Perils of B-cell Activation. AB - Recent studies have linked aberrant B-cell activation in the context of aberrant immune responses to infectious pathogens to malignant transformation and development of leukemia and lymphoma. A new study in this issue demonstrates that common infections can be drivers of clonal evolution of premalignant B-cell precursors toward childhood leukemia. PMID- 26637658 TI - RNF2 E3 or Not to E3: Dual Roles of RNF2 Overexpression in Melanoma. AB - RNF2/RING1B is amplified and overexpressed in numerous tumors and contributes to tumorigenicity; however, the biologic importance is poorly understood. Surprisingly, the role of RNF2 in tumorigenesis and invasion can be separated into catalytically independent and catalytically dependent processes. PMID- 26637660 TI - William E. Paul, M.D. (1936-2015), President, The American Association of Immunologists, 1986-1987. PMID- 26637662 TI - Correction: Langerhans Cells Suppress CD49a+ NK Cell-Mediated Skin Inflammation. PMID- 26637661 TI - The Complement System and Antibody-Mediated Transplant Rejection. AB - Complement activation is an important cause of tissue injury in patients with Ab mediated rejection (AMR) of transplanted organs. Complement activation triggers a strong inflammatory response, and it also generates tissue-bound and soluble fragments that are clinically useful markers of inflammation. The detection of complement proteins deposited within transplanted tissues has become an indispensible biomarker of AMR, and several assays have recently been developed to measure complement activation by Abs reactive to specific donor HLA expressed within the transplant. Complement inhibitors have entered clinical use and have shown efficacy for the treatment of AMR. New methods of detecting complement activation within transplanted organs will improve our ability to diagnose and monitor AMR, and they will also help guide the use of complement inhibitory drugs. PMID- 26637663 TI - Correction: The TNF-Family Ligand TL1A and Its Receptor DR3 Promote T Cell Mediated Allergic Immunopathology by Enhancing Differentiation and Pathogenicity of IL-9-Producing T Cells. PMID- 26637664 TI - Correction: PD-1 Upregulated on Regulatory T Cells during Chronic Virus Infection Enhances the Suppression of CD8+ T Cell Immune Response via the Interaction with PD-L1 Expressed on CD8+ T Cells. PMID- 26637665 TI - Correction: Decreased T Follicular Regulatory Cell/T Follicular Helper Cell (T(FH)) in Simian Immunodeficiency Virus-Infected Rhesus Macaques May Contribute to Accumulation of T(FH) in Chronic Infection. PMID- 26637666 TI - Hierarchal autophagic divergence of hematopoietic system. PMID- 26637667 TI - Control of PD-L1 Expression by Oncogenic Activation of the AKT-mTOR Pathway in Non-Small Cell Lung Cancer. AB - Alterations in EGFR, KRAS, and ALK are oncogenic drivers in lung cancer, but how oncogenic signaling influences immunity in the tumor microenvironment is just beginning to be understood. Immunosuppression likely contributes to lung cancer, because drugs that inhibit immune checkpoints like PD-1 and PD-L1 have clinical benefit. Here, we show that activation of the AKT-mTOR pathway tightly regulates PD-L1 expression in vitro and in vivo. Both oncogenic and IFNgamma-mediated induction of PD-L1 was dependent on mTOR. In human lung adenocarcinomas and squamous cell carcinomas, membranous expression of PD-L1 was significantly associated with mTOR activation. These data suggest that oncogenic activation of the AKT-mTOR pathway promotes immune escape by driving expression of PD-L1, which was confirmed in syngeneic and genetically engineered mouse models of lung cancer where an mTOR inhibitor combined with a PD-1 antibody decreased tumor growth, increased tumor-infiltrating T cells, and decreased regulatory T cells. PMID- 26637670 TI - Is arthroscopy of the knee completely useless? Meta-analysis--a reviewer's nightmare. PMID- 26637668 TI - Recurrent MLK4 Loss-of-Function Mutations Suppress JNK Signaling to Promote Colon Tumorigenesis. AB - MLK4 is a member of the mixed-lineage family of kinases that regulate the JNK, p38, and ERK kinase signaling pathways. MLK4 mutations have been identified in various human cancers, including frequently in colorectal cancer, where their function and pathobiological importance have been uncertain. In this study, we assessed the functional consequences of MLK4 mutations in colon tumorigenesis. Biochemical data indicated that a majority of MLK4 mutations are loss-of-function (LOF) mutations that can exert dominant-negative effects. In seeking to understand the abrogated activity of these mutants, we elucidated a new MLK4 catalytic domain structure. To determine whether MLK4 is required to maintain tumorigenic phenotypes, we reconstituted its signaling axis in colon cancer cells harboring MLK4-inactivating mutations. We found that restoring MLK4 activity reduced cell viability, proliferation, and colony formation in vitro and delayed tumor growth in vivo. Mechanistic investigations established that restoring the function of MLK4 selectively induced the JNK pathway and its downstream targets, cJUN, ATF3, and the cyclin-dependent kinase inhibitors CDKN1A and CDKN2B. Our work indicates that MLK4 is a novel tumor-suppressing kinase harboring frequent LOF mutations that lead to diminished signaling in the JNK pathway and enhanced proliferation in colon cancer. PMID- 26637671 TI - The use of plots in orthopaedic literature. AB - Plots are an elegant and effective way to represent data. At their best they encourage the reader and promote comprehension. A graphical representation can give a far more intuitive feel to the pattern of results in the study than a list of numerical data, or the result of a statistical calculation. The temptation to exaggerate differences or relationships between variables by using broken axes, overlaid axes, or inconsistent scaling between plots should be avoided. A plot should be self-explanatory and not complicated. It should make good use of the available space. The axes should be scaled appropriately and labelled with an appropriate dimension. Plots are recognised statistical methods of presenting data and usually require specialised statistical software to create them. The statistical analysis and methods to generate the plots are as important as the methodology of the study itself. The software, including dates and version numbers, as well as statistical tests should be appropriately referenced. Following some of the guidance provided in this article will enhance a manuscript. PMID- 26637672 TI - Tranexamic acid reduces the blood loss and blood transfusion requirements following peri-acetabular osteotomy. AB - We have investigated the effect of using tranexamic acid (TXA) during peri acetabular osteotomy (PAO) on peri-operative blood loss and blood transfusion requirements. In addition we analysed whether the use of TXA was associated with an increased risk of venous thromboembolism (VTE) following this procedure. A consecutive series of 96 PAOs, performed by a single surgeon, were reviewed. A total of 48 patients received TXA and 48 did not. The TXA group received a continuous infusion of TXA at a rate of 10 mg/kg/h. The primary outcome measure was the requirement for blood transfusion. Secondary outcomes included total blood loss, the decrease in the level of haemoglobin in the blood, the length of hospital stay, and the complications of this treatment. The mean rate of transfusion was significantly lower in the TXA group (62.5% vs 12.5%, p < 0.001). The mean blood loss was also significantly reduced in the TXA group (1.9 L (standard deviation (SD) 0.9) vs 1.5 L (SD 0.7), p < 0.01). No post-operative episodes of VTE were identified in either group. The use of TXA reduced the blood loss and the rate of transfusion after PAO significantly, without adverse effects such as an increased rate of VTE. PMID- 26637673 TI - A randomised controlled trial of cemented and cementless femoral components for metal-on-metal hip resurfacing: a bone mineral density study. AB - The primary purpose of this study of metal-on-metal (MoM) hip resurfacing was to compare the effect of using a cementless or cemented femoral component on the subsequent bone mineral density (BMD) of the femoral neck. This was a single centre, prospective, double-blinded control trial which randomised 120 patients (105 men and 15 women) with a mean age of 49.4 years (21 to 68) to receive either a cemented or cementless femoral component. Follow-up was to two years. Outcome measures included total and six-point region-of-interest BMD of the femoral neck, radiological measurements of acetabular inclination, neck-shaft and stem-shaft angles, and functional outcome scores including the Harris hip score, the Western Ontario and McMaster Universities Osteoarthritis Index and the University of California at Los Angeles activity scale. In total, 17 patients were lost to follow-up leaving 103 patients at two years. There were no revisions in the cementless group and three revisions (5%) in the cemented group (two because of hip pain and one for pseudotumour). The total BMD was significantly higher in the cementless group at six months (p < 0.001) and one year (p = 0.01) than in the cemented group, although there was a loss of statistical significance in the difference at two years (p = 0.155). All patient outcomes improved significantly: there were no significant differences between the two groups. The results show better preservation of femoral neck BMD with a cementless femoral component after two years of follow-up. Further investigation is needed to establish whether this translates into improved survivorship. PMID- 26637674 TI - Do post-operative changes of neck-shaft angle and femoral component anteversion have an effect on clinical outcome following uncemented total hip arthroplasty? AB - The accurate reconstruction of hip anatomy and biomechanics is thought to be important in achieveing good clinical outcomes following total hip arthroplasty (THA). To this end some newer hip designs have introduced further modularity into the design of the femoral component such that neck-shaft angle and anteversion, which can be adjusted intra-operatively. The clinical effect of this increased modularity is unknown. We have investigated the changes in these anatomical parameters following conventional THA with a prosthesis of predetermined neck shaft angle and assessed the effect of changes in the hip anatomy on clinical outcomes. In total, 44 patients (mean age 65.3 years (standard deviation (SD) 7); 17 male/27 female; mean body mass index 26.9 (kg/m2) (SD 3.1)) underwent a pre- and post-operative three-dimensional CT scanning of the hip. The pre- and post operative neck-shaft angle, offset, hip centre of rotation, femoral anteversion, and stem alignment were measured. Additionally, a functional assessment and pain score were evaluated before surgery and at one year post-operatively and related to the post-operative anatomical changes. The mean pre-operative neck-shaft angle was significantly increased by 2.8 degrees from 128 degrees (SD 6.2; 119 degrees to 147 degrees ) to 131 degrees (SD 2.1; 127 degrees to 136 degrees ) (p = 0.009). The mean pre-operative anteversion was 24.9 degrees (SD 8; 7.9 to 39.1) and reduced to 7.4 degrees (SD 7.3; -11.6 degrees to 25.9 degrees ) post operatively (p < 0.001). The post-operative changes had no influence on function and pain. Using a standard uncemented femoral component, high pre- and post operative variability of femoral anteversion and neck-shaft angles was found with a significant decrease of the post-operative anteversion and slight increase of the neck-shaft angles, but without any impact on clinical outcome. PMID- 26637675 TI - Revision of hemiarthroplasty to total hip arthroplasty using the cement-in-cement technique. AB - Revision of a cemented hemiarthroplasty of the hip may be a hazardous procedure with high rates of intra-operative complications. Removing well-fixed cement is time consuming and risks damaging already weak bone or perforating the femoral shaft. The cement-in-cement method avoids removal of intact cement and has shown good results when used for revision total hip arthroplasty (THA). The use of this technique for the revision of a hemiarthroplasty to THA has not been previously reported. A total of 28 consecutive hemiarthroplasties (in 28 patients) were revised to a THA using an Exeter stem and the cement-in-cement technique. There were four men and 24 women; their mean age was 80 years (35 to 93). Clinical and radiographic data, as well as operative notes, were collected prospectively and no patient was lost to follow-up. Four patients died within two years of surgery. The mean follow up of the remainder was 70 months (25 to 124). Intra-operatively there was one proximal perforation, one crack of the femoral calcar and one acetabular fracture. No femoral components have required subsequent revision for aseptic loosening or are radiologically loose. Four patients with late complications (14%) have since undergone surgery (two for a peri-prosthetic fracture, and one each for deep infection and recurrent dislocation) resulting in an overall major rate of complication of 35.7%. The cement-in-cement technique provides reliable femoral fixation in this elderly population and may reduce operating time and rates of complication. PMID- 26637676 TI - Comparison of four different techniques for performing an osteotomy: a biomechanical, radiological and histological study on rabbits tibias. AB - This animal study compares different methods of performing an osteotomy, including using an Erbium-doped Yttrium Aluminum Garnet laser, histologically, radiologically and biomechanically. A total of 24 New Zealand rabbits were divided into four groups (Group I: multihole-drilling; Group II: Gigli saw; Group III: electrical saw blade and Group IV: laser). A proximal transverse diaphyseal osteotomy was performed on the right tibias of the rabbits after the application of a circular external fixator. The rabbits were killed six weeks after the procedure, the operated tibias were resected and radiographs taken. The specimens were tested biomechanically using three-point bending forces, and four tibias from each group were examined histologically. Outcome parameters were the biomechanical stability of the tibias as assessed by the failure to load and radiographic and histological examination of the osteotomy site. The osteotomies healed in all specimens both radiographically and histologically. The differences in the mean radiographic (p = 0.568) and histological (p = 0.71) scores, and in the mean failure loads (p = 0.180) were not statistically significant between the groups. Different methods of performing an osteotomy give similar quality of union. The laser osteotomy, which is not widely used in orthopaedics is an alternative to the current methods. PMID- 26637677 TI - Are lateral compartment osteophytes a predictor for lateral cartilage damage in varus osteoarthritic knees?: Data from the Osteoarthritis Initiative. AB - We studied whether the presence of lateral osteophytes on plain radiographs was a predictor for the quality of cartilage in the lateral compartment of patients with varus osteoarthritic of the knee (Kellgren and Lawrence grade 2 to 3). The baseline MRIs of 344 patients from the Osteoarthritis Initiative (OAI) who had varus osteoarthritis (OA) of the knee on hip-knee-ankle radiographs were reviewed. Patients were categorised using the Osteoarthritis Research Society International (OARSI) osteophyte grading system into 174 patients with grade 0 (no osteophytes), 128 grade 1 (mild osteophytes), 28 grade 2 (moderate osteophytes) and 14 grade 3 (severe osteophytes) in the lateral compartment (tibia). All patients had Kellgren and Lawrence grade 2 or 3 arthritis of the medial compartment. The thickness and volume of the lateral cartilage and the percentage of full-thickness cartilage defects in the lateral compartment was analysed. There was no difference in the cartilage thickness or cartilage volume between knees with osteophyte grades 0 to 3. The percentage of full-thickness cartilage defects on the tibial side increased from < 2% for grade 0 and 1 to 10% for grade 3. The lateral compartment cartilage volume and thickness is not influenced by the presence of lateral compartment osteophytes in patients with varus OA of the knee. Large lateral compartment osteophytes (grade 3) increase the likelihood of full-thickness cartilage defects in the lateral compartment. PMID- 26637678 TI - Knee manipulation under anaesthetic following total knee arthroplasty: a matched cohort design. AB - The purpose of this study was to compare clinical outcomes of total knee arthroplasty (TKA) after manipulation under anaesthesia (MUA) for post-operative stiffness with a matched cohort of TKA patients who did not requre MUA. In total 72 patients (mean age 59.8 years, 42 to 83) who underwent MUA following TKA were identified from our prospective database and compared with a matched cohort of patients who had undergone TKA without subsequent MUA. Patients were evaluated for range of movement (ROM) and clinical outcome scores (Western Ontario and McMaster Universities Arthritis Index, Short-Form Health Survey, and Knee Society Clinical Rating System) at a mean follow-up of 36.4 months (12 to 120). MUA took place at a mean of nine weeks (5 to 18) after TKA. In patients who required MUA, mean flexion deformity improved from 10 degrees (0 degrees to 25 degrees ) to 4.4 degrees (0 degrees to 15 degrees ) (p < 0.001), and mean range of flexion improved from 79.8 degrees (65 degrees to 95 degrees ) to 116 degrees (80 degrees to 130 degrees ) (p < 0.001). There were no statistically significant differences in ROM or functional outcome scores at three months, one year, or two years between those who required MUA and those who did not. There were no complications associated with manipulation. At most recent follow-up, patients requiring MUA achieved equivalent ROM and clinical outcome scores when compared with a matched control group. While other studies have focused on ROM after manipulation, the current study adds to current literature by supplementing this with functional outcome scores. PMID- 26637679 TI - Similar levels of pain are reported in forefoot surgery after management as a day case and admission for 48 hours: A continuous prospective study of 317 patients. AB - While many forefoot procedures may be performed as a day case, there are no specific guidelines as to which procedures are suitable. This study assessed the early post-operative pain after forefoot surgery performed a day case, compared with conventional inpatient management. A total of 317 consecutive operations performed by a single surgeon were included in the study. Those eligible according to the criteria of the French Society of Anaesthesia (SFAR) were managed as day cases (127; 40%), while the remainder were managed as inpatients. The groups were comparable in terms of gender, body mass index and smoking status, although the mean age of the inpatients was higher (p < 0.001) and they had higher mean American Society of Anaesthesiologists scores (p = 0.002). The most severe daily pain was on the first post-operative day, but the levels of pain were similar in the two groups; (4.2/10, SD 2.5 for day cases, 4.4/10, SD 2.4 for inpatients; p = 0.53). Overall, 28 (9%) of patients who had their surgery as a day case and 34 (11%) of inpatients reported extreme pain (>= 8/10). There were more day case patients rather than inpatients that declared their pain disappeared seven days after the surgery (p = 0.02). One day-case patient with excessive bleeding was admitted post-operatively. Apart from the most complicated cases, forefoot surgery can safely be performed as a day case without an increased risk of pain, or complications compared with management as an inpatient. PMID- 26637681 TI - Acromioclavicular joint reconstruction using the LockDown synthetic implant: a study with cadavers. AB - Dislocation of the acromioclavicular joint is a relatively common injury and a number of surgical interventions have been described for its treatment. Recently, a synthetic ligament device has become available and been successfully used, however, like other non-native solutions, a compromise must be reached when choosing non-anatomical locations for their placement. This cadaveric study aimed to assess the effect of different clavicular anchorage points for the Lockdown device on the reduction of acromioclavicular joint dislocations, and suggest an optimal location. We also assessed whether further stability is provided using a coracoacromial ligament transfer (a modified Neviaser technique). The acromioclavicular joint was exposed on seven fresh-frozen cadaveric shoulders. The joint was reconstructed using the Lockdown implant using four different clavicular anchorage points and reduction was measured. The coracoacromial ligament was then transferred to the lateral end of the clavicle, and the joint re-assessed. If the Lockdown ligament was secured at the level of the conoid tubercle, the acromioclavicular joint could be reduced anatomically in all cases. If placed medial or 2 cm lateral, the joint was irreducible. If the Lockdown was placed 1 cm lateral to the conoid tubercle, the joint could be reduced with difficulty in four cases. Correct placement of the Lockdown device is crucial to allow anatomical joint reduction. Even when the Lockdown was placed over the conoid tubercle, anterior clavicle displacement remained but this could be controlled using a coracoacromial ligament transfer. PMID- 26637680 TI - Comparison of ceiling effects between two patient-rating scores and a physician rating score in the assessment of outcome after the surgical treatment of distal radial fractures. AB - We compared the ceiling effects of two patient-rating scores, the Disability of the Arm, Shoulder and Hand (DASH) and Patient-Rated Wrist Evaluation (PRWE), and a physician-rating score, the Modified Mayo Wrist Score (MMWS) in assessing the outcome of surgical treatment of an unstable distal radial fracture. A total of 77 women with a mean age of 64.2 years (50 to 88) who underwent fixation using a volar locking plate for an unstable distal radial fracture between 2011 and 2013 were enrolled in this study. All completed the DASH and PRWE questionnaires one year post-operatively and were assessed using the MMWS by the senior author. The ceiling effects in the outcome data assessed for each score were estimated. The data assessed with both patient-rating scores, the DASH and PRWE, showed substantial ceiling effects, whereas the data assessed with MMWS showed no ceiling effect. Researchers should be aware of a possible ceiling effect in the assessment of the outcome of the surgical treatment of distal radial fractures using patient-rating scores. It could also increase the likelihood of a type II error. PMID- 26637682 TI - The use of a modular system to convert an anatomical total shoulder arthroplasty to a reverse shoulder arthroplasty: Clinical and radiological results. AB - If a modular convertible total shoulder system is used as a primary implant for an anatomical total shoulder arthroplasty, failure of the prosthesis or the rotator cuff can be addressed by converting it to a reverse shoulder arthroplasty (RSA), with retention of the humeral stem and glenoid baseplate. This has the potential to reduce morbidity and improve the results. In a retrospective study of 14 patients (15 shoulders) with a mean age of 70 years (47 to 83) we reviewed the clinical and radiological outcome of converting an anatomical shoulder arthroplasty (ASA) to a RSA using a convertible prosthetic system (SMR system, Lima, San Daniele, Italy). The mean operating time was 64 minutes (45 to 75). All humeral stems and glenoid baseplates were found to be well-fixed and could be retained. There were no intra-operative or early post-operative complications and no post-operative infection. The mean follow-up was 43 months (21 to 83), by which time the mean visual analogue scale for pain had decreased from 8 pre operatively to 1, the mean American Shoulder and Elbow Surgeons Score from 12 to 76, the mean Oxford shoulder score from 3 to 39, the mean Western Ontario Osteoarthritis of the Shoulder Score from 1618 to 418 and the mean Subjective shoulder value from 15 to 61. On radiological review, one patient had a lucency around the humeral stem, two had stress shielding. There were no fatigue fractures of the acromion but four cases of grade 1 scapular notching. The use of a convertible prosthetic system to revise a failed ASA reduces morbidity and minimises the rate of complications. The mid-term clinical and radiological results of this technique are promising. PMID- 26637683 TI - Disproportionate growth between the spine and pelvis in patients with thoracic adolescent scoliosis: a new look into the pattern's growth. AB - A self-control ratio, the spine-pelvis index (SPI), was proposed for the assessment of patients with adolescent idiopathic scoliosis (AIS) in this study. The aim was to evaluate the disproportionate growth between the spine and pelvis in these patients using SPI. A total of 64 female patients with thoracic AIS were randomly enrolled between December 2010 and October 2012 (mean age 13 years, standard deviation (sd) 2.17; 9 to 18) and a further 73 healthy female patients with a mean age of 12.4 years (mean age 12.4 years, sd 2.24; 9 to 18), were randomly selected from a normal control database at our centre. The radiographic parameters measured included length of spine (LOS), height of spine (HOS), length of thoracic vertebrae (LOT), height of thoracic vertebrae (HOT), width of pelvis (WOP), height of pelvis (HOP) and width of thorax (WOT). SPI was defined as the ratio LOS/HOP. The SPI and LOT/HOP in patients with AIS showed a significant increase when compared with normal girls (p < 0.001 and p < 0.001 respectively), implying an abnormal pattern of growth of the spine relative to the pelvis in patients with AIS. No significant difference in SPI was found in different age groups in the control group, making the SPI an age-independent parameter with a mean value of 2.219 (2.164 to 2.239). We also found that the SPI was not related to maturity in the control group. This study, for the first time, used a self control ratio to confirm the disproportionate patterns of growth of the spine and pelvis in patients with thoracic AIS, highlighting that the SPI is not affected by age or maturity. PMID- 26637684 TI - Outcome of surgical treatment of lumbar disc herniation in young individuals. AB - Lumbar disc herniation (LDH) is uncommon in youth and few cases are treated surgically. Very few outcome studies exist for LDH surgery in this age group. Our aim was to explore differences in gender in pre-operative level of disability and outcome of surgery for LDH in patients aged <= 20 years using prospectively collected data. From the national Swedish SweSpine register we identified 180 patients with one-year and 108 with two-year follow-up data <= 20 years of age, who between the years 2000 and 2010 had a primary operation for LDH. Both male and female patients reported pronounced impairment before the operation in all patient reported outcome measures, with female patients experiencing significantly greater back pain, having greater analgesic requirements and reporting significantly inferior scores in EuroQol (EQ-5D-index), EQ-visual analogue scale, most aspects of Short Form-36 and Oswestry Disabilities Index, when compared with male patients. Surgery conferred a statistically significant improvement in all registered parameters, with few gender discrepancies. Quality of life at one year following surgery normalised in both males and females and only eight patients (4.5%) were dissatisfied with the outcome. Virtually all parameters were stable between the one- and two-year follow-up examination. LDH surgery leads to normal health and a favourable outcome in both male and female patients aged 20 years or younger, who failed to recover after non-operative management. PMID- 26637685 TI - Spinal imaging update: an introduction to techniques for advanced MRI. AB - The widespread use of MRI has revolutionised the diagnostic process for spinal disorders. A typical protocol for spinal MRI includes T1 and T2 weighted sequences in both axial and sagittal planes. While such an imaging protocol is appropriate to detect pathological processes in the vast majority of patients, a number of additional sequences and advanced techniques are emerging. The purpose of the article is to discuss both established techniques that are gaining popularity in the field of spinal imaging and to introduce some of the more novel 'advanced' MRI sequences with examples to highlight their potential uses. PMID- 26637686 TI - Ilizarov management of Schatzker IV to VI fractures of the tibial plateau: 105 fractures at a mean follow-up of 7.8 years. AB - This study aimed to determine the long-term functional, clinical and radiological outcomes in patients with Schatzker IV to VI fractures of the tibial plateau treated with an Ilizarov frame. Clinical, functional and radiological assessment was carried out at a minimum of one year post-operatively. A cohort of 105 patients (62 men, 43 women) with a mean age of 49 years (15 to 87) and a mean follow-up of 7.8 years (1 to 19) were reviewed. There were 18 type IV, 10 type V and 77 type VI fractures. All fractures united with a mean time to union of 20.1 weeks (10.6 to 42.3). No patient developed a deep infection. The median range of movement (ROM) of the knee was 110( degrees ) and the median Iowa score was 85. Our study demonstrates good long-term functional outcome with no deep infection; spanning the knee had no detrimental effect on the ROM or functional outcome. High-energy fractures of the tibial plateau may be treated effectively with a fine wire Ilizarov fixator. PMID- 26637687 TI - The prognostic and therapeutic factors which influence the oncological outcome of parosteal osteosarcoma. AB - The aim of this study was to evaluate the prognostic and therapeutic factors which influence the oncological outcome of parosteal osteosarcoma. A total of 80 patients with a primary parosteal osteosarcoma were included in this retrospective study. There were 51 females and 29 males with a mean age of 29.9 years (11 to 78). The mean follow-up was 11.2 years (1 to 40). Overall survival was 91.8% at five years and 87.8% at ten years. Local recurrence occurred in 14 (17.5%) patients and was associated with intralesional surgery and a large volume of tumour. On histological examination, 80% of the local recurrences were dedifferentiated high-grade tumours. A total of 12 (14.8%) patients developed pulmonary metastases, of whom half had either a dedifferentiated tumour or a local recurrence. Female gender and young age were good prognostic factors. Local recurrence was a poor prognostic factor for survival. Medullary involvement or the use of chemotherapy had no impact on survival. The main goal in treating a parosteal osteosarcoma must be to achieve a wide surgical margin, as inadequate margins are associated with local recurrence. Local recurrence has a significant negative effect on survival, as 80% of the local recurrences are high-grade dedifferentiated tumours, and half of these patients develop metastases. The role of chemotherapy in the treatment of parosteal osteosarcoma is not as obvious as it is in the treatment of conventional osteosarcoma. The mainstay of treatment is wide local excision. PMID- 26637688 TI - The radiological evaluation of the hip joint after prosthetic arthroplasty of the proximal femur in patients with a tumour using a bipolar femoral head. AB - Excision of the proximal femur for tumour with prosthetic reconstruction using a bipolar femoral head places a considerable load on the unreplaced acetabulum. We retrospectively reviewed the changes which occur around the affected hip joint by evaluating the post-operative radiographs of 65 consecutive patients who underwent proximal prosthetic arthroplasty of the femur, and in whom an acetabular component had not been used. There were 37 men and 28 women with a mean age of 57.3 years (17 to 93). Radiological assessment included the extent of degenerative change in the acetabulum, heterotopic ossification, and protrusio acetabuli. The mean follow-up was 9.1 years (2 to 11.8). Degenerative changes in the acetabulum were seen in three patients (4.6%), Brooker grade 1 or 2 heterotopic ossification in 17 (26%) and protrusion of the prosthetic head in nine (13.8%). A total of eight patients (12.3%) needed a revision. Five were revised to the same type of prosthesis and three (4.6%) were converted to a total hip arthroplasty. We conclude that radiological evidence of degenerative change, heterotopic ossification and protrusion occur in a few patients who undergo prosthetic arthroplasty of the proximal femur for tumour. The limited extent of these changes and the lack of associated symptoms do not justify the routine arthroplasty of the acetabulum in these patients. PMID- 26637689 TI - The relationship of calcaneal apophyseal ossification and Sanders hand scores to the timing of peak height velocity in adolescents. AB - The accurate assessment of skeletal maturity is essential in the management of orthopaedic conditions in the growing child. In order to identify the time of peak height velocity (PHV) in adolescents, two systems for assessing skeletal maturity have been described recently; the calcaneal apophyseal ossification method and the Sanders hand scores. The purpose of this study was to compare these methods in assessing skeletal maturity relative to PHV. We studied the radiographs of a historical group of 94 healthy children (49 females and 45 males), who had been followed longitudinally between the ages of three and 18 years with serial radiographs and physical examination. Radiographs of the foot and hand were undertaken in these children at least annually between the ages of ten and 15 years. We reviewed 738 radiographs of the foot and 694 radiographs of the hand. PHV was calculated from measurements of height taken at the time of the radiographs. Prior to PHV we observed four of six stages of calcaneal apophyseal ossification and two of eight Sanders stages. Calcaneal stage 3 and Sanders stage 2 was seen to occur about 0.9 years before PHV, while calcaneal stage 4 and Sanders stage 3 occurred approximately 0.5 years after PHV. The stages of the calcaneal and Sanders systems can be used in combination, offering better assessment of skeletal maturity with respect to PHV than either system alone. PMID- 26637690 TI - Outcomes following subcapital osteotomy for severe slipped upper femoral epiphysis. AB - Slipped upper femoral epiphysis (SUFE) is the most common hip disorder to affect adolescents. Controversy exists over the optimal treatment of severe slips, with a continuing debate between in situ fixation versus corrective surgery. We present our experience in a series of 57 patients presenting with severe unilateral SUFE (defined > 50 degrees ) managed with a subcapital cuneiform osteotomy. Between 2001 and 2011, 57 patients (35 male, 22 female) with a mean age of 13.1 years (9.6 to 20.3, SD 2.3) were referred to our tertiary referral institution with a severe slip. The affected limb was rested in slings and springs before corrective surgery which was performed via an anterior Smith Petersen approach. Radiographic analysis confirmed an improvement in mean head shaft slip angle from 53.8( degrees ) (standard deviation (SD) 3.2) pre operatively to 9.1( degrees ) (SD 3.1) post-operatively, with minimal associated femoral neck shortening. In total 50 (88%) patients were complication free at a mean follow-up of seven years (2.8 to 13.9 years, SD 3). Their mean Oxford hip score was 44 (37 to 48) and median visual analogue pain score was 0 out of 10 (interquartile range 0 to 4). A total of six patients (10.5%) developed avascular necrosis requiring further surgery and one (1.8%) patient developed chondrolysis but declined further intervention. This is a technically demanding operation with variable outcomes reported in the literature. We have demonstrated good results in our tertiary centre. PMID- 26637692 TI - Errata/Corrigenda. PMID- 26637691 TI - Resection of a physeal bar with complete transverse osteotomy at the metaphysis and Ilizarov external fixation. AB - The traditional techniques involving an oblique tunnel or triangular wedge resection to approach a central or mixed-type physeal bar are hindered by poor visualisation of the bar. This may be overcome by a complete transverse osteotomy at the metaphysis near the growth plate or a direct vertical approach to the bar. Ilizarov external fixation using small wires allows firm fixation of the short physis-bearing fragment, and can also correct an associated angular deformity and permit limb lengthening. We accurately approached and successfully excised ten central- or mixed-type bars; six in the distal femur, two in the proximal tibia and two in the distal tibia, without damaging the uninvolved physis, and corrected the associated angular deformity and leg-length discrepancy. Callus formation was slightly delayed because of periosteal elevation and stretching during resection of the bar. The resultant resection of the bar was satisfactory in seven patients and fair in three as assessed using a by a modified Williamson Staheli classification. PMID- 26637693 TI - Game of clones: the genomic evolution of severe congenital neutropenia. AB - Severe congenital neutropenia (SCN) is a genetically heterogeneous condition of bone marrow failure usually diagnosed in early childhood and characterized by a chronic and severe shortage of neutrophils. It is now well-established that mutations in HAX1 and ELANE (and more rarely in other genes) are the genetic cause of SCN. In contrast, it has remained unclear how these mutations affect neutrophil development. Innovative models based on induced pluripotent stem cell technology are being explored to address this issue. These days, most SCN patients receive life-long treatment with granulocyte colony-stimulating factor (G-CSF, CSF3). CSF3 therapy has greatly improved the life expectancy of SCN patients, but also unveiled a high frequency of progression toward myelodysplastic syndrome (MDS) and therapy refractory acute myeloid leukemia (AML). Expansion of hematopoietic clones with acquired mutations in the gene encoding the G-CSF receptor (CSF3R) is regularly seen in SCN patients and AML usually descends from one of these CSF3R mutant clones. These findings raised the questions how CSF3R mutations affect CSF3 responses of myeloid progenitors, how they contribute to the pre-leukemic state of SCN, and which additional events are responsible for progression to leukemia. The vast (sub)clonal heterogeneity of AML and the presence of AML-associated mutations in normally aged hematopoietic clones make it often difficult to determine which mutations are responsible for the leukemic process. Leukemia predisposition syndromes such as SCN are unique disease models to identify the sequential acquisition of these mutations and to interrogate how they contribute to clonal selection and leukemic evolution. PMID- 26637694 TI - Iron deficiency: new insights into diagnosis and treatment. AB - Iron deficiency and iron deficiency anemia are common conditions worldwide affecting especially children and young women. In developing countries, iron deficiency is caused by poor iron intake and/or parasitic infection, whereas vegetarian dietary choices, poor iron absorption, and chronic blood loss are common causes in high-income countries. Erythropoiesis stimulating agents can result in functional iron deficiency for erythropoiesis even when stores are iron replete. Diagnosis of iron deficiency is straightforward, except when it occurs in the context of inflammatory disorders. Oral iron salts correct absolute iron deficiency in most patients, because low hepcidin levels facilitate iron absorption. Unfortunately frequent side effects limit oral iron efficacy. Intravenous iron is increasingly utilized, because currently available preparations allow rapid normalization of total body iron even with a single infusion and are effective also in functional iron deficiency and in iron deficiency associated with inflammatory disorders. The evidence is accumulating that these preparations are safe and effective. However, long-term safety issues of high doses of iron need to be further explored. PMID- 26637695 TI - Understanding anemia of chronic disease. AB - The anemia of chronic disease is an old disease concept, but contemporary research in the role of proinflammatory cytokines and iron biology has shed new light on the pathophysiology of the condition. Recent epidemiologic studies have connected the anemia of chronic disease with critical illness, obesity, aging, and kidney failure, as well as with the well-established associations of cancer, chronic infection, and autoimmune disease. Functional iron deficiency, mediated principally by the interaction of interleukin-6, the iron regulatory hormone hepcidin, and the iron exporter ferroportin, is a major contributor to the anemia of chronic disease. Although anemia is associated with adverse outcomes, experimental models suggest that iron sequestration is desirable in the setting of severe infection. Experimental therapeutic approaches targeting interleukin-6 or the ferroportin-hepcidin axis have shown efficacy in reversing anemia in either animal models or human patients, although these agents have not yet been approved for the treatment of the anemia of chronic disease. PMID- 26637696 TI - Diagnosis and treatment of sideroblastic anemias: from defective heme synthesis to abnormal RNA splicing. AB - The sideroblastic anemias are a heterogeneous group of inherited and acquired disorders characterized by the presence of ring sideroblasts in the bone marrow. X-linked sideroblastic anemia (XLSA) is caused by germline mutations in ALAS2. Hemizygous males have a hypochromic microcytic anemia, which is generally mild to moderate and is caused by defective heme synthesis and ineffective erythropoiesis. XLSA is a typical iron-loading anemia; although most patients are responsive to pyridoxine, treatment of iron overload is also important in the management of these patients. Autosomal recessive sideroblastic anemia attributable to mutations in SLC25A38, a member of the mitochondrial carrier family, is a severe disease: patients present in infancy with microcytic anemia, which soon becomes transfusion dependent. Conservative therapy includes regular red cell transfusion and iron chelation, whereas allogenic stem cell transplantation represents the only curative treatment. Refractory anemia with ring sideroblasts (RARS) is a myelodysplastic syndrome characterized mainly by anemia attributable to ineffective erythropoiesis. The clinical course of RARS is generally indolent, but there is a tendency to worsening of anemia over time, so that most patients become transfusion dependent in the long run. More than 90% of these patients carry somatic mutations in SF3B1, a gene encoding a core component of the RNA splicing machinery. These mutations cause misrecognition of 3' splice sites in downstream genes, resulting in truncated gene products and/or decreased expression attributable to nonsense-mediated RNA decay; this explains the multifactorial pathogenesis of RARS. Variants of RARS include refractory cytopenia with multilineage dysplasia and ring sideroblasts, and RARS associated with marked thrombocytosis; these variants involve additional genetic lesions. Inhibitors of molecules of the transforming growth factor-beta superfamily have been shown recently to target ineffective erythropoiesis and ameliorate anemia both in animal models of myelodysplastic syndrome and in RARS patients. PMID- 26637697 TI - The long and short of it: using the new factor products. AB - Hemophilia A (HA) and B (HB) are classified as mild (>5%-40%) moderate (1%-5%) and severe (<1%) disease based on plasma factor activity. Severity of bleeding is commensurate with baseline factor levels in general; however, heterogeneity of bleeding in patients is well described. Recurrent bleeding with painful and disabling musculoskeletal complications is the largest source of morbidity for persons with hemophilia (PWH) but treatment advances through the years has led to improved outcomes. In the early 20(th) century, only whole blood and fresh frozen plasma (FFP) was available to treat bleeding episodes. In 1959, cryoprecipitate was discovered and became an option for treatment of HA in 1965. In the 1970s plasma fractionation led to the first standard half-life (SHL) concentrates. These products ushered in the use prophylactic therapy to prevent bleeding episodes. However, viral contamination slowed the use of prophylaxis until the 1980s when viral attenuation steps increased the safety of plasma concentrates. In the 1990s recombinant concentrates were developed and prophylactic therapy is increasing widely yet not yet universally used. However even with frequent SHL concentrate infusions outcomes are not optimal as PWH spend the majority of time with factor levels below the normal range and are at increased risk for bleeding. In 2014, the first extended half-life (EHL) products were approved for use and have begun to change the landscape of hemophilia care. Challenges of EHL implementation include patient selection, product selection, dose and schedule of infusions, monitoring for safety, efficacy and outcomes, and managing economic aspects of care. PMID- 26637698 TI - Emerging genetic and pharmacologic therapies for controlling hemostasis: beyond recombinant clotting factors. AB - For more than 3 decades, the scientific community has pursued gene correction of hemophilia, with the goal that an individual with congenitally deficient factor VIII or factor IX might synthesize adequate endogenous clotting factor to be relieved of burdensome repeated clotting factor infusions, as well as the emotional weight of continuous hemorrhage risk. Recent reports of successful factor IX gene therapy and partial correction of the bleeding phenotype have raised the bar for success for a robust crop of new clinical gene therapy efforts for both hemophilia A and B. At the same time that gene therapy is gaining momentum, suggesting the possibility of relief from regular intravenous coagulation protein replacement, a number of innovative technologies that enhance hemostatic potential independently of replacement factor administration are demonstrating success in human clinical application. Human clinical trial progress is reviewed regarding a recombinant bispecific IgG antibody to factors IXa and X that mimics factor VIII cofactor activity, as well as monoclonal antibody and short interfering RNA strategies that demonstrate hemostatic efficacy via opposing inhibitors of coagulation. These strategies, associated with prolonged hemostatic potential following subcutaneous (ACE910, ALN-AT3, Concizumab) or single administration (eg, gene therapy) make it possible to imagine a day when recombinant clotting factor administration, rather than being a daily preoccupation, is relegated to an adjunctive role in supporting more novel standard of care therapies. PMID- 26637699 TI - Managing older patients with hemophilia. AB - With access to safe factor products, the life expectancy of persons with hemophilia (PWHs) has increased almost 10-fold over the past 7 decades. Unfortunately, hand in hand with this success comes the burden of aging. As PWHs age, they are subject to develop many of the same risk factors as the general population, including increasing rates of hypertension, obesity, and diabetes. Such comorbidities predispose them to chronic diseases, such as cardiovascular disease and chronic kidney disease, although how their coagulopathy affects the expression of these conditions remains unclear. The older hemophilia population faces additional challenges, such as chronic joint arthropathy, which provokes falls and fractures, and complications related to HIV and hepatitis C infections, which greatly affect the incidence of cancer and liver disease. In light of the paucity of evidence-based guidelines to direct therapy, a new challenge has arisen for hematologists to optimally manage these complex age-related issues. In general, elderly PWHs should be treated similarly to their peers without hemophilia, with the addition of factor replacement therapy as appropriate. Primary prevention of risk factors should be emphasized, and close coordination between specialties is essential. This review will focus on common complications affecting the older hemophilia population, including cardiovascular disease, malignancy, liver disease, renal insufficiency, and joint disease. PMID- 26637700 TI - Perinatal thrombosis: implications for mothers and neonates. AB - Stroke is more likely to occur in the perinatal period than any other time in childhood, and these events can lead to a lifetime of intellectual and motor disabilities, epilepsy, and behavioral challenges. This review describes the epidemiology and natural history of perinatal arterial ischemic stroke (PAIS) and cerebral sinovenous thrombosis (CSVT), risk factors for these complications, recent evidence regarding treatment strategies, and current gaps in knowledge. Existing evidence demonstrates the multifactorial etiology of symptomatic ischemic stroke in neonates, which includes a combination of maternal, delivery, and neonatal factors. The importance of inherited thrombophilia in the pathophysiology and long-term outcomes of perinatal stroke requires additional study. At this time, there is no evidence to support routine extensive thrombophilia screening outside of a research setting. Despite the frequency of perinatal stroke and its association with substantial morbidity, treatment strategies are currently limited, and prevention strategies are nonexistent. Anticoagulation is rarely indicated in PAIS, and more work needs to focus on neuroprotective prevention and alternate treatment strategies. Anticoagulation does appear to be safe in CSVT and may prevent thrombus progression but clinical equipoise remains, and clinical trials are needed to obtain evidence regarding short- and long-term efficacy outcomes. PMID- 26637702 TI - Mechanical circulatory support: balancing bleeding and clotting in high-risk patients. AB - Mechanical circulatory support (MCS) provides a bridge to heart transplant in children and adults with life-threatening heart failure and sustains patients ineligible for transplant. Extracorporeal membrane oxygenation (ECMO) provides temporary support for patients in cardiac or pulmonary failure through external gas exchange and continuous flow of blood. Because the median time to heart transplant exceeds event-free time on ECMO, pulsatile left ventricular assist devices (LVADs) are used to support infants and children. Continuous flow LVADs are preferred in adolescents and adults due to increased pump durability and improved overall survival. The shear stress created by the mechanical pumps cause changes in the hematologic system; acquired von Willebrand syndrome occurs in almost all patients treated with MCS. Despite the improvements in survival, major bleeding occurs in one-third of patients with a LVAD and ischemic stroke and LVAD thrombosis can affect 12% of adults and 29% of children. An antithrombotic strategy to mitigate LVAD bleeding and thrombotic complications has been tested in a randomized trial in children, but intensity of antithrombotic therapy in adults varies widely. Consensus guidelines for antithrombotic therapy during ECMO were created due to significant differences in management across centers. Because of the high risk for both bleeding and thrombotic complications, experts in hemostasis can significantly impact care of patients requiring mechanical circulatory support and are a necessary part of the management team. PMID- 26637701 TI - The antiphospholipid syndrome: still an enigma. AB - Antiphospholipid syndrome (APS) is defined by clinical manifestations that include thrombosis and/or fetal loss or pregnancy morbidity in patients with antiphospholipid antibodies (aPL). Antiphospholipid antibodies are among the most common causes of acquired thrombophilia, but unlike most of the genetic thrombophilias are associated with both venous and arterial thrombosis. Despite an abundance of clinical and basic research on aPL, a unified mechanism that explains their prothrombotic activity has not been defined; this may reflect the heterogeneity of aPL and/or the fact that they may influence multiple pro- and/or antithrombotic pathways. Antiphospholipid antibodies are directed primarily toward phospholipid binding proteins rather than phospholipid per se, with the most common antigenic target being beta2-glycoprotein 1 (beta2GPI) although antibodies against other targets such as prothrombin are well described. Laboratory diagnosis of aPL depends upon the detection of a lupus anticoagulant (LA), which prolongs phospholipid-dependent anticoagulation tests, and/or anticardiolipin and anti-beta2-glycoprotein 1 antibodies. Indefinite anticoagulation remains the mainstay of therapy for thrombotic APS, although new strategies that may improve outcomes are emerging. Preliminary reports suggest caution in the use of direct oral anticoagulants in patients with APS-associated thrombosis. Based on somewhat limited evidence, aspirin and low molecular weight heparin are recommended for obstetrical APS. There remains a pressing need for better understanding of the pathogenesis of APS in humans, for identification of clinical and laboratory parameters that define patients at greatest risk for APS related events, and for targeted treatment of this common yet enigmatic disorder. PMID- 26637703 TI - Checkpoint blockade in lymphoma. AB - Immune checkpoint blockade therapy (CBT) was born of the combination of several elements: the understanding of some of the important immune regulation pathways in humans; the recognition that tumors can engage those pathways to evade immune responses; and the clinical development of monoclonal antibodies targeting checkpoint receptors to restore effective anti-tumor immunity. This form of therapy, focused to date mostly on the cytotoxic T-lymphocyte associated protein 4 (CTLA-4) and programmed-death 1 (PD-1) pathways, has already revolutionized the treatment of several solid tumors. Hematologic malignancies (HMs) offer a promising testing ground for this strategy, and several trials have already demonstrated evidence of therapeutic activity with checkpoint blockade, especially in lymphoma. This review will discuss the current clinical results of CBT in lymphoma in the context of their scientific underpinning, and build from this summary a projection of how the field may evolve in the near future. PMID- 26637704 TI - What is the role of autologous transplant for lymphoma in the current era? AB - The role of autologous hematopoietic stem cell transplantation (ASCT) in the management of non-Hodgkin's lymphoma (NHL) is evolving, in the era of novel agents. Multiple histologies and remission stages have been impacted with changing outcomes. In the 1990s, ASCT could cure 50% of relapsed chemosensitive aggressive NHL; now the percentage maybe as low as 20% for patients relapsing within 1 year of completing rituximab-containing induction. Yet recent trials have clarified the value of first remission ASCT for high-grade NHL, the utility of augmented preparative regimens, the efficacy of ASCT in primary CNS lymphoma and in the elderly and analyses have defined strategies to reduce transplant related myeloid malignancies. In addition, optimizing nontransplant induction therapy for mantle cell and double-hit NHL is leading to improved outcomes and a re-examination of the use of ASCT in first complete remission. Caution is needed, however, as delaying transplants may mean that patients will need more morbid allogeneic transplants to achieve long-term control of refractory disease. As an alternative, maintenance therapy trials to improve ASCT outcome in high-risk patients are starting, based on the efficacy of lenolidomide and brentuximab in myeloma and Hodgkin's lymphoma, respectively. In addition, efforts to define early high-risk patients by minimal residual disease (MRD) assessments and genetic profiling, are beginning even for those with "indolent" phenotypes not currently autotransplanted. These efforts should not only refine but also enhance the value of early potentially curative ASCT, especially if novel agents only delay but do not prevent relapse for patients with NHL. PMID- 26637706 TI - Eosinophilia: a pragmatic approach to diagnosis and treatment. AB - Eosinophilia is associated with a wide variety of allergic, rheumatologic, infectious, neoplastic, and rare idiopathic disorders. Clinical manifestations range from benign asymptomatic presentations to life-threatening complications, including endomyocardial fibrosis and thromboembolism. The prognosis and choice of treatment depend not only on the degree of eosinophilia and severity of organ involvement, but also on the etiology of the eosinophilia. Unfortunately, despite recent advances in molecular and immunologic techniques, the etiology remains unproven in the overwhelming majority of cases. This review presents a practical approach to the diagnosis and treatment of patients presenting with unexplained marked eosinophilia. A brief overview of the mechanisms of eosinophilia and eosinophil pathogenesis is also provided. PMID- 26637705 TI - B-cell receptor pathway modulators in NHL. AB - With the recent success of the Bruton's tyrosine kinase (BTK) inhibitor, ibrutinib, and the phosphoinositide-3-kinase (PI3K) inhibitor, idelalisib, in the treatment of patients with relapsed or refractory non-Hodgkin's lymphoma (NHL), a number of new agents targeting the B-cell receptor (BCR) pathway are in clinical development. In addition, multiple trials combining these agents with conventional cytotoxic chemotherapy, immunomodulatory agents, monoclonal antibodies, or other kinase inhibitors are underway. This review will summarize the current data with the use of single agent and combination therapy with BCR inhibitors in NHL. In addition, commonly encountered as well as serious toxicities and hypothesized resistance mechanisms will be discussed. Lastly, this review will examine the future of these agents and opportunities to maneuver them into the front-line setting in selected NHL subtypes. PMID- 26637707 TI - Diagnosis and management of mastocytosis: an emerging challenge in applied hematology. AB - Mastocytosis is a unique and rare neoplasm defined by abnormal expansion and accumulation of clonal mast cells (MCs) in one or multiple organ systems. Most adult patients are diagnosed to have systemic mastocytosis (SM). Based on histological findings and disease-related organ damage, SM is classified into indolent SM (ISM), smoldering SM (SSM), SM with an associated hematologic non-MC lineage disease (SM-AHNMD), aggressive SM (ASM), and MC leukemia (MCL). The clinical picture, course, and prognosis vary profoundly among these patients. Nonetheless, independent of the category of SM, neoplastic cells usually exhibit the KIT point-mutation D816V. However, in advanced SM, additional molecular defects are often detected and are considered to contribute to disease progression and drug resistance. These lesions include, among others, somatic mutations in TET2, SRSF2, ASXL1, CBL, RUNX1, and RAS. In SM-AHNMD, such mutations are often found in the "AHNMD component" of the disease. Clinical symptoms in mastocytosis result from (1) the release of proinflammatory and vasoactive mediators from MCs, and (2) SM-induced organ damage. Therapy of SM has to be adjusted to the individual patient and the SM category: in those with ISM and SSM, the goal is to control mediator secretion and/or mediator effects, to keep concomitant allergies under control, and to counteract osteoporosis, whereas in advanced SM (ASM, MCL, and SM-AHNMD) anti-neoplastic drugs are prescribed to suppress MC expansion and/or to keep AHNMD cells under control. Novel drugs directed against mutated KIT and/or other oncogenic kinase targets are tested currently in these patients. In rapidly progressing and drug-resistant cases, high-dose polychemotherapy and stem cell transplantation have to be considered. PMID- 26637708 TI - Lymphocytosis, lymphadenopathy: benign or malignant? AB - The increasing use of immunophenotypic and molecular analysis in the routine evaluation of patients with lymphocytosis, lymphadenopathy, or other hematologic disorders has led to the identification of unexpected small clonal lymphoid populations. These clones, sometimes with disease-specific markers, such as the t(14;18), are especially challenging for the clinician because of their unknown biologic potential and uncertain clinical behavior. Study of these early lymphoid lesions is providing important clues to the process of lymphomagenesis, and may provide the rationale for preemptive therapy in the future. More and more, the hematologist/oncologist is consulted regarding otherwise healthy individuals with lymphadenopathy and/or lymphocytosis, and pathology reports that confound the referring internist or surgeon. The report does not name a malignant lymphoproliferative disorder, but is not completely "normal". Does the patient have a benign or malignant condition? How should they be evaluated? Is treatment indicated? These patients prove challenging for the consulting hematologist as well as the referring physician. In this review, we will focus on some of these scenarios and attempt to provide guidance for their management. PMID- 26637709 TI - Anticoagulants in children and adolescents. AB - Thrombotic complications are increasing at a steady and significant rate in children, resulting in the more widespread use of anticoagulation in this population. Anticoagulant drugs in children can be divided into the older multitargeted agents (heparin, low-molecular-weight heparin, and warfarin) and the newer targeted agents (argatroban, bivalirudin, and fondaparinux). This review will compare and contrast the multitargeted and targeted anticoagulants and suggest situations in which it may be appropriate to use argatroban, bivalirudin, and fondaparinux. The various agents differ in their pharmacokinetics, requirements for therapeutic drug monitoring, frequency of administration, efficacy, and adverse effects. The targeted anticoagulants have properties that may make them more attractive for use in specific clinical situations. Prospective clinical trial data are presented supporting the current and future use of these agents in children. PMID- 26637710 TI - Monitoring and reversal of direct oral anticoagulants. AB - Although the direct oral anticoagulants (DOACs) do not require routine monitoring and reduce bleeding compared with warfarin, there are special circumstances in which laboratory measurement or reversal of their anticoagulant effect may be indicated. The dilute thrombin time and ecarin-based assays are able to quantify dabigatran across a broad range of concentrations, but are not widely available. A normal thrombin time excludes clinically relevant levels and a normal activated partial thromboplastin time probably excludes excess levels of dabigatran. Factor Xa inhibitors may be quantified with an anti-Xa assay calibrated with drug specific standards. A normal prothrombin time probably excludes excess levels of rivaroxaban and edoxaban, but not apixaban. Patients with minor and moderate DOAC associated bleeding can be treated with supportive care and general hemostatic measures. Nonspecific reversal agents (eg, prothrombin complex concentrate, activated prothrombin complex concentrate) are of unproven benefit, carry a risk of thrombosis, and should be reserved for severe bleeding. Specific reversal agents, such as idarucizumab (a monoclonal antibody fragment that binds dabigatran) and andexanet alfa (a recombinant factor Xa variant that binds factor Xa inhibitors but lacks coagulant activity), are in clinical development. PMID- 26637711 TI - Using direct oral anticoagulants (DOACs) in cancer and other high-risk populations. AB - The major practical advantage of the direct oral anticoagulants (DOACs), comprising the thrombin inhibitor dabigatran and the factor Xa inhibitors apixaban, edoxaban, and rivaroxaban, over vitamin K antagonists is their fixed dosing without the need for laboratory monitoring. With the recent, rapid introduction of the DOACs for the treatment of acute venous thromboembolism (VTE), clinicians are now faced with various questions regarding the efficacy and safety of these compounds overall and in specific high-risk populations. The collective evidence from 6 large clinical trials involving 27,000 patients has demonstrated that DOACs are as effective as vitamin K antagonists (VKA) in preventing recurrent VTE while being associated with a significantly lower risk of major bleeding. These findings are consistent in subgroups of patients with pulmonary embolism, the elderly, and those patients with a high body weight or moderate renal insufficiency, making these agents suitable for a broad spectrum of patients with VTE. DOACs are also an attractive treatment option in patients with VTE and concomitant cancer, thrombotic antiphospholipid syndrome, or heparin induced thrombocytopenia, but the currently available clinical data is insufficient to make evidence-based recommendations on the use of DOACs in these settings. Several studies evaluating the efficacy and safety of DOACs in these high-risk populations are underway. PMID- 26637712 TI - Postpartum hemorrhage: a continuing challenge. AB - Obstetric hemorrhage remains a leading cause of maternal morbidity and mortality worldwide. Many postpartum hemorrhages (PPHs) do not have identifiable risk factors; maternity units should therefore have obstetric hemorrhageprotocols in place for all parturients as every pregnancy has the potential to be complicated by hemorrhage. This review will examine the epidemiology of PPH as well as current recommendations for key elements in obstetric hemorrhage protocols. Recent advances in hematologic management of PPH will be also be reviewed, including: (1) recognition of hypofibrinogenemia as a risk factor for severe PPH, (2) use of antifibrinolytic therapy, and (3) strategies for fibrinogen replacement therapy. PMID- 26637713 TI - Fertility issues in patients with hematologic malignancies. AB - An essential component of a cancer patient's comprehensive care is addressing potential threats to his or her reproductive health. Providers should discuss the risk of infertility with newly diagnosed patients and offer the chance to consult with a reproductive specialist as early as possible. Standard fertility preservation options include embryo or oocyte cryopreservation for women and sperm banking for men; all options for pre-pubertal children are experimental. Patients with hematologic malignancies are a distinct population in whom standard options may present special challenges, and alternative management strategies are being explored. Unique approaches in hematologic malignancy patients include experimental techniques, such as hormonal therapy, referrals to reproductive specialists after cancer treatment, or discontinuation of tyrosine kinase inhibitor therapy in appropriate chronic myelogenous leukemia patients. Importantly, expedited communication between hematologists and reproductive specialists may greatly enhance the quality of care for these patients. Facilitation of referrals will both improve the quality-of-life and expand the prospect of parenthood in survivors. There are ample opportunities to advance the field of oncofertility through additional research, especially in hematologic malignancy patients. PMID- 26637714 TI - Hemolytic disease of the fetus and newborn: managing the mother, fetus, and newborn. AB - Hemolytic disease of the fetus and newborn (HDFN) affects 3/100 000 to 80/100 000 patients per year. It is due to maternal blood group antibodies that cause fetal red cell destruction and in some cases, marrow suppression. This process leads to fetal anemia, and in severe cases can progress to edema, ascites, heart failure, and death. Infants affected with HDFN can have hyperbilirubinemia in the acute phase and hyporegenerative anemia for weeks to months after birth. The diagnosis and management of pregnant women with HDFN is based on laboratory and radiographic monitoring. Fetuses with marked anemia may require intervention with intrauterine transfusion. HDFN due to RhD can be prevented by RhIg administration. Prevention for other causal blood group specificities is less studied. PMID- 26637715 TI - Using genetic diagnostics in hemophilia and von Willebrand disease. AB - Most bleeding disorders encountered in clinical practice will be diagnosed, at least initially, by phenotypic assays. However, since the characterization of the genes that encode coagulation factors in the 1980s, significant progress has been made in translating this knowledge for diagnostic and therapeutic purposes. For hemophilia A and B, molecular genetic testing to determine carrier status, prenatal diagnosis, and likelihood of inhibitor development or anaphylaxis to infused coagulation factor concentrates is an established component of comprehensive clinical management. In contrast, although significant recent advances in our understanding of the molecular genetic basis of von Willebrand disease (VWD) have allowed for the development of rational approaches to genetic diagnostics, questions remain about this complex genetic disorder and how to incorporate emerging knowledge into diagnostic strategies. This article will review the state-of-the-art for molecular diagnostics for both hemophilia and VWD. PMID- 26637717 TI - Using red blood cell genomics in transfusion medicine. AB - Blood types (blood group antigens) are heritable polymorphic antigenic molecules on the surface of blood cells. These were amongst the first human Mendelian traits identified, and the genetic basis of nearly all of the hundreds of blood types is known. Clinical laboratory methods have proven useful to identify selected blood group gene variants, and use of genetic blood type information is becoming widespread. However, the breadth and complexity of clinically relevant blood group genetic variation poses challenges. With recent advances in next generation sequencing technologies, a more comprehensive DNA sequence-based genetic blood typing approach is now feasible. This chapter introduces the practitioner to high-resolution genetic blood typing beginning with an overview of the genetics of blood group antigens, the clinical problem of allosensitization, current blood type testing methods, and then discussion of next-generation sequencing and its application to the problem of genetic blood typing. PMID- 26637716 TI - Sickle cell trait diagnosis: clinical and social implications. AB - The sickle hemoglobin (HbS) point mutation has independently undergone evolutionary selection at least five times in the world because of its overwhelming malarial protective effects in the heterozygous state. In 1949, homozygous Hb S or sickle cell disease (SCD) became the first inherited condition identified at the molecular level; however, since then, both SCD and heterozygous Hb S, sickle cell trait (SCT), have endured a long and complicated history. Hasty adoption of early mass screening programs for SCD, recent implementation of targeted screening mandates for SCT in athletics, and concerns about stigmatization have evoked considerable controversy regarding research and policy decisions for SCT. Although SCT is a largely protective condition in the context of malaria, clinical sequelae, such as exercise-related injury, renal complications, and venous thromboembolism can occur in affected carriers. The historical background of SCD and SCT has provided lessons about how research should be conducted in the modern era to minimize stigmatization, optimize study conclusions, and inform genetic counseling and policy decisions for SCT. PMID- 26637718 TI - Pathophysiology and epidemiology of hemophagocytic lymphohistiocytosis. AB - Hemophagocytic lymphohistiocytosis (HLH) is a syndrome characterized by extreme immune activation, resulting in pathologic inflammation. The diagnosis includes a spectrum of inherited or acquired defects in cytotoxic lymphocyte function, often with uncontrolled infections. HLH may also arise as the result of persistent antigen stimulation due to autoimmune disease or malignancy. HLH is often described in binary terms as "primary," indicating Mendelian inheritance of gene mutations resulting in cytotoxic lymphocyte dysfunction, or "secondary" indicating an acquired reactive disorder. Increasing evidence describes HLH as more complex phenomenon, resulting from specific immune challenges in patients with a susceptible genetic background. Early recognition of HLH and evaluation of potential causes is critically important, as survival generally requires urgent treatment with immune suppression and resolution of the activating antigen. However, the diagnosis of HLH is challenged by the myriad of pathways that lead to pathologic inflammation and the clinical overlap with other conditions. Further improvements in therapy will require prospective trials to define optimal strategies for each patient based on the individual paths that lead to pathologic inflammation. PMID- 26637719 TI - The unique aspects of presentation and diagnosis of hemophagocytic lymphohistiocytosis in adults. AB - Hemophagocytic lymphohistiocytosis (HLH) was initially described as an inflammatory condition affecting young children but is increasingly diagnosed in adults. Presenting features such as fever, cytopenias, phagocytosis, elevated ferritin, and increased levels of soluble IL-2 receptor are common in both age groups, but the prevalence of several clinical and biochemical criteria differ between pediatric and adult patients. Specifically, an elevated ferritin level does not have the same specificity for HLH in adults, and many other inflammatory conditions need to be considered in the differential. In contrast to the high incidence of infectious triggers seen in pediatric HLH, HLH in adults is often precipitated by a hematologic malignancy. Malignancy-associated HLH has unique manifestations and a uniformly very poor prognosis. Given these differences, diagnostic scoring systems unique to adult HLH have been proposed, and additional prognostic clinical and immunologic parameters are being explored. Although a genetic predisposition is increasingly found to underlie cases of adult-onset HLH, the mutations are less likely to be bi-allelic and differ slightly from those seen in pediatric cases of familial HLH. The facilitating genetic and environmental factors governing presentation of HLH in adults remain elusive. Understanding the clinical aspects and pathophysiology specific to adults with HLH is necessary to tailor therapies derived in pediatric disease to this under recognized population. PMID- 26637720 TI - Treatment of hemophagocytic lymphohistiocytosis in adults. AB - Treatment of hemophagocytic lymphohistiocytosis (HLH) has been developed primarily in pediatric centers, where familial HLH (FHL) is the leading cause of HLH in newborns and toddlers. The Histiocyte Society Study Group for HLH developed the HLH-94 and HLH-2004 treatment protocols, and these are frequently also used by centers treating HLH in adults (aHLH). These protocols contain etoposide, dexamethasone, and cyclosporine A; these agents all have strong activity against proliferation of cytotoxic T/NK-cells and macrophages, as well as inhibitory activity against the cytokine storm that induces, and maintains HLH. In children with predominantly hereditary disease, the HLH-94 protocol can be regarded as a "one size fits all" algorithm. HLH in adults is a much more heterogeneous syndrome requiring a more individualized approach depending on the underlying trigger, disease severity and course, as well as genetic background. Additionally, treatment in adults usually needs to be modified in the face of the preceding disease history and comorbidities. Interdisciplinary patient care with rheumatologists, gastroenterologists, neurologists, pediatricians, the transplant team, and pathologists is a prerequisite to successful treatment. The preferred approach should reflect a disease- and risk-adapted treatment that includes rigorous supportive care with continuous reassessment of sequential therapeutic measures. It should be recognized that the algorithm of HLH treatment in adults is based more on expert opinion than on extensive scientific evidence. PMID- 26637721 TI - Incidentally found pulmonary embolism: what's the clinician to do? AB - Incidental pulmonary embolism (IPE) is a management challenge for the unsuspecting clinician. Patients with IPE frequently have signs or symptoms that are unrecognized as PE related, and their clots occur predominantly in the proximal pulmonary vasculature. There is uniformity in recommending anticoagulation for patients with IPE proximal to the subsegmental pulmonary vasculature, but prospective data are not currently available to guide the duration of therapy in this population. Several studies suggest that outcomes, including recurrence, mortality, and bleeding, are similar for patients with IPE and suspected PE, especially among those who also have cancer. Patients with isolated incidental subsegmental pulmonary embolism (ISSPE) are particularly challenging because some studies suggest that they can be managed without anticoagulation. Therefore, an algorithm is proposed to guide the evaluation and treatment of patients with ISSPE. PMID- 26637722 TI - Current challenges in diagnostic imaging of venous thromboembolism. AB - Because the clinical diagnosis of deep-vein thrombosis and pulmonary embolism is nonspecific, integrated diagnostic approaches for patients with suspected venous thromboembolism have been developed over the years, involving both non-invasive bedside tools (clinical decision rules and D-dimer blood tests) for patients with low pretest probability and diagnostic techniques (compression ultrasound for deep-vein thrombosis and computed tomography pulmonary angiography for pulmonary embolism) for those with a high pretest probability. This combination has led to standardized diagnostic algorithms with proven safety for excluding venous thrombotic disease. At the same time, it has become apparent that, as a result of the natural history of venous thrombosis, there are special patient populations in which the current standard diagnostic algorithms are not sufficient. In this review, we present 3 evidence-based patient cases to underline recent developments in the imaging diagnosis of venous thromboembolism. PMID- 26637723 TI - Venous clot lysis and stenting. AB - Venous thromboembolism (VTE) continues to represent a major source or mortality and morbidity. Although anticoagulation is the mainstay of therapy, adjunctive catheter-based interventions have shown substantial potential to improve clinically meaningful patient outcomes in patients with deep vein thrombosis (DVT), pulmonary embolism (PE), and the post-thrombotic syndrome (PTS). Catheter directed thrombolysis (CDT) has been shown in a randomized trial to reduce the risk of PTS in patients with acute proximal DVT; data from a larger NIH trial is expected shortly. The use of CDT is being increasingly used for patients with submassive or massive pulmonary embolism. Preliminary studies suggest that endovascular stent placement and ablative therapies can improve quality-of-life in carefully selected patients with established PTS. In this article, we summarize the current status of thrombus removal and stent placement procedures for VTE and PTS, with the main purpose being to guide clinicians in individualizing treatment decisions for their challenging patients. PMID- 26637724 TI - Immune reconstitution following stem cell transplantation. PMID- 26637725 TI - Use of alternative donors for allogeneic stem cell transplantation. AB - For patients without a human leukocyte antigen (HLA)-matched sibling or unrelated donor, options include transplantation from HLA-mismatched related donors, HLA mismatched unrelated donors, or unrelated cord blood units. Graft failure remains a problem in 10%-20% of cord blood transplants that contain a limited number of hematopoietic cells. Many approaches are tested in clinical trials to offset the risk of graft failure after cord blood transplantation. GVHD remains a hurdle with any HLA mismatched graft. The use of post-transplant cyclophosphamide holds the promise to overcome the HLA barrier and prevent GVHD despite donor mismatch for a full HLA haplotype. Priority should be given to enrolling patients onto transplant protocols addressing the fundamental problems of engraftment, GVHD, relapse or treatment-related mortality tested with one or more of the alternative stem cell sources. Principles for prioritization of alternative stem cell sources are discussed separately for children and adults who cannot be enrolled on clinical trials. It is difficult ranking currently available sources in the face of multiple factors affecting outcomes, rapidly changing transplant technology and without results from comparative trials. PMID- 26637726 TI - Graft-versus-host disease versus graft-versus-leukemia. AB - Graft-versus-host disease (GVHD) is a significant clinical problem after allogenic hematopoietic cell transplantation (HCT) associated with substantial morbidity and mortality that limits the potential utility of transplantation. Associated with GVHD is the well-recognized phenomenon of the graft-versus leukemia (GVL) effect that results in reduced risk of disease relapse. GVL effects have been observed after treatment for a broad range of hematological malignancies. Both GVHD and GVL are the results of T cell-effector functions that frames a major question in the field of how linked are these two phenomena. A major goal of basic science and translational research has been to develop strategies to reduce the risk of GVHD while maintaining or enhancing GVL. In this review, a number of different strategies developed from preclinical animal models will be explored with a focus on those approaches that have been extended to the clinic in an attempt to achieve this goal. Needless to say, there is no proven strategy; however, with the use of modern technology and clinical translation, there has been substantial progress toward this goal of reducing the risks of GVHD while promoting and enhancing GVL responses. PMID- 26637727 TI - Acquired bleeding disorders in the elderly. AB - The hemostatic balance changes with advancing age which may be due to factors such as platelet activation, increase of certain clotting factor proteins, slowing of the fibrinolytic system, and modification of the endothelium and blood flow. Generally, this predisposes the elderly to thrombosis rather than bleeding. It often necessitates antiplatelet or anticoagulation therapy, which can cause significant bleeding problems in an aging population. Additionally, changing renal function, modification in immune regulation, and a multitude of other disease processes, can give rise to acquired bleeding disorders. Bleeding can prove difficult to treat in a dynamic environment and in a population that may have underlying thrombotic risk factors.This article discusses some specific challenges of acquired bleeding arising in the elderly. The use of anticoagulation and nonsteroidal anti-inflammatory medications is prevalent in the treatment of the elderly and predisposes them to increased bleeding risk as their physiology changes. When prescribing and monitoring these therapies, it is exceedingly important to weigh thrombotic versus bleeding risks. There are additional rare acquired bleeding disorders that predominantly affect the elderly. One of them is acquired hemophilia, which is an autoimmune disorder arising from antibodies against factor VIII. The treatment challenge rests in the use of hemostatic agents in a population that is already at increased risk for thrombotic complications. Another rare disorder of intensifying interest, acquired von Willebrand syndrome, has a multitude of etiologic mechanisms. Understanding the underlying pathophysiology is essential in making a treatment decision for this disorder. PMID- 26637728 TI - Bleeding complications in immune thrombocytopenia. AB - Bleeding manifestations in patients with immune thrombocytopenia (ITP) range from mild skin bruises to life-threatening intracranial hemorrhage (ICH). Severe bleeding is distinctly uncommon when the platelet count is >30 * 10(9)/L and usually only occurs when the platelet count falls <10 * 10(9)/L. Based on estimates from clinical studies, ITP registries and administrative databases, the frequency of ICH in patients with ITP is ~0.5% in children and 1.5% in adults. Estimates of severe (non-ICH) bleeding are difficult to obtain because of the lack of standardized case definitions; the lack of a universally accepted, ITP specific bleeding assessment tool; and the omission of reporting bleeding outcomes in many clinical studies. In practice, the presence of bleeding should dictate whether or not treatment is needed because many patients, especially children, can be safely managed with observation alone. Guiding principles for the management of ITP, based on the bleeding risk are: (1) Decide when treatment is needed and when it can safely be withheld; (2) for patients with chronic ITP, use the least toxic treatment at the lowest dose; (3) emergency treatment of severe thrombocytopenia-associated bleeding requires combination therapy; and (4) early aggressive therapy may result in durable platelet count responses. PMID- 26637729 TI - Coagulopathy in liver disease: a balancing act. AB - Liver disease results in complex alterations of all 3 phases of hemostasis. It is now recognized that hemostasis is rebalanced in chronic liver disease. The fall in clotting factor levels is accompanied by a parallel fall in anticoagulant proteins. High von Willebrand factor levels counteract defects in primary hemostasis. Conventional coagulation tests do not fully reflect the derangement in hemostasis and do not accurately predict the risk of bleeding. Global coagulation assays (thrombin generation, thromboelastography) reflect the interaction between procoagulant factors, anticoagulant factors, platelets, and the fibrinolytic system and show promise for assessing bleeding risk and guiding therapy. These assays are not yet commercially approved or validated. Prevention of bleeding should not be aimed at correcting conventional coagulation tests. Thrombopoietin receptor agonists were shown to increase the platelet count in cirrhotic patients undergoing invasive procedures but may increase the risk of thrombosis. Rebalanced hemostasis in liver disease is precarious and may be tipped toward hemorrhage or thrombosis depending on coexisting circumstantial risk factors. Bacterial infection may impair hemostasis in cirrhosis by triggering the release of endogenous heparinoids. There are no evidence-based guidelines for hemostatic therapy of acute hemorrhage in liver disease. There is currently inadequate evidence to support the use of recombinant FVIIa, prothrombin complex concentrates, or tranexamic acid in acute variceal or other hemorrhage. PMID- 26637730 TI - Is there a best TKI for chronic phase CML? AB - The development of BCR/ABL1 tyrosine kinase inhibitors (TKIs) over the past 20 years has dramatically improved the outcomes for patients with every stage of Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML). Clinicians now have access to 5 oral, generally well-tolerated, and highly effective TKIs. How should these agents be used for an individual patient to ensure the best possible duration and quality-of-life, to avoid treatment-related complications, and potentially to achieve a cure at an affordable cost? Because CML patients may need to continue TKI therapy indefinitely, the long-term safety of each treatment option must be considered. Evidence-based care requires an understanding of the optimal use of these drugs, their specific early and late toxicities, the prognostic significance of achieving treatment milestones, and the critical importance of molecular monitoring. Efficacy is important, but treatment choice does not depend only on efficacy. Choosing among various treatment options is informed by understanding the distinct benefits and risks of each agent, along with careful consideration of patient-specific factors, such as risk status, age, and comorbidities. PMID- 26637731 TI - Molecular monitoring in CML and the prospects for treatment-free remissions. AB - Monitoring treatment responses in chronic myeloid leukemia (CML) is based on complete blood counts (CBCs) to determine hematologic response, karyotyping of bone marrow metaphase cells to delineate cytogenetic response and quantitative reverse transcription polymerase chain reaction (qPCR) to quantify expression of BCR-ABL1 mRNA (molecular response; MR) in peripheral blood. Fluorescence in situ hybridization (FISH) to identify BCR-ABL1 in interphase nuclei and mutational analysis of the BCR-ABL1 kinase domain (KD) are used in certain clinical circumstances. As most patients treated with tyrosine kinase inhibitors (TKIs) achieve complete cytogenetic responses (CCyRs), qPCR with its increased sensitivity and dynamic range has become the main tool used to monitor CML patients. Landmark analyses of large TKI trials have established MR milestones that identify patients with high risk of failure, are the basis of consensus management guidelines, and have led to a strong push toward qPCR test standardization. Today many laboratories report BCR-ABL1 qPCR results on the international scale (IS), a system based on the conversion of laboratory-specific numerical values to conform to a universal scale. The fact that qPCR is technically demanding and liable to assay variations poses considerable challenges for its routine clinical use. This is important as the prevalence of patients on chronic TKI therapy increases and critical clinical decisions are made based on qPCR results, for example if discontinuation of TKI therapy should be considered. Here we will review the current state of molecular monitoring in CML, focusing on qPCR, the definition of TKI failure and the results of TKI discontinuation studies. PMID- 26637732 TI - What's different about atypical CML and chronic neutrophilic leukemia? AB - Atypical chronic myeloid leukemia (aCML) and chronic neutrophilic leukemia (CNL) are rare myeloid neoplasms defined largely by morphologic criteria. The discovery of CSF3R mutations in aCML and CNL have prompted a more comprehensive genetic profiling of these disorders. These studies have revealed aCML to be a genetically more heterogeneous disease than CNL, however, several groups have reported that SETBP1 and ASXL1 mutations occur at a high frequency and carry prognostic value in both diseases. We also report a novel finding-our study reveals a high frequency of U2AF1 mutations at codon Q157 associated with CSF3R mutant myeloid neoplasms. Collectively, these findings will refine the WHO diagnostic criteria of aCML and CNL and help us understand the genetic lesions and dysregulated signaling pathways contributing to disease development. Novel therapies that emerge from these genetic findings will need to be investigated in the setting of a clinical trial to determine the safety and efficacy of targeting various oncogenic drivers, such as JAK1/2 inhibition in CSF3R-T618I-positive aCML and CNL. In summary, recent advances in the genetic characterization of CNL and aCML are instrumental toward the development of new lines of therapy for these rare leukemias that lack an established standard of care and are historically associated with a poor prognosis. PMID- 26637733 TI - Evolving diagnostic criteria for multiple myeloma. AB - Multiple myeloma (MM) is a plasma cell malignancy historically defined by the presence of end-organ damage, specifically, hypercalcemia, renal failure, anemia, and bone lesions (CRAB features) that can be attributed to the neoplastic process. In 2014, the International Myeloma Working Group (IMWG) updated the diagnostic criteria for MM to add specific biomarkers that can be used to make the diagnosis of the disease in patients who did not have CRAB features. In addition, the update allows modern imaging methods including computed tomography (CT) and positron emission tomography-CT to diagnose MM bone disease. These changes enable early diagnosis, and allow the initiation of effective therapy to prevent the development of end-organ damage in patients who are at the highest risk. This article reviews these and several other clarifications and revisions that were made to the diagnostic criteria for MM and related disorders. The updated disease definition for MM also automatically resulted in a revision to the diagnostic criteria for the asymptomatic phase of the disease termed smoldering MM (SMM). Thus the current diagnosis and risk-stratification of SMM is also reviewed in this article. Using specific prognostic factors, it is possible to identify a subset of patients with SMM who have a risk of progression to MM of 25% per year (high-risk SMM). An approach to the management of patients with low- and high-risk SMM is discussed. PMID- 26637734 TI - Maintenance therapy for multiple myeloma in the era of novel agents. AB - Despite many recent advances in the treatment of multiple myeloma, the course of the disease is characterized by a repeating pattern of periods of remission and relapse as patients cycle through the available treatment options. Evidence is mounting that long-term maintenance therapy may help suppress residual disease after definitive therapy, prolonging remission and delaying relapse. For patients undergoing autologous stem cell transplantation (ASCT), lenalidomide maintenance therapy has been shown to improve progression-free survival (PFS); however, it is still unclear whether this translates into extended overall survival (OS). For patients ineligible for ASCT, continuous therapy with lenalidomide and low-dose dexamethasone was shown to improve PFS and OS (interim analysis) compared with a standard, fixed-duration regimen of melphalan, prednisone, and thalidomide in a large phase 3 trial. Other trials have also investigated thalidomide and bortezomib maintenance for ASCT patients, and both agents have been evaluated as continuous therapy for those who are ASCT ineligible. However, some important questions regarding the optimal regimen and duration of therapy must be answered by prospective clinical trials before maintenance therapy, and continuous therapy should be considered routine practice. This article reviews the available data on the use of maintenance or continuous therapy strategies and highlights ongoing trials that will help to further define the role of these strategies in the management of patients with newly diagnosed multiple myeloma. PMID- 26637735 TI - Novel combination approaches for myeloma. PMID- 26637736 TI - Reclassifying myelodysplastic syndromes: what's where in the new WHO and why. AB - A revision to the 4th edition of the WHO Classification of myelodysplastic syndromes (MDSs), originally published in 2008, is expected in mid-2016. Based on recommendations of a Clinical Advisory Committee, the revision will aim to incorporate new discoveries in MDS that impact existing disease categories. Although the basic diagnostic principles of the WHO classification remain unchanged, several changes to the classification are proposed. All revisions are considered preliminary until the actual publication of the monograph and online document. Proposals for change include abandoning the routine use of "refractory anemia/cytopenia" in the various disease names, including the prognostic significance of gene mutations in MDS, revising the diagnostic criteria for MDS entities with ring sideroblasts based on the detection of SF3B1 mutations, modifying the cytogenetic criteria for MDS with isolated del(5q), reclassifying most cases of the erythroid/myeloid type of acute erythroleukemia, and recognizing the familial link in some cases of MDS. This review will provide details of the major proposed changes as well as rationale for the revisions. PMID- 26637737 TI - The shadowlands of MDS: idiopathic cytopenias of undetermined significance (ICUS) and clonal hematopoiesis of indeterminate potential (CHIP). AB - The WHO classification provides the best diagnostic approach to myelodysplastic syndromes (MDS). However, biologic and analytic limitations have emerged in the criteria currently adopted to establish the diagnosis and to classify MDS. The provisional category of idiopathic cytopenia of undetermined significance (ICUS) has been proposed to describe patients in whom MDS is possible but not proven. To formulate a diagnosis of ICUS, a thorough diagnostic work-up is required and repeated tests should be performed to reach a conclusive diagnosis. Recent studies provided consistent evidence of age-related hematopoietic clones (clonal hematopoiesis of indeterminate potential; CHIP), driven by mutations of genes that are recurrently mutated in myeloid neoplasms and associated with increase in the risk of hematologic cancer. A subset of mutated genes, mainly involved in epigenetic regulation, are likely initiating lesions driving the expansion of a premalignant clone. However, in a fraction of subjects the detected clone may be a small malignant clone expanding under the drive of the detected and additional undetected mutations. In addition, several experimental evidences suggest the potential relevance of an abnormal bone marrow environment in the selection and evolution of hematopoietic clones in MDS. The spreading of massively parallel sequencing techniques is offering translational opportunities in the clinical approach to myeloid neoplasms. Although several issues remain to be clarified, targeted gene sequencing may be of potential value in the dissection between clonal myelodysplasia, nonclonal cytopenia, and clonal hematopoiesis arising upon aging or in the context of acquired marrow failure. PMID- 26637738 TI - Nine years without a new FDA-approved therapy for MDS: how can we break through the impasse? AB - The myelodysplastic syndromes (MDSs) are a heterogeneous collection of clonal hematopoietic malignancies that compromise a large subgroup of the myeloid neoplasms and collectively are the most common acquired adult bone marrow failure syndromes. Currently, only 3 agents are approved for the treatment of MDS by the US Food and Drug Administration (FDA): azacitidine, decitabine, and lenalidomide. The latter drug, approved in 2006, is the most recent agent approved by the FDA for MDS and there has been mediocre success with novel agents for the past 9 years. The heterogeneity of MDS as a disease group is likely to be a strong contributor to this slow progress but recent developments in molecular characterization of MDS are improving diagnostic accuracy, providing insights into pathogenesis and refining our prognostic ability in the field. With the advent of these developments, appropriately chosen therapeutics or even targeted agents may be able to improve patient outcomes in the future. PMID- 26637739 TI - Do somatic mutations in de novo MDS predict for response to treatment? AB - A 68-year-old male with history of hypertension and arthritis presented with bruising and increasing fatigue over several months. He was found to be thrombocytopenic (platelets 30), WCB 2.0 K/mm(3), Hg 11.6 g/dL, ANC 870, and 1% circulating blasts. Bone marrow biopsy revealed 40%-50% cellular with multilineage dysplasia and 10% blasts. Cytogenetic genetic studies showed trisomy 2, and translocation (3;21). FISH studies for 5q, 7p, 8, 17p, and 20q abnormalities were negative. Molecular diagnostics were sent to a commercial laboratory to aid in prognostication. These studies showed mutations in TET2 (exons 1- 9 tested) and PHF6 (exons 1-9 tested). No abnormalities in other epigenetic regulators (DNMT3A, ASXL1), RNA splicing (SF3B1, SRSF2, URAF1, ZRSR2), transcription factors (RUNX1 or ETV6), or signaling (CBL, NRAS, KIT, JAK2, MPL) were detected. He was referred for consultation regarding initial treatment. In this elderly patient with preserved organ function and good performance status who is being considered for reduced intensity conditioned allogeneic hematopoietic cell transplant, what should the initial treatment be and can we use the molecular diagnostic results to guide therapy? PMID- 26637740 TI - Looking forward: novel therapeutic approaches in chronic and advanced phases of myelofibrosis. AB - Myelofibrosis (MF) is complex at the pathobiologic level and heterogeneous at the clinical level. The advances in molecular characterization of MF provide important insight into the mechanisms driving this chronic myeloid malignancy, refine risk stratification, offer novel therapeutic targets, and serve to measure therapeutic response. Although JAK2 inhibition has been the focus of laboratory and clinical efforts over the last decade, current experimental therapeutic approaches have broadened to include inhibitors of key alternative signaling pathways, epigenetic modulators, anti-fibrotics, and immunotherapies. Based on compelling preclinical rationale, a number of JAK2 inhibitor based combination therapies are now actively being evaluated in the clinic with the goal of disease course modification. The role and timing of hematopoietic stem cell transplant (HSCT) for MF has been challenged with the availability of commercial ruxolitinib and the plethora of experimental treatment options that exist. Integration of preconditioning JAK2 inhibition, reduced intensity conditioning regimens, and alternative donor sources are all being explored in an attempt to optimize this potentially curative modality. This review will summarize modern MF risk stratification, current clinical research approaches to chronic and advance phase MF focusing on novel agents alone and in combination, and update the reader on new directions in HSCT. PMID- 26637741 TI - Management of symptoms in polycythemia vera and essential thrombocythemia patients. AB - The BCR-ABL-negative myeloproliferative neoplasms (MPNs) are clonal stem cell derived malignancies, which include polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF). The MPNs are characterized by dysregulated JAK-STAT signaling pathways. PV and ET are associated with an increased risk of thrombo-hemorrhagic complications, risk of progression to MF and leukemia. Presentation of patients with PV and ET is variable and usually as a result of abnormal full blood count indices (raised hemoglobin and hematocrit, leukocytosis, and thrombocytosis). Presentation with thrombosis or splenomegaly occurs in ~30% of patients. Historically thought of as indolent compared with MF, patients with PV and ET have significant disease symptom burden which does not directly correlate to the current clinical prognostic classifications. The mainstay of therapy is reserved for patients with high-risk disease and thus excludes a population of patients with significant symptom related morbidity impacting their quality-of-life and survival. Recent treatment strategies have aimed to incorporate disease burden assessment into the selection of therapeutic interventions such as JAK2 inhibitors and HDAC inhibitors. We will review the advances in the field of MPN symptom assessment and symptom burden experienced by ET and PV patients. We will also discuss the risk-stratified management of ET and PV patients alongside symptom assessment and the impact of potential novel therapies, for patients who fail to respond to conventional treatment. PMID- 26637742 TI - Surveying the landscape of MDS/MPN research: overlap among the overlap syndromes? AB - The myelodysplastic/myeloproliferative neoplasms (MDS/MPNs) lie at the interphase of phenotypically opposing bone marrow malignancies. They are characterized by concomitant features of bone marrow failure and myeloproliferation and are generally associated with a poor prognosis. Although much is unknown with respect to the clinical course and molecular biology of MDS/MPNs, emerging research is beginning to uncover the key defining characteristics of this designation. In this review, we will discuss the features of MDS/MPN diseases that unify there clinical and molecular course and those that define distinct disease entities. We will discuss advances in genetics and MDS/MPN modeling, as well as translational discoveries that are anticipated to inform the diagnosis, prognostication, and treatment of MDS/MPNs in the near future. PMID- 26637743 TI - Patterns of resistance to B cell-receptor pathway antagonists in chronic lymphocytic leukemia and strategies for management. AB - Small-molecule kinase inhibitors, especially the two Food and Drug Administration approved agents idelalisib and ibrutinib, have changed the treatment landscape for patients with relapsed or refractory chronic lymphocytic leukemia (CLL). However, with these positive changes comes the new challenge of managing patients who relapse after these agents. The number of patients who have relapsed after taking idelalisib and ibrutinib is low, but as the drugs gain wider use and patients are treated for longer, this number is likely to grow. Because these patients can be challenging to manage effectively, coordinated efforts now to determine how and why patients relapse along with optimal treatment strategies are required to better serve our patients in the future. As well, identification of mechanisms of resistance is crucial to develop rational strategies for management. Current work has identified mechanisms of resistance to ibrutinib, and resistance to idelalisib is also under active investigation. In this review, we will discuss these mechanisms of resistance, as well as current and potential strategies for the management of kinase inhibitor-resistant CLL. PMID- 26637744 TI - Management of prolymphocytic leukemia. AB - B-cell (B-PLL) and T-cell (T-PLL) prolymphocytic leukemias are rare, poor prognosis lymphoid neoplasms with similar presentation characterized by symptomatic splenomegaly and lymphocytosis. They can be distinguished from each other and from other T- and B-cell leukemias by careful evaluation of morphology, immunophenotyping, and molecular genetics. The clinical behavior is typically aggressive, although a subset of patients may have an indolent phase of variable length. First-line therapy for T-PLL is with intravenous alemtuzumab and for B PLL is with combination purine analog-based chemo-immunotherapy. New B-cell receptor inhibitors, such as ibrutinib and idelalisib, may have a role in the management of B-PLL, especially for the patients harboring abnormalities of TP53. Allogenic stem cell transplantation should still be considered for eligible patients and may be the only current therapy capable of delivering a cure. In the past few years, many of the molecular mechanisms underlying disease pathogenesis and progression have been revealed and are likely to lead to the development of novel targeted approaches. PMID- 26637745 TI - Prognostic markers and standard management of chronic lymphocytic leukemia. AB - Chronic lymphocytic leukemia (CLL) is usually diagnosed in early stage, asymptomatic patients, and, although a wealth of prognostic parameters have been identified, the standard approach is a "watch and wait" strategy irrespective of risk factors. Therapy is only indicated if "active disease" criteria (International Workshop on Chronic Lymphocytic Leukemia guidelines) are met, and the routine upfront treatment is a combination of CD20 antibody (rituximab, ofatumumab or obinutuzumab) and chemotherapy (fludarabine /cyclophosphamide, bendamustine, chlorambucil), with the choice mainly determined by physical fitness of the patient. The major subgroup in which this approach does not result into satisfactory efficacy is in CLL with 17p deletion (17p-) or TP53 mutation (TP53mut). Likewise, patients with a short initial response duration (i.e., <24 26 months) have a dismal outcome with chemoimmunotherapy salvage. Therefore, these patients have been referred to as "ultra high risk," and, in these subgroups, novel agents such as signaling kinase inhibitors (also termed B-cell receptor signaling inhibitors; e.g., ibrutinib targeting Bruton tryosine kinase, idelalisib targeting phosphoinositide 3-kinase) and BCL2 antagonists (venetoclax, formerly ABT-199/GDC-0199) have shown dramatic efficacy. Ibrutinib and idelalisib are currently approved for the treatment of relapsed or refractory CLL or frontline treatment of 17p-/TP53mut CLL regardless of fitness. Therefore, these agents are challenging the concept of adjusting treatment to fitness and TP53 status, because they offer remarkable efficacy combined with exceptional tolerability. Nevertheless, it appears that 17p-/TP53mut retains an adverse prognostic impact, making additional improvement a primary research goal aimed at the development of the best combinations and/or sequences of these new agents, as well as prognostic and predictive markers guiding their use. PMID- 26637746 TI - Management of hemolytic anemia following allogeneic stem cell transplantation. AB - Hemolytic anemia (HA) is a frequent condition with variable pathophysiology. Hematopoietic stem cell transplantation (HSCT) is unique because it is performed across the ABO blood group barrier. Thereby, there is a transfer of plasma, red blood cells, and immunocompetent cells from the donor to the recipient, possibly leading to HA, due to red blood cell incompatibility. The underlying disease, drugs (particularly those used for conditioning and immunosuppressants), infections, graft-versus-host disease, and autoimmune diseases may all contribute to the clinical and laboratory picture of HA. Additionally, transplantation associated thrombotic microangiopathy (TA-TMA) may occur and is associated with significant morbidity and mortality. This review highlights the current knowledge on HA after allogeneic HSCT, particularly due to ABO incompatibility. We follow the timeline of the transplantation process and discuss investigations, differential diagnosis, and prophylactic measures including graft processing to avoid hemolysis in case of ABO incompatibility. Finally, current therapeutic approaches for both TA-TMA and post-HSCT autoimmune HA, which are associated with high morbidity and mortality, are discussed. PMID- 26637747 TI - Complement in hemolytic anemia. AB - Complement is increasingly being recognized as an important driver of human disease, including many hemolytic anemias. Paroxysmal nocturnal hemoglobinuria (PNH) cells are susceptible to hemolysis because of a loss of the complement regulatory proteins CD59 and CD55. Patients with atypical hemolytic uremic syndrome (aHUS) develop a thrombotic microangiopathy (TMA) that in most cases is attributable to mutations that lead to activation of the alternative pathway of complement. For optimal therapy, it is critical, but often difficult, to distinguish aHUS from other TMAs, such as thrombotic thrombocytopenic purpura; however, novel bioassays are being developed. In cold agglutinin disease (CAD), immunoglobulin M autoantibodies fix complement on the surface of red cells, resulting in extravascular hemolysis by the reticuloendothelial system. Drugs that inhibit complement activation are increasingly being used to treat these diseases. This article discusses the pathophysiology, diagnosis, and therapy for PNH, aHUS, and CAD. PMID- 26637748 TI - Diagnosis and management of rare congenital nonimmune hemolytic disease. AB - Rare, congenital nonimmune hemolytic disorders of the erythrocyte, although uncommon, are important causes of anemia in the child and adult. These are a heterogeneous group of diseases that disrupt normal erythrocyte structure and function in varying ways. Predominant are abnormalities of hemoglobin stability, defects of erythrocyte metabolism, and disorders of erythrocyte hydration. Unstable hemoglobinopathies may lead to chronic or episodic hemolysis. Perturbation of critical enzymes of the Embden-Meyerhof pathway lead to altered erythrocyte metabolism and chronic hemolysis. Disorders of erythrocyte hydration are an under-recognized cause of hemolytic anemia. Beyond pathophysiologic mechanisms of disease, clinical, laboratory, and genetic heterogeneity characterize this group of disorders. Often, they are underdiagnosed or misdiagnosed. This review discusses pathophysiology, inheritance, clinical findings, laboratory manifestations, and management considerations in several rare nonimmune hemolytic diseases including the unstable hemoglobins, disorders of erythrocyte metabolism, and abnormalities of erythrocyte hydration. PMID- 26637749 TI - The use of novel monoclonal antibodies in the treatment of acute lymphoblastic leukemia. AB - Regardless of age, patients with relapsed or refractory acute lymphoblastic leukemia (ALL) have extremely poor outcomes. The success of reinduction chemotherapy remains dismal, because complete remission rates are low and seldom durable. Clearly, new and novel strategies are needed to improve the outcome of patients with relapsed or refractory ALL. Patients with early relapse, especially those still receiving chemotherapy, tend to have a much poorer outcome and are often chemotherapy resistant. Although high-dose approaches may overcome chemotherapy resistance, long-term disease-free and overall survival remains limited. Several approaches have been used to target antigens, including cluster of differentiation (CD) 19, CD20, CD22, and CD52, on the surface of the malignant lymphoblast with striking efficacy. This review will focus on the clinical application of the major classes of antibodies, including naked antibodies, drug antibody conjugates, immunotoxins, and T cell-engaging bispecific antibodies. Hopefully, these novel monoclonal antibodies will result in a significant improvement in the outcome of patients with relapsed or refractory ALL. PMID- 26637750 TI - Management of adult Ph-positive acute lymphoblastic leukemia. AB - Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) has been regarded for decades as the ALL subgroup with the worse outcome. It represents the most frequent genetic subtype of adult ALL, and increases progressively with age. The introduction of tyrosine kinase inhibitors (TKIs) has enabled to obtain complete hematologic remissions (CHRs) in virtually all patients, including the elderly, to improve disease-free survival and overall survival, as well as to increase the percentage of patients who can undergo an allogeneic stem cell transplant (allo SCT).The current management of adult Ph+ ALL patients relies on the use of a TKI with or without chemotherapy followed by an allo-SCT, which still remains the only curative option. Minimal residual disease screening is permitting not only a better stratification of patients, but has also allowed to reconsider the role of autologous stem cell transplant for a set of patients who do not have a donor or are not eligible for an allo-SCT. At present, clinical challenges are represented by the emergence of resistant mutations, particularly the gatekeeper T315I, for which alternative approaches, comprising novel TKIs or therapies based on the combination of TKI with immunotherapeutic strategies, are being considered in order to overcome resistance. PMID- 26637751 TI - How can we improve on the already impressive results in pediatric ALL? AB - The past 70 years have seen childhood acute lymphoblastic leukemia move from a fatal disease with a survival of barely 4 months to a curable disease in >85% of patients. It has become clear that as treatment has intensified, more children are cured but at the expense of increased toxicity which for some can cause significant long-term morbidity and even mortality. The drive in more recent years has been to identify sensitive markers of disease and response to treatment to allow a reduction in therapy in those who do not require it and more intensive treatment in those who do. Clinical characteristics have been used to stratify patients into different risk groups and this, coupled with following response at a molecular level, has done much to tailor treatment to the patient. Considerable research has been focused on the molecular characteristics of the leukemia itself to elucidate the biologic mechanisms underlying both the disease and the comparative or absolute resistance of some types of leukemia. These molecular markers can also act as targets for novel therapies, which require newer trial methodologies to prove their utility. There has been less focus on the biology of the patient but it is clear that some patients are more susceptible to adverse events and toxicities than others. Through the use of pharmacogenomics, modification to therapy may be appropriate in certain patients based on their genetic profile. As novel therapies become available, suitable controlled trials in children are essential for their safe use in this population and will ensure that children are not denied timely access to advances in treatment. PMID- 26637752 TI - The five key things you need to know to manage adult patients with sickle cell disease. AB - The lack of a strong evidence base to guide the management of adults with sickle cell disease (SCD) makes it difficult for patients to receive high quality care outside of specialty centers. As there is a dearth of providers with sickle cell expertise, the purpose of this article is to identify some of the key things every provider who manages the care of adults with SCD should know. Managing adults with SCD requires excellent clinical skills, as it can affect every organ and cause life-threatening complications but it also requires a willingness to manage patients who often have psychosocial issues that are complex and impact care and care delivery in very significant ways. We have chosen topics for which there is a limited evidence base but which have significant clinical consequences if left unrecognized or poorly managed. The topics that will be addressed include chronic pain, neurocognitive dysfunction, renal disease, venous thromboembolism, and avoiding the inappropriate use of red cell transfusions. PMID- 26637753 TI - Can selectin and iNKT cell therapies meet the needs of people with sickle cell disease? AB - Recent insights into the pathogenesis of microvascular occlusion downstream of the sickled red cell have revealed new therapeutic targets for sickle cell disease (SCD). After the formation of sickle cells, tissue injury spurs inflammation, which leads to receptor-mediated contacts between sickle cells, leukocytes, and vascular endothelium. Specifically, selectins decelerate sickled red cells and leukocytes in the circulation to facilitate endothelial adhesion and other cell-cell interactions, ultimately leading to vascular occlusion. Invariant NKT (iNKT) cells, activated during reperfusion, generate a broad inflammatory response, which further increases cellular adhesion and vascular occlusion. Novel therapies are in development that target selectins and iNKT cells to prevent or interrupt the vicious cycle of adhesion and inflammation. Although the therapies hold promise for the treatment of SCD, an underappreciated threat to their development is poor access to care for people with SCD. Unless the majority of people with SCD have access to consistent, high-quality care, they will not have the opportunity to participate in a clinical trial or receive any new therapy, regardless of its efficacy. PMID- 26637754 TI - Sickle solubility test to screen for sickle cell trait: what's the harm? PMID- 26637755 TI - Optimizing hydroxyurea therapy for sickle cell anemia. AB - Hydroxyurea has proven efficacy in numerous clinical trials as a disease modifying treatment for patients with sickle cell anemia (SCA) but is currently under-used in clinical practice. To improve the effectiveness of hydroxyurea therapy, efforts should be directed toward broadening the clinical treatment indications, optimizing the daily dosage, and emphasizing the benefits of early and extended treatment. Here, various issues related to hydroxyurea treatment are discussed, focusing on both published evidence and clinical experience. Specific guidance is provided regarding important but potentially unfamiliar aspects of hydroxyurea treatment for SCA, such as escalating to maximum tolerated dose, treating in the setting of cerebrovascular disease, switching from chronic transfusions to hydroxyurea, and using serial phlebotomy to alleviate iron overload. Future research directions to optimize hydroxyurea therapy are also discussed, including personalized dosing based on pharmacokinetic modeling, prediction of fetal hemoglobin responses based on pharmacogenomics, and the risks and benefits of hydroxyurea for non-SCA genotypes and during pregnancy/lactation. Another critical initiative is the introduction of hydroxyurea safely and effectively into global regions that have a high disease burden of SCA but limited resources, such as sub-Saharan Africa, the Caribbean, and India. Final considerations emphasize the long-term goal of optimizing hydroxyurea therapy, which is to help treatment become accepted as standard of care for all patients with SCA. PMID- 26637756 TI - Implementing a blood utilization program to optimize transfusion practice. AB - Blood utilization review programs educate clinicians on guidelines for appropriate transfusion, review local transfusion practice, and provide feedback on transfusion trends. To gather data on transfusion practice, modern blood utilization programs leverage electronic medical records and computerized physician order entry with automated decision support. Data may be collected and feedback may be given in real-time for individual transfusions or retrospectively with aggregated data. Important elements for a successful program include a multidisciplinary group that can champion the effort, adequate documentation and data capture for transfusions, and regular discussions about trends with ordering clinicians. Blood utilization programs are popular because they can lower transfusion risk, improve quality outcomes, and lower costs. PMID- 26637757 TI - Plasma versus prothrombin complex concentrate for warfarin-associated major bleeding: a systematic review. PMID- 26637758 TI - Red blood cell transfusion for hematologic disorders. AB - Randomized clinical trials (RCTs) have determined, in surgical and critically ill patients, relatively safe hemoglobin (Hb) thresholds of 7-8 g/dL to guide restrictive transfusion of red blood cells (RBCs). However, in patients with various hematologic disorders, strong evidence in support of such an approach is sparse and the optimal transfusion practice is yet to be defined. This review focuses on RBC transfusion practice in three hematologic diseases and a treatment strategy, including autoimmune hemolytic anemia, thalassemia, myelodysplastic syndrome, and hematopoietic stem cell transplantation. These entities manifest in a broad spectrum of anemia, acute or chronic, in patients with different comorbidities and degrees of transfusion requirement. Thus the nuances in the indications of RBC transfusion and the goals to achieve in these specific situations may have been underappreciated. The limited data available highlight the importance of titrating RBC transfusion based on the clinical context and patient characteristics. Future RCTs are necessary to firmly establish the Hb thresholds associated with improved outcomes relevant to these specific patient populations, which will facilitate the personalized decision-making in RBC transfusion. PMID- 26637759 TI - Platelet transfusion goals in oncology patients. AB - Despite the advances in platelet component preparation and transfusion support over the years, platelet products remain a limited resource due to their short (5 day) shelf life, and therefore their optimal use in the non-bleeding thrombocytopenic patient continue to draw much attention. There have been a number of national and international guidelines for platelet transfusion therapy in patients with hematologic diseases, some within the last 1-2 years that have incorporated key randomized controlled trials (RCTs) which address issues, such as the optimal platelet dose, the most appropriate threshold for prophylactic platelet transfusions, and whether prophylactic platelet transfusions are superior to therapeutic-only platelet transfusion practices for the prevention life-threatening bleeding in patients with hypoproliferative thrombocytopenia. This review highlights key RCTs and recent systematic reviews focused on optimal platelet transfusion therapy in adult and pediatric patients with hypoproliferative thrombocytopenia secondary to chemotherapy or hematopoietic stem cell transplant (HSCT), discuss how recent innovations in platelet component processing may affect transfusion efficiency, and introduce renewed concepts on adjuvant therapies to prevent bleeding in the hypoproliferative thrombocytopenic patient. PMID- 26637760 TI - When and why should patients with hematologic malignancies see a palliative care specialist? AB - Palliative care is a multidisciplinary approach to symptom management, psychosocial support, and assistance in treatment decision-making for patients with serious illness and their families. It emphasizes well-being at any point along the disease trajectory, regardless of prognosis. The term "palliative care" is often incorrectly used as a synonym for end-of-life care, or "hospice care". However, palliative care does not require a terminal diagnosis or proximity to death, a misconception that we will address in this article. Multiple randomized clinical trials demonstrate the many benefits of early integration of palliative care for patients with cancer, including reductions in symptom burden, improvements in quality-of-life, mood, and overall survival, as well as improved caregiver outcomes. Thus, early concurrent palliative care integrated with cancer directed care has emerged as a standard-of-care practice for patients with cancer. However, patients with hematologic malignancies rarely utilize palliative care services, despite their many unmet palliative care needs, and are much less likely to use palliative care compared to patients with solid tumors. In this article, we will define "palliative care" and address some common misconceptions regarding its role as part of high-quality care for patients with cancer. We will then review the evidence supporting the integration of palliative care into comprehensive cancer care, discuss perceived barriers to palliative care in hematologic malignancies, and suggest opportunities and triggers for earlier and more frequent palliative care referral in this population. PMID- 26637761 TI - Early integration of palliative care into the care of patients with cancer. PMID- 26637762 TI - Spanning the canyon between stem cell transplantation and palliative care. AB - Stem cell transplantation (SCT) and palliative care (PC) may initially appear to be distant extremes in the continuum of care of patients with hematologic malignancies, opposed by multiple obstacles preventing their integration. Rather, we will posit that both fields share many similarities and have much to learn from one another. PC has increasing relevance in cancer care given recent studies that link PC to improved quality-of-life, survival, and decreased cost of care. Understanding modern conceptualizations of PC and its role within SCT is key. Through the report of a single academic medical center experience with an integrated SCT and PC model over the last decade, we will discuss future opportunities for strengthening collaboration between SCT and PC. PC in SCT should be considered from the day of diagnosis and tied to need, not to prognosis. PMID- 26637763 TI - Palliative care in pediatric patients with hematologic malignancies. AB - Children with advanced cancer, including those with hematologic malignancies, can benefit from interdisciplinary palliative care services. Palliative care includes management of distressing symptoms, attention to psychosocial and spiritual needs, and assistance with navigating complex medical decisions with the ultimate goal of maximizing the quality-of-life of the child and family. Palliative care is distinct from hospice care and can assist with the care of patients throughout the cancer continuum, irrespective of prognosis. While key healthcare organizations, including the Institute of Medicine, the American Academy of Pediatrics and the American Society of Clinical Oncology among many others endorse palliative care for children with advanced illness, barriers to integration of palliative care into cancer care still exist. Providing assistance with advance care planning, guiding patients and families through prognostic uncertainty, and managing transitions of care are also included in goals of palliative care involvement. For patients with advanced malignancy, legislation, included in the Patient Protection and Affordable Health Care Act allows patients and families more options as they make the difficult transition from disease directed therapy to care focused on comfort and quality-of-life. PMID- 26637764 TI - Patient-reported outcomes in drug development for hematology. AB - Patient-reported outcomes (PROs) are any outcome evaluated directly by the patient himself and based on the patient's perception of a disease and its treatment(s). PROs are direct outcome measures that can be used as clinical meaningful endpoints to characterize treatment benefit. They provide unique and important information about the effect of treatment from a patient's view. However, PROs will only be considered adequate if the assessment is well-defined and reliable. In 2009, the FDA has issued a guidance, which defines good measurement principles to consider for PRO measures intended to give evidence of treatment benefit in drug development. In hematologic clinical trials, when applied rigorously, they may be used to evaluate overall treatment effectiveness, treatment toxicity, and quality of patient's well-being at short-term and long term after treatment from a patient's perspective. In situations in which multiple treatment options exist with similar survival outcome or if a new therapeutic strategy needs to be evaluated, the inclusion of PROs as an endpoint can provide additional data and help in clinical decision making. Given the diversity of the hematological field, the approach to measurement needs to be tailored for each specific situation. The importance of PROs in hematologic diseases has been highlighted in a number of international recommendations. In addition, new perspectives in the regulatory field will enhance the inclusion of PRO endpoints in clinical trials in hematology, allowing the voice of the patients with hematologic diseases to be taken into greater consideration in the development of new drugs. PMID- 26637765 TI - Patient-reported outcomes in clinical practice. AB - Patient-reported outcome (PRO) measurement plays an increasingly important role in health care and understanding health outcomes. PROs are any report of a patient's health status that comes directly from the patient, and can measure patient symptoms, patient function, and quality-of-life. PROs have been used successfully to assess impairment in a clinical setting. Use of PROs to systematically quantify the patient experience provides valuable data to assist with clinical care; however, initiating use of PROs in clinical practice can be daunting. Here we provide suggestions for implementation of PROs and examples of opportunities to use PROs to tailor individual patient therapy to improve patient outcomes, patient-physician communication, and the quality of care for hematology/oncology patients. PMID- 26637766 TI - Acute myeloid leukemia in children and adolescents: identification of new molecular targets brings promise of new therapies. AB - Recent reports of recurrent mutations in childhood acute myeloid leukemia (AML) have identified potential targets for new therapeutic strategies. Acute promyelocytic leukemia (APL) is characterized commonly by a fusion between the PML gene and the RARA gene, genes targetable by arsenic (ATO) and retinoic acid (ATRA), respectively. A mutation in GATA1, common in AML of Down syndrome (ML DS), renders cells more susceptible to cytarabine and anthracyclines, thus permitting targeted dose reductions to preserve high survival rates while reducing toxicity. In all other patients, Ras pathway mutations, KMT2A and other methyltransferase mutations, FLT3 mutations, and KIT mutations are all relatively common in childhood AML and all are potentially "druggable". The focus of this review is on those therapies likely to be clinically available in the near future. The preclinical and clinical data providing a rationale for testing in children of specific agents in children is discussed. Whether the expression of a potential target is sufficient to predict response to a targeted therapy is an open question in childhood AML. Development of clinical trials to evaluate targeted therapies in small molecularly defined subsets of AML will be the next great challenge for all cooperative groups in North America and Europe. PMID- 26637767 TI - Hodgkin lymphoma in children and adolescents: improving the therapeutic index. AB - Hodgkin lymphoma (HL) is a highly curable form of childhood cancer, with estimated 5 year survival rates exceeding 98%. However, the establishment of a "standard of care" approach to its management is complicated by the recognition that long-term overall survival declines in part from delayed effects of therapy and that there continue to be subgroups of patients at risk for relapse for which prognostic criteria cannot adequately define. This challenge has resulted in the development of various strategies aimed at identifying the optimal balance between maintaining overall survival and avoidance of long-term morbidity of therapy, often representing strategies quite different from those used for adults with HL. More precise risk stratification and methods for assessing the chemosensitivity of HL through imaging studies and biomarkers are in evolution. Recent advances in the understanding of the biology of HL have led to the introduction of targeted therapies in both the frontline and relapsed settings. However, significant barriers exist in the development of new combination therapies, necessitating collaborative studies across pediatric HL research consortia and in conjunction with adult groups for the adolescent and young adult (AYA) population with HL. PMID- 26637768 TI - Advances in therapies for non-Hodgkin lymphoma in children. AB - Pediatric patients with newly diagnosed, non-Hodgkin Lymphoma (NHL) have an excellent overall survival. However, therapy regimens are associated with acute toxicity and late effects. Furthermore, patients with relapsed or refractory disease have relatively few options with proven clinical benefit. Both histologic and molecular differences exist between adult and pediatric NHL preventing simple translation of adult NHL successes into improvements in pediatric NHL treatment. This review summarizes the introduction of targeted therapies into frontline treatments for patients with anaplastic large-cell lymphoma and CD20-positive tumors, with the goal of improving overall survival while limiting both short- and long-term toxicities. In addition, newer approaches that have limited data in children but may have a significant role in how we treat pediatric NHL in the future are reviewed, which include CD19 directed therapy, Notch inhibition, the tri-functional antibody, FBTA05, and EZH2 inhibition. PMID- 26637770 TI - Zebras and hen's teeth: recognition and management of rare T and NK lymphomas. AB - Although all the peripheral T-cell lymphomas are uncommon, there are some entities that are truly rare. Subtypes, such as enteropathy-associated T-cell lymphoma, hepatosplenic T-cell lymphoma, extranodal NK/T-cell lymphoma, and subcutaneous panniculitis-like T-cell lymphoma, have an approximate annual incidence in United States of <500 each. In these very rare subtypes, there is limited data to guide clinical decision-making. As such, our treatment decisions are often based on extrapolation, case series, personal experience, and biases. We summarize the existing data regarding initial management of these entities and compare how that management follows paradigms established for the more common T cell lymphomas. PMID- 26637769 TI - Choosing a systemic treatment for advanced stage cutaneous T-cell lymphoma: mycosis fungoides and Sezary syndrome. PMID- 26637771 TI - Peripheral T-cell lymphoma, NOS, and anaplastic large cell lymphoma. AB - Peripheral T-cell lymphomas (PTCL), with the exception of anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL), have a very poor prognosis. Although current first line chemotherapy continues to be a CHOP-like (cyclophosphamide, doxorubicin, vincristine, prednisone) regimen there is now data suggesting that the addition of etoposide in younger patients improves outcomes. Even for those patients who do have a response to therapy, the risk of relapse remains quite high. Although autologous transplant in first remission is often used, its role as consolidation therapy in first remission remains unclear and may preferentially benefit low-risk patients. In the relapsed setting, major advances have occurred with Food and Drug Administration (FDA) approval of 4 new agents (pralatrexate, romidepsin, belinostat, brentuximab vedotin) for relapsed/refractory PTCL since 2009. These 4 drugs represent the first agents ever approved specifically for this indication. Unfortunately, with the exception of ALCL for which brentuximab vedotin will likely substantially change our approach to treatment, there are still many patients for whom available drugs will not be effective, and it is for these patients that further advances are urgently needed. PMID- 26637772 TI - Biological and clinical significance of somatic mutations in Langerhans cell histiocytosis and related histiocytic neoplastic disorders. AB - Langerhans cell histiocytosis (LCH), juvenile xanthogranuloma (JXG), and Erdheim Chester disease (ECD) represent histiocytic disorders with a wide range of clinical manifestations. Until recently, mechanisms of pathogenesis have been speculative and debate has focused on classification of these conditions as reactive versus neoplastic. Genomic studies have been challenged by scarce tissue specimens, as well as heterogeneous nature of the lesions with variable infiltration of pathologic histiocytes. Whole-exome sequencing recently revealed a very low frequency of somatic mutations in LCH, JXG, and ECD compared to other neoplastic disorders. However, at least in the cases of LCH and ECD, there is a very high frequency of activating mutations in MAPK pathway genes, most notably BRAF-V600E, as well as MAP2K1, in LCH and NRAS in ECD. In ECD, recurrent mutations in the PI3K pathway gene PIK3CA have also been described. The heterogeneous clinical manifestations of these disorders may therefore be the cumulative result of activation of MAPK mutations (along with modifying signals from other pathways) at distinct stages of myeloid differentiation. Implications of this model include redefinition of LCH, JXG, and ECD as a group of clinically diverse myeloid neoplastic disorders with a common mechanism of pathogenesis. This model supports refocusing therapeutic strategies for these diseases on a personalized approach based on specific mutations and the cell(s) of origin. PMID- 26637773 TI - Treatment of Langerhans cell histiocytosis: role of BRAF/MAPK inhibition. AB - Langerhans cell histiocytosis (LCH) is a clonally derived neoplasm with a highly variable clinical course. Although LCH was once considered a disorder of immune regulation, the identification of activating mutations in the proto-oncogene BRAF V600E in ~50%-60% of cases and MEK and ERK phosphorylation in 100% of examined cases, has changed the definition of LCH to a dendritic cell neoplasm with a strong inflammatory component. Current international LCH trials are focused on further improving the outcome of high-risk multisystem LCH patients, by decreasing the reactivation rate, optimizing early salvage regimens, and preventing late sequelae. Anecdotal responses to vemurafenib, a BRAF-V600E inhibitor, have been reported in a few cases of LCH and Erdheim-Chester disease. However, the development of resistance, as well as the potential risks of cutaneous and pancreatic cancers in patients with BRAF-V600E-mutated melanoma treated with single inhibitors, suggest the need for prospective trials with BRAF inhibitors, alone or in combination with other inhibitors of this pathway, for patients with refractory or multiply-relapsed LCH. The recent discovery of somatic mutations in ARAF and in MAP2K1, which lead to activation of the RAS-RAF MEK -ERK pathway in the setting of wild-type BRAF, as well as the finding that activating mutation in MAP2K1 are relatively insensitive to MEK inhibitors, suggest that a more detailed understanding of this pathway in LCH may be necessary for the development of more effective targeted therapies. PMID- 26637774 TI - Uncommon histiocytic disorders: Rosai-Dorfman, juvenile xanthogranuloma, and Erdheim-Chester disease. AB - Rosai-Dorfman disease (RDD), juvenile xanthogranuloma (JXG), and Erdheim-Chester disease (ECD) are non-Langerhans cell (non-LCH) disorders arising from either a dendritic or a macrophage cell. RDD is a benign disorder that presents with massive lymphadenopathy, but can have extranodal involvement. In most cases, RDD is self-limited and observation is the standard approach. Treatment is restricted to patients with life-threatening, multiple-relapsing, or autoimmune-associated disease. JXG is a pediatric histiocytosis characterized by xanthomatous skin lesions that usually resolve spontaneously. In a minority of cases, systemic disease can occur and can be life threatening. Juvenile myelomonocytic leukemia (JMML), as well as germline mutations in NF1 and NF2, have been reported in children with JXG. Recent whole-exome sequencing of JXG cases did not show the BRAF-V600E mutation, although 1 patient had PI3KCD mutation. ECD is an adult histiocytosis characterized by symmetrical long bone involvement, cardiovascular infiltration, a hairy kidney, and retroperitoneal fibrosis. Central nervous system involvement is a poor prognostic factor. Interferon-alpha is the standard as front-line therapy, although cladribine and anakinra can be effective in a few refractory cases. More than one-half of ECD patients carry the BRAF-V600E mutation. Currently, >40 patients worldwide with multisystemic, refractory BRAF V600E(+) ECD have been treated with vemurafenib, a BRAF inhibitor, which was found to be highly effective. Other recurrent mutations of the MAP kinase and PI3K pathways have been described in ECD. These discoveries may redefine ECD, JXG, and LCH as inflammatory myeloid neoplasms, which may lead to new targeted therapies. PMID- 26637775 TI - Molecularly targeted therapies for acute myeloid leukemia. AB - The past 15 years have seen major leaps in our understanding of the molecular genetic mutations that act as drivers of acute myeloid leukemia (AML). Clinical trials of agents against specific mutant proteins, such as FLT3-internal tandem duplications (ITDs) and isocitrate dehydrogenase mutations (IDHs) are ongoing. This review discusses agents in clinical trials that target specific gene mutations and/or epigenetic targets. PMID- 26637776 TI - Antigen-specific immunotherapies for acute myeloid leukemia. AB - Antigen-specific immunotherapies have emerged as important components of curative treatment algorithms for many cancers. In acute myeloid leukemia (AML), success has been less obvious. Nonetheless, among the few drugs shown to improve survival in recent randomized trials is the CD33 antibody-drug conjugate gemtuzumab ozogamicin. Significant antileukemic activity is also well documented for radioimmunoconjugates targeting CD33, CD45, or CD66. These therapeutics can intensify conditioning before hematopoietic cell transplantation, but their effect on patient outcomes needs clarification. Emerging data now suggest clinical antileukemic activity of several novel antibodies and perhaps some adoptive T-cell immunotherapies and vaccines. In parallel, numerous other agents targeting a wider variety of antigens are currently being explored. However, the antigenic heterogeneity characteristic of AML is a considerable limitation for all these therapeutics, and many important questions related to the ideal target antigen(s), disease situation in which to use these therapies, most suitable patient populations, exact treatment modalities, and details of supportive care needs remain open. Addressing such questions in upcoming studies will be required to ensure that antigen-directed therapies become an effective tool in AML, a disease for which outcomes with standard "3 + 7"-based chemotherapy have remained unsatisfactory in many patients. PMID- 26637777 TI - New approaches to transplantation in acute myelogenous leukemia. AB - Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative therapeutic option for acute myelogenous leukemia (AML). This is due to the combined effect of chemo/radiation therapy and the immunologic graft-versus leukemia effect. The field of HSCT has benefited from advances in a variety of "fronts," including our increasing ability to break the human leukocyte antigen barrier, which has led to greater access to transplantation. Furthermore, progress in the biologic, genetic, and pharmacologic arenas is creating a scenario where traditional borders between transplant and non-transplant therapies are less clear. This overlap is exemplified by new approaches to pharmacologic maintenance of remission strategies after HSCT. In addition, cellular adoptive immunotherapy has the potential to exploit narrowly targeted anti-tumor effects within or outside the allogeneic HSCT "frame," holding the promise of avoiding off target side effects, such as graft-versus-host disease. Here we discuss these and other lines of active investigation designed to improve outcomes of HSCT for AML. PMID- 26637778 TI - Update in large cell lymphoma: understanding the pathology report. AB - The diffuse aggressive large B-cell lymphomas are a heterogeneous group of B-cell malignancies. Although many are readily recognized due to characteristic clinical and pathologic features, several problematic areas still exist in diagnosis of these lymphomas due to a variety of reasons that include imprecise or difficult to-apply diagnostic criteria, gaps in our understanding of lymphoma biology, and limitations in technologies available in the clinical laboratory compared to the research laboratory. This may result in some degree of confusion in the pathology report, particularly if the issues are not clearly explained, leading to frustration or misinterpretation on the part of the reader. In this review, I will discuss the pathologic features of a subset of the WHO 2008 classification diffuse aggressive large B-cell lymphomas, focusing on areas in which difficulties exist in diagnosis and/or biomarker marker assessment. A deeper understanding of the issues and areas of uncertainty due to limitations in our knowledge about the biology of these diseases should lead to better communication between pathologists and clinicians. PMID- 26637779 TI - Using the pathology report in initial treatment decisions for diffuse large B cell lymphoma: time for a precision medicine approach. AB - Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non Hodgkin lymphoma in the Western world, and is potentially curable with standard R-CHOP chemoimmunotherapy. Historically, clinical risk assessments provided prognostic information, but did not define treatment approach. We are now in an era where the heterogeneity of DLBCL is defined genetically and molecularly, and rational subset-specific therapeutic targets are guiding clinical trials. Primary mediastinal DLBCL is a unique clinicopathologic entity, and alternatives to R CHOP may confer superior outcome. Rearrangement of the myc oncogene occurs in ~10% of patients with DLBCL, and confers a very poor prognosis with standard R CHOP, particularly when there is concomitant rearrangement of bcl-2, a condition referred to as "double-hit" DLBCL. A larger subset of DLBCL demonstrates overexpression of both myc and bcl-2 by immunohistochemistry. Cell of origin, determined by gene expression analysis, immunohistochemistry algorithms, or a novel Lymph2Cx platform, provides prognostic information, and guides therapeutic decisions in both relapsed and de novo disease. This article will define specific subsets of DLBCL and provide subtype-specific treatment options, including novel approaches under investigation. Understanding these key features of the pathology report, and limitations of these assays defining subsets of DLBCL, allows for an evolving precision medicine approach to this disease. PMID- 26637780 TI - Treatment of patients with transformed lymphoma. AB - Histologic transformation (HT) is a frequent event in the clinical course of patients with indolent lymphoma. Most of the available data in the literature comes from studies on transformation of follicular lymphoma (FL), as this is the most common indolent lymphoma; however, HT is also well documented following small lymphocytic lymphoma/chronic lymphocytic leukaemia (SLL/CLL), lymphoplasmacytic lymphoma (LPL), or marginal zone lymphoma (MZL), amongst other types of lymphoma, albeit most of the studies on transformation in these subtypes are case reports or short series. The outcome of patients with HT has traditionally been considered dismal with a median overall survival (OS) of around 1 year in most of the published studies. This prompted many authors to include stem cell transplant (SCT) as part of the treatment strategy for young and fit patients with HT. However, recent articles suggest that the outcome of patients with transformed lymphoma might be improving, questioning the need for such intensive therapies. The management of patients with HT is challenged by the heterogeneity of the population in terms of previous number and type of therapy lines and from their exclusion from prospective clinical trials. This review will examine whether the advent of new therapies has impacted on the prognosis of HT and on current treatment strategies. PMID- 26637781 TI - What's new in the diagnosis and pathophysiology of thrombotic thrombocytopenic purpura. AB - Severe ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) deficiency causes thrombotic thrombocytopenic purpura (TTP), which is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and the absence of oliguric or anuric renal failure. However, some patients with this constellation of findings do not have ADAMTS13 deficiency, and some patients with ADAMTS13 deficiency have renal failure or relatively normal blood counts. Consequently, many investigators and clinicians have incorporated severe ADAMTS13 deficiency into the case definition of TTP. This change has facilitated the timely initiation of treatment for patients with atypical clinical features who otherwise would not be recognized as having TTP. Conversely, excluding severe ADAMTS13 deficiency focuses attention on the diagnosis and treatment of other causes of thrombotic microangiopathy that require different treatment. The rapid return of ADAMTS13 data is important to make the best use of this information. PMID- 26637782 TI - Treatment of thrombotic thrombocytopenic purpura beyond therapeutic plasma exchange. AB - Daily therapeutic plasma exchange (TPE) transformed the historically fatal prognosis of acquired, anti-ADAMTS13 antibody-mediated thrombotic thrombocytopenic purpura (TTP), leading to the current overall survival rates of 80%-85%. However, relapses occur in ~40% of patients and refractory disease with fatal outcomes still occurs. In this context, the introduction of rituximab has probably been the second major breakthrough in TTP management. Rituximab is now routinely recommended during the acute phase, typically in patients with a suboptimal response to treatment, or even as frontline therapy, with high response rates. In more severe patients, salvage strategies may include twice daily TPE, pulses of cyclophosphamide, vincristine, as well as splenectomy in more desperate cases. In this life-threatening disease, relapse prevention represents a major goal. Persistent severe acquired ADAMTS13 deficiency in patients who are otherwise in remission is associated with a high risk of relapse and preemptive treatment with rituximab may be considered in this context. In the coming years, the TTP therapeutic landscape should be enriched by original strategies stemming from clinical experience and new agents that are currently being evaluated in large, ideally international, clinical trials. Promising agents under evaluation include N-acetylcysteine, bortezomib, recombinant ADAMTS13, and inhibitors of the glycoprotein-Ib/IX-von Willebrand factor axis. PMID- 26637783 TI - Syndromes of thrombotic microangiopathy associated with pregnancy. AB - When a pregnant or postpartum woman presents with sudden and severe microangiopathic hemolytic anemia (MAHA) and thrombocytopenia, three syndromes that require urgent care must be considered: (1) preeclampsia with severe features/hemolysis, elevated liver function tests, low platelets (PE/HELLP) syndrome; (2) thrombotic thrombocytopenic purpura (TTP); and (3) complement mediated thrombotic microangiopathy (C-TMA; also referred to as atypical hemolytic-uremic syndrome). The distinction among these three syndromes is often unclear because they share multiple clinical features. Overlap between PE/HELLP syndrome and the other two syndromes is also apparent from the fact that pregnancy can be a trigger for both TTP and C-TMA both before and after delivery and also the increased frequency of PE/HELLP syndrome in women who have recovered from TTP. When diagnostic criteria for PE/HELLP syndrome are present, management of hypertension and delivery is curative. Absence of improvement or actual progression of MAHA, thrombocytopenia, and kidney function abnormalities after delivery requires consideration of TTP and C-TMA. Minimal kidney involvement with severe thrombocytopenia suggests TTP and the need for treatment with plasma exchange; progressive kidney injury (in the absence of a cause for acute tubular necrosis) suggests C-TMA and the need for anti-complement treatment. We describe how we use these criteria to evaluate and manage pregnant/postpartum women with MAHA and thrombocytopenia. PMID- 26637784 TI - Evidence for Janus kinase (JAK) inhibitors for the prevention of major morbid events in patients with myeloproliferative neoplasms (MPNs). AB - A 69-year-old man presents with a Dynamic International Prognostic Scoring System (DIPSS) intermediate-risk 2 post polycythemia vera myelofibrosis with significant splenomegaly, 30 pound weight loss, constitutional symptoms, and 2% peripheral blood blasts. He has no other significant past medical history and no other major comorbid conditions. You are asked by the hematology fellow you are supervising whether or not treating this patient with a Janus kinase (JAK) inhibitor will decrease major morbid events. PMID- 26637785 TI - Evens AM, Kostakoglu L. The role of FDG-PET in defining prognosis of Hodgkin lymphoma for early-stage disease. Hematology Am Soc Hematol Educ Program. 2014;2014:135-143. PMID- 26637786 TI - A spiral scaffold underlies cytoadherent knobs in Plasmodium falciparum-infected erythrocytes. AB - Much of the virulence of Plasmodium falciparum malaria is caused by cytoadherence of infected erythrocytes, which promotes parasite survival by preventing clearance in the spleen. Adherence is mediated by membrane protrusions known as knobs, whose formation depends on the parasite-derived, knob-associated histidine rich protein (KAHRP). Knobs are required for cytoadherence under flow conditions, and they contain both KAHRP and the parasite-derived erythrocyte membrane protein PfEMP1. Using electron tomography, we have examined the 3-dimensional structure of knobs in detergent-insoluble skeletons of P falciparum 3D7 schizonts. We describe a highly organized knob skeleton composed of a spiral structure coated by an electron-dense layer underlying the knob membrane. This knob skeleton is connected by multiple links to the erythrocyte cytoskeleton. We used immuno electron microscopy (EM) to locate KAHRP in these structures. The arrangement of membrane proteins in the knobs, visualized by high-resolution freeze-fracture scanning EM, is distinct from that in the surrounding erythrocyte membrane, with a structure at the apex that likely represents the adhesion site. Thus, erythrocyte knobs in P falciparum infection contain a highly organized skeleton structure underlying a specialized region of membrane. We propose that the spiral and dense coat organize the cytoadherence structures in the knob, and anchor them into the erythrocyte cytoskeleton. The high density of knobs and their extensive mechanical linkage suggest an explanation for the rigidification of the cytoskeleton in infected cells, and for the transmission to the cytoskeleton of shear forces experienced by adhering cells. PMID- 26637788 TI - The NFkappaB-inducing kinase is essential for the developmental programming of skin-resident and IL-17-producing gammadelta T cells. AB - gammadelta T cells contribute to first line immune defense, particularly through their ability for rapid production of proinflammatory cytokines. The cytokine profile of gammadelta T cells is hard-wired already during thymic development. Yet, the molecular pathways underlying this phenomenon are incompletely understood. Here we show that signaling via the NFkappaB-inducing kinase (NIK) is essential for the formation of a fully functional gammadelta T cell compartment. In the absence of NIK, development of Vgamma5(+) dendritic epidermal T cells (DETCs) was halted in the embryonic thymus, and impaired NIK function caused a selective loss of IL-17 expression by gammadelta T cells. Using a novel conditional mutant of NIK, we could show in vivo that NIK signaling in thymic epithelial cells is essential for the thymic hardwiring of gammadelta T cell cytokine production. PMID- 26637789 TI - Balloon-occluded retrograde transvenous obliteration versus transjugular intrahepatic portosystemic shunt for treatment of gastric varices due to portal hypertension: A meta-analysis. AB - BACKGROUND AND AIM: The aim of this study was to compare the feasibility and safety of both balloon-occluded retrograde transvenous obliteration (BRTO) versus transjugular intrahepatic portosystemic shunt (TIPS) for treatment of gastric varices due to portal hypertension through the method of meta-analysis. METHODS: PubMed, Embase, and Cochrane Library were searched for both randomized controlled trials and cohort studies concerning BRTO compared with TIPS in the treatment of gastric varices from their inception to April 26, 2015. The Cochrane network RevMan 5.3 software was used for statistic analysis. The primary markers that need to be evaluated contained technical success rate, hemostasis rate, incidence rate of postoperative rebleeding, incidence rate of hepatic encephalopathy, and postoperative procedure-related complication. Study-specific odds ratios (ORs) were combined to calculate pooled value by using random effects model. RESULTS: Five original studies were included in total. Meta-analysis showed that BRTO and TIPS had no difference in aspects of technical success rate (OR, 0.19; 95% confidence interval [CI], 0.03-1.08; P = 0.06), hemostasis rate (OR, 3.41; 95% CI, 0.33-35.40; P = 0.30), and incidence rate of postoperative procedure-related complication (OR, 1.98; 95% CI, 0.44-8.84; P = 0.37). However, BRTO had a lower incidence rate of post-operative rebleeding (OR, 0.27; 95% CI, 0.09-0.81; P = 0.02) and a lower incidence rate of postoperative encephalopathy (OR, 0.05; 95% CI, 0.02-0.13; P < 0.00001). CONCLUSIONS: Balloon-occluded retrograde transvenous obliteration was a technically feasible as well as a secure method for the treatment of gastric varices originated from portal hypertension. It may have the potential to be an alterative shunt approach of TIPS, when suitable patients selected. PMID- 26637787 TI - Targeting of the bone marrow microenvironment improves outcome in a murine model of myelodysplastic syndrome. AB - In vitro evidence suggests that the bone marrow microenvironment (BMME) is altered in myelodysplastic syndromes (MDSs). Here, we study the BMME in MDS in vivo using a transgenic murine model of MDS with hematopoietic expression of the translocation product NUP98-HOXD13 (NHD13). This model exhibits a prolonged period of cytopenias prior to transformation to leukemia and is therefore ideal to interrogate the role of the BMME in MDS. In this model, hematopoietic stem and progenitor cells (HSPCs) were decreased in NHD13 mice by flow cytometric analysis. The reduction in the total phenotypic HSPC pool in NHD13 mice was confirmed functionally with transplantation assays. Marrow microenvironmental cellular components of the NHD13 BMME were found to be abnormal, including increases in endothelial cells and in dysfunctional mesenchymal and osteoblastic populations, whereas megakaryocytes were decreased. Both CC chemokine ligand 3 and vascular endothelial growth factor, previously shown to be increased in human MDS, were increased in NHD13 mice. To assess whether the BMME contributes to disease progression in NHD13 mice, we performed transplantation of NHD13 marrow into NHD13 mice or their wild-type (WT) littermates. WT recipients as compared with NHD13 recipients of NHD13 marrow had a lower rate of the combined outcome of progression to leukemia and death. Moreover, hematopoietic function was superior in a WT BMME as compared with an NHD13 BMME. Our data therefore demonstrate a contributory role of the BMME to disease progression in MDS and support a therapeutic strategy whereby manipulation of the MDS microenvironment may improve hematopoietic function and overall survival. PMID- 26637790 TI - Neuronal Inhibition under the Spotlight. AB - In this issue of Neuron,Lin et al. (2015) report an optical method to precisely manipulate the activity of GABAA receptors by designing a mutant receptor that binds photosensitive compounds. This allows for studying GABAA receptors in situ and represents a valuable tool to investigate how inhibition affects brain physiology. PMID- 26637791 TI - Letting Go of JuNK by Disassembly of Adhesive Complexes. AB - Immature neural circuits form excessive synaptic connections that are later refined through pruning of exuberant branches. In this issue, Bornstein et al. identify a role for JNK signaling in selective axon elimination through disassembly of cell adhesion complexes. PMID- 26637792 TI - Astrocytes, Makers of New Neurons. AB - Manipulating neurotransmitter release from astrocytes neighboring the developing new neurons in the course of adult hippocampal neurogenesis, Sultan et al. (2015) reveal that glial influence on neurogenesis ranges from controlling basic precursor cell function well into the establishment of functional circuitry. This extends the concept of the "neurogenic niche" and its key role into advanced stages of adult neuronal development. PMID- 26637793 TI - I Want It All and I Want It Now: How a Neural Circuit Encodes Odor with Speed and Accuracy. AB - A study by Jeanne and Wilson (2015) describes a circuit and determines the distinct neural circuit mechanisms that allow a signal to be represented with both speed and accuracy in the Drosophila olfactory system. PMID- 26637794 TI - Interactionist Neuroscience. AB - We argue that bidirectional interaction between animal and human studies is essential for understanding the human brain. The revolution in meso-scale study of circuits in non-human species provides a historical opportunity. However, to fully realize its potential requires integration with human neuroscience. We describe three strategies for successful interactionist neuroscience. PMID- 26637795 TI - Mechanisms of Long Non-coding RNAs in Mammalian Nervous System Development, Plasticity, Disease, and Evolution. AB - Only relatively recently has it become clear that mammalian genomes encode tens of thousands of long non-coding RNAs (lncRNAs). A striking 40% of these are expressed specifically in the brain, where they show precisely regulated temporal and spatial expression patterns. This begs the question, what is the functional role of these many lncRNA transcripts in the brain? Here we canvass a growing number of mechanistic studies that have elucidated central roles for lncRNAs in the regulation of nervous system development and function. We also survey studies indicating that neurological and psychiatric disorders may ensue when these mechanisms break down. Finally, we synthesize these insights with evidence from comparative genomics to argue that lncRNAs may have played important roles in brain evolution, by virtue of their abundant sequence innovation in mammals and plausible mechanistic connections to the adaptive processes that occurred recently in the primate and human lineages. PMID- 26637796 TI - C9orf72 BAC Transgenic Mice Display Typical Pathologic Features of ALS/FTD. AB - Noncoding expansions of a hexanucleotide repeat (GGGGCC) in the C9orf72 gene are the most common cause of familial amyotrophic lateral sclerosis and frontotemporal dementia. Here we report transgenic mice carrying a bacterial artificial chromosome (BAC) containing the full human C9orf72 gene with either a normal allele (15 repeats) or disease-associated expansion (~100-1,000 repeats; C9-BACexp). C9-BACexp mice displayed pathologic features seen in C9orf72 expansion patients, including widespread RNA foci and repeat-associated non-ATG (RAN) translated dipeptides, which were suppressed by antisense oligonucleotides targeting human C9orf72. Nucleolin distribution was altered, supporting that either C9orf72 transcripts or RAN dipeptides promote nucleolar dysfunction. Despite early and widespread production of RNA foci and RAN dipeptides in C9 BACexp mice, behavioral abnormalities and neurodegeneration were not observed even at advanced ages, supporting the hypothesis that RNA foci and RAN dipeptides occur presymptomatically and are not sufficient to drive neurodegeneration in mice at levels seen in patients. PMID- 26637797 TI - Human C9ORF72 Hexanucleotide Expansion Reproduces RNA Foci and Dipeptide Repeat Proteins but Not Neurodegeneration in BAC Transgenic Mice. AB - A non-coding hexanucleotide repeat expansion in the C9ORF72 gene is the most common mutation associated with familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). To investigate the pathological role of C9ORF72 in these diseases, we generated a line of mice carrying a bacterial artificial chromosome containing exons 1 to 6 of the human C9ORF72 gene with approximately 500 repeats of the GGGGCC motif. The mice showed no overt behavioral phenotype but recapitulated distinctive histopathological features of C9ORF72 ALS/FTD, including sense and antisense intranuclear RNA foci and poly(glycine-proline) dipeptide repeat proteins. Finally, using an artificial microRNA that targets human C9ORF72 in cultures of primary cortical neurons from the C9BAC mice, we have attenuated expression of the C9BAC transgene and the poly(GP) dipeptides. The C9ORF72 BAC transgenic mice will be a valuable tool in the study of ALS/FTD pathobiology and therapy. PMID- 26637798 TI - Targeted DNA Sequencing from Autism Spectrum Disorder Brains Implicates Multiple Genetic Mechanisms. AB - Single nucleotide variants (SNVs), particularly loss-of-function mutations, are significant contributors to autism spectrum disorder (ASD) risk. Here we report the first systematic deep sequencing study of 55 postmortem ASD brains for SNVs in 78 known ASD candidate genes. Remarkably, even without parental samples, we find more ASD brains with mutations that are protein-altering (26/55 cases versus 12/50 controls, p = 0.015), deleterious (16/55 versus 5/50, p = 0.016), or loss of-function (6/55 versus 0/50, p = 0.028) compared to controls, with recurrent deleterious mutations in ARID1B, SCN1A, SCN2A, and SETD2, suggesting these mutations contribute to ASD risk. In several cases, the identified mutations and medical records suggest syndromic ASD diagnoses. Two ASD and one Fragile X premutation case showed deleterious somatic mutations, providing evidence that somatic mutations occur in ASD cases, and supporting a model in which a combination of germline and/or somatic mutations may contribute to ASD risk on a case-by-case basis. PMID- 26637801 TI - Thoracoscopic Repair of Diaphragmatic Hernia in Infants: A New Modification of the Technique. AB - Purpose The objective of this study is to evaluate a novel simplified technique of thoracoscopic repair of congenital diaphragmatic hernia (CDH) in infants. Methods A retrospective review of the new simplified technique in 12 CDH patients admitted between March 2013 and March 2015 was performed. A needle with nonabsorbable 2-0 sutures threaded in the lumen was used to approximate edges of the hernia defect. Results A total of 12 infants with CDH underwent the repair successfully using this new technique. There were 7 boys and 5 girls with a median age of 104.7 days (range, 1 days-17 months). The mean operative time was 65 minutes (range, 35-125 minutes). No conversion or synthetic patch was required. The patients were followed up for 6 to 30 months (mean, 17.5 +/- 8.5 months). There was no mortality and no recurrence. Conclusion The new modified technique of thoracoscopic diaphragmatic hernia repair reduces the difficulty of intracorporal suturing under tension. PMID- 26637799 TI - Presynaptic Deletion of GIT Proteins Results in Increased Synaptic Strength at a Mammalian Central Synapse. AB - A cytomatrix of proteins at the presynaptic active zone (CAZ) controls the strength and speed of neurotransmitter release at synapses in response to action potentials. However, the functional role of many CAZ proteins and their respective isoforms remains unresolved. Here, we demonstrate that presynaptic deletion of the two G protein-coupled receptor kinase-interacting proteins (GITs), GIT1 and GIT2, at the mouse calyx of Held leads to a large increase in AP evoked release with no change in the readily releasable pool size. Selective presynaptic GIT1 ablation identified a GIT1-specific role in regulating release probability that was largely responsible for increased synaptic strength. Increased synaptic strength was not due to changes in voltage-gated calcium channel currents or activation kinetics. Quantitative electron microscopy revealed unaltered ultrastructural parameters. Thus, our data uncover distinct roles for GIT1 and GIT2 in regulating neurotransmitter release strength, with GIT1 as a specific regulator of presynaptic release probability. PMID- 26637800 TI - Heterosynaptic Plasticity Underlies Aversive Olfactory Learning in Drosophila. AB - Although associative learning has been localized to specific brain areas in many animals, identifying the underlying synaptic processes in vivo has been difficult. Here, we provide the first demonstration of long-term synaptic plasticity at the output site of the Drosophila mushroom body. Pairing an odor with activation of specific dopamine neurons induces both learning and odor specific synaptic depression. The plasticity induction strictly depends on the temporal order of the two stimuli, replicating the logical requirement for associative learning. Furthermore, we reveal that dopamine action is confined to and distinct across different anatomical compartments of the mushroom body lobes. Finally, we find that overlap between sparse representations of different odors defines both stimulus specificity of the plasticity and generalizability of associative memories across odors. Thus, the plasticity we find here not only manifests important features of associative learning but also provides general insights into how a sparse sensory code is read out. PMID- 26637802 TI - Using occupancy-based surveys and multi-model inference to estimate abundance and distribution of crested gibbons (Nomascus spp.) in central Laos. AB - Reliable assessments of species' status are prerequisites for monitoring the success of conservation programmes. However, survey conditions such as terrain and inaccessibility, compounded by the low densities of many species across Southeast Asia and other parts of the world are considerable barriers to obtaining robust populations estimates. We used an occupancy-based approach and multi-model inference to generate occupancy and abundance estimates for northern white-cheeked crested gibbons Nomascus leucogenys and southern white-cheeked crested gibbons N. siki in the Nam Kading National Protected Area (NKNPA) in central Lao Peoples' Democratic Republic (hereafter Laos). We present these estimates for gibbons within the context of a strategy designed to monitor multiple species and discuss the practical challenges to obtaining sufficient data for robust population estimates to detect change in gibbon status over time. We surveyed approximately 210 km2 of habitat and estimate an abundance of 45 (SE = 17, CV = 37%) groups, giving an average site abundance of 0.21 (SE = 0.08, CV = 37%) groups per km2 . We make recommendations for ongoing gibbon monitoring and discuss the wider implications for cost effective wildlife monitoring in Laos. Am. J. Primatol. 78:462-472, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26637803 TI - Storage Duration and Other Measures of Quality of Red Blood Cells for Transfusion. PMID- 26637804 TI - Body mass in wild bearded capuchins, (Sapajus libidinosus): Ontogeny and sexual dimorphism. AB - Body mass is fundamental for understanding growth, health, and aspects of life history but records of body mass are rarely available for wild primates. We documented the body mass of all individuals in a group of wild bearded capuchin monkeys (Sapajus libidinosus) at annual intervals for seven consecutive years. Sexual dimorphism in body mass was more pronounced than reported in the literature for adults in this genus: females in our sample were relatively light (average 2.1 kg), while males had average body mass (3.5 kg). Three other notable differences between males and females were evident. First, males grew more rapidly and for a longer period than females. We estimate that males attained full body mass at 9.8 years of age and females at 7.5 years. Second, males showed greater inter-individual variability than females in growth rates and adult mass. Third, males gained about 20% above their baseline body mass upon becoming alpha, and lost that amount when they lost that status, but body mass in females was unrelated to social status. We also report preliminary data on mass and age of natal males at dispersal and mass and age at first reproduction for one female. The pattern of sexual dimorphism in ontogeny and inter-individual variability in body mass in bearded capuchins suggests different competitive risks in the two sexes commensurate with a mating system characterized by female choice of mates in multi-male, multi-female groups. Am. J. Primatol. 78:473-484, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26637806 TI - Molecular heterogeneity of glioblastomas: does location matter? AB - Glioblastomas in adults are highly heterogeneous tumors that can develop throughout the brain. To date no predictive-location marker has been identified. We previously derived two glioblastoma cell lines from cortical and periventricular locations and demonstrated distinct transcriptomic profiles. Based on these preliminary results, the aim of this study was to correlate glioblastoma locations with the expression of ten selected genes (VEGFC, FLT4, MET, HGF, CHI3L1, PROM1, NOTCH1, DLL3, PDGFRA, BCAN). Fifty nine patients with newly diagnosed glioblastomas were retrospectively included. Tumors were classified into cortical and periventricular locations, which were subsequently segregated according to cerebral lobes involved: cortical fronto-parietal (C-FP), cortical temporal (C-T), periventricular fronto-parietal (PV-FP), periventricular temporal (PV-T), and periventricular occipital (PV-O). Gene expression levels were determined using RT-qPCR. Compared to cortical glioblastomas, periventricular glioblastomas were characterized by a higher expression of two mesenchymal genes, VEGFC (p = 0.001) and HGF (p = 0.001). Among cortical locations, gene expressions were homogeneous. In contrast, periventricular locations exhibited distinct expression profiles. PV-T tumors were associated with higher expression of two proneural and cancer stem cell genes, NOTCH1 (p = 0.028) and PROM1 (p = 0.033) while PV-FP tumors were characterized by high expression of a mesenchymal gene, CHI3L1 (p = 0.006). Protein expression of NOTCH1 was correlated with RNA expression levels. PV-O glioblastomas were associated with lower expression of VEGFC (p = 0.032) than other periventricular locations, whereas MET overexpression remained exceptional. These data suggest a differential gene expression profile according to initial glioblastoma location. PMID- 26637805 TI - Whole-genome duplication increases tumor cell sensitivity to MPS1 inhibition. AB - Several lines of evidence indicate that whole-genome duplication resulting in tetraploidy facilitates carcinogenesis by providing an intermediate and metastable state more prone to generate oncogenic aneuploidy. Here, we report a novel strategy to preferentially kill tetraploid cells based on the abrogation of the spindle assembly checkpoint (SAC) via the targeting of TTK protein kinase (better known as monopolar spindle 1, MPS1). The pharmacological inhibition as well as the knockdown of MPS1 kills more efficiently tetraploid cells than their diploid counterparts. By using time-lapse videomicroscopy, we show that tetraploid cells do not survive the aborted mitosis due to SAC abrogation upon MPS1 depletion. On the contrary diploid cells are able to survive up to at least two more cell cycles upon the same treatment. This effect might reflect the enhanced difficulty of cells with whole-genome doubling to tolerate a further increase in ploidy and/or an elevated level of chromosome instability in the absence of SAC functions. We further show that MPS1-inhibited tetraploid cells promote mitotic catastrophe executed by the intrinsic pathway of apoptosis, as indicated by the loss of mitochondrial potential, the release of the pro apoptotic cytochrome c from mitochondria, and the activation of caspases. Altogether, our results suggest that MPS1 inhibition could be used as a therapeutic strategy for targeting tetraploid cancer cells. PMID- 26637807 TI - Zerumbone suppresses the motility and tumorigenecity of triple negative breast cancer cells via the inhibition of TGF-beta1 signaling pathway. AB - Aberrant transforming growth factor-beta (TGF-beta) plays an important role in the development of cancer such as tumor metastasis and invasion. TGF-beta responsive gene signature is highly activated in chemotherapy-treated triple negative breast cancer (TNBC). Here, we investigated the effect of zerumbone (ZER) on TGF-beta1 signaling pathway and tumorigenecity of TNBC cells. Our results showed that the level of TGF-beta1 mRNA expression and cell invasiveness were higher in TNBC cells than in non-TNBC cells. On the other hand, the cell motility of TNBC cells was completely suppressed by LY2109761, a novel selective TGF-beta receptor type I/II (TbetaRI/II) dual inhibitor. In addition, FN and MMP 2 expression, which play an important role on cell motility in various cancer cells, were dose-dependently decreased by LY2109761. TGF-beta1 increased FN, MMP 2 and MMP-9 expression in HCC1806 TNBC cells. TGF-beta1-induced MMP-9 expression was decreased by both a MEK inhibitor, UO126, and a smad3 inhibitor, SIS3. Induction of FN and MMP-2 by TGF-beta1 was just decreased by SIS3. Overexpression of smad3 significantly increased FN, MMP-2, and MMP-9 expression. Interestingly, ZER significantly suppressed TGF-beta1-induced FN, MMP-2, and MMP-9 expression in HCC1806 cells. In addition, ZER completely decreased TGF-beta1-induced the phosphorylation of smad3. Finally, we observed that ZER suppressed the tumorigenecity such as tumor volume, weight, Ki67 expression, and metastasis in TNBC cells xenograft models. Taken together, we demonstrated that ZER suppresses TGF-beta1-induced FN, MMP-2, and MMP-9 expression through the inactivation of smad3 and inhibits the tumorigenecity of TNBC cells. Therefore, we suggest that ZER may act as a promising drug for treatment of TNBC. PMID- 26637808 TI - Long non-coding RNAs in colorectal cancer. AB - Colorectal cancer (CRC) is one of the leading causes of cancer-related death worldwide. Despite substantial progress in understanding the molecular mechanisms and treatment of CRC in recent years, the overall survival rate of CRC patients has not improved dramatically. The development of CRC is multifactor and multistep processes, in which abnormal gene expression may play an important role. With the advance of human tumor molecular biology, a series of studies have highlighted the role of long non-coding RNAs (lncRNAs) in the development of CRC. CRC-related lncRNAs have been demonstrated to regulate the genes by various mechanisms, including epigenetic modifications, lncRNA-miRNA and lncRNA-protein interactions, and by their actions as miRNA precursors or pseudogenes. Since some lncRNAs can be detected in human body fluid and have good specificity and accessibility, they have been suggested to be used as novel potential biomarkers for CRC diagnosis and prognosis as well as in the prediction of the response to therapy. Therefore, in this review, we will focus on lncRNAs in CRC development, the mechanisms and biomarkers of lncRNAs in CRC. PMID- 26637809 TI - MicroRNA-17-5p-activated Wnt/beta-catenin pathway contributes to the progression of liver fibrosis. AB - Aberrant Wnt/beta-catenin pathway contributes to the development of liver fibrosis. MicroRNAs (MiRNAs) are found to act as regulators of the activation of hepatic stellate cell (HSC) in liver fibrosis. However, whether miRNAs activate Wnt/beta-catenin pathway in activated HSCs during liver fibrosis is largely unknown. In this study, we found that Salvianolic acid B (Sal B) treatment significantly inhibited liver fibrosis in CCl4-treated rats, HSC-T6 cells and rat primary HSCs, resulting in the suppression of type I? collagen and alpha-smooth muscle actin. Also, Sal B suppressed HSC activation and cell proliferation in vitro. Interestingly, Sal B treatment induced the inactivation of Wnt/beta catenin pathway, with an increase in P-beta-catenin and Wnt inhibitory factor 1 (WIF1). We demonstrated that the anti-fibrotic effects caused by Sal B were, at least in part, via WIF1. Moreover, our study revealed that miR-17-5p was reduced in vivo and in vitro after Sal B treatment. As confirmed by luciferase activity assays, WIF1 was a direct target of miR-17-5p. Notably, the suppression of HSCs induced by Sal B was almost inhibited by miR-17-5p mimics. Collectively, we demonstrated that miR-17-5p activates Wnt/beta-catenin pathway to result in HSC activation through inhibiting WIF1 expression. PMID- 26637810 TI - Saikosaponin A inhibits influenza A virus replication and lung immunopathology. AB - Fatal influenza outcomes result from a combination of rapid virus replication and collateral lung tissue damage caused by exaggerated pro-inflammatory host immune cell responses. There are few therapeutic agents that target both biological processes for the attenuation of influenza-induced lung pathology. We show that Saikosaponin A, a bioactive triterpene saponin with previouslyestablished anti inflammatory effects, demonstrates both in vitro and in vivo anti-viral activity against influenza A virus infections. Saikosaponin A attenuated the replication of three different influenza A virus strains, including a highly pathogenic H5N1 strain, in human alveolar epithelial A549 cells. This anti-viral activity occurred through both downregulation of NF-kappaB signaling and caspase 3 dependent virus ribonucleoprotein nuclear export as demonstrated by NF-kappaB subunit p65 and influenza virus nucleoprotein nuclear translocation studies in influenza virus infected A549 cells. Critically, Saikosaponin A also attenuated viral replication, aberrant pro-inflammatory cytokine production and lung histopathology in the widely established H1N1 PR8 model of influenza A virus lethality in C57BL/6 mice. Flow cytometry studies of mouse bronchoalveolar lavage cells revealed that SSa exerted immunomodulatory effects through a selective attenuation of lung neutrophil and monocyte recruitment during the early peak of the innate immune response to PR8 infection. Altogether, our results indicate that Saikosaponin A possesses novel therapeutic potential for the treatment of pathological influenza virus infections. PMID- 26637811 TI - Plasma microRNA expression profiles in Chinese patients with rheumatoid arthritis. AB - The outstanding characteristics of circulatory microRNAs (miRNAs) attract much attention in research on disease biomarkers and disease pathogenesis. This study aimed to identify the expression profiles of plasma miRNAs in patients with rheumatoid arthritis (RA). Thirty-three miRNAs were screened using an miRNA array, of which 9 miRNAs were validated as differentially expressed in the plasma of RA patients compared with healthy controls (HCs). miRNA-4634 (miR-4634), miR 181d and miR-4764-5p expression levels were increased, whereas miR-342-3p, miR 3926, miR-3925-3p, miR-122-3p, miR-9-5p and miR-219-2-3p expression levels were decreased in RA patients. The areas under the curve (AUCs) were generated to estimate the sensitivity and specificity of each miRNA or the panel of all 9 miRNAs as biomarkers for RA. AUCs for 9 individual miRNAs ranged from 0.6254 to 0.818; however, the AUC for the panel of 9 miRNAs reached 0.964. Levels of miR 122-3p, miR-3925-3p, miR-342-3p and miR-4764-5p expression showed significant differences between RA and other control groups. miR-4764-5p, miR-4634, miR-9-5p and miR-219-2-3p exhibited significant correlations with either plasma cytokine and chemokine levels or clinical features. In conclusion, this study identified 9 plasma miRNAs signature in Chinese patients with RA which may serve as noninvasive biomarkers for the diagnosis of RA. PMID- 26637813 TI - Aquitalea pelogenes sp. nov., isolated from mineral peloid. AB - Strain P1297T was isolated in the frame of a project aimed on the psychrotolerant microbiota occurring in water sources. The strain initially identified as a tentative species of the genus Aeromonas was rod-shaped, Gram-stain-negative, facultatively anaerobic and oxidase-positive. Subsequently, 16S rRNA gene sequence analysis placed strain P1297T within the class Betaproteobacteria and showed Aquitalea magnusonii TRO-001DR8T as the closest phylogenetic relative with 99.28 % 16S rRNA gene sequence similarity. Digital DDH and average nucleotide identity (ANI) were determined to evaluate the genomic relationship between strain P1297T and Aquitalea magnusonii CCM 7607T. Digital DDH estimation (31.3 +/ 2.46 %) as well as ANI (85.6001 %; reciprocal value 85.3277 %) proved the dissimilarity of strain P1297T. Further investigation using phenotyping, automated ribotyping, whole-cell protein profiling and PCR-fingerprinting methods showed a distinct taxonomic position of strain P1297T among hitherto described species of the genus Aquitalea. DNA-DNA hybridization experiments revealed low binding values between strain P1297T and Aquitalea magnusonii CCM 7607T (57 +/- 3 %) and Aquitalea denitrificans CCM 7935T (41 +/- 5 %). The DNA G+C content of strain P1297T was 60.3 mol%. The predominant fatty acids were C16 : 1omega7c/ iso C15 : 0 2-OH (47.0 %), C16 : 0 (24.5 %) and C18 : 1omega7c (10.6 %), and the quinone system contained predominantly ubiquinone Q-8. The polar lipids detected were diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, two unidentified phospholipids and one unidentified aminophospholipid. Obtained results of genotypic and chemotaxonomic methods clearly proved that strain P1297T represents a novel species of the genus Aquitalea, for which the name Aquitalea pelogenes sp. nov. is proposed. The type strain is P1297T ( = CCM 7557T = LMG 28989T = CCUG 67440T). PMID- 26637812 TI - Effect of Transfusion of Red Blood Cells With Longer vs Shorter Storage Duration on Elevated Blood Lactate Levels in Children With Severe Anemia: The TOTAL Randomized Clinical Trial. AB - IMPORTANCE: Although millions of transfusions are given annually worldwide, the effect of red blood cell (RBC) unit storage duration on oxygen delivery is uncertain. OBJECTIVE: To determine if longer-storage RBC units are not inferior to shorter-storage RBC units for tissue oxygenation as measured by reduction in blood lactate levels and improvement in cerebral tissue oxygen saturation among children with severe anemia. DESIGN, SETTING, AND PARTICIPANTS: Randomized noninferiority trial of 290 children (aged 6-60 months), most with malaria or sickle cell disease, presenting February 2013 through May 2015 to a university affiliated national referral hospital in Kampala, Uganda, with a hemoglobin level of 5 g/dL or lower and a lactate level of 5 mmol/L or higher. INTERVENTIONS: Patients were randomly assigned to receive RBC units stored 25 to 35 days (longer storage group; n = 145) vs 1 to 10 days (shorter-storage group; n = 145). All units were leukoreduced prior to storage. All patients received 10 mL/kg of RBCs during hours 0 through 2 and, if indicated per protocol, an additional 10 mL/kg during hours 4 through 6. MAIN OUTCOMES AND MEASURES: The primary outcome was the proportion of patients with a lactate level of 3 mmol/L or lower at 8 hours using a margin of noninferiority equal to an absolute difference of 25%. Secondary measures included noninvasive cerebral tissue oxygen saturation during the first transfusion, clinical and laboratory changes up to 24 hours, and survival and health at 30 days after transfusion. Adverse events were monitored up to 24 hours. RESULTS: In the total population of 290 children, the mean (SD) presenting hemoglobin level was 3.7 g/dL (1.3) and mean lactate level was 9.3 mmol/L (3.4). Median (interquartile range) RBC unit storage was 8 days (7-9) for shorter storage vs 32 days (30-34) for longer storage without overlap. The proportion achieving the primary end point was 0.61 (95% CI, 0.52 to 0.69) in the longer storage group vs 0.58 (95% CI, 0.49 to 0.66) in the shorter-storage group (between-group difference, 0.03 [95% CI, -0.07 to infinity], P < .001), meeting the prespecified margin of noninferiority. Mean lactate levels were not statistically different between the 2 groups at 0, 2, 4, 6, 8, or 24 hours. Kaplan-Meier analysis and global nonlinear regression revealed no statistical difference in lactate reduction between the 2 groups. Clinical assessment, cerebral oxygen saturation, electrolyte abnormalities, adverse events, survival, and 30-day recovery were also not significantly different between the groups. CONCLUSIONS AND RELEVANCE: Among children with lactic acidosis due to severe anemia, transfusion of longer-storage compared with shorter-storage RBC units did not result in inferior reduction of elevated blood lactate levels. These findings have relevance regarding the efficacy of stored RBC transfusion for patients with critical tissue hypoxia and lactic acidosis due to anemia. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01586923. PMID- 26637815 TI - Aetherobacter fasciculatus gen. nov., sp. nov. and Aetherobacter rufus sp. nov., novel myxobacteria with promising biotechnological applications. AB - Bacterial strains SBSr002T and SBSr003T were isolated in 2007 from dried soil samples containing decaying plant material. The organisms were recognized as myxobacteria by growth-stage characteristics, forming swarming colonies and fruiting bodies on agar and on filter paper. These strains were unusual for their ring-like or halo colony appearance in an agar. Both isolates were characterized as bacteriolytic, non-cellulolytic, mesophilic, aerobic and chemoheterotrophic and showed resistance to various antibiotics. GC-MS analysis of their cellular fatty acids revealed rather large quantities of docosahexaenoic acid, and they also both contained eicosapentaenoic acid, arachidonic acid and docosapentaenoic acid. Strain SBSr003T was previously identified as the producer organism of a novel class of potent antiviral metabolites that were called aetheramides. The G+C content of the genomic DNA was 68.0-68.9 mol%. Phylogenetic analysis revealed that both strains belong within the family Polyangiaceae, suborder Sorangiineae, order Myxococcales. Their 16S rRNA gene sequences showed the highest similarity (97-99 %) to sequences derived from clones of uncultured bacteria, 95-96 % similarity to Byssovorax cruenta and Sorangium cellulosum and 94 % similarity to Chondromyces apiculatus. The results of a polyphasic taxonomic characterization suggested that strains SBSr002T and SBSr003T represent two distinct species of a novel genus, Aetherobacter gen. nov., for which the names Aetherobacter fasciculatus sp. nov. (type strain SBSr002T = DSM 24601T = NCCB 100377T) and Aetherobacter rufus sp. nov. (type strain SBSr003T = DSM 24628T = NCCB 100378T) are proposed. The type species of Aetherobacter is Aetherobacter fasciculatus. PMID- 26637816 TI - Sellimonas intestinalis gen. nov., sp. nov., isolated from human faeces. AB - A Gram-stain-positive and obligately anaerobic bacterial strain, BR72T, forming ivory yellow colonies was isolated from a faecal sample of a healthy Korean woman. 16S rRNA gene sequence analysis indicated that strain BR72T belongs to Clostridium cluster XIVa and represents a distinct phyletic line within the family Lachnospiraceae. The most closely related strains were Clostridium nexile DSM 1787T (94.1 % 16S rRNA gene sequence similarity), Coprococcus comes ATCC 27758T (93.5 %), Ruminococcus torques ATCC 27756T (93.5 %), Ruminococcus lactaris ATCC 29176T (93.5 %), Clostridium aerotolerans DSM 5434T (93.1 %) and Eubacterium fissicatena DSM 3598T (92.9 %). The DNA G+C content of strain BR72T based on its genome sequence was 45.3 mol%. The major cellular fatty acids were C16 : 0, C14 : 0, and iso-C17 : 1 I and/or anteiso-C17 : 1 B. Acetic acid was produced from glucose fermentation. Other physiological and biochemical comparisons allowed the phenotypic differentiation of strain BR72T from the members of the family Lachnospiraceae. Based on the phylogenetic and phenotypic findings, this strain is considered to represent a novel species of a new genus belonging to the family Lachnospiraceae and the name Sellimonas intestinalis gen. nov., sp. nov. is proposed. The type strain of Sellimonas intestinalis is BR72T ( = KCTC 15479T = JCM 30749T). PMID- 26637817 TI - Isolation and characterization of Flexilinea flocculi gen. nov., sp. nov., a filamentous, anaerobic bacterium belonging to the class Anaerolineae in the phylum Chloroflexi. AB - A novel obligately anaerobic bacterium, designated strain TC1T, was isolated from methanogenic granular sludge in a full-scale mesophilic upflow anaerobic sludge blanket reactor treating high-strength starch-based wastewater. Cells had a multicellular filamentous morphology, stained Gram-negative and were non-motile. The filaments were flexible, generally >100 MUm long and 0.3-0.4 MUm wide. Growth of the isolate was observed at 25-43 degrees C (optimum 37 degrees C) and pH 6.0-8.5 (optimum pH 7.0). Strain TC1T grew chemo-organotrophically on a range of carbohydrates under anaerobic conditions. Yeast extract was required for growth. The major fermentative end products of glucose, supplemented with yeast extract, were acetate, lactate, succinate, propionate, formate and hydrogen. Co cultivation with the hydrogenotrophic methanogen Methanospirillum hungatei DSM 864T enhanced growth of the isolate. The DNA G+C content was determined experimentally to be 42.1 mol%. The major cellular fatty acids were anteiso-C15 : 0, iso-C15 : 0 and iso-C17 : 0 3-OH. Based on 16S rRNA gene sequence analysis, strain TC1T belonged to the class Anaerolineae in the phylum Chloroflexi, in which Ornatilinea apprima P3M-1T was its closest phylogenetic relative (88.3 % nucleotide identity). Phylogenomic analyses using 38 and 83 single-copy marker genes also supported the novelty of strain TC1T at least at the genus level. Based on phylogenetic, genomic and phenotypic characteristics, we propose that strain TC1T represents a novel species of a new genus, for which we suggest the name Flexilinea flocculi gen. nov., sp. nov. The type strain of Flexilinea flocculi is strain TC1T ( = JCM 30897T = CGMCC 1.5202T). PMID- 26637818 TI - Enterobacter bugandensis sp. nov., isolated from neonatal blood. AB - A total of 17 Enterobacter-like isolates were obtained from blood during a septicaemia outbreak in a neonatal unit, Tanzania, that could not be assigned based on phenotypic test to any existing Enterobacter species. Eight representative outbreak isolates were investigated in detail. Fermentation characteristics, biochemical assays and fatty acid profiles for taxonomic analysis were determined and supplemented with information derived from whole genome sequences. Phenotypic and morphological tests revealed that these isolates were Gram-stain-negative, rod-shaped, highly motile and facultatively anaerobic. The fatty acid profile was similar to those of the type strains for all recognized Enterobacter species, with quantitative differences in C17 : 0, C18 : 1omega7c and C17 : 0 cyclo fatty acids. Whole genome sequencing was used to identify taxonomically relevant characteristics, i.e. for 16S rRNA gene sequence analysis, multi-locus sequence analysis (MLSA), in silico DNA-DNA hybridization (isDDH) and average nucleotide identity (ANI). Draft genomes were approximately 4.9 Mb in size with a G+C content of 56.0 mol%. The 16S rRNA gene sequence of these eight isolates showed >97 % similarity to all Enterobacter species, while MLSA clustered them closely with the type strains of Enterobacter xiangfangensis and Enterobacter hormaechei. These eight strains showed less than 70 % isDDH identity with the type strains of Enterobacter species. In addition, less than 95 % ANI to the type strains of Enterobacter species was observed. From these results, it is concluded that these isolates possess sufficient characteristics to differentiate them from all recognized Enterobacter species, and should therefore be considered as representing a novel species. The name Enterobacter bugandensis sp. nov. is proposed with EB-247T ( = DSM 29888T = NCCB 100573T) as the type strain. PMID- 26637819 TI - Description of Domibacillus iocasae sp. nov., isolated from deep-sea sediment, and emended description of the genus Domibacillus. AB - In this study, we report a novel Gram-stain-positive bacterium, designated strain S6T, isolated from deep-sea sediment in Okinawa Trough. Growth of strain S6T occurred at 10-45 degrees C (optimum, 35 degrees C), at pH 6.0-11.0 (optimum, 8.0) and with 0-8 % (w/v) NaCl (optimum, 3 %). Phylogenetic analysis based on the 16S rRNA gene sequence indicated that strain S6T belonged to the genus Domibacillus. The closest phylogenetic neighbours of strain S6T were Domibacillus robiginosus WS 4628T ( = DSM 25058T) (98.6 %16S rRNA gene sequence similarity), D. indicus SD111T ( = DSM 28032T) (97.6 %), D. enclensis NIO-1016T ( = DSM 25145T) (97.6 %), and 'D. tundrae' PAMC 80007 ( = DSM 29572) (97.6 %). Levels of similarity between strain S6T and other close relatives were below 96 %. The levels of DNA-DNA relatedness between strain S6T and its closest relatives in the genus Domibacillus were well below 70 %. The genomic DNA G+C content of strain S6T was 44.4 mol%. The major menaquinone was MK-6. The polar lipids of strain S6T contained diphosphatidylglycerol, phosphatidylglycerol, phosphatidylinositol mannosides, phosphatidylethanolamine and three unknown phospholipids. Strain S6T harboured meso-diaminopimelic acid as the diagnostic diamino acid and an A1gamma type of peptidoglycan. The major cell-wall sugars of strain S6T were xylose and glucose. Phylogenetic, physiological, biochemical and morphological analyses suggest that this strain represents a novel species of the genus Domibacillus, for which the name Domibacillus iocasae sp. nov. is proposed. The type strain is S6T ( = DSM 29979T = CCTCC AB 2015183T). An emended description of the genus Domibacillus is also provided. PMID- 26637820 TI - Erwinia endophytica sp. nov., isolated from potato (Solanum tuberosum L.) stems. AB - We analysed, using a polyphasic taxonomic approach, two bacterial strains coded BSTT30T and BSTT40, isolated in the course of a study of endophytic bacteria occurring in the stems and roots of potatoes growing in soil from Salamanca, Spain. The 16S rRNA gene sequence was identical in both strains and had 98.4 % identity with respect to the closest relatives Erwinia tasmaniensis Et1/99T and Erwinia rhapontici ATCC29283T. Erwinia billingiae E63T and Erwinia toletana A37T were also closely related with 98.2 % sequence similarities, so the novel strains were classified within the genus Erwinia. The analysis of the housekeeping genes gpd, gyrB and rpoD confirmed the phylogenetic affiliation of strains BSTT30T and BSTT40 with similarities of lower than 90 % in all cases with respect to the closest relatives mentioned above. The respiratory quinone of strain BSTT30T was Q8. The major fatty acids were C16 : 0, C16 : 1omega7c/16 : 1omega6c in summed feature 3 and C18 : 1omega7c/18 : 2omega6,9c in summed feature 8. The novel strains were oxidase-negative and catalase-positive. Glucose was fermented without gas production. They were negative for arginine dihydrolase, urease and indole production. The strains could grow at 35 degrees C and at pH 10. DNA G+C content was 50.1 mol%. DNA-DNA hybridization results showed values of lower than 29 % relatedness with respect to the type strains of the four most closely related species. Therefore, the combined genotypic, phenotypic and chemotaxonomic data support the classification of strains BSTT30T and BSTT40 into a novel species of the genus Erwinia, for which the name Erwinia endophytica sp. nov. is proposed. The type strain is BSTT30T ( = LMG 28457T, CECT 8692T). PMID- 26637821 TI - Acetobacter musti sp. nov., isolated from Bobal grape must. AB - An acetic acid bacterium (strain Bo7T), obtained during a study of the microbial diversity of spontaneous fermentations of Bobal grape must, was subjected to a taxonomic study using a polyphasic approach. Phylogenetic analysis based on 16S rRNA gene sequences allocated strain Bo7T to the genus Acetobacter, and revealed Acetobacter aceti and Acetobacter oeni to be nearest neighbours (99.57 % 16S rRNA gene sequence similarity between strain Bo7T and A. oeni CECT 5830T, and 98.76 % between strain Bo7T and A. aceti CECT 298T). Cells of strain Bo7T are Gram negative, motile rods, catalase-positive and oxidase-negative. The DNA G+C content of strain Bo7T was 58.0 mol%. DNA-DNA hybridizations demonstrated that strain Bo7T belongs to a single novel genospecies that can be differentiated from its nearest phylogenetic neighbours by the following phenotypic characteristics: no production of 5-keto-d-gluconic acid from d-glucose, growth with glycerol but not with methanol or maltose as sole carbon sources, and growth on yeast extract with 30 % d-glucose. The major fatty acid was C18 : 1omega7c/C18 : 1omega6c (summed feature 8; approx. 56 %); other fatty acids in significant amounts (>5 %) were C16 : 0 2-OH (11 %), C16 : 0 (7 %), C14 : 0 2-OH (7 %) and C14 : 0 3-OH/iso C16 : 1 I (summed feature 2; 6 %). The results obtained indicate that strain Bo7T represents a novel species of the genus Acetobacter, for which the name Acetobacter musti sp. nov. is proposed. The type strain is Bo7T ( = DSM 23824T = CECT 7722T). PMID- 26637822 TI - Luteimonas notoginsengisoli sp. nov., isolated from rhizosphere. AB - A Gram-staining-negative, yellow-pigmented strain, designated SYP-B804T, was isolated from the rhizosphere of Panax notoginseng. The strain was rod-shaped with a single polar flagellum. The optimum temperature and pH required for growth of the strain were 28-32 degrees C and pH 7-8, respectively. 16S rRNA gene sequence analysis indicated that strain SYP-B804T showed highest 16S rRNA gene sequence similarity with Luteimonas mephitis DSM 12574T (98.0 %). However, the DNA-DNA relatedness value between them (38.1 +/- 0.6 %) was less than the threshold value for the delineation of genomic species. Ubiquinone-8 (Q-8) was the predominant quinone. The major fatty acids were iso-C15 : 0 and iso-C17 : 1omega9c. The major polar lipids of the strain were diphosphatidylglycerol, phosphatidylglycerol and phosphatidylethanolamine. The G+C content of the genomic DNA was 71 %. On the basis of phenotypic, chemotaxonomic and molecular characteristics, strain SYP-B804T merits recognition as a representative of a novel species of the genus Luteimonas, for which the name Luteimonas notoginsengisoli sp. nov. is proposed, with SYP-B804T ( = KCTC 42211T = JCM 30329T) as the type strain. PMID- 26637823 TI - Actinorectispora indica gen. nov., sp. nov. isolated from soil, a member of the family Pseudonocardiaceae. AB - The taxonomic positions of three Gram-stain-positive, aerobic strains, designated YIM 75722, 75726 and 75728T, and isolated from a soil sample collected from Kurnool of Andhra Pradesh province, India, were assessed using a polyphasic approach. Growth was observed at pH 7.0-10.0 (optimum pH 7.0), 15-28 degrees C (optimum 28 degrees C) and 0-8 % (w/v) NaCl (grew without NaCl). Strains showed cylindrical spores with straight-chain morphology on aerial mycelium, but did not reveal sporangium-like structures or fragmentation of the substrate mycelium. Whole-cell hydrolysates of all strains contained galactose and ribose as the diagnostic sugars and meso-diaminopimelic acid as the diamino acid. The predominant menaquinone was MK-9(H4); MK-9 (H6) and MK-10 (H4) were present in smaller amounts. The phospholipid pattern consisted mainly of diphosphatidylglycerol, phosphatidylglycerol and phosphatidylcholine. The major fatty acids were i-C15 : 0, ai-C15 : 0, i-C17 : 0 and ai-C17 : 0. The genomic DNA G+C content was 68.0 mol%. Phylogenetic analysis, based on 16S rRNA gene sequences, revealed that strain YIM 75728T should be placed within the family Pseudonocardiaceae, in which the strain formed a distinct lineage. The combination of phylogenetic analysis, phenotypic characteristics and chemotaxonomic data support the conclusion that strain YIM 75728T represents a novel species of a novel genus of the family Pseudonocardiaceae for which the name Actinorectispora indica gen. nov., sp. nov., is proposed. Strain YIM 75728T ( = DSM 45410T = CCTCC AA 209065T) is the type strain of Actinorectispora indica. Strain YIM 75728T was considered as the type strain over the other two strains based on the highest sequence read length of the strain. PMID- 26637824 TI - Anemia Screening and Treatment Outcomes of Children in a Low-resource Community in the Dominican Republic. AB - Iron is often initiated for children with low hemoglobin values in the absence of other indicators of iron deficiency in low-resource settings. Unfortunately, there are few reports describing outcomes from such an approach outside of clinical trials. This study examined outcomes of an anemia screening and treatment service in a low-resource community in the Dominican Republic. Complete blood counts (CBC) and receipt of iron supplementation were extracted from health records of young children participating in a well-baby clinic in the targeted community. Of the 265 children screened, 68.7% had hemoglobin values <11.0 g/dl; 61.5% of these anemic children had follow-up CBCs. While 72.3% of those with follow-up CBCs picked-up some iron supplements, only 21.4% had a follow-up hemoglobin >=11.0 g/dl. Amount of iron given was not related to change in hemoglobin at follow-up. More follow-up monitoring of quality and impact of community care is required with associated evidence-informed benchmark targets. PMID- 26637825 TI - Modular protein switches derived from antibody mimetic proteins. AB - Protein switches have potential applications as biosensors and selective protein therapeutics. Protein switches built by fusion of proteins with the prerequisite input and output functions are currently developed using an ad hoc process. A modular switch platform in which existing switches could be readily adapted to respond to any ligand would be advantageous. We investigated the feasibility of a modular protein switch platform based on fusions of the enzyme TEM-1 beta lactamase (BLA) with two different antibody mimetic proteins: designed ankyrin repeat proteins (DARPins) and monobodies. We created libraries of random insertions of the gene encoding BLA into genes encoding a DARPin or a monobody designed to bind maltose-binding protein (MBP). From these libraries, we used a genetic selection system for beta-lactamase activity to identify genes that conferred MBP-dependent ampicillin resistance to Escherichia coli. Some of these selected genes encoded switch proteins whose enzymatic activity increased up to 14-fold in the presence of MBP. We next introduced mutations into the antibody mimetic domain of these switches that were known to cause binding to different ligands. To different degrees, introduction of the mutations resulted in switches with the desired specificity, illustrating the potential modularity of these platforms. PMID- 26637826 TI - Comparison of clinical outcome with radiological findings after trapeziectomy with ligament reconstruction and tendon interposition. AB - The aim of our study was to investigate if pre- and postoperative radiographic thumb carpometacarpal position is correlated with clinical and subjective outcomes. Radiographs of 105 patients undergoing trapeziectomy with ligament reconstruction and tendon interposition were analysed before, as well as 1 year after, surgery for dorsal subluxation and proximal migration of the thumb metacarpal bone. Furthermore, key pinch strength was measured and patients completed the Michigan Hand Outcomes Questionnaire. Baseline dorsal subluxation and scaphometacarpal distances significantly decreased from 8.2 mm and 11.0 mm to 5.2 mm and 5.1 mm at 1 year, respectively. There was no correlation between the amount of subluxation or proximal migration and the Michigan Hand Outcomes Questionnaire score or key pinch strength. These results suggest that postoperative position of the metacarpal base of the thumb does not affect clinical or subjective outcomes after trapeziectomy with ligament reconstruction and tendon reposition of the thumb carpometacarpal joint. LEVEL OF EVIDENCE: Level 3. PMID- 26637827 TI - The European thoracic data quality project: An Aggregate Data Quality score to measure the quality of international multi-institutional databases. AB - OBJECTIVES: To describe the methodology for the development of data quality metrics in multi-institutional databases, deriving a cumulative data quality score [Aggregate Data Quality score (ADQ)]. The ESTS database was used to create and apply the metrics. The Units contributing to the ESTS database were ranked for the quality of data uploaded using the ADQ. METHODS: We analysed data obtained from 96 Units contributing with at least 100 major lung resections (January 2007 to December 2014). The Units were anonymized assigning a casual numeric code. The following metrics were developed for measuring the data quality of each Unit: (i) record Completeness (COM); rate of present variables on 16 expected variables for all the records uploaded [1 - ('null values'/total expected values for the Unit) * 100, the concept of 'null value' was defined for each variable]; (ii) record Reliability (REL); rate of consistent checks on 9 checks tested for all the records uploaded [1 - (valid controls/total possible controls for the Unit) * 100, specific reliability control queries were defined]. These two metrics were rescaled using the mean and standard deviation of the entire dataset and summed, obtaining: (iii) ADQ score: [COM rescaled + REL rescaled]; it measures the cumulative data quality of a given dataset. The ADQ was used to rank the contributors. RESULTS: The COM of ESTS database contributors varied from 98.6 to 43% and the REL from 100 to 69%. Combining the rescaled metrics, the obtained ADQ ranged between 2.67 (highest data quality) and -7.85 (lowest data quality). Comparing the rating using just the COM value to the one obtained using the ADQ, 93% of Units changed their position. The major change was the drop of 66 positions considering the ADQ list. CONCLUSIONS: We described a reproducible method for data quality assessment in clinical multi-institutional databases. The ADQ is a unique indicator able to describe data quality and to compare it among centres. It has the potential of objectively guiding projects of data quality management and improvement. PMID- 26637828 TI - Prevalence and risk factors for intimate partner violence among Grade 8 learners in urban South Africa: baseline analysis from the Skhokho Supporting Success cluster randomised controlled trial. AB - BACKGROUND: Intimate partner violence (IPV) is a serious public health problem among adolescents. This study investigated the prevalence of and factors associated with Grade 8 girls' experience and boys' perpetration of IPV in South Africa. METHODS: Participants were interviewed using interviewer-administered questionnaires about IPV, childhood violence, bullying, gender attitudes, alcohol use and risky sexual behaviours. Multiple logistic regression analysis was conducted to assess factors associated with girls' experience and boys' perpetration of IPV. Structural equation modelling (SEM) was conducted to assess the pathways to IPV experience and perpetration. RESULTS: Results show dating relationships are common among girls (52.5%) and boys (70.7%) and high prevalence of sexual or physical IPV experience by girls (30.9%; 95% CI: 28.2-33.7) and perpetration by boys (39.5%; 95% CI: 36.6-42.3). The logistic regression model showed factors associated with girls' experience of IPV include childhood experience of violence, individual gender inequitable attitudes, corporal punishment at home and in school, alcohol use, wider communication with one's partner and being more negative about school. We found three pathways from childhood trauma to IPV experience and perpetration in both models and these are through inequitable gender attitudes and risky sex, bullying and alcohol use. CONCLUSIONS: Prevention of IPV in children needs to encompass prevention of exposure to trauma in childhood and addressing gender attitudes and social norms to encourage positive disciplining approaches. : The trial is registered on ClinicalTrials.gov as NCT02349321. PMID- 26637830 TI - Reply: First do no harm: continuing the uterine NK cell debate. PMID- 26637831 TI - The absence of evidence is not the evidence of absence. PMID- 26637829 TI - Autophagy regulation in the development and treatment of breast cancer. AB - Autophagy is a major catabolic process in which intracellular membrane structures, protein complexes, and lysosomes are formed as lysoautophagosome to degrade and renew cytoplasmic components. Autophagy is physiologically a strategy and mechanism for cellular homeostasis as well as adaptation to stress, and thus alterations in the autophagy machinery may lead to diverse pathological conditions. The role of autophagy in cancer is complex, and the current literature reflects this as a 'double-edged sword'. Autophagy shows promise as a novel therapeutic target in various types of breast cancer, inhibiting or increasing treatment efficacy in a context- and cell-type-dependent manner. This review aims to summarize the recent advances in the understanding of the mechanisms by which key modulators of autophagy participate in cancer metastasis, highlight different autophagy-deficient murine models for breast cancer study, and provide further impetus for the modulation of autophagy in anticancer therapy. PMID- 26637832 TI - Testosterone: a hormone preventing cardiovascular disease or a therapy increasing cardiovascular events? AB - Decreasing testosterone levels with ageing is a well-known condition in older men named 'low T', 'manopause', or hypogonadism. Observational studies suggested an association between low endogenous testosterone levels and a high cardio metabolic profile (increased blood pressure, dyslipidaemia, insulin resistance, atherosclerosis, thrombosis), as well as a modest increase in total and cardiovascular (CV) mortality. Controversies persist regarding the need for screening 'low T' in older men, as well as what precisely should be the indication(s) for testosterone replacement therapy. So far, no data have shown that normalization of testosterone levels reduce CV events. Although testosterone replacement therapy seems to have beneficial effects on male quality of life or physical condition, some data suggest serious adverse events, such as CV events. In addition, there is a lack of consensus on the threshold for treatment indication in men with non-specific symptoms or borderline levels of testosterone. Available data from clinical practice setting suggest an increase in testosterone prescription over time and possible overtreatment. In recent years, pharmaceutical companies have promoted 'low T' as a treatable disease, suggesting that testosterone replacement may help restore energy, positive mood and sexuality, and despite ageing. Currently, well-designed, adequately powered randomized controlled trials are needed to assess the impact of testosterone replacement therapy on CV clinically relevant CV outcomes within age-specific ranges to strengthen the evidence for clinical practice guidelines. PMID- 26637833 TI - Repetition rescues regenerative reserve. PMID- 26637835 TI - Postoperative CT Evaluation After EVAR: A Comparison of Image Assessment. AB - PURPOSE: To compare the postoperative computed tomography angiography (CTA) assessment made by vascular surgeons and interventional radiologists after endovascular aneurysm repair (EVAR) at a tertiary vascular clinic to an outside core review facility. METHODS: One hundred patients (mean age 78.7 years, range 88-55; 84 men) with consecutive, elective, routine CTA controls after EVAR were retrospectively studied. Consultant vascular surgeons or radiologists had evaluated all original scans and written the original report. All scans were then reevaluated by an independent core clinic. Findings were classified as vascular or extravascular and stratified as clinically significant or clinically nonsignificant by an independent external reviewer. RESULTS: The number of vascular findings detected by the vascular clinic was 72 vs 69 by the core clinic. The vascular clinic reported more clinically significant findings (primarily stent compression or kinks) as well as endoleaks and their origin. The core clinic reported more pseudoaneurysms (24 vs 12). None of the patients with puncture complications needed reintervention. Interrater analysis of all findings between the 2 clinics showed good agreement when comparing endoleaks overall (without subclassification) and moderate agreement when assessing aneurysm growth. The core clinic reported extravascular findings in 58 patients; 37 of these were classified as clinically significant. The vascular clinic reported extravascular findings in 23 patients; 7 of these were clinically significant. The core clinic also reported 2 cases of suspected malignancies, which had not been reported by the vascular clinic. CONCLUSION: During routine CTA follow-up after EVAR, a significant number of vascular and nonvascular findings are detected. Whereas a highly dedicated vascular clinic identifies most vascular findings regardless of the specialty of the reader, some extravascular findings are missed. However, the frequency of clinically significant findings or findings that might warrant reintervention was low in this study. PMID- 26637834 TI - Ascertainment, classification, and impact of neoplasm detection during prolonged treatment with dual antiplatelet therapy with prasugrel vs. clopidogrel following acute coronary syndrome. AB - AIMS: Studies have suggested increased cancer incidence associated with long-term dual antiplatelet therapy (DAPT) for acute coronary syndrome (ACS). We evaluated cancer incidence and treatment-related differences in an analysis of DAPT for ACS. METHODS AND RESULTS: The Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes trial enrolled 9326 participants with ACS, who received aspirin plus clopidogrel or prasugrel. Median treatment exposure was 15 months. Cancer history and screening procedures were collected. Suspected non-benign neoplasm events were reported and adjudicated. The primary outcome was detection of new, non-benign neoplasm. Factors associated with neoplasm events, the relationship of these events to cardiovascular and bleeding endpoints, and treatment-related differences in neoplasm detection were studied. Among 9240 participants who received >=1 dose of study drug, 1.8% had a confirmed neoplasm event. The efficacy composite of cardiovascular death, myocardial infarction, or stroke occurred more frequently among those with a neoplasm event vs. those without (18.2 vs. 13.5%) as did Global Use of Strategies to Open Occluded Coronary Arteries severe/moderate bleeding (11.2 vs. 1.5%). Screening rates were substantially higher in North America and Western Europe/Scandinavia vs. other regions. Factors most strongly associated with detection of neoplasm events were older age, region, male sex, and current/recent smoking. Among the pre-specified population without a history of neoplasm or previous curative treatment for neoplasm (n = 9105), the incidence of neoplasm events was similar with prasugrel vs. clopidogrel (1.8 vs. 1.7%; HR = 1.04; 95% CI 0.77-1.42; P = 0.79). CONCLUSIONS: Neoplasm events were infrequent during long term DAPT after ACS, were associated with differential cancer-screening practices across regions, and the frequency of neoplasm detection was similar with prasugrel vs. clopidogrel. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00699998. PMID- 26637836 TI - Intravascular Ultrasound in Lower Extremity Peripheral Vascular Interventions: Variation in Utilization and Impact on In-Hospital Outcomes From the Nationwide Inpatient Sample (2006-2011). AB - PURPOSE: To examine the impact of intravascular ultrasound (IVUS) utilization during lower limb endovascular interventions as regards postprocedural complications and amputation. METHODS: The study cohort was derived from the Healthcare Cost and Utilization Project Nationwide Inpatient Sample database between the years 2006 and 2011. Peripheral endovascular interventions were identified using appropriate ICD-9 procedure codes. Two-level hierarchical multivariate mixed models were created. The co-primary outcomes were in-hospital mortality and amputation; the secondary outcome was postprocedural complications. Model results are given as the odds ratio (OR) and 95% confidence interval (CI). Hospitalization costs were also assessed. RESULTS: Overall, among the 92,714 patients extracted from the database during the observation period, IVUS was used in 1299 (1.4%) patients. IVUS utilization during lower extremity peripheral vascular procedures was independently predictive of a lower rate of postprocedural complications (OR 0.80, 95% CI 0.66 to 0.99, p=0.037) as well as lower amputation rates (OR 0.59, 95% CI 0.45 to 0.77, p<0.001) without any significant impact on in-hospital mortality. Multivariate analysis also revealed IVUS utilization to be predictive of a nonsignificant increase in hospitalization costs ($1333, 95% CI -$167 to +$2833, p=0.082). CONCLUSION: IVUS use during lower limb endovascular interventions is predictive of lower postprocedural complication and amputation rates with a nonsignificant increase in hospitalization costs. PMID- 26637837 TI - Neuromonitoring, Cerebrospinal Fluid Drainage, and Selective Use of Iliofemoral Conduits to Minimize Risk of Spinal Cord Injury During Complex Endovascular Aortic Repair. AB - PURPOSE: To review outcomes of continuous motor/somatosensory-evoked potential (MEP/SSEP) monitoring, cerebrospinal fluid drainage, and selective use of iliofemoral conduits in patients undergoing endovascular repair of descending thoracic aneurysm (DTA) and thoracoabdominal aortic aneurysms (TAAAs). METHODS: The clinical data of 49 patients (mean age 75+/-8 years; 38 men) who underwent endovascular repair of DTA and TAAAs (2011-2014) were reviewed. All patients had cerebrospinal fluid drainage, permissive hypertension (mean arterial pressure >=80 mm Hg), and MEP/SSEP monitoring. There were 44 (90%) patients with TAAAs and 5 (10%) with DTA. Types I and II TAAAs were repaired in staged procedures. Iliofemoral conduits were used for small iliac arteries and to minimize time of lower extremity ischemia in patients with difficult anatomy. In patients with changes in MEP/SSEPs, a standardized protocol was employed to optimize spinal cord perfusion and restore lower extremity blood flow. Endpoints were mortality, spinal cord injury (SCI), and lower extremity ischemic complications. RESULTS: Sixteen (33%) patients had staged TAAA repair. A total of 163 visceral arteries were targeted by fenestrations and branches (mean 3.7+/-1.0 vessels/patient). Temporary iliofemoral conduits were used in 16 limbs/14 patients. A stable MEP/SSEP was achieved in all patients. Thirty-one (63%) patients had a >=75% decrease in MEP/SSEP amplitude in 50 limbs starting on average 75+/-28 minutes after obtaining vascular access. MEP/SSEP amplitude improved with maneuvers in 12 (39%) patients and returned to baseline with restoration of lower extremity flow in all except 1 patient who developed immediate SCI. Thirty-day mortality was 4%. Three (6%) patients had SCI, 2 permanent and 1 temporary at 14 days. There were no lower extremity ischemic complications. CONCLUSION: Neuromonitoring predicted immediate SCI and allowed use of a protocol to optimize spinal cord and lower extremity perfusion during complex endovascular aortic repair. Larger clinical experience is needed to evaluate the efficacy of neuromonitoring to prevent SCI. PMID- 26637838 TI - Use of the Off-the-Shelf t-Branch Device to Treat an Acute Type Ia Endoleak in a Symptomatic Juxtarenal Abdominal Aortic Aneurysm. AB - PURPOSE: To report the use of the off-the-shelf Zenith t-Branch Thoracoabdominal Endovascular Graft for the treatment of a symptomatic acute type Ia endoleak subsequent to previous infrarenal bifurcated endovascular aneurysm repair. CASE REPORT: A 72-year-old man presented 4 years after implantation of an Anaconda stent-graft with sac expansion and type II endoleak, which was treated over the next 18 months with repeated coil and glue embolization of the leak and sac. Six months after the last attempt, imaging disclosed a new type Ia endoleak. Sac enlargement became symptomatic, and emergent treatment was performed using the off-the-shelf Zenith b-Branch device. The 4 visceral arteries were bridged with Fluency stent-grafts. The Anaconda stent-graft precluded the use of a standard Zenith universal distal body bifurcated device below the t-Branch graft, so a reversed tapered 16*20*82-mm iliac limb was placed to bridge the t-Branch to the larger Anaconda limb; the smaller 12-mm contralateral Anaconda limb was occluded. The procedure was concluded with a femorofemoral bypass. At 10 months after the procedure, the patient is well; the sac diameter has decreased, and there is no endoleak on imaging. CONCLUSION: The multibranched Zenith t-branch device may be useful in treating proximal endoleaks in bifurcated stent-grafts. PMID- 26637839 TI - Positive Bias in Teenage Drivers With ADHD Within a Simulated Driving Task. AB - OBJECTIVE: Youth with ADHD exhibit positive bias, an overestimation of ability, relative to external indicators. The positive bias construct is understudied in adolescents, particularly in the domain of driving. Study is needed as youth with ADHD experience greater negative outcomes in driving relative to typically developing teens. METHOD: Positive bias on a driving simulator task was investigated with 172 teenagers with ADHD, combined type. Youth participated in a driving simulation task and rated driving performance afterward. RESULTS: Compared with external ratings of driving performance, youth overestimated driving competence for specific driving behaviors as well as globally. The global rating demonstrated a greater degree of positive bias. Greater positive bias on global ratings of driving ability also predicted greater rates of risky driving behaviors during the simulator exercise independent from disruptive behavior disorder symptoms. CONCLUSION: Results inform prevention and intervention efforts for teenage drivers with ADHD. PMID- 26637840 TI - Longitudinal Evaluation of the Cognitive-Behavioral Model of ADHD in a Sample of College Students With ADHD. AB - OBJECTIVE: The primary aim of this study was to evaluate longitudinal pathways to impairment as outlined in the cognitive-behavioral model of ADHD in a sample of 59 college students diagnosed with ADHD. METHOD: Serial mediation models were used to test whether underachievement, defined as prior year GPA, would longitudinally predict self-reported impairment at the end of the next school year, through negative self-concept and associated changes in symptoms of anxiety and depression, while controlling for baseline impairment and changes in ADHD symptoms. RESULTS: Findings supported the cognitive-behavioral model of ADHD. The association between prior year GPA and overall impairment at the end of the year was fully mediated through self-concept and symptoms of depression. CONCLUSION: These results help explain why impairment often persists even when ADHD symptoms remit and suggests that internalizing symptoms may be an important target for intervention in college students with ADHD. PMID- 26637841 TI - Exploring Behavioral Sleep Problems in Children With ADHD and Comorbid Autism Spectrum Disorder. AB - OBJECTIVE: This study (a) compared behavioral sleep problems in children with comorbid ADHD and autism spectrum disorder (ASD) with those with ADHD and (b) examined child/family factors associated with sleep problems. METHOD: Cross sectional study comparison of 392 children with a confirmed ADHD diagnosis (ADHD+ASD, n=93, ADHD, n=299) recruited from 21 peadiatric practises in Victoria, Australia. Data were collected from parents. Key measures included the Child Sleep Habits Questionnaire (CSHQ). RESULTS: Children with ADHD + ASD experienced similar levels and types of behavioral sleep problems compared with those with ADHD. In both groups, the presence of co-occurring internalizing and externalizing comorbidities was associated with sleep problems. Sleep problems were also associated with parent age in the ADHD + ASD group and poorer parent mental health in the ADHD group. CONCLUSION: Findings suggest comorbid ASD is not associated with increased behavioral sleep problems in children with ADHD and that co-occurring internalizing and externalizing comorbidities may flag children in these groups with sleep problems. PMID- 26637842 TI - Early Visual Foraging in Relationship to Familial Risk for Autism and Hyperactivity/Inattention. AB - OBJECTIVE: Information foraging is atypical in both autism spectrum disorders (ASDs) and ADHD; however, while ASD is associated with restricted exploration and preference for sameness, ADHD is characterized by hyperactivity and increased novelty seeking. Here, we ask whether similar biases are present in visual foraging in younger siblings of children with a diagnosis of ASD with or without additional high levels of hyperactivity and inattention. METHOD: Fifty-four low risk controls (LR) and 50 high-risk siblings (HR) took part in an eye-tracking study at 8 and 14 months and at 3 years of age. RESULTS: At 8 months, siblings of children with ASD and low levels of hyperactivity/inattention (HR/ASD-HI) were more likely to return to previously visited areas in the visual scene than were LR and siblings of children with ASD and high levels of hyperactivity/inattention (HR/ASD+HI). CONCLUSION: We show that visual foraging is atypical in infants at risk for ASD. We also reveal a paradoxical effect, in that additional family risk for ADHD core symptoms mitigates the effect of ASD risk on visual information foraging. PMID- 26637843 TI - Clinical Effects of ADHD Subtypes in Patients With Social Anxiety Disorder. AB - OBJECTIVE: Our aim in this study is to evaluate the impacts of inattentive and combined types of childhood ADHD (ADHD-I, ADHD-C) in patients with social anxiety disorder (SAD). METHODS: A total of 142 adult outpatients with a primary diagnosis of SAD were included. All patients were assessed by using the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I), Schedule for Affective Disorders and Schizophrenia for School Age Children-Present and Lifetime Version (K-SADS-PL), ADHD module and a clinical and sociodemographic data form and scales were filled out. RESULTS: Childhood ADHD comorbidity rates was found to be 88 (62%) in patients with SAD, and 63 of these patients had the diagnosis of ADHD-I. ADHD-I group had higher scores of social anxiety and avoidance and had earlier onset of SAD than the ADHD-C group. CONCLUSION: The inattentive subtype of ADHD may have a more specific relationship with SAD than ADHD-C. PMID- 26637844 TI - Long-term BCR-ABL1 Tyrosine Kinase Inhibitor Therapy in Chronic Myeloid Leukemia. AB - With the success of tyrosine kinase inhibitor (TKI) therapy for the treatment of patients with chronic myeloid leukemia (CML), CML is now treated as a chronic disease. As such, the community of oncologists may see patients with CML more often than the primary-care physician and must focus on long-term management of adverse events and adherence. BCR-ABL1 TKIs are effective therapies in CML but are associated with distinct safety profiles. Thus, selection of long-term treatment with any TKI requires assessment of patient comorbidities and regular monitoring to identify the potential emergence of adverse effects or new risk factors. With a focus on long-term safety, this review provides a holistic picture of the primary care needs of patients with CML, emphasizing on the importance of community oncologists who in many cases act as both oncologists and primary-care physicians. PMID- 26637845 TI - Increased Production of Lysozyme Associated with Bacterial Proliferation in Barrett's Esophagitis, Chronic Gastritis, Gluten-induced Atrophic Duodenitis (Celiac Disease), Lymphocytic Colitis, Collagenous Colitis, Ulcerative Colitis and Crohn's Colitis. AB - The mucosa of the esophagus, the stomach, the small intestine, the large intestine and rectum are unremittingly challenged by adverse micro-environmental factors, such as ingested pathogenic and non-pathogenic bacteria, and harsh secretions with digestive properties with disparate pH, as well as bacteria and secretions from upstream GI organs. Despite the apparently inauspicious mixture of secretions and bacteria, the normal GI mucosa retains a healthy state of cell renewal. To by-pass the tough microenvironment, the epithelia of the GI react by speeding-up cell exfoliation, by increasing peristalsis, eliminating bacteria through secretion of plasma cell-immunoglobulins and by increasing production of natural antibacterial enzymes (lysozyme) and host defense peptides (defensin-5). Lysozyme was recently found up-regulated in Barrett's esophagitis, in chronic gastritis, in gluten-induced atrophic duodenitis (celiac disease), in collagenous colitis, in lymphocytic colitis and in Crohn's colitis. This up-regulation is a response directed towards the special types of bacteria thriving in the microenvironment in each of the aforementioned clinical inflammatory maladies. The purpose of that up-regulation is to protect the mucosa affected by the ongoing chronic inflammation. Bacterial antibiotic resistance continues to exhaust our supply of effective antibiotics. The future challenge is how to solve the increasing menace of bacterial resistance to anti-bacterial drugs. Further research on natural anti-bacterial enzymes such as lysozyme, appears mandatory. PMID- 26637846 TI - Curcumin for the Treatment of Glioblastoma. AB - Glioblastoma multiforme is a highly aggressive primary cancer of the brain associated with a poor prognosis. Modest increases in survival can sometimes be achieved with the use of temozolomide and radiation therapy after surgery, but second-line therapy after recurrence has a limited efficacy. Curcumin has demonstrated promising results against this form of cancer in experimental models. The reported activity of curcumin against cancer stem cells, a major cause of glioblastoma resistance to therapy, and its ability to augment the apoptotic effects of ceramides, suggest it would have a synergistic effect with cytotoxic chemotherapy agents currently used in second-line therapy, such as lomustine. PMID- 26637847 TI - Extracellular Vesicles as Biomarkers and Therapeutic Targets in Breast Cancer. AB - Cancer-derived extracellular vesicles (EVs) contain various cancer-associated molecules, such as mutated or overexpressed oncoproteins, glycoproteins, mRNAs, various non-coding RNAs and DNA fragments. They have been shown to propagate phenotypic traits, such as drug resistance, increased proliferation rate, invasiveness and stemness across cancer cells and to mediate cancer-induced immunosuppression. Therefore, cancer-derived EVs have gained increasing attention as cancer biomarkers and therapeutic targets. Unlike circulating tumor cells they are highly abundant in biofluids and, on the contrary to single-molecule circulating biomarkers, they protect their molecular cargo against degradation and may carry molecular signatures associated with specific phenotypes. Herein, we summarize studies investigating EVs as biomarkers in breast cancer and propose scenarios for various clinical applications of EV-based biomarkers in the management of breast cancer. Furthermore, we provide an overview of recent findings regarding the cancer-promoting effects of breast cancer-derived EVs and discuss opportunities for blocking EV-mediated signaling as a therapeutic strategy for breast cancer. PMID- 26637848 TI - Innovative Therapeutic Strategies in the Treatment of Meningioma. AB - Few medical options are available for progressive/recurrent and atypical/anaplastic meningiomas. New developments in chemotherapeutic options for meningiomas have been explored over the past decade. We review the more recent literature to recognize studies investigating recent medical and chemotherapeutic agents that have been experienced or are currently being tested for meningiomas. Combination therapies affecting multiple molecular targets are currently opening up and present significant promise as adjuvant therapeutic options. However, there is an evident need for new molecular studies in order to better understand the biology of meningiomas and, thus, to identify new and more specific therapeutic targets. PMID- 26637849 TI - Expression of PAX2 and PTEN Correlates to Therapy Response in Endometrial Hyperplasia. AB - AIM: To investigate if a levonorgestrel-impregnated intrauterine system (LNG-IUS) was more efficient compared to oral progestin in the clearance of the paired box 2 gene (PAX2) - and phosphatase and tensin homolog (PTEN)-null endometrial glands and assess the significance of PAX2- and PTEN-null glands as markers for therapy response in endometrial hyperplasia. PATIENTS AND METHODS: Immunohistochemical staining using antibodies against PAX2 and PTEN was performed in 141 pre- and post-treatment endometrial biopsies comparing the effect of LNG-IUS, 10 mg medroxyprogesterone acetate (MPA) taken continuously, or 10 mg MPA taken 10 days per cycle for six months. PAX2- and PTEN-null glands were investigated by light microscopy in pre-and post-treatment biopsies. RESULTS: Clearance of PAX2- and PTEN-null glands was significantly more efficient by LNG-IUS compared to oral MPA (p<0.000 and p=0.008, respectively) and significantly related to therapy response (p<0.000 and p=0.002, respectively). PMID- 26637850 TI - Enhanced Systemic Bioavailability of Curcumin Through Transmucosal Administration of a Novel Microgranular Formulation. AB - BACKGROUND/AIM: Curcumin is a promising nutraceutical for chemoprevention of head and neck squamous cell carcinoma (HNSCC). Capsular formulations of curcumin demonstrate low systemic bioavailability. We aimed to determine if curcumin levels were higher in healthy volunteers and cancer patients with microgranular curcumin that allows for transmucosal absorption and identify a consistent biomarker. PATIENTS AND METHODS: Eight healthy volunteers and 15 HNSCC patients completed the trials. Serum levels of curcumin were measured by HPLC. Biological activity of curcumin was assessed with Multiplex Immunoassay and immunohistochemistry. RESULTS: We achieved higher serum levels of curcumin compared to trials using capsular formulation. In cancer patients a significant decrease in expression of fibroblast growth factor-2 (FGF-2) in post-biopsy samples and decreased serum levels of FGF-2, granulocyte macrophage colony stimulating factor (GM-CSF) and interleukin-17 (IL-17) (p<0.05) was observed. CONCLUSION: Transmucosal administration of microgranular curcumin leads to enhanced curcumin bioavailability that is associated with significant biological effects. PMID- 26637851 TI - Celecoxib and LLW-3-6 Reduce Survival of Human Glioma Cells Independently and Synergistically with Sulfasalazine. AB - Gliomas are among the most commonly diagnosed central nervous system tumors. Celecoxib has been utilized with success in the treatment of several types of cancer, including gliomas. The present study examined the antiproliferative effects of celecoxib and its benzimidazole-based analog, LLW-3-6, when used as co treatment with sulfasalazine against human glioma LN18 cells. At 48-h treatment, the glioma cells maintained 60% viability in the presence of celecoxib or LLW-3-6 at the maximum concentration tested (40 MUM). Co-treatment of glioma cells under a non-lethal dose (50 MUM) of sulfasalazine and either celecoxib or LLW-3-6 (administered at different concentrations) resulted in improved inhibition of cell viability. The concentration of the molecules required to reduce cell growth in the combined treatment was significantly less than that needed when either molecule was administered independently. Based on computational values, LLW-3-6 has physiochemical characteristics that should allow for improved bioavailability in comparison to that of celecoxib. PMID- 26637852 TI - Novel Nanoscale Delivery Particles Encapsulated with Anticancer Drugs, All-trans Retinoic Acid or Curcumin, Enhance Apoptosis in Lymphoma Cells Predominantly Expressing CD20 Antigen. AB - BACKGROUND: Mantle cell lymphoma (MCL), a B-cell lymphoma, pursues a relatively aggressive course, is resistant to long-term remission, and is associated with a poor prognosis. There is a pressing need for innovative treatment approaches against MCL. One such approach is targeted delivery of cytotoxic drugs to MCL cells. MATERIALS AND METHODS: In the current investigation, we pursued a strategy to employ retinoid-based or curcumin-based nanoscale delivery particles, called nanodisks (NDs), for targeted drug delivery to MCL cells (Granta), and human follicular lymphoma (HF-1) cells. The cells were incubated with NDs made of CD20 single-chain variable antibody fragment (scFv)/apolipoprotein A-1 fusion protein, and loaded with either all-trans retinoic acid (ATRA) or curcumin, and cell apoptosis was measured using flow cytometry. RESULTS AND CONCLUSION: At 10 MUM, curcumin-ND induced cell death more effectively than ATRA-ND. Combination of curcumin-ND and ATRA-ND significantly enhanced the biological activity of these drugs against lymphoma cells compared to individual treatments. PMID- 26637853 TI - Establishment of a Novel In Vitro Model for Predicting Incidence and Severity of Microtubule-targeting Agent-induced Peripheral Neuropathy. AB - Peripheral neuropathy (PN) is a major dose-limiting side-effect of microtubule targeting agents (MTAs), considered to be induced by inhibition of axonal microtubules. Therefore, it was thought that a useful method for predicting the frequencies of severe sensory-PN (FPN) would be to evaluate the neurite disrupting effects of MTAs. Using neurite outgrowth from neuron-like cell lines, we comprehensively evaluated the neurite-disrupting effects of several anti cancer drugs including MTAs, and the reversibility of the effects of MTAs. MTAs that induce PN showed neurite-disrupting effects more strongly than MTAs and anticancer drugs that do not induce PN, but the effects were not related to the FPN. On the other hand, MTAs with high FPN exhibited lower reversibility than those with low FPN. These findings suggest that neurite-disrupting effects are associated with the incidence of PN, and the reversibility of the effects is associated with FPN. PMID- 26637854 TI - Evidence of 18F-FCH Uptake in Human T98G Glioblastoma Cells. AB - AIM: Tumor and chemo/radiotherapy-damaged brain tissues are hardly distinguishable by conventional morphological imaging. (18)F-FCH was compared against (18)F-FDG in the T98G glioblastoma cell line with regard to their radiopharmaceutical uptake, in order to test its diagnostic power on brain tumor lesions. MATERIALS AND METHODS: Equimolar amounts of (18)F-FCH and (18)F-FDG were added to human glioblastoma T98G cells and human dermal fibroblasts for 20, 40, 60, 90 and 120 min of incubation. Radiopharmaceutical uptake was expressed as a percentage of the administered dose. Cold choline was used for binding competition experiments. RESULTS: In T98G cells (18)F-FCH was taken-up in higher amounts than 18F-FDG after 60 min. In fibroblasts, uptake was lower than 1% for both radiopharmaceuticals. Cold choline reduced the uptake of FCH to 1% similarly to fibroblasts. CONCLUSION: Our results prove the efficacy of (18)F-FCH as a promising tracer, better than (18)F-FDG in establishing the tumor-to-background ratio in brain tumors. PMID- 26637855 TI - Patterns of Chromosomal Abnormalities that Can Improve Diagnosis of Uterine Smooth Muscle Tumors. AB - BACKGROUND/AIM: Compared to leiomyomas, smooth muscle tumors of uncertain malignant potential (STUMP), and leiomyosarcomas (LMS) originating from the Muellerian duct are very rare. Their molecular pathogenesis remains poorly understood. The present article aims at performing genetic analyses of these tumors that may help assist histopathological examination. MATERIALS AND METHODS: Ten tumors (four STUMP and six LMS) were investigated by copy number arrays. RESULTS: Two tumors, both classified as STUMP were shown to carry MED12 mutations with one of them presenting with a detectable copy number alteration. All other tumors had multiple copy number changes with a clear predominance of losses. Five chromosomal arms (1p, 13q, 14q, 16q, 22q) were affected by overlapping lost segments in at least four tumors including two cases with biallelic losses of the retinoblastoma gene locus. CONCLUSION: Besides the general presence of copy number alterations and particular genetic alterations, heterogeneity and ongoing karyotypic evolution indicate malignancy or approaching malignancy. PMID- 26637856 TI - Comparison of Methods to Identify Lymphatic and Blood Vessel Invasion and their Prognostic Value in Patients with Primary Operable Colorectal Cancer. AB - BACKGROUND/AIM: Lymphatic and blood vessel invasion are important independent prognostic factors in colorectal cancer, but identification of the separate components remains difficult. The aim of the present study was to compare routine hematoxylin and eosin (H&E) and elastica staining with immunohistochemistry using D2-40 and CD31. MATERIALS AND METHODS: A total of 75 surgical specimens of colorectal cancer were examined for blood and lymphatic vessel invasion, by comparing stains. RESULTS: The minimum clinical follow-up of survivors was 5 years. During that time, 45 patients died, 34 from their cancer. Lymphatic invasion by H&E was found in 19% compared to 40% detected with D2-40 (p<0.001). Lymphatic invasion was not associated with T-stage (H&E, p=0.923; D2-40, p=0.724) but was significantly associated with N-stage, (H&E, p=0.001; D2-40, p<0.001). No significant association between lymphatic invasion (H&E or D2-40) and cancer specific survival was found on univariate analysis. Blood vessel invasion by elastic detection was detected in 53% compared to 32% detected with CD31 (p=0.090). Blood vessel invasion was associated with T-stage, (elastica, p=0.028; CD31, p=0.839) but was not associated with N-stage (elastica, p=0.377; CD31, p=0.519). On univariate analysis of blood vessel invasion was associated with cancer-specific survival (elastica, p=0.009) when detected by elastica, but not when detected by CD31, (p=0.611). Lymphatic invasion (D2-40) was associated with blood vessel invasion (elastic) (p=0.019). On multivariate analysis, blood vessel invasion with elastica had independent prognostic value (hazard ratio=2.55, 95% confidence interval=1.23-5.28; p=0.012). CONCLUSION: The results of the present study indicate that immunohistochemistry using D2-40 improves the identification of lymphatic invasion compared to use of H&E staining only; however, its prognostic value was limited. Elastica staining improves the detection rate of blood vessel invasion (compared to CD31) and venous invasion detected with elastica had independent prognostic value in patients undergoing curative resection for colorectal cancer. PMID- 26637857 TI - Increased Peroxiredoxin 6 Expression Predicts Biochemical Recurrence in Prostate Cancer Patients After Radical Prostatectomy. AB - BACKGROUND/AIM: Elevated levels of oxidative stress biomarkers have been shown to associate with more aggressive behavior in malignancies. The aim of the present study was to determine the relationship between the expression of peroxiredoxins (Prx) and sulfiredoxin (Srx) in localized prostate cancer (PC) with clinicopathological parameters and outcome after radical prostatectomy (RP). MATERIALS AND METHODS: Samples of 240 RP patients were analyzed for Prx1, 2, 5 and 6 and Srx expression by immunohistochemistry and the results were correlated with clinicopathological data, biochemical recurrence-free survival (BFS), prostate cancer-specific survival (PCS) and overall survival (OS). RESULTS: Augmented Prx2 and Prx6 expression was associated with several conventional prognostic factors. Increased Prx2 and Prx6 expression predicted for shortened BFS (p=0.027 and p=0.020) and worse OS (p=0.045 and p=0.033). In the multivariate analysis, Prx6 expression was an independent predictor of BFS (p=0.030). CONCLUSION: Elevated Prx6 expression associates with a worse prognosis after RP for clinically localized PC. PMID- 26637858 TI - Ferredoxin Reductase Is Useful for Predicting the Effect of Chemoradiation Therapy on Esophageal Squamous Cell Carcinoma. AB - BACKGROUND: Ferredoxin reductase (Fdxr) is the mitochondrial cytochrome P-450 NADPH reductase. Fdxr overexpression increases the sensitivity of tumor cells to apoptosis in response to chemotherapy through reactive oxygen species (ROS) production. The aim of the present study was to examine the Fdxr expression in esophageal squamous cell carcinoma (ESCC) and determine if the expression is useful for predicting response to chemoradiation therapy (CRT). MATERIALS AND METHODS: Fdxr expression in biopsy specimens from 50 patients before neoadjuvant CRT were immunohistochemically examined. Then, the correlation between Fdxr expression and response to CRT were analyzed. RESULTS: Both clinically and histologically, significant correlations were found between positive Fdxr expression and favorable response to CRT. Furthermore, Fdxr was significantly correlated with postoperative outcomes and was found to be an independent prognostic factor. CONCLUSION: Fdxr expression was found to be closely related to the effect of CRT and could predict the CRT outcome in patients with ESCC. PMID- 26637859 TI - Down-regulation of HDGF Inhibits the Growth of Hepatocellular Carcinoma Cells In Vitro and In Vivo. AB - BACKGROUND: Hepatoma-derived growth factor (HDGF) is a growth factor of various malignant diseases. However, the in vivo effects of HDGF suppression targeting for hepatocellular carcinoma (HCC) have not been clarified to date. MATERIALS AND METHODS: We stably transfected HDGF shRNA into SK-HEP-1 human HCC cells and investigated the effects of HDGF reduction on HCC growth using a cell proliferation assay and a murine xenograft model. The effects of HDGF reduction on VEGF expression and in vivo angiogenesis were also investigated with real-time PCR and immunostaining analyses, respectively. RESULTS: HDGF reduction resulted in a decreased proliferative activity of SK-HEP-1 cells both in vitro and in vivo. The in vivo anti-tumor effects of HDGF were particularly higher than that expected in vitro. HDGF-reduction suppressed VEGF expression in SK-HEP-1 cells and in vivo angiogenesis of developed tumors. CONCLUSION: These findings suggest that targeted inhibition of HDGF may be a novel anti-HCC therapy. PMID- 26637860 TI - A Biomimicking Tumor Tissue Model Using Hepatocellular Carcinoma Cell Sheet in a Collagen Sandwich System. AB - Cytotoxic efficacy of anticancer drugs has been widely studied with monolayer cultured cancer cells. However, the drug efficacy under two-dimensional (2D) culture conditions usually differs from that of three-dimensional (3D) culture conditions. In the present study, an in vitro tumor tissue model was constructed by sandwiching a cancer cell monolayer (cancer cell sheet) between two collagen layers as a biomimicking tumor tissue model, and the in vitro cytotoxic efficacy of doxorubicin was investigated. In the biomimicking tumor tissue model, hypoxic areas were observed, and the secretion of vascular endothelial growth factor increased time-dependently. Additionally, cell growth inside the model was significantly slower than that of the 2D culture system. The in vitro cytotoxicity of doxorubicin with the 3D system decreased compared to the 2D system, suggesting that the surrounding collagen layer acted as a barrier much like cancer stroma does. Consequently, this study successfully demonstrated that the cancer cell sheet in collagen sandwich configuration provides a useful in vitro tumor tissue model. PMID- 26637861 TI - Co-expression of Cytoskeletal Protein Adducin 3 and CD133 in Neurospheres and a Temozolomide-resistant Subclone of Glioblastoma. AB - BACKGROUND: Glioma stem cells are associated for temozolomide-resistance in glioblastoma. Adducin 3 (ADD3) is a cytoskeletal protein associated with chemoresistance but its role in glioblastoma has not been investigated. MATERIALS AND METHODS: Using an in vitro model of glioblastoma cells with acquired temozolomide resistance (D54-MG-R), the expressions of ADD3 and cancer stem cell markers were compared to those in temozolomide-sensitive glioblastoma cells (D54 MG-S). Immunofluorescence staining was used to investigate the expression patterns of ADD3 and cancer stem cell markers in temozolomide resistance and neurospheres of glioblastoma. RESULTS: Chemoresistant cells were found to have up regulation of ADD3 and CD133 expression. A sub-population of D54-MG-R cells and glioma neurospheres exhibited coexpression of ADD3 with CD133. CONCLUSION: To our knowledge, this is the first report of a possible link between cytoskeletal protein expression, cancer stem cell phenotype and temozolomide resistance in human glioblastoma. This report lays the foundation for further investigation for ADD3 as a potential biomarker and therapeutic target in temozolomide-resistant glioma cells. PMID- 26637862 TI - Comparative Chemosensitivity of VX2 and HCC Cell Lines to Drugs Used in TACE. AB - AIM: To compare the cytotoxic effects of 11 anticancer agents against VX2 and HepG2 cells in order to establish candidate drugs that can be tested preclinically on VX2 tumor model for transarterial chemoembolization (TACE) of hepatocellular carcinoma (HCC). MATERIALS AND METHODS: VX2 and HepG2 cells were incubated with different drug concentrations. The half-maximal inhibitory concentration (IC50) values were determined by total cell protein assay for anthracyclines, platins, irinotecan, mytomicin-C (MMC), 5-fluorouracil (5-FU) and antiangiogenics. RESULTS: IC50 values for VX2 and HepG2 were found close for doxorubicin (0.8 MUM vs. 1.1 MUM), MMC (13.9 MUM vs. 8.7 MUM), sunitinib (32.7 vs. 33.7 MUM), sorafenib (10.3 vs. 8.9 MUM), lapatinib (30 vs. 18.3 MUM) and different for platins and irinotecan. Oxaliplatin was less active against VX2 than HepG2 (IC50=41 MUM vs. 2.7 MUM), cisplatin was more active against VX2 than HepG2 (IC50=8.0 MUM vs. 15.9 MUM), whereas carboplatin had a low toxicity against both cell lines (70.4 MUM vs. 538.3 MUM). The toxicity of 5-FU against VX2 and HepG2 was low (IC50=560.6 MUM vs. 323.2 MUM). Irinotecan was less active against VX2 vs. HepG2 (IC50=44.5 MUM vs. 15.3 MUM). Bevacizumab had no effect on either of the cell lines up to 6.7 MUM. CONCLUSION: Drugs recommended for pre-clinical trials of TACE in the VX2 model are doxorubicin, sunitinib, sorafenib, MMC, lapatinib and 5-FU. PMID- 26637863 TI - Molecular Docking Analysis of Steroid-based Copper Transporter 1 Inhibitors. AB - Copper transporter 1 (CTR1) represents an important determinant of cisplatin resistance. A series of 35 semi-substituted steroids were recently investigated on cisplatin-resistant CTR1-expressing A2780cis ovarian carcinoma cells as well as their parental sensitive counterparts regarding their cytotoxic and resistance reversing features. In the present investigation, three compounds ( 4: , 5: , 25: ) were selected for molecular docking analysis on the homology-modelled human CTR1 transmembrane domain. Steroids 4: , 5: and 25: interacted with CTR1 at a similar docking pose and with even higher binding affinities than the known CTR1 inhibitor, cimetidine. Applying the defined docking mode, the binding energies were found to be -7.15+/-<0.001 kcal/mol (compound 4: ), -8.71+/-0.06 kcal/mol (compound 5: ), -7.63+/-0.01 kcal/mol (compound 25: ), and -5.05+/-0.02 kcal/mol (for cimetidine). These steroids have the potential for further development as CTR1 inhibitors overcoming cisplatin resistance. PMID- 26637864 TI - Vascular Innervation in Benign Neurofibromas of Patients with Neurofibromatosis Type 1. AB - Neurofibroma constitutes a heterogeneous group of solid tumours occurring sporadically or in association with syndromes. The aspect of these peripheral nerve sheath tumours may vary considerably, with disseminated tumours covering various parts of the body or nodular/diffuse plexiform neurofibroma that can grow to an impressive size. Although neurofibromas have vascular density comparable to that of normal tissue, they have tendency to bleed upon surgery which is poorly understood. Herein we investigated whether this finding may result from alterations of peripheral vasculature innervation. Different types of neurofibroma and controls were evaluated with special reference to nerve fibre topography and vessel density. MATERIALS AND METHODS: Seventy-six formalin-fixed and paraffin-embedded tissue samples (63 neurofibromas and 13 skin biopsies) were retrieved from the archives of the Institute of Neuropathology, University Medical Center Hamburg-Eppendorf. Nerve fibres and blood vessels were differentiated immunohistochemically on 10-MUm-thick tumour slices using antibodies against smooth muscle actin (arteries), protein gene product 9.5 (PGP9.5) and neurofilament (nerve fibres). Skin samples served as controls. Nerve fibre and vessel densities were quantified morphometrically. RESULTS: Nerve fibre density varied considerably. However, vascular innervation did not statistically significantly differ between the different tumour sub-groups and controls. Vessel density was not significantly increased in tumours compared to skin biopsies. Within the tumour sub-groups, diffuse plexiform neurofibroma presented a significantly higher vascular density than atypical neurofibroma (p=0.006). CONCLUSION: Blood vessel density and vascular innervation in the whole cohort of neurofibromas did not significantly differ from that of controls. Thus, the source of prolonged and intense bleeding of neurofibroma during surgical procedures cannot be explained by increased vessel density or loss of innervation, but may be attributed to other factors such as alterations in the structure of the vascular wall. PMID- 26637865 TI - Cytological and Immunocytological Monitoring of Oropharyngeal Dysplasia and Squamous Cell Carcinomas. AB - BACKGROUND/AIM: Due to the high recurrence rates of squamous cell carcinoma of the head and neck (SCCHN) and de-novo local secondary carcinomas, a close monitoring of patients is mandatory. In doubtful cases, a clearance by histological biopsy is necessary. This, however, bears potential complications. We analyzed the application of combined cytology and immunocytology in cytological brush smears for diagnosing pre-malignant and malignant lesions of the oral/oropharyngeal cavity. MATERIALS AND METHODS: Brush biopsies of 30 subsequently histologically-confirmed oral/oropharyngo-/laryngeal cavity cancer cases (all then in a recurrence status) and normal mucosa were obtained for routine cytology and immunocytology for cytokeratin-8 (CK-8). Additionally 20 samples with inflammatory lesions were investigated. RESULTS: Our results showed a high rate for positive prediction of oral/oropharyngo-/laryngeal dysplasia/cancer cases. Accordingly, 82% of all subsequently confirmed cases were detected by cytology alone (sensitivity). The specificity, however, of cytology was distinctly lower since several doubtful cases contained only inflammatory lesions (specificity 85%). The addition of CK-8-immunocytology did not increase the sensitivity, since the rate of detected cases by immunocytology was comparable to routine cytology (79%); however, the addition of immunocytology significantly increased the specificity (up to 90%). CONCLUSION: Routine cytology is a simple, non-invasive and cost-effective method for routine control and screening of dysplastic oral/oropharyngo-/laryngeal lesions. In doubtful cases, the addition of CK-8-immunocytology is very helpful for the distinction of reactive from neoplastic cases. PMID- 26637866 TI - Endostatin Effects on Tumor Cells and Vascular Network of Human Renal Cell Carcinoma Implanted on Chick Embryo Chorioallantoic Membrane. AB - Rare and inconsistent data are reported for chorioallantoic tumor models of renal cell carcinoma and none of them has used endostatin as an inhibitory agent of tumor development. We aimed to perform a comparative analysis of tumor cells and blood vessels from renal cell carcinoma on endostatin-treated and non-treated chorioallantoic membrane (CAM) implants by the assessment of endoglin, vascular endothelial growth factor (VEGF) and smooth muscle actin expression. Endostatin triple action on tumor, endothelial and perivascular cells was observed in the present study. Differential impact of endostatin treatment on intratumor and peritumor blood vessels was noticed on the VEGF expression and behaviour of tumor cells between clear cell and papillary components of RCC. Based on our findings, a high tumor heterogenity response to endostatin has been highlighted. Interplay between VEGF, endoglin and endostatin in RCC could support a combined targeted therapy to improve prognosis of patients with RCC and reduce therapy resistance often developed by monotherapy. PMID- 26637867 TI - Suppression of AKT Potentiates Synergistic Cytotoxicity of Apigenin with TRAIL in Anaplastic Thyroid Carcinoma Cells. AB - BACKGROUND: We studied the effect of apigenin in combination with tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) on cell survival and the influence of AKT inhibition on the combined effect of apigenin with TRAIL in anaplastic thyroid carcinoma (ATC) cells. MATERIALS AND METHODS: The human 8505C and CAL62 ATC cell lines were used. RESULTS: Apigenin in combination with TRAIL, compared to apigenin alone, reduced cell viability and Bcl2 protein levels, elevated the percentage of dead cells, as well as the protein levels of cleaved PARP and phospho-ERK1/2. The protein levels of Bcl-xL, Bax, Bid, total ERK1/2, and total and phospho-AKT were unchanged. Administration of wortmannin further reduced cell viability, and elevated the percentage of dead cells, cytotoxic activity and cleaved PARP protein levels. CONCLUSION: Apigenin synergizes with TRAIL through regulation of Bcl2 family proteins in inducing cytotoxicity, and suppression of AKT potentiates synergistic cytotoxicity of apigenin with TRAIL in ATC cells. PMID- 26637868 TI - Tumour Progression and Spontaneous Regression in the Lewis Rat Sarcoma Model. AB - Spontaneous regression of tumours is a fascinating phenomenon rarely observed in oncological patients. We used a Lewis rat sarcoma model in which subcutaneous tumours developed after inoculation of the R5-28/clone C4 cells. Rats with tumour progression showed splenomegaly and anaemia. Tumour growth was associated with leucocytosis, granulocytosis, decrease in lymphocyte and CD161(+) population in peripheral blood and increase in serum MCP1 concentration. Animals with spontaneous regression of tumours initially showed an increase in white blood cells number and proportion of granulocytes. Between the 42nd and 49th day, however, values of these parameters dropped in correlation with reduction of tumour size. In spontaneously regressed tumours, vascularization was higher and on the contrary, progressive tumours had more necrotic areas with a high number of infiltrating granulocytes. In conclusion, progression and spontaneous regression of tumours in the Lewis rat sarcoma model is associated with distinct changes in populations of blood cells and immune cells which participate in these completely different processes of tumourigenesis. PMID- 26637869 TI - Pattern of Melanotransferrin Expression in Human Colorectal Tissues: An Immunohistochemical Study on Potential Clinical Application. AB - BACKGROUND: Our previous liquid chromatography-tandem mass spectrometry (LC MS/MS) study on colorectal cancer proteome resulted in identification of 10,000 differentially expressed proteins. We observed a significantly changed expression of 25% of all identified proteins between patient and matched adjacent normal mucosa, carcinoma and colorectal adenoma, including melanotransferrin. Herein, we consider this protein as a potential biomarker of colorectal cancer. MATERIALS AND METHODS: Immunohistochemical detection of melanotransferrin was carried-out to localize its expression pattern within the colorectal tissues by tissue microarray. The diagnostic utility of melanotransferrin was evaluated in patient serum by enzyme-linked immunosorbent assay (ELISA). RESULTS: Strong melanotransferrin expression was found to be related to clinicopathological characteristics, lymph node involvement (p=0.008), tumor localization in colon (p=0.001), presence of mucin (p<0.013) and increasing tumor grade (p<0.001). Melanotransferrin level in serum from patients with colorectal cancer was significantly higher than that in healthy controls (p<0.001). CONCLUSION: We provide novel evidence that melanotransferrin may be involved in transformation from benign tumor to malignancy and is a marker of an invasive tumor phenotype. PMID- 26637870 TI - Phosphatidylinositol Derivatives Induce Gastric Cancer Cell Apoptosis by Accumulating AIF and AMID in the Nucleus. AB - BACKGROUND: The present study investigated the mechanism underlying the apoptosis of MKN28 human gastric cancer cells induced by the phosphatidylinositol (PI) derivative 1,2-O-bis-[8-{2-(2-pentyl-cyclopropylmethyl)-cyclopropyl}-octanoyl]-sn glycero-3-phosphatidyl-D-1-inositol (diDCP-LA-D-PI) and its enantiomer diDCP-LA-L PI. MATERIALS AND METHODS: 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H tetrazolium bromide (MTT) assay, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining, enzymatic caspase assay, real-time reverse transcription-polymerase chain reaction (RT-PCR), and western blotting were carried-out. RESULTS: Both diDCP-LA-D-PI and diDCP-LA-L-PI induced caspase independent apoptosis of MKN28 cells, with the potential for diDCP-LA-L-PI being much greater than that of diDCP-LA-D-PI. diDCP-LA-D-PI and diDCP-LA-L-PI accumulated apoptosis-inducing factor (AIF) and AIF-homologous mitochondrion associated inducer of death (AMID) in the nucleus. CONCLUSION: diDCP-LA-D-PI and diDCP-LA-L-PI induce caspase-independent apoptosis of MKN28 cells by accumulating AIF and AMID in the nucleus, with different potentials. PMID- 26637871 TI - Bioluminescence Imaging of Adoptively Transferred Lymphocytes During Allogeneic Tumor Rejection. AB - AIM: The aim of the present study was to analyze the survival, spatial distribution and proliferation of adoptively transferred lymphocytes in allogeneic tumor rejection. MATERIALS AND METHODS: Transgenic beta-actin-luc mice that express luciferase were sensitized against SL2 tumors and were used as lymphocyte donors to study the anti-tumor effect in SL2 tumor-bearing lymphocyte deficient RAG(-/-) mice. Whole-body bioluminescence images of recipient mice were obtained to track the adoptively transferred lymphocytes. Proliferation of lymphocytes was estimated by quantification of photon emission. RESULTS: T lymphocytes sensitized against allogeneic SL2 tumors cured the majority of SL2 tumor-bearing RAG(-/-) mice. Bioluminescence imaging showed that transferred T lymphocytes survived in the spleen and lymph nodes. Tumor rejection was associated with lymphocyte proliferation and migration to the tumor site. CONCLUSION: Sensitized T lymphocytes from transgenic beta-actin-luc mice reject allogeneic SL2 tumors in RAG(-/-) mice and can be tracked in vivo using bioluminescence imaging. PMID- 26637872 TI - Microarray Analysis of Gene Expression at the Tumor Front of Colon Cancer. AB - Budding or the presence poorly differentiated clusters at the boundary of cancer tissue is a pathologically important finding and serves as a prognostic factor in colorectal cancer. However, few studies have examined the cancer tissue boundary in clinical samples. The purpose of the present study was to examine gene expression at the tumor front of colon cancer in surgically resected samples. Cancer tissues were obtained by laser microdissection of 20 surgically resected specimens. Genes with significantly different microarray signals between the tumor front and the tumor center were identified. Among genes showing significant up-regulation at the tumor front were six chemokines [chemokine c-c motif ligand (CCL)2 and -18, chemokine (C-X-C motif) ligand (CXCL)9-11, and interleukin 8 (IL8)], and two apoptosis-related molecules [ubiquitin D (UBD) and baculoviral iap repeat-containing 3 (BIRC3)]. Expression of laminin gamma 2 (LAMC2), matrix metallopeptidase 7 (MMP7) and epithelial-mesenchymal transition (EMT)-related molecules were elevated in the tumor front, but their fold changes were smaller than those of the aforementioned genes. These results suggest that chemokines, in addition to EMT-related molecules, may play important roles in invasion of colon cancer. PMID- 26637873 TI - Potentiation of Acute Promyelocytic Leukemia Cell Differentiation and Prevention of Leukemia Development in Mice by Oleanolic Acid. AB - Although differentiation therapy with all-trans retinoic acid (ATRA) induces complete remission in most acute promyelocytic leukemia (APL) patients, it is associated with organ toxicity. The present study focused on investigating the effects of the natural compounds oleanolic acid (OA) and ursolic acid (UA) on proliferation and differentiation of human APL HL-60 cells in vitro and murine APL WEHI-3 cells in vivo. Results demonstrated that OA and UA significantly inhibited cellular proliferation of HL-60 in a concentration- and time-dependent manner. Non-cytotoxic concentration of OA exhibited a marked differentiation inducing effect on HL-60 and enhanced ATRA-induced HL-60 differentiation. In contrast, UA showed only a moderate effect. Activation of MAPK/NF-kappaB signaling pathway was likely found to be involved in the mechanism. Moreover, OA increased survival duration of WEHI-3 transplanted BALB/c mice, and decreased leukemia cells infiltration in the liver and spleen. Thus, these results may provide new insight for developing alternative therapy in APL patients. PMID- 26637874 TI - Clinical Significance of Expression of Nephroblastoma Overexpressed (NOV) in Patients with Colorectal Cancer. AB - BACKGROUND: The nephroblastoma overexpressed (NOV) gene, which belongs to the cysteine-rich, angiogenic inducer 61/connective tissue growth factor/nephroblastoma overexpressed (CCN) family, is located in the 8q24 region and promotes migration and invasiveness in several types of malignancies. We explored the clinical significance of NOV expression in colorectal cancer (CRC). MATERIALS AND METHODS: NOV expression in CRC specimens and CRC cell lines were evaluated. The association between the clinicopathlogical factors and NOV mRNA expression of tumor tissues was assessed in 126 patients with CRC. We assessed the relationships between NOV expression and overall survival in public databases. We performed overexpression experiments in vitro. RESULTS: CRC specimens and CRC cell lines showed high NOV expression. High NOV mRNA expression was correlated with poorer overall survival and higher Union for International Cancer Control (UICC) T factor. In public databases, high NOV expression was associated with poorer prognoses. Overexpression of NOV promoted invasiveness of CRC cells. CONCLUSION: NOV may be an indicator of poor prognosis and a therapeutic target in CRC. PMID- 26637875 TI - CD133 Expression in Lymph Node Metastases Is Associated with Tumor Aggressiveness During Lymph Node Metastasis in Colorectal Cancer. AB - BACKGROUND: Recently, two meta-analysis reports have suggested that CD133 expression in the primary tumor is significantly associated with shorter survival in colorectal cancer (CRC), and that CD133 may play an important role in CRC progression. However, the expression of CD133 in lymph node metastases as well as in primary tumors in CRC remains to be elucidated. MATERIALS AND METHODS: We analyzed CD133 expression in both primary tumors and lymph node metastases in stage III CRC by immunohistochemistry, and its correlation with clinicopathological factors and outcomes. RESULTS: Through immunohistochemistry we demonstrated that 69.6% of CRC primary tumors and 62.3% of lymph node metastases were CD133-positive. High CD133 expression in lymph node metastases was significantly associated with the number of lymph node metastases. Moreover, patients with CD133-negative staining of either primary tumor or lymph node metastases had a higher overall survival rate than those with CD133-positive staining, although this finding was not statistically significant. CONCLUSION: CD133-positive cancers may be more aggressive than CD133-negative ones during the process of lymph node metastasis. Further investigation of the role of CD133 positive cells in lymph node metastases in CRC is required. PMID- 26637876 TI - GSKJ4, A Selective Jumonji H3K27 Demethylase Inhibitor, Effectively Targets Ovarian Cancer Stem Cells. AB - BACKGROUND/AIM: Global increase in the trimethylation of histone H3 at lysine 27 (H3K27me3) has been associated with the differentiation of normal stem cells and cancer cells, however, the role of H3K27me3 in the control of cancer stem cells (CSCs) remains poorly understood. We investigated the impact of increased H3K27me3 on CSCs using a selective H3K27 demethylase inhibitor GSKJ4. MATERIALS AND METHODS: The effect of GSKJ4 on the viability as well as on the self-renewal and tumor-initiating capacity of CSCs derived from the A2780 human ovarian cancer cell line was examined. RESULTS: GSKJ4 induced cell death in A2780 CSCs at a concentration non-toxic to normal human fibroblasts. GSKJ4 also caused loss of self-renewal and tumor-initiating capacity of A2780 CSCs surviving GSKJ4 treatment. CONCLUSION: Our findings suggest that H3K27 methylation may have an inhibitory role in the maintenance of CSCs and that GSKJ4 may represent a novel class of CSC-targeting agents. PMID- 26637877 TI - Up-regulation of PER3 Expression Is Correlated with Better Clinical Outcome in Acute Leukemia. AB - BACKGROUND: Altered expression of circadian clock genes has been linked to various types of cancer. This study aimed to investigate whether these genes are also altered in acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL). MATERIALS AND METHODS: The expression profiles of nine circadian clock genes of peripheral blood (PB) leukocytes from patients with newly-diagnosed AML (n=41), ALL (n=23) and healthy individuals (n=51) were investigated. RESULTS: In AML, the expression of period 1 (PER1), period 2 (PER2), period 3 (PER3), cryptochrome 1 (CRY1), cryptochrome 2 (CRY2), brain and muscle aryl hydrocarbon receptor nuclear translocator (ARNT)-like 1 (BMAL1), and timeless (TIM) was significantly down regulated, while that of CK1epsilon was significantly up-regulated. In ALL, the expression of PER3 and CRY1 was significantly down-regulated, whereas those of CK1epsilon and TIM were significantly up-regulated. Recovery of PER3 expression was observed in both patients with AML and those with ALL who achieved remission but not in patients who relapsed after treatment. CONCLUSION: Circadian clock genes are altered in patients with acute leukemia and up-regulation of PER3 is correlated with a better clinical outcome. PMID- 26637878 TI - 2-Deoxy-D-glucose Sensitizes Cancer Cells to Barasertib and Everolimus by ROS independent Mechanism(s). AB - The aim of the present study was to investigate: (i) the possibility of sensitizing cancer cells to anticancer drugs using the redox modulator 2-deoxy-D glucose (2-DDG); (ii) to find such combinations with synergistic cytotoxic effect; (iii) and to clarify the role of reactive oxygen species (ROS) for induction of apoptosis and cytotoxicity through these combinations. The study covers 15 anticancer drugs--both conventional and new-generation. Four parameters were analyzed simultaneously in Jurkat leukemia cells, treated by drugs or 2-DDG (separately or in combination): cell viability, induction of apoptosis, levels of ROS, and level of protein-carbonyl products. Very well-expressed synergistic cytotoxic effects were found after 48-h treatment of Jurkat cells with 2-DDG in combination with: palbociclib, everolimus, lonafarnib, bortezomib, and barasertib. The synergistic cytotoxic effect of everolimus with 2-DDG was accompanied by very strong induction of apoptosis in cells, but a very strong reduction of ROS level. Changes in the levels of protein-carbonyl products were not detected. The synergistic cytotoxic effect of barasertib with 2-DDG was accompanied by very strong induction of apoptosis in cells, without any increase of ROS levels, but with an enhancement of protein-carbonyl products. PMID- 26637879 TI - Molecular Pathogenesis of Human Papillomavirus Type 16 in Tonsillar Squamous Cell Carcinoma. AB - AIM: The present study aimed to explore the etiological role of human papillomavirus (HPV) in tonsillar squamous cell carcinoma (TSCC). MATERIALS AND METHODS: HPV status, including viral load and E6 variants, and the expression of P53, p16(INK4A), and FANCD2, in tissues of TSCC (n=24) and tonsillitis (n=31) were investigated. RESULTS: The frequency of high-risk HPV (HPV-16) in TSCCs (42%) was higher than that of tonsillitis (16%). HPV-16 genome was partially or fully integrated in all HPV-16-positive TSCCs. However, the viral genome was partially integrated in three out of five HPV-16-positive tonsillitis cases (p=0.037). HPV-16-positive TSCCs showed a higher frequency of p16(INK4A) expression than HPV-16-negative TSCCs and tonsillitis (p=0.011). Regardless of HPV status, TSCCs had a lower expression of FANCD2 than tonsillitis (p=0.008). CONCLUSION: The present study supports the etiological role of HPV-16 in the development of TSCC, and p16(INK4A) overexpression can be applied as a surrogate marker for the detection of high-risk-HPV in TSCC. PMID- 26637880 TI - Fumarate Hydratase-deficient Cell Line NCCFH1 as a New In Vitro Model of Hereditary Papillary Renal Cell Carcinoma Type 2. AB - BACKGROUND/AIM: Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a rare autosomal dominant disorder characterized by fumarate hydratase (FH) gene mutation. It is associated with the development of very aggressive kidney tumors, characterized by early onset and high metastatic potential, and has no effective therapy. The aim of the study was to establish a new preclinical platform for investigating morphogenetic and metabolic features, and alternative therapy of metastatic hereditary papillary renal cell carcinoma type 2 (PRCC2). MATERIALS AND METHODS: Fresh cells were collected from pleural fluid of a patient with metastatic hereditary PRCC2. Morphogenetic and functional characteristics were evaluated via microscopy, FH gene sequencing analysis, real-time polymerase chaine reaction and enzymatic activity measurement. We performed bioenergetic analysis, gene-expression profiling, and cell viability assay with 19 anti neoplastic drugs. RESULTS: We established a new in vitro model of hereditary PRCC2 - the NCCFH1 cell line. The cell line possesses a c.1162 delA - p.Thr375fs frameshift mutation in the FH gene. Our findings indicate severe attenuation of oxidative phosphorylation and glucose-dependent growth of NCCFH1 cells that is consistent with the Warburg effect. Furthermore, gene-expression profiling identified that the most prominent molecular features reflected a high level of apoptosis, cell adhesion, and cell signaling. Drug screening revealed a marked sensitivity of FH(-/-) cells to mitoxantrone, epirubicin, topotecan and a high sensitivity to bortezomib. CONCLUSION: We demonstrated that the NCCFH1 cell line is a very interesting preclinical model for studying the metabolic features and testing new therapies for hereditary PRCC2, while bortezomib may be a potential efficient therapeutic option. PMID- 26637881 TI - Targeting Fibroblast Growth Factor Receptor (FGFR) with BGJ398 in a Gastric Cancer Model. AB - AIM: To assess the efficacy of targeting fibroblast growth factor receptor (FGFR) with the pan-FGFR inhibitor BGJ398 in a gastric cancer (GC) model. MATERIALS AND METHODS: Expression of FGFRs was determined in GC cell lines (KKLS, MKN-45, TMK 1). Impact of the FGFR inhibitor BGJ398 on growth, motility, signaling, expression of transcription factors and secretion of vascular endothelial growth factor-A (VEGFA) was determined in vitro. Results were validated in subcutaneous tumor models. RESULTS: In vitro, FGFR inhibition was most effective in KKLS cells (high FGFR1, FGFR2IIIc, no FGFR2IIIb expression) with inhibition of growth, motility, signaling, c-MYC expression and VEGFA secretion. BGJ398 showed some activity in MKN-45 cells (intermediate FGFR1, high FGFR2IIIb, low FGFR2IIIc expression), while TMK-1 cells (low FGFR1, no FGFR2IIIb and FGFR2IIIc expression) did not respond. Results were confirmed in vivo with strongest efficacy on growth in KKLS tumors and only minor impairment of TMK-1 lesions. CONCLUSION: Efficacy of FGFR inhibition is dependent on FGFR1 and FGFR2IIIc expression in GC models. PMID- 26637882 TI - HER2 Codon 655 (Ile/Val) Polymorphism and Breast Cancer in Austrian Women. AB - BACKGROUND: The overexpression of the human epidermal growth factor receptor 2 (HER2) in breast cancer (BC) is associated with impaired prognosis. Data concerning the HER2 codon 655 polymorphism (Ile/Val) and BC risk are conflicting. MATERIALS AND METHODS: We studied the HER2 codon 655 (rs1136201) polymorphism in 80 Austrian patients with BC and 100 healthy volunteers by pyrosequencing and polymerase chain reaction. Associations between codon 655 allelic variants and clinicopathological variables (e.g. age, stage of disease, tumor type, grading, and receptor status) were studied with 2*2 tables. RESULTS: The genotypic distributions in patients with BC (AA: 63.75%, AG: 32.5%, GG: 3.75%) and controls (AA: 63%, AG: 34%, GG: 3.7%) were virtually identical (odds ratio=1.03, 95% confidence interval=0.56-1.90). A non-significant link between carrying at least one G allele and more aggressive tumor type (estrogen receptor-negative p=0.08, G3 tumor p=0.19) was observed. CONCLUSION: Genotypic variation within the codon 655 of HER2 does not alter the BC risk in Caucasian Austrian women. The association between the G allele and more aggressive tumor types requires further investigation. PMID- 26637883 TI - Effects of Cabazitaxel in Renal Cell Carcinoma Cell Lines. AB - BACKGROUND/AIM: Advanced renal cell carcinoma is treated with mammalian target of rapamycin (mTOR) inhibitors or tyrosine kinase inhibitors (TKIs). The effects of these drugs are, however, limited and novel treatment strategies are required. Clear-cell type renal cell carcinoma (ccRCC) is chemo-resistant, in part, due to expression of multidrug resistance proteins such as p-glycoprotein. Cabazitaxel, a tubulin-binding taxane drug used for castration-resistant prostate cancer, has less affinity for p-glycoprotein compared to docetaxel. In the current study, the effects of docetaxel and cabazitaxel on ccRCC cells were investigated. MATERIALS AND METHODS: The expression of p-glycoprotein was evaluated in the ccRCC cell lines, Caki-1, KMRC-1 and OS-RC-2 by western blotting. Cells were treated with cabazitaxel or docetaxel, and growth kinetics and tubulin polymerization were determined by the WST-1 assay and cell-based tubulin polymerization assay, respectively. Intracellular drug concentrations were measured by chromatography. AKT activation after treatment was examined by western blotting. RESULTS: All ccRCC cell lines expressed p-glycoprotein. Cabazitaxel inhibited cell growth and induced tubulin polymerization more potently than docetaxel. The intracellular concentration of cabazitaxel was much higher than docetaxel in all cell lines. Both docetaxel and cabazitaxel inhibit AKT phosphorylation at 5 min among three cells. CONCLUSION: Cabazitaxel inhibits growth of ccRCC cells expressing p glycoprotein and could thus be possibly used for advanced ccRCC patients in combination with targeted-therapy enhancing their effects. PMID- 26637884 TI - Synergistic Cytotoxicity of Bendamustine and the BTK Inhibitor in a Mantle Cell Lymphoma Cell Line. AB - BACKGROUND: Bendamustine is effective in B-cell malignancies, including mantle cell lymphoma (MCL), alone and in combination with other agents. This study investigated the combination effect of bendamustine and the Bruton tyrosine kinase (BTK) inhibitor PCI-32765 on MCL cell death and the underlying mechanisms. MATERIALS AND METHODS: Cytotoxicity was examined by the 3-(4,5-dimethylthiazol-2 yl)-2,5-diphenyltetrazolium bromide (MIT) assay. Apoptosis was assessed by annexin V/propidium iodide staining and protein expression was analyzed by western blotting. RESULTS: When combined with bendamustine, PCI-32765 showed a synergistic effect on growth inhibition of the MCL cell line Jeko-1. Cleavage of caspase-3 and poly-(ADP-ribose) polymerase was increased, indicating enhanced apoptosis induction. In addition, this combination decreased the protein expression of cyclin D1. Phosphorylated v-akt murine thymoma viral oncogene homolog 1 (AKT) (Ser473) was also down-regulated, suggesting a suppression of the phosphatidylinositol 3-kinase/AKT signaling pathway. CONCLUSION: Combination treatment with bendamustine and a BTK inhibitor may be effective in MCL therapy. PMID- 26637885 TI - Amentoflavone Induces Anti-angiogenic and Anti-metastatic Effects Through Suppression of NF-kappaB Activation in MCF-7 cells. AB - The aim of the present study was to investigate whether amentoflavone induces anti-angiogenic and anti-metastatic effects through suppression of NF-kappaB activation in breast cancer in vitro. Effects of NF-kappaB inhibitor 4-N-[2-(4 phenoxyphenyl) ethyl] quinazoline-4, 6-diamine (QNZ) and amentoflavone on the expression and secretion of angiogenesis- and metastasis-related proteins and cell invasion were investigated by western blotting, enzyme-linked immunosorbent assay (ELISA), and invasion assays. We also verified the effects of QNZ and amentoflavone on lipopolysaccharides (LPS)-activated cell invasion. Obtained results indicated that both QNZ and amentoflavone reduce NF-kappaB activation, expression and secretion of angiogenesis- and metastasis-related proteins, and cell invasion. QNZ and amentoflavone also reverse LPS-activated cell invasion. In conclusion, inhibition of NF-kappaB activation decreases expression and secretion of angiogenesis- and metastasis-related proteins. Amentoflavone may induce anti angiogenic and anti-metastatic effects through suppression of NF-kappaB activation. PMID- 26637886 TI - Multicenter Phase II Study of Nedaplatin and Irinotecan for Patients with Squamous Cell Carcinoma of the Lung: Thoracic Oncology Research Group 0910. AB - Squamous cell carcinoma (SCC) of the lung is moderately responsive to anticancer drugs, but no specific chemotherapy regimens have yet been established. We conducted a multicenter phase II study of nedaplatin (NP) and irinotecan (CPT) for SCC of the lung. Fifty patients underwent 4 to 6 cycles of chemotherapy comprising of NP at 100 mg/m(2) on day 1 and CPT at 60 mg/m(2) on days 1 and 8 every 4 weeks. Twenty-seven patients received 4 to 6 cycles of chemotherapy (median=4 cycles). Major toxicities included neutropenia (46.0%), grade 3 or 4 anorexia (22.0%), febrile neutropenia (16.0%), diarrhea (12.0%), hyponatremia (12.0%), grade 4 anemia (10.0%), thrombocytopenia (10.0%) and infection (10.0%). There were no treatment-related deaths. One patient achieved a complete response and 16 a partial response, with an overall response rate of 34.0%. The median survival time was 11.8 months (95% CI=8.3-15.8 months) and the 2-year survival rate was 22.0%. In conclusion, the NP and CPT regimen is not recommend for further evaluation for patients with advanced SCC of the lung. PMID- 26637887 TI - Malignant Ovarian Germ Cell Tumors in Postmenopausal Patients: The Royal Marsden Experience and Literature Review. AB - BACKGROUND: Ovarian germ cell tumors (OGCT) account for 2-5% of ovarian malignancies, with an annual incidence of 1:100,000, and typically occur in young women and adolescents. The yolk sac tumor (YST) is the second most common subtype of OGCTs and has an aggressive phenotype. Their rarity in postmenopausal women has the potential to cause initial diagnostic uncertainty and lead to delayed or sub-optimal treatment. In this article, we report two cases. The first case is a 67-year-old woman with a pure YST and the second refers to a 59-year-old patient with YST with neuroendocrine differentiation. We also review and summarise the current literature. DISCUSSION: YSTs in older women, either in association with ovarian epithelial tumors or without an identifiable epithelial precursor, are a challenging clinical situation. The disease is aggressive and the outcome remains poor. Thirty-seven cases, including the two reported in this article, have been described in the literature to date. 12/ 37 described patients with malignant OGCTs died within 8 months of diagnosis. CONCLUSION: Ovarian cancer with a YST component in postmenopausal women has an aggressive behaviour and adjuvant platinum-based chemotherapy should be considered. PMID- 26637888 TI - Pressurized Intraperitoneal Aerosol Chemotherapy with Cisplatin and Doxorubicin in Women with Peritoneal Carcinomatosis: A Cohort Study. AB - AIM: We aimed to assess the objective tumor response (OTR) to laparoscopic pressurized intraperitoneal aerosol chemotherapy (PIPAC) in women with peritoneal carcinomatosis (PC). PATIENTS AND METHODS: We carried-out a retrospective cohort study of women with PC undergoing repeated courses of PIPAC with 7.5 mg/m(2) of cisplatin and 1.5 mg/m(2) of doxorubicin. OTR was defined as histological regression. Peritoneal carcinomatosis index (PCI) improvement on video laparoscopy and ascites volume reduction were secondary outcomes. Quality of life was assessed by the European Organization for Research & Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-30+3. RESULTS: A total of 252 PIPACs were performed in 99 women with PC and ovarian (n=84), primary peritoneal (n=6), cervical (n=3), endometrial (n=3), fallopian tube (n=1), and breast (n=1) cancer and pseudomyxoma peritonei (n=1). Laparoscopic non-access rate was 17% (17/99). Fifty women had more than one PIPAC procedures, with an OTR of 76% (38/50) and PCI improvement in 64% (32/50). Ascites volume significantly decreased from 762+/ 1170 ml to 167+/-456 ml (p=0.02). A high initial Karnofsky Index was correlated with receiving more than one PIPAC (p<0.0001) and a high number of previous surgeries with laparoscopic non-access (p=0.01). Twenty adverse events of Common Terminology Criteria for Adverse Events grade 3 or more were noted. Absence of ascites (odds ratio=8.45, 95% confidence interval=1.9-3.6; p<0.0001), but not patient age, serum cancer antigen-125, and Karnofsky Index independently predicted OTR. EORTC QLQ-30+3 scores for global physical health, nausea/vomiting, appetite loss, and constipation improved during therapy. CONCLUSION: PIPAC with cisplatin and doxorubicin is an active treatment in women with PC and preserves quality of life. Appropriate patient selection regarding performance status and the number of prior surgeries is important. PMID- 26637889 TI - High RRM1 Expression Is Associated with Adverse Outcome in Patients with Cisplatin/Vinorelbine-treated Malignant Pleural Mesothelioma. AB - BACKGROUND/AIM: A possible predictive impact of ribonucleotide-reductase subunit 1 (RRM1) on vinorelbine efficacy in non-small cell lung cancer (NSCLC) has been previously reported. The present study aimed to further explore this finding in malignant pleural mesothelioma (MPM). MATERIALS AND METHODS: Seventy-one patients with MPM receiving first-line chemotherapy with cisplatin-vinorelbine (CiV group, n=54) or carboplatin-pemetrexed (CaP group, n=17) were included. Formalin-fixed paraffin-embedded tumor specimens were analyzed by immunohistochemistry (IHC) for RRM1 expression using an H-score. RESULTS: In 66 patients eligible for IHC, the H score was >=upper quartile in 21 (RRM1-positive) and =2,000 MUm). The histological change from the primary lesion to the recurrent lesion was classified as 'No change pattern', from well- to moderately-differentiated (W/M) to an expanding lesion; as 'Change pattern', from W/M to an infiltrating lesion. RESULTS: Re-recurrence-free survival was better in 'R0 longness' than 'R0 shortness' groups and showed that 'No change pattern' cases had considerably better prognosis than 'Change pattern' cases. CONCLUSION: Ensuring a CRM >2,000 MUm during resection of LRRC is more likely to prevent re-recurrence. Cases with poorly differentiated carcinoma from the primary lesion to the recurrent lesion tend to have poor prognoses. PMID- 26637892 TI - Assessing Response to New Treatments and Prognosis in Melanoma Patients, by the Biomarker S-100beta. AB - BACKGROUND/AIM: Malignant melanoma incidence is increasing over the last years, while mortality is strongly decreasing due to improved early detection, close monitoring of patients including disease biomarkers as well as introduction of new therapies. The aim of the present study was to evaluate biomarkers, mainly S 100beta in melanoma patients, regarding its ability to assess treatment response, especially to new immunotherapies (anti-BRAF, ipilimumab, anti-PD-1) and evaluation of prognosis of those patients. PATIENTS AND METHODS: We evaluated both retrospectively and prospectively 137 malignant melanoma patients. Blood biomarker levels were evaluated by conventional ELISA assays. Correlations of marker levels to disease stage, metastases, response to new immunotherapies and survival, were performed. RESULTS: Serum levels of biomarkers, mainly S-100beta, were significantly higher in all patients before various therapies were applied (5.1+0.7 MUg/L) and decreased thereafter (1.3+0.4 MUg/L). Significantly higher levels of S-100beta were demonstrated in advanced disease including metastases, (5.95+0.62 MUg/L) as opposed to early disease (0.32+0.06 MUg/L) and NED patients (0.18+0.03 MUg/L). When comparing melanoma deceased patients who had extremely high levels of S-100beta, (2.2+0.45 MUg/L) we showed significantly lower levels in alive patients (0.26+0.02 MUg/L) and certainly in normal controls (0.07+0.02 MUg/L). In individual patients, kinetic evaluations showed earlier response to therapy, or recurrence and non-response, as shown only later by CT evaluations. CONCLUSION: S-100beta can serve as a useful biomarker for the assessment of treatment response and prognosis, especially after using new immunological treatments, such as anti-BRAF, ipilimumab or anti-PD1 in malignant melanoma patients. Additional biomarkers, such as LDH, beta2M and TK may also serve as part of a biomarkers panel, for improved detection of recurrence and metastasis of melanoma patients. PMID- 26637893 TI - Fluorouracil-induced Hyperammonemia in a Patient with Colorectal Cancer. AB - Fluorouracil (5-FU; Adrucil(r)) is a pyrimidine analog antineoplastic chemotherapy agent which works by interfering with DNA and RNA synthesis. It has an uncommon toxicity called hyperammonemic encephalopathy. This neurotoxicity is associated with a high-dose administration of 5-FU (2,600 mg/m(2)/week), with an incidence rate of 5.7%, and is not normally seen with the current dose of 1,200 mg/m(2) infused over 46 h. The mechanism behind this neurotoxicity is not known but is possibly due to accumulation of fluorocitrate, a byproduct of 5-FU metabolism. This by-product inhibits the Krebs cycle, which causes impairment of the adenosine triphosphate-dependent urea cycle. By impairing this cycle, ammonia is not converted to urea, which in turn this leads to an accumulation of ammonia. The accumulated ammonia in the brain is metabolized to glutamine, which has been suggested to cause an increase in intracranial pressure and cerebral edema. This case report discusses how a 40-year-old male with colorectal cancer experienced 5FU-induced hyperammonemia and was treated for it and how reducing the dose by 50% led to resolution of this symptom from reoccurring. PMID- 26637894 TI - Predictors of Gastric Neoplasia in Cases Negative for Helicobacter pylori Antibody and with Normal Pepsinogen. AB - BACKGROUND/AIM: Individuals negative for Helicbacter pylori antibody and with a normal pepsinogen test (group A) are regarded as being at low risk in serum gastric cancer screening known as the ABC method, and endoscopy is not recommended; however, this group may include 2-10% of gastric cancer cases. PATIENTS AND METHODS: A total of 345 individuals who underwent upper gastrointestinal endoscopy and were classified by ABC as group A (H. pylori antibody titer <10 U/ml, and pepsinogen-I >70 ng/ml or I/II ratio >3) were enrolled, and predictors of gastric neoplasia were investigated. RESULTS: Ten gastric neoplasia cases (gastric cancer and adenoma) were found to be included. Multiple logistic regression analyses identified H. pylori antibody titer >=3 U/ml (odds ratio=14.4, 95% confidence interval=2.7-76.9; p<0.01) and pepsinogen I/II ratio <=4.3 ng/ml (odds ratio=10.0, 95% confidence interval=2.1-47.9; p<0.01), but not age as independent predictive factors of neoplasia. CONCLUSION: Endoscopy should be considered in individuals with H. pylori antibody titer of >=3 U/ml and a pepsinogen-I/II ratio of <=4.3 in those classed as group A by ABC method. PMID- 26637895 TI - Changes in Pulmonary Function After Stereotactic Body Radiotherapy and After Surgery for Stage I and II Non-small Cell Lung Cancer, a Description of Two Cohorts. AB - AIM: To evaluate changes in pulmonary function tests (PFTs) at different follow up durations after stereotactic body radiotherapy (SBRT) and surgery in stage I and II non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Differences between pre-treatment- and follow-up PFTs were analyzed in 93 patients treated with surgery and 30 patients treated with SBRT for NSCLC. Follow-up durations were categorized into: early (0-9 months), middle (10-21 months) and late (>=22 months). Wilcoxon signed-rank test was used to analyze differences between pre treatment and follow-up PFTs. RESULTS: Forced expiratory volume in one second, forced vital capacity and diffusion capacity for carbon monoxide corrected for the actual hemoglobin level significantly diminished after surgery for all follow up durations: 11-17% of predicted values. After SBRT, PFTs remained stable, but a declining trend of 6% (p=0.1) was observed after 22 months. CONCLUSION: SBRT might lead to less treatment-related toxicity measured by PFTs than surgery in both the short and long term. PMID- 26637896 TI - D-dimer Level Changes During Systemic Chemotherapy Can Predict Prognosis of High grade Musculoskeletal Sarcoma Patients. AB - BACKGROUND/AIM: Plasma D-dimer levels have been known to be associated with tumor progression; we, therefore, investigated whether the D-dimer levels during preoperative systemic chemotherapy can be prognostic indicators in patients with high-grade musculoskeletal sarcoma. PATIENTS AND METHODS: We investigated 28 cases of high-grade sarcomas, and evaluated the utility of D-dimer levels for preoperative evaluation of the effects of systemic chemotherapy. RESULTS: Among the candidate parameters determined based on D-dimer levels at several time points of neoadjuvant chemotherapy and several oncological outcomes, the plasma D dimer level completion of the second course of chemotherapy and the ratio of plasma D-dimer levels at completion of preoperative chemotherapy to the level of plasma D-dimer on referral, could significantly predict patient prognosis (p=0.049 and p=0.02, respectively). CONCLUSION: D-dimer level changes could be a helpful marker for preoperative evaluation of the effect of systemic chemotherapy in terms of prognosis prediction in high-grade musculoskeletal sarcoma patients. PMID- 26637897 TI - Detection of Bone Metastases Using 11C-Acetate PET in Patients with Prostate Cancer with Biochemical Recurrence. AB - AIM: To evaluate the diagnostic accuracy of (11)C-acetate positron-emission tomography (PET) in the detection of bone metastasis in patients with prostate cancer with biochemical recurrence. PATIENTS AND METHODS: Ninety patients (100%) with rising prostate-specific antigen (PSA) levels (>0.2 ng/ml) after radical prostatectomy, who had both (11)C-acetate PET and bone scan performed and who had clinical follow-up/imaging follow-up for bone metastasis, considered a gold standard, were included. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for (11)C-acetate PET were calculated on a per-patient basis. RESULTS: (11)C-Acetate PET and (99m)Tc-dicarboxypropane diphosphonate findings were concordant in 84 (93.3%) patients [35 (38.9%) true positive, 49 (54.4%) true-negative]. Discordant findings were observed in six patients (6.7%). (11)C-Acetate PET presented two (2.2%) false-positive and four (4.4%) false-negative findings. The sensitivity, specificity, PPV, and NPV for (11)C-acetate PET were 89.7%, 96.1%, 94.6%, and 92.2%, respectively. The median PSA of patients with multiple skeletal metastases (median=23.64 ng/ml, range=3.16 551.1 ng/ml) differed significantly (p=0.018) from that of patients with focal metastases (median=6.7 ng/ml, range=0.31-12.8 ng/ml). CONCLUSION: (11)C-Acetate PET is a useful tool for patients with prostate cancer with biochemical recurrence, as it can depict multiple sites of recurrence and in particularly shows a high diagnostic value equivalent to that of bone scan for the detection of bone metastases. PMID- 26637898 TI - Predicting the Risk of New Cerebral Lesions After Stereotactic Radiosurgery (SRS) for Brain Metastases from Breast Cancer. AB - AIM: To generate a tool that estimates the probability of developing new cerebral metastases after stereotactic radiosurgery (SRS) in breast cancer patients. PATIENTS AND METHODS: SRS dose plus seven characteristics (age, performance score, number of cerebral metastases, maximum diameter of all metastases, location of metastases, extra-cerebral spread and time from breast cancer diagnosis until SRS) were analyzed regarding their ability to predict the probability of new cerebral metastases development following SRS. For those characteristics deemed significant, points of 0 (higher risk of new lesions) or 1 (lower risk) were given. Scores were generated by adding the points of significant characteristics. RESULTS: Performance score (p=0.013) and maximum diameter of all metastases (p=0.022) were associated with development of subsequent brain metastases. Two groups were created, 0-1 and 2 points. Freedom from new cerebral metastases rates were 27% and 92%, respectively, at 15 months (p=0.003). CONCLUSION: This tool helps select breast cancer with few cerebral metastases receiving SRS who may benefit from additional whole-brain irradiation. PMID- 26637899 TI - Cancer Incidence in Patients with Atypical Endometrial Hyperplasia Managed by Primary Hysterectomy or Fertility-sparing Treatment. AB - AIM: To compare the risk of developing endometrial carcinoma (EC) in young women with atypical endometrial hyperplasia (AEH) undergoing fertility-sparing management compared to women treated by primary hysterectomy. PATIENTS AND METHODS: In this multicentric retrospective study, 111 patients with a diagnosis of AEH by endometrial biopsy were included. EC incidence was compared in two groups: 32 patients treated with fertility-sparing management and 79 older patients treated with primary hysterectomy. RESULTS: The rates of EC diagnosed by pathology of hysterectomy specimens were comparable between the groups. The probability of developing EC at 12, 24 and 36 months were 14%, 21% and 26%, respectively, in patients managed conservatively, and 29%, 37% and 37%, respectively, in patients treated with primary hysterectomy. CONCLUSION: Fertility-sparing management of AEH does not increase the risk of diagnosing EC from the hysterectomy specimen. PMID- 26637900 TI - Radiosurgery Using Tomotherapy for Patients with Brain Oligo-metastasis: A Retrospective Analysis on Feasibility and Tolerance. AB - AIM: Aim of the study was to evaluate feasibility and toxicities of exclusive radiosurgery using tomotherapy in patients with brain oligo-metastases. PATIENTS AND METHODS: Between 2008 and 2013 68 patients underwent stereotactic radiosurgery (SRS). Mean patient age was 63 years. Brain was the only site involved in 32 patients, while 36 had extracranial disease. Pre-SRS MRI 56 patients had sovratentorial lesions, 10 subtentorial and 2 patients had both. Fifty-two patients had 1 brain lesion, 11 had 2, and 5 patients had three. All patients underwent SRS using Tomotherapy. The median delivered dose was 18 Gy. RESULTS: After a mean follow-up of 13 months, 14 patients were alive, while 54 patients had died. Two patients had complete response, 32 had partial response, 21 stable disease and 13 disease progression. Overall response rate was 80.9%. One- and two-year overall survival were 41,2% and 24,7%, while local control 61.5% and 37.7%. Toxicity was acceptable. CONCLUSION: SRS using tomotherapy has been proven feasible as non-invasive exclusive treatment for oligometastatic patients with good prognostic score. PMID- 26637901 TI - Ipsilateral Sphenoid Wing Dysplasia, Orbital Plexiform Neurofibroma and Fronto Parietal Dermal Cylindroma in a Patient with Segmental Neurofibromatosis. AB - Neurofibromatosis type 1 (NF1) is an autosomal-dominant inherited disease affecting various parts of the body. Penetrance is almost complete but the phenotype varies considerably. Recently, mosaicism in NF1 has come into the focus of scientific interest. This report refers to a patient with orbitotemporal confined neurofibromatosis who developed a rare skin tumor in the region. PMID- 26637902 TI - Loss of ARID1A, ARID1B, and ARID2 Expression During Progression of Gastric Cancer. AB - BACKGROUND/AIM: Gastric cancer is a common cancer worldwide. Chromatin remodeling complexes have emerged as tumor suppressors and include AT-rich interaction domain-containing proteins (ARIDs) 1A, 1B, and 2. We examined their expression and clarified their roles in gastric carcinogenesis. MATERIALS AND METHODS: The expression of ARIDs was studied by immunohistochemistry in 469 gastric carcinoma and 47 adenoma samples and was analyzed according to clinicopathological factors. RESULTS: Low expression rates of ARID1A, 1B, and 2 in gastric carcinoma were 20%, 10%, and 15% respectively. ARIDs are correlated to each other. Low expression of ARID1A was related to advanced tumor and vessel infiltration. Loss of ARID1B and ARID2 was also related to tumor progression, but their relationship was weaker than that of ARID1A. CONCLUSION: ARID1A is the strongest tumor suppressor in gastric carcinogenesis among ARIDs. Their aberration might be caused by shared mechanisms such as mutation and methylation. PMID- 26637903 TI - Retrograde Jejunojejunal Intussusception After Gastrectomy: Report of Four Cases. AB - BACKGROUND: Retrograde intussusception of the small bowel is extremely rare. We experienced four cases of retrograde jejunojejunal intussusception that needed emergency surgery. The aim of the present report was to expand awareness of retrograde jejunojejunal intussusception as an urgent complication following gastrectomy. PMID- 26637904 TI - Comparison of Failure Patterns Between Conventional and Intensity-modulated Radiotherapy for Stage III and IV Head and Neck Squamous Cell Carcinoma. AB - BACKGROUND: We compared the patterns of failure between 3-dimensional radiotherapy (3D-RT) and intensity-modulated radiotherapy (IMRT) for head and neck squamous cell carcinoma (HNSCC). PATIENTS AND METHODS: We reviewed the medical records of 49 patients with stage III-IV HNSCC treated with concurrent chemoradiotherapy. The treatment outcome, patterns of failure, and toxicities were compared between 3D-RT and IMRT. RESULTS: There were 13 locoregional recurrences as initial failure sites. Eight recurrences were local, three were regional, and two were both local and regional. The recurrence pattern did not differ between the 3D-RT- and IMRT-treated groups, while toxicities were reduced in the IMRT-treated group. All recurrences were within the high-risk planning target volume except for one case in IMRT. CONCLUSION: IMRT did not increase the risk of locoregional recurrence neither did it change the pattern of failure in patients with stage III-IV locally advanced HNSCC, although it did reduce toxicities. PMID- 26637905 TI - Correlation Between Different ADC Fractions, Cell Count, Ki-67, Total Nucleic Areas and Average Nucleic Areas in Meningothelial Meningiomas. AB - BACKGROUND: Meningioma is the most common intracranial tumor. The aim of the present study was to correlate apparent diffusion coefficient (ADC) values with cellularity, Ki-67 and nucleic area in meningioma cases. PATIENTS AND METHODS: Twenty-four meningothelial meningiomas were included in the study. Diffusion weighted imaging was performed using a multi-slice single-shot echo-planar imaging sequence. In all lesions minimal ADC values (ADCmin), mean ADC values (ADCmean), and maximal ADC values (ADCmax) were estimated. Additionally, true ADC values (D) were calculated. All tumors were resected and analyzed histopathologically. The tumor proliferation index was estimated on Ki-67 antigen stained specimens. Cell density was calculated in every case as an average cell count per five high-power fields. All histological samples were analyzed for estimation of nucleic size and nucleic area. The ImageJ software 1.48v was used for analysis. Analyses of the estimated parameter were performed by means of two sided t-tests. Correlation analysis was performed using the Pearson's product moment correlation. RESULTS: The mean values of ADCmin, ADCmean, ADCmax, and D were 0.64+/-0.11, 0.89+/-0.13, 1.15+/-0.27, and 0.75+/-0.20*10-3 mm(2)s(-1), respectively. The estimated mean cell count was 1160.08+/-33.86 cells and the mean level of the proliferation index was 3.46+/-2.84%. The mean values of average nucleic area and total nucleic area were 65.42+/-19.38 MUm(2) and 64481.87+/-21120.02 MUm(2), respectively ADCmean correlated significant with Ki 67 level, average nucleic area, and total nucleic area, but not with cell count. ADCmin and D correlated significant with cell count and total nucleic area, but not with Ki-67. D was also associated with average nucleic area. ADCmax correlated slightly with cell count. CONCLUSION: Several relationships between ADC and histological parameters in meningioma were assessed. ADCmean was negatively associated with Ki-67 level, average nucleic area, and total nucleic area. There was no significant correlation between ADCmean and cell count. ADCmin and D correlated well with total nucleic areas and cell count, but not with Ki 67. ADCmax correlated slightly with cell count. PMID- 26637906 TI - Adjuvant Ovarian Suppression, High-dose Chemotherapy and Immunotherapy for Premenopausal Patients with High-risk Breast Cancer. AB - BACKGROUND: Premenopausal patients with breast cancer and more than 10 positive axillary nodes (BC>10) have a poor prognosis: In these patients the best adjuvant therapy (CT) has not yet been established. PATIENTS AND METHODS: Forty-two BC>10 received, in sequence, the following adjuvant treatments: luteinizing hormone releasing hormone (LH-RH) analog for 5 years; anthracycline-based induction chemotherapy; radiation therapy; platinum-based high-dose CT, with autologous bone marrow transplantation; immunotherapy with interleukin 2 (IL2) and 13-cis retinoic acid (RA); anastrazole given 5 years to estrogen receptor-positive patients. Primary endpoints of the study were disease-free survival (DFS) and overall (OS) survival. A secondary endpoint was toxicity. RESULTS: The median age of patients was 41 years, and the mean number of positive axillary nodes was 14. Estrogen and progesterone receptors were positive in 57% and 29% of patients respectively, while 14% of patients had triple-negative disease. With a median follow-up of 120 months for patients remaining alive at the end of study, median DFS and OS, had not yet been reached. The 20-year DFS and OS rates were 63.8%, and 81.6%, respectively. One to two years after the end of the therapy, three patients had had four full-term pregnancies. CONCLUSION: Treatment with LH-RH analog, high-dose CT, peripheral blood progenitor cells and IL2 with RA for patients with BC>10 is feasible, has moderate toxicity, while preserving ovarian function, seems to improve the expected DFS and OS for these high-risk patients. PMID- 26637907 TI - Hepatic Resection for Hepatocellular Carcinoma in the Elderly: Selecting Hepatectomy Procedures Based on Patient Age. AB - BACKGROUND: The number of elderly patients who undergo hepatectomy for hepatocellular carcinoma (HCC) has been increasing. Therefore, criteria for selection of an appropriate hepatectomy procedure are required. PATIENTS AND METHODS: Two hundred and twenty-nine HCC patients undergoing hepatectomy were enrolled in the present study. Patients were classified into two groups: the elderly group (age >=75 years, n=34) and the non-elderly group (age <75 years, n=195). The hepatectomy procedure was selected based on the prognostic score (PS) formula, that includes patient age as a variable. RESULTS: The incidence of non anatomical resection was higher (p=0.015) and the weight of resected specimens was lower (p=0.019) in the elderly group than in the non-elderly group. No significant difference was observed in the postoperative complication rate between the two groups. The 5-year survival rates were comparable between the two groups. CONCLUSION: Favorable short- and long-term outcomes can be obtained based on cautious selection criteria for hepatectomy procedures, while considering patient age, in the treatment of elderly patients with HCC. PMID- 26637908 TI - Concurrent Chemoradiotherapy with Docetaxel, Cisplatin and 5-Fluorouracil (TPF) in Patients with Nasopharyngeal Carcinoma. AB - BACKGROUND/AIM: Several randomized trials have shown that concurrent chemoradiotherapy (CCRT) either with or without adjuvant chemotherapy is more effective than radiotherapy-alone for treating nasopharyngeal carcinoma (NPC). The present study retrospectively evaluated the efficacy and toxicity of CCRT with docetaxel, cisplatin, and 5-fluorouracil (TPF) chemotherapy in patients with NPC. PATIENTS AND METHODS: The study regimen consisted of two cycles of TPF chemotherapy [docetaxel (90 mg/m(2)), cisplatin (60 mg/m(2)), and continuous 5 fluorouracil (600 mg/m(2)/day: 5 days)] during definitive radiotherapy. Radiotherapy was performed 5 days a week with a single daily fraction of 1.8 or 2.0 Gy totalling to 70-Gy doses. A total of 24 patients with NPC were enrolled and evaluated. RESULTS: Treatment completion rate was 70.8%, with an overall response rate of 100%. The 5-year overall survival rate was 82.4%, and 5-year progression-free survival rate was 78.3%. CONCLUSION: CCRT with TPF resulted in excellent survival rates for patients with NPC. PMID- 26637909 TI - Treosulfan in the Treatment of Advanced Ovarian Cancer - Results of a German Multicenter Non-interventional Study. AB - BACKGROUND: Data on routine systemic treatment of patients with ovarian cancer are currently available only to a limited degree. The alkylating agent treosulfan is approved in oral (p.o.) and intravenous (i.v.) form for the treatment of ovarian carcinoma. The present non-interventional study analyzed the clinical use of treosulfan in Germany, evaluating the mode of application, toxicity, and response and survival rate. PATIENTS AND METHODS: Two hundred and forty-eight ovarian cancer patients in 57 Centers, who received treosulfan mainly either i.v. (5,000-8,000 mg/m(2) d1, q21d or q28d) or p.o. (400-600 mg/m(2) d1-14 or 21, q28d) for at least one therapy cycle were evaluable and were included in the study. RESULTS: With a median age of 70 years (range=36-92 years), predominantly elderly patients received treosulfan treatment. Most participants presented serous histology (131, 52.8%) and advanced-stage FIGO III (122, 49%) or IV (55, 22%) disease. Median ECOG status was 1 (range=0-2), whereas cardiac co-morbidity was common (31%). Treosulfan was usually administered as second- (26%), third- (21%) or fourth-line (17%) therapy. Two hundred and one patients received i.v. and 47 p.o. TREATMENT: The most common reason for dose modifications was due to hematological toxicity (46%). The main reason for a therapy discontinuation was progressive disease (38.5%). Response was observed in 25.8% of participants, disease stabilization in 28.6 % and progress in 45.6%. The median progression free and overall survival was 196 and 405 days, respectively. CONCLUSION: In predominantly elderly and heavily pre-treated patients with recurrent ovarian cancer, treosulfan featured a clinical relevant efficacy and well-manageable, mostly hematological, toxicity, which resulted in a positive therapeutic index. PMID- 26637910 TI - The Role of Re-resection for Breast Cancer Liver Metastases-a Single Center Experience. AB - The aim of the present study was to evaluate the effectiveness and safety of hepatic re-resection for breast cancer liver metastases. PATIENTS AND METHODS: Between January 2004 and December 2014 seven patients were submitted to liver re resection for breast cancer liver metastases at our Center. The main inclusion criteria were presence of isolated liver metastases and absence of systemic recurrent disease Results: The median age at the time of breast surgery was 51 years (range=39-69 years). The first liver resection was performed after a median period of 34.7 months and consisted of minor hepatectomies in six and major hepatectomy in one patient. The second liver resection was performed after a median interval of 22 months from the first liver resection and consisted of major resection in one case and minor resection in the other six cases. Postoperative complications occurred in a single case after the first liver surgery and in two cases after the second hepatic resection, all cases being successfully managed conservatively. Overall postoperative mortality was 0. The median overall survival after the second liver resection was 28 months. CONCLUSION: Re-resection for breast cancer liver metastases can be safely performed and may bring survival benefit. PMID- 26637911 TI - The Role of Percutaneous Biopsy and Prognostic Factors of Malignancy in Solitary Breast Papilloma: A Retrospective Multicenter Study of 259 Cases. AB - AIM: Management of papillary breast lesions is a controversial issue, as complete excision implies surgery of numerous benign lesions. The purpose of this study was to assess concordance between percutaneous and surgical biopsy of papillomas along with factors predictive of malignancy. PATIENTS AND METHODS: The study consisted of a retrospective review of papilloma cases between 2009 and 2013 at three breast cancer centers. All cases of papilloma histologically diagnosed by percutaneous biopsy and confirmed by surgical specimen were included. The biopsy results were compared with final surgical pathology. Lesion size and clinical and radiological features were recorded. RESULTS: A total of 259 cases were included (188 simple and 71 complex papillomas). Concordance between histology after percutaneous and surgical biopsy was lower for complex papillomas, regardless of type, than for simple papillomas (p<0.001). The risk of having a complex papilloma was shown to be significantly higher in postmenopausal patients (p=0.023), and was 20 times higher if the percutaneous biopsy was malignant as opposed to benign (p<2.10). However, the false-negatives for percutaneous biopsy in complex papilloma cases were mainly related to atypical and in situ lesions. CONCLUSION: Percutaneous biopsy does not appear adequate for identifying papillomas requiring surgical excision due to the risk of underestimation of cancerous lesions. However, certain factors predictive of malignancy may assist with surgical management, such as age and menopausal status, lesions peripheral to the nipple, and atypia on percutaneous biopsy. PMID- 26637912 TI - Undetermined Margins After Colonoscopic Polypectomy for Malignant Polyps: The Need for Radical Resection. AB - AIM: The aim of the present study was to analyze the clinicopathological features of patients with colorectal cancer (CRC) who underwent radical operation after malignant polyp removal by colonoscopic procedure. PATIENTS AND METHODS: Between 2009 and 2013, radical colorectal resection was performed in 50 patients with CRC after colonoscopic polypectomy. RESULTS: Nine cases (18%) had residual cancer. Lymph node (LN) metastasis was found in three cases (6.0%) and tumor deposit without LN metastasis (N1c) was found in two cases (4.0%). The indications for radical operation were an undetermined resection margin (23 cases), positive lateral margin (15 cases). Out of the nine cases with residual cancer, five cases had LN metastasis or tumor deposit without residual tumor in the main lesion. One fourth of cases with an undetermined margin had residual cancer (six out of 23 cases), three of whom had stage III disease. CONCLUSION: Undetermined margins may be considered as an indication for additional radical operation. PMID- 26637913 TI - Biomarker Analysis in a Phase II Study of Sunitinib in Patients with Advanced Melanoma. AB - AIM: To investigate the efficacy of sunitinib in patients with advanced melanoma and to correlate angiogenic biomarkers with response and survival. PATIENTS AND METHODS: We performed a phase II study in patients with advanced pre-treated melanoma. The primary endpoint was tumor response. Blood samples for biomarker analysis including vascular endothelial growth factor (VEGF), and its receptors VEGFR1 and -2, placental growth factor (PlGF) and circulating endothelial cells (CEC) were collected at baseline and during the first cycle. RESULTS: Four out of 39 patients (13%) achieved a partial response and eight (26%) stable disease. Time to progression was at least six months in seven patients. High baseline VEGFR1 levels and high baseline PlGF levels were both associated with a non significant worse survival (p=0.08 for both). CONCLUSION: Sunitinib demonstrates limited activity in unselected patients with refractory advanced melanoma, but a minority of patients experienced long-term disease control. Identification of these patients remains a challenge. PMID- 26637914 TI - Capecitabine as a Radiosensitizer in Adjuvant Chemoradiotherapy for Pancreatic Cancer: A Retrospective Study. AB - AIM: Pancreatic cancer remains one of the deadliest cancer diagnoses and is the fourth leading cause of cancer-related deaths in the U.S. Surgery is the mainstay of treatment for the 20% for whom the tumor is resectable, however, controversy exists over the appropriate adjuvant therapy where local recurrence rates remain strikingly high (50-85%). We aimed to evaluate the safety and efficacy of adding capecitabine (a known radiosensitizer by direct and abscopal effects) to concurrent radiation in the adjuvant setting after resection of pancreatic adenocarcinoma. PATIENTS AND METHODS: We conducted a retrospective study of 63 patients diagnosed from 2004-2013 with histopathologically-confirmed stage I/II pancreatic cancer treated with a surgical resection followed by adjuvant concurrent chemoradiation to at least 45 Gy using 3D planning and capecitabine at 1,600 mg/m(2)/day (Monday-Friday) for 6 weeks. This was combined with either 4 months of gemcitabine at 1,000 mg/m(2) weekly for 3 out of 4 weeks or capecitabine at 2,000 mg/m(2) for 14 days every 3 weeks for a total of 4 months. RESULTS: The majority of patients were over 65 years old (71%), male (60%), had negative surgical margins (79%), had pancreatic head or neck involvement (71%), Eastern Cooperative Oncology Group performance score of 1 (71%), and a cancer antigen 19-9 in the range of 11-100 U/ml at the time of diagnosis (51%). Of the 63 patients reviewed, 61 patients (97%) completed concurrent chemoradiotherapy. Treatment was halted in one patient due to gastritis and a second for gastrointestinal bleeding. Otherwise, adverse reactions during concurrent chemoradiotherapy were well-tolerated and the majority were Common Terminology Criteria for Adverse Events grades 1 and 2. Grade 3 toxicity was anorexia (n=2) and hand and foot syndrome (n=2) and GI bleeding (n=1). The only grade 4 toxicities were anorexia (n=1) and fatigue (n=1). The median follow-up of patients at the time of analysis was 36 months. The median survival of the entire cohort was 23.5 (range=8.5-42) months. The 1-, 2- and 3-year survival rates were 80%, 35% and 25%, respectively. CONCLUSION: Concurrent chemoradiation using capecitabine as a radiosensitizer in the adjuvant setting for pancreatic cancer was completed by the vast majority of patients in this series. Treatment was relatively well-tolerated, and its efficacy seems comparable to that for historical controls. This study probably represents the largest yet reported using capecitabine in this setting. Future studies including an increased sample size are required. PMID- 26637915 TI - One-stage Procedure for Concomitant Abdominal Aortic Aneurysm and Gastric Cancer. AB - BACKGROUND/AIM: A concise surgical strategy for concomitant abdominal aortic aneurysm (AAA) and operable gastric cancer remains unknown. We assessed a one stage procedure that included endovascular abdominal aortic aneurysm repair (EVAR) and gastric resection. PATIENTS AND METHODS: Forteen patients who underwent surgery for an infrarenal AAA and gastric cancer between 1990 and 2012 were retrospectively reviewed. Demographic characteristics, aneurysm size, comorbid conditions, length of postoperative hospital stay, complications within 30 days of surgery, and survival in patients in EVAR (n=4) were compared against patients who had an open AAA repair (n=10). RESULTS: Demographic characteristics, aneurysm size, and comorbid conditions were similar in the EVAR and open-AAA repair group. The mean length of hospitalization was significantly shorter in the EVAR group (15.2 days vs. 34.9 days; p=0.005), and the rate of postoperative complications was significantly lower (p<0.05). The overall survival rates in the EVAR and open-AAA-repair groups were, respectively, 100% and 80% at 1 year and 75% and 60% at 3 years; the differences between groups were not significant (p=0.788). CONCLUSION: In patients with concomitant AAA and gastric cancer who are eligible for EVAR, use of a one-stage procedure including EVAR and gastric resection is feasible. PMID- 26637917 TI - Long-term Survivors After Liver Resection for Ovarian Cancer Liver Metastases. AB - Ovarian cancer is one of the most aggressive gynecological malignancies and most patients are diagnosed at an advanced stage of disease. In these cases, the best therapeutic approach in order to provide good control remains an aggressive surgical approach leading to complete R0 resection. The experience provided by performing liver resection for colorectal hepatic metastases in association with the observation that residual disease remains the most important prognostic factor in ovarian cancer encouraged surgeons worldwide to include hepatic resection as part of the therapeutic armamentarium in ovarian cancer liver metastases. PATIENTS AND METHODS: Data of patients submitted to liver resection for ovarian cancer liver metastases were retrospectively reviewed. The main inclusion criterion for the current study was a reported survival greater than 5 years after hepatic resection. RESULTS: Eight patients were eligible for study inclusion: four cases were submitted to liver resection during primary cytoreduction, two cases were submitted to liver resection as part of secondary cytoreduction while the other two cases underwent hepatic resection at the moment of tertiary cytoreduction. In all cases R0 resection was achieved. Postoperatively one patient developed an abdominal abscess requiring for percutaneous drainage and one patient developed a hemoperitoneum necessitating re operation. The mean overall survival was 123 months for patients submitted to liver resection as part of primary cytoreduction; patients submitted to liver resection as part of secondary cytoreduction experienced an overall survival of 66 and 73 months, respectively, while patients submitted to liver resection as part of tertiary cytoreductive surgery are alive at 5-year follow-up. CONCLUSION: In selected cases liver resection for ovarian cancer liver metastases can be associated with a significant increase of the overall survival. PMID- 26637916 TI - Long-term Survivors After Liver Resection for Breast Cancer Liver Metastases. AB - Although breast cancer liver metastases are considered a sign of systemic recurrence and are considered a poor prognostic factor that transforms the patient into a candidate for palliative chemotherapy, surgery might be performed with good results. Success reported after liver resection for colorectal hepatic metastases encouraged the oncological surgeon to apply similar protocols in breast cancer liver metastases. PATIENTS AND METHODS: Data of patients submitted to hepatectomies for breast cancer liver metastases in the "Dan Setlacec" Center of Gastrointestinal Disease and Liver Transplantation, Fundeni Clinical Institute, Bucharest were retrospectively reviewed. RESULTS: Among five cases survival after liver surgery surpassed 5 years and was considered long-term survival. One of the five cases was submitted to a second liver resection. Most often long-term survivors were reported among patients with single, metachronous and smaller than 5-cm lesions. CONCLUSION: In selected cases liver resection for breast cancer liver metastases can be associated with a significant increase in survival. PMID- 26637918 TI - Prognostic Impact of Serum Testosterone and Body Mass Index Before Androgen deprivation Therapy in Metastatic Prostate Cancer. AB - AIM: Although the impact of testosterone or obesity on the efficacy of androgen deprivation therapy (ADT) has been reported, there exist few comprehensive analyses on the impact of these factors on ADT outcome. Therefore, in the present study, we investigated the relationship between serum testosterone or body mass index (BMI) and prognosis among men treated with primary ADT for metastatic prostate cancer. PATIENTS AND METHODS: The study included fifty-six Japanese patients with prostate cancer treated at our Institution from 2000 through 2012. The relationship between serum testosterone or BMI and progression-free survival, cancer-specific survival, and overall survival among men with metastatic prostate cancer treated with primary ADT was examined. RESULTS: The median of serum testosterone and BMI were 397 ng/dl (interquartile range (IQR), 278-464 ng/dl) and 21.9 kg/m(2) (IQR, 19.2-23.6 kg/m(2)), respectively. Median progression-free survival, cancer-specific survival, and overall survival were 23.2 months, 68.9 months, and 68.1 months, respectively. Among clinicopathological parameters, the lowest-quartile group of serum testosterone level was a significant predictor of poor cancer-specific survival and overall survival as well as survival from castration resistance. However, BMI was not associated with prognosis. CONCLUSION: Serum testosterone level, but not obesity, is a prognostic factor for outcome including survival after getting castration-resistant prostate cancer in men with metastatic prostate cancer having undergone primary ADT. PMID- 26637919 TI - Biochemical Effects of Levothyroxine Withdrawal in Patients with Differentiated Thyroid Cancer. AB - BACKGROUND: Patients with differentiated thyroid carcinoma (DTC) are submitted to withdrawal of levothyroxine (LT4) aftter thyroidectomy, in order to undergo radiodine ((131)I) treatment. PATIENTS AND METHODS: A total of 345 patients with a history of DTC were enrolled in the study. Their biochemical profile and serum free triiodothyronine (FT3), free thyroxine (FT4) and thyrotropin (TSH) levels were measured during withdrawal of LT4 treatment, and several months after restarting LT4. RESULTS: During withdrawal, the intra-individual percentage increase in total cholesterol, low density lipoprotein-cholesterol, very low density lipoprotein-cholesterol and triglycerides was of the order of 60-80% and that for high density lipoprotein-cholesterol 30%. Creatinine increased by 30%, whereas Na and K levels decreased by 1%. The increase for creatine phosphate kinase was around 200-300%, for aspartate aminotransferase and alanine aminotransferase 50-80%, for gamma-glutamyl transpeptidase 10-20%, and for lactate dehydrogenase 25%. Glucose decreased by 1-4%. CONCLUSION: Short-term, acute hypothyroidism in patients with DTC induces significant alterations in several biochemical parameters. The presence of other deteriorating diseases should be considered before submitting these patients to LT4 withdrawal. PMID- 26637921 TI - Is There a Role for Tertiary (TCR) and Quaternary (QCR) Cytoreduction in Recurrent Ovarian Cancer? AB - BACKGROUND: The aim of the present study was to evaluate the efficacy of tertiary and quaternary cytoreduction in recurrent ovarian cancer patients. PATIENTS AND METHODS: Between January 1997 and December 2014, 53 patients were submitted to cytoreductive surgery for second and third ovarian cancer recurrence at our Unit. RESULTS: Median age at first diagnosis was 48 years (range=20-69). Forty-six patients (86.8%) underwent tertiary cytoreduction. At the time of surgery, isolated and diffuse disease was observed in 48 (90.6%) and 5 (9.4%) patients, respectively. Complete and optimal cytoreduction was obtained in 41 (77.5%) and in 1 (1.9%) patients, respectively. We did not observe any statistically significant survival differences according to residual tumor. Patients with TFI >12 months showed longer PFS (38 vs. 7 months, p<0.002) than those with TFI <12 months. In 18 of these patients a third recurrence was observed. In 12 patients (66.7%) a complete quaternary cytoreduction was performed. Longer PFS (16 vs. 21 months; p=0.032) and OS (152 vs. 116 months; p=0.015) in patients submitted to cytoreduction with respect to those treated with chemotherapy were observed. CONCLUSION: Our data suggest that selected ovarian cancer patients who develop a secondary and tertiary recurrence may benefit from additional cytoreductive attempts. The benefit seems to be greater in patients with TFI >12 months showing a single-site recurrence disease, in which complete cytoreduction is achievable. Further studies are required to better-define the role of tertiary and quaternary cytoreduction in recurrent ovarian cancer patients. PMID- 26637920 TI - Factors Associated with the Selection of First-line Bevacizumab plus Chemotherapy and Clinical Response in HER2-negative Metastatic Breast Cancer: ONCOSUR AVALOX Study. AB - AIM: To evaluate factors associated with the selection of first-line bevacizumab plus chemotherapy and clinical response in HER2-negative metastatic breast cancer (MBC) in clinical practice in Spain. PATIENTS AND METHODS: All consecutive adult female patients with HER2-negative MBC who had received first-line bevacizumab plus chemotherapy for at least 3 months were enrolled in the present study. RESULTS: A total of 292 evaluable patients were included; 25% had triple-negative breast cancer (TNBC) and 75% had hormone receptor-positive breast cancer (HRPBC). Nearly 40% of patients had >=3 metastatic sites, mainly located in the bone (48%) and liver (40%). Bevacizumab was mostly combined with paclitaxel (67.1%). ER positive tumors were only identified as an independent factor associated with the choice of treatment (odds ratio (OR): 0.538; p=0.02). The overall response rate (ORR) was 63.7% (TNBC: 57.5%; HRPBC: 65.9%). Patients aged 36-50 years (OR: 3.03; p=0.028) and those with metastases at sites other than the bone (OR: 0.38; p=0.001) and >=3 metastatic sites (OR: 1.41; p=0.018) were more likely to achieve objective responses. CONCLUSION: First-line bevacizumab plus chemotherapy, mainly paclitaxel, is an effective and well-tolerated treatment option for HER2-negative MBC, particularly in more aggressive disease. PMID- 26637922 TI - Comparison of Gefitinib Versus Chemotherapy in Patients with Non-small Cell Lung Cancer with Exon 19 Deletion. AB - BACKGROUND: Second-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) afatinib as first-line treatment has been demonstrated to improve overall survival (OS) in patients with non-small cell lung cancer (NSCLC) harboring an exon 19 deletion (del19) of EGFR compared to platinum-doublet chemotherapy. However, it is unclear whether first-generation EGFR-TKIs improve OS in patients with del19 in the first-line treatment. PATIENTS AND METHODS: We performed a post-hoc analysis of patients with del19 or L858R mutation of EGFR who received gefitinib in the NEJ002 study, which compared gefitinib to carboplatin-paclitaxel. RESULTS: A total of 58 patients and 57 patients with del19 EGFR received gefitinib and carboplatin-paclitaxel, respectively. No OS differences were observed between patients receiving gefitinib and carboplatin paclitaxel irrespective of del19 (29.3 months vs. 29.7 months, p=0.53) or L858R (28.4 months vs. 25.1 months, p=0.45). CONCLUSION: In contrast to afatinib, it is suggested that first-line gefitinib does not improve OS in patients with del19 of EGFR compared with platinum-doublet chemotherapy. PMID- 26637923 TI - Favorable Prognosis in Patients with Sustained Virological Response to Antiviral Therapy, Including Interferon, for Chronic Hepatitis C Before Hepatic Resection for Hepatocellular Carcinoma. AB - BACKGROUND: A sustained virological response (SVR) to interferon (IFN) therapy for chronic hepatitis C virus (HCV) reduces but does not eliminate the risk of hepatocellular carcinoma (HCC). The prognosis after hepatectomy for HCC in patients with SVR has not been fully clarified. PATIENTS AND METHODS: Between 1998 and 2011, 494 patients with chronic hepatitis C underwent hepatic resection for HCC at four high-volume Centers in Japan. Out of these, 188 underwent IFN therapy for HCV. In 92 patients, SVR to IFN therapy had been achieved at the time of hepatectomy (SVR group) while in 96 patients, SVR had not (non-SVR group) had not been achieved. In the other 306 patients, IFN therapy had never been performed at all (no IFN group). The clinicopathological factors and long-term outcomes were retrospectively reviewed and compared among SVR, non-SVR and no IFN groups. RESULTS: The mean time from achievement of SVR to hepatectomy for HCC was 6.2 years (range=2 months to 20 years). The preoperative serum alanine transaminase, albumin, prothrombin time, indocyanine green retention test at 15 min were significantly preserved in the SVR group. The overall survival and recurrence-free survival rates were significantly higher in the SVR group compared to patients in non-SVR and no IFN groups. CONCLUSION: In patients undergoing hepatectomy for HCC, those with SVR had good liver function and a more favorable long-term prognosis than those without SVR. Early detection of HCC after SVR and meticulous hepatectomy with small blood loss is important in patients with HCC after hepatectomy. PMID- 26637924 TI - Investigation of Potentially Deleterious Alleles for Response to Cancer Treatment with 5-Fluorouracil. AB - AIM: To investigate polymorphisms that are probable indicators of response variability during cancer treatment with 5-fluorouracil (rs16430, rs2279198, rs1801159 and rs17878362). MATERIALS AND METHODS: We investigated 1,038 individuals regarding allele distribution from different populations, out of which we genotyped 127 individuals from a Brazilian admixed population. Similarity analyses with parental populations were performed. Prevalence of potentially deleterious alleles was also evaluated. RESULTS: Thirty-seven percent of the population had at least three potentially deleterious alleles and 38.6% had at least one potentially deleterious allele in homozygosis. CONCLUSION: Potentially deleterious alleles are present under diverse frequencies in different populations. Therefore, genotyping prior to 5-fluorouracil administration should be recommended. PMID- 26637925 TI - Diagnostic Value of Circulating CXC Chemokines in Non-small Cell Lung Cancer. AB - BACKGROUND/AIM: To evaluate the diagnostic value of circulating CXC chemokines as biomarkers for non-small cell lung cancer and compare them against a standard panel of already existing cancer biomarkers. MATERIALS AND METHODS: A total of 90 individuals were enrolled in the study. We analyzed 30 patients with stage IA-IIB carcinoma of the lung who underwent pulmonary resection, 30 patients with metastatic NSCLC, and 30 healthy volunteers. The biomarkers levels were measured in plasma blood samples, by ELISA and immunoassays. RESULTS: The levels of circulating CXCL4, CXCL8, CXCL9, CXCL10 and CXCL11 were higher and those of circulating CXCL1 were lower in patients with early-stage NSCLC compared to metastatic NSCLC patients and controls (p<0.05). CXCL4, CXCL9 and CXCL11 were included in the panel that showed a sensitivity of 100% versus 60% for CEA, CA125 and CYFRA21-1 (p<0.001). CONCLUSION: Combination of CXCL4, CXCL9 and CXCL11 has a high diagnostic value. PMID- 26637926 TI - Prognostic Value of FDG-PET/CT Total Lesion Glycolysis for Patients with Resectable Distal Bile Duct Adenocarcinoma. AB - AIM: We investigated the prognostic value of clinicopathological factors in patients with a distal bile duct adenocarcinoma after curative resection. PATIENTS AND METHODS: This retrospective study included 25 patients who underwent (18)F-fluorodeoxyglucose positron-emission tomography/computed tomography (FDG PET/CT) before surgery. The maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were measured using FDG PET/CT. FDG-PET/CT parameters and other clinicopathological factors were assessed to evaluate survival. RESULTS: Univariate survival analysis showed that high TLG, high MTV, and high SUVmax were significant prognostic predictors for poor overall survival. For progression-free survival, high TLG and large tumor size were significant predictors for a poor prognosis. After multivariate survival analysis, only high TLG was an independent prognostic predictor for poor overall survival (p=0.025). CONCLUSION: Preoperative assessment of TLG by FDG-PET/CT might be a useful prognostic predictor in patients with a distal bile duct adenocarcinoma after curative resection. PMID- 26637927 TI - Errata. PMID- 26637929 TI - Antibodies specific for Epstein-Barr virus nuclear antigen-1 cross-react with human heterogeneous nuclear ribonucleoprotein L. AB - Epstein-Barr virus (EBV) is associated with multiple sclerosis (MS), and antibodies to the EBV nuclear antigen-1 (EBNA-1) are consistently increased in MS patients. The hypothesis of this study is that anti-EBNA-1 antibodies cross-react with a self antigen in MS patients. We affinity purified anti-EBNA-1 antibodies from human plasma, used the anti-EBNA-1 to immunoprecipitate antigens from human brain, and identified bound antigens with mass spectrometry. Anti-EBNA-1 consistently bound heterogeneous nuclear ribonucleoprotein L (HNRNPL). We expressed both the long and short isoforms of this protein, and verified with Western blots and ELISA that the long isoform cross-reacts with EBNA-1. Immunohistochemistry demonstrated that anti-EBNA-1 bound to an antigen in the nucleus of cultured rat central nervous system cells. ELISA demonstrated the presence of antibodies to HNRNPL in the plasma of both healthy controls and MS patients, but anti-HNRNPL was not increased in MS patients. We conclude that HNRNPL is an autoantigen which cross-reacts with EBNA-1. The relevance of this autoantigen to MS and other autoimmune diseases remains to be investigated. PMID- 26637931 TI - Emotion biases voluntary vertical action only with visible cues. AB - Emotional information influences our bodily experiences according to the space valence metaphor (positive/negative is up/down). In the present study, we examined whether visible and invisible emotional stimuli could also modulate voluntary action. After observing an emotional image (e.g., positive, neutral, or negative), participants used a joystick to arbitrarily position a dot stimulus in a display. The emotional image was either masked (masked condition) or not (unmasked condition) via a continuous flash suppression technique, i.e., dynamic interocular masking. We found that in the unmasked condition, the placed position of the dot was significantly higher after observing the positive image compared with the negative image, but this difference was not present in the masked condition. Our findings suggest that conscious emotional information is necessary for activating sensorimotor representations of vertical directions, and voluntary action is performed based on these activations. PMID- 26637930 TI - Ctenopharyngodon idella PKZ facilitates cell apoptosis through phosphorylating eIF2alpha. AB - PKZ, protein kinase containing Z-DNA binding domains, is a novel member of eIF2alpha kinase in fish. PKZ can be up-regulated in response to Poly I:C or heat stress, and it has a typical eIF2alpha kinase activity. However, the relationship between fish PKZ and apoptosis remains unclear. In the present study, effects of PKZ on apoptosis were explored. Initially, we found that PKZ and PKR were up regulated by poly I:C in a time-dependent manner. Q-PCR analysis showed that the change of Caspase-3 mRNA was consistent with that of PKZ under the stimulation of poly I:C or transfection with PKZ siRNA in CIK cells. It suggested that PKZ might mediate the induction of apoptosis. Knockdown and overexpression assays indicated that a significant increase of apoptotic cell number was observed in the wild type PKZ (PKZ-wt) transfected PKZ-deficient cells, while mutant PKZ-K198R lost this ability. MTT also showed that overexpression of PKZ-wt in CIK cells resulted in a striking decrease of cell viability rate to about 32.5%, whereas the viability of cell with PKZ-K198R was about 88.1%. Likewise, when transfected eIF2alpha-wt or phosphomimetic eIF2alpha (S51D), CIK cells displayed higher apoptotic rate than the controls. In contrast, overexpression of phosphodeficient eIF2alpha (S51A) blocked induction of apoptosis. In addition, levels of eIF2alpha phosphorylation were significantly related to apoptosis in these CIK cells. Furthermore, when mutant eIF2alpha (S51A) was transiently transfected into the PKZ/PKR knockdown cells that transfected with wildtype PKZ previously, the apoptotic rates and levels of eIF2alpha phosphorylation were dramatically decreased. Overall, these results suggested that PKZ could facilitate apoptosis via eIF2alpha phosphorylation. PMID- 26637932 TI - Contingent attentional capture across multiple feature dimensions in a temporal search task. AB - The present study examined whether attention can be flexibly controlled to monitor two different feature dimensions (shape and color) in a temporal search task. Specifically, we investigated the occurrence of contingent attentional capture (i.e., interference from task-relevant distractors) and resulting set reconfiguration (i.e., enhancement of single task-relevant set). If observers can restrict searches to a specific value for each relevant feature dimension independently, the capture and reconfiguration effect should only occur when the single relevant distractor in each dimension appears. Participants identified a target letter surrounded by a non-green square or a non-square green frame. The results revealed contingent attentional capture, as target identification accuracy was lower when the distractor contained a target-defining feature than when it contained a nontarget feature. Resulting set reconfiguration was also obtained in that accuracy was superior when the current target's feature (e.g., shape) corresponded to the defining feature of the present distractor (shape) than when the current target's feature did not match the distractor's feature (color). This enhancement was not due to perceptual priming. The present study demonstrated that the principles of contingent attentional capture and resulting set reconfiguration held even when multiple target feature dimensions were monitored. PMID- 26637933 TI - Fin whales and microplastics: The Mediterranean Sea and the Sea of Cortez scenarios. AB - The impact that microplastics have on baleen whales is a question that remains largely unexplored. This study examined the interaction between free-ranging fin whales (Balaenoptera physalus) and microplastics by comparing populations living in two semi-enclosed basins, the Mediterranean Sea and the Sea of Cortez (Gulf of California, Mexico). The results indicate that a considerable abundance of microplastics and plastic additives exists in the neustonic samples from Pelagos Sanctuary of the Mediterranean Sea, and that pelagic areas containing high densities of microplastics overlap with whale feeding grounds, suggesting that whales are exposed to microplastics during foraging; this was confirmed by the observation of a temporal increase in toxicological stress in whales. Given the abundance of microplastics in the Mediterranean environment, along with the high concentrations of Persistent Bioaccumulative and Toxic (PBT) chemicals, plastic additives and biomarker responses detected in the biopsies of Mediterranean whales as compared to those in whales inhabiting the Sea of Cortez, we believe that exposure to microplastics because of direct ingestion and consumption of contaminated prey poses a major threat to the health of fin whales in the Mediterranean Sea. PMID- 26637934 TI - The cystatin C/creatinine ratio, a marker of glomerular filtration quality: associated factors, reference intervals, and prediction of morbidity and mortality in healthy seniors. AB - The ratio of cystatin C (cysC) to creatinine (crea) is regarded as a marker of glomerular filtration quality associated with cardiovascular morbidities. We sought to determine reference intervals for serum cysC-crea ratio in seniors. Furthermore, we sought to determine whether other low-molecular weight molecules exhibit a similar behavior in individuals with altered glomerular filtration quality. Finally, we investigated associations with adverse outcomes. A total of 1382 subjectively healthy Swiss volunteers aged 60 years or older were enrolled in the study. Reference intervals were calculated according to Clinical & Laboratory Standards Institute (CLSI) guideline EP28-A3c. After a baseline exam, a 4-year follow-up survey recorded information about overall morbidity and mortality. The cysC-crea ratio (mean 0.0124 +/- 0.0026 mg/MUmol) was significantly higher in women and increased progressively with age. Other associated factors were hemoglobin A1c, mean arterial pressure, and C-reactive protein (P < 0.05 for all). Participants exhibiting shrunken pore syndrome had significantly higher ratios of 3.5-66.5 kDa molecules (brain natriuretic peptide, parathyroid hormone, beta2-microglobulin, cystatin C, retinol-binding protein, thyroid-stimulating hormone, alpha1-acid glycoprotein, lipase, amylase, prealbumin, and albumin) and creatinine. There was no such difference in the ratios of very low-molecular weight molecules (urea, uric acid) to creatinine or in the ratios of molecules larger than 66.5 kDa (transferrin, haptoglobin) to creatinine. The cysC-crea ratio was significantly predictive of mortality and subjective overall morbidity at follow-up in logistic regression models adjusting for several factors. The cysC-crea ratio exhibits age- and sex-specific reference intervals in seniors. In conclusion, the cysC-crea ratio may indicate the relative retention of biologically active low-molecular weight compounds and can independently predict the risk for overall mortality and morbidity in the elderly. PMID- 26637935 TI - The effect of lubricant constituents on lubrication mechanisms in hip joint replacements. AB - The aim of the present paper is to provide a novel experimental approach enabling to assess the thickness of lubricant film within hip prostheses in meaning of the contribution of particular proteins. Thin film colorimetric interferometry was combined with fluorescent microscopy finding that a combination of optical methods can help to better understand the interfacial lubrication processes in hip replacements. The contact of metal femoral head against a glass disc was investigated under various operating conditions. As a test lubricant, the saline solution containing the albumin and gamma-globulin in a concentration 2:1 was employed. Two different mean speeds were applied, 5.7 and 22mm/s, respectively. The measurements were carried out under pure rolling, partial negative and partial positive sliding conditions showing that kinematic conditions substantially affects the formation of protein film. Under pure rolling conditions, an increasing tendency of lubricant film independently on rolling speed was detected, while the total thickness of lubricant film can be attributed mainly to albumin. When the ball was faster than the disc (negative sliding), a very thin lubricant film was observed for lower speed with no significant effect of particular proteins. The increase in sliding speed led to the increase of film thickness mainly caused due to the presence of gamma-globulin. On the contrary, when the disc was faster than the ball (positive sliding), the film formation was very complex and time dependent while both of the studied proteins have shown any qualitative change during the test, however the effect of albumin seems to be much more important. Since a very good agreement of the results was obtained, it can be concluded that the approach consisting of two optical methods can provide the fundamental information about the lubricant film formation in meaning of particular proteins while the simultaneous presence of other constituents in model synovial fluid. PMID- 26637936 TI - Direct Conversion Provides Old Neurons from Aged Donor's Skin. AB - Modeling human neuronal aging at a cellular level remains challenging. Human neurons are accessible from iPSCs, but during reprogramming age-associated traits of somatic cells get lost. In this issue of Cell Stem Cell, Mertens et al. (2015) demonstrate that neurons obtained by direct cell conversion retain age-associated transcriptional traits and functional deficits of the donor cell population. PMID- 26637937 TI - More Frequent than Desired: Midgut Stem Cell Somatic Mutations. AB - The accumulation of somatic mutations in adult stem cells contributes to the decline of tissue functions and cancer initiation. In this issue of Cell Stem Cell, Siudeja et al. (2015) investigate the rate and mechanism of naturally occurring mutations in Drosophila midgut intestinal stem cells during aging and find high-frequency mutations arising from multiple mechanisms. PMID- 26637938 TI - Human SCNT Gets a Boost from Histone Demethylation. AB - Human somatic cell nuclear transfer (SCNT) holds great potential in regenerative medicine; however, its applicability has been limited by great variability in reprogramming efficiencies. A new study in this issue of Cell Stem Cell reports a simple way to expand human SCNT to hard-to-reprogram oocytes (Chung et al., 2015). PMID- 26637939 TI - Leukemogenic Activity of Cohesin Rings True. AB - Cohesin complex components are frequently mutated in human myeloid cancers. Three new studies now show that cohesin mutations disrupt the differentiation of normal hematopoietic stem and progenitor cells and enhance self-renewal, shedding light on how these alterations may contribute to leukemic transformation. PMID- 26637940 TI - Illuminating the Properties of Prostate Luminal Progenitors. AB - The identification of tumor-initiating cells represents a significant challenge for studies of prostate cancer. In a recent issue of Cell Reports, Agarwal and colleagues use organoid culture to ascertain two distinct luminal progenitors in a mouse model of prostate cancer, shedding new light on lineage relationships in the prostate epithelium. PMID- 26637941 TI - BindDB: An Integrated Database and Webtool Platform for "Reverse-ChIP" Epigenomic Analysis. PMID- 26637943 TI - Dynamic Reorganization of Extremely Long-Range Promoter-Promoter Interactions between Two States of Pluripotency. AB - Serum-to-2i interconversion of mouse embryonic stem cells (mESCs) is a valuable in vitro model for early embryonic development. To assess whether 3D chromatin organization changes during this transition, we established Capture Hi-C with target-sequence enrichment of DNase I hypersensitive sites. We detected extremely long-range intra- and inter-chromosomal interactions between a small subset of H3K27me3 marked bivalent promoters involving the Hox clusters in serum-grown cells. Notably, these promoter-mediated interactions are not present in 2i ground state pluripotent mESCs but appear upon their further development into primed like serum mESCs. Reverting serum mESCs to ground-state 2i mESCs removes these promoter-promoter interactions in a spatiotemporal manner. H3K27me3, which is largely absent at bivalent promoters in ground-state 2i mESCs, is necessary, but not sufficient, to establish these interactions, as confirmed by Capture Hi-C on Eed(-/-) serum mESCs. Our results implicate H3K27me3 and PRC2 as critical players in chromatin alteration during priming of ESCs for differentiation. PMID- 26637944 TI - Aorta-to-arm pulse wave transit time ratio: Better prediction of coronary artery disease and stroke than pulse wave velocity. PMID- 26637942 TI - Metabolic Reprogramming of Stem Cell Epigenetics. AB - For many years, stem cell metabolism was viewed as a byproduct of cell fate status rather than an active regulatory mechanism; however, there is now a growing appreciation that metabolic pathways influence epigenetic changes associated with lineage commitment, specification, and self-renewal. Here we review how metabolites generated during glycolytic and oxidative processes are utilized in enzymatic reactions leading to epigenetic modifications and transcriptional regulation. We discuss how "metabolic reprogramming" contributes to global epigenetic changes in the context of naive and primed pluripotent states, somatic reprogramming, and hematopoietic and skeletal muscle tissue stem cells, and we discuss the implications for regenerative medicine. PMID- 26637945 TI - The immunomodulation potential of the synthetic derivatives of benzothiazoles: Implications in immune system disorders through in vitro and in silico studies. AB - Benzothiazole and its natural or synthetic derivatives have been used as precursors for several pharmacological agents for neuroprotective, anti bacterial, and anti-allergic activities. The objective of the present study was to evaluate effects of benzothiazole analogs (compounds 1-26) for their immunomodulatory activities. Eight compounds (2, 4, 5, 8-10, 12, and 18) showed potent inhibitory activity on PHA-activated peripheral blood mononuclear cells (PBMCs) with IC50 ranging from 3.7 to 11.9 MUM compared to that of the standard drug, prednisolone <1.5 MUM. Some compounds (2, 4, 8, and 18) were also found to have potent inhibitory activities on the production of IL-2 on PHA/PMA-stimulated PBMCs with IC50 values ranging between <4.0 and 12.8 MUM. The binding interaction of these compounds was performed through silico molecular docking. Compounds 2, 8, 9, and 10 significantly suppressed oxidative burst ROS production in phagocytes with IC50 values between <4.0 and 15.2 MUM. The lipopolysaccharide (LPS)-induced nitrites in murine macrophages cell line J774 were found to be inhibited by compounds 4, 8, 9, and 18 at a concentration of 25 MUg/mL by 56%, 91%, 58%, and 78%, respectively. Furthermore, compounds 5, 8, 12, and 18 showed significant (P<0.05) suppressive activity on Th-2 cytokine, interleukin 4 (IL-4) with an IC50 range of <4.0 to 40.3 MUM. Interestingly compound 4 has shown a selective inhibitory activity on IL-2 and T cell proliferation (naive T cell proliferation stage) rather than on IL-4 cytokine, while compound 12 displayed an interference with T-cell proliferation and IL-4 generation. Moreover compound 8 and 18 exert non-selective inhibition on both IL-2 and IL-4 cytokines, indicating a better interference with stage leading to humoral immune response and hence possible application in autoimmune diseases. PMID- 26637946 TI - Benzimidazole derivatives as new alpha-glucosidase inhibitors and in silico studies. AB - Newly synthesized benzimidazole hydrazone derivatives 1-26 were evaluated for their alpha-glucosidase inhibitory activity. Compounds 1-26 exhibited varying degrees of yeast alpha-glucosidase inhibitory activity with IC50 values between 8.40 +/- 0.76 and 179.71 +/- 1.11 MUM when compared with standard acarbose. In this assay, seven compounds that showed highest inhibitory effects than the rest of benzimidazole series were identified. All the synthesized compounds were characterized by different spectroscopic methods adequately. We further evaluated the interaction of the active compounds with enzyme with the help of docking studies. PMID- 26637947 TI - Processing of space, time, and number contributes to mathematical abilities above and beyond domain-general cognitive abilities. AB - The current study investigated whether processing of number, space, and time contributes to mathematical abilities beyond previously known domain-general cognitive abilities in a sample of 8- to 10-year-old children (N=133). Multiple regression analyses revealed that executive functions and general intelligence predicted all aspects of mathematics and overall mathematical ability. Working memory capacity did not contribute significantly to our models, whereas spatial ability was a strong predictor of achievement. The study replicates earlier research showing that non-symbolic number processing seems to lose predictive power of mathematical abilities once the symbolic system is acquired. Novel findings include the fact that time discrimination ability was tied to calculation ability. Therefore, a conclusion is that magnitude processing in general contributes to mathematical achievement. PMID- 26637948 TI - Maltreated and non-maltreated children's true and false memories of neutral and emotional word lists in the Deese/Roediger-McDermott task. AB - Maltreated (n=26) and non-maltreated (n=31) 7- to 12-year-old children were tested on the Deese/Roediger-McDermott (DRM) false memory task using emotional and neutral word lists. True recall was significantly better for non-maltreated than maltreated children regardless of list valence. The proportion of false recall for neutral lists was comparable regardless of maltreatment status. However, maltreated children showed a significantly higher false recall rate for the emotional lists than non-maltreated children. Together, these results provide new evidence that maltreated children could be more prone to false memory illusions for negatively valenced information than their non-maltreated counterparts. PMID- 26637949 TI - Identification and expression profiling of the auxin response factors (ARFs) in the tea plant (Camellia sinensis (L.) O. Kuntze) under various abiotic stresses. AB - Auxin response factor (ARF) proteins are a multigene family of regulators involved in various physiological and developmental processes in plants. However, their modes of action in the tea plant (Camellia sinensis) remain largely unknown. In this study, we identified 15 members of the tea ARF gene family, using the public information about C. sinensis, both in our laboratory, as well as in other laboratories, and analyzed their phylogenetic relationships, conserved domains and the compositions of the amino acids in the middle region. A comprehensive expression analysis in different tissues and organs revealed that many ARF genes were expressed in a tissue-specific manner, suggesting they have different functions in the growth and development processes of the tea plant. The expression analysis under three forms of auxin (indole-3-acetic acid, 2,4 dichlorophenoxyacetic acid, naphthylacetic acid) treatment showed that the majority of the ARF genes were down-regulated in the shoots and up-regulated in the roots, suggesting opposite action mechanisms of the ARF genes in the shoots and roots. The expression levels of most ARF genes were changed under various phytohormone and abiotic stresses, indicating the ARF gene family plays important roles in various phytohormone and abiotic stress signals and may mediate the crosstalk between phytohormones and abiotic stresses. The current study provides basic information for the ARF genes of the tea plant and will pave the way for deciphering the precise role of ARFs in tea developmental processes and breeding stress-tolerant tea varieties. PMID- 26637951 TI - Simultaneous determination of parabens, alkylphenols, phenylphenols, bisphenol A and triclosan in human urine, blood and breast milk by continuous solid-phase extraction and gas chromatography-mass spectrometry. AB - A highly sensitive gas chromatography-mass spectrometry (GC-MS) method for the determination of endocrine disrupting chemicals (EDCs) including parabens, alkylphenols, phenylphenols, bisphenol A and triclosan in human breast milk, blood and urine samples is proposed. Blood and milk require a pretreatment to remove proteins and other substances potentially interfering with the continuous solid-phase extraction (SPE) system used; on the other hand, urine samples can be directly introduced into the system after filtering. Analytes are retained on a LiChrolut EN column and derivatized by silylation following elution with acetonitrile. The resulting trimethylsilyl derivatives are determined by GC-MS. The proposed method exhibited good linearity (r(2)>0.995) for all target EDCs over the concentration range 0.7-10,000ng/l in urine, and 3.3-50,000ng/l in blood and milk. Also, it provided low limits of detection (0.2-1.8ng/l in urine, and 1.0-9.0ng/l in blood and milk), good precision (relative standard deviations less than 7%) and recoveries from 86 to 104%. A total of 24 human fluid samples were analyzed and most found to contain some target EDC at concentrations from 0.10 to 14MUg/l. PMID- 26637950 TI - Microspectroscopic investigation of the membrane clogging during the sterile filtration of the growth media for mammalian cell culture. AB - Growth media for mammalian cell culture are very complex mixtures of several dozens of ingredients, and thus the preparation of qualified media is critical to viable cell density and final product titers. For liquid media prepared from powdered ingredients, sterile filtration is required prior to use to safeguard the cell culture process. Recently one batch of our prepared media failed to pass through the sterile filtration due to the membrane clogging. In this study, we report the root cause analysis of the failed sterile filtration based on the investigations of both the fouling media and the clogged membranes with multiple microspectroscopic techniques. Cellular particles or fragments were identified in the fouling media and on the surfaces of the clogged membranes, which were presumably introduced to the media from the bacterial contamination. This study demonstrated that microspectroscopic techniques may be used to rapidly identify both microbial particles and inorganic precipitates in the cell culture media. PMID- 26637952 TI - Clonidine complexation with hydroxypropyl-beta-cyclodextrin: From physico chemical characterization to in vivo adjuvant effect in local anesthesia. AB - Clonidine (CND), an alpha-2-adrenergic agonist, is used as an adjuvant with local anesthetics. In this work, we describe the preparation and characterization of an inclusion complex of clonidine in hydroxypropyl-beta-cyclodextrin (HP-beta-CD), as revealed by experimental (UV-vis absorption, SEM, X-ray diffraction, DOSY- and ROESY-NMR) and theoretical (molecular dynamics) approaches. CND was found to bind to HP-beta-CD (Ka=20M(-1)) in 1:1 stoichiometry. X-ray diffractograms and SEM images provided evidence of inclusion complex formation, which was associated with changes in the diffraction patterns of the pure compounds. NMR experiments revealed changes in the chemical shift of H3HP-beta-CD hydrogens (Delta=0.026ppm) that were compatible with the insertion of CND in the hydrophobic cavity of the cyclodextrin. Molecular dynamics simulation with the three CND species that exist at pH 7.4 revealed the formation of intermolecular hydrogen bonds, especially for the neutral imino form of CND, which favored its insertion in the HP-beta-CD cavity. In vitro assays revealed that complexation retarded drug diffusion without changing the intrinsic toxicity of clonidine, while in vivo tests in rats showed enhanced sensory blockade after the administration of 0.15% CND, with the effect decreasing in the order: CND:HP-beta CD+bupivacaine>CND+bupivacaine>bupivacaine>CND:HP-beta-CD>clonidine. The findings demonstrated the suitability of the complex for use as a drug delivery system for clinical use in antinociceptive procedures, in association with local anesthetics. PMID- 26637953 TI - Cervical leukocytes and spontaneous preterm birth. AB - The objective was to characterise cervical leukocyte populations and inflammatory mediators associated with term and recurrent spontaneous preterm birth (SPTB) in pregnant women with a history of SPTB. A prospective observational study was undertaken on 120 women with a history of SPTB. A cytobrush was used to sample cells from the cervix at 12-25 weeks' gestation. Cells were enumerated and characterised by flow cytometry. Cytokines and chemokines were also measured. Participants were then grouped according to delivery at term (>36+6 weeks), late SPTB (34-36+6 weeks) or early SPTB (<34 weeks). Differences in leukocyte sub populations, cytokine and chemokine levels were compared with outcome. Cervical leukocytes comprised up to 60% of the host-derived cells. Most of these (90-100%) were polymorphonuclear cells (PMN). Most of the remaining cells were mucosal macrophages expressing CD68 and CD103 in addition to markers shared with blood borne monocytes. Failure to detect cervical macrophages in at least 250,000 cervical epithelial cells was a feature of women who experienced early SPTB (6 out of 6 cases, 95% CI 61-100%) compared with 34% (30 out of 88 cases, 95% CI 25 43%, P<0.001) of women delivering after 34 weeks. CCL2 (MCP-1) was also low in SPTB before 34 weeks and levels above 75 ng/g and/or the presence of macrophages increased the specificity for birth after 34 weeks from 66% to 82% (55 out of 67 cases, 95% CI 73-91%). Absence of cervical macrophages and low CCL2 may be features of pregnancies at risk of early SPTB. PMID- 26637954 TI - Genomic changes during evolution of animal parasitism in eukaryotes. AB - Understanding how pathogens have evolved to survive in close association with their hosts is an important step in unraveling the biology of host-pathogen interactions. Comparative genomics is a powerful tool to approach this problem as an increasing number of genomes of multiple pathogen species and strains become available. The ever-growing catalog of genome sequences makes comparison of organisms easier, but it also allows us to reconstitute the evolutionary processes occurring at the genomic level that may have led to the acquisition of pathogenic or parasitic mechanisms. PMID- 26637955 TI - Adrenocortical tumors and insulin resistance: What is the first step? AB - The pathogenetic mechanisms underlying the onset of adrenocortical tumors (ACTs) are still largely unknown. Recently, more attention has been paid to the role of insulin and insulin-like growth factor (IGF) system on general tumor development and progression. Increased levels of insulin, IGF-1 and IGF-2 are associated with tumor cell growth and increased risk of cancer promotion and progression in patients with type 2 diabetes. Insulin resistance and compensatory hyperinsulinemia may play a role in adrenal tumor growth through the activation of insulin and IGF-1 receptors. Interestingly, apparently non-functioning ACTs are often associated with a high prevalence of insulin resistance and metabolic syndrome. However, it is unclear if ACT develops from a primary insulin resistance and compensatory hyperinsulinemia or if insulin resistance is only secondary to the slight cortisol hypersecretion by ACT. The aim of this review is to summarize the current evidence regarding the relationship between hyperinsulinemia and adrenocortical tumors. PMID- 26637956 TI - Suppressive effect of Sanmiao formula on experimental gouty arthritis by inhibiting cartilage matrix degradation: An in vivo and in vitro study. AB - Sanmiao formula (SM) is a compound prescription, which has been used in traditional Chinese medicine since the Ming Dynasty for gouty and rheumatoid arthritis treatments. However, no evidence has been unfolded to show the relationship between SM and gouty arthritis (GA), particularly inhibiting cartilage matrix degradation. In the present study, we undertook a characterization of anti-GA activity of SM using an in vivo rat model induced by potassium oxonate and cold bath together with in vitro studies with chondrocytes for further molecular characterization. Potassium oxonate and cold bath rats were treated with SM at doses of 7.2g/kg per day for 5days. SM treatments significantly suppressed the swelling rate and the severe pathologic changes in the joints of the animals in gout model. Inflammatory factors count by ELISA analysis, SM exhibited inhibition on IL-1beta and TNF-alpha. Moreover, histological analysis of the joints and SM-serum substantially interfered with the MSU-induced expression of glycosaminoglycans (GAG), up-regulated the content of proteoglycan. Importantly, SM interfered with GA-augmented expression of matrix metalloproteinases (MMPs) -3 and aggrecanases (ADAMTS)-4, which are considered to be key enzymes in cartilage matrix degradation, and simultaneously augmented GA-reduced tissue inhibitors of metalloproteinases (TIMPs) -1 and -3 expression in the joints and chondrocytes. Therefore, SM is looking forward to be a potential novel agent that could prevent cartilage matrix degradation effectively in gouty arthritis, and this provides a new target for development of new medicines. PMID- 26637957 TI - The protective effects of curculigoside A on adjuvant-induced arthritis by inhibiting NF-kB/NLRP3 activation in rats. AB - The purpose of this study was to investigate the protective effects of curculigoside A (CA) on adjuvant arthritis (AA) rats and explore its possible mechanisms. AA was induced by intradermal injection of Freund's complete adjuvant (FCA). Male SD rats were treated with CA(10 and 20mg/kg) from days 18 to 24 after immunization. The levels of interleukin (IL)-6, IL-1beta, tumor necrosis factor alpha (TNF-alpha) and prostaglandin E2 (PGE2) in serum were determined by ELISA. Moreover, the levels of super oxide dismutase (SOD) and malondialdehyde (MDA) were determined using commercial kits. In particular, NLRP3 inflammasome and NF kB pathway were detected by Western blot. As expected, CA at 10 and 20mg/kg significantly relieved the hind paw swelling and arthritis index, reduced the levels of IL-6 IL-1beta, PGE2, TNF-alpha, MDA and increased SOD activity in serum. In addition, CA effectively down-regulated the expression of NF-kB/NLRP3 pathway. These findings showed that CA exerted beneficial effects on rheumatoid arthritis in rats. PMID- 26637958 TI - Intense Seasonal A/H1N1 Influenza in Mexico, Winter 2013-2014. Time for Preventive Medicine? PMID- 26637959 TI - Effects of anti-obesity messages on women's body image and eating behaviour. AB - OBJECTIVES: It has been suggested that obesity stigmatization contributes to negative mental health outcomes, particularly among overweight individuals. This study examined the effects of exposure to media-portrayed anti-obesity messages on women's state self-esteem, body esteem, and food intake. It was hypothesized that exposure to anti-obesity messages would result in decreased state self esteem and body esteem and in increased food intake, and that these effects would be more pronounced in individuals with either higher BMI or stronger perceived pressure to be thin. METHOD: Participants were randomly assigned to one of three experimental conditions in which they either: read a fictitious media article containing either anti-obesity messages or non-obesity-related health messages, or completed a neutral control task (word search). State self-esteem and body esteem were measured before and after the manipulation. Participants also completed a candy taste rating task and ad lib consumption was surreptitiously measured. RESULTS: There was no main effect of condition on either psychological outcome variable or on grams consumed. Higher perceived sociocultural pressure to be thin was associated with a decrease in body esteem after reading the anti obesity article only. Having a higher BMI was associated with greater candy intake in the word search condition. This trend was also apparent in the sun exposure condition, but not in the anti-obesity condition. DISCUSSION: Exposure to anti-obesity messages appears to decrease weight-related body esteem in women who already feel strong pressure to be thin, and may lead heavier women to suppress their food intake. PMID- 26637960 TI - Beyond cell proliferation in avian facial morphogenesis. AB - The upper jaw in vertebrates forms from several prominences that arise around the stomodeum or primitive mouth. These prominences undergo coordinated growth and morphogenesis to fuse and form the face. Undirected, regionalized cell proliferation is thought to be the driving force behind the morphogenesis of the facial prominences. However, recent findings suggest that directed cell behaviors in the mesenchyme (e.g., directed cell division, directed cell movement, convergent extension) might be required for successful face formation. Here we discuss the evidence for this view and how directed behaviors may interact with the basement membrane to regulate morphogenesis of the facial region. We believe that future research in these largely unexplored areas could significantly impact our understanding of facial morphogenesis. PMID- 26637961 TI - A shortened interval between vaccinations with the trivalent inactivated influenza vaccine increases responsiveness in the aged. AB - We tested antibody responses to the trivalent inactivated influenza vaccine (TIV) in 34 aged individuals (>65 yrs) during the 2012/13 vaccination seasons. Nearly all had been vaccinated the previous year although the time interval between the two vaccine doses differed. One subgroup was re-vaccinated in 2012/13 within 6-9 months of their 2011/12 vaccination, the other received the two doses of vaccine in the typical ~12 month interval. Unexpectedly the sub-cohort with early revaccination exhibited significantly increased response rates and antibody titers to TIV compared to their normally re-vaccinated aged counter parts. Microarray analyses of gene expression in whole blood RNA taken at the day of the 2012/13 re-vaccination revealed statistically significant differences in expression of 754 genes between the individuals with early re-vaccination compared to subjects vaccinated in a normal 12 month interval. These observations suggest that TIV has long-lasting effects on the immune system affecting B cell responses as well as the transcriptome of peripheral blood mononuclear cells and this residual effect may augment vaccination response in patients where the effect of the previous vaccination has not yet diminished. PMID- 26637962 TI - Which is more important for reducing the odds of metabolic syndrome in men: Cardiorespiratory or muscular fitness? AB - OBJECTIVE: To examine combined associations of cardiorespiratory fitness (CRF) and muscular fitness (MF) with metabolic syndrome (MetSy) in a sample of young men. METHODS: Participants were 557 men aged 19-47 years. CRF was quantified as peak oxygen uptake measured during an incremental treadmill test by a metabolic cart, while a composite MF score was calculated as the sum of z-scores from a push-ups and sit-ups test. The presence of MetSy was defined according to the updated NCEP-ATP III criteria. RESULTS: We found a graded inverse relationship between CRF and MetSy presence. The most aerobically fit individuals had 90% lower odds of having MetSy compared to their least fit counterparts, independent of MF (odds ratio [OR] = 0.10, 95% CI = 0.04-0.21). Conversely, an increment in MF across the first three quartiles was not associated with lower odds of MetSy; only the most muscularly fit men were 2.5 times less likely to have MetSy (OR = 0.41, 95% CI = 0.21-0.78). Finally, participants with high CRF but low MF exhibited a 50% decrease in odds of having MetSy (OR = 0.49, 95% CI = 0.26-0.91), while no protective effect was found for having high MF but low CRF (OR = 0.95, 95% CI = 0.55-1.62). CONCLUSIONS: CRF exhibited a strong protective effect against having MetSy, while the effect of MF was less pronounced. PMID- 26637963 TI - Physical health promotion in people with schizophrenia: why we should consider the ultra high-risk state. PMID- 26637964 TI - Using synchronous distance education to deliver a weight loss intervention: A randomized trial. AB - OBJECTIVE: To implement a randomized trial to evaluate the effectiveness of a weight loss program delivered using synchronous distance education compared with a wait-list control group with 6-month follow-up. METHODS: Adults with a body mass index (BMI) >=25 were randomized to the intervention (n = 42) or wait-list control group (n = 38). The intervention group participated in a synchronous, online, 15-week weight loss program; weight loss was the primary outcome. Secondary measures included height, BMI, and confidence in ability to be physically active and eat healthy. Assessments occurred at three and four time points in the intervention and control group, respectively. RESULTS: Participants who completed the program lost significantly more weight (1.8 kg) than those in the wait-list control group (0.25 kg) at week 15 [F(1,61) = 6.19, P = 0.02] and had a greater reduction in BMI (0.71 vs. 0.14 kg/m(2) ), [F(1,61) = 7.45, P = 0.01]. There were no significant differences between the intervention and the wait-list control groups for change in confidence in ability to be physically active or eat healthy. Weight loss was maintained at 6 months. CONCLUSIONS: Use of synchronous distance education is a promising approach for weight loss. The results of this study will help to inform future research that employs Web-based interventions. PMID- 26637965 TI - Germ cells influence cord formation and Leydig cell gene expression during mouse testis development. AB - BACKGROUND: It is widely accepted that, during the development of testes in the mammalian embryo, male germ cells are influenced by signals from the surrounding somatic cells, but not vice versa, so that germ cells are dispensable for the formation of testes. RESULTS: We now demonstrate that development of the mouse fetal testis is compromised in the absence of germ cells. Using two- and three dimensional imaging techniques, we reveal that W(e)/W(e) mutant testes devoid of germ cells have misshapen and poorly organized cords. We also found that mutant gonads have fewer Sertoli cells than normal and that the Leydig cells express key markers at higher than normal levels. CONCLUSIONS: These observations point to the existence of germ cell-derived signals that directly or indirectly affect the Sertoli and Leydig cell populations, and provide a new paradigm for the organogenesis of the mammalian testes. PMID- 26637966 TI - Google Glass Glare: disability glare produced by a head-mounted visual display. AB - PURPOSE: Head mounted displays are a type of wearable technology - a market that is projected to expand rapidly over the coming years. Probably the most well known example is the device Google Glass (or 'Glass'). Here we investigate the extent to which the device display can interfere with normal visual function by producing monocular disability glare. METHODS: Contrast sensitivity was measured in two normally sighted participants, 32 and 52 years of age. Data were recorded for the right eye, the left eye and then again in a binocular condition. Measurements were taken both with and without the Glass in place, across a range of stimulus luminance levels using a two-alternative forced-choice methodology. RESULTS: The device produced a significant reduction in contrast sensitivity in the right eye (>0.5 log units). The level of disability glare increased as stimulus luminance was reduced in a manner consistent with intraocular light scatter, resulting in a veiling retinal illuminance. Sensitivity in the left eye was unaffected. A significant reduction in binocular contrast sensitivity occurred at lower luminance levels due to a loss of binocular summation, although binocular sensitivity was not found to fall below the sensitivity of the better monocular level (binocular inhibition). CONCLUSIONS: Head mounted displays such as Google Glass have the potential to cause significant disability glare in the eye exposed to the visual display, particularly under conditions of low luminance. They can also cause a more modest binocular reduction in sensitivity by eliminating the benefits of binocular summation. PMID- 26637967 TI - Alterations of telomere length and DNA methylation in hairdressers: A cross sectional study. AB - Working as hairdressers has been associated with increased risk for cancer, particularly bladder cancer. To evaluate if current hairdressers have elevated risks of adverse health effects, we measured several biomarkers related to cancer related DNA alterations. We enrolled 295 hairdressers and 92 non-hairdressers (all female non-smokers) from Stockholm and southern Sweden. Questionnaire data were collected for each participant, including work tasks for the hairdressers. We measured telomere length in peripheral blood leucocytes using quantitative PCR and DNA methylation status of genes relevant for bladder cancer using methylation sensitive high resolution melting analysis. The hairdressers had shorter telomeres (beta = -0.069, P = 0.019) compared with non-hairdressers. Shorter telomeres were found in hairdressers up to 32 years old performing hair waving more than once per week as compared with hairdressers in the same age group performing hair waving less often (beta = -0.12, P = 0.037). Hair waving was associated with less frequent CDKN2A methylation (odds ratio, OR = 0.19, P = 0.033). Shorter telomeres in hairdressers may indicate a genotoxic effect. Performing hair waving was associated with short telomere length, although the effect was only observed in young hairdressers. No clear patterns were discerned with regard to DNA methylation of bladder cancer-related genes. The observed changes of methylation were not all in the expected direction and warrant further investigation. PMID- 26637968 TI - A single bout of meditation biases cognitive control but not attentional focusing: Evidence from the global-local task. AB - Recent studies show that a single bout of meditation can impact information processing. We were interested to see whether this impact extends to attentional focusing and the top-down control over irrelevant information. Healthy adults underwent brief single bouts of either focused attention meditation (FAM), which is assumed to increase top-down control, or open monitoring meditation (OMM), which is assumed to weaken top-down control, before performing a global-local task. While the size of the global-precedence effect (reflecting attentional focusing) was unaffected by type of meditation, the congruency effect (indicating the failure to suppress task-irrelevant information) was considerably larger after OMM than after FAM. Our findings suggest that engaging in particular kinds of meditation creates particular cognitive-control states that bias the individual processing style toward either goal-persistence or cognitive flexibility. PMID- 26637969 TI - On the alleged memory-undermining effects of daydreaming. AB - In three experiments, we examined the memory-undermining effects of daydreaming for (un)related stimuli. In Experiments 1 and 2, we tested whether daydreaming fosters forgetting of semantically interrelated material and hence, catalyzes false memory production. In Experiment 3, we examined the memory effects of different daydreaming instructions. In Experiment 1, daydreaming did not undermine correct recall of semantically interrelated words, nor did it affect false memories. In Experiment 2, we again failed to find that daydreaming exerted memory-undermining effects a. In Experiment 3, no memory effects were obtained using different daydreaming instructions. Together, our studies fail to show appreciable memory-undermining effects of daydreaming. PMID- 26637970 TI - Mutant p53 in concert with an interleukin-27 receptor alpha deficiency causes spontaneous liver inflammation, fibrosis, and steatosis in mice. AB - The cellular and molecular etiology of unresolved chronic liver inflammation remains obscure. Whereas mutant p53 has gain-of-function properties in tumors, the role of this protein in liver inflammation is unknown. Herein, mutant p53(R172H) is mechanistically linked to spontaneous and sustained liver inflammation and steatosis when combined with the absence of interleukin-27 (IL27) signaling (IL27RA), resembling the phenotype observed in nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) patients. Indeed, these mice develop, with age, hepatocyte necrosis, immune cell infiltration, fibrosis, and micro- and macrosteatosis; however, these phenotypes are absent in mutant p53(R172H) or IL27RA(-/-) mice. Mechanistically, endothelin A receptor (ETAR)-positive macrophages are highly accumulated in the inflamed liver, and chemical inhibition of ETAR signaling reverses the observed phenotype and negatively regulates mutant p53 levels in macrophages. CONCLUSION: The combination of mutant p53 and IL27RA(-/-) causes spontaneous liver inflammation, steatosis, and fibrosis in vivo, whereas either gene alone in vivo has no effects on the liver. PMID- 26637971 TI - Blockade of senescence-associated microRNA-195 in aged skeletal muscle cells facilitates reprogramming to produce induced pluripotent stem cells. AB - The low reprogramming efficiency in cells from elderly patients is a challenge that must be overcome. Recently, it has been reported that senescence-associated microRNA (miR)-195 targets Sirtuin 1 (SIRT1) to advance cellular senescence. Thus, we hypothesized that a blockade of miR-195 expression could improve reprogramming efficiency in old skeletal myoblasts (SkMs). We found that miR-195 expression was significantly higher in old SkMs (24 months) isolated from C57BL/6 mice as compared to young SkMs (2 months, 2.3-fold). Expression of SIRT1 and telomerase reverse transcriptase (TERT) was downregulated in old SkMs, and transduction of old SkMs with lentiviral miR-195 inhibitor significantly restored their expression. Furthermore, quantitative in situ hybridization analysis demonstrated significant telomere elongation in old SkMs transduced with anti-miR 195 (1.7-fold increase). It is important to note that blocking miR-195 expression markedly increased the reprogramming efficiency of old SkMs as compared to scramble (2.2-fold increase). Transduction of anti-miR-195 did not alter karyotype or pluripotency marker expression. Induced pluripotent stem cells (iPSCs) from old SkMs transduced with anti-miR-195 successfully formed embryoid bodies that spontaneously differentiated into three germ layers, indicating that deletion of miR-195 does not affect pluripotency in transformed SkMs. In conclusion, this study provided novel evidence that the blockade of age-induced miR-195 is a promising approach for efficient iPSC generation from aging donor subjects, which has the potential for autologous transplantation of iPSCs in elderly patients. PMID- 26637972 TI - Endogenously elevated n-3 polyunsaturated fatty acids alleviate acute ethanol induced liver steatosis. AB - Effective means for the prevention of alcohol-induced liver disease, a global health problem, have yet to be developed. We evaluated whether the high endogenous levels of omega-3 polyunsaturated acids (n-3 PUFA) in fat-1 transgenic mice could protect them against acute ethanol-induced liver steatosis. We induced alcoholic liver steatosis in 9-week-old male heterozygous fat-1 mice and their wild-type (WT) male littermates through three oral gavages of 60% ethanol at 4.7 g/kg body weight. Hepatic lipid accumulation was significantly increased in both alcohol treatment groups, but by much less in the fat-1 group compared with the WT group. Fat-1 mice exhibited significantly lower levels of total hepatic/plasma TG and plasma alanine aminotransferase activity. Accordingly, hepatic expression of lipogenesis-related genes (e.g., SREBP-1c, FAS, and SCD-1) and plasma levels of inflammatory cytokines (e.g., IL-6, TNF-alpha, and MCP-1) were reduced in the fat-1 mice. Furthermore, decreased hepatic expression of cytochrome P450 2E1 (CYP2E1) and increased hepatic levels of PPAR-alpha and HO-1 were observed in the fat-1 mice, compared to the WT mice. These findings show that elevated tissue n-3 PUFA protect against acute ethanol-induced liver steatosis in fat-1 mice, possibly through the down-regulation of hepatic lipogenesis, inflammatory response, and oxidative stress. PMID- 26637973 TI - Identification of Ourmiavirus 30K movement protein amino acid residues involved in symptomatology, viral movement, subcellular localization and tubule formation. AB - Several plant viruses encode movement proteins (MPs) classified in the 30K superfamily. Despite a great functional diversity, alignment analysis of MP sequences belonging to the 30K superfamily revealed the presence of a central core region, including amino acids potentially critical for MP structure and functionality. We performed alanine-scanning mutagenesis of the Ourmia melon virus (OuMV) MP, and studied the effects of amino acid substitutions on MP properties and virus infection. We identified five OuMV mutants that were impaired in systemic infection in Nicotiana benthamiana and Arabidopsis thaliana, and two mutants showing necrosis and pronounced mosaic symptoms, respectively, in N. benthamiana. Green fluorescent protein fusion constructs (GFP:MP) of movement defective MP alleles failed to localize in distinct foci at the cell wall, whereas a GFP fusion with wild-type MP (GFP:MPwt) mainly co-localized with plasmodesmata and accumulated at the periphery of epidermal cells. The movement defective mutants also failed to produce tubular protrusions in protoplasts isolated from infected leaves, suggesting a link between tubule formation and the ability of OuMV to move. In addition to providing data to support the importance of specific amino acids for OuMV MP functionality, we predict that these conserved residues might be critical for the correct folding and/or function of the MP of other viral species in the 30K superfamily. PMID- 26637974 TI - Responsive materials based on magnetic polyelectrolytes and graphene oxide for water clean-up. AB - HYPOTHESIS: Owing to attractive interactions between negatively charged graphene oxide (GO) and a paramagnetic cationic polyelectrolyte (polyallydimethylammonium chloride with a FeCl4(-) counterion (Fe-polyDADMAC) it should be possible to generate magnetic materials. The benefit of using charge-based adsorption is that the need to form covalently linked magnetic materials is offset, which is expected to significantly reduce the time, energy and cost to make such responsive materials. These systems could have a wide use and application in water treatment. EXPERIMENTS: Non-covalent magnetic materials were formed through the mixing of Fe-pDADMAC and GO. A systematic study was conducted by varying polymer concentration at a fixed GO concentration. UV-Vis was used to confirm and quantify polymer adsorption onto GO sheets. The potential uses of the systems for water purification were demonstrated. FINDINGS: Fe-polyDADMAC adsorbs to the surface of GO and induces flocculation. Low concentrations of the polymer (<9mmol/L) favour flocculation, whereas higher concentrations (>20mmol/L) induce restabilization. Difficult-to-recover gold nanoparticles can be separated from suspensions as well as the pollutant antibiotic tetracycline. Both harmful materials can be magnetically recovered from the dispersions. This system therefore has economical and practical applications in decontamination and water treatment. PMID- 26637975 TI - Mutations in Either TUBB or MAPRE2 Cause Circumferential Skin Creases Kunze Type. AB - Circumferential skin creases Kunze type (CSC-KT) is a specific congenital entity with an unknown genetic cause. The disease phenotype comprises characteristic circumferential skin creases accompanied by intellectual disability, a cleft palate, short stature, and dysmorphic features. Here, we report that mutations in either MAPRE2 or TUBB underlie the genetic origin of this syndrome. MAPRE2 encodes a member of the microtubule end-binding family of proteins that bind to the guanosine triphosphate cap at growing microtubule plus ends, and TUBB encodes a beta-tubulin isotype that is expressed abundantly in the developing brain. Functional analyses of the TUBB mutants show multiple defects in the chaperone dependent tubulin heterodimer folding and assembly pathway that leads to a compromised yield of native heterodimers. The TUBB mutations also have an impact on microtubule dynamics. For MAPRE2, we show that the mutations result in enhanced MAPRE2 binding to microtubules, implying an increased dwell time at microtubule plus ends. Further, in vivo analysis of MAPRE2 mutations in a zebrafish model of craniofacial development shows that the variants most likely perturb the patterning of branchial arches, either through excessive activity (under a recessive paradigm) or through haploinsufficiency (dominant de novo paradigm). Taken together, our data add CSC-KT to the growing list of tubulinopathies and highlight how multiple inheritance paradigms can affect dosage-sensitive biological systems so as to result in the same clinical defect. PMID- 26637976 TI - Multiple Hepatic Regulatory Variants at the GALNT2 GWAS Locus Associated with High-Density Lipoprotein Cholesterol. AB - Genome-wide association studies (GWASs) have identified more than 150 loci associated with blood lipid and cholesterol levels; however, the functional and molecular mechanisms for many associations are unknown. We examined the functional regulatory effects of candidate variants at the GALNT2 locus associated with high-density lipoprotein cholesterol (HDL-C). Fine-mapping and conditional analyses in the METSIM study identified a single locus harboring 25 noncoding variants (r(2) > 0.7 with the lead GWAS variants) strongly associated with total cholesterol in medium-sized HDL (e.g., rs17315646, p = 3.5 * 10(-12)). We used luciferase reporter assays in HepG2 cells to test all 25 variants for allelic differences in regulatory enhancer activity. rs2281721 showed allelic differences in transcriptional activity (75-fold [T] versus 27-fold [C] more than the empty-vector control), as did a separate 780-bp segment containing rs4846913, rs2144300, and rs6143660 (49-fold [AT(-) haplotype] versus 16-fold [CC(+) haplotype] more). Using electrophoretic mobility shift assays, we observed differential CEBPB binding to rs4846913, and we confirmed this binding in a native chromatin context by performing chromatin-immunoprecipitation (ChIP) assays in HepG2 and Huh-7 cell lines of differing genotypes. Additionally, sequence reads in HepG2 DNase-I-hypersensitivity and CEBPB ChIP-seq signals spanning rs4846913 showed significant allelic imbalance. Allelic-expression imbalance assays performed with RNA from primary human hepatocyte samples and expression-quantitative-trait-locus (eQTL) data in human subcutaneous adipose tissue samples confirmed that alleles associated with increased HDL-C are associated with a modest increase in GALNT2 expression. Together, these data suggest that at least rs4846913 and rs2281721 play key roles in influencing GALNT2 expression at this HDL-C locus. PMID- 26637977 TI - Mutations Preventing Regulated Exon Skipping in MET Cause Osteofibrous Dysplasia. AB - The periosteum contributes to bone repair and maintenance of cortical bone mass. In contrast to the understanding of bone development within the epiphyseal growth plate, factors that regulate periosteal osteogenesis have not been studied as intensively. Osteofibrous dysplasia (OFD) is a congenital disorder of osteogenesis and is typically sporadic and characterized by radiolucent lesions affecting the cortical bone immediately under the periosteum of the tibia and fibula. We identified germline mutations in MET, encoding a receptor tyrosine kinase, that segregate with an autosomal-dominant form of OFD in three families and a mutation in a fourth affected subject from a simplex family and with bilateral disease. Mutations identified in all families with dominant inheritance and in the one simplex subject with bilateral disease abolished the splice inclusion of exon 14 in MET transcripts, which resulted in a MET receptor (MET(Delta14)) lacking a cytoplasmic juxtamembrane domain. Splice exclusion of this domain occurs during normal embryonic development, and forced induction of this exon-exclusion event retarded osteoblastic differentiation in vitro and inhibited bone-matrix mineralization. In an additional subject with unilateral OFD, we identified a somatic MET mutation, also affecting exon 14, that substituted a tyrosine residue critical for MET receptor turnover and, as in the case of the MET(Delta14) mutations, had a stabilizing effect on the mature protein. Taken together, these data show that aberrant MET regulation via the juxtamembrane domain subverts core MET receptor functions that regulate osteogenesis within cortical diaphyseal bone. PMID- 26637978 TI - Autosomal-Recessive Intellectual Disability with Cerebellar Atrophy Syndrome Caused by Mutation of the Manganese and Zinc Transporter Gene SLC39A8. AB - Manganese (Mn) and zinc (Zn) are essential divalent cations used by cells as protein cofactors; various human studies and animal models have demonstrated the importance of Mn and Zn for development. Here we describe an autosomal-recessive disorder in six individuals from the Hutterite community and in an unrelated Egyptian sibpair; the disorder is characterized by intellectual disability, developmental delay, hypotonia, strabismus, cerebellar atrophy, and variable short stature. Exome sequencing in one affected Hutterite individual and the Egyptian family identified the same homozygous variant, c.112G>C (p.Gly38Arg), affecting a conserved residue of SLC39A8. The affected Hutterite and Egyptian individuals did not share an extended common haplotype, suggesting that the mutation arose independently. SLC39A8 is a member of the solute carrier gene family known to import Mn, Zn, and other divalent cations across the plasma membrane. Evaluation of these two metal ions in the affected individuals revealed variably low levels of Mn and Zn in blood and elevated levels in urine, indicating renal wasting. Our findings identify a human Mn and Zn transporter deficiency syndrome linked to SLC39A8, providing insight into the roles of Mn and Zn homeostasis in human health and development. PMID- 26637979 TI - SLC39A8 Deficiency: A Disorder of Manganese Transport and Glycosylation. AB - SLC39A8 is a membrane transporter responsible for manganese uptake into the cell. Via whole-exome sequencing, we studied a child that presented with cranial asymmetry, severe infantile spasms with hypsarrhythmia, and dysproportionate dwarfism. Analysis of transferrin glycosylation revealed severe dysglycosylation corresponding to a type II congenital disorder of glycosylation (CDG) and the blood manganese levels were below the detection limit. The variants c.112G>C (p.Gly38Arg) and c.1019T>A (p.Ile340Asn) were identified in SLC39A8. A second individual with the variants c.97G>A (p.Val33Met) and c.1004G>C (p.Ser335Thr) on the paternal allele and c.610G>T (p.Gly204Cys) on the maternal allele was identified among a group of unresolved case subjects with CDG. These data demonstrate that variants in SLC39A8 impair the function of manganese-dependent enzymes, most notably beta-1,4-galactosyltransferase, a Golgi enzyme essential for biosynthesis of the carbohydrate part of glycoproteins. Impaired galactosylation leads to a severe disorder with deformed skull, severe seizures, short limbs, profound psychomotor retardation, and hearing loss. Oral galactose supplementation is a treatment option and results in complete normalization of glycosylation. SLC39A8 deficiency links a trace element deficiency with inherited glycosylation disorders. PMID- 26637981 TI - Somatic Activating PIK3CA Mutations Cause Venous Malformation. AB - Somatic mutations in TEK, the gene encoding endothelial cell tyrosine kinase receptor TIE2, cause more than half of sporadically occurring unifocal venous malformations (VMs). Here, we report that somatic mutations in PIK3CA, the gene encoding the catalytic p110alpha subunit of PI3K, cause 54% (27 out of 50) of VMs with no detected TEK mutation. The hotspot mutations c.1624G>A, c.1633G>A, and c.3140A>G (p.Glu542Lys, p.Glu545Lys, and p.His1047Arg), frequent in PIK3CA associated cancers, overgrowth syndromes, and lymphatic malformation (LM), account for >92% of individuals who carry mutations. Like VM-causative mutations in TEK, the PIK3CA mutations cause chronic activation of AKT, dysregulation of certain important angiogenic factors, and abnormal endothelial cell morphology when expressed in human umbilical vein endothelial cells (HUVECs). The p110alpha specific inhibitor BYL719 restores all abnormal phenotypes tested, in PIK3CA- as well as TEK-mutant HUVECs, demonstrating that they operate via the same pathogenic pathways. Nevertheless, significant genotype-phenotype correlations in lesion localization and histology are observed between individuals with mutations in PIK3CA versus TEK, pointing to gene-specific effects. PMID- 26637980 TI - De Novo GMNN Mutations Cause Autosomal-Dominant Primordial Dwarfism Associated with Meier-Gorlin Syndrome. AB - Meier-Gorlin syndrome (MGS) is a genetically heterogeneous primordial dwarfism syndrome known to be caused by biallelic loss-of-function mutations in one of five genes encoding pre-replication complex proteins: ORC1, ORC4, ORC6, CDT1, and CDC6. Mutations in these genes cause disruption of the origin of DNA replication initiation. To date, only an autosomal-recessive inheritance pattern has been described in individuals with this disorder, with a molecular etiology established in about three-fourths of cases. Here, we report three subjects with MGS and de novo heterozygous mutations in the 5' end of GMNN, encoding the DNA replication inhibitor geminin. We identified two truncating mutations in exon 2 (the 1(st) coding exon), c.16A>T (p.Lys6(*)) and c.35_38delTCAA (p.Ile12Lysfs(*)4), and one missense mutation, c.50A>G (p.Lys17Arg), affecting the second-to-last nucleotide of exon 2 and possibly RNA splicing. Geminin is present during the S, G2, and M phases of the cell cycle and is degraded during the metaphase-anaphase transition by the anaphase-promoting complex (APC), which recognizes the destruction box sequence near the 5' end of the geminin protein. All three GMNN mutations identified alter sites 5' to residue Met28 of the protein, which is located within the destruction box. We present data supporting a gain-of-function mechanism, in which the GMNN mutations result in proteins lacking the destruction box and hence increased protein stability and prolonged inhibition of replication leading to autosomal-dominant MGS. PMID- 26637983 TI - One-year outcomes of an intense workplace cardio-metabolic risk reduction program among high-risk employees: The My Unlimited Potential. AB - OBJECTIVE: This study details 6- and 12-month cardio-metabolic outcomes of an intense 12-week workplace lifestyle intervention program, the My Unlimited Potential (MyUP), conducted in a large healthcare organization. METHODS: This study was conducted among 230 employees of Baptist Health South Florida with high cardiovascular disease (CVD) risk. Employees were considered at high risk and eligible for the study if they had two or more of the following cardio-metabolic risk factors: total cholesterol >= 200 mg/dl, systolic blood pressure (SBP) >= 140 mmHg or diastolic blood pressure (DBP) >= 90 mmHg, hemoglobin A1C (HbA1c) >= 6.5%, body mass index (BMI) >= 30 kg/m(2) . RESULTS: At the end of 12 weeks, there was significant reduction in the mean BMI, SBP and DBP, serum lipids, and HbA1c among persons with diabetes. At 1 year, there was significant decline in the mean BMI, SBP and DBP, HbA1c, and high-sensitivity C-reactive protein, and in the prevalence of poor BP control, BMI >= 35 kg/m(2) , and abnormal HbA1c among all persons and those with diabetes. CONCLUSIONS: This intensive 12-week lifestyle change program was successful at improving cardio-metabolic risk factors at 1 year. This study provides a template for other workplace programs aimed at improving CVD risk in high-risk employees. PMID- 26637984 TI - Accurate potential energy functions, non-adiabatic and spin-orbit couplings in the ZnH(+) system. AB - A high-level ab initio calculation on the ZnH(+) cation has been carried out with the multi-reference configuration interaction method plus Davison correction (MRCI+Q). The scalar relativistic effect is included by using the Douglas-Kroll Hess (DKH) method. The calculated potential energy curves (PECs) of the 7 Lambda S states are associated with the dissociation limits of Zn(+)((2)Sg)+H((2)Sg), Zn((1)Sg)+H(+)((1)Sg), and Zn(+)((2)Pu)+H((2)Sg), respectively (The Lambda-S state is labeled as (2S+1)Lambda, in which Lambda is the quantum number for the projection along the internuclear axis of the total electronic orbital angular momentum and S is the total electron spin). The spectroscopic constants of the bound states are determined and in good agreement with the available theoretical and experimental results. The permanent dipole moments (PDMs) of Lambda-S states and the spin-orbit (SO) matrix elements between Lambda-S states are also computed. The results show that the abrupt changes of the PDMs and SO matrix elements come into being for the reason of the avoided crossing between the states with the same symmetry. In addition, the non-adiabatic couplings matrix elements between Lambda-S states are also evaluated. Finally, the spin-orbit couplings (SOCs) for the low-lying states are considered with Breit-Pauli operator. The SOC effect makes the 7 Lambda-S states of the ZnH(+) cation split into 12 Omega states (Omega=Lambda+Sz, in which Sz is projection of the total electron spin S along the internuclear Z-axis). For the (3)0(+) state, the two energy minima exhibit in the potential, which could be attributed to the formation of the new avoided crossing point. The transition dipole moments (TDMs), Franck-Condon factors, and the radiative lifetimes of the selected transitions (2)0(+)-X0(+), (3)0(+)-X0(+), (2)1-X0(+) and (3)1-X0(+) have been reported. PMID- 26637982 TI - TAF1 Variants Are Associated with Dysmorphic Features, Intellectual Disability, and Neurological Manifestations. AB - We describe an X-linked genetic syndrome associated with mutations in TAF1 and manifesting with global developmental delay, intellectual disability (ID), characteristic facial dysmorphology, generalized hypotonia, and variable neurologic features, all in male individuals. Simultaneous studies using diverse strategies led to the identification of nine families with overlapping clinical presentations and affected by de novo or maternally inherited single-nucleotide changes. Two additional families harboring large duplications involving TAF1 were also found to share phenotypic overlap with the probands harboring single nucleotide changes, but they also demonstrated a severe neurodegeneration phenotype. Functional analysis with RNA-seq for one of the families suggested that the phenotype is associated with downregulation of a set of genes notably enriched with genes regulated by E-box proteins. In addition, knockdown and mutant studies of this gene in zebrafish have shown a quantifiable, albeit small, effect on a neuronal phenotype. Our results suggest that mutations in TAF1 play a critical role in the development of this X-linked ID syndrome. PMID- 26637986 TI - Weaving together peer assessment, audios and medical vignettes in teaching medical terms. AB - OBJECTIVE: The current study aims at exploring the possibility of aligning peer assessment, audiovisuals, and medical case-report extracts (vignettes) in medical terminology teaching. In addition, the study wishes to highlight the effectiveness of audio materials and medical history vignettes in preventing medical students' comprehension, listening, writing, and pronunciation errors. The study also aims at reflecting the medical students' attitudes towards the teaching and learning process. METHODS: The study involved 161 medical students who received an intensive medical terminology course through audio and medical history extracts. Peer assessment and formative assessment platforms were applied through fake quizzes in a pre- and post-test manner. An 18-item survey was distributed amongst students to investigate their attitudes and feedback towards the teaching and learning process. Quantitative and qualitative data were analysed using the SPSS software. RESULTS: The students did better in the posttests than on the pretests for both the quizzes of audios and medical vignettes showing a t-test of -12.09 and -13.60 respectively. Moreover, out of the 133 students, 120 students (90.22%) responded to the survey questions. The students gave positive attitudes towards the application of audios and vignettes in the teaching and learning of medical terminology and towards the learning process. CONCLUSIONS: The current study revealed that the teaching and learning of medical terminology have more room for the application of advanced technologies, effective assessment platforms, and active learning strategies in higher education. It also highlights that students are capable of carrying more responsibilities of assessment, feedback, and e-learning. PMID- 26637985 TI - Effects of maternal lifestyle intervention during pregnancy on untreated partner weight: Results from fit for delivery study. AB - OBJECTIVE: To test the hypothesis that untreated partners of pregnant women receiving a prenatal lifestyle intervention (vs. standard care) would lose more weight during pregnancy and postpartum. METHODS: Fit for Delivery was a study of 401 pregnant women with overweight/obesity (OW/OB) and normal weight (NW) randomized to prenatal lifestyle intervention or standard care. Mother's self report of partners' weight was obtained at study entry (<16 weeks gestation), 30 weeks gestation, and 6 and 12 months postpartum. RESULTS: At study entry, 157 of 200 (78%) of intervention mothers and 144 of 201 (72%) of standard care mothers reported having a partner. In intent-to-treat analyses, there was no significant treatment * time effects on partner weight (P = 0.67). In secondary analyses, partners of OW/OB intervention women lost weight from study entry to 6 and 12 months postpartum (-0.5 +/- 9.5 kg, -1.0 +/- 9.3 kg; P < 0.05), while partners of standard care women gained weight during the same time frame (+2.5 +/- 6.7 kg, +2.9 +/- 7.4 kg; P < 0.05); adjusting for partner study entry BMI removed these effects. CONCLUSIONS: Lifestyle intervention delivered to pregnant women did not significantly reduce weight of untreated partners. Future research is needed to test prenatal interventions that engage partners and use objective measures of weight. PMID- 26637987 TI - Persistence of seropositivity among persons vaccinated for hepatitis A during infancy by maternal antibody status: 15-year follow-up. AB - The effect of passively transferred maternal antibody to hepatitis A virus (anti HAV) on the duration of seropositivity after hepatitis A vaccination during infancy and early childhood is unclear. We obtained levels of anti-HAV at intervals through age 15-16 years among three groups of Alaskan Native children who initiated a two-dose inactivated hepatitis A vaccination series at ages 6 months (group 1), 12 months (group 2), and 15 months (group 3), each group randomized according to maternal anti-HAV status. Seropositivity (anti-HAV >=20 mIU/mL) 30 years after the second vaccine dose among the three groups was predicted using a random effects model. One hundred eighty-three children participated in the study; follow-up did not differ significantly by vaccine group or maternal anti-HAV status. Although the frequency of seropositivity among all participants through age 10 years was high (100% among groups 2 and 3 and >90% among group 1), there was a decrease thereafter through age 15-16 years among group 1 children, who initiated vaccination at age 6 months (50%-75%), and among maternal anti-HAV-positive children in groups 2 and 3 (67%-87%), who initiated vaccination at ages 12 months and 15 months, respectively. Nonetheless, the model indicated that anti-HAV seropositivity should persist for >=30 years after vaccination in 64% of all participants; among those seropositive at age 15 16 years, 84% were predicted to remain so for >=30 years. CONCLUSION: Most children vaccinated during early childhood available for sampling maintained seropositivity through age 15-16 years; however, seropositivity was less frequent among those starting vaccination at age 6 months and among maternal antibody positive participants who started vaccination at age 12 months or 15 months; overall, our findings support current vaccine recommendations and continued follow-up of this cohort. PMID- 26637988 TI - NI ESPPERE: A Novel Mnemonics in Spanish for Secondary Headaches. PMID- 26637989 TI - Loss of Residual Renal Function is Associated With Vascular Calcification in Hemodialysis Patients. AB - Vascular calcification is common in chronic hemodialysis (HD) patients and can be measured using abdominal aortic calcification (AAC). Loss of residual renal function (RRF) is associated with increased mortality in HD patients. However, the association between loss of RRF and vascular calcification is unknown. The aim of the study was to analyze the association between loss of RRF and VC in HD patients. All chronic HD (HD for more than 3 months) patients of China Medical University Hospital in 2014 were included. AAC scores were measured semi quantitatively based on later lumbar radiographs. Loss of RRF was defined as urine output less than 200 mL per day. The association between loss of RRF and AAC was analyzed using logistic regression. Four hundred and thirty-eight chronic HD patients with a mean age of 63 +/- 12 years were analyzed. The median (interquartile range) AAC score of all patients was 7 (2-13). The AAC score of patients with loss of RRF was 9 (3-22), significantly higher than that of patients with RRF 5 (0-17) (P = 0.004). Loss of RRF, independent of patients' age, diabetes, C-reactive protein, calcium-phosphorus product and vintage of dialysis was associated with higher AAC scores. Loss of RRF was associated with vascular calcification in HD patients. PMID- 26637990 TI - Meta-analysis on the effectiveness of alcohol screening with brief interventions for patients in emergency care settings. AB - BACKGROUND AND AIMS: Despite ambiguous evidence for the effectiveness of alcohol screening with brief interventions (BI) in emergency departments (ED), ambition for their widespread implementation continues to grow. To clarify whether such an application of BI is justifiable, we conducted a systematic review and meta analysis on studies testing the impact of BI on alcohol consumption. METHODS: We included peer-reviewed, randomized controlled studies investigating the effects of BI on alcohol consumption in injured and/or intoxicated patients, published January 2002-September 2015. Changes from baseline in consumption quantity, intensity and number of heavy drinking episodes were assessed at 3-, 6- and 12 month follow-up, resulting in nine separate random-effects meta-analyses of standardized mean differences (SMD). Moderation effects of intervention mode, length, type of interventionist, intensity of control intervention and study quality were assessed using subgroup comparisons and meta-regression. RESULTS: We considered 33 publications (28 separate studies) including 14 456 patients. Six of nine comparisons revealed small significant effects in favour of BI, with the highest SMD at 0.19 [95% confidence interval (CI) = 0.08-0.31]. No significant moderators could be identified, and statistical heterogeneity (I(2) ) was below 40%. CONCLUSIONS: In a large meta-analysis of randomized controlled trials in emergency care settings, there was evidence for very small effects of brief interventions on alcohol consumption reductions. More intensive interventions showed no benefit over shorter approaches. Non-face-to-face interventions appear to be comparably effective, but this finding remains tentative due to the low number of non-face-to-face studies. PMID- 26637991 TI - Differential methylation in inflammation and type 2 diabetes genes in siblings born before and after maternal bariatric surgery. AB - OBJECTIVE: Siblings born before (BMS) and after (AMS) maternal biliopancreatic diversion (BPD) show differences in the methylome. The objective was to use a sibling-pair design to examine the effects from interpregnancy weight loss as a consequence of maternal bariatric surgery, other than BPD, on the methylome comparing BMS and AMS. METHODS: Women with at least one child born before and one after bariatric surgery were identified in Swedish national registers. Whole blood samples from BMS (N = 31) and AMS (N = 31) siblings were collected for epigenetic methylation analysis while maternal information was collected from antenatal medical records. RESULTS: In total 3,074 genes, with corresponding 23,449 CpG methylation sites, were differently methylated and associated with an overrepresentation of differently methylated CpG sites in genes involved with insulin receptor signaling, type 2 diabetes signaling, and leptin signaling in obesity, while the most significant differently methylated genes were HLA-DQA1, HLA-DQB1, and TSPAN18, when comparing BMS and AMS siblings. CONCLUSIONS: These results suggest that maternal bariatric surgery, with subsequent weight loss between pregnancies, is associated with alterations in the methylome of genes involved in insulin receptor signaling, type 2 diabetes signaling, and leptin signaling in obesity in a comparison of BMS and AMS siblings. PMID- 26637992 TI - Extracorporeal shock wave therapy in the treatment of primary bone marrow edema syndrome of the knee: a prospective randomised controlled study. AB - BACKGROUND: The aim of this prospective study was to evaluate the effectiveness of extracorporeal shock wave therapy (ESWT) in normalizing the symptoms and imaging features of primary bone marrow edema syndrome (BMES) of the knee. METHODS: This study compared the outcomes of ESWT (Group A) (n = 20) and intravenously applied prostacyclin and bisphosphonate (Group B) (n = 20) in the treatment of BMES of the knee in our department between 2011 and 2013. The Visual Analog Scale for pain (VAS, 100 mm), the Western Ontario and McMaster University Osteoarthritis Index (WOMAC), the SF-36 scores and MRI scans as well as plain radiographs were obtained before and after therapy between two groups. RESULTS: Compared with Group B, we found greater improvement in VAS, the WOMAC Osteoarthritis Index and SF-36 score at 1, 3 and 6 months post-treatment in Group A (P < 0.05). Furthermore, MRI scans showed a higher incidence of distinct reduction and complete regression of bone marrow edema at 6 months in Group A (95 vs. 65 %; P = 0.018). The MRI at 1 year follow-up showed complete regression in all patients in Group A. However, two cases in Group B continued to normalize over the subsequent follow-up period. CONCLUSIONS: ESWT can produce rapid pain relief and functional improvement. It may be an effective, reliable, and non invasive technique for rapid treatment of BMES of the knee. TRIAL REGISTRATION: Research Registry UIN 528, September 03, 2015. PMID- 26637994 TI - Potential of Alginate Encapsulated Ferric Saccharate Microemulsions to Ameliorate Iron Deficiency in Mice. AB - Iron deficiency is one of the most prominent mineral deficiencies around the world, which especially affects large population of women and children. Development of new technologies to combat iron deficiency is on high demand. Therefore, we developed alginate microcapsule with encapsulated iron that had better oral iron bioavailability. Microcapsules containing iron with varying ratios of sodium alginate ferric(III)-saccharide were prepared using emulsification method. In vitro studies with Caco-2 cells suggested that newly synthesized microemulsions had better iron bioavailability as compared to commercially available iron dextran formulations. Ferrozine in vitro assay showed that alginate-encapsulated ferric galactose microemulsion (AFGM) had highest iron bioavailability in comparison to other four ferric saccharate microemulsions, namely AFGlM, AFMM, AFSM, and AFFM synthesized in our laboratory. Mice studies also suggested that AFGM showed higher iron absorption as indicated by increased serum iron, hemoglobin, and other hematopoietic measures with almost no toxicity at tested doses. Development of iron-loaded microemulsions leads to higher bioavailability of iron and can provide alternative strategies to treat iron deficiency. PMID- 26637993 TI - The Danish Cardiovascular Screening Trial (DANCAVAS): study protocol for a randomized controlled trial. AB - BACKGROUND: The significant increase in the average life expectancy has increased the societal challenge of managing serious age-related diseases, especially cancer and cardiovascular diseases. A routine check by a general practitioner is not sufficient to detect incipient cardiovascular disease. DESIGN: Population based randomized clinically controlled screening trial. METHODS: PARTICIPANTS: 45,000 Danish men aged 65-74 years living on the Island of Funen, or in the surrounding communities of Vejle and Silkeborg. No exclusion criteria are used. INTERVENTIONS: One-third will be invited to cardiovascular seven-faceted screening examinations at one of four locations. The screening will include: (1) low-dose non-contrast CT scan to detect coronary artery calcification and aortic/iliac aneurysms, (2) brachial and ankle blood pressure index to detect peripheral arterial disease and hypertension, (3) a telemetric assessment of the heart rhythm, and (4) a measurement of the cholesterol and plasma glucose levels. Up-to-date cardiovascular preventive treatment is recommended in case of positive findings. OBJECTIVE: To investigate whether advanced cardiovascular screening will prevent death and cardiovascular events, and whether the possible health benefits are cost effective. OUTCOME: Registry-based follow-up on all cause death (primary outcome), and costs after 3, 5 and 10 years (secondary outcome). RANDOMIZATION: Each of the 45,000 individuals is, by EPIDATA, given a random number from 1-100. Those numbered 67+ will be offered screening; the others will act as a control group. BLINDING: Only those randomized to the screening will be invited to the examination;the remaining participants will not. Numbers randomized: A total of 45,000 men will be randomized 1:2. Recruitment: Enrollment started October 2014. OUTCOME: A 5% reduction in overall mortality (HR=0.95), with the risk for a type 1 error=5% and the risk for a type II error=80%, is expected. We expect a 2-year enrollment, a 10-year follow-up, and a median survival of 15 years among the controls. The attendance to screening is assumed to be 70%. DISCUSSION: The primary aim of this so far stand-alone population based, randomized trial will be to evaluate the health benefits and costeffectiveness of using non-contrast full truncus computer tomography (CT) scans (to measure coronary artery calcification (CAC) and identify aortic/iliac aneurysms) and measurements of the ankle brachial blood pressure index (ABI) as part of a multifocal screening and intervention program for CVD in men aged 65 74. Attendance rate and compliance to initiated preventive actions must be expected to become of major importance. TRIAL REGISTRATION: Current Controlled Trials: ISRCTN12157806 (21 March 2015). PMID- 26637995 TI - Chemical and mineralogical changes of waste and tailings from the Murgul Cu deposit (Artvin, NE Turkey): implications for occurrence of acid mine drainage. AB - Being one of the largest copper-producing resources in Turkey, the Murgul deposit has been a source of environmental pollution for very long time. Operated through four open pits with an annual production of about 3 million tons of ore at an average grade of about 0.5% Cu, the deposit to date has produced an enormous pile of waste (exceeding 100 million tons) with tailings composed of 36 % SiO2, 39% Fe2O3 and 32% S, mainly in the form of pyrite and quartz. Waters in the vicinity of the deposit vary from high acid-acid (2.71-3.85) and high-extremely metal rich (34.48-348.12 mg/l in total) in the open pits to near neutral (6.51-7.83) and low metal (14.39-973.52 MUg/l in total) in downstream environments. Despite low metal contents and near neutral pH levels of the latter, their suspended particle loads are extremely high and composed mainly of quartz and clay minerals with highly elevated levels of Fe (3.5 to 24.5% Fe2O3; 11% on average) and S (0.5 to 20.6% S; 7% on average), showing that Fe is mainly in the form of pyrite and lesser hematite. They also contain high concentrations of As, Au, Ba, Cu, Pb, and Zn. Waters collected along the course of polluted drainages are supersaturated with respect to Fe phases such as goethite, hematite, maghemite, magnetite, schwertmannite and ferrihydrite. Secondary phases such as Fe-sulphates are only found near the pits, but not along the streams due to neutral pH conditions, where pebbles are covered and cemented by Fe-oxides and hydroxides indicating that oxidation of pyrite has taken place especially at times of low water load. It follows, then, that the pyrite-rich sediment load of streams fed by the waste of the Murgul deposit is currently a big threat to the aquatic life and environment and will continue to be so even after the closure of the deposit. In fact, the oxidation will be enhanced and acidity increased due to natural conditions, which necessitates strong remedial actions to be taken. PMID- 26637996 TI - Astonishing 35S rDNA diversity in the gymnosperm species Cycas revoluta Thunb. AB - In all eukaryotes, the highly repeated 35S ribosomal DNA (rDNA) sequences encoding 18S-5.8S-26S ribosomal RNA (rRNA) typically show high levels of intragenomic uniformity due to homogenisation processes, leading to concerted evolution of 35S rDNA repeats. Here, we compared 35S rDNA divergence in several seed plants using next generation sequencing and a range of molecular and cytogenetic approaches. Most species showed similar 35S rDNA homogeneity indicating concerted evolution. However, Cycas revoluta exhibits an extraordinary diversity of rDNA repeats (nucleotide sequence divergence of different copies averaging 12 %), influencing both the coding and non-coding rDNA regions nearly equally. In contrast, its rRNA transcriptome was highly homogeneous suggesting that only a minority of genes (<20 %) encode functional rRNA. The most common SNPs were C > T substitutions located in symmetrical CG and CHG contexts which were also highly methylated. Both functional genes and pseudogenes appear to cluster on chromosomes. The extraordinary high levels of 35S rDNA diversity in C. revoluta, and probably other species of cycads, indicate that the frequency of repeat homogenisation has been much lower in this lineage, compared with all other land plant lineages studied. This has led to the accumulation of methylation-driven mutations and pseudogenisation. Potentially, the reduced homology between paralogs prevented their elimination by homologous recombination, resulting in long-term retention of rDNA pseudogenes in the genome. PMID- 26637997 TI - Evaluation of microleakage in class V composite restorations using dye penetration and micro-CT. AB - OBJECTIVES: The aim of this study was the evaluation of microleakage in class V cavities using micro-CT imaging and dye penetration. MATERIALS AND METHODS: Sixty class V cavities were prepared, randomly divided into five groups (Adper Single Bond Plus (ASB), ExciTE (EX), iBond TE (ITE), Optibond Solo Plus (OSP), Prime & Bond NT (PB)) and restored with Venus Diamond. After thermocycling and dye penetration test with 50 wt% ammoniacal silver nitrate, eight samples per group were sectioned longitudinally and evaluated under a coaxial incident light microscope (enamel (E) and dentin (D) measurement in mm). The remaining samples were analyzed by counting voids in the coronal and cervical adhesive areas by means of micro-CT. RESULTS: In dentin, no statistically significant difference in dye penetration was found. In enamel, OSP showed significant higher microleakage than all other adhesives (p < 0.001). Groups ITE, ASB, PB, and EX showed a significantly lower penetration depth in E than in D (p < 0.001). The results of the micro-CT examination in dentin are contrary to the findings of the microleakage evaluation. Regarding enamel, only group PB showed significant more voids than EX in enamel (p < 0.02). Within the adhesive groups, PB showed significantly more voids in E than in D (p < 0.04). CONCLUSIONS: This test method must be optimized by developing a new leakage tracer for a better differentiation between hard tissues and dental materials. CLINICAL RELEVANCE: The micro-CT is not yet a vulnerable tool to evaluate the marginal integrity of resin composites. PMID- 26637998 TI - Disk abnormality coexists with any degree of synovial and osseous abnormality in the temporomandibular joints of children with juvenile idiopathic arthritis. AB - BACKGROUND: MRI manifestation of temporomandibular joint arthritis is frequently reported in children with juvenile idiopathic arthritis. However, little attention has been paid to temporomandibular joint disk abnormalities. OBJECTIVE: To assess combinations of MRI findings in the symptomatic temporomandibular joint in children with juvenile idiopathic arthritis with focus on disk abnormalities. MATERIALS AND METHODS: This was a retrospective study of 46 patients with juvenile idiopathic arthritis, mean age 12 years (range: 5-17 years). Mean disease duration was 70 months (standard deviation: 61 months). MR images of 92 temporomandibular joints were scored for thickness of abnormally enhancing synovium (synovitis), joint effusion, bone marrow oedema, abnormal bone shape, bone erosion and disk abnormalities. RESULTS: The 92 temporomandibular joints were categorized as A: No synovitis and normal bone shape (30/92; 33%), B: Synovitis and normal bone shape (14/92: 15%), C: Synovitis and abnormal bone shape (38/92; 41%) and D: No synovitis but abnormal bone shape (10/92; 11%). Thirty-six of the 46 patients (78%) had synovitis and 33/46 (72%) had abnormal bone shape, most frequently in combination (30/46; 65%). Disk abnormalities (flat disk, fragmented disk, adherent disk and displaced disk) were found in 29/46 patients (63%). Disk abnormalities were found in all categories of juvenile idiopathic arthritis involved temporomandibular joints (B: 8/14 [57%]; C: 25/38 [66%] and D: 7/10 [70%]). Disk displacement was found in half of the joints (7/14) in category B. Synovitis was most pronounced in this category. CONCLUSION: Disk abnormalities were frequent. Disk displacement also occurred in joints with early temporomandibular joint arthritis, i.e., with normal bone shape. Other disk abnormalities were found in joints with bone abnormalities. Attention should be paid to disk abnormalities both in early and long-standing temporomandibular joint arthritis in children with juvenile idiopathic arthritis. PMID- 26637999 TI - Tonsil ultrasound: technical approach and spectrum of pediatric peritonsillar infections. AB - Peritonsillar infections are one of the most common deep neck space infections, particularly in adolescents. Inaccurate diagnosis can lead to delay in management and potentially life-threatening complications. Contrast-enhanced computed tomography (CT) scan of the neck traditionally has been used to diagnose suspected peritonsillar abscess. With growing concern over radiation exposure, there has been increasing utilization of ultrasound (US) using intraoral and transcutaneous approaches. We chose the transcutaneous US technique due to its ease of performance in children. The purpose of this article is twofold: a) to describe our technique of performing transcutaneous US of the tonsil showing sonographic appearance of normal tonsil, highlighting pertinent anatomy and unique considerations for this modality in children, and b) to illustrate the sonographic findings in the spectrum of pediatric peritonsillar infections, which includes uncomplicated tonsillitis, peritonsillar cellulitis, small intratonsillar abscess and frank peritonsillar abscess. Parapharyngeal abscess can sometimes be detected. PMID- 26638000 TI - MR enterography-histology comparison in resected pediatric small bowel Crohn disease strictures: can imaging predict fibrosis? AB - BACKGROUND: Crohn disease is a chronic inflammatory condition that can lead to intestinal strictures. The presence of fibrosis within strictures alters optimal management but is not reliably detected by current imaging methods. OBJECTIVE: To correlate the MRI features of surgically resected small-bowel strictures in pediatric Crohn disease with histological inflammation and fibrosis scoring. MATERIALS AND METHODS: We included children with Crohn disease who had symptomatic small-bowel strictures requiring surgical resection and had preoperative MR enterography (MRE) within 3 months of surgery (n = 20). Two blinded radiologists reviewed MRE examinations to document stricture-related findings. A pediatric pathologist scored stricture histological specimens for fibrosis (0-4) and inflammation (0-4). MRE findings were correlated with histological data using Spearman correlation (rho) and exact logistic regression analysis. RESULTS: There was significant positive correlation between histological bowel wall fibrosis and inflammation in resected strictures (rho = 0.55; P = 0.01). Confluent transmural histological fibrosis was associated with pre-stricture upstream small-bowel dilatation >3 cm at univariate (odds ratio [OR] = 51.7; 95% confidence interval [CI]: 7.6- > 999.9; P = 0.0002) and multivariate (OR = 43.4; 95% CI: 6.1- > 999.9; P = 0.0006, adjusted for age) analysis. The degree of bowel wall T2-weighted signal intensity failed to correlate with histological bowel wall fibrosis or inflammation (P-values >0.05). There were significant negative correlations between histological fibrosis score and patient age at resection (rho = -0.48, P = 0.03), and time from diagnosis to surgery (rho = -0.73, P = 0.0002). CONCLUSION: Histological fibrosis and inflammation co-exist in symptomatic pediatric Crohn disease small-bowel strictures and are positively correlated. Pre-stenotic upstream small-bowel dilatation greater than 3 cm is significantly associated with confluent transmural fibrosis. PMID- 26638001 TI - Gastrointestinal autonomic neuropathy in diabetes: the unattended borderline between diabetology and gastroenterology. PMID- 26638002 TI - Activity of Phosphate-Dependent Glutaminase in the Brain of Rats Exposed to Prenatal Hypoxia during Organogenesis. AB - We studied the effect of hypoxia (days 9-15 of pregnancy) on phosphate-dependent glutaminase activity in the brain of rat offspring aging 18 days and 1, 3, and 6 months. Activity of glutaminase significantly increased in mitochondria from the orbital, visual, and limbic cortex, hypothalamus, and midbrain of 17-day-old offspring. Activity of this enzyme in all brain regions increased at the age of 1 month, but significantly decreased in animals aging 3 and 6 months and prenatally exposed to hypoxia (during organogenesis). Changes in glutaminase activity in various structures of the brain are probably associated with activation of the glutamatergic and GABAergic systems and serve as an adaptive and compensatory reaction of the brain. PMID- 26638003 TI - Influence of cancer treatment on the Candida albicans isolated from the oral cavities of cancer patients. AB - PURPOSE: Cancer treatment causes mucositis and the manifestation of oral candidiasis. This study investigated the virulence properties and antifungal susceptibilities of Candida albicans isolated from cancer patients undergoing therapy. METHODS: C. albicans were isolated from 49 patients on cancer treatment and 21 healthy individuals and their virulence attributes measured. A correlation was determined between the length of treatment and the fungal counts and their virulence factors. RESULTS: Although Candida carriage was similar in all the study groups, high quantities of C. albicans and variety of Candida were found in cancer patients. Germ tubes were produced by all the strains. Significantly high number of yeast isolated from radiotherapy and chemotherapy produced large quantities of phospholipase compared to healthy individuals (p < 0.01). The length of chemotherapy was associated with an increase in the phospholipase production (p = 0.03) by the C. albicans. Proteinase production was seen in a significant number of isolates from the radiotherapy group (p < 0.01). Type of cancer treatment had no effect. Resistance to antifungal agents was low. CONCLUSIONS: High quantities of phospholipase were produced by C. albicans in cancer patients on therapy which also increased with the length of chemotherapy suggesting enhanced risk of oral and systemic infection. Therefore, during treatment, prophylactic topical antifungal therapy may be considered. PMID- 26638004 TI - Satisfaction with cancer care among American Indian and Alaska Natives in Oregon and Washington State: a qualitative study of survivor and caregiver perspectives. AB - PURPOSE: To better understand satisfaction with care among American Indian and Alaska Native (AI/AN) persons with cancer, we explored dimensions of the provider relationship that contributed to satisfaction among caregivers and survivors who received cancer treatment in Oregon and Washington State. METHODS: Between November 2011 and April 2013, the project team interviewed 11 caregivers and 71 AI/AN cancer survivors residing in Oregon and Washington State. Interview questions aimed to elicit participant experiences with care providers and factors associated with cancer care satisfaction. Interviews were analyzed using an inductive content analysis approach in which concepts were identified and themes derived from interview data. RESULTS: Three overarching themes, each with two sub themes, emerged from the data: (1) universal factors: bolstering understanding, involvement, and empathy in care; (2) minority-specific factors: incorporating culture and community into care; and (3) AI/AN-unique factors: interacting with Indian health clinics and Indian Health Service (IHS). CONCLUSIONS: The results of our study suggest that satisfaction with care among survivors and their caregivers must be examined within the context of culture and community, particularly among minority patients. Our study demonstrates providers' critical role in ensuring AI/AN patients emerge satisfied with cancer treatment by honoring their AI/AN-specific needs, such as respect for integration of traditional healing modalities and navigation of specialty care coordination. PMID- 26638005 TI - CT imaging features of atrioventricular shunts: what the radiologist must know. AB - In the last decade, cardiac computed tomography (CT) has gained mainstream acceptance for the noninvasive exclusion of significant coronary disease in a selected population. Improvements in electrocardiogram (ECG)-triggered imaging techniques also allow, by extension, a proper evaluation of the complete heart anatomy. Given the increasing worldwide clinical implementation of cardiac CT for coronary artery evaluation, radiologists can, incidentally, be confronted with unfamiliar and previously unsuspected non-coronary cardiac pathologies, including congenital morphological defects. This presence of congenital heart disease (CHD) should not be overlooked, being the most common form of birth defect, with a total birth prevalence of 9.1 per 1000 live births worldwide [1]. The prevalence of adult patients with CHD is estimated to be 3000 per million adults [2]. Ventricular septal defects (VSDs) are the most frequent subtypes of CHD, accounting together with atrial septal defects (ASDs) for nearly half of all CHD cases [1]. While some small defects are rarely symptomatic and can go undetected for life, others are clinically significant and require adequate and timely medical intervention. In this article, we present the CT imaging features of atrioventricular (AV) shunts, highlighting both their embryological origins and associated relevant clinical features. TEACHING POINTS: * Congenital heart disease (CHD) is the most common birth defect. * Ventricular and atrial septal defects account for nearly half of CHD cases. * Atrioventricular defects can frequently be detected on a cardiac CT. * Radiologists must be able to identify clinically significant atrioventricular defects. PMID- 26638006 TI - Imaging the postoperative patient: long-term complications of gastrointestinal surgery. AB - OBJECTIVES: The objectives of this review are (1) to become acquainted with the long-term complications of surgery of the gastrointestinal tract, and (2) to appreciate the appropriate use of imaging in the assessment of long-term complications. BACKGROUND: Gastrointestinal tract surgery comprises a group of procedures performed for a variety of both benign and malignant diseases. In the late postoperative setting, adhesions and internal hernias are the most important complications. and they can be further complicated by volvulus and ischemia. At present, computed tomography (CT) is the workhorse for evaluating late postoperative complications. Accurate imaging assessment of patients is essential for adequate treatment planning. IMAGING FINDINGS OR PROCEDURE DETAILS: In this pictorial essay we will review the most frequent long-term complications after gastrointestinal surgery, including adhesions, afferent loop syndrome, closed loop obstruction, strangulated obstruction, internal hernias, external hernias, anastomotic strictures and disease recurrence. Examples will be depicted using iconography from the authors' imaging department. CONCLUSIONS: Knowledge of the most frequent complications after gastrointestinal surgery in the late postoperative period is of paramount importance for every radiologist, so that potentially life-threatening situations can be promptly diagnosed and adequate therapy can be planned. TEACHING POINTS: * Long-term postoperative complications of gastrointestinal tract surgery can be divided into procedure-related and disease-related categories. * The most common procedure-related complications are internal hernias and adhesions. * The most frequent disease-related complications are mainly associated with neoplastic or inflammatory recurrence. * Computed tomography is the most useful examination when such complications are suspected. PMID- 26638007 TI - Down-Regulation of miR-148a Promotes Metastasis by DNA Methylation and is Associated with Prognosis of Skin Cancer by Targeting TGIF2. AB - BACKGROUND MicroRNAs (miRNA) dysregulation has been considered to be significantly related to the occurrence and development of cancers. Several studies had proved that DNA methylation is an important cause of the abnormal expression of miRNAs. The purpose of this study was to investigate the methylation status of miR-148a and its effects on the metastasis and prognosis of skin cancer, as well as the interaction with TGIF2 gene. MATERIAL AND METHODS According to the qRT-PCR analysis, the expression of miR-148a was down-regulated in tumor tissues compared with the adjacent tissues and healthy controls (P<0.05). In vitro cell metastasis assay revealed that miR-148a could inhibit cell metastasis and its down-regulation promoted metastasis. Luciferase reporter assay found that TGIF2 gene was a target gene and its expression was suppressed by miR-148a in skin cancer. RESULTS Methylation-specific PCR demonstrated that DNA methylation rate of miR-148a was higher in tumor tissues than in adjacent tissues and healthy tissues (P<0.05). miR-148a expression was proved to be epigenetically regulated after the demethylation of it by 5-aza-20-deoxycytidine treatment and qRT-PCR analysis. miR-148a methylation was significantly influenced by many clinicopathologic characteristics such as age (P=0.000), pathological differentiation (P=0.000), and lymph node metastasis (P=0.000). Besides, Kaplan Meier analysis showed patients with miR-148a methylation lived shorter than those without that (P<0.001). Cox regression analysis manifested that miR-148a methylation (HR=0.053, 95CI%=0.005-0.548, P=0.014) could be serve as an independent prognostic marker for skin cancer. CONCLUSIONS Taken together, the expression of miR-148a was regulated by DNA methylation and targeted by TGIF2. Its methylation may be a potential prognostic indicator in skin cancer. PMID- 26638008 TI - Photochemical studies and nanomolar photodynamic activities of phthalocyanines functionalized with 1,4,7-trioxanonyl moieties at their non-peripheral positions. AB - Manganese(III), cobalt(II), copper(II), magnesium(II), zinc(II) and metal-free phthalocyanines, possessing 1,4,7-trioxanonyl substituents, at their non peripheral positions, were subjected to photochemical, photodynamic and biological activity studies. Demetallated phthalocyanine and its metallated d block analogues, with copper(II), cobalt(II), manganese(III) chloride, were found to be less efficient singlet oxygen generators in comparison to the zinc(II) analogue and zinc(II) phthalocyanine reference. Irradiation of several phthalocyanines for short time periods resulted in a substantially increased cytostatic activity against both suspension (leukemic/lymphoma at 85nM) and solid (cervix carcinoma at 72nM and melanoma at 81nM) tumour cell lines (up to 200 fold). Noteworthy is that enveloped viruses, such as for herpesvirus and influenza A virus, but not, non-enveloped virus strains, such as Coxsackie B4 virus and reovirus-1, exposed to irradiation in the presence of the phthalocyanines, markedly lost their infectivity potential. PMID- 26638009 TI - Second sphere control of spin state: Differential tuning of axial ligand bonds in ferric porphyrin complexes by hydrogen bonding. AB - An iron porphyrin with a pre-organized hydrogen bonding (H-Bonding) distal architecture is utilized to avoid the inherent loss of entropy associated with H Bonding from solvent (water) and mimic the behavior of metallo-enzyme active sites attributed to H-Bonding interactions of active site with the 2nd sphere residues. Resonance Raman (rR) data on these iron porphyrin complexes indicate that H-Bonding to an axial ligand like hydroxide can result in both stronger or weaker Fe(III)-OH bond relative to iron porphyrin complexes. The 6-coordinate (6C) complexes bearing water derived axial ligands, trans to imidazole or thiolate axial ligand with H-Bonding stabilize a low spin (LS) ground state (GS) when a complex without H-Bonding stabilizes a high spin (HS) ground state. DFT calculations reproduce the trend in the experimental data and provide a mechanism of how H-Bonding can indeed lead to stronger metal ligand bonds when the axial ligand donates an H-Bond and lead to weaker metal ligand bonds when the axial ligand accepts an H-Bond. The experimental and computational results explain how a weak Fe(III)-OH bond (due to H-Bonding) can lead to the stabilization of low spin ground state in synthetic mimics and in enzymes containing iron porphyrin active sites. H-Bonding to a water ligand bound to a reduced ferrous active site can only strengthen the Fe(II)-OH2 bond and thus exclusion of water and hydrophilic residues from distal sites of O2 binding/activating heme proteins is necessary to avoid inhibition of O2 binding by water. These results help demonstrate the predominant role played by H-Bonding and subtle changes in its orientation in determining the geometric and electronic structure of iron porphyrin based active sites in nature. PMID- 26638010 TI - Efficacy and safety of adding alirocumab to rosuvastatin versus adding ezetimibe or doubling the rosuvastatin dose in high cardiovascular-risk patients: The ODYSSEY OPTIONS II randomized trial. AB - OBJECTIVE: To compare lipid-lowering efficacy of adding alirocumab to rosuvastatin versus other treatment strategies (NCT01730053). METHODS: Patients receiving baseline rosuvastatin regimens (10 or 20 mg) were randomized to: add-on alirocumab 75 mg every-2-weeks (Q2W) (1-mL subcutaneous injection via pre-filled pen); add-on ezetimibe 10 mg/day; or double-dose rosuvastatin. Patients had cardiovascular disease (CVD) and low-density lipoprotein cholesterol (LDL-C) >=70 mg/dL (1.8 mmol/L) or CVD risk factors and LDL-C >=100 mg/dL (2.6 mmol/L). In the alirocumab group, dose was blindly increased at Week 12 to 150 mg Q2W (also 1-mL volume) in patients not achieving their LDL-C target. Primary endpoint was percent change in calculated LDL-C from baseline to 24 weeks (intent-to-treat). RESULTS: 305 patients were randomized. In the baseline rosuvastatin 10 mg group, significantly greater LDL-C reductions were observed with add-on alirocumab ( 50.6%) versus ezetimibe (-14.4%; p < 0.0001) and double-dose rosuvastatin ( 16.3%; p < 0.0001). In the baseline rosuvastatin 20 mg group, LDL-C reduction with add-on alirocumab was -36.3% compared with -11.0% with ezetimibe and -15.9% with double-dose rosuvastatin (p = 0.0136 and 0.0453, respectively; pre-specified threshold for significance p < 0.0125). Overall, ~80% alirocumab patients were maintained on 75 mg Q2W. Of alirocumab-treated patients, 84.9% and 66.7% in the baseline rosuvastatin 10 and 20 mg groups, respectively, achieved risk-based LDL C targets. Treatment-emergent adverse events occurred in 56.3% of alirocumab patients versus 53.5% ezetimibe and 67.3% double-dose rosuvastatin (pooled data). CONCLUSIONS: The addition of alirocumab to rosuvastatin provided incremental LDL C lowering versus adding ezetimibe or doubling the rosuvastatin dose. PMID- 26638011 TI - ADMA and arginine derivatives in relation to non-invasive vascular function in the general population. AB - OBJECTIVE: Nitric oxide produced from l-arginine is central to vascular homeostasis. Little is known about the relationship between arginine derivatives including asymmetric dimethylarginine (ADMA) and non-invasive vascular function measures in the general population. APPROACH AND RESULTS: In 5000 individuals (median age 56; 25th/75th percentile: 46, 65; 49% women) taking part in the population-based Gutenberg Health Study (Mainz area, Germany), we measured the relationship between the arginine derivatives asymmetric dimethylarginine (ADMA), N-monomethyl l-arginine (NMMA), symmetric dimethylarginine (SDMA) and l-arginine with flow-mediated dilation (FMD) and peripheral arterial tonometry (PAT). Weak bivariate correlations were observed between all measured arginine derivatives and vascular function measures, except of l-arginine and FMD and SDMA and PAT ratio. In multivariate adjusted linear regression analyses we could show statistically significant relationships between arginine derivatives and vascular function measures, which were influenced by age, sex and body mass index (BMI). Thus, a negative relationship between ADMA and FMD in females who were normal (beta: -0.095, P < 0.001) to overweight (beta: -0.071, P < 0.001) and a negative association of SDMA and FMD for middle-aged females was seen. The relationship between ADMA and PAT was negative for males who were normal (beta: -0.089, P < 0.001) to overweight (beta: -0.051, P = 0.007) and positive for obese females (beta: 0.073, P = 0.021). CONCLUSIONS: We showed small but significant correlations between ADMA and related arginine derivatives and non-invasive vascular function measures representative of different vascular regions. The associations were markedly influenced by age, sex and BMI. These findings support a complex interplay of arginine metabolism and vascular function. PMID- 26638012 TI - Isoniazid and rifampin drug susceptibility testing: application of 2,3,5 triphenyl tetrazolium chloride assay and microscopic-observation drug susceptibility assay directly on Ziehl-Neelsen smear positive sputum specimens. AB - The current study was aimed to evaluate the performance of direct 2,3,5-triphenyl tetrazolium chloride assay and direct microscopic observation drug susceptibility assay with indirect Lowenstein-Jensen proportion method directly on Ziehl-Neelsen smear positive sputum specimens. METHODS: Direct acid fast bacilli smear positive sputum specimens (n=264) were subjected to isoniazid and rifampicin drug susceptibility testing by direct 2,3,5-triphenyl tetrazolium chloride assay, direct microscopic observation drug susceptibility assay, and the performances were compared with indirect Lowenstein-Jensen proportion method. RESULTS: The direct 2,3,5-triphenyl tetrazolium chloride assay demonstrated an overall sensitivity, specificity, positive predictive value, and negative predictive value of 99.2%, 82.4%, 99.2%, and 88.5%, respectively, for the detection of isoniazid and rifampicin resistant Mycobacterium tuberculosis isolates when compared to indirect Lowenstein-Jensen proportion method. Likewise, the overall sensitivity, specificity, positive predictive value and negative predictive value of direct microscopic observation drug susceptibility assay were 98.8%, 82.4%, 99.2%, and 78.2%, respectively. CONCLUSION: The direct 2,3,5-triphenyl tetrazolium chloride assay was found to be an economical alternative method for the rapid and accurate detection of isoniazid and rifampicin resistance from direct acid fast bacilli smear positive sputum specimens. PMID- 26638013 TI - The accuracy of the SONOBREAST statistical model in comparison to BI-RADS for the prediction of malignancy in solid breast nodules detected at ultrasonography. AB - OBJECTIVE: The objective of the present study was to compare the accuracy of SONOBREAST for the prediction of malignancy in solid breast nodules detected at ultrasonography with that of the BI-RADS system and to assess the agreement between these two methods. STUDY DESIGN: This prospective study included 274 women and evaluated 500 breast nodules detected at ultrasonography. The probability of malignancy was calculated based on the SONOBREAST model, available at www.sonobreast.com.br, and on the BI-RADS system, with results being compared with the anatomopathology report. RESULTS: The lesions were considered suspect in 171 cases (34.20%), according to both SONOBREAST and BI-RADS. Agreement between the methods was perfect, as shown by a Kappa coefficient of 1 (p<0.001). SONOBREAST and BI-RADS proved identical insofar as sensitivity (95.40%), specificity (78.69%), positive predictive value (48.54%), negative predictive value (98.78%) and accuracy (81.60%) are concerned. With respect to the categorical variables (BI-RADS categories 3, 4 and 5), the area under the receiver operating characteristic (ROC) curve was 94.41 for SONOBREAST (range 92.20-96.62) and 89.99 for BI-RADS (range 86.60-93.37). CONCLUSIONS: The accuracy of the SONOBREAST model is identical to that found with BI-RADS when the same parameters are used with respect to the cut-off point at which malignancy is suspected. Regarding the continuous probability of malignancy with BI-RADS categories 3, 4 and 5, SONOBREAST permits a more precise and individualized evaluation. PMID- 26638014 TI - Agronomic and remedial benefits and risks of applying biochar to soil: Current knowledge and future research directions. AB - 'Biochar' represents an emerging technology that is increasingly being recognized for its potential role in carbon sequestration, reducing greenhouse gas emissions, waste management, renewable energy, soil improvement, crop productivity enhancement and environmental remediation. Published reviews have so far focused mainly on the above listed agronomic and environmental benefits of applying biochar, yet paid little or no attention to its harmful effects on the ecological system. This review highlights a balanced overview of the advantages and disadvantages of the pyrolysis process of biochar production, end-product quality and the benefits versus drawbacks of biochar on: (a) soil geochemistry and albedo, (b) microflora and fauna, (c) agrochemicals, (d) greenhouse gas efflux, (e) nutrients, (f) crop yield, and (g) contaminants (organic and inorganic). Future research should focus more on the unintended long-term consequences of biochar on biological organisms and their processes in the soil. PMID- 26638015 TI - Associations between plasma concentrations of PCB 28 and possible indoor exposure sources in Danish school children and mothers. AB - BACKGROUND: Polychlorinated biphenyls (PCBs) are ubiquitously present in the environment and are suspected of carcinogenic, neurotoxic and immunotoxic effects. Significantly higher plasma concentrations of the congener PCB 28 occur in children compared to adults. Exposure in schools may contribute to this difference. OBJECTIVE: To determine whether increased blood plasma concentrations of PCB 28 in Danish school children and mothers are associated with living in homes or attending schools constructed in the PCB period (1959-1977). METHODS: PCB 28 was analyzed in plasma samples from 116 children aged 6-11years and 143 mothers living in an urban and a rural area in Denmark and participating in the European pilot project DEMOCOPHES (Demonstration of a study to COordinate and Perform Human Biomonitoring on a European Scale). In Denmark, PCBs were used in construction in the period 1950-1977, and year of construction or renovation of the homes and schools was used as a proxy for indoor PCB exposure. Linear regression models were used to assess the association between potential PCB exposure from building materials and lipid adjusted concentrations of PCB 28 in plasma, with and without adjustment for potential confounders. RESULTS: Among the 116 children and 143 mothers, we were able to specify home construction period in all but 4 children and 5 mothers leaving 111 children and 138 mothers for our analyses. The median lipid adjusted plasma PCB 28 concentration was 3 (range: 1 28) ng/g lipid in the children and 2 (range: 1-8) ng/g lipid in the mothers. Children living in homes built in the PCB period had significantly higher lipid adjusted plasma PCB 28 concentrations compared to children living in homes built before or after the PCB period. Following adjustment for covariates, PCB 28 concentrations in children were 40 (95% CI: 13; 68) percent higher than concentrations of children living in homes constructed at other times. Furthermore, children attending schools built or substantially refurbished in the PCB period also had significantly higher (46%, 95% CI: 22; 70) PCB 28 concentrations compared to children attending schools constructed before or after the PCB period, while their mothers had similar concentrations. Adjustment for the most prevalent congener, PCB 153, did not change this effect of home or school construction. When both home and school construction year were included in the models, the increase in lipid adjusted plasma PCB 28 for children living in or attending schools from the PCB period was no longer statistically significant. The individual effect of home and school construction periods could not be evaluated further with the available data. CONCLUSION: Our results suggest that PCB exposure in the indoor environment in schools and homes constructed during the PCB period may contribute significantly to children's plasma PCB 28 concentration. Efforts to minimize PCB exposure in indoor environments should be considered. PMID- 26638017 TI - Living near nuclear power plants and thyroid cancer risk: A systematic review and meta-analysis. AB - There has been public concern regarding the safety of residing near nuclear power plants, and the extent of risk for thyroid cancer among adults living near nuclear power plants has not been fully explored. In the present study, a systematic review and meta-analysis of epidemiologic studies was conducted to investigate the association between living near nuclear power plants and the risk of thyroid cancer. A comprehensive literature search was performed on studies published up to March 2015 on the association between nuclear power plants and thyroid cancer risk. The summary standardized incidence ratio (SIR), standardized mortality ratio (SMR), and 95% confidence intervals (CIs) were calculated using a random-effect model of meta-analysis. Sensitivity analyses were performed by study quality. Thirteen studies were included in the meta-analysis, covering 36 nuclear power stations in 10 countries. Overall, summary estimates showed no significant increased thyroid cancer incidence or mortality among residents living near nuclear power plants (summary SIR=0.98; 95% CI 0.87-1.11, summary SMR=0.80; 95% CI 0.62-1.04). The pooled estimates did not reveal different patterns of risk by gender, exposure definition, or reference population. However, sensitivity analysis by exposure definition showed that living less than 20 km from nuclear power plants was associated with a significant increase in the risk of thyroid cancer in well-designed studies (summary OR=1.75; 95% CI 1.17 2.64). Our study does not support an association between living near nuclear power plants and risk of thyroid cancer but does support a need for well-designed future studies. PMID- 26638016 TI - An interlaboratory comparison of nanosilver characterisation and hazard identification: Harmonising techniques for high quality data. AB - Within the FP7 EU project NanoValid a consortium of six partners jointly investigated the hazard of silver nanoparticles (AgNPs) paying special attention to methodical aspects that are important for providing high-quality ecotoxicity data. Laboratories were supplied with the same original stock dispersion of AgNPs. All partners applied a harmonised procedure for storage and preparation of toxicity test suspensions. Altogether ten different toxicity assays with a range of environmentally relevant test species from different trophic levels were conducted in parallel to AgNP characterisation in the respective test media. The paper presents a comprehensive dataset of toxicity values and AgNP characteristics like hydrodynamic sizes of AgNP agglomerates and the share (%) of Ag(+)-species (the concentration of Ag(+)-species in relation to the total measured concentration of Ag). The studied AgNP preparation (20.4+/-6.8 nm primary size, mean total Ag concentration 41.14 mg/L, 46-68% of soluble Ag(+) species in stock, 123.8+/-12.2 nm mean z-average value in dH2O) showed extreme toxicity to crustaceans Daphnia magna, algae Pseudokirchneriella subcapitata and zebrafish Danio rerio embryos (EC50<0.01 mg total Ag/L), was very toxic in the in vitro assay with rainbow trout Oncorhynchus mykiss gut cells (EC50: 0.01-1 mg total Ag/L); toxic to bacteria Vibrio fischeri, protozoa Tetrahymena thermophila (EC50: 1-10 mg total Ag/L) and harmful to marine crustaceans Artemia franciscana (EC50: 10-100 mg total Ag/L). Along with AgNPs, also the toxicity of AgNO3 was analyzed. The toxicity data revealed the same hazard ranking for AgNPs and AgNO3 (i.e. the EC50 values were in the same order of magnitude) proving the importance of soluble Ag(+)-species analysis for predicting the hazard of AgNPs. The study clearly points to the need for harmonised procedures for the characterisation of NMs. Harmonised procedures should consider: (i) measuring the AgNP properties like hydrodynamic size and metal ions species in each toxicity test medium at a range of concentrations, and (ii) including soluble metal salt control both in toxicity testing as well as in Ag(+)-species measurements. The present study is among the first nanomaterial interlaboratory comparison studies with the aim to improve the hazard identification testing protocols. PMID- 26638018 TI - The contribution of translesion synthesis polymerases on geminiviral replication. AB - Geminiviruses multiply primarily in the plant phloem, but never in meristems. Their Rep protein can activate DNA synthesis in differentiated cells. However, when their single-stranded DNA is injected into the phloem by insects, no Rep is present for inducing initial complementary strand replication. Considering a contribution of translesion synthesis (TLS) polymerases in plants, four of them (Poleta, Polzeta, Polkappa, Rev1) are highly and constitutively expressed in differentiated tissues like the phloem. Two geminiviruses (Euphorbia yellow mosaic virus, Cleome leaf crumple virus), inoculated either biolistically or by whiteflies, replicated in Arabidopsis thaliana mutant lines of these genes to the same extent as in wild type plants. Comparative deep sequencing of geminiviral DNAs, however, showed a high exchange rate (10(-4)-10(-3)) similar to the phylogenetic variation described before and a significant difference in nucleotide substation rates if Poleta and Polzeta were absent, with a differential response to the viral DNA components. PMID- 26638019 TI - The comparison of pathology in ferrets infected by H9N2 avian influenza viruses with different genomic features. AB - H9N2 avian influenza virus circulates widely in poultry and has been responsible for sporadic human infections in several regions. Few studies have been conducted on the pathogenicity of H9N2 AIV isolates that have different genomic features. We compared the pathology induced by a novel reassortant H9N2 virus and two currently circulating H9N2 viruses that have different genomic features in ferrets. The results showed that the three viruses can induce infections with various amounts of viral shedding in ferrets. The novel H9N2 induced respiratory infection, but no pathological lesions were observed in lung tissues. The other two viruses induced mild to intermediate pathological lesions in lung tissues, although the clinical signs presented mildly in ferrets. The pathological lesions presented a diversity consistent with viral replication in ferrets. PMID- 26638020 TI - Whole grains in the finishing of culled ewes in pasture or feedlot: Performance, carcass characteristics and meat quality. AB - In order to evaluate the performance, carcass characteristics and meat quality of culled ewes finished in pasture or exclusivelywith grain, 41 culled Polwarth ewes, were assigned to six treatments: RY (ryegrass pasture), RYGO (ryegrass and whole grain oats), RYGM (ryegrass and whole grain maize), GM (whole grain maize), GO (whole grain oats), GS (whole grain sorghum). The finishing systemof the ewes influenced weight gain,wherein the GM and GS treatments increased daily weight gain. The GO treatment decreased the dressing percentage. Nonetheless, a*, h*, pH, cooking loss and tenderness were similar across dietary treatments. Using principal component analysis, the variables C18:2n6, h*, n6/n3, TBARS, total lipids, L* and b* were assigned as characteristics of meat from the feedlot animals, while the pasture finishing system produced meat with higher CLA and n-3 fatty acids but lower TBARS values indicating lipid stability. PMID- 26638021 TI - Polymorphisms in the regulatory region of the porcine MYLPF gene are related to meat quality traits in the Large White breed. AB - The MYLPF gene encodes fast myosin regulatory light chain, and is a positional and functional candidate gene for meat quality. The aim of this study was to identify associations between SNPs in the promoter region of the porcine MYLPF gene and meat quality traits. A total of 22 SNPs were identified in a population of crossbred animals (n=86) and based on minor allele frequency and proximity to the transcription start site, five SNPs were genotyped in purebred; Large White (n=98), Duroc (n=99) and Pietrain (n=98) pigs. No associations were observed in the Pietrain breed, while the Duroc breed was almost monomorphic for all SNPs. In the Large White breed SNP g-1314A>G and linked SNPS g.-871T>G, g.-566T>C, g. 403C>G were associated with ultimate pH and driploss (P<0.05). This study identified associations between MYLPF and meat quality and highlights the importance of considering the genetic background within gene-assisted selection programmes. PMID- 26638022 TI - Applications of Discrete Molecular Dynamics in biology and medicine. AB - Discrete Molecular Dynamics (DMD) is a physics-based simulation method using discrete energetic potentials rather than traditional continuous potentials, allowing microsecond time scale simulations of biomolecular systems to be performed on personal computers rather than supercomputers or specialized hardware. With the ongoing explosion in processing power even in personal computers, applications of DMD have similarly multiplied. In the past two years, researchers have used DMD to model structures of disease-implicated protein folding intermediates, study assembly of protein complexes, predict protein protein binding conformations, engineer rescue mutations in disease-causative protein mutants, design a protein conformational switch to control cell signaling, and describe the behavior of polymeric dispersants for environmental cleanup of oil spills, among other innovative applications. PMID- 26638024 TI - Re: Should the Urologist Treat Castration Resistant Prostate Cancer? Yes/No. PMID- 26638025 TI - Re: Primary Endoscopic Realignment of Urethral Disruption Injuries-A Double-Edged Sword?: N. V. Johnsen, R. R. Dmochowski, S. Mock, W. S. Reynolds, D. F. Milam and M. R. Kaufman J Urol 2015;194:1022-1026. PMID- 26638027 TI - Cross-clade protective immune responses of NS1-truncated live attenuated H5N1 avian influenza vaccines. AB - BACKGROUND: H5N1 highly pathogenic avian influenza (HPAI) has raised global concern for causing huge economic losses in poultry industry, and an effective vaccine against HPAI is highly desirable. Live attenuated influenza vaccine with trunctated NS1 protein as a potential strategy will be extremely useful for improving immune efficacy. METHODS: A series of H5N1 avian influenza virus reassortants harboring amino-terminal 48, 70, 73, and 99 aa in NS1 proteins, along with a modified low pathogenic HA protein was generated, and named as S HALo/NS48, S-HALo/NS70, S-HALo/NS73, and S-HALo/NS99, respectively. In addition, their biological and immunological characteristics were further analyzed. RESULTS: The viruses S-HALo/NS70, S-HALo/NS73, and S-HALo/NS99, but not S HALo/NS48, had a comparable growth property with the full-length NS1 virus, S HALo/NSFu. Mice and chickens studies demonstrated that the viruses with truncated NS1 protein were further attenuated when compared to the virus S-HALo/NSFu. Vaccination with the virus S-HALo/NS73 in chickens induced significant cross protection against homologous clade 2.3.4 H5 virus and heterologous clade 7.2, 2.3.2.1, and 2.3.4.4 H5 viruses. CONCLUSION: A 70-aa amino-terminal fragment of NS1 protein may be long enough for viral replication. The recombinant virus S HALo/NS73 is a broad-spectrum live attenuated H5N1 avian influenza vaccine candidate in chickens. PMID- 26638028 TI - Association between high expression macrophage migration inhibitory factor (MIF) alleles and West Nile virus encephalitis. AB - Infection with mosquito-borne West Nile virus (WNV) is usually asymptomatic but can lead to severe WNV encephalitis. The innate cytokine, macrophage migration inhibitory factor (MIF), is elevated in patients with WNV encephalitis and promotes viral neuroinvasion and mortality in animal models. In a case-control study, we examined functional polymorphisms in the MIF locus in a cohort of 454 North American patients with neuroinvasive WNV disease and found patients homozygous for high-expression MIF alleles to be >20-fold (p=0.008) more likely to have WNV encephalitis. These data indicate that MIF is an important determinant of severity of WNV neuropathogenesis and may be a therapeutic target. PMID- 26638029 TI - Influence of genetic polymorphisms of cytokine genes in the outcome of HLA matched allogeneic stem cell transplantation in a South East Asian population. AB - Non-HLA gene polymorphisms have been shown to be associated with the risk of graft-versus-host disease (GVHD) and outcome of allogeneic haematopoietic stem cell transplantation (AHSCT). This study aims to investigate the role of IL6, TNFalpha, IL10, IL2 and IL12 gene polymorphisms in the outcome of AHSCT in a South East Asian population. A total of 67 patients and 59 donors who underwent HLA-identical matched sibling AHSCT were available for analysis. There was no significant association between the different cytokine genotypes of patients with the incidence and severity of acute GVHD. Patients with IL2 166*T allele and patients who received donor stem cells who had IL2 166*G allele appeared to have reduced incidence of cGVHD. Patients who received donor stem cells with IL12 1188*C allele are found to be associated with better disease free survival. These results suggest a possible role of IL2 and IL12 gene polymorphisms in the outcome of AHSCT in a South East Asian population. PMID- 26638031 TI - Simultaneous detection and comparative pharmacokinetics of amoxicillin, clavulanic acid and prednisolone in cows' milk by UPLC-MS/MS. AB - Amoxicillin (AMOX), clavulanic acid (CLAV) and prednisolone (PSL) are widely used in combination for the treatment of mastitis in lactating dairy cows. However, no method has been reported to detect these three chemicals in milk in a single assay. In the present work, a reliable and sensitive UPLC-MS/MS method was developed and validated for simultaneous determination of AMOX, CLAV and PSL in cow's milk. The analytes were determined by a positive and negative ionization electrospray mass spectrometer via multiple reaction monitoring. The linear ranges of AMOX, CLAV and PSL were from 2 to 1000ng/mL, 20-1000ng/mL and 1 1000ng/mL, respectively, with the correlation coefficients greater than 0.999. The limits of quantification (LOQs) were 2ng/mL (AMOX), 20ng/mL (CLAV) and 1ng/mL (PSL). Recoveries of the analytes of interest in milk samples were in the ranges of 84.2-101.4%. The intra-day and inter-day precisions ranged from 1.8% to 11.9%. This method was successfully applied to investigate the pharmacokinetics of AMOX, CLAV and PSL in milk from healthy and mastitic cows. The elimination times of AMOX and PSL in mastitic cows were longer than that in healthy cows, but the elimination times of CLAV did not show significant difference. PMID- 26638030 TI - Yersinia versus host immunity: how a pathogen evades or triggers a protective response. AB - The human pathogenic Yersinia species cause diseases that represent a significant source of morbidity and mortality. Despite this, specific mechanisms underlying Yersinia pathogenesis and protective host responses remain poorly understood. Recent studies have shown that Yersinia disrupt cell death pathways, perturb inflammatory processes and exploit immune cells to promote disease. The ensuing host responses following Yersinia infection include coordination of innate and adaptive immune responses in an attempt to control bacterial replication. Here, we highlight current advances in our understanding of the interactions between the pathogenic yersiniae and host cells, as well as the protective host responses mobilized to counteract these pathogens. Together, these studies enhance our understanding of Yersinia pathogenesis and highlight the ongoing battle between host and microbe. PMID- 26638032 TI - Pharmacokinetic analysis of levo-tetrahydropalmatine in rabbit plasma by rapid sample preparation and liquid chromatography-tandem mass spectrometry. AB - A rapid extraction method was developed and validated for levo tetrahydropalmatine (l-THP) determination in rabbit plasma by liquid chromatography tandem-mass spectrometry (LC-MS/MS). The sample preparation included a single-step acetonitrile extraction and salting out liquid-liquid partitioning from the water in plasma with MgSO4. Berberine was used as internal standard. The mass spectrometry source was negative electrospray ionization. The method showed good performance in the concentration range from 5 to 200ngmL(-1). The limit of quantification (LOQ) was 1ngmL(-1). The method was successfully applied to a pharmacokinetic study in rabbit comparing the two drug formulation of l-THP including the raw material and the self-microemulsifying drug delivery system pellet. PMID- 26638033 TI - The mitochondrial DNA sequence specificity of the anti-tumour drug bleomycin using end-labeled DNA and capillary electrophoresis and a comparison with genome wide DNA sequencing. AB - The DNA sequence specificity of the cancer chemotherapeutic agent, bleomycin, was investigated in two human mitochondrial DNA sequences. Bleomycin was found to cleave preferentially at 5'-TGT*A-3' DNA sequences (where * is the cleavage site). The bleomycin analysis using capillary electrophoresis with laser-induced fluorescence was determined on both DNA strands and each strand was independently fluorescently labelled at the 3'- and 5'-ends. There was a high level of correlation between the intensity of bleomycin cleavage sites analysed by 3'- and 5'-end labelling. This is the first occasion that a comprehensive comparison has been made between these two end-labelling procedures to quantify cleavage by a DNA damaging agent and to investigate end-label bias. A comparison was also made between the bleomycin DNA sequence specificity obtained from genome-wide next generation sequencing with that obtained from purified plasmid DNA sequences. This was accomplished by cloning sections of human mitochondrial DNA and comparing these identical mitochondrial DNA in the human mitochondrial genome. At individual sites, there was a very low level of correlation between bleomycin cleavage in plasmid sequencing and genome-wide sequencing. However, the overall bleomycin DNA sequence specificity was very similar in the two environments, namely 5'-TGT*A-3'. PMID- 26638034 TI - Label-free assay based on immobilized capillary enzyme reactor of Leishmania infantum nucleoside triphosphate diphosphohydrolase (LicNTPDase-2-ICER-LC/UV). AB - Nucleoside triphosphate diphosphohydrolase (NTPDase) is an enzyme belonging to the apyrase family that participates in the hydrolysis of the nucleosides di- and triphosphate to the corresponding nucleoside monophosphate. This enzyme underlies the virulence of parasites such as Leishmania. Recently, an NTPDase from Leishmania infantum (LicNTPDase-2) was cloned and expressed and has been considered as a new drug target for the treatment of leishmaniasis. With the intent of developing label-free online screening methodologies, LicNTPDase-2 was covalently immobilized onto a fused silica capillary tube in the present study to create an immobilized capillary enzyme reactor (ICER) based on LicNTPDase-2 (LicNTPDase-2-ICER). To perform the activity assays, a multidimensional chromatographic method was developed employing the LicNTPDase-2-ICER in the first dimension, and an analytical Ascentis C8 column was used in the second dimension to provide analytical separation of the substrates and products. The validated LicNTPDase-2-ICER method provided the following kinetic parameters of the immobilized enzyme: KM of 2.2 and 1.8mmolL(-1) for the ADP and ATP substrates, respectively. Suramin (1mmolL(-1)) was also shown to inhibit 32.9% of the enzymatic activity. The developed method is applicable to kinetic studies and enables the recognition of the ligands. Furthermore, a comparison of the values of LicNTPDase-2-ICER with those obtained with an LC method using free enzyme in solution showed that LicNTPDase-2-ICER-LC/UV was an accurate and reproducible method that enabled automated measurements for the rapid screening of ligands. PMID- 26638035 TI - Determination of tulobuterol in rat plasma using a liquid chromatography-tandem mass spectrometry method and its application to a pharmacokinetic study of tulobuterol patch. AB - A sensitive and accurate liquid chromatography-tandem mass spectrometry (LC MS/MS) method has been developed and validated for determination of tulobuterol in rat plasma for the first time. Plasma samples were extracted by liquid-liquid extraction method with methyl tert-butyl ether and the analyte and clenbuterol (IS) were separated on a Venusil MP C18 column (100mm*2.1mm, 3MUm) using 0.1% formic acid-water-methanol as mobile phase, with a runtime of 5min. The analyte was detected in multiple reaction monitoring (MRM) mode with positive electrospray ionization. Transitions of m/z 228.2->154.0 for tulobuterol and m/z 277.1->203.0 for the clenbuterol were monitored. The linear range was 0.5 100ng/ml (r=0.9967) for tulobuterol with the lower limit of quantitation of 0.5ng/ml. The intra-day and inter-day precisions were less than 10.3% for the analyte and the accuracy was less than -8.6%. The RSD of matrix effect and recovery yield were within +/-15% of nominal concentrations and tulobuterol was stable during stability studies. The validated method has been successfully applied to a pharmacokinetic study of three doses of tulobuterol patch in rats for the first time. PMID- 26638036 TI - Bar adsorptive microextraction (BAMUE) coated with mixed sorbent phases-Enhanced selectivity for the determination of non-steroidal anti-inflammatory drugs in real matrices in combination with capillary electrophoresis. AB - The present work proposes the application of bar adsorptive microextraction coated with mixed sorbent phases (n-vinylpyrrolidone and divinylbenzene polymers with strong and weak anion exchangers), combined with liquid desorption followed by capillary electrophoresis with diode array detection (BAMUE(PMIX)-LD/CE-DAD) for the determination of trace levels of non-steroidal anti-inflammatory drugs (NSAIDs: salicylic acid, mefenamic acid, diclofenac and naproxen as model compounds) in urine and water matrices. Assays performed on 25mL of water samples spiked at the 80.0MUg/L level, yielded average recoveries between 86.6 and 104.% for all the NSAIDs under study using optimized experimental conditions. The proposed analytical methodology demonstrated suitable detection limits (0.3MUg/L) and good linear dynamic ranges (2.5-320.0MUg/L) with determination coefficients higher than 0.9981. By using the standard addition methodology, the present analytical approach was applied on urine and water samples, where good selectivity and sensitivity were achieved. The proposed method, which operated under the floating sampling technology, proved to be a suitable sorption-based static microextraction alternative for monitoring trace levels of NSAIDs in urine and water samples. The methodology showed to be easy to implement, demonstrating good reproducibility and robustness, allowing the possibility to choose the most selective sorbent, or mixed sorbent phases, according to the compounds of interest. PMID- 26638037 TI - A standardized diagnostic approach and ongoing feedback improves outcome in psychogenic nonepileptic seizures. AB - INTRODUCTION: Psychogenic nonepileptic seizures (PNES) are episodic alterations in behavior presumed to reflect a physical manifestation of underlying psychological distress. Standardized treatment approaches for PNES care are lacking. We evaluated common approaches to PNES management that do not require significant commitment of time and resources. METHODOLOGY: Patients with PNES established with video-EEG monitoring were randomized to one of the following three groups: 1) PNES diagnosis delivered per the discretion of the attending physician with advice to seek mental health assistance in the community (n=12), 2) scripted PNES diagnosis provided and inpatient psychiatry consult obtained (n=10), and 3) weekly follow-up phone calls made in addition to scripted diagnosis and inpatient psychiatry consultation (n=15). Reduction in event frequency measured at 8weeks following hospital discharge represented the primary outcome variable. Secondary variables analyzed included exploration of change in self-reported mood, quality of life, and healthcare utilization. RESULTS: No significant improvements were noted in patients simply given a PNES diagnosis and advised to seek outside care on any measure. In contrast, patients receiving a scripted diagnosis and psychiatric consultation demonstrated decreased PNES frequency accompanied by improved quality of life (QOL). Patients also receiving weekly phone calls not only demonstrated decreased PNES frequency and improvements in QOL but also exhibited improved mood. DISCUSSION: These findings demonstrate that providing diagnostic information regarding PNES is insufficient by itself to meaningfully affect patient outcome. Structured feedback and psychiatric consultation appeared adequate to significantly reduce PNES frequency and improve aspects of quality of life, while the addition of a weekly phone contact also led to improved mood. PMID- 26638038 TI - Factors affecting gas migration and contaminant redistribution in heterogeneous porous media subject to electrical resistance heating. AB - A series of intermediate-scale laboratory experiments were completed in a two dimensional flow cell to investigate gas production and migration during the application of electrical resistance heating (ERH) for the removal of dense non aqueous phase liquids (DNAPLs). Experiments consisted of heating water in homogeneous silica sand and heating 270 mL of trichloroethene (TCE) and chloroform (CF) DNAPL pools in heterogeneous silica sands, both under flowing groundwater conditions. Spatial and temporal distributions of temperature were measured using thermocouples and observations of gas production and migration were collected using front-face image capture throughout the experiments. Post treatment soil samples were collected and analyzed to assess DNAPL removal. Results of experiments performed in homogeneous sand subject to different groundwater flow rates showed that high groundwater velocities can limit subsurface heating rates. In the DNAPL pool experiments, temperatures increased to achieve DNAPL-water co-boiling, creating estimated gas volumes of 131 and 114 L that originated from the TCE and CF pools, respectively. Produced gas migrated vertically, entered a coarse sand lens and subsequently migrated laterally beneath an overlying capillary barrier to outside the heated treatment zone where 31-56% of the original DNAPL condensed back into a DNAPL phase. These findings demonstrate that layered heterogeneity can potentially facilitate the transport of contaminants outside the treatment zone by mobilization and condensation of gas phases during ERH applications. This underscores the need for vapor phase recovery and/or control mechanisms below the water table during application of ERH in heterogeneous porous media during the co-boiling stage, which occurs prior to reaching the boiling point of water. PMID- 26638039 TI - Reduced graphene oxide-Hemin-Au nanohybrids: Facile one-pot synthesis and enhanced electrocatalytic activity towards the reduction of hydrogen peroxide. AB - A facile and effective strategy is demonstrated for the synthesis of ternary reduced graphene oxide-Hemin-Au (rGO-H-Au) nanohybrids. The nanohybrids were synthesized through a one-pot in situ reduction of GO and HAuCl4 under alkaline conditions using GO, Hemin and HAuCl4 as the starting materials. The synthesis process can be finished within 1h in a solution phase, without adding any additional surfactant, stabilizing agent and toxic or harsh chemical reducing agents. The resulting nanohybrids were characterized by UV-vis spectroscopy, Raman spectroscopy, transmission electron microscopy (TEM), and so on. Electrochemical measurements showed that the rGO-H-Au nanohybrids exhibited good electrocatalytic activity for the reduction of hydrogen peroxide (H2O2). Based on this property, a simple and highly sensitive amperometric biosensor for H2O2 had been developed. The linear relationships were obtained from 0.1 uM to 40 uM and the detection limit was estimated to be 30 nM. The simple and sensitive sensing platform showed great promising applications in the pharmaceutical, clinical and industrial detection of H2O2. PMID- 26638040 TI - A sensitive aptasensor for colorimetric detection of adenosine triphosphate based on the protective effect of ATP-aptamer complexes on unmodified gold nanoparticles. AB - Adenosine triphosphate (ATP) is the most direct source of energy in organisms. This study is the first to demonstrate that ATP-aptamer complexes provide greater protection for unmodified gold nanoparticles (AuNPs) against salt-induced aggregation than either aptamer or ATP alone. This protective effect was confirmed using transmission electron microscopy, dynamic light scattering, Zeta potential measurement, and fluorescence polarization techniques. Utilizing controlled particle aggregation/dispersion as a gauge, a sensitive and selective aptasensor for colorimetric detection of ATP was developed using ATP-binding aptamers as the identification element and unmodified AuNPs as the probe. This aptasensor exhibited a good linear relationship between the absorbance and the logarithm concentration of ATP within a 50-1000 nM range. ATP analogs such as guanosine triphosphate, uridine triphosphate and cytidine triphosphate resulted in little or no interference in the determination of ATP. PMID- 26638041 TI - Anti-herpetic and anti-dengue activity of abietane ferruginol analogues synthesized from (+)-dehydroabietylamine. AB - The abietane-type diterpenoid (+)-ferruginol (1), a bioactive compound isolated from several plants, has attracted much attention as consequence of its pharmacological properties, which includes antibacterial, antifungal, antimicrobial, cardioprotective, anti-oxidative, anti-plasmodial, leishmanicidal, anti-ulcerogenic, anti-inflammatory and antitumor actions. In this study, we report on the antiviral evaluation of ferruginol (1) and several analogues synthesized from commercial (+)-dehydroabietylamine. Thus, the activity against Human Herpesvirus type 1, Human Herpesvirus type 2 and Dengue Virus type 2, was studied. Two ferruginol analogues showed high antiviral selectivity index and reduced viral plaque-size in post-infection stages against both Herpes and Dengue viruses. A promising lead, compound 8, was ten-fold more potent (EC50 = 1.4 MUM) than the control ribavirin against Dengue Virus type 2. Our findings suggest that the 12-hydroxyabieta-8,11,13-triene skeleton, which is characteristic of the diterpenoid ferruginol (1), is an interesting molecular scaffold for development of novel antivirals. In addition, the cytotoxic and antifungal activities of the synthesized ferruginol analogues have also been investigated. ((c))20155 Elsevier Science. All rights reserved. PMID- 26638042 TI - Discovery of novel hybrids of diaryl-1,2,4-triazoles and caffeic acid as dual inhibitors of cyclooxygenase-2 and 5-lipoxygenase for cancer therapy. AB - Inflammation plays a key role in cancer initiation and propagation. Cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX), two important enzymes in inflammatory responses are up-regulated in various tumor types. Dual inhibition of COX-2 and 5-LOX constitutes a rational concept for the design of more efficacious anti-tumor agents with an improved safety profile. We have previously reported a series of diaryl-1,2,4-triazole derivatives as selective COX-2 inhibitors. Herein, we hybridized the diaryl-1,2,4-triazoles with caffeic acid (CA) which was reported to display 5-LOX inhibitory and anti-tumor activities, affording a novel class of COX-2/5-LOX dual inhibitors as anti-tumor drug candidates. Most of these compounds exhibited potent COX-2/5-LOX inhibitory and antiproliferative activities in vitro. And the most potent compound 22b could significantly inhibit tumor growth in vivo. Furthermore, mechanistic investigation showed that the representative compound 15c blocked cell cycle in G2 phase and induced apoptosis in human non-small cell lung cancer A549 cells in a dose-dependent manner. Our preliminary investigation results would provide new clues for the cancer theatment with COX-2/5-LOX dual inhibitors. PMID- 26638043 TI - Structural refinement of pyrazolo[4,3-d]pyrimidine derivatives to obtain highly potent and selective antagonists for the human A3 adenosine receptor. AB - In previous research, we identified some 7-oxo- and 7-acylamino-substituted pyrazolo[4,3-d]pyrimidine derivatives as potent and selective human (h) A3 adenosine receptor (AR) antagonists. Herein we report on the structural refinement of this class of antagonists aimed at achieving improved receptor ligand recognition. Hence, substituents with different steric bulk, flexibility and lipophilicity (Me, Ar, heteroaryl, CH2Ph) were introduced at the 5- and 2 positions of the bicyclic scaffold of both the 7-oxo and 7-amino derivatives, and acyl residues were appended on the 7-amino group of the latter. All the 2 phenylpyrazolo[4,3-d]pyrimidin-7-amines and 7-acylamines bearing a 4 methoxyphenyl- or a 2-thienyl group at the 5-position showed high hA3 affinity and selectivity. In particular, the 2-phenyl-5-(2-thienyl)-pyrazolo[4,3 d]pyrimidin-7-(4-methoxybenzoyl)amine 25 (Ki = 0.027 nM) is one of the most potent and selective hA3 antagonists reported so far. By using an in silico receptor-driven approach the obtained binding data were rationalized and the molecular bases of the observed hA3 AR affinities were critically described. PMID- 26638044 TI - Synthesis and antimalarial activity of quinones and structurally-related oxirane derivatives. AB - A series of eighteen quinones and structurally-related oxiranes were synthesized and evaluated for in vitro inhibitory activity against the chloroquine-sensitive 3D7 clone of the human malaria parasite Plasmodium falciparum. 2-amino and 2 allyloxynaphthoquinones exhibited important antiplasmodial activity (median inhibitory concentrations (IC50) < 10 MUM). Oxiranes 6 and 25, prepared respectively by reaction of alpha-lapachone and tetrachloro-p-quinone with diazomethane in a mixture of ether and ethanol, exhibited the highest antiplasmodial activity and low cytotoxicity against human fibroblasts (MCR-5 cell line). The active compounds could represent a good prototype for an antimalarial lead molecule. PMID- 26638046 TI - Reduced asymmetry in motor skill learning in left-handed compared to right-handed individuals. AB - Hemispheric specialization for motor control influences how individuals perform and adapt to goal-directed movements. In contrast to adaptation, motor skill learning involves a process wherein one learns to synthesize novel movement capabilities in absence of perturbation such that they are performed with greater accuracy, consistency and efficiency. Here, we investigated manual asymmetry in acquisition and retention of a complex motor skill that requires speed and accuracy for optimal performance in right-handed and left-handed individuals. We further determined if degree of handedness influences motor skill learning. Ten right-handed (RH) and 10 left-handed (LH) adults practiced two distinct motor skills with their dominant or nondominant arms during separate sessions two-four weeks apart. Learning was quantified by changes in the speed-accuracy tradeoff function measured at baseline and one-day retention. Manual asymmetry was evident in the RH group but not the LH group. RH group demonstrated significantly greater skill improvement for their dominant-right hand than their nondominant-left hand. In contrast, for the LH group, both dominant and nondominant hands demonstrated comparable learning. Less strongly-LH individuals (lower EHI scores) exhibited more learning of their dominant hand. These results suggest that while hemispheric specialization influences motor skill learning, these effects may be influenced by handedness. PMID- 26638045 TI - Synthesis, experimental evaluation and molecular modelling of hydroxamate derivatives as zinc metalloproteinase inhibitors. AB - Enzymes of the M4 family of zinc-metalloproteinases are virulence factors secreted from gram-positive or gram-negative bacteria, and putative drug targets in the treatment of bacterial infections. In order to have a therapeutic value such inhibitors should not interfere with endogenous zinc-metalloproteinases. In the present study we have synthesised a series of hydroxamate derivatives and validated the compounds as inhibitors of the M4 enzymes thermolysin and pseudolysin, and the endogenous metalloproteinases ADAM-17, MMP-2 and MMP-9 using experimental binding studies and molecular modelling. In general, the compounds are stronger inhibitors of the MMPs than of the M4 enzymes, however, an interesting exception is LM2. The compounds bound stronger to pseudolysin than to thermolysin, and the molecular modelling studies showed that occupation of the S2(') subpocket by an aromatic group is favourable for strong interactions with pseudolysin. PMID- 26638047 TI - Influence of prolonged wearing of unstable shoes on upright standing postural control. AB - OBJECTIVE: To study the influence of prolonged wearing of unstable shoes on standing postural control in prolonged standing workers. METHODS: The participants were divided into two groups: one wore unstable shoes while the other wore conventional shoes for 8weeks. Stabilometry parameters related to centre of pressure (CoP), rambling (RM) and trembling (TR) as well as the total agonist/antagonist muscle activity, antagonist co-activation and reciprocal activation were evaluated during upright standing, before and after the 8weeks period. In both moments, the subjects were evaluated wearing the unstable shoes and in barefoot. RESULTS: The unstable shoe condition presented increased CoP displacement related variables and decreased co-activation command compared to barefoot before and after the intervention. The prolonged wearing of unstable shoes led to: (1) reduction of medial-lateral CoP root mean square and area; (2) decreased anteroposterior RM displacement; (3) increased anteroposterior RM mean velocity and mediolateral RM displacement; (4) decreased anteroposterior TR RMS; and (5) increased thigh antagonist co-activation in the unstable shoe condition. CONCLUSION: The unstable shoe condition is associated to a higher destabilising effect that leads to a selection of more efficient and accurate postural commands compared to barefoot. Prolonged wearing of unstable shoes provides increased effectiveness and performance of the postural control system, while wearing of unstable shoes in upright standing, that are reflected by changes in CoP related variables and by a reorganisation of postural control commands. PMID- 26638048 TI - Differences in children's thinking and learning during attentional focus instruction. AB - Considerable evidence supports the motor learning advantage associated with an external focus of attention; however, very few studies have investigated attentional focus effects with children despite individual functional constraints that have the potential to impact use of instructional content. Thus, the purpose of this study was to determine the effect of attentional focus instruction on motor learning in children. Participants (n=42) aged 9-11years were randomly assigned to one of three gender-stratified groups: (1) control, (2) internal focus, or (3) external focus. Following initial instructions and task demonstration, participants performed 100 modified free throws over two days while receiving additional cues respective to their attentional focus condition and returned approximately 48h later to perform 20 additional free throws. Results revealed no significant learning differences between groups. However, responses to retrospective verbal reports suggest that the use of external focus content during practice may have contributed to some participants' superior performance in retention. Future research should continue to examine attentional focus effects across a variety of ages and incorporate retrospective verbal reports in order to examine children's thoughts during attentional focus instruction. PMID- 26638049 TI - Simultaneous segmentation and generalisation of non-adjacent dependencies from continuous speech. AB - Language learning requires mastering multiple tasks, including segmenting speech to identify words, and learning the syntactic role of these words within sentences. A key question in language acquisition research is the extent to which these tasks are sequential or successive, and consequently whether they may be driven by distinct or similar computations. We explored a classic artificial language learning paradigm, where the language structure is defined in terms of non-adjacent dependencies. We show that participants are able to use the same statistical information at the same time to segment continuous speech to both identify words and to generalise over the structure, when the generalisations were over novel speech that the participants had not previously experienced. We suggest that, in the absence of evidence to the contrary, the most economical explanation for the effects is that speech segmentation and grammatical generalisation are dependent on similar statistical processing mechanisms. PMID- 26638050 TI - Listeners use speaker identity to access representations of spatial perspective during online language comprehension. AB - Little is known about how listeners represent another person's spatial perspective during language processing (e.g., two people looking at a map from different angles). Can listeners use contextual cues such as speaker identity to access a representation of the interlocutor's spatial perspective? In two eye tracking experiments, participants received auditory instructions to move objects around a screen from two randomly alternating spatial perspectives (45 degrees vs. 315 degrees or 135 degrees vs. 225 degrees rotations from the participant's viewpoint). Instructions were spoken either by one voice, where the speaker's perspective switched at random, or by two voices, where each speaker maintained one perspective. Analysis of participant eye-gaze showed that interpretation of the instructions improved when each viewpoint was associated with a different voice. These findings demonstrate that listeners can learn mappings between individual talkers and viewpoints, and use these mappings to guide online language processing. PMID- 26638051 TI - Burdens of non-conformity: Motor execution reveals cognitive conflict during deliberate rule violations. AB - Rule compliance is pivotal for the regulation of social behavior. Still, humans deliberately violate rules at times - be it for personal reasons or for a higher good. Whereas previous research has studied the preconditions and consequences of rule violations, essentially nothing is known about the cognitive processes right at the moment a rule violation takes place. Here we show that merely labeling an action as rule violation induces substantial conflict between rule violation and compliance, as revealed by participants' bias towards rule-complying motor actions. Moreover, conflict that comes with violating a rule was much stronger than conflict that comes with following an alternative rule, even if both decisions result in the same observable behavior. These observations open a new theoretical perspective on rule violation behavior, shifting the focus toward the cognitive processes operating during the very act of rule violation. PMID- 26638052 TI - The association of serum cotinine and congestive heart failure diagnosis among never smokers: Considerations by physical activity behavior. PMID- 26638053 TI - Periodontal disease and carotid atherosclerosis: A meta-analysis of 17,330 participants. AB - BACKGROUND AND OBJECTIVES: The association between periodontal disease and carotid atherosclerosis has been evaluated primarily in single-center studies, and whether periodontal disease is an independent risk factor of carotid atherosclerosis remains uncertain. This meta-analysis aimed to evaluate the association between periodontal disease and carotid atherosclerosis. METHODS: We searched PubMed and Embase for relevant observational studies up to February 20, 2015. Two authors independently extracted data from included studies, and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for overall and subgroup meta-analyses. Statistical heterogeneity was assessed by the chi-squared test (P<0.1 for statistical significance) and quantified by the I(2) statistic. Data analysis was conducted using the Comprehensive Meta-Analysis (CMA) software. RESULTS: Fifteen observational studies involving 17,330 participants were included in the meta-analysis. The overall pooled result showed that periodontal disease was associated with carotid atherosclerosis (OR: 1.27, 95% CI: 1.14-1.41; P<0.001) but statistical heterogeneity was substantial (I(2)=78.90%). Subgroup analysis of adjusted smoking and diabetes mellitus showed borderline significance (OR: 1.08; 95% CI: 1.00-1.18; P=0.05). Sensitivity and cumulative analyses both indicated that our results were robust. CONCLUSIONS: Findings of our meta analysis indicated that the presence of periodontal disease was associated with carotid atherosclerosis; however, further large-scale, well-conducted clinical studies are needed to explore the precise risk of developing carotid atherosclerosis in patients with periodontal disease. PMID- 26638054 TI - Correlation between cardio-pulmonary exercise test variables and health-related quality of life among children with congenital heart diseases. AB - BACKGROUND: Health-related quality of life (HR-QoL) stands as a determinant "patient-related outcome" and correlates with cardio-pulmonary exercise test (CPET) in adults with chronic heart failure or with a congenital heart disease (CHD). No such correlation has been established in pediatric cardiology. METHODS AND RESULTS: 202 CHD children aged 8 to 18 performed a CPET (treadmill n=96, cycle-ergometer n=106). CHD severity was stratified into 4 groups. All children and parents filled out the Kidscreen HR-QoL questionnaire. Peak VO2, anaerobic threshold (AT), and oxygen pulse followed a downward significant trend with increasing CHD severity and conversely for VE/VCO2 slope. Self-reported and parent-reported physical well-being HR-QoL scores correlated with peak VO2 (respectively r=0.27, p<0.0001 and r=0.43, p<0.0001), percentage of predicted peak VO2 (r=0.28, p=0.0001 and r=0.41, p<0.0001), and percentage of predicted VO2 at AT (r=0.22, p<0.01 and r=0.31, p<0.0001). Significant correlations were also observed between several HR-QoL dimensions and dead space to tidal volume ratio (VD/VT), oxygen uptake efficiency slope (OUES), oxygen pulse but never with VE/VCO2 slope. The strongest correlations were observed in the treadmill group, especially between peak VO2 and physical well-being for parents (r=0.57, p<0.0001) and self (r=0.40, p<0.0001) reported HR-QoL. CONCLUSIONS: Peak VO2 and AT are the two CPET variables that best correlated with HR-QoL in this large pediatric cohort, parents' reports being more accurate. If HR-QoL is involved as a "PRO" in a pediatric cardiology clinical trial, we suggest using parents related physical well-being HR-QoL scores. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (number NCT01202916). PMID- 26638055 TI - Cardiac contractility modulation signals improve exercise intolerance and maladaptive regulation of cardiac key proteins for systolic and diastolic function in HFpEF. PMID- 26638057 TI - Temporal trends in acute myocardial infarction: What about survival of hospital survivors? Disparities between STEMI & NSTEMI remain. Soroka acute myocardial infarction II (SAMI-II) project. AB - BACKGROUND: Contemporary data on trends of acute myocardial infarction (AMI), particularly outcomes of hospital survivors by AMI type is sparse. METHODS: Analysis of 11,107 consecutive AMI patients in a tertiary hospital in Israel throughout 2002-2012. The annual incidence of ST-segment elevation (STEMI) and non-ST-segment elevation (NSTEMI) admissions was calculated using age-gender ethnicity direct adjustment. A multivariate prognostic model was built to evaluate in-hospital and 1-year post-discharge all-cause-mortality, adjusted for patients' risk factors. RESULTS: A decline in the adjusted incidence of AMI admissions (per-1000 persons) was documented (2002 vs. 2012) for STEMI: 4.70 vs. 1.38 (p<0.001) and non-significant tendency of increase for NSTEMI: 1.86 vs. 2.37 (p=0.109). The prevalence of most cardiovascular risk-factors, some non cardiovascular comorbidities and invasive interventions increased. In-hospital mortality declined significantly for STEMI: 10.8% vs. 7.7% (p<0.001) and with no change for NSTEMI: 5.0% vs. 5.5% (p=0.137). Consistently, 1-year post-discharge mortality declined for STEMI: 13% vs. 5.9% (p<0.001) and with a non-significant increase for NSTEMI: 12.6% vs. 17.0% (p=0.377). Adjusting for the risk factors, an increase of one year was associated with a decline of in-hospital mortality for STEMI: AdjOR=0.86 (p<0.001) and for NSTEMI: AdjOR=0.92 (p<0.001). However, the risk for post-discharge mortality increased for STEMI: AdjOR=1.11 (p<0.001) and for NSTEMI: AdjOR=1.12 (p<0.001). CONCLUSIONS: Throughout 2002-2012 significant decline in the incidence and of in-hospital mortality of STEMI were found. However, adjusted post-discharge mortality rates increased significantly with time. Measures for improving incidence and outcomes of AMI patients focusing on NSTEMI and hospital-survivors are warranted. PMID- 26638058 TI - Underutilization of implantable cardioverter-defibrillator in studies proposing risk scores to predict death in Chagas heart disease: Just a reflection of the real world. PMID- 26638056 TI - The metabolic exercise test data combined with Cardiac And Kidney Indexes (MECKI) score and prognosis in heart failure. A validation study. AB - BACKGROUND: The Metabolic Exercise test data combined with Cardiac and Kidney Indexes (MECKI) score is a prognostic model to identify heart failure (HF) patients at risk for cardiovascular mortality (CVM) and urgent heart transplantation (uHT) based on 6 routine clinical parameters: hemoglobin, sodium, kidney function by the Modification of Diet in Renal Disease (MDRD) equation, left ventricle ejection fraction (LVEF), percentage of predicted peak oxygen consumption (VO2) and VE/VCO2 slope. OBJECTIVES: MECKI score must be generalizable to be considered useful: therefore, its performance was validated in a new sequence of HF patients. METHODS: Both the development (MECKI-D) and the validation (MECKI-V) cohorts were composed of consecutive HF patients with LVEF <40% able to perform a symptom-limited cardiopulmonary exercise testing. The CVM or uHT rates were analyzed at one, two and three years in both cohorts: all patients with a censoring time shorter than the scheduled follow-up were excluded, while those with events occurring after 1, 2 and 3 years were considered as censored. RESULTS: MECKI-D and MECKI-V consisted of 2009 and 992 patients, respectively. MECKI-V patients had a higher LVEF, higher peak VO2 and lower VE/VCO2 slope, higher prescription of beta-blockers and device therapy: after the 3-year follow-up, CVM or uHT occurred in 206 (18%) MECKI-D and 44 (13%) MECKI-V patients (p<0.000), respectively. MECKI-V AUC values at one, two and three years were 0.81 +/- 0.04, 0.76 +/- 0.04, and 0.80 +/- 0.03, respectively, not significantly different from MECKI-D. CONCLUSIONS: MECKI score preserves its predictive ability in a HF population at a lower risk. PMID- 26638059 TI - We're All in this Bus Together. PMID- 26638061 TI - A New Golden Age of Natural Products Drug Discovery. AB - The 2015 Nobel Prize in Physiology or Medicine has been awarded to William C. Campbell, Satoshi Omura, and Youyou Tu for the discovery of avermectins and artemisinin, respectively, therapies that revolutionized the treatment of devastating parasite diseases. With the recent technological advances, a New Golden Age of natural products drug discovery is dawning. PMID- 26638062 TI - Celebrating DNA's Repair Crew. AB - This year, the Nobel Prize in Chemistry has been awarded to Tomas Lindahl, Aziz Sancar, and Paul Modrich for their seminal studies of the mechanisms by which cells from bacteria to man repair DNA damage that is generated by normal cellular metabolism and stress from the environment. These studies beautifully illustrate the remarkable power of DNA repair to influence life from evolution through disease susceptibility. PMID- 26638064 TI - Driving the Early Auditory Network the Old-Fashioned Way. AB - Spontaneous neuronal activity during the development of the auditory sensory system is important in establishing mature connectivity. Wang et al. show that glia-like cells drive spontaneous spiking in neighboring cochlear inner hair cells via a process that involves osmotic cell shrinkage and the secretion of potassium ions. PMID- 26638065 TI - A Metabolic Switch for Th17 Pathogenicity. AB - T helper 17 (Th17) cells are critical for host defense but can also drive autoimmunity. This divergent behavior is explored by Gaublomme et al. and Wang et al., who identify inflammation-associated genes by measuring gene expression in nearly 1,000 individual Th17 cells and show that CD5L affects the expression of pro-inflammatory genes by altering lipid synthesis. PMID- 26638066 TI - Interleukin-18: The Bouncer at the Mucosal Bar. AB - The fidelity of the intestinal barrier is critical to maintaining a healthy relationship between the immune system and the microbiota. Levy et al. and Nowarski et al. reveal how microbiota-derived metabolites modulate the activation of the inflammasome to influence the expression of the cytokine IL-18, intestinal barrier function, and intestinal inflammation. PMID- 26638067 TI - Genome Sequencing Fishes out Longevity Genes. AB - Understanding the molecular basis underlying aging is critical if we are to fully understand how and why we age-and possibly how to delay the aging process. Up until now, most longevity pathways were discovered in invertebrates because of their short lifespans and availability of genetic tools. Now, Reichwald et al. and Valenzano et al. independently provide a reference genome for the short-lived African turquoise killifish, establishing its role as a vertebrate system for aging research. PMID- 26638068 TI - Microscopy-Based High-Content Screening. AB - Image-based screening is used to measure a variety of phenotypes in cells and whole organisms. Combined with perturbations such as RNA interference, small molecules, and mutations, such screens are a powerful method for gaining systematic insights into biological processes. Screens have been applied to study diverse processes, such as protein-localization changes, cancer cell vulnerabilities, and complex organismal phenotypes. Recently, advances in imaging and image-analysis methodologies have accelerated large-scale perturbation screens. Here, we describe the state of the art for image-based screening experiments and delineate experimental approaches and image-analysis approaches as well as discussing challenges and future directions, including leveraging CRISPR/Cas9-mediated genome engineering. PMID- 26638069 TI - From Hype to Hope: The Gut Microbiota in Enteric Infectious Disease. AB - One of the clearest functions of the gut microbiota in humans is resistance to colonization by enteric bacterial pathogens. Reconstitution of the microbiota offers an exciting therapeutic approach, but great challenges must be overcome. PMID- 26638070 TI - Gut Microbiota Orchestrates Energy Homeostasis during Cold. AB - Microbial functions in the host physiology are a result of the microbiota-host co evolution. We show that cold exposure leads to marked shift of the microbiota composition, referred to as cold microbiota. Transplantation of the cold microbiota to germ-free mice is sufficient to increase insulin sensitivity of the host and enable tolerance to cold partly by promoting the white fat browning, leading to increased energy expenditure and fat loss. During prolonged cold, however, the body weight loss is attenuated, caused by adaptive mechanisms maximizing caloric uptake and increasing intestinal, villi, and microvilli lengths. This increased absorptive surface is transferable with the cold microbiota, leading to altered intestinal gene expression promoting tissue remodeling and suppression of apoptosis-the effect diminished by co-transplanting the most cold-downregulated strain Akkermansia muciniphila during the cold microbiota transfer. Our results demonstrate the microbiota as a key factor orchestrating the overall energy homeostasis during increased demand. PMID- 26638071 TI - Redox Signaling by the RNA Polymerase III TFIIB-Related Factor Brf2. AB - TFIIB-related factor 2 (Brf2) is a member of the family of TFIIB-like core transcription factors. Brf2 recruits RNA polymerase (Pol) III to type III gene external promoters, including the U6 spliceosomal RNA and selenocysteine tRNA genes. Found only in vertebrates, Brf2 has been linked to tumorigenesis but the underlying mechanisms remain elusive. We have solved crystal structures of a human Brf2-TBP complex bound to natural promoters, obtaining a detailed view of the molecular interactions occurring at Brf2-dependent Pol III promoters and highlighting the general structural and functional conservation of human Pol II and Pol III pre-initiation complexes. Surprisingly, our structural and functional studies unravel a Brf2 redox-sensing module capable of specifically regulating Pol III transcriptional output in living cells. Furthermore, we establish Brf2 as a central redox-sensing transcription factor involved in the oxidative stress pathway and provide a mechanistic model for Brf2 genetic activation in lung and breast cancer. PMID- 26638072 TI - Microbiota-Modulated Metabolites Shape the Intestinal Microenvironment by Regulating NLRP6 Inflammasome Signaling. AB - Host-microbiome co-evolution drives homeostasis and disease susceptibility, yet regulatory principles governing the integrated intestinal host-commensal microenvironment remain obscure. While inflammasome signaling participates in these interactions, its activators and microbiome-modulating mechanisms are unknown. Here, we demonstrate that the microbiota-associated metabolites taurine, histamine, and spermine shape the host-microbiome interface by co-modulating NLRP6 inflammasome signaling, epithelial IL-18 secretion, and downstream anti microbial peptide (AMP) profiles. Distortion of this balanced AMP landscape by inflammasome deficiency drives dysbiosis development. Upon fecal transfer, colitis-inducing microbiota hijacks this microenvironment-orchestrating machinery through metabolite-mediated inflammasome suppression, leading to distorted AMP balance favoring its preferential colonization. Restoration of the metabolite inflammasome-AMP axis reinstates a normal microbiota and ameliorates colitis. Together, we identify microbial modulators of the NLRP6 inflammasome and highlight mechanisms by which microbiome-host interactions cooperatively drive microbial community stability through metabolite-mediated innate immune modulation. Therefore, targeted "postbiotic" metabolomic intervention may restore a normal microenvironment as treatment or prevention of dysbiosis-driven diseases. PMID- 26638073 TI - Epithelial IL-18 Equilibrium Controls Barrier Function in Colitis. AB - The intestinal mucosal barrier controlling the resident microbiome is dependent on a protective mucus layer generated by goblet cells, impairment of which is a hallmark of the inflammatory bowel disease, ulcerative colitis. Here, we show that IL-18 is critical in driving the pathologic breakdown of barrier integrity in a model of colitis. Deletion of Il18 or its receptor Il18r1 in intestinal epithelial cells (Delta/EC) conferred protection from colitis and mucosal damage in mice. In contrast, deletion of the IL-18 negative regulator Il18bp resulted in severe colitis associated with loss of mature goblet cells. Colitis and goblet cell loss were rescued in Il18bp(-/-);Il18r(Delta/EC) mice, demonstrating that colitis severity is controlled at the level of IL-18 signaling in intestinal epithelial cells. IL-18 inhibited goblet cell maturation by regulating the transcriptional program instructing goblet cell development. These results inform on the mechanism of goblet cell dysfunction that underlies the pathology of ulcerative colitis. PMID- 26638074 TI - Amyloidogenic Oligomerization Transforms Drosophila Orb2 from a Translation Repressor to an Activator. AB - Memories are thought to be formed in response to transient experiences, in part through changes in local protein synthesis at synapses. In Drosophila, the amyloidogenic (prion-like) state of the RNA binding protein Orb2 has been implicated in long-term memory, but how conformational conversion of Orb2 promotes memory formation is unclear. Combining in vitro and in vivo studies, we find that the monomeric form of Orb2 represses translation and removes mRNA poly(A) tails, while the oligomeric form enhances translation and elongates the poly(A) tails and imparts its translational state to the monomer. The CG13928 protein, which binds only to monomeric Orb2, promotes deadenylation, whereas the putative poly(A) binding protein CG4612 promotes oligomeric Orb2-dependent translation. Our data support a model in which monomeric Orb2 keeps target mRNA in a translationally dormant state and experience-dependent conversion to the amyloidogenic state activates translation, resulting in persistent alteration of synaptic activity and stabilization of memory. PMID- 26638075 TI - A Dynamic Protein Interaction Landscape of the Human Centrosome-Cilium Interface. AB - The centrosome is the primary microtubule organizing center of the cells and templates the formation of cilia, thereby operating at a nexus of critical cellular functions. Here, we use proximity-dependent biotinylation (BioID) to map the centrosome-cilium interface; with 58 bait proteins we generate a protein topology network comprising >7,000 interactions. Analysis of interaction profiles coupled with high resolution phenotypic profiling implicates a number of protein modules in centriole duplication, ciliogenesis, and centriolar satellite biogenesis and highlights extensive interplay between these processes. By monitoring dynamic changes in the centrosome-cilium protein interaction landscape during ciliogenesis, we also identify satellite proteins that support cilia formation. Systematic profiling of proximity interactions combined with functional analysis thus provides a rich resource for better understanding human centrosome and cilia biology. Similar strategies may be applied to other complex biological structures or pathways. PMID- 26638076 TI - Simple, Scalable Proteomic Imaging for High-Dimensional Profiling of Intact Systems. AB - Combined measurement of diverse molecular and anatomical traits that span multiple levels remains a major challenge in biology. Here, we introduce a simple method that enables proteomic imaging for scalable, integrated, high-dimensional phenotyping of both animal tissues and human clinical samples. This method, termed SWITCH, uniformly secures tissue architecture, native biomolecules, and antigenicity across an entire system by synchronizing the tissue preservation reaction. The heat- and chemical-resistant nature of the resulting framework permits multiple rounds (>20) of relabeling. We have performed 22 rounds of labeling of a single tissue with precise co-registration of multiple datasets. Furthermore, SWITCH synchronizes labeling reactions to improve probe penetration depth and uniformity of staining. With SWITCH, we performed combinatorial protein expression profiling of the human cortex and also interrogated the geometric structure of the fiber pathways in mouse brains. Such integrated high-dimensional information may accelerate our understanding of biological systems at multiple levels. PMID- 26638077 TI - Insights into Sex Chromosome Evolution and Aging from the Genome of a Short-Lived Fish. AB - The killifish Nothobranchius furzeri is the shortest-lived vertebrate that can be bred in the laboratory. Its rapid growth, early sexual maturation, fast aging, and arrested embryonic development (diapause) make it an attractive model organism in biomedical research. Here, we report a draft sequence of its genome that allowed us to uncover an intra-species Y chromosome polymorphism representing-in real time-different stages of sex chromosome formation that display features of early mammalian XY evolution "in action." Our data suggest that gdf6Y, encoding a TGF-beta family growth factor, is the master sex determining gene in N. furzeri. Moreover, we observed genomic clustering of aging related genes, identified genes under positive selection, and revealed significant similarities of gene expression profiles between diapause and aging, particularly for genes controlling cell cycle and translation. The annotated genome sequence is provided as an online resource (http://www.nothobranchius.info/NFINgb). PMID- 26638079 TI - SnapShot: Renal Cell Carcinoma. AB - This SnapShot summarizes current knowledge about the key features in mutational landscape, major pathways, and tumor evolution and heterogeneity in renal cell carcinoma, as well as the most recent advances in therapeutic development. To view this SnapShot, open or download the PDF. PMID- 26638078 TI - The African Turquoise Killifish Genome Provides Insights into Evolution and Genetic Architecture of Lifespan. AB - Lifespan is a remarkably diverse trait ranging from a few days to several hundred years in nature, but the mechanisms underlying the evolution of lifespan differences remain elusive. Here we de novo assemble a reference genome for the naturally short-lived African turquoise killifish, providing a unique resource for comparative and experimental genomics. The identification of genes under positive selection in this fish reveals potential candidates to explain its compressed lifespan. Several aging genes are under positive selection in this short-lived fish and long-lived species, raising the intriguing possibility that the same gene could underlie evolution of both compressed and extended lifespans. Comparative genomics and linkage analysis identify candidate genes associated with lifespan differences between various turquoise killifish strains. Remarkably, these genes are clustered on the sex chromosome, suggesting that short lifespan might have co-evolved with sex determination. Our study provides insights into the evolutionary forces that shape lifespan in nature. PMID- 26638080 TI - Emotional intelligence as a crucial component to medical education. AB - OBJECTIVE: The primary focus of this review was to discover what is already known about Emotional Intelligence (EI) and the role it plays within social relationships, as well as its importance in the fields of health care and health care education. This article analyzes the importance of EI in the field of health care and recommends various ways that this important skill can be built into medical programs. METHODS: Information was gathered using various database searches including EBSCOHOST, Academic Search Premier and ERIC. The search was conducted in English language journals from the last ten years. Descriptors include: Emotional Intelligence, medical students and communication skills, graduate medical education, Emotional Intelligence and graduate medical education, Emotional Intelligence training programs, program evaluation and development. RESULTS: Results of the study show a direct correlation between medical education and emotional intelligence competencies, which makes the field of medical education an ideal one in which to integrate further EI training. CONCLUSIONS: The definition of EI as an ability-based skill allows for training in specific competencies that can be directly applied to a specialized field. When EI is conceptualized as an ability that can be taught, learned, and changed, it may be used to address the specific aspects of the clinician-patient relationship that are not working well. For this reason, teaching EI should be a priority in the field of medical education in order to better facilitate this relationship in the future. PMID- 26638081 TI - Evaluation of host Hsp(s) as potential biomarkers for the diagnosis of tuberculous meningitis. AB - OBJECTIVES: Diagnosis of tuberculosis meningitis (TBM) remains challenging in tuberculosis (TB) endemic countries. The need for TB biomarkers arises, in part, from the difficulty of accurately diagnosing TBM with the available methods. PATIENTS AND METHODS: To explore the potential of host Hsps (Hsp 25, Hsp 60, Hsp 70 and Hsp 90) as an alternative marker in TBM diagnosis, we evaluated cerebrospinal fluid (CSF) sample of TBM (n=49), Pyogenic Meningitis (PM) (n=20), Viral Meningitis (VM) (n=09), Fungal Meningitis (FM) (n=04) and non infectious control (n=79) patients using indirect ELISA. RESULTS: Out of four Hsps, Hsp 70 and Hsp 90 yields 89% & 88% sensitivity and 82% & 89% specificity, respectively. The positive (PPV) and negative (NPV) predictive values yielded in TBM group for Hsp 70 was 86.27% (73.74-94.27) and 93.51% (85.48-97.83), respectively. For Hsp 90 the obtained PPV was 89.36% (76.88-96.41) and NPV was 91.36% (82.99-96.44). In 86% of TBM patients all the four Hsps were found to be positive and none of the patient was found to be negative for all Hsps in the same group. CONCLUSIONS: The data presented in the study indicate that host Hsp 70 and Hsp 90 shows good sensitivity and specificity and have potential in the diagnosis of TBM disease. The combined use of all Hsps (Hsp 25, Hsp 60, Hsp 70 and Hsp 90) effectively distinguishes patients with TBM from other disease controls. PMID- 26638082 TI - The Arabidopsis thaliana K(+)-uptake permease 7 (AtKUP7) contains a functional cytosolic adenylate cyclase catalytic centre. AB - Adenylate cyclases (ACs) catalyse the formation of the second messenger cyclic adenosine 3',5'-monophosphate (cAMP) from adenosine 5'-triphosphate (ATP). Although cAMP is increasingly recognised as an important signalling molecule in higher plants, ACs have remained somewhat elusive. Here we used a search motif derived from experimentally tested guanylyl cyclases (GCs), substituted the residues essential for substrate specificity and identified the Arabidopsis thaliana K(+)-uptake permease 7 (AtKUP7) as one of several candidate ACs. Firstly, we show that a recombinant N-terminal, cytosolic domain of AtKUP7(1-100) is able to complement the AC-deficient mutant cyaA in Escherichia coli and thus restoring the fermentation of lactose, and secondly, we demonstrate with both enzyme immunoassays and mass spectrometry that a recombinant AtKUP7(1-100) generates cAMP in vitro. PMID- 26638111 TI - Reply. PMID- 26638110 TI - Clear cell hepatocellular carcinoma diagnosed by bile duct brushing cytology. AB - Clear cell hepatocellular carcinoma (CCHCC) is an uncommon morphologic variant of HCC and rarely invades into the main bile ducts. Here we describe a case of CCHCC that was diagnosed by bile duct brushing cytology. Liquid-based preparation of brushing specimen showed clusters of atypical epithelial cells with abundant clear cytoplasm, round nuclei, and occasional intranuclear inclusions. The tumor cells were positive for HepPar-1 and arginase 1, suggestive of their hepatic origin. The overall morphologic and immunophenotypic features were consistent with CCHCC. The cytological diagnosis was confirmed by histopathologic examination of the resected tumor. PMID- 26638112 TI - Lack of NG2 exacerbates neurological outcome and modulates glial responses after traumatic brain injury. AB - Traumatic brain injury (TBI) is a major cause of death and disability. The underlying pathophysiology is characterized by secondary processes including neuronal death and gliosis. To elucidate the role of the NG2 proteoglycan we investigated the response of NG2-knockout mice (NG2-KO) to TBI. Seven days after TBI behavioral analysis, brain damage volumetry and assessment of blood brain barrier integrity demonstrated an exacerbated response of NG2-KO compared to wild type (WT) mice. Reactive astrocytes and expression of the reactive astrocyte and neurotoxicity marker Lcn2 (Lipocalin-2) were increased in the perilesional brain tissue of NG2-KO mice. In addition, microglia/macrophages with activated morphology were increased in number and mRNA expression of the M2 marker Arg1 (Arginase 1) was enhanced in NG2-KO mice. While TBI-induced expression of pro inflammatory cytokine genes was unchanged between genotypes, PCR array screening revealed a marked TBI-induced up-regulation of the C-X-C motif chemokine 13 gene Cxcl13 in NG2-KO mice. CXCL13, known to attract immune cells to the inflamed brain, was expressed by activated perilesional microglia/macrophages seven days after TBI. Thirty days after TBI, NG2-KO mice still exhibited more pronounced neurological deficits than WT mice, up-regulation of Cxcl13, enhanced CD45+ leukocyte infiltration and a relative increase of activated Iba-1+/CD45+ microglia/macrophages. Our study demonstrates that lack of NG2 exacerbates the neurological outcome after TBI and associates with abnormal activation of astrocytes, microglia/macrophages and increased leukocyte recruitment to the injured brain. These findings suggest that NG2 may counteract neurological deficits and adverse glial responses in TBI. PMID- 26638113 TI - Preparation of silk fibroin carriers for controlled release. AB - Silk fibroin provides a new option for controlled release systems as a result of its excellent biodegradability, biocompatibility, and mechanical properties. As the core material, silk fibroin can be designed and widely used in drug/gene delivery, regenerative medicine, and other biomedical fields. This review focuses on the preparation methods, loading molecules, and applications of silk fibroin based controlled release systems including microspheres, microcapsules, films, microparticles, microneedles, liposomes, and hydrogels. These systems provide numerous advantages such as high encapsulation efficiency, avoiding loss of bioactivity and maintaining desirable range without peaks and valleys in comparison to the traditional administration approaches. Microsc. Res. Tech. 80:312-320, 2017. (c) 2015 Wiley Periodicals, Inc. PMID- 26638114 TI - Protein source in a high-protein diet modulates reductions in insulin resistance and hepatic steatosis in fa/fa Zucker rats. AB - OBJECTIVE: High-protein diets are being promoted to reduce insulin resistance and hepatic steatosis in metabolic syndrome. Therefore, the effect of protein source in high-protein diets on reducing insulin resistance and hepatic steatosis was examined. METHODS: Fa/fa Zucker rats were provided normal-protein (15% of energy) casein, high-protein (35% of energy) casein, high-protein soy, or high-protein mixed diets with animal and plant proteins. RESULTS: The high-protein mixed diet reduced area under the curve for insulin during glucose tolerance testing, fasting serum insulin and free fatty acid concentrations, homeostatic model assessment index, insulin to glucose ratio, and pancreatic islet cell area. The high-protein mixed and the high-protein soy diets reduced hepatic lipid concentrations, liver to body weight ratio, and hepatic steatosis rating. These improvements were observed despite no differences in body weight, feed intake, or adiposity among high-protein diet groups. The high-protein casein diet had minimal benefits. CONCLUSIONS: A high-protein mixed diet was the most effective for modulating reductions in insulin resistance and hepatic steatosis independent of weight loss, indicating that the source of protein within a high-protein diet is critical for the management of these metabolic syndrome parameters. PMID- 26638115 TI - Wnt signaling in the heart fields: Variations on a common theme. AB - Wnt signaling plays an essential role in development and differentiation. Heart development is initiated with the induction of precardiac mesoderm requiring the tightly and spatially controlled regulation of canonical and noncanonical Wnt signaling pathways. The role of Wnt signaling in subsequent development of the heart fields is to a large extent unclear. We will discuss the role of Wnt signaling in the development of the arterial and venous pole of the heart, highlighting the dual roles of Wnt signaling with respect to its time- and dosage dependent effects and the balance between the canonical and noncanonical signaling. Canonical signaling appears to be involved in retaining the cardiac precursors in a proliferative and precursor state, whereas noncanonical signaling promotes their differentiation. Thereafter, both canonical and noncanonical signaling regulate specific steps in differentiation of the cardiac compartments. Because heart development is a contiguous, rather than a sequential, process, analyses tend only to show a single timeframe of development. The repetitive alternating and reciprocal effect of canonical and noncanonical signaling is lost when studied in homogenates. Without the simultaneous in vivo visualization of the different Wnt signaling pathways, the mechanism of Wnt signaling in heart development remains elusive. PMID- 26638116 TI - Long-term health-related quality of life in bariatric surgery patients: A systematic review and meta-analysis. AB - OBJECTIVE: Bariatric surgery results in significant weight loss in the majority of patients. Improvement in health-related quality of life (HRQoL) is an equally important outcome; however, there are few studies reporting long-term (>=5 years) HRQoL outcomes. This study assesses the quality of evidence and effectiveness of surgery on HRQoL >= 5 years. METHODS: PubMed, Cochrane Review, EmBase, CINANL, PsycInfo, obesity conference abstracts, and reference lists were searched. Keywords were bariatric surgery, obesity, and quality of life. Studies were included if (1) there was >=5 years follow-up, (2) patients had class II or III obesity, (3) individuals completed a validated HRQoL survey, and (4) there was a nonsurgical comparison group with obesity. Two reviewers independently assessed each study. RESULTS: From 1376 articles, 9 studies were included in the systematic review (SR) and 6 in the meta-analysis (MA). Inconsistent results for long-term improvements in physical and mental health emerged from the SR. In contrast, the MA found significant improvements in these domains >=5 years after surgery. CONCLUSIONS: Study findings provide evidence for a substantial and significant improvement in physical and mental health favoring the surgical group compared with controls spanning 5 to 25 years after surgery. PMID- 26638117 TI - Glenohumeral joint reaction forces increase with critical shoulder angles representative of osteoarthritis-A biomechanical analysis. AB - Osteoarthritis (OA) of the glenohumeral joint constitutes the most frequent indication for nontraumatic shoulder joint replacement. Recently, a small critical shoulder angle (CSA) was found to be associated with a high prevalence of OA. This study aims to verify the hypothesis that a small CSA leads to higher glenohumeral joint reaction forces during activities of daily living than a normal CSA. A shoulder simulator with simulated deltoid (DLT), supraspinatus (SSP), infraspinatus/teres minor (ISP/TM), and subscapularis (SSC) musculotendinous units was constructed. The DLT wrapping on the humerus was simulated using a pulley that could be horizontally adjusted to simulate the 28 degrees CSA found in OA or the 33 degrees CSA found in disease-free shoulders. Over a range of motion between 6 degrees and 82 degrees of thoracohumeral abduction joint forces were measured using a six-axis load cell. An OA-associated CSA yielded higher net joint reaction forces than a normal CSA over the entire range of motion. The maximum difference of 26.4 N (8.5%) was found at 55 degrees of thoracohumeral abduction. Our model thus suggests that a CSA typical for OA predisposes the glenohumeral joint to higher joint reaction forces and could plausibly play a role in joint overloading and development of OA. (c) 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1047-1052, 2016. PMID- 26638118 TI - IGF1 and adipose tissue homeostasis. PMID- 26638119 TI - Memantine for Prophylactic Treatment of Migraine Without Aura: A Randomized Double-Blind Placebo-Controlled Study. AB - BACKGROUND: Uncontrolled studies in human have suggested that memantine might be a suitable option for migraine prophylaxis. OBJECTIVE: To assess the efficacy and tolerability of memantine for migraine prophylaxis. METHODS: This was a 12-week randomized double-blind placebo-controlled parallel-group study. Sixty patients with migraine without aura were randomized using a computer-generated list to receive memantine (10 mg/day) or placebo for 12 weeks. The primary outcome was the difference in change from baseline in the monthly attack frequency at week 12 between the two groups (using migraine diary). Secondary efficacy measures were assessed using several clinical, functional, and psychological instruments. We performed both complete case (CC) and intention-to-treat analyses (ITT). RESULTS: Twenty-five patients in the memantine group and 27 patients in the placebo group completed the study. Patients in the memantine group showed significantly greater reduction (mean change; 3.4; 95%CI, 2.3-4.4) in the monthly attack frequency than the placebo group (mean change, 1.0; 95%CI, 0.3-1.7) (mean difference [MD], 2.3; 95%CI, 1.1-3.5, P < .001). Both CC (MD, 4.9; 95%CI, 2.6-7.2 days), and ITT analyses (MD, 5.2; 95%CI, 2.0-8.5) showed significantly higher reduction in the mean number of migraine days in the memantine group than the placebo group (P < .01). Patients in the memantine group experienced greater reduction in the number of work absence days, severity, and disability score than the patients in the placebo group in both ITT and CC analyses. Changes in quality of life, sleep, depression, and anxiety did not differ between the two groups. Three patients in the memantine group complained of sedation, mild vertigo and nausea, and drowsiness. In the placebo group, one patient complained of nausea and another patient discontinued treatment after 2 weeks due to vertigo. CONCLUSION: Memantine might be a tolerable and efficacious option for prophylaxis in patients with migraine without aura. Tolerability, short duration required for titration, and safety profile in pregnancy might give memantine an advantage over other antimigraine medications. The study was registered in the Iranian Registry of Clinical Trials (Registration number: IRCT2013120115616N1). PMID- 26638121 TI - Purification of a thermostable antinociceptive lectin isolated from Andira anthelmia. AB - Andira anthelmia (tribe Dalbergieae), a plant from Brazilian Amazon, possesses a seed lectin that was purified by affinity chromatography in sepharose-mannose. This novel Dalbergieae lectin, named AAL, agglutinated rabbit erythrocytes treated with trypsin. The hemagglutinating activity of AAL was maintained after incubation at a wide range of temperature (40 to 70 degrees C) and pH, was shown to be dependent on divalent cations, and was inhibited by d-mannose and d sucrose. AAL showed an electrophoretic profile in sodium dodecyl sulfate polyacrylamide gel electrophoresis similar to other lectins of the tribe Dalbergieae, presenting a double band of molecular weight with approximately 20 kDa and other minor bands of 17, 15, and 13 kDa, being the smaller fragment glycosylated. AAL injected by intravenous route in mice showed antinociceptive activity in two behavioral tests (writhing and formalin). In the writhing test induced by acetic acid, AAL showed inhibitory effect at 0.01 mg/kg (68%), 0.1 mg/kg (46%) and 1 mg/kg (74%). In the formalin test, AAL (0.1 mg/kg) inhibited by 48% the licking time in the inflammatory phase, an effect that was recovered by the lectin association with mannose. In conclusion, AAL presents analgesic effect involving the lectin domain via peripheral mechanisms of inflammatory nociception. This activity highlights the importance of lectins as tools to be used for understanding the interaction of protein-carbohydrate in processes associated to inflammatory pain. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26638120 TI - Retinoid regulation of antiviral innate immunity in hepatocytes. AB - Persistent infection of hepatitis C virus (HCV) is one of the leading causes of end-stage liver disease (ESLD), such as decompensated cirrhosis and liver cancer. Of particular note, nearly half of HCV-infected people in the United States are reported to be heavy drinkers. This particular group of patients is known to rapidly progress to the ESLD. Although accelerated disease progression among alcohol abusers infected with HCV is clinically well recognized, the molecular pathophysiology behind this manifestation has not been well elucidated. Hepatocytes metabolize ethanol (EtOH) primarily through two steps of oxidative catabolism in which alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) play central roles. The ADH-ALDH pathway also governs the metabolism of retinol (vitamin A) to its transcriptionally active metabolite, retinoic acid (RA). In this study, we defined that the ADH-ALDH pathway serves as a potent antiviral host factor in hepatocytes, which regulates the expression of interferon (IFN) stimulated genes (ISGs) by biogenesis of RA. ISGs constitute over 300 antiviral effectors, which cooperatively govern intracellular antiviral innate immunity. Our study revealed that intracellular RA levels greatly influence ISG expression under basal conditions. Moreover, RA augments ISG induction in response to viral infection or exposure to IFN in a gene-specific manner. Lastly, our results demonstrated that EtOH attenuates the antiviral function of the ADH-ALDH pathway, which suggests the possibility that EtOH-retinol metabolic competition is one of the molecular mechanisms for the synergism between HCV and alcohol abuse in liver disease progression. CONCLUSIONS: RA plays a critical role in the regulation of intracellular antiviral innate immunity in hepatocytes. (Hepatology 2016;63:1783 1795). PMID- 26638122 TI - On the autofluorescence of aged fingermarks. AB - Fingermark autofluorescence changes with time, both spectrally and in total intensity. In this study we investigate which components in the aged fingermarks cause this change in autofluorescent signal. Thin layer chromatography combined with fluorescence spectroscopy was used to identify fluorescent aging products. Based on our results, tryptophan derivatives, including indoleacetic acid, (nor)harman and xanthurenic acid are indicated as important contributors to the autofluorescence of aged fingermarks. Knowledge about which fluorescent aging products are present in fingermarks might be useful in the development of fingermark age estimation methods. This work is part of a larger project of which the major goal is to develop a method to estimate the time of deposition of fingermarks. Additionally, by selective targeting of aging products the development of aged fingermarks might be improved. PMID- 26638123 TI - Associations between obesity and cognition in the pre-school years. AB - OBJECTIVE: To test the hypothesis that obesity is associated with impaired cognitive outcomes in the pre-school years. METHODS: Associations were examined between weight status at age 3-5 years and cognitive performance at age 5 years. Cognitive outcome measures were tests of pattern construction (visuospatial skills), naming vocabulary (expressive language skills), and picture similarity (reasoning skills). The sample was the UK Millennium Cohort Study (n = 12,349 participants). RESULTS: Boys with obesity at 3 years had significantly lower performance in pattern construction at age 5 years compared to those of a healthy weight, even after controlling for confounders (beta = -0.029, P = 0.03). Controlling for confounders, boys who developed obesity between the ages of 3 and 5 years had lower scores in pattern construction (beta = -0.03, P = 0.03). "Growing out" of obesity had a positive association with picture similarity performance in girls (beta = 0.03, P = 0.04). CONCLUSIONS: Obesity in the pre school years was associated with poorer outcomes for some cognitive measures in this study. Stronger relationships between obesity and cognition or educational attainment may emerge later in childhood. PMID- 26638124 TI - Effects of a Novel Peritoneal Dialysis: The Open Versus Laparoscopic Preperitoneal Tunneling Technique. AB - The key to achieving adequate continuous ambulatory peritoneal dialysis (CAPD) is that a functioning catheter should enable unrestricted inflow and outflow of the dialysate liquid from the peritoneal cavity with an intact peritoneal membrane. Despite its advantages, complications, such as outflow obstruction, catheter related infection, and dialysate leakage are still problematic. Various laparoscopic techniques for catheter placement have been investigated. The main purpose of this study was to compare the laparoscopic and open surgical peritoneal dialysis (PD) catheter insertion techniques in a retrospective manner according to catheter survival, complications and the safety of both techniques. The study included end stage renal disease patients in our hospital in whom a PD catheter was placed between 2007 and 2014. Patients were divided into two groups: the open technique (OT) group and the laparoscopic preperitoneal tunneling approach (LA) group. Extracted data included patient demographics, operative data, catheter-related complications and follow-up data. Sixty-nine patients were enrolled into the study. CAPD catheters were placed into 35 patients via LA and 34 via OT. We found that the LA group patients had better survival rates compared with the OT group, especially the long-term survivals. All of the CAPD-related complications, (peritonitis, malposition, outflow obstruction, leakage) were lower in the LA group. However, the peritonitis, malposition and groin hernia rates were also statistically significantly lower in the LA group. When compared with the published data, we recommend laparoscopic CAPD catheter placement with a preperitoneal tunneling technique. The technique is safe and offers a better outcome. PMID- 26638125 TI - Kite Shield-Shaped Wedge Recession for Treatment of Medial Patellar Luxation in Seven Small-Breed Dogs. AB - OBJECTIVE: To document the trochlear depth (TD) and clinical outcome after kite shield-shaped wedge (K-wedge) recession trochleoplasty in toy-breed dogs with medial patellar luxation (MPL). STUDY DESIGN: Case series. ANIMALS: Seven toy breed dogs (<5 kg) with uni- or bilateral grades II-IV MPL (10 stifles). METHODS: A K-wedge recession trochleoplasty was performed in all dogs in combination with other surgical procedures as treatment for MPL. The TD, the ratio of the proximal TD to patella thickness, and the presence of osteophytes were determined from computed tomography images taken pre-, and 1 and 12 months postoperative. Lameness scores and MPL grade were also recorded. RESULTS: The TD and the ratio of proximal TD to patella thickness increased significantly immediately postoperative and remained increased at 1 and 12 months postoperative. The osteophyte score was significantly higher at 12 months postoperative than preoperative. All dogs had a reduction in MPL grade and improvement in lameness postoperative. CONCLUSION: K-wedge recession trochleoplasty was successful in treating MPL in a series of toy-breed dogs and offers an alternate to other trochlear recession techniques. PMID- 26638126 TI - Financial incentives to promote extended smoking abstinence in opioid-maintained patients: a randomized trial. AB - BACKGROUND AND AIMS: Prior studies by our group demonstrated the efficacy of a brief but intensive behavioral intervention for producing initial smoking abstinence among opioid-dependent patients. In the present study, our aim was to promote longer-duration abstinence in this population. Following an initial 2 week incentive intervention for smoking abstinence, we examined whether a 10-week maintenance arm involving continuation of contingent reinforcement will produce greater smoking abstinence than a similar duration of noncontingent reinforcement. DESIGN: Randomized, 12-week, parallel-group study. SETTING: Out patient research clinic in Burlington, Vermont, USA. PARTICIPANTS: Opioid maintained smokers (n = 88) who provided breath carbon monoxide and urinary cotinine specimens and received contingent reinforcement for smoking abstinence during weeks 1-2 (phase 1), with 63 randomized on day 14 to an extended contingent (EC; n = 31) or extended noncontingent (EN; n = 32) experimental condition for weeks 3-12 (phase 2). INTERVENTION AND CONTROL: The EC condition consisted of voucher values that escalated across consecutive negative samples until they reached $30, after which they remained at $30 per negative sample. A positive or a missing sample resulted in no vouchers for that day and reset the value of the next negative same to $9. Two consecutive negatives returned the schedule to the pre-reset value. The EN control condition consisted of vouchers delivered for providing scheduled samples, but independent of smoking status. MEASUREMENTS: The primary outcome was percentage of biochemically abstinent samples during phase 2. Secondary measures included abstinence status at final study visit, complete abstinence, participants' longest duration of continuous abstinence, cotinine and carbon monoxide (CO) levels and self-reported cigarettes per day. FINDINGS: EC participants achieved greater smoking abstinence during phase 2 than EN participants [46.7 versus 23.5% negative samples, respectively; odds ratio (OR) = 2.98, 95% confidence interval (CI) = 1.16-7.65, chi(2) 1 (=) 5.0, P = 0.02]. When longest duration of continuous abstinence was compared between experimental groups, EC participants achieved twice the mean duration of continuous abstinence compared with EN participants (3.31 versus 1.68 weeks; t61 = 1.83, P = 0.07). An effect of experimental condition was also seen on mean cotinine levels (42.5 versus 210.6 ng/ml, respectively; F1,61 =5.9, P = 0.02). CONCLUSIONS: Among opioid-maintained smokers receiving an initial period of daily contingent incentives, a contingent reinforcement intervention appears to be more effective at extending smoking abstinence than noncontingent reinforcement over 10 weeks. PMID- 26638127 TI - Modulation of IL-27 in adipocytes during inflammatory stress. AB - OBJECTIVE: While it is well established that adipose tissue-derived inflammation plays an important role in the pathogenic mechanisms linking obesity with metabolic dysfunction, the inflammatory mediators involved have not been fully elucidated. Here, we explored IL-12 family cytokines with a focus on IL-27 during obesity-induced inflammation in mice and cultured adipocytes (ADs) following exposure to inflammatory stimuli. METHODS: Relative mRNA abundance of IL-12 cytokines was assessed by reverse transcription polymerase chain reaction (RT PCR) in genetically obese B6-ob/ob mice as well as C57BL/6J mice fed a high-fat diet and in ADs following exposure to inflammatory stimuli. Protein secretion of cytokines into culture media was assessed by ELISA, and the biological outcome of IL-27 stimulation was assessed by RT-PCR and immunoblotting. RESULTS: Heterodimeric subunits constituting IL-27 were significantly induced in obese mice. While all IL-12 genes were markedly induced by inflammatory stress in cultured ADs, IL-27 protein was the only cytokine secreted into culture media in response to inflammatory stress. Cultured ADs also responded to IL-27 stimulation with divergent outcomes that were dependent on the inflammatory milieu of target cells. CONCLUSIONS: These findings support the premise of autocrine/paracrine mechanisms involving IL-27 in ADs under conditions of inflammatory stress that may link obesity with inflammatory diseases. PMID- 26638128 TI - Sarcopenia is associated with significant liver fibrosis independently of obesity and insulin resistance in nonalcoholic fatty liver disease: Nationwide surveys (KNHANES 2008-2011). AB - Sarcopenia is associated with nonalcoholic fatty liver disease (NAFLD). This study investigated whether sarcopenia is associated with significant liver fibrosis in subjects with NAFLD. Data from the Korean National Health and Nutrition Examination Surveys 2008-2011 database were analyzed. NALFD was defined by NAFLD liver fat score, comprehensive NAFLD score, or hepatic steatosis index. Degree of liver fibrosis was assessed by NAFLD fibrosis score (NFS), FIB-4, and Forns index. Significant liver fibrosis was defined as FIB-4 >=2.67 and the highest quartile values of NFS and Forns index. Sarcopenia index (= total appendicular skeletal muscle mass [kg]/body mass index (kg/m(2) ]) was calculated using dual-energy X-ray absorptiometry. Using the NAFLD liver fat score, NAFLD was identified in 2761 (28.5%) of 9676 subjects. Of subjects with NAFLD, sarcopenia was identified in 337 (12.2%). Sarcopenia was significantly associated with significant liver fibrosis assessed in fibrosis prediction models (all P < 0.05). In subgroups stratified according to body mass index and homeostasis model assessment of insulin resistance, a significant association between sarcopenia and significant liver fibrosis by NFS was consistently present (odds ratio = 1.76 2.68 depending on the subgroup, all P < 0.05). Multivariate logistic regression analysis demonstrated an independent association between SI and significant liver fibrosis by NFS after adjusting for other confounders (odds ratio = 0.52-0.67, all P < 0.01). Other NAFLD (comprehensive NAFLD score, hepatic steatosis index) and fibrosis prediction models (FIB-4 and Forns index) produced similar results. CONCLUSION: Sarcopenia is associated with significant liver fibrosis in subjects with NAFLD, and the association is independent of obesity and insulin resistance. PMID- 26638129 TI - The pathogenicity factor HrpF interacts with HrpA and HrpG to modulate type III secretion system (T3SS) function and t3ss expression in Pseudomonas syringae pv. averrhoi. AB - To ensure the optimal infectivity on contact with host cells, pathogenic Pseudomonas syringae has evolved a complex mechanism to control the expression and construction of the functional type III secretion system (T3SS) that serves as a dominant pathogenicity factor. In this study, we showed that the hrpF gene of P. syringae pv. averrhoi, which is located upstream of hrpG, encodes a T3SS dependent secreted/translocated protein. Mutation of hrpF leads to the loss of bacterial ability on elicitation of disease symptoms in the host and a hypersensitive response in non-host plants, and the secretion or translocation of the tested T3SS substrates into the bacterial milieu or plant cells. Moreover, overexpression of hrpF in the wild-type results in delayed HR and reduced t3ss expression. The results of protein-protein interactions demonstrate that HrpF interacts directly with HrpG and HrpA in vitro and in vivo, and protein stability assays reveal that HrpF assists HrpA stability in the bacterial cytoplasm, which is reduced by a single amino acid substitution at the 67th lysine residue of HrpF with alanine. Taken together, the data presented here suggest that HrpF has two roles in the assembly of a functional T3SS: one by acting as a negative regulator, possibly involved in the HrpSVG regulation circuit via binding to HrpG, and the other by stabilizing HrpA in the bacterial cytoplasm via HrpF-HrpA interaction prior to the secretion and formation of Hrp pilus on the bacterial surface. PMID- 26638131 TI - [Accelerated partial breast irradiation using interstitial multicatheter brachytherapy: A valid treatment option for breast cancer patients with a low risk profile?]. PMID- 26638130 TI - Randomized controlled trial of the effect of regular paracetamol on influenza infection. AB - BACKGROUND AND OBJECTIVE: Anti-pyretic treatment is recommended in the management of influenza infection. In animal models anti-pyretic treatment increases mortality from influenza. We investigated the effects of paracetamol on viral and clinical outcomes in adults with influenza infection. METHODS: This is a randomized, double-blind, placebo-controlled trial of adults aged 18-65 years with influenza-like illness and positive influenza rapid antigen test. Treatments were 1 g paracetamol four times a day, or matching placebo, for 5 days. Pernasal swabs were taken for influenza quantitative RT-PCR at Baseline and Days 1, 2 and 5. Temperature and symptom scores were recorded for 5-14 days or time of resolution respectively. The primary outcome variable was area under the curve (AUC) for quantitative PCR log10 viral load from Baseline to Day 5. RESULTS: A total of 80 participants were randomized: no one was lost to follow up, and one withdrew after 4 days. There were 22 and 24 participants who were influenza PCR positive in placebo and in paracetamol groups respectively. Mean (SD) AUC PCR log10 viral load was 4.40 (0.91) in placebo and 4.64 (0.88) in paracetamol; difference was -0.24, 95% CI: -0.78 to 0.29, P = 0.36. In all participants there were no differences in symptom scores, temperature, time to resolution of illness and health status, with no interaction between randomized treatment and whether influenza was detected by PCR. CONCLUSION: Regular paracetamol had no effect on viral shedding, temperature or clinical symptoms in patients with PCR-confirmed influenza. There remains an insufficient evidence base for paracetamol use in influenza infection. CLINICAL TRIAL REGISTRATION: ACTRN12611000497909 at the Australian New Zealand Clinical Trials Registry. PMID- 26638132 TI - Association of maternal pre-pregnancy weight, weight gain during pregnancy, and smoking with small-for-gestational-age infants in Japan. AB - AIM: The aim of this study was to evaluate the associations of maternal pre pregnancy body mass index (BMI), weight gain during pregnancy, and smoking, with small-for-gestational-age (SGA) births among Japanese women. MATERIALS AND METHODS: Subjects were pregnant women who gave birth to single, term infants (37 42 weeks) at a clinic and hospital in the Nagasaki area between 2012 and 2013. To examine associations with SGA, 49 underweight (BMI<18.5 kg/m(2)) and 579 normal weight (18.5 <= BMI<25.0 kg/m(2)) Japanese women with either appropriate-for gestational-age or SGA infants were selected and analyzed. RESULTS: The prevalence of SGA infants was 6.8%. Seven percent of women were current smokers. Prevalence of pre-pregnancy underweight and gestational weight gain less than recommendation were 20.8% and 16.7%, respectively. Multivariate logistic regression was performed to assess factors affecting SGA infants in the pregnant women. After adjusting for covariates, the amount of maternal weight gain below recommendation (odds ratio (OR), 2.72; 95% confidence interval (CI), 1.37-5.39) and maternal smoking status (OR, 2.80; 95% CI, 1.14-6.91) were significantly and independently associated with SGA births. Pre-pregnancy maternal weight status showed a borderline association (OR, 1.91; 95% CI, 0.96-3.83, p=0.067). CONCLUSION: To prevent SGA births, education regarding the adequate nutrition and the adverse effect of maternal smoking is important for the women of reproductive age. PMID- 26638133 TI - Rapid degradation of p-arsanilic acid with simultaneous arsenic removal from aqueous solution using Fenton process. AB - Although banned in some developed countries, p-arsanilic acid (p-ASA) is still used widely as a feed additive for swine production in many countries. With little uptake and transformation in animal bodies, nearly all the p-ASA administered to animals is excreted chemically unchanged in animal wastes, which can subsequently release the more toxic inorganic arsenic species upon degradation in the environment. For safe disposal of the animal wastes laden with p-ASA, we proposed a method of leaching the highly water-soluble p-ASA out of the manure first, followed by treatment of the leachate using the Fenton process to achieve fast oxidation of p-ASA and removal of the inorganic arsenic species released (predominantly arsenate) from solution simultaneously. The effects of solution pH, dosages of H2O2 and Fe(2+), and the presence of dissolved organic matter (DOM) on the treatment efficiency were systematically investigated. Under the optimum treatment conditions (0.53 mmol L(-1) Fe(2+), 2.12 mmol L(-1) H2O2, and initial pH of 3.0), p-ASA (10 mg-As L(-1)) could be completely oxidized to As(V) within 30 min in pure water and 4 natural water samples, and at the final pH of 4.0, the residual arsenic levels in solution phase were as low as 1.1 and 20.1-43.4 MUg L(-1) in the two types of water matrixes, respectively. The presence of humic acid significantly retarded the oxidation of p-ASA by scavenging HO, and inhibited the As(V) removal through competitive adsorption on ferric hydroxide. Due to the high contents of DOM in the swine manure leachate samples (TOC at ~500 mg L(-1)), much higher dosages of Fe(2+) (10.0 mmol L(-1)) and H2O2 (40.0 mmol L(-1)) and a longer treatment time (120 min) were required to achieve near complete oxidation of p-ASA (98.0%), while maintaining the levels of residual arsenic in the solution at <70.0 MUg L(-1). The degradation pathway of p ASA in the Fenton process was proposed based on the major degradation products detected. Together, the results demonstrate that the Fenton process is promising as an efficient, robust, and low-cost treatment method for controlling the risk of p-ASA in the animal wastes generated at factory farms. PMID- 26638134 TI - The role of autoinducer-2 in aerobic granulation using alternating feed loadings strategy. AB - Quorum sensing (QS) plays an important role in aerobic granulation while how QS system regulates the formation of aerobic granules needs further discussion. This study cultivated activated sludge in two identical sequencing batch reactors (R1 and R2) at different influent organic loading rate (OLR) strategies: R1 was operated using constant OLR (around 8.0kg/m(3)d), while R2 was operated at alternating OLR (4.0-17.0kg/m(3)d). Microbial aggregates appeared in R2 on day 19, while the morphology of sludge in R1 changed little compared with the initial sludge. The concentration of autoinducer-2 (AI-2) in R2 showed an ascending trend, along with the increase of cell adhesiveness. The total extracellular polymeric substances (EPS) amount and large molecular weight EPS of R2 rose steadily, which was different from R1. Some bacteria able to self-aggregate and promote EPS secretion were exclusive in R2. A mechanism about aerobic granulation at alternating OLR was proposed. PMID- 26638135 TI - Understanding of polyhydroxybutyrate production under carbon and phosphorus limited growth conditions in non-axenic continuous culture. AB - In a waste into resource strategy, a selection of polyhydroxybutyrate (PHB) accumulating organisms from activated sludge was achieved in an open continuous culture under acetic acid and phosphorus limitation. Once the microbial population was selected at a dilution rate (D), an increase in phosphorus limitation degree was applied in order to study the intracellular phosphorus plasticity of selected bacteria and the resulting capacity to produce PHB. Whatever D, all selected populations were able to produce PHB. At a D, the phosphorus availability determined the phosphorus-cell content which in turn fixed the amount of cell. All the remaining carbon was thus directed toward PHB. By decreasing D, microorganisms adapted more easily to higher phosphorus limitation leading to higher PHB content. A one-stage continuous reactor operated at D=0.023h(-)(1) gave reliable high PHB productivity with PHB content up to 80%. A two-stage reactor could ensure better productivity while allowing tuning product quality. PMID- 26638136 TI - Intrinsic kinetic parameters of Thermococcus onnurineus NA1 strains and prediction of optimum carbon monoxide level for ideal bioreactor operation. AB - This study determines and compares the intrinsic kinetic parameters (Ks and Ki) of selected Thermococcus onnurineus NA1 strains (wild-type (WT), and mutants MC01, MC02, and WTC156T) using the substrate inhibition model. Ks and Ki values were used to find the optimum dissolved CO (CL) conditions inside the reactor. The results showed that in terms of the maximum specific CO consumption rates (qCO(max)) of WT, MC01, MC02, and WTC156T the optimum activities can be achieved by maintaining the CL levels at 0.56mM, 0.52mM, 0.58mM, and 0.75mM, respectively. The qCO(max) value of WTC156T at 0.75mM was found to be 1.5-fold higher than for the WT strain, confirming its superiority. Kinetic modeling was then used to predict the conditions required to maintain the optimum CL levels and high cell concentrations in the reactor, based on the kinetic parameters of the WTC156T strain. PMID- 26638137 TI - Effect of kelp waste extracts on the growth and lipid accumulation of microalgae. AB - Kelp waste extracts (KWE) contained massive soluble sugars, amino acids and various mineral elements. To probe the effects of KWE on microalgal physiological and biochemical responses, the cultures were carried out under the different dilutions. The results showed that 8.0% KWE increased the biomass productivities and total lipid contents of Chlorella strains dramatically, which were 1.83-31.86 times and 20.78-25.91% higher than that of the control. Phaeodactylum tricornutum and Spirulina maxima presented a better growth performance in 1.0% and 4.0% treatment respectively, while their lipid accumulation were not enhanced. In Chlorella-Arc, Chlorella sorokiniana and P. tricornutum, the contents of saturated and monounsaturated fatty acids could be increased, and polyunsaturated fatty acids could be decreased under the conditions of high concentration of KWE (6.0-8.0%). Briefly, KWE facilitated to enhance the biomass productivity and lipid content of Chlorella strains, also improved the fatty acid compositions for biodiesel production. PMID- 26638138 TI - Electrical resistivity tomography to quantify in situ liquid content in a full scale dry anaerobic digestion reactor. AB - The electrical resistivity tomography (ERT) method is a non-intrusive method widely used in landfills to detect and locate liquid content. An experimental set up was performed on a dry batch anaerobic digestion reactor to investigate liquid repartition in process and to map spatial distribution of inoculum. Two array electrodes were used: pole-dipole and gradient arrays. A technical adaptation of ERT method was necessary. Measured resistivity data were inverted and modeled by RES2DINV software to get resistivity sections. Continuous calibration along resistivity section was necessary to understand data involving sampling and physicochemical analysis. Samples were analyzed performing both biochemical methane potential and fiber quantification. Correlations were established between the protocol of reactor preparation, resistivity values, liquid content, methane potential and fiber content representing liquid repartition, high methane potential zones and degradations zones. ERT method showed a strong relevance to monitor and to optimize the dry batch anaerobic digestion process. PMID- 26638139 TI - In-situ transesterification of seeds of invasive Chinese tallow trees (Triadica sebifera L.) in a microwave batch system (GREEN(3)) using hexane as co-solvent: Biodiesel production and process optimization. AB - In-situ transesterification (simultaneous extraction and transesterification) of Chinese tallow tree seeds into methyl esters using a batch microwave system was investigated in this study. A high degree of oil extraction and efficient conversion of oil to biodiesel were found in the proposed range. The process was further optimized in terms of product yields and conversion rates using Doehlert optimization methodology. Based on the experimental results and statistical analysis, the optimal production yield conditions for this process were determined as: catalyst concentration of 1.74wt.%, solvent ratio about 3 (v/w), reaction time of 20min and temperature of 58.1 degrees C. H(+)NMR was used to calculate reaction conversion. All methyl esters produced using this method met ASTM biodiesel quality specifications. PMID- 26638140 TI - Catalytic supercritical water gasification of primary paper sludge using a homogeneous and heterogeneous catalyst: Experimental vs thermodynamic equilibrium results. AB - H2, CH4, CO and CO2 yields were measured during supercritical water gasification (SCWG) of primary paper waste sludge (PWS) at 450 degrees C. Comparing these yields with calculated thermodynamic equilibrium values offer an improved understanding of conditions required to produce near-equilibrium yields. Experiments were conducted at different catalyst loads (0-1g/gPWS) and different reaction times (15-120min) in a batch reactor, using either K2CO3 or Ni/Al2O3 SiO2 as catalyst. K2CO3 up to 1g/gPWS increased the H2 yield significantly to 7.5mol/kgPWS. However, these yields and composition were far from equilibrium values, with carbon efficiency (CE) and energy recovery (ER) of only 29% and 20%, respectively. Addition of 0.5-1g/gPWS Ni/Al2O3-SiO2 resulted in high H2 and CH4 yields (6.8 and 14.8mol/kgPWS), CE of 84-90%, ER of 83% and a gas composition relatively close to the equilibrium values (at hold times of 60-120min). PMID- 26638141 TI - Does anti-androgen, flutamide cancel out the in vivo effects of the androgen, dihydrotestosterone on sexual development in juvenile Murray rainbowfish (Melanotaenia fluviatilis)? AB - The aim of the present study was to investigate if the effects of the androgen, dihydrotestosterone (DHT) on the sexual development in juvenile Murray rainbowfish (Melanotaenia fluviatilis) are canceled out by the anti-androgen, flutamide. Fish (60 days post hatch) were exposed to 250ng/L of DHT, 25MUg/L of flutamide (Flu-low), 250MUg/L of flutamide (Flu-high), DHT+Flu low and DHT+Flu high. After 35 days of exposure, lengths and weights of the fish were measured and the condition factor (CF) calculated; vitellogenin (VTG) concentrations were measured in tail tissue; sex steroid hormones (17beta-estradiol [E2] and 11-keto testosterone [11-KT]) were measured in the head tissue and abdominal regions were used in histological investigation of the gonads. Treatment with DHT reduced the body-length of both male and female fish, an effect which was canceled out by low and high concentrations of flutamide. However, flutamide (low or high) could not nullify the DHT-induced reduction in the CF in either sex. The E2 levels were reduced only in female fish after exposure to DHT but returned to normal after treatment with Flu-high. DHT increased the levels of 11-KT and decreased the E2/11-KT ratio in both sexes. Flu-high, but not Flu-low, could nullify these effects. Both DHT and flutamide (low or high) induced VTG production and this effect persisted when both chemicals were co-administered. Treatment with DHT did not affect gonadal cell development in the testes. However, the female fish treated with DHT contained ovaries in early-vitellogenic stage in comparison to the pre-vitellogenic ovaries in control fish. Co-treatment with flutamide (low or high) resulted in oocyte atresia. The results from the present study suggest that treatment with Flu-high could cancel out DHT-induced effects only on the hormonal profile and body-length in both male and female fish. Juvenile fish co-treated with DHT and flutamide (low or high) had high VTG levels and low CF. In addition, the ovaries in female fish were atretic. These data represent potential adverse effects on the ability of the fish to reproduce successfully. PMID- 26638142 TI - Stigma and the etiology of depression among the obese: An agent-based exploration. AB - BACKGROUND: Obesity and depression are comorbid more often than chance predicts. However, depression among the obese is more common in settings where obesity is less common. This suggests that body habitus norms and social stigmatization may play a role in the etiology of depression among the obese. METHODS: We developed an agent-based social network model to explore mechanisms by which deviance from normative body habitus may contribute to social isolation in the obese. At each of 240 simulated months (20 years), each agent updated its body mass index based on environmental, peer influence, and stochastic factors. At each month, each agent was subject to social ostracization and consequent depression if its body mass index deviated from that of its peers and the network-wide mean. We compared risk of depression as a function of obesity and obesity norms through simulations of a high-obesity context simulating the US state of Mississippi and a low obesity context simulating the US state of Colorado, then explored the relationship between global obesogenic forces and agent-specific resistance to the forces. RESULTS: Over 1000 simulations in each context, 25 percent of obese agents in simulated Colorado were ever-depressed as compared to 21 percent in simulated Mississippi, although 10 percent overall were ever-depressed in both settings. High and low levels of resistance to obesogeneity prevented the most depression, whereas medium resistance levels were more depressogenic. CONCLUSIONS: Social stigma and ostracization that occur as a consequence of deviance from body habitus norms may be a plausible mechanism by which weight stigma may influence depression in the obese. Public health interventions targeting individuals rather than obesogenic environments may modify body habitus norms with the unintended consequence of increasing stigma-based social isolation among those who remain obese. PMID- 26638143 TI - "I was on the way to the hospital but delivered in the bush": Maternal health in Ghana's Upper West Region in the context of a traditional birth attendants' ban. AB - This study examines perceptions and experiences of mothers, traditional birth attendants (TBA), and skilled birth attendants (SBA) regarding Ghana's recent policy that forbids TBAs from undertaking deliveries and restricts their role to referrals. In the larger context of Ghana's highly underdeveloped and geographically uneven health care system, this study draws on the political ecology of health framework to explore the ways global safe motherhood policy discourses intersect with local socio-cultural and political environments of Ghana's Upper West Region (UWR). This study reveals that futile improvements in maternal health and the continued reliance on TBAs illustrate the government's inability to understand local realities marked by poor access to SBAs or modern health care services. Using focus group discussions (FGDs) (n = 10) and in-depth interviews (IDIs) (n = 48) conducted in Ghana's UWR, the findings suggest that mothers generally perceive TBAs as better placed to conduct deliveries in rural isolated communities, where in most cases no SBAs are present or easily accessible. The results indicate that by adhering to the World Health Organization's guidelines, the local government may be imposing detrimental, unintended consequences on maternal and child health in remote rural locations. In addition, the findings suggest that the new policy has resulted in considerable confusion among TBAs, many of whom remain oblivious or have not been officially notified about the new policy. Furthermore, participant accounts suggest that the new policy is seen as contributing to worsening relations and tensions between TBAs and SBAs, a situation that undermines the delivery of maternal health services in the region. The study concludes by suggesting relevant policy recommendations. PMID- 26638144 TI - Performance of 14 rubella IgG immunoassays on samples with low positive or negative haemagglutination inhibition results. AB - BACKGROUND: Rubella IgG testing is routinely done in prenatal care and seroepidemiological studies. Recently concern was raised that seropositivity rates were decreasing questioning vaccination policies. Manufacturers of rubella IgG assays and authors of seroepidemiological studies use different cut-offs for the definition of seropositivity. As rubella virus circulation is reduced since many years, seronegativity rates might be overestimated using an inappropriate cut-off. OBJECTIVES: Using different cut-off definitions we compared fourteen current rubella IgG immunoassays for sensitivity and qualitative result concordance in samples with low positive or negative haemagglutination inhibition (HI) titre. STUDY DESIGN: 150 clinical samples from patients and health care workers were included in the study. All samples were measured in 14 different rubella IgG immunoassays. Seropositivity was defined using recombinant rubella IgG immunoblot as reference standard. RESULTS: The concordance of qualitative results using the manufacturers cut-off definitions was 56.4% if grey-zone results were analysed separately and 69.8% if grey-zone results were defined as positive. Using universal cut-offs of 10 IU/ml or 15 IU/ml the concordance was 70% and 61.4% respectively. Using the different cut-off definitions up to 71 out of the 124 immunoblot-positive samples tested negative in the immunoassays. The mean coefficient of variation (CV) of quantitative results in positive samples was 51% (range 19-113%). CONCLUSIONS: Determination of rubella immunity by measurement of rubella-IgG in a population with high vaccination coverage with current assays leads to a high number of false negative results. The value of routine rubella antibody testing in countries with high vaccination coverage should be discussed. PMID- 26638145 TI - "Wan Kanyakla" (We are together): Community transformations in Kenya following a social network intervention for HIV care. AB - BACKGROUND: In sub-Saharan Africa, failure to initiate and sustain HIV treatment contributes to significant health, psychosocial, and economic impacts that burden not only infected individuals but diverse members of their social networks. Yet, due to intense stigma, the responsibility for managing lifelong HIV treatment rests solely, and often secretly, with infected individuals. We introduce the concept of "HIV risk induction" to suggest that social networks of infected individuals share a vested interest in improving long-term engagement with HIV care, and may represent an underutilized resource for improving HIV/AIDS outcomes within high prevalence populations. METHODS: In 2012, we implemented a 'microclinic' intervention to promote social network engagement in HIV/AIDS care and treatment. A microclinic is a therapy management collective comprised of a small group of neighbors, relatives, and friends who are trained as a team to provide psychosocial and adherence support for HIV-infected members. Our study population included 369 patients on ART and members of their social networks on Mfangano Island, Kenya, where HIV prevalence approaches 30%. Here we report qualitative data from 18 focus group discussions conducted with microclinic participants (n = 82), community health workers (n = 40), and local program staff (n = 39). RESULTS: Participants reported widespread acceptability and enthusiasm for the microclinic intervention. Responses highlight four overlapping community transformations regarding HIV care and treatment, namely (1) enhanced HIV treatment literacy (2) reduction in HIV stigma, (3) improved atmosphere for HIV status disclosure and (4) improved material and psychosocial support for HIV infected patients. Despite challenges, participants describe an emerging sense of "collective responsibility" for treatment among HIV-infected and HIV-uninfected members of social networks. DISCUSSION: The lived experiences and community transformations highlighted by participants enrolled in this social network intervention in Western Kenya suggest opportunities to reframe the continuum of HIV care from a secretive individual journey into a network-oriented cycle of engagement. PMID- 26638146 TI - A simple, fast and inexpensive method to assess salt stress tolerance of aerial plant part: Investigations in the mandarin group. AB - For grafted plants, salt stress tolerance of the aerial plant part is poorly documented. Thus, we developed a simple, fast and inexpensive method to identify tolerant genotypes. Twigs of 14 mandarin accessions that we previously analyzed as seedlings were cut in solution to prevent embolism and were then evaluated in salt stress condition for a week. Physiological parameters such as gas exchanges, leaf Cl(-) and Na(+), as well as the presence of H2O2 and the activity of enzymes involved in ROS synthesis and detoxification processes were analyzed. One accession known to be tolerant as rootstock was shown to be sensitive with limited Cl(-) translocation from the solution to the shoot while sensitive accessions when grown as seedlings presented limited wilting symptoms and accumulated large leaf Cl(-) content. A model is proposed to explain the different strategies of the plant to cope with high toxic ion content. This method allows separation of the root compartment, where ion exclusion mechanisms may exist and have an impact on the salt stress tolerance of the whole plant. PMID- 26638147 TI - Integrating new practices: a qualitative study of how hospital innovations become routine. AB - BACKGROUND: Hospital quality improvement efforts absorb substantial time and resources, but many innovations fail to integrate into organizational routines, undermining the potential to sustain the new practices. Despite a well-developed literature on the initial implementation of new practices, we have limited knowledge about the mechanisms by which integration occurs. METHODS: We conducted a qualitative study using a purposive sample of hospitals that participated in the State Action on Avoidable Rehospitalizations (STAAR) initiative, a collaborative to reduce hospital readmissions that encouraged members to adopt new practices. We selected hospitals where risk-standardized readmission rates (RSRR) had improved (n = 7) or deteriorated (n = 3) over the course of the first 2 years of the STAAR initiative (2010-2011 to 2011-2012) and interviewed a range of staff at each site (90 total). We recruited hospitals until reaching theoretical saturation. The constant comparative method was used to conduct coding and identification of key themes. RESULTS: When innovations were successfully integrated, participants consistently reported that a small number of key staff held the innovation in place for as long as a year while more permanent integrating mechanisms began to work. Depending on characteristics of the innovation, one of three categories of integrating mechanisms eventually took over the role of holding new practices in place. Innovations that proved intrinsically rewarding to the staff, by making their jobs easier or more gratifying, became integrated through shifts in attitudes and norms over time. Innovations for which the staff did not perceive benefits to themselves were integrated through revised performance standards if the innovation involved complex tasks and through automation if the innovation involved simple tasks. CONCLUSIONS: Hospitals have an opportunity to promote the integration of new practices by planning for the extended effort required to hold a new practice in place while integration mechanisms take hold. By understanding how integrating mechanisms correspond to innovation characteristics, hospitals may be able to foster integrating mechanisms most likely to work for particular innovations. PMID- 26638148 TI - Robust tooth surface reconstruction by iterative deformation. AB - Digital design technologies have been applied extensively in dental medicine, especially in the field of dental restoration. The all-ceramic crown is an important restoration type of dental CAD systems. This paper presents a robust tooth surface reconstruction algorithm for all-ceramic crown design. The algorithm involves three necessary steps: standard tooth initial positioning and division; salient feature point extraction using Morse theory; and standard tooth deformation using iterative Laplacian Surface Editing and mesh stitching. This algorithm can retain the morphological features of the tooth surface well. It is robust and suitable for almost all types of teeth, including incisor, canine, premolar, and molar. Moreover, it allows dental technicians to use their own preferred library teeth for reconstruction. The algorithm has been successfully integrated in our Dental CAD system, more than 1000 clinical cases have been tested to demonstrate the robustness and effectiveness of the proposed algorithm. PMID- 26638149 TI - ARWAR: A network approach for predicting Adverse Drug Reactions. AB - Predicting novel drug side-effects, or Adverse Drug Reactions (ADRs), plays an important role in the drug discovery process. Existing methods consider mainly the chemical and biological characteristics of each drug individually, thereby neglecting information hidden in the relationships among drugs. Complementary to the existing individual methods, in this paper, we propose a novel network approach for ADR prediction that is called Augmented Random-WAlk with Restarts (ARWAR). ARWAR, first, applies an existing method to build a network of highly related drugs. Then, it augments the original drug network by adding new nodes and new edges to the network and finally, it applies Random Walks with Restarts to predict novel ADRs. Empirical results show that the ARWAR method presented here outperforms the existing network approach by 20% with respect to average Fmeasure. Furthermore, ARWAR is capable of generating novel hypotheses about drugs with respect to novel and biologically meaningful ADR. PMID- 26638151 TI - Central serous chorioretinopathy and systemic corticosteroids in rheumatic diseases: report of three cases. AB - BACKGROUND: Central serous chorioretinopathy is a disorder often related to systemic corticosteroids, drugs commonly used in rheumatologists' clinical practice. Central serous chorioretinopathy prognosis is generally good but in some cases, it may lead to substantial loss of vision resulting in an important functional limitation for patients. It is very important to distinguish this pathology from other diseases involving retinal detachment. When central serous chorioretinopathy and uveitis coexist, it is mandatory to distinguish serous retinal detachment from a uveitis worsening, as the respective treatments can be radically different. CASE PRESENTATION: We describe three cases of central serous chorioretinopathy in patients taking systemic corticosteroids due to rheumatological diseases (ankylosing spondylitis, systemic lupus erythematosus and Behcet's disease). They were diagnosed and managed at our Multidisciplinary (Rheumatology-Ophthalmology) Uveitis Clinic. All three cases improved after corticosteroids dose tapering. CONCLUSION: Central serous chorioretinopathy must be kept in mind by rheumatologists as it is related to systemic corticosteroids. PMID- 26638150 TI - Clinical and morphological pattern of brain arteriovenous malformations (BAVMs) in a tertiary care hospital in Bangladesh. AB - BACKGROUND: We have conducted this study to examine the clinical and morphological pattern of brain arteriovenous malformations (BAVMs) along with their treatment and short term outcome in a tertiary care hospital in Bangladesh. This retrospective chart review was carried out from the records of neuro endovascular division at Department of Neurology, Dhaka Medical College Hospital (DMCH) from January 2010 to June 2013. A total 60 patients were evaluated. All the necessary information regarding the demographic, clinical, morphologic and treatment profile was gathered through a predesigned questionnaire. To our knowledge, we have the largest cohort of BAVM patients in Bangladesh and this is the first of this kind of study done in Bangladesh. RESULTS: The mean age at diagnosis was 30.3 years with a standard deviation of +/-14.3 and the majority was teenagers (30%). Intracerebral hemorrhage was the commonest (70%) type of presentation at diagnosis, followed by headache (50%), altered consciousness (50%), vomiting (40%) and seizure (40%). Majority of the AVMs had feeders from anterior circulation (50%) and most of the AVMs (73.3%) were supplied from the main feeders, whereas the rest from distal vessels. Regarding venous drainage, AVMs drained mostly either to superficial (43.3%) or deep (40%) venous system. AVMs frequently had larger (40%) nidus size and a slow to medium flow (60%), through the nidus. An eloquent AVM location was found in 50% of the patients. Intranidal aneurysm was found in 10% AVM and angiopathic AVM in 13.3%. Patients were treated by endovascular embolization (31) or surgical excision (11) or conservative approach. There was one event of death, both in embolization group and surgically treated group before discharge. The patients were followed up for 1.3 +/- 0.8 years. The rate of rebleed was 6.6, 30 and 60% during follow up in endovascular, surgical and conservatively treated group. Though five patients in conservative group died during this time, no deaths reported in intervention group (endovascular or surgery). CONCLUSION: Intracerebral hemorrhages, headache, altered consciousness and seizure are common clinical presentations of AVM at diagnosis. The remarkable morphologic features are larger AVM size at eloquent location, medium to slow flow with frequent feeders from main vessels of anterior circulation and drainage to superficial venous systems. Endovascular embolization or surgical excision of AVM are relatively safe and effective and provides better short term outcome than conservative approach. PMID- 26638152 TI - Treatment strategy for cerebral hypotension caused by spontaneous cerebrospinal fluid leaks. AB - OBJECTIVE: Spontaneous spinal cerebrospinal fluid (CSF) leaks are rare (5 per 100,000 per year). Treatment generally consists of conservative therapy or interventional therapy with epidural blood patching. Surgical treatment is conducted rarely, usually in cases when conservative or interventional treatment has failed. The aim of our case series was to assess the clinical outcome after surgery. METHODS: Our clinical database was reviewed for patients with spontaneous spinal CSF leaks who underwent surgical exploration between 2010 and 2013. Etiology, symptoms, preoperative imaging, type of required surgical method, intraoperative findings, and clinical outcome were reported. RESULTS: We identified five patients with a mean age of 62 years with spontaneous spinal CSF leaks who were treated surgically. Two patients received surgery after failure of interventional treatment. The origin of the CSF leak could be identified intraoperatively in three cases. Surgical technique in all cases consisted of an interlaminar fenestration or hemilaminectomy and a complete foraminotomy to explore the thecal sack and the exiting nerve roots and identify the CSF leak. After surgery, the preoperative symptoms improved in all patients. In one case, there was a relapse after 4 weeks. CONCLUSIONS: Preoperative identification of a CSF leak with MRI was positive in only one case. In all other cases, a post myelography CT had to be performed. In all cases, the preoperative symptoms improved after surgery. Surgical treatment is an effective treatment of spontaneous cerebrospinal fluid leaks in cases of refractory symptoms after failed conservative or interventional treatment. PMID- 26638153 TI - Perception and Awareness of Bariatric Surgery in Canada: a National Survey of General Surgeons. AB - BACKGROUND: The objective of this study was to assess Canadian general surgeons' knowledge of bariatric surgery and perceived availability of resources to manage bariatric surgery patients. METHODS: A self-administered questionnaire was developed using a focus group of general surgeons. The questionnaire was distributed at two large general surgery conferences in September and November 2012. The survey was also disseminated via membership association electronic newsletters in November and December 2012. RESULTS: One hundred sixty-seven questionnaires were completed (104 practicing surgeons, 63 general surgery trainees). Twenty respondents were bariatric surgeons. Among 84 non-bariatric surgeons, 68.3 % referred a patient in the last year for bariatric surgery, 79 % agreed that bariatric surgery resulted in sustained weight loss, and 81.7 % would consider referring a family member. Knowledge gaps were identified in estimates of mortality and morbidity associated with bariatric procedures. The majority of surgeons surveyed have encountered patients with complications from bariatric surgery in the last year. Over 50 % of surgeons who do not perform bariatric procedures reported not feeling confident to manage complications, 35.4 % reported having adequate resources and equipment to manage morbidly obese patients, and few are able to transfer patients to a bariatric center. Of the respondents, 73.3 % reported residency training provided inadequate exposure to bariatric surgery, and 85.3 % felt that additional continuing medical education resources would be useful. CONCLUSIONS: There appears to be support for bariatric surgery among Canadian general surgeons participating in this survey. Knowledge gaps identified indicate the need for more education and resources to support general surgeons managing bariatric surgical patients. PMID- 26638154 TI - Evaluation of the prevalence, type, severity, and risk factors of urinary incontinence and its impact on quality of life among women in Turkey. AB - INTRODUCTION AND HYPOTHESIS: Our purpose was to determine prevalence, type, and risk factors of urinary incontinence (UI) and their impacts on quality of life (QoL) of women in Turkey. METHODS: This cross-sectional study was performed on 150 women aged 18-80 years at the Yildirim Beyazit University Hospital's Gynecology Outpatient Clinic in Turkey between May 2013 and September 2013. Data were collected using an individual information form and an incontinence QoL questionnaire (I-QOL). Following data distribution, we used the Mann-Whitney U test, Bonferroni-corrected Kruskal-Walis H test, logistic regression analysis, Fisher's exact test, and the chi-square test. RESULTS: Mean age of the study population was 48.7 +/- 14.3 years and UI prevalence 86.7 %. The distribution of UI types was 37.7 % stress incontinence (SUI), 3.1 % urge (UUI), and 59.2 % mixed (MUI). I-QOL general average was 56.7 +/- 23.28 (min 22, max 110). Most women had experienced UI for at least 5 continuous years and reported a negative impact on QoL; 43.2 % of incontinence women had not received medical therapy. Postmenopause, uterine prolapsus, episiotomy, use of hormone replacement therapy (HRT), smoking, caffeine intake, family history of UI, macrosomia, and multiparity were risk factors for UI (p < 0.05). CONCLUSION: In this study, the prevalence of UI in women was substantial, and UI had a significantly negative impact on all aspects of QoL. However, these women had not sought medical help for the problem. Therefore, health professionals should query women of all ages about symptoms of this prevalent condition and offer treatment if it is detected. PMID- 26638155 TI - The adsorption/desorption of phosphorus in freshwater sediments from buffer zones: the effects of sediment concentration and pH. AB - Riparian buffer zones adjacent to reservoirs and lakes protect aquatic ecosystems from polluted surface runoff. Sediments, collected from the buffer zones of Danjiangkou Reservoir (SR) and Honghu Lake (SL) in an ecologically fragile region in central China, were evaluated to reveal their phosphorus-adsorbing/desorbing properties and storage capacities. A nonlinear regression method was used to fit the pseudo-second-order kinetic and the modified crossover-type Langmuir isotherm models to the experimental data. It is shown that the adsorption of phosphorus onto the studied sediments followed the pseudo-second-order kinetic expression. The modified crossover-type Langmuir isotherm model was found to be a suitable method for describing adsorption/desorption processes in the experimental sediments. The maximum adsorption capacities (Q m), partitioning coefficients (K p), native adsorbed exchangeable phosphorus (NAP), and equilibrium phosphorus concentration (EPC0) were subsequently obtained for the experimental sediments. The effects of sediment concentration and pH were also investigated by batch experiments and Fourier transformation infrared and scanning electron microscopy analyses. The adsorption/desorption characteristics of different phosphate species on the sediments from reservoir and lake buffer zones were identified. PMID- 26638156 TI - Soil carbon fractions under maize-wheat system: effect of tillage and nutrient management. AB - Soil organic carbon plays a major role in sustaining agroecosystems and maintaining environmental quality as it acts as a major source and sink of atmospheric carbon. The present study aims to assess the impact of agricultural management practices on soil organic carbon pools in a maize-wheat cropping system of Indo-Gangetic Plains, India. Soil samples from a split plot design with two tillage systems (bed planting and conventional tillage) and six nutrient treatments (T1 = control, T2 = 120 kg urea-N ha(-1), T3 = T2 (25 % N substituted by FYM), T4 = T2 (25 % N substituted by sewage sludge), T5 = T2 + crop residue, T6 = 100 % organic source (50 % FYM + 25 % biofertilizer + 25 % crop residue) were used for determining the organic carbon pools. Results show that there was a significant improvement in Walkley and Black carbon in soil under integrated and organic nutrient management treatments. KMnO4-oxidizable carbon content of soil varied from 0.63 to 1.50 g kg(-1) in soils and was found to be a better indicator for monitoring the impact of agricultural management practices on quality of soil organic carbon than microbial biomass carbon. Tillage and its interaction were found to significantly influence only those soil organic carbon fractions closely associated with aggregate stability viz, labile polysaccharides and glomalin. The highest amount of C4-derived carbon was found to be in plots receiving recommended doses of N as urea (29 %) followed by control plots (25 %). The carbon management index ranged between 82 to 195 and was better in integrated nutrient sources than ones receiving recommended doses of nutrients through mineral fertilizers alone. PMID- 26638157 TI - Immunophenotypic features of immaturity of neural elements in ovarian teratoma. AB - Neural components in mature teratomas are common and the general assumption is that they are quite similar to those in the mature central nervous system (CNS). We investigated 44 ovarian teratomas by immunohistochemistry to determine cellular and structural immaturity of neural elements. Most teratomas contained cells differentiating into astrocytes positive for nestin, a neural stem cell marker. These nestin-positive astrocytes generally co-expressed glial fibrillary acidic protein-delta, an immature astrocyte marker. Olig2-positive cells were randomly scattered. Areas comprising cells that differentiated into neurons were positive for NeuN and synaptophysin. The border between white and gray matter was ill-defined and more NeuN-positive cells were distributed in areas that were positive for myelin basic protein, indicating that the distribution of neurons and glial cells was disturbed. Peripheral nerve bundles positive for Schwann/2E, an antigen specific for myelinating Schwann cells, were mixed within CNS-like tissues. These results show that apparently mature teratomas are not in fact mature, at least in terms of neural elements, as they harbor immature cells and structural abnormalities. The neural elements of surgically resected teratomas might represent a premature state of the human CNS, and thus be potentially useful for studies of developmental neurobiology as well as gliomagenesis. PMID- 26638158 TI - Carcinoma ex-pleomorphic adenoma of the salivary glands has a high risk of progression when the tumor invades more than 2.5 mm beyond the capsule of the residual pleomorphic adenoma. AB - Carcinoma ex-pleomorphic adenoma (CPA) is subclassified based on the extent of penetration of the malignant component beyond the fibrous capsule of the pre existing pleomorphic adenoma (PA). These subclasses are considered to be prognostically significant since the non-invasive/minimally invasive groups have an excellent outcome. Nevertheless, there is no consensus as to the cutoff value to distinguish between minimal and wide invasion, even though the 2005 WHO classification defines 1.5 mm as cutoff. The objective of this study is to evaluate a consecutive series of CPA, in order to establish what the effect is of the extent of extra-capsular invasion on prognosis. Fifty-eight cases of CPA were reviewed to obtain demographic and pathological information. Extent of invasion was measured. Eleven cases were non-invasive, 9 had <=1.5 mm invasion, and for the remainder, the depth of invasion ranged between 2.5 and >10 mm. Distant metastases or death did not occur in the first two groups. In the group with >=2.5 mm invasion, 15 patients had progressive disease and 9 of them died. The minimum extent of invasion associated with tumor progression and death was 2.5 mm. Two histologically non-invasive carcinomas had regional lymph node metastasis. CPA with <=1.5 mm depth of invasion has good prognosis. Nevertheless, the lymph node metastases found in two cases of this group question the concept that intracapsular/minimally invasive CPA has a prognosis similar to that of PA. The minimum extent of invasion associated with death was 2.5 mm, which is at variance with findings in other recent series. Thirteen cases with depth of invasion exceeding 2.5 mm did well, confirming that additional factors should be considered in the clinical management of these patients. PMID- 26638160 TI - A case of temporal arteritis in Filippino Lippi's (1459-1504) Saint Frediano? PMID- 26638159 TI - Canine and Equine Mesenchymal Stem Cells Grown in Serum Free Media Have Altered Immunophenotype. AB - Mesenchymal stem cell (MSC) therapy is being increasingly used to treat dogs and horses with naturally-occurring diseases. However these animals also serve as critical large animal models for ongoing translation of cell therapy products to the human market. MSC manufacture for clinical use mandates improvement in cell culture systems to meet demands for higher MSC numbers and removal of xeno proteins (i.e. fetal bovine serum, FBS). While serum-free media (SFM) is commercially available, its affects on MSC phenotype and immunomodulatory functions are not fully known. The objective of this study was to determine if specific MSC culture conditions, MSC expansion in HYPERFlasks(r) or MSC expansion in a commercially available SFM, would alter MSC proliferation, phenotype or immunomodulatory properties in vitro. MSCs cultured in HYPERFlasks(r) were similar in phenotype, proliferative capacity and immunomodulatory functions to MSCs grown in standard flasks however MSC yield was markedly increased. HYPERFlasks(r) therefore provide a viable option to generate greater cell numbers in a streamlined manner. Canine and equine MSCs expanded in SFM displayed similar proliferation, surface phenotype and inhibitory effect on lymphocyte proliferation in vitro. However, MSCs cultured in the absence of FBS secreted significantly less PGE2, and were significantly less able to inhibit IFNgamma secretion by activated T-cells. Immunomodulatory functions altered by expansion in SFM were species dependent. Unlike equine MSCs, in canine adipose-derived MSCs, the inhibition of lymphocyte proliferation was not principally modulated by PGE2. The removal of FBS from both canine and equine MSC culture systems resulted in altered immunomodulatory properties in vitro and warrants further investigation prior to moving towards FBS-free culture conditions. PMID- 26638161 TI - Pharmacokinetic properties of low-dose SoluMatrix meloxicam in healthy adults. AB - SoluMatrix(r) meloxicam has been developed using SoluMatrix Fine Particle TechnologyTM to produce a meloxicam drug product with enhanced absorption properties to enable treatment at lower doses than available oral meloxicam drug products. This follows recognition of serious dose-dependent adverse events (AEs) associated with nonsteroidal anti-inflammatory drugs, including meloxicam. This study investigated the pharmacokinetic (PK) properties of SoluMatrix meloxicam 5 mg (fasting conditions) and 10-mg capsules (fasting and fed conditions) and compared SoluMatrix meloxicam 10-mg capsules with meloxicam 15-mg tablets under fasting conditions. This four-period crossover study randomized 28 healthy adult participants to receive single doses of SoluMatrix meloxicam 5-mg capsules (fasting) and 10-mg capsules (fasting or fed) and meloxicam tablets 15 mg (fasting). Meloxicam plasma concentrations were assessed through 96 h postdose. Safety was assessed. Twenty-five participants (89.3 %) completed the study. Under fasting conditions, SoluMatrix meloxicam 10 mg [1252.8 (254.22) ng/mL] produced similar meloxicam mean (standard deviation (SD)) maximum plasma concentrations vs meloxicam 15-mg tablets [1288.8 (424.40) ng/mL]. The overall mean (SD) systemic meloxicam exposure was 33 % lower for SoluMatrix meloxicam 10 mg [29,173.01 (11,042.09) ng*h/mL] vs meloxicam 15-mg tablets [40,875.6 (11,733.47) ng*h/mL]. The median time to maximum plasma meloxicam levels occurred earlier following SoluMatrix meloxicam 5 mg (2.0 h) and 10 mg (2.0 h) administration vs meloxicam 15-mg tablets (4.0 h). Few study-medication-related AEs were reported. SoluMatrix meloxicam 10 mg was more rapidly absorbed and associated with a lower overall exposure compared with meloxicam 15-mg tablets in this study in healthy adults under fasting conditions. PMID- 26638162 TI - A systematic review of interventions to improve knowledge and self-management skills concerning contraception, pregnancy and breastfeeding in people with rheumatoid arthritis. AB - This systematic review aimed to determine the effectiveness of interventions for improving knowledge and/or self-management skills concerning contraception, pregnancy and breastfeeding in people with rheumatoid arthritis (RA). We searched four databases (MEDLINE, CINAHL, Cochrane Trials, PsycINFO) using a comprehensive search strategy. Studies were eligible if they were prospective, published in English from 2004 to 2015, included participants with RA and tested an intervention designed to improve knowledge and/or self-management skills relating to family planning, pregnancy or breastfeeding. As no studies met the latter criterion, the search strategy was expanded to include all prospective studies evaluating RA educational and/or self-management interventions. Data on study characteristics, participant characteristics and programme content were extracted to summarise the evidence base for interventions to support people with RA during their reproductive years. Expanded literature searches identified 2290 papers, of which 68 were eligible. Of these, nine papers (13%) specifically excluded pregnant women/breastfeeding mothers or recruited only older people. Only one study (1%) explicitly evaluated pregnancy-focused education via a motherhood decision aid, while eight studies (12%) incorporated relevant (albeit minor) components within broader RA educational or self-management interventions. Of these, three studies provided methotrexate education in relation to conception/pregnancy/breastfeeding; three incorporated discussions on RA and relationships, impact of RA on the family or sexual advice; one provided information regarding contraception and fertility; and one issued a warning regarding use of biologic therapy in pregnancy/breastfeeding. In conclusion, information regarding family planning, pregnancy or breastfeeding represents a negligible part of published RA educational interventions, with scope to develop targeted resources. PMID- 26638163 TI - Dual-energy CT-based iodine quantification for differentiating pulmonary artery sarcoma from pulmonary thromboembolism: a pilot study. AB - OBJECTIVES: The purpose of this study was to determine whether dual-energy computed tomography (DECT) angiography could differentiate pulmonary thromboembolism (PTE) from pulmonary artery sarcoma (PAS). METHODS: We prospectively enrolled 19 patients that had a filling defect in the main pulmonary artery on DECT. Six patients who had PAS and underwent DECT were retrospectively enrolled for comparison. Pathological results or follow-up CT after anticoagulation therapy were used to make the final diagnosis. Two investigators measured the following parameters at the filling defect in the main pulmonary artery: CT attenuation density [Hounsfield units (HU)], iodine-related HU (IHU) and iodine concentration (IC, mg/ml). RESULTS: From a total of 25 patients (M:F = 10:15; mean age, 65 years old), 19 were categorised into the PTE group and six were categorised into the PAS group. The mean HU values were not significantly different between the PTE and PAS groups (45.5 +/- 15.9 vs 47.1 +/- 9.2 HU; P = 0.776). However, the mean IHU and IC values of the lesions were significantly different between the PTE and PAS groups (10.6 +/- 7.2 vs 27.9 +/- 9.1 HU; P = 0.004, and 0.61 +/- 0.39 vs 1.49 +/- 0.57; P = 0.001). CONCLUSIONS: DECT angiography using a quantitative analytic methodology can be used to differentiate PTE and PAS. KEY POINTS: * DECT can be useful for differentiation of PAS and PTE. * With quantitative analysis, DECT offers tissue characterisation by detecting lesion parameter increases. * The patients without predisposing factors for PTE can be candidates for DECT. PMID- 26638164 TI - Magnetic resonance imaging of pulmonary nodules: accuracy in a granulomatous disease-endemic region. AB - OBJECTIVE: To estimate the diagnostic accuracy of signal intensity of the lesion to-spinal cord ratio (LSR) and apparent diffusion coefficient (ADC) in diffusion weighted (DW) magnetic resonance imaging of pulmonary nodules suspicious for lung cancer in granulomatous lung disease-endemic regions. METHODS: Forty-nine patients with indeterminate solitary pulmonary nodules detected by chest computed tomography and histopathologically confirmed diagnoses were included in the study. DW images were analysed semiquantitatively by focusing regions of interest on the lesion and spinal cord at the same level (for LSR calculation). ADCs were estimated from ratios of the two image signal intensities. Ratios of T1 and T2 signal intensity between nodules and muscle were calculated for comparison. RESULTS: Mean ADCs +/- standard deviations for lung cancer and benign lesions were 0.9 +/- 0.2 and 1.3 +/- 0.2 * 10(-3) mm(2)/s, respectively. Mean LSRs were 1.4 +/- 0.3 for lung cancer and 1 +/- 0.1 for benign lesions. ADCs and LSRs differed significantly between malignant and benign lesions (P < 0.001). Mean T2 signal intensity ratios also differed significantly between benign and malignant lesions (0.8 +/- 0.2 vs. 1.6 +/- 0.2; P < 0.05). CONCLUSIONS: DWI can help to differentiate malignant from benign lesions according to ADC and the LSR with good accuracy. KEY POINTS: * DW imaging can help differentiate malignant from benign pulmonary nodules. * ADC and LSR signal intensities had only small overlap between malignant and benign pulmonary nodules. * Mean T2 signal intensity ratios differed significantly between benign and malignant lesions. PMID- 26638165 TI - Normal spectrum of pulmonary parametric response map to differentiate lung collapsibility: distribution of densitometric classifications in healthy adult volunteers. AB - OBJECTIVES: Pulmonary parametric response map (PRM) was proposed for quantitative densitometric phenotypization of chronic obstructive pulmonary disease. However, little is known about this technique in healthy subjects. The purpose of this study was to describe the normal spectrum of densitometric classification of pulmonary PRM in a group of healthy adults. METHODS: 15 healthy volunteers underwent spirometrically monitored chest CT at total lung capacity (TLC) and functional residual capacity (FRC). The paired CT scans were analyzed by PRM for voxel-by-voxel characterization of lung parenchyma according to 4 densitometric classifications: normal lung (TLC >= -950 HU, FRC >= -856 HU); expiratory low attenuation area (LAA) (TLC >= -950 HU, FRC < -856 HU); dual LAA (TLC<-950 HU, FRC < -856 HU); uncharacterized (TLC < -950 HU, FRC >= -856 HU). RESULTS: PRM spectrum was 78 % +/- 10 % normal lung, 20 % +/- 8 % expiratory LAA, and 1 % +/- 1 % dual LAA. PRM was similar between genders, there was moderate correlation between dual LAA and spirometrically assessed TLC (R = 0.531; p = 0.042), and between expiratory LAA and VolExp/Insp ratio (R = -0.572; p = 0.026). CONCLUSIONS: PRM reflects the predominance of normal lung parenchyma in a group of healthy volunteers. However, PRM also confirms the presence of physiological expiratory LAA seemingly related to air trapping and a minimal amount of dual LAA likely reflecting emphysema. KEY POINTS: * Co-registration of inspiratory and expiratory computed tomography allows dual-phase densitometry. * Dual-phase co registered densitometry reflects heterogeneous regional changes in lung function. * Quantification of lung in healthy subjects is needed to set reference values. * Expiratory low attenuation areas <30 % could be considered within normal range. PMID- 26638166 TI - Expression and clinical implication of S100A12 in gastric carcinoma. AB - S100 protein family has been implicated in multiple stages of tumorigenesis and progression in which S100A12 is one of the subtypes. However, the role of S100A12 in gastric carcinoma (GC) has not been elucidated yet. This study was aimed to investigate the expression of S100A12 in GC tissues and evaluate the clinical significance of S100A12 in GC patients. S100A12 protein was detected in 207 GC and 52 paired non-cancerous mucosal tissues by immunohistochemistry, while messenger RNA (mRNA) was investigated by Oncomine database analysis. Moreover, survival analysis was performed and the correlation between S100A12 and ubiquitin specific protease 10 (USP10) and p53 was determined. As for tumor cells, the expression of S100A12 protein and mRNA in GC was proved to be lower than that in non-cancerous mucosa tissues (p < 0.05). Clinicopathological analysis showed that S100A12 protein was negatively associated with tumor size (p = 0.004), depth of invasion (p = 0.022), tumor node metastasis (TNM) stage (p = 0.018), Lauren classification (p < 0.000), and cell differentiation (p < 0.000). In contrast, a positive correlation was found between S100A12 and USP10 protein (p < 0.000). However, no relationship was detected between S100A12 and p53. Moreover, the survival analysis indicated that S100A12 protein was a favorable factor of prognosis of GC (p < 0.05). Although the expression of S100A12 in the stromal cells was detected higher than that in the tumor cells, no relationship between S100A12 protein in stromal cells and the clinicopathological features described above was found (p > 0.05). Our findings suggested that low expression of S100A12 might be served as a new marker in the tumorigenesis and progression of GC. PMID- 26638167 TI - Genetic variants in IL-6/JAK/STAT3 pathway and the risk of CRC. AB - Interleukin (IL)-6 and the downstream Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway have previously been reported to be important in the development of colorectal cancer (CRC), and several studies have shown the relationship between the polymorphisms of related genes in this pathway with the risk of CRC. However, the findings of these related studies are inconsistent. Moreover, there has no systematic review and meta-analysis to evaluate the relationship between genetic variants in IL-6/JAK/STAT3 pathway and CRC susceptibility. Hence, we conducted a meta-analysis to explore the relationship between polymorphisms in IL-6/JAK/STAT3 pathway genes and CRC risk. Eighteen eligible studies with a total of 13,795 CRC cases and 18,043 controls were identified by searching PubMed, Web of Science, Embase, and the Cochrane Library databases for the period up to September 15, 2015. Odds ratios (ORs) and their 95 % confidence intervals (CIs) were used to calculate the strength of the association. Our results indicated that IL-6 genetic variants in allele additive model (OR = 1.05, 95 % CI = 1.00, 1.09) and JAK2 genetic variants (OR = 1.40, 95 % CI = 1.15, 1.65) in genotype recessive model were significantly associated with CRC risk. Moreover, the pooled data revealed that IL-6 rs1800795 polymorphism significantly increased the risk of CRC in allele additive model in Europe (OR = 1.07, 95 % CI = 1.01, 1.14). In conclusion, the present findings indicate that IL 6 and JAK2 genetic variants are associated with the increased risk of CRC while STAT3 genetic variants not. We need more well-designed clinical studies covering more countries and population to definitively establish the association between genetic variants in IL-6/JAK/STAT3 pathway and CRC susceptibility. PMID- 26638168 TI - Flavones induce immunomodulatory and anti-inflammatory effects by activating cellular anti-oxidant activity: a structure-activity relationship study. AB - Flavonoids impart a variety of biological activities, including anti-oxidant, anti-inflammatory, and anti-genotoxic effects. This study investigated the effects of flavone luteolin and apigenin on immune cell functions, including proliferation, natural killer (NK) cell activity, and cytotoxic T lymphocyte (CTL) activity of isolated murine splenocytes. We report for the first time that flavones enhance lymphocyte proliferation at 10 MUM. Luteolin and apigenin significantly promote lipopolysaccharide (LPS)-stimulated splenocyte proliferation and enhance humoral immune responses. Luteolin induces a weak cell proliferation of lectin-stimulated splenic T cells, when compared to apigenin. In addition, both flavones significantly enhance NK cell and CTL activities. Furthermore, our study demonstrated that both flavones could inhibit lysosomal enzyme activity, suggesting a potential anti-inflammatory effect. The anti inflammatory activity was concomitant with the cellular anti-oxidant effect detected in macrophages, red blood cells, and splenocytes. We conclude from this study that flavones exhibited an immunomodulatory effect which could be ascribed, in part, to its cytoprotective capacity via its anti-oxidant activity. PMID- 26638169 TI - Regulatory B cells contribute to the impaired antitumor immunity in ovarian cancer patients. AB - Multiple factors in the tumor microenvironment were found to inhibit antitumor adaptive immune responses, allowing tumor persistence and growth. In this study, ascites from ovarian cancer patients were collected. We observed that a population of interleukin-10(+) B (IL-10(+) B) cells was preferentially enriched in the ascites. This population was associated with naive B cell phenotype or IgM or class-switched memory B cell phenotypes. The frequencies of IL-10(+) B cells were negatively correlated with the frequencies of interferon gamma-producing (IFN-g(+)) CD8(+) T cells and were positively correlated with the frequencies of Foxp3(+) CD4(+) T cells. To examine whether increased IL-10(+) B cells in ascites could directly result in increased suppression of IFN-g production by CD8(+) T cells, we cocultured CD8(+) T cells with autologous blood B cells or ascitic B cells and found that CD8(+) T cells cocultured with ascitic B cells demonstrated significantly suppressed IFN-g production. This suppression was in part mediated by IL-10 as well as low CD80/CD86 expression, since depletion of IL-10 and stimulation of CD28 partially reverted IL-10(+) B cell-mediated suppression. Together, these data demonstrated an additional regulatory mechanism in the tumor microenvironment, which utilizes IL-10(+) B cells. PMID- 26638170 TI - Norcantharidin induces autophagy-related prostate cancer cell death through Beclin-1 upregulation by miR-129-5p suppression. AB - Norcantharidin (NCTD) has an anticancer potential to allow it to be used in the treatment of some malignant cancers. However, whether NCTD may have similar anticancer effects on prostate cancer (PC) is unknown. Here, we aimed to examine the effects of NCTD on PC cells and the underlying mechanisms. We found that NCTD dose-dependently inhibited the PC cell growth, in either a cell counting kit-8 (CCK-8) assay or a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Moreover, NCTD dose-dependently increased the PC cell autophagy, through upregulation of Beclin-1. Furthermore, the Beclin-1 protein, but not mRNA, was regulated by NCTD in PC cells, suggesting post-transcriptional control of Beclin-1 by NCTD. Finally, microRNA (miR)-129-5p was found to be regulated by NCTD, and bioinformatics analyses showed that miR-129-5p targeted the 3'-UTR of Beclin-1 mRNA to inhibit its translation, which was confirmed by luciferase reporter assay. Together, these data suggest that NCTD may upregulate Beclin-1 through suppression of miR-129-5p to induce autophagic cell death and cell proliferation arrest in PC cells. Our study sheds light on using NCTD as a novel treatment for PC. PMID- 26638172 TI - Replication Origin Specification Gets a Push. AB - During the gap between G1 and S phases when replication origins are licensed and fired, it is possible that DNA translocases could disrupt pre-replicative complexes (pre-RCs). In this issue of Molecular Cell, Gros et al. (2015) find that pre-RCs can be pushed along DNA and retain the ability to support replication. PMID- 26638171 TI - Immunomonitoring in glioma immunotherapy: current status and future perspectives. AB - Given the continued poor clinical outcomes and refractory nature of glioblastoma multiforme to traditional interventions, immunotherapy is gaining traction due to its potential for specific tumor-targeting and long-term antitumor protective surveillance. Currently, development of glioma immunotherapy relies on overall survival as an endpoint in clinical trials. However, the identification of surrogate immunologic biomarkers can accelerate the development of successful immunotherapeutic strategies. Immunomonitoring techniques possess the potential to elucidate immunological mechanisms of antitumor responses, monitor disease progression, evaluate therapeutic effect, identify candidates for immunotherapy, and serve as prognostic markers of clinical outcome. Current immunomonitoring assays assess delayed-type hypersensitivity, T cell proliferation, cytotoxic T lymphocyte function, cytokine secretion profiles, antibody titers, and lymphocyte phenotypes. Yet, no single immunomonitoring technique can reliably predict outcomes, relegating immunological markers to exploratory endpoints. In response, the most recent immunomonitoring assays are incorporating emerging technologies and novel analysis techniques to approach the goal of identifying a competent immunological biomarker which predicts therapy responsiveness and clinical outcome. This review addresses the current status of immunomonitoring in glioma vaccine clinical trials with emphasis on correlations with clinical response. PMID- 26638173 TI - Get in LINE: Competition for Newly Minted Retrotransposon Proteins at the Ribosome. AB - In this issue, Ahl et al. (2015) and Doucet et al. (2015) illuminate structural and functional features of substrates that promote integration of RNA molecules into the human genome by LINE retrotransposons, contributing to the ~ 50% of the human genome that has been colonized by mobile genetic elements. PMID- 26638174 TI - Coordinated Ribosomal ITS2 RNA Processing by the Las1 Complex Integrating Endonuclease, Polynucleotide Kinase, and Exonuclease Activities. AB - The rapidly evolving internal transcribed spacer 2 (ITS2) in the pre-ribosomal RNA is one of the most commonly applied phylogenetic markers at species and genus level. Yet, during ribosome biogenesis ITS2 is removed in all eukaryotes by a common, but still unknown, mechanism. Here we describe the existence of an RNA processome, assembled from four conserved subunits, Las1-Grc3-Rat1-Rai1, that carries all the necessary RNA processing enzymes to mediate coordinated ITS2 rRNA removal. Las1 is the long-sought-after endonuclease cleaving 27SB pre-rRNA at site C2 to yield a 5'-OH end at the 26S pre-rRNA and 2',3' cyclic phosphate at the 3' end of 7S pre-rRNA. Subsequently, polynucleotide kinase Grc3 catalyzes ATP dependent 5'-OH phosphorylation of 26S pre-rRNA, which in turn enables Rat1-Rai1 exonuclease to generate 25S' pre-rRNA. ITS2 processing is reminiscent of tRNA splicing, but instead of subsequent tRNA ligation, the Las1 complex carries along an exonuclease tool to degrade the ITS2 rRNA. PMID- 26638175 TI - A Regression-Based Analysis of Ribosome-Profiling Data Reveals a Conserved Complexity to Mammalian Translation. AB - A fundamental goal of genomics is to identify the complete set of expressed proteins. Automated annotation strategies rely on assumptions about protein coding sequences (CDSs), e.g., they are conserved, do not overlap, and exceed a minimum length. However, an increasing number of newly discovered proteins violate these rules. Here we present an experimental and analytical framework, based on ribosome profiling and linear regression, for systematic identification and quantification of translation. Application of this approach to lipopolysaccharide-stimulated mouse dendritic cells and HCMV-infected human fibroblasts identifies thousands of novel CDSs, including micropeptides and variants of known proteins, that bear the hallmarks of canonical translation and exhibit translation levels and dynamics comparable to that of annotated CDSs. Remarkably, many translation events are identified in both mouse and human cells even when the peptide sequence is not conserved. Our work thus reveals an unexpected complexity to mammalian translation suited to provide both conserved regulatory or protein-based functions. PMID- 26638176 TI - Surface modification of PLGA nanoparticles with biotinylated chitosan for the sustained in vitro release and the enhanced cytotoxicity of epirubicin. AB - In this study, poly(d,l-lactide-co-glycolide) nanoparticles (PLGA NPs) with biotinylated chitosan (Bio-CS)-surface modification were prepared to be usded as a tumor-targeted and prolonged delivery system for anticancer drugs. Epirubicin (EPB), as a model drug, was encapsulated into Bio-CS surface modified PLGA (Bio CS-PLGA) NPs with a drug encapsulation efficiency of 84.1 +/- 3.4%. EPB-loaded Bio-CS-PLGA NPs were spherical shaped, and had a larger size and higher positive zeta potential compared to the unmodfied EPB-loaded PLGA NPs. The in vitro drug releases showed that EPB-loaded Bio-CS-PLGA NPs exhibited relatively constant drug release kinetics during the first 48 h and the drug burst release significantly decreased in comparison to the unmodified PLGA NPs. The results of MTS assays showed that Bio-CS-PLGA NPs markedly increased the cytotoxicity of EPB, compared to both the unmodified PLGA NPs and the CS-PLGA NPs. The uptakes of NPs in human breast cancer MCF-7 cells were evaluated by the flow cytometry and the confocal microscope. The results revealed that Bio-CS-PLGA NPs exhibited a greater extent of cellular uptake than the unmodified PLGA NPs and CS-PLGA NPs. Moreover, the cellular uptake of Bio-CS-PLGA NPs was evidently inhibited by the endocytic inhibitors and the receptor ligand, indicating that biotin receptor mediated endocytosis was perhaps involved in the cell entry of Bio-CS-PLGA NPs. In MCF-7 tumor-bearing nude mice, EPB-loaded Bio-CS-PLGA NPs were efficiently accumulated in the tumors. In summary, Bio-CS-PLGA NPs displayed great potential for application as the carriers of anticancer drugs. PMID- 26638177 TI - Interactions of EPS with soil minerals: A combination study by ITC and CLSM. AB - The adsorption of extracellular polymeric substances (EPS) from Pseudomonas putida on montmorillonite, kaolinite and goethite was investigated as a function of pH using batch studies coupled with confocal laser scanning microscopy (CLSM) and isothermal titration calorimetry (ITC). Characterization by Raman spectroscopy, X-ray photoelectron spectroscopy (XPS) and Fourier transform infrared (FTIR) spectroscopy showed that the extracted EPS contained carboxyl, phosphoryl, amino, and hydroxyl on functional groups as well as polysaccharides, protein and nucleic acid on components. The mass fraction of EPS adsorption on minerals decreased with the final pH increased from 3.0 to 9.0. The mass fraction of EPS-N adsorption varied with pH values and was higher than that of EPS-C or EPS-P on montmorillonite and kaolinite, while the mass fraction of EPS-P adsorption was the highest on goethite. CLSM results further demonstrated that proteins were predominantly distributed on the montmorillonite and kaolinite surfaces, while nucleic acids were mainly on the goethite surface. ITC results revealed that the adsorption process in all mineral systems was exothermic, and pH altered the heat effect of EPS-mineral reactions. The data obtained in this study would facilitate a better understanding of the adsorption mechanisms of EPS on minerals. PMID- 26638178 TI - Kinetics characterization of c-Src binding to lipid membranes: Switching from labile to persistent binding. AB - Cell signaling by the c-Src proto-oncogen requires the attachment of the protein to the inner side of the plasma membrane through the myristoylated N-terminal region, known as the SH4 domain. Additional binding regions of lower affinity are located in the neighbor intrinsically disordered Unique domain and the structured SH3 domain. Here we present a surface plasmon resonance study of the binding of a myristoylated protein including the SH4, Unique and SH3 domains of c-Src to immobilized liposomes. Two distinct binding processes were observed: a fast and a slow one. The second process lead to a persistently bound form (PB) with a slower binding and a much slower dissociation rate than the first one. The association and dissociation of the PB form could be detected using an anti-SH4 antibody. The kinetic analysis revealed that binding of the PB form follows a second order rate law suggesting that it involves the formation of c-Src dimers on the membrane surface. A kinetically equivalent PB form is observed in a myristoylated peptide containing only the SH4 domain but not in a construct including the three domains but with a 12-carbon lauroyl substituent instead of the 14-carbon myristoyl group. The PB form is observed with neutral lipids but its population increases when the immobilized liposomes contain negatively charged lipids. We suggest that the PB form may represent the active signaling form of c-Src while the labile form provides the capacity for fast 2D search of the target signaling site on the membrane surface. PMID- 26638179 TI - Telomere length is a prognostic biomarker in elderly advanced ovarian cancer patients: a multicenter GINECO study. AB - PURPOSE: Age induces a progressive decline in functional reserve and impacts cancer treatments. Telomere attrition leads to tissue senescence. We tested the hypothesis that telomere length (TL) could predict patient vulnerability and outcome with cancer treatment. PATIENTS AND METHODS: An ancillary study in the Elderly Women GINECO Trial 3 was performed to evaluate the impact of geriatric covariates on survival in elderly advanced ovarian cancer patients receiving six cycles of carboplatin. TL was estimated from peripheral blood at inclusion using standard procedures. RESULTS: TL (in base pairs) was estimated for 109/111 patients (median 6.1 kb; range [4.5-8.3 kb]). With a cut-off of 5.77 kb, TL discriminated two patient groups, long telomere (LT) and short telomeres (ST), with significantly different treatment completion rates of 0.80 (95% CI [0.71 0.89]) and 0.59 (95% CI [0.41-0.76]), respectively (odds ratio [OR]=2.8, p=0.02). ST patients were at higher risk of serious adverse events (SAE, OR=2.7; p=0.02) and had more unplanned hospital admissions (OR=2.1; p=0.08). After adjustment on FIGO stage, TL shorter than 6 kb was a risk factor of premature death (HR=1.57; p=0.06). CONCLUSION: This exploratory study identifies TL as predictive factor of decreased treatment completion, SAE risk, unplanned hospital admissions and OS after adjustment on FIGO stage. PMID- 26638180 TI - Unexpected red blood cell antibody distributions in Chinese people by a systematic literature review. AB - BACKGROUND: Unexpected antibodies are frequently associated with hemolytic disease of the fetus and newborn (HDFN) and hemolytic transfusion reactions (HTRs), and screening for those unexpected antibodies is critical for the safety and effectiveness of transfusion. Different populations differ in the prevalence of significant antibodies and also the low-frequency red blood cell (RBC) antigens. In China, antibody screening has been a common practice for pretransfusion testing for more than 10 years. However, there has been no national guidelines regarding the minimum antigens on the screening cells, thus making the antibody screening tests unsatisfactory. STUDY DESIGN AND METHODS: By a literature review, we systematically searched major databases from their inception to 2014, for publications regarding unexpected RBC antibodies, HTRs, and HDFNs in Chinese people, to explore the frequencies and clinical significance of unexpected RBC antibodies. RESULTS: The overall prevalence of unexpected antibodies was approximately 0.2% (14,095/6,102,361). A total of 2241 patients suffered HTRs (693 patients) or HDFN (1548 patients). Among all the reported antibodies, antibodies of the Rh blood group system were the most, followed by MNS, Lewis, Kidd, Duffy, Diego, and Kell systems. Several rare but clinically significant unexpected antibodies were reported: four anti-Le(x) , three anti Lu(a) , one anti-Tj(a) , and one anti-Hm . CONCLUSION: All the commonly seen RBC antibodies are reported in Chinese people. However, anti-K is very rare. Besides, anti-Mur, anti-Di(a) are clinically significant. We propose that in China, the antigens on the antibody screening cells should include those recommended by the AABB and British Committee for Standards in Haematology, as well as Di(a) and Mur antigens. PMID- 26638181 TI - Discordance between sonographic and cytological diagnoses of solid thyroid nodules: Retrospective Doppler U.S. examination is mandatory. PMID- 26638182 TI - Headache Rounds: Sudden Onset Chronic Daily Headache. PMID- 26638184 TI - Murine Mesenchymal Stem Cell Commitment to Differentiation Is Regulated by Mitochondrial Dynamics. AB - Mouse skin mesenchymal stem cells (msMSCs) are dermis CD105(+) CD90(+) CD73(+) CD29(+) CD34(-) mesodermal precursors which, after in vitro induction, undergo chondro, adipo, and osteogenesis. Extensive metabolic reconfiguration has been found to occur during differentiation, and the bioenergetic status of a cell is known to be dependent on the quality and abundance of the mitochondrial population, which may be regulated by fusion and fission. However, little is known regarding the impact of mitochondrial dynamics on the differentiation process. We addressed this knowledge gap by isolating MSCs from Swiss female mice, inducing these cells to differentiate into osteo, chondro, and adipocytes and measuring changes in mass, morphology, dynamics, and bioenergetics. Mitochondrial biogenesis was increased in adipogenesis, as evaluated through confocal microscopy, citrate synthase activity, and mtDNA content. The early steps of adipo and osteogenesis involved mitochondrial elongation, as well as increased expression of mitochondrial fusion proteins Mfn1 and 2. Chondrogenesis involved a fragmented mitochondrial phenotype, increased expression of fission proteins Drp1, Fis1, and 2, and enhanced mitophagy. These events were accompanied by profound bioenergetic alterations during the commitment period. Moreover, knockdown of Mfn2 in adipo and osteogenesis and the overexpression of a dominant negative form of Drp1 during chondrogenesis resulted in a loss of differentiation ability. Overall, we find that mitochondrial morphology and its regulating processes of fission/fusion are modulated early on during commitment, leading to alterations in the bioenergetic profile that are important for differentiation. We thus propose a central role for mitochondrial dynamics in the maintenance/commitment of mesenchymal stem cells. PMID- 26638185 TI - Randomized trial of a prevention intervention that embeds weight-related messages within a general parenting program. AB - OBJECTIVE: To assess the extent to which an obesity prevention intervention that embeds obesity-related messages within a parenting program, compared with controls who received weekly mailings, resulted in a smaller increase in children's BMI (primary outcome) and improvements in weight-related behaviors from baseline to 9-month follow-up. METHODS: Fifty-six families were randomly assigned to the intervention and 56 to control. Children were primarily Hispanic (58%) or Black/African American (23%). Intervention included nine weekly: group parenting sessions, children's sessions, and homework assignments. At baseline, post-intervention, and 9-month follow-up, staff assessed children's weight and height. Parents completed surveys assessing parenting skills, feeding behaviors, and children's weight-related behaviors. RESULTS: From baseline to 9-month follow up, BMI decreased by a mean of 0.13 kg m(-2) among children in the intervention and increased by 0.21 kg m(-2) among children in the control, resulting in a nonsignificant difference (multivariate adjusted difference = -0.36; 95% confidence interval [CI] -1.23, 0.51; P = 0.41). Parents in the intervention decreased restrictive feeding practices relative to control (-0.30; 95% CI -0.53, -0.07; P = 0.01). Intervention and control arms showed similar changes in children's weight-related behaviors. CONCLUSIONS: The intervention improved restrictive feeding but did not influence children's BMI or weight-related behaviors compared to controls who received weekly mailings. PMID- 26638186 TI - Coelomic epithelium-derived cells in visceral morphogenesis. AB - Coelomic cavities of vertebrates are lined by a mesothelium which develops from the lateral plate mesoderm. During development, the coelomic epithelium is a highly active cell layer, which locally is able to supply mesenchymal cells that contribute to the mesodermal elements of many organs and provide signals which are necessary for their development. The relevance of this process of mesenchymal cell supply to the developing organs is becoming clearer because genetic lineage tracing techniques have been developed in recent years. Body wall, heart, liver, lungs, gonads, and gastrointestinal tract are populated by cells derived from the coelomic epithelium which contribute to their connective and vascular tissues, and sometimes to specialized cell types such as the stellate cells of the liver, the Cajal interstitial cells of the gut or the Sertoli cells of the testicle. In this review we collect information about the contribution of coelomic epithelium derived cells to visceral development, their developmental fates and signaling functions. The common features displayed by all these processes suggest that the epithelial-mesenchymal transition of the embryonic coelomic epithelium is an underestimated but key event of vertebrate development, and probably it is shared by all the coelomate metazoans. PMID- 26638183 TI - Pediatric gliomas as neurodevelopmental disorders. AB - Brain tumors represent the most common solid tumor of childhood, with gliomas comprising the largest fraction of these cancers. Several features distinguish them from their adult counterparts, including their natural history, causative genetic mutations, and brain locations. These unique properties suggest that the cellular and molecular etiologies that underlie their development and maintenance might be different from those that govern adult gliomagenesis and growth. In this review, we discuss the genetic basis for pediatric low-grade and high-grade glioma in the context of developmental neurobiology, and highlight the differences between histologically-similar tumors arising in children and adults. PMID- 26638187 TI - Lifetime indirect cost of childhood overweight and obesity: A decision analytic model. AB - OBJECTIVE: To estimate the indirect lifetime cost of childhood overweight and obesity for Germany. METHODS: The lifetime cohort model consisted of two parts: (a) Model I used data from the German Interview and Examination Survey for Children on prevalence of BMI categories during childhood to evaluate BMI trajectories before the age of 18; and (b) Model II estimated lifetime excess indirect cost based on the history of childhood BMI. Indirect costs were defined as the opportunity cost of lost productivity due to mortality and morbidity and were identified through a systematic literature review. RESULTS: Our analysis showed that the majority of children with overweight and obesity remained in the same BMI category during their adult life, resulting in significant indirect lifetime costs. We estimated that overweight and obesity during childhood resulted in an excess lifetime cost per person of ?4,209 (men) and ?2,445 (women). For the current prevalent German population, the excess lifetime cost was ?145 billion. CONCLUSIONS: Our study showed that childhood obesity results in significant economic burden on the society. Therefore, cost-effective strategies targeted at reducing the prevalence of obesity during the early years of life can significantly reduce both healthcare and nonhealthcare costs over the lifetime. PMID- 26638188 TI - Impact of sleep duration on food intake regulation: Different mechanisms by sex? PMID- 26638189 TI - Assessing elements of a family approach to reduce adolescent drinking frequency: parent-adolescent relationship, knowledge management and keeping secrets. AB - AIMS: To estimate (1) the associations between parent-adolescent relationship, parental knowledge and subsequent adolescent drinking frequency and (2) the influence of alcohol use on parental knowledge. DESIGN: Path analysis of school based cohort study with annual surveys. SETTING: Post-primary schools from urban and intermediate/rural areas in Northern Ireland. PARTICIPANTS: A total of 4937 post-primary school students aged approximately 11 years in 2000 followed until approximately age 16 years in 2005. MEASUREMENTS: Pupil-reported measures of: frequency of alcohol use; parent-child relationship quality; subdimensions of parental monitoring: parental control, parental solicitation, child disclosure and child secrecy. FINDINGS: Higher levels of parental control [ordinal logistic odds ratio (OR) = 0.86, 95% confidence interval (CI) = 0.78, 0.95] and lower levels of child secrecy (OR = 0.83, 95% CI = 0.75, 0.92) were associated subsequently with less frequent alcohol use. Parental solicitation and parent child relationship quality were not associated with drinking frequency. Weekly alcohol drinking was associated with higher subsequent secrecy (beta -0.42, 95% CI = -0.53, -0.32) and lower parental control (beta -0.15, 95% CI = -0.26, 0.04). Secrecy was more strongly predictive of alcohol use at younger compared with older ages (P = 0.02), and alcohol use was associated less strongly with parental control among families with poorer relationships (P = 0.04). CONCLUSIONS: Adolescent alcohol use appears to increase as parental control decreases and child secrecy increases. Greater parental control is associated with less frequent adolescent drinking subsequently, while parent-child attachment and parental solicitation have little influence on alcohol use. PMID- 26638190 TI - Screening for familial and hereditary prostate cancer. AB - Prostate cancer (PC) has the highest degree of genetic transmission of any form of malignancy. In some families, the hereditary pattern is so strong as to mimic an autosomal dominance trait. We reviewed the known predisposing genetic markers to assess possible strategies for screening of families at risk. We carried out a systematic literature search using the Pubmed service of the National Center for Biotechnology Information (NCBI) and several gene libraries, including the NCBI SNP Library, the Online Mendelian Inheritance in Man(r) Catalog of Human Genes and Genetic Disorders (OMIM) and SNPedia to obtain known gene loci, SNPs and satellite markers associated with PC. We further cross referenced information on identified loci comparing data from different articles and gene reference sites. Whenever possible, we recorded the odds ratio (OR) for the allele associated with PC. In multiple different linkage studies, many independent PC associated loci have been identified on separate chromosomes. Genome-wide association studies have added many more markers to the set derived from linkage investigations. A subset of the alleles is associated with early onset and aggressive cancer. Due to the great heterogeneity, the OR for any one allele predicting future development of this malignancy is low. The strongest predictors are the BRCA2 mutations, and the highly penetrant G84E mutation in HOXB13. The presence of multiple risk alleles is more highly predictive than a single allele. Technical limitations on screening large panels of alleles are being overcome. It is appropriate to begin supplementing prostate specific antigen testing with alleles, such as BRCA2 and HOXB13, disclosed by targeted genomic analysis in families with an unfavorable family cancer history. Future population studies of PC should include genomic sequencing protocols, particularly in families with a history of PC and other malignancies. PMID- 26638191 TI - HEDGEHOG Signal in hepatocytes mediates macrophage recruitment: A new mechanism and potential therapeutic target for fatty liver disease. PMID- 26638192 TI - Weight loss on low-fat vs. low-carbohydrate diets by insulin resistance status among overweight adults and adults with obesity: A randomized pilot trial. AB - OBJECTIVE: To test for differential weight loss response to low-fat (LF) vs. low carbohydrate (LC) diets by insulin resistance status with emphasis on overall quality of both diets. METHODS: Sixty-one adults, BMI 28-40 kg/m(2) , were randomized in a 2 * 2 design to LF or LC by insulin resistance status in this pilot study. Primary outcome was 6-month weight change. Participants were characterized as more insulin resistant (IR) or more insulin sensitive (IS) by median split of baseline insulin-area-under-the-curve from an oral glucose tolerance test. Intervention consisted of 14 one-hour class-based educational sessions. RESULTS: Baseline % carbohydrate:% fat:% protein was 44:38:18. At 6 months, the LF group reported 57:21:22 and the LC group reported 22:53:25 (IR and IS combined). Six-month weight loss (kg) was 7.4 +/- 6.0 (LF-IR), 10.4 +/- 7.8 (LF-IS), 9.6 +/- 6.6 (LC-IR), and 8.6 +/- 5.6 (LC-IS). No significant main effects were detected for weight loss by diet group or IR status; there was no significant diet * IR interaction. Significant differences in several secondary outcomes were observed. CONCLUSIONS: Substantial weight loss was achieved overall, but a significant diet * IR status interaction was not observed. Opportunity to detect differential response may have been limited by the focus on high diet quality for both diet groups and sample size. PMID- 26638195 TI - Portal inflammation is independently associated with fibrosis and metabolic syndrome in pediatric nonalcoholic fatty liver disease. AB - Pediatric nonalcoholic fatty liver disease (NAFLD) histology demonstrates variable amounts of portal inflammation, which may be associated with more severe liver disease and fibrosis. We assessed the relationship between portal inflammation, hepatic fibrosis, and the metabolic syndrome in pediatric NAFLD. Children with biopsy-proven NAFLD were eligible for inclusion. Histology was assessed using Kleiner fibrosis stage and the Nonalcoholic Steatohepatitis Clinical Research Network system for portal inflammation. Patients were divided by histology into type 1, type 2, and overlap NAFLD. Multivariable ordinal logistic regression was used to determine factors associated with fibrosis and portal inflammation. The 430 Caucasian children were divided into 52 with type 1, 95 with type 2, and 283 with overlap NAFLD. Those with type 2 had a more severe metabolic phenotype, with higher body mass index z score (2.0 versus 1.6, P < 0.0001), waist circumference centile (96th versus 90th, P < 0.0001), and triglycerides (84 versus 77 mg/dL, P = 0.01) and lower high-density lipoprotein (46 versus 60 mg/dL, P = 0.004) than those with type 1. Similarly, those with overlap NAFLD had a more severe phenotype. Stage 2-3 fibrosis was present in 69/283 (24%) with overlap NAFLD. Portal inflammation was associated with stage 2 3 fibrosis on multivariable analysis (95% confidence interval 1.4-5.2, odds ratio = 3.7). Waist circumference centile was associated with portal inflammation (95% confidence interval 1.2-3.4, odds ratio = 2.0). CONCLUSION: Portal inflammation is associated with more advanced pediatric NAFLD and features of the metabolic syndrome. PMID- 26638193 TI - Impact of adiposity on cellular adhesion: The Multi-Ethnic Study of atherosclerosis (MESA). AB - OBJECTIVE: At the cellular level, how excess adiposity promotes atherogenesis is not fully understood. One pathway involves secretion of adipokines that stimulate endothelial dysfunction through increased expression of adhesion molecules. However, the relationship of adiposity to adhesion molecules that promote atherosclerosis is largely unknown. METHODS: Linear regression models were used to assess the sex-specific associations of soluble cellular adhesion molecules (sP- and sL-selectin, sICAM-1, sVCAM-1, and sHGF) and adiposity in 5,974 adults examined as part of the Multi-Ethnic Study of Atherosclerosis (MESA). Adiposity measures included body mass index (BMI), waist-to-hip-ratio (WHR), and computed tomography measures of subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT). RESULTS: The mean age was 64 years and 52% were female. In multivariable models adjusting for traditional cardiovascular risk factors, sHGF was positively associated with BMI, WHR, and VAT in both males and females, and sP-selectin with WHR and VAT in males. sVCAM-1 was inversely associated with VAT in females only. CONCLUSIONS: Our results showed the relation of adiposity to soluble cellular adhesion proteins was similar across adiposity measures and for both sexes. However, the relationship between adiposity and sVCAM-1 and P selectin may be modified by sex and the measure used to assess adiposity. PMID- 26638194 TI - Single-cell functional analysis of parathyroid adenomas reveals distinct classes of calcium sensing behaviour in primary hyperparathyroidism. AB - Primary hyperparathyroidism (PHPT) is a common endocrine neoplastic disorder caused by a failure of calcium sensing secondary to tumour development in one or more of the parathyroid glands. Parathyroid adenomas are comprised of distinct cellular subpopulations of variable clonal status that exhibit differing degrees of calcium responsiveness. To gain a clearer understanding of the relationship among cellular identity, tumour composition and clinical biochemistry in PHPT, we developed a novel single cell platform for quantitative evaluation of calcium sensing behaviour in freshly resected human parathyroid tumour cells. Live-cell intracellular calcium flux was visualized through Fluo-4-AM epifluorescence, followed by in situ immunofluorescence detection of the calcium sensing receptor (CASR), a central component in the extracellular calcium signalling pathway. The reactivity of individual parathyroid tumour cells to extracellular calcium stimulus was highly variable, with discrete kinetic response patterns observed both between and among parathyroid tumour samples. CASR abundance was not an obligate determinant of calcium responsiveness. Calcium EC50 values from a series of parathyroid adenomas revealed that the tumours segregated into two distinct categories. One group manifested a mean EC50 of 2.40 mM (95% CI: 2.37-2.41), closely aligned to the established normal range. The second group was less responsive to calcium stimulus, with a mean EC50 of 3.61 mM (95% CI: 3.45-3.95). This binary distribution indicates the existence of a previously unappreciated biochemical sub-classification of PHPT tumours, possibly reflecting distinct etiological mechanisms. Recognition of quantitative differences in calcium sensing could have important implications for the clinical management of PHPT. PMID- 26638196 TI - Beyond catecholamines: Measuring autonomic responses to psychosocial context. AB - Despite longstanding interest among human biologists in autonomic responses to socioecological context or culture change, the adoption of autonomic measures has been limited by methodological challenges. Catecholamine secretion is the most direct measure, but not all study designs are amenable to urinary sampling, and blood pressure lacks specificity to the parasympathetic or sympathetic division of the autonomic nervous system. This article reviews three alternative approaches for measuring autonomic responses: salivary alpha-amylase as a nonspecific autonomic marker, respiratory sinus arrhythmia as a specific parasympathetic marker, and the pre-ejection period as a specific sympathetic marker. Study design considerations are discussed in detail, including ambulatory sampling protocols that permit the evaluation of autonomic responses to everyday life. Researchers interested in how culture and social experience "get under the skin," as well as those concerned with the evolution of social engagement, can benefit from these well-validated biomarkers that are nevertheless relatively novel in human biology. Am. J. Hum. Biol. 28:309-317, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26638197 TI - Fetal epicardial fat thickness in diabetic and non-diabetic pregnancies: A retrospective cross-sectional study. AB - OBJECTIVE: To evaluate fetal epicardial fat thickness (EFT) in diabetic and control pregnancies. METHODS: A retrospective cross-sectional study was performed in which fetal EFT was measured in the second trimester in 28 diabetics and 28 non-diabetic patients. Maternal BMI, estimated fetal weight, birth weight, fetal abdominal circumference, and subcutaneous fat thickness were also collected. Statistical analysis was carried out by means of chi-square, Wilcoxon rank-sum test, Student's T test, and linear regression as appropriate. RESULTS: EFT was significantly higher in diabetic (1.43 mm) vs. control fetuses (1.16 mm), P = 0.02. This relationship remained significant when controlling for covariates. CONCLUSIONS: EFT was higher in fetuses of diabetic mothers vs. fetuses from controls. If confirmed in prospective studies, this may represent a novel marker for altered fetal metabolism due to maternal diabetes. PMID- 26638198 TI - Predicting risk in primary biliary cholangitis. PMID- 26638199 TI - Structural biology of tumor necrosis factor demonstrated for undergraduates instruction by computer simulation. AB - This work presents a three-dimensional (3D) modeling exercise for undergraduate students in chemistry and health sciences disciplines, focusing on a protein group linked to immune system regulation. Specifically, the exercise involves molecular modeling and structural analysis of tumor necrosis factor (TNF) proteins, both wild type and mutant. The structure of the tumor necrosis factor type 1 receptor (TNF-R1) is also briefly explored. TNF and TNF-R1 play major roles in maintaining human immune-system homeostasis. Upon binding with TNFR-1, the TNF can activate the nuclear factor kappa B (NF-kappaB), eventually resulting in apoptosis or cell death. These essential features of the clinically relevant TNF family is explored within the frame work of a readily adaptable tutorial. (c) 2015 by The International Union of Biochemistry and Molecular Biology, 44:246 255, 2016. PMID- 26638200 TI - Optical coherence tomography in polypoidal choroidal vasculopathy disease. PMID- 26638201 TI - Twenty-four-hour intraocular pressure measurement in glaucoma. PMID- 26638202 TI - We can, but should we? The place of new technology in ophthalmology. PMID- 26638204 TI - Corrigendum. PMID- 26638206 TI - Biomarker validity in the critically ill: all must face the (continuous) renal replacement challenge! PMID- 26638207 TI - Low dose triterpene-quinone fraction from Ardisia crispa root precludes chemical induced mouse skin tumor promotion. AB - BACKGROUND: Drastic increment of skin cancer incidence has driven natural product based chemoprevention as a promising approach in anticancer drug development. Apart from its traditional usages against various ailments, Ardisia crispa (Family: Myrsinaceae) specifically its triterpene-quinone fraction (TQF) which was isolated from the root hexane extract (ACRH) was recently reported to exert antitumor promoting activity in vitro. This study aimed at determining chemopreventive effect of TQF against chemically-induced mouse skin tumorigenesis as well as elucidating its possible pathway(s). METHODS: Mice (n = 10) were initiated with single dose of 7,12-dimethylbenz[alpha]anthracene (DMBA) (390 nmol/100 MUl) followed by, a week later, repeated promotion (twice weekly; 20 weeks) with 12-O-tetradecanoylphorbol-13-acetate (TPA) (1.7 nmol/100 MUl). TQF (10, 30 and 100 mg/kg) and curcumin (10 mg/kg; reference) were, respectively, applied topically to DMBA/TPA-induced mice 30 min before each TPA application. Upon termination, histopathological and biochemical analysis, as well as Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and transcription factor enzyme-linked immunosorbent assay (ELISA) assays were performed to elucidate the potential mechanism of TQF. RESULTS: With comparison to the carcinogen control, results revealed that lower dose of TQF (10 mg/kg) conferred antitumor promoting effect via significant (P < 0.05) suppression against lipid peroxidation (LPO), apoptotic index (cell death) and nuclear factor-kappa B (NF kappaB), along with reduction of keratinocyte proliferation; whilst its higher dose (100 mg/kg) was found to promote tumorigenesis by significantly (P < 0.05) increasing LPO and apoptotic index, in addition to aggravating keratinocyte proliferation. CONCLUSIONS: This study evidenced that TQF, particularly at its lower dosage (10 mg/kg), ameliorated DMBA/TPA-induced mouse skin tumorigenesis. Though, future investigations are warranted to determine the lowest possible therapeutic dose of TQF in subsequent in vivo chemopreventive studies. PMID- 26638210 TI - Development of a Loop-Mediated Isothermal Amplification Assay for Rapid and Specific Identification of ACT Producing Alternaria alternata, the Agent of Brown Spot Disease in Tangerine. AB - Rapid, accurate, and easy identification of pathogenic agents has always been important in medicine, veterinary, and agriculture. The brown spot infection is among the most common diseases in tangerine caused by Alternaria alternata. Due to the existence of seven various pathotypes of A. alternata species, it is challenging and time consuming to detect a pathotype responsible for citrus brown spot. In this study, we were seeking a rapid and specific approach to identify the tangerine pathotype within the A. alternata-pathogenic species, using the loop-mediated isothermal amplification (LAMP) method and actts2 gene as a marker molecule. Nine pathogenic samples were obtained from the region of Ramsar, Iran, and certified as A. alternata-pathogenic isolates. Specific primers were designed for regions coding for Alternaria citri toxin (ACT), and the PCR and LAMP reactions were performed. Our data showed that the primers designed for the tangerine pathotype of A. alternata were specific, and in both reactions, positive results were only observed in desired pathotypes. In the other pathotypes of this species as well as other standard fungal samples as negative controls, no positive result was observed. Therefore, our results suggest the possibility to detect the tangerine-specific A. alternata pathotype from other related species with a high accuracy and in early stages of the disease. PMID- 26638208 TI - Salt-stress-responsive chloroplast proteins in Brassica juncea genotypes with contrasting salt tolerance and their quantitative PCR analysis. AB - Brassica juncea is mainly cultivated in the arid and semi-arid regions of India where its production is significantly affected by soil salinity. Adequate knowledge of the mechanisms underlying the salt tolerance at sub-cellular levels must aid in developing the salt-tolerant plants. A proper functioning of chloroplasts under salinity conditions is highly desirable to maintain crop productivity. The adaptive molecular mechanisms offered by plants at the chloroplast level to cope with salinity stress must be a prime target in developing the salt-tolerant plants. In the present study, we have analyzed differential expression of chloroplast proteins in two Brassica juncea genotypes, Pusa Agrani (salt-sensitive) and CS-54 (salt-tolerant), under the effect of sodium chloride. The chloroplast proteins were isolated and resolved using 2DE, which facilitated identification and quantification of 12 proteins that differed in expression in the salt-tolerant and salt-sensitive genotypes. The identified proteins were related to a variety of chloroplast-associated molecular processes, including oxygen-evolving process, PS I and PS II functioning, Calvin cycle and redox homeostasis. Expression analysis of genes encoding differentially expressed proteins through real time PCR supported our findings with proteomic analysis. The study indicates that modulating the expression of chloroplast proteins associated with stabilization of photosystems and oxidative defence plays imperative roles in adaptation to salt stress. PMID- 26638209 TI - Effects of the adenosinergic system on the expression and acquisition of sensitization to conditioned place preference in morphine-conditioned rats. AB - In the presented study, we attempt to investigate if the sensitization to conditioned place preference (CPP) induced by low doses of morphine was developed in rats which have been previously conditioned with morphine. The experiments were performed in the CPP test. Firstly, it has been demonstrated that administration of ineffective dose of morphine on the 9th day induces the increase in time spent of rats at a morphine-paired compartment, confirming that sensitization to CPP has been developed in these animals. Secondly, it has been shown that stimulation of A1 receptor significantly inhibits the expression of morphine-induced of sensitization, and blockade of these receptors produces the opposite effect. Finally, it has been indicated that both stimulation and blockade of A1 and/or A2A receptors inhibit the acquisition of sensitization to CPP. The obtained results have strongly supported the significance of adenosinergic system in both expression and acquisition of studied sensitization. These results seem to be important for the identification of connections in the central nervous system which can help finding new strategies to attenuate rewarding action of morphine. PMID- 26638211 TI - A Novel Mesophilic Anaerobic Digestion System for Biogas Production and In Situ Methane Enrichment from Coconut Shell Pyroligneous. AB - A novel mesophilic anaerobic digestion process with detoxification-treated coconut shell pyroligneous was established, exhibiting an effective advantage in biogas production. The pyroligneous collected contained 166.2 g l(-1) acetic acid, indicating great potential for biogas production. Detoxification was an effective way of simultaneously enriching biodegradable ingredients and removing inhibitors (mainly as phenols and organic acids) for digestion process. The digestion process lasted 96 h and fermentation characteristics (chemical oxygen demand (COD) removal ratio, volatile fatty acid (VFA) consumptions, pH, total gas, methane yield, and phenol removal efficiency) were measured. The experiments successfully explored the optimum detoxification parameters, oxidized with 10 % H2O2 followed by overliming, and demonstrated 89.3 % COD removal, 91.4 % methane content, 0.305 LCH4/g COD removed CH4 yield, and 88.81 % phenol removal ratio. This study provided clues to overcome the negative effects of inhibitors in pyroligneous on biogas production. The findings could contribute to significant process in detoxified pretreatment of pyroligneous and develop an economically feasible technology for treating pyroligneous after producing charcoal. PMID- 26638213 TI - Alprazolam for essential tremor. AB - BACKGROUND: Essential tremor (ET) is one of the most common movement disorders. Treatment is based primarily on pharmacological agents. On this basis, although primidone and propranolol are well-established treatments in clinical practice, they could be ineffective in 25% to 55% of patients and can produce serious adverse events (AEs) in a large percentage of individuals. For these reasons, evaluating treatment alternatives for ET may be a worthwhile pursuit. Alprazolam has been suggested as a potentially useful agent for treatment of individuals with ET, but its efficacy and safety are uncertain. OBJECTIVES: PrimaryTo assess the efficacy and safety of alprazolam in the treatment of individuals with ET. SecondaryTo examine effects of alprazolam treatment on the quality of life of people with ET. SEARCH METHODS: We carried out a systematic search without language restrictions to identify all relevant trials. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (January 1966 to September 2015), EMBASE (January 1988 to September 2015), the National Institute for Health and Care Excellence (NICE) (1999 to September 2015), ClinicalTrials.gov (1997 to September 2015) and the World Health Organiza tion (WHO) International Clinical Trials Registry Platform (ICTRP) (2004 to September 2015). We handsearched grey literature and examined the reference lists of identified studies and reviews. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) of alprazolam versus placebo or any other treatment. We included studies in which ET was diagnosed according to accepted and validated diagnostic criteria. We excluded studies that included patients presenting with secondary forms of tremor or reporting only neurophysiological parameters for the pur p ose of assessing outcomes. DATA COLLECTION AND ANALYSIS: Two review authors independently collected and extracted data using a data collection form. We assessed risk of bias and the body of evidence. We used inverse variance methods for continuous outcomes and measurement scales. We compared differences between treatment groups as mean differences. We used Review Manager software for management and analysis of data. MAIN RESULTS: We included in this review one trial that compared alprazolam versus placebo (24 participants). It was judged to have high overall risk of bias. We graded the overall quality of evidence as very low. Compared with those given placebo, participants treated with alprazolam showed a significant reduction in tremor severity (mean difference (MD) -0.75, 95% confidence interval (CI) -0.83 to -0.67). Nine alprazolam-treated participants (75%) developed AEs, mainly represented by sedation (50%), constipation (17%) and dry mouth (9%). No participants in the alprazolam group and no p articipants in the placebo group discontinued treatment and dropped out of the study. AUTHORS' CONCLUSIONS: Currently available data reveal evidence insufficient for assessment of the efficacy and safety of alprazolam treatment for individuals with ET. PMID- 26638214 TI - Heat strain imposed by personal protective ensembles: quantitative analysis using a thermoregulation model. AB - The objective of this paper is to study the effects of personal protective equipment (PPE) and specific PPE layers, defined as thermal/evaporative resistances and the mass, on heat strain during physical activity. A stepwise thermal manikin testing and modeling approach was used to analyze a PPE ensemble with four layers: uniform, ballistic protection, chemical protective clothing, and mask and gloves. The PPE was tested on a thermal manikin, starting with the uniform, then adding an additional layer in each step. Wearing PPE increases the metabolic rates [Formula: see text], thus [Formula: see text] were adjusted according to the mass of each of four configurations. A human thermoregulatory model was used to predict endurance time for each configuration at fixed [Formula: see text] and at its mass adjusted [Formula: see text]. Reductions in endurance time due to resistances, and due to mass, were separately determined using predicted results. Fractional contributions of PPE's thermal/evaporative resistances by layer show that the ballistic protection and the chemical protective clothing layers contribute about 20 %, respectively. Wearing the ballistic protection over the uniform reduced endurance time from 146 to 75 min, with 31 min of the decrement due to the additional resistances of the ballistic protection, and 40 min due to increased [Formula: see text] associated with the additional mass. Effects of mass on heat strain are of a similar magnitude relative to effects of increased resistances. Reducing resistances and mass can both significantly alleviate heat strain. PMID- 26638215 TI - Effect of estrogen and/or progesterone administration on traumatic brain injury caused brain edema: the changes of aquaporin-4 and interleukin-6. AB - The role of aquaporin-4 (AQP4) and interleukin-6 (IL-6) in the development of brain edema post-traumatic brain injury (TBI) has been indicated. The present study was designed to investigate the effect(s) of administration of progesterone (P) and/or estrogen (E) on brain water content, AQP4 expression, and IL-6 levels post-TBI. The ovariectomized rats were divided into 11 groups: sham, one vehicle, two vehicles, E1, E2, P1, P2, E1 + P1, E1 + P2, E2 + P1, and E2 + P2. The brain AQP4 expression, IL-6 levels, and water content were evaluated 24 h after TBI induced by Marmarou's method. The low (E1 and P1) and high (E2 and P2) doses of estrogen and progesterone were administered 30 min post-TBI. The results showed that brain water content and AQP4 expression decreased in the E1, E2, P1, and P2 treated groups. The administration of E1 decreased IL-6 levels. Addition of progesterone decreased the inhibitory effect of E1 and E2 on the accumulation of water in the brain. Administration of E1 + P1 and E1 + P2 decreased the inhibitory effect of E1 on the IL-6 levels and AQP4 protein expression. Our findings suggest that estrogen or progesterone by itself has more effective roles in decrease of brain edema than combination of both. Possible mechanism may be mediated by the alteration of AQP4 and IL-6 expression. However, further studies are required to verify the exact mechanism. PMID- 26638212 TI - N-glycoprotein macroheterogeneity: biological implications and proteomic characterization. AB - Glycosylation is a co- and post-translational modification that is critical for the regulation of the biophysical properties and biological activities of diverse proteins. Biosynthetic pathways for protein glycosylation are inherently inefficient, resulting in high structural diversity in mature glycoproteins. Macroheterogeneity is the structural diversity due to the presence or absence of glycans at specific glycosylation sites, and is caused by inefficiency in the initial transfer of glycans to proteins. Here, we review the enzymatic and evolutionary mechanisms controlling macroheterogeneity, its biological consequences in physiological and disease states, its relevance to heterologous production and glycoengineering of glycoproteins, and mass spectrometry based methods for its analysis. We highlight the importance of the analysis of macroheterogeneity for a complete understanding of glycoprotein biosynthesis and function, and emphasize how advances in mass spectrometry glycoproteomics will enable analysis of this critical facet of glycoprotein structural diversity. PMID- 26638216 TI - Nosocomial dissemination of VIM-2-producing ST235 Pseudomonas aeruginosa in Lithuania. AB - Pseudomonas aeruginosa multidrug resistance, and particularly the production of carbapenemases linked to international high-risk clones, is of growing concern. While high levels of carbapenem resistance (>60 %) have been reported in Lithuania, so far, there is no information on the underlying mechanisms. Thus, the aim of this work was to determine the molecular epidemiology and prevalence of acquired carbapenemases among 73 carbapenem-resistant P. aeruginosa isolates recovered in a hospital from Kaunas, Lithuania in 2011-2012. The presence of acquired carbapenemases was evaluated through phenotypic (modified Hodge test, cloxacillin inhibition test, double-disc synergy test) and genetic methods [polymerase chain reaction (PCR) and sequencing]. Clonal relatedness was assessed by pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST). Acquired beta-lactamases were detected in 19 (26 %) of the isolates, whereas resistance was exclusively chromosomal (OprD inactivation +/- AmpC hyperproduction) in the remaining 54 (74 %) isolates. The acquired beta lactamases detected included 16 VIM-2, one PER-1 and two GES enzymes. PFGE revealed that 15 of the 16 VIM-2 isolates belonged to a single clone, identified as the international high-risk clone ST235 by MLST. bla VIM-2 was preceded by aacA7 in a class I integron, similar to epidemic ST235 isolates described in nearby countries. Additionally, sequencing of bla GES revealed the presence of the carbapenem-hydrolysing enzyme GES-5 in one of the isolates and a novel GES variant, designated GES-27, in the other. GES-27 differed from GES-5 by a single amino acid substitution, proline 167, that was replaced by glutamine. Increasing emergence and dissemination of concerning resistance mechanisms and international clones warrants global surveillance and control strategies. PMID- 26638217 TI - Reactivation of coccidioidomycosis: a prosthetic joint infection in Spain. AB - A resident of Spain was found to have a prosthetic knee infection due to coccidioidomycosis. He had a history of having pneumonia which resolved while living in an area of California endemic for Coccidioides in 1957-1961. The patient left California in 1961 returned to Spain and never left Spain thereafter. In 2006, a total knee replacement was done. In 2013, a prosthetic knee infection was documented due to coccidioidomycosis. By molecular DNA analysis, Coccidioides immitis was identified from the knee tissue, a species most commonly found in California. This represents reactivation of a Coccidioides infection 56 years after leaving the endemic area. PMID- 26638218 TI - Ulcerate colitis and protein C system: is there a link of causality. PMID- 26638220 TI - Of truths, concepts and social constructions. PMID- 26638219 TI - A Randomized Depression Prevention Trial Comparing Interpersonal Psychotherapy- Adolescent Skills Training to Group Counseling in Schools. AB - Given the rise in depression disorders in adolescence, it is important to develop and study depression prevention programs for this age group. The current study examined the efficacy of Interpersonal Psychotherapy-Adolescent Skills Training (IPT-AST), a group prevention program for adolescent depression, in comparison to group programs that are typically delivered in school settings. In this indicated prevention trial, 186 adolescents with elevated depression symptoms were randomized to receive IPT-AST delivered by research staff or group counseling (GC) delivered by school counselors. Hierarchical linear modeling examined differences in rates of change in depressive symptoms and overall functioning from baseline to the 6-month follow-up assessment. Cox regression compared rates of depression diagnoses. Adolescents in IPT-AST showed significantly greater improvements in self-reported depressive symptoms and evaluator-rated overall functioning than GC adolescents from baseline to the 6-month follow-up. However, there were no significant differences between the two conditions in onset of depression diagnoses. Although both intervention conditions demonstrated significant improvements in depressive symptoms and overall functioning, results indicate that IPT-AST has modest benefits over groups run by school counselors which were matched on frequency and duration of sessions. In particular, IPT-AST outperformed GC in reduction of depressive symptoms and improvements in overall functioning. These findings point to the clinical utility of this depression prevention program, at least in the short-term. Additional follow-up is needed to determine the long-term effects of IPT-AST, relative to GC, particularly in preventing depression onset. PMID- 26638221 TI - Child and adolescent mental health nursing seen through a social constructionist lens. AB - AIM: To discuss the theoretical framework of social constructivism and justify it s appropriateness for and compatibility with an interpretive approach to child adolescent mental health (CAMH) nursing research. BACKGROUND: Recent changes to national nursing legislation in Australia have resulted in the removal of the separate register with regulatory authorities that existed for the specialty of mental health nursing. Aspects of mental health nursing age are not easily defined, with some being tacit. CAMH nursing is a sub-specialty area of mental health in which the role and function of these nurses is also not overtly understood. DATA SOURCE: An interpretive research study was designed to develop a deeper understanding of the role and work of CAMH nurses when working in an inpatient setting. REVEW METHODS: An interpretive enquiry methodology was used fro the study, with three sequential stages of data collection: document analysis, focus group interviews and semi-structured individual interviews. DISCUSSION: Social constructionism was the chosen theoretical framework for this study as it provided a useful lens for interpreting and understanding the work of the CAMH nurse. CONCLUSION: The social constructionist lens was simpatico with mental health nursing, as they both involved making meaning of or assessing information and understanding of social processes and interactions. IMPLICATIONS FOR REEARCH/PRACTICE: A useful lens for further research into mental health nursing practice. PMID- 26638222 TI - African Programme for Onchocerciasis Control: progress report, 2014-2015. PMID- 26638223 TI - Performance of acute flaccid paralysis (AFP) surveillance and incidence of poliomyelitis, 2015. PMID- 26638224 TI - Medicaid Program; Mechanized Claims Processing and Information Retrieval Systems (90/10). Final rule. AB - This final rule will extend enhanced funding for Medicaid eligibility systems as part of a state's mechanized claims processing system, and will update conditions and standards for such systems, including adding to and updating current Medicaid Management Information Systems (MMIS) conditions and standards. These changes will allow states to improve customer service and support the dynamic nature of Medicaid eligibility, enrollment, and delivery systems. PMID- 26638226 TI - The Author's Reply. PMID- 26638227 TI - The authors respond. PMID- 26638228 TI - The downfalls of gestation stalls. PMID- 26638229 TI - The authors respond. PMID- 26638231 TI - [Nobel prize laureates: Jean Dausset]. PMID- 26638230 TI - Hurricane Katrina's aftermath beyond New Orleans. PMID- 26638232 TI - [Identification of the Gene Encoding Nucleostemin in the Eye Tissues of Pleurodeles waltl]. AB - Nucleotide sequences were identified in the eye tissues (lens, retina, and retinal pigment epithelium) of the adult newt Pleurodeles waltl by the polymerase chain reaction with primers for the Ns gene. Sequencing showed that these nucleotide sequences belong to the Ns gene of the newt P. walt, which encodes the nucleolar protein nucleostemin. Structural analysis revealed a high homology of Ns nucleotide sequences of P. walt! with those of newts. Cynops pyrrhogaster and Notophthalmus viridescens. The expression of the Ns gene of P. walt, identified in the specialized eye cells of adult newts of the studied species, indicates that these differentiated cells retain some of the molecular characteristics inherent to the undifferentiated cells. PMID- 26638233 TI - [Alternative Ways of Pinus sylvestris L. Migration from Southern Siberia to Europe and Asia Minor]. AB - Allozyme analysis of the parameters of the Nei genetic distances and gene flow between the populations of Scots pine Pinus sylvestris L. along two hypothetical alternative ways of their migrations in the Miocene-Pliocene from Southern Siberia to the Balkans, Central Europe, and Asia Minor was used; a lower probability of their settlement on the southern shores of the East Paratethys than on the northern ones was identified. It is suggested that the Middle Araks Strait of Paratethys in the Miocene and extreme aridity of the climate in the Pliocene headed the migration of the populations on the southern way, while on the northern way there were no essential water and mountain barriers for pine dispersal. PMID- 26638234 TI - [Mechanisms of the Effects of Probiotics on Symbiotic Digestion]. AB - The published data and our own data on the mechanisms of the influence of microbial probiotics, prebiotics, and their combinations on the processes of symbiotic digestion have been considered and generalized. It is shown that the effects on an organism are associated with the enhanced metabolic activity of intestinal bacteria: stimulation of bacterial fermentation of carbohydrates and formation of short-chained fatty acids, an increase in the blotting capacity of the intestines due to elongation of villi and deepening of crypts, and a decrease in secretion of toxic proteolytic products (ammonia, phenols, thiols, indoles, etc.). It has been shown that a combination of probiotics and prebiotic enhances the biological efficiency of a complex preparation, which contributes to activation of carbohydrate, protein, and mineral metabolism. PMID- 26638235 TI - [Ecotopic Differentiation of Yellow-Anthered and Red-Anthered Forms of Scots Pine by Karyological Traits and Nuclear DNA Content]. AB - A comparative study of yellow-anthered and red-anthered forms of Scots pine, growing in hydrothermally contrasting bog and upland ecotopes, was performed by karyological traits and nuclear DNA content. Some differences were revealed between yellow-anthered and red-anthered forms of pine as components of intraspecific diversity in'the frequency of occurrence of violations in the number of chromosomes, chromosome sizes (total length of diploid set, absolute and relative lengths), the centromeric index, the localization of secondary constrictions in chromosomes, and the amount of DNA. PMID- 26638236 TI - [The Influence of a Weak Horizontal Permanent Magnetic Field on the Composition and Content of Lipids in Lettuce Leaves]. AB - The lipid composition and content were analyzed in lettuce Lactica sativa L. (variety Stone head) leaves grown in a weak horizontal permanent magnetic field (PMF) produced by Helmholtz coils of 400 A/m strength under controlled conditions of illumination and temperature in phytothrone. Control plants were grown under the same conditions in a geomagnetic field. PMF decreased the total lipid content by 40% due to a significant decrease in polar and neutral lipids. Among polar lipids, the fractions of glycolipids and phospholipids diminished. Among glycolipids, the content of monogalactosyldiacylglycerols was lower by 25-52%. The content of phospholipids decreased, too, namely phosphatidylglycerols were lower by 17-51%, phosphatidylcholines by 21-24%, phosphatidylethanolamines by 12 20%, and phosphatidylinositols by 12-41%. Therefore, weak PMF reduced the content of lipids in membranes, including the chloroplast, mitochondrial, and cytoplasmic membranes. PMID- 26638237 TI - [General Brain Structure of Newly Hatched Larva and Neuroblasts in Larval Mushroom Bodies in Pterostichus niger Deg. (Coleoptera: Carabidae)]. AB - It is revealed that the larval brain of Pterostichus niger, an active predator with well-developed long-distance sense organs (the set of antennal sensilla and lateral ocelli, or stemmata) at hatching already contains optic lobes, which include two groups of optic neuropils and complex antennal lobes of glomerular neuropil. It is shown that the central complex of the protocerebrum is represented by a bipartite protocerebral bridge and the upper part of the central body and the mushroom bodies include, numerous Kenyon cells, a well-developed calyx, a peduncular apparatus, and numerous neuroblasts. PMID- 26638238 TI - [The Effect of Coprophagy on the Size of Plant Fibers in the Digestive Tract of Hares Lepus europaeus and L. timidus (Lagomorpha, Leporidae)]. AB - We have studied the distribution of plant fibers of different sizes in the digestive tracts of two hare species: the brown hare (Lepus euopaeus) and the mountain hare (L. timidus). In all studied hares (18 specimens), the highest amount of fine-sized fibers (less than 0.25 mm length) was observed in the cecum (50-70% of the total fiber mass). It was found out that the fine-sized content in the digestive tract, and especially in the cecum, is provided not only by the separation mechanism of the colon, but also by coprophagy. It was shown that repeated passage of food through the digestive tract compensates small volume of the cecum and increases the period of digestion of the same portions of food. PMID- 26638239 TI - [Strategies for Conservation of Endangered Amphibian and Reptile Species]. AB - Strategies for conservation of endangered amphibian and reptile species are discussed. One-fifth of all vertebrates belongs to the category of "endangered species," and amphibians are first on the list (41%). Every fifth reptile species is in danger of extinction, and insufficient information is characteristic of every other fifth. As has been demonstrated, efficient development of a network of nature conservation areas, cryopreservation, and methods for laboratory breeding and reintroduction play.the key roles in adequate strategies for preservation of amphibians and reptiles. PMID- 26638240 TI - [Correction of Metabolic Processes in Rats during Chronic Endotoxicosis using Isotope (D/H) Exchange Reactions]. AB - The effect of isotope exchange reactions (deuterium/protium, D/H) on morphofunctional indices and the state of the antioxidant blood system in rats was studied under physiological conditions and during experimental chronic endotoxicosis of hepatorenal genesis. It was demonstrated that introduction of water with a decreased content of deuterium in the food rations of rats results in a decrease in its concentration in the blood plasma by 32-36% (to 98-106 ppm) and in lyophilized liver, kidney, and heart tissues by 13-17% (to 123-128 ppm). It was noted that it is accompanied by correction of metabolic processes, an increase in the functional activity of nonspecific protection system, and an increase in the body weight growth by the 42nd day in the group of animals that passed (for 14 days) the stage of preliminary adaptation with a change in the D/H ratio in the organism. PMID- 26638241 TI - [Interannual Variations in Abundance and Biomass of Planktonic Copepods Oithona in the Barents Sea]. AB - The distribution patterns of the common arctic zooplankton species Oithona similis and Oithona atlantica were investigated in the Barents Sea during warm and temperate years. The maximum abundance and biomass of Oithona spp. (159 x 10(3) ind./m2 and 38.8 mgC/m2, respectively) were recorded in the waters of Atlantic origin. O. atlantica occurred in Arctic waters only during anomalously warm years. It has been found that the quantitative characteristics of O. similis were negatively correlated with salinity and the winter NAO index, whereas the abundance of O. atlantica in Atlantic waters was positively correlated with the temperature anomaly. It is found that the abundance and biomass of Oithona pp. were comparable with the values recorded in other Arctic regions. PMID- 26638242 TI - [The Effect of Cadmium on the Efficiency of Development of Legume-Rhizobium Symbiosis]. AB - Screening of nodule bacteria (rhizobia) forming symbiotic relationships with legumes has been performed in order to isolate strains resistant to cadmium ions in a wide range of concentrations (6-132 mg/kg). The effect ofcadmium salts (6, 12, 24 mg/kg) on the legume-rhizobium symbiosis ofthe pea Pisum sativum L. with Rhizobium leguminosarum and of the fodder galega Galega orientalis Lam. with Rhizobium galegae has been studied under experimental laboratory conditions. No statistically significant differences have been revealed in the growth and biomass of plants with regard to the control in the range of concentrations given above. However, it was found that cadmium inhibited nodulation in P. sativum and stimulated it in G. orientalis. PMID- 26638243 TI - [Study of the Microbiome of the Intestine of the Comephorus dybowski Korotneff, 1904]. AB - Data on metagenomic analysis of the microbial community of the intestine of the Comephorus dybowski are presented for the first time. It was established that the bacterial community is characterized by a significant species diversity. In its composition 301 phylotypes (OTU) belonging to 23 phyla (out of which six are candidate, including the Thermobaculum, Gracilibacteria, Candidatus Saccharibacteria, TM6, Latescibacteria, and Parcubacteria) were detected. It was demonstrated that species richness estimated by means of the non-parametric ACE and Chao1 criteria was 568 and 504, respectively; and the species diversity by the Shannon index was 4.05. The analysis ofunique peculiarities of the C. dybowski ecology and biology allows us to explain some of the data obtained on the intestinal microbiome of this specie. PMID- 26638244 TI - [Zooplankton of Reservoirs in the Upper Reaches of the Kenti River System (Northern Karelia) under Long-Term Industrial Pollution Conditions]. AB - An assessment is given for the contemporary state of zooplankton community in the waters of the upper reaches of the Kenti River system under the conditions of long-term potash-sulfate industrial pollution. This article presents a number of structural indicators of the zooplankton community that show simplification in the structure of species diversity and its reduction, as well as the disappearance of a number of systematic groups. It is noted that the number of zooplankton taxa increases with distance from the source of pollution (Kostomukshskoe and Kento lakes), and the average quantitative indicators also increase in this case. A comparison with the results that were previously obtained for the reservoirs of the studied environment has been carried out. PMID- 26638246 TI - How Can you Avoid a Data Breach? PMID- 26638245 TI - Women Dentists Bring Change. PMID- 26638247 TI - When Patients Say No. PMID- 26638248 TI - Then and Now. PMID- 26638249 TI - The Truth about ASORN. PMID- 26638250 TI - Insight: No Eyesight Needed. PMID- 26638251 TI - Ocular Emergencies: Screening Tool and Alert Protocol. AB - Ocular emergencies such as central retinal artery occlusion, open globe injuries, eye chemical burns, retrobulbar hemorrhage, retinal detachment, and acute angle closure glaucoma can result in vision loss. Diagnosis is based on astute screening, which can be guided by the OAP screening tool used by ophthalmic nurses engaged in triaging patients presenting with symptoms indicative of emergent vision or eye changes. The OAP provides direction to ophthalmic team members for treatment and management of ocular emergencies. PMID- 26638252 TI - What Factors Affect Intraocular Lens Power Calculation? AB - Obtaining precise postoperative target refraction is of utmost importance in today's modern cataract and refractive surgery. Emerging literature has linked postoperative surprises to corneal curvature, axial length, and estimation of the effective IOL position. As demonstrated in this case presentation, an inaccuracy in the axial length measurement can lead to a myopic surprise. A review of the literature has demonstrated that prevention of postoperative refractive surprises requires highly experienced nurses, technicians, and/ or biometrists to take meticulous measurements using biometry devices, and surgeons to re-evaluate these calculations prior to the surgery. PMID- 26638253 TI - Five Considerations for RNs Facing Ethical Challenges on the Job. PMID- 26638254 TI - Cole Eye Institute's Approach to the Choroidal Melanoma Patient. PMID- 26638256 TI - His Name is Alex. PMID- 26638255 TI - Aligning Strabismus Surgery with Duane Syndrome. AB - Initial consideration for surgical intervention tends to be resection and recession of affected muscles for strabismus. Resection of eye muscles in patients with Duane syndrome is often avoided because this increases retraction, thus decreasing eye movement and resulting binocular field of vision. Recession is the mainstay of surgical treatment in Duane syndrome to achieve straight eye alignment, increased binocular vision, and decreased head turn. PMID- 26638257 TI - DID YOU KNOW? OCTOBER IS MORE THAN . . . PMID- 26638258 TI - Medical Error or Gross Negligence? S.371 in North Carolina. PMID- 26638259 TI - Noreen E. Smith, RN. PMID- 26638260 TI - Necessary, not "nice to have". PMID- 26638261 TI - Primary health care vs. Primary care. PMID- 26638262 TI - RNs one step close to obtaining prescribing authority. PMID- 26638263 TI - REDUCE THE RISK OF VASCULAR DISEASE through healthy eating and physical exercise. PMID- 26638264 TI - CAMP NURSING GUIDELINES FOR RNS. PMID- 26638265 TI - CNPS infoLAW: Communicating with the Police. PMID- 26638266 TI - An interview with Valerie Grdisa. PMID- 26638267 TI - PEACE OF MIND. Model of dementia care accepts and embraces patient's reality. PMID- 26638268 TI - Death Associated with Inadequate Reassessment of Venous Thromboembolism Prophylaxis at and after Hospital Discharge. AB - Venous thromboembolism (VTE) prophylaxis, also known as thromboprophylaxis, reduces the risk of deep vein thrombosis, pulmonary embolism, and associated complications, including death, in high-risk patients. VTE prophylaxis is recommended for acutely ill, hospitalized medical patients at risk of thrombosis. Anticoagulants, the pharmacologic agents of choice to prevent VTE, are considered high-alert medications. By definition, therefore, anticoagulants bear a hightened risk of causing significant patient harm when they are used in error. As part of ongoing collaboration with a provincial death investigation service, ISMP Canada received a report of a fatal incident that involved continuation of VTE prophylaxis with enoxaparin for a patient discharge to a long-term care (LTC) facility from an acute care setting. The findings and recommendations from this case are charged to highlight the need to build routine reassessment of VTE prophylaxis into the process for discharging patients from the acute care setting and upon transfer to another facility or to primary care. CONCLUSION: The incident described in this bulletin highlights the importance of continually reassessing the need for VTE prophylaxis, especially at transitions of care, such as discharge from an acute care setting. Evidence and guidelines confirm the benefits of VTE prophylaxis in certain patients during a hospital stay for an acute illness, but the balance of benefits and risks may become unfavourable once the patient is discharged. Clear documentation from the acute care facility can assist the receiving facility and health-care providers, as well as family caregivers, when determining whether thromboprophylaxis is still warranted. Until clear guidance to continue thromboprophylaxis after acute care is available, health-care organizations and practitioners across the spectrum of care are urged to share and consider the strategies presented in this bulletin to ensure the safe use of VTE prophylaxis and improved communication among health-care providers. ISMP Canada will be integrating the learning from this case in an update of the Hospital-Self-Assessment for Anticoagulant Safety. This assessment is available on a complimentary basis to all facilities across Canada after sign up at HTTPS://mssa.ismp-canada.org/hsasas/. PMID- 26638269 TI - Helping women manage pregnancy weight gain. PMID- 26638270 TI - A catalyst for change. PMID- 26638271 TI - Update: Healthy Michigan Plan. PMID- 26638272 TI - Medicare Rules Change Delayed. PMID- 26638273 TI - Dental Insurance Myths - Get the Most of Your Dental Care. PMID- 26638274 TI - Evidence vs. Opinion. PMID- 26638275 TI - Is It Malpractice to Not Use the Newest Oral Cancer Screens? PMID- 26638277 TI - Helping YOU Succeed. PMID- 26638276 TI - Overtime Rules Are Going to Change - Are You Ready? PMID- 26638278 TI - Answering Your TOP 10 Most-Asked Dental Benefit Questions. PMID- 26638279 TI - Radiolucency of the Jaw Associated with an Unerupted Tooth. PMID- 26638280 TI - The Wheel of Life. PMID- 26638281 TI - The Laser Controversy. PMID- 26638282 TI - Editorial. PMID- 26638283 TI - Where to start with research. PMID- 26638284 TI - Prospective roles for Canadian oncology nurses in breast cancer rapid diagnostic clinics. AB - The introduction of rapid diagnostic clinics for breast cancer increases oncology nurses' (ONs) responsibility for patient education and coordination of multidisciplinary care. Developed as an outcome of the E-Mentorship Oncology Nursing Program, this paper proposes new roles for these nurses to respond effectively and competently to such diagnostic innovation. The Oslo Manual Conceptual Framework of Innovation inspired the idea of change in prospective ONs' roles, corroborated by the Canadian Association of Nurses in Oncology's Standards of Practice and Competencies. New roles for ONs that are informed by the domain of information dynamics and evidence-based care are proposed. PMID- 26638285 TI - Supportive care needs of rural individuals living with cancer: A literature review. AB - Regardless of geographic location, the cancer journey is an extremely difficult experience for both patients and their families. The aim of this literature review is to explore the impact of rural or remote residence on the supportive care needs of individuals living with cancer. This review included ten qualitative, seven quantitative, and six mixed design studies. Data collection, analysis, and evaluation were guided using a multi-domain supportive care framework based on seven domains: physical, emotional, informational, psychological, spiritual, social, and practical (Fitch, 2009). This review will suggest that there are distinct experiences that present both challenges and benefits to individuals living with cancer in rural areas. These findings will be detailed with recommendations, and grounding for future research outlined. PMID- 26638286 TI - Taking action: An exploration of the actions of exemplary oncology nurses when there is a sense of hopelessness and futility perceived by registered nurses at diagnosis, during treatment, and in palliative situations. AB - "There is nothing more that can be done" is a phrase that may occasionally cross the minds of oncology nurses. This paper reports on the actions of exemplary oncology nurses who were faced with such situations where their colleagues gave up or turned away. The research question, "What actions do exemplary clinical oncology nurses (RNs) undertake in patient-care situations where further nursing interventions seem futile?" prefaced data collection via a secure website where 14 Canadian clinical oncology registered nurses (RNs) provided narratives documenting their actions. Thematic analysis utilized QRS NVivo 10 software and hand coding. Four themes were generated from data analysis: advocacy, not giving up, genuine presence, and moral courage. Implications for practice and future research are provided. PMID- 26638287 TI - Piloting an integrated education pathway as a strategy to prepare for and encourage oncology specialty certification. AB - Although continuing nursing education is crucial to improve professional and patient outcomes, programs in oncology nursing remain scarce, piecemeal, and focused on one modality of treatment, which limits the effectiveness of education interventions. The objectives of this paper are to describe the development and implementation of a longitudinal specialized oncology nursing education pathway program, and the evaluation results of a year-long pilot of the first stage of the program at a large university-affiliated cancer centre. Preliminary findings indicated that participants' perceived competence in health assessment and symptom management was improved after one year of enrolment in the education pathway. Next steps following this pilot, including implications for participants with regards to attaining oncology certification are also discussed. PMID- 26638288 TI - The limits of conscientious objection. PMID- 26638289 TI - INTERNATIONAL PERSPECTIVE. PMID- 26638290 TI - Meeting nursing standards in chemotherapy administration education: One province's approach. PMID- 26638291 TI - Fostering mentorship through professional development. PMID- 26638292 TI - Preliminary data on the lived experience of having multiple primary cancer diagnoses. AB - Approximately one in two Canadians will develop some form of cancer, and some will live long enough to be diagnosed with multiple primary cancers. There is some indication that multiple primary cancer diagnoses negatively impact survivors' mental and physical status, and quality of life. Existing research studies do not fully capture the complexity of what it is like to have multiple primary cancer diagnoses. Accordingly, a qualitative study was conducted to elicit detailed descriptions of the lived experiences of having multiple primary cancer diagnoses. Participants included 10 individuals from Atlantic Canada with a history of two or more cancer diagnoses. Data were captured through semi structured interviews and participant-generated photographs. Interviews were transcribed and reviewed for common meanings. Preliminary data analyses suggest that the essential meaning of having cancer multiple times is that cancer is "unwanted encore". This study yields findings that can provide empirically-based guidance to healthcare providers to help support cancer survivors in a more holistic way throughout the extended continuum of care and ultimately improve the health of individuals who have had multiple primary cancers. PMID- 26638293 TI - Assessment of 68 Prosthodontic Crowns in 41 Pet and Working Dogs (2000-2012). AB - A search of the medical and dental records at the Matthew J. Ryan Veterinary Hospital of the University of Pennsylvania was conducted to identify dogs that received full or partial prosthodontic crowns over a 13-year period (2000-2012). Forty-one dogs with a total of 68 prosthodontic crowns were identified. Further criteria for acceptance into the study included presence of complete medical records containing adequate information pertaining to the procedures performed, and current follow-up either by telephone, electronic mail, or via in-person examination. Treatment was considered to be successful when the prosthodontic crown was in place and there was no further structural injury to the tooth upon making contact with the client or at the time of death of the dog confirmed by the client. The mean number of days the prosthodontic crowns remained in place without further injury to the tooth was 1,598 (range, 161-4, 464 days [median, 1,414 days], standard deviation 1,093 days). Bond failure between the cement and the tooth or the cement and the prosthodontic crown occurred in 3 cases (4.4%). Fracture of the prosthodontically treated tooth occurred in an additional 7 cases (10.3%). Treatment was classified as successful in 58 cases (85.3%). The results suggest that prosthodontic crown therapy is a successful, practical, and durable treatment option for protection of previously injured teeth in pet and working dogs. PMID- 26638294 TI - The Influence of Crown Height to Diameter Ratio on the Force to Fracture of Canine Teeth in Dogs. AB - Previous work suggests that the tooth height to diameter ratio (H/D) may have an influence on the fracture resistance of dog canine teeth. Thus, it can be hypothesized that canine teeth with distal abrasion or teeth already requiring pulpal manipulation may benefit from a reduction in height and that an ideal H/D exists that balances tooth fracture resistance and tooth function. Therefore, a study was performed to investigate the influence of H/D on force to fracture and probability of fracture of canine teeth in dogs. Thirty extracted canine teeth from laboratory Beagle dogs were standardized by hard tissue volume and evenly distributed among three groups; unaltered H/D (group A), 10% reduction in H/D (group B), and 20% reduction in H/D (group C). The teeth were potted in clear autopolymerizing orthodontic acrylic and then secured within a universal materials testing machine. A displacement was applied at a speed of 1-mm/min to the distoocclusal line angle at an angle of 45 degrees to the long axis of the crown. The maximum measured force at the time of fracture represented the maximum force to fracture. A linear regression model showed a significant inverse relationship between H/D and force to fracture (p = 0.043; 95% CI-55.2 to -0.09). A margin of safety (MoS) analysis was performed to determine the probability of fracture by comparing normal force distributions of the measured force at fracture to that reported in a previous study, representative of normal biting pulling loads on canine teeth. When 100% of the load was applied to a single unaltered canine tooth the probability of fracture was 36.7%. Decreases in H/D of 10% and 20% resulted in a decreased probability of fracture by 24.1% and 60.4%, respectively. A paired MoS analysis was conducted wherein the applied loads were distributed across 2 maxillary canine teeth according to their relative heights. Within the pair, a 20% decrease in H/D decreased the probability of fracture of that tooth by 86.5%, but increased the probability of fracture of the unaltered contralateral canine tooth by 54.4%. The findings of this study support the hypothesis that teeth with a lower H/D are more resistant to fracture. However, given the potential impact of crown reduction of a single canine tooth on the load redistribution to the remaining unaltered canine teeth, further investigation is needed to determine what H/D would be ideal. In addition, future studies could elucidate in which clinical scenarios the concept of H/D reduction could be implemented. The results of this study may have implications on the successful long-term management of traumatized canine teeth in dogs. PMID- 26638295 TI - Lingual Malignant Peripheral Nerve Sheath Tumor in a Chinese Pug Dog. AB - A 9-year-old spayed/female Chinese Pug dog presented for evaluation of a mass located on the rostral aspect of the tongue. An incisional biopsy was acquired, submitted, and interpreted as a possible granular cell tumor based on hematoxylin and eosin, and periodic acid Schiff histopathologic staining characteristics. The diagnosis was supported by immunohistochemical evaluation that was positive for S 100, vimentin, and neuron-specific enolase. Based on the absence of mitotic figures in the incisional biopsy, a partial glossectomy was performed with gross margins of at least 1-cm. The excisional biopsy revealed significant features of malignancy, with neoplastic cells in close association with peripheral nerves, consistent with malignant peripheral nerve sheath tumor. Tumor-free margins were obtained, and the glossectomy had expected healing with no recurrence apparent 6 months following surgery. PMID- 26638296 TI - Measurement of Incisor Overjet and Physiological Diastemata Parameters in Quarter Horse Foals. AB - Cephalometric studies are important to quantify abnormalities of jaw length and positioning. In this study, 4 to 7-month-old Quarter horse foals (n = 51) were examined to determine overjet (horizontal overlap) prevalence and measure the size of the physiological diastemata. Results were analyzed in relation to age, sex, and lineage. Another aim of this study was to develop a simple field technique for measuring incisor malocclusion and physiological diastemata dimensions that could be used to monitor the growth of the rostral components of maxilla, incisive bone, and mandible. The overall prevalence of overjet lesions in these foals was 51%. Females were overrepresented (61.5%). Overjet occurred more commonly in show foals (50% prevalence) than other working (7.7%) and race (42.3%) lineage foals. Significant differences were found between maxillary and mandibular physiological diastemata lengths in foals of all ages and, as expected, there was a positive statistical correlation between age and maxillary and mandibular physiological diastemata measurements. Incisor overjet was present in 44.4% of 4-month-old foals, 45.5% of 5-month-old foals, 58.3% of 6-month-old foals, and 60% of 7-month-old foals. There was a weak positive correlation between age and the presence of incisor overjet. It was concluded that incisor overiet was common among Quarter horse foals, especially those from show and race lineages. The field technique for physiological diastema measurements was considered effective. PMID- 26638297 TI - Carbon Dioxide Laser Excision of Lingual Calcinosis Circumscripta in a Dog. PMID- 26638298 TI - Fluoride-Releasing Restorative Materials. PMID- 26638299 TI - Lateral Approach for Surgical Management of Feline Sublingual Sialocele. PMID- 26638300 TI - Ventral Approach for Surgical Management of Feline Sublingual Sialocele. PMID- 26638301 TI - Interpreting HRSA's Latest Dentist Workforce Projections. AB - With the U.S. health care system in the midst of a major transition spurred on by the Affordable Care Act (ACA), there is renewed debate over key health workforce policy issues. Health insurance coverage is expanding under the ACA, which will likely lead to increased demand for health care services. Longer-term, there will be increased emphasis on value, efficiency, and accountability within the health care system. These developments have major implications for the health care workforce. One key issue is whether the U.S. will face health care provider shortages as health insurance coverage expands and several health care occupations experience aging and other demographic transitions. Another key issue is how the move away from fee-for-service payment to more value-or outcome-based reimbursement models could potentially change the role of--and, therefore, demand for--different types of providers within the health care delivery team. PMID- 26638302 TI - Medicare Provider or Not? PMID- 26638303 TI - Should I enroll in Medicare? PMID- 26638304 TI - Patient Injuries? AB - An injured patient may be the last thing dentists want to think about. However, in reality, patients can be injured during dental treatment or as the result of an incident such as a slip and fall in the office. Treatment-related injuries can run the gamut and include burns, lacerations, swallowed objects and allergic reactions, according to The Dentists Insurance Company. PMID- 26638305 TI - Don't Commit Assume-icide. Part 1. PMID- 26638306 TI - Using Email to Stand Out in Dentistry. PMID- 26638307 TI - How Can I Be Part of a Plan When I Didn't Sign Up?(Hint: Network Leasing and Affiliate Carriers). PMID- 26638308 TI - By George! PMID- 26638309 TI - My 'big data' identity crisis. PMID- 26638310 TI - Data and email, free and wild. Can IT professionals save us from ourselves? PMID- 26638311 TI - Build your defense! Develop a strategic plan of action to combat cybercrime. PMID- 26638313 TI - Crafting a continuous engagement program. How mobile apps are changing the face of maternity care. PMID- 26638312 TI - Leverage member data to increase revenue, improve care. Thanks to analytics, healthcare organizations can get to know their consumers. PMID- 26638314 TI - The advantages of self-service screenings. Patient-centric technology improves data collections. PMID- 26638315 TI - UDI: Not just for manufacturers anymore. PMID- 26638316 TI - Simplifying workflows to improve patient transfers. Software allows Hershey Medical Center to streamline referrals. PMID- 26638317 TI - Information Exchange. What APIs bring to EMR/EHR interoperability. PMID- 26638318 TI - Cultivating a great physician champion. PMID- 26638319 TI - [Foreword]. PMID- 26638320 TI - [Bioethics: the ability to understand man, the power to standardize the facts]. PMID- 26638321 TI - [The French bioethics laws are 20 years old!]. PMID- 26638322 TI - [Summing up]. PMID- 26638323 TI - [The desired access to the origins: Which access?]. PMID- 26638324 TI - [Circumcision and excision: towards a non-law of bioethics?]. PMID- 26638325 TI - [Transsexualism]. PMID- 26638326 TI - [Medically assisted procreation and homosexual couples]. PMID- 26638327 TI - [Preserving fertility and future death]. PMID- 26638328 TI - [Postmortem paternity]. PMID- 26638329 TI - [The right to privacy: a donor's identity of donated gametes]. PMID- 26638330 TI - [Surrogacy: towards legalization?]. PMID- 26638331 TI - [The right to a chromosomally perfect child]. PMID- 26638332 TI - [Embryo research: the risks of eugenic drifts]. PMID- 26638333 TI - [The legal status of elements and products of the human body: object or subject of law?]. PMID- 26638334 TI - [The use and storage of stem cells and cord blood: French and English law comparative approach]. PMID- 26638335 TI - [Selected ethical issues in oncogenetics]. PMID- 26638337 TI - THE USE OF THE NOTION OF HUMANITY IN FRENCH LAW. PMID- 26638336 TI - [Euthanasia and assisted suicide]. PMID- 26638338 TI - Letter to the Editor: Salute to the Archivists and OHS Co-Founders. PMID- 26638339 TI - Update on the Archives & Museum of Optometry. PMID- 26638340 TI - A History of Optometry in Louisiana. PMID- 26638341 TI - Noah Bixler (1884-1959): Friend of James Whitcomb Riley and Prominent Indiana Optometrist. PMID- 26638342 TI - [Highlights of Finnish nutrition research]. AB - The main focus of Finnish nutritional science has been on the elucidation of causative factors of chronic diseases playing a central role in public health. The research has yielded important data about the population's nutrition, and these data have been utilized through several actions at the population level. The most important achievement is suppression of the epidemic of coronary artery disease, based on strong scientific evidence about the central reasons of the epidemic. Careful planning and implementation of the studies along with large sample sizes improve the reliability of the studies. PMID- 26638343 TI - [Possibilities of outpatient uterine surgery]. AB - The lines of operation in the treatment of gynecologic hemorrhagic disorders have developed towards a more conservative direction: the number of hysterectomies has decreased year by year, mini-invasive hysteroscopies having become more common. Endometrial polyps and submucosal leiomyomas can be treated in hysteroscopy, and destruction of the endometrium (thermoablation) is available along with drug therapies for the treatment of excessive bleedings. Hysteroscopy can be utilized also in elucidating infertility of uterine origin. With developing endoscopic techniques it will be possible to transfer the majority of intrauterine procedures from the operating room to gynecologic outpatient clinics, whereby operation is patient-centered and cost-effective. PMID- 26638344 TI - [Quality of treatment of atrial fibrillation patients and indicators utilized in monitoring--results of quality assessment at eleven healthcare centers]. AB - BACKGROUND: Several studies indicate a great need for improvement in the care of atrial fibrillation (AF). Failures in antitrombotic treatment can result in stroke. MATERIAL: A sample of consecutive patients with AF was gathered from eleven health centers (1,156 patients). RESULTS: 57.5% of all warfarin-treated patients (N = 1 125) were in good balance of anticoagulation. Of patients who had INR (International Normalized Ratio) for a period of at least 90 days (N = 531), 75.3% were in good balance. Severe symptoms of AF were experienced by 5.0% of patients. CONCLUSIONS: Treatment of AF has to be improved, especially in anticoagulation. Anticoagulation should simply be stopped or new anticoagulants should be used, if intensifying of warfarin treatment is not successful. PMID- 26638345 TI - [Bleeding during operations]. AB - Unnecessary use of blood products should be avoided, but excessive caution may on the other hand lead to complications and increase mortality. Attempts to more closely define the indications for use of blood products and reduce perioperative bleeding have over the past five years resulted in an approximately 20% decrease in the consumption of red blood cells. A generally applicable hemoglobin limit for red blood cell transfusions cannot be defined. The guideline often cited in recommendations (80 g/l) is subject to justifiable criticism, whereby a more liberal threshold for transfusion can be favored. Sparing fluid therapy of a surgical patient has been shown to promote recovery and reduce complications. PMID- 26638346 TI - [Treatment of postoperative pain]. AB - The quality and intensity of acute postoperative pain vary according to operation and patient-specific factors, whereby pain measurement is the starting point for the treatment. The principle of multimodal pain relief should be applied in the treatment in order to be able to improve pain relief. The quality of care can be improved and costs reduced with the assistance of an acute pain management team. The future aim is to systematically identify already before the operation those patients who are susceptible to intense postoperative pain and to the progression of pain into a chronic state, as well as an individual, research evidence based pain management plan. PMID- 26638347 TI - [Is it possible to measure the depth of anesthesia using electroencephalogram?]. AB - Although anesthetic monitoring has rapidly developed over the past few years, accidental awareness during general anesthesia still remains a significant clinical problem. It occurs in one out of thousand surgical patients. In addition to conventional clinical signs, the adequacy of anesthesia can be assessed for instance by monitoring the changes occurring in the electroencephalogram (EEG). The EEG effects of different anesthetics are, however, highly varied, and attempts to develop an unequivocal neurophysiological measure or quantity for human consciousness or unconsciousness have so far been unsuccessful. PMID- 26638348 TI - [Glycocalyx and fluid therapy]. AB - Glycocalyx consisting of proteins and carbohydrates is lining the complete healthy vascular endothelium. Being in continuous interaction with plasma proteins and other plasma components, the glycocalyx forms an endothelial surface layer playing an important role as protective mechanism of the vascular wall, in blood coagulation and regulation of permeability. Tissue swelling is a common problem in the treatment of surgical, trauma and intensive care patients. The extent of tissue swelling is also connected with morbidity and mortality. The question about the volume effect of infusion solutions and, on the other hand, prevention of permeability disturbance still remains highly actual. PMID- 26638350 TI - Noise, not action, likely as Congress gets back to business. PMID- 26638349 TI - [Optimization of working in the operating room by minimizing losses and improving flow]. AB - The need for development of practices within the Finnish healthcare system is immense. Economic threats will force the system to streamline treatment processes without sacrificing quality. Surgical operations bind resources and represent one of the most expensive units in the hospital. By developing the respective procedures it is possible to achieve significant changes in the patient's entire care pathway. Lean is a practical management philosophy involving fairly expedient and structured methods of work development. On the basis of available research results and practical experiences Lean is very well suited for a method of development of practices within healthcare. PMID- 26638351 TI - CMS cost-sharing test viewed as model. PMID- 26638352 TI - Some states iffy on extending 'duals' demo. PMID- 26638353 TI - States' ICD-10 coding workaround may cause problems, IT experts warn. PMID- 26638354 TI - Winning environments. Best designs fuse healing atmosphere, efficient workplaces with flair. PMID- 26638355 TI - Memorial Sloan Kettering Cancer Center, West Harrison, N.Y. PMID- 26638356 TI - St. Charles Cancer Center, Bend, Ore. PMID- 26638357 TI - Prebys Cardiovascular Institute, San Diego. PMID- 26638358 TI - Center for Advanced Care at Advocate Illinois Masonic Medical Center, Chicago. PMID- 26638359 TI - Innovation by necessity. Medicaid emerges as aggressive laboratory for delivery system reform. PMID- 26638360 TI - A better way to end balance billing. PMID- 26638361 TI - Flexible facility design, management approach critical in era of unprecedented industry change. PMID- 26638362 TI - Using big data to optimize post-acute care. PMID- 26638363 TI - It's 'schizophrenic' balancing current growth with healthcare reform. PMID- 26638364 TI - By the numbers. Largest revenue-cycle management firms. Ranked by total number of healthcare revenue-cycle contracts, 2014. PMID- 26638365 TI - Breeding in America: Neglected tropical diseases taking hold in U.S. PMID- 26638366 TI - States on hook for rising Medicare premiums. PMID- 26638368 TI - Tech firms refocus to address Stage 3. PMID- 26638367 TI - The long shadow of Flint's lead crisis. PMID- 26638369 TI - LOST APPETITE. The expected surge in insurers buying physician practices never materialized. PMID- 26638370 TI - Keep the Cadillac tax. PMID- 26638371 TI - Medical groups should work collaboratively with non-physician providers to improve access. PMID- 26638372 TI - Using software to avoid misdiagnoses. PMID- 26638373 TI - By the numbers. Most frequently billed DRGs. Ranked by 2013 Medicare patient discharges. PMID- 26638374 TI - Offeringequilibrium .Best Places promote culture that lets staff balance personal, professional obligations. PMID- 26638375 TI - The Best Places to Work in Healthcare 2015. PMID- 26638376 TI - Ranking of the Best Places to Work/Providers and Insurers. PMID- 26638377 TI - Putting patients first. Memorial Healthcare frees workers to break the rules to help improve patient experience. PMID- 26638378 TI - Making employee well-being a priority. Managers at Doctors Hospital of Sarasota work to keep their staffers happy. PMID- 26638379 TI - Creating a positive environment. Physicians Surgical Hospitals works hard to keep turnover low. PMID- 26638380 TI - The Best Places to Work in Healthcare SUPPLIERS. PMID- 26638381 TI - A few goofy diversions never hurt anybody. Athenahealth eases workers' tension with a little fun. PMID- 26638382 TI - RNnetwork helps staff by putting 'people first'. Employees well-being a core value. PMID- 26638383 TI - Where workers have the CEO's ear. Feedback from Liquid Agents staffers seen as crucial by their boss. PMID- 26638384 TI - A Risky Arms Race in Space. PMID- 26638385 TI - Racial Bias in Medicine. PMID- 26638387 TI - Over-the-Counter Monkey Meds. PMID- 26638386 TI - The Great Brain Drain. PMID- 26638388 TI - A Sooty North Pole Ahead. PMID- 26638390 TI - A Partner for Plutonium. PMID- 26638389 TI - Fake Weed, Real Crisis. PMID- 26638391 TI - New Cook Arrives in Life's Kitchen. PMID- 26638392 TI - Deep-Sea Sampler. PMID- 26638393 TI - Gone without a Bang. PMID- 26638394 TI - Super Fan. PMID- 26638395 TI - Overreaction. PMID- 26638397 TI - The Pyramid Effect. PMID- 26638396 TI - Hackers at the Wheel. PMID- 26638398 TI - Seeing in the dark. PMID- 26638399 TI - DISEASE DETECTOR. PMID- 26638400 TI - The Battle of Olives. PMID- 26638401 TI - ROBOTS WITH HEART. PMID- 26638403 TI - Where Is Here? PMID- 26638402 TI - BABY TALK. PMID- 26638404 TI - Perception Deception. PMID- 26638405 TI - A Southward Invasion. PMID- 26638406 TI - CMS care-management fees help medical home practices. PMID- 26638407 TI - Despite political support, state right-to-try bills show no takeup. PMID- 26638408 TI - FTC guidance means state medical boards may need to revamp. PMID- 26638409 TI - Counseling impaired docs. Help programs may need retooling as hospitals expand physician employment. PMID- 26638410 TI - REITs on hospital hunt. Capital-hungry operators given enviable choice with real estate prices rising. PMID- 26638411 TI - Enrollment opens as elections loom. PMID- 26638412 TI - Let skilled-nursing providers take risk in bundled-payment demonstration. PMID- 26638413 TI - Nurses devise their own innovations. PMID- 26638414 TI - 'We can provide almost unlimited amounts of capital' to help health systems grow. PMID- 26638415 TI - By the numbers. Largest post-acute companies. Ranked by net revenue for the organization's fiscal 2014. PMID- 26638416 TI - The Games We Play ... So now it's ICD 10. PMID- 26638417 TI - PRESIDENT'S PAGE. PMID- 26638418 TI - A Practical Guide to Postoperative Delirium. AB - In conclusion, delirium is a common postoperative complication that especially impacts the elderly population. It contributes to a significant increase in morbidity, mortality, length of inpatient stay, and medical costs. Even with preventive efforts, many patients will develop postoperative delirium. While the gold standard treatment is to correct the underlying disorder, many therapies ranging from the use of antipsychotics to patient comfort measures are used to decrease the severity and duration of postoperative delirium. The most practical approach for physicians is continuous vigilance for the emergence of postoperative delirium. Movement toward increased use of multidisciplinary inpatient ward teams, early psychiatric consultation during postoperative delirium, larger clinical trials of prophylactic medications, and future research on delirium's pathogenesis will decrease complications of this common clinical problem. PMID- 26638419 TI - Changes in Non-Small Cell Lung Cancer Tumor Location Secondary to Gastric Distension, Implications in the Context of Stereotactic Body Radiation Therapy. AB - OBJECTIVE: Stereotactic body radiation therapy (SBRT) facilitates highly conformal dose distributions to a targe tumor volume. Accurate tumor localization is extremely important, and lung tumors pose a unique challenge due to respiratory motion. Patients are required to fast before PET/CT but not before CT simulation and daily treatment, introducing potential variability from gastric distension. METHODS: A case was reviewed involving a patient with early-stage NSCLC which was simulated and treated with SBRT. PET/CT performed while fasting showed an isolated left lower lobe lesion. Following CT simulation, CT and PET/CT images were superimposed for comparison and treatment planning. RESULTS: Tumor location variation was apparent following image superimposition. Simulation CT showed significant gastric distension compared to PET/CT. The patient was resimulated while fasting, resulting in accurate and reproducible tumor localization for treatment planning. CONCLUSIONS: Gastric distension can alter tumor location and treatment volumes for radiotherapy planning, possibly resulting in inaccurate treatment administration. PMID- 26638420 TI - Update on Medical Marijuana. PMID- 26638421 TI - Delaware Physicians' Knowledge and Opinions on Medical Marijuana. PMID- 26638422 TI - Delayed Unilateral Adrenal Hemorrhage Complicating Pneumococcal Septic Shock. AB - An 80-year-old male presented to the hospital after being found unresponsive at home. He was found to have pneumococcal pneumonia complicated by septic shock. He was treated in the medical ICU briefly with vasopressors and received intravenous antibiotics. He achieved a full recovery and was discharged after 10 days. He returned within 24 hours with vague abdominal and chest pain. His complaints of pain were difficult to localize--radiating from back to chest and abdomen. He received an extensive work-up to exclude acute coronary syndrome, pulmonary embolism, pancreatitis, cholecystitis, and rib fracture. He was ultimately found to have a symptomatic unilateral adrenal hemorrhage, likely secondary to the acute stress of septic shock. PMID- 26638423 TI - Obituary. DENE T. WALTERS, MD. PMID- 26638424 TI - [Change in Serum Levels of New Hepatic Fibrosis Marker "Mac-2 Binding Protein Glycosylation isomer (M2BPGi)" in Patients with Chronic Hepatitis C during the Treatment of Pegylated Interferon and Ribavirin]. AB - The sustained virological response (SVR) rate in the patients with HCV has currently reached to 90% by the progression of anti-viral therapy. However, several reports demonstrated that hepatocellular carcinoma develops even in the patients with SVR. It is widely accepted that liver fibrosis plays a pivotal role in hepatocellular carcinogenesis. Thus, an accurate staging for liver fibrosis is necessary to improve long-term prognosis of hepatitis C patients. Recently, Mac-2 binding protein glycosylation isomer (M2BPGi) was identified as a novel hepatic fibrosis marker. In the present study, we compared the value of M2BPGi in serum before and after the anti-viral therapy in hepatitis C patients. The value of M2BPGi in patients with F2, F3, or F4 stagings was significantly higher than that in F1 staging. Moreover, the value of M2BPGi significantly decreased after the treatment with pegylated interferon plus ribavirin similarly to other liver fibrosis-related markers. In addition, the value of M2BPGi in patients with SVR was significantly decreased after the anti-viral therapy (P < 0.0001). The reduction of M2BPGi in SVR patients was thought to reflect the improvement of liver fibrosis, in conjunction with the reduction of viral load, after the treatment. In conclusion, the measurement of M2BPGi in serum might be useful in monitoring the improvement of liver fibrosis by anti-viral therapy. PMID- 26638425 TI - [Comparative Study for Anti-Hepatitis B Surface Antigen Titers Based on Two Measurement Methods: Using Monoclonal Antibodies Isolated from Hepatitis B Vaccinated Recipients]. AB - BACKGROUND: As anti-hepatitis B surface antigen (anti-HBs) titers vary depending on the measurement methods, we compared two different methods to measure anti-HBs titers in sera and HBs monoclonal antibodies. METHODS: The sera from 182 HB virus resolved patients who were negative for HBsAg but positive for antiHB core protein (HBc) and/or anti-HBs were obtained. The measurement of anti-HBs was compared using either Lumipulse G1200 or Architect i2000SR. Six different monoclonal antibody (mAbs) clones isolated from healthy individuals inoculated with hepatitis B vaccine Bimmugen (genotype C) were used. RESULTS: A statistically significant correlation in anti-HBs titers was found between the two methods tested (Y = 0.951X + 100.7, R = 0.813, p < 0.001), although anti-HBs titers in 72 samples (39.6%) measured by Architect were less than 50% of that by Lumipulse and 12 (6.6%) were opposite results. Measuring 2 mAbs with HBV neutralizing activity, the titers of the 116 antibody (1.0 MUg/mL) were comparable (689.3 mIU/mL by Lumipulse and 440.7 mIU/mL by Architect), whereas those of the 478 antibody (1.0 MUg/mL) were much lower by Architect than by Lumipulse (42.6 vs. 818.6 mIU/mL, respectively). Of four other mAbs without HBV neutralizing activity, equal titers were observed for one; two mAbs had less anti HB titers by Architect; and one was below the cut-off index (< 5 mIU/mL). CONCLUSIONS: Anti-HBs titers measured by Architect are likely to be lower than by Lumipulse, and the potential ability to detect the 478 antibody with neutralizing activity is low, indicating that Architect might underestimate anti-HBs titers. Future studies should standardize the anti-HBs titer measurement system. PMID- 26638426 TI - Analysis of OXA23 and AmpCbeta-Lactamase Genes in Clinically Isolated Multidrug Resistant Acinetobacter baumannii Clonal Complex 92. AB - Multidrug-resistant Acinetobacter baumannii, which is resistant to carbapenems, amino glycosides, and fluoroquinolones, was isolated from the wound of an outpatient. We performed Multi Locus Sequence Typing and analyzed the structures of the AmpC beta-lactamase and OXA23 carbapenemase genes. This strain was assigned as ST451, a member of clonal complex 92, by its MLST scheme. The structures of ISAba1-AmpC beta-lactamase and ISAba1-OXA23 carbapenemase were revealed and the major globally prevalent clone of carbapenem-resistant A. baumannii was identified. PMID- 26638427 TI - [The Significance and Efforts to Promote External Quality Control Surveys and Skills Tests--Chairmen's Introductory Remarks]. AB - Not only is the role of "clinical testing" becoming increasingly important in diagnosis, but also the accurate management of clinical testing is growing in significance in order to examine "the reliability of data" obtained from such testing. For the purpose of assuring the reliability of data based on international conformity associated with an increase in global clinical trials, the Ministry of Health, Labour and Welfare advocates appropriate accuracy management, involving certification by a third party. Regardless of clinical trials, the Ministry of Health, Labour and Welfare states that the accurate management of a standard laboratory test is also a critically important issue. The value of clinical testing is fundamental to offering reliable clinical test data for clinical practice, and the mission of a clinical test department is to embody the principal of accuracy assurance and reflect it in routine clinical testing. Concerning external quality control surveys and skills tests in Japan, we asked both test sponsors and examinees to provide opinions on survey efforts, the purpose of participation, etc. PMID- 26638428 TI - [Overview of Proficiency Testing and External Quality Assessment Programs of Laboratory Tests from the Standpoint of International Standardization]. AB - In Japan, laboratory comparison, by means of proficiency testing or external quality assessment, has been conducted with separate programs on a nationwide basis, markedly contributing to quality improvement of clinical laboratory testing. However, from the standpoint of international standardization, there are issues to be addressed. Performance is evaluated once a year in each program, with time-consuming studies and different methods for data collection, analysis, and its assessment among programs, thus not leading to real-time monitoring and correction of the performance. Only the examination procedure of routine laboratory testing is focused on, while the entire process of the examination needs to be properly performed from the pre-examination down to the post examination procedures. The development of proficiency testing for esoteric tests is needed, since both routine and esoteric ones have been provided by most medical laboratories, and a combination of them is used for decision-making in patient care. As molecular-genetic tests have been widely used, demand for the development of laboratory comparison programs has increased. In order to comprehensively evaluate the performance of laboratory, medical imaging and biophysical examination are also necessary. The overall performance of the medical laboratory must be assured along with the availability of proficiency testing or external quality assessment programs for each test to be performed, in order to contribute to optimal patient care. PMID- 26638429 TI - [Intention and Current Situation of External Quality Assurance Program Supervised by the Japan Medical Association]. AB - The Japan Medical Association (JMA) has provided the external quality assurance (EQA) program in clinical laboratory testing. About 3,200 clinical laboratories recently participated. The EQA program shows us the current situation of clinical laboratory testing as well as the evaluation of each clinical laboratory. Moreover, it aims for the harmonization of clinical laboratory testing, resulting in common objective data, common diagnostic criteria, and medical standardization. The EQA program examines and educates regarding the measurement method (JSCC transferable method or not), analyzer, reagent, traceability, calibrator, unit, temperature, cut-off value, and lower decision limit, in order to strengthen the foundation of clinical laboratories. Clinical laboratory testing consists of pre-pre-analytical, pre-analytical, analytical, post analytical, and post-post-analytical phases. The EQA program investigates not only the analytical phase but also a part of pre-analytical and post-analytical phases. We should know that the role of a clinical laboratory is not just analysis or measurement. It is truly expected that we will earnestly participate in the EQA program to check the validity of our own ordinary and not champion results, and to understand the harmonization of total laboratory testing phases. PMID- 26638430 TI - [Utilization of CAP Survey, Based on Questionnaire Results from Survey Participants]. AB - The survey provided by the College of American Pathologists (CAP) is chosen as one of the proficiency testing programs in Japan, and, recently, the numbers of participating facilities have increased. CAP provides 754 programs, and more than 1,000 tests were provided in 2014. Materials are translated as the "CAP global inter-laboratory comparison program" under the instruction of the Japanese Society of Laboratory Medicine (JSLM) selected from CAP surveys in Japan, and 68 programs and 261 items are provided. The total number of participating facilities was 174. CAP itself and the other services CAP provides are not well-known, while recognition of "the CAP survey as the proficiency test" has increased. The question "What is CAP and the CAP survey" was analyzed as a result of the questionnaire surveys conducted in 2014, and the advantage of the CAP survey and how to utilize it were considered. A questionnaire survey was conducted about the CAP survey for Japanese participants in 2014. Fifty-three questions were asked about their satisfaction level, intended use, and improvement. Eighty replies were analyzed. As a result, most CAP survey participants are satisfied. They intend to mainly use the CAP survey for their quality control. Furthermore, they can continuously monitor their systems throughout all testing phases as the survey has numbers of shipments a year and several specimens per each mailing. This helps in laboratory performance improvement. The Evaluation and Participant Summary (PSR) also effectively improves the laboratories' performance. CAP accredited laboratories are required to participate in all survey programs concerning the test menu which they provide. Therefore, they have become accustomed to reviewing the evaluation and performing self-evaluation with a high usage rate of the Evaluation and PSR of the CAP survey. The questionnaire proved that performing the CAP survey properly enhanced the laboratories' quality control, and this meets the participants' needs. PMID- 26638431 TI - [Cardiovascular Ultrasonography and Laboratory Tests--More Valuable Support for Clinical Practice--Chairmen's Introductory Remarks]. AB - Many examinations have limitations, including low sensitivity or specificity. Therefore, multiple examinations are combined for practical diagnosis to facilitate treatment. In symposium 15 (cardiovascular ultrasound and clinical examination), 5 speakers presented how to combine diagnostic methods in their clinical practice. Dr. Tokuko Nakano emphasized the specificity of bacteria detected by blood culture according to the etiology. Dr. Masaaki Takeuchi emphasized the importance of combining clinical manifestations with echocardiographic findings for the management of patients with heart failure. Dr. Naoko Mizukami emphasized the utility of combining echocardiography, lower leg ultrasound, and blood examination for patients with suspected pulmonary embolism. Dr. Hiromi Umeda reported the utility of echocardiography with blood examination of troponin I. Dr. Hiroki Oe reported the importance of echocardiography for the routine screening of patients with arterial pulmonary hypertension. He also emphasized the important role of respiratory function examination for further specific diagnosis. All presentations highlighted the importance of the comprehensive management of multiple examinations for optimal patient care. PMID- 26638432 TI - [Infective Endocarditis--Blood Culture and Echocardiography]. AB - Infective endocarditis (IE) is a systemic septic disease that is a microbial infection of the endothelial surface of the heart. Despite advances in medical, surgical, and critical care interventions, IE remains a life-threatening illness. Therefore, it is important to promptly diagnose it using the modified Duke criteria. These criteria integrate factors predisposing patients to the development of IE, the blood-culture isolates and persistence of bacteremia, and echocardiographic findings, along with other clinical and laboratory information. Positive blood culture and a positive echocardiogram are the cornerstones of IE diagnosis. Identification of the infecting organisms is of primary importance because this knowledge guides antibiotic therapy. For the detection of vegetation, transesophageal echocardiography has a sensitivity of 76-100%, whereas that of transthoracic echocardiography ranges from 50 to 60%. Transesophageal echocardiography is particularly useful in patients with prosthetic valves and sparse vegetation. Recent studies reported that causative microorganisms of IE are changing. Staphylococcus aureus is now the most common cause of IE in Western countries. This shift is due in part to a higher rate of Staphylococcus aureus infection in patients with cardiac devices (for example, prosthetic valve, pacemaker, and implantable cardioverter defibrillator [ICD]). PMID- 26638433 TI - [Practical Use of Doppler Ultrasonography of the Cardiovascular System and Clinical Laboratory Tests for the Management of Pulmonary Embolism]. AB - Acute or chronic pulmonary embolism (PE) is a serious disease, and the risk of mortality is increased if untreated. In 90% of cases the embolus source is deep vein thrombosis (DVT) of the lower limbs or pelvic cavity. Therefore, it is necessary to recognize these as venous thromboembolism (VTE) which includes both DVT and PE. I suggest that Doppler ultrasonography of cardiovascular and clinical laboratory tests provide very valuable medical support for the management of VTE. Specifically, in the early diagnosis of VTE and the prevention of fatal PE, Doppler ultrasonography (cardiac and vascular) can provide very useful information. On the other hand, blood coagulation and thrombophilia tests are important to determine the risk of VTE and evaluate the effect of anticoagulant therapy on VTE. In this paper, I explain the main points of each examination of VTE by describing representative cases. I also show the results on investigating cases in our hospital involving diseases related to VTE and the onset site of DVT. In addition, I introduce how we convey the results of analysis to the clinical side. PMID- 26638434 TI - [Echocardiography and Biochemical Examination in the Treatment of Ischemic Heart Disease]. AB - The importance of echocardiography is generally known for acute coronary syndrome. However, assessing cardiac biomarker elevation is important together with echocardiography as poor images are obtained in some cases and patients may show unstable angina or angina on effort without asynergy. We examined the usefulness of high sensitive troponin I (hs-cTnI) in 60 patients from October 2014. We performed hs-cTnI and echocardiography in 10 cases (acute myocardial infarction: 8, unstable angina: 1, angina on effort: 1) among those patients. In the 8 acute myocardial infarction cases, asynergy was noted in all cases on echocardiography, but CK, CK-MB, and H-FABP cardiac biomarkers showed mixed negativity and positivity. Also, the unstable angina and angina on effort did not show asynergy but hs-cTnI was positive, the case of unstable angina showed elevation over time, but the case of angina on effort did not show elevation with time. We suggest that echocardiography and hs-cTnI are useful for acute myocardial infarction, although care may be necessary when assessing ACS patients with no detected asynergy in echocardiographs or non-ACS patients with acutely elevated hs-cTnI). In addition, it was suggested that confirmation of a change over time of hs-cTnI is necessary in angina patients. PMID- 26638435 TI - [Echocardiography and Respiratory Function Testing for Pulmonary Arterial Hypertension]. AB - Pulmonary hypertension (PH) is a hemodynamic and pathophysiologic condition characterized by elevated pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR), defined as an increase in the mean PAP of more than 20 mmHg at rest. PH can be a progressive and fatal disease if not treated appropriately. In the advanced stage of PH, the right ventricular (RV) function may be impaired, and it is associated with poor outcomes in PH. PH, however, can be easily misdiagnosed until the disease is at an advanced stage, because of its nonspecific and subtle symptoms in the early stages. PH is also a multi-factorial disease, it can be due to a primary elevation of pressure in the pulmonary arterial system alone (pulmonary arterial hypertension), or secondary to elevations of pressure in the pulmonary venous and pulmonary capillary systems (pulmonary venous hypertension). Establishing its etiology is also important for the early diagnosis of PH. Echocardiography is an important modality to assess the presence or absence of PH and its etiology, and it has been used to screen for this disease, determine the left and right heart structure and function, and assess the response to therapy in persons with PH. The pulmonary function test is also useful in PH, especially PH in chronic lung disorders. PH patients may also display mild to moderate ventilatory impairment in the absence of any evidence of lung airway or parenchymal disease, mainly in the form of airway obstruction. In this review, we discuss the diagnostic and prognostic role of clinical echocardiography and pulmonary function testing in clinical practice for pulmonary hypertension in this modern era. PMID- 26638436 TI - [Clinical Laboratory Test Using Proteomics: The Usefulness of Proteomic Techniques for Amyloid Typing]. AB - Amyloidosis is a heterogeneous group of disorders characterized by the deposition of amyloid fibrils. To diagnose amyloidosis, it is important to detect amyloid deposits and identify the amyloid precursor protein in specimens, such as tissues and serum. Mass spectrometry is a powerful tool to measure the molecular weight and identify the protein. Recently, mass spectrometries such as liquid chromatography/tandem mass spectrometry and surface-enhanced laser desorption/ionization time of flight mass spectrometry, have made a contribution to amyloid typing. In the paper, we describe the usefulness of mass spectrometric analyses for the typing of amyloidosis. PMID- 26638437 TI - [Issues of Personalized Medicine from the Viewpoint of Laboratory Medicine]. AB - Personalized medicine is expected to provide patients with safe and effective treatment compared to conventional medical care in which patients are treated based on the diagnosis and/or histology. In personalized medicine, patients are treated based on their genetic makeup and genetic characteristics of tumor tissues in the case of cancer chemotherapy. Genomic biomarker tests are used to molecularly characterize host and tumor tissues and stratify patients for the appropriate drugs. Drugs targeting the causative genetic changes have been developed along with companion diagnostics to test such genetic changes. In this paper, I introduce the technical guidance for companion diagnostics and related drugs issued by the Pharmaceutical and Medical Devices Agency of Japan, and discuss how to carry out a concordance study of diagnostic tests for the ALK fusion gene when new ALK inhibitors are approved. The regulations for companion diagnostics should be revised frequently to keep up with advances in this area. PMID- 26638438 TI - [ICT Utilization for Healthcare and Personalized Medicine]. AB - Through medical ICT, a greater quality and efficiency of health care, improved convenience for patients and other people, strengthening of research and development and industrial competitiveness, and the efficiency of social security costs will be offered. In order to achieve these objectives, it is necessary to have an intellectual foundation on which a medical platform is digitally constructed by the ICT for the creation of new services and medical technology. In other words, a system that, based on information systems in the medical field, etc., depending on the purpose of utilization, makes it possible to collect reusable data at the minimum required level will be established and we will then adjust and operate it. In order to enable the reuse of data, the following two mechanisms have to be created: one in which data generated by multiple agencies can be shared among stakeholders through structuring and standardization, and another in which comparable information can be used as a history attributable to individuals over a long period of time. PMID- 26638439 TI - [Picture of the month. Dorsiflexion of the foot to better visualize the lower cervical spine]. PMID- 26638440 TI - [How I Treat. An Anterior Temporomandibular Joint Dislocation]. AB - Anterior dislocation of the temporomandibular joint is not uncommon and requires prompt management. A defect of dislocation reduction can lead to severe functional impairment of a complex, and often active joint. The diagnosis is clinical and relatively obvious. It is made by the frontline medical team, general practitioner or emergency doctor. Recurrent cases are a matter for maxillofacial surgeons. This article describes a conventional technique for anterior dislocation reduction, to achieve urgently. The second part of the article deals with the specialized surgical treatment of relapsing forms. PMID- 26638441 TI - [TRAUMATIC RUPTURE OF THE AORTIC ISTHMUS: MODERN PERSPECTIVES]. AB - Traumatic aortic rupture of the thoracic aorta (usually at the isthmus) is frequently associated with concomitant life-threatening injuries. Historically, the conventional care consisted of surgical repair of the lesion performed as soon as possible. However, in spite of constant technical improvements the morbi mortality remains high because of these associated lesions. In addition, their management can have priority and delay aortic surgery. The endovascular approach has been shown to be a feasible and efficient technique and currently represents a valuable alternative to open surgery for patients with multiple traumas. We report a patient presenting with a traumatic aortic rupture of the aortic isthmus, which was successfully treated by delayed combined endovascular (thoracic aortic stentgrafting) and open approach (hemiaortic arch debranching). PMID- 26638442 TI - [INITIATING AND INTENSIFYING INSULIN THERAPY IN GENERAL PRACTICE: INSUSTAR, AN OBSERVATIONAL BELGIAN PROSPECTIVE STUDY IN TYPE 2 DIABETES]. AB - Initiating or intensifying insulin therapy is often considered as a challenge in general practice. The observational prospective Belgian study InsuStar was performed in 2011-2013 among 150 representative general practitioners, who were invited to initiate or intensify insulin therapy when necessary in 523 patients with type 2 diabetes (mean age: 65.5 years; mean HbAk: 8.8%). The initiation of insulin therapy (glargine in > 50%) was justified by insufficient glycaemic control (96%) and its intensification (replacement of insulin NPH or premixed insulins by insulin glargine, eventually with the addition of a short-acting insulin analogue) aimed at improving glucose control (58%), avoiding hypoglycaemia (17%) or both (17%). After a follow up of 6:1 months, HbAlc level decreased from 8.79% to 7.52% (-1.27%; 95% confidence interval: -1.43, -1.11; p<0.001). Overall 27.6% of patients reached an HbAl, < 7% versus 5.9% at inclusion (p<0.001), with rather few hypoglycaemia and a high physi- cian confidence level regarding insulin therapy. These results should encourage general practitioners to initiate insulin therapy at an earlier stage and to intensify it when necessary in patients with insufficiently controlled type 2 diabetes. PMID- 26638443 TI - [MANAGEMENT OF NON-SMALL CELL LUNG CANCER]. AB - Already known as the first cause of mortality in men, non-small cell lung cancer (NSCLC) is nowadays a major cause of cancer-related death in women. Its approach relies on a thorough locoregional and extra-thoracic assessment allowing a precise staging which not only has prognostic value, but also determines the therapeutic options. This review presents the current multidisciplinary strategy agreement or the treatment of NSCLC. PMID- 26638444 TI - [A CASE OF FLECAINIDE INTOXICATION]. AB - Flecainide acetate is an antiarrhythmic agent commonly used in clinical practice, in particular, for the treatment of supraventricular tachycardias. We report a rare case of voluntary poisoning by flecainide. The patient was successfully resuscitated.A review of the literature related to this type of intoxication is presented. PMID- 26638445 TI - [GAZING INTO A CRYSTAL BALL AND DETECTING SUBJECTS AT RISK FOR DEVELOPING CUTANEOUS MELANOMA]. AB - Cutaneous melanoma is the deadliest skin cancer showing an increasingly growing incidence in white populations of Europe and United States. Intensive research in recent years has begun to unlock its molecular pathogenesis. Screening the neoplasm at an early stage remains primordial. Hence, targeting populations at risk is likely efficient. In such an attempt, the regular clinical examination benefits from a series of non invasive procedures such as skin surface biopsies, in vivo confocal microscopy, dermoscopy and specular fluorescent light reflectance. PMID- 26638446 TI - [ACUTE CORONARY SYNDROME AND LIPID-LOWERING THERAPY. DOES THE IMPROVE-IT STUDY MAKE ANY DIFFERENCE?]. AB - Statins reduce both LDL cholesterol (LDL-C) levels and the risk of cardiovascular events in patients with and without cardiovascular disease. Intensive statin therapy, compared with moderate-dose statin therapy, incrementally lowers LDL-C levels and rates of cardiovascular events in patients presenting with acute coronary syndrome. Ezetimibe, by diminishing the absorption of cholesterol from the intestine, additionally reduces LDL-C when added to statins. In this article, we discuss the potential benefits of the combination of simvastatin and ezetimibe for the long-term management of patients with acute coronary syndrome through an analysis of the IMPROVE-IT results (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial). This randomised double blind trial included 18,144 patients with a LDL-C of 50 to 100 (with statin) or 125 (without statin) mg/dl and had a median follow-up of 6 years. The objective of the study was to test the efficacy of simvastatin 40 mg versus simvastatin 40 mg and 10 mg ezetimibe. The primary endpoint included cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina and coronary revascularization. The addition of ezetimibe to simvastatin resulted in an incremental lowering of LDL-C (reached value 53.2 versus 69.9 mg/dl, p < 0.001) and a further improvement of the patient prognosis (relative reduction of primary endpoint: -6.4%, p = 0.016). In addition, the combined therapy showed no significant adverse effects, particularly regarding the risk of cancers, which confirms the safety of ezetimibe. In acute coronary syndrome, the prescription of ezetimibe should be considered (class HA, level of evidence B) in patients with a LDL-C a 70 mg/dl despite maximally tolerated dose of statin. PMID- 26638447 TI - [Critical analysis of classical conservative treatments of tendinopathies]. AB - Classic "passive" therapeutics (anti-inflammatory drugs, infiltrations of corticosteroids...) of tendinopathies, which are used relatively empirically, reduce pain and inflammation, without fundamentally changing the tendon structure. The eccentric rehabilitation has been applied to chronic tendinopathies, not only due to the failure of conventional therapies but also due to a better pathophysiological understanding of tendinopathies. Various studies underscore the effectiveness of eccentric rehabilitation which, after 20 30 sessions, leads to healing and especially prevents the risk of chronicity. Shockwave therapy, amending the tendinous structure, would lead to a long term healing. PMID- 26638448 TI - [ABOUT JUVENILE NASOPHARYNGEAL ANGIOFIBROMA]. AB - We report the case of a young man with a juvenile nasopharyngeal angiofibroma. In this paper, we will first remind the clinical signs of this pathology and its radiological appearance (localisation and extensions). Then we will explain how radioembolisation techniques were used to facilitate the surgical intervention. Finally we will discuss the histology of this tumor. PMID- 26638449 TI - [DIAGNOSTIC APPROACH OF THE PATHOPHYSIOLOGICAL TRIAD LEADING TO A DIABETIC FOOT]. AB - Diabetic foot is a common complication of diabetes mellitus. Its pathophysiology is most often complex with the interconnection of three different components: diabetic neuropathy, arterial disease and infection. The diagnostic approach should specify the respective role of each component, firstly thanks to a thorough medical interview and a careful clinical examination. Afterwards, well selected complementary exams will confirm the hypotheses generated by the initial clinical approach. Consequently, a specific care strategy will be implemented, ideally with the help of a multidisciplinary team. This educational clinical case is devoted to the sequential diagnostic approach of a patient with a foot ulcer in the context of a diabetic foot. PMID- 26638450 TI - [EMPAGLIFLOZIN (JARDIANCE) :Nw SGLT2 COTRANSPORTER INHIBITOR FOR TREATING TYPE 2 DIABETES]. AB - Empagliflozin is a new inhibitor of sodiumglucose cotransporters type 2 (SGLT2) for the treatment of type 2 diabetes mellitus (T2DM). Its specific action inhibits glucose reabsorption in renal tubules and thus promotes glucosuria. This effect results in a reduction in fasting and postprandial glycaemia and a decrease of glycated haemoglobin (HbA(Ic)), independently of insulin. Furthermore, calorie urinary loss promotes weight reduction and osmotic diuresis lowers arterial blood pressure. The efficacy of empagliflozin increases according to the level of hyperglycaemia but decreases in patients with renal insufficiency. In 24 to 104-week controlled trials versus placebo, empagliflozin reduces HbA(1c) (approximately 0.8%), without hypoglycaemia (except in patients already treated with insulin or sulphonylureas). This improvement in glucose control is rather similar to that observed with active comparators (metformin, glimepiride or sitagliptin), with the advantage for empagliflozin of reducing body weight (approximately 2 kg) and blood pressure (systolic approximately 4 mm Hg and diastolic approximately 2 mm Hg). Empagliflozin has shown a cardiovascular protection in the EMPA-REG OUTCOME trial. Mycotic genital infections occur more frequently, especially in women, while a negligible increase in mild urinary tract infections may be observed. The risk of hypotension and volume depletion is low, although it should be carefully checked in more fragile and at risk patients. Empagliflozin (Jardiance), which is commercialized at the doses of 10 mg and 25 mg once daily, is indicated for the treatment of T2DM and reimbursed in Belgium with conditions as add-on to a background glucose-lowering therapy. PMID- 26638451 TI - Back to Basics: The Importance of Patient Respect. PMID- 26638452 TI - The AANA Foundation Malpractice Closed Claims Study: A Descriptive Analysis. AB - The AANA Foundation Closed Claims Researchers evaluated 245 closed claims spanning from 2003-2012. The majority of claims comprised CRNA providers whom are mainly male, independent contractors, certified between 1980-1999, and with malpractice coverage limits of $1 million/$3 million. The median age for all claimants was 50 years old, and 63.7% of claimants were female. For those claims where race was known, 54% of claimants were Caucasian. Most adverse events occurred in a hospital with an outpatient admission status. The majority of adverse events were identified as intra-anesthesia. The top five surgical procedures associated with these claims were orthopedic general surgery, cosmetic, obstetric, and neurologic procedures. An adverse event leading to death occurred in 35.1% of claims. Regardless of severity of injury, reviewers determined that 45.5% of negative outcomes were preventable, 32.7% of the anesthesia treatment was inappropriate, and 29% of negative outcomes were caused by CRNAs' actions. Reviewers found that no AANA Standards were breached in 45.7% of claims; however, Standards 4, 5, and 3 were the most common standards breached. The most costly severity classification was major permanent injury (ie, paraplegia, blindness, loss of two limbs, or brain ddamage) with a median payment of $299,810. PMID- 26638453 TI - Alternative Use of an Oral Endotracheal Tube Fastener in a Patient with Junctional Epidermolysis Bullosa. AB - This case report describes the alternative use of an oral endotracheal tube fastener in a pediatric patient with junctional epidermolysis bullosa. The patient underwent dental treatment in the operating room under general anesthesia and had a medical history of junctional epidermolysis bullosa, prior secondary anemia, clubbed feet, and past methicillin-resistant Staphylococcus aureus infection secondary to blistering. The oral endotracheal tube fastener was used in a nontraditional manner to avoid contact of the oral tube and tape with the epidermis and thus prevent blistering. Lubricated gauze was applied to the patient's eyes for protection, and lubricant was applied to the lips and perioral skin before intubation and during dental treatment. Postoperatively the patient exhibited minimal blistering secondary to intubation and dental treatment. PMID- 26638454 TI - The Noncompete Clause and the Nurse Anesthetist: An Assessment of Knowledge, Perception, and Experience. AB - Economic pressures and the challenge to maintain competitive advantage have resulted in many healthcare entities requiring their practitioners to contractually enter into noncompete clauses (NCCs). Many student registered nurse anesthetists (SRNAs) and Certified Registered Nurse Anesthetists (CRNAs) are unaware of NCCs in employee contracts. An anonymous, web-based questionnaire regarding NCCs was distributed to SRNAs and CRNAs nationwide. Of 242 practicing CRNAs who responded, 147 (60.7%) were employed without a noncompete clause and 22 (9.1%) were unaware whether they had such a provision in their employment contracts. The knowledge level of the nurse anesthetist respondents was low (average score of 55.3%). There was a significant difference in knowledge level between independently practicing CRNAs and group-practice CRNAs (P = .007) as well as practicing CRNAs vs SRNAs (n = 8, P = .006). Independent CRNAs had more experience with declining positions, changing positions, and loss of employment due to NCCs. More CRNAs believed the NCC is not applicable to practice, and no evidence existed to show a relationship between geographic location and having an NCC. Business-minded CRNAs with a practical knowledge of keyterms, concepts, and legal implications of NCCs are in a better position to bargain and negotiate against objectionable provisions. PMID- 26638455 TI - Far Forward Anesthesia and Massive Blood Transfusion: Two Cases Revealing the Challenge of Damage Control Resuscitation in an Austere Environment. AB - Since the beginning of Operation Enduring Freedom and Operation Iraqi Freedom, the US military has treated more than 51,000 casualties and sustained more than 6,600 deaths. The past decade of conflict has solidified major advances in the use of blood component therapy and the liberal use of fresh whole blood during damage control resuscitation. This resuscitation strategy, combined with far forward damage control surgery, rapid aeromedical evacuation, and major improvements in critical care air transportation and personal protective equipment has led to a 90% to 92% survival rate in US casualties. We describe 2 cases treated by a Forward Surgical Team serving in Afghanistan during Operation Enduring Freedom in 2014. Both patients suffered severe trauma and required massive blood transfusion and damage control surgery. In describing these 2 cases, we wish to share our experience with damage control, resuscitation in an austere environment, as well as advocate for the critical role of the Certified Registered Nurse Anesthetist in advancing the knowledge and execution of this lifesaving strategy in both military and civilian trauma centers. In addition, we suggest alternatives to the current transfusion strategy, which will mitigate limitations currently encountered. PMID- 26638456 TI - What to Consider Before Beginning Graduate Education: A Pilot Study. AB - The literature supports a general theme that college students lack metacognitive awareness about learning, which leads to poor examination performance and ultimately high attrition rates. However, the literature emphasizes that when college students receive instruction about learning, examination performance goes up and attrition goes down. This pilot study focused on a specific subset of learners: graduate students in a nurse anesthesia program. Given new evidence based wellness approaches to learning, the nurse anesthesia program conducted a descriptive study aimed at exploring student perceptions. The study goals were to provide students with evidence-based information about wellness factors that influence learning. The book The New Science of Learning by Doyle and Zakrajsek (Stylus Publishing, 2013) was used to provide students with neuroscience evidence about learning that might assist their transition to graduate school. The book was mailed to 34 student registered nurse anesthetists before matriculation. An 8 item Likert-style online survey evaluated the students' perceptions of the book along with identifying any changes the students made in anticipation of starting the rigorous nurse anesthesia program. The study demonstrated that student registered nurse anesthetists could benefit from instruction about wellness approaches that enhance learning before matriculation. Additionally, the study provided the framework for future research. PMID- 26638457 TI - Process Improvement: Addressing Attrition from the Uniformed Services University of the Health Sciences Nurse Anesthesia Program. AB - This retrospective cohort study examined the Uniformed Services University of the Health Sciences Registered Nurse Anesthesia program to identify reasons for high attrition rates. Relevant data were examined for 180 students enrolled in classes from 2005 through 2011. During that period, 40 students were dismissed or disenrolled, with the highest attrition rate (35%) occurring in the class of 2010. Evidence from this investigation indicates students who completed the program were younger, earned higher grade point averages while completing their undergraduate bachelor of science in nursing, and achieved higher analytic and total Graduate Record Examination scores than did students who withdrew or were dismissed. Gender differences were noted, as a greater proportion of women completed the program compared with men. Personal, family, and other issues frequently overlapped, with academic performance problems leading to attrition. Based on these findings, a number of important changes were made in the admission process to the USUHS RNA program and in the nonacademic mentoring and assistance offered to students. PMID- 26638458 TI - Ultrasound-Guided Ankle Blocks: A Review of Current Practices. AB - Ankle blocks are routinely indicated for surgical anesthesia and postoperative analgesia of procedures involving the foot. Traditionally, ankle blocks have been performed by relying on landmark identification of nerves. The literature regarding the performance and efficacy of ankle blocks is inconsistent. This can be attributed to several variables, such as provider technique, differences in patient populations, and the type and volume of local anesthetics administered. As with other peripheral nerve blocks originally performed using landmark technique, ultrasound imaging is now being incorporated into these procedures. Ultrasound guidance provides the anesthetist with several advantages over landmark techniques. The ability to identify peripheral nerves, view needle movements in real-time, and observe the spread of local anesthetic has been shown to result in greater block efficacy, even with reduced volumes of local anesthetic. Additionally, ultrasound imaging gives the provider the option to perform regional anesthesia in specific patient populations not considered possible when using landmark technique. Despite the limited literature on ultrasound-guided ankle blocks, outcome metrics seem to be consistent with those of other peripheral nerve blocks performed using this technology. PMID- 26638459 TI - [Russian Federation implementation of WHO global efforts plan on workers health care]. AB - The article deals with problems of implementing global WHO efforts plan on workers health care, Target program of World Labor Organization on work and occupational environment safety "For safe labor", some WLO conventions. The authors justify priority directions of governmental policy on health care for working population in Russia. PMID- 26638460 TI - [Topical problems of pulmonology in contemporary occupational medicine]. AB - Respiratory tract diseases are very common in occupational medicine. The present literature review is aimed to specify topical directions of research in this sphere. The review is based on search in databases (e. library.ru, pubmed. com and Cocran library). Molecular genetic and proteome studies make a fundamental basis for better prophylaxis, diagnosis and treatment of occupational respiratory diseases. Other problems of maximal scientific and practical importance are: phenotyping of chronic obstructive lung disease (COLD) for differential approach to patients management, new methods for early diagnosis of COLD, improved classification of pneumoconiosis according to contemporary view of occupational interstitial lung diseases pathogenesis, studies of immune suppression efficiency in rapidly progressing pneumoconiosis, understanding etiology of infectious complications of lung diseases with subsequent specifying the recommendations on rational antibacterial therapy. PMID- 26638461 TI - [TREATMENT OF REFRACTORY RHINOSINUSITIS IN PATIENTS WITH IGE-DEFICIENCY]. AB - The most significant:clinical manifestation of isolated IgE-deficiency is chronic and recurrent sinopulmonary diseases. A few papers about treatment of IgE deficiency, which shows the effect of intravenous immunoglobulin (IVIG) at a dose of 300-400 mg/kg was found. The results of such studies has level of evidence D. In our study we included IgE-deficient patients with refractory rhinosinusitis, which confirmed the diagnosis on the basis of at least two-fold examination with an interval of 1 month in the absence of obvious causes of secondary immunosuppression. In the study group included 82 patients (49 female, 34 male) aged 18 to 61, with the refractory rhinosinusitis combined with deficient IgE, total--33 (group 1) and partial--4 patients (group 2). In 22 patients (26.8%) immunoglobulin E deficiency combined with decreased serum concentrations of IgG sub-classes and other classes. The control group are 33 patients with refractory rhinosinusitis who refused IVIG. Immunoglobulinl intramuscularly administered at a dose of 0.3-0.4 ml/kg body weight for 3 days in a row 2-3 courses at intervals of 2-3 weeks. In the absence of clinical effect of said treatment for 2-3 months, we used IVIG at a dose of 200-400 mg/kg 1 month 1-3 courses with the consent of the patient. The clinical ohserved in 49 patients (87%), which was to reduce the number, severity and duration of exacerhations course rhinosinusitis. After IVIG were marked with significantly higher serum concentrations of total IgE in patients with total and partial deficiency compared with the results of intramuscular immunoglobulin. During treatment significantly increased serum concentration not only IgE (from 3.05 IU/ml +/- 1.21 IU/ml to 12.5/IU/ml +/- 1.86 IU/ml in total deficit; P < 0.01; 7.23 IU/ml +/- 1.37 IU/ml to 15.66 IU/ml +/- 1.66 IU/ml at partial dcficiency), but significantly increased serum concentrations of total IgG and subclasses IgG1, IgG2. So we found clinical and immunological effect of the intramuscularly and ivig in patients with refractory rhinosinusitis deficient IgE. This clinical and immunological effects we regarded as the influence of small doses of immunoglobulin to Fc-receptors on B lymphocytes mediated by regulatory mechanism of antibody production (Bayry J. et al). PMID- 26638462 TI - [THE CLINICAL SIGNIFICANCE OF GENETIC MUTATIONS IN ACUTE MYELOID LEUKEMIA]. AB - Acute myeloid leukemia (AML) is a hematologic malignancy with great variability in the pathogenesis, clinical features and treatment outcomes. Advances in molecular research have greatly improved our understanding of the leukemogenesis in AML. In addition to the conventional risk factors molecular genetic alterations, such as mutations of NPM1, CEBPA, c-KIT, AML1/RUNX1, WT1, FLT3 and others, are also important prognostic factors in AML patients. Risk-adapted treatment may not only improve the prognosis, but also reduce the toxicity from the chemotherapy in patients with AML. PMID- 26638463 TI - [PREDICTORS OF ATHEROSCLEROSIS: NEW DEVELOPMENTS]. AB - The article describes known atherosclerosis predictors of endothelial origin, which are diagnostic criteria for identifying's early stages of atherosclerosis, and can prevent the development of this disease and are used to monitor the effectiveness of the therapy The authors analyzed the possibility of using heparin as an early marker of atherosclerosis, based on the fact that the inhibition of lipoprotein lipase activity due hyperheparinemia resulting from depletion of mast cells due to endothelial dysfunction, leads to the disorders of lipid transporting system in the form of the resistant hyperlipidemia with the phenomena of dyslipidemia. PMID- 26638464 TI - [PATIENTS WITH HAVE A LEVEL OF ENDOTHELIN-1 AN ANTIFOSFOLIPID SYNDROME: CONNECTION IS WITH MOTION OF DISEASE, DISFUNCTION OF ENDOTHELIA AND ATHEROSCLEROSIS]. AB - In the article the concentration of endothelin-1 in patients with different variants of APS was analyzed and its relationship with disease course, dyslipidemia, levels of antiphospholipid antibodies and ath rosclerotic vascular lesions was assessed. It was established that high levels of endothelin-1 is a circulating marker of early atherosclerosis, since !it was closely associated'with subclinical manifestations of atherosclerotic vascular lesions, lipid profile. The concentration of endothelin-1 significantly increased with active inflammation and with high levels of antiphospholipid antibodies and does not depend on age, sex, smoking, obesity and physical inactivity. PMID- 26638465 TI - [DEFINITION OF INTERRELATION BETWEEN AMINOACID COMPOSITION OF URINE AND BONE TISSUE DENSITY AT CHILDREN WITH ACUTE LEUKAEMIA FOR ONCOHEMATOLOGICAL PATHOLOGY RISK GROUP FORMATION]. AB - Age and sexual indexies of densitometry at patients with acute leukemia (AL) and healthy children are presented. 31% of children with AL during the initial period of disease had manifestations of the osteopenic syndrome. At patients with AL more often than at healthy children anomalies of development of front part of skull are defined. The partial contribution of free and peptides-connencted oxyproline in urine at AL patients differs in comparison with control group that is caused by modification or deficiency of the corresponding enzymes. 30% of patients with AL had raised concentration of free oxyproline in urine, and lowered glycine concentration that testifies to the increased disintegration of collagen and deficiency of tile plastic material necessary for collagene-forming processes. The obtained data should be considered for forming of risk group on oncohematological pathology at children. PMID- 26638466 TI - [IMMUNOHISTOCHEMICAL FACTORS OF SMALL-CELL LYMPHOMAS AND CHOICE OF TREATMENT WTTH LEVEL INCLUSION]. AB - Diagnosis and treatment patients with lymphoma is still obe of the main problems in theoretical and clinical oncology. Observing increasing tendency of lymphoma incidence in Ukraine it should be noted that the disease is prevalent in young and working-age population. Therefore it is important to improve effectiveness of treatment in primary diagnosed non-Hodgkin lymphoma. PMID- 26638468 TI - [THE RESULTS OF CLINICAL AND PSYCHOPATHOLOGICAL AND PSYCHOLOGICAL DIAGNOSTIC INVESTIGATIONS EMPLOYEES OF FINANCIAL INSTITUTIONS WHICH WERE IDENTIFIED NEUROTIC DISORDERS]. AB - The article presents the results of the clinical and psychopathological and psychological diagnostic, investigations mental health employees of financial institutions, description and analysis of clinical forms identified disorders. PMID- 26638467 TI - [POSITIVE EFFECTS OF MODERN IMMUNOCORRECTION ACCORDING TO THE ANALYSIS OF CYTOKINES AND SLPI IN PATIENTS WITH PYELONEPHRITIS]. AB - The peculiarities of cytokines as compounds of immunogenesis are shown in the patients having acute (A) and chronic (Ch) pyelonephritis (PN). The combination of antibacterial therapy with Nukleinat and Galavit promotes the positive changes of cytokin-producing ability of immunocompetent cells and decrease in the level of proinflammation cytokines in blood and urine, secretory leucocyte protease inhibitor (SLPI) in urine. In children with PN and adult patients with diagnostically elevated titres of antibodies (IgG) to Herpes simplex virus, Cytomegalovirus are shown the positive effects of Kanephron(r) H and Proteflazidum, accordingly. Clinico-immunological effects of immunomodulators testify to the expediency of this usage in complex therapy with the aim to modulate the cytokine link of immunity for improvement of the effective treatment in APN and the protection against aggravation of kidney functioning in ChPN. PMID- 26638469 TI - [THE USE OF PROBIOTICS IN PATIENTS WITH RHEUMATOID ARTHRITIS]. AB - The results of biological research of colon microbiota of patients with rheumatoid arthritis (RA) is in article presented. The signs of III degree dysbiosis, by reducing the concentration of Bacteroides spp., Bifidobacterium spp., Lactobacillus spp. populations, typical strain E. coli. But over growth of populations Klebsiella spp., Proteus spp., Staphylococcus spp., atypical forms of E. coli, Candida spp. The scheme for the correction of the colon microflora of patients with (RA) by was proposed bifiform. Increasing of populations concentration of Bifidobacterium spp., Bacteroides spp., Lactobacillus spp., typical E. coli, Enterococcus spp. and selective decontamination of Enterococcus (Hly+), Klebsiella spp., Proteus spp., Staphylococcus spp., lactosonegative and E.coli (Hly+) confirmed after using of this eubiotics. PMID- 26638470 TI - [REPRODUCTIVE HEALTH IN ADOLESCENT GIRLS IN PUBERTY, BORN WITH UNDERWEIGHT]. AB - Deficiency birth weight adversely affects menstrual function. The menstruation in adolescent girls born with underweight begins late 2 to 6 months. Most of it is expressed in teenage girls who live in the region lack natural iodine. The dysmenorrhea occurs much more often in adolescent girls born with underweight, and it need of prevention and treatment measures. PMID- 26638471 TI - [TREATMENT OF SHORT STATURE PATIENTS WITH NOPMAL GROWTH HORMONE SECRETION OF HYPOPHIS]. AB - The article presents the treatment outcome in 86 children with short stature associated with different endocrine pathology and saved growth hormone secretion (congenital adrenal hyperplasia chondrodystrophy, Turner syndrome, idiopathic short stature, syndrome biologically inactive growth hormone and other genetically determined pathology). This study extends prior knowledge about the outcomes of the treatment with recombinant growth hormone and luteinizing hormone -releasing hormone analogue (alone or in combination) in short patients with poor prognosis of final height. PMID- 26638472 TI - [DENTAL STATUS OF PATIENTS WITH INTRAUTERINE GROWTH RESTRICTION IN PAST HISTORY DURING PERIOD OF REMOVABLE AND PERMANENT DENTITION]. AB - The analysis of the dental status in patients with IUGR in past history in period of removable and permanent dentition was conducted. 39 patients with intrauterine growth retardation in past history were examined. The clinical, statistical methods were held. Concluded that the child, who was born with IUGR, later in future life, has a great risk of dental diseases. The most considerable violations were found in patients with "symmetrical" form of intrauterine growth retardation. It is proposed to use clinical markers as possible predictors of periodontal diseases. PMID- 26638473 TI - [THE ROLE OF ANTIHYPOXANTS AND ANTIOXIDANT IN TREATMENT OF ODONTOGENIC OF MAXILLOFACIAL AREA]. AB - The aim of this work is the systematization of the literature data for the most clearly defined directions of study of the effectiveness of antioxidant and antihypoxant drugs in complex treatment of patients with purulent inflammatory diseases of the maxillofacial area. The authors attempt to analyze the results of the use of antioxidant and antihypoxant therapy at pyoinflammatory pro- cesses of different localization. Areas of research of the impact of antioxidant and antihypoxants therapy on physical and biochemical parameters of the maxillofacial area and the organism of the patient as a whole are defined. PMID- 26638474 TI - [AN EXPERIMENTAL STUDY OF THE HISTOLOGICAL FIBRO GENESIS ABILITIES IN THE AREA OF IMPLANTATION OF ALOTRANSPLANTATES APPLYING INTRAABDOMINAL AND PREPERITONEAL PLASTIC SURGERY]. AB - The histological fibro genesis abilities in the area of implantation of allotransplantates applying intraabdominal and preperitoneal plastic surgery were examined during experimental research. The experiment involved 12 Russian chinchilla rabbits. The animals were spitted into two groups: I group--operated using IPOM methodology (intraperitonealonlaymesh, n = 6) with the installation "Proceed" mesh made by "Ethicon", group II--modeling preperitoneal plastics with the installation of "Ethicon's Ultrapro" mesh (n = 6). After removing the animals from the experiment, the implants with adhering musculo-aponeurotic tissue layer were excised and sent for histological examination. At the same time the severity of the inflammatory process were rated, the composition of the inflammatory infiltrate, germination of the connective tissue through the pores of the prosthesis and neovascularization. Analyzing the research data of histological connective abilities complexes formed in the area of the allotransplants implantation using intra-abdominal and pre-peritoneal plastic during the experiment, we can conclude that intra-abdominal installation of mesh prostheses reduces the severity of inflammatory changes surrounding tissues and reduces the probability of seroma formation in comparison with the placement of the pre peritoneal implant. PMID- 26638475 TI - [THE USE OF OZONATED SEA BUCKTHORN OIL IN THE PREVENTION AND TREATMENT OF TOBACCO DEPENDENCE PERIODONTITIS IN THE EXPERIMENT]. AB - Therapeutic and prophylactic properties ozonated of sea buckthorn oil in the experiment on the model of generalized periodontitis in Wistar rats induced by action of extracted products of incomplete combustion of tobacco smoke was investigated. It is proved that the proposed method of ozone therapy in combination with fitooil prevents and corrects metabolic disturbances in the periodontal tissues, caused a by high therapeutic effect of the drug. PMID- 26638476 TI - [ECONOMIC EFFICIENCY TECHNOLOGIES DIAGNOSIS OF ISCHEMIC HEART DISEASE BY MAHNITOTOKARDIOHRAFIYI]. AB - The article is devoted to clinical--economic analysis of modern diagnostic technology--magnetocardiography by analyzing the "cost-effectiveness". Economic effectiveness of diagnosis of coronary artery disease using magnetocardiography in terms of cost/effectivness is shown. The economicaly optimal sequence of several noninvasive methods for diagnosis of coronary artery disease is defined. PMID- 26638477 TI - [FEATURES OF PTSD IN THE PARTICIPANTS OF THE ANTI-TERRORIST OPERATION--UKRAINIAN SYNDROME]. AB - The article gives information about the results of research of characteristics of post traumatic stress disorder (PTSD) in the participants of the anti-terrorist operation (ATO), and refugees. Drawn attention to the fact that the demonstration took place in the study of PTSD patients, in the form of the following options: invasion (penetration); avoiding (displacement); hyperactivation. In the study took part 71 serviceman (69 men and 2 women) aged from 22 to 35 years (average age 26,2 years) that have closed traumatic brain injury , in the form of a brain concussions, contusions and suffered on PTSD (main group), studies conducted in 3 6 months after received closed traumatic brain injury. In the group of comparison included 37 patients (34 women and 3 men) aged 27-42 years (average age 32,2 years) that have had PTSD. In a group that included military personnel, in which in addition to PTSD, the clinical picture had existing consequences of craniocerebral injury observed in asthenic symptom complex--27 patients (38.1%); the anxious-phobic--in 19 patients (26.7%); hysterical--in 8 patients (11.3%); a depressive--in 17 patients (23.9%). In a group of patients and refugees from the ATO was: asthenic symptom complex--in 12 patients (32.4%), the anxious-phobic--in 11 patients (29.7%), hysterical--in 6 patients (16.2%), a depressive--in 8 patients (21.7%). PMID- 26638478 TI - [XXII Congress of the EACMFS-European Association for Cranio-Maxillo-Facial Surgery]. PMID- 26638479 TI - [GLUCOSE METABOLISM IN SURFACTANTS PRODUCER NOCARDIA VACCINII IMV B-7405]. AB - Key enzymes of glucose metabolism were detected in the cells of surfactants producer Nocardia vaccinii IMV B-7405 grown on this substrate. It has been established that glucose catabolism is performed through gluconate (FAD(+) dependent glucose dehydrogenase activity 698 +/- 35 nmol x min(-1) x mg(-1) of protein). Oxidation of gluconate to 6-phosphogluconate is catalised by gluconokinase (178 +/- 9 nmol x min(-1) x mg(-1) of protein). 6-Phosphogluconate was involved into pentose phosphate cycle by constitutive NADP(+)-dependent 6 phosphogluconate dehydrogenase (activity 357 +/- 17 nmol x min(-1) x mg(-1) of protein). The data obtained serve as the basis for theoretical calculations of optimal molar ratio of concentrations of energetically nonequivalent substrates for intensifying the surfactants synthesis on their mixture. PMID- 26638480 TI - [DIFFERENTIAL SENSITIVITY OF MICROORGANISMS TO POLYHEXAMETHYLENEGUANIDINE]. AB - Factors identified that affect the sensitivity of microorganisms to polyhexamethyleneguanidine (PHMG). Salts of PHMG chloride, valerate, maleate, succinate was to use. Test strains of Esherichia coli, Staphylococcus aureus, Bacillus cereus, Leptospira interrogans, Paenibacillus larvae, Mycobacterium bovis, M. avium, M. fortuitum, Aspergillus niger and some strains of viruses are taken as objects of research. We have determined that the cytoplasm membrane phospholipids is main "target" for the polycation molecules of PHMG. A differential sensitivity of the microorganisms to this drug is primarily determined by relative amount of lipids in membrane and their accessibility. Such trends exist: increase the relative contents of anionic lipids and more negative surface electric potential of membrane, and reduction of the sizes fat acid remainder of lipids bring to increase of microorganism sensitivity. Types of anion salt PHMG just have a certain value. Biocide activity of PHMG chloride is more, than its salts with organic acid. Feasibility of combining PHMG with other biocides in the multicomponent disinfectants studied and analyzed. This combination does not lead to a significant increase in the sensitivity of microorganisms tested in most cases. Most species of pathogenic bacteria can be quickly neutralized by aqueous solutions of PHMG in less than 1% concentrations. PMID- 26638481 TI - [USAGE OF FUMARATE BY SULPHATE-REDUCING BACTERIA DESULFOMICROBIUM SP. CrR3 AND DESULFOTOMACULUM SP]. AB - Sulphate-reducing bacteria Desulfomicrobium sp. CrR3 and Desulfotomaculum. sp. are able to use fumarate as electron donor and acceptor. When they use fumarate as an electron acceptor succinate accumulates in the medium. If fumarate serves as electron donor, minor amounts of citrate, isocitrate and acetate are detected except succinate. In the case of simultaneous introduction of fumarate, SO4(2-) and Cr2O7(2-), the last inhibits usage of fumarate and SO4(2-). PMID- 26638482 TI - [INFLUENCE OF AZOSPIRILLUM BRASILENSE 10/1 ON ASSOCIATIVE NITROGEN FIXATION AND INTRAVARIETAL POLYMORPHISM OF SPRING TRITICALE]. AB - It is shown, that the perspective Ukrainian sorts of spring triticale characterizes by considerable polymorphism by associative N2-fixing ability in root zone of plants. Application of active strain Azospirillum brasilense 10/1 promotes the decline of variability of this sign within the limits of sort, increase potential nitrogen activity is on the average in 3,2-4,7 times and also distributing normalizations in the selections of the inoculated plants. PMID- 26638483 TI - [GROWTH OF MICROMYCETES FROM DIFFERENT ECOLOGICAL NICHES ON AGAR NUTRIENT MEDIA]. AB - Radial growth rate of (K(r)) 153 strains 6 species of micromycetes from different ecological niches was studied on 7 agar media: three standard (malt extract agar, potato-dextrose agar, Czapek's agar), and on agar media with plant polymers (carboxymethylcellulose, xylan, soluble starch and apple pectin). Endophytic and plant pathogenic strains (biotrophs) of all studied species did not differ significantly in their ability to grow on nutrient media of different composition -average values of K(r) for these two groups were the same (0,200 and 0,199 mm/h, respectively). Soil micromycetes (saprophytes) characterized by the lowest average growth rate (0,169 mm/h) and significantly differed from the endophytic and plant pathogenic ones. Average of the radial growth rates of studied microscopic fungi were higher on standard nutrient media than with plant polymers ones. Growth parameters of endophytes and plant pathogens of all studied species on various agar media differed from the soil strains. High growth rate of endophytic and plant pathogenic strains of Fusarium poae, Alternaria alternata and Ceratocystis sp. provides them the rapid colonization of plants. Penicillium funiculosum strains equally can exist as saprophytes in soil and as endophytic plant symbionts. A wide range of K(r) variation of endophytic dark pigmented Mycelia sterilia indicates the presence in this group of different species of micromycetes, which have no sporulation. PMID- 26638484 TI - [FATTY ACID COMPOSITION ALTEROMONAS-LIKE BACTERIA ISOLATED FROM THE BLACK SEA WATER]. AB - Alteromonas macleodii strains isolated from the Black sea water were similar in their fatty acids composition with the type strain of this species. Analysis of lipid composition of 10 A. macleodii strains isolated from the deep and surface water layers in different World ocean regions including the Black sea water has shown that the deep and surface isolates of this species formed two groups different in their fatty acids profiles. The Black sea isolates of Pseudoalteromonas haloplanktis, P. citrea, P. flavipulchra conformed to these species type strains in their fatty acids composition. On the basis of the fatty acids spectra similarity of three Pseudoalteromonas species strains with Plipolytica described in 2010 has been established. Presence of three isomers C16:1psi7, C 16:1psi9 and C16:1psi6--components of hexadecenic acid in the Black sea isolates of Shewanella baltica has been shown. PMID- 26638485 TI - [THE MYCOBIOTA IN STUDYING THE RESISTANCE OF GYPSUM PLASTERBOARD TO MICROSCOPIC FUNGI]. AB - The resistance of two types of gypsum plasterboard: ordinary and water-resistant to microscopic fungi was studied. It was found that under conditions of high relative humidity and direct influence of water at constant temperature (29 +/- 2) degrees C all samples of plasterboard were not resistant to fungi. Furthermore, the contaminating mycobiota of uninfected fragments of plasterboard was revealed under these conditions. It was discovered that the test cultures Aspergillus terreus and Trichoderma viride were the most active at the stage of developed mycelium. PMID- 26638486 TI - [PATHOGENIC MIKO,- AND MICROFLORA OF FRAXINUS EXCELSIOR IN PODOLYA UKRAINE]. AB - The article summarizes our research results of pathogenic myco- and microflora, as well as harmful entomofauna on European Ash. It is shown that the most common and harmful diseaseis tuberculosis (its causal agent--bacteria Pseudomonas syringae pv.savastanoi (Smith 1908), which affects trunks, branches, twigs and buds of European Ash. It describes a number of pathogens and representatives mikofitozov malicious entomofauna that by virtue of its activities significantly weaken the growth, development and underestimate the qualitative characteristics of wood European Ash. PMID- 26638487 TI - [THE INFLUENCE OF B-IRRADIATION ON MICROMYCETES ISOLATED FROM THE ZONE OF RADIONUCLIDE CONTAMINATION]. AB - The resistance of the micromycetes to beta-irradiation had been studied. The study was conducted on two species: Cladosporium sphaerospermum Penz. and Alternaria alternata (Fr.) Keissl., each of them was represented by six strains. Half of strains were isolated from the inner locations of the "Shelter" object (SO), which were characterized by different levels of radionuclide contamination. For C. sphaerospermum strains maximum resistance to beta-radiation was observed among 20-day-old cultures. The greatest resistance to beta-radiation had been demonstrated by two strains: 5-1 (isolated from SO location with the highest level of contamination) and 852 (control). For A. alternata strains maximum resistance to beta-radiation was observed among 40-day-old cultures. As the most resistant were characterized 56 and 105 isolates from the SO inner location with a high level of the radionuclide contamination. Based on the obtained results we concluded about high resistance to irradiation of both studied species of anamorphic fungi, which achieved through different life strategies: C. sphaerospermum strains survive due to rapid and abundant formation of conidia, whereas conidia of A. alternata strains are formed slowly, but they have greater advantage under irradiation due to their multicellular structure and large sizes. PMID- 26638488 TI - [DATABASE FOR DEPOSITARY DEPARTMENT OF MICROORGANISMS]. AB - The database on microorganism culture depositary is designed with using MS Access 2010. Three major modules, namely general description, administration, storage, compound database kernel. Description of information in these modules is given. Web page of the depositary is developed on the database. PMID- 26638489 TI - [DEFINITION OF WOMEN REPRODUCTIVE TRACT MICROFLORA COMPOSITION USING TEST-SYSTEM "FEMOFLOR-17"]. AB - The data about composition of the vaginal microflora of women with use of the test system "Femoflor-17" was analyzed. Established that 92.7% of samples contained lactobacilli. For quantitaty of lactobacilli vaginal flora characterized as normobiosis. The dysbiosis in the background detection of mycoplasma, ureaplasma and yeast of genus Candida identified for 38.2% of the samples. Mycoplasma, ureaplasma and candida as monoinfection detected in 71% of cases and as an association of two pathogens in 29% of cases. In establishing compliance obtained by the test system "Femoflor-17" results to clinical and bacteriological markers of vaginal dysbiosis characterized as moderate anaerobic dysbiosis--6% of the samples, moderate aerobic dysbiosis--10%, moderate anaerobic aerobic dysbiosis--35%, pronounced anaerobic dysbiosis--12% of the samples, expressed aerobic dysbiosis--10%, anaerobic-aerobic expressed dysbiosis--27% of the samples. Showing dominance of obligate anaerobic microorganisms associations among other microorganisms. PMID- 26638490 TI - [AUXINS AND CYTOKININES SYNTHESIS BY BRADYRHIZOBIUM JAPONICUM UNDER FLAVONOIDS INFLUENCE]. AB - AIM: Research the ability of different by effectiveness symbiotic nitrogen-fixing soybean bacteria Bradyrhizobium japonicum to the synthesis of phytohormones stimulators auxins and cytokinins for the actions of plant flavonoids genistein and naringenin. METHODS: Extracellular phytohormonal compound isolated from the supernatant culture liquid of the soybean rhizobia by redistribution of phytohormones in two phases solvent immiscible with each other. Auxins and cytokinins were determined by thin layer spectra densitometry chromatography. RESULTS: Shown the ability of symbiotic diastrophic soybean strains to synthesize auxins (4-1067 mg/g of absolutely dry biomass) and cytokinins (141-1554 mg/g of absolutely dry biomass). Cultivation soybean rhizobia in the presence of flavonoid compounds genistein and naringenin leads to the narrowing of the range and reducing the number of phytohormones: unchecked synthesis of indole-3 carboxylic acid, indole-3-carbinol, indole-3-acetic acid hydrazide and zeatin. CONCLUSIONS: Depressing effect of flavonoids on the phytohormones in soybean rhizobia synthesis is probably due to changes in metabolism microsymbiotic bacteria that are not aimed at the synthesis of secondary metabolites and to launch effective nodulating mechanisms, and also the concentration of flavonoid compounds in the nutrient medium. PMID- 26638491 TI - [BIOINFORMATIC SEARCH AND PHYLOGENETIC ANALYSIS OF THE CELLULOSE SYNTHASE GENES OF FLAX (LINUM USITATISSIMUM)]. AB - A bioinformatic search of sequences encoding cellulose synthase genes in the flax genome, and their comparison to dicots orthologs was carried out. The analysis revealed 32 cellulose synthase gene candidates, 16 of which are highly likely to encode cellulose synthases, and the remaining 16--cellulose synthase-like proteins (Csl). Phylogenetic analysis of gene products of cellulose synthase genes allowed distinguishing 6 groups of cellulose synthase genes of different classes: CesA1/10, CesA3, CesA4, CesA5/6/2/9, CesA7 and CesA8. Paralogous sequences within classes CesA1/10 and CesA5/6/2/9 which are associated with the primary cell wall formation are characterized by a greater similarity within these classes than orthologous sequences. Whereas the genes controlling the biosynthesis of secondary cell wall cellulose form distinct clades: CesA4, CesA7, and CesA8. The analysis of 16 identified flax cellulose synthase gene candidates shows the presence of at least 12 different cellulose synthase gene variants in flax genome which are represented in all six clades of cellulose synthase genes. Thus, at this point genes of all ten known cellulose synthase classes are identify in flax genome, but their correct classification requires additional research. PMID- 26638492 TI - PUTATIVE FERROXIDASES IN THE FLAVINOGENIC YEAST PICHIA GUILLIERMONDII ARE REGULATED BY IRON ACQUISITION. AB - Using similarity search we identified Candida (Pichia) guilliermondii genes involved in iron acquisition. This yeast possesses at least four genes potentially coding for ferri-reductases, four genes encoding iron permeases and two genes codingforferroxidases. Identified C.(P.) guilliermondii genes encoding ferroxidases possess different patterns of expression under iron repletion conditions whereas their expression is activated under iron deficiency conditions or in mutant strains defective in regulation of iron acquisition. C.(P.) guilliermondii has no homologue of Saccharomyces cerevisiae transcriptional regulator of iron metabolism, Aft1p and possess an iron regulatory network similar to that of Candida albicans. Since most of C.(P.) guilliermondii known strains are not pathogenic, in contrast to that of C. albicans, we propose C.(P.) guilliermondii as safe and useful model for studying iron-dependent regulation of metabolism in yeasts belonging to CUG clade. PMID- 26638493 TI - [MOLECULAR-GENETIC POLYMORPHISM OF chs_H1 GENE IN UKRAINIAN HOP VARIETIES]. AB - Polymorphism of chs_H1 gene encoding the "true" chalcone synthase was determined by alignment of sequences. The polymorphism associates with single nucleotide changes, insertions or deletions (indels) in the promoter, exons, intron, 3' untranslated region. The molecular-genetic polymorphism in gene chs_H1 different regions of hop varieties of Polessye Agriculture Institute' breeding NAAS was analyzed. PMID- 26638494 TI - [THE GENETIC DIVERSITY OF PIG BREEDS ON TEN PRODUCTION QUANTITATIVE TRAITS LOCI]. AB - Genetic structure of 11 pig breeds and lines of different origins and production specialization for 10 quantitative traits loci: RYR1, GH, IGF2, CTSL, CTSS, CTSB, CTSK, MC4R, ESR1 & PRLR was analyzed. The results allow us to suppose that the uniqueness of genetic structure of each breed is largely determined by features of the allelic structure of a number of loci. Breeds of different production specialization differ significantly for such QTL, as RYR1, MC4R, ESR1 and IGF2. However, we have found that the loci CTSB, CTSL, CTSK, CTSS and PRLR in most of investigated breeds showed similar distribution of alleles, significant genetic differentiation between breeds and within breeds for these loci is missing. The exception is the Large Black breed for the CTSB locus and Ukrainian steppe spotted breed for the CTSL locus. Also, it can be assumed that allelic structure of some of investigated loci are more connected with the origins of pig breeds than to the selection on production traits. This refers, for example, to the growth hormone gene, the using of which in marker assisted selection could be effective only in some populations. The genetic distance between breeds and lines was defined and the dendrogram of the genetic relationship was built. Breeds are grouped in connection with the production specialization, as well as by their origins. PMID- 26638496 TI - [DIALLEL ANALYSIS OF STOMATAL TRAITS IN TRITICUM AESTIVUM L]. AB - The guard cell size and stomatal density are important interdependent traits (r = -0.67 +/- 0.146) of plant adaptive response to environmental stresses. The purpose of this study was to determine the types of inheritance, the number and effects of genes controlling phenotype of the above-mentioned leaf stomata characteristics. Hybrid F1 values, resulting from crossing by 7 x 7 half diallel crosses and values, and parental midpoints were used. Genetic control of the trait "length of guard cells" is based on the complete domination of the larger length. In the inheritance of "stomata density" the additive components were significant. It was established that recessive alleles are responsible for the increasing of stomata density (r = 0.93 +/- 0.07) and their number was highest in Cultivar Odesskaya 16. PMID- 26638495 TI - OBTAINING OF THE TRANSGENIC HELIANTHUS TUBEROSUS L. PLANTS, CALLUS AND "HAIRY" ROOT CULTURES ABLE TO EXPRESS THE RECOMBINANT HUMAN INTERFERON ALPHA-2b GENE. AB - This work is the first to our knowledge to describe the successful attempt of Agrobacterium rhizogenes-mediated transformation of topinambour in order to obtain the transgenic H. tuberosus plants, callus and "hairy" root cultures. The plasmid vectors contained the sequence of interferon gene fused with Nicotiana plumbagenifolia L. calreticulin apoplast targeting signal driven by 35S CaMV promoter or root-specific Mll promoter. Nearly 75% isolated Ri-root lines and callus cultures were proved (by PCR analysis) to contain HuINFa-2b transgene. We also managed to obtain H. tuberosus transgenic plants through somatic embryogenesis on the transgenic "hairy" root culture. The obtained transgenic H. tuberosus cultures exhibited high-level antiviral activity that ranged from 2000 to 54500 IU/g FW that makes this crop considered a promising source of recombinant interferon alpha 2b protein. PMID- 26638497 TI - [INTRASPECIFIC CHROMOSOME POLYMORPHISM OF IRIS PUMILA L. FROM THE TERRITORY OF UKRAINE]. AB - Cytogenetic analysis of Iris pumila L. plants from different habitats in Ukraine revealed the intrachromosomal polymorphism. Chromosome number 2n = 32 was established for plants of this species. Root meristem of I. pumila seedlings of all populations showed high level of mixoploidy. The differences in the percentage of aneuploid cells and anaphase aberration were found between the sampled populations. Anaphase analysis revealed the level of chromosomal rearrangements that reached 9.2% in some populations reached. PMID- 26638498 TI - CYTOGENETIC AND MOLECULAR RESPONSES OF AMMONIUM SULPHATE APPLICATION FOR TOLERANCE TO EXTREME TEMPERATURES IN VICIA FABA L. AB - Effects of ammonium sulphate [(NH4)2SO4] on mitosis, cell cycle and chromosomes in Vicia faba L. seeds exposed to extreme temperatures were investigated using flowcytometric and cytogenetic analysis. Seeds germinated at high and low temperatures showed a signiicant decrease in mitotic index as compared to those of optimum temperature conditions. Application of 50 and 1000 uM (NH4)2SO4 were successful in alleviating the negative effects of low and high temperature on mitotic activity, respectively. 50 uM (NH4)2SO4 showed the most positive effect on cell cycle at the extreme temperatures. This concentration increased the cell division removing or decreasing the negative effects of temperature stress. Namely, the highest G2/M and S phase percentages under stress conditions were obtained with application of 50 uM (NH4)2SO4. Chromosomal aberrations were not observed in cells of seeds germinated in distilled water and also at any temperatures. However, the frequency of chromosomal aberrations increased significantly by increasing (NH4)2SO4 concentration. The highest aberration frequency in all temperature degree tested was found at 1000 uM (NH4)2SO4 concentration. PMID- 26638499 TI - [SIGNAL MEDIATORS IN PLANTS RESPONSES AGAINST ABIOTIC STRESSORS: CALCIUM, REACTIVE OXYGEN AND NITROGEN SPECIES]. AB - The perception of signals of abiotic stressors by plant cells is accompanied by the increase of cytosolic calcium concentration, content of reactive oxygen species (ROS) and nitrogen monoxide (NO) which execute the role of signal mediators at the activation of gene expression, supervising protective reactions. Calcium ions, ROS, and NO are in the multiple functional interactions which provides the intensifying and transduction of signals into genetic apparatus as well as their attenuation. The increase of content, at least, of one of these signal mediators in cells can cause activation of some signal cascades and formation of plant adaptive reactions. PMID- 26638500 TI - The Case for a National Health Social Work Practice-Based Research Network in Addressing Health Equity. PMID- 26638501 TI - "When Things Are Really Complicated, We Call the Social Worker": Post-Hip Fracture Care Transitions for Older People. AB - Social workers play a key role in the delivery of interdisciplinary health care. However, in the past decade, concerns have been raised about social work's sustainability and contributions in a changing health care sector. These changes come at a time when older patients are more complex and vulnerable than ever before. In this article, using a strengths-based approach, the authors examine the key contributions made by social workers working with older patients with hip fracture as they strive to achieve successful care transitions. Twenty-five interviews with health care professionals (HCPs) were conducted and then analyzed using an analytical coding framework. Although social workers are vital, they are often underused and overlooked in the care of hip fracture patients. The authors sketch the important contributions that social workers make to care transitions after hip fracture, specifically informational continuity; patient-HCP relational continuity; conflict resolution; mediation among family, patient, and HCP (for example, doctors and nurses); collaboration with family caregivers and community supports; and relocation counseling. PMID- 26638502 TI - Solution-Focused Strategies for Effective Sexual Health Communication among African American Parents and Their Adolescents. AB - The high rates of sexual risk behaviors, particularly among African American youths who may not be aware of their HIV status, provide indication that, unless prevention efforts are enhanced, this vulnerable group of youths will remain at greater risk for negative health status outcomes. Parents are important in efforts to reduce risk among youths and often have a willingness to be sexuality educators for their children; however, communication barriers often impede their ability to provide preventive sexual health knowledge to their youths. Social workers are often presented with opportunities to help parents develop effective sexual health communication skills in informal settings when formal interventions are not feasible. The present effort considers solution-focused strategies social workers can use to help parents overcome barriers and communicate more positively with their youths about sexual health. PMID- 26638503 TI - A Review of Sexual Assault Information on College Web Sites. AB - This article presents a comprehensive review of information available on campus Web sites at all four-year colleges and universities in New Jersey. This study used a descriptive, content analysis methodology with a sample that consisted of 28 college and university Web pages. To evaluate the Web sites, ecological approaches were rated with a checklist created to document the presence and extent of information about sexual assault, including five key areas: (1) general information about sexual assault, (2) the availability of services for students, (3) information about how to report an incident of sexual assault, (4) whether there was a department exclusively dedicated to the school's response to sexual assault, and (5) information about the existence of a policy prohibiting sexual assault on campus. Almost all of the schools provided policies and information about services for students. However, the comprehensiveness of the information and the ease of finding it varied greatly by campus. The article concludes with a discussion of the implications for social workers and those responding to survivors of sexual assault on a college campus. PMID- 26638504 TI - Application of Attachment Theory in Clinical Social Work. AB - This article proposes the use of attachment theory in clinical social work practice. This theory is very appropriate in this context because of its fit with social work concepts of person-in-situation, the significance of developmental history in the emergence of psychosocial problems, and the content of human behavior in the social environment. A literature review supports the significance of the theory. Included are ideas about how attachment styles and working models may be used in assessment and treatment to help clients achieve a secure attachment style. PMID- 26638505 TI - Qualitative Study: Exploring the Experiences of Family Caregivers within an Inpatient Neurology and Neurosurgery Hospital Setting. AB - The aim of this study was to further understanding of what it means for family caregivers to be included in their relatives' care and identify what type of care they are providing. This study used a qualitative research design to recruit 12 participants, who were family caregivers, from the adult neurology and neurosurgery units at a hospital located in Toronto, Ontario, Canada. The data were collected using semistructured interviews, which were conducted in person and ranged between 30 and 60 minutes in length. Analysis of the data was conducted using phenomenological guidelines and principles. Upon review, the results indicated that the participants shared common experiences that were grouped into three main themes: (1) unfamiliarity with the hospital environment and procedures, (2) identifying the hidden realities of families and caregivers, and (3) strengthening collaborative dialogues and opportunities. Overall, this study exemplified that the need to continue to recognize family caregivers' experiences and their involvement is paramount in being able to understand how and in what way patient care can be better optimized collaboratively, during treatment delivery and recovery stages. PMID- 26638506 TI - Puerto Rican-Born Women in the United States: Contextual Approach to Immigration Challenges. AB - This study focused on how acculturative stress and psychological distress affect Puerto Rican-born women residing in the United States. Mediation path analysis was used to estimate relationships between contextual factors, acculturative stress, and psychological distress. The fit of the data to the final model was adequate as estimated using chi-square analysis, comparative fit index, Tucker Lewis Index, and root-mean-square error of approximation. Racial discrimination (b = 0.38, p = .01), difficulties visiting family abroad (b = 0.26, p = .03), and age at immigration (b = 0.19, p = .03) were positively associated with acculturative stress. The factor English skills (b = -0.31, p = .02) was negatively associated with acculturative stress. Racial discrimination had the strongest effect on acculturative stress, followed by English skills, difficulties visiting family abroad, and age at immigration. Racial discrimination (b = 0.39, p = .01) and financial constraints (b = 0.30, p = .01) were positively associated with psychological distress. Racial discrimination affected the women's psychological distress the most, followed by economic contexts (financial constraints). This study informs practitioners in considering the significant contextual factors relevant to the psychological distress of Puerto Rican-born women. PMID- 26638507 TI - The Cost of Organ Donation: Potential Living Kidney Donors' Perspectives. AB - Living kidney transplantation is a treatment option for some people with end stage kidney disease. The procedure has low complication rates and positive outcomes; despite this evidence, the number of living kidney donations has decreased in recent years, and the causes are not well understood. This qualitative study sought to explore the experiences of potential living kidney donors before the transplantation. A total of 19 semistructured interviews were conducted with potential living kidney donors in Perth, Western Australia. Results reported here relate to participants' experience of the employment and financial implications of living kidney donation. Participants incurred direct and indirect costs during the time leading up to the transplantation, and many had concerns about the potential financial impact during the recovery period. Employment status, occupation type, and financial commitments affected participants' experiences, and financial concerns were exacerbated for those who were donating to their partners. Results suggest that potential living kidney donors would benefit from tailored financial planning advice to help them prepare for the time of the surgery and the recovery period. PMID- 26638508 TI - Youth Homelessness: Prevalence and Associations with Weight in Three Regions. AB - This study investigated the utility of the Youth Risk Behavior Survey (YRBS) to document associations between homeless status and weight while estimating the prevalence of youth homelessness in three regions. A school-based survey, the YRBS includes youths who have been difficult to involve in past research. Analysis of 2011 YRBS data produced population-weighted estimates of youth homelessness prevalence separately for Connecticut, Delaware, and Philadelphia. Public high school students anonymously reported their housing status, height, and weight on the YRBS. Height and weight were converted to body mass index (BMI) percentile-for-age scores. Homelessness was associated with higher BMI percentile scores for youths compared with nonhomeless peers. Associations between BMI percentile and different forms of homelessness (homeless with family, unaccompanied homeless without family) were explored at each site. Estimates of one-month homelessness prevalence ranged from 3.9 percent to 5.9 percent at each site. Homelessness, especially family homelessness, is associated with risk for higher BMI. The YRBS is an informative tool for estimating the prevalence of youth homelessness, expanding on what is known through other, more commonly used methods. PMID- 26638509 TI - Caregiving and Traumatic Brain Injury: Coping with Grief and Loss. PMID- 26638510 TI - Psychosocial Needs Assessment and Interventions in a Chinese Postdisaster Community. PMID- 26638511 TI - [Too few antibiotics: the second path to resistance]. PMID- 26638512 TI - [Lyme serology: what's the deal?]. AB - Lyme serology is too commonly prescribed in absence of a well established differential diagnosis. Its low positive predictive value is very often unusable. IgG and IgM positive results are tricky to interpret and often lead to clinically unjustified antibiotherapy. Clinical and epidemiological approaches must integrate the serological results. The microbiologist should have all available information to be able to communicate an appropriate interpretation with the results. This way can propose adequate analysis leading to higher predictive values. We present essentials and pitfalls of the Lyme serology, suggesting new possibilities and reminding physicians as to which tests have not yet brought any proof of benefit to the patient. PMID- 26638513 TI - [Acute pericarditis]. AB - Acute pericarditis is an inflammation of the pericardium. Different etiologies are known, and can be classified in three groups: infectious, neoplastic and auto immun. The diagnosis is based essentially on clinical signs and should be raised by position and respiratory dependent chest pain, especially when it follows a viral infection, and a pericardial friction rub on cardiac auscultation. An ECG and an echocardiography should be performed to assess the presence of a pericardial effusion. A diffuse and concave ST elevation permits the distinction with myocardial ischemia. The first line therapy is an association between NSAR and colchicine, the latter has shown to reduce the risk of recurrence. PMID- 26638514 TI - [Microbiological diagnosis of Clostridium difficile infection]. AB - The clinical microbiology laboratory plays an essential role in the management of Clostri- dium difficile infections, showing an increase in frequency and severity. Many tests (culture, EIA, PCR), detecting bacteria or their antigens, toxin genes or free toxins, allow the microbio- logist to provide the clinician and the infection control specialist with a reliable diagnosis as- sistance, which meet essential criteria for ra- pidity, sensitivity and specificity. This review presents the diagnostic algorithms currently used. PMID- 26638515 TI - [Loco-regional complications of pharyngitis: the example of Lemierre's syndrome]. AB - Pharyngitis is a common cause of consultation in ambulatory medicine. Although it is benign in most cases, serious complications may happen and must be recognized quickly. Lemierre's syndrome is one of them. It consists in the association of thrombosis of the internal jugular vein and septic emboli that generally involve the lungs and is classically associated with Fusobacterium necrophorum. It is usually found in young and healthy adults and has an estimated mortality of 5%. Diagnosis relies essentially on the characteristic presentation of the disease. Therapy consists of surgical drainage of purulent collections and necrotic tissues associated with a prolonged course of antibiotics. Some authors also recommend a anticoagulation. PMID- 26638516 TI - [Infectious causes of cerebral ring-enhancing lesions]. AB - Diagnosis of cerebral ring enhancing lesions on CT or MRI studies is quite frequent. Their differential diagnosis is diverse, including infectious, tumoral, demyelinating and vascular diseases. Information provided by cranial imaging, notably by the different sequences on magnetic resonance imaging (TI, T2, FLAIR and diffusion-weight imaging) is helpful to differentiate between the different causes. The aim of this article is to discuss some of infection which may occur in our region and presenting as a cerebral lesion with annular enhancement. We consider infection in immunocompetent and immunocompromised patient. PMID- 26638517 TI - [Advice for those that want to specialize in infectious diseases in Switzerland]. AB - In Switzerland the specialty of Infectious Diseases attracts many young physicians. In this article we describe the place of infec- tious diseases in Switzerland. We review its usefulness for patients, the requirements to obtain a title of specialist, its different subs- pecialists and the potential job openings of this training. PMID- 26638518 TI - [HIV sleeping, sleeping...]. PMID- 26638519 TI - [Fight against antibiotic resistance is now a medical and political emergency]. PMID- 26638520 TI - ["Borderline state"]. PMID- 26638521 TI - [What of "personalized medicine" is really the name?]. PMID- 26638522 TI - [Eat spicy and you will live long]. PMID- 26638523 TI - [Smoking, emotional, genetic and ovarian miscellany]. PMID- 26638524 TI - [Already leader of care centers in German-speaking Switzerland, Migros aims for Western Switzerland]. PMID- 26638525 TI - [A symposium on the critical examination of our practices]. PMID- 26638526 TI - [Increase in premiums, a fascinating impasse]. PMID- 26638527 TI - CRISPR-Cas Systems in Prokaryotes. AB - Prokaryotic organisms possess numerous strategies that enable survival in hostile conditions. Among others, these conditions include the invasion of foreign nucleic acids such as bacteriophages and plasmids. The clustered regularly interspaced palindromic repeats-CRISPR-associated proteins (CRISPR-Cas) system provides the majority of bacteria and archaea with adaptive and hereditary immunity against this threat. This mechanism of immunity is based on short fragments of foreign DNA incorporated within the hosts genome. After transcription, these fragments guide protein complexes that target foreign nucleic acids and promote their degradation. The aim of this review is to summarize the current status of CRISPR-Cas research, including the mechanisms of action, the classification of different types and subtypes of these systems, and the development of new CRISPR-Cas-based molecular biology tools. PMID- 26638528 TI - Role of SAP7-10 and Morphological Regulators (EFG1, CPH1) in Candida albicans' Hypha Formation and Adhesion to Colorectal Carcinoma Caco-2. AB - Secreted aspartic proteases (Saps) are considered as key virulence factors of Candida albicans. Hopefully our outlook will widen the knowledge of SAP7's role in C. albicans pathogenesis. The goal of our study was to investigate SAP7 expression during C. albicans adhesion to intestinal human cells. Another objective was to study the role of SAP8-10 and transcriptional regulators: EFG1 and CPH1, using the mutants: Deltasap, Deltaefg1, Deltacph1 during growth on Caco 2 monolayer. SAP7 expression was analyzed using real time RT-PCR; relative quantification was normalized against ACT1 in cells after growth on Caco-2. Adherence assay of C. albicans to Caco-2 was performed in a 24-well-plate. The results proved that SAP7 can play a role during the initial adaptation of C. albicans to intestinal tract and decreases over time. Up-regulation of SAP7 occured in the absence of SAP8 and SAP10 (genetic alternations dependence). SAP7 can be regulated by the morphogensis' regulators during C. albicans growth on epithelium. Adhesion of the mutants was indistinguishable from SC5314. The lack of neither SAP8-10 nor EFG1/CPH1 influences the adhesive behaviour of C. albicans. Deletion of SAP8-10 resulted in no filamentation defects. The results help better understand the role of SAP7 during adhesion and morphogenesis in C. albicans. PMID- 26638529 TI - The Participation of p53 and bcl-2 Proteins in Gastric Carcinomas Associated with Helicobacterpylori and/or Epstein-Barr Virus (EBV). AB - In the presented studies p53 and bcl-2 proteins expression were evaluated in samples of gastric carcinomas in patients with Helicobacter pylori or EBV or without H. pylori/EBV infection. The studies were conducted on 64 adult patients with gastric adenocarcinomas: 16 patients with H. pylori (cagA+)-positivity (group 1), 14 with EBV-positive tumours (group 2), 12 with H. pylori/EBV-positive tumours (group 3) and 22 patients with H. pylori/EBV-negative tumours (group 4). H. pylori presence in gastric tumour specimens was detected using Giemsa staining and bacterial culture technique. Moreover, cagA gene was detected using PCR. EBV infection was detected based on EBER presence in the tissue by RNA in situ hybridization. Expressions of p53 and bcl-2 proteins were analysed using immunohistochemistry. Expression of p53 was noted in 14 (84%) patients from group 1, 8 (57%) patients from group 2, 7 (58%) patients from group 3, and 19 (86%) patients from group 4, whereas expression of bcl-2 was noted in 12 (75%) patients from group 1, in 10 (71%) patients from group 2, 9 (75%) patients from group 3, and 6 (27%) patients from group 4. The obtained results allow the conclusion, that H. pylori (cagA+)-associated development of the gastric adenocarcinoma is determined by abnormalities in the p53 protein function and overexpression of anti-apoptotic bcl-2 protein, whereas EBV-associated adenocarcinomas seem to be related with apoptosis resistance associated with bcl-2 overexpression. PMID- 26638530 TI - Bloodstream Infections due to Enterobacteriaceae Among Neonates in Poland- Molecular Analysis of the Isolates. AB - Bloodstream infections (BSIs) are associated with a significantly increased risk of fatality. No report has been found about the molecular epidemiology of Enterobacteriaceae causing BSI in neonates in Poland. The aim of this work was to determine the antibiotic resistance profiles, virulence gene prevalence, the epidemiological and genetic relationships among the isolates from Enterobacteriaceae causing BSI in neonates with birth weight < 1501 g. Antimicrobial susceptibility testing was performed. PCR was performed to identify the presence of common beta-lactamase genes, virulence genes. PFGE and MLST were performed. The surveillance group contained 1,695 newborns. The incidence rate for BSIs was 5.9%, the fatality rate 15%. The most common species were Escherichia coli (n = 24) and Klebsiella pneumoniae (n = 16). CTX-M-15 was found in 6 E. coli, 8 K. pneumoniae, 1 Enterobacter cloacae strains. Among E. coli fimH (83.3%), ibeA (37.5%), neuC (20.8%) were the most frequent. PFGE demonstrated unique pulsotypes among E. coli. E. coli ST131 clone was found in 7 E. coli strains. PFGE of 16 K. pneumoniae strains showed 8 pulsotypes. Five isolates from one NICU belonged to one clone. MLST typing revealed 7 different ST with ST336 as the most prevalent. This study provides information about resistance, virulence and typing of Enterobacteriaceae strains causing BSI among neonates. E. coli and Klebsiella spp. isolated in this study have completely different epidemiology from each other. PMID- 26638531 TI - Optimization of Culture Parameters for Maximum Polyhydroxybutyrate Production by Selected Bacterial Strains Isolated from Rhizospheric Soils. AB - The enormous applications of conventional non-biodegradable plastics have led towards their increased usage and accumulation in the environment. This has become one of the major causes of global environmental concern in the present century. Polyhydroxybutyrate (PHB), a biodegradable plastic is known to have properties similar to conventional plastics, thus exhibiting a potential for replacing conventional non-degradable plastics. In the present study, a total of 303 different bacterial isolates were obtained from soil samples collected from the rhizospheric area of three crops, viz., wheat, mustard and sugarcane. All the isolates were screened for PHB (Poly-3-hydroxy butyric acid) production using Sudan Black staining method, and 194 isolates were found to be PHB positive. Based upon the amount of PHB produced, the isolates were divided into three categories: high, medium and low producers. Representative isolates from each category were selected for biochemical characterization; and for optimization of various culture parameters (carbon source, nitrogen source, C/N ratio, different pH, temperature and incubation time periods) for maximizing PHB accumulation. The highest PHB yield was obtained when the culture medium was supplemented with glucose as the carbon source, ammonium sulphate at a concentration of 1.0 g/l as the nitrogen source, and by maintaining the C/N ratio of the medium as 20:1. The physical growth parameters which supported maximum PHB accumulation included a pH of 7.0, and an incubation temperature of 30 degrees C for a period of 48 h. A few isolates exhibited high PHB accumulation under optimized conditions, thus showing a potential for their industrial exploitation. PMID- 26638532 TI - Phytoremediation of Polycyclic Aromatic Hydrocarbons in Soils Artificially Polluted Using Plant-Associated-Endophytic Bacteria and Dactylis glomerata as the Bioremediation Plant. AB - The reaction of soil microorganisms to the contamination of soil artificially polluted with polycyclic aromatic hydrocarbons (PAHs) was evaluated in pot experiments. The plant used in the tests was cock's foot (Dactylis glomerata). Three different soils artificially contaminated with PAHs were applied in the studies. Three selected PAHs (anthracene, phenanthrene, and pyrene) were used at the doses of 100, 500, and 1000 mg/kg d.m. of soil and diesel fuel at the doses of 100, 500, and 1000 mg/kg d.m. of soil. For evaluation of the synergistic effect of nitrogen fixing bacteria, the following strains were selected: associative Azospirillum spp. and Pseudomonas stutzerii. Additionally, in the bioremediation process, the inoculation of plants with a mixture of the bacterial strains in the amount of 1 ml suspension per 500 g of soil was used. Chamber pot tests were carried out in controlled conditions during four weeks of plant growth period. The basic physical, microbiological and biochemical properties in contaminated soils were determined. The obtained results showed a statistically important increase in the physical properties of soils polluted with PAHs and diesel fuel compared with the control and also an important decrease in the content of PAHs and heavy metals in soils inoculated with Azospirillum spp. and P. stutzeri after cock's foot grass growth. The bioremediation processes were especially intensive in calcareous rendzina soil artificially polluted with PAHs. PMID- 26638533 TI - Characteristics of Newly Isolated Geobacillus sp. ZY-10 Degrading Hydrocarbons in Crude Oil. AB - An obligately thermophilic strain ZY-10 was isolated from the crude oil in a high temperature oilfield, which was capable of degrading heavy crude oil. Phenotypic and phylogenetic analysis demonstrated that the isolate should be grouped in the genus Geobacillus, which shared thd highest similarity (99%) of the 16S rDNA sequence to Geobacillus stearothermophilus. However, the major cellular fatty acid iso-15:0 (28.55%), iso-16:0 (24.93%), iso-17:0 (23.53%) and the characteristics including indole production, tolerance to NaN3 and carbohydrate fermentation showed some difference from the recognized species in the genus Geobacillus. The isolate could use tridecane, hexadecane, octacosane and hexatridecane as sole carbon source for cell growth, and the digesting rate of long-chain alkane was lower than that of short-chain alkane. When the isolate was cultured in the heavy crude oil supplement with inorganic salts and trace yeast extract, the concentration of short-chain alkane was significantly increased and the content of long-chain alkane was decreased, suggesting that the larger hydrocarbon components in crude oil were degraded into shorter-chain alkane. Strain ZY-10 would be useful for improving the mobility of crude oil and upgrading heavy crude oil in situ. PMID- 26638534 TI - Evaluation of Two Lactic Acid Bacteria Starter Cultures for the Fermentation of Natural Black Table Olives (Olea europaea L cv Kalamon). AB - The production of Greek-style natural black table olives remains an empirical process relying on spontaneous fermentation despite its economic significance. For this reason producers often resort to increased NaCl concentration of the brine to secure quality of the product. In this study we employ two lactic acid bacteria Leuconostoc mesenteroides subsp. mesenteroides Lm139 and Lactobacillus pentosus DSM 16366 as starters in separate laboratory low salinity fermentations of "Kalamon" cultivar olives, processed according to the Greek-style method. L. mesenteroides subsp. mesenteroides Lm139 was previously isolated from Kalamon olives laboratory spontaneous fermentations, while L. pentosus DSM 16366 was isolated from fermenting green olives prepared according to the Spanish-style method. Spontaneous olives fermentation was also performed as a control. Microbiological and physicochemical analyses of the brines revealed that the use of the starters had a significant effect on the olives fermentation, leading to a faster acidification due to the more efficient consumption of soluble sugars in the brines. The final pH value reached by each starter culture used indicates a successful lactic fermentation. The production of lactic acid by the starters and the concomitant drop of the pH value proved to inhibit enterobacteria in a shorter period of time compared to the spontaneous fermentation. Concluding, the use of either of the two lactic acid bacteria as starters in Greek-style Kalamon olives fermentation could lead to a more controllable fermentation at lower salinities. The resulting product could be of higher quality with extended shelf life while being at the same time safer for the consumer. PMID- 26638535 TI - Activity of Natural Polyether Ionophores: Monensin and Salinomycin against Clinical Staphylococcus epidermidis Strains. AB - Staphylococcus epidermidis, a coagulase-negative Staphylococcus, is the most important pathogen responsible for chronic nosocomial infections. These bacteria produce extracellular slime and form biofilms on various biotic and abiotic surfaces. Bacterial biofilms are very resistant to standard antimicrobial therapy and difficult to eradicate, so it is important to search for new more effective anti-biofilm agents, for example in the group of natural substances. The aim of the study was to examine the activity of two ionophores-salinomycin and monensin against clinical S. epidermidis strains, using MIC/MBC method and biofilm formation inhibition assay. Bacterial strains were tested also for slime production using Congo Red Agar. Both tested ionophore antibiotics showed the highest activity against planktonic bacteria of clinical as well as standard S. epidermidis strains and effectively inhibited the formation of bacterial biofilm. PMID- 26638536 TI - Chaperone DnaJ Influences the Formation of Biofilm by Escherichia coli. AB - DnaJ chaperone, a member of the so called DnaK-DnaJ-GrpE chaperone machine plays an important role in cell physiology. The ability of Escherichia coli DeltadnaJ mutant to form biofilm was studied. It was shown that this mutant is impaired in biofilm development when exposed to 42 degrees C for 2 h. The impairment in biofilm development was observed when the heat shock was applied either at the onset of biofilm formation or 2 h later. The biofilm formed was thinner and its structure was changed as compared to wild-type strain. This defect could be complemented by the introduction of a wild-type gene on a low-copy plasmid. PMID- 26638537 TI - Characterization of Extended-Spectrum-beta-Lactamases Produced by Escherichia coli Strains Isolated from Dogs in Poland. AB - Escherichia coli is a common cause of infections in companion animals. In recent years the increasing prevalence of resistance to beta-lactams, including extended spectrum cephalosporins, antimicrobials frequently used in small animal veterinary practice, was observed in canine isolates of E. coli. The aim of this study was to detect and to characterize extended-spectrum beta-lactamases (ESBLs) produced by E. coli isolated from diseased dogs in Poland. Four isolates out of 119 studied (3.4%) were ESBL-positive. They harbored the bla(SHV-12), bla(CTX-M 15), and bla(TEM-116) genes. This study provides the first report of the occurrence of ESBL-producing E. coli in dogs in Poland. PMID- 26638538 TI - Epidemiological Analysis of Mycobacterium tuberculosis Strains Isolated from Patients of Small Communities Living in the South-East of Poland. AB - The diversity of Mycobacterium tuberculosis clinical isolates, collected from a single hospital, was analyzed by ligation-mediated PCR techniques: FLiP and FLAP, and hybridization technique, IS6110-RFLP. The isolated strains were divided in terms of location (3 towns of Podkarpackie voivodeship differing in population size) and relationship (8 members of 4 families, each represented by 2 patients). Within each family identical DNA profiles, as well as drug resistance patterns were identified indicating a great chance of transmission of strains within the same family. Identical, or very similar patterns were also shared by strains isolated from unrelated patients living in a very small town (1 200 inhabitants) or hospitalized in the same place and time. PMID- 26638539 TI - Relapsing Bacteraemia due to Corynebacterium striatum in a Patient with Peripheral Arterial Disease. AB - We describe the first reported case of Corynebacterium striatum (C. striatum) relapsing bacteraemia in a patient with peripheral arterial disease and proven Corynebacterium species colonization of a chronic foot ulcer, focusing on the difficulties in the management of the patient. We conclude that the optimal duration of the antibiotic treatment for relapsing C. striatum bacteraemia from a chronic ulcer should be 6 weeks together with surgical treatment. PMID- 26638540 TI - N-Substituted N'-(2-alkylthio-4-chloro-5-methylbenzenesulfonyl)guanidines- Antibacterial, Cytotoxic Activities and Some Structure-Activity Relationships. AB - A series of N-substituted N'-(2-alkylthio-4-chloro-5 methylbenzenesulfonyl)guanidine derivatives bearing sulfonamide moiety have been screened in vitro for antibacterial activity against isolates from patients with infections of oral cavity, respiratory tract and intestinal tract. The majority of compounds exhibited good antibacterial potency. 1-[4-Chloro-5-methyl-2-(4 trifluoromethylbenzylthio)benzenesulfonyl]-3-(3-sulfamoylphenyl)guanidine (13) showed very strong activity, with MIC <= 6.2 MUg/ml against eleven bacteria strains belonged to Gram-positive anaerobes and aerobes. Furthermore, compound 13 exhibited promising activity toward highly resistant microorganisms such as methicillin-resistant Staphylococcus aureus and Enterococcusfaecalis. It was found that Parvimonas micra, Finegoldia magna, Peptostreptococcus anaerobius, Propionibacterium acnes showed the highest susceptibility toward the investigated guanidines. PMID- 26638541 TI - The Effect of Fe3O4 Nanoparticles on Survival of Probiotic Bacteria Lactobacillus acidophilus PCM2499 at Lower pH. AB - This paper presents a description of an experiment in which the survival rate of the probiotic bacteria Lactobacillus acidophilus PCM2499 was increased only due to the presence of Fe3O4 magnetic nanoparticles. The survival rate increased from 1.3 to 10 times compare to the control. It has been shown that the minimum concentration of NPs with a positive effect equals 8 mg/ml and the maximum concentration of the NPs equals 24 mg/ml. PMID- 26638542 TI - [Central retinal sensitivity assessment with microperimetry in patients with primary open angle glaucoma]. AB - INTRODUCTION: Visual field defects in glaucomatous patients found in perimetry are analysed using increasingly more sophisticated methods. One of these methods is microperimetry, which enables detecting the progression of changes in particular central retinal quadrants in eyes with primary open angle glaucoma, especially at early stages of the disease. MATERIAL AND METHODS: 99 eyes of 57 patients--men and women aged 40 to 65 years--were enrolled in the study. Retinal sensitivity in the central perimacular, 12-degree area divided into four quadrants (temporal, nasal, superior and inferior) plus the fovea was assessed with microperimetry. The mean visual field defects in particular areas were compared and analysed using the ANOVA rank Kruskal-Wallis test. RESULTS: The biggest defect in the visual field was found in both superior quadrants. Only slightly milder defects were demonstrated within the fovea. The defects were the least pronounced within the inferior temporal and nasal quadrants. CONCLUSIONS: Microperimetry enables detection and appreciation of changes in sensitivity of individual central retinal quadrants, which is of significance in the diagnosis of early glaucoma. PMID- 26638543 TI - [Posterior vitrectomy with gas endotamponade and retinal laser therapy in treatment of patients with macular complications of the optic disc pit]. AB - PURPOSE: Retrospective evaluation of functional and anatomical treatment outcomes in patients with macular cornplications of optic disc pit. MATERIAL AND METHODS: 9 patients (eyes) underwent central posterior vitrectomy in conjunction with posterior vitreous detachment, retinal laser therapy to the optic disc pit area and endotamponade with expansile gas. It was followed by the patient's forced positioning (recommended for a few days especially at night), which ended the treatment protocol. RESULTS: Improved anatomical relationships, accompanied by functional improvement were achieved in each reported case. The resolution of macular lesions was slow, lasting even for several months. Too long delay in performing the surgery (over 5 months since the onset of visual impairment) was associated with the development of retinal complications, mainly macular hole formation, most likely caused by the long-term ischemia. CONCLUSIONS: The central posterior vitrectomy combined with posterior vitreous detachment, laser therapy, andd expansile gas tamponade offers good outcomes in patients with retinal complications of optic disc pit. Surgery performed shortly after the onset of visual dysfunction gives the best functional outcomes. Restoration of normal anatomical relationships is a long-term process. In some cases, though, these abnormalities may not resolve completely. PMID- 26638544 TI - [Large hang-back recession of superior rectus muscles as effective treatment of patients with dissociated vertical deviation]. AB - PURPOSE: The aim of this study is to report the results of large bilateral superior rectus hang-back recession in patients with dissociated vertical deviation. MATERIAL AND METHODS: Retrospective analysis of patients with dissociated vertical deviation treated in the Department of Ophthalmology between 2011 and 2013. Our enrolment criteria included vertical strabismus angle over 15Delta and the absence of inferior or superior oblique overaction in patients who underwent bilateral superior rectus recession ranging from 8 mm to 12 mm. The surgical outcomes were evaluated. RESULTS: Nine patients at the age of 14 to 46 years were included in the study. The mean vertical angle of deviation in the non dominant eye was 22.8Delta +/- 5.3Delta. The mean amount of recession was 9.8 +/- 1.4 mm. CONCLUSIONS: Large bilateral hang-back recession of the superior rectus muscles effectively reduces the vertical angle in patients with dissociated vertical deviation without concomitant oblique muscle overaction. dissociated vertical deviation (OVO), strabismus surgery, large recession of superior rectus muscles. PMID- 26638545 TI - Bilateral choroidal melanoma--case analysis and literature review. AB - Uveal melanoma is the most common primary intraocular neoplasm in adults. Its bilateral localization is extremely rare. The aim of the paper is analysis of the cases of bilateral uveal melanoma. Five bilateral uveal melanoma patients were diagnosed in the Department of Ophtalmology and Ocular Oncology beetwen 1980 and 2014. Both eyes of four patients were threated with brachytherapy. Final enulcleation of the one eye was performed in three patients. It was the primary treatment in one patient. The presence of uveal melanoma was confirmed by pathological examination in all cases after surgical removal of eyeball and in one after local resection of iris tumor. Metastatic lesions were diagnosed in lungs and liver in two patients. Three patients are still followed-up at our institution. The possibility of bilateral uveal melanoma should considered although it is extremely rare. bilateral uveal melanoma, brachytherapy, enucleation. PMID- 26638546 TI - Acute retinal necrosis--a case report. AB - Acute retinal necrosis (ARN) is a rare but very severe form of retinitis. In contrast to progressive outer retinal necrosis acute retinal necrosis typically affects immunocompetent individuals. Herpes Simplex and Varicella-zoster viruses play the main role in the development of the disease. We report a case study of a healthy, young male who presented to the ophthalmologist with unilateral visual acuity decrease and eye irritation. The acute retinal necrosis was diagnosed and a therapy was started including both systemic and local anti-viral agents, as well as an oral anticoagulant. Additional systemic steroid therapy was introduced a week later. The regression of retinal inflammatory changes and the improvement of visual acuity were observed. The polymerase chain reaction assay for the presence of viral DNA in serum was negative. The IgM antibody assay for potential causal pathogens was negative, but the level of Varicella-zoster virus IgG antibodies was markedly elevated. During the follow-up, the patient developed retinal detachment and pars plana vitrectomy with silicone oil endotamponade was performed. Although the surgery resulted in the successful retinal reattachment, the final visual acuity remained decreased. Six months after the surgery, the eye was free of the intraocular inflammation and the visual acuity slightly improved. PMID- 26638547 TI - Effective treatment of cytomegalovirus retinitis and neuritis with retrobulbar ganciclovir after treosulfan-based autologous bone marrow transplant. AB - We describe the case of a 16-month-old girl with neuroblastoma and chronic lymphocytopenia due to chemotherapy and treosulfan-containing megatherapy who developed cytomegalovirus retinitis and neuritis. Intravenous ganciclovir and anti-cytomegalovirus immunoglobulin were used with a transient benefit; however, retrobulbar gancyclovir resulted in a complete remission. This report emphasizes the need for close monitoring of viral infections in patients undergoing treosulfan-containing megatherapy, highlighting the immunosuppressive effects of this agent, and indicates the potential use of retrobulbar ganciclovir as the alternative method of drug delivery. PMID- 26638548 TI - [Total upper and lower eyelid reconstruction using an expanded forehead flap supplied by the frontal branch of superficial temporal artery]. AB - Eyelids form the protective eye apparatus. Loss of upper or lower eyelid can lead to infection, vision impairment or even blindness. Although there are many techniques for upper or lower eyelid reconstruction, there are only few articles to report simultaneous reconstruction of both eyelids. The aim of this study is to present a two-stage eyelid reconstruction method using the forehead flap. A 60 year-old woman was admitted to our Department with animal bite wounds in the left periorbital area. During the first operation, the eyelid defect was covered with forehead flap and in the second stage, horizontal incision was created in the flap above the eyeball to form a palpebral fissure. During this two-step surgical treatment, both eyelids of the left eye were reconstructed. The length and width of palpebral fissure were 30 mm and 14 mm, respectively. The patient was satisfied with the surgery outcomes. Reconstruction of both eyelids with forehead flap supplied by the frontal branch of the superficial temporal artery provides the elementary protection to the eyeball, enables vision preservation and offers good aesthetic result. PMID- 26638549 TI - [Orbital cellulitis with concomitant bacteraemia (Stenotrophomonas maltophilia) as a complication of an intraorbital foreign body--a case report and literature review]. AB - This is a case report of a 53-year-old man, who presented in the Department of Ophthalmology with signs of orbital cellulitis on the right side, which developed over a few days following an injury. Computed tomography revealed inflammatory infiltration of the orbital soft tissues, penetrating to the sella turcica. Orbital swab and blood cultures revealed the presence of Enterobacter and Peptostreptococcus spp. as well as Stenotrophomonas maltophilia, respectively. Review of the literature relevant to the presented case was performed based on the PubMed databasesearch, using the following keywords: intraorbital foreign body, orbital cellulitis, neuroinfection, Stenotrophomonas maltophiia.. Summarizing, the orbital injury-associated infections can be potentially life threatening, due to the proximity of the anterior cranial fossa. Hence, they require prompt diagnosis and intensive treatment. PMID- 26638550 TI - [The interpretation of normal and pathological optical coherence tomography retinal image as compared to their histological cross-sections]. AB - Due to technological advances that have taken place in recent years, optical coherence tomography retinal imaging provides qualitative data of informational value similar to the one of data obtained with conventional histological techniques. Correlation of optical coherence tomography images with histological retinal cross-sections enables the identification of the major retinal layers and anatomical structures. If the retina is pathologically altered, it is possible to visualize pathophysiological processes responsible for reflectivity changes, such as: activation of apoptosis and necrosis, phagocytic cell infiltration and dye accumulation in glial cells. PMID- 26638551 TI - [Geographic atrophy imaging using fundus autofluorescence method]. AB - Geographic atrophy is a manifestation of the advanced age-related macular degeneration and form of irreversible atrophy of retinal pigment epithelium and photoreceptor layer. Early detection of changes and the ability to evaluate disease progression accurately constitute a key problem in diagnosis and treatment planning. Fundus autofluorescence is a relatively new imaging method considered nowadays to be the best in diagnosis and observing the natural or treatment-altered course of disease. High resolution images showing the 3D distribution of retinal pigment epithelium autofluorescence as lipofuscin index can be obtained owing to the launch of the confocal scanning laser ophthalmoscope. PMID- 26638552 TI - [A review of safety and efficacy of levofloxacin 0.5% ophthalmic solution in the treatment of external ocular infections and in prophylaxis of postoperative endophthalmitis]. AB - Levofloxacin 0.5% ophthalmic solution is a fluoroquinolone antibacterial agent with a broad spectrum of activity against Gram positive and negative bacteria. For those reasons it is highly effective in treating common external infections of the eye including blepharitis, conjunctivitis, keratitis. In terms of microbial eradication and clinical cure rate it is significantly more effective than ofloxacin 0.3% ophthalmic solution, and non inferior to moxifloxacin ophthalmic solution. After topical administration of levofloxacin 0.5% ophthalmic solution it achieves concentration exceeding MIC90 for most clinically relevant pathogenes in tears, conjunctiva, cornea as well as anterior chamber. Thus it can be used in prophylaxis in patients undergoing ocular surgery. Because of its postantibiotic effect and high concentration in tears three times daily regimen is as effective as most frequent administration in patients with conjunctivitis, which leads to better compliance. Despite the wide use of topical and systemic levofloxacin, most common ocular pathogens remain clinically susceptible. Topical levofloxacin is well tolerated, it rarely causes systemic or ocular adverse events with the majority of treatment-related adverse effects being of mild to moderate severity. It also does not effect the wound healing. PMID- 26638553 TI - [The genetic variability of complement system in pathogenesis of age-related macular degeneration]. AB - Age-related macular degeneration is the leading cause of irreversible central vision impairment in people aged over 50 in developed countries. Age-related macular degeneration is a complex disease derived from environmental, immune and genetic factors. The complement pathway has been implicated in the pathogenesis of many diseases. Recently, variants in several genes, such as complement H (CFH), complement factor B (CFB), complement 2 (C2), and complement 3 (C3), encoding complement pathway proteins, have been identified as associated with age related macular degeneration. However, the associations between these genes and age-related macular degeneration varied due to genetic variation within populations and various ethnics groups. The strongest association was found between the age-related macular degeneration and SNP Y402H rs 1061170 variant of CFH gene, which is present in 30% to 50% of age-related macular degeneration patients in Caucasian population and which is a risk factor for the development of age-related macular degeneration. Cohort studies showed that polymorphism Arg102Gly (SNP rs 2230199) of C3 protein could serve as a high-risk genetic marker for the development of age-related macular degeneration. Other rare variants of C3 (Lys155Gln, Lys65Gln, Arg735Trp, Ser1619Arg), may also be associated with a high incidence of age-related macular degeneration in some ethnic groups. A protective haplotype of variants E318D and IVS10 in the C2 gene as well as L9H and R320 in the BF were associated with age-related macular degeneration but only in Caucasians. The genetic findings in age-related macular degeneration patients stress the importance of detailed phenotyping to identify age-related macular degeneration subtypes, which may be associated with the presence of different polymorphisms and various environmental risk factors in any population. Further studies may be helpful to improve the effectiveness of prophylaxis and therapeutic options in age-related macular degeneration oatients. PMID- 26638554 TI - [Retinal vascular tumors in the material of the Department of Ophthalmology and Ocular Oncology of Jagiellonian University Collegium Medicum in Cracow]. AB - Retinal vascular tumours are congenital and acquired lesions of variable clinical manifestation. They are classified as benign, but their presence leads to vision impairment due to the development of complications. Each retinal vascular tumour possesses characteristic clinical features and is often associated with certain systemic disorders. Thus, a correct diagnosis is crucial for providing individualised treatment and expanded diagnostic management as well as prognostic assessment. The aim of the study was to present retinal vascular tumour cases of patients treated at the Department of Ophtalmology and Ocular Oncology of Jagiellonian University Collegium Medicum in Cracow. PMID- 26638556 TI - Taking the temperature of NZNO. PMID- 26638555 TI - [Jozef Talko (1838-1907)--the ophthalmology pioneer in Lublin]. AB - Jozef Talko (1838-1907), a Polish military ophthalmologist. He studied medicine at St. Vladimir University in Kiev, where in 1861 he was awarded with the Doctor of Medicine title. In 1871 he became the head of the Department of Ophthalmology in Lublin, and since 1876 he worked as an ophthalmologist in Warsaw Military District. J6zef Talko wrote over 200 research papers published in Polish, Russian, German and French, where he addressed such issues as neuro ophthalmology, diagnosis and treatment of cataract, developmental disorders of the eye, retinal detachment, and infectious eye diseases in soldiers. He was also interested in the history of ophthalmology. PMID- 26638557 TI - Criticism and prejudice do not reflect the views of the majority. PMID- 26638558 TI - 'Toxic culture' exists in nursing. PMID- 26638559 TI - Judging on looks vs competency. PMID- 26638560 TI - Tattoos and piercings, anyone.... PMID- 26638561 TI - ...or stretched ear piercings? PMID- 26638562 TI - Green, striped or purple hair.... PMID- 26638563 TI - ...or blue hair perhaps? PMID- 26638564 TI - Let's remember the person. PMID- 26638565 TI - Photo doesn't reflect members. PMID- 26638566 TI - Actors should be paid. PMID- 26638567 TI - Nurses need to 'up their game'. PMID- 26638568 TI - The Kaiwhakahaere comments. PMID- 26638569 TI - Author reply: To PMID 26548063. PMID- 26638570 TI - Capnography: monitoring CO2. AB - MONITORING RESPIRATORY and metabolic function by using capnography to measure end tidal carbon dioxide is standard practice in anaesthesia. It is also becoming more common in intensive care units and during procedural sedation. End tidal carbon dioxide (EtCO2) monitoring may also be used to assess effectiveness of cardiopulmonary resuscitation. Capnography is now emerging in general medical and surgical wards to monitor respiratory depression in patients using opioid analgesics. Using EtCO2 to monitor respiratory function offers many benefits over pulse oximetry. It is important to understand the differences between these two monitoring methods, and why capnography is increasingly favoured in many situations. An understanding of the physiological processes involved in CO2 excretion allows nurses to use capnography in a safe and meaningful way, while monitoring at-risk patients in acute care. PMID- 26638571 TI - Ensuring anaesthetic nurses get a fair deal. PMID- 26638572 TI - Perioperative Nurses Embracing Capability. PMID- 26638573 TI - Developing a procedural checklist for robotic-assisted prostatectomy. PMID- 26638574 TI - How can nurses keep safe? PMID- 26638575 TI - Providing holistic perioperative care. PMID- 26638577 TI - What do smokers really want? PMID- 26638576 TI - Remembering the Anzac nurses. PMID- 26638578 TI - The ongoing struggle for pay equity. PMID- 26638579 TI - Compassion as powerful as medicine. PMID- 26638580 TI - Benefit increase not enough - nurses. PMID- 26638581 TI - [Preface]. PMID- 26638582 TI - [My moon stones. Professional autobiographical essay]. PMID- 26638583 TI - [20th century view of Poland by Russian historians. An account of: Pol'sza XX wiekie w: oczerki politiczeskoj istorii [Poland in the twentieth century: political history essays], Indryk, Moskwa, 2012, 949 p]. PMID- 26638584 TI - CK-MB Activity, Any Additional Benefit to Negative Troponin in Evaluating Patients with Suspected Acute Myocardial Infarction in the Emergency Department. AB - BACKGROUND: Coronary heart disease is now the leading cause of death. Diagnosing myocardial infraction (MI) needs cardiac marker in case of equivocal clinical presentations and EKG interpretations. Troponin yields high sensitivity and specificity and could be used as a single screening assay. However, in actual practice, clinicians send CK-MB activity (CKMBa) as a combined marker with an expectation of providing additional diagnostic value due to large historical data. Discordant results from both markers lead to unclear management. Our study was to determine whether CKMBa has potential benefit for initial screening of MI in addition to cardiac troponin T (cTpT) in the Emergency Department (ED), and can this marker be safely removed from the routine laboratory panel in the emergency setting in Thailand. MATERIAL AND METHOD: We conducted a retrospective cohort single-center study to examine the usefulness of CKMBa in the ED from 907 patients who presented with clinically suspected acute M, and investigated with both biomarkers (CKMBa and cTpT). In these patients, 97 patients were included in the final analysis as they had negative cTpT associated with positive CKMBa or CKMBa turned to be positive within 24 hours after serial biomarkers measurements. The outcome was assessed by the final diagnosis, the cause of death if patients died during admission, and the 180-day mortality from medical chart review. In patients highly suspectedfor MI, further investigations were done including echocardiogram, exercise stress test, and coronay angiogram by experienced cardiologists. RESULTS: During the studyperiod, cTpTwere sent 1,772 times and most (95.2%) ofthe samples were associated with CKMBa results. The outcome showed that no one with negative cTpT was diagnosed as MI on a discharge diagnosis. Fourteen patients died during admission. The definitive cause was not defined as MI. The 180-day mortality was zero. During the follow-up, there was no MI suspected issues that needed further cardiac evaluations. The positive predictive value of CKMBa with negative cTpT was 0% (95% CI, 0-0.047). CONCLUSION: CKMBa added no benefit to cTpT in diagnosing acute MI in ED. Removing CKMBa from emergency panel could be considered. PMID- 26638585 TI - Clinical Results of Left Atrial Appendage Closure with Watchman Device in Patients with Atrial Fibrillation. AB - BACKGROUND: In patient with non-valvular atrial fibrillation (AF), over 90% of thrombus accumulation originates in the left atrial appendage (LAA). Warfarin significantly reduces risk of stroke. However, long-term anticoagulant therapy is associated with a significant risk of major bleeding, particularly in elderly. Transcatheter occlusion of left atrial appendage with Watchman device has proved to be non-inferior to warfarin in preventing stroke in non-valvular AF patients. No previous report of transcatheter occlusion of LAA was found in Thailand OBJECTIVE: To evaluate short-term results of left atrial appendage closure with the Watchman(r) device in patient with non-valvular AF performed at King Chulalongkorn Memorial Hospital (KCMH). MATERIAL AND METHOD: Between November 2012 and December 2014, 12 consecutives patients underwent percutaneous transcatheter left atrial appendage closure. Data included patient's characteristics, embolic risk factors, bleeding risk score, procedural finding, complications, in-hospital outcomes, and antithrombotic management were retrospectively reviewed RESULTS: Percutaneous LAA occlusion was successfully performed in all 12 patients. The mean age was 71.2 +/- 8.1 years. The history of previous bleeding was seen in four patients (33%). All patients had good left ventricular systolic function. The mean CHADS2 score was 3.2 +/- 1.3, the mean CHA2DS2-VASc score was 4.8 +/- 1.6 and the mean HAS-BLED score was 2.5 +/- 0.9. The average LAA orifice diameter was 21.7 +/- 3.4 mm, and the median implant size was 27.0 mm. The compression ratio was 15.2 +/- 6.2%. Three patients (25%) were performed under general anesthesia, nine patients (75%) were performed with local anesthesia. The averageprocedure time was 61.2 +/- 18.5 minutes. The average fluoroscopy time was 6.8 +/- 3.3 minutes. There was no device embolization or pericardial effusion. There was no periprocedural cerebral event, assess site bleeding, or death during hospital admission. Mild peridevice leak was observed in three patients (25%), and all had disappeared on TEE performed at the 45-day follow-up. The median length of stay was two days. CONCLUSION: The result of the present study showed that percutaneous LAA occlusion with the Watchman device was feasible and safe. The successfulness of the procedures and periprocedural complications were similar to standard in literature. PMID- 26638586 TI - The Expressions of P53, Bcl-2, and P-Glycoprotein and Prognostic Impact in Patients with Peripheral T-Cell Lymphoma (PTCL). AB - OBJECTIVE: To define the expressions of p53, Bcl-2, and p-glycoprotein and prognostic impact in patients with peripheral T-cell lymphoma (PTCL). MATERIAL AND METHOD: Adult patients with newly diagnosed as PTCL were reviewedfrom 2001 to 2012. Clinical parameters and outcome data were extracted The specimens were stained for p53, Bcl-2, and p-glycoprotein. The results were analyzed for association with disease stage, International Prognostic Index (IPI), Prognostic Index for T-cell lymphoma (PIT), overall response rate (ORR), and overall survival (OS). RESULTS: Of eligible 159 patients (113 males, 46 females), median age was 53 years old The histological subtypes included peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) 35.8%, angioimmunoblastic T-cell lymphoma (AITL) 18.2%, extranodal NK/T-cell lymphoma (ENKL) 17.0%, subcutaneous panniculitis-like T-cell lymphoma (SPTCL) 12.6%, cutaneous T-cell lymphoma (CTCL) 11.3%, anaplastic large cell lymphoma (ALCL) 4.4%, and enteropathy-associated T cell lymphoma (EATL) 0.6%. Tissue samples were obtainedfor analysis in 135 patients. P53, Bcl-2, and p-glycoprotein were positive in 87%, 49%, and 28%, respectively. Median OS was 25 months. The expressions of p53, Bcl-2, and p glycoprotein were not significantly correlated with advanced stage, high prognostic scores, ORR, and OS. However Bcl-2 expression was statistically associated with histological subtypes. From Cox regression analyses, advanced stage, high prognostic scores, and histological subtypes were independent prognostic factors for OS. CONCLUSION: The biomarker expressions varied in different types of PTCL and did not show any correlation with prognostic factors, ORR, or OS. PMID- 26638587 TI - Energy and Macronutrient Intakes and Food Sources in Preschool Children: Thai NHES IV. AB - OBJECTIVE: Examine intakes of energy and macronutrients, and identify their food sources, in Thai preschool children. MATERIAL AND METHOD: Data from the Thai National Health Examination Survey (NHES) IV were used. Mothers/caregivers were interviewed regarding their children's 24-hour-dietary intake. Dietary data were analyzed for energy and macronutrients, and their food sources were investigated. Due to skewed data, Mann-Whitney U test was used to compare energy and macronutrient intake between sexes and age groups. RESULTS: Among 256 preschool children, more than 90% had protein intakes higher than the recommended level. Only 12.7 to 29.0% met the recommended intake for energy. Amounts of carbohydrate and fat consumed varied from below to above the Dietary Reference Intake (DRI) recommendation. Intakes of carbohydrate in boys and fat in girls were statistically different between age groups (p < 0.05). Fifty to 60% of energy came from dairy products, grains and starchy products. The major carbohydrate contributors were grains and starchy products. Dairy products were the main source of protein. Important food sources of fat were dairy products for one- to three-year-old children and fat and oils for four- to five-year-old children. CONCLUSION: Thai preschool children have inappropriate intakes of energy and macronutrients. Dairy products and grains and/or starchy products were the main sources of energy, carbohydrate, and protein. Dietary fat sources varied by age group. PMID- 26638588 TI - The Validity and Reliability of the Thai Version of Children's Dermatology Life Quality Index (CDLQI). AB - OBJECTIVE: To evaluate the validity and reliability of the Thai version of Children Dermatology Life Quality Index (CDLQI). MATERIAL AND METHOD: CDLQI was translated to Thai and approved by Lewis-Jones MS and Finlay AY The patients, 4- to 15-year-old, with skin diseases and with problems unrelated to the skin were included to complete this questionnaire. Some patients with skin diseases were randomly selected to complete the CDLQI again seven days later to test the reliability. The time to complete the questionnaire was recorded. RESULTS: Two hundred six children, which consisted of 113 patients with skin diseases (26 of this group answered the questionnaire twice) and 93 patients without skin diseases, were enrolled in the study. The mean age and sex distribution of the two groups were not statistically different (p 0.84, p 0.60, respectively). The mean CDLQI score of the patients with skin diseases was 7.5 +/- 6.1. The validity of the CDLQI Thai version was p < 0.001 by comparing the scores from a variety of skin diseases with controls. Good reliability was demonstrated by assessing repeatability, which showed strong correlation coefficient of test-retest data with Spearman rank correlation coefficient r(s) 0.94 (p < 0.001). The Cronbach's coefficient alphas showed high internal consistency of the individual item (0.87). The average time to complete all questions was 4.5 +/- 2.5 minutes. The younger age group spent longer time than the older age group (p < 0.001). CONCLUSION: The Thai version of CDLQI has good validity and reliability. It should be used to measure quality of life in the management of skin diseases in Thai pediatric patients. PMID- 26638589 TI - Treatment Outcomes of the Uncomplicated Upper Respiratory Tract Infection and Acute Diarrhea in Preschool Children Comparing Those with and without Antibiotic Prescription. AB - BACKGROUND: Upper respiratory tract infection (URI) and acute diarrhea are the two most common reasons for ambulatory visits among young children. Unnecessary use of antibiotics to treat such conditions pose significant financial burden and can result in untoward side effects as well as risk of antimicrobial resistance. On the other hand, inadequate antibiotic treatment in certain cases may increase the risk of suppurative complications and/or invasive infection in this population. OBJECTIVE: To compare the treatment outcomes between those with and without antibiotic treatment for the uncomplicated upper respiratory tract infection and acute diarrhea in young children. MATERIAL AND METHOD: A prospective observational study was conducted in two groups of previously healthy children presenting with acute uncomplicated URI (aged 2 to 5 years) or acute diarrhea (aged 6 months to 5 years). On initial enrolment date, patients were treated by a pediatrician who was not a member of the study investigators. The decision for antibiotic prescription was based entirely on attending physicians' discretion. Data regarding clinical presentations, diagnosis, treatment options, and reasons for antibiotic prescription (if any) were collected. Follow-up phone interviews were conducted on day 3 of enrolment to evaluate treatment outcomes. RESULTS: Two hundred nine cases with symptoms compatible with acute URI, and/or 199 cases with acute diarrhea were enrolled between August and November 2013. Antibiotic prescription rates for URI and diarrhea groups were 30.2% and 13.6%, respectively. Among children presenting with URI symptoms, 80.4% (n = 168) were classified as having upper respiratory tract infection e.g., common cold, acute sinusitis, pharyngitis whereas the other 19.6% were diagnosed with other conditions e.g., lower respiratory tract infection, pneumonia, viral exanthema after evaluation by a pediatrician. Overall improvement rates on day 3 were 92.3% and 86.9%for uncomplicated URIand diarrhea group, respectively. Among URI group, parental satisfaction rates were 100% and 96.6% in those received and did not receive antibiotic, respectively (p = 0.188), whereas in the diarrhea group, there were 100% and 92.7, (p = 0.35), respectively. Univariate analyses indicated that the crude odds ratios (OR) and 95% confidence intervals (CI) of treatment failure comparing those with and without antibiotics were 0.5 (0.2, 1.7) and 1.5 (0.6, 3.7) for URI and diarrhea, respectively. Logistic regression analyses indicated that antibiotic treatment was not significantly associated with better treatment outcomes for both URI and diarrhea cases i.e., adjusted ORs and 95% CI of antibiotic for requirement of additional treatment were 1.06 (0.14, 8.15) for URI cases. Further adjusted OR and 95% CI of antibiotic for treatment failure was 0.8 (0.2, 2.9) for acute diarrhea cases. CONCLUSION: Antibiotic did not appear to provide clinical benefit in the management of uncomplicated URI and/or acute diarrhea among previously healthy young children. PMID- 26638590 TI - Five-Year Review Outcome of Microvascular Free Flap in Siriraj Hospital. AB - BACKGROUND: Microvascular free flap operation has become the preferred reconstructive technique at many medical centers to cover complex defects from tumor ablative surgery or trauma and for reconstructive procedure such as functioning muscle transfer. There are many clinical reports about free tissue transfer since the beginning of microvascular technique in the early 1960s. The overall success rate is about 90 to 98% but there may be postoperative complications. OBJECTIVE: Retrospectively analyze outcome and complications of consecutive series of microvascular free flap procedures, and compare with series published by other center. MATERIAL AND METHOD: The chart review was conducted of all patients that underwent microvascular free tissue transfer in our hospital between January 2007 and December 2011. The age, gender underlying disease, other risk factors (smoking, obesity, pre-operative radiation on recipient site), American Society of Anesthesiologists (ASA) classification, indication for surgery, location of defect, type of flap, operative time, inflow and outflow vessel, type of anastomosis, vein graft usage, ischemic time, length of hospital stay, length of intensive unit stay, flap success rate, re-exploration surgery, salvage rate, and perioperative complications of all patient were noted. These data were collected in database and were available for statistical analysis. RESULTS: Between January 2007 and December 2011, 153 microvascular tissue transfers were performed to coverage and reconstruct various kind of defects and diseases. There were 102 men and 51 women, age ranged from 11 to 84 years (mean 48 years). There were 50 patients over 60 years old (33%). Among the 153 procedures, there were 124 defects from tumor ablation, 14 procedures for wound coverage including defect from acute trauma in five patients, and other procedure such as functioning muscle transfer and sex reassignment surgery. The microvascular free flap reconstruction of various kinds of indication all over the body showed success rate of 92.8%. Re-explorative surgery andASA class more than 1 were significant factors influence with flap failure rate. Only signficant factor associated with wound complication was age more than 60 years. ASA class more than 1 and age more than 60 years were significant factors that increasing general medical complication. CONCLUSION: Microvascular free flap was the versatile reconstructive option. The failure rate of them should not be more than 5%. Factors associated with flap failure were re-exploration, ASA classification and factors that affect complications were preoperative morbidity level (ASA) and elderly patient. PMID- 26638592 TI - Direct Field Block with 40 ML of 0.125% Bupivacaine in Conjunction with Intrathecal Morphine for Analgesia after Cesarean Section: A Randomized Controlled Trial. AB - OBJECTIVE: To investigate the effect of direct field block with 40 ml of 0.125% bupivacaine on the top of intrathecal morphine on postoperative pain free period. MATERIAL AND METHOD: The present prospective randomized controlled trial was undertaken in 56 pregnant patients that underwent elective cesarean delivery at Siriraj Hospital. All patients were randomized into two groups to receive spinal block with intrathecal morphine as a control group, or direct field block on the top of spinal block with intrathecal morphine as a study group. The assessment ofpain score, 24-hour morphine usage, satisfaction score, pruritus, nausea and vomiting, sedation score, and motor power were recorded. RESULTS: Both groups had similar pain score. The number of subjects who had pain free period during the 24 hours in the direct field block group was seven of 28, while in the control group it was four of 28. Median time of pain free period was 2.10 hours in control group and 2.36 hours in direct field block group. There was no significant difference in 24-hour morphine consumption, satisfaction score, pruritus, nausea, vomiting, and sedation score. Motor power was fully recovered within six hours postoperative in both groups. CONCLUSION: Direct field block with 40 ml of 0.125% bupivacaine in conjunction with intrathecal morphine for cesarean section did not increase pain free period or decrease morphine consumption. PMID- 26638591 TI - Neurological Recovery Determined by C-Reactive Protein, Erythrocyte Sedimentation Rate and Two Different Posterior Decompressive Surgical Procedures: A Retrospective Clinical Study of Patients with Spinal Tuberculosis. AB - BACKGROUND: C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR) not only are useful in the diagnosis but also are reliable parameters in evaluating the response to treatment and prognosis of tuberculous spondylodiscitis. OBJECTIVE: To analyze the correlation between neurological recovery and declination of CRP or ESR after two different posterior spinal procedures. MATERIAL AND METHOD: The patients who had neurological deficit due to spinal tuberculosis and undergone spinal surgery between January 2009 and June 2013 were analyzed retrospectively. Posterior transforaminal decompression and interbody fusion were done in group I, whereas posterior transpedicular decompression and posterolateralfusion were performed on group II. Both groups were stabilized with pedicle screw instrumentation. Rapid recovery represented by improvement of at least one Frankel grade within 6 weeks after operation, otherwise it was slow recovery. Inflammatory markers were evaluated at initial diagnosis and at 6-week, 3-month, 6-month, and 1-year post-operation. RESULTS: There were 31 patients. Group I included 14 cases and group II consisted of 17 cases. The median CRP and ESR at diagnosis were 80.4 mg/L and 78.0 mm/hour respectively. Rapid neurological recovery significantly related to the earlier declination of CRP within the first 6 weeks (p < 0.001). Considering the type of spinal procedures especially at thoracic and thoracolumbar level, neurological recovery in group I was significantly faster than in group II (p = 0.02; relative risk, 2.67; 95% confidence interval, 1.02 to 6.91). CONCLUSION: Earlier declination of CRP within six weeks post-operation could determine rapid neurological recovery. Posterior transforaminal decompression and interbody fusion with instrumentation may be a suitable optionfor thoracic and thoracolumbar lesions. PMID- 26638593 TI - 18F-FDG PET/Contrast-Enhanced CT for Initial Staging and Strategic Treatment of Non-Small Cell Lung Cancer: A Prospective Study. AB - BACKGROUND: Selection of the best treatment option for non-small cell lung cancer (NSCLC) depends on optimal initial staging. OBJECTIVE: Evaluate the clinical impact of 18F-FDG PET/CT on the management of Thai patients with NSCLC. MATERIAL AND METHOD: Twenty-four patients with NSCLC underwent FDG PET/CTfor initial staging. The best treatment options between pre- and post-FDG PET/CT staging were identified for each patient. Changes in treatment management decisions and the diagnostic values (sensitivity, specificity, positive predictive value, negative predictive value, and accuracy) of nodal and distant metastases were assessed. RESULTS: Pre-FDG PET/CT staging included five patients with stage IA, four patients with stage IB, one patient with stage IIB, three patients with stage IIIA, and 11 patients with stage IV disease. A difference between pre- and post FDG PET/CT staging was noted in 10/24 patients (41.7%). FDG PET/CT examination resulted in upstaging in 7/24 patients (29%) and downstaging in three patients (12.5%). The pre-FDG PET/CT staging was accurate in 14/24 patients (58.3%) while the post-FDG PET/CTstaging was accurate in 19/24 patients (79.2%). The treatment management decisions were changed in 5/24 patients (20.8%). FDG PET/CT prevented futile surgery in two patients. CONCLUSION: FDG PET/CT has an important role in NSCLC staging. Additional PET/CT information could influence therapeutic options and reduced unnecessary surgery in patients with metastatic disease. PMID- 26638594 TI - Radiofrequency Ablation of Lung Metastasis Not Suitable for Surgery: Experience in Siriraj Hospital. AB - BACKGROUND: Percutaneous image-guided radiofrequency ablation (RFA) is being promoted as a novel technique with low morbidity rate in treatment of inoperable lung tumor either primary lung tumor or metastatic disease. OBJECTIVE: To report our experiences of RFA treated for lung metastasis in Siriraj Hospital and to evaluate the efficacy and complication of RFA. MATERIAL AND METHOD: All patients who underwent RFA for lung metastasis at Siriraj Hospital, between January 2007 and December 2013, were included in the present study. Clinical data, pre procedure image findings including lesion size, location, post-procedure image findings, complications, and outcome were retrospectively reviewed. RESULTS: Fourteen patients (10 male, 4 female) with 27 lung metastasis were treated with RFA. The ablated lung nodules consist of metastasis from hepatocellular carcinoma (n = 13), colorectal adenocarcinoma (n = 9), insular cell thyroid carcinoma (n = 3), and adenocarcinoma of prostate gland (n = 2). Mean patient age was 50 years (age range 28-67 years). Size of the ablated nodules range from 0.5 to 5.0 cm (median = 1.3 cm). The most common complication was pneumothorax, occurring in 71% (10 of 14 patients). Other complications included surgical site infection, atelectasis, loculated hemothorax, loculated empyema, and bronchopleural fistula, occurred in one patient each. Post-procedure image findings showed complete ablations without local tumor recurrence in 81% (22 of 27 nodules). Local tumor recurrences were seen in 19% (5 of 27 nodules). CONCLUSION: Radiofrequency ablation for lung metastasis can be considered as a relatively safe, effective alternative treatment for lung metastasis. Risk factors that may associate with local recurrence include large size nodules and subpleural location. PMID- 26638595 TI - Tobacco Use, Exposure to Secondhand Smoke and Cessation Training among Third-Year Medical Technology Students in Thailand. AB - OBJECTIVE: Compare tobacco use, exposure to second-hand smoke, and smoking cessation training among third-year medical technology students in Thailand between 2006 and 2011. MATERIAL AND METHOD: The medical technology student survey was carried out with Global Health Professions Student Survey (GHPSS) between October and November 2011. The population of the present study was all students in nine medical technology schools. There were 773 students enrolled in this study yielding a response rate of 95.1%. RESULTS: The prevalence of current cigarette smokers had decreased from 2006 to 2011 (4.8% to 1.4%, respectively). Rates of exposure to second-hand smoke at home were 36.3% in 2006 and 39.7% in 2011, while rates of exposure to second-hand smoke in other places did not change. Most students recognized that they should give patients counseling to quit smoking, but only 20.6% in 2006 and 28.4% in 2011 of them had received formal training in tobacco cessation counseling. CONCLUSION: There were low percentages of current cigarette smoking but high percentages of exposure to second-hand smoke among medical technology students. The percentage of cessation training was still low among students. Therefore, medical technology schools should provide formal training in tobacco cessation for all students to help improve their ability in providing advice to patients. PMID- 26638596 TI - Liddle's Syndrome: A Case Report. AB - A thirty-eight years old female presented with frequent proximal weakness, severe hypertension, and persistent kaliuresis despite hypokalemia. After normalized serum potassium level, hyporeninemic hypoaldosteronism was detected Pedigree study supported an autosomal dominant inherited disease. A causative mutation for Liddle's syndrome (LS) in this patient was identified to be a novel frameshift mutation. DNA sequencing resulted in exon 13 of SCNN1B gene: SCNN1B NM_000336.2:c.1 724_1730dupGGCCCAC [p.Pro5 75Argfs*17]. Since LS is a rare existing clinical syndrome in Thailand, correct diagnosis should be confirmed by genetic studies. Therefore, proper management could be given. PMID- 26638597 TI - The Treatment of Flexion Myelopathy of the Thoracic Spine in Pierre Robin Sequence: A Case Report. AB - BACKGROUND: A few studies had reported the spinal deformity associated with neurological symptoms in PRS patients. OBJECTIVE: To report the management of myelopathy fromflexible thoracic kyphoscoliosis in Pierre Robin sequence (PRS) patient. MATERIAL AND METHOD: A 15-year-old PRS patient with thoracic kyphoscolsis developed myelopathy symptom for 4 months. Posterior instrumentation (Cotrel-Dubousset) from T1-T9 was done to correct her deformity without decompression. RESULTS: Her motor power improved to grade 5/5 two months after operation. Her urological symptom returned to normal at 4-month postoperatively. CONCLUSION: Myelopathy from flexible kyphotic deformity in PRS patients can be successfully treated by posterior correction and fusion without decompression. PMID- 26638598 TI - Human Immunodeficiency Virus Infection and Male Hypogonadism: A Review. AB - Hypogonadism is a common complication among HIV infected patients. The prevalence of hypogonadism is 30 to 50% in HIV infected men with wasting syndrome and 20 to 25% in those without wasting syndrome. HIV infection affects the entire hypothalamus-pituitary-gonadal axis via both direct and indirect effects, which are defined in four categories, 1) direct effect of HIV particles, 2) opportunistic infections, 3) HIV-related malignancy and its treatment, and 4) medications that are used for HIV infection or its opportunistic infection. The association between HIV infection, hypogonadism, and cardiovascular diseases has yet to be determined; however, there are data that HIV infection and its treatment, particularly protease inhibitors, worsened the metabolic profiles, which were surrogate markers of cardiovascular diseases. Considerably more attention should be paid to the diagnosis of hypogonadism in this group particularly because HIV infection increases both sex hormone-binding globulin and total testosterone level. Testosterone replacement shows benefits on mood, body composition, and seems to benefit the metabolic profile in HIV infected men with low body mass index. PMID- 26638599 TI - ON PARTY CONFERENCE SEASON. Politicians offer complacency or hysteria. PMID- 26638600 TI - DEFUSE THE DIABETES TIMEBOMB. PMID- 26638601 TI - WHAT CIRCLE HAS LEARNED FROM BEDFORD. PMID- 26638602 TI - TECHNOLOGY. PAPER AND CUTS. PMID- 26638603 TI - THE HUNT FOR THE PERFECT. PMID- 26638604 TI - WISDOM OF THE GLOBAL CROWD: ANSWERS TO SOME KEY QUESTIONS. PMID- 26638605 TI - SOCAL CARE. SUCCESSFUL TOGETHER. PMID- 26638606 TI - OLDER PEOPLE'S SERVICES. HELP PATIENTS SELF-MANAGE. PMID- 26638607 TI - Bringing together health and housing. PMID- 26638608 TI - Building a better hospital. PMID- 26638609 TI - BRINGING SYSTEMS TOGETHER. Standardizing operations to connect facilities. PMID- 26638610 TI - Back to nature. Using light, color and texture to bring the outdoors inside. PMID- 26638611 TI - PROJECT SUCCESS FACTORS. Considerations that apply to all delivery models. PMID- 26638612 TI - Nurse call upgrades. Planning for advanced communication systems. PMID- 26638613 TI - Developing a plan to handle clean textiles. PMID- 26638614 TI - Ready for the future of health care. How facility managers can develop career skills. PMID- 26638615 TI - [Foreword]. PMID- 26638616 TI - [Kakiuchi Samuro Special Award--The Founder of the Japanese Biochemical Society and JB]. PMID- 26638617 TI - [Ppp6c deficiency predisposes mouse skin tissue to carcinogenesis]. PMID- 26638618 TI - [Spatial regulation of calcineurin by RNA granules]. PMID- 26638619 TI - [Regulation of cellular functions by protein phosphatase PPM family members]. PMID- 26638620 TI - [Function of Proto-oncogene Product PPM1D and Development of PPM1D Inhibitors for Cancer Chemotherapy]. PMID- 26638621 TI - [Receptor-type protein tyrosine phosphatases as drug targets their physiological functions and signaling mechanism]. PMID- 26638622 TI - [Functional role of R3-subtype protein tyrosine phosphatases and their implication in human diseases]. PMID- 26638623 TI - [Helicobacter pylori-mediated carcinogenesis and tyrosine phosphatases]. PMID- 26638624 TI - [Physiological significance of distinct expression of gangIioside moleculer species as bioactive lipids]. PMID- 26638625 TI - [ES/iPS cells-derived definitive endodermal tissue]. PMID- 26638626 TI - [Thermostable NADP(+-)dependent D-amino acid dehydrogenase created by site directed mutation: characteristics and application]. PMID- 26638627 TI - [Production and characterization of cancer resistant mouse: Toward development of molecular preventive medicine of cancer]. PMID- 26638628 TI - [Chemical chaperone therapy for lysosomal storage diseases]. PMID- 26638629 TI - [Nuclear IkappaB-zeta controls inflammatory responses]. PMID- 26638630 TI - [Exploring evolutionary roots of "social brain": Central role of terminal nerve GnRH3 neurons in social decision making]. PMID- 26638631 TI - [Roles of Lu/B-CAM in tumor cell adhesion and migration on laminin-511]. PMID- 26638632 TI - [The physiological role of G protein-coupled receptor kinase]. PMID- 26638633 TI - [Molecular mechanisms of metabolism-epigenome crosstalk]. PMID- 26638634 TI - [The roles of histone modifier complexes in tissue-specific transcriptional regulation]. PMID- 26638635 TI - [Structural insight into the regulation mechanism of proton leakage based on crystal structure of voltage-gated proton channel (VSOP)]. PMID- 26638636 TI - [Roles of actin family proteins in functional organization of chromatin and the nucleus]. PMID- 26638637 TI - [Peroxisomal regulation by phospholipase A/acyltransferase-3]. PMID- 26638638 TI - [Targeted protein quantitation using Selected Reaction Monitoring]. PMID- 26638639 TI - The 'rights' battle. PMID- 26638640 TI - Midwives supporting women's rights. PMID- 26638641 TI - Midwives must act to care for asylum seekers. PMID- 26638642 TI - End detention of pregnant women, says RCM. PMID- 26638643 TI - Warning on changes to registration renewal. PMID- 26638644 TI - Shortage of midwives is the reason for high agency staff costs, says RCM. PMID- 26638645 TI - Bosses hinder pregnant women from accessing antenatal care. PMID- 26638646 TI - Midwives act to protect their right to strike. PMID- 26638647 TI - Reflection of a birth reflections midwife. AB - Supporting a woman's emotional recovery following what can sometimes be a traumatic event is becoming an important part of postnatal care. That simple question, "How was the birth?" can be the first step in allowing a woman to acknowledge and voice her innermost anxieties around the birth of her baby, and put her on the right path towards feeling better about it, if need be. The birth reflections service has been running in our area for almost six years and its purpose is two fold: firstly it provides women with a safe environment in which to talk about their labour and birth, where they can become better informed about the birth and where they can express themselves freely. Secondly, it provides first hand feedback for the maternity service about the care that's been given, enabling us to change practice for the better. PMID- 26638648 TI - Reflections on human rights as a reality for women and midwives. AB - We often speak of a woman's right to choose the way she wishes to give birth. This article discusses how 'real' that right is. Some of the legal background to human rights as they relate to childbirth is set out, centred on the 2010 European Court of Human Rights ruling in the home birth case, Ternovszky v Hungary. The limitations of this case point to why resorting to the law to achieve their rights about birth may not be the most fruitful remedy for women. Instead the argument is made for creating equality of voice in the clinical area to achieve a stronger collective voice for anchoring human rights in practice. PMID- 26638649 TI - Mental illness in pregnancy: midwives supporting women and safeguarding babies. AB - The relationship between parental mental illness and safeguarding concerns is well documented. The role of the midwife in supporting women with mental health problems can sometimes be a balancing act, especially when perinatal mental health services are few and far between. The midwife needs to be able to remain objective with regards to safeguarding and be proactive in instigating early help assessments. There should be organised joint working within a multi disciplinary team including social workers and psychiatric nurses which addresses the needs of both mother and baby. This can lead to a less problematic handover to health visiting services. Continuity of care and an open honest approach will be instrumental in providing a supportive relationship that doesn't lose sight of the baby. PMID- 26638650 TI - To stop walking on egg shells. AB - A collaborative project between a community midwife and midwifery educationalist has developed a model of compassionate woman-centred care for women with high BMI. The project aim was to test a model of care that would increase midwives' confidence in caring for women with high BMI. It was important that any new model should not involve what would be perceived as time-consuming activities that would add significantly to the midwives' workload. After searching the literature a five-stage brief interventions model based on motivational interviewing (MI) theory was piloted with a team of community midwives in rural Scotland. Leaflets were developed containing information and activities based on MI principles providing women with a tool to work with. The Swinscoe-Walsh model has been well received and evaluated by both midwives and women and is being considered for wider implementation by public health services for pregnant women. PMID- 26638651 TI - Antenatal GBS screening: an Australian perspective. AB - Women in Australia are offered a variety of options for screening and treatment of group B streptococcus (GBS), depending on which health service they are engaged with, including a risk-based approach or universal screening. The difficulty for midwives when addressing the evidence supporting these differing policies is that there is no unified national policy on GBS screening in Australia. Furthermore, the Australian population is a discerning one, questioning the implications of procedures and exploring all options. This paper discusses the varying evidence and limitations that midwives need to be aware of in order to inform women, empower their decision-making and provide holistic woman-centred care. PMID- 26638652 TI - Why women stop breastfeeding in the early days. AB - Increasing breastfeeding prevalence rates has been identified as key to improving health and well being outcomes for mothers and babies. (Dyson et al 2008, Unicef 2013; Renfrew et al 2012a; Renfrew et al 2012b). Within one maternity unit in England, in 2014, 80 per cent of women initiated breastfeeding at birth, but by day 10, only 45 per cent were breastfeeding exclusively, identifying a drop off rate of 35 per cent. As part of achieving the Unicef UK Baby Friendly standards, retrospective audit was undertaken to investigate why women were not continuing to exclusively breastfeed. Findings from the study identified that when a baby received a supplement of formula milk before 72 hours of age, the mother was less likely to be exclusively breastfeeding at 10 days. This was statistically significant (Sharp 2014). An innovation was implemented for some mothers to receive additional one-to-one feeding support in hospital and the community, as a result of which supplementation rates decreased. PMID- 26638653 TI - Providing hope: midwifery teaching in Bangladesh. AB - Bangladesh is recognised as a resource-poor country that has made some very positive steps to reducing maternal mortality over the last decade. However the death rate of women directly caused by pregnancy and childbirth still remains much higher than countries such as the UK, often due to lack of access to good quality and affordable basic health care. In this article, Anna Kent writes of her experiences teaching obstetric emergency clinical skills to Bangladesh's first ever student midwives. The students were recruited from rural villages to complete a three-year fully funded Midwifery Diploma Programme at one of seven education centres across the country. The goal of the programme is for the students to eventually return and practise as midwives in their home communities, enabling greater access for women to good quality basic health care, directly reducing maternal mortality across Bangladesh. PMID- 26638654 TI - Women's lived experiences of domestic violence during pregnancy (2). AB - This paper is a follow up paper to a study which explored women's experiences of domestic violence before, during and after pregnancy. Findings from this study suggested that women would like midwives to be able to recognise the signs of domestic violence and to be able to offer them an appropriate response and support. Midwives are well placed to recognise the signs of domestic violence and provide appropriate support. This paper addresses some of the challenges and dilemmas for midwives when identifying and supporting women who have experienced domestic violence and provides some key messages for midwifery practice. PMID- 26638655 TI - I can be a midwife! PMID- 26638656 TI - Midwifery Basics: preceptorship. 1. Success at last! PMID- 26638657 TI - Pondering placentophagy. Part 1. PMID- 26638658 TI - Fight for rights: a mother's perspective. PMID- 26638660 TI - [When and for whom to start dialytic therapy?]. AB - Patients with increasingly multiple diseases are admitted to dialytic therapies. In acute situations, the indications for dialytic therapy are refractory hyperkalemia, acidosis, fluid load and other symptoms of uremia. In chronic insufficiency the treatment is started when the estimated glomerular filtration rate (eGFR) is 5 to 10 ml/min/1.73m2 and the patient presents with symptoms of renal insufficiency. Dialytic therapy is not the best choice for everybody, because the alleviation of symptoms achieved with the therapy remains minor in comparison with the impairment of the quality of life and the risk of various complications associated with the therapy. PMID- 26638659 TI - [Moisture and mold damages of buildings in relation to health]. AB - Moisture damages of buildings increase respiratory symptoms and the risk of development of new cases of asthma. Scientific evidence of possible other health effects of moisture damages is scanty but they cause plenty of concern. The management of indoor air problems is further hampered by the lack of health-based limit values. Patients having symptoms from indoor air present a challenge to the doctor, because our ability to apply scientific data to an individual building or patient is very limited Although the factors increasing asthma and respiratory symptoms in buildings with moisture damage are not known in detail, every attempt should be made to prevent and correct the moisture damages. PMID- 26638661 TI - [HPV and cancer]. AB - Almost all acquire a genital HPV infection at some point in their life. Oral infections are also common. The majority of the infections are asymptomatic and get cleared, spontaneously. There are 180 HPV genotypes, of which HPV16 is the main cause of cervical cancer in addition to other carcinomas. HPV-related oropharyngeal cancer incidence has almost tripled in the last 30 years in Finland. Of the eight genes of HPV, E6 and E7 are the most important oncogenes. HPV vaccinations have been effective in reducing female genital and anal dysplastic lesions, but their effectiveness on head and neck infections requires further research. PMID- 26638662 TI - [Is endometriosis a premalignant condition to ovarian carcinoma?]. AB - Endometriosis is an estrogen dependent disease, which causes chronic inflammation and may lead to pelvic pain and infertility. Women with endometriosis have a 1.5 to 2-fold risk for ovarian epithelial cancer. The risk is increased especially for the endometrioid and clear cell histological types of ovarian carcinoma. Endometriosis and its atypical form are often found in the proximity of these cancers, and molecular changes similar to those in cancer have been detected in nearby endometriosis. The risk of cancer is associated with ovarian endometriosis, i.e. endometriomas and is increased by prolonged disease and/or older age at diagnosis and infertility. The progression of endometriosis to cancer is usually slow, possibly enabling diagnosis at an early stage of the disease. PMID- 26638663 TI - [Treatment of severe scoliosis]. AB - Untreated severe scoliosis results in a serious malposition of the back, restrictive lung disease and increases mortality compared with the normal population. Idiopathic scoliosis rarely reaches a severe degree. In the treatment of severe scoliosis, preoperative head traction of several weeks' duration has proven a safe and effective method of correcting the malposition, and will also make scoliosis surgery technically easier. Most cases of severe scoliosis can be treated with anterior pedicle screw instrumentation, and vertebrectomy is only seldom required. PMID- 26638664 TI - [Treatment of adult tracheal stenosis]. AB - Tracheal stenosis is a rare condition with symptoms mimicking asthma or COPD. The most frequent benign tracheal stenosis is caused by lesions related either to intubation or tracheostomy. Primary tracheal tumors or secondary malignancies such as locally advanced esophageal cancer are rare causes. As a rare disease the diagnosis and treatment are often delayed. Endoscopic therapy is the primary treatment for tracheal stenosis. Tracheal resection is indicated in resectable malignant tumors and in benign stenosis which do not respond to endoscopic treatment or require repeated therapy. In these situations, surgery provides a safe and a long-term solution. Currently, surgery is rarely an option in long segment tracheal lesions. Advances in stem cell technology, tracheal transplantation and tissue engineering may, however, provide a solution for these problems in the future. PMID- 26638665 TI - [Axillary ultrasound for a breast cancer patient and changing international treatment practices]. AB - INTRODUCTION: We explored the effects of novel treatment practices on radiological examinations of the axilla in Finland. PATIENTS AND METHODS: Axillary ultrasound was performed for 178 new breast cancer patients preoperatively. A core biopsy was taken from the suspected lymph nodes, and the finding was compared with the postoperative results. RESULTS: Ultrasound in combination with the core biopsy detects 61.6% of the macrometastases. Ultrasound detected almost all axilla having a high tumor burden. CONLUSIONS: Preoperative axillary ultrasound and core biopsy for suspected lymph nodes before the operation is still recommended for all breast cancer patients. Frozen section examination of the sentinel lymph node can be omitted if preoperatively the primary tumour is unifocal, less than 15mm and the axillary ultrasound finding negative. PMID- 26638666 TI - [Respiratory disturbance during sleep induced by vagus nerve stimulator]. AB - Vagus nerve stimulation can be used in parallel with drug therapy as adjuvant therapy for severe epilepsy. In approximately half of the patients the number of seizures decreases by at least 50%. The most common adverse effects reported for the therapy include mild laryngeal and upper respiratory tract symptoms and dysfunctions, and in some cases, also development of respiratory disturbances during sleep. We describe two patients in whom vagus nerve stimulation induced sleep apnea. The problem was resolved by changing the settings of the stimulator. Sleep apnea syndrome should be kept in mind when planning vagus nerve stimulation therapy and monitoring the response to therapy. PMID- 26638668 TI - More Than the Minimum. PMID- 26638667 TI - [Update on Current Care Guideline: Migraine]. AB - Mild migraine attack can be treated with acetaminophen or NSAIDs either alone or combined with metoclopramide. In severe and devastating attacks triptans should be taken immediately, and not afterwards, when first line NSAIDs have proven ineffektive. No significant differences between triptans can be shown in clinical practice, when recommended doses are used. Opioid analgesics should not be used in the treatment of migraine. The recommended drugs for migraine attacks in children are acetaminophen or ibuprophen. Also intranasal sumatriptan can be used. The first line drugs for prophylactic treatment of migraine are non-ISA betablockers or candesartan and amitriptyline. PMID- 26638669 TI - PM 2.5 Airborne Particulates Near Frac Sand Operations. AB - The rapid growth of hydraulic fracturing for oil and gas extraction in the U.S. has led to 135 active "frac" sand mines, processing plants, and rail transfer stations in Wisconsin. Potential environmental health risks include increased truck traffic, noise, ecosystem loss, and groundwater, light, and air pollution. Emitted air contaminants include fine particulate matter (PM2.5) and respirable crystalline silica. Inhalation of fine dust particles causes increased mortality, cardiovascular disease, lung disease, and lung cancer. In the authors' pilot study, use of a filter-based ambient particulate monitor found PM2.5 levels of 5.82-50.8 ug/m3 in six 24-hour samples around frac sand mines and processing sites. Enforcement of the existing U.S. Environmental Protection Agency annual PM2.5 standard of 12 ug/m3 is likely to protect the public from silica exposure risks as well. PM2.5 monitoring around frac sand sites is needed to ensure regulatory compliance, inform nearby communities, and protect public health. PMID- 26638670 TI - Chlorhexidine to Maintain Cleanliness of Restroom Door Handles. AB - Restroom internal door handles have the potential to become contaminated by pathogenic bacteria, particularly because frequent breakdowns occur in hand hygiene. Cleaning these door handles periodically could reduce this cross contamination risk. The sustained effect following cleaning with chlorhexidine could be beneficial in restroom facilities as cleaning episodes are of necessity at time intervals. The cleaning efficacies and residual effects of Sani Cloth CHG 2% wipes were investigated in a double-blinded randomized crossover controlled trial in a school setting. No significant difference occurred in initial cleaning efficacy; however, following a six-hour period of use by pupils of the restroom facilities, the internal door handles wiped with Sani-Cloth CHG 2% wipes were significantly less contaminated than those with the control wipe (14% v. 32%, p = .02). Cleaning with Sani-Cloth CHG 2% wipes demonstrated significant improvements in the continuous cleanliness of restroom door handles during use with this simple and inexpensive technique. PMID- 26638671 TI - 2014 Ebola Outbreak: Implications for Environmental Health Practice. AB - Environmental health practitioners deal with assessing risk of potential environmental contaminants from a variety of sources, including infectious disease such as Ebola virus disease (EVD). Therefore, they are uniquely qualified to contribute to epidemiological discussions of the interactions between agent host-environment and how those interactions might be disrupted to stop the spread of EVD. Occupational health contributions on the proper use of personal protective equipment are particularly relevant for diseases lacking vaccination and treatment such as EVD. Occupations that may be at increased risk of exposure include health workers, laboratory workers, cleaning crews (for hospitals, ambulances, travel facilities, etc.), transportation workers (e.g., airlines, public transportation, taxis), sanitation workers, and morgue workers. Raising awareness professionally and publicly is an important step to stopping the spread of EVD. PMID- 26638672 TI - Mentoring Is for Everyone--Make a Plan, Find Your Role. PMID- 26638673 TI - Using soilSHOPs to Reduce Community Exposures to Lead in Soils. PMID- 26638674 TI - Rodent Control and Public Health: A Description of Local Rodent Control Programs. PMID- 26638675 TI - U.S. Department of Housing and Urban Development Secretary's Awards for Healthy Homes. PMID- 26638676 TI - The Aqueous Solution. PMID- 26638677 TI - Controlled sp(2) Functionalization of Boron Doped Diamond as a Route for the Fabrication of Robust and Nernstian pH Electrodes. AB - The development of a voltammetric boron doped diamond (BDD) pH sensor is described. To obtain pH sensitivity, laser micromachining (ablation) is utilized to introduce controlled regions of sp(2) carbon into a high quality polycrystalline BDD electrode. The resulting sp(2) carbon is activated to produce electrochemically reducible quinone groups using a high temperature acid treatment, followed by anodic polarization. Once activated, no further treatment is required. The quinone groups show a linear (R(2) = 0.999) and Nernstian (59 mV/(pH unit)) pH-dependent reductive current-voltage response over a large analyzable pH range, from pH 2 to pH 12. Using the laser approach, it is possible to optimize sp(2) coverage on the BDD surface, such that a measurable pH response is recorded, while minimizing background currents arising from oxygen reduction reactions on sp(2) carbon in the potential region of interest. This enables the sensor to be used in aerated solutions, boding well for in situ analysis. The voltammetric response of the electrode is not compromised by the presence of excess metal ions such as Pb(2+), Cd(2+), Cu(2+), and Zn(2+). Furthermore, the pH sensor is stable over a 3 month period (the current time period of testing), can be stored in air between measurements, requires no reactivation of the surface between measurements, and can be reproducibly fabricated using the proposed approach. The efficacy of this pH sensor in a real-world sample is demonstrated with pH measurements in U.K. seawater. PMID- 26638678 TI - Phylogeny of Aging and Related Phenoptotic Phenomena. AB - The interpretation of aging as adaptive, i.e. as a phenomenon genetically determined and modulated, and with an evolutionary advantage, implies that aging, as any physiologic mechanism, must have phylogenetic connections with similar phenomena. This review tries to find the phylogenetic connections between vertebrate aging and some related phenomena in other species, especially within those phenomena defined as phenoptotic, i.e. involving the death of one or more individuals for the benefit of other individuals. In particular, the aim of the work is to highlight and analyze similarities and connections, in the mechanisms and in the evolutionary causes, between: (i) proapoptosis in prokaryotes and apoptosis in unicellular eukaryotes; (ii) apoptosis in unicellular and multicellular eukaryotes; (iii) aging in yeast and in vertebrates; and (iv) the critical importance of the DNA subtelomeric segment in unicellular and multicellular eukaryotes. In short, there is strong evidence that vertebrate aging has clear similarities and connections with phenomena present in organisms with simpler organization. These phylogenetic connections are a necessary element for the sustainability of the thesis of aging explained as an adaptive phenomenon, and, on the contrary, are incompatible with the opposite view of aging as being due to the accumulation of random damages of various kinds. PMID- 26638679 TI - Contribution of Quantitative Methods of Estimating Mortality Dynamics to Explaining Mechanisms of Aging. AB - Accumulation of various types of unrepaired damage of the genome because of increasing production of reactive oxygen species and decreasing efficiency of the antioxidant defense system and repair systems can cause age-related diseases and emergence of phenotypic signs of senescence. This should lead to increasing vulnerability and to mortality monotonously increasing with age independently of the position of the species on the evolutionary tree. In this light, the survival, mortality, and fertility curves for 45 animal and plant species and one alga published by the Max Planck Institute for Demographic Research (Germany/Denmark) are of special interest (Jones, O. R., et al. (2014) Nature, 505, 169-173). We divided all species treated in that study into four groups according to the ratio of mortality at the terminal age (which corresponds to 5% survival) and average mortality during the entire studied period. For animals of group IV (long-lived and senescent), including humans, the Jones method makes it possible to trace mortality during the entire life cycle. The same applies to short-lived animals (e.g. nematodes or the tundra vole), whether they display the Gompertz type of senescence or not. However, in long-lived species with a less pronounced increase in mortality with age (e.g. the freshwater crocodile, hermit crab, or Scots pine), as well as in animals of average lifespan that reach the terminal age earlier than they could have enough time to become senescent, the Jones method is capable of characterizing only a small part of the life cycle and does not allow judging how senescence manifests itself at late stages of the life cycle. Thus, it is known that old trees display signs of biological senescence rather clearly; although Jones et al. consider them non-senescent organisms because less than 5% of sexually mature individuals survive to display the first manifestations of these characters. We have concluded that the classification proposed by Jones et al. makes it possible to approximately divide animals and plants only by their levels of the Gompertz type of senescence (i.e. actuarial senescence), whereas susceptibility to biological senescence can be estimated only when principally different models are applied. PMID- 26638680 TI - Diseases and Aging: Gender Matters. AB - At first glance, biological differences between male and female sex seem obvious, but, in fact, they affect a vast number of deeper levels apart from reproductive function and related physiological features. Such differences affect all organizational levels including features of cell physiology and even functioning of separate organelles, which, among other things, account for such global processes as resistance to diseases and aging. Understanding of mechanisms underlying resistance of one of the sexes to pathological processes and aging will allow taking into consideration gender differences while developing drugs and therapeutic approaches, and it will provide an opportunity to reproduce and enhance such resistance in the more vulnerable gender. Here we review physiological as well as cellular and biological features of disease course including aging that are affected by gender and discuss potential mechanisms behind these processes. Such mechanisms include features of oxidative metabolism and mitochondrial functioning. PMID- 26638681 TI - DNA Methylation, Mitochondria, and Programmed Aging. AB - DNA methylation is a key epigenetic process involved in the regulation of nuclear gene expression. Progress in the study of genomic DNA methylation led to the precise identification of methylation sites reflecting biological age of cells and tissues. However, the functional significance of mitochondrial DNA (mtDNA) methylation remains unknown. Growing evidence suggests that mtDNA methylation is linked to aging and oxidative stress. This mini-review summarizes information about the methylation of nuclear and mtDNA in mammals, indicating the connection of these processes to programmed aging. PMID- 26638682 TI - Alzheimer's Disease: An Exacerbation of Senile Phenoptosis. AB - Alzheimer's disease is characterized by progressive memory loss and cognitive decline accompanied by degeneration of neuronal synapses, massive loss of neurons in the brain, eventually resulting in complete degradation of personality and death. Currently, the cause of the disease is not fully understood, but it is believed that the person's age is the major risk factor for development of Alzheimer's disease. People who have survived after cerebral stroke or traumatic brain injury have substantially increased risk of developing Alzheimer's disease. Social exclusion, low social activity, physical inactivity, poor mental performance, and low level of education are among risk factors for development of this neurodegenerative disease, which is consistent with the concept of phenoptosis (Skulachev, V. P., et al. (1999) Biochemistry (Moscow), 64, 1418 1426; Skulachev, M. V., and Skulachev, V. P. (2014) Biochemistry (Moscow), 79, 977-993) stating that rate of aging is related to psychological and social aspects in human behavior. Here we assumed that Alzheimer's disease might be considered as an exacerbation of senile phenoptosis. If so, then development of this disease could be slowed using mitochondria-targeted antioxidants due to the accumulated data demonstrating a link between mitochondrial dysfunction and oxidative stress both with normal aging and Alzheimer's disease. PMID- 26638683 TI - Age-Related Changes in Ultrastructure of Mitochondria. Effect of SkQ1. AB - For many years, investigators have attempted to identify unique ultrastructural conditions of mitochondria related to aging. However, this did not result in definitive results. At present, this issue has again become of topical interest due to development of the mitochondrial theory of aging and of engineering of a novel antioxidant class known as mitochondria-targeted antioxidants. The review briefly discusses experimental results that, from our perspective, allow the most objective understanding regarding age-related changes in mitochondrial ultrastructure. PMID- 26638684 TI - Uncoupling and Toxic Action of Alkyltriphenylphosphonium Cations on Mitochondria and the Bacterium Bacillus subtilis as a Function of Alkyl Chain Length. AB - A series of permeating cations based on alkyl derivatives of triphenylphosphonium (C(n)-TPP(+)) containing linear hydrocarbon chains (butyl, octyl, decyl, and dodecyl) was investigated in systems of isolated mitochondria, bacteria, and liposomes. In contrast to some derivatives (esters) of rhodamine-19, wherein butyl rhodamine possessed the maximum activity, in the case of C(n)-TPP a stimulatory effect on mitochondrial respiration steadily increased with growing length of the alkyl radical. Tetraphenylphosphonium and butyl-TPP(+) at a dose of several hundred micromoles exhibited an uncoupling effect, which might be related to interaction between C(n)-TPP(+) and endogenous fatty acids and induction of their own cyclic transfer, resulting in transport of protons across the mitochondrial membrane. Such a mechanism was investigated by measuring efflux of carboxyfluorescein from liposomes influenced by C(n)-TPP(+). Experiments with bacteria demonstrated that dodecyl-TPP(+), decyl-TPP(+), and octyl-TPP(+) similarly to quinone-containing analog (SkQ1) inhibited growth of the Gram positive bacterium Bacillus subtilis, wherein the inhibitory effect was upregulated with growing lipophilicity. These cations did not display toxic effect on growth of the Gram-negative bacterium Escherichia coli. It is assumed that the difference in toxic action on various bacterial species might be related to different permeability of bacterial coats for the examined triphenylphosphonium cations. PMID- 26638685 TI - Influence of SkQ1 on Expression of Nrf2 Gene, ARE-Controlled Genes of Antioxidant Enzymes and Their Activity in Rat Blood Leukocytes under Oxidative Stress. AB - The study demonstrated that oxidative stress induced by hyperoxia (0.5 MPa for 90 min) resulted in reduction of mRNA levels of transcription factor Nrf2 and Nrf2 induced genes encoding antioxidant enzymes (SOD1, CAT, GPx4) in peripheral blood leukocytes of rats. The changes in gene expression profiles under hyperoxia were accompanied by disbalance of activity of antioxidant enzymes in the leukocytes, namely activation of superoxide dismutase and inhibition of catalase, glutathione peroxidase, and glutathione-S-transferase. Pretreatment of rats with SkQ1 (50 nmol/kg for five days) significantly increased mRNA levels of transcription factor Nrf2 and Nrf2-induced genes encoding antioxidant enzymes SOD2 and GPx4 and normalized the transcriptional activity of the SOD1 and CAT genes in the leukocytes in hyperoxia-induced oxidative stress. At the same time, the activity of catalase and glutathione peroxidase was increased, and the activity of superoxide dismutase and glutathione-S-transferase returned to the control level. It is hypothesized that protective effect of SkQ1 in hyperoxia-induced oxidative stress can be realized via a direct antioxidant property and the stimulation of the Keap1/Nrf2 redox-sensitive signaling system. PMID- 26638686 TI - Influence of 10-(6'-Plastoquinonyl)decyltriphenylphosphonium (SkQ1) on Oxidative Status in Rats with Protamine Sulfate-Induced Hyperglycemia. AB - An influence of 10-(6'-plastoquinonyl)decyltriphenylphosphonium (SkQ1) on oxidative status and activity of some antioxidant enzymes in the liver and blood serum from rats was examined during experimental hyperglycemia developed after injecting protamine sulfate. It was found that SkQ1 lowered glycemic level in rats treated with protamine sulfate. Moreover, it was also accompanied by restoration of the normal range of biochemiluminescence parameters indicating the rate of ongoing free radical processes, magnitude of primary products of lipid peroxidation such as diene conjugates, activity of aconitate hydratase, and level of citrate in rat liver and blood. Hence, it was demonstrated that activity of superoxide dismutase and catalase, increasing during hyperglycemia, was decreased after administering SkQ1. This might be related to the ability of SkQ1 to normalize free-radical homeostasis imbalanced during hyperglycemia. PMID- 26638687 TI - Effect of SkQ1 on Activity of the Glutathione System and NADPH-Generating Enzymes in an Experimental Model of Hyperglycemia. AB - We studied the effect of mitochondria-targeted antioxidant 10-(6' plastoquinonyl)decyltriphenylphosphonium (SkQ1) on the antioxidant activity of the glutathione system and NADPH-generating enzymes in liver and blood serum of rats with hyperglycemia induced by protamine sulfate. It was found that intraperitoneal injection of SkQ1 prevented both decrease in reduced glutathione level and increase in activity of glutathione system enzymes--glutathione peroxidase, glutathione reductase, and glutathione transferase. Activity of NADPH generating enzymes--glucose-6-phosphate dehydrogenase and NADP-isocitrate dehydrogenase--was also attenuated by SkQ1. Probably, in this model of hyperglycemia, decreased level of reactive oxygen species in mitochondria led to the decreased burden on the glutathione antioxidant system and NADPH-generating enzymes. Thus, SkQ1 appears to be a promising compound for the treatment and/or prevention of the adverse effects of hyperglycemia. PMID- 26638688 TI - Early Thymus Involution--Manifestation of an Aging Program or a Program of Development? AB - "I see no physical reason why it should not have been possible for life to construct ageless individuals", said Carl von Weizsacker in 1979 at the Conference on DNA. An obvious biological reason for senescence may be the action of a built-in aging program. Many gerontologists believe that early thymic involution is an argument in favor of the existence of such a program. On the other hand, this involution may be a result of the program of development rather than aging. According to the concepts of noninfectious immunology, the immune system of vertebrates is also designed for immune surveillance over initial tumor development and for tissue-specific regulation of cell proliferation both in ontogenesis and during physiological and reparative regeneration of organs and tissues. Natural anti-tissue autoantibodies are the main effectors of such regulation. Therefore, the number of inherited genes of the variable part of immunoglobulin (V-genes) is not less than the number of all proliferative competent cell types (~100). For the same reason, the maximal rate of growth, which is usually observed in the prepubertal period, coincides with the maximal thymus index and the maximal number of immunoglobulin-secreting cells as well as the minimal force of mortality during ontogeny. Thus, the circa-pubertal beginning of thymic involution is probably caused by the programmed deceleration of the growth rate in ontogeny, and not by the early manifestation of an aging program. This approach allows us to understand the mechanism of the well-known antitumor effect of the regeneration process of the organ homologous to the tumor, and hence we can try to use it in practical oncology. PMID- 26638689 TI - Effect of Long-Term Treatment with Antioxidant SkQ1 Added to Drinking Water on Cytochromes P450 Level in Rat Liver. AB - Mitochondria-targeted cationic antioxidant plastoquinonyl decyltriphenylphosphonium (SkQ1) added to drinking water in therapeutic doses (250 nmol/kg per day) for a long time (up to 24 months) does not induce cytochromes P450 in rat liver. PMID- 26638690 TI - Thymic Involution in Ontogenesis: Role in Aging Program. AB - In most mammals, involution of the thymus occurs with aging. In this issue of Biochemistry (Moscow) devoted to phenoptosis, A. V. Khalyavkin considered involution of a thymus as an example of the program of development and further- of proliferation control and prevention of tumor growth. However, in animals devoid of a thymus (e.g. naked mice), stimulation of carcinogenesis, but not its prevention was observed. In this report, we focus on the involution of the thymus as a manifestation of the aging program (slow phenoptosis). We also consider methods of reversal/arrest of this program at different levels of organization of life (cell, tissue, and organism) including surgical manipulations, hormonal effects, genetic techniques, as well as the use of conventional and mitochondria targeted antioxidants. We conclude that programmed aging (at least on the model of age-dependent thymic atrophy) can be inhibited. PMID- 26638691 TI - Ultrastable-Stealth Large Gold Nanoparticles with DNA Directed Biological Functionality. AB - The stability of gold nanoparticles (AuNPs) in biological samples is very important for their biomedical applications. Although various molecules such as polystyrenesulfonate (PSS), phosphine, DNA, and polyethylene glycol (PEG) have been used to stabilize AuNPs, it is still very difficult to stabilize large AuNPs. As a result, biomedical applications of large (30-100 nm) AuNPs are limited, even though they possess more favorable optical properties and are easier to be taken up by cells than smaller AuNPs. To overcome this limitation, we herein report a novel method of preparing large (30-100 nm) AuNPs with a high colloidal stability and facile chemical or biological functionality, via surface passivation with an amphiphilic polymer polyvinylpyrrolidone (PVP). This PVP passivation results in an extraordinary colloidal stability for 13, 30, 50, 70, and 100 nm AuNPs to be stabilized in PBS for at least 3 months. More importantly, the PVP capped AuNPs (AuNP-PVP) were also resistant to protein adsorption in the presence of serum containing media and exhibit a negligible cytotoxicity. The AuNP-PVPs functionalized with a DNA aptamer AS1411 remain biologically active, resulting in significant increase in the uptake of the AuNPs (~12,200 AuNPs per cell) in comparison with AuNPs capped by a control DNA of the same length. The novel method developed in this study to stabilize large AuNPs with high colloidal stability and biological activity will allow much wider applications of these large AuNPs for biomedical applications, such as cellular imaging, molecular diagnosis, and targeted therapy. PMID- 26638694 TI - Evaluation of bone deformities of the femur, tibia, and patella in Toy Poodles with medial patellar luxation using computed tomography. AB - OBJECTIVES: To evaluate morphological parameters of the femur, tibia, and patella in Toy Poodles with medial patellar luxation (MPL) using three-dimensional (3D) computed tomography (CT) and to compare these parameters between radiography and CT. METHODS: Thirty-five hindlimbs of Toy Poodles were divided into normal and grade 2 and 4 MPL groups. The anatomical and mechanical lateral proximal femoral angle, anatomical and mechanical lateral distal femoral angle (aLDFA, mLDFA), femoral varus angle (FVA), inclination of the femoral head angle, procurvation angle, anteversion angle (AA), frontal angle of the femoral neck, mechanical medial proximal or distal tibial angle, mechanical cranial proximal or distal tibial angle, tibial plateau angle, tibial torsion angle (TTA), Z angle, relative tibial tuberosity width, ratio of the medial distance of tibial tuberosity to the proximal tibial width (MDTT/PTW), patella size, and the patellar ligament length: patellar length (L:P) ratio were evaluated on radiography and 3D CT. RESULTS: The aLDFA, mLDFA, FVA, and TTA were significantly larger and the AA, MDTT/PTW, and patella were significantly smaller in the grade 4 MPL group. There were significant differences in many parameters between imaging tools, and CT was considered less susceptible to potential artefacts and rotational deformities. CLINICAL SIGNIFICANCE: Toy Poodles with grade 4 MPL had significant femoral varus deformity, medial displacement of the tibial tuberosity, internal torsion of the proximal tibia, and hypoplasia of the patella. PMID- 26638693 TI - USAT: A Unified Score-Based Association Test for Multiple Phenotype-Genotype Analysis. AB - Genome-wide association studies (GWASs) for complex diseases often collect data on multiple correlated endo-phenotypes. Multivariate analysis of these correlated phenotypes can improve the power to detect genetic variants. Multivariate analysis of variance (MANOVA) can perform such association analysis at a GWAS level, but the behavior of MANOVA under different trait models has not been carefully investigated. In this paper, we show that MANOVA is generally very powerful for detecting association but there are situations, such as when a genetic variant is associated with all the traits, where MANOVA may not have any detection power. In these situations, marginal model based methods, however, perform much better than multivariate methods. We investigate the behavior of MANOVA, both theoretically and using simulations, and derive the conditions where MANOVA loses power. Based on our findings, we propose a unified score-based test statistic USAT that can perform better than MANOVA in such situations and nearly as well as MANOVA elsewhere. Our proposed test reports an approximate asymptotic P-value for association and is computationally very efficient to implement at a GWAS level. We have studied through extensive simulations the performance of USAT, MANOVA, and other existing approaches and demonstrated the advantage of using the USAT approach to detect association between a genetic variant and multivariate phenotypes. We applied USAT to data from three correlated traits collected on 5, 816 Caucasian individuals from the Atherosclerosis Risk in Communities (ARIC, The ARIC Investigators []) Study and detected some interesting associations. PMID- 26638695 TI - The metabolism and de-bromination of bromotyrosine in vivo. AB - During inflammation, leukocyte-derived eosinophil peroxidase catalyses the formation of hypobromous acid, which can brominate tyrosine residues in proteins to form bromotyrosine. Since eosinophils are involved in the pathogenesis of allergic reactions, such as asthma, urinary bromotyrosine level has been used for the assessment of children with asthma. However, little is known about the metabolism and disposition of bromotyrosine in vivo. The aim of this study was to identify the major urinary metabolites formed during bromotyrosine metabolism and to develop mass spectrometric methods for their quantitation. Deuterium-labeled bromotyrosine was synthesized by deuterium exchange. [D3]bromotyrosine (500 nmole) was injected intraperitoneally into Sprague-Dawley rats and urine was collected for 24h in a metabolic cage. (13)C-labeled derivatives of bromotyrosine and its major urinary metabolite were synthesized and used as internal standards for quantitation. Following solid phase extraction, urine samples were derivatized to the pentafluorobenzyl ester, and analyzed using isotope dilution gas chromatography and negative-ion chemical ionization mass spectrometry. A novel brominated metabolite, 3-bromo-4-hydroxyphenylacetic acid (bromo-HPA), was identified as the major brominated metabolite of bromotyrosine. Bromo-HPA only accounted for 0.43 +/- 0.04% of infused [D3]bromotyrosine and 0.12 +/- 0.02% of infused [D3]bromotyrosine was excreted in the urine unchanged. However, ~1.3% (6.66 +/- 1.33 nmole) of infused [D3]bromotyrosine was excreted in the urine as the de-brominated metabolite, [D3]4-hydroxyphenylacetic acid, which is also a urinary metabolite of tyrosine in mammals. We also tested whether or not iodotyrosine dehalogenase can catalyse de-bromination of bromotyrosine and showed that iodotyrosine dehalogenase is able to de-brominate free bromotyrosine in vitro. We identified bromo-HPA as the main brominated urinary metabolite of bromotyrosine in rats. However, de-halogenation of bromotyrosine is the major metabolic pathway to eliminate free brominated tyrosine in vivo. PMID- 26638696 TI - Urodynamic studies in children: Standardized transurethral video-urodynamic evaluation. AB - OBJECTIVE: The aim was too demonstrate standardized video-urodynamic study (VUDS) in children using a transurethral catheter and pressure transducers. METHODS: Data necessary to obtain urodynamic evaluation of bladder sphincter function were gathered by concomitant measurement of bladder, urethral, and abdominal pressure. A 7F transurethral triple-lumen water-filled catheter was used for measuring the bladder and sphincter pressures and a water-filled 8F catheter connected to a pressure transducer was inserted into the rectum for pressure measurement. Cystometry was combined with fluoroscopy, providing simultaneous voiding cystourethrography information. Detrusor activity, bladder sensation, capacity, and compliance were measured during filling cystometry. Voiding cystometry consisted of recording pressures in the bladder sphincter and abdomen with simultaneous urinary flow measurement. RESULTS: Transurethral VUDS was safely and easily performed in a clinical setting adapted to children. CONCLUSIONS: A good and reproducible UDS is mandatory for correct therapeutic decisions. A standardized study associated with fluoroscopic assessment is presented in this video. PMID- 26638697 TI - Side-by-Side Alterations in Glycocalyx Thickness and Perfused Microvascular Density During Acute Microcirculatory Alterations in Cardiac Surgery. AB - OBJECTIVES: Endothelial glycocalyx injury causes microcirculatory perfusion disturbances in experimental studies, but the relevance in a clinical setting remains unknown. We investigated whether glycocalyx dimensions are reduced after onset of CPB and whether this is associated with alterations in microvascular perfusion. METHODS: The current observational study included 36 patients undergoing cardiac surgery without or with CPB, using either nonpulsatile or pulsatile flow. Sublingual microcirculatory perfusion was assessed perioperatively and analyzed for perfused vessel density and PBR, an inverse parameter of endothelial glycocalyx dimensions. RESULTS: Perfused vessel density decreased after onset of CPB in parallel with an increase in PBR in both pulsatile and nonpulsatile groups. In the nonpulsatile CPB group, these alterations were still persistent in the ICU (PVD: T1 19.8 +/- 2.8 mm/mm(2) vs. T3 15.3 +/- 2.6 mm/mm(2) ; p = 0.004. PBR: T1 2.40 +/- 0.35 MUm vs. T3 2.60 +/- 0.31 MUm; p = 0.020). In the off-pump group, perfused vessel density remained unaltered. An inverse correlation between perfused vessel density and PBR was detected. CONCLUSIONS: This study shows that endothelial glycocalyx dimensions decrease after onset of CPB and are closely related to microvascular perfusion when assessed with a novel, noninvasive technique. PMID- 26638698 TI - SERUM IMMUNOGLOBULIN IgE IN A PEDIATRIC POPULATION: A RETROSPECTIVE ANALYSIS. AB - Allergic sensitization is mediated by immunoglobulin E (IgE) and an increase of their total value is frequently used to complete a correct diagnosis of atopy. Serum IgE may be considered a typical biomarker for the allergic phenotype. The aim of this study was to evaluate total serum IgE, according to sensitizations and to find a cut off to discriminate between atopic and non-atopic subjects. Seven hundred and ninety-five patients were enrolled in this study. Serum levels of total IgE were measured by a fluorescence immunoassay (ImmunoCAP; ThermoFisher, Uppsala, Sweden) while specific IgE levels were measured by immunofluorometric assay (ImmunoCAP; ThermoFisher, Uppsala, Sweden). Both tests were expressed in kU/L, according to manufacturer?s instructions. RESULTS: A difference for total IgE, according to the gender, has been found (p = 0,0012 ) with higher values for males than for females. A correlation has been found between total IgE and specific IgE, even distinguishing the population in sensitized and non-sensitized. A statistically significant difference has been found according to the presence or the absence of sensitization (p less than 0.0001) and also considering mono-sensitized and polysensitized patients (p less than 0.0001). ROC analysis has been performed to define a cut off for total serum IgE, according to sensitization and to the type of sensitization (mono sensitization or poly-sensitization). Finally multiple regression models have been performed to describe total IgE response (positive or negative) and to predict total IgE values. Since clinical limitations are well known, total IgE provide a useful aid to define atopy, allowing the clinician to carry out further investigations in patients with total IgE values beyond normal limits. PMID- 26638713 TI - A Simple Synthesis of Alliin and allo-Alliin: X-ray Diffraction Analysis and Determination of Their Absolute Configurations. AB - A simple method for the isolation of the bioactive compound alliin from garlic, as well as a method for the synthesis of diastereomerically pure alliin and allo alliin on a preparative laboratory scale, was developed. The absolute configuration of the sulfur atom in alliin and allo-alliin was assigned on the basis of enzyme reactivity, optical rotatory dispersion, and circular dichroism analyses. A comparison of the results from these analyses, in combination with an X-ray diffraction study on a protected allo-alliin derivative, revealed S and R configurations of the sulfur atoms in alliin and allo-alliin, respectively. In addition, the same (1)H NMR spectrum was observed for synthetic and natural alliin. The absolute configuration of natural alliin was assigned for the first time on the basis of the NMR spectrum and X-ray coordinates. PMID- 26638714 TI - Genome wide identification of C1-2i zinc finger proteins and their response to abiotic stress in hexaploid wheat. AB - The C1-2i wheat Q-type C2H2 zinc finger protein (ZFP) transcription factor subclass has been reported to play important roles in plant stress responses. This subclass of ZFPs has not been studied in hexaploid wheat (Triticum aestivum) and we aimed to identify all members of this subclass and evaluate their responses to different abiotic stresses causing oxidative stress. Exploiting the recently published wheat draft genome sequence, we identified 53 members (including homoeologs from A, B and D genomes) of the C1-2i wheat Q-type C2H2 ZFPs (TaZFPs) representing 21 genes. Evolution analysis revealed that 9 TaZFPs members are directly inherited from the parents Triticum urartu and Aegilops tauschii, while 15 diverged through neoploidization events. This TaZFP subclass is responsive to the oxidative stress generator H2O2 and to high light, drought stress and flooding. Most TaZFPs are responsive to H2O2 (37/53), high light (44/53), flooding (31/53) or drought (37/53); 32 TaZFPs were up-regulated by at least 3 stresses and 16 were responsive to all stresses tested. A large number of these TaZFPs were physically mapped on different wheat draft genome sequences with known markers useful for QTL mapping. Our results show that the C1-2i subclass of TaZFPs is associated with responses to different abiotic stresses and that most TaZFPs (30/53 or 57 %) are located on group 5 chromosomes known to be involved in environment adaptation. Detailed characterization of these novel wheat TaZFPs and their association to QTL or eQTL may help to design wheat cultivars with improved tolerance to abiotic stress. PMID- 26638715 TI - Primary intraosseous squamous cell carcinoma arising in an odontogenic keratocyst previously treated with marsupialization: case report and immunohistochemical study. AB - A rare case of primary intraosseous squamous cell carcinoma arising in an odontogenic keratocyst (OKC) is presented here, with the clinical and histologic features of the first biopsy showing characteristics of OKC and the second biopsy disclosing a squamous cell carcinoma. Immunoprofile of this case was compared with five cases of classical OKC by using cytokeratins CK5, CK14, and CK19, CD138, p63, Ki-67, p53, and bcl-2. Classic OKCs showed expected positivity, mainly in the basal and/or suprabasal layers with most antibodies, except for p53, which was negative, whereas the present case showed irregular positivity in all layers, indicating that this can be useful for differential diagnosis and suggesting a possible role in malignant transformation into primary intraosseous squamous cell carcinoma. In conclusion, immunohistochemical differences between the first biopsy of the present case and classic OKC suggest that immunohistochemistry can be helpful in cases with areas of subtle initial malignant transformation. PMID- 26638716 TI - Response to letter to editor. PMID- 26638717 TI - What are the risks of hormonal contraceptive use in middle-aged women? PMID- 26638726 TI - Genetic screening for gynecological cancer: where are we heading? AB - The landscape of cancer genetics in gynecological oncology is rapidly changing. The traditional family history-based approach has limitations and misses >50% mutation carriers. This is now being replaced by population-based approaches. The need for changing the clinical paradigm from family history-based to population based BRCA1/BRCA2 testing in Ashkenazi Jews is supported by data that demonstrate population-based BRCA1/BRCA2 testing does not cause psychological harm and is cost effective. This article covers various genetic testing strategies for gynecological cancers, including population-based approaches, panel and direct-to consumer testing as well as the need for innovative approaches to genetic counseling. Advances in genetic testing technology and computational analytics have facilitated an integrated systems medicine approach, providing increasing potential for population-based genetic testing, risk stratification, and cancer prevention. Genomic information along-with biological/computational tools will be used to deliver predictive, preventive, personalized and participatory (P4) and precision medicine in the future. PMID- 26638718 TI - Satureja bachtiarica ameliorate beta-amyloid induced memory impairment, oxidative stress and cholinergic deficit in animal model of Alzheimer's disease. AB - Extracellular deposition of Beta-amyloid peptide (Abeta) is the main finding in the pathophysiology of Alzheimer's disease (AD), which damages cholinergic neurons through oxidative stress and reduces the cholinergic neurotransmission. Satureja bachtiarica is a medicinal plant from the Lamiaceae family which was widely used in Iranian traditional medicine. The aim of the present study was to investigate possible protective effects of S. bachtiarica methanolic extract on Abeta induced spatial memory impairment in Morris Water Maze (MWM), oxidative stress and cholinergic neuron degeneration. Pre- aggregated Abeta was injected into the hippocampus of each rat bilaterally (10 MUg/rat) and MWM task was performed 14 days later to evaluate learning and memory function. Methanolic extract of S.bachtiarica (10, 50 and 100 mg/Kg) was injected intraperitoneally for 19 consecutive days, after Abeta injection. After the probe test the brain tissue were collected and lipid peroxidation, Acetylcholinesterase (AChE) activity and Cholin Acetyl Transferees (ChAT) immunorectivity were measured in the hippocampus. Intrahipocampal injection of Abeta impaired learning and memory in MWM in training days and probe trail. Methanolic extract of S. bachtiarica (50 and 100 mg/Kg) could attenuate Abeta-induced memory deficit. ChAT immunostaining revealed that cholinergic neurons were loss in Abeta- injected group and S. bachtiarica (100 mg/Kg) could ameliorate Abeta- induced ChAT reduction in the hippocampus. Also S. bachtiarica could ameliorate Abeta-induced lipid peroxidation and AChE activity increase in the hippocampus. In conclusion our study represent that S.bachtiarica methanolic extract can improve Abeta-induced memory impairment and cholinergic loss then we recommended this extract as a candidate for further investigation in treatment of AD. PMID- 26638727 TI - Body Weight Gain and Hyperphagia After Administration of SGLT-2 Inhibitor: A Case Report. AB - BACKGROUND: A detailed description is given of a case we encountered in which unexpectedly marked weight gain occurred following a treatment switch from a GLP 1 receptor agonist to an SGLT-2 inhibitor CASE REPORT: The patient, a 44-year-old man with type 2 diabetes mellitus, had gained about 10 kg in weight in the previous year. Therefore, metformin was replaced with liraglutide to obtain reduction of body weight. Although the patient lost about 8 kg (7%), during the 18-month period on the medication, the weight loss stabilized; therefore, the treatment was again switched to tofogliflozin to obtain further reduction of body weight. However, the patient reported increasing hunger and an exaggerated appetite from week 3 onward after the start of tofogliflozin, and gained about 9 kg in weight within 2 weeks, associated with a tendency towards increased HbA1c; therefore, tofogliflozin was discontinued. Immediate reinstitution of liraglutide resulted in reduction of the increased appetite, weight, and HbA1c level. CONCLUSIONS: Caution should be exercised against hyperphagia and weight gain due to hunger that may occur following discontinuation of a GLP-1 receptor agonist and/or initiation of an SGLT-2 inhibitor. PMID- 26638728 TI - The Effect of Body Mass on Eccentric Knee-Flexor Strength Assessed With an Instrumented Nordic Hamstring Device (Nordbord) in Football Players. AB - PURPOSE: To examine the effect of body mass (BM) on eccentric knee-flexor strength using the Nordbord and offer simple guidelines to control for the effect of BM on knee-flexor strength. METHODS: Data from 81 soccer players (U17, U19, U21, senior 4th French division, and professionals) and 41 Australian Football League (AFL) players were used for analysis. They all performed 1 set of 3 maximal repetitions of the bilateral Nordic hamstring exercise, with the greatest strength measure used for analysis. The main regression equation obtained from the overall sample was used to predict eccentric knee-flexor strength from a given BM (moderate TEE, 22%). Individual deviations from the BM-predicted score were used as a BM-free index of eccentric knee- flexor strength. RESULTS: There was a large (r = .55, 90% confidence limits .42;.64) correlation between eccentric knee-flexor strength and BM. Heavier and older players (professionals, 4th French division, and AFL) outperformed their lighter and younger (U17-U21) counterparts, with the soccer professionals presenting the highest absolute strength. Professional soccer players were the only ones to show strength values likely slightly greater than those expected for their BM. CONCLUSIONS: Eccentric knee-flexor strength, as assessed with the Nordbord, is largely BM-dependent. To control for this effect, practitioners may compare actual test performances with the expected strength for a given BM, using the following predictive equation: Eccentric strength (N) = 4 * BM (kg) + 26.1. Professional soccer players with specific knee-flexor-training history and enhanced neuromuscular performance may show higher than expected values. PMID- 26638729 TI - Effect of N- and T-type calcium channel blocker on proteinuria, blood pressure and kidney function in hypertensive patients: a meta-analysis. PMID- 26638730 TI - Side-stream tobacco smoke-induced airway hyperresponsiveness in early postnatal period is involved nerve growth factor. AB - Epidemiological studies have shown that children are more susceptible to adverse respiratory effects of passive smoking than adults. The goal of this study is to elucidate the possible neural mechanism induced by exposure to passive smoking during early life. Postnatal day (PD) 2 and PD 21 mice were exposed to side stream tobacco smoke (SS), a surrogate to secondhand smoke, or filtered air (FA) for 10 consecutive days. Pulmonary function, substance P (SP) airway innervation, neurotrophin gene expression in lung and nerve growth factor (NGF) release in bronchoalveolar lavage (BAL) fluid were measured at different times after the last SS or FA exposure. Exposure to SS significantly altered pulmonary function in PD2, accompanied with an enhanced SP innervation in airway. However, exposure to SS during the later developmental period (PD21) did not appear to affect pulmonary function and SP innervation of the airways. Interestingly, SS exposure in PD2 group significantly induced an increased gene expression on NGF, and decreased NGF receptor P75 in lung; parallel with high levels of NGF protein in BAL. Furthermore, pretreatment with NGF antibody significantly diminished SS induced airway hyperresponsivenss and the increased SP airway innervation in the PD2 group. These findings suggest that enhanced NGF released in the lung contributes to SS-enhanced SP tracheal innervation and airway responsiveness in early life. PMID- 26638731 TI - Be alert and stay safe. AB - In this issue of Emergency Nurse, we report on the latest NHS Protect figures on health service staff who have been assaulted ( page 6 ). PMID- 26638732 TI - Survival rate after emergency diagnosis of cancer is 'shocking'. AB - ONE QUARTER of patients diagnosed with cancer after attending a London emergency department will die within two months, latest research suggests. Study author Kathy Pritchard-Jones, chief medical officer for London Cancer, said the 'shocking figures' confirm that early diagnosis makes a huge difference to the chances of surviving cancer. PMID- 26638733 TI - Attacks on acute care staff are 'barometer' for underlying pressures. AB - NEW FIGURES show attacks on nurses and other acute care staff in England have risen in the past year. PMID- 26638734 TI - Patients' vital signs should be taken early to spot sepsis. AB - A FULL vital sign assessment should be carried out on arrival for every emergency department (ED) patient, according to the National Confidential Enquiry into Patient Outcome and Death (NCEPOD). PMID- 26638736 TI - Chancellor promises budget boost for front line services. AB - EXTRA MONEY earmarked for the NHS in England should help relieve pressures on the front line this winter, health bosses say. PMID- 26638737 TI - Longer shifts mean higher risk of injury among clinicians. AB - EMERGENCY SERVICES staff are at a greater risk of injury and illness the more hours they work, according to a US study, and the risk rises in tandem with the length of a shift. PMID- 26638738 TI - Capital system saves lives. AB - RESEARCH FROM Queen Mary University of London (QMUL) has revealed how the London trauma system is saving lives. PMID- 26638740 TI - RCN Wales honours nurse for her innovative emergency care study. AB - SENIOR NURSE at Cwm Taf University Health Board Bethan Lewis has been honoured for her work in improving services for vulnerable patients attending emergency departments (EDs). PMID- 26638741 TI - Accident-prevention initiative needed for children under five. AB - THE GOVERNMENT is being urged to implement a nationwide programme to relieve pressure on emergency departments (EDs) by preventing accidental injuries to under-fives. PMID- 26638742 TI - Better use of technology can cut emergency admissions. AB - HOSPITAL STAFF are bracing themselves for a surge in emergency admissions this winter, but a new report claims the effect of the rise could be mitigated if financial savings are made elsewhere in the NHS. PMID- 26638743 TI - Sara Morgan - The bigger picture. AB - 'TIS THE season for tipples and toasts, and festive alcohol-related visits to the emergency department (ED). PMID- 26638746 TI - Board's eye view - The weekend effect. AB - AS THE festive season approaches, the government will reassure the public that the NHS is sufficiently prepared to avoid a winter crisis. However, winter preparations coincide with a junior doctors' pay campaign and a perceived need for 'seven-day services' because of the 'weekend effect'. PMID- 26638748 TI - A different way of learning. AB - HAVE YOU ever had the feeling you know what you want to say, but just can't find the right words to say it? It's frustrating, and it plays on your mind after the situation is over. This is how dyslexia makes a lot of people feel. PMID- 26638749 TI - Noticeboard. AB - Courses, events, grants, and awards to progress your career. PMID- 26638751 TI - Alcohol misuse and self-harm. AB - Alcohol use and misuse in patients who self-harm has risen in recent years, especially in women, research reveals. PMID- 26638752 TI - Cost-effective flu prevention. AB - Extending the national flu vaccination programme to five to 16 year olds is a cost effective way to reduce disease in the general population, latest study results suggest. PMID- 26638753 TI - Measuring pain in children. AB - The aim of this Norwegian study was to understand how pain in children is measured and handled by emergency primary care physicians. PMID- 26638754 TI - Developments in emergency nursing education in Ghana. AB - Providing effective emergency nursing is challenging in low- to middle-income countries because of limited resources and an inadequate infrastructure. The role of the emergency nurse is growing throughout sub-Saharan Africa and this will help decrease the burden of acute illness and trauma on both the people and the economies in the area. However, there is a gap in education for emergency nurses in this part of the world which needs to be addressed. This article describes an emergency nursing degree programme in Ghana which was developed in collaboration with a university in the United States and one in Ghana. It also outlines the development and content of the programme and discusses its success and challenges. PMID- 26638755 TI - Diagnosing and treating cannabinoid hyperemesis. AB - Cannabinoid hyperemesis is a newly emerging syndrome that manifests as intractable nausea and vomiting in people who regularly smoke cannabis. The signs and symptoms are relieved by bathing in hot water and by stopping smoking cannabis but are unresponsive to antiemetics. This article briefly examines the possible causes and clinical presentation of the condition and uses a case study to describe the management of patients. PMID- 26638756 TI - Management of acute heart failure in the emergency department. AB - Acute heart failure (AHF) is a leading cause of hospital admission in the UK and is associated with significant mortality. The National Institute for Health and Care Excellence ( 2014 ) has published guidelines for the management of AHF but, after a clinical event in which a patient's management differed from that recommended in the guidelines occurred in the author's emergency department, he conducted a critical analysis of them. This article provides a case study of the clinical event, reviews the treatment methods adopted and explores the rationale for taking a different approach from that recommended in the guidelines. The evidence base for the use of diuretics, nitrates and non-invasive ventilation in the management of patients with AHF is also appraised. PMID- 26638757 TI - An emerging star. AB - AN EYE for detail landed Judy Coyle the moniker 'Eagle Eye' and won her a prestigious prize. Named Scottish Clinical Research Nurse of the Year 2015, Ms Coyle has been rewarded for 20 years of pioneering work in clinical research and for her contribution to the Royal Infirmary of Edinburgh's (RIE) emergency department (ED). PMID- 26638759 TI - Subgroup differences in the lexical tone mismatch negativity (MMN) among Mandarin speakers with congenital amusia. AB - The association/dissociation of pitch processing between music and language is a long lasting debate. We examined this music-language relationship by investigating to what extent pitch deficits in these two domains were dissociable. We focused on a special neurodevelopmental pitch disorder - congenital amusia, which primarily affects musical pitch processing. Recent research has also revealed lexical tone deficits in speech among amusics. Approximately one-third of Mandarin amusics exhibits behavioural difficulties in lexical tone perception, which is known as tone agnosia. Using mismatch negativities (MMNs), our current work probed lexical tone encoding at the pre attentive level among the Mandarin amusics with (tone agnosics) and without (pure amusics) behavioural lexical tone deficits compared with age- and IQ-matched controls. Relative to the controls and the pure amusics, the tone agnosics exhibited reduced MMNs specifically in response to lexical tone changes. Their tone-consonant MMNs were intact and similar to those of the other two groups. Moreover, the tone MMN reduction over the left hemisphere was tightly linked to behavioural insensitivity to lexical tone changes. The current study thus provides the first psychophysiological evidence of subgroup differences in lexical tone processing among Mandarin amusics and links amusics' behavioural tone deficits to impaired pre-attentive tone processing. Despite the overall music pitch deficits, the subgroup differences in lexical tone processing in Mandarin-speaking amusics suggest dissociation of pitch deficits between music and speech. PMID- 26638758 TI - Iron-overload injury and cardiomyopathy in acquired and genetic models is attenuated by resveratrol therapy. AB - Iron-overload cardiomyopathy is a prevalent cause of heart failure on a world wide basis and is a major cause of mortality and morbidity in patients with secondary iron-overload and genetic hemochromatosis. We investigated the therapeutic effects of resveratrol in acquired and genetic models of iron overload cardiomyopathy. Murine iron-overload models showed cardiac iron overload, increased oxidative stress, altered Ca(2+) homeostasis and myocardial fibrosis resulting in heart disease. Iron-overload increased nuclear and acetylated levels of FOXO1 with corresponding inverse changes in SIRT1 levels in the heart corrected by resveratrol therapy. Resveratrol, reduced the pathological remodeling and improved cardiac function in murine models of acquired and genetic iron-overload at varying stages of iron-overload. Echocardiography and hemodynamic analysis revealed a complete normalization of iron-overload mediated diastolic and systolic dysfunction in response to resveratrol therapy. Myocardial SERCA2a levels were reduced in iron-overloaded hearts and resveratrol therapy restored SERCA2a levels and corrected altered Ca(2+) homeostasis. Iron-mediated pro-oxidant and pro-fibrotic effects in human and murine cardiomyocytes and cardiofibroblasts were suppressed by resveratrol which correlated with reduction in iron-induced myocardial oxidative stress and myocardial fibrosis. Resveratrol represents a clinically and economically feasible therapeutic intervention to reduce the global burden from iron-overload cardiomyopathy at early and chronic stages of iron-overload. PMID- 26638760 TI - Novel, ERP-based, concealed information detection: Combining recognition-based and feedback-evoked ERPs. AB - The present study introduced a novel variant of the concealed information test (CIT), called the feedback-CIT. By providing participants with feedbacks regarding their memory concealment performance during the CIT, we investigated the feedback-related neural activity underlying memory concealment. Participants acquired crime-relevant memories via enacting a lab crime, and were tested with the feedback-CIT while EEGs were recorded. We found that probes (e.g., crime relevant memories) elicited larger recognition-P300s than irrelevants among guilty participants. Moreover, feedback-related negativity (FRN) and feedback P300 could also discriminate probes from irrelevants among guilty participants. Both recognition- and feedback-ERPs were highly effective in distinguishing between guilty and innocent participants (recognition-P300: AUC=.73; FRN: AUC=.95; feedback-P300: AUC=.97). This study sheds new light on brain-based memory detection, such that feedback-related neural signals can be employed to detect concealed memories. PMID- 26638762 TI - Heart rate variability and cognitive processing: The autonomic response to task demands. AB - This study investigated variations in heart rate variability (HRV) as a function of cognitive demands. Participants completed an execution condition including the psychomotor vigilance task, a working memory task and a duration discrimination task. The control condition consisted of oddball versions (participants had to detect the rare event) of the tasks from the execution condition, designed to control for the effect of the task parameters (stimulus duration and stimulus rate) on HRV. The NASA-TLX questionnaire was used as a subjective measure of cognitive workload across tasks and conditions. Three major findings emerged from this study. First, HRV varied as a function of task demands (with the lowest values in the working memory task). Second, and crucially, we found similar HRV values when comparing each of the tasks with its oddball control equivalent, and a significant decrement in HRV as a function of time-on-task. Finally, the NASA TLX results showed larger cognitive workload in the execution condition than in the oddball control condition, and scores variations as a function of task. Taken together, our results suggest that HRV is highly sensitive to overall demands of sustained attention over and above the influence of other cognitive processes suggested by previous literature. In addition, our study highlights a potential dissociation between objective and subjective measures of mental workload, with important implications in applied settings. PMID- 26638763 TI - The Endocannabinoid Signaling System in the CNS: A Primer. AB - The purpose of this chapter is to provide an introduction to the mechanisms for the regulation of endocannabinoid signaling through CB1 cannabinoid receptors in the central nervous system. The processes involved in the synthesis and degradation of the two most well-studied endocannabinoids, 2-arachidonoylglycerol and N-arachidonylethanolamine are outlined along with information regarding the regulation of the proteins involved. Signaling mechanisms and pharmacology of the CB1 cannabinoid receptor are outlined, as is the paradigm of endocannabinoid/CB1 receptor regulation of neurotransmitter release. The reader is encouraged to appreciate the importance of the endocannabinoid/CB1 receptor signaling system in the regulation of synaptic activity in the brain. PMID- 26638761 TI - Blunted neural response to errors as a trait marker of melancholic depression. AB - Identification of biomarkers of vulnerability for Major Depressive Disorder is a high priority, but heterogeneity of the diagnosis can hinder research. Biomarkers of vulnerability should also be present in the absence of the diagnosis. The present study examined the magnitude of the error-related negativity (ERN), an event-related potential component following errors in a sample with remitted melancholic depression (N=17), remitted non-melancholic depression (N=33), and healthy controls (N=55). Remitted melancholic depression was uniquely characterized by a blunted ERN relative to the other two groups. Individuals with remitted non-melancholic depression did not differ from controls in the magnitude of the ERN. This was the case despite the fact that the melancholic and non melancholic groups did not differ in course or severity of their past illnesses, or in their current functioning. Results suggest that the blunted ERN may be a viable vulnerability marker for melancholia. PMID- 26638764 TI - Evidence for a Role of Adolescent Endocannabinoid Signaling in Regulating HPA Axis Stress Responsivity and Emotional Behavior Development. AB - Adolescence is a period characterized by many distinct physical, behavioral, and neural changes during the transition from child- to adulthood. In particular, adolescent neural changes often confer greater plasticity and flexibility, yet with this comes the potential for heightened vulnerability to external perturbations such as stress exposure or recreational drug use. There is substantial evidence to suggest that factors such as adolescent stress exposure have longer lasting and sometimes more deleterious effects on an organism than stress exposure during adulthood. Moreover, the adolescent neuroendocrine response to stress exposure is different from that of adults, suggesting that further maturation of the adolescent hypothalamic-pituitary-adrenal (HPA) axis is required. The endocannabinoid (eCB) system is a potential candidate underlying these age-dependent differences given that it is an important regulator of the adult HPA axis and neuronal development. Therefore, this review will focus on (1) the functionality of the adolescent HPA axis, (2) eCB regulation of the adult HPA axis, (3) dynamic changes in eCB signaling during the adolescent period, (4) the effects of adolescent stress exposure on the eCB system, and (5) modulation of HPA axis activity and emotional behavior by adolescent cannabinoid treatment. Collectively, the emerging picture suggests that the eCB system mediates interactions between HPA axis stress responsivity, emotionality, and maturational stage. These findings may be particularly relevant to our understanding of the development of affective disorders and the risks of adolescent cannabis consumption on emotional health and stress responsivity. PMID- 26638765 TI - The Endocannabinoid System and Its Role in Regulating the Intrinsic Neural Circuitry of the Gastrointestinal Tract. AB - Endocannabinoids are important neuromodulators in the central nervous system. They regulate central transmission through pre- and postsynaptic actions on neurons and indirectly through effects on glial cells. Cannabinoids (CBs) also regulate neurotransmission in the enteric nervous system (ENS) of the gastrointestinal (GI) tract. The ENS consists of intrinsic primary afferent neurons, interneurons, and motor neurons arranged in two ganglionated plexuses which control all the functions of the gut. Increasing evidence suggests that endocannabinoids are potent neuromodulators in the ENS. In this review, we will highlight key observations on the localization of CB receptors and molecules involved in the synthesis and degradation of endocannabinoids in the ENS. We will discuss endocannabinoid signaling mechanisms, endocannabinoid tone and concepts of CB receptor metaplasticity in the ENS. We will also touch on some examples of enteric neural signaling in relation neuromuscular, secretomotor, and enteroendocrine transmission in the ENS. Finally, we will briefly discuss some key future directions. PMID- 26638766 TI - Endocannabinoid Mechanisms Influencing Nausea. AB - One of the first recognized medical uses of Delta(9)-tetrahydrocannabinol was treatment of chemotherapy-induced nausea and vomiting. Although vomiting is well controlled with the currently available non-cannabinoid antiemetics, nausea continues to be a distressing side effect of chemotherapy and other disorders. Indeed, when nausea becomes conditionally elicited by the cues associated with chemotherapy treatment, known as anticipatory nausea (AN), currently available antiemetics are largely ineffective. Considerable evidence demonstrates that the endocannabinoid system regulates nausea in humans and other animals. In this review, we describe recent evidence suggesting that cannabinoids and manipulations that enhance the functioning of the natural endocannabinoid system are promising treatments for both acute nausea and AN. PMID- 26638767 TI - Endocannabinoid Regulation of Neuroendocrine Systems. AB - The hypothalamus is a part of the brain that is critical for sustaining life through its homeostatic control and integrative regulation of the autonomic nervous system and neuroendocrine systems. Neuroendocrine function in mammals is mediated mainly through the control of pituitary hormone secretion by diverse neuroendocrine cell groups in the hypothalamus. Cannabinoid receptors are expressed throughout the hypothalamus, and endocannabinoids have been found to exert pronounced regulatory effects on neuroendocrine function via modulation of the outputs of several neuroendocrine systems. Here, we review the physiological regulation of neuroendocrine function by endocannabinoids, focusing on the role of endocannabinoids in the neuroendocrine regulation of the stress response, food intake, fluid homeostasis, and reproductive function. Cannabis sativa (marijuana) has a long history of recreational and/or medicinal use dating back to ancient times. It was used as an analgesic, anesthetic, and antianxiety herb as early as 2600 B.C. The hedonic, anxiolytic, and mood-elevating properties of cannabis have also been cited in ancient records from different cultures. However, it was not until 1964 that the psychoactive constituent of cannabis, Delta(9) tetrahydrocannabinol, was isolated and its chemical structure determined (Gaoni & Mechoulam, 1964). PMID- 26638768 TI - The Role of the Brain's Endocannabinoid System in Pain and Its Modulation by Stress. AB - Stress has a complex, bidirectional modulatory influence on pain. Stress may either reduce (stress-induced analgesia) or exacerbate (stress-induced hyperalgesia) pain depending on the nature, duration, and intensity of the stressor. The endogenous cannabinoid (endocannabinoid) system is present throughout the neuroanatomical pathways that mediate and modulate responses to painful stimuli. The specific role of the endocannabinoid system in the brain in pain and the modulation of pain by stress is reviewed herein. We first provide a brief overview of the endocannabinoid system, followed by a review of the evidence that the brain's endocannabinoid system modulates pain. We provide a comprehensive evaluation of the role of the endocannabinoid system supraspinally, and particularly in the rostral ventromedial medulla, periaqueductal gray, amygdala, and prefrontal cortex, in pain, stress-induced analgesia, and stress induced hyperalgesia. Increased understanding of endocannabinoid-mediated regulation of pain and its modulation by stress will inform the development of novel therapeutic approaches for pain and its comorbidity with stress-related disorders. PMID- 26638769 TI - Endocannabinoid Signaling in Motivation, Reward, and Addiction: Influences on Mesocorticolimbic Dopamine Function. AB - Evidence suggests that the endocannabinoid system has been conserved in the animal kingdom for 500 million years, and this system influences many critical behavioral processes including associative learning, reward signaling, goal directed behavior, motor skill learning, and action-habit transformation. Additionally, the neurotransmitter dopamine has long been recognized to play a critical role in the processing of natural rewards, as well as of motivation that regulates approach and avoidance behavior. This motivational role of dopamine neurons is also based upon the evidence provided by several studies investigating disorders of dopamine pathways such as drug addiction and Parkinson's disease. From an evolutionary point of view, individuals engage in behaviors aimed at maximizing and minimizing positive and aversive consequences, respectively. Accordingly, those with the greatest fitness have a better potential to survival. Hence, deviations from fitness can be viewed as a part of the evolutionary process by means of natural selection. Given the long evolutionary history of both the endocannabinoid and dopaminergic systems, it is plausible that they must serve as fundamental and basic modulators of physiological functions and needs. Notably, endocannabinoids regulate dopamine neuronal activity and its influence on behavioral output. The goal of this chapter is to examine the endocannabinoid influence on dopamine signaling specifically related to (i) those behavioral processes that allow us to successfully adapt to ever-changing environments (i.e., reward signaling and motivational processes) and (ii) derangements from behavioral flexibility that underpin drug addiction. PMID- 26638770 TI - Preface. PMID- 26638771 TI - Genetic diversity and antimicrobial susceptibility of Nocardia species among patients with nocardiosis. AB - The aim of this multicenter study was to determine the genetic diversity and antibiotic susceptibility of clinically isolated Nocardia species. One hundred twenty-seven patients with nocardiosis were randomly selected from 5 provinces of Iran. Molecular diagnosis of Nocardia species was performed using multilocus sequence analysis of gyrase B of the beta subunit of DNA topoisomerase (gyrB), and 16S rRNA and subunit A of SecA preproteintranslocase (secA1). Antimicrobial susceptibility testing was performed following the Clinical and Laboratory Standards Institute recommendations. Thirty-five N. cyriacigeorgica, 30 N. asteroides, 26 N. farcinica, 12 N. otitidiscaviarum, and 10 N. abscessus cultures were studied. All isolates were susceptible to linezolid. All isolates of N. cyriacigeorgica, N. asteroides, N. abscessus, and N. otitidiscaviarum were susceptible to trimethoprim-sulfamethoxazole, while 8% of N. farcinica isolates were resistant to this drug. All N. otitidiscaviarum isolates were highly resistant to imipenem, but N. cyriacigeorgica, N. asteroides, N. farcinica, and N. abscessus were only moderate resistant. The susceptibility patterns vary with different species of Nocardia. Resistance to trimethoprim-sulfamethoxazole in Iran is low and this drug should be first line therapy, unless drug susceptibility testing shows resistance. Linezolid also covers Nocardia well and could be a second line agent. PMID- 26638772 TI - Qualitative assessment of bone density at the distal articulating surface of the third metacarpal in Thoroughbred racehorses with and without condylar fracture. AB - REASONS FOR PERFORMING STUDY: Changes in subchondral bone density, induced by the repetitive cyclical loading of exercise, may potentiate fatigue damage and the risk of fracture. OBJECTIVES: To use computed tomography (CT) to characterise bone density patterns at the articular surface of the third metacarpal bone in racehorses with and without lateral condylar fractures. STUDY DESIGN: Case control METHODS: Computed tomographic images of the distal articulating surface of the third metacarpal bone were obtained from Thoroughbred racehorses subjected to euthanasia in the UK. Third metacarpal bones were divided into 3 groups based on lateral condyle status; fractured (FX, n = 42), nonfractured contralateral condyle (NFX, n = 42) and control condyles from horses subjected to euthanasia for reasons unrelated to the third metacarpal bone (control, n = 94). Colour CT images were generated whereby each colour represented a range of pixel values and thus a relative range of bone density. A density value was calculated qualitatively by estimating the percentage of each colour within a specific region. Subchondral bone density was assessed in 6 regions from dorsal to palmar and 1 mm medial and lateral to the centre of the lateral parasagittal groove in NFX and control condyles and 1 mm medial and lateral to the fracture in FX condyles. RESULTS: Bone density was significantly higher in the FX and NFX condyles compared with control condyles for all 6 regions. A significantly higher bone density was observed in FX condyles relative to NFX condyles in the lateral middle and lateral palmar regions. Fractured condyles had increased heterogeneity in density among the 6 regions of interest compared with control and NFX condyles. CONCLUSIONS: Adjacent to the fracture, a focal increase in bone density and increased heterogeneity of density were characteristic of limbs with lateral condylar fractures compared with control and NFX condyles. These differences may represent pathological changes in bone density that increase the risk for lateral condylar fractures in racehorses. PMID- 26638774 TI - RNA voyeurism: A coming of age story. AB - Studies of gene expression are typically carried out by a molecular analysis that averages entire populations of cells in culture, or in a tissue. This approach cannot detect cell to cell variability, or collect subcellular information, such as spatial distribution. At the transcriptional level, it is evident that even a robust transcriptional response in ensemble measurements is not uniform among all cells in a population. At the post-transcriptional level, mRNAs and proteins can be trafficked to specific sub-cellular compartments allowing spatiotemporal regulation of gene expression, but these critical spatial relationships are lost with common molecular biology approaches. Through direct visualization of mRNA during the biogenesis process and analyzing the distribution of single mRNA molecules in cells we have gained a deeper understanding of gene expression at many levels. Recent technical advances have made these types of analysis more accessible than ever. The utility of this approach toward studying transcriptional events is underscored throughout many of the articles within this volume. Techniques such as fluorescent in situ hybridization (FISH) are being applied to single molecule studies in fixed cells with far-reaching results, but they are limited in their ability to provide information about the dynamic nature of mRNA in vivo, so methodology to visualize single mRNA molecules in living cells has become desirable. In this article, we will discuss the state-of-the-art tagging systems used for real-time imaging of mRNAs that have been developed. We will present an overview of how these approaches have been applied to impacting our view of gene expression. PMID- 26638773 TI - Cryo electron microscopy to determine the structure of macromolecular complexes. AB - Cryo-electron microscopy (cryo-EM) is a structural molecular and cellular biology technique that has experienced major advances in recent years. Technological developments in image recording as well as in processing software make it possible to obtain three-dimensional reconstructions of macromolecular assemblies at near-atomic resolution that were formerly obtained only by X-ray crystallography or NMR spectroscopy. In parallel, cryo-electron tomography has also benefitted from these technological advances, so that visualization of irregular complexes, organelles or whole cells with their molecular machines in situ has reached subnanometre resolution. Cryo-EM can therefore address a broad range of biological questions. The aim of this review is to provide a brief overview of the principles and current state of the cryo-EM field. PMID- 26638775 TI - Paralogue Interference Affects the Dynamics after Gene Duplication. AB - Proteins tend to form homomeric complexes of identical subunits, which act as functional units. By definition, the subunits are encoded from a single genetic locus. When such a gene is duplicated, the gene products are suggested initially to cross-interact when coexpressed, thus resulting in the phenomenon of paralogue interference. In this opinion article, we explore how paralogue interference can shape the fate of a duplicated gene. One important outcome is a prolonged time window in which both copies remain under selection increasing the chance to accumulate mutations and to develop new properties. Thereby, paralogue interference can mediate the coevolution of duplicates and here we illustrate the potential of this phenomenon in light of recent new studies. PMID- 26638777 TI - Epilepsy After Febrile Seizures: Twins Suggest Genetic Influence. AB - BACKGROUND: A history of complex febrile seizures can increase the risk of epilepsy, but the role of genetic factors is unclear. This analysis evaluated the relationship between febrile seizures and epilepsy. METHODS: Information on the history of seizures was obtained by a questionnaire from twin pairs in the Mid Atlantic, Danish, and Norwegian Twin Registries. The information was verified using medical records and detailed clinical and family interviews. The initial study evaluated the genetic epidemiology of febrile seizures in this population. Further information was analyzed and used to evaluate genetic associations of different febrile seizure subtypes. RESULTS: Histories of febrile seizures were validated in 1051 twins in 900 pairs. The febrile seizure type was classified as simple, complex, or febrile status epilepticus. There were 61% simple, 12% complex, and 7% febrile status epilepticus. There were 78 twins who developed epilepsy. The highest rate of epilepsy (22.2%) occurred in the febrile status epilepticus group. Concordance was highest in simple group. CONCLUSION: A twin with febrile status epilepticus is at the highest risk of developing epilepsy, but simple febrile seizures gave the highest risk for the unaffected twin to develop seizures or other neurological issues. These results are consistent with previous findings. There is a subgroup of febrile seizures that can be associated with long-term consequences. This subgroup can be associated with a significant financial and emotional burden. It is currently not possible to accurately identify which children will develop recurrent febrile seizures, epilepsy, or neuropsychological comorbidities. PMID- 26638778 TI - MMP2-Targeting and Redox-Responsive PEGylated Chlorin e6 Nanoparticles for Cancer Near-Infrared Imaging and Photodynamic Therapy. AB - A unique matrix metalloproteinase 2-targeted photosensitizer delivery platform was developed in this study for tumor-targeting imaging and photodynamic therapy. The model photosensitizer therapeutic agent chlorin e6 (Ce6) was first covalently conjugated with matrix metalloproteinase 2-cleavable polypeptide and then modified with polyethylene glycol via a redox-responsive cleavable disulfide linker. The resultant matrix metalloproteinase 2-cleavable polypeptide modified PEGylated Ce6 (PEG-SS-Ce6-MMP2) nanoparticles, which formed via self-assembly, were observed to be monodisperse and significantly stable in aqueous solution. In addition, owing to their cellular redox-responsiveness at the cleavable disulfide linker, the PEG-SS-Ce6-MMP2 nanoparticles were able to release Ce6 rapidly. Despite displaying enhanced intracellular internalization, the synthesized PEG-SS Ce6-MMP2 nanoparticles did not compromise their phototoxic effects toward A549 cancer cells when compared with free Ce6 and PEGylated Ce6 nanoparticles. In vivo experiments further revealed that, in contrast with the free Ce6 or with the PEGylated Ce6 nanoparticles, the PEG-SS-Ce6-MMP2 nanoparticles showed a remarkable increase in tumor-targeting ability and a significantly improved photodynamic therapeutic efficiency in A549 tumor-bearing mice. These results suggest that the PEG-SS-Ce6-MMP2 nanoparticles hold great potential for tumor targeting imaging and photodynamic therapy. PMID- 26638776 TI - Whole-genome sequencing reveals activation-induced cytidine deaminase signatures during indolent chronic lymphocytic leukaemia evolution. AB - Patients with chromosome 13q deletion or normal cytogenetics represent the majority of chronic lymphocytic leukaemia (CLL) cases, yet have relatively few driver mutations. To better understand their genomic landscape, here we perform whole-genome sequencing on a cohort of patients enriched with these cytogenetic characteristics. Mutations in known CLL drivers are seen in only 33% of this cohort, and associated with normal cytogenetics and unmutated IGHV. The most commonly mutated gene in our cohort, IGLL5, shows a mutational pattern suggestive of activation-induced cytidine deaminase (AID) activity. Unsupervised analysis of mutational signatures demonstrates the activities of canonical AID (c-AID), leading to clustered mutations near active transcriptional start sites; non canonical AID (nc-AID), leading to genome-wide non-clustered mutations, and an ageing signature responsible for most mutations. Using mutation clonality to infer time of onset, we find that while ageing and c-AID activities are ongoing, nc-AID-associated mutations likely occur earlier in tumour evolution. PMID- 26638779 TI - Participation as a leader in immersion weight loss treatment: a 1-year follow-up study. AB - Non-overweight individuals may follow aggressive weight management approaches alongside overweight/obese friends or family members; thus, research has begun to evaluate subsequent effects among non-overweight populations. A prior study evaluated the short-term effects of an immersion weight loss programme on healthy young adult staff leaders. Results indicated that participation seemed to benefit, not harm, the young adults. The current investigation examined 1-year eating disorder and weight trajectories in this sample. The total sample (N = 244) consisted of staff leaders (44.3%) and demographically similar comparison participants who completed eating disorder and weight assessments across four time points: baseline, end of summer, 6-week follow-up and 1-year follow-up. Forty-seven per cent of the original sample responded to all time points (staff leaders n = 60; comparison n = 55). Over the course of 1 year, risk trajectories did not differ between groups. Staff leaders did not report significant changes in body mass index, suggesting that they maintained healthy weight over the course of 1 year. Participation as an immersion weight loss programme leader appeared to be protective against weight gain, without increasing eating disorder risk, for healthy young adults. This provides further support for using weight management interventions across a wide range of individuals. PMID- 26638781 TI - [The molecular pathology of pancreatic cancers]. PMID- 26638782 TI - [Surgical oncology for pancreatic cancer; future perspective]. PMID- 26638780 TI - mRNA Levels of Imprinted Genes in Bovine In Vivo Oocytes, Embryos and Cross Species Comparisons with Humans, Mice and Pigs. AB - Twenty-six imprinted genes were quantified in bovine in vivo produced oocytes and embryos using RNA-seq. Eighteen were detectable and their transcriptional patterns were: largely decreased (MEST and PLAGL1); first decreased and then increased (CDKN1C and IGF2R); peaked at a specific stage (PHLDA2, SGCE, PEG10, PEG3, GNAS, MEG3, DGAT1, ASCL2, NNAT, and NAP1L5); or constantly low (DIRAS3, IGF2, H19 and RTL1). These patterns reflect mRNAs that are primarily degraded, important at a specific stage, or only required at low quantities. The mRNAs for several genes were surprisingly abundant. For instance, transcripts for the maternally imprinted MEST and PLAGL1, were high in oocytes and could only be expressed from the maternal allele suggesting that their genomic imprints were not yet established/recognized. Although the mRNAs detected here were likely biallelically transcribed before the establishment of imprinted expression, the levels of mRNA during these critical stages of development have important functional consequences. Lastly, we compared these genes to their counterparts in mice, humans and pigs. Apart from previously known differences in the imprinting status, the mRNA levels were different among these four species. The data presented here provide a solid reference for expression profiles of imprinted genes in embryos produced using assisted reproductive biotechnologies. PMID- 26638783 TI - [The progress of chemotherapy for advanced pancreatic cancer]. PMID- 26638784 TI - [Chemoradiotherapy for pancreatic cancer]. PMID- 26638785 TI - [mFOLFOX6 chemotherapy enabling curative resection in a patient with locally advanced duodenal adenocarcinoma and lymph node metastases]. AB - A 65-year-old man was referred to our hospital with a primary complaint of unintentional weight loss. Upper gastrointestinal endoscopy showed a large duodenal tumor, and computed tomography (CT) showed tumor invasion of the pancreatic head, associated with lymph node swelling around the tumor and abdominal aorta. After 4 courses of chemotherapy with 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6), follow-up upper gastrointestinal endoscopy and biopsy showed no evidence of a duodenal tumor. However, follow-up CT showed persistent lymph node swelling near the superior mesenteric artery. The patient therefore underwent pancreaticoduodenectomy with curative intent. At 18 months after the surgery, there were no findings suggestive of tumor recurrence. PMID- 26638786 TI - [A case of stomal variceal hemorrhage successfully treated using sclerotherapy]. AB - A 72-year-old man underwent transverse colostomy for sigmoid colon cancer with multiple liver metastases. Subsequent chemotherapy effectively reduced liver metastases, and sigmoidectomy was performed. However, the liver metastases recurred and the patient developed stomal varices due to portal hypertension. To control the resulting massive variceal bleeding, we performed percutaneous sclerotherapy through a varicose vein, which was puncutured directly under ultrasound (US) guidance. Although the patient recovered from variceal bleeding, he eventually died due to the primary cancer. PMID- 26638787 TI - [A case of gastric arteriovenous fistula causing intraperitoneal hemorrhage]. AB - We report abdominal bleeding caused by an arteriovenous fistula (AVF) of the gastroepiploic artery. A 20-year-old man visited our hospital with epigastric pain and hypovolemic shock. Contrast-enhanced abdominal computed tomography revealed a high-density region within a huge low-density mass. Angiography revealed AVF of the gastroepiploic artery. Therefore, we performed transcatheter arterial embolization using n-butyl-2-cyanoacrylate (Histoacryl((r))) to control the intraperitoneal hemorrhage. PMID- 26638788 TI - [A case of acute progressive primary inflammatory fibrosarcoma of the retroperitoneum]. AB - A 70-year-old man with liver cirrhosis presented to us with abdominal distention. Computed tomography revealed a giant retroperitoneal tumor. Examination of a biopsy specimen led to a diagnosis of primary inflammatory fibrosarcoma of the retroperitoneum. However, disease progression was rapid, and the patient died 6 weeks after the onset of the disease. Autopsy revealed that the tumor arose from the retroperitoneum and infiltrated the omentum and mesentery. Prognosis of inflammatory fibrosarcoma is poor if resection is incomplete. Establishment of treatment for unresectable cases is necessary. PMID- 26638789 TI - [A case of hepatic cryptococcosis complicated by adult T-cell leukemia]. AB - A woman in her 80s was admitted to our hospital on account of jaundice, abnormal liver function tests, and leukocytosis. She was diagnosed with adult T-cell leukemia on the basis of the presence of anti-human T-cell leukemia virus type I (HTLV-I) and the results of flow cytometric analysis of peripheral blood. She also showed lung consolidation and cavitation, and a sputum smear and culture revealed cryptococcal infection. Therefore, she was diagnosed with pulmonary cryptococcosis. However, the cause of the abnormal liver function tests and jaundice remained unclear, and the patient subsequently died. On autopsy, multiple granulomas were observed throughout the liver, consistent with cryptococcal bodies. Herein we report this rare case of hepatic cryptococcosis with predominant hepatobiliary complaints. PMID- 26638790 TI - [Recurrent hepatocellular carcinoma and adrenal metastasis without intrahepatic metastasis detected 22 years after hepatic resection: a case report]. AB - A 55-year-old man presented with general malaise in May 2012. On reviewing his clinical records in 1989, we found that he had a hepatocellular carcinoma (HCC) in the left lobe, for which he had undergone left lobectomy in November 1989. However, there was no record of any follow-up examination from 1996 to 2011. Computed tomography in May 2012 revealed a right adrenal gland tumor measuring 8.5*6.5cm, which we treated by right adrenalectomy. Postoperative pathological examination showed this to be a metastasis of poorly differentiated HCC. To the best of our knowledge, no previous study has reported HCC recurrence such a long duration after HCC resection. PMID- 26638791 TI - A synthetic modular approach for modeling the role of the 3D microenvironment in tumor progression. AB - Here, we demonstrate the flexibility of peptide-functionalized poly(ethylene glycol) (PEG) hydrogels for modeling tumor progression. The PEG hydrogels were formed using thiol-ene chemistry to incorporate a matrix metalloproteinase degradable peptide crosslinker (KKCGGPQG?IWGQGCKK) permissive to proteolytic remodeling and the adhesive CRGDS peptide ligand. Tumor cell function was investigated by culturing WM239A melanoma cells on PEG hydrogel surfaces or encapsulating cells within the hydrogels, and either as monocultures or indirect (non-contact) cocultures with primary human dermal fibroblasts (hDFs). WM239A cluster size and proliferation rate depended on the shear elastic modulus for cells cultured on PEG hydrogels, while growth was inhibited by coculture with hDFs regardless of hydrogel stiffness. Cluster size was also suppressed by hDFs for WM239A cells encapsulated in PEG hydrogels, which is consistent with cells seeded on top of hydrogels. Notably, encapsulated WM239A clusters and single cells adopted invasive phenotypes in the hDF coculture model, which included single cell and collective migration modes that resembled invasion from human melanoma patient-derived xenograft tumors encapsulated in equivalent PEG hydrogels. Our combined results demonstrate that peptide-functionalized PEG hydrogels provide a useful platform for investigating aspects of tumor progression in 2D and 3D microenvironments, including single cell migration, cluster growth and invasion. PMID- 26638793 TI - Adiponectin: An Endothelium-Derived Vasoprotective Factor? AB - Adipose tissue (AT) is now widely accepted as a key secretary organ, as well as an energy storage depot. It secretes a series of cytokines, hormones and bioactive molecules: adipokines. Adiponectin is an abundant systemic adipokine that uniquely is reduced in obesity and increases on weight loss, is anti inflammatory, promotes insulin sensitivity and affords cardiometabolic protection. It was considered a true adipokine, in that it is exclusively generated by the adipocytes of the adipose tissue. However, recent evidence points to it being secreted by a range of other organs. This review summarizes the non-adipose sources of adiponectin especially that derived from the endothelium, its vasoprotective role and intracellular signalling pathways. Endothelium derived adiponectin may potentially be a new target for clinical intervention in cardiovascular disease. PMID- 26638792 TI - Do antioxidant supplements interfere with skeletal muscle adaptation to exercise training? AB - A popular belief is that reactive oxygen species (ROS) and reactive nitrogen species (RNS) produced during exercise by the mitochondria and other subcellular compartments ubiquitously cause skeletal muscle damage, fatigue and impair recovery. However, the importance of ROS and RNS as signals in the cellular adaptation process to stress is now evident. In an effort to combat the perceived deleterious effects of ROS and RNS it has become common practice for active individuals to ingest supplements with antioxidant properties, but interfering with ROS/RNS signalling in skeletal muscle during acute exercise may blunt favourable adaptation. There is building evidence that antioxidant supplementation can attenuate endurance training-induced and ROS/RNS-mediated enhancements in antioxidant capacity, mitochondrial biogenesis, cellular defence mechanisms and insulin sensitivity. However, this is not a universal finding, potentially indicating that there is redundancy in the mechanisms controlling skeletal muscle adaptation to exercise, meaning that in some circumstances the negative impact of antioxidants on acute exercise response can be overcome by training. Antioxidant supplementation has been more consistently reported to have deleterious effects on the response to overload stress and high-intensity training, suggesting that remodelling of skeletal muscle following resistance and high-intensity exercise is more dependent on ROS/RNS signalling. Importantly there is no convincing evidence to suggest that antioxidant supplementation enhances exercise-training adaptions. Overall, ROS/RNS are likely to exhibit a non-linear (hormetic) pattern on exercise adaptations, where physiological doses are beneficial and high exposure (which would seldom be achieved during normal exercise training) may be detrimental. PMID- 26638794 TI - Vascular Endothelium and Hypovolemic Shock. AB - Endothelium is a site of metabolic activity and has a major reservoir of multipotent stem cells. It plays a vital role in the vascular physiological, pathophysiological and reparative processes. Endothelial functions are significantly altered following hypovolemic shock due to ischemia of the endothelial cells and by reperfusion due to resuscitation with fluids. Activation of endothelial cells leads to release of vasoactive substances (nitric oxide, endothelin, platelet activating factor, prostacyclin, mitochondrial N-formyl peptide), mediators of inflammation (tumor necrosis factor alpha, interleukins, interferons) and thrombosis. Endothelial cell apoptosis is induced following hypovolemic shock due to deprivation of oxygen required by endothelial cell mitochondria; this lack of oxygen initiates an increase in mitochondrial reactive oxygen species (ROS) and release of apoptogenic proteins. The glycocalyx structure of endothelium is compromised which causes an impairment of the protective endothelial barrier resulting in increased permeability and leakage of fluids in to the tissue causing edema. Growth factors such as angiopoetins and vascular endothelial growth factors also contribute towards pathophysiology of hypovolemic shock. Endothelium is extremely active with numerous functions, understanding these functions will provide novel targets to design therapeutic agents for the acute management of hypovolemic shock. Hypovolemic shock also occurs in conditions such as dengue shock syndrome and Ebola hemorrhagic fever, defining the role of endothelium in the pathophysiology of these conditions will provide greater insight regarding the functions of endothelial cells in vascular regulation. PMID- 26638795 TI - Is Erectile Dysfunction an Example of Abnormal Endothelial Function? AB - Erectile dysfunction (ED) affects approximately half of men during middle age. Erectile dysfunction is often an early symptom of systemic vascular disease, which may precipitate significant cardiac events. The pathophysiology of ED and cardiovascular disease is closely linked. Endothelial dysfunction occurs at an early stage in ED and cardiovascular disease (CVD). In normal conditions, nitric oxide dependent and independent mechanisms regulate penile vascular tone ensuring an appropriate balance of vasoconstriction and vasodilatation. A normal endothelium is responsible for mediating the effect of pro-erectile mediators derived from the endothelium and is critical in normal erectile function. Endothelial dysfunction disrupts the homeostatic mechanisms responsible for regulation of smooth muscle contraction and penile vascular tone. Reduced bioavailability of nitric oxide (NO) occurs as a response to endothelial damage. Phosphodiesterases further degrade levels of cyclic guanosine monophosphate (cGMP) and impair smooth muscle relaxation and erectile function. A number of endothelium derived NO independent mediators of erectile function have been described and are known to contribute to ED in the presence of endothelial damage. This review provides an up to date analysis of the role of the endothelium in ED describing the pathways involved and how these represent current and potential therapeutic targets. PMID- 26638796 TI - The Emerging Role of Arginase in Endothelial Dysfunction in Diabetes. AB - Diabetes mellitus is a major risk factor for the development of cardiovascular disease due to increased vascular inflammatory and oxidative stress favouring atherogenesis. Endothelial dysfunction has received increasing attention as a potential contributor to the pathogenesis of vascular disease in diabetes mellitus. Although the underlying cause of endothelial dysfunction is multifactorial, a key factor is impairment of the bioavailability of nitric oxide (NO). Emerging evidence suggest that upregulation of arginase is of central importance for reduced NO bioavailability due to competition for the substrate L arginine between arginase and the endothelial form of NO synthase. Arginase is also associated with increased oxidative stress, further impairing NO bioavailability. Upregulation of arginase has been suggested to be a key factor driving endothelial dysfunction in diabetes. The present review describes the regulation of arginase in relation to diabetes and arginase as a potential therapeutic target to improve endothelial function in experimental models and the clinical setting of diabetes mellitus. PMID- 26638797 TI - Valve Endothelial Cells - Not Just Any Old Endothelial Cells. AB - Heart valves are sophisticated cellularised structures that perform a complex series of dynamic functions during each cardiac cycle. The endothelial cells (ECs) that cover both surfaces of the valve, play an important role in ensuring that the valve functions are in an optimal manner. They are also postulated to protect the valve against calcific disease. These functions include a role in embryonic development, regulation of cellular attachment, modulation of the mechanical properties of the valve, prevention of valve interstitial cell differentiation into pathological cell phenotypes and regulation of the valve extracellular matrix. It is believed that valve endothelial cells (VECs) are a specialised population of ECs which have a distinctive range of properties not seen elsewhere in the vasculature. This allows them to function in a unique haemodynamic environment. Each surface of the valve is exposed to vastly different patterns of blood flow and levels of shear stress, resulting in further specialisation of the VECs on the aortic and ventricular surfaces of the valve. This review will examine the role of VECs on either surface of the valve and demonstrate how they contribute to the function and durability of heart valves. PMID- 26638798 TI - Regulation of Vascular Endothelium Inflammatory Signalling by Shear Stress. AB - The vascular endothelium plays a pivotal role in regulating vascular homeostasis. Blood flow exerts several mechanical forces on the luminal surface of the Endothelial Cell (EC) including pressure, circumferential stretch, and shear stress. It is widely believed that shear stress plays a central role in regulating EC inflammatory responses and the pathogenesis of atherosclerosis. High shear stress can induce an antiinflammatory status in EC, which is partially mediated by the production of proteins and transcription factors able to suppress different proinflammatory signalling pathways. In this review, we summarise the available evidence regarding the effect of shear stress on vascular EC and smooth muscle cells, the regulation of MAPK and NF-kappaB including the production of different negative regulators of inflammation such as MKP-1 and NRF2, and the production of microRNAs. We also discuss the possible links between shear stress and the development of atherosclerosis. PMID- 26638799 TI - Purinergic Signalling and Endothelium. AB - Purinergic signalling is involved in the control of vascular tone and remodelling. Endothelial cells release purines and pyrimidines in response to changes in blood flow (evoking shear stress) and hypoxia. They then act on P2Y, P2X and P1 receptors on endothelial cells leading to release of EDRF mediated by nitric oxide and prostaglandins and EDHF, resulting in vasodilatation. The therapeutic potential of purinergic compounds for the treatment of vascular diseases, including hypertension, ischaemia, atherosclerosis, migraine and coronary artery and diabetic vascular disease as well as vasospasm is discussed. PMID- 26638800 TI - Endothelial Lessons. AB - This essay focuses on nine important lessons learned during more than thirty years of endothelial research. They include: the danger of hiding behind a word, the confusion generated by abbreviations, the need to define the physiological role of the response studied, the local role of endothelium- dependent responses, the strength of pharmacological analyses, endothelial dysfunction as consequence and cause of disease, the importance of rigorous protocols, the primacy of in vivo studies and the importance of serendipity. PMID- 26638801 TI - [Molecular, preclinical, and clinical comparative data regarding different strains of bacillus Calmette-Guerin (BCG): Review by the French Urological Association Oncology Committee (CCAFU)]. AB - OBJECTIVE: To review the differences between the BCG strains used for the treatment of non-muscle invasive bladder cancer (NMIBC) at the molecular level, regarding cytotoxicity, immunogenicity, clinical efficiency, and safety. MATERIAL AND METHOD: A systematic review of the literature search was performed from the database MedLine, focused on the following keywords: BCG; bladder; strain; genome; cytotoxicity; immune response; efficiency; safety. RESULTS: Genetic differences between BCG strains have been identified and correlated to their time to differentiation from their initial cultures start, assuming a lower resistance to the host immune defenses of Tice and Danish strains compared to the Connaught strain. Preclinical comparative data showed superior cytotoxic effect and immunogenicity of the Connaught strain compared to Tice and Danish strains. The phase III trials have shown superior efficiency of BCG Connaught compared to BCG Tice and BCG Danish compared to BCG Tice regarding recurrence-free survival. CONCLUSIONS: Among BCG strains used in France in NMIBC treatment, preclinical and clinical efficiency of Connaught strain was higher than that of the Tice strain. The limits of the currently available studies lie primarily in the lack of use of maintenance therapy. PMID- 26638802 TI - [Microbiological evaluation of cystoscope reprocessing at Brest university hospital from January 2007 through December 2014]. AB - PURPOSE: Flexible cystoscopes are high temperature sensitive devices that must undergo high-level disinfection according to Spaulding classification. The objective of this study is to provide epidemiological data on the monitoring of microbiological quality of cystoscopes used in a teaching hospital, in order to determine the compliance rate of disinfection and to describe the main identified microorganisms. MATERIAL: Prospective study of all the results of microbiological samples taken for 8 years at the Brest teaching hospital. The analysis results were interpreted according to the ministerial recommendations. RESULTS: During the study, 87 microbiological tests were performed. The rate of non-compliant samples was 19.5% (17/87). This rate reached 24.5% (12/49) of the programmed controls. The microorganisms identified were present in small amounts, corresponding mainly to bacteria from the environment. CONCLUSION: The rate of non-compliance of the microbiological tests performed on cystoscopes is relatively high (19.5%), but the infectious risk seems limited. Hidden microorganisms are present in small quantities and identified germs are not known to be responsible for urinary tract infections. Educating professionals responsible for cystoscopes reprocessing and conducting regular audits may help to ensure a good level of cystoscope disinfection. PMID- 26638803 TI - Critically reflecting on Loh's "Trends and structural shifts in health tourism". PMID- 26638804 TI - Outcomes of Influenza Infections in Hematopoietic Cell Transplant Recipients: Application of an Immunodeficiency Scoring Index. AB - Hematopoietic cell transplant (HCT) recipients have lower immune response to influenza vaccination and are susceptible to lower respiratory tract infection (LRI) and death. We determined clinical characteristics and outcomes of laboratory-confirmed influenza, including 2014/H3N2 infection, in 146 HCT recipients. An immunodeficiency scoring index (ISI) was applied to identify patients at high risk for LRI and death. Thirty-three patients (23%) developed LRI and 7 (5%) died within 30 days of diagnosis. Most patients received antiviral therapy (83%); however, only 18% received it within 48 hours of symptom onset. The incidence of LRI was significantly higher in the ISI high-risk group than it was in the low-risk group (P < .001). Receiving early antiviral therapy was associated with a substantial reduction in LRI for all ISI risk groups with the greatest risk reduction observed in the high-risk group. When compared with previous seasons, no significant differences in patient outcomes were observed during the 2014/H3N2 season; however, antiviral therapy was more promptly initiated in the latter season. The ISI that was originally developed for respiratory syncytial virus may help identify HCT recipients at risk for progression to LRI and mortality after influenza infection. These patients should be monitored more closely. Early initiation of antiviral therapy for influenza in HCT recipients, regardless of the ISI risk group, may improve morbidity as well as mortality. PMID- 26638805 TI - Software for computerised analysis of cardiotocographic traces. AB - Despite the widespread use of cardiotocography in foetal monitoring, the evaluation of foetal status suffers from a considerable inter and intra-observer variability. In order to overcome the main limitations of visual cardiotocographic assessment, computerised methods to analyse cardiotocographic recordings have been recently developed. In this study, a new software for automated analysis of foetal heart rate is presented. It allows an automatic procedure for measuring the most relevant parameters derivable from cardiotocographic traces. Simulated and real cardiotocographic traces were analysed to test software reliability. In artificial traces, we simulated a set number of events (accelerations, decelerations and contractions) to be recognised. In the case of real signals, instead, results of the computerised analysis were compared with the visual assessment performed by 18 expert clinicians and three performance indexes were computed to gain information about performances of the proposed software. The software showed preliminary performance we judged satisfactory in that the results matched completely the requirements, as proved by tests on artificial signals in which all simulated events were detected from the software. Performance indexes computed in comparison with obstetricians' evaluations are, on the contrary, not so satisfactory; in fact they led to obtain the following values of the statistical parameters: sensitivity equal to 93%, positive predictive value equal to 82% and accuracy equal to 77%. Very probably this arises from the high variability of trace annotation carried out by clinicians. PMID- 26638806 TI - Changes in c-erbB-2 Immunoexpression in Feline Endometrial Adenocarcinomas. AB - Human epidermal growth factor receptor type 2 (c-erbB-2), an oncoprotein with potential prognostic marker and therapeutic use, is overexpressed in several human and animal tumours. But information regarding this molecule in feline tumours is scarce. This study aimed to assess the changes in the immunohistochemical expression of c-erbB-2 in feline endometrial adenocarcinomas (FEA) compared to normal endometrium. An immunohistochemistry assay using a specific antibody against c-erbB-2 was performed in FEA samples (n = 34) and in normal endometrium in the follicular (FS; n = 12) and luteal (LS; n = 11) stages. In FEA, the c-erbB-2 immunoexpression was assessed in neoplastic epithelial cells whilst in normal endometria it was individually evaluated in the surface and the superficial and deep glandular epithelia (SE, SGE and DGE, respectively). In FS and in LS, all the epithelia were positive for c-erbB-2; positivity was higher in the SE and the SGE than in DGE. Twenty of the 34 FEA samples (58.8%) were positive for c-erbB-2 immunolabelling. Nevertheless, its expression was higher in all the epithelia in the FS compared to FEA (p <= 0.0001) or the LS (p = 0.016). The results presented herein suggest that c-erbB-2 molecule is differently expressed in the feline endometrium through the oestrous cycle and though it may also be involved in feline endometrial carcinogenesis, a question remains unanswered on the importance of additional pathways of epithelial proliferation in the neoplastic changes in feline endometrium. PMID- 26638807 TI - Copy number variation and microdeletions of the Y chromosome linked genes and loci across different categories of Indian infertile males. AB - We analyzed 34 azoospermic (AZ), 43 oligospermic (OS), and 40 infertile males with normal spermiogram (INS) together with 55 normal fertile males (NFM) from the Indian population. AZ showed more microdeletions in the AZFa and AZFb regions whereas oligospermic ones showed more microdeletions in the AZFc region. Frequency of the AZF partial deletions was higher in males with spermatogenic impairments than in INS. Significantly, SRY, DAZ and BPY2 genes showed copy number variation across different categories of the patients and much reduced copies of the DYZ1 repeat arrays compared to that in normal fertile males. Likewise, INS showed microdeletions, sequence and copy number variation of several Y linked genes and loci. In the context of infertility, STS deletions and copy number variations both were statistically significant (p = 0.001). Thus, semen samples used during in vitro fertilization (IVF) and assisted reproductive technology (ART) must be assessed for the microdeletions of AZFa, b and c regions in addition to the affected genes reported herein. Present study is envisaged to be useful for DNA based diagnosis of different categories of the infertile males lending support to genetic counseling to the couples aspiring to avail assisted reproductive technologies. PMID- 26638808 TI - Binge Drinkers Are Fast, Able to Stop - but They Fail to Adjust. AB - Binge drinking leads to brain damage. However, at present few studies have taken into account the continuity in the binge drinking phenomenon, and treated binge drinking as a clearly separable category from other types of drinking patterns. The aim of the present study was to investigate whether severity of binge drinking can predict specific neurocognitive changes in healthy young adults. A total of 121 students aged 18 to 25 were assessed by means of the three last questions of the Alcohol Use Questionnaire combined into binge score. The binge score was entered as a predictor of cognitive performance of the CANTAB Stop Signal Task including reaction time, inhibition processing time, and response adjustment. Anxiety and depression symptoms were also measured. Binge score significantly predicted less adjustment following failures, and faster reaction times. Binge score did not predict inhibition performance. Symptoms of depression and anxiety were not significantly related to binge score. Binge drinking in healthy young adults predicts impairment in response adjustment and fast reaction time, but is unrelated to inhibition. The study supports the view that binge drinking is a continuous phenomenon, rather than discrete category, and the findings are possibly shedding light on why binge drinkers continue their drinking pattern despite negative consequences. (JINS, 2016, 22, 38-46). PMID- 26638809 TI - A scoping review of evaluated interventions addressing developmental transitions for youth with mental health disorders. AB - BACKGROUND: Youth with mental health disorders often experience challenges when transitioning into adult roles (e.g. independent living, work and community engagement). Health interventions that address the needs of youth with mental health disorders during these challenges in their development (i.e. developmental transitions) have not been reviewed in the literature. This scoping review examines the peer-reviewed research that describes evaluated interventions addressing developmental transitions for youth with mental health disorders. METHODS: A search of four prominent health literature databases (CINAHL, Embase, MEDLINE and PsycINFO) was conducted to identify evaluated developmental transition interventions for adolescents and youth (12-25 years) with mental health disorders. Study selection and analysis were guided by a methodological framework for conducting scoping reviews. Selected studies were described, assessed for quality and collated based on ten dimensions from two notable conceptual frameworks in developmental transitions and disability. RESULTS: Nine studies met the inclusion criteria. The interventions within these studies demonstrated five specialized and four multi-faceted programmes (i.e. multiple domains). All domains from the two conceptual frameworks were represented differently across studies. The sub-domains from these studies were most frequently related to vocational-focused interventions, least frequently related to social activities and living situation and did not explicitly map onto the sexuality sub-domain. Three multi-faceted interventions incorporated all domains and utilized each intervention approach. Study quality was rated for seven of the nine studies. Quantitative methodology for five of the seven studies was rated as higher quality. CONCLUSIONS: Evaluated interventions described in the transitions literature for youth with mental health disorders predominantly focus on vocational needs. The least studied areas were the personal and interpersonal domains. These domains were only incorporated within interventions addressing multiple domains of developmental transitions. These insights can be helpful in guiding evidence-based practice and policy development, as well as informing gaps for future research programmes. PMID- 26638824 TI - Tailoring Thermodynamics and Kinetics for Hydrogen Storage in Complex Hydrides towards Applications. AB - Solid-state hydrogen storage using various materials is expected to provide the ultimate solution for safe and efficient on-board storage. Complex hydrides have attracted increasing attention over the past two decades due to their high gravimetric and volumetric hydrogen densities. In this account, we review studies from our lab on tailoring the thermodynamics and kinetics for hydrogen storage in complex hydrides, including metal alanates, borohydrides and amides. By changing the material composition and structure, developing feasible preparation methods, doping high-performance catalysts, optimizing multifunctional additives, creating nanostructures and understanding the interaction mechanisms with hydrogen, the operating temperatures for hydrogen storage in metal amides, alanates and borohydrides are remarkably reduced. This temperature reduction is associated with enhanced reaction kinetics and improved reversibility. The examples discussed in this review are expected to provide new inspiration for the development of complex hydrides with high hydrogen capacity and appropriate thermodynamics and kinetics for hydrogen storage. PMID- 26638823 TI - Corticostriatal pathways contribute to the natural time course of positive mood. AB - The natural time course of mood includes both acute responses to stimuli and spontaneous fluctuations. To date, neuroimaging studies have focused on either acute affective responses or spontaneous neural fluctuations at rest but no prior study has concurrently probed both components, or how mood disorders might modulate these processes. Here, using fMRI, we capture the acute affective and neural responses to naturalistic positive mood induction, as well as their spontaneous fluctuations during resting states. In both healthy controls and individuals with a history of depression, our manipulation acutely elevates positive mood and ventral striatum activation. Only controls, however, sustain positive mood over time, and this effect is accompanied by the emergence of a reciprocal relationship between the ventral striatum and medial prefrontal cortex during ensuing rest. Findings suggest that corticostriatal pathways contribute to the natural time course of positive mood fluctuations, while disturbances of those neural interactions may characterize mood disorder. PMID- 26638825 TI - Adverse drug reactions reporting: a questionnaire-based study on Egyptian pharmacists' attitudes following an awareness workshop. AB - RATIONALE, AIMS AND OBJECTIVES: Hospital pharmacists can promote medication safety through spontaneous reporting of adverse drug reactions (ADRs). However, different educational interventions and different factors (socio-demographic and professional) have been implicated to influence the reporting process. The aims of this study were to assess the impact of pharmacovigilance awareness workshop on knowledge of hospital pharmacists; and to identify the main factors and barriers that influence ADRs reporting. METHODS: Two validated self-administered questionnaires were distributed to pharmacists attending an awareness workshop (pre and post); and a telephone survey was completed three months after the workshop. ADR reports (yellow cards) received from participating pharmacists were monitored for six months, and analysed for quality (validity and seriousness) and reporter demographic and professional factors. RESULTS: Two hundred and eighty one pharmacists (95.25%) and 270 pharmacists (91.52%) completed pre- and post workshop questionnaires respectively. A comparison of their knowledge of ADRs to report before and after the workshop showed significant difference (Wilcoxon test P < 0.05). Two hundred and four pharmacists (72.6%) completed the follow-up questionnaire, with lack of time, administrative barriers and inability to complete patient details being the most frequent reasons for not reporting. A total of 163 yellow cards were received from 49 pharmacists (17.44%) over 6 months, of which 126 reports (77.3%) were serious ADRs. Demographics of reporting pharmacists showed significance for completion of post-graduate studies, ministry of health hospitals and pharmacist post in hospital. CONCLUSION: Despite pharmacists' adequate knowledge after the workshop, they failed to maintain consistent reporting. Addressing the barriers to reporting and the personal factors influencing the process may be needed. PMID- 26638826 TI - Treatment Planning Studies in Patient Data With Scanned Carbon Ion Beams for Catheter-Free Ablation of Atrial Fibrillation. AB - INTRODUCTION: Catheter ablation with isolation of the pulmonary veins is a common treatment option for atrial fibrillation but still has insufficient success rates and carries several interventional risks. These treatment planning studies assessed if high-dose single fraction treatment with scanned carbon ions (12C) can be reliably delivered for AF ablation, while sparing risk structures and considering respiratory and contractile target motion. METHODS AND RESULTS: Time resolved CT scans of complete respiratory and cardiac cycles of 9 and 5 patients, respectively, were obtained. Ablation lesions and organs at risk for beam delivery were contoured. Single fraction intensity-modulated particle therapy with target doses of 25 and 40 Gy were studied and motion influences on these deliveries mitigated. Respiration had a large influence on lesion displacement (<= 2 cm). End expiration could be exploited as a stable gating window. Smaller, but less predictable, heartbeat displacements (< 6 mm) remained to be mitigated because cardiac contraction resulted in insufficient dose coverage (V95 < 90%) if uncompensated. Repeated irradiation (12C beam rescanning) during breath hold was used to accommodate contractile motion, resulting in good dose coverage. Dose depositions to all organs at risk were carefully examined and did not exceed values for X-ray cancer treatment. CONCLUSION: Treatment planning of 12C with delivery of physical ionizing radiation doses that have been described to induce complete block is feasible for AF ablation, considering human anatomy, dose constraints, and encasing underlying motion patterns from respiration and cardiac contraction at the LA-PV junction into treatment planning. PMID- 26638828 TI - High subcortical sacrectomy: a novel approach to facilitate complete resection of locally advanced and recurrent rectal cancer with high (S1-S2) sacral extension. AB - AIM: R0 resection of locally advanced or recurrent rectal cancer is the key determinant of outcome. Disease extension high on the sacrum has been considered a contraindication to surgery because of associated morbidity and difficulty in achieving complete pathological resection. Total sacrectomy has a high morbidity with poor function. METHOD: We describe a novel technique of high subcortical sacrectomy (HiSS) to facilitate complete resection of disease extending to the upper sacrum at S1 and S2 to avoid high or total sacrectomy or a nonoperative approach to management. Details of patient demographics, radiology, operative details, postoperative histology, length of hospital stay and complications were entered into a prospectively maintained electronic patient database. All patients had had preoperative chemoradiotherapy. RESULTS: During 2013-2014, five patients, including three with advanced primary cancer and two with recurrent rectal cancer, underwent excision using this approach. All patients had an R0 resection. Four patients had a minor postoperative complication (Clavien-Dindo Grades I and II) and one had a major complication (Clavien-Dindo Grade IIIb). There was no mortality at 90 days, and four patients were disease free at a median of 18 months. CONCLUSION: Patients with locally advanced and recurrent rectal cancer involving the upper sacrum may be rendered suitable for potentially curative radical resection with a modified approach to sacral resection. This pilot series suggests that this novel technique results in a high rate of complete pathological resection with acceptable morbidity in patients for whom the alternatives would have been an incomplete resection, a total sacrectomy or nonoperative management. PMID- 26638827 TI - Ice-templated synthesis of multifunctional three dimensional graphene/noble metal nanocomposites and their mechanical, electrical, catalytic, and electromagnetic shielding properties. AB - In-situ homogeneous dispersion of noble metals in three-dimensional graphene sheets is a key tactic for producing macroscopic architecture, which is desirable for practical applications, such as electromagnetic interference shielding and catalyst. We report a one-step greener approach for developing porous architecture of 3D-graphene/noble metal (Pt and Ag) nanocomposite monoliths. The resulting graphene/noble metal nanocomposites exhibit a combination of ultralow density, excellent elasticity, and good electrical conductivity. Moreover, in order to illuminate the advantages of the 3D-graphene/noble metal nanocomposites, their electromagnetic interference (EMI) shielding and electrocatalytic performance are further investigated. The as-synthesized 3D-graphene/noble metal nanocomposites exhibit excellent EMI shielding effectiveness when compared to bare graphene; the effectiveness has an average of 28 dB in the 8.2-12.4 GHz X band range. In the electro-oxidation of methanol, the 3D-graphene/Pt nanocomposite also exhibits significantly enhanced electrocatalytic performance and stability than compared to reduced graphene oxide/Pt and commercial Pt/C. PMID- 26638829 TI - A Wide-angle Multi-Octave Broadband Waveplate Based on Field Transformation Approach. AB - Transformation optics (TO) offers a geometrical approach in designing optical components of any shapes. Although it has been proven to be a versatile and robust mathematical tool, TO has, however, limited control over electromagnetic (EM) field polarization in the process of coordinate transformation. Such a technique can be extended to a so-called "Field transformation (FT)" which provides direct control over the impedance and polarization signature of an arbitrary object. In this work, we demonstrate a FT application by designing and manufacturing a novel waveplate, which defies the fundamental limit of bandwidth and incident angles and has the ability of converting between TE (transverse electric) and TM (transverse magnetic) as well as LCP (left-handed circular polarization) and RCP (right-handed circular polarization). Such a waveplate can also be applied to different operating modes for both transmitted and reflected waves by adjusting its thickness and adding an optional metallic ground plane. The proposed design approach presents a remarkable degree of advance for designing future devices with arbitrary polarization controls, artificial waveguides or antenna substrates and polarization-enabled resonators with angle insensitive functionalities. Our approach has far reaching implications applicable from radio to optical frequencies. PMID- 26638830 TI - A Probabilistic Model for Estimating the Depth and Threshold Temperature of C fiber Nociceptors. AB - The subjective experience of thermal pain follows the detection and encoding of noxious stimuli by primary afferent neurons called nociceptors. However, nociceptor morphology has been hard to access and the mechanisms of signal transduction remain unresolved. In order to understand how heat transducers in nociceptors are activated in vivo, it is important to estimate the temperatures that directly activate the skin-embedded nociceptor membrane. Hence, the nociceptor's temperature threshold must be estimated, which in turn will depend on the depth at which transduction happens in the skin. Since the temperature at the receptor cannot be accessed experimentally, such an estimation can currently only be achieved through modeling. However, the current state-of-the-art model to estimate temperature at the receptor suffers from the fact that it cannot account for the natural stochastic variability of neuronal responses. We improve this model using a probabilistic approach which accounts for uncertainties and potential noise in system. Using a data set of 24 C-fibers recorded in vitro, we show that, even without detailed knowledge of the bio-thermal properties of the system, the probabilistic model that we propose here is capable of providing estimates of threshold and depth in cases where the classical method fails. PMID- 26638831 TI - Long-term orthognathic surgical outcomes in Treacher Collins patients. AB - INTRODUCTION: Treacher Collins syndrome is a rare disorder characterized by several orofacial findings including malar deficiency and hypoplastic mandibles. These patients often require a combined orthodontic-orthognathic approach to correct their malocclusion. This is most often characterized by a short posterior vertical height and an anterior open bite. Orthognathic correction often requires Le Fort I and bilateral sagittal split osteotomies. No long-term stability results have been reported after bimaxillary surgery in Treacher Collins patients. METHODS: A retrospective review of all Treacher Collins patients evaluated for orthognathic surgery by a single surgeon from 1993 to 2007 was performed. Patients were divided into groups who required surgery and those who did not. Part I analyzed the cephalometric differences between the surgical (S) and nonsurgical (NS) groups. Part II of the study assessed the preorthodontic treatment (T1), preoperative (T2), immediate postoperative (T3), and 1-year postoperative (T4) cephalometric measurement variables to determine the net surgical movement (T3 - T2) and relapse (T4 - T3). RESULTS: Twenty-two patients met the inclusion criteria, of which 11 had occlusal relationships requiring orthognathic surgery. Nine out of 11 chose to have surgery. At baseline, surgical patients exhibited a statistically significant retruded maxilla as measured by SNA and midface length compared to the NS group. In addition, the S group also had an increased gonial angle. There were significant movements in all maxillary and mandibular measurements. There was a significant relapse in the palatal plane angle when the maxilla was anteriorly impacted, with a 2.8-mm average relapse of the advancement. Relapse of the counterrotation movement of the mandible was identified, but this was not significant. Relapse did not affect the final occlusal result, which may have been compensated with postsurgical orthodontic treatment. CONCLUSION: Bimaxillary orthognathic surgery in the Treacher Collins patients may be performed safely with long-term dental and skeletal stability. PMID- 26638832 TI - Diversity matters: parent input predicts toddler verb production. AB - The contribution of parent input to children's subsequent expressive verb diversity was explored in twenty typically developing toddlers with small verb lexicons. Child developmental factors and parent input measures (i.e. verb quantity, verb diversity, and verb-related structural cues) at age 1;9 were examined as potential predictors of children's verb production in spontaneous language samples at age 2;3. Parent verb input diversity, rather than input quantity, was the primary input factor contributing to children's subsequent verb diversity. Regression analysis showed that verb diversity in parent input at age 1;9 accounted for 30% of the variance in children's verb production six months later, with children's total vocabulary size at age 1;9 accounting for an additional 16% of the variance. These findings demonstrate the relative contributions of developmental and input factors to individual differences in toddlers' language development and establish the importance of input diversity to verb acquisition. PMID- 26638834 TI - Sensory feedback - Dependent neural de-orchestration: The effect of altered sensory feedback on Musician's Dystonia. AB - PURPOSE: Musician's dystonia (MD) is a task-specific movement disorder related to extensive expert music performance training. Similar to other forms of focal dystonia, MD involves sensory deficits and abnormal patterns of sensorimotor integration. The present study investigated the impaired cortical sensorimotor network of pianists who suffer from MD by employing altered auditory and tactile feedback during scale playing with multichannel EEG. METHODS: 9 healthy professional pianists and 9 professional pianists suffering from right hand MD participated in an experiment that required repeated scale playing on a MIDI piano under altered sensory feedback while EEG was measured. RESULTS: The comparison of EEG data in healthy pianists and pianists suffering from MD revealed a higher degree of inter-regional phase synchronisation between the frontal and parietal regions and between the temporal and central regions in the patient group and in conditions that are relevant to the long-trained auditory motor coupling (normal auditory feedback and complete deprivation of auditory feedback), but such abnormalities decreased in conditions with delayed auditory feedback and altered tactile feedback. CONCLUSIONS: These findings support the hypothesis that the impaired sensorimotor integration of MD patients is specific to the type of overtrained task that the patients were trained for and can be modified with altered sensory feedback. PMID- 26638833 TI - The effects of varenicline on methamphetamine self-administration and drug-primed reinstatement in female rats. AB - While research has revealed heightened vulnerability to meth addiction in women, preclinical models rarely use female subjects when investigating meth seeking and relapse. The goal of the present study was to examine the effects of varenicline (Chantix((r))), a partial alpha4beta2 and full alpha7 nicotinic acetylcholine receptor agonist, on meth self-administration and reinstatement in female rats. Sprague-Dawley rats were surgically implanted with an indwelling jugular catheter. Half of the rats were then trained to self-administer meth (0.056 mg/kg/infusion) on a variable ratio 3 schedule of reinforcement; the other half earned intravenous saline during daily, 2h sessions. When responding stabilized, varenicline (0.0, 0.3, 1.0, 3.0mg/kg) was tested to determine how it altered meth taking. Varenicline was probed on 4 test days; each test separated by 2 standard self-administration sessions to assure responding remained stable. Following this testing was 15 extinction sessions. Twenty-four hours after the last extinction session were four consecutive days of meth-primed reinstatement. The same 4 doses of varenicline were examined to determine how it altered reinstatement triggered by 0.3mg/kg meth (IP). Rats readily self-administered meth. The higher doses of varenicline did not affect meth-taking in a specific fashion as active lever pressing was also slightly reduced in rats that has access to saline in the self administration phase. Female rats displayed robust meth-primed reinstatement. Notably, the lower doses of varenicline increased meth-primed reinstatement. This amplified susceptibility to reinstatement (i.e., relapse) may be an impediment for the use of varenicline as a therapeutic to treat meth use disorder. PMID- 26638835 TI - Distribution of calcium-binding proteins in the pigeon visual thalamic centers and related pretectal and mesencephalic nuclei. Phylogenetic and functional determinants. AB - Multichannel processing of environmental information constitutes a fundamental basis of functioning of sensory systems in the vertebrate brain. Two distinct parallel visual systems - the tectofugal and thalamofugal exist in all amniotes. The vertebrate central nervous system contains high concentrations of intracellular calcium-binding proteins (CaBPrs) and each of them has a restricted expression pattern in different brain regions and specific neuronal subpopulations. This study aimed at describing the patterns of distribution of parvalbumin (PV) and calbindin (CB) in the visual thalamic and mesencephalic centers of the pigeon (Columba livia). We used a combination of immunohistochemistry and double labeling immunofluorescent technique. Structures studied included the thalamic relay centers involved in the tectofugal (nucleus rotundus, Rot) and thalamofugal (nucleus geniculatus lateralis, pars dorsalis, GLd) visual pathways as well as pretectal, mesencephalic, isthmic and thalamic structures inducing the driver and/or modulatory action to the visual processing. We showed that neither of these proteins was unique to the Rot or GLd. The Rot contained i) numerous PV-immunoreactive (ir) neurons and a dense neuropil, and ii) a few CB-ir neurons mostly located in the anterior dorsal part and associated with a light neuropil. These latter neurons partially overlapped with the former and some of them colocalized both proteins. The distinct subnuclei of the GLd were also characterized by different patterns of distribution of CaBPrs. Some (nucleus dorsolateralis anterior, pars magnocellularis, DLAmc; pars lateralis, DLL; pars rostrolateralis, DLAlr; nucleus lateralis anterior thalami, LA) contained both CB- and PV-ir neurons in different proportions with a predominance of the former in the DLAmc and DLL. The nucleus lateralis dorsalis of nuclei optici principalis thalami only contained PV-ir neurons and a neuropil similar to the interstitial pretectal/thalamic nuclei of the tectothalamic tract, nucleus pretectalis and thalamic reticular nucleus. The overlapping distribution of PV and CB immunoreactivity was typical for the pretectal nucleus lentiformis mesencephali and the nucleus ectomamillaris as well as for the visual isthmic nuclei. The findings are discussed in the light of the contributive role of the phylogenetic and functional factors determining the circuits' specificity of the different CaBPr types. PMID- 26638836 TI - Attending to auditory memory. AB - Attention to memory describes the process of attending to memory traces when the object is no longer present. It has been studied primarily for representations of visual stimuli with only few studies examining attention to sound object representations in short-term memory. Here, we review the interplay of attention and auditory memory with an emphasis on 1) attending to auditory memory in the absence of related external stimuli (i.e., reflective attention) and 2) effects of existing memory on guiding attention. Attention to auditory memory is discussed in the context of change deafness, and we argue that failures to detect changes in our auditory environments are most likely the result of a faulty comparison system of incoming and stored information. Also, objects are the primary building blocks of auditory attention, but attention can also be directed to individual features (e.g., pitch). We review short-term and long-term memory guided modulation of attention based on characteristic features, location, and/or semantic properties of auditory objects, and propose that auditory attention to memory pathways emerge after sensory memory. A neural model for auditory attention to memory is developed, which comprises two separate pathways in the parietal cortex, one involved in attention to higher-order features and the other involved in attention to sensory information. This article is part of a Special Issue entitled SI: Auditory working memory. PMID- 26638837 TI - Voltage-gated calcium and sodium channels mediate Sema3A retrograde signaling that regulates dendritic development. AB - Growing axons rely on local signaling at the growth cone for guidance cues. Semaphorin3A (Sema3A), a secreted repulsive axon guidance molecule, regulates synapse maturation and dendritic branching. We previously showed that local Sema3A signaling in the growth cones elicits retrograde retrograde signaling via PlexinA4 (PlexA4), one component of the Sema3A receptor, thereby regulating dendritic localization of AMPA receptor GluA2 and proper dendritic development. In present study, we found that nimodipine (voltage-gated L-type Ca(2+) channel blocker) and tetrodotoxin (TTX; voltage-gated Na(+) channel blocker) suppress Sema3A-induced dendritic localization of GluA2 and dendritic branch formation in cultured hippocampal neurons. The local application of nimodipine or TTX to distal axons suppresses retrograde transport of Venus-Sema3A that has been exogenously applied to the distal axons. Sema3A facilitates axonal transport of PlexA4, which is also suppressed in neurons treated with either TTX or nimodipine. These data suggest that voltage-gated calcium and sodium channels mediate Sema3A retrograde signaling that regulates dendritic GluA2 localization and branch formation. PMID- 26638838 TI - Functional connectivity among multi-channel EEGs when working memory load reaches the capacity. AB - Evidence from behavioral studies has suggested a capacity existed in working memory. As the concept of functional connectivity has been introduced into neuroscience research in the recent years, the aim of this study is to investigate the functional connectivity in the brain when working memory load reaches the capacity. 32-channel electroencephalographs (EEGs) were recorded for 16 healthy subjects, while they performed a visual working memory task with load 1-6. Individual working memory capacity was calculated according to behavioral results. Short-time Fourier transform was used to determine the principal frequency band (theta band) related to working memory. The functional connectivity among EEGs was measured by the directed transform function (DTF) via spectral Granger causal analysis. The capacity was 4 calculated from the behavioral results. The power was focused in the frontal midline region. The strongest connectivity strengths of EEG theta components from load 1 to 6 distributed in the frontal midline region. The curve of DTF values vs load numbers showed that DTF increased from load 1 to 4, peaked at load 4, then decreased after load 4. This study finds that the functional connectivity between EEGs, described quantitatively by DTF, became less strong when working memory load exceeded the capacity. PMID- 26638861 TI - Rigidifying Nonplanar Perylene Diimides by Ring Fusion Toward Geometry-Tunable Acceptors for High-Performance Fullerene-Free Solar Cells. AB - Rigid fused perylene diimide (PDI) dimers bridged with heterocycles exhibit superior photovoltaic performance compared to their unfused semiflexible analogues. Changing the chalcogen atoms in the aromatic bridges gradually increases the twist angles between the two PDI planes, leading to a varied morphology in which the one bridged by thiophene achieves a balance and shows the best efficiency of 6.72%. PMID- 26638862 TI - Current challenges in HER2-positive breast cancer. AB - The introduction of trastuzumab into routine clinical practice has had a dramatic effect on the outlook for patients with HER2-positive breast cancer. Nevertheless, answers to some long unresolved questions about the optimal use of trastuzumab (such as its role in small tumors or low-risk disease, cardiac safety in the elderly, and treatment duration) have emerged only relatively recently. Moreover, with the availability of new highly effective HER2-directed therapies, including pertuzumab and trastuzumab-emtansine (T-DM1), the treatment algorithm for HER2-positive breast cancer continues to evolve. This review provides a summary of the latest evidence providing insight into the management of early and advanced HER2-positive breast cancer and delineates future perspectives of study and treatment for these patients. PMID- 26638863 TI - Addressing the expected survival benefit for clinical trial design in metastatic castration-resistant prostate cancer: Sensitivity analysis of randomized trials. AB - We performed a sensitivity analysis, cumulating all randomized clinical trials (RCTs) in which patients with metastatic castration-resistant prostate cancer (mCRPC) received systemic therapy, to evaluate if the comparison of RCTs may drive to biased survival estimations. An overall survival (OS) significant difference according to therapeutic strategy was more likely be determined in RCTs evaluating hormonal drugs versus those studies testing immunotherapy, chemotherapy or other strategies. With regard to control arm, an OS significant effect was found for placebo-controlled trials versus studies comparing experimental treatment with active therapies. Finally, regarding to docetaxel (DOC) timing, the OS benefit was more likely to be proved in Post-DOC setting in comparison with DOC and Pre-DOC. These data suggest that clinical trial design should take into account new benchmarks such as the type of treatment strategy, the choice of the comparator and the phase of the disease in relation to the administration of standard chemotherapy. PMID- 26638865 TI - Mycobacterium tuberculosis-specific CD4+ T-cell response is increased, and Treg cells decreased, in anthelmintic-treated patients with latent TB. AB - In many settings, adults with active or latent tuberculosis will also be coinfected with helminths. Our study aimed to investigate how anthelmintic treatment modulates antimycobacterial immunity, in a setting where helminth reinfection should not occur. We investigated the potential impact of helminth infection on immune responses to Mycobacterium tuberculosis (Mtb) in patients with latent Mtb infection with or without helminth infection (Strongyloides or Schistosoma), and tested T-cell responses before and after anthelmintic treatment. The study was performed in migrants resident in the United Kingdom, where reexposure and reinfection following anthelmintic treatment would not occur. The frequency of CD4(+) IFN-gamma(+) T cells was measured following stimulation with Mtb Purified Protein Derivative or ESAT-6/CFP-10 antigen, and concentrations of IFN-gamma in culture supernatants measured by ELISA and multiplex bead array. Helminth infection was associated with a lower frequency of CD4(+) IFN-gamma(+) T cells, which increased following treatment. Patients with helminth infection showed a significant increase in CD4(+) FoxP3(+) T cells (Treg) compared to those without helminth infection. There was a decrease in the frequency of Treg cells, and an associated increase in CD4(+) IFN-gamma(+) T cells after the anthelmintic treatment. Here, we show a potential role of Treg cells in reducing the frequency and function of antimycobacterial CD4(+) IFN gamma(+) T cells, and that these effects are reversed after anthelmintic treatment. PMID- 26638866 TI - Heterogeneity of Cognitive Anosognosia and its Variation with the Severity of Dementia in Patients with Alzheimer's Disease. AB - Currently, the lack of awareness of deficits, i.e., anosognosia, is a major obstacle in the healthcare circuit that delays the diagnosis of Alzheimer's disease (AD). However, a clear framework is lacking in the literature related to this phenomenon in terms of its definition, mechanisms, and objects. The aim of this study is to assess the different levels of cognitive anosognosia using a prediction-performance procedure and to identify the potential correlates of these levels. A sample of patients with probable AD was divided into three groups according to the severity of dementia (mild (MiD), moderate (MoD), and moderately severe (MSD) dementia), ranked according to the results of the Mini-Mental State Examination. We observed the following three scores: the real score, the prediction score, and the anosognosia score. These scores were calculated based on the prediction-performance task MISAwareness from the Dementia Rating Scale for cognitive processes (i.e., Attention, Initiation, Conceptualization, Construction, and Memory). We obtained a strong plateau effect between the MiD and MoD groups for anosognosia scores for actual performance or prediction for both the level of overall functioning and for specific processes. The sole exception was the result for memory processes. Moreover, the profiles of the patients' responses on the Memory subscale were substantially different and, indeed, opposite from those for the other processes. The main results confirm the multidimensionality of anosognosia and its variability with the stage of dementia and specifically implicate memory processes that indicate a cleavage between memory and other cognitive functions. PMID- 26638867 TI - Direct Evidence of Internalization of Tau by Microglia In Vitro and In Vivo. AB - The microtubule-associated protein (MAP) tau plays a critical role in the pathogenesis of tauopathies. Excess tau can be released into the extracellular medium in a physiological or pathological manner to be internalized by surrounding neurons-a process that contributes to the spread of this protein throughout the brain. Such spreading may correlate with the progression of the abovementioned diseases. In addition to neurons, tau can be internalized into other cells. Here we demonstrate that microglia take up tau in vitro and in vivo. In this regard, microglia from primary cultures internalized soluble (human recombinant tau42) and insoluble (homogenates derived from human AD brain) tau in vitro. Furthermore, using stereotaxic injection of tau in mice in vivo, we show that murine microglia internalize human tau. In addition, we demonstrate, for the first time, that microglia colocalize with various forms of tau in postmortem brain tissue of patients with Alzheimer's disease and non-demented control subjects. Our data reveal a potential role of microglia in the internalization of tau that might be relevant for the design of strategies to enhance the clearance of extracellular tau in neurodegenerative diseases characterized by the accumulation of this protein. PMID- 26638864 TI - Functional role of inorganic trace elements in angiogenesis part III: (Ti, Li, Ce, As, Hg, Va, Nb and Pb). AB - Many essential elements exist in nature with significant influence on human health. Angiogenesis is vital in developmental, repair, and regenerative processes, and its aberrant regulation contributes to pathogenesis of many diseases including cancer. Thus, it is of great importance to explore the role of these elements in such a vital process. This is third in a series of reviews that serve as an overview of the role of inorganic elements in regulation of angiogenesis and vascular function. Here we will review the roles of titanium, lithium, cerium, arsenic, mercury, vanadium, niobium, and lead in these processes. The roles of other inorganic elements in angiogenesis were discussed in part I (N, Fe, Se, P, Au, and Ca) and part II (Cr, Si, Zn, Cu, and S) of these series. The methods of exposure, structure, mechanisms, and potential activities of these elements are briefly discussed. An electronic search was performed on the role of these elements in angiogenesis from January 2005 to April 2014. These elements can promote and/or inhibit angiogenesis through different mechanisms. The anti-angiogenic effect of titanium dioxide nanoparticles comes from the inhibition of angiogenic processes, and not from its toxicity. Lithium affects vasculogenesis but not angiogenesis. Nanoceria treatment inhibited tumor growth by inhibiting angiogenesis. Vanadium treatment inhibited cell proliferation and induced cytotoxic effects through interactions with DNA. The negative impact of mercury on endothelial cell migration and tube formation activities was dose and time dependent. Lead induced IL-8 production, which is known to promote tumor angiogenesis. Thus, understanding the impact of these elements on angiogenesis will help in development of new modalities to modulate angiogenesis under various conditions. PMID- 26638869 TI - Prognostic Value of Cardiac Sympathetic Nerve Imaging Using Long-Term Follow-up Data - Ischemic vs. Non-Ischemic Heart Failure Etiology. AB - BACKGROUND: Although there are several known prognostic determinants in heart failure (HF), individual risk profiles can vary, in particular between ischemic and non-ischemic HF background. This study investigated the difference in prognostic efficacy of cardiac (123)I-meta-iodobenzylguanidine (MIBG) imaging between the 2 etiologies. METHODS AND RESULTS: All 1,322 patients with HF were enrolled and followed up at most after 10 years. The HF patients were divided into 2 groups: an ischemic group (n=362) and non-ischemic group (n=960), and Cox proportional hazards model was used for data analysis. During 10 years of follow up, 296 (22.4%) of 1,322 patients died; the mortality rates were 21.8% and 22.6% for the ischemic and non-ischemic groups, respectively. The ischemic group had greater prevalence of sudden death and lethal acute myocardial infarction, and the non-ischemic group had a higher rate of pump failure death. On multivariate Cox proportional hazards analysis using categorized variables, in the ischemic group, delayed heart-to-mediastinum ratio (HMR; P<0.0001), age (P=0.0002) and LVEF (P=0.03) were the independent significant predictors of lethal events. In the non-ischemic group, delayed HMR (P<0.0001), NYHA class (P<0.0001) and age (P<0.0001) were significant determinants of lethal outcome. CONCLUSIONS: Cardiac MIBG imaging has nearly identical prognostic value in both ischemic and non ischemic HF, independent of cause of cardiac death. PMID- 26638868 TI - Fine-tuned SRF activity controls asymmetrical neuronal outgrowth: implications for cortical migration, neural tissue lamination and circuit assembly. AB - The stimulus-regulated transcription factor Serum Response Factor (SRF) plays an important role in diverse neurodevelopmental processes related to structural plasticity and motile functions, although its precise mechanism of action has not yet been established. To further define the role of SRF in neural development and distinguish between cell-autonomous and non cell-autonomous effects, we bidirectionally manipulated SRF activity through gene transduction assays that allow the visualization of individual neurons and their comparison with neighboring control cells. In vitro assays showed that SRF promotes survival and filopodia formation and is required for normal asymmetric neurite outgrowth, indicating that its activation favors dendrite enlargement versus branching. In turn, in vivo experiments demonstrated that SRF-dependent regulation of neuronal morphology has important consequences in the developing cortex and retina, affecting neuronal migration, dendritic and axonal arborization and cell positioning in these laminated tissues. Overall, our results show that the controlled and timely activation of SRF is essential for the coordinated growth of neuronal processes, suggesting that this event regulates the switch between neuronal growth and branching during developmental processes. PMID- 26638870 TI - The Registry Report of Heart Transplantation in Japan (1999-2014). PMID- 26638871 TI - Novel Scoring System to Predict Ineligibility for Bridge to Implantable Left Ventricular Assist Device as Destination Therapy Before Extracorporeal Ventricular Assist Device Implantation - For the Coming Era of Destination Therapy in Japan. AB - BACKGROUND: Although destination therapy (DT) is now expected to be a promising strategy for those who are not suitable for heart transplantation in Japan, there has not been any investigation into ineligibility for bridging to implantable left ventricular assist device (I-LVAD) as DT among patients with extracorporeal LVAD. METHODS AND RESULTS: We retrospectively studied 85 patients who had received an extracorporeal LVAD. To assess ineligibility for a bridge to I-LVAD for DT, we defined DT ineligibility (DTI) as BiVAD requirement, death within 6 months, and persistent end-organ dysfunction (medium or high J-VAD risk score) at 6 months after extracorporeal LVAD implantation. DTI was recorded for 32 patients. Uni/multivariate analysis showed that smaller left ventricular diastolic dimension (<64 mm; [odds ratio (OR) 4.522]), continuous hemodiafiltration (OR 4.862), past history of cardiac surgery (OR 6.522), and low serum albumin level (<3.1 g/dl; OR 10.064) were significant predictors of DTI. By scoring 2, 2, 3, 4 points, respectively, considering each OR, we constructed a novel scoring system for DTI (DTI score), which stratified patients into 3 risk strata: low (0-3 points), medium (4-6 points), and high (7-11 points), from the view point of DTI risk (low 8%, medium 46%, high 93%, respectively). CONCLUSIONS: DTI score is a promising tool for predicting ineligibility for I-LVAD as DT before extracorporeal VAD implantation. PMID- 26638872 TI - Early Recurrence After Pulmonary Vein Isolation of Paroxysmal Atrial Fibrillation With Different Ablation Technologies - Prospective Comparison of Radiofrequency vs. Second-Generation Cryoballoon Ablation. AB - BACKGROUND: Inflammation plays a prominent role in the etiology of the early recurrence of atrial fibrillation (ERAF). We prospectively compared the proportion of ERAF and time-course patterns of biomarkers between radiofrequency (RF) and cryoballoon (CB) ablation. METHODS AND RESULTS: We enrolled 82 consecutive paroxysmal AF patients undergoing pulmonary vein (PV) isolation, performed with either a 28-mm 2nd-generation CB and 3-min freeze technique or point-by-point RF ablation. Each group had 41 patients. In the RF group, all PVs were successfully isolated with 28.9 +/- 6.5 min of RF delivery. In the CB group, a mean of 5.3 +/- 1.4 applications/patient was delivered. The proportion of ERAF was similar between the groups. The time-course patterns significantly differed between the groups for high-sensitivity C-reactive protein (hs-CRP) value (P=0.006) and myocardial injury markers (P<0.0001). Greater myocardial injury was observed in the CB than in the RF group (P<0.0001), whereas the peak hs-CRP value was comparable between the groups. The 2-day post-procedure hs-CRP value was the sole factor correlating with ERAF as identified by the multivariable analysis (hazard ratio 1.697; 95% confidence interval, 1.005-2.865; P=0.048) in the RF, but not the CB group. CONCLUSIONS: The proportion of ERAF was comparable after RF and 2nd-generation CB ablation. Despite CB ablation exhibiting greater myocardial injury than RF ablation, the inflammatory responses were comparable between the groups. The inflammatory response extent predicted ERAF post-RF ablation but not post-CB ablation. PMID- 26638873 TI - "Treat-and-Repair" Strategy for Atrial Septal Defect and Associated Pulmonary Arterial Hypertension. PMID- 26638874 TI - Versatile Aerogel Fabrication by Freezing and Subsequent Freeze-Drying of Colloidal Nanoparticle Solutions. AB - A versatile method to fabricate self-supported aerogels of nanoparticle (NP) building blocks is presented. This approach is based on freezing colloidal NPs and subsequent freeze drying. This means that the colloidal NPs are directly transferred into dry aerogel-like monolithic superstructures without previous lyogelation as would be the case for conventional aerogel and cryogel fabrication methods. The assembly process, based on a physical concept, is highly versatile: cryogelation is applicable for noble metal, metal oxide, and semiconductor NPs, and no impact of the surface chemistry or NP shape on the resulting morphology is observed. Under optimized conditions the shape and volume of the liquid equal those of the resulting aerogels. Also, we show that thin and homogeneous films of the material can be obtained. Furthermore, the physical properties of the aerogels are discussed. PMID- 26638875 TI - Environmental reconstruction and biostratigraphy of late Middle Pleistocene lakeshore deposits at Schoningen. AB - The Pleistocene sequence of Schoningen provides a key link between unglaciated and glaciated areas in western Central Europe and is an important point of reference for the subdivision of the glaciated late Middle Pleistocene. This locality yields paleoecological and geological evidence of at least four interglacial periods prior to the Holocene and younger than the Elsterian glaciation. The Pleistocene deposits at Schoningen are valuable archives of climate, landscape, and human evolution, containing outstanding information on past environmental changes and human adaptation. This paper presents paleoenvironmental and biostratigraphical results from the Middle Pleistocene archaeological lakeshore site of Schoningen, focusing on the so-called reference profile Schoningen 13 II of 2003. We discuss the lithological, palynological, and macrobotanical evidence and present a revised subdivision and reinterpretation of late phases of the Reinsdorf Interglacial. PMID- 26638876 TI - Carboranylphosphinic Acids: A New Class of Purely Inorganic Ligands. AB - Purely inorganic carboranyl phosphinates were prepared, and the influence of the cluster on the reactivity of the phosphinate group was studied. Electron withdrawal by the carboranyl carbon atoms, combined with space-filling efficiency and enhanced aromaticity of the cluster cage, renders the phosphorus more difficult to oxidize. This enables carboranyl phosphinates to survive harsh oxidizing conditions, a property which is uncommon in organic phosphinates. PMID- 26638877 TI - New hope for the survival of the Amur leopard in China. AB - Natural range loss limits the population growth of Asian big cats and may determine their survival. Over the past decade, we collected occurrence data of the critically endangered Amur leopard worldwide and developed a distribution model of the leopard's historical range in northeastern China over the past decade. We were interested to explore how much current range area exists, learn what factors limit their spatial distribution, determine the population size and estimate the extent of potential habitat. Our results identify 48,252 km(2) of current range and 21,173.7 km(2) of suitable habitat patches and these patches may support 195.1 individuals. We found that prey presence drives leopard distribution, that leopard density exhibits a negative response to tiger occurrence and that the largest habitat patch connects with 5,200 km(2)of Russian current range. These insights provide a deeper understanding of the means by which endangered predators might be saved and survival prospects for the Amur leopard not only in China, but also through imperative conservation cooperation internationally. PMID- 26638879 TI - MicroRNA Expression Signature Is Altered in the Cardiac Remodeling Induced by High Fat Diets. AB - Recent studies have revealed the involvement of microRNAs (miRNAs) in the control of cardiac hypertrophy and myocardial function. In addition, several reports have demonstrated that high fat (HF) diet induces cardiac hypertrophy and remodeling. In the current study, we investigated the effect of diets containing different percentages of fat on the cardiac miRNA expression signature. To address this question, male C57Bl/6 mice were fed with a low fat (LF) diet or two HF diets, containing 45 kcal% fat (HF45%) and 60 kcal% fat (HF60%) for 10 and 20 weeks. HF60% diet promoted an increase on body weight, fasting glycemia, insulin, leptin, total cholesterol, triglycerides, and induced glucose intolerance. HF feeding promoted cardiac remodeling, as evidenced by increased cardiomyocyte transverse diameter and interstitial fibrosis. RNA sequencing analysis demonstrated that HF feeding induced distinct miRNA expression patterns in the heart. HF45% diet for 10 and 20 weeks changed the abundance of 64 and 26 miRNAs in the heart, respectively. On the other hand, HF60% diet for 10 and 20 weeks altered the abundance of 27 and 88 miRNAs in the heart, respectively. Bioinformatics analysis indicated that insulin signaling pathway was overrepresented in response to HF diet. An inverse correlation was observed between cardiac levels of GLUT4 and miRNA-29c. Similarly, we found an inverse correlation between expression of GSK3beta and the expression of miRNA-21a-3p, miRNA-29c-3p, miRNA-144-3p, and miRNA-195a-3p. In addition, miRNA-1 overexpression prevented cardiomyocyte hypertrophy. Taken together, our results revealed differentially expressed miRNA signatures in the heart in response to different HF diets. J. Cell. Physiol. 231: 1771-1783, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26638878 TI - Effectiveness of Foot Orthoses Versus Rocker-Sole Footwear for First Metatarsophalangeal Joint Osteoarthritis: Randomized Trial. AB - OBJECTIVE: To compare the effectiveness of prefabricated foot orthoses to rocker sole footwear in reducing foot pain in people with first metatarsophalangeal (MTP) joint osteoarthritis (OA). METHODS: Participants (n = 102) with first MTP joint OA were randomly allocated to receive individualized, prefabricated foot orthoses or rocker-sole footwear. The primary outcome measure was the pain subscale on the Foot Health Status Questionnaire (FHSQ) at 12 weeks. Secondary outcome measures included the function, footwear, and general foot health subscales of the FHSQ; the Foot Function Index; severity of pain and stiffness at the first MTP joint; perception of global improvement; general health status; use of rescue medication and co-interventions to relieve pain; physical activity; and the frequency of self-reported adverse events. RESULTS: The FHSQ pain subscale scores improved in both groups, but no statistically significant difference between the groups was observed (adjusted mean difference 2.05 points, 95% confidence interval [95% CI] -3.61, 7.71; P = 0.477). However, the footwear group exhibited lower adherence (mean +/- SD total hours worn 287 +/- 193 versus 448 +/ 234; P < 0.001), were less likely to report global improvement in symptoms (39% versus 62%; relative risk [RR] 0.63, 95% CI 0.41, 0.99; P = 0.043), and were more likely to experience adverse events (39% versus 16%; RR 2.47, 95% CI 1.12, 5.44; P = 0.024) compared to the orthoses group. CONCLUSION: Prefabricated foot orthoses and rocker-sole footwear are similarly effective at reducing foot pain in people with first MTP joint OA. However, prefabricated foot orthoses may be the intervention of choice due to greater adherence and fewer associated adverse events. PMID- 26638880 TI - A mathematical model for the vessel recruitment in coronary microcirculation in the absence of active autoregulation. AB - This paper proposes a mathematical model for vessel recruitment in the microvascular coronary network. The model is based on microvascular network units (MVNUs), where we define a MVNU as a portion of the microvascular network comprising seven generations of identical, parallel-arranged vessels (upstream arteries, large and small arterioles, capillaries, small and large venules, and downstream veins). The model implements a new mechanism to describe the variation in the number of MVNU in response to sudden variations of the local input pressure. In particular, it describes a recruitment mechanism dependent on distal pressure which operates in the coronary microcirculatory network even in maximally dilated conditions. We apply the model to interpret data from 29 patients who underwent revascularization by percutaneous coronary intervention (PCI). Treated vessels were the left anterior descending coronary artery, the left circumflex and the right coronary artery in 26, 2 and 1 patients, respectively. Following intracoronary adenosine administration, distal coronary pressure and blood flow were 48 +/- 18 mmHg and 45 +/- 30 ml/min before PCI, respectively, and significantly increased afterwards to 80 +/- 17 mmHg and 68 +/- 32 ml/min (p<0.001). The model predicts an increase in MVNU number in patients with preserved wall motion in the myocardial region which underwent PCI. On the contrary, a decrease in MVNU number is predicted by the model in patients with regional dysfunction and implies a relatively lower response of maximal flow to revascularization. PMID- 26638881 TI - Vitamin B12 and derivatives--In vitro permeation studies across Caco-2 cell monolayers and freshly excised rat intestinal mucosa. AB - The purpose of this study was to compare the intestinal permeation of vitamin B12 and various derivatives thereof. Permeation behavior and cytotoxicity of four derivatives (coenzyme B12, hydroxocobalamin, methylcobalamin and 4 ethylphenylcobalamin) in comparison to vitamin B12 were evaluated in two different in vitro models, Caco-2 cells and freshly excised rat intestinal mucosa. Resazurin assay was used to evaluate cytotoxicity of the test substances. All test compounds were used at a concentration of 200 MUg/ml. Permeation experiments were carried out for 3h and test compounds were quantified via reversed phase high performance liquid chromatography (HPLC). Cytotoxicity studies showed all test compounds are not toxic to cells. HPLC analyses of test compounds revealed the following rank order of increasing hydrophobicity: hydroxocobalamin=3 weeks), on protein content (PC) response was identified for proteins CD36, FABPpm and CAV1. Messenger ribonucleic acid (mRNA) data did not always correspond to functional PC, supporting previous suggestions of a disconnect due to potentially limiting factors post gene expression. The large array of study designs, cohorts, and primary dependent variables within the studies included in the present review elucidate the complexity of the interaction between exercise and LCFA transport proteins. Summary of the results in the present review validate the need for further targeted investigation within this topic, and provide an important information base for such research. J. Cell. Physiol. 231: 1671-1687, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26638981 TI - The visuospatial functions in children after cerebellar low-grade astrocytoma surgery: A contribution to the pediatric neuropsychology of the cerebellum. AB - The aim of this study was to specify whether cerebellar lesions cause visuospatial impairments in children. The study sample consisted of 40 children with low-grade cerebellar astrocytoma, who underwent surgical treatment and 40 healthy controls matched with regard to age and sex. Visuospatial abilities were tested using the spatial WISC-R subtests (Block Design and Object Assembly), Rey Osterrieth Complex Figure, Benton Judgment of Line Orientation Test, PEBL Mental Rotation Task, and Benton Visual Retention Test. To exclude general diffuse intellectual dysfunction, the WISC-R Verbal Intelligence IQ, Performance IQ, and Full-Scale IQ scores were analysed. Post-surgical medical consequences were measured with the International Cooperative Ataxia Rating Scale. Compared to controls, the cerebellar group manifested problems with mental rotation of objects, visuospatial organization, planning, and spatial construction processes which could not be explained by medical complications or general intellectual retardation. The intensity of visuospatial syndrome highly depends on cerebellar lesion side. Patients with left-sided cerebellar lesions display more severe spatial problems than those with right-sided cerebellar lesions. In conclusion, focal cerebellar lesions in children affect their visuospatial ability. The impairments profile is characterized by deficits in complex spatial processes such as visuospatial organization and mental rotation, requiring reconstruction of visual stimuli using the imagination, while elementary sensory analysis and perception as well as spatial processes requiring direct manipulation of objects are relatively better preserved. This pattern is analogous to the one previously observed in adult population and appears to be typical for cerebellar pathology in general, regardless of age. PMID- 26638982 TI - Interfacial Structure of a Liquid Crystal/Nanoparticle Nanocomposite Studied by X ray Scattering: Indirect Evidence for the Role of Faceting of the Nanoparticles. AB - The interfacial structure in a liquid crystal/nanoparticle nanocomposite is dictated by the type of nanoparticle and its functionalization compound. Nanocomposites consisting of smectic liquid crystals and nanoparticles have been studied for their applications in devices such as photovoltaics and to model biological devices. With the use of a model system, this paper presents evidence of an interfacial structure close to the vicinity of the nanoparticles that is more disordered than that of the bulk liquid crystal but is still in the smectic phase, and it seems to follow the faceting of the structure the nanoparticles adopt when they coalesce or recluster after the liquid crystal is added. PMID- 26638983 TI - Hybrid integrated biological-solid-state system powered with adenosine triphosphate. AB - There is enormous potential in combining the capabilities of the biological and the solid state to create hybrid engineered systems. While there have been recent efforts to harness power from naturally occurring potentials in living systems in plants and animals to power complementary metal-oxide-semiconductor integrated circuits, here we report the first successful effort to isolate the energetics of an electrogenic ion pump in an engineered in vitro environment to power such an artificial system. An integrated circuit is powered by adenosine triphosphate through the action of Na(+)/K(+) adenosine triphosphatases in an integrated in vitro lipid bilayer membrane. The ion pumps (active in the membrane at numbers exceeding 2 * 10(6) mm(-2)) are able to sustain a short-circuit current of 32.6 pA mm(-2) and an open-circuit voltage of 78 mV, providing for a maximum power transfer of 1.27 pW mm(-2) from a single bilayer. Two series-stacked bilayers provide a voltage sufficient to operate an integrated circuit with a conversion efficiency of chemical to electrical energy of 14.9%. PMID- 26638984 TI - Angiogenic Type I Collagen Extracellular Matrix Integrated with Recombinant Bacteriophages Displaying Vascular Endothelial Growth Factors. AB - Here, a growth-factor-integrated natural extracellular matrix of type I collagen is presented that induces angiogenesis. The developed matrix adapts type I collagen nanofibers integrated with synthetic colloidal particles of recombinant bacteriophages that display vascular endothelial growth factor (VEGF). The integration is achieved during or after gelation of the type I collagen and the matrix enables spatial delivery of VEGF into a desired region. Endothelial cells that contact the VEGF are found to invade into the matrix to form tube-like structures both in vitro and in vivo, proving the angiogenic potential of the matrix. PMID- 26638985 TI - Tract Orientation and Angular Dispersion Deviation Indicator (TOADDI): A framework for single-subject analysis in diffusion tensor imaging. AB - The purpose of this work is to develop a framework for single-subject analysis of diffusion tensor imaging (DTI) data. This framework is termed Tract Orientation and Angular Dispersion Deviation Indicator (TOADDI) because it is capable of testing whether an individual tract as represented by the major eigenvector of the diffusion tensor and its corresponding angular dispersion are significantly different from a group of tracts on a voxel-by-voxel basis. This work develops two complementary statistical tests based on the elliptical cone of uncertainty, which is a model of uncertainty or dispersion of the major eigenvector of the diffusion tensor. The orientation deviation test examines whether the major eigenvector from a single subject is within the average elliptical cone of uncertainty formed by a collection of elliptical cones of uncertainty. The shape deviation test is based on the two-tailed Wilcoxon-Mann-Whitney two-sample test between the normalized shape measures (area and circumference) of the elliptical cones of uncertainty of the single subject against a group of controls. The False Discovery Rate (FDR) and False Non-discovery Rate (FNR) were incorporated in the orientation deviation test. The shape deviation test uses FDR only. TOADDI was found to be numerically accurate and statistically effective. Clinical data from two Traumatic Brain Injury (TBI) patients and one non-TBI subject were tested against the data obtained from a group of 45 non-TBI controls to illustrate the application of the proposed framework in single-subject analysis. The frontal portion of the superior longitudinal fasciculus seemed to be implicated in both tests (orientation and shape) as significantly different from that of the control group. The TBI patients and the single non-TBI subject were well separated under the shape deviation test at the chosen FDR level of 0.0005. TOADDI is a simple but novel geometrically based statistical framework for analyzing DTI data. TOADDI may be found useful in single-subject, graph-theoretic and group analyses of DTI data or DTI-based tractography techniques. PMID- 26638986 TI - Macrophage Recruitment and Polarization During Collateral Vessel Remodeling in Murine Adipose Tissue. AB - OBJECTIVE: During autologous flap transplantation for reconstructive surgeries, plastic surgeons use a surgical pre-treatment strategy called "flap delay," which entails ligating a feeding artery into an adipose tissue flap 10-14 days prior to transfer. It is believed that this blood flow alteration leads to vascular remodeling in the flap, resulting in better flap survival following transfer; however, the structural changes in the microvascular network are poorly understood. Here, we evaluate microvascular adaptations within adipose tissue in a murine model of flap delay. METHODS AND RESULTS: We used a murine flap delay model in which we ligated an artery supplying the inguinal fat pad. Although the extent of angiogenesis appeared minimal, significant diameter expansion of pre existing collateral arterioles was observed. There was a 5-fold increase in recruitment of CX3CR1(+) monocytes to ligated tissue, a threefold increase in CD68(+) /CD206(+) macrophages in ligated tissue, a 40% increase in collateral vessel diameters supplying ligated tissue, and a 6-fold increase in the number of proliferating cells in ligated tissue. CONCLUSIONS: Our study describes microvascular adaptations in adipose in response to altered blood flow and underscores the importance of macrophages. Our data supports the development of therapies that target macrophages in order to enhance vascular remodeling in flaps. PMID- 26638987 TI - Investigation of long chain omega-3 PUFAs on arterial blood pressure, vascular reactivity and survival in angiotensin II-infused Apolipoprotein E-knockout mice. AB - Abdominal aortic aneurysm (AAA) is an inflammatory vascular disease. Long chain omega-3 polyunsaturated fatty acids (LC n-3 PUFAs) decrease inflammation and oxidative stress in an angiotensin II-infused apolipoprotein E-knockout (ApoE(-/ )) mouse model of AAA. This study investigated the effects of LC n-3 PUFAs on blood pressure and vascular reactivity in fourteen angiotensin II-infused ApoE(-/ ) male mice. Blood pressure was obtained using a non-invasive tail cuff method and whole blood was collected by cardiac puncture. Vascular reactivity of the thoracic aorta was assessed using wire myography and activation of endothelial nitric oxide synthase (eNOS) was determined by immunohistochemistry. A high LC n 3 PUFA diet increased the omega-3 index and reduced the n-6 to n-3 PUFA ratio. At day 10 post-infusion with angiotensin II, there was no difference in systolic blood pressure or diastolic blood pressure in mice fed the high or low n-3 PUFA diets. The high LC n-3 PUFA diet resulted in a non-significant trend for delay in time to death from abdominal aortic rupture. Vascular reactivity and eNOS activation remained unchanged in mice fed the high compared to the low LC n-3 PUFA diet. This study argues against direct improvement in vascular reactivity in ApoE(-/-) mice that were supplemented with n-3 PUFA for 8 weeks prior to infusion with angiotensin II. PMID- 26638988 TI - Comparing dynamic treatment regimes using repeated-measures outcomes: modeling considerations in SMART studies. AB - A dynamic treatment regime (DTR) is a sequence of decision rules, each of which recommends a treatment based on a patient's past and current health status. Sequential, multiple assignment, randomized trials (SMARTs) are multi-stage trial designs that yield data specifically for building effective DTRs. Modeling the marginal mean trajectories of a repeated-measures outcome arising from a SMART presents challenges, because traditional longitudinal models used for randomized clinical trials do not take into account the unique design features of SMART. We discuss modeling considerations for various forms of SMART designs, emphasizing the importance of considering the timing of repeated measures in relation to the treatment stages in a SMART. For illustration, we use data from three SMART case studies with increasing level of complexity, in autism, child attention deficit hyperactivity disorder, and adult alcoholism. In all three SMARTs, we illustrate how to accommodate the design features along with the timing of the repeated measures when comparing DTRs based on mean trajectories of the repeated-measures outcome. PMID- 26638990 TI - The value of SPaCE in delivering patient feedback. AB - BACKGROUND: The use of simulated patients (SPs) within undergraduate medical curricula is an established and valued learning opportunity. Within the context of simulation, it is imperative to capture feedback from all participants within the simulation activity. The Simulated Patient Candidate Evaluation (SPaCE) tool was developed to deliver SP feedback following a simulation activity. SpaCE is a closed feedback tool that allows SPs to rate a student's performance, using a five-point Likert scale, in three domains: attitude; interaction skills; and management. This research study examined the value of the SPaCE tool and how it contributes to the overall feedback that a student receives. METHODS: Classical test theory was used to determine the reliability of the SPaCE tool. An evaluation of all SP responses was conducted to observe trends in scoring patterns for each question. Qualitative data were collected via a free-text questionnaire and subsequent focus group discussion. It is imperative to capture feedback from all participants within the simulation activity RESULTS: Classical test theory determined that the SPaCE tool had a reliability co-efficient of 0.89. A total of 13 SPs replied to the questionnaire. A thematic analysis of all questionnaire data identified that the SPaCE tool provides a structure that allows patient feedback to be given effectively following a simulation activity. These themes were discussed further with six SPs who attended the subsequent focus group session. DISCUSSION: The SPaCE tool has been shown to be a reliable closed feedback tool that allows SPs to discriminate between students, based on their performance. The next stage in the development of the SPaCE tool is to test the wider applicability of this feedback tool. PMID- 26638989 TI - Cytoplasmic hnRNPK interacts with GSK3beta and is essential for the osteoclast differentiation. AB - Osteoclast differentiation is a complex and finely regulated physiological process that involves a variety of signaling pathways and factors. Recent studies suggested that the Ser9 phosphorylation of Glycogen synthase kinase-3beta (GSK3beta) is required for the osteoclast differentiation. However, the precise underlying mechanism remains unclear. We have previously identified the heterogeneous nuclear ribonucleoprotein K (hnRNPK) as a putative GSK3beta interactor. In the present study, we demonstrate that, during the RANKL-induced osteoclast differentiation, the PI3K/Akt-mediated Ser9 phosphorylation of GSK3beta provokes the nuclear-cytoplasmic translocation of hnRNPK in an ERK dependent manner, enhancing the cytoplasmic co-localization and interaction of GSK3beta and hnRNPK. We show that hnRNPK is essential for the osteoclast differentiation, and is involved in several reported functions of GSK3beta, including the activation of NF-kappaB, the expression of NFATc1, and the acetylation of tubulin, all known to be critical for osteoclast differentiation and functions. We find that hnRNPK is localized in the actin belt, and is important for the mature osteoclast formation. Taken together, we demonstrate here the critical role of hnRNPK in osteoclast differentiation, and depict a model in which the cytoplasmic hnRNPK interacts with GSK3beta and regulates its function. PMID- 26638991 TI - Recovery and purification of chitosanase produced by Bacillus cereus using expanded bed adsorption and central composite design. AB - This study presents a system for expanded bed adsorption for the purification of chitosanase from broth extract in a single step. A chitosanase-producing strain was isolated and identified as Bacillus cereus C-01 and used to produce chitosanases. The expanded bed adsorption conditions for chitosanase purification were optimized statistically using STREAMLINE(TM) DEAE and a homemade column (2.6 * 30.0 cm). Dependent variables were defined by the quality criteria purification factor (P) and enzyme yield to optimize the chromatographic process. Statistical analyses showed that the optimum conditions for the maximum P were 150 cm/h load flow velocity, 6.0 cm settled bed height, and 7.36 cm distributor height. Distributor height had a strong influence on the process, considerably affecting both the P and enzyme yield. Optimizing the purification variables resulted in an approximately 3.66-fold increase in the P compared with the value under nonoptimized conditions. This system is promising for the recovery of chitosanase from B. cereus C-01 and is economically viable because it promotes the reduction steps. PMID- 26638992 TI - Rapid RNA-ligand interaction analysis through high-information content conformational and stability landscapes. AB - The structure and biological properties of RNAs are a function of changing cellular conditions, but comprehensive, simultaneous investigation of the effect of multiple interacting environmental variables is not easily achieved. We have developed an efficient, high-throughput method to characterize RNA structure and thermodynamic stability as a function of multiplexed solution conditions using Forster resonance energy transfer (FRET). In a single FRET experiment using conventional quantitative PCR instrumentation, 19,400 conditions of MgCl2, ligand and temperature are analysed to generate detailed empirical conformational and stability landscapes of the cyclic diguanylate (c-di-GMP) riboswitch. The method allows rapid comparison of RNA structure modulation by cognate and non-cognate ligands. Landscape analysis reveals that kanamycin B stabilizes a non-native, idiosyncratic conformation of the riboswitch that inhibits c-di-GMP binding. This demonstrates that allosteric control of folding, rather than direct competition with cognate effectors, is a viable approach for pharmacologically targeting riboswitches and other structured RNA molecules. PMID- 26638994 TI - Integration of CdSe/CdSexTe1-x Type-II Heterojunction Nanorods into Hierarchically Porous TiO2 Electrode for Efficient Solar Energy Conversion. AB - Semiconductor sensitized solar cells, a promising candidate for next-generation photovoltaics, have seen notable progress using 0-D quantum dots as light harvesting materials. Integration of higher-dimensional nanostructures and their multi-composition variants into sensitized solar cells is, however, still not fully investigated despite their unique features potentially beneficial for improving performance. Herein, CdSe/CdSe(x)Te(1-x) type-II heterojunction nanorods are utilized as novel light harvesters for sensitized solar cells for the first time. The CdSe/CdSe(x)Te(1-x) heterojunction-nanorod sensitized solar cell exhibits ~33% improvement in the power conversion efficiency compared to its single-component counterpart, resulting from superior optoelectronic properties of the type-II heterostructure and 1-octanethiol ligands aiding facile electron extraction at the heterojunction nanorod-TiO(2) interface. Additional ~31% enhancement in power conversion efficiency is achieved by introducing percolation channels of large pores in the mesoporous TiO(2) electrode, which allow 1-D sensitizers to infiltrate the entire depth of electrode. These strategies combined together lead to 3.02% power conversion efficiency, which is one of the highest values among sensitized solar cells utilizing 1-D nanostructures as sensitizer materials. PMID- 26638995 TI - Implications of supermarket access, neighbourhood walkability and poverty rates for diabetes risk in an employee population. AB - OBJECTIVE: Diabetes is a growing public health problem, and the environment in which people live and work may affect diabetes risk. The goal of the present study was to examine the association between multiple aspects of environment and diabetes risk in an employee population. DESIGN: This was a retrospective cross sectional analysis. Home environment variables were derived using employees' zip code. Descriptive statistics were run on all individual- and zip-code-level variables, stratified by diabetes risk and worksite. A multivariable logistic regression analysis was then conducted to determine the strongest associations with diabetes risk. SETTING: Data were collected from employee health fairs in a Midwestern health system, 2009-2012. SUBJECTS: The data set contains 25 227 unique individuals across four years of data. From this group, using an individual's first entry into the database, 15 522 individuals had complete data for analysis. RESULTS: The prevalence of high diabetes risk in this population was 2.3 %. There was significant variability in individual- and zip-code-level variables across worksites. From the multivariable analysis, living in a zip code with higher percentage of poverty and higher walk score was positively associated with high diabetes risk, while living in a zip code with higher supermarket density was associated with a reduction in high diabetes risk. CONCLUSIONS: Our study underscores the important relationship between poverty, home neighbourhood environment and diabetes risk, even in a relatively healthy employed population, and suggests a role for the employer in promoting health. PMID- 26638996 TI - Honokiol abrogates chronic restraint stress-induced cognitive impairment and depressive-like behaviour by blocking endoplasmic reticulum stress in the hippocampus of mice. AB - The primary objective of our study is to investigate the neuroprotective efficacy of honokiol and imipramine against restraint stress (RS)-induced cognitive impairment and depressive-like behaviour in mice. We examined whether the neuroprotective activity of honokiol and imipramine mediates through the inhibition of endoplasmic reticulum stress. Adult Swiss albino mice were restrained for 6h/day for 28 days. Honokiol (3 and 10mg/kg) and Imipramine (10 and 30mg/kg) were administered for last 7 days to the different groups. Cognitive function was assessed by Morris water maze and novel object recognition test. Forced swimming test and tail suspension test were performed to evaluate the restraint stress-induced depressive-like behaviour. Proinflammatory cytokines, brain-derived neurotrophic factor, and ER stress markers i.e. 78-kDa glucose regulated protein (GRP78) and C/EBP homologous protein (CHOP) were quantified in the hippocampus. We observed cognitive impairment and depressive-like behaviour in RS-exposed animals. Honokiol (10mg/kg) treated group depicted marked reduction in cognitive impairment and depressive-like behaviour. However, imipramine (10 and 30mg/kg) prevented the depressive-like behaviour but failed to prevent RS induced cognitive impairment. Moreover, proinflammatory cytokines, GRP78 and CHOP were elevated in the hippocampus of stressed mice as compared to unstressed mice. Honokiol (10mg/kg) significantly prevented the RS-induced elevated levels of proinflammatory cytokines and endoplasmic reticulum stress markers. Our results clearly suggest the beneficial potential of honokiol in restraint stress through inhibition of proinflammatory cytokines and endoplasmic reticulum stress. Honokiol could be an intriguing therapeutic approach in endoplasmic reticulum stress related neuro-pathophysiological conditions. PMID- 26638997 TI - Downstream modulation of extrinsic apoptotic pathway in streptozotocin-induced Alzheimer's dementia in rats: Erythropoietin versus curcumin. AB - Erythropoietin and curcumin showed promising neuroprotective effects in various models of Alzheimer's dementia. This study was designed to compare the beneficial effects of erythropoietin and/or curcumin in intracerebro-ventricular (ICV) streptozotocin-induced Alzheimer's like disease in rats. Rats received ICV injection of either saline (control, n=8 rats), or streptozotocin. Three weeks following surgery, streptozotocin-injected rats were assigned into 4 groups (8 rats each); vehicle, curcumin (80mg/kg/day, orally), erythropoietin (500 IU/kg every other day, intraperitoneally) and combined (curcumin and erythropoietin) treated groups. After 3 months of treatment, rats were subjected to neurobehavioral testing, and then killed for biochemical and histological assessment of hippocampus. Fas ligand protein and caspase-8 activity as mediators of extrinsic apoptotic pathway, oxidative stress markers (malondialdehyde and reduced glutathione) and beta-amyloid (1-40 and 1-42) peptides were measured. The results showed that administration of erythropoietin suppressed extrinsic apoptosis better than curcumin, while curcumin was more effective in combating oxidative stress in ICV-streptozotocin injected rats. Both erythropoietin and curcumin treatments (individually or combined) equally reduced the hippocampal beta-amyloid accumulation and improved cognitive impairment in Morris water maze and passive avoidance tasks. The combined treatment was the most effective in ameliorating apoptosis and oxidative stress rather than behavioral responses or beta-amyloid burden. In conclusion, ICV-streptozotocin-induced Alzheimer's dementia activates hippocampal Fas ligand-mediated apoptosis, which could be reduced by erythropoietin and/or curcumin treatment. Curcumin supplementation alone could ameliorate cognitive deficits and reverse biochemical alterations in ICV-streptozotocin Alzheimer's rat model without the hazardous polycythemic effect of long-term erythropoietin injection. PMID- 26638998 TI - Aurora-B and HDAC synergistically regulate survival and proliferation of lymphoma cell via AKT, mTOR and Notch pathways. AB - Aurora-B is a protein kinase that functions mainly in the attachment of the mitotic spindle to the centromere. Overexpression of Aurora-B causes unequal distribution of genetic information, creating aneuploidy cells, a hallmark of cancer. Histone deacetylases (HDACs) are a class of enzymes that remove acetyl groups from a epsilon-N-acetyl lysine amino acid on a histone, allowing the histones to wrap the DNA more tightly, thus globally regulating gene transcription. Additionally, these HDACs can also modify non-histone proteins. Inhibition of HDACs is a potent strategy for cancer treatment. Here, we report that inhibition of Aurora-B and HDAC exerts similar tumor suppressive effects in cells. Knockdown of Aurora-B or inhibition of HDAC achieved the same effect on repression of cell proliferation. Furthermore, we found that the tumor suppressive effect of Aurora-B and HDAC inhibition is due to the induction of cell cycle arrest and/or apoptosis. Mechanistically, we demonstrated that Aurora B and HDAC can cooperatively regulate AKT, mTOR and Notch pathways. PMID- 26638999 TI - Expression of human CYP27A1 in B. megaterium for the efficient hydroxylation of cholesterol, vitamin D3 and 7-dehydrocholesterol. AB - In the current work the ability of Bacillus megaterium to take up hydrophobic substrates and efficiently express eukaryotic membrane proteins was utilized for establishing a CYP27A1-based biocatalyst. The human mitochondrial cytochrome P450CYP27A1 was co-expressed with its redox partners adrenodoxin reductase (Adr) and adrenodoxin (Adx). CYP27A1 could be localized at the cell's polyhydroxybutyrate (PHB) granules, carbon storage serving organelle-like vesicles that can take up cholesterol, resulting in bioreactor-like structures in B. megaterium . The resulting whole cell system allowed the efficient biotechnological conversion of the CYP27A1 substrates cholesterol, 7 dehydrocholesterol (7-DHC) and vitamin D3. After 48 h, nearly 100% of cholesterol was metabolized producing a final concentration of 113.14 mg/l 27 hydroxycholesterol (27-HC). Moreover, 70% of vitamin D3 was converted into 25 hydroxyvitamin D3 (25-OH-D3) with a final concentration of 80.81 mg/l. Also more than 97% of 7-DHC were found to be metabolized into two products, corresponding to 26/27-hydroxy-7-dehydrocholesterol (P1) and 25-hydroxy-7-dehydrocholesterol (P2). To our knowledge this is the first CYP27A1-based whole-cell system, allowing the efficient and low-cost production of pharmaceutically interesting metabolites of this enzyme from relatively cheap substrates. PMID- 26639009 TI - Climate and soil properties limit the positive effects of land use reversion on carbon storage in Eastern Australia. AB - Australia's "Direct Action" climate change policy relies on purchasing greenhouse gas abatement from projects undertaking approved abatement activities. Management of soil organic carbon (SOC) in agricultural soils is an approved activity, based on the expectation that land use change can deliver significant changes in SOC. However, there are concerns that climate, topography and soil texture will limit changes in SOC stocks. This work analyses data from 1482 sites surveyed across the major agricultural regions of Eastern Australia to determine the relative importance of land use vs. other drivers of SOC. Variation in land use explained only 1.4% of the total variation in SOC, with aridity and soil texture the main regulators of SOC stock under different land uses. Results suggest the greatest potential for increasing SOC stocks in Eastern Australian agricultural regions lies in converting from cropping to pasture on heavy textured soils in the humid regions. PMID- 26639000 TI - Epigenetic events in plant male germ cell heat stress responses. AB - KEY MESSAGE: A review on pollen epigenetics. Plants grow in an ever-changing environment and are used to environmental fluctuations such as high and low temperatures during their life cycles. To cope with adverse conditions, plants have evolved intricate short-term and long-term mechanisms to respond and adapt to external stresses. The plant's ability to respond to stresses largely depends on its capacity to modulate the transcriptome rapidly and specifically. Epigenetic mechanisms, including DNA methylation, chromatin dynamics and small RNAs, play an essential role in the regulation of stress-responsive gene expression. Stress-related covalent modifications of DNA and histones can be passed on during mitosis and meiosis to the next generation and provide a memory that enables the plant and even its offspring to adopt better to a subsequent stress. Plant reproduction, in particular pollen development, is the most stress sensitive process in the life cycle of the organism. In particular, developmental stages around the meiotic and mitotic divisions are the most vulnerable. In this review, we highlight the current understanding of epigenetic mechanisms involved in pollen development and speculate on their roles in pollen heat stress response. PMID- 26639011 TI - Multiple sclerosis: Etiology, symptoms, incidence and prevalence, and implications for community living and employment. AB - BACKGROUND: This article presents an overview of multiple sclerosis (MS), one of the most common neurological disorders in the Western Hemisphere. We explore the impacts of MS on employment, career development, and community living, and the implications for rehabilitation professionals. OBJECTIVE: The objective in this article is to provide a current and comprehensive review of the etiology and symptoms, incidence and prevalence, and current treatment strategies for MS, and the effects of MS on vocational and psychosocial outcomes. METHODS: This analysis represents a comprehensive review of the relevant medical, vocational, community living, and rehabilitation research literature. RESULTS: Living with MS is associated with wide-ranging and unpredictable effects on employment, career development, and community independence. Effective responses by health and rehabilitation professionals require a comprehensive understanding of this progressive and complex condition and its psychosocial impacts. CONCLUSIONS: Customized interventions from allied health professionals and rehabilitation counselors that are grounded in the unique features of MS and that reflect current best practices in Vocational Rehabilitation are required to improve rehabilitation outcomes for people with MS. PMID- 26639010 TI - Meta-Analysis of Rare Variant Association Tests in Multiethnic Populations. AB - Several methods have been proposed to increase power in rare variant association testing by aggregating information from individual rare variants (MAF < 0.005). However, how to best combine rare variants across multiple ethnicities and the relative performance of designs using different ethnic sampling fractions remains unknown. In this study, we compare the performance of several statistical approaches for assessing rare variant associations across multiple ethnicities. We also explore how different ethnic sampling fractions perform, including single ethnicity studies and studies that sample up to four ethnicities. We conducted simulations based on targeted sequencing data from 4,611 women in four ethnicities (African, European, Japanese American, and Latina). As with single ethnicity studies, burden tests had greater power when all causal rare variants were deleterious, and variance component-based tests had greater power when some causal rare variants were deleterious and some were protective. Multiethnic studies had greater power than single-ethnicity studies at many loci, with inclusion of African Americans providing the largest impact. On average, studies including African Americans had as much as 20% greater power than equivalently sized studies without African Americans. This suggests that association studies between rare variants and complex disease should consider including subjects from multiple ethnicities, with preference given to genetically diverse groups. PMID- 26639012 TI - Quality of life among people with multiple sclerosis: Replication of a three factor prediction model. AB - BACKGROUND: This article presents a replication of Rumrill, Roessler, and Fitzgerald's 2004 analysis of a three-factor model of the impact of multiple sclerosis (MS) on quality of life (QOL). The three factors in the original model included illness-related, employment-related, and psychosocial adjustment factors. OBJECTIVE: To test hypothesized relationships between QOL and illness related, employment-related, and psychosocial variables using data from a survey of the employment concerns of Americans with MS (N = 1,839). METHODS: An ex post facto, multiple correlational design was employed incorporating correlational and multiple regression analyses. RESULTS: QOL was positively related to educational level, employment status, job satisfaction, and job-match, and negatively related to number of symptoms, severity of symptoms, and perceived stress level. The three-factor model explained approximately 37 percent of the variance in QOL scores. CONCLUSIONS: The results of this replication confirm the continuing value of the three-factor model for predicting the QOL of adults with MS, and demonstrate the importance of medical, mental health, and vocational rehabilitation interventions and services in promoting QOL. PMID- 26639013 TI - From the Editor. PMID- 26639014 TI - Job dictionaries can make a difference in early return to work (RTW) for workers. PMID- 26639015 TI - Assessment of thermal treatment via irrigation of external ear to reduce cisplatin-induced hearing loss. AB - Systemic and local changes in body temperature can have a profound effect on traumatic injuries including those to the inner ear. Therefore, we investigated the effects of acutely increasing or decreasing the temperature of the external ear canal on cisplatin-induced hearing loss. The external auditory canals of male guinea pigs were acutely irrigated with warm (44 degrees C), euthermic (37 degrees C), or cool (30 degrees C) water and subsequently injected with cisplatin (12 mg/kg, i.p.). Hearing was assessed by the auditory brainstem response and cochleograms were prepared to determine loss of hair cells. Ear canal irrigation with warm water potentiated cisplatin-induced hearing loss and outer hair cell loss whereas cool ear canal irrigation showed significant protection from cisplatin-induced hearing loss and outer hair cell loss. These results suggest that non-invasive cool water ear canal irrigation may be highly effective clinical procedure for protecting against cisplatin-induced hearing loss. PMID- 26639016 TI - FGF22 protects hearing function from gentamycin ototoxicity by maintaining ribbon synapse number. AB - Inner hair cell (IHC) ribbon synapses of cochlea play important role in transmitting sound signal into auditory nerve and are sensitive to ototoxicity. However, ototoxic damage of ribbon synapses is not understood clearly. Roles of fibroblast growth factor 22 (FGF22) on synapse formation were explored under gentamycin ototoxicity. 6-week-old mice were injected intraperitoneally once daily with 50-150 mg/kg gentamicin for 10 days. Immunostaining with anti- GluR2&3/CtBP2 was used to estimate the number of ribbon synapses in the cochlea. Expression of FGF22 and myocyte enhancer factor 2D (MEF2D) was assayed with RT PCR. Expression and localization of FGF22 protein were visualized with anti-FGF22 immunostaining. Hearing thresholds were assessed using auditory brainstem responses. Gentamicin administration caused reduction in ribbon synapse number and hearing impairment without effect on hair cells in CBA/J mouse model. Immunohistochemistry showed that FGF22 protein was expressed in IHCs, but not OHCs of cochlea. Gentamycin attenuated expression of FGF22 but enhanced expression of MEF2D. Cochlear infusion of recombinant FGF22 inhibited expression of MEF2D, preserved ribbon synapses, and restored hearing function impaired by gentamycin. FGF22 restores hearing loss through maintaining ribbon synapse number, likely via inhibition of MEF2D. Activating FGF22 might provide the conceptual basis for the therapeutic strategies. PMID- 26639017 TI - Detecting and classifying three different hand movement types through electroencephalography recordings for neurorehabilitation. AB - Brain-computer interfaces can be used for motor substitution and recovery; therefore, detection and classification of movement intention are crucial for optimal control. In this study, palmar, lateral and pinch grasps were differentiated from the idle state and classified from single-trial EEG using only information prior to the movement onset. Fourteen healthy subjects performed the three grasps 100 times, while EEG was recorded from 25 electrodes. Temporal and spectral features were extracted from each electrode, and feature reduction was performed using sequential forward selection (SFS) and principal component analysis (PCA). The detection problem was investigated as the ability to discriminate between movement preparation and the idle state. Furthermore, all task pairs and the three movements together were classified. The best detection performance across movements (79 +/- 8 %) was obtained by combining temporal and spectral features. The best movement-movement discrimination was obtained using spectral features: 76 +/- 9 % (2-class) and 63 +/- 10 % (3-class). For movement detection and discrimination, the performance was similar across grasp types and task pairs; SFS outperformed PCA. The results show it is feasible to detect different grasps and classify the distinct movements using only information prior to the movement onset, which may enable brain-computer interface-based neurorehabilitation of upper limb function through Hebbian learning mechanisms. PMID- 26639018 TI - Rationality, practice variation and person-centred health policy: a threshold hypothesis. AB - Variation in practice of medicine is one of the major health policy issues of today. Ultimately, it is related to physicians' decision making. Similar patients with similar likelihood of having disease are often managed by different doctors differently: some doctors may elect to observe the patient, others decide to act based on diagnostic testing and yet others may elect to treat without testing. We explain these differences in practice by differences in disease probability thresholds at which physicians decide to act: contextual social and clinical factors and emotions such as regret affect the threshold by influencing the way doctors integrate objective data related to treatment and testing. However, depending on a theoretical construct each of the physician's behaviour can be considered rational. In fact, we showed that the current regulatory policies lead to predictably low thresholds for most decisions in contemporary practice. As a result, we may expect continuing motivation for overuse of treatment and diagnostic tests. We argue that rationality should take into account both formal principles of rationality and human intuitions about good decisions along the lines of Rawls' 'reflective equilibrium/considered judgment'. In turn, this can help define a threshold model that is empirically testable. PMID- 26639020 TI - Engaging Living Kidney Donors in a New Paradigm of Postdonation Care. AB - Recent studies have highlighted the need for better understanding of the long term health outcomes of living donors. Barriers to establishment of a dedicated long-term donor follow-up data system in the United States include infrastructure costs and donor retention. We propose providing all previous and future living donors with a lifelong health insurance benefit for the primary purpose of facilitating acquisition of health information after donation as an alternative to establishment of a dedicated donor follow-up data system. Donors would consent to allow collection and analysis of their medical data, and continuation of insurance coverage would require completion of regular health assessments. The extension of health insurance would be analogous to the established practice of paying people for participation in a research study and would provide a mechanism to engage donors in a new paradigm of postdonation care in which donors are actively involved in their own health maintenance. Rather than acting as an inducement for donation, providing donors with the ability to easily contribute information about their health status represents a practical strategy to acquire the long-term medical information necessary to better inform future generations of living kidney donors. PMID- 26639019 TI - Effect of maternal PCOS and PCOS-like phenotype on the offspring's health. AB - Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine disorder with both reproductive and metabolic abnormalities affecting women of reproductive age. While the exact origin of PCOS is unknown, observations from clinical and animal studies suggest that maternal hyperandrogenism may be a contributing factor. Because women with PCOS manifest hyperandrogenism during pregnancy, changes in the gestational endocrine milieu may play a role in the vertical transmission of this syndrome. This review discusses the potential developmental origins of PCOS, the impact of maternal PCOS on the offspring's health and contributions of the postnatal environment, capitalizing on findings from animal models that exhibit a PCOS-like phenotype. In addition, this review highlights the scarcity of data at early gestational stages in humans and the importance of animal experimentation to better understand the cellular and molecular mechanisms involved in the programming of adult diseases, therefore, helping identify therapeutic targets for preventive and treatment strategies. PMID- 26639021 TI - Oxydifluoromethylation of Alkenes by Photoredox Catalysis: Simple Synthesis of CF2H-Containing Alcohols. AB - We have developed a novel and simple protocol for the direct incorporation of a difluoromethyl (CF2 H) group into alkenes by visible-light-driven photoredox catalysis. The use of fac-[Ir(ppy)3] (ppy=2-pyridylphenyl) photocatalyst and shelf-stable Hu's reagent, N-tosyl-S-difluoromethyl-S-phenylsulfoximine, as a CF2 H source is the key to success. The well-designed photoredox system achieves synthesis of not only beta-CF2 H-substituted alcohols but also ethers and an ester from alkenes through solvolytic processes. The present method allows a single-step and regioselective formation of C(sp(3))-CF2 H and C(sp(3))-O bonds from C=C moiety in alkenes, such as hydroxydifluoromethylation, regardless of terminal or internal alkenes. Moreover, this methodology tolerates a variety of functional groups. PMID- 26639023 TI - Evolution of Plasmonic Metamolecule Modes in the Quantum Tunneling Regime. AB - Plasmonic multinanoparticle systems exhibit collective electric and magnetic resonances that are fundamental for the development of state-of-the-art optical nanoantennas, metamaterials, and surface-enhanced spectroscopy substrates. While electric dipolar modes have been investigated in both the classical and quantum realm, little attention has been given to magnetic and other "dark" modes at the smallest dimensions. Here, we study the collective electric, magnetic, and dark modes of colloidally synthesized silver nanosphere trimers with varying interparticle separation using scanning transmission electron microscopy (STEM) and electron energy-loss spectroscopy (EELS). This technique enables direct visualization and spatially selective excitation of individual trimers, as well as manipulation of the interparticle distance into the subnanometer regime with the electron beam. Our experiments reveal that bonding electric and magnetic modes are significantly impacted by quantum effects, exhibiting a relative blueshift and reduced EELS amplitude compared to classical predictions. In contrast, the trimer's electric dark mode is not affected by quantum tunneling for even Angstrom-scale interparticle separations. We employ a quantum-corrected model to simulate the effect of electron tunneling in the trimer which shows excellent agreement with experimental results. This understanding of classical and quantum-influenced hybridized modes may impact the development of future quantum plasmonic materials and devices, including Fano-like molecular sensors and quantum metamaterials. PMID- 26639022 TI - Characterization of the 26S proteasome network in Plasmodium falciparum. AB - In eukaryotic cells, the ubiquitin-proteasome system as a key regulator of protein quality control is an excellent drug target. We therefore aimed to analyze the 26S proteasome complex in the malaria parasite Plasmodium falciparum, which still threatens almost half of the world's population. First, we established an affinity purification protocol allowing for the isolation of functional 26S proteasome complexes from the parasite. Subunit composition of the proteasome and component stoichiometry were studied and physiologic interacting partners were identified via in situ protein crosslinking. Furthermore, intrinsic ubiquitin receptors of the plasmodial proteasome were determined and their roles in proteasomal substrate recognition were analyzed. Notably, PfUSP14 was characterized as a proteasome-associated deubiquitinase resulting in the concept that targeting proteasomal deubiquitinating activity in P. falciparum may represent a promising antimalarial strategy. The data provide insights into a profound network orchestrated by the plasmodial proteasome and identified novel drug target candidates in the ubiquitin-proteasome system. PMID- 26639024 TI - A novel metric for quantification of homogeneous and heterogeneous tumors in PET for enhanced clinical outcome prediction. AB - Oncologic PET images provide valuable information that can enable enhanced prognosis of disease. Nonetheless, such information is simplified significantly in routine clinical assessment to meet workflow constraints. Examples of typical FDG PET metrics include: (i) SUVmax, (2) total lesion glycolysis (TLG), and (3) metabolic tumor volume (MTV). We have derived and implemented a novel metric for tumor quantification, inspired in essence by a model of generalized equivalent uniform dose as used in radiation therapy. The proposed metric, denoted generalized effective total uptake (gETU), is attractive as it encompasses the abovementioned commonly invoked metrics, and generalizes them, for both homogeneous and heterogeneous tumors, using a single parameter a. We evaluated this new metric for improved overall survival (OS) prediction on two different baseline FDG PET/CT datasets: (a) 113 patients with squamous cell cancer of the oropharynx, and (b) 72 patients with locally advanced pancreatic adenocarcinoma. Kaplan-Meier survival analysis was performed, where the subjects were subdivided into two groups using the median threshold, from which the hazard ratios (HR) were computed in Cox proportional hazards regression. For the oropharyngeal cancer dataset, MTV, TLG, SUVmax, SUVmean and SUVpeak produced HR values of 1.86, 3.02, 1.34, 1.36 and 1.62, while the proposed gETU metric for a = 0.25 (greater emphasis on volume information) enabled significantly enhanced OS prediction with HR = 3.94. For the pancreatic cancer dataset, MTV, TLG, SUVmax, SUVmean and SUVpeak resulted in HR values of 1.05, 1.25, 1.42, 1.45 and 1.52, while gETU at a = 3.2 (greater emphasis on SUV information) arrived at an improved HR value of 1.61. Overall, the proposed methodology allows placement of differing degrees of emphasis on tumor volume versus uptake for different types of tumors to enable enhanced clinical outcome prediction. PMID- 26639025 TI - Deciphering Genomic Underpinnings of Quantitative MRI-based Radiomic Phenotypes of Invasive Breast Carcinoma. AB - Magnetic Resonance Imaging (MRI) has been routinely used for the diagnosis and treatment of breast cancer. However, the relationship between the MRI tumor phenotypes and the underlying genetic mechanisms remains under-explored. We integrated multi-omics molecular data from The Cancer Genome Atlas (TCGA) with MRI data from The Cancer Imaging Archive (TCIA) for 91 breast invasive carcinomas. Quantitative MRI phenotypes of tumors (such as tumor size, shape, margin, and blood flow kinetics) were associated with their corresponding molecular profiles (including DNA mutation, miRNA expression, protein expression, pathway gene expression and copy number variation). We found that transcriptional activities of various genetic pathways were positively associated with tumor size, blurred tumor margin, and irregular tumor shape and that miRNA expressions were associated with the tumor size and enhancement texture, but not with other types of radiomic phenotypes. We provide all the association findings as a resource for the research community (available at http://compgenome.org/Radiogenomics/). These findings pave potential paths for the discovery of genetic mechanisms regulating specific tumor phenotypes and for improving MRI techniques as potential non-invasive approaches to probe the cancer molecular status. PMID- 26639026 TI - Three-dimensional Nitrogen-Doped Graphene Supported Molybdenum Disulfide Nanoparticles as an Advanced Catalyst for Hydrogen Evolution Reaction. AB - An efficient three-dimensional (3D) hybrid material of nitrogen-doped graphene sheets (N-RGO) supporting molybdenum disulfide (MoS(2)) nanoparticles with high performance electrocatalytic activity for hydrogen evolution reaction (HER) is fabricated by using a facile hydrothermal route. Comprehensive microscopic and spectroscopic characterizations confirm the resulting hybrid material possesses a 3D crumpled few-layered graphene network structure decorated with MoS(2) nanoparticles. Electrochemical characterization analysis reveals that the resulting hybrid material exhibits efficient electrocatalytic activity toward HER under acidic conditions with a low onset potential of 112 mV and a small Tafel slope of 44 mV per decade. The enhanced mechanism of electrocatalytic activity has been investigated in detail by controlling the elemental composition, electrical conductance and surface morphology of the 3D hybrid as well as Density Functional Theory (DFT) calculations. This demonstrates that the abundance of exposed active sulfur edge sites in the MoS(2) and nitrogen active functional moieties in N-RGO are synergistically responsible for the catalytic activity, whilst the distinguished and coherent interface in MoS(2)/N-RGO facilitates the electron transfer during electrocatalysis. Our study gives insights into the physical/chemical mechanism of enhanced HER performance in MoS(2)/N-RGO hybrids and illustrates how to design and construct a 3D hybrid to maximize the catalytic efficiency. PMID- 26639027 TI - Comparing two different daily disposable lenses for improving discomfort related to contact lens wear. AB - PURPOSE: This study aimed to compare two daily disposable lenses to reduce lens induced discomfort (CLD) among different populations of symptomatic wearers. METHODS: This was a multicenter, crossover, study. Subjects were contact lens wearers reporting CLD. Subjects (76) were randomly assigned to wear Nelfilcon A (NF) then Delefilcon A (DF)- group A- or vice-versa (group B). Tear break-up time (TBUT), corneal (CS) and conjunctival staining (CJS) were graded at every visit. Subjects'symptoms were evaluated with Contact Lens Dry Eye Questionnaire (CLDEQ 8) and a research questionnaire (Universite de Montreal). RESULTS: Compared to baseline (BL), TBUT did not vary (BL) 6.7+2.1s vs. 6.7+1.8s (NF) vs. 6.4+1.9 (DF) (F=1.69; p=0.201) NF wearers were more at risk of developing moderate CJS (odds ratio 14.324; 95% CI 3.103-66.126) and more likely to show increased CS (odds ratio 8.754; 95% CI 2.181-35.146). Comfortable hours of wear reported at BL (7.6+2.3h) did not improve significantly with NF lenses (8.5+ 2.6h; F=1.095; p=0.394) but increased by 22% with DF lenses (10.7+3.0h; F=2.434; p=0.031). The total CLDEQ-8 score was improved with DF lenses (BL 17.2 vs. NF 16.1, p=0.397; vs. DF 8.3, p<0.001), especially on more symptomatic subjects. In the end, 92% of patients preferred to switch over DD lenses, 78% selecting DF material for the future. CONCLUSION: Outcome from switching CLD wearers to DD lenses is material related. It seems that initial severity of the symptoms could be also a factor to consider. PMID- 26639028 TI - Left Free Wall Accessory Pathway Ablation in the Presence of a Mechanical Mitral Prosthesis. PMID- 26639029 TI - Iron Oxide with Different Crystal Phases (alpha- and gamma-Fe2O3) in Electroanalysis and Ultrasensitive and Selective Detection of Lead(II): An Advancing Approach Using XPS and EXAFS. AB - Iron oxide with different crystal phases (alpha- and gamma-Fe2O3) has been applied to electrode coatings and been demonstrated to ultrasensitive and selective electrochemical sensing toward heavy metal ions (e.g., Pb(II)). A range of Pb(II) contents in micromoles (0.1 to 1.0 MUM) at alpha-Fe2O3 nanoflowers with a sensitivity of 137.23 MUA MUM(-1) cm(-2) and nanomoles (from 0.1 to 1.0 nM) at gamma-Fe2O3 nanoflowers with a sensitivity of 197.82 MUA nM(-1) cm(-2) have been investigated. Furthermore, an extended X-ray absorption fine structure (EXAFS) technique was applied to characterize the difference of local structural environment of the adsorbed Pb(II) on the surface of alpha- and gamma-Fe2O3. The results first showed that alpha- and gamma-Fe2O3 had diverse interaction between Pb(II) and iron (hydro)oxides, which were consistent with the difference of electrochemical performance. Determining the responses of Cu(II) and Hg(II) as the most appropriate choice for comparison, the stripping voltammetric quantification of Pb(II) with high sensitivity and selectivity at gamma-Fe2O3 nanoflower has been demonstrated. This work reveals that the stripping performances of a nanomodifier have to be directly connected with its intrinsic surface atom arrangement. PMID- 26639031 TI - Influence of demographic and clinical factors on the mortality rate of a rheumatoid arthritis cohort: A 20-year survival study. AB - OBJECTIVES: To describe the mortality rate (MR) and standardized MR (SMR) of an incident cohort of rheumatoid arthritis (RA) patients followed up for 20 years, and to analyze the influence on morality risk of different demographic and clinical variables, including radiographic joint damage. METHODS: Retrospective longitudinal study that included 2271 RA patients attending the rheumatology outpatient clinic of the Hospital Clinico San Carlos (Madrid, Spain), enrolled from January 1994 to February 2013 and followed up from RA diagnosis to patients' death or September 2013. Disability and disease activity were measured as the averaged value of the Heath Assessment Questionnaire and the erythrocyte sedimentation rate, respectively, of the first 2 years after RA diagnosis. Radiographic joint damage of hands and wrists was assessed with the Sharp/van der Heijde score. Indirect SMRs with a 95% of confidence interval (95% CI) were calculated. Cox bivariate and multivariate regression models were performed to assess risk factors for death. RESULTS: A total of 431 patients died (19%) during the observation time (18,482 person-years), resulting in a MR of 23 subjects per 1000 patient-years [95% CI: 21-26]. SMR was 1.89 (1.72-2.08). In the multivariate analysis, men, older age at diagnosis, the presence of rheumatoid factor, higher number of hospital admissions, greater disease activity, and greater radiographic joint damage were independently associated with greater mortality risk. CONCLUSIONS: RA patients have an excess mortality compared with the general population. Radiological joint damage and early disease activity are independent mortality risk factors. A tighter control at early stages may be necessary to reduce mortality. PMID- 26639032 TI - Kawasaki disease after all. PMID- 26639033 TI - A review of the effects of statins in systemic sclerosis. AB - OBJECTIVES: We performed a literature review assessing possible benefits of statins in systemic sclerosis (SSc). METHODS: PubMed, Embase, Cochrane Databases, and Medline were searched. Full-text English publications were identified in which the effects of statins in SSc were examined. Letters, review articles, and studies on morphea were excluded. RESULTS: In all, 18 of 404 studies were relevant. In vitro, statins decreased transcription and translation of IL-6 and collagen, with reversal via mevalonate. Animal studies demonstrated reduced production of Ras (a protein superfamily of GTPases), Rho (part of the Ras superfamily), and extracellular signal-regulated kinases (ERK), less fibrosis and myofibroblast transdifferentiation, and improved macrovasculature. In human studies, IL-6, an inflammatory cytokine, was reduced. Usually endothelial progenitor cell concentrations increased, and flow-mediated dilatation improved. Raynaud's phenomenon, digital ulcers, and physician global assessments improved in the majority of studies of statin treatment in SSc. None of the 256 patients receiving statins experienced transaminitis or myopathy. CONCLUSIONS: Not all findings were consistent. However, in general, in vitro, animal, and human studies demonstrated benefit in SSc pathophysiology, likely mediated through inhibition of lipid intermediate synthesis. Clinical improvement in SSc circulatory complications was observed. Statins seemed safe and well tolerated in SSc. Larger longer-term multi-site randomized trials are needed to further determine the role of statins as adjunctive treatment of this complex, heterogeneous connective tissue disease. PMID- 26639034 TI - Multiscale Origami Structures as Interface for Cells. AB - A DNA-based platform was developed to address fundamental aspects of early stages of cell signaling in living cells. By site-directed sorting of differently encoded, protein-decorated DNA origami structures on DNA microarrays, we combine the advantages of the bottom-up self-assembly of protein-DNA nanostructures and top-down micropatterning of solid surfaces to create multiscale origami structures as interface for cells (MOSAIC). In a proof-of-principle, we use this technology to analyze the activation of epidermal growth factor (EGF) receptors in living MCF7 cells using DNA origami structures decorated on their surface with distinctive nanoscale arrangements of EGF ligand entities. MOSAIC holds the potential to present to adhered cells well-defined arrangements of ligands with full control over their number, stoichiometry, and precise nanoscale orientation. It therefore promises novel applications in the life sciences, which cannot be tackled by conventional technologies. PMID- 26639036 TI - Vascular mTOR-dependent mechanisms linking the control of aging to Alzheimer's disease. AB - Aging is the strongest known risk factor for Alzheimer's disease (AD). With the discovery of the mechanistic target of rapamycin (mTOR) as a critical pathway controlling the rate of aging in mice, molecules at the interface between the regulation of aging and the mechanisms of specific age-associated diseases can be identified. We will review emerging evidence that mTOR-dependent brain vascular dysfunction, a universal feature of aging, may be one of the mechanisms linking the regulation of the rate of aging to the pathogenesis of Alzheimer's disease. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock. PMID- 26639035 TI - Ceramides And Stress Signalling Intersect With Autophagic Defects In Neurodegenerative Drosophila blue cheese (bchs) Mutants. AB - Sphingolipid metabolites are involved in the regulation of autophagy, a degradative recycling process that is required to prevent neuronal degeneration. Drosophila blue cheese mutants neurodegenerate due to perturbations in autophagic flux, and consequent accumulation of ubiquitinated aggregates. Here, we demonstrate that blue cheese mutant brains exhibit an elevation in total ceramide levels; surprisingly, however, degeneration is ameliorated when the pool of available ceramides is further increased, and exacerbated when ceramide levels are decreased by altering sphingolipid catabolism or blocking de novo synthesis. Exogenous ceramide is seen to accumulate in autophagosomes, which are fewer in number and show less efficient clearance in blue cheese mutant neurons. Sphingolipid metabolism is also shifted away from salvage toward de novo pathways, while pro-growth Akt and MAP pathways are down-regulated, and ER stress is increased. All these defects are reversed under genetic rescue conditions that increase ceramide generation from salvage pathways. This constellation of effects suggests a possible mechanism whereby the observed deficit in a potentially ceramide-releasing autophagic pathway impedes survival signaling and exacerbates neuronal death. PMID- 26639037 TI - At pains to consent: A narrative inquiry into women's attempts of natural childbirth. AB - BACKGROUND: With only 1.2% of all annual U.S. births registered as out-of hospital births, national trends show an increase in medicalised hospital births. Caesarean sections have become the most common surgical procedure in the U.S.; Caesarean section rates have increased from 20.6% in 1997 to 31.5% in 2009. Furthermore, in 2009, 67% of hospital births utilised epidural analgesia and 26% used oxytocin augmentation. In response to the increased medicalisation of childbirth within the U.S., some women resist standardised medical procedures and instead choose to labour and birth without medical intervention. AIM: The purpose of this study was to understand and contextualise the childbirth experiences of first-time mothers who planned to have a natural childbirth (without medical intervention) in the Midsouthern United States. METHODS: Using narrative inquiry, we collected data from six participants through semi-structured life-story interviews. FINDINGS: Utilising thematic analysis, four recurring themes emerged: (1) benefits and limitations of pre-labour self-education; (2) labouring women's experiences of relationality; (3) the importance of birth stories and expectations; and (4) the creation of false dilemmas and complexities of "informed choice." DISCUSSION AND CONCLUSION: The women's stories suggest that U.S. medical establishments, the media, and society need to empower pregnant and birthing women by creating new narratives of labour and positive spaces of relationality. Furthermore, health care professionals need to critically examine their usage of the medical model of care while respecting women's choices and agency. PMID- 26639038 TI - Immediate and Intermediate Outcome After Transapical Versus Transfemoral Transcatheter Aortic Valve Replacement. AB - A few studies recently reported controversial results with transfemoral transcatheter aortic valve replacement (TF-TAVR) versus transapical transcatheter aortic valve replacement (TA-TAVR), often without adequate adjusted analysis for baseline differences. Data on patients who underwent TF-TAVR and TA-TAVR from the Observational Study of Effectiveness of avR-tavI procedures for severe Aortic stenosis Treatment study were analyzed with propensity score 1-to-1 matching. From a cohort of 1,654 patients (1,419 patients underwent TF-TAVR and 235 patients underwent TA-TAVR), propensity score matching resulted in 199 pairs of patients with similar operative risk (EuroSCORE II: TF-TAVR 8.1 +/- 7.1% vs TA TAVR, 8.4 +/- 7.3%, p = 0.713). Thirty-day mortality was 8.0% after TA-TAVR and 4.0% after TF-TAVR (p = 0.102). Postoperative rates of stroke (TA-TAVR, 2.0% vs TF-TAVR 1.0%, p = 0.414), cardiac tamponade (TA-TAVR, 4.1% vs TF-TAVR 1.5%, p = 0.131), permanent pacemaker implantation (TA-TAVR, 8.7% vs TF-TAVR 13.3%, p = 0.414), and infection (TA-TAVR, 6.7% vs TF-TAVR 3.6%, p = 0.180) were similar in the study groups but with an overall trend in favor of TF-TAVR. Higher rates of major vascular damage (7.2% vs 1.0%, p = 0.003) and moderate-to-severe paravalvular regurgitation (7.8% vs 5.2%, p = 0.008) were observed after TF-TAVR. On the contrary, TA-TAVR was associated with higher rates of red blood cell transfusion (50.0% vs 30.4%, p = 0.0002) and acute kidney injury (stages 1 to 3: 44.4% vs 21.9%, p <0.0001) compared with TF-TAVR. Three-year survival rate was 69.1% after TF-TAVR and 57.0% after TA-TAVR (p = 0.006), whereas freedom from major adverse cardiovascular and cerebrovascular events was 61.9% after TF-TAVR and 50.4% after TA-TAVR (p = 0.011). In conclusion, TF-TAVR seems to be associated with significantly higher early and intermediate survival compared with TA-TAVR. The transfemoral approach, whenever feasible, should be considered the route of choice for TAVR. PMID- 26639039 TI - Impact of Hemoglobin A1c Levels on Residual Platelet Reactivity and Outcomes After Insertion of Coronary Drug-Eluting Stents (from the ADAPT-DES Study). AB - An increasing hemoglobin A1c (HbA1c) level portends an adverse cardiovascular prognosis; however, the association between glycemic control, platelet reactivity, and outcomes after percutaneous coronary intervention (PCI) with drug eluting stents (DES) is unknown. We sought to investigate whether HbA1c levels are associated with high platelet reactivity (HPR) in patients loaded with clopidogrel and aspirin, thereby constituting an argument for intensified antiplatelet therapy in patients with poor glycemic control. In the prospective, multicenter Assessment of Dual Antiplatelet Therapy With Drug Eluting Stents registry, HbA1c levels were measured as clinically indicated in 1,145 of 8,582 patients, stratified by HbA1c <6.5% (n = 551, 48.12%), 6.5% to 8.5% (n = 423, 36.9%), and >8.5% (n = 171, 14.9%). HPR on clopidogrel and aspirin was defined after PCI as P2Y12 reaction units (PRU) >208 and aspirin reaction units >550, respectively. HPR on clopidogrel was frequent (48.3%), whereas HPR on aspirin was not (3.9%). Patients with HbA1c >8.5% were younger, more likely non-Caucasian, had a greater body mass index, and more insulin-treated diabetes and acute coronary syndromes. Proportions of PRU >208 (42.5%, 50.2%, and 62.3%, p <0.001) and rates of definite or probable stent thrombosis (ST; 0.9%, 2.7%, and 4.2%, p = 0.02) increased progressively with HbA1c groups. Clinically relevant bleeding was greatest in the intermediate HbA1c group (8.2% vs 13.1% vs 9.5%, p = 0.04). In adjusted models that included PRU, high HbA1c levels (>8.5) remained associated with ST (hazard ratio 3.92, 95% CI 1.29 to 12.66, p = 0.02) and cardiac death (hazard ratio 4.24, 95% CI 1.41 to 12.70) but not bleeding at 2-year follow-up. There was no association between aspirin reaction units >550 and HbA1c levels. In conclusion, in this large-scale study, HbA1c and HPR were positively associated, but the clinical effect on adverse outcome was driven by poor glycemic control, which predicted ST and cardiac death after PCI regardless of PRU levels, warranting efforts to improve glycemic control after DES implantation in patients with diabetes mellitus. PMID- 26639040 TI - Meta-Analysis of Transcatheter Aortic Valve Replacement Versus Surgical Aortic Valve Replacement in Patients With Severe Aortic Valve Stenosis. AB - Transcatheter aortic valve replacement (TAVR) is a viable option in the treatment of severe aortic stenosis in patients at high risk for surgery. We sought to further investigate outcomes in patients at low to intermediate risk with aortic stenosis who underwent surgical aortic valve replacement (SAVR) versus TAVR. We systematically searched the electronic databases, MEDLINE, PubMed, EMBASE, and Cochrane for prospective cohort studies of the effects of TAVR versus SAVR on clinical outcomes (30-day mortality, all-cause mortality, stroke and myocardial infarction, major vascular complications, paravalvular regurgitation, permanent pacemaker implantation, major bleeding, and acute kidney injury). We identified 5 clinical studies, examining 1,618 patients in the TAVR group and 1,581 patients in the SAVR group with an average follow-up of 1.05 years. No difference in all cause mortality, stroke, and myocardial infarction between the 2 approaches was found. TAVR was associated with higher rates of vascular complications, permanent pacemaker implantation, and moderate or severe paravalvular regurgitation (p <0.001 for all), whereas more major bleeding events were seen in the SAVR group (p <0.001). In conclusion, TAVR was found to have similar survival and stroke rates and lower major bleeding rates as compared with SAVR in patients at low or intermediate surgical risk. However, SAVR was associated with less pacemaker placements and paravalvular regurgitation rates. PMID- 26639042 TI - Is the Standard Treatment for Early Syphilis Sufficient to Prevent Cardiovascular and Neurologic Syphilis? PMID- 26639041 TI - Patterns of Cardiovascular Mortality for HIV-Infected Adults in the United States: 1999 to 2013. AB - With widespread availability and the use of antiretroviral therapy, patients with human immunodeficiency virus (HIV) in the United States are living long enough to experience non-AIDS-defining illnesses. HIV is associated with an increased risk for cardiovascular disease (CVD) because of traditional CVD risk factors, residual virally mediated inflammation despite HIV treatment, and side effects of antiretroviral therapy. No United States population-wide studies have evaluated patterns of CVD mortality for HIV-infected subjects. Our central hypothesis was that the proportionate mortality from CVD (CVD mortality/total mortality) in the HIV-infected population increased from 1999 to 2013. We used the Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research online database of the United States public health data to assess proportionate CVD mortality from 1999 to 2013 in the HIV-infected, general, and inflammatory polyarthropathy populations; the inflammatory polyarthropathy population was included as a positive control group. Total mortality in the HIV infected population decreased from 15,739 in 1999 to 8,660 in 2013; however, CVD mortality increased from 307 to 400 during the same period. Thus, proportionate CVD mortality for the HIV-infected population increased significantly from 1999 to 2013 (p <0.0001); this pattern was consistent across races, particularly for men. In contrast, proportionate CVD mortality decreased for the general and inflammatory polyarthropathy populations from 1999 to 2013. In conclusion, CVD has become an increasingly common cause of death in HIV-infected subjects since 1999; understanding evolving mortality risks in the HIV-infected population is essential to inform routine clinical care of HIV-infected subjects as well as CVD prevention and treatment. PMID- 26639044 TI - First case report of bacteremia due to 'Campylobacter-like organism 3'. AB - A case of bacteremia caused by a rare Helicobacter species, Campylobacter-like organism 3 (CLO-3), in a 75-year-old man with prostate cancer and an indwelling urethral catheter for urinary retention, is reported. Oral levofloxacin (500mg per day) was effective, although the results of antimicrobial susceptibility testing were unknown. Non-film-like, small, clear colonies were isolated on blood agar after 72h of microaerobic incubation at 37 degrees C. Biochemical testing indicated that the isolates were catalase-positive, negative for nitrate reduction and urease activity, and positive for indoxyl acetate hydrolysis. The isolate was identified as CLO-3 by sequence analysis of the 16S rRNA and hsp60 genes. Although CLO-3 is known to cause enterocolitis, bacteremia due to CLO-3 has not been described. There have been an increasing number of reports of bacteremia caused by Helicobacter cinaedi and Helicobacter fennelliae, which were first reported as CLO-1 and CLO-2, and CLO-3 may represent another emerging cause of Helicobacter-induced bacteremia. PMID- 26639043 TI - Expression and pharmacological modulation of visceral pain-induced conditioned place aversion in mice. AB - Pain encompasses both a sensory as well as an affective dimension and these are differentially processed in the brain and periphery. It is therefore important to develop animal models to reflect the non-reflexive assays in pain. In this study, we compared effects of the mu opioid receptor agonist morphine, the nonsteroidal anti-inflammatory drug ketoprofen and the kappa receptor opioid agonist U50,488H and antagonist JDTic on acetic acid-induced stretching and acetic acid-induced aversion in the condition place aversion (CPA) test in male ICR mice. Intraperitoneal administration of acetic acid (0.32-1%) was equipotent in stimulating stretching and CPA. Ketoprofen, morphine and U50,488H all inhibited the acid-induced stretching. Ketoprofen and morphine also blocked the acid induced CPA but U50,488H failed to do so. The reversal ability of ketoprofen and morphine on acid-induced CPA is unique to pain-stimulated place aversion since these drugs failed to reduce non-noxious LiCl-induced CPA. Overall, this study characterized and validated a preclinical mouse model of pain-related aversive behavior that can be used to assess genetic and biological mechanisms of pain as well as improving the predictive validity of preclinical studies on candidate analgesics. PMID- 26639050 TI - Clinical findings of bacteremic septic arthritis according to the site of acquisition: The overlap between health care-related and community- and nosocomial-acquired cases. AB - BACKGROUND: The site of acquisition of infection may have a major impact on outcome. The health care-related (HCR) environment has recently come under scrutiny. In a group of patients with bacteremic septic arthritis (SA), we compared their characteristics, type of SA, microbiology and prognosis according to the site of acquisition: community-acquired (CA), nosocomial-acquired (NA), and HCR. METHODS: We studied all patients with bacteremic SA seen at our institution between 1985 and 2013. Data were obtained from a protocol of prospectively recorded bacteremia cases. RESULTS: There were 273 cases of bacteremic SA (CA: 51%; NA: 31%; and HCR: 18%). NA and HCR sites were more frequent in older and fragile patients. SA of peripheral joints was the most common presentation; infections of the axial skeleton predominated in CA and HCR (24%), and prosthetic joint infection in NA (44%). MRSA and Pseudomonas aeruginosa were mainly found in NA (21% and 6% respectively) and HCR (14% and 8% respectively), whereas Streptococcus spp. was more frequent in CA (30%) and HCR (28%). The 30-day mortality rates were: CA 7%, HCR 18%, and NA 26%. CONCLUSION: The characteristics of HCR-SA overlapped with those of the CA or NA-SA cases. The HCR and NA cases presented more advanced age, greater fragility, and the predominance of difficult-to-treat microorganisms, while the HCR and CA cases presented an involvement of the axial skeleton, streptococcal etiology, and a lower number of prosthetic joint infections. Our data show that the site of acquisition should be considered when planning diagnostic and therapeutic management for SA. PMID- 26639051 TI - Association between particulate air pollution and venous thromboembolism: A systematic literature review. AB - Air pollution is a leading global problem for public health. A number of ambient pollutants have been involved, including carbon monoxide (CO), nitrogen dioxide (NO2), sulfur dioxide (SO2), ozone (O3) and particulate matter (PM). Although exposure to PM has been linked to a wide array of cardiovascular and respiratory disorders, its effect on venous thrombotic disorders is still uncertain. To elucidate this issue, we have performed a systematic review on the existing literature on the association between PM and venous thromboembolism (VTE), using MEDLINE, EMBASE and Cochrane electronic databases. Of the 158 reviewed studies, 11 of them (3 case-crossover studies, 2 time-series studies, 2 case-control studies, 2 prospective cohort studies, 2 retrospective studies) involving more than 500,000 events fulfilled the inclusion criteria and results are presented here. Because there was substantial heterogeneity in study design, duration of follow-up, statistical measure of effects, clinical outcomes and threshold, we refrained to perform a quantitative analysis of the available data and carried out only a systematic review. Overall, the literature data suggest a link between PM and VTE, but further trials on larger populations of patients with homogeneous study designs and outcomes are warranted. PMID- 26639052 TI - CD147 monoclonal antibody mediated by chitosan nanoparticles loaded with alpha hederin enhances antineoplastic activity and cellular uptake in liver cancer cells. AB - An antibody that specifically interacts with an antigen could be applied to an active targeting delivery system. In this study, CD147 antibody was coupled with alpha-hed chitosan nanoparticles (alpha-Hed-CS-NPs). alpha-Hed-CS-CD147-NPs were round and spherical in shape, with an average particle size of 148.23 +/- 1.75 nm. The half-maximum inhibiting concentration (IC50) of alpha-Hed-CS-CD147-NPs in human liver cancer cell lines HepG2 and SMMC-7721 was lower than that of free alpha-Hed and alpha-Hed-CS-NPs. alpha-Hed-induced cell death was mainly triggered by apoptosis. The increase in intracellular accumulation of alpha-Hed-CS-CD147 NPs was also related to CD147-mediated internalization through the Caveolae dependent pathway and lysosomal escape. The higher targeting antitumor efficacy of alpha-Hed-CS-CD147-NPs than that alpha-Hed-CS-NPs was attributed to its stronger fluorescence intensity in the tumor site in nude mice. PMID- 26639054 TI - Global exponential periodicity and stability of recurrent neural networks with multi-proportional delays. AB - In this paper, a class of recurrent neural networks with multi-proportional delays is studied. The nonlinear transformation transforms a class of recurrent neural networks with multi-proportional delays into a class of recurrent neural networks with constant delays and time-varying coefficients. By constructing Lyapunov functional and establishing the delay differential inequality, several delay-dependent and delay-independent sufficient conditions are derived to ensure global exponential periodicity and stability of the system. And several examples and their simulations are given to illustrate the effectiveness of obtained results. PMID- 26639053 TI - Incorporation of fractional-order dynamics into an existing PI/PID DC motor control loop. AB - The problem of changing the dynamics of an existing DC motor control system without the need of making internal changes is considered in the paper. In particular, this paper presents a method for incorporating fractional-order dynamics in an existing DC motor control system with internal PI or PID controller, through the addition of an external controller into the system and by tapping its original input and output signals. Experimental results based on the control of a real test plant from MATLAB/Simulink environment are presented, indicating the validity of the proposed approach. PMID- 26639055 TI - On the fragility of fractional-order PID controllers for FOPDT processes. AB - This paper analyzes the fragility issue of fractional-order proportional-integral derivative controllers applied to integer first-order plus-dead-time processes. In particular, the effects of the variations of the controller parameters on the achieved control system robustness and performance are investigated. Results show that this kind of controllers is more fragile with respect to the standard proportional-integral-derivative controllers and therefore a significant attention should be paid by the user in their tuning. PMID- 26639057 TI - [Intravenous immunoglobulin therapy in Morvan syndrome secondary to recurrent thymic carcinoma]. AB - Morvan's syndrome is a rare autoimmune channelopathy. A case of Morvan's syndrome is presented as a paraneoplastic syndrome associated to the recurrence of a well differentiated thymic carcinoma, which showed a good clinical response to treatment with intravenous immunoglobulin. PMID- 26639056 TI - An outbreak caused by GII.17 norovirus with a wide spectrum of HBGA-associated susceptibility. AB - During the past norovirus (NoV) epidemic season, a new GII.17 variant emerged as a predominant NoV strain, surpassed the GII.4 NoVs, causing outbreaks of acute gastroenteritis (AGE) in China. Here we report a study of an AGE outbreak in an elementary school in December 2014 caused by the new GII.17 NoV to explore the potential mechanism behind the sudden epidemics of the GII.17 NoV. A total of 276 individuals were sick with typical NoV infection symptoms of vomiting (93.4%), abdominal pain (90.4%), nausea (60.0%), and diarrhea (10.4%) at an attack rate of 5.7-16.9%. Genotyping of the symptomatic patients showed that individuals with a secretor positive status, including those with A, B, and O secretors and Lewis positive blood types, were sensitive to the virus, while the non-secretors and the Lewis negative individual were not. Accordingly, the recombinant capsid P protein of the GII.17 isolate showed a wide binding spectrum to saliva samples of all A, B, and O secretors. Thus, the broad binding spectrum of the new GII.17 variant could explain its widely spread nature in China and surrounding areas in the past two years. PMID- 26639059 TI - Critical Appraisal of the Milwaukee Protocol for Rabies: This Failed Approach Should Be Abandoned. AB - The Milwaukee protocol has been attributed to survival in rabies encephalitis despite a lack of scientific evidence supporting its therapeutic measures. We have reviewed the literature with reference to specific treatment recommendations made within the protocol. Current literature fails to support an important role for excitotoxicity and cerebral vasospasm in rabies encephalitis. Therapies suggested in the Milwaukee protocol include therapeutic coma, ketamine infusion, amantadine, and the screening/prophylaxis/management of cerebral vasospasm. None of these therapies can be substantiated in rabies or other forms of acute viral encephalitis. Serious concerns over the current protocol recommendations are warranted. The recommendations made by the Milwaukee protocol warrant serious reconsideration before any future use of this failed protocol. PMID- 26639061 TI - Hepatoma cell-derived leptin downregulates the immunosuppressive function of regulatory T-cells to enhance the anti-tumor activity of CD8+ T-cells. AB - The adaptive immune response against hepatocellular carcinoma (HCC) could be a therapeutic target to restrain HCC initiation and growth. The interactions between hepatoma cells and immune cells modify the anti-tumor immunity to influence hepatoma cell survival. To explore the potential interplay between hepatoma cells and anti-HCC T-cells, we conducted a HCC induction mouse model to analyze the phenotypic and functional alterations of T-cell subsets. We found that both hepatoma tissues and hepatoma cell lines substantially produced higher leptin, which is an adipokine usually expressed in fat tissue, than normal liver tissue or hepatocytes. We also found that regulatory T-cells (Tregs), effector CD4(+) T-cells and CD8(+) T-cells upregulated expression of leptin receptor (LEPR) in spleens and livers after HCC induction. In vitro study showed that macrophages and dendritic cells isolated from HCC livers upregulated LEPR expression on T-cells. Leptin inhibited Treg activation and function in vitro, demonstrated by lower expression of TGF-beta, IL-10, CTLA4 and GITR in Tregs, as wells weaker suppression of CD8(+) T-cell proliferation and production of cytotoxic mediators. In addition, silencing LEPR in Tregs favored tumor growth in a hepatoma cell line allograft model. Taken together, our study suggests that hepatoma cells could enhance anti-HCC immunity through secreting leptin to down regulate Treg activity and subsequently promote CD8(+) T-cell response. PMID- 26639062 TI - Transanal rectal resection: an initial experience of 20 cases. AB - AIM: Low anterior resection (LAR) can present a formidable surgical challenge, particularly for tumours located in the distal third of the rectum. Transanal total mesorectal excision (taTME) aims to overcome some of these difficulties. We report our initial experience with this technique. METHOD: From June 2013 to September 2014, 20 selected patients underwent transanal rectal resection for various malignant and benign low rectal pathologies. All patients with rectal cancer were discussed at a multidisciplinary team meeting. Data were entered into a prospective managed international database. RESULTS: Of the 20 patients (14 male), seventeen (85%) had rectal cancer lying at a median distance of 2 cm (range 0-7) from the anorectal junction. The operations performed included LAR (16). Abdominoperineal excision (2) and completion proctectomy (2), all of which were performed by a minimally invasive approach with three conversions. The mean operation time was 315.3 min. There were six postoperative complications of which two (10%) were Clavien-Dindo Grade IIIb (pelvic haematoma and a late contained anastomotic leakage). The median length of stay was 7 days. The TME specimen was intact in 94.1% of cancer cases. The mean number of harvested lymph nodes was 23.2. There was only one positive circumferential resection margin (tumour deposit; R1 rate 5.9%). One patient developed a distant recurrence (median follow up 10 months, range 6-21). CONCLUSION: TaTME was safe in this small series of patients. It is especially attractive in patients with a narrow and irradiated pelvis and a tumour in the lower third of the rectum. TaTME is technically demanding, but the good outcomes should prompt randomized studies and prospective registration of all taTME cases in an international registry. PMID- 26639063 TI - The circulating microRNome demonstrates distinct lymphocyte subset-dependent signatures. AB - Upon activation, lymphocytes release vesicles containing microRNAs (miRNAs). However, little is known as to whether this release results in modulation of circulating miRNAs (the miRNome) in the serum. The present work aims to identify lymphocyte subset-specific signatures of miRNAs within the serum circulating miRNome. We therefore assessed serum miRNA expression profiles in wild-type mice; in mice lacking either CD4(+) T cells, CD8(+) T cells, invariant natural killer T (iNKT) cells, or B cells; and, as a control, in mice in which Dicer has been ablated in T lymphocytes. We found that specific serum miRNAs are differentially modulated when different lymphocyte subsets are lacking. In particular, the serum level of miR-181b-5p, previously demonstrated to be fundamental for the development of iNKT cells, is specifically reduced in mice in which iNKT cells are absent. Interestingly, our results indicate a direct link between the biological role of a single miRNA in lymphocyte development and its serum level, and prove that even a population composed of relatively few cells in vivo, such as iNKT lymphocytes, has a measurable effect on the serum circulating miRNome. PMID- 26639064 TI - General Hospital Psychiatry: a vision for the coming years. PMID- 26639065 TI - Ultrasound Elastography Combined With BI-RADS-US Classification System: Is It Helpful for the Diagnostic Performance of Conventional Ultrasonography? AB - PURPOSE: To evaluate the additive diagnostic performance of ultrasound elastography (UE) to ultrasound (US) with the 2003 or 2013 Breast Imaging Reporting and Data System (BI-RADS)-US classification systems for the differentiation of benign and malignant breast lesions. METHODS: From June 2010 to December 2012, 738 women with 770 breast lesions were recruited into this retrospective study. Breast lesions were evaluated separately by US, UE, and both. US assessment was based on the 2003 or 2013 BI-RADS-US, and UE assessment was based on a previously reported 5-point scale. Diagnostic performance of US, UE, and both was compared. RESULTS: Before category 4 lesions were subdivided, the area under the receiver operating characteristic curve (AUC) for US, UE, and both were, respectively, 0.735, 0.877, 0.878 (P < .01). When subcategories of 4 lesions were considered, the AUC for US, UE, and both were, respectively, 0.865, 0.877, and 0.883 (P > .05). Adding UE to analysis of 4A lesions can decrease the percentages of malignancy to 2.56%. CONCLUSION: When the 2003 BI-RADS was considered, UE could give US some help in differentiating breast lesions. However, when the 2013 BI-RADS was considered, UE gave little help to US, although it reduced unnecessary biopsies of benign category 4A lesions. PMID- 26639066 TI - High Prevalence of MRI-Detected Contralateral and Ipsilateral Malignant Findings in Patients With Invasive Ductolobular Breast Cancer: Impact on Surgical Management. AB - INTRODUCTION: Invasive breast cancer comprises a spectrum of histologic changes with purely lobular and purely ductal cancer on either side and mixed lesions in between. Our aim was to evaluate to what extent preoperative magnetic resonance imaging (MRI) leads to the finding of additional malignancies and the effect on surgical management in the subcategory of women with invasive ductolobular disease. PATIENTS AND METHODS: From 2007 to 2012, 109 patients diagnosed with breast cancer containing a lobular component underwent preoperative MRI. The MRI findings were compared with the findings from mammography and ultrasonography. Clinically relevant additional MRI findings were verified histologically. The histologic slides were reviewed, and the percentage of the lobular component was determined. In a multidisciplinary setting, the TNM classification and surgical policy were determined using the conventional imaging findings and as a scenario that included preoperative MRI. RESULTS: MRI revealed additional malignant foci in 28 of 109 patients (26%). More extensive disease was seen in 25 patients (23%). The preoperative MRI findings changed the TNM classification in 42% of the patients and altered the surgical policy in 37%. No correlation was found between the lobular component and the probability of detecting additional malignant foci, more extensive disease, or the frequency of a change in TNM classification or surgical policy. According to the final pathology report, the change in surgical policy was justified in 85% of the patients. CONCLUSION: In patients with breast cancer presenting with lobular differentiation at biopsy, preoperative MRI can lead to the detection of additional malignancies and clinically relevant changes in surgical policy in a high percentage of patients, irrespective of the lobular component. The use of MRI as a part of the standard workup of such patients deserves consideration. PMID- 26639067 TI - Prognostic Impact of New-Onset Atrial Fibrillation in Patients With Chronic Heart Failure - A Report From the CHART-2 Study. AB - BACKGROUND: The prognostic impact of new-onset atrial fibrillation (AF) is not fully elucidated. METHODS AND RESULTS: We examined 4,818 consecutive stage C/D chronic heart failure (CHF) patients in the Chronic Heart Failure Analysis and Registry in the Tohoku District-2 (CHART-2) Study (n=10,219). At enrollment, 1,859 (38.6%) of them had AF. Compared with the 2,953 patients without AF, AF patients were characterized by higher age (71 vs. 68 years), lower estimated glomerular filtration rate (58.9 vs. 61.9 ml/min/1.73 m(2)), higher brain natriuretic peptide (152 vs. 74.5 pg/ml), similar left ventricular ejection fraction (56.8 vs. 56.5%), and a similar prescription rate of beta-blockers (48.1 vs. 50.6%) and renin-angiotensin system (RAS) inhibitors (72.9 vs. 71.6%). Among the patients without AF at enrollment, 106 (3.6%) developed new AF during the median 3.2-year follow-up, which was associated with increased mortality (adjusted hazard ratio, 1.72; P=0.013). In contrast, neither paroxysmal nor chronic AF at enrollment was associated with increased mortality. The mortality rate was significantly high in the first year after the onset of new AF. On inverse probability of treatment weighting analysis using propensity score, RAS inhibitors and statins were associated with reduced incidence of new AF, and diuretics were associated with increase of new AF. CONCLUSIONS: Onset of new AF, but not a history of AF, is associated with increased mortality in CHF patients, especially in the first year. PMID- 26639068 TI - Inverse Correlation Between Calcium Accumulation and the Expansion Rate of Abdominal Aortic Aneurysms. AB - BACKGROUND: When the maximal diameter of an abdominal aortic aneurysm (AAA) exceeds a threshold, the likelihood of catastrophic rupture increases markedly. Therefore, surveillance at optimal intervals should be offered to patients with AAA. However, other than AAA diameter, there is no useful marker or index for predicting the expansion rate of an AAA or determining the optimal intervals for surveillance. The aim of this study was to evaluate the usefulness of calcium accumulation in the AAA for predicting its expansion rate. METHODS AND RESULTS: We performed a retrospective cohort study in 414 patients with infrarenal AAA who visited The University of Tokyo Hospital. The maximal diameter and extent of calcification of each AAA were evaluated by multidetector-row computed tomography imaging. There was an inverse correlation between the extent of calcification and the subsequent AAA expansion. A lower extent of calcification in the AAA as well as the AAA diameter and absence of coronary artery disease correlated with an accelerated expansion of the AAA. CONCLUSIONS: In AAA, a lower extent of calcification correlated with accelerated expansion. The calcification index of an AAA can be a useful predictor of its expansion rate. The study findings also support the theory that the mechanisms for progression in atherosclerosis with calcification and external expansion of an aneurysm are distinct. PMID- 26639069 TI - Use of a topical haemoglobin spray for oxygenating pressure ulcers: healing outcomes. AB - A published evaluation ( Tickle, 2015 ) of the use of a topical haemoglobin spray plus standard care in 18 patients with pressure ulcers showed that, following 4 weeks of treatment, the wound size reduced in 17 wounds and there was a progression toward healing in all 18. All but one of the wounds were over 2 months in duration at baseline. This article reports the results of the healing rates at 3 months of the 11 patients who continued to be treated with the haemoglobin spray. Nine of the 11 wounds healed, and 2 reduced in size by week 12 (i.e. 1 wound reduced from 30 cm(2) at baseline to 7 cm(2), while the other reduced from 6 cm(2) to 4 cm(2)). Of the 10 patients who were experiencing wound pain at baseline, 9 were pain free by week 8. Rapid elimination of slough was observed in all patients. The 82% healing rate achieved at 3 months and the fact that most patients continued to receive the same standard care as they had in the 4 weeks before recruitment into the evaluation increases the likelihood that the clinical outcomes observed here can be attributed to the haemoglobin spray. Topical haemoglobin shows promise in terms of its ability to accelerate healing in chronic pressure ulcers. PMID- 26639070 TI - Diagnosing and managing venous leg ulcers in patients in the community. AB - Venous leg ulcers (VLUs) are a chronic condition affecting between 0.1% and 0.3% of the population in the UK. Healing rates are variable and recurrence rates are high. The diagnosis, assessment, and management of this patient group is primarily carried out in the community. Assessment of this patient group requires skill and competence to ensure a correct diagnosis is made. When carrying out the assessment, it is important to consider the patient's past medical history, medication, and allergies, as well as to record the ankle brachial pressure index (ABPI), pain level, palpation of pulses, and ankle joint movement, among other aspects of the assessment. VLUs heal with compression therapy, and practitioners should be knowledgeable about the various compression systems available in order to offer patients the most suitable and informed choices. PMID- 26639072 TI - The Wellbeing Project, awards, and more. PMID- 26639071 TI - Assessing an adherent silicone foam dressing: a clinical evaluation across five NHS trusts. AB - The wound contact layer of UrgoTul Absorb Border (Urgo Medical) foam dressing contains a Technology Lipido Colloid (TLC) Healing Matrix, which includes hydrocolloid and lipophilic substances designed to stimulate fibroblast proliferation and thus promote granulation tissue formation. A multicentre, noncomparative, clinical evaluation of UrgoTul Absorb Border investigated whether use of the dressing promoted granulation tissue formation and the management of wound exudate. Other parameters evaluated included: pain-free dressing changes, protection and improvement of surrounding tissue, ease of application, conformability, ability to remain in place, wear time, effect on peri-wound skin, durability, ease of removal, and patient comfort. There were 43 patients recruited into the evaluation. Results show that 8 wounds (19%) achieved full epithelialisation and 34 (81%) improved. All participating clinicians rated the dressing's overall performance, including its ability to manage exudate, as excellent, very good, or good. PMID- 26639073 TI - Case study: Knighton Leg Club. PMID- 26639074 TI - Heartfelt thanks from a grateful veteran to WoundCare4Heroes. PMID- 26639075 TI - Is cost saving the nemesis of good wound care? PMID- 26639076 TI - It's time to Stop the Pressure: importance of pressure ulcer prevention in community care. PMID- 26639077 TI - Aetiology and management of atrophie blanche in chronic venous insufficiency. AB - The presence of chronic venous insufficiency results in venous hypertension, which can lead to the development of venous leg ulceration. Patients often present with oedema of the lower limb and skin changes, for example, the presence of haemosiderin and lipodermatosclerosis, as well as ulceration. In some instances, patients can also develop atrophie blanche (AB)-white fibrotic areas on the skin adjacent to the ulcer. AB remains an ambiguous term owing to the use of many synonyms. Hence, health professionals need to be aware of the clinical presentation of AB and should be able to clearly differentiate between scarring caused by previous ulcers and that caused by the presence of AB. In this article, the authors discuss the underlying diseases associated with AB and explore the treatment of AB in patients with chronic venous insufficiency. PMID- 26639078 TI - Eating behaviours are different in youth with obesity and severe obesity. AB - The study purposes were to: (i) Investigate eating behaviours among patients in a paediatric weight management clinical practice and (ii) Compare eating behaviour phenotypes between children with severe obesity and obesity. This was a retrospective cross-sectional study using data collected during clinical encounters. Participants were included if they were 2-12 years old, had a body mass index >=95th percentile and if a parent or guardian completed the Child Eating Behaviour Questionnaire (CEBQ). Participants (n = 149) were children with severe obesity (n = 108) and obesity (n = 41). The mean Satiety Responsiveness score was significantly lower for children with severe obesity than for children with obesity. Girls with severe obesity had significantly higher Enjoyment of Food and significantly lower Satiety Responsiveness and Slowness in Eating than girls with obesity. The findings demonstrate the potential clinical utility of the CEBQ for informing tailored treatment strategies through identifying eating behaviour phenotypes. PMID- 26639079 TI - Use of sub-renal capsule transplantation in developmental biology. AB - The sub-renal capsule graft site for in vivo growth and development of developing organs can be used to great advantage in the "rescue" of organ rudiments from "embryonic" or "birth" lethal mutant mice, which permits examination of the full impact of gene knockout in all phases of development from morphogenesis to adult functional differentiation. Another use of the sub-renal capsule graft site is the examination of normal and "chemically perturbed" development of human fetal organs. Tissue recombinants composed of various types of epithelium and mesenchyme, when grafted under the renal capsule undergo normal development and in 3-4 weeks achieve full adult functional cytodifferentiation. The investigator can control many of the developmental parameters of the graft such as endocrine status of the host and treatment of the host with a variety of biologically active agents to assess their effects on development and differentiation. PMID- 26639080 TI - Assessment of quantitative polymerase chain reaction for equine herpesvirus-5 in blood, nasal secretions and bronchoalveolar lavage fluid for the laboratory diagnosis of equine multinodular pulmonary fibrosis. AB - REASONS FOR PERFORMING STUDY: The ante mortem diagnosis of equine multinodular pulmonary fibrosis (EMPF) relies on histopathological results and polymerase chain reaction (PCR)-positive equine herpesvirus (EHV)-5 testing of lung tissue. Polymerase chain reaction detection of EHV-5 in bronchoalveolar lavage fluid (BALF) is commonly used to support a diagnosis of EMPF. However, the diagnostic power of EHV-5 testing on BALF and other biological samples such as blood and nasal secretions has yet to be shown to support a diagnosis of EMPF. OBJECTIVES: To determine the frequency of detection and the viral loads of EHV-5 by quantitative PCR (qPCR) in blood, nasal secretions and BALF from horses confirmed with EMPF, healthy horses and horses with non-EMPF pulmonary diseases. STUDY DESIGN: Prospective study. METHODS: The study population consisted of 70 adult horses divided into 4 groups based on a combination of clinical findings, cytology of BALF, imaging studies of the thoracic cavity and histopathology of pulmonary tissue: control group (n = 14), EMPF group (n = 11); inflammatory airway disease group (n = 32); and non-EMPF interstitial lung disease group (n = 13). For each horse, whole blood, nasal secretions and BALF were available for EHV-5 qPCR testing. Sensitivities, specificities and their respective 95% confidence intervals were calculated for viral loads from blood, nasal secretions and BALF. In addition, these measures were calculated for combined use of blood and nasal secretions. RESULTS: The detection of EHV-5 in BALF was strongly associated with EMPF (sensitivity 91%, specificity 98.3%). Detection of EHV-5 in blood was, independent of the viral loads, strongly associated with EMPF with a sensitivity of 91% and specificity of 83.1%. The detection of EHV-5 in nasal secretions displayed the highest sensitivity (72.7%) and specificity (83.1%) at a level of >245,890 glycoprotein B target genes/million cells to support a diagnosis of EMPF. Dually positive blood and nasal secretions at any viral loads in support of EMPF yielded a sensitivity and specificity of 90% and 89.8%, respectively. CONCLUSIONS: Although histopathological confirmation (lung biopsy) is considered the gold standard for EMPF diagnosis, results of qPCR testing of BALF or a combination of whole blood and nasal secretions should be regarded as clinically useful in support of this diagnosis. The latter testing may be relevant when dealing with horses in respiratory distress, for which invasive procedures such as BALF collection or lung biopsies may be detrimental to their health. PMID- 26639081 TI - The course of diaphragm atrophy in ventilated patients assessed with ultrasound: a longitudinal cohort study. AB - INTRODUCTION: Mechanical ventilation and the effect of respiratory muscle unloading on the diaphragm cause ventilator-induced diaphragmatic dysfunction (VIDD). Atrophy of the diaphragmatic muscle is a major part of VIDD, and has a rapid onset in most animal models. We wanted to assess the clinical evolution and risk factors for VIDD in an adult intensive care unit (ICU) by measuring diaphragm thickness using ultrasound. METHOD: We performed a single-centre observational cohort study, including 54 mechanically ventilated patients. The right hemidiaphragm was measured daily at the zone of apposition on the midaxillary line. RESULTS: Mean baseline thickness was 1.9 mm (SD +/- 0.4 mm), and mean nadir was 1.3 mm (SD +/- 0.4 mm), corresponding with a mean change in thickness of 32 % (95 % CI 27-37 %). Length of mechanical ventilation (MV) was associated with the degree of atrophy, whereas other known risk factors for muscle atrophy in an ICU were not. The largest decrease in thickness occurred during the first 72 hours of MV. CONCLUSIONS: Diaphragm atrophy occurs quickly in mechanically ventilated patients and can accurately be monitored using ultrasound. Length of MV, as opposed to other variables, is associated with the degree of atrophy. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov NCT02299986 . Registered 10/11/2014. PMID- 26639082 TI - Improvement of water and light availability after thinning at a xeric site: which matters more? A dual isotope approach. AB - Thinning fosters individual tree growth by increasing the availability of water, light and nutrients. At sites where water rather than light is limiting, thinning also enhances soil evaporation and might not be beneficial. Detailed knowledge of the short- to long-term physiological response underlying the growth responses to thinning is crucial for the management of forests already suffering from recurrent drought-induced dieback. We applied a dual isotope approach together with mechanistic isotope models to study the physiological processes underlying long-term growth enhancement of heavily thinned Pinus sylvestris in a xeric forest in Switzerland. This approach allowed us to identify and disentangle thinning-induced changes in stomatal conductance and assimilation rate. At our xeric study site, the increase in stomatal conductance far outweighed the increase in assimilation, implying that growth release in heavily thinned trees is primarily driven by enhanced water availability rather than increased light availability. We conclude that in forests with relatively isohydric species (drought avoiders) that are growing close to their physiological limits, thinning is recommended to maintain a less negative water balance and thus foster tree growth, and ultimately the survival of forest trees under drought. PMID- 26639084 TI - Genetic factors and epigenetic mechanisms of longevity: current perspectives. AB - The exceptional longevity phenotype, defined as living beyond the age of 95, results from complex interactions between environmental and genetic factors. Epigenetic mechanisms, such as DNA methylation and histone modifications, mediate the interaction of these factors. This review will provide an overview of animal model studies used to examine age-related epigenetic modifications. Key human studies will be used to illustrate the progress made in the identification of the genetic loci associated with exceptional longevity, including APOE and FOXO3 and genes/loci that are also differentially methylated between long-lived individuals and younger controls. Future studies should focus on elucidating whether identified longevity genetic loci directly influence epigenetic mechanisms, especially on differentially methylated regions associated with longevity. PMID- 26639083 TI - Single-Cell Migration in Complex Microenvironments: Mechanics and Signaling Dynamics. AB - Cells are highly dynamic and mechanical automata powered by molecular motors that respond to external cues. Intracellular signaling pathways, either chemical or mechanical, can be activated and spatially coordinated to induce polarized cell states and directional migration. Physiologically, cells navigate through complex microenvironments, typically in three-dimensional (3D) fibrillar networks. In diseases, such as metastatic cancer, they invade across physiological barriers and remodel their local environments through force, matrix degradation, synthesis, and reorganization. Important external factors such as dimensionality, confinement, topographical cues, stiffness, and flow impact the behavior of migrating cells and can each regulate motility. Here, we review recent progress in our understanding of single-cell migration in complex microenvironments. PMID- 26639085 TI - Improving results of surgery for fecal peritonitis due to perforated colorectal disease: A single center experience. AB - PURPOSE: fecal peritonitis due to colorectal perforation is a dramatic event characterized by high mortality. Our study aims at determining how results of sigmoid resection (eventually extended to upper rectum) for colorectal perforation with fecal peritonitis changed in recent years and which factors affected eventual changes. METHOD: Seventy-four patients were operated on at our institution (2005-2014) for colorectal perforation with fecal peritonitis and were divided into two numerically equal groups (operated on before (ERA1-group) and after (ERA2-group) May 2010). Mannheim Peritonitis Index (MPI) was calculated for each patient. Characteristics of two groups were compared. Predictors of postoperative outcomes were identified. RESULTS: Postoperative overall complications, major complications, and mortality occurred in 59%, 28%, and 18% of cases, respectively, and were less frequent in ERA2-group (51%, 16%, and 8%, respectively), compared to ERA1-group (68%, 41%, and 27%, respectively; p = .155, .02, and .032, respectively). Such results paralleled lower MPI values in ERA2 group, compared to ERA1-group (23(16-39) vs. 28(21-43), p = .006). Using receiver operating characteristic analysis, the best cut-off value for MPI for predicting postoperative complications and mortality was 28.5. MPI>28 was the only independent predictor of postoperative overall (p = .009, OR = 4.491) and major complications (p < .001, OR = 23.182) and was independently associated with a higher risk of mortality (p = .016, OR = 13.444), as well as duration of preoperative peritonitis longer than 24 h (p = .045, OR = 17.099). CONCLUSIONS: results of surgery for colorectal perforation with fecal peritonitis have improved over time, matching a concurrent decrease of MPI values and a better preoperative patient management. MPI value may help in selecting patients benefitting from surgical treatment. PMID- 26639086 TI - What is the most appropriate intraoperative baseline parathormone? A prospective cohort study. AB - INTRODUCTION: The time of drawing pre-incision intraoperative parathyroid hormone (ioPTH) is crucial to provide the right baseline for post-excision PTH measurement. The objective of this study was to identify the optimal time and the numbers of baseline PTH samples that best predict excision of all hypercellular parathyroid tissue when compared with 10-min post-excision PTH level. MATERIALS AND METHODS: In this prospective study, two pre-incision (pre-induction and 10 min post-induction) baseline ioPTH samples along with pre- and post-excision ioPTH were collected and analyzed for 352 parathyroidectomies in 341 patients for sporadic primary hyperparathyroidism at a University hospital. Paired Wilcoxan signed rank test was used to compare the pre-incision ioPTH levels and their percent drop to 10-min post-excision levels. Sensitivity, specificity, predictive values and receiver operating characteristic (ROC) curves were used to compare the predictability of the two pre-incision levels. RESULTS: The difference between pre- and post-induction baseline PTH levels was highly significant (p < 0.001). In 4% cases the criterion of post-excision PTH drop of >=50% was achieved only with the post-induction baseline PTH and not with pre-induction PTH measurement. Using pre-induction baseline, ioPTH had an overall accuracy of 90% whereas >=50% fall in the post-excision PTH from the post-induction baseline PTH had the accuracy of 94.85%. DISCUSSION: There was a significant difference between pre- and post-induction PTH levels and Miami criteria was met in 95.45% cases with post-induction baseline. CONCLUSIONS: The optimal time for drawing pre incision baseline PTH sample is at 10 min post-induction of general anesthesia and positioning of patient. PMID- 26639087 TI - Homodiselenacalix[4]arenes: Molecules with Unique Channelled Crystal Structures. AB - A synthetic route towards homodiselenacalix[4]arene macrocycles is presented, based on the dynamic covalent chemistry of diselenides. The calixarene inner rim is decorated with either alkoxy or tert-butyl ester groups. Single-crystal X-ray analysis of two THF solvates with methoxy and ethoxy substituents reveals the high similarity of their molecular structures and alterations on the supramolecular level. In both crystal structures, solvent channels are present and differ in both shape and capacity. Furthermore, the methoxy-substituted macrocycle undergoes a single-crystal-to-single-crystal transformation during which the molecular structure changes its conformation from 1,3-alternate (loaded with THF/water) to 1,2-alternate (apohost form). Molecular modelling techniques were applied to explore the conformational and energetic behaviour of the macrocycles. PMID- 26639088 TI - Primary phospholipase C and brain disorders. AB - In the brain, the primary phospholipase C (PLC) proteins, PLCbeta, and PLCgamma, are activated primarily by neurotransmitters, neurotrophic factors, and hormones through G protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs). Among the primary PLC isozymes, PLCbeta1, PLCbeta4, and PLCgamma1 are highly expressed and differentially distributed, suggesting a specific role for each PLC subtype in different regions of the brain. Primary PLCs control neuronal activity, which is important for synapse function and development. In addition, dysregulation of primary PLC signaling is linked to several brain disorders including epilepsy, schizophrenia, bipolar disorder, Huntington's disease, depression and Alzheimer's disease. In this review, we included current knowledge regarding the roles of primary PLC isozymes in brain disorders. PMID- 26639090 TI - In Situ Crystallization of Al-Containing Silicate Nanosheets on Monodisperse Amorphous Silica Microspheres. AB - The fine crystals of an Al-containing layered silicate, whose negative layer charge is generated by an isomorphous substitution in the tetrahedral SiO4 framework, successfully grew on monodisperse amorphous silica microspheres with diameters of 1.0 and 2.6 MUm. The fine, plate-like crystals were observed to thoroughly cover the surface of the silica spheres, irrespective of their size, by the hydrothermal reactions of the silica powder in aqueous alkali solution containing Al and Mg ions in a rotating Teflon-lined autoclave. The crystal size increased when the concentration of the precursors was low. The presence of fluorine in the reaction media enlarged the crystalline phase in the direction of the layer stacking while reducing the plate size. The difference in the crystal size affected the kinetics on the hinokitiol desorption in n-hexane from the layered silicates modified with organoammonium ions. The organically modified layered silicate behaved as an exfoliated nanosheet in the nonpolar solvent. The less harmful elements in this hybrid suggest that it can be used in cosmetic and pharmaceutical applications as a drug support, without flaking off the fine layers on the microspherical substrates. PMID- 26639089 TI - Investigating the effect of arachidonate supplementation on the phosphoinositide content of MCF10a breast epithelial cells. AB - Phosphoinositides in primary mammalian tissue are highly enriched in a stearoyl/arachidonyl (C38:4) diacylgycerol backbone. However, mammalian cells grown in culture typically contain more diverse molecular species of phosphoinositides, characterised by a reduction in arachidonyl content in the sn 2 position. We have analysed the phosphoinositide species in MCF10a cells grown in culture by mass spectrometry. Under either serum or serum starved conditions the most abundant species of PI, PIP, PIP2 and PIP3 had masses which corresponded to C36:2, C38:4, C38:3, C38:2 and C36:1 diacylglycerol backbones and the relative proportions of each molecular species were broadly similar between each phosphoinositide class (approx. 50%, 25%, 10%, 10% and 10% respectively, for the species listed above). Supplementing the culture medium with BSA-loaded arachidonic acid promoted a rapid increase in the proportion of the C38:4 species in all phosphoinositide classes (from approx. 25%-60% of total species within 24 h), but the total amount of all combined species for each class remained remarkably constant. Stimulation of cells, cultured in either normal or arachidonate-enriched conditions, with 2 ng/ml EGF for 90 s caused substantial activation of Class I PI3K and accumulation of PIP3. Despite the increased proportion of C38:4 PIP3 under the arachidonate-supplemented conditions, the total amount of all combined PIP3 species accumulating in response to EGF was the same, with or without arachidonate supplementation; there were however small but significant preferences for the conversion of some PIP2 species to PIP3, with the polyunsaturated C38:4 and C38:3 species being more favoured over other species. These results suggest the enzymes which interconvert phosphoinositides are able to act on several different molecular species and homoeostatic mechanisms are in place to deliver similar phosphoinositide pool sizes under quite different conditions of arachidonate availability. They also suggest enzymes regulating PIP3 levels downstream of growth factor stimulation (i.e. PI3Ks and PIP3 phosphatases) show some acyl selectivity and further work should be directed at assessing whether different acyl species of PIP3 exhibit differing signalling potential. PMID- 26639091 TI - Successive MRI Findings of Reversible Cerebral White Matter Lesions in a Patient with Cystathionine beta-Synthase Deficiency. AB - Cystathionine beta-synthase (CBS) deficiency, well known as classical homocystinuria, is a rare autosomal recessive inborn error of homocysteine and sulfur metabolism. CBS converts homocysteine to cystathionine. The clinical features of untreated CBS deficiency include myopia, ectopia lentis, mental retardation, skeletal anomalies resembling Marfan syndrome, and thromboembolic events. Cerebral white matter lesions (CWMLs), identified in magnetic resonance imaging (MRI), are related to various clinical conditions including ischemia, inflammation, demyelination, infection, a tumor, and metabolic disorders such as phenylketonuria. The presence of CWMLs is, however, believed to be a very rare condition in CBS-deficient patients. Herein, we report reversible CWMLs associated with hypermethioninemia caused by poor protein restriction and betaine therapy in a 21-year-old male with pyridoxine-nonresponsive CBS deficiency. T2 weighted images (T2WI) and fluid-attenuated inversion-recovery (FLAIR) images showed diffuse high signal intensity in subcortical areas extending to the deep white matter. Diffusion-weighted images (DWI) showed high signal intensity, while apparent diffusion coefficient (ADC) map demonstrated decreased ADC value in the lesions. The course of improvement after correct methionine restriction was successively followed by brain MRI. The CWMLs had regressed at 1 month after restriction, and disappeared after 5 months. ADC values were very low before proper methionine restriction, but normalized after 2 months. Use of betaine in the presence of elevated plasma methionine may increase the risk of reversible CWMLs in some CBS-deficient patients. PMID- 26639092 TI - Eldecalcitol, in Combination with Bisphosphonate, Is Effective for Treatment of Japanese Osteoporotic Patients. AB - Alfacalcidol (ALF) and eldecalcitol (ELD) are vitamin D analogues that can be combined with anti-resorption drugs, such as bisphosphonate (BP) for the treatment of osteoporosis (OP). There has been no report comparing the effects of those vitamin D analogs in combination with BPs. Twenty female patients with OP were enrolled, and all of them were treated with ALF and BPs. After switching from ALF to ELD, we examined the effectiveness of ALF and ELD. The averaged age was 69.4 years and the period of BP usage was between 1 to 13.4 years (mean period was 3.7 years). Serum corrected calcium, serum inorganic phosphorus, serum bone specific alkaline phosphatase (BAP), and serum tartrate-resistant acid phosphatase (TRACP)-5b were measured prior to ELD and at 6 months afterwards. Bone mineral density (BMD) of the lumbar spine (L-BMD), femoral neck, and total hip BMD were assessed one year before, prior to, and one year after ELD therapy commencement. Six months after switching from ALF to ELD, BAP and TRACP-5b values significantly decreased. After one year of ALF therapy, L-BMD, total hip BMD and femoral neck H-BMD values slightly increased. In contrast, a year following the change from ALF to ELD, L-BMD significantly increased and femoral neck BMD slightly increased, but total hip BMD did not. These results suggest that the treatment with ELD after ALF significantly suppressed bone turnover and increased L-BMD. Thus, the combined therapy with ELD is more effective for OP treatment than that with ALF. PMID- 26639093 TI - Evaluation of abdominal circumference and salivary amylase activities after unsedated colonoscopy using carbon dioxide and air insufflations. AB - OBJECTIVE: To assess and compare abdominal distention and stress in unsedated colonoscopy using carbon dioxide (CO2 ) and air insufflations. METHODS: Two hundred and five patients underwent colonoscopic examinations without sedation using either CO2 or air insufflation. Abdominal circumference and salivary amylase (sAMY) activities before and 0 and 15 min after colonoscopy were measured by a nurse who was blinded to the grouping of the patients. RESULTS: In all, 102 and 103 patients were randomly recruited in the CO2 and air insufflation groups, respectively. sAMY activities before and 0 and 15 min after colonoscopy were not significantly different between the two groups. Abdominal circumference measured immediately and 15 min after colonoscopy was significantly smaller in CO2 insufflation group than in the air insufflation group (81.2 cm vs 84.0 cm, and 79.7 cm vs 83.6 cm, respectively; P <0.05). The increasing ratio of abdominal circumference immediately after colonoscopy was not significantly different between the two groups; however, the ratio at 15 min after colonoscopy using CO2 insufflation was significantly lower than that in the air insufflation group (1.007 vs 1.028, P <0.001). CONCLUSION: sAMY activities after unsedated colonoscopy using CO2 insufflation were not improved; however, CO2 insufflation decreases abdominal circumference after colonoscopy compared with air insufflation. PMID- 26639094 TI - The Relevance of JAK2 in the Regulation of Cellular Transport. AB - Janus kinase-2 (JAK2) is a non-receptor tyrosine kinase signaling molecule that mediates the effects of various hormones and cytokines, including interferon, erythropoietin, leptin, and growth hormone. It also fosters tumor growth and modifies the activity of several nutrient transporters. JAK2 contributes to the regulation of the cell volume, protectS cells during energy depletion, proliferation, and aids the survival of tumor cells. Recently, JAK2 was identified as a powerful regulator of transport processes across the plasma membrane. Either directly or indirectly JAK2 may stimulate or inhibit transporter proteins, including ion channels, carriers and Na(+)/K(+) pumps. As a powerful regulator of transport mechanisms across the cell membrane, JAK2 regulates a wide variety of potassium, calcium, sodium and chloride ion channels, multiple Na+ coupled cellular carriers including EAAT1-4, NaPi-IIa, SGLT1, BoaT1, PepT1-2, CreaT1, SMIT1, and BGT1 as well as Na(+)/K(+)-ATPase. These cellular transport regulations contribute to various physiological and pathophysiological processes and thus exerting JAK2-sensitive effects. Future investigations will be important to determine whether JAK2 regulates cell-surface expression of other transporters and further elucidate underlying mechanisms governing JAK2 actions. PMID- 26639095 TI - Therapeutic Potential of the Modulation of Sphingosine-1-Phosphate Receptors. AB - It is accepted that sphingolipids (SL) are not only structural lipids in cellular membranes, but also key regulators of different cell process. Sphingosine-1 phosphate (S1P) is a member of this family involved, inter alia, in cell migration, angiogenesis and cell proliferation processes, being able to play different intracellular and extracellular roles. When S1P is transported out of the cell, it binds S1P specific G protein-coupled receptors, which are mainly involved in the regulation of the immune, vascular and nervous systems. These effects account for the vast diversity of functions that arise from the activation of S1P receptors. Deregulation of S1P levels is correlated with several pathologies, such as autoimmune disorders and cancer. Consequently, the correct modulation of these receptors represents a valuable approach for the development of new therapeutic strategies. Along this line, the non-selective S1P receptor agonist fingolimod (FTY720) has been commercialized recently for the treatment of multiple sclerosis and several related S1P receptor modulators are ongoing clinical trials. However, despite the progress in this field, the biological functions of S1P receptors are not still well elucidated. For this reason, several studies are being developed in order to better understand the functions of these receptors, making use of new selective S1P receptor agonists and antagonists as pharmacological tools. PMID- 26639096 TI - Essential Roles of Toll-Like Receptors in Atherosclerosis. AB - Atherosclerosis is driven by inflammation with an involvement of innate and adaptive immune responses. Toll-like receptors, the well-defined pattern recognition receptors of the immune system, play a central role in macrophage activation. Toll-like receptors recognize pathogen-associated molecular patterns expressed by a wide range of infectious agents and provide a strong link between local innate and adaptive immunity. Activation of these receptors triggers an intracellular signaling cascade mediated through myeloid differentiation factor 88 or toll/interleukin-1 receptor-domain-containing adapter-inducing interferon beta, leading to the secretion of proand anti-inflammatory cytokines. Engagement of Toll-like receptors with their ligands induces leukocyte recruitment and enhances matrix metalloproteinase expression within atherosclerotic lesions. Recently certain Toll-like receptors have shown a protective role in atherosclerosis. TLRs, therefore, represent an important link between inflammation and atheroma, making them attractive targets for the treatment of atherosclerosis. This review will briefly describe the general biological structure and potential roles of Toll-like receptors as therapeutic targets for the treatment of atherosclerosis and highlight the potential challenges on Toll like receptor- based therapy in cardiovascular disease. PMID- 26639097 TI - Class I Homeobox Genes, "The Rosetta Stone of the Cell Biology", in the Regulation of Cardiovascular Development. AB - Class I homeobox genes (Hox in mice and HOX in humans), encode for 39 transcription factors and display a unique genomic network organization mainly involved in the regulation of embryonic development and in the cell memory program. The HOX network controls the aberrant epigenetic modifications involving in the cell memory program. In details, the HOX cluster plays a crucial role in the generation and evolution of several diseases: congenic malformation, oncogenesis, metabolic processes and deregulation of cell cycle. In this review, I discussed about the role of HOX gene network in the control of cardiovascular development. PMID- 26639098 TI - Diabetes and Pancreas: Why So Difficult? Potential Mechanisms of Elevated Serum Pancreatic Enzymes. AB - Diabetes mellitus has been associated with a higher risk of exocrine pancreas disorders despite inconsistencies among studies, presumably due to the presence of several (often unmeasured) confounding factors. As a direct consequence of this uncertainty, the relationship between anti-diabetic therapies and pancreatic adverse reactions is difficult to evaluate and remains far from being clarified. Indeed, the on going debate on the safety of incretin-based therapies does not lie in any definite conclusion. Serum level of amylases and lipase reflects the balance between production from different tissues and clearance, but it may be also influenced by numerous molecular, cellular, and systems mechanisms. The present review tries to provide an overview of potential biochemical pathways that may underlie pancreatic hyperenzymemia in health and diabetes mellitus. PMID- 26639099 TI - Microvascular Plasticity: Angiogenesis in Health and Disease--Preface. AB - This Special Topic Issue is concerned with the mechanisms that determine the structure of microvascular networks. The vast number of vessels and the highly plastic character of the microcirculation give evidence that microvascular network structures emerge as a result of responses of individual vessels and cells to the local stimuli that they experience, through a combination of angiogenesis, remodeling and pruning. The articles in this issue of Microcirculation address a range of cellular and molecular mechanisms involved in these processes. PMID- 26639100 TI - Dispersing towards Madagascar: Biogeography and evolution of the Madagascan endemics of the Spermacoceae tribe (Rubiaceae). AB - Despite the close proximity of the African mainland, dispersal of plant lineages towards Madagascar remains intriguing. The composition of the Madagascan flora is rather mixed and shows besides African representatives, also floral elements of India, Southeast Asia, Australia, and the Neotropics. Due to its proportionally large number of Madagascan endemics, the taxonomically troublesome Spermacoceae tribe is an interesting group to investigate the origin and evolution of the herbaceous Rubiaceae endemic to Madagascar. The phylogenetic position of these endemics were inferred using four plastid gene markers. Age estimates were obtained by expanding the Spermacoceae dataset with representatives of all Rubiaceae tribes. This allowed incorporation of multiple fossil-based calibration points from the Rubiaceae fossil record. Despite the high morphological diversity of the endemic herbaceous Spermacoceae on Madagascar, only two colonization events gave rise to their current diversity. The first clade contains Lathraeocarpa, Phylohydrax and Gomphocalyx, whereas the second Madagascan clade includes the endemic genera Astiella, Phialiphora, Thamnoldenlandia and Amphistemon. The tribe Spermacoceae is estimated to have a Late Eocene origin, and diversified during Oligocene and Miocene. The two Madagascan clades of the tribe originated in the Oligocene and radiated in the Miocene. The origin of the Madagascan Spermacoceae cannot be explained by Gondwanan vicariance but only by means of Cenozoic long distance dispersal events. Interestingly, not only colonization from Africa occurred but also long distance dispersal from the Neotropics shaped the current diversity of the Spermacoceae tribe on Madagascar. PMID- 26639101 TI - High genetic diversity but low population structure in the frog Pseudopaludicola falcipes (Hensel, 1867) (Amphibia, Anura) from the Pampas of South America. AB - Relative to South America's ecoregions, the temperate grasslands of the Pampas have been poorly studied from a phylogeographic perspective. Based on an intermediate biogeographic setting between subtropical forest (Atlantic Forest) and arid ecosystems (Chaco and Patagonia), Pampean species are expected to show unstable demographic histories due to the Quaternary climatic oscillations. Herein, we investigate the phylogenetic relatedness and phylogeographic history of Pseudopaludicola falcipes, a small and common frog that is widely distributed across the Pampean grasslands. First, we use molecular data to assess if P. falcipes represents a single or multiple, separately evolving cryptic lineages. Because P. falcipes is a small-size species (<20mm) with extensive coloration and morphological variation, we suspected that it might represent a complex of cryptic species. In addition, we expected strong genetic and geographic structuring within Pseudopaludicola falcipes due to its large geographic distribution, potentially short dispersal distances, and multiple riverine barriers. We found that P. falcipes is a single evolutionary lineage with poor geographic structuring. Furthermore, current populations of P. falcipes have a large effective population size, maintain ancestral polymorphisms, and have a complex network of gene flow. We conclude that the demographic history of P. falcipes, combined with its ecological attributes and the landscape features of the Pampas, favored a unique combination among anurans of small body size, large population size, high genetic variability, but high cohesiveness of populations over a wide geographic distribution. PMID- 26639102 TI - Phylogeny of Allium L. subgenus Anguinum (G. Don. ex W.D.J. Koch) N. Friesen (Amaryllidaceae). AB - The disjunct distribution of the subgenus Anguinum of the genus Allium makes it a good candidate to test models of Northern hemisphere biogeography. Here we conduct phylogenetic analysis with the nuclear marker ITS and three different chloroplast markers (rps16 intron, rbcL-atpB spacer, rpl32-trnL spacer). Divergence time estimations (Beast) relying on published ITS substitution rates and ancestral range reconstructions were calculated to elucidate the biogeographical history of the subgenus. Additionally we compiled distribution maps for all species with data taken from the literature, herbariums and data from field observations. The main radiation of the subgenus took place in the last one million years and is still going on. They have their origins in the mid Miocene in East Asia and were highly influenced by the climate fluctuations in the Pliocene/Pleistocene period. Conflicting tree topologies between nuclear and cpDNA markers of Allium tricoccum Solander indicate that the species is of hybridogenous origin. Cloning the ITS sequence revealed the parental copies and confirmed our conclusion. One originated from the Eurasian and the other from the East Asian clade. We were able to show that it reached North America most likely via the Beringia around 2.5mya (95% HPD of 0.35-5.26mya). Our data suggest that Allium victorialis L. is only distributed in mountain pastures in Europe as it forms a well-supported clade in the ITS tree. In the analysis of the molecular markers we found two distinct types of Allium ochotense Prokh. and we suggest splitting the species based on Prokhanov's (1930) proposal. Taxonomical remarks and an identification key to all species of the subgenus Anguinum is provided. PMID- 26639104 TI - How to Get Better Care with Lower Costs? See the Person, Not the Patient. AB - The U.S. health system perceives people as "patients" almost exclusively as they enter and exit the healthcare system, but with this emphasis on context, have we lost sight of the people who should be in the foreground of care? Does such a view impede care effectiveness and efficiency? How can we shift our frame of reference moving forward? To foster this needed conceptual shift, a group of national thought-leaders convened by the American Geriatrics Society (AGS) defined "person-centered care" to reorient the perspective toward individuals remaining in the center of pursuing high-quality care. This article explores how a person-centered care approach can improve healthcare effectiveness and efficiency, particularly for older adults with heightened health and daily living needs, and healthcare costs. The process for supporting a person-centered program is outlined, three critical indicators that define person-centered quality are highlighted, and several models that embrace the person-centered paradigm are briefly noted. Although there is no one-size-fits-all schematic, how and why overall success entails fidelity to essential elements of person-centered programs as the AGS expert panel identified is explained. PMID- 26639103 TI - Photocleavable Hydrogels for Light-Triggered siRNA Release. AB - A photocleavable hydrogel system for on-demand delivery of genetic material is reported. The release of short interfering RNAs can be triggered by the application of UV light without any loss in bioactivity. This approach provides a promising external stimulus-based nucleic acid delivery platform for applications in disease therapeutics and tissue regeneration. PMID- 26639105 TI - E11/Podoplanin Protein Stabilization Through Inhibition of the Proteasome Promotes Osteocyte Differentiation in Murine in Vitro Models. AB - The transmembrane glycoprotein E11 is considered critical in early osteoblast osteocyte transitions (osteocytogenesis), however its function and regulatory mechanisms are still unknown. Using the late osteoblast MLO-A5 cell line we reveal increased E11 protein/mRNA expression (P < 0.001) concomitant with extensive osteocyte dendrite formation and matrix mineralization (P < 0.001). Transfection with E11 significantly increased mRNA levels (P < 0.001), but immunoblotting failed to detect any correlative increases in E11 protein levels, suggestive of post-translational degradation. We found that exogenous treatment of MLO-A5 and osteocytic IDG-SW3 cells with 10 MUM ALLN (calpain and proteasome inhibitor) stabilized E11 protein levels and induced a profound increase in osteocytic dendrite formation (P < 0.001). Treatment with other calpain inhibitors failed to promote similar osteocytogenic changes, suggesting that these effects of ALLN rely upon its proteasome inhibitor actions. Accordingly we found that proteasome-selective inhibitors (MG132/lactacystin/ Bortezomib/Withaferin-A) produced similar dose-dependent increases in E11 protein levels in MLO-A5 and primary osteoblast cells. This proteasomal targeting was confirmed by immunoprecipitation of ubiquitinylated proteins, which included E11, and by increased levels of ubiquitinylated E11 protein upon addition of the proteasome inhibitors MG132/Bortezomib. Activation of RhoA, the small GTPase, was found to be increased concomitant with the peak in E11 levels and its downstream signaling was also observed to promote MLO-A5 cell dendrite formation. Our data indicate that a mechanism reliant upon blockade of proteasome-mediated E11 destabilization contributes to osteocytogenesis and that this may involve downstream targeting of RhoA. This work adds to our mechanistic understanding of the factors regulating bone homeostasis, which may lead to future therapeutic approaches. PMID- 26639106 TI - Arp2/3-mediated F-actin formation controls regulated exocytosis in vivo. AB - The actin cytoskeleton plays crucial roles in many cellular processes, including regulated secretion. However, the mechanisms controlling F-actin dynamics in this process are largely unknown. Through 3D time-lapse imaging in a secreting organ, we show that F-actin is actively disassembled along the apical plasma membrane at the site of secretory vesicle fusion and re-assembled directionally on vesicle membranes. Moreover, we show that fusion pore formation and PIP2 redistribution precedes actin and myosin recruitment to secretory vesicle membranes. Finally, we show essential roles for the branched actin nucleators Arp2/3- and WASp in the process of secretory cargo expulsion and integration of vesicular membranes with the apical plasma membrane. Our results highlight previously unknown roles for branched actin in exocytosis and provide a genetically tractable system to image the temporal and spatial dynamics of polarized secretion in vivo. PMID- 26639107 TI - Beneficial cilostazol therapeutic effects in mdx dystrophic skeletal muscle. AB - This study evaluated the possible protective effects of cilostazol against myonecrosis in dystrophic diaphragm muscle in vivo, focusing on oxidative stress, the inflammatory response and angiogenesis. Young mdx mice, the experimental animal for Duchenne muscular dystrophy, received cilostazol for 14 days. A second group of mdx mice and a control group of C57BL/10 mice received a saline solution. In the mdx mice, cilostazol treatment was associated with reduced loss of muscle strength (-34.4%), decreased myonecrosis, reduced creatine kinase levels (-63.3%) and muscle fibres stained for immunoglobulin G in dystrophic diaphragm muscle (-81.1%), and a reduced inflammatory response, with a decreased inflammatory area (-22%), macrophage infiltration (-44.9%) and nuclear factor kappaB (-24%) and tumour necrosis factor-alpha (-48%) content in dystrophic diaphragm muscle. Furthermore, cilostazol decreased oxidative stress and attenuated reactive oxygen species production (-74%) and lipid peroxidation ( 17%) in dystrophic diaphragm muscle, and promoted the up-regulation of angiogenesis, increasing the number of microvessels (15%). In conclusion, the present results show that cilostazol has beneficial effects in dystrophic muscle. More research into the potential of cilostazol as a novel therapeutic agent for the treatment of dystrophinopathies is required. PMID- 26639108 TI - Pure spin-Hall magnetoresistance in Rh/Y3Fe5O12 hybrid. AB - We report an investigation of anisotropic magnetoresistance (AMR) and anomalous Hall resistance (AHR) of Rh and Pt thin films sputtered on epitaxial Y(3)Fe(5)O(12) (YIG) ferromagnetic insulator films. For the Pt/YIG hybrid, large spin-Hall magne toresistance (SMR) along with a sizable conventional anisotropic magnetoresistance (CAMR) and a nontrivial temperature dependence of AHR were observed in the temperature range of 5-300 K. In contrast, a reduced SMR with negligible CAMR and AHR was found in Rh/YIG hybrid. Since CAMR and AHR are characteristics for all ferromagnetic metals, our results suggest that the Pt is likely magnetized by YIG due to the magnetic proximity effect (MPE) while Rh remains free of MPE. Thus the Rh/YIG hybrid could be an ideal model system to explore physics and devices associated with pure spin current. PMID- 26639109 TI - Retroperitoneal and mediastinal follicular dendritic cell sarcoma: report of 3 cases with review of literature. AB - Follicular dendritic cell sarcoma (FDCS) is a rare malignant histiocytic proliferation of antigen presenting follicular dendritic cell. It is an uncommon primary malignancy first described by Monda et al. in 1986. Most commonly reported cases are lymph nodal. Occasional cases occur in extra nodal sites. Here, we describe the clinicopathological features, histomorphology and outcome of three patients with extranodal FDCS along with a concise review of literature on the topic. All three patients were adult females. Two patients were in third decade, and one had age of 50 years. Among the three cases, two cases are presented as retroperitoneal mass and one as mediastinal mass. CT scans revealed heterogeneously enhancing masses. All the cases showed ovoid to spindle neoplastic cells arranged predominantly in whorling, fascicular and storiform patterns with inflammatory infiltrate. Immunohistochemically, the tumor cells are positive for CD21, CD23, CD35 and Clustrin. In view of rarity and variable clinical presentation in FDCS, accurate diagnosis is necessary. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26639111 TI - Integration of HIV in child survival platforms: a novel programmatic pathway towards the 90-90-90 targets. AB - INTRODUCTION: Integration of HIV into child survival platforms is an evolving territory with multiple connotations. Most literature on integration of HIV into other health services focuses on adults; however promising practices for children are emerging. These include the Double Dividend (DD) framework, a new programming approach with dual goal of improving paediatric HIV care and child survival. In this commentary, the authors discuss why integrating HIV testing, treatment and care into child survival platforms is important, as well as its potential to advance progress towards global targets that call for, by 2020, 90% of children living with HIV to know their status, 90% of those diagnosed to be on treatment and 90% of those on treatment to be virally suppressed (90-90-90). DISCUSSION: Integration is critical in improving health outcomes and efficiency gains. In children, integration of HIV in programmes such as immunization and nutrition has been associated with an increased uptake of HIV infant testing. Integration is increasingly recognized as a case-finding strategy for children missed from prevention of mother-to-child transmission programmes and as a platform for diffusing emerging technologies such as point-of-care diagnostics. These support progress towards the 90-90-90 targets by providing a pathway for early identification of HIV-infected children with co-morbidities, prompt initiation of treatment and improved survival. There are various promising practices that have demonstrated HIV outcomes; however, few have documented the benefits of integration on child survival interventions. The DD framework is well positioned to address the bidirectional impacts for both programmes. CONCLUSIONS: Integration provides an important programmatic pathway for accelerated progress towards the 90-90-90 targets. Despite this encouraging information, there are still challenges to be addressed in order to maximize the benefits of integration. PMID- 26639110 TI - Tuberculosis: opportunities and challenges for the 90-90-90 targets in HIV infected children. AB - INTRODUCTION: In 2014 the Joint United Nations Programme on HIV/AIDS defined the ambitious 90-90-90 targets for 2020, in which 90% of people living with HIV must be diagnosed, 90% of those diagnosed should be on sustained therapy and 90% of those on therapy should have an undetectable viral load. Children are considered to be a key focus population for these targets. This review will highlight key components of the epidemiology, prevention and treatment of tuberculosis (TB) in HIV-infected children in the era of increasing access to antiretroviral therapy (ART) and their relation to the 90-90-90 targets. DISCUSSION: The majority of HIV infected children live in countries with a high burden of TB. In settings with a high burden of both diseases such as in sub-Saharan Africa, up to 57% of children diagnosed with and treated for TB are HIV-infected. TB results in substantial morbidity and mortality in HIV-infected children, so preventing TB and optimizing its treatment in HIV-infected children will be important to ensuring good long term outcomes. Prevention of TB can be achieved by increasing access to ART to both children and adults, and appropriate provision of isoniazid preventative therapy. Co-treatment of HIV and TB is complicated by drug-drug interactions particularly due to the use of rifampicin; these may compromise virologic outcomes if appropriate corrective actions are not taken. There remain substantial operational challenges, and improved integration of paediatric TB and HIV services, including with antenatal and routine under-five care, is an important priority. CONCLUSIONS: TB may be an important barrier to achievement of the 90-90-90 targets, but specific attention to TB care in HIV-infected children may provide important opportunities to enhance the care of both TB and HIV in children. PMID- 26639112 TI - Patching the gaps towards the 90-90-90 targets: outcomes of Nigerian children receiving antiretroviral treatment who are co-infected with tuberculosis. AB - INTRODUCTION: Nigeria has a high burden of children living with HIV and tuberculosis (TB). This article examines the magnitude of TB among children receiving antiretroviral treatment (ART), compares their ART outcomes with their non-TB counterparts and argues that addressing TB among children on ART is critical for achieving the 90-90-90 targets. METHODS: This was a facility-based, retrospective analysis of medical records of children aged <15 years who were newly initiated on ART between 2011 and 2012. Structured tools were used to collect data. STATA software was used to perform descriptive, survival and multivariate analyses. RESULTS: A total of 1142 children with a median age of 3.5 years from 20 selected facilities were followed for 24 months. Of these, 95.8% were assessed for TB at ART initiation and 14.7% had TB. Children on ART were more likely to have TB if they were aged 5 years or older (p<0.01) and had delayed ART initiation (p<0.05). The cotrimoxazole and isoniazid prophylaxes were provided to 87.9 and 0.8% of children, respectively. The rate of new TB cases was 3 (2.2-4.0) per 100 person-years at six months and declined to 0.2 (0.06-1.4) per 100 person-years at 24 months. TB infection [adjusted hazard ratio (aHR): 4.3; 2.3-7.9], malnutrition (aHR: 5.1; 2.6-9.8), delayed ART initiation (aHR: 3.2; 1.5 6.7) and age less than 1 year at ART initiation (aHR: 4.0; 1.4-12.0) were associated with death. Additionally, patients with TB (aHR: 1.3; 1.1-1.6) and children below the age of 1 at ART initiation (aHR: 2.9; 1.7-5.2) were more likely to be lost to follow-up (LFU). CONCLUSIONS: Children on ART with TB are less likely to survive and more likely to be LFU. These risks, along with low isoniazid uptake and delayed ART initiation, present a serious challenge to achieving the 90-90-90 targets and underscore an urgent need for inclusion of childhood TB/HIV in global plans and reporting mechanisms. PMID- 26639113 TI - Achieving 90-90-90 in paediatric HIV: adolescence as the touchstone for transition success. AB - INTRODUCTION: The number of children less than 15 years estimated to be living with HIV globally approximated 3.2 million in 2013. Young people aged 15 to 24 years living with HIV approximated 4 million. The survival of these children and adolescents into adulthood poses new and urgent challenges of transition from the paediatric to adolescent to adult healthcare settings due to emerging developmental, psychosocial and comorbid issues. In order to achieve treatment targets of 90-90-90 across the continuum of care for paediatric HIV by 2020, focused efforts on the implementation of appropriate healthcare transition plans across the lifespan, with a focus on adolescence, should be prioritized. DISCUSSION: Published data or empirical evidence examining implementation of transition models and association with clinical outcomes are limited. While some guidelines do exist that offer recommendations about how to promote seamless transitions, very few data are available to assess the adequacy of these guidelines and whether they are effectively adhered to in clinical care settings globally. Furthermore, paediatric and adolescent HIV infection, either acquired perinatally or behaviourally, is set apart from other chronic illnesses as a highly stigmatizing disease that disproportionately affects poor, minority and often marginalized populations. Focused efforts on adolescence as the touchstone for transition practices and policies need to be implemented. CONCLUSIONS: Optimal healthcare for these vulnerable populations, particularly in resource limited settings, will require HIV-specific transitional care services and programmes that are coordinated, collaborative, integrated and, importantly, evidence-based. PMID- 26639115 TI - Social protection: potential for improving HIV outcomes among adolescents. AB - INTRODUCTION: Advances in biomedical technologies provide potential for adolescent HIV prevention and HIV-positive survival. The UNAIDS 90-90-90 treatment targets provide a new roadmap for ending the HIV epidemic, principally through antiretroviral treatment, HIV testing and viral suppression among people with HIV. However, while imperative, HIV treatment and testing will not be sufficient to address the epidemic among adolescents in Southern and Eastern Africa. In particular, use of condoms and adherence to antiretroviral therapy (ART) remain haphazard, with evidence that social and structural deprivation is negatively impacting adolescents' capacity to protect themselves and others. This paper examines the evidence for and potential of interventions addressing these structural deprivations. DISCUSSION: New evidence is emerging around social protection interventions, including cash transfers, parenting support and educational support ("cash, care and classroom"). These interventions have the potential to reduce the social and economic drivers of HIV risk, improve utilization of prevention technologies and improve adherence to ART for adolescent populations in the hyper-endemic settings of Southern and Eastern Africa. Studies show that the integration of social and economic interventions has high acceptability and reach and that it holds powerful potential for improved HIV, health and development outcomes. CONCLUSIONS: Social protection is a largely untapped means of reducing HIV-risk behaviours and increasing uptake of and adherence to biomedical prevention and treatment technologies. There is now sufficient evidence to include social protection programming as a key strategy not only to mitigate the negative impacts of the HIV epidemic among families, but also to contribute to HIV prevention among adolescents and potentially to remove social and economic barriers to accessing treatment. We urge a further research and programming agenda: to actively combine programmes that increase availability of biomedical solutions with social protection policies that can boost their utilization. PMID- 26639116 TI - Sequencing paediatric antiretroviral therapy in the context of a public health approach. AB - INTRODUCTION: As access to prevention of mother-to-child transmission (PMTCT) efforts has increased, the total number of children being born with HIV has significantly decreased. However, those children who do become infected after PMTCT failure are at particular risk of HIV drug resistance, selected by exposure to maternal or paediatric antiretroviral drugs used before, during or after birth. As a consequence, the response to antiretroviral therapy (ART) in these children may be compromised, particularly when non-nucleoside reverse transcriptase inhibitors (NNRTIs) are used as part of the first-line regimen. We review evidence guiding choices of first- and second-line ART. DISCUSSION: Children generally respond relatively well to ART. Clinical trials show the superiority of protease inhibitor (PI)- over NNRTI-based treatment in young children, but observational reports of NNRTI-containing regimens are usually favourable as well. This is reassuring as national guidelines often still recommend the use of NNRTI-based treatment for PMTCT-unexposed young children, due to the higher costs of PIs. After failure of NNRTI-based, first-line treatment, the rate of acquired drug resistance is high, but HIV may well be suppressed by PIs in second-line ART. By contrast, there are currently no adequate alternatives in resource-limited settings (RLS) for children failing either first- or second-line, PI-containing regimens. CONCLUSIONS: Affordable salvage treatment options for children in RLS are urgently needed. PMID- 26639114 TI - The physical and psychological effects of HIV infection and its treatment on perinatally HIV-infected children. AB - INTRODUCTION: As highly active antiretroviral therapy (HAART) transforms human immunodeficiency virus (HIV) into a manageable chronic disease, new challenges are emerging in treating children born with HIV, including a number of risks to their physical and psychological health due to HIV infection and its lifelong treatment. METHODS: We conducted a literature review to evaluate the evidence on the physical and psychological effects of perinatal HIV (PHIV+) infection and its treatment in the era of HAART, including major chronic comorbidities. RESULTS AND DISCUSSION: Perinatally infected children face concerning levels of treatment failure and drug resistance, which may hamper their long-term treatment and result in more significant comorbidities. Physical complications from PHIV+ infection and treatment potentially affect all major organ systems. Although treatment with antiretroviral (ARV) therapy has reduced incidence of severe neurocognitive diseases like HIV encephalopathy, perinatally infected children may experience less severe neurocognitive complications related to HIV disease and ARV neurotoxicity. Major metabolic complications include dyslipidaemia and insulin resistance, complications that are associated with both HIV infection and several ARV agents and may significantly affect cardiovascular disease risk with age. Bone abnormalities, particularly amongst children treated with tenofovir, are a concern for perinatally infected children who may be at higher risk for bone fractures and osteoporosis. In many studies, rates of anaemia are significantly higher for HIV-infected children. Renal failure is a significant complication and cause of death amongst perinatally infected children, while new data on sexual and reproductive health suggest that sexually transmitted infections and birth complications may be additional concerns for perinatally infected children in adolescence. Finally, perinatally infected children may face psychological challenges, including higher rates of mental health and behavioural disorders. Existing studies have significant methodological limitations, including small sample sizes, inappropriate control groups and heterogeneous definitions, to name a few. CONCLUSIONS: Success in treating perinatally HIV infected children and better understanding of the physical and psychological implications of lifelong HIV infection require that we address a new set of challenges for children. A better understanding of these challenges will guide care providers, researchers and policymakers towards more effective HIV care management for perinatally infected children and their transition to adulthood. PMID- 26639117 TI - Optimizing drugs to reach treatment targets for children and adolescents living with HIV. AB - INTRODUCTION: As the global community makes progress towards the 90-90-90 targets by 2020, a key challenge is ensuring that antiretroviral drugs for children and adolescents are suitable to the context of resource-limited settings. Drug optimization aims to support the expanded use of more simplified, less toxic drug regimens with high barriers to drug resistance that require minimal clinical monitoring while maintaining therapeutic efficacy. This manuscript summarizes the progress made and outlines further critical steps required to ensure that the right drugs are available to start children and adolescents on treatment and to keep them virologically suppressed. DISCUSSION: Building upon previous work in drug optimization, several important steps were taken in 2014 to ensure alignment between WHO dosing recommendations and the requirements of regulatory bodies, to accelerate drug development, to reduce intellectual property barriers to generic production of combined formulations and rationalize drug selection in countries. The priority for the future is to improve access to antiretroviral therapy (ART) at the two ends of the paediatric age spectrum--infants and adolescents--where the treatment gap is greatest, and optimize drug sequencing with better use of available medicines for second- and third-line ART. Future efforts in this area will require continuous collaboration and coordination, and the promotion of innovative approaches to accelerate access to new drugs and formulations. CONCLUSIONS: While significant progress has been made, additional efforts are needed to ensure that treatment targets are reached by 2020. PMID- 26639118 TI - The last and first frontier--emerging challenges for HIV treatment and prevention in the first week of life with emphasis on premature and low birth weight infants. AB - INTRODUCTION: There is new emphasis on identifying and treating HIV in the first days of life and also an appreciation that low birth weight (LBW) and preterm delivery (PTD) frequently accompany HIV-related pregnancy. Even in the absence of HIV, PTD and LBW contribute substantially to neonatal and infant mortality. HIV exposed and -infected infants with these characteristics have received little attention thus far. As HIV programs expand to meet the 90-90-90 target for ending the HIV pandemic, attention should focus on newborn infants, including those delivered preterm or of LBW. DISCUSSION: In high prevalence settings, infant diagnosis of HIV is usually undertaken after the neonatal period. However, as in utero infection may be diagnosed at birth, earlier initiation of therapy may limit viral replication and prevent early damage. Globally, there is growing awareness that preterm and LBW infants constitute a substantial proportion of births each year. Preterm infants are at high risk for vertical transmission. Feeding difficulties, apnoea of prematurity and vulnerability to sepsis occur commonly. Feeding intolerance, a frequent occurrence, may compromise oral administration of medications. Although there is growing experience with post exposure prophylaxis for HIV-exposed term newborn infants, there is less experience with preterm and LBW infants. For treatment, there are even fewer options for preterm infants. Only zidovudine has adequate dosing recommendations for treating term and preterm infants and has an intravenous formulation, essential if feeding intolerance occurs. Nevirapine dosing for prevention, but not treatment, is well established for both term and preterm infants.HIV diagnosis at birth is likely to be extremely stressful for new parents, more so if caring for preterm or LBW infants. Programs need to adapt to support the medical and emotional needs of young infants and their parents, where interventions may be lifesaving. CONCLUSIONS: New focus is required for the newborn baby, including those born preterm, with LBW or small for gestational age to consolidate gains already made in early diagnosis and treatment of young children. PMID- 26639119 TI - 90-90-90--Charting a steady course to end the paediatric HIV epidemic. AB - INTRODUCTION: The new "90-90-90" UNAIDS agenda proposes that 90% of all people living with HIV will know their HIV status, 90% of all people with diagnosed HIV infection will receive sustained antiretroviral therapy and 90% of all people receiving antiretroviral therapy will have viral suppression by 2020. By focusing on children, the global community is in the unique position of realizing an end to the paediatric HIV epidemic. DISCUSSION: Despite vast scientific advances in the prevention and treatment of paediatric HIV infection over the last two decades, in 2014 there were an estimated 220,000 new paediatric infections attributed to mother-to-child HIV transmission (MTCT) and 150,000 HIV-related paediatric deaths. Furthermore, adolescents remain at particularly high risk for acquisition of new HIV infections, and HIV/AIDS remains the second leading cause of death in this age group. Among the estimated 2.6 million children less than 15 years of age living with HIV infection, only 32% were receiving life-saving antiretroviral treatment. After decades of languishing, good progress is now being made to prevent MTCT. Unfortunately, efforts to scale up HIV treatment services have been less robust for children and adolescents compared with adult populations. These discrepancies reflect substantial gaps in essential services and numerous missed opportunities to prevent HIV transmission and provide effective life-saving antiretroviral treatment to children, adolescents and families. The road to an AIDS-free generation will require bridging the gaps in HIV services and addressing the particular needs of children across the developmental spectrum from infancy through adolescence. To reach the ambitious new targets, innovations and service improvements will need to be rapidly escalated at each step along the prevention-treatment cascade. CONCLUSIONS: Charting a successful course to reach the 90-90-90 targets will require sustained political and financial commitment as well as the rapid implementation of a broad set of systematic improvements in service delivery. The prospect of a world where HIV no longer threatens the lives of infants, children and adolescents may finally be within reach. PMID- 26639120 TI - Reducing mortality in HIV-infected infants and achieving the 90-90-90 target through innovative diagnosis approaches. AB - INTRODUCTION: Despite significant gains in access to early infant diagnosis (EID) over the past decade, most HIV-exposed infants still do not get tested for HIV in the first two months of life. For those who are tested, the long turnaround time between when the sample is drawn and when the results are returned leads to a high rate of loss to follow-up, which in turn means that few infected infants start antiretroviral treatment. Consequently, there continues to be high mortality from perinatally acquired HIV, and the ambitious goals of 90% of infected children identified, 90% of identified children treated and 90% of treated children with sustained virologic suppression by 2020 seem far beyond our reach. The objective of this commentary is to review recent advances in the field of HIV diagnosis in infants and describe how these advances may overcome long standing barriers to access to testing and treatment. DISCUSSION: Several innovative approaches to EID have recently been described. These include point-of care testing, use of SMS printers to connect the central laboratory and the health facility through a mobile phone network, expanding paediatric testing to other entry points where children access the health system and testing HIV exposed infants at birth as a rapid way to identify in utero infection. Each of these interventions is discussed here, together with the opportunities and challenges associated with scale-up. Point-of-care testing has the potential to provide immediate results but is less cost-effective in settings where test volumes are low. Virological testing at birth has been piloted in some countries to identify those infants who need urgent treatment, but a negative test at birth does not obviate the need for additional testing at six weeks. Routine testing of infants in child health settings is a useful strategy to identify exposed and infected children whose mothers were not enrolled in programmes for the prevention of mother-to-child transmission. Facility-based SMS printers speed up the return of laboratory results and may be of value for other testing services apart from HIV infant diagnosis. CONCLUSIONS: New tools and strategies for HIV infant diagnosis could have a significant positive impact on the identification and retention of HIV-infected infants. In order to be most effective, national programmes should carefully consider which ideas to implement and how best to integrate novel strategies into existing systems. There is no single solution that will work everywhere. Rather, a number of approaches need to be considered and should be linked in order to achieve the greatest impact on the continuum of care from testing to treatment. PMID- 26639121 TI - Targeting 90-90-90--don't leave children and adolescents behind. PMID- 26639123 TI - Handover education improves skill and confidence. AB - BACKGROUND: Despite the frequency of patient-care handovers and vulnerability to errors, medical schools infrequently teach handover skills. Our study evaluated the impact of a medical school handover curriculum on students' performance, as rated by faculty members, peers and self-assessment. METHODS: Nineteen fourth year medical students participated in a handover curriculum that included a workshop and three directly observed patient handovers, with feedback from faculty members. Multivariate repeated-measures analysis evaluated faculty member, peer, and self-rated performance over time. Students' self-assessed confidence in performing handovers prior to, at the end of, and 8-12 months after the curriculum was also analysed. RESULTS: Faculty member, peer and self assessments showed that students' performance significantly improved after the curriculum, on handover content, clinical judgment and overall performance (p < 0.05). Students rated the curriculum as effective and characterised themselves as more prepared to perform handovers, with these findings persisting for 8-12 months (p <= 0.001). Medical schools infrequently teach handover skills DISCUSSION: A handover curriculum appears to improve medical students' handover performance, as evaluated by independent ratings from faculty members, peers and the students themselves, in addition to improving the students' confidence. PMID- 26639124 TI - Solid-phase purification and extraction for the determination of trace neonicotinoid pesticides in tea infusion. AB - An analytical protocol that includes solid-phase purification and extraction is successfully developed for the determination of trace neonicotinoid pesticides in tea infusion. The method consists of a purification on amino-functionalized mesoporous silica SBA-15 followed by a solid-phase extraction based on graphene oxide before ultra high performance liquid chromatography with tandem mass spectrometry analysis. Parameters that significantly affected the extraction of the neonicotinoids onto graphene oxide, such as the amount of adsorbent, extraction time, pH, elution solvent, etc. were optimized. The amino functionalized mesoporous silica SBA-15 has been proved to be an efficient adsorbent for removal of polyphenols especially catechins from tea infusion. Graphene oxide exhibits a very rapid adsorption rate (within 10 min) and high adsorption capacities for neonicotinoids at low initial concentration (0.01-0.5 mg/L). The analysis method gave a good determination coefficient (r(2) > 0.99) for each pesticide and high recoveries in the range of 72.2-95.0%. Powder X-ray diffraction, Raman spectroscopy, transmission electron microscopy, and UV-vis spectroscopy were utilized to identify the structure and morphology of graphene oxide. The adsorption driving force of neonicotinoids on graphene oxide mainly depends on pi-pi electron donor-acceptor interaction and electrostatic interaction. PMID- 26639125 TI - Photovoltaic Performance of Perovskite Solar Cells with Different Grain Sizes. AB - Perovskite solar cells exhibit improved photovoltaic parameters with increasing perovskite grain size. The larger photocurrent is due to the enhanced absorption efficiency for thicker perovskite layers. The larger open-circuit voltage (VOC ) is ascribed to the reduced trap-assisted recombination for the larger grains. As a result, the power conversion efficiency exceeds 19% at best. Further improvement in VOC would be possible if the trap density were reduced. PMID- 26639147 TI - Room-temperature in situ nuclear spin hyperpolarization from optically pumped nitrogen vacancy centres in diamond. AB - Low detection sensitivity stemming from the weak polarization of nuclear spins is a primary limitation of magnetic resonance spectroscopy and imaging. Methods have been developed to enhance nuclear spin polarization but they typically require high magnetic fields, cryogenic temperatures or sample transfer between magnets. Here we report bulk, room-temperature hyperpolarization of (13)C nuclear spins observed via high-field magnetic resonance. The technique harnesses the high optically induced spin polarization of diamond nitrogen vacancy centres at room temperature in combination with dynamic nuclear polarization. We observe bulk nuclear spin polarization of 6%, an enhancement of ~170,000 over thermal equilibrium. The signal of the hyperpolarized spins was detected in situ with a standard nuclear magnetic resonance probe without the need for sample shuttling or precise crystal orientation. Hyperpolarization via optical pumping/dynamic nuclear polarization should function at arbitrary magnetic fields enabling orders of magnitude sensitivity enhancement for nuclear magnetic resonance of solids and liquids under ambient conditions. PMID- 26639148 TI - Inhibition of Ape1 Redox Activity Promotes Odonto/osteogenic Differentiation of Dental Papilla Cells. AB - Dentinogenesis is the formation of dentin, a substance that forms the majority of teeth, and this process is performed by odontoblasts. Dental papilla cells (DPCs), as the progenitor cells of odontoblasts, undergo the odontogenic differentiation regulated by multiple cytokines and paracrine signal molecules. Ape1 is a perfect paradigm of the function complexity of a biological macromolecule with two major functional regions for DNA repair and redox regulation, respectively. To date, it remains unclear whether Ape1 can regulate the dentinogenesis in DPCs. In the present study, we firstly examed the spatio temporal expression of Ape1 during tooth germ developmental process, and found the Ape1 expression was initially high and then gradually reduced along with the tooth development. Secondly, the osteo/odontogenic differentiation capacity of DPCs was up-regulated when treated with either Ape1-shRNA or E3330 (a specific inhibitor of the Ape1 redox function), respectively. Moreover, we found that the canonical Wnt signaling pathway was activated in this process, and E3330 reinforced-osteo/odontogenic differentiation capacity was suppressed by Dickkopf1 (DKK1), a potent antagonist of canonical Wnt signaling pathway. Taken together, we for the first time showed that inhibition of Ape1 redox regulation could promote the osteo/odontogenic differentiation capacity of DPCs via canonical Wnt signaling pathway. PMID- 26639150 TI - Orbital color Doppler ultrasound as noninvasive tool in the diagnosis of anterior draining carotid-cavernous fistula. AB - PURPOSE: To investigate the role of orbital color Doppler ultrasound (OCDUS) in the diagnosis of carotid-cavernous fistula (CCF) with anterior drainage and particularly whether a negative OCDUS could avoid an invasive diagnostic cerebral angiography (DSA). MATERIALS AND METHODS: Twenty-two consecutive patients with ophthalmic signs suspecting CCF were submitted to ophthalmologic examination, OCDUS and DSA. CCF diagnosis with OCDUS was based on the finding of a reversed, arterialized and low-resistive-index (RI <0.5) blood flow in the superior ophthalmic vein (SOV). Sensibility, specificity, PPV, NPV, and accuracy of OCDUS were calculated considering both patients and eyes, using DSA as gold standard. RESULTS: DSA demonstrated 20 CCFs in 18 patients. Considering the patients, in 18/22 CCF diagnosis was positive at OCDUS and DSA while 4/22 were negative at both. Considering the eyes, in 24/43 CCF diagnosis was positive at both DSA and OCDUS (total eyes = 43, due to one case of SOV thrombosis). In 19/43 eyes diagnosis was negative at both OCDUS and DSA. So sensitivity, specificity, PPV, NPV, and accuracy of OCDUS in the patients and eyes analysis were all 100 %. CONCLUSIONS: OCDUS is a reliable, noninvasive tool in the diagnosis of CCF; a negative OCDUS could avoid an invasive DSA in patients suspected for anterior draining CCF. PMID- 26639151 TI - Leaf concentrate compared with skimmed milk as nutritional supplementation for HIV-infected children: a randomized controlled trial in Burundi. AB - OBJECTIVE: The effectiveness of leaf concentrate powder (LCP) as a nutritional supplement was established in trials conducted among adolescent girls and pregnant women in India. Here we evaluate LCP, compared with skimmed milk powder (SMP), as a supplement for antiretroviral-naive children living with HIV in a sub Saharan African country. DESIGN: Randomized controlled, two-arm, 6-month trial comparing effects of isoproteic (5 g) LCP (10 g daily) and SMP (15 g daily) on HIV-1 viral load, CD4+ cell count/percentage, weight/height-for-age, general blood parameters, diarrhoea, respiratory and HIV-related opportunistic infections. SETTING: Bujumbura and Kirundo, Burundi. SUBJECTS: Eighty-three HIV positive, antiretroviral-naive children aged 5-14 years: median (range) CD4+ count, 716 (361-1690) cells/mm3; log10 HIV-1 viral load, 4.39 (1.79-6.00). RESULTS: LCP was equivalent to SMP in relation to HIV-specific blood parameters and did not demonstrate superiority over SMP in relation to Hb. Three children in each arm (LCP, 7.1 % (3/42); SMP, 7.3 % (3/41)) proceeded to antiretroviral therapy because their CD4+ counts fell below 350 cells/mm3. Children in the LCP group reported higher levels of appetite and overall health at 6 months. There were no differences in clinical events or any other outcome measures. LCP was less palatable than SMP to the children in this population, but there were few negative perceptions of appearance, texture and taste. CONCLUSIONS: LCP appears to be equivalent to SMP as a nutritional supplement in this population, despite slightly lower palatability. In relation to viral load and CD4+ count, equivalence may indicate no effect in either group. Effectiveness relative to no supplementation remains to be determined. PMID- 26639149 TI - Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia. AB - BACKGROUND: Chronic lymphocytic leukemia (CLL) primarily affects older persons who often have coexisting conditions in addition to disease-related immunosuppression and myelosuppression. We conducted an international, open label, randomized phase 3 trial to compare two oral agents, ibrutinib and chlorambucil, in previously untreated older patients with CLL or small lymphocytic lymphoma. METHODS: We randomly assigned 269 previously untreated patients who were 65 years of age or older and had CLL or small lymphocytic lymphoma to receive ibrutinib or chlorambucil. The primary end point was progression-free survival as assessed by an independent review committee. RESULTS: The median age of the patients was 73 years. During a median follow-up period of 18.4 months, ibrutinib resulted in significantly longer progression free survival than did chlorambucil (median, not reached vs. 18.9 months), with a risk of progression or death that was 84% lower with ibrutinib than that with chlorambucil (hazard ratio, 0.16; P<0.001). Ibrutinib significantly prolonged overall survival; the estimated survival rate at 24 months was 98% with ibrutinib versus 85% with chlorambucil, with a relative risk of death that was 84% lower in the ibrutinib group than in the chlorambucil group (hazard ratio, 0.16; P=0.001). The overall response rate was higher with ibrutinib than with chlorambucil (86% vs. 35%, P<0.001). The rates of sustained increases from baseline values in the hemoglobin and platelet levels were higher with ibrutinib. Adverse events of any grade that occurred in at least 20% of the patients receiving ibrutinib included diarrhea, fatigue, cough, and nausea; adverse events occurring in at least 20% of those receiving chlorambucil included nausea, fatigue, neutropenia, anemia, and vomiting. In the ibrutinib group, four patients had a grade 3 hemorrhage and one had a grade 4 hemorrhage. A total of 87% of the patients in the ibrutinib group are continuing to take ibrutinib. CONCLUSIONS: Ibrutinib was superior to chlorambucil in previously untreated patients with CLL or small lymphocytic lymphoma, as assessed by progression-free survival, overall survival, response rate, and improvement in hematologic variables. (Funded by Pharmacyclics and others; RESONATE-2 ClinicalTrials.gov number, NCT01722487.). PMID- 26639152 TI - Single-cell analysis of peptide expression and electrophysiology of right parietal neurons involved in male copulation behavior of a simultaneous hermaphrodite. AB - Male copulation is a complex behavior that requires coordinated communication between the nervous system and the peripheral reproductive organs involved in mating. In hermaphroditic animals, such as the freshwater snail Lymnaea stagnalis, this complexity increases since the animal can behave both as male and female. The performance of the sexual role as a male is coordinated via a neuronal communication regulated by many peptidergic neurons, clustered in the cerebral and pedal ganglia and dispersed in the pleural and parietal ganglia. By combining single-cell matrix-assisted laser mass spectrometry with retrograde staining and electrophysiology, we analyzed neuropeptide expression of single neurons of the right parietal ganglion and their axonal projections into the penial nerve. Based on the neuropeptide profile of these neurons, we were able to reconstruct a chemical map of the right parietal ganglion revealing a striking correlation with the earlier electrophysiological and neuroanatomical studies. Neurons can be divided into two main groups: (i) neurons that express heptapeptides and (ii) neurons that do not. The neuronal projection of the different neurons into the penial nerve reveals a pattern where (spontaneous) activity is related to branching pattern. This heterogeneity in both neurochemical anatomy and branching pattern of the parietal neurons reflects the complexity of the peptidergic neurotransmission involved in the regulation of male mating behavior in this simultaneous hermaphrodite. PMID- 26639153 TI - Wild medicinal and food plants used by communities living in Mopane woodlands of southern Angola: Results of an ethnobotanical field investigation. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Mopane woodlands play an important role in the livelihood strategies of local populations; however, they have been scarcely investigated by ethnobiologists and very little is currently known about plants traditionally used by local communities, especially about medicinal plants. AIM OF THE STUDY: Our investigation was aimed to document ethnobotanical knowledge in seven communities living in conditions of extreme poverty in a Mopane area of southern Angola (Namibe province). We focused on plants used as medicines and/or food, in order to highlight the role of wild plants in the livelihood of local communities, and possibly to find out plants with potential pharmacological interest. METHODS: Ethnobotanical data were recorded through semi-structured interviews, filed in a database and quantitatively analyzed. The following synthetic indexes were used: Cultural Importance index (CI), Informant Consensus Factor (FIC), Fidelity Level (FL). RESULTS: Sixty-six informants (26 males, 40 females) were interviewed. A total of 1247 citations were recorded, concerning 132 ethnospecies (folk taxonomic units not necessarily corresponding to single botanical species); 104 were identified at different taxonomic levels. For medicinal purposes, 116 ethnospecies and 20 different uses (650 citations) were reported; for food purposes, 33 ethnospecies and 8 different uses (597 citations). The main used parts resulted to be fruit (471 citations; 21 ethnospecies), followed by underground organs (288, 82) and leaves (175, 41). According to CI values, Berchemia discolor, Ximenia americana var. americana and Adansonia digitata have the highest cultural value in the investigated communities. All of them are woody plants, as well as most of the identified ethnospecies (trees 34.6%, shrubs 32.7%, perennials 21.2%, annuals 8.7%, others 2.8%). Medicinal plants are especially used to treat disorders of the gastrointestinal tract (52 ethnospecies, 205 citations), obstetric/gynecological troubles (27, 40) and colds and respiratory tract diseases (25, 54). The highest values of FIC were recorded for body care (FIC=1.0), circulatory diseases (FIC=0.91), malaria (FIC=0.81) and digestive disorders (FIC=0.55). The plants showing the highest informants' consensus (FL) were Myrothamnus flabellifolia used to treat colds and respiratory diseases (FL=100%), Terminalia prunioides for digestive diseases (93%) and Euphorbia subsalsa for backache (86%). For five plants cited as medicinal by the informants, no reports were found in the consulted ethnobotanical and ethnopharmacological literature; many uses of several already known medicinal plants were also unrecorded. Food products obtained from wild plants include fresh fruit (20 ethnospecies, 287 citations), alcoholic (11, 107) and non-alcoholic (10, 44) beverages, massa, i.e. a kind of mash, (4, 65), vegetables (10, 40), and others. CONCLUSIONS: Results show that people living in Mopane communities of southern Angola hold a valuable knowledge of the uses of plant resources and that some of the plants cited by the informants represent an important component of the local livelihood strategies. We also found some plants worthy of more in-depth investigations on their possible pharmacological activity, including: (i) those used to treat diseases which reached the highest FIC, like malaria and various disorders of the gastrointestinal tract; (ii) plants with a high FL; (iii) plants not previously reported in ethnomedical literature, especially those cited by different informants; (iv) plants with possible nutraceutical or pharma-food properties, i.e. plants with considerable contents in vitamins and/or micronutrients and plants whose food and medicinal uses are closely related. CLASSIFICATIONS: Anthropological and historical studies in ethnopharmacology, quality traditional medicines. GIVEN KEYWORDS: Botany, Traditional medicine, Africa, Diarrhea, Malaria. PMID- 26639155 TI - Reduced mitochondrial DNA copy number is a biomarker of Parkinson's disease. AB - Like any organ, the brain is susceptible to the march of time and a reduction in mitochondrial biogenesis is a hallmark of the aging process. In the largest investigation of mitochondrial copy number in Parkinson's disease (PD) to date and by using multiple tissues, we demonstrate that reduced Parkinson DNA (mitochondrial DNA mtDNA) copy number is a biomarker for the etiology of PD. We used established methods of mtDNA quantification to assess the copy number of mtDNA in n = 363 peripheral blood samples, n = 151 substantia nigra pars compacta tissue samples and n = 120 frontal cortex tissue samples from community-based PD cases fulfilling UK-PD Society brain bank criteria for the diagnosis of PD. Accepting technical limitations, our data show that PD patients suffer a significant reduction in mtDNA copy number in both peripheral blood and the vulnerable substantia nigra pars compacta when compared to matched controls. Our study indicates that reduced mtDNA copy number is restricted to the affected brain tissue, but is also reflected in the peripheral blood, suggesting that mtDNA copy number may be a viable diagnostic predictor of PD. PMID- 26639154 TI - Pseudo-immortalization of postnatal cochlear progenitor cells yields a scalable cell line capable of transcriptionally regulating mature hair cell genes. AB - The mammalian cochlea is a highly specialized organ within the inner ear. Sensory hair cells (HC) in the cochlea detect and transduce sound waves into electrical impulses that are sent to the brain. Studies of the molecular pathways regulating HC formation are hindered by the very sparse nature of HCs, where only ~3300 are found within an entire mouse cochlea. Current cell lines mimic certain aspects of HCs but lack terminal HC marker expression. Here we successfully "pseudo immortalized" cochlear progenitor cells using the "conditional reprogramming" technique. These cells, termed "Conditionally Reprogrammed Otic Stem Cells" (CR OSC), are able to bypass the senescence inherent to cochlear progenitor cells without genetic alterations, allowing for the generation of over 15 million cells from a single cochlea. These cells can be differentiated and up-regulate both early and terminal differentiation genes associated with HCs, including the terminal HC differentiation marker prestin. CR-OSCs also respond to known HC cues, including upregulation of HC genes in response to Atoh1 overexpression, and upregulation of prestin expression after thyroid hormone application. Overall, we describe the creation of a HC line capable of regulated expression of HC genes that can easily be recreated in any laboratory from any mouse of interest. PMID- 26639156 TI - Mutation analysis of CHCHD2 in Canadian patients with familial Parkinson's disease. AB - Recently, several CHCHD2 mutations were reported to be associated with autosomal dominant Parkinson's disease (PD) in a Japanese population. However, an association between CHCHD2 and PD was not observed in 2 Caucasian data sets. The present study searched for CHCHD2 coding variants in Canadian PD patients. Sanger sequencing of all CHCHD2 exons revealed no coding mutations in 155 familial cases. Moreover, 3 coding CHCHD2 polymorphisms available on the NeuroX array (Pro2Leu, Pro14Ser, and Ile118Met) were homozygous for the major allele in an additional 85 PD patients. Our study suggests that CHCHD2 mutations may not account for PD in Canadian patients. PMID- 26639157 TI - Somatic mtDNA variation is an important component of Parkinson's disease. AB - There is a growing body of evidence linking mitochondrial dysfunction, mediated either through inherited mitochondrial DNA (mtDNA) variation or mitochondrial proteomic deficit, to Parkinson's disease (PD). Yet, despite this, the role of somatic mtDNA point mutations and specifically point-mutational burden in PD is poorly understood. Here, we take advantage of recent technical and methodological advances to examine the role of age-related and acquired mtDNA mutation in the largest study of mtDNA in postmortem PD tissue to date. Our data show that PD patients suffer an increase in mtDNA mutational burden in, but no limited to, the substantia nigra pars compacta when compared to matched controls. This mutational burden appears increased in genes encoding cytochrome c oxidase, supportive of previous protein studies of mitochondrial dysfunction in PD. Accepting experimental limitations, our study confirms the important role of age-related mtDNA point mutation in the etiology of PD, moreover, by analyzing 2 distinct brain regions, we are able to show that PD patient brains are more vulnerable to mtDNA mutation overall. PMID- 26639158 TI - Two distinct clinical features and cognitive impairment in amyotrophic lateral sclerosis patients with TARDBP gene mutations in the Chinese population. AB - Mutations in the TARDBP gene have been identified as a major causative factor in amyotrophic lateral sclerosis (ALS). However, few reports have analyzed the relationship of genotype-phenotype, especially in Chinese ALS patients. Our study investigated the presence and frequency of TARDBP mutations in Chinese patients with ALS. Additionally, we investigated correlations among clinical features and TARDBP gene mutations in a large ALS family with the p.M337 V mutation and one sporadic ALS (SALS) patient with the p.S393 L mutation. The pedigree with the p.M337 V mutation showed variable clinical features with a long lifespan, particularly cognitive impairment. One patient carrying the p.S393 L mutation experienced ALS with cognitive impairment; the patient also had a family history of frontotemporal dementia (FTD). This is the first report of detailed genetic and clinical characterizations of the TARDBP gene in a Chinese population. This research is also the first to demonstrate that the p.M337 V and the p.S393 L mutations are related to cognitive impairment in ALS patients. The mutation frequency of TARDBP was 5.6% in Chinese, SOD1-negative familial ALS (FALS), which was much higher than that reported in previous studies conducted with Caucasian populations, whereas the TARDBP mutation frequency was lower in the Chinese population with regard to SALS patients. Our results emphasize the importance of the genetic and clinical characterization of TARDBP mutations in ALS, which allows us to understand the genotype-phenotype relationship and relative frequencies in different populations. PMID- 26639159 TI - Probabilistic models and numerical calculation of system matrix and sensitivity in list-mode MLEM 3D reconstruction of Compton camera images. AB - This paper addresses the problem of evaluating the system matrix and the sensitivity for iterative reconstruction in Compton camera imaging. Proposed models and numerical calculation strategies are compared through the influence they have on the three-dimensional reconstructed images. The study attempts to address four questions. First, it proposes an analytic model for the system matrix. Second, it suggests a method for its numerical validation with Monte Carlo simulated data. Third, it compares analytical models of the sensitivity factors with Monte Carlo simulated values. Finally, it shows how the system matrix and the sensitivity calculation strategies influence the quality of the reconstructed images. PMID- 26639160 TI - CSI (Crime Scene Induction): Creating False Memories of Committing Crime. AB - We describe two merging lines of empirical inquiry: entire false memories for autobiographical events and false confessions. A recent study showed that people can be led to remember, and confess to, perpetrating serious crimes that never occurred when confronted with suggestive interview tactics commonly used in police interrogations. PMID- 26639161 TI - Single-Component Phosphinous Acid Ruthenium(II) Catalysts for Versatile C-H Activation by Metal-Ligand Cooperation. AB - Well-defined ruthenium(II) phosphinous acid (PA) complexes enabled chemo-, site-, and diastereoselective C-H functionalization of arenes and alkenes with ample scope. The outstanding catalytic activity was reflected by catalyst loadings as low as 0.75 mol %, and the most step-economical access reported to date to angiotensin II receptor antagonist blockbuster drugs. Mechanistic studies indicated a kinetically relevant C-X cleavage by a single-electron transfer (SET) type elementary process, and provided evidence for a PA-assisted C-H ruthenation step. PMID- 26639162 TI - Statins and atherosclerosis: the role of epigenetics. AB - Atherosclerosis is an immune-inflammatory disease, in which pathophysiological mechanisms include inflammation patterns and epigenetic changes that alter gene expression of several inflammatory and non-inflammatory mediators. Epigenetics is offering explanations on how diet, environmental factors and lifestyle can influence the onset and progression of the disease, and how these alterations can be transmitted to the following generations without any changes in DNA sequences. Statins, through their pleiotropic effects, provide a useful tool in controlling the progression of plaques and their subsequent impact. PMID- 26639163 TI - Coordinated loss of microRNA group causes defenseless signaling in malignant lymphoma. AB - Biological robustness is exposed to stochastic perturbations, which should be controlled by intrinsic mechanisms; the promiscuous signaling network without appropriate alleviation is the true nature of cancer cells. B cell receptor (BCR) signaling is a major source of gene expression signature important for B cell. It is still unclear the mechanism by which the expression of functionally important genes is continuously deregulated in malignant lymphomas. Using RISC-capture assay, we reveal that multiple BCR signaling factors are persistently regulated by microRNA (miRNA) in human B cells. Clinical samples from patients with diffuse large B-cell lymphoma (DLBCL, n = 83) show loss of an essential miRNA set (miR 200c, miR-203, miR-31). Conventional screening and RISC profiling identify multiple targets (CD79B, SYK, PKCbetaII, PLCgamma1, IKKbeta, NIK, MYD88, PI3K class I (alpha/beta/delta/gamma), RasGRP3); signaling network habitually faces interference composed by miRNA group in normal B cells. We demonstrate that simultaneous depletion of the key miRNAs enhances translation of the multiple targets and causes chronic activation of NF-kappaB, PI3K-Akt, and Ras-Erk cascades, leading to B cell transformation. This study suggests that compensatory actions by multiple miRNAs rather than by a single miRNA ensure robustness of biological processes. PMID- 26639164 TI - Probing Membrane Fouling via Infrared Attenuated Total Reflection Mapping Coupled with Multivariate Curve Resolution. AB - Understanding membrane fouling induced by dissolved organic matter (DOM) is of primary importance for developing effective fouling control and prevention strategies. In this work, we combine multivariate curve resolution-alternating least squares analysis with infrared attenuated total reflection mapping to explore the fouling process of microfiltration and ultrafiltration membranes caused by two typical DOMs, humic acid (HA) and bovine serum albumin (BSA). The spectral contributions of different foulants and the membrane substrate were successfully discriminated, thereby enabling the diagnosis of fouling origins. Membrane fouling caused by HA is more severe than that by BSA. Three periods, the initial adsorption stage, the equilibrium stage, and the accumulation stage, were observed for the HA-induced fouling process. The integrated approach presented herein elegantly demonstrates the spatial and temporal characterization of membrane fouling processes, along with relative concentrations of the involved species, and suggests a promising perspective for understanding the interaction mechanisms between foulant species and membranes at the molecular level. PMID- 26639165 TI - Fragmentation of Fast Josephson Vortices and Breakdown of Ordered States by Moving Topological Defects. AB - Topological defects such as vortices, dislocations or domain walls define many important effects in superconductivity, superfluidity, magnetism, liquid crystals, and plasticity of solids. Here we address the breakdown of the topologically-protected stability of such defects driven by strong external forces. We focus on Josephson vortices that appear at planar weak links of suppressed superconductivity which have attracted much attention for electronic applications, new sources of THz radiation, and low-dissipative computing. Our numerical simulations show that a rapidly moving vortex driven by a constant current becomes unstable with respect to generation of vortex-antivortex pairs caused by Cherenkov radiation. As a result, vortices and antivortices become spatially separated and accumulate continuously on the opposite sides of an expanding dissipative domain. This effect is most pronounced in thin film edge Josephson junctions at low temperatures where a single vortex can switch the whole junction into a resistive state at currents well below the Josephson critical current. Our work gives a new insight into instability of a moving topological defect which destroys global long-range order in a way that is remarkably similar to the crack propagation in solids. PMID- 26639166 TI - Wide QRS Complex Tachycardia in a Patient With Complete Heart Block: What Is the Mechanism? PMID- 26639167 TI - The work of faculty-in-residence: An introduction and literature review. AB - BACKGROUND: The unique work of faculty-in-residence (FIRs) is premised on a substantial amount of research, which demonstrates that faculty-student engagement benefits students positively. Still, there is a dearth of literature that focuses on FIR work. In particular, there is no published research on the historical context for FIRs and no published research that provides an overarching analysis of literature germane to FIR work. OBJECTIVE: The objective of this article is to fill these gaps in the research literature by producing a historical study of FIR work and a review of research about FIR work. METHODS: Qualitative methods were used for this study; namely, the authors employed both historical research methods and a literature review. RESULTS: This study is the first of its kind to trace the history of FIR work and to provide an overarching analysis of the limited literature on this topic. CONCLUSIONS: By filling in the gaps in the research literature and describing the current state of FIR work, this study contributes to a research base for future, iterative studies of FIR work. This study also offers a discussion of future directions for both the research and practice of FIR work on college campuses. PMID- 26639169 TI - Pause for breath: Emerging tremor during syncopated deep brain stimulation. PMID- 26639170 TI - The Loudness Dependence of Auditory Evoked Potentials (LDAEP) in individuals at risk for developing bipolar disorders and schizophrenia. AB - OBJECTIVES: The Loudness Dependence of Auditory Evoked Potentials (LDAEP) is considered as an indicator of central serotonergic activity. Alteration of serotonergic neurotransmission was reported in bipolar disorders and schizophrenia. In line with previous reports on clinically manifest disorders, we expected a weaker LDAEP in subjects at risk for bipolar disorders and schizophrenia compared to healthy controls. METHODS: We analyzed LDAEP of individuals at risk for developing bipolar disorders (n=27), with high-risk status (n=74) and ultra-high-risk status for schizophrenia (n=86) and healthy controls (n=47). RESULTS: The LDAEP did not differ between subjects at risk for schizophrenia or bipolar disorders and controls. Among subjects without medication (n=122), the at-risk-bipolar group showed a trend towards a weaker LDAEP than both the high-risk and the ultra-high-risk groups for schizophrenia. CONCLUSIONS: The LDAEP did not appear as a vulnerability marker for schizophrenia or bipolar disorders. This suggests that an altered LDAEP may not be measurable until the onset of clinically manifest disorder. However, the hypothesis that pathogenic mechanisms leading to bipolar disorders may differ from those leading to schizophrenia is supported. SIGNIFICANCE: This is the first study investigating LDAEP in a population at risk for bipolar disorders. PMID- 26639171 TI - Facial emotion memory in schizophrenia: From encoding to maintenance-related EEG. AB - OBJECTIVE: Persons with schizophrenia exhibit deficits recognizing facial emotions, which may impact social functioning. Whether these deficits reflect aberrant sensory processing, an inability to maintain information in memory, or dysfunctional integration of these two functions remains unclear. METHODS: A facial emotion memory paradigm was administered to 38 schizophrenia patients (SZ) and 42 healthy controls (HC). P100, N170 and N250 ERP amplitudes were measured to assess sensory processing. Evoked theta power during the delay interval was quantified to assess memory maintenance. RESULTS: The N170 ERP was larger to negative compared to neutral facial expressions in both groups, while SZ exhibited increased evoked theta power during the delay interval. Increased theta power was associated with worse behavioral performance in response to sad and fearful expressions for HC, but this relationship was only found in response to fearful expressions for SZ. Finally, only HC showed consistent correlations between N170 amplitude and theta power during the delay interval. CONCLUSIONS: Integration between measures of sensory processing and memory functioning may be affected in SZ. SIGNIFICANCE: These findings may indicate that the oscillatory networks subserving emotion processing and sustained attention are intertwined, and comprise part of the social brain network that is affected in schizophrenia. PMID- 26639172 TI - Effects of rate (0.3-40/s) on simultaneously recorded auditory brainstem, middle and late responses using deconvolution. AB - OBJECTIVE: Auditory evoked potentials (AEPs) are typically acquired in either transient (low-rate) or steady state (high-rate) conditions. This study utilizes deconvolution to obtain transient responses over a range of rates from 0.3 to 40/s, to establish a rate profile of transient responses employing uniform recording conditions. METHODS: Deconvolution is used to obtain transient responses from quasi steady state recordings for rates 3.5-40/s, and components are scored and waveform morphologies are compared across rates. RESULTS: All component latencies remain stable across all rates other than P2, which decreases for rates up to 3.5/s. Amplitudes for brainstem (V, Na), middle latency (Pa, Nb), and late (Pb/P1, N1 and P2) responses increased for rates below 1, 2 and 3.5/s, respectively. Rates between 3.5 and 25/s undergo a gradual morphology transition, above which oscillations begin to occur after 100 ms. CONCLUSIONS: Auditory brainstem, middle and late latency components other than P2 show stable latencies across 0.3-40/s with varying amplitude rate dependencies. SIGNIFICANCE: Obtaining a transient response rate profile utilizing uniform acquisition parameters is useful for an improved understanding of how individual AEP components interact with stimulation rate, and can provide a more comprehensive assessment of the ascending auditory pathway and primary auditory cortices. PMID- 26639174 TI - The QATSDD critical appraisal tool: comments and critiques. AB - RATIONALE, AIMS AND OBJECTIVES: The aim of this research note is to reflect on the effectiveness of the QATSDD tool for its intended use in critical appraisals of synthesis work such as integrative reviews. METHODS: A seven-member research team undertook a critical appraisal of qualitative and quantitative studies using the QATSDD. RESULTS AND CONCLUSION: We believe that the tool can spur useful dialogue among researchers and increase in-depth understanding of reviewed papers, including the strengths and limitations of the literature. To increase the clarity of the process, we suggest further definition of the language in each indicator and inclusion of explicit examples for each criterion. We would also like to see the authors outline clear parameters around the use of the tool, essentially stating that the tool should be used in synthesis work for studies of mixed methods or work that includes qualitative and quantitative research informed by a positivist paradigm. In the context of an appropriate team composition, the tool can be a useful mechanism for guiding people who are coming together to discuss the merits of studies across multiple methodologies and disciplines. PMID- 26639173 TI - Lipid droplets and steroidogenic cells. AB - Lipid droplets (LDs) in steroidogenic tissues have a cholesteryl ester (CE) core surrounded by a phospholipid monolayer that is coated with associated proteins. Compared with other tissues, they tend to be smaller in size and more numerous in numbers. These LDs are enriched with PLIN1c, PLIN2 and PLIN3. Both CIDE A and B are found in mouse ovary. Free cholesterol (FC) released upon hormone stimulation from LDs is the preferred source of cholesterol substrate for steroidogenesis, and HSL is the major neutral cholesterol esterase mediating the conversion of CEs to FC. Through the interaction of HSL with vimentin and StAR, FC is translocated to mitochondria for steroid hormone production. Proteomic analyses of LDs isolated from loaded primary ovarian granulosa cells, mouse MLTC-1 Leydig tumor cells and mouse testes revealed LD associated proteins that are actively involved in modulating lipid homeostasis along with a number of steroidogenic enzymes. Microscopy analysis confirmed the localization of many of these proteins to LDs. These studies broaden the role of LDs to include being a platform for functional steroidogenic enzyme activity or as a port for transferring steroidogenic enzymes and/or steroid intermediates, in addition to being a storage depot for CEs. PMID- 26639175 TI - Forensic genetic value of a 27 Y-STR loci multiplex (Yfiler((r)) Plus kit) in an Italian population sample. AB - The analysis of Y chromosome short tandem repeat (Y-STR) haplotypes provides important information that can be used for investigative purposes and in population studies. The Yfiler((r)) Plus PCR Amplification kit (Yfiler((r)) Plus, Thermo Fisher Scientific, Waltham, MA, USA) allows the multiplex amplification of 27 Y-STRs, including 7 rapidly mutating markers (RM Y-STRs). In this study, 203 unrelated males from Italy, which were subdivided into 4 different geographical groups (North, Center, South and Sardinia) were analyzed. Several intra population diversity indexes were computed and compared to those obtained using only loci either from the minimal haplotype or the 17-plex (Yfiler((r)), Thermo Fisher Scientific, Waltham, MA, USA). In addition, inter-population diversity analysis (RST) among the four Italian samples was performed. The same analysis was also used to compare the Italian sub-sets to other European populations where the Yfiler((r)) Plus haplotype frequency data were available. The Sardinians were significantly differentiated from the other three Italian groups, thus requiring a specific sub-national Y-STR haplotype database. The Yfiler((r)) Plus kit showed a high power of discrimination which is useful for criminal investigations, principally due to the inclusion of RM Y-STRs. PMID- 26639176 TI - Dynamically reorganized chromatin is the key for the reprogramming of somatic cells to pluripotent cells. AB - Nucleosome positioning and histone modification play a critical role in gene regulation, but their role during reprogramming has not been fully elucidated. Here, we determined the genome-wide nucleosome coverage and histone methylation occupancy in mouse embryonic fibroblasts (MEFs), induced pluripotent stem cells (iPSCs) and pre-iPSCs. We found that nucleosome occupancy increases in promoter regions and decreases in intergenic regions in pre-iPSCs, then recovers to an intermediate level in iPSCs. We also found that nucleosomes in pre-iPSCs are much more phased than those in MEFs and iPSCs. During reprogramming, nucleosome reorganization and histone methylation around transcription start sites (TSSs) are highly coordinated with distinctively transcriptional activities. Bivalent promoters gradually increase, while repressive promoters gradually decrease. High CpG (HCG) promoters of active genes are characterized by nucleosome depletion at TSSs, while low CpG (LCG) promoters exhibit the opposite characteristics. In addition, we show that vitamin C (VC) promotes reorganizations of canonical, H3K4me3- and H3K27me3-modified nucleosomes on specific genes during transition from pre-iPSCs to iPSCs. These data demonstrate that pre-iPSCs have a more open and phased chromatin architecture than that of MEFs and iPSCs. Finally, this study reveals the dynamics and critical roles of nucleosome positioning and chromatin organization in gene regulation during reprogramming. PMID- 26639177 TI - Polymeric micellar nanoplatforms for Fenton reaction as a new class of antibacterial agents. AB - Reactive oxygen species (ROS) produced by host phagocytes exert antibacterial action against a variety of pathogens and ROS-induced oxidative stress is the governing mechanism for the antibacterial activity of major bactericidal antibiotics. In particular, hydroxyl radical is a strong and nonselective oxidant which can damage biomolecules such as DNA, proteins and lipids. Ferrous ion is known to convert mild oxidant hydrogen peroxide (H2O2) into highly reactive and toxic hydroxyl radicals, referred to as Fenton reaction. Herein, we report a new class of antibacterial agents based on Fenton reaction-performing nanostructures, composed of H2O2-generating polymer (PCAE) and iron-containing ferrocene. Amphiphilic PCAE was designed to incorporate H2O2-generating cinnamaldehyde through acid-cleavable linkages and self-assemble to form thermodynamically stable micelles which could encapsulate ferrocene in their hydrophobic core. All the experiments in vitro display that ferrocene-loaded PCAE micelles produce hydroxyl radicals to kill Escherichia coli and Pseudomonas aeruginosa through membrane damages. Intraperitoneally injected ferrocene-loaded PCAE micelles significantly reduced the lung damages and therefore increased the survival rate of mice infected with drug resistant P. aeruginosa. Given their potent antibacterial activity, ferrocene-loaded PCAE micelles hold great potential as a new class of ROS-manipulating antibacterial agents. PMID- 26639178 TI - Hidden symmetry and protection of Dirac points on the honeycomb lattice. AB - The honeycomb lattice possesses a novel energy band structure, which is characterized by two distinct Dirac points in the Brillouin zone, dominating most of the physical properties of the honeycomb structure materials. However, up till now, the origin of the Dirac points is unclear yet. Here, we discover a hidden symmetry on the honeycomb lattice and prove that the existence of Dirac points is exactly protected by such hidden symmetry. Furthermore, the moving and merging of the Dirac points and a quantum phase transition, which have been theoretically predicted and experimentally observed on the honeycomb lattice, can also be perfectly explained by the parameter dependent evolution of the hidden symmetry. PMID- 26639179 TI - MY APPROACH to genetic testing in cardiology practice. PMID- 26639180 TI - Epigenetic regulation of gene expression by Ikaros, HDAC1 and Casein Kinase II in leukemia. PMID- 26639182 TI - Consecutive Gated Injection-Based Microchip Electrophoresis for Simultaneous Quantitation of Superoxide Anion and Nitric Oxide in Single PC-12 Cells. AB - As important reactive oxygen species (ROS) and reactive nitrogen species (RNS), cellular superoxide anion (O2(*-)) and nitric oxide (NO) play significant roles in numerous physiological and pathological processes. Cellular O2(*-) and NO also have a close relationship and always interact with each other. Thus, the simultaneous detection of intracellular O2(*-) and NO, especially at the single cell level, is important. In this paper, we present a novel method to simultaneously detect and quantify O2(*-) and NO in single cells using microchip electrophoresis based on a new consecutive gated injection method. This novel injection method achieved consecutive manipulation of single cells, guaranteeing an almost constant volumetric flow rate and thus good quantitative reproducibility. After cellular content separation by microchip electrophoresis and detection by laser-induced fluorescence (MCE-LIF), O2(*-) and NO in single PC 12 cells were simultaneously quantified in an automated fashion. This is the first report of consecutive absolute quantitation at the single-cell level. The quantitative results obtained from single cells is beneficial for deep understanding of the biological roles of cellular O2(*-) and NO. This new method constitutes a consecutive, accurate way to study the synergistic function of O2(* ) and NO and other biomolecules in various biological events at the single-cell level. PMID- 26639181 TI - A complementary role of multiparameter flow cytometry and high-throughput sequencing for minimal residual disease detection in chronic lymphocytic leukemia: an European Research Initiative on CLL study. AB - In chronic lymphocytic leukemia (CLL) the level of minimal residual disease (MRD) after therapy is an independent predictor of outcome. Given the increasing number of new agents being explored for CLL therapy, using MRD as a surrogate could greatly reduce the time necessary to assess their efficacy. In this European Research Initiative on CLL (ERIC) project we have identified and validated a flow cytometric approach to reliably quantitate CLL cells to the level of 0.0010% (10( 5)). The assay comprises a core panel of six markers (i.e. CD19, CD20, CD5, CD43, CD79b and CD81) with a component specification independent of instrument and reagents, which can be locally re-validated using normal peripheral blood. This method is directly comparable to previous ERIC-designed assays and also provides a backbone for investigation of new markers. A parallel analysis of high throughput sequencing using the ClonoSEQ assay showed good concordance with flow cytometry results at the 0.010% (10(-4)) level, the MRD threshold defined in the 2008 International Workshop on CLL guidelines, but it also provides good linearity to a detection limit of 1 in a million (10(-6)). The combination of both technologies would permit a highly sensitive approach to MRD detection while providing a reproducible and broadly accessible method to quantify residual disease and optimize treatment in CLL. PMID- 26639183 TI - Modeling X Chromosome Data Using Random Forests: Conquering Sex Bias. AB - Machine learning methods, including Random Forests (RF), are increasingly used for genetic data analysis. However, the standard RF algorithm does not correctly model the effects of X chromosome single nucleotide polymorphisms (SNPs), leading to biased estimates of variable importance. We propose extensions of RF to correctly model X SNPs, including a stratified approach and an approach based on the process of X chromosome inactivation. We applied the new and standard RF approaches to case-control alcohol dependence data from the Study of Addiction: Genes and Environment (SAGE), and compared the performance of the alternative approaches via a simulation study. Standard RF applied to a case-control study of alcohol dependence yielded inflated variable importance estimates for X SNPs, even when sex was included as a variable, but the results of the new RF methods were consistent with univariate regression-based approaches that correctly model X chromosome data. Simulations showed that the new RF methods eliminate the bias in standard RF variable importance for X SNPs when sex is associated with the trait, and are able to detect causal autosomal and X SNPs. Even in the absence of sex effects, the new extensions perform similarly to standard RF. Thus, we provide a powerful multimarker approach for genetic analysis that accommodates X chromosome data in an unbiased way. This method is implemented in the freely available R package "snpRF" (http://www.cran.r-project.org/web/packages/snpRF/). PMID- 26639184 TI - Evidence of male hypogonadism at an early age as a familial risk of type 2 diabetes. AB - OBJECTIVE: Previous investigations provide evidence of an association of hypogonadism with type 2 diabetes in men, and low testosterone levels have been regarded a risk factor for the disease. Since a strong genetic predisposition to type 2 diabetes has been demonstrated, here we investigate a possible tendency towards hypogonadism in young male offspring of diabetic parents. MATERIAL AND METHODS: The study compares 32 male offspring of diabetic parents with 31 male offspring of nondiabetic parents matched by age. The subjects comprised boys (9 17 years) and young adults (19-25 years). Anthropomorphic measurements were made in all subjects. Fasting blood samples were analyzed for glucose and serum concentrations of testosterone (T), sex hormone-binding globulin (SHBG), luteinizing hormone (LH), insulin and leptin were measured by ELISA. Free testosterone (FT) was calculated using T and SHBG levels. RESULTS: Serum T, FT and bioavailable T (BAT) levels in offspring of diabetic parents were significantly lower than those of offspring of nondiabetic parents across all age groups. Mean serum LH levels were also lower in offspring of diabetic parents compared to the controls. Although LH levels in young adults with diabetic parents, tended to be lower than those of age-matched controls but the difference was not statistically significant. Serum insulin and leptin, and insulin resistance measured by HOMA-IR were significantly raised in older offspring of diabetic parents but were within the normal range. CONCLUSION: Whereas hypogonadism was the only indicator of a possible predisposition to metabolic dysfunction in peripubertal children of diabetic parents, a significant change in other metabolic markers becomes apparent at a more advanced age. PMID- 26639185 TI - Questioning the pathogenic role of the pTyr791Phe mutation of the RET proto oncogene: Insight from a case report. AB - The pTyr791Phe mutation of the RET proto-oncogene is associated with a low penetrance of medullar thyroid carcinoma (MTC). Thus, there is a lack in guidelines on management of these patients presenting without a thyroid disease. CLINICAL CASE: A 27-year-old woman presented with a history of severe hypertension, paroxysmal tachycardia, diaphoresis and headaches. Twenty-four-hour urinary norepinephrine and normetanephrine levels were exclusively up to 20 times the normal limit. CT-scan and MRI found a 35-mm diameter right adrenal tumor, highly intense in T2- and hypo-intense in T1-weighted image, enhanced after gadolinium injection. After alpha-adrenergic blocker treatment, a surgical resection of the tumor was performed; this latter proved to be a pheochromocytoma. Genetic screening only revealed a germline pTyr791Phe mutation of the RET proto-oncogene. However, the patient showed no evidence of MEN2: basal calcitonin was normal and calcium infusion test was negative. Thyroid ultrasound revealed a TIRADS 3 nodule with benign cytology. Total thyroidectomy was suggested but withheld due to the patient's refusal and a close follow-up was decided. CONCLUSION: This rare case of pTyr791Phe mutation-related pheochromocytoma without evidence of MTC questions the indication for prophylactic thyroidectomy in mutation carriers, as recent data challenges its pathogenicity. PMID- 26639186 TI - Efficacy and safety of denosumab for the treatment of osteoporosis: A systematic review. AB - Denosumab is an anti-RANK ligand (RANKL) monoclonal antibody approved for the treatment of postmenopausal osteoporosis and prevention of skeletal metastasis complications. Administered subcutaneously every 6 months, it reduces the risk of vertebral fracture by 70% and of hip fracture by 40%. Its safety profile is acceptable. Denosumab may be used to treat patients with moderate to severe renal insufficiency. It has anti-fracture activity equivalent to that of zoledronic acid, but no residual effect, and no action at all beyond 6 months. In France, denosumab is reimbursed as a second-line treatment after a first attempt with bisphosphonate. PMID- 26639189 TI - Investigating the association between medication adherence and health-related quality of life in COPD: Methodological challenges when using a proxy measure of adherence. AB - BACKGROUND: The association between non-adherence to medication and health related quality-of-life (HRQoL) in Chronic Obstructive Pulmonary Disease (COPD) remains poorly understood. Different ways to deal with methodological challenges to estimate this association have probably contributed to conflicting results. AIM: To investigate the association between medication adherence and HRQoL, thereby illustrating methodological challenges that need to be addressed. METHODS: We used longitudinal patient-level data from a cluster-randomized controlled trial (i.e. RECODE) including three-year data on type and dose of COPD maintenance medication prescribed and HRQoL (Clinical COPD Questionnaire [CCQ], st. George Respiratory Questionnaire [SGRQ], EuroQol 5-dimensions [EQ-5D]) of 511 patients. A linear mixed model was used to assess the association between adherence and HRQoL using a fixed cut-off of 80% of the proportion of days covered (PDC) to define adherence. Subsequently, we investigated the impact of differences in disease severity; lifestyle; and reversed causality, representing the methodological challenges. Additionally, we investigated the impact of changing the definition of adherence. RESULTS: In unadjusted analyses, and analyses adjusting for demographic characteristics only, SGRQ score was worse in the adherent compared to the non-adherent group. This association disappeared when correcting for disease severity and/or lifestyle. A better SGRQ score was predictive of decreased adherence in the following year. However, accounting for the previous HRQoL did not result in positive associations between adherence and HRQoL. When defining four categories of adherence, patients with a PDC between 80 and 99% had a significantly worse SGRQ score compared to patients with a PDC <60%, even after correction for lifestyle. There was no significant association between adherence and CCQ or EQ-5D. CONCLUSION: This study showed persistent methodological challenges in the investigation of the effect of medication adherence on HRQoL in COPD. A positive association of adherence and HRQoL was not found, even after adjusting for lifestyle, disease severity, and previous HRQoL. PMID- 26639191 TI - High Chromaticity Aluminum Plasmonic Pixels for Active Liquid Crystal Displays. AB - Chromatic devices such as flat panel displays could, in principle, be substantially improved by incorporating aluminum plasmonic nanostructures instead of conventional chromophores that are susceptible to photobleaching. In nanostructure form, aluminum is capable of producing colors that span the visible region of the spectrum while contributing exceptional robustness, low cost, and streamlined manufacturability compatible with semiconductor manufacturing technology. However, individual aluminum nanostructures alone lack the vivid chromaticity of currently available chromophores because of the strong damping of the aluminum plasmon resonance in the visible region of the spectrum. In recent work, we showed that pixels formed by periodic arrays of Al nanostructures yield far more vivid coloration than the individual nanostructures. This progress was achieved by exploiting far-field diffractive coupling, which significantly suppresses the scattering response on the long-wavelength side of plasmonic pixel resonances. In the present work, we show that by utilizing another collective coupling effect, Fano interference, it is possible to substantially narrow the short-wavelength side of the pixel spectral response. Together, these two complementary effects provide unprecedented control of plasmonic pixel spectral line shape, resulting in aluminum pixels with far more vivid, monochromatic coloration across the entire RGB color gamut than previously attainable. We further demonstrate that pixels designed in this manner can be used directly as switchable elements in liquid crystal displays and determine the minimum and optimal numbers of nanorods required in an array to achieve good color quality and intensity. PMID- 26639190 TI - TLR4 drives the pathogenesis of acquired cholesteatoma by promoting local inflammation and bone destruction. AB - Acquired cholesteatoma is a chronic inflammatory disease characterized by both hyperkeratinized squamous epithelial overgrowth and bone destruction. Toll-like receptor (TLR) activation and subsequent inflammatory cytokine production are closely associated with inflammatory bone disease. However, the expression and function of TLRs in cholesteatoma remain unclear.We observed inflammatory cell infiltration of the matrix and prematrix of human acquired cholesteatoma, as well as dramatically increased expression of TLR4 and the pro-inflammatory cytokines TNF-alpha and IL-1beta. TLR2 exhibited an up-regulation that was not statistically significant. TLR4 expression in human acquired cholesteatoma correlated with disease severity; the number of TLR4-positive cells increased with an increased degree of cholesteatoma, invasion, bone destruction, and hearing loss. Moreover, TLR4 deficiency was protective against experimental acquired cholesteatoma-driven bone destruction and hearing loss, as it reduced local TNF-alpha and IL-1beta expression and impaired osteoclast formation by decreasing expression of the osteoclast effectors receptor activator of nuclear factor (NF)-kappaB ligand (RANKL) and tartrate-resistant acid phosphatase (TRAP). TLR2 deficiency did not relieve disease severity, inflammatory responses, or osteoclast formation. Moreover, neither TLR2 nor TLR4 deficiency had an effect on antimicrobial peptides, inducible iNOS,BD-2 expression or bacterial clearance. Therefore, TLR4 may promote cholesteatoma-induced bone destruction and deafness by enhancing inflammatory responses and osteoclastogenesis. PMID- 26639192 TI - Lifetime Insurance Benefit for Living Donors: Is It Necessary and Could It Be Coercive? PMID- 26639193 TI - Blockage of caspase-1 activation ameliorates bone marrow inflammation in mice after hematopoietic stem cell transplantation. AB - Conditioning regimens before hematopoietic stem cell transplantation (HSCT), cause damage to bone marrow and inflammation. Whether inflammasomes are involved in bone marrow inflammation remains unclear. The study aims to evaluate the role of inflammasomes in bone marrow inflammation after HSCT. On days 7, 14, 21 and 28 after HSCT, mice were sacrificed for analysis of bone marrow inflammation, pro inflammatory cytokines secretion, inflammasomes expression and caspase-1 activation. Bone marrow inflammation with neutrophils and macrophages infiltration was observed after HSCT. Secretion of IL-1beta, IL-18, TNF-alpha and IL-6 were elevated, with increased caspase-1 activation and inflammasomes expression. Caspase-1 inhibitor administration after HSCT significantly reduced infiltration of neutrophils and macrophages into bone marrow and increased the numbers of megakaryocytes and platelets. In conclusion, inflammasomes activation is involved in bone marrow inflammation after HSCT and caspase-1 inhibition attenuates bone marrow inflammation and promoted hematopoietic reconstitution, suggesting targeting caspase-1 might be beneficial for improving HSCT outcomes. PMID- 26639194 TI - IL-10/IFNgamma co-expressing CD4(+) T cells induced by IL-10 DC display a regulatory gene profile and downmodulate T cell responses. AB - Induced regulatory T cells (iTreg) are imperative for tolerance induction and spreading of infectious tolerance. Ex vivo generated tolerogenic dendritic cells (tDCs) have strong therapeutic potential to induce antigen-specific iTreg. We previously demonstrated that IL-10 tDC-primed T cells are very suppressive and produce IL-10. Here, we show that the majority of IL-10(+) T cells co-express IFNgamma, giving rise to the question whether these cells are proinflammatory or regulatory. Whole genome gene expression analysis revealed a strong regulatory gene profile and a suppressed Th1 gene profile for IL-10/IFNgamma co-expressing CD4(+) T cells. Protein analysis confirmed an extensive regulatory phenotype for IL-10(+)/IFNgamma(+) T cells, with specific enhanced expression of GARP and PD-1. In line with these data, isolated IL-10(+)/IFNgamma(+) T cells displayed potent suppressive capacity. Thus, IL-10/IFNgamma co-expressing CD4(+) T cells induced by IL-10 tDC show dominance of immunomodulation over Th1-mediated immunoactivation and can contribute to induction or spreading of immunological tolerance. PMID- 26639195 TI - Bone morphogenetic proteins in tumour associated angiogenesis and implication in cancer therapies. AB - Bone morphogenetic protein (BMP) belongs to transforming growth factor-beta superfamily. To date, more than 20 BMPs have been identified in humans. BMPs play a critical role in embryonic and postnatal development, and also in maintaining homeostasis in different organs and tissues by regulating cell differentiation, proliferation, survival and motility. They play important roles in the development and progression of certain malignancies, including prostate cancer, breast cancer, lung cancer, etc. Recently, more evidence shows that BMPs are also involved in tumour associated angiogenesis. For example BMP can either directly regulate the functions of vascular endothelial cells or indirectly influence the angiogenesis via regulation of angiogenic factors, such as vascular endothelial growth factor (VEGF). Such crosstalk can also be reflected in the interaction with other angiogenic factors, like hepatocyte growth factor (HGF) and basic fibroblast growth factor (bFGF). All these factors are involved in the orchestration of the angiogenic process during tumour development and progression. Review of the relevant studies will provide a comprehensive prospective on current understanding and shed light on the corresponding therapeutic opportunity. PMID- 26639196 TI - The homing receptor CD44 is involved in the progression of precancerous gastric lesions in patients infected with Helicobacter pylori and in development of mucous metaplasia in mice. AB - Infection with Helicobacter pylori (H. pylori) leads to inflammatory events that can promote gastric cancer development. Immune cells transition from the circulation into the infected mucosa through the interaction of their receptors and ligands in the endothelial compartment. CD44 expression is increased in advanced gastric lesions. However, the association of this molecule with the progression of these lesions over time has not been investigated. In addition, there is a lack of understanding of the CD44-dependent cellular processes that lead to gastritis, and possibly to gastric cancer. Here we studied H. pylori positive subjects with gastric lesions that ranged from multifocal atrophic gastritis to dysplasia to determine gene expression changes associated with disease progression over a period of 6 years. We report that CD44 expression is significantly increased in individuals whose gastric lesions progressed along the gastric precancerous cascade. We also show that CD44-/- mice develop less severe and less extensive H. pylori-induced metaplasia, and show fewer infiltrating Gr1+ cells compared to wild type mice. We present data suggesting that CD44 is associated with disease progression. Mechanisms associated with these effects include induction of interferon gamma responses. PMID- 26639197 TI - Bone marrow PMN-MDSCs and neutrophils are functionally similar in protection of multiple myeloma from chemotherapy. AB - Multiple myeloma (MM) is an incurable cancer of plasma cells localized preferentially in the bone marrow (BM). Resistance to chemotherapy represents one of the main challenges in MM management. BM microenvironment is known to play a critical role in protection of MM cells from chemotherapeutics; however, mechanisms responsible for this effect are largely unknown. Development of MM is associated with accumulation of myeloid-derived suppressor cells (MDSCs) mostly represented by pathologically activated relatively immature polymorphonuclear neutrophils (PMN-MDSCs). Here, we investigated whether PMN-MDSCs are responsible for BM microenvironment-mediated MM chemoresistance. Using in vivo mouse models allowing manipulation of myeloid cell number, we demonstrated a critical role for myeloid cells in MM growth and chemoresistance. PMN-MDSCs isolated from MM bearing host are immunosuppressive and thus, functionally distinct from their counterpart in tumor-free host neutrophils. We found, however, that both PMN MDSCs and neutrophils equally promote MM survival from doxorubicin and melphalan and that this effect is mediated by soluble factors rather than direct cell-cell contact. Our data indicate that targeting PMN-MDSCs would enhance chemotherapy efficacy in MM. PMID- 26639198 TI - Cisplatin, Gemcitabine, and Lapatinib as Neoadjuvant Therapy for Muscle-Invasive Bladder Cancer. AB - PURPOSE: We sought to investigate the safety and efficacy of gemcitabine, cisplatin, and lapatinib (GCL) as neoadjuvant therapy in patients with muscle invasive bladder cancer (MIBC) planned for radical cystectomy. MATERIALS AND METHODS: Four cycles of GCL were administered as neoadjuvant therapy for patients with MIBC. Although initially designed as a phase II efficacy study with a primary endpoint of pathologic complete response at the time of radical cystectomy, the dose selected for investigation proved excessively toxic. A total of six patients were enrolled. RESULTS: The initial four patients received gemcitabine 1,000 mg/m(2) intravenously on days 1 and 8 and cisplatin 70 mg/m(2) intravenously on day 1 of each 21-day treatment cycle. Lapatinib was administered as 1,000 mg orally daily starting one week prior to the initiation of cycle 1 of gemcitabine and cisplatin (GC) and continuing until the completion of cycle 4 of GC. These initial doses were poorly tolerated, and the final two enrolled patients received a reduced lapatinib dose of 750 mg orally daily. However, reduction of the lapatinib dose did not result in improved tolerance or drug delivery, and the trial was terminated early due to excessive toxicity. Grade 3/4 toxicities included diarrhea (33%), nausea/vomiting (33%), and thrombocytopenia (33%). CONCLUSION: The addition of lapatinib to GC as neoadjuvant therapy for MIBC was limited by excessive treatment-related toxicity. These findings highlight the importance of thorough dose-escalation investigation of combination therapies prior to evaluation in the neoadjuvant setting, as well as the limitations of determination of maximum tolerated dose for novel targeted combination regimens. PMID- 26639200 TI - Commentary on "A Case of Paratesticular Leiomyosarcoma Successfully Treated with Orchiectomy and Chemotherapy". PMID- 26639199 TI - Variation in Practice Patterns of Korean Radiation Oncologists for Spine Metastasis between 2009 and 2014. AB - PURPOSE: The Korean Society of Radiation Oncologists (KOSRO) conducted the Patterns of Care Study (PCS) of radiotherapy (RT) for spine metastases in 2009. The current study was conducted to investigate current practice patterns and compare them with the results of the PCS. MATERIALS AND METHODS: The survey questionnaire was composed of 10 questions regarding general information and seven questions for each of two clinical scenarios. RESULTS: Fifty-four members of the KOSRO answered at least one question on the web-based questionnaire. The yearly number of patients treated who underwent palliative spine RT was greater than 200 in 14 (25.9%), 51 to 100 in 13 (24.1%), and 31 to 50 in 11 respondents (20.4%). Scenario 1 described a patient presenting with cord compressive spine metastasis in multiple bones and liver metastasis from non-small cell lung cancer. Thirty gray (Gy) in 10 fractions was chosen by 35 respondents (64.8%). Scenario 2 described a case of a single spine metastasis without progression after targeted therapy. Thirty Gy in 10 fractions was chosen by 19 respondents (35.2%), and a single fraction or less than four fractions of stereotactic ablative radiotherapy (SABR) were selected by 18 respondents (33.3%). When compared with the 2009 PCS, practice patterns of Korean radiation oncologists had not changed significantly over 5 years, except that SABR emerged as a new treatment modality in the selected population. CONCLUSION: The 2014 PCS demonstrated that multiple fraction RT is still preferred in a considerable proportion of Korean radiation oncologists. PMID- 26639201 TI - Visualization of drug translocation in the nasal cavity and pharmacokinetic analysis on nasal drug absorption using positron emission tomography in the rat. AB - We performed positron emission tomography (PET) using 2-deoxy-2-[(18)F]fluoro-D glucose ([(18)F]FDG) to evaluate the pharmacokinetics of nasal drug absorption in the rat. The dosing solution of [(18)F]FDG was varied in volume (ranging from 5 to 25 MUl) and viscosity (using 0% to 3% concentrations of hydroxypropylcellulose). We modeled the pharmacokinetic parameters regarding the nasal cavity and pharynx using mass balance equations, and evaluated the values that were obtained by fitting concentration-time profiles using WinNonlin(r) software. The regional nasal permeability was also estimated using the active surface area derived from the PET images. The translocation of [(18)F]FDG from the nasal cavity was visualized using PET. Analysis of the PET imaging data revealed that the pharmacokinetic parameters were independent of the dosing solution volume; however, the viscosity increased the absorption rate constant and decreased the mucociliary clearance rate constant. Nasal permeability was initially higher but subsequently decreased until the end of the study, indicating regional differences in permeability in the nasal cavity. We concluded that the visualization of drug translocation in the nasal cavity in the rat using PET enables quantitative analysis of nasal drug absorption, thereby facilitating the development of nasal formulations for human use. PMID- 26639202 TI - Cardiac autonomic activity has a circadian rhythm in summer but not in winter in non-lactating pregnant dairy cows. AB - This investigation was conducted to examine circadian and seasonal rhythms of heart rate and heart rate variability (HRV) by means of hour-by-hour recordings over 24h in a large population of non-lactating Holstein-Friesian pregnant cows [N=56, summer (June-July); N=61, winter (November-December)]. Data were collected during a 5-day period from each animal. Besides parameters of cardiac autonomic function [the high-frequency (HF) component of HRV and the ratio between the low frequency (LF) and the HF components (LF/HF ratio)], the RR triangular index and Lmax were calculated. A clear circadian profile was observed for every parameter in summer. Heart rate elevated gradually with the course of the day from 7:00 to 17:00 o'clock and then slightly decreased from 18:00 to 6:00. Sympathovagal balance shifted towards sympathetic dominance during the daytime (increased LF/HF ratio), whereas parasympathetic activity was predominant during the night (increased HF). Lmax reflected a chaotic behavior of heart rate fluctuations during the afternoon in summer. Decreased values of RR triangular index indicated a sensitive period for cows between 14:00 and 16:00 o'clock in summer. During winter, except for the RR triangular (RRtri) index reflecting a high overall variability in R-R intervals between 12:00 and 23:00 o'clock, heart rate and HRV showed no periodicity over the 24-h period. The results suggest an impaired cardiac autonomic function during daytime in summer. HF, Lmax and RRtri index showed seasonal differences for both daytime and nighttime. Heart rate was higher in summer than in winter during the daytime, whereas the LF/HF ratio was higher in winter during the nighttime. Circadian and seasonal rhythms of cardiovascular function are presumably related to the differing temperature, and animal activity associated with summer and winter. As all of the investigated parameters are commonly used in bovine HRV research, these findings have practical implications for behavioral, physiological and welfare studies on dairy cattle. PMID- 26639203 TI - Microvesicles of pregnant women receiving low molecular weight heparin improve trophoblast function. AB - INTRODUCTION: Microvesicles including exosomes and microparticles, participate in the placental-maternal crosstalk in normal pregnancies and gestational vascular complications (GVC). Low molecular weight heparin (LMWH) is known to reduce the risk of placenta-mediated pregnancy complications. This study was aimed to characterize microvesicles of pregnant women receiving LMWH and explore microvesicle involvement in trophoblast and endothelial cell function. MATERIALS AND METHODS: Microvesicles were isolated from blood samples obtained from non pregnant women, healthy pregnant women (HP) and pregnant woman treated with LMWH. Microvesicle protein contents were assessed by protein array and ELISA. Microvesicle effects on early stage trophoblasts, term trophoblasts and endothelial cell migration, angiogenesis and apoptosis were evaluated. RESULTS: Microvesicles derived from the group treated with LMWH contained higher levels of several proangiogenic proteins compared to those of HP women. Exposure of endothelial cells to circulating microvesicles derived from HP and LMWH treated groups induced significantly higher cell migration and branch tube formation compared to untreated cells. The effect of microvesicles from HP- and LMWH groups on early-stage trophoblast migration was similar. Microvesicles derived from these two study groups significantly decreased early-stage trophoblast apoptosis, while microvesicles derived from the HP-group (but not from the LMWH-group) significantly increased the term trophoblast apoptosis (TUNEL assay) compared to untreated cells. CONCLUSION: Therapy with LMWH affects patients' microvesicle content, leading to normalization of invasion, angiogenesis activity and survival of endothelial and trophoblast cells in vitro. The effects of LMWH on microvesicles may point to an additional mechanism of heparin action in high-risk pregnancy. PMID- 26639204 TI - Platelet function and coagulation in patients with STEMI and peri-interventional clopidogrel plus heparin vs. prasugrel plus bivalirudin therapy (BRAVE 4 substudy). AB - INTRODUCTION: In this prespecified BRAVE 4 substudy we examined the antiplatelet and anticoagulant efficacy of clopidogrel plus heparin vs. prasugrel plus bivalirudin in patients with ST-segment elevation myocardial infarction. METHODS: 26 patients received clopidogrel/heparin, 25 patients received prasugrel/bivalirudin and 20 additional untreated patients served as controls. Platelet aggregation was tested using whole blood impedance aggregometry. Dynamic platelet adhesion and aggregate formation to collagen were quantified under flow conditions. Coagulation tests included activated partial thromboplastin time (aPTT), international normalized ratio (INR) as well as rotational thrombelastography (ROTEM(r)). Analyses were performed 3 and 72h after drug administration. RESULTS: At 3, but not at 72h we observed a significant increase in the inhibition of platelet aggregation in response to adenosine diphosphate (P<0.01), but not to arachidonic acid, collagen or thrombin receptor agonist in the prasugrel/bivalirudin group compared to the clopidogrel/heparin group. Inhibition of platelet adhesion to collagen under flow was significantly stronger in the prasugrel/bivalirudin group at 3 and 72h after drug administration (P<0.01). APTT was significantly higher in the clopidogrel/heparin group (P<0.05) and INR was significantly higher in the prasugrel/bivalirudin group (P<0.01) 3h after drug administration. Concerning ROTEM(r) analysis the drug combinations did not differ in reducing clot formation time (CFT) and both combinations did not influence maximum clot firmness (MCF) compared to the controls. CONCLUSIONS: We could demonstrate a more pronounced inhibition of platelet aggregation as well as platelet adhesion and aggregate formation to collagen under flow in prasugrel plus bivalirudin treated patients. PMID- 26639213 TI - A Survey of Infection Prevention and Control Practices among Hematopoietic Stem Cell Transplant Centers. AB - This survey of the American Society of Transplantation Infectious Disease Community of Practice demonstrates variations in clinical practices among hematopoietic stem cell transplant centers on selected infection prevention and control practices. Our findings highlight a need and emphasize an opportunity to optimize patient care through standardization of practices in this vulnerable population. PMID- 26639214 TI - Outcome Assessments of Patients with Posttraumatic "Ultra-Time Vascular Injuries" of the Extremities. AB - The management of posttraumatic vascular injury that presents after 8 h, or "ultra-time vascular injury", is daunting, and inciting recognition of this injury is vital. We retrospectively analyzed 29 patients with ultra-time vascular injuries to determine the patients' demographic characteristics and identify the determinants for amputation and disability. The age distribution of the high-risk population was from 18 years to 40 years, which indicated that these patients had plenty of productive life remaining. Injuries to the lower limbs (79.31%) were over four times more common than injuries to the upper limbs (17.24%), and open and blunt injuries occurred most commonly. The overall rate of limb salvage was 82.76% (24/29) and limb function is excellent in 45.83% (11/24) of the patients. The remaining patients experienced different degrees of disability in their limbs, which was determined by the anatomic location of the injury, and the presence of a combined arterial and venous injury, nerve injury, and complex soft tissue injury, as well as the occurrence of compartment syndrome. Hence, we recommend limb-salvage treatment for patients with traumatic ultra-time vascular injuries, particularly for those aged between 18 years and 40 years. Furthermore, we encourage the development of limb-salvage techniques for ultra-time vascular injuries. PMID- 26639215 TI - Multicomponent Cascade Synthesis of Trifluoroethyl Isoquinolines from Alkynes and Vinyl Azides. AB - A multicomponent cascade reaction is described that provides concise access to the trifluoroethyl isoquinolines using a Rh(III)-Cu(II) bimetallic system and readily available Togni's reagent. The system tolerates various vinyl azides and internal alkynes. Experimental results suggest that Togni's reagent might act as a CF3 radical supplier. PMID- 26639216 TI - Preparation of water stable methyl-modified metal-organic framework 5/polyacrylonitrile composite nanofibers via electrospinning and their application for solid-phase extraction of two estrogenic drugs in urine samples. AB - The nanofibers of methyl-modified metal-organic framework-5/polyacrylonitrile composite (CH3MOF-5/PAN) were successfully synthesized and used as a solid-phase extraction (SPE) sorbent for pre-concentration of two estrogenic drugs, levonorgestrel and megestrol acetate, in urine samples. A simple, cheap and accessible electrospinning method was employed to prepare a water stable CH3MOF 5/PAN composite. The nanofibers were packed into the mini-disc cartridges to be used as SPE devices. They were also characterized by scanning electron microscopy, thermogravimetric analysis, Fourier transform infrared spectroscopy, X-ray diffraction and N2 adsorption-desorption experiments. The effects of different parameters influencing the extraction efficiency including the type of eluent and its volume, the amount of the sorbent, pH, the ionic strength, the sample volume and the reusability of the sorbent were investigated and optimized. Under the optimized conditions, the linearity varied in range of 0.05-100MUgL(-1) with R(2) values higher than 0.999. The limit of detection for both of the analytes was 0.02MUgL(-1). The applicability of the method was examined by analyzing the analytes in the urine samples. The recovery of the analytes varied in the range of 82.8-94.8% which shows capability of the method for the determination of the drugs in the urine samples. PMID- 26639217 TI - A glass capillary based microfluidic electromembrane extraction of basic degradation products of nitrogen mustard and VX from water. AB - In this work, a glass capillary based microfluidic electromembrane extraction (MU EME) was demonstrated for the first time. The device was made by connecting an auxillary borosilicate glass tubing (O.D. 3mm, I.D. 2mm) perpendicular to main borosilicate glass capillary just below one end of the capillary (O.D. 8mm, I.D. 1.2mm). It generated the distorted T-shaped device with inlet '1' and inlet '2' for the introduction of sample and acceptor solutions, respectively. At one end of this device (inlet '2'), a microsyringe containing acceptor solution along with hollow fiber (O.D. 1000MUm) was introduced. This configuration creates the micro-channel between inner wall of glass capillary and outer surface of hollow fiber. Sample solution was pumped into the system through another end of glass capillary (inlet '1'), with a micro-syringe pump. The sample was in direct contact with the supported liquid membrane (SLM), consisted of 20% (w/w) di-(2 ethylhexyl)phosphate in 2-nitrophenyl octyl ether immobilized in the pores of the hollow fiber. In the lumen of the hollow fiber, the acceptor phase was present. The driving force for extraction was direct current (DC) electrical potential sustained over the SLM. Highly polar (logP=-2.5 to 1.4) basic degradation products of nitrogen mustard and VX were selected as model analytes. The influence of chemical composition of SLM, extraction time, voltage and pH of donor and acceptor phase were investigated. The model analytes were extracted from 10MUL of pure water with recoveries ranging from 15.7 to 99.7% just after 3min of operation time. Under optimized conditions, good limits of detection (2 50ngmL(-1)), linearity (from 5-1000 to 100-1000ngmL(-1)), and repeatability (RSDs below 11.9%, n=3) were achieved. Applicability of the proposed MU-EME was proved by recovering triethanolamine (31.3%) from 10MUL of five times diluted original water sample provided by the Organization for the Prohibition of Chemical Weapons during 28th official proficiency test. PMID- 26639218 TI - Pseudogout in a patient with bilateral total knee prosthesis: A challenging diagnosis. PMID- 26639219 TI - Coexistence of rheumatoid arthritis and TEMPI syndrome: New insight in microangiogenic-related diseases. PMID- 26639220 TI - Physical activity in patients with rheumatoid arthritis. AB - INTRODUCTION: Rheumatoid arthritis (RA) is the most common chronic inflammatory joint disease and is associated with an excess risk of cardiovascular disease. For the general population, the World Health Organization has issued detailed recommendations on the type of physical activity appropriate for decreasing the cardiovascular risk. The objective of this work is to review available data on the effects of physical activity in patients with RA. RESULTS: RA is responsible for a marked decrease in physical activity. Physical activity significantly diminishes both the cardiovascular risk and the DAS 28. Vascular benefits from physical activity include improved endothelial function and slowing of the atherosclerotic process. Physical activity also has favorable effects on bone, slowing radiographic disease progression in small joints and increasing bone mineral density at the femoral neck, although these effects are not statistically significant. Finally, engaging in physical activity increases self-esteem, alleviates symptoms of depression, improves sleep quality, and decreases pain perception. Aerobic exercise is the most commonly advocated type of physical activity. Most interventions were of short duration (4 weeks) and involved aerobic activity (running or cycling) for 60minutes a day 5 days a week. Resistance training has been shown to decrease systemic inflammation and increase muscle strength. The main obstacles to physical activity in patients with RA are related to both the patients, who lack both motivation and knowledge, and the rheumatologists, who also lack knowledge and place insufficient emphasis on promoting physical activity. CONCLUSION: Physical activity provides many benefits in patients with RA and should be widely performed. Promoting physical activity should be among the objectives of therapeutic patient education for RA. PMID- 26639221 TI - Therapeutic immunomodulation in eosinophilic granulomatosis with polyangiitis (Churg-Strauss). PMID- 26639222 TI - New autoantibodies associated with rheumatoid arthritis recognize posttranslationally modified self-proteins. AB - Citrullination, carbamylation and oxidation are posttranslational modifications of proteins that produce neoepitopes. Rheumatoid arthritis (RA) is an autoimmune disease of which one distinctive feature is the development of B-cell-mediated immunity against these neoepitopes. Antibodies to citrullinated proteins (ACPAs) were identified nearly two decades ago and are now widely used in clinical practice. The identification of additional citrullinated proteins as potential autoantibody targets has suggested new pathophysiological hypotheses and prompted studies of potential associations with disease severity or specific disease patterns. Carbamylation is a nonenzymatic posttranslational modification that produces homocitrullines, against which newly identified autoantibodies different from ACPAs have been found in over 15% of patients with RA. Finally, the development of antibodies to oxidized type II collagen reflects immunization against collagen modified by oxidation in relation to intraarticular oxidative stress. These new autoantibodies are both sensitive and specific and may therefore serve as early disease markers and as useful tools for therapeutic monitoring. PMID- 26639223 TI - Brain Cholesterol Synthesis and Metabolism is Progressively Disturbed in the R6/1 Mouse Model of Huntington's Disease: A Targeted GC-MS/MS Sterol Analysis. AB - BACKGROUND: Cholesterol has essential functions in neurological processes that require tight regulation of synthesis and metabolism. Perturbed cholesterol homeostasis has been demonstrated in Huntington's disease, however the exact role of these changes in disease pathogenesis is not fully understood. OBJECTIVE: This study aimed to comprehensively examine changes in cholesterol biosynthetic precursors, metabolites and oxidation products in the striatum and cortex of the R6/1 transgenic mouse model of Huntington's disease. We also aimed to characterise the progression of the physical phenotype in these mice. METHODS: GC MS/MS was used to quantify a broad range of sterols in the striatum and cortex of R6/1 and wild type mice at 6, 12, 20, 24 and 28 weeks of age. Motor dysfunction was assessed over 28 weeks using the RotaRod and the hind-paw clasping tests. RESULTS: 24(S)-Hydroxycholesterol and 27-hydroxycholesterol were the major cholesterol metabolites that significantly changed in R6/1 mice. These changes were specifically localised to the striatum and were detected at the end stages of the disease. Cholesterol synthetic precursors (lathosterol and lanosterol) were significantly reduced in the cortex and striatum by 6 weeks of age, prior to the onset of motor dysfunction, as well as the cognitive and affective abnormalities previously reported. Elevated levels of desmosterol, a substrate of delta(24)-sterol reductase (DHCR24), were also detected in R6/1 mice at the end time-point. Female R6/1 mice exhibited a milder weight loss and hind paw clasping phenotype compared to male R6/1 mice, however, no difference in the brain sterol profile was detected between sexes. CONCLUSION: Several steps in cholesterol biosynthetic and metabolic pathways are differentially altered in the R6/1 mouse brain as the disease progresses and this is most severe in the striatum. This provides further insights into early molecular mediators of HD onset and disease progression and identifies candidate molecular targets for novel therapeutic approaches. PMID- 26639224 TI - B-cell anergy induces a Th17 shift in a novel B lymphocyte transgenic NOD mouse model, the 116C-NOD mouse. AB - Autoreactive B lymphocytes play a key role as APCs in diaebetogenesis. However, it remains unclear whether B-cell tolerance is compromised in NOD mice. Here, we describe a new B lymphocyte transgenic NOD mouse model, the 116C-NOD mouse, where the transgenes derive from an islet-infiltrating B lymphocyte of a (8.3-NODxNOR) F1 mouse. The 116C-NOD mouse produces clonal B lymphocytes with pancreatic islet beta cell specificity. The incidence of T1D in 116C-NOD mice is decreased in both genders when compared with NOD mice. Moreover, several immune selection mechanisms (including clonal deletion and anergy) acting on the development, phenotype, and function of autoreactive B lymphocytes during T1D development have been identified in the 116C-NOD mouse. Surprisingly, a more accurate analysis revealed that, despite their anergic phenotype, 116C B cells express some costimulatory molecules after activation, and induce a T-cell shift toward a Th17 phenotype. Furthermore, this shift on T lymphocytes seems to occur not only when both T and B cells contact, but also when helper T (Th) lineage is established. The 116C-NOD mouse model could be useful to elucidate the mechanisms involved in the generation of Th-cell lineages. PMID- 26639225 TI - Non-inferiority and networks: inferring efficacy from a web of data. AB - In the absence of placebo-controlled trials, the efficacy of a test treatment can be alternatively examined by showing its non-inferiority to an active control; that is, the test treatment is not worse than the active control by a pre specified margin. The margin is based on the effect of the active control over placebo in historical studies. In other words, the non-inferiority setup involves a network of direct and indirect comparisons between test treatment, active controls, and placebo. Given this framework, we consider a Bayesian network meta analysis that models the uncertainty and heterogeneity of the historical trials into the non-inferiority trial in a data-driven manner through the use of the Dirichlet process and power priors. Depending on whether placebo was present in the historical trials, two cases of non-inferiority testing are discussed that are analogs of the synthesis and fixed-margin approach. In each of these cases, the model provides a more reliable estimate of the control given its effect in other trials in the network, and, in the case where placebo was only present in the historical trials, the model can predict the effect of the test treatment over placebo as if placebo had been present in the non-inferiority trial. It can further answer other questions of interest, such as comparative effectiveness of the test treatment among its comparators. More importantly, the model provides an opportunity for disproportionate randomization or the use of small sample sizes by allowing borrowing of information from a network of trials to draw explicit conclusions on non-inferiority. PMID- 26639226 TI - Clinical and economic impact of antimicrobial stewardship interventions with the FilmArray blood culture identification panel. AB - The purpose of this study was to evaluate the impact of the FilmArray Blood Culture Identification (BCID) Panel on the management of patients with blood cultures growing gram positive cocci and Candida. We retrospectively compared clinical and economic outcomes between patients during the BCID testing period and a matched historical control group before BCID testing was introduced. A total of 84 BCID patients were matched to 252 historical controls. BCID identification of coagulase negative staphylococci contaminants resulted in shorter post-culture length of stay (P < 0.008) and saved roughly $30,000 per 100 patients tested. The BCID led to shorter duration of empirical vancomycin for patients with contaminated blood cultures (P = 0.005) and methicillin-susceptible Staphylococcus aureus bacteremia (P < 0.001). Patients with vancomycin-resistant enterococcal bacteremia received active therapy earlier than historical controls (P = 0.047). The BCID, coupled with antimicrobial stewardship intervention, was a cost effective tool to improve patient care. PMID- 26639227 TI - Impact of hyperglycemia on outcomes of patients with Pseudomonas aeruginosa bacteremia. AB - Bacteremia caused by Pseudomonas aeruginosa is associated with significant morbidity and mortality. In other bacterial infections, hyperglycemia has been identified as a risk factor for mortality in nondiabetic patients. The objective of this study was to determine the impact of early hyperglycemia on outcomes in diabetic and nondiabetic patients with P. aeruginosa bacteremia. A retrospective cohort study was performed in adult patients (>=18 years old) with P. aeruginosa bacteremia. Patients received at least 1 drug empirically to which the isolate was susceptible in vitro. Classification and regression tree analysis was used to determine the threshold breakpoint for average blood glucose concentration within 48 hours of positive blood culture (BG48). Logistic regression was used to explore independent risk factors for 30-day mortality. A total of 176 bacteremia episodes were identified; patients in 66 episodes were diabetic. Diabetic patients had higher BG48 (165.2+/-64.8 mg/dL versus 123.7+/-31.5 mg/dL, P<0.001) and lower 30-day mortality (10.7% versus 22.7%, P=0.046) than nondiabetic patients. Multivariate regression revealed 30-day mortality in nondiabetic patients was associated with Acute Physiology and Chronic Health Evaluation II score (odds ratio [OR] 1.1; 95% confidence interval [CI] 1.0-1.2) and BG48 >168 mg/dL (OR 6.3; 95% CI 1.7-23.3). However, blood glucose concentration was not identified as an independent risk factor for mortality in diabetic patients by multivariate regression analysis. Hyperglycemia did not appear to affect outcomes in diabetic patients, whereas nondiabetic patients had a higher risk of mortality from P. aeruginosa bacteremia. Prospective studies evaluating the impact of glycemic control in these patients are needed. PMID- 26639229 TI - Circulating cell-free DNAs and miRNAs as promising non-invasive biomarkers for early detection of gastric cancer. AB - Early diagnosis of gastric cancer is critical to decrease the mortality of this globally fatal disease. Currently, endoscopic biopsy is the gold standard for diagnosis of gastric cancer. However, invasiveness and high expense limit its application. Hence, non-invasive and cost-effective biomarkers for early detection and subsequent management are crucial steps to monitor gastric cancer. Recent studies suggest that circulating cell-free nucleic acids, including circulating tumor DNAs and microRNAs (miRNAs), are promising for various applications. Development of such blood-based biomarkers is expected to facilitate detection, predict prognosis, monitor chemotherapeutic response and manage recurrence of human cancers. In this review, the characteristics of circulating cell-free DNAs and miRNAs will be elucidated, including their origin and dysregulation. Mutations and hypermethylation of circulating DNAs, abnormal alternations of expression of circulating miRNAs will be revealed as aberrant changes indicating gastric cancer. The roles of circulating DNAs and miRNAs for early detection of gastric cancer will be focused on, as well as the challenges of developing circulating nucleic acids as biomarkers. PMID- 26639228 TI - Bacterial coinfection is associated with severity of avian influenza A (H7N9), and procalcitonin is a useful marker for early diagnosis. AB - Patients contracting avian influenza A (H7N9) often develop severe disease. However, information on the contribution of bacterial coinfection to the severity of H7N9 is limited. We retrospectively studied 83 patients with confirmed H7N9 infection from April 2013 to February 2014. The severity of patients with bacterial coinfection and markers for early diagnosis of bacterial coinfection in H7N9 were analyzed. We found Staphylococcus aureus was the most prevalent pathogen. Higher Acute Physiology and Chronic Health Evaluation II score, shock, renal replacement treatment, mechanical ventilation, and extracorporeal membrane oxygenation treatment were more frequently observed in patients with bacterial coinfection. Procalcitonin is more sensitive than C-reactive protein in determining bacterial coinfection in H7N9 patients. In conclusion, H7N9 infection patients with bacterial coinfection had a more severe condition. Elevated procalcitonin is an accurate marker for diagnosing bacterial coinfection in H7N9 patients, thus enabling earlier antibiotic therapy. PMID- 26639230 TI - Circulating tumor cells in breast cancer patients. AB - Circulating tumor cells (CTCs) represent a potential non-invasive substitute for real-time tissue biopsy. Moreover, detection of CTCs in breast cancer patients has been reported as a strong prognostic factor. Biomarkers on CTCs have been analysed and correlated to tissue biopsies from breast cancer patients. Discordance in expression of potential biomarkers between primary tumor, metastatic sites and CTCs has been observed. Potential analytical confounding factors include lack of analytical consistency, varying sensitivities and specificities of used assays and differences in analytical ranges among various reported studies. Besides, clonal evolution within primary tumor (and metastatic sites) that leads to intratumor heterogeneity must be accounted for. Nevertheless, several on-going trials are exploring CTCs detection and biomarker profiling in view of personalising cancer treatment based on these real-time results. In this work, we will review CTCs in breast cancer patients and focus on identification of novel prognostic biomarkers. PMID- 26639231 TI - Cathepsin L is involved in proliferation and invasion of breast cancer cells. AB - Cathepsin L(CTSL), a lysosomal endopeptidase was found overexpressed in Breast cancer (BC). The purpose of this work was to investigate the possible role of CTSL in the development of BC. RNA interference(RNAi) with a CTSL small hairpin RNAs(CTSL-shRNA) and plasmid with CTSL were used to identify the effects of CTSL on malignant behaviors of BC. MCF-7 and SKBR-3 were selected as cell models in vitro and in vivo. The results showed that down-regulation of CTSL can significantly inhibit the proliferative and invasive ability of MCF-7 cell, while up-regulation of CTSL in SKBR-3 cells had opposite effects. Comparing to parental BC cells, CTSL knockdown cells exhibited attenuated capacities in developing tumor in nude mice, furthermore, the growth of these xenografts were dramatically regressed. In conclusion, our findings suggest that CTSL contributes to the proliferation and metastasis of BC and might be a potent molecular target for BC treatment. PMID- 26639232 TI - In vitro and in vivo antitumor activity of a novel chlorin derivative for photodynamic therapy. AB - In presented paper, a new chlorin derivative 5,10,15,20-tetrakis[(5-N morpholino)pentyl] chlorin (TMC) was investigated as a photosensitizer in photodynamic therapy (PDT). Cellular uptake, cytotoxicity, intracellular location, biodistribution and antitumor effects were studied using human esophageal cancer cells (Eca-109) and human cervical cancer cells (Hela) in vitro and an esophageal cancer model in BALB/c nude mice. Cellular uptake and biodistribution of TMC were measured by fluorescence spectrophotometer. Cytotoxicity of TMC against Eca-109 and Hela cells was determined by MTT assay. The intracellular location of TMC was detected with a confocal microscopy. It was showed that TMC could rapidly accumulate in tumor cells and localize in cytoplasm. TMC was found to be low-toxic in dark but extensively photosensitive in vitro. A fast clearance rate of TMC was observed in Eca-109-bearing mice. In particular, TMC could significantly inhibit the tumor growth and exhibit a notable antitumor efficacy for PDT in vivo. PMID- 26639233 TI - MAGE-A is frequently expressed in triple negative breast cancer and associated with epithelial-mesenchymal transition. AB - Epithelial-mesenchymal transition (EMT) is a crucial step in tumor metastasis. Triple negative (TN) breast cancer, a high metastasis phenotype, has been verified to be associated with EMT. Melanoma associated antigen-A (MAGE-A) is exclusively expressed in cancers with high aggressiveness as well as unfavorable prognosis and likely to be associated with EMT of triple negative breast cancer (TNBC). The aim of the study is to analyze the expression profile of MAGE-A in breast cancer and the correlation between MAGE-A and EMT of TNBC. Immunohistochemistry (IHC) was performed to assess the prevalence of MAGE-A, vimentin, E-cadherin and beta-catenin in breast cancer tissues and correlate them with clinical pathological parameters. The association between MAGE-A and EMT markers was also evaluated. Scratch assay and transwell invasion assay were carried out to evaluate the impact of MAGE-A down-regulation on migration and invasion of the breast cancer cells. Real-time PCR was also conducted to evaluate alterations in EMT markers with decrease in MAGE-A. The results showed that MAGE A was absent in normal tissue but expressed in tumor samples with the incidence of 49.17% (P=0.008). MAGE-A staining was higher in TNBC (76.47%, 13/17), followed by HER-2(+) (53.85%, 7/13) and Luminal set (43.33%, 39/90), and it was significantly correlated with ER (-), PR (-), HER-2 (-), lymph nodes involvement and higher histological grade (P<0.05). E-cadherin-positivity was frequent in Luminal set (94.44%, 85/90) and linked to ER (+), negative lymph nodes and lower histological grade (P<0.05). Vimentin expression was often observed in TNBC (70.56%, 12/17) and ER (-), PR (-), lymph nodes (+) groups (P<0.05). Expression of beta-catenin was prevalent in Luminal set (93.33%, 84/90) and correlated with ER (+), PR (+) and lower histological grade (P<0.05). MAGE-A was inversely associated with E-cadherin (P=0.011) and beta-catenin (P=0.048) but expressed in the same trend with vimentin (P=0.000). Migration and invasion of MDA-MB-231 were inhibited when MAGE-A decreased. Increase in epithelial markers and decline in mesenchymal indicators were also seen with MAGE-A reduction. Snail, Slug, ZEB1 and ZEB2 were also down-regulated. In conclusion, MAGE-A may be responsible for high aggressiveness and EMT of TNBC and can be a new choice for targeted therapy. PMID- 26639234 TI - Identification of driver pathways in cancer based on combinatorial patterns of somatic gene mutations. AB - With the availability of high-throughput technologies, a huge number of biological data (e.g., somatic mutation, DNA methylation and gene expression) in multiple cancers have been generated. A major challenge is to identify functional and vital driver mutation import for the initiation and progression of cancer. In this paper, we introduce a novel method, named Co-occurring mutated metagene Genetic Algorithm (CoGA), to solve the maximum weight submatrix problem, with the aim of distinguishing mutated driver pathways in cancer. The algorithm relies on the combinatorial properties of mutations in the same pathways: high coverage and mutual exclusivity, and the possible properties of mutations in different pathways: co-occurring pattern. We carried out the experiment with glioblastoma multiform (GBM) data. The experimental results show that compared with the original model, our algorithm has more potential to identify driver pathways in cancer with biological significance. PMID- 26639235 TI - IARS2 silencing induces non-small cell lung cancer cells proliferation inhibition, cell cycle arrest and promotes cell apoptosis. AB - The purpose of this study was to investigate the potential role of Ileucyl-tRNA synthetase (IARS2) silencing in non-small cell lung cancer (NSCLC). The silencing of IARS2 in H1299 cells and A549 cells were performed by lentivirus encoding shRNAs. The efficiency of IARS2 silencing was detected by quantitative real time PCR and western blot. The effects of IARS2 silencing on cell growth, cell apoptosis, cell cycle and cell colony formation ability were assessed by cells counting, MTT assay, flow cytometer analysis and soft agar colony formation assay, respectively. Compared with negative control group, IARS2 was significantly knockdown by transfection with lentivirus encoding shRNA of IARS2. The IARS2 silencing significantly inhibited the cells proliferation and cells colony formation ability, induced cell cycle arrest at G1/S phase and promoted cell apoptosis. IARS2 silencing induced NSCLC cells growth inhibition, cell cycle arrest and promoted cell apoptosis. These results suggest that IARS2 may be a novel target for the treatment of NSCLC. PMID- 26639236 TI - 10-Hydroxycamptothecin induces apoptosis in human neuroblastoma SMS-KCNR cells through p53, cytochrome c and caspase 3 pathways. AB - Neuroblastoma (NB), the most common extracranial solid tumor in childhood, remains one of the most challenging types of cancer to treat. Therefore, the search for novel effective drugs for its treatment is essential. The present study used 10-hydroxycamptothecin (HCPT), which is a naturally occurring alkaloid anticancer agent extracted from the Chinese tree, Camptotheca acuminata, and has a strong anticancer activity in vitro and in vivo. HCPT is able to induce apoptosis in cells of various tumor types. However, few studies have been conducted on its efficacy in NB, and its apoptosis-inducing mechanism has not been elucidated. In the present study, the in vitro effects of HCPT on apoptosis in the human NB cell line, SMS-KCNR, and its underlying molecular mechanisms were investigated. Cell proliferation was measured by an MTT assay and apoptosis was measured using DAPI staining and flow cytometric analysis. In addition, western blot analysis was used to evaluate the apoptosis-associated signaling pathways. HCPT was observed to markedly inhibit cell proliferation and induce apoptosis in SMS-KCNR cells at a relatively low concentration (2.5-20 nM). DAPI staining revealed typical apoptotic feature, namely apoptotic body formation. The flow cytometric analysis revealed that the number of apoptotic cells increased from 20.89% (for 2.5 nM) to 97.66% (for 20 nM) following HCPT treatment for 48 h. Western blot analysis revealed that p53, cytoplasmic cytochrome c, cleaved caspase-3 and poly ADP-ribose polymerase (PARP) proteins were significantly upregulated, while the mitochondrial cytochrome c and pro-caspase-3 proteins were downregulated. However, the B-cell lymphoma 2 and Bcl-2-associated X proteins were unaffected. The results indicated that HCPT may inhibit proliferation and induce apoptosis in the SMS-KCNR cells. The possible mechanism of apoptosis induction is the p53-mediated mitochondrial apoptotic signaling pathway, which promotes cytochrome c release and induces apoptosis by activating caspase-3 and PARP. Our study provides experimental evidence for HCPT as a potent therapeutic drug in NB treatment. PMID- 26639237 TI - The effect of PI3K inhibitor LY294002 and gemcitabine hydrochloride combined with ionizing radiation on the formation of vasculogenic mimicry of Panc-1 cells in vitro and in vivo. AB - This research's purpose was to explore the existence of vasculogenic mimicry (VM) in both 3-D matrices of Panc-1 cells in vitro and orthotopic Panc-1 xenografts in vivo and to test the hypothesis that PI3K inhibitor LY294002 and gemcitabine hydrochloride would offer clear treatment benefit when integrated into ionizing radiation (IR) therapeutic regimens for treatment of pancreatic cancer. We explored the existence of VM in both 3-D matrices of Panc-1 cells and orthotopic Panc-1 xenografts. We subsequently investigated the activation of the PI3K/MMPs/Ln-5gamma2 signaling pathway in response to IR. LY294002 and gemcitabine hydrochloride were then evaluated for their radiosensitizing effect solely and in combination. We found that VM existed in both 3-D matrices of Panc 1 cells in vitro and orthotopic Panc-1 xenografts in vivo. The expressions of p Akt and MMP- 2 were found to increase in response to IR. LY294002 and gemcitabine hydrochloride combined with IR better inhibited cell migration, VM formation and MMP-2 mRNA expression of Panc-1 cells in vitro, and we also proved that the novel therapeutic regimen better inhibited tumor growth, tumor metastasis and VM formation of orthotopic Panc-1 xenografts by suppressing the PI3K/MMPs/Ln-5gamma2 signaling pathway in vivo. Our present study is among the first to prove the VM formation in orthotopic Panc-1 xenografts. Furthermore, our current study is also among the first to provide preliminary evidence for the use of the novel therapeutic regimen LY294002 and gemcitabine hydrochloride combined with IR for treatment of pancreatic cancer. PMID- 26639238 TI - Clinical significance of angiopoietin-like protein 3 expression in patients with glioblastoma. AB - There is strong evidence that angiopoietin-like peptide family is involved in the invasiveness and metastasis of cancer. Angiopoietin-like protein 3 (ANGPTL3) is proven to be involved in angiogenesis and tumor development. However, there is no published data on the role ANGPLT3 plays in glioblastomas. The present study was conducted to examine ANGPLT3 proteins expression and its association with clinicopathological factors and prognosis in human glioblastomas. Immunohistochemistry was used to evaluate the expression of ANGPTL3, EGFR and VEGFR. We found that 33 cases (57.9%) that showed strong immunostaining for ANGPTL3 proteins. However, there was no significant difference between the expression of ANGPTL3 and the proangiogenic factors, including EGFR or VEGFR. Patients with high/moderate expression of ANGPTL3 had a significantly shorter survival time (6.3 months) than those (median survival time 13.8 months) with low/negative expression. The overall survival (OS) was also investigated and analyzed by the Kaplan-Meier method, which showed a significant difference (P=0.0045, Breslow test). The present data leads to new insights into the role of ANGPTL3 in glioblastomas and provides an independent predictive factor. PMID- 26639239 TI - The efficacy of stereotactic radiotherapy for metastases from renal cell carcinoma. AB - Our purpose was to evaluate the efficacy of stereotactic radiotherapy (SRT) for intracranial and extracranial metastases in patients with renal cell carcinoma. The retrospective analysis of 85 patients (151 tumors) treated with SRT was performed. SRT was the sole treatment in 35% of tumors, the other 65% had received additional treatment such as surgery, palliative radiotherapy, immunotherapy or chemotherapy. In 60% and 40% of patients SRT was delivered to brain and extracranial lesions, respectively. The assessment of the efficacy of SRT was based on a radiological imaging (Computed Tomography or Magnetic Resonance Imaging) and estimation of Local Control (LC) as well as Overall Survival (OS). Single fraction was used for 104 tumors and fractionated treatment for 47 tumors. The crude LC for evaluable lesions was 81%, stratified by tumor location: brain LC=94%, extracranial tumors LC=70% (p=0.049). The median OS was 9.4 months; 1-year and 2-year OS were 40% and 29%, respectively. The additional treatment did not lead to a better local response (p=0,543), but resulted in a benefit in OS (7 vs 13 months, p=0,01). A positive relationship between the biologically effective dose (BED) and local response was noted, but the BED was influenced by a tumor volume (R=-0,38; p<0,00001). The presence of multi-organ metastases reduced the OS rate (8.7 vs 19.1 months; p=0,01). The interval between the diagnosis of the metastasis and its treatment with SRT was inversely related to OS (P=0.0001). SRT results in a good local response, which is more beneficial for brain than extracranial lesions. The local efficacy of the SRT depends on the radiation dose. Multidisciplinary treatment and earlier application of SRT improves the prognosis of patients. PMID- 26639240 TI - Human papillomavirus and Epstein-Barr virus in nasopharyngeal carcinoma in a non endemic eastern european population. AB - Nasopharyngeal carcinoma (NPC) is a rare malignancy in the Czech Republic and Slovakia, with the standardized incidence rate of < 1:100000 person-years. Viral status of NPC in these non-endemic Eastern European regions is currently unknown. In a retrospective study, we evaluated the presence of EBV and HPV in 62 NPC cases. EBV status was determined by the use of in situ hybridization (ISH) for EBV encoded small RNA 1 (EBER1). HPV status was examined with p16 immunohistochemistry, DNA ISH and DNA polymerase chain reaction. Sixty-one studied cases showed non-keratinizing morphology and one was keratinizing squamous cell carcinoma. Only one NPC with non-keratinizing morphology was scored as p16-positive (nuclear and cytoplasmic staining >= 70% of tumor cells). This case was positive for high-risk HPV by ISH and the DNA PCR confirmed the presence of HPV18 type. At the same time, this case was found negative for EBV. Remaining sixty-one cases that were scored as p16-negative were all found HPV-negative by ISH and the DNA PCR. EBV was detected in 85.5% (53/62) of cases and 9 cases were EBV-negative, including the case of keratinizing NPC. In contrast with previous reports on the prevalence of EBV-positivity in Caucasian patients with NPC, the majority of patients coming from this non-endemic region show EBV-positivity; therefore, they may be candidates for novel EBV-targeting therapies. Conversely, HPV-positive NPC is very rare and HPV does not seem to play a significant role in the etiopathogenesis of NPC in these Eastern European populations. PMID- 26639241 TI - Loss at 16q22.1 identified as a risk factor for intrahepatic recurrence in hepatocellular carcinoma and screening of differentially expressed genes. AB - Copy number alteration (CNA) of chromosome 16, a frequent genetic event in tumors including hepatocellular carcinoma (HCC), has been associated with HCC etiology of hepatitis B virus (HBV) and with clinical outcomes in multiple types of cancer. This study identified CNAs in chromosome 16 in relation to intrahepatic recurrence of HCC in a population with high HBV prevalence, and further screened for differentially expressed genes in recurrence-related CNAs. Array comparative genomic hybridization and expression arrays were used to detect CNAs and gene expression differences, respectively. The associations between CNAs and intrahepatic recurrence were analyzed on 66 patients, follow-up period of 3-73 months. One hundred and nine cases were further evaluated regarding the differentially expressed genes. Losses at 16q and 16p were detected in 62.1% and 51.5% of the 66 cases, respectively. The most recurrent CNAs (with frequency >20%) were losses at 16p13.3-13.2, 16p13.11, 16q11.2-22.1, 16q22.1, 16q22.2-24.2 and 16q24.2. Of the CNAs, 16q22.1 loss was significantly associated with unfavorable intrahepatic recurrence-free survival (P = 0.025). Multivariate Cox analysis identified 16q22.1 loss as an independent risk factor for intrahepatic recurrence (HR = 2.32, 95% CI = 1.26-4.27). A panel of 21 genes, including TRADD, PSMB10, THAP11, CTCF and ESRP2, were significantly downregulated in HCCs with 16q22.1 loss compared to those without the loss. These results suggest that loss at 16q22.1 was associated with increased risk for intrahepatic recurrence of HCC, at least in the HBV-prevalence population. Multiple downregulated genes correlated with the loss were screened. PMID- 26639242 TI - Supernatant versus exosomal urinary microRNAs. Two fractions with different outcomes in gynaecological cancers. AB - MicroRNAs (miRNAs) are key regulatory molecules implicated in fundamental cell processes. Recent investigations have been focused to investigate their diagnostic potential also in various body fluids. Plasma and serum are widely used for these purposes. Urinary miRNAs, as the easily available type of sample, have been explored particularly in urological diseases recently. However, we have shown previously that differential expression of urinary cell-free miRNAs may be observed also in gynaecological cancers, such as ovarian and endometrial cancers. In the present article, we focus on the differences in particular urine cell-free miRNA abundance among different samples including particularly ovarian and endometrial cancers and rare gynaecological diagnoses involved in the study. Using raw abundance miRNA expression data, we confirmed significant up-regulation of miR-92a in ovarian cancer, and significant down-regulation of miR-106b in endometrial cancers. As miR-21 appeared up-regulated in the endometrial cancer similarly as in the verification process, where also miR-106b resulted in significant down-regulation in ovarian cancer, these miRNAs may be good candidates for further evaluation as novel diagnostics. To find out why supernatant but not exosomal urine miRNAs fraction resulted in significant results in regards to de-regulation of expression, we performed a comparison of the same urine samples isolated by these two manners. We show that diagnostic potential of cell-free urinary miRNAs may depend on the urine fraction used for the isolation. While particular urinary miRNAs may be enriched, other may reveal unchanged or diminished expression in the exosomal fraction in comparison with supernatant fraction, giving differences also between cancer and control samples. More research will be needed to further explore which kind of cell-free samples would give better results for diagnostic purposes in various diagnoses using urinary samples and investigating cell-free miRNAs expression. Meanwhile, different urine fractions should be explored for their miRNA expression to establish novel diagnostic urinary miRNA markers. PMID- 26639243 TI - Clinical significance of survivin and vascular endothelial growth factor mRNA detection in the peripheral whole blood of breast cancer patients. AB - Survivin and vascular endothelial growth factor (VEGF) have been reported to overexpress in various human cancer tissues and peripheral blood, but have rarely been studied in the whole blood of breast cancer patients. So we want to investigate the mRNA expression of survivin and VEGF in whole blood of patients with breast cancer and explore the value of these two factors as biomarkers for possible early detection. Levels of survivin and VEGF mRNA expression in the whole blood of 43 early stage breast cancer patients and 25 normal controls were detected by qRT-PCR and the receiver operating characteristic (ROC) curve for each factor was constructed. As a result, the levels of suvivin and VEGF mRNA in breast cancer patients were 2.24 and 2.92 folds compared to normal controls, respectively and the difference was significant (P=0.0003 and P<0.0001, respectively). The cutoff value for differentiating breast cancer patients and normal people was 8.081*10-3 for survivin and 13.23 *10-3 for VEGF. At the cutoff value, the area under ROC curve (AUC) for survivin was 0.7674, the sensitivity and specificity were 83.72% and 64%, respectively; For VEGF, it was 0.9163, the sensitivity and specificity were 93.02% and 88%, respectively. When combined the two factors, the AUC was 0.8981, the sensitivity and specificity reached to 95.35% and 84%, respectively. Furthermore we found that there was a significant correlation between survivin and VEGF mRNA (r=0.3970, p=0.0084). No significant difference was found between the expression levels of these two factors and the clinical pathological data. Thus, we came to a conclusion that it was a convenient and sensitive method to detect survivin and VEGF mRNA in the whole blood using qRT-PCR, and these two factors could be useful tumor biomarkers for early detection of breast cancer. PMID- 26639244 TI - Altered levels of plasma chemokines in breast cancer and their association with clinical and pathological characteristics. AB - Chemokines are a family of small, structurally related cytokines with chemoattractant and activation properties. In breast cancer, both epithelial cancer cells and cells within the microenvironment secrete chemokines with either tumor-promoting or anti-malignant potential. The equilibrium between these two chemokine activities plays a key role in the biology of the developing tumor, including its ability to metastasize. Here we evaluated the expression of chemokines in breast tumors and the plasma of breast cancer patients before treatment in order to identify a blood-based signature that could distinguish between malignant and non-malignant processes. We screened the mRNA expression of chemokine genes using cDNA microarray on homogenous, laser-capture microdissected breast cancer specimens. Further, using a protein array approach, we determined the levels of selected chemokines in the plasma of patients with breast cancer, benign breast tumors and healthy women. Finally, we analyzed the association between the levels of chemokines in breast and blood samples with the pathological characteristics of the disease. At mRNA level, 27 chemokines and 11 chemokine receptors were differentially expressed in cancers when compared with normal breast tissue. When compared to benign tumors, the only chemokine significantly upregulated in cancers was CXCL10. At protein level, with the exception of CXCL13, nine out of the ten selected chemokines (CCL2, CCL7, CCL18, CCL22, CXCL8, CXCL9, CXCL10, CXCL11 and osteoprotegerin) were significantly overexpressed in the plasma of breast cancers patients compared to healthy controls. After grouping, CXCL8, CXCL9 and CCL22 proved to be significant predictors for breast cancers as compared to healthy controls in a model of logistic regression. We found upregulation of CXCL8, CXCL11 and CXCL9 in triple negative carcinomas, CXCL9 in low proliferative carcinomas, and CXCL10, CCL7 and osteoprotegerin in poorly differentiated carcinomas. Furthermore, CXCL9 was overexpressed in lymph node negative tumors, whereas CXCL8 and CCL18 were higher in advanced stage carcinomas. We identified a panel of chemokines dysregulated in breast cancer that could be further investigated as prospective novel diagnostic markers or for therapeutic and prognostic applications. PMID- 26639245 TI - Prognostic significance of the Musashi-2 (MSI2) gene in childhood acute lymphoblastic leukemia. AB - The prognostic value of the Musashi-2 (MSI2) gene has not yet been studied in childhood acute lymphoblastic leukemia (ALL). In our study, MSI2 mRNA levels of 119 childhood patients with newly-diagnosed ALL were examined and analyzed with regard to clinical characteristics and outcomes. ALL patients demonstrated significantly higher MSI2 mRNA levels than healthy controls. In addition, MSI2 mRNA levels were correlated with the disease status and IK6 mutation status. Survival analyses showed that higher MSI2 mRNA levels predicted worse outcomes in patients with childhood ALL. Moreover, in multivariate analyses, MSI2 mRNA overexpression retained its value as an independent risk factor for overall survival (OS), but not for event free survival (EFS). We conclude that high MSI2 mRNA level predicts adverse prognosis and seems to be useful as a novel prognostic factor for patients with childhood ALL. PMID- 26639246 TI - Radiotherapy effects on brain/bone metastatic adenocarcinoma lung cancer and the importance of EGFR mutation test. AB - This study proposed to retrospectively analyze the efficacy of radiotherapy on brain/bone metastases in patients with stage IV lung adenocarcinoma and to evaluate the correlation between overall survival after radiotherapy and other factors including metastatic sites and EGFR mutation status. 115 patients with Stage IV lung adenocarcinoma admitted to our center from March, 2011 to December, 2013 were enrolled. They presented with metastases to no other solid organs except the bone or brain and had received no prior treatment. 50 patients received EGFR mutation test with 32 detected as EGFR mutant and 18 wild-type. Patients with brain metastases were treated with 40 Gy whole brain irradiation (WBI) in 2 Gy fractions; patients with bone metastases were treated with 30 Gy local irradiation in 3 Gy fractions or 40 Gy in 2 Gy fractions. All the patients received systemic therapy during or after radiotherapy and 68 received targeted therapy.The median overall survival of patients with solitary brain metastases, solitary bone metastases or combined brain and bone metastases were 8.50 months, 8.50 months and 9.50 months respectively, revealing no significant difference (p=0.57). The median overall survival of patients with EGFR mutations was 10.25 months, longer than the 8.75 months of patients without EGFR mutations, revealing no significant difference (p=0.57). The median overall survival of EGFR mutant patients with solitary bone metastases, solitary brain metastases or combined brain and bone metastases were 7.50 months, 10.50 months and 11.50 months respectively, revealing no significant difference (p=0.91). 36 patients with untested EGFR mutation status received EGFR-TKI. Among EGFR mutant patients, 10 didn't receive targeted therapy; 8 were administered Erlotinib and 14 Gefitinib with median overall survival of 10.25 months and 14.5 months, showing no significant difference (p=0.11) between the two drugs. When patients with stage IV lung adenocarcinoma have been treated by early radiotherapy, the overall survival doesn't correlate with metastatic sites. Radiotherapy could extend survival for EGFR mutant patients with stage IV lung adenocarcinoma. EGFR mutation test should be performed before treatment of the disease. PMID- 26639247 TI - Prediction of toxicities of prostate cancer radiotherapy. AB - We treated a cohort of 116 patients with prostate cancer with three-dimensional conformal hypofractionated radiotherapy to a total dose of 52.8 Gy in 16 fractions (3.3 Gy per fraction). The correlation between acute and late gastrointestinal (GI) and genitourinary (GU) toxicity and dose-volume parameters was analysed. Comparison of observed incidence of toxicity and normal tissue complication probability calculated from dose-volume histograms (DVH) of all patients using radiobiological Lyman-Kutcher-Burman model was performed. The results of our study suggest that acute gastrointestinal toxicity >= grade 2 (G2) is the significant predictor of late toxicity >= G2 (p=0.006). Observed incidence of acute and late GI toxicities >= G2 was 9.7% and 11.5%, respectively. NTCPs of acute and late GI complications >= G2 were 11.3% and 2.5%. Observed incidence of late GU toxicity >= G2 was 14.2%, NTCP was 0.8%. Comparison of calculated probability of acute GI toxicity >= G2 and observed incidence indicates that parameters of radiobiological models are set appropriately. Comparison of observed incidence of late GI and GU complications >= G2 and calculated NTCPs shows the need of refinement of LKB model parameters for acute and late GI and GU complications >= G2. KEYWORDS: prostate cancer, radiotherapy, acute and late toxicity, radiobiological modeling. PMID- 26639249 TI - Double 'take' threatens the future of nursing. AB - Most chancellors of the exchequer give with one hand and take with the other, but George Osborne hit nursing with a double whammy last week. First he announced that nursing students starting courses from 2017 will have to pay tuition fees, then added to the woe by revealing that they would not receive a bursary either. So the next generation of newly qualified nurses will start their careers on not much more than L21,000 and have debts that will take years to clear. PMID- 26639248 TI - Sequential binding of calcium ions to the B-repeat domain of SdrD from Staphylococcus aureus. AB - Biofilms of live bacteria forming on medical devices and implants contribute significantly to bacterial blood dissemination and to the spread of nosocomial infections. Cell surface SdrD protein plays a key role in the attachment of Staphylococcus aureus to the extracellular matrix (ECM) and in the formation of biofilm. SdrD binds calcium ions using its B1-B5 region bearing EF-hand Ca binding sites, leading to conformational changes in the structure of SdrD. This alters the distance between the bacterial surface and the ECM-interacting domain of SdrD in a spring-like fashion, participating in bacterial attachment. In this study we investigated calcium binding to EF-hand sites of SdrD using isothermal titration calorimetry and determined the impact of this process on SdrD's thermodynamic stability. This allowed us to propose a model of B1-B5 reorganization upon binding of calcium and to get new insight into the molecular mechanism of SdrD's action. PMID- 26639251 TI - Grateful patient names racehorse after his Macmillan nurse. AB - Many patients have sent a card or some chocolates to thank healthcare staff, but David Barker went further by naming his racehorse after his nurse. PMID- 26639252 TI - Debts could deter nursing entry as student loans replace bursaries. AB - The government's decision to scrap bursaries for nursing students in England and replace them with loans will saddle many graduates with debt and deter entry into the profession, nursing unions and students warn. PMID- 26639254 TI - Banking fines to fund completion of Seacole statue. AB - The Mary Seacole Memorial Statue Appeal is to benefit from L240,000 gathered in banking fines, chancellor George Osborne announced in his autumn statement. PMID- 26639253 TI - Help to buy plan will not ease burden of London house prices, says union. AB - Chancellor George Osborne's plans for interest-free loans to cover up to 40% of the costs of newly-built homes in London will do little to help the capital's nurses get on the housing ladder, say health worker unions. PMID- 26639255 TI - Public health cuts will 'diminish services further'. AB - Fears have been raised that cuts to public health services outlined in the government's comprehensive spending review last week will undermine the L3.8 billion cash injection promised for front line NHS services for 2016/17. PMID- 26639256 TI - Delays to FtP hearings expected to rise as new system settles in. AB - The Nursing and Midwifery Council (NMC) has said the proportion of its fitness to practise hearings not concluded within 15 months could rise to around a third between now and March. PMID- 26639259 TI - CNO summit brings nurses together. AB - About 500 nurses, academics and other healthcare professionals were expected to attend the chief nursing officer (CNO) for England's summit in Birmingham this week. PMID- 26639257 TI - Fabulous award for staffing app. AB - A safe staffing app giving up-to-date information on the number of nurses on the wards at Nottingham University Hospitals NHS Trust scooped top prize at the inaugural Academy of Fabulous NHS Stuffawards in London last week. PMID- 26639260 TI - Junior doctors set to walk out if conciliation bid fails. AB - The RCN has advised nurses to continue to work as normal during planned industrial action by junior doctors. PMID- 26639261 TI - Trust takes HIV testing to the streets of Blackpool. AB - Blackpool Teaching Hospitals NHS Foundation Trust's sexual health team has held HIV testing events in the town as part of a national initiative. PMID- 26639262 TI - Avoidable sepsis deaths prompt call for universal formal protocols. AB - An acute care nurse consultant who contributed to a national report on sepsis has questioned why all hospitals do not have formal protocols for its diagnosis and treatment. PMID- 26639263 TI - Fall in staff assaults is recorded but acute care attacks on the rise. AB - The number of reported physical assaults against all NHS staff in England in 2014/15 has fallen slightly on the previous year - down from 68,683 in 2013/14 to 67,864. PMID- 26639269 TI - Bronchiolitis. AB - Essential facts Bronchiolitis is a common lung infection affecting babies and young children. Around 30,000 infants are admitted to hospital in England each year with the illness. About one third of children in the UK will have the infection in the first year of life, and most will have had it by the age of two. PMID- 26639270 TI - Select the very best tools for the job. PMID- 26639271 TI - The home front on pressure ulcers. PMID- 26639282 TI - Baby Check app. AB - For parents worried about their baby's health and unsure whether to consult a health professional, the Baby Check app from the charity Lullaby Trust provides information that can help allay fears and create a clearer perspective. PMID- 26639283 TI - The best of the week's health-related TV and radio. PMID- 26639284 TI - Using unregistered staff may cut costs but more patients will die. AB - Doreen Crawford is justified in raising the alarm about the danger of a nursing underclass re-emerging (letters November 18). PMID- 26639285 TI - Junior doctors are now in the same boat as nurses regarding pay. AB - It was great to see so much support for junior doctors among nurses at Barts Health NHS Trust in London (analysis November 18). But where is the RCN in supporting the junior doctors? PMID- 26639286 TI - An unfair imbalance between NHS staff must be addressed. AB - I am sure I am not the only one to have observed, with much incredulity, how quickly the junior doctors have managed to get people to listen to them. PMID- 26639288 TI - Drop in bed numbers in north Devon raises concerns. AB - In the past two years the number of beds for older people in north Devon has fallen from more than 100 to 40 and this is being replicated across the county. PMID- 26639290 TI - Psychosexual care is important after prostate cancer treatment. AB - We thank Robert McConkey for highlighting the effect of erectile dysfunction after prostate cancer treatment (art & science November 18). PMID- 26639291 TI - How to administer an enema. AB - Rationale and key points This article aims to help nurses to undertake the administration of enemas in a safe, effective and patient-centred manner, ensuring privacy and dignity. The administration of an enema is a common healthcare procedure, which can be used to deliver medication or aid bowel evacuation. ? The administration of an enema should be undertaken by a competent nurse. ? An enema is a liquid preparation inserted into the rectum. ? The nurse must explain the procedure to the patient and should assist the individual before, during and after the procedure. ? The nurse should document all care given. Reflective activity Clinical skills articles can help update your practice and ensure it remains evidence based. Apply this article to your practice. Reflect on and write a short account of: 1. How you felt performing this intimate procedure. 2. The positive elements of care delivery and those that could be enhanced. Subscribers can upload their reflective accounts at: rcni.com/portfolio . PMID- 26639292 TI - Managing COPD using pulmonary rehabilitation: a literature review. AB - This article presents a literature review of the benefits of pulmonary rehabilitation in the management of chronic obstructive pulmonary disease (COPD). Pulmonary rehabilitation has been shown to decrease patient mortality and hospital admissions. The literature search resulted in 13 articles being selected for review. Three themes were identified: improvement in exercise tolerance, improvement in breathlessness and improvement in health-related quality of life. This review enhances our knowledge of the mechanisms through which pulmonary rehabilitation benefits patients and provides an evidence base to guide nursing decisions regarding patient education, health promotion and psychological support. PMID- 26639293 TI - Developing a structured approach to safeguarding education. AB - Safeguarding vulnerable adults and children is a legal requirement and is essential in nursing and healthcare practice. This article describes the development and establishment of a structured approach to safeguarding education and student support in one pre-registration nursing programme in the UK. This approach involved the development of an academic safeguarding lead role, extensive curriculum development, and implementation of policies and procedures for raising and escalating concerns. The authors suggest that this integrative and comprehensive model should be used in all higher education institutions providing nurse education. PMID- 26639294 TI - Understanding bullying in healthcare organisations. AB - Bullying is a pervasive problem in healthcare organisations. Inquiries and reports on patient care and poor practice in the NHS have emphasised the substantial negative effects this behaviour may have on patient care. If bullying is to be addressed, it is crucial we develop clarity about what behaviours constitute bullying and how these behaviours differ from other negative behaviours in the workplace. It is important that we recognise the extent of the problem; statistics on the prevalence of bullying are likely to be an underestimate because of under-reporting of bullying. Effective interventions may only be designed and implemented if there is knowledge about what precipitates bullying and the magnitude of the changes required in organisations to tackle bullying. Individuals should also be aware of the options that are available to them should they be the target of bullying behaviour and what they should do if they witness bullying in their workplace. PMID- 26639295 TI - Critiquing research. AB - Literature reviews can help to improve evidence-based practice and promote positive change in nursing. They aim to analyse, evaluate and clarify ideas presented by various authors and summarise them. After reading the CPD article on critiquing research literature, I have gained an understanding of the process that I would use to carry out a literature review. PMID- 26639296 TI - Make the connection. AB - Since I started my mental health nurse training in 1991, it has been my mission to improve the health and wellbeing of people with psychosis, a condition that affects around 1% of the UK's adult population. PMID- 26639297 TI - A career-enriching experience. AB - Docked in Toamasina, on the east coast of Madagascar, the world's largest floating hospital ship is home to hundreds of nurses delivering health care to the world's fourth-largest island nation. PMID- 26639299 TI - 'Funding my trips has not been difficult'. AB - I trained as a children's nurse in York for three years, working on a ward for five years. Throughout my career, I kept returning to Mercy Ships because I am passionate about helping people without access to hospitals. PMID- 26639300 TI - Student life - Stay fit to make the grade. AB - Nurse training can be notoriously difficult, and can take its toll on your physical, mental and emotional health. The demands of nurse training can also put stress on your personal relationships and social life. PMID- 26639301 TI - Measuring Femoral Torsion In Vivo Using Freehand 3-D Ultrasound Imaging. AB - Despite variation in bone geometry, muscle and joint function is often investigated using generic musculoskeletal models. Patient-specific bone geometry can be obtained from computerised tomography, which involves ionising radiation, or magnetic resonance imaging (MRI), which is costly and time consuming. Freehand 3-D ultrasound provides an alternative to obtain bony geometry. The purpose of this study was to determine the accuracy and repeatability of 3-D ultrasound in measuring femoral torsion. Measurements of femoral torsion were performed on 10 healthy adults using MRI and 3-D ultrasound. Measurements of femoral torsion from 3-D ultrasound were, on average, smaller than those from MRI (mean difference = 1.8 degrees ; 95% confidence interval: -3.9 degrees , 7.5 degrees ). MRI and 3-D ultrasound had Bland and Altman repeatability coefficients of 3.1 degrees and 3.7 degrees , respectively. Accurate measurements of femoral torsion were obtained with 3-D ultrasound offering the potential to acquire patient-specific bone geometry for musculoskeletal modelling. Three-dimensional ultrasound is non invasive and relatively inexpensive and can be integrated into gait analysis. PMID- 26639302 TI - Ex vivo comparison of the giant and transfixing knot in equine open and closed castration. AB - REASONS FOR PERFORMING STUDY: In equine castration, application of a ligature on the spermatic cord to prevent complications such as haemorrhage and evisceration has been reported with controversial results. Characteristics of commonly used knots have not been studied. OBJECTIVES: To compare the modified transfixing and giant knots and the emasculator in open and closed equine castration techniques. STUDY DESIGN: Ex vivo experiment. METHODS: A total of 144 testicles were randomly assigned to 2 groups for open or closed castration. Both groups were divided into 3 subgroups of 18 specimens each: emasculator only, emasculator plus giant knot and emasculator plus transfixing knot and the open castration group also contained 2 further subgroups of 18 testicles each: giant knot only and transfixing knot only. The length of suture material used was measured for each knot and the leaking pressure of the testicular artery measured using dye injection. In the closed castration group, parietal tunic tensile strength was measured with a tensiometer. RESULTS: Leaking pressure was higher in open compared with closed castration, with no significant difference among subgroups. In the closed castration group, minimum leaking pressure for the emasculator plus transfixing knot and emasculator only subgroups were close to standard physiological arterial pressures. The giant knot required less suture material than the transfixing knot. Parietal tunic tensile strength was higher when ligatures were applied. CONCLUSIONS: The giant and transfixing knot techniques have comparable haemostatic capability and parietal tunic tensile strength, but the giant knot requires less suture material. In open castration, using the emasculator alone may produce adequate haemostasis. In closed castration, using the giant knot in combination with the emasculator increases the bursting pressure and possibly reduces the incidence of haemorrhage. In closed castration, application of a ligature may reduce the risk of evisceration. PMID- 26639303 TI - SET DOMAIN GROUP 708, a histone H3 lysine 36-specific methyltransferase, controls flowering time in rice (Oryza sativa). AB - As a key epigenetic modification, the methylation of histone H3 lysine 36 (H3K36) modulates chromatin structure and is involved in diverse biological processes. To better understand the language of H3K36 methylation in rice (Oryza sativa), we chose potential histone methylation enzymes for functional exploration. In particular, we characterized rice SET DOMAIN GROUP 708 (SDG708) as an H3K36 specific methyltransferase possessing the ability to deposit up to three methyl groups on H3K36. Compared with the wild-type, SDG708-knockdown rice mutants displayed a late-flowering phenotype under both long-day and short-day conditions because of the down-regulation of the key flowering regulatory genes Heading date 3a (Hd3a), RICE FLOWERING LOCUS T1 (RFT1), and Early heading date 1 (Ehd1). Chromatin immunoprecipitation experiments indicated that H3K36me1, H3K36me2, and H3K36me3 levels were reduced at these loci in SDG708-deficient plants. More importantly, SDG708 was able to directly target and effect H3K36 methylation on specific flowering genes. In fact, knockdown of SDG708 led to misexpression of a set of functional genes and a genome-wide decrease in H3K36me1/2/3 levels during the early growth stages of rice. SDG708 is a methyltransferase that catalyses genome-wide deposition of all three methyl groups on H3K36 and is involved in many biological processes in addition to flowering promotion. PMID- 26639304 TI - Transgelin is upregulated in stromal cells of lymph node positive breast cancer. AB - Transgelin and transgelin-2 have been discussed as potential markers of various cancers. Here we identified increased transgelin level in lymph node positive vs. negative, low grade primary breast cancer tissues using 2-DE in the cohort of 12 patients. We further clinically validated 2-DE results in an independent cohort of 48 low grade breast cancer patients through untargeted and targeted proteomics analysis (iTRAQ-2D-LC-MS/MS, mTRAQ-SRM), at transcript level and using immunohistochemistry. Another group of 48 high grade tumors of different breast cancer subtypes was analyzed together with the low grade samples to test transgelin specificity for low grade tumors and to study transgelin relation to known molecular markers and histological features. The results confirmed transgelin connection with the lymph node metastasis. As a marker of a reactive tumor stroma, transgelin can be connected with the higher risk of metastasis development. Moreover, we observed significant down-regulation of transgelin in high vs. low grade tumors caused by decreased content of stromal cells (mainly expressing transgelin) in high grade tumor tissue. We also analyzed expression of transgelin-2 in the second cohort using proteomics and immunohistochemistry. Transgelin-2 was mainly expressed by epithelial cancer cells and its levels were increased in metastatic and poorly differentiated tumors. BIOLOGICAL SIGNIFICANCE: Both transgelin and transgelin-2 have been previously described as potential markers of many types of cancer. We are specifying this connection to metastatic affection of lymph nodes and cell differentiation in breast cancer. In the wider context, the results of our study highlight tumor stroma as a source of cancer biomarkers and point out how measured levels of tissue markers can actually reflect cellular feature of cancer mass. PMID- 26639305 TI - Identification of multiple transferrin species in the spleen and serum from mice with collagen-induced arthritis which may reflect changes in transferrin glycosylation associated with disease activity: The role of CD38. AB - Collagen type II-induced arthritis (CIA) is an inflammatory and autoimmune disease. Spleen protein extracts were subjected to 2D-DiGE and MS-MALDI-TOF/TOF analysis to identify protein species that differ in abundance in CD38-KO versus B6 WT mice either with arthritis or with inflammation. Using multivariate analyses, in Col-II-immunized mice, 23 distinct spleen protein species were able to discriminate between WT and CD38-KO mice. Among them, several citrullinated proteins and multiple serotransferrin (Tf) species were identified. In contrast, in CFA/IFA-treated mice, the distinct protein profile, which discriminates between CD38-KO and WT mice, was unrelated with Tf, but not with citrullination. Unexpectedly, non-immunized CD38-KO mice showed a distinct proteome profile as compared with that in non-immunized WT mice, and again multiple protein species were identified as Tf. By using a MULC-TOF-MS method to separate and detect Tf glycopeptide glycoforms, increases in fucosylation and glycan branching was observed in sera from mice CIA(+) versus non-immunized, and between WT and CD38 KO with arthritis. Data on 2-DE Tf spots indicated differences in glycosylation related with NeuGc content. Thus, Tf changed significantly in its glycosylation pattern in arthritic mice. The MS data have been deposited to the ProteomeXchange Consortium with the dataset identifiers: PXD002644, PXD002643, PXD003183, and PXD003163. SIGNIFICANCE: 2-DE followed by MULC-TOF-MS could be implemented to identify Tf glycoforms linked to specific protein species, and correlate a particular Tf species to a function. To gain insight into the relationship between transferrin glycoforms and its biological function it is particularly interesting to study putative differences in the glycosylation pattern of Tf in specific tissues associated with the disease (i.e.: joints), or in specific compartments such as exosomes/microvesicles, which are highly enriched in Tf receptors. PMID- 26639307 TI - Transcriptional activity of endogenous retroviruses in multiple sclerosis: a sign of deficient chromatin-mediated silencing. PMID- 26639308 TI - Structure-Activity Relationships of JMV4463, a Vectorized Cathepsin D Inhibitor with Antiproliferative Properties: The Unique Role of the AMPA-Based Vector. AB - Cathepsin D (CathD) is overexpressed and secreted by several solid tumors and stimulates their growth, the mechanism of which is still not understood. In this context, the pepstatin bioconjugate JMV4463 [Ac-arg-O2 Oc-(Val)3-Sta-Ala-Sta (AMPA)4-NH2; O2 Oc=8-amino-3,6-dioxaoctanoyl, Sta=statine, AMPA=ortho aminomethylphenylacetyl], containing a new kind of cell-penetrating vector, was previously shown to exhibit potent antiproliferative effects in vitro and to delay the onset of tumors in vivo. In this study, we performed a structure activity relationship analysis to evaluate the significance of the inhibitor and vector moieties of JMV4463. By modifying both statine residues of pepstatin we found that the antiproliferative activity is correlated with CathD inhibition, supporting a major role of the catalytic activity of intracellular CathD in cancer cell proliferation. Replacing the vector composed of four AMPA units with other vectors was found to abolish cytotoxicity, although all of the conjugates enabled pepstatin transport into cells. In addition, the AMPA4 vector must be localized at the C terminus of the bioconjugate. The unexpected importance of the vector structure and position for cytotoxic action suggests that AMPA4 enables pepstatin to inhibit the proteolysis of critical CathD substrates involved in cell proliferation via a unique mechanism of action. PMID- 26639309 TI - Approximate Analytic Expression for the Electrophoretic Mobility of Moderately Charged Cylindrical Colloidal Particles. AB - An approximate analytic expression for the electrophoretic mobility of an infinitely long cylindrical colloidal particle in a symmetrical electrolyte solution in a transverse electric field is obtained. This mobility expression, which is correct to the order of the third power of the zeta potential zeta of the particle, considerably improves Henry's mobility formula correct to the order of the first power of zeta (Proc. R. Soc. London, Ser. A 1931, 133, 106). Comparison with the numerical calculations by Stigter (J. Phys. Chem. 1978, 82, 1417) shows that the obtained mobility formula is an excellent approximation for low-to-moderate zeta potential values at all values of kappaa (kappa = Debye Huckel parameter and a = cylinder radius). PMID- 26639310 TI - Computed Tomography of the Esophagus in Scleroderma and Lung Disease. AB - Systemic sclerosis, or scleroderma, is a collagen vascular disease characterized by hardening of the skin and involvement of internal organs, most commonly the esophagus. The most frequent cause of death in these patients is lung disease. Esophageal dysfunction has been implicated in the pathogenesis of interstitial lung disease. We previously developed a standard for the esophageal diameter on chest computed tomography (CT) and hypothesized that patients with esophageal dilation would be more likely to have interstitial lung disease than those without. In this study, we test this in 121 systemic sclerosis patients with interstitial lung disease and 48 of those without interstitial lung disease. For controls, we evaluated 121 patients followed at a general pulmonary clinic and the previously studied normal healthy standards. This study demonstrated that esophageal dilation is common in systemic sclerosis patients (66.3% for the maximal esophageal diameter more than or equal to 15 mm), that systemic sclerosis patients with interstitial lung disease have more dilated esophagi than those without interstitial lung disease (median 19.4 mm vs. 14.1 mm), and that esophageal parameters are negatively correlated with pulmonary function. We also found that patients from general pulmonary clinic were more likely to have dilated esophagi than normal controls (median 12.1 mm vs. 9.7 mm). The CT measurement of esophageal diameter may be a useful marker of patients at risk for developing lung disease. PMID- 26639311 TI - [Malakoplakia of the submandibular gland in a renal transplant patient]. AB - INTRODUCTION: Malakoplakia (MP) is a rare granulomatous disease, usually occurring in immunocompromised patients, linked to Escherichia coli infection. The lesions are usually located in the genitourinary tract, but there is a great variability in the topography and the clinical presentation. CASE REPORT: A 70 year-old diabetic kidney transplant patient under immunosuppressive treatment presented with a voluminous submandibular chronic lesion, involving the skin, associated with a burgeoning lesion of the oral mucosa. Histological examination of biopsies concluded to MP and bacteriological samples were positive for E. coli. Antibiotic treatment allowed for the regression of the lesion before surgical removal. Histological examination of resected material confirmed the diagnosis of invasive MP of the submandibular gland. DISCUSSION: The diagnosis of MP relies on histological examination, showing the presence of von Hansemann's cells and Michaelis- Gutmann bodies. The treatment is based on active antibiotics targeted against intracellular bacteria, possibly associated with surgery. We report the first case of MP involving the submandibular gland. PMID- 26639312 TI - Innovative molecular diagnosis of Trichinella species based on beta-carbonic anhydrase genomic sequence. AB - Trichinellosis is a helminthic infection where different species of Trichinella nematodes are the causative agents. Several molecular assays have been designed to aid diagnostics of trichinellosis. These assays are mostly complex and expensive. The genomes of Trichinella species contain certain parasite-specific genes, which can be detected by polymerase chain reaction (PCR) methods. We selected beta-carbonic anhydrase (beta-CA) gene as a target, because it is present in many parasites genomes but absent in vertebrates. We developed a novel beta-CA gene-based method for detection of Trichinella larvae in biological samples. We first identified a beta-CA protein sequence from Trichinella spiralis by bioinformatic tools using beta-CAs from Caenorhabditis elegans and Drosophila melanogaster. Thereafter, 16 sets of designed primers were tested to detect beta CA genomic sequences from three species of Trichinella, including T. spiralis, Trichinella pseudospiralis and Trichinella nativa. Among all 16 sets of designed primers, the primer set No. 2 efficiently amplified beta-CA genomic sequences from T. spiralis, T. pseudospiralis and T. nativa without any false-positive amplicons from other parasite samples including Toxoplasma gondii, Toxocara cati and Parascaris equorum. This robust and straightforward method could be useful for meat inspection in slaughterhouses, quality control by food authorities and medical laboratories. PMID- 26639313 TI - Print-Tuning Lateralization and Handedness: an Event-Related Potential Study in Dyslexic Higher Education Students. AB - Despite their ample reading experience, higher education students with dyslexia still show deficits in reading and reading-related skills. Lateralized print tuning, the early sensitivity to print of the left parietal cortex signalled by the N1 event-related potential (ERP) component, differs between beginning dyslexic readers and controls. For adults, the findings are mixed. The present study aims to investigate whether print tuning, as indexed by the N1 component, differs between 24 students with dyslexia and 15 non-dyslexic controls. Because handedness has been linked to lateralization, first, a separate analysis was conducted including only right-handed participants (n = 12 in both groups), like in most previous studies. ERPs were measured during a judgement task, requiring visual, phonological, or semantic judgments. In both groups, the N1 was earlier and stronger in the left than in the right hemisphere. However, when only strongly right-handed participants were evaluated, the N1 was less left lateralized for participants with dyslexia as compared with controls. Participants with dyslexia had longer reaction times during the ERP experiment and performed worse on many reading (-related) tasks. These findings suggest that abnormal print tuning can still be found among higher education students with dyslexia and that handedness should be regarded in the study of print tuning. PMID- 26639314 TI - Maximising the use of freshly isolated human hepatocytes. AB - INTRODUCTION: Freshly isolated human hepatocytes are the best model for predicting adverse drug reactions. However, their preparation and use present the investigator with many variables that are beyond their control. These include operation continuity and timing, size and number of cut surfaces on liver tissue and the prior history of the patient. To exploit the potential of freshly isolated human hepatocytes a method is required to preserve the cells in their initial in vivo like state. This experimental pausing allows experiments to be prioritised at convenient times of the day. METHODS: A novel approach for selecting viable human hepatocytes by functional attachment to a gelatin gel is described rather than relying on their physical characteristics. The cells are preserved as a monolayer on the semi-solid support at 10 degrees C as single spherical entities. RESULTS: The hepatocytes can be released into suspension, when required, by a temperature transition to 37 degrees C for 20min. The cells can be used in suspension or as a monolayer. The length of preservation depends upon the source tissue. Hepatocytes from normal liver can be maintained for at least 4days and demonstrated to have the same level of CYP3A4 and the enzymes involved in glucuronidation and sulphation as freshly isolated cells. Cells from fatty liver, attached to gelatin, vary in their preservation time but it is at least 24h and so confluent monolayers, that survive at 37 degrees C can be generated the following day. DISCUSSION: The technique enables freshly isolated human hepatocytes to be used more effectively. They can be preserved in times of plenty so more experimentation is possible. Alternatively, with poorer fatty cells the initial attachment on gelatin enables confluent monolayers of lipid rich cells to be studied. PMID- 26639315 TI - High throughput chromatography strategies for potential use in the formal process characterization of a monoclonal antibody. AB - High throughput experimental strategies are central to the rapid optimization of biologics purification processes. In this work, we extend common high throughput technologies towards the characterization of a multi-column chromatography process for a monoclonal antibody (mAb). Scale-down strategies were first evaluated by comparing breakthrough, retention, and performance (yields and clearance of aggregates and host cell protein) across miniature and lab scale columns. The process operating space was then evaluated using several integrated formats, with batch experimentation to define process testing ranges, miniature columns to evaluate the operating space, and comparison to traditional scale columns to establish scale-up correlations and verify the determined operating space. When compared to an independent characterization study at traditional lab column scale, the high throughput approach identified the same control parameters and similar process sensitivity. Importantly, the high throughput approach significantly decreased time and material needs while improving prediction robustness. Miniature columns and manufacturing scale centerpoint data comparisons support the validity of this approach, making the high throughput strategy an attractive and appropriate scale-down tool for the formal characterization of biotherapeutic processes in the future if regulatory acceptance of the miniature column data can be achieved. Biotechnol. Bioeng. 2016;113: 1273-1283. (c) 2015 Wiley Periodicals, Inc. PMID- 26639317 TI - Intervals for the assessment of measurement agreement: Similarities, differences, and consequences of incorrect interpretations. AB - Several intervals have been proposed to quantify the agreement of two methods intended to measure the same quantity in the situation where only one measurement per method and subject is available. The limits of agreement are probably the most well-known among these intervals, which are all based on the differences between the two measurement methods. The different meanings of the intervals are not always properly recognized in applications. However, at least for small-to moderate sample sizes, the differences will be substantial. This is illustrated both using the width of the intervals and on probabilistic scales related to the definitions of the intervals. In particular, for small-to-moderate sample sizes, it is shown that limits of agreement and prediction intervals should not be used to make statements about the distribution of the differences between the two measurement methods or about a plausible range for all future differences. Care should therefore be taken to ensure the correct choice of the interval for the intended interpretation. PMID- 26639316 TI - DARPP-32 interaction with adducin may mediate rapid environmental effects on striatal neurons. AB - Environmental enrichment has multiple effects on behaviour, including modification of responses to psychostimulant drugs mediated by striatal neurons. However, the underlying molecular and cellular mechanisms are not known. Here we show that DARPP-32, a hub signalling protein in striatal neurons, interacts with adducins, which are cytoskeletal proteins that cap actin filaments' fast-growing ends and regulate synaptic stability. DARPP-32 binds to adducin MARCKS domain and this interaction is modulated by DARPP-32 Ser97 phosphorylation. Phospho-Thr75 DARPP-32 facilitates beta-adducin Ser713 phosphorylation through inhibition of a cAMP-dependent protein kinase/phosphatase-2A cascade. Caffeine or 24-h exposure to a novel enriched environment increases adducin phosphorylation in WT, but not T75A mutant mice. This cascade is implicated in the effects of brief exposure to novel enriched environment on dendritic spines in nucleus accumbens and cocaine locomotor response. Our results suggest a molecular pathway by which environmental changes may rapidly alter responsiveness of striatal neurons involved in the reward system. PMID- 26639320 TI - A parallel curriculum in lifestyle medicine. AB - BACKGROUND: Less than 50 per cent of US primary care doctors routinely provide guidance to their patients on lifestyle behaviours such as diet, physical activity or weight control, despite the prediction by the World Health Organization that by 2020, two-thirds of disease worldwide will be the result of poor lifestyle choices. This gap in patient-clinician dialogue is perhaps the result of a lack of structured training in medical school surrounding the components of lifestyle medicine. CONTEXT: Although Harvard Medical School does have a required course in nutrition, there are no requirements for the other components of lifestyle medicine, including physical activity, behaviour change and self-care. INNOVATION: Since 2009 Harvard Medical School has addressed this absence in the curriculum by developing a student-led, faculty member-advised, parallel curriculum in lifestyle medicine. Medical student participants were invited to take part in anonymous questionnaires between 2009 and 2013, which gathered data about personal ability and attitude in counselling patients on lifestyle behaviours, as well as subjective data on the curriculum content and applications to effective medical practice. Less than 50 per cent of US primary care doctors routinely provide guidance to their patients on lifestyle behaviours IMPLICATION: Each year, students have pointed to a lack of lifestyle medicine knowledge because of a gap in the traditional curriculum surrounding topics such as physical activity, nutrition and behaviour-change strategies, and indicated that the inclusion of this knowledge and these skills was an important component of medical education. Although participation is currently voluntary, this is the first such curriculum of this type and addresses a critical gap in undergraduate medical education. PMID- 26639319 TI - The prognostic significance of rapid peripheral blood blast clearance during the initial course of induction chemotherapy in young patients with de novo acute myeloid leukemia. AB - The early clearance of blast cells in peripheral blood (PB) during induction chemotherapy can predict the clinical outcome in acute leukemia. We retrospectively analyzed the kinetics of white blood cell (WBC) count, blast cell percentage (BCP), and blast cell count (BCC) in PB in 78 patients with de novo acute myeloid leukemia who underwent a uniform induction chemotherapy between December 2001 and December 2015 at Jichi Medical University. By a repeated measures analysis of variance, the interaction of the decline in BCP with the achievement of complete remission (CR) was stronger than those of the decline in WBC or BCC. A receiver operating characteristic curve analysis for the achievement of CR showed that the areas under the curve for the decline in WBC, BCP, and BCC were 0.592, 0.703, and 0.634, respectively, and a decline in BCP of 9.25%/day within 4 or 5 days from induction chemotherapy was the optimal cutoff value. A multivariate analysis showed that a rapid decline in BCP (>=9.25%/day) was a significant predictive factor for CR, independent of the cytogenetic risk (p = 0.0096). A rapid decline in BCP during the first 5 days of induction chemotherapy may be a good predictor of CR. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26639318 TI - Prenatal caffeine exposure induces a poor quality of articular cartilage in male adult offspring rats via cholesterol accumulation in cartilage. AB - Epidemiological investigations indicate that osteoarthritis is associated with intrauterine growth retardation (IUGR) and abnormal cholesterol metabolism. Our previous studies showed that prenatal caffeine exposure (PCE) induced chondrogenesis retardation in IUGR offspring rats. The current study sought to investigate the effects of PCE on male IUGR offspring rats' articular cartilage, and the mechanisms associated with abnormal cholesterol metabolism. Based on the results from both male fetal and adult fed a high-fat diet (HFD) studies of rats that experienced PCE (120 mg/kg.d), the results showed a poor quality of articular cartilage and cholesterol accumulation in the adult PCE group. Meanwhile, the serum total cholesterol and low-density lipoprotein-cholesterol concentrations were increased in adult PCE offspring. We also observed lower expression of insulin-like growth factor1 (IGF1) and impaired cholesterol efflux in adult articular cartilage. Furthermore, the expression of cartilage functional genes, components of the IGF1 signaling pathway and cholesterol efflux pathway related genes were decreased in PCE fetal cartilage. In conclusion, PCE induced a poor quality of articular cartilage in male adult offspring fed a HFD. This finding was shown to be due to cholesterol accumulation in the cartilage, which may have resulted from intrauterine reduced activity of the IGF1 signaling pathway. PMID- 26639321 TI - Pressurized liquid extraction followed by liquid chromatography with tandem mass spectrometry to determine pharmaceuticals in mussels. AB - An analytical method based on pressurized liquid extraction and solid-phase extraction with a mixed-mode Oasis((r)) MAX sorbent as cleanup, followed by liquid chromatography with electrospray ionization and tandem mass spectrometry was developed and validated for the determination of seven widely used pharmaceuticals in mussel species. The optimization of the pressurized liquid extraction and the solid-phase extraction parameters is described. The method provided extraction recoveries ranging from 61 to 90%, and limits of detection ranging from 2 to 50 ng/g (dry weight). The repeatability and reproducibility of the method, expressed as relative standard deviation, were lower than 15 and 19%, respectively. The method was successfully applied to the analysis of mussel samples from different locations. The analyses showed that salicylic acid was present in mussels at concentrations up to 177 ng/g (dry weight). PMID- 26639322 TI - Stretchable Hydrogel Electronics and Devices. AB - Stretchable hydrogel electronics and devices are designed by integrating stretchable conductors, functional chips, drug-delivery channels, and reservoirs into stretchable, robust, and biocompatible hydrogel matrices. Novel applications include a smart wound dressing capable of sensing the temperatures of various locations on the skin, delivering different drugs to these locations, and subsequently maintaining sustained release of drugs. PMID- 26639346 TI - Ontogeny of the maxilla in Neanderthals and their ancestors. AB - Neanderthals had large and projecting (prognathic) faces similar to those of their putative ancestors from Sima de los Huesos (SH) and different from the retracted modern human face. When such differences arose during development and the morphogenetic modifications involved are unknown. We show that maxillary growth remodelling (bone formation and resorption) of the Devil's Tower (Gibraltar 2) and La Quina 18 Neanderthals and four SH hominins, all sub-adults, show extensive bone deposition, whereas in modern humans extensive osteoclastic bone resorption is found in the same regions. This morphogenetic difference is evident by ~5 years of age. Modern human faces are distinct from those of the Neanderthal and SH fossils in part because their postnatal growth processes differ markedly. The growth remodelling identified in these fossil hominins is shared with Australopithecus and early Homo but not with modern humans suggesting that the modern human face is developmentally derived. PMID- 26639347 TI - Absolute measurement of the 1S0 - 3P0 clock transition in neutral 88Sr over the 330 km-long stabilized fibre optic link. AB - We report a stability below 7 * 10(-17) of two independent optical lattice clocks operating with bosonic (88)Sr isotope. The value (429 228 066 418 008.3(1.9)(syst) (0.9)(stat) Hz) of the absolute frequency of the (1)S(0) - (3)P(0) transition was measured with an optical frequency comb referenced to the local representation of the UTC by the 330 km-long stabilized fibre optical link. The result was verified by series of measurements on two independent optical lattice clocks and agrees with recommendation of Bureau International des Poids et Mesures. PMID- 26639348 TI - Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia. AB - BACKGROUND: New treatments have improved outcomes for patients with relapsed chronic lymphocytic leukemia (CLL), but complete remissions remain uncommon. Venetoclax has a distinct mechanism of action; it targets BCL2, a protein central to the survival of CLL cells. METHODS: We conducted a phase 1 dose-escalation study of daily oral venetoclax in patients with relapsed or refractory CLL or small lymphocytic lymphoma (SLL) to assess safety, pharmacokinetic profile, and efficacy. In the dose-escalation phase, 56 patients received active treatment in one of eight dose groups that ranged from 150 to 1200 mg per day. In an expansion cohort, 60 additional patients were treated with a weekly stepwise ramp-up in doses as high as 400 mg per day. RESULTS: The majority of the study patients had received multiple previous treatments, and 89% had poor prognostic clinical or genetic features. Venetoclax was active at all dose levels. Clinical tumor lysis syndrome occurred in 3 of 56 patients in the dose-escalation cohort, with one death. After adjustments to the dose-escalation schedule, clinical tumor lysis syndrome did not occur in any of the 60 patients in the expansion cohort. Other toxic effects included mild diarrhea (in 52% of the patients), upper respiratory tract infection (in 48%), nausea (in 47%), and grade 3 or 4 neutropenia (in 41%). A maximum tolerated dose was not identified. Among the 116 patients who received venetoclax, 92 (79%) had a response. Response rates ranged from 71 to 79% among patients in subgroups with an adverse prognosis, including those with resistance to fludarabine, those with chromosome 17p deletions (deletion 17p CLL), and those with unmutated IGHV. Complete remissions occurred in 20% of the patients, including 5% who had no minimal residual disease on flow cytometry. The 15-month progression-free survival estimate for the 400-mg dose groups was 69%. CONCLUSIONS: Selective targeting of BCL2 with venetoclax had a manageable safety profile and induced substantial responses in patients with relapsed CLL or SLL, including those with poor prognostic features. (Funded by AbbVie and Genentech; ClinicalTrials.gov number, NCT01328626.). PMID- 26639349 TI - Heavy-resistance exercise-induced increases in jump performance are not explained by changes in neuromuscular function. AB - Post-activation potentiation (PAP) is the increased involuntary muscle twitch response to stimulation following strong contraction. The enhancement to whole body explosive muscular performance (PE) after heavy-resistance exercise is often attributed to modulations in neuromuscular function that are proposed to reflect PAP, but the evidence to support this is equivocal. We assessed the neuromuscular basis of PE using transcranial magnetic stimulation (TMS) of the primary motor cortex, and electrical stimulation of the femoral nerve. Eleven male athletes performed heavy-resistance exercise with measures of countermovement jump (CMJ) pre- and 8 min post-exercise. Pre-exercise and after the final CMJ, single- and paired-pulse TMS were delivered during submaximal isometric knee-extensor contractions to measure corticospinal excitability, short-interval intracortical inhibition (SICI), and intracortical facilitation (ICF), with motor evoked potentials recorded from rectus femoris. Twitch responses to motor nerve stimulation during and post maximum-knee-extensor contractions were studied to quantify voluntary activation (VA) and potentiated twitch (Qtw,pot ). The experimental protocol successfully induced PE (+4 +/- 1% change in CMJ, P = 0.01), but no changes were observed for maximum voluntary force, VA, corticospinal excitability, SICI or ICF (all P > 0.05), and Qtw,pot declined (P < 0.001). An enhancement of muscular performance after heavy-resistance exercise was not accompanied by PAP, or changes in measures of neuromuscular function. PMID- 26639350 TI - Egg storage duration and hatch window affect gene expression of nutrient transporters and intestine morphological parameters of early hatched broiler chicks. AB - In recent years, researchers have given emphasis on the differences in physiological parameters between early and late hatched chicks within a hatch window. Considering the importance of intestine development in newly hatched chicks, however, changes in gene expression of nutrient transporters in the jejunum of early hatched chicks within a hatch window have not been studied yet. This study was conducted to determine the effects of egg storage duration before incubation and hatch window on intestinal development and expression of PepT1 (H+ dependent peptide transporter) and SGLT1 (sodium-glucose co-transporter) genes in the jejunum of early hatched broiler chicks within a 30 h of hatch window. A total of 1218 eggs obtained from 38-week-old Ross 308 broiler breeder flocks were stored for 3 (ES3) or 14 days (ES14) and incubated at the same conditions. Eggs were checked between 475 and 480 h of incubation and 40 chicks from each egg storage duration were weighed; chick length and rectal temperature were measured. The chicks were sampled to evaluate morphological parameters and PepT1 and SGLT1 expression. The remaining chicks that hatched between 475 and 480 h were placed back in the incubator and the same measurements were conducted with those chicks at the end of hatch window at 510 h of incubation. Chick length, chick dry matter content, rectal temperature and weight of small intestine segments increased, whereas chick weight decreased during the hatch window. The increase in the jejunum length and villus width and area during the hatch window were higher for ES3 than ES14 chicks. PepT1 expression was higher for ES3 chicks compared with ES14. There was a 10.2 and 17.6-fold increase in PepT1 and SGLT1 expression of ES3 chicks at the end of hatch window, whereas it was only 2.3 and 3.3-fold, respectively, for ES14 chicks. These results suggested that egg storage duration affected development of early hatched chicks during 30 h of hatch window. It can be concluded that the ES14 chicks would be less efficiently adapted to absorption process for carbohydrates and protein than those from ES3 at the end of the hatch window. PMID- 26639351 TI - Dynamic Covalent Assembly of Peptoid-Based Ladder Oligomers by Vernier Templating. AB - Dynamic covalent chemistry, in conjunction with template-directed assembly, enables the fabrication of extended nanostructures that are both precise and tough. Here we demonstrate the dynamic covalent assembly of peptoid-based molecular ladders with up to 12 rungs via scandium(III)-catalyzed imine metathesis by employing the principle of Vernier templating, where small precursor units with mismatched numbers of complementary functional groups are coreacted to yield larger structures with sizes determined by the respective precursor functionalities. Owing to their monomer diversity and synthetic accessibility, sequence-specific oligopeptoids bearing dynamic covalent pendant groups were employed as precursors for molecular ladder fabrication. The generated structures were characterized using matrix-assisted laser desorption/ionization mass spectrometry and gel permeation chromatography, confirming successful molecular ladder fabrication. PMID- 26639353 TI - Molecular Assembly of Clostridium botulinum progenitor M complex of type E. AB - Clostridium botulinum neurotoxin (BoNT) is released as a progenitor complex, in association with a non-toxic-non-hemagglutinin protein (NTNH) and other associated proteins. We have determined the crystal structure of M type Progenitor complex of botulinum neurotoxin E [PTC-E(M)], a heterodimer of BoNT and NTNH. The crystal structure reveals that the complex exists as a tight, interlocked heterodimer of BoNT and NTNH. The crystal structure explains the mechanism of molecular assembly of the complex and reveals several acidic clusters at the interface responsible for association at low acidic pH and disassociation at basic/neutral pH. The similarity of the general architecture between the PTC-E(M) and the previously determined PTC-A(M) strongly suggests that the progenitor M complexes of all botulinum serotypes may have similar molecular arrangement, although the neurotoxins apparently can take very different conformation when they are released from the M complex. PMID- 26639352 TI - Acute effect of mineralocorticoid receptor antagonism on vascular function in healthy older adults. AB - Mineralocorticoid receptor (MR) activation by aldosterone may regulate vascular function in health or contribute to vascular dysfunction in cardiovascular disease. Whether the effects are beneficial or detrimental to vascular function appear to be dependent on the integrity of the vascular endothelium and whether the responses are short-term or chronic. Acute modulation of MR activation has resulted in conflicting outcomes on vascular function in young healthy adults. Little is known about the vascular role of aldosterone and MR activation in healthy human aging. The primary objective of this study was to examine whether acute inhibition of MR by the selective antagonist eplerenone, influences vascular function in healthy older adults. We performed a randomized, double blind, placebo-controlled crossover study in 22 adults (61+/-1 years; mean+/-SE, 53-79 years) who were free from overt clinical cardiovascular disease. We measured brachial artery flow-mediated endothelium-dependent dilation and endothelium-independent dilation to sublingual nitroglycerin (0.4 mg) following eplerenone (100 mg/dose, 2 doses, 24h between doses) or placebo. In response to acute MR antagonism, flow-mediated dilation decreased by 19% (from 6.9+/-0.5 to 5.6+/-0.6%, P=0.02; placebo vs. eplerenone). Endothelial nitric oxide synthase (eNOS) activity also decreased following MR antagonism based on the ratio of phosphorylated eNOS(Ser1177) to total eNOS (1.53+/-0.08 vs. 1.29+/-0.06, P=0.02). Nitroglycerin-induced dilation and blood pressure were unaffected (nitroglycerin induced dilation: 21.9+/-1.9 vs. 21.0+/-1.5%, P=0.5 and systolic/diastolic blood pressure: 135/77+/-4/2 vs. 134/77+/-4/2 mmHg, P>=0.6). In conclusion, acute MR antagonism impairs vascular endothelial function in healthy older adults without influencing vascular smooth muscle responsiveness to exogenous nitric oxide or blood pressure. PMID- 26639354 TI - Autoantibodies against beta1-adrenoceptor induce blood glucose enhancement and insulin insufficient via T lymphocytes. AB - Diabetes mellitus is a chronic metabolic disorder with a high morbidity and mortality, but its pathogenesis is not fully understood. An increasing amount of evidence indicates that an immune mechanism plays an important role in the pathogenesis of diabetes. We demonstrated previously that the long-term presence of autoantibodies against the second extracellular loop of the beta1-adrenoceptor (beta1-AA) could change the ratio of peripheral CD4+T/CD8+T in rats, which was accompanied by lymphocytes infiltration in the rat heart, liver, and kidneys. To investigate whether beta1-AA is involved in the pathogenesis of diabetes, BALB/c or nude mice were passively immunized with monoclonal antibodies against beta1-AR (beta1-AR mAb). Compared with vehicle control mice, beta1-AA-positive BALB/c mice exhibited significantly increased blood glucose (P < 0.01) and increased fasting insulin (P < 0.05). However, the same changes did not occur in the nude mice. And altered islet morphology was found at week 28 in beta1-AA immunization group compared with vehicle control. The basal insulin level of NIT-1 beta-cells was decreased markedly (P < 0.01), and the lactate dehydrogenase level was increased (P < 0.01) after the administration of conditioned media from T lymphocytes that had been treated with beta1-AA alone. However, these effects were reversed by treatment with metoprolol or peptides of the second extracellular loop of beta1 adrenoceptor (beta1-AR-ECII). These results suggest that beta1-AA could induce hyperglycemia in both rats and mice, and also impair insulin secretion and change islet structure. T lymphocytes may play a key role in the pathogenesis of these changes in the islets. PMID- 26639355 TI - CD28-mediated T cell response is upregulated by exogenous application of autologous Hsp70-peptide complex in a tumor-bearing host. AB - Hsp70, a highly conserved protein, has gained plenty of attention by virtue of its adjuvant capability to induce peptide-specific cytotoxic T lymphocyte responses. In this study, we have investigated the effect of autologous Hsp70 peptide complex (or simply autologous Hsp70) on the expression of CD28 on T cells and its effector functions through macrophage activation. Further, we investigated the effect of Hsp70 on the expression of CD80 and CD86 on macrophages isolated from normal and tumor-bearing host to provide costimulatory signal for T cell activation and secretion of IL-2 and IFN-gamma during interaction. We found that treatment of autologous Hsp70 effectively activated TAMs to induce higher expression of CD28 on T cells through T cells-macrophage interaction. Treatment of autologous Hsp70 induces higher expression of CD80 and CD86 on TAMs, as a result, increases B7/CD28 interaction, which in turns activates T cells and induces higher production of IL-2 and IFN-gamma, thereby increasing antigen-specific T cell proliferation. With our novel study, we have provided the strong insights into the role of extracellular Hsp70 on the expression of CD28 costimulatory molecule on T cells, which helps in the activation and generation of antigen-specific T cell effector functions in a tumor-bearing host to curb malignancy. PMID- 26639356 TI - Mechanisms of diabetic autoimmunity: I--the inductive interface between islets and the immune system at onset of inflammation. AB - The mechanisms of autoimmune reactivity onset in type 1 diabetes (T1D) remain elusive despite extensive experimentation and discussion. We reconsider several key aspects of the early stages of autoimmunity at four levels: islets, pancreatic lymph nodes, thymic function and peripheral immune homeostasis. Antigen presentation is the islets and has the capacity to provoke immune sensitization, either in the process of physiological neonatal beta cell apoptosis or as a consequence of cytolytic activity of self-reactive thymocytes that escaped negative regulation. Diabetogenic effectors are efficiently expanded in both the islets and the lymph nodes under conditions of empty lymphoid niches during a period of time coinciding with a synchronized wave of beta cell apoptosis surrounding weaning. A major drive of effector cell activation and expansion is inherent peripheral lymphopenia characteristic of neonates, though it remains unclear when is autoimmunity triggered in subjects displaying hyperglycemia in late adolescence. Our analysis suggests that T1D evolves through coordinated activity of multiple physiological mechanisms of stimulation within specific characteristics of the neonate immune system. PMID- 26639358 TI - Hemodynamics of the renal artery ostia with implications for their structural development and efficiency of flow. AB - BACKGROUND: Energy losses at tube or blood vessel orifices depend on the extent of flare as measured by the dimensionless ratio of the fillet radius of curvature to diameter (r/D). OBJECTIVE: The goal of this study was to assess the effect of ostial fillet radii on energy losses at the aorta-renal artery junctions since as much as a quarter of cardiac output passes through the kidneys. METHOD: Pressure loss coefficients K for the renal artery ostia as a function of r/D have been determined for representative anatomical variants using finite volume simulations. Estimates of fillet radii in humans from image analysis were employed in simulations for comparison of loss coefficients. RESULTS: Values for K drop 45% as r/D increases over the range 0-1.3. Image analysis indicates that the ostia are not symmetric in humans with (r/D)superior much larger than (r/D)inferior. Simulations show the loss coefficient depends almost entirely on the superior fillet radius. CONCLUSIONS: Superior fillet radii for both renal arteries are similar to the optimal value to reduce energy losses while the inferior radii are not. Ostial asymmetry may have been induced by higher levels of shear stress present on the superior portion of a developing symmetric ostium of small r/D. PMID- 26639357 TI - Atrial natriuretic peptide down-regulates neutrophil recruitment on inflamed endothelium by reducing cell deformability and resistance to detachment force. AB - BACKGROUND: Recombinant atrial natriuretic peptide (ANP) is administered in patients with acute heart failure in Japan to improve renal function and hemodynamics, but its anti-inflammatory effect on activated leukocytes may also contribute to its therapeutic efficacy. OBJECTIVE: Examine unconventional role of ANP in neutrophil adhesion to inflamed endothelium. METHODS: Human neutrophils were perfused over endothelial monolayers in a microfluidic lab-chip assay. Cell rheology was assessed by micropipette aspiration to assess changes in cortical tension and viscosity. Fluorescence microscopy was applied to measure adhesive contact area and beta2-integrin focal bond formation. RESULTS: ANP inhibited neutrophil rolling and firm adhesion without influencing the upregulation of cellular adhesion molecules on endothelium or the regulation of high affinity CD18 and shedding of L-selectin during neutrophil activation. Exposed to fluid shear, integrin mediated arrest was disrupted with ANP treatment, which elicited formation of long tethers and diminished cell spreading and contact. This correlated with a ~40% increase in neutrophil viscosity and a reduction in the adhesive footprint. CONCLUSIONS: A decrease in cell deformation and neutrophil flattening with ANP results in fewer integrin bond clusters, which translates to higher tensile forces and impaired adhesion strengthening and cell detachment. PMID- 26639360 TI - Preface. PMID- 26639359 TI - Using cell monolayer rheology to probe average single cell mechanical properties. AB - The cell monolayer rheology technique consists of a commercial rotational rheometer that probes the mechanical properties of a monolayer of isolated cells. So far we have described properties of an entire monolayer. In this short communication, we show that we can deduce average single cell properties. Results are in very good agreement with earlier work on single cell mechanics. Our approach provides a mean of 105-106 adherent cells within a single experiment. This makes the results very reproducible. We extend our work on cell adhesion strength and deduce cell adhesion forces of fibroblast cells on fibronectin coated glass substrates. PMID- 26639361 TI - Laudatio for Harry Goldsmith. PMID- 26639362 TI - Laudatio for Harry Goldsmith. PMID- 26639363 TI - Daily alcohol use as an independent risk factor for HIV seroconversion among people who inject drugs. AB - AIMS: To estimate the relationship between daily alcohol use and HIV seroconversion among people who inject drugs (PWID) in a Canadian setting. DESIGN AND SETTING: Data from an open prospective cohort study of PWID in Vancouver, Canada, recruited via snowball sampling and street outreach between May 1996 and November 2013. An interviewer-administered questionnaire including standardized behavioural assessment and HIV antibody testing were conducted semi-annually. Baseline HIV-seronegative participants completing >= 1 follow-up visits were eligible for the present analysis. PARTICIPANTS: A total of 1683 eligible participants, were followed for a median of 79.8 [interquartile range (IQR) = 33.3-119.1] months. MEASUREMENTS: The primary end-point was time to HIV seroconversion, with the date of HIV seroconversion estimated as the mid-point between the last negative and the first positive antibody test results. The primary explanatory variable was self-reported daily alcohol use in the previous 6 months assessed semiannually. Other covariates considered included demographic, behavioural, social/structural and environmental risk factors for HIV infection among PWID (e.g. daily cocaine injection, methadone use, etc.). FINDINGS: Of 1683 PWID, there were 176 HIV seroconversions during follow-up with an incidence density of 1.5 [95% confidence interval (CI) = 1.3-1.7] cases per 100 person years. At baseline, 339 (20.1%) consumed alcohol at least daily in the previous 6 months. In multivariable extended Cox regression analyses, daily alcohol use remained associated independently with HIV seroconversion (adjusted hazard ratio: 1.48; 95% CI = 1.00-2.17). CONCLUSIONS: Daily alcohol use appears to be an independent risk factor for HIV seroconversion among our cohort of PWID. PMID- 26639365 TI - [Not Available]. PMID- 26639364 TI - Production and application of polyclonal and monoclonal antibodies against Spiroplasma eriocheiris. AB - A new species of spiroplasma, Spiroplasma eriocheiris (S. eriocheiris), was identified as a lethal pathogen of tremor disease (TD) in Chinese mitten crab recently. In order to acquire appropriate biological and diagnostic tools for characterizing this newly discovered pathogen, 5 monoclonal antibodies (mAbs) and a polyclonal antibody (pAb) against S. eriocheiris were produced. Among the mAbs, 6F5, 7C8 and 12H5 lead to the deformation of S. eriocheiris. A peptide sequence, YMRDMQSGLPRY was identified as a mimic motif of MreB that is the cell shape determining protein of S. eriocheiris interacting with 3 mAbs. Furthermore, a double antibody sandwich enzyme-linked immunosorbent assay (DAS-ELISA) for detection of S. eriocheiris was established using the mAb and pAb we prepared. It detected as low as 0.1 MUg/mL of S. eriocheiris. No cross-reaction was observed with three other common bacteria (Pseudomonas aeruginosa, Escherichia coli, and Bacillus subtilis) and the hemolymph samples of healthy Eriocheir sinensis. Collectively, our results indicated that the mAbs and pAb we prepared could be used in the analysis of S. eriocheiris membrane proteins mimotope and development of a diagnostic kit for S. eriocheiris infections. PMID- 26639366 TI - Is early antiretroviral therapy initiation useful in HIV(+) adults without co infections? AB - HIV infection is a worldwide epidemic. Antiretroviral therapy has dramatically changed the outcome of the disease but there is still controversy about the best time to initiate it, especially in patients with CD4 counts over 350 cells/uL. Searching in Epistemonikos database, which is maintained by screening 30 databases, we identified two systematic reviews including four pertinent randomized controlled trials overall. We concluded early initiation of antiretroviral therapy probably reduces mortality, risk of opportunistic infections and tuberculosis, but increases the risk of important adverse effects. PMID- 26639367 TI - Properties of Apolar Solutes in Alkyl Imidazolium-Based Ionic Liquids: The Importance of Local Interactions. AB - The solvation and the dynamic properties of apolar model solutes in alkyl imidazolium-based ionic liquids (IL) are studied by using all-atom molecular dynamics simulations. In regards to specific IL effects, we focused on the often used 1-ethyl-3-methyl imidazolium cation in combination with the anions tetrafluoroborate, acetate, and bis(trifluoromethanesulfonyl)imide. Our findings reveal that the size of the anion crucially influences the accumulation behavior of the cations, which results in modified IL solvation properties. Deviations between the different alkyl imidazolium-based IL combinations can be also observed with regard to the results for the radial distribution functions, the number of surrounding molecules, and the molecular orientation. The analysis of the van Hove function further shows pronounced differences in the dynamic behavior of the solutes. The simulations verify that the solute mobilities are mainly influenced by the composition of the local solvent shell and the properties of the underlying Lennard-Jones interactions. Additional simulations with regard to modified short-range dispersion energies for alkyl imidazolium based ILs validate our conclusions. PMID- 26639368 TI - Evolutionary conserved brainstem circuits encode category, concentration and mixtures of taste. AB - Evolutionary conserved brainstem circuits are the first relay for gustatory information in the vertebrate brain. While the brainstem circuits act as our life support system and they mediate vital taste related behaviors, the principles of gustatory computations in these circuits are poorly understood. By a combination of two-photon calcium imaging and quantitative animal behavior in juvenile zebrafish, we showed that taste categories are represented by dissimilar brainstem responses and generate different behaviors. We also showed that the concentration of sour and bitter tastes are encoded by different principles and with different levels of sensitivity. Moreover, we observed that the taste mixtures lead to synergistic and suppressive interactions. Our results suggest that these interactions in early brainstem circuits can result in non-linear computations, such as dynamic gain modulation and discrete representation of taste mixtures, which can be utilized for detecting food items at broad range of concentrations of tastes and rejecting inedible substances. PMID- 26639373 TI - New Mexico Community Health Councils: Documenting Contributions to Systems Changes. AB - CONTEXT: Coalition research has shifted from delineating structures and processes to identifying intermediate, systems changes (e.g., changes in policies) that contribute to longterm community health improvement. OBJECTIVE: The University of New Mexico, the New Mexico Department of Health, and community health councils entered a multiyear participatory evaluation process to answer: What actions did health councils take that led to improving health through intermediate, systems changes? DESIGN: The evaluation system was created over several phases through an iterative, participatory process. Data were collected for councils' health priority areas (e.g., substance abuse) from 2009 to 2011. PARTICIPANTS: Twenty three community health councils participated. MAIN OUTCOME MEASURES: Intermediate systems changes were measured: 1) networking and partnering, 2) joint planning of strategies, programs, and services, 3) leveraging resources, and 4) policy initiatives. RESULTS: Health councils reported data for each intermediate outcome by health priority area. Data showed councils identified local public health priorities and addressed those priorities through strengthening networks and partnerships, which lead to the creation and enhancement of strategies, services, and programs. Data also showed councils influenced policies in several ways (e.g., developing policy, identifying new policy, or sponsoring informational forums). Additionally, data showed councils leveraged $1.10 for every dollar invested by the state. When funding was suspended in July 2010, data showed dramatic decreases in activity levels from 2010 to 2011. CONCLUSIONS: The data demonstrate the feasibility and utility of an Internet-based system designed to gather intermediate systems changes evaluation data. This process is a model for similar efforts to capture common outcomes across diverse coalitions and partnerships. PMID- 26639369 TI - The Effects of Workplace Clean Indoor Air Law Coverage on Workers' Smoking Related Outcomes. AB - This study investigated the effects of workplace clean indoor air law (CIAL) coverage on worksite compliance with CIALs, smoking participation among indoor workers, and secondhand smoke (SHS) exposure among nonsmoker indoor workers. This study improved on previous research by using the probability of a resident in a county covered by workplace CIALs, taking into account the state, county, and city legislation. The county-level probability of being covered by a CIAL is merged into two large nationally representative US surveys on smoking behaviors: Tobacco Use Supplement of the Current Population Survey (2001-2010) and Behavioral Risk Factor Surveillance System (2000-2006) based on the year of the survey and respondent's geographic location to identify respondents' CIAL coverage. This study estimated several model specifications of including and not including state or county fixed effects, and the effects of workplace CIALs are consistent across models. Increased coverage by workplace CIALs significantly increased likelihood of reporting a complete smoking restriction by 8% and 10% for the two different datasets, decreased smoking participation among indoor workers by 12%, and decreased SHS exposure among nonsmokers by 28%. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26639374 TI - Differential Role of Social Connectedness in Geriatric Depression Among Southeast Asian Ethnic Groups. AB - BACKGROUND: There is little empirical evidence on the effects of social connectedness on geriatric depression for Southeast Asians. Studies have rarely examined interethnic differences in the resilience factors for depression in this diverse population. Greater understanding is needed as the number of older Southeast Asians in the United States increases. OBJECTIVES: We sought to examine the association between social connectedness and depressive symptoms in Vietnamese, Laotian, and Cambodian elders. METHODS: Using a community-based participatory research (CBPR) approach, bilingual/bicultural staff collected demographics, the Lubben Social Network Scale, and the Geriatric Depression Scale (GDS). Univariate and multivariate regression models were constructed for the full aggregated sample and for each ethnic subgroup. RESULTS: In the full aggregated sample analysis, Southeast Asian elders were at increased risk for depression and had low social connectedness. Marriage and English proficiency were resilience factors, whereas social connectedness did not play a significant role. In disaggregated analyses, high social connectedness, marriage, and younger age were resilience factors for Vietnamese elders. English proficiency was the only significant resilience factor for Laotians, and age at the time of immigration was the only significant resilience factor for Cambodian elders. CONCLUSIONS: This study underscores the need for researchers to disaggregate data for ethnic subgroups in the Asian American population. Southeast Asian elders are at increased risk for depression and have low social connectedness. There exist important interethnic differences in resilience factors for geriatric depression, suggesting the need for more studies and interventions that are sensitive to subtle cultural differences among Southeast Asian subgroups. PMID- 26639376 TI - ASHA: Using Participatory Methods to Develop an Asset-building Mental Health Intervention for Bangladeshi Immigrant Women. AB - BACKGROUND: Common mental disorder (CMD) is highly prevalent among low-income immigrant women, yet few receive effective treatment. This underutilization is partly owing to a lack of conceptual synchrony between biopsychiatric theories underlying conventional mental treatments and explanatory models in community settings. The Action to Improve Self-esteem and Health through Asset building (ASHA) program is a depression intervention designed by and for South Asian women immigrants. ASHA helps women to build psychological, social, and financial assets. OBJECTIVES: This paper describes the development and a preliminary pilot evaluation of the ASHA intervention. METHODS: Researchers, clinicians, activists, and women from the Bronx Bangladeshi community collaboratively designed a depression intervention that would synchronize with local concepts of distress. In addition to providing mental health treatment, ASHA addresses social isolation and financial dependence. ASHA was evaluated in a pilot study described in this paper. Participants were assigned to intervention or delayed intervention (control) groups. Data collection at baseline and time 2 (6 months) included the Patient Health Questionnaire-9 (PHQ-9) and an indigenous measure of psychological and somatic distress. RESULTS: Eighty percent of intervention participants completed the 6-month program. After treatment, mean PHQ-9 scores in the intervention group decreased from 9.90 to 4.26 (p < .001). Participants saved an average of $10 per week. To date, participants have applied their skills and savings toward such activities as starting small businesses and enrolling in community college. CONCLUSIONS: ASHA was effective in improving depression and increasing financial independence. Using a culturally synchronous approach to psychological treatment may be effective in ameliorating distress in immigrant populations. PMID- 26639377 TI - Applying Cognitive Interviewing to Inform Measurement of Partnership Readiness: A New Approach to Strengthening Community-Academic Research. AB - BACKGROUND: Partnerships between academic and community-based organizations (CBOs) can richly inform the research process and speed translation of findings. Although immense potential exists to co-conduct research, a better understanding of how to create and sustain equitable relationships between entities with different organizational goals, structures, resources, and expectations is needed. OBJECTIVE: We sought to engage community leaders in the development of an instrument to assess CBOs' interest and capacity to engage with academia in translational research partnerships. METHODS: Leaders from CBOs partnered with our research team in the design of a 50-item instrument to assess organizational experience with applying for federal funding and conducting research studies. Respondents completed a self-administered, paper/pencil survey and a follow-up structured cognitive interview (n = 11). A community advisory board (CAB; n = 8) provided further feedback on the survey through guided discussion. Thematic analysis of the cognitive interviews and a summary of the CAB discussion informed survey revisions. RESULTS: Cognitive interviews and discussion with community leaders identified language and measurement issues for revision. Importantly, they also revealed an unconscious bias on the part of researchers and offered an opportunity, at an early research stage, to address imbalances in the survey perspective and to develop a more collaborative, equitable approach. CONCLUSIONS: Engaging community leaders enhanced face and content validity and served as a means to form relationships with potential community co-investigators in the future. Cognitive interviewing can enable a bidirectional approach to partnerships, starting with instrument development. PMID- 26639378 TI - Health Care Engagement of Limited English Proficient Latino Families: Lessons Learned from Advisory Board Development. AB - BACKGROUND: Specific information on the development and evaluation of patient/family engagement in health care improvement for populations with limited English proficiency (LEP) is lacking. OBJECTIVES: We sought to provide information for use by other health care organizations aiming to engage LEP populations through advisory groups. METHODS: Informed by community-based research principles, we formed a family advisory board of LEP Latino families and conducted a multimodal evaluation of initial implementation and partnership development. RESULTS: The board met process measures goals for sustained engagement of LEP families and for establishing a group structure and process. Board outcomes included contributions to clinic educational materials and initiation of a project to increase the child friendliness of the physical space. Mothers on the board reported satisfaction with their participation. CONCLUSIONS: We successfully sustained engagement of LEP Latino families in health care improvement using an advisory board. To promote patient-centered care and address health care disparities, LEP populations should be included in patient engagement programs. PMID- 26639379 TI - Improving Interactive Health Literacy Skills of Older Adults: Lessons Learned From Formative Organizational Research With Community Partners. AB - BACKGROUND: Meals on Wheels (MOW) organizations are ideal community partners for delivering social support relating to health information exchange for vulnerable and home-bound older adults. OBJECTIVES: This article illustrates how formative organizational evaluation can be used to adapt health literacy interventions delivered by community partners. METHODS: Key informant interviews and ethnographic observations were conducted as part of a formative organizational evaluation of potential community partners. LESSONS LEARNED: The observed brevity of volunteer-client interaction led program planners to incorporate substantial emphasis on communicating with older adults into the health literacy coach training curriculum. Ethnographic observations made clear that program materials had to be portable and fit it in with the mobile nature of MOW delivery. CONCLUSIONS: Formative organizational research can greatly increase the chance of successful implementation of public health interventions when those interventions will be implemented in partnerships with community-based organizations in diverse settings and with varying practices. PMID- 26639380 TI - A Participatory Model for Evaluating a Multilevel Farmers' Market Intervention. AB - BACKGROUND: Well-designed evaluation is necessary to document the impact of farmers' markets (FMs) on health, economic, and community outcomes. However, the complex nature of FMs poses challenges for evaluation. OBJECTIVE: Our goal is to describe a participatory, multilevel framework used to evaluate a FM implemented at a federally qualified health center (FQHC) in a rural community in the Southeastern United States. METHODS: An iterative, collaborative process involving three feedback loops was used to engage community stakeholders in the development, implementation, and utilization of the multilevel evaluation plan. LESSONS LEARNED: A participatory approach helped to navigate the complexities of evaluating FMs and promoted stakeholder engagement. The evaluation became a core element of the intervention that informed continuous quality improvement (CQI). The development of strong university- community partnerships facilitated the ongoing use of results. CONCLUSIONS: The evaluation framework presented may be used to promote community engagement and rigor for evaluation of future FMs. PMID- 26639381 TI - Measuring Community-Based Participatory Research Partnerships: The Initial Development of an Assessment Instrument. AB - BACKGROUND: Although the partnership between academic researchers and community members is paramount to community-based research efforts, a limited number of measures exist to evaluate this construct. Of those in existence, no assessment measures include a comprehensive coverage of the many dimensions of partnerships. In addition, these measures were not designed through an extensive community based participatory research (CBPR) model, in which the strengths of traditional assessment techniques were integrated with input from stakeholders. OBJECTIVES: The purpose of this article was to describe the creation of a measure to evaluate key dimensions of partnerships forged between researchers and community members using a CBPR approach to measurement development. METHODS: The iterative process of developing this measure consisted of integrating valuable feedback from community partners and researchers, via multiple rounds of item sorting and qualitative interviewing. RESULTS: The resultant measure, titled Partnership Assessment In community-based Research (PAIR), consists of 32 items, and comprises 5 dimensions: communication, collaboration, partnership values, benefits, and evaluation. The innovative process of using CBPR in the development of measures, the benefits of this approach, and the lessons learned are highlighted. CONCLUSIONS: PAIR was developed out of a need identified jointly by community members and researchers, and is intended to characterize the range of relationships between researchers and community members engaging in community based research and programming. PMID- 26639382 TI - "Hear(ing) New Voices": Peer Reflections from Community-Based Survey Development with Women Living with HIV. AB - BACKGROUND: The Canadian HIV Women's Sexual and Reproductive Health Cohort Study (CHIWOS) engaged in an innovative community-based survey development process. OBJECTIVES: We sought to provide 1) an overview of the survey development process, and 2) personal reflections from women living with human immunodeficiency virus (HIV; "peers") on their own observations of strengths and short-comings of the process and opportunities for improvement. METHODS: Guided by the principles of community-based research (CBR) and meaningful involvement of women living with HIV (WLWH), CHIWOS coordinated a national, multidisciplinary research team, and facilitated a community based survey development process. LESSONS LEARNED: Four key lessons emerged highlighting the importance of 1) accommodating different preferences for feedback collection, 2) finding the right combination of people and skills, 3) formalizing mentorship, and 4) creating guidelines on survey item reduction and managing expectations from the outset. CONCLUSIONS: Peers discussed the strengths and weaknesses of participatory methodologies in survey development. PMID- 26639383 TI - A Community-Engaged Approach to Translating Research into Practice: A Physical Education Story. AB - BACKGROUND: The National Institutes of Health's Clinical and Translational Sciences Award program emphasizes the need to speed up the process of putting evidence-based practices into place. One strategy they promote is community engagement; however, few studies describe a process for meaningfully engaging communities in the translation process. OBJECTIVE: This article describes steps taken by a university- community partnership to create a plan for implementing evidence-based physical education (PE) practices in rural schools. This partnership's efforts resulted in the acquisition of a $1.86 million grant to implement the plan. METHODS: Qualitative data collected during the planning process were analyzed using content analysis. RESULTS: Key steps included undertaking a baseline assessment of community needs, reviewing and selecting evidence-based practices, developing a multilevel, community-driven action plan and establishing its feasibility with community stakeholders. LESSONS LEARNED: These steps could be applied to other health topics across a variety of settings. Several strategies that made the process successful are described. Recommendations are made for expanding the roles of Clinical and Translational Science Awards (CTSAs) and local health foundations in supporting community engaged translational research. CONCLUSIONS: University-community partnerships have the potential to create plans and obtain large-scale funding for translating evidence-based research into practice. PMID- 26639384 TI - A Pilot Investigation to Enhance Behavioral Health Referral for Perinatal, Low Income Women With Mood Disorders. AB - BACKGROUND: Perinatal, low-income, ethnic minority women with mood disorders underutilize behavioral health treatment. A community-academic partnership was used to address behavioral health initiation among this population. OBJECTIVES: We sought to examine the feasibility, acceptability, and preliminary outcomes of a behavioral health referral intervention with low-income, ethnic minority perinatal women diagnosed with mood disorders. METHODS: An open trial pilot study was conducted with 38 perinatal women. The behavioral health referral intervention consisted of two sessions of manualized referral strategies to enhance access to care. The main outcome was attendance at a behavioral health appointment. RESULTS: Approximately 55% of the perinatal women attended a behavioral health appointment within 2 months (i.e., initiated treatment). Intervention participation rates and ratings were high. Depression scores decreased from baseline to after the intervention. CONCLUSIONS: The findings demonstrated favorable outcomes compared with other referral interventions. The behavioral health referral intervention shows promise for implementation in community settings. PMID- 26639385 TI - Electronic Health Records: Optimizing Communication to Support the Nonverbal Medical Patient With Developmental Disabilities. AB - BACKGROUND: A comprehensive look at health status in developmentally disabled populations shows poorer physical, oral, and vision health, and higher rates of heart disease and obesity. Generally, individuals with developmental disabilities have difficulty locating able providers, and face significant barriers in accessing health services. The health care system's failure to achieve effective collaboration between medical, mental health, and residential providers too often results in substandard care and poor outcomes for these populations. METHODS: A creative partnership between two organizations in rural upstate New York, Ulster Green ARC and the Institute for Family Health, has made substantial inroads toward addressing this problem. The organizations have transformed a relationship borne of a financially failing health care model into a successful, comprehensive care network for a severely developmentally disabled population-based in a Federally Qualified Health Center. CONCLUSIONS: The success of this effort is largely owing to an innovative use of health information technology to share information. PMID- 26639386 TI - Engaging Underrepresented Minorities in Research: Our Vision for a "Research Friendly Community". AB - This article introduces our "Research-Friendly Community" vision, placing research in the arena of social justice by giving citizens a voice and opportunity to actively determine research agendas in their community. The mission of Tri-County Rural Health Network, a minority-owned, community-based nonprofit serving 16 counties in Arkansas' Mississippi River Delta region, is to increase access to health-related services and opportunities to both participate in and shape research. Tri-County has built trust with the community through the use of Deliberative Democracy Forums, a model devised by the Kettering Foundation and through a community health worker program called Community Connectors. Over time, a partnership was formed with investigators at the University of Arkansas for Medical Sciences (UAMS). Tri-County serves as a boundary spanner to link community members, other community organizations, local politicians, policy maker, and researchers. We describe our experience for other nonprofits or universities who might want to develop a similar program. PMID- 26639387 TI - Concept Mapping as an Approach to Facilitate Participatory Intervention Building. AB - BACKGROUND: A challenge to addressing community-defined need through community based participatory intervention building is ensuring that all collaborators' opinions are represented. Concept mapping integrates perspectives of individuals with differing experiences, interests, or expertise into a common visually depicted framework, and ranks composite views on importance and feasibility. OBJECTIVES: To describe the use of concept mapping to facilitate participatory intervention building for a school-based, teacher-focused, positive youth development (PYD) promotion program for Latino, Hmong, and Somali youth. Particiants were teachers, administrators, youth, parents, youth workers, and community and university researchers on the projects' community collaborative board. We incorporated previously collected qualitative data into the process. METHODS: In a mixed-methods process we 1) generated statements based on key informant interview and focus group data from youth workers, teachers, parents, and youth in multiple languages regarding ways teachers promote PYD for Somali, Latino and Hmong youth; 2) guided participants to individually sort statements into meaningful groupings and rate them by importance and feasibility; 3) mapped the statements based on their relation to each other using multivariate statistical analyses to identify concepts, and as a group identified labels for each concept; and 4) used labels and statement ratings to identify feasible and important concepts as priorities for intervention development. RESULTS: We identified 12 concepts related to PYD promotion in schools and prioritized 8 for intervention development. CONCLUSIONS: Concept mapping facilitated participatory intervention building by formally representing all participants' opinions, generating visual representation of group thinking, and supporting priority setting. Use of prior qualitative work increased the diversity of viewpoints represented. PMID- 26639388 TI - Long-term evolution of acinar-to-ductal metaplasia and beta-cell mass after radiofrequency-assisted transection of the pancreas in a controlled large animal model. AB - BACKGROUND: Pancreatic duct ligation (PDL) has been used as a model of chronic pancreatitis and as a model to increase beta-cell mass. However, studies in mice have demonstrated acinar regeneration after PDL, questioning the long-term validity of the model. We aim to elucidate whether RF-assisted transection (RFAT) of the main pancreatic duct is a reliable PDL model, both in short (ST, 1-month) and long-term (LT, 6-months) follow-ups. METHODS: Eleven pigs were subjected to RFAT. Biochemical (serum/peripancreatic amylase and glucose) and histological changes (including a semiautomatic morphometric study of over 1000 images/pancreas and IHC analysis) were evaluated after ST or LT follow-up and also in fresh pancreas specimens that were used as controls for 1 (n = 4) and 6 months (n = 6). RESULTS: The distal pancreas in the ST was characterized by areas of acinar-to-ductal metaplasia (56%) which were significantly reduced at LT (21%) by fibrotic replacement and adipose tissue. The endocrine mass showed a normal increase. CONCLUSION: RFAT in the pig seems to be an appropriate PDL model without restoration of pancreatic drainage or reduction of endocrine mass. PMID- 26639391 TI - Profession's Identity Challenged by the Language it Uses. PMID- 26639390 TI - Stratifying primary Sjogren's syndrome: killers in the balance? AB - The article by Seror et al. in Arthritis Research & Therapy reports data from the 15 French patients in the open-label BELISS (Efficacy and Safety of Belimumab in Subjects With Primary Sjogren's Syndrome, NCT01160666) study of belimumab in primary Sjogren's syndrome. The study identifies that higher baseline levels of natural killer cells in the peripheral blood and salivary glands are associated with non-response to belimumab therapy. Although caution is required given the open-label nature of the trial, this study adds to data already suggesting a role for natural killer cells in primary Sjogren's syndrome and, importantly, indicates a need for therapeutic stratification. PMID- 26639389 TI - Light-induced pH changes in the intact retinae of normal and early diabetic rats. AB - Double-barreled H(+)-selective microelectrodes were used to measure local extracellular concentration of H(+) ([H(+)]o) in the retina of dark-adapted anesthetized Long-Evans rats. The microelectrode advanced in steps of 30 MUm throughout the retina from the vitreal surface to retinal pigment epithelium and then to the choroid, recording changes in [H(+)]o evoked by light stimulation. Recordings were performed in diabetic rats 1-3 months after intraperitoneal injection of streptozotocin and the results were compared with data obtained in age-matched control animals. Brief light stimulation (2.5 s) evoked changes of [H(+)]o with amplitudes of a few nM. Throughout the retina, there was a transient initial acidification for ~200 ms followed by steady alkalinization, although amplitudes and kinetics of these components were slightly variable in different retinal layers. No significant difference was found when the light-induced [H(+)]o changes recorded in various retinal layers of early diabetic rats were compared with the [H(+)]o changes from corresponding layers of control animals. Also, when H(+)-selective microelectrodes were located in the retinal pigment epithelium (RPE) layer, an increase in H(+) was recorded, whose time course and amplitude were similar in control and diabetic rats. However, a striking difference between light-induced [H(+)]o changes in controls and diabetics was observed in the choriocapillaris, in the thin layer (10-20 MUm) distal to the basal membrane of the RPE. In control rats, choroidal [H(+)]o decreased in a few cases, but much more often practically did not change. In contrast, diabetic rats demonstrated either an increase (in half of the cases) or no change in choroidal [H(+)]o. The data suggest that the active participation of the choroidal blood supply in stabilization of [H(+)]o could be partially compromised already at early stages of diabetes in rats. Interestingly, it appeared that the acid removal by the choroidal circulation was compromised most after 1 month of diabetes and tended to improve later. PMID- 26639392 TI - Gene therapy of Wilson disease: A "golden" opportunity using rAAV on the 50th anniversary of the discovery of the virus. PMID- 26639393 TI - Model-guided identification of a therapeutic strategy to reduce hyperammonemia in liver diseases. AB - BACKGROUND & AIMS: Recently, spatial-temporal/metabolic mathematical models have been established that allow the simulation of metabolic processes in tissues. We applied these models to decipher ammonia detoxification mechanisms in the liver. METHODS: An integrated metabolic-spatial-temporal model was used to generate hypotheses of ammonia metabolism. Predicted mechanisms were validated using time resolved analyses of nitrogen metabolism, activity analyses, immunostaining and gene expression after induction of liver damage in mice. Moreover, blood from the portal vein, liver vein and mixed venous blood was analyzed in a time dependent manner. RESULTS: Modeling revealed an underestimation of ammonia consumption after liver damage when only the currently established mechanisms of ammonia detoxification were simulated. By iterative cycles of modeling and experiments, the reductive amidation of alpha-ketoglutarate (alpha-KG) via glutamate dehydrogenase (GDH) was identified as the lacking component. GDH is released from damaged hepatocytes into the blood where it consumes ammonia to generate glutamate, thereby providing systemic protection against hyperammonemia. This mechanism was exploited therapeutically in a mouse model of hyperammonemia by injecting GDH together with optimized doses of cofactors. Intravenous injection of GDH (720 U/kg), alpha-KG (280 mg/kg) and NADPH (180 mg/kg) reduced the elevated blood ammonia concentrations (>200 MUM) to levels close to normal within only 15 min. CONCLUSION: If successfully translated to patients the GDH-based therapy might provide a less aggressive therapeutic alternative for patients with severe hyperammonemia. PMID- 26639394 TI - Uric acid regulates hepatic steatosis and insulin resistance through the NLRP3 inflammasome-dependent mechanism. AB - BACKGROUND & AIMS: Hyperuricemia significantly increases risk of non-alcoholic fatty liver disease (NAFLD) and insulin resistance. However, the mechanisms responsible for this association are as yet unclear. This study aimed to investigate the effects and underlying mechanisms of uric acid on development of NAFLD and insulin resistance. METHODS: We initially analyzed the impact of uric acid on the development of hepatic steatosis and insulin resistance in mice and in two cell models, HepG2 and L02. Subsequently, we studied the role of the NOD like receptor family pyrin domain containing 3 (NLRP3) inflammasome in uric acid induced fat accumulation and insulin signaling impairment. RESULTS: We found that uric acid directly induces hepatocyte fat accumulation, insulin resistance, and insulin signaling impairment both in vivo and in vitro. We also found that uric acid-induced NLRP3 inflammasome activation, whereas lowering uric acid by allopurinol inhibited NLRP3 inflammasome activation in a high fat diet mouse model of NAFLD. Moreover, knocking down NLRP3 expression significantly attenuated uric acid-induced fat accumulation both in HepG2 cells and L02 cells. Knocking down NLRP3 expression also rescued uric acid-induced insulin signaling impairment in both cell types. CONCLUSIONS: Uric acid regulates hepatic steatosis and insulin resistance through the NLRP3 inflammasome. Uric acid may be a new therapeutic target for NAFLD and insulin resistance. PMID- 26639395 TI - Decreased expression of the glucocorticoid receptor-GILZ pathway in Kupffer cells promotes liver inflammation in obese mice. AB - BACKGROUND & AIMS: Kupffer cells (KC) play a key role in the onset of inflammation in non-alcoholic steatohepatitis (NASH). The glucocorticoid receptor (GR) induces glucocorticoid-induced leucine zipper (GILZ) expression in monocytes/macrophages and is involved in several inflammatory processes. We hypothesized that the GR-GILZ axis in KC may contribute to the pathophysiology of obesity-induced liver inflammation. METHODS: By using a combination of primary cell culture, pharmacological experiments, mice deficient for the Gr specifically in macrophages and transgenic mice overexpressing Gilz in macrophages, we explored the involvement of the Gr-Gilz axis in KC in the pathophysiology of obesity-induced liver inflammation. RESULTS: Obesity was associated with a downregulation of the Gr and Gilz, and an impairment of Gilz induction by lipopolysaccharide (LPS) and dexamethasone (DEX) in KC. Inhibition of Gilz expression in isolated KC transfected with Gilz siRNA demonstrated that Gilz downregulation was sufficient to sensitize KC to LPS. Conversely, liver inflammation was decreased in obese transgenic mice specifically overexpressing Gilz in macrophages. Pharmacological inhibition of the Gr showed that impairment of Gilz induction in KC by LPS and DEX in obesity was driven by a downregulation of the Gr. In mice specifically deficient for Gr in macrophages, Gilz expression was low, leading to an exacerbation of obesity-induced liver inflammation. CONCLUSIONS: Obesity is associated with a downregulation of the Gr-Gilz axis in KC, which promotes liver inflammation. The Gr-Gilz axis in KC is an important target for the regulation of liver inflammation in obesity. PMID- 26639396 TI - Macrophage activation markers predict mortality in patients with liver cirrhosis without or with acute-on-chronic liver failure (ACLF). AB - BACKGROUND & AIMS: Activation of liver macrophages plays a key role in liver and systemic inflammation and may be involved in development and prognosis of acute on-chronic liver failure (ACLF). We therefore measured the circulating macrophage activation markers soluble sCD163 and mannose receptor (sMR) and related them to the short-(1-3 months) and long-term (6 months) mortality in the cirrhosis patients of the CANONIC study. METHODS: Eighty-six cirrhosis patients had no ascites and no ACLF, 580 had ascites but no ACLF; 100, 66, and 19 had ACLF-grade I (ACLF-I), ACLF-II, and ACLF-III, respectively. The patients' clinical course was registered and their MELD, CLIF-C Acute Decompensation (AD), and CLIF-C ACLF scores computed at inclusion. RESULTS: We found a stepwise increase (p<0.001) in median sCD163 (5.68 (IQR: 3.86-9.60); 8.26 (5.02-12.34); 9.50 (5.37-17.91); 15.68 (10.12-19.42); 20.18 (15.26-32.20) mg/L) and sMR (0.60 (0.40-0.84); 0.81 (0.57 1.12); 0.81 (0.61-1.26); 1.17 (0.89-1.62); 1.41 (1.14-1.79)mg/L) with increasing grades of ACLF. Both sCD163 and sMR were independently associated with short and long-term mortality and showed equal or higher predictive accuracy than MELD, CLIF-C ACLF and CLIF-C AD scores. Addition of the macrophage markers to the clinical scores improved the prognostic efficacy: In ACLF patients sCD163 improved prediction of short-term mortality (C-index: 0.74 (0.67-0.80)) and in patients without ACLF sMR improved prediction of long-term mortality (C-index: 0.80 (0.76-0.85)). CONCLUSIONS: The severity related increase in sCD163 and sMR and close association with mortality suggest a primary importance of inflammatory activation of liver macrophages in the emergence and course of ACLF. Accordingly, supplementation of the macrophage biomarkers to the platform of the clinical scores improved the prognostic performance beyond that of the original scores. PMID- 26639397 TI - Monocytes promote liver carcinogenesis in an oncogene-specific manner. AB - BACKGROUND & AIMS: The leukocyte composition of tumors is heterogeneous, as is the involvement of each leukocyte subset in promoting or restraining tumorigenesis. This heterogeneity reflects the tissue of origin, tumor stage, and the functional state of leukocyte activation, but its biological roots remain poorly understood. Since tumorigenesis is driven by various genetic events, we assessed the role of driver genes in shaping the profiles and the roles of leukocytes in tumorigenesis. METHODS: Mouse liver tumors were induced by hepatic overexpression of either MYC or the combination of myristoylated AKT and NRAS(V12) oncogenes via hydrodynamic transfection. A comparative, flow cytometry- and histology-based immunophenotyping of liver-infiltrating leukocytes was performed at various stages of liver tumorigenesis. The roles of the most abundant leukocyte subsets in tumorigenesis were addressed by immunodepletion. The contribution of liver injury was assessed by comparing the injury-inducing hydrodynamic transfection model to a model in which MYC is an inducible transgene. RESULTS: Myristoylated AKT and NRAS(V12) promoted a marked recruitment of CD11b(+)Ly6G(hi)Ly6C(int) neutrophils and CD11b(+)Ly6G(-)Ly6C(hi) monocytes to the liver, but their immunodepletion did not alter tumorigenesis. In contrast, despite minimal invasion by monocytes/neutrophils during MYC-driven tumorigenesis, immunodepletion of these cells reduced MYC tumor burden and extended survival. MYC-driven tumor initiation was augmented specifically by Ly6C+ monocytes and their ability to promote liver injury. CONCLUSIONS: Our results demonstrate that leukocyte profiles do not necessarily predict their involvement in tumorigenesis, the functional role of leukocytes can be shaped by oncogenes, and that monocyte-dependent tissue injury selectively cooperates with MYC during tumorigenesis. PMID- 26639398 TI - Overexpression of Sirtuin 6 suppresses cellular senescence and NF-kappaB mediated inflammatory responses in osteoarthritis development. AB - The aim of our study was to evaluate if Sirt6, a NAD + dependent histone deacetylase, plays a protective role in cartilage degeneration by suppressing cellular senescence and inflammatory responses. The expression level of sirt6 in normal and OA human knee articular cartilage was compared by immunofluorescence and western blotting. The effect of sirt6 overexpression on replicative senescence of chondrocytes and NF-kappaB target genes expression was evaluated. Histological assessment of OA mice knee joint was carried out to assess the in vivo effects of sirt6 overexpression on mice chondrocytes. We found sirt6 level was significantly decreased in the articular chondrocytes of OA patients compare to normal human. SA-beta-gal staining revealed that overexpression of sirt6 suppressed replicative senescence of chondrocytes. Meanwhile, the expression of NF-kappaB dependent genes were significantly attenuated by sirt6 overxpression. Safranin-O staining and OARSI score of knee joint cartilage in OA mice revealed that Lenti-Sirt6 intraarticular injection could protect mice chondrocytes from degeneration. These data strongly suggest that overexpression of Sirt6 can prevent OA development by reducing both the inflammatory response and chondrocytes senescence. Therefore, the development of specific activators of Sirt6 may have therapeutic potential for the treatment of OA. PMID- 26639399 TI - Self-directed exploration provides a Ncs1-dependent learning bonus. AB - Understanding the mechanisms of memory formation is fundamental to establishing optimal educational practices and restoring cognitive function in brain disease. Here, we show for the first time in a non-primate species, that spatial learning receives a special bonus from self-directed exploration. In contrast, when exploration is escape-oriented, or when the full repertoire of exploratory behaviors is reduced, no learning bonus occurs. These findings permitted the first molecular and cellular examinations into the coupling of exploration to learning. We found elevated expression of neuronal calcium sensor 1 (Ncs1) and dopamine type-2 receptors upon self-directed exploration, in concert with increased neuronal activity in the hippocampal dentate gyrus and area CA3, as well as the nucleus accumbens. We probed further into the learning bonus by developing a point mutant mouse (Ncs1(P144S/P144S)) harboring a destabilized NCS 1 protein, and found this line lacked the equivalent self-directed exploration learning bonus. Acute knock-down of Ncs1 in the hippocampus also decoupled exploration from efficient learning. These results are potentially relevant for augmenting learning and memory in health and disease, and provide the basis for further molecular and circuit analyses in this direction. PMID- 26639401 TI - Strategies and Pitfalls of Motor-Evoked Potential Monitoring during Supratentorial Aneurysm Surgery. AB - BACKGROUND: The aims of this study were to reveal the strategies and pitfalls of motor-evoked potential (MEP) monitoring methods during supratentorial aneurysm surgery, and to discuss the drawbacks and advantages of each method by reviewing our experiences. METHODS: Intraoperative MEP monitoring was performed in 250 patients. Results from 4 monitoring techniques using combinations of 2 stimulation sites and 2 recording sites were analyzed retrospectively. RESULTS: MEP was recorded successfully in 243 patients (97.2%). Direct cortical stimulation (DCS)-spinal recorded MEP (sMEP) was used in 134 patients, DCS-muscle recorded MEP (mMEP) in 97, transcranial electrical stimulation (TES)-mMEP in 11 and TES-sMEP in 1. TES-mMEP during closure of the skull was used in 21 patients. DCS-mMEP was able to detect waveforms from upper and/or lower limb muscles. Alternatively, DCS-sMEP (direct [D]-wave) could accurately estimate amplitude changes. A novel "early warning sign" indicating ischemia was found in 21 patients, which started with a transiently increased amplitude of D-wave and then decreased after proximal interruption of major arteries. False-negative findings in MEP monitoring in 2 patients were caused by a blood insufficiency in the lenticulostriate artery and by a TES-sMEP recording, respectively. CONCLUSIONS: The results of this study suggest that to perform accurate MEP monitoring, DCS mMEP or DCS-sMEP recording should be used as the situation demands, with combined use of TES-mMEP recording during closure of the skull. DCS-sMEP is recommended for accurate analysis of waveforms. We also propose a novel "early warning sign" of blood insufficiency in the D-wave. PMID- 26639402 TI - Pure Hemiparkinsonism Secondary to Contralateral Lacunar Stroke in the Substantia Nigra. AB - There are different etiologies of hemiparkinsonism. A few patients with hemiparkinsonism secondary to infarction in the contralateral substantia nigra have been reported in the literature, and only one of these patients presented with pure hemiparkinsonism. This paper reports the unusual case of a patient presenting with pure hemiparkinsonism secondary to a lacunar stroke in the substania nigra. A 66-year-old man who presented with a 5-year history of left sided hemiparkinsonism manifested by tremor, rigidity, and bradykinesia located mainly on the upper extremity. Magnetic resonance imaging of the brain revealed a lacunar infarct located in the right substantia nigra. Patients experiencing sudden hemiparkinsonism should be investigated to rule out any abnormality in the contralateral substantia nigra. This case points to the significance of neuroimaging in the evaluation of unilateral parkinsonism. PMID- 26639403 TI - Wake-up Stroke and Stroke within the Therapeutic Window for Thrombolysis Have Similar Clinical Severity, Imaging Characteristics, and Outcome. AB - BACKGROUND: Wake-up stroke (WUS) represents 25% of all ischemic strokes. There is conflicting evidence concerning clinical severity, imaging characteristics, and outcome when WUS is compared with stroke of known time of onset. Our aim was to compare WUS patients with patients with ischemic stroke within the therapeutic window (STW) for thrombolysis. METHODS: This is a retrospective hospital-based study of all consecutive patients hospitalized for acute ischemic stroke during 2013. Patients with STW, WUS, and WUS with computed tomography (CT) at 3 hours or less after awakening (WUS<=3h) were selected for the study. The methods used include a review of clinical records, an independent quantification of early signs of ischemia on admission CT scan, and determination of functional outcome on follow-up. RESULTS: Of 554 patients evaluated, 190 had STW, 113 had WUS (20.4%), and 25 had WUS<=3h. Among all WUS patients, 33.6% did not have any other formal contraindication for thrombolysis besides undetermined time of onset. WUS patients had demographic characteristics, vascular risk factors, and clinical severity similar to STW patients. Mild or absent early signs of ischemia on admission CT in WUS<=3h patients were similar to those in STW patients when adjusted for clinical severity (odds ratio [OR] = .50, 95% confidence interval [CI]=.17-1.47). Favorable prognosis in WUS<=3h was similar to STW when adjusted for age, clinical severity, and thrombolysis (OR = .53, 95% CI=.09-3.14). CONCLUSIONS: This study strengthens the evidence that clinical and early imaging characteristics of WUS patients are similar to those of patients with stroke who are eligible for thrombolysis based on the time window criteria, and patients with WUS do not have a worse short outcome. PMID- 26639404 TI - Clonal Dynamics In Vivo of Virus Integration Sites of T Cells Expressing a Safety Switch. AB - Safety switches are becoming relevant for the clinical translation of T-cell based immunotherapies. In patients receiving an allogeneic hematopoietic stem cell transplant, the inducible caspase-9 gene (iC9) safety switch expressed by donor-derived T lymphocytes efficiently controls acute graft versus host disease (GvHD). However, in vivo elimination of iC9-T cells by the chemical inducer of dimerization (CID) that activates the iC9 protein is incomplete. To study this effect, we characterized the clonal diversity and dynamics of vector insertion sites (VIS) in iC9-T cells pre- and post-CID administration in four patients who developed GvHD. We identified 3,203 VIS among four patients and followed their in vivo clonal dynamics up to 161 days post-CID. VIS were categorized by their proximity to host genome elements, gene associations, and cis-modulatory relationship to mapped promoters. We found that VIS are preferentially located near open chromatin and promoter regions; furthermore, there was no evidence for selection bias among VIS surviving the CID treatment. The majority of iC9-T cells with high normalized VIS copy number at the time of GvHD onset were eliminated by CID, while iC9-T cells detectable post-CID generally have low normalized VIS copy number. We propose that suboptimal iC9 transgene expression is responsible for the incomplete elimination of iC9-T cells and illustrate here by simple model how cis-modulatory influences of local genome context and T-cell receptor activation status at time of CID treatment contribute to stochastic sparing of iC9-T cells. PMID- 26639406 TI - Ionic Current Rectification in a pH-Tunable Polyelectrolyte Brushes Functionalized Conical Nanopore: Effect of Salt Gradient. AB - The behavior of ionic current rectification (ICR) in a conical nanopore with its surface modified by pH-tunable polyelectrolyte (PE) brushes connecting two large reservoirs subject to an applied electric field and a salt gradient is investigated. Parameters including the solution pH, types of ionic species, strength of applied salt gradient, and applied potential bias are examined for their influences on the ionic current and rectification factor, and the mechanisms involved are investigated comprehensively. The ICR behavior depends highly on the charged conditions of the PE layer, the level of pH, the geometry of nanopore, and the thickness of the double layer. In particular, the distribution of ionic species and the local electric field near the nanopore openings play a key role, yielding profound and interesting results that are informative to device design as well as experimental data interpretation. PMID- 26639405 TI - A Comprehensive Map of CNS Transduction by Eight Recombinant Adeno-associated Virus Serotypes Upon Cerebrospinal Fluid Administration in Pigs. AB - Cerebrospinal fluid administration of recombinant adeno-associated viral (rAAV) vectors has been demonstrated to be effective in delivering therapeutic genes to the central nervous system (CNS) in different disease animal models. However, a quantitative and qualitative analysis of transduction patterns of the most promising rAAV serotypes for brain targeting in large animal models is missing. Here, we characterize distribution, transduction efficiency, and cellular targeting of rAAV serotypes 1, 2, 5, 7, 9, rh.10, rh.39, and rh.43 delivered into the cisterna magna of wild-type pigs. rAAV9 showed the highest transduction efficiency and the widest distribution capability among the vectors tested. Moreover, rAAV9 robustly transduced both glia and neurons, including the motor neurons of the spinal cord. Relevant cell transduction specificity of the glia was observed after rAAV1 and rAAV7 delivery. rAAV7 also displayed a specific tropism to Purkinje cells. Evaluation of biochemical and hematological markers suggested that all rAAV serotypes tested were well tolerated. This study provides a comprehensive CNS transduction map in a useful preclinical large animal model enabling the selection of potentially clinically transferable rAAV serotypes based on disease specificity. Therefore, our data are instrumental for the clinical evaluation of these rAAV vectors in human neurodegenerative diseases. PMID- 26639409 TI - Monitoring Network Confirms Land Use Change is a Substantial Component of the Forest Carbon Sink in the eastern United States. AB - Quantifying forest carbon (C) stocks and stock change within a matrix of land use (LU) and LU change is a central component of large-scale forest C monitoring and reporting practices prescribed by the Intergovernmental Panel on Climate Change (IPCC). Using a region-wide, repeated forest inventory, forest C stocks and stock change by pool were examined by LU categories. In eastern US forests, LU change is a substantial component of C sink strength (~37% of forest sink strength) only secondary to that of C accumulation in forests remaining forest where their comingling with other LUs does not substantially reduce sink strength. The strongest sinks of forest C were study areas not completely dominated by forests, even when there was some loss of forest to agriculture/settlement/other LUs. Long term LU planning exercises and policy development that seeks to maintain and/or enhance regional C sinks should explicitly recognize the importance of maximizing non-forest to forest LU changes and not overlook management and conservation of forests located in landscapes not currently dominated by forests. PMID- 26639408 TI - Melatonin attenuated early brain injury induced by subarachnoid hemorrhage via regulating NLRP3 inflammasome and apoptosis signaling. AB - Subarachnoid hemorrhage (SAH) is a devastating condition with high morbidity and mortality rates due to the lack of effective therapy. Nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation associated with the upregulation of apoptotic signaling pathway has been implicated in various inflammatory diseases including hemorrhagic insults. Melatonin is reported to possess substantial anti inflammatory properties, which is beneficial for early brain injury (EBI) after SAH. However, the molecular mechanisms have not been clearly identified. This study was designed to investigate the protective effects of melatonin against EBI induced by SAH and to elucidate the potential mechanisms. The adult mice were subjected to SAH. Melatonin or vehicle was injected intraperitoneally 2 hr after SAH. Melatonin was neuroprotective, as shown by increased survival rate, as well as elevated neurological score, greater survival of neurons, preserved brain glutathione levels, and reduced brain edema, malondialdehyde concentrations, apoptotic ratio, and blood-brain barrier (BBB) disruption. Melatonin also attenuated the expressions of NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), cleaved caspase-1, interleukin 1beta (IL-1beta), and interleukin-6 (IL-6); these changes were also associated with an increase in the anti-apoptotic factor (Bcl2) and reduction in the pro apoptotic factor (Bim). In summary, our results demonstrate that melatonin treatment attenuates the EBI following SAH by inhibiting NLRP3 inflammasome associated apoptosis. PMID- 26639410 TI - Cloud-based decision framework for waste-to-energy plant site selection - A case study from China. AB - Waste-to-energy (WtE) plant site selection is crucially important during the whole life cycle. Currently, the scholars launch some research in the WtE plant site selection. However, there are still two great problems in the present methods. Firstly, the uncertainty of information is not fully described. Secondly, the correlation among criteria lacks rationality, which is mainly manifested in two aspects: one is ignoring the correlation, and the other is measuring unreasonably. Firstly cloud model is introduced to describe the fuzziness and randomness of the information fully and precisely. Secondly, the 2 order additive fuzzy measures based on the Mobius transform and correlation coefficient matrix is introduced for fuzzy measure scientifically and reasonably. Thirdly, Cloud Choquet integral (CCI) operator is constructed to evaluate the alternatives. Finally, a case from China proves the effectiveness. PMID- 26639411 TI - Wastes from bioethanol and beer productions as substrates for l(+) lactic acid production - A comparative study. AB - Waste substrates from bioethanol and beer productions are cheap, abundant and renewable substrates for biorefinery production of lactic acid (LA) and variability in their chemical composition presents a challenge in their valorisation. Three types of waste substrates, wasted bread and wasted potato stillage from bioethanol production and brewers' spent grain hydrolysate from beer production were studied as substrates for the production of l(+) LA and probiotic biomass by Lactobacillus rhamnosus ATCC 7469. The correlation of the content of free alpha amino nitrogen and the production of LA was determined as a critical characteristic of the waste media for efficient LA production by L. rhamnosus on the substrates which contained equal amount of fermentable sugars. A maximal LA productivity of 1.54gL(-1)h(-1) was obtained on wasted bread stillage media, whilst maximal productivities achieved on the potato stillage and brewers' spent grain hydrolysate media were 1.28gL(-1)h(-1)and 0.48gL(-1)h(-1), respectively. A highest LA yield of 0.91gg(-1) was achieved on wasted bread stillage media, followed by the yield of 0.81gg(-1) on wasted potato stillage and 0.34gg(-1) on brewers' spent grain hydrolysate media. The kinetics of sugar consumption in the two stillage substrates were similar while the sugar conversion in brewers' spent grain hydrolysate was slower and less efficient due to significantly lower content of free alpha amino nitrogen. The lignocellulosic hydrolysate from beer production required additional supplementation with nitrogen. PMID- 26639412 TI - Dealing with Confounding pH-Dependent Surface Charges in Immobilized Artificial Membrane HPLC Columns. AB - The retention capacity factor (k(IAM)) on immobilized artificial membrane chromatography columns (IAM-HPLC) is widely used as experimental descriptor of lipophilicity. For predominantly ionized compounds, however, unexpected and significant effects of pH, buffers, and salinity on k(IAM) have been reported. Besides zwitterionic phospholipids, IAM particles contain acidic silanol moieties and positively charged propylamine groups. The electrostatic model and experimental k(IAM) values presented in this study for organic cations show that the net IAM surface charge is positive below pH 5 and negative above pH 5. The resulting confounding electrostatic repulsion/attraction is strongly influenced by eluent salinity: k(IAM) values for cations differ by more than 2 orders of magnitude over the tested range of aqueous eluents. In phosphate buffered saline medium the actual lipophilicity of cationic drugs (K(PLIPW,cation)) is overestimated by at least a factor of 2. The K(PLIPW,cation) can be readily determined by IAM-HPLC in any 10 mM buffered eluent at pH 5. Accounting for, or avoiding, confounding electrostatic effects in IAM-HPLC considerably advances assessments of (phospho)lipophilicity for drug discovery and for environmental risk assessment of organic cations. PMID- 26639413 TI - The Efficacy of Motivational Interviewing in Adults With Chronic Pain: A Meta Analysis and Systematic Review. AB - Motivational interviewing (MI) has become a popular approach for increasing adherence. In this study we investigated whether MI is effective in improving adherence, and pain and physical function for patients with chronic pain. A literature search of randomized controlled trials identified 7 eligible studies with 962 participants with chronic pain. There was a small to moderate overall effect of MI on increased adherence to treatment from baseline to after intervention, but not from baseline to follow-up. Although significant short-term effects of MI were also observed for pain intensity, analyses revealed that this finding might be due to publication bias. There were insufficient studies to examine physical functioning meta-analytically, however, none of the 3 available studies showed that MI resulted in gains in physical function compared with the control group. These results indicate that MI can probably increase short-term adherence to chronic pain treatments, although publication bias cannot be ruled out. Further, it is as yet unclear whether these effects result in improvements in patient function. Although the studies were methodologically strong, they investigated MI in relation to a number of treatments for chronic pain. Future research on the efficacy of MI on adherence to evidence-based self-management interventions for chronic pain is needed. PERSPECTIVE: MI significantly increased adherence to prescribed chronic pain treatments in the short term, however, effect sizes were small to moderate and publication bias was likely. MI showed some promise in promotion of adherence to pain treatments, but more research is required to confirm its efficacy. PMID- 26639421 TI - Abstracts of the RCOG National Trainees Conference (NTC) 2015, 10-11 December 2015, London, UK. PMID- 26639423 TI - Proliferation and differentiation of rat bone marrow stem cells by 400MUT electromagnetic field. AB - The interaction between environment electromagnetic field (EMF) and cells can effect on various physiological processes. EMF as an external inducing factor, could effect on proliferation or differentiation of cells. The purpose of this study was to evaluate the influence of the electromagnetic field on the viability, proliferation and differentiation rate of bone marrow stem cells (BMSCs) to neuron. BMSCs were obtained from 42 adult male rats. The cells incubated and cultured in 96-wells and 6-wells plates and exposed to electromagnetic field (40 or 400MUT) with a selected waveform: AC (alternative current), rectified half wave (RHW) and rectified full wave (RFW), for a week. To assess the viability and proliferation rate of treated cells, MTT assay was done, and then immunocytochemistry staining Neu N was used to evaluate cell differentiation to neuron. Results showed that EMF decreases the viability and proliferation in treated groups. But in AC group's reduction was significant. Minimum viability and proliferation rate was observed in RHW 400MUT group compared with sham. Immunocytochemistry showed that EMF can induce BMSC differentiation into neuron in AC 400MUT and RFW 400MUT. Evidences of this research support the hypothesis that EMF can induce differentiation of BMSCs to neuron. PMID- 26639422 TI - BK Polyomavirus Replication in Renal Tubular Epithelial Cells Is Inhibited by Sirolimus, but Activated by Tacrolimus Through a Pathway Involving FKBP-12. AB - BK polyomavirus (BKPyV) replication causes nephropathy and premature kidney transplant failure. Insufficient BKPyV-specific T cell control is regarded as a key mechanism, but direct effects of immunosuppressive drugs on BKPyV replication might play an additional role. We compared the effects of mammalian target of rapamycin (mTOR)- and calcineurin-inhibitors on BKPyV replication in primary human renal tubular epithelial cells. Sirolimus impaired BKPyV replication with a 90% inhibitory concentration of 4 ng/mL by interfering with mTOR-SP6-kinase activation. Sirolimus inhibition was rapid and effective up to 24 h postinfection during viral early gene expression, but not thereafter, during viral late gene expression. The mTORC-1 kinase inhibitor torin-1 showed a similar inhibition profile, supporting the notion that early steps of BKPyV replication depend on mTOR activity. Cyclosporine A also inhibited BKPyV replication, while tacrolimus activated BKPyV replication and reversed sirolimus inhibition. FK binding protein 12kda (FKBP-12) siRNA knockdown abrogated sirolimus inhibition and increased BKPyV replication similar to adding tacrolimus. Thus, sirolimus and tacrolimus exert opposite effects on BKPyV replication in renal tubular epithelial cells by a mechanism involving FKBP-12 as common target. Immunosuppressive drugs may therefore contribute directly to the risk of BKPyV replication and nephropathy besides suppressing T cell functions. The data provide rationales for clinical trials aiming at reducing the risk of BKPyV replication and disease in kidney transplantation. PMID- 26639424 TI - Effects of dopamine D1 receptor activation and blockade on dopamine and noradrenaline levels in the rat brain. AB - The noradrenergic and dopaminergic systems are associated with the motor system and have anatomical and functional connections that have not yet been studied. The present study aimed to examine the specific role of D1 receptors (D1Rs) on noradrenergic and dopaminergic responses in the rat brain. Male Wistar rats were assigned to eight groups to receive systemic injection of a D1R agonist (SKF 38393) at 0, 1, 5 or 10mg/kg or injection of a D1R antagonist (SCH-23390) at 0, 0.25, 0.5 or 1mg/kg. Dopamine (DA) and noradrenaline (NA) levels were measured using high-performance liquid chromatography. Injection of SKF-38393 alone at 1, 5 and 10mg/kg did not alter DA levels in the midbrain, cerebral cortex or pons, while it significantly increased these levels in the striatum (at 1 and 10mg/kg), hippocampus (at 1mg/kg) and cerebellum (at 1 and 5mg/kg). Administration of SKF 38393 at 1, 5, and 10mg/kg decreased the NA levels in the midbrain, pons, hippocampus (except at 1mg/kg) and cortex (except at 5mg/kg), whereas the opposite effect was observed in the striatum. SCH-23390 decreased the DA levels in the cortex (at 0.25 and 0.5mg/kg) and pons (at 0.5mg/kg). In contrast, 0.25, 0.5 and 1mg/kg SCH-23390 increased the DA levels in the cerebellum, whereas no differences from the control levels were observed for the DA levels in the striatum, midbrain and hippocampus. SCH-23390 at 0.5 and 1mg/kg increased the NA levels in the striatum. In contrast, the midbrain, hippocampus, cortex, pons and cerebellum did not exhibit altered NA levels. Our results demonstrate that the activation of D1Rs modulates the response of the noradrenergic system in nearly all of the investigated brain structures; thus, the blockade of D1Rs attenuates the effects induced by D1R activation. PMID- 26639425 TI - Activation of AMPA receptor in the infralimbic cortex facilitates extinction and attenuates the heroin-seeking behavior in rats. AB - Infralimbic cortex (IL) is proposed to suppress cocaine seeking after extinction, but whether the IL regulates the extinction and reinstatement of heroin-seeking behavior is unknown. To address this issue, the male SD rats were trained to self administer heroin under a FR1 schedule for consecutive 14 days, then the rats underwent 7 daily 2h extinction session in the operant chamber. The activation of IL by microinjection PEPA, an allosteric AMPA receptor potentiator into IL before each of extinction session facilitated the extinction responding after heroin self-administration, but did not alter the locomotor activity in an open field testing environment. Other rats were first trained under a FR1 schedule for heroin self-administration for 14 days, followed by 14 days of extinction training, and reinstatement of heroin-seeking induced by cues was measured for 2h. Intra-IL microinjecting of PEPA at 15min prior to test inhibited the reinstatement of heroin-seeking induced by cues. Moreover, the expression of GluR1 in the IL and NAc remarkably increased after treatment with PEPA during the reinstatement. These finding suggested that activation of glutamatergic projection from IL to NAc shell may be involved in the extinction and reinstatement of heroin-seeking. PMID- 26639426 TI - Alterations of the electrophysiological properties from cortical layer 5 pyramidal neurons in temporary rapamycin-treated rodent brain slices. AB - The mammalian target of rapamycin (mTOR) signaling pathway is involved in neuro developmental/degenerative and neuropsychiatric abnormalities. Rapamycin, a specific and potent inhibitor of mTOR signaling, could regulate synaptic plasticity and synaptic transmission of glutamatergic neurons following prolonged treatment. Its immediate effects on electrophysiological properties of cortical layer 5 (L5) pyramidal neurons where the information undergoes a sophisticated processing remain unknown. Here, we found that acute (within 2min) bath application of rapamycin (0.5MUgml(-1)) was able to depolarize the current-clamp baseline potentials significantly at postnatal day (P) 4, P10 in rats and P90 in mice (P<0.05), and altered the membrane current/voltage (I/V) curves in an age dependent manner. Rapamycin not only increased the standard deviation or the peak amplitude of baseline membrane potential, but also increased the frequencies of spontaneous action potentials in more mature neurons (P10 and P90). In addition, rapamycin decreased the burst-firing frequencies of cortical L5 burst-spiking neurons from mature brains, and further switched their firing modes to regular spiking ones. These findings suggest that acute inhibition of mTOR signaling by rapamycin induces an immediate impact on L5 pyramidal neurons' electrophysiological properties, indicating that its effects might involve mechanisms of ion channel's regulation. PMID- 26639427 TI - Targeting different pathophysiological events after traumatic brain injury in mice: Role of melatonin and memantine. AB - The tissue damage that emerges during traumatic brain injury (TBI) is a consequence of a variety of pathophysiological events, including free radical generation and over-activation of N-methyl-d-aspartate-type glutamate receptors (NMDAR). Considering the complex pathophysiology of TBI, we hypothesized that combination of neuroprotective compounds, targeting different events which appear during injury, may be a more promising approach for patients. In this context, both NMDAR antagonist memantine and free radical scavenger melatonin are safe in humans and promising agents for the treatment of TBI. Herein, we examined the effects of melatonin administered alone or in combination with memantine on the activation of signaling pathways, injury development and DNA fragmentation. Both compounds reduced brain injury moderately and the density of DNA fragmentation significantly. Notably, melatonin/memantine combination decreased brain injury and DNA fragmentation significantly, which was associated with reduced p38 and ERK-1/2 phosphorylation. As compared with melatonin and memantine groups, SAPK/JNK-1/2 phosphorylation was also reduced in melatonin/memantine combined animals. In addition, melatonin, memantine and their combination decreased iNOS activity significantly. Here, we provide evidence that melatonin/memantine combination protects brain from traumatic injury, which was associated with decreased DNA fragmentation, p38 phosphorylation and iNOS activity. PMID- 26639428 TI - TGFbeta regulates Galectin-3 expression through canonical Smad3 signaling pathway in nucleus pulposus cells: implications in intervertebral disc degeneration. AB - Galectin-3 is highly expressed in notochordal nucleus pulposus (NP) and thought to play important physiological roles; however, regulation of its expression remains largely unexplored. The aim of the study was to investigate if TGFbeta regulates Galectin-3 expression in NP cells. TGFbeta treatment resulted in decreased Galectin-3 expression. Bioinformatic analysis using JASPAR and MatInspector databases cross-referenced with published ChIP-Seq data showed nine locations of highly probable Smad3 binding in the LGALS3 proximal promoter. In NP cells, TGFbeta treatment resulted in decreased activity of reporters harboring several 5' deletions of the proximal Galectin-3 promoter. While transfection of NP cells with constitutively active (CA)-ALK5 resulted in decreased promoter activity, DN-ALK5 blocked the suppressive effect of TGFbeta on the promoter. The suppressive effect of Smad3 on the Galectin-3 promoter was confirmed using gain- and loss-of-function studies. Transfection with DN-Smad3 or Smad7 blocked TGFbeta mediated suppression of promoter activity. We also measured Galectin-3 promoter activity in Smad3 null and wild type cells. Noteworthy, promoter activity was suppressed by TGFbeta only in wild type cells. Likewise, stable silencing of Smad3 in NP cells using sh-Smad3 significantly blocked TGFbeta-dependent decrease in Galectin-3 expression. Treatment of human NP cells isolated from tissues with different grades of degeneration showed that Galectin-3 expression was responsive to TGF-beta-mediated suppression. Importantly, Galectin-3 synergized effects of TNF-alpha on inflammatory gene expression by NP cells. Together these studies suggest that TGFbeta, through Smad3 controls Galectin-3 expression in NP cells and may have implications in the intervertebral disc degeneration. PMID- 26639429 TI - Use of computational modeling approaches in studying the binding interactions of compounds with human estrogen receptors. AB - Estrogens have a whole host of physiological functions in many human organs and systems, including the reproductive, cardiovascular, and central nervous systems. Many naturally-occurring compounds with estrogenic or antiestrogenic activity are present in our environment and food sources. Synthetic estrogens and antiestrogens are also important therapeutic agents. At the molecular level, estrogen receptors (ERs) mediate most of the well-known actions of estrogens. Given recent advances in computational modeling tools, it is now highly practical to use these tools to study the interaction of human ERs with various types of ligands. There are two common categories of modeling techniques: one is the quantitative structure activity relationship (QSAR) analysis, which uses the structural information of the interacting ligands to predict the binding site properties of a macromolecule, and the other one is molecular docking-based computational analysis, which uses the 3-dimensional structural information of both the ligands and the receptor to predict the binding interaction. In this review, we discuss recent results that employed these and other related computational modeling approaches to characterize the binding interaction of various estrogens and antiestrogens with the human ERs. These examples clearly demonstrate that the computational modeling approaches, when used in combination with other experimental methods, are powerful tools that can precisely predict the binding interaction of various estrogenic ligands and their derivatives with the human ERs. PMID- 26639430 TI - Synthesis and chemical reactions of the steroidal hormone 17alpha methyltestosterone. AB - Structural modifications of natural products with complex structures like steroids require great synthetic effort. A review of literature is presented on the chemistry of the steroidal hormone 17alpha-methyltestosterone that is approved by Food and Drug Administration (FDA) in the United States as an androgen for estrogen-androgen hormone replacement therapy treatment. The analog also offers special possibilities for the prevention/treatment of hormone sensitive cancers. The testosterone skeleton has important functionalities in the molecule that can act as a carbonyl component, an active methylene compound, alpha,beta-unsaturated enone and tertiary hydroxyl group in various chemical reactions to access stereoisomeric steroidal compounds with potent activity. In addition, microbiological methods of synthesis and transformation of this hormone are presented. PMID- 26639431 TI - Progesterone promotes cell migration, invasion and cofilin activation in human astrocytoma cells. AB - Astrocytomas are the most common and aggressive primary brain tumors in humans. Invasiveness of these tumors has been attributed in part to deregulation of cell motility-dependent cytoskeletal dynamics that involves actin-binding proteins such as cofilin. Progesterone (P4) has been found to induce migration and invasion of cells derived from breast cancer and endothelium. However, the role of P4 in migration and invasion of astrocytoma cells as well as its effects on astrocytomas cytoskeleton remodeling is not known. In this work we evaluated these aspects in D54 and U251 cells derived from human astrocytomas from the highest degree of malignancy (grade IV, glioblastoma). Our results showed that in scratch-wound assays P4 increased the number of D54 and U251 cells migrating from 3 to 48 h. Both RU486, a P4 receptor (PR) antagonist, and an oligonucleotide antisense against PR significantly blocked P4 effects. Transwell assays showed that P4 significantly increased the number of invasive cells at 24h. As in the case of migration, this effect was blocked by RU486. Finally, by Western blotting, an increase in the cofilin/p-cofilin ratio at 15 and 30 min and a decrease at 30 and 60 min in U251 and D54 cells, respectively, was observed after P4, P4+RU486 and RU486 treatments. These data suggest that P4 increases human astrocytoma cells migration and invasion through its intracellular receptor, and that cofilin activation by P4 is independent of PR action. PMID- 26639432 TI - Proposal for a Modified Dreyfus and Miller Model with simplified competency level descriptions for performing self-rated surveys. AB - In competency-based education, it is important to frequently evaluate the degree of competency achieved by establishing and specifying competency levels. To self appraise one's own competency level, one needs a simple, clear, and accurate description for each competency level. This study aimed at developing competency stages that can be used in surveys and conceptualizing clear and precise competency level descriptions. In this paper, the author intends to conceptualize a simple competency level description through a literature review. The author modified the most widely quoted competency level models-Dreyfus' Five-stage Model and Miller's Pyramid-and classified competency levels into the following: The Modified Dreyfus Model comprises absolute beginner, beginner, advanced beginner, competent, proficient, and expert, while the Modified Miller Model uses the levels of knows little, knows and knows how, exercised does, selected does, experienced does, and intuitive does. The author also provided a simple and clear description of competency levels. The precise description of competency levels developed in this study is expected to be useful in determining one's competency level in surveys. PMID- 26639440 TI - The RIFLE versus AKIN classification for incidence and mortality of acute kidney injury in critical ill patients: A meta-analysis. AB - The sensitivity and accuracy of the Risk/Injury/Failure/Loss/End-stage (RIFLE) versus acute kidney injury Network (AKIN) criteria for acute kidney injury (AKI) in critically ill patients remains uncertain. Therefore, we performed a systematic review and meta-analysis to investigate the incidence and prognostic value of the RIFLE versus AKIN criteria for AKI in critically ill patients. Literatures were identified by searching Medline, Embase, PubMed, and China National Knowledge Infrastructure (CNKI) database. Nineteen studies with 171,889 participants were included. The pooled estimates of relative risk (RR) were analyzed. We found that the RIFLE and AKIN criteria is different for the incidence of AKI in intensive care unit (ICU) patients (P = 0.02, RR = 0.88), while not for cardiac surgery patients (P = 0.30, RR = 0.93). For AKI-related hospital mortality, the AKIN criteria did not show a better ability in predicting hospital mortality in either ICU (P = 0.19, RR = 1.01) or cardiac surgery patients (P = 0.61, RR = 0.98) compared to RIFLE criteria. Our findings supported that the AKIN criteria can identify more patients in classifying AKI compared to RIFLE criteria, but not showing a better ability in predicting hospital mortality. Moreover, both RIFLE and AKIN criteria for AKI in cardiac surgery patients had better predictive ability compared with the ICU patients. PMID- 26639442 TI - Utility of Bifunctional N-Heterocyclic Phosphine (NHP)-Thioureas for Metal-Free Carbon-Phosphorus Bond Construction toward Regio- and Stereoselective Formation of Vinylphosphonates. AB - An efficient and practical protocol for completely regioselective and highly stereoselective synthesis of vinyldiazaphosphonates from N-heterocyclic phosphine (NHP) and allenes via phospha-Michael/intramolecular nucleophilic substitution reaction has been developed. This transformation enabled the synthesis of valuable densely functionalized vinyldiazaphosphonates with a beta-, gamma unsaturated ester moiety under mild reaction conditions. Synthetic utility of vinyldiazaphosphonates was demonstrated by a series of synthetic manipulations. PMID- 26639441 TI - Antimicrobial Stewardship Barriers and Goals in Pediatric Oncology and Bone Marrow Transplantation: A Survey of Antimicrobial Stewardship Practitioners. AB - We undertook a cross-sectional survey of antimicrobial stewardship clinicians in North America and Australasia regarding practices, goals, and barriers to implementation of stewardship for pediatric oncology patients. Goals and barriers were similar regardless of clinician or institutional characteristics and geographic location. Strategies addressing these factors could help optimize antimicrobial use. PMID- 26639443 TI - Heart rate variability analysed by Poincare plot in patients with metabolic syndrome. AB - INTRODUCTION: The SD1 and SD2 indexes (standard deviations in two orthogonal directions of the Poincare plot) carry similar information to the spectral density power of the high and low frequency bands but have the advantage of easier calculation and lesser stationarity dependence. METHODS: ECG signals from metabolic syndrome (MetS) and control group patients during tilt table test under controlled breathing (20 breaths/minute) were obtained. SD1, SD2, SDRR (standard deviation of RR intervals) and RMSSD (root mean square of successive differences of RR intervals) were evaluated for 31 control group and 33 MetS subjects. RESULTS: Statistically significant lower values were observed in MetS patients in supine position (SD1: p=0.03, SD2: p=0.002, SDRR: p=0.006, RMSSD: p=0.01) and during tilt (SD2: p=0.004, SDRR: p=0.007). CONCLUSION: SD1 and SD2 combining the advantages of time and frequency domain methods, distinguish successfully between MetS and control subjects. PMID- 26639444 TI - Structural stabilization of transthyretin by a new compound, 6-benzoyl-2-hydroxy 1H-benzo[de]isoquinoline-1,3(2H)-dione. AB - Familial amyloid polyneuropathy (FAP) is a genetic, adult-onset, neurodegenerative disorder caused by amyloid formation of transthyretin (TTR), a thyroxine-binding protein. Mutation in TTR causes a propensity of TTR tetramer to dissociate to monomer, which is the first step to amyloidosis. Thus, a drug that can stabilize the tetramer structure will have therapeutic benefit. Here, by virtual screening and biochemical assays, we identified small molecule 6-benzoyl 2-hydroxy-1H-benzo[de]isoquinoline-1,3(2H)-dione (L6) that can prevent the dissociation of TTR to monomer. X-ray crystallography reveals that L6 binds to the T4 binding pocket of TTR. These findings show that L6 is a candidate TTR stabilizer. PMID- 26639445 TI - Potentiation activity of multiple antibacterial agents by Salvianolate from the Chinese medicine Danshen against methicillin-resistant Staphylococcus aureus (MRSA). AB - Salvianolate (SAL) is a prescribed medicine from the Chinese herb Danshen (Salvia miltiorrhiza Bunge). It has been widely used in treatment of coronary and other diseases with significant effects. The in vitro antimicrobial activities of SAL against infectious pathogens were assayed and its combined effects on 10 clinical isolates of SCCmec III type methicillin-resistant Staphylococcus aureus (MRSA) with ten antibiotics were evaluated. Susceptibility to each agent alone was tested using a broth microdilution method, and the chequerboard and time-kill experiments were used for the combined activities. The results showed MIC was 128 256 mg/L for SAL used alone against MRSA. Significant synergies were observed for SAL/Ampicillin (Fosfomycin, Erythromycin, Piperacillin-tazobactam or Clindamycin) combination against over half of the isolates, with their MICs reduced by times of dilution (TOD) to 4-32 (FICIs 0.375-0.5), respectively. SAL/AMP combination showed the best combined effect of synergy on bacteriostatic and bactericidal activities, while SAL/AMK combination reversed the resistance of MRSA to AMK. The results demonstrated that SAL enhanced widely the in vitro anti-MRSA efficacy of the ten antibacterial agents, which had potential for combinatory therapy of patients infected with MRSA and warrants further investigations. PMID- 26639446 TI - Impact of Falls on Physical Activity in People with Parkinson's Disease. AB - BACKGROUND: A complex relationship exists between motor impairment, physical activity (sedentary behavior, standing and ambulatory activity) and falls in people with Parkinson's disease (PD). OBJECTIVE: To explore associations between recent fall history and the ability to retain an active lifestyle as determined by the volume, pattern and variability of physical activity in people with PD. METHODS: Forty-eight participants with PD were recruited from the Norwegian ParkWest study. Body posture and ambulatory activity were monitored objectively over 7 days using the activPAL3 accelerometer. Clinical assessments included the Hoehn and Yahr stage, Unified Parkinson's Disease Rating Scale motor section and Falls Efficacy Scale-International. Structured interviews were performed to obtain information about demographics, fall history last 6 months, mobility and dementia. RESULTS: Participants with a fall history (n = 20) spent more time sedentary and less time standing than non-falling participants (n = 28). There were no significant differences regarding pattern or variability of sedentary behavior, standing or ambulatory activity in falling versus non-falling participants. Confidence in being able to get up from floor contributed significantly to time spent in sedentary behavior and ambulatory activity in participants with fall history, whereas motor impairment was significantly associated with time spent in all facets of physical activity for non-falling participants. CONCLUSIONS: Fall history in our PD cohort was associated with a more sedentary lifestyle, but not less ambulatory activity. More emphasis on improving the capacity to safely complete activities of daily living and increase confidence in getting up from floor may reduce sedentary behavior in people with PD. PMID- 26639447 TI - Creative Thinking, Professional Artists, and Parkinson's Disease. AB - BACKGROUND: An increase in artistic-like production in Parkinson's disease (PD) has been associated with compulsive and repetitive behaviours after the introduction of dopaminergic treatment (DT). Recent data suggest that it could be due to the emergence of artistic-like skills triggered by DT. OBJECTIVE: In order to evaluate whether artistic production and creative thinking are influenced by DT or linked to artistic-like skills, we characterize creativity features in PD and healthy controls (HC) including professional artists. METHODS: Three groups of PD out-patients were included consecutively: professional artists (PD-A), patients with (PD-C) and without artistic-like production (PD-NC). Twenty-four gender and age-matched HC were included: professional artists (HC-A) and non artists (HC-NC). All patients were evaluated by means of a) a battery of neuropsychological tests and a semi-structured interview; b) the Abbreviated Torrance Test for Adults (ATTA) for creative thinking; c) the Minnesota Impulsive Disorders Interview (mMIDI) and a screening for impulse control disorders (ICDs) for compulsive behaviour. RESULTS: ATTA total score was significantly higher in HC-A and PD-A than in the other groups. Although PD-NC showed the lowest ATTA total score the difference vs HC-NC was not significant. ATTA scores were not significantly correlated with DT dosage and duration. mMIDI tests were positive only in PD. There were no differences in ICDs among PD groups. CONCLUSIONS: Our results do not support a relationship between DT and the emergence of artistic creativity. We believe that DT may increase the drive to create and that further studies in "on" and "off" medication are needed to clarify this issue. PMID- 26639448 TI - An Efficient Procedure for Removal and Inactivation of Alpha-Synuclein Assemblies from Laboratory Materials. AB - BACKGROUND: Preformed alpha-synuclein fibrils seed the aggregation of soluble alpha-synuclein in cultured cells and in vivo. This, and other findings, has kindled the idea that alpha-synuclein fibrils possess prion-like properties. OBJECTIVE: As alpha-synuclein fibrils should not be considered as innocuous, there is a need for decontamination and inactivation procedures for laboratory benches and non-disposable laboratory material. METHODS: We assessed the effectiveness of different procedures designed to disassemble alpha-synuclein fibrils and reduce their infectivity. We examined different commercially available detergents to remove alpha-synuclein assemblies adsorbed on materials that are not disposable and that are most found in laboratories (e.g. plastic, glass, aluminum or stainless steel surfaces). RESULTS: We show that methods designed to decrease PrP prion infectivity neither effectively remove alpha synuclein assemblies adsorbed to different materials commonly used in the laboratory nor disassemble the fibrillar form of the protein with efficiency. In contrast, both commercial detergents and SDS detached alpha-synuclein assemblies from contaminated surfaces and disassembled the fibrils. CONCLUSIONS: We describe three cleaning procedures that effectively remove and disassemble alpha-synuclein seeds. The methods rely on the use of detergents that are compatible with most non-disposable tools in a laboratory. The procedures are easy to implement and significantly decrease any potential risks associated to handling alpha-synuclein assemblies. PMID- 26639449 TI - Identification of the anti-oxidant components in a two-step solvent extract of bovine bile lipid: Application of reverse phase HPLC, mass spectrometry and fluorimetric assays. AB - An ether extract of nine different bacterial metabolites in combination with two solvent extract (ether followed by ethanol) of bile lipids from ox gall bladder is used as an immune stimulator drug. Over the years bile acids are discussed regarding their anti-oxidant and lipid peroxidation properties. Since some of the bile acids are known to be potent antioxidants, presence of similar activity in the solvent extract of ox bile lipid was investigated using TLC and reverse phase HPLC systems. Fractions from HPLC were analyzed with mass spectrometry using electrospray ionization. The presence of twelve different bile acids along with other substances in small proportions including fatty acids, sulfate conjugates and bile pigments were confirmed. The twelve separated peaks had similar retention times as those of tauroursodeoxycholic acid, glycoursodeoxycholic acid, taurocholic acid, glycocholic acid, glycochenodeoxycholic acid, taurochenodeoxycholic acid, taurodeoxycholic acid, cholic acid, ursodeoxycholic acid, chenodeoxycholic acid, deoxycholic acid, and lithocholic acid. Subsequently, all fractions were tested for their anti-oxidative property on HepG2 cells exposed to H2O2 that served as an oxidative injury model. Four fluorescent dyes H2DCF DA, MitoSOX red, Amplex red and DAF-2 DA were used for estimation of reactive radicals in the HepG2 cells. Among the separated bile acids, tauroursodeoxycholic acid, glycoursodeoxycholic acid and ursodeoxycholic acid prevented the HepG2 cells from H2O2-induced oxidative stress. PMID- 26639450 TI - Extraordinary conservation of entire chromosomes in insects over long evolutionary periods. AB - Comparison of the genomes of different Drosophila species has shown that six different chromosomes, the so-called ''Muller elements," constitute the building blocks for all Drosophila species. Here, we confirm previous results suggesting that this conservation of the Muller elements extends far beyond Drosophila, to at least tephritid fruit flies, thought to have diverged from drosophilids 60-70 mYr ago. Less than 10 percent of genes differ in chromosome location between the two insect groups. Within chromosomes, however, the order is highly scrambled, as expected from the comparison between Drosophila species. The data also support the notion that the sex chromosomes of tephritid flies originated from an ancestor of the dot chromosome 4 of Drosophila. Overall, therefore, no new chromosome has been created for perhaps a billion generations over the two evolutionary lines. This stability at the chromosome level, which appears to extend to all Diptera including mosquitoes, is in stark contrast to other groups such as mammals, birds, fish and plants, in which chromosome numbers and organization vary enormously among species that have diverged over much fewer generations. PMID- 26639451 TI - SPERCS-A tool for environmental emission estimation. AB - The European Union (EU) chemicals regulation Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) requires a hazardous substance registration to identify the uses of a substance and the corresponding conditions of safe use. This requirement includes a human and an environmental safety assessment. Exposure scenarios are developed and employed for estimating emissions resulting from the uses of hazardous substances. To support the environmental assessments, the REACH guidance documents define 22 environmental release categories (ERCs) with conservative release factors (RFs) to water, air, and soil. Several industry associations target the ERCs to more specific uses and respective emission scenarios to enable more realistic emission estimations. They have developed more than 190 specific ERCs (SPERCs) as standardized descriptions of operational conditions (OCs) and risk management measures (RMMs). SPERCs reflect the current good practice and are documented in factsheets. These factsheets contain the information necessary for environmental emission modeling. Key parameters are the substance use rate, the efficiency of the risk management measures (if applicable), and the RFs. These parameters can be based on literature or measured company data or are justified by qualitative arguments. The majority of SPERCs have been implemented as realistic worst-case emission values in screening-level chemical safety assessment (CSA) tools. Three regulatory reviews in Europe have established requirements for documenting the SPERCs and for justifying the RFs. In addition, each of the reviews included recommendations for improving the SPERCs. The latest review proposed a condensed factsheet that focuses on the essentials for exposure assessment and subsequent communication in safety data sheets. It is complemented with a background document for providing details on the emission scenarios and justifications. In the EU the SPERCs will be further progressed in a consensus process using the multi-stakeholder expert network on exposure scenarios. The SPERCs have the potential to be used in environmental risk assessments within other regulatory frameworks or in other geographical regions. Integr Environ Assess Manag 2016;12:772-781. (c) 2015 SETAC. PMID- 26639452 TI - Abnormal brain activation during directed forgetting of negative memory in depressed patients. AB - The frequent occurrence of uncontrollable negative thoughts and memories is a troubling aspect of depression. Thus, knowledge on the mechanism underlying intentional forgetting of these thoughts and memories is crucial to develop an effective emotion regulation strategy for depressed individuals. Behavioral studies have demonstrated that depressed participants cannot intentionally forget negative memories. However, the neural mechanism underlying this process remains unclear. In this study, participants completed the directed forgetting task in which they were instructed to remember or forget neutral or negative words. Standard univariate analysis based on the General Linear Model showed that the depressed participants have higher activation in the inferior frontal gyrus (IFG), superior frontal gyrus (SFG), superior parietal gyrus (SPG), and inferior temporal gyrus (ITG) than the healthy individuals. The results indicated that depressed participants recruited more frontal and parietal inhibitory control resources to inhibit the TBF items, but the attempt still failed because of negative bias. We also used the Support Vector Machine to perform multivariate pattern classification based on the brain activation during directed forgetting. The pattern of brain activity in directed forgetting of negative words allowed correct group classification with an overall accuracy of 75% (P=0.012). The brain regions which are critical for this discrimination showed abnormal activation when depressed participants were attempting to forget negative words. These results indicated that the abnormal neural circuitry when depressed individuals tried to forget the negative words might provide neurobiological markers for depression. PMID- 26639453 TI - A brachytic dwarfism trait (dw) in peach trees is caused by a nonsense mutation within the gibberellic acid receptor PpeGID1c. AB - Little is known about the genetic factors controlling tree size and shape. Here, we studied the genetic basis for a recessive brachytic dwarfism trait (dw) in peach (Prunus persica) that has little or no effect on fruit development. A sequencing-based mapping strategy positioned dw on the distal end of chromosome 6. Further sequence analysis and fine mapping identified a candidate gene for dw as a non-functional allele of the gibberellic acid receptor GID1c. Expression of the two GID1-like genes found in peach, PpeGID1c and PpeGID1b, was analyzed. GID1c was predominantly expressed in actively growing vegetative tissues, whereas GID1b was more highly expressed in reproductive tissues. Silencing of GID1c in plum via transgenic expression of a hairpin construct led to a dwarf phenotype similar to that of dw/dw peaches. In general, the degree of GID1c silencing corresponded to the degree of dwarfing. The results suggest that PpeGID1c serves a primary role in vegetative growth and elongation, whereas GID1b probably functions to regulate gibberellic acid perception in reproductive organs. Modification of GID1c expression could provide a rational approach to control tree size without impairing fruit development. PMID- 26639454 TI - CYP2C19 drug-drug and drug-gene interactions in ED patients. AB - BACKGROUND: CYP450 polymorphisms result in variable rates of drug metabolism. CYP drug-drug interactions can contribute to altered drug effectiveness and safety. STUDY OBJECTIVES: The primary objective was to determine the percentage of emergency department (ED) patients with cytochrome 2C19 (CYP2C19) drug-drug interactions. The secondary objective was to determine the prevalence of CYP2C19 polymorphisms in a US ED population. METHODS: We conducted a prospective observational study in an urban academic ED with 72,000 annual visits. Drug ingestion histories for the 48 hours preceding ED visit were obtained; each drug was coded as CYP2C19 substrate, inhibitor, inducer, or not CYP2C19 dependent. Ten percent of patients were randomized to undergo CYP2C19 genotyping using the Roche Amplichip. RESULTS: A total of 502 patients were included; 61% were female, 65% were white, and median age was 39 years (interquartile range, 22-53). One hundred thirty-one (26.1%) patients had taken at least 1 CYP2C19-dependent home drug. Eighteen (13.7%) patients who were already taking a CYP2C19-dependent drug were given or prescribed a CYP2C19-dependent drug while in the ED. Among the 53 patients genotyped, 52 (98%) were extensive metabolizers and 1 was a poor metabolizer. CONCLUSIONS: In a population of ED patients, more than a quarter had taken a CYP2C19-dependent drug in the preceding 48 hours, but few were given or prescribed another CYP2C19-dependent drug in the ED. On genotyping analysis, CYP2C19 polymorphisms were uncommon in our cohort. We conclude that changing prescribing practice due to CYP2C19 drug-drug interaction or genotype is unlikely to be useful in most US ED populations. PMID- 26639455 TI - Contrast-enhanced ultrasound as imaging technique for patients with acute flank pain into the ED. PMID- 26639456 TI - China's research status in emergency medicine: a 15-year survey of literature. AB - OBJECTIVES: To investigate the research status of emergency medicine in China through literature search of international emergency medicine journals and retrospectively compare the outputs of emergency medicine articles of the 3 major regions of China-Mainland (ML), Taiwan (TW), and Hong Kong (HK). METHODS: Emergency medicine journals were selected category from Science Citation Index Expand. Articles from the ML, TW, and HK were retrieved from PubMed database. The total number of articles, publication types, research contents, impact factors (IF), and articles published in each journal were conducted for quantity and quality comparisons. RESULTS: A total of 1760 articles from 19 emergency medicine journals were searched, of which 395 were from ML, 1210 from TW, and 155 from HK. Accumulated IF of articles from TW (2451.109) was much higher than that of ML (851.832) and HK (328.579), whereas the average IF of articles from TW (2.02) was the lowest. The number of case reports was the highest, which was, 69 from ML, 637 from TW, and 25 from HK, respectively. Although emergency medicine was involved with multiple organs and multiple systems, the reports of trauma accounted for 25% of the research contents. CONCLUSIONS: The total number of articles from both China and the rest of the world increased significantly from 2000 to 2014, especially ML. The total number of articles from TW was still much more than that of ML and HK, whereas the quality of articles from TW was not as good as ML and HK. Case report had the highest share of publication types, whereas the proportions of meta-analysis and observational study were the lowest. As for research contents, the proportion of trauma was still the highest. PMID- 26639459 TI - Current Drug Managements of Wilson's Disease: From West to East. AB - Wilson's disease (WD), also called hepatolenticular degeneration, is an autosomal recessive inheritance disorder of copper metabolism characterized by the multiple mutations in the ATP-ase 7B gene of chromosome 13q. About half of the WD patients have neurological or psychiatric symptoms. As WD is a kind of medicable or nearly curable neurodegenerative disease in the field of medicine, early consideration/examination and without delay/ life-long treatment usually lead to better prognoses. The drugs, also named as anticopper agents, are commonly used in clinics including D-penicillamine, trientine, sodium dimercaptosuccinate, dimercaptosuccinic acid, zinc and tetrathiomolybdate. This provides detailed reviews about these medicines. PMID- 26639457 TI - LPS-induced Murine Neuroinflammation Model: Main Features and Suitability for Pre clinical Assessment of Nutraceuticals. AB - Neuroinflammation is an important feature in the pathogenesis and progression of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal dementia and amyotrophic lateral sclerosis. Based on current knowledge in the field, suggesting that targeting peripheral inflammation could be a promising additional treatment/prevention approach for neurodegenerative diseases, drugs and natural products with anti-inflammatory properties have been evaluated in animal models of neuroinflammation and neurodegeneration. In this review, we provide an extensive analysis of one of the most important and widely used animal models of peripherally induced neuroinflammation and neurodegeneration - lipopolysaccharide (LPS)-treated mice, and address the data reproducibility in published research. We also summarize briefly basic features of various natural products, nutraceuticals, with known anti-inflammatory effects and present an overview of data on their therapeutic potential for reducing neuroinflammation in LPS-treated mice. PMID- 26639460 TI - Benign Acute Childhood Myositis due to Toxoplasmosis. PMID- 26639458 TI - mGlu5, Dopamine D2 and Adenosine A2A Receptors in L-DOPA-induced Dyskinesias. AB - Patients with Parkinson's disease (PD) receiving L-3,4-dihydroxyphenylalanine (L DOPA, the gold-standard treatment for this disease) frequently develop abnormal involuntary movements, termed L-DOPA-induced dyskinesias (LID). Glutamate overactivity is well documented in PD and LID. An approach to manage LID is to add to L-DOPA specific agents to reduce dyskinesias such as metabotropic glutamate receptor (mGlu receptor) drugs. This article reviews the contribution of mGlu type 5 (mGlu5) receptors in animal models of PD. Several mGlu5 negative allosteric modulators acutely attenuate LID in 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) monkeys and 6-hydroxydopamine(6-OHDA)-lesioned rats. Chronic administration of mGlu5 negative allosteric modulators to MPTP monkeys and 6-OHDA rats also attenuates LID while maintaining the antiparkinsonian effect of L-DOPA. Radioligand autoradiography shows an elevation of striatal mGlu5 receptors of dyskinetic L-DOPA-treated MPTP monkeys but not in those without LID. The brain molecular correlates of the long-term effect of mGlu5 negative allosteric modulators treatments with L-DOPA attenuating development of LID was shown to extend beyond mGlu5 receptors with normalization of glutamate activity in the basal ganglia of L-DOPA-induced changes of NMDA, AMPA, mGlu2/3 receptors and VGlut2 transporter. In the basal ganglia, mGlu5 receptor negative allosteric modulators also normalize the L-DOPA-induced changes of dopamine D2receptors, their associated signaling proteins (ERK1/2 and Akt/GSK3beta) and neuropeptides (preproenkephalin, preprodynorphin) as well as the adenosine A2A receptors expression. These results show in animal models of PD reduction of LID with mGlu5 negative allosteric modulation associated with normalization of glutamate, dopamine and adenosine receptors suggesting a functional link of these receptors in chronic treatment with L-DOPA. PMID- 26639461 TI - Management of Children with Juvenile Idiopathic Arthritis. AB - Juvenile idiopathic arthritis (JIA) comprises a group of heterogeneous disorders of chronic arthritis in childhood and remains the commonest pediatric rheumatic disease associated with significant long-term morbidity. Advances in understanding of the pathogenesis, better definition of disease control/remission measures, and the arrival of biological agents have improved the outcomes remarkably. Methotrexate (Mtx) remains the first-line disease modifying (DMARD) therapy for most children with JIA due to its proven efficacy and safety. Sulphosalazine (SSz) (especially for enthesitis) and leflunomide may also have a secondary role. Tumor necrosis factor inhibitors (TNF-I), alone or in combination with Mtx have shown tremendous benefit in children with polyarticular JIA, enthesitis related arthritis (ERA) and psoriatic arthritis. Tocilizumab appears very efficacious in systemic arthritis and abatacept and tocilizumab also appear to benefit polyarticular JIA; the role of rituximab remains unclear, though clearly beneficial in adult RA. TNF-I with Mtx is also effective in uveitis associated with JIA. Biologicals have demonstrated an impressive safety record in children with JIA, although close monitoring for rare but potentially dangerous adverse events, such as tuberculosis and other infections; paradoxical development of additional autoimmune diseases; and possibly an increased risk of cancers is warranted. PMID- 26639462 TI - Release of Pro-Aggregation Substances from Rabbit Leukocytes Exposed to UV Light: Role of Photo-Induced Apoptosis. AB - Accumulation of pro-aggregation substances in the incubation medium of isolated UV-irradiated rabbit leukocytes showed stronger correlation with photo-induced apoptotic death of leukocytes (r=0.92) than with their photo-induced necrotic death (r=0.70). It can be suggested that pro-aggregation substances release form leukocytes exposed to irradiation during preparation of these cells to apoptosis after UV irradiation. PMID- 26639463 TI - Incidence of Autoantibodies to C1Q Complement Component in Women with Miscarriages and Autoantibodies to Phospholipids and Chorionic Gonadotropin. AB - Autoantibodies to C1q complement component are often detected in patients with autoimmune diseases. The complement system is involved in the pathophysiology of gestosis. The incidence of anti-C1q autoantibodies was studied in women with miscarriages and autoantibodies to phospholipids and chorionic gonadotropin. Serum C3 and C4 complement components and anti-C1Q autoantibodies (IgG) were measured by ELISA. The median levels of C3 and C4 in patients with miscarriages were lower than in healthy women. Anti-C1q autoantibodies were more often found in the patients than in controls; patients with autoantibodies to phospholipids formed a risk group. Median levels of anti-C1q autoantibodies were higher in the patients with autoantibodies to phospholipids and chorionic gonadotropin than in healthy women. Hence, activation of the complement system and hyperproduction of anti-C1q autoantibodies were unfolding in patients with miscarriages, mainly in the patients with autoantibodies to phospholipids. PMID- 26639464 TI - Analysis of Populations of Memory T-Helper Cells Expressing CXCR3 and CCR6 Chemokine Receptors in Peripheral Blood of Patients with Chronic Viral Hepatitis C. AB - Flow cytometry was employed to examine the content of major populations of memory T helper cells and expression of chemokine receptors CXCR3 and CCR6 on their surface in peripheral blood drawn from virtually healthy people and the patients with chronic viral hepatitis C. The following combination of monoclonal antibodies had been used: CD62LFITC/CD45RA-PE/CD3-ECD/CCR6-PC7/CXCR3-APC/CD4-APC Cy7. In comparison with control group, the patients with chronic hepatitis C had a smaller number of populations of naive CD4(+) T cells and central memory CD4(+) T cells but a greater number of terminally differentiated effector memory CD4(+) T cells and effector memory CD4(+) T cells. No differences were revealed between CD4(+) T cell populations of both groups in expression of CXCR3 and CCR6 receptors. PMID- 26639465 TI - Sex Differences in the Hemorheological Effect of Antidiuretic Hormone. AB - Experiments on rats showed that treatment with desmopressin in combination with water load contributes to the general nonspecific response of the blood. Increased blood viscosity, fibrinogen concentration, and erythrocyte aggregation were observed. Hemorheological changes in comparison with the control were less pronounced in females. Sex differences in erythrocyte aggregation were most significant. PMID- 26639466 TI - Antioxidant Effect of Erythropoietin during Experimental Chronic Renal Failure. AB - The effects of erythropoietin (Epokrin, 900 U/kg) on the parameters of free radical oxidation in the plasma and lymphocytes of peripheral blood were studied in rats with chronic renal failure. We observed accumulation of primary (diene conjugates) and secondary (ketodienes, and conjugated trienes) LPO products in the heptane and isopropanol fractions of blood plasma and a decrease in superoxide dismutase and catalase activities in blood plasma. In lymphocytes, the concentration of primary, secondary and end-products (Schiff bases) of LPO increased in the isopropanol fraction of lipid extract. Treatment with erythropoietin was followed by a decrease in the level of primary and end products of LPO in the isopropanol fraction of lipid extract of the plasma and lymphocytes and an increase in of superoxide dismutase and catalase activities in the plasma. The content of primary LPO products in the isopropanol fraction of the plasma progressively decreased with increasing superoxide dismutase and catalase activities in the plasma. PMID- 26639467 TI - Age-Specific Peculiarities of Modulation of Blood Aldo-Keto Reductase Isoenzyme Spectrum. AB - The aldo-keto reductase spectrum of the blood was studied at different stages of ontogeny to elucidate the role of reduction pathway in utilization of the carbonyl products of free radical oxidation in modulation of organism sensitivity to the damaging effect of stress during ontogeny. The studies revealed the age specific changes in aldo-keto reductase spectrum in the blood. An analogy of the aldo-keto reductase spectrum structure in animals of early maturity and in old rats was found. The appearance of age specificity of the aldo-keto reductase spectrum in the blood creates metabolic prerequisites for changes in the efficiency of utilization of carbonyl products of free radical oxidation via their reductive transformation. PMID- 26639468 TI - pH-Dependent Changes in the Mechanisms of Transport of Chlorine e6 and Its Derivatives in the Blood. AB - We studied the effects of medium pH on steady-state distribution of chlorine e6 and its derivatives between the main transport proteins of human blood plasma. The decrease in medium pH from weakly alkaline (pH 7.4) to acid (pH 5.0) was followed by an increase in relative affinity of chlorines to lipoproteins and reduced their affinity to serum albumin. pH-Dependent changes in the parameters of distribution of photosensitizers between the plasma and blood cells was revealed. We discussed the role of charge and polarity degree of photosensitizer molecule in the mechanism of binding to serum albumin. A possible role of changes in hydrogen ion activity in the processes of selective accumulation of chlorines by tumor cells is discussed. PMID- 26639469 TI - Antiarrhythmic Activity of Taurepar during Ischemic and Reperfusion Damage to Myocardium. AB - The antiarrhythmic effect of taurepar, an N-phenylalkyl derivative of taurine, was examined in experiments on rats subjected to acute myocardial ischemia/reperfusion leading to arrhythmia development. During acute ischemia, taurepar (25 mg/kg) completely prevented early postocclusion arrhythmias including extrasystoles, ventricular tachycardia, and ventricular fibrillation. During postischemic reperfusion, taurepar (25 mg/kg) did not prevent extrasystoles and ventricular tachycardia, but precluded the development of ventricular fibrillation and the death of animals. The antiarrhythmic potency of taurepar surpassed that of lidocaine during acute myocardial ischemia and that of propranolol during ischemia/reperfusion injury. The results suggest that taurepar is a promising antiarrhythmic drug with high antifibrillation activity. PMID- 26639470 TI - Effect of Arachidonic Acid on the Rate of Oxygen Consumption in Isolated Cardiomyocytes from Intact Rats and Animals with Ischemic or Diabetic Injury to the Heart. AB - We studied the rate of oxygen consumption by isolated cardiomyocytes from intact rats and animals with experimental myocardial infarction or streptozotocin induced diabetes mellitus. The measurements were performed in standard incubation medium under various conditions of oxygenation and after addition of arachidonic acid (20 MUmol/liter). Under normoxic conditions, arachidonic acid improves respiration of cardiomyocytes from intact animals, but reduces this parameter in cells isolated from animals with pathologies. The intensity of O2 consumption by cardiomyocytes from intact rats and animals with pathologies was shown to decrease during hypoxia. Addition of arachidonic acid aggravated inhibition of respiration for cardiomyocytes from intact rats and specimens with myocardial infarction, but had no effect in diabetes mellitus. The effect of arachidonic acid on oxygen consumption rate is probably mediated by a nonspecific mechanism realized at the mitochondrial level. PMID- 26639471 TI - Activity of Heme Synthesis Enzymes in the Bone Marrow and Liver of August and Wistar Rats During the Neonatal Period and After Acute Postnatal Hypoxia. AB - Activity of heme synthesis enzymes in newborn August and Wistar rats was studied after acute hypoxic hypoxia. Daily production of erythrocytes and activities of aminolevulinate synthase, aminolevulinate dehydratase, and heme synthetase were measured in the bone marrow (15-30 min after birth and on days 1 and 3 of life) and liver (day 3 after birth). Hypoxia was followed by a decrease in activity of heme synthesis enzymes in the liver (especially in August rats) and reduction of the daily erythrocyte production (especially in Wistar rats). Our results suggest that the response of heme synthesis enzymes to hypoxic exposure in newborn rats is genetically determined. The observed changes are more pronounced in Wistar rats. PMID- 26639472 TI - Histopathological evaluation of gastro protective effect of Berberis vulgaris (Zereshk) seeds against aspirin induced ulcer in albino mice. AB - The present study was carried out to investigate the antiulcer activity of Berberis vulgaris (Zereshk) seeds in albino mice. After acclimatization, animals were divided into six equal groups. Aspirin 150 mg/kg was used to induce gastric ulcer in all groups except normal control. Omeprazole 20mg/kg was used as synthetic anti ulcer drug in study. Three dose levels of B. vulgaris seed powder 300 mg/kg, 600 mg/kg and 900 mg/kg were used respectively orally. Histopathological analysis was carried out to evaluate the gastroprotective activity of B. vulgaris seed powder. Results of the study showed that in case of aspirin treated mice gastric luminal mucosa villi were decreased in height or were absent. In the glandular region there was connective tissue proliferation and also infiltration of cells. Similar infiltration of cells was present on muscularis mucosa. In esophageal region tumor cells were present. However three dose levels of B. vulgaris significantly reduced the tissue proliferation, infiltration of cells and sloughing induced by aspirin. Highest dose of B. vulgaris (900 mg/kg) showed similar results as synthetic antiulcer drug omeprazole. PMID- 26639473 TI - Preparation, biodistribution and scintigraphic evaluation of (99m)Tc-lincomycin. AB - A complex of lincomycin was synthesized with technetium-99m. The synthesis was carried out by using SnCl2.2H2O as reducing agent and ascorbic acid as stabilizer. The effect of various parameters such as amount of ligand/reducing agent, pH value and reaction time on radio labeling process was studied. The characterization of the (99m)Tc-Lincomycin was performed by HPLC and electrophoresis Biodistribution studies were carried out by analyzing the model of bacterial infectious rats (Sprague-Dawley). The uptake of infectious lesions at different time interval was also studied by using scintigraphic technique. The complex showed effective target to non-target ratio for various inflammatory or infectious lesions. The (99m)Tc-Lincomycin effective binding to living bacteria and could be used successfully as an infection imaging agent. PMID- 26639474 TI - Efficacy of grape seed and skin extract against doxorubicin-induced oxidative stress in rat liver. AB - Doxorubicin (Dox) is an anthracycline used in chemotherapy, although it causes toxicity and oxidative stress. Grape seed and skin extract (GSSE) is a mixture of polyphenolic compounds with antioxidant properties. To evaluate the hepato toxicity of Dox on healthy rats as well as the protective effect of GSSE, rats were treated with GSSE (500mg/kg bw) during 8 days. At the 4th day of treatment, they received a single dose of Dox (20 mg/kg bw). After the treatment (9th day), livers were collected and processed for oxidative stress status. Dox increased MDA (+ 900%), decreased catalase (-60%) and increased peroxidase (+90%) and superoxide dismutase (+100%) activities. In this latter case Dox mainly increased the iron isoform. Furthermore Dox altered intracellular mediators as catalytic free iron (-75%), H2O2(-75%) and calcium (+30%). Dox also affected liver function by elevating plasma triacylglycerol and transaminases and liver morphology by altering its typical architecture. Importantly all Dox-induced liver disturbances were alleviated upon GSSE treatment. Dox induced liver toxicity and an oxidative stress mainly characterized by increased lipoperoxidation but not protein carbonylation. GSSE efficiently protected the liver from Dox-induced toxicity and appeared as a safe adjuvant that could be incorporated into chemotherapy protocols. PMID- 26639475 TI - Simultaneous quantitation of Ofloxacin, Fexofenadine HCl and Diclofenac Potassium in affixed dose combinative formulation by HPLC-UV method. AB - A high-pressure liquid chromatography (HPLC-UV) based simple and specific method for simultaneous quantitative determination of Ofloxacin, Fexofenadine HCl and Diclofenac Potassium has been developed and validated according to ICH guidelines. Chromatographic separation of the three drugs was carried out on 4.6 x 250 mm x 5 u Licrospher RP Select B Column, using mobile phase constituted of methanol and phosphate buffer pH 3.5 (650: 350), pH adjusted to 3.5 +/- 0.05 with dilute ortho-phosphoric acid and delivered at a flow rate of 1 ml/min. The eluents were detected at UV wavelength of 220 nm and the retention times for Ofloxacin, Fexofenadine HCl and Diclofenac Potassium were 2.5 minutes, 4 minutes and 11.5 minutes, respectively. This method is suitable and specific for the three drugs and was found to be linear (R2 > 0.996), accurate, specific, reproducible and robust over a concentration range of 0.05 to 0.15 mg/ml for Ofloxacin, 0.015 to 0.045 mg/ml for Fexofenadine HCl and 0.0125 to 0.0375 mg/ml for Diclofenac Potassium. The proposed method is simple and convenient, hence easily utilized for the characterization and quantitation of the three drugs in a single formulation for combination therapy of rheumatoid arthritis, sepsis, infection with fever and flu. PMID- 26639476 TI - Pluronic F127 as a drug vehicle used in chick embryo chorioallantoic membrane shell-less model. AB - The developing vascular network is grown on the surface of chick embryo chorioallantoic membrane (CAM), so CAM is widely used as an in vivo model to study the angiogenesis. Because the CAM is hindered or wrinkled by the vehicle, the drug effect is difficult to be observed. In the present study, we firstly introduced the pluronic F127 aquogel to deliver drugs for the CAM model. The biocompatibility and advantage of this vehicle was shown by applied ranibizumab pluronic F127 mix on the CAM. The results were showed that, the growth of blood vessels was not impaired by pluronic F127 gel, and the gel was almost imperceptible on the CAM, at the same time, the degradation of blood capillaries caused by ranibizumab was clearly visible. In conclusion, pluronic F127 was a good vehicle for angiogenesis research. PMID- 26639477 TI - Formulation and clinical evaluation of topical dosage forms of Indian Penny Wort, walnut and turmeric in eczema. AB - Eczema is characterized by itching, lichenification, scaling, oedema and erythema. Current management strategies include corticosteroids, which are limited due to side effects. Many herbal remedies are used traditionally but unfortunately have not been validated in controlled clinical trials. Three popular traditional treatments of eczema include Indian pennywort, Walnut and Turmeric. In this study three topical formulations (micro emulsion, gel and ointment) were prepared from extracts of Indian pennywort, Walnut and Turmeric. These formulations were monitored for stability for a period of three months. Controlled clinical trials were conducted on 360 eczema patients. Clinical parameters observed were degree of erythema, oedema, scaling, itching and lichenification. Effects of each formulation on these clinical parameters were compared with placebo formulations. Micro emulsion formulations in all cases proved to be more effective in reducing semi quantitative scores of erythema and oedema. Itching was relieved more by gel formulation. The ointment showed more efficacy towards scaling and lichenification. Comparison of the effects of placebo and the specific formulations was performed by chi-square statistics and found to be highly significant. In summary it is concluded that all the formulations could be used as promising source for treatment of eczema. PMID- 26639478 TI - First report about pharmaceutical properties and phytochemicals analysis of Rosa abyssinica R. Br. ex Lindl. (Rosaceae). AB - In vitro antimicrobial efficacy of seven solvent extracts from leaves and hips of Saudi Arabian weed Rosa abyssinica against a variety of human pathogenic bacteria and Candida species have been evaluated using well diffusion methods. Phytochemicals present in the leaves and hips of Rosa abyssinica has been characterized using Gas Chromatogram Mass spectrometry analysis. The extracts comparative efficacy against tested microbes gained from the fresh and dry leaves exhibited more prominent activity than fresh and dry hips. The methanol, chloroform, petroleum ether, acetone and diethyl ether extracts have a greater lethal effect on pathogenic microbes than hot water extracts, while cold-water extracts showed no activity. Twenty-four phytochemicals have been characterized from ethanol extract of the leaves of Rosa abyssinica and fifteen from hips by GC MS. The major compounds detected in the leaves were squalene (38.21%), ethane, 1,1-diethoxy- (9.65%), beta-D-glucopyranose, 1,6-anhydro- (8.55%), furfural (5.50%) and 2-furancarboxaldehyde 5-(hydroxymethyl)- (5.19%). The major compounds in the hips were 2-furancarboxaldehyde 5-(hydroxymethyl)- (51.27%), beta-D glucopyranose, 1,6-anhydro- (8.18%), 4H-pyran-4-one, 2,3-dihydro-3,5-dihydroxy-6 methyl- (7.42%), 2,5-furandione, dihydro-3-methylene- (6.79%) and furfural (5.99%). Current findings indicate that extract from leaves and hips of Rosa abyssinica and the bioactive components present could be used as pharmaceutical agents. PMID- 26639479 TI - Evaluation of Medicago sativa L. sprouts as antihyperlipidemic and antihyperglycemic agent. AB - Medicago sativa L. (Alfalfa) is traditionally used to treat diabetes. This study was designed to investigate the potential antihyperlipidemic and antihyperglycemic activity of M. sativa sprouts in streptozotocin (STZ) induced diabetes via i.p. injection of 55 mg/kg of STZ. Experimental animals were divided into the following groups: GP1 (normal), GP2 (STZ-hyperlipidemic), GP3 (rouvastatin), GP4 (metformin), GP 5-9 (diabetic treated with methanolic, petroleum ether, chloroform, ethyl acetate and butanol extracts). The administration of the total methanolic extract (500 mg/kg), the petroleum ether (32.5mg) and butanol fractions (60 mg) for 4 weeks significantly decreased (p<0.05) triglycerides (TG), total cholesterol (TC), low-density lipoproteins (LDL) and very low density lipoproteins (VLDL) in comparison to rouvastatin. Petroleum ether fraction proved to exhibit the best activity as antihyperlipidemic agent (12.23%). On the other hand, ethyl acetate fraction retained the best activity (vs. metformin) as antihyperglycemic agent. Histopathological evidences on liver, pancreas and spleen were in agreement with the above mentioned results. Purification, characterization, and identification of isolated compounds from the active fractions afforded 9 compounds: beta sitosterol and stigmasterol from the petroleum ether fraction; 10-hydroxy coumestrol, apigenin, genistein, p-hydroxy-benzoic-acid, 7, 4'- dihydroxyflavone, quercetin-3-glucoside and sissotrin from the ethyl acetate fraction. PMID- 26639480 TI - Synergistic antibacterial activity of Curcumin with antibiotics against Staphylococcus aureus. AB - This study evaluated the synergistic antibacterial activity of Curcumin with 8 different antibiotic groups. Two reference, one clinical and ten environmental strains of Staphylococcus aureus (S. aureus) were tested. Disc diffusion assay with 25 MUg/mL Curcumin demonstrated synergism in combination with a majority of tested antibiotics against S. aureus. However, checkerboard micro dilution assay only showed synergism, fractional inhibitory concentration index (FICI) <0.5 in three antibiotics i.e. Gentamicin, Amikacin, and Ciprofloxacin. Other antibiotics showed indifferent interactions but no antagonism was observed. In time-kill curve, appreciable reduction of bacterial cells was also observed in combination therapy (Curcumin + antibiotics) compared to monotherapy (Curcumin or antibiotic(s) alone). The antibiotics with higher synergistic interaction with Curcumin are arranged in a decreasing order: Amikacin > Gentamicin > Ciprofloxacin. PMID- 26639481 TI - Hepatic histological alterations and biochemical changes induced by sildenafil overdoses. AB - Sildenafil is used for the treatment of erectile dysfunction and is helping millions of men around the world to achieve and maintain a long lasting erection. Fifty healthy male rabbits (Oryctolagus cuniculus) were used in the present study and exposed daily to sildenafil (0, 1, 3, 6, 9 mg/kg) for 5 days per week for 7 weeks to investigate the biochemical changes and alterations in the hepatic tissues induced by this drug overdosing. In comparison with respective control rabbits, sildenafil overdoses elevated significantly (p-value<0.05, ANOVA test) alanine aminotransferase (ALT), aspartate aminotransferase (AST), testosterone, follicular stimulating hormone and total protein, while creatinine and urea were lowered with no significant alteration was observed in uric acid and luteinizing hormone concentration. Also sildenafil provoked hepatocytes nuclear alterations, necrosis, hydropic degeneration, bile duct hyperplasia, Kupffer cells hyperplasia, inflammatory cells infiltration, hepatic vessels congestion and evident partial depletion of glycogen content. The results show that subchronic exposure to sildenafil overdoses exhibits significant biochemical and alterations in the hepatic tissues that might affect the functions of the liver and other vital organs. PMID- 26639482 TI - Bacopa monnieri: An evaluation of antihyperglycemic and antinociceptive potential of methanolic extract of whole plants. AB - Antihyperglycemic and antinociceptive activity studies were carried out with methanolic extract of whole plants of Bacopa monnieri, respectively, through oral glucose tolerance test and gastric pain model induced by acetic acid in Swiss albino mice. In OGTT (oral glucose tolerance tests) conducted with glucose challenged mice, the extract, administered at four doses of 50, 100, 200 and 400mg per kg body weight, dose-dependently and significantly inhibited the increase in serum glucose concentrations, respectively, by 33.3, 34.2, 42.1 and 44.2%. A standard antihyperglycemic drug, glibenclamide, when administered at a dose of 10mg per kg body weight, inhibited increase in serum glucose concentration by 50.7%. From the results, it can be concluded that the methanolic extract of the plant possess significant antihyperglycemic potential. In antinociceptive activity tests, administration of the extract at the aforementioned four doses also significantly and dose-dependently reduced the number of acetic acid-induced gastric constrictions in mice. The percent inhibitions in gastric constrictions were, respectively, 43.4, 46.6, 50.0, and 53.4 at the above four doses. A reference antinociceptive drug, aspirin, when administered at a dose of 200 mg per kg body weight, reduced the number of gastric constrictions by 40.0%. Thus the extract at even the lowest dose of 50 mg, demonstrated antinociceptive activity better than that of aspirin, and which activity was much more than aspirin at the other three higher doses tested. The results demonstrate that the plant can be an excellent candidate for further studies towards isolation of antihyperglycemic and pain-killing compounds. PMID- 26639483 TI - Assessment of sub-chronic, hematological and histopathological toxicities of a herbal combination. AB - The herbal combination under study consists of Withania somnifera, Tribulus terrestris, Mucuna pruriens and Argyria speciosa. Present study is mainly designed to investigate the gross physical, sub-chronic, hematological and histopathological effects of the combination widely used for its stimulating, revitalizing and fertility boosting effects in Pakistan. Sub-chronic, hematological and histopathological outcomes of herbal combination were assessed on 27 albino rabbits weighing from 1000 gm-1500 gm after giving herbal combination for 60 days in two doses 27 and 81 mg/kg against control. No significant toxicity was revealed during the entire period of study, however some biochemical changes were observed in kidney and liver but these changes did not coincide with histopathological findings. There was no mortality and evidence of systemic toxicity including hematological toxicity following 60 days administration of herbal combination. Results of present study suggest that further studies are required on large number of animals before reaching to a definite conclusion, more over clinical studies should also be conducted to confirm the possible toxic effects of the herbal combination. PMID- 26639484 TI - Determination of total phenolics, flavonoid contents and antioxidant activity of different mBHT fractions: A polyherbal medicine. AB - In this study, antioxidant activity, total phenolic and flavonoids content of four different fractions from the traditional Korean polyherbal medicine of Modified Bo-yang-Hwan-o-Tang (mBHT) was determined using spectrophotometric methods. Antioxidant activity of fractions was expressed as percentage of DPPH radicals inhibition and IC50 values (MUg/ml). Values in percentage ranged from 48.35 to 77.43%. The reducing powers of all the extracts were comparable with that of positive control sample of Butylated hydroxyl tolune (BHT) and ascorbic acid which was found to be dose dependent. Total phenolic content ranged from 106.83 +/- 0.002 to 188.661 +/- 0.002 mg/g, expressed as gallic acid equivalents. The total flavonoid contents varied from 28.44 +/- 0.001 to 105.25 +/- 0.001 mg/g, expressed as quarcetin equivalents. Ethyl acetate fractions of mBHT showed the highest phenolic (188.66 mg GAE/g) and flavonoids (105.25 mg QAE/g) contents and strong antioxidant activity. Total phenolics and flavonoid content of all the mBHT fractions were found reasonably correlated with IC50 of DPPH (R2=0.980 and 0.932, respectively). The high contents of phenolic compounds indicated that these compounds responsible for antioxidant activity. Therefore, ethyl acetate fractions of mBHT can be regarded as promising candidates for natural plant sources of antioxidants. PMID- 26639485 TI - Synthesis, Spectral investigation (1H, 13C) and Anti-microbial Screening of benzophenone imines. AB - New series of benzophenone imines with general formula Ph2-C=NR; R = Benzyl, 4 Fluorobenzyl, Naphthyl, Phenyl, 4-Nitrophenyl were synthesized by condensation of dichlorodiphenylmethane and different aromatic primary amines (1:1) Those imines were characterized by different physiochemical and spectroscopic techniques like melting point, elemental analysis, FT-IR, multinuclear NMR (1H, 13C). After characterization, imines were subjected to anti-microbial activities. All compounds showed promising activity against different bacterial strains like Escherichia coli, Bacillussubtilis, Pasturellam ultocida and Staphylococcus aureus as well as fungal strains like Alternata alternaria, Ganoderma lucidium, Penicillium notatum and Trichoderma harzianum using Amoxicillin and Flucanazole as a standard drugs respectively. PMID- 26639486 TI - Short Communication: Perception and attitude of pharmacy students towards learning tools. AB - Use of technology in education has increased worldwide. Teaching methodologies are shifting from traditional classroom lectures to e-learning and computer-based learning. Pakistani students are also now fathoming necessity of acquiring tools for strengthening their knowledge and skills. The objective of present study was to analyze the shifting trends (perception and attitudes) of Pakistani Pharmacy students towards learning tools. A survey based study conducted on 296 students from various years of Pharmacy, studying in a state owned university, Karachi, Pakistan. This study was initially piloted and Cronbach's-alpha was computed for evaluation of internal consistency of questionnaire (for perception; 0.660, for attitude; 0.777 respectively). Data was computed by SPSS, version 16 (Crosstab) and Chisquare (P=0.05). Most of the students strongly agreed (53%; chi2 =495;P<0.05) that introducing technology will improve learning; books are reliable reading source (53%; chi2 =437.23; P<0.05) or book-reading is essential (50%; chi2 =360.36; P<0.05) while others disagreed that they only study from class lectures (31%; chi2 =17.22; P<0.05); not take classes (41%; chi2 =48.21; P<0.05); have used software (44%; chi2 =46.54; P<0.05). Majority of the students agreed on incorporating technology to improve learning. Other factors such as unavailability and expenditure of books influenced their ability to learn. This study might assist policy makers in developing policies that could improve learning. PMID- 26639487 TI - Study of levan productivity from Bacillus subtilis Natto by surface response methodology and its antitumor activity against HepG2 cells using metabolomic approach. AB - Levan productivity of Bacillus subtilis Natto was evaluated in submerged culture varying the pH, temperature and culture time, using factorial design and response surface methodology. The characterization of levan molecular weight was performed by HPSEC and its antitumor activity against HepG2 cells using metabolomic approach was also evaluated. At first, the variables investigated, as well as their interactions, demonstrated significant effect. Further, a second design using the same variables at different levels was developed. Thus, according to the model, an optimized value corresponding to 5.82 g.L-1.h-1 was achieved at pH 8, 39.5 degrees C in 21 hours, the highest value reported so far. After analysis by HPSEC, two molecular weights were obtained corresponding to 72.37 and 4146 kDa. The levan promoted an increase of acetate, alanine, lactate and phosphocreatine in HepG2 cells suggesting an alteration in the bioenergetics pathways and cellular homeostasis by intracellular accumulation of lactate, justifying its antitumor activity. PMID- 26639488 TI - Apomorphine induced conditioned place preference and sensitization is greater in rats exposed to unpredictable chronic mild stress. AB - CNS stimulants are the class of the drugs that may be used to get relief from depression. Apomorphine is a D1 and D2 receptor agonist with a CNS stimulatory effect used for the treatment of Parkinson's disease is also abused. Although many drugs of abuse produce tolerance and dependence. Long term use of pshycostimulants produce reverse tolerance described as sensitization. These drugs also have a number of other beneficial effects but their therapeutic use is limited because of abuse potential. Conditioned place preference (CPP) test is used to monitor the reinforcing effect of drugs of abuse. Stress is an important factor that precipitates and potentiates addictive effects of different drugs of abuse. The present study was designed to investigate the addictive effect of apomorphine (1mg/kg) in rats previously exposed to repeated unpredictable chronic mild stress for 10 days (animal model of depression). Results from present study illustrate that unpredictable chronic mild stress potentiates the reinforcing effects of apomorphine as the number of entries and the time spent in the CPP compartment associated with drug administration is increased. Motor activity was taken as a parameter for behavioral sensitization which is induced by repeated administration of apomorphine, monitored as the number of cage crossings in light compartment of the CPP apparatus, also increased. PMID- 26639489 TI - Biotransformation of swertiamarin by Aspergillus niger. AB - The biotransforamtion of swertiamarin has been carried out using Aspergillus niger. The results showed that 60% swertiamarin were metabolized into two metabolites during the 5 days of biotransformation. The metabolites were identified as erythrocentaurin and 5-ethylidene-8-hydroxy-3,4,5,6,7,8-hexahydro 1Hpyrano[3,4-c]-pyridine-1-one, a novel alkaloid, with NMR and MS. The hydrolysis of glucosidic bond catalyzed by beta-D-glucosidase was found to be the rate limiting reaction in pathway of biotransformation of swertiamarin. PMID- 26639490 TI - Role of nutrients and environmental conditions for the production of dextransucrase from L. mesenteroides KIBGE-IB26. AB - The bacterial strains capable of producing dextransucrase enzyme were isolated from different fruits and vegetables sources. In primary screening, five strains were selected on the basis dextransucrase production and among them L. mesenteroides KIBGE- IB26 isolated from bottle gourd (Lagenaria Vulgaris) was selected for further studies. For the enhancement of enzyme production, different physicochemical parameters were optimized. Maximum production of dextransucrase was achieved after 06 hrs using sucrose (20.0 g/l) as a substrate at 25 degrees C. Maximum dextransucrase production was achieved when medium pH was kept 7.5 before sterilization. In addition, medium was also supplemented with CaCl2 and K2HPO4 and maximum enzyme production was achieved at 0.0025 g/dl calcium chloride and 2.0 g/dl K2HPO4with enzyme activity of 87 DSU/ml/hr. Production of dextransucrase in shorter period of time makes this strain an attractive candidate for commercial production of dextransucrase. PMID- 26639491 TI - Coumarins and flavonoid from Murraya paniculata (L.) Jack: Antibacterial and anti inflammation activity. AB - The ethyl acetate extract of leaves of Murraya paniculata (L.) Jack was described in the previous in vitro study on the inhibition effect on the growth of periodontopathic bacteria and the reduction of cytokines from LPS-stimulated macrophages. In this study, four coumarins including murrangatin (1), murrangatin acetate (2), murranganonesenecionate (3), micropubescin (4) and one flavonoid, 3', 4', 5', 7-tetramethoxyflavone (5) were isolated from the leaves of ethyl acetate extract of M. paniculata. MTT assay was used to test cytotoxicity on human gingival fibroblast and monocytes. The isolated compounds were evaluated for their antibacterial effect against Porphyromonas gingivalis (ATCC33277) and anti-inflammation on lipopolysaccharide-stimulated inflammation using monocyte cells. All isolated compounds exhibited antibacterial activity against P. gingivalis (ATCC 33277). Murranganonesenecionate (3) was highly potent anti inflammation properties. The coumarin constituents from M. paniculata leaves might be potential lead molecules for the development of antimicrobial drugs for treating periodontal disease. PMID- 26639492 TI - Hypo and hyperglycemia among tramadol overdose patients in Loghman Hakim Hospital, Tehran, Iran. AB - Tramadol is a synthetic and centrally active analgesic. Hypoglycemia as another possible major side effect among abusers has not been known well. Our objective is evaluation of the Blood Glucose Level (BGL) among tramadol-overdosed patients. This prospective cross-sectional study was performed from Feb to June 2013; BGL was measured at the time of admission, 8 and 12 hours later. All patients with hypoglycemia received infusion of 0.5-1 gr/kg of hypertonic dextrose and their BGL was checked every hour until normal BGL. Patients' demographic, clinical and paraclinical data were collected. Totally, 128 patients with a mean (SD) age of 24.5 (6.9) years were recruited; 127 (99.2%) were male. Seizure occurred in 59.4% cases. Mean +/- SD admission BGL was 94.88 +/- 21.5mg/dL. Fourteen patients experienced hypoglycemia within 12 hours period. Hyperglycemia was experienced in 8 patients (6.25%) on admission day. There was no significant relation between the dose of tramadol and BGL. In conclusion, hypoglycemia must be considered as an important side effect of tramadol-overdose. It is suggested that serial BGL monitoring in cases of Tramadol-overdose should be done for early recognition of hypoglycemia and its timely management. Also hyperglycemia may be revealed. PMID- 26639493 TI - Antimicrobial activity of Nigella sativa L. seed oil against multi-drug resistant Staphylococcus aureus isolated from diabetic wounds. AB - Microbial resistance to existing antibiotics has led to an increase in the use of medicinal plants that show beneficial effects for various infectious diseases. The study evaluates the susceptibility of multidrug resistant Staphylococcus aureus to Nigella sativa oil. Staphylococcus aureus was isolated from 34 diabetic patient's wounds attending the Renaissance hospital, Nsukka, Southeast Nigeria. The isolates were characterized and identified using standard microbiological techniques. Isolates were cultured and a comparative In vitro antibiotic susceptibility test was carried out using the disk diffusion method. Of the 34 samples collected, 19(56%) showed multidrug resistance to the commonly used antibiotics. Nigella sativa oil was then studied for antibacterial activity against these multidrug resistant isolates of Staphylococcus aureus in varying concentration by well diffusion method. The oil showed pronounced dose dependent antibacterial activity against the isolates. Out of 19 isolates, 8(42%) were sensitive to undiluted oil sample; 4(21%) of these showed sensitivity at 200 mg/ml, 400 mg/ml and 800 mg/ml respectively. Eleven (58%) of the isolates were completely resistant to all the oil concentrations. The present study, reports the isolation of multi-drug resistant S. aureus from diabetic wounds and that more than half of isolates were susceptible to different concentrations N. sativa oil. PMID- 26639494 TI - Ultra structural study of the rat cheek epithelium treated with Neem extract. AB - The purpose of this study was to investigate the effects of neem extract (Azadirachta indica A. Juss) on the ultrastructure of the rat oral epithelium, because neem extract has been added in the tooth paste as an anti-plaque-forming substance in Asian countries. The non-toxic dose of 2000 mg/kg body weight of Neem extract (NBE) was applied daily to the surface of buccal epithelium for four weeks and controls did not receive Neem extract. After four weeks cheek epithelial tissues were excised and processed for light microscopy, scanning and transmission electron microscopy. Light microscopy did not show significant differences between NBE-treated and control epithelium. Difference between control and treated rats weight was non-significant. Moreover, time period was also non-significant. Irregular cell surfaces were noticed when compared to control specimens when examined by scanning electron microscopy. Under transmission electron microscopy, wider intercellular spaces were observed in the treated epithelial spinous cellular layers when compared to control. Further, more keratohyalin granules were present in experimental granular cells. It was concluded that present study showed differences between Neem-treated and control in epithelial tissues but these structural differences may not be related to adverse side effects of the Neem extract. PMID- 26639495 TI - Formulation and in-vitro evaluation of floating bilayer tablet of lisinopril maleate and metoprolol tartrate. AB - The purpose of this study was to introduce the technology for the development of rate-controlled oral drug delivery system to overcome various physiological problems. Several approaches are being used for the purpose of increasing the gastric retentive time, including floating drug delivery system. Gastric floating lisinopril maleate and metoprolol tartrate bilayer tablets were formulated by direct compression method using the sodium starch glycolate, crosscarmellose sodium for IR layer. Eudragit L100, pectin, acacia as sustained release polymers in different ratios for SR metoprolol tartrate layer and sodium bicarbonate, citric acid as gas generating agents for the floating extended release layer. The floating bilayer tablets of lisinopril maleate and metoprolol tartrate were designed to overcome the various problems associated with conventional oral dosage form. Floating tablets were evaluated for floating lag time, drug contents and in-vitro dissolution profile and different kinetic release models were applied. It was clear that the different ratios of polymers affected the drug release and floating time. L2 and M4 showed good drug release profile and floating behavior. The linear regression and model fitting showed that all formulation followed Higuchi model of drug release model except M4 that followed zero order kinetic. From the study it is evident that a promising controlled release by floating bilyer tablets of lisinopril maleate and metoprolol tartrate can be developed successfully. PMID- 26639496 TI - Apoptotic and antioxidant activities of methanol extract of Mussaenda roxburghii leaves. AB - roxburghii. Anticancer activity of MMR has been carried out on Ehrlich ascites carcinoma (EAC) cells with three different doses (20, 40 and 60 mg/kg/day) by observing different parameters such as tumor weight, survival time of EAC-bearing mice, growth inhibition of EAC cells, morphological changes and nuclear damage of EAC cells etc. whereas antioxidant activity was determined by measuring total antioxidant, DPPH free radical scavenging, ferrous reducing capacity assay. The extract showed highest anticancer activity at 60 mg/kg day!--1(i.p.). It caused 81.4% (P<0.01) cells growth inhibition and reduced tumor burden significantly (78.5%; P<0.001) in comparison to control. It also increased life span of EAC bearing mice significantly (73.5%; P<0.01). MMR treated EAC cells showed membrane blebbing, chromatin condensation, nuclear fragmentation (apoptotic feature) in Hoechst 33342 staining under fluorescence microscope. DNA fragmentation assay in agarose gel (1.5%) electrophoresis also rectified that it causes EAC cells death by apoptosis. MMR also exhibited moderate antioxidant properties in dose dependent manner. Thus, this plant can therefore be considering a resource for natural chemo-preventive drugs as well as a possible pharmaceutical supplement. PMID- 26639497 TI - Industrially important hydrolytic enzyme diversity explored in stove ash bacterial isolates. AB - Extreme environments merit special attention and significance because of the possible existence of thermophilic microorganisms in such ecological niches. Keeping this in mind indigenous stove ash samples were explored for extremophilic bacteria in term of their biodiversity. Accordingly, this study reports 37 bacterial isolates from the local wood run oven (Tandoor) ash samples. All the isolated strains belong to genus Bacillus on the bases of morpho-cultural and biochemical considerations. The average temperature tolerance profile was >45 degrees C thereby, indicating towards the thermophilic nature of the isolated strains. The Bacillus isolates were screened for 10 different hydrolytic enzymes (cellulase, xylanase, amylase, pectinase, caseinase, keratinase, lipase, esterase, dextranase and beta-galactosidase) by plate screening method using the medium incorporated with specific substrate(s). It was found that keratinase was produced by all the isolates while, 36 (97.2%) isolates showed caseinase and esterase production. Amylase was produced by 35(94.6%) isolates and 34 (91.8%) isolates were able to degrade Tween-80 and xylan as substrate for lipase and xylanase respectively. The enzyme, beta-galactosidase was produced by 31 (89.1%) of the isolates. Cellulase and dextranase were produced by 26 (70.2%) and 22 (59.4%) isolates respectively. None of the isolates could (under the existing conditions) produce pectin-hydrolyzing enzyme. According to the Tukey's post hoc test, significant difference was found between the mean enzyme index of all the (screened) enzymes. Thus, the isolated bacterial strains with diverse hydrolytic potential may be of great value and relevance for the existing (national) industrial setups. PMID- 26639498 TI - Preparation and characterization of two new forced degradation products of letrozole and development of a stability-indicating RP-LC method for its determination. AB - Two new hydrolytic products of letrozole were identified and proved to be true degradation products obtained by alkaline and acidic degradation of the drug. The acid and amide forms of the nitrile groups of letrozole were prepared and identified by IR and mass spectroscopic techniques. Subsequently, a simple, precise and selective stability-indicating RPLC method was developed and validated for the determination of letrozole in the presence of its degradation products. Letrozole was subjected to alkali and acid hydrolysis, oxidation, thermal degradation and photo-degradation. The degradation products were well isolated from letrozole. The chromatographic method was achieved using gradient elution of the drug and its degradation products on a reversed phase Zorbax Eclipse C18 column (100mm x 4.6mm, 3.5 MUm) using a mobile phase consisting of 0.01M KH2PO4and methanol at a flow rate of 1 mL min-1. Quantitation was achieved with UV detection at 230 nm. Linearity, accuracy and precision were found to be acceptable over the concentration range of 0.01-80 MUgmL-1. The proposed method was successfully applied to the determination of letrozole in bulk, plasma and in its pharmaceutical preparation. PMID- 26639499 TI - Potent AChE enzyme inhibition activity of Zizyphus oxyphylla: A new source of antioxidant compounds. AB - The purpose of this study was to assess the antioxidant potential and enzyme inhibition of various fractions of Zizyphus oxyphylla. The plant metabolites were extracted in methanol and partitioned with n-hexane, chloroform, ethyl acetate and n-butanol successively. Phytochemical screening showed presence of alkaloids, terpenoids and flavonoids in ethyl acetate and n-butanol fractions. The antioxidant potential and acetylcholine esterase assay of all these fractions and remaining aqueous fraction was evaluated by using reported methods. The results revealed that chloroform soluble fraction exhibited highest percent inhibition of DPPH radical as compared to other fractions. It showed 95.01 +/- 0.37% inhibition of DPPH radical at a concentration of 120 MUg/mL. The IC50 of this fraction was 13.20 +/- 0.27 MUg/mL, relative to butylated hydroxytoluene (BHT, a reference standard), having IC50 of 12.10 +/- 0.29 MUg/mL. It also showed highest total antioxidant activity i.e. 1.723 +/- 0.34 as well as highest FRAP value (339.5 +/- 0.57 TE MUm/mL) and highest total phenolic contents (142.65 +/- 1.20 GAE mg/g) as compared to the other studied fractions. The fractions were also studied for Acetylcholine esterase enzyme (AChE) enzyme inhibition activity and n-butanol soluble fraction exhibited maximum inhibition (95.5 +/- 0.13 mg/mL with IC50 =9.58 +/- 0.08 mg/mL relative to galanthamine (13.26 +/- 0.73 mg/mL), while n- hexane soluble fraction (165.15 +/- 0.94 mg/mL) showed non-significant. We are still working to isolate pure compounds for active fractions targeting potent inhibition responsible for some activities. PMID- 26639500 TI - Cadmium-glutathione complex formation in human t-cell and b-cell lymphocytes after their incubation with organo-cadmium diacetate. AB - Cadmium intake is associated with oxidative stress that causes depletion of intracellular as well as extra cellular reduced glutathione. There is strong evidence indicating that reactive oxygen species and reactive nitrogen species generated in the presence of cadmium could be responsible for its toxic effects in many cells and tissues. Depletion of reduced glutathione in various cells, especially in T and B-lymphocytes, causes extreme damage to the antioxidant defense system of body. The aim of this research work was to investigate the metabolic changes that occur in T and B lymphocytes after their incubation with organ cadmium diacetate by using Ellman's spectrophotometric method of thiol quantification. The results of the present study indicate that cadmium depleted T and B lymphocytes GSH to a harmful extent. It is proposed that this depletion is due to the bivalent cadmium glutathione complex formation, oxidation of reduced glutathione (GSH) to its oxidized form, or both. PMID- 26639501 TI - Development and validation of a LC-MS/MS method for determination of pinoresinol diglucoside in rat plasma: Application to pharmacokinetic study. AB - Pinoresinol diglucoside (PD), a typical marker compound in Ecommia ulmoides Oliv., is an important and natural antihypertensive drug. A selective, sensitive, and rapid liquid chromatography tandem mass spectrometric (LC-MS/MS) analytical method was developed for the determination of PD in rats. After simple protein precipitation with acetonitrile, chromatographic separation of PD was conducted using a reversed-phase ZORBAX SB C18 analytical column (4.6mm * 150 mm, 5 MUm particles) with a mobile phase of 10mM ammonium acetate-methanol-acetic acid (50:50:0.15, v/v/v) and quantified by selected reaction monitoring mode under positive electrospray ionization condition. The chromatographic run time was 3.4 min for each sample, in which the retention times of PD and the internal standard were 2.87 and 2.65 min, respectively. The calibration curves were linear over the range of 1.00~3000 ng/mL and the lower limit of quantification was 1.00 ng/mL in rat plasma. The precision expressed by relative standard deviations were <8.9% for intra-batch precision and <2.0% for inter-batch precision, and the intra- and inter-batch accuracy by relative error was within the range of -3.9% ~7.3%, which met acceptable criteria. The LC-MS/MS method was successfully applied to investigate the pharmacokinetics and oral bioavailability of PD in rats, with the bioavailability being only 2.5%. PMID- 26639502 TI - Antimicrobial activity of different tea varieties available in Pakistan. AB - In this antimicrobial study, various extracts of Green and Black tea (Camellia sinensis) and Lemon grass (Cymbopogon citrates) were evaluated for antimicrobial activities against six bacterial strains including both human pathogenic bacteria (Escherichia coli, Pseudomonas aeuroginosa, Staphylococcus aureus and Salmonella typhi) and plant pathogenic bacteria (Erwinia carotovora, Agro bacterium tumifaciens) and one fungal strain Candida albicans by disc diffusion susceptibility method. Of human pathogens, P. aeruginosa was most susceptible to all three different tea varieties; though rest of the strains also demonstrated prominent sensitivity. In comparison, black tea extracts were less activities than green tea and lemon grass. However, all the three tea varieties illustrated profound activity against plant pathogenic bacteria. Similarly, when extracts of tea were tested against C. albicans, green tea and lemon grass exhibited significant activity while black tea was mostly inactive. PMID- 26639503 TI - Hypoglycemic effects of three Iranian edible plants; jujube, barberry and saffron: Correlation with serum adiponectin level. AB - One of the most common disorders of the endocrine system is diabetes mellitus. This disease is associated with dyslipidemia. Adiponectin is a protein hormone that secreted by adipocytes and has an important role in regulating of glucose and fatty acid metabolic pathways. This study was designed to investigate the changes in serum level of adiponectin in diabetic rats treated with hydroalcoholic extracts of three medicinal plants; jujube (Ziziphus jujuba), barberry (Berberis vulgaris) and saffron (Crocus sativus) in comparison with quercetin. Streptozotocin -induced diabetic male rats were gavaged with specified doses of the extracts (25 and 100mg/kg) for two weeks. At the end of treatment period, fasting blood specimens were collected. The levels of adiponectin, fasting blood sugar (FBS), total Cholesterol, triglycerides, HDL-C and LDL-C were measured. Statistical analysis showed that serum levels of triglyceride and VLDL decreased significantly (P<0.05) in all treated groups. FBS level in all treated groups, decreased significantly and reach to normoglycemic level (P<0.05). Except Jujube, other plant extracts had no effect on cholesterol. Jujube in two doses (25 and 100mg/kg) could increased significantly HDL-C (P<0.05) with no effect on total cholesterol and LDL-C. Serum adiponectin level increased in all treated groups. These beneficial effects of C. sativus, B. vulgaris and Z. jujube extracts and quercetin in diabetic rats may be associated with increase in adiponectin level. PMID- 26639504 TI - Estimation of sulfolax and antimicrobial preservatives in laxative drops. AB - A simple, fast, precise, economic, selective and accurate HPLC method for simultaneous estimation of sorbicacid, sodium picosulphate and methyl parabensodium in laxative drops has been developed and subsequently validated. Chromatographic separation was achieved using gradient elution with mix phosphate buffer pH 7.0 and acetonitrile. The column used was purospherstar C18, 5 MUm, 25 cm * 4.6mm kept at 25 degrees C with 1 ml/min flow rate using detection (PDA) at 263 nm. The retention times of sorbicacid, sodium picosulphate and methyl paraben sodium were found to be 4.6, 7.4 and 11.4 minutes respectively. The proposed method was found to be linear over a concentration range of 8-12 MUg/ml for sorbic acid, 60-90 MUg/ml for sodium picosulphate and 16-24 MUg/ml formethyl paraben sodium respectively. The recovery was found to be 99.13-101.68% for sorbic acid, 99.81-100.21% for sodium picosulphate and 99.84-100.09% for methyl paraben sodium respectively. The limit of detection (LOD) for sorbicacid, sodium picosulphate and methyl parabensodium were found to be 0.032 MUg/ml, 0.337 MUg/ml and 0.131 MUg/ml respectively and limit of quantitation (LOQ) for sorbicacid, sodium picosulphate and methyl parabensodium were found to be 0.097 MUg/ml, 1.023 MUg/ml and 0.399 MUg/ml respectively. The method was validated with respect to specificity, precision, accuracy, linearity and robustness according to guidelines of ICH. PMID- 26639505 TI - Clinical assessment of coded Unani formulation D-worm and mebandazole for the treatment of hook worm, roundworm and whip worm. AB - A case control, multicenter, prospective randomized two arm parallel group clinical trials was conducted on 190 patients. The main objective of this study is to provide comparative efficacy results of both trialed medicines. The comparison was done in between herbal medicine D-Worm and Mebandazole allopathic drug for the treatment of helminthiasis. All the rules of GCP (Good Clinical Practices) were followed including clinical history, clinical presentation, examination findings and stool tests. Stool D/R and Parasite antigen tests were performed before and after treatment. The comparison of symptoms were also done including the improvement in abdominal pain, worms in stool, anal itching, nausea and vomiting, loss of appetite, and fatigue etc. The data on clinical proforma was gathered and subjected to statistical analysis. Parasite specific antigen test and stool D/R is considered as gold standard test for the diagnosis and confirmation of helminthes infection. Different parameter i.e. age, sex, and other clinical sign and symptoms were studied and compared between two treatment groups (Control and Test groups) at baseline and end of therapeutic application. Consent of patient was taken at first before the start of examination. Majority of the patients (90%) included in this study group get cured after herbal treatment. The statistical analysis used for the assessment of the effect of the treatment also showed significant improvement after treatment. PMID- 26639506 TI - Antimicrobial and antioxidant screening of Nc-substituted sulphonyl and benzoyl derivatives of 4-Pyridine carboxylic acid hydrazide. AB - In this research program, the antibacterial, antifungal and antioxidant activities of six N'-substituted sulfonyl and benzoyl derivatives of lead molecule PCH were reported. Out of these compounds, sulphonyl derivatives 2,3 and benzoyl derivative 5 showed moderate to good activity against different strains of gram-positive and gram-negative bacteria including B. cereus, B. subtilis, B. thruingiensis and S. pyogenes, S. fecalis and E. coli ATCC 8739. Moreover, upon antifungal screening, the compound, Nc-[(2,4,6-trimethylbenzene) sulfonyl]pyridine-4-carbohydrazide possessed good antifungal activity against Candida species, a causative agent of systemic fungal infections. Antioxidant study demonstrated more than 50% inhibition in DPPH assay for sulphonyl derivative 2 indicating its potential as antioxidant while the other derivatives expressed low level of radical scavenging property. PMID- 26639507 TI - Effect of creatine monohydrate supplementation on relative serum level of IL-6 and IL-18 following neonatal hypoxia ischemia in male albino mouse. AB - IL-6 has been reported to have neuroprotective effects against cerebral ischemia while IL-8 is a pro inflammatory cytokine structurally related to interleukin-1 family. In the present study, we tried to determine whether 2% Creatine monohydrate supplementation for variable duration influence the IL-6 and 18 concentrations in the serum of male albino mouse following right common carotid artery ligation and hypoxia (8% oxygen) for 25 minutes. Our result revealed that serum concentration of IL6 (P=0.0001) as well as IL-18 (P=0.003) were significantly higher in mice supplemented with creatine monohydrate for 15 weeks than in male albino mice on normal rodent diet following hypoxic ischemic insult indicating that long term creatine monohydrate supplementation up regulates the IL-6 and IL-18 concentrations triggering the neuroinflammatory and neuroprotective responses. PMID- 26639508 TI - Formulation and evaluation of gastroretentive controlled release tablets of alfuzosin hydrochloride. AB - Alfuzosin hydrochloride is a novel drug used in the treatment of urinary incontinency. The purpose of this research was to develop controlled release floating matrix formulations of Alfuzosin HCl. Floating matrix tablets of Alfuzosin HCl were prepared using hydroxypropyl methylcellulose (HPMC), Polyethylene oxide (PEO), Carbopol 971P NF polymer (Direct compressible) and Blend of Polyvinyl Acetate and Povidone 30 (80:19:1(0.8% sodium laury sulfate and 0.2% silica)). Combination of citric acid and sodium bicarbonate were also used as gas forming agent. Matrix formulations were prepared by direct compression method and evaluated for floating, in vitro drug release profile and swelling characteristics. The mechanism of drug release was found to follow non-Fickian or anomalous type. The data obtained from the invitro release studies demonstrated that the floating matrix tablets containing HPMC 100K CR (controlled-release) and carbopol along with sodium CMC were found to sustain the release of drug over a period of 12 hours. Formulations containing 25% PEO 303WSR was also capable of sustaining delivery the release of Alfuzosin HCl. PMID- 26639509 TI - Preparation of bisoprolol fumarate nasal spray and its nasal delivery in rats. AB - The aim of the present work was to prepare a nasal spray of bisoprolol fumarate (BF). The Pharmacokinetics and relative bioavailability of the BF nasal formulation were evaluated in Wistar rats. The BF nasal spray after administration exhibited very fast absorption and higher plasma drug concentration. The maximum plasma concentration (C(max)) and the time to reach it (T(max)) were 409.5 ng/ml and 3.6 min for the BF nasal spray, 39.4 ng/ml and 26.7 min for the drug solution, respectively. The bioavailability of the BF nasal spray was greater than 1500.0%. Meantime, the effect of the BF nasal spray on nasal mucociliary movement was also studied with a toad palate model. The BF nasal preparation showed minor ciliotoxicity, but the adverse effect was temporary and reversible. PMID- 26639510 TI - Antimalarial and insecticidal activities of newly synthesized derivatives of Benzimidazole. AB - The bioactive benzimidazole and corresponding substituted phenacyl halides has been synthesized (11) new derivatives out of three compounds 8, 10 and 11 were found to inhibit the Plasmodium falciparum moderately after 72 hours of incubation hence acting as antimalarial agents. While these derivatives were exhibited negligible insecticidal activity too when analyzed by impregnated filter paper method. PMID- 26639511 TI - Report: Cytotoxic flavonoids from the young twigs and leaves of Caesalpinia bonduc (Linn) Roxb. AB - The extraction, fractionation and recognition of flavonoids from the ethanolic extract of young twigs and leaves of C. bonduc were carried out. In addition, cytotoxic study of the flavonoids on two cancer cell lines, BGC-823 and HeLa was carried our using sulphorhodamine B assay. Seven flavonoids, six of which are being reported for the first time in this plant, were isolated. Their structures were identified by MS and NMR spectroscopic methods. Petroleum ether, ethyl acetate and water fractions exhibited moderate cytotoxic activity against HeLa cells. Five compounds showed cytotoxic activity against HeLa cell in comparison with Paclitaxel, while only one compound showed a good degree of cytotoxic activity against BGC-823 cell in comparison to Paclitaxel. The results obtained showed a structure - activity relationship. PMID- 26639512 TI - Review: The market of probiotics. AB - The advertising of probiotics in diary products on the market has claimed several health-improving properties, including prevention and treatment of obesity, cardiovascular diseases and cancer prophylaxis, osteoporosis and arthritis treatment, diabetes management and control of hypercholesterolemia. Therefore, it is reasonable to emphasize the perspective of a new self-care and integrative medicine season, where food industry is turned to research-oriented management with putative clinical goals to be achieved. We searched Pubmed/Medline using the terms "probiotics" and "market". Selected papers until 2013 were chosen on the basis of their content (clinical evidence-based quality). We performed an accurate investigation on the so-called "probiotic market", leading to better understanding the role of nutraceutical products in the human clinical nutrition physiology. As nutraceutical products are sold all over the world, information, provided by this review may be useful to evaluate their potential impact on human health. PMID- 26639513 TI - Review: Human guanidinoacetate n-methyl transferase (GAMT) deficiency: A treatable inborn error of metabolism. AB - The creatine biosynthetic pathway is essential for cellular phosphate associated energy production and storage, particularly in tissues having higher metabolic demands. Guanidinoacetate N-Methyl transferase (GAMT) is an important enzyme in creatine endogenous biosynthetic pathway, with highest expression in liver and kidney. GAMT deficiency is an inherited autosomal recessive trait that was the first among creatine deficiency syndrome to be reported in 1994 having characteristic features of no comprehensible speech development, severe mental retardation, muscular hypotonia, involuntary movements and seizures that partly cannot be treated with anti-epileptic drugs. Due to problematic endogenous creatine biosynthesis, systemic depletion of creatine/phosphocreatine and accumulation of guanidinoacetate takes place that are the diagnostic features of this disease. Dietary creatine supplementation alone or along with arginine restriction has been reported to be beneficial for all treated patients, although to various extent. However, none of the GAMT deficient patient has been reported to return to complete normal developmental level. PMID- 26639514 TI - Bis-p-Sulfonatocalix[4]arene-Based Supramolecular Amphiphiles with an Emergent Lower Critical Solution Temperature Behavior in Aqueous Solution and Hydrogel. AB - An unexpected lower critical solution temperature (LCST) phenomenon is observed in a bis-p-sulfonatocalix[4]arene-based supramolecular amphiphile system, and the mechanism of this intriguing phenomenon is studied. The unusual macroscopic thermoresponsive behavior is based on the switch of the system from water-soluble assemblies to insoluble netlike cross-linked nanoparticles under temperature stimulus, which is regulated by multiple weak interactions, including hydrophilic and hydrophobic interactions, pi-pi stacking, and host-guest recognition. By using the LCST solution as the dispersion medium, a hydrogel with LCST behavior can be fabricated. This work contributes toward better understanding about calixarene-induced aggregation (CIA) and thermoresponsive self-assembled systems. It will also help to enrich the designing of complexed supramolecular amphiphile systems and develop their potential applications in hydrogels. PMID- 26639515 TI - DNA Superresolution Structure of Reed-Sternberg Cells Differs Between Long Lasting Remission Versus Relapsing Hodgkin's Lymphoma Patients. AB - Recent developments in microscopy have led to superresolution microscopy images of cells. Structured illumination microscopy was used before to reveal new details in the DNA structure and the structure of the DNA-free space in the DAPI stained cell nuclei of the Hodgkin's lymphoma HDLM-2 cell line. This study extends this technology to primary pre-treatment classical Hodgkin's lymphoma samples of ten patients. Significant differences in both the DNA structure and the structure of the DNA-free space were detected between lymphocytes and malignant cells. Both types of structures were similar for lymphocytes of different patients. When the patients were un-blinded and grouped based on their clinical outcome, either non-relapsed or relapsed, a significant difference in the DNA structure of their Reed-Sternberg (RS) cells was found. Since, RS cells develop from mono-nucleated Hodgkin (H) cells, these data suggest distinct architectural restructuring of nuclei during RS cell formation in patients going to long-lasting remission versus relapse. J. Cell. Biochem. 117: 1633-1637, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26639519 TI - Genome-engineered Sinorhizobium meliloti for the production of poly(lactic-co-3 hydroxybutyric) acid copolymer. AB - Economically competitive commercial production of biodegradable bioplastics with desirable properties is an important goal. In this study, we demonstrate the use of chromosome engineering of an alternative bacterial host, Sinorhizobium meliloti, for production of the copolymer, poly(lactate-co-3-hydroxybutyrate). Codon-optimized genes for 2 previously engineered enzymes, Clostridium propionicum propionate CoA transferase (Pct532Cp) and Pseudomonas sp. strain MBEL 6-19 polyhydroxyalkanoate (PHA) synthase 1 (PhaC1400Ps6-19), were introduced into S. meliloti Rm1021 by chromosome integration, replacing the native phbC gene. On the basis of phenotypic analysis and detection of polymer product by gas chromatography analysis, synthesis and accumulation of the copolymer was confirmed. The chromosome integrant strain, with the introduced genes under the control of the native phbC promoter, is able to produce over 15% cell dry mass of poly(lactate-co-3-hydroxybutyrate), containing 30 mol% lactate, from growth on mannitol. We were also able to purify the polymer from the culture and confirm the structure by NMR and GC-MS. To our knowledge, this is the first demonstration of production of this copolymer in the Alphaproteobacteria. Further optimization of this system may eventually yield strains that are able to produce economically viable commercial product. PMID- 26639520 TI - Screening Health Questionnaires and Patient-Reported Outcomes: Will Shortened Versions Overcome the Barriers to Their Implementation. PMID- 26639524 TI - Association between serum resistin level and outcomes in kidney transplant recipients. AB - Resistin is an adipocytokine that is associated with inflammation, coronary artery disease, and other types of cardiovascular disease among patients with normal kidney function. However, little is known about the association of resistin with outcomes in kidney transplant recipients. We collected socio demographic and clinical parameters, medical and transplant history, and laboratory data from 988 prevalent kidney transplant recipients enrolled in the Malnutrition-Inflammation in Transplant-Hungary Study (MINIT-HU study). Serum resistin levels were measured at baseline. Associations between serum resistin level and death with a functioning graft over a 6-year follow-up period were examined in unadjusted and adjusted models. The mean+/-SD age of the study population was 51 +/- 13 years, among whom 57% were men and 21% were diabetics. Median serum resistin concentrations were significantly higher in patients who died with a functioning graft as compared to those who did not die during the follow-up period (median [IQR]: 22[15-26] vs. 19[14-22] ng/ml, respectively; P < 0.001). Higher serum resistin level was associated with higher mortality risk in both unadjusted and fully adjusted models: HRs (95% CI): 1.33(1.16-1.54) and 1.21(1.01-1.46), respectively. In prevalent kidney transplant recipients, serum resistin was an independent predictor of death with a functioning graft. PMID- 26639525 TI - Structure-Reactivity Relationships in Lithiated Evans Enolates: Influence of Aggregation and Solvation on the Stereochemistry and Mechanism of Aldol Additions. AB - Aldol additions to isobutyraldehyde and cyclohexanone with lithium enolates derived from acylated oxazolidinones (Evans enolates) are described. Previously characterized trisolvated dimeric enolates undergo rapid addition to isobutyraldehyde to give a 12:1 syn:syn selectivity in high yield along with small amounts of one anti isomer. The efficacy of the addition depends critically on aging effects and the reaction quench. Unsolvated tetrameric enolates that form on warming the solutions are unreactive toward isobutyraldehyde and undergo retroaldol reaction under forcing conditions. Additions to cyclohexanone are relatively slow but form a single isomeric adduct in >80% yield. The ketone derived aldolates are robust. All attempts to control stereoselectivity by controlling aggregation failed. Rate studies of addition to cyclohexanone trace the lack of aggregation-dependent selectivities to a monomer-based mechanism. The synthetic implications and possible utility of lithium enolates in Evans aldol additions are discussed. PMID- 26639526 TI - The effect of potential electronic nicotine delivery system regulations on nicotine product selection. AB - AIMS: To estimate the effect of potential regulations of electronic nicotine delivery systems (ENDS) among adult smokers, including increasing taxes, reducing flavor availability and adding warning labels communicating various levels of risk. DESIGN: We performed a discrete choice experiment (DCE) among a national sample of 1200 adult smokers. We examined heterogeneity in policy responses by age, cigarette quitting interest and current ENDS use. Our experiment overlapped January 2015 by design, providing exogenous variation in cigarette quitting interest from New Year resolutions. SETTING: KnowledgePanel, an online panel of recruited respondents. PARTICIPANTS: A total of 1200 adult smokers from the United States. MEASUREMENTS: Hypothetical purchase choice of cigarettes, nicotine replacement therapy and a disposable ENDS. FINDINGS: Increasing ENDS prices from $3 to $6 was associated with a 13.6 percentage point reduction in ENDS selection (P < 0.001). Restricting flavor availability in ENDS to tobacco and menthol was associated with a 2.1 percentage point reduction in ENDS selection (P < 0.001). The proposed Food and Drug Administration (FDA) warning label was associated with a 1.1 percentage point reduction in ENDS selection (P < 0.05) and the MarkTen warning label with a 5.1 percentage point reduction (P < 0.001). We estimated an ENDS price elasticity of -1.8 (P < 0.001) among adult smokers. Statistically significant interaction terms (P < 0.001) imply that price responsiveness was higher among adult smokers 18-24 years of age, smokers who have vaped over the last month and smokers with above the median quitting interest. Young adult smokers were 3.7 percentage points more likely to choose ENDS when multiple flavors were available than older adults (P < 0.001). Young adult smokers and those with above the median cigarette quitting interest were also more likely to reduce cigarette selection and increase ENDS selection in January 2015 (P < 0.001), potentially in response to New Year's resolutions to quit smoking. CONCLUSIONS: Increased taxes, a proposed US Food and Drug Administration warning label for electronic nicotine delivery systems and a more severe warning label may discourage adult smokers from switching to electronic nicotine delivery systems. Reducing the availability of flavors may reduce ENDS use by young adult smokers. PMID- 26639528 TI - Ustilago maydis produces itaconic acid via the unusual intermediate trans aconitate. AB - Itaconic acid is an important biomass-derived chemical building block but has also recently been identified as a metabolite produced in mammals, which has antimicrobial activity. The biosynthetic pathway of itaconic acid has been elucidated in the ascomycetous fungus Aspergillus terreus and in human macrophages. In both organisms itaconic acid is generated by decarboxylation of the tricarboxylic acid (TCA) cycle intermediate cis-aconitate. Here, we show that the basidiomycetous fungus Ustilago maydis uses an alternative pathway and produces itaconic acid via trans-aconitate, the thermodynamically favoured isomer of cis-aconitate. We have identified a gene cluster that contains all genes involved in itaconic acid formation. Trans-aconitate is generated from cis aconitate by a cytosolic aconitate-Delta-isomerase (Adi1) that belongs to the PrpF family of proteins involved in bacterial propionate degradation. Decarboxylation of trans-aconitate is catalyzed by a novel enzyme, trans aconitate decarboxylase (Tad1). Tad1 displays significant sequence similarity with bacterial 3-carboxy-cis,cis-muconate lactonizing enzymes (CMLE). This suggests that U. maydis has evolved an alternative biosynthetic pathway for itaconate production using the toxic intermediate trans-aconitate. Overexpression of a pathway-specific transcription factor (Ria1) or a mitochondrial tricarboxylic acid transporter (Mtt1) resulted in a twofold increase in itaconate yield. Therefore, our findings offer new strategies for biotechnological production of this valuable biomass-derived chemical. PMID- 26639529 TI - BCG vaccine fails to prevent the reactivation of latent tuberculosis. PMID- 26639550 TI - Photoinduced Nonlinear Mixing of Terahertz Dipole Resonances in Graphene Metadevices. AB - The first experimental demonstration of nonlinear terahertz difference-frequency generation in a hybrid graphene metadevice is reported. Decades of research have revealed that terahertz-wave generation is impossible in single-layer graphene. This limitation is overcome and nonlinear terahertz generation by ultra-short optical pulse injection is demonstrated. This device is an essential step toward atomically thin, nonlinear terahertz optoelectronic components. PMID- 26639552 TI - Reduced Graphene Oxide-Ag3PO4 Heterostructure: A Direct Z-Scheme Photocatalyst for Augmented Photoreactivity and Stability. AB - A visible light driven, direct Z-scheme reduced graphene oxide-Ag3PO4 (RGO-Ag3 PO4 ) heterostructure was synthesized by means of a simple one-pot photoreduction route by varying the amount of RGO under visible light illumination. The reduction of graphene oxide (GO) and growth of Ag3PO4 took place simultaneously. The effect of the amount of RGO on the textural properties and photocatalytic activity of the heterostructure was investigated under visible light illumination. Furthermore, total organic carbon (TOC) analysis confirmed 97.1 % mineralization of organic dyes over RGO-Ag3PO4 in just five minutes under visible light illumination. The use of different quenchers in the photomineralization suggested the presence of hydroxyl radicals ((.)OH), superoxide radicals ((.)O2 ( )), and holes (h(+)), which play a significant role in the mineralization of organic dyes. In addition to that, clean hydrogen fuel generation was also observed with excellent reusability. The 4 RGO-Ag3PO4 heterostructure has a high H2 evolution rate of 3690 MUmol h(-1) g(-1), which is 6.15 times higher than that of RGO. PMID- 26639551 TI - The orphan response regulator EpsW is a substrate of the DifE kinase and it regulates exopolysaccharide in Myxococcus xanthus. AB - Here we attempted to identify the downstream target of the DifE histidine kinase in the regulation of exopolysaccharide (EPS) production in the Gram-negative bacterium Myxococcus xanthus. This bacterium is an important model system for the studies of Type IV pilus (T4P) because it is motile by social (S) motility which is powered by T4P retraction. EPS is critical for S motility because it is the preferred anchor for T4P retraction in this bacterium. Previous studies identified the Dif chemosensory pathway as crucial for the regulation of EPS production. However, the downstream target of the DifE kinase in this pathway was unknown. In this study, EpsW, an orphan and single-domain response regulator (RR), was identified as a potential DifE target first by bioinformatics. Subsequent experiments demonstrated that epsW is essential for EPS biosynthesis in vivo and that EpsW is directly phosphorylated by DifE in vitro. Targted mutagenesis of epsW suggests that EpsW is unlikely the terminal RR of the Dif pathway. We propose instead that EpsW is an intermediary in a multistep phosphorelay that regulates EPS in M. xanthus. PMID- 26639553 TI - Is it still correct to differentiate between early and very early onset psychosis? AB - OBJECTIVE: It remains unclear whether very early onset psychosis (VEOP; <=12years of age) and early onset psychosis (EOP; onset 13-17years of age) are homogeneous in their clinical presentation. We investigated the predictive value of age of psychosis onset for severity, functioning and demographic variation by: 1) comparing groups based on traditional cut-offs for age of psychosis onset, and 2) using receiver operating characteristic (ROC)-curve calculations, without a priori age of onset cut-offs. METHOD: Participants were 88 (45 female, 43 male) children and adolescents with a recent onset of psychosis (age range=6.7 17.5years; M=13.74, SD=2.37). RESULTS: The VEOP group had significantly shorter duration of untreated illness and untreated psychosis, and lower functioning than the EOP group. The VEOP and EOP groups did not differ significantly on gender proportion, urbanicity, psychotic diagnosis, family history of psychotic disorder, psychotic, depressive and anxiety symptoms or IQ. When applying ROC curves to the lowest three quartiles of positive psychotic symptoms scores, the optimal age-cut-off was 14.0years (sensitivity=0.62; specificity=0.75). For the highest quartile of functioning scores, the optimal differentiating cut-off for age of psychosis onset was 14.7years (sensitivity=0.71; specificity=0.70). CONCLUSIONS: Larger samples of patients, assessed at presentation and followed up, are necessary to clearly examine clinical presentation and outcome as a function of social and neural development to better understand if the differentiation between VEOP and EOP is justified. This will aid the development of predictive diagnostic tools, more accurate prognosis prediction, and age tailored therapeutic interventions. PMID- 26639554 TI - Mendelian randomization: applications and limitations in epigenetic studies. PMID- 26639556 TI - In memoriam: Prof Christopher J Froelich (1951-2015). PMID- 26639555 TI - Cell cycle and p53 gate the direct conversion of human fibroblasts to dopaminergic neurons. AB - The direct conversion of fibroblasts to induced dopaminergic (iDA) neurons and other cell types demonstrates the plasticity of cell fate. The low efficiency of these relatively fast conversions suggests that kinetic barriers exist to safeguard cell-type identity. Here we show that suppression of p53, in conjunction with cell cycle arrest at G1 and appropriate extracellular environment, markedly increase the efficiency in the transdifferentiation of human fibroblasts to iDA neurons by Ascl1, Nurr1, Lmx1a and miR124. The conversion is dependent on Tet1, as G1 arrest, p53 knockdown or expression of the reprogramming factors induces Tet1 synergistically. Tet1 knockdown abolishes the transdifferentiation while its overexpression enhances the conversion. The iDA neurons express markers for midbrain DA neurons and have active dopaminergic transmission. Our results suggest that overcoming these kinetic barriers may enable highly efficient epigenetic reprogramming in general and will generate patient-specific midbrain DA neurons for Parkinson's disease research and therapy. PMID- 26639558 TI - China Diabetes Society 2016: a call for papers. PMID- 26639557 TI - RESOLFT nanoscopy with photoswitchable organic fluorophores. AB - Far-field optical nanoscopy has been widely used to image small objects with sub diffraction-limit spatial resolution. Particularly, reversible saturable optical fluorescence transition (RESOLFT) nanoscopy with photoswitchable fluorescent proteins is a powerful method for super-resolution imaging of living cells with low light intensity. Here we demonstrate for the first time the implementation of RESOLFT nanoscopy for a biological system using organic fluorophores, which are smaller in size and easier to be chemically modified. With a covalently-linked dye pair of Cy3 and Alexa647 to label subcellular structures in fixed cells and by optimizing the imaging buffer and optical parameters, our RESOLFT nanoscopy achieved a spatial resolution of ~74 nm in the focal plane. This method provides a powerful alternative for low light intensity RESOLFT nanoscopy, which enables biological imaging with small organic probes at nanoscale resolution. PMID- 26639559 TI - Neuroprotective effects of docosahexaenoic acid on hippocampal cell death and learning and memory impairments in a valproic acid-induced rat autism model. AB - Prenatal exposure to valproic acid (VPA) in rat offspring is capable of inducing experimental autism with neurobehavioral aberrations. This study investigated the effect of docosahexaenoic acid (DHA) on hippocampal cell death, learning and memory alteration in an experimental rat autism model. We found that DHA supplementation (75, 150 or 300 mg/kg/day, 21 days) rescued the VPA (600 mg/kg) induced DHA reduction in plasma and hippocampus in a dose-dependent manner, increased the levels of hippocampal p-CaMKII and p-CREB without affecting total protein level, and altered BDNF-AKT-Bcl-2 signaling pathway, as well as inhibited the activity of caspase-3. DHA also influenced the content of malondialdehyde (MDA) and the activities of antioxidant enzymes in the VPA-treated offspring. Consistent with the previous results, we also observed that 300 mg/kg DHA supplementation markedly increased the cell survival, decreased the cell apoptosis, and increased mature neuronal cell in the hippocampus in VPA-treated offspring. Utilizing the Morris water maze test, we found that DHA prevented cognitive impairment in offspring of VPA-treated rats. The data suggested that DHA may play a neuroprotective role in hippocampal neuronal cell and ameliorates dysfunctions in learning and memory in this rat autism model. Thus, DHA could be used as treatment intervention for mitigating behavioral dysfunctions in autism spectrum disorder (ASD). PMID- 26639560 TI - Ambient air pollution and preterm birth: A prospective birth cohort study in Wuhan, China. AB - IMPORTANCE: Although studies in western countries suggest that ambient air pollution is positively associated with adverse pregnancy outcomes, the upper levels of pollutant exposures have been relatively low, thus eroding confidence in the conclusions. Meanwhile, in Asia, where upper levels of exposure have been greater, there have been limited studies of the association between air pollution and adverse pregnancy outcomes. OBJECTIVE: The primary objective was to evaluate whether high levels of pollution, including particulate matter pollution with a mass median aerodynamic diameter of less than 2.5 MUm (PM2.5) and 10 MUm (PM10), sulfur dioxide (SO2), nitrogen dioxide (NO2), ozone (O3), and carbon monoxide (CO) are related to increased occurrence of preterm birth (PTB). METHODS: We conducted a population-based study in Wuhan, China in a cohort of 95,911 live births during a two-year period from 2011 to 2013. The exposure was estimated based on daily mean concentrations of pollutants estimated using the pollutants' measurements from the nine closest monitors. Logistic regressions were performed to determine the relationships between exposure to each of the pollutants during different pregnancy periods and PTB while controlling for key covariates. RESULTS: We found 3% (OR=1.03; 95% CI: 1.02, 1.05), 2% (OR=1.02; 95% CI: 1.02, 1.03), 15% (OR=1.15; 95% CI: 1.11, 1.19), and 5% (OR=1.05; 95% CI: 1.02, 1.07) increases in risk of PTB with each 5-MUg/m(3) increase in PM2.5 and PM10 concentrations, 100-MUg/m(3) increase in CO concentrations, and 10-MUg/m(3) increase in O3 concentrations, respectively. There was negligible evidence for associations for SO2 and NO2. The effects from two-pollutant models were similar to the estimated effects from single pollutant models. No critical exposure windows were identified consistently: the strongest effect for PTB was found in the second trimester for PM2.5, PM10, and CO, but for SO2 it was in the first trimester, second month, and third month. For NO2 it was in the first trimester and second month, and for O3, the third trimester. CONCLUSION: Findings reveal an association between air pollutants and PTB. However, more toxicological studies and prospective cohort studies with improved exposure assessments are needed to establish causality related to specific pollutants. PMID- 26639562 TI - ['Autonometer'. Proposal of a scale to assess independence in the elderly]. AB - INTRODUCTION: The demographic forecast predicts an aging population in all developed countries, and this will lead to an increase of frailty in the elderly. Gerontology professionals need tools to detect frailty in advance. A test is presented for assessing multidimensional independence, consisting of a questionnaire and a test. MATERIAL AND METHOD: A test of cognitive functional assessment was designed for the elderly, consisting of a questionnaire of 40 questions (Autonometro-Q) and a test of 26 tasks (Autonometro-T) that can be used together or independently. RESULTS: Autonometro-T test obtained a Cronbach alpha of 0.85 with four dimensions, and a Kappa coefficient of 0.40. Autonometro-Q is a five-dimensional short questionnaire with a Cronbach alpha of 0.94, a Kappa coefficient of 0.63 and has a sensitivity of 85% and a specificity of 87%, with positive and negative predictive values of 73% and 94%, respectively, using Autonometro-T as the reference standard. CONCLUSIONS: Autonometro is a useful tool for frailty screening in the elderly, which examines the physical markers related to daily living activities, using an objective test. PMID- 26639563 TI - Morphometric and quantitative evaluation of the gastroepiploic artery. AB - BACKGROUND: The gastroepiploic artery (GEA) has been described in various ways by anatomical texts and surgical manuals. Currently, there are no studies that have investigated the thickness and length of GEA using gross anatomical methods. In the present study, we measured the length, circumference, area, and major axis of GEA, and quantitatively evaluated the differences between right and left GEA (RGEA and LGEA), using gross anatomical and morphometric methods for the first time. MATERIALS AND METHOD: Seventeen cadavers were selected. The median age of the cadavers was 82 years. We observed and evaluated GEA with naked eyes, as well as under a stereoscopic microscope. RESULTS: RGEA was significantly longer than LGEA (p < 0.0001). The mean length of RGEA and LGEA were 26.51 +/- 5.15 cm and 14.05 +/- 3.12 cm, respectively. The mean area of RGEA, LGEA, and the anastomotic point were 3.31 +/- 1.71 mm(2), 1.33 +/- 1.01 mm(2), and 0.51 +/- 0.28 mm(2) respectively. CONCLUSION: RGEA was significantly longer and thicker than LGEA. The results also showed that in almost all of the cases RGEA and LGEA anastomosed with each other and grew thinner as they approached the middle of the greater curvature of the stomach. PMID- 26639561 TI - BIM and mTOR expression levels predict outcome to erlotinib in EGFR-mutant non small-cell lung cancer. AB - BIM is a proapoptotic protein that initiates apoptosis triggered by EGFR tyrosine kinase inhibitors (TKI). mTOR negatively regulates apoptosis and may influence response to EGFR TKI. We examined mRNA expression of BIM and MTOR in 57 patients with EGFR-mutant NSCLC from the EURTAC trial. Risk of mortality and disease progression was lower in patients with high BIM compared with low/intermediate BIM mRNA levels. Analysis of MTOR further divided patients with high BIM expression into two groups, with those having both high BIM and MTOR experiencing shorter overall and progression-free survival to erlotinib. Validation of our results was performed in an independent cohort of 19 patients with EGFR-mutant NSCLC treated with EGFR TKIs. In EGFR-mutant lung adenocarcinoma cell lines with high BIM expression, concomitant high mTOR expression increased IC50 of gefitinib for cell proliferation. We next sought to analyse the signalling pattern in cell lines with strong activation of mTOR and its substrate P-S6. We showed that mTOR and phosphodiesterase 4D (PDE4D) strongly correlate in resistant EGFR-mutant cancer cell lines. These data suggest that the combination of EGFR TKI with mTOR or PDE4 inhibitors could be adequate therapy for EGFR-mutant NSCLC patients with high pretreatment levels of BIM and mTOR. PMID- 26639564 TI - Observation of maxillary incisive canal using dry skulls between Hellman's dental age IA and IIIC. AB - The maxillary incisive canals were observed in childhood from infancy to school aged children to clarify their development. Cone-beam computed tomography was performed to investigate 44 dry child skulls. Two-dimensional images of various planes in the maxillary incisive canal were reconstructed on a computer using 3 dimensional visualization and measurement software. Then, antero-posterior angulation, and antero-posterior and lateral axes of the maxillary incisive canal were measured at the inferior and middle levels. The mean difference of angulation between the inferior and middle levels was 2.3 degrees in IIC, and 11.1 degrees in IIIC. The mean ratio of the lateral axis to antero-posterior axis at the middle level was 2.54 in IIC, and 1.93 in IIIC. In conclusion, it was antero-posteriorly straight from IA to IIC, and, after IIIA, it curved at the middle level. The cross-sectional shape in IIC was depressed with a larger lateral axis. PMID- 26639565 TI - Phenotypic changes of AADC-only-immunoreactive cells in the alimentary canal of the laboratory shrew, Suncus murinus, induced by systemic administration of monoamine precursors. AB - In order to elucidate the function of anti-aromatic acid decarboxylase (AADC) only-positive cells in the alimentary canal, 5-hydroxy-L-tryptophan (5-HTP) or L 3,4-dihydroxyphenylalanine (L-DOPA) was intraperitoneally injected into the laboratory shrew, Suncus murinus, and immunohistochemical studies were conducted on continuous sections of the alimentary canal using specific antisera against tyrosine hydroxylase (TH), AADC, dopamine (DA), and serotonin (5-HT). AADC-only positive cells localized to the epithelial layer of the alimentary canal from the stomach to the large intestine. These AADC-only-positive cells became DA- and AADC-positive cells after L-DOPA injection, and 5-HT- and AADC-positive cells after 5-HTP injection. These results strongly indicate that the AADC-only positive cells in the alimentary canal of Suncus murinus are capable of synthesizing DA and 5-HT simultaneously upon administration of L-DOPA and 5-HTP. PMID- 26639569 TI - Epigenetics: Making marks in oocyte development. PMID- 26639570 TI - Complex traits: A diamond in the ruff. PMID- 26639571 TI - Beverage intake and obesity in early childhood: evidence form primary health care clients in Northwest Argentina. AB - Sugar sweetened beverages (SSB) are thought to play an important role in weight gain. We examined the relationship between the intake of caloric and noncaloric beverages (SSB and water) and the nutritional status of children. In 2014, we randomly selected 16 public health clinics in four cities of Northwest Argentina and conducted a survey among mothers of children 0-6 years of age. Children's beverage intake was ascertained by 24-h dietary recall provided by the mothers. Children's weight and height measures were obtained from clinic's registries. We calculated the body mass index using the International Obesity Task Force standards. The analysis included 562 children 25 months to 6 years of age with normal or above normal nutritional status. Children's beverage consumption was as follows, water 81.8%, carbonated soft drinks (CSD) 49.7%, coffee/tea/cocoa 44.0%, artificial fruit drinks 35.6%, flavored water 17.9%, natural fruit juice 14.5%. In multivariate logistic regression models the likelihood of being obese v. being overweight or having normal weight doubled with an intake of one to five glasses of CSD (OR=2.2) and increased by more than three-fold with an intake of more than five glasses (OR=3.5). Drinking more than five glasses of water decreased the likelihood of being obese by less than half (OR=0.3). The percentage of children drinking more than five glasses of other beverages was low (3.3-0.9%) and regression models did not yield significant results. The study contributed evidence for reducing children's CSD intake and for promoting water consumption, together with the implementation of comprehensive regulatory public health policies. PMID- 26639572 TI - Scalable lithography from Natural DNA Patterns via polyacrylamide gel. AB - A facile strategy for fabricating scalable stamps has been developed using cross linked polyacrylamide gel (PAMG) that controllably and precisely shrinks and swells with water content. Aligned patterns of natural DNA molecules were prepared by evaporative self-assembly on a PMMA substrate, and were transferred to unsaturated polyester resin (UPR) to form a negative replica. The negative was used to pattern the linear structures onto the surface of water-swollen PAMG, and the pattern sizes on the PAMG stamp were customized by adjusting the water content of the PAMG. As a result, consistent reproduction of DNA patterns could be achieved with feature sizes that can be controlled over the range of 40%-200% of the original pattern dimensions. This methodology is novel and may pave a new avenue for manufacturing stamp-based functional nanostructures in a simple and cost-effective manner on a large scale. PMID- 26639574 TI - Simultaneous occurrence of amoebic liver abscess and cecal ameboma. PMID- 26639573 TI - Sulforaphane reduces lipopolysaccharide-induced proinflammatory markers in hippocampus and liver but does not improve sickness behavior. AB - OBJECTIVES: Acute peripheral infection is associated with central and peripheral inflammation, increased oxidative stress, and adaptive sickness behaviors. Sulforaphane (SFN) activates the transcription factor nuclear factor E2-related factor 2 (Nrf2), which upregulates antioxidant genes and lowers inflammation. The objectives of this study were to examine the effects of SFN on proinflammatory markers and Nrf2 target genes in hippocampus and liver of mice challenged with lipopolysaccharide (LPS), and to evaluate sickness response following the LPS immune challenge. METHODS: Adult Balb/c mice received SFN (50 mg/kg, i.p.) for 3 days before being injected i.p. with LPS (1 ug) to mimic an acute peripheral infection. Sickness behaviors were measured at baseline and 6 hours after LPS. Expression of proinflammatory mediators and antioxidant genes were analyzed in hippocampus and liver 6 hours after LPS. RESULTS: SFN elevated Nrf2 target genes and reduced expression of proinflammatory mediators in hippocampus and liver, but did not improve LPS-induced sickness response. DISCUSSION: The nutritional bioactive SFN displays potent anti-inflammatory properties against LPS-induced inflammation in vitro, but has not been previously assessed in vivo during peripheral infection as a potential treatment for sickness behavior. These data indicate that SFN has anti-inflammatory effects in both brain and periphery, but that longer exposure to SFN may be necessary to reduce sickness behavior. PMID- 26639575 TI - Bacteria may contribute to distant species recognition in ant-aphid mutualistic relationships. AB - Mutualistic interactions between ant and aphid species have been the subject of considerable historical and contemporary investigations, the primary benefits being cleaning and protection for the aphids and carbohydrate-rich honeydew for the ants. Questions remained, however, as to the volatile semiochemical factor influencing this relationship. A recent study highlighted the role of bacterial honeydew volatile compounds in ant attraction. Here, ant's ability to distantly discriminate 2 aphid species was investigated based on bacterial honeydew semiochemicals emissions using a two-way olfactometer. Both the mutualistic aphid Aphis fabae L. and the nonmyrmecophilous aphid Acyrthosiphon pisum Harris were found to be attractive for the ant Lasius niger L. The level of attraction was similar in both assays (control vs. one of the aphid species). However, when given a choice between these 2 aphid species, ants showed a significant preference for Aphis fabae. Honeydew volatiles, mostly from bacterial origins, are known to be a key element in ant attraction. Using the same olfactometry protocol, the relative attractiveness of volatiles emitted by honeydews collected from each aphid species and by bacteria isolated from each honeydew was investigated. Again, ants significantly preferred volatiles released by Aphis fabae honeydew and bacteria. This information suggests that microbial honeydew volatiles enable ants to distantly discriminate aphid species. These results strengthen the interest of studying the occurrence and potential impact of microorganisms in insect symbioses. PMID- 26639576 TI - Why Are Men Satisfied or Dissatisfied with Penile Implants? A Mixed Method Study on Satisfaction with Penile Prosthesis Implantation. AB - INTRODUCTION: Studies have demonstrated high levels of satisfaction with penile prosthesis implantation (PPI). However, qualitative research exploring the experience of PPI through men's narratives is scarce. AIM: The main goals were to analyze (i) the level of sexual satisfaction (quantitatively), and (ii) the reasons for satisfaction and/or dissatisfaction with PPI (qualitatively). METHOD: Participants were 47 men with erectile dysfunction who underwent surgery between 2003 and 2012, placed by a single surgeon. Structured telephone interviews were carried out. MAIN OUTCOME MEASURES: Satisfaction with PPI was a qualitative and quantitative measure assessed through the following four items: (i) "Would you repeat the PPI surgery?"; (ii) "Would you recommend the PPI surgery?"; (iii) "How satisfied are you with the PP?"; and (iv) "Could you explain the motives of your satisfaction/dissatisfaction?". RESULTS: The majority of men (79%) reported to be satisfied with PPI. Content analysis revealed four main themes for men's satisfaction with the PPI: (i) psychological factors were reported 54 times (n = 54) and included positive emotions, self-esteem, confidence, enhancement of male identity, major live change, and self-image; (ii) improvement of sexual function was reported 54 times (n = 54) and referred to achievement of vaginal penetration, increase of sexual desire, sexual satisfaction, penis size, and improvement of erectile function; (iii) relationship factors were reported 11 times (n = 11) and referred to relationship improvement and the possibility of giving pleasure to the partner; and (iv) improvement in urinary function (n = 3). CONCLUSIONS: The level of satisfaction with the implementation of penile prostheses is very high, therefore constituting a treatment for erectile dysfunction with a positive impact on the experience of men at sexual, psychological and relational level. PMID- 26639577 TI - Fibronectin-targeted drug delivery in cancer. AB - Fibronectin is an extracellular matrix protein with pivotal physiological and pathological functions in development and adulthood. Alternative splicing of the precursor mRNA, produced from the single copy fibronectin gene, occurs at three sites coding for the EDA, EDB and IIICS domains. Fibronectin isoforms comprising the EDA or EDB domains are known as oncofetal forms due to their developmental importance and their re-expression in tumors, contrasting with restricted presence in normal adult tissues. These isoforms are also recognized as important markers of angiogenesis, a crucial physiological process in development and required by tumor cells in cancer progression. Attributed to this feature, EDA and EDB domains have been extensively used for the targeted delivery of cytokines, cytotoxic agents, chemotherapy drugs and radioisotopes to fibronectin expressing tumors to exert therapeutic effects on primary cancers and metastatic lesions. In addition to drug delivery, the EDA and EDB domains of fibronectin have also been utilized to develop imaging strategies for tumor tissues. Furthermore, EDA and EDB based vaccines seem to be promising for the treatment and prevention of certain cancer types. In this review, we will summarize recent advances in fibronectin EDA and EDB-based therapeutic strategies developed to treat cancer. PMID- 26639579 TI - Persistence of Multi-Drug Resistance Plasmids in Sterile Water under Very Low Concentrations of Tetracycline. AB - The persistence of the multi-drug resistance plasmids pAQU1 and IncFIB was examined in bacterial populations under very low selective pressure. We herein demonstrated that these plasmids stably remained not only in the original host, but also in a transconjugant, even after being in a non-culturable state. In seawater microcosms containing Photobacterium damselae 04Ya311 possessing pAQU1, no significant loss of pAQU1 was observed during a 30-d starvation period. The copy numbers of pAQU1 and IncFIB in E. coli were constant. The results of the present study suggest that these plasmids have the ability to remain among various bacteria under oligotrophic conditions with low antibiotic selection pressure. PMID- 26639580 TI - Identification and Detection of Prokaryotic Symbionts in the Ciliate Metopus from Anaerobic Granular Sludge. AB - The aim of the present study was to investigate the prokaryotic community structure of the anaerobic ciliate, Metopus sp. using rRNA sequencing, fluorescence in situ hybridization (FISH), and transmission electron microscopy (TEM). Metopus sp. was physically separated from anaerobic granular sludge in a domestic wastewater treatment plant and anoxically cultivated for 7 d. 16S rRNA gene sequences from the prokaryotes Methanoregula boonei and Clostridium aminobutyricum were abundantly detected in Metopus ciliates. The FISH analysis using the oligonucleotide probes Mg1200b and Cla568 demonstrated that these prokaryotes were localized within Metopus cells. These results identify M. boonei and C. aminobutyricum-like prokaryotes as novel endosymbionts of Metopus ciliates. PMID- 26639578 TI - Polysaccharide-based nanoparticles for theranostic nanomedicine. AB - Polysaccharides are natural biological molecules that have numerous advantages for theranostics, the integrated approach of therapeutics and diagnostics. Their derivable reactive groups can be leveraged for functionalization with a nanoparticle-enabling conjugate, therapeutics (small molecules, proteins, peptides, photosensitizers) and/or diagnostic agents (imaging agents, sensors). In addition, polysaccharides are diverse in size and charge, biodegradable and abundant and show low toxicity in vivo. Polysaccharide-based nanoparticles are increasingly being used as platforms for simultaneous drug delivery and imaging and are therefore becoming popular theranostic nanoparticles. The review focuses on the method of nanoparticle formation (self-assembled, physical or chemical cross-linked) when engineering polysaccharide-based nanoparticles for theranostic nanomedicine. We highlight recent examples of polysaccharide-based theranostic systems from literature and their potential for use in the clinic, particularly chitosan- and hyaluronic acid-based NPs. PMID- 26639604 TI - Perceptions of nursing students trained in a new model teaching ward in Malawi. AB - This study aimed to investigate the perceptions of nursing students trained in a new model teaching ward in Malawi. A total of 90students from five nursing colleges were randomly assigned to one model ward and two ordinary wards in a single teaching hospital. The students were administered a revised version of the Student Evaluation of Clinical Education Environment questionnaire. Significant differences among the three wards were found in all items in the communication/feedback subscale, with the exception of the item "nursing staff provided constructive feedback" (P=0.162). Within the learning opportunities subscale all items showed significant differences among the three wards, whereas 50% of the items in the learning support/assistance subscale had significantly different responses among the three wards. Within the department atmosphere subscale, no significant differences were found in the items assessing whether an adequate number and variety of patients were present in the ward (P=0.978). The strategies that are being implemented to improve the educational environment showed positive results. Students scored the model teaching ward highly. Students who underwent precepting in the model teaching wards reported having more learning opportunities and a positive learning environment. PMID- 26639605 TI - Smartphone-based evaluations of clinical placements-a useful complement to web based evaluation tools. AB - PURPOSE: Web-based questionnaires are currently the standard method for course evaluations. The high rate of smartphone adoption in Sweden makes possible a range of new uses, including course evaluation. This study examines the potential advantages and disadvantages of using a smartphone app as a complement to web based course evaluationsystems. METHODS: An iPhone app for course evaluations was developed and interfaced to an existing web-based tool. Evaluations submitted using the app were compared with those submitted using the web between August 2012 and June 2013, at the Faculty of Medicine at Uppsala University, Sweden. RESULTS: At the time of the study, 49% of the students were judged to own iPhones. Over the course of the study, 3,340 evaluations were submitted, of which 22.8% were submitted using the app. The median of mean scores in the submitted evaluations was 4.50 for the app (with an interquartile range of 3.70-5.20) and 4.60 (3.70-5.20) for the web (P=0.24). The proportion of evaluations that included a free-text comment was 50.5% for the app and 49.9% for the web (P=0.80). CONCLUSION: An app introduced as a complement to a web-based course evaluation system met with rapid adoption. We found no difference in the frequency of free-text comments or in the evaluation scores. Apps appear to be promising tools for course evaluations. web-based course evaluation system met with rapid adoption. We found no difference in the frequency of free-text comments or in the evaluation scores. Apps appear to be promising tools for course evaluations. PMID- 26639606 TI - Early-onset dermatosis papulosa nigra. PMID- 26639608 TI - Atomically precise semiconductor--graphene and hBN interfaces by Ge intercalation. AB - The full exploration of the potential, which graphene offers to nanoelectronics requires its integration into semiconductor technology. So far the real-world applications are limited by the ability to concomitantly achieve large single crystalline domains on dielectrics and semiconductors and to tailor the interfaces between them. Here we show a new direct bottom-up method for the fabrication of high-quality atomically precise interfaces between 2D materials, like graphene and hexagonal boron nitride (hBN), and classical semiconductor via Ge intercalation. Using angle-resolved photoemission spectroscopy and complementary DFT modelling we observed for the first time that epitaxially grown graphene with the Ge monolayer underneath demonstrates Dirac Fermions unaffected by the substrate as well as an unperturbed electronic band structure of hBN. This approach provides the intrinsic relativistic 2D electron gas towards integration in semiconductor technology. Hence, these new interfaces are a promising path for the integration of graphene and hBN into state-of-the-art semiconductor technology. PMID- 26639607 TI - Functional properties of resting state networks in healthy full-term newborns. AB - Objective, early, and non-invasive assessment of brain function in high-risk newborns is critical to initiate timely interventions and to minimize long-term neurodevelopmental disabilities. A prerequisite to identifying deviations from normal, however, is the availability of baseline measures of brain function derived from healthy, full-term newborns. Recent advances in functional MRI combined with graph theoretic techniques may provide important, currently unavailable, quantitative markers of normal neurodevelopment. In the current study, we describe important properties of resting state networks in 60 healthy, full-term, unsedated newborns. The neonate brain exhibited an efficient and economical small world topology: densely connected nearby regions, sparse, but well integrated, distant connections, a small world index greater than 1, and global/local efficiency greater than network cost. These networks showed a heavy tailed degree distribution, suggesting the presence of regions that are more richly connected to others ('hubs'). These hubs, identified using degree and betweenness centrality measures, show a more mature hub organization than previously reported. Targeted attacks on hubs show that neonate networks are more resilient than simulated scale-free networks. Networks fragmented faster and global efficiency decreased faster when betweenness, as opposed to degree, hubs were attacked suggesting a more influential role of betweenness hub in the neonate network. PMID- 26639609 TI - Carbon Nanotubes Grown on Metal Microelectrodes for the Detection of Dopamine. AB - Microelectrodes modified with carbon nanotubes (CNTs) are useful for the detection of neurotransmitters because the CNTs enhance sensitivity and have electrocatalytic effects. CNTs can be grown on carbon fiber microelectrodes (CFMEs) but the intrinsic electrochemical activity of carbon fibers makes evaluating the effect of CNT enhancement difficult. Metal wires are highly conductive and many metals have no intrinsic electrochemical activity for dopamine, so we investigated CNTs grown on metal wires as microelectrodes for neurotransmitter detection. In this work, we successfully grew CNTs on niobium substrates for the first time. Instead of planar metal surfaces, metal wires with a diameter of only 25 MUm were used as CNT substrates; these have potential in tissue applications due to their minimal tissue damage and high spatial resolution. Scanning electron microscopy shows that aligned CNTs are grown on metal wires after chemical vapor deposition. By use of fast-scan cyclic voltammetry, CNT-coated niobium (CNT-Nb) microelectrodes exhibit higher sensitivity and lower DeltaEp value compared to CNTs grown on carbon fibers or other metal wires. The limit of detection for dopamine at CNT-Nb microelectrodes is 11 +/- 1 nM, which is approximately 2-fold lower than that of bare CFMEs. Adsorption processes were modeled with a Langmuir isotherm, and detection of other neurochemicals was also characterized, including ascorbic acid, 3,4 dihydroxyphenylacetic acid, serotonin, adenosine, and histamine. CNT-Nb microelectrodes were used to monitor stimulated dopamine release in anesthetized rats with high sensitivity. This study demonstrates that CNT-grown metal microelectrodes, especially CNTs grown on Nb microelectrodes, are useful for monitoring neurotransmitters. PMID- 26639610 TI - Environmental marine pathogen isolation using mesocosm culture of sharpsnout seabream: striking genomic and morphological features of novel Endozoicomonas sp. AB - Aquaculture is a burgeoning industry, requiring diversification into new farmed species, which are often at risk from infectious disease. We used a mesocosm technique to investigate the susceptibility of sharpsnout seabream (Diplodus puntazzo) larvae to potential environmental pathogens in seawater compared to control borehole water. Fish exposed to seawater succumbed to epitheliocystis from 21 days post hatching, causing mortality in a quarter of the hosts. The pathogen responsible was not chlamydial, as is often found in epitheliocystis, but a novel species of the gamma-proteobacterial genus Endozoicomonas. Detailed characterisation of this pathogen within the infectious lesions using high resolution fluorescent and electron microscopy showed densely packed rod shaped bacteria. A draft genome sequence of this uncultured bacterium was obtained from preserved material. Comparison with the genome of the Endozoicomonas elysicola type strain shows that the genome of Ca. Endozoicomonas cretensis is undergoing decay through loss of functional genes and insertion sequence expansion, often indicative of adaptation to a new niche or restriction to an alternative lifestyle. These results demonstrate the advantage of mesocosm studies for investigating the effect of environmental bacteria on susceptible hosts and provide an important insight into the genome dynamics of a novel fish pathogen. PMID- 26639612 TI - Subcategorization of atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS): a study applying Thyroid Imaging Reporting and Data System (TIRADS). AB - OBJECTIVE: To evaluate the clinical significance and compare the imaging features according to the Thyroid Image Reporting and Data System (TIRADS) between atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) subcategories. DESIGN & PATIENTS: A total of 192 thyroid nodules in 188 patients (mean age: 50.2 +/- 11.8 years) that had been initially diagnosed as AUS/FLUS on US-guided fine needle aspiration (US-FNA) were included. One cytopathologist retrospectively reviewed the cytology slides, subcategorizing cytology results into AUS and FLUS. A TIRADS category was assigned to each thyroid nodule according to the number of suspicious US features. Clinical, US features and malignancy rates were compared between the two subcategories. RESULTS: Of the 192 AUS/FLUS lesions, 149 (77.6%) were subcategorized as AUS and 43 (22.4%) as FLUS. Of the 192 AUS/FLUS nodules, 82 (42.7%) were malignant. The malignancy rates between AUS and FLUS subcategories were not significantly different, 45.6% to 32.6%, respectively (P = 0.127). When applying TIRADS, significant differences were seen in TIRADS category between benign and malignant nodules in the AUS subcategory (P < 0.001), but not in the FLUS subcategory (P = 0.414). The malignancy rates in TIRADS categories 3, 4a, 4b, 4c and 5 were 15.4%, 22.2%, 33.3%, 57.1% and 80.0% (P < 0.001) in AUS nodules and 40.0%, 50.0%, 23.5%, 22.2% and 0.0% (P = 0.414) in FLUS nodules, respectively. CONCLUSION: Suspicious US features are useful in predicting malignancy among AUS subcategories but not in FLUS subcategories. Subcategorization into AUS and FLUS cytology may be helpful in deciding upon treatment or management of thyroid nodules. PMID- 26639611 TI - Ultrahigh-throughput discovery of promiscuous enzymes by picodroplet functional metagenomics. AB - Unculturable bacterial communities provide a rich source of biocatalysts, but their experimental discovery by functional metagenomics is difficult, because the odds are stacked against the experimentor. Here we demonstrate functional screening of a million-membered metagenomic library in microfluidic picolitre droplet compartments. Using bait substrates, new hydrolases for sulfate monoesters and phosphotriesters were identified, mostly based on promiscuous activities presumed not to be under selection pressure. Spanning three protein superfamilies, these break new ground in sequence space: promiscuity now connects enzymes with only distantly related sequences. Most hits could not have been predicted by sequence analysis, because the desired activities have never been ascribed to similar sequences, showing how this approach complements bioinformatic harvesting of metagenomic sequencing data. Functional screening of a library of unprecedented size with excellent assay sensitivity has been instrumental in identifying rare genes constituting catalytically versatile hubs in sequence space as potential starting points for the acquisition of new functions. PMID- 26639615 TI - Evaluation of different solvent mixtures in esterifiable lipids extraction from microalgae Botryococcus braunii for biodiesel production. AB - Non-polar and polar solvents as well as their mixtures were tested for the extraction of microalgae lipids and thus, to evaluate their effect on total and esterifiable lipids extraction yields with potential to be converted to biodiesel. The obtained results show an increase in lipids and esterifiable lipids extraction yields when non-polar and polar solvent mixtures were used. The higher esterifiable lipids extraction yield was 19.2%wt (based on dry biomass) using a chloroform-methanol mixture (75%v/v of methanol), corresponding to a 98.9%wt esterifiable lipids extraction. In addition, esterifiable lipids extraction yield of 18.9%wt (based on dry biomass) was obtained when a petroleum ether-methanol mixture (75%v/v of methanol) was used, corresponding to a 96.9%wt esterifiable lipids extraction. PMID- 26639616 TI - Long term storage of dilute acid pretreated corn stover feedstock and ethanol fermentability evaluation. AB - This study reported a new solution of lignocellulose feedstock storage based on the distributed pretreatment concept. The dry dilute sulfuric acid pretreatment (DDAP) was conducted on corn stover feedstock, instead of ammonia fiber explosion pretreatment. Then the dry dilute acid pretreated corn stover was stored for three months during summer season with high temperature and humidity. No negative aspects were found on the physical property, composition, hydrolysis yield and ethanol fermentability of the long term stored pretreated corn stover, plus the additional merits including no chemicals recovery operation, anti-microbial contaminant environment from stronger acid and inhibitor contents, as well as the mild and slow hydrolysis in the storage. The new pretreatment method expanded the distributed pretreatment concept of feedstock storage with potential for practical application. PMID- 26639617 TI - Trypanosoma cruzi: single cell live imaging inside infected tissues. AB - Although imaging the live Trypanosoma cruzi parasite is a routine technique in most laboratories, identification of the parasite in infected tissues and organs has been hindered by their intrinsic opaque nature. We describe a simple method for in vivo observation of live single-cell Trypanosoma cruzi parasites inside mammalian host tissues. BALB/c or C57BL/6 mice infected with DsRed-CL or GFP-G trypomastigotes had their organs removed and sectioned with surgical blades. Ex vivo organ sections were observed under confocal microscopy. For the first time, this procedure enabled imaging of individual amastigotes, intermediate forms and motile trypomastigotes within infected tissues of mammalian hosts. PMID- 26639618 TI - Transformation of Face Transplants: Volumetric and Morphologic Graft Changes Resemble Aging After Facial Allotransplantation. AB - Facial allotransplantation restores normal anatomy to severely disfigured faces. Although >30 such operations performed worldwide have yielded promising short term results, data on long-term outcomes remain scarce. Three full-face transplant recipients were followed for 40 months. Severe changes in volume and composition of the facial allografts were noted. Data from computed tomography performed 6, 18 and 36 months after transplantation were processed to separate allograft from recipient tissues and further into bone, fat and nonfat soft tissues. Skin and muscle biopsies underwent diagnostic evaluation. All three facial allografts sustained significant volume loss (mean 19.55%) between 6 and 36 months after transplant. Bone and nonfat soft tissue volumes decreased significantly over time (17.22% between months 6 and 18 and 25.56% between months 6 and 36, respectively), whereas fat did not. Histological evaluations showed atrophy of muscle fibers. Volumetric and morphometric changes in facial allografts have not been reported previously. The transformation of facial allografts in this study resembled aging through volume loss but differed substantially from regular aging. These findings have implications for risk benefit assessment, donor selection and measures counteracting muscle and bone atrophy. Superior long-term outcomes of facial allotransplantation will be crucial to advance toward future clinical routine. PMID- 26639619 TI - geoRge: A Computational Tool To Detect the Presence of Stable Isotope Labeling in LC/MS-Based Untargeted Metabolomics. AB - Studying the flow of chemical moieties through the complex set of metabolic reactions that happen in the cell is essential to understanding the alterations in homeostasis that occur in disease. Recently, LC/MS-based untargeted metabolomics and isotopically labeled metabolites have been used to facilitate the unbiased mapping of labeled moieties through metabolic pathways. However, due to the complexity of the resulting experimental data sets few computational tools are available for data analysis. Here we introduce geoRge, a novel computational approach capable of analyzing untargeted LC/MS data from stable isotope-labeling experiments. geoRge is written in the open language R and runs on the output structure of the XCMS package, which is in widespread use. As opposed to the few existing tools, which use labeled samples to track stable isotopes by iterating over all MS signals using the theoretical mass difference between the light and heavy isotopes, geoRge uses unlabeled and labeled biologically equivalent samples to compare isotopic distributions in the mass spectra. Isotopically enriched compounds change their isotopic distribution as compared to unlabeled compounds. This is directly reflected in a number of new m/z peaks and higher intensity peaks in the mass spectra of labeled samples relative to the unlabeled equivalents. The automated untargeted isotope annotation and relative quantification capabilities of geoRge are demonstrated by the analysis of LC/MS data from a human retinal pigment epithelium cell line (ARPE-19) grown on normal and high glucose concentrations mimicking diabetic retinopathy conditions in vitro. In addition, we compared the results of geoRge with the outcome of X(13)CMS, since both approaches rely entirely on XCMS parameters for feature selection, namely m/z and retention time values. To ensure data traceability and reproducibility, and enabling for comparison with other existing and future approaches, raw LC/MS files have been deposited in MetaboLights (MTBLS213) and geoRge is available as an R script at https://github.com/jcapelladesto/geoRge. PMID- 26639620 TI - Hippocampal neurogenesis in the APP/PS1/nestin-GFP triple transgenic mouse model of Alzheimer's disease. AB - Alzheimer's disease (AD) is one of the most common causes of dementia. Although the exact mechanisms of AD are not entirely clear, the impairment in adult hippocampal neurogenesis has been reported to play a role in AD. To assess the relationship between AD and neurogenesis, we studied APP/PS1/nestin-green fluorescent protein (GFP) triple transgenic mice, a well-characterized mouse model of AD, which express GFP under the control of the nestin promoter. Different ages of AD mice and their wild-type littermates (WT) were used in our study. Immunofluorescent staining showed that neurogenesis occurred mainly in the subgranular zone (SGZ) of the dentate gyrus (DG) and subventricular zone (SVZ) of the lateral ventricles (LVs). The expression of neural stem cells (NSCs) (nestin) and neural precursors such as doublecortin (DCX) and GFAP in AD mice were decreased with age, as well as there being a reduction in 5-bromo-2-deoxyuridine (BrdU)-positive cells, when compared to WT. However, the number of maturate neurons (NeuN) was not significantly different between AD mice and wild-type controls, and NeuN changed only slightly with age. By Golgi-Cox staining, the morphologies of dendrites were observed, and significant differences existed between AD mice and wild-type controls. These results suggest that AD has a far reaching influence on the regulation of adult hippocampal neurogenesis, leading to a gradual decrease in the generation of neural progenitors (NPCs), and inhibition of the differentiation and maturation of neurons. PMID- 26639621 TI - Origin, evolution and function of the hemipteran perimicrovillar membrane with emphasis on Reduviidae that transmit Chagas disease. AB - The peritrophic matrix is a chitin-protein structure that envelops the food bolus in the midgut of the majority of insects, but is absent in some groups which have, instead, an unusual extra-cellular lipoprotein membrane named the perimicrovillar membrane. The presence of the perimicrovillar membrane (PMM) allows these insects to exploit restricted ecological niches during all life stages. It is found only in some members of the superorder Paraneoptera and many of these species are of medical and economic importance. In this review we present an overview of the midgut and the digestive system of insects with an emphasis on the order Paraneoptera and differences found across phylogenetic groups. We discuss the importance of the PMM in Hemiptera and the apparent conservation of this structure among hemipteran groups, suggesting that the basic mechanism of PMM production is the same for different hemipteran species. We propose that the PMM is intimately involved in the interaction with parasites and as such should be a target for biological and chemical control of hemipteran insects of economic and medical importance. PMID- 26639622 TI - The relative contributions of function, perceived psychological burden and partner support to cognitive distress in bladder cancer. AB - OBJECTIVE: Bladder cancer is a genitourinary disease of increasing incidence. Despite improvements in treatment, outcomes remain equivocal with high recurrence rates. It is associated with poor psychosocial outcomes due to reduced functioning of the genitourinary system. The objective of these analyses was to query whether reported loss of function or the perception of psychological burden caused by this functional impedance was the key to understanding psychosocial outcomes. METHODS: The sample comprised 119 participants with a confirmed diagnosis of bladder cancer. They completed a self-report questionnaire comprising the Bladder Cancer Index, Mini-mental Adjustment to Cancer Scale, Psychosocial Adjustment to Illness Scale and standard sociodemographic details. Simple mediation and serial mediation were used to explore the potential for psychological burden to mediate associations between loss of function and cognitive distress, and the potential additional contribution of positive partner support on these relationships. Age and duration of cancer were considered as covariates. RESULTS: Simple mediation demonstrated that the association between function and cognitive distress was fully mediated by perceived psychological burden. Serial mediation, which allowed for the addition of partner support, again demonstrated full mediation, with partner support being the key predictive variable. CONCLUSIONS: These analyses emphasise the importance of an appreciation of individuals' interpretation of the burden occasioned by bladder cancer and the role of a supportive partner. The implications for management discussions and support services in alleviating negative psychological outcomes in bladder cancer are highlighted. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26639630 TI - The Council on Anthropology and Reproduction (CAR) Opposes Legislation that Creates Barriers to Safe Abortion Care. PMID- 26639623 TI - Reoperation after in-theater combat spine surgery. AB - BACKGROUND CONTEXT: The ideal timing of surgical decompression or stabilization following combat-related spine injury remains unclear. PURPOSE: The study aims to determine the etiology and factors related to reoperation following evacuation to the United States after undergoing in-theater spine surgery. STUDY DESIGN: This is a retrospective analysis. PATIENT SAMPLE: The sample includes 13 patients with combat-related spine injuries undergoing revision spine surgery. OUTCOME MEASURES: The outcome measures were time to arrival in the United States, time to reoperation, indications for revision, operative details, further revision surgery, infection rate, complications after reoperation, and most recent clinical follow-up information. METHODS: This is a retrospective analysis of patients undergoing spine surgery designated as injured during the Global War on Terrorism between July 2003 and July 2013. Inpatient and outpatient medical records, operative reports, and imaging studies were reviewed. RESULTS: The mean time to index surgery was 1.6 days. The mechanisms of injury included five gunshot wounds, three improvised explosive devices (IED), two helicopter crashes, one motor vehicle accident, and two other mechanisms (fall and crush injury). The mean injury severity score (ISS) was 22.7 (range: 13-45). There were six cervical, seven thoracic, eight lumbar, and two sacral injuries, with a mean of 1.8+/-1.0 spinal regions injured per patient. Twelve patients had a spinal cord injury, four of which were AIS (American Spinal Association Impairment Scale). Three patients underwent spinal stabilization on the date of injury, and one patient had three separate spine surgeries while downrange before arrival. Four patients underwent fixation in theater. There was a mean of 5.5 days from injury to arrival in the United States, and the mean time to revision fixation was 11.2 days post-index surgery (range: 4-14 days). Revision indications included instability or progressive kyphosis (N=6), and two of these patients had decompression without instrumentation downrange. Other indications included inadequate decompression (N=4), infection, persistent drainage, and epidural hematoma. At a mean of 5.5-year follow-up, all patients were medically retired from service, with minimal neurologic improvement. CONCLUSIONS: Our study found that instability or progressive kyphosis and incomplete decompression were the most common indications for reoperation after evacuation to the United States. Our data provide additional understanding of the potential etiologies of failure and reoperation following in-theater combat spine surgery, and may help avoid such complications. PMID- 26639631 TI - Community day care with carer support versus usual nursing home-based day care: effects on needs, behavior, mood, and quality of life of people with dementia. AB - BACKGROUND: Several studies have shown that the combined community-based Meeting Centres Support Programme (MCSP) for people with mild to moderate dementia and their carers were more effective in reducing behavior and mood problems of people with dementia than traditional nursing home-based (NH) day care. We therefore investigated in this study whether community-based (CO) psychogeriatric day care for people with mild to severe dementia combined with carer support (in accordance with the MCSP), is more effective than regular NH day care. METHODS: A pre-test-post-test control group design was used to compare the effect of CO and NH day care on care needs, behavior and mood problems, and quality of life of people with dementia. 138 dyads of people with mild to severe dementia and family carers participated in the study: 70 from (new and longer existing) CO day cares (experimental group), and 68 from NH day cares (control group). ANCOVAs were performed at post-tests, including baseline data as covariates. RESULTS: After six months, no overall differences on outcome measures were found between CO and NH day cares. However, participants of recently started CO day cares showed fewer neuropsychiatric symptoms, whereas carers in the longer existing CO day cares reported fewer care needs compared to the control group (large effects). Persons with dementia cohabiting with their carer benefitted most from CO day care. CONCLUSIONS: This study shows that combined CO day care has promising added value compared to NH day care, especially for participants with dementia cohabiting with their carer. PMID- 26639633 TI - C-Alkylation of Ketones and Related Compounds by Alcohols: Transition-Metal Catalyzed Dehydrogenation. AB - Transition-metal-catalyzed C-alkylation of ketones and secondary alcohols, with alcohols, avoids use of organometallic or environmentally unfriendly alkylating agents by means of borrowing hydrogen (BH) or hydrogen autotransfer (HA) activation of the alcohol substrates. Water is formed as the only by-product, thus making the BH process atom-economical and environmentally benign. Diverse homogeneous and heterogeneous transition-metal catalysts, ketones, and alcohols can be used for this transformation, thus rendering the BH process promising for replacing those procedures that use traditional alkylating agents. This Minireview summarizes the advances during the last five years in transition-metal catalyzed BH alpha-alkylation of ketones, and beta-alkylation of secondary alcohols with alcohols. A discussion on the application of the BH strategy for C C bond formation is included. PMID- 26639632 TI - Detection of gene communities in multi-networks reveals cancer drivers. AB - We propose a new multi-network-based strategy to integrate different layers of genomic information and use them in a coordinate way to identify driving cancer genes. The multi-networks that we consider combine transcription factor co targeting, microRNA co-targeting, protein-protein interaction and gene co expression networks. The rationale behind this choice is that gene co-expression and protein-protein interactions require a tight coregulation of the partners and that such a fine tuned regulation can be obtained only combining both the transcriptional and post-transcriptional layers of regulation. To extract the relevant biological information from the multi-network we studied its partition into communities. To this end we applied a consensus clustering algorithm based on state of art community detection methods. Even if our procedure is valid in principle for any pathology in this work we concentrate on gastric, lung, pancreas and colorectal cancer and identified from the enrichment analysis of the multi-network communities a set of candidate driver cancer genes. Some of them were already known oncogenes while a few are new. The combination of the different layers of information allowed us to extract from the multi-network indications on the regulatory pattern and functional role of both the already known and the new candidate driver genes. PMID- 26639634 TI - Solvent Polarity Tunes the Barrier Height for Twisted Intramolecular Charge Transfer in N-Pyrrolobenzonitrile (PBN). AB - 4-(1H-pyrrol-1-yl)benzonitrile (PBN) is a typical intramolecular donor-acceptor (D/A) molecule that shows dual fluorescence in weakly polar environments. In this work the underlying photochemical reaction mechanism is investigated theoretically by using high-level ab initio methods including the recently implemented third order algebraic diagrammatic construction of the polarization propagator (ADC(3)). Solvation effects have been considered by using different sophisticated continuum model approaches. Our results conclusively explain all available experimental findings including the effects of excitation wavelength, temperature and solvent polarity. After photoexcitation in gas phase to the bright 2A (S2, pipi*) state, PBN relaxes on the 2A state surface until a conical intersection with the energetically close-lying dark 1B (S1, LE) state is reached. After passing this conical intersection PBN further relaxes on the LE state surface toward a minimum from which emission can occur. In polar environments this picture changes. Then the polar 2B (S3, CT) state is stabilized and an energy barrier along the twisting coordinate vanishes. As a consequence population of the twisted 2B state minimum becomes the dominating decay channel and red-shifted fluorescence occurs. PMID- 26639635 TI - Intensification of biogas production using pretreatment based on hydrodynamic cavitation. AB - The present work investigates the application of hydrodynamic cavitation (HC) for the pretreatment of wheat straw with an objective of enhancing the biogas production. The hydrodynamic cavitation reactor is based on a stator and rotor assembly. The effect of three different speeds of rotor (2300, 2500, 2700 rpm), wheat straw to water ratios (0.5%, 1% and 1.5% wt/wt) and also treatment times as 2, 4 and 6 min have been investigated in the work using the design of experiments (DOE) approach. It was observed that the methane yield of 31.8 ml was obtained with untreated wheat straw whereas 77.9 ml was obtained with HC pre-treated wheat straw confirming the favourable changes during the pre-treatment. The combined pre-treatment using KOH and HC gave maximum yield of biogas as 172.3 ml. Overall, it has been established that significant enhancement in the biogas production can be obtained due to the pretreatment using HC which can also be further intensified by combination with chemical treatment. PMID- 26639636 TI - New methods for analysis of oxysterols and related compounds by LC-MS. AB - Oxysterols are oxygenated forms of cholesterol or its precursors. They are formed enzymatically and via reactive oxygen species. Oxysterols are intermediates in bile acid and steroid hormone biosynthetic pathways and are also bioactive molecules in their own right, being ligands to nuclear receptors and also regulators of the processing of steroid regulatory element-binding proteins (SREBPs) to their active forms as transcription factors regulating cholesterol and fatty acid biosynthesis. Oxysterols are implicated in the pathogenesis of multiple disease states ranging from atherosclerosis and cancer to multiple sclerosis and other neurodegenerative diseases including Alzheimer's and Parkinson's disease. Analysis of oxysterols is challenging on account of their low abundance in biological systems in comparison to cholesterol, and due to the propensity of cholesterol to undergo oxidation in air to generate oxysterols with the same structures as those present endogenously. In this article we review the mass spectrometry-based methods for oxysterol analysis paying particular attention to analysis by liquid chromatography-mass spectrometry (LC-MS). PMID- 26639637 TI - Evidence for altered osteoclastogenesis in splenocyte cultures from Cyp27b1 knockout mice. AB - The association between increased serum 25-hydroxyvitamin D (25D) and reduced osteoclastic bone resorption is well known. Previously, we have demonstrated that mechanism by which this occurs, may include the conversion of 25D to 1,25 dihydroxyvitamin D (1,25D) by osteoclasts, catalysed by the CYP27B1 enzyme. Local 1,25D synthesis in osteoclasts was shown to regulate osteoclastogenesis and moderating resorptive activity. Thus, we hypothesised that osteoclasts differentiated from mice with global deletion of the Cyp27b1 gene (Cyp27b1 KO) would display enhanced resorptive capacity due to the lack of an ameliorating effect of 1,25D. Splenocytes isolated from Cyp27b1 KO mice or their wild-type (WT) littermates between 6 and 8 weeks of age were cultured under osteoclast forming conditions for up to 14 days. Osteoclast formation was measured by staining for the osteoclast marker tartrate resistant acid phosphatase (TRAP). Bone resorption activity was measured by plating the cells on a bone-like substrate. In Cyp27b1 KO cultures, osteoclastogenesis was reduced, as indicated by fewer TRAP-positive multinucleated cells at all time points measured (p<0.05) when compared to wild-type (WT) levels. However, Cyp27b1 KO osteoclasts demonstrated greater resorption on a per cell basis than their WT counterparts (p<0.03). In addition, the ratio of expression of the pro-apoptotic gene Bax to the pro-survival gene Bcl-2 was decreased in Cyp27b1 KO cultures, implying that these smaller osteoclasts survive longer than WT osteoclasts. Our data indicate abnormal osteoclastogenesis due to the absence of CYP27B1 expression, consistent with the notion that endogenous metabolism of 25D optimises osteoclastogenesis and ameliorates the resulting activity of mature osteoclasts. PMID- 26639639 TI - The Effect of a Payer-Mandated Decrease in Buprenorphine Dose on Aberrant Drug Tests and Treatment Retention Among Patients with Opioid Dependence. AB - BACKGROUND: The optimal dose for office-based buprenorphine therapy is not known. This study reports on the effect of a change in payer policy, in which the insurer of a subset of patients in an office-based practice imposed a maximum sublingual buprenorphine dose of 16 mg/day, thereby forcing those patients on higher daily doses to decrease their dose. This situation created conditions for a natural experiment, in which treatment outcomes for patients experiencing this dose decrease could be compared to patients with other insurance who were not challenged with a dose decrease. METHODS: Subjects were 297 patients with opioid use disorder in a primary care practice who were prescribed buprenorphine continuously for at least 3 months. Medical records were retrospectively reviewed for urine drug test results and treatment retention. Rates of aberrant urine drug tests were calculated in the period before the dose decrease and compared to rate after it with patients serving as their own controls. Comparison groups were formed from patients with the same insurance on buprenorphine doses of 16 mg/day or lower, patients with different insurance on 16 mg/day or lower, and patients with different insurance on greater than 16 mg/day. Rates of aberrant drug tests and treatment retention of patients on 16 mg/day or less of buprenorphine were compared to that of patients on higher daily doses. RESULTS: The rate of aberrant urine drug tests among patients who experienced a dose decrease rose from 27.5% to 34.2% (p=0.043). No comparison group showed any significant change in aberrant drug test rates. Moreover, all groups who were prescribed buprenorphine doses greater than 16 mg/day displayed lower rates of aberrant urine drug tests than groups prescribed lower doses. Retention in treatment was also highest among those prescribed greater than 16 mg/day (100% vs. 86.8%, 90.1%, and 84.4% p=0.010). DISCUSSION: An imposed buprenorphine dose decrease was associated with an increase in aberrant drug tests. Patients in a control group with higher buprenorphine doses had greater retention in treatment. These findings suggest that buprenorphine doses greater than 16 mg/day are more effective for some patients and that dose limits at this level or lower are harmful. PMID- 26639638 TI - The Dynamics and Regulatory Mechanism of Pronuclear H3k9me2 Asymmetry in Mouse Zygotes. AB - H3K9 methylation is an important histone modification that is correlated with gene transcription repression. The asymmetric H3K9 dimethylation (H3K9me2) pattern between paternal and maternal genomes is generated soon after fertilization. In the present study, we carefully determined the dynamics of H3K9me2 changes in mouse zygotes, and investigated the regulatory mechanisms. The results indicated that histone methyltransferase G9a, but not GLP, was involved in the regulation of asymmetric H3K9me2, and G9a was the methyltransferase that induced the appearance of H3K9me2 in the male pronucleus of the zygote treated with cycloheximide. We found that there were two distinct mechanisms that regulate H3K9me2 in the male pronucleus. Before 8 h of in vitro fertilization (IVF), a mechanism exists that inhibits the association of G9a with the H3K9 sites. After 10 h of IVF the inhibition of G9a activity depends on yet unknown novel protein(s) synthesis. The two mechanisms of transfer take place between 8 10 h of IVF, and the novel protein failed to inhibit G9a activity in time, resulting in the appearance of a low level de novo H3K9me2 in the male pronucleus. PMID- 26639640 TI - Efficacy of a single intramuscular injection of porcine FSH in hyaluronan prior to ovum pick-up in Holstein cattle. AB - Plasma FSH profiles, in vitro embryo production (IVP) after ovum pickup (OPU), and establishment of pregnancy with IVP embryos were compared in untreated Holstein oocyte donors and those superstimulated with multiple injections or a single intramuscular (IM) injection of porcine FSH (pFSH) in hyaluronan (HA). Plasma FSH profiles were determined in 23 heifers randomly allocated to one of four groups. Controls received no treatment, whereas the F200 group received 200 mg of pFSH in four doses, 12 hours apart. The F200HA and F300HA groups received 200- or 300-mg pFSH in 5 mL or 7.5 mL, respectively of a 0.5% HA solution by a single IM injection. Plasma FSH levels were determined before the first pFSH treatment and every 6 hours over 96 hours. All data were analyzed by orthogonal contrasts. Circulating FSH area under curve (AUC) in pFSH-treated animals was greater than that in the control group (P = 0.02). Although the AUC did not differ among FSH-treated groups (P = 0.56), the total period with elevated plasma FSH was greater in the F200 group than in the HA groups (P < 0.0001). However, the F300HA group had a greater AUC than the F200HA group (P = 0.006), with a similar total period with elevated plasma FSH (P = 0.17). The IVP was performed in 90 nonlactating Holstein cows randomly allocated to one of the four treatment groups as in the first experiment. A greater proportion of medium-sized (6-10 mm) follicles was observed in cows receiving pFSH, regardless of the treatment group (P < 0.0001). Also, numbers of follicles (P = 0.01), cumulus-oocyte complexes (COCs) retrieved (P = 0.01) and matured (P = 0.02), cleavage rates (P = 0.002), and blastocysts produced per OPU session (P = 0.06) were greater in cows receiving pFSH, regardless of the treatment group. Cows in the F200HA group had a greater recovery rate (P = 0.009), number of COCs cultured (P = 0.04), and blastocysts produced per OPU session (P = 0.06) than cows in the F300HA group. Similar pregnancy rates were observed 50 to 60 days after transferring IVP embryos from donors in the different treatment groups (P > 0.05). In conclusion, a single IM injection of pFSH combined in 0.5% HA resulted in similar plasma FSH profiles as twice-daily pFSH treatments. Treatment of nonlactating donors with pFSH, with or without HA, resulted in increased IVP over untreated controls. A single dose of 200 mg of pFSH in 0.5% HA resulted in greater IVP than 300-mg pFSH in HA. Finally, pregnancy rates with IVP embryos were similar, regardless donor treatment. PMID- 26639641 TI - Does the inclusion of protease inhibitors in the insemination extender affect rabbit reproductive performance? AB - The bioavailability of buserelin acetate when added to the seminal dose appears to be determined by the activity of the existing aminopeptidases. Thus, the addition of aminopeptidase inhibitors to rabbit semen extenders could be a solution to decrease the hormone degradation. This study was conducted to evaluate the effect of the protease activity inhibition on rabbit semen quality parameters and reproductive performance after artificial insemination. Seminal quality was not affected by the incubation with protease inhibitors, being the values of motility, viability, and acrosome integrity not significantly different between the protease inhibitors and the control group. In addition, seminal plasma aminopeptidase activity was inhibited in a 55.1% by the protease inhibitors. On the other hand, regarding the effect of protease inhibitors on reproductive performance, our results showed that the presence of protease inhibitors affected the prolificacy rate (9.2 +/- 0.26 and 9.3 +/- 0.23 vs. 8.2 +/- 0.22 total born per litter for negative control, positive control, and aminopeptidase inhibitors group, respectively; P < 0.05), having this group one kit less per delivery. We conclude that the addition of a wide variety of protease inhibitors in the rabbit semen extender negatively affects prolificacy rate. Therefore, the development of new extenders with specific aminopeptidase inhibitors would be one of the strategies to increase the bioavailability of GnRH analogues without affecting the litter size. PMID- 26639642 TI - Cryopreservation of Day 8 equine embryos after blastocyst micromanipulation and vitrification. AB - Pregnancy rates after cryopreservation of large equine blastocyst stage embryos have remained lower than other domesticated livestock species. It is generally accepted that the embryonic capsule is the primary barrier to cryoprotectant entry into the embryo proper and techniques need to be developed to circumvent this obstacle. Therefore, the objective of this study was to develop an efficient Day 8 equine embryo cryopreservation protocol through blastocyst micromanipulation and vitrification. Grade 1 and 2 embryos recovered from mares (n = 15) 8 days after ovulation were used in these experiments. In experiment 1, the effect of either one- or two-puncture treatments before aspiration of blastocoel fluid and exposure to vitrification solutions was evaluated. No difference was detected in mean embryo volume across treatment groups after exposure to vitrification solutions or after 1, 24, 48, and 72 hours of culture. Percent of embryos re-expanding at 24 hours and percent of embryos showing diameter increase at 48 and 72 hours during in vitro culture were 100%, 83%, and 75% compared with 93%, 67%, and 50% for one- and two-puncture treatment groups, respectively. Capsule loss was 25% for one-puncture and 50% for two-puncture treatment groups. In experiment 2, no difference was detected in mean embryo volume for indirect introduction (aspiration of blastocoel fluid + equilibration) and direct introduction (injection of cryoprotectant into blastocoel cavity) treatment groups, after exposure to dilution solution or to culture medium. There was no difference in mean embryo volume for the indirect and direct introduction treatment groups after 1, 24, 48, and 72 hours of culture. Percent of embryos re expanding at 24 hours and percent of embryos showing diameter increases at 48 and 72 hours during in vitro culture were 100%, 76.9%, and 69.2%, respectively, for both treatment groups. Those embryos subjected to the direct introduction treatment had a higher (P = 0.05) percent capsule loss (70%) compared with the indirect introduction treatment group (31%). The pregnancy rate after transfer of vitrified expanded Grade 1 blastocysts using the indirect introduction method was 83% (5/6). Three pregnancies were allowed to continue to term and resulted in the birth of three healthy foals. The vitrification protocol used in this study has the potential to become a key tool for the successful cryopreservation of equine expanded blastocysts. PMID- 26639643 TI - [Prevention and treatment of the complications of polycystic ovarian syndrome- the significance of evidence-based, interdisciplinary management]. AB - Polycystic ovary syndrome is the most common hormonal and metabolic disorder likely to affect women. The syndrome is often associated with obesity, hyperinsulinemia and adversely affects endocrine, metabolic, and cardiovascular health. The complex feature of the syndrome requires an interdisciplinary approach to treatment, where cooperation of paediatrician, internist, gynaecologist, endocrinologist, dermatologist, psychologist and oncologist is essential. The prevention and the treatment should be based on the best available evidence. This should include physical examination, laboratory tests for hormones, serum insulin, glucose, lipids, in addition patient's preferences should be considered, too. To maximise health gain of polycystic ovarian syndrome, adequate, effective, efficient and safe treatment is necessary. This article summarises the highest available evidence provided by meta-analyses and systematic reviews of the prevention of metabolic and cardiovascular complications of the syndrome, and discusses the relevant evidence published in the literature. PMID- 26639644 TI - [Psychosocial aspects of preeclampsia]. AB - Distress conditions during pregnancy may contribute to the development of preeclampsia by altering functions of the neuroendocrine and immune systems, e.g. activation of the hypothalamic-pituitary-adrenal axis and increase in plasma proinflammatory cytokines. Preeclampsia may also precipitate mental health problems due to long-term hospitalization or unpredictable and uncontrollable events such as preterm labor and newborn complications. Besides, preeclampsia may induce persistent neurocognitive complaints with a negative impact on patients' quality of life. As growing evidence indicates that poor maternal mental health has an adverse effect on pregnancy outcome and fetal development, psychosocial interventions may be beneficial for women with preeclampsia. PMID- 26639645 TI - [Health status of the Hungarian population between 2000-2010]. AB - INTRODUCTION: So far, the latest survey which used the EQ-5D questionnaire to measure the health status of the Hungarian population was carried out in 2000. AIM: To explore the health state of the Hungarian population by socio-demographic characteristics, and to compare it with the results from 2000. METHOD: As part of an international research project, a cross-sectional, online survey was carried out among the general population in 2010 using the EQ-5D-3L questionnaire. RESULTS: In total, 2281 respondents (female: 62.3%) completed the questionnaire with an average age of 40.8 years. The EQ-5D score ranged from 0.902 (in age group 18-24) to 0.795 (65+). The authors found significant association between the EQ-5D score and all the socio-demographic variables (gender, age, education, income) included in the regression model (F(4,1967)=35.12, p=0.000). The results did not differ significantly from the health survey in 2000, except for the youngest population group (age 18-24), where significantly lower scores were found in the sample. CONCLUSIONS: While life expectance increased by 3 years between 2000 and 2010, the health status of the Hungarian population did not change significantly, and might even decreased among young adults in fact. Inequalities in health status by income and education remain significant. In international comparison, the health status of the Hungarian population remains among the worst ones. PMID- 26639646 TI - [Removal of weremit from the abdomen. Interpretation and efficacy of an ancient Egyptian prescription by the newest scientific results]. AB - Significant percentage of today's knowledge of ancient Egyptian medicine has been acquired from papyri left behind from various periods of Egyptian history. The longest and the most comprehensive is the Ebers papyrus, kept at the University Museum of Leipzig, which was written more than one thousand years before Hippocrates (c. 460-377 BC). One of the riddles among the prescriptions of the Ebers papyrus Eb20 has been used in order to remove the so called "wemyt" weremit from the abdomen with the help of a drink, which consists of "jnnk", Conyza dioscoridis in milk or sweet beer. The authors assume that the disease could be an infection of Schistosoma haematobium and/or Schistosoma mansoni. Nowadays the tea of Conyza dioscoridis is widely used as an important part of traditional medicine against rheumatism, intestinal distention and cramps, as well as an antiperspirant, and with external use for wound healing. The authors' intent is to interpret the efficacy of the above-mentioned ancient prescription with the help of modern medical and pharmaceutical knowledge. PMID- 26639647 TI - [Is there protection against copying? Thoughts about plagiarism]. AB - There are at least two reasons why more and more cases of suspected plagiarism are perceived in the scientific literature. On one hand, the ever increasing pressure for publication makes it easier for authors, reviewers and editors to infringe or overlook this serious ethical misdemeanor; on the other hand, with the development of text analysis software, detecting text similarities has become a simple task. The judgement of actual cases, however, requires well-grounded professional knowledge and prudent human decisions. PMID- 26639649 TI - Non-pharmacological interventions for caregivers of patients with schizophrenia: A meta-analysis. AB - It has been estimated that about 50-80% of patients with schizophrenia live with or closely contact with their caregivers, and rely on them for housing, and emotional and financial supports. Caregiving experience is usually described as stressful for their caregivers. Non-pharmacological interventions seem to be beneficial to improving life quality. However, there is still no meta-analysis focused on this topic to give an overview.We searched the electronic databases includingPubMed, EMBASE, CINAHL, Cochrane Library and China National Knowledge Infrastructure, respectively from the beginning of database to July 2015 for all the randomized controlled trialsevaluating the caregiver interventions. Continuous data were expressed mean differences (MD) with 95% confidential intervals (CIs). Standardized mean difference was planned to express, if different scales were used to measure the same outcome. We pooled the results using a random-effect model.As a result, nine studies met the inclusion criteria, comprising 608 randomized participants. In which, 321 participants were in interventional group, while 287 participants were in control group. Concerning the care burden, there was significant difference found between non pharmacological interventions and control groups (n=290, MD -2.10, 95% CI -3.46 to -0.74, P=0.002; level of heterogeneity tau(2)=1.81, chi(2)=62.13, df=3, P<0.00001, I(2)=95%). However, no differences were found in family support, family functioning and satisfaction. Of note, our meta-analysis demonstrated the efficacy of non-pharmacological interventions for caregivers of schizophrenia, and supported the application in the clinical practice. However, all the conclusions should be explained cautiously and further confirmation is required by well-designed trials with large sample. PMID- 26639650 TI - Inhibition and response to error in remitted major depression. AB - Depression is a common illness which tends to have a relapsing progression. Revealing vulnerability factors is an important step towards improved treatment and prevention. Previous studies of individuals in remission indicate that inhibitory control is more strongly impaired than other cognitive functions. Studies have mostly used Stroop tasks; it is unclear how this population performs on other measures of inhibition. Abnormal reactions to errors may also promote depression relapse, but this has rarely been studied in remitted depression. We used a Stop Signal task and Stroop inhibition task to investigate inhibitory function and post-error reaction time adjustments in 54 individuals with a history of depression and 185 never-depressed controls. Inhibitory processing was slower among the remitted depressed individuals on the Stop Signal task, but no difference was found in Stroop inhibition. The groups were not different on post error adjustments. This finding extends the understanding of inhibitory deficiency in this population and offers insight into trait markers of depression. PMID- 26639651 TI - Target genes involved in corticosterone-induced PC12 cell viability and neurite disorders: A potential molecular mechanism of major depressive disorder. AB - Past studies confirmed that hypothalamic-pituitary-adrenal (HPA)-axis hormones involved in major depressive disorder (MDD) development. This study used corticosterone treated PC12 cells to explore the potential role of MAPK signal transduction pathway in response to corticosterone stimulation. The results showed that both live cell numbers and cellular neurite outgrowth were remarkably reduced in response to corticosterone treatments. qPCR results demonstrated that the expression levels of four MAPK pathway genes were significantly increased after corticosterone stimulation. In conclusion, glucocorticoids stimulation can affect neuronal cell viability and neurite outgrowth due to the over expression of a group of MAPK pathway genes. PMID- 26639652 TI - Effect of temporal and spatial variability on the classification of the Ecological Quality Status using the CARLIT Index. AB - Methodologies developed by European Member States to assess the environmental quality of their coastal waters under the EU Water Framework Directive (WFD, 2000/60/EC) may have an associated source of uncertainty. Here we identify and quantify the level of uncertainty in the CARLIT (Cartography of littoral and upper-sublittoral communities) methodology to test its effectiveness and reliability. The outcomes show that the effect of temporal variability (among years) within each water body is low when CARLIT is performed every year along the entire rocky coast. The spatial variability within a water body is also low. According to these results, CARLIT could be performed every 3 years across all the water body or, alternatively, every year considering at least 60% of each water body, without a significant reduction of the confidence in the classification of the Ecological Quality Status (EQS). PMID- 26639653 TI - Monitoring of trace metals in coastal sediments around Korean Peninsula. AB - Spatial distributions and temporal variations of trace metals in Korean coastal sediments were investigated by determining seven metals (As, Cd, Cr, Cu, Hg, Pb, and Zn) in sediment collected from 71 stations between 2004 and 2010 (n=491). High metal concentrations were found in the southeastern coast, where there are many cities and industrial complexes, indicating that metal concentrations in Korean coastal sediment are significantly influenced by human activities associated with urbanization and industrialization. However, metal concentrations in sediment did not markedly vary temporally, which was because the coast is managed sustainably and because of the characteristics of the sediment environments. Based on the sediment quality guidelines and geoaccumulation index, Korean coastal sediments are practically unpolluted with Cd, Cr, Cu, Hg, Pb and Zn but moderately polluted with As. More intensive monitoring is required to determine the potential As sources and to understand the As geochemical cycles in Korean coastal sediments. PMID- 26639654 TI - How fresh is maple syrup? Sugar maple trees mobilize carbon stored several years previously during early springtime sap-ascent. AB - While trees store substantial amounts of nonstructural carbon (NSC) for later use, storage regulation and mobilization of stored NSC in long-lived organisms like trees are still not well understood. At two different sites with sugar maple (Acer saccharum), we investigated ascending sap (sugar concentration, delta(13) C, Delta(14) C) as the mobilized component of stored stem NSC during early springtime. Using the bomb-spike radiocarbon approach we were able to estimate the average time elapsed since the mobilized carbon (C) was originally fixed from the atmosphere and to infer the turnover time of stem storage. Sites differed in concentration dynamics and overall delta(13) C, indicating different growing conditions. The absence of temporal trends for delta(13) C and Delta(14) C indicated sugar mobilization from a well-mixed pool with average Delta(14) C consistent with a mean turnover time (TT) of three to five years for this pool, with only minor differences between the sites. Sugar maple trees hence appear well buffered against single or even several years of negative plant C balance from environmental stress such as drought or repeated defoliation by insects. Manipulative investigations (e.g. starvation via girdling) combined with Delta(14) C measurements of this mobilized storage pool will provide further new insights into tree storage regulation and functioning. PMID- 26639655 TI - Self-awareness in Mild Cognitive Impairment: Quantitative evidence from systematic review and meta-analysis. AB - Here we quantitatively summarized evidence of impaired awareness in Mild Cognitive Impairment (MCI) and meta-analytically explored the relationship between Subjective Cognitive Complaints (SCC) and actual cognitive impairment. Twenty-three studies were included, 14 comparing awareness measures in MCI and healthy elderly subjects, and 16 also exploring the neuropsychological underpinnings of impaired awareness. Moderator analyses were conducted to determine whether self-awareness varied according to patient group, the particular state in relation to which insight was assessed, or the approach to measuring awareness. The meta-analysis shows that MCI patients have knowledge of their neuropsychological deficits and that level of awareness varies according to cognitive status, language and memory abilities. The assessment technique employed impacted on the insight phenomena. Specifically, MCI patients seem particularly accurate in evaluating the current state of their performance during an ongoing task and this could be essential in regulating their behavior so that compensative strategies are practiced and greater cognitive independence is achieved. Thus, assessment technique and cognitive status are crucial factors that influence level of awareness and should be taken into consideration in awareness evaluation and rehabilitation. PMID- 26639656 TI - EMT is associated with, but does not drive resistance to ALK inhibitors among EML4-ALK non-small cell lung cancer. AB - ALK gene fusion occurs in approximately 3-7% of non-small cell lung cancer (NSCLC). For patients with ALK positive NCSLC, crizotinib and ceritinib are FDA approved ALK inhibitors, however, patients inevitably acquire resistance to such therapies typically within one to two years. Interrogation of in vitro ALK positive NSCLC cell line models of acquired resistance to first and second generation ALK inhibitors revealed acquired epithelial-to-mesenchymal transition (EMT) mechanisms. Here we demonstrated that knockdown of upregulated mesenchymal markers in acquired resistant lines decreased the invasive and migratory capabilities of the cells, however, it did not restore sensitivity to ALK inhibitors. Removing drug for 5 weeks from H3122 cell line that acquired resistance to ceritinib restored its sensitivity to ceritinib. In addition, HSP90 inhibitors ganetespib and 17-AAG were potent in inducing cell death in cell lines resistant to crizotinib and ceritinib. Taken together, EMT does not drive resistance to ALK inhibitors and HSP90 inhibition demonstrates more efficacy when further ALK inhibition may not. This study warrants more exploration of HSP90 inhibitors for ALK-positive patients who progress on 1st and 2nd line ALK inhibitor therapy. PMID- 26639657 TI - Genetic profiling of tumours using both circulating free DNA and circulating tumour cells isolated from the same preserved whole blood sample. AB - Molecular information obtained from cancer patients' blood is an emerging and powerful research tool with immense potential as a companion diagnostic for patient stratification and monitoring. Blood, which can be sampled routinely, provides a means of inferring the current genetic status of patients' tumours via analysis of circulating tumour cells (CTCs) or circulating tumour DNA (ctDNA). However, accurate assessment of both CTCs and ctDNA requires all blood cells to be maintained intact until samples are processed. This dictates for ctDNA analysis EDTA blood samples must be processed with 4 h of draw, severely limiting the use of ctDNA in multi-site trials. Here we describe a blood collection protocol that is amenable for analysis of both CTCs and ctDNA up to four days after blood collection. We demonstrate that yields of circulating free DNA (cfDNA) obtained from whole blood CellSave samples are equivalent to those obtained from conventional EDTA plasma processed within 4 h of blood draw. Targeted and genome-wide NGS revealed comparable DNA quality and resultant sequence information from cfDNA within CellSave and EDTA samples. We also demonstrate that CTCs and ctDNA can be isolated from the same patient blood sample, and give the same patterns of CNA enabling direct analysis of the genetic status of patients' tumours. In summary, our results demonstrate the utility of a simple approach that enabling robust molecular analysis of CTCs and cfDNA for genotype-directed therapies in multi-site clinical trials and represent a significant methodological improvement for clinical benefit. PMID- 26639658 TI - Two unique TUBB3 mutations cause both CFEOM3 and malformations of cortical development. AB - One set of missense mutations in the neuron specific beta tubulin isotype 3 (TUBB3) has been reported to cause malformations of cortical development (MCD), while a second set has been reported to cause isolated or syndromic Congenital Fibrosis of the Extraocular Muscles type 3 (CFEOM3). Because TUBB3 mutations reported to cause CFEOM had not been associated with cortical malformations, while mutations reported to cause MCD had not been associated with CFEOM or other forms of paralytic strabismus, it was hypothesized that each set of mutations might alter microtubule function differently. Here, however, we report two novel de novo heterozygous TUBB3 amino acid substitutions, G71R and G98S, in four patients with both MCD and syndromic CFEOM3. These patients present with moderately severe CFEOM3, nystagmus, torticollis, and developmental delay, and have intellectual and social disabilities. Neuroimaging reveals defective cortical gyration, as well as hypoplasia or agenesis of the corpus callosum and anterior commissure, malformations of hippocampi, thalami, basal ganglia and cerebella, and brainstem and cranial nerve hypoplasia. These new TUBB3 substitutions meld the two previously distinct TUBB3-associated phenotypes, and implicate similar microtubule dysfunction underlying both. PMID- 26639660 TI - Intraindividual Variability of Nonmotor Fluctuations in Advanced Parkinson's Disease. AB - Nonmotor symptoms (NMS) fluctuate in conjunction with motor oscillations in advanced Parkinson's disease (PD), though little is known about the variability of NMS fluctuations in individual patients. We aimed to assess within-patient variability in frequency and severity of NMS during a series of five patient perceived motor On and Off periods in 38 fluctuating PD patients from the multicenter NonMotorFluctuations in PD study using a visual analogue scale. NMS frequency and severity appeared moderately variable in both motor states within individual patients. Symptom severity ranges between motor states showed high variability and were larger in motor Off states for most NMS. PMID- 26639659 TI - Post-Stroke Walking Behaviors Consistent with Altered Ground Reaction Force Direction Control Advise New Approaches to Research and Therapy. AB - Recovery of walking after stroke requires an understanding of how motor control deficits lead to gait impairment. Traditional therapy focuses on removing specific observable gait behaviors that deviate from unimpaired walking; however, those behaviors may be effective compensations for underlying problematic motor control deficits rather than direct effects of the stroke. Neurological deficits caused by stroke are not well understood, and thus, efficient interventions for gait rehabilitation likely remain unrealized. Our laboratory has previously characterized a post-stroke control deficit that yields a specific difference in direction of the ground reaction force (F, limb endpoint force) exerted with the hemiplegic limb of study participants pushing on both stationary and moving pedals while seated. That task was not dependent on F to retain upright posture, and thus, the task did not constrain F direction. Rather, the F direction was the product of neural preference. It is not known if this specific muscle coordination deficit causes the observed walking deviations, but if present during walking, the deficit would prevent upright posture unless counteracted by compensatory behaviors. Compensations are presented that mechanically counteract the F misdirection to allow upright posture. Those compensations are similar to behaviors observed in stroke patients. Based on that alignment between predictions of this theory and clinical observations, we theorize that post stroke gait results from the attempt to compensate for the underlying F misdirection deficit. Limb endpoint force direction has been shown to be trainable in the paretic upper limb, making it a feasible goal in the lower limb. If this F misdirection theory is valid, these ideas have tremendous promise for advancing the field of post-stroke gait rehabilitation. PMID- 26639661 TI - Predictors of Functional Decline in Early Parkinson's Disease: NET-PD LS1 Cohort. AB - BACKGROUND: Data on predictors of decline in PD are largely based on de-novo populations and limited to the use of motor outcomes that fail to capture the full scope of disease. OBJECTIVE: Determine the clinical predictors of decline in early treated PD using a novel multi-domain measure. METHODS: Data from NINDS Exploratory Trials in PD Long-Term Study 1 (NET-PD LS1), a multicenter Phase 3 study of creatine in early treated PD, were analyzed. Functional decline was defined by a global outcome metric (GO) that consisted of: Schwab and England ADL scale, PD 39-item Questionnaire, Unified PD Rating Scale, Ambulatory Capacity Score, Symbol Digit Modalities Test, and Modified Rankin Scale. Univariate and multivariate models were used to test the association of predictors of interest with a standardized rank-sum of the GO. RESULTS: 765 of 1741 participants completed five-year assessments and were included. Older age at disease onset (p < 0.0001), higher baseline levodopa equivalent dose (p = 0.01), and worse Scales for Outcomes of Parkinson's Disease Cognition score (p = 0.001) at baseline were the strongest predictors of functional decline in multivariate analysis. PD symptom subtype was not a significant predictor of outcome (p = 0.42). The full model was only a modest predictor of change in GO (R2 = 0.186). CONCLUSIONS: This is the largest study to systematically assess predictors of functional decline in early treated PD over several years, and the first to use a multi-domain outcome measure of decline. Older age at disease onset and worse cognition, and not PD subtype, were predictors of decline. PMID- 26639662 TI - Irrational exuberance for resolved species trees. AB - Phylogenomics has largely succeeded in its aim of accurately inferring species trees, even when there are high levels of discordance among individual gene trees. These resolved species trees can be used to ask many questions about trait evolution, including the direction of change and number of times traits have evolved. However, the mapping of traits onto trees generally uses only a single representation of the species tree, ignoring variation in the gene trees used to construct it. Recognizing that genes underlie traits, these results imply that many traits follow topologies that are discordant with the species topology. As a consequence, standard methods for character mapping will incorrectly infer the number of times a trait has evolved. This phenomenon, dubbed "hemiplasy," poses many problems in analyses of character evolution. Here we outline these problems, explaining where and when they are likely to occur. We offer several ways in which the possible presence of hemiplasy can be diagnosed, and discuss multiple approaches to dealing with the problems presented by underlying gene tree discordance when carrying out character mapping. Finally, we discuss the implications of hemiplasy for general phylogenetic inference, including the possible drawbacks of the widespread push for "resolved" species trees. PMID- 26639663 TI - Anti-Inflammatory Activity of Tanshinone IIA in LPS-Stimulated RAW264.7 Macrophages via miRNAs and TLR4-NF-kappaB Pathway. AB - Inflammation is a physiological response to infection or injury and involves the innate and adaptive immune system. Tanshinone IIA (Tan IIA) is a well-known flavonoid that elicits an important therapeutic effect by inhibiting inflammatory response. In this study, we examined whether Tan IIA exerts anti-inflammatory activity and investigated the possible mechanisms, including Toll-like receptor 4 (TLR4)-MyD88-nuclear factor kappa B (NF-kappaB) signaling pathway and microRNA expression in lipopolysaccharide (LPS)-induced RAW264.7 cells. Tan IIA could attenuate the inflammatory reaction via decreasing cytokine, chemokine, and acute phase protein production, including GM-CSF, sICAM-1, cxcl-1, MIP-1alpha, and tumor necrosis factor alpha (TNF-alpha), analyzed by Proteome profile array in LPS-induced RAW264.7 cells. Concurrently, the messenger RNA (mRNA) expressions of IL-1beta, TNF-alpha, and COX-2 were also significantly reduced by Tan IIA. Additionally, Tan IIA decreased LPS-induced NF-kappaB activation and downregulated TLR4 and MyD88 protein expression levels. We also observed reduced microRNA-155, miR-147, miR-184, miR-29b, and miR-34c expression levels, while LPS induced microRNA-105, miR-145a, miR-194, miR-383, miR-132, and miR-451a expression levels were upregulated using microRNA (miRNA) qPCR array. Our results indicate that Tan IIA could exert an anti-inflammatory effect on LPS-induced RAW264.7 cells by decreasing TLR4-MyD88-NF-kappaB signaling pathway and regulating a series of cytokine production and miRNA expression. PMID- 26639664 TI - First- and second-generation biochemicals from sugars: biosynthesis of itaconic acid. PMID- 26639667 TI - The action of neuropeptide AF on passive avoidance learning. Involvement of neurotransmitters. AB - Neuropeptide AF (NPAF) is an amidated octadecapeptide, which is member of the RFamide peptide family. NPAF is encoded by the farp-1 gene and acts through the G protein coupled NPFF-1 and NPFF-2 receptors. NPAF is involved in several physiological functions of the central nervous system, however we have little evidence about the involvement of NPAF in learning and memory. Therefore, the aim of the present study was to investigate the action of NPAF on consolidation of memory in a passive avoidance learning paradigm in mice. We have also investigated the underlying neurotransmissions and the action of NPAF on beta amyloid-induced memory impairment. Accordingly, mice were pretreated with a nonselective muscarinic acetylcholine receptor antagonist, atropine, a non selective 5-HT2 serotonergic receptor antagonist, cyproheptadine, a mixed 5-HT1/5 HT2 serotonergic receptor antagonist, methysergide, a D2, D3, D4 dopamine receptor antagonist, haloperidol, a non-selective opioid receptor antagonist, naloxone, a nitric oxide synthase inhibitor, nitro-l-arginine, a alpha1/alpha2beta-adrenergic receptor antagonist, prazosin, a nonselective beta adrenergic receptor antagonist, propranolol or beta-amyloid 25-35 in combination with NPAF administration. Our results demonstrate for the first time that NPAF improves the consolidation of passive avoidance learning. This effect is mediated through muscarinic cholinergic, 5HT1- and 5HT2-serotoninergic, dopaminergic, nitrergic and alpha- and beta-adrenergic neurotransmissions, but not by opioid transmission, since atropine, cyproheptadine, methysergide, haloperidol, nitro-l arginine, prazosin and propranolol reversed the action of NPAF, whereas naloxone was ineffective. The present study also shows that NPAF reverses the beta-amyloid 25-35-induced memory impairment. PMID- 26639665 TI - The styrene-maleic acid copolymer: a versatile tool in membrane research. AB - A new and promising tool in membrane research is the detergent-free solubilization of membrane proteins by styrene-maleic acid copolymers (SMAs). These amphipathic molecules are able to solubilize lipid bilayers in the form of nanodiscs that are bounded by the polymer. Thus, membrane proteins can be directly extracted from cells in a water-soluble form while conserving a patch of native membrane around them. In this review article, we briefly discuss current methods of membrane protein solubilization and stabilization. We then zoom in on SMAs, describe their physico-chemical properties, and discuss their membrane solubilizing effect. This is followed by an overview of studies in which SMA has been used to isolate and investigate membrane proteins. Finally, potential future applications of the methodology are discussed for structural and functional studies on membrane proteins in a near-native environment and for characterizing protein-lipid and protein-protein interactions. PMID- 26639669 TI - NEURODEM: assessment of the iatrogenic alert indicator for nursing home patients with Alzheimer's or Alzheimer-like disease. AB - INTRODUCTION: Neuroleptics are known to induce Parkinsonism, tardive dyskinesia and their long-term use was associated with increased risk of hip fractures and impaired cognitive function and even death. METHODS: The primary objective of Neurodem study was to determine the IAI of patients with Alzheimer's disease in French NH. RESULTS: 1022 patients were enrolled. The IAI was 24.8 %. Multivariate logistic analysis showed that having a severe form of dementia, resident without MMS evaluation the last 12 months and having a prescription for an anxiolytic drug were associated with a higher risk of having a prescription for an antipsychotic drug. CONCLUSION: The results from our study show that the percentage of patients receiving an antipsychotic drug (24.8 %) was higher than the national average (18 %). Effective educational activities about appropriate use of antipsychotic drugs in patients with Alzheimer's disease are needed. PMID- 26639668 TI - Resveratrol Treatment after Status Epilepticus Restrains Neurodegeneration and Abnormal Neurogenesis with Suppression of Oxidative Stress and Inflammation. AB - Antiepileptic drug therapy, though beneficial for restraining seizures, cannot thwart status epilepticus (SE) induced neurodegeneration or down-stream detrimental changes. We investigated the efficacy of resveratrol (RESV) for preventing SE-induced neurodegeneration, abnormal neurogenesis, oxidative stress and inflammation in the hippocampus. We induced SE in young rats and treated with either vehicle or RESV, commencing an hour after SE induction and continuing every hour for three-hours on SE day and twice daily thereafter for 3 days. Seizures were terminated in both groups two-hours after SE with a diazepam injection. In contrast to the vehicle-treated group, the hippocampus of animals receiving RESV during and after SE presented no loss of glutamatergic neurons in hippocampal cell layers, diminished loss of inhibitory interneurons expressing parvalbumin, somatostatin and neuropeptide Y in the dentate gyrus, reduced aberrant neurogenesis with preservation of reelin + interneurons, lowered concentration of oxidative stress byproduct malondialdehyde and pro-inflammatory cytokine tumor necrosis factor-alpha, normalized expression of oxidative stress responsive genes and diminished numbers of activated microglia. Thus, 4 days of RESV treatment after SE is efficacious for thwarting glutamatergic neuron degeneration, alleviating interneuron loss and abnormal neurogenesis, and suppressing oxidative stress and inflammation. These results have implications for restraining SE-induced chronic temporal lobe epilepsy. PMID- 26639671 TI - Randomized trials in top dermatological journals, 2009-13. PMID- 26639670 TI - Absolute bioavailability of evacetrapib in healthy subjects determined by simultaneous administration of oral evacetrapib and intravenous [(13) C8 ] evacetrapib as a tracer. AB - This open-label, single-period study in healthy subjects estimated evacetrapib absolute bioavailability following simultaneous administration of a 130-mg evacetrapib oral dose and 4-h intravenous (IV) infusion of 175 ug [(13) C8 ] evacetrapib as a tracer. Plasma samples collected through 168 h were analyzed for evacetrapib and [(13) C8 ]-evacetrapib using high-performance liquid chromatography/tandem mass spectrometry. Pharmacokinetic parameter estimates following oral and IV doses, including area under the concentration-time curve (AUC) from zero to infinity (AUC[0-infinity]) and to the last measureable concentration (AUC[0-tlast ]), were calculated. Bioavailability was calculated as the ratio of least-squares geometric mean of dose-normalized AUC (oral : IV) and corresponding 90% confidence interval (CI). Bioavailability of evacetrapib was 44.8% (90% CI: 42.2-47.6%) for AUC(0-infinity) and 44.3% (90% CI: 41.8-46.9%) for AUC(0-tlast ). Evacetrapib was well tolerated with no reports of clinically significant safety assessment findings. This is among the first studies to estimate absolute bioavailability using simultaneous administration of an unlabeled oral dose with a (13) C-labeled IV microdose tracer at about 1/1000(th) the oral dose, with measurement in the pg/mL range. This approach is beneficial for poorly soluble drugs, does not require additional toxicology studies, does not change oral dose pharmacokinetics, and ultimately gives researchers another tool to evaluate absolute bioavailability. PMID- 26639672 TI - Post-Event Processing across Multiple Anxiety Presentations: Is it Specific to Social Anxiety Disorder? AB - BACKGROUND: Post-event processing (PEP) occurs when individuals engage in cognitive rumination following an event or interaction. Although the relation between PEP and social anxiety has been clearly demonstrated, it remains unclear whether PEP is limited to individuals with elevated social anxiety, or if it is also problematic among people with other anxiety presentations. AIMS: The present study assessed PEP after the first session of group cognitive behavioural therapy (CBT) in individuals with a variety of anxiety presentations. METHOD: Participants with a principal diagnosis of SAD (N = 25), those diagnosed with a principal other anxiety disorder with comorbid SAD (N = 18), and those with principal other anxiety diagnoses with no SAD (N = 43) completed baseline measures of social anxiety severity and state anxiety at their first session of CBT and measures of PEP one week later. RESULTS: Participants with a principal diagnosis of SAD experienced the most PEP in the week following the first CBT session, while those with no comorbid SAD experienced the least. Those with comorbid SAD experienced intermediate levels of PEP. The strongest predictor of PEP was state anxiety during the first session. CONCLUSIONS: Results suggest that PEP is more problematic for clients with SAD as part of their clinical presentation. Clinical and theoretical implications are discussed. PMID- 26639673 TI - The Potential of High Resolution Magnetic Resonance Microscopy in the Pathologic Analysis of Resected Breast and Lymph Tissue. AB - Pathologic evaluation of breast specimens requires a fixation and staining procedure of at least 12 hours duration, delaying diagnosis and post-operative planning. Here we introduce an MRI technique with a custom-designed radiofrequency resonator for imaging breast and lymph tissue with sufficient spatial resolution and speed to guide pathologic interpretation and offer value in clinical decision making. In this study, we demonstrate the ability to image breast and lymphatic tissue using 7.0 Tesla MRI, achieving a spatial resolution of 59 * 59 * 94 MUm(3) with a signal-to-noise ratio of 15-20, in an imaging time of 56 to 70 minutes. These are the first MR images to reveal characteristic pathologic features of both benign and malignant breast and lymph tissue, some of which were discernible by blinded pathologists who had no prior training in high resolution MRI interpretation. PMID- 26639674 TI - Temperature-Directed Self-Assembly of Multifunctional Polymeric Tadpoles. AB - Multicompartment tadpole nano-objects are a rare and intriguing class of structures with potential in a wide range of applications. Here, we demonstrate the synthesis of chemically multifunctional polymer tadpoles made at high weight fractions of polymer (>10 wt %). The tadpoles are synthesized using two different thermoresponsive MacroCTAs with either alkyne or pyridyldisulfide end-groups, allowing chemical functionality in the head, tail, or both. Water-soluble molecules or polymers were coupled to either the head, tail or both without a change in tadpole configuration. In addition, the tadpoles can be dried, rehydrated, and stored in water for 5 months without a change in shape. This method represents a new and an important synthetic development in the design of nano-objects. PMID- 26639675 TI - Tripeptide Emulsifiers. AB - A series of tripeptides is shown to form emulsions with sequence tunable properties. Using a combination of simulations and experiments, it is shown that two types of oil-in-water emulsions may be produced, either forming stable interfacial nanofiber networks with remarkable stability, or more conventional surfactant-like monolayers. PMID- 26639676 TI - Direct Tissue Profiling of Protein Complexes: Toward Native Mass Spectrometry Imaging. AB - Native mass spectrometry seeks to probe noncovalent protein interactions in terms of protein quaternary structure, protein-protein and protein-ligand complexes. The ultimate goal is to link the understanding of protein interactions to the protein environment by visualizing the spatial distribution of noncovalent protein interactions within tissue. Previously, we have shown that noncovalently bound protein complexes can be directly probed via liquid extraction surface analysis from dried blood spot samples, where hemoglobin is highly abundant. Here, we show that the intact hemoglobin complex can be sampled directly from thin tissue sections of mouse liver and correlated to a visible vascular feature, paving the way for native mass spectrometry imaging. PMID- 26639677 TI - Polystyrene-Core-Silica-Shell Hybrid Particles Containing Gold and Magnetic Nanoparticles. AB - Polystyrene-core-silica-shell hybrid particles were synthesized by combining the self-assembly of nanoparticles and the polymer with a silica coating strategy. The core-shell hybrid particles are composed of gold-nanoparticle-decorated polystyrene (PS-AuNP) colloids as the core and silica particles as the shell. PS AuNP colloids were generated by the self-assembly of the PS-grafted AuNPs. The silica coating improved the thermal stability and dispersibility of the AuNPs. By removing the "free" PS of the core, hollow particles with a hydrophobic cage having a AuNP corona and an inert silica shell were obtained. Also, Fe3O4 nanoparticles were encapsulated in the core, which resulted in magnetic core shell hybrid particles by the same strategy. These particles have potential applications in biomolecular separation and high-temperature catalysis and as nanoreactors. PMID- 26639678 TI - Medical treatments for opioid use disorder in Iran: a randomized, double-blind placebo-controlled comparison of buprenorphine/naloxone and naltrexone maintenance treatment. AB - AIMS: With the broad goals of developing a clinical research and training program and disseminating effective opioid use disorder treatments in Iran, this pilot clinical trial compared the effectiveness of oral naltrexone (NTX) and sublingual buprenorphine/naloxone (BNX). DESIGN: Twelve-week single-site, two-group parallel randomized double-blind clinical trial. SETTING: An out-patient clinical research program in Tehran, Iran. PARTICIPANTS: Following medically assisted withdrawal, participants with opioid use disorder were assigned randomly to NTX (n = 51) or BNX (n = 51). INTERVENTION: Medications were administered three times per week, double-blind, double-dummy for 12 weeks. All participants received weekly group drug counseling. MEASUREMENTS: The primary outcome was initial duration of opioid abstinence verified by urine toxicology tests. Secondary outcomes included the number of opioid-negative urine tests, treatment retention and proportions with sustained, verified opioid-abstinence for 12 weeks. FINDINGS: Mean [95% confidence interval (CI)] number of days of initial duration of verified abstinence was 28.8 (20.0-37.5) with BNX and 21.6 (14.4-28.7) with NTX (P = 0.205). The mean (95% CI) number of opioid-negative urine tests was 19.7 (17.7 21.6) with BNX and 15.4 (13.1-17.8) with NTX (P = 0.049). The mean (95% CI) number of days in treatment was 70.6 (63.6-77.7) with BNX versus 56.5 (47.8-65.3) with NTX (P = 0.013). The rate of sustained, 12-week opioid abstinence was 16% (8/51) in the BNX group and 8% (4/51) in the NTX group (P = 0.219). CONCLUSIONS: Among patients with opioid use disorder in Iran, sublingual buprenorphine/naloxone was associated with a greater number of opioid-negative urine tests and treatment retention than oral naltrexone, but not significantly greater initial abstinence duration or proportions with sustained abstinence. PMID- 26639679 TI - Amantadine resistance among highly pathogenic avian influenza viruses (H5N1) isolated from India. AB - Emergence of antiviral resistance among H5N1 avian influenza viruses is the major challenge in the control of pandemic influenza. Matrix 2 (M2) inhibitors (amantadine and rimantadine) and neuraminidase inhibitors (oseltamivir and zanamivir) are the two classes of antiviral agents that are specifically active against influenza viruses and are used for both treatment and prophylaxis of influenza infections. Amantadine targets the M2 ion channel of influenza A virus and interrupts virus life cycle through blockade of hydrogen ion influx. This prevents uncoating of the virus in infected host cells which impedes the release of ribonucleoprotein required for transcription and replication of virion in the nucleus. The present study was carried out to review the status of amantadine resistance in H5N1 viruses isolated from India and to study their replicative capability. Results of the study revealed resistance to amantadine in antiviral assay among four H5N1 viruses out of which two viruses had Serine 31 Asparagine (AGT-AAT i.e., S31N) mutation and two had Valine 27 Alanine (GTT-GCT i.e., V27A) mutation. The four resistant viruses not only exhibited significant difference in effective concentration 50% (EC50) values of amantadine hydrochloride from that of susceptible viruses (P < 0.0001) but also showed significant difference between two different types (S31N and V27A) of mutant viruses (P < 0.05). Resistance to amantadine could also be demonstrated in a simple HA test after replication of the viruses in MDCK cells in presence of amantadine. The study identifies the correlation between in vitro antiviral assay and presence of established molecular markers of resistance, the retention of replicative capacity in the presence of amantadine hydrochloride by the resistant viruses and the emergence of resistant mutations against amantadine among avian influenza viruses (H5N1) without selective drug pressure. PMID- 26639681 TI - Materials from the International Conference: "Evidence-Based Medicine: Achievements and Barriers", 7-8 December 2015, Kazan Federal University, Russian Federation. PMID- 26639680 TI - Langerhans cells (CD1a and CD207), dermal dendrocytes (FXIIIa) and plasmacytoid dendritic cells (CD123) in skin lesions of leprosy patients. AB - The clinical course of infection with Mycobacterium leprae varies widely and depends on the pattern of the host immune response. Dendritic cells play an important role in the activation of the innate and adaptive immune system and seem to be essential for the development of the disease. To analyze the presence of epidermal dendritic cells (CD1a and CD207), plasmacytoid dendritic cells (CD123) and dermal dendrocytes (factor XIIIa) in lesion fragments of leprosy patients, skin samples from 30 patients were studied. These samples were submitted to immunohistochemistry against CD1a, CD207, FXIIIa, and CD123. The results showed a larger number of Langerhans cells, detected with the CD1a or CD207 marker, dermal dendrocytes and plasmacytoid dendritic cells in patients with the tuberculoid form. A positive correlation was observed between the Langerhans cell markers CD1a and CD207 in both the tuberculoid and lepromatous forms, and between Langerhans cells and dermal dendrocytes in samples with the tuberculoid form. The present results indicate the existence of a larger number of dendritic cells in patients at the resistant pole of the disease (tuberculoid) and suggest that the different dendritic cells studied play a role, favoring an efficient immune response against infection with M. leprae. PMID- 26639682 TI - Paradoxes of evidence in Russian addiction medicine. AB - BACKGROUND: For many years, clinical protocols for treatment of drug abuse patients and treatment standards in Russian Federation were not grounded on the principles of evidence-based medicine [1]. Recommendations for use of certain drugs were not accompanied by any indication of the level of credibility of the evidence supporting it. The appearance in 2014 of such indications in clinical recommendations can be considered a significant step forward for the science of addiction medicine [2]. OBJECTIVE: To compare Russian evidence and practice in addiction medicines with international standards. METHODS: Situation and literature analysis. RESULTS: The analysis shows that in the wording of recommendations on the use of medicines, some were subject of serious methodological errors. For some drugs globally there is high quality evidence supporting effects of certain drugs globally, but this is not recognized in Russia. As a result, Russian standards of clinical care for the treatment of dependency syndrome are radically different to the standards of therapy, presented in the WHO recommendations. This is due both to the disregard of the meta-analyses presented in the Cochrane reviews and also to the specific bioethical preferences in drug treatment in Russia.It is known that there is no convincing data on the effectiveness and safety of antipsychotics in the treatment of alcohol dependence syndrome [3]. 13 randomized trials with a double blind placebo-controlled design involving 1593 patients assessing effects of amisulpride, aripiprazole, flupentixolum dekonoat, olanzapine, quetiapine, tiapride showed that antipsychotics do not result in abstinence, do not reduce abuse and do not stop craving in alcoholic patients: "Antipsychotics should not be used in patients with a primary diagnosis of dependence. Appointment of antipsychotics for the treatment of substance abuse disorders are contraindicated, since not only does it not improve the condition of patients, but it can even worsen the course of the disease, leading to a reduction in the duration and quality of the remission, and is fraught with serious side effects that threaten the health of patients."SSRI antidepressants indirectly improve the results of treatment of comorbid alcoholism in depressed patients, without affecting alcohol dependence per se. Also, there is currently no convincing evidence of the efficacy of anticonvulsants in the treatment of dependence syndrome, particularly alcohol.Despite the fact that traditional psychotherapeutic interventions remain widespread in practice, and treatment of alcohol dependence syndrome showed high efficiency, there is no convincing evidence for long-term benefits as opposed to short-term benefits.The Cochrane Review with data based on 146 scientific studies involving 21,404 patients confirmed the effectiveness of opioid receptor agonists in treatment of opioid dependence. This therapy showed a statistically significant reduction in the use of illegal drugs, HIV transmission and risky sexual behavior, and was significantly more effective compared to the conventional maintenance therapy with opioid receptor antagonists. In countries, where law prohibits prescribing and use of opioid agonists for opioid dependence treatment, the drugs of choice are antagonists.A meta-analysis of thirteen randomized placebo-controlled trials of oral form of naltrexone (1158 subjects), did not show any advantages of this type of treatment both for management and prevention of relapse compared with placebo [4]. Special studies also showed no inclination to reduce the use of opiates in patients receiving naltrexone [5]. However, studies carried out in Russia, showed the best results for daily intake of naltrexone after detoxification, which increased the duration of remission [6]. It was noted that the effect is associated with higher levels of adherence and family support in the examined population.An overview based on controlled clinical studies on the use of antipsychotic drugs (neuroleptics) in patients dependent on opioids revealed no evidence of effectiveness of this approach. It was concluded that the use of antipsychotics is justified only in the presence of co-morbid psychiatric problems in patients [7]. In a recent meta-analytic review on the use of atypical antipsychotics for off-label indications (off-label), there was a lack of data to support the effectiveness of their use in substance abuse [8, 9]. The effectiveness of anticonvulsants in the treatment of opioid dependence syndrome has not been proven.In connection with the above puzzling fact, for Russian standards of treatment (clinical guidelines) the level of credibility of the effectiveness of antipsychotics and antidepressants in treatment of substance abuse is assessed as A or B. This paradox raises the question of the methodology for determining the level of credibility of evidence. It should be noted that Russian recommendations for inclusion of certain drugs and therapies are based on sufficient consensus of experts rather than on the results of meta-analyses [2]. CONCLUSIONS: This fact casts doubt on credibility and validity of scientific recommendations. Thus, one may say that Russian addiction medicine is not based on evidence, which is, in our view, erroneous and may impair the quality of care. PMID- 26639683 TI - Decision support systems in clinical practice: The case of venous thromboembolism prevention. AB - BACKGROUND: Today medicine is facing a "knowledge crisis" in that explosively expanding medical knowledge encounters limited abilities to disseminate new practices [1]. Clinical practice guidelines (CPGs) are intended to promote high standards of care in specific areas of medicine by summarizing best clinical practice based on careful reviews of current research. However, doctors are often short of time to study these documents and check their updates, have little motivation for strict adherence to them. A systematic review of 11 studies reporting on 29 recommendations has found that median adherence to all recommendations was 34%, suggesting that potential benefits for patients from health research may be lost [2].Clinical decision support systems (CDSS) can serve as a knowledge translation tool, mediator between clinical guidelines and physicians by providing the right information to the right person at the right time. OBJECTIVE: To evaluate the effectiveness of implementation of international and national CPGs for venous thromboembolism (VTE) prevention with the help of CDSS in a general hospital. METHODS: A multifunctional CDSS based on national and international guidelines on the VTE prevention was developed and implemented in the Medical Center of the Bank of Russia (MC). The system has the following functionalities: 1) it supports the decision on the VTE prevention based on individual risk assessment of thrombosis (scales of Caprini, Rogers and Khorana, Padua Prediction Score, additional risk factors) and bleeding (IMPROVE scale for non-surgical patients, major bleeding scale for surgical patients and major orthopedic surgeries, hemorrhagic complications risk in cancer patients); 2) generates the summary containing the grade of recommendations and the level of evidence, personalized recommendations on regimen and duration of preventive antithrombotic therapy, dose correction according to creatinine clearance; 3) provides an audit form for and statistical analysis of VTE cases; 3) automatically generates a quality register for VTE prevention.CDSS was implemented in June 2014. We analyzed VTE cases identified by triggers (deep vein thrombosis diagnosed by Doppler ultrasound and pulmonary embolism at the chest CT) that occurred in 2014 before and after CDSS implementation, as well as in the first half of 2015. Patients with VTE diagnosed during the first 48 hours of hospitalization or receiving anticoagulants in therapeutic doses were excluded from the analysis. Chi-square test for linear trend and non-parametric methods of descriptive statistics were used for data analysis. RESULTS: CDSS utilization was regulated by a special hospital-wide policy; lectures were organized to educate doctors how to use the system. Although international recommendations require VTE risk assessment for all hospitalized patients (except those receiving anticoagulant in therapeutic doses), the doctors filled forms for only 306 patients during the first 6 months of CDSS functioning (14.1% of discharges with length of stay >48 hours during this period). In the first half of 2015 the coverage of VTE risk assessment with CDSS was 19% (n = 506). Correctness of filling out the forms was 78.4%, in the rest of cases doctors made mistakes in choosing patient's profile or when filling in risk scales.Doctors adhere to given recommendations in 85.4% of cases. Most often (47.5%) pharmacotherapy with low molecular weight heparin (LMWH), preventive doses, was recommended by the system, and in this category the adherence to recommended practice was the lowest (74.6%). Among patients who underwent pharmacoprophylaxis, in 21.1% cases the use of anticoagulants was inconsistent with clinical guidelines or drug package insert (typically inappropriate choice of LMWH prophylactic doses, delaying or reducing the duration of prophylaxis).The rate of hospital-acquired VTE significantly decreased after CDSS implementation and was 11.71, 8.28 and 4.84 per 1,000 hospitalizations in the first and second half of 2014 and in the first half of 2015, respectively (chi2 = 7.325, df = 1, p = 0.0068). The rate of postoperative VTE for the same period amounted to 8.76, 3.39 and 4.17 per 1,000 operations, respectively (chi2 = 7.266, df = 1, p = 0.007), reaching a level of the correspondent AHRQ safety indicator (4.99 per 1,000 operations) [3]. Deviations from clinical guidelines or anticoagulant package inserts were revealed in 74% of VTE cases; and more than 1/3 of deviations affected treatment outcomes. CONCLUSIONS: Coverage of hospitalized patients with documented VTE risk assessment gradually increased after the CDSS implementation, but remained at a low level (19% of eligible patients). Partly it may be attributed to the lack of CDSS integration in electronic health record or computerized physician order entry systems that would facilitate routine documentation of VTE and bleeding risks. However, the introduction of CDSS has allowed reducing significantly the rate of hospital-acquired VTE. This can be explained by drawing doctor's attention to the VTE problem and by training effect of CDSS. After receiving appropriate recommendations doctors adhere to them, on average, in 85.4% of cases, although for LMWH pharmacoprophylaxis this level was lower (74.6%). Development of hospital-acquired VTE in most cases (74%) was accompanied by non compliance with CPGs recommendations, emphasizing the importance of additional measures for better adherence to evidence-based clinical practices. PMID- 26639684 TI - Improving data retrieval quality: Evidence based medicine perspective. AB - BACKGROUND: The actively developing approach in modern medicine is the approach focused on principles of evidence-based medicine. The assessment of quality and reliability of studies is needed. However, in some cases studies corresponding to the first level of evidence may contain errors in randomized control trials (RCTs). Solution of the problem is the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. Studies both in the fields of medicine and information retrieval are conducted for developing search engines for the MEDLINE database [1]; combined techniques for summarization and information retrieval targeted to solving problems of finding the best medication based on the levels of evidence are being developed [2]. OBJECTIVE: Based on the relevance and demand for studies both in the field of medicine and information retrieval, it was decided to start the development of a search engine for the MEDLINE database search on the basis of the Saint-Petersburg State University with the support of Pavlov First Saint-Petersburg State Medical University and Tashkent Institute of Postgraduate Medical Education. Novelty and value of the proposed system are characterized by the use of ranking method of relevant abstracts. It is suggested that the system will be able to perform ranking based on studies level of evidence and to apply GRADE criteria for system evaluation. METHODS: The assigned task falls within the domain of information retrieval and machine learning. Based on the results of implementation from previous work [3], in which the main goal was to cluster abstracts from MEDLINE database by subtypes of medical interventions, a set of algorithms for clustering in this study was selected: K-means, K-means ++, EM from the sklearn (http://scikit-learn.org) and WEKA (http://www.cs.waikato.ac.nz/~ml/weka/) libraries, together with the methods of Latent Semantic Analysis (LSA) [4] choosing the first 210 facts and the model "bag of words" [5] to represent clustered documents. During the process of abstracts classification, few algorithms were tested including: Complement Naive Bayes [6], Sequential Minimal Optimization (SMO) [7] and non linear SVM from the WEKA library. RESULTS: The first step of this study was to markup abstracts of articles from the MEDLINE by containing and not containing a medical intervention. For this purpose, based on our previous work [8] a web-crawler was modified to perform the necessary markuping. The next step was to evaluate the clustering algorithms at the markup abstracts. As a result of clustering abstracts by two groups, when applying the LSA and choosing first 210 facts, the following results were obtained:1) K-means: Purity = 0,5598, Normalized Entropy = 0.5994;2)K-means ++: Purity = 0,6743, Normalized Entropy = 0.4996;3)EM: Purity = 0,5443, Normalized Entropy = 0.6344.When applying the model "bag of words":1)K means: Purity = 0,5134, Normalized Entropy = 0.6254;2)K-means ++: Purity = 0,5645, Normalized Entropy = 0.5299;3)EM: Purity = 0,5247, Normalized Entropy = 0.6345.Then, studies which contain medical intervention have been considered and classified by the subtypes of medical interventions. At the process of classification abstracts by subtypes of medical interventions, abstracts were presented as a "bag of words" model with the removal of stop words. THE RESULTS: 1)Complement Naive Bayes: macro F-measure = 0.6934, micro F-measure = 0.7234;2)Sequantial Minimal Optimization: macro F-measure = 0.6543, micro F measure = 0.7042;3)Non linear SVM: macro F-measure = 0.6835, micro F-measure = 0.7642. CONCLUSIONS: Based on the results of computational experiments, the best results of abstract clustering by containing and not containing medical intervention were obtained using the K-Means ++ algorithm together with LSA, choosing the first 210 facts. The quality of classification abstracts by subtypes of medical interventions value for existing ones [8] has been improved using non linear SVM algorithm, with "bag of words" model and the removal of stop words. The results of clustering obtained in this study will help in grouping abstracts by levels of evidence, using the classification by subtypes of medical interventions and it will be possible to extract information from the abstracts on specific types of interventions. PMID- 26639685 TI - Cognitive IT-systems for big data analysis in medicine. AB - BACKGROUND: Rapid development of medicine requires regular update of clinical data evidence. This task accomplishment requires participation of numerous specialists in evidence-based medicine, who are proficient in various statistical methods and can work with big data analysis tools in biomedical sciences. This, in turn, requires significant time and other resources. Today, at the peak of IT development, cognitive systems in the field of medicine with special technologies of data collection and analysis, is the start of a new trend. OBJECTIVE: The development of cognitive IT system for drug prescription with the potential to analyze automatically the information about drugs effectiveness and safety on the basis of clinical practice experience and scientific data according to evidence levels and patients' personal characteristics. METHODS: The cognitive system was developed with the use of United Medical Knowledge Base (UMKB). UMKB is a semantic network of medical knowledge, which is structured according to the medical ontologies and the theory of fuzzy logic. UMKB is being filled simultaneously in all the areas of medicine. From one side it is filled by means of the linguistic module analyzing medical texts, from the second side - by academic institutions, from the third side - by the cognitive IT systems with the data from electronic health records (EHRs). Native language of UMKB is Russian. It is designed primarily for use in the Russian clinical practice. However the platform for filling knowledge is multilingual and supports any other languages. This means that the practice of world schools may also be integrated and used in UMKB. The peculiarity lies in the fact that UMKB is presented as a semantic network where biomedical knowledge are structured according to certain medical ontologies (special rules of information storage that ??carries?? data: phenomena, processes, simple and complex concepts in medicine, - in the form of interrelated objects). The keystone underlying UMKB is the model of medical knowledge representation, which is able to describe any area of medicine. With the help of this model one can accurately simulate risk factors, etiology, and pathogenesis of a disease (probability, time of development and the sequence of pathological signs at each stage of a disease). While describing pathological and compensatory mechanisms the database provides an opportunity to clarify a lot of conditions that affect this mechanism. It is also simple to simulate structural and functional features of the concept and its relationships (for example, compensatory mechanisms, reflexes, complex anatomical structures, all the features of variant anatomy and other characteristics), which form reactivity and resistance of the organism. All this is very important for cognitive IT systems concerning personalized and evidence-based medicine. When describing medical knowledge there are often situations of uncertainty, lack of sufficiently complete and accurate data on the subject area, poorly understood phenomena, conflicting theories or imprecise concepts. Semantic network of UMKB presents complex relationships among medical concepts characterized by the following features: type and direction of relationship, its weight and value, accuracy and personalization of the weight or value of relationship, date of actualization. Multifactorial influence on the weight or value of relationship, a lot of elementary and intermediate traits that influence weight, the moment of actualization are supported to formalize. United Medical Knowledge Base is a large-scale project, its main goal is to increase the quality and duration of life through personalized care based on evidence that can only be achieved by combining medical big data from various fields of biomedical sciences. RESULTS: On the basis of UMKB a prototype of the cognitive IT system PharmExpert with analytical potential was developed. PharmExpert is a clinical decision support system for drug prescribing, which is integrated into medical information system at health institutions and analyzes electronic health records (EHRs) in any format of the background mode, correcting drug therapy according to personal patient's profile and data about compatibility of the drugs. The system has a very important function - self-learning that will help it to absorb a huge mountain of medical data from routine clinical practice in the nearest future. Now it works on the basis of data from UMKB, handbooks in pharmacology, summaries of medical products characteristics (SmPCs), available reviews of scientific literature and clinical guidelines on drugs interactions and compatibility. In the short term, at the stage of clinical testing, PharmExpert memorizing all the cases of clinical experience and the reaction of the physicians (accepting or ignoring the recommendations of the system), will be able to realize self learning function by rebuilding ties and remodeling knowledge of the semantic network according to clinical data and generating the best standards of drug therapy taking into account personal characteristics of the patient and levels of data evidence. Working in the background mode is one of the most important advantages of the system. The physician is not asked to enter any additional data beyond that the specialist enters into the EHR on an everyday basis. Now PharmExpert is installed in the medical information systems of the range of clinical centers in the Russian Federation. CONCLUSIONS: We developed a prototype of cognitive IT system for drug prescription with the potential to analyze automatically the information about drugs effectiveness and safety on the basis of clinical practice experience and scientific data according to evidence levels and patients' personal characteristics. The system is based on the structured semantic network of medical knowledge from UMKB. PMID- 26639686 TI - Pharmacists' knowledge of the safety of antibiotics for systemic use. AB - BACKGROUND: Patients decide to take antibiotics themselves in 21% of cases of acute respiratory viral infections, influenza and acute respiratory infections [1]. The main factor of drug purchase at a pharmacy is pharmacist's recommendation. In 14% of cases of purchase of antibiotics, patients describe the symptoms and do not name a specific drug. This provides opportunity for drug selection at a pharmacy [2]. In these circumstances the role of pharmacists in ensuring the rational use of antimicrobial agents increases significantly. OBJECTIVE: To evaluate the knowledge of pharmacists about antibiotics for systemic use. METHODS: Pharmacoepidemiological study was based on surveying pharmaceutical workers using a questionnaire. The questionnaire included 2 groups of questions: general questions aimed at identifying the socio-demographic characteristics of respondents (gender, age) and professional status (level of qualification, work experience), as well as specific questions aimed at identifying perceptions and knowledge of respondents about the studied group of drugs (range of used drugs, the factors determining and limiting the choice of drug, properties of individual drugs, etc.). The study involved 182 pharmaceutical workers at the age of 20 to 52 years. When processing the received data, we used Microsoft Excel and BioStat, and methods of nonparametric statistics (chi2-test). The survey was conducted anonymously, informed consent of the participants was not required. According to the recommendations of Ethical Committee of Saratov State Medical University n.a. V.I. Razumovsky (protocol No. 8 from 01.04.2014) the study is consistent with the basics of medical ethics. RESULTS: Interviewed pharmaceutical workers were mostly women (97%) with secondary pharmaceutical education (84%). The average age of the respondents was 27.0 +/- 0.5 years. The work experience of the respondents ranged from 0.5 to 34 years (average experience 5.64 +/- 0.41 years).Almost all pharmacists (97%) reported that they dispense antimicrobial drugs every day and consult patients about the choice and characteristics of antibiotic (99.5%). However, only 20% of the respondents indicated that they refuse to recommend antibiotics to the pharmacy visitors and send them to the doctor. Most often pharmaceutical employees recommended azithromycin (45%), amoxicillin in combination with clavulanic acid (41%), amoxicillin (26%). According to respondents, the choice of recommended antibiotic mostly depends (score on a scale of 1-5) on pharmacological characteristics of the drug: the effectiveness (of 4.66 +/- 0.04) and safety (4.16 +/- 0.07). Thus, pharmaceutical specialist should be knowledgeable about characteristics of antimicrobial agents to conduct proper consultation.According to the results of self-assessment of respondents' knowledge about antibiotics it is at an average level. 36.3% of respondents state that they are familiar with the range and features of most of the drugs. 41.8% of professionals are familiar with the range of the most popular drugs and their main features. Only 16.5% of respondents assess their knowledge about antibiotics at the highest level, indicating that they are fully familiar with the range and features of the drugs.Aiming at identifying knowledge about the side effects of antibiotics pharmacists were asked to compare the most commonly prescribed drugs and their respective side effects, to position the drugs and groups of drugs in the range according to the degree of toxicity and to indicate which antibiotics can be used during pregnancy. Knowledge of pharmaceutical workers is mainly limited to the perceptions of non-specific side reactions that can occur when taking any antibiotic (dyspepsia, allergic reactions, headache, candidiasis). 54.9% of respondents rightly pointed out nonspecific reactions for all 7 mentioned drug, for individual drugs the proportion of correct answers varied from 65,4% (linezolid) to 81,3% (amoxicillin+clavulanic acid). The analysis revealed no relationship between respondents' answers and their qualifications (chi2 = 0,053; p = 0,818), work experience (chi2 = 6,956; p = 0,096) and self assessed knowledge about antimicrobial drugs (chi2 = 1,272; p = 1,000). There were no respondents who correctly reported specific adverse reactions (hearing disorder for azithromycin, hemopoiesis oppression for linezolid, etc.) for each antibiotic. The proportion of correct answers ranged from 6,0% for the combination amoxicillin+clavulanic acid to 43,4% for cefixime and doxycycline. The relationship between knowledge of respondents and frequency of recommendations of the same group of drugs could not be determined.Pharmacists assume that the safest antibiotics are macrolides (average rank place of 2,99 +/- 0,15 of 8), cephalosporins (3,12 +/- 0,15) and penicillins (3,38 +/- 0,22), the most toxic are tetracyclines (5,61 +/- 0,17). It should be noted that average rank places are quite similar, which means serious differences of opinion between the specialists. When assessing the toxicity of individual drugs a combination of amoxicillin+clavulanic acid (average rank place of 2,92 +/- 0,29 of 15) and ampicillin (of 4,88 +/- 0,36) were considered as the safest, the most toxic were tetracycline (10,13 +/- 0,30) and gentamicin (10,14 +/- 0,33). These perceptions are generally consistent with the views on the safety of antibiotics in outpatient practice [3].Half of the respondents (51,1%) correctly identified the antibiotics that can be used during pregnancy (FDA category B). 45,1% of respondents said that no antibiotics can be used during pregnancy. Only 2,7% of respondents named drugs contraindicated during pregnancy (category C and D) - gentamicin, doxycycline, ciprofloxacin. CONCLUSIONS: The study identified gaps in the knowledge of pharmacists about the safety of antimicrobial agents. Views of professionals about antibiotics are mostly consistent with current data about the properties of drugs. However, detailed analysis shows that such views are not supported by clear knowledge of the properties of each drug and are mostly intuitive. In terms of the prevalence of self-medication with antibiotics and OTC dispensing of antimicrobial drugs it is necessary to improve the professional knowledge of pharmaceutical workers on antibiotics for systemic use. PMID- 26639687 TI - Screening for colon cancer: A test for occult blood. AB - BACKGROUND: The relevance of the problem of colorectal cancer (CRC) is evident because of extremely high morbidity and mortality rates, associated with this disease. CRC is mostly diagnosed only at very advanced stages. The reduction of mortality can be achieved by the popularization of screening-methods for early identification of CRC and adenomatous polyps of the colon, which are proved to be precancerous condition. Fecal occult blood test is a well-known method of screening for CRC. The advantages of this method when compared, for example, with colonoscopy are its simplicity and cost-effectiveness.Two techniques are usually used for detection of occult blood in the stool: Hemoccult (Guaiac) test and immunochemical test for hemoglobin. There is no consensus among researchers regarding the validity of these tests for the diagnosis of colorectal cancer. For example, J.S. Mandel (1996) notes 60% sensitivity of Guaiac-test for the detection of the early forms of colorectal cancer, while O.I. Kit (2014) suggets that it is not higher than 30%. There are also various opinions about specificity of these two tests. OBJECTIVE: To review the literature on the validity of the fecal occult blood tests for the diagnosis of CRC. METHODS: We looked for articles (electronic versions) available for free in the full-text versions, published from June 1, 1990 to December 31, 2014 in Russian or English. The following databases were used for search: E-LIBRARY; Cochrane; MEDLINE; EMBASE; Google search. Only original research papers were analyzed. Literature reviews or systematic reviews were not taken for analyses. SELECTION CRITERIA: 1) use of Guaiac and/or immunochemical fecal occult blood test as screening-tests for the detection of colorectal cancer and/or colon polyps (1 cm or more in diameter) in people older than 45 years; 2) comparing of results with the results of colonoscopy (colonoscopy is counted by majority of the authors as a "gold standard" for the diagnosis of CRC and adenomatous polyps). RESULTS: Initial keyword search returned 803 000 results, of which 449 sources were selected. After reading the abstracts, 29 articles that met inclusion criteria were kept. 10 other articles were excluded after that because they did not contain enough data for extraction or did not contain a control group. At the final step 19 articles were used for meta-analysis.Forest plot and Rock curve, which were developed with inclusion of the data from all studies, showed heterogeneity of the data. Additional analyzes were performed in subgroups with different diagnoses and various tests.The sensitivity of the Guaiac test for the diagnosis of colorectal cancer varied from 0.13 to 1.00, and specificity - from 0.69 to 0.99. The sensitivity of the immunochemical test for the diagnosis of CRC ranged from 0.42 to 0.94 with specificity ranging from 0.40 to 1.00.The sensitivity of the Guaiac test for the diagnosis of the colon polyps was between 0.05 and 0.69, and its specificity - from 0.67 to 0.98. The sensitivity of the immunochemical test for the diagnosis of polyps was from 0.24 to 0.75, and its specificity - from 0.40 to 0.97.Bivariate analysis of the validity of Guaiac test and immunochemical method for the diagnosis of colorectal cancer showed better results for the immunochemical test compared to Guaiac test. The tests showed very similar results when used for the diagnosis of polyposis. Bivariate analysis, comparing the validity of tests for the diagnosis of colorectal cancer versus polyposis demonstrated better results for CRC.Multivariate analysis of the validity of the Guaiac and immunochemical tests for the diagnosis of colorectal cancer and polyps also showed better results for detection of colorectal cancer compared with the polyps for both tests. At the same time the highest validity for the diagnosis of CRC was demonstrated for immunochemical analysis. CONCLUSIONS: 1. The sensitivity of the Guaiac test for occult blood in stool is lower than its specificity.2. Broad dispersion of the validity characteristics of the fecal occult blood tests was observed.3. The validity of tests for occult blood was higher when they were used for detection of colorectal cancer than of colon polyposis.4. The highest validity rate has been demonstrated for the immunochemical test when it was used for colon cancer screening. PMID- 26639688 TI - Russian translations for Cochrane. AB - BACKGROUND: Cochrane collaboration has made a huge contribution to the development of evidence-based medicine; Cochrane work is the international gold standard of independent, credible and reliable high-quality information in medicine. Over the past 20 years the Cochrane Collaboration helped transforming decision-making in health and reforming it significantly, saving lives and contributing to longevity [1]. Until recently, Cochrane evidence were available only in English, which represents a significant barrier to their wider use in non English speaking countries. To provide access to evidence, obtained from Cochrane Reviews, for health professionals and general public (from non-English-speaking countries), bypassing language barriers, Cochrane collaboration in 2014 initiated an international project of translating Plain language summaries of Cochrane Reviews into other languages [2, 3]. Russian translations of Plain language summaries were started in May 2014 by the team from Kazan Federal University (Department of Basic and Clinical Pharmacology; 2014-2015 as an Affiliated Centre in Tatarstan of the Nordic Cochrane Centre, since August 2015 as Cochrane Russia, a Russian branch of Cochrane Nordic, Head - Liliya Eugenevna Ziganshina) on a voluntary basis. OBJECTIVE: To assess the quality of Russian translations of Cochrane Plain Language Summaries (PLS) and their potential impact on the Russian speaking community through user feedback with the overarching aim of furthering the translations project. METHODS: We conducted the continuous online survey via Google Docs. We invited respondents through the electronic Russian language discussion forum on Essential Medicines (E-lek), links to survey on the Russian Cochrane.org website, invitations to Cochrane contributors registered in Archie from potential Russian-speaking countries. We set up the survey in Russian and English. The respondents were asked to respond to the questionnaire regarding the relevance and potential impact of the Cochrane Russian translations project, topics of interest in the field of health and health care, the quality and clarity of translated content, the preferred style of presentation and suggestions to improve the quality of translations of Plain language summaries of Cochrane Reviews. RESULTS: Currently the team of translators includes volunteers from the staff, Masters and PhD students of the Department of Basic and Clinical Pharmacology of the Kazan Federal University, and Kazan Medical University, our colleagues from Kazan and other cities of Russia, from the Republic of Armenia and the USA. By September 20th 2015, 446 Plain language summaries of Cochrane Reviews were translated into Russian and published on the web-site http://www.cochrane.org/ru/evidence. Our project "Russian translations for Cochrane" has already covered a wide range of health priority areas with translations of Plain language summaries and abstracts of the most topical and priority Cochrane reviews. During the period from 03.03.2015 to 20.09.2015 we received 113 answers from our respondents (103 answers in Russian and 10 answers in English). These were representatives of the medical and pharmaceutical professions (60%), representatives of non-medical professions (17%), students/graduate students (16%), retirees (4%) and others categories of citizens among the respondents. Half of the respondents (50%) belonged to the age group of 36-60 years, followed by the group of 18-35 years (41%). According to the survey the vast majority of respondents consider that the Cochrane Russian translations project is needed for Russia and Russian speaking countries (94%; n = 106), it is needed for their work, studies, and life in general (91%; n = 103). Nobody answered "No" to the question: "Do you think that this project is needed for Russia and Russian-speaking countries?" Information from the Cochrane evidence can affect (change) individual practice and/or attitude to drugs or diagnostic procedures of 87% (n = 98) of respondents. Only two people answered negatively to this question. However, only one third of respondents would like to become volunteer members of the translations project. The Russian texts of translations of Cochrane summaries and their main message were completely understandable or mostly clear to the vast majority of respondents (92%; n = 104). Respondents, proficient in English (n = 61), answered that the Russian-language translations fully complied (43%; n = 26) or in general corresponded to (57%; n = 35) the original English text. The majority of respondents (85%, n = 96) rated the quality of the translated texts as excellent and good. "More than half of respondents (61%; n = 69) would prefer the translations to be adapted to the usual style of presentation in Russian. The respondents agreed that mistakes, or typos or both very few. Our respondents provided valuable suggestions for further improvement of the Russian translations project. We would like to present here some of these: "More translations needed", "The ultimate goal... is to try to adapt the summaries to Russian language style as much as possible. This is a very challenging task, however and at present format the summaries are already great", "Go great as you do!" "Move forward and be efficient!" "Distribute information about the project through social networks and different means of social media", "Studying Cochrane Database should be included in the Russian medical school's curriculum at a much larger extent than it is included (if at all) now. It would be beneficial for high school students as well." CONCLUSIONS: The survey provided positive feedback on the Russian translations project concerning the clarity and quality of Russian texts and overall satisfaction of the readers. It confirmed the importance and relevance of the Russian translations project for Russian speaking audience, representing various professions and age groups. The survey results with detailed feedback contribute to further improvement of the Russian translations project. LIMITATIONS: Selective and subjective evaluation of translations by the respondents, difficulties with clear criteria for the objective evaluation. Further quality improvement of original PLS texts would contribute to higher translation quality. ACKNOWLEDGMENTS: We would like to thank Juliane Reed, Coordinator of the Cochrane Translations Project, Professor Peter C Gotzsche, Director of the Cochrane Nordic, co-founder of the Cochrane Collaboration, Cochrane leadership and the global Cochrane network together with the leadership of the Kazan Federal University for continuous encouragement, spirit and support. PMID- 26639689 TI - Antimicrobial use at a multi-disciplinary hospital. AB - BACKGROUND: The problem of antimicrobial resistance has become topical and alarming all over the world, including Kazakhstan. Nosocomial strains of microorganisms are widespread, being resistant to the majority of available antimicrobials. This results in longer periods of hospital stay, increases in financial expenditures, and sometimes, in lethal outcomes. The social importance of antimicrobial resistance is preconditioned by the spread of resilient strains of microorganism beyond the hospital environment, which leads to lower effectiveness of antibiotic therapy against infectious diseases and growth in their incidence [1, 2].Our in-patient health facility is a multifunctional one. It provides therapeutic, surgical and oncology and hematology care including organ transplantation. Measures to reduce antibiotic resistance are very important. OBJECTIVE: To develop a standardized approach to the use of antimicrobial drugs aimed at reducing of antimicrobial resistance, postoperative complications and mortality rates along with financial expenditures. The expected result of this approach should be the enhancement of quality of care. METHODS: In September 2014 we developed and introduced a local protocol of the antimicrobials use, namely antibiotics for surgical prophylaxis and treatment, based on the evidence of international clinical guidelines evidence-based medicine approach, taking into account the microbial landscape and antibiotic resistance patterns to major pathogens: Staphylococcus aureus, Pseudomonas aeruginosa, Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae [3]. We planned to assess the effectiveness of this policy by the following criteria: the percentage of post surgical sequela, the number of bed days, the percentage of resistant cases and antibiotic expenditures. In order to improve the quality of bacteriological studies, together with microbiologists we trained the medical staff on the methods of obtaining of biological material for microbiological testing. RESULTS: We analyzed the indicators of antibiotic resistance from October 2014 to March 2015 (hereafter period I) on the basis of the data from the microbiological laboratory with data of April-August 2015 (hereafter period II). The analysis on the basis of other criteria has yet to be carried out. The bio-material was obtained from different loci, including blood. The results of the oncology and hematology were analyzed separately. We received the following results of sensitivity of the listed microorganisms to various antimicrobials in the period I and the period II respectively expressed as percentages:Staphylococcus aureus: Oxacillin - 95% and 100%, Azythromycin - 62% and 100%, Vancomycin - 100% and 100%, Levofloxacin/Moxifloxacin - 100% and 100%.Pseudomonas aeruginosa: Ceftazidime - 34% and 67%, Piperacillin/Tazobactam - 91% and 84%, Cefepime - 59% and 81%, Amikacin - 95% and 100%, Meropenem - 100% and 100%, Ciprofloxacin - 97% and 100%.Escherichia coli: Gentamicin - 93% and 96%, Piperacillin/Tazobactam - 86% and 92%, Ceftriaxone - 82% and 100%, Amikacin - 99% and 100%,Ciprofloxacin - 69% and 80%, Amoxycillin/Clavulanate - 44% and 46% respectively.Klebsiella pneumoniae: Gentamicin - 50% and 100%, Piperacillin/Tazobactam - 95% and 100%, Cefepime - 100% and 100%, Ceftriaxone - 96% and 100%, Amikacin - 99% and 100%, Ciprofloxacin - 100% and 100%, Amoxycillin/Clavulanate - 22% and 23%.Acinetobacter baumannii: Gentamicin - 83% and 83%, Piperacillin/Tazobactam - 33% and 58%, Cefepime - 0% and 33%, Ceftriaxone - 0% and 33%, Amikacin - 50% and 83%, Ciprofloxacin - 83% and 67%, Meropenem/Imipenem-Cilastin - 83% and 83%. CONCLUSIONS: During the analyzed periods we observed some improvement in the sensitivity of the main pathogens to antibiotics. At the same time, the resistance of Acinetobacter baumannii to carbapenems and fluoroquinolones increased.Limitations of the studyThere are many other than antibiotic use factors, which influence these results. Further analysis is planned to be carried out. Nevertheless, this analysis makes us believe that we are, probably, on the right path for improving the use of antibacterial drugs. PMID- 26639690 TI - ABCB1 polymorphism and acenocoumarol safety in patients with valvular atrial fibrillation. AB - BACKGROUND: Oral anticoagulant drugs (AD) are commonly used to treat patients with thromboembolic diseases. The ADs have narrow therapeutic index and wide pharmacokinetic and pharmacodynamic interindividual variability. Some genetic variations could influence interindividual variability in response to AD. Acenocoumarol (AC) is a coumarin, vitamin K derivate with antagonistic activity, used as anticoagulant therapy mainly in Central Europe and Latin America. P - glycoprotein (PGP), a transporter encoded by the ABCB1 gene, plays a major role in the drug disposition [1]. PGP is expressed in normal tissues, where it performs a defensive role against potentially toxic substances in intestinal cells and endothelial cells of the brain capillary endothelium. ABCB1 - is highly polymorphic, C3435T polymorphism in exon 26 has been associated with the expression of PGP [2]. There is some evidence that PGP could influence coumarin sensitivity. OBJECTIVE: To assess effects of the ABCB1 pilymorphisms on safety profile and dosing regimen of acenocoumarol in the patients with valvular atrial fibrillation. METHODS: 50 patients (34 male and 16 female), 40-70 years of age were included. All patients received acenocoumarol at doses of 1-6 mg daily with a target international normalized ratio (INR) of 2.0 to 3.0. Genotyping for polymorphism marker C3435T of ABCB1 gen was performed using PCR and RFLP (restriction fragment length polymorphisms) techniques. Statistics were performed by Fishers exact tests. All enrolled patients provided written informed consent. RESULTS: Genotype CC was found in 10 patients (20%), genotype CT in 25 patients (50%) and genotype TT in 15 patients (30%). In the CC group (n = 10) bleeding was found in 1 patient (2%). There were 19 patients (38%) with bleedings in combined group of CT and TT genotype (p = 0.0366). We compared the average doses of acenocoumarol in groups identified according to their genotypes: CC (3.45 mg/day), CT (2.64 mg/day), TT (3.07 mg/day) and found no significant differences. CONCLUSIONS: ABCB1 CT and TT genotypes were found to be significantly associated with higher risk of bleeding. There was no influence of ABCB1 polymorphisms on dosing regimens of acenocoumarol. PMID- 26639691 TI - VKORC1 polymorphisms and warfarin maintenance dose in population of Sakha (Yakuts). AB - BACKGROUND: Vitamin K antagonists are effective in the prevention and treatment of thromboembolic disorders. Warfarin is one of the most widely prescribed vitamin K antagonists in the world [1, 2]. It has a narrow therapeutic range and a given dose may result in a large inter-individual variation of response. Insufficient dose may fail to prevent thromboembolism, while an overdose increases the risk of bleeding. Patient-specific factors (e.g., age, body size, race, concurrent diseases, and medications) explain some of the variability in warfarin dosage, but genetic factors influencing warfarin response explain a significantly higher proportion of this variability [3]. Molecular analysis of the gene that encodes the target enzyme vitamin K epoxide reductase complex 1 (VKORC1) strongly suggests that its genetic variations greatly affect the individual response to oral anticoagulants [4-7]. OBJECTIVE: To evaluate effects of VKORC1 polymorphisms on warfarin dose excess anticoagulation (INR >4.0) in the population of Sakha (S) patients. METHODS: 53 patients (29-women, 24-men) with atrial fibrillation (68%), congestive heart failure (60%), hypertension (49%) and cardiac valve replacement (26%) were recruited. The age range was 26-80 years, with a mean age of 62.87 +/- 12.57 years.International normalized ratio and plasma warfarin concentrations were determined. Genotyping was carried out by RT PCR (real-time PCR). The three genetic polymorphisms of the gene VKORC1 G3673A (rs9923231) were studied: normal (GG), heterozygous (GA) and homozygous (AA). Fisher exact probability test and chi-square test (with Yates correction) were applied to compare data among the AA and GG + GA groups; also Mann-Whitney test was used. RESULTS: The median maintenance daily dose of warfarin among AA carriers was 3.0 mg/day [1.25-7.5 mg], while in GG and GA patients it was 3.13 mg/day [1.88-7.92 mg]. The mean daily warfarin dosage was higher in GG and GA genotype carriers 4.05 mg/day (SD +/- 1.7) than in patients with AA genotype 3.13 (SD +/- 1.5). Differences are of borderline significance (p = 0.054). Of the 41 patients who required warfarin doses of less than 5 mg, 28 (63%) were found to be AA carriers and 14 (37%) were GG, GA carriers. Differences were not quite significant (p = 0.072). Among 31 homozygous polymorphism carriers 2 (4%) patients developed overanticoagulation (INR >4.0), while among 22 normal and heterozygous polymorphisms carriers only 3 (6%) patients developed overanticoagulation (INR >4.0). Differences were not statistically significant (p = 0.36). CONCLUSIONS: No significant association between VKORC1 polymorphisms and the frequency of excess anticoagulation (INR >4.0) was found. This may be explained by the number of cases included. AA polymorphisms compared to other polymorphisms shows borderline difference in the warfarin dose. The results can be used for the development of a pharmacogenetic-guided warfarin dosing algorithm. PMID- 26639692 TI - Congenital anomalies in Primorsky region. AB - BACKGROUND: According to WHO hereditary diseases and congenital malformations contribute significantly to the health of population. Thus, the problems of epidemiology, clinical presentation, diagnosis and treatment of congenital abnormalities are of interest for many researchers [2]. In addition, the dynamic accounting for the incidence of congenital malformations and hereditary diseases allows the researchers to assess the ecological situation in the region [1]. The occurrence of congenital anomalies in the world varies; it depends heavily on how carefully the data is collected [4]. Multifactorial or polygenic diseases develop under the influence of environmental factors in the presence of defective genes. They can constitute up to 90% of all chronic pathology [2-5]. OBJECTIVE: To determine the incidence of congenital anomalies under the influence of environmental factors. METHODS: The study used the methodology of system evaluation of congenital anomalies incidence in Primorsky region, depending on bio-climatic and environmental conditions. The authors used health statistics for the period from 2000 to 2014, F.12 class for congenital abnormalities in adolescents and children that were compared in geographical and temporal aspects with environmental factors of 33 settlements in Primorsky region. The environment is represented by nature and climate (6 factor modules) and sanitation (7 factor modules) blocks of factors. When formalizing the information database of the environment a specially developed 10-point assessment scale was used. Statistical processing of the information was carried out using Pearson's chi-squared test and multiple regression method from SSPS application program package. RESULTS: The study found that over the 15-year period the level of congenital abnormalities in children increased by 27.5% and in adolescents - by 35.1%, and in 2014 it amounted to 1687.6 and 839.3 per 100 000 people, respectively. The predictive model shows a steady further growth of this pathology. The incidence has increased dramatically since 2000. This was due to the beginning of activities of medicogenetic service since 1998: the legal framework and information database were created, the flow of pregnant women was formed actively, and invasive prenatal diagnosis was introduced.Incidence of congenital anomalies has a reliable statistical association (chi-square) with bioclimatic zones and ecological situation. The high level of pathology is observed in both teenagers and children in the critical environmental situation areas, where there are enterprises of coal, mining and chemical industry, ship repair, construction, engineering sites, and areas with intensive chemical use and improvement of agriculture. For the most part these are cities and districts of the region where more than a half of the major manufacturing plants of the 1st and 2nd hazard classes are located. Exceeding the maximum allowable concentrations (MAC) of harmful substances in the air, soil, and water in these areas often reaches tenfold. It should be noted that in the territories with the critical environmental situation a relatively high level of malformations is observed in adolescents in the continental bioclimatic zone, and in children - on the coast, suggesting the influence of different climatic factors. Also a high level of the same congenital anomalies was revealed in children in bioclimatic zones of the coast and transition zones with the intense environmental situation.According to the results of the regression analysis, the varying degrees of influence of ecological and hygienic factors on the incidence of congenital anomalies were determined. In children, up to 77.3% of the spread of pathology depends on the complex of parameters of the environment; the proportion of the influence of sanitary and hygienic indicators is 63.1%, and natural and climatic indicators - 14.2%. Such factors as the characteristics of the soil condition, the level of air pollution, chemical pollution and adverse physical factors in urban and rural settlements, transport load, the presence of hazard-class companies, and observance of sanitary protection zones are of the most significance. The influence of a complex of ecological and hygienic factors on the incidence of pathology in adolescents was 60.0%. The contribution of sanitary and hygienic parameters was 44.5%, and natural and climatic ones - 15.5%. Chemical pollution and adverse physical factors in urban and rural areas, the level of air pollution, traffic loads, and condition of the soil influence the most. Assessing the results of the analysis one should note that the incidence of congenital abnormalities in both children and adolescents depends largely on the same modular sanitary factors, but with varying degrees of influence. At the same time the natural and climatic block of factors has almost the same degree of influence in these age groups. CONCLUSIONS: A significant increase of congenital anomalies in children and adolescents is registered in Primorsky Region, and the same is projected for the next 5 years.- The incidence of congenital anomalies in the region depends on bioclimatic zones and ecological situation. The highest level of pathology is observed in children in the coastal bioclimatic zone, and in adolescents, in the continental bioclimatic zone in areas with critical environmental situation.- Varied degree of influence on the level of congenital anomalies by a complex of sanitary and climatic factors is determined. The leading role (44.5-63.1%) belongs to sanitary and hygienic parameters of the life environment.- The results obtained make it possible to develop a set of organizational, diagnostic and treatment, and preventive measures for the correction of health of the population. PMID- 26639693 TI - Patients in need of medicine information. AB - BACKGROUND: Reliable medicine information is important not only for physicians and pharmacists, but also for patients [6]. However, the results of studies implemented in some countries show that patients may have slightly different needs and preferences in using sources of information [1, 4, 5, 7]. The main objective of patient medicines information is assisting consumers to achieve safe and effective use of pharmaceuticals [2, 3]. OBJECTIVE: To identify patients' needs in medicine information and sources they use to receive it. METHODS: We interviewed 1059 people who had visited community pharmacies in 10 regions of Armenia and Yerevan. Previously developed questionnaire was used for interviewing patients. Statistical analysis was conducted using SPSS program. RESULTS: We found that consumers need medicine information. 68.9% of respondents often use pharmaceuticals only if necessary medicines information is available. The majority of them believe that it is important to have information about therapeutic indications of pharmaceuticals to be used (91.8%), their dosage and method of administration (91.1%), contraindications (82.4%), adverse reactions (81.9%) and the simultaneous use of multiple medicines (76.5%). 58.9% of consumers value information about medicine's price. More than 70% of patients often seek information from health professionals and use medicines package information leaflets (PIL), and more than 75% of respondents mainly trust the same sources. 71.5% of respondents read package leaflets, while 42.0% of consumers do this several times. Only 36.7% of respondents completely understand information in a leaflet. CONCLUSIONS: Patients in Armenia need medicine information. They prefer to receive information from sources they trust.Many patients do not understand the content of package information leaflets (PILs) due to barriers, which can be removed by introducing appropriate regulatory provisions for their content and readability. PMID- 26639694 TI - CYP3A4 activity and haloperidol effects in alcohol addicts. AB - BACKGROUND: Haloperidol is one of the most commonly used typical antipsychotics [2]. It has a powerful antipsychotic activity blocking mesolimbic postsynaptic dopamine receptors. Unwanted adverse effects accompany the use of haloperidol. Therefore alcohol abusers' attitudes towards haloperidol are ambiguous and often negative, which sometimes limits it's use in patients with addictive disorders [3]. Cytosolic carbonyl reductase reduces haloperidol to reduced form, which has 10-20% of the activity of the parent molecule. It is further metabolized by CYP3A4 to a tetrahydropyridine and then conjugated by glucuronidation and sulphation. Reduced haloperidol is back-oxidized to haloperidol by CYP3A4 and CYP2D6. Haloperidol is N-dealkylated by CYP3A4 and CYP2D6 to 4-chlorophenyl-4 hydroxypiperidine and p-fluorobenzoyl propionic acid. The correlation between CYP2D6 and CYP3A4 activity and the rate of biotransformation of haloperidol was demonstrated in a number of studies on patients with schizophrenia [1, 2, 5]. At the same time other studies deny or disaffirm this correlation [4]. OBJECTIVE: To estimate the correlation between CYP3A4 isoenzyme activity and the efficacy and safety of haloperidol in patients with alcohol abuse during the exacerbation of the addiction. METHODS: The study involved 15 men, alcohol abusers, in exacerbation of their addiction, who were hospitalized in Moscow Research and Practical Centre for Narcology of the Departament of Public Health. All 15 patients received haloperidol in tablets and injections. Determination of CYP3A4 activity was performed using high performance liquid chromatography with mass spectrometry (HPLC/ MS) by determination of endogenous substrate of this isoenzyme and its metabolite in urine - the ratio: cortisol/6-beta hydroxycortisol. We used international psychometric scales to assess efficacy of haloperidol (the scale of determining the severity of addiction of The National Research Center on Addictions of the Ministry of Health Of Russia, Hamilton Anxiety Research Scale (HARS)). The safety of haloperidol was estimated by the UKU Side-Effect Rating Scale. Scales express the clinical picture of the abuse. The higher the score, the more pronounced the addiction is. Calculating the differences in scores of the scales allowed for clinical assessment of haloperidol effects. The larger the difference in scores was, the more pronounced were the changes in clinical picture of abuse, and the higher the efficacy of therapy was assumed. Statistical analysis of the results of the study was performed by non-parametric statistics by the program STATISTICA v10.0 ("StatSoft Inc.", USA). The normality of sample distribution was estimated by Shapiro-Wilk's W-test, and the homogeneity of dispersion, that was estimated by Fisher's T-test (in case of comparison of two samples). The differences were evaluated as significant in case of p < 0,05 (statistic power >80%). To determine the correlation between the quantitative characteristics Spearman rank R coefficient was calculated. The value of correlation coefficient r from 0,3 to 0,7 (p < 0,05) indicated positive moderate, but significant correlation between the characteristics, r>0,7 (p < 0,05) - strong and significant correlation, negative value of r indicated inverse correlation. RESULTS: Data analysis demonstrated a correlation between the activity of isoenzyme CYP3A4 and the scores of pathological addiction (r1 = -0,36), HARS (r2 = -0,45), UKU Side-Effect Rating Scale (r3 = -0.15) in the entire group (p < 0.05). In a group of patients, who received the higher doses of haloperidol (more than 7.5 mg per day in tablets or 5 mg per day in injections), the following results were received in the same groups of data: r1 = -0.68, r2 = -0.71, r3 = -0.76 (p < 0.05). CONCLUSIONS: The results demonstrate the correlation between CYP3A4 activities and the efficacy and safety of haloperidol in alcohol abusers during the exacerbation of the addiction. The inverse correlation indicates that the higher the activity of CYP3A4 is, the lower the efficacy of haloperidol is. Also it can be assumed that the presence of strong correlation between the activity of CYP3A4 and the efficacy of haloperidol in group of patients, who received higher doses of haloperidol, may indicate that CYP3A4 is involved in haloperidol metabolism when it is used at higher doses. LIMITATIONS OF THE STUDY: It should be noted that in this research the activity of CYP3A4 was determined using high performance liquid chromatography with mass spectrometry (HPLC/MS) by determination the ratio of cortisol/6-beta-hydroxycortisol for the fist time. To increase the level of our confidence in the results further studies with a larger number of people are necessary. PMID- 26639695 TI - Pharmacogenetic testing in population of South Ural. AB - BACKGROUND: Drug resistance is a phenomenon that has received serious attention in recent years in everyday medical practice. This may also be described as responsiveness or non-responsiveness to drugs, as patients respond partially to medical treatment or have no response at all [1]. The non-responsiveness to clopidogrel in cardiac patients of different populations is due to genetic variations in the cytochrome P450 (CYP) gene [2]. Carriers of at least one 'poor metabolizer allele' of CYP2C19 (either *2 or *3) have lower levels of the active metabolite of clopidogrel and have reduced platelet inhibition [3]. Furthermore, the significant inter-ethnic variability in the allelic frequencies of CYP2C19*2 has been associated with differential clopidogrel resistance [4]. Such mutations in this variant allele are responsible for the inability of the CYP enzyme to convert clopidogrel into its active metabolite, which may result in the increased risk of death, heart attack or stroke among patients who have undergone percutaneous coronary intervention (PCI) [5]. South Ural is a multinational region, a subject of the Russian Federation, where genetic variations have not been studied fully yet. OBJECTIVE: To examine prevalence of mutant alleles in population of South Ural. METHODS: We conducted pharmacogenetic testing for specific single nucleotide polymorphisms in 54 patients. The present research was conducted in the alleles CYP2C19*2 and CYP2C19*3. The data were processed using the program SPSS Statistics. RESULTS: The mean age of patients was 58, 4 years (from 26 to 79 years). Among all patients 59.3% were male, 40.7% of female patients.Among the studied patients in allele CYP2C19*2, the "wild" type GG was detected in 75,9% of patients, GA type in 22.2% and AA variant was detected in 1.9% of all patients. Allele CYP2C19*3 is often found among alleles with reduced function and also associated with resistance to clopidogrel. Functional drug response is observed in patients with type GG. All of the studied patients were carriers of this type. According to literature data the frequency of genotypes associated with resistance to clopidogrel in the Russian population is 11.4%, which is comparable with European ethnic groups [6]. CONCLUSIONS: It was revealed that 75,9% of patients were sensitive to clopidogrel, and for them this drug in its standard dosage will be effective, and 24,1% of patients were not sensitive, therefore, they would require replacement of clopidogrel with another drug. PMID- 26639696 TI - Clinical and electrophysiological aspects of tics in children. AB - BACKGROUND: Tics are diverse in nature inappropriate movements or vocalizations. They significantly degrade patients' quality of life, lead to social difficulties, and disturbance of learning especially during exacerbations. The prevalence of tics among children ranges from 4% to 24%, thus emphasizing the relevance of the problem. OBJECTIVE: To study clinical and electrophysiological features of tics in children with development of new treatment methods. METHODS: We conducted a comprehensive clinical and electrophysiological examination of 50 patients with tics, aged 5 to 15 years. The control group consisted of 20 healthy children. The research included a thorough study of the history, neurological examination, manual testing of skeletal muscles, psychological testing. Electrophysiological examination included a review of the functional state of corticospinal tract (CST) by the method of magnetic stimulation (MS), study of polysynaptic reflex excitability (PRE) according to a late component of the blink reflex (BR). Statistical analysis included parametric and nonparametric methods of data processing. RESULTS: All children of the study group showed signs of minimal brain dysfunction (MBD), they had complicated antenatal and postnatal history (trauma, disease, occurring with intoxication). There was a trend towards the increase of MBD signs with worsening of tics. Manual diagnosis in patients identified functional blockade at different levels of the vertebral column, sacroiliac joints, we identified latent myofascial trigger points (MFTP) mainly in the cervical-collar zone, in the area of the paravertebral muscles, periosteal triggers in the area of the sacroiliac joints.The research allowed determining decrease in propagation velocity of excitation (PVE) throughout CST in patients with tics. Correlation analysis revealed a negative correlation between the severity of tics and PVE (r = -0.38; p < 0.001).When studying polysynaptic reflex excitability (PRE) a significant predominance of hyper-excited types of blink reflex (BR) (90% of cases) was revealed. However, in 10% of patients there was a moderate decrease in propagation velocity of excitation (PVE), which allowed us to identify two subgroups of patients with tics: I - low and moderate type of reflex responses; and II - high type of reflex responses. Collation of data of MS and BR revealed a significant decrease of PVE in patients of the subgroup I, which probably reflects a deeper disturbance of the neuro-motor apparatus. The presence of numerous myofascial trigger points (MFTP) in patients of the subgroup I with moderately low polysynaptic reflex excitability (p < 0.05) was characteristic. CONCLUSIONS: The data show extraordinary sensitivity of neuromuscular system of children to various physiological and pathological stimuli, occurring in the body in the ontogenesis or diseases, and multifactorial origin of the pain syndrome in tics.The results suggest that one of the main mechanisms of development of pathological process is dysfunction of descending inhibitory control. However, further clarification of the type of polysynaptic reflex excitability in a certain patient is needed, that will allow to develop individualized approach to the choice of therapeutic interventions. PMID- 26639697 TI - Pharmacovigilance. PMID- 26639698 TI - The Importance of Evidence: The Legacy of Archie Cochrane. PMID- 26639699 TI - Safety and efficacy of valproic acid preparations. AB - BACKGROUND: Rising of the cost of drug therapy is one of the most notable negative tendencies of modern medicine. The main reasons for this trend are the increased costs for preclinical and clinical phases of drug development. Reproduction of drugs after cessation of patent protection is much less costly. Replacement of the original (reference) drug to generics would greatly reduce the cost of drug therapy. However, the use of generic drugs should provide maintaining quality of medication similar to achieved using the original drug. Thus, the original and generic medicines should be interchangeable and this factor largely determines the fate of the generics. In the Russian Federation the concept of drug interchangeability is entered by the Federal law of Russian Federation No 429-FZ from 22.12.2014. According to this law interchangeable drug is a drug with proven therapeutic equivalence or bioequivalence against the reference drug, having equivalent qualitative and quantitative composition, composition of active ingredients, the composition of excipients, same dosage form and route of administration. Especially the problem of interchangeability is particularly relevant for the drugs with a narrow range of therapeutic action, which include some anticonvulsants [1-3]. OBJECTIVE: In this regard the comparative analysis of indicators efficiency/risk using the data from the Federal database of adverse drug reaction in group of the patients treated with preparations of valproic acid is of interest [4]. METHODS: Assessment of the degree of certainty of causality between the development of adverse reactions and the use of the drugs of valproic acid in our research was assessed with Naranjo scale [5]. This method involves the use of the questionnaire focused on the obtaining concrete answers that are measured quantitatively in points. A certain number of points correspond to a certain degree of reliability.The category of the degrees of reliability of the relationship "medicine - no" on a scale Naranjo as a result of answers to 10 questions are defined as: the certain......9 and more points the probable.....5-8 points the possible.....1-4 points the doubtful.....0 and less pointsAfter determining the degree of certainty of causality, spontaneous reports only having a high degree of reliability reports (definite, probable and possible) were exposed to the further analysis. RESULTS: The Federal database of adverse drug reaction contains 753 spontaneous reports on the development of adverse reactions after the use of valproic acid preparations during the study period. Among 753 reports, 216 (29%) contained information about replacing one drug with another. The analysis of the action of drugs have shown that on the replacement of different drug forms of the original brand, adverse reactions occurred in 23 cases (14.6%), but on the replacement of the original drug on generic - in 135 (85,4%) cases. On the basis of clinical picture and assessment of severity of adverse reactions it was found that in 127 (77%) cases adverse reactions were serious. The criteria for seriousness of adverse reaction most often were clinically significant event and hospitalization or its prolongation.Analysis of the distribution of adverse reactions on replacement of drug preparations showed that 122 (77%) of 158 spontaneous reports were due to the problems of replacing the original drug to generic. CONCLUSIONS: Thus, replacement of the original preparation of valproic acid with generics should be considered as an independent risk factor for development of complications of drug therapy. In clinical practice, in case of successful seizure control substitutions of different preparations of valproic acid should be avoided. PMID- 26639700 TI - Monitoring drug safety in Astrakhan, Russia. AB - BACKGROUND: The problem of drug safety will never disappear as new drugs are delivered in increasing numbers. They have high biological activity and adverse drug reactions (ADR) [1]. Currently, adverse drug reactions are the fourth leading cause of death for patients.There are databases of ADRs (Vigibase, Eudravigilance), but we know that ADR manifestations may vary in different countries and regions, due to the demographic, genetic characteristics of the population and the quality of manufactured drugs [2]. In this regard, the study of the ADR at the regional level is very relevant. We aimed to optimize the work on monitoring drug safety in Astrakhan region through pharmacoepidemiological research and development of computer database for analysis of information coming to the center for drug safety monitoring (CDSM). OBJECTIVE: 1. To study the rates of ADR reporting and the structure in the Astrakhan region at the regional center for drug safety monitoring.2. To analyze the outcomes of registered adverse drug reactions.3. To determine the causality of adverse drug reactions.4. To identify reports on the ineffectiveness of drugs.5. To analyze the rates and structure of ADR reporting for drugs prescribed off-label. METHODS: We studied spontaneous adverse event reporting. The adverse event reports received by the regional CDSM for the period of 2010 to 2014 was analyzed. The groups of drugs were categorized according by Anatomical Therapeutic Chemical classification system. The data were analyzed using Microsoft Office Excel. The likelihood of whether an ADR was actually due to the drugs was assessed with the Naranjo algorithm. RESULTS: The analysis of the results showed that the establishment of the CDSM in September 2010, contributed to improvement of drug safety monitoring in health facilities of the region. Noteworthy was the increasing the number of adverse event reports in 2011 and 2012, compared with the beginning of the year 2010, when the CDSM was not yet functioning.The decrease of adverse event reporting in 2013 and 2014 was due to the fact that doctors in the region had access to better ADR drug information. Along with the increasing number of adverse event reporting we also noted the increase in the number of health facilities that monitored drug safety. The number of health facilities that reported, doubled from 2010 to 2014. We observed the increase in the number of adverse event reports submitted by pharmaceutical companies. General anti-infective drugs for systemic use (class J) were the most common cause of all registered ADRs (44%). Drugs for treatment of tuberculosis (group J04A) were the cause of adverse drug reactions in 34% of reports. ADRs associated with drugs used for treating diseases of cardiovascular system accounted for 16% of case-reports; drugs belonging to the group of Alimentary tract and metabolism (class A) and to the group of Nervous System (class A) were reported to cause ADRs in 10% of cases each. Type A adverse drug reactions, which are usually a consequence of a drug's primary pharmacological effect, were detected in 45% of cases. These reactions were often registered for drugs affecting cardiovascular system (class C), nervous system (class N), dlood and blood forming organs (class B). Type B ADRs were reported in 54% of cases. These were "idiosyncratic" reactions, which could not be predicted on the basis of the drug's main pharmacological action, were not dose-related and were severe [3]. The most frequent cause of type B adverse drug reactions was the General anti-infective medicines for systemic use (Class J). The fatality rate associated with ADRs was 0.3%. Type A adverse drug reactions resulted in death in 38% of cases. Type B ADR (anaphylactic shock) accounted for 62% of the patient's deaths. The Naranjo scale determined the causality of ADRs. The "definite" ADRs were detected in 14% of reports, "probable" - in 47%, and "possible" - in 39% of cases. The rate of reporting associated with ineffectiveness of drugs amounted to 1%. Most often the lack of therapeutic effect was reported in patients receiving drugs of class C (Cardiovascular system, 31% of all cases of inefficiency of drugs). These drugs were used in accordance with their official instructions for use. The proportion of ADR reports for drugs prescribed off-label was 1.4%. CONCLUSIONS: The results substantiate the need to continue drug safety monitoring in the Astrakhan region. We plan to further improve the software for ADR analysis. PMID- 26639701 TI - Medical Law. PMID- 26639702 TI - Fighting trafficking of falsified and substandard medicinal products in Russia. AB - BACKGROUND: The trafficking of falsified and substandard medicinal products is a global socio-economic problem, which poses a serious threat to economy and health of populations of most countries, including the Russian Federation. OBJECTIVE: To identify the main achievements and challenges in the fight against trafficking of falsified and substandard medicinal products in the Russian Federation, to formulate possible solutions to these problems. METHODS: The study of criminal cases and statistical information about the level of crime in the Russian Federation; legal analysis of regulatory legal acts in the sphere of criminal law and turnover of medicinal products; review of scientific and practical publications. RESULTS: The problem of trafficking of falsified and substandard medicinal products in the Russian Federation was publicly discussed in the late 1990s - early 2000-ies, first in the media and special editions, later this phenomenon was the subject of extensive discussions at international conferences, in public authorities and public circles. However, the most significant results in tackling this problem were achieved only in the last 5 years.Thus, in 2010, the Russian Federation first joined the annual international police operation under the code name Pangaea, held since 2008 on the initiative of Interpol and the Medicines and Healthcare products Regulatory Agency of the World Health Organization (MHRA WHO). From year to year, the special operation Pangea unites the efforts of many countries from different continents and aims to eliminate transnational criminal groups operating through a global network the Internet. In 2010, as a result of large-scale international inspections 1 200 Internet sites were revealed, through which the fake medicines were spread and 10,000 boxes of medicines were seized, making more than a million falsified tablets in the amount of 2.6 million USA dollars. In 2011, in a special operation Pangea IV was attended by 165 different organizations from 81 countries, including 72 customs, 30 regulators, 26 police and representatives of Interpol from 37 countries. Closed 13 495 illegal websites, seized about 8,000 packages of fake medicines, containing about 2.5 million doses. In 2015, the special operation Pangea VIII was held on the territory of 115 member States of Interpol. In the Russian Federation this operation was carried out jointly by the Ministry of internal Affairs, Federal customs service, the Federal Service on Surveillance in Healthcare of Russian Federation, the Federal Drug Control Service of the Russian Federation and their regional subdivisions. As a result of this operation 34 criminal cases were initiated in our country in connection with hard drugs, falsified and substandard medicinal products and biologically active additives under the guise of high-performance drugs. Special attention during the operation was given to uncontrolled Internet sale of medicinal products and biologically active additives at a price, which was significantly higher than the actual costs, under the guise of highly effective means of treatment for various diseases. In General, in the Russian Federation 448 administrative offences were identified, which resulted in withdrawal of more than 268 thousand units of medicines from illegal circulation, worth over 9 million rubles; 40 thousand falsified and substandard preparations Contex and Durex for personal contraception were withdrawn. The mobile laboratory has conducted screening program of quality in respect of 294 samples of medicines. It identified 20 parties of dubious authenticity. A message about 264 Internet sites which sell medicines in violation of applicable Russian legislation was sent to the coordinating headquarters of the General Secretariat of Interpol. An official statement with Internet service providers on cessation of activities at these sites was issued [1].On 26-28 October 2011, Moscow hosted an international high level conference on counterfeiting of medicinal products, which was attended by more than 750 professionals in the field of law and pharmacy from different countries, including USA, China, countries of the European Council and the Commonwealth of Independent States. At the end of the conference the Convention on the counterfeiting of medicinal products and similar crimes involving threats to public health, was signed, which was called Medicrime [2]. The Convention was signed by representatives of Austria, Germany, Israel, Iceland, Italy, Cyprus, Portugal, Russian Federation, Finland, France, Ukraine, Switzerland. The Medicrime Convention is the first legal agreement in the field of criminal law aimed at criminalizing the trafficking of falsified and substandard medicinal products, as well as aimed at providing legal support for the investigation of these crimes at the international level. The positive side of the Convention of the Council of Europe Medicrime is that it is open for signature not only by member States of the Council of Europe and the European Union, but also by States that are not members of the Council of Europe, but participated in the elaboration of a Convention or have observer status with the Council of Europe. In addition, the Convention is open for signature by any other state at the invitation of the Committee of Ministers of the Council of Europe. The Convention introduces the responsibility for the production, storage and distribution of falsified medicinal products, active substances, excipients, components, materials and supplies; the use of falsified documents related to the trafficking of medicinal products (Articles 5, 6, 7). This legal act regulates the cooperation between the health authorities, customs, police and other competent authorities at international and national level (Articles 17, 21, 22).One of the results of the legal implementation of the rules of the Convention Medicrime in the Russian legislation was the adoption of the Federal law of the Russian Federation dated 31.12.2014 No. 532-FZ On amendments to certain legislative acts of the Russian Federation on countering the trafficking of falsified, counterfeit, substandard and unregistered medicines, medicinal devices and falsified biologically active additives [3]. The law came into force on 23 January 2015. In accordance with the Federal Law of the Russian Federation Criminal Code is supplemented by three new articles: Article 235.1. Illegal manufacture of medicines and medicinal devices; article 238.1. Circulation of falsified, substandard and unregistered medicines, medicinal devices and trafficking in falsified biologically active additives; article 327.2. Forgery of documents on medicines or medicinal devices or the packaging of medicines or medicinal devices [4].Although there are some deficiencies in the wording of these penal regulations, we believe their introduction in the Criminal Code is a serious step forward by the state to neutralize the trafficking of falsified and substandard medicinal products, and consequently to ensure the safety of the nation's health and economic security of the country. The inclusion of these special articles in the Criminal Code will allow to analyze statistical information on their practical application by the authorities, to investigate crimes, to fully implement the monitoring, prediction and prevention of these socially dangerous acts. It will contribute to the development and implementation of effective management decisions on the identification and investigation of crimes of this type.In recent years, in the framework of the joint preventive measures to combat the circulation of falsified and substandard medicinal products there has been some constructive interaction between law enforcement and regulatory authorities, primarily by the bodies of internal Affairs and units of the Federal Service on Surveillance in Healthcare of Russian Federation. During 2010-2013 researches in the field of Economics, International and Criminal Law, Criminology, Criminalistics, Operatively-search activity, devoted to the development of measures to neutralize trafficking of falsified and substandard medicinal products, were developed as reserved dissertations. The legislation in the sphere of protection of public health and the turnover of medicines was updated.Thus, trafficking of falsified and substandard medicinal products in the Russian Federation at present is not an appeal and not a theory, but there is a real activity of specialists in the field of law and pharmacy, with a certain legal framework, scientific and methodological support.However, this problem is not yet solved. The Indicator of withdrawn from circulation of falsified and substandard drugs remains high. In Russia by the end of 2014, 1 109 batches of substandard, falsified and counterfeit medicines were detected and withdrawn from circulation. The volume of state quality control of medicines coming into circulation accounted for 16,3% [5]. A serious danger is the increased level of falsification of pharmaceutical substances, 80% of which is imported to the Russian Federation on indirect contracts from China and India without proper control at customs posts.The study of criminal cases and statistics about the trafficking of falsified and substandard medicinal products in the Russian Federation leads to the conclusion that this crime is of a latent character. Every year about 50 crimes are detected, for only 30-35 of them criminal cases are initiated, and only 15-20 of the investigated criminal cases are submitted to court. This indicates serious problems in proving the guilt of the perpetrators of these crimes and bringing them to justice. The fight against this crime requires long and reliable operational development of criminal groups, qualified investigation and trial. (ABSTRACT TRUNCATED) PMID- 26639703 TI - Essential Medicines, Clinical Guidelines and Rational Use of Medicines. PMID- 26639704 TI - Essential medicines for children in Armenia. AB - BACKGROUND: Drug therapy plays a key role in pediatrics. Effective treatment in pediatric practice means that medicines should be both effective and safe for children. However, there is not enough data on effectiveness and safety of medicines for children due to small number of clinical trials [1]. Access to medicines for children remains a serious problem worldwide [2]. The World Health Organization (WHO) has significantly increased the efforts in the field of pediatric pharmaceuticals in order to improve the situation [4]. In 2007, the World Health Organization (WHO) Model List of Essential Medicines for Children (EMLc) was firstly developed. Although WHO promotes access to essential medicines for children in countries by encouraging inclusion of these medicines in national essential medicines lists (EMLs) and treatment guidelines, many essential medicines are not covered by (EMLs) in some countries. The results of a study performed in 14 countries has shown that of 20 surveyed medicines the proportion included in national EMLs ranged from 50% to 90% and some medicines of the EML were not included in local standard treatment guidelines [3]. OBJECTIVE: To examine the current situation with access to essential medicines for children in the Republic of Armenia (RA). METHODS: The Armenian Essential Medicines Lists (AEML) of 2007 and 2013, as well as the Lists of medicines registered in Armenia have been analyzed (2011 - 2013). The following indicators have been calculated: the percentage of medicines from the WHO EMLc, which were included on the current AEML, the percentage of medicines from the WHO EMLc which were registered in Armenia and the percentage of medicines from the WHO EMLc which were included in approved clinical guidelines. Also, recommendations on prescribing of medicines for pneumonia, included in Armenian clinical guidelines, were analyzed. RESULTS: The analysis of the use of pharmaceuticals from the WHO Model List of Essential Medicine for Children (WHO EMLc) by medicines supply system in the Armenia has revealed that in 2013 only 57.7% of all the medicines from WHO EMLc were included on the National List of Essential Medicines of RA (AEML) and only 68.5% were registered. The results of studies carried out in 2011, 2012, 2013 showed that the situation in regard to the coverage of medicines from the WHO EMLc (without taking into account drug formulations and strengths) by AEML and clinical guidelines used in RA has not changed considerably during that period of time, while the percentage of essential medicines for children recommended by WHO, which were registered in Armenia and available in the pharmaceutical market, slightly increased.Analysis of recommendations on prescribing medicines for pneumonia treatment, included in clinical guidelines used in Armenia, has revealed that these recommendations slightly differ in terms of recommended medicines and other treatment details. Accordingly, approval and use of a single set of criteria for selecting medicines to be included into pediatric clinical guidelines should be considered as an effective approach for optimizing supply of medicines for children. CONCLUSIONS: Access to essential medicines for children in Armenia is unsatisfactory. Essential medicines for children recommended by the WHO are only partially covered by the medicines supply system for children in Armenia. Development of the List of Essential Medicines for children in Armenia is an approach to solve this problem. Currently actions are being taken in this direction. It is also considered appropriate to develop national clinical guidelines on the most common childhood diseases in Armenia. PMID- 26639705 TI - Evidence-based clinical guidelines in Kyrgyz Republic. AB - BACKGROUND: Improving quality of care in many countries is one of the priorities of health systems. At the same time one of the most important methods of improving quality of care is the widespread use of methods and principles of evidence-based medicine (EBM) [1]. The implementation of EBM in public health practice provides for the optimization of quality of care in terms of safety, efficacy and cost, one way of which is the use of clinical guidelines. Clinical guidelines developed with the use of EBM, provide an opportunity to use the latest and accurate information to optimize or neutralize impact on physician decision-making of subjective factors such as intuition, expertise, opinion of respected colleagues, recommendations of popular manuals and handbooks, etc. OBJECTIVE: To assess and analyze the developed clinical guidelines (CG) and protocols (CP) in the Kyrgyz Republic in the period from 2008 to 2014 and evaluate their implementation in practical healthcare. METHODS: Retrospective analysis of the developed clinical guidelines and protocols according to the approved methodology, interviewing leaders, questioning doctors and patients for their implementation. All participants gave informed consent for voluntary participation in the study. RESULTS: Within the framework of the National Program "Manas Taalimi" "Strategy for development of evidence-based medicine in the Kyrgyz Republic for 2006-2010" (MOH Order No490 from 09.04.06) was developed and approved for use. Its main purpose was to create a sustainable system of development, deployment and monitoring of the CG and CP and further promotion of EBM into practical health care, education and science. As a result, a number of documents ("Expert Council for assessing the quality of clinical guidelines/protocols", "AGREE instrument to assess the methodological content of clinical guidelines" [2], "The methodology of development and adaptation of clinical guidelines based on evidence-based medicine") were approved by the Order of the Ministry of Health from 31.12.2008 No704.This methodology was based on the international guideline SIGN-50 [3], as part of the strategy, it was decided to adapt clinical guidelines of the advanced countries of the world to the organizational characteristics of health care in the Kyrgyz Republic. According to the adopted methodology, the development of clinical guidelines should include the following steps: choose a theme, create a multidisciplinary group to conduct a search of existing clinical guidelines and assess their quality, if necessary, conduct an additional search of evidence, make recommendations and draw up the text of clinical guidelines, conduct peer review and consultations, approve clinical guidelines in the pilot, approve the clinical management of the Ministry of Health, publish and distribute, put into practice, monitor the effectiveness of implementation, provide for the revision and updating of clinical guidelines as new credible information appears. In the future, these CGs will be considered as a basis for the development of the CP in accordance with the possibilities of health care organizations of the country. Figuratively speaking, the CG answers the question - "What can be done in an ideal situation? ', And CP -" What should be done in a country?".The Ministry of Health over the period 2008-2014 years approved 41 CGs and 118 CPs for common diseases. It should be noted that only 31.7% of them were represented by the corresponding CGs. Among the approved CPs only 15.3% were based on the corresponding CGs. All of the CGs and CPs (100%) identified experts who prepared the documents and to whom they are addressed. The search strategy information was available only in 24.3% of cases, and only 18.1% used the criteria for selection of international guidelines, which were found in the CGs. 100% of the CGs and CPs indicated no conflict of interest of their developers, but it should be noted that 89% of the CG and CP were developed with the financial assistance of donor organizations supporting the Kyrgyz health reform. The degree of evidence of the recommendations was presented in 100% of the documents, but grading scales were different: in one CG manual grading was used with 3 levels of evidence (A, B, C), in the other - 4 levels (A, B, C, D ), and in the third - tier 5-6 (I, II, III, IV, V), which is not the approved methodology, which was based on gradation - A, B, C, D. In the process of approval of CGs and CPs, 100% did not specify points of methodological quality evaluation.To assess the implementation of approved CG in the practice (training, availability of the CG and CP for each doctor, informing patients about the CG and CP, monitoring use) we interviewed the leaders of health care organizations (20), surveyed 200 doctors and 100 patients. Only 10% of leaders said that they participated in the training on the CG and CP. 5% of them confirmed that every doctor had the corresponding copies of CGs and CPs, 100% of the leaders conduct internal audits on the use of the CG and CP, in 95% of cases the developed CGs and CPs do not take into account local health systems conditions (drugs, equipments etc.). 100% of respondents followed the CGs and CPs, as penalties were introduces by the Ministry of Health, Health Insurance Fund for violation of these recommendations. 25% of respondents reported improved clinical outcomes. To the question "How to improve the practice of medicine with the use of CGs and CPs?" 100% of the managers answered that they needed trainings: trainings for physicians, trainings for the developers of these documents. The survey of doctors showed that only 5% of them were trained in the use of CGs and CPs, 100% of them had the copies of CGs and CPs, 100% of doctors answered that the CGs and CPs not always were suitable for their practice. Questioning patients revealed the following: 100% of them never heard of the CGs and CPs, 2% of patients noted some improvement in healthcare delivery, and 20% of patients were referred to private laboratories for diagnostic tests, and 100% of the patients-respondents bought their drugs for their own pocket money. CONCLUSIONS: It is very important to ensure equal opportunities in access to medical interventions designed accordingly to the CGs and CPs at all health facilities that will prevent discrimination, depending on territorial distribution, administrative subordination, and other factors in the provision of health care. Implementation of CG and CP recommendations depends not only on the level of health care, knowledge and judgment of a clinician, but also on affordability of a particular diagnostic or therapeutic technologies for a patient. Cases when effective services are not unaffordable for patients should be considered from ethical perspective. PMID- 26639706 TI - Rational use of medicines - Indian perspective! AB - BACKGROUND: India, the largest democracy in the world, is with a federal structure of 29 states and 7 union territories. With a population of more than 1.2 billion, resource is always a constraint and so is in the health system too. In the federal structure, providing healthcare is largely the responsibility of state governments. Medicines are important component of health care delivery system and quality care is dependent on the availability and proper use of quality medicines. In spite of being known as pharmacy of the third world, poor access to medicines in the country is always a serious concern. Realizing the need of quality use of medicines, several initiatives have been initiated. RESULTS: As early as 1994, seeds of rational use of medicines were sown in the country with two initiatives: establishment of a civil society, Delhi Society for Promoting Rational Use of Drugs (DSPURD) and establishment of government agency in Tamil Nadu, a southern state, called Tamil Medical Services Corporation Limited (TNMSCL). DSPUD was in official association with World Health Organization Country Office for implementing essential medicine programme in the country for two biennia. In addition to organizing sensitising and training programme for healthcare professionals throughout the country, it looked after the procurement and appropriate use of medicines in Delhi government health facilities. TNMSCL has made innovations in medicine management including procurement directly from manufacturers as a part of pooled procurement, establishing warehouses with modern storage facilities and Information Technology enabled management of whole process. TNMSCL Model is now replicated in almost the entire country and even in some small other countries as it is successful in improving access to medicines.The National Government and the State Governments have developed strategies to promote rational use of medicines as a part of improving access and quality care in public health facilities. National Government developed policies and regulations for combating antimicrobial resistance, controlling the prices of medicines, establishing generic medicines stores and advocating for the need for improvement of medicine logistics at state level and prescription auditing system. There is wide variation in medicine procurement and management system among the states. Spending on medicines ranges from as small as 2% of health budget to as high as 17%. The procurement system varies from individual facilities to partial pooled procurement to complete centralised system.There are attempts of developing essential medicine lists, standard treatment guidelines and costing of treatment of common illnesses. Except for the few states, essential medicine list remains an ornamental showpiece. However, with apex court's intervention, the prices are now controlled for all 348 medicines listed in national list. The pharmaceutical companies continue to violate price regulations either through making the medicines at different strengths or new fixed dose combinations (FDCs). Perhaps the largest number of FDCs and many of them with no valid justification are available in the country. Decisions on compulsory licensing have made the new anticancer medicines affordable. Other countries have also benefited from this decision. CONCLUSIONS: While some progress has been made for appropriate use of medicines in public health facilities, there are little efforts in private sectors and at community levels. Availability of prescription medicines without much control and free drug advertising are other concerns. Like all other countries irrational use of medicines continues to be of concern in India despite of several attempts of improving use of medicines both in the health system as well as in community. But efforts continue to be made for improving the use of medicines! PMID- 26639708 TI - Patient Safety. PMID- 26639707 TI - Furthering benefit/risk ratio and cost effectiveness of anticancer drugs. AB - BACKGROUND: In Russia, the incidence of melanoma is increasing steadily. The approved standard of specialized medical care for melanoma of the skin defined the range of drugs, recommended for the provision of quality health care. However, it appears that the most effective innovative and safe medicines are at the same time the most expensive drugs. The most important is the assessment of drug use, taking into account their relative efficacy, safety (risk/benefit) and cost (economic efficiency), which may help to create the conditions for controlling their use. Based on this analysis, it is necessary to introduce drugs on the lists of drugs within the framework of the provision of state guarantees of free medical care to citizens (patients). OBJECTIVE: To analyze the drug use according to the standard of specialized medical care for melanoma of the skin, to perform information retrieval in specialized libraries and databases Cochrane, Pubmed, Medline, as well as in the database of the state register of medicines (GRLS) of Russian Ministry of Health. METHODS: The nomenclature of drugs was determined according to the standards of specialized medical care for 2006 and 2012, to the data of GRLS; information searches were performed in specialized libraries and databases Cochrane, Pubmed, Medline. RESULTS: Analysis of anticancer drugs for melanoma of the skin consisted of determining of nomenclature of drugs, included in the standard of specialized medicine care. The standard of specialized medicine care for patients with malignant melanoma of the skin (with specialized assistance) (Order dated December 6, 2006 No 828) includes the following anticancer drugs: dacarbazine (alkylating agents), vinblastine (antineoplastic agent - an alkaloid), cisplatin (platinum), lomustine (nitrosoureas), bleomycin (antitumor agent, an antibiotic) [1]. The standard of specialized medical care in melanoma skin generalization or recurrent disease (chemotherapy) (Order of November 7, 2012 No 604n) includes the following anticancer drugs: lomustine and fotemustine (nitrosoureas), dacarbazine and temozolomide (alkylating agents), cisplatin (platinum) [2]. So, the standard of specialized medical care for for melanoma of the skin by 2012 compared with the standard of care by 2006 includes temozolomide and fotomustin and excludes vinblastine and bleomycin. Based on the database GRLS of Russian Ministry of Health Care [3], as well as information retrieval in databases of Cochrane, Pubmed, Medline the efficacy and safety of melanoma of the skin have proven innovative products, in particular, such as vemurafenib (Zelboraf) dobrafenib (Tafinlar) and trametinib (Mekinist) that are already registered in Russia. At the stage of the clinical study are targeted drugs, such as GSK1120212, AMG 678, pembrolizumab, ipilimumab, tremilimumab, nivolumab and etc. The inclusion or exclusion of data from the restrictive drug lists, such as lists of "Vital and essential medicines", "Drugs for certain categories of citizens", the "Minimum range", according to the Russian Government Decree No871 of 28.08.2014 [4] is carried out after the risk/benefit ratio and cost effectiveness assessment to increase their availability. The availability of high-quality, effective and safe drugs for medical use within the reduced budget, taking into account the formation of a rational and balanced system of health care is the main task of the strategy of the drug provision of the population of Russia for the period till 2025 [5]. CONCLUSIONS: The most rational use of limited resources and cost containment within the framework of state regulation refers to modern trends in the health care of the Russian Federation. There is a need to develop targets aimed at all subjects of the pharmaceutical market, to increase the availability of innovative drugs for melanoma of the skin treatment. This strategy should be based on evidence and assessments of the efficacy, safety and economic viability of anticancer drugs. PMID- 26639709 TI - Developing drug formularies for the "National Medical Holding" JSC. AB - BACKGROUND: One of the main problems of drug provision of multidisciplinary hospitals is the necessity to improve the efficiency of budget spending. Despite the efforts undertaken in Kazakhstan for improving the mechanism of drug distribution (creation of the Kazakhstan National Formulary, Unified National Health System, the handbook of medicines (drugs) costs in the electronic register of inpatients (ERI), having a single distributor), the number of unresolved issues still remain."National Medical Holding" JSC (NMH) was established in 2008 and unites 6 innovational healthcare facilities with up to 1431 beds (700 children and 731 adults), located in the medical cluster - which are "National Research Center for Maternal and Child Health" JSC (NRCMC), "Republic Children's Rehabilitation Center" JSC (RCRC), "Republican Diagnostic Center" JSC (RDC), "National Centre for Neurosurgery" JSC (NCN), "National Research Center for Oncology and Transplantation" JSC (NRCOT) and "National Research Cardiac Surgery Center" JSC (NRCSC). The main purpose of NMH is to create an internationally competitive "Hospital of the Future", which will provide the citizens of Kazakhstan and others with a wide range of medical services based on advanced medical technology, modern hospital management, international quality and safety standards. These services include emergency care, outpatient diagnostic services, obstetrics and gynecology, neonatal care, internal medicine, neurosurgery, cardiac surgery, transplantation, cancer care for children and adults, as well as rehabilitation treatment. OBJECTIVE: To create a program of development of a drug formulary of NMH and its subsidiaries. METHODS: In order to create drug formularies of NMH, analytical, software and statistical methods were used.AII subsidiary organizations of NMH (5 out of 6) except for the NRCOT have been accredited by Joint Commission International (JCI) standards, which ensure the safety of patients and clinical staff, by improving the technological infrastructure, management systems, production environments, and developing program for medications management and use (MMU), etc.MMU is the Chapter 7 of the 5th edition of the standard JCI [1] which is an up-to-date recognized international standard for hospital drug supply and includes 7 points of medication management lifecycle for inpatient hospitals: drug management and organization; selection and procurement; storage; prescription; preparation and distribution; administering medications; monitoring.Due to the developed MMU program of subsidiary organizations the drug provision system was rationalized, starting from defining the individual therapy of a patient and ending with the drug procurement strategy. The practical activity was introduced to the use of drugs committeees with reliable evidence-based performance with obligatory consideration of cost-benefit analysis for each diagnosis-related group. RESULTS: Pre-collected applications for drugs for the year 2015 were submitted in a uniform format in accordance with the structure of the Republican form of the drug [2]. In view of the evidence-base physicians-clinical pharmacologists performed discussions and review of 851 drugs included on the uniform format of the list. Totally 51 (6%) positions were excluded from the list; it was suggested that the format of the application for Paracetamol and Ibuprofen in injectable form be revised; the committee revised the sections on the list for "Antianaemia drugs", iron preparations and methods of prevention of venous thromboembolism with oral anticoagulants.On the basis of this work, the new format, consisting of 449 international nonproprietary names was developed, representing 795 positions with pediatric formulations. In view of the exisitng data and the move to bring to the common standards and uniformity prices of drugs purchased for 2016, the NMH program of clinical pharmacology content with on-line and open access to physicians was created. Within 60 days the DSCHC work was carried out with consultations, selection, definition of requirements of generic and therapeutic substitution. CONCLUSIONS: Summing up, drug applications for 2016 with dosage forms include 802 positions and the total bid in monetary terms was by 4,7% lower than in 2015.For the establishment of NMH rational and balanced system of medicine provision to patients and in order to increase availability of quality, safe and effective drugs, we need to have an open and transparent program of the MMU, developed in accordance with the standards of JCI, with the NMH drug formulary, indicating the reference price values of the lower units (tablet, capsule, ampoule, vial, etc.), including the drug lists for a single distributor.To improve drug supply of the NMH DSCHC we have to further cooperation with clinical pharmacologists for the rational use of medicines, guided by the principles of evidence-based medicine. PMID- 26639710 TI - Adherence to EBM guidelines in clinical practice. AB - BACKGROUND: Adequate and rational pharmacotherapy is an important element of rehabilitation of patients with myocardial infarction. Orders of the Ministry of Health of the Russian Federation, domestic and international guidelines, and scientific publications - all contain a complete algorithm for rational pharmacotherapy [1, 2]. These documents are based on the principles of evidence based medicine (EBM) and help practicing physicians to carry out individualized and rational pharmacotherapy. However, clinical studies have shown low adherence of physicians to clinical guidelines. In the Russian Federation the death rate from cardiovascular diseases is higher than in developed countries. Thus, studies of the causes of high cardiovascular mortality are needed. OBJECTIVE: To assess adherence of practicing physicians to principles of evidence-based medicine in treating patients after myocardial infarction at the stage of rehabilitation. METHODS: A retrospective analysis of 157 cases of patients in rehabilitation after myocardial infarction for the years 2006 and 2009 was undertaken.We analyzed the list of drugs, prescribed to patients during the period of rehabilitation, drug combinations, regimens and pharmacoepidemiological parameters. We used the following rehabilitation criteria: blood pressure control, smoking cessation, and weight control. Recommendations of controlled physical activities have also been studied. Patient care was compared with the guideline recommendations. Statistical analysis was performed using the OLAP system. RESULTS: 65 patients with myocardial infarction received rehabilitation therapy in 2006, and 92 - in 2009. It was found, that in 2006 physicians prescribed an average of 4.5 drugs per patient, and in 2009 - 4.6 drugs per patient. The average number of cardiovascular drugs (category C of ATC classification) per patient was 2.9 in 2006, and 2.6 - in 2009. Polypharmacy was found in half of the patients.In terms of evidence-based medicine, an important element in the rehabilitation of patients is smoking cessation and normalization of body weight. Nicotine replacement therapy and prescriptions of drugs for weight loss is one of the strategies to achieve goals. According to our study, drugs for smoking cessation and overweight were not prescribed at all. In terms of evidence-based medicine, the use of beta-blockers and ACE inhibitors for a long time by all patients is an important element of secondary prevention.The frequency of prescribing of beta-blockers was 86.1% and 91.1 %% in 2006 and 2009 respectively. The frequency of prescribing of subgroup C09 "Agents acting on the renin-angiotensin system (RAAS)" was 67.7% and 44.4% in 2006 and 2009 respectively. Beta-blockers had the highest frequency of use, while the subgroup RAAS drugs were second to them.We found that the following recommendations of clinical guidelines, based on the principles of evidence-based medicine, were not followed. We found low rates of ACE inhibitors prescribing. The structure of prescribed ACE inhibitors varied in 2006 and 2009. In 2006, 58.4% of all prescriptions were for enalapril. In 2009 enalapril use decreased to 30%, while prescribing of lisinopril increased from 0 in 2006 to 13.3%. Among angiotensin II antagonists (C09C) only losartan was used in 3.1% and 1.1% of cases in 2006 and 2009, respectively. Fixed drug combinations were not used at all.The proportion of patients who had hypertension was 73.9% and 61.9 %% in 2006 and 2009, respectively. The rate of Antihypertensive use (C02), namely Guanfacine and Moxonidine was less than 2% in both 2006 and 2009.In accordance with evidence based principles the strategy for prevention of recurrent myocardial infarction with prescription of lipid-lowering drugs was used. Lipid-lowering drugs were prescribed to 13.8% of patients in 2006 and to 82.2% of patients in 2009. Doctors used atorvastatin and simvastatin only from the list of drugs of this group. We found that in clinical practice physicians used drugs, not supported by evidence, in particular trimetazidine was frequently used. Antiarrhythmic drugs were not prescribed at all, while part of the patients had arrhythmias. Standards of rehabilitation of patients with myocardial infarction do not contain a section on pharmacotherapy and could not be used for quality assessment. CONCLUSIONS: Pharmacotherapy of patients aimed at secondary prevention of myocardial infarction did not fully conform to the principles of evidence-based medicine. Standards for rehabilitation after myocardial infarction require revision based on existing clinical guidelines and evidence-based medicine. PMID- 26639711 TI - Timing of treatment initiation in West's syndrome. AB - BACKGROUND: Infantile spasms (called the West's Syndrome) represent a severe epileptic syndrome which is characterized by a peculiar type of epileptic seizures, spasms, and by electroencephalographic (EEG) abnormalities often called hypsarrhythmia [1]. Infantile spasms are usually resistant to conventional antiepileptic drugs (AEDs) and adrenocorticotrophic hormone (the synthetic analog - tetracosactide) has been the preferred treatment since 1958. The evidence for other antiepileptic drugs is extremely limited compared with vigabatrin. Most recent studies deal only with short-term drug effects and fail to use clinically meaningful outcome measures. Furthermore, attention needs to be given to dropout rates in the studies, because some studies include a majority of patients with primarily favourable outcome [2]. Effective treatment is now defined as complete cessation of the spasms plus abolition of hypsarrhythmia ('all-or-none response') [3]. So far there has been no consensus on dosage or duration of therapy, influence of early initiation of treatment on the outcomes of West syndrome therapy. OBJECTIVE: To assess if the timing of treatment initiation (early or late) influences the outcomes of West syndrome therapy. METHODS: We conducted a retrospective observational study at the Kazan Municipal children's hospital No 8 among children with West syndrome. When treatment with tetracosactide (synacthen depot) or antiepileptic drugs was initiated within 1 month after the onset of seizures we defined it as "early treatment initiation". If this therapy was started after 1 month of the onset of seizures, we defined it as "late treatment initiation". We used was the number of seizure-free patients after 2 months, 6 months and 1 year from the start of the treatment as the favorable outcome measure. We calculated risk ratios (RR) for favorable outcomes and their confidence intervals (CI) using RevMan 5.3 Software, comparing outcomes of early and late treatments. RESULTS: We analyzed medical records of 150 children with infantile spasms. The diagnosis of West syndrome was confirmed by video-EEG monitoring findings and by clinical examinations. Gender distribution of patients with West syndrome was with some predominance of boys: 93 boys (62%) and 57 girls (38%), which corresponded to the published literature data. The duration of follow-up was at least 3.5 years. The mean age of patients at the time of analysis was 6 years, from 4 years (min) to 14 years 5 months (max). We divided all of the children into four groups:Group IA - early treatment initiation - included children who were started on tetracosactide within 1 month from the onset of seizures (30 patients).Group IB - late treatment initiation - included children who were started on tetracosactide after 1 month of the onset of seizures (60 patients).Group IIA - early treatment initiation - included children who were started on antiepileptic drugs as mono- or polytherapy within 1 month from the onset of seizures (22 patients).Group IIB - late treatment initiation - included children who were started on antiepileptic drugs after 1 month of the onset of seizures (38 patients).Children in all groups were similar with respect to age, sex, severity of the disease. Effectiveness of tetracosactide in the group IA and in the group IB at 2 months, 6 months and 1 year of follow up (from the beginning of treatment) was comparable: RR = 1.00; 95% CI [0.79, 1.27]; P = 1,00; RR = 0.96; 95% CI [0.74, 1.24]; P = 0,74; RR = 1.00; 95% CI [0.75, 1.33]; P = 1,00; respectivelyComparative analysis of the effectiveness of treatment with antiepileptic drugs (without tetracosactide) at 2 months, 6 months and 1 year of follow up (from the initiation of treatment) demonstrated that the number of patients achieving clinical remission was higher in the group IIA, in which the therapy was started within 1 month of the onset of the disease versus the "late treatment initiation" group IIB: RR = 2.76; 95% CI [1.03, 7.41]; P = 0,04; RR = 1.62; 95% CI [1.01, 2.59]; P = 0,04; RR = 1.37; 95% CI [1.02, 1.84]; P = 0,04; respectively. CONCLUSIONS: The timing of initiation of tetracosactide therapy did not influence the outcomes of West syndrome therapy. The early initiation of treatment with antiepileptic drugs (but without tetracosactide) resulted in a greater number of patients achieving remission, compared with late treatment initiation. PMID- 26639712 TI - Antibiotics for skin and soft tissues infections in type 2 diabetes mellitus. AB - BACKGROUND: Type 2 diabetes mellitus is a chronic pathology characterized by high prevalence, high morbidity and mortality. According to the data of the Ministry of Health of Volgograd region the number of patients with type 2 diabetes was 68,227 people on 01.01.2014. Medical and social significance of type 2 diabetes mellitus is determined by its complications. Skin and soft tissue infections (SSTIs) in patients with type 2 diabetes are among the main factors of hospitalization and mortality [1]. Diabetic foot syndrome is found in 30-80% of patients [2]. OBJECTIVE: Pharmacoepidemiological analysis of the structure of skin and soft tissues infections in patients with type 2 diabetes, taking into account data on pathogens, parameters of their sensitivity, analysis of prescribed medicines and evaluation of their compliance with current clinical guidelines and standards. METHODS: A retrospective descriptive cross-sectional pharmacoepidemiological study using randomization by random numbers. The sample consisted of 253 medical records of patients with SSTIs and type 2 diabetes. These were patients admitted to the surgical departments of hospitals of the city of Volgograd for the period from January 2011 to December 2014. Gender structure was the following: 51.4% - women, 48.6% - men. The average age of patients was 64.5 years. The average number of hospital days was 19,5 +/- 14,9. RESULTS: Diabetic foot syndrome was found in 81.3% of cases (n-204). The most common forms of diabetic foot syndrome were the following: gangrene of the lower extremities - 28% (n-58), ulcers of the skin - 26% (n-53), mixed forms of SSTIs - 18% (n-37 ). Surgical manipulations were performed in 39.1% of cases (n-99), including amputations in 65.7% (n-65) of cases. The blood glucose level on admission was studied in 97.6% (n-247), at discharge - in 89% (n-225). Urine analysis on admission was performed in 66.4% of patients (n-168), at discharge - in 51% of patients (n-129). The glycemic profile was studied in 81.4% of patients (n-206). Bacteriological sowing was carried out in 19% (n-48) of cases: blood - 4,2% (n 2), urine - 6,2% (n-3) (the growth of microorganisms was not detected in 100%); bacteriological sowing from the wound - in 89.6% (n-43), the growth of microorganisms were identified in 95.7% (n-44). Most common pathogens were: St. aureus - 28%, E. coli - 19%, St. epidermidis - 14%. Antibacterial medications were prescribed in 86% (n-216). These were: cephalosporin of the III generation - ceftriaxone (49.4%), other synthetic antibacterials - metronidazole (21%), fluoroquinolone - ciprofloxacin (7.5%). The highest levels of bacterial resistance of SSTIs pathogens were found to beta-lactam antibiotics (amoxicillin/clavulanic acid, ceftriaxone, and ampicillin), rifampin, and gentamicin. The highest levels of sensitivity of SSTIs pathogens were observed to levofloxacin, to vancomycin and meropenem. CONCLUSIONS: There is a vicious circle in patients with type 2 diabetes: the infectious process leads to decompensation of carbohydrate metabolism parameters; in turn, hyperglycemia leads to increase of severity of SSTIs. Normalization of glucose levels promotes prompt relief of symptoms of infection and bacterial eradication, rational treatment of infection contributes to rapid correction of glucose level. Therefore, an essential element of comprehensive treatment of this group of patients should be rational antibiotic therapy; the choice of medication should be based on the severity of the disease and potential etiologic agents [3]. The analysis of the degree of conformity of the pharmacotherapy to existing standards is a way to optimize the treatment of the given group of patients [4]. PMID- 26639713 TI - Towards the rational use of medicines. AB - BACKGROUND: Rational use of medicines remains to be one of the most challenging problems in health systems worldwide [1, 2]. ABC/VEN-analysis has been recommended for use by the World Health Organization (WHO) and has been used in health care practice globally since 1981. It represents the simple and effective method of analysis of medicine expenditures, identifying priority groups of medicines, the use of which, when improved, may provide the greatest clinical and economic impact. ABC analysis provides an accurate and objective picture of budget expenditures on medicines. VEN-analysis helps to prioritize between various medicines in their selection for procurement and use within a drug supply system [3-5]. OBJECTIVE: To assess the impact of introduction of evidence-based principles in the practice of medicine procurement and use on budget expenditures on medicines of a multidisciplinary health facility for the period of four years (2011-2014). METHODS: ABC/VEN analysis was carried out in a multidisciplinary health facility with over 1000 beds (an average number of beds for three years), which is responsible for provision of care to the population of about 1.4 million people. The analysis was carried out on the basis of information on medicine expenditures for 4 years: 2011 (1st year), 2012 (2nd year), 2013 (3rd year) and 2014 (4th year). When assigning VEN categories of medicines we used expert method: assignment of categories was carried out by clinical pharmacologists after reviewing all available evidence on effectiveness, safety and cost effectiveness compared to other drugs in this group. In 2013, we implemented educational intervention, including detailed discussion of the results of the ABC/VEN-analysis for the years 2011-2012 from the standpoint of evidence-based pharmacology and recommendations for medicine procurement. In 2014, we delivered training workshop for the heads of clinical departments on evidence-based principles in clinical pharmacology and rational use of medicines. RESULTS: Medicines expenditures of the studied health facility for the year 2014 were less than for the year 2013, which was the important decrease reversing the trend of increasing medicines expenditures of the last three years: 2011 - 59,868,963 roubles; 2012 - 85,324,084 roubles, 2013 - 107 303 390 roubles, and 2014 - 74,416,692 roubles. The number of International Non-proprietary Names (INN) of medicines used in 2014 was 519, which was the highest number for the four years of the study: 2011 - 429 INN, 2012 - 432 INN, 2013 - 513 INN, and 2014 - 519 INN. Nearly 40% of the funds spent in 2014 on medicines have been used for Vital medicines: 2011 - 26%, 2012 - 39%, 2013 - 25%. Expenditures on Non-essential medicines in 2014 were about the same as in previous years - 14% of total medicine expenditures: 2011 - 16%, 2012 - 13%, 2013 - 15%. However in absolute numbers (roubles) expenditures on non-essential medicines decreased compared to the years 2013 and 2012: 2011 - 9,428,135 roubles, 2012 - 11,129,388 roubles, 2013 - 15,578,325 roubles, 2014 - 10,616,023 roubles.Expenditures on solutions for infusion (sodium chloride, Ringer's solution, dextran, glucose, hydroxyethyl starch) decreased as compared to the year 2013, but still remained high, thus indicating on the abuse of parenteral methods of drug administration. The portion of expenditures on isotonic sodium chloride solution and hydroxyethyl starch in 2014 decreased compared to the year 2013. We found a positive trend in the structure of expenditures on antibacterial agents: in 2014 expenditures on fluoroquinolones decreased nearly fivefold compared to 2013, expenditures on cephalosporins also decreased, but not so dramatically. However, there was a significant increase in expenditures on carbapenems, more than twofold compared with the year 2013. In 2014 we noted a twofold decrease in expenditures on medicines affecting blood, including antithrombotic agents, hemostatics and antianemic medicines, as compared to the values of the year 2013. In 2014 there was also a decrease in expenditures of cardio-vascular medicines, medicines affecting nervous system, alimentary tract and metabolism. CONCLUSIONS: Introduction of evidence-based principles through educational interventions at a multidisciplinary health facility resulted in a number of changes towards more rational medicine use. Regular educational interventions for practicing physicians and heads of clinical departments of health facilities that promote rational prescribing are needed. PMID- 26639715 TI - Molecular Mechanisms Contributing to the Evidence-Base. PMID- 26639714 TI - Regional specifics of microbial landscape in outpatients with lower respiratory tract infections. AB - BACKGROUND: The last years have witnessed progressive growth of antimicrobial resistance (AMR) both in hospital-acquired and community-acquired respiratory infections. Regional guidelines (2006) presented standard approaches to pharmacotherapy and provided an important contribution to improvement of antimicrobial therapy at healthcare facilities of both the City of Stavropol and the Stavropol Region. At the same time, recent years have witnessed substantial changes in sensitivity to antimicrobials; besides, newer antibiotics have become available now. This substantiates the need for update of the regional guidelines [1]. OBJECTIVE: To determine the issues related to standardization of antibiotic therapy of lower respiratory tract (LRT) infections at an outpatient setting; to assess regional changes (2007-2012) in the spectrum of pathogens causing LRT diseases in patients of the regional healthcare facilities in view of their age and the diagnosis as compared with the years of 2003-2006. METHODS: In 2007-2012, we examined sputum microbiology of patients with LRT infections at the bacteriological laboratory of the Centre for Clinical Pharmacology and Pharmacotherapy (Stavropol, Russia), following the methodology guidelines [2]. The comparison was carried out with the results of the microbiological examination of 7051 sputum samples (held in 2003-2006). Statistical analysis was carried out using arithmetic means, standard errors, and Student's t test involving a software package STATISTICA 6.0. RESULTS: In the outpatient practice, half of the patients with LRT infections were identified to have Str. Pneumoniae. The sputum of every fifth examined patient allowed isolating Enterobacteriaceae family members such as Klebsiella spp. (Klebsiella pneumoniae in most cases), Serratiaspp., E. coli, and Enterobacter spp. It is essential to note that almost a quarter of the patients were found to have M. pneumoniae. C. Pneumonia was detected quite often as well (19%). Str. pneumoniae, M. pneumoniae, and C. pneumoniae were found in virtually 80% of all the cases of community-acquired pneumonia in adults. H. influenzae and M. pneumoniae were 2-3 times more often isolated from the sputum of patients with chronic obstructive pulmonary disease (COPD) and chronic non-obstructive bronchitis.Along with an increase in the patients' age, regardless of the diagnosis, the proportion of pneumococci, Haemophilus influenzae and various members of the Enterobacteriaceae family went up, while the share of mycoplasmas went down. However, even in patients over 60 years of age M. pneumoniae accounted for a significant share in the overall spectrum of pathogens, which indicates the need for microbiological monitoring, especially as far as COPD is concerned.In contrast to the previous years, only 35% of the patients (previously 60%) underwent bacteriological examination (p<0.05) while receiving antibiotic therapy. Significant prevalence of mycoplasmas in the structure of the isolated microorganisms was found in patients who had been previously treated with beta-lactam antibiotics.Associations of pathogens were detected in 14% of cases, which is half the rate found 2-3 years ago. The associations were found to reveal more frequent presence of H. influenzae in patients with acute exacerbation of chronic non-obstructive bronchitis, and Enterobacteriaceae - in patients with COPD and pneumonia. The recent years have shown that, combined with other microorganisms, there can be detected pneumococci (p<0.05), H. influenzae, as well M. pneumoniae, while there have been fewer cases of enterococci and enterobacteria; as for non-filterable bacteria, they have been never detected again (p<0.05).Strains of H. influenzae maintained high sensitivity to aminopenicillins, including the protected ones. The antibiotic resistance possessed by Str. pneumoniae to aminopenicillins doubled (12.4% strains vs. 6.4% 3 years ago, p<0.05). The resistance to Co trimoxazole and Ofloxacin was 27.9% and to macrolides it was 17.9%. Various representatives of the Enterobacteriaceae family maintained high sensitivity to aminopenicillins, second and third generation cephalosporins, fluoroquinolones.Of the 20 M. pneumoniae strains that were tested, 8 (40%) displayed resistance to one or more antimicrobials. The highest numbers of cases with resistance were detected to Ciprofloxacin (25%) and Erythromycin (20%). 10% strains of mycoplasma showed resistance to Doxycycline and Ofloxacin, while only 5% of mycoplasmas were identified as having non-sensitivity to Clarithromycin and Azithromycin. CONCLUSIONS: The results of the research carried out in the recent years in comparison with the data of the previous years, call for reviewing of the standard approaches to the choice of antimicrobial agents in respiratory tract infections. In order to improve the standard of care, the choice of medicines should be based on a number of factors, namely the age, the severity of the respective pathological condition, previous antimicrobial use, and the level of care. PMID- 26639716 TI - Towards effective and stable probiotics. AB - BACKGROUND: Probiotics are live microorganisms, generally either lactobacilli or bifidobacteria, which when administered in adequate amounts confer a health benefit to the host [1]. Due to the growing evidence of health benefits associated with their use, probiotics are of increasing interest and represent now a significant growth area in the functional foods industry [2]. However, to be effective, orally administered probiotics should survive preparation of dosage forms and passage through acidic environment of the gastrointestinal tract (GIT). Reaching the intestine, these microorganisms should be able to establish themselves, remain viable and perform their beneficial actions. In this context, oral formulations have to protect probiotic bacteria from gastric acidity and delay their release in the small intestine in order to allow their complete release in the colon. OBJECTIVE: To evaluate effects of starch formulations of lactobacilli on their survival in gastric environment and probiotic properties. METHODS: Nineteen Lactobacillus strains belonging to the species L. fermentum (14 strains), L. plantarum (4 strains), and L. rhamnosus (1 strain), were isolated from dairy products and probiotics, and were used in this study. Lactobacilli were cultured in de Man, Rogosa, Sharpe (MRS) broth (Merck, Germany) under microaerobic conditions at 37 degrees C.Amylolytic activity of lactobacilli, cultured for 3-5 days on MRS agar supplemented with 1% soluble potato starch (SPS), was determined with iodine reagent (0.01 M I2-KI solution).Loading in starch was performed with L. plantarum 8PA3 bacteria ("Dry lactobacterin", Perm, Russia), which were resuspended to the concentration 1010 cells/mL in 10 mL of 0.85% NaCl solution and added to 90 mL of 2.5% SPS solution. Resulting mixture was frozen at -18 degrees C and then lyophilized (Martin Christ Alpha 1-2 LDplus, Germany).Atomic force microscopy (AFM) images of formulated L. plantarum 8PA3 cells were acquired in air by a Solver P47H atomic force microscope (NT-MDT, Moscow, Russia).Starch swelling and dissolution was studied in simulated colonic fluid (SCF), prepared according to [3] and in distilled water (pH = 6.0) as control. Amylase from Aspergillus oryzae (A8220, Sigma) was added to the solutions to study the influence of amylase. The formulation form was examined visually during 14 h incubation time.Fluorescence microscopy images were obtained with a Leica DM6000B (Germany) fluorescent microscope using Leica FW4000 software.L. plantarum 8PA3 loaded in SPS were placed either in HCl solution (pH 2), or in 2% oxgall bile solution, or in 0.85% NaCl solution. Viability was tested after 2, 4 and 6 h incubation at 37 degrees C by plating diluted aliquots onto MRS agar with subsequent counting of bacterial colony forming units (CFU). In addition, viability was determined using LIVE/DEAD BacLight bacterial viability kit L-7012 (Molecular Probes, Invitrogen) as described elsewhere [4]. Fluorescence in the stained samples was estimated with BD FACS Canto II (USA) flow cytometer or fluorescent microscope.Nitric oxide (NO) production was assessed with DAF-FM DA and DAA fluorescent dyes as described earlier [4]. Each experiment was performed in triplicate. RESULTS: In the present study we studied the probiotic composition comprising of SPS and bacteria L. plantarum 8PA3. We used AFM to confirm effective fixation of the cells to carbohydrate. The compositions were found to swell quickly (~5 min) in aqueous solutions either containing amylase, or not. Tested starch formulations disintegrated during the first 5-10 min of incubation in amylase solutions whereas in amylase-free probes dissolution was less intensive (after ~30 min). Amylolysis of starch excipients was less pronounced in aqueous amylase solution than in SCF, supplemented with amylase. None of 19 studied Lactobacillus strains hydrolyzed SPS when growing on MRS agar supplemented with it. The amount of viable L. plantarum 8PA3 cells formulated with SPS was high and did not change when stored for 6 months at 4 degrees C. The bacterial viability tests also demonstrated that after 6 h treatment with 2% bile or HCl (pH 2) L. plantarum 8PA3 exhibited increased sensitivity (viability 14% and 0.4%, respectively). However, in similar conditions no significant differences were noticed between bacterial viability obtained for formulated with starch and non-formulated bacteria. Furthermore, we showed that loading into SPS had no effect on bacterial production of nitric oxide (NO) - a pluripotent regulatory molecule in human organism. CONCLUSIONS: Overall, the results strongly support that formulation with polymeric matrices on the basis of SPS represent an appealing technology of probiotics production. It provides slow release of bacteria in target environment and does not alter their viability and NO biosynthesis. However, SPS excipient does not preserve the bacteria from harsh conditions of upper GIT. Therefore, we conclude that for oral administration the composition should be loaded in acid-resistant capsules. PMID- 26639717 TI - Anti-inflammatory and anti-oxidant properties: Is there a link? AB - BACKGROUND: It is believed that the anti-inflammatory activity of medicines is closely related to their antioxidant activity. However, in clinical practice rigorous evidence-based medicine approach fails to reveal important effects of antioxidants on patient important outcomes in inflammatory disorders, as has been shown by a number of Cochrane reviews [1-3]. OBJECTIVE: To evaluate anti inflammatory and antioxidant effects of newly developed pharmacological agents: dimephosphone and its structural analogues ephorane and mephoprane, and xymedon, in comparison with prednisolone and etidronate in experimental animal model of adjuvant arthritis. METHODS: Experiments were conducted in 64 white mongrel rats of both sexes weighing 180-200 g, which were divided into 8 groups 8 rats each (4 males and 4 females each), kept under standard vivarium conditions with certified feeding ration (kombikorm). The study was approved by the local ethics committee. We induced adjuvant arthritis by administration under the plantar aponeurosis of the left hind paw of 0.1 ml of Freund's adjuvant (Sigma) in rats of 7 study groups. The groups were as follows: 1st group - intact animals (control); 2nd group - animals to whom the solvent (distilled water) was administered with intra gastric tube in corresponding volume (control of the model); 3rd - 8th study groups, in which animals were administered with study agents each at a dose of 1 mmol/kg body weight: dimephosphone, ephorane, mephoprane, xymedon, etindronate and prednisolone. The intensity of the modeled arthritis was determined by measurements of paw volumes with plethysmometer (UgoBasile). We calculated the difference in rat paw volume before the administration (baseline) and after administration of Freund's adjuvant at 3, 7, 11, 15, 20, 27, 31, 38, 41 days. The development of secondary arthritis was documented by the increase in volume of both hind and fore paws and tails. On the 41st day of the experiment the animals were sacrificed under light ether anesthesia and exsanguinated. The blood was used to determine the activity of catalase and peroxidase, the content of the total, reduced and oxidized glutathione, the level of ceruloplasmin, conjugated dienes of unsaturated fatty acids (DC), TBA-interacting products (MDA), and the total antioxidant activity of serum (AOA). The results were processed statistically using the Student's t-test. RESULTS: The primary reaction to the Freund's adjuvant in a form of swelling of the ankle joint of the left hind paw was observed at 24 hours after its injection. External clinical manifestations of the modeled disease were more pronounced on the third day: local inflammatory reaction (redness, swelling, ulceration) was seen in all the animals at the injection site with the increase of the paw volume. On the 11th day of the experiment 20% of the animals developed secondary arthritis. The study agents dimephosphone, ephorane, and prednisone exerted anti-inflammatory effect decreasing the volume of left hind paws by 45%, 46% i 27% respectively on the 40th day of experiment. Mephoprane did not affect the primary inflammatory response to the Freund's adjuvant (rats' left hind paws), however it reduced the volume of the contralateral right paw (secondary arthritis) by 90% on the 20th day of the experiement. This ant-inflammatory effect was accompanied by documented antioxidant activity in case of dimephosphone, ephorane, prednisolone, but not mephoprane. Dimephosphone reduced the levels of lipid peroxidation products in rats blood by 46% (DC) and by 25% (MDA). Ephorane also reduced the levels of lipid peroxidation products in the blood by 46% (DC) and by 25% (MDA), increasing the level of glutathione by nearly half, both the total and the reduced form. Prednisolone reduced the level of lipid peroxidation products in blood by 61% (DC), but not the TBA-interacting products. Mefopran did not affect the blood level of lipid peroxidation products. Xymedon and etidronate showed no anti-inflammatory effect. Xymedon demonstrated anti-oxidant properties, decreasing the blood levels of lipid peroxidation products, while etidronate seemed to behave in pro-oxidant mode, increasing the blood levels of lipid peroxidation products. CONCLUSIONS: The effects of studied agents on the intensity of inflammation and lipid peroxidation were inconsistent. The results of the study did not show a clear link between anti-inflammatory and anti-oxidant activity. Further research in potential anti-inflammatory activity of new drugs exhibiting antioxidant properties needs to be done before recommending their use in clinical practice. PMID- 26639718 TI - 6-Methyluracil derivatives as acetylcholinesterase inhibitors for treatment of Alzheimer's disease. AB - BACKGROUND: Alzheimer's disease (AD) is the major age-related progressive neurodegenerative disorder. The brain of AD patients suffers from loss of cholinergic neurons and decreased number of synapses [1]. AD is caused by an imbalance between Abeta production and clearance, resulting in increased amount of Abeta in various forms [2]. Reduction of Abeta production and increasing clearance of Abeta pathogenic forms are key targets in the development of potential therapeutic agents for AD treatment. Unfortunately, only nosotropic approaches for treatment of AD are currently effective in humans. These approaches mainly focus on the inhibition of brain acetyl-cholinesterase (AChE) to increase lifetime of cerebral acetylcholine [3]. It is important to emphasize that AChE itself promotes the formation of Abeta fibrils in vitro and Abeta plaques in the cerebral cortex of transgenic mouse models of AD [4]. This property of AChE results from interaction between Abeta and the peripheral anionic site of the enzyme (PAS) [5]. Dual binding site inhibitors of both catalytic active site (CAS) and PAS can simultaneously improve cognition and slow down the rate of Abeta-induced neural degeneration. Unfortunately, the assortment of AChE PAS ligands is still extremely limited. OBJECTIVE: To study putative advantages of AChE non-charged PAS inhibitors based on 6-methyluracil derivatives for the treatment of Alzheimer's disease. METHODS: In vitro studies. Concentration of drug producing 50% of AChE/BuChE activity inhibition (IC50) was measured using the method of Ellman et al. [6]. Toxicological experiments were performed using IP injection of the different compounds in mice. LD50, dose (in mg/kg) causing lethal effects in 50% of animals was taken as a criterion of toxicity [7]. The ability of compound to block in vitro AChE-induced Abeta1-40 aggregation was studied using a thioflavin T (ThT) fluorescent probe [8].In vivo biological assays. For in vivo blood-brain barrier permeation assay brains were removed 30 min after IP injection of LD50 dose of tested compound injection. The inhibitory potency was measured using the method of Ellman.Scopolamine and transgenic models of AD were used to evaluate the influence of compound 35 on spatial memory performance.Water solution of scopolamine was injected to mice (ip) 20 minutes before starting memory test during 14 days [9]. Mice were assigned to 7 groups, including 4 groups receiving injection (ip) of compound in different dosages, donepezil-treated mice (donepezil is conventionally used to treat Alzheimer's disease), positive and negative control groups. Double transgenic (APP/PS1) mice expressing a chimeric mouse/human amyloid precursor protein and a mutant of human presenilin-1 [10] were assigned to 4 groups, including transgenic animals injected (ip) with compound 35 or donepezil solution, positive (transgenes injected with water) and negative (wild-type mice) controls.To evaluate spatial memory performance, mice were trained on a reward alternation task using a conventional T-maze [11]. The criterion for a mouse having learned the rewarded alternation task was 3 consecutive days of at least 5 correct responses out of the 6 free trials.For beta-amyloid peptide load was evaluated quantitatively as a number and summary area of Thioflavine S fluorescent spots in cerebral cortex and hippocampal images using Image J program. Statistical analyses were performed using the Mann-Whitney test. RESULTS: We evaluated the acute toxicity of the most active compounds. The most potent AChE inhibitor compound 35 (IC50 (AChE) = 5 +/- 0.5 nM) exhibited the lowest LD50 values (51 mg/kg) and inhibited brain AChE by more than 71 +/- 1%. Compound 35 at 10 nM, exhibited a significant (35 +/- 9%) inhibitory activity toward human AChE-induced Abeta aggregation.Scopolamine injection induced significant decrease in correct choice percentage in T-maze, as well as decrease in percentage of mice reaching criterion for learning the task by day 14. This memory deficit was relieved to some extent either by compound 35 (5 mg/kg) or donepezil (reference compound) treatment (0.75 mg/kg). Interestingly, higher doses of compound 35 (10 and 15 mg/kg) produced less therapeutic effect on spatial memory deficit.Group of APP/PS1 mice showed 3 times lower percentage of reaching behavioral criterion and lower percentage of correct choice in T-maze alternation task comparing to WT mice, whereas compound 35 (5 mg/kg) or Donepezil treatment effectively improved these parameters in APP/PS1 mice.Compound 35 treatment (5 mg/kg) during 14 days significantly reduced percentage of summary area and number of beta-amyloid peptide (betaAP) deposits visualized in sections of cerebral cortex, dentate gyrus, and hippocampal CA3 area in APP/PS1 mice. The most prominent reduction of betaAP load by compound 35 treatment was found in CA3 area and cerebral cortex. Meanwhile, Donepezil treatment (1 mg/kg) during 14 days significantly reduced betaAP load in cerebral cortex but not in dentate gyrus and CA3 area. CONCLUSIONS: Experiments showed that the most potent AChE inhibitor compound 35 (6-methyluracil derivative) permeated the blood-brain barrier, improved working memory in the APP/PS1 transgenic mice and significantly reduced the number and area of Abeta plaques in the brain. Thus, compound 35 is a promising candidate as a bi-functional inhibitor of AChE for treatment of AD. PMID- 26639719 TI - Mild anemia as a protective factor against pregnancy loss. AB - BACKGROUND: Iron deficiency anemia is traditionally considered to be a pathological condition during pregnancy. According to the standards, prescription of iron supplements to pregnant women is required at hemoglobin levels of 110 g/l and lower. Numerous studies at different periods showed the relationship of anemia and premature birth [5], preeclampsia [1], low birth-weight [2]. Meanwhile, physiological hemodilution carries in pregnancy an important adaptive function. It is well known, that in the second half of pregnancy physiological hypercoagulability develops (increased activity of the plasma clotting factors, platelet aggregation, decreased activity and blood concentrations of physiological anticoagulants) aimed at implementing adequate hemostasis in labor. Under these conditions, moderate hemodilution is an effective mechanism for preventing the development of severe disseminated intravascular coagulation (DIC) in labor, during surgery, in various forms of obstetric pathology. OBJECTIVE: To study the effect of anemia of varying severity on the pregnancy course and outcomes. METHODS: We conducted a "case-control" study based on cohort. The study included 421 pregnant women who received outpatient care under the monitoring of pregnancy in the antenatal clinic of the South Ural State Medical University and the antenatal clinic of Chelyabinsk Clinical Hospital No6. The inclusion period was from January to March 2014. Inclusion criteria were: confirmed pregnancy, informed consent to participate in the study. Exclusion criteria were multiple pregnancy, induced pregnancy, late first appearance in the antenatal clinic (after 25 weeks' gestation), change of residence and medical supervision during pregnancy, the presence of severe mental disorders, severe somatic diseases in decompensation stage, HIV infection, cancer, active tuberculosis. Study design complies with the legislation of the Russian Federation, international ethical standards and was approved by the Ethics Committee of the South Ural State Medical University. Prospective observation was conducted. All pregnancy complications were registered, in particular, preeclampsia, placental insufficiency (violation of utero-placental blood flow), the presence and severity of anemia during pregnancy, as well as outcomes: the duration and mode of delivery, fetal weight at birth. The criteria for the diagnosis of anemia during pregnancy were: decrease of hemoglobin levels below 110 g/l. All pregnant women with confirmed anemia were treated with iron supplements. After the completion of follow-up the odds ratios analysis of presenting anemia was performed in subgroups: 1) a patient gave birth to a live child, and patient with the loss of the fetus at various stages of gestation; 2) patients who have given birth in time, and patients with premature birth; 3) patients with placental insufficiency (violation of utero-placental blood flow) during pregnancy and patients without placental insufficiency; 4) patients with preeclampsia and patients without pre-eclampsia; 5) patients who have delivered live births weighing less than 2,500 grams and birth weight over 2500. In each case, odds ratios (ORs) and confidence intervals (95% CI) were calculated. Statistical calculations were performed using the software package SPSS 22.0. RESULTS: Among all patients (n = 421) anemia of varying severity has been diagnosed in 190 (45.13%), including mild anemia in 161 (38.24%), moderate or severe anemia - in 29 patients (6.88%). In 16 (3.8%) cases, the pregnancy resulted in miscarriage or fetal death. Premature birth of live fetus before 34 weeks of gestation was recorded in 13 cases (3.2%; n = 405). Preeclampsia was diagnosed in 15 women (3.56%). Live births with weights less than 2,500 g were registered in 23 cases (5.67%; n = 405).An analysis of odds ratios was performed to compare the groups of women with anemia of any severity and without anemia, with mild anemia compared with women without anemia, and moderate/severe anemia compared to women with mild anemia or without anemia.According to our results, there was a statistically significant reduction in the chance of having anemia of any severity in patients whose pregnancy was completed by fetal loss. For mild anemia odds ratio in these subgroups was even lower. Thus, the odds of having mild anemia in the group of women who completed a pregnancy to a live birth, was 90.3%, which may indicate a protective role of mild anemia against the loss of the fetus.In all other cases, statistically significant results were not received. Thus, we didn't receive significant positive association between anemia and development of preeclampsia, placental insufficiency during pregnancy, low birth weight and premature birth. There are other publications that show a protective role of anemia in pregnancy. Case control study [3] showed a protective role of anemia against the development of pre-eclampsia (n = 636, p = 0,01). In [4] anemia was a protective factor against stillbirth. There is evidence [6] of the higher risk of stillbirth in women with high hemoglobin level (146 g/l and above), while the link of the risk of stillbirth with anemia has not been confirmed (n = 1404). CONCLUSIONS: Our data suggest a protective role of mild anemia during pregnancy in relation to pregnancy loss. PMID- 26639720 TI - Macrocyclic derivatives of 6-methyluracil: New ligands of the peripheral anionic site of acetylcholinesterase. AB - BACKGROUND: Acetylcholinesterase (AChE) inhibitors are widely used in medicine for pharmacological correction of cholinergic neurotransmission pathologies such as myasthenia gravis (MG) and Alzheimer's disease [1, 2]. The efficacy of anti AChE drugs is based on their ability to potentiate the effects of acetylcholine (ACh) due to a decrease in the rate of AChE-catalyzed hydrolysis of ACh. Crystallographic studies showed that the active site of AChE is located at the bottom of a deep gorge [3]. It was shown that, in addition to its catalytic center, AChE has other sites that are crucial for the proper functioning of the enzyme. In particular, the so-called peripheral anionic site (PAS) located at the entrance of the active site gorge is responsible for: 1) allosteric modulation of the catalytic center; 2) enzyme inhibition at high substrate concentration; 3) and non-catalytic functions such as enhancement of cell adhesion and neurite outgrowth. OBJECTIVE: Especially interesting is the relationship between the PAS and pathological beta-amyloid deposition. This led to a new hypothesis for rational design of more effective anti-Alzheimer drugs [4]. METHODS: Concentration of drug producing 50% of AChE activity inhibition (IC50) was measured using the method of Ellman et al. [5]. Toxicological experiments were performed using IP injection of the different compounds in mice. LD50, dose (in mg/kg) causing lethal effects in 50% of animals was taken as a criterion of toxicity [6]. Molecular docking was performed with Autodock 4.2.6 software. RESULTS: We described previously a new class of selective mammalian AChE vs. butyrylcholinesterase (BChE) inhibitors based on alkylammonium derivatives of 6 methyluracil of acyclic topology [7]. In the present study, taking acyclic derivatives of 6-methyluracil as a model AChE inhibitor, we attempted to develop AChE inhibitors that specifically bind to the PAS with weak binding to the active site of AChE. We attempted to increase the size of AChE ligands to restrict specific binding to the PAS of AChE. To this aim we synthesized pyrimidinophanes bearing two o-nitrobenzylethyldialkylammonium heads. Almost all of synthesized pyrimidinophanes inhibited AChE in the nanomolar range. Based on molecular docking simulations, it was suggested that compounds bind AChE to the active center as well as to the PAS or only to the PAS. Thus, we found that introduction of the spacer, flexible or rigid, between [5-(o-nitrobenzylethylammonium)pentyl] units at N atoms of the 6-methyluracil moiety allows tuning the binding of 6 methyluracil derivatives with AChE. CONCLUSIONS: In conclusion, it can be stated that pyrimidinophanes are promising lead scaffold structures for further design of specific ligands for the PAS of AChE. Also AChE inhibitors with a 6 methyluracil moiety may be considered as potential drugs for the treatment of pathological muscle weakness syndromes. PMID- 26639721 TI - Molecular modeling of mechanism of action of anti-myasthenia gravis slow-binding inhibitor of acetylcholinesterase. AB - BACKGROUND: Myasthenia gravis (MG) is a chronic autoimmune neuromuscular disorder characterized by fluctuating weakness of voluntary skeletal muscles. The cause of autoimmune response is unknown and only symptomatic therapies for MG are currently available. Pharmacological correction of synaptic failure underlying MG, involves partial inhibition acetyl- and butyrylcholinesterase. Effectiveness of cholinesterase inhibitors in the symptomatic treatment of MG is based on their ability to potentiate the effects of acetylcholine by decreasing the rate of its enzymatic hydrolysis at neuromuscular junctions. Several new inhibitors of AChE were tested in animal model of MG and may be considered as valuable candidates for the treatment of pathological muscle weakness syndromes. In this study, we have investigated mechanisms of ChE inhibition by one of the most active 6 methyluracil derivatives (C547), as well as the possible benefits of using this compound for MG treatment compared to traditionally used pyridostigmine bromide.It was experimentally shown that C547 is a "pseudo-irreversible" slow binding inhibitor of human AChE. Human BChE is reversibly inhibited by C547 with an affinity about 4 orders of magnitude lower than that of human AChE. Slow binding inhibition of AChE leads to a lasting (over 24 hours) effect on the symptoms of muscle weakness in animal model of MG after a single administration of C547. OBJECTIVE: The aim of the present molecular modeling study was to reveal mechanism of AChE inhibition by C547 and elucidate its apparent "pseudo irreversibility". METHODS: Two principle methods used in the present study were molecular docking and molecular dynamics (MD). Molecular docking was performed with Autodock 4.2.6 software, Lamarckian Genetic Algorithm to obtain structure of protein inhibitor complexes and Local Search for MD snapshots to compare relative binding affinity. For MD simulations NAMD 2.10 software with Charrm 36 force field was used, for the ligand C547 Charmm General Force Field was used, and missing parameters were obtained with quantum mechanical calculations. Unconstrained MD, steered MD (SMD) and free energy calculations with adaptive biasing force were performed. RESULTS: During unconstrained MD, C547 very rapidly binded to the peripheral anionic site (PAS) of AChE. To pass the bottleneck, application of the external force was required (SMD). Both SMD modelling and free energy calculation revealed that after crossing the AChE bottleneck, C547 falls into very favorable position. At the same time the rupture of interactions as well as overcoming the bottleneck gates in the course of pulling out procedure requires application of much higher force than during the pulling-in process. This difference between binding and dissociating processes explains apparent "pseudo-irreversibility" of the inhibitor. CONCLUSIONS: These findings are in good agreement with kinetics study showing that C-547 is a slow-binding inhibitor of type B, i.e. after rapid initial binding of inhibitor, the enzyme-inhibitor complex undergoes an isomerization step. Position obtained by SMD is in good agreement with X-ray data obtained by F. Nachon, IBS, France. PMID- 26639722 TI - Rat paw oedema modeling and NSAIDs: Timing of effects. AB - BACKGROUND: Non-steroidal anti-inflammatory agents (NSAIDs), steroids and representatives of other pharmacological groups [1, 2] are widely used for pharmacological regulation of inflammation. However, their anti-inflammatory effects are accompanied by serious adverse reactions [3, 4]. There was a hope that newer NSAIDs, selective inhibitors of COX-2, would be safer, but their longer-term use appeared to cause an increased risk of heart attacks and stroke [5]. Carrageenan rat paw oedema model is traditionally used for search and development of new NSAIDs with assessment of effects after 3 to 5 hours after oedema induction [6, 7], neglecting longer-term effects [8]. OBJECTIVE: To compare effects of traditional NSAIDs (indomethacin, naproxen) on the development, duration and intensity of carrageenan rat paw oedema. METHODS: Carrageenan paw oedema was induced in 18 rats by sub-plantar injection into the right hind paw of the animals of 0.1 ml of 1% aqueous gel of carrageenan-lambda (22049 SIGMA lambda-Carrageenan plant-mucopolysaccharide, Sigma-Aldrich). We assessed the intensity of the oedema development and its duration by measurements of rat paw volume using plethysmometer 37140 (UgoBasile, Italy). Measurements were made prior to induction of oedema (base-line volume) and at 1, 2, 3, 4, 5, 24, 48, 72, 96, 120, 144, 168 and 192 hours after sub-plantar carrageenan injection. Calculating the percentage of increase in paw volume assessed the intensity of the oedema. The base-line paw volume was taken for 100%.Animals were divided into 3 groups of 6 rats each; group 1: control (solvent); group 2: naproxen 15 mg/kg and group 3: indomethacin 10 mg/kg. These doses are known as ED50 (effective doses 50) on carrageenan rat paw oedema with single-dose NSAIDs administration [9]. To get the most accurate estimate of the intensity of the simulated by carrageenan inflammatory response and the potential effects of some NSAIDs with their longer-term use we calculated areas under the curve "increase in paw volume - time" using standard method of numerical integration - trapezoidal method. Statistical analysis was performed using Microsoft Office Excel 2007 with the calculation of arithmetic means M, their standard deviations (delta) and standard errors (m). We applied Student's t-test and accepted as significant the differences with P values equal to or less than 0.05. RESULTS: The inflammatory reaction induced by carrageenan, developed in a form of swelling/oedema with an increase in the rat paw volume up to 55% of the baseline volume. The maximum volume of oedema was observed in the control group at 3 h after the injection of carrageenan, which is in accordance with the literature data on the development of carrageenan paw edema in rats [10, 11]. Naproxen at a dose of 15 mg/kg showed anti-inflammatory activity at 1, 2, 3, 4 and 5 hours after administration of carrageenan with suppression of oedema development by 59, 81, 73, 60 and 39% (p = 0.03; 0.001; 0.001; 0.001 and 0.01), respectively. There was no oedema inhibition by naproxen at later time-points. Indomethacin at a dose of 10 mg/kg showed anti-inflammatory effect at 2, 3, 4, and 5 hours after carrageenan oedema induction with inhibition of oedema development by 54, 54, 54 and 33% (p = 0.01, 0.004, 0.001 and 0.01) respectively. Again there was no oedema inhibition by indomethacin at the later time-points.When comparing the calculated areas under the curve "increase in paw volume - time" we found no differences between the values of control and study groups: naproxen (15 mg/kg) and indomethacin (10 mg/kg). We think that these values of areas under the curve "increase in paw volume - time" represent the total inflammatory reaction induced by carrageenan and need to be used for the assessment of future potential anti inflammatory agents which should not only produce short-term symptomatic oedema suppression, but change the nature of the oedema response, potentially with alternative mechanisms of action. Our experimental findings are in accordance with the well-known lack of effects of NSAIDs on the outcomes of chronic inflammatory diseases [12]. This may be due to the fact that they suppress the development and symptoms of inflammation at the early stages, but the reaction to inflammatory stimuli develops fully over the longer period of time and takes its full course nonetheless. This proves that traditional modeling approaches to future potential anti-inflammatory agents development needs re-assessment. CONCLUSIONS: Single-dose administration of naproxen (15 mg/kg) or indomethacin (10 mg/kg) exerts decrease in rat paw oedema volume at no later than 5 hours after oedema induction by carrageenan. Evaluating anti-inflammatory activity by the areas under the curve "increase in paw volume - time" proves that a single dose NSAID's administration has no effect on the inflammatory response when evaluated not by single time-point index (at 3 or 5 hours), but by assessing the oedema development and duration over 192 hours (8 days). PMID- 26639723 TI - Pirimidine derivatives as hepatoprotective agents. AB - BACKGROUND: Research and development of effective hepatoprotective medicines is one of the priority areas of research in Russia. Literature data shows that active research and development of hepatoprotectors is carried out both in Russian and other countries [1-6]. Pirimidines are used as hepatoprotective medicines stimulating protein synthesis and reparation of hepatocytes in toxical and infectious liver disorders [7]. In our previous work ee have shown hepatoprotective properties of pyrimidine derivative, named Xymedon [8]. This research, funded by the Russian Science Foundation, is aimed at identifying the most effective hepatoprotectors among pirimidine derivatives. OBJECTIVE: To test hepatoprotective properties of one of the new Xymedon (Xym) derivative - L ascorbate 1-(2-hydroxyethyl)-4,6-dimethyl-1,2-dihydro-pirimidine-2-one (Asc-Xym) on the toxic liver damage model induce by carbon tetrachloride (CTC, CCl4). METHODS: The toxic liver damage in rats was modeled by subcutaneous injection of CTC (CCl4) in vegetable oil (mixed at 1:1 ratio) at a dose of 2 ml per kg. The experiments were carried out under two schemes: 1) oral administration of Xym or Asc-Xym preparations by gavage at the doses of 10 and 20 mg/kg followed by subcutaneous injection of CTC 1 hour after pyrimidine oral administration and continued for 3-4 days; - this was the design of preventive pyrimidine use, 2) liver damage modeling by CTC subcutaneous injections for 3 days followed by oral administration of Xym, Asc-Xym or Thiotriazolin (Thi) preparations at the doses of 20 mg/kg for 5 days; - this was the design of therapeutic scheme. The rats of control groups were injected with CTC according to the same schemes, but did not get any preparations. We looked at some biochemical parameters of blood serum: alanine aminotran-sferase (AlAT), aspartate aminotransferase (AsAT), their ratio (de Rytis coefficient), and the total protein level as the markers of toxic liver damage. We performed statistical data analysis by rank nonparametric Mann-Whitney U-criterion for comparison of two independent groups. We evaluated pathomorphologic characteristics of liver damage on the histological slices colored with hematoxylin and eosin. RESULTS: Carbon tetrachloride (CTC) caused profound changes in the studied biochemical parameters of rats' blood serum. The AlAT activity level in the serum of control animals in the preventive scheme was 116,23 (the median) with the lower quartile and the upper quartile of 76,96 and 211,71 U/l respectively; the AsAT level was 230,08/201,49-290,03 U/l; this was the increase in comparison with the reference values. De Rytis coefficient was 1,76 /1,47-2,67. This was the decrease in comparison with the reference values of intact group (36,37/28,18-43,3 U/l; 132,95 /118,24-164,00 U/l and 4,26/3,03-5,23 respectively). The differences were statistically significant at P < 0,001. In the experimental groups the changes of the biochemical parameters with respect to the reference values were less marked than in Control. The AlAT level was 89,86/87,06-165,15; 103,23/38,19-270,87 U/l; 80,28/6,12-141,82 and 100,33/62,24 144,64 U/l in the groups of rats treated with Xym at the doses of 10 and 20 mg/kg or Asc-Xym at the doses of 10 and 20 mg/kg respectively. Similarly, in the same groups the AsAT level was 211,19/170,20-250,16; 193,61 /181,57-274,69 U/l; 190,91 /65,21-198,65 and 173,25/135,50-210,70 U/l respectively. The differences of the AsAT level were statistically significant at P < 0,05 in comparison with Control in the both groups treated with Asc-Xym.Nnearly 2 times increase of the AlAT level (67,60/1,22-94,60 U/l) (P = 0,00002) was shown in comparison with the reference values in the rats of Control group in the therapeutic scheme. However the AsAT level (163,80/130,1-178,8 U/l) was only slightly higher than reference values. De Rytis coefficient (2,07/1,78-3,48) was significantly lower than the reference values (P = 0,001). The total protein level (59,36/55,17-60,10 g/l) was lower than the reference values (65,06/62,06-68,98 g/l) by 8,4%. The differences of biochemical parameters as compared with the reference values in rats of experimental groups treated with Xym, Thi and Asc-Xym at the doses 20 mg/kg were less than those in the Control groups. They were: AlAT 52,49/44,64-62,30 and 61,42/53,20-96,66 U/l, AsAT 105,00/94,7-142,3 and 235,35/111,7-335,6 U/l, de Rytis coefficient 2,09/1,87-2,28 and 3,24/1,86-4,53, total protein 63,10/62,46 64,27 and 62,46/58,70-64,43 g/l respectively in the groups treated with Xym and Thi. The values of the studied biochemical parameters AlAT (39,04/32,46-44,24 U/l), AsAT (111,9/105,27-155 U/l), de Rytis coefficient (2,87/2,72-3,30), total protein (62,89/61,46-68,14 g/l) of the rats, treated with Asc-Xym, were the most close to the reference values in comparison with other experimental groups.The analysis of histological slices revealed large areas of steatosis and necrosis of hepatocytes in Control groups in both schemes. These were less pronounced in experimental groups than in Control groups and particularly in rats, treated with Asc-Xym. CONCLUSIONS: Hepatoprtotective properties of the new compound L ascorbate 1-(2-hydroxyethyl)-4,6-dimethyl-1,2-dihydropirimidine-2-one were established. The hepatoprotective efficacy of the compound is higher than that of Xymedon and Thiotriazolin. PMID- 26639724 TI - Human butyrylcholinesterase polymorphism: Molecular modeling. AB - BACKGROUND: Prolonged apnoea following injection of ester-containing myoralaxants was first described in 1953. Because a large part of administered succinylcholine is shortly hydrolyzed by plasma butyrylcholinesterase (BChE) under normal conditions, prolonged apnoea was attributed to deficiency in BChE. It was found that BChE deficiency was due to genetic variations. Human BChE gene shows a large polyallelism. About 75 natural mutations of the BCHE gene have been documented so far [1]. Most of them cause alteration in BChE activity through point mutation effect on catalytic activity. Frame shifts and stop codons may also affect expression, or cause truncations in the sequence. OBJECTIVE: Recently, two novel BChE "silent" variants, Val204Asp [2] and Ala34Val [3], causing prolonged neuromuscular block after administration of mivacurium, were discovered. Mutations were genetically and kinetically characterized. The aim of the current study was to understand how these mutations determine "silent" phenotype. METHODS: Molecular dynamics studies were carried out with NAMD 2.9 software at the Lomonosov supercomputer. Charmm 36 force field was used, periodical boundary conditions, 1 atm pressure, 298 K. 100 ns molecular dynamics runs were performed for the wild-type BChE and its mutants Val204Asp and Ala34Val. RESULTS: Unlike wild-type BChE, which retained its operative catalytic triad through the whole MD simulation, the catalytic triad of mutants was disrupted, making chemical step impossible. Val204Asp mutation leads to reorganization of hydrogen bonding network around the catalytic triad, which in turn increases the distance between catalytic residue main chains. Mutation Ala34Val, located on the protein surface, leads to increased fluctuations in the Omega-loop and subsequent disruption of the gorge structure, including disruption of the catalytic triad and formation of new hydrogen bonds involving catalytic center residues. CONCLUSIONS: Comparative study of the "silent" Ala328Asp mutant and the catalytically active mutant Ala328Cys shows that MD approach can discriminate between the differential effects of point mutations at a same position. PMID- 26639725 TI - ATP-induced changes in rat skeletal muscle contractility. AB - BACKGROUND: Extracellular purine compounds, adenosine triphosphate (ATP) and adenosine, are involved in regulation of many cell functions, engaging in rapid and long-term cellular processes. The nucleotides, including ATP, exert their extracellular effects by influencing membrane P2 receptors. ATP outside of the cell rapidly is metabolized by the ecto-enzyme system to produce adenosine, which acts on separate adenosine (P1) receptors. Since adenosine and ATP often are functional antagonists, ATP degradation not only limits its effect, but also brings new ligand with different, often opposing, properties. Great variety and widespread of P2 and adenosine receptors in the body emphasize the important physiological and pathophysiological significance of these receptors, and make them very attractive as targets for potential drug action.The existence of several subtypes of P2 and adenosine receptors has been shown in the skeletal muscles. ATP as a co-transmitter is densely packed together with classical neurotransmitters in the presynaptic vesicles of vertebral motor units but until recently ATP was refused to have its own functional role there and was recognized only as a source of adenosine. However, on the eve of the third millennium there appeared data that ATP, released from the nerve ending and acting on presynaptic P2 receptors, suppresses subsequent quantum release of acetylcholine. The final product of its degradation, adenosine, performs a similar inhibitory effect acting on presynaptic adenosine receptors.Despite the fact that the mechanisms of presynaptic inhibitory action of ATP and other purines were studied earlier, the object of those studies was usually neuromuscular synapse of cold-blooded animals. The few studies, in which experiments were carried out on preparations of warm-blooded animals, described the basic effects of purines. These often were guided by the convenience of preparation of the synapses of the diaphragm. We think that those results cannot be considered as typical effects of ATP and other purines on skeletal muscles and could not be extrapolated to all warm-blooded animals. Furthermore the role of ATP and its derivatives in the accumulation of vertebrate muscular effort has not been investigated.It is known that in physiological conditions vertebrates may mobilize only up to a third of the maximum muscle force. Why the two-thirds of muscular strength are not used normally but may be used at stress, remains unknown.It is known that the body's adaptive response to stress is a change in the activity of the endocrine system. The leading role in this is given to catechol amines and glucocorticoids, mobilized in significant quantities in blood under stress.We have found previously that incubation of frog sartorius muscle with hydrocortisone resulted in a decrease of contraction amplitude. However, when hydrocortisone was used in combination with ATP, its inhibitory effect on contractile responses disappeared. It is interesting that hydrocortisone had no effect on the inhibitory effect of adenosine. In the following experiments, assessing the effect of hydrocortisone on rat soleus muscle, it was established that hydrocortisone and purines had similar inhibitory effect. When ATP and hydrocortisone were given together the same oppression occurred. OBJECTIVE: To study the effects of ATP and adenosine on contraction parameters of rat skeletal muscle and assess the impact of the catechol amines on these processes. METHODS: Contractions of rat soleus muscles were recorded isometrically by mechanical sensor Linton FSG-01 (UK) according to standard procedures. The average of muscle parameters received within 30 seconds (30 responses) was treated as one result. Amplitude and time characteristics of the curve reductions were estimated. During all experiments standard Krebs solution flowed through the bath continuously to which agents were added at necessary concentrations. All experimental animals were maintained and prepared for dissection under the European Convention for the Protection of Vertebrate Animals used in scientific experiments. All agents used in the study were supplied by Sigma Chemical Company Ltd. (UK), Tocris Cookson and Research Biochemicals International (USA). RESULTS: The concentration of 100 MUM for adenosine is close to saturation [1], and for its predecessor ATP this concentration is created after the passage of a pulse through the synapse [2]. We used this concentration of purines to study the mechanism of action of adenosine and ATP on neuromuscular synapse.The effect of adenosine was partially inhibited in the presence of 100 MUM 8-SPT, an antagonist of adenosine receptors. The contraction force of "fast" and "slow" rat skeletal muscles was raised by half in the presence of norepinephrine. In the presence of norepinephrine adenosine exerted its effect fully, but ATP by half reduced its depressor effect on the contraction force of both muscles. CONCLUSIONS: 1. Norepinephrine increases half times of the reduction of "fast" and "slow" skeletal muscle.2. In the presence of norepinephrine, inhibitory effect of adenosine on contraction force is maintained.3. Inhibitory effect of ATP on contraction force of studied skeletal muscles becomes twice less pronounced in the presence of norepinephrine.We think that reduction of ATP depressive effect on the skeletal muscle by norepinephrine may be an adaptive response to acute stress. PMID- 26639726 TI - Approaching Evidence-Based Medicine. PMID- 26639727 TI - Pharmaceutical counseling: Between evidence-based medicine and profits. AB - BACKGROUND: The number of pharmacies, which produce drug formulations locally, has recently considerably reduced in Russia. Pharmacies mainly operate as retailers of industrially manufactured drugs.Pharmaceutical consultation of customers at pharmacies aimed at responsible self-medication is the most popular and accessible feature of pharmaceutical care. In Russia there is a significant list of medicines approved for sale in pharmacies on a non-prescription basis that is specified in the product label. In this regard, the role of pharmacists in public health in Russia increases. Pharmacist, working directly with population, is an important figure for the rational use of medicines. This type of work requires high level of professional training and appropriate ethics. OBJECTIVE: To explore the current status of pharmaceutical counseling in Russia. METHODS: Situation analysis, surveys of pharmacists. RESULTS: Our experience in the system of postgraduate professional education, the results of the survey of pharmacists, and the long-term dialogue with pharmacists allowed us to identify several unresolved issues in the work of a pharmacist selling non-prescription drugs.Lack of differentiation in the functions of a pharmacist with a higher education and pharmaceutical technologist: In production/industrial pharmacy technicians are engaged in manufacturing of pharmaceutical formulations. However, due to the loss of production functions technologists had to move away from production laboratories of apothecaries to the sales area. Currently, the apothecary's assignment to receive prescriptions and dispense medications can be fulfilled by either a pharmacist or a pharmaceutical technician. It significantly discerns the pharmacy from the medical organization with clearly delineated functions of doctors and nurses. Russian regulations should consider the level of education required for high-quality pharmaceutical counseling.Contradiction between the pharmacist's special functions and trade procedure with the lack of pharmaceutical counseling standards: Article 1.1 "Code of Ethics of the pharmaceutical worker of Russia" states: "The main task of the professional activity of the pharmaceutical worker - protection of human health", Article 1.3 states that a pharmaceutical worker must take professional decisions solely in the interests of a patient [1]. However, the pharmacy is a trade organization, thus as a retailer the pharmacy is directly interested in making profits and increasing sales of pharmaceutical products, including non-prescription medicines. Moreover, while the clinical medicine is monitored for unjustified prescribing and measures are being taken to prevent polypharmacy, for a pharmacist the growing sales of over-the-counter drugs, active promotion of dietary supplements, homeopathic medicines, medical devices, and, consequently, an increase of financial indicators (particularly "average purchase size") - all are characteristics of success [2].Rational use of over-the-counter medicines requires introduction of pharmaceutical counseling standards (pharmaceutical care) according to symptoms - major reasons to visit a pharmacy as part of responsible self-medication (cold, sore throat, headache, diarrhea, etc.). Standards of pharmaceutical counseling should be objective, reliable and up-to date and contain recommendations for the rational use of over-the-counter drugs as well as indications requiring treatment to the doctor. Standardization of pharmaceutical counseling in terms of Evidence-based Pharmacy would enhance the efficiency, safety and cost-effectiveness of over-the-counter medicines.Currently, the lack of clinical component in the higher pharmaceutical education and the lack of approved standards of pharmaceutical counseling lead to the introduction of cross-selling technologies (which are broadly applied in other areas of trade, for example, the offer of a boot-polish during the sale of shoes) to the pharmaceutical practice [2, 3]. However, drugs belong to a special group of products, proper selection of which requires special education, and the consumer is not always able to evaluate the quality of the recommendations. Marketing cross-selling recommendations are aimed at promotion of the over-the counter medicines for customers buying prescription drugs. For example, business coaches recommend the pharmacists to make additional offers: with the purchase of physician-prescribed antibiotics - offer of vitamins, with prescribed nonsteroidal anti-inflammatory drugs - commercially available ointment with non steroidal topical formulation ("to enhance the effect") and others. These recommendations do not agree with evidence-based medicine and lead to inefficient use of over-the-counter drugs and unjustified financial expenses. CONCLUSIONS: Thus, to ensure the rational use of medicines permitted for free (non prescription) dispensing at the pharmacies, pharmaceutical information needs standardization on the basis of evidence-based medicine as well as standardization of the pharmaceutical counseling service. The development of practical recommendations on the rational use of over-the counter medicines by doctors and pharmacists with further adoption at the state level, the recommendation of most secure, efficient and cost-effective over-the-counter medications during pharmaceutical counseling in pharmacies will contribute to the restoration and preservation of public health. PMID- 26639728 TI - Meta-analysis: Problems with Russian Publications. AB - BACKGROUND: Meta-analysis is a powerful tool to identify Evidence Based medical technologies (interventions) for use in every day practice. Meta-analysis uses statistical approaches to combine results from multiple studies in an effort to increase power (over individual studies), improve estimates of the size of the effect and/or to resolve uncertainty when reports disagree. Meta-analysis is a quantitative, formal study design used to systematically assess previous research studies to derive conclusions from this research. Meta-analysis may provide more precise estimate of the effect of treatment or risk factor for a disease, or other outcomes, than any individual study contributing to the pooled analysis.We have quite a substantial number of Russian medical publications, but not so many Meta-Analyses published in Russian. Russian publications are cited in English language papers not so often. A total of 90% of clinical studies included in published Meta-Analyses incorporate only English language papers. International studies or papers with Russian co-authors are published in English language. OBJECTIVE: The main question is: what is the problem with inclusion of Russian medical publications in Meta-Analysis? RESULTS: The main reasons for this are the following: 1) It is difficult to find Russian papers, difficult to work with them and to work with Russian journals:a. There are single Russian Biomedical Journals, which are translated into English and are included in databases (PubMed, Scopus and other), despite the fact that all of them have English language abstracts.b. The majority the meta-analyses authors use in their work different citation management software such as the Mendeley, Reference Manager, ProCite, EndNote, and others. These citation management systems allow scientists to organize their own literature databases with internet searches and have adds on for the Office programs what makes process of literature citation very convenient. The Internet sites of the majority of International Journals have built-in tools for saving citations to reference manager software. The majority of articles in Russian journals cannot be captured by citation management systems: they do not have special coding of articles descriptors.c. Some journals still have PDF files of the whole journal issue without dividing it into articles and do not provide any descriptors, making manual time-consuming input of information the only possibility. Moreover the context search of the article content is unavailable for search engines.2) The quality of research. This problem has been discussed for more than twenty years already. Still we have too many publications of poor quality of study design and statistical analysis. With the exception of pharmacological clinical tails, designed and supervised by international Pharma industry, many interventional studies, conducted in Russia, have methodological flaws inferring a high risk of bias:a. Absence of adequate control,b. No standard endpoints, duration of therapy and follow up,c. Absence of randomization and blinding,d. Low power of studies: sample sizes are calculated (if calculated at all) in such a way, that the main goal is to have as small sample size as possible. Very often statisticians have to solve the problem how to substantiate a small number of subjects, that sponsor could afford, instead of calculating the needed sample size to reach enough power.e. No standards of statistical analysis.f. Russian journals do not have standards for description and presentation of study results, in particular, results of statistical analysis (a reader even cannot see what is presented: standard deviation (SD) or standard error of the mean (SEM).We have a long standing experience in analysis of methodological and statistical quality of Russian biomedical publications and have found up to 80% publications with statistical and methodological errors and high risk of bias.In our practice, we had tried to perform two Meta-analyses for two local pharmaceutical products for prevention of stroke recurrence. For the first product, we did not found even two single Russian language studies suitable for the analysis (incomparable populations, different designs, endpoints, doses etc.). For the second product, only four studies had comparable populations and standard internationally approved scales for effectiveness analysis. However, the combinations of scales, the length of treatment and follow up differed widely, so that we could combine the results of only 2 or 3 studies for each end point. CONCLUSIONS: Russian researchers have to follow internationally recognised standards in study design, selection of endpoint, timelines and therapy regimens, data analysis and presentation of results. Russian journals need to develop consolidate rules for authors of clinical trials and epidemiological research of result reporting close to international standards. In this case the international Network EQUATOR (Enhancing the QUAlity and Transparency Of health Research http://www.equator-network.org/) is one to be taken into account. In addition, Russian Journals have to improve their online information for better interaction with search engines and citation managers. PMID- 26639729 TI - Acute kidney injury in neonatal intensive care: Medicines involved. AB - BACKGROUND: The incidence of acute kidney injury (AKI) in neonates in the intensive care units and neonatal intensive care (NICU) according Plotz et al. ranges from 8% to 22% [3]. According to Andreoli, neonatal death due to AKI in NICU amounts up to 10-61% [1]. It should be in the reasons of AKI emphasize.The role of certain drugs, which are widely used in modern neonatology: nonsteroidal anti-inflammatory drugs (NSAIDs), antibiotics (aminoglycosides, glycopeptides, carbapenems, 3rd generation cephalosporins), furosemide, enalapril, in contributing to AKI should be emphasized [2]. OBJECTIVE: To identify risk factors for acute kidney injury in neonates in intensive care units and intensive care. METHODS: We performed a prospective observational case-control study of full-term newborns who were treated in the intensive care unit and neonatal intensive care of the "Children's city hospital No1" Kazan and NICU No3 "Children's Republican Clinical Hospital" in 2011-2014 years.The study included 86 term infants in critical condition, who were hospitalized to the NICU on the first days of life, the main group. The main criterion of AKI in neonates according to neonatal AKIN classification (2011) is a serum creatinine concentration >=1.5 mg/dL. We subdivided the main group into two subgroups:subgroup I, AKI+ consisted of 12 term infants in critical condition with the serum creatinine level >= 1,5 mg/dL at the age of not younger than 48 hours after birth, which was 14% of all full term newborns who were at the NICU;subgroup II, AKI- consisted of 74 term infants in critical condition with the serum creatinine level <1.5 mg/dL at the age of not younger than 48 hours after birth.The control group was formed by random sampling, it consisted of 26 somatically healthy term infants. We used conventional methods for evaluating renal function, and enzyme immunoassay (ELISA) for the urine biomarker of AKI, IL-18.Statistical analysis was performed using SPSS, Statistics 20, and the IBM and Microsoft Office Excel 2007. The study results were subjected to statistical analysis using parametric and non parametric methods of analysis. We present the findings as arithmetic means (M) with, standard deviation (sigma) and standard error of the mean (m) according to standard formulas. RESULTS: All children were admitted to primary and emergency care with subsequent transfer to the NICU at 1-2 days of life and further treatment in the department of pathology of newborns (DPN). The duration of hospitalization of infants at the NICU for the main group averaged 5,9 +/- 0,44 days; at the DPN (subsequent stage of nursing) - 11,42 +/- 0,51 days; for the subgroup I, AKI+ newborns these were 7,83 +/- 1,23 days and 13,75 +/- 3,34 days, respectively; for the subgroup II, AKI- newborns these were 5,58 +/- 0,47 (3-30) and 11,04 +/- 0,3 (0-47) days, respectively. Neonates received daily average of 16,5 +/- 0,3 various medicines while at NICU and 9,1 +/- 0,7 while at DPN. Overall, over the entire period of hospitalization neonates of the main group received on average 25,6 +/- 1,8 medicines. Of these, 2,9 +/- 0,4 drugs were antibiotics, possessing nephrotoxic properties (aminoglycosides, cephalosporins, carbapenems, fluoroquinolones). Children of the main group in 100% (n = 86) of cases were treated with 3rd generation cephalosporins (ceftriaxone, cephaperazone/sulbactam (sulperazon)), in 55% od cases (n = 47) - with aminoglycosides (amikacin, gentamicin), in 1% (n = 1) - with vancomycin, in 7% (n = 6) - with carbapenems. Diuretics were prescribed to 57% (n = 49) of infants. Often, patients were treated with a combination of nephrotoxic medications. Aminoglycoside were prescribed statistically more often to neonates of the subgroup I, than of the subgroup II (p <0.01). Diuretic drugs were used more frequently and for longer periods of time in neonates of the subgroup I (AKI+), than in newborns of the subgroup II (AKI-), namely, in 83% (n = 10) for 4,6 +/- 1.34 days versus 53% of cases (n = 39) for 2.84 +/- 0.49 days, respectively (p <0.05). IL-18 urine level in neonates of subgroup I (AKI+) was 2 times higher than that in neonates of the subgroup II (AKI-), and 13 times higher than in neonates of the control group.The fact that the IL-18 urine level increased with progression of kidney damage, caused by nephrotoxic therapy, suggests that a significant role in the development and progression of AKI in neonates at NICU belongs to drug therapy. CONCLUSIONS: Full-term newborns in intensive care units are at high risk of AKI when they are treated with aminoglycosides in combination with diuretics for longer than 4.5 days. PMID- 26639730 TI - Clinical conferences for physicians: Who sets the agenda? AB - BACKGROUND: Clinical conferences are generally defined as scheduled events at which practicing physicians themselves present to their colleagues interesting clinical cases, share their new experiences and learn about the latest achievements of medical science and practice. The value of a clinical conference is thought to be in direct communication between physicians, in analysis of topical issues in a given specialty with the aim to improve the quality of care. Speakers based on their own observations and studies reveal the most urgent problems, analyze results and offer potential decisions to their colleagues interested in the same questions. The event format may be different: workshops, highly specialized sections, round tables and seminars with participation of the leading specialists in a given field. These conferences are generally organised by the Ministries and Departments of Health, by leading research and/or educational institutions in the field, by recognised medical centres and other institutions. Recently pharmaceutical companies got actively involved in medical events, acting as sponsors of various scientific conferences and congresses, however threatening the mission of these events [1]. This brings up some uneasy questions: who are the medical conferences for? Who is in charge of setting the conference agenda? Do they contribute to evidence-based medicine; do they contribute to better health? Unfortunately, there is a trend to duplication or multiplication of conferences: various agencies and departments deliver the same conferences, presentations at which are often pre-arranged by pharmaceutical companies and do not have clear scientific novelty, while the conferences themselves have largely transformed into advertising of new pharmaceuticals or new technologies [2]. Pharmaceutical corporations sponsor invited speakers paying for their trips and paying honoraria, organising cocktail parties as part of medical activities. With the help of leading experts with impressive titles serving as speakers at the conferences, pharmaceutical companies are trying to be as close as possible to routine practice of prescribing of certain drugs, manipulating evidence, controlling scientific societies as well as the process of clinical guideline development and publication of research results [3]. The degree of expert involvement depends on their level of influence [4]. OBJECTIVE: We aimed to study how often regular medical practitioners attend these conferences; to analyse who were keynote speakers and where they were coming from; to identify which organizations were responsible for organisation of these conferences and for sending out invitations to these conferences and for disseminating information about them. METHODS: We summarized all the invitations (printed on paper) received by one regular medical practitioner employed with the outpatient clinical of the city of Kazan for the period of two years (2012-2013). RESULTS: During the study period (2012-2013), a regular medical practitioner received 47 printed paper invitations to scientific conferences: 22 in 2012 and 25 in 2013. The conferences were not distributed evenly over the months of the years. November appeared to be the month with the highest density/number of medical conferences: 7 conferences in 2012 and 10 in 2013. If the distribution was even, then we could calculate the number per month dividing the number per year by 9 active months (excluding July, August and September). This resulted in 2.4 and 2.8 conferences per month. Among these studied conferences 4 were organized by public health agencies: invitation tickets were accompanied by the corresponding official order to organise a conference, issued by the Health Department. Noteworthy, that 2 of these conferences were held in conference rooms of the largest hotels of the city. Forty-one out of 47 medical conferences were sponsored by big pharma: either jointly with the major medical higher educational institutions of the city or plainly by pharmaceutical companies. Seventeen conferences were held during official working hours, in the first half of the day. Not only the logo of the pharmaceutical companies was printed on invitation tickets, but there was also an advert of the promoted pharmaceutical brand.Nine conference invitations contained invitation to dinner. In one of the invitations to a conference on neuroscience it was written: "dinner under the unforgettable music". Two conference invitations contained invitation to a lunch. Programs of 20 conferences (which were included) listed guest lecturers, coming from the leading medical universities in Moscow and St. Petersburg. Opinion leaders' involvement: some of the leading experts acted as speakers from 4 to 7 conferences a month in this sample conference invitations package of a regular polyclinic physician. CONCLUSIONS: In 2012-2013 health practitioners were invited to attend medical conferences regularly, at least 2 times a month, with November being the busiest month. The keynote speakers were the opinion leaders from the local medical educational institutions and visitors from Moscow and St. Petersburg; their involvement with the conferences was repetitive. Governmental institutions jointly with big pharma were responsible for organisation of these conferences and attracting audience.Limitations of these observations:Unfortunately, the information on printed-paper conference invitations was not complete because not all tickets have survived. From the interview with the physician we know that in addition to these printed on paper invitations there were many invitations and alerts sent out by e-mail, SMS messages and personal phone calls, making the regularity of these conferences much higher. The physician, who kindly provided this information to us, asked not to be named or thanked in any public presentation of the results of these analyses. PMID- 26639731 TI - Quality of postgraduate medical education. AB - BACKGROUND: In recent years, huge efforts to improve quality control process and efficiency of healthcare were put in advancing health systems in Russia. There are measurable and noteworthy achievements, there are unresolved issues.It's impossible to manage the process of improving the quality and efficiency of care without high-quality training of respective troops. However, in the last decade a phrase about the poor quality of postgraduate medical education has been heard periodically in the speeches of the leaders at various levels. The source is unknown, but this information continues to be spread by word of mouth as a regular component of speeches about health issues. Considering that the "poor quality" of postgraduate education has not been substantiated by solid evidence, this informational spam, of course, needs to be overcome. It is not only harmful to health system overall, it is harmful in particular for the process of formation of personnel reserve, but it also discredits the whole system of postgraduate education and a titanic work of thousands of teachers, who work as enthusiasts, most of them performing valuable research, teaching and organizational work. OBJECTIVE: To provide situation analysis in the field of postgraduate medical education. RESULTS: First of all, it begs the question - how and who measures the quality of education. What indicators in the evaluation process are key? As a rule, when assessing quality in any field, preference is given to the opinion of the consumer.Our direct customers are the heads of health organs and institutions who regularly undergo advanced training in the specialty "Public Health and Health Care" at sub-faculty. After the completion of each cycle of training and exams, each participant fills out a questionnaire, which points out the level of quality of pedagogical activity of the sub-faculty. The analysis of these questionnaires shows that the students generally give high assessment of the quality of pedagogical process. The health authorities of subjects of Russia that send the heads of their subordinate medical organizations to study public health and healthcare are satisfied with the work of sub-faculty, professorial teaching staff, they send thank-you letters to the educational organization.In this regard, natural questions related to the overall methodology for the assessment of the quality of education in the system of postgraduate training of doctors arise, which today is still very insufficiently developed.The quality of education in the system of continuous medical education of physicians can be assessed in the following levels with the help of quality indicators, which have to be developed appropriately for each particular level. In our opinion, the following levels should be included:1)The level of the sub faculty2)The level of the faculty3)The level of the medical organization4)The level of the territorial health authority5)The level of the subject of the federation. CONCLUSIONS: Multidimensional assessment of the results of evaluation in the mentioned levels will allow providing an integrated assessment system of quality of continuous medical education in the country. PMID- 26639732 TI - Evidence-based medicine Training: Kazakhstan experience. AB - BACKGROUND: Understanding principles of evidence-based medicine is of vital importance for improving quality of care, promoting public health and health system development. Understanding principles of evidence-based medicine allows using the most powerful information source, which have ever existed in medicine. OBJECTIVE: To evaluate the effectiveness of teaching Evidence-Based Medicine, including long-term outcomes of training. METHODS: The study was conducted at the Medical University of Astana, where the Scientific and Educational Center of Evidence-Based Medicine was established in 2010 with the help of the corresponding project of the World Bank. The participants of the study were the faculty trained in Evidence-Based Medicine at the workshop "Introduction to Evidence-Based Medicine" for the period of 2010-2015 years. There were a total of 16 workshops during the period, and 323 employees were trained. All participants were asked to complete our questionnaire two times: before the training - pre training (to determine the initial level of a listener) and after the training - post-training (to determine the acquired level and get the feedback). Questionnaires were prepared in such a way, that the majority of questions before and after training were identical. Thus, it provided a clear picture of the effectiveness of training. Questions in the survey were open-ended so that the respondents had the opportunity to freely and fully express their views. The main part of the questionnaires included the following questions: "Do you understand what evidence-based medicine is", "how do you understand what the study design means", "what is randomization", "how research is classified", "do you know the steps of decision-making according to Evidence-Based Medicine, list them", "what literature do you prefer to use when searching for information (print, electronic, etc.)", "what resources on the Internet do you prefer to use". RESULTS: Only 30-35% of respondents gave correct answers to the questions on understanding EBM, understanding study designs, randomization. There were no correct or complete answers to the question on study classification. Again, 35% of respondents provided correct answer to the question about the stages of decision-making process from the perspective of EBM, 65% - provided no answer. One fourth (25%) of the respondents preferred using printed literature. Only very few respondents indicated Cochrane Library, Medline (PubMed), Tripdatabasa as preferred Internet sources of information, with 40% indicating Google and 60% - other sources.The results of post-training survey showed that nearly 90% of the respondents gave correct answers to all the questions.With the aim to identify knowledge survival (the long-term training outcomes) we conducted the third survey in May 2014 in previously trained people at the seminar "Introduction to Evidence-Based Medicine". The respondents were asked to answer 4 questions, and to assess previously obtained information on the basics of Evidence-Based Medicine on a 10-point scale.We found that 100% of the respondents answered "Yes" to the question: "Have you changed your behavior after the seminar?" To the question: "Have you encountered difficulties in implementing the principles of evidence-based medicine in the educational process?" 56% of the respondents answered that they had not encountered any difficulties. The other 44% faced the difficulties associated with implementation of Evidence-Based Medicine: lack of understanding by students, low knowledge survival rate among students, too many questions from the students, difficult disputes and discussions.To the question: "Have you encountered difficulties in implementing the principles of Evidence Based Medicine in practical health-care?" only 37.5% of the respondents answered that they had not encountered difficulties. But the remaining 62.5% of the respondents faced the problems and difficulties in implementing the principles of evidence-based medicine in their practice. These were: failure in implementing, lack of understanding on the part of colleagues, commitment to traditional obsolete methods of treatment, discrepancy between some of the existing standards of diagnosis and treatment and principles of evidence-based medicine.To the question: "Are there any end products after listening to the seminar?" 67% of the respondents answered in affirmative. The end products were mainly marked by the publication of articles and abstracts, including international publications, and participation in the working group on the revision and development of clinical protocols. CONCLUSIONS: Barriers to implementation of Evidence-Based Medicine in education and practice are lack of funding to provide access to reliable sources of information, websites; outdated research methodology skills in medical education, lack of skills in critical evaluation of medical information; tradition of authoritarian relationships, use of past experience stencils; failure to comply with continuing education programs ("from training to professional development"). Knowledge of Evidence-Based Medicine, skills to perform searches for scientific data, to evaluate their validity and to transform scientific data into practical solutions are necessary for health workers in their daily activities. This culture needs to be rooted in modern medical education. PMID- 26639733 TI - Evidence-based pharmacogenetics: Is it possible? AB - BACKGROUND: For improving quality, safety and efficiency of care, health systems perform a paradigm change towards personalized medicine, also referred to as genomic medicine. It uses combined knowledge (genomics, transcriptomics, proteomics, metabolomics) about a person to predict disease susceptibility, disease prognosis or treatment response and thereby to improve the person's health. The last decade has witnessed a steady embrace of personalized medicine by senior government officials, industry leadership and health care providers [1]. On the 12th December of 2013 Russian President Vladimir Putin in his annual address to the Federal Assembly said: "The Ministry of Health and the Russian Academy of Sciences must give priority to fundamental and applied research in medicine, including genomic studies" [2]. A year earlier, in 2012 the Ministry of Health of the Russian Federation, headed by Veronika Skvortsova established the strategy of personalized medicine development in Russia [3]. But still a lot of work is focused on using clinical research findings to aid the delivery of optimum clinical care to patients. Pharmacogenetic testing (using genetic information to guide drug therapy) is an actively developing field of personalized medicine and its current state indicates that it can be usefully introduced into clinical practice in the nearest future. In Russia pharmacogenetic testing is already used for personalizing prescription of certain drugs [4]. OBJECTIVE: To assess the extent of genetic testing use for improving use of medicines. METHODS: PubMed and E-Library searches for the period of 2004 2015. RESULTS: The number of publications retrieved in PubMed search for the term "pharmacogenetics" for 2004 year was 538 and was more than 15500 publications for 2015. 800 Russian-language publications in total were retrieved using a domestic scientific database E-Library search for the term "pharmacogenetics" for 2015 year. The sharp rise in the number of publications (including Russia) reflects growing interest not only among scientists, but also among practitioners. However evidence that is actually available on some key topics may not be of sufficiently high quality to support confident conclusions. As a rule, retrospective cohort studies, also known as historical cohort studies, are carried out. The number of randomized, prospective studies is not large, though in recent years, there has been an increase in their number. However, surrogate outcomes are commonly used in the mentioned studies as trial end points. The main reason for this is the lack of sponsorship. Quite often studies are not interesting for pharmaceutical companies and are carried out within the confines of the small grants. Nevertheless, systematic reviews and meta-analyses of some pharmacogenetic tests provide the high level of evidence (pharmacogenetic testing for clopidogrel, abacavir and antineoplastic drugs) so they appear even in clinical guidelines with the evidence level IIb. It is important to mention that for certain drugs FDA has already approved pharmacogenetic testing [5]. CONCLUSIONS: Evidence is often inconsistent. This leads to the fact that clinical use of pharmacogenetic testing seems to be most appropriate for the management of patients with high risk of adverse drug reactions. PMID- 26639734 TI - Effects of balance training on post-sprained ankle joint instability. AB - BACKGROUND: Ankle sprain is a medical condition when ankle ligaments are totally or partially torn. The primary cause of ankle sprain is sharp movements like turning or rolling the foot [1]. The ankle sprain needs to be treated right after the trauma, because if not treated it could lead to decreased stability of the ankle joint and lead to chronic ankle instability, which is characterized by increased risk of the ankle sprain [2] . We suppose that rehabilitation after the ankle sprain could significantly increase the performance of sportsmen. OBJECTIVE: To investigate effects of balance exercise training on instable ankle due to the previous ankle sprain injury. In addition, the secondary aim of this systematic review was to find the effectiveness of different balance training exercises on instable ankle in order to find better opportunities for rehabilitation of sportsmen. METHODS: The studies were selected from PubMed and Scopus using the library of the Friedrich-Alexander University of Erlangen Nuremberg (further-UB FAU), we used full texts, and only texts in English were included in this review. The literature search was conducted at the end of December 2014. Texts included randomised controlled trials, which were published in the last 5 years (2009-2014). The literature was included in this review only if it was published in English and if the randomised controlled trial was conducted in the study and if the full text was available from UB FAU. The articles, which were found only in PubMed search, were excluded during Scopus search.PubMed search.First MeSH term was "Balance training for the ankle sprain" and 44 articles were found in PubMed. Then 29 articles were filtered by title and excluded from the study. Remaining 15 articles were assessed reading their abstracts, 6 of them were excluded and only 4 articles were left. The second MeSH term was "Balance training for ankle injury". Four additional articles were found by initial search. Two of them were filtered by the title and 2 were excluded at the stage of reading abstracts. The third MeSH term was "Balance exercises for instable ankle". One additional article was found by initial search and was excluded after reading the abstract.Scopus search.The same MeSH terms were used as in PubMed search. With the first MeSH term one article was found and filtered by the title. With the second MeSH term no results were found in the initial search and with the third term 2 articles were picked up by the initial search. One of these articles was filtered by the title. The other one was filtered after reading the abstract. Overall 8 articles were taken into consideration for conducting a systematic review. Nevertheless, three of them could not be downloaded for free even using UB FAU up to the 28th of December, 2014. Thus, five articles were taken for the systematic review. After reading all 5 articles, one article by Maraike Alice Wortmann and Carrie L. Docherty was excluded from the study because it was a systematic review per se and at the same time it was not mentioned neither in the article title, nor in the abstract that the current study was a systematic review [3]. Also the article by Borreani et al. 2014 [4] was excluded after reading the paragraph "Methods" as this was not an RCT but a descriptive study. Therefore, 3 articles were taken for conducting a systematic review. RESULTS: The first article by Janssen et al. 2011 [5] was a 3-way randomised controlled trial with 1 year follow-up. Participants aged from 12 to 70 years used this intervention. People with active participation in sports with a lateral ankle sprain during the last 2 months were eligible for inclusion in the study. Participants were divided into 3 groups. Group 1 undertook an 8 week neuromuscular training programme. Group 2 wore sports brace during their sport activities for the duration of 1 year, and group 3 was a control group and used the combination of neuromuscular training program and wore sports brace for 8 weeks. There were 122 participants in the neuromuscular training group, 126 in the brace group and 136 in combined group. The drawback of this intervention was that there was no control over the care provid.In the second study by Ben Moussa Zouita, A et al. 2013 [6] the objective was to investigate how the proprioceptive exercises effect the postural balance and isokinetic strength in athletes with ankle sprain. 16 participants were recruited in the study and divided into two groups. The experimental group consisted of 8 participants with unilateral ankle sprain symptoms. The control group included another 8 participants with bilateral non-injured ankles. The training programme included 24 sessions during 8 weeks, every session lasted between 20 and 30 minutes. Four prescribed exercises were used during the intervention: one exercise without any material, one exercise with a ball only, one exercise with a balance board only and one exercise with a ball and a balance board. As a result, after 8 weeks of proprioceptive rehabilitation a significant improvement in extensor and flexor strength of ankle at a speed of 60-deg/sec was registered.The third study by Emery, Meeuwisse 2010 [7] was aimed to examine the effectiveness of the neuromuscular prevention strategy in youth soccer players. The inclusion criteria were adolescents between 13 and 18 years of age. The exclusion criteria were injury within 6 weeks and the history of systemic disease in anamnesis (i.e. cerebral palsy, head injury). 82 soccer teams were invited to take part in the intervention. 12 trainers declined the invitation, other 10 teams declined participation. Overall 60 teams took part in the intervention programme. The teams were randomised by a club. 32 training group teams (n = 380 players) and 28 control group players (n = 364 players) took part in the intervention. The training programme included dynamic stretching exercises, agility, jumping and balance and eccentric strength. The control programme was a standardized warm-up including static, dynamic and aerobic components and home-based stretching programme using 16-inch diameter wobble board used for 15 minutes during exercises. The injury rate in the training group was 2.08 injuries/1000 player-hours, and in the control group 3.35 injuries/1000 player-hours. The neuromuscular training programme was protective in injuries of youth soccer players. CONCLUSIONS: Balance training is an effective training method for rehabilitation of instable ankle. Different approaches to balance training provide in general similar improvement for sprained ankle.Implications for future studies:More RCTs on chronic ankle instability are needed with large sample size and use of different intensities of exercises. It would be better for the UB FAU to provide access to articles so that students and researches could download articles for free from different electronic sources. PMID- 26639735 TI - Health-related quality of life in patients with primary open-angle glaucoma. An Italian multicentre observational study. AB - PURPOSE: As a progressive condition, glaucoma may impair health-related quality of life (HRQoL), due to vision loss and other factors. This study evaluated HRQoL in a cohort of patients treated for primary open-angle glaucoma (POAG) and assessed its association with clinical features. METHODS: This was an Italian, multicentre, cross-sectional, observational study with the subgroup of newly diagnosed patients with POAG prospectively followed up for one year. Patients with previous or new diagnosis (or strong clinical suspicion) of POAG aged >18 years were considered eligible. Information was collected on demographic characteristics, medical history, clinical presentation and POAG treatments. HRQoL was measured using the 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) and Glaucoma Symptom Scale (GSS). Subscale and total scores were obtained and a Pearson correlation coefficient between instruments' scores calculated. RESULTS: A total of 3227 patients were enrolled from 2012 to 2013 and 3169 were analysed. Mean age was 66.9 years. A total of 93.8% had a previous diagnosis (median duration: 8.0 years). Median values for mean deviation and pattern standard deviation were 3.9 and 3.6 dB, respectively. Mean scores on most subscales of the NEI-VFQ-25 exceeded 75.0 and mean GSS subscale scores ranged between 70.8 and 79.7 (with a total mean score of 74.8). HRQoL scores on both scales were significantly inversely associated with POAG severity. CONCLUSION: In this large sample of Italians treated for POAG, disease severity was limited and HRQoL scores were high. QoL decreased with advancing disease severity. These findings confirm the role of vision loss in impairing QoL in POAG, underlying the importance of timely detection and appropriate treatment. PMID- 26639737 TI - Body adiposity and bone parameters of male rats from mothers fed diet containing flaxseed flour during lactation. AB - Obesity and osteoporosis may have their origins in early postnatal life. This study was designed to evaluate whether flaxseed flour use during lactation period bears effect on body adiposity and skeletal structure of male rat pups at weaning. At birth, male Wistar rats were randomly assigned to control and experimental (FF) groups, whose dams were treated with control or flaxseed flour diet, respectively, during lactation. At 21 days of age, pups were weaned to assess body mass, length and composition by dual-energy X-ray absorptiometry. The animals were then sacrificed to carry out analysis of serum profile, intra abdominal adipocyte morphology and femur characteristics. Differences were considered significant when P<0.05. The FF group displayed the following characteristics (P<0.05): higher body mass, length, bone mineral content, bone area and concentrations of osteoprotegerin, osteocalcin and high-density lipoprotein cholesterol; higher levels of stearic, alpha-linolenic, eicosapentaenoic and docosapentaenoic acids and lower levels of arachidonic acid and cholesterol; smaller adipocyte area; and higher mass, epiphysis distance, diaphysis width, maximal load, break load, resilience and stiffness of femur. Flaxseed flour intake during lactation period promoted adipocyte hypertrophy down regulation and contributed to pup bone quality at weaning. PMID- 26639736 TI - Liver natural killer cells: subsets and roles in liver immunity. AB - The liver represents a frontline immune organ that is constantly exposed to a variety of gut-derived antigens as a result of its unique location and blood supply. With a predominant role in innate immunity, the liver is enriched with various innate immune cells, among which natural killer (NK) cells play important roles in host defense and in maintaining immune balance. Hepatic NK cells were first described as 'pit cells' in the rat liver in the 1970s. Recent studies of NK cells in mouse and human livers have shown that two distinct NK cell subsets, liver-resident NK cells and conventional NK (cNK) cells, are present in this organ. Here, we review liver NK cell subsets in different species, revisiting rat hepatic pit cells and highlighting recent progress related to resident NK cells in mouse and human livers, and also discuss the dual roles of NK cells in liver immunity. PMID- 26639738 TI - Structural Factors of the Middle East Respiratory Syndrome Coronavirus Outbreak as a Public Health Crisis in Korea and Future Response Strategies. AB - The recent Middle East respiratory syndrome coronavirus (MERS-CoV) outbreak has originated from a failure in the national quarantine system in the Republic of Korea as most basic role of protecting the safety and lives of its citizens. Furthermore, a number of the Korean healthcare system's weaknesses seem to have been completely exposed. The MERS-CoV outbreak can be considered a typical public health crisis in that the public was not only greatly terrorized by the actual fear of the disease, but also experienced a great impact to their daily lives, all in a short period of time. Preparedness for and an appropriate response to a public health crisis require comprehensive systematic public healthcare measures to address risks comprehensively with an all-hazards approach. Consequently, discussion regarding establishment of post-MERS-CoV improvement measures must focus on the total reform of the national quarantine system and strengthening of the public health infrastructure. In addition, the Korea Centers for Disease Control and Prevention must implement specific strategies of action including taking on the role of "control tower" in a public health emergency, training of Field Epidemic Intelligence Service officers, establishment of collaborative governance between central and local governments for infection prevention and control, strengthening the roles and capabilities of community-based public hospitals, and development of nationwide crisis communication methods. PMID- 26639739 TI - Implementation of Quaternary Prevention in the Korean Healthcare System: Lessons From the 2015 Middle East Respiratory Syndrome Coronavirus Outbreak in the Republic of Korea. AB - Quaternary prevention should be implemented to minimize harm to patients because the ultimate goal of medicine is to prevent disease and promote health. Primary care physicians have a major responsibility in quaternary prevention, and the establishment of clinical epidemiology as a distinct field of study would create a role charged with minimizing patient harm arising from over-medicalization. PMID- 26639740 TI - Costly Lessons From the 2015 Middle East Respiratory Syndrome Coronavirus Outbreak in Korea. AB - Since the Middle East respiratory syndrome (MERS) outbreak in the Republic of Korea (hereafter Korea) began on May 11, 2015, a total of 186 persons have been infected by the MERS coronavirus, 38 of whom have died. With this number, Korea becomes second only to the Kingdom of Saudi Arabia in the ranking of cumulative MERS cases. In this paper Korea's unique experience of an outbreak of MERS will be summarized and discussed briefly. PMID- 26639741 TI - A New Measure for Assessing the Public Health Response to a Middle East Respiratory Syndrome Coronavirus Outbreak. AB - Contact monitoring is an essential component of the public health response to a Middle East respiratory syndrome coronavirus outbreak, and is required for an effective quarantine to contain the epidemic. The timeliness of a quarantine is associated with its effectiveness. This paper provides a conceptual framework to describe the process of contact monitoring, and proposes a new measure called the "timely quarantined proportion" as a tool to assess the adequacy of a public health response. PMID- 26639742 TI - Hormonal Replacement Therapy and the Risk of Lung Cancer in Women: An Adaptive Meta-analysis of Cohort Studies. AB - OBJECTIVES: Approximately 10% to 15% of lung cancer cases occur in never-smokers. Hormonal factors have been suggested to lead to an elevated risk of lung cancer in women. This systematic review (SR) aimed to investigate the association between hormonal replacement therapy (HRT) and the risk of lung cancer in women using cohort studies. METHODS: We first obtained previous SR articles on this topic. Based on these studies we made a list of refereed, cited, and related articles using the PubMed and Scopus databases. All cohort studies that evaluated the relative risk of HRT exposure on lung cancer occurrence in women were selected. Estimate of summary effect size (sES) with 95% confidence intervals (CIs) were calculated. RESULTS: A total of 14 cohort studies were finally selected. A random effect model was applied due to heterogeneity (I-squared, 64.3%). The sES of the 14 articles evaluating the impact of HRT exposure on lung cancer occurrence in women indicated no statistically significant increase in lung cancer risk (sES, 0.99; 95% CI, 0.90 to 1.09). CONCLUSIONS: These results showed that HRT history had no effect on the risk of lung cancer in women, even though the sES of case-control studies described in previous SR articles indicated that HRT had a protective effect against lung cancer. It is necessary to conduct a pooled analysis of cohort studies. PMID- 26639743 TI - Determinants of Poor Self-rated Health in Korean Adults With Diabetes. AB - OBJECTIVES: Self-rated health is a measure of perceived health widely used in epidemiological studies. Our study investigated the determinants of poor self rated health in middle-aged Korean adults with diabetes. METHODS: A cross sectional study was conducted based on the Health Examinees Study. A total of 9759 adults aged 40 to 69 years who reported having physician-diagnosed diabetes were analyzed with regard to a range of health determinants, including sociodemographic, lifestyle, psychosocial, and physical variables, in association with self-rated health status using multivariate logistic regression models. A p value <0.05 was considered to indicate statistical significance. RESULTS: We found that negative psychosocial conditions, including frequent stress events and severe distress according to the psychosocial well-being index, were most strongly associated with poor self-rated health (odds ratio [OR](Frequent stress events), 5.40; 95% confidence interval [CI], 4.63 to 6.29; OR(Severe distress), 11.08; 95% CI, 8.77 to 14.00). Moreover, younger age and being underweight or obese were shown to be associated with poor self-rated health. Physical factors relating to participants' medical history of diabetes, such as a younger age at diagnosis, a longer duration of diabetes, insulin therapy, hemoglobin A1clevels of 6.5% or more, and comorbidities, were other correlates of poor reported health. CONCLUSIONS: Our findings suggest that, in addition to medical variables, unfavorable socioeconomic factors, and adverse lifestyle behaviors, younger age, being underweight or obese, and psychosocial stress could be distinc factors in predicting negative perceived health status in Korean adults with diabetes. PMID- 26639744 TI - A 9-year Trend in the Prevalence of Allergic Disease Based on National Health Insurance Data. AB - OBJECTIVES: To investigate trends in the prevalence of allergic disease over a 9 year period. METHODS: Using National Health Insurance Service (NHIS) data, the annual number of patients with allergic disease was obtained for each regional subdivisions (small cities, counties, and districts) from 2003 to 2011. Annual populations for each sub-region were obtained and used to calculate the standardized prevalence. To compare prevalence within the study period, data was standardized spatially and temporally. For standardization, demographic data was used to obtain the registered population and demographic structure for 2010, which was used to perform direct standardization of previous years. In addition, a geographic information system (GIS) was used to visualize prevalence for individual sub-regions, and allergic diseases were categorized into five groups according to prevalence. RESULTS: The nationwide outpatient prevalence of allergic rhinitis increased approximately 2.3-fold, from 1.27% in 2003 to 2.97% in 2013, while inpatient prevalence also increased approximately 2.4-fold,. The outpatient prevalence of asthma increased 1.2-fold, and inpatient prevalence increased 1.3-fold. The outpatient prevalence of atopic dermatitis decreased approximately 12%, and inpatient prevalence decreased 5%. CONCLUSIONS: There was a large difference between prevalence estimated from actual treatment data and prevalence based on patients' self-reported data, particularly for allergic rhinitis. Prevalence must continually be calculated and trends should be analyzed for the efficient management of allergic diseases. To this end, prevalence studies using NHIS claims data may be useful. PMID- 26639745 TI - The Relationship of Socioeconomic and Behavioral Risk Factors With Trends of Overweight in Korea. AB - OBJECTIVES: Previous studies have shown that overweight (including obesity) has increased significantly in Korea in recent decades. However, it remains unclear whether this change has been uniform among all Koreans and to what extent socioeconomic and behavioral factors have contributed to this increase. METHODS: Changes in overweight were estimated using data from the 1998, 2001, 2005, 2007 2009, and 2010-2012 Korea National Health and Nutrition Examination Survey (n=55 761). RESULTS: Overweight increased significantly among men but not among women between 1998 and 2012. Changes in socioeconomic and behavioral factors over the time period were not associated with overall trends for both men and women. However, we found significant differences in the prevalence of overweight relative to key risk factors. For men, overweight increased at a significantly greater rate among the non-exercising (predicted probability [PP] from 0.23 to 0.32] and high-calorie (PP from 0.18 to 0.37) groups compared to their active and lower-calorie counterparts, respectively. For women, overweight increased only among the non-exercising (PP from 0.27 to 0.28) and low-income (PP from 0.31 to 0.36) groups during this period. CONCLUSIONS: These findings suggest that programs aimed at reducing overweight should target Korean men and women in specific socioeconomic and behavioral risk groups differentially. PMID- 26639746 TI - Factors Determining Children's Private Health Insurance Enrolment and Healthcare Utilization Patterns: Evidence From the 2008 to 2011 Health Panel Data. AB - OBJECTIVES: Parental socioeconomic status (SES) exerts a substantial influence on children's health. The purpose of this study was to examine factors determining children's private health insurance (PHI) enrolment and children's healthcare utilization according to PHI coverage. METHODS: Korea Health Panel data from 2011 (n=3085) was used to explore the factors determining PHI enrolment in children younger than 15 years of age. A logit model contained health status and SES variables for both children and parents. A fixed effects model identified factors influencing healthcare utilization in children aged 10 years or younger, using 2008 to 2011 panel data (n=9084). RESULTS: The factors determining children's PHI enrolment included children's age and sex and parents' educational status, employment status, and household income quintile. PHI exerted a significant effect on outpatient cost, inpatient cost, and number of admissions. Number of outpatient visits and total length of stay were not affected by PHI status. The interaction between PHI and age group increased outpatient cost significantly. CONCLUSIONS: Children's PHI enrolment was influenced by parents' SES, while healthcare utilization was affected by health and disability status. Therefore, the results of this study suggest disparities in healthcare utilization according to PHI enrollment. PMID- 26639747 TI - Current Status of Infection Prevention and Control Programs for Emergency Medical Personnel in the Republic of Korea. AB - OBJECTIVES: Emergency medical personnel (EMPs) are pre-hospital emergency responders who are at risk of exposure to infections and may also serve as a source for the transmission of infections. However, few studies of infection control have specifically addressed EMPs in the Republic of Korea (hereafter Korea). The goal of this study was to assess the current status of infection prevention and control programs (IPCPs) for EMPs in Korea. METHODS: A cross sectional survey was conducted to quantitatively assess the resources and activities of IPCPs. A total of 907 EMPs in five metropolitan cities completed a structured questionnaire from September 2014 to January 2015. The data were analyzed using descriptive statistics, multi-response analysis, and the chi square test. RESULTS: The mean age of the participants was 34.8+/-15.1 years. IPCPs were found to have weaknesses with regard to the following resources: the assignment of infection control personnel (ICP) (79.5%), hand hygiene resources such as waterless antiseptics (79.3%), the use of paper towels (38.9%), personal protective equipment such as face shields (46.9%), and safety containers for sharps and a separated space for the disposal of infectious waste (10.1%). Likewise, the following activities were found to be inadequately incorporated into the workflow of EMPs: education about infection control (77.5%), post exposure management (35.9%), and the decontamination of items and spaces after use (88.4%). ICP were found to have a significant effect on the resources and activities of IPCPs (p<0.001). The resources and activities of IPCPs were found to be significantly different among the five cities (p<0.001). CONCLUSIONS: IPCPs for EMPs showed some limitations in their resources and activities. IPCPs should be actively supported, and specific IPCP activities for EMPs should be developed. PMID- 26639748 TI - Relationship between left ventricular diastolic function and myocardial sympathetic denervation measured by (123)I-meta-iodobenzylguanidine imaging in Anderson-Fabry disease. AB - PURPOSE: Whether cardiac sympathetic nervous function abnormalities may be present in patients with Anderson-Fabry disease (AFD) remains unexplored. We investigated the relationship between left ventricular (LV) function and cardiac sympathetic nervous function in patients with AFD. METHODS: Twenty-five patients (12 men, mean age 43 +/- 13 years) with genetically proved AFD and preserved LV ejection fraction and ten age and gender-matched control subjects underwent speckle tracking echocardiography and (123)I-meta-iodobenzylguanidine (MIBG) imaging from which early and late heart to mediastinum (H/M) ratios and myocardial washout rate values were calculated. RESULTS: In AFD patients, a significant correlation between late H/M ratio and LV mass index (r = -61, p = 0.001), left atrial volume (r = -0.72, p < 0.001), systolic pulmonary artery pressure (r = -0.75, p < 0.001), and early diastolic untwisting rate (r = -0.66, p < 0.001) was found. Ten AFD patients exhibited a late H/M ratio below two fold standard deviation of control subjects (<=1.75). Patients showing late H/M ratio <= 1.75 had significantly higher LV mass index, relative wall thickness, left atrial volume and systolic pulmonary artery pressure, lower systolic longitudinal strain and an early diastolic untwisting rate compared to patients with late H/M ratio > 1.75. At multivariable linear regression analysis, early diastolic untwisting rate was the only independent predictor of late H/M ratio <= 1.75 (odds ratio 1.15, 95 % confidence interval 1.07-1.31, p < 0.05). CONCLUSION: The present findings provide the first demonstration of a cardiac sympathetic derangement in AFD patients with preserved LV ejection fraction, which is mostly related to LV diastolic dysfunction. PMID- 26639749 TI - Self-Reported Prevalence and Risk Factors for Shaking and Smothering Among Mothers of 4-Month-Old Infants in Japan. AB - BACKGROUND: To estimate the prevalence of shaking and smothering and to determine risk factors in a population-based sample of mothers with 4-month-old infants in Japan. METHODS: We administered a questionnaire to women who participated in a 4 month health checkup program in Aichi Prefecture, Japan (n = 6487; valid response rate, 66.8%), and assessed frequency of shaking and smothering during the past 1 month, as well as maternal, infant, and familial characteristics. Associations of shaking, smothering, and either shaking or smothering with possible risk factors were analyzed using multiple logistic regression. RESULTS: Self-reported prevalence of shaking, smothering, and either shaking or smothering at least once during the past month was 3.9% (95% confidence interval [CI], 3.5%-4.4%), 2.7% (95% CI, 2.3%-3.1%), and 5.4% (95% CI, 4.9%-6.0%) respectively. Several different risk factors were found for shaking and smothering. Risk factors for either shaking or smothering were age 34 years or younger (especially 24 years or younger), age 40 years or older, full-time working, later attendance at 4-months health checkup, primiparity, living in a detached house, living on the 2nd floor or higher (especially on the 10th floor or higher), economic adversity, perceived excessive crying, and postpartum depression. Protective factors against infant abuse were living in a four-room house and having a larger number of people to consult with. CONCLUSIONS: Self-reported prevalences of shaking and smothering among mothers in Japan were similar to prevalences reported in western countries. These finding may be useful for identifying mothers at increased risk of shaking and smothering their infants. PMID- 26639750 TI - Accuracy of Death Certificates and Assessment of Factors for Misclassification of Underlying Cause of Death. AB - BACKGROUND: Cause of death (COD) information taken from death certificates is often inaccurate and incomplete. However, the accuracy of Underlying CODs (UCODs) recorded on death certificates has not been comprehensively described when multiple diseases are present. METHODS: A total of 450 consecutive autopsies performed at a geriatric hospital in Japan between February 2000 and August 2002 were studied. We evaluated the concordance rate, sensitivity, and specificity of major UCODs (cancer, heart disease, and pneumonia) reported on death certificates compared with a reference standard of pathologist assessment based on autopsy data and clinical records. Logistic regression analysis was performed to assess the effect of sex, age, comorbidity, and UCODs on misclassification. RESULTS: The concordance rate was relatively high for cancer (81%) but low for heart disease (55%) and pneumonia (9%). The overall concordance rate was 48%. Sex and comorbidity did not affect UCOD misclassification rates, which tended to increase with patient age, although the association with age was also not significant. The strongest factor for misclassification was UCODs (P < 0.0001). Sensitivity and specificity for cancer were very high (80% and 96%, respectively), but sensitivity for heart disease and pneumonia was 60% and 46%, respectively. Specificity for each UCOD was more than 85%. CONCLUSIONS: Researchers should be aware of the accuracy of COD data from death certificates used as research resources, especially for cases of elderly patients with pneumonia. PMID- 26639751 TI - Effects of the Great East Japan Earthquake on Secondary Sex Ratio and Perinatal Outcomes. AB - BACKGROUND: The effect of natural disasters on secondary sex ratio (SSR) and perinatal outcomes has been suggested. This study aimed to examine effects of the Great East Japan Earthquake on perinatal outcomes using vital statistics of Japan. METHODS: Birth registration data from vital statistics of Japan between March 2010 and March 2012 were used. Pregnant women who experienced the earthquake were categorized according to their gestational period as of March 11, 2011, as follows: gestational weeks 4-11, 12-19, 20-27, and 28-36 (2011 group). Similarly, pregnant women who did not experience the earthquake were categorized according to their gestational period as of March 11, 2010 and used as controls (2010 group). We also categorized prefectures as "extremely affected", "moderately affected", and "slightly or unaffected" regions. SSR, birth weight, and gestational period were compared between both groups. RESULTS: The number of singleton births was 688,479 in the 2010 group and 679,131 in the 2011 group. In the extremely affected region, the SSR among women at 4-11 weeks of gestation was significantly lower in the 2011 group compared with the 2010 group (49.8% vs 52.1%, P = 0.009). In the extremely affected region, children born to women who experienced the earthquake at 28-36 weeks of gestation had significantly lower birth weights. CONCLUSIONS: The SSR declined among women who experienced the earthquake during early pregnancy, particularly in the extremely affected region. However, no apparent negative effect of the earthquake on perinatal outcomes was observed, although birth weight of infants who were born to women who experienced the earthquake at 28-36 weeks of gestation were lower. PMID- 26639752 TI - Etiology and Risk Factors of Acute Gastroenteritis in a Taipei Emergency Department: Clinical Features for Bacterial Gastroenteritis. AB - BACKGROUND: The causative pathogen is rarely identified in the emergency department (ED), since the results of cultures are usually unavailable. As a result, antimicrobial treatment may be overused. The aim of our study was to investigate the pathogens, risk factors of acute gastroenteritis, and predictors of acute bacterial gastroenteritis in the ED. METHODS: We conducted a matched case-control study of 627 stool samples and 612 matched pairs. RESULTS: Viruses (41.3%) were the leading cause of gastroenteritis, with noroviruses (32.2%) being the most prevalent, followed by bacteria (26.8%) and Giardia lamblia (12.4%). Taking antacids (adjusted odds ratio [aOR] 4.10; 95% confidence interval [CI], 2.57-6.53), household members/classmates with gastroenteritis (aOR 4.69; 95% CI, 2.76-7.96), attending a banquet (aOR 2.29; 95% CI, 1.64-3.20), dining out (aOR 1.70; 95% CI, 1.13-2.54), and eating raw oysters (aOR 3.10; 95% CI, 1.61-5.94) were highly associated with gastroenteritis. Elders (aOR 1.04; 05% CI, 1.02 1.05), those with CRP >10 mg/L (aOR 2.04; 95% CI, 1.15-3.62), or those who were positive for fecal leukocytes (aOR 2.04; 95% CI, 1.15-3.62) or fecal occult blood (aOR 1.97; 95% CI, 1.03-3.77) were more likely to be hospitalized in ED. In addition, presence of fecal leukocytes (time ratio [TR] 1.22; 95% CI, 1.06-1.41), abdominal pain (TR 1.20; 95% CI, 1.07-1.41), and frequency of vomiting (TR 0.79; 95% CI, 0.64-0.98) were significantly associated with the duration of acute gastroenteritis. Presence of fecal leukocytes (aOR 2.08; 95% CI, 1.42-3.05), winter season (aOR 0.45; 95% CI, 0.28-0.74), frequency of diarrhea (aOR 1.69; 95% CI, 1.01-2.83), and eating shrimp or crab (aOR 1.53; 95% CI, 1.05-2.23) were highly associated with bacterial gastroenteritis. The area under the receiver operating characteristic curve of the final model was 0.68 (95% CI, 0.55-0.63). CONCLUSIONS: Acute bacterial gastroenteritis was highly associated with season, frequency of diarrhea, frequency of vomiting, and eating shrimp or crab. PMID- 26639753 TI - A Cross-Sectional Study on Socioeconomic Systems Supporting Outpatients With Parkinson's Disease in Japan. AB - OBJECTIVES: We conducted a cross-sectional study to evaluate the socioeconomic systems supporting outpatients with Parkinson's disease (PD) in Japan. METHODS: The study was performed in 2013 at two private hospitals and one clinic in Hokkaido Prefecture, Japan. A survey was conducted with 248 consecutive PD patients, and the data from 237 PD outpatients were analyzed after excluding 11 patients who did not meet inclusion criteria. Monthly medical and transportation payments as a PD outpatient were selected as outcome variables, and their association with various explanatory variables, such as utilization of support systems for PD outpatients, were evaluated using logistic regression model analysis. RESULTS: After controlling for potential confounding variables, the utilization of the system providing financial aid for treatment for patients with intractable disease was significantly inversely associated with monthly medical payment among PD outpatients (OR 0.46; 95% CI, 0.22-0.95). Experience of hospital admission for PD treatment was significantly positively associated with monthly transportation payment (OR 4.74; 95% CI, 2.18-10.32). Monthly medical payment was also significantly positively associated with monthly transportation payment (OR 4.01; 95% CI, 2.23-7.51). CONCLUSIONS: Use of Japanese public financial support systems may be associated with reductions in medical payments for PD outpatients. However, those systems may not have supported transportation payments, and higher transportation payments may be associated with an increased risk of hospitalization. PMID- 26639754 TI - Is Survival After Out-of-Hospital Cardiac Arrests Worse During Days of National Academic Meetings in Japan? A Population-Based Study. AB - BACKGROUND: Outcomes after out-of-hospital cardiac arrests (OHCAs) might be worse during academic meetings because many medical professionals attend them. METHODS: This nationwide population-based observation of all consecutively enrolled Japanese adult OHCA patients with resuscitation attempts from 2005 to 2012. The primary outcome was 1-month survival with a neurologically favorable outcome. Calendar days at three national meetings (Japanese Society of Intensive Care Medicine, Japanese Association for Acute Medicine, and Japanese Circulation Society) were obtained for each year during the study period, because medical professionals who belong to these academic societies play an important role in treating OHCA patients after hospital admission, and we identified two groups: the exposure group included OHCAs that occurred on meeting days, and the control group included OHCAs that occurred on the same days of the week 1 week before and after meetings. Multiple logistic regression analysis was used to adjust for confounding variables. RESULTS: A total of 20 143 OHCAs that occurred during meeting days and 38 860 OHCAs that occurred during non-meeting days were eligible for our analyses. The proportion of patients with favorable neurologic outcomes after whole arrests did not differ during meeting and non-meeting days (1.6% [324/20 143] vs 1.5% [596/38 855]; adjusted odds ratio 1.02; 95% confidence interval, 0.88-1.19). Regarding bystander-witnessed ventricular fibrillation arrests of cardiac origin, the proportion of patients with favorable neurologic outcomes also did not differ between the groups. CONCLUSIONS: In this population, there were no significant differences in outcomes after OHCAs that occurred during national meetings of professional organizations related to OHCA care and those that occurred during non-meeting days. PMID- 26639755 TI - PDGFRalpha plays a crucial role in connective tissue remodeling. AB - Platelet derived growth factor (PDGF) plays a pivotal role in the remodeling of connective tissues. Emerging data indicate the distinctive role of PDGF receptor alpha (PDGFRalpha) in this process. In the present study, the Pdgfra gene was systemically inactivated in adult mouse (alpha-KO mouse), and the role of PDGFRalpha was examined in the subcutaneously implanted sponge matrices. PDGFRalpha expressed in the fibroblasts of Pdgfra-preserving control mice (Flox mice), was significantly reduced in the sponges in alpha-KO mice. Neovascularized areas were largely suppressed in the alpha-KO mice than in the Flox mice, whereas the other parameters related to the blood vessels and endothelial cells were similar. The deposition of collagen and fibronectin and the expression of collagen 1a1 and 3a1 genes were significantly reduced in alpha-KO mice. There was a significantly decrease in the number and dividing fibroblasts in the alpha-KO mice, and those of macrophages were similar between the two genotypes. Hepatocyte growth factor (Hgf) gene expression was suppressed in Pdgfra-inactivated fibroblasts and connective tissue. The findings implicate the role of PDGFRalpha dependent ECM and HGF production in fibroblasts that promotes the remodeling of connective tissue and suggest that PDGFRalpha may be a relevant target to regulate connective tissue remodeling. PMID- 26639756 TI - Obsessive-Compulsive Disorder: The Process of Parental Adaptation and Implications for Genetic Counseling. AB - Obsessive-compulsive disorder (OCD) has primarily pediatric onset and well documented unique impacts on family functioning. Limited research has assessed the understanding that parents of children with OCD have of the etiology of the condition, and there are no data regarding potential applications of genetic counseling for this population. We recruited 13 parents of 13 children diagnosed with OCD from the OCD Registry at British Columbia Children's Hospital, and conducted qualitative semi-structured telephone interviews to explore participants' experiences with their child's OCD, causal attributions of OCD, and perceptions of two genetic counseling vignettes. Interviews were audio-recorded, transcribed, and analyzed using elements of grounded theory qualitative methodology. Analysis revealed key components and contextual elements of the process through which parents adapt to their child's OCD. This adaptation process involved conceptualizing the meaning of OCD, navigating its impact on family dynamics, and developing effective illness management strategies. Adaptation took place against a backdrop of stigmatization and was shaped by participants' family history of mental illness and their child's specific manifestations of OCD. Parents perceived genetic counseling, as described in the vignettes, as being empowering, alleviating guilt and blame, and positively impacting treatment orientation. These data provide insight into the process of parental adaptation to pediatric OCD, and suggest that genetic counseling services for families affected by OCD may help facilitate adaptation to this illness. PMID- 26639757 TI - Genomic amplification upregulates estrogen-related receptor alpha and its depletion inhibits oral squamous cell carcinoma tumors in vivo. AB - The ESRRA gene encodes a transcription factor and regulates several genes, such as WNT11 and OPN, involved in tumorigenesis. It is upregulated in several cancers, including OSCC. We have previously shown that the tumor suppressor miR 125a targets ESRRA, and its downregulation causes upregulation of ESRRA in OSCC. Upregulation of ESRRA in the absence of downregulation of miR-125a in a subset of OSCC samples suggests the involvement of an alternative mechanism. Using TaqMan((r)) copy number assay, here we report for the first time that the genomic amplification of ESRRA causes its upregulation in a subset of OSCC samples. Ectopic overexpression of ESRRA led to accelerated cell proliferation, anchorage independent cell growth and invasion, and inhibited apoptosis. Whereas, knockdown of ESRRA expression by siRNA led to reduced cell proliferation, anchorage independent cell growth and invasion, and accelerated apoptosis. Furthermore, the delivery of a synthetic biostable ESRRA siRNA to OSCC cells resulted in regression of xenografts in nude mice. Thus, the genomic amplification of ESRRA is another novel mechanism for its upregulation in OSCC. Based on our in vitro and in vivo experiments, we suggest that targeting ESRRA by siRNA could be a novel therapeutic strategy for OSCC and other cancers. PMID- 26639758 TI - Effective directional self-gathering of drops on spine of cactus with splayed capillary arrays. AB - We report that the fast droplet transport without additional energy expenditure can be achieved on the spine of cactus (Gymnocalycium baldianum) with the assistance of its special surface structure: the cactus spine exhibits a cone like structure covered with tilted scales. A single scale and the spine surface under it cooperatively construct a splayed capillary tube. The arrays of capillary tube formed by the overlapping scales build up the out layer of the spine. The serial drops would be driven by the asymmetric structure resulted from tilt-up scales-by-scales on the cone-shaped spine, and move directionally toward the bottom from top of spine, by means of the Laplace pressure in differences. In addition, after the past of the first droplet, thin liquid film of drop is trapped in the splayed capillary micro-tube on the surface of spine, which greatly reduces the friction of subsequential droplet transport in efficiency. This finding provides a new biological model which could be used to transport droplet spontaneously and directionally. Also this work offers a way to reduce the surface adhesion by constructing liquid film on the surface, which has great significance in prompting droplet transport efficiency. PMID- 26639760 TI - Electron beam irradiated silver nanowires for a highly transparent heater. AB - Transparent heaters have attracted increasing attention for their usefulness in vehicle windows, outdoor displays, and periscopes. We present high performance transparent heaters based on Ag nanowires with electron beam irradiation. We obtained an Ag-nanowire thin film with 48 ohm/sq of sheet resistance and 88.8% (substrate included) transmittance at 550 nm after electron beam irradiation for 120 sec. We demonstrate that the electron beam creates nano-soldering at the junctions of the Ag nanowires, which produces lower sheet resistance and improved adhesion of the Ag nanowires. We fabricated a transparent heater with Ag nanowires after electron beam irradiation, and obtained a temperature of 51 degrees C within 1 min at an applied voltage of 7 V. The presented technique will be useful in a wide range of applications for transparent heaters. PMID- 26639761 TI - Synthesis, antibacterial and anti-MRSA activity, in vivo toxicity and a structure activity relationship study of a quinoline thiourea. AB - We report the synthesis, antibacterial evaluation of a series of thiourea containing compounds. 1-(3,5-Bis(trifluoromethyl)phenyl)-3-((S)-(6 methoxyquinolin-4-yl)-((1S,2S,4S,5R)-5-vinylquinuclidin-2-yl)methyl)thiourea 5, was the most active against a range of Gram-positive and Gram-negative bacteria, and exhibited bacteriostatic activity against methicillin resistant Staphylococcus aureus (MRSA) comparable to that of the well-known antibacterial agent vancomycin. Quinoline thiourea 5 was subjected to a detailed structure activity relationship study, with 5 and its derivatives evaluated for their bacteriostatic activity against both Gram-negative and Gram-positive bacteria. A number of structural features important for the overall activity of quinoline thiourea 5 have been identified. A selection of compounds, including 5, was also evaluated for their in vivo toxicity using the larvae of the Greater wax moth, Galleria mellonella. Compound 5, and a number of derivatives, were found to be non-toxic to the larvae of Galleria mellonella. A new class of antibiotic can result from the further development of this family of compounds. PMID- 26639759 TI - Porphyromonas gingivalis initiates a mesenchymal-like transition through ZEB1 in gingival epithelial cells. AB - The oral anaerobe Porphyromonas gingivalis is associated with the development of cancers including oral squamous cell carcinoma (OSCC). Here, we show that infection of gingival epithelial cells with P. gingivalis induces expression and nuclear localization of the ZEB1 transcription factor, which controls epithelial mesenchymal transition. P. gingivalis also caused an increase in ZEB1 expression as a dual species community with Fusobacterium nucleatum or Streptococcus gordonii. Increased ZEB1 expression was associated with elevated ZEB1 promoter activity and did not require suppression of the miR-200 family of microRNAs. P. gingivalis strains lacking the FimA fimbrial protein were attenuated in their ability to induce ZEB1 expression. ZEB1 levels correlated with an increase in expression of mesenchymal markers, including vimentin and MMP-9, and with enhanced migration of epithelial cells into matrigel. Knockdown of ZEB1 with siRNA prevented the P. gingivalis-induced increase in mesenchymal markers and epithelial cell migration. Oral infection of mice by P. gingivalis increased ZEB1 levels in gingival tissues, and intracellular P. gingivalis were detected by antibody staining in biopsy samples from OSCC. These findings indicate that FimA driven ZEB1 expression could provide a mechanistic basis for a P. gingivalis contribution to OSCC. PMID- 26639762 TI - 4-Aminoindazolyl-dihydrofuro[3,4-d]pyrimidines as non-covalent inhibitors of mutant epidermal growth factor receptor tyrosine kinase. AB - The treatment of epidermal growth factor receptor (EGFR)-driven non-small cell lung cancers with the T790M resistance mutation remains a significant unmet medical need. We report the identification of 4-aminoindazolyl-dihydrofuro[3,4 d]pyrimidines as non-covalent inhibitors of EGFR, with excellent activity against the T790M resistance double mutants and initial single activating mutants. Using an optimization strategy focused on structure-based design and improving PK properties through metabolite identification, we obtained advanced leads with high oral exposure. PMID- 26639763 TI - Glutathione-triggered activation of the model of pro-oligonucleotide with benzyl protecting groups at the internucleotide linkage. AB - We have examined substituted benzyl protecting groups for the phosphodiester in oligodeoxyribonucleotides. Stability of the protecting groups in buffer and rates of deprotection by glutathione (GSH) were strongly influenced by benzyl ring substituents. PMID- 26639765 TI - Total Synthesis and Biological Assessment of Mandelalide A. AB - A new convergent total synthesis of the marine macrolide mandelalide A (1) has been developed that is based on macrocyclic ring closure by a Shiina-type macrolactonization and the construction of the requisite precursor seco acid by a highly efficient Sonogashira cross-coupling reaction between two fragments of comparable complexity. Key steps in the elaboration of the acid building block were the enantioselective, catalytic addition of a protected acetylene to crotonaldehyde and the construction of the tetrahydropyran unit that is embedded in the macrocycle by means of an acid-catalyzed Prins reaction. The synthesis of the alcohol fragment features the formation of the trisubstituted tetrahydrofuran ring through an acetal cleavage/epoxide opening cascade reaction and a rarely used radical alkynylation of a primary alkyl iodide. Intriguingly, the dihydroxylation of a terminal double bond as part of the synthesis of this building block gave the same major product for both the alpha- and beta-AD-mix reagents, albeit with moderate or low selectivity. Synthetic mandelalide A (1) was a potent proliferation inhibitor of A549, HT460, and H1299 human lung cancer cells in vitro, but not of SK-N-SH neuroblastoma cells. However, in no case did we observe complete cell kill even at the highest compound concentration tested (5 MUm). PMID- 26639764 TI - Synthesis and biological activity of diisothiocyanate-derived mercapturic acids. AB - This Letter deals with new non-natural diisothiocyanates, their mercapturic acid derivatives-conjugated with N-acetylcysteine as well as their antiproliferative activity towards human colon cancer cell lines and their inhibitory potency towards histone deacetylase activity. The activity of analysed isothiocyanates is not significantly different than their N-acetylcysteine conjugates. In comparison to simple mono-isothiocyanate analogues, aliphatic diisothiocyanates and their conjugates are much more active than the simple presence of two isothiocyanate functionalities could indicate. PMID- 26639766 TI - HTR1B gene variants associate with the susceptibility of Raynauds' phenomenon in workers exposed hand-arm vibration. AB - OBJECTIVE: To explore whether polymorphic variants of the HTR1B gene are associated with the susceptibility of Raynauds' Phenomenon (RP) coursed by vibration. METHODS: 148 subjects exposed to vibration for more than 2 years were classified into either induced white finger (VWF) group (n = 72), or non-VWF group (n = 76). Vibration exposure levels were measured and assessed following ISO 5349-1:2001 protocol. All workers were genotyped by sequencing for the single nucleotide polymorphisms (SNPs) in the 5'-flanking and coding region of HTR1B. Genetic characteristics and linkage disequilibrium (LD) were analyzed with Haploview. Serum serotonin levels of each subject were detected using ELISA. The association between the susceptibility of vascular damage and genotype was analyzed via logistic regression. RESULTS: 7 known SNPs were obtained and their allele frequencies were inserted into the Hardy-Weinberg equilibrium. rs6297 variant genotype had an increased risk of VWF compared with wild genotype (OR = 2.14, 95% CI = 1.04- 4.58, P < 0.05). rs6298 mutant type (AG+GG) was found to have a significant interaction on vibration exposure LN(CEI), accounting for VWF occurrence. LN(5-HT) level is significantly different between the VWF group (x-+/ s= 1.99+/-1.09 ng/mL) and the non-VWF group (x-+/-s= 2.72+/-1.47 ng/mL). CONCLUSIONS: Serotonin levels may affect the progression of secondary RP. Polymorphic variants of the HTR1B gene are associated with the susceptibility of secondary RP in vibration-exposed occupational populations of Chinese Han people. PMID- 26639767 TI - The microcirculatory failure could not weaken the increase of systematic oxygen extraction rate in septic shock: An observational study in canine models. AB - OBJECT: This study aimed at exploring what level of the microcirculation alteration could weaken the decrease of ScvO2 (or the increase of O2ER) and further result in an abnormally elevated ScvO2. METHODS: Beagles were randomly assigned into control (n = 5) and shock group (n = 5). The canines in shock group were intravenously injected with live E. coli (3.5*108 cfu/kg), and the ones in control group were injected with sterile saline. The experiment continued to the animals' death or for a maximum of 24 hours. Hemodynamic parameters, blood gas and inflammatory cytokines level were collected. Microcirculatory parameters were assessed with Sidestream Dark Field (SDF) imaging. The correlation between the microcirculation and oxygen metabolism or inflammatory cytokine, meanwhile the correlation between the oxygen metabolism and inflammatory cytokine was assessed. RESULTS: E. coli infusion induced hypodynamic shock. The correlation between microcirculation and oxygen metabolism or inflammatory cytokine, and The correlation between the oxygen metabolism and inflammatory cytokine (O2ER vs. MFI: r = -0.700, P < 0.01; O2ER vs. PVD: r = -0.677, P < 0.01; O2ER vs. PPV: r = 0.538, P < 0.01; MFI vs. IL-6: r = -0.780, P < 0.01; PPV vs. IL-6: r = -0.621, P < 0.01; MFI vs. TNF-alpha: r = -0.636, P < 0.01; PPV vs. TNF-alpha: r = -0.561, P < 0.01) were observed. CONCLUSIONS: The increase of O2ER cannot be weakened by the microcirculatory failure. PMID- 26639768 TI - The effect of hypoxia on intra-ocular, mean arterial, retinal venous and ocular perfusion pressures. AB - INTRODUCTION: High altitude hypoxia is linked to decreased blood oxygen saturation with a related increase of Endothelin-1 (ET-1) blood plasma levels. As a consequence of such elevated ET-1 levels, alterations of retinal venous and ocular perfusion pressures are suspected. PURPOSE: To measure the effect of hypoxia on intra-ocular pressure, mean arterial pressure, retinal venous pressure and to calculate ocular perfusion pressure. METHOD: An experimental, prospective cohort study with 33 healthy subjects was conducted in which the subjects were confronted with long-term (days) environmental hypoxia at high altitudes. Mean arterial pressure, arterial blood oxygen saturation, intra-ocular pressure, retinal venous and ocular perfusion pressure were measured at 300 m/1'000 ft (baseline), 4200 m/13'800 ft and 6000 m/19'700 ft above sea level. RESULTS: Arterial oxygen saturation (-13.06% +/- 4.69, p = < 0.001; -23.46% +/- 5.7,p = < 0.001), retinal venous pressure (+7.16 m Hg+/-8.2, p = < 0.001;+9.9 mm Hg+/-8.5, p = < 0.001) and ocular perfusion pressure (-8.49 mm Hg+/-10.6, p = < 0.001; 6.02 mm hg+/-11.2, p = 0.006) changed significantly from baseline at both high altitude of 4200 and 6000 m. Intra-ocular pressure did not change significantly at all altitudes (+1.16 mm Hg+/-4.5, p = 0.227; +0.84 mm Hg+/-4.8, p = 0.286) and mean arterial pressure changed significantly only at an altitude of 6000 m (+3,8 mm Hg+/-21.1, p = 0.005) from baseline. CONCLUSION: As hypoxia increases with higher altitude, arterial oxygen saturation and ocular perfusion pressure decreased, retinal venous pressure increased, intra-ocular pressure remains stable and mean arterial pressure was elevated only at 6000 m. PMID- 26639769 TI - Adsorption capacity of poly(ether imide) microparticles to uremic toxins. AB - Uremia is a phenomenon caused by retention of uremic toxins in the plasma due to functional impairment of kidneys in the elimination of urinary waste products. Uremia is presently treated by dialysis techniques like hemofiltration, dialysis or hemodiafiltration. However, these techniques in use are more favorable towards removing hydrophilic than hydrophobic uremic toxins. Hydrophobic uremic toxins, such as hydroxy hipuric acid (OH-HPA), phenylacetic acid (PAA), indoxyl sulfate (IDS) and p-cresylsulfate (pCRS), contribute substantially to the progression of chronic kidney disease (CKD) and cardiovascular disease. Therefore, objective of the present study is to test adsorption capacity of highly porous microparticles prepared from poly(ether imide) (PEI) as an alternative technique for the removal of uremic toxins. Two types of nanoporous, spherically shaped microparticles were prepared from PEI by a spraying/coagulation process.PEI particles were packed into a preparative HPLC column to which a mixture of the four types of uremic toxins was injected and eluted with ethanol. Eluted toxins were quantified by analytical HPLC. PEI particles were able to adsorb all four toxins, with the highest affinity for PAA and pCR. IDS and OH-HPA showed a partially non reversible binding. In summary, PEI particles are interesting candidates to be explored for future application in CKD. PMID- 26639770 TI - Effect of extracts of poly(ether imide) microparticles on cytotoxicity, ROS generation and proinflammatory effects on human monocytic (THP-1) cells. AB - Current haemodialysis techniques are not capable to remove efficiently low molecular weight hydrophobic uremic toxins from the blood of patients suffering from chronic renal failure. With respect to the hydrophobic characteristics and the high level of protein binding of these uremic toxins, hydrophobic adsorber materials might be an alternative to remove these substances from the plasma of the chronic kidney disease (CKD) patients. Here nanoporous microparticles prepared from poly(ether imide) (PEI) with an average diameter of 90 +/- 30 MUm and a porosity around 88 +/- 2% prepared by a spraying/coagulation process are considered as candidate adsorber materials. A prerequisite for the clinical application of such particles is their biocompatibility, which can be examined i.e. indirectly in cell culture experiments with the particles' extracts. In this work we studied the effects of aqueous extracts of PEI microparticles on the viability of THP-1 cells, a human leukemia monocytic cell line, as well as their macrophage differentiation, reactive oxygen species (ROS) generation and inflammation.A high cell viability of around 99 +/- 18% and 99 +/- 5% was observed when THP-1 cells were cultured in the presence of aqueous extracts of the PEI microparticles in medium A and medium B respectively. The obtained microscopic data suggested that PEI particle extracts have no significant effect on cell death, oxidative stress or differentiation to macrophages. It was further found that the investigated proinflammatory markers in THP-1 cells were not up regulated. These results are promising with regard to the biocompatibility of PEI microparticles and in a next step the hemocompatibility of the microparticles will be examined. PMID- 26639771 TI - Effect of temperature on platelet adherence. AB - BACKGROUND: Thrombogenicity is one of the main parameters tested in vitro to evaluate the hemocompatibility of artificial surfaces. While the influence of the temperature on platelet aggregation has been addressed by several studies, the temperature influence on the adherence of platelets to body foreign surfaces as an important aspect of biomedical device handling has not yet been explored. Therefore, we analyzed the influence of two typically applied incubation temperatures (22 degrees C and 37 degrees C) on the adhesion of platelets to biomaterials. MATERIAL AND METHODS: Thrombogenicity of three different polymers - medical grade poly(dimethyl siloxane) (PDMS), polytetrafluoroethylene (PTFE) and polyethylene terephthalate (PET) - were studied in an in vitro static test. Platelet adhesion was studied with stringently characterized blood from apparently healthy subjects. Collection of whole blood and preparation of platelet rich plasma (PRP) was carried out at room temperature (22 degrees C). PRP was incubated with the polymers either at 22 degrees C or 37 degrees C. Surface adherent platelets were fixed, fluorescently labelled and assessed by an image-based approach. RESULTS AND DISCUSSION: Differences in the density of adherent platelets after incubation at 22 degrees C and 37 degrees C occurred on PDMS and PET. Similar levels of adherent platelets were observed on the very thrombogenic PTFE. The covered surface areas per single platelet were analyzed to measure the state of platelet activation and revealed no differences between the two incubation temperatures for any of the analyzed polymers. Irrespective of the observed differences between the low and medium thrombogenic PDMS and PET and the higher variability at 22 degrees C, the thrombogenicity of the three investigated polymers was evaluated being comparable at both incubation temperatures. PMID- 26639772 TI - Exploring the Structure and Content of Hospital-Based Pediatric Nurse Residency Programs. AB - This paper presents the results of a national survey of pediatric nurse residency programs (NRP). DESIGN AND METHODS: The Pediatric Nursing Certification Board (PNCB) database was used to identify 316 hospitals with pediatric units, including children's hospitals and community hospitals with pediatric services. The Residency Task Force of the Institute of Pediatric Nursing (IPN) developed the survey, Exploring Pediatric Nurse Residency Programs. Survey items addressed structure, content, outcomes, benefits and challenges of NRPs, including a comparison with orientation programs and use of preceptors. RESULTS: Of the 316 hospitals contacted, 65 provided usable information and 45 reported having an NRP. Most (94%) of the hospitals have an orientation program, and 70% had an NRP. The NRPs were typically internally developed (60%) and a year in length (46.5%). Most common content (>80%) included critical thinking, stress management, small group support, professional role transition, pediatric resuscitation, and evidence based practice. Evaluation of the NRPs included measures of satisfaction, turnover rates, and standardized measures, primarily the Casey-Fink Graduate Nurse Experience Survey (48.7%). Challenges include obtaining financial support from the organization, developing content relevant across units, providing time away from clinical units, and maintaining preceptors. Benefits noted included development of professional role confidence and peer support networks, increased safe nursing practices, and a decrease in nursing turnover. CONCLUSIONS AND PRACTICE IMPLICATIONS: In the ongoing development of NRPs in children's hospitals, issues such as appropriate content, optimal length, standardization across settings, impact on nurse retention, safe practice and patient outcomes all need to be addressed. PMID- 26639775 TI - Regadenoson stress for myocardial perfusion imaging. AB - Noninvasive functional imaging plays a major role in the diagnosis of hemodynamically significant coronary artery disease (CAD) by means of the detection of abnormal myocardial perfusion. For this, cardiac stressors are essential as they induce hypoperfusion in the presence of flow-limiting coronary stenosis. Several pharmacological stressors are currently available and it is important that clinicians who are involved in the care and management of patients with CAD become familiar with their indications, contraindications and protocols. Among the primary coronary vasodilator agents, regadenoson is increasingly used as the default stressor or as an alternative to other modalities of stress. This article provides an updated review of regadenoson stress for the assessment of patients with suspected or known CAD and describes its pharmacological properties, stress protocol, efficacy and safety profile. PMID- 26639773 TI - Death Rituals Reported by White, Black, and Hispanic Parents Following the ICU Death of an Infant or Child. AB - To examine rituals (disposing remains, wakes, funerals/burials, celebrations) of White, Black, Hispanic parents post ICU infant/child death. DESIGN AND METHODS: Qualitative design, 63 parents completed English or Spanish semi-structured interviews at 7 & 13months after infant's/child's death. Interviews were audio recorded, transcribed verbatim, and entered into Atlas.ti for analysis. An inductive approach to thematization was used to develop codes. RESULTS: Parents: mean age 35.1years (SD=9.03); 33% Black, 27% White, 40% Hispanic; from 17 countries. Three themes emerged: immediately after death - shock and stress, needing help with arrangements, decisions on burial or cremation (conflicts due to finances, religion, culture), when and where to hold wakes, funerals/burials. Wakes and funerals--who prepares child's body, appropriate dress (deceased child, mourners), who can come (cultural restrictions),--by child age, parent choice, culture, religion, country. After burial/cremation--being with family, milestone celebrations. CONCLUSION: Child death is devastating for parents, other children, grandparents, and family members. PRACTICE IMPLICATIONS: Rituals after child death require decisions about the child's remains, wakes, funerals/burials at time of great pain for parents. This is especially true for newly immigrated parents and those with language barriers where making arrangements is especially hard and often very isolating. Health professionals who provide support need to be cognizant of practice differences based on religion, culture, economics, family traditions, and individual preference and provide as much support and resource as possible. A list of religious leaders representing the community's cultures and funeral service providers who may provide lower cost burials/cremations is helpful. PMID- 26639774 TI - Modified motor unit number index: A simulation study of the first dorsal interosseous muscle. AB - The motor unit number index (MUNIX) technique has provided a quick and convenient approach to estimating motor unit population changes in a muscle. Reduction in motor unit action potential (MUAP) amplitude can lead to underestimation of motor unit numbers using the standard MUNIX technique. This study aims to overcome this limitation by developing a modified MUNIX (mMUNIX) technique. The mMUNIX uses a variable that is associated with the area of compound muscle action potential (CMAP) rather than an arbitrary fixed value (20 mV ms) as used in the standard MUNIX to define the output. The performance of the mMUNIX was evaluated using motoneuron pool and surface electromyography (EMG) models. With a fixed motor unit number, the mMUNIX output remained relatively constant with varying degrees of MUAP amplitude changes, while the standard MUNIX substantially underestimated the motor unit number in such cases. However, when MUAP amplitude remained unchanged, the mMUNIX showed less sensitivity than the standard MUNIX in tracking motor unit loss. The current simulation study demonstrated both the advantages and limitations of the standard and modified MUNIX techniques, which can help guide appropriate application and interpretation of MUNIX measurements. PMID- 26639776 TI - Antiviral Action of Diphenyl Diselenide on Herpes Simplex Virus 2 Infection in Female BALB/c Mice. AB - Diphenyl diselenide, (PhSe)2 , is an organoselenium compound with pharmacological actions mostly related to antioxidant and anti-inflammatory properties. The study investigated its antiviral and virucidal actions against herpes simplex virus 2 (HSV-2) infection in vitro and in a vaginal infection model in mice. The plaque reduction assay indicated that (PhSe)2 showed virucidal and antiviral actions reducing infectivity in 70.8% and 47%, respectively. The antiviral action of (PhSe)2 against HSV-2 vaginal infection was performed by infecting mice (10(5) PFU/ml(-1) ) at day 6. The treatment with (PhSe)2 (5 mg/kg/day, intragastric [i.g.]) followed 5 days before and for more 5 days after infection. The extravaginal lesion score was evaluated from days 6 to 10. At day 11, animals were killed, and histological evaluation, determination of viral load, and TNF alpha and IFN-gamma levels were performed in supernatants of homogenized vaginal tissue. The levels of reactive species (RS), protein carbonyl, non-protein thiols (NPSH), nitrate/nitrite (NOx), and malondialdehyde (MDA), and the activities of myeloperoxidase (MPO), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione reductase (GR) were determined. (PhSe)2 reduced the histological damage, extravaginal lesion scores, the viral load of vaginal tissue, and the activity of MPO, but increased the levels of TNF-alpha, IFN gamma. (PhSe)2 attenuated the increase of RS, MDA, NOx levels and the activity of GR caused by infection. (PhSe)2 also attenuated the reduction of NPSH content and the inhibition of CAT, SOD, and GPx activities. The antiviral action of (PhSe)2 against HSV-2 infection was related to its immunomodulatory, antioxidant, and anti-inflammatory properties. J. Cell. Biochem. 117: 1638-1648, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26639778 TI - Microbiome: Microbiota-based nutrition plans. PMID- 26639777 TI - Dengue vaccine: hypotheses to understand CYD-TDV-induced protection. AB - Dengue virus (DENV) is a human pathogen with a large impact on public health. Although no vaccine against DENV is currently licensed, a recombinant vaccine - chimeric yellow fever virus-DENV tetravalent dengue vaccine (CYD-TDV) - has shown efficacy against symptomatic dengue disease in two recent Phase III clinical trials. Safety observations were also recently reported for these trials. In this Opinion article, we review the data from recent vaccine clinical trials and discuss the putative mechanisms behind the observed efficacy of the vaccine against different forms of the disease, focusing on the interactions between the infecting virus, pre-existing host immunity and vaccine-induced immune responses. PMID- 26639781 TI - Commitment issues in Plasmodium. PMID- 26639782 TI - Bacterial physiology: Cropping up in an aerobic niche. PMID- 26639779 TI - Mechanistic insights into bacterial AAA+ proteases and protein-remodelling machines. AB - To maintain protein homeostasis, AAA+ proteolytic machines degrade damaged and unneeded proteins in bacteria, archaea and eukaryotes. This process involves the ATP-dependent unfolding of a target protein and its subsequent translocation into a self-compartmentalized proteolytic chamber. Related AAA+ enzymes also disaggregate and remodel proteins. Recent structural and biochemical studies, in combination with direct visualization of unfolding and translocation in single molecule experiments, have illuminated the molecular mechanisms behind these processes and suggest how remodelling of macromolecular complexes by AAA+ enzymes could occur without global denaturation. In this Review, we discuss the structural and mechanistic features of AAA+ proteases and remodelling machines, focusing on the bacterial ClpXP and ClpX as paradigms. We also consider the potential of these enzymes as antibacterial targets and outline future challenges for the field. PMID- 26639783 TI - Curcumin pretreatment attenuates inflammation and mitochondrial dysfunction in experimental stroke: The possible role of Sirt1 signaling. AB - The effects of curcumin (CCM) on cerebral ischemia/reperfusion injury are not well understood. The aim of this study was to investigate whether CCM attenuates inflammation and mitochondrial dysfunction in a rat model of cerebral ischemia/reperfusion injury and whether Sirt1 is involved in these potential protective effects. Sirtinol, a Sirt1 inhibitor, was used to elucidate the underlying mechanism. Rats were subjected to 2h of transient middle cerebral artery occlusion (MCAO), followed by reperfusion for 24h. Brain magnetic resonance imaging (MRI) was used to detect infarct volumes. Neurological scores and brain water content were also assessed. Levels of tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6) in the brain were detected using commercial enzyme-linked immunosorbent assay (ELISA) kits. Expression of SIRT1, acetylated p53 (Ac-p53), Bcl-2, and Bax was measured by western blotting. Our results suggested that CCM exerted a neuroprotective effect, as shown by reduced infarct volumes and brain edema and improved neurological scores. CCM also exerted anti inflammatory effects, as indicated by decreased TNF-alpha and IL-6 levels in the brain. CCM elevated mitochondrial membrane potential, mitochondrial complex I activity, and mitochondrial cytochrome c levels, but reduced cytosolic cytochrome c levels. Moreover, CCM upregulated SIRT1 and Bcl-2 expression and downregulated Ac-p53 and Bax expression. These effects of CCM were abolished by sirtinol. In conclusion, our results demonstrate that CCM treatment attenuates ischemic stroke induced brain injury via activation of SIRT1. PMID- 26639780 TI - Pore-forming toxins: ancient, but never really out of fashion. AB - Pore-forming toxins (PFTs) are virulence factors produced by many pathogenic bacteria and have long fascinated structural biologists, microbiologists and immunologists. Interestingly, pore-forming proteins with remarkably similar structures to PFTs are found in vertebrates and constitute part of their immune system. Recently, structural studies of several PFTs have provided important mechanistic insights into the metamorphosis of PFTs from soluble inactive monomers to cytolytic transmembrane assemblies. In this Review, we discuss the diverse pore architectures and membrane insertion mechanisms that have been revealed by these studies, and we consider how these features contribute to binding specificity for different membrane targets. Finally, we explore the potential of these structural insights to enable the development of novel therapeutic strategies that would prevent both the establishment of bacterial resistance and an excessive immune response. PMID- 26639785 TI - The Origin of The Acheulean: The 1.7 Million-Year-Old Site of FLK West, Olduvai Gorge (Tanzania). AB - The appearance of the Acheulean is one of the hallmarks of human evolution. It represents the emergence of a complex behavior, expressed in the recurrent manufacture of large-sized tools, with standardized forms, implying more advance forethought and planning by hominins than those required by the precedent Oldowan technology. The earliest known evidence of this technology dates back to c. 1.7 Ma. and is limited to two sites (Kokiselei [Kenya] and Konso [Ethiopia]), both of which lack functionally-associated fauna. The functionality of these earliest Acheulean assemblages remains unknown. Here we present the discovery of another early Acheulean site also dating to c. 1.7 Ma from Olduvai Gorge. This site provides evidence of the earliest steps in developing the Acheulean technology and is the oldest Acheulean site in which stone tools occur spatially and functionally associated with the exploitation of fauna. Simple and elaborate large-cutting tools (LCT) and bifacial handaxes co-exist at FLK West, showing that complex cognition was present from the earliest stages of the Acheulean. Here we provide a detailed technological study and evidence of the use of these tools on the butchery and consumption of fauna, probably by early Homo erectus sensu lato. PMID- 26639784 TI - GLUT3 and PKM2 regulate OCT4 expression and support the hypoxic culture of human embryonic stem cells. AB - Human embryonic stem cells (hESCs) have the capacity to differentiate into all cell types and thus have great potential for regenerative medicine. hESCs cultured at low oxygen tensions are more pluripotent and display an increased glycolytic rate but how this is regulated is unknown. This study therefore aimed to investigate the regulation of glucose metabolism in hESCs and whether this might impact OCT4 expression. In contrast to the glucose transporter GLUT1, GLUT3 was regulated by environmental oxygen and localised to hESC membranes. Silencing GLUT3 caused a reduction in glucose uptake and lactate production as well as OCT4 expression. GLUT3 and OCT4 expression were correlated suggesting that hESC self renewal is regulated by the rate of glucose uptake. Surprisingly, PKM2, a rate limiting enzyme of glycolysis displayed a nuclear localisation in hESCs and silencing PKM2 did not alter glucose metabolism suggesting a role other than as a glycolytic enzyme. PKM2 expression was increased in hESCs cultured at 5% oxygen compared to 20% oxygen and silencing PKM2 reduced OCT4 expression highlighting a transcriptional role for PKM2 in hESCs. Together, these data demonstrate two separate mechanisms by which genes regulating glucose uptake and metabolism are involved in the hypoxic support of pluripotency in hESCs. PMID- 26639786 TI - Construction and Characterization of a Synthetic MicroRNA Cluster for Multiplex RNA Interference in Mammalian Cells. AB - RNA interference (RNAi) technology is widely used in basic and translational research. By mimicking a natural primary microRNA (pri-miRNA) cluster, multiple engineered hairpins can be transcribed as a single transcript from the same Pol II promoter, enabling the formation of multiplex RNAi in mammalian cells. However, constructing a synthetic miRNA cluster is still time-consuming, and the processing and function of a miRNA cluster are incompletely understood. Here, we identified a miRNA precursor architecture that allows precise miRNA maturation. We established a hierarchical cloning method for the efficient construction of a synthetic miRNA cluster harboring up to 18 miRNA precursors. We demonstrated that the maturation and function of individual miRNA precursors were independent of their positions in the cluster. We then analyzed the integration efficiency of miRNA clusters having a varied number of miRNA precursors by using CRISPR/Cas9 mediated integration, a piggyBac transposon system, and a lentiviral system. This synthetic miRNA cluster system provides an important tool for multiplex RNAi in mammalian cells. PMID- 26639788 TI - The importance of ultrasound in the strategy of a difficult airway extubation, after a prolonged facial and cervical area surgery. AB - On many occasions we are faced with complex and long-lasting surgeries affecting the cervicofacial region, seriously compromising the time of extubation and presenting before us a high-risk position. To avoid this, we will plan our activities bearing in mind all the possible complications and the different alternative plans, considering the ultrasound as a useful diagnostic method in the daily management of the airway. PMID- 26639789 TI - Hospital mortality in postoperative critically ill patients older than 80 years. Can we predict it at an early stage? AB - OBJECTIVES: To determine the incidence of in-hospital mortality throughout the post-surgical period of patients aged 80 or over who were admitted to the post surgical critical care unit, as well as to assess the predictive capacity of those variables existing in the first 48hours on the in-hospital mortality. MATERIAL AND METHODS: An observational retrospective cohort study conducted on postsurgical patients up to 80years old who were admitted to the unit between June 2011 and December 2013. Univariate and multivariate binary logistic regression was used to determine the association between mortality and the independent variables. RESULTS: Of the 186 patients included, 9 (4.8%) died in the critical care unit, and 22 (11.8%) died in wards during hospital admission, giving a hospital mortality of 31 (16.7%). Among the 78 patients (42%) that underwent acute surgery, and the 108 who underwent elective surgery, there was a mortality rate of 19 (10.2%) and 12 (6.5%), respectively. As regards the variables analysed during the first 48hours of admission that showed to be hospital mortality risk factor were the need for mechanical ventilation over 48h, with an OR: 7.146 (95%CI: 1.563-32.664, P=.011) and the degree of the severity score on the APACHE II scale in the first 24hours, with an OR: 1.102 (95%CI: 1.005-1.208, P=.039). CONCLUSION: The incidence of hospital mortality in very old patients found in our study is comparable to that reported by other authors. Patients who need mechanical ventilation over 48h, and with higher scores in the APACHE II scale could be at a higher risk of in-hospital mortality. PMID- 26639787 TI - The Caries Management System: are preventive effects sustained postclinical trial? AB - OBJECTIVES: To report, at two and 4 years post-trial, on the potential legacy of a 3-year randomized controlled clinical trial (RCT) of the Caries Management System (CMS) at private general dental practices. The CMS was designed to reduce caries risk and need for restorative care. METHODS: Nineteen dental practices located in city, urban, and rural locations in both fluoridated and nonfluoridated communities participated in the RCT. Eight practices were lost to follow-up post-trial; however, baseline mean DMFT balance between CMS and control practices was maintained. At the control practices, caries management following usual practice continued to be delivered. The patient outcome measure was the cumulative increment in the DMFT index score, and the practice outcome measures included the practice-mean and practice-median increments of patient DMFT index scores. In covariable analysis (patient-level unit of analysis), as the patients were clustered by practices, mean DMFT increments were determined through multilevel modeling analysis. Practice-mean DMFT increments (practice-level unit of analysis) and practice-median DMFT increments (also practice level) were determined through general linear modeling analysis of covariance. In addition, a multiple variable logistic regression analysis of caries risk status was conducted. RESULTS: The overall 4-year post-trial result (years 4-7) for CMS patients was a DMFT increment of 2.44 compared with 3.39 for control patients (P < 0.01), a difference equivalent to 28%. From the clinical trial baseline to the end of the post-trial follow-up period, the CMS and control increments were 6.13 and 8.66, respectively, a difference of 29% (P < 0.0001). Over the post-trial period, the CMS and control practice-mean DMFT increments were 2.16 and 3.10 (P = 0.055) and the respective increments from baseline to year 7 were 4.38 and 6.55 (P = 0.029), difference of 33%. The practice-median DMFT increments during the 4 year post-trial period for CMS and control practices were 1.25 and 2.36 (P = 0.039), and the respective increments during the period from baseline to year 7 were 2.87 and 5.36 (P < 0.01), difference of 47%. Minimally elevated odds of being high risk were associated with baseline DMFT (OR = 1.17). Patients attending the CMS practices had lower odds of being high risk than those attending control practices (OR = 0.23, 95% CI = 0.06, 0.88). CONCLUSION: In practices where adherence to the CMS protocols was maintained during the 4-year post-trial follow-up period, patients continued to benefit from a reduced risk of caries and, therefore, experienced lower needs for restorative treatment. PMID- 26639790 TI - Hydrogen peroxide-induced secondary necrosis in conidia of Aspergillus fumigatus. AB - Aspergillus fumigatus conidia have been linked to severe aspergillosis in immunocompromised patients. Recently, the cytotoxic effect of secondary metabolites from A. fumigatus conidia was reported. In the present work, a methodology used to detect cell death markers in fungal hyphae was adapted to study conidia cell death. Additionally, the mechanism of H2O2-induced cell death was studied in A. fumigatus conidia for the first time. Data presented in this work reveal that the H2O2-induced conidial cell death was associated with a marked increase of TUNEL- and PI-positive cells. It is therefore suggested that conidia cell death occurs in a dose-dependent manner through a secondary necrosis mechanism. The knowledge of conidia cell death machinery may provide insights into the molecular mechanism of conidia-mediated toxicity to the respiratory tract and may pave the way for improved therapeutic approaches against A. fumigatus conidia-mediated diseases. PMID- 26639792 TI - Characterizing mixed phosphonic acid ligand capping on CdSe/ZnS quantum dots using ligand exchange and NMR spectroscopy. AB - The ligand capping of phosphonic acid functionalized CdSe/ZnS core-shell quantum dots (QDs) was investigated with a combination of solution and solid-state (31) P nuclear magnetic resonance (NMR) spectroscopy. Two phosphonic acid ligands were used in the synthesis of the QDs, tetradecylphosphonic acid and ethylphosphonic acid. Both alkyl phosphonic acids showed broad liquid and solid-state (31) P NMR resonances for the bound ligands, indicative of heterogeneous binding to the QD surface. In order to quantify the two ligand populations on the surface, ligand exchange facilitated by phenylphosphonic acid resulted in the displacement of the ethylphosphonic acid and tetradecylphosphonic acid and allowed for quantification of the free ligands using (31) P liquid-state NMR. After washing away the free ligand, two broad resonances were observed in the liquids' (31) P NMR corresponding to the alkyl and aromatic phosphonic acids. The washed samples were analyzed via solid-state (31) P NMR, which confirmed the ligand populations on the surface following the ligand exchange process. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26639791 TI - Meaning in Life in People with Borderline Personality Disorder. AB - : Low feelings of meaning in life are associated with depression, hopelessness and suicide, substance abuse and emotional dysregulation. The aim of this study is to offer results about the importance of the construct meaning in life in the psychopathology of BPD. In study 1, the sample was made up of 223 participants, 141 participants with BPD and 82 participants with another mental disorder but without BPD. In study 2, the sample was made up of 80 participants with BPD. Study 1 indicated that the participants with BPD had a lower feeling of meaning in life than the participants with mental disorders but without a BPD. Study 2 indicated that meaning in life was highly negatively correlated with the symptoms of BPD. The model composed of emotional dysregulation, and meaning in life was significantly associated with BPD psychopathology. The present study supports the association between meaning in life with the psychopathology of BPD. Copyright (c) 2015 John Wiley & Sons, Ltd. KEY PRACTITIONER MESSAGE: The results of this study suggest that meaning in life is a relevant variable in the psychopathology of BPD The results of this study suggest that meaning in life is associated with non-suicide self injuries This study suggests that current therapies for BPD should focus on increasing the meaning in life in these patients. PMID- 26639793 TI - Utilizing an integrated infrastructure for outcomes research: a systematic review. AB - OBJECTIVE: To explore the ability of an integrated health information infrastructure to support outcomes research. METHODS: A systematic review of articles published from 1983 to 2012 by Regenstrief Institute investigators using data from an integrated electronic health record infrastructure involving multiple provider organisations was performed. Articles were independently assessed and classified by study design, disease and other metadata including bibliometrics. RESULTS: A total of 190 articles were identified. Diseases included cognitive, (16) cardiovascular, (16) infectious, (15) chronic illness (14) and cancer (12). Publications grew steadily (26 in the first decade vs. 100 in the last) as did the number of investigators (from 15 in 1983 to 62 in 2012). The proportion of articles involving non-Regenstrief authors also expanded from 54% in the first decade to 72% in the last decade. During this period, the infrastructure grew from a single health system into a health information exchange network covering more than 6 million patients. Analysis of journal and article metrics reveals high impact for clinical trials and comparative effectiveness research studies that utilised data available in the integrated infrastructure. DISCUSSION: Integrated information infrastructures support growth in high quality observational studies and diverse collaboration consistent with the goals for the learning health system. More recent publications demonstrate growing external collaborations facilitated by greater access to the infrastructure and improved opportunities to study broader disease and health outcomes. CONCLUSIONS: Integrated information infrastructures can stimulate learning from electronic data captured during routine clinical care but require time and collaboration to reach full potential. PMID- 26639794 TI - Could tight junctions regulate the barrier function of the aged skin? AB - The skin is known to be the largest organ in human organism creating interface with outer environment. The skin provides protective barrier against pathogens, physical and chemical insults, and against uncontrolled loss of water. The barrier function was primarily attributed to the stratum corneum (SC) but recent studies confirmed that epidermal tight junctions (TJs) also play important role in maintaining barrier properties of the skin. Independent observations indicate that barrier function and its recovery is impaired in aged skin. However, trans epidermal water loss (TEWL) values remains rather unchanged in elderly population. UV radiation as major factor of photoageing impairs TJ proteins, but TJs have great self-regenerative potential. Since it may be possible that TJs can compensate TEWL in elderly due to its regenerative and compensatory capabilities, important question remains to be answered: how are TJs regulated during skin ageing? This review provides an insight into TJs functioning as epidermal barrier and summarizes current knowledge about the impact of ageing on the barrier function of the skin and epidermal TJs. PMID- 26639795 TI - Corrigendum: Resistive switching and its suppression in Pt/Nb:SrTiO3 junctions. PMID- 26639818 TI - Mutation spectra of the ITGB2 gene in Iranian families with leukocyte adhesion deficiency type 1. AB - Leukocyte adhesion deficiency type 1 (LAD1) is an autosomal recessive disorder clinically characterized by severe, recurrent bacterial infections, impaired pus formation and wound healing. It is caused by mutation in the ITGB2 gene, encoding the beta2 integrin subunit of the leukocyte adhesion cell molecule. This study aimed to identify disease causing mutations in 19 consanguineous families diagnosed with LAD1. Blood samples were collected after informed and written consent was obtained. Genomic DNA was extracted from peripheral blood of patients and their parents. PCR amplification of the ITGB2 gene was done using specific primers followed by sequencing for mutation detection. A total number of 14 alterations scattered throughout the ITGB2 gene were ascertained in which 10 mutations were previously reported, including c.329-6C>A, c.382G>T, c.715G>A, c.843delC, c.897+1G>A, c.1062A>T, c.1143delC, c.1877+2T>C, c.1907delA and c.2147G>C. Four novel likely pathogenic mutations consisting of c.576dupC (Asn193GlnfsX72), c.706G>A (Gly236Arg), c.897+1G>T and c.1030G>T (Glu344(*)), were identified. The majority of these mutations were located in exon six, suggesting this exon as a hotspot region probably. This study emphasis on allelic heterogeneity of the ITGB2 gene in Iranian patients diagnosed with LAD1. Our results suggest that every population should develop a mutation database for rare genetic disorders to take advantage in genetic counseling clinic as well as genetic testing for rapid diagnostic purposes. PMID- 26639819 TI - Middle-aged to elderly women have a higher asymptomatic infection rate with Mycobacterium avium complex, regardless of body habitus. AB - Mycobacterium avium complex (MAC) pulmonary disease is prevalent in middle-aged to elderly women with a thin body habitus. By comparing the rate of serologically diagnosed asymptomatic MAC infection and body mass index among 1033 healthy subjects, we find that middle-aged to elderly women became infected with MAC, regardless of their body habitus. PMID- 26639820 TI - Splanchnic extraction of phenylalanine in mature mares was not affected by threonine supplementation. AB - This study determined splanchnic extraction of phenylalanine at two intakes of threonine. Six Thoroughbred mares were supplemented with isonitrogenous amounts of either threonine or glutamate. Dietary threonine intakes were 119 (+Thr) and 58 (Basal) mg/kg/day, respectively. Each horse received each diet twice and each was studied once with an oral and once with an intravenous (IV) infusion of [1 (13)C]phenylalanine. A 2-h primed, constant IV infusion of [(13)C]sodium bicarbonate and a 4-h primed, constant infusion of [1-(13)C]phenylalanine, either orally or IV, were used to measure isotopic enrichments. Phenylalanine kinetics were not affected by diet (P > 0.05). Values for the splanchnic extraction of phenylalanine were 26 +/- 5% and 27 +/- 3% for the +Thr and Basal supplemented diets, respectively. These values will improve the accuracy of future equine indicator amino acid oxidation studies. PMID- 26639821 TI - Comparison of two tourniquet application times for regional intravenous limb perfusions with amikacin in sedated or anesthetized horses. AB - Regional limb perfusion (RLP) in horses has proven to be a simple and effective technique for the treatment of synovial and musculoskeletal infections in the distal portion of the limbs. The ideal tourniquet time needed to achieve therapeutic synovial concentrations remains unknown. The pharmacokinetic effects of general anesthesia (GA) versus standing sedation (SS) RLP on synovial amikacin concentrations are not completely understood. This study investigated the pharmacokinetic effects of RLP under general anesthesia (GA) versus standing sedation (SS) on synovial amikacin concentration following 20 or 30 min tourniquet time. Using 1 g of amikacin RLP was performed in two groups of six horses (GA and SS). A pneumatic tourniquet was applied proximal to the carpus and maintained for 20 or 30 min. Two weeks later, the opposite treatment (20 or 30 min) was randomly performed in the opposite limb of horses in each group (GA and SS). Synovial fluid samples were collected from the metacarpophalangeal (MCP) and radiocarpal (RC) joints. Amikacin was quantified by a fluorescence polarization immunoassay. Regardless of the group, no significant difference in the synovial amikacin concentrations was noted between 20 and 30 min RLP. Mean synovial concentrations of amikacin in the standing sedated horses were significantly higher in the MCP joint at 30 min (P = 0.003) compared to horses under general anesthesia. No significant difference was noted for the RC joint. PMID- 26639822 TI - Differential effects of propofol and isoflurane on the relationship between EEG Narcotrend index and clinical stages of anaesthetic depth in sheep undergoing experimental cardiac surgery. AB - The electroencephalogram (EEG) Narcotrend index (NI) has been shown to improve anaesthetic depth monitoring in isoflurane-anaesthetised sheep. Data obtained from 13 anaesthetised juvenile female sheep were analysed retrospectively in order to assess the relationship between clinical stages of anaesthesia (CS) and NI during both propofol and isoflurane anaesthesia. Polynomial regression analysis revealed no significant association between CS and NI for propofol (R = 0.374, R(2) = 0.140, P = 0.403) but for isoflurane anaesthesia (R = 0.548, R(2) = 0.301, P = 0.010) there was a significant relationship. Furthermore, a strong correlation existed between end-tidal isoflurane concentration (ISOET) and CS (r = -0.463, P = 0.008). A combination of assessment of clinical signs and analogous EEG patterns is recommended during propofol anaesthesia. PMID- 26639823 TI - Saddles and seats in animal and human sports: Where is your smart, wearable, real time feedback? PMID- 26639824 TI - Adelmidrol increases the endogenous concentrations of palmitoylethanolamide in canine keratinocytes and down-regulates an inflammatory reaction in an in vitro model of contact allergic dermatitis. AB - This study aimed to investigate potential new target(s)/mechanism(s) for the palmitoylethanolamide (PEA) analogue, adelmidrol, and its role in an in vitro model of contact allergic dermatitis. Freshly isolated canine keratinocytes, human keratinocyte (HaCaT) cells and human embryonic kidney (HEK)-293 cells, wild type or transfected with cDNA encoding for N-acylethanolamine-hydrolysing acid amidase (NAAA), were treated with adelmidrol or azelaic acid, and the concentrations of endocannabinoids (anandamide and 2-arachidonoylglycerol) and related mediators (PEA and oleoylethanolamide) were measured. The mRNA expression of PEA catabolic enzymes (NAAA and fatty acid amide hydrolase, FAAH), and biosynthetic enzymes (N-acyl phosphatidylethanolamine-specific phospholipase D, NAPE-PLD) and glycerophosphodiester phosphodiesterase 1, was also measured. Brain or HEK-293 cell membrane fractions were used to assess the ability of adelmidrol to inhibit FAAH and NAAA activity, respectively. HaCaT cells were stimulated with polyinosinic-polycytidylic acid and the release of the pro-inflammatory chemokine, monocyte chemotactic protein-2 (MCP-2), was measured in the presence of adelmidrol. Adelmidrol increased PEA concentrations in canine keratinocytes and in the other cellular systems studied. It did not inhibit the activity of PEA catabolic enzymes, although it reduced their mRNA expression in some cell types. Adelmidrol modulated the expression of PEA biosynthetic enzyme, NAPE-PLD, in HaCaT cells, and inhibited the release of the pro-inflammatory chemokine MCP-2 from stimulated HaCaT cells. This study demonstrates for the first time an 'entourage effect' of adelmidrol on PEA concentrations in keratinocytes and suggests that this effect might mediate, at least in part, the anti-inflammatory effects of this compound in veterinary practice. PMID- 26639825 TI - Sleeping and resting respiratory rates in dogs and cats with medically-controlled left-sided congestive heart failure. AB - Sleeping and resting respiratory rates (SRR and RRR, respectively) are commonly used to monitor dogs and cats with left-sided cardiac disease and to identify animals with left-sided congestive heart failure (L-CHF). Dogs and cats with subclinical heart disease have SRRmean values <30 breaths/min. However, little is known about SRR and RRR in dogs and cats with CHF that is well controlled with medical therapy. In this study, SRR and RRR were measured by the owners of 51 dogs and 22 cats with stable, well-controlled CHF. Median canine SRRmean was 20 breaths/min (7-39 breaths/min); eight dogs were >=25 breaths/min and one dog only was >=30 breaths/min. Canine SRRmean was unrelated to pulmonary hypertension or diuretic dose. Median feline SRRmean was 20 breaths/min (13-31 breaths/min); four cats were >=25 breaths/min and only one cat was >=30 breaths/min. Feline SRRmean was unrelated to diuretic dose. SRR remained stable during collection in both species with little day-to-day variability. The median canine RRRmean was 24 breaths/min (12-44 breaths/min), 17 were >=25 breaths/min, seven were >=30 breaths/min, two were >40 breaths/min. Median feline RRRmean was 24 breaths/min (15-45 breaths/min); five cats had RRRmean >=25 breaths/min; one had >=30 breaths/min, and two had >=40 breaths/min. These data suggest that most dogs and cats with CHF that is medically well-controlled and stable have SRRmean and RRRmean <30 breaths/min at home. Clinicians can use these data to help determine how best to control CHF in dogs and cats. PMID- 26639826 TI - Long-lasting concentrations of cefovecin after subcutaneous and intramuscular administration to Patagonian sea lions (Otaria flavescens). AB - Cefovecin is a third-generation cephalosporin developed as an aqueous solution for use by the subcutaneous route in dogs and cats. This study evaluated the duration of cefovecin plasma concentrations after single intramuscular (IM) or subcutaneous (SC) injection at different doses in 10 Patagonian sea lions (Otaria flavescens). Blood samples were collected serially from the day of the injection up to 60-90 days post-injection. Plasma drug concentrations were determined by high performance liquid chromatography-UV detection and pharmacokinetic parameters were calculated by non-compartmental analysis. No reactions or side effects associated with the drug were observed in any of the studied animals. Both routes showed very similar pharmacokinetic behaviour. Elimination half-life (11.3-21.6 days, SC; 13.1-15.9 days, IM) and mean residence time (17.6-36.8 days SC; 16.5-25.4 days IM) were, in all cases and doses, considerably longer than those previously reported for any other species. Based on these findings, and preliminary data on specific pathogen sensitivity, cefovecin was found to be a very promising antimicrobial for Patagonian sea lions, in particular those that are difficult to access or that are under certain rehabilitation conditions. PMID- 26639827 TI - Mycobacterium spp. in wild game in Slovenia. AB - Wildlife species are an important reservoir of mycobacterial infections that may jeopardise efforts to control and eradicate bovine tuberculosis (bTB), caused by Mycobacterium bovis. Slovenia is officially free of bTB, but no data on the presence of mycobacteria in wild animals has been reported. In this study, samples of liver and lymph nodes were examined from 306 apparently healthy free range wild animals of 13 species in Slovenia belonging to the families Cervidae, Suidae, Canidae, Mustelidae and Bovidae. Mycobacteria were isolated from 36/306 (11.8%) animals (red deer, roe deer, fallow deer, wild boar and jackal) and identified by PCR, commercial diagnostic kits and sequencing. Non-tuberculous mycobacteria identified in five species were Mycobacterium peregrinum, M. avium subsp. hominissuis, M. intracellulare, M. confluentis, M. fortuitum, M. terrae, M. avium subsp. avium, M. celatum, M. engbaekii, M. neoaurum, M. nonchromogenicum and M. vaccae. PMID- 26639829 TI - A single-blinded phenobarbital-controlled trial of levetiracetam as mono-therapy in dogs with newly diagnosed epilepsy. AB - Treatment of canine epilepsy is problematic. Few antiepileptic drugs have proven efficacy in dogs and undesirable adverse effects and pharmacoresistance are not uncommon. Consequently, the need for investigation of alternative treatment options is ongoing. The objective of this study was to investigate the efficacy and tolerability of levetiracetam as mono-therapy in dogs with idiopathic epilepsy. The study used a prospective single-blinded parallel group design. Twelve client-owned dogs were included and were randomised to treatment with levetiracetam (30 mg/kg/day or 60 mg/kg/day divided into three daily dosages) or phenobarbital (4 mg/kg/day divided twice daily). Control visits were at days 30, 60 and then every 3 months for up to 1 year. Two or more seizures within 3 months led to an increase in drug dosage (levetiracetam: 10 mg/kg/day, phenobarbital: 1 mg/kg/day). Five of six levetiracetam treated dogs and one of six phenobarbital treated dogs withdrew from the study within 2-5 months due to insufficient seizure control. In the levetiracetam treated dogs there was no significant difference in the monthly number of seizures before and after treatment, whereas in the phenobarbital treated dogs there were significantly (P = 0.013) fewer seizures after treatment. Five phenobarbital treated dogs were classified as true responders (>=50% reduction in seizures/month) whereas none of the levetiracetam treated dogs fulfilled this criterion. Adverse effects were reported in both groups but were more frequent in the phenobarbital group. In this study levetiracetam was well tolerated but was not effective at the given doses as mono therapy in dogs with idiopathic epilepsy. PMID- 26639828 TI - The pharmacokinetics of the beta2-adrenoceptor agonist, tulobuterol, in Beagle dogs following transdermal and intravenous administration. AB - Tulobuterol is a beta2-adrenergic agonist that was the first bronchodilator approved as a transdermal patch for humans. Previous studies have examined the pharmacokinetics of tulobuterol in humans but not in the veterinary species. In this study, the pharmacokinetics of tulobuterol was examined in healthy Beagle dogs after transdermal and intravenous administration. The Cmax was 2.09 ng/mL at 16.0 h for a 0.2 mg/kg patch and 4.85 ng/mL at 13.6 h for a 0.4 mg/kg patch. The effective blood level in humans is 1-3 ng/mL, a concentration achieved using the 0.2 mg/kg patch in dogs. In conclusion, application of a 0.2 mg/kg tulobuterol patch to healthy dogs led to an apparently effective blood concentration for 24 h. PMID- 26639831 TI - A test of the universal applicability of a commonly used principle of hoof balance. AB - This study used a UK trimming protocol to determine whether hoof balance is achieved (as defined by equivalence of geometric proportions) in cadaver limbs (n = 49) and two cohorts of horses (shod, n = 6, and unshod, n = 20; three trimming cycles). To determine equivalence, dorsal hoof wall length (DHWL), distance from the heel buttress to the centre of pressure (HBUT-COP) and distance from dorsal toe to centre of rotation (DT-COR) were calculated as a proportion of bearing border length (BBL) using digital photography. Geometric proportions were tested using Fieller's test of equivalence with limits of difference of 2.8%. In 22 cadaver limbs the location of external COR and COP was also mapped radiographically to the extensor process of the third phalanx and the centre of rotation of the distal interphalangeal joint. Equivalence of geometric proportions was not present following trimming in cadaver limbs or in the two cohorts. Although the dorsal hoof wall to heel wall ratio improved in cadaver and unshod horses after trimming, dorsal hoof wall and lateral heel parallelism was absent in all groups and COP was not consistently in line with the extensor process. Increased COP-COR distance occurred in shod horses and may relate to solar arch flattening. Palmar heel migration, however, occurred more in unshod horses. The study shows that equivalence of geometric proportions as a measure of static hoof balance was not commonly present and widely published measures and ratios of hoof balance rarely occurred in this sample population of horses. PMID- 26639830 TI - Clinical and microbiological effects of a subantimicrobial dose of oral doxycycline on periodontitis in dogs. AB - Doxycycline is regarded as an effective treatment for periodontal inflammation. In humans, it has been shown that the long-term administration of a subantimicrobial dose of doxycycline (SDD) does not induce antimicrobial effects on the subgingival microflora and furthermore does not affect antimicrobial susceptibility. The present study was designed to evaluate the influence of oral administration of SDD on normal periodontal microflora and antimicrobial susceptibility in dogs. Experimental periodontitis was induced in 12 experimental dogs using a silk and wire-twisted ligature for 60 days. After the periodontitis induction period, the ligature was removed, and dental cleaning (subgingival and supragingival ultrasonic scaling) was performed. The dogs were randomly assigned to one of two groups: an SDD group with six dogs receiving 2 mg/kg PO once daily and a control group with six dogs receiving a placebo. At weeks 0, 4 and 8, clinical periodontal parameters were evaluated. After the clinical assessments, subgingival plaque was sampled and then cultured in an anaerobic system for one week, and the total anaerobes, Porphyromonas spp., Bacteroides spp. and Pasteurella spp. counts were investigated. Using the agar dilution method, the minimum bactericidal concentration of doxycycline was evaluated and the resistance for doxycycline was monitored during this experimental phase. The clinical periodontal status of the SDD group was significantly improved compared to the control group (P <0.05). Bacterial counts were not significantly different between the two experimental groups (P > 0.05), and antibacterial resistance was not established in the SDD group during the experimental periods (P <0.05). These results suggest that the once daily oral regimen of 2 mg/kg of doxycycline could serve as a SDD in dogs. PMID- 26639832 TI - Myoepithelial cells in canine mammary tumours. AB - Mammary tumours are the most common neoplasms of female dogs. Compared to mammary tumours of humans and cats, myoepithelial (ME) cell involvement is common in canine mammary tumours (CMT) of any subtype. Since ME cell involvement in CMT influences both histogenetic tumour classification and prognosis, correct identification of ME cells is important. This review describes immunohistochemical methods for identification of canine mammary ME cells used in vivo. In addition, phenotypic and genotypic methods to isolate ME cells for in vitro studies to analyse tumour-suppressor protein production and gene expression are discussed. The contribution of ME cells to both histogenetic classifications and the prognosis of CMT is compared with other species and the potential use of ME cells as a method to identify carcinoma in situ is discussed. PMID- 26639833 TI - Pharmacokinetics and pharmacodynamics of ramipril and ramiprilat after intravenous and oral doses of ramipril in healthy horses. AB - The pharmacokinetics and pharmacodynamics (PK/PD) of the angiotensin-converting enzyme inhibitor (ACEI) ramiprilat after intravenous (IV) and oral (PO) administration of ramipril have not been evaluated in horses. This study was designed to establish PK profiles for ramipril and ramiprilat as well as to determine the effects of ramiprilat on serum angiotensin converting enzyme (ACE) and to select the most appropriate ramipril dose that suppresses ACE activity. Six healthy horses in a cross-over design received IV ramipril 0.050 mg/kg, PO at a dose of 0 (placebo), and 0.050, 0.10, 0.20, 0.40 and 0.80 mg/kg ramipril. Blood pressures were measured and blood samples obtained at different times. Serum ramipril and ramiprilat concentrations and serum ACE activity were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and spectrophotometry, respectively. Systemic bioavailability of ramiprilat after PO ramipril was 6-9%. Percentages of maximum ACE inhibitions from baseline were 98.88 (IV ramipril), 5.31 (placebo) and 27.68, 39.27, 46.67, 76.13 and 84.27 (the five doses of PO ramipril). Blood pressure did not change during the experiments. Although oral availability of ramiprilat was low, ramipril has sufficient enteral absorption and bioconversion to ramiprilat to induce serum ACE inhibitions of almost 85% after a dose of 0.80 mg/kg ramipril. Additional research on ramipril administration in equine patients is indicated. PMID- 26639834 TI - Migraine Triggers and Oxidative Stress: A Narrative Review and Synthesis. AB - BACKGROUND: Blau theorized that migraine triggers are exposures that in higher amounts would damage the brain. The recent discovery that the TRPA1 ion channel transduces oxidative stress and triggers neurogenic inflammation suggests that oxidative stress may be the common denominator underlying migraine triggers. OBJECTIVE: The aim of this review is to present and discuss the available literature on the capacity of common migraine triggers to generate oxidative stress in the brain. METHODS: A Medline search was conducted crossing the terms "oxidative stress" and "brain" with "alcohol," "dehydration," "water deprivation," "monosodium glutamate," "aspartame," "tyramine," "phenylethylamine," "dietary nitrates," "nitrosamines," "noise," "weather," "air pollutants," "hypoglycemia," "hypoxia," "infection," "estrogen," "circadian," "sleep deprivation," "information processing," "psychosocial stress," or "nitroglycerin and tolerance." "Flavonoids" was crossed with "prooxidant." The reference lists of the resulting articles were examined for further relevant studies. The focus was on empirical studies, in vitro and of animals, of individual triggers, indicating whether and/or by what mechanism they can generate oxidative stress. RESULTS: In all cases except pericranial pain, common migraine triggers are capable of generating oxidative stress. Depending on the trigger, mechanisms include a high rate of energy production by the mitochondria, toxicity or altered membrane properties of the mitochondria, calcium overload and excitotoxicity, neuroinflammation and activation of microglia, and activation of neuronal nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. For some triggers, oxidants also arise as a byproduct of monoamine oxidase or cytochrome P450 processing, or from uncoupling of nitric oxide synthase. CONCLUSIONS: Oxidative stress is a plausible unifying principle behind the types of migraine triggers encountered in clinical practice. The possible implications for prevention and for understanding the nature of the migraine attack are discussed. PMID- 26639837 TI - Complement Interference Is Not the Same as a Prozone Phenomenon. PMID- 26639839 TI - Systematic comparison of variant calling pipelines using gold standard personal exome variants. AB - The success of clinical genomics using next generation sequencing (NGS) requires the accurate and consistent identification of personal genome variants. Assorted variant calling methods have been developed, which show low concordance between their calls. Hence, a systematic comparison of the variant callers could give important guidance to NGS-based clinical genomics. Recently, a set of high confident variant calls for one individual (NA12878) has been published by the Genome in a Bottle (GIAB) consortium, enabling performance benchmarking of different variant calling pipelines. Based on the gold standard reference variant calls from GIAB, we compared the performance of thirteen variant calling pipelines, testing combinations of three read aligners--BWA-MEM, Bowtie2, and Novoalign--and four variant callers--Genome Analysis Tool Kit HaplotypeCaller (GATK-HC), Samtools mpileup, Freebayes and Ion Proton Variant Caller (TVC), for twelve data sets for the NA12878 genome sequenced by different platforms including Illumina2000, Illumina2500, and Ion Proton, with various exome capture systems and exome coverage. We observed different biases toward specific types of SNP genotyping errors by the different variant callers. The results of our study provide useful guidelines for reliable variant identification from deep sequencing of personal genomes. PMID- 26639836 TI - Infectious Progeny of 2009 A (H1N1) Influenza Virus Replicated in and Released from Human Neutrophils. AB - Various reports have indicated that a number of viruses could infect neutrophils, but the multiplication of viruses in neutrophils was abortive. Based on our previous finding that avian influenza viral RNA and proteins were present in the nucleus of infected human neutrophils in vivo, we investigated the possibility of 2009 A (H1N1) influenza viral synthesis in infected neutrophils and possible release of infectious progeny from host cells. In this study we found that human neutrophils in vitro without detectable level of sialic acid expression could be infected by this virus strain. We also show that the infected neutrophils can not only synthesize 2009 A (H1N1) viral mRNA and proteins, but also produce infectious progeny. These findings suggest that infectious progeny of 2009 A (H1N1) influenza virus could be replicated in and released from human neutrophils with possible clinical implications. PMID- 26639840 TI - Formation of Gel-like Nanodomains in Cholesterol-Containing Sphingomyelin or Phosphatidylcholine Binary Membrane As Examined by Fluorescence Lifetimes and (2)H NMR Spectra. AB - In this study, we measured the time-resolved fluorescence of trans-parinaric acid (tPA), steady-state fluorescence anisotropy of diphenylhexatriene (DPH), and (2)H NMR of 10,10-d2-stearoyl lipids in stearoyl sphingomyelin with cholesterol (SSM/Chol) and l-palmitoyl-2-stearoyl-sn-glycero-3-phosphocholine with Chol (PSPC/Chol) binary membranes. The results suggest that the membrane order obtained from the fluorescence experiments shows a similar temperature dependency as those of the (2)H NMR data. More importantly, the time-resolved fluorescence data implied the presence of at least two types of domains, cholesterol-poor gel like domains (CPGLD) and cholesterol-enriched liquid-ordered (Lo) domains. These domains appear on a nano-to-micro second time scale for both SSM-Chol and PSPC Chol membranes. The relative size of the gel-like domain was also estimated from the temperature-dependent lifetime measurements and (2)H NMR spectral changes. The results imply that the size of the gel-like domains is very small, probably on the nanometer scale, and smaller in SSM-Chol membrane than those in PSPC-Chol bilayers, which could account for the higher thermal stability of SM-Chol membranes. The present study demonstrates that gel-like nanodomains occur in SM Chol binary membrane even with Chol content of over 33 mol %, which has been thought to consist exclusively of Lo phase, implying that not only Lo domains but also gel-like nanodomains are important for formation of lipid-ordered phase in SM-Chol and PC-Chol membranes. PMID- 26639841 TI - The leafminer Liriomyza trifolii (Diptera: Agromyzidae) encapsulates its koinobiont parasitoid Halticoptera circulus (Hymenoptera: Pteromalidae): implications for biological control. AB - The koinobiont parasitoid Halticoptera circulus (Walker) is a potential biological control agent of leafminers, but it has only rarely been collected from the invasive leafminer, Liriomyza trifolii (Burgess), in Japan. To understand why this is the case, parasitism and development of H. circulus in L. trifolii was compared with parasitism and development in two indigenous leafminer species, Liriomyza chinensis Kato and Chromatomyia horticola (Goureau). There was no significant difference in parasitism rates by H. circulus in the three leafminer species and the eggs and larvae successfully developed in L. chinensis and C. horticola. However, H. circulus failed to develop in L. trifolii, where developmental stages were encapsulated by host haemocytes. This parasitoid may be a good agent to control indigenous leafminers such as L. chinensis and C. horticola but is unlikely to be useful for the biological control of the invasive L. trifolii in Japan. PMID- 26639842 TI - Effects of Fatty Liver Induced by Excess Orotic Acid on B-Group Vitamin Concentrations of Liver, Blood, and Urine in Rats. AB - Fatty liver is caused when rats are given orotic acid of the pyrimidine base in large quantities. The lack of B-group vitamins suppresses the biosynthesis of fatty acids. We investigated how orotic acid-induced fatty liver affects the concentrations of liver, blood, and urine B-group vitamins in rats. The vitamin B6 and B12 concentrations of liver, blood, and urine were not affected by orotic acid-induced fatty liver. Vitamin B2 was measured only in the urine, but was unchanged. The liver, blood, and urine concentrations of niacin and its metabolites fell dramatically. Niacin and its metabolites in the liver, blood, and urine were affected as expected. Although the concentrations of vitamin B1, pantothenic acid, folate, and biotin in liver and blood were decreased by orotic acid-induced fatty liver, these urinary excretion amounts showed a specific pattern toward increase. Generally, as for the typical urinary excretion of B group vitamins, these are excreted when the body is saturated. However, the ability to sustain vitamin B1, pantothenic acid, folate, and biotin decreased in fatty liver, which is hypothesized as a specific phenomenon. This metabolic response might occur to prevent an abnormally increased biosynthesis of fatty acids by orotic acid. PMID- 26639843 TI - Long-Term Vitamin E-Deficient Mice Exhibit Cognitive Dysfunction via Elevation of Brain Oxidation. AB - Vitamin E inhibits oxidative processes in living tissues. We produced vitamin E deficient mice by feeding them a vitamin E-deficient diet to verify the influence of chronic vitamin E deficiency on cognitive function. We measured cognitive function over a 5-d period using the Morris water maze task, as well as antioxidant enzyme activity and lipid peroxidation in discrete brain regions, and total serum cholesterol content. Three- and six-mo-old vitamin E-deficient and age-matched control mice were used. In addition, 24-mo-old mice were used as an aged-model. In the 3-mo-old mice, cognitive function in the vitamin E-deficient (short-term vitamin E-deficient) group was significantly impaired compared to age matched controls. Although the lipid peroxidation products in the cerebral cortex, cerebellum and hippocampus did not significantly differ in 3-mo-old mice, the levels in the 6-mo-old vitamin E-deficient (long-term vitamin E-deficient) mice were significantly increased compared to age-matched controls. Serum cholesterol content was also significantly increased in the short- and long-term vitamin E-deficient mice compared to their respective age-matched controls. These results indicate that chronic vitamin E deficiency may slowly accelerate brain oxidation. Thus, vitamin E concentrations may need to be monitored in order to prevent the risk of cognitive dysfunction, even under normal conditions. PMID- 26639844 TI - Characterization of Thiamin Phosphate Kinase in the Hyperthermophilic Archaeon Pyrobaculum calidifontis. AB - Thiamin pyrophosphate is an essential cofactor in all living systems. In its biosynthesis, the thiamin structure is initially formed as thiamin phosphate from a thiazole and a pyrimidine moiety, and then thiamin pyrophosphate is synthesized from thiamin phosphate. Many eubacterial cells directly synthesize thiamin pyrophosphate by the phosphorylation of thiamin phosphate by thiamin phosphate kinase (ThiL), whereas this final step occurs in two stages in eukaryotic cells and some eubacterial cells: hydrolysis of thiamin phosphate to free thiamin and its pyrophosphorylation by thiamin pyrophosphokinase. In addition, some eubacteria have thiamin kinase, a salvage enzyme that converts the incorporated thiamin from the environment to thiamin phosphate. This final step in thiamin biosynthesis has never been experimentally investigated in archaea, although the putative thiL genes are found in their genome database. In this study, we observed thiamin phosphate kinase activity in the soluble fraction of the hyperthermophilic archaeon Pyrobaculum calidifontis. On the other hand, neither thiamin pyrophosphokinase nor thiamin kinase activity was detected, suggesting that in this archaeon the phosphorylation of thiamin phosphate is only way to synthesize thiamin pyrophosphate and it cannot use exogenous thiamin for the salvage synthesis of thiamin pyrophosphate. We also investigated the kinetic properties of thiamin phosphate kinase activity using the recombinant ThiL protein from P. calidifontis. Furthermore, the results obtained by site-directed mutagenesis suggest that the Ser196 of ThiL protein plays a pivotal role in the catalytic process. PMID- 26639845 TI - Glycyrrhiza glabra L. Extract Inhibits LPS-Induced Inflammation in RAW Macrophages. AB - Glycyrrhiza glabra has been used in medicine for thousands of years. Our previous study revealed that the methanolic extract of Glycyrrhiza glabra L. (EGGR) exhibits significant nitric oxide (NO) inhibitory effect on lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages among 100 other extracts. Accordingly, the aim of the present study was to investigate the potential anti-inflammatory effect of EGGR. The anti-inflammatory effect of EGGR on LPS-stimulated RAW 264.7 macrophages was measured by MTT assay, NO content analysis, reactive oxygen species (ROS) level analysis, RT-PCR, Western blot analysis, and ELISA assay. Low doses of EGGR were non-toxic to macrophages and imparted protective effect against LPS induced cell death. Incubation of LPS-treated macrophages with 100 MUg/mL EGGR led to an increase in cell viability from 66.6 to 99%. Moreover, EGGR led to down regulation of NO (NO2+NO3) and ROS productions in a dose-dependent manner. In particular, 100 MUg/mL EGGR led to a reduction in NO2+NO3 level from 336.2 to 24.1 pM/mL, and ROS level from 483.5 to 128.4%. Consistent with the result related to NO production, EGGR suppressed the ability of LPS to induce mRNA and protein expressions of nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) cytokines, tumor necrosis factor-alpha (TNF-alpha), interleukin 1beta (IL 1beta), and IL-6 productions which were analyzed by an ELISA assay. These results provide a comprehensive approach into the anti-inflammatory effect of EGGR on LPS stimulated macrophages; however, efforts are underway on gaining detailed insight into anti-inflammatory signaling pathways. PMID- 26639846 TI - Zinc Deficiency Increases Serum Concentrations of Parathyroid Hormone through a Decrease in Serum Calcium and Induces Bone Fragility in Rats. AB - We hypothesized that a zinc-deficient diet alters the mineral (calcium, magnesium, and phosphorus) components of bones, as well as hormones related to bone remodeling, and negatively affects bone metabolism. Four-week-old male Wistar rats were randomly assigned to one of three groups for 4 wk: a zinc adequate group (C, 30 ppm); a zinc-deficient group (ZD, 1 ppm); and a pair-fed group (PF, 30 ppm), which was pair-fed to the ZD group. Bone mineral density and bone mechanical properties were reduced in the ZD group compared to the C and PF groups. Compared with the C and PF groups, serum osteocalcin, a bone formation marker, was reduced in the ZD group. Conversely, urine deoxypyridinoline, a bone resorption marker, was increased in the ZD group compared to the C and PF groups. Calcium and phosphorus concentrations in bone were not different among all groups. The bone magnesium concentration was significantly higher in the ZD group than in the PF and C groups. Interestingly, compared with the C and PF groups, the ZD group showed a reduction in serum calcium concentration along with an increase in serum parathyroid hormone (PTH) concentration. Although serum 1,25 dihydroxycholecalciferol concentration was significantly higher in the ZD and PF groups than in the C group, the rate of apparent calcium absorption was significantly lower in the ZD group than in the C and PF groups. Therefore, zinc deficiency is suspected to cause an increase in serum PTH concentration owing to an inability to maintain calcium homeostasis, resulting in bone fragility. PMID- 26639847 TI - The Impact of Different Amounts of Calcium Intake on Bone Mass and Arterial Calcification in Ovariectomized Rats. AB - Reduced estrogen secretion and low calcium (Ca) intake are risk factors for bone loss and arterial calcification in female rodents. To evaluate the effects of Ca intake at different amounts on bone mass changes and arterial calcification, 8-wk old female Wistar rats were randomly placed in ovariectomized (OVX) control and OVX with vitamin D3 plus nicotine (VDN) treatment groups. The OVX with VDN rats were then divided into six groups to receive different amounts of Ca in their diets: 0.01%, 0.1%, 0.3%, 0.6%, 1.2%, or 2.4% Ca. After 8 wk of administration, low Ca intake groups with 0.01% and 0.1% Ca diets had significantly reduced bone mineral density (BMD) and bone mechanical properties as compared with those of the other groups, whereas high Ca intake groups with 1.2% and 2.4% Ca diets showed no differences as compared with the 0.6% Ca intake group. For both the 0.01% and 2.4% Ca intake groups, Ca levels in their thoracic arteries were significantly higher as compared with those of the 0.6% Ca diet group, and that was highly correlated with serum PTH levels. An increase in relative BMP-2 mRNA expression in the arterial tissues of the 0.01% and 2.4% Ca diet groups was also observed. These results suggested that extremely low Ca intake during periods of estrogen deficiency may be a possible risk for the complications of reduced BMD and arterial calcification and that extremely high Ca intake may promote arterial calcification with no changes in BMD. PMID- 26639848 TI - Rush Oral Immunotherapy Does Not Reduce Allergic Response in Mice with Mild Allergy to Egg White Ovomucoid. AB - Oral immunotherapy (OIT) is a promising therapeutic approach for treating food allergy. Past studies have shown that OIT reduces allergic response only in severe allergy model mice. We worked to establish mild allergy model mice, and investigated whether 'rush' OIT for 10 d improved the allergic response and biomarkers in these mice. Balb/c mice were sensitized to ovomucoid (OM) in alum. The rush OIT was done for 10 d. Oral OM challenge was used to determine the impact of OIT on the allergic response. We measured allergic biomarkers, such as vascular permeability in the skin, plasma levels of total IgE, OM-specific IgE, IgG1 and IgG2a and cytokines in splenocyte culture supernatant. OIT for 10 d did not improve allergy symptoms and increased vascular permeability. Total IgE in the plasma of OIT-treated mice was significantly higher than in that of non treated mice. OM-specific IgG1 and IgG2a plasma levels were not significantly different between OIT-treated and non-treated mice. Among the cytokine secretion of splenocyte from OIT-treated mice, IFN-gamma and IL-10 were significantly lower than in non-treated mice, and IL-4 and IL-5 were significantly higher. Total TGF beta in the OIT-treated group was not detected. The IFN-gamma/IL-4 ratio of the OIT-treated group was about 1/8 that of the non-treated group. OIT for 10 d was not effective and some biomarkers showed negative responses in the mild allergy model mice. We suggest OIT should be used very carefully as this treatment carries a risk of worsening allergy symptoms for mice with mild allergy. PMID- 26639849 TI - Enhancement of Fat Oxidation by Licorice Flavonoid Oil in Healthy Humans during Light Exercise. AB - Licorice flavonoid oil (LFO) is a new functional food ingredient consisting of hydrophobic licorice polyphenols in medium-chain triglycerides. Recent studies reported that LFO prevented and ameliorated diet-induced obesity via the regulation of lipid metabolism-related gene expression in the livers of mice and rats, while it reduced body weight in overweight human subjects by reducing total body fat. However, the direct effects of LFO on energy metabolism have not been studied in human subjects. Therefore, we investigated the effects of ingestion of LFO on energy metabolism, including fat oxidation, by measuring body surface temperature under resting conditions and respiratory gas analysis under exercise conditions in healthy humans. We showed that ingestion of a single 600 mg dose of LFO elevated body trunk skin temperature when measured in a slightly cooled air conditioned room, and increased oxygen consumption and decreased the respiratory exchange ratio as measured by respiratory gas analysis during 40% Vo2max exercise with a cycle ergometer. Furthermore, repeated ingestion of 300 mg of LFO for 8 d decreased respiratory exchange during the recovery period following 40 min of 30% Vo2max exercise on a treadmill. These results suggest that LFO enhances fat oxidation in humans during light exercise. PMID- 26639850 TI - Comparison of the Effects of Ornithine and Arginine on the Brain Protein Synthesis Rate in Young Rats. AB - Brain protein synthesis and the plasma concentration of growth hormone (GH) are sensitive to dietary ornithine. The purpose of this study was to determine whether dietary arginine, the metabolite of ornithine, affects the brain protein synthesis, and to that end, the effects of arginine on brain protein synthesis were compared with that of ornithine treatment in young rats. Two experiments were done on five or three groups of young rats (5-wk-old) given 0%, 0.25%, 0.5%, 0.7% arginine or 0.7% ornithine-HCl added to a 20% casein diet for 1 d (only one 3 h period) (Experiment 1), or given a diet containing 0% or 0.7% ornithine-HCl or 0.7% arginine added to a 20% casein diet (Experiment 2). The concentrations of plasma growth hormone (GH) and fractional rates of protein synthesis in the brains increased significantly with the 20% casein+0.7% arginine diet and still more with the 20% casein+0.7% ornithine diet compared with the 20% casein diet alone. In the cerebral cortex and cerebellum, the RNA activity [g protein synthesized/(g RNA*d)] significantly correlated with the fractional rate of protein synthesis. The RNA concentration (mg RNA/g protein) was also related to the fractional rate of protein synthesis in these organs. The results suggest that the treatment with arginine is likely to increase the concentrations of GH and the rate of brain protein synthesis in rats, and that the effects of arginine on brain protein synthesis and GH concentration were lower than that of ornithine. The RNA activity is at least partly related to the fractional rate of brain protein synthesis. PMID- 26639851 TI - Little Effect of Supplementation with 0.6% Energy Trans Fatty Acids on Serum Cholesterol Levels in Adult Japanese Women. AB - The excessive intake of trans fatty acids (TFAs) increases serum LDL-cholesterol and reduces HDL-cholesterol. Limited data exist regarding the low-level intake of TFAs, and the tolerable upper-limit level remains to be fully elucidated. A randomized, double-blind, parallel trial was conducted to assess the effects of a low level of TFA supplementation on serum cholesterol levels in healthy adult Japanese women. The volunteers who participated in this examination took in approximately 0.4% of energy (%E) TFAs from daily meals. Fifty-one volunteers consumed one cookie containing 0.6%E (TFA) or 0.04%E (control) of TFAs every day for 4 wk, and blood was harvested after overnight fasting. The mean TFA intakes of the control and TFA groups during the experimental period were 0.4%E and 1.1%E, respectively. There were no significant differences in serum total, LDL- or HDL-cholesterol levels between the control and TFA groups. The serum glucose and insulin levels were not influenced by TFA supplementation. These results confirm that dietary supplementation with 0.6%E TFAs (a total TFA intake of approximately 1%E) would have little effect on serum cholesterol levels in healthy adult Japanese women. PMID- 26639852 TI - The Frequency of Fish-Eating Could Negatively Associate with Visceral Adiposity in Those Who Eat Moderately. AB - Visceral fat accumulation is regarded as one of the major phenotypes of metabolic syndrome. There have not been enough data on the relationship between the fish eating habit and visceral adiposity. A total of 94 male participants received abdominal CT for the measurement of the visceral fat area (VFA), serum sampling for the fatty acid composition and questionnaires about their life-style. We divided the participants into two groups: whether they ate their fill (group F, n=70) or they ate in moderation (group M, n=24). Stepwise multiple linear regression analyses showed that usual alcohol consumption and lower daily physical activity in group F, and infrequent fish-eating and frequent fat-rich deserts in group M were the significant positive correlates with the VFA. The serum eicosapentaenoic acid (EPA)/arachidonic acid (AA) ratio showed significant correlation with the frequency of fish-eating in both groups. Interestingly, in group M, the serum EPA/AA ratio negatively correlated with the VFA, while it failed in group F. In conclusion, the present data suggest that the fish-eating habit might negatively associate with visceral fat accumulation only in those who are moderate in eating in the general population. PMID- 26639854 TI - LRP12 silencing during brain development results in cortical dyslamination and seizure sensitization. AB - Correct positioning and differentiation of neurons during brain development is a key precondition for proper function. Focal cortical dysplasias (FCDs) are increasingly recognized as causes of therapy refractory epilepsies. Neuropathological analyses of respective surgical specimens from neurosurgery for seizure control often reveal aberrant cortical architecture and/or aberrantly shaped neurons in FCDs. However, the molecular pathogenesis particularly of FCDs with aberrant lamination (so-called FCD type I) is largely unresolved. Lipoproteins and particularly low-density lipoprotein receptor-related protein 12 (LRP12) are involved in brain development. Here, we have examined a potential role of LRP12 in the pathogenesis of FCDs. In vitro knockdown of LRP12 in primary neurons results in impaired neuronal arborization. In vivo ablation of LRP12 by intraventricularly in utero electroporated shRNAs elicits cortical maldevelopment, i.e. aberrant lamination by malpositioning of upper cortical layer neurons. Subsequent epilepsy phenotyping revealed pentylenetetrazol (PTZ) induced seizures to be aggravated in cortical LRP12-silenced mice. Our data demonstrates IUE mediated cortical gene silencing as an excellent approach to study the role of distinct molecules for epilepsy associated focal brain lesions and suggests LRP12 and lipoprotein homeostasis as potential molecular target structures for the emergence of epilepsy-associated FCDs. PMID- 26639853 TI - Modulation of serotonergic transmission by eltoprazine in L-DOPA-induced dyskinesia: Behavioral, molecular, and synaptic mechanisms. AB - L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesias (LIDs) represent the main side effect of Parkinson's Disease (PD) therapy. Among the various pharmacological targets for novel therapeutic approaches, the serotonergic system represents a promising one. In experimental models of PD and in PD patients the development of abnormal involuntary movements (AIMs) and LIDs, respectively, is accompanied by the impairment of bidirectional synaptic plasticity in key structures such as striatum. Recently, it has been shown that the 5-HT1A/1B receptor agonist, eltoprazine, significantly decreased LIDs in experimental PD and human patients. Despite the fact that several papers have tested this and other serotonergic drugs, nothing is known about the electrophysiological consequences on this combined serotonin receptors modulation at striatal neurons. The present study demonstrates that activation of 5-HT1A/1B receptors reduces AIMs via the restoration of Long-Term Potentiation (LTP) and synaptic depotentiation in a sub-set of striatal spiny projection neurons (SPNs). This recovery is associated with the normalization of D1 receptor-dependent cAMP/PKA and ERK/mTORC signaling pathways, and the recovery of NMDA receptor subunits balance, indicating these events as key elements in AIMs induction. Moreover, we analyzed whether the manipulation of the serotonergic system might affect motor behavior and cognitive performances. We found that a defect in locomotor activity in parkinsonian and L-DOPA-treated rats was reversed by eltoprazine treatment. Conversely, the impairment in the striatal-dependent learning was found exacerbated in L-DOPA-treated rats and eltoprazine failed to recover it. PMID- 26639856 TI - Strategies to reduce perinatal mortality. PMID- 26639855 TI - Electrocorticography reveals beta desynchronization in the basal ganglia-cortical loop during rest tremor in Parkinson's disease. AB - The pathophysiology of rest tremor in Parkinson's disease (PD) is not well understood, and its severity does not correlate with the severity of other cardinal signs of PD. We hypothesized that tremor-related oscillatory activity in the basal-ganglia-thalamocortical loop might serve as a compensatory mechanism for the excessive beta band synchronization associated with the parkinsonian state. We recorded electrocorticography (ECoG) from the sensorimotor cortex and local field potentials (LFP) from the subthalamic nucleus (STN) in patients undergoing lead implantation for deep brain stimulation (DBS). We analyzed differences in measures of network synchronization during epochs of spontaneous rest tremor, versus epochs without rest tremor, occurring in the same subjects. The presence of tremor was associated with reduced beta power in the cortex and STN. Cortico-cortical coherence and phase-amplitude coupling (PAC) decreased during rest tremor, as did basal ganglia-cortical coherence in the same frequency band. Cortical broadband gamma power was not increased by tremor onset, in contrast to the movement-related gamma increase typically observed at the onset of voluntary movement. These findings suggest that the cortical representation of rest tremor is distinct from that of voluntary movement, and support a model in which tremor acts to decrease beta band synchronization within the basal ganglia cortical loop. PMID- 26639858 TI - Physcomitrella patens DNA methyltransferase 2 is required for recovery from salt and osmotic stress. AB - DNA methyltransferase 2 (DNMT2) unlike other members of the cytosine DNA methyltransferase gene family has dual substrate specificity and it methylates cytosines in both the DNA and transfer RNA (tRNA). Its role in plants, however, has remained obscure to date. In this study, we demonstrate that DNMT2 from Physcomitrella patens accumulates in a temporal manner under salt and osmotic stress showing maximum accumulation during recovery, i.e. 24 h after plants are transferred to normal growth medium. Therefore, to study its role in stress tolerance, we generated PpDNMT2 targeted knockout plants (ppdnmt2ko). Mutant plants show increased sensitivity to salt and osmotic stress and are unable to recover even after 21 days of growth on optimal growth media. ppdnmt2ko, however, accumulate normal levels of dehydrin-like and small heat shock protein encoding transcripts under stress but show dramatic reduction in levels of tRNA(A) (sp-) (GUC) . The levels of tRNA(A) (sp-) (GUC) , in contrast, increase ~ 25-30-fold in ppdnmt2ko under non-stress conditions and > 1200-fold in wild-type plants under stress. The role of PpDNMT2 in modulating biogenesis/stability of tRNA(A) (sp-) (GUC) under salt and osmotic stress is discussed in the light of these observations. PMID- 26639870 TI - Elastic staining does not assist detection of venous invasion in cutaneous melanoma. AB - The aim of the present study was to determine the benefit of orcein elastic staining of primary cutaneous melanoma specimens in detecting venous invasion. Primary cutaneous melanomas in vertical growth phase were assessed for vascular invasion. All tumour blocks were stained with haematoxylin and eosin (H&E) and orcein. The cases were reviewed by two pathologists. Vascular invasion was not identified more frequently on orcein stained slides than on H&E stained ones. Elastosis and periappendiceal elastic fibres interfered with vascular invasion detection with elastic staining. Based on our study, we conclude that elastic stains such as orcein do not improve the detection rate of venous invasion in primary cutaneous melanomas. PMID- 26639857 TI - Cost and cost-effectiveness of newborn home visits: findings from the Newhints cluster-randomised controlled trial in rural Ghana. AB - BACKGROUND: Every year, 2.9 million newborn babies die worldwide. A meta-analysis of four cluster-randomised controlled trials estimated that home visits by trained community members in programme settings in Ghana and south Asia reduced neonatal mortality by 12% (95% CI 5-18). We aimed to estimate the costs and cost effectiveness of newborn home visits in a programme setting. METHODS: We prospectively collected detailed cost data alongside the Newhints trial, which tested the effect of a home-visits intervention in seven districts in rural Ghana and showed a reduction of 8% (95% CI -12 to 25%) in neonatal mortality. The intervention consisted of a package of home visits to pregnant women and their babies in the first week of life by community-based surveillance volunteers. We calculated incremental cost-effectiveness ratios (ICERs) with Monte Carlo simulation and one-way sensitivity analyses and characterised uncertainty with cost-effectiveness planes and cost-effectiveness acceptability curves. We then modelled the potential cost-effectiveness for baseline neonatal mortality rates of 20-60 deaths per 1000 livebirths with use of a meta-analysis of effectiveness estimates. FINDINGS: In the 49 zones randomly allocated to receive the Newhints intervention, a mean of 407 (SD 18) community-based surveillance volunteers undertook home visits for 7848 pregnant women who gave birth to 7786 live babies in 2009. Annual economic cost of implementation was US$203 998, or $0.53 per person. In the base-case analysis, the Newhints intervention cost a mean of $10 343 (95% CI 2963 to -7674) per newborn life saved, or $352 (95% CI 104 to -268) per discounted life-year saved, and had a 72% chance of being highly cost effective with respect to Ghana's 2009 gross domestic product per person. Key determinants of cost-effectiveness were the discount rate, protective effectiveness, baseline neonatal mortality rate, and implementation costs. In the scenarios modelled with the meta-analysis results, the ICER increased from $127 per life-year saved at a neonatal mortality rate of 60 deaths per 1000 livebirths, to $379 per life-year saved at a rate of 20 deaths per 1000 livebirths. The strategy had at least a 99% probability of being highly cost effective for lower-middle-income countries in all neonatal mortality rate scenarios modelled, and at least a 95% probability of being highly cost effective for low-income countries at neonatal mortality rates of 30 or more deaths per 1000 livebirths. INTERPRETATION: Our findings show that the seemingly modest mortality reductions achieved by a newborn home-visit strategy might in fact be cost effective. In Ghana, such strategies are also likely to be affordable. Our findings support recommendations from WHO and UNICEF that low-income and middle income countries implement newborn home visits. FUNDING: The Bill & Melinda Gates Foundation, UK Department for International Development, WHO. PMID- 26639871 TI - Anaerococcus nagyae sp. nov., isolated from human clinical specimens. AB - We describe a new Anaerococcus species isolated from human clinical specimens. Analyses of 16S rRNA gene sequences of three strains showed <98% similarity with its closest relative Anaerococcus octavius. Phylogenetically the isolated strains form a cluster and can be differentiated from other species of the genus Anaerococcus based on its phenotypic characteristics and its MALDI-TOF MS profile. We propose the name Anaerococcus nagyae, with A. nagyae DSM101193 (accession number KU043522) as the type strain. PMID- 26639872 TI - MoD Special issue on "Upstream and Downstream of Hox Genes. PMID- 26639892 TI - Gershoni-Baruch syndrome: First report of a surviving child. AB - Gershoni-Baruch syndrome is an extremely rare malformation complex characterized by omphalocele, diaphragmatic hernia, radial ray defects, and cardiovascular abnormalities. Autosomal recessive inheritance was suggested. To date, academic literature described only seven patients fulfilling the diagnostic criteria for the condition. None survived the neonatal period. This study reports the first individual with Gershoni-Baruch syndrome surviving past early infancy. PMID- 26639893 TI - Biomimetic Superhydrophobic/Superoleophilic Highly Fluorinated Graphene Oxide and ZIF-8 Composites for Oil-Water Separation. AB - Superhydrophobic/superoleophilic composites HFGO@ZIF-8 have been prepared from highly fluorinated graphene oxide (HFGO) and the nanocrystalline zeolite imidazole framework ZIF-8. The structure-directing and coordination-modulating properties of HFGO allow for the selective nucleation of ZIF-8 nanoparticles at the graphene surface oxygen functionalities. This results in localized nucleation and size-controlled ZIF-8 nanocrystals intercalated in between HFGO layers. The composite microstructure features fluoride groups bonded at the graphene. Self assembly of a unique micro-mesoporous architecture is achieved, where the micropores originate from ZIF-8 nanocrystals, while the functionalized mesopores arise from randomly organized HFGO layers separated by ZIF-8 nanopillars. The hybrid material displays an exceptional high water contact angle of 162 degrees and low oil contact angle of 0 degrees and thus reveals very high sorption selectivity, fast kinetics, and good absorbencies for nonpolar/polar organic solvents and oils from water. Accordingly, Sponge@HFGO@ZIF-8 composites are successfully utilized for oil-water separation. PMID- 26639894 TI - An evaluation of patients' experienced usability of a diabetes mHealth system using a multi-method approach. AB - OBJECTIVE: mHealth systems are becoming more common to aid patients in their diabetes self-management, but recent studies indicate a need for thorough evaluation of patients' experienced usability. Current evaluations lack a multi method design for data collection and structured methods for data analyses. The purpose of this study was to provide a feasibility test of a multi-method approach for both data collection and data analyses for patients' experienced usability of a mHealth system for diabetes type 2 self-management. MATERIALS AND METHODS: A random sample of 10 users was selected from a larger clinical trial. Data collection methods included user testing with eight representative tasks and Think Aloud protocol, a semi-structured interview and a questionnaire on patients' experiences using the system. The Framework Analysis (FA) method and Usability Problem Taxonomy (UPT) were used to structure, code and analyze the results. A usability severity rating was assigned after classification. RESULTS: The combined methods resulted in a total of 117 problems condensed into 19 usability issues with an average severity rating of 2.47 or serious. The usability test detected 50% of the initial usability problems, followed by the post-interview at 29%. The usability test found 18 of 19 consolidated usability problems while the questionnaire uncovered one unique issue. Patients experienced most usability problems (8) in the Glucose Readings View when performing complex tasks such as adding, deleting, and exporting glucose measurements. The severity ratings were the highest for the Glucose Diary View, Glucose Readings View, and Blood Pressure View with an average severity rating of 3 (serious). Most of the issues were classified under the artifact component of the UPT and primary categories of Visualness (7) and Manipulation (6). In the UPT task component, most issues were in the primary category Task-mapping (12). CONCLUSIONS: Multiple data collection methods yielded a more comprehensive set of usability issues. Usability testing uncovered the largest volume of usability issues, followed by interviewing and then the questionnaire. The interview did not surface any unique consolidated usability issues while the questionnaire surfaced one. The FA and UPT were valuable in structuring and classifying problems. The resulting descriptions serve as a communication tool in problem solving and programming. We recommend the usage of multiple methods in data collection and employing the FA and UPT in data analyses for future usability testing. PMID- 26639896 TI - A rodent model of the human psychomotor vigilance test: Performance comparisons. AB - BACKGROUND: The human Psychomotor Vigilance Test (PVT) is commonly utilized as an objective risk assessment tool to quantify fatigue and sustained attention in laboratory, clinical, and operational settings. NEW METHOD: Recent studies have employed a rodent version of the PVT (rPVT) to measure various aspects of attention (lapses in attention, reaction times) under varying experimental conditions. RESULTS: Data are presented here to evaluate the short- and long-term utility of the rPVT adapted for laboratory rats designed to track the same types of performance variables as the human PVT-i.e., motor speed, inhibitory control ("impulsivity"), and attention/inattention. Results indicate that the rPVT is readily learned by rats and requires less than two weeks of training to acquire the basic procedure. Additional data are also presented on the effects of radiation exposure on these performance measures that indicate the utility of the procedure for assessing changes in neurobehavioral function in rodents across their lifespans. COMPARISON WITH EXISTING METHOD(S): Once stable performances are obtained, rats evidence a high degree of similarity to human performance measures, and include similarities in terms of lapses and reaction times, in addition to percent correct and premature responding. Similar to humans, rats display both a vigilance decrement across time on task and a response-stimulus interval effect. CONCLUSIONS: The rPVT is a useful tool in the investigation of the effects of a wide range of variables on vigilance performance that compares favorably to the human PVT and for developing potential prophylactics, countermeasures, and treatments for neurobehavioral dysfunctions. PMID- 26639897 TI - Routine assessment of performance status during palliative chemotherapy when approaching end-of-life. AB - PURPOSE: Palliative chemotherapy treatment (PCT) offered late in the cancer disease trajectory may be problematic. It is not easy to accurately calculate whether the potential benefits will outweigh the side-effects. This study investigates whether routine use of the Performance Status in Palliative Chemotherapy questionnaire (PSPC) affects the proportions of patients receiving PCT during the last month of life, care utilization, and documentation routines. A secondary aim was to gather registered nurses' experiences of the PSPC in routine use. METHODS: Eighty incurable patients with cancer who had used the PSPC before PCT were compared to 160 matched controls, using non-parametric tests. Nurses' reflections on the PSPC were collected and reviewed. RESULTS: No significant differences were found between users and non-users of the PSPC in terms of proportions receiving PCT during the last month of life. Higher proportions of patients older than 74 years received PCT than in previous studies (40% versus 17%). Nurses considered the questionnaires to be a valuable complement to verbal information when trying to acquire an accurate picture of patients' performance status. CONCLUSION: At this point in the development of the PSPC we did not find any significant decreases in the proportion of patients receiving PCT during the last month in life. However, as the nurses valued the PSPC, it can be used as a complementary tool in assessment of performance status until further research is conducted. PMID- 26639895 TI - Role of EP2 and EP4 receptors in airway microvascular leak induced by prostaglandin E2. AB - BACKGROUND AND PURPOSE: Airway microvascular leak (MVL) involves the extravasation of proteins from post-capillary venules into surrounding tissue. MVL is a cardinal sign of inflammation and an important feature of airway inflammatory diseases such as asthma. PGE2, a product of COX-mediated metabolism of arachidonic acid, binds to four receptors, termed EP1-4. PGE2 has a wide variety of effects within the airway, including modulation of inflammation, sensory nerve activation and airway tone. However, the effect of PGE2 on airway MVL and the receptor/s that mediate this have not been described. EXPERIMENTAL APPROACH: Evans Blue dye was used as a marker of airway MVL, and selective EP receptor agonists and antagonists were used alongside EP receptor-deficient mice to define the receptor subtype involved. KEY RESULTS: PGE2 induced significant airway MVL in mice and guinea pigs. A significant reduction in PGE2-induced MVL was demonstrated in Ptger2-/- and Ptger4-/- mice and in wild-type mice pretreated simultaneously with EP2 (PF-04418948) and EP4 (ER-819762) receptor antagonists. In a model of allergic asthma, an increase in airway levels of PGE2 was associated with a rise in MVL; this change was absent in Ptger2-/- and Ptger4-/- mice. CONCLUSIONS AND IMPLICATIONS: PGE2 is a key mediator produced by the lung and has widespread effects according to the EP receptor activated. Airway MVL represents a response to injury and under 'disease' conditions is a prominent feature of airway inflammation. The data presented highlight a key role for EP2 and EP4 receptors in MVL induced by PGE2. PMID- 26639898 TI - Recruitment of Pontin/Reptin by E2f1 amplifies E2f transcriptional response during cancer progression. AB - Changes in gene expression during tumorigenesis are often considered the consequence of de novo mutations occurring in the tumour. An alternative possibility is that the transcriptional response of oncogenic transcription factors evolves during tumorigenesis. Here we show that aberrant E2f activity, following inactivation of the Rb gene family in a mouse model of liver cancer, initially activates a robust gene expression programme associated with the cell cycle. Slowly accumulating E2f1 progressively recruits a Pontin/Reptin complex to open the chromatin conformation at E2f target genes and amplifies the E2f transcriptional response. This mechanism enhances the E2f-mediated transactivation of cell cycle genes and initiates the activation of low binding affinity E2f target genes that regulate non-cell-cycle functions, such as the Warburg effect. These data indicate that both the physiological and the oncogenic activities of E2f result in distinct transcriptional responses, which could be exploited to target E2f oncogenic activity for therapy. PMID- 26639899 TI - Synergistic effect of high-mobility group box-1 and lipopolysaccharide on cytokine induction in bovine peripheral blood mononuclear cells. AB - High-mobility group box 1 (HMGB1) is one of the potent endogenous adjuvants released by necrotic and activated innate immune cells. HMGB1 modulates innate and adaptive immune responses in humans and mice by mediating immune cells crosstalk. However, the immuno-modulatory effects of HMGB1 in the bovine immune system are not clearly known. In this study, the effect of bovine HMGB1 alone or in combination with LPS on the expression kinetics of cytokines upon in vitro stimulation of bovine peripheral blood mononuclear cells (PBMCs) was investigated by quantitative PCR assay. The biological activity of bovine HMGB1 expressed in this prokaryotic expression system was confirmed by its ability to induce nitric oxide secretion in RAW 264.7 cells. The present results indicate that HMGB1 induces a more delayed TNF-alpha response than does LPS in stimulated PBMCs. However, IFN-gamma, IFN-beta and IL-12 mRNA transcription peaked at 6 hr post stimulation after both treatments. Further, HMGB1 and LPS heterocomplex up regulated TNF-alpha, IFN-gamma and IL-12 mRNA expression significantly than did individual TLR4 agonists. The heterocomplex also enhanced the expression of TLR4 on bovine PBMCs. In conclusion, the data indicate that HMGB1 and LPS act synergistically and enhance proinflammatory cytokines, thereby eliciting Th1 responses in bovine PBMCs. These results suggest that HMGB1 can act as an adjuvant in modulating the bovine immune system and thus lays a foundation for using HMGB1 as an adjuvant in various bovine vaccine preparations. PMID- 26639900 TI - Real-Space Imaging of the Atomic Structure of Organic-Inorganic Perovskite. AB - Organic-inorganic perovskite is a promising class of materials for photovoltaic applications and light emitting diodes. However, so far commercialization is still impeded by several drawbacks. Atomic-scale effects have been suggested to be possible causes, but an unequivocal experimental view at the atomic level is missing. Here, we present a low-temperature scanning tunneling microscopy study of single crystal methylammonium lead bromide CH3NH3PbBr3. Topographic images of the in situ cleaved perovskite surface reveal the real-space atomic structure. Compared to the bulk we observe modified arrangements of atoms and molecules on the surface. With the support of density functional theory we explain these by surface reconstruction and a substantial interplay of the orientation of the polar organic cations (CH3NH3)(+) with the position of the hosting anions. This leads to structurally and electronically distinct domains with ferroelectric and antiferroelectric character. We further demonstrate local probing of defects, which may also impact device performance. PMID- 26639901 TI - The Relative Contributions of Experiential Avoidance and Distress Tolerance to OC Symptoms. AB - BACKGROUND: Obsessive beliefs account for substantial (but not all) obsessive compulsive (OC) symptoms. Intolerance of internal experiences (IIE), which encompasses the constructs of experiential avoidance (EA) and distress tolerance (DT), refers to difficulty managing unwanted thoughts, emotions, and other internal states, and might add to current explanatory models. Although IIE appears to be conceptually relevant to obsessive-compulsive (OC) symptoms, scant research has examined this relationship empirically. AIM: The present study examined the relative contributions of EA and DT as predictors of OC symptom dimensions. METHOD: A nonclinical sample (n = 496) completed self-report questionnaires measuring general distress, EA, DT and OC symptom dimensions. RESULTS: All variables of interest were significantly (all ps <= .001) correlated with one another, such that higher general distress, higher EA, and lower DT were associated with greater OC symptom severity for all symptom dimensions; however, only EA independently predicted obsessional symptoms, but not other OC symptom dimensions. CONCLUSIONS: One's willingness to endure (i.e. EA), rather than their ability to tolerate (i.e. DT) unpleasant internal experiences best predicts obsessional symptoms (i.e. obsessing) above and beyond general distress. Potential implications for understanding, assessing, and treating OC symptoms are discussed. PMID- 26639910 TI - Polymer-Metal Schottky Contact with Direct-Current Outputs. AB - A freestanding conducting polymer plate with one side forming a Schottky contact and the other side an Ohmic contact with two different metal electrodes can generate a DC voltage with an output current density as high as 218.6 MUA cm(-2) upon mechanical deformation. PMID- 26639902 TI - A highly efficient CMOS nanoplasmonic crystal enhanced slow-wave thermal emitter improves infrared gas-sensing devices. AB - The application of plasmonics to thermal emitters is generally assisted by absorptive losses in the metal because Kirchhoff's law prescribes that only good absorbers make good thermal emitters. Based on a designed plasmonic crystal and exploiting a slow-wave lattice resonance and spontaneous thermal plasmon emission, we engineer a tungsten-based thermal emitter, fabricated in an industrial CMOS process, and demonstrate its markedly improved practical use in a prototype non-dispersive infrared (NDIR) gas-sensing device. We show that the emission intensity of the thermal emitter at the CO(2) absorption wavelength is enhanced almost 4-fold compared to a standard non-plasmonic emitter, which enables a proportionate increase in the signal-to-noise ratio of the CO(2) gas sensor. PMID- 26639911 TI - Direct Analysis of Lipophilic Antioxidants of Olive Oils Using Bicontinuous Microemulsions. AB - Quantitative analyses of olive oil for lipophilic antioxidants, such as alpha tocopherol and phenolics, by simple electrochemical measurements were conducted in a bicontinuous microemulsion (BME), which was bicontinuously composed of saline and toluene microphases with a surfactant system. Lipophilic antioxidants in oils were directly monitored in BME solutions using a lipophilic, fluorinated nanocarbon-film electrode (F-ECR). The combination of a well-balanced BME and extremely biased electrodes, such as strongly hydrophilic indium/tin oxide and strongly lipophilic (hydrophobic) F-ECR, allowed individual monitoring of hydrophilic and lipophilic antioxidants in the same BME solution without any required extraction. Furthermore, values for the charge Q, integrated from observed currents, showed good linear relationships with the results of conventional assays for antioxidant activity, namely, total phenolics and oxygen radical absorbance capacity assays, even with practical food samples. This proposed methodology provided a very simple, rapid, easily serviceable, and highly reproducible analysis that possesses great potential for applications to a wide range of chemical mixtures, in terms of analyte and media, beyond food oils. PMID- 26639912 TI - Histomorphological changes in testes of broad-snouted caimans (Caiman latirostris) associated with in ovo exposure to endocrine-disrupting chemicals. AB - Studies regarding the effects of endocrine-disrupting chemicals (EDCs) on the reproductive functions of wild animals have raised increasing concern. Thus, here we evaluated the consequences of in ovo exposure to endosulfan (END) and bisphenol A (BPA) in testes from neonatal to juvenile (Juv) caimans (Caiman latirostris). Caiman eggs were collected from areas with low to moderate anthropogenic intervention and incubated at male-producing temperature. At stage 20 of embryonic development (previous to gonad sex determination), eggs were exposed to either END (20 ppm) or BPA (1.4 ppm) and male gonad histomorphology examined in 10-day-old, 90-day-old, and Juv caimans. The relative seminiferous tubular area (RTA) was measured in testes and the proliferation index and the expression of estrogen receptor alpha (ERalpha) were quantified in intratubular cells. Regardless of the treatment, all eggs resulted in male hatchlings. The testes of EDC-exposed caimans presented tortuous seminiferous tubules with empty tubular lumens. The RTA of 10-day-old caimans exposed to BPA was decreased. The percentage of cells expressing ERalpha was not different after in ovo treatment with EDCs (compared to the Control group), although caimans exposed to END showed a different ERalpha distribution pattern. The proliferation index was lower in 90 day-old caimans exposed to END, and higher in Juv caimans exposed to BPA. In ovo exposure to END or BPA modified sensitive parameters of C. latirostris male gonads. The alterations described here might compromise not only the sexual maturation but also the reproductive performance of adult caimans. J. Exp. Zool. 325A:84-96, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26639913 TI - Transseptal Puncture Guided by CT-Derived 3D-Augmented Fluoroscopy. AB - BACKGROUND: Transseptal puncture for left atrial (LA) access is still mainly performed using fluoroscopy and transesophageal or intracardiac echocardiography. We present an easily applicable approach for the guidance of transseptal puncture that uses the combination of a 3D-mapping system and CT-derived 3D-overlayed anatomy. METHODS AND RESULTS: A computer tomographic (CT) LA-angiography was performed in n = 65 patients prior to a scheduled atrial fibrillation ablation procedure. The CARTO3 (Biosense Webster, Diamond Bar, CA, USA) segmentation tool was used to create a 3D-reconstruction of cardiac anatomy and the spine. The CARTO UNIVU module was then used to overlay and register the segmented 3D-anatomy onto fluoroscopy. The 3D-reconstructed spine and cardiac anatomy were congruently aligned to their fluoroscopic counterparts in fluoroscopic views. The feasibility of the technique, its safety, and accuracy (assessed as contour offsets between 3D-overlay and angiographic LA anatomy) were evaluated. Overlay registration accuracy was analyzed by CARTO3 registration matrices. Transseptal puncture was feasible without complications in all 65 patients using the new 3D-overlay technique. Three-dimensional-overlay contour offsets were 1.6 +/- 1.2 mm in left PV, 1.7 +/- 1.2 mm in right PV, and 1.3 +/- 1.0 mm in the LA roof region. Overlay registration accuracy was 4.9 +/- 2.7 mm. The average time needed for anatomy segmentation was 204 +/- 61 seconds, time needed for overlay registration was 18 +/- 8 seconds. CONCLUSIONS: Three-dimensional-augmented fluoroscopy is feasible, safe, and easy to apply as guidance for transseptal puncture and demonstrates a high level of accuracy. PMID- 26639914 TI - Understanding and Editing the Zebrafish Genome. AB - In the last two decades, zebrafish has become one of the fastest growing model organisms in terms of publications, however it has been plagued with the absence of a key tool in the genetics toolbox: the ability to systematically make targeted mutations in the genome. That all changed with the recent emergence of custom-built, sequence-specific nucleases, i.e., zinc finger nucleases (ZFNs), TAL-effector nucleases (TALENs), or clustered regulatory interspaced short palindromic repeat (CRISPR)/Cas9. Here, we provide a comprehensive review of the application of these genome-editing tools to generate targeted knockout and knock in mutants in zebrafish. These technologies have allowed us to transition from targeted knockouts in zebrafish being a difficult, resource intensive undertaking, to something that can be done in virtually any lab with modest molecular biology experience. Furthermore, this review provides a comprehensive listing of genetic and genomic resources and online tools that zebrafish researchers can use to help find a desired mutation or design effective ZFNs, TALENs, or CRISPR guide RNAs for their targeting experiments. PMID- 26639915 TI - Life without Food and the Implications for Neurodegeneration. AB - Food availability determines developmental rate, behavior, and survival of animals. Animals that enter diapause or hibernate in response to lack of food have a double advantage: they are able to adapt to environmental and cellular challenges and survive to these challenges for a prolonged time. The metabolic and physiological adaptations that make possible diapause and hibernation also provide a favorable cellular environment for tissue protection. This review highlights the benefits of dormancy on neuronal protection in the model organism Caenorhabditis elegans and small mammals such as squirrels. Additionally, I discuss the link between metabolic restructuring occurring in diapause and changes in gene expression with the increased capacity of diapausing animals to protect neurons from degeneration and potentially foster their regeneration. PMID- 26639916 TI - Decoding Advances in Psychiatric Genetics: A Focus on Neural Circuits in Rodent Models. AB - Appropriately powered genome-wide association studies combined with deep sequencing technologies offer the prospect of real progress in revealing the complex biological underpinnings of schizophrenia and other psychiatric disorders. Meanwhile, recent developments in genome engineering, including CRISPR, constitute better tools to move forward with investigating these genetic leads. This review aims to assess how these advances can inform the development of animal models for psychiatric disease, with a focus on schizophrenia and in vivo electrophysiological circuit-level measures with high potential as disease biomarkers. PMID- 26639917 TI - Around the Fungal Clock: Recent Advances in the Molecular Study of Circadian Clocks in Neurospora and Other Fungi. AB - Night follows day and as a consequence, organisms have evolved molecular machineries that allow them to anticipate and respond to the many changes that accompany these transitions. Circadian clocks are precise yet plastic pacemakers that allow the temporal organization of a plethora of biological process. Circadian clocks are widespread across the tree of life and while their exact molecular components differ among phyla, they tend to share common design principles. In this review, we discuss the circadian system of the filamentous fungus Neurospora crassa. Historically, this fungus has served a key role in the genetic and molecular dissection of circadian clocks, aiding in their detailed mechanistic understanding. Recent studies have provided new insights into the daily molecular dynamics that constitute the Neurospora circadian oscillator, some of which have questioned traditional paradigms describing timekeeping mechanisms in eukaryotes. In addition, recent reports support the idea of a dynamic network of transcription factors underlying the rhythmicity of thousands of genes in Neurospora, many of which oscillate only under specific conditions. Besides Neurospora, which harbors the best characterized circadian system among filamentous fungi, the recent characterization of the circadian system of the plant-pathogenic fungus Botrytis cinerea has provided additional insights into the physiological impact of the clock and potential additional functions of clock proteins in fungi. Finally, we speculate on the presence of FRQ or FRQ-like proteins in diverse fungal lineages. PMID- 26639918 TI - Large Spin-Valley Polarization in Monolayer MoTe2 on Top of EuO(111). AB - The electronic properties of monolayer MoTe2 on top of EuO(111) are studied by first-principles calculations. Strong spin polarization is induced in MoTe2 , which results in a large valley polarization. In a longitudinal electric field this will result in a valley and spin-polarized charge Hall effect. The direction of the Hall current as well as the valley and spin polarizations can be tuned by an external magnetic field. PMID- 26639919 TI - Using State Space Methods to Reveal Dynamical Associations Between Cortisol and Depression. AB - Despite extensive research, the link between etiological factors and depression remains poorly understood. This may in part be due to a focus on strictly linear definitions of causality, derived at the group level. However, etiological relations in depression are likely to be dynamical, nonlinear and potentially unquantifiable with traditional statistics. Therefore the aim of this study was to evaluate the use of the convergent cross-mapping (CCM) method in investigating possible nonlinear relationships between supposed etiological factors and depressive symptomatology. Time series data from six healthy individuals were used to model the relationship between 24-h urinary free cortisol and negative affect using CCM and dewdrop embeddings. CCM is a nonlinear measure of causality, based on state space reconstruction with lagged coordinate embeddings. The results showed that nonlinear dynamical relationships between cortisol and negative affect may be present within participants, as demonstrated by a positive cross-map convergence from negative affect to cortisol. However, analyses also showed that noise and influential points had considerable impact on the results. Convergent crossmapping can be used to reveal possible nonlinear dynamical relationships between etiological factors and psychopathology that may remain undetected with traditional linear causality measures. PMID- 26639920 TI - Dynamics of Resilient and Non-resilient Mood. AB - Individuals with affective disorders show losses in the complexity of their mood variation. We hypothesized that this complexity is a mechanism by which resilient individuals respond to everyday-life adversity, a response that would be disrupted in patients with affective disorders. Participants were outpatients with affective disorders (N=17) and matched controls (N=10) who self-recorded their daily mood over a mean duration of 233 days. Complexity was measured by sample entropy. The load of adversity was conveyed by the proportion of severely negative-affective days. Results showed that, in both controls and patients, complexity increased with adversity but patients displayed substantial disruptions in this complexity response by: (a) weaker associations between complexity and adversity (Pearson's r=0.54 to 0.59 vs. 0.59 to 0.70);(b) lower complexity for the same load of adversity (ANCOVA, p<0.01), representing losses of up to 29% of the complexity expected from controls (Mann-Whitney, p<0.005). We concluded that patients with affective disorders fail to increase the complexity of their mood variation to the same extent as resilient individuals when exposed to the same load of adversity, and propose that rigid emotion regulation processes may be causing this attenuated response. Resilience implies complex mood for complicated lives. PMID- 26639921 TI - Physiological Synchronization in a Vigilance Dual Task. AB - The synchronization of autonomic arousal levels and other physio-logical responses between people is a potentially important component of work team performance, client-therapist relationships, and other types of human interaction. This study addressed several problems: What statistical models are viable for identifying synchronization for loosely coupled human systems? How is the level of synchronization related to psychosocial variables such as empathy, subjective ratings of workload, and actual performance? Participants were 70 undergraduates who worked in pairs on a vigilance dual task in which they watched a virtual reality security camera, rang a bell when they saw the target intruder, and completed a jig-saw puzzle. Event rates either increased or decreased during the 90 min work period. The average R2 values for each person were .66, .66, .62, and .53 for the linear autoregressive model, linear autoregressive model with a synchronization component, the nonlinear autoregressive model, and the nonlinear autoregressive model with a synchronization component, respectively. All models were more accurate at a lag of 20 sec compared to 50 sec or customized lag lengths. Although the linear models were more accurate overall, the nonlinear synchronization parameters were more often related to psychological variables and performance. In particular, greater synchronization was observed with the nonlinear model when the target event rate increased, compared to when it decreased, which was expected from the general theory of synchronization. Nonlinear models were also more effective for uncovering inhibitory or dampening relationships between the co-workers as well as mutually excitatory relationships. Future research should explore the comparative model results for tasks that induce higher levels of synchronization and involve different types of internal group coordination. PMID- 26639922 TI - Community Viral Load Management: Can Attractors Contribute to Developing an Improved Bio-social Response to HIV Risk-reduction? AB - This article reports on the first twelve months of a pilot study that was designed to improve community responses to HIV/AIDS in rural South Africa. The framework was designed to enable the modification of emergent attractor landscapes. Specifically, we report on the introduction of a primary probe; the secondary, community initiated probes and the attractors that emerged through the process. Probes were designed to stimulate frame changes amongst participants that would influence social practices. Attractors represent the empirically visible culmination of discrete patterns that influence the dynamic landscape. Managing or modifying these patterns, thus changing the landscape, including social practices, is the principle that underpins the framework. The findings were analysed using a qualitative methodology called causal layered analysis. Six attractors emerged that contribute to reducing the aggregate community viral load, and three attractors emerged that detract from that ambition. The first pilot has provided insights into improving the framework and has had an impact at multiple scales suggesting that the framework is a promising tool for engaging with the bio-social aspects of the contemporary epidemic. PMID- 26639923 TI - Accessing Creativity: Jungian Night Sea Journeys, Wandering Minds, and Chaos. AB - NDS theory has been meaningfully applied to the dynamics of creativity and psychology. These complex systems have much in common, including a broad definition of "product" as new order emerging from disorder, a new whole (etymologically, 'health') out of disintegration or destabilization. From a nonlinear dynamical systems perspective, this paper explores the far-from equilibrium zone of creative incubation: first in the Jungian night sea journey, a primordial myth of psychological and creative transformation; then in the neuroscience of mind wandering, the well-spring of creative ideation within the larger neural matrix. Finally, chaos theory grounds the elusive subject of creativity, modeling chaotic generation of idea elements that tend toward strange attractors, combine unpredictably, and produce change by means of tension between opposites, particularly notes consciousness (light) and the poetic unconscious (darkness). Examples from my own artwork illustrate this dialectical process. Considered together, the unconscious mythic sea journey, the unknowing wandering mind, and the generative paradigm of deterministic chaos suggest conditions that facilitate creativity across disciplines, providing fresh indications that the darkness of the unknown or irrational is, paradoxically, the illuminative source and strength of creativity. PMID- 26639924 TI - Cytotoxic interactions of bare and coated NaGdF4:Yb(3+):Er(3+) nanoparticles with macrophage and fibroblast cells. AB - The lanthanide nano-compounds are well suited to serve as fluorescent and magnetic contrast agents and luminescent labels. Although they are considered as promising materials for bio-imaging and bio-sensors in vivo or in vitro, the amount of data is still insufficient for deep understanding the toxicity of these nanomaterials. This knowledge is of great importance in the light of growing use of the biofunctionalized nanoparticles, which raises some questions about safety of these materials. Despite lanthanide-doped NaGdF4 nanocrystals are considered as non-toxic, here we present the data showing the fatal effect of newly synthetized NaGdF4:Yb(3+):Er(3+) on chosen types of cells. Our studies were performed on two cell lines NIH3T3 fibroblasts, and RAW264.7 macrophages. Cytotoxic properties of NaGdF4:Yb(3+):Er(3+) nanoparticles and their biological effects were studied by assessing cell culture viability (MTS), proliferation and apoptosis. Bare NaGdF4:Yb(3+):Er(3+) nanocrystals were cytotoxic and induced apoptosis of both NIH3T3 and RAW264.7 cells. Their cytotoxicity was reduced by PEGylation, at the expense of minimizing direct interactions between the compound and the cell. On the other hand, coating with silica reduced cell death induced by Yb(3+):Er(3+) codoped NaGdF4 nanocrystals (but proliferation was still inhibited). The NH2-modified silica coated nanoparticles were clearly less cytotoxic than pristine nanoparticles, which suggests that both, silica and PEG coatings are reasonable approaches to decrease cytotoxicity of the nanocrystal labels. The silica and PEG shell, should also enable and simplify further bio functionalization of these luminescent labels. The authors acknowledge the financial support from: Institute of Immunology and Experimental Therapy, Polish Academy of Sciences (IITD PAN) grant no. 3/15, Polish Ministry of Science and Higher Education, Grant N N507 499538 and from the Wroclaw Research Centre EIT+ within the project "The Application of Nanotechnology in Advanced Materials" - NanoMat (POIG.01.01.02-02-002/08) financed by the European Regional Development Fund (Operational Program Innovative Economy, 1.1.2). PMID- 26639925 TI - Standard form of the Boston Naming Test: Normative data for the Latin American Spanish speaking adult population. AB - OBJECTIVE: To generate normative data on the Boston Naming Test (BNT) across 10 countries in Latin America, with country-specific adjustments for gender, age, and education, where appropriate. METHOD: The sample consisted of 3,779 healthy adults who were recruited from Argentina, Bolivia, Chile, Cuba, El Salvador, Guatemala, Mexico, Paraguay, Peru, and, Puerto Rico. Each subject was administered the BNT as part of a larger neuropsychological battery. A standardized five-step statistical procedure was used to generate the norms. RESULTS: The final multiple linear regression models explained between 3-32% of the variance in BNT scores. Although t-tests showed significant differences between men and women for Mexico, Argentina, Chile, Cuba, Guatemala, and Bolivia on the BNT, none of the six countries had an effect size larger than 0.3. As a result, gender-adjusted norms were not generated. CONCLUSIONS: This is the first normative multicenter study conducted in Latin America to generate norms for the BNT; this study will have substantial repercussions for the practice of neuropsychology throughout the global region. PMID- 26639926 TI - Stroop Color-Word Interference Test: Normative data for the Latin American Spanish speaking adult population. AB - OBJECTIVE: To generate normative data on the Stroop Test across 11 countries in Latin America, with country-specific adjustments for gender, age, and education, where appropriate. METHOD: The sample consisted of 3,977 healthy adults who were recruited from Argentina, Bolivia, Chile, Cuba, El Salvador, Guatemala, Honduras, Mexico, Paraguay, Peru, and, Puerto Rico. Each subject was administered the Stroop Test, as part of a larger neuropsychological battery. A standardized five step statistical procedure was used to generate the norms. RESULTS: The final multiple linear regression models explained 14-36% of the variance in Stroop Word scores, 12-41% of the variance in the Stoop Color, 14-36% of the variance in the Stroop Word-Color scores, and 4-15% of variance in Stroop Interference scores. Although t-tests showed significant differences between men and women on the Stroop test, none of the countries had an effect size larger than 0.3. As a result, gender-adjusted norms were not generated. CONCLUSIONS: This is the first normative multicenter study conducted in Latin America to create norms for the Stoop Test in a Spanish-Speaking sample. This study will therefore have important implications for the future of neuropsychology research and practice throughout the region. PMID- 26639927 TI - Symbol Digit Modalities Test: Normative data for the Latin American Spanish speaking adult population. AB - OBJECTIVE: To generate normative data on the Symbol Digit Modalities Test (SDMT) across 11 countries in Latin America, with country-specific adjustments for gender, age, and education, where appropriate. METHOD: The sample consisted of 3,977 healthy adults who were recruited from Argentina, Bolivia, Chile, Cuba, El Salvador, Guatemala, Honduras, Mexico, Paraguay, Peru, and, Puerto Rico. Each subject was administered the SDMT as part of a larger neuropsychological battery. A standardized five-step statistical procedure was used to generate the norms. RESULTS: The final multiple linear regression models explained 29-56% of the variance in SDMT scores. Although there were gender differences on the SDMT in Mexico, Honduras, Paraguay, and Guatemala, none of the four countries had an effect size greater than 0.3. As a result, gender-adjusted norms were not generated. CONCLUSIONS: This is the first normative multicenter study conducted in Latin America to create norms for the SDMT; this study will have an impact on the future practice of neuropsychology throughout the global region. PMID- 26639928 TI - Brief Test of Attention: Normative data for the Latin American Spanish speaking adult population. AB - OBJECTIVE: To generate normative data on the Brief Test of Attention (BTA) across 11 countries in Latin America, with country-specific adjustments for gender, age, and education, where appropriate. METHOD: The sample consisted of 3,977 healthy adults who were recruited from Mexico, Argentina, Peru, Paraguay, Honduras, Chile, Cuba, Puerto Rico, Guatemala, El Salvador, and Bolivia. Each subject was administered the BTA as part of a larger neuropsychological battery. A standardized five-step statistical procedure was used to generate the norms. RESULTS: The final multiple linear regression models explained between 11-41% of the variance in BTA scores. Although men had higher scores on the BTA in Honduras, there were no other significant gender differences, and this one effect size was small. As a result, gender-adjusted norms were not generated. CONCLUSIONS: This is the first normative multicenter study conducted in Latin America to create norms for the BTA; this study will have an impact on the future practice of neuropsychology throughout Latin America. PMID- 26639929 TI - Rey-Osterrieth Complex Figure - copy and immediate recall: Normative data for the Latin American Spanish speaking adult population. AB - OBJECTIVE: To generate normative data on the Rey-Osterrieth Complex Figure Test (ROCF) across 11 countries in Latin America, with country-specific adjustments for gender, age, and education, where appropriate. METHOD: The sample consisted of 3,977 healthy adults who were recruited from Argentina, Bolivia, Chile, Cuba, El Salvador, Guatemala, Honduras, Mexico, Paraguay, Peru, and, Puerto Rico. Each subject was administered the ROCF as part of a larger neuropsychological battery. A standardized five-step statistical procedure was used to generate the norms. RESULTS: The final multiple linear regression models explained 7-34% of the variance in ROCF copy scores and 21-41% of the variance in immediate recall scores. Although t-tests showed significant differences between men and women on ROCF copy and immediate recall scores, none of the countries had an effect size larger than 0.3. As a result, gender-adjusted norms were not generated. CONCLUSIONS: The present study is the first to create norms for the ROCF in Latin America. As a result, this study will have important implications for the formation and practice of neuropsychology in this region. PMID- 26639930 TI - Verbal fluency tests: Normative data for the Latin American Spanish speaking adult population. AB - OBJECTIVE: To generate normative data for the Verbal Fluency Tests across 11 countries in Latin America, with country-specific adjustments for gender, age, and education, where appropriate. METHOD: The sample consisted of 3,977 healthy adults who were recruited from Argentina, Bolivia, Chile, Cuba, El Salvador, Guatemala, Honduras, Mexico, Paraguay, Peru, and, Puerto Rico. Each subject was administered the Verbal Fluency Test as part of a larger neuropsychological battery. A standardized five-step statistical procedure was used to generate the norms. RESULTS: The final multiple linear regression models for the letter F explained 8-30% of the variance, 7-32% for letter A, 8-32% for the letter S, and 16-43% for the animal category in Verbal Fluency Test scores. Although t-tests showed significant differences between men and women on the Verbal Fluency Test, they did not have an effect size larger than 0.3. As a result, gender-adjusted norms were not generated. CONCLUSIONS: This is the first normative multicenter study conducted in Latin America aiming to create norms for the Verbal Fluency Test; this study will have important outcomes for the future of neuropsychology in the region. PMID- 26639931 TI - Modified Wisconsin Card Sorting Test (M-WCST): Normative data for the Latin American Spanish speaking adult population. AB - OBJECTIVE: To generate normative data on the Modified Card Sorting Test (M-WCST) across 11 countries in Latin America, with country-specific adjustments for gender, age, and education, where appropriate. METHOD: The sample consisted of 3,977 healthy adults who were recruited from Argentina, Bolivia, Chile, Cuba, El Salvador, Guatemala, Honduras, Mexico, Paraguay, Peru, and Puerto Rico. Each subject was administered the M-WCST as part of a larger neuropsychological battery. A standardized five-step statistical procedure was used to generate the norms. RESULTS: The final multiple linear regression models explained between 2 33% of the variance in M-WCST scores. Although t-tests showed significant differences between men and women from seven different countries on the M-WCST, the effect sizes were small. As a result, gender-adjusted norms were not generated. CONCLUSIONS: This is the first normative multicenter study conducted in in Latin America aiming to create norms for the M-WCST; this study will have important implications for the future of neuropsychology in the region. PMID- 26639932 TI - Trail Making Test: Normative data for the Latin American Spanish speaking adult population. AB - OBJECTIVE: To generate normative data on the Trail Making Test (TMT) across 11 countries in Latin America, with country-specific adjustments for gender, age, and education, where appropriate. METHOD: The sample consisted of 3,977 healthy adults who were recruited from Mexico, Argentina, Peru, Paraguay, Honduras, Chile, Cuba, Puerto Rico, Guatemala, El Salvador, and Bolivia. Each subject was administered the TMT as part of a larger neuropsychological battery. A standardized five-step statistical procedure was used to generate the norms. RESULTS: The final multiple linear regression models for the TMT-A explained 23- 50% of the variance, and the final multiple linear models for the TMT-B explained 22- 49% of the variance. Although there were gender differences on the TMT in Mexico, Peru, Paraguay, and Honduras, only Honduras had an effect size greater than 0.3. As a result, gender-adjusted norms were generated for the Trail Making Test-A, but not B, in this country. CONCLUSIONS: The present study is the first to create norms for the TMT in Latin America. As a result, this study will have important implications for the practice of neuropsychology in the future. PMID- 26639933 TI - Hopkins Verbal Learning Test- Revised: Normative data for the Latin American Spanish speaking adult population. AB - OBJECTIVE: To generate normative data on the Hopkins Verbal Learning Test- Revised (HVLT-R) across 11 countries in Latin America, with country-specific adjustments for gender, age, and education, where appropriate. METHOD: The sample consisted of 3,977 healthy adults who were recruited from Argentina, Bolivia, Chile, Cuba, El Salvador, Guatemala, Honduras, Mexico, Paraguay, Peru, and, Puerto Rico. Each subject was administered the HVLT-R as part of a larger neuropsychological battery. A standardized five-step statistical procedure was used to generate the norms. RESULTS: The final multiple linear regression models explained 17- 45% of the variance in HVLT-R scores. Although t-tests showed significant differences between men and women in Guatemala on the HVLT-R, it was a small effect size. As a result, gender-adjusted norms were not generated. CONCLUSIONS: The results from this study will have a substantial impact on the practice of neuropsychology in Latin America, as this is the first normative multicenter study to develop norms for the HVLT-R in this region. PMID- 26639934 TI - Test of Memory Malingering (TOMM): Normative data for the Latin American Spanish speaking adult population. AB - BACKGROUND: The Test of Memory Malingering (TOMM) is an instrument used to assess purposeful embellishment or fabrication of memory difficulties for personal gain. Although the TOMM can be use in non-English speaking cultures, it has not been validated in Spanish-speaking Central and South American contexts. OBJECTIVE: To generate normative data on TOMM across 7 countries in Latin America, with country specific adjustments for gender, age, and education, where appropriate. METHOD: The sample consisted of 2,266 healthy adults who were recruited from Argentina, Bolivia, Chile, Mexico, Paraguay, Peru, and Puerto Rico. Each subject was administered the TOMM as part of a larger neuropsychological battery. A standardized five-step statistical procedure was used to generate the norms. RESULTS: t-tests did not show significant differences in TOMM performance between men and women in any countries of the TOMM Trial 1 or 2. As a result, gender adjusted norms were not generated. CONCLUSIONS: The results from this study will have a large impact on the practice of neuropsychology in Latin America, as this is the first normative multicenter study to create norms for the TOMM in this global region. PMID- 26639935 TI - Flatfoot and obesity in school-age children: a cross-sectional study. AB - Childhood obesity exerts abnormally high stresses on developing foot structures which can lead to structural deformity of the foot. Screening for foot problems in children with overweight helps detect interior risks restricting normal lifestyle in these individuals. The purpose of this study was to investigate the effects of excess weight on the structure and function of the developing foot in students aged 7-14 years. A total of 667 participants were recruited for this cross-sectional study via a multi-level cluster sampling method (randomization was used within each cluster). All subjects (340 boys and 327 girls) attended primary and secondary schools in Isfahan City, Iran. The children's feet were evaluated using clinical assessments and footprint-based measures whilst fully weight bearing. Significant differences were observed in the frequency of flatfoot between normal weight, overweight and obese groups (P < 0.001); participants who were more overweight had flatter feet. Children with higher weight also had a more pronated heel, less dorsiflexion range and higher reported pain within physical activity. This study indicated that childhood obesity is associated with structural foot and ankle deformities and activity-related foot pain. PMID- 26639936 TI - Coarctation of the aorta in adolescents and adults: A review of clinical features and CT imaging. AB - Coarctation of the aorta (CoA), while usually identified and treated in the neonatal/infant period, is increasingly seen in adults, either primarily or (more often) following repair. Imaging plays a crucial role in the diagnosis, therapeutic planning, and follow-up of patients with CoA. Clinical management of CoA in adults optimally involves a multidisciplinary team; accordingly, imagers should be familiar with the underlying pathology, associations, and management of CoA in addition to imaging protocoling and interpretation. We will review the relevant clinical and imaging features of CoA, with an emphasis on patients beyond childhood. PMID- 26639937 TI - Chemical Pleurodesis Using Mistletoe Extraction (ABNOVAviscum((r)) Injection) for Malignant Pleural Effusion. AB - PURPOSE: Malignant pleural effusion (MPE) is common in patients with advanced cancer. Chemical pleurodesis can be considered for MPE that do not respond to chemotherapy, radiotherapy, or therapeutic thoracentesis. However, it is not yet clear which agent is more effective and safer in chemical pleurodesis. METHODS: This study was designed as a single arm, multicenter, and open-label phase III clinical trial to evaluate efficacy and safety of chemical pleurodesis using mistletoe extraction (ABNOVAviscum((r)) Injection). References of other agents in chemical pleurodesis were investigated to compare efficacy and safety. Efficacy was evaluated by followed up chest X-ray and changes of clinical symptoms and Karnofsky performance scale. Safety was evaluated by serious adverse event (SAE) and changes of laboratory findings. A follow-up period was 4 weeks after last pleurodesis. RESULTS: Of 62 patients, 49 (79.0%) had complete response, 11 (17.7%) had partial response, and two had no response. Mean response rate was significantly different in this study comparing with reference response rate which was 64% (p <0.0001). There were two SAEs, but all were recovered without sequelas. CONCLUSION: The results of this study suggest that mistletoe extraction (ABNOVAviscum((r)) Injection) could be an effective and safe agent of chemical pleurodesis in patients with MPE. PMID- 26639938 TI - Gender differences in the association between cigarette smoking, alcohol consumption and depressive symptoms: a cross-sectional study among Chinese adolescents. AB - The aim of this study was to examine the association between cigarette smoking, alcohol consumption and depressive symptoms among adolescents, with a particular focus on gender differences. A total of 19,578 middle and high school students in Chongqing Province were surveyed. Self-reported cigarette smoking, alcohol consumption, depressive symptoms, and family- and school-related factors were assessed. A total of 8.8% adolescents reported smoking cigarettes. Tobacco use by boys (16.5%) was significantly higher than by girls (1.9%). Approximately 23.5% of adolescents reported alcohol consumption. Consumption in boys (31.5%) was significantly higher than in girls (16.2%). Depressive symptoms were prevalent in 9.1% of the sample. Girls reported significantly more symptoms (10.4%) than boys (7.7%). Multiple logistic regression analyses showed that the association between alcohol consumption and depressive symptoms was stronger among girls (AOR = 2.1, 95% CI = 1.8-2.5) than boys (AOR = 1.7, 95% CI = 1.4-2.1). A significant association (AOR = 2.3, 95% CI = 1.6-3.4) between cigarette smoking and depressive symptoms was revealed in girls only. The significant gender differences found above may provide a basis for the early identification of individuals at high risk for depression. PMID- 26639939 TI - Hyalinizing trabecular tumor of the thyroid: diagnosis of a rare tumor using ultrasonography, cytology, and intraoperative frozen sections. AB - PURPOSE: The goal of this study was to evaluate the clinicopathological and imaging features of thyroid nodules surgically diagnosed as hyaline trabecular tumor (HTT), and to assess the role of cytology and frozen sections (FS) in the diagnosis of HTT. METHODS: This study included 21 thyroid nodules in 21 patients treated from August 2005 to March 2015 (mean age, 53.3 years) who were either diagnosed as HTT or had HTT suggested as a possible diagnosis based on cytology, FS, or the final pathology report. Patients' medical records were retrospectively reviewed for cytopathologic results and outcomes during the course of follow-up. Sonograms were reviewed and categorized. RESULTS: Twelve nodules from 12 patients were surgically confirmed as HTT. Ultrasonography (US)-guided fine needle aspiration (FNA) was performed on 11 nodules, of which six (54.5%) were papillary thyroid carcinoma (PTC) or suspicious for PTC and three (27.3%) were HTT or suspicious for HTT. Intraoperative FS suggested the possibility of HTT in seven nodules, of which four (57.1%) were confirmed as HTT. US-FNA suggested the diagnosis of HTT in 10 nodules, of which three (30.0%) were confirmed as HTT. Common US features of the 12 pathologically confirmed cases of HTT were hypoechogenicity or marked hypoechogenicity (83.4%), absence of calcifications (91.7%), parallel shape (100.0%), presence of vascularity (75.0%), and probable benignity (58.3%). CONCLUSION: HTT should be included in the differential diagnosis of solid tumors with hypoechogenicity or marked hypoechogenicity and otherwise benign US features that have been diagnosed as PTC through cytology. PMID- 26639940 TI - Projections from a single NUCB2/nesfatin-1 neuron in the paraventricular nucleus to different brain regions involved in feeding. AB - The anorexigenic neuropeptide NEFA/nucleobindin 2 (NUCB2)/nesfatin-1-containing neurons are distributed in the brain regions involved in feeding regulation, including the hypothalamic paraventricular nucleus (PVN). Functionally, NUCB2/nesfatin-1 neurons in the PVN regulate feeding through the hypothalamus and brain stem. However, the neural network of PVN NUCB2/nesfatin-1 neurons has yet to be elucidated. Axon collateral branches allow individual neurons to target multiple neurons. In some cases, each target neuron can be located in different nuclei. Here we show that a single neuron in the PVN projects axonal collaterals to both the dorsal vagal complex (DVC) and the arcuate nucleus (ARC), which are important brain regions for feeding regulation. In this study, after injection of different retrograde tracers into the DVC and ARC, both tracer-labeled neurons were detected in the identical PVN neuron, indicating the axon collateral projections from the single PVN neuron to the DVC and ARC. Furthermore, immunohistochemical analysis revealed that approximately 50 % of the neurons with axon collateral projections from the PVN to the DVC and ARC were found to be NUCB2/nesfatin-1 neurons. Our data suggest that a single NUCB2/nesfatin-1 neuron in the PVN projects to both the ARC and the DVC with axon collateral projection. Although the physiological significance remains to be elucidated, our data offer new perspectives on NUCB2/nesfatin-1 function at the neural network level and food intake regulation. PMID- 26639941 TI - Observation of Bloch oscillations in complex PT-symmetric photonic lattices. AB - Light propagation in periodic environments is often associated with a number of interesting and potentially useful processes. If a crystalline optical potential is also linearly ramped, light can undergo periodic Bloch oscillations, a direct outcome of localized Wannier-Stark states and their equidistant eigenvalue spectrum. Even though these effects have been extensively explored in conservative settings, this is by no means the case in non-Hermitian photonic lattices encompassing both amplification and attenuation. Quite recently, Bloch oscillations have been predicted in parity-time-symmetric structures involving gain and loss in a balanced fashion. While in a complex bulk medium, one intuitively expects that light will typically follow the path of highest amplification, in a periodic system this behavior can be substantially altered by the underlying band structure. Here, we report the first experimental observation of Bloch oscillations in parity-time-symmetric mesh lattices. We show that these revivals exhibit unusual properties like secondary emissions and resonant restoration of PT symmetry. In addition, we present a versatile method for reconstructing the real and imaginary components of the band structure by directly monitoring the light evolution during a cycle of these oscillations. PMID- 26639942 TI - Practice reduces task relevant variance modulation and forms nominal trajectory. AB - Humans are capable of achieving complex tasks with redundant degrees of freedom. Much attention has been paid to task relevant variance modulation as an indication of online feedback control strategies to cope with motor variability. Meanwhile, it has been discussed that the brain learns internal models of environments to realize feedforward control with nominal trajectories. Here we examined trajectory variance in both spatial and temporal domains to elucidate the relative contribution of these control schemas. We asked subjects to learn reaching movements with multiple via-points, and found that hand trajectories converged to stereotyped trajectories with the reduction of task relevant variance modulation as learning proceeded. Furthermore, variance reduction was not always associated with task constraints but was highly correlated with the velocity profile. A model assuming noise both on the nominal trajectory and motor command was able to reproduce the observed variance modulation, supporting an expression of nominal trajectories in the brain. The learning-related decrease in task-relevant modulation revealed a reduction in the influence of optimal feedback around the task constraints. After practice, the major part of computation seems to be taken over by the feedforward controller around the nominal trajectory with feedback added only when it becomes necessary. PMID- 26639943 TI - Sodium-glucose cotransporter 2 inhibitor luseogliflozin improves glycaemic control, assessed by continuous glucose monitoring, even on a low-carbohydrate diet. AB - This randomized, double-blind, placebo-controlled, crossover study was the first to determine the effects of luseogliflozin in combination with a low-carbohydrate diet (LCD) on 24-h glucose variability, assessed by continuous glucose monitoring (CGM). A total of 18 Japanese patients with type 2 diabetes were randomized into two groups, in which patients first received luseogliflozin 2.5 mg once daily then placebo for 8 days each, or vice versa. Patients took luseogliflozin or placebo with a normal-carbohydrate diet (NCD) on day 7 and with the LCD on day 8. CGM was performed on both days. Luseogliflozin significantly reduced glucose exposure in terms of the area under the curve over the course of 24 h when administered with the NCD (difference vs placebo: -555.6 mg/dl.h [1 mg/dl = 0.0556 mmol/l]; p < 0.001) or with the LCD (-660.7 mg/dl.h; p < 0.001). No hypoglycaemia was observed over 24 h with either diet. Although glucose levels were lower with the LCD than with the NCD in the placebo treatment period, luseogliflozin with the LCD improved glycaemic control throughout the day to nearly the same extent as luseogliflozin with the NCD, without inducing hypoglycaemia. PMID- 26639944 TI - Superdiffusive motion of membrane-targeting C2 domains. AB - Membrane-targeting domains play crucial roles in the recruitment of signalling molecules to the plasma membrane. For most peripheral proteins, the protein-to membrane interaction is transient. After proteins dissociate from the membrane they have been observed to rebind following brief excursions in the bulk solution. Such membrane hops can have broad implications for the efficiency of reactions on membranes. We study the diffusion of membrane-targeting C2 domains using single-molecule tracking in supported lipid bilayers. The ensemble-averaged mean square displacement (MSD) exhibits superdiffusive behaviour. However, traditional time-averaged MSD analysis of individual trajectories remains linear and does not reveal superdiffusion. Our observations are explained in terms of bulk excursions that introduce jumps with a heavy-tail distribution. These hopping events allow proteins to explore large areas in a short time. The experimental results are shown to be consistent with analytical models of bulk mediated diffusion and numerical simulations. PMID- 26639945 TI - Benzenesulfonamides incorporating bulky aromatic/heterocyclic tails with potent carbonic anhydrase inhibitory activity. AB - Three series of sulfonamides incorporating long, bulky tails were obtained by applying synthetic strategies in which substituted anthranilic acids, quinazolines and aromatic sulfonamides have been used as starting materials. They incorporate long, bulky diamide-, 4-oxoquinazoline-3-yl- or quinazoline-4-yl moieties in their molecules, and were investigated for the inhibition of four physiologically relevant carbonic anhydrase (CA, EC 4.2.1.1) isoforms, the cytosolic human (h) hCA I and II, as well as the transmembrane hCA IX and XII. Most of the new sulfonamides showed excellent inhibitory effects against the four isoforms, with KIs of 7.6-322nM against hCA I, of 0.06-85.4nM against hCA II; of 6.7-152nM against hCA IX and of 0.49-237nM against hCA XII; respectively. However no relevant isoform-selective behavior has been observed for any of them, although hCA II and XII, isoforms involved in glaucoma-genesis were the most inhibited ones. The structure-activity relationship for inhibiting the four CAs with these derivatives is discussed in detail. PMID- 26639946 TI - Defining knee pain trajectories in early symptomatic knee osteoarthritis in primary care: 5-year results from a nationwide prospective cohort study (CHECK). AB - BACKGROUND: GPs have high consultation rates for symptoms related to knee osteoarthritis (OA). Many risk factors for symptomatic knee OA progression remain unknown. AIM: To define distinct knee pain trajectories in individuals with early symptomatic knee OA and determine the risk factors for these pain trajectories. DESIGN AND SETTING: Data were obtained from the multicentre prospective Cohort Hip and Cohort Knee study in the Netherlands. Participants with knee OA, according to the clinical criteria of the American College of Rheumatology, and a completed 5-year follow-up were included. METHOD: Baseline demographic, anamnestic, and physical examination characteristics were assessed. Outcome was annually assessed by the Numeric Rating Scale for pain. Pain trajectories were retrieved by latent class growth analysis. Multinomial logistic regression was used to calculate relative risk ratios. RESULTS: In total, 705 participants were included. Six distinct pain trajectories were identified with favourable and unfavourable courses. Statistically significant differences were found in baseline characteristics, including body mass index (BMI), symptom severity, and pain coping strategies between the different trajectories. Higher BMI, lower level of education, greater comorbidity, higher activity limitation scores, and joint space tenderness were more often associated with trajectories characterised by more pain at first presentation and pain progression--compared with the reference group with a mild pain trajectory. No association was found for baseline radiographic features. CONCLUSION: These results can help differentiate those patients who require more specific monitoring in the management of early symptomatic knee OA from those for whom a 'wait-and-see' policy seems justifiable. Radiography provided no additional benefit over clinical diagnosis of early symptomatic knee OA in general practice. PMID- 26639947 TI - Antibiotic prescribing and patient satisfaction in primary care in England: cross sectional analysis of national patient survey data and prescribing data. AB - BACKGROUND: Concerns about adverse effects on patient satisfaction may be an important obstacle to attempts to curtail antibiotic prescribing. AIM: To determine the relationship between antibiotic prescribing in general practice and reported patient satisfaction. DESIGN AND SETTING: Retrospective cross-sectional study of general practices in England. METHOD: Data were obtained from the General Practice Patient Survey (GPPS) in 2012 (2.7 million questionnaires in England; 982 999 responses; response rate 36%); the national Quality and Outcomes Framework dataset for England, 2011-2012 (8164 general practices); and general practice and demographic characteristics. Standardised measures of antibiotic prescribing volumes were obtained for each practice in England during 2012-2013, together with 12 other nationally available prescribing variables. The role of antibiotic prescribing volume was identified as a determinant of GPPS scores and adjusted for demographic and practice factors using multiple linear regression. RESULTS: The final dataset consisted of 7800 (95.5%) practices. A total of 33.7 million antibiotic prescriptions were issued to a registered population of 53.8 million patients. Antibiotic prescribing volume was a significant positive predictor of all 'doctor satisfaction' and 'practice satisfaction' scores in the GPPS, and was the strongest predictor of overall satisfaction out of 13 prescribing variables. A theoretical 25% reduction in antibiotic prescribing volume would be associated with 0.5-1.0% lower patient satisfaction scores, a drop of 3-6 centile points in national satisfaction ranking. CONCLUSION: Patients were less satisfied in practices with frugal antibiotic prescribing. A cautious approach to antibiotic prescribing may require a trade-off in terms of patient satisfaction. PMID- 26639948 TI - Provision of smoking cessation support in UK primary care: impact of the 2012 QOF revision. AB - BACKGROUND: Before 2012, UK GPs were paid only to offer cessation advice to smokers and only to those with smoking-related disease, a minority of all smokers. From 2012, GPs are now paid to offer all smokers referral for behavioural support and medication to assist cessation at least once every 2 years. AIM: To quantify the impact of this new recommendation and payment on indicators of smoking cessation activity. DESIGN AND SETTING: Interrupted time series analysis of data from general practices in England contributing data to The Health Improvement Network (THIN). METHOD: Data were extracted on monthly rates of recorded delivery of smoking cessation advice, referral to NHS Stop Smoking Services, and prescription of smoking cessation medications, among an average of 3.3 million patients aged >16 years registered each month in THIN. ARIMA models were used to quantify changes in rates of cessation activity after the 2012 Quality and Outcomes Framework (QOF) revision compared with beforehand. RESULTS: The proportion of patients each month with a record of advice to quit smoking increased by 19.6% (95% CI = 7.9 to 31.4) in the year after the introduction of payments compared with the 8 years beforehand; the recording of referral to Stop Smoking Services increased by 38.8% (95% CI = 15.2 to 62.4). There was no significant change in prescription of smoking cessation medication, 7.7% (95% CI = -21.6 to 6.2). CONCLUSION: Paying GPs to intervene with all smokers and offer support rather than just advice to quit is associated with an increase in recording of advice and referring patients for behavioural support to stop smoking, but no change in prescribing pharmacotherapy for cessation. PMID- 26639949 TI - Seeking support after hospitalisation for injury: a nested qualitative study of the role of primary care. AB - BACKGROUND: In the UK, studies suggest that the transition from hospital to home after an injury can be a difficult time and many patients report feeling inadequately prepared. Patients often use primary care services after hospital discharge. These consultations provide opportunities to consider problems that patients experience and to facilitate recovery. Little is known, however, about how patients and service providers view care after hospital discharge and the role played by primary care services, specifically GPs. AIM: To identify good practice and unmet needs in respect of post-discharge support for injured patients. DESIGN AND SETTING: Qualitative study using semi-structured interviews at four sites (Bristol, Leicester/Loughborough, Nottingham, and Surrey). METHOD: Qualitative interviews with 40 service providers and 45 hospitalised injured patients. RESULTS: Although there were examples of well-managed hospital discharges, many patients felt they were not provided with the information they needed about their injury, what to expect in terms of recovery, pain control, return to work, psychological problems, and services to help meet their needs. They also described difficulty accessing services such as physiotherapy or counselling. Service providers identified problems with communication between secondary and primary care, lack of access to physiotherapy, poor communication about other services that may help patients, GP service and resource constraints, and difficulties in providing information to patients concerning likely prognosis. CONCLUSION: Discharge from hospital after an injury can be problematic for patients. Changes in both secondary and primary care are required to resolve this problem. PMID- 26639950 TI - Molluscum contagiosum and associations with atopic eczema in children: a retrospective longitudinal study in primary care. AB - BACKGROUND: Molluscum contagiosum (MC) is a common skin condition in children. Consultation rates and current management in primary care, and how these have changed over time, are poorly described. An association between the presence of atopic eczema (AE) and MC has been shown, but the subsequent risk of developing MC in children with a diagnosis of AE is not known. AIM: To describe the consultation rate and management of MC in general practice in the UK over time, and test the hypothesis that a history of AE increases the risk of developing MC in childhood. DESIGN AND SETTING: Two studies are reported: a retrospective longitudinal study of MC cases and an age-sex matched case-cohort study of AE cases, both datasets being held in the UK Clinical Practice Research Datalink from 2004 to 2013. METHOD: Data of all recorded MC and AE primary care consultations for children aged 0 to 14 years were collected and two main analyses were conducted using these data: a retrospective longitudinal analysis and an age-sex matched case-cohort analysis. RESULTS: The rate of MC consultations in primary care for children aged 0 to 14 years is 9.5 per 1000 (95% CI = 9.4 to 9.6). The greatest rate of consultations for both sexes is in children aged 1-4 years and 5-9 years (13.1 to 13.0 (males) and 13.0 to 13.9 (females) per 1000 respectively). Consultation rates for MC have declined by 50% from 2004 to 2013. Children were found to be more likely to have an MC consultation if they had previously consulted a GP with AE (OR 1.13; 95% CI = 1.11 to 1.16; P<0.005). CONCLUSION: Consultations for MC in primary care are common, especially in 1-9-year-olds, but they declined significantly during the decade under study. A primary care diagnosis of AE is associated with an increased risk of a subsequent primary care diagnosis of MC. PMID- 26639951 TI - Metal-Ligand Misfits: Facile Access to Rhenium-Oxo Corroles by Oxidative Metalation. AB - With the exception of a single accidental synthesis, rhenium corroles are unknown, but of great interest as catalysts and potential radiopharmaceuticals. Oxidative metalation of meso-triarylcorroles with [Re2 (CO)10 ] in refluxing decalin has provided a facile and relatively high-yielding route to rhenium(V) oxo corroles. The complexes synthesized could all be fully characterized by single-crystal X-ray structure analyses. PMID- 26639952 TI - Mindfulness in the Maintenance of Cognitive Capacities in Alzheimer's Disease: A Randomized Clinical Trial. AB - BACKGROUND: The Canary Islands longitudinal study on non-pharmacological treatments showed the overall effectiveness of mindfulness in Alzheimer's disease (AD). However, no specific data on the maintenance of cognitive capacities were presented. OBJECTIVE: To determine whether the practice of mindfulness modifies the course of cognitive impairment in AD. METHODS: DESIGN: Longitudinal, non inferiority and equivalence, randomized clinical trial, repeated-measures design, with three experimental groups and one control group. PARTICIPANTS: Patients with AD who voluntarily attended the Lidia Garcia Foundation (n = 502). Only those who were treated with donepezil and MMSE >=18 were included (n = 120). INTERVENTION: Over a two-year period, each group carried out three weekly sessions of stimulation based on mindfulness, cognitive stimulation therapy, and progressive muscle relaxation. MEASURES: Cognitive assessment CAMDEX-R (MMSE and CAMCOG). STATISTICAL ANALYSIS: Repeated-measures ANOVA (p < 0.05) and the effect size Cohen's d were performed. RESULTS: The mindfulness group showed significant scores compared with the control and muscle relaxation groups (p < 0.05), while mindfulness and cognitive stimulation therapy were equivalent (p>=0.05). Group cognitive stimulation evolved better than the control (p < 0.05) group but not better than the muscle relaxation group (p>=0.05). The effect size compared over two years was large for the mindfulness group (p>=0.80), moderate for the relaxation group (p>=0.50), and low for the cognitive stimulation group (p>=0.20). CONCLUSION: The practice of mindfulness maintained cognitive function over a period of two years. This longitudinal study suggests that mindfulness can be used as a non-pharmacological treatment to slow cognitive impairment in AD. PMID- 26639953 TI - Characterizing Aging, Mild Cognitive Impairment, and Dementia with Blood-Based Biomarkers and Neuropsychology. AB - BACKGROUND: Current treatment in Alzheimer's disease (AD) is initiated at a stage where the brain already has irreversible structural deteriorations. Therefore, the concept of treatment prior to obvious cognitive deficits has become widely accepted, and simple biochemical tests to discriminate normal aging from prodromal or demented stages are now common practice. OBJECTIVE: The objective of the study was the differentiation of controls, mild cognitive impairment (MCI) and AD patients by novel blood-based assays in combination with neuropsychological tests. METHODS: In a cross-sectional study, 143 subjects aged 18 to 85 years were recruited. All participants were classified by a comprehensive neuropsychological assessment. Blood samples were analyzed for several amyloid-beta (Abeta) species, pro-inflammatory markers, anti-Abeta autoantibodies, and ApoE allele status, respectively. RESULTS: Plasma Abeta1-42 was significantly decreased in MCI and AD compared to age-matched controls, whereas Abeta1-40 did not differ, but increases with age in healthy controls. The Abeta1-42 to Abeta1-40 ratio was stepwise decreased from age-matched controls via MCI to AD, and shows a clear correlation with memory scores. Reduced Abeta1-42 and Abeta1-42 to Abeta1-40 ratio have strongly correlated with carrying ApoE E4 allele. Autoantibodies against pyroglutamate-modified Abeta, but only a certain subclass, were significantly decreased in AD compared to MCI and age-matched controls, whereas autoantibodies against the unmodified N-terminus of Abeta did not differ. CONCLUSION: Comprehensive sample preparation and assay standardization enable reliable usage of plasma Abeta for diagnosis of MCI and AD. Anti-pGlu-Abeta autoantibodies correlate with cognition, but not with ApoE, supporting the associated plasma Abeta analysis with additional and independent information. PMID- 26639954 TI - Exercise Plus Cognitive Performance Over and Above Exercise Alone in Subjects with Mild Cognitive Impairment. AB - BACKGROUND: Epidemiological studies highlight the relevance of regular exercise interventions to enhance or maintain neurocognitive function in subjects with cognitive impairments. OBJECTIVES: The aim of this study was to ascertain the effect of aerobic exercise associated with cognitive enrichment on cognitive performance in subjects with mild cognitive impairment (MCI). METHOD: Eight participants with MCI (72 +/- 2 years) were enrolled in a 9-month study that consisted of two 3-months experimental interventions separated by a training cessation period of 3 months. The interventions included either aerobic exercise alone or aerobic exercise combined with cognitive enrichment. The exercise program involved two 20-min cycling exercise bouts per week at an intensity corresponding to 60% of the heart rate reserve. Cognitive performance was assessed using a task of single reaction time (SRT) and an inhibition task (Go-no Go) before, immediately after, and 1 month after each intervention. RESULTS: The exercise intervention improved the speed of responses during the Go-no-Go task without any increase in errors. This improvement was enhanced by cognitive enrichment (6 +/- 1% ; p > 0.05), when compared with exercise alone (4 +/- 0.5% ,). Following exercise cessation, this positive effect disappeared. No effect was observed on SRT performance. CONCLUSION: Regular aerobic exercise improved cognitive performance in MCI subjects and the addition of cognitive tasks during exercise potentiated this effect. However, the influence of aerobic exercise on cognitive performance did not persist after cessation of training. Studies involving a larger number of subjects are necessary to confirm these results. PMID- 26639955 TI - Palmomental Reflex a Relevant Sign in Early Alzheimer's Disease Diagnosis? AB - BACKGROUND: Sophisticated and expensive biomarkers are proposed for the diagnostic of Alzheimer's disease (AD). The amyloid process seems to be early in AD, and brain amyloid load affects the frontal lobe. OBJECTIVE: To determine if certain simple clinical signs, especially frontal-related signs, could help reach an earlier and better diagnosis. METHODS: In the frame of the 3-City cohort, we conducted a nested case-control study comparing incident cases of AD to controls matched for age, gender, and education. The standardized neurological exam included extrapyramidal signs (akinesia, rigidity, rest tremor), pyramidal symptoms (spastic rigidity, Babinski reflex), primitive reflexes (snout, palmomental reflex grasping), and tremor (essential, intentional, head) at the time of diagnosis and two years before. RESULTS: We compared 106 incident AD subjects (mean age at diagnosis 82.2 (SD = 5.9); median MMSE at diagnosis = 23) to 208 matched controls. In patients younger than 80, palmomental reflexes were more frequent in AD than controls, two years before diagnosis (25.0 versus 7.0% , p = 0.03) and at time of diagnosis (30.3 versus 12.3% , p = 0.02). No difference was observed for other signs two years before diagnosis or for patients older than 80. CONCLUSION: Before diagnosis, the clinical examination of AD patients is not strictly normal; the primitive reflexes appear to be pathological. It might be in connection with the frontal amyloid load at an early stage of the disease. Clinical examination can reveal simple and interesting signs that deserve consideration as well as the other more invasive and expensive biomarkers. PMID- 26639956 TI - Subjective Memory Complaints in APOEE4 Carriers are Associated with High Amyloid beta Burden. AB - BACKGROUND: APOEE4 genotype and aging have been identified as risk factors for Alzheimer's disease (AD). In addition, subjective memory complaints (SMC) might be a first clinical expression of the effect of AD pathology on cognitive functioning. OBJECTIVE: To assess whether APOEE4 genotype, age, SMC, and episodic memory are risk factors for high amyloid-beta (Abeta) burden in cognitively normal elderly. METHODS: 307 cognitively normal participants (72.7 +/- 6.8 years, 53% female, 55% SMC) from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study underwent amyloid PET and APOE genotyping. Logistic regression analyses were performed to determine the association of APOEE4 genotype, age, SMC, and episodic memory with Abeta pathology. RESULTS: Odds of high Abeta burden were greater at an older age (OR = 3.21; 95% CI = 1.68-6.14), when SMC were present (OR = 1.90; 95% CI = 1.03-3.48), and for APOEE4 carriers (OR = 7.49; 95% CI = 3.96-14.15), while episodic memory was not associated with odds of high Abeta burden. Stratified analyses showed that odds of SMC for high Abeta burden were increased in specifically APOEE4 carriers (OR = 4.58, 95% CI = 1.83-11.49) and younger participants (OR = 3.73, 95% CI = 1.39-10.01). CONCLUSION: Aging, APOEE4 genotype, and SMC were associated with high Abeta burden. SMC were especially indicative of high Abeta burden in younger participants and in APOEE4 carriers. These findings suggest that selection based on the presence of SMC, APOEE4 genotype and age may help identify healthy elderly participants with high Abeta burden eligible for secondary prevention trials. PMID- 26639957 TI - Changes in Brain Volume with Bapineuzumab in Mild to Moderate Alzheimer's Disease. AB - BACKGROUND: Bapineuzumab, an anti-amyloid-beta monoclonal antibody, was evaluated in two placebo-controlled trials in APOE*E4 carriers and noncarriers, respectively, with Alzheimer's disease. OBJECTIVES: A volumetric magnetic resonance imaging substudy was performed to determine if bapineuzumab altered brain volume rate of change. METHODS: Bapineuzumab dosages included 0.5 mg/kg in carriers and 0.5 or 1.0 mg/kg in noncarriers, every 13 weeks for 78 weeks. Volumetric outcomes included annualized brain, ventricular, and mean hippocampal boundary shift integrals (BBSI; VBSI; HBSI) up to Week 71. Treatment differences were estimated using mixed models for repeated measures. RESULTS: For BBSI and HBSI, there were no significant treatment-related differences within either study, but, compared to pooled carriers and noncarriers receiving placebo, noncarriers receiving1.0 mg/kg bapineuzumab had greater increases in these measures. Bapineuzumab-treated patients showed significantly greater VBSI rates compared with placebo for 0.5 mg/kg in carriers and 1.0 mg/kg (but not 0.5 mg/kg) in noncarriers. CONCLUSIONS: Bapineuzumab produced an increase in ventricular volume compared with placebo. Etiology for this increase is unclear but may be related to amyloid-beta clearance or its consequences. PMID- 26639958 TI - Vascular Health Indices and Cognitive Domain Function: Singapore Longitudinal Ageing Studies. AB - BACKGROUND: Few studies have comprehensively evaluated the relationship between vascular disease and cognition of older adults without cardiac disease. OBJECTIVE: We explored the associations of structural atherosclerosis, vascular stiffness, and reactivity with global, memory, attention, language, visuospatial ability, and executive function in community-dwelling, non-demented older Asians without cardiac diseases. METHODS: Cognition was assessed by Mini-Mental State Examination (MMSE) (n = 308) and detailed neuropsychological tests (n = 155). Vascular measures included carotid intima-media thickness; aortic stiffness [carotid-femoral pulse wave velocity (CFPWV), aortic augmentation index (AI), and aortic pulse pressure (PP)]; carotid stiffness [elasticity modulus (Ep), beta index (beta), arterial compliance (AC), carotid AI]; and endothelial function [reactive hyperemia index (RHI)]. Multivariable analyses controlled for potential confounding by demographics, apolipoprotein E genotype and cardiovascular risk factors. RESULTS: The participants' mean age was 63.0 +/- 6.1 years. Inverse associations with MMSE were found for AC (beta= 0.128, p = 0.019), Ep (beta= 0.151, p = 0.008), beta index (beta= -0.122, p = 0.029), carotid stiffness z score (beta= -0.154, p = 0.007); with executive function for CFPWV (beta= -0.209, p = 0.026), AC (beta= 0.214, p = 0.005), Ep (beta= -0.160, p = 0.050), beta index (beta= -0.165, p = 0.041), and both aortic (beta= -0.229, p = 0.010) and carotid (beta= -0.208, p = 0.010) stiffness z-scores; with verbal memory for AI (beta= 0.229, p = 0.004) and aortic (beta= -0.263, p = 0.004) stiffness z-score; with language for AI (beta= -0.155, p = 0.025), aortic stiffness z-score (beta= 0.196, p = 0.011). RHI positively correlated with visuospatial ability (beta= 0.195, p = 0.013) and executive function (beta= 0.151, p = 0.045). CONCLUSION: The results support a link between systemic vascular health and neurocognitive function in older Asian adults. Subclinical noninvasive measures of arterial stiffness and reactivity may identify individuals vulnerable to cognitive impairment. PMID- 26639959 TI - Lifelong Reading Disorder and Mild Cognitive Impairment: Implications for Diagnosis. AB - Although neuropsychological tests are commonly used in the evaluation of possible mild cognitive impairment (MCI), poor test scores may be indicative of factors other than neurological compromise. The current study assessed the role of lifelong reading disorder on MCI classification. Community dwelling older adults with a suspected developmental reading disorder were identified by inference based on reading test performance. Individuals with a suspected reading disorder were significantly more likely to perform at a level consistent with MCI on several commonly used neuropsychological tests. The findings suggest a relationship between a history of reading disorder and MCI classification. PMID- 26639961 TI - Resting-State Cardiac Workload is Related to Both Increased Neocortical Aggregation of Amyloid-beta and Relative Impairments in Spatial Working Memory in Pre-Clinical Alzheimer's Disease. AB - We sought to determine whether there is any association between a cardiac workload marker, rate pressure product (RPP), working memory, and cortical amyloid-beta (Abeta) burden in 63 cognitively normal midlife adults (Mage = 62.8 years; range = 55 to 75 years) at risk for Alzheimer's disease (AD). The results show a small-to-moderate relationship between increasing cardiac workload (at rest) and neocortical amyloidosis in individuals at the preclinical stage of AD. Moreover, increasing RPP was linearly related to increasing relative impairments on a spatial working memory task (R2 = 0.30), but only for those individuals with neuroimaging evidence suggestive of preclinical AD. These results support a relationship between the aggregation of Abeta protein plaques in the neocortex, increased cognitive impairment, and more inefficient myocardial oxygen use in the absence of significant metabolic demands. PMID- 26639960 TI - Empirically Defining Trajectories of Late-Life Cognitive and Functional Decline. AB - BACKGROUND: Alzheimer's disease (AD) is associated with variable cognitive and functional decline, and it is difficult to predict who will develop the disease and how they will progress. OBJECTIVE: This exploratory study aimed to define latent classes from participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) database who had similar growth patterns of both cognitive and functional change using Growth Mixture Modeling (GMM), identify characteristics associated with those trajectories, and develop a decision tree using clinical predictors to determine which trajectory, as determined by GMM, individuals will most likely follow. METHODS: We used ADNI early mild cognitive impairment (EMCI), late MCI (LMCI), AD dementia, and healthy control (HC) participants with known amyloid-beta status and follow-up assessments on the Alzheimer's Disease Assessment Scale - Cognitive Subscale or the Functional Activities Questionnaire (FAQ) up to 24 months postbaseline. GMM defined trajectories. Classification and Regression Tree (CART) used certain baseline variables to predict likely trajectory path. RESULTS: GMM identified three trajectory classes (C): C1 (n = 162, 13.6%) highest baseline impairment and steepest pattern of cognitive/functional decline; C3 (n = 819, 68.7%) lowest baseline impairment and minimal change on both; C2 (n = 211, 17.7%) intermediate pattern, worsening on both, but less steep than C1. C3 had fewer amyloid- or apolipoprotein-E E4 (APOE4) positive and more healthy controls (HC) or EMCI cases. CART analysis identified two decision nodes using the FAQ to predict likely class with 82.3% estimated accuracy. CONCLUSIONS: Cognitive/functional change followed three trajectories with greater baseline impairment and amyloid and APOE4 positivity associated with greater progression. FAQ may predict trajectory class. PMID- 26639962 TI - Shared Genetic Etiology between Type 2 Diabetes and Alzheimer's Disease Identified by Bioinformatics Analysis. AB - Type 2 diabetes (T2D) and Alzheimer's disease (AD) are two major health issues, and increasing evidence in recent years supports the close connection between these two diseases. The present study aimed to explore the shared genetic etiology underlying T2D and AD based on the available genome wide association studies (GWAS) data collected through August 2014. We performed bioinformatics analyses based on GWAS data of T2D and AD on single nucleotide polymorphisms (SNPs), gene, and pathway levels, respectively. Six SNPs (rs111789331, rs12721046, rs12721051, rs4420638, rs56131196, and rs66626994) were identified for the first time to be shared genetic factors between T2D and AD. Further functional enrichment analysis found lipid metabolism related pathways to be common between these two disorders. The findings may have important implications for future mechanistic and interventional studies for T2D and AD. PMID- 26639963 TI - Clinical Dementia Rating Scale Detects White Matter Changes in Older Adults at Risk for Alzheimer's Disease. AB - This study investigated the putative changes in regional gray matter and cingulum bundle segments in mild cognitive impairment (MCI) by using two diagnostic criteria. Participants comprised 50 older adults with MCI and 22 healthy older controls (HC). The older adults with MCI were further divided into two groups defined by a global Clinical Dementia Rating (CDR) score of 0.5 and with (the CDR/NPT MCI group) or without (the CDR MCI group) objective cognitive impairments determined using neuropsychological tests (NPTs). Comparable regional gray matter integrity was observed among the three groups. However, the integrity of the right inferior segment of the cingulum bundle in the two MCI groups was more reduced than that in the HC group, and the CDR/NPT MCI group exhibited additional disruption in the left inferior cingulum bundle. The results also demonstrated that neuropsychological measures have greater predictive value for changes in white matter beyond the contribution of an informant-based instrument alone. Overall, the findings confirm the utility of informant-based assessment in detecting microstructural brain changes in high-risk older adults, even before objective cognitive impairment is evident. The findings also suggest that combining the neuropsychological measures with the informant-based assessment provided the greatest predictive value in assessing white matter disruption. The essential role of the white matter measurement as a biomarker for detecting individuals at a high risk of developing dementia was highlighted. PMID- 26639964 TI - Economic Analysis of Formal Care, Informal Care, and Productivity Losses in Primary Care Patients who Screened Positive for Dementia in Germany. AB - BACKGROUND: The majority of people with dementia (PwD) live at home and require professional formal care and informal care that is generally provided by close relatives. OBJECTIVE: To determine the utilization and costs of formal and informal care for PwD, indirect costs because of productivity losses of caregivers, and the associations between cost, socio-demographic and clinical variables. METHODS: The analysis includes the data of 262 community-dwelling PwD and their caregivers. Socio-demographics, clinical variables, and the utilization of formal care were assessed within the baseline assessment. To evaluate informal care costs, the Resource Utilization in Dementia (RUD) questionnaire was used. Costs were calculated from a social perspective. Associations were evaluated using multiple linear and logistic regression models. RESULTS: Formal care services were utilized less (26.3%) than informal care (85.1%), resulting in a cost ratio of one to ten(1,646 ?; 16,473 ?, respectively). In total, 29% of caregivers were employed, and every seventh (14.3%) experienced productivity losses, which corresponded to 1,258 ? annually. Whereas increasing deficits in daily living activities were associated with higher formal and higher informal costs, living alone was significantly associated with higher formal care costs and the employment of a caregiver was associated with lower informal care costs. CONCLUSION: Informal care contributes the most to total care costs. Living alone is a major cost driver for formal costs because of the lower availability of potential informal care. The availability of informal care is limited and productivity losses are increased when a caregiver is employed. PMID- 26639965 TI - Usefulness of an Integrated Analysis of Different Memory Tasks to Predict the Progression from Mild Cognitive Impairment to Alzheimer's Disease: The Episodic Memory Score (EMS). AB - Taking into the account both the severity and the consistency of performances obtained on memory tests by patients with amnestic mild cognitive impairment (aMCI) could improve the power to predict their progression to Alzheimer's disease. For this purpose, we constructed the Episodic Memory Score (EMS), which is obtained by subdividing in tertiles performances obtained at baseline in verbal (RAVLT) and visual episodic memory (Rey-Osterrieth Figure-delayed recall) and giving a score ranging from 1 (worst result) to 3 (best result) to results falling within each tertile. The EMS was computed for each patient by summing the tertile score obtained on each memory task, so that the total score ranged from 4 (worst performance) to 12 (best performance). The aMCI sample consisted of 198 subjects who completed the two-year follow-up, at the end of which 55 subjects had converted to dementia. The mean EMS score obtained by aMCI converters was significantly lower than that of aMCI-stable patients. In detecting conversion to dementia, the comparison between EMS and individual memory scores obtained at baseline was made by computing ROC curves, and estimating the respective area under the curve (AUC). The EMS had a larger AUC than the individual memory scores. At baseline aMCI converters performed worse than non-converters not only on memory tasks, but also on executive functions tasks. However, in a multiple variables logistic regression analysis in which all scores showing statistically significant differences between aMCI-converters and aMCI-stable were entered, the EMS was the only reliable predictor of progression from aMCI to dementia. PMID- 26639966 TI - Cerebrospinal Fluid Anti-Amyloid-beta Autoantibodies and Amyloid PET in Cerebral Amyloid Angiopathy-Related Inflammation. AB - We report a biomarker and genetic evaluation of four patients with cerebral amyloid angiopathy-related inflammation (CAA-ri) treated with corticosteroids. Patients presented with focal symptomatology and cognitive impairment. MRI revealed cortical microbleeds and asymmetrical hyperintense white matter lesions (WML). Cerebrospinal fluid (CSF) biomarker analyses showed increased anti-Abeta autoantibodies, t-Tau, and p-Tau and decreased Abeta40 and Abeta42. After treatment, focal symptomatology disappeared, and WML and anti-Abeta autoantibodies decreased. The APOEE4 allele was overrepresented. Florbetapir-PET showed cortical deposition with lower retention in swollen areas. In the case of suspected CAA-ri, both CSF anti-Abeta autoantibodies levels and Florbetapir-PET could provide highly useful data to guide the correct diagnosis. PMID- 26639967 TI - Biomarkers Differentiating Dementia with Lewy Bodies from Other Dementias: A Meta Analysis. AB - BACKGROUND: Several nuclear imaging and cerebrospinal fluid (CSF) biomarkers are under investigation, aimed at facilitating the differential diagnosis of dementias. OBJECTIVE: To quantitatively synthesize data on test performance in differentiating dementia with Lewy bodies (DLB) from other dementias. METHODS: We searched PubMed (January 2000- March 2015) for English-language publications that assessed a selected set of five imaging and three CSF biomarkers for this purpose. We meta-analyzed measures of agreement between biomarker results and clinical diagnosis. RESULTS: Forty-five publications were eligible. The majority of evidence was based on studies that enrolled representative disease populations. For differentiating between DLB and Alzheimer's disease (AD) or other dementias, metaiodobenzylguanidine scintigraphy and dopamine transporter (DAT) single photon emission computed tomography (SPECT) showed, respectively, excellent (summary kappa = 0.85; 95% confidence interval [95% CI], 0.74-0.96) and good (summary kappa = 0.71; 95% CI, 0.43-0.99) agreement. Metaiodobenzylguanidine scintigraphy appeared superior to fluorodeoxyglucose- positron emission tomography (summary kappa = 0.53; 95% CI, 0.36-0.69) and cerebral blood flow SPECT (summary kappa = 0.40; 95% CI, 0.33-0.47). For differentiating DLB from AD, CSF t-tau levels (summary kappa = 0.68; 95% CI, 0.55-0.82) performed comparably to metaiodobenzylguanidine scintigraphy and DAT SPECT. Sparse direct comparative evidence failed to corroborate these indirect comparisons. CONCLUSION: Metaiodobenzylguanidine scintigraphy and DAT SPECT are highly concordant with clinical diagnosis in differentiating DLB from other dementias. However, given the limitations in the study design, the applicability of these results to real world differential diagnosis remains unclear. Prospective studies targeting patients with atypical presentations that adopt gold standard tests would reliably estimate the true test performance of these promising biomarkers. PMID- 26639968 TI - A Mitochondrial Role of SV2a Protein in Aging and Alzheimer's Disease: Studies with Levetiracetam. AB - Aberrant neuronal network activity associated with neuronal hyperexcitability seems to be an important cause of cognitive decline in aging and Alzheimer's disease (AD). Out of many antiepileptics, only levetiracetam improved cognitive dysfunction in AD patients and AD animal models by reducing hyperexcitability. As impaired inhibitory interneuronal function, rather than overactive neurons, seems to be the underlying cause, improving impaired neuronal function rather than quieting overactive neurons might be relevant in explaining the lack of activity of the other antiepileptics. Interestingly, improvement of cognitive deficits by levetiracetam caused by small levels of soluble Abeta was accompanied by improvement of synaptic function and plasticity. As the negative effects of Abeta on synaptic plasticity strongly correlate with mitochondrial dysfunction, wehypothesized that the effect of levetiracetam on synaptic activity might be raised by an improved mitochondrial function. Accordingly, we investigated possible effects of levetiracetam on neuronal deficits associated with mitochondrial dysfunction linked to aging and AD. Levetiracetam improved several aspects of mitochondrial dysfunction including alterations of fission and fusion balance in a cell model for aging and early late-onset AD. We demonstrate for the first time, using immunohistochemistry and proteomics, that the synaptic vesicle protein 2A (SV2a), the molecular target of levetiracetam, is expressed in mitochondria. In addition, levetiracetam shows significant effect on the opening of the mitochondrial permeability transition pore. Importantly, the effects of levetiracetam were significantly abolished when SV2a was knockdown using siRNA. In conclusion, interfering with the SV2a protein at the mitochondrial level and thereby improving mitochondrial function might represent an additional therapeutic effect of levetiracetam to improve symptoms of late-onset AD. PMID- 26639969 TI - Decreased Levels of VAMP2 and Monomeric Alpha-Synuclein Correlate with Duration of Dementia. AB - Alpha-synuclein (alpha-syn) aggregations are the key pathological hallmark of dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), but are also frequently present in Alzheimer's disease (AD). Much remains unknown about the role of alpha-syn in the synapse and the wider role of synaptic dysfunction in these dementias. Changes in concentrations of key 'SNAP (Soluble N ethylmaleimide Sensitive Factor Attachment Protein) Receptor' (SNARE) proteins as a consequence of alterations in the aggregation state of alpha-syn may contribute to synaptic dysfunction in patients with DLB, PDD, and AD and result in impaired cognition. We have studied a large cohort (n = 130) of autopsy confirmed DLB, PDD, AD, and control brains. Using semi-quantitative western blotting, we have demonstrated significant changes across the diagnostic groups of DLB, PDD, and AD in the SNARE and vesicle proteins syntaxin, Munc18, VAMP2, and monomeric alpha syn in the prefrontal cortex, with a significant reduction of Munc18 in AD patients (p < 0.001). This correlated to the final MMSE score before death (p = 0.016). We also identified a significant negative correlation between the duration of dementia and the levels of the binding partners VAMP2 (p = 0.0004) and monomeric alpha-syn (p = 0.0002). Our findings may indicate that an upregulation of SNARE complex related proteins occurs in the early stages of disease as an attempt at compensating for failing synapses, prior to widespread deposition of pathological alpha-syn. PMID- 26639970 TI - Cohort Effects in the Prevalence and Survival of People with Dementia in a Rural Area in Northern Sweden. AB - BACKGROUND: Recent studies suggest that trends in cardiovascular risk may result in a decrease in age-specific prevalence of dementia. Studies in rural areas are rare. OBJECTIVES: To study cohort effects in dementia prevalence and survival of people with dementia in a Swedish rural area. METHODS: Participants were from the 1995-1998 Nordanstig Project (NP) (n = 303) and the 2001-2003 Swedish National study on Aging and Care in Nordanstig (SNAC-N) (n = 384). Overall 6-year dementia prevalence and mortality in NP and SNAC-N were compared for people 78 years and older. Logistic regression analyses were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for dementia occurrence using the NP study population as the reference group. Cox regression models were used to analyze time to death. RESULTS: The crude prevalence of dementia was 21.8% in NP and 17.4% in SNAC-N. When the NP cohort was used as the reference group, the age- and gender-adjusted OR of dementia was 0.71 (95% CI 0.48-1.04) in SNAC-N; the OR was 0.47 (0.24-0.90) for men and 0.88 (0.54-1.44) for women. In the extended model, the OR of dementia was significantly lower in SNAC-N than in the NP cohort as a whole (0.63; 0.39-0.99) and in men (0.34; 0.15-0.79), but not in women (0.81; 0.46-1.44). The Cox regression models indicated that the hazard ratio of dying was lower in the SNAC-N than NP population. CONCLUSIONS: Trends toward a lower prevalence of dementia in high-income countries seem to be evident in this Swedish rural area, at least in men. PMID- 26639971 TI - Gene Expression Profiling in the APP/PS1KI Mouse Model of Familial Alzheimer's Disease. AB - Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by early intraneuronal amyloid-beta (Abeta) accumulation, extracellular deposition of Abeta peptides, and intracellular hyperphosphorylated tau aggregates. These lesions cause dendritic and synaptic alterations and induce an inflammatory response in the diseased brain. Although the neuropathological characteristics of AD have been known for decades, the molecular mechanisms causing the disease are still under investigation. Studying gene expression changes in postmortem AD brain tissue can yield new insights into the molecular disease mechanisms. To that end, one can employ transgenic AD mouse models and the next-generation sequencing technology. In this study, a whole-brain transcriptome analysis was carried out using the well-characterized APP/PS1KI mouse model for AD. These mice display a robust phenotype reflected by working memory deficits at 6 months of age, a significant neuron loss in a variety of brain areas including the CA1 region of the hippocampus and a severe amyloid pathology. Based on deep sequencing, differentially expressed genes (DEGs) between 6-month-old WT or PS1KI and APP/PS1KI were identified and verified by qRT PCR. Compared to WT mice, 250 DEGs were found in APP/PS1KI mice, while 186 DEGs could be found compared to PS1KI control mice. Most of the DEGs were upregulated in APP/PS1KI mice and belong to either inflammation-associated pathways or lysosomal activation, which is likely due to the robust intraneuronal accumulation of Abeta in this mouse model. Our comprehensive brain transcriptome study further highlights APP/PS1KI mice as a valuable model for AD, covering molecular inflammatory and immune responses. PMID- 26639973 TI - A Meta-Analysis of Alzheimer's Disease Incidence and Prevalence Comparing African Americans and Caucasians. AB - BACKGROUND: Several studies have shown higher Alzheimer's disease (AD) incidence rates are in African-Americans (AAs) than Caucasians (CCs). If this finding is consistent across studies, it raises important etiologic questions regarding factors responsible for this discrepancy. It also affects the likely public health burden of AD in the US in the future, as the non-Caucasian population becomes the majority. OBJECTIVE: Estimate the AA/CC rate ratio for AD incidence across all available studies. METHODS: We conducted a meta-analysis of population based studies for the rate ratio (RR) of AD incidence for AAs versus CCs, after identifying six relevant studies from the literature. We calculated an AA/CC rate ratio across all studies using inverse-variance weighting, and assessed inter study heterogeneity. Using these incidence data, as well as data on survival after diagnosis, and on all-cause mortality, we also estimated the US prevalence of AD among AAs and CCs. RESULTS: There were six population-based studies with data comparing AD incidence between AAs and CCs, with an estimated 370 AA and 640 CC incident cases. The meta-analysis RR showed that the AD rate for AAs was 64% higher than for CCs (RR = 1.64 (95% CI 1.35-2.00)) 1.35-2.00)), with no evidence of heterogeneity. We estimated the current US AD prevalence for ages 65-90 to be 5.5% for CCs, and 8.6% for AAs (prevalence ratio 1.56). CONCLUSION: AAs have an increased risk of incident and prevalent AD compared to CCs for reasons which are unknown, but are hypothesized to reflect biological, psychological, and socioeconomic factors. PMID- 26639972 TI - Tobacco Smoke-Induced Brain White Matter Myelin Dysfunction: Potential Co-Factor Role of Smoking in Neurodegeneration. AB - BACKGROUND: Meta-analysis studies showed that smokers have increased risk for developing Alzheimer's disease (AD) compared with non-smokers, and neuroimaging studies revealed that smoking damages white matter structural integrity. OBJECTIVE: The present study characterizes the effects of side-stream (second hand) cigarette smoke (CS) exposures on the expression of genes that regulate oligodendrocyte myelin-synthesis, maturation, and maintenance and neuroglial functions. METHODS: Adult male A/J mice were exposed to air (8 weeks; A8), CS (4 or 8 weeks; CS4, CS8), or CS8 followed by 2 weeks recovery (CS8 + R). The frontal lobes were used for histology and qRT-PCR analysis. RESULTS: Luxol fast blue, Hematoxylin and Eosin stained histological sections revealed CS-associated reductions in myelin staining intensity and narrowing of the corpus callosum. CS exposures broadly decreased mRNA levels of immature and mature oligodendrocyte myelin-associated, neuroglial, and oligodendrocyte-related transcription factors. These effects were more prominent in the CS8 compared with CS4 group, suggesting that molecular abnormalities linked to white matter atrophy and myelin loss worsen with duration of CS exposure. Recovery normalized or upregulated less than 25% of the suppressed genes; in most cases, inhibition of gene expression was either sustained or exacerbated. CONCLUSION: CS exposures broadly inhibit expression of genes needed for myelin synthesis and maintenance. These adverse effects often were not reversed by short-term CS withdrawal. The results support the hypothesis that smoking contributes to white matter degeneration, and therefore could be a key risk factor for a number of neurodegenerative diseases, including AD. PMID- 26639974 TI - Platelet Membrane beta-Secretase Activity in Mild Cognitive Impairment and Conversion to Dementia: a Longitudinal Study. AB - A blood-based biomarker to complement the clinical and neuropsychological assessments used to evaluate the risk of individuals with mild cognitive impairment (MCI) developing Alzheimer's disease (AD) would be invaluable. Previous pilot studies by our group identified elevated platelet membrane beta secretase activity in patients with AD and MCI, as compared to controls, and this activity was influenced by membrane cholesterol levels. The present study investigated baseline platelet membrane beta-secretase activity and cholesterol levels in 97 MCI participants and 85 controls and explored whether these parameters differed in individuals with stable MCI, as compared to those who subsequently developed AD. To evaluate signal specificity, beta-secretase activity assays were conducted in the presence and absence of beta-site amyloid beta protein precursor-cleaving enzyme (BACE) inhibitors. Baseline platelet membrane beta-secretase activity did not differ significantly in MCI participants, as compared to controls, and platelet membrane cholesterol levels were significantly lower in the MCI group. The longitudinal study indicated that the activities inhibited by two different BACE inhibitors did not predict conversion to AD; however, the activity that was not affected by BACE inhibitors was significantly (40%) higher in individuals with stable MCI, as compared with those who subsequently developed AD. These findings indicated that further research into the source of this activity could contribute to a measure facilitating prediction of the risk of conversion from MCI to AD. PMID- 26639975 TI - Blood-Borne Activity-Dependent Neuroprotective Protein (ADNP) is Correlated with Premorbid Intelligence, Clinical Stage, and Alzheimer's Disease Biomarkers. AB - Biomarkers for Alzheimer's disease (AD) are vital for disease detection in the clinical setting. Discovered in our laboratory, activity-dependent neuroprotective protein (ADNP) is essential for brain formation and linked to cognitive functions. Here, we revealed that blood borne expression of ADNP and its paralog ADNP2 is correlated with premorbid intelligence, AD pathology, and clinical stage. Age adjustment showed significant associations between: 1) higher premorbid intelligence and greater serum ADNP, and 2) greater cortical amyloid and lower ADNP and ADNP2 mRNAs. Significant increases in ADNP mRNA levels were observed in patients ranging from mild cognitive impairment (MCI) to AD dementia. ADNP2 transcripts showed high correlation with ADNP transcripts, especially in AD dementia lymphocytes. ADNP plasma/serum and lymphocyte mRNA levels discriminated well between cognitively normal elderly, MCI, and AD dementia participants. Measuring ADNP blood-borne levels could bring us a step closer to effectively screening and tracking AD. PMID- 26639976 TI - An Optimized Combination of Ginger and Peony Root Effectively Inhibits Amyloid beta Accumulation and Amyloid-beta-Mediated Pathology in AbetaPP/PS1 Double Transgenic Mice. AB - The progressive aggregation of amyloid-beta protein (Abeta) into senile plaques is a major pathological factor of Alzheimer's disease (AD) and is believed to result in memory impairment. We aimed to investigate the effect of an optimized combination of ginger and peony root (OCGP), a standardized herbal mixture of ginger and peony root, on Abeta accumulation and memory impairment in amyloid beta protein precursor (AbetaPP)/presenilin 1 (PS1) double-transgenic mice. In an in vitro thioflavin T fluorescence assay, 100 MUg/ml OCGP inhibited Abeta accumulation to the same extent as did 10 MUM curcumin. Furthermore, AbetaPP/PS1 double-transgenic mice treated with OCGP (50 or 100 mg/kg/day given orally for 14 weeks) exhibited reduced Abeta plaque accumulation in the hippocampus and lower levels of glial fibrillary acid protein and cyclooxygease-2 expression compared with vehicle-treated controls. These results suggest that OCGP may prevent memory impairment in AD by inhibiting Abeta accumulation and inflammation in the brain. PMID- 26639977 TI - Response to Shill and colleagues. PMID- 26639978 TI - Interactions of visual hallucinations, rapid eye movement sleep behavior disorder and cognitive impairment in Parkinson's disease: A review. AB - Patients with Parkinson's disease may develop various non-motor symptoms during the course of the illness. Visual hallucinations (VH) and cognitive impairment (CI) are two common non-motor symptoms of Parkinson's disease. Studies have reported association of both VH and CI with presence of rapid eye movement sleep behavior disorder (RBD). Presence of visual hallucinations and cognitive impairment has been described as risk factors for emergence of each other. There is marked overlap in the risk factors for development of RBD, VH and CI in patients with PD. Results of clinical and epidemiological studies as well as studies based on neuroimaging, electrophysiology especially transcranial magnetic stimulation and neuropsycholgical evaluations in PD patients have suggested presence of certain common neurobiological process leading to emergence of RBD, VH and CI. Structural neuroimaging studies using voxel-based morphometry have often reported grey matter atrophy of hippocampus and parahippocampal cortices in PD patients with RBD, VH and CI. Cholinergic dysfunction is common in PD patients with RBD, VH and CI. This review explores the complex interactions of RBD, VH and CI in patients with PD and their potential implications. PMID- 26639979 TI - Deep brain stimulation in early stage Parkinson's disease may reduce the relative risk of symptom worsening. PMID- 26639980 TI - Loss of awareness of hyposmia is associated with mild cognitive impairment in Parkinson's disease. AB - BACKGROUND: Hyposmia is a common non-motor symptom in Parkinson's disease (PD). However, patients with PD are sometimes unaware of their olfactory dysfunction, resulting in an under-diagnosis of this symptom. To determine whether the loss of awareness of hyposmia results from cognitive impairment in patients with PD, we investigated the relationship between the degree of hyposmia self-awareness and the cognitive status of non-demented PD patients. METHODS: Thirty-one non demented patients with PD and 20 healthy controls (HC) were assessed via a self reported olfactory questionnaire and an odor identification test. PD patients were sub-classified as having mild cognitive impairment (PD-MCI) or as cognitively normal (PD-CN) (according to the current PD-MCI criteria). We compared the degree of hyposmia self-awareness between the PD-MCI and PD-CN groups. RESULTS: The PD-MCI group scored the lowest on the odor identification test among all groups, whereas PD-MCI patients tended to rate their olfactory function higher on the self-reported olfactory questionnaire than PD-CN patients. Differences in the scores of subjective and objective olfactory measures between the PD-MCI and PD-CN groups were significant (p = 0.0069). CONCLUSIONS: The loss of awareness of hyposmia is closely associated with mild cognitive impairment (MCI) in PD patients. PMID- 26639981 TI - Reduced after-effects following podokinetic adaptation in people with Parkinson's disease and freezing of gait. AB - INTRODUCTION: Gait dysfunction is common in people with Parkinson's disease (PD). Freezing of gait (FOG) is one such gait disturbance that significantly impacts mobility and quality of life in PD. Recent evidence suggests that cerebellar connectivity may differ in people with PD and FOG (PD+FOG) relative to those without FOG (PD-FOG). Investigation of gait adaptation, or the ability to change gait patterns in response to external perturbations, is cerebellum-dependent, is a practical means of probing cerebellar integrity and may provide additional insights regarding the FOG phenomenon. METHODS: In this study, we investigated gait adaptation in PD and FOG by measuring after-effects, namely whole-body rotation, following stepping on a rotating disc in PD+FOG compared to PD-FOG and older healthy adults. We refer to the period of stepping on the rotating disc as the podokinetic (PK) stimulation and after-effects as podokinetic after-rotation (PKAR). Our primary measure of adaptation was the magnitude and rate of decay of the after-effects. RESULTS: We noted that PKAR was diminished in PD+FOG compared to the other groups, indicating reduced storage of the adapted gait pattern in PD+FOG. In the PD groups, FOG explained about 20% of the variability in peak velocity. Furthermore, these differences were independent of stepping cadence or motor sign severity. CONCLUSION: Our results show that gait adaptation is impaired in PD+FOG, suggesting the cerebellum may be differentially impacted in PD+FOG compared to PD-FOG. This supports previous neuroimaging evidence of cerebellar dysfunction in PD+FOG. Overall, these data further our understanding of gait deficits in PD+FOG. PMID- 26639982 TI - Orthostatic hypotension, cerebral hypoperfusion, and visuospatial deficits in Lewy body disorders. AB - BACKGROUND: Orthostatic hypotension and cognitive impairment are two non-motor attributes of Lewy body spectrum disorders that impact independence. This proof of-concept study examined cerebral blood flow (perfusion) as a mediator of orthostatic hypotension and cognition. METHODS: In fifteen patients with Lewy body disorders, we estimated regional perfusion using pseudo-continuous arterial spin labeling MRI, and quantified orthostatic hypotension from the change in systolic blood pressure between supine and standing positions. Executive, visuospatial, attention, memory, and language domains were characterized by neuropsychological tests. A matching sample of non-demented adults with cerebral small vessel disease was obtained to contrast perfusion patterns associated with comorbid vascular pathology. RESULTS: Compared to the vascular group, patients with Lewy body disorders exhibited lower perfusion to temporal and occipital lobes than to frontal and parietal lobes (q < 0.05). A greater orthostatic drop in systolic pressure was associated with lower occipito-parietal perfusion in these patients (uncorrected p < 0.005; cluster size >= 20 voxels). Although orthostatic hypotension and supine hypertension were strongly correlated (r = 0.79, p < 0.001), the patterns of association for each with perfusion were distinct. Specifically, supine hypertension was associated with high perfusion to anterior and middle cerebral arterial territories, as well as with low perfusion to posterior regions. Perfusion within orthostatic hypotension-defined regions was directly related to performance on visuospatial and attention tasks, independent of dementia severity (p < 0.05). CONCLUSIONS: These findings provide new insight that regional cerebral hypoperfusion is related to orthostatic hypotension, and may be involved in domain-specific cognitive deficits in Lewy body disorders. PMID- 26639983 TI - Does Increased Coefficient of Friction of Highly Porous Metal Increase Initial Stability at the Acetabular Interface? AB - BACKGROUND: Highly porous metal acetabular components illustrate a decreased rate of aseptic loosening in short-term follow-up compared with previous registry data. This study compared the effect of component surface roughness at the bone implant interface and the quality of the bone on initial pressfit stability. The null hypothesis is that a standard porous coated acetabular cup would show no difference in initial stability as compared with a highly porous acetabular cup when subjected to a bending moment. Second, would bone mineral density (BMD) be a significant variable under these test conditions. METHODS: In a cadaveric model, acetabular cup micromotion was measured during a 1-time cantilever bending moment applied to 2 generations of pressfit acetabular components. BMD data were also obtained from the femoral necks available for associated specimen. RESULTS: The mean bending moment at 150 MUm was not found to be significantly different for Gription (24.6 +/- 14.0 N m) cups vs Porocoat (25 +/- 10.2 N m; P > .84). The peak bending moment tolerated by Gription cups (33.9 +/- 20.3 N m) was not found to be significantly different from Porocoat (33.5 +/- 12.2 N m; P > .92). No correlation between BMD and bending moment at 150 MUm of displacement could be identified. CONCLUSION: The coefficient of friction provided by highly porous metal acetabular shells used in this study did not provide better resistance to migration under bending load when compared with a standard porous coated component. PMID- 26639984 TI - How Do Previous Solid Organ Transplant Recipients Fare After Primary Total Knee Arthroplasty? AB - INTRODUCTION: Total knee arthroplasty (TKA) has been proven to increase knee outcome scores after solid organ transplantation (SOT), but many authors are concerned about a higher complication rate. The purpose of this study is to evaluate the complication profile of TKA after previous SOT. METHODS: A search of the entire Medicare database from 2005 to 2011 was performed using International Classification of Disease, version 9, codes to identify 3339 patients who underwent TKA after 1 or more solid organ transplants including the kidney (2321), liver (772), lung (129), heart (412), and pancreas (167). A cohort of 1,685,295 patients served as a control with minimum 2-year follow-up. Postoperative complications at 30-day, 90-day, and overall time points were compared between the 2 cohorts. RESULTS: Patients with any SOT were younger (age: <65, odds ratio [OR]: 6.58, P < .001), male (OR: 1.88, P < .001), and medically complex (significant increase in 28 of 29 Elixhauser comorbidities, P < .05). There was a significant increase (P < .05) in 11 of 13 (84.6%) recorded postoperative medical complications rates at 90 days. There was a significant increase overall in periprosthetic infection (OR: 2.11, P < .001), periprosthetic fracture (OR: 1.78, P < .001), and TKA revision (OR: 1.36, P < .001). When analyzed by individual organ, heart and lung transplants carried the fewest medical and surgical complications. CONCLUSION: The results of this study demonstrate that patients with previous SOT who undergo elective primary TKA have more postoperative complications in the global period and at short-term follow up. Yet, complication profiles by individual organ varied significantly. PMID- 26639985 TI - Are Range of Motion Measurements Needed When Calculating the Harris Hip Score? AB - BACKGROUND: Often the patient-reported outcome (PRO) component of the Harris Hip Score (HHS) is completed, but the physician-assessed range of motion (ROM) component is not. The PRO component only is called a modified Harris Hip Score (mHHS). The purpose of this study was to determine if a statistically significant or clinically meaningful difference existed when calculating the HHS with and without the physician-reported ROM portion. METHODS: Included patients had complete HHS data (both physician and PRO components). Surgical procedure (primary or revision) was recorded for each subject. American Society of Anesthesiologists score was divided into low and high groups. Body mass index was divided into 4 categories. The study used a repeated measures design. RESULTS: Data on 483 patients were collected between 12 and 60 months postoperatively (mean follow-up: 32.5 months, mean age: 55.9 +/- 13.5 years). A mean difference of 4 points existed between the 2 groups: HHS group average score was 84.56 +/- 13.18, and mHHS group average score was 88.74 +/- 13.77. American Society of Anesthesiologists score, body mass index, and surgical type demonstrated a significant interaction with the HHS calculation method (P < .001). Primary total joint patients demonstrated a greater difference between the 2 scoring methods compared with revision patients. CONCLUSION: No clinically meaningful difference in outcomes was found between the mHHS and the HHS. The calculation of the HHS is dependent on the inclusion of the ROM measurement. However, the small point difference between the HHS and mHHS indicates that the mHHS is still useful as an accurate determinant of patient clinical outcome, and ROM assessment is not essential. PMID- 26639986 TI - Local Infiltration Analgesia Versus Continuous Femoral Nerve Block in Pain Relief After Total Knee Arthroplasty: A Randomized Controlled Trial. AB - BACKGROUND: Although both local infiltration analgesia (LIA) and continuous femoral nerve block (FNB) are common analgesic modalities for pain relief after total knee arthroplasty (TKA), we are aware of no parallel-group, randomized controlled trial that has solely compared the efficacy of LIA and continuous FNB. METHODS: We conducted a prospective, 2-arm, parallel-group, randomized controlled trial involving patients scheduled for TKA. A total of 45 patients were randomly assigned to either the LIA or the continuous FNB group. Except for the analgesic modality, perioperative managements were identical in both groups. The primary outcome was postoperative pain score at rest 1 day after surgery, measured using a 100-mm visual analog scale. RESULTS: Patients in the LIA group had a significantly lower visual analog scale score at rest 1 day after surgery than those in the continuous FNB group (34 +/- 10 vs 42 +/- 13 mm; P = .028). The opioid consumption during the initial 24 hours was significantly lower in the LIA group (12 +/- 4 vs 16 +/- 7 mg; P = .031). There were no differences in the rate of complications between the groups. CONCLUSION: LIA was associated with better pain relief with a comparable complications rate for patients undergoing TKA than FNB. We recommend LIA for pain relief after TKA. PMID- 26639987 TI - Aggregation of Ribosomal Protein S6 at Nucleolus Is Cell Cycle-Controlled and Its Function in Pre-rRNA Processing Is Phosphorylation Dependent. AB - Ribosomal protein S6 (rpS6) has long been regarded as one of the primary r proteins that functions in the early stage of 40S subunit assembly, but its actual role is still obscure. The correct forming of 18S rRNA is a key step in the nuclear synthesis of 40S subunit. In this study, we demonstrate that rpS6 participates in the processing of 30S pre-rRNA to 18S rRNA only when its C terminal five serines are phosphorylated, however, the process of entering the nucleus and then targeting the nucleolus does not dependent its phosphorylation. Remarkably, we also find that the aggregation of rpS6 at the nucleolus correlates to the phasing of cell cycle, beginning to concentrate in the nucleolus at later S phase and disaggregate at M phase. J. Cell. Biochem. 117: 1649-1657, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26639988 TI - Hypertension: Oxidative stress and immune activation in hypertension. PMID- 26639989 TI - Antiplatelet therapy: Net benefit of ticagrelor in patients with chronic kidney disease. PMID- 26639990 TI - The complete mitochondrial genome of the golden mussel Limnoperna fortunei and comparative mitogenomics of Mytilidae. AB - Here we describe the mitochondrial genome of the golden mussel Limnoperna fortunei, an Asian bivalve which has become one of the most aggressive invasive species in Japan and South America. The mitochondrial genome of L. fortunei does not present conserved gene arrangement when compared to the other Mytilidae species suggesting a high degree of gene recombination in the mitochondria of this clade. In addition, the golden mussel mitogenome encodes two copies of tRNA(Lys) and presents a putative pseudogene for the atp8 gene sequence that encodes a 27 amino acid peptide containing an in-frame stop codon. The presence of this pseudogene raises the question as to whether atp8 is encoded in some bivalve mitochondrial genomes or not. The phylogenetic analysis of all complete mitochondrial genomes available from Mytilidae mussels confirmed the close evolutionary relationships among bivalves from the genus Mytilys and placed L. fortunei coming from a more ancestral branch on the family. The supermatrix phylogeny described used the concatenation of all 12 genes from the mitochondria and disputed the monophyly of the genus Perna, as Perna perna was shown to be more closely related to Brachidontes exustus than to Perna viridis. The comparative analysis of mitogenome synteny also confirmed the polyphyly of the genus Perna. The complete and annotated mitogenome has been published in GenBank under the accession number KP756905. PMID- 26639991 TI - A colostrum trypsin inhibitor gene expressed in the Cape fur seal mammary gland during lactation. AB - The colostrum trypsin inhibitor (CTI) gene and transcript were cloned from the Cape fur seal mammary gland and CTI identified by in silico analysis of the Pacific walrus and polar bear genomes (Order Carnivora), and in marine and terrestrial mammals of the Orders Cetartiodactyla (yak, whales, camel) and Perissodactyla (white rhinoceros). Unexpectedly, Weddell seal CTI was predicted to be a pseudogene. Cape fur seal CTI was expressed in the mammary gland of a pregnant multiparous seal, but not in a seal in its first pregnancy. While bovine CTI is expressed for 24-48 h postpartum (pp) and secreted in colostrum only, Cape fur seal CTI was detected for at least 2-3 months pp while the mother was suckling its young on-shore. Furthermore, CTI was expressed in the mammary gland of only one of the lactating seals that was foraging at-sea. The expression of beta-casein (CSN2) and beta-lactoglobulin II (LGB2), but not CTI in the second lactating seal foraging at-sea suggested that CTI may be intermittently expressed during lactation. Cape fur seal and walrus CTI encode putative small, secreted, N glycosylated proteins with a single Kunitz/bovine pancreatic trypsin inhibitor (BPTI) domain indicative of serine protease inhibition. Mature Cape fur seal CTI shares 92% sequence identity with Pacific walrus CTI, but only 35% identity with BPTI. Structural homology modelling of Cape fur seal CTI and Pacific walrus trypsin based on the model of the second Kunitz domain of human tissue factor pathway inhibitor (TFPI) and porcine trypsin (Protein Data Bank: 1TFX) confirmed that CTI inhibits trypsin in a canonical fashion. Therefore, pinniped CTI may be critical for preventing the proteolytic degradation of immunoglobulins that are passively transferred from mother to young via colostrum and milk. PMID- 26639993 TI - Endoplasmic reticulum stress in the brain subfornical organ contributes to sex differences in angiotensin-dependent hypertension in rats. AB - AIM: Endoplasmic reticulum (ER) stress in the brain subfornical organ (SFO), a key cardiovascular regulatory centre, has been implicated in angiotensin (ANG) II induced hypertension in males; however, the contribution of ER stress to ANG II induced hypertension in females is unknown. Female hormones have been shown to prevent ER stress in the periphery. We tested the hypothesis that females are less susceptible to ANG II-induced SFO ER stress than males, leading to sex differences in hypertension. METHODS: Male, intact and ovariectomized (OVX) female rats received a continuous 2-week subcutaneous infusion of ANG II or saline. Additional male, intact and OVX female rats received intracerebroventricular (ICV) injection of ER stress inducer tunicamycin. RESULTS: ANG II, but not saline, increased blood pressure (BP) in both males and females, but intact females exhibited smaller increase in BP and less depressor response to ganglionic blockade compared with males or OVX females. Molecular studies revealed that ANG II elevated expression of ER stress biomarkers and Fra like activity in the SFO in both males and females; however, elevations in these parameters were less in intact females than in males or OVX females. Moreover, ICV tunicamycin induced smaller elevation in BP and less increase in expression of ER stress biomarkers in the SFO in intact females compared with males or OVX females. CONCLUSION: The results suggest that differences in ANG II-induced brain ER stress between males and females contribute to sex differences in ANG II mediated hypertension and that oestrogen protects females against ANG II-induced brain ER stress. PMID- 26639994 TI - Uterine Development After Estrogen Replacement Therapy in Women with Different Etiologies of Primary Hypogonadism. AB - STUDY OBJECTIVE: To evaluate uterine development with estrogen replacement therapy in patients with primary amenorrhea due to hypogonadism. DESIGN AND SETTING: Retrospective study. PARTICIPANTS: Thirty-five women. INTERVENTIONS AND MAIN OUTCOME MEASURES: Women who were younger than 20 years of age and who had primary amenorrhea and an immaturely shaped uterus were included. Changes in uterine cross-sectional area (UXA) and uterine maturity in pelvic ultrasound after 2 year of estrogen replacement therapy were assessed on the basis of the etiology of primary hypogonadism. RESULTS: Patients were classified into three groups according to the etiology of primary hypogonadism: Turner syndrome (n = 19), hypogonadotropic hypogonadism after brain surgery (n = 10), and premature ovarian insufficiency after cancer treatment (n = 6). Overall, the mean UXA significantly increased (from 3.1 +/- 1.8 to 11.6 +/- 4.9 cm(2)) after estrogen replacement therapy (P < .001), but the final UXA was significantly smaller in patients with premature ovarian insufficiency compared with other etiologies. In logistic regression analysis, etiology and the cumulative dose of estrogen were associated with uterine maturation (P = .011 and .004, respectively). CONCLUSION: Estrogen replacement therapy induced growth of the uterus in patients with primary hypogonadism. However, the response to estrogen replacement therapy varied on the basis of the total cumulative dose of estrogen and etiology of primary hypogonadism. PMID- 26639992 TI - Antibiotic monensin synergizes with EGFR inhibitors and oxaliplatin to suppress the proliferation of human ovarian cancer cells. AB - Ovarian cancer is the most lethal gynecologic malignancy with an overall cure rate of merely 30%. Most patients experience recurrence within 12-24 months of cure and die of progressively chemotherapy-resistant disease. Thus, more effective anti-ovarian cancer therapies are needed. Here, we investigate the possibility of repurposing antibiotic monensin as an anti-ovarian cancer agent. We demonstrate that monensin effectively inhibits cell proliferation, migration and cell cycle progression, and induces apoptosis of human ovarian cancer cells. Monensin suppresses multiple cancer-related pathways including Elk1/SRF, AP1, NFkappaB and STAT, and reduces EGFR expression in ovarian cancer cells. Monensin acts synergistically with EGFR inhibitors and oxaliplatin to inhibit cell proliferation and induce apoptosis of ovarian cancer cells. Xenograft studies confirm that monensin effectively inhibits tumor growth by suppressing cell proliferation through targeting EGFR signaling. Our results suggest monensin may be repurposed as an anti-ovarian cancer agent although further preclinical and clinical studies are needed. PMID- 26639995 TI - "It's Part of Me, Not All of Me": Young Women's Experiences of Receiving a Diagnosis Related to Diverse Sex Development. AB - STUDY OBJECTIVE: To understand young women's experiences of receiving a diagnosis related to diverse sex development. DESIGN: A qualitative narrative analysis of interviews. SETTING: Karolinska University Hospital. PARTICIPANTS: Nine women (aged 20-26 years) with complete androgen insensitivity syndrome, XY or XX gonadal dysgenesis. INTERVENTIONS: Semistructured interviews. MAIN OUTCOME MEASURES: A narrative approach was used to analyze the interviews. This involved identification of individual narratives of receiving the diagnosis, as well as identification of key issues that were common across interviews. RESULTS: The analysis showed how participants' prediagnosis life experiences framed how medical information was perceived upon diagnosis. All participants had been informed about their condition before the study, but not all remembered the name of their diagnosis. Participants described positive characteristics of health professionals, such as being flexible and able to adapt to patients' individual needs. Clinicians' strategies, such as normalizing patients' experiences, were usually perceived as supportive, but were not always considered helpful. After the diagnosis, participants were worried about potential social, practical, and philosophical issues. CONCLUSION: This research highlighted the importance of clinicians taking an exploratory and individualized approach to the sensitive process of disclosing a diagnosis related to diverse sex development to young adults. There are various strategies health professionals can use that might help young people to develop their knowledge about their condition: (1) repeating information to help the patient remember; (2) using language that is not too medicalized; and (3) communicating in a way that is meaningfully connected to patients' everyday lives. PMID- 26639996 TI - Chromosome Xq13.2 Microduplication Involving an X-Inactivation Gene in a Girl with Short Stature, Madelung Deformity, and von Willebrand Disease. AB - BACKGROUND: The objective of the study was to describe a novel Xp13.2 chromosome microduplication in a child with some features of Turner syndrome but with menorrhagia after normal menarche. We used clinical evaluation and high resolution chromosome (microarray) analysis. CASE: A 15-year-old girl with typical (short stature, pulmonic stenosis, widely-spaced nipples) and atypical (Madelung deformity, menorrhagia) manifestations of Turner syndrome had a novel chromosome constitution with extra material (microduplication) at band Xq13.2 that contained the X-inactive-specific-transcript locus. She also had connective tissue laxity, suggestive of vessel fragility as a contributor to her menorrhagia as well as her diagnosis of von Willebrand disease. This first case of selective X-inactive-specific-transcript locus duplication suggests a role for gene repression in Turner syndrome and other disorders that affect ovarian function. CONCLUSION: High-resolution chromosome (microarray) analysis, now a standard of care, will provide new insights into adolescents with abnormal growth and reproductive tract symptoms, especially when accompanied by congenital anomalies. PMID- 26639997 TI - Internal Fixation of Cervical Fractures in Three Horses. AB - OBJECTIVE: To describe the surgical treatment outcome of cervical fractures in 3 horses. STUDY DESIGN: Case report. ANIMALS: Three client-owned horses with cervical vertebral fractures. METHODS: Three horses were refered for neck stiffness, pain, and ataxia after a cervical trauma because of a fall. Radiographic examination showed an oblique displaced fracture of the caudal aspect of the body of the second cervical vertebra (C2) in horse 1, an oblique displaced fracture of the caudal aspect of C4 involving the disc between C4 and C5 in horse 2, and a displaced transverse fracture of the body of the axis (C2) extending to the lateral arches and involving the vertebral canal in horse 3. In horse 1, the fracture was reduced and stabilized using a 14-hole narrow DCP plate, applied ventrally, and fixed with cancellous screws. A cervical fusion was performed. In horses 2 and 3, fracture fixation was performed using a 5-hole narrow LCP and 5 mm locking screws. RESULTS: All horses showed improvement and returned to full activity. The fracture healed in all horses. CONCLUSION: Internal fixation of cervical fracture in these horses was associated with minimal complications, and was associated with healing and a highly functional outcome in all horses. The LCP was preferred and would be recommended for ventral stabilization of selected cases of vertebral fractures. PMID- 26639998 TI - Dielectric behaviors of Aurivillius Bi5Ti3Fe0.5Cr0.5O15 multiferroic polycrystals: Determining the intrinsic magnetoelectric responses by impedance spectroscopy. AB - Bismuth layer ferroelectrics (BLFs) pioneered by Aurivillius about sixty years ago have been revived recently because of the fatigue- and lead-free behaviors and high Curie temperature, and especially the robust magnetoelectric (ME) effect. However, discerning the intrinsic ME nature, and the inherence between charged defect dipole induced relaxation and spin-related behaviors are still an arduous task. Here, we report a quantitative analysis to reveal the intrinsic spin-lattice coupling in Aurivillius Cr-doped Bi(5)Ti(3)FeO(15) (BTFCO) multiferroic polycrystals. Dielectric responses are systemically investigated by the temperature-dependent dielectric, module, impedance spectroscopy and equivalent circuit model, and two different dielectric relaxation processes occurred in grain interior of Aurivillius BTFCO polycrystals are clarified. One relaxation is proposed to associate with localized transfer of electrons between Fe(3+) and Fe(2+) while another one arises from the competition interaction of localized hopping of electrons between Fe(3+) and Fe(2+) and short-range migration of holes between Cr(3+) and Cr(6+). The variation of the intrinsic permittivity unambiguously confirms the coupling between spin and dipolar orderings in BTFCO polycrystals. These results offer a vital avenue for identifying the intrinsic and extrinsic signals of the electric and ME responses, and will give significant impetus to exploring the ME electronic devices of Aurivillius materials. PMID- 26639999 TI - Coupled circuit based representation of piezoelectric structures modeled using the finite volume method. AB - This paper presents the methodology of generating a corresponding electrical circuit for a simple piezoelectric plate modeled with the finite volume method. The corresponding circuit is implemented using a circuit simulation software and the simulation results are compared to the finite volume modeling results for validation. It is noticed that both, the finite volume model and its corresponding circuit, generate identical results. The results of a corresponding circuit based on the finite volume model are also compared to the results of a corresponding circuit based on a simplified analytical model for a long piezoelectric plate, and to finite element simulation results for the same plate. It is observed that, for one control volume, the finite volume model corresponding circuit and the simplified analytical model corresponding circuit generate close results. It is also noticed that the results of the two corresponding circuits are different from the best approximation results obtained with high resolution finite element simulations due to the approximations made in the simplified analytical model and the fact that only one finite volume was used in the finite volume model. The implementation of the circuit can be automated for higher order systems by a program that takes as an input the matrix of the system and the forcing function vector, and returns a net list for the circuit. PMID- 26640001 TI - Science transfer: oral health and general health - the links between periodontitis, atherosclerosis and diabetes. PMID- 26640000 TI - Exploitation of a "hockey-puck" phenotype to identify pilus and biofilm regulators in Serratia marcescens through genetic analysis. AB - Pili are essential adhesive determinants for many bacterial pathogens. A suppressor mutation screen that takes advantage of a pilus-mediated self aggregative "hockey-puck" colony phenotype was designed to identify novel regulators of type I pili in Serratia marcescens. Mutations that decreased pilus biosynthesis mapped to the fimABCD operon; to the genes alaT, fkpA, and oxyR; upstream of the flagellar master regulator operon flhDC; and to an uncharacterized gene encoding a predicted DUF1401 domain. Biofilm formation and pilus-dependent agglutination assays were used to characterize the relative importance of the identified genes in pilus biosynthesis. Additional mutagenic or complementation analysis was used to verify the role of candidate genes in pilus biosynthesis. Presented data support a model that CRP negatively regulates pilus biosynthesis through increased expression of flhDC and decreased expression of oxyR. Further studies are warranted to determine the mechanism by which these genes mediate pilus biosynthesis or function. PMID- 26640008 TI - Bioactive Nitrogenous Compounds from Acorus tatarinowii. PMID- 26640031 TI - Cognitive Therapy for Social Anxiety Disorder in Adolescents: A Development Case Series. AB - BACKGROUND: Social anxiety disorder is common and typically starts in childhood or adolescence. Cognitive Therapy for Social Anxiety Disorder (CT-SAD) in adults is a well-established treatment that shows strong evidence of differential effectiveness when compared to other active treatments. In contrast, CBT approaches to social anxiety in young people have yet to demonstrate differential effectiveness and there is some evidence that young people with social anxiety disorder respond less well than those with other anxiety disorders. AIMS: To adapt CT-SAD for use with adolescents and conduct a pilot case series. METHOD: Five adolescents, aged 11-17 years, with a primary DSM-5 diagnosis of social anxiety disorder received a course of CT-SAD adapted for adolescents. Standardized clinical interview and questionnaire assessments were conducted at pre and posttreatment, and 2 to 3-month follow-up. RESULTS: All five participants reported severe social anxiety at baseline and achieved remission by the end of treatment. Significant improvements were also observed in general anxiety, depression, concentration in the classroom, and putative process measures (social anxiety related thoughts, beliefs and safety behaviours). CONCLUSIONS: An adapted form of CT-SAD shows promise as a treatment for adolescents. PMID- 26640009 TI - Biopsychosocial Correlates of Binge Eating Disorder in Caucasian and African American Women with Obesity in Primary Care Settings. AB - This study examined racial differences in eating-disorder psychopathology, eating/weight-related histories, and biopsychosocial correlates in women (n = 53 Caucasian and n = 56 African American) with comorbid binge eating disorder (BED) and obesity seeking treatment in primary care settings. Caucasians reported significantly earlier onset of binge eating, dieting, and overweight, and greater number of times dieting than African American. The rate of metabolic syndrome did not differ by race. Caucasians had significantly elevated triglycerides whereas African Americans showed poorer glycaemic control (higher glycated haemoglobin A1c [HbA1c]), and significantly higher diastolic blood pressure. There were no significant racial differences in features of eating disorders, depressive symptoms, or mental and physical health functioning. The clinical presentation of eating-disorder psychopathology and associated psychosocial functioning differed little by race among obese women with BED seeking treatment in primary care settings. Clinicians should assess for and institute appropriate interventions for comorbid BED and obesity in both African American and Caucasian patients. PMID- 26640032 TI - Dispersion and Functionalization of Nanoparticles Synthesized by Gas Aggregation Source: Opening New Routes Toward the Fabrication of Nanoparticles for Biomedicine. AB - The need to find new nanoparticles for biomedical applications is pushing the limits of the fabrication methods. New techniques with versatilities beyond the extended chemical routes can provide new insight in the field. In particular, gas aggregation sources offer the possibility to fabricate nanoparticles with controlled size, composition, and structure out of thermodynamics. In this context, the milestone is the optimization of the dispersion and functionalization processes of nanoparticles once fabricated by these routes as they are generated in the gas phase and deposited on substrates in vacuum or ultra-high vacuum conditions. In the present work we propose a fabrication route in ultra-high vacuum that is compatible with the subsequent dispersion and functionalization of nanoparticles in aqueous media and, which is more remarkable, in one single step. In particular, we will present the fabrication of nanoparticles with a sputter gas aggregation source using a Fe50B50 target and their further dispersion and functionalization with polyethyleneglycol (PEG). Characterization of these nanoparticles is carried out before and after PEG functionalization. During functionalization, significant boron dissolution occurs, which facilitates nanoparticle dispersion in the aqueous solution. The use of different complementary techniques allows us to prove the PEG attachment onto the surface of the nanoparticles, creating a shell to make them biocompatible. The result is the formation of nanoparticles with a structure mainly composed by a metallic Fe core and an iron oxide shell, surrounded by a second PEG shell dispersed in aqueous solution. Relaxivity measurements of these PEG-functionalized nanoparticles assessed their effectiveness as contrast agents for magnetic resonance imaging (MRI) analysis. Therefore, this new fabrication route is a reliable alternative for the synthesis of nanoparticles for biomedicine. PMID- 26640033 TI - The diversity and expansion of the trans-sialidase gene family is a common feature in Trypanosoma cruzi clade members. AB - Trans-sialidase (TS) is a polymorphic protein superfamily described in members of the protozoan genus Trypanosoma. Of the eight TS groups recently described, TS group I proteins (some of which have catalytic activity) are present in the distantly related Trypanosoma brucei and Trypanosoma cruzi phylogenetic clades, whereas other TS groups have only been described in some species belonging to the T. cruzi clade. In the present study we analyzed the repertoire, distribution and phylogenetic relationships of TS genes among species of the T. cruzi clade based on sequence similarity, multiple sequence alignment and tree-reconstruction approaches using TS sequences obtained with the aid of PCR-based strategies or retrieved from genome databases. We included the following representative isolates of the T. cruzi clade from South America: T. cruzi, T. cruzi Tcbat, Trypanosoma cruzi marinkellei, Trypanosoma dionisii, Trypanosoma rangeli and Trypanosoma conorhini. The cloned sequences encoded conserved TS protein motifs Asp-box and VTVxNVxLYNR but lacked the FRIP motif (conserved in TS group I). The T. conorhini sequences were the most divergent. The hybridization patterns of TS probes with chromosomal bands confirmed the abundance of these sequences in species in the T. cruzi clade. Divergence and relationship analysis placed most of the TS sequences in the groups defined in T. cruzi. Further examination of members of TS group II, which includes T. cruzi surface glycoproteins implicated in host cell attachment and invasion, showed that sequences of T. cruzi Tcbat grouped with those of T. cruzi genotype TcI. Our analysis indicates that different members of the T. cruzi clade, with different vertebrate hosts, vectors and pathogenicity, share the extensive expansion and sequence diversification of the TS gene family. Altogether, our results are congruent with the evolutionary history of the T. cruzi clade and represent a contribution to the understanding of the molecular evolution and role of TS proteins in trypanosomes. PMID- 26640034 TI - Site-Specific Polymer Conjugation Stabilizes Therapeutic Enzymes in the Gastrointestinal Tract. AB - The site-specific conjugation of polymers to multiple engineered cysteine residues of a prolyl endopeptidase leads to its stabilization in the gastrointestinal tract of rats, without compromising the activity relative to the native enzyme. The importance of polymer attachment sites is investigated, as well as the significance of polymer structure. PMID- 26640035 TI - A survey of overall life satisfaction and its association with breast diseases in Chinese women. AB - To investigate the association between overall life satisfaction and healthy lifestyle, knowledge of breast cancer, physical examination, and detection rate of breast cancer and benign breast disease in Chinese women. In a multicentered breast disease screening program in China, we enrolled 33,057 women aged 45-65 years without prior diagnosis of breast cancer. After completing an epidemiological questionnaire, all participants were examined by clinical breast examination, breast ultrasound, and mammography independently. All breast cancer cases and a selected sample of benign breast diseases were confirmed pathologically. Univariate and multivariate odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to estimate the association between life satisfaction and lifestyle, knowledge of breast cancer, physical examination, and detection rate of breast diseases. Overall life satisfaction was positively associated with women's healthy lifestyle. Compared with less satisfied women, satisfied women were less likely to be smokers (OR = 0.54; 95% CI: 0.47-0.62), have more exercise (OR = 1.49; 95% CI: 1.26-1.75), eat less fried (OR = 0.60; 95% CI: 0.50-0.71), smoked (OR = 0.54, 95% CI: 0.47-0.63), pickled (OR = 0.66, 95% CI: 0.55-0.79), and grilled (OR = 0.63, 95% CI: 0.54-0.74) foods. Satisfied women were more likely to have knowledge of breast cancer (OR = 1.48, 95% CI: 1.29 1.70), and have regular physical examinations (OR = 1.11, 95% CI: 1.01-1.12). Compared to less satisfied women, we found significantly lower detection rate of benign breast diseases (OR = 0.90, 95% CI: 0.82-0.99), and lower but nonsignificant detection rate of breast cancer (OR = 0.66, 95% CI: 0.35-1.25) in satisfied women. Women with a higher overall life satisfaction are more likely to have healthy lifestyle, knowledge of breast cancer, and regular physical examination, thus resulting in a lower detection rate of breast diseases in screening. PMID- 26640036 TI - S-1 plus leucovorin versus S-1 plus leucovorin and oxaliplatin versus S-1 plus cisplatin in patients with advanced gastric cancer: a randomised, multicentre, open-label, phase 2 trial. AB - BACKGROUND: Although leucovorin enhances the efficacy of fluorouracil, the anti tumour activity of S-1 and leucovorin and their combination with oxaliplatin for patients with advanced gastric cancer is unknown. We compared the activity and safety of S-1 plus leucovorin, S-1 plus leucovorin and oxaliplatin, and S-1 plus cisplatin as first-line chemotherapy for advanced gastric cancer. METHODS: In this multicentre, randomised, open-label, phase 2 trial, we recruited chemotherapy-naive patients with unresectable or recurrent gastric cancer with measurable lesions aged 20 years or older from 25 general hospitals and specialist centres in Japan. Patients were randomly assigned (1:1:1) centrally to receive S-1 plus leucovorin (S-1 40-60 mg orally plus oral leucovorin 25 mg twice a day for 1 week, every 2 weeks), S-1 plus leucovorin and oxaliplatin (S-1 plus leucovorin and intravenous oxaliplatin 85 mg/m(2) on day 1, every 2 weeks), or S 1 plus cisplatin (S-1 40-60 mg orally twice a day for 3 weeks, plus intravenous cisplatin 60 mg/m(2) on day 8, every 5 weeks). Randomisation was done with the minimisation method using performance status (0 vs 1) and tumour stage (stage IV vs recurrent) as stratification factors. The primary endpoint was independently reviewed overall response in the full analysis set. This trial is registered with Japic CTI, number 111635. FINDINGS: Between Oct 20, 2011, and Dec 17, 2012, we enrolled and randomly assigned 145 patients: 49 patients were assigned to S-1 plus leucovorin, 47 to S-1 plus leucovorin and oxaliplatin, and 49 to S-1 plus cisplatin. An objective response assessed by the independent review committee was achieved in 20 (43% [95% CI 28.3-57.8]) of the 47 patients in the S-1 plus leucovorin group, 31 (66% [50.7-79.1]) of the 47 patients in the S-1 plus leucovorin and oxaliplatin group, and 22 (46% [31.4-60.8]) of the 48 patients in the S-1 plus cisplatin group (Fisher's exact test, p=0.84 for S-1 plus leucovorin vs S-1 plus cisplatin, p=0.063 for S-1 plus leucovorin and oxaliplatin vs S-1 plus cisplatin, and p=0.038 for S-1 plus leucovorin and oxaliplatin vs S-1 plus leucovorin). The most common grade 3-4 adverse events were neutropenia (three [6%] of 48 patients in the S-1 plus leucovorin group vs 12 [26%] of 47 patients in the S-1 plus leucovorin and oxaliplatin group vs 17 [35%] of 49 patients in the S-1 plus cisplatin group), decreased appetite (six [13%] vs 14 [30%] vs 12 [24%]), anaemia (five [10%] vs seven [15%] vs 13 [27%]), and hyponatraemia (two [4%] vs two [4%] vs nine [18%]). INTERPRETATION: S-1 plus leucovorin and oxaliplatin was more active than S-1 plus leucovorin or S-1 plus cisplatin with acceptable toxic effects for patients with advanced gastric cancer. A phase 3 trial comparing S-1 plus leucovorin and oxaliplatin with S-1 plus cisplatin is underway. FUNDING: Taiho Pharmaceutical. PMID- 26640037 TI - A new standard of care for mantle cell lymphoma? PMID- 26640038 TI - S-1 with leucovorin for gastric cancer: how far can it go? PMID- 26640039 TI - Ibrutinib in combination with rituximab in relapsed or refractory mantle cell lymphoma: a single-centre, open-label, phase 2 trial. AB - BACKGROUND: Ibrutinib is approved in the EU, USA, and other countries for patients with mantle cell lymphoma who received one previous therapy. In a previous phase 2 study with single-agent ibrutinib, the proportion of patients who achieved an objective response was 68%; 38 (34%) of 111 patients had transient lymphocytosis. We hypothesised that adding rituximab could target mantle cell lymphoma cells associated with redistribution lymphocytosis, leading to more potent antitumour activity. METHODS: Patients with a confirmed mantle cell lymphoma diagnosis (based on CD20-positive and cyclin D1-positive cells in tissue biopsy specimens), no upper limit on the number of previous treatments received, and an Eastern Cooperative Oncology Group performance status score of 2 or less were enrolled in this single-centre, open-label, phase 2 study. Patients received continuous oral ibrutinib (560 mg) daily until progressive disease or unacceptable toxic effects. Rituximab 375 mg/m(2) was given intravenously once per week for 4 weeks during cycle 1, then on day 1 of cycles 3-8, and thereafter once every other cycle up to 2 years. The primary endpoint was the proportion of patients who achieved an objective response in the intention-to-treat population and safety assessed in the as-treated population. The study is registered with ClinicalTrials.gov, number NCT01880567, and is still ongoing, but no longer accruing patients. FINDINGS: Between July 15, 2013, and June 30, 2014, 50 patients were enrolled. Median age was 67 years (range 45-86), and the median number of previous regimens was three (range 1-9). At a median follow-up of 16.5 months (IQR 12.09-19.28), 44 (88%, 95% CI 75.7-95.5) patients achieved an objective response, with 22 (44%, 30.0-58.7) patients achieving a complete response, and 22 (44%, 30.0-58.7) a partial response. The only grade 3 adverse event in >=10% of patients was atrial fibrillation, which was noted in six (12%) patients. Grade 4 diarrhoea and neutropenia occurred in one patient each. Adverse events led to discontinuation of therapy in five (10%) patients (atrial fibrillation in three [6%] patients, liver infection in one [2%], and bleeding in one [2%]). Two patients died while on-study from cardiac arrest and septic shock; the latter was deemed possibly related to treatment. INTERPRETATION: Ibrutinib combined with rituximab is active and well tolerated in patients with relapsed or refractory mantle cell lymphoma. Our results provide preliminary evidence for the activity of this combination in clinical practice. A phase 3 trial is warranted for more definitive data. FUNDING: Pharmacyclics LLC, an AbbVie Company. PMID- 26640041 TI - Graphical content of medicinal package inserts: an exploratory study to evaluate potential legibility issues. AB - BACKGROUND: The graphical content of the Medicines Package Inserts (MPIs), such as illustrations and typographic features should be legible and appropriate, as required by international pharmaceutical regulations. OBJECTIVES: To study: (1) the frequency and type of MPIs' key graphic elements, (2) their compliance with regulations and (3) how educated people understand them. METHODS: Descriptive study: characterisation of the graphical content of 651 MPIs. Usability study: illustrations and tables (purposively selected) were evaluated with questionnaires in three groups of humanities undergraduates (illustrations only, illustrations plus text and text only). RESULTS: Descriptive study: illustrations and tables were respectively identified in 6.3% and 11.8% of the MPIs. The illustrations were mainly related to how to take/use the medicine. Non recommended graphical representations were found (e.g. italic or underline). Usability test: legibility issues were identified, especially for the group of isolated illustrations. DISCUSSION & CONCLUSIONS: The scarce use of illustrations and tables possibly affected the legibility of the MPIs. Compulsory legibility tests are needed to guarantee the MPIs' proper use, thus contributing to a safe use of medicines. Overall, this study highlighted the need to carefully revise/assess the MPIs' design and probably increase health information experts' awareness on this issue. PMID- 26640040 TI - Elevated levels of TRF2 induce telomeric ultrafine anaphase bridges and rapid telomere deletions. AB - The shelterin protein TRF2 is essential for chromosome-end protection. Depletion of TRF2 causes chromosome end-to-end fusions, initiating genomic instability that can be cancer promoting. Paradoxically, significant increased levels of TRF2 are observed in a subset of human cancers. Experimental overexpression of TRF2 has also been shown to induce telomere shortening, through an unknown mechanism. Here we report that TRF2 overexpression results in replication stalling in duplex telomeric repeat tracts and the subsequent formation of telomeric ultrafine anaphase bridges (UFBs), ultimately leading to stochastic loss of telomeric sequences. These TRF2 overexpression-induced telomere deletions generate chromosome fusions resembling those detected in human cancers and in mammalian cells containing critically shortened telomeres. Therefore, our findings have uncovered a second pathway by which altered TRF2 protein levels can induce end-to end fusions. The observations also provide mechanistic insight into the molecular basis of genomic instability in tumour cells containing significantly increased TRF2 levels. PMID- 26640042 TI - High-density lipoprotein contribute to G0-G1/S transition in Swiss NIH/3T3 fibroblasts. AB - High density lipoproteins (HDLs) play a crucial role in removing excess cholesterol from peripheral tissues. Although their concentration is lower during conditions of high cell growth rate (cancer and infections), their involvement during cell proliferation is not known. To this aim, we investigated the replicative cycles in synchronised Swiss 3T3 fibroblasts in different experimental conditions: i) contact-inhibited fibroblasts re-entering cell cycle after dilution; ii) scratch-wound assay; iii) serum-deprived cells induced to re enter G1 by FCS, HDL or PDGF. Analyses were performed during each cell cycle up to quiescence. Cholesterol synthesis increased remarkably during the replicative cycles, decreasing only after cells reached confluence. In contrast, cholesteryl ester (CE) synthesis and content were high at 24 h after dilution and then decreased steeply in the successive cycles. Flow cytometry analysis of DiO-HDL, as well as radiolabeled HDL pulse, demonstrated a significant uptake of CE-HDL in 24 h. DiI-HDL uptake, lipid droplets (LDs) and SR-BI immunostaining and expression followed the same trend. Addition of HDL or PDGF partially restore the proliferation rate and significantly increase SR-BI and pAKT expression in serum deprived cells. In conclusion, cell transition from G0 to G1/S requires CE-HDL uptake, leading to CE-HDL/SR-BI pathway activation and CEs increase into LDs. PMID- 26640045 TI - Knee loading asymmetries during gait and running in early rehabilitation following anterior cruciate ligament reconstruction: A longitudinal study. AB - BACKGROUND: Normalization of gait is expected 8-12 weeks after anterior cruciate ligament reconstruction and is a criterion for progression to running. Long-term persistence of sagittal knee loading deficits suggests that early goals are not met. Magnitude and progression of deficits in gait during this time and their relationship to deficits in running are not known. METHODS: 12 individuals status post reconstruction (5 males) underwent 3-dimensional motion analysis of gait after surgery: one (T1) and three (T2) months and at initiation of running (T3); and running T3. Repeated measures ANOVAs (limb * time) assessed differences in knee flexion, extensor moment impulse and negative work in gait; paired t-tests compared limbs during running; and Pearson's correlations determined associations between limb ratios (moment and work) in gait and running. FINDINGS: Less flexion (-4.4 (0.63) degrees; mean (SE)), 35% smaller extensor moment (-0.15 (0.006) Nm*s/kg) and 47% less work (-0.03 (0.008) J/kg) were observed in the surgical knee during gait across time. Moment and work were 1.7 (-0.1 (0.03) Nm*s/kg) and 1.6 times greater (-0.23 (0.047) J/kg) in non-surgical knee during running. Moment and work limb asymmetries correlated across time during gait (r=0.778 0.929, P<0.001) and to asymmetries during running. INTERPRETATION: Limb asymmetries in knee loading present one month after reconstruction persist 4 months post-reconstruction. Correlations between limb asymmetries during gait across time and to running suggest that early gait behaviors relate to longer term loading. Greater attention should be placed on early gait training. PMID- 26640046 TI - Protective role of E. coli outer membrane vesicles against antibiotics. AB - The outer membrane vesicles (OMVs) from bacteria are known to posses both defensive and protective functions and thus participate in community related functions. In the present study, outer membrane vesicles have been shown to protect the producer bacterium and two other bacterial species from the growth inhibitory effects of some antibiotics. The OMVs isolated from E. coli MG1655 protected the bacteria against membrane-active antibiotics colistin, melittin. The OMVs of E. coli MG1655 could also protect P. aeruginosa NCTC6751 and A. radiodioresistens MMC5 against these membrane-active antibiotics. However, OMVs could not protect any of these bacteria against the other antibiotics ciprofloxacin, streptomycin and trimethoprim. Hence, OMVs appears to protect the bacterial community against membrane-active antibiotics and not other antibiotics, which have different mechanism of actions. The OMVs of E. coli MG1655 sequester the antibiotic colistin, whereas their protein components degrade the antimicrobial peptide melittin. Proteomic analysis of OMVs revealed the presence of proteases and peptidases which appear to be involved in this process. Thus, the protection of bacteria by OMVs against antibiotics is situation dependent and the mechanism differs for different situations. These studies suggest that OMVs of bacteria form a common defense for the bacterial community against specific antibiotics. PMID- 26640047 TI - Characterization and upregulation of bifunctional phosphoglucomutase/phosphomannomutase enzyme in an exobiopolymer overproducing strain of Acinetobacter haemolyticus. AB - Several members of the Acinetobacter spp. produce exobiopolymer (EBP) of considerable biotechnological interest. In a previous study, we reported phosphate removal capacity of EBP produced by Acinetobacter haemolyticus. Insertional mutagenesis was attempted to develop EBP-overproducing strains of A. haemolyticus and mutant MG606 was isolated. In order to understand the underlying mechanism of overproduction, the EBP overproducing mutant MG606 was analyzed and compared with the wild type counterpart for its key EBP synthetic enzymes. The EBP produced by MG606 mutant was 650 mg/L compared to 220 mg/L in its wild type counterpart. Significantly high (p<0.05) levels of phosphoglucomutase/phosphomannomutase (PGM/PMM) in MG606 mutant was noted, whereas activities of other enzymes responsible for EBP synthesis showed no significant change (p>0.05). The up-regulation of PGM/PMM expression in mutant was further confirmed by real time reverse transcriptase (RT)-PCR of PGM/PMM transcripts. The optimal conditions for PGM/PMM activity were found to be 35 degrees C and pH 7.5; PGM/PMM activity was inhibited by ions such as lithium, zinc, nickel. Further, incubation of cells with a PGM inhibitor (lithium) resulted in a concentration-dependent decrease in EBP production further confirming the role of PGM/PMM overexpression in enhanced EBP production by the mutant. Overall the results of our study indicate a key role of PGM/PMM in enhanced EBP production, as evident from enhanced enzyme activity, increased PGM/PMM transcripts and reduction in EBP synthesis by a PGM inhibitor. We envisage a potential exploitation of the insights so obtained to effectively engineer strains of Acinetobacter for overproducing phosphate binding EBP. PMID- 26640048 TI - Biosynthesis of paenibacillin, a lantibiotic with N-terminal acetylation, by Paenibacillus polymyxa. AB - Paenibacillin, a recently-discovered lantibiotic from Paenibacillus polymyxa OSY DF, showed potency against Listeria monocytogenes, methicillin-resistant Staphylococcus aureus and other Gram-positive bacteria. The chemical structure of paenibacillin has been determined previously. This study was initiated to investigate the biosynthesis of paenibacillin, and to reveal unique features in its biosynthetic pathway. Paenibacillin structural gene (paeA) was identified by polymerase chain reaction (PCR) analysis. The complete biosynthetic gene cluster was revealed by whole genome sequencing of the producer strain. The paenibacillin gene cluster (11.7 kb) comprises 11 open reading frames (ORFs) encoding proteins for production, modification, regulation, immunity and transportation of the lantibiotic. Disruption of the gene encoding lantibiotic dehydratase (PaeB) completely eliminated the production of paenibacillin. The cluster includes a gene encoding a putative acetylase (PaeN), which may catalyze the N-terminal acetylation of paenibacillin during its biosynthesis. This finding supports the results of a previous chemical analysis, reporting an acetyl moiety uniquely located at paenibacillin N-terminus. Results of this study may expedite efforts to design effective lantibiotic drugs and facilitate attempts to increase the productivity of the lantibiotic-producing strain. PMID- 26640049 TI - Paradox of plant growth promotion potential of rhizobacteria and their actual promotion effect on growth of barley (Hordeum vulgare L.) under salt stress. AB - From the rhizosphere of two salt tolerant plant species, Hordeum secalinum and Plantago winteri growing in a naturally salt meadow, 100 strains were isolation on enrichment media for various plant growth-promoting (PGP) functions (ACC deaminase activity, auxin synthesis, calcium phosphate mobilization and nitrogen fixation). Based on the taxonomic affiliation of the isolated bacteria and their enrichment medium 22 isolates were selected to test their growth promotion effect on the crop barley (Hordeum vulgare) under salt stress in pot experiment. In parallel the isolates were characterized in pure culture for their plant growth promoting activities. Surprisingly the best promotors did not display a promising set of PGP activities. Isolates with multiple PGP-activities in pure culture like Microbacterium natoriense strain E38 and Pseudomonas brassicacearum strain E8 did not promote plant growth. The most effective isolate was strain E108 identified as Curtobacterium flaccumfaciens, which increased barley growth up to 300%. In pure culture strain E108 showed only two out of six plant growth promoting activities and would have been neglected. Our results highlight that screening based on pure culture assays may not be suitable for recognition of best plant growth promotion candidates and could preclude the detection of both new PGPR and new plant promotion mechanisms. PMID- 26640050 TI - Illumina MiSeq investigations on the changes of microbial community in the Fusarium oxysporum f.sp. cubense infected soil during and after reductive soil disinfestation. AB - Although reductive soil disinfestation (RSD) is increasingly used for the control of soil-borne diseases, its impact on the soil microbial community during and after RSD remains poorly understood. MiSeq pyrosequencing, real-time PCR and denaturing gradient gel electrophoresis were performed to investigate the changes of microbial community in the Fusarium oxysporum f. sp. cubense (FOC) infected soil during RSD and at the simulative banana cultivation after RSD. The results showed that RSD significantly increased soil microbial populations and a different microbial community with the pathogenic soil was established after RSD. Specifically, the number of Firmicutes mainly containing Ruminococcus and Coprococcus followed by a small part of Clostridium which were the dominant bacterial genera significantly increased during RSD. In contrast, Symbiobacterium and Flavisolibacter were the dominant genera in the flooding soil. When the soils were recovered under aerobic condition, the relative abundances of the bacteria belonging to the phylum Bacteroidetes, Acidobacteria, Planctomycetes increased as alternatives to the reducing Firmicutes. For fungi, the population of F. oxysporum significantly decreased during RSD accompanied with the pH decline, which resulted in the significant decrease of relative abundance in the phylum Ascomycota. Alternatively, the relative abundances of some other fungal species increased, such as Chaetomium spp. and Penicillium spp. belonging to Ascomycota and the family Clavulinaceae belonging to Basidiomycota. Then, the relative abundance of Ascomycota re-increased after RSD with Podospora and Zopfiella as dominant genera, whereas the relative abundance of Fusarium further decreased. Overall, the microbial populations and community re-established by RSD made the soil more disease-suppressive and beneficial to the soil nutrient cycling and plant growth compared with the previous pathogenic soil. PMID- 26640051 TI - The roles of the virulence factor IpaB in Shigella spp. in the escape from immune cells and invasion of epithelial cells. AB - Shigellosis is an acute invasive enteric infection by the Gram negative pathogen Shigella, which causes human diarrhea. Shigella, which are highly epidemic and pathogenic, have become a serious public health problem. The virulence plasmid is a large plasmid essential to the infected host cells. Many virulence factors are encoded in the ipa-mxi-spa region by the virulence plasmid. IpaB is a multifunctional and essential virulence factor in the infection process. In this review article, we introduce the recent studies of the effect of IpaB in Shigella infected host cells. IpaB is involved in a type III secretion system (T3SS) structure. It also controls the secretion of virulence factors and Shigella adhesion to host cells. In addition, it forms the ion pore, destroys phagosomes, and induces the immune cell's apoptosis or necrosis. Moreover, IpaB can become a potential antigen for Shigella vaccine development. PMID- 26640052 TI - Acid tolerance response of Bordetella bronchiseptica in avirulent phase. AB - Bordetella bronchiseptica is a Gram-negative bacterium responsible for respiratory diseases in many mammalian hosts, including humans. This pathogen has been shown as able to persist inside the host cells, even in the phagosomes that are acidified to pH 4.5-5.0 after bacterial infection. Here we evaluated the resistance of B. bronchiseptica to survive under acidic conditions. In particular we analyzed the bacterial capacity to develop the mechanism known as acid tolerance response (ATR). Our studies were mainly focused on the avirulent phase of the bacteria since this phenotypic phase was reported to be more resistant to environmental stress conditions than the virulent phase. Results from B. bronchiseptica in virulent phase were also included for comparison purposes. In fact, for B. bronchiseptica 9.73 bacteria in virulent phase we observed that the viability of bacteria does not decrease significantly when grown at pH as low as 4.5, but it is affected when the pH of the medium was equal to or less than 4.0. After acid-adaptation at pH 5.5 for several hours, the survival rate of B. bronchiseptica 9.73 at lethal pH 4.0 for 6h was increased. Interestingly, the avirulent phase mediated by the two-component BvgAS system conferred further resistance to lethal acid challenge and a marked increase in the magnitude of the expressed ATR. The ATR for this avirulent phase seems to be associated with changes in LPS and surface protein profiles. 2D-gel electrophoresis revealed at least 25 polypeptides differentially expressed, 17 of which were only expressed or over-expressed under acid conditions. Using MALDI-TOF mass spectrometry, 10 of these differentially expressed polypeptides were identified. PMID- 26640053 TI - Activities of Aureobasidium pullulans cell filtrates against Monilinia laxa of peaches. AB - The Aureobasidium pullulans L1 and L8 strains are known as efficient biocontrol agents against several postharvest fungal pathogens. In order to better understand the mechanism of action underneath the antifungal activity of L1 and L8 strains, yeast cell filtrates grown at different times were evaluated in vivo against Monilinia laxa on peach. Lesion diameters on peach fruit were reduced by L1 and L8 culture filtrates of 42.5% and 67% respectively. The ability of these filtrates to inhibit M. laxa conidia germination and germ tube elongation was studied by in vitro assays. The results showed a 70% reduction of conidia germination for both strains while for germ tube elongation, it was 52% and 41% for L1 and L8 culture filtrates respectively. Finally, the activity of cell wall hydrolytic enzymes such as chitinase and glucanase in cell filtrates was analysed and the expression of genes encoding these activities was quantified during yeast growth. From 24h onward, both culture filtrates contained beta,1-3,glucanase and. chitinase activities, the most pronounced of which was N-beta acetylglucosaminidase. Gene expression level encoding for these enzymes in L1 and L8 varied according to the strain. These results indicate that L1 and L8 strains culture filtrates retain the yeast antagonistic activity and suggest that the production of hydrolytic enzymes plays an important role in this activity. PMID- 26640054 TI - Effects of inoculating Lachnum and Cadophora isolates on the growth of Vaccinium corymbosum. AB - The roots of ericaceous plants harbour a diversity of fungal taxa, which confer eco-physiological benefits to the host. Some of the fungi have been established to form ericoid mycorrhizal (ERM) associations and enhance plant growth in certain ericaceous genera. Although, Lachnum and Cadophora isolates have frequently been identified from the roots of this family, the status of their association and functional roles is still vague. The aims of this study were to identify Lachnum and Cadophora isolates; determine the root-fungal interactive structures formed in associations with Vaccinium corymbosum L. (blueberry) hosts and to examine inoculation effects of the fungal associates using several varieties of the blueberry. Lachnum and Cadophora were isolated and identified from Erica cerinthoides L. and Erica demmissa Klotzsch ex Benth using morphological and molecular techniques. Micropropagated blueberry varieties (Bluecrop, Elliott, Spartan, Chandler and Brightwell) were inoculated with respective fungi and plant growth evaluated. Both fungi colonised the roots and did not have any pathogenic effect. Lachnum isolate did not form any particular mycorrhizal structures whereas; Cadophora inoculated plants showed typical ericoid mycorrhizal coils. Inoculation with both fungi enhanced the shoot growth of Brightwell and Elliott varieties. However neutral effects were observed in the remaining varieties. In conclusion, Cadophora and Lachnum isolates have potential to promote growth of selected blueberry varieties. PMID- 26640055 TI - NLRC4 inflammasomes: 'their appearance and their work was a wheel in the middle of a wheel'. PMID- 26640056 TI - The family donation conversation: time to move to evidence-based practice. PMID- 26640058 TI - Nucleosome levels and toll-like receptor expression during high cut-off haemofiltration: a pilot assessment. AB - OBJECTIVES: To measure plasma nucleosome levels and expression of toll-like receptors (TLRs) in a pilot cohort of patients with severe acute kidney injury (AKI) within a randomised controlled trial of continuous venovenous haemofiltration with high cut-off filters (CVVH-HCO) v standard filters (CVVH std). METHODS: We measured plasma nucleosome levels using the Cell Death Detection ELISA PLUS (10X) assay kit. We analysed plasma levels for correlation with disease severity and compared the effects of CVVH-HCO and CVVH-std on plasma nucleosome levels over the first 72 hours. We studied cell surface TLR expression on CD14-positive monocytes in a subcohort of CVVH-HCO patients. RESULTS: We did not detect nucleosomes in normal human plasma, but found elevated nucleosome levels in patients with severe AKI. Nucleosome levels at randomisation correlated weakly with Acute Physiology and Chronic Health Evaluation III scores (Pearson rho=0.475, P=0.016). Treatment with CVVH-HCO or CVVH-std had no effect on nucleosome levels over 72 hours. The mean fluorescence intensity (MFI) ratios of TLR2 and TLR4 expression were elevated throughout the 72-hour period (range for TLR2, 0.97-3.98; range for TLR4, 0.91-10.18) and did not appear to decrease as a result of treatment with CVVH-HCO. CONCLUSIONS: Nucleosome concentration was elevated in the plasma of patients with severe AKI and mildly correlated with disease severity, but was not affected by treatment with CVVH-HCO or CVVH-std. Similarly, levels of TLR2 and TLR4 expression did not decrease over time during CVVHCrit HCO treatment. PMID- 26640057 TI - Towards a national model for organ donation requests in Australia: evaluation of a pilot model. AB - OBJECTIVE: To evaluate whether structural elements of a collaborative requesting model were observed in practice, and explore the impact of specialised communications training and elements of the model on consent rates. DESIGN: A national observational study captured staff observations of the organ donation requesting process. SETTING: DonateLife staff in 15 hospitals collected data from medical, nursing and allied health professionals who participated in the donation requesting process over a 12-month period. PARTICIPANTS: Data were collected from 201 family donation conversations (FDCs). MAIN OUTCOME MEASURES: Whether structural elements of the model were observed in practice, and rates of consent to donate. RESULTS: For most cases, there was a team planning meeting (87.0%); a gap in time between the meeting at which family understands brain death or the inevitability of death and the FDC for most cases (72.0%); and at least one trained requester present at the FDC (80.7%). Consent rates were significantly different according to who led the FDC: an untrained treating clinical specialist (45.2%); a trained treating clinical specialist (54.8%); or a trained requester who was not part of the treating clinical team (74.5%) (chi2=11.92, P=0.003). Logistic regression showed that the odds ratio (OR) for consent was significantly greater when the patient was on the Australian Organ Donor Register (OR, 9.3; CI, 3.5-24.5) and when the FDC was led by an FDC-trained requester who was not part of the treating clinical team (OR, 6.8; CI, 2.3-19.9). CONCLUSIONS: Structural elements of the model were observed in most cases, indicating that the model is feasible and acceptable. We showed that the highest consent rates were achieved when FDCs were led by professionals who had completed the specialised communications training and were not part of the treating clinical team for that patient. PMID- 26640059 TI - Characteristics and outcomes of patients reviewed by intensive care unit liaison nurses in Australia: a prospective multicentre study. AB - BACKGROUND: Intensive care unit liaison nurse (ICU LN) services are one strategy to manage deteriorating hospital patients. Studies on the characteristics and outcomes of patients reviewed by ICU LNs have been from single centres and surveys. OBJECTIVES AND METHODS: To conduct a 20-hospital, prospective observational study on the characteristics and outcomes of patients reviewed by Australian ICU LNs over 2 months. PARTICIPANTS AND OUTCOME MEASURES: All patients screened by ICU LNs over the study period were included. Details included the source of initial review, patient demographics and initial physiological parameters, case load, interventions and patient outcome. RESULTS: Only two hospitals provided a 24-hour, 7-day service, and in 14 hospitals, an ICU LN participated in the rapid response team (RRT). There were 3799 patients screened (54.6% men, mean age 62.9 years [SD, 19.4 years]), of whom 1330 (35%) had no interventions (were screened only). The remaining 2469 patients received interventions; 978 (39.6%) were reviewed once, and 1491 (60.4%) were reviewed multiple times. The three commonest reasons for screening patients were after ICU discharge (1734 [45.6%]), as part of the RRT review (914 [24.1%]), or for a ward patient review meeting with a "worried" criterion (412 [10.8%]). Patients who did not receive interventions were younger, more likely to be surgical patients, less likely to have dementia, less likely to be seen during an RRT review, had more favourable vital signs and were less likely to be discharged to a nursing home or die in hospital. The commonest interventions included ordering a diagnostic test, administration of medication, initiating an interprofessional referral and increasing limitations of therapy. The inhospital mortality was 10.2% overall, and 4.6% in patients who were screened but did not receive any interventions. Several predictors of inhospital mortality were identified. CONCLUSIONS: Most ICU LN reviews occur after ICU discharge or in association with an RRT review. The inhospital mortality of ICU LN-reviewed patients is high (about 10%). ICU LNs effectively screen patients and often participate in end-of-life care planning. PMID- 26640061 TI - Physiological status during emergency department care: relationship with inhospital death after clinical deterioration. AB - OBJECTIVE: To examine the relationship between patient physiological status in the emergency department (ED) and inhospital mortality after rapid response team (RRT) or cardiac arrest team (CAT) activations within 72 hours of emergency admission to medical or surgical wards. DESIGN, SETTING AND PARTICIPANTS: A multisite, retrospective, cohort study of 660 randomly selected (220 patients per site) adult medical or surgical patients who were admitted from the ED during 2012 and who had had an RRT or CAT activation within 72 hours of admission, at three hospitals in Melbourne, Australia. MAIN OUTCOME MEASURE: Inhospital mortality. RESULTS: There were 825 RRT activations (for 634 patients) and 42 CAT activations (for 35 patients). The median time to the first RRT or CAT activation was 18.8 hours and was significantly shorter in patients who died in hospital (14.6 v 20.6 hours, P=0.036). Compared with survivors, patients who died were more likely to have at least one observation meeting RRT criteria during their ED stay (45.9% v 34.8%; P=0.029): tachypnoea (21.1% v 13.4%, P=0.039), hypotension (20.2% v 11.8%, P=0.018), hypoxaemia (8.3% v 3.1%, P=0.001) and altered conscious state (6.2% v 1.3%, P=0.001) were more common in patients who died. The risk adjusted odds ratio (OR) for inhospital death was highest for patients with an altered conscious state during their ED stay (OR, 4.633; 95% CI, 1.365-15.728; P=0.014). CONCLUSIONS: In patients who needed an RRT or CAT activation within the first 72 hours of emergency admission to medical or surgical wards, there was a strong association between physiological derangement during ED care and inhospital death. PMID- 26640060 TI - Arteriovenous blood gas agreement in intensive care patients with varying levels of circulatory compromise: a pilot study. AB - OBJECTIVE: Venous blood gas (VBG) analysis is suggested as an alternative to arterial blood gas (ABG) analysis. In haemodynamically stable patients, there is clinically acceptable arteriovenous (AV) agreement for pH and bicarbonate (HCO3-) concentration, but in haemodynamically unstable patients, evidence is conflicting. We aimed to evaluate the level of AV agreement for the values of pH, PCO2, base excess, HCO3- and lactate between ABGs and VBGs in critically ill patients with varying degrees of hypotension. DESIGN AND SETTING: A prospective cohort study of a convenience sample of patients in an intensive care unit of a metropolitan teaching hospital. INTERVENTION: Paired ABG and central VBG samples were drawn within 5 minutes of each other from existing arterial lines and central venous lines, and analysed for AV agreement of pH, PCO2, base excess, HCO3- and lactate. The outcome of interest was AV agreement with varying levels of blood pressure (BP). Analysis was by descriptive statistics, box whisker plot and Bland-Altman bias plot analysis. RESULTS: We studied 50 patients with 117 paired ABG and VBG samples. The AV differences (venous-arterial) were: pH, -0.04; HCO3-, -0.37 mmmol/L; base excess, 0.08 mEq/ L; and lactate, 0.16 mmol/L. There was not a clinically relevant deterioration in agreement for these parameters with falling BP. CONCLUSION: In critically ill patients with varying degrees of hypotension in the ICU, there is clinically acceptable AV agreement for the values of pH, HCO3-, base excess and lactate, an agreement that does not deteriorate significantly with falling blood pressure. PMID- 26640062 TI - Sodium reduction during cardiopulmonary bypass: Plasma-Lyte 148 versus trial fluid as pump primes. AB - OBJECTIVES: We compared effects on plasma sodium concentrations plus calculated plasma tonicity of two "balanced" crystalloid solutions used as 2 L pump primes during cardiopulmonary bypass (CPB): Plasma-Lyte 148 (sodium concentration, 140 mmol/L; potassium concentration, 5 mmol/L) versus a bicarbonate-balanced fluid (sodium concentration, 140 mmol/L; potassium concentration, 0 mmol/L). DESIGN, SETTING AND PARTICIPANTS: We analysed pooled data from two prospective interventional studies performed in university-affiliated hospitals, from 50 patients undergoing elective cardiac surgery. INTERVENTIONS: Participants were allocated equally to Plasma-Lyte 148 or bicarbonate-balanced fluid, with plasma electrolytes measured by direct ion selective electrodes immediately before bypass (pre-CPB), within 3 minutes of commencement (T2), and before bypass cessation (end-CPB). RESULTS: Plasma sodium fell at T2 in 46 patients (92%) (P<0.0005). With Plasma-Lyte 148, the mean sodium decreased by 3.0 mmol/L (SD, 1.7 mmol/L), and with bicarbonate-balanced fluid it decreased by 2.2 mmol/L (SD, 1.1 mmol/L) (P=0.002). The mean tonicity fell by >5 mOsm/kg for both groups (P<0.0005). At end-CPB, the mean sodium for both groups remained reduced by >2 mmol/L (P<0.0005). In the group receiving Plasma-Lyte 148, 52% of patients were hyponatraemic (sodium<135 mmol/L) at T2 and end-CPB. CONCLUSIONS: Sodium reductions were common with both priming solutions, but more severe with Plasma Lyte 148. Crystalloid priming solutions require sodium concentrations>140mmol/L to ensure normonatraemia throughout CPB. PMID- 26640063 TI - Characteristics and outcomes of patients with a haematological malignancy admitted to the intensive care unit for a neurological event. AB - OBJECTIVES: Patients with haematological malignancies are at risk of concomitant critical neurological events warranting intensive care unit admission. We aimed to examine the characteristics and outcomes of this patient population, as more knowledge could facilitate decision making on ICU admission and treatment. DESIGN, SETTING AND PARTICIPANTS: A retrospective cohort study of 68 patients in adult ICUs of six Dutch university hospitals between 2003 and 2011. RESULTS: The median Acute Physiology and Chronic Health Evaluation (APACHE) II score was 23 (IQR, 16-27), and 77% of patients needed mechanical ventilation within the first 24 hours of admission. Forty percent of patients had received an allogeneic stem cell transplantation, and 22% were neutropenic on admission. The most frequent underlying haematological condition was non-Hodgkin lymphoma (27%). Seizures were the most common neurological event for ICU admission (29%). The median ICU length of stay was 5 days (IQR, 1-13 days). ICU mortality (28%), hospital mortality (37%) and 3-month mortality (50%) were comparable with other studies of ICU patients with haematological malignancies. Factors associated with 3-month survival were baseline platelet count (113*10(9)/L in survivors v 39*10(9)/L in non-survivors, P<0.01) and APACHE II score (20 in survivors v 25 in non survivors, P=0.02). CONCLUSIONS: Patients with a history of haematological malignancy presenting with a critical neurological event have comparable survival rates with other patients with a haematologic malignancy admitted to the ICU. Our findings suggest that restrictions in ICU care are not justified for this patient population. PMID- 26640064 TI - A randomised study of the effect of external distractors on the quality of ventilation in a simulated adult cardiac arrest. AB - OBJECTIVE: To establish the role of distraction in learner performance and workload when ventilating a mannequin during a simulated cardiac arrest. DESIGN, SETTING AND PARTICIPANTS: Observational, randomised simulation study of critical care doctors and nurses, set in the critical care department of Waikato Hospital, Hamilton, New Zealand INTERVENTIONS: Participants ventilated a mannequin for 1 minute in a neutral scenario that acted as a control, before immediately continuing to ventilate the mannequin in two experimental scenarios for 2 minutes each. Scenarios included one in which participants were asked questions based on resuscitation algorithms, and one in which the participants had to play the children's game hangman. The order of the experimental scenarios was randomised. MAIN OUTCOME MEASURES: The primary clinical performance measure was ventilatory rate. Secondary performance measures of peak airway and mean airway pressures were also analysed. Individual workload was assessed using a questionnaire based on the National Aeronautics and Space Administration task load index. RESULTS: We found no significant difference in any performance variable between the three scenarios. Workload was significantly lower in the control scenario. We found no difference in workload between the clinical and hangman scenarios. Doctors and nurses performed equally. Randomisation group had no effect on performance. CONCLUSIONS: Our study suggests that simple distractors have a potent effect on perceived clinician workload, even when performing the most simple of tasks, but may not strongly influence the objective performance of the task. PMID- 26640066 TI - Preclinical research in critical care--the Australasian perspective. PMID- 26640065 TI - Diabetic ketoacidosis precipitated by therapy with antidiabetic agents SGLT2 inhibitors: two cases. PMID- 26640067 TI - Correction: Oxygenation targets and monitoring in the critically ill: a point prevalence study of clinical practice in Australia and New Zealand (Crit Care Resusc 2015; 17: 202-207). PMID- 26640068 TI - Antipredator behavior of the new mass-reared unisexual strain of the Mexican Fruit Fly. AB - Tephritid pests controlled through the sterile insect technique (SIT) are mass reared and subsequently released in affected areas. Several quality parameters are currently used to test adults, but none take into account interactions with a predator. When sterile males are released in the field, they will need to avoid predators until they reach sexual maturity and survive long enough to mate with wild females. Spiders are one of the most common predators that flies may encounter in release sites. In this study, we evaluated the antipredator behavior of a mass-reared sterile unisexual strain ('Tapachula-7') of the Mexican fruit fly Anastrepha ludens (Diptera: Tephritidae) against their spider predators. We sampled spiders in citrus trees to determine which families could be more common. We established the baseline activity rates of sterile Tapachula-7 (Tap-7) flies in comparison with wild flies. We also tested the behavior of the fertile and sterile bisexual strain and wild flies against hunting spiders (Family Salticidae) and orb building spiders (Family Tetragnathidae). We recorded 18 spider families, with Salticidae being the most dominant. Tap-7 flies diminished their activity in comparison with wild males at 1800 h but showed similar activity levels earlier in the day. When exposed to orb-web spiders (Leucauge venusta), Tap-7, fertile and sterile males from the bisexual strain had similar rates of survival, but Tap-7 males showed lower survival than wild males. Against hunting spiders (Phidippus audax), wild males had higher probability of defensive wing displays, but there was no difference in spider attack rates. In general, sterile Tap -7 males performed as well as males from the bisexual strain, although they had lower survival than wild males. This could be due to either mass-rearing and/or irradiation effects. We recommend the use of the defensive wing display behavior as a quality parameter and propose a rapid and effective method to evaluate fly activity. The efficiency of SIT will be improved if released sterile males have the same antipredator repertoire as their wild counterparts. PMID- 26640069 TI - Fluconazole use and birth defects in the National Birth Defects Prevention Study. AB - BACKGROUND: Low-dose fluconazole is used commonly to treat vulvovaginal candidiasis, a condition occurring frequently during pregnancy. Conflicting information exists on the association between low-dose fluconazole use among pregnant women and the risk of major birth defects. OBJECTIVE: We used data from the National Birth Defects Prevention Study to examine this association. STUDY DESIGN: The National Birth Defects Prevention Study is a multisite, population based, case-control study that includes pregnancies with estimated delivery dates from 1997 to 2011. Information on fluconazole use in early pregnancy was collected by self-report from 31,645 mothers of birth defect cases and 11,612 mothers of unaffected controls. Adjusted odds ratios and 95% confidence intervals were estimated for birth defects with 5 or more exposed cases; crude odds ratios and exact 95% confidence intervals were estimated for birth defects with 3-4 exposed cases. RESULTS: Of the 43,257 mothers analyzed, 44 case mothers and 6 control mothers reported using fluconazole. Six exposed infants had cleft lip with cleft palate, 4 had an atrial septal defect, and each of the following defects had 3 exposed cases: hypospadias, tetralogy of Fallot, d-transposition of the great arteries, and pulmonary valve stenosis. Fluconazole use was associated with cleft lip with cleft palate (odds ratio = 5.53; confidence interval = 1.68 18.24) and d-transposition of the great arteries (odds ratio = 7.56; confidence interval = 1.22-35.45). CONCLUSIONS: The associations between fluconazole and both cleft lip with cleft palate and d-transposition of the great arteries are consistent with earlier published case reports but not recent epidemiologic studies. Despite the larger sample size of the National Birth Defects Prevention Study, fluconazole use was rare. Further investigation is needed in large studies, with particular emphasis on oral clefts and conotruncal heart defects. PMID- 26640070 TI - Reply. PMID- 26640071 TI - Value of base deficit. PMID- 26640072 TI - Development and validation of a laparoscopic hysterectomy cuff closure simulation model for surgical training. AB - BACKGROUND: The number of robotically assisted hysterectomies is increasing, and therefore, the opportunities for trainees to become competent in performing traditional laparoscopic hysterectomy are decreasing. Simulation-based training is ideal for filling this gap in training. OBJECTIVE: The objective of the study was to design a surgical model for training in laparoscopic vaginal cuff closure and to present evidence of its validity and reliability as an assessment and training tool. STUDY DESIGN: Participants included gynecology staff and trainees at 2 tertiary care centers. Experienced surgeons were also recruited at the combined International Urogynecologic Association and American Urogynecologic Society scientific meeting. Participants included 19 experts and 21 trainees. All participants were recorded using the laparoscopic hysterectomy cuff closure simulation model. The model was constructed using the an advanced uterine manipulation system with a sacrocolopexy tip/vaginal stent, a vaginal cuff constructed from neoprene material and lined with a swimsuit material (nylon and spandex) secured to the vaginal stent with a plastic cable tie. The uterine manipulation system was attached to the fundamentals of laparoscopic surgery laparoscopic training box trainer using a metal bracket. Performance was evaluated using the Global Operative Assessment of Laparoscopic Skills scale. In addition, needle handling, knot tying, and incorporation of epithelial edge were also evaluated. The Student t test was used to compare the scores and the operating times between the groups. Intrarater reliability between the scores by the 2 masked experts was measured using the interclass correlation coefficient. RESULTS: Total and annual experience with laparoscopic suturing and specifically vaginal cuff closure varied greatly among the participants. For the construct validity, the participants in the expert group received significantly higher scores in each of the domains of the Global Operative Assessment of Laparoscopic Skills Scale and for each of the 3 added items than did the trainees. The median total Global Operative Assessment of Laparoscopic Skills Scale score (maximum 20) for the experts was 18.8 (range, 11-20), whereas the median total Global Operative Assessment of Laparoscopic Skills Scale score for the trainees was 10 (range, 8-18) (P = .001). The overall score that included the 3 new domains (maximum 35) was 33 (range, 18-35) for the experts and 17.5 (range, 14-31.5) for trainees (P = .001). For the face validity testing, the majority of the study participants (32 [85%]) agreed or strongly agreed that the model is realistic and all participants agreed or strongly agreed that the model appears to be useful for improving technique required for this task. For the interrater reliability, the scores assigned by each observer had an interclass correlation coefficient of 0.8 (95% confidence interval, 0.7-0.93). CONCLUSION: This model is easily constructed and has an acceptable cost. We have demonstrated evidence of construct validity. This is a valuable education tool that can serve to improve skills, which are essential to the gynecological surgeon but are often lacking in residency training because of national changes in practice patterns. PMID- 26640073 TI - Degree of obesity at delivery and risk of preeclampsia with severe features. AB - BACKGROUND: The risk of preeclampsia increases as maternal body mass index (BMI) increases. The link between increasing maternal BMI and preeclampsia with severe features is less well-established. OBJECTIVE: To estimate the effect of increasing severity of obesity on risk of preeclampsia with severe features, stratified by early-onset and late-onset disease. STUDY DESIGN: We performed a retrospective cohort study of consecutive singleton live births at a tertiary care facility from 2004 to 2008. Women were included in the cohort if they delivered a singleton live birth and maternal height and weight was measured on admission. The primary exposure was maternal weight category on presentation for delivery, defined as normal (BMI 18.5-24.9; referent group, n = 1473), overweight (BMI 25-29.9, n = 3081), obese (BMI 30-39.9, n = 4196), and morbidly obese (BMI >=40, n = 1446). The primary outcome was preeclampsia with severe features. Secondary outcome was early-onset preeclampsia with severe features at <34 weeks or late-onset preeclampsia with severe features at >=34 weeks. Multivariable logistic regression was used to adjust for confounders. RESULTS: Of the 10,196 patients meeting inclusion criteria, 1119 developed preeclampsia. Of those, 881 (8.6%) women developed preeclampsia with severe features. Overall, the risk of preeclampsia with severe features was not significantly different in the 4 BMI categories. Of the 10,196 women in the cohort, 1072 delivered <34 weeks and 9124 delivered >=34 weeks. When stratifying by gestational age at delivery, there was a statistically significant increased risk of developing late-onset preeclampsia with severe features at >=34 weeks in overweight (4.5%, adjusted odds ratio [aOR] 1.4, 95% confidence interval [CI] 1.0-2.1), obese (6.2%, aOR 2.0, 95% CI 1.4-2.8) and morbidly obese (6.8%, aOR 2.0, 95% CI 1.3-2.9) women compared with normal weight women (2.9%). CONCLUSION: Increasing maternal weight was not associated with preeclampsia with severe features in the total cohort; however, overweight, obese, and morbidly obese women are at increased risk of developing late-onset preeclampsia with severe features. PMID- 26640074 TI - Uterine rupture vs dehiscence. PMID- 26640075 TI - Synthetic and natural small molecule TLR4 antagonists inhibit motoneuron death in cultures from ALS mouse model. AB - Increasing evidence indicates that inflammatory responses could play a critical role in the pathogenesis of motor neuron injury in amyotrophic lateral sclerosis (ALS). Recent findings have underlined the role of Toll-like receptors (TLRs) and the involvement of both the innate and adaptive immune responses in ALS pathogenesis. In particular, abnormal TLR4 signaling in pro-inflammatory microglia cells has been related to motoneuron degeneration leading to ALS. In this study the effect of small molecule TLR4 antagonists on in vitro ALS models has been investigated. Two different types of synthetic glycolipids and the phenol fraction extracted from commercial extra-virgin olive oil (EVOO) were selected since they efficiently inhibit TLR4 stimulus in HEK cells by interacting with the TLR4.MD-2 complex and CD14 co-receptor. Here, TLR4 antagonists efficiently protected motoneurons from LPS-induced lethality in spinal cord cultures, and inhibited the interleukine-1beta production by LPS-stimulated microglia. In motoneurons/glia cocultures obtained from wild type or SOD1 G93A mice, motoneuron death induced by SOD1mut glia was counteracted by TLR4 antagonists. The release of nitric oxide by LPS treatment or SOD1mut glia was also inhibited by EVOO, suggesting that the action of this natural extract could be mainly related to the modulation of this inflammatory mediator. PMID- 26640076 TI - Increased context-dependent conditioning to amphetamine in mice lacking TAAR1. AB - Given the recent evidence indicating that amphetamine derivatives may also act as direct agonists of the G protein-coupled trace amine-associated receptor 1 (TAAR1), we hypothesized that TAAR1 could contribute to the reinforcing and addictive properties of amphetamines. Accordingly, the present study aimed to investigate the role of TAAR1 in the effects of psychostimulants by analyzing context-dependent sensitization and conditioned place preference (CPP) to d amphetamine (AMPH) in TAAR1-KO mice. In context-dependent sensitization experiment, TAAR1-KO mice showed higher conditioned locomotor responses compared to wild-type mice. In the CPP test, TAAR1-KO animals were also more sensitive to priming-induced reinstatement of AMPH-induced conditioned place preference (CPP) than wild type mice. Importantly, saline-treated and AMPH-treated mice lacking TAAR1 demonstrated significant alterations in the total levels and phosphorylation of the critical subunit of NMDA glutamate receptors, GluN1, in the striatum, suggesting a role of TAAR1 in the modulation of frontostriatal glutamate transmission; this effect could underlie the observed alterations in conditioning processes. In conclusion, our data suggest that TAAR1 receptors play an inhibitory role with respect to conditioned responses to AMPH by modulating, at least in part, corticostriatal glutamate transmission. PMID- 26640077 TI - Role of nasal positive end expiratory pressure valve as an alternative treatment for obstructive sleep apnoea in Chinese patients. AB - BACKGROUND AND OBJECTIVE: As compliance of continuous positive airway pressure (CPAP) for treatment of obstructive sleep apnoea (OSA) is often suboptimal, a less cumbersome treatment is desirable. We explored the clinical usefulness of nasal positive end expiratory pressure (nPEEP) valves. METHODS: Symptomatic OSA patients (apnoea hypopnea index (AHI) >5/h by polysomnography (PSG) or >10/h by type III devices), who declined CPAP, were recruited. A nPEEP valve was attached to each nostril before bed. After successful acclimatization for 1 week, treatment was continued for 4 weeks. The nPEEP valves provided expiratory resistance to build up PEEP. PSG was performed at week 4. RESULTS: Among 196 subjects, 46 (23%) failed acclimatization and 14 (7%) withdrew. Among the 120 patients with a valid PSG, 72 (60%) and 75 (63%) had >50% reduction in mean (standard deviation) overall AHI 26 (16)/h to 18 (18)/h and mean supine AHI 31 (19)/h to 11(16)/h, respectively, P < 0.001. Compared with responders, patients with <50% reduction in AHI had a higher mean overall AHI (30/h vs 23/h, P = 0.03), higher mean supine AHI (35/h vs 26/h, P = 0.04), more severe mean oxygen desaturation nadir (76.7% vs 82.7%, P < 0.01) and longer mean period of desaturation <90% SaO2 (7.7 vs 2.4, P = 0.02). Breathing discomfort and dry mouth were the most common side effects. Compared with a dental device, there was a larger mean reduction in supine AHI using nPEEP (29 (14)/h vs 16 (17)/h). CONCLUSION: nPEEP valves were useful in selected patients with mild or positional related OSA. PMID- 26640078 TI - Equine grass sickness, but not botulism, causes autonomic and enteric neurodegeneration and increases soluble N-ethylmaleimide-sensitive factor attachment receptor protein expression within neuronal perikarya. AB - REASONS FOR PERFORMING STUDY: Equine grass sickness (EGS) is of unknown aetiology. Despite some evidence suggesting that it represents a toxico-infection with Clostridium botulinum types C and/or D, the effect of EGS on the functional targets of botulinum neurotoxins, namely the soluble N-ethylmaleimide-sensitive factor attachment receptor (SNARE) proteins, is unknown. Further, while it is commonly stated that, unlike EGS, equine botulism is not associated with autonomic and enteric neurodegeneration, this has not been definitively assessed. OBJECTIVES: To determine: 1) whether botulism causes autonomic and enteric neurodegeneration; and 2) the effect of EGS on the expression of SNARE proteins within cranial cervical ganglion (CCG) and enteric neuronal perikarya. STUDY DESIGN: Descriptive study. METHODS: Light microscopy was used to compare the morphology of neurons in haematoxylin-eosin stained sections of CCG and ileum from 6 EGS horses, 5 botulism horses and 6 control horses. Immunohistochemistry was used to compare the expression of synaptosomal-associated protein-25, synaptobrevin (Syb) and syntaxin within CCG neurons, and of Syb in enteric neurons, from horses with EGS, horses with botulism and control horses. The concentrations of these SNARE proteins in extracts of CCG from EGS and control horses were compared using quantitative fluorescent western blotting. RESULTS: EGS, but not botulism, was associated with autonomic and enteric neurodegeneration and with increased immunoreactivity for SNARE proteins within neuronal perikarya. Quantitative fluorescent western blotting confirmed increased concentrations of synaptosomal-associated protein-25, Syb and syntaxin within CCG extracts from EGS vs. control horses, with the increases in the latter 2 proteins being statistically significant. CONCLUSIONS: The occurrence of autonomic and enteric neurodegeneration, and increased expression of SNARE proteins within neuronal perikarya, in EGS but not botulism, suggests that EGS may not be caused by botulinum neurotoxins. Further investigation of the aetiology of EGS is therefore warranted. PMID- 26640079 TI - Ketamine-based procedural sedation and analgesia for botulinum toxin A injections in children with cerebral palsy. AB - INTRODUCTION: Adequate procedural sedation and analgesia (PSA) is essential to reduce pain and distress for children undergoing intramuscular botulinum toxin (BoNT-A) injections. This study describes our institution's experience with ketamine-based PSA in terms of safety and efficacy in children with cerebral palsy receiving BoNT-A injections. MATERIAL AND METHODS: This is an analysis of ketamine-based PSA for children undergoing BoNT-A injections between January 2000 and October 2014. All patients received PSA according to our institution's sedation protocol. From 2000 to 2012, intravenous ketamine and midazolam PSA was administered. From 2013 onwards, intravenous ketamine was used as a sole agent for PSA. RESULTS: A total of 152 BoNT-A procedures were performed successfully on 87 children. The median age of the children was 5 years 5 months with 9 children younger than 36 months. Ten procedures (6.6%) were associated with acute transient self-limiting side effects: Four developed rashes, three had nausea and vomiting, one child had limb tremors and another child complained of mild headache. One child reported nightmares on the evening of the procedure during the two-week post-procedure review. No child experienced serious adverse events. CONCLUSION: Administration of ketamine-based PSA for intramuscular BoNT-A procedures in children can be both safe and efficacious. PMID- 26640080 TI - A syndrome of microcephaly, short stature, polysyndactyly, and dental anomalies caused by a homozygous KATNB1 mutation. AB - Using whole-exome sequencing, we identified a homozygous acceptor splice-site mutation in intron 6 of the KATNB1 gene in a patient from a consanguineous Turkish family who presented with congenital microcephaly, lissencephaly, short stature, polysyndactyly, and dental abnormalities. cDNA analysis revealed complete loss of the natural acceptor splice-site resulting either in the usage of an alternative, exonic acceptor splice-site inducing a frame-shift and premature protein truncation or, to a minor extent, in complete skipping of exon 7. Both effects most likely lead to complete loss of KATNB1 function. Homozygous and compound heterozygous mutations in KATNB1 have very recently been described as a cause of microcephaly with brain malformations and seizures. We extend the KATNB1 associated phenotype by describing a syndrome characterized by primordial dwarfism, lissencephaly, polysyndactyly, and dental anomalies, which is caused by a homozygous truncating KATNB1 mutation. PMID- 26640081 TI - Developmental exposure to Ethinylestradiol affects transgenerationally sexual behavior and neuroendocrine networks in male mice. AB - Reproductive behavior and physiology in adulthood are controlled by hypothalamic sexually dimorphic neuronal networks which are organized under hormonal control during development. These organizing effects may be disturbed by endocrine disrupting chemicals (EDCs). To determine whether developmental exposure to Ethinylestradiol (EE2) may alter reproductive parameters in adult male mice and their progeny, Swiss mice (F1 generation) were exposed from prenatal to peripubertal periods to EE2 (0.1-1 MUg/kg/d). Sexual behavior and reproductive physiology were evaluated on F1 males and their F2, F3 and F4 progeny. EE2 exposed F1 males and their F2 to F4 progeny exhibited EE2 dose-dependent increased sexual behavior, with reduced latencies of first mount and intromission, and higher frequencies of intromissions with a receptive female. The EE2 1 MUg/kg/d exposed animals and their progeny had more calbindin immunoreactive cells in the medial preoptic area, known to be involved in the control of male sexual behavior in rodents. Despite neuroanatomical modifications in the Gonadotropin-Releasing Hormone neuron population of F1 males exposed to both doses of EE2, no major deleterious effects on reproductive physiology were detected. Therefore EE2 exposure during development may induce a hypermasculinization of the brain, illustrating how widespread exposure of animals and humans to EDCs can impact health and behaviors. PMID- 26640082 TI - [Granulomatous tattoo reaction confined to red pigment]. PMID- 26640083 TI - Charge Master: Friend or Foe? AB - Prices charged for imaging services can be found in the charge master, a catalog of retail list prices for medical goods and services. This article reviews the evolution of reimbursement in the United States and provides a balanced discussion of the factors that influence charge master prices. Reduced payments to hospitals have pressured hospitals to generate additional revenue by increasing charge master prices. An unfortunate consequence is that those least able to pay for health care, the uninsured, are subjected to the highest charges. Yet, differences in pricing also represent an opportunity for radiology practices, which provide imaging services that are larger in scope or superior in quality to promote product differentiation. Physicians, hospital executives, and policy makers need to work together to improve the existing reimbursement system to promote high-quality, low-cost imaging. PMID- 26640084 TI - Prognostic Impact of QRS Axis Deviation in Patients Treated With Cardiac Resynchronization Therapy. AB - INTRODUCTION: QRS duration and morphology are currently recognized as recommended criteria for the selection of CRT candidates. It has recently been shown that patients with left bundle branch block (LBBB) derive substantial clinical benefit from CRT. The aim of this study is to investigate the prognostic impact of QRS axis deviation (AD) in HF patients with LBBB undergoing CRT. METHODS AND RESULTS: We retrospectively evaluated 707 HF patients with LBBB who underwent CRT at five centers. Baseline QRS axis was defined as normal (NA: -30 degrees to 90 degrees ), right axis deviation (RAD: 90 degrees to 180 degrees ) and left axis deviation (LAD: <-30 degrees ). The primary endpoint was a composite of all cause death/HF hospitalization. The risk of endpoint by AD was evaluated with both Kaplan-Meier and Cox proportional hazard analysis. Among 707 patients (73% M, median age: 71 [62,77] years), 323 (46%) had NA, 359 (51%) LAD, and 25 (3.5%) RAD. Baseline clinical characteristics were similar between the three groups. Over a mean follow-up of 32 +/- 25 months, 141 deaths occurred (21%) and 36% (n = 255) met with the composite endpoint. A significantly higher proportion of RAD patients (52%) reached the endpoint (LAD 40%, NA 30%). KM analysis showed that RAD and LAD patients had worse event free survival and in multivariate analysis both LAD (HR: 1.40; 95% CI: 1.05-1.86; P = 0.021) and RAD (HR: 2.49; 95% CI: 1.31 4.74; P = 0.005) were independently associated with worse clinical outcome. CONCLUSIONS: Right or left axis deviation in the presence of LBBB in HF patients undergoing CRT are independent predictors of poor prognosis. PMID- 26640085 TI - Tetrazole Photoclick Chemistry: Reinvestigating Its Suitability as a Bioorthogonal Reaction and Potential Applications. AB - The bioorthogonality of tetrazole photoclick chemistry has been reassessed. Upon photolysis of a tetrazole, the highly reactive nitrile imine formed undergoes rapid nucleophilic reaction with a variety of nucleophiles present in a biological system, along with the expected cycloaddition with alkenes. The alternative use of the tetrazole photoclick reaction was thus explored: tetrazoles were incorporated into Bodipy and Acedan dyes, providing novel photo crosslinkers with one- and two-photon fluorescence Turn-ON properties that may be developed into protein-detecting biosensors. Further introduction of these photo activatable, fluorogenic moieties into staurosporine resulted in the corresponding probes capable of photoinduced, no-wash imaging of endogenous kinase activities in live mammalian cells. PMID- 26640088 TI - Preclinical modeling of hematopoietic stem cell transplantation - advantages and limitations. AB - Hematopoietic stem cell transplantation, which was first successfully performed in the 1950s, remains a critical therapeutic modality for treatment of a diverse array of diseases, including a multitude of hematological malignancies, autoimmune disorders, amyloidosis and inherited genetic hematological disorders. Although great advances have been made in understanding and application of this therapy, significant complications still exist, warranting further investigation. Of critical importance, graft-versus-host disease (GVHD), in both acute and chronic forms, remains a major complication of hematopoietic stem cell transplantation, responsible for both the development of chronic illness and morbidity, as well as mortality. Use of an appropriate preclinical model may provide significant insight into the mechanistic pathways leading to the development and progression of graft-versus-host disease, as well as cancer in general. However, existing preclinical modeling systems exhibit significant limitations, and development of models that recapitulate the complex and comprehensive clinical scenario and provide a tool by which therapeutic intervention may be developed and assessed is of utmost importance. Here, we review the present status of the field of graft-versus-host disease research. We discuss and summarize the preclinical models currently in use, as well as their advantages and limitations. PMID- 26640089 TI - Tuning the properties of polyhydroxybutyrate films using acetic acid via solvent casting. AB - Biodegradable polyhydroxybutyrate (PHB) films were fabricated using acetic acid as an alternative to common solvents such as chloroform. The PHB films were prepared using a solvent casting process at temperatures ranging from 80 degrees C to 160 degrees C. The crystallinity, mechanical properties and surface morphology of the films cast at different temperatures were characterized and compared to PHB films cast using chloroform as a solvent. Results revealed that the properties of the PHB film varied considerably with solvent casting temperature. In general, samples processed with acetic acid at low temperatures had comparable mechanical properties to PHB cast using chloroform. This acetic acid based method is environmentally friendly, cost efficient and allows more flexible processing conditions and broader ranges of polymer properties than traditional methods. PMID- 26640113 TI - Combining selected immunomodulatory Propionibacterium freudenreichii and Lactobacillus delbrueckii strains: Reverse engineering development of an anti inflammatory cheese. AB - SCOPE: Inflammatory bowel disease (IBD) constitutes a growing public health concern in western countries. Bacteria with anti-inflammatory properties are lacking in the dysbiosis accompanying IBD. Selected strains of probiotic bacteria with anti-inflammatory properties accordingly alleviate symptoms and enhance treatment of ulcerative colitis in clinical trials. Such properties are also found in selected strains of dairy starters such as Propionibacterium freudenreichii and Lactobacillus delbrueckii (Ld). We thus investigated the possibility to develop a fermented dairy product, combining both starter and probiotic abilities of both lactic acid and propionic acid bacteria, designed to extend remissions in IBD patients. METHODS AND RESULTS: We developed a single strain Ld-fermented milk and a two-strain P. freudenreichii and Ld-fermented experimental pressed cheese using strains previously selected for their anti inflammatory properties. Consumption of these experimental fermented dairy products protected mice against trinitrobenzenesulfonic acid induced colitis, alleviating severity of symptoms, modulating local and systemic inflammation, as well as colonic oxidative stress and epithelial cell damages. As a control, the corresponding sterile dairy matrix failed to afford such protection. CONCLUSION: This work reveals the probiotic potential of this bacterial mixture, in the context of fermented dairy products. It opens new perspectives for the reverse engineering development of anti-inflammatory fermented foods designed for target populations with IBD, and has provided evidences leading to an ongoing pilot clinical study in ulcerative colitis patients. PMID- 26640114 TI - Quadratic Fermi node in a 3D strongly correlated semimetal. AB - Strong spin-orbit coupling fosters exotic electronic states such as topological insulators and superconductors, but the combination of strong spin-orbit and strong electron-electron interactions is just beginning to be understood. Central to this emerging area are the 5d transition metal iridium oxides. Here, in the pyrochlore iridate Pr2Ir2O7, we identify a non-trivial state with a single-point Fermi node protected by cubic and time-reversal symmetries, using a combination of angle-resolved photoemission spectroscopy and first-principles calculations. Owing to its quadratic dispersion, the unique coincidence of four degenerate states at the Fermi energy, and strong Coulomb interactions, non-Fermi liquid behaviour is predicted, for which we observe some evidence. Our discovery implies that Pr2Ir2O7 is a parent state that can be manipulated to produce other strongly correlated topological phases, such as topological Mott insulator, Weyl semimetal, and quantum spin and anomalous Hall states. PMID- 26640115 TI - Gaining myocytes or losing fibroblasts: Challenges in cardiac fibroblast reprogramming for infarct repair. AB - Unlike most somatic tissues, the heart possesses a very limited inherent ability to repair itself following damage. Attempts to therapeutically salvage the myocardium after infarction, either by sparing surviving myocytes or by injection of exogenous cells of varied provenance, have met with limited success. Cardiac fibroblasts are numerous, resistant to hypoxia, and amenable to phenotype reprogramming to cardiomyocytes - a potential panacea to an intractable problem. However, the long-term effects of mass conversion of fibroblasts are as-yet unknown. Since fibroblasts play key roles in normal cardiac function, treating these cells as a ready source of replacements for myocytes may have the effect of swapping one problem for another. This review briefly examines the roles of cardiac fibroblasts, recaps the strides made so far in their reprogramming to cardiomyocytes both in vitro and in vivo, and discusses the potential ramifications of large-scale cellular identity swapping. While such therapy offers great promise, the potential repercussions require consideration and careful study. PMID- 26640116 TI - A long-term risk-benefit analysis of low-dose aspirin in primary prevention. AB - BACKGROUND: The long-term risk-benefit effect of occasional and regular use of low-dose aspirin (<= 100 mg per day) in primary prevention of vascular diseases and cancers was calculated. METHODS: One representative database of 1 000 000 participants from Taiwan's National Health Insurance scheme in 1997-2000 was used. The potential study subjects were those aged 30-95 years, were found not to have been prescribed aspirin before 1 January 2000, but to have first been prescribed low-dose aspirin (<= 100 mg per day) after that date and were followed up to 31 December 2009. Participants prescribed low-dose aspirin < 20% during the study period were considered occasional users and those prescribed >= 80% regular users. After the propensity score matching, rate differences of haemorrhage, ischaemia and cancer between these users were calculated their net clinical risk. RESULTS: A total of 1720 pairs were analysed. During the study period, haemorrhage and ischaemia occurred in 25 (1.45%) and 67 participants (3.90%) in occasional users and 69 (4.01%) and 100 participants (5.81%) in regular users, whereas cancer occurred in 32 participants (1.86%) in occasional users and 26 participants (1.51%) in regular users. The crude and adjusted net clinical risks of low-dose aspirin use between the two frequency of users (>= 80% vs. < 20%) were 4.12% (95% CI = 2.19%, 6.07%; P < 0.001) and 3.93% (95% CI = 2.01%, 5.84%; P < 0.001). CONCLUSIONS: A long-term regular use of low-dose aspirin might not be better than occasional use in the primary prevention against major vascular diseases and cancer. PMID- 26640117 TI - Stage-dependent remodeling of the nuclear envelope and lamina during rabbit early embryonic development. AB - Utilizing 3D structured illumination microscopy, we investigated the quality and quantity of nuclear invaginations and the distribution of nuclear pores during rabbit early embryonic development and identified the exact time point of nucleoporin 153 (NUP153) association with chromatin during mitosis. Contrary to bovine early embryonic nuclei, featuring almost exclusively nuclear invaginations containing a small volume of cytoplasm, nuclei in rabbit early embryonic stages show additionally numerous invaginations containing a large volume of cytoplasm. Small-volume invaginations frequently emanated from large-volume nuclear invaginations but not vice versa, indicating a different underlying mechanism. Large- and small-volume nuclear envelope invaginations required the presence of chromatin, as they were restricted to chromatin-positive areas. The chromatin free contact areas between nucleolar precursor bodies (NPBs) and large-volume invaginations were free of nuclear pores. Small-volume invaginations were not in contact with NPBs. The number of invaginations and isolated intranuclear vesicles per nucleus peaked at the 4-cell stage. At this stage, the nuclear surface showed highly concentrated clusters of nuclear pores surrounded by areas free of nuclear pores. Isolated intranuclear lamina vesicles were usually NUP153 negative. Cytoplasmic, randomly distributed NUP153-positive clusters were highly abundant at the zygote stage and decreased in number until they were almost absent at the 8-cell stage and later. These large NUP153 clusters may represent a maternally provided NUP153 deposit, but they were not visible as clusters during mitosis. Major genome activation at the 8- to 16-cell stage may mark the switch from a necessity for a deposit to on-demand production. NUP153 association with chromatin is initiated during metaphase before the initiation of the regeneration of the lamina. To our knowledge, the present study demonstrates for the first time major remodeling of the nuclear envelope and its underlying lamina during rabbit preimplantation development. PMID- 26640118 TI - Time trends in never smokers in the relative frequency of the different histological types of lung cancer, in particular adenocarcinoma. AB - The increasing proportion of lung cancers classified as adenocarcinoma has been a topic of interest and research. The main objective of the analyses reported here is to summarize how the proportion of adenocarcinoma varies in never smokers by time, sex and region based on published evidence on the distribution of lung cancer types available from epidemiological studies. Based on 219 sex- and period specific blocks of data drawn from 157 publications, there appears to be a clear time-related increase in the proportion of lung cancers in never smokers that are adenocarcinoma, which is evident in both sexes, and not specific to any region. It is seen whether the denominator of the proportion is made up of adenocarcinoma plus squamous cell carcinoma cases, cases of the four major types combined, or all lung cancer cases. The ratio of adenocarcinoma to squamous cell carcinoma rose continuously from 1950 to 69 to be almost 4 times higher for the data from 2000 onwards. We discuss factors that may have contributed to the observed findings, including changes in lung cancer classification. Our findings argue against the hypothesis that increases in the ratio arise from changes in cigarette design and composition. PMID- 26640119 TI - Anomalous Electronic Anisotropy Triggered by Ferroelastic Coupling in Multiferroic Heterostructures. AB - The ferroelastic strain coupling in multiferroic heterostructures is explored aiming at novel physical effects and fascinating functionality. Ferroelastic domain walls in manganites induced by a stripe BiFeO3 template can modulate the electronic transfer and sufficiently block the magnetic ordering, creating a vast anisotropy. The findings suggest the great importance of ferroelastic strain engineering in material modifications. PMID- 26640120 TI - The steeper PR interval/HR slope is better in patients with long PR interval during stress test. PMID- 26640121 TI - Characterization of the single cycle replication of HIV-1 expressing Gaussia luciferase in human PBMCs, macrophages, and in CD4(+) T cell-grafted nude mouse. AB - In this study, we have described a sensitive HIV-1 single cycle replicating virus that expresses a secreted Gaussia luciferase (Gluc) as a biomarker. This single cycle replicating virus was produced by the co-transfection of 293T cells with a multiple gene-deleted HIV provirus (DeltaRI/DeltaE/Gluc) and CMVin-Gag/Pol and viral envelope glycoprotein (Env) plasmids. The results showed that this HIV-1 virus efficiently infected and was restricted to one replication cycle in primary CD4+ T cells, macrophages and CD4+ T cell-grafted nude mouse. Because the viral genomic DNA lacks reverse transcriptase and integrase genes and has a partial deletion in the env gene, this trans-complemented virus could not be converted into the wild type virus after multiple passages in highly susceptible CD4+ C8166 T cells, demonstrating the safety of this system. Furthermore, infection with this virus was easily monitored by detecting the Gluc activity in the cell culture supernatants or in the animal peritoneal fluid or blood, which was shown to be more sensitive than the anti-p24 ELISA assay. This trans-complemented virus system is valuable for various HIV single cycle infection and viral expression studies in the laboratory where a biosafety level-3 containment facility is not accessible. PMID- 26640122 TI - Comparative analytical evaluation of the respiratory TaqMan Array Card with real time PCR and commercial multi-pathogen assays. AB - In this study, a multicenter evaluation of the Life Technologies TaqMan((r)) Array Card (TAC) with 21 custom viral and bacterial respiratory assays was performed on the Applied Biosystems ViiATM 7 Real-Time PCR System. The goal of the study was to demonstrate the analytical performance of this platform when compared to identical individual pathogen specific laboratory developed tests (LDTs) designed at the Centers for Disease Control and Prevention (CDC), equivalent LDTs provided by state public health laboratories, or to three different commercial multi-respiratory panels. CDC and Association of Public Health Laboratories (APHL) LDTs had similar analytical sensitivities for viral pathogens, while several of the bacterial pathogen APHL LDTs demonstrated sensitivities one log higher than the corresponding CDC LDT. When compared to CDC LDTs, TAC assays were generally one to two logs less sensitive depending on the site performing the analysis. Finally, TAC assays were generally more sensitive than their counterparts in three different commercial multi-respiratory panels. TAC technology allows users to spot customized assays and design TAC layout, simplify assay setup, conserve specimen, dramatically reduce contamination potential, and as demonstrated in this study, analyze multiple samples in parallel with good reproducibility between instruments and operators. PMID- 26640123 TI - Focusing particles by induced charge electrokinetic flow in a microchannel. AB - A novel method of sheathless particle focusing by induced charge electrokinetic flow in a microchannel is presented in this paper. By placing a pair of metal plates on the opposite walls of the channel and applying an electrical field, particle focusing is achieved due to the two pairs of vortex that constrain the flow of the particle solution. As an example, the trajectories of particles under different electrical fields with only one metal plate on one side channel wall were numerically simulated and experimentally validated. Other flow focusing effects, such as the focused width ratio (focused width/channel width) and length ratio (focused length/half-length of metal plate) of the sample solution, were also numerically studied. The results show that the particle firstly passes through the gaps between the upstream vortices and the channel walls. Afterwards, the particle is focused to pass through the gap between the two downstream vortices that determine the focused particle position. Numerical simulations show that the focused particle stream becomes thin with the increases in the applied electrical field and the length of the metal plates. As regards to the focused length ratio of the focused stream, however, it slightly increases with the increase in the applied electrical field and almost keeps constant with the increase in the length of the metal plate. The size of the focused sample solution, therefore, can be easily adjusted by controlling the applied electrical field and the sizes of the metal plates. PMID- 26640124 TI - Buckling assisted and lithographically micropatterned fully flexible sensors for conformal integration applications. AB - Development of flexible sensors/electronics over substrates thicker than 100 MUm is of immense importance for its practical feasibility. However, unlike over ultrathin films, large bending stress hinders its flexibility. Here we have employed a novel technique of fabricating sensors over a non-planar ridge topology under pre-stretched condition which not only helps in spontaneous generation of large and uniform parallel buckles upon release, but also acts as stress reduction zones thereby preventing Poisson's ratio induced lateral cracking. Further, we propose a complete lithography compatible process to realize flexible sensors over pre-stretched substrates thicker than 100 MUm that are released through dissolution of a water soluble sacrificial layer of polyvinyl alcohol. These buckling assisted flexible sensors demonstrated superior performance along different flexible modalities. Based on the above concept, we also realized a micro thermal flow sensor, conformally wrapped around angiographic catheters to detect flow abnormalities for potential applications in interventional catheterization process. PMID- 26640125 TI - Formation of Carbonized Polystyrene Sphere/hemisphere Shell Arrays by Ion Beam Irradiation and Subsequent Annealing or Chloroform Treatment. AB - Heat-resistant two-dimensional (2D) sphere/hemisphere shell array is significant for the fabrication of novel nanostructures. Here large-area, well-ordered arrays of carbonized polystyrene (PS) hollow sphere/hemisphere with controlled size and morphology are prepared by combining the nanosphere self-assembly, kV Ag ion beam modification, and subsequent annealing or chloroform treatment. Potential mechanisms for the formation and evolution of the heat-resistant carbonized PS spherical shell with increasing ion fluence and energy are discussed. Combined with noble metal or semiconductor, these modified PS sphere arrays should open up new possibilities for high-performance nanoscale optical sensors or photoelectric devices. PMID- 26640127 TI - [A case of bilateral blephaloptosis resulting from midbrain lesions caused by diffuse large B-cell lymphoma]. AB - We report the case of a patient with bilateral blephaloptosis associated with a recurrence of diffuse large B-cell lymphoma (DLBCL) in the midbrain. A 70-year old man experienced acute onset bilateral blephaloptosis; the other ocular movements, except for medial rectus muscle in the right eye, were not impaired. Pupils were isocoric and light reflexes were prompt. Other cranial nerves were intact. Gadolinium-enhanced MRI revealed abnormal enhancement in the midbrain and peri-ventricular regions. FDG-PET revealed an abnormal positive signal in the midbrain, similar to the distribution seen in the MRI scan. Cytology of the cerebrospinal fluid showed large atypical lymphocytes. These findings suggest that the recurrence of DLBCL in the midbrain caused bilateral blephaloptosis. The oculomotor fascicle is localized in the paramedian ventral midbrain. The fascicular fibers are divided topographically into four regions; the lateral, medial, rostral and caudal regions. In three-dimensional arrangement of the oculomotor fascicle, the fibers to the levator palpebrae superioris muscle and medial rectus muscles are located adjacently in caudal regions. Thus, we speculate that recurrence of DLBCL in the midbrain involving the right oculomotor fascicle caused blephaloptosis in the right eye, and then, infiltration of DLBCL to the left oculomotor fascicle subsequently caused blephaloptosis in the left eye. This is a valuable case to be documented in which neurological site of lesions consistent with those are found in radiological study. PMID- 26640126 TI - Identification of an allosteric binding site for RORgammat inhibition. AB - RORgammat is critical for the differentiation and proliferation of Th17 cells associated with several chronic autoimmune diseases. We report the discovery of a novel allosteric binding site on the nuclear receptor RORgammat. Co crystallization of the ligand binding domain (LBD) of RORgammat with a series of small-molecule antagonists demonstrates occupancy of a previously unreported allosteric binding pocket. Binding at this non-canonical site induces an unprecedented conformational reorientation of helix 12 in the RORgammat LBD, which blocks cofactor binding. The functional consequence of this allosteric ligand-mediated conformation is inhibition of function as evidenced by both biochemical and cellular studies. RORgammat function is thus antagonized in a manner molecularly distinct from that of previously described orthosteric RORgammat ligands. This brings forward an approach to target RORgammat for the treatment of Th17-mediated autoimmune diseases. The elucidation of an unprecedented modality of pharmacological antagonism establishes a mechanism for modulation of nuclear receptors. PMID- 26640128 TI - [Posterior reversible encephalopathy syndrome of the midbrain and hypothalamus - a case report of uremic encephalopathy presenting with hypersomnia]. AB - We report the case of a 73-year-old woman presenting with hypersomnia and loss of appetite. She suffered from diabetic nephropathy without receiving dialysis, in addition to hypertension, which was well controlled without marked fluctuation. There were no objective neurological findings. Her laboratory findings showed renal failure with 3.7 mg/dl of serum creatinine and decreased serum sodium and potassium. Brain magnetic resonance imaging (MRI) showed posterior reversible encephalopathy syndrome (PRES) with vasogenic edema, which was distributed in the dorsal midbrain, medial thalamus, and hypothalamus. After we addressed the electrolyte imbalance and dehydration, her symptoms and MRI findings gradually improved, but faint high signals on MRI were still present 3 months later. Orexin in the cerebrospinal fluid was decreased on admission, but improved 6 months later. We diagnosed uremic encephalopathy with atypical form PRES showing functional disturbance of the hypothalamus. PMID- 26640129 TI - Glucagon-like peptide-1 receptor agonist exenatide has no acute effect on MRI measured exocrine pancreatic function in patients with type 2 diabetes: a randomized trial. AB - AIMS: To investigate the effect of infusion of the glucagon-like peptide-1 (GLP 1) receptor agonist exenatide on exocrine pancreatic function. METHODS: This was a randomized, placebo-controlled, double-blind, crossover study in 12 male patients with type 2 diabetes, treated with oral glucose-lowering agents. On two separate occasions, exenatide or placebo (saline 0.9%) were administered intravenously, in randomized order. Exocrine pancreatic function was measured using secretin-enhanced magnetic resonance cholangiopancreatography. The primary outcome measure was defined as secretin-stimulated pancreatic excretion volume. Secondary outcome measures were maximum secretion speed and the time to reach this maximum. In addition, changes in pancreatic duct (PD) diameter were measured. RESULTS: Exenatide did not change secretin-stimulated pancreatic excretion volume, as compared with placebo (mean +/- standard error of the mean 142.2 +/- 15.6 ml vs 142.6 +/- 8.5 ml, respectively; p = 0.590). Also, exenatide did not change the maximum secretion speed (33.1 +/- 1.4 vs 36.9 +/- 2.2; p = 0.221), nor the time to reach this maximum (both 4 min 30 s). No differences in PD diameter were observed between the two groups. CONCLUSIONS: Infusion of exenatide did not directly influence MRI-measured exocrine pancreatic excretion in patients with type 2 diabetes. Although long-term studies are warranted, these findings suggest that potential adverse pancreatic effects of GLP-1 receptor agonists are not mediated by changes in exocrine pancreatic secretion. PMID- 26640132 TI - Intervention types and outcomes of integrated care for diabetes mellitus type 2: a systematic review. AB - RATIONALE, AIMS AND OBJECTIVES: The delivery of integrated care is a priority in many countries' efforts to improve health outcomes for people at risk of or with diabetes. This study aims to provide an overview of the different types of integrated care interventions for type 2 diabetes and to report their outcomes. METHODS: A systematic literature search was conducted in PubMed and Cochrane for the period 2003-2013. Article selection and data extraction were performed independently by three researchers and results were discussed together. The chronic care model (CCM) was used to describe intervention types. RESULTS: Forty four articles met the inclusion criteria. Most interventions included all CCM components and a variety of sub-components. Most studies reported positive patient, process and health service utilization measures. The information on costs was limited and inconsistent. The low number of articles reporting comparable outcome measures made it difficult to make meaningful statements about an association between intervention type and outcomes. CONCLUSIONS: Future research would benefit from a more uniform understanding of integrated care as well as intermediate outcome measurements that allow for the establishment of a chain of evidence from specific intervention types to specific outcomes achieved. It is expected that such a comprehensive approach will reveal important insights as to which integrated care intervention types and settings are most conducive to successful implementation and would thereby be of relevance to policy makers and practitioners involved in the financing, management and delivery of integrated care. PMID- 26640133 TI - [Woman with sudden neck pain and neurological impairment]. PMID- 26640131 TI - Structural basis of DNA gyrase inhibition by antibacterial QPT-1, anticancer drug etoposide and moxifloxacin. AB - New antibacterials are needed to tackle antibiotic-resistant bacteria. Type IIA topoisomerases (topo2As), the targets of fluoroquinolones, regulate DNA topology by creating transient double-strand DNA breaks. Here we report the first co crystal structures of the antibacterial QPT-1 and the anticancer drug etoposide with Staphylococcus aureus DNA gyrase, showing binding at the same sites in the cleaved DNA as the fluoroquinolone moxifloxacin. Unlike moxifloxacin, QPT-1 and etoposide interact with conserved GyrB TOPRIM residues rationalizing why QPT-1 can overcome fluoroquinolone resistance. Our data show etoposide's antibacterial activity is due to DNA gyrase inhibition and suggests other anticancer agents act similarly. Analysis of multiple DNA gyrase co-crystal structures, including asymmetric cleavage complexes, led to a 'pair of swing-doors' hypothesis in which the movement of one DNA segment regulates cleavage and religation of the second DNA duplex. This mechanism can explain QPT-1's bacterial specificity. Structure based strategies for developing topo2A antibacterials are suggested. PMID- 26640134 TI - ["Doctor, I have Chikungunya". Conceptual systematisation of specific epidemiological implications in family medicine]. PMID- 26640135 TI - [Severe bullous emphysema in a young adult cannabis user]. PMID- 26640136 TI - [Idarucizumab and dabigatran. Data from the RE-VERSE AD study]. PMID- 26640137 TI - Effect of computer-based cognitive rehabilitation (CBCR) for people with stroke: A systematic review and meta-analysis. PMID- 26640138 TI - High central venous-to-arterial CO2 difference/arterial-central venous O2 difference ratio is associated with poor lactate clearance in septic patients after resuscitation. AB - OBJECTIVE: Recently, the central venoarterial carbon dioxide difference/arterial central venous oxygen difference (P(v-a)CO2/C(a-v)O2) ratio has been suggested as an additional indicator of anaerobic metabolism. We investigated the relationship between the P(v-a)CO2/C(a-v)O2 ratio and 8-hour lactate clearance (LC) in septic patients after resuscitation. METHODS AND RESULTS: We prospectively obtained 168 sets of measurements from 84 septic patients. The arterial and central venous blood gases were measured simultaneously at enrollment and 8 hours after resuscitation. The P(v-a)CO2/C(a-v)O2 (r = -0.24, P = .028) at T8 was negatively correlated with 8-hour LC after resuscitation in all patients. The patients with 8-hour LC >= 10% exhibited significantly lower P(v-a)CO2/C(a-v)O2 ratios and intensive care unit mortality after resuscitation than the patients with 8-hour LC < 10%. The area under the receiver operating characteristic curve of the P(v a)CO2/C(a-v)O2 ratio for the detection of LC >= 10% was the greatest and was significantly better than that of the central venous oxygen saturation and similar to that of the P(v-a)CO2. Moreover, a P(v-a)CO2/C(a-v)O2 < 1.23 at T8 is related to poor 8-hour LC rate (LC >= 10%) in the patients with normalized central venous oxygen saturation values (>=70%) after resuscitation. CONCLUSIONS: The high P(v-a)CO2/C(a-v)O2 ratio is associated with poor LC after resuscitation. The P(v-a)CO2/C(a-v)O2 ratio may provide useful information for assessing the LC potential and optimizing the LC rate. PMID- 26640139 TI - Urinary metabolites from mango (Mangifera indica L. cv. Keitt) galloyl derivatives and in vitro hydrolysis of gallotannins in physiological conditions. AB - SCOPE: The absorption, metabolism, and excretion of mango galloyl derivatives (GD) has not yet been investigated in humans, and studies investigating repeated dosages of polyphenols are limited. METHODS AND RESULTS: In this human pilot trial, healthy volunteers (age = 21-38 y, n = 11) consumed 400 g/day of mango pulp (cv. Keitt) for 10 days, and seven metabolites of gallic acid (GA) were characterized and quantified in urine excreted over a 12 h period. Pyrogallol-O sulfate and deoxypyrogallol-O-sulfate were found to be significantly more excreted between days 1 and 10 (p < 0.05) from 28.5 to 55.4 mg and 23.6 to 47.7 mg, respectively. Additionally, the in vitro hydrolysis of gallotannins (GTs) was monitored at physiological pH and temperature conditions, and after 4 h a significant (p < 0.05) shift in composition from relativity high to low molecular weight GTs was observed. CONCLUSION: Seven metabolites of GA were identified in the urine of healthy volunteers, and two microbial metabolites were found to be significantly more excreted following 10 days of mango consumption. Mango GTs were also found to release free GA in conditions similar to the intestines. GTs may serve as a pool of pro-GA compounds that can be absorbed or undergo microbial metabolism. PMID- 26640140 TI - The PR status of the originating cell of ER/PR-negative mouse mammary tumors. AB - Progesterone receptor (PR) is usually co-localized with estrogen receptor (ER) in normal mammary cells. It is not known whether ER/PR-negative human breast cancer arises from an ER/PR-negative cell or from an ER/PR-positive cell that later lost ER/PR. Using intraductal injection of a lentivirus to deliver both an oncogene (ErbB2) and a floxed green fluorescent protein (GFP) in PR(Cre/+)mice, whose Cre gene is under the control of the PR promoter, we were able to trace the PR status of the infected cells as they progressed to cancer. We found that the resulting early lesions stained negative for PR in most of the cells and usually retained GFP. The resulting tumors lacked ER and PR, and 75% (15/20) of them retained the GFP signal in all tumor cells, suggesting PR was never expressed throughout the evolution of a majority of these tumors. In conclusion, our data demonstrate that ErbB2-initiated ER/PR-negative mammary tumors primarily originate from the subset of the mammary epithelium that is negative for PR and probably ER as well. These findings also provide an explanation for why antihormonal therapy fails to prevent ER-negative breast cancers. PMID- 26640141 TI - PIK3CA(H1047R)- and Her2-initiated mammary tumors escape PI3K dependency by compensatory activation of MEK-ERK signaling. AB - Human breast cancers that have HER2 amplification/overexpression frequently carry PIK3CA mutations, and are often associated with a worse prognosis. However, the role of PIK3CA mutations in the initiation and maintenance of these breast cancers remains elusive. In the present study, we generated a compound mouse model that genetically mimics HER2-positive breast cancer with coexisting PIK3CA(H1047R). Induction of PIK3CA(H1047R) expression in mouse mammary glands with constitutive expression of activated Her2/Neu resulted in accelerated mammary tumorigenesis with enhanced metastatic potential. Interestingly, inducible expression of mutant PIK3CA resulted in a robust activation of phosphatidylinositol-3-kinase (PI3K)/AKT signaling but attenuation of Her2/Her3 signaling, and this can be reversed by deinduction of PIK3CA(H1047R) expression. Strikingly, although these Her2(+) PIK3CA(H1047R)-initiated primary mammary tumors are refractory to HER2-targeted therapy, all tumors responded to inactivation of the oncogenic PIK3CA(H1047R), a situation closely mimicking the use of a highly effective inhibitor specifically targeting the mutant PIK3CA/p110a. Notably, these tumors eventually resumed growth, and a fraction of them escaped PI3K dependence by compensatory ERK activation, which can be blocked by combined inhibition of Her2 and MEK. Together, these results suggest that PIK3CA-specific inhibition as a monotherapy followed by combination therapy targeting MAPK and HER2 in a timely manner may be an effective treatment approach against HER2-positive cancers with coexisting PIK3CA-activating mutations. PMID- 26640142 TI - Targeting glutamine metabolism in multiple myeloma enhances BIM binding to BCL-2 eliciting synthetic lethality to venetoclax. AB - Multiple myeloma (MM) is a plasma cell malignancy that is largely incurable due to development of resistance to therapy-elicited cell death. Nutrients are intricately connected to maintenance of cellular viability in part by inhibition of apoptosis. We were interested to determine if examination of metabolic regulation of BCL-2 proteins may provide insight on alternative routes to engage apoptosis. MM cells are reliant on glucose and glutamine and withdrawal of either nutrient is associated with varying levels of apoptosis. We and others have demonstrated that glucose maintains levels of key resistance-promoting BCL-2 family member, myeloid cell leukemic factor 1 (MCL-1). Cells continuing to survive in the absence of glucose or glutamine were found to maintain expression of MCL-1 but importantly induce pro-apoptotic BIM expression. One potential mechanism for continued survival despite induction of BIM could be due to binding and sequestration of BIM to alternate pro-survival BCL-2 members. Our investigation revealed that cells surviving glutamine withdrawal in particular, enhance expression and binding of BIM to BCL-2, consequently sensitizing these cells to the BH3 mimetic venetoclax. Glutamine deprivation-driven sensitization to venetoclax can be reversed by metabolic supplementation with TCA cycle intermediate alpha-ketoglutarate. Inhibition of glucose metabolism with the GLUT4 inhibitor ritonavir elicits variable cytotoxicity in MM that is marginally enhanced with venetoclax treatment, however, targeting glutamine metabolism with 6-diazo-5-oxo-l-norleucine uniformly sensitized MM cell lines and relapse/refractory patient samples to venetoclax. Our studies reveal a potent therapeutic strategy of metabolically driven synthetic lethality involving targeting glutamine metabolism for sensitization to venetoclax in MM. PMID- 26640143 TI - The transcribed-ultraconserved regions in prostate and gastric cancer: DNA hypermethylation and microRNA-associated regulation. AB - The transcribed-ultraconserved regions (T-UCRs) are a novel class of non-coding RNAs, which are absolutely conserved (100%) between the orthologous regions of the human, rat and mouse genomes. Previous studies have described that several T UCRs show differential expressions in cancers and might be involved in cancer development. We investigated the transcriptional levels of representative 26 T UCRs and determined the regions that were differently expressed in prostate cancer (PCa) and gastric cancer (GC). A quantitative reverse transcription polymerase chain reaction analysis revealed the downregulation of Uc.158+A expression by a DNA methylation-associated mechanism, which was restored by 5-Aza dC (5-aza-2'-deoxycytidine) treatment. Bisulfite genomic sequencing using cell lines and tissue samples demonstrated cancer-specific CpG hypermethylation in both GC and PCa. However, Uc.416+A was only overexpressed in GC and we identified an miR-153 binding site in the possible regulatory region of Uc.416+A using online databases. Along with a forced expression or knockdown of miR-153 in MKN 74 GC cells, the transcriptional levels of Uc.416+A were significantly disturbed. A luciferase reporter gene assay supported the direct regulation of Uc.416+A expression by miR-153. Furthermore, Uc.416+A was associated with cell growth through the regulation of IGFBP6 (insulin-like growth factor-binding protein 6) in GC. These findings suggest an oncogenic role of Uc.416+A in GC, which suggests that our approach would provide new insights into functional studies of T-UCRs in cancer biology. PMID- 26640144 TI - HDAC inhibition impedes epithelial-mesenchymal plasticity and suppresses metastatic, castration-resistant prostate cancer. AB - PI3K (phosphoinositide 3-kinase)/AKT and RAS/MAPK (mitogen-activated protein kinase) pathway coactivation in the prostate epithelium promotes both epithelial mesenchymal transition (EMT) and metastatic castration-resistant prostate cancer (mCRPC), which is currently incurable. To study the dynamic regulation of the EMT process, we developed novel genetically defined cellular and in vivo model systems from which epithelial, EMT and mesenchymal-like tumor cells with Pten deletion and Kras activation can be isolated. When cultured individually, each population has the capacity to regenerate all three tumor cell populations, indicative of epithelial-mesenchymal plasticity. Despite harboring the same genetic alterations, mesenchymal-like tumor cells are resistant to PI3K and MAPK pathway inhibitors, suggesting that epigenetic mechanisms may regulate the EMT process, as well as dictate the heterogeneous responses of cancer cells to therapy. Among differentially expressed epigenetic regulators, the chromatin remodeling protein HMGA2 is significantly upregulated in EMT and mesenchymal-like tumors cells, as well as in human mCRPC. Knockdown of HMGA2, or suppressing HMGA2 expression with the histone deacetylase inhibitor LBH589, inhibits epithelial mesenchymal plasticity and stemness activities in vitro and markedly reduces tumor growth and metastasis in vivo through successful targeting of EMT and mesenchymal-like tumor cells. Importantly, LBH589 treatment in combination with castration prevents mCRPC development and significantly prolongs survival following castration by enhancing p53 and androgen receptor acetylation and in turn sensitizing castration-resistant mesenchymal-like tumor cells to androgen deprivation therapy. Taken together, these findings demonstrate that cellular plasticity is regulated epigenetically, and that mesenchymal-like tumor cell populations in mCRPC that are resistant to conventional and targeted therapies can be effectively treated with the epigenetic inhibitor LBH589. PMID- 26640145 TI - MicroRNA-16 mediates the regulation of a senescence-apoptosis switch in cutaneous T-cell and other non-Hodgkin lymphomas. AB - Multiple sequential genetic and epigenetic alterations underlie cancer development and progression. Overcoming cellular senescence is an early step in cancer pathogenesis. Here, we demonstrate that a noncoding regulatory RNA, microRNA-16 (miR-16), has the potential to induce cellular senescence. First, we examined the expression of miR-16 in primary cutaneous T-cell lymphoma (CTCL) and other non-Hodgkin T/natural killer (NK)-cell lymphomas and found that miR-16 was downregulated than that in the corresponding normal cells. Notably, miR-16 expression was reduced as the primary CTCL progressed from the early stage to the advanced stage. Next, we transduced CTCL cells with miR-16 to examine whether this miRNA exhibited tumor-suppressive effects in CTCL cells. In CTCL cells expressing wild-type p53, forced expression of miR-16 enhanced p21 expression via downregulation of the polycomb group protein Bmi1, thereby inducing cellular senescence. Alternatively, in CTCL cells lacking functional p53, miR-16 induced compensatory apoptosis. The miR-16 transfection significantly decreased senescent cells and increased apoptotic cells in p21-knockdown CTCL cells expressing wild type p53, suggesting that the presence or absence of p21 may be the most important condition in the senescence-apoptosis switch in CTCL lymphomagenesis. Furthermore, we found that the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) restored the expression of miR-16 and its essential targets, induced senescence in CTCL cells expressing wild-type p53 and promoted apoptosis in cells with nonfunctional p53. Moreover, we found that other T/NK cell lymphoma cell lines showed similar tumor-suppressive effects in response to miR-16 and SAHA and that these effects were dependent on p53 status. These results suggested that epigenetic silencing of miR-16 may be a key step during lymphoma development. Elucidation of the essential targets of miR-16 and SAHA provides a basis for the clinical application of SAHA in the treatment of CTCL and other non-Hodgkin T/NK-cell lymphomas. PMID- 26640146 TI - ASXL2 promotes proliferation of breast cancer cells by linking ERalpha to histone methylation. AB - Estrogen receptor alpha (ERalpha) has a pivotal role in breast carcinogenesis by associating with various cellular factors. Selective expression of additional sex comb-like 2 (ASXL2) in ERalpha-positive breast cancer cells prompted us to investigate its role in chromatin modification required for ERalpha activation and breast carcinogenesis. Here, we observed that ASXL2 interacts with ligand E2 bound ERalpha and mediates ERalpha activation. Chromatin immunoprecipitation sequencing analysis supports a positive role of ASXL2 at ERalpha target gene promoters. ASXL2 forms a complex with histone methylation modifiers including LSD1, UTX and MLL2, which all are recruited to the E2-responsive genes via ASXL2 and regulate methylations at histone H3 lysine 4, 9 and 27. The preferential binding of the PHD finger of ASXL2 to the dimethylated H3 lysine 4 may account for its requirement for ERalpha activation. On ASXL2 depletion, the proliferative potential of MCF7 cells and tumor size of xenograft mice decreased. Together with our finding on the higher ASXL2 expression in ERalpha-positive patients, we propose that ASXL2 could be a novel prognostic marker in breast cancer. PMID- 26640147 TI - Identification and analysis of CXCR4-positive synovial sarcoma-initiating cells. AB - Synovial sarcoma accounts for almost 10% of all soft tissue sarcomas, and its prognosis is poor with 5-year survival rates at 36%. Thus, new treatments and therapeutic targets for synovial sarcoma are required. Tumor-initiating cells have been defined by the ability for self-renewal and multipotent differentiation, and they exhibit higher tumorigenic capacity, chemoresistance and radiation resistance, expecting to be a new therapeutic target. In synovial sarcoma, the presence of such stemness remains largely unclear; thus, we analyzed whether synovial sarcoma possessed tumor-initiating cells and explored specific markers, and we discovered that synovial sarcoma cell lines possessed heterogeneity by way of containing a sphere-forming subpopulation highly expressing NANOG, OCT4 and SOX2. By expression microarray analysis, CXCR4 was identified to be highly expressed in the sphere subpopulation and correlated with stem-cell-associated markers. Inhibition of CXCR4 suppressed the cell proliferation of synovial sarcoma cell lines in vitro. The tumor-initiating ability of CXCR4-positive cells was demonstrated by xenograft propagation assay. CXCR4-positive cells showed higher tumorigenicity than negative ones and possessed both self-renewal and multipotent differentiation ability. Immunohistochemical analysis of 39 specimens of synovial sarcoma patients revealed that CXCR4 strongly correlated with poor prognosis of synovial sarcoma. Thus, we conclude that CXCR4 is the marker of synovial sarcoma-initiating cells, a new biomarker for prognosis and a new potential therapeutic target. PMID- 26640148 TI - Cell type-dependent ROS and mitophagy response leads to apoptosis or necroptosis in neuroblastoma. AB - A limiting factor in the therapeutic outcome of children with high-risk neuroblastoma is the intrinsic and acquired resistance to common chemotherapeutic treatments. Here we investigated the molecular mechanisms by which the hemisynthetic cardiac glycoside UNBS1450 overcomes this limitation and induces differential cell death modalities in both neuroblastic and stromal neuroblastoma through stimulation of a cell-type-specific autophagic response eventually leading to apoptosis or necroptosis. In neuroblastic SH-SY5Y cells, we observed a time-dependent production of reactive oxygen species that affects lysosomal integrity inducing lysosome-associated membrane protein 2 degradation and cathepsin B and L activation. Subsequent mitochondrial membrane depolarization and accumulation of mitochondria in phagophores occurred after 8h of UNBS1450 treatment. Results were confirmed by mitochondrial mass analysis, electron microscopy and co-localization of mitochondria with GFP-LC3, suggesting the impaired clearance of damaged mitochondria. Thus, a stress-induced defective autophagic flux and the subsequent lack of clearance of damaged mitochondria sensitized SH-SY5Y cells to UNBS1450-induced apoptosis. Inhibition of autophagy with small inhibitory RNAs against ATG5, ATG7 and Beclin-1 protected SH-SY5Y cells against the cytotoxic effect of UNBS1450 by inhibiting apoptosis. In contrast, autophagy progression towards the catabolic state was observed in stromal SK-N-AS cells: here reactive oxygen species (ROS) generation remained undetectable preserving intact lysosomes and engulfing damaged mitochondria after UNBS1450 treatment. Moreover, autophagy inhibition determined sensitization of SK N-AS to apoptosis. We identified efficient mitophagy as the key mechanism leading to failure of activation of the apoptotic pathway that increased resistance of SK N-AS to UNBS1450, triggering rather necroptosis at higher doses. Altogether we characterize here the differential modulation of ROS and mitophagy as a main determinant of neuroblastoma resistance with potential relevance for personalized anticancer therapeutic approaches. PMID- 26640149 TI - Combined loss of PUMA and p21 accelerates c-MYC-driven lymphoma development considerably less than loss of one allele of p53. AB - The tumor suppressor p53 is mutated in ~50% of human cancers. P53 is activated by a range of stimuli and regulates several cellular processes, including apoptotic cell death, cell cycle arrest, senescence and DNA repair. P53 induces apoptosis via transcriptional induction of the BH3-only proteins PUMA (p53-upregulated modulator of apoptosis) and NOXA, and cell cycle arrest via p21. Induction of these processes was proposed to be critical for p53-mediated tumor suppression. It is therefore surprising that mice lacking PUMA, NOXA and p21, as well as mice bearing mutations in p53 that impair the transcriptional activation of these genes, are not tumor prone, unlike mice lacking p53 function, which spontaneously develop tumors with 100% incidence. These p53 target genes and the processes they regulate may, however, impact differently on tumor development depending on the oncogenic drivers. For example, loss of PUMA enhances c-MYC-driven lymphoma development in mice, but, interestingly, the acceleration was less impressive compared with that caused by the loss of even a single p53 allele. Different studies have reported that loss of p21 can accelerate, delay or have no impact on tumorigenesis. In an attempt to resolve this controversy, we examined whether loss of p21-mediated cell cycle arrest cooperates with PUMA deficiency in accelerating lymphoma development in EMU-Myc mice (overexpressing c-MYC in B lymphoid cells). We found that EMU-Myc mice lacking both p21 and PUMA (EMU Myc;Puma(-/-);p21(-/-)) developed lymphoma at a rate comparable to EMU-Myc;Puma( /-) animals, notably with considerably longer latency than EMU-Myc;p53(+/-)mice. Loss of p21 had no impact on the numbers, cycling or survival of pre-leukemic EMU Myc B-lymphoid cells, even when PUMA was lost concomitantly. These results demonstrate that even in the context of deregulated c-MYC expression, p53 must suppress tumor development by activating processes apart from, or in addition to, PUMA-mediated apoptosis and p21-induced cell cycle arrest. PMID- 26640150 TI - Gene amplification-associated overexpression of the RNA editing enzyme ADAR1 enhances human lung tumorigenesis. AB - The introduction of new therapies against particular genetic mutations in non small-cell lung cancer is a promising avenue for improving patient survival, but the target population is small. There is a need to discover new potential actionable genetic lesions, to which end, non-conventional cancer pathways, such as RNA editing, are worth exploring. Herein we show that the adenosine-to-inosine editing enzyme ADAR1 undergoes gene amplification in non-small cancer cell lines and primary tumors in association with higher levels of the corresponding mRNA and protein. From a growth and invasion standpoint, the depletion of ADAR1 expression in amplified cells reduces their tumorigenic potential in cell culture and mouse models, whereas its overexpression has the opposite effects. From a functional perspective, ADAR1 overexpression enhances the editing frequencies of target transcripts such as NEIL1 and miR-381. In the clinical setting, patients with early-stage lung cancer, but harboring ADAR1 gene amplification, have poor outcomes. Overall, our results indicate a role for ADAR1 as a lung cancer oncogene undergoing gene amplification-associated activation that affects downstream RNA editing patterns and patient prognosis. PMID- 26640152 TI - Heterozygous PALB2 c.1592delT mutation channels DNA double-strand break repair into error-prone pathways in breast cancer patients. AB - Hereditary heterozygous mutations in a variety of DNA double-strand break (DSB) repair genes have been associated with increased breast cancer risk. In the Finnish population, PALB2 (partner and localizer of BRCA2) represents a major susceptibility gene for female breast cancer, and so far, only one mutation has been described, c.1592delT, which leads to a sixfold increased disease risk. PALB2 is thought to participate in homologous recombination (HR). However, the effect of the Finnish founder mutation on DSB repair has not been investigated. In the current study, we used a panel of lymphoblastoid cell lines (LCLs) derived from seven heterozygous female PALB2 c.1592delT mutation carriers with variable health status and six wild-type matched controls. The results of our DSB repair analysis showed that the PALB2 mutation causes specific changes in pathway usage, namely increases in error-prone single-strand annealing (SSA) and microhomology mediated end-joining (MMEJ) compared with wild-type LCLs. These data indicated haploinsufficiency regarding the suppression of error-prone DSB repair in PALB2 mutation carriers. To the contrary, neither reduced HR activities, nor impaired RAD51 filament assembly, nor sensitization to PARP inhibition were consistently observed. Expression of truncated mutant versus wild-type PALB2 verified a causal role of PALB2 c.1592delT in the shift to error-prone repair. Discrimination between healthy and malignancy-presenting PALB2 mutation carriers revealed a pathway shift particularly in the breast cancer patients, suggesting interaction of PALB2 c.1592delT with additional genomic lesions. Interestingly, the studied PALB2 mutation was associated with 53BP1 accumulation in the healthy mutation carriers but not the patients, and 53BP1 was limiting for error-prone MMEJ in patients but not in healthy carriers. Our study identified a rise in error-prone DSB repair as a potential threat to genomic integrity in heterozygous PALB2 mutation carriers. The used phenotypic marker system has the capacity to capture dysfunction caused by polygenic mechanisms and therefore offers new strategies of cancer risk prediction. PMID- 26640153 TI - Twenty years of monitoring of persistent organic pollutants in Greenland biota. A review. AB - The Arctic Monitoring and Assessment Programme (AMAP) is a working group under the Arctic Council with the aim to monitor and assess temporal trends of contaminants in Arctic ecosystems. The Greenland AMAP Core programme was established to contribute to this effort. The Core programme includes three main components; routine monitoring, retrospective studies and new POP screening studies. The programme is based on an adaptive approach, which has led to changes throughout the years. An overview of the temporal trends during the last two to three decades is presently given together with selected examples of different characteristic trends of POPs. The results show how tissue banked samples and retrospective studies has helped in establishing time-series of compounds of emerging concern. Lastly, the statistical power of the Greenlandic time-series is discussed. The lesson learned is that trend monitoring improves with samples over time, and only pays off after decades of data are generated. PMID- 26640154 TI - The Effect of Adult Day Program Attendance on Emergency Room Registrations, Hospital Admissions, and Days in Hospital: A Propensity-Matching Study. AB - Purpose of the Study: This study is an investigation of the effect of adult day program attendance by home care clients 65 years of age and older on numbers and rates of emergency room registrations, hospital admissions, and days in hospital. Design and Methods: Each adult day program attendee was matched to a single unique nonattendee (n = 812) on the basis of similar propensity scores which had been estimated from 19 demographic, psychosocial, clinical, and functional covariates. Evaluation of the propensity-matching procedure indicated that balance had been achieved on the covariates. Results: Subsequent analyses revealed significantly lower mean 100-day rates of emergency room registrations, hospital admissions, and days in hospitals for attendees, compared to matched nonattendees. Although lower rates were largely attributable to longer stays in the home care program for attendees, attendees' mean number of days in hospital was still significantly lower compared to nonattendees. Implications: Findings replicate and extend results from previous research that reported a decreased reliance on costly health care services by seniors who attend adult day programs. PMID- 26640155 TI - Heterologous expression of newly identified galectin-8 from sea urchin embryos produces recombinant protein with lactose binding specificity and anti-adhesive activity. AB - Galectin family members specifically bind beta-galactoside derivatives and are involved in different cellular events, including cell communication, signalling, apoptosis, and immune responses. Here, we report a tandem-repeat type galectin from the Paracentrotus lividus sea urchin embryo, referred to as Pl-GAL-8. The 933nt sequence encodes a protein of 34.73 kDa, containing the conserved HFNPRF and WGxExR motifs in the two highly similar carbohydrate-recognition domains (CRD). The three-dimensional protein structure model of the N-CRD confirms the high evolutionary conservation of carbohydrate binding sites. The temporal gene expression is regulated during development and transcripts localize at the tip of the archenteron at gastrula stage, in a subset of the secondary mesenchyme cells that differentiate into blastocoelar (immune) cells. Functional studies using a recombinant Pl-GAL-8 expressed in bacteria demonstrate its hemo-agglutinating activity on human red blood cells through the binding to lactose, as well as its ability in inhibiting the adhesion of human Hep-G2 cells to the substrate. The recent implications in autoimmune diseases and inflammatory disorders make Gal-8 an attractive candidate for therapeutic purposes. Our results offer a solid basis for addressing the use of the new Pl-GAL-8 in functional and applicative studies, respectively in the developmental and biomedical fields. PMID- 26640156 TI - The Role of Non-suicidal Self-Injury and Binge-Eating/Purging Behaviours in the Caregiving Experience Among Mothers and Fathers of Adolescents with Eating Disorders. AB - This study investigated the caregiving experiences of mothers and fathers of restrictive and binge-eating/purging eating disordered (ED) inpatients with and without non-suicidal self-injury (NSSI). Sixty-five mothers and 65 fathers completed the Experience of Caregiving Inventory. All inpatients completed the Self-Injury Questionnaire-Treatment Related to assess NSSI and the Eating Disorder Evaluation Scale to assess eating disorder symptoms. Mothers reported significant more negative and more positive caregiving experiences compared with fathers. Mothers (but not fathers) of restrictive ED patients reported more positive caregiving experiences compared with mothers of binge-eating/purging patients. The presence of NSSI in ED patients was associated with more negative caregiving experiences of both parents. Mothers and fathers of ED inpatients differ in caregiving experiences, and both binge-eating behaviours and NSSI negatively affect their caregiving experience. Therefore, supportive interventions for parents of ED patients are necessary, especially of those patients who engage in NSSI. PMID- 26640157 TI - Biomechanical Effects of Prefabricated Foot Orthoses and Rocker-Sole Footwear in Individuals With First Metatarsophalangeal Joint Osteoarthritis. AB - OBJECTIVE: To evaluate the effects of prefabricated foot orthoses and rocker-sole footwear on spatiotemporal parameters, hip and knee kinematics, and plantar pressures in people with first metatarsophalangeal (MTP) joint osteoarthritis (OA). METHODS: A total of 102 people with first MTP joint OA were randomly allocated to receive prefabricated foot orthoses or rocker-sole footwear. The immediate biomechanical effects of the interventions (compared to usual footwear) were examined using a wearable sensor motion analysis system and an in-shoe plantar pressure measurement system. RESULTS: Spatiotemporal/kinematic and plantar pressure data were available from 88 and 87 participants, respectively. The orthoses had minimal effect on spatiotemporal or kinematic parameters, while the rocker-sole footwear resulted in reduced cadence, percentage of the gait cycle spent in stance phase, and sagittal plane hip range of motion. The orthoses increased peak pressure under the midfoot and lesser toes. Both interventions significantly reduced peak pressure under the first MTP joint, and the rocker sole shoes also reduced peak pressure under the second through fifth MTP joints and heel. When the effects of the orthoses and rocker-sole shoes were directly compared, there was no difference in peak pressure under the hallux, first MTP joint, or heel; however, the rocker-sole shoes exhibited lower peak pressure under the lesser toes, second through fifth MTP joints, and midfoot. CONCLUSION: Prefabricated foot orthoses and rocker-sole footwear are effective at reducing peak pressure under the first MTP joint in people with first MTP joint OA, but achieve this through different mechanisms. Further research is required to determine whether these biomechanical changes result in improvements in symptoms. PMID- 26640158 TI - Reply to the Letter to the Editor: "The need for differentiating between exercise, physical activity, and training." Budde et al. Autoimmun Rev (2015). PMID- 26640151 TI - Molecular mechanisms of target recognition by lipid GPCRs: relevance for cancer. AB - Over the past decade the importance of lipids for cancer cell metabolism and cancer-related processes such as proliferation, metastasis and chemotherapy resistance has become more apparent. The mechanisms by which lipid signals are transduced are poorly understood, but frequently involve G-protein Coupled Receptors (GPCRs), which can be explored as druggable targets. Here, we discuss how GPCRs recognize four classes of cancer-relevant lipids (lysophospholipids, phospholipids, fatty acids and eicosanoids). We compare the ligand-binding properties of >50 lipid receptors, we examine how their dysregulation contributes to tumorigenesis and how they may be therapeutically exploited. PMID- 26640159 TI - Survival and prognostic factors of systemic lupus erythematosus-associated pulmonary arterial hypertension: A PRISMA-compliant systematic review and meta analysis. AB - OBJECTIVE: This study aims to evaluate the survival of patients with systemic lupus erythematosus (SLE)-associated pulmonary arterial hypertension (PAH) by a systematic review and meta-analysis. METHODS: Studies were searched from MEDLINE (OVID), EMBASE, Cochrane Central Register of Controlled Trial and Scopus databases, and were selected according to the inclusion and exclusion criteria. Two independent reviewers extracted data from selected studies. Quality assessments were also performed using the Newcastle-Ottawa Scale. All pooled analyses were conducted both for random-effects model and fixed-effects model. Subgroup analysis and sensitivity analysis were conducted to investigate the origins of heterogeneity. Publication bias was evaluated using Begg's funnel plots and Egger's test. RESULTS: Six studies encompassing 323 patients with SLE associated PAH were included in the meta-analysis. The pooled 1-, 3- and 5-year survival rates were 88% (95% CI, 0.80-0.93), 81% (95% CI, 0.67-0.90) and 68% (95% CI, 0.52-0.80), respectively. No significant publication bias was shown. WHO Functional class (Fc) III/IV was found to be an independent prognostic factor of mortality. Higher mean pulmonary arterial pressure (mPAP), higher pulmonary vascular resistance (PVR), lower six minutes walking distance (6MWD), higher brain natriuretic peptide (BNP) and higher N-terminal proBNP (NT-proBNP) level were also related to poor survival. CONCLUSION: The long-term survival of patients with SLE-associated PAH is poor, which is worth paying greater clinical and academic attention. This study suggested that early diagnosis and management are recommended in patients with SLE-associated PAH for a better outcome of survival. PMID- 26640160 TI - Behcet disease presenting with movement disorders and antibasal ganglia antibodies. PMID- 26640161 TI - Comment on "Tibor Ganti and Robert Rosen" by Athel Cornish-Bowden. PMID- 26640163 TI - Increasing the vocalizations of individuals with autism during intervention with a speech-generating device. AB - This study aimed to teach individuals with autism spectrum disorder (ASD) and limited vocal speech to emit target vocalizations while using a speech-generating device (SGD). Of the 4 participants, 3 began emitting vocal word approximations with SGD responses after vocal instructional methods (delays, differential reinforcement, prompting) were introduced. Two participants met mastery criterion with a reinforcer delay and differential reinforcement, and 1 met criterion after fading an echoic model and prompt delay. For these participants, vocalizations initiated before speech outputs were shown to increase, and vocalizations generalized to a context in which the SGD was absent. The 4th participant showed high vocalization rates only when prompted. The results suggest that adding vocal instruction to an SGD-based intervention can increase vocalizations emitted along with SGD responses for some individuals with ASD. PMID- 26640162 TI - Exploring the automaticity of language-perception interactions: Effects of attention and awareness. AB - Previous studies have shown that language can modulate visual perception, by biasing and/or enhancing perceptual performance. However, it is still debated where in the brain visual and linguistic information are integrated, and whether the effects of language on perception are automatic and persist even in the absence of awareness of the linguistic material. Here, we aimed to explore the automaticity of language-perception interactions and the neural loci of these interactions in an fMRI study. Participants engaged in a visual motion discrimination task (upward or downward moving dots). Before each trial, a word prime was briefly presented that implied upward or downward motion (e.g., "rise", "fall"). These word primes strongly influenced behavior: congruent motion words sped up reaction times and improved performance relative to incongruent motion words. Neural congruency effects were only observed in the left middle temporal gyrus, showing higher activity for congruent compared to incongruent conditions. This suggests that higher-level conceptual areas rather than sensory areas are the locus of language-perception interactions. When motion words were rendered unaware by means of masking, they still affected visual motion perception, suggesting that language-perception interactions may rely on automatic feed forward integration of perceptual and semantic material in language areas of the brain. PMID- 26640165 TI - Placenta Mesenchymal Stem Cell Derived Exosomes Confer Plasticity on Fibroblasts. AB - Mesenchymal stem cell (MSC)-conditioned medium (MSC-CM) has been reported to enhance wound healing. Exosomes contain nucleic acids, proteins, and lipids, and function as an intercellular communication vehicle for mediating some paracrine effects. However, the function of MSC-derived exosomes (MSC-exo) remains elusive. In this study, we isolated human placenta MSC (PlaMSC)-derived exosomes (PlaMSC exo) and examined their function in vitro. PlaMSCs were isolated from human term placenta using enzymatic digestion. PlaMSC-exo were prepared from the conditioned medium of PlaMSC (PlaMSC-CM) by ultracentrifugation. The expression of stemness related genes, such as OCT4 and NANOG, in normal adult human dermal fibroblasts (NHDF) after incubation with PlaMSC-exo was measured by real-time reverse transcriptase PCR analysis (real-time PCR). The effect of PlaMSC-exo on OCT4 transcription activity was assessed using Oct4-EGFP reporter mice-derived dermal fibroblasts. The stimulating effects of PlaMSC-exo on osteoblastic and adipocyte differentiation of NHDF were evaluated by alkaline phosphatase (ALP), and Alizarin red S- and oil red O-staining, respectively. The expression of osteoblast- and adipocyte-related genes was also assessed by real-time PCR. The treatment of NHDF with PlaMSC-exo significantly upregulated OCT4 and NANOG mRNA expression. PlaMSC-exo also enhanced OCT4 transcription. The NHDF treated with PlaMSC-exo exhibited osteoblastic and adipocyte-differentiation in osteogenic and adipogenic induction media. PlaMSC-exo increase the expression of OCT4 and NANOG mRNA in fibroblasts. As a result, PlaMSC-exo influence the differentiation competence of fibroblasts to both osteoblastic and adipocyte-differentiation. It shows a new feature of MSCs and the possibility of clinical application of MSC exo. J. Cell. Biochem. 117: 1658-1670, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26640164 TI - Bicyclol attenuates tetracycline-induced fatty liver associated with inhibition of hepatic ER stress and apoptosis in mice. AB - Endoplasmic reticulum (ER) stress is known to be involved in the development of several metabolic disorders, including non-alcoholic fatty liver disease (NAFLD). Tetracycline can cause hepatic steatosis, and ER stress may be involved in tetracycline-induced fatty liver. Our previous study showed that bicyclol has been proven to protect against tetracycline-induced fatty liver in mice, and ER stress may also be involved in bicyclol's hepatoprotective effect. Therefore, this study was performed to investigate the underlying mechanisms associated with ER stress and apoptosis, by which bicyclol attenuated tetracycline-induced fatty liver in mice. Bicyclol (300 mg/kg) was given to mice by gavage 3 times. Tetracycline (200 mg/kg, intraperitoneally) was injected at 1 h after the last dose of bicyclol. At 6 h and 24 h after single dose of tetracycline injection, serum ALT, AST, TG, CHO and hepatic histopathological examinations were performed to evaluate liver injuries. Hepatic steatosis was assessed by the accumulation of hepatic TG and CHO. Moreover, hepatic apoptosis and ER stress related markers were determined by TUNEL, real-time PCR, and western blot. As a result, bicyclol significantly protected against tetracycline-induced fatty liver as evidenced by the decrease of elevated serum transaminases and hepatic triglyceride, and the attenuation of histopathological changes in mice. In addition, bicyclol remarkably alleviated hepatic apoptosis and the gene expression of caspase-3, and increased the gene expression of XIAP. The gene expressions of ER stress-related markers, including CHOP, GRP78, IRE-1alpha, and ATF6, which were downregulated by bicyclol pretreatment in tetracycline-injected mice. These results suggested that bicyclol protected tetracycline-induced fatty liver partly due to its ability of anti-apoptosis associated with ER stress. PMID- 26640166 TI - Future directions in preterm birth research. AB - The problem of preterm birth continues to pose one of the most significant research challenges that we face due to its immense scope and complexity. With evidence that 95% of cases of spontaneous preterm birth are intractable to current interventions, our best hope in resolving this problem may lie in new, innovative ideas. Novel approaches to researching preterm birth are currently underway, building upon our prior discoveries and probing into the unknown on multiple fronts. Here we discuss some of the major focuses of future investigation that provide a promising outlook for discovery, including advanced techniques to evaluate the cervix, new strategies to identify the role of the microbiome, and advances in molecular and epigenetic-based research. PMID- 26640167 TI - Connecting the brain of the child from synapses to screen-based activity. AB - The connectome of the brain is constructed during foetal life by neurogenesis, arborisation of the neurons and synaptogenesis. The optimal neuronal connections are selected by endogenous spontaneous neuronal activity and sensory input from the external world, particularly after birth. The development of the social brain depends on interaction, particularly with the parents. Infants start to imitate adults from birth and soon learn to recognise faces. They also absorb phonemes like magnets, particularly if they are sitting on their mother's lap and she is speaking motherese. External coupling of the brain to TV, DVDs, iPads and smartphones cannot replace this direct multisensory interaction and does not seem to have the same advantageous effects for children under two years of age that it may have for older children. PMID- 26640168 TI - A High Efficiency Nonfullerene Organic Solar Cell with Optimized Crystalline Organizations. AB - A well-organized donor-acceptor crystalline structure is examined for high performance nonfullerene solar cells. By thermal annealing, nanoscale structures of both donor and acceptor domains are successfully modulated, followed by significant changes in the resulting -photovoltaic characteristics. When annealed at 90 degrees C, a maximum power conversion efficiency of 7.64% with a remarkable open-circuit voltage of 1.03 V is obtained. PMID- 26640169 TI - Effects of cocaine history on postsynaptic GABA receptors on dorsal raphe serotonin neurons in a stress-induced relapse model in rats. AB - The serotonin (5-hydroxytryptamine, 5-HT) system plays an important role in stress-related psychiatric disorders and substance abuse. Stressors and stress hormones can inhibit the dorsal raphe nucleus (DRN)-5-HT system, which composes the majority of forebrain-projecting 5-HT. This inhibition is mediated via stimulation of GABA synaptic activity at DRN-5-HT neurons. Using swim stress induced reinstatement of morphine conditioned place-preference, recent data from our laboratory indicate that morphine history sensitizes DRN-5-HT neurons to GABAergic inhibitory effects of stress. Moreover, GABAA receptor-mediated inhibition of the serotonergic DRN is required for this reinstatement. In our current experiment, we tested the hypothesis that GABAergic sensitization of DRN 5-HT neurons is a neuroadaptation elicited by multiple classes of abused drugs across multiple models of stress-induced relapse by applying a chemical stressor (yohimbine) to induce reinstatement of previously extinguished cocaine self administration in Sprague-Dawley rats. Whole-cell patch-clamp recordings of GABA synaptic activity in DRN-5-HT neurons were conducted after the reinstatement. Behavioral data indicate that yohimbine triggered reinstatement of cocaine self administration. Electrophysiology data indicate that 5-HT neurons in the cocaine group exposed to yohimbine had increased amplitude of inhibitory postsynaptic currents compared to yoked-saline controls exposed to yohimbine or unstressed animals in both drug groups. These data, together with previous findings, indicate that interaction between psychostimulant or opioid history and chemical or physical stressors may increase postsynaptic GABA receptor density and/or sensitivity in DRN-5-HT neurons. Such mechanisms may result in serotonergic hypofunction and consequent dysphoric mood states which confer vulnerability to stress-induced drug reinstatement. PMID- 26640171 TI - The need for practical input data for modeling odor nuisance effects due to a municipal solid waste landfill in the surrounding environment. PMID- 26640172 TI - The effect of temperature on organic carbon degradation in marine sediments. AB - The degradation of sedimentary particulate organic carbon (POC) is a key carbon cycle process that fuels the deep subseafloor biosphere. The reactivity of POC is expected to decrease with increasing sediment age, severely restricting the energy available to microorganisms. Conversely, increasing temperatures during burial have been proposed to stimulate POC degradation, possibly supplying significant energy to the deep biosphere. To test the importance of temperature, we assembled POC measurements in two global sets of drill sites where sediments underwent either relatively low or high temperatures during burial, which should have resulted in different rates of POC degradation. For ages 5-10 Ma, the decrease of the average POC content with burial is clearly more pronounced in the sites with high temperature histories. Our results support the hypothesis that temperature is one of the fundamental controls on the rate of POC degradation within deeply buried marine sediments. PMID- 26640170 TI - Stanniocalcin-1 inhibits thrombin-induced signaling and protects from bleomycin induced lung injury. AB - Thrombin-induced and proteinase-activated receptor 1 (PAR1)-mediated signaling increases ROS production, activates ERK, and promotes inflammation and fibroblast proliferation in bleomycin-induced lung injury. Stanniocalcin-1 (STC1) activates anti-oxidant pathways, inhibits inflammation and provides cytoprotection; hence, we hypothesized that STC1 will inhibit thrombin/PAR1 signaling and protect from bleomycin-induced pneumonitis. We determined thrombin level and activity, thrombin-induced PAR-1-mediated signaling, superoxide generation and lung pathology after intra-tracheal administration of bleomycin to WT and STC1 Tg mice. Lungs of bleomycin-treated WT mice display: severe pneumonitis; increased generation of superoxide; vascular leak; increased thrombin protein abundance and activity; activation of ERK; greater cytokine/chemokine release and infiltration with T-cells and macrophages. Lungs of STC1 Tg mice displayed none of the above changes. Mechanistic analysis in cultured pulmonary epithelial cells (A549) suggests that STC1 inhibits thrombin-induced and PAR1-mediated ERK activation through suppression of superoxide. In conclusion, STC1 blunts bleomycin-induced rise in thrombin protein and activity, diminishes thrombin-induced signaling through PAR1 to ERK, and inhibits bleomycin-induced pneumonitis. Moreover, our study identifies a new set of cytokines/chemokines, which play a role in the pathogenesis of bleomycin-induced lung injury. These findings broaden the array of potential therapeutic targets for the treatment of lung diseases characterized by thrombin activation, oxidant stress and inflammation. PMID- 26640173 TI - A Water-Soluble Copper-Polypyridine Complex as a Homogeneous Catalyst for both Photo-Induced and Electrocatalytic O2 Evolution. AB - The water-soluble polypyridine copper complex [Cu(F3TPA)(ClO4)2] [1; F3TPA=tris(2 fluoro-6-pyridylmethyl)amine] catalyzes water oxidation in a pH 8.5 borate buffer at a relatively low overpotential of 610 mV. Assisted by photosensitizer and an electron acceptor, 1 also exhibits activity as a homogeneous catalyst for photo induced O2 evolution with a maximum turnover frequency (TOF) of (1.58 +/- 0.03) * 10(-1) s(-1) and a maximum turnover number (TON) of 11.61 +/- 0.23. In comparison, the reference [Cu(TPA)(ClO4)2] [TPA=tris(2-pyridylmethyl)amine] displayed almost no activity under either set of conditions, implying the crucial role of the ligand in determining the behavior of the catalyst. Experimental evidence indicate the molecular catalytic nature of 1, leading to a potentially practical strategy to apply the copper complex in a photoelectrochemical device for water oxidation. PMID- 26640174 TI - Development of an Amino Acid-Functionalized Fluorescent Nanocarrier to Deliver a Toxin to Kill Insect Pests. AB - Large-scale cultivation of Bacillus thuringiensis Berliner (Bt) crops has led to the rapid development of drug resistance. Herein, a fluorescent star poly(amino acid) is synthesized with l-isoleucine functionalization for the efficient delivery of either positively or negatively charged exogenous proteins into live cells. Poly(amino acid)s (P1)/Cry1Ab complexes greatly increase the cytotoxicity of the Bt toxin, Cry1Ab, and efficiently kill Bt-resistant pests. PMID- 26640198 TI - In-Vitro Study of the Contamination Remaining on Used Healing Abutments after Cleaning and Sterilizing in Dental Practice. AB - BACKGROUND: Reuse or "recycle" of dental implant healing abutments in clinical practice is common, primarily for economic rational. PURPOSE: To determine of this practice results in reuse of components that carry with them some degree of contamination between patients, even following thorough cleaning and sterilization. MATERIALS AND METHODS: One hundred healing abutments were collected from eight clinicians following patient use. The abutments were cleaned, sterilized, and then collected. The samples were treated with a protein specific stain (Phloxine B), and photographed. RESULTS: Ninety-nine percent of the abutments showed protein contamination at one or more sites following cleaning and sterilization. CONCLUSION: Reuse of healing abutments between patients should be reevaluated in light of this data. PMID- 26640223 TI - Tenofovir alafenamide: A novel prodrug of tenofovir for the treatment of Human Immunodeficiency Virus. AB - Despite substantial progress in the development of antiretroviral regimens that durably suppress Human Immunodeficiency Virus (HIV) infection, new agents that maintain high efficacy while further optimizing the safety of lifelong, chronic therapy are needed. Tenofovir alafenamide (TAF; formerly known as GS-7340) is a novel prodrug of the antiviral acyclic nucleoside phosphonate tenofovir (TFV) with improved properties relative to tenofovir disoproxil fumarate (TDF). Although potent and generally well tolerated, TDF therapy has been associated with changes in markers of renal function, decreases in bone mineral density and a rare occurrence of serious renal adverse events, including Fanconi's Syndrome. The renal and bone toxicity observed with TDF is associated with high circulating plasma levels of TFV. TAF was discovered to be a more efficient prodrug able to further refine HIV therapy and better address life-long therapy in an older and increasingly comorbid HIV infected population. By enhancing stability in biological matrices while being rapidly activated in cells, TAF produces higher levels of intracellular TFV diphosphate, the pharmacologically active metabolite, in HIV-target cells at substantially reduced oral doses of TFV equivalents. All TFV released in the body is eventually eliminated renally; therefore, lowering the TFV equivalents administered reduces off-target kidney exposure. Effective therapy is thus achieved at approximately 90% lower systemic exposure to TFV, translating to statistically and clinically significant improvement in safety parameters associated with bone mineral density and markers of renal function. PMID- 26640224 TI - Synergistic effects by combination of ganciclovir and tricin on human cytomegalovirus replication in vitro. AB - It has been demonstrated as the first report that combination treatment with ganciclovir (GCV) and tricin (4',5,7-trihydroxy-3',5' -dimethoxyflavone), a derivative of Sasa albo-marginata, after human cytomegalovirus (HCMV) infection has synergistic effects on both infectious virus production and HCMV DNA synthesis in the human embryonic fibroblast cell line MRC-5. In this paper, we examined the anti-HCMV effects of GCV plus various concentrations of tricin, and tricin plus various concentrations of GCV in MRC-5 cells. We found that expression of the HCMV UL54 gene was significantly inhibited by combination of GCV with tricin when compared with GCV mono-treatment. These results suggest that tricin is a novel compound for combination therapy with GCV against HCMV replication. In addition, reduced-dose combination therapy may provide a direction for treatment in patients with HCMV infection while reducing drug toxicity. PMID- 26640225 TI - Preparedness for physiotherapy in private practice: Novices identify key factors in an interpretive description study. AB - BACKGROUND: Physiotherapists in Australia deliver services to a diverse range of clients, across many settings, however little research exists examining graduate preparedness for practice, even in the populous field of private practice. OBJECTIVES: To explore novice physiotherapist perspectives on preparedness for work in private practice. DESIGN: The qualitative approach of interpretive description was used to guide in-depth interviews with 8 novice physiotherapists from 3 universities working in 5 private practices in Melbourne. METHODS: All interviews were digitally recorded, transcribed verbatim and analyzed thematically. FINDINGS: Four main themes influencing graduate preparedness for work in private practice were identified: 1) non-curricular experiences (e.g. sports training) 2) elective curricular: practicum experiences; 3) curricular: attainment of skills specific to private practice; and 4) the private practice setting: supportive colleagues. This combination of non-curricular, curricular, and practice setting factors offered the necessary scaffolding for the graduates to report feeling prepared for work in private practice. CONCLUSIONS: Non curricular activities, radiological instruction, clinical placements, building supportive colleague relations and professional development in private practice are recommended as potential means of building preparedness in novice therapists. Findings have implications for physiotherapy students, educators and private practice clinics looking to recruit new graduates. PMID- 26640226 TI - Calreticulin mRNA expression and clinicopathological characteristics in acute myeloid leukemia. AB - Calreticulin, encoded by CALR, is a multifunctional protein with roles in calcium homeostasis and chaperoning molecular processes. This study aimed to evaluate calreticulin mRNA expression levels in acute myeloid leukemia (AML) compared with other hematologic malignancies, and to investigate the clinicopathological characteristics associated with expression in AML patients. The study group included 43 patients diagnosed with AML, 57 with other hematologic malignancies, and 21 benign hematologic conditions. CALR mRNA quantification using real-time polymerase chain reaction revealed it to be significantly higher in AML compared with other hematologic malignancies (P < 0.0001). There was no difference in CALR mRNA expression between AML subgroups by karyotype (P = 0.3201). No differences were found in age, white blood cell counts, platelet counts, bone marrow blast percentage, calcium, lactate dehydrogenase or CD34 expression rate between the high and low CALR groups (CALR mRNA >= 1.2 fold and <1.2 fold, respectively), although hemoglobin and sex differences were observed. Although statistically not significant, there was a trend that Relapse rate was lower (54.5% vs. 84.6%) (P = 0.1063) and disease-free survival was longer (22 months vs. 7 months) (P = 0.0784) in low CALR group, whereas overall survival was similar between the two groups (11 months and 8 months). The clinical relevance of CALR expression in AML remains to be clarified in a larger cohort. PMID- 26640227 TI - Report of two novel mutations in PTHLH associated with brachydactyly type E and literature review. AB - Autosomal-dominant brachydactyly type E is a congenital limb malformation characterized by small hands and feet as a result of shortened metacarpals and metatarsals. Alterations that predict haploinsufficiency of PTHLH, the gene coding for parathyroid hormone related protein (PTHrP), have been identified as a cause of this disorder in seven families. Here, we report three patients affected with brachydactyly type E, caused by PTHLH mutations expected to result in haploinsufficiency, and discuss our data compared to published reports. PMID- 26640228 TI - Peripheral leukocyte profile in people with temporal lobe epilepsy reflects the associated proinflammatory state. AB - INTRODUCTION: Markers of low-grade peripheral inflammation have been reported amongst people with epilepsy. The mechanisms underlying this phenomenon are unknown. We attempted to characterize peripheral immune cells and their activation status in people with temporal lobe epilepsy (TLE) and healthy controls. METHODS AND RESULTS: Twenty people with TLE and 19 controls were recruited, and peripheral blood lymphocyte and monocyte subsets evaluated ex vivo by multi-color flow cytometry. People with TLE had higher expression of HLA-DR, CD69, CTLA-4, CD25, IL-23R, IFN-gamma, TNF and IL-17 in CD4(+) lymphocytes than controls. Granzyme A, CTLA-4, IL-23R and IL-17 expression was also elevated in CD8(+) T cells from people with TLE. Frequency of HLA-DR in CD19(+) B cells and regulatory T cells CD4(+)CD25(+)Foxp3(+) producing IL-10 was higher in TLE when compared with controls. A negative correlation between CD4(+) expressing co stimulatory molecules (CD69, CD25 and CTLA-4) with age at onset of seizures was found. The frequency of CD4(+)CD25(+)Foxp3(+) cells was also positively correlated with age at onset of seizures. CONCLUSION: Immune cells of people with TLE show an activation profile, mainly in effector T cells, in line with the low grade peripheral inflammation. PMID- 26640229 TI - Making sense of plant autoimmunity and 'negative regulators'. AB - Genetics studies the structure/function of genes via the characterization of their mutant phenotypes. In plants, a readily scorable mutant phenotype comprises macroscopic lesions symptomatic of disease in the absence of pathogens. Such mutants therefore exhibit autoimmune phenotypes. Many of these mutants are considered to be associated with immunity and the corresponding genes have been described as 'negative regulators' of immunity and/or cell death. Pathogens deliver effectors into host cells to increase infectivity by modifying or removing host proteins. Plants detect effectors via nucleotide-binding, leucine rich repeat (NLR) immune receptors, which monitor host effector targets. In response to effector-mediated target tampering, NLR proteins potentiate immunity. The guard hypothesis proposes that NLRs 'guard' host 'guardees' targeted by pathogen effectors. An obvious corollary to this guard model is that forms of plant autoimmunity are a result of inappropriate NLR protein activation. In this review, we discuss what is known about some of the 'negative regulators' of immunity, and propose simple strategies that may help to characterize autoimmune mutants. PMID- 26640230 TI - HUR mRNA expression in ovarian high-grade serous carcinoma effusions is associated with poor survival. AB - The objective of this study was to analyze the expression and clinical role of the RNA-binding molecule HuR in metastatic high-grade ovarian serous carcinoma (HGSC). HUR mRNA expression by reverse-transcription polymerase chain reaction was analyzed in 66 effusions from patients diagnosed with HGSC. Protein expression was analyzed in 262 HGSC effusions using immunohistochemistry. HUR mRNA was detected in all 66 effusions. HUR mRNA levels were unrelated to clinicopathological parameters. However, higher HUR mRNA levels were significantly related to poor overall survival in the entire cohort (P=.023), as well as in analysis limited to patients with prechemotherapy primary diagnosis specimens (P=.001) in univariate analysis. Cox multivariate analysis showed an independent prognostic role for HUR mRNA in the entire cohort (P=.033) and in patients with prechemotherapy primary diagnosis specimens (P=.002). HuR protein was detected in the nucleus and cytoplasm of tumor cells in 258 (98%) of 262 and 153 (58%) of 262 effusions, respectively. Higher HuR protein expression was associated with higher serum Cancer Antigen (CA) 125 levels at diagnosis (P=.01), but its presence at both cellular compartments was otherwise unrelated to clinicopathological parameters or survival. In conclusion, HuR is widely expressed in metastatic HGSC at both the mRNA and protein level. Higher HUR mRNA levels are associated with poor survival in metastatic HGSC, whereas protein expression has no prognostic value. PMID- 26640231 TI - Search for regulatory factors of the pituitary-specific transcription factor PROP1 gene. AB - Pituitary-specific transcription factor PROP1, a factor important for pituitary organogenesis, appears on rat embryonic day 11.5 (E11.5) in SOX2-expressing stem/progenitor cells and always coexists with SOX2 throughout life. PROP1 positive cells at one point occupy all cells in Rathke's pouch, followed by a rapid decrease in their number. Their regulatory factors, except for RBP-J, have not yet been clarified. This study aimed to use the 3 kb upstream region and 1st intron of mouse prop1 to pinpoint a group of factors selected on the basis of expression in the early pituitary gland for expression of Prop1. Reporter assays for SOX2 and RBP-J showed that the stem/progenitor marker SOX2 has cell type dependent inhibitory and activating functions through the proximal and distal upstream regions of Prop1, respectively, while RBP-J had small regulatory activity in some cell lines. Reporter assays for another 39 factors using the 3 kb upstream regions in CHO cells ultimately revealed that 8 factors, MSX2, PAX6, PIT1, PITX1, PITX2, RPF1, SOX8 and SOX11, but not RBP-J, regulate Prop1 expression. Furthermore, a synergy effect with SOX2 was observed for an additional 10 factors, FOXJ1, HES1, HEY1, HEY2, KLF6, MSX1, RUNX1, TEAD2, YBX2 and ZFP36Ll, which did not show substantial independent action. Thus, we demonstrated 19 candidates, including SOX2, to be regulatory factors of Prop1 expression. PMID- 26640232 TI - Regulator of G-protein signaling 4: A novel tumor suppressor with prognostic significance in non-small cell lung cancer. AB - Regulator of G-protein signaling (RGS) family members are regulatory molecules which act as GTPase activating proteins (GAPs) for G alpha subunits of heterotrimeric G proteins. Emerging data indicated that RGS members were involved with tumorigenesis and metastasis. In the current study, we identified RGS4 as a novel tumor suppressor with prognostic significance in non-small cell lung cancer (NSCLC). To be specific, we found that RGS4 expression was higher in normal lung tissues than NSCLC specimens (P = 0.003). Further studies demonstrated that RGS4 was generally down-regulated in NSCLC specimens compared with the matched normal lung tissues, both at mRNA and protein levels. In addition, correlational analysis indicated that RGS4 expression levels negatively correlated with lymph node metastasis (P = 0.009) and TNM stage (P = 0.008). Survival analysis demonstrated that patients with lower RGS4 protein expression exhibited a much worse 5-year overall survival and 5-year disease-free survival than those with high expression. More importantly, we proved that over-expression of RGS4 in NSCLC cells decreased invasion and migration due to inhibition of MMP2/9 and reversal of EMT while down-regulation of RGS4 in normal lung cell lines promoted invasion and migration. At last, nude mice metastatic model proved that over expression of RGS4 suppressed tumor metastasis in vivo. All of these results confirmed the critical role of RGS4 in NSCLC progression. PMID- 26640233 TI - Regional incidence and outcome of out-of-hospital cardiac arrest associated with overdose. AB - BACKGROUND: The frequency of lethal overdose due to prescription and non prescription drugs is increasing in North America. The aim of this study was to estimate overall and regional variation in incidence and outcomes of out-of hospital cardiac arrest due to overdose across North America. METHODS: We conducted a retrospective cohort study using case data for the period 2006-2010 from the Resuscitation Outcomes Consortium, a clinical research network with 10 regional clinical centers in United States and Canada. Cases of out-of-hospital cardiac arrest due to drug overdose were identified through review of data derived from prehospital clinical records. We calculated incidence of out-of hospital cardiac arrest due to overdose per 100,000 person-years and proportion of the same among all out-of-hospital cardiac arrests. We analyzed the association between overdose cardiac arrest etiology and resuscitation outcomes. RESULTS: Included were 56,272 cases, of which 1351 were due to overdose. Regional incidence of out-of-hospital cardiac arrest due to overdose varied between 0.5 and 2.7 per 100,000 person years (p<0.001), and proportion of the same among all treated out-of-hospital cardiac arrests ranged from 0.8% to 4.0%. Overdose cases were younger, less likely to be witnessed, and less likely to present with a shockable rhythm. Compared to non-overdose, overdose was directly associated with return of spontaneous circulation (OR: 1.55; 95% CI: 1.35-1.78) and survival (OR: 2.14; 95% CI: 1.72-2.65). CONCLUSIONS: Overdose made up 2.4% of all out-of hospital cardiac arrest, although incidence varied up to 5-fold across regions. Overdose cases were more likely to survive than non-overdose cases. PMID- 26640234 TI - Determination of (222)Rn absorption properties of polycarbonate foils by liquid scintillation counting. Application to (222)Rn measurements. AB - This work demonstrates that a Liquid Scintillation Counting (LSC) technique using a Triple to Double Coincidence Ratio counter with extending dead-time is very appropriate for the accurate measurement of (222)Rn activity absorbed in thin polycarbonate foils. It is demonstrated that using a toluene-based LS cocktail, which dissolves polycarbonates, the (222)Rn activity absorbed in thin Makrofol N foil can be determined with a relative standard uncertainty of about 0.7%. A LSC based application of the methodology for determination of the diffusion length of (222)Rn in thin polycarbonate foils is proposed and the diffusion length of (222)Rn in Makrofol N (38.9+/-1.3um) and the partition coefficient of (222)Rn in Makrofol N from air (112+/-12, at 20 degrees C) and from water (272+/-17, at 21 degrees C) are determined. Calibration of commercial LS spectrometers for (222)Rn measurements by LSC of thin polycarbonate foils is performed and the minimum detectable activities by this technique are estimated. PMID- 26640235 TI - Measurement of the (109)Cd half-life. AB - A new determination of the (109)Cd half-life was made by a time series of measurements of an aqueous sample using a re-entrant type ionisation chamber. The measurement campaign covered a period of 6 years or approximately 4.7 half-lives of (109)Cd. The resulting value of 462.1 (3) days is in good agreement with the recently published values of 462.29 (30) days and 462.3 (8) days. This new half life determination will allow evaluators to specify a recommended value of the (109)Cd half-life making it more accurate and precise. PMID- 26640236 TI - Metrological tests of a 200 L calibration source for HPGE detector systems for assay of radioactive waste drums. AB - In this work we present test procedures, approval criteria and results from two metrological inspections of a certified large volume (152)Eu source (drum about 200L) intended for calibration of HPGe gamma assay systems used for activity measurement of radioactive waste drums. The aim of the inspections was to prove the stability of the calibration source during its working life. The large volume source was designed and produced in 2007. It consists of 448 identical sealed radioactive sources (modules) apportioned in 32 transparent plastic tubes which were placed in a wooden matrix which filled the drum. During the inspections the modules were subjected to tests for verification of their certified characteristics. The results show a perfect compliance with the NIST basic guidelines for the properties of a radioactive certified reference material (CRM) and demonstrate the stability of the large volume CRM-drum after 7 years of operation. PMID- 26640237 TI - Vaspin prevents elevation of blood pressure through inhibition of peripheral vascular remodelling in spontaneously hypertensive rats. AB - AIM: Visceral adipose tissue-derived serine protease inhibitor (vaspin) is a relatively novel adipocytokine with protective effects on metabolic diseases including obesity and type II diabetes. We have previously demonstrated that vaspin exerts anti-inflammatory and antimigratory roles through antioxidative effects in vascular smooth muscle cells. As inflammatory responses and migration of smooth muscle in peripheral vascular wall are key mechanisms for the pathogenesis of hypertension, we hypothesized that vaspin could prevent the development of hypertension in in vivo hypertensive animal model. METHODS: Vaspin (1 MUg kg(-1) day(-1) ) was administered intraperitoneally to 5-week-old male spontaneously hypertensive rats (SHR) for 4 weeks. Superior mesenteric artery was isolated and used for measurement of isometric contraction and histological analysis. RESULTS: Long-term vaspin treatment significantly prevented an elevation of systolic blood pressure (SBP) at 8 weeks of age. Vaspin had no effect on reactivity of isolated mesenteric artery from SHR. In contrast, vaspin significantly inhibited mesenteric arterial wall hypertrophy in SHR. Moreover, vaspin significantly inhibited an increase of tumour necrosis factor-alpha expression and a production of reactive oxygen species in isolated mesenteric artery from SHR. CONCLUSION: This study for the first time demonstrates that vaspin prevents the increase of SBP in SHR through inhibiting peripheral vascular hypertrophy possibly via antioxidative and anti-inflammatory mechanisms. PMID- 26640239 TI - Piperine impairs the migration and T cell-activating function of dendritic cells. AB - Piperine, a major alkaloid found in the fruits of black and long pepper plants, has anti-inflammatory properties; however, piperine's effect on dendritic cell (DC) migration and T cell-activating function has not been investigated. Bone marrow-derived mouse DCs that were matured in the presence of 100 MUM piperine showed reduced in vitro migration in response to CCL21, as well as reduced in vivo migration to lymph nodes. In addition, piperine-treated DCs had reduced CCR7 expression and elevated CCR5 expression, as well as reduced expression of CD40 and class II major histocompatibility complex molecules and decreased nuclear accumulation of RelB. DC production of interleukin (IL)-6, tumor necrosis factor alpha, and monocyte chemoattractant protein-1 in response to lipopolysaccharide stimulation was also reduced following piperine treatment. Exposure to piperine during maturation therefore caused DCs to retain an immature phenotype, which was associated with a reduced capacity to promote T cell activation since co-culture of ovalbumin (OVA323-339)-specific T cells with OVA323-339-pulsed DCs that were previously matured in the presence of piperine showed reduced interferon-gamma and IL-2 expression. OVA323-339-specific T cell proliferation was also reduced in vivo in the presence of piperine-treated DCs. Inhibition of DC migration and function by piperine may therefore be a useful strategy to down-regulate potentially harmful DC-driven T cell responses to self-antigens and transplantation antigens. PMID- 26640238 TI - Role of glutamate receptors in tetrabrominated diphenyl ether (BDE-47) neurotoxicity in mouse cerebellar granule neurons. AB - The polybrominated diphenyl ether (PBDE) flame retardants are developmental neurotoxicants, as evidenced by numerous in vitro, animal and human studies. PBDEs can alter the homeostasis of thyroid hormone and directly interact with brain cells. Induction of oxidative stress, leading to DNA damage and apoptotic cell death is a prominent mechanism of PBDE neurotoxicity, though other mechanisms have also been suggested. In the present study we investigated the potential role played by glutamate receptors in the in vitro neurotoxicity of the tetrabromodiphenyl ether BDE-47, one of the most abundant PBDE congeners. Toxicity of BDE-47 in mouse cerebellar neurons was diminished by antagonists of glutamate ionotropic receptors, but not by antagonists of glutamate metabotropic receptors. Antagonists of NMDA and AMPA/Kainate receptors also inhibited BDE-47 induced oxidative stress and increases in intracellular calcium. The calcium chelator BAPTA-AM also inhibited BDE-47 cytotoxicity and oxidative stress. BDE-47 caused a rapid increase of extracellular glutamate levels, which was not antagonized by any of the compounds tested. The results suggest that BDE-47, by still unknown mechanisms, increases extracellular glutamate which in turn activates ionotropic glutamate receptors leading to increased calcium levels, oxidative stress, and ultimately cell death. PMID- 26640240 TI - Exendin-4 reduces tau hyperphosphorylation in type 2 diabetic rats via increasing brain insulin level. AB - Type 2 diabetes (T2D) is a high risk factor for Alzheimer's disease (AD). Our previous study identified that hyperphosphorylation of tau protein, which is one of the pathophysiologic hallmarks of AD, also occurred in T2D rats' brain; while glucagon-like peptide-1 (GLP-1) mimetics, a type of drug used in T2D, could decrease the phosphorylation of tau, probably via augmenting insulin signaling pathway. The purpose of this study was to further explore the mechanisms that underlie the effect of exendin-4 (ex-4, a GLP-1 receptor agonist) in reducing tau phosphorylation. We found that peripheral ex-4 injection in T2D rats reduced hyperphosphorylation of tau protein in rat hippocampus, probably via increasing hippocampal insulin which activated insulin signaling. Furthermore, we found that ex-4 could neither activate insulin signaling, nor reduce tau phosphorylation in HT22 neuronal cells in the absence of insulin. These results suggested that insulin is required in reduction of tau hyperphosphorylation by ex-4 in brain rats with T2D. PMID- 26640242 TI - Vitronectin promotes the progress of the initial differentiation stage in cerebellar granule cells. AB - Vitronectin (VN), which is an extracellular matrix protein, is known to be involved in the proliferation and differentiation of primary cultured cerebellar granule cell precursors (CGCPs); however, the effect of VN is not fully understood. In this study, we analyzed the effects of VN loss on the proliferation and differentiation of CGCPs in VN knockout (VNKO) mice in vivo. First, immunohistochemistry showed that VN was distributed in the region from the inner external granule layer (iEGL) through the internal granule layer (IGL) in wild-type (WT) mice. Next, we observed the formation of the cerebellar cortex using sagittal sections of VNKO mice at postnatal days (P) 5, 8 and 11. Loss of VN suppressed the ratio of NeuN, a neuronal differentiation marker, to positive cerebellar granule cells (CGCs) in the external granule layer (EGL) and the ratio of CGCs in the IGL at P8, indicating that the loss of VN suppresses the differentiation into CGCs. However, the loss of VN did not significantly affect the proliferation of CGCPs. Next, the effect of VN loss on the initial differentiation stage of CGCPs was examined. The loss of VN increased the expression levels of Transient axonal glycoprotein 1 (TAG1), a marker of neurons in the initial differentiation stage, in the cerebella of VNKO mice at P5 and 8 and increased the ratio of TAG1-positive cells in the primary culture of VNKO derived CGCPs, indicating that the loss of VN accumulates the CGCPs in the initial differentiation stage. Taken together, these results demonstrate that VN promotes the progress of the initial differentiation stage of CGCPs. PMID- 26640241 TI - Human pluripotent stem cell models of Fragile X syndrome. AB - Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and autism. The causal mutation in FXS is a trinucleotide CGG repeat expansion in the FMR1 gene that leads to human specific epigenetic silencing and loss of Fragile X Mental Retardation Protein (FMRP) expression. Human pluripotent stem cells (PSCs), including human embryonic stem cells (ESCs) and particularly induced PSCs (iPSCs), offer a model system to reveal cellular and molecular events underlying human neuronal development and function in FXS. Human FXS PSCs have been established and have provided insight into the epigenetic silencing of the FMR1 gene as well as aspects of neuronal development. PMID- 26640243 TI - Long-term Impact of Childhood Adiposity on Adult Metabolic Syndrome Is Modified by Insulin Resistance: The Bogalusa Heart Study. AB - Childhood adiposity and insulin resistance are well-known risk factors for adult metabolic syndrome (MetS). This study aims to examine whether the association between childhood adiposity and adult MetS is modified by insulin resistance. The cohort consisted of 1,593 black and white subjects, aged 19-50 years at follow up, who were examined 19 years apart on average as children and adults for MetS variables. The prevalence of adult MetS was compared between the insulin sensitive obesity and insulin-resistant obesity groups in childhood. Adult MetS prevalence was higher in the insulin-resistant obesity group than in the insulin sensitive obesity group (34.9% vs. 24.3%, p = 0.008). In multivariable logistic regression analyses adjusted for age, race, gender, and follow-up years, individuals with insulin-resistant obesity in childhood were 1.7 times (p = 0.011) more likely to have MetS 19 years later on average than those with insulin sensitive obesity in childhood. Odds ratio did not differ significantly between blacks and whites (p = 0.724). ORs for the association of childhood BMI with adult MetS significantly increased with increasing tertiles of childhood HOMA (p < 0.001 for trend). These findings suggest that insulin resistance amplifies the association between childhood adiposity and adult MetS and underscore the importance of preventing both adiposity and insulin resistance in early life. PMID- 26640245 TI - ErbB2/HER2-Specific NK Cells for Targeted Therapy of Glioblastoma. AB - BACKGROUND: Glioblastoma (GBM) is the most common and malignant intracranial tumor in adults and currently incurable. To specifically target natural killer (NK) cell activity to GBM, we employed NK-92/5.28.z cells that are continuously expanding human NK cells expressing an ErbB2-specific chimeric antigen receptor (CAR). METHODS: ErbB2 expression in 56 primary tumors, four primary cell cultures, and seven established cell lines was assessed by immunohistochemistry and flow cytometry. Cell killing activity of NK-92/5.28.z cells was analyzed in in vitro cytotoxicity assays. In vivo antitumor activity was evaluated in NOD SCID IL2Rgamma(null) (NSG) mice carrying orthotopic human GBM xenografts (6 to 11 mice per group) and C57BL/6 mice carrying subcutaneous and orthotopic ErbB2 expressing murine GBM tumors (5 to 8 mice per group). Statistical tests were two sided. RESULTS: We found elevated ErbB2 protein expression in 41% of primary GBM samples and in the majority of GBM cell lines investigated. In in vitro assays, NK-92/5.28.z in contrast to untargeted NK-92 cells lysed all ErbB2-positive established and primary GBM cells analyzed. Potent in vivo antitumor activity of NK-92/5.28.z was observed in orthotopic GBM xenograft models in NSG mice, leading to a marked extension of symptom-free survival upon repeated stereotactic injection of CAR NK cells into the tumor area (median survival of 200.5 days upon treatment with NK-92/5.28.z vs 73 days upon treatment with parental NK-92 cells, P < .001). In immunocompetent mice, local therapy with NK-92/5.28.z cells resulted in cures of transplanted syngeneic GBM in four of five mice carrying subcutaneous tumors and five of eight mice carrying intracranial tumors, induction of endogenous antitumor immunity, and long-term protection against tumor rechallenge at distant sites. CONCLUSIONS: Our data demonstrate the potential of ErbB2-specific NK-92/5.28.z cells for adoptive immunotherapy of glioblastoma, justifying evaluation of this approach for the treatment of ErbB2 positive GBM in clinical studies. PMID- 26640244 TI - Changes in Receipt of Cancer Screening in Medicare Beneficiaries Following the Affordable Care Act. AB - BACKGROUND: The Affordable Care Act (ACA) removed copayments for screening mammography and colonoscopy in Medicare beneficiaries, but its clinical impact is unknown. METHODS: Using a 5% random sample of Medicare claims from 2009 through 2012 in individuals age 70 years or older who were due for screening, we examined claims for screening mammography and screening or surveillance colonoscopy for two years prior to ACA (2009-2010) and two years post-ACA (2011-2012). Receipt of the procedures at the patient level was compared across years using generalized estimating equations. Statistical tests were two-sided. RESULTS: Compared with 2009, we found an increase in mammography uptake during the ACA coverage period, with multivariable odds ratios (MOR) of 1.22 (95% confidence interval [CI] = 1.20 to 1.25, P < .001) for 2011 and 1.17 (95% CI = 1.15 to 1.20, P < .001) for 2012 and less change in 2010 (OR = 1.03, 95% CI = 1.01 to 1.05, P = .01). In contrast to mammography, uptake of screening or surveillance colonoscopy decreased in 2012 (MOR = 0.95, 95% CI = 0.92 to 0.98, P = .002) compared with 2009, with no change in 2010 (MOR = 1.01, 95% CI = 0.99 to 1.04, P = .47) or 2011 (MOR = 1.01, 95% CI = 0.99 to 1.04, P = .34). Other factors associated with procedure receipt included younger age and prior preventive health visits. In an analysis restricted to patients age 70 to 74 years, colonoscopy use increased slightly in 2011 but was unchanged in 2012, and the findings by year for mammography were consistent with the main analysis. CONCLUSIONS: Following ACA implementation with concomitant reduction in out-of-pocket expenditures, there was a statistically significant increment in mammography uptake but not colonoscopy. This suggests that affordability is a necessary but not sufficient facilitator of preventive services. PMID- 26640246 TI - Evaluating impact of clinical guidelines using a realist evaluation framework. AB - RATIONALE, AIMS AND OBJECTIVES: The Remote Primary Health Care Manuals (RPHCM) project team manages the development and publication of clinical protocols and procedures for primary care clinicians practicing in remote Australia. The Central Australian Rural Practitioners Association Standard Treatment Manual, the flagship manual of the RPHCM suite, has been evaluated for accessibility and acceptability in remote clinics three times in its 20-year history. These evaluations did not consider a theory-based framework or a programme theory, resulting in some limitations with the evaluation findings. With the RPHCM having an aim of enabling evidence-based practice in remote clinics and anecdotally reported to do so, testing this empirically for the full suite is vital for both stakeholders and future editions of the RPHCM. METHODS: The project team utilized a realist evaluation framework to assess how, why and for what the RPHCM were being used by remote practitioners. A theory regarding the circumstances in which the manuals have and have not enabled evidence-based practice in the remote clinical context was tested. The project assessed this theory for all the manuals in the RPHCM suite, across government and aboriginal community-controlled clinics, in three regions of Australia. CONCLUSION: Implementing a realist evaluation framework to generate robust findings in this context has required innovation in the evaluation design and adaptation by researchers. This article captures the RPHCM team's experience in designing this evaluation. PMID- 26640247 TI - Progesterone causes metabolic changes involving aminotransferases and creatine kinase in cryopreserved bovine spermatozoa. AB - Progesterone (P4) is capable of inducing acrosome reaction in many species. The objective of this study was to determine the activity of enzymes involved in metabolism that contribute to the redox state and supply energy for acrosome reaction in cryopreserved bull spermatozoa. To accomplish this aim, acrosome reaction was induced by P4 in capacitated and non-capacitated samples. Alanine and aspartate aminotransferases (ALT, AST) and creatine kinase (CK) activities were measured spectrophotometrically at 340 nm after acrosome reaction with P4. Oxygen consumption was measured polarographically. ALT and AST activities increased by the addition of P4 capacitated and non-capacitated samples. P4 addition provoked an increase in CK activity in non-capacitated spermatozoa compared to heparin capacitated spermatozoa with or without P4 addition. P4 increased oxygen consumption, the percentage of acrosome reacted spermatozoa as well as the absence of acrosome integrity in both capacitated and non-capacitated bovine spermatozoa, but oxygen consumption in P4 samples was significantly lower than in heparin capacitated spermatozoa (P<0.05). Acrosome reaction induction by P4 required different creatine kinase activity with the same oxygen consumption and transaminases level to maintain oxidative metabolism and redox state through reducing equivalents transfer between cytosolic and mitochondrial compartment. In conclusion, P4 induces a lower oxidative metabolism during acrosome reaction in bovine cryopreserved spermatozoa, compared to heparin induced capacitation process. PMID- 26640248 TI - Nanosized titanium dioxide influences copper-induced toxicity during aging as a function of environmental conditions. AB - Titanium dioxide nanoparticles (TiO2 -NPs) adsorb co-occurring heavy metals in surface waters, modulating their toxicity for freshwater invertebrates. The processes triggering this interaction may be influenced by several environmental parameters; however, their relative importance remains unclear. The present study assessed the implications of aging on the joint acute toxicity of copper (Cu) and TiO2 -NPs for Daphnia magna over a duration of up to 72 h. The influences of aging duration as well as ionic strength, pH, and presence of different qualities of organic matter during aging were assessed. The results indicated that the presence of TiO2 -NPs often reduced the Cu-induced toxicity for daphnids after aging (albeit with varying extent), which was displayed by up to 3-fold higher EC50 (50% effective concentration) values compared to the absence of TiO2 -NPs. Moreover, the Cu speciation, influenced by the ionic composition and the pH as well as the presence of organic additives in the medium, strongly modulated the processes during aging, with partly limited implications of the aging duration on the ecotoxicological response of D. magna. Nonetheless, the present study underpins the potential of TiO2 -NPs to modify toxicity induced by heavy metals in freshwater ecosystems under various environmental conditions. This pattern, however, needs further verification using heavy metal ions with differing properties in combination with further environmental factors, such as ultraviolet irradiation. Environ Toxicol Chem 2016;35:1766-1774. (c) 2015 SETAC. PMID- 26640249 TI - Decompression for thyroid eye disease: An evolving trend of multidisciplinary approach. PMID- 26640275 TI - Contextualizing Parasympathetic Hyperactivity in Functionally Overreached Athletes With Perceptions of Training Tolerance. AB - PURPOSE: Heart-rate variability (HRV) as a measure of autonomic function may increase in response to training interventions leading to increases or decreases in performance, making HRV interpretation difficult in isolation. This study aimed to contextualize changes in HRV with subjective measures of training tolerance. METHODS: Supine and standing measures of vagally mediated HRV (root mean-square difference of successive normal RR intervals [RMSSD]) and measures of training tolerance (Daily Analysis of Life Demands for Athletes questionnaire, perception of energy levels, fatigue, and muscle soreness) were recorded daily during 1 wk of light training (LT), 2 wk of heavy training (HT), and 10 d of tapering (T) in 15 male runners/ triathletes. HRV and training tolerance were analyzed as rolling 7-d averages at LT, HT, and T. Performance was assessed after LT, HT, and T with a 5-km treadmill time trial (5TTT). RESULTS: Time to complete the 5TTT likely increased after HT (effect size [ES] +/- 90% confidence interval = 0.16 +/- 0.06) and then almost certainly decreased after T (ES = -0.34 +/- 0.08). Training tolerance worsened after HT (ES >= 1.30 +/- 0.41) and improved after T (ES >= 1.27 +/- 0.49). Standing RMSSD very likely increased after HT (ES = 0.62 +/- 0.26) and likely remained higher than LT at the completion of T (ES = 0.38 +/- 0.21). Changes in supine RMSSD were possible or likely trivial. CONCLUSIONS: Vagally mediated HRV during standing increased in response to functional overreaching (indicating potential parasympathetic hyperactivity) and also to improvements in performance. Thus, additional measures such as training tolerance are required to interpret changes in vagally mediated HRV. PMID- 26640276 TI - Tetrandrine ameliorates collagen-induced arthritis in mice by restoring the balance between Th17 and Treg cells via the aryl hydrocarbon receptor. AB - Tetrandrine is an alkaloid constituent of the root of Stephania tetrandra S. Moore. The long-term clinical uses of tetrandrine for treatments of rheumatalgia and arthralgia as well as the inhibition of rat adjuvant-induced arthritis imply that tetrandrine may have therapeutic potential in rheumatoid arthritis (RA). Here, we explored its anti-RA mechanism in collagen-induced arthritis (CIA) in relation to the balance between T helper (Th) 17 cells and regulatory T (Treg) cells. DBA/1 mice were immunized with chicken type II collagen and were orally administered tetrandrine for 14 consecutive days. Then, the mice were sacrificed, their joints were removed for histological analysis, and spleens and mesenteric lymph nodes (MLNs) were removed to examine the Th17 and Treg cells. Tetrandrine markedly alleviated the severity of arthritis, reduced the serum levels of pro inflammatory cytokines, and restored the Th17/Treg balance, as demonstrated by the serum levels of their related cytokines (IL-17 and IL-10) and the proportion of each cell type. Tetrandrine inhibited Th17 cell differentiation and induced Treg cell differentiation in vitro . Notably, aryl hydrocarbon receptor (AhR) was proven to play a crucial role in tetrandrine-mediated T cell differentiation. The correlation between AhR activation, regulation of Th17/Treg and amelioration of arthritis by tetrandrine was verified in the CIA mice. Moreover, tetrandrine might be a ligand of AhR because it facilitated the expression of the AhR target gene cytochrome P450 1A1 (CYP1A1) and the activation of its downstream signaling pathways. Taken together, tetrandrine exerts its anti-arthritis efficacy by restoring Th17/Treg balance via AhR. PMID- 26640278 TI - Effect of Extraction Method on the Phenolic and Cyanogenic Glucoside Profile of Flaxseed Extracts and their Antioxidant Capacity. AB - The application of flaxseed extracts as food ingredients is a subject of interest to food technologists and nutritionists. Therefore, the influence of the extraction method on the content and composition of beneficial compounds as well as anti-nutrients is important. In the study, the effects of two solvent extraction methods, aqueous and 60 % ethanolic, on phenolic and cyanogenic glucoside profiles of flaxseed extract were determined and compared. The impact of extracted phenolic compounds on the antioxidant capacity of the extracts was also investigated. Defatted meals from brown and golden flax varieties were used as extraction material. The ethanolic extraction was more selective for phenolics (100.8-131.7 mg g-1) than the aqueous one (11.5-15.7 mg g-1). However, the contribution of particular phenolic compounds to total phenolics was much more dependent on flax variety than extraction method. A strong relationship was observed between both radical scavenging and ferric reducing activity and the content of phenolics (particularly secoisolariciresinol diglucoside). The correlation between extract chelating ability and phenolics was moderate suggesting that other flaxseed compounds are involved in this activity. The extraction method strongly affected cyanogenic glucoside content of flaxseed extracts; the aqueous extraction caused 96 % reduction in cyanogenic glucoside content (0.56-0.62 mmol g-1) when compared to the content in defatted meal (9.1 11.6 mmol g-1). On the contrary, ethanolic extraction resulted in the high cyanogenic glucoside content in the extracts (71-89 mmol g-1). The results reveals that ethanolic extraction gives extracts rich in antioxidant lignans; aqueous extracts have lower antioxidant activity than ethanolic but cyanogenic glucosides are significantly reduced. PMID- 26640277 TI - The Theory of Industrial Society and Cultural Schemata: Does the "Cultural Myth of Stigma" Underlie the WHO Schizophrenia Paradox? AB - The WHO's International Studies of Schizophrenia conclude that schizophrenia may have a more benign course in "developing" societies than in the West. The authors focus on this finding's most common corollary: cultural schemata are shaped by the transition from agrarian to industrial society. Developing societies are viewed as traditional, gemeinschaft cultures lacking the stigmatizing beliefs about persons with mental illness held in modern, gesellschaft cultures of developed societies. The Stigma in Global Context-Mental Health Study formalized the cultural myth of public stigma (CMPS) with propositions linking level of development to intolerant, exclusionary, and individualistic attitudes. In 17 countries, the authors find no support for the corollary; where support is found, the findings are opposite expectations, with developed societies reporting lower stigma levels. Reconceptualizing of the cultural landscape on more specific dimensions also produces null or contrary findings. This correction to nostalgic myths of cultural context in developing societies thwarts misguided treatment, policy, and stigma-reduction efforts. PMID- 26640279 TI - The Effect of Type of Oil and Degree of Degradation on Glycidyl Esters Content During the Frying of French Fries. AB - The aim of the study was to determine the effect of oil degradation on the content of glycidyl esters (GEs) in oils used for the frying of French fries. As frying media, refined oils such as rapeseed, palm, palm olein and blend were used. French fries were fried for 40 h in oils heated to 180 degrees C in 30-min cycles. After every 8 h of frying, fresh oil and samples were analyzed for acid and anisidine values, color, refractive index, fatty acid composition, and content and composition of the polar fraction. GEs were determined by LC-MS. Hydrolysis and polymerization occurred most intensively in palm olein, while oxidation was reported for rapeseed oil. The degradation of oil caused increased changes in the RI of frying oils. Losses of mono- and polyunsaturated fatty acids were observed in all samples, with the largest share in blend. The highest content of GE found in fresh oil was in palm olein (25 mg kg-1) and the lowest content of GE was found in rapeseed oil (0.8 mg kg-1). The palm oil, palm olein and blend were dominated by GEs of palmitic and oleic acids, while rapeseed oil was dominated by GE of oleic acid. With increasing frying time, the content of GEs decreased with losses from 47 % in rapeseed oil to 78 % in palm oil after finishing frying. PMID- 26640280 TI - The Phase Behavior of gamma-Oryzanol and beta-Sitosterol in Edible Oil. AB - The phase behavior of binary mixtures of gamma-oryzanol and beta-sitosterol and ternary mixtures of gamma-oryzanol and beta-sitosterol in sunflower oil was studied. Binary mixtures of gamma-oryzanol and beta-sitosterol show double eutectic behavior. Complex phase behavior with two intermediate mixed solid phases was derived from differential scanning calorimetry (DSC) and small-angle X ray scattering (SAXS) data, in which a compound that consists of gamma-oryzanol and beta-sitosterol molecules at a specific ratio can be formed. SAXS shows that the organization of gamma-oryzanol and beta-sitosterol in the mixed phases is different from the structure of tubules in ternary systems. Ternary mixtures including sunflower oil do not show a sudden structural transition from the compound to a tubule, but a gradual transition occurs as gamma-oryzanol and beta sitosterol are diluted in edible oil. The same behavior is observed when melting binary mixtures of gamma-oryzanol and beta-sitosterol at higher temperatures. This indicates the feasibility of having an organogelling agent in dynamic exchange between solid and liquid phase, which is an essential feature of triglyceride networks. PMID- 26640281 TI - DETERMINANTS OF FIRST ANTENATAL CARE VISIT BY PREGNANT WOMEN AT COMMUNITY BASED EDUCATION, RESEARCH AND SERVICE SITES IN NORTHERN UGANDA. AB - BACKGROUND: Antenatal care (ANC) aims mainly at prevention, early detection and management of general medical and pregnancy associated disorders. Early booking is recommended for maximum utilisation. OBJECTIVE: To investigate the determinants of first ANC visit and trimesters at which pregnant mothers enrol for ANC at the COBERS sites of Northern Uganda. DESIGN: A descriptive cross sectional study. SETTING: Five community based Education, Research and Service sites (COBERS) of Atiak, Madi Opei, Mungula, Namukora and Pajule health centre, fours (HC IV) in the five respective districts of Amuru, Lamwo, Adjumani, Kitgum and Pader, Northern Uganda, from April to July 2013. SUBJECTS: Four hundred and seventeen (417) pregnant women attending antenatal care (ANC) in five health centres and ten purposively selected midwives were interviewed using questionnaires. RESULTS: Of the 417 respondents, only 11.5% (n = 48) had their first ANC at the recommended period of 0-16 weeks. Prevalence of late entry to ANC was 88.5% (n = 369). Mean gestational age at booking was 22.6 +/- 5.7 weeks. Paternal level of education, outcome of previous pregnancy, previous ANC attendance, weeks of amenorrhea, convenience of opening hours at ANC facility, commuting distance from home to health facility, knowing the right time for ANC enrollment and pregnancy planning remained significant predictors governing early booking. CONCLUSION: Late ANC booking is still a major public health concern that demands public enlightenment and paternal education coupled with women empowerment will reduce the magnitude of the problem. PMID- 26640282 TI - Health Services Research and Health Economy - Quality Care Training in Gynaecology, with Focus On Gynaecological Oncology. AB - In the era of cost increases and reduced resources in the German healthcare system, the value of health services research and health economics is increasing more and more. Health services research attempts to develop concepts for the most effective ways to organise, manage, finance and deliver high-quality care and evaluates the implementation of these concepts with regard to daily routine conditions. Goals are the assessment of benefits and the economic advantages and disadvantages of new and established diagnostic methods, drugs and vaccines. Regarding these goals, it is clear that health services research goes hand in hand with health economics, which evaluates the benefits of diagnostic and therapeutic procedures in relation to the costs. Both scientific fields have focus principally on gynaecology and particularly on gynaecological oncology in Germany, as can be seen by numerous publications. These present several advantages compared with clinical trials - they uncover gaps in health care, question the material, staffing and consequently the financial resources required and they allow the estimation of value and the comparison of different innovations to identify the best options for our patients. PMID- 26640283 TI - Chronic Pain Syndromes in Gynaecological Practice: Endometriosis and Fibromyalgia. AB - As gynaecologists frequently function as "general practitioners" for women, gynaecologists are frequently confronted with questions which initially appear to have only a tenuous connection to their field. Chronic pain syndromes represent a particular challenge, especially as pain syndromes are often associated with severe psychosocial stress for the affected woman. This article discusses some of the psychometric aspects of chronic pain in endometriosis and fibromyalgia together with practical therapeutic approaches. PMID- 26640284 TI - Preeclampsia - Aetiology, Current Diagnostics and Clinical Management, New Therapy Options and Future Perspectives. AB - Preeclampsia is a multisystem disease for which the exact causes have not yet been sufficiently clarified. However, in the past few years it has become clear that a placental imbalance between angiogenic and anti-angiogenic proteins is the decisive pathogenetic factor for the occurrence of preeclampsia. With the possibility to measure these angiogenic factors (sFlt-1/PlGF ratio) in maternal blood full new diagnostic possibilities have been opened that enable the certain diagnosis or exclusion of the diseases as well as a short-term prognosis to be made. In secondary prevention the current data situation for ASA confirms a moderate but measurable utility. The management concept depends on gestational age. In the case of early clinical manifestations (< 34th week of pregnancy) the clinical management in a perinatal centre remains unchanged with foeto-maternal monitoring and induction of pulmonary maturation, symptomatic therapy under careful blood pressure lowering and determination of the optimal delivery time. A balance must be made here between foetal immaturity and maternal risks upon prolongations. The pathomechanism of anti-angiogenic overload with sFlt-1 provides a starting point for first therapeutic interventions. The present article gives an overview of current diagnostic options and presents possible future therapeutic perspectives for discussion. PMID- 26640285 TI - Advances in Breast Cancer - Looking Back over the Year. AB - Treatment options as well as the characteristics for therapeutic decisions in patients with primary and advanced breast cancer are increasing in number and variety. New targeted therapies in combination with established chemotherapy schemes are broadening the spectrum, yet not every new, promising combination achieves a better result. New data from the field of pharmacogenomics point to prognostic and predictive factors that take not only the properties of the tumour but also the genetic disposition of the patient into consideration. Current therapeutic decision-making is thus based on a combination of classical clinical and modern molecular biomarkers. Health-economic concerns are also being taken into consideration more frequently, meaning political decisions may also become a factor. This review presents the trends over the past year. PMID- 26640286 TI - Breast Cancer: State of the Art and New Findings. AB - Advances in research have a highly influential role to play in the strategy of early detection, treatment and aftercare of breast cancer and therefore everyday clinical practice. Newly-defined prognosis factors and a new form of molecular subtype classification, for example, are intended to help identify patients who will actually benefit from chemotherapy. In the field of neoadjuvant chemotherapy, the inclusion of the angiogenesis inhibitor Bevacizumab and dual antiHER2 therapy is being discussed. What's more, where defined criteria are met, even with positive sentinel lymph nodes, axillary dissection is not performed; besides bisphosphonates RANKL antibody Denosumab is now an option in the treatment of bone metastases. PMID- 26640287 TI - Full Field Digital Mammography (FFDM) versus CMOS Technology versus Tomosynthesis (DBT) - Which System Increases the Quality of Intraoperative Imaging? AB - Aim: The aim of this prospective clinical study was to assess whether it would be possible to reduce the rate of re-excisions and improve the quality using CMOS technology or digital breast tomosynthesis (DBT) compared to a conventional FFDM system. Material and Methods: An invasive breast cancer (BI-RADS 5) was diagnosed in 200 patients in the period from 5/2011 to 1/2012. After histological verification, a breast-conserving therapy was performed with intraoperative imaging. Three different imaging systems were used: 1) InspirationTM (Siemens, Erlangen, Germany), amorphous selenium, tungsten source, focus 0.1 mm, resolution 85 um pixel pitch, 8 l/mm as the standard; 2) BioVisionTM (Bioptics, Tucson, USA), flat panel photodiode array, tungsten source, focus 0.05, resolution 50 um pixel pitch, 12 l/mm; 3) Tomosynthesis (Siemens, Erlangen, Germany), amorphous selenium, tungsten source, focus 0.1 mm, resolution 85 um pixel pitch, 8 l/mm, range: 50 degrees , 25 projections, scan time > 20 s, geometry: uniform scanning, reconstruction: filtered back projection. The 600 radiograms were prospectively shown to 3 radiologists. Results: Out of a total of 200 patients with histologically confirmed breast cancer (BI-RADS 6) 156 patients required no further operative therapy (re-excision) after breast-conserving therapy. A retrospective analysis (n = 44) showed an increase in sensitivity with tomosynthesis compared to the BioVisionTM (CMOS technology) and the InspirationTM at a magnification of 1.0 : 1.0 of 8 % (p < 0.05), i.e. re-excision would not have been necessary in 16 patients with tomosynthesis. Conclusions: The sensitivity of tomosynthesis for intraoperative radiography is significantly (p < 0.05) higher compared to both CMOS technology and an FFDM system with a conventional detector. Additional studies using higher magnification, e.g. 2.0 : 1.0, but no zooming will be necessary to evaluate the method further. PMID- 26640288 TI - Prevention of Labour-Associated Pelvic Floor Injuries - What is Known for Sure. AB - In order to avoid pelvic floor injuries a caesarean section is on the one hand often requested by the pregnant women and, on the other hand, offered by obstetric staff. For both forms of delivery, comprehensive risk-benefit analyses should be carried out before deciding in favour of the surgical procedure. The present brief review summarizes the current evidence on the avoidance of pelvic floor injuries. PMID- 26640289 TI - Chemotherapy-Induced Amenorrhea - An Update. AB - Because of the heterogeneity in the definition of chemotherapy-induced amenorrhea (CIA) there are distinct differences in the literature with regard to its incidence as well as its dependence on various influencing factors. The occurrence of CIA varies greatly depending on the applied chemotherapy. The pathogenesis of CIA is especially based on a reduction of ovarian reserves. Various sonographic and biochemical factors can be used to exclude or confirm CIA. This is particularly important when an endocrine therapy with tamoxifen is not possible and the use of aromatase inhibitors is under consideration. CIA and especially the frequently thereby resulting early menopause can lead to pronounced restrictions in the quality of life of the affected patients, not least due to the resulting infertility. On the other hand, various studies have shown that CIA may have a positive prognostic significance. Thus, the identification of measures to prevent CIA (for example, through the use of GnRH analogues) is of particular importance. PMID- 26640290 TI - Biomarkers in Breast Cancer - An Update. AB - The therapy of choice for breast cancer patients requiring adjuvant chemo- or radiotherapy is increasingly guided by the principle of weighing the individual effectiveness of the therapy against the associated side effects. This has only been made possible by the discovery and validation of modern biomarkers. In the last decades and in the last few years some biomarkers have been integrated in clinical practice and a number have been included in modern study concepts. The importance of biomarkers lies not merely in their prognostic value indicating the future course of disease but also in their use to predict patient response to therapy. Due to the many subgroups, mathematical models and computer-assisted analysis are increasingly being used to assess the prognostic information obtained from established clinical and histopathological factors. In addition to describing some recent computer programmes this overview will focus on established molecular markers which have already been extensively validated in clinical practice and on new molecular markers identified by genome-wide studies. PMID- 26640291 TI - Risk-reducing Surgery in Women at Risk for Familial Breast or Ovarian Cancer. AB - An estimated 5 % of breast cancers and 10 % of ovarian cancers may be due to inherited autosomal dominant breast and ovarian cancer alleles BRCA1 und BRCA2. According to population-based studies 1 or 2 women per 1000 carry such a risk allele. The cumulative cancer risk for healthy women with a BRCA-mutation is between 60 and 85 % for breast cancer and between 20 and 60 % for ovarian cancer. Recent studies have reported an increased risk for contralateral breast cancer in women after unilateral breast cancer. Since 1997 the German Cancer Aid has supported an interdisciplinary approach for high-risk women consisting of genetic testing, counselling and prevention in 12 specialised centres. Since 2005 this concept has received additional support from health insurance companies, and results have been assessed with regard to outcomes (e.g. reduced mortality due to more intensive early diagnosis). The number of centres has increased to 15 at various university hospitals. These interdisciplinary centres offer women the opportunity to participate in a structured screening programme for the early diagnosis of breast cancer and provide non-directive counselling on the options for risk-reducing surgery, e.g., prophylactic bilateral salpingo-oophorectomy, prophylactic bilateral mastectomy or contralateral prophylactic mastectomy after unilateral breast cancer. Such surgical interventions can significantly reduce the risk of disease, the respective disease-specific mortality and - particularly prophylactic bilateral salpingo-oophorectomy - total mortality in BRCA-mutation carriers. PMID- 26640292 TI - Response of the Uterus Commission of AGO to the Comment of M. Kolben, C. Dannecker and R. Kurzl. PMID- 26640294 TI - The effect of ultrafast laser wavelength on ablation properties and implications on sample introduction in inductively coupled plasma mass spectrometry. AB - We investigated the role of femtosecond (fs) laser wavelength on laser ablation (LA) and its relation to laser generated aerosol counts and particle distribution, inductively coupled plasma-mass spectrometry (ICP-MS) signal intensity, detection limits, and elemental fractionation. Four different NIST standard reference materials (610, 613, 615, and 616) were ablated using 400 nm and 800 nm fs laser pulses to study the effect of wavelength on laser ablation rate, accuracy, precision, and fractionation. Our results show that the detection limits are lower for 400 nm laser excitation than 800 nm laser excitation at lower laser energies but approximately equal at higher energies. Ablation threshold was also found to be lower for 400 nm than 800 nm laser excitation. Particle size distributions are very similar for 400 nm and 800 nm wavelengths; however, they differ significantly in counts at similar laser fluence levels. This study concludes that 400 nm LA is more beneficial for sample introduction in ICP-MS, particularly when lower laser energies are to be used for ablation. PMID- 26640293 TI - Sarcoma of the Uterus. Guideline of the DGGG (S2k-Level, AWMF Registry No. 015/074, August 2015). AB - Purpose: Official guideline published and coordinated by the German Society of Gynecology and Obstetrics (DGGG). Due to their rarity and their heterogeneous histopathology uterine sarcomas remain challenging tumors to manage and need a multidisciplinary approach. To our knowledge so far there is no evidence-based guideline on the appropiate management of these heterogeneous tumors. Methods: This S2k-guideline is the work of an representative committee of experts from a variety of different professions who were commissioned by the DGGG to carry out a systematic literature review of uterine sarcoma. Members of the participating scientific societies developed a structured consensus in a formal procedure. Recommendations: 1. The incidence and histopathologic classification of uterine sarcoma. 2. The clinical manifestations, diagnosis and staging of uterine sarcoma. 3. The management of leiomyosarcoma. 4. The management of endometrial stromal sarcoma and undifferentiated uterine sarcoma. 5. The management of adenosarcoma as well as carcinosarcomas. 6. The management of morcellated uterine sarcoma. PMID- 26640295 TI - Efficacy of Narrative Writing as an Intervention for PTSD: Does the Evidence Support Its Use? AB - Although a number of effective psychotherapies for posttraumatic stress disorder (PTSD) are available, there is a need to develop alternative treatments for those who may not respond optimally to these treatments or who may not have access to clinicians who can competently deliver them. Narrative writing, which involves repeated recounting about a traumatic event in writing, is one treatment that deserves further examination as a potential alternative. In this paper, we describe the most commonly used narrative writing treatment protocols for those with either a diagnosis of PTSD or probable PTSD and discuss the available efficacy data for each of these protocols. We conclude with recommendations for using narrative writing to treat those with PTSD and offer recommendations for future work in this area. PMID- 26640296 TI - Intergenerational Exchange and Expected Support Among the Young-Old. AB - The authors used data from the Wisconsin Longitudinal Study (N = 5,023) to determine how 3 attributes of intergenerational exchange (content, direction, and recency) are associated with older adults' expected sick care and comfort from their adult children. They found more like-kind associations (expecting same types of support that had been exchanged before) than spillover associations (expecting different types of support than that had been exchanged before). Same patterns of like-kind associations were found for expected sick care and comfort, regardless of the direction and recency of exchange, but expected sick care and comfort had different patterns of spillover associations. Specifically, recent emotional transfer, upward or downward, was related to expected sick care, but only recent upward instrumental transfer was related to expected comfort. This study advances the gerontological literature by elucidating the complex relations between each of the 3 attributes of intergenerational exchange and expected support among older adults. PMID- 26640297 TI - Applying a random encounter model to estimate lion density from camera traps in Serengeti National Park, Tanzania. AB - The random encounter model (REM) is a novel method for estimating animal density from camera trap data without the need for individual recognition. It has never been used to estimate the density of large carnivore species, despite these being the focus of most camera trap studies worldwide. In this context, we applied the REM to estimate the density of female lions (Panthera leo) from camera traps implemented in Serengeti National Park, Tanzania, comparing estimates to reference values derived from pride census data. More specifically, we attempted to account for bias resulting from non-random camera placement at lion resting sites under isolated trees by comparing estimates derived from night versus day photographs, between dry and wet seasons, and between habitats that differ in their amount of tree cover. Overall, we recorded 169 and 163 independent photographic events of female lions from 7,608 and 12,137 camera trap days carried out in the dry season of 2010 and the wet season of 2011, respectively. Although all REM models considered over-estimated female lion density, models that considered only night-time events resulted in estimates that were much less biased relative to those based on all photographic events. We conclude that restricting REM estimation to periods and habitats in which animal movement is more likely to be random with respect to cameras can help reduce bias in estimates of density for female Serengeti lions. We highlight that accurate REM estimates will nonetheless be dependent on reliable measures of average speed of animal movement and camera detection zone dimensions. (c) 2015 The Authors. Journal of Wildlife Management published by Wiley Periodicals, Inc. on behalf of The Wildlife Society. PMID- 26640298 TI - THEORIZING HYBRIDITY: INSTITUTIONAL LOGICS, COMPLEX ORGANIZATIONS, AND ACTOR IDENTITIES: THE CASE OF NONPROFITS. AB - We propose a novel approach to theorizing hybridity in public and nonprofit organizations. The concept of hybridity is widely used to describe organizational responses to changes in governance, but the literature seldom explains how hybrids arise or what forms they take. Transaction cost and organizational design literatures offer some solutions, but lack a theory of agency. We use the institutional logics approach to theorize hybrids as entities that face a plurality of normative frames. Logics provide symbolic and material elements that structure organizational legitimacy and actor identities. Contradictions between institutional logics offer space for them to be elaborated and creatively reconstructed by situated agents. We propose five types of organizational hybridity - segmented, segregated, assimilated, blended, and blocked. Each type is theoretically derived from empirically observed variations in organizational responses to institutional plurality. We develop propositions to show how our approach to hybridity adds value to academic and policy-maker audiences. PMID- 26640299 TI - Benefits and Pitfalls of Multimedia and Interactive Features in Technology Enhanced Storybooks: A Meta-Analysis. AB - A meta-analysis was conducted on the effects of technology-enhanced stories for young children's literacy development when compared to listening to stories in more traditional settings like storybook reading. A small but significant additional benefit of technology was found for story comprehension (g+ = 0.17) and expressive vocabulary (g+ = 0.20), based on data from 2,147 children in 43 studies. When investigating the different characteristics of technology-enhanced stories, multimedia features like animated pictures, music, and sound effects were found beneficial. In contrast, interactive elements like hotspots, games, and dictionaries were found to be distracting. Especially for children disadvantaged because of less stimulating family environments, multimedia features were helpful and interactive features were detrimental. Findings are discussed from the perspective of cognitive processing theories. PMID- 26640300 TI - Dengue: what it is and why there is more. AB - In 2014, China experienced the worst outbreak of dengue fever in the last decade with over 40,000 dengue cases including six deaths by the end of October. As one of the "neglected" tropical diseases, dengue is affecting substantially increasing number of people and proportion of global population due to factors including globalization, human settlement, and possibly climate change. Here, the authors summarized the most recent data about dengue outbreaks in China and reviewed the global trend of dengue epidemiology. Future directions for dengue surveillance, control and prevention are also introduced. PMID- 26640301 TI - The secret garden? Elite metropolitan geographies in the contemporary UK. AB - There is an enduring, indeed increasing awareness of the role of spatial location in defining and reinforcing inequality in this country and beyond. In the UK, much of the debate around these issues has focussed on the established trope of a long-standing 'north-south divide', a divide which appears to have deepened in recent decades with the inexorable de-industrialisation of northern Britain presented in stark counterpoint to the burgeoning concentration of wealth in London and the south-east, driven by the financial and ancillary services sectors. Due to a lack of available data, such debates have tended to focus solely on economic inequalities between places, and until now there was little understanding of how these disparities played out in the social and cultural domains. This paper significantly advances our understanding of the true meaning of spatial inequality in the UK by broadening that definition to encompass not only the economic, but also the social and cultural arenas, using data available from the BBC's Great British Class Survey experiment. We argue that these data shine a light not only on the economic inequalities between different parts of the country which existing debates have already uncovered but to understand how these are both reinforced and mediated across the social and cultural dimensions. Fundamentally, we concur with a great many others in seeing London and the south east as a vortex for economic accumulation but it is also much more than that; it is a space where the coming together of intense economic, social and cultural resources enables the crystallisation of particular and nuanced forms of elite social class formations, formations in which place is not incidental but integral to their very existence. PMID- 26640302 TI - Class in contemporary Britain: comparing the Cultural Capital and Social Exclusion (CCSE) project and the Great British Class Survey (GBCS). AB - The paper discusses the salience of class in Britain in relation to the experiment of the BBC-academic partnership of the Great British Class Survey (GBCS). It addresses the claimed inauguration of a third phase in class analysis in the UK sparked by the experiment. This is done by considering three main issues. First, the GBCS experiment is situated in the context of various explorations of cultural class analyses, and chiefly in relation to the Cultural Capital and Social Exclusion (CCSE) project (ESRC funded 2003-6). Secondly, the focus is on the influence of the academic turn to big data for the procedures and claims of the project, and some implications of the methodological choices. Thirdly, attention is turned to the deleterious effects of commercial and institutional pressures on the current research culture in which the experiment exists. PMID- 26640304 TI - Preparation of 3-benzyloxy-2-pyridinone functional linkers: Tools for the synthesis of 3,2-hydroxypyridinone (HOPO) and HOPO/hydroxamic acid chelators. AB - In contrast to 2,3-dihydroxypyridine, the 3-benzyloxy protected derivative, 2, undergoes facile alkylation at ambient temperatures with a variety of functionalized alkyl halides in good yields. This alkylation has been used to prepare a number of linkers that permit the attachment of 3,2-HOPO moieties onto various scaffolds using a wide range of coupling methods. The Mitsunobu reaction of 2 with representative alcohols was found to be of limited value due to competing O-alkylation that led to product mixtures. The phthalimide 3j can be converted in two steps to HOPO isocyanate 6 in excellent yields. Isocyanate 6 can be coupled to amines at room temperature or to alcohols in refluxing dichloroethane to obtain the corresponding urea or carbamate linked ligand systems. The coupling of isocyanate 6 with TREN followed by deprotection gave the tris-HOPO 10, an interesting target as it has both cationic and anionic binding sites. The HOPO hydroxylamine linker 11 was shown to be especially valuable as its coupling with carboxylic acids proceeds with the concomitant generation of an additional hydroxamate ligand moiety in the framework. The utility of this linker was shown by the preparation of two mixed HOPO-hydroxamate chelators, 16 and 19, based on the structure of desferrioxamine, a well-known trihydroxamate siderophore. PMID- 26640303 TI - Recent Advances in the C-H-Functionalization of the Distal Positions in Pyridines and Quinolines. AB - This review summarizes recent developments in the C-H-functionalization of the distal positions of pyridines, quinolines and related azaheterocycles. While the functionalization of the C2 position has been known for a long time and is facilitated by the proximity to N1, regioselective reactions in the distal positions are more difficult to achieve and have only emerged in the last decade. Recent advances in the transition metal-catalyzed distal C-H-functionalization of these synthetically-important azaheterocycles are discussed in detail, with the focus on the scope, site-selectivity and mechanistic aspects of the reactions. PMID- 26640305 TI - Chapter 13. A3 Adenosine Receptors. PMID- 26640306 TI - Socioeconomic status and the growth of intelligence from infancy through adolescence. AB - Low socioeconomic status (SES) children perform on average worse on intelligence tests than children from higher SES backgrounds, but the developmental relationship between intelligence and SES has not been adequately investigated. Here, we use latent growth curve (LGC) models to assess associations between SES and individual differences in the intelligence starting point (intercept) and in the rate and direction of change in scores (slope and quadratic term) from infancy through adolescence in 14,853 children from the Twins Early Development Study (TEDS), assessed 9 times on IQ between the ages of 2 and 16 years. SES was significantly associated with intelligence growth factors: higher SES was related both to a higher starting point in infancy and to greater gains in intelligence over time. Specifically, children from low SES families scored on average 6 IQ points lower at age 2 than children from high SES backgrounds; by age 16, this difference had almost tripled. Although these key results did not vary across girls and boys, we observed gender differences in the development of intelligence in early childhood. Overall, SES was shown to be associated with individual differences in intercepts as well as slopes of intelligence. However, this finding does not warrant causal interpretations of the relationship between SES and the development of intelligence. PMID- 26640307 TI - Resolving Contested Elections: The Limited Power of Post-Vote Vote-Choice Data. AB - In close elections, the losing side has an incentive to obtain evidence that the election result is incorrect. Sometimes this evidence comes in the form of court testimony from a sample of invalid voters, and this testimony is used to adjust vote totals (Borders v King County, 2005; Belcher v Mayor of Ann Arbor, 1978). However, while courts may be reluctant to make explicit findings about out-of sample data (e.g. invalid voters that do not testify), when samples are used to adjust vote totals, the court is implicitly making findings about this out-of sample data. In this paper, we show that the practice of adjusting vote totals on the basis of potentially unrepresentative samples can lead to incorrectly voided election results. More generally, we show that given the difficulties of sampling and non-response in this context, even when frame error is minimal and if voter testimony is accurate, such testimony has limited power to detect incorrect election results without precinct level polarization or the acceptance of large Type I error rates. Therefore in U.S. election disputes, even high quality post vote vote-choice data will often not be sufficient to resolve contested elections without modeling assumptions (whether or not these assumptions are acknowledged). PMID- 26640308 TI - An energy-optimized collimator design for a CZT-based SPECT camera. AB - In single photon emission computed tomography, it is a challenging task to maintain reasonable performance using only one specific collimator for radio tracers over a broad spectrum of diagnostic photon energies, since photon scatter and penetration in a collimator differ with the photon energy. Frequent collimator exchanges are inevitable in daily clinical SPECT imaging, which hinders throughput while subjecting the camera to operational errors and damage. Our objective is to design a collimator, which independent of the photon energy performs reasonably well for commonly used radiotracers with low- to medium energy levels of gamma emissions. Using the Geant4 simulation toolkit, we simulated and evaluated a parallel-hole collimator mounted to a CZT detector. With the pixel-geometry-matching collimation, the pitch of the collimator hole was fixed to match the pixel size of the CZT detector throughout this work. Four variables, hole shape, hole length, hole radius/width and the source-to collimator distance were carefully studied. Scatter and penetration of the collimator, sensitivity and spatial resolution of the system were assessed for four radionuclides including 57Co, 99m Tc, 123I and 111In, with respect to the aforementioned four variables. An optimal collimator was then decided upon such that it maximized the total relative sensitivity (TRS) for the four considered radionuclides while other performance parameters, such as scatter, penetration and spatial resolution, were benchmarked to prevalent commercial scanners and collimators. Digital phantom studies were also performed to validate the system with the optimal square-hole collimator (23 mm hole length, 1.28 mm hole width, 0.32 mm septal thickness) in terms of contrast, contrast-to-noise ratio and recovery ratio. This study demonstrates promise of our proposed energy-optimized collimator to be used in a CZT-based gamma camera, with comparable or even better imaging performance versus commercial collimators such as low-energy high resolution (LEHR) and medium energy general purpose (MEGP) collimators. PMID- 26640309 TI - Investigation of spatial resolution characteristics of an in vivo micro computed tomography system. AB - The spatial resolution characteristics of an in vivo micro computed tomography (CT) system was investigated in the in-plane (x-y), cross plane (z) and projection imaging modes. The micro CT system utilized in this study employs a flat panel detector with a 127 MUm pixel pitch, a micro focus x-ray tube with a focal spot size ranging from 5-30 MUm, and accommodates three geometric magnifications (M) of 1.72, 2.54 and 5.10. The in-plane modulation transfer function (MTF) curves were measured as a function of the number of projections, geometric magnification (M), detector binning and reconstruction magnification (MRecon). The in plane cutoff frequency (10% MTF) ranged from 2.31 lp/mm (M=1.72, 2*2 binning) to 12.56 lp/mm (M=5.10, 1*1 binning) and a bar pattern phantom validated those measurements. A slight degradation in the spatial resolution was observed when comparing the image reconstruction with 511 and 918 projections, whose effect was visible at the lower frequencies. Small value of MRecon has little or no impact on the in-plane spatial resolution owning to a stable system. Large value of MRecon has implications on the spatial resolution and it was evident when comparing the bar pattern images reconstructed with MRecon=1.25 and 2.5. The cross plane MTF curves showed that the spatial resolution increased as the slice thickness decreased. The cutoff frequencies in the projection imaging mode yielded slightly higher values as compared to the in-plane and cross plane modes at all the geometric magnifications (M). At M=5.10, the cutoff resolution of the projection and cross plane on an ultra-high contrast resolution bar chip phantom were 14.9 lp/mm and 13-13.5 lp/mm. Due to the finite focal spot size of the x-ray tube, the detector blur and the reconstruction kernel functions, the system's spatial resolution does not reach the limiting spatial resolution as defined by the Nyquist's detector criteria with an ideal point source. The geometric magnification employed in the micro CTs provide a tradeoff between field of view and spatial resolution for a wide range of applications. PMID- 26640310 TI - A Sequential Algorithm for Multiblock Orthogonal Projections to Latent Structures. AB - Methods of multiblock bilinear factorizations have increased in popularity in chemistry and biology as recent increases in the availability of information-rich spectroscopic platforms has made collecting multiple spectroscopic observations per sample a practicable possibility. Of the existing multiblock methods, consensus PCA (CPCA-W) and multiblock PLS (MB-PLS) have been shown to bear desirable qualities for multivariate modeling, most notably their computability from single-block PCA and PLS factorizations. While MB-PLS is a powerful extension to the nonlinear iterative partial least squares (NIPALS) framework, it still spreads predictive information across multiple components when response uncorrelated variation exists in the data. The OnPLS extension to O2PLS provides a means of simultaneously extracting predictive and uncorrelated variation from a set of matrices, but is more suited to unsupervised data discovery than regression. We describe the union of NIPALS MB-PLS with an orthogonal signal correction (OSC) filter, called MB-OPLS, and illustrate its equivalence to single block OPLS for regression and discriminant analysis. PMID- 26640311 TI - RESURGENCE OF MANDS FOLLOWING FUNCTIONAL COMMUNICATION TRAINING. AB - Experimental conditions similar to those described by Lieving and Lattal (2003) were used within two experiments to evaluate the resurgence of mands with humans. Two mands from the same operant class were trained with three participants with developmental disabilities during Experiment 1 and with two participants with developmental disabilities and a history of problem behavior during Experiment 2. The two mands were then placed on extinction. Both persisted, but showed different response strength during extinction. The mand with the weaker response strength was targeted for additional functional communication training and the alternative mand was placed on extinction. Following steady levels of occurrence of the targeted mand and no occurrences of the alternative mand, both mands were placed on extinction again. At least one instance of resurgence of the alternative mand occurred with every participant and resurgence of problem behavior occurred for both participants during Experiment 2. PMID- 26640312 TI - Waiting with purpose: A reliable but small association between purpose in life and impulsivity. AB - Purpose in life contributes to health and wellbeing. We examine the link between purpose and behavioral impulsivity that may account for these benefits. In a community sample of 503 adults, we found a small yet reliable positive association between purpose and valuing future rewards on a delayed discounting task, a behavioral index of impulsivity. This bootstrapped correlation remained after accounting for Big-5 personality traits, positive affect, and demographic characteristics, suggesting a unique and robust link between purpose and impulsivity (r = .1). We interpret this connection as evidence that purpose enables a broader life view, which serves to inhibit impulsive distractions. PMID- 26640313 TI - Birds of a Feather Have Babies Together?: Family Structure Homogamy and Union Stability among Cohabiting Parents. AB - The association between childhood family structure and offspring wellbeing is well-documented. Recent research shows that adult children of divorced parents will likely marry someone whose parents' divorced (i.e., family structure homogamy) and are subsequently likely to divorce themselves. This literature has focused primarily on marital unions, despite the rise in cohabitation and nonmarital childbearing. Research suggests that marriage and cohabitation are different types of unions and have different implications for the wellbeing of children. Therefore, we extend the literature by examining the role of family structure homogamy in matching patterns and union stability among unmarried, cohabiting couples. Data from the Fragile Families and Child Wellbeing Study suggest that unmarried, cohabiting mothers and fathers are both more likely to be from nonintact childhood family structures and are significantly more likely to dissolve their unions compared to married parents who both tend to be from intact childhood family structures. PMID- 26640314 TI - Toward community engagement: Can the built environment help? Grassroots participation and communal space in Chinese urban communities. AB - The scholarship in building community capacity by way of cultivating community social capital and community spirit through neighborhood design has spawned heated debates in urban and community studies. This paper contributes to this scholarship by examining the neighborhood contexts of grassroots participation in Chinese contemporary urban communities. In particular, it explores the relationship between neighborhood communal space and community participation, using a city-wide survey of 1,809 households in 39 commodity housing estates in the city of Guangzhou. It is found that local residents' participation in community affairs is conditioned by both the social milieu (measured by the overall level of social cohesion) and the physical environment (indicated by effects of communal space) of a neighborhood. Notably, communal space exerts positive indirect effects on grassroots participation by facilitating the development of place-based social capital and neighborhood attachment. These findings point to a civic virtue of communal space and provide nascent evidence regarding neighborhood contexts of grassroots participation in urban China. PMID- 26640315 TI - Association of Cytokeratin and Vimentin Protein in the Genesis of Transitional Cell Carcinoma of Urinary Bladder Patients. AB - The aim of study was to examine the localization and distribution of cytokeratin (CK) and vimentin protein and their association with clinical outcome of the TCC patients. Expression pattern of cytokeratin and vimentin was evaluated by immunohistochemistry in TCC cases and inflammatory lesions. Cytoplasmic expression of CK was noticed in 52.17% of TCC cases and its expression was not observed in inflammatory lesions of bladder specimens. Vimentin showed expression in 69.00% cases of TCC. Significant differences were noticed in expression pattern of CK and vimentin in inflammatory lesion and Transitional Cell Carcinoma cases. Vimentin expression increased with the grade of TCC and this difference was statistically significant whereas expression of CK decreased according to the grade of TCC. Furthermore, it was also observed that expression pattern of vimentin was high in >=55 years as compared to <55 age group patients and these differences were significant in men as compared to women. Expression pattern of CK did not show any significant relation with age and gender. Therefore, it can be concluded that cytokeratin and vimentin will be helpful markers in the early diagnosis of Transitional Cell Carcinoma/bladder carcinoma. PMID- 26640316 TI - Inhibition of HIF-1alpha Affects Autophagy Mediated Glycosylation in Oral Squamous Cell Carcinoma Cells. AB - Purpose. To validate the function of autophagy with the regulation of hypoxia inhibitor-induced glycosylation in oral squamous cell carcinoma cell. Methods. Human Tca8113 cell line was used to detect autophagy and glycosylation related protein expression by western blotting and immunofluorescence with HIF-1alpha inhibitor. Short interfering RNA (siRNA) transfection blocked human ATG12 and ATG1. Results. HIF-1alpha inhibitor PX-478 reduced the amount of LC3-II and LC3-I in Tca8113 cells. PX-478 decreased the expression of O-GlcNAc and OGT and increased OGA expression. The tendency of O-GlcNAc showed a similar pattern to OGT. PX-478 gradually decreased OGT expression in Tca8113 cells. Protein level of O-GlcNAc and OGT increased in ATG12 and ATG1 depletion. The expression of OGT decreased at first and then rose slowly with the treatment of Atg12 and Atg1 siRNA and PX-478 fluctuant. Autophagy affected the stability of OGT when HIF 1alpha signaling was blocked. Conclusions. Autophagy reduced by hypoxic stress inhibited. HIF-1alpha inhibitor decreased glycosylation. OGT became unstable in the absence of autophagy when HIF-1alpha signaling was blocked. PMID- 26640317 TI - Gender in Marriage and Life Satisfaction Under Gender Imbalance in China: The Role of Intergenerational Support and SES. AB - This study examined gender differences in the influence of marital status and marital quality on life satisfaction. The roles of intergenerational support and perceived socioeconomic status in the relationship between marriage and life satisfaction were also explored. The analysis was conducted with data from the Chinese General Social Survey (CGSS) in 2006, representing 1,317 women and 1,152 men at least 25 years old. Chi-squared tests and logistic regression models were used in this process. Marriage, including marital status and relationship quality, has a protective function for life satisfaction. Marital status is more important for males, but marital quality is more important for females. The moderating roles of intergenerational support and perceived socioeconomic status are gender specific, perhaps due to norms that ascribe different roles to men and women in marriage. PMID- 26640318 TI - Privacy in the Genomic Era. AB - Genome sequencing technology has advanced at a rapid pace and it is now possible to generate highly-detailed genotypes inexpensively. The collection and analysis of such data has the potential to support various applications, including personalized medical services. While the benefits of the genomics revolution are trumpeted by the biomedical community, the increased availability of such data has major implications for personal privacy; notably because the genome has certain essential features, which include (but are not limited to) (i) an association with traits and certain diseases, (ii) identification capability (e.g., forensics), and (iii) revelation of family relationships. Moreover, direct to-consumer DNA testing increases the likelihood that genome data will be made available in less regulated environments, such as the Internet and for-profit companies. The problem of genome data privacy thus resides at the crossroads of computer science, medicine, and public policy. While the computer scientists have addressed data privacy for various data types, there has been less attention dedicated to genomic data. Thus, the goal of this paper is to provide a systematization of knowledge for the computer science community. In doing so, we address some of the (sometimes erroneous) beliefs of this field and we report on a survey we conducted about genome data privacy with biomedical specialists. Then, after characterizing the genome privacy problem, we review the state-of-the art regarding privacy attacks on genomic data and strategies for mitigating such attacks, as well as contextualizing these attacks from the perspective of medicine and public policy. This paper concludes with an enumeration of the challenges for genome data privacy and presents a framework to systematize the analysis of threats and the design of countermeasures as the field moves forward. PMID- 26640319 TI - Adaptive Modeling Procedure Selection by Data Perturbation. AB - Many procedures have been developed to deal with the high-dimensional problem that is emerging in various business and economics areas. To evaluate and compare these procedures, modeling uncertainty caused by model selection and parameter estimation has to be assessed and integrated into a modeling process. To do this, a data perturbation method estimates the modeling uncertainty inherited in a selection process by perturbing the data. Critical to data perturbation is the size of perturbation, as the perturbed data should resemble the original dataset. To account for the modeling uncertainty, we derive the optimal size of perturbation, which adapts to the data, the model space, and other relevant factors in the context of linear regression. On this basis, we develop an adaptive data-perturbation method that, unlike its nonadaptive counterpart, performs well in different situations. This leads to a data-adaptive model selection method. Both theoretical and numerical analysis suggest that the data adaptive model selection method adapts to distinct situations in that it yields consistent model selection and optimal prediction, without knowing which situation exists a priori. The proposed method is applied to real data from the commodity market and outperforms its competitors in terms of price forecasting accuracy. PMID- 26640320 TI - Psychometric Properties of the Dutch Eyberg Child Behavior Inventory (ECBI) in a Community Sample and a Multi-Ethnic Clinical Sample. AB - The Eyberg Child Behavior Inventory (ECBI) is an established parent rating scale to measure disruptive behavior problems in children aged between 2 and 16 years. The present study examined the psychometric properties of the Dutch translation, including analysis on the one-dimensional structure of the ECBI scales using item response theory. Data from two samples from the Netherlands were used, a community sample (N = 326; 51 % boys) and a multi-ethnic clinical sample (N = 197; 62 % boys). The one-dimensional structure of the ECBI Intensity and Problem Scales were confirmed in both of these samples. The results also indicated good internal consistency, test-retest reliability (community sample), and good convergent and divergent validity. The ECBI Intensity Scale was able to differentiate between diagnostic groups (no diagnosis, ADHD, ODD, and CD symptoms), demonstrating good discriminative validity. Findings support the use of the ECBI as a reliable measure for child disruptive behavior problems in a Dutch population. Suggestions for the optimal use of the both ECBI scales for research and screening purposes are made. Also, cultural issues regarding the use of the ECBI are discussed and additional research into the validity of the ECBI is recommended. PMID- 26640321 TI - Choosing l p norms in high-dimensional spaces based on hub analysis. AB - The hubness phenomenon is a recently discovered aspect of the curse of dimensionality. Hub objects have a small distance to an exceptionally large number of data points while anti-hubs lie far from all other data points. A closely related problem is the concentration of distances in high-dimensional spaces. Previous work has already advocated the use of fractional l p norms instead of the ubiquitous Euclidean norm to avoid the negative effects of distance concentration. However, which exact fractional norm to use is a largely unsolved problem. The contribution of this work is an empirical analysis of the relation of different l p norms and hubness. We propose an unsupervised approach for choosing an l p norm which minimizes hubs while simultaneously maximizing nearest neighbor classification. Our approach is evaluated on seven high dimensional data sets and compared to three approaches that re-scale distances to avoid hubness. PMID- 26640322 TI - User perceptions of and willingness to pay for household container-based sanitation services: experience from Cap Haitien, Haiti. AB - Household-level container-based sanitation (CBS) services may help address the persistent challenge of providing effective, affordable sanitation services for which low-income urban households are willing to pay. Little is known, however, about user perceptions of and demand for household CBS services. This study presents the results of a pilot CBS service programme in Cap Haitien, Haiti. One hundred and eighteen households were randomly selected to receive toilets and a twice-weekly collection service. After three months, changes in these households' satisfaction with their sanitation situation, along with feelings of pride, modernity and personal safety, were compared to 248 households in two comparison cohorts. Following the service pilot, 71 per cent of participating households opted to continue with the container-based sanitation service as paying subscribers. The results from this study suggest that, in the context of urban Haiti, household CBS systems have the potential to satisfy many residents' desire for safe, convenient and modern sanitation services. PMID- 26640323 TI - Acute Respiratory Distress Syndrome: Role of Oleic Acid-Triggered Lung Injury and Inflammation. AB - Lung injury especially acute respiratory distress syndrome (ARDS) can be triggered by diverse stimuli, including fatty acids and microbes. ARDS affects thousands of people worldwide each year, presenting high mortality rate and having an economic impact. One of the hallmarks of lung injury is edema formation with alveoli flooding. Animal models are used to study lung injury. Oleic acid induced lung injury is a widely used model resembling the human disease. The oleic acid has been linked to metabolic and inflammatory diseases; here we focus on lung injury. Firstly, we briefly discuss ARDS and secondly we address the mechanisms by which oleic acid triggers lung injury and inflammation. PMID- 26640324 TI - Inflammation as a Keystone of Bone Marrow Stroma Alterations in Primary Myelofibrosis. AB - Primary myelofibrosis (PMF) is a clonal myeloproliferative neoplasm where severity as well as treatment complexity is mainly attributed to a long lasting disease and presence of bone marrow stroma alterations as evidenced by myelofibrosis, neoangiogenesis, and osteosclerosis. While recent understanding of mutations role in hematopoietic cells provides an explanation for pathological myeloproliferation, functional involvement of stromal cells in the disease pathogenesis remains poorly understood. The current dogma is that stromal changes are secondary to the cytokine "storm" produced by the hematopoietic clone cells. However, despite therapies targeting the myeloproliferation-sustaining clones, PMF is still regarded as an incurable disease except for patients, who are successful recipients of allogeneic stem cell transplantation. Although the clinical benefits of these inhibitors have been correlated with a marked reduction in serum proinflammatory cytokines produced by the hematopoietic clones, further demonstrating the importance of inflammation in the pathological process, these treatments do not address the role of the altered bone marrow stroma in the pathological process. In this review, we propose hypotheses suggesting that the stroma is inflammatory-imprinted by clonal hematopoietic cells up to a point where it becomes "independent" of hematopoietic cell stimulation, resulting in an inflammatory vicious circle requiring combined stroma targeted therapies. PMID- 26640325 TI - Clinical Trial and In Vitro Study for the Role of Cartilage and Synovia in Acute Articular Infection. AB - OBJECTIVE: Osteoarthritis is a long-term complication of acute articular infections. However, the roles of cartilage and synovia in this process are not yet fully understood. METHODS: Patients with acute joint infections were enrolled in a prospective clinical trial and the cytokine composition of effusions compared in patients with arthroplasty (n = 8) or with intact joints (n = 67). Cytokines and cell function were also analyzed using a human in vitro model of joint infection. RESULTS: Synovial IL-1beta levels were significantly higher in patients with arthroplasty (p = 0.004). Higher IL-1beta concentrations were also found in the in vitro model without chondrocytes (p < 0.05). The anti inflammatory cytokines IL-4 and IL-10 were consistently expressed in vivo and in vitro, showing no association with the presence of cartilage or chondrocytes. In contrast, FasL levels increased steadily in vitro, reaching higher levels without chondrocytes (p < 0.05). Likewise, the viability of synovial fibroblasts (SFB) during infection was higher in the presence of chondrocytes. The cartilage metabolism markers aggrecan and bFGF were at higher concentrations in intact joints, but also synthesized by SFB. CONCLUSIONS: Our data suggest an anti inflammatory effect of cartilage associated with the SFBs' increased resistance to infections, which displayed the ability to effectively synthesize cartilage metabolites.The trial is registered with DRKS 00003536, MISSinG. PMID- 26640326 TI - The Effect of Therapeutic Blockades of Dust Particles-Induced Ca2+ Signaling and Proinflammatory Cytokine IL-8 in Human Bronchial Epithelial Cells. AB - Bronchial epithelial cells are the first barrier of defense against respiratory pathogens. Dust particles as extracellular stimuli are associated with inflammatory reactions after inhalation. It has been reported that dust particles induce intracellular Ca(2+) signal, which subsequently increases cytokines production such as interleukin- (IL-) 8. However, the study of therapeutic blockades of Ca(2+) signaling induced by dust particles in human bronchial epithelial cells is poorly understood. We investigated how to modulate dust particles-induced Ca(2+) signaling and proinflammatory cytokine IL-8 expression. Bronchial epithelial BEAS-2B cells were exposed to PM10 dust particles and subsequent mediated intracellular Ca(2+) signaling and reactive oxygen species signal. Our results show that exposure to several inhibitors of Ca(2+) pathway attenuated the PM10-induced Ca(2+) response and subsequent IL-8 mRNA expression. PM10-mediated Ca(2+) signal and IL-8 expression were attenuated by several pharmacological blockades such as antioxidants, IP3-PLC blockers, and TRPM2 inhibitors. Our results show that blockades of PLC or TRPM2 reduced both of PM10 mediated Ca(2+) signal and IL-8 expression, suggesting that treatment with these blockades should be considered for potential therapeutic trials in pulmonary epithelium for inflammation caused by environmental events such as seasonal dust storm. PMID- 26640328 TI - Network Model-Assisted Inference from Respondent-Driven Sampling Data. AB - Respondent-Driven Sampling is a widely-used method for sampling hard-to-reach human populations by link-tracing over their social networks. Inference from such data requires specialized techniques because the sampling process is both partially beyond the control of the researcher, and partially implicitly defined. Therefore, it is not generally possible to directly compute the sampling weights for traditional design-based inference, and likelihood inference requires modeling the complex sampling process. As an alternative, we introduce a model assisted approach, resulting in a design-based estimator leveraging a working network model. We derive a new class of estimators for population means and a corresponding bootstrap standard error estimator. We demonstrate improved performance compared to existing estimators, including adjustment for an initial convenience sample. We also apply the method and an extension to the estimation of HIV prevalence in a high-risk population. PMID- 26640327 TI - Th1 and Th17 Cells in Tuberculosis: Protection, Pathology, and Biomarkers. AB - The outcome of Mycobacterium tuberculosis (Mtb) infection ranges from a complete pathogen clearance through asymptomatic latent infection (LTBI) to active tuberculosis (TB) disease. It is now understood that LTBI and active TB represent a continuous spectrum of states with different degrees of pathogen "activity," host pathology, and immune reactivity. Therefore, it is important to differentiate LTBI and active TB and identify active TB stages. CD4(+) T cells play critical role during Mtb infection by mediating protection, contributing to inflammation, and regulating immune response. Th1 and Th17 cells are the main effector CD4(+) T cells during TB. Th1 cells have been shown to contribute to TB protection by secreting IFN-gamma and activating antimycobacterial action in macrophages. Th17 induce neutrophilic inflammation, mediate tissue damage, and thus have been implicated in TB pathology. In recent years new findings have accumulated that alter our view on the role of Th1 and Th17 cells during Mtb infection. This review discusses these new results and how they can be implemented for TB diagnosis and monitoring. PMID- 26640329 TI - Diagnosis and therapies for gastric non-invasive neoplasia. AB - There has been a great discrepancy of pathological diagnosis for gastric non invasive neoplasia/dysplasia between Japanese and western pathologists. In Japan, lesions that most western pathologists diagnose as dysplasia are often considered adenocarcinoma based on nuclear and structural atypia regardless of the presence of invasion. In the Vienna classification, gastric non-invasive intraepithelial neoplasia (NIN) were divided into low grade and high grade (including intra mucosal cancer of Japanese criteria). The diagnosis by both endoscopy and pathology of biopsy specimen is difficult. Recent advances of diagnostic modality such as magnified endoscopy and imaged enhanced endoscopy is expected to improve the diagnostic yield for NIN. There are two treatment strategies for NIN, observation and diagnostic therapy by endoscopic resection (ER). ER is acceptable because of its less invasiveness and high local control rate, on the other hand, cancer-developing rate of low-grade NIN is reported to be low. Therefore there is controversy for the treatment of gastric NIN. Prospective study based on unified pathological definition is required in the future. PMID- 26640331 TI - Hepatic applications of endoscopic ultrasound: Current status and future directions. AB - The diagnosis and staging of various gastrointestinal malignancies have been made possible with the use of endoscopic ultrasound, which is a relatively safe procedure. The field of endoscopic ultrasound is fast expanding due to advancements in therapeutic endoscopic ultrasound. Though various studies have established its role in gastrointestinal malignancies and pancreatic conditions, its potential in the field of hepatic lesions still remains vastly untapped. In this paper the authors attempt to review important and landmark trials, case series and case studies involving hepatic applications of endoscopic ultrasound, thus not only providing an overview of utilization of endoscopic ultrasound in various liver conditions but also speculating its future role. PMID- 26640330 TI - Update on pathogenesis and predictors of response of therapeutic strategies used in inflammatory bowel disease. AB - The search for biomarkers that characterize specific aspects of inflammatory bowel disease (IBD), has received substantial interest in the past years and is moving forward rapidly with the help of modern technologies. Nevertheless, there is a direct demand to identify adequate biomarkers for predicting and evaluating therapeutic response to different therapies. In this subset, pharmacogenetics deserves more attention as part of the endeavor to provide personalized medicine. The ultimate goal in this area is the adjustment of medication for a patient's specific genetic background and thereby to improve drug efficacy and safety rates. The aim of the following review is to utilize the latest knowledge on immunopathogenesis of IBD and update the findings on the field of Immunology and Genetics, to evaluate the response to the different therapies. In the present article, more than 400 publications were reviewed but finally 287 included based on design, reproducibility (or expectancy to be reproducible and translationable into humans) or already measured in humans. A few tests have shown clinical applicability. Other, i.e., genetic associations for the different therapies in IBD have not yet shown consistent or robust results. In the close future it is anticipated that this, cellular and genetic material, as well as the determination of biomarkers will be implemented in an integrated molecular diagnostic and prognostic approach to manage IBD patients. PMID- 26640332 TI - Hepatitis B virus therapy: What's the future holding for us? AB - Hepatitis B is one of the leading causes of liver cancer worldwide and unfortunately the number of people affected with hepatitis B virus (HBV) infection is still on the rise. Although the HBV has been known to cause fatal illness since decades but the population effected by this lethal virus have still only a few options for its management. The major treatment strategies include interferons and nucleos(t)ide analogues. These agents have so far produced unsatisfactory results in terms of complete virus eradication. Interferons cannot be used for long term therapy because of their potential side effects. Prolong treatment with nucleos(t)ide analogues has also been reported to cause serious side effects besides the increasing resistance by the virus. The need for new innovative solutions for treatment of HBV has been realized by global research institutes and pharmaceutical industry. Present review focuses in detail on the new ideas that are being transformed into therapeutic tools for use as future therapies in HBV infection. Modern drug designing and screening methods have made the drug discovery process shorter and more reliable. HBV therapeutics will take a new turn in coming years owing to these intelligent drug designing and screening methods. Future therapy of HBV is aiming to include the use of vaccines (both prophylactic and therapeutic), immunomodulators such as antibodies, non nucleoside antivirals such as RNAi and inhibitors of viral life cycle. PMID- 26640333 TI - Mucosal healing effect of nilotinib in indomethacin-induced enterocolitis: A rat model. AB - AIM: To investigate the effects of nilotinib in a rat model of indomethacin induced enterocolitis. METHODS: Twenty-one Wistar albino female rats obtained from Dokuz Eylul University Department of Laboratory Animal Science were divided into the following three groups: control (n = 7), indomethacin (n = 7) and nilotinib (n = 7). A volume of 0.25 mL of physiological serum placebo was administered to the control and indomethacin groups through an orogastric tube for 13 d. To induce enterocolitis, the indomethacin and nilotinib groups received 7.5 mL/kg indomethacin dissolved in 5% sodium bicarbonate and administered subcutaneously in a volume of 0.5 mL twice daily for three days. Nilotinib was administered 20 mg/kg/d in two divided doses to the nilotinib group of rats for 13 d through an orogastric tube, beginning on the same day as indomethacin administration. For 13 d, the rats were fed a standard diet, and their weights were monitored daily. After the rats were sacrificed, the intestinal and colonic tissue samples were examined. The macroscopic and microscopic pathology scores were evaluated. The pathologist stained all tissue samples using terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling method. Mucosal crypts and apoptotic cells were quantified. The platelet-derived growth factor receptor (PDGFR) alpha and beta scores assessed by immunohistochemical staining method and tissue and serum tumor necrosis factor (TNF) alpha levels were determined by enzyme-linked immunosorbent assay. RESULTS: Between days 1 and 13, the rats in the nilotinib and indomethacin groups lost significantly more weight than the controls (-11 g vs +14.14 g, P = 0.013; -30 g vs +14.14 g, P = 0.003). In the small intestinal and colonic tissues, the macroscopic scores were significantly lower in the nilotinib group than in the indomethacin group (1.14 +/- 0.38 and 7.29 +/- 2.98, P = 0.005; 1.14 +/- 0.38 and 7.43 +/- 2.64, P = 0.001, respectively), but the values of the nilotinib and indomethacin groups were similar to the control group. In the small intestinal and colonic tissues, the microscopic scores were significantly lower in the nilotinib group than in the indomethacin group (3.43 +/- 2.99 and 7.67 +/- 3.67, P = 0.043; 2.29 +/- 0.76 and 8.80 +/- 2.68, P = 0.003, respectively), but the values were similar to the control group. The PDGFR beta scores in the small intestine and colon were significantly lower in the nilotinib group than in the indomethacin group (1.43 +/- 0.79 and 2.43 +/- 0.54, P = 0.021; 1.57 +/- 0.54 and 3 +/- 0, P =0.001), and the values were similar to controls. The colonic PDGFR alpha scores were significantly lower in the nilotinib group than in the indomethacin group (1.71 +/- 0.49 and 3 +/- 0, P = 0.001). The colonic apoptosis scores were significantly lower in the controls than in the nilotinib group (1.57 +/- 1.13 and 4 +/- 1.29, P = 0.007). Furthermore, the serum and tissue TNF-alpha levels were similar between the nilotinib and indomethacin groups. CONCLUSION: In the indomethacin induced enterocolitis rat model, nilotinib has a positive effect on the macroscopic and microscopic pathologic scores, ensuring considerable mucosal healing. Nilotinib decreases PDGFR alpha and beta levels and increases the colonic apoptotic scores, but it has no significant effects on weight loss and the TNF-alpha levels. PMID- 26640334 TI - Hepatitis B virus infection and genotype in asymptomatic people from 10 ethnic groups in Yunnan, China. AB - AIM: To evaluate the infection and genotype distribution of hepatitis B virus (HBV) in ethnic groups in Yunnan, China. METHODS: Two thousand five hundred and eighty-four asymptomatic local people from 10 ethnic groups were investigated in Yunnan, China. Infection and genotype distribution were evaluated by serological and genetic methods. Genotyping was verified by sequencing. Ethnic genotype distribution was compared by proportion test. RESULTS: Four types of infection model based on HBV serum markers were identified, and the average HBV infection rate was 5.7% in those asymptomatic local people. The genotype prevalence was 59.6% for B, 21.1% for C and 19.3% BC; subgenotypes Ba, Cs and Ce were identified in this study. Hepatitis B surface antigen-positive rate and the proportion of genotype B were significantly lower in ethnic groups with a northern origin compared to those with a southern origin (50% vs 73.9%, P = 0.037; 4.2% vs 10.5%, P = 0.000). CONCLUSION: Genotype B is dominant and genotype BC has high occurrence in asymptomatic local ethnic groups in Yunnan. HBV infection status and genotype distribution may associate with ethnic origin. PMID- 26640335 TI - Potential effect of chronic Helicobacter pylori infection on glucose metabolism of Mongolian gerbils. AB - AIM: To assess the effect of Helicobacter pylori (H. pylori) infection on metabolic parameters in Mongolian gerbils. METHODS: A total of 40 male, 5- to 8 wk-old, specific-pathogen-free Mongolian gerbils (30-50 g) were randomly allocated into two groups: a control group (n = 20) and an H. pylori group (n = 20). After a two-week acclimation period, the control group was administered Brucella broth and the H. pylori group was challenged intra-gastrically five times every other day with approximately 10(9)/CFU H. pylori ATCC43504 (CagA+, VacA+). Each group was then divided into two subgroups, which were sacrificed at either 6 or 12 mo. The control and H. pylori subgroups each contained 10 Mongolian gerbils. Body weight, abdominal circumference, and body length were measured, and body mass index (BMI) and Lee's index were calculated. Biochemical assays were used to detect serum indexes, including glucose, glycated hemoglobin (GHb), glycated hemoglobin A1c (HbA1c), triacylglycerol, and total cholesterol, using an automatic biochemistry analyzer. Inflammatory cytokines, including interleukin (IL)-1beta, IL-2, IL-4, IL-10, IL-12, tumor necrosis factor-alpha (TNF-alpha) and interferon (IFN)-gamma, were assayed using ELISA. The expression of insulin and insulin-like growth factor 1 (IGF-1) was detected by immunohistochemistry, and islet apoptosis was measured using the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay. RESULTS: At each time point, body weight, abdominal circumference, BMI, and Lee's index were increased after H. pylori infection. However, these differences were not significant. H. pylori infection significantly increased the GHb (5.45 +/- 0.53 vs 4.98 +/- 0.22, P < 0.05) and HbA1c (4.91 +/- 0.61 vs 4.61 +/- 0.15, P < 0.05) levels at 12 mo. We observed no significant differences in serum biochemical indexes, including fasting blood glucose, triacylglycerol and total cholesterol, at 6 or 12 mo after infection. H. pylori infection significantly increased the expression of IGF-1 (P < 0.05). Insulin levels from the pancreas and the apoptotic rate of islet beta-cells remained unchanged. Also, we observed no significant differences among cytokines levels, including IL-1beta, IL-2, IL 4, IL-10, IL-12, TNF-alpha and IFN-gamma. IL-4 was the only exception, which increased at 6 (44.36 +/- 25.17 vs 17.38 +/- 3.47, P < 0.05) and 12 mo (33.41 +/- 10.00 vs 18.91 +/- 5.31, P < 0.05) after H. pylori infection. CONCLUSION: Long term H. pylori infection is significantly associated with high levels of HbA1c in Mongolian gerbils, indicating a potential role of H. pylori infection in glucose dysregulation. PMID- 26640336 TI - Studied microRNA gene expression in human hepatocellular carcinoma by microRNA microarray techniques. AB - AIM: To achieve a better understanding of the molecular mechanisms of microRNA expression changes involved in hepatocellular carcinoma. METHODS: In this research process, patients were not treated with antivirals, immunosuppressants or immunomodulators for at least 6 mo before collecting serum. The study population was composed of 35 outpatient hepatitis B virus (HBV) cases and 12 healthy control cases from the Affiliated Hospital of Inner Mongolia Medical University (Inner Mongolia, China) from July 2013 to April 2014. The 35 HBV cases were divided into two groups: a hepatocirrhosis group with 20 cases and a liver cancer group with 15 cases. All 35 cases carried HBsAg. The diagnostic criteria followed the European Association for the Study of the Liver 2012 (EASL2012) standards. MicroRNA (miRNA) was extracted from a control group of patients, a group with hepatocirrhosis and a group with liver cancer and its quality was analyzed using the human V2 microRNA expression beadchip. Cluster analysis and a radar chart were then applied to the miRNA changes. RESULTS: The miRNA-qualified rate of human serum samples was 93%. The concentration of a single sample was > 200 ng/MUL and the volume was > 5 MUL. All miRNA serum samples were uncontaminated by the genome. The Mann-Whitney test showed significant differences in miRNA between each group, with a detection P-value of < 0.05. Illumina software was set up with Diff Score set to +/- 13, meaning that P = 0.001.There were significant changes in miRNA expression between the three groups. miRNA-183 was the most up-regulated, followed by miRNA-373. miRNA-129 and miRNA-188 were both strongly down-regulated and miRNA-378 was down-regulated a small amount. The liver cancer group had greater changes, which indicated that changes in miRNA expression levels were caused by hepatocirrhosis. The liver cancer disease course then further increased these changes. In the pentagon created by these five miRNAs, three groups showed significant deviation. The liver cancer group had a bigger deviation trend. The chart indicated that miRNA expression changes occurred in the hepatocirrhosis group, which increased in the liver cancer disease course and were irreversible. CONCLUSION: There was a significant relationship between the irreversible up-regulation of miRNA-183/373 and down-regulation of miRNA-129/188/378 and incidences of hepatocirrhosis and liver cancer. PMID- 26640337 TI - Laparoscopic gastric bypass vs sleeve gastrectomy in obese Korean patients. AB - AIM: To compare the mid-term outcomes of laparoscopic sleeve gastrectomy (LSG) and laparoscopic Roux-en-Y gastric bypass (LRYGB) in obese Korean patients. METHODS: All consecutive patients who underwent either LSG or LRYGB with primary to treat morbid obesity between January 2011 and December 2012 were retrospectively reviewed. Patients with a body mass index (BMI) >= 30 kg/m(2) with inadequately controlled obesity-related comorbidities (e.g., diabetes, obstructive sleep apnea, hypertension, or obesity-related arthropathy) or BMI >= 35 kg/m(2) were considered for bariatric surgery according to the International Federation for the Surgery of Obesity-Asia Pacific Chapter Consensus statements in 2011. The decision regarding the procedure type was made on an individual basis following extensive discussion with the patient about the specific risks associated with each procedure. All operative procedures were performed laparoscopically by a single surgeon experienced in upper gastrointestinal surgeries. Baseline demographics, perioperative surgical outcomes, and postoperative anthropometric data from a prospectively established database were thoroughly reviewed and compared between the two surgical approaches. RESULTS: One hundred four patients underwent LSG, and 236 underwent LRYGB. Preoperative BMI in the LSG group was significantly higher than that of the LRYGB group (38.6 kg/m(2) vs 37.2 kg/m(2), P = 0.024). Patients with diabetes were more prevalent in the LRYGB group (18.3% vs 35.6%, P = 0.001). Operating time and hospital stay were significantly shorter in the LSG group compared with the LRYGB group (100 min vs 130 min, P < 0.001; 1 d vs 2 d, P = 0.003), but the incidence of perioperative complications was similar between the groups (P = 0.351). The mean percentage of excess weight loss (%EWL) was 71.2% for LRYGB, while it was 63.5% for LSG, at mean follow-up periods of 18.0 and 21.0 mo, respectively (P = 0.073). The %EWL at 1, 3, 6, 12, 18, 24, and 36 mo was equivalent between the groups. Four patients required surgical revision after LSG (4.8%), while revision was only required in one case following LRYGB (0.4%; P = 0.011). CONCLUSION: Both LSG and LRYGB are effective procedures that induce comparable weight loss in the mid term and similar surgical risks, except for the higher revision rate after LSG. PMID- 26640338 TI - Perihepatic nodes detected by point-of-care ultrasound in acute hepatitis and acute-on-chronic liver disease. AB - AIM: To study the manifestations of perihepatic lymph nodes during the episode of acute hepatitis flare by point-of-care ultrasonography. METHODS: One hundred and seventy-six patients with an episode of acute hepatitis flare (ALT value > 5 * upper normal limit) were enrolled retrospectively. Diagnosis of etiology of the acute hepatitis flare was based on chart records and serological and virological assays. The patients were categorized into two groups (viral origin and non-viral origin) and further defined into ten subgroups according to the etiologies. An ultrasonograpy was performed within 2 h to 72 h (median, 8 h). The maximum size of each noticeable lymph node was measured. Correlation between clinical parameters and nodal manifestations was analyzed RESULTS: Enlarged lymph nodes (width >= 5mm) were noticeable in 110 (62.5%) patients, mostly in acute on chronic hepatitis B (54.5%). The viral group had a higher prevalence rate (89/110 = 80.9%) and larger nodal size (median, 7 mm) than those of the non-viral group (21/66 = 31.8%; median, 0 mm) (P < 0.001 for both). Meanwhile, there were significant differences in the nodal size between acute and chronic viral groups (P < 0.01), and between acute hepatitis A and non-hepatitis A viral groups (P < 0.001). In logistical regression analysis, the nodal width still showed strong significance in multivariate analysis (P < 0.0001) to stratify the two groups. The area under the curve of ROC was 0.805, with a sensitivity of 80.9%, a specificity of 68.2%, positive predictive value of 80.92%, negative predictive value of 68.18%, and an accuracy of 76.14%. CONCLUSION: Point-of-care ultrasonography to detect perihepatic nodal change is valuable for clarifying the etiologies in an episode of acute hepatitis flare. PMID- 26640339 TI - Peripheral portal vein-oriented non-dilated bile duct puncture for percutaneous transhepatic biliary drainage. AB - AIM: To evaluate the efficacy of peripheral portal vein (PV)-oriented non-dilated bile duct (BD) puncture for percutaneous transhepatic biliary drainage (PTBD). METHODS: Thirty-five patients with non-dilated BDs underwent PTBD for the management of various biliary disorders, including benign bilioenteric anastomotic stricture (n = 24), BD stricture (n = 5) associated with iatrogenic BD injury, and postoperative biliary leakage (n = 6). Under ultrasonographic guidance, percutaneous transhepatic puncture using a 21-G needle was performed along the running course of the peripheral targeted non-dilated BD (preferably B6 for right-sided approach, and B3 for left-sided approach) or along the accompanying PV when the BD was not well visualized. This technique could provide an appropriate insertion angle of less than 30 degrees between the puncture needle and BD running course. The puncture needle was then advanced slightly beyond the accompanying PV. The needle tip was moved slightly backward while injecting a small amount of contrast agent to obtain the BD image, followed by insertion of a 0.018-inch guide wire (GW). A drainage catheter was then placed using a two-step GW method. RESULTS: PTBD was successful in 33 (94.3%) of the 35 patients with non-dilated intrahepatic BDs. A right-sided approach was performed in 25 cases, while a left-sided approach was performed in 10 cases. In 31 patients, the first PTBD attempt proved successful. Four cases required a second attempt a few days later to place a drainage catheter. PTBD was successful in two cases, but the second attempt also failed in the other two cases, probably due to poor breath-holding ability. Although most patients (n = 26) had been experiencing cholangitis with fever (including septic condition in 8 cases) before PTBD, only 5 (14.3%) patients encountered PTBD procedure-related complications, such as transient hemobilia and cholangitis. No major complications such as bilioarterial fistula or portal thrombosis were observed. There was no mortality in our series. CONCLUSION: Peripheral PV-oriented BD puncture for PTBD in patients with non-dilated BDs is a safe and effective procedure for BD stricture and postoperative bile leakage. PMID- 26640340 TI - Management and associated factors of delayed perforation after gastric endoscopic submucosal dissection. AB - AIM: To identify the actual clinical management and associated factors of delayed perforation after gastric endoscopic submucosal dissection (ESD). METHODS: A total of 4943 early gastric cancer (EGC) patients underwent ESD at our hospital between January 1999 and June 2012. We retrospectively assessed the actual management of delayed perforation. In addition, to determine the factors associated with delayed perforation, after excluding 123 EGC patients with perforations that occurred during the ESD procedure, we analyzed the following clinicopathological factors among the remaining 4820 EGC patients by comparing the ESD cases with delayed perforation and the ESD cases without perforation: age, sex, chronological periods, clinical indications for ESD, status of the stomach, location, gastric circumference, tumor size, invasion depth, presence/absence of ulceration, histological type, type of resection, and procedure time. RESULTS: Delayed perforation occurred in 7 (0.1%) cases. The median time until the occurrence of delayed perforation was 11 h (range, 6-172 h). Three (43%) of the 7 cases required emergency surgery, while four were conservatively managed without surgical intervention. Among the 4 cases with conservative management, 2 were successfully managed endoscopically using the endoloop-endoclip technique. The median hospital stay was 18 d (range, 15-45 d). There were no delayed perforation-related deaths. Based on a multivariate analysis, gastric tube cases (OR = 11.0; 95%CI: 1.7-73.3; P = 0.013) were significantly associated with delayed perforation. CONCLUSION: Endoscopists must be aware of not only the identified factors associated with delayed perforation, but also how to treat this complication effectively and promptly. PMID- 26640341 TI - Single center experience in selecting the laparoscopic Frey procedure for chronic pancreatitis. AB - AIM: To share our experience regarding the laparoscopic Frey procedure for chronic pancreatitis (CP) and patient selection. METHODS: All consecutive patients undergoing duodenum-preserving pancreatic head resection from July 2013 to July 2014 were reviewed and those undergoing the Frey procedure for CP were included in this study. Data on age, gender, body mass index (BMI), American Society of Anesthesiologists score, imaging findings, inflammatory index (white blood cells, interleukin (IL)-6, and C-reaction protein), visual analogue score score during hospitalization and outpatient visit, history of CP, operative time, estimated blood loss, and postoperative data (postoperative mortality and morbidity, postoperative length of hospital stay) were obtained for patients undergoing laparoscopic surgery. The open surgery cases in this study were analyzed for risk factors related to extensive bleeding, which was the major reason for conversion during the laparoscopic procedure. Age, gender, etiology, imaging findings, amylase level, complications due to pancreatitis, functional insufficiency, and history of CP were assessed in these patients. RESULTS: Nine laparoscopic and 37 open Frey procedures were analyzed. Of the 46 patients, 39 were male (85%) and seven were female (16%). The etiology of CP was alcohol in 32 patients (70%) and idiopathic in 14 patients (30%). Stones were found in 38 patients (83%). An inflammatory mass was found in five patients (11%). The time from diagnosis of CP to the Frey procedure was 39 +/- 19 (9-85) mo. The BMI of patients in the laparoscopic group was 20.4 +/- 1.7 (17.8-22.4) kg/m(2) and was 20.6 +/- 2.9 (15.4-27.7) kg/m(2) in the open group. All patients required analgesic medication for abdominal pain. Frequent acute pancreatitis or severe abdominal pain due to acute exacerbation occurred in 20 patients (43%). Pre operative complications due to pancreatitis were observed in 18 patients (39%). Pancreatic functional insufficiency was observed in 14 patients (30%). Two laparoscopic patients (2/9) were converted. In seven successful laparoscopic cases, the mean operative time was 323 +/- 29 (290-370) min. Estimated intra operative blood loss was 57 +/- 14 (40-80) mL. One patient had a postoperative complication, and no mortality was observed. Postoperative hospital stay was 7 +/ 2 (5-11) d. Multiple linear regression analysis of 37 open Frey procedures showed that an inflammatory mass (P < 0.001) and acute exacerbation (P < 0.001) were risk factors for intra-operative blood loss. CONCLUSION: The laparoscopic Frey procedure for CP is feasible but only suitable in carefully selected patients. PMID- 26640342 TI - Xanthogranulomatous cholecystitis mimicking gallbladder carcinoma: An analysis of 42 cases. AB - AIM: To review and evaluate the diagnostic dilemma of xanthogranulomatous cholecystitis (XGC) clinically. METHODS: From July 2008 to June 2014, a total of 142 cases of pathologically diagnosed XGC were reviewed at our hospital, among which 42 were misdiagnosed as gallbladder carcinoma (GBC) based on preoperative radiographs and/or intra-operative findings. The clinical characteristics, preoperative imaging, intra-operative findings, frozen section (FS) analysis and surgical procedure data of these patients were collected and analyzed. RESULTS: The most common clinical syndrome in these 42 patients was chronic cholecystitis, followed by acute cholecystitis. Seven (17%) cases presented with mild jaundice without choledocholithiasis. Thirty-five (83%) cases presented with heterogeneous enhancement within thickened gallbladder walls on imaging, and 29 (69%) cases presented with abnormal enhancement in hepatic parenchyma neighboring the gallbladder, which indicated hepatic infiltration. Intra-operatively, adhesions to adjacent organs were observed in 40 (95.2%) cases, including the duodenum, colon and stomach. Thirty cases underwent FS analysis and the remainder did not. The accuracy rate of FS was 93%, and that of surgeon's macroscopic diagnosis was 50%. Six cases were misidentified as GBC by surgeon's macroscopic examination and underwent aggressive surgical treatment. No statistical difference was encountered in the incidence of postoperative complications between total cholecystectomy and subtotal cholecystectomy groups (21% vs 20%, P > 0.05). CONCLUSION: Neither clinical manifestations and laboratory tests nor radiological methods provide a practical and effective standard in the differential diagnosis between XGC and GBC. PMID- 26640343 TI - Capsule enteroscopy is useful for the therapeutic management of Crohn's disease. AB - AIM: To analyze therapeutic changes in Crohn's disease (CD) patients following video capsule endoscopy (VCE) and to assess the usefulness of Lewis score and the Patency Capsule. METHODS: Patency Capsule was performed in every patient that had indication for VCE, and those with negative patency did not undergo VCE. Patients with established CD that underwent VCE between January 2011 and February 2014 were selected for this study; those with suspected CD were excluded, independent of VCE results, since our purpose was to address differences in therapeutic regimen in CD patients before and after VCE. Patients with inconclusive VCE were also excluded. Patients had to be free of non-steroidal anti-inflammatories for at least 1 mo. Those patients who met these criteria were allocated into one of three groups: Staging group (asymptomatic CD patients that underwent VCE for staging of CD), Flare group (patients with active CD), or Post-op group (CD patients evaluated for post-operative recurrence). Lewis score was calculated for every VCE procedure. Statistical analysis was performed to address the impact of VCE findings on the therapeutic management of CD patients and to evaluate the utility of the Lewis score. RESULTS: From a total of 542 VCEs, 135 were performed in patients with CD. Patency capsule excluded nearly 25% of the patients who were supposed to undergo VCE. No videocapsule retention during VCE was reported. From these 135 patients, 29 were excluded because CD diagnosis was not established at the time of VCE. Therefore, a total of 106 patients were included in the final analysis. From these, the majority were in the Staging group (n = 73, 69%), and the remaining were in the Flare (n = 23, 22%) or Post-op (n = 10, 9%) group. Median time between diagnosis and VCE was 5.5 years. Overall, VCE determined changes in the treatment of 40% of patients: only 21% remained free of immunosuppressors after VCE compared to 44% before VCE (P < 0.001). The differences in therapy before and after VCE achieved statistical significance in the Staging and Flare groups. In addition, patients were significantly different when stratified regarding time since diagnosis to the date of VCE. A higher Lewis score was associated with therapeutic modifications (P < 0.0001); where a score higher than 1354 was related to 90% probability of changing therapy [area under the receiver operative characteristic (AUROC) 0.80 (95%CI: 0.69-0.88)]. CONCLUSION: VCE significantly changed the therapeutic management of CD patients, even in those with long-term disease. Systematic use of Patency capsule allowed for no videocapsule retention. PMID- 26640344 TI - Evaluation of a multiplex PCR assay for detection of cytomegalovirus in stool samples from patients with ulcerative colitis. AB - AIM: To evaluate a multiplex PCR assay for the detection of bacterial and viral enteropathogens in stool samples from patients with ulcerative colitis (UC). METHODS: We prospectively analyzed 300 individuals, including immunocompetent patients, immunocompromised patients, and patients with UC. Stool samples were collected from the recto-sigmoid region of the colon by endoscopy. The samples were qualitatively analyzed for bacterial and viral enteropathogens with a multiplex PCR assay using a Seeplex((r)) Kit. Additional clinical and laboratory data were collected from the medical records. RESULTS: A multiplex PCR assay detected 397 pathogens (191 bacteria and 206 viruses) in 215 samples (71.7%). The most frequently detected bacteria were Escherichia coli H7, 85 (28.3%); followed by Aeromonas spp., 43 (14.3%); and Clostridium perfringens, 36 (12.0%) samples. The most prevalent viruses were Epstein-Barr virus (EBV), 90 (30.0%); followed by human herpes virus-6 (HHV-6), 53 (17.7%); and cytomegalovirus (CMV), 37 (12.3%) samples. The prevalence rate of CMV infection was significantly higher in the immunocompromised group than in the immunocompetent group (P < 0.01). CMV infection was more common in patients with UC (26/71; 36.6%) than in the immunocompetent patients excluding UC (6/188; 3.2%) (P < 0.01). CMV infection was more prevalent in UC active patients (25/58; 43.1%) than in UC inactive patients (1/13; 7.7%) (P < 0.05). Among 4 groups which defined by the UC activity and immunosuppressive drugs, the prevalence rate of CMV infection was highest in the UC active patients with immunosuppressive drugs (19/34; 55.8%). Epstein-Barr virus (EBV) infection was more common in the immunocompromised patients excluding UC (18/41; 43.9%) than in the immunocompetent patients excluding UC (47/188; 25.0%) (P < 0.05). The simultaneous presence of CMV and EBV and/or HHV6 in UC active patients (14/58; 24.1%) was greater than in immunocompromised patients excluding UC (5/41; 12.2%) (P < 0.05). CONCLUSION: The multiplex PCR assay that was used to analyze the stool samples in this study may serve as a non-invasive approach that can be used to exclude the possibility of CMV infection in patients with active UC who are treated with immunosuppressive therapy. PMID- 26640345 TI - Gastric cancer risk in relation to tobacco use and alcohol drinking in Kerala, India--Karunagappally cohort study. AB - AIM: To assess the risk of gastric cancer (GC) in relation to tobacco use and alcohol drinking in the Karunagappally cohort in Kerala, South India. METHODS: This study examined the association of tobacco use and alcohol drinking with GC incidence among 65553 men aged 30-84 in the Karunagappally cohort. During the period from 1990-2009, 116 GC cases in the cohort were identified as incident cancers. These cases were identified from the population-based cancer registry. Information regarding risk factors such as socioeconomic factors and tobacco and alcohol habits of cohort members were collected from the database of the baseline survey conducted during 1990-1997. The relative risks (RRs) and the corresponding 95% confidence intervals (95%CIs) for tobacco use were obtained from Poisson regression analysis of grouped survival data, considering age, follow-up period, occupation and education. RESULTS: Bidi smoking was associated with GC risk (P = 0.042). The RR comparing current versus never smokers was 1.6 (95%CI: 1.0-2.5). GC risk was associated with the number of bidis smoked daily (P = 0.012) and with the duration of bidi smoking (P = 0.036). Those who started bidi smoking at younger ages were at an elevated GC risk; the RRs for those starting bidi smoking under the age of 18 and ages 18-22 were 2.0 (95%CI: 1.0-3.9) and 1.8 (95%CI: 1.1 2.9), respectively, when their risks were compared with lifetime non-smokers of bidis. Bidi smoking increased the risk of GC among never cigarette smokers more evidently (RR = 2.2; 95%CI: 1.3-4.0). GC risk increased with the cumulative amount of bidi smoking, which was calculated as the number of bidis smoked per day x years of smoking (bidi-year; P = 0.017). Cigarette smoking, tobacco chewing or alcohol drinking was not significantly associated with GC risk. CONCLUSION: Among a male cohort in South India, gastric cancer risk increased with the number and duration of bidi smoking. PMID- 26640346 TI - Transanal total mesorectal excision: Towards standardization of technique. AB - AIM: To describe the role of Transanal total mesorectal excision (TaTME) in minimally invasive rectal cancer surgery, to examine the differences in patient selection and in reported surgical techniques and their impacts on postoperative outcomes and to discuss the future of TaTME. METHODS: MEDLINE (PubMed), EMBASE, and The Cochrane Library were systematically searched through the 1(st) of March 2015 using a predefined search strategy. RESULTS: A total of 20 studies with 323 patients were included. Most studies were single-arm prospective studies with fewer than 100 patients. Multiple transanal access platforms were used, and the laparoscopic approach was either multi- or single port. The procedure was initiated transanally or transabdominally. If a simultaneous approach with 2 operating surgeons was chosen, the operative time was significantly reduced. CONCLUSION: TaTME was also associated with better TME specimens and a longer distal resection margin. TaTME is thus feasible in expert hands, but the learning curve and safety profile are not well defined. Long-term follow-up regarding anal function and oncological outcomes should be performed in the future. PMID- 26640347 TI - Probe based confocal laser endomicroscopy of the pancreatobiliary system. AB - AIM: To review applications of confocal laser endomicroscopy (CLE) in pancreatobiliary lesions and studies that assessed training and interpretation of images. METHODS: A computerized literature search was performed using OVID MEDLINE, EMBASE, Cochrane library, and the ISI Web of Knowledge from 1980 to October 2014. We also searched abstracts from major meetings that included the Digestive Disease Week, Canadian Digestive Disease Week and the United European Gastroenterology Week using a combination of controlled vocabulary and text words related to pCLE, confocal, endomicroscopy, probe-based confocal laser endomicroscopy, and bile duct to identify reports of trials. In addition, recursive searches and cross-referencing was performed, and manual searches of articles identified after the initial search was also completed. We included fully published articles and those in abstract form. Given the relatively recent introduction of CLE we included randomized trials and cohort studies. RESULTS: In the evaluation of indeterminate pancreatobiliary strictures CLE with ERCP compared to ERCP alone can increase the detection of cancerous strictures with a sensitivity of (98% vs 45%) and has a negative predictive value (97% vs 69%), but decreased the specificity (67% vs 100%) and the positive predictive value (71% vs 100%) when compared to index pathology. Modifications in the classification systems in indeterminate biliary strictures have increased the specificity of pCLE from 67% to 73%. In pancreatic cystic lesions there is a need to develop similar systems to interpret and characterize lesions based on CLE images obtained. The presence of superficial vascular network predicts serous cystadenomas accurately. Also training in acquiring and interpretation of images is feasible in those without any prior knowledge in CLE in a relatively simple manner and computer-aided diagnosis software is a promising innovation. CONCLUSION: The role of pCLE in the evaluation of pancreatobiliary disorders might be better suited for those with an intermediate and low probability. PMID- 26640348 TI - Perforated duodenal ulcer: An unusual manifestation of allergic eosinophilic gastroenteritis. AB - Spontaneous perforation of a duodenal ulcer secondary to allergic eosinophilic gastroenteritis (EGE) has not been previously reported. We present such a case in a teenager who presented with peritonitis. After exploration and operative repair of his ulcer, he continued to experience intermittent abdominal pain, and further evaluation revealed eosinophilic gastroenteritis in the setting of multiple food allergies. His EGE resolved after adhering to a restrictive diet. Both duodenal ulcers and EGE are very rarely seen in pediatric patients. EGE has a variable presentation depending on the layer(s) of bowel wall affected and the segment of the gastrointestinal tract that is involved. Once diagnosed, it may respond to dietary changes in patients with recognized food allergies, or to steroids in patients in whom an underlying cause is not identified. Our case highlights the need to keep EGE in the differential diagnosis when treating pediatric patients with duodenal ulcers. The epidemiology, pathophysiology, and treatment of EGE are also discussed, along with a review of the current literature. PMID- 26640349 TI - Characteristic clinical features of Aspergillus appendicitis: Case report and literature review. AB - This work aims to facilitate diagnosing Aspergillus appendicitis, which can be missed clinically due to its rarity, by proposing a clinical pentad for Aspergillus appendicitis based on literature review and one new case. The currently reported case of pathologically-proven Aspergillus appendicitis was identified by computerized search of pathology database at William Beaumont Hospital, 1999-2014. Prior cases were identified by computerized literature search. Among 10980 pathology reports of pathologically-proven appendicitis, one case of Aspergillus appendicitis was identified (rate = 0.01%). A young boy with profound neutropenia, recent chemotherapy, and acute myelogenous leukemia presented with right lower quadrant pain, pyrexia, and generalized malaise. Abdominal computed tomography scan showed a thickened appendiceal wall and periappendiceal inflammation, suggesting appendicitis. Emergent laparotomy showed an inflamed, thickened appendix, which was resected. The patient did poorly postoperatively with low-grade-fevers while receiving antibacterial therapy, but rapidly improved after initiating amphotericin therapy. Microscopic examination of a silver stain of the appendectomy specimen revealed fungi with characteristic Aspergillus morphology, findings confirmed by immunohistochemistry. Primary Aspergillus appendicitis is exceptionally rare, with only 3 previously reported cases. All three cases presented with (1)-neutropenia, (2)-recent chemotherapy, (3)-acute leukemia, and (4)-suspected appendicitis; (5)-the two prior cases initially treated with antibacterial therapy, fared poorly before instituting anti-Aspergillus therapy. The current patient satisfied all these five criteria. Based on these four cases, a clinical pentad is proposed for Aspergillus appendicitis: clinically-suspected appendicitis, neutropenia, recent chemotherapy, acute leukemia, and poor clinical response if treated solely by antibacterial/anti-candidial therapy. Patients presenting with this proposed pentad may benefit from testing for Aspergillus infection by silver stains/immunohistochemistry and considering empirical anti-Aspergillus therapy pending a tissue diagnosis. PMID- 26640350 TI - Successful resection of metachronous para-aortic, Virchow lymph node and liver metastatic recurrence of rectal cancer. AB - A 66-year-old female presented with the main complaint of defecation trouble and abdominal distention. With diagnosis of rectal cancer, cSS, cN0, cH0, cP0, cM0 cStage II, Hartmann's operation with D3 lymph node dissection was performed and a para-aortic lymph node and a disseminated node near the primary tumor were resected. Histological examination showed moderately differentiated adenocarcinoma, pSS, pN3, pH0, pP1, pM1 (para-aortic lymph node, dissemination) fStage IV. After the operation, the patient received chemotherapy with FOLFIRI regimen. After 12 cycles of FOLFIRI regimen, computed tomography (CT) detected an 11 mm of liver metastasis in the postero-inferior segment of right hepatic lobe. With diagnosis of liver metastatic recurrence, we performed partial hepatectomy. Histological examination revealed moderately differentiated adenocarcinoma as a metastatic rectal cancer with cut end microscopically positive. After the second operation, the patient received chemotherapy with TS1 alone for 2 years. Ten months after the break, CT detected a 20 mm of para-aortic lymph node metastasis and a 10 mm of lymph node metastasis at the hepato-duodenal ligament. With diagnosis of lymph node metastatic recurrences, we performed lymph node dissection. Histological examination revealed moderately differentiated adenocarcinoma as metastatic rectal cancer in para-aortic and hepato-duodenal ligament areas. After the third operation, we started chemotherapy with modified FOLFOX6 regimen. After 2 cycles of modified FOLFOX6 regimen, due to the onset of neutropenia and liver dysfunction, we switched to capecitabine alone and continued it for 6 mo and then stopped. Eleven months after the break, CT detected two swelling 12 mm of lymph nodes at the left supraclavicular region. With diagnosis of Virchow lymph node metastatic recurrence, we started chemotherapy with capecitabine plus bevacizumab regimen. Due to the onset of neutropenia and hand foot syndrome (Grade 3), we managed to continue capecitabine administration with extension of interval period and dose reduction. After 2 years and 2 mo from starting capecitabine plus bevacizumab regimen, Virchow lymph nodes had slowly grown up to 17 mm. Because no recurrence had been detected besides Virchow lymph nodes for this follow up period, considering the side effects and quality of life, surgical resection was selected. We performed left supraclavicular lymph node dissection. Histological examination revealed moderately differentiated adenocarcinoma as a metastatic rectal cancer. After the fourth operation, the patient selected follow up without chemotherapy. Now we follow up her without recurrence and keep her quality of life high. PMID- 26640351 TI - Management of early hepatic artery occlusion after liver transplantation with failed rescue. AB - Hepatic artery thrombosis is a serious complication after liver transplantation which often results in biliary complications, early graft loss, and patient death. It is generally thought that early hepatic artery thrombosis without urgent re-vascularization or re-transplantation almost always leads to mortality, especially if the hepatic artery thrombosis occurs within a few days after transplantation. This series presents 3 cases of early hepatic artery thrombosis after living donor liver transplantation, in which surgical or endovascular attempts at arterial re-vascularization failed. Unexpectedly, these 3 patients survived with acceptable graft function after 32 mo, 11 mo, and 4 mo follow-up, respectively. The literatures on factors affecting this devastating complication were reviewed from an anatomical perspective. The collective evidence from survivors indicated that modified nonsurgical management after liver transplantation with failed revascularization may be sufficient to prevent mortality from early hepatic artery occlusion. Re-transplantation may be reserved for selected patients with unrecovered graft function. PMID- 26640352 TI - What's working in working memory training? An educational perspective. AB - Working memory training programs have generated great interest, with claims that the training interventions can have profound beneficial effects on children's academic and intellectual attainment. We describe the criteria by which to evaluate evidence for or against the benefit of working memory training. Despite the promising results of initial research studies, the current review of all of the available evidence of working memory training efficacy is less optimistic. Our conclusion is that working memory training produces limited benefits in terms of specific gains on short-term and working memory tasks that are very similar to the training programs, but no advantage for academic and achievement-based reading and arithmetic outcomes. PMID- 26640353 TI - Thermally Activated Deformation Behavior of ufg-Au: Environmental Issues During Long-Term and High-Temperature Nanoindentation Testing. AB - For testing time-dependent material properties by nanoindentation, in particular for long-term creep or relaxation experiments, thermal drift influences on the displacement signal are of prime concern. To address this at room and elevated temperatures, we tested fused quartz at various contact depths at room temperature and ultra-fine grained (ufg) Au at various temperatures. We found that the raw data for fused quartz are strongly affected by thermal drift, but corrected by use of dynamic stiffness measurements all the datasets collapse. The situation for the ufg Au shows again that the data are only useful with drift correction, but with this applied it turns out that there is a significant change of elastic and plastic properties when exceeding 200 degrees C, which is also reflected by an increasing strain rate sensitivity. PMID- 26640354 TI - Interpretation of Anaphoric Dependencies in Russian-speaking Children with and without Developmental Language Disorder. AB - We examined anaphora resolution in children with and without Developmental Language Disorder (DLD) to clarify whether 1) DLD is best understood as missing knowledge of certain linguistic operations/elements or as unreliable performance and 2) if comprehension of sentences with anaphoric expressions as objects and exceptionally case marked (ECM) subjects supports a particular theoretical account of anaphora. Fifty-four native-Russian-speaking children (age M = 7;6, SD = 1;9) were tested on a picture selection task. Children with DLD (n=18) underperformed overall, but displayed similar patterns to the typically developing (TD) group with respect to the extra difficulty of the ECM relative to the transitive and ECM pronouns relative to all other conditions. However, whereas pronouns were more difficult than reflexives for the TD children, this effect was not significant for the DLD group, whose reduced accuracy on reflexives washed out the effect of pronouns in that group. These results are consistent with performance-level vulnerability in DLD, arguably related to weaknesses in lexical processing and with the Reflexivity framework of Binding phenomena. PMID- 26640355 TI - Sibling Facilitation Mediates the Association Between Older and Younger Sibling Alcohol Use in Late Adolescence. AB - Previous research has shown adolescent siblings are similar in their alcohol use and that this similarity is largely due to their shared environment. Using a genetically-informed sibling sample (196 full-biological pairs, 384 genetically unrelated pairs), we confirmed that the extent to which older siblings facilitate younger siblings' alcohol use (i.e., help them get alcohol) was one factor contributing to this shared environmental association. All analyses controlled for parent and peer influences. Findings were not moderated by sibling differences in genetic relatedness, gender, or ethnicity. Proximity in sibling age strengthened these associations, somewhat. Results were especially strong for sibling pairs where the older sibling was of legal drinking age. Implications for prevention and intervention are discussed. PMID- 26640356 TI - Early Adolescent Peer Foundations of Late Adolescent and Young Adult Psychological Adjustment. AB - The long-term impacts of failing to establish autonomy and relatedness within close friendships are poorly understood. Adolescent behaviors undermining autonomy and relatedness in friendships at 13 were examined as predictors of friendship competence at 18 and depressive symptoms and social withdrawal at 21. A diverse community sample of 184 adolescents participated in self, peer, and observational assessments. Teens' inability to establish autonomy and connection with friends at 13 predicted decreases in friendship competence at 18 (beta=-.20, p=.02). Direct links to increases in depressive symptoms (beta=.34, p<.001) and social withdrawal (beta=.18, p=.03) were observed, with friendship competence partially mediating these relations. Results highlight the importance of problematic adolescent peer relationships as risk factors for the development of young adult internalizing symptoms. PMID- 26640357 TI - Recurrent Streptococcus Pneumoniae Meningitis in a Child with Split Hand and Foot Malformation and Undiagnosed Mondini Dysplasia. AB - Recurrent bacterial meningitis is a life-threatening infection of the central nervous system that is mostly connected with anatomical abnormalities of the skull, chronic parameningeal infections and immunodeficiencies. It's rarely seen, but when it occurs an extensive investigation should be carried out to discover the responsible factor, so that further episodes can be prevented. We report on a child with split hand and foot (SHFM), confirmed incorrect karyotype 46, XY, t(7:12)(q21.2;q21.3) and a fourth episode of fulminant meningitis caused by penicillin-resistant Streptococcus pneumoniae. After a broad evaluation of factors predisposing to recurrent meningitis, the undiagnosed malformation of his inner and middle ears - Mondini dysplasia was found. We suggest examining all children with SHFM for hearing impairment before they develop recurrent meningitis. The time when the radiological procedure for searching for inner ear dysplasia should be performed could be a controversial issue: before or after the first episode of meningitis. From the epidemiological point of view, high resolution computer tomography scanning of the temporal bones should be considered after the diagnosis of deafness in a child with SHFM related to 7q21 deletion. PMID- 26640358 TI - The Distress of Citizen-Children with Detained and Deported Parents. AB - In immigration enforcement, many undocumented immigrants with children are often detained and deported. But it is their US-born citizen-children that have been overlooked in immigration debates and enforcement policies and practices. Citizen children are at risk for negative psychological outcomes when families are fractured and destabilized by arrest, detention, and deportation. The children risk being torn from their parents and, often, their undocumented siblings. To add to the small but growing empirical base on the effects of living under the threat of deportation and actual deportation of parents, we compared the psychological status of three groups of citizen-children: (1) a group living in Mexico with their deported parents; (2) a group in the US with parents affected by detention or deportation; and (3) a comparison group of citizen-children whose undocumented parents were not affected by detention or deportation. We compared children on self-report and parent-report measures of behavioral adjustment, depression, anxiety, and self-concept. Across the three groups we found elevated levels of distress, and differences between children who had experienced a parent's detention or deportation and those who had not. We discuss findings in the context of children's clinical needs, future research, and implications for immigration enforcement policy and practices. PMID- 26640359 TI - Solutions to the Inverse LQR Problem with Application to Biological Systems Analysis. AB - In this paper, we present a set of techniques for finding a cost function to the time-invariant Linear Quadratic Regulator (LQR) problem in both continuous- and discrete-time cases. Our methodology is based on the solution to the inverse LQR problem, which can be stated as: does a given controller K describe the solution to a time-invariant LQR problem, and if so, what weights Q and R produce K as the optimal solution? Our motivation for investigating this problem is the analysis of motion goals in biological systems. We first describe an efficient Linear Matrix Inequality (LMI) method for determining a solution to the general case of this inverse LQR problem when both the weighting matrices Q and R are unknown. Our first LMI-based formulation provides a unique solution when it is feasible. Additionally, we propose a gradient-based, least-squares minimization method that can be applied to approximate a solution in cases when the LMIs are infeasible. This new method is very useful in practice since the estimated gain matrix K from the noisy experimental data could be perturbed by the estimation error, which may result in the infeasibility of the LMIs. We also provide an LMI minimization problem to find a good initial point for the minimization using the proposed gradient descent algorithm. We then provide a set of examples to illustrate how to apply our approaches to several different types of problems. An important result is the application of the technique to human subject posture control when seated on a moving robot. Results show that we can recover a cost function which may provide a useful insight on the human motor control goal. PMID- 26640360 TI - Petrography, stable isotope compositions, microRaman spectroscopy, and presolar components of Roberts Massif 04133: A reduced CV3 carbonaceous chondrite. AB - Here, we report the mineralogy, petrography, C-N-O-stable isotope compositions, degree of disorder of organic matter, and abundances of presolar components of the chondrite Roberts Massif (RBT) 04133 using a coordinated, multitechnique approach. The results of this study are inconsistent with its initial classification as a Renazzo-like carbonaceous chondrite, and strongly support RBT 04133 being a brecciated, reduced petrologic type >3.3 Vigarano-like carbonaceous (CV) chondrite. RBT 04133 shows no evidence for aqueous alteration. However, it is mildly thermally altered (up to approximately 440 degrees C); which is apparent in its whole-rock C and N isotopic compositions, the degree of disorder of C in insoluble organic matter, low presolar grain abundances, minor element compositions of Fe,Ni metal, chromite compositions and morphologies, and the presence of unequilibrated silicates. Sulfides within type I chondrules from RBT 04133 appear to be pre-accretionary (i.e., did not form via aqueous alteration), providing further evidence that some sulfide minerals formed prior to accretion of the CV chondrite parent body. The thin section studied contains two reduced CV3 lithologies, one of which appears to be more thermally metamorphosed, indicating that RBT 04133, like several other CV chondrites, is a breccia and thus experienced impact processing. Linear foliation of chondrules was not observed implying that RBT 04133 did not experience high velocity impacts that could lead to extensive thermal metamorphism. Presolar silicates are still present in RBT 04133, although presolar SiC grain abundances are very low, indicating that the progressive destruction or modification of presolar SiC grains begins before presolar silicate grains are completely unidentifiable. PMID- 26640361 TI - Progress Towards Synthetic Chlorins with Graded Polarity, Conjugatable Substituents, and Wavelength Tunability. AB - Advances in chlorin synthetic chemistry now enable the de novo preparation of diverse chlorin-containing molecular architectures. Five distinct molecular designs have been explored here, including hydrophobic bioconjugatable (oxo)chlorins; a hydrophilic bioconjugatable chlorin; a trans-ethynyl/iodochlorin building block; a set of chlorins bearing electron-rich (methoxy, dimethylamino, methylthio) groups at the 3-position; and a set of ten 3,13-disubstituted chlorins chiefly bearing groups with extended pi-moieties. Altogether 23 new chlorins (17 targets, 6 intermediates) have been prepared. The challenge associated with molecular designs that encompass the combination of "hydrophilic, bioconjugatable and wavelength-tunable" chiefly resides in the nature of the hydrophilic unit. PMID- 26640362 TI - Time-limited, structured youth mentoring and adolescent problem behaviors. AB - Youth mentoring can have a profound impact on the lives of high-risk youth. This study presents the Campus Corps program, a time-limited (12-week), structured mentoring program for high-risk youth (ages 11-18), and results from a quasi experimental pilot evaluation. Baseline and post-intervention problem behavior data from 315 offending youth were used in multiple regression analyses. After accounting for baseline group differences, pre-intervention scores, and demographic covariates, Campus Corps participants (n=187, 63.1% male) reported less engagement in problem behavior, lower acceptance of problem behavior, and greater sense of autonomy from marijuana use post-intervention than participants in the comparison condition (n=128, 66.4% male). Conversely, post-intervention group differences were not observed for peer refusal skills or autonomy from alcohol use. A description of the Campus Corps program design and supplemental preliminary findings contribute to the growing knowledge base of youth mentoring program designs and outcomes. PMID- 26640363 TI - Segmenting the Human Genome into Isochores. AB - The human genome is a mosaic of isochores, which are long (>200 kb) DNA sequences that are fairly homogeneous in base composition and can be assigned to five families comprising 33%-59% of GC composition. Although the compartmentalized organization of the mammalian genome has been investigated for more than 40 years, no satisfactory automatic procedure for segmenting the genome into isochores is available so far. We present a critical discussion of the currently available methods and a new approach called isoSegmenter which allows segmenting the genome into isochores in a fast and completely automatic manner. This approach relies on two types of experimentally defined parameters, the compositional boundaries of isochore families and an optimal window size of 100 kb. The approach represents an improvement over the existing methods, is ideally suited for investigating long-range features of sequenced and assembled genomes, and is publicly available at https://github.com/bunop/isoSegmenter. PMID- 26640364 TI - Organ-on-a-Chip: New Platform for Biological Analysis. AB - Direct detection and analysis of biomolecules and cells in physiological microenvironment is urgently needed for fast evaluation of biology and pharmacy. The past several years have witnessed remarkable development opportunities in vitro organs and tissues models with multiple functions based on microfluidic devices, termed as "organ-on-a-chip". Briefly speaking, it is a promising technology in rebuilding physiological functions of tissues and organs, featuring mammalian cell co-culture and artificial microenvironment created by microchannel networks. In this review, we summarized the advances in studies of heart-, vessel , liver-, neuron-, kidney- and Multi-organs-on-a-chip, and discussed some noteworthy potential on-chip detection schemes. PMID- 26640365 TI - Significance of the disc damage likelihood scale objectively measured by a non mydriatic fundus camera in preperimetric glaucoma. AB - PURPOSE: To assess the correlation between the disc damage likelihood scale (DDLS) objectively measured by a non-mydriatic fundus camera, Heidelberg Retina Tomograph 3, and optic coherence tomography in preperimetric glaucoma. METHODS: One-hundred-twenty-five patients with preperimetric primary open-angle glaucoma (POAG) and pseudoexfoliation glaucoma (n=30) were included (mean age 58.9+/-15.9 years). All three devices graded the optic disc topography: Diagnosis 1 was defined as "outside normal limits", while Diagnosis 2 as "borderline or outside normal limits". RESULTS: For Diagnosis 1, a significant correlation was shown between DDLS and Moorfields regression analysis (P=0.022), and for Diagnosis 2 with glaucoma probability score analysis (P=0.024), in POAG. In pseudoexfoliation glaucoma, DDLS did not correlate significantly with Heidelberg Retina Tomograph 3 and optic coherence tomography. Regarding the area under the curve the highest predictive power was demonstrated by the objective DDLS (0.513-0.824) compared to Burk (0.239-0.343) and Mikelberg (0.093-0.270) coefficients. CONCLUSIONS: The DDLS showed a significant correlation to the Moorfields regression analysis in preperimetric POAG. The objective DDLS showed the highest predictive power and thus is an additive tool in diagnosing preperimetric glaucoma. PMID- 26640366 TI - Geographic atrophy in patients with advanced dry age-related macular degeneration: current challenges and future prospects. AB - Geographic atrophy (GA) of the retinal pigment epithelium (RPE) is a devastating complication of age-related macular degeneration (AMD). GA may be classified as drusen-related (drusen-associated GA) or neovascularization-related (neovascular associated GA). Drusen-related GA remains a large public health concern due to the burden of blindness it produces, but pathophysiology of the condition is obscure and there are no proven treatment options. Genotyping, cell biology, and clinical imaging point to upregulation of parainflammatory pathways, oxidative stress, and choroidal sclerosis as contributors, among other factors. Onset and monitoring of progression is accomplished through clinical imaging instrumentation such as optical coherence tomography, photography, and autofluorescence, which are the tools most helpful in determining end points for clinical trials at present. A number of treatment approaches with diverse targets are in development at this time, some of which are in human clinical trials. Neovascular-associated GA is a consequence of RPE loss after development of neovascular AMD. The neovascular process leads to a plethora of cellular stresses such as ischemia, inflammation, and dramatic changes in cell environment that further taxes RPE cells already dysfunctional from drusen-associated changes. GA may therefore develop secondary to the neovascular process de novo or preexisting drusen-associated GA may continue to worsen with the development of neovascular AMD. Neovascular-associated GA is a prominent cause of continued vision loss in patients with otherwise successfully treated neovascular AMD. Clearly, treatment with vascular endothelial growth factor (VEGF) inhibitors early in the course of the neovascular disease is of great clinical benefit. However, there is a rationale and some suggestive evidence that anti-VEGF agents themselves could be toxic to RPE and enhance neovascular-associated GA. The increasing prevalence of legal blindness from this condition due to the aging of the general population lends urgency to the search for a therapy to ameliorate GA. PMID- 26640367 TI - Development of oral dispersible tablets containing prednisolone nanoparticles for the management of pediatric asthma. AB - The purpose of the present study was to develop oral dispersible tablets containing prednisolone (PDS)-loaded chitosan nanoparticles using microcrystalline cellulose (MCC 101), lactose, and croscarmellose sodium (CCS). The PDS-loaded chitosan nanoparticles were formulated by ionotropic external gelation technique in order to enhance the solubility of PDS in salivary pH. Prepared nanoparticles were used for the development of oral fast disintegrating tablets by direct compression method. The prepared tablets were evaluated for disintegration time (DT), in vitro drug release (DR), thickness, weight variation, drug content uniformity, friability, and hardness. The effect of concentrations of the dependent variables (MCC, lactose, CCS) on DT and in vitro DR was studied. Fast disintegrating tablets of PDS can be prepared by using MCC, CCS, and lactose with enhanced solubility of PDS. The minimum DT was found to be 15 seconds, and the maximum DR within 30 minutes was 98.50%. All independent variables selected for the study were statistically significant. Oral fast disintegrating tablets containing PDS nanoparticles could be the better choice for the pediatric patients that would result in better patient compliance. From this study, it can be concluded that fast disintegrating tablets could be a potential drug delivery technology for the management of asthma in pediatrics. PMID- 26640368 TI - Protective effects of alginate-chitosan microspheres loaded with alkaloids from Coptis chinensis Franch. and Evodia rutaecarpa (Juss.) Benth. (Zuojin Pill) against ethanol-induced acute gastric mucosal injury in rats. AB - Zuojin Pill (ZJP), a traditional Chinese medicine formula, consists of Coptis chinensis Franch. and Evodia rutaecarpa (Juss.) Benth. in a ratio of 6:1 (w/w) and was first recorded in "Danxi's experiential therapy" for treating gastrointestinal disorders in the 15th century. However, the poor solubility of alkaloids from ZJP restricted the protective effect in treating gastritis and gastric ulcer. The aim of the study was to investigate the protective mechanism of mucoadhesive microspheres loaded with alkaloids from C. chinensis Franch. and E. rutaecarpa (Juss.) Benth. on ethanol-induced acute gastric mucosal injury in rats. Surface morphology, particle size, drug loading, encapsulation efficiency, in vitro drug release, mucoadhesiveness, and fluorescent imaging of the microspheres in gastrointestinal tract were studied. The results showed that the mucoadhesive microspheres loaded with alkaloids could sustain the release of drugs beyond 12 hours and had gastric mucoadhesive property with 82.63% retention rate in vitro. The fluorescence tracer indicated high retention of mucoadhesive microspheres within 12 hours in vivo. The mucoadhesive microspheres loaded with alkaloids could reduce the gastric injury by decreasing the mucosal lesion index, increasing the percentage of inhibition and increasing the amount of mucus in the gastric mucosa in an ethanol-induced gastric mucosal injury rat model. Moreover, the mucoadhesive microspheres loaded with alkaloids reduce the inflammatory response by decreasing the levels of tumor necrosis factor-alpha (TNF-alpha), interleukin 1beta (IL-1beta), downregulating the mRNA expression of inducible nitric oxide synthase, TNF-alpha, and IL-1beta in gastric mucosa. All the results indicate that mucoadhesive microspheres loaded with alkaloids could not only increase the residence time of alkaloids in rat stomach, but also exert gastroprotective effects through reducing the inflammatory response on ethanol induced gastric mucosal damage. Thus, these microspheres could be developed as a potential controlled release drug for treatment of gastric ulcer. PMID- 26640369 TI - Influence of glucosamine on the bioactivity of insulin delivered subcutaneously and in an oral nanodelivery system. AB - The aim of the work reported herein was to study the effect of glucosamine HCl (GlcN.HCl) on the bioactivity (BA) of insulin, administered via subcutaneous (SC) and oral routes, in adult male Sprague Dawley rats. The oral insulin delivery system (insulin-chitosan reverse micelle [IC-RM]) was prepared by solubilizing insulin-chitosan (13 kDa) polyelectrolyte complex in a RM system consisting of oleic acid, PEG-8 caprylic/capric glycerides, and polyglycerol-6-dioleate. The BA of insulin in vivo was evaluated by measuring blood glucose level using a blood glucose meter; the results revealed that the extent of hypoglycemic activity of SC insulin was GlcN.HCl dose dependent when they were administered simultaneously. A significant reduction in blood glucose levels (P<0.05) was found for the insulin:GlcN.HCl at mass ratios of 1:10 and 1:20, whereas lower ratios (eg, 1:1 and 1:4) showed no significant reduction. Furthermore, enhancement of the action of SC insulin was achieved by oral administration of GlcN.HCl for 5 consecutive days prior to insulin injection (P<0.05). For oral insulin administration via the IC-RM system, the presence of GlcN.HCl increased the hypoglycemic activity of insulin (P<0.05). The relative BA were 6.7% and 5.4% in the presence and absence of GlcN.HCl (ie, the increase in the relative BA was approximately 23% due to incorporating GlcN.HCl in the IC-RM system), respectively. The aforementioned findings offer an opportunity to incorporate GlcN.HCl in oral insulin delivery systems in order to enhance a reduction in blood glucose levels. PMID- 26640370 TI - Prospective study on nanoparticle albumin-bound paclitaxel in advanced breast cancer: clinical results and biological observations in taxane-pretreated patients. AB - BACKGROUND: There is a deep need to improve the care of metastatic breast cancer (MBC) patients, since even today it remains an incurable disease. Taxanes are considered the most effective cytotoxic drugs for the treatment of MBC, both in monotherapy and in combined schedules, but the need for synthetic solvents contributes to the severe toxicities and may have a negative impact on the efficacy. Nanoparticle albumin-bound paclitaxel (Nab-paclitaxel) is a colloidal suspension of paclitaxel and human serum albumin initially developed to avoid the toxicities associated with conventional taxanes. PATIENTS AND METHODS: The aim of this prospective, single-center open-label, noncomparative study was to evaluate the efficacy and safety of nab-paclitaxel in MBC patients pretreated with taxanes. The patients were treated with nab-paclitaxel as a single agent, 260 mg/m(2) on day 1 of each 3-week cycle or 125 mg/m(2) weekly. The primary endpoint was the overall response rate (ORR). Secondary objectives were duration of response, clinical benefit rate, progression-free survival (PFS), overall survival, and safety. RESULTS: A total of 42 patients (median age 48 years, median Eastern Cooperative Oncology Group performance status 0, triple-negative MBC 19%, all pretreated with a taxane-based therapy, mainly in advanced disease) were enrolled in the study. The ORR was 23.8%, including one complete response (2.4%) and nine partial responses (21.4%); the disease control rate was 50%. The median duration of response was 7.2 months. After a median follow-up of 9 months, the median PFS was 4.6 months. ORR and PFS were similar irrespective of the previous chemotherapy lines, metastatic sites, and biomolecular expression. Nab paclitaxel was well tolerated, and the most frequent treatment-related toxicities were mild to moderate (grades 1-2). CONCLUSION: This real-life study shows that nab-paclitaxel has a significant antitumor activity and a manageable safety profile in patients pretreated with taxanes and experiencing a treatment failure after at least one line of chemotherapy. PMID- 26640371 TI - Spotlight on tavaborole for the treatment of onychomycosis. AB - Onychomycosis is a fungal nail plate infection that has been increasing in prevalence. A variety of oral and topical anti-fungal agents are currently available but their use is limited by their adverse effect profile, drug-drug interactions, and limited efficacy. Therefore, there is a great need for newer anti-fungal agents. Tavaborole is one of these newer agents and was approved by the US Food and Drug Administration in July 2014 for the topical treatment of mild to moderate toenail onychomycosis. Tavaborole is a novel, boron-based anti fungal agent with greater nail plate penetration than its predecessors, due to its smaller molecular weight. It has proven through several Phase II and III trials that it can be a safe and effective topical agent for the treatment of mild to moderate toenail onychomycosis without the need for debridement. In this paper, we review the landscape of topical and systemic treatment of onychomycosis, with particular attention to the pharmacokinetics, safety, and efficacy of topical tavaborole. PMID- 26640372 TI - Complex antithrombotic therapy: determinants of patient preference and impact on medication adherence. AB - PURPOSE: For years, older patients have been prescribed multiple blood-thinning medications (complex antithrombotic therapy [CAT]) to decrease their risk of cardiovascular events. These therapies, however, increase risk of adverse bleeding events. We assessed patient-reported trade-offs between cardioprotective benefit, gastrointestinal bleeding risk, and burden of self-management using adaptive conjoint analysis (ACA). As ACA could be a clinically useful tool to obtain patient preferences and guide future patient-centered care, we examined the clinical application of ACA to obtain patient preferences and the impact of ACA on medication adherence. PATIENTS AND METHODS: An electronic ACA survey led 201 respondents through medication risk-benefit trade-offs, revealing patients' preferences for the CAT risk/benefit profile they valued most. The post-ACA prescription regimen was categorized as concordant or discordant with elicited preferences. Adherence was measured using VA pharmacy refill data to measure persistence of use prior to and 1 year following preference-elicitation. Additionally, we analyzed qualitative interviews of 56 respondents regarding their perception of the ACA and the preference elicitation experience. RESULTS: Participants prioritized 5-year cardiovascular benefit over preventing adverse events. Medication side effects, medication-associated activity restrictions, and regimen complexity were less important than bleeding risk and cardioprotective benefit. One year after the ACA survey, a 15% increase in adherence was observed in patients prescribed a preference-concordant CAT strategy. An increase of only 6% was noted in patients prescribed a preference-discordant strategy. Qualitative interviews showed that the ACA exercise contributed to increase inpatient activation, patient awareness of preferences, and patient engagement with clinicians about treatment decisions. CONCLUSION: By working through trade-offs, patients actively clarified their preferences, learning about CAT risks, benefits, and self-management. Patients with medication regimens concordant with their preferences had increased medication adherence at 1 year compared to those with discordant medication regimens. The ACA task improved adherence through enhanced patient engagement regarding treatment preferences. PMID- 26640373 TI - Treatment adherence in multiple sclerosis: a survey of Belgian neurologists. AB - BACKGROUND: Poor treatment adherence is common among patients with multiple sclerosis (MS). This survey evaluated neurologists' perception of treatment adherence among MS patients. MATERIALS AND METHODS: This questionnaire-based survey of Belgian neurologists treating MS patients was conducted between June and July 2014. Face-to-face interviews with the neurologists were based on a semistructured questionnaire containing questions regarding the perception of the treatment-adherence level. RESULTS: A total of 41 neurologists participated in the survey. Of these, 88% indicated frequent discussions about treatment adherence as beneficial for treatment efficacy. The mean time spent on the treatment-adherence discussion during the initial consultation was 11 minutes, with 24% of doctors spending 5 minutes and 24% of doctors spending 10 minutes discussing this issue. The majority of neurologists (56%) perceived the adherence level in MS as good, and 12% perceived it as excellent. The majority of neurologists (64%) indicated intolerance as a main cause of poor adherence, and all neurologists reported insufficient efficacy as a consequence of nonadherence. The importance of adherence in the neurologists' practice was evaluated on a scale of 1-10, with 1= "not very important" and 10= "very important": 44% of doctors indicated a score of 10, and the mean score was 9.0. CONCLUSION: Belgian neurologists consider treatment adherence in MS as essential for the benefits of therapies. However, although neurologists are aware of the consequences of nonadherence, they generally spend limited time discussing the importance of treatment adherence with their patients. PMID- 26640374 TI - Nanotechnology-based inhalation treatments for lung cancer: state of the art. AB - Considering the challenges associated with conventional chemotherapy, targeted and local delivery of chemotherapeutics via nanoparticle (NP) carriers to the lungs is an emerging area of interest. Recent studies and growing clinical application in cancer nanotechnology showed the huge potential of NPs as drug carriers in cancer therapy, including in lung carcinoma for diagnosis, imaging, and theranostics. Researchers have confirmed that nanotechnology-based inhalation chemotherapy is viable and more effective than conventional chemotherapy, with lesser side effects. Recently, many nanocarriers have been investigated, including liposomes, polymeric micelles, polymeric NPs, solid lipid NPs, and inorganic NPs for inhalation treatments of lung cancer. Yet, the toxicity of such nanomaterials to the lungs tissues and further distribution to other organs due to systemic absorption on inhalation delivery is a debatable concern. Here, prospect of NPs-based local lung cancer targeting through inhalation route as well as its associated challenges are discussed. PMID- 26640375 TI - Cross-species Transcriptomic Comparison of In Vitro and In Vivo Mammalian Neural Cells. AB - The mammalian brain is characterized by distinct classes of cells that differ in morphology, structure, signaling, and function. Dysregulation of gene expression in these cell populations leads to various neurological disorders. Neural cells often need to be acutely purified from animal brains for research, which requires complicated procedure and specific expertise. Primary culture of these cells in vitro is a viable alternative, but the differences in gene expression of cells grown in vitro and in vivo remain unclear. Here, we cultured three major neural cell classes of rat brain (ie, neurons, astrocytes, and oligodendrocyte precursor cells [OPCs]) obtained from commercial sources. We measured transcript abundance of these cell types by RNA sequencing (RNA-seq) and compared with their counterparts acutely purified from mouse brains. Cross-species RNA-seq data analysis revealed hundreds of genes that are differentially expressed between the cultured and acutely purified cells. Astrocytes have more such genes compared to neurons and OPCs, indicating that signaling pathways are greatly perturbed in cultured astrocytes. This dataset provides a powerful resource to demonstrate the similarities and differences of biological processes in mammalian neural cells grown in vitro and in vivo at the molecular level. PMID- 26640376 TI - Atomoxetine treatment may decrease striatal dopaminergic transporter availability after 8 weeks: pilot SPECT report of three cases. AB - Attention deficit/hyperactivity disorder is one of the most common neurodevelopmental disorders. The pathophysiology is thought to involve noradrenaline and dopamine. The role of dopamine transporter (DAT) was evaluated in imaging studies using mostly dopamine reuptake inhibitors. Atomoxetine is a selective noradrenaline reuptake inhibitor. Here we report the results of a pilot study conducted to evaluate changes in striatal DAT after 8 weeks of atomoxetine treatment. Our results suggest that 8 weeks of atomoxetine treatment may change striatal DAT bioavailability as measured via SPECT but that change was not correlated with genotype or clinical improvement. PMID- 26640377 TI - Prefrontocerebellar transcranial direct current stimulation increases amplitude and decreases latency of P3b component in patients with euthymic bipolar disorder. AB - INTRODUCTION: Neurocognitive impairments have been observed in patients with bipolar disorder (BD) even during the euthymic phase of the disease, potentially representing trait-associated rather than state-associated characteristics of the disorder. In the present study, we used transcranial direct current stimulation (tDCS) applied to cerebellar and prefrontal cortices to improve the neurophysiological performances of patients with euthymic BD. METHODS: Twenty five outpatients with BD underwent open-label prefrontocerebellar tDCS for 3 consecutive weeks. Neurophysiological performances were assessed through the examination of the P3b and P3a subcomponents of P300 event-related potential at baseline and after stimulation. RESULTS: Compared to baseline, P3b component after tDCS showed significantly higher amplitude and shorter latency (latency: Fz P=0.02, Cz P=0.03, and Pz P=0.04; amplitude: Fz P=0.24, Cz P=0.02, and Pz P=0.35). CONCLUSION: In our sample of patients with euthymic BD, concomitant prefrontoexcitatory and cerebellar-inhibitory modulations led to improved brain information processing stream. This improvement may at least partially result from neuroplastic modulation of prefrontocerebellar circuitry activity. PMID- 26640378 TI - Serum endocan levels in women with restless legs syndrome. AB - BACKGROUND: Endocan is a recently introduced marker of endothelial dysfunction. The objective of this study was to compare serum endocan levels in patients with restless legs syndrome (RLS) and control subjects in order to elucidate whether RLS is associated with endothelial dysfunction. METHODS: A total of 31 drug naive female patients with RLS and 31 age- and BMI-matched women were included in the study. Patients with pathological or physiological conditions or with a history of medication use that could potentially influence endothelial functions were excluded, as well as those with alcohol or drug abuse history. The two groups were compared with routine blood tests and serum endocan levels. RESULTS: Patients with RLS had lower serum endocan levels than the controls (P=0.037). There was a negative bivariate correlation between RLS severity score and serum endocan levels (r=-0.406, P=0.023). While white blood cell count was significantly higher in RLS group, 25-hydroxy vitamin D3, vitamin B12, transferrin saturation rate, and HDL-cholesterol were significantly lower. Creatininemia and diastolic blood pressure were also marginally insignificantly lower in RLS group. Due to the presence of differences between two groups in these variables, a linear regression analysis was performed that showed a positive association between endocan and creatininemia (beta=0.310, P=0.022), and a negative association between endocan and RLS (beta=-0.502, P<0.001). CONCLUSION: The results of this study seem to suggest that patients with RLS may have better endothelial functions when compared with the general population and that these patients may be better protected against atherosclerosis. PMID- 26640379 TI - Relationship between remnant hippocampus and amygdala and memory outcomes after stereotactic surgery for mesial temporal lobe epilepsy. AB - BACKGROUND AND PURPOSE: Mesial temporal structures play an important role in human memory. In mesial temporal lobe epilepsy (MTLE), seizure activity is generated from the same structures. Surgery is the definitive treatment for medically intractable MTLE. In addition to standard temporal lobe microsurgical resection, stereotactic radiofrequency amygdalohippocampectomy (SAHE) is used as an alternative MTLE treatment. While memory impairments after standard epilepsy surgery are well known, it has been shown that memory decline is not a feature of SAHE. The aim of the present study was to correlate the volume of the remnant hippocampus and amygdala in patients treated by SAHE with changes in memory parameters. MATERIALS AND METHODS: Thirty-seven MTLE patients treated by SAHE (ten right, 27 left) were included. Patients underwent magnetic resonance imaging examinations including hippocampal and amygdalar volumetry and neuropsychological evaluation preoperatively and 1 year after surgery. RESULTS: Using Spearman correlation analyses, larger left-sided hippocampal reductions were associated with lower verbal memory performance (rho=-0.46; P=0.02). On the contrary, improvement of global memory quotient (MQ) was positively correlated with larger right-sided hippocampal reduction (rho=0.66; P=0.04). Similarly, positive correlations between the extent of right amygdalar reduction and verbal MQ (rho=0.74; P=0.02) and global MQ change (rho=0.69; P=0.03) were found. Thus, larger right hippocampal and amygdalar reduction was associated with higher global and verbal MQ change after SAHE. CONCLUSION: Larger left-sided hippocampal reductions were associated with lower verbal memory performance. This finding is in accordance with the material-specific model of human memory, which states that the dominant hemisphere is specialized for the learning and recall of verbal information. We hypothesize that larger right-sided ablations enable the left temporal lobe to support memory more effectively, perhaps as a consequence of epileptiform discharges spreading from remnants of right mesiotemporal structures to the left. PMID- 26640380 TI - Long-term safety and efficacy of infliximab for the treatment of ankylosing spondylitis. AB - The introduction of TNFalpha blockers has revolutionized the treatment of ankylosing spondylitis (AS). The objectives of this review are to summarize the most up-to-date data on long-term efficacy and safety of infliximab in AS, with special emphasis on axial and extra-articular disease, predictors of response, and radiological response. The general consensus of this literature search was that infliximab is highly efficacious in the treatment of AS. Most studies have demonstrated good clinical outcomes after 3 years of treatment, as measured by Spondyloarthritis International Society response in 75%-85% of treated AS patients. Reports on the long-term effects of infliximab as documented by radiological findings, however, are controversial. While some studies reported a similar progression rate as that of the historical OASIS cohort, others have suggested that infliximab may halt new bone formation. The long-term safety of infliximab is well known, mainly from data stored in national registries. While it has been suggested that side effects of infliximab may be fewer in AS compared to rheumatoid arthritis, data on this issue are sparse, with most of the information on long-term safety pertaining to rheumatoid arthritis. It can however be concluded that the long-term efficacy of infliximab is apparently maintained in AS and with an acceptable safety profile. PMID- 26640381 TI - A case of Descemet's membrane detachments and tears during phacoemulsification. AB - Descemet's membrane detachment is an important reason for corneal endothelial decompensation after intraocular surgery. During cataract surgery, it is an unusual complication. We report a case of Descemet's membrane detachment in which approximately 60% of Descemet's membrane (DM) involving approximately the upper two-thirds of the cornea was torn out during a routine phacoemulsification. It caused diffuse corneal edema and blurred vision in the 2 months following the surgery. Topical prednisolone acetate (1%) and sodium chloride (5%) had been used for treatment, with slow improvement in the patient's symptoms and vision. Interestingly, the cornea regained clarity 2 months after surgery without further surgical treatment. PMID- 26640382 TI - Profile of bevacizumab and its potential in the treatment of cervical cancer. AB - Blocking angiogenesis is an effective antitumor strategy proven in many disease sites. Anti-angiogenic therapies are fulfilling the promise of improved outcomes in cervical cancer as demonstrated in several recent trials. With its overall survival improvement in metastatic or recurrent cervical cancer, a frame shift in the management of these patients has occurred. The US Food and Drug Administration approval of bevacizumab in advanced cervical cancer has led to national guidelines, including the US National Comprehensive Cancer Network guidelines for cervical cancer, including systemic regimens containing bevacizumab as first line combination therapy. Future trials will build on this anti-angiogenesis backbone via targeting additional novel pathways and potentially leading to further improved outcomes in cervical cancer. PMID- 26640383 TI - Diagnostic value of SHOX2 DNA methylation in lung cancer: a meta-analysis. AB - The diagnostic value of SHOX2 DNA methylation in patients with lung cancer remains controversial. Thus, we performed a systematic review and meta-analysis to assess diagnostic accuracy of SHOX2 DNA methylation in the lymph node, bronchial aspirates, pleural effusion, plasma, and tumor tissue for lung cancer. We conducted a comprehensive literature search in PubMed, Ovid, the Cochrane library, and Web of Science databases in May 2015. The diagnostic sensitivity (SEN), specificity (SPE), positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and summary receiver operating characteristic (SROC) curve were pooled using STATA 12.0 software. A total of 2,296 subjects included 1,129 lung cancer patients in eight studies were recruited in this meta-analysis. The summary estimates for SHOX2 DNA methylation in the diagnosis of lung cancer in these studies were pooled SEN =0.70 (95% confidence interval [CI]: 0.46-0.87), SPE =0.96 (95% CI: 0.91-0.99), PLR 20.01 (95% CI: 6.96-57.52), NLR 0.31 (95% CI: 0.15-0.64), and DOR 65.11 (95% CI: 13.10 323.61), and the area under the curve (AUC) was 0.96 (95% CI: 0.94-0.97). SHOX2 DNA methylation has greater diagnostic value in detecting lung cancer. In addition, considering the potential publication bias and high heterogeneity, further research studies with more well-designed and large sample sizes are needed in the future. PMID- 26640384 TI - Differences in clinical features between laparoscopy and open resection for primary tumor in patients with stage IV colorectal cancer. AB - PURPOSE: To identify differences in clinical features between laparoscopy and open resection for primary tumor in patients with stage IV colorectal cancer. We also evaluated short-term and oncologic outcomes after laparoscopy and open surgery. METHODS: A total of 100 consecutive stage IV patients undergoing open (n=61) or laparoscopic (n=39) major resection were analyzed. There were four cases (10%) of conversion to laparotomy in the laparoscopy group. RESULTS: Pathological T4 tumors (56% vs 26%), primary colon cancers (74% vs 51%), and larger tumor diameter (6 vs 5 cm) were more commonly managed with open surgery. Right colectomy was more common in the open surgery group (39%) and low anterior resection was more common in the laparoscopy group (39%, P=0.002). Hepatic metastases in segments II, III, IVb, V, and VI were more frequently resected with laparoscopy (100%) than with open surgery (56%), although the difference was not statistically significant. In colon and rectal cancers, mean operative time and 30-day complication rates of laparoscopy and open surgery did not differ. In both cancers, mean time to soft diet and length of hospital stay were shorter in the laparoscopy group. Mean time from surgery to chemotherapy commencement was significantly shorter with laparoscopy than with open surgery. In colon and rectal cancers, 2-year cancer-specific and progression-free survival rates were similar between the laparoscopy and open surgery groups. CONCLUSION: Based on our findings, laparoscopy can be selected as an initial approach in patients with a primary tumor without adjacent organ invasion and patients without primary tumor related symptoms. In selected stage IV patients, tumor factors such as primary rectal tumor, peritoneal carcinomatosis, or liver metastasis may not be absolute contraindications for a laparoscopic approach. PMID- 26640385 TI - High DEPTOR expression correlates with poor prognosis in patients with esophageal squamous cell carcinoma. AB - OBJECTIVE: The disheveled, Egl-10, and pleckstrin (DEP) domain containing mammalian target of rapamycin (mTOR)-interacting protein (DEPTOR) is a binding protein containing mTOR complex 1 (mTORC1), mTOR complex 2 (mTORC2), and an endogenous mTOR inhibitor. DEPTOR shows abnormal expressions in numerous types of solid tumors. However, how DEP-TOR is expressed in esophageal squamous cell carcinoma (ESCC) remains elusive. METHODS: The expression of DEPTOR in 220 cases of ESCC and non-cancerous adjacent tissues was detected by immunohistochemistry. DEPTOR levels in ESCC and paired normal tissue were quantified using reverse transcription-polymerase chain reaction and Western blot analysis to verify the immunohistochemical results. The relationship between DEPTOR expression and the clinicopathological features of ESCC was analyzed based on the results of immunohistochemistry. Finally, we analyzed the relationship between DEPTOR expression and the prognosis of patients with ESCC. RESULTS: Immunohistochemical staining showed that the expression rate of DEPTOR in ESCC tissues was significantly increased. DEPTOR mRNA and protein expression was significantly higher in ESCC tissues than in normal adjacent esophageal squamous tissues. High DEPTOR expression was significantly correlated with regional lymph node status in the TNM stage of patients with ESCC. Kaplan-Meier survival curves showed that the rate of overall survival was significantly lower in patients with high DEPTOR expression than in those with low DEPTOR expression. Additionally, high DEPTOR expression was an independent prognostic predictor for ESCC patients. CONCLUSION: High DEPTOR expression is an independent prognostic biomarker indicating a worse prognosis for patients with ESCC. PMID- 26640386 TI - Yttrium-90 radioembolization for advanced inoperable hepatocellular carcinoma. AB - BACKGROUND: Advanced inoperable hepatocellular carcinoma (HCC) conferring a grave prognosis may benefit from yttrium-90 ((90)Y) radioembolization. METHODS: Thirty patients with advanced inoperable HCC including those with any lesion >8 cm in maximal diameter or multiple bi-lobar lesions (totally more than five lesions), or portal vein thrombosis treated with radioembolization were reviewed. Treatment efficacy and safety were evaluated. Univariate and multivariate analyses were performed for identifying potential prognostic factors. RESULTS: After a median follow-up of 18.3 months, the response rate was 30.0%, and the disease control rate was 50.0%. Median overall progression-free survival (PFS) and overall survival (OS) were 3.3 months and 13.2 months, respectively. Longer median PFS was noted in those who had transarterial chemoembolization before radioembolization (7.3 months vs 3.1 months; P=0.021) and duration of alfafeto protein (AFP) response >=6 months (11.8 months vs 3.0 months; P<0.001). Longer median OS was also revealed in those without portal vein thrombosis (17.1 months vs 4.4 months; P=0.015) and those whose duration of AFP response was >=6 months (21.2 months vs 8.6 months; P=0.001). Seventeen patients (56.7%) developed treatment-related complications including five (16.7%) grade 3 events. Multivariate analysis revealed that treatment responders (P=0.001) and duration of AFP response >=6 months (P=0.006) were prognostic of PFS, whereas the absence of portal vein invasion (P=0.025), treatment responders (P=0.010), and duration of AFP response >=6 months (P=0.001) were prognostic of OS. CONCLUSION: (90)Y radioembolization is an alternative treatment with a promising outcome for poor risk advanced inoperable HCC. PMID- 26640388 TI - Vitamin D status and cholecalciferol supplementation in chronic kidney disease patients: an Italian cohort report. AB - This study investigated the factors associated with hypovitaminosis D, in a cohort of 405 prevalent patients with chronic kidney disease (CKD) stages 2-4, living in Italy and followed-up in tertiary care. The effect of cholecalciferol 10,000 IU once-a-week for 12 months was evaluated in a subgroup of 100 consecutive patients with hypovitaminosis D. Vitamin D deficiency was observed in 269 patients (66.4%) whereas vitamin D insufficiency was found in 67 patients (16.5%). In diabetic patients, 25-hydroxyvitamin D deficiency was detected in 80% of cases. In patients older than 65 years, the prevalence of hypovitaminosis D was 89%. In the univariate analysis, 25-hydroxyvitamin D was negatively related to age, parathyroid hormone (PTH), proteinuria, and Charlson index, while a positive relationship has emerged with hemoglobin level. On multiple regression analysis, only age and PTH levels were independently associated with 25 hydroxyvitamin D levels. No relationship emerged between vitamin D deficiency and renal function. Serum levels of 25-hydroxyvitamin D or prevalence of hypovitaminosis D did not differ between patients on a free-choice diet and on a renal diet, including low-protein, low-phosphorus regimens. Twelve-month oral cholecalciferol administration increased 25-hydroxyvitamin D and reduced PTH serum levels. In summary, hypovitaminosis D is very prevalent in CKD patients (83%) in Italy, and it is similar to other locations. PTH serum levels and age, but not renal function, are the major correlates of hypovitaminosis D. Implementation of renal diets is not associated with higher risk of vitamin D depletion. Oral cholecalciferol administration increased 25-hydroxyvitamin D and mildly reduced PTH serum levels. Oral cholecalciferol supplementation should be recommended as a regular practice in CKD patients, also when serum 25 hydroxyvitamin D determination is not available or feasible. PMID- 26640387 TI - Polo-like kinase 2 acting as a promoter in human tumor cells with an abundance of TAp73. AB - BACKGROUND: TAp73, a member of the p53 tumor suppressor family, is frequently overexpressed in malignant tumors in humans. TAp73 abundance and phosphorylation modification result in variations in transcriptional activity. In a previous study, we found that the antitumor function of TAp73 was reactivated by dephosphorylation in head and neck squamous cell carcinomas. Polo-like kinase 2 (PLK2) displayed a close relationship with the p53 family in affecting the fate of cells. Herein, we investigate the hypothesis that PLK2 phosphorylates TAp73 and inhibits TAp73 function. MATERIALS AND METHODS: Head and neck squamous cell carcinoma cell lines and osteosarcoma cell lines were used as natural models of the different expression levels of TAp73. Phosphorylation predictor software Scansite 3.0 and the predictor GPS-polo 1.0 were used to analyze the phosphorylation sites. Coimmunoprecipitation, phosphor-tag Western blot, metabolic labeling, and indirect immunofluorescence assays were used to determine the interactions between PLK2 and TAp73. TAp73 activity was assessed by Western blot and reverse transcription polymerase chain reaction, which we used to detect P21 and PUMA, both downstream genes of TAp73. The physiological effects of PLK2 cross talk with TAp73 on cell cycle progress and apoptosis were observed by flow cytometry and terminal deoxynucleotidyl transferase dUTP nick end labeling assays. RESULTS: PLK2 binds to and phosphorylates TAp73. PLK2 phosphorylates TAp73 at residue Ser48 and prohibits TAp73 translocation to the nucleus. Additionally, PLK2 inhibition combined with a DNA-damaging drug upregulated p21 and PUMA mRNA expression to a greater extent than DNA-damaging drug treatment alone. Inhibiting PLK2 in TAp73-enriched cells strengthened the effects of the DNA-damaging drug on both G1 phase arrest and apoptosis. Pretreatment with TAp73 siRNA weakened these effects. CONCLUSION: These findings reveal a novel PLK2 function (catalyzed phosphorylation of TAp73) which suppresses TAp73 functions. PLK2 promotes the survival of human tumor cells, a novel insight into the workings of malignant tumors characterized by TAp73 overexpression, and one that could speed the development of therapies. PMID- 26640390 TI - Durable response using regorafenib in an elderly patient with metastatic colorectal cancer: case report. AB - Regorafenib, an oral multikinase inhibitor, was approved in September 2012 by the US Food and Drug Administration for the treatment of patients with metastatic colorectal cancer. Since this time, however, few case reports outlining real world usage have been published in the literature. Here, we detail the clinical history of an elderly woman with KRAS wild-type colon cancer who received regorafenib after prior treatment with other agents. We show that by employing dose modification strategies to address adverse events, this patient was able to remain on therapy for 11 months and achieve stable disease. PMID- 26640389 TI - Cancer Metastases: Early Dissemination and Late Recurrences. AB - BACKGROUND: Metastatic cells from a primary tumor can occur before the primary cancer is detected. Metastatic cells can also remain in the patient for many years after removal of the primary tumor without proliferating. These dormant malignant cells can awaken and cause recurrent disease decades after the primary treatment. The purpose of this article is to review the clinical evidence for early dissemination and late recurrences in human malignant tumors. We used the following definitions: dormancy of cells may be defined as a nonproliferating state or an arrest in the cell cycle that results in a prolonged G0 phase. If one accepts the term "late metastases" to indicate a period exceeding 10 years from the removal of the primary tumor, then the two malignancies in which this occurs most frequently are cutaneous malignant melanoma (CMM) and renal cell carcinoma (RCC). METHODS: PubMed, Web of Science, and Scopus were searched with the keywords "metastases," "early dissemination," "late recurrences," "inadvertently transmitted cancer," "tumor growth rate," "dormancy," "circulating tumor cells," and "transplantation of cancer." RESULTS: Several case reports of early dissemination and late recurrences of various types of malignancies were found. Analyses of the growth rates of several malignant tumors in the original host indicated that the majority of cancers had metastasized years before they were detected. CMM, RCC, and malignant glioblastoma were the three most common malignancies resulting from an organ transplantation. CMM and RCC were also the two most common malignancies that showed dormancy. In several cases of transplanted CMM and RCC, the donor did not have any known malignancy or had had the malignancy removed so long ago that the donor was regarded as cured. CONCLUSION: (1) Metastases can frequently exist prior to the detection of the primary tumor. (2) Metastatic cells may reside in organs in the original host that are not usually the site of detectable secondary tumors, for example, the kidneys and heart. (3) Metastatic cells remain dormant for decades after the primary tumor has been removed. (4) Dormancy might be reversible and lead to late recurrences. PMID- 26640391 TI - Protecting care home residents from mistreatment and abuse: on the need for policy. AB - With a rising older person population with increasing life expectancies, the demand for care homes will increase in the future. Older people in care homes are particularly vulnerable due to their dependencies related to cognitive and/or functional self-care challenges. Although many care homes provide good care, maltreatment and abuse of older people can and does occur. One major step in preventing and addressing maltreatment in care homes is having comprehensive and responsive policy, which delineates national expectations that are locally implemented. This paper examines the literature related to maltreatment in care homes and argues for policy based on a multisystems approach. Policy needs to firstly acknowledge and address general societal issues which tacitly impact on older person care delivery, underpin how care homes and related systems should be operationalized, and finally delineate expected standards and outcomes for individual experience of care. Such a policy demands attention at every level of the health care and societal system. Furthermore, contemporary issues central to policy evolution in care homes are discussed, such as safeguarding education and training and fostering organization whistle-blowing protection. PMID- 26640392 TI - Clinical and laboratory characteristics associated with a high optical density anti-platelet factor 4 ELISA test. AB - PURPOSE: Diagnosing heparin-induced thrombocytopenia, a potentially catastrophic immune-mediated disorder, continues to pose significant challenges for clinicians, as both clinical and laboratory tools lack specificity. There is mounting evidence supporting a positive correlation between definitive heparin induced thrombocytopenia and optical density (OD) positivity from the widely available anti-platelet factor 4 enzyme-linked immunosorbent assays (PF4 ELISAs). However, the clinical features distinguishing these patients remain poorly understood. PATIENTS AND METHODS: To better characterize this group, we conducted a case-controlled, retrospective chart review of patients from two large, urban academic institutions who underwent a PF4 ELISA at a central laboratory. Associations between OD and 18 clinical characteristics were calculated using the Fisher's exact test for categorical variables and Wilcoxon rank-sum test for continuous variables. RESULTS: In total, 184 negative patients (OD <0.7), and 121 positive patients (OD >0.7), including 74 low-positive patients (0.7< OD <1.4) and 47 high-positive patients (OD >1.4) were identified. Several clinical variables were significantly different in the negative group compared with the positive group, including hospital day (P<0.001), previous admission within the past 3 months (P<0.001), and the presence of a new thrombus (P=0.003). However, many of these variables were not different between the negative and low-positive group, and were only distinct between the negative and high-positive group. When the low-positive and high-positive groups were compared, only the 4T score was significantly different (P=0.003). CONCLUSION: These data indicate that those with OD >1.4 form a distinct clinical group and support the clinical utility of the 4T score. PMID- 26640393 TI - Studying the Impact of Presence of Alpha Acid Glycoprotein and Protein Glycoprotein in Chronic Myeloid Leukemia Patients Treated with Imatinib Mesylate in the State of Qatar. AB - Despite the efficacy of imatinib mesylate (IM) in treating chronic myeloid leukemia (CML), there is a high degree of resistance. Alpha- 1-acid glycoprotein may reduce drug efficacy through its ability to interact with IM and blocks it from reaching its target, while protein glycoprotein (PGP) may reduce the intracellular concentration of the drug via an active pump mechanism. We thus investigated the correlation between AGP and PGP levels and the resistance/response to treatment. A total of 26 CML patients were investigated for AGP and PGP levels at diagnosis and during treatment. There was no significant difference or correlation between AGP levels and the different groups of patients. There was also no significant difference in the fluorescence intensities of PGP levels among the different patient groups. The resistance observed in our CML patient population could not be correlated with AGP and PGP levels. There was no significant pattern of AGP and PGP expression, irrespective of the response or resistance to treatment. PMID- 26640394 TI - Clinical Evaluation of the Hemodynamic Effects of the High-Flow Nasal Cannula Therapy on the Fontan Circulation. AB - High-flow nasal cannula (HFNC) therapy supports respiratory effort with a minimal elevation in airway pressure. We examined hemodynamic effects of HFNC therapy in a 10-year-old girl with Fontan circulation, in which positive airway pressure has deleterious hemodynamic effects. The HFNC therapy at 30 L/min improved oxygenation without an increase in central venous pressure. It also reduced heart rate, and systemic and pulmonary vascular resistance, and increased cardiac output. In addition, the HFNC therapy improved the cerebral circulation measured by near-infrared spectroscopy. Thus, HFNC therapy may be a potentially useful noninvasive ventilation modality, particularly for patients with Fontan circulation. PMID- 26640396 TI - Regression calibration with instrumental variables for longitudinal models with interaction terms, and application to air pollution studies. AB - In this paper, we derive forms of estimators and associated variances for regression calibration with instrumental variables in longitudinal models that include interaction terms between two unobservable predictors and interactions between these predictors and covariates not measured with error; the inclusion of the latter interactions generalize results we previously reported. The methods are applied to air pollution and health data collected on children with asthma. The new methods allow for the examination of how the relationship between health outcome leukotriene E4 (LTE4, a biomarker of inflammation) and two unobservable pollutant exposures and their interaction are modified by the presence or absence of upper respiratory infections. The pollutant variables include secondhand smoke and ambient (outdoor) fine particulate matter. Simulations verify the accuracy of the proposed methods under various conditions. PMID- 26640397 TI - More than Skew: Asymmetric Wave Propagation in a Reaction-Diffusion-Convection System. AB - Convection-induced instability in reaction-diffusion systems produces complicated patterns of oscillations behind propagating wavefronts. We transform the system twice: into lambda-omega form, then into polar variables. We find analytical estimates for the wavefront speed which we confirm numerically. Our previous work examined a simpler system [E. H. Flach, S. Schnell, and J. Norbury, Phys. Rev. E 76, 036216 (2007)]; the onset of instability is qualitatively different in numerical solutions of this system. We modify our estimates and connect the two different behaviours. Our estimate explains how the Turing instability fits with pattern found in reaction-diffusion-convection systems. Our results can have important applications to the pattern formation analysis of biological systems. PMID- 26640395 TI - Galectin-3 as a Potential Target to Prevent Cancer Metastasis. AB - Interactions between two cells or between cell and extracellular matrix mediated by protein-carbohydrate interactions play pivotal roles in modulating various biological processes such as growth regulation, immune function, cancer metastasis, and apoptosis. Galectin-3, a member of the beta-galactoside-binding lectin family, is involved in fibrosis as well as cancer progression and metastasis, but the detailed mechanisms of its functions remain elusive. This review discusses its structure, carbohydrate-binding properties, and involvement in various aspects of tumorigenesis and some potential carbohydrate ligands that are currently investigated to block galectin-3 activity. PMID- 26640398 TI - A model-based approach for imputing censored data in source apportionment studies. AB - Sources of particulate matter (PM) air pollution are generally inferred from PM chemical constituent concentrations using source apportionment models. Concentrations of PM constituents are often censored below minimum detection limits (MDL) and most source apportionment models cannot handle these censored data. Frequently, censored data are first substituted by a constant proportion of the MDL or are removed to create a truncated dataset before sources are estimated. When estimating the complete data distribution, these commonly applied methods to adjust censored data perform poorly compared with model-based imputation methods. Model-based imputation has not been used in source apportionment and may lead to better source estimation. However if the censored chemical constituents are not important for estimating sources, censoring adjustment methods may have little impact on source estimation. We focus on two source apportionment models applied in the literature and provide a comprehensive assessment of how censoring adjustment methods, including model-based imputation, impact source estimation. A review of censoring adjustment methods critically informs how censored data should be handled in these source apportionment models. In a simulation study, we demonstrated that model-based multiple imputation frequently leads to better source estimation compared with commonly used censoring adjustment methods. We estimated sources of PM in New York City and found estimated source distributions differed by censoring adjustment method. In this study, we provide guidance for adjusting censored PM constituent data in common source apportionment models, which is necessary for estimation of PM sources and their subsequent health effects. PMID- 26640399 TI - Attention during visual search: The benefit of bilingualism. AB - AIMS AND OBJECTIVES/PURPOSE/RESEARCH QUESTIONS: Following reports showing bilingual advantages in executive control (EC) performance, the current study investigated the role of selective attention as a foundational skill that might underlie these advantages. DESIGN/METHODOLOGY/APPROACH: Bilingual and monolingual young adults performed a visual search task by determining whether a target shape was present amid distractor shapes. Task difficulty was manipulated by search type (feature or conjunction) and by the number and discriminability of the distractors. In feature searches, the target (e.g., green triangle) differed on a single dimension (e.g., color) from the distractors (e.g., yellow triangles); in conjunction searches, two types of distractors (e.g., pink circles and turquoise squares) each differed from the target (e.g., turquoise circle) on a single but different dimension (e.g., color or shape). DATA AND ANALYSIS: Reaction time and accuracy data from 109 young adults (53 monolinguals and 56 bilinguals) were analyzed using a repeated-measures analysis of variance. Group membership, search type, number and discriminability of distractors were the independent variables. FINDINGS/CONCLUSIONS: Participants identified the target more quickly in the feature searches, when the target was highly discriminable from the distractors and when there were fewer distractors. Importantly, although monolinguals and bilinguals performed equivalently on the feature searches, bilinguals were significantly faster than monolinguals in identifying the target in the more difficult conjunction search, providing evidence for better control of visual attention in bilinguals. ORIGINALITY: Unlike previous studies on bilingual visual attention, the current study found a bilingual attention advantage in a paradigm that did not include a Stroop-like manipulation to set up false expectations. SIGNIFICANCE/IMPLICATIONS: Thus, our findings indicate that the need to resolve explicit conflict or overcome false expectations is unnecessary for observing a bilingual advantage in selective attention. Observing this advantage in a fundamental skill suggests that it may underlie higher order bilingual advantages in EC. PMID- 26640400 TI - C-terminal peptide extension via gas-phase ion/ion reactions. AB - The formation of peptide bonds is of great importance from both a biological standpoint and in routine organic synthesis. Recent work from our group demonstrated the synthesis of peptides in the gas-phase via ion/ion reactions with sulfo-NHS reagents, which resulted in conjugation of individual amino acids or small peptides to the N-terminus of an existing 'anchor' peptide. Here, we demonstrate a complementary approach resulting in the C-terminal extension of peptides. Individual amino acids or short peptides can be prepared as reagents by incorporating gas phase-labile protecting groups to the reactive C-terminus and then converting the N-terminal amino groups to the active ketenimine reagent. Gas phase ion/ion reactions between the anionic reagents and doubly protonated "anchor" peptide cations results in extension of the "anchor" peptide with new amide bond formation at the C-terminus. We have demonstrated that ion/ion reactions can be used as a fast, controlled, and efficient means for C-terminal peptide extension in the gas phase. PMID- 26640403 TI - Divergent Effect of Dezocine, Morphine and Sufentanil on Intestinal Motor Function in Rats. AB - BACKGROUND: Opioid induced bowel dysfunction is the most common side effect of preoperatively administrated morphine, fentanyl and its derivative. However, the influence of dezocine on intestinal mobility is rarely reported. This study was designed to investigate the effects of dezocine, morphine and sufentanil on both intestinal smooth muscle contraction and propulsion in rats. METHODS: Contractile tension and frequency of isolated rat small intestine smooth muscle were measured using tension transducer after incubation with different concentrations of dezocine, morphine and sufentanil. The propulsive rate of methylene blue in rat intestinal tract was measured 30 minutes after intraperitoneal injection of morphine, sufentanil and dezocine. Percent of change in contractile tension and contraction frequency compared to baseline level were calculated to evaluate muscle contraction. Propulsive rate of methylene blue was calculated as the percentage of methylene blue moving distance in intestinal tract compared to the length of the small intestine. RESULTS: Morphine and sufentanil significantly increased the contractile tension of isolated small intestine smooth muscle at high doses. The contraction frequency did not change significantly among the 3 tested doses. Increasing the dose of dezocine from 1.7 mg.L(-1) to 10.2 mg.L(-1) did not change either the contractile tension or the contraction frequency. The propulsive rate of methylene blue in intestinal tract was significantly decreased after the treatment with morphine, sufentanil and dezocine (45.6%, 43.7%, and 42.1% respectively) compared to control group(57.1%), while the difference among the 3 drug groups were not significant. CONCLUSION: Morphine and sufentanil may dose dependently increase the contractile tension and contraction ability of isolated rat small intestine smooth muscle, while dezocine has no significant effect on intestine smooth muscle contraction. However, all these opioids might impair small intestinal propulsion. PMID- 26640402 TI - Role and New Insights of Pirfenidone in Fibrotic Diseases. AB - Pirfenidone (PFD) is a non-peptide synthetic molecule issued as a broad-spectrum anti-fibrotic drug with the ability to decrease TGF-beta1, TNF-alpha, PDGF and COL1A1 expression, which is highly related to prevent or remove excessive deposition of scar tissue in several organs. Basic and clinical evidence suggests that PFD may safely slow or inhibit the progressive fibrosis swelling after tissue injuries. Furthermore, a number of evidence suggests that this molecule will have positive effects in the treatment of other inflammatory diseases. This review contains current research in which PFD has been used as the treatment of several diseases, and focus mainly in the outcomes related to improve inflammation and fibrogenesis. Therefore, the main goal of this review is to focus on the novel findings of PFD efficacy rather than deepen in the chemical aspects of the molecule. PMID- 26640404 TI - The Differential Expression and Function of the Inflammatory Chemokine Receptor CXCR5 in Benign Prostatic Hyperplasia and Prostate Cancer. AB - BACKGROUND: Chemokine and chemokine receptors could have played an important role in tumor angiogenesis and distant metastasis. The mechanism of inflammation, expression and function of chemokines and chemokine receptors in benign prostatic hyperplasia (BPH) and prostate cancer (PCa) remain unclear. The purpose of present study is to detect differential expression and function of chemokines and chemokine receptors (CCRs) in BPH and PCa. METHODS: BPH-1 and peripheral blood mononuclear cells (PBMCs) were co-cultured in Transwell chambers, and human normal prostate (NP) tissues, BPH tissues and PCa tissues were collected. CCR gene-chips were used to analyze and compare the differential expression of CCRs in BPH-1 cells, BPH-1 cells co-cultured with PBMCs, and LNCaP cells. The differential expression of CCRs was detected and validated using real-time PCR, western blotting and immunofluorescence (IF). The proliferation of LNCaP cells was also investigated after the knockdown CXCR5. RESULTS: RESULTS of gene-chips indicated that there was low or no expression of CCR10, CXCR1, CXCR3 and CXCR5 in BPH-1 cells, whereas the expression of these receptors in BPH-1 cells was increased by PBMCs, and the expression was high in LNCaP cells. Furthermore, real time PCR and western blotting confirmed the above mentioned results. IF verified no or low expression of CXCR1, CXCR3 and CXCR5 in NP tissues, low or moderate expression in BPH and high expression in PCa. However, CCR10 was not expressed at detectable levels in the three groups. The growth and proliferation of LNCaP cells was markedly inhibited after down-regulation of CXCR5. CONCLUSIONS: PCa cells expressed high levels of CCR10, CXCR1, CXCR3 and CXCR5. Although BPH cells did not express these factors, their expression was up-regulated when BPH-1 cells were incubated with inflammatory cells. Finally, down-regulation of CXCR5 inhibited the growth and proliferation of LNCaP cells. PMID- 26640405 TI - The Effectiveness of Ropivacaine and Mepivacaine in the Postoperative Pain after Third Lower Molar Surgery. AB - AIM: To compare the efficacy of 0.75% ropivacaine with 3% mepivacaine for pain control in the first 24 hours after surgical removal of lower third molars, using a quantitative measurement such as VAS. The secondary objective involved rescue analgesia. METHODS: Forty-five patients, 21 females and 24 males, mean age 23,2 +/- 3 years, underwent surgical removal of third molars in two separate sessions. A split-mouth design was chosen, so each patient underwent both the first and second surgeries, having for each extraction a different anesthetic. The second extraction was carried out 1 month later. Parameters evaluated were: onset of anesthesia, duration of surgery, lip numbness, timing of pain appearance and first analgesic intake. RESULTS: No significant differences about onset of anesthesia, duration of surgical procedures, and timing of first analgesic intake were found. Lower lip numbness, on the other hand, was more prolonged after using ropivacaine (p < 0.0001) and the onset of postoperative pain was more delayed after anesthesia with ropivacaine (p=0.0048). Pain scores at 1 and 2 hours after surgery were 3.5 +/- 2.0 and 4.1 +/- 1.3 after injection of mepivacaine, and 2.7 +/- 2.2 and 2.9 +/- 2.4 after ropivacaine (p value =0.006 for both time points). No significant differences in pain score were recorded between the two anesthetics at 12 and 24 hours post surgery. CONCLUSIONS: With the use of ropivacaine, the discomfort caused by prolonged lip numbness is counterbalanced by less postoperative discomfort after surgery. In addition, when compared with other long-acting anesthetics, ropivacaine ensures a safer anesthetic profile for medically complex patients. PMID- 26640406 TI - Effects of Notch2 and Notch3 on Cell Proliferation and Apoptosis of Trophoblast Cell Lines. AB - AIMS: To investigate the effect of Notch2 and Notch3 on cell proliferation and apoptosis of two trophoblast cell lines, BeWo and JAR. METHODS: Notch2 and Notch3 expression in BeWo and JAR cells was upregulated or downregulated using lentivirus-mediated overexpression or RNA interference. The effect of Notch2 and Notch3 on cell proliferation was assessed by the CCK-8 assay. The effect of Notch2 and Notch3 on the apoptosis of BeWo and JAR cells was evaluated by flow cytometry using the Annexin V-PE Apoptosis kit. Lentivirus-based overexpression vectors were constructed by cloning the full-length coding sequences of human Notch2 and Notch3 C-terminally tagged with GFP or GFP alone (control) into a lentivirus-based expression vector. Lentivirus-based gene silencing vectors were prepared by cloning small interfering sequences targeting human Notch2 and Notch3 and scrambled control RNA sequence into a lentivirus-based gene knockdown vector. The effect of Notch2 and Notch3 on cell proliferation was assessed by the CCK-8 assay. And the effect of Notch2 and Notch3 on the apoptosis of BeWo and JAR cells was evaluated by flow cytometry using the Annexin V PE Apoptosis kit. RESULTS: We found that the downregulation of Notch2 and Notch3 gene expression in BeWo and JAR cells resulted in an increase in cell proliferation, while upregulation of Notch3 and Notch2 expression led to a decrease in cell proliferation. Moreover, the overexpression of Notch3 and Notch2 in BeWo and JAR cells reduced apoptosis in these trophoblast cell lines, whereas apoptosis was increased in the cells in which the expression of Notch3 and Notch2 was downregulated. CONCLUSIONS: Notch2 and Notch3 inhibited both cell proliferation and cell apoptosis in BeWo and JAR trophoblast cell lines. PMID- 26640407 TI - Association study of polymorphisms in miRNAs with T2DM in Chinese population. AB - Accumulated evidence indicates that microRNA (miRNA or miR) is involved in the development of type 2 diabetes (T2DM). Several studies have shown that single nucleotide polymorphisms (SNPs) located in miRNAs are associated with T2DM in Caucasian populations. The association studies of miRNA's SNPs with T2DM in Asian are rarely reported, and there are distinct genetic differences between Caucasian and Asian populations. The focus of this study, therefore, is the association of T2DM with five SNPs (rs895819 in miR-27a, rs531564 in miR-124a, rs11888095 in miR 128a, rs3820455 in miR-194a and rs2910164 in miR-146a) located in five miRNAs in a Han Chinese population. A total of 738 subjects with T2DM and 610 non-diabetic subjects were genotyped using the TaqMan method. Next, the associations between the five SNPs with T2DM and individual metabolic traits were evaluated. Our data showed that the C allele of rs531564 in miR-124a may protect against T2DM (P=0.009, OR=0.758; 95%CI: 0.616-0.933). Conversely, the C allele of rs2910164 in miR-146a may increase the risk of developing T2DM (P<0.001, OR=1.459; 95%CI: 1.244-1.712). However, these five SNPs did not exhibit significant associations with individual metabolic traits in either the T2DM or non-diabetic groups. Our results revealed that genetic variations in miRNAs were associated with T2DM susceptibility in a Han Chinese population, and these results highlight the need to study the functional effects of these variants in miRNAs on the risk of developing T2DM. PMID- 26640408 TI - FOXO1 Is Involved in the Effects of Cigarette Smoke Extract on Osteoblastic Differentiation of Cultured Human Periosteum-derived Cells. AB - Cigarette smoke is associated with delayed fracture healing, alterations in mineral content, and osteoporosis, however, its effects on osteoblastic differentiation of osteoprogenitor cells are not fully understood. In the present study, we examined the effects of cigarette smoke extract (CSE) on osteoblastic differentiation of cultured human periosteum-derived cells. We found that CSE inhibited alkaline phosphatase (ALP) activity, mineralization and Runx2 transactivation of the periosteum-derived cells. Nucleofection of RUNX2 into the periosteum-derived cells increased expression of endogenous osteocalcin (OC) and ALP genes in osteogenic induction medium and increased OC expression in non osteogenic medium. Treatment of the periosteum-derived cells with CSE resulted in decreased phosphorylation of AKT and forkhead box protein O1 (FOXO1). The AKT phosphorylation-resistant mutant, FOXO1-A3, inhibited transcriptional activity of RUNX2 in the periosteum-derived cells. The current study suggests one mechanism by which CSE exposure leads to inhibition of osteoblastic differentiation of cultured human periosteum-derived cells. PMID- 26640409 TI - Fimasartan, a Novel Angiotensin-Receptor Blocker, Protects against Renal Inflammation and Fibrosis in Mice with Unilateral Ureteral Obstruction: the Possible Role of Nrf2. AB - OBJECTIVES: A newly developed angiotensin II receptor blocker, fimasartan, is effective in lowering blood pressure through its action on the renin-angiotensin system. Renal interstitial fibrosis, believed to be due to oxidative injury, is an end-stage process in the progression of chronic kidney disease. Nuclear factor erythroid 2-related factor 2 (Nrf2) is known to regulate cellular oxidative stress and induce expression of antioxidant genes. In this study we investigated the role of Nrf2 in fimasartan-mediated antioxidant effects in mice with renal fibrosis induced by unilateral ureteral obstruction (UUO). MATERIALS AND METHODS: UUO was induced surgically in mice, followed by either no treatment with fimasartan or the intraperitoneal administration of fimasartan (3 mg/kg/day). On day 7, we evaluated the changes in the renin-angiotensin system (RAS) and the expression of Nrf2 and its downstream antioxidant genes, as well as renal inflammation, apoptosis, and fibrosis in the obstructed kidneys. The effect of fimasartan on the Nrf2 pathway was also investigated in HK-2 cells stimulated by tumor necrosis factor-alpha. RESULTS: The mice with surgically induced UUO showed increased renal inflammation and fibrosis as evidenced by histopathologic findings and total collagen content in the kidney. These effects were attenuated in the obstructed kidneys of the fimasartan-treated mice. Fimasartan treatment inhibited RAS activation and the expression of Nox1, Nox2, and Nox4. In contrast, fimasartan upregulated the renal expression of Nrf2 and its downstream signaling molecules (such as NQO1; HO-1; GSTa2 and GSTm3). Furthermore, it increased the expression of antioxidant enzymes, including CuSOD, MnSOD, and catalase. The fimasartan-treated mice had significantly less apoptosis on TUNEL staining, with decreased levels of pro-apoptotic protein and increased levels of anti-apoptotic protein. In the HK-2 cells, fimasartan treatment inhibited RAS activation, decreased expression of mitogen-activated protein kinases (MAPKs), and upregulated the Nrf2 pathway. CONCLUSIONS: These results suggest that fimasartan has beneficial effects in reducing renal oxidative stress, inflammation, and fibrosis. Possible mechanisms to explain these effects are inhibition of RAS and MAPKs and upregulation of Nrf2 signaling, with subsequent induction of antioxidant pathways. PMID- 26640410 TI - Tension Force Downregulates Matrix Metalloproteinase Expression and Upregulates the Expression of Their Inhibitors through MAPK Signaling Pathways in MC3T3-E1 cells. AB - OBJECTIVE: Matrix metalloproteinases (MMPs), produced by osteoblasts, catalyze the turnover of extracellular matrix (ECM) molecules in osteoid, and the regulation of MMP activity depends on interactions between MMPs and tissue inhibitors of metalloproteinases (TIMPs). We focused on the degradation process of ECM in osteoid that was exposed to mechanical strain, and conducted an in vitro study using MC3T3-E1 osteoblastic cells to examine the effects of tension force (TF) on the expression of MMPs and TIMPs, and activation of mitogen activated protein kinase (MAPK) pathways. DESIGN: Cells were incubated on flexible-bottomed culture plates and stimulated with or without cyclic TF for 24 hours. The expression of MMPs and TIMPs was examined at mRNA and protein levels by real-time RT-PCR and Western blotting, respectively. The phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, p38 MAPK, and stress-activated protein kinases/c-jun N-terminal kinases (SAPK/JNK) were examined by Western blotting. RESULTS: TF decreased the expression of MMP-1, -3, -13 and phosphorylated ERK1/2. In contrast, TF increased the expression of TIMP-2, -3 and phosphorylated SAPK/JNK. The expression of MMP-2, -14, TIMP-1, -4 and phosphorylated p38 MAPK was unaffected by TF. MMP-1, -3 and -13 expression decreased in cells treated with the ERK inhibitor PD98059 compared with untreated control cells. The JNK inhibitor SP600125 inhibited the TF-induced upregulation of TIMP-2 and -3. CONCLUSIONS: The results suggest that TF suppresses the degradation process that occurs during ECM turnover in osteoid via decreased production of MMP-1, -3 and -13, and increased production of TIMP-2 and -3 through the MAPK signaling pathways in osteoblasts. PMID- 26640411 TI - Bisphenol A, Dichlorodiphenyltrichloroethane (DDT) and Vinclozolin Affect ex-vivo Uterine Contraction in Rats via Uterotonin (Prostaglandin F2alpha, Acetylcholine and Oxytocin) Related Pathways. AB - Bisphenol-A (BPA), dichrolodiphenyltrichloroethane (DDT) and vinclozolin were found able to induce abnormal uterine contraction. The mechanisms involved remains unclear. We hypothesized that the effect of these compounds were mediated via the uterotonin pathways. Therefore, in this study, effects of BPA, vinclozolin and DDT-only and in combination with uterotonins (PGF-2alpha, acetylcholine and oxytocin) on the force and pattern of uterine contraction were observed. METHODS: Uteri were harvested from intact adult female rats 24 hours after a single injection (1 mg/kg/b.w) of estrogen to synchronize their oestrous cycle. The uterine horns were subjected for ex-vivo contraction studies in an organ bath connected to Powerlab data acquisition system. Different doses of BPA, vinclozolin and DDT were added into the bathing solution and changes in the pattern and strength of uterine contraction were recorded. Further, increasing doses of uterotonins were concomitantly administered with these compounds and changes in the force and pattern of contraction were observed. RESULTS: In the absence of uterotonins, uterine contractile force decreased with increasing doses of BPA and DDT. However, vinclozolin induced sharp increase in the contractile forces which then gradually decrease. Administration of BPA, DDT and vinclozolin alone reduced the force of uterine contraction following stimulation of contraction by uterotonins. However, BPA, vinclozolin or DDT effects were relieved upon co-administration with uterotonins at increasing doses. CONCLUSIONS: The antagonizing effect of uterotonins on BPA, vinclozolin and DDT actions could explain the mechanism underlying the adverse effect of these compounds on uterine contraction. PMID- 26640412 TI - Studies on Inhibition of Proliferation of Enterovirus-71 by Compound YZ-LY-0. AB - In recent years, hand-foot-and-mouth disease (HFMD), which is caused by Enteroviruses, has emerged as a serious illness. It affects mainly children under the age of five and results in high fatality rates. Enterovirus 71 (EV71) is the main causative agent of HFMD in China and currently there are no effective anti viral drugs available to treat HFMD. In the present study, we screened compounds for inhibition of proliferation of EV71. Compound YZ-LY-0 stalled the life cycle of EV71. The inhibitor exhibited EC50 value of 0.29 MUm against SK-EV006 strain of EV71. Notably, YZ-LY-0 had low cytotoxicity (CC50 > 100 MUM) and a high selectivity index (over 300) in Vero and RD cells. YZ-LY-0 in combination with an EV71 RdRp inhibitor or an entry inhibitor showed an antagonistic effect at very low concentrations. However, at higher concentrations the inhibitors exhibited a synergistic effect in inhibiting viral replication. Preliminary results on investigation of the mechanism of inhibition indicate that YZ-LY-0 does not block the entry of the virus in the host cell, but instead inhibits an early stage of EV71 replication. Our studies provide a potential clinical therapeutic option against EV71 infections and suggest that a combined application of YZ-LY-0 with other inhibitors could be more effective in the treatment of HFMD. PMID- 26640413 TI - Minimizing Air Pollution Exposure: A Practical Policy to Protect Vulnerable Older Adults from Death and Disability. AB - Air pollution causes an estimated 200,000 deaths per year in the United States alone. Older adults are at greater risk of mortality caused by air pollution. Here we quantify the number of older adult facilities in Los Angeles County that are exposed to high levels of traffic derived air pollution, and propose policy solutions to reduce pollution exposure to this vulnerable subgroup. Distances between 20,362 intersections and 858 elder care facilities were estimated, and roads or highways within 500 of facilities were used to estimate traffic volume exposure. Of the 858 facilities, 54 were located near at least one major roadway, defined as a traffic volume over 100,000 cars/day. These 54 facilities house approximately 6,000 older adults. Following standards established for schools, we recommend legislation mandating the placement of new elder care facilities a minimum of 500 feet from major roadways in order to reduce unnecessary mortality risk from pollution exposure. PMID- 26640414 TI - Aspirin for primary prevention of cardiovascular disease. AB - Although aspirin has a well-established role in preventing adverse events in patients with known cardiovascular disease (CVD), its benefit in patients without a history of CVD remains under scrutiny. Current data have provided insight into the risks of aspirin use, particularly bleeding, compared with its benefits in primary CVD prevention. Although aspirin is inexpensive and widely available, especially in developing countries, there is lack of evidence that the benefits outweigh the adverse events with continuous aspirin use in primary CVD prevention. Therefore, the decision to initiate aspirin therapy should be an individual clinical judgment that weighs the absolute benefit in reducing the risk of a first cardiovascular event against the absolute risk of major bleeding, and tailored to the patient's CVD risk. This risk must be calculated, based on accurate and cost-benefit locally developed risk assessment tools, the most discriminating threshold be identified. Additionally, patients preferences should be taken into account when making the decision to initiate aspirin therapy in primary prevention of CVD or not. Physicians should continuously be trained to calculate their patients CVD risk, and concomitant strategies be emphasized. PMID- 26640415 TI - Population aging, macroeconomic changes, and global diabetes prevalence, 1990 2008. AB - BACKGROUND: Diabetes is an important contributor to global morbidity and mortality. The contributions of population aging and macroeconomic changes to the growth in diabetes prevalence over the past 20 years are unclear. METHODS: We used cross-sectional data on age- and sex-specific counts of people with diabetes by country, national population estimates, and country-specific macroeconomic variables for the years 1990, 2000, and 2008. Decomposition analysis was performed to quantify the contribution of population aging to the change in global diabetes prevalence between 1990 and 2008. Next, age-standardization was used to estimate the contribution of age composition to differences in diabetes prevalence between high-income (HIC) and low-to-middle-income countries (LMICs). Finally, we used non-parametric correlation and multivariate first-difference regression estimates to examine the relationship between macroeconomic changes and the change in diabetes prevalence between 1990 and 2008. RESULTS: Globally, diabetes prevalence grew by two percentage points between 1990 (7.4 %) and 2008 (9.4 %). Population aging was responsible for 19 % of the growth, with 81 % attributable to increases in the age-specific prevalences. In both LMICs and HICs, about half the growth in age-specific prevalences was from increasing levels of diabetes between ages 45-65 (51 % in HICs and 46 % in LMICs). After age standardization, the difference in the prevalence of diabetes between LMICs and HICs was larger (1.9 % point difference in 1990; 1.5 % point difference in 2008). We found no evidence that macroeconomic changes were associated with the growth in diabetes prevalence. CONCLUSIONS: Population aging explains a minority of the recent growth in global diabetes prevalence. The increase in global diabetes between 1990 and 2008 was primarily due to an increase in the prevalence of diabetes at ages 45-65. We do not find evidence that basic indicators of economic growth, development, globalization, or urbanization were related to rising levels of diabetes between 1990 and 2008. PMID- 26640416 TI - Support for Patients and Family Caregivers in Lung Cancer: Educational Components of an Interdisciplinary Palliative Care Intervention. AB - Consistent with the recommendations of the Institute of Medicine Report on quality cancer care, attention to symptom management and quality of life concerns of patients with lung cancer should be addressed throughout the disease trajectory. As part of a NCI-funded Program Project grant, this paper reports on the patient and family caregiver education component of a nurse-lead, tailored palliative care intervention for patients with early (I-III, n=130) and late (IV, n=142) stage lung cancer. Patients and family caregivers received 4 separate educational sessions organized around the Quality of Life model domains (physical, psychological, social, and spiritual well-being). Each patient and caregiver was presented at a weekly interdisciplinary case conference which also informed the educational sessions. Based on needs and team suggestions, an individualized palliative care plan was created and a tailored educational intervention was designed based on topics chosen by each participant. The most common topics chosen by patients in each domain were fatigue, worry and fear, social support/isolation, and hope. Family caregivers most commonly chose fatigue, worry and fear, communication, and purpose and meaning in life. The mean time spent in each teaching session ranged from 31 to 44 minutes for patients and 25 to 35 minutes for family caregivers. There is a vital need for interdisciplinary palliative care interventions for patients across all stages and across the disease trajectory. Nurses are vital to integrating palliative care into routine care. Providing a tailored educational intervention is an important aspect of palliative care for patients and family caregivers. This paper focuses on the process of the tailored educational intervention. PMID- 26640417 TI - Eighteen-Month-Olds, but not 14-Month-Olds, Use Social Context to Bind Action Sequences. AB - We demonstrate that 18-month-olds, but not 14-month-olds, can anticipate others' actions based on an interpretation of shared goals that bind together individual actions into a collaborative sequence. After viewing a sequence of actions performed by two people who socially interact, 18-month-olds bound together the socially engaged actors' actions such that they later expected the actors to share the same final goal. Eighteen-month-olds who saw nonsocially engaged actors did not have this expectation and neither did 14-month-olds when viewing either socially or nonsocially engaged actors. The results are discussed in light of the possibility that experience in collaborations could be necessary for understanding collaboration from a third-person perspective. PMID- 26640418 TI - CrystPro: Spatiotemporal Analysis of Protein Crystallization Images. AB - Thousands of experiments corresponding to different combinations of conditions are set up to determine the relevant conditions for successful protein crystallization. In recent years, high throughput robotic set-ups have been developed to automate the protein crystallization experiments, and imaging techniques are used to monitor the crystallization progress. Images are collected multiple times during the course of an experiment. Huge number of collected images make manual review of images tedious and discouraging. In this paper, utilizing trace fluorescence labeling, we describe an automated system called CrystPro for monitoring the protein crystal growth in crystallization trial images by analyzing the time sequence images. Given the sets of image sequences, the objective is to develop an efficient and reliable system to detect crystal growth changes such as new crystal formation and increase of crystal size. CrystPro consists of three major steps- identification of crystallization trials proper for spatio-temporal analysis, spatio-temporal analysis of identified trials, and crystal growth analysis. We evaluated the performance of our system on 3 crystallization image datasets (PCP-ILopt-11, PCP-ILopt-12, and PCP-ILopt 13) and compared our results with expert scores. Our results indicate a) 98.3% accuracy and .896 sensitivity on identification of trials for spatio-temporal analysis, b) 77.4% accuracy and .986 sensitivity of identifying crystal pairs with new crystal formation, and c) 85.8% accuracy and 0.667 sensitivity on crystal size increase detection. The results show that our method is reliable and efficient for tracking growth of crystals and determining useful image sequences for further review by the crystallographers. PMID- 26640419 TI - "You need to get them where they feel it": Conflicting Perspectives on How to Maximize the Structure of Text-Message Psychological Interventions for Adolescents. AB - Mobile psychological interventions are of growing interest, particularly for populations with little access to traditional mental health services. Optimum structural components of these interventions are unknown. In this study, twenty one adolescents (age 13-17) with past two week depressive symptoms were recruited from the emergency department to participate in a semi-structured interview, to inform development of a text-message-based depression prevention intervention. Teens expressed conflict about intervention structure. Although trust and reliability were essential to sustain engagement, teens disagreed about how to best maintain reliability; whether the program should be "pushed" or "pulled"; and what the ideal degree of human interaction would be. These findings highlight the challenges in automating psychological interventions that are normally delivered face-to-face. Data indicate a broad desire for developing tailoring methods for system design (duration, frequency, and level of interactivity). The paper closes with thoughts about potential solutions to these structural issues for mobile psychological interventions. PMID- 26640420 TI - Restorative Retelling for Violent Death: An Investigation of Treatment Effectiveness, Influencing Factors, and Durability. AB - Many adults who have lost a loved one to violent death suffer from depression, posttraumatic stress disorder (PTSD), and complicated grief. Limited research has examined structured group interventions for violent death survivors or characteristics (e.g., types of loss, quality and type of relationship with the deceased) that may impact response to intervention. This records review of 91 survivors examined the effectiveness of Restorative Retelling (RR), a brief structured group intervention for violent loss survivors. Participants completed depression, PTSD, and complicated grief measures at pre- and post-treatment and at 1-year follow-up for a subset of participants. Findings revealed statistically significant changes in depression and PTSD symptoms (Cohen's d values ranged from .33-.46) at post-treatment, with significant changes observed across all domains at 1-year follow-up. Treatment response appeared to be influenced by high distress, gender, and relationship with the deceased. Results imply a large-scale randomized control trial to determine treatment efficacy. PMID- 26640421 TI - Statistical Power of Alternative Structural Models for Comparative Effectiveness Research: Advantages of Modeling Unreliability. AB - The advantages of modeling the unreliability of outcomes when evaluating the comparative effectiveness of health interventions is illustrated. Adding an action-research intervention component to a regular summer job program for youth was expected to help in preventing risk behaviors. A series of simple two-group alternative structural equation models are compared to test the effect of the intervention on one key attitudinal outcome in terms of model fit and statistical power with Monte Carlo simulations. Some models presuming parameters equal across the intervention and comparison groups were underpowered to detect the intervention effect, yet modeling the unreliability of the outcome measure increased their statistical power and helped in the detection of the hypothesized effect. Comparative Effectiveness Research (CER) could benefit from flexible multi-group alternative structural models organized in decision trees, and modeling unreliability of measures can be of tremendous help for both the fit of statistical models to the data and their statistical power. PMID- 26640422 TI - Anthropometric geography applied to the analysis of socioeconomic disparities: cohort trends and spatial patterns of height and robustness in 20th-century Spain. AB - Anthropometrics have been widely used to study the influence of environmental factors on health and nutritional status. In contrast, anthropometric geography has not often been employed to approximate the dynamics of spatial disparities associated with socioeconomic and demographic changes. Spain exhibited intense disparity and change during the middle decades of the 20th century, with the result that the life courses of the corresponding cohorts were associated with diverse environmental conditions. This was also true of the Spanish territories. This paper presents insights concerning the relationship between socioeconomic changes and living conditions by combining the analysis of cohort trends and the anthropometric cartography of height and physical build. This analysis is conducted for Spanish male cohorts born 1934-1973 that were recorded in the Spanish military statistics. This information is interpreted in light of region level data on GDP and infant mortality. Our results show an anthropometric convergence across regions that, nevertheless, did not substantially modify the spatial patterns of robustness, featuring primarily robust northeastern regions and weak Central-Southern regions. These patterns persisted until the 1990s (cohorts born during the 1970s). For the most part, anthropometric disparities were associated with socioeconomic disparities, although the former lessened over time to a greater extent than the latter. Interestingly, the various anthropometric indicators utilized here do not point to the same conclusions. Some discrepancies between height and robustness patterns have been found that moderate the statements from the analysis of cohort height alone regarding the level and evolution of living conditions across Spanish regions. PMID- 26640423 TI - Efficient Execution of Microscopy Image Analysis on CPU, GPU, and MIC Equipped Cluster Systems. AB - High performance computing is experiencing a major paradigm shift with the introduction of accelerators, such as graphics processing units (GPUs) and Intel Xeon Phi (MIC). These processors have made available a tremendous computing power at low cost, and are transforming machines into hybrid systems equipped with CPUs and accelerators. Although these systems can deliver a very high peak performance, making full use of its resources in real-world applications is a complex problem. Most current applications deployed to these machines are still being executed in a single processor, leaving other devices underutilized. In this paper we explore a scenario in which applications are composed of hierarchical data flow tasks which are allocated to nodes of a distributed memory machine in coarse-grain, but each of them may be composed of several finer-grain tasks which can be allocated to different devices within the node. We propose and implement novel performance aware scheduling techniques that can be used to allocate tasks to devices. We evaluate our techniques using a pathology image analysis application used to investigate brain cancer morphology, and our experimental evaluation shows that the proposed scheduling strategies significantly outperforms other efficient scheduling techniques, such as Heterogeneous Earliest Finish Time - HEFT, in cooperative executions using CPUs, GPUs, and MICs. We also experimentally show that our strategies are less sensitive to inaccuracy in the scheduling input data and that the performance gains are maintained as the application scales. PMID- 26640425 TI - Axial-Stereo 3-D Optical Metrology for Inner Profile of Pipes Using a Scanning Laser Endoscope. AB - As the rapid progress in the development of optoelectronic components and computational power, 3D optical metrology becomes more and more popular in manufacturing and quality control due to its flexibility and high speed. However, most of the optical metrology methods are limited to external surfaces. This paper proposed a new approach to measure tiny internal 3D surfaces with a scanning fiber endoscope and axial-stereo vision algorithm. A dense, accurate point cloud of internally machined threads was generated to compare with its corresponding X-ray 3D data as ground truth, and the quantification was analyzed by Iterative Closest Points algorithm. PMID- 26640424 TI - The 1994-1995 National Health Interview Survey on Disability (NHIS-D): A Bibliography of 20 Years of Research. AB - The 1994-1995 National Health Interview Survey on Disability (NHIS-D) has been one of the most unique and important data sources for studying disability, impairment, and health in the United States. In celebration of the NHIS-D's twenty-year anniversary, we created an extensive bibliography (n=212) of research that has used these data. PMID- 26640426 TI - Alginate Hydrogel Microencapsulation Inhibits Devitrification and Enables Large Volume Low-CPA Cell Vitrification. AB - Cryopreservation of stem cells is important to meet their ever-increasing demand by the burgeoning cell-based medicine. The conventional slow freezing for stem cell cryopreservation suffers from inevitable cell injury associated with ice formation and the vitrification (i.e., no visible ice formation) approach is emerging as a new strategy for cell cryopreservation. A major challenge to cell vitrification is intracellular ice formation (IIF, a lethal event to cells) induced by devitrification (i.e., formation of visible ice in previously vitrified solution) during warming the vitrified cells at cryogenic temperature back to super-zero temperatures. Consequently, high and toxic concentrations of penetrating cryoprotectants (i.e., high CPAs, up to ~8 M) and/or limited sample volumes (up to ~2.5 MUl) have been used to minimize IIF during vitrification. We reveal that alginate hydrogel microencapsulation can effectively inhibit devitrification during warming. Our data show that if ice formation were minimized during cooling, IIF is negligible in alginate hydrogel microencapsulated cells during the entire cooling and warming procedure of vitrification. This enables vitrification of pluripotent and multipotent stem cells with up to ~4 times lower concentration of penetrating CPAs (up to 2 M, low CPA) in up to ~100 times larger sample volume (up to ~250 MUl, large volume). PMID- 26640427 TI - Whole-Brain In-vivo Measurements of the Axonal G-Ratio in a Group of 37 Healthy Volunteers. AB - The g-ratio, quantifying the ratio between the inner and outer diameters of a fiber, is an important microstructural characteristic of fiber pathways and is functionally related to conduction velocity. We introduce a novel method for estimating the MR g-ratio non-invasively across the whole brain using high fidelity magnetization transfer (MT) imaging and single-shell diffusion MRI. These methods enabled us to map the MR g-ratio in vivo across the brain's prominent fiber pathways in a group of 37 healthy volunteers and to estimate the inter-subject variability. Effective correction of susceptibility-related distortion artifacts was essential before combining the MT and diffusion data, in order to reduce partial volume and edge artifacts. The MR g-ratio is in good qualitative agreement with histological findings despite the different resolution and spatial coverage of MRI and histology. The MR g-ratio holds promise as an important non-invasive biomarker due to its microstructural and functional relevance in neurodegeneration. PMID- 26640428 TI - Arterial Hypertension Aggravates Innate Immune Responses after Experimental Stroke. AB - Arterial hypertension is not only the leading risk factor for stroke, but also attributes to impaired recovery and poor outcome. The latter could be explained by hypertensive vascular remodeling that aggravates perfusion deficits and blood brain barrier disruption. However, besides vascular changes, one could hypothesize that activation of the immune system due to pre-existing hypertension may negatively influence post-stroke inflammation and thus stroke outcome. To test this hypothesis, male adult spontaneously hypertensive rats (SHRs) and normotensive Wistar Kyoto rats (WKYs) were subjected to photothrombotic stroke. One and 3 days after stroke, infarct volume and functional deficits were evaluated by magnetic resonance imaging and behavioral tests. Expression levels of adhesion molecules and chemokines along with the post-stroke inflammatory response were analyzed by flow cytometry, quantitative real-time PCR and immunohistochemistry in rat brains 4 days after stroke. Although comparable at day 1, lesion volumes were significantly larger in SHR at day 3. The infarct volume showed a strong correlation with the amount of CD45 highly positive leukocytes present in the ischemic hemispheres. Functional deficits were comparable between SHR and WKY. Brain endothelial expression of intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and P selectin (CD62P) was neither increased by hypertension nor by stroke. However, in SHR, brain infiltrating myeloid leukocytes showed significantly higher surface expression of ICAM-1 which may augment leukocyte transmigration by leukocyte leukocyte interactions. The expression of chemokines that primarily attract monocytes and granulocytes was significantly increased by stroke and, furthermore, by hypertension. Accordingly, ischemic hemispheres of SHR contain considerably higher numbers of monocytes, macrophages and granulocytes. Exacerbated brain inflammation in SHR may finally be responsible for larger infarct volumes. These findings provide an immunological explanation for the epidemiological observation that existing hypertension negatively affects stroke outcome and mortality. PMID- 26640429 TI - A Newly Identified Frontal Path from Fornix in Septum Pellucidum with 7.0T MRI Track Density Imaging (TDI) - The Septum Pellucidum Tract (SPT). AB - The high anatomical contrast achieved with the newly emerging MRI tractographic technique of super-resolution track density imaging (TDI) encouraged us to search for a new fiber tract in the septum pellucidum. Although this septum pellucidum tract (SPT) has been observed previously, its connections were unclear due to ambiguity and limited resolution of conventional MRI images. It is now possible to identify detailed parts of SPT with the increased resolution of TDI, which involves diffusion MRI imaging, whole-brain tractography, and voxel subdivision using the track-count information. Four healthy male subjects were included in the study. The experiment was performed with 7.0T MRI, following the guidelines of the institute's institutional review board. Data were processed with the super resolution TDI technique to generate a tractographic map with 0.18 mm isotropic resolution. The SPT was identified in all subjects. Based on additional seed tracking method with inter-axis correlation search, we have succeeded in identifying a new frontal lobe pathway in the SPT. We hypothesize that the tract is connected as a superior dorsal branch of the fornix that leads to the prefrontal cortex. PMID- 26640430 TI - Detection of Stimulus Displacements Across Saccades is Capacity-Limited and Biased in Favor of the Saccade Target. AB - Retinal image displacements caused by saccadic eye movements are generally unnoticed. Recent theories have proposed that perceptual stability across saccades depends on a local evaluation process centered on the saccade target object rather than on remapping and evaluating the positions of all objects in a display. In three experiments, we examined whether objects other than the saccade target also influence perceptual stability by measuring displacement detection thresholds across saccades for saccade targets and a variable number of non saccade objects. We found that the positions of multiple objects are maintained across saccades, but with variable precision, with the saccade target object having priority in the perception of displacement, most likely because it is the focus of attention before the saccade and resides near the fovea after the saccade. The perception of displacement of objects that are not the saccade target is affected by acuity limitations, attentional limitations, and limitations on memory capacity. Unlike previous studies that have found that a postsaccadic blank improves the detection of displacement direction across saccades, we found that postsaccadic blanking hurt the detection of displacement per se by increasing false alarms. Overall, our results are consistent with the hypothesis that visual working memory underlies the perception of stability across saccades. PMID- 26640432 TI - Empirical Bayes for DCM: A Group Inversion Scheme. AB - This technical note considers a simple but important methodological issue in estimating effective connectivity; namely, how do we integrate measurements from multiple subjects to infer functional brain architectures that are conserved over subjects. We offer a solution to this problem that rests on a generalization of random effects analyses to Bayesian inference about nonlinear models of electrophysiological time-series data. Specifically, we present an empirical Bayesian scheme for group or hierarchical models, in the setting of dynamic causal modeling (DCM). Recent developments in approximate Bayesian inference for hierarchical models enable the efficient estimation of group effects in DCM studies of multiple trials, sessions, or subjects. This approach estimates second (e.g., between-subject) level parameters based on posterior estimates from the first (e.g., within-subject) level. Here, we use empirical priors from the second level to iteratively optimize posterior densities over parameters at the first level. The motivation for this iterative application is to finesse the local minima problem inherent in the (first level) inversion of nonlinear and ill-posed models. Effectively, the empirical priors shrink the first level parameter estimates toward the global maximum, to provide more robust and efficient estimates of within (and between-subject) effects. This paper describes the inversion scheme using a worked example based upon simulated electrophysiological responses. In a subsequent paper, we will assess its robustness and reproducibility using an empirical example. PMID- 26640431 TI - Effects of Rapamycin Treatment on Neurogenesis and Synaptic Reorganization in the Dentate Gyrus after Controlled Cortical Impact Injury in Mice. AB - Post-traumatic epilepsy (PTE) is one consequence of traumatic brain injury (TBI). A prominent cell signaling pathway activated in animal models of both TBI and epilepsy is the mammalian target of rapamycin (mTOR). Inhibition of mTOR with rapamycin has shown promise as a potential modulator of epileptogenesis in several animal models of epilepsy, but cellular mechanisms linking mTOR expression and epileptogenesis are unclear. In this study, the role of mTOR in modifying functional hippocampal circuit reorganization after focal TBI induced by controlled cortical impact (CCI) was investigated. Rapamycin (3 or 10 mg/kg), an inhibitor of mTOR signaling, was administered by intraperitoneal injection beginning on the day of injury and continued daily until tissue collection. Relative to controls, rapamycin treatment reduced dentate granule cell area in the hemisphere ipsilateral to the injury two weeks post-injury. Brain injury resulted in a significant increase in doublecortin immunolabeling in the dentate gyrus ipsilateral to the injury, indicating increased neurogenesis shortly after TBI. Rapamycin treatment prevented the increase in doublecortin labeling, with no overall effect on Fluoro-Jade B staining in the ipsilateral hemisphere, suggesting that rapamycin treatment reduced posttraumatic neurogenesis but did not prevent cell loss after injury. At later times post-injury (8-13 weeks), evidence of mossy fiber sprouting and increased recurrent excitation of dentate granule cells was detected, which were attenuated by rapamycin treatment. Rapamycin treatment also diminished seizure prevalence relative to vehicle treated controls after TBI. Collectively, these results support a role for adult neurogenesis in PTE development and suggest that suppression of epileptogenesis by mTOR inhibition includes effects on post-injury neurogenesis. PMID- 26640433 TI - Contingency Awareness Shapes Acquisition and Extinction of Emotional Responses in a Conditioning Model of Pain-Related Fear. AB - As a fundamental learning process, fear conditioning promotes the formation of associations between predictive cues and biologically significant signals. In its application to pain, conditioning may provide important insight into mechanisms underlying pain-related fear, although knowledge especially in interoceptive pain paradigms remains scarce. Furthermore, while the influence of contingency awareness on excitatory learning is subject of ongoing debate, its role in pain related acquisition is poorly understood and essentially unknown regarding extinction as inhibitory learning. Therefore, we addressed the impact of contingency awareness on learned emotional responses to pain- and safety predictive cues in a combined dataset of two pain-related conditioning studies. In total, 75 healthy participants underwent differential fear acquisition, during which rectal distensions as interoceptive unconditioned stimuli (US) were repeatedly paired with a predictive visual cue (conditioned stimulus; CS(+)) while another cue (CS(-)) was presented unpaired. During extinction, both CS were presented without US. CS valence, indicating learned emotional responses, and CS US contingencies were assessed on visual analog scales (VAS). Based on an integrative measure of contingency accuracy, a median-split was performed to compare groups with low vs. high contingency accuracy regarding learned emotional responses. To investigate predictive value of contingency accuracy, regression analyses were conducted. Highly accurate individuals revealed more pronounced negative emotional responses to CS(+) and increased positive responses to CS(-) when compared to participants with low contingency accuracy. Following extinction, highly accurate individuals had fully extinguished pain-predictive cue properties, while exhibiting persistent positive emotional responses to safety signals. In contrast, individuals with low accuracy revealed equally positive emotional responses to both, CS(+) and CS(-). Contingency accuracy predicted variance in the formation of positive responses to safety cues while no predictive value was found for danger cues following acquisition and for neither cue following extinction. Our findings underscore specific roles of learned danger and safety in pain-related acquisition and extinction. Contingency accuracy appears to distinctly impact learned emotional responses to safety and danger cues, supporting aversive learning to occur independently from CS-US awareness. The interplay of cognitive and emotional factors in shaping excitatory and inhibitory pain-related learning may contribute to altered pain processing, underscoring its clinical relevance in chronic pain. PMID- 26640434 TI - Neural Correlates of Decision-Making Under Ambiguity and Conflict. AB - HIGHLIGHTS We use a simple gambles design in an fMRI study to compare two conditions: ambiguity and conflict.Participants were more conflict averse than ambiguity averse.Ambiguity aversion did not correlate with conflict aversion.Activation in the medial prefrontal cortex correlated with ambiguity level and ambiguity aversion.Activation in the ventral striatum correlated with conflict level and conflict aversion. Studies of decision making under uncertainty generally focus on imprecise information about outcome probabilities ("ambiguity"). It is not clear, however, whether conflicting information about outcome probabilities affects decision making in the same manner as ambiguity does. Here we combine functional magnetic resonance imaging (fMRI) and a simple gamble design to study this question. In this design the levels of ambiguity and conflict are parametrically varied, and ambiguity and conflict gambles are matched on expected value. Behaviorally, participants avoided conflict more than ambiguity, and attitudes toward ambiguity and conflict did not correlate across participants. Neurally, regional brain activation was differentially modulated by ambiguity level and aversion to ambiguity and by conflict level and aversion to conflict. Activation in the medial prefrontal cortex was correlated with the level of ambiguity and with ambiguity aversion, whereas activation in the ventral striatum was correlated with the level of conflict and with conflict aversion. These novel results indicate that decision makers process imprecise and conflicting information differently, a finding that has important implications for basic and clinical research. PMID- 26640436 TI - The Neural Signatures of Processing Semantic End Values in Automatic Number Comparisons. AB - The brain activity associated with processing numerical end values has received limited research attention. The present study explored the neural correlates associated with processing semantic end values under conditions of automatic number processing. Event-related potentials (ERPs) were recorded while participants performed the numerical Stroop task, in which they were asked to compare the physical size of pairs of numbers, while ignoring their numerical values. The smallest end value in the set, which is a task irrelevant factor, was manipulated between participant groups. We focused on the processing of the lower end values of 0 and 1 because these numbers were found to be automatically tagged as the "smallest." Behavioral results showed that the size congruity effect was modulated by the presence of the smallest end value in the pair. ERP data revealed a spatially extended centro-parieto-occipital P3 that was enhanced for congruent versus incongruent trials. Importantly, over centro-parietal sites, the P3 congruity effect (congruent minus incongruent) was larger for pairs containing the smallest end value than for pairs containing non-smallest values. These differences in the congruency effect were localized to the precuneus. The presence of an end value within the pair also modulated P3 latency. Our results provide the first neural evidence for the encoding of numerical end values. They further demonstrate that the use of end values as anchors is a primary aspect of processing symbolic numerical information. PMID- 26640437 TI - Daily Carnosine and Anserine Supplementation Alters Verbal Episodic Memory and Resting State Network Connectivity in Healthy Elderly Adults. AB - Carnosine and anserine are strong antioxidants, previously demonstrated to reduce cognitive decline in animal studies. We aimed to investigate their cognitive and neurophysiological effects, using functional MRI, on humans. Thirty-one healthy participants (age 40-78, 10 male/21 female) were recruited to a double-blind placebo-controlled study. Participants were assigned to twice-daily doses of imidazole dipeptide formula (n = 14), containing 500 mg (carnosine/anserine, ratio 1/3) or an identical placebo (n = 17). Functional MRI and neuropsychological assessments were carried out at baseline and after 3 months of supplementation. We analyzed resting state functional connectivity with the FSL fMRI analysis package. There were no differences in neuropsychological scores between the groups at baseline. After 3 months of supplementation, the carnosine/anserine group had better verbal episodic memory performance and decreased connectivity in the default mode network, the posterior cingulate cortex and the right fronto parietal network, as compared with the placebo group. Furthermore, there was a correlation between the extents of cognitive and neuroimaging changes. These results suggest that daily carnosine/anserine supplementation can impact cognitive function and that network connectivity changes are associated with its effects. PMID- 26640438 TI - Editorial: Heme Oxygenases: Novel Regulators of Reproductive Processes. PMID- 26640435 TI - A Hierarchical Generative Framework of Language Processing: Linking Language Perception, Interpretation, and Production Abnormalities in Schizophrenia. AB - Language and thought dysfunction are central to the schizophrenia syndrome. They are evident in the major symptoms of psychosis itself, particularly as disorganized language output (positive thought disorder) and auditory verbal hallucinations (AVHs), and they also manifest as abnormalities in both high-level semantic and contextual processing and low-level perception. However, the literatures characterizing these abnormalities have largely been separate and have sometimes provided mutually exclusive accounts of aberrant language in schizophrenia. In this review, we propose that recent generative probabilistic frameworks of language processing can provide crucial insights that link these four lines of research. We first outline neural and cognitive evidence that real time language comprehension and production normally involve internal generative circuits that propagate probabilistic predictions to perceptual cortices - predictions that are incrementally updated based on prediction error signals as new inputs are encountered. We then explain how disruptions to these circuits may compromise communicative abilities in schizophrenia by reducing the efficiency and robustness of both high-level language processing and low-level speech perception. We also argue that such disruptions may contribute to the phenomenology of thought-disordered speech and false perceptual inferences in the language system (i.e., AVHs). This perspective suggests a number of productive avenues for future research that may elucidate not only the mechanisms of language abnormalities in schizophrenia, but also promising directions for cognitive rehabilitation. PMID- 26640439 TI - The Hydrophobic Effect Contributes to the Closed State of a Simplified Ion Channel through a Conserved Hydrophobic Patch at the Pore-Helix Crossing. AB - Ion selectivity-filter structures are strikingly similar throughout the large family of K(++) channels and other p-loop-like receptors (i.e., glutamate receptors). At the same time, the triggers for opening these channels, or gating, are diverse. Two questions that remain unanswered regarding these channels are: (1) what force(s) stabilize the closed non-conducting channel-pore conformation? And (2) what is the free energy associated with transitioning from a closed (non conducting) to an open (conducting) channel-pore conformation? The effects of charge and hydrophobicity on the conformational states of a model tetrameric biological ion channel are shown utilizing the amino acid sequence from the K(+) channel KcsA as the model "channel". Its widely conserved hydrophobic bundle crossing located adjacent to the lipid head-groups at the intracellular side of the membrane was calculated to have a 5 kcal/mol free energy difference between modeled open and closed conformations. Simulated mutants of amino acids within the hydrophobic region significantly contribute to the size of this difference. Specifically for KcsA, these residues are part of the pH sensor important for channel gating and our results are in agreement with published electrophysiology data. Our simulations support the idea that the hydrophobic effect contributes significantly to the stability of the closed conformation in tetrameric ion channels with a hydrophobic bundle crossing positioned in proximity to the lipid head groups of the biological membrane. PMID- 26640440 TI - The Averaged EMGs Recorded from the Arm Muscles During Bimanual "Rowing" Movements. AB - The main purpose was to analyze quantitatively the the average surface EMGs of the muscles that function around the elbow and shoulder joints of both arms in bimanual "rowing" movements, which were produced under identical elastic loads applied to the levers ("oars"). The muscles of PM group ("pulling" muscles: elbow flexors, shoulder extensors) generated noticeable velocity-dependent dynamic EMG components during the pulling and returning phases of movement and supported a steady-state activity during the hold phase. The muscles of RM group ("returning" muscles: elbow extensors, shoulder flexors) co-contracted with PM group during the movement phases and decreased activity during the hold phase. The dynamic components of the EMGs strongly depended on the velocity factor in both muscle groups, whereas the side and load factors and combinations of various factors acted only in PM group. Various subjects demonstrated diverse patterns of activity redistribution among muscles. We assume that central commands to the same muscles in two arms may be essentially different during execution of similar movement programs. Extent of the diversity in the EMG patterns of such muscles may reflect the subject's skilling in motor performance; on the other hand, the diversity can be connected with redistribution of activity between synergic muscles, thus providing a mechanism directed against development of the muscle fatigue. PMID- 26640441 TI - Prognostic Value of Troponin I for Infarct Size to Improve Preclinical Myocardial Infarction Small Animal Models. AB - Coronary artery ligations to induce myocardial infarction (MI) in mice and rats are widely used in preclinical investigation. However, myocardial ischemic damage and subsequent infarct size are highly variable. The lack of standardization of the model impairs the probability of effective translation to the clinic. Cardiac Troponin I (cTnI) is a major clinically relevant biomarker. AIM: In the present study, we investigated the prognostic value of cTnI for early estimation of the infarct size. METHODS AND RESULTS: Infarcts of different sizes were induced in mice and rats by ligation, at a random site, of the coronary artery. Kinetics of the plasma levels of cTnI were measured. Heart function was evaluated by echocardiography, the percentage of infarcted left ventricle and infarct expansion index were assessed from histological section. We observed that plasma cTnI level peaked at 24 h in the infarcted rats and between 24 and 48 h in mice. Sham operated animals had a level of cTnI below 15 ng/mL. Infarct expansion index (EI) assessed 4 weeks after ligation showed a large variation coefficient of 63 and 71% in rats and mice respectively. We showed a significative correlation between cTnI level and the EI demonstrating its predictive value for myocardial injury in small animal models. CONCLUSION: we demonstrated the importance of cTnI plasma level as a major early marker to assist in the optimal and efficient management of MI in laboratory animals model. The presented results stress the need for comparable biomarkers in the animal model and clinical trials for improved translation. PMID- 26640442 TI - Dual-Energy X-Ray Absorptiometry, Skinfold Thickness, and Waist Circumference for Assessing Body Composition in Ambulant and Non-Ambulant Wheelchair Games Players. AB - Field-based assessments provide a cost-effective and accessible alternative to dual-energy X-ray absorptiometry (DXA) for practitioners determining body composition in athletic populations. It remains unclear how the range of physical impairments classifiable in wheelchair sports may affect the utility of field based body composition techniques. The present study assessed body composition using DXA in 14 wheelchair games players who were either wheelchair dependent (non-walkers; n = 7) or relied on a wheelchair for sports participation only (walkers; n = 7). Anthropometric measurements were used to predict body fat percentage with existing regression equations established for able-bodied persons by Sloan and Weir, Durnin and Womersley, Lean et al, Gallagher et al, and Pongchaiyakul et al. In addition, linear regression analysis was performed to calculate the association between body fat percentage and BMI, waist circumference, sum of 6 skinfold thickness and sum of 8 skinfold thickness. Results showed that non-walkers had significantly lower total lean tissue mass (46.2 +/- 6.6 kg vs. 59.4 +/- 8.2 kg, P = 0.006) and total body mass (65.8 +/- 4.2 kg vs. 79.4 +/- 14.9 kg; P = 0.05) than walkers. Body fat percentage calculated from most existing regression equations was significantly lower than that from DXA, by 2 to 9% in walkers and 8 to 14% in non-walkers. Of the anthropometric measurements, the sum of 8 skinfold thickness had the lowest standard error of estimation in predicting body fat content. In conclusion, existing anthropometric equations developed in able-bodied populations substantially underestimated body fat content in wheelchair athletes, particularly non-walkers. Impairment specific equations may be needed in wheelchair athletes. PMID- 26640443 TI - Retraction: Physiology and Pharmacology of the Cardiovascular Adrenergic System. AB - [This retracts the article on p. 240 in vol. 4, PMID: 24027534.]. PMID- 26640444 TI - The Dynamic Reactance Interaction - How Vested Interests Affect People's Experience, Behavior, and Cognition in Social Interactions. AB - In social interactions, individuals may sometimes pursue their own interests at the expense of their interaction partner. Such self-interested behaviors impose a threat to the interaction partner's freedom to act. The current article investigates this threat in the context of interdependence and reactance theory. We explore how vested interests influence reactance process stages of an advisor client interaction. We aim to explore the interactional process that evolves. In two studies, participants took the perspective of a doctor (advisor) or a patient (client). In both studies we incorporated a vested interest. In Study 1 (N = 82) we found that in response to a vested interest of their interaction partner, patients indicated a stronger experience of reactance, more aggressive behavioral intentions, and more biased cognitions than doctors. A serial multiple mediation revealed that a vested interest engendered mistrust toward the interaction partner and this mistrust led to an emerging reactance process. Study 2 (N = 207) further demonstrated that doctors expressed their reactance in a subtle way: they revealed a classic confirmation bias when searching for additional information on their preliminary decision preference, indicating stronger defense motivation. We discuss how these findings can help us to understand how social interactions develop dynamically. PMID- 26640447 TI - Resilience Building in Students: The Role of Academic Self-Efficacy. AB - Self-efficacy relates to an individual's perception of their capabilities. It has a clear self-evaluative dimension leading to high or low perceived self-efficacy. Individual differences in perceived self-efficacy have been shown to be better predictors of performance than previous achievement or ability and seem particularly important when individuals face adversity. The study investigated the nature of the association between academic self-efficacy (ASE) and academic resilience. Undergraduate student participants (N = 435) were exposed to an adverse situation case vignette describing either personal or vicarious academic adversity. ASE was measured pre-exposure and academic resilience was measured post-exposure. ASE was correlated with, and a significant predictor of, academic resilience and students exhibited greater academic resilience when responding to vicarious adversity compared to personal adversity. Identifying constructs that are related to resilience and establishing the precise nature of how such constructs influence academic resilience will assist the development of interventions aimed at promoting resilience in students. PMID- 26640446 TI - Mediation of Short and Longer Term Effects of an Intervention Program to Enhance Resilience in Immigrants from Mainland China to Hong Kong. AB - Few clinical trials report on the active intervention components that result in outcome changes, although this is relevant to further improving efficacy and adapting effective programs to other populations. This paper presents follow-up analyses of a randomized controlled trial to enhance adaptation by increasing knowledge and personal resilience in two separate brief interventions with immigrants from Mainland China to Hong Kong (Yu et al., 2014b). The present paper extends our previous one by reporting on the longer term effect of the interventions on personal resilience, and examining whether the Resilience intervention worked as designed to enhance personal resilience. The four-session intervention targeted at self-efficacy, positive thinking, altruism, and goal setting. In this randomized controlled trial, 220 immigrants were randomly allocated to three arms: Resilience, Information (an active control arm), and Control arms. Participants completed measures of the four active components (self efficacy, positive thinking, altruism, and goal setting) at baseline and immediately after the intervention. Personal resilience was assessed at baseline, post-intervention, and 3- and 6-month follow-ups. The results showed that the Resilience arm had greater increases in the four active components post intervention. Changes in each of the four active components at the post intervention assessment mediated enhanced personal resilience at the 3-month follow-up in the Resilience arm. Changes in self-efficacy and goal setting showed the largest effect size, and altruism showed the smallest. The arm effects of the Resilience intervention on enhanced personal resilience at the 6-month follow-up were mediated by increases of personal resilience post-intervention (Resilience vs. Control) and at the 3-month follow-up (Resilience vs. Information). These findings showed that these four active components were all mediators in this Resilience intervention. Our results of the effects of short term increases in personal resilience on longer term increase in personal resilience in some models suggest how changes in intervention outcomes might persist over time. PMID- 26640445 TI - Music in Research and Rehabilitation of Disorders of Consciousness: Psychological and Neurophysiological Foundations. AB - According to a prevailing view, the visual system works by dissecting stimuli into primitives, whereas the auditory system processes simple and complex stimuli with their corresponding features in parallel. This makes musical stimulation particularly suitable for patients with disorders of consciousness (DoC), because the processing pathways related to complex stimulus features can be preserved even when those related to simple features are no longer available. An additional factor speaking in favor of musical stimulation in DoC is the low efficiency of visual stimulation due to prevalent maladies of vision or gaze fixation in DoC patients. Hearing disorders, in contrast, are much less frequent in DoC, which allows us to use auditory stimulation at various levels of complexity. The current paper overviews empirical data concerning the four main domains of brain functioning in DoC patients that musical stimulation can address: perception (e.g., pitch, timbre, and harmony), cognition (e.g., musical syntax and meaning), emotions, and motor functions. Music can approach basic levels of patients' self consciousness, which may even exist when all higher-level cognitions are lost, whereas music induced emotions and rhythmic stimulation can affect the dopaminergic reward-system and activity in the motor system respectively, thus serving as a starting point for rehabilitation. PMID- 26640449 TI - Inter-Group Conflict and Cooperation: Field Experiments Before, During and After Sectarian Riots in Northern Ireland. AB - The idea that cooperative groups out-compete less cooperative groups has been proposed as a theoretical possibility for the evolution of cooperation through cultural group selection. Previous studies have found an association between increased cooperation and exposure to inter-group violence, but most have not been able to identify the specific target of cooperation and are based on correlational data making it difficult to establish causality. In this study we test the hypothesis that inter-group conflict promotes parochial altruism (i.e., in-group altruism and out-group hostility) by using longitudinal data of a real world measure of cooperation-charity and school donations-sampled before, during and after violent sectarian riots between Catholics and Protestants in Belfast, Northern Ireland. We find that conflict is associated with reductions in all types of cooperation, with reduced donations to a neutral charity, and both in group and out-group primary schools. After the conflict, both in-group and out group donations increased again. In this context we find no evidence that inter group conflict promotes parochial altruism. PMID- 26640448 TI - The Effects of tDCS Across the Spatial Frequencies and Orientations that Comprise the Contrast Sensitivity Function. AB - Transcranial Direct Current Stimulation (tDCS) has recently been employed in traditional psychophysical paradigms in an effort to measure direct manipulations on spatial frequency channel operations in the early visual system. However, the effects of tDCS on contrast sensitivity have only been measured at a single spatial frequency and orientation. Since contrast sensitivity is known to depend on spatial frequency and orientation, we ask how the effects of anodal and cathodal tDCS may vary according to these dimensions. We measured contrast sensitivity with sinusoidal gratings at four different spatial frequencies (0.5, 4, 8, and 12 cycles/ degrees ), two orientations (45 degrees Oblique and Horizontal), and for two stimulus size conditions [fixed size (3 degrees ) and fixed period (1.5 cycles)]. Only contrast sensitivity measured with a 45 degrees oblique grating with a spatial frequency of 8 cycles/ degrees (period = 1.5 cycles) demonstrated clear polarity specific effects of tDCS, whereby cathodal tDCS increased and anodal tDCS decreased contrast sensitivity. Overall, effects of tDCS were largest for oblique stimuli presented at high spatial frequencies (i.e., 8 and 12 cycles/ degrees ), and were small or absent at lower spatial frequencies, other orientations and stimulus size. Thus, the impact of tDCS on contrast sensitivity, and therefore on spatial frequency channel operations, is opposite in direction to other behavioral effects of tDCS, and only measurable in stimuli that generally elicit lower contrast sensitivity (e.g., oblique gratings with period of 1.5 cycles at spatial frequencies above the peak of the contrast sensitivity function). PMID- 26640450 TI - On the Creation of Representative Samples of Random Quasi-Orders. AB - Dependencies between educational test items can be represented as quasi-orders on the item set of a knowledge domain and used for an efficient adaptive assessment of knowledge. One approach to uncovering such dependencies is by exploratory algorithms of item tree analysis (ITA). There are several methods of ITA available. The basic tool to compare such algorithms concerning their quality are large-scale simulation studies that are crucially set up on a large collection of quasi-orders. A serious problem is that all known ITA algorithms are sensitive to the structure of the underlying quasi-order. Thus, it is crucial to base any simulation study that tries to compare the algorithms upon samples of quasi orders that are representative, meaning each quasi-order is included in a sample with the same probability. Up to now, no method to create representative quasi orders on larger item sets is known. Non-optimal algorithms for quasi-order generation were used in previous studies, which caused misinterpretations and erroneous conclusions. In this paper, we present a method for creating representative random samples of quasi-orders. The basic idea is to consider random extensions of quasi-orders from lower to higher dimension and to discard extensions that do not satisfy the transitivity property. PMID- 26640452 TI - The Role of Reading Fluency in Children's Text Comprehension. AB - Understanding a written text requires some higher cognitive abilities that not all children have. Some children have these abilities, since they understand oral texts; however, they have difficulties with written texts, probably due to problems in reading fluency. The aim of this study was to determine which aspects of reading fluency are related to reading comprehension. Four expositive texts, two written and two read by the evaluator, were presented to a sample of 103 primary school children (third and sixth grade). Each text was followed by four comprehension questions. From this sample we selected two groups of participants in each grade, 10 with good results in comprehension of oral and written texts, and 10 with good results in oral and poor in written comprehension. These 40 subjects were asked to read aloud a new text while they were recorded. Using Praat software some prosodic parameters were measured, such as pausing and reading rate (number and duration of the pauses and utterances), pitch and intensity changes and duration in declarative, exclamatory, and interrogative sentences and also errors and duration in words by frequency and stress. We compared the results of both groups with ANOVAs. The results showed that children with less reading comprehension made more inappropriate pauses and also intersentential pauses before comma than the other group and made more mistakes in content words; significant differences were also found in the final declination of pitch in declarative sentences and in the F0 range in interrogative ones. These results confirm that reading comprehension problems in children are related to a lack in the development of a good reading fluency. PMID- 26640451 TI - A Cognitive Profile of Obesity and Its Translation into New Interventions. AB - Change your lifestyle: decrease your energy intake and increase your energy expenditure, is what obesity experts tell people who need to lose weight. Though the advice might be correct, it appears to be extremely difficult to change one's lifestyle. Unhealthy habits usually are ingrained and hard to change, especially for people with an "obese cognitive profile." Knowledge of the cognitive mechanisms that maintain unhealthy eating habits is necessary for the development of interventions that can change behavior effectively. This paper discusses some cognitive processes that might maintain unhealthy eating habits and make healthier eating difficult, like increased food cue reactivity, weak executive skills and attention bias. An effort is also done to translate these basic scientific findings into new interventions which aim to tackle the sabotaging cognitive processes. Preliminary studies into the effectiveness of these interventions, if available, are presented. PMID- 26640455 TI - Forgetting the Past and Neglecting the Future. Commentary: A Crisis in Comparative Psychology: Where Have All the Undergraduates Gone? PMID- 26640454 TI - Reintroducing the Concept of Complementarity into Psychology. AB - Central to quantum theory is the concept of complementarity. In this essay, we argue that complementarity is also central to the emerging field of quantum cognition. We review the concept, its historical roots in psychology, and its development in quantum physics and offer examples of how it can be used to understand human cognition. The concept of complementarity provides a valuable and fresh perspective for organizing human cognitive phenomena and for understanding the nature of measurements in psychology. In turn, psychology can provide valuable new evidence and theoretical ideas to enrich this important scientific concept. PMID- 26640453 TI - Merge in the Human Brain: A Sub-Region Based Functional Investigation in the Left Pars Opercularis. AB - Language is thought to represent one of the most complex cognitive functions in humans. Here we break down complexity of language to its most basic syntactic computation which hierarchically binds single words together to form larger phrases and sentences. So far, the neural implementation of this basic operation has only been inferred indirectly from studies investigating more complex linguistic phenomena. In the present sub-region based functional magnetic resonance imaging (fMRI) study we directly assessed the neuroanatomical nature of this process. Our results showed that syntactic phrases-compared to word-list sequences-corresponded to increased neural activity in the ventral-anterior portion of the left pars opercularis [Brodmann Area (BA) 44], whereas the adjacently located deep frontal operculum/anterior insula (FOP/aINS), a phylogenetically older and less specialized region, was found to be equally active for both conditions. Crucially, the functional activity of syntactic binding was confined to one out of five clusters proposed by a recent fine grained sub-anatomical parcellation for BA 44, with consistency across individuals. Neuroanatomically, the present results call for a redefinition of BA 44 as a region with internal functional specializations. Neurocomputationally, they support the idea of invariance within BA 44 in the location of activation across participants for basic syntactic building processing. PMID- 26640456 TI - Personality Traits Moderate the Effect of Workload Sources on Perceived Workload in Flying Column Police Officers. AB - Previous research has suggested that personality traits of the Five Factor Model play a role in worker's response to workload. The aim of this study was to investigate the association of personality traits of first responders with their perceived workload in real-life tasks. A flying column of 269 police officers completed a measure of subjective workload (NASA-Task Load Index) after intervention tasks in a major public event. Officers' scores on a measure of Five Factor Model personality traits were obtained from archival data. Linear Mixed Modeling was used to test the direct and interaction effects of personality traits on workload scores once controlling for background variables, task type and workload source (mental, temporal and physical demand of the task, perceived effort, dissatisfaction for the performance and frustration due to the task). All personality traits except extraversion significantly interacted at least with one workload source. Perceived workload in flying column police officers appears to be the result of their personality characteristics interacting with the workload source. The implications of these results for the development of support measures aimed at reducing the impact of workload in this category of workers are discussed. PMID- 26640457 TI - Cerebrospinal Fluid Abeta40 Improves the Interpretation of Abeta42 Concentration for Diagnosing Alzheimer's Disease. AB - The combination of decreased amyloid beta42 (Abeta42) and increased total tau proteins (T-Tau) and phosphorylated tau (P-Tau) in cerebrospinal fluid (CSF) has recently been considered as a biological diagnostic criterion of Alzheimer's disease (AD). Previous studies showed significant heterogeneity in CSF Abeta42 levels to discriminate AD from non-AD patients. It was also suggested that the CSF amyloid peptide beta42/beta40 ratio has better diagnostic performance than Abeta42 alone. The objective of the present study was to investigate the potential added value of determining CSF amyloid beta40 peptide (Abeta40) for biological diagnosis of AD when CSF Abeta42 levels failed. CSF AD biomarkers were run in 2,171 samples from 1,499 AD and 672 non-AD patients. The following pathologic thresholds were used to define an AD-positive CSF biomarker profile: T Tau >= 400 ng/L, P-Tau181 >= 60 ng/L, and Abeta42 <= 700 ng/L. CSF Abeta40 was assayed in AD patients with CSF Abeta42 levels above 700 ng/L and non-AD patients with CSF Abeta42 levels below 700 ng/L. CSF Abeta40 levels were higher in AD than non-AD patients. The receiver operator characteristic curves of CSF Abeta40 and the Abeta42/Abeta40 ratio defined AD cut-off values at 12,644 ng/L and 0.06, respectively. In AD patients with non-pathological CSF Abeta42, CSF Abeta40 concentration was able to correct 76.2% of cases when expressed as CSF Abeta42/Abeta40 ratio and 94.7% of cases when used alone. Using CSF Abeta42 and then CSF Abeta40, the percentage of misinterpreted AD patients fell to 1.0%. CSF Abeta40 concentration improved interpretation of Abeta42 level for the diagnosis of AD. CSF Abeta40 alone showed better diagnostic performance than the amyloid peptide Abeta42/Abeta40 ratio. The added value of determining CSF Abeta40 in AD diagnosis now needs confirming in a cohort of definite AD patients and to be completed with novel amyloid cascade biomarkers. PMID- 26640458 TI - Parkinson's Is Time on Your Side? Evidence for Difficulties with Sensorimotor Synchronization. AB - There is lack of consistent evidence as to how well PD patients are able to accurately time their movements across space with an external acoustic signal. For years, research based on the finger-tapping paradigm, the most popular paradigm for exploring the brain's ability to time movement, has provided strong evidence that patients are not able to accurately reproduce an isochronous interval [i.e., Ref. (1)]. This was undermined by Spencer and Ivry (2) who suggested a specific deficit in temporal control linked to emergent, rhythmical movement not event-based actions, which primarily involve the cerebellum. In this study, we investigated motor timing of seven idiopathic PD participants in event based sensorimotor synchronization task. Participants were asked to move their finger horizontally between two predefined target zones to synchronize with the occurrence of two sound events at two time intervals (1.5 and 2.5 s). The width of the targets and the distance between them were manipulated to investigate impact of accuracy demands and movement amplitude on timing performance. The results showed that participants with PD demonstrated specific difficulties when trying to accurately synchronize their movements to a beat. The extent to which their ability to synchronize movement was compromised was found to be related to the severity of PD, but independent of the spatial constraints of the task. PMID- 26640459 TI - A New Zamilon-like Virophage Partial Genome Assembled from a Bioreactor Metagenome. AB - Virophages replicate within viral factories inside the Acanthamoeba cytoplasm, and decrease the infectivity and replication of their associated giant viruses. Culture isolation and metagenome analyses have suggested that they are common in our environment. By screening metagenomic databases in search of amoebal viruses, we detected virophage-related sequences among sequences generated from the same non-aerated bioreactor metagenome as recently screened by another team for virophage capsid-encoding genes. We describe here the assembled partial genome of a virophage closely related to Zamilon, which infects Acanthamoeba with mimiviruses of lineages B and C but not A. Searches for sequences related to amoebal giant viruses, other Megavirales representatives and virophages were conducted using BLAST against this bioreactor metagenome (PRJNA73603). Comparative genomic and phylogenetic analyses were performed using sequences from previously identified virophages. A total of 72 metagenome contigs generated from the bioreactor were identified as best matching with sequences from Megavirales representatives, mostly Pithovirus sibericum, pandoraviruses and amoebal mimiviruses from three lineages A-C, as well as from virophages. In addition, a partial genome from a Zamilon-like virophage, we named Zamilon 2, was assembled. This genome has a size of 6716 base pairs, corresponding to 39% of the Zamilon genome, and comprises partial or full-length homologs for 15 Zamilon predicted open reading frames (ORFs). Mean nucleotide and amino acid identities for these 15 Zamilon 2 ORFs with their Zamilon counterparts were 89% (range, 81-96%) and 91% (range, 78-99%), respectively. Notably, these ORFs included two encoding a capsid protein and a packaging ATPase. Comparative genomics and phylogenetic analyses indicated that the partial genome was that of a new Zamilon-like virophage. Further studies are needed to gain better knowledge of the tropism and prevalence of virophages in our biosphere and in humans. PMID- 26640460 TI - The Anti-Phytophthora Effect of Selected Potato-Associated Pseudomonas Strains: From the Laboratory to the Field. AB - Late blight, caused by the oomycete Phytophthora infestans, is the most devastating disease of potato. In organic farming, late blight is controlled by repeated applications of copper-based products, which negatively impact the environment. To find alternative solutions for late blight management, we have previously isolated a large collection of bacteria from the phyllosphere and the rhizosphere of potatoes. Here we report the antagonistic potential of these strains when co-cultivated with P. infestans as well as with other potato pathogens. We then focused on three Pseudomonas strains and compared their protective impact against late blight to that of well-known biocontrol strains in planta using a high-throughput leaf disk assay with automated picture analysis. When sprayed on the leaves of potatoes in the greenhouse, the strains were able to survive for at least 15 days. Under field conditions, populations decreased faster but all tested strains could still be retrieved after 8 days. The most active strain in vitro, P. chlororaphis R47, was also the best protectant on leaf disks from plants grown in the greenhouse experiment, but its protection potential could not be verified in the field due to unfavorable infection conditions. However, its protective effect against P. infestans in planta, its survival in the phyllosphere as well as its ability to colonize the potato rhizosphere in very high population densities, suggest a potential for field application, e.g., in the form of tuber treatment or leaf spray. PMID- 26640461 TI - Editorial: Why Vaccines to HIV, HCV, and Malaria Have So Far Failed-Challenges to Developing Vaccines Against Immunoregulating Pathogens. PMID- 26640462 TI - The Community Structures of Prokaryotes and Fungi in Mountain Pasture Soils are Highly Correlated and Primarily Influenced by pH. AB - Traditionally, conservation and management of mountain pastures has been managed solely on the basis of visible biota. However, microorganisms play a vital role for the functioning of the soil ecosystem and, hence, pasture sustainability. Here, we studied the links between soil microbial (belowground) community structure (using amplicon sequencing of prokaryotes and fungi), other soil physicochemical and biological properties and, finally, a variety of pasture management practices. To this aim, during two consecutive years, we studied 104 environmental sites characterized by contrasting elevation, habitats, bedrock, and pasture management; located in or near Gorbeia Natural Park (Basque Country/Spain). Soil pH was found to be one of the most important factors in structuring soil microbial diversity. Interestingly, we observed a striking correlation between prokaryotic, fungal and macrofauna diversity, likely caused by interactions between these life forms. Further studies are needed to better understand such interactions and target the influence of different management practices on the soil microbial community, in face of the significant heterogeneity present. However, clearing of bushes altered microbial community structure, and in sites with calcareous bedrock also the use of herbicide vs. mechanical clearing of ferns. PMID- 26640463 TI - Hantaviral Proteins: Structure, Functions, and Role in Hantavirus Infection. AB - Hantaviruses are the members of the family Bunyaviridae that are naturally maintained in the populations of small mammals, mostly rodents. Most of these viruses can easily infect humans through contact with aerosols or dust generated by contaminated animal waste products. Depending on the particular Hantavirus involved, human infection could result in either hemorrhagic fever with renal syndrome or in Hantavirus cardiopulmonary syndrome. In the past few years, clinical cases of the Hantavirus caused diseases have been on the rise. Understanding structure of the Hantavirus genome and the functions of the key viral proteins are critical for the therapeutic agents' research. This paper gives a brief overview of the current knowledge on the structure and properties of the Hantavirus nucleoprotein and the glycoproteins. PMID- 26640464 TI - Behavioral Microbiomics: A Multi-Dimensional Approach to Microbial Influence on Behavior. AB - The role of microbes as a part of animal systems has historically been an under appreciated aspect of animal life histories. Recently, evidence has emerged that microbes have wide-ranging influences on animal behavior. Elucidating the complex relationships between host-microbe interactions and behavior requires an expanded ecological perspective, involving the host, the microbiome and the environment; which, in combination, is termed the holobiont. We begin by seeking insights from the literature on host-parasite interactions, then expand to consider networks of interactions between members of the microbial community. A central aspect of the environment is host nutrition. We describe how interactions between the nutrient environment, the metabolic and behavioral responses of the host and the microbiome can be studied using an integrative framework called nutritional geometry, which integrates and maps multiple aspects of the host and microbial response in multidimensional nutrient intake spaces. PMID- 26640465 TI - Classification and Taxonomy of Vegetable Macergens. AB - Macergens are bacteria capable of releasing pectic enzymes (pectolytic bacteria). These enzymatic actions result in the separation of plant tissues leading to total plant destruction. This can be attributed to soft rot diseases in vegetables. These macergens primarily belong to the genus Erwinia and to a range of opportunistic pathogens namely: the Xanthomonas spp., Pseudomonas spp., Clostridium spp., Cytophaga spp., and Bacillus spp. They consist of taxa that displayed considerable heterogeneity and intermingled with members of other genera belonging to the Enterobacteriaceae. They have been classified based on phenotypic, chemotaxonomic and genotypic which obviously not necessary in the taxonomy of all bacterial genera for defining bacterial species and describing new ones These taxonomic markers have been used traditionally as a simple technique for identification of bacterial isolates. The most important fields of taxonomy are supposed to be based on clear, reliable and worldwide applicable criteria. Hence, this review clarifies the taxonomy of the macergens to the species level and revealed that their taxonomy is beyond complete. For discovery of additional species, further research with the use modern molecular methods like phylogenomics need to be done. This can precisely define classification of macergens resulting in occasional, but significant changes in previous taxonomic schemes of these macergens. PMID- 26640467 TI - Seasonal Patterns of Fine Root Production and Turnover in a Mature Rubber Tree (Hevea brasiliensis Mull. Arg.) Stand- Differentiation with Soil Depth and Implications for Soil Carbon Stocks. AB - Fine root dynamics is a main driver of soil carbon stocks, particularly in tropical forests, yet major uncertainties still surround estimates of fine root production and turnover. This lack of knowledge is largely due to the fact that studying root dynamics in situ, particularly deep in the soil, remains highly challenging. We explored the interactions between fine root dynamics, soil depth, and rainfall in mature rubber trees (Hevea brasiliensis Mull. Arg.) exposed to sub-optimal edaphic and climatic conditions. A root observation access well was installed in northern Thailand to monitor root dynamics along a 4.5 m deep soil profile. Image-based measurements of root elongation and lifespan of individual roots were carried out at monthly intervals over 3 years. Soil depth was found to have a significant effect on root turnover. Surprisingly, root turnover increased with soil depth and root half-life was 16, 6-8, and only 4 months at 0.5, 1.0, 2.5, and 3.0 m deep, respectively (with the exception of roots at 4.5 m which had a half-life similar to that found between depths of 1.0 and 2.5 m). Within the first two meters of the soil profile, the highest rates of root emergence occurred about 3 months after the onset of the rainy season, while deeper in the soil, root emergence was not linked to the rainfall pattern. Root emergence was limited during leaf flushing (between March and May), particularly within the first two meters of the profile. Between soil depths of 0.5 and 2.0 m, root mortality appeared independent of variations in root emergence, but below 2.0 m, peaks in root emergence and death were synchronized. Shallow parts of the root system were more responsive to rainfall than their deeper counterparts. Increased root emergence in deep soil toward the onset of the dry season could correspond to a drought acclimation mechanism, with the relative importance of deep water capture increasing once rainfall ceased. The considerable soil depth regularly explored by fine roots, even though significantly less than in surface layers in terms of root length density and biomass, will impact strongly the evaluation of soil carbon stocks. PMID- 26640466 TI - Bioengineering Lantibiotics for Therapeutic Success. AB - Several examples of highly modified antimicrobial peptides have been described. While many such peptides are non-ribosomally synthesized, ribosomally synthesized equivalents are being discovered with increased frequency. Of the latter group, the lantibiotics continue to attract most attention. In the present review, we discuss the implementation of in vivo and in vitro engineering systems to alter, and even enhance, the antimicrobial activity, antibacterial spectrum and physico chemical properties, including heat stability, solubility, diffusion and protease resistance, of these compounds. Additionally, we discuss the potential applications of these lantibiotics for use as therapeutics. PMID- 26640468 TI - Systems Genetic Validation of the SNP-Metabolite Association in Rice Via Metabolite-Pathway-Based Phenome-Wide Association Scans. AB - In the post-GWAS (Genome-Wide Association Scan) era, the interpretation of GWAS results is crucial to screen for highly relevant phenotype-genotype association pairs. Based on the single genotype-phenotype association test and a pathway enrichment analysis, we propose a Metabolite-pathway-based Phenome-Wide Association Scan (M-PheWAS) to analyze the key metabolite-SNP pairs in rice and determine the regulatory relationship by assessing similarities in the changes of enzymes and downstream products in a pathway. Two SNPs, sf0315305925 and sf0315308337, were selected using this approach, and their molecular function and regulatory relationship with Enzyme EC:5.5.1.6 and with flavonoids, a significant downstream regulatory metabolite product, were demonstrated. Moreover, a total of 105 crucial SNPs were screened using M-PheWAS, which may be important for metabolite associations. PMID- 26640469 TI - A Decade of Molecular Understanding of Withanolide Biosynthesis and In vitro Studies in Withania somnifera (L.) Dunal: Prospects and Perspectives for Pathway Engineering. AB - Withania somnifera, a multipurpose medicinal plant is a rich reservoir of pharmaceutically active triterpenoids that are steroidal lactones known as withanolides. Though the plant has been well-characterized in terms of phytochemical profiles as well as pharmaceutical activities, limited attempts have been made to decipher the biosynthetic route and identification of key regulatory genes involved in withanolide biosynthesis. This scenario limits biotechnological interventions for enhanced production of bioactive compounds. Nevertheless, recent emergent trends vis-a-vis, the exploration of genomic, transcriptomic, proteomic, metabolomics, and in vitro studies have opened new vistas regarding pathway engineering of withanolide production. During recent years, various strategic pathway genes have been characterized with significant amount of regulatory studies which allude toward development of molecular circuitries for production of key intermediates or end products in heterologous hosts. Another pivotal aspect covering redirection of metabolic flux for channelizing the precursor pool toward enhanced withanolide production has also been attained by deciphering decisive branch point(s) as robust targets for pathway modulation. With these perspectives, the current review provides a detailed overview of various studies undertaken by the authors and collated literature related to molecular and in vitro approaches employed in W. somnifera for understanding various molecular network interactions in entirety. PMID- 26640471 TI - Optimization of Ammonium Sulfate Concentration for Purification of Colorectal Cancer Vaccine Candidate Recombinant Protein GA733-FcK Isolated from Plants. AB - A protein purification procedure is required to obtain high-value recombinant injectable vaccine proteins produced in plants as a bioreactor. However, existing purification procedures for plant-derived recombinant proteins are often not optimized and are inefficient, with low recovery rates. In our previous study, we used 25-30% ammonium sulfate to precipitate total soluble proteins (TSPs) in purification process for recombinant proteins from plant leaf biomass which has not been optimized. Thus, the objective in this study is to optimize the conditions for plant-derived protein purification procedures. Various ammonium sulfate concentrations (15-80%) were compared to determine their effects on TSPs yield. With 50% ammonium sulfate, the yield of precipitated TSP was the highest, and that of the plant-derived colorectal cancer-specific surface glycoprotein GA733 fused to the Fc fragment of human IgG tagged with endoplasmic reticulum retention signal KDEL (GA733(P)-FcK) protein significantly increased 1.8-fold. SDS-PAGE analysis showed that the purity of GA733(P)-FcK protein band appeared to be similar to that of an equal dose of mammalian-derived GA733-Fc (GA733(M)-Fc). The binding activity of purified GA733(P)-FcK to anti-GA733 mAb was as efficient as the native GA733(M)-Fc. Thus, the purification process was effectively optimized for obtaining a high yield of plant-derived antigenic protein with good quality. In conclusion, the purification recovery rate of large quantities of recombinant protein from plant expression systems can be enhanced via optimization of ammonium sulfate concentration during downstream processes, thereby offering a promising solution for production of recombinant GA733-Fc protein in plants. PMID- 26640470 TI - Genomic Tools in Pea Breeding Programs: Status and Perspectives. AB - Pea (Pisum sativum L.) is an annual cool-season legume and one of the oldest domesticated crops. Dry pea seeds contain 22-25% protein, complex starch and fiber constituents, and a rich array of vitamins, minerals, and phytochemicals which make them a valuable source for human consumption and livestock feed. Dry pea ranks third to common bean and chickpea as the most widely grown pulse in the world with more than 11 million tons produced in 2013. Pea breeding has achieved great success since the time of Mendel's experiments in the mid-1800s. However, several traits still require significant improvement for better yield stability in a larger growing area. Key breeding objectives in pea include improving biotic and abiotic stress resistance and enhancing yield components and seed quality. Taking advantage of the diversity present in the pea genepool, many mapping populations have been constructed in the last decades and efforts have been deployed to identify loci involved in the control of target traits and further introgress them into elite breeding materials. Pea now benefits from next generation sequencing and high-throughput genotyping technologies that are paving the way for genome-wide association studies and genomic selection approaches. This review covers the significant development and deployment of genomic tools for pea breeding in recent years. Future prospects are discussed especially in light of current progress toward deciphering the pea genome. PMID- 26640472 TI - Genome-Wide Association Mapping for Tomato Volatiles Positively Contributing to Tomato Flavor. AB - Tomato volatiles, mainly derived from essential nutrients and health-promoting precursors, affect tomato flavor. Taste volatiles present a major challenge for flavor improvement and quality breeding. In this study, we performed genome-wide association studies (GWAS) to investigate potential chromosome regions associated with the tomato flavor volatiles. We observed significant variation (1200x) among the selected 28 most important volatiles in tomato based on their concentration and odor threshold importance across our sampled accessions. Using 174 tomato accessions, GWAS identified 125 significant associations (P < 0.005) among 182 SSR markers and 28 volatiles (27 volatiles with at least one significant association). Several significant associations were co-localized in previously identified quantitative trait loci (QTL). This result provides new potential candidate loci affecting the metabolism of several volatiles. PMID- 26640473 TI - Integrated Physiological, Biochemical, and Molecular Analysis Identifies Important Traits and Mechanisms Associated with Differential Response of Rice Genotypes to Elevated Temperature. AB - In changing climatic conditions, heat stress caused by high temperature poses a serious threat to rice cultivation. A multiple organizational analysis at physiological, biochemical, and molecular levels is required to fully understand the impact of elevated temperature in rice. This study was aimed at deciphering the elevated temperature response in 11 popular and mega rice cultivars widely grown in India. Physiological and biochemical traits specifically membrane thermostability (MTS), antioxidants, and photosynthesis were studied at vegetative and reproductive phases, which were used to establish a correlation with grain yield under stress. Several useful traits in different genotypes were identified, which will be an important resource to develop high temperature tolerant rice cultivars. Interestingly, Nagina22 emerged as the best performer in terms of yield as well as expression of physiological and biochemical traits at elevated temperature. It showed lesser relative injury, lesser reduction in chlorophyll content, increased super oxide dismutase, catalase and peroxidase activities, lesser reduction in net photosynthetic rate (P N ), high transpiration rate (E), and other photosynthetic/fluorescence parameters contributing to least reduction in spikelet fertility and grain yield at elevated temperature. Furthermore, expression of 14 genes including heat shock transcription factors and heat shock proteins was analyzed in Nagina22 (tolerant) and Vandana (susceptible) at flowering phase, strengthening the fact that N22 performed better at molecular level also during elevated temperature. This study shows that elevated temperature response is complex and involves multiple biological processes that are needed to be characterized to address the challenges of extreme conditions of future climate. PMID- 26640474 TI - Ethylene Participates in the Regulation of Fe Deficiency Responses in Strategy I Plants and in Rice. AB - Iron (Fe) is very abundant in most soils but its availability for plants is low, especially in calcareous soils. Plants have been divided into Strategy I and Strategy II species to acquire Fe from soils. Strategy I species apply a reduction-based uptake system which includes all higher plants except the Poaceae. Strategy II species apply a chelation-based uptake system which includes the Poaceae. To cope with Fe deficiency both type of species activate several Fe deficiency responses, mainly in their roots. These responses need to be tightly regulated to avoid Fe toxicity and to conserve energy. Their regulation is not totally understood but some hormones and signaling substances have been implicated. Several years ago it was suggested that ethylene could participate in the regulation of Fe deficiency responses in Strategy I species. In Strategy II species, the role of hormones and signaling substances has been less studied. However, in rice, traditionally considered a Strategy II species but that possesses some characteristics of Strategy I species, it has been recently shown that ethylene can also play a role in the regulation of some of its Fe deficiency responses. Here, we will review and discuss the data supporting a role for ethylene in the regulation of Fe deficiency responses in both Strategy I species and rice. In addition, we will review the data about ethylene and Fe responses related to Strategy II species. We will also discuss the results supporting the action of ethylene through different transduction pathways and its interaction with other signals, such as certain Fe-related repressive signals occurring in the phloem sap. Finally, the possible implication of ethylene in the interactions among Fe deficiency responses and the responses to other nutrient deficiencies in the plant will be addressed. PMID- 26640475 TI - Identification of Putative Candidate Genes for Water Stress Tolerance in Canola (Brassica napus). AB - Drought stress can directly inhibit seedling establishment in canola (Brassica napus), resulting in lower plant densities and reduced yields. To dissect this complex trait, 140 B. napus accessions were phenotyped under normal (0.0 MPa, S0) and water-stressed conditions simulated by polyethylene glycol (PEG) 6000 (-0.5 MPa, S5) in a hydroponic system. Phenotypic variation and heritability indicated that the root to shoot length ratio was a reliable indicator for water stress tolerance. Thereafter, 66 accessions (16 water stress tolerant, 34 moderate and 16 sensitive lines) were genotyped using 25,495 Brassica single nucleotide polymorphisms (SNPs). Genome-wide association studies (GWAS) identified 16 loci significantly associated with water stress response. Two B. napus accessions were used for RNA sequencing, with differentially-expressed genes under normal and water-stressed conditions examined. By combining differentially-expressed genes detected by RNA sequencing with significantly associated loci from GWAS, 79 candidate genes were identified, of which eight were putatively associated with drought tolerance based on gene ontology of Arabidopsis. Functional validation of these genes may confirm key drought-related genes for selection and breeding in B. napus. Our results provide insight into the genetic basis of water stress tolerance in canola. PMID- 26640477 TI - Identification of Low-Confidence Regions in the Pig Reference Genome (Sscrofa10.2). AB - Many applications of high throughput sequencing rely on the availability of an accurate reference genome. Variant calling often produces large data sets that cannot be realistically validated and which may contain large numbers of false positives. Errors in the reference assembly increase the number of false positives. While resources are available to aid in the filtering of variants from human data, for other species these do not yet exist and strict filtering techniques must be employed which are more likely to exclude true-positives. This work assesses the accuracy of the pig reference genome (Sscrofa10.2) using whole genome sequencing reads from the Duroc sow whose genome the assembly was based on. Indicators of structural variation including high regional coverage, unexpected insert sizes, improper pairing and homozygous variants were used to identify low quality (LQ) regions of the assembly. Low coverage (LC) regions were also identified and analyzed separately. The LQ regions covered 13.85% of the genome, the LC regions covered 26.6% of the genome and combined (LQLC) they covered 33.07% of the genome. Over half of dbSNP variants were located in the LQLC regions. Of copy number variable regions identified in a previous study, 86.3% were located in the LQLC regions. The regions were also enriched for gene predictions from RNA-seq data with 42.98% falling in the LQLC regions. Excluding variants in the LQ, LC, or LQLC from future analyses will help reduce the number of false-positive variant calls. Researchers using WGS data should be aware that the current pig reference genome does not give an accurate representation of the copy number of alleles in the original Duroc sow's genome. PMID- 26640476 TI - The Role of Ethylene in Plants Under Salinity Stress. AB - Although the roles of ethylene in plant response to salinity and other stresses have been extensively studied, there are still some obscure points left to be clarified. Generally, in Arabidopsis and many other terrestrial plants, ethylene signaling is indispensable for plant rapid response and tolerance to salinity stress. However, a few studies showed that functional knock-out of some ACSs increased plant salinity-tolerance, while overexpression of them caused more sensitivity. This seems to be contradictory to the known opinion that ethylene plays positive roles in salinity response. Differently, ethylene in rice may play negative roles in regulating seedling tolerance to salinity. The main positive ethylene signaling components MHZ7/OsEIN2, MHZ6/OsEIL1, and OsEIL2 all negatively regulate the salinity-tolerance of rice seedlings. Recently, several different research groups all proposed a negative feedback mechanism of coordinating plant growth and ethylene response, in which several ethylene-inducible proteins (including NtTCTP, NEIP2 in tobacco, AtSAUR76/77/78, and AtARGOS) act as inhibitors of ethylene response but activators of plant growth. Therefore, in addition to a summary of the general roles of ethylene biosynthesis and signaling in salinity response, this review mainly focused on discussing (i) the discrepancies between ethylene biosynthesis and signaling in salinity response, (ii) the divergence between rice and Arabidopsis in regulation of salinity response by ethylene, and (iii) the possible negative feedback mechanism of coordinating plant growth and salinity response by ethylene. PMID- 26640478 TI - Indian scorpions collected in Karnataka: maintenance in captivity, venom extraction and toxicity studies. AB - BACKGROUND: Maintenance of scorpions under laboratory conditions is ideal for long-term venom collection to explore the therapeutic applications of scorpion venom. Collection of venom by electrical stimulation requires a reliable stimulator and effective restrainer. Thus, the present study was conducted to develop a convenient method to maintain scorpions and to extract their venom for toxicity studies via a modified restrainer and stimulator. METHODS: Four different scorpion species were collected, among which three species were maintained in the laboratory in containers that mimic their natural habitat. Venom was extracted from Hottentotta rugiscutis by electrical stimulation at 8 V for 18 months and LD50 was estimated by the graphic method of Miller and Tainter. RESULTS: A total of 373 scorpions including Hottentotta rugiscutis, Hottentotta tamulus, Lychas tricarinatus and Heterometrus swammerdami were collected, identified and maintained successfully, achieving a 97 % survival rate. Hottentotta rugiscutis yielded 6.0 mL of venom by electrical stimulation. The LD50 of H. rugiscutis venom was estimated to be 3.02 mg/kg of body weight in female Swiss albino mice. CONCLUSIONS: Scorpions were successfully maintained for 18 months. Herein we have also documented a simple, cost-effective method of venom extraction by electrical stimulation using a modified restrainer. Furthermore, Hottentotta rugiscutis was reported for the first time in Karnataka. PMID- 26640479 TI - Pulmonary Toxicity, Distribution, and Clearance of Intratracheally Instilled Silicon Nanowires in Rats. AB - Silicon nanowires (Si NWs) are being manufactured for use as sensors and transistors for circuit applications. The goal was to assess pulmonary toxicity and fate of Si NW using an in vivo experimental model. Male Sprague-Dawley rats were intratracheally instilled with 10, 25, 50, 100, or 250 MUg of Si NW (~20-30 nm diameter; ~2-15 MUm length). Lung damage and the pulmonary distribution and clearance of Si NW were assessed at 1, 3, 7, 28, and 91 days after-treatment. Si NW treatment resulted in dose-dependent increases in lung injury and inflammation that resolved over time. At day 91 after treatment with the highest doses, lung collagen was increased. Approximately 70% of deposited Si NW was cleared by 28 days with most of the Si NW localized exclusively in macrophages. In conclusion, Si NW induced transient lung toxicity which may be associated with an early rapid particle clearance; however, persistence of Si NW over time related to dose or wire length may lead to increased collagen deposition in the lung. PMID- 26640480 TI - Network inference through synergistic subnetwork evolution. AB - Study of signaling networks is important for a better understanding of cell behaviors e.g., growth, differentiation, metabolism, proptosis, and gaining deeper insights into the molecular mechanisms of complex diseases. While there have been many successes in developing computational approaches for identifying potential genes and proteins involved in cell signaling, new methods are needed for identifying network structures that depict underlying signal cascading mechanisms. In this paper, we propose a new computational approach for inferring signaling network structures from overlapping gene sets related to the networks. In the proposed approach, a signaling network is represented as a directed graph and is viewed as a union of many active paths representing linear and overlapping chains of signal cascading activities in the network. Gene sets represent the sets of genes participating in active paths without prior knowledge of the order in which genes occur within each path. From a compendium of unordered gene sets, the proposed algorithm reconstructs the underlying network structure through evolution of synergistic active paths. In our context, the extent of edge overlapping among active paths is used to define the synergy present in a network. We evaluated the performance of the proposed algorithm in terms of its convergence and recovering true active paths by utilizing four gene set compendiums derived from the KEGG database. Evaluation of results demonstrate the ability of the algorithm in reconstructing the underlying networks with high accuracy and precision. PMID- 26640481 TI - A Biologically Inspired Computational Model of Basal Ganglia in Action Selection. AB - The basal ganglia (BG) are a subcortical structure implicated in action selection. The aim of this work is to present a new cognitive neuroscience model of the BG, which aspires to represent a parsimonious balance between simplicity and completeness. The model includes the 3 main pathways operating in the BG circuitry, that is, the direct (Go), indirect (NoGo), and hyperdirect pathways. The main original aspects, compared with previous models, are the use of a two term Hebb rule to train synapses in the striatum, based exclusively on neuronal activity changes caused by dopamine peaks or dips, and the role of the cholinergic interneurons (affected by dopamine themselves) during learning. Some examples are displayed, concerning a few paradigmatic cases: action selection in basal conditions, action selection in the presence of a strong conflict (where the role of the hyperdirect pathway emerges), synapse changes induced by phasic dopamine, and learning new actions based on a previous history of rewards and punishments. Finally, some simulations show model working in conditions of altered dopamine levels, to illustrate pathological cases (dopamine depletion in parkinsonian subjects or dopamine hypermedication). Due to its parsimonious approach, the model may represent a straightforward tool to analyze BG functionality in behavioral experiments. PMID- 26640482 TI - A Review of the Literature on Primary Leiomyosarcoma of the Prostate Gland. AB - Primary leiomyosarcoma of the prostate (PLSOP) is rare, with less than 200 cases reported so far. PLSOPs present with lower urinary tract symptoms, haematuria, and perineal pain; may or may not be associated with a history of previous treatment for adenocarcinoma of prostate by means of radiotherapy and or hormonal treatment; may afflict children and adult male. Examination may reveal benign enlarged prostate and hard enlarged mass. PLSOPs may be diagnosed by histological examination findings of spindle-shaped carcinoma cells in prostate specimens. Immunohistochemical staining tends to be positive for vimentin, CD44, smooth muscle actin, and calponin, focally positive for desmin, and at times positive for keratin. They stain negatively for PSA, S-100, CD34, CD117, and cytokeratin. Cytogenetic study on primary leiomyosarcoma of the prostate gland may show clonal chromosomal rearrangement involving Chromosomes 2, 3, 9, 11, and 19. On the whole the prognosis is poor. Surgery with or without chemotherapy would appear to be the mainstay of treatment for PLSOPs that are operable, but generally there is no consensus opinion on the best therapeutic approach. Most cases of PLSOPs are diagnosed in an advanced stage of the disease. A global multicenter trial is required to find therapies that would improve the prognosis. PMID- 26640483 TI - Feasibility of Telerehabilitation Implementation as a Novel Experience in Rehabilitation Academic Centers and Affiliated Clinics in Tehran: Assessment of Rehabilitation Professionals' Attitudes. AB - Introduction. This study aimed to assess rehabilitation professionals' attitude toward implementation and application of telerehabilitation technology as a novel study in rehabilitation academic centers and affiliated clinics in Tehran. Methods. It was a descriptive cross-sectional study. To collect data, a researcher-designed questionnaire was developed. 141 rehabilitation experts participated in the study. Results. A majority of faculty members (78%) and clinicians (89.7%) either were in "definite agreement" or "somewhat agreed" with implementation and application of this technology, which demonstrates an overall positive attitude. Discussion. Based on the positive attitudes of the majority of participants toward implementation and application of this technology and their preferences in offering different telerehabilitation services, it seems that there is an appropriate and desirable acceptance and administrative culture to implement this technology among rehabilitation experts in Tehran. It is thus expected that implementation and application of this technology will be a promising experience in rehabilitation academic centers and affiliate clinics in Tehran. PMID- 26640484 TI - Comment on "Depth of Anesthesia as a Risk Factor for Perioperative Morbidity". PMID- 26640485 TI - High-Throughput Quantification of Phenotype Heterogeneity Using Statistical Features. AB - Statistical features are widely used in radiology for tumor heterogeneity assessment using magnetic resonance (MR) imaging technique. In this paper, feature selection based on decision tree is examined to determine the relevant subset of glioblastoma (GBM) phenotypes in the statistical domain. To discriminate between active tumor (vAT) and edema/invasion (vE) phenotype, we selected the significant features using analysis of variance (ANOVA) with p value < 0.01. Then, we implemented the decision tree to define the optimal subset features of phenotype classifier. Naive Bayes (NB), support vector machine (SVM), and decision tree (DT) classifier were considered to evaluate the performance of the feature based scheme in terms of its capability to discriminate vAT from vE. Whole nine features were statistically significant to classify the vAT from vE with p value < 0.01. Feature selection based on decision tree showed the best performance by the comparative study using full feature set. The feature selected showed that the two features Kurtosis and Skewness achieved a highest range value of 58.33-75.00% accuracy classifier and 73.88-92.50% AUC. This study demonstrated the ability of statistical features to provide a quantitative, individualized measurement of glioblastoma patient and assess the phenotype progression. PMID- 26640486 TI - In Silico Investigation of Flavonoids as Potential Trypanosomal Nucleoside Hydrolase Inhibitors. AB - Human African Trypanosomiasis is endemic to 37 countries of sub-Saharan Africa. It is caused by two related species of Trypanosoma brucei. Current therapies suffer from resistance and public accessibility of expensive medicines. Finding safer and effective therapies of natural origin is being extensively explored worldwide. Pentamidine is the only available therapy for inhibiting the P2 adenosine transporter involved in the purine salvage pathway of the trypanosomatids. The objective of the present study is to use computational studies for the investigation of the probable trypanocidal mechanism of flavonoids. Docking experiments were carried out on eight flavonoids of varying level of hydroxylation, namely, flavone, 5-hydroxyflavone, 7-hydroxyflavone, chrysin, apigenin, kaempferol, fisetin, and quercetin. Using AutoDock 4.2, these compounds were tested for their affinity towards inosine-adenosine-guanosine nucleoside hydrolase and the inosine-guanosine nucleoside hydrolase, the major enzymes of the purine salvage pathway. Our results showed that all of the eight tested flavonoids showed high affinities for both hydrolases (lowest free binding energy ranging from -10.23 to -7.14 kcal/mol). These compounds, especially the hydroxylated derivatives, could be further studied as potential inhibitors of the nucleoside hydrolases. PMID- 26640487 TI - Influence of Acarbose on Plasma Glucose Fluctuations in Insulin-Treated Patients with Type 2 Diabetes: A Pilot Study. AB - Background and Aims. To evaluate the effect of adding acarbose on glycemic excursions measured by continuous glucose monitoring system (CGMS) in patients with type 2 diabetes mellitus (T2DM) already on insulin therapy. Materials and Methods. This was an opened and unblended study. 134 patients with T2DM were recruited. After initial rapidly corrected hyperglycaemia by continuous subcutaneous insulin infusion (CSII) for 7 d, a 4-6-day premixed insulin titration period subsequently followed. Patients were then randomized 1 : 1 to acarbose plus insulin group or insulin therapy group for 2 weeks. CGMS was used to measure glucose fluctuations for at least 3 days after therapy cessation. Results. Patients in acarbose plus insulin group achieved a significant improvement of MAGE compared to that of insulin therapy only group (5.56 +/- 2.16 versus 7.50 +/- 3.28 mmol/L, P = 0.044), accompanied by a significant decrease in the incremental AUC of plasma glucose concentration above 10.0 mmol/L (0.5 [0.03, 0.9] versus 0.85 [0.23,1.4] mmol/L per day, P = 0.037). Conclusions. Add-on acarbose to insulin therapy further improves glucose fluctuation in patients with T2DM. This study was registered with ClinicalTrials.gov registration number ChiCTR-TRC-11001218. PMID- 26640401 TI - Measurement of the differential cross section for top quark pair production in pp collisions at [Formula: see text]. AB - The normalized differential cross section for top quark pair ([Formula: see text]) production is measured in pp collisions at a centre-of-mass energy of 8[Formula: see text] at the CERN LHC using the CMS detector in data corresponding to an integrated luminosity of 19.7[Formula: see text]. The measurements are performed in the lepton[Formula: see text]jets ([Formula: see text][Formula: see text]jets) and in the dilepton ([Formula: see text], [Formula: see text], and [Formula: see text]) decay channels. The [Formula: see text] cross section is measured as a function of the kinematic properties of the charged leptons, the jets associated to b quarks, the top quarks, and the [Formula: see text] system. The data are compared with several predictions from perturbative quantum chromodynamic up to approximate next-to-next-to-leading-order precision. No significant deviations are observed relative to the standard model predictions. PMID- 26640488 TI - Stereotactic Ablative Radiotherapy for the Treatment of Clinically Localized Renal Cell Carcinoma. AB - Thermal ablation is currently the most studied treatment option for medically inoperable patients with clinically localized renal cell carcinoma (RCC). Recent evidence suggests that stereotactic ablative radiotherapy (SABR) may offer an effective noninvasive alternative for these patients. In this review, we explore the current literature on SABR for the primary treatment of RCC and make recommendations for future studies so that an accurate comparison between SABR and other ablative therapies may be conducted. PMID- 26640489 TI - Extraction and Analysis of Strontium in Water Sample Using a Sr (2+) Selective Polymer as the Absorbent Phase. AB - A kind of Sr(2+) selective resin was applied as an absorption phase to extract Sr(2+) ion from an aqueous solution, and the amount of Sr(2+) was determined using inductively coupled plasma optical emission spectrometer. Factors, including absorption time, temperature, stirring rate, salt-out effect, desorption, and the pH of the aqueous solution, were investigated to optimize the absorption efficiency of Sr(2+). Foreign ions were examined to observe their effects on the absorption behavior of Sr(2+). The optimum condition was absorption time at 20 min, pH of aqueous solution 7, temperature of 35 degrees C, and 600 rpm stirring rate. A 10 mL solution of 0.1 mol/L HCl is used as the desorption agent. The linear range of Sr(2+) concentrations from 50 to 1200 MUg/L was investigated with the slope of 183 MUg/L. The limit of detection was 21 MUg/L with 4.23% relative standard deviation. The correlation coefficient was found to be 0.9947. Under the optimized conditions, the concentrations of Sr(2+) in four water samples were detected by the developed method. We propose that this method effectively extracts strontium ion from environmental water samples. PMID- 26640490 TI - Extraction, Characterization, and Molecular Weight Determination of Senna tora (L.) Seed Polysaccharide. AB - The objective of the present work was extraction of polysaccharide from Senna tora L. seed and its characterization as a pharmaceutical excipient. Polysaccharide extraction was based on mechanical separation of the endosperm of seeds of Senna tora, water dissolution, centrifugation, and precipitation with acetone. Standard procedures were used to study the viscosity, micromeritic properties, and microbial bioburden. Accelerated stability study was carried out on isolated polysaccharide for six months at 40 degrees C/75 RH as per ICH guidelines. The gum obtained from S. tora seeds was an amorphous free flowing odourless powder with dull brown colour (yield = 35% w/w). The bulk density, tapped density, and angle of repose data reveal that S. tora gum possesses good flow property. The intrinsic viscosity obtained was 1.568 dL/g. The average molecular weight of purified S. tora gum was found to be 198 kDa by intrinsic viscosity method. The results indicated that viscosity of gum solution increases with increase in temperature. FTIR study revealed the absence of degradation or decomposition of polysaccharide at accelerated stability conditions for six months. It has been concluded that extracted polysaccharide can be used as pharmaceutical excipient in terms of flow behavior, microbial properties, and stability. PMID- 26640492 TI - Bilateral Malrotation and a Congenital Pelvic Kidney with Varied Vasculature and Altered Hilar Anatomy. AB - Variations of structure and position of the kidney along with variations of renal vessels are most frequently reported. Rotational variations form a rare entity that are not cited in most embryology textbooks. During an educational cadaveric dissection of a 42-year-old male, a complex picture of bilateral anatomical variants was encountered. Malrotation of both kidneys and a left lobulated ectopic kidney along with open hilum was observed. The left kidney showed a pelvic position in front of sacral promontory with three renal arteries retaining its embryological aortoiliac branches and two renal veins draining into right common iliac vein. These variations have an embryological base. Pelvic kidney with rotational variation though comparatively rare assumes great importance in view of present-day surgical procedures like laparoscopic radical nephrectomy, percutaneous nephrectomy, and renal transplantation. PMID- 26640491 TI - Bolus Residue Scale: An Easy-to-Use and Reliable Videofluoroscopic Analysis Tool to Score Bolus Residue in Patients with Dysphagia. AB - Background. We aimed to validate an easy-to-use videofluoroscopic analysis tool, the bolus residue scale (BRS), for detection and classification of pharyngeal retention in the valleculae, piriform sinuses, and/or the posterior pharyngeal wall. Methods. 50 randomly selected videofluoroscopic images of 10 mL swallows (recorded in 18 dysphagia patients and 8 controls) were analyzed by 4 experts and 6 nonexpert observers. A score from 1 to 6 was assigned according to the number of structures affected by residue. Inter- and intrarater reliabilities were assessed by calculation of intraclass correlation coefficients (ICCs) for expert and nonexpert observers. Sensitivity, specificity, and interrater agreement were analyzed for different BRS levels. Results. Intrarater reproducibility was almost perfect for experts (mean ICC 0.972) and ranged from substantial to almost perfect for nonexperts (mean ICC 0.835). Interjudge agreement of the experts ranged from substantial to almost perfect (mean ICC 0.780), but interrater reliability of nonexperts ranged from substantial to good (mean 0.719). BRS shows for experts a high specificity and sensitivity and for nonexperts a low sensitivity and high specificity. Conclusions. The BRS is a simple, easy-to-carry out, and accessible rating scale to locate pharyngeal retention on videofluoroscopic images with a good specificity and reproducibility for observers of different expertise levels. PMID- 26640493 TI - Child Health in the Peruvian Amazon: Prevalence and Factors Associated with Referred Morbidity and Health Care Access in the City of Inapari. AB - Introduction. Children under 5 years of age are more susceptible to developing morbidities such as diarrhea, respiratory infections, anemia, and malnutrition. The objective of the study is to evaluate the prevalence of reported morbidities in this age group in the city of Inapari (Peru) and the access to health services in this municipality. Methods. Data collection using interviews that assessed socioeconomic and demographic conditions, child morbidity, and access to health services was performed in 2011. Statistical analysis was performed using SPSS 13.0. Results. Regarding morbidities that occurred during lifetime, 39.8% reported previous anemia and intestinal parasite infection. About 53.7% of the children reported any type of morbidities in the last 15 days before interview, being most frequent respiratory symptoms (38.9%), diarrhea (23,4%), and fever (23,1%). Only 63.1% of those reporting recent morbidities sought health care. These morbidities were associated with precarious sanitation and lack of infrastructure, the presence of other comorbidities, and poor access to health services. Conclusion. The main referred morbidities in Amazonian Peruvian children were diarrhea, respiratory symptoms, anemia, and vomiting. Incentives and improvements in the health and sanitation conditions would be important measures to improve the quality of life of the Amazonian child population. PMID- 26640494 TI - The gender, age and risk factor distribution differs in self-reported allergic and non-allergic rhinitis: a cross-sectional population-based study. AB - BACKGROUND: Few population-based studies have assessed the prevalence and the risk factors of non-allergic rhinitis (NAR) in comparison to allergic rhinitis (AR). Moreover, epidemiologic data on rhinitis in the elderly subjects and in southern Europe are scarce. OBJECTIVE: This study aimed at estimating the prevalence and at comparing the risk factor distribution of AR and NAR in a general population sample aged 20-84 years in Italy. METHODS: A questionnaire on respiratory symptoms and risk factors was administered to random samples of the Italian population aged 20-44 (n = 10,494) 45-64 (n = 2167) and 65-84 (n = 1030) in the frame of the Gene Environment Interactions in Respiratory Diseases (GEIRD) study. Current AR and NAR were defined according to the self-reported presence of nasal allergies or of nasal symptoms without a cold or the flu. RESULTS: NAR showed a significant descending pattern in females from 12.0 % (95 % CI 11.1, 13.1) in the 20-44 year age class, to 7.5 % (5.4, 10.3) in the 65-84 year age class (p = 0.0009), and a roughly stable pattern in males, from 10.2 % (9.3, 11.2) to 11.1 % (8.4, 13.9) (p = 0.5261). AR decreased from 26.6 % (25.7, 27.6) in 20-44 years age class to 15.6 % (13.3, 18.0) in the 65-84 years age class (p < 0.0001), without gender difference. Subjects living near industrial plants and ex and current smokers had a higher risk of NAR. Current smokers had a lower risk and subjects living in a Mediterranean climate a higher risk of AR. CONCLUSION: AR and NAR are fairly distinct conditions, as they have a different age, gender and risk factor distribution. PMID- 26640495 TI - Effects of a Mindfulness Meditation Course on Learning and Cognitive Performance among University Students in Taiwan. AB - Mindfulness training has recently gained much research interest because of its putative benefits for both mental and physical health. However, little is available in its effects on Asian students. Therefore, a quasi-experimental pre/posttest design was used to assess the effects of a one-semester mindfulness meditation course in 152 first-year Taiwanese university students and compared with 130 controls. The Chinese version of the College Learning Effectiveness Inventory (CLEI) and a computer software program focused on specific cognitive tasks were used for the evaluation. Results from the analysis of covariance revealed that while the score of the full CLEI scale was significantly higher in the intervention group compared with the control (P = 0.022), none of the comparisons between the nine CLEI subscales were significantly different between the two groups. For the computer cognitive tasks, the intervention group exhibited significantly better performance in the accuracy of the digital vigilance task (P = 0.048), choice reaction time (P = 0.004), spatial working memory (P = 0.042), and digital vigilance task reaction time (P = 0.004). This study showed that a one-semester mindfulness meditation course was able to improve learning effectiveness and both attention and memory aspects of cognitive performance among Taiwanese university students. PMID- 26640496 TI - Sharp-Hook Acupuncture (Feng Gou Zhen) for Patients with Periarthritis of Shoulder: A Randomized Controlled Trial. AB - The Feng Gou Zhen (sharp-hook acupuncture) as a traditional form of ancient acupuncture is said to be particularly effective for managing periarthritis of shoulder. We conducted this randomized controlled trial to evaluate the effectiveness of Feng Gou Zhen as an add-on compared to conventional analgesics for patients with PAS. 132 patients were randomly assigned in a 1 : 1 ratio to either a acupuncture group receiving sharp-hook acupuncture plus acupoint injection with conventional analgesics or a control group. Patients from both groups were evaluated at week 0 (baseline), week 1, and week 4. The primary outcome measure was the change from baseline shoulder pain, measured by Visual Analogue Scale at 7 days after treatment. Secondary outcome measures include the (i) function of shoulder joint and (ii) McGill pain questionnaire. The results showed that patients in acupuncture group had better pain relief and function recovery compared with control group (P < 0.05) at 1 week after treatment. Moreover, there were statistical differences between two groups in VAS and shoulder joint function and McGill pain questionnaire at 4 weeks after treatment (P < 0.05). Therefore, the sharp-hook acupuncture helps to relieve the pain and restore the shoulder function for patients with periarthritis of shoulder. PMID- 26640497 TI - Cobrotoxin from Naja naja atra Venom Ameliorates Adriamycin Nephropathy in Rats. AB - Chronic kidney disease (CKD) becomes a global health problem with high morbidity and mortality. Adriamycin- (ADR-) induced rodent chronic nephropathy is a classic experimental model of human minimal lesion nephrotic syndrome. The present study investigated the effect of cobrotoxin (CTX) on ADR-induced nephropathy. Rats were given 6 mg/kg ADR once through the tail vein to replicate ADR nephropathy model. CTX was administered to rats daily by placing a fast dissolving CTX membrane strip under the tongue starting from 5 days prior to ADR administration until the end of experiment. The results showed that CTX ameliorated the symptoms of ADR nephropathy syndrome with reduced body weight loss, proteinuria, hypoalbuminemia, dyslipidemia, serum electrolyte imbalance, oxidative stress, renal function abnormities, and kidney pathological lesions. Anti-inflammatory cytokine IL-10 expression was elevated after CTX administration in ADR nephropathy model. CTX inhibited the phosphorylation of IkappaB-alpha and NF-kappaB p65 nuclear translocation. Meanwhile, CTX upregulated the protein level of podocyte-specific nephrin and downregulated the level of fibrosis-related TGF-beta. These findings suggest that CTX may be a potential drug for chronic kidney diseases. PMID- 26640498 TI - Comparison of Body, Auricular, and Abdominal Acupuncture Treatments for Insomnia Differentiated as Internal Harassment of Phlegm-Heat Syndrome: An Orthogonal Design. AB - Objective. To identify the optimum treatment protocol for insomnia among auricular, body, and abdominal needling methods. Methods. A three-factor (3 needling protocols) and three-level experimental scheme was designed based on orthogonal method. 54 patients of insomnia differentiated as internal harassment of phlegm-heat syndrome were given two courses of acupuncture treatment (each with 20 times of acupuncture). The therapeutic effects were evaluated by comparing the Pittsburgh sleep quality index (PSQI), Hamilton Depression Scale (HAMD) scores, and Hamilton Anxiety Scale (HAMA) scores of patients before treatment, after one course of treatment, and after two courses of treatment as well as one month after treatment. Results. Body, auricular, and abdominal acupuncture treatments all alleviated symptoms of insomnia, depression, and anxiety, but body and auricular acupuncture had stronger therapeutic effects. Conclusions. Body acupuncture at basic points shall be given priority in protocol selection for insomnia. The second-best choice is auricular acupuncture with basic points combined with points based on Traditional Chinese Medicine (TCM) theories. Abdominal needling with very quick effect can be an alternative protocol with basic points combined with syndrome differentiation points. PMID- 26640499 TI - Shikonin Inhibits Inflammatory Response in Rheumatoid Arthritis Synovial Fibroblasts via lncRNA-NR024118. AB - Background. Shikonin is a major chemical component of zicao that possesses anti inflammatory properties and the ability to mediate cellular and humoral immunity, especially in rheumatoid arthritis (RA). We investigated the impact of shikonin on inflammatory response in RA synovial fibroblasts using the CAIA model. Methods. Severe polyarticular arthritis was induced in Balb/c female mice. Expressions of lncRNA-NR024118, SOCS3, proinflammatory cytokines, and MMPs were evaluated using RT-RCR. Histone acetylation and SOCS3 protein expression were assessed by ChIP assay and western blot, respectively. Results. Mice treated with shikonin showed an abrogation of soft tissue and bone lesions. Shikonin remarkably enhanced the expression of NR024118 and SOCS3 and suppressed the secretion and expression of IL-6, IL-8, and MMPs. Proliferation of cultured RA synovial fibroblasts in the presence of IL-1beta was also significantly inhibited by shikonin. Moreover, shikonin dose-dependently increased acetylation of histone H3 at the promoter of NR024118. Finally, NR024118 overexpression and interference significantly changed SOCS3 expression and NR024118 interference could reverse regulation of shikonin on SOCS3, proinflammatory cytokines, and MMPs expression level in MH7A cells. Conclusion. Our results reveal that, in the CAIA mouse model of RA, shikonin has disease modifying activity that is attributable to the inhibition of inflammatory response via lncRNA-NR024118. PMID- 26640500 TI - Erratum to "Whole-Body Vibration Exercise for Knee Osteoarthritis: A Systematic Review and Meta-Analysis". AB - [This corrects the article DOI: 10.1155/2015/758147.]. PMID- 26640501 TI - The Effects of Guided Imagery on Patients Being Weaned from Mechanical Ventilation. AB - The study purpose was to assess the effects of guided imagery on sedation levels, sedative and analgesic volume consumption, and physiological responses of patients being weaned from mechanical ventilation. Forty-two patients were selected from two community acute care hospitals. One hospital served as the comparison group and provided routine care (no intervention) while the other hospital provided the guided imagery intervention. The intervention included two sessions, each lasting 60 minutes, offered during morning weaning trials from mechanical ventilation. Measurements were recorded in groups at baseline and 30- and 60-minute intervals and included vital signs and Richmond Agitation-Sedation Scale (RASS) score. Sedative and analgesic medication volume consumption were recorded 24 hours prior to and after the intervention. The guided imagery group had significantly improved RASS scores and reduced sedative and analgesic volume consumption. During the second session, oxygen saturation levels significantly improved compared to the comparison group. Guided imagery group had 4.88 less days requiring mechanical ventilation and 1.4 reduction in hospital length of stay compared to the comparison group. Guided imagery may be complementary and alternative medicine (CAM) intervention to provide during mechanical ventilation weaning trials. PMID- 26640502 TI - Phytochemical Constituents, Antioxidant and Antiproliferative Properties of a Liverwort, Lepidozia borneensis Stephani from Mount Kinabalu, Sabah, Malaysia. AB - The study aimed to investigate the phytochemical contents, antioxidant and antiproliferative activity of 80% methanol extract of Lepidozia borneensis. The total phenolic and total flavonoid contents were analysed using Folin-Ciocalteu and aluminium chloride colorimetric methods. Antioxidant properties were evaluated by using FRAP, ABTS, and DPPH assays while the effects of L. borneensis on the proliferation of MCF-7 cell line were evaluated by using MTT assay. The results showed that the total phenolic and flavonoid contents were 12.42 +/- 0.47 mg GAE/g and 9.36 +/- 1.29 mg CE/g, respectively. The GC-MS analysis revealed the presence of at least 35 compounds. The extract was found to induce cytotoxicity against MCF-7 cell line with IC50 value of 47.33 +/- 7.37 ug/mL. Cell cycle analysis showed that the extract induced significant arrest at G0/G1 at 24 hours of treatment. After 72 hours of treatment, the proportion of cells in G0/G1 and G2-M phases had decreased significantly as compared to their control. Apoptosis occurred during the first 24 hours and significantly increased to 30.8% after 72 hours of treatment. No activation of caspase 3 was observed. These findings suggest that L. borneensis extract has the potential as natural antioxidant and anticancer agents. PMID- 26640503 TI - Medicinal Plants and Their Inhibitory Activities against Pancreatic Lipase: A Review. AB - Obesity is recognized as a major life style disorder especially in developing countries and it is prevailing at an alarming speed in new world countries due to fast food intake, industrialization, and reduction of physical activity. Furthermore, it is associated with a vast number of chronic diseases and disabilities. To date, relatively effective drugs, from either natural or synthetic sources, are generally associated with serious side effects, often leading to cessation of clinical trials or even withdrawal from the market. In order to find new compounds which are more effective or with less adverse effects compared to orlistat, the drug that has been approved for obesity, new compounds isolated from natural products are being identified and screened for antiobesity effects, in particular, for their pancreatic lipase inhibitory effect. Pancreatic lipase inhibitory activity has been extensively used for the determination of potential efficacy of natural products as antiobesity agents. In attempts to identify natural products for overcoming obesity, more researches have been focused on the identification of newer pancreatic lipase inhibitors with less unpleasant adverse effects. In this review, we consider the potential role of plants that have been investigated for their pancreatic lipase inhibitory activity. PMID- 26640504 TI - Probiotic strain Bacillus subtilis CU1 stimulates immune system of elderly during common infectious disease period: a randomized, double-blind placebo-controlled study. AB - BACKGROUND: Bacillus probiotics health benefits have been until now quite poorly studied in the elderly population. This study aimed to assess the effects of Bacillus subtilis CU1 consumption on immune stimulation and resistance to common infectious disease (CID) episodes in healthy free-living seniors. RESULTS: One hundred subjects aged 60-74 were included in this randomized, double-blind, placebo-controlled, parallel-arms study. Subjects consumed either the placebo or the probiotic (2.10(9) B. subtilis CU1 spores daily) by short periodical courses of 10 days intermittently, alternating 18-day course of break. This scheme was repeated 4 times during the study. Symptoms of gastrointestinal and upper/lower respiratory tract infections were recorded daily by the subjects throughout the study (4 months). Blood, saliva and stool samples were collected in a predefined subset of the first forty-four subjects enrolled in the study. B. subtilis CU1 supplementation did not statistically significantly decrease the mean number of days of reported CID symptoms over the 4-month of study (probiotic group: 5.1 (7.0) d, placebo group: 6.6 (7.3) d, P = 0.2015). However, in the subset of forty four randomized subjects providing biological samples, we showed that consumption of B. subtilis CU1 significantly increased fecal and salivary secretory IgA concentrations compared to the placebo. A post-hoc analysis on this subset showed a decreased frequency of respiratory infections in the probiotc group compared to the placebo group. CONCLUSION: Taken together, our study provides evidence that B. subtilis CU1 supplementation during the winter period may be a safe effective way to stimulate immune responses in elderly subjects. PMID- 26640505 TI - Peripheral blood T-cell signatures from high-resolution immune phenotyping of gammadelta and alphabeta T-cells in younger and older subjects in the Berlin Aging Study II. AB - BACKGROUND: Aging and latent infection with Cytomegalovirus (CMV) are thought to be major factors driving the immune system towards immunosenescence, primarily characterized by reduced amounts of naive T-cells and increased memory T-cells, potentially associated with higher morbidity and mortality. The composition of both major compartments, gammadelta as well as alphabeta T-cells, is altered by age and CMV, but detailed knowledge of changes to the gammadelta subset is currently limited. RESULTS: Here, we have surveyed a population of 73 younger (23 35 years) and 144 older (62-85 years) individuals drawn from the Berlin Aging Study II, investigating the distribution of detailed differentiation phenotypes of both gammadelta and alphabeta T-cells. Correlation of frequencies and absolute counts of the identified phenotypes with age and the presence of CMV revealed a lower abundance of Vdelta2-positive and a higher amount of Vdelta1-positive cells. We found higher frequencies of late-differentiated and lower frequencies of early-differentiated cells in the Vdelta1+ and Vdelta1-Vdelta2-, but not in the Vdelta2+ populations in elderly CMV-seropositive individuals confirming the association of these Vdelta2-negative cells with CMV-immunosurveillance. We identified the highest Vdelta1:Vdelta2 ratios in the CMV-seropositive elderly. The observed increased CD4:CD8 ratios in the elderly were significantly lower in CMV-seropositive individuals, who also possessed a lower naive and a larger late differentiated compartment of CD8+ alphabeta T-cells, reflecting the consensus in the literature. CONCLUSIONS: Our findings illustrate in detail the strong influence of CMV on the abundance and differentiation pattern of gammadelta T cells as well as alphabeta T-cells in older and younger people. Mechanisms responsible for the phenotypic alterations in the gammadelta T-cell compartment, associated both with the presence of CMV and with age require further clarification. PMID- 26640506 TI - Ultrastructural study of vitellogenesis of Ligula intestinalis (Diphyllobothriidea) reveals the presence of cytoplasmic-like cell death in cestodes. AB - BACKGROUND: The tapeworm Ligula intestinalis (Diphyllobothriidea) is one of the most fascinating cestode parasites because it may cause parasitic castration of its second intermediate host, teleost freshwater fishes, due to inhibition of production of fish gonadotropic hormones. Large-sized (length up to 1 m) larvae called plerocercoids develop several months in the body cavity of freshwater fish and affect host behavior to facilitate transmission to the final host, a fish eating bird. Vitellogenesis, i.e. formation of vitellocytes, is a key process in formation and nutrition of female gametes, oocytes in many flatworms, mainly parasitic Neodermata. The present study provides the first ultrastructural evidence in flatworms (Platyhelminthes) of the process that is interpreted as cytoplasmic-like cell death, i.e. a special case of programmed cell death (paraptosis) in vitellocytes of L. intestinalis. RESULTS: As molecular markers for paraptosis are not yet available, its identification was based on morphological criteria. Electron microscopy analyses revealed evident structural changes in vitellocytes associated with progressive cytoplasmatic vacuolation, swelling of the granular endoplasmic reticulum and mitochondria. In addition, the present study has shown that vitellocytes of L. intestinalis share numerous features in common with the members of other earliest evolved eucestodes. CONCLUSIONS: The present study indicates that paraptotic-like cell death may occur in parasitic flatworms (Neodermata). The presence of GER-bodies in mature vitellocytes indicates close relationship between the Diphyllobothriidea, Caryophyllidea and Spathebothriidea, which are considered as the earliest evolved groups of the Eucestoda. Beyond the general similarities, however, a number of differences exist between the morphology, chemical composition and amount of these inclusions which could be due to the variations in their embryonic development, life cycle strategies and definitive host groups. PMID- 26640507 TI - Stressful Life Events and Predictors of Post-traumatic Growth among High-Risk Early Emerging Adults. AB - Stressful life events (SLEs) may elicit positive psychosocial change among youth, referred to as Post-traumatic Growth (PTG). We assessed types of SLEs experienced, degree to which participants reported PTG, and variables predicting PTG across 24 months among a sample of high risk, ethnically diverse early emerging adults. Participants were recruited from alternative high schools (n = 564; mean age=16.8; 65% Hispanic). Multi-level regression models were constructed to examine the impact of environmental (SLE quantity, severity) and personal factors (hedonic ability, perceived stress, developmental stage, future time orientation) on a composite score of PTG. The majority of participants reported positive changes resulted from their most life-altering SLE of the past two years. Predictors of PTG included fewer SLEs, less general stress, having a future time perspective, and greater identification with the developmental stage of Emerging Adulthood. Findings suggest intervention targets to foster positive adaptation among early emerging adults who experience frequent SLEs. PMID- 26640508 TI - Attitude, reporting behavour and management practice of occupational needle stick and sharps injuries among hospital healthcare workers in Bale zone, Southeast Ethiopia: a cross-sectional study. AB - BACKGROUND: Although the prevalence of blood borne pathogens in many developing countries is high, documentation of infections due to occupational exposure is limited. Seventy percent of the world's HIV infected population lives in Sub Saharan Africa, but only 4 % of cases are reported from this region. Under reporting of needle stick and/or sharps injuries in healthcare facilities was common. METHODS: An institutional based cross-sectional study was conducted in December 2014 among healthcare workers in four hospitals of Bale zone, Southeast Ethiopia. A total of 362 healthcare workers were selected randomly from each of the working departments. Data were collected using self-administered questionnaire and were entered using Epi-Info version 3.5 and analysed using SPSS version 20.0. Multivariable logistic regression analysis was used to identify independent effect of each variable on the reporting behaviour of needle stick and/or sharp injury. RESULTS: Nearly six out of ten injuries (58.7 %) were not reported to the concerned body. The main reasons for not reporting the injuries were time constraint (35.1 %), sharps which caused injury were not used on any patient (27.0 %), the source patients did not have disease of concern (20.3 %), and lack of knowledge that it should be reported (14.9 %). Half of healthcare workers (HCWs) those who experienced injury had sought medical care next to self based action. Respondents with monthly salary of 450 to 1000 Ethiopian Birr (1 US Dollar = 22.00 Ethiopian Birr) were about six times more likely to report occupational needle stick and/or sharps injury (NSSI) than HCWs with salary of 2001 to 8379 birr (AOR = 5.73). However, HCWs who had no knowledge about probability of infection transmission through NSSI and not taking any self based measures after occurrence of injury were 45 % (AOR = 0.55) and 93 % (AOR = 0.07) less likely to report occupational injury than their counterparts, respectively. CONCLUSIONS: Occupational needle stick and/or sharps injuries are common among HCWs at the study area. Even though majority of respondents were concerned about the risk of NSSI exposure, most respondents did not report it to the concerned body. Therefore, provision of on job training on the risk of occupational NSSI exposure may strengthen HCWs to practice timely reporting and its management in case of occupational injury exposure. PMID- 26640509 TI - Providing ethical guidance for collaborative research in developing countries. AB - Experience has shown that the application of ethical guidelines developed for research in developed countries to research in developing countries can be, and often is, impractical and raises a number of contentious issues. Various attempts have been made to provide guidelines more appropriate to the developing world context; however, to date these efforts have been dominated by the fields of bioscience, medical research and nutrition. There is very little advice available for those seeking to undertake collaborative social science or natural science research in developing countries and what is there tends to be held within disparate sources. Charting the development of a set of ethics documentation for future use by the Ecosystem Services for Poverty Alleviation (ESPA) programme research community, this paper outlines past and present attitudes towards ethics procedures amongst this community and suggests ways in which ethics procedures might be made more relevant and user-friendly to researchers working in this area. PMID- 26640512 TI - Wireless Sensor-Based Smart-Clothing Platform for ECG Monitoring. AB - The goal of this study is to use wireless sensor technologies to develop a smart clothes service platform for health monitoring. Our platform consists of smart clothes, a sensor node, a gateway server, and a health cloud. The smart clothes have fabric electrodes to detect electrocardiography (ECG) signals. The sensor node improves the accuracy of QRS complexes detection by morphology analysis and reduces power consumption by the power-saving transmission functionality. The gateway server provides a reconfigurable finite state machine (RFSM) software architecture for abnormal ECG detection to support online updating. Most normal ECG can be filtered out, and the abnormal ECG is further analyzed in the health cloud. Three experiments are conducted to evaluate the platform's performance. The results demonstrate that the signal-to-noise ratio (SNR) of the smart clothes exceeds 37 dB, which is within the "very good signal" interval. The average of the QRS sensitivity and positive prediction is above 99.5%. Power-saving transmission is reduced by nearly 1980 times the power consumption in the best case analysis. PMID- 26640513 TI - The Vertex Version of Weighted Wiener Number for Bicyclic Molecular Structures. AB - Graphs are used to model chemical compounds and drugs. In the graphs, each vertex represents an atom of molecule and edges between the corresponding vertices are used to represent covalent bounds between atoms. We call such a graph, which is derived from a chemical compound, a molecular graph. Evidence shows that the vertex-weighted Wiener number, which is defined over this molecular graph, is strongly correlated to both the melting point and boiling point of the compounds. In this paper, we report the extremal vertex-weighted Wiener number of bicyclic molecular graph in terms of molecular structural analysis and graph transformations. The promising prospects of the application for the chemical and pharmacy engineering are illustrated by theoretical results achieved in this paper. PMID- 26640511 TI - Engineered Materials for Cancer Immunotherapy. AB - Immunotherapy is a promising treatment modality for cancer as it can promote specific and durable anti-cancer responses. However, limitations to current approaches remain. Therapeutics administered as soluble injections often require high doses and frequent re-dosing, which can result in systemic toxicities. Soluble bolus-based vaccine formulations typically elicit weak cellular immune responses, limiting their use for cancer. Current methods for ex vivo T cell expansion for adoptive T cell therapies are suboptimal, and achieving high T cell persistence and sustained functionality with limited systemic toxicity following transfer remains challenging. Biomaterials can play important roles in addressing some of these limitations. For example, nanomaterials can be employed as vehicles to deliver immune modulating payloads to specific tissues, cells, and cellular compartments with minimal off-target toxicity, or to co-deliver antigen and danger signal in therapeutic vaccine formulations. Alternatively, micro-to macroscale materials can be employed as devices for controlled molecular and cellular delivery, or as engineered microenvironments for recruiting and programming immune cells in situ. Recent work has demonstrated the potential for combining cancer immunotherapy and biomaterials, and the application of biomaterials to cancer immunotherapy is likely to enable the development of effective next-generation platforms. This review discusses the application of engineered materials for the delivery of immune modulating agents to the tumor microenvironment, therapeutic cancer vaccination, and adoptive T cell therapy. PMID- 26640514 TI - Phase Response Synchronization in Neuronal Population with Time-Varying Coupling Strength. AB - We present the dynamic model of global coupled neuronal population subject to external stimulus by the use of phase sensitivity function. We investigate the effect of time-varying coupling strength on the synchronized phase response of neural population subjected to external harmonic stimulus. For a time-periodic coupling strength, we found that the stimulus with increasing intensity or frequency can reinforce the phase response synchronization in neuronal population of the weakly coupled neural oscillators, and the neuronal population with stronger coupling strength has good adaptability to stimulus. When we consider the dynamics of coupling strength, we found that a strong stimulus can quickly cause the synchronization in the neuronal population, the degree of synchronization grows with the increasing stimulus intensity, and the period of synchronized oscillation induced by external stimulation is related to stimulus frequency. PMID- 26640510 TI - Nanoparticle Uptake: The Phagocyte Problem. AB - Phagocytes are key cellular participants determining important aspects of host exposure to nanomaterials, initiating clearance, biodistribution and the tenuous balance between host tolerance and adverse nanotoxicity. Macrophages in particular are believed to be among the first and primary cell types that process nanoparticles, mediating host inflammatory and immunological biological responses. These processes occur ubiquitously throughout tissues where nanomaterials are present, including the host mononuclear phagocytic system (MPS) residents in dedicated host filtration organs (i.e., liver, kidney spleen, and lung). Thus, to understand nanomaterials exposure risks it is critical to understand how nanomaterials are recognized, internalized, trafficked and distributed within diverse types of host macrophages and how possible cell-based reactions resulting from nanomaterial exposures further inflammatory host responses in vivo. This review focuses on describing macrophage-based initiation of downstream hallmark immunological and inflammatory processes resulting from phagocyte exposure to and internalization of nanomaterials. PMID- 26640515 TI - Acute appendicitis: proposal of a new comprehensive grading system based on clinical, imaging and laparoscopic findings. AB - Advances in the technology and improved access to imaging modalities such as Computed Tomography and laparoscopy have changed the contemporary diagnostic and management of acute appendicitis. Complicated appendicitis (phlegmon, abscess and/ or diffuse peritonitis), is now reliably distinguished from uncomplicated cases. Therefore, a new comprehensive grading system for acute appendicitis is necessary. The goal is review and update the laparoscopic grading system of acute appendicitis and to provide a new standardized classification system to allow more uniform patient stratification. During the last World Society of Emergency Surgery Congress in Israel (July, 2015), a panel involving Acute Appendicitis Experts and the author's discussed many current aspects about the acute appendicitis between then, it will be submitted a new comprehensive disease grading system. It was idealized based on three aspect of the disease (clinical and imaging presentation and laparoscopic findings). The new grading system may provide a standardized system to allow more uniform patient stratification for appendicitis research. In addition, may aid in determining optimal management according to grade. Lastly, what we want is to draw a multicenter observational study within the World Society of Emergency Surgery (WSES) based on this design. PMID- 26640516 TI - The sorting of blood group active proteins during enucleation. AB - Enucleation represents the critical stage during red blood cell development when the nucleus is extruded from an orthochromatic erythroblast in order to generate a nascent immature reticulocyte. Extrusion of the nucleus results in loss of a proportion of the erythroblast plasma membrane, which surrounds the nucleus, the bulk of the endoplasmic reticulum and a small region of cytoplasm. For this reason enucleation provides an important point in erythroblast differentiation at which proteins not required for the function of the erythrocyte can be lost, whilst those that are important for the structure-function properties of the mature erythrocyte must be efficiently retained in the reticulocyte plasma membrane. Disturbances in protein distribution during enucleation are envisaged to occur during human diseases such as Hereditary Spherocytosis. This article will discuss the current knowledge of erythroblast enucleation in the context of retention and loss of proteins that display antigenic blood group sites and that exist within multiprotein complexes within the erythrocyte membrane. PMID- 26640517 TI - Research highlights for issue 10: understanding complex lifecycles. PMID- 26640518 TI - Epidemiological and evolutionary management of plant resistance: optimizing the deployment of cultivar mixtures in time and space in agricultural landscapes. AB - The management of genes conferring resistance to plant-pathogens should make it possible to control epidemics (epidemiological perspective) and preserve resistance durability (evolutionary perspective). Resistant and susceptible cultivars must be strategically associated according to the principles of cultivar mixture (within a season) and rotation (between seasons). We explored these questions by modeling the evolutionary and epidemiological processes shaping the dynamics of a pathogen population in a landscape composed of a seasonal cultivated compartment and a reservoir compartment hosting pathogen year round. Optimal deployment strategies depended mostly on the molecular basis of plant-pathogen interactions and on the agro-ecological context before resistance deployment, particularly epidemic intensity and landscape connectivity. Mixtures were much more efficient in landscapes in which between-field infections and infections originating from the reservoir were more prevalent than within-field infections. Resistance genes requiring two mutations of the pathogen avirulence gene to be broken down, rather than one, were particularly useful when infections from the reservoir predominated. Combining mixture and rotation principles were better than the use of the same mixture each season as (i) they controlled epidemics more effectively in situations in which within-field infections or infections from the reservoir were frequent and (ii) they fulfilled the epidemiological and evolutionary perspectives. PMID- 26640519 TI - Multidimensional environmental influences on timing of breeding in a tree swallow population facing climate change. AB - Most phenological traits are extremely sensitive to current climate change, and advances in the timing of important life-history events have been observed in many species. In birds, phenotypic plasticity in response to temperature is thought to be the main mechanism underlying yearly adjustment in the timing of breeding. However, other factors could be important and interact to affect the levels of plastic responses between and/or within-individuals. Here, we use long term individual-based data on tree swallow (Tachycineta bicolor) to identify the spatial and environmental drivers affecting plasticity in laying date and to assess their importance at both population and individual levels. We found that laying date has advanced by 4.2 days over 10 years, and that it was mainly influenced by latitude and an interaction between spring temperature and breeder density. Analyses of individual plasticity showed that increases in temperature, but not in breeder density, resulted in within-individual advances in laying date. Our results suggest that females can adjust their laying date as a function of temperature, but that this adjustment will be partly constrained in habitats with lower breeder densities. Such potential constraint is especially worrying for the broad array of species already declining as a result of climate change. PMID- 26640520 TI - Temporal variation in antibiotic environments slows down resistance evolution in pathogenic Pseudomonas aeruginosa. AB - Antibiotic resistance is a growing concern to public health. New treatment strategies may alleviate the situation by slowing down the evolution of resistance. Here, we evaluated sequential treatment protocols using two fully independent laboratory-controlled evolution experiments with the human pathogen Pseudomonas aeruginosa PA14 and two pairs of clinically relevant antibiotics (doripenem/ciprofloxacin and cefsulodin/gentamicin). Our results consistently show that the sequential application of two antibiotics decelerates resistance evolution relative to monotherapy. Sequential treatment enhanced population extinction although we applied antibiotics at sublethal dosage. In both experiments, we identified an order effect of the antibiotics used in the sequential protocol, leading to significant variation in the long-term efficacy of the tested protocols. These variations appear to be caused by asymmetric evolutionary constraints, whereby adaptation to one drug slowed down adaptation to the other drug, but not vice versa. An understanding of such asymmetric constraints may help future development of evolutionary robust treatments against infectious disease. PMID- 26640521 TI - Effectiveness of managed gene flow in reducing genetic divergence associated with captive breeding. AB - Captive breeding has the potential to rebuild depressed populations. However, associated genetic changes may decrease restoration success and negatively affect the adaptive potential of the entire population. Thus, approaches that minimize genetic risks should be tested in a comparative framework over multiple generations. Genetic diversity in two captive-reared lines of a species of conservation interest, Chinook salmon (Oncorhynchus tshawytscha), was surveyed across three generations using genome-wide approaches. Genetic divergence from the source population was minimal in an integrated line, which implemented managed gene flow by using only naturally-born adults as captive broodstock, but significant in a segregated line, which bred only captive-origin individuals. Estimates of effective number of breeders revealed that the rapid divergence observed in the latter was largely attributable to genetic drift. Three independent tests for signatures of adaptive divergence also identified temporal change within the segregated line, possibly indicating domestication selection. The results empirically demonstrate that using managed gene flow for propagating a captive-reared population reduces genetic divergence over the short term compared to one that relies solely on captive-origin parents. These findings complement existing studies of captive breeding, which typically focus on a single management strategy and examine the fitness of one or two generations. PMID- 26640522 TI - Impacts of local adaptation of forest trees on associations with herbivorous insects: implications for adaptive forest management. AB - Disruption of species interactions is a key issue in climate change biology. Interactions involving forest trees may be particularly vulnerable due to evolutionary rate limitations imposed by long generation times. One mitigation strategy for such impacts is Climate matching - the augmentation of local native tree populations by input from nonlocal populations currently experiencing predicted future climates. This strategy is controversial because of potential cascading impacts on locally adapted animal communities. We explored these impacts using abundance data for local native gallwasp herbivores sampled from 20 provenances of sessile oak (Quercus petraea) planted in a common garden trial. We hypothesized that non-native provenances would show (i) declining growth performance with increasing distance between provenance origin and trial site, and (ii) phenological differences to local oaks that increased with latitudinal differences between origin and trial site. Under a local adaptation hypothesis, we predicted declining gallwasp abundance with increasing phenological mismatch between native and climate-matched trees. Both hypotheses for oaks were supported. Provenance explained significant variation in gallwasp abundance, but no gall type showed the relationship between abundance and phenological mismatch predicted by a local adaptation hypothesis. Our results show that climate matching would have complex and variable impacts on oak gall communities. PMID- 26640523 TI - Specialisation versus special interest - the Australian podiatry experience. AB - BACKGROUND: Ensuring efficient and effective delivery of health care to an ageing population has been a major driver for a review of the health workforce in Australia. As part of this process a National Registration and Accreditation Scheme (NRAS) has evolved with one goal being to improve workforce flexibility within a nationally consistent model of governance. In addition to increased flexibility, there have been discussions about maintaining standards and the role of specialisation. This study aims to explore the association between practitioners' self-perceptions about their special interest in musculoskeletal, diabetes related and podopaediatric foot care and the actual podiatry services they deliver in Australia. METHODS: A cross sectional on-line survey was administered on behalf of the Australasian Podiatry Council and its' state based member associations. Self-reported data were collected over a 3-week interval and captured information about the practitioners by gender, years of clinical experience, area of work by state, work setting, and location. For those participants that identified with an area of special interest or specialty, further questions were asked regarding support for the area of special interest through education, and activities performed in treating patients in the week prior to survey completion. Queensland University of Technology Human Research Ethics approval was sought and confirmed exemption from review. RESULTS: 218 podiatrists participated in the survey. Participants were predominately female and worked in private practices. The largest area of personal interest by the podiatrists was related to the field of musculoskeletal podiatry (n = 65), followed closely by diabetes foot care (n = 61), and a third area identified was in the management of podopaediatric conditions (n = 26). CONCLUSIONS: Health workforce reform in Australia is in part being managed by the federal government with a goal to meet the health care needs of Australians into the future. The recognition of a specialty registration of podiatric surgery and endorsement for scheduled medicines was established with this workforce reform in mind. Addition of new subspecialties may be indicated based on professional development, to maintain high standards and meet community expectations. PMID- 26640524 TI - Impacts of Temperature and its Variability on Mortality in New England. AB - Rapid buildup of greenhouse gases is expected to increase the Earth surface mean temperature, with unclear effects on temperature variability1-3. This adds urgency to better understand the direct effects of the changing climate on human health. However, the effects of prolonged exposures to temperatures, which are important for understanding the public health burden, are unclear. Here we demonstrate that long-term survival was significantly associated with both seasonal mean values and standard deviations (SDs) of temperature among the Medicare population (aged 65+) in New England, and break that down into long-term contrasts between ZIP codes and annual anomalies. A rise in summer mean temperature of 1 degrees C was associated with 1.0% higher death rate whereas an increase in winter mean temperature corresponded to 0.6% lower mortality. Increases in temperature SDs for both summer and winter were harmful. The increased mortality in warmer summers was entirely due to anomalies, while it was long term average differences in summer SD across ZIP codes that drove the increased risk. For future climate scenarios, seasonal mean temperatures may in part account for the public health burden, but excess public health risk of climate change may also stem from changes of within season temperature variability. PMID- 26640525 TI - Comment on "Rapid visual detection of blood cyanide" by C. Mannel-Croise and F. Zelder, Analytical Methods, 2012, 4, 2632. AB - Cyanide poisoning from Inhaled HCN is all too common in victims of smoke inhalation in fires. While the toxic effects arise primarily from its inhibitory effects on cytochrome c oxidase, the majority of the cyanide binds to methemoglobin (metHb) in the blood. It can be considered as the detoxification mechanism: one of the antidotes used earlier was nitrite which primarily works by converting hemoglobin to metHb (normally present to the extent of ~1% of the total hemoglobin). Vitamin B12 (hydroxocobalamin) and related analogs have long been known to have high affinity for cyanide and has been used as antidotes - the binding of cyanide to many compounds in this general family also results in a significant change in color that can be used for analytical purposes. Mannel Croise and Zelder (Anal. Methods, 2012, 4, 2632) have advocated direct addition of a related compound to blood samples and isolating the colored measurand on a solid phase extraction cartridge. While they demonstrated attractive rapid measurement of cyanide in spiked blood samples, we believe that this is not a practically usable procedure regardless of the exact chromogenic reagent used. Cyanide bound to metHb dissociates too slowly for a 1 min reaction to work as suggested - we believe for reasons unknown (eg., metHb levels in their blood samples unusually low), cyanide added to their blood samples did not (have time to) bind to metHb and these samples may not resemble real situations where significant amount of the cyanide will be bound to metHb. PMID- 26640526 TI - Influence of Molecular Weight of Carriers and Processing Parameters on the Extrudability, Drug Release, and Stability of Fenofibrate Formulations Processed by Hot-Melt Extrusion. AB - The objective of this study was to investigate the extrudability, drug release, and stability of fenofibrate (FF) formulations utilizing various hot-melt extrusion processing parameters and polyvinylpyrrolidone (PVP) polymers of various molecular weights. The different PVP grades selected for this study were Kollidon(r) 12 PF (K12), Kollidon(r) 30 (K30), and Kollidon(r) 90 F (K90). FF was extruded with these polymers at three drug loadings (15%, 25%, and 35% w/w). Additionally, for FF combined with each of the successfully extruded PVP grades (K12 and K30), the effects of two levels of processing parameters for screw design, screw speed, and barrel temperature were assessed. It was found that the FF with (K90) was not extrudable up to 35% drug loading. With low drug loading, the polymer viscosity significantly influenced the release of FF. The crystallinity remaining was vital in the highest drug-loaded formulation dissolution profile, and the glass transition temperature of the polymer significantly affected its stability. Modifying the screw configuration resulted in more than 95% post-extrusion drug content of the FF-K30 formulations. In contrast to FF-K30 formulations, FF release and stability with K12 were significantly influenced by the extrusion temperature and screw speed. PMID- 26640528 TI - Brain hypothermia therapy for childhood acute encephalopathy based on clinical evidence. AB - Although previous studies have reported on the effectiveness of brain hypothermia therapy in childhood acute encephalopathy, additional studies in this field are necessary. In this review, we discussed brain hypothermia therapy methods for two clinical conditions for which sufficient evidences are currently available in the literature. The first condition is known as hypoxic-ischemic encephalopathy and occurs in newborns and the second condition is acute encephalopathy which occurs in adults following cardiopulmonary resuscitation associated with out-of-hospital cardiac arrest state resulting from ventricular arrhythmia. Furthermore, we assessed the prospects of applying these therapies to acute encephalopathy in children. PMID- 26640527 TI - Biological and therapeutic activities, and anticancer properties of curcumin. AB - Curcumin (diferuloylmethane) is a polyphenol derived from the Curcuma longa plant. Curcumin has been used extensively in Ayurvedic medicine, as it is nontoxic and exhibits a variety of therapeutic properties, including antioxidant, analgesic, anti-inflammatory and antiseptic activities. Recently, certain studies have indicated that curcumin may exert anticancer effects in a variety of biological pathways involved in mutagenesis, apoptosis, tumorigenesis, cell cycle regulation and metastasis. The present study reviewed previous studies in the literature, which support the therapeutic activity of curcumin in cancer. In addition, the present study elucidated a number of the challenges concerning the use of curcumin as an adjuvant chemotherapeutic agent. All the studies reviewed herein suggest that curcumin is able to exert anti-inflammatory, antiplatelet, antioxidative, hepatoprotective and antitumor activities, particularly against cancers of the liver, skin, pancreas, prostate, ovary, lung and head neck, as well as having a positive effect in the treatment of arthritis. PMID- 26640529 TI - Effects and mechanism of Xin Mai Jia in a rabbit model of atherosclerosis. AB - The aim of this study was to investigate the protective effects of Xin Mai Jia (XMJ) on atherosclerosis (AS) in rabbits and to explore the underlying mechanisms in order to provide experimental evidence for the clinical application of XMJ. An intraperitoneal injection of vitamin D3, combined with a high-fat diet and sacculus injury, was utilized to establish the AS rabbit model. Following the oral administration of lovastatin, Zhibituo and different dosages of XMJ, respectively, blood was drawn from each rabbit for the detection of blood rheological indicators, such as serum lipids. The pathological changes in the right common carotid artery were observed. Vascular function experiments and the expression detection of common carotid artery-related proteins by immunohistochemistry were conducted. XMJ was observed to decrease the blood lipid levels of the AS rabbits; increase the concentration of high-density lipoprotein and apolipoprotein A; decrease blood viscosity, erythrocyte sedimentation rate and hematocrit; elevate the levels of endothelial nitric oxide synthase (eNOS) and Na+/H+ exchanger 1 in vascular tissues and decrease the levels of angiotensin II receptor, type 1 (AT-1) and endothelin-1 (ET-1). In conclusion, XMJ was shown to lower the blood lipid levels of the experimental AS rabbits, improve the abnormal changes in hemorheology, increase the eNOS content in the vascular tissue, decrease the AT-1 and ET-1 levels and increase the endothelium-dependent vasodilation reaction. XMJ therefore has an anti-AS effect. PMID- 26640530 TI - Effect of dexmedetomidine on early postoperative cognitive dysfunction and peri operative inflammation in elderly patients undergoing laparoscopic cholecystectomy. AB - The use of intravenous dexmedetomidine during surgery has been shown to suppress inflammatory cytokines peri-operatively. It has also been demonstrated that dexmedetomidine may benefit cognitive function in elderly patients following surgery; however, it is not clear whether dexmedetomidine reduces postoperative cognitive dysfunction (POCD) via the suppression of inflammatory cytokines. The aim of the present study was to investigate the effects of dexmedetomidine on early POCD and inflammatory cytokines in elderly patients undergoing laparoscopic cholecystectomy (LC). The study comprised 120 elderly patients undergoing selective LC, who were randomly allocated to receive either dexmedetomidine intravenously (DEX group, n=60) or the same volume of normal saline (control group, n=60). Cognitive function was assessed by Mini-Mental State Examination (MMSE) scores 1 day prior to surgery, 6 h following surgery and postoperatively on days 1 and 2. Interleukin (IL)-1beta, IL-6 and C-reactive protein (CRP) levels were also measured at these time-points. On the basis of whether the patients had POCD on the first day after surgery, patients were divided into a POCD group and a non-POCD group. Blood cytokine levels were compared between the patients with and without POCD. A total of 100 patients completed both pre- and postoperative MMSE tests. At 1 day following surgery, POCD occurred in 10/50 (20%) patients in the DEX group and in 21/50 (42%) patients in the control group (P=0.017). At 6 h following surgery, IL-1beta, IL-6 and CRP levels showed significant increases (P<0.01) compared with the baseline levels in the two groups. Furthermore, in the control group, CRP levels showed a significant increase on day 1 (P<0.001) and day 2 (P=0.017) postoperatively. In the DEX group compared with the control group, IL-1beta, IL-6 and CRP levels were markedly decreased at 6 h and 1 day after surgery (P<0.01). Concentrations of IL-1beta, IL-6 and CRP were significantly higher in patients who developed POCD on day 1 following surgery than in the patients who did not develop POCD (P<0.05). The findings of the current study support the hypothesis that dexmedetomidine administration during anesthesia decreases the incidence of early POCD, most likely by the mechanism of reduction of the inflammatory response level. PMID- 26640531 TI - Protective effect of Xingnaojia formulation on rats with brain and liver damage caused by chronic alcoholism. AB - The aim of this study was to observe the effect of a formulation of traditional Chinese medicine extracts known as Xingnaojia (XNJ) on the liver function, learning ability and memory of rats with chronic alcoholism and to verify the mechanism by which it protects the brain and liver. A rat model of chronic alcoholism was used in the study. The spatial learning ability and memory of the rats were tested. The rats were then sacrificed and their brains and hepatic tissues were isolated. The activity of superoxide dismutase (SOD) and levels of glutamate (Glu), N-methyl D-aspartate receptor subtype 2B (NR2B), cyclin dependent kinase 5 (CDK5) and cannabinoid receptor 1 (CB1) in the hippocampus were analyzed. The ultrastructure of the hepatic tissue was observed by electron microscopy. In addition, the activities of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) in serum were tested and the levels of low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides (TG) and total cholesterol (TCHOL) were analyzed. XNJ enhanced the learning and memory of rats with chronic alcoholism. Treatment with XNJ increased the activity of SOD, and decreased the expression levels of NR2B mRNA and NR2B, CB1 and CDK5 proteins in the brain tissues compared with those in the model rats. It also increased the activity of ALDH in the serum and liver, decreased the serum levels of LDL, TG and TCHOL and increased the serum level of HDL. These results indicate that XNJ exhibited a protective effect against brain and liver damage in rats with chronic alcoholism. PMID- 26640532 TI - Acromial approach for treating glenoid fractures: A report of two cases and a literature review. AB - Surgery is usually recommended for displaced glenoid fractures, with open reduction and internal fixation as the standard operative treatment. Three approaches have been recommended in the reduction of glenoid fractures: Anterior, posterior and combined; however, a traditional approach may be difficult due to a high position or a comminuted Ideberg type III fracture. The combined approach results in a longer incision and more soft tissue injury when associated with an acromial fracture. The present study describes two complicated glenoid fractures: One case was a comminuted Ideberg type III fracture associated with an Ogawa type II acromial fracture; the second case was an Ideberg type IV fracture with associated superior shoulder suspensory complex injuries. In these cases, the acromial approach was modified to achieve satisfactory exposure and fixation of the complicated fracture. After a 1-year follow-up, the patients had a satisfactory outcome. PMID- 26640533 TI - Mesenchymal stem cells suppress CaN/NFAT expression in the pulmonary arteries of rats with pulmonary hypertension. AB - Inflammation and hyperproliferation of pulmonary artery smooth muscle cells (PASMCs) is considered the primary pathological feature of pulmonary hypertension (PH). The present study determined that mesenchymal stem cells (MSCs) suppress the expression of calcineurin (CaN) and nuclear factor of activated T-cells (NFAT) in the pulmonary arteries of rats, and this may exert a therapeutic effect on PH. The potential therapeutic effects of MSCs on PH were assessed via the transplantation of human umbilical cord-derived MSCs, which were cultured in serum-free medium, into a monocrotaline (MCT)-induced PH rat model. Subsequently, the expression levels of tumor necrosis factor (TNF)-alpha in lung tissue and plasma, and of CaN and NFATc2 in pulmonary arteries were assessed. In the rat model of MCT-induced PH, investigated in the present study, TNF-alpha expression levels were detected in the lung tissue, and the levels of TNF-alpha in the plasma were increased. Furthermore, in addition to hemodynamic changes and the evident medial hypertrophy of the pulmonary muscular arterioles, CaN and NFATc2 expression levels were significantly upregulated in the pulmonary arteries. In the present study, the transplantation of MSCs, cultured in serum-free medium, decreased the levels of TNF-alpha in the lung tissue and plasma of rats, and downregulated CaN and NFATc2 expression in the pulmonary arteries. Furthermore, hemodynamic abnormalities and medial hypertrophy of the pulmonary muscular arterioles were notably improved. Therefore, the results of the present study may suggest that the administration of MSCs in PH may suppress the production of TNF alpha, and downregulate the expression of CaN and NFATc2 in pulmonary arteries, which may provide an effective treatment for PH by suppressing the pathological proliferation of PASMCs. PMID- 26640534 TI - Levonorgestrel intrauterine system versus thermal balloon ablation for the treatment of heavy menstrual bleeding: A meta-analysis of randomized controlled trials. AB - At present, there have been no standard research outcomes as to whether the levonorgestrel intrauterine system (LNG-IUS) or thermal balloon ablation (TBA) is superior for the treatment of patients suffering from heavy menstrual bleeding (HMB). Therefore, in the present study, a meta-analysis of randomized controlled trials (RCTs) was conducted in order to compare the effectiveness and affordability of the LNG-IUS with TBA in the treatment of HMB. A literature search of the following electronic databases was conducted: PubMed, EMBASE, the Cochrane Library, Google Scholar, the Chinese Scientific Journals Database, and the China National Knowledge Infrastructure; and a statistical analysis was performed using RevMan 5.2 software. Seven RCTs involving 467 patients (235 LNG IUS, 232 TBA) met the inclusion criteria for the present study. As assessed by pictorial blood loss assessment chart (PBAC) scores, the LNG-IUS significantly reduced menstrual bleeding after 24 months [standardized mean difference (SMD), 0.86; 95% confidence interval (CI), -1.22 to -0.50; P<0.00001]. Furthermore, the total treatment cost of the LNG-IUS was lower than that of TBA (SMD, -2.35; 95% CI, -2.98 to -1.72; P<0.00001). However, at the 24 month follow-up, side effects such as amenorrhea occurred more frequently in patients treated with the LNG-IUS, as compared with TBA (relative risk, 2.49; 95% CI, 1.46-4.25; P=0.0008). No significant differences in hemoglobin levels and quality of life were demonstrated between the two treatment groups. The results of the present meta analysis suggest that the LNG-IUS may be more effective and affordable than TBA as a long-term treatment (24 months) for HMB. However, following 12-24 months of treatment, side effects such as amenorrhea may be more frequent in patients treated with the LNG-IUS. When considering short-term treatment for HMB, controversy remains regarding the two methods and further studies are required to precisely evaluate the outcomes. PMID- 26640535 TI - Bone fracture in a rat femoral fracture model is associated with the activation of autophagy. AB - Autophagy, which is a mechanism for the turnover of intracellular molecules and organelles, protects cells during stress responses; however, the role of autophagy in the stages of bone fracture remains to be elucidated. The aim of the present study was to investigate the process of autophagy in bone tissue at different time-points after fracture. A femur fracture model was established in male adult Wistar rats via surgery. The protein expression of microtubule associated protein II light chain 3 (LC3-II) was analyzed in a femur fracture (experimental) group and a sham-surgery group using immunofluorescence. The protein expression of proliferating cell nuclear antigen (PCNA) was used to investigate the cell proliferation in bone tissue following fracture via immunohistochemical analysis. The correlation between cell proliferation and autophagy was analyzed using linear regression. LC3-II protein was constitutively expressed in the sham-surgery group; however, compared with the expression in the sham-surgery group, the LC3-II expression in the experimental group was significantly increased at each time-point (P<0.05). Similarly, immunohistochemistry revealed that the number of PCNA-positive cells in each section was significantly increased following fracture injury (P<0.01). A comparison of the LC3-II- and PCNA-positive rates in the experimental group rats at each time-point revealed a linear correlation (R2=0.43, P<0.01). In conclusion, surgically induced fracture in rats is associated with an increase in LC3-II and PCNA protein expression during the initial stages of fracture injury, and a correlation exists between the expression of the two proteins. These results suggest that potential treatment aimed at improving fracture healing should target the process of autophagy. PMID- 26640536 TI - Assessment of the potential health benefits of certain total extracts from Vitis vinifera, Aesculus hyppocastanum and Curcuma longa. AB - A number of recent studies have illustrated the active role of food/natural components in the prevention of chronic diseases and in the improvement of the quality of life. In the present study, we aimed to obtain and characterize certain extracts from Vitis vinifera L., Aesculus hippocastanum L. and Curcuma longa L., focusing on their antioxidant effects in vitro. Three vegetal extracts were obtained for each plant: in water, 50% water-alcohol and in 96% ethanol. These extracts were then analyzed for their qualitative composition by high performance thin layer chromatography (HPTLC) and total phenolic content by ultraviolet-visible spectrophotometry (UV-VIS). The antioxidant activity of the extracts was assessed in vitro by 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay; the effects of lipid peroxidation on the cell membrane were evaluated using Jurkat cells in two experimental models: normoglycemic and hyperglycemic medium, in order for the results to be able to be translated into clinical practice. In addition, the resistance of the extracts to acid and alkaline hydrolysis was investigated. The obtained extracts had 0.4-39 ug phenolics/mg total extract. The largest amount of phenolics was found in the Cucurma longa extracts, while the lowest was found in the Aesculus hippocastanum extacts. HPTLC analysis identified the main phenolic compounds in the extracts which were ferulic acid, gallic acid, caffeic acid and coumaric acid, as well as quercetin, kaempferol, apigenin, curcumin, luteolin and esculetin. The Aesculus hippocastanum extracts had a low antioxidant efficacy, while both the Curcuma longa and Vitis vinifera extracts had a high antioxidant activity; the products resulting from alkaline hydrolisis were significantly more efficient in scavenging DPPH radicals compared to the products resulting from acid hydrolisis. The antioxidant effects of the Curcuma longa extracts exerted on the membranes of Jurkat cells were the most prominent under both normal and hyperglycemic conditions. The results of the present study may be translated into clinical practice and demonstrate that Curcuma longa extracts may be effective in both the prevention of diabetes mellitus and in attenuating the development of complications associated with the disease. PMID- 26640537 TI - A voluminous mass as an initial clinical symptom of multiple myeloma: A case report. AB - Extramedullary multiple myeloma (EMM) is a type of multiple myeloma (MM) that is defined by the presence of extraskeletal (soft tissue or visceral) clonal plasma cell infiltrates, which may be present at the time of initial diagnosis or at the time of relapse. Although extramedullary lesions may be present with other clinical features at the time of diagnosis, the onset of a solid formation as a first clinical symptom of MM is unusual. The present study reports the case of a 77-year-old male who was admitted to the Hematology Unit of the National Cancer Research Center, Istituto Tumori 'Giovanni Paolo II' (Bari, Italy) with a mass protruding from the right side of his lower back. Serum immunofixation revealed positivity for monoclonal protein (M-protein) and Bence Jones proteinuria was positive. In addition, a computed tomography scan of the abdomen, which was confirmed by magnetic resonance imaging, revealed a voluminous solid formation resembling a sarcoma. M-protein is known to be present in numerous diseases encountered in clinical practice, including hematological or other diseases; thus, a Tru-Cut biopsy of the lesion was performed, which revealed an infiltration of plasma cells. In addition, a bone marrow biopsy revealed the presence of 70% plasma cells, and a diagnosis of primary EMM was established. In conclusion, EMM should be included in the differential diagnosis of a mass, particularly in patients where M-protein is detected in the blood and/or urine. PMID- 26640538 TI - Pretreatment with oral contraceptive pills to identify poor responders that may benefit from rLH supplementation during GnRH-antagonist treatment for IVF: A pilot perspective study proposal. AB - Controlled ovarian stimulation, using a gonadotrophin-releasing hormone (GnRH) antagonist protocol, is a potential treatment option for women with a low response to other fertility treatments as it appears to be at least as effective as GnRH agonists (long protocol). However, previous studies have indicated that the administration of GnRH antagonist may cause an excessive reduction in endogenous luteinizing hormone (LH) levels. The use of recombinant LH (rLH) supplementation during ovarian stimulation is controversial. The present article proposes a future study focused on women aged >=40 years old, with the aim of identifying patients who are poor responders to GnRH-antagonist treatment that may benefit from rLH supplementation. We hypothesize that patients with suppressed hypothalamic-pituitary-axis activity may benefit from rLH supplementation, as GnRH-antagonist administration has the potential to induce a marked reduction in LH levels in such patients compared with that in patients that exhibit a regular recovery following the administration of oral contraceptive pills (OCPs). Furthermore, patients with hyper-responsive hypothalamic-pituitary-axis activity may be affected by 'low-gonadotropin responsiveness', similar to that observed in patients with any mutation in the follicle-stimulating hormone (FSH) receptor, who are known to benefit from rLH supplementation. The proposed pilot study would include 120 women who are predicted to be poor responders to GnRH-antagonist treatment. All subjects will be allocated at random (using 2:1 computerized randomization) into two study groups: Group A (OCP-treated) and group B (control). For all patients, the serum values of FSH, LH and 17beta estradiol (E2) will be detected on day 3 of the menstrual cycle preceding OCP treatment (baseline) and at day 4 following OCP treatment. The Delta-variation from baseline levels for all markers, the FSH/LH ratio and the E2/FSH ratio will be determined. Delta-variation from the baseline of the FSH and LH values will be used to further categorize group A patients into subgroups A1-4, based on respective quartile numbers (Q1-4). Patients admitted to each of the four subgroups A1-4, based on their FSH quartile, will be selected at random to receive rLH supplementation (ratio, 1:1) during ovarian stimulation. If the resulting data are able to identify women that may benefit from rLH supplementation during ovarian stimulation, a large part of inconclusive evidence regarding rLH supplementation will be clarified. If patients supplemented with rLH (according to abnormal recovery of hypothalamic-pituitary-axis activity after OCP treatment) exhibit an improved ovarian response during in vitro fertilization (IVF) and subsequent pregnancy rate, the pre-IVF OCP test could be adopted as a useful tool for improving the success rate of assisted reproductive technologies in poorly-responding patients. PMID- 26640539 TI - Inhibition of duck hepatitis B virus replication by mimic peptides in vitro. AB - The aim of the present study was to investigate the inhibitory effect of specific mimic peptides targeting duck hepatitis B virus polymerase (DHBVP) on duck hepatitis B virus (DHBV) replication in primary duck hepatocytes. Phage display technology (PDT) was used to screen for mimic peptides specifically targeting DHBVP and the associated coding sequences were determined using DNA sequencing. The selected mimic peptides were then used to treat primary duck hepatocytes infected with DHBV in vitro. Infected hepatocytes expressing the mimic peptides intracellularly were also prepared. The cells were divided into mimic peptide groups (EXP groups), an entecavir-treated group (positive control) and a negative control group. The medium was changed every 48 h. Following a 10-day incubation, the cell supernatants were collected. DHBV-DNA in the cellular nucleus, cytoplasm and culture supernatant was analyzed by quantitative polymerase chain reaction (qPCR). Eight mimic peptides were selected following three PDT screening rounds for investigation in the DHBV-infected primary duck hepatocytes. The qPCR results showed that following direct treatment with mimic peptide 2 or 7, intracellular expression of mimic peptide 2 or 7, or treatment with entecavir, the DHBV-DNA levels in the culture supernatant and cytoplasm of duck hepatocytes were significantly lower than those in the negative control (P<0.05). The cytoplasmic DHBV-DNA content of the cells treated with mimic peptide 7 was lower than that in the other groups (P<0.05). In addition, the DHBV-DNA content of the nuclear fractions following the intracellular expression of mimic peptide 7 was significantly lower than that in the other groups (P<0.05). Mimic peptides specifically targeting DHBVP, administered directly or expressed intracellularly, can significantly inhibit DHBV replication in vitro. PMID- 26640540 TI - Relapse of choroidal neovascularization in Bietti's crystalline retinopathy following anti-vascular endothelial growth factor therapy: A case report. AB - Choroidal neovascularization secondary to retinitis pigmentosa is rarely observed in clinical practice. The present study describes a case of atypical retinitis pigmentosa, crystalline retinal pigmentary degeneration, complicated by choroidal neovascularization (CNV) in a 26-year-old man presenting with blurred vision in the right eye. Heidelberg multimodality imaging was performed to achieve a confirmed diagnosis. Bevacizumab was injected once intravitreally. The 3-month follow-up included visualization of the lesion's regression with spectral domain optical coherence tomography (SD-OCT). However, at 3 months after the injection, the CNV reoccurred. To the best of our knowledge, this is the first time that a case of CNV secondary to retinitis pigmentosa, in which the diagnosis was confirmed via multimodality imaging and the therapeutic efficacy was evaluated by SD-OCT, has been reported in China. PMID- 26640541 TI - Extrapleural locating method in computed tomography-guided needle biopsies of 1,106 lung lesions. AB - Transthoracic needle biopsy is considered to be safe and effective for the diagnosis of focal lung lesions. The aim of the present study was to evaluate factors affecting the accuracy and safety of automated cutting needle lung biopsy (ACNB) using a new extrapleural locating (EPL) method. Computed tomography (CT) guided needle biopsies were performed on 1,065 patients between March 2005 and May 2012 using the EPL method. The locating needle remained in the chest following extrapleural positioning, while the radiologist confirmed the puncture angle and distance between the locating needle and lesion. The biopsy instrument was advanced into the lung, and the core needle was subsequently fired into the lesion based on the direction indicated by the locating needle. Univariate and multivariate regression analyses were used to evaluate the diagnostic accuracy and safety of the procedure. The sensitivity, specificity, positive predictive value and negative predictive value of the extrapleural method were 91.9, 100, 100 and 82.9%, respectively, and the overall diagnostic accuracy was 94.2%. Significant risk factors affecting accuracy were younger age, atelectasis, hemoptysis and lesion depth (P<0.03). Multivariate logistic regression analysis revealed that the risk of malignant lesions receiving a false-negative diagnosis decreased for each additional year of subject age [odds ratio (OR), 0.97; P=0.027] and increased with each millimeter increase in lesion depth (OR, 1.03; P=0.008). Among the 1,106 lesions biopsied, 207 were associated with pneumothorax, 251 with hemorrhage and 58 with hemoptysis. Multivariate analysis revealed that lesion size and emphysema affected pneumothorax incidence, while age, lesion location and depth and emphysema significantly affected hemorrhage incidence (P<0.05). In conclusion, low-dose, CT-guided ACNB with the EPL method provides a safe and accurate diagnosis. PMID- 26640542 TI - CXCR7 functions in colon cancer cell survival and migration. AB - C-X-C chemokine receptor 7 (CXCR7) is a known promoter of tumor progression and metastasis; however, little is known about its role in colon cancer. The aim of the present study was to investigate the function of CXCR7 in human colon cancer cells. CXCR7 mRNA levels were examined in HT-29 and SW-480 human colon cancer cell lines using a quantitative polymerase chain reaction. CXCR7-knockdown was performed with small interfering RNA and lentiviral-mediated gene delivery. Immunofluorescence (IF) was conducted to examine CXCR7 expression and localization in colon cancer cells. Cell survival and migration were evaluated using MTT and migration assays, respectively. HT-29 cells expressed higher levels of CXCR7 mRNA and were therefore used in subsequent experiments. IF staining revealed that the CXCR7 protein was expressed on the cell membrane, and its expression decreased following CXCR7-short hairpin RNA lentiviral transfection. Lentiviral CXCR7-knockdown resulted in decreased cell survival and migration; however, MTT assays revealed that the lentiviral vector itself was cytotoxic. This cytotoxicity was indicated as the cell survival of the negative control group cells was significantly decreased compared with that of the blank control group cells (P<0.05). In conclusion, it is becoming increasingly evident that CXCR7 plays a role in colon cancer promotion, suggesting that CXCR7 is a promising biomarker for chemokine receptor-based drug development. Furthermore, the fact that CXCR7 is expressed on the membrane and not intracellularly makes it a prime target for drug-based intervention. PMID- 26640543 TI - Inhibition of focal adhesion kinase induces apoptosis in bladder cancer cells via Src and the phosphatidylinositol 3-kinase/Akt pathway. AB - Focal adhesion kinase (FAK) is a 125-kDa, cytosolic, non-receptor, protein tyrosine kinase localized at focal adhesions that can be activated by multiple inputs and in different manners. FAK is implicated in signaling pathways regulating cell movement, invasion, survival, gene expression and cancer stem cell self-renewal. The aim of the present study was to investigate whether FAK plays a role in the apoptosis of bladder cancer cells. The study employed in situ deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling and Annexin V labeling flow cytometry. It was found that both the knockdown of FAK and the suppression of FAK phosphorylation were able to induce apoptosis in bladder cancer cells. Caspase-3 was activated during the apoptosis induced by the suppression of FAK phosphorylation. Src was involved in FAK-regulated apoptosis in bladder cancer cells, while the suppression of Src phosphorylation was able to inhibit FAK tyrosine phosphorylation and induce apoptosis. Furthermore, phosphatidylinositol 3-kinase (PI3K)/Akt signaling was inhibited via the suppression of FAK tyrosine phosphorylation. Conversely, the expression of neither the general nor the tyrosine-phosphorylated FAK was regulated by inhibiting PI3K/Akt, which suggested that PI3K/Akt acted downstream of FAK to regulate apoptosis in bladder cancer cells. These findings indicate the presence of a mechanism of apoptosis involving FAK-mediated oncogenic signaling. FAK may function as an important regulator of extracellular signaling-mediated apoptosis in bladder cancer and be used as a novel therapeutic target in the treatment of the condition. PMID- 26640544 TI - iTRAQ-based proteomic analysis of hepatic tissues from patients with hepatitis B virus-induced acute-on-chronic liver failure. AB - The pathogenesis of hepatitis B virus (HBV)-induced acute-on-chronic liver failure (ACLF), a serious and prevalent medical condition, is not clear, particularly with regard to which proteins are expressed in the course of the disease. The aim of the present study was to identify the differences in hepatic tissue protein expression between normal human subjects and patients with ACLF using isobaric tags for relative and absolute quantification (iTRAQ)-based proteomic analysis and to verify the results using western blot analysis. The iTRAQ method was used to analyze the protein contents of hepatic tissue samples from 3 patients with HBV-induced ACLF and 3 normal healthy subjects. The results were verified by subjecting the hepatic tissues from 2 patients with HBV-induced ACLF and 4 healthy subjects to western blot analysis. In total, 57 proteins with >=1.5-fold differences between patients with HBV-induced ACLF and healthy subjects were identified using iTRAQ. Among these 57 proteins, 4 with the most marked differences in their expression and the most significant association with liver disease were selected to be verified through western blot analysis: Keratin, type-I cytoskeletal 19; alpha-1-acid glycoprotein 1 (alpha1-AGP); carbonic anhydrase-1; and serpin peptidase inhibitor and clade A (alpha-1 anti proteinase, antitrypsin) member 1 (SERPINA1). The results of the western blot analyses were nearly identical to the iTRAQ results. Identifying the differences in liver protein expression in patients with HBV-induced ACLF may provide a basis for studies on the pathogenesis of ACLF. Future studies should focus particularly on alpha1-AGP, carbonic anhydrase 1 and SERPINA1. PMID- 26640545 TI - Plasma von Willebrand factor level is transiently elevated in a rat model of acute myocardial infarction. AB - The von Willebrand factor (vWF) is a plasma glycoprotein that plays an essential role in hemostasis by supporting platelet adhesion and thrombus formation in response to vascular injury. Plasma levels of vWF are an independent risk factor for patients with acute myocardial infarction (AMI); however, clinical data have demonstrated a marked variation of vWF levels in patients with AMI, the reason for which has not yet been identified. In the present study, a rat model of ST segment elevation AMI was established, and cardiac and peripheral blood was collected for a time-course examination of the plasma levels of vWF and tumor necrosis factor-alpha (TNF-alpha). The level of vWF in the blood plasma increased, peaked at 1 h and decreased to normal levels by day 7 following AMI, while the level of TNF-alpha peaked at 24 h and remained elevated until day 7. The effects of TNF-alpha on vWF secretion and expression were examined in cultured human umbilical vascular endothelial cells (HUVECs). TNF-alpha treatment increased vWF secretion from the HUVECs but inhibited the mRNA and protein expression of vWF in the HUVECs. These results indicate that vWF secretion from endothelial cells is transiently elevated following AMI, and then decreases as the expression of vWF is inhibited by TNF-alpha. The present study increases the understanding of the pathophysiology of vWF and indicates that the determination of vWF levels may be useful in the clinical evaluation of AMI. PMID- 26640546 TI - Oxidative stress contributes to the impaired sonic hedgehog pathway in type 1 diabetic mice with myocardial infarction. AB - Our previous study demonstrated that an impaired sonic hedgehog (Shh) pathway contributed to cardiac dysfunction in type 1 diabetic mice with myocardial infarction (MI). The present study aimed to test the hypothesis that oxidative stress may contribute to the impaired Shh pathway and cardiac dysfunction in type 1 diabetic mice with MI. Streptozotocin-induced type 1 diabetic mice (C57/Bl6, male) and rat neonatal cardiomyocytes were used in the present study. Mice were randomly assigned to undergo ligation of the coronary artery or pseudosurgery. A potent antioxidant Tempol was administered in vivo and in vitro. Cardiac function was assessed by echocardiography, capillary density by immunohistochemisty, percentage of myocardial infarct using Massons trichrome staining, reactive oxygen species detection using dihydroethidium dye or 2,7-dichlorofluorescein diacetate probe and protein expression levels of the Shh pathway by western blot analysis. The antioxidant Tempol was shown to significantly increase myocardial protein expression levels of Shh and patched-1 (Ptc1) at 7-18 weeks and improved cardiac function at 18 weeks in type 1 diabetic mice, as compared with mice receiving no drug treatment. Furthermore, myocardial protein expression levels of Shh and Ptc1 were significantly upregulated on day 7 after MI, and capillary density was enhanced. In addition, the percentage area of myocardial infarct was reduced, and the cardiac dysfunction and survival rate were improved on day 21 in diabetic mice treated with Tempol. In vitro, treatment of rat neonatal cardiomyocytes with a mixture of xanthine oxidase and xanthine decreased protein expression levels of Shh and Ptc1 in a concentration-dependent manner, and Tempol attenuated this effect. These results indicate that oxidative stress may contribute to an impaired Shh pathway in type 1 diabetic mice, leading to diminished myocardial healing and cardiac dysfunction. Antioxidative strategies aimed at restoring the endogenous Shh pathway may offer a useful means for improving diabetic cardiac function. PMID- 26640547 TI - Phylogenetic reconstruction and polymorphism analysis of BK virus VP2 gene isolated from renal transplant recipients in China. AB - BK polyomavirus (BKV) is important pathogen for kidney transplant recipients, as it is frequently re-activated, leading to nephropathy. The aim of this study was to investigate the phylogenetic reconstruction and polymorphism of the VP2 gene in BKV isolated from Chinese kidney transplant recipients. Phylogenetic analysis was carried out in the VP2 region from 135 BKV-positive samples and 28 reference strains retrieved from GenBank. The unweighted pair-group method with arithmetic mean (UPGMA) grouped all strains into subtypes, but failed to subdivide strains into subgroups. Among the plasma and urine samples, all plasma (23/23) and 82 urine samples (82/95) were identified to contain subtype I; the other 10 urine samples contained subtype IV. A 86-bp fragment was identified as a highly conserved sequence. Following alignment with 36 published BKV sequences from China, 92 sites of polymorphism were identified, including 11 single nucleotide polymorphisms (SNPs) prevalent in Chinese individuals and 30 SNPs that were specific to the two predominant subtypes I and IV. The limitations of the VP2 gene segment in subgrouping were confirmed by phylogenetic analysis. The conserved sequence and polymorphism identified in this study may be helpful in the detection and genotyping of BKV. PMID- 26640548 TI - Anti-candidal activity of a novel peptide derived from human chromogranin A and its mechanism of action against Candida krusei. AB - Candida species (Candida spp.) are important fungal pathogens, which cause numerous clinical diseases associated with significant mortality and morbidity in healthcare settings. In our previous study, we identified a recombinant peptide, chromogranin A (CGA)-N46, corresponding to the N-terminal Pro31-Gln76 sequence of human CGA, that exhibited antifungal activity against Candida albicans. The present study investigated the antifungal activity of CGA-N46, and its underlying mechanism, against numerous Candida spp. CGA-N46 inhibited the growth of all of the tested Candida spp., of which Candida krusei exhibited the greatest sensitivity. CGA-N46 was able to disrupt the stability of the phospholipid monolayer without damaging the integrity and permeability of the outer membrane of C. krusei cells, and induced cytoplasm vacuolization and mitochondrial damage. In addition, treatment of C. krusei with CGA-N46 was associated with decreased levels of intracellular reactive oxygen species, a reduction in the mitochondrial membrane potential, and DNA synthesis inhibition. The results of the present study suggested that CGA-N46 was able to pass through the cell membrane of Candida spp. by temporarily destabilizing the phospholipid membrane, which in turn led to mitochondrial dysfunction and inhibition of DNA synthesis. Therefore, CGA-N46 may be considered a novel antifungal compound for the treatment of patients with C. krusei infections. PMID- 26640549 TI - Liraglutide reduces fatty degeneration in hepatic cells via the AMPK/SREBP1 pathway. AB - Recent studies have suggested that liraglutide could have a potential function in improving non-alcoholic fatty liver disease (NAFLD); however, the underlying molecular mechanism remains unclear. The aim of the present study was to investigate the role of the AMP-activated protein kinase (AMPK)/sterol regulatory element binding protein 1 (SREBP1) pathway in mediating the effect of liraglutide in reducing fatty degeneration in an in vitro NAFLD model. To resemble the NAFLD condition in vitro, L-02 cells were treated with 0.5 mM free fatty acids (FFAs) for 24 h. Liraglutide could affect the expression of AMPKalpha1, phosphorylated AMPKalpha1 and SREBP1 in a dose-dependent manner in FFA-exposed L-02 cells, as demonstrated by western blot analysis. The intracellular lipid accumulation was significantly decreased, as shown by oil red O staining. A significant decrease in the content of triglyceride and total cholesterol was observed when the FFA exposed L-02 cells were incubated with liraglutide. In addition, the increased expression of liver-type fatty acid-binding protein in FFA-exposed L-02 cells was suppressed by liraglutide. These effects were reversed by compound C, an AMPK inhibitor. In conclusion, this study has demonstrated that liraglutide can reduce fatty degeneration induced by FFAs in hepatocytes, and this effect may be partially mediated by the AMPK/SREBP1 pathway. PMID- 26640550 TI - Significance of the expression of MRP1 and MRP2 in peripheral blood mononuclear cells of children with intractable epilepsy. AB - Intactable epilepsy (IE) is relatively common in pediatric epilepsy. The resistance mechanism of IE has been previously investigated. Multidrug-resistant associated protein 1 (MRP1) and MRP2 are associated with drug transport. The aim of the present study was to investigate the expression of MRP1 and MRP2 in peripheral blood mononuclear cells of children with IE. Fifty outpatient or inpatient children were included in the study as the experimental group. Additionally, 50 children with epilepsy controlled by anti-epileptic drugs (AEDs) and 50 healthy children without epilepsy, who served as the control group, were included in the present study. Expression of MRP1 and MRP2 in the peripheral blood mononuclear cells of children in all the groups was detected using RT-PCR and western blot analysis. The results showed that the relative expression of MRP1 and MRP2 mRNA in the peripheral blood mononuclear cells of children with IE (MRP1, 0.795+/-0.042; MRP2, 0.804+/-0.023) was higher than that in epilepsy controlled by AEDs (MRP1, 0.682+/-0.030; MRP2, 0.675+/-0.021) and healthy children without epilepsy (MRP1, 0.665+/-0.031; MRP2, 0.654+/-0.029) (P<0.01). The mean relative expression of MRP1 and MRP2 protein in the peripheral blood mononuclear cells of children with IE (MRP1, 2.027+/-0.034; MRP2, 1.902+/-0.021) was higher than that in children with epilepsy controlled by AEDs (MRP1, 1.131+/ 0.042; MRP2, 1.086+/-0.027) and healthy children without epilepsy (MRP1, 1.093+/ 0.023; MRP2, 1.045+/-0.018) (P<0.01). The difference in the MRP1 and MRP2 mRNA and protein expression between the children with epilepsy controlled by AEDs and healthy children without epilepsy was not statistically significant (P>0.05). In conclusion, a higher expression of MRP1 and MRP2 in the peripheral blood mononuclear cells of children with IE may be relevant to the drug-resistant mechanism of IE. PMID- 26640551 TI - Single-cell microinjection assay indicates that 7-hydroxycoumarin induces rapid activation of caspase-3 in A549 cancer cells. AB - Coumarins have attracted intense interest in recent years due to their apoptogenic effects. The aim of the present study was to determine whether 7 hydroxycoumarin (7-HC) induces changes in caspase-3 (C-3) activity in A549 human lung carcinoma cells. A range of analytical techniques, including colorimetric and fluorometric assays, western blotting, single-cell microinjection, fluorescence microscopy and image analysis were conducted to elucidate the effects of 7-HC. A 24-h exposure to 1.85 mM 7-HC induced a 65% increase in C-3 activity, and a notable conversion of procaspase-3 to C-3, in addition to poly(ADP-ribose)polymerase cleavage. Furthermore, morphological changes associated with apoptosis were observed. Exposure of the cells to 7-HC for 3 or 6 h increased calcium conductance by 27%. By performing the single-cell microinjection of a specific fluorescent substrate of C-3 into previously 7-HC exposed cells, a typical enzymatic kinetic profile of C-3 activation was identified a number of hours prior to the morphological and biochemical changes associated with apoptosis being observed. These results suggest that the rapid in vivo activation of C-3 is induced by 7-HC, the most relevant biotransformation product of coumarin in humans. PMID- 26640553 TI - Quantitative analysis of contrast-enhanced ultrasonography in acute radiation induced liver injury: An animal model. AB - The aim of the present study was to examine and assess contrast-enhanced ultrasound in the early diagnosis of acute radiation-induced liver injury in a rat model. Sixty female rats were used, with 50 rats being utilized to produce an animal model of liver injury with a single dose of stereotactic X-ray irradiation of 20 Gy. Ten rats from the injury group and 2 rats from the control group were randomly selected on days 3, 7, 14, 21 and 28, and examined by contrast-enhanced ultrasound and histopathology of liver specimens. The rats were divided into four groups: the normal control group, mild, moderate, and severe radioactive liver injury groups based on the histopathological examination results. Hepatic artery arriving time (HAAT) and hepatic vein arriving time (HVAT) were recorded, and hepatic artery to vein transit time (HA-HVTT) was calculated. The time-intensity curve of liver parenchyma, the time to peak (TTP) and peak intensity (PI) were also obtained. Significant differences were observed between liver injury and control groups for PI and HA-HVTT (P<0.05). PI and HA-HVTT were shorter in the severe liver injury group compared to the mild and moderate liver injury groups (P<0.05). Compared to the control group, higher TTP was recorded in all the liver injury groups (P<0.05), and the highest TTP level was observed in the severe liver injury group compared to the mild or moderate group (P<0.05). However, no significant difference was observed between the mild and moderate groups for PI, HA-HVTT and TTP. In conclusion, the results showed that contrast-enhanced ultrasonography is useful for an earlier diagnosis in a rat model of acute radiation-induced liver injury. PMID- 26640552 TI - Identification of critical genes and gene interaction networks that mediate osteosarcoma metastasis to the lungs. AB - Osteosarcoma (OS) is the most commonly diagnosed bone tumor in young adults under the age of 20. Metastasis is considered an important factor underlying cancer associated morbidity and mortality, and, as a result, the survival rate of patients with metastatic OS is low. In spite of this, the mechanisms underlying metastasis in OS are currently not well understood. The present study compared gene expression levels between five non-metastatic and four metastatic OS tumor samples, using an Affymetrix microarray. A total of 282 genes were differentially expressed in the metastatic samples, as compared with the non-metastatic samples. Of these differentially expressed genes (DEGs), 212 were upregulated and 70 were downregulated. The following DEGs were associated with metastasis: Homeobox only protein; lysosomal-associated membrane protein-3; chemokine (C-C motif) ligand 18; carcinoembryonic antigen-related cell adhesion molecule-6; keratin-19; prostaglandin-endoperoxide synthase-2; clusterin; and nucleoside diphosphate kinase-1. Subsequently, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment pathway analyses were conducted, which identified 529 biological processes (P<0.01) and 10 KEGG pathways (P<0.05) that were significantly over-represented in the metastatic samples, as compared with the non-metastatic samples. Interaction networks for the DEGs were constructed using the corresponding GO terms and KEGG pathways, and these identified numerous genes that may contribute to OS metastasis. Among the enriched biological processes, four DEGs were consistently over-represented: Jun proto-oncogene, caveolin-1, nuclear factor-kappaB-inhibitor-alpha and integrin alpha-4; thus suggesting that they may have key roles in OS metastasis, and may be considered potential therapeutic targets in the treatment of patients with OS. PMID- 26640554 TI - Effect of vitamin D on the recurrence rate of rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is an autoimmune disease that is characterized by chronic inflammation affecting target tissues including the joints, bones, and synovial membrane. However, the etiology and pathogenesis of RA remains to be determined, and investigations into the treatment of RA are imperative. Vitamin D (Vit D) was previously found to be associated with the activity of RA and exerts therapeutic benefits. The aim of the present study was to investigate the effect of Vit D on the recurrence rate of RA. A total of 377 patients with RA at remission stage were divided into the normal Vit D group and the Vit D-deficient group according to their Vit D levels at baseline. The patients in the Vit D deficient group were further randomly allocated to receive treatment with or without Vit D. The patients were followed up for 24 months, and the visual analogue scale, as well as the number of pain and swelling joints were recorded every 2-3 months. In addition, C-reactive protein and the blood sedimentation rate were measured every 2-3 months to assess the recurrence of RA based on disease activity score 28 (DAS28). The recurrence rate of RA was 16.7, 19.0 and 29.5% for the normal Vit D group (n=168), Vit D treatment subgroup (n=84), and non-Vit D treatment subgroup (n=88), respectively. The recurrence rate of the normal Vit D group was lower, compared to the non-Vit D treatment subgroup, and the difference was statistically significant. However, the difference was not statistically significant between the Vit D treatment subgroup and non-Vit D treatment subgroup. In conclusion, a decreased level of Vit D is a risk factor for the recurrence of RA. PMID- 26640555 TI - Traditional Chinese medicine Qili qiangxin inhibits cardiomyocyte apoptosis in rats following myocardial infarction. AB - The aim of the present study was to examine the effect of the traditional Chinese medicine Qili qiangxin on cardiomyocyte apoptosis following myocardial infarction (MI) in a rat model. MI was induced in rats by ligation of the anterior descending coronary artery. Survivors were randomly divided into the sham operation, MI, and Qili qiangxin groups (4 g/kg per day). After 28 days, infarction size was measured. In the non-infarcted zones (NIZ), the apoptotic index (AI) was measured by terminal deoxynucleotidyl transferase (TdT)-mediated digoxigenin-conjugated dUTP nick-end labeling (TUNEL). Expression of Fas was detected by immunohistochemistry, and the expression of xanthine oxidase (XO) and caspase-3 by western blot analysis. In addition, the XO and .O2-, .OH-scavenging activity of myocardial tissue in NIZ was measured by colorimetry. Compared to the MI group, AI and the expression of Fas and caspase-3 were significantly decreased in NIZ. The activity of XO was also considerably reduced while .O2- and .OH scavenging activity was significantly increased in the Qili qiangxin group. Ventricular remodeling was attenuated but there were no significant differences in infarct size (IS) or XO expression levels between the Qili qiangxin and MI groups. In conclusion, the results suggest that Qili qiangxin may inhibit cardiomyocyte apoptosis in NIZ in rats. The potential mechanism involved may be associated with its ability to reduce reactive oxygen species (ROS) and to depress the expression of Fas and caspase-3. PMID- 26640556 TI - Clinical significance of dynamic monitoring of blood lactic acid, oxygenation index and C-reactive protein levels in patients with severe pneumonia. AB - The aim of the present study was to analyze the clinical significance of the dynamic monitoring of blood lactic acid levels, the oxygenation index and C reactive protein (CRP) levels in patients with severe pneumonia. The clinical data of 34 cases with severe pneumonia were collected. According to the clinical outcome, the patients were divided into a survival group (n=26) and a fatality group (n=8). Various factors, including the blood lactic acid level, oxygenation index, CRP level and acute physiology and chronic health evaluation II (APACHE II) score, were retrospectively analyzed in order to investigate whether these values had clinical significance for the prognosis of the patients. No statistically significant differences with regard to age, gender, initial concentrations of blood lactic acid and CRP, and APACHE II scores were observed between the two groups at admission to the Intensive Care Unit. However, the blood lactic acid levels were found to decrease to a normal level within 12-24 h after treatment in the survival group, while the levels were maintained at a higher concentration in the fatality group, even at 72 h after treatment (P<0.05). Furthermore, the oxygenation index in the survival group was significantly higher when compared with that in the fatality group. The oxygenation index was maintained at a normal level in the survival group, while the oxygenation index levels were below normal and continued to decline in the fatality group. A positive correlation was observed between the blood lactic acid level and the APACHE II scores (r=0.656, P<0.05). Therefore, the present study demonstrated that dynamic monitoring of blood lactic acid, oxygenation index and CRP levels in patients with severe pneumonia can be used to evaluate the therapeutic efficiency, in addition to serving as a prognosis indicator, for patients with severe pneumonia. PMID- 26640557 TI - Bafilomycin A1 inhibits the growth and metastatic potential of the BEL-7402 liver cancer and HO-8910 ovarian cancer cell lines and induces alterations in their microRNA expression. AB - The vacuolar H+-ATPase (V-ATPase) is commonly highly activated in cancer cells and is a potential target of anti-cancer therapy. Bafilomycin A1 is a specific inhibitor of the c subunit of V-ATPase. In the present study, the effects of bafilomycin A1 on the BEL-7402 hepatocellular carcinoma and HO-8910 ovarian cancer cell lines were respectively studied. In addition, the bafilomycin A1 induced alterations in the mRNAs and microRNAs (miRNAs) in the cells were detected using microarray methods. The results demonstrated that the growth of the two cell lines was retarded and the metastatic potential was inhibited by bafilomycin A1. Transmission electron microscopy and assays of capsase-3 and -9 suggested that bafilomycin A1 induced apoptosis. Gene Ontology analysis of the microarrays of mRNA-miRNA integrity showed altered pathways following bafilomycin A1 treatment, including pathways regulating glucose or lipid metabolism, DNA repair or duplication and lysosomes. Quantitative polymerase chain reaction analysis confirmed that miR-923, miR-1246, miR-149*, miR-638 and miR-210 were upregulated and miR-99a, miR-181a-2* and miR-339-5p were downregulated following bafilomycin A1 treatment. The overlapped altered miRs may be effective targets for the two types of solid tumor, and may have potential for application to the treatment of other types of solid tumor. PMID- 26640558 TI - Detection of gastric cancer using transabdominal ultrasonography is associated with tumor diameter and depth of invasion. AB - Gastric cancer is occasionally diagnosed using transabdominal ultrasonography (US) during screening or investigation of patients with abdominal symptoms. Therefore, the present study analyzed the association of the tumor diameter, pathological T (pT) staging and depth of invasion with the detection of gastric cancer using US. Patient records were analyzed retrospectively and 13 patients were enrolled, who underwent US screening prior to endoscopic mucosal resection, endoscopic submucosal dissection or surgery. In total, 5 patients were diagnosed with gastric cancer using US (positive detection group), while US was unable to detect the gastric cancer in 8 patients (negative detection group). The tumor diameter and depth of invasion were determined by pathologists. One-way analysis of variance or the chi2 test was performed. Wall thickness in gastric cancer cases ranged between 7 and 20 mm (mean, 12.2+/-5.9 mm), as measured using abdominal US. The hemoglobin level was significantly lower in the positive detection patients compared with the negative detection patients (P=0.0455). In addition, the diameters of the gastric wall in the negative and positive detection patients were 24.5+/-16.4 and 54.4+/-26.2 mm, respectively (P=0.0266). These results indicate that gastric cancer in the positive detection patients were at a more advanced-stage compared with that in the negative detection patients. Furthermore, gastric cancer with a stage over pT2 was diagnosed using abdominal US (P=0.0242), whereas stage pT1a gastric cancer was not detected by abdominal US. Gastric tumors invading deeper than the submucosa were diagnosed using US (P=0.0242). However, the gastric cancer cases limited to the mucosa remained undetected. In conclusion, the detection of gastric cancer correlated well with the tumor diameter, pT staging and depth of invasion. PMID- 26640559 TI - Effect of a bioabsorbable, super-high molecular weight poly-D,L-lactic acid plate containing recombinant human bone morphogenetic protein-2 for fracture healing. AB - The aim of this study was to investigate the effect of a bioabsorbable, super high molecular weight poly-D,L-lactic acid (PDLLA) plate exhibiting the sustained release of recombinant human bone morphogenetic protein-2 (rhBMP-2) (PDLLA-rhBMP 2) on the treatment of fracture with internal fixation. A total of 32 New Zealand rabbits were randomly allocated to one of four groups (2, 4, 8 and 12 weeks), and a 2.5-mm middle ulnar osteotomy was performed bilaterally. The right side (experimental side) was fixed internally with PDLLA-rhBMP-2, and the left side (control side) was fixed with a normal PDLLA plate. At 2, 4, 8 and 12 weeks after surgery, the gross pathology of the ulnas was examined and radiographic, histological and computer image analyses were performed. The results demonstrated that the ulna fractures were fixed stably with the two bioactive plates at 2, 4, 8 and 12 weeks after surgery. At the 8-week time-point, 7 rabbits exhibited good healing at the osteotomy site on the experimental side. At 12 weeks after surgery, 8 rabbits exhibited good healing at the osteotomy site on both sides, but the experimental side showed enhanced compatibility between the plates and surrounding tissue, faster bone formation, a greater bone regeneration mass and better medullary canal structure compared with the control side. In conclusion, PPLLA-rhBMP-2 may be effectively used to treat fracture or nonunion at a non weight-bearing site. PMID- 26640560 TI - Hedyotis diffusa Willd overcomes 5-fluorouracil resistance in human colorectal cancer HCT-8/5-FU cells by downregulating the expression of P-glycoprotein and ATP-binding casette subfamily G member 2. AB - Previous studies have demonstrated that Hedyotis diffusa Willd (HDW), a traditional Chinese herbal medicine, exhibits potent anticancer activity in models of colorectal cancer (CRC). Aggressive forms of CRC exhibit resistance to widely used chemotherapeutic drugs, including the antimetabolite, 5-fluorouracil (5-FU); however, less is known with regard to the activity of HDW against 5-FU resistant cancer. In the present study, the mechanism of action and the potency of ethanol extracts of HDW (EEHDW) were investigated on a multidrug-resistant CRC HCT-8/5-FU cell line. Using an MTT cell proliferation assay, EEHDW treatment was shown to significantly reduce the cell viability of HCT-8/5-FU cells in a dose- and time-dependent manner. Furthermore, EEHDW significantly increased the retention of the ATP-binding cassette (ABC) transporter substrate, rhodamine-123, as compared with the untreated controls. To further investigate the molecular mechanisms targeted by EEHDW in the resistant cells, the expression levels of the ABC drug transporter protein, P-glycoprotein (P-gp), and ABC subfamily G member 2 (ABCG2), were analyzed using reverse-transcription polymerase chain reaction and western blot analysis. The mRNA and protein expression levels of P-gp and ABCG2 were reduced in the HCT-8/5-FU cells following EEHDW treatment, indicating that EEHDW inhibits ABCG2-mediated drug resistance by downregulating the expression of ABCG2 and P-gp. Therefore, the potential application of EEHDW as a chemotherapeutic adjuvant represents a promising alternative approach to the treatment of drug-resistant CRC. PMID- 26640561 TI - Beneficial effect of human umbilical cord-derived mesenchymal stem cells on an endotoxin-induced rat model of preeclampsia. AB - Mesenchymal stem cells (MSCs), which exhibit the property of immune-modulation, have been shown to treat various diseases, including pulmonary hypertension. There is a functional similarity between the pulmonary circulation and the placenta, but it remains to be elucidated whether MSCs can be applied to treat endotoxin-induced hypertension during pregnancy; therefore, the aim of the present study was to investigate the therapeutic effect of a human umbilical cord derived MSC infusion on endotoxin-induced hypertension during pregnancy. Rats were randomly divided into three groups (n=7 per group): Control, endotoxin treated and endotoxin + MSCs. The model of preeclampsia (PE) was established via the intravenous injection of endotoxin. In the endotoxin + MSCs group, MSCs at 2*106 cells/rat were injected via the vena caudalis. The blood pressure, urine protein and number of white blood cells were measured. In addition, the protein expression levels of the pro-inflammatory cytokines interleukin (IL)-1beta and tumor necrosis factor-alpha (TNF-alpha) and the anti-inflammatory cytokine IL-10 were examined by ELISA. The blood pressure, levels of urine protein and number of white blood cells in the endotoxin-treated group were significantly higher than those in the control group (P<0.05); however, this increase was significantly attenuated in the endotoxin + MSCs group (P<0.05). In addition, the application of MSCs significantly reduced the levels of pro-inflammatory TNF-alpha and IL 1beta and increased the levels of anti-inflammatory IL-10 in the endotoxin treated rats. In conclusion, umbilical cord-derived MSCs have a protective effect in an endotoxin-induced model of PE, and this effect is likely elicited through the suppression of inflammatory factors. Umbilical cord-derived MSC-based therapy may provide a potential therapeutic method for endotoxin-induced hypertension during pregnancy. PMID- 26640562 TI - Effects of bone marrow-derived mesenchymal stem cells transfected with survivin on pulmonary fibrosis in mice. AB - The aim of the present study was to investigate the effects of bone marrow derived mesenchymal stem cells (BMSCs) transfected with survivin on lung fibrosis in mice. Mice with bleomycin-induced pulmonary fibrosis were allocated at random to group A, B or C, and injected with 1*106 survivin gene-expressing BMSCs, 1*106 BMSCs or normal saline, respectively. A total of 6 mice were sacrificed from each group on days 7, 14 and 28 after treatment. The extent of alveolitis and pulmonary fibrosis was assessed and the apoptotic rates of the BMSCs and survivin expressing BMSCs were detected. The content of surfactant protein A (SP-A) in the lung and hydroxyproline (Hyp) in the serum was measured. The mRNA expression levels of transforming growth factor (TGF)-beta1 and matrix metalloproteinase (MMP)-9 in the lung tissue of the mice was detected. Furthermore, the protein expression levels of caspase-3 and -9 were detected. The apoptotic rates of the BMSCs (group B) and survivin-expressing BMSCs (group A) were 14.466+/-1.953 and 7.718+/-0.493%, respectively. The degree of lung fibrosis in groups A and B was reduced compared with that in group C. The hydroxyproline content in groups A and B was reduced compared with that in group C, and the SP-A content in groups A and B was increased compared with that in group C. The mRNA expression levels of TGF beta1 in group A were reduced compared with those in group B, and the levels in group B were reduced compared with those in group C. By contrast, the mRNA expression levels of MMP-9 in group A were increased compared with those in groups B and C, and the levels in group B were increased compared with those in group A. The expression levels of caspase-3 and -9 in group A were elevated compared with those in groups B and C. In conclusion, BMSCs are effective in preventing bleomycin-induced lung fibrosis, and survivin may enhance the protective effects of BMSCs. PMID- 26640563 TI - A modified ultra-long pituitary downregulation protocol improved endometrial receptivity and clinical outcome for infertile patients with polycystic ovarian syndrome. AB - There are currently various protocols for in vitro fertilization (IVF). For patients with polycystic ovarian syndrome (PCOS), an optimized protocol for the downregulation of pituitary follicle stimulating hormone and luteinizing hormone via gonadotropin-releasing hormone agonist (GnRHa) remains a challenge. In the present study, the primary endpoint of an ultra-long and a conventional long GnRHa protocol for intracytoplasmic sperm injection/IVF treatments of patients with PCOS was retrospectively compared. In the modified ultra-long protocol group, endometrial thickness, morphology, and blood flow were significantly improved, as compared with in the conventional long protocol group. Furthermore, the serum progestogen (P) concentrations and P/estrogen (E2) [(Px1,000/E2)] ratio on the day of human chorionic gonadotrophin administration were significantly decreased in the modified ultra-long downregulation group, whereas the pregnancy and implantation rates were significantly higher. There were no significant differences in the average number of obtained oocytes, good quality embryo rates, cancel rates, fertilization rates, abortion rates, serious ovarian hyperstimulation syndrome incidences, ectopic pregnancy rates or gonadotropin (Gn) dosages between the two groups. These results suggest that the modified ultra-long protocol plus human menopausal Gn medication may be superior to the conventional long protocol, and may lead to improved implantation and pregnancy outcomes for infertile patients with PCOS. PMID- 26640564 TI - Comparative analysis between 64- and 320-slice spiral computed tomography in the display of coronary artery stents and diagnosis of in-stent restenosis. AB - The aim of the present study was to compare the accuracy of 64-multi-slice spiral computed tomography (64-MSCT) and 320-MSCT in the display of coronary artery stents and diagnosis of in-stent restenosis. The data collected from the 64- and 320-MSCT coronary angiography of 93 patients following coronary artery stent implantation were retrospectively analyzed. The 64-MSCT group comprised 30 cases with 57 stents and the 320-MSCT group comprised 63 cases with 93 stents. The image quality, heart rate of the patients and the radiation effective dose (ED) they were subjected to, were compared. Furthermore, the diagnostic abilities of 64-and 320-MSCT coronary angiography for in-stent restenosis were evaluated using invasive coronary angiography results as the gold standards. Statistically significant differences were observed in the heart rate and ED of the patients from the two groups (P<0.05), but no significant difference was identified in the accuracy index (P>0.05). The sensitivity, specificity, positive and negative predictive value and accuracy of the 64-MSCT group were found to be 100% (7/7), 93.94% (31/33), 77.78% (7/9), 100% (31/31) and 95% (38/40), respectively, and those in the 320-MSCT group were found to be 100% (16/16), 95.89% (70/73), 84.21% (16/19), 100% (70/70) and 96.63% (86/89), respectively. The present findings suggest that both 64-MSCT and 320-MSCT can be used for follow-up and curative effect evaluation following coronary stent implantation; however, 320-MSCT has fewer requirements of the patients' heart rate and uses a lower radiation dose. PMID- 26640565 TI - Thymocytes maintain immune activity through telomere elongation in rats under hypoxic conditions. AB - The main purpose of the present study was to investigate the change in thymocyte telomere length of rats exposed to different hypoxic conditions for different periods of time, as well as its effect on the immune system. A total of 110 male Wistar rats were randomly assigned to one of the three following groups: i) Sea level (SL) group, in which 10 rats were maintained at an altitude of 10 m; ii) moderate altitude (MA) group, in which 50 rats were maintained at an altitude of 2,260 m and then randomly sacrificed on days 1, 3, 7, 15 and 30 (n=10 each); and iii) simulated high altitude (SHA) group, in which 50 rats were maintained at a simulated altitude of 5,000 m, and then randomly sacrificed on days 1, 3, 7, 15 and 30 (n=10 each). The morphological changes of the thymus were observed, while the telomere length, the mRNA and protein expression levels of telomerase reverse transcriptase (TERT), and the peripheral blood lymphocyte count were measured. The results indicated that hypoxia induced morphological changes and apoptosis in thymocytes, as well as atrophy of the thymus tissue, and resulted in a significant increase in telomere length and TERT mRNA and protein expression levels. This effect appeared to be more pronounced in the SHA group compared with that in the MA group; however, no statistically significant changes were observed in the peripheral blood lymphocyte count. Based on these findings, the hypoxia associated loss of thymic function appears to be only quantitative and not qualitative, and the thymus may be able to maintain its immune function even under hypoxic conditions. PMID- 26640566 TI - Attenuation of oxygen fluctuation-induced endoplasmic reticulum stress in human lens epithelial cells. AB - Cataractogenic stresses are associated with the induction of endoplasmic reticulum (ER) stress. However, little is known about oxygen (O2)-induced ER stress in the lens. Cataract research has focused on elevated levels of O2 in lens epithelial cells (LECs). Excessive levels or a lack of O2 are known to induce ER stress whereas chronic ER stress activates the unfolded protein response (UPR). The present study investigated the hypothesis that the fluctuation of O2 levels induces a UPR, and may be controlled by maintaining human LECs (hLECs) in a specific concentration of O2. Human LECs were cultured in different atmospheric levels of O2. Hypoxic conditions were determined by the level of hypoxia-inducible factor (HIF)-1alpha. 2',7'-Dichlorodihydrofluorescein diacetate and ethidium homodimer-1 staining were conducted to detect reactive oxygen species (ROS) and cell death, respectively. Protein blot analyses were performed with antibodies specific to antioxidant and UPR-specific proteins. Reverse transcription-quantitatative polymerase chain reaction assays were performed to quantify the mRNA levels of activated NF-E2-related factor 2 (Nrf2) and kelch-like ECH-associated protein 1 (Keap1). The treatment of human LECs with 0 and 20% atmospheric O2 activated Nrf2/Keap1. The LECs shifted to 1% atmospheric O2 from 0, 4 or 20% for 24 h showed decreased levels of Keap1. By contrast, hLECs cultured in 1% atmospheric O2 for 24 h and then shifted to 0, 4 or 20% O2 exhibited a significant upregulation of Nrf2. These results suggest that oxidative stress proteins were not expressed in a 1% O2 environment. The O2 levels in the culture medium were equilibrated within 2 h in the cell culture plates. These results showed that an appropriate oxygen environment for the culture of LECs is ~1 % atmospheric O2. Either 0 or 20% of atmospheric O2 activated the UPR and the Nrf2/Keap1-mediated antioxidant system in LECs and chronic exposure to O2 fluctuation led to ROS production and cell death. This study revealed that O2 fluctuation-induced UPR/ER stress could be prevented by maintaining the cells in a 1% O2 environment. PMID- 26640567 TI - Breast infarction during pregnancy and lactation: A case report. AB - Spontaneous infarction is a rare condition associated with the physiological hyperplasia of breast tissue associated with pregnancy and lactation. The causes of and mechanism underlying the occurrence of this complication remain largely unknown. The present study describes a rare case of breast infarction occurring during pregnancy and lactation in a 20-year-old woman. At 2 months of gestation, the patient noticed a soft and painless lump (size, ~5*4 cm) in the right breast. The lump grew to eventually occupy the entire breast. The patient was hospitalized 1 month after delivery and underwent a mastectomy. Histopathological study of the resected breast tissue revealed that 90% of the breast tissue had undergone infarction, with the infarct located centrally, under the areola. Involution of the breast tissue and small focal hemorrhages were noted, along with acute or chronic inflammatory cell infiltration in the interstitial tissue. Some breast ducts showed cystic dilatation, while some small blood vessels showed dilatation and congestion. Postoperative recovery of the patient was uneventful. This was a case of breast infarction with irregular, high-grade fever. The findings of core-biopsy were inconclusive, which highlights the importance of MammotomeTM biopsy or surgical excision in the diagnosis in such cases. PMID- 26640568 TI - Aplasia cutis congenita: A case report and literature review. AB - Aplasia cutis congenita (ACC) is a rare condition with an unclear pathogenic mechanism, although the condition has been suggested to occur as a result of the disrupted development or degeneration of skin in utero. ACC associated with fetus papyraceus has been described in numerous studies. Although there have been several reports of ACC, surgical treatment of ACC using the head as a site of donor skin is rarely reported. The present study describes the case of a 1-week old patient with ACC that was healed by skin grafting, using the scalp as the donor site. The outcome of the procedure showed that the use of the scalp as a donor skin site for grafting is an effective treatment for large and deep ACC lesions arising on sites other than the head. PMID- 26640569 TI - Predictors of prognosis in patients with temporal lobe epilepsy after anterior temporal lobectomy. AB - The aim of this study was to evaluate the predictive value of prognostic factors for the surgical outcome of patients with mesial temporal lobe epilepsy (MTLE) using Engel seizure classification. The clinical data of 121 patients with MTLE who underwent anterior temporal lobectomy (ATL) and received a 1-year minimum follow-up were collected between January 2005 and December 2008. Patients were divided into seizure and seizure-free groups according to the Engel seizure classification. Univariate analysis and multivariate logistic regression analysis were used to analyze the potential predictive and prognostic factors, including medical history, clinical features of seizures, magnetic resonance imaging (MRI) and video-electroencephalogram (EEG) monitoring results. Univariate analysis indicated no statistically significant differences in gender, age at seizure onset, age at surgery, history of traumatic brain injury, perinatal anoxia, intracranial infection, family history of seizure, auras or site of surgery between the two groups; however, significant differences were detected in pre surgical seizure duration, history of febrile seizures, seizure types, MRI and video-EEG results. Multivariate logistic regression analysis demonstrated that a pre-surgical seizure duration of <10 years, history of positive febrile seizures, simple complex partial seizure, positive MRI results and unilateral local video EEG spikes may be considered as predictors of a good prognosis. These results indicate that remission may be achieved in patients with MTLE via the collection of accurate clinical information and adequate pre-surgical evaluation. PMID- 26640570 TI - Expression of focal adhesion kinase in the eutopic endometrium of women with adenomyosis varies with dysmenorrhea and pelvic pain. AB - The aim of the present study was to examine whether the expression of focal adhesion kinase (FAK) is altered in the eutopic endometrium of female patients with adenomyosis, as compared with that of females without adenomyosis. The expression of FAK was assessed by immunohistochemical, western blot and reverse transcription-quantitative polymerase chain reaction analyses. An elevated expression of FAK mRNA and protein was identified in the eutopic endometrium of patients with adenomyosis compared with patients without adenomyosis (P<0.05). In addition, a positive correlation was detected between FAK protein expression and dysmenorrhea and pelvic pain in females with adenomyosis (P<0.05). The significant increase of FAK expression identified in the eutopic endometrium of females with adenomyosis, as well as the association of FAK protein expression with dysmenorrhea and pelvic pain, suggested that FAK may play a role in the pathogenesis of adenomyosis. PMID- 26640571 TI - Protective effects of Tougu Xiaotong capsule on tumor necrosis factor-alpha injured UMR-106 cells. AB - Tumor necrosis factor-alpha (TNF-alpha) plays an important role in the abnormal metabolism of osteoblasts (OBs), which leads to subchondral bone (SB) alterations in osteoarthritis. In the present study, Tougu Xiaotong capsule (TXC), a traditional Chinese medicine, was used to treat TNF-alpha-injured OB-like cells. The cellular viability, mortality and ultramicroscopic morphology were evaluated. Thereafter, the activity of alkaline phosphatase (ALP), secretion of osteocalcin (OCN) and mineralization of nodules were analyzed. The results showed that TXC treatment significantly promoted cell proliferation, reduced cellular mortality and improved cellular ultrastructure, particularly that of the endoplasmic reticulum and nucleus. These data indicate that TXC is able to promote cell growth, as well as prevent inflammation in OB-like cells. Furthermore, the activity of ALP, secretion of OCN and mineralization of nodules were accelerated, and the calcium content of the TNF-alpha-injured OB-like cells was promoted by TXC treatment. These results indicate that TXC protected the OB-like cells from TNF-alpha-induced injuries. This may be a potential mechanism through which TXC regulates SB remodeling in the clinical treatment of osteoarthritis. PMID- 26640572 TI - Concurrence of Fahr's disease and brain tumor: A case report and review of the literature. AB - Fahr's disease is a rare entity characterized by abnormal calcification in the bilateral basal ganglion regions and cerebellum. Concurrence of Fahr's disease with brain tumor is associated with an even lower incidence; the present study describes the fifth such case, in which a 32-year-old female presented with a 1 month history of headache and unsteady walking. Pathology and imaging studies resulted in a diagnosis of low-grade astrocytoma with calcified deposition. The patient recovered uneventfully. Following a review of the literature, several similarities among the reported cases were revealed. Patients were relatively young at the onset of the disease. The pathological diagnosis for all brain tumors was astrocytoma. The cerebellum was the predominant location of the brain tumor. The imaging studies of these cerebral astrocytomas were almost identical, with a cystic glioma occurring adjacent to a neighboring calcified dentate nucleus. Furthermore, the development of astrocytoma in the bilateral cerebellar hemisphere was not uncommon, which warrants close follow-up for these patients. PMID- 26640573 TI - Effects of mitochondrial haplogroup N9a on type 2 diabetes mellitus and its associated complications. AB - A case-control study was conducted with the aim of identifying the predominant haplogroups associated with type 2 diabetes mellitus (T2DM) and its complications. In addition, the role of N9a in T2DM risk and complications was analyzed. Sequencing of the entire mitochondrial DNA was conducted in 235 patients and 244 controls in cohort 1, and six haplogroups (F, B4, D4, D5, M8a and N9a) associated with T2DM were classified. The frequency of N9a was further determined in cohort 2 (440 patients and 244 controls) and examined in two combined cohorts, including 675 patients with T2DM and 649 non-diabetic controls. Multivariate logistic regression analysis and association analysis were performed to investigate the association between genotypes, T2DM and diabetic nephropathy. M8a [P=0.011; odds ratio (OR), 3.49; 95% confidence interval (CI), 1.26-9.69] and haplogroup N9a (P=0.023; OR, 2.60; 95% CI, 1.11-6.05) were associated with an increased risk of T2DM. The frequency of N9a was higher in T2DM patients compared with that in the controls (6.2% vs. 4.3%) and associated with a mild risk (P=0.10; OR, 1.51; 95% CI, 0.92-2.49). N9a was significantly associated with an increased risk of diabetic nephropathy (P=0.024; OR, 2.15; 95% CI, 1.11-4.19). Previous findings of N9a being protective against T2DM were not replicated in the present study, although this haplogroup was associated with an increased risk of diabetic nephropathy. PMID- 26640574 TI - Analysis of the correlation between serum resistin and the variability of erythropoietin responsiveness in patients with chronic kidney disease. AB - Chronic kidney disease (CKD) is commonly accompanied by inflammation and anemia; however, the pathogenesis of CKD is unclear. Expression of resistin, a cysteine rich secretory plasma protein, is correlated with the expression of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6 and lipoprotein-associated phospholipase A2, indicating that resistin may be involved in inflammatory events. In addition, inflammation inhibits the activity of erythropoietin (EPO) and, thus, erythropoiesis. The aim of the present study was to analyze the correlation between serum resistin and the variability of EPO responsiveness in CKD patients. The levels of serum creatinine (SCr), C-reactive protein (CRP), total cholesterol, triglycerides, IL-6 and serum resistin were measured in the samples obtained from 138 CKD patients and healthy control subjects. The levels of serum resistin in the CKD groups with and without hemodialysis were significantly higher than those observed in the normal control group (P<0.01) and the levels of serum resistin in the hemodialysis CKD group were higher than those observed in the CKD group without dialysis (P<0.01). The levels of serum resistin in patients in the randomly selected CKD group (with hemodialysis) were positively correlated with the duration of dialysis and the levels of SCr and CRP (P<0.05), however, were negatively correlated with the estimated glomerular filtration rate. The EPO resistance index (ERI) was identified to be associated with body mass index and the levels of CRP and resistin; furthermore, EPO reactivity was correlated with the level of resistin and ERI. The levels of serum resistin were correlated with the variability in EPO responsiveness that was observed in the CKD patients. Therefore, the measurement of serum resistin may aid with understanding the mechanisms, clinical diagnosis and treatment of CKD. PMID- 26640575 TI - Clinical, pathological and genetic characteristics of a pedigree with myotonic dystrophy type 1. AB - The aim of the present study was to investigate the clinical, pathological and molecular genetic characteristics of a pedigree with myotonic dystrophy type 1 (DM1). A series of clinical data from a pedigree with DM1 were collected. Muscle biopsy revealed a typical nuclear ingression within numerous muscle fibers following hematoxylin and eosin staining. Genomic DNA was extracted from the venous blood of two patients and the triplet-primed polymerase chain reaction method was performed to amplify the dystrophia myotonic protein kinase (DMPK) gene. The amplified products were subjected to gene sequencing by capillary fluorescence electrophoresis, and a pathogenic mutation in the DMPK gene comprising >50 cytosine-thymine-guanine repeat sequences was found. DM1 includes multi-system damage, as well as skeletal muscle involvement, and can affect the central nervous system, endocrine glands, skin and heart. A skeletal muscle biopsy and genetic testing can confirm the diagnosis and clarify the severity of the disease. In addition, it is necessary to distinguish DM1 from DM2. PMID- 26640576 TI - Associations among glycemic excursions, glycated hemoglobin and high-sensitivity C-reactive protein in patients with poorly controlled type 2 diabetes mellitus. AB - The aim of the present study was to explore the associations among glycemic excursions, glycated hemoglobin (HbA1c) and high-sensitivity C-reactive protein (hs-CRP) in patients with poorly controlled type 2 diabetes mellitus (T2DM) using a continuous glucose monitoring system (CGMS). Sixty-three patients with T2DM whose HbA1c levels were >7% wore a CGMS device for 72 h. According to their HbA1c levels, patients were divided into three groups as follows: Group A (HbA1c <=9.32%), group B (9.32%< HbA1c <=11.76%) and group C (HbA1c >11.76%). Patients were also divided into two groups according to the mean amplitude of glycemic excursions (MAGE) as follows: Low glycemic excursion group (MAGE, <3.9 mmol/l) and high glycemic excursion group (MAGE, >=3.9 mmol/l). Clinical data and the hs CRP levels in different groups were compared. No significant difference was observed in the MAGE among groups A, B and C (P>0.05). The level of hs-CRP was significantly higher in group C compared with that in groups A and B, and in group B compared with that in group A (P<0.05). Multivariate stepwise regression analysis indicated that HbA1c correlated with hs-CRP (P<0.05). MAGE and HbA1c were independent indices for the assessment of glycemic control. In addition, HbA1c had a considerable effect on the serum hs-CRP level. PMID- 26640577 TI - Successful treatment of refractory chronic hand eczema with calcipotriol/betamethasone ointment: A report of three cases. AB - Chronic hand eczema (CHE) is a common skin disorder with frequent relapses, and its treatment comprises a challenge due to its uncertain etiology. In particular, certain cases of CHE exhibiting severe keratinization have a very poor response to various treatments. The Daivobet ointment, a complex product comprising calcipotriol and betamethasone, has been successfully used for the treatment of patients with plaque-type psoriasis for ~10 years; however, there are few reports on the effect of the ointment on other skin disorders of abnormal keratinization, such as eczema. The present study reported 3 cases of refractory hyperkeratotic eczema of the hand that did not respond to several treatments, but responded well to topical Daivobet treatment. PMID- 26640578 TI - Expression of immune checkpoint molecules in endometrial carcinoma. AB - The main obstacle in the development of an effective tumor vaccine is the inherent ability of tumors to evade immune responses. Tumors often use common immune mechanisms and regulators to evade the immune system. The present study aimed to analyze the expression levels of indoleamine 2,3-dioxygenase (IDO), programmed death-ligand (PD-L) 1, PD-L2, B7-H4, galectin-1 and galectin-3 in tissue samples from patients with endometrial carcinoma, in order to detect the immunosuppressive environment of endometrial carcinomas. The levels of IDO, PD L1, PD-L2 and B7-H4 were analyzed by immunohistochemical methods, and the levels of galectin-1 and galectin-3 in tumor lysates were determined using ELISA. PD-L2 was expressed at low levels in the majority of tumor samples. IDO expression was detected in 38, 63 and 43% of primary endometrial carcinoma, recurrent endometrial carcinoma, and metastatic endometrial carcinoma specimens, respectively. Positive expression rates for PD-L1 were 83% in primary endometrial carcinoma, 68% in recurrent endometrial carcinoma, and 100% in metastatic endometrial carcinoma, whereas B7-H4 expression was detected in 100% of both primary endometrial carcinoma and recurrent endometrial carcinoma samples, and in 96% of metastatic endometrial carcinoma specimens. The expression levels of galectin-1 and galectin-3 were not significantly different between the normal and tumor specimens. The results of the present study suggest that the interaction between PD-1/PD-L1 and B7-H4 may be a potential target for immune intervention in the treatment of endometrial carcinoma. Furthermore, the results may provide the basis for immunosuppressant therapy in the treatment of patients with uterine cancer. PMID- 26640579 TI - Association between PTPN22 C1858T polymorphism and alopecia areata risk. AB - Alopecia areata (AA) is a skin condition in which hair is lost from certain or all areas of the body. This condition has been described as an immune-mediated complex genetic disease, characterized by the presence of lymphocytes that are directed to the hair follicles in the anagen phase. The gene encoding the protein tyrosine phosphatase, non-receptor type 22 (PTPN22), which is exclusively expressed in immune cells, has been considered as a risk factor associated with a number of autoimmune diseases. In AA, the single nucleotide polymorphism, rs2476601, has been identified as a risk factor in several populations. The aim of the present study was to investigate the effect of PTPN22 C1858T inherited genetic polymorphism on the predisposition to severe forms of AA, in a case control study on individuals. The study included 64 unrelated patients diagnosed with several types of AA, as well as 225 healthy unrelated subjects. The DNA samples were genotyped for PTPN22 C1858T polymorphism using the polymerase chain reaction-restriction fragment length polymorphism technique. Causal associations were determined by chi2 test and their respective odds ratio (OR) was assessed in a 2*2 contingency table. The results demonstrated a significant association of the T allele [P=0.040; OR=3.196; 95% confidence interval (CI), 0.094-10.279] and the CT genotype (P=0.038; OR=3.313; 95% CI, 1.008-10.892) with patchy AA. In conclusion, the results of the present study suggested the possible involvement of the T allele of the PTPN22 C1858T SNP as a genetic risk factor for this type of AA in the population studied. PMID- 26640580 TI - Malate dehydrogenase-2 inhibitor LW6 promotes metabolic adaptations and reduces proliferation and apoptosis in activated human T-cells. AB - Activated T cells rely on aerobic glycolysis and glutaminolysis in order to proliferate and differentiate into effector cells. Therefore, intervention in these metabolic pathways inhibits proliferation. The aim of the present study was to evaluate the effects of Krebs' cycle inhibition at the level of malate dehydrogenase-2 (MDH2) in human activated T cells using the MDH2 inhibitor LW6. Activated T cells from healthy volunteers were cultured in the presence or absence of LW6 and cytotoxicity, cell proliferation and the expression levels of hypoxia-inducible factor (HIF)-1alpha, c-Myc, p53, cleaved caspase-3 and certain enzymes involved in glucose metabolism and glutaminolysis were evaluated. The results revealed that LW6 was not toxic and decreased apoptosis and the levels of the pro-apoptotic tumor suppressor p53. In addition, LW6 inhibited T-cell proliferation and decreased the levels of c-Myc, HIF-1alpha, glucose transporter 1, hexokinase-II, lactate dehydrogenase-A and phosphorylated pyruvate dehydrogenase. By contrast, LW6 increased the levels of pyruvate dehydrogenase. These alterations may lead to decreased production of pyruvate, which preferentially enters into the Krebs' cycle. Furthermore, LW6 decreased the levels of glutaminase-2, while increasing those of glutaminase-1, which may preserve glutaminolysis, and possibly pyruvate-malate cycling, potentially protecting the cells from energy collapse. In summary, the inhibition of MDH2 in activated T cells abrogates proliferation without adversely affecting cell survival. Adaptations of cellular glucose and glutamine metabolism may prevent energy collapse. PMID- 26640582 TI - Ectopic splenic autotransplantation following traumatic injury: A case report. AB - A 41-year-old male patient was admitted to the General Hospital of Guangzhou Military Command due to upper abdominal pain persisting for 12 h. Computed tomography (CT) and positron emission tomography/CT scans revealed multiple soft tissue shadows in the abdominal cavity, peritoneum and Glisson's capsule, but the metabolic activity was at normal levels. A small area of low-density shadows near the tail of the pancreas and multiple shadows of enlarged lymph nodes were identified around the porta hepatis and the pancreas, with a mildly increased metabolic activity. On the basis of the CT images the patient was diagnosed with pancreatitis. Radionuclide imaging showed the absence of the spleen from its normal position (following splenectomy), but abnormal phagocytosis of multiple red blood cells was observed in the abdomen, which was diagnosed as ectopic splenic autotransplantation (ESAT). The patient subsequently recovered well following symptomatic treatment. ESAT in trauma patients requires urgent surgery in order to remove the damaged spleen and artificially cultivate partial splenic tissue. PMID- 26640581 TI - Stress alters the expression of aquaporins in cultured rat intestinal epithelial cells. AB - Aquaporins (AQPs) are widely-expressed small water channel proteins that provide the major route for water transport across plasma membranes in various cell types. Although the quantity of water transported in the intestinal tract is second only to that in the kidney, the precise role of AQPs in this organ remains largely uncertain. The present study reports the effects of hypertonic stress and ischemia/reperfusion injury on the expression of AQPs in intestinal epithelial cells. Cultured rat intestinal epithelial cells were incubated in 300 mM mannitol containing, hypertonic culture medium or subjected to simulated ischemia/reperfusion treatment. The cell viability was evaluated by MTT assay, and the expression of AQPs was determined by semi-quantitative reverse transcription polymerase chain reaction and western blotting. Despite reduced viability, the cells exposed to hypertonic stress for 16 h demonstrated enhanced expression of AQP1 mRNA and protein. AQP9 and glycosylated AQP11 proteins were also markedly upregulated. Ischemia alone did not affect the cell viability, but subsequent reperfusion significantly reduced viability. The mRNA expression levels of all the tested AQPs were not altered by ischemia alone or by ischemia/reperfusion; however, AQP8 protein was markedly reduced by ischemic injury. In addition, treatment with ischemia alone eradicated the normally expressed, non-glycosylated AQP11 protein whilst inducing pronounced expression of the glycosylated form. These observations may indicate that AQPs function in the intestinal epithelia in response to stress. PMID- 26640583 TI - Chenodeoxycholic acid increases the induction of CYP1A1 in HepG2 and H4IIE cells. AB - Bile acids are considered to promote carcinogenesis. Cytochrome P450 1A1 (CYP1A1) plays a critical role in the biotransformation of drugs and procarcinogens. This study aimed to investigate the ability of bile acids to modulate CYP1A1 expression. Treatment of HepG2 cells with chenodeoxycholic acid (CDCA) and Sudan III (S.III) upregulated CYP1A1 transcriptional activity in HepG2 cells and CYP1A1 mRNA expression in H4IIE cells. Pretreatment of the HepG2 and H4IIE cells with CDCA upregulated the S.III-induced CYP1A transcriptional activity and mRNA expression. The CDCA-induced enhancement of CYP1A1 was not abolished by the p38 inhibitor SB203580. However, exposure of the cells to the mitogen-activated protein kinase kinase (MEK)1/2 inhibitor PD98059 suppressed the CDCA-induced enhancement of CYP1A1. These results show the ability of CDCA to upregulate CYP1A1 transcription and expression, which may explain the hepatocarcinogenesis inducing effect of cholestasis. The CDCA-induced upregulation of CYP1A1 most probably proceeded through MEK1/2 activation, indicating that this may be a therapeutic target to prevent the cancer-promoting effects of excessive amounts of bile acids. PMID- 26640584 TI - Correlation between the expression of S100A4 and the efficacy of TAC neoadjuvant chemotherapy in breast cancer. AB - The aim of this study was to investigate the correlation between the expression of S100A4 and the efficacy of neoadjuvant chemotherapy in breast cancer. A total of 65 patients with invasive breast cancer were treated with neoadjuvant chemotherapy using the TAC regimen. The expression of S100A4 was detected by an immunohistochemical two-step method prior to treatment, after 2 cycles of chemotherapy and after 4 cycles of chemotherapy. Pathological evaluations of the chemotherapy were performed using the Miller and Payne (MP) grading system and their correlation with the changes of S100A4 expression during and after the treatment were explored. Between pre-neoadjuvant chemotherapy and 4 cycles post chemotherapy, there was a significant difference in the expression of S100A4 (P<0.05); S100A4 expression was associated with neoadjuvant chemotherapy. However, between pre-neoadjuvant chemotherapy and 2 cycles post-chemotherapy, there was no significant difference in the expression of S100A4 (P>0.05). The intensity and changes of S100A4 expression were positively correlated with the efficacy of neoadjuvant chemotherapy (r=0.259, P<0.05). When patients with an MP grade of I or II following the second cycle of neoadjuvant chemotherapy were continually treated with the original chemotherapy for another 2 cycles, the desired effect was generally not achieved. S100A4 may be used as a predictor of the efficacy of neoadjuvant chemotherapy in breast cancer, guiding the formulation of individualized programs to improve the effectiveness of the treatment. For patients with an MP grade level of I or II after 2 cycles of neoadjuvant chemotherapy, the use of alternative chemotherapy regimens should be considered. PMID- 26640585 TI - Association between polymorphisms of estrogen receptor 2 and benign prostatic hyperplasia. AB - Estrogens and estrogen receptors (ESRs) have been implicated in the stimulation of aberrant prostate growth and the development of prostate diseases. The aim of the present study was to investigate four single nucleotide polymorphisms (SNPs) of the ESR2 gene in order to examine whether ESR2 is a susceptibility gene for benign prostatic hyperplasia (BPH). In order to evaluate whether an association exists between ESR2 and BPH risk, four polymorphisms [rs4986938 (intron), rs17766755 (intron), rs12435857 (intron) and rs1256049 (Val328Val)] of the ESR2 gene were genotyped by direct sequencing. A total of 94 patients with BPH and 79 control subjects were examined. SNPStats and Haploview version 4.2 we used for the genetic analysis. Multiple logistic regression models (codominant1, codominant2, dominant, recessive and log-additive) were produced in order to obtain the odds ratio, 95% confidence interval and P-value. Three SNPs (rs4986938, rs17766755 and rs12435857) showed significant associations with BPH (rs4986938, P=0.015 in log-additive model; rs17766755, P=0.033 in codominant1 model, P=0.019 in dominant model and P=0.020 in log-additive model; rs12435857, P=0.023 in dominant model and P=0.011 in log-additive model). The minor alleles of these SNPs increased the risk of BPH, and the AAC haplotype showed significant association with BPH (chi2=6.34, P=0.0118). These data suggest that the ESR2 gene may be associated with susceptibility to BPH. PMID- 26640586 TI - Retrospective imaging study on the diagnosis of pathological false positive iodine-131 scans in patients with thyroid cancer. AB - Iodine-131 (I-131) therapy and post-therapy I-131 scanning are essential in the management of differentiated thyroid cancer (DTC). However, pathological false positive I-131 scans can lead to misdiagnosis and inappropriate I-131 treatment. This retrospective study aimed to investigate the best imaging modality for the diagnosis of pathological false positive I-131 scans in a DTC patient cohort, and to determine its incidence. DTC patient data archived from January 2008 to January 2010 was retrieved. Post-therapeutic I-131 scans were conducted and interpreted. The imaging modalities of magnetic resonance imaging (MRI), computed tomography and ultrasonography were applied and compared to check all suspected lesions. Biopsy or needle aspiration was conducted for patients who consented to the acquisition of histopathological confirmation. Data for 156 DTC patients were retrieved. Only 6 cases of pathological false-positives were found among these (incidence, 3.85%), which included 3 cases of thymic hyperplasia in the mediastinum, 1 case of pleomorphic adenoma in the parapharyngeal space and 1 case of thyroglossal duct cyst in the neck. MRI was demonstrated as the best imaging modality for diagnosis due to its superior soft tissue resolution. However, no imaging modality was able to identify the abdominal false positive-lesions observed in 2 cases, one of whom also had thymic hyperplasia. In conclusion, pathological false positive I-131 scans occurred with an incidence of 3.85%. MRI was the best imaging modality for diagnosing these pathological false-positives. PMID- 26640587 TI - Hsa-miR-301a-3p Acts as an Oncogene in Laryngeal Squamous Cell Carcinoma via Target Regulation of Smad4. AB - Laryngeal squamous cell carcinoma (LSCC) is the second most common malignant head and neck squamous cell carcinoma. Exploring the molecular indicators of malignant behavior will enhance our knowledge of this type cancer and provide novel options for its prevention, diagnosis, and treatment. MicroRNA might exert regulatory roles as oncogenes or anti-oncogenes. We studied the expression of miR-301a-3p in LSCC tissues and cell lines and conducted a functional analysis of miR-301a-3p to confirm if miR-301a-3p functions as an oncogene in LSCC. We found Smad4 to be one of the potential target genes of miR-301a-3p, and it functioned as a tumor suppressor in LSCC. Hsa-miR-301a-3p participated in the epithelial-mesenchymal transition (EMT) process, which is considered to be linked to the process of LSCC development. Our present findings indicate that miR-301a-3p acts as an oncogene by directly regulating the anti-oncogene Smad4, thereby playing a role in the occurrence and development of LSCC. The present findings are expected to help in the development of novel targets for the prevention and treatment of LSCC. PMID- 26640588 TI - Serum Unsaturated Free Fatty Acids: A Potential Biomarker Panel for Differentiating Benign Thyroid Diseases from Thyroid Cancer. AB - BACKGROUND: Serum free fatty acids (FFAs) are correlated with pathological status, and change in serum FFA levels may be associated with thyroid diseases. MATERIALS AND METHODS: In this study, 664 serum samples from 322 healthy controls, 129 patients with benign thyroid disease (BTD), and 213 patients with thyroid cancer (TC) were collected. Chip-based direct-infusion nanoelectrospray mass spectrometry was performed to simultaneously quantify six serum FFAs (i.e., C16:1, C18:1, C18:2, C18:3, C20:4, and C22:6.), with the excellent correlation coefficients of > 0.99 and relative standard deviation of <18% for all analysts. The Mann-Whitney U test was used to compare the differences in serum FFA levels between three above-mentioned groups. RESULTS: Significant increase in the levels of C16:1, C18:1, C18:2, C18:3, C20:4, and C22:6 in healthy controls relative to TC patients and BTD patients was observed, and the levels of C16:1, C18:2, C20:4, and C22:6 in BTD patients were significantly decreased relative to TC patients. Receiver operating characteristic (ROC) analysis indicated that a combination of C16:1, C18:2, C20:4, and C22:6 has excellent diagnostic performance to differentiate BTD patients from TC patients, with an area under the ROC curve of 0.857, a sensitivity of 76.8%, and a specificity of 83.7%. CONCLUSIONS: Change in serum levels of FFAs is closely correlated with thyroid diseases, and a biomarker panel (C16:1, C18:2, C20:4, and C22:6) should be of benefit to differentiate BTD patients from TC patients. PMID- 26640589 TI - A Novel Treatment Method for Lymph Node Metastasis Using a Lymphatic Drug Delivery System with Nano/Microbubbles and Ultrasound. AB - Chemotherapy based on hematogenous administration of drugs to lymph nodes (LNs) located outside the surgically resected area shows limited tissue selectivity and inadequate response rates, resulting in poor prognosis. Here, we demonstrate proof of concept for a lymphatic drug delivery system using nano/microbubbles (NMBs) and ultrasound (US) to achieve sonoporation in LNs located outside the dissection area. First, we demonstrated the in vitro effectiveness of doxorubicin (Dox) delivered into three different tumor cell lines by sonoporation. Sonoporation increased the Dox autofluorescence signal and resulted in a subsequent decrease in cell viability. Next, we verified the antitumor effects of Dox in vivo using MXH10/Mo-lpr/lpr mice that exhibit systemic lymphadenopathy, with some peripheral LNs reaching 10 mm in diameter. We defined the subiliac LN (SiLN) as the upstream LN within the dissection area, and the proper axillary LN (PALN) as the downstream LN outside the dissection area. Dox and NMBs were injected into the SiLN and delivered to the PALN via lymphatic vessels; the PALN was then exposed to US when it had filled with solution. We found that sonoporation enhanced the intracellular uptake of Dox leading to high cytotoxicity. We also found that sonoporation induced extravasation of Dox from lymphatic endothelia and penetration of Dox into tumor tissues within the PALN. Furthermore, our method inhibited tumor growth and diminished blood vessels in the PALN while avoiding systemic toxic effects of Dox. Our findings indicate that a lymphatic drug delivery system with sonoporation represents a promising method for treating metastatic LNs located outside the dissection area. PMID- 26640590 TI - MiR-182 Is Associated with Growth, Migration and Invasion in Prostate Cancer via Suppression of FOXO1. AB - BACKGROUND: MicroRNA (miRNA) have been shown to regulate gene expression in many cancers. MiR-182 has recently been found to be prognostic for patients treated with radical prostatectomy for prostate cancer. We sought to assess miR-182 as a prognostic marker and understand its role in prostate cancer progression and metastasis. METHODS: We analysed miR-182 expression among 147 men treated for prostate cancer using biochemical recurrence and metastasis as the endpoints. We examined miR-182 expression in prostate cancer cells and created cell lines that overexpressed miR-182 for functional assays. Finally, we examined pathways through which miR-182 may function using prediction algorithms and confirmed by Western blotting and knock-down assays. RESULTS: We found that miR-182 was not associated with biochemical recurrence (p=0.1111) or metastasis (p=0.9268) following radical prostatectomy. However, in mechanistic assays, we found that miR-182 expression was higher among aggressive prostate cancer cells and that ectopic miR-182 expression resulted in increased proliferation, migration and invasion in vitro. We identified FOXO1 as regulated by miR-182 in prostate cancer cells, confirmed that ectopic miR-182 expression resulted in diminished FOXO1 levels, and showed that miR-182 inhibition results in increased FOXO1 levels. Expression of FOXO1 (p=0.0014) in tumors from patients who developed biochemical recurrence compared to tumors from patients who were recurrence-free five years after their radical prostatectomy. CONCLUSIONS: Our findings suggest that miR-182 may act to increase prostate cancer proliferation, migration and invasion through suppression of FOXO1. This may be valuable in the development of further therapeutic interventions. PMID- 26640591 TI - Comprehensive Two- and Three-Dimensional RNAi Screening Identifies PI3K Inhibition as a Complement to MEK Inhibitor AS703026 for Combination Treatment of Triple-Negative Breast Cancer. AB - Triple-negative breast cancer (TNBC) is a major cause of death among breast cancer patients that results from intrinsic and acquired resistance to systemic chemotherapies. To identify novel targets for effective treatment of TNBC through combination strategies with MEK inhibitor (AS703026), we used a novel method of combining high-throughput two- and three-dimensional (2D and 3D) RNAi screening. TNBC cells were transfected with a kinome siRNA library comprising siRNA targeting 790 kinases under both 2D and 3D culture conditions with or without AS703026. Molecule activity predictor analysis revealed the PI3K pathway as the major target pathway in our RNAi combination studies in TNBC. We found that PI3K inhibitor SAR245409 (also called XL765) combined with AS703026 synergistically inhibited proliferation compared with either drug alone (P < 0.001). Reduced in vitro colony formation (P < 0.001) and migration and invasion ability were also observed with the combination treatment (P<0.01). Our data suggest that SAR245409 combined with AS703026 may be effective in patients with TNBC. We conclude that a novel powerful high-throughput RNAi assays were able to identify anti-cancer drugs as single or combinational agents. Integrated and multi-system RNAi screening methods can complement difference between in vitro and in vivo culture conditions, and enriches targets that are close to the in vivo condition. PMID- 26640592 TI - PLX4032 Mediated Melanoma Associated Antigen Potentiation in Patient Derived Primary Melanoma Cells. AB - Over expression of various immunogenic melanoma associated antigens (MAAs) has been exploited in the development of immunotherapeutic melanoma vaccines. Expression of MAAs such as MART-1 and gp100 is modulated by the MAPK signaling pathway, which is often deregulated in melanoma. The protein BRAF, a member of the MAPK pathway, is mutated in over 60% of melanomas providing an opportunity for the identification and approval by the FDA of a small molecule MAPK signaling inhibitor PLX4032 that functions to inactivate mutant BRAF(V600E). To this end, we characterized five patient derived primary melanoma cell lines with respect to treatment with PLX4032. Cells were treated with 5MUM PLX4032 and harvested. Western blotting analysis, RT-PCR and in vitro transwell migration and invasion assays were utilized to determine treatment effects. PLX4032 treatment modulated phosphorylation of signaling proteins belonging to the MAPK pathway including BRAF, MEK, and ERK and abrogated cell phenotypic characteristics such as migration and invasion. Most significantly, PLX4032 led to an up regulation of many MAA proteins in three of the four BRAF mutated cell lines, as determined at the protein and RNA level. Interestingly, MAGE-A1 protein and mRNA levels were reduced upon PLX4032 treatment in two of the primary lines. Taken together, our findings suggest that the BRAF(V600E) inhibitor PLX4032 has therapeutic potential over and above its known target and in combination with specific melanoma targeting vaccine strategies may have further clinical utility. PMID- 26640593 TI - Low Dose, Low Cost Estradiol Pellets Can Support MCF-7 Tumour Growth in Nude Mice without Bladder Symptoms. AB - MCF-7 cells are a slow growing estrogen receptor (ER) positive human breast cancer cell line that is commonly used to model estrogen responsive breast cancer cell growth in-vitro and tumour growth in-vivo. These tumours require estrogen supplementation, and in-vivo doses of between 0.72mg and 2mg estradiol pellets are commonly implanted in the dorsal flank of ovariectomised, immunocompromised mice. We wanted to grow MCF-7 tumours in immunocompromised mice without the need to be ovariectomised. When we treated immunocompromised mice with 0.72mg pellets to induce MCF7 tumour growth, the mice developed urosepsis. We have now shown that lower doses of estradiol pellets, 0.3mg and 0.5mg, induce elevated serum estrogen levels and maintain tumour growth, without causing urosepsis. Supplementation for only one week did not support sustained MCF7 tumour growth. In conclusion, 0.3mg and 0.5mg silastic pellets can be used to stimulate ER+ breast cancer growth in ovary-intact, immune compromised mice. PMID- 26640594 TI - Knockdown of hTERT and Treatment with BIBR1532 Inhibit Cell Proliferation and Invasion in Endometrial Cancer Cells. AB - Telomerase activity and expression of the catalytic protein hTERT are associated with cell proliferation and advanced stage in endometrial cancer. Our objective was to evaluate the effect of inhibition of hTERT by siRNA and BIBR1532 on cell growth, apoptosis and invasion in endometrial cancer cells. Knockdown of hTERT or treatment of the cells with BIBR1532 decreased telomerase activity, inhibited cell proliferation, induced apoptosis, and reduced cell invasion in Ishikawa and ECC-1 cells. Either hTERT siRNA or BIBR1532 in combination with paclitaxel promoted a synergistic inhibitory effect on cell growth through induction of Annexin V expression and a remarkable reduction in cell invasion through reduction of protein expression of MMP9, MMP2, and MMP3. Increased telomerase activity and hTERT protein expression by transfections enhanced the protein expression of MMPs and increased the cell invasion ability. BIBR1532 significantly antagonized cell invasion induced by increased hTERT expression. These findings suggest that telomerase and hTERT facilitate cell invasion via MMP family in human endometrial cancer cells. PMID- 26640595 TI - Identification of Regulatory-RNAs for Alternative Splicing of Ron Proto-Oncogene. AB - RON receptor tyrosine kinase is a proto-oncogene that induces cell migration and matrix invasion. RONDelta160 protein, which is produced by exclusion of exon 5 and 6, promotes cell migration, matrix invasion and protection from apoptosis. Alternative splicing regulation of exon 5 and 6 is not well understood. In this manuscript, we identified several new RNA regulatory elements for alternative splicing of Ron proto-oncogene. Firstly, we demonstrated that RNA sequences from EcoRI cleavage sites regulate alternative splicing of Ron exon 5 and 6. Secondly, we showed that the ~30 nt RNA at upstream end of exon 4 and the ~33 nt RNA at downstream end of exon 7 also modulate splicing of exon 5 and 6. Thirdly, our results indicate that the RNA sequences of the ends in exon 4 and 7 are required for the regulatory functions of the RNA from restriction enzyme cleavage sites. Our results provide a new insight for regulation of alternative splicing of Ron proto-oncogene. PMID- 26640596 TI - Expression and Transport of alpha-Synuclein at the Blood-Cerebrospinal Fluid Barrier and Effects of Manganese Exposure. AB - The choroid plexus maintains the homeostasis of critical molecules in the brain by regulating their transport between the blood and cerebrospinal fluid (CSF). The current study was designed to investigate the potential role of the blood-CSF barrier (BCSFB) in alpha-synuclein (a-Syn) transport in the brain as affected by exposure to manganese (Mn), the toxic metal implicated in Parkinsonian disorders. Immunohistochemistry was used to identify intracellular a-Syn expression at the BCSFB. Quantitative real-time PCR was used to quantify the change in a-Syn mRNA expression following Mn treatments at the BCSFB in vitro. ELISA was used to quantify a-Syn levels following in vivo and in vitro treatments of Mn, copper (Cu), and/or external a-Syn. Thioflavin-T assay was used to investigate a-Syn aggregation after incubating with Mn and/or Cu in vitro. A two-chamber Transwell system was used to study a-Syn transport by BCSFB monolayer. Data revealed the expression of endogenous a-Syn in rat choroid plexus tissue and immortalized choroidal epithelial Z310 cells. The cultured primary choroidal epithelia from rats showed the ability to take up a-Syn from extracellular medium and transport a-Syn across the cellular monolayer from the donor to receiver chamber. Exposure of cells with Mn induced intracellular a-Syn accumulation without causing any significant changes in a-Syn mRNA expression. A significant increase in a-Syn aggregation in a cell-free system was observed with the presence of Mn. Moreover, Mn exposure resulted in a significant uptake of a-Syn by primary cells. These data indicate that the BCSFB expresses a-Syn endogenously and is capable of transporting a-Syn across the BCSFB monolayer; Mn exposure apparently increases a Syn accumulation in the BCSFB by facilitating its uptake and intracellular aggregation. PMID- 26640597 TI - An efficient protocol for Agrobacterium-mediated transformation of the biofuel plant Jatropha curcas by optimizing kanamycin concentration and duration of delayed selection. AB - Jatropha curcas is considered a potential biodiesel feedstock crop. Currently, the value of J. curcas is limited because its seed yield is generally low. Transgenic modification is a promising approach to improve the seed yield of J. curcas. Although Agrobacterium-mediated genetic transformation of J. curcas has been pursued for several years, the transformation efficiency remains unsatisfying. Therefore, a highly efficient and simple Agrobacterium-mediated genetic transformation method for J. curcas should be developed. We examined and optimized several key factors that affect genetic transformation of J. curcas in this study. The results showed that the EHA105 strain was superior to the other three Agrobacterium tumefaciens strains for infecting J. curcas cotyledons, and the supplementation of 100 mM acetosyringone slightly increased the transient transformation frequency. Use of the appropriate inoculation method, optimal kanamycin concentration and appropriate duration of delayed selection also improved the efficiency of stable genetic transformation of J. curcas. The percentage of beta-glucuronidase positive J. curcas shoots reached as high as 56.0 %, and 1.70 transformants per explant were obtained with this protocol. Furthermore, we optimized the root-inducing medium to achieve a rooting rate of 84.9 %. Stable integration of the T-DNA into the genomes of putative transgenic lines was confirmed by PCR and Southern blot analysis. Using this improved protocol, a large number of transgenic J. curcas plantlets can be routinely obtained within approximately 4 months. The detailed information provided here for each step of J. curcas transformation should enable successful implementation of this transgenic technology in other laboratories. PMID- 26640598 TI - Haptotaxis is cell type specific and limited by substrate adhesiveness. AB - Motile cells navigate through tissue by relying on tactile cues from gradients provided by extracellular matrix (ECM) such as ligand density or stiffness. Mesenchymal stem cells (MSCs) and fibroblasts encounter adhesive or 'haptotactic' gradients at the interface between healthy and fibrotic tissue as they migrate towards an injury site. Mimicking this phenomenon, we developed tunable RGD and collagen gradients in polyacrylamide hydrogels of physiologically relevant stiffness using density gradient multilayer polymerization (DGMP) to better understand how such ligand gradients regulate migratory behaviors. Independent of ligand composition and fiber deformation, haptotaxis was observed in mouse 3T3 fibroblasts. Human MSCs however, haptotaxed only when cell-substrate adhesion was indirectly reduced via addition of free soluble matrix ligand mimetic peptides. Under basal conditions, MSCs were more contractile than fibroblasts. However, the presence of soluble adhesive peptides reduced MSC-induced substrate deformations; increased contractility may contribute to limited migration, but modulating cytoskeletal assembly was ineffective at promoting MSC haptotaxis. When introduced to gradients of increased absolute ligand concentrations, 3T3s displayed increased contractility and no longer haptotaxed. These data suggest that haptotactic behaviors are limited by adhesion and that although both cell types may home to tissue to aid in repair, fibroblasts may be more responsive to ligand gradients than MSCs. PMID- 26640599 TI - Critical behavior of subcellular density organization during neutrophil activation and migration. AB - Physical theories of active matter continue to provide a quantitative understanding of dynamic cellular phenomena, including cell locomotion. Although various investigations of the rheology of cells have identified important viscoelastic and traction force parameters for use in these theoretical approaches, a key variable has remained elusive both in theoretical and experimental approaches: the spatiotemporal behavior of the subcellular density. The evolution of the subcellular density has been qualitatively observed for decades as it provides the source of image contrast in label-free imaging modalities (e.g., differential interference contrast, phase contrast) used to investigate cellular specimens. While these modalities directly visualize cell structure, they do not provide quantitative access to the structures being visualized. We present an established quantitative imaging approach, non interferometric quantitative phase microscopy, to elucidate the subcellular density dynamics in neutrophils undergoing chemokinesis following uniform bacterial peptide stimulation. Through this approach, we identify a power law dependence of the neutrophil mean density on time with a critical point, suggesting a critical density is required for motility on 2D substrates. Next we elucidate a continuum law relating mean cell density, area, and total mass that is conserved during neutrophil polarization and migration. Together, our approach and quantitative findings will enable investigators to define the physics coupling cytoskeletal dynamics with subcellular density dynamics during cell migration. PMID- 26640600 TI - New developments in the pathology of malignant lymphoma: a review of the literature published from May 2015-September 2015. PMID- 26640601 TI - Random Effects Model for Multiple Pathway Analysis with Applications to Type II Diabetes Microarray Data. AB - Close to three percent of the world's population suffer from diabetes. Despite the range of treatment options available for diabetes patients, not all patients benefit from them. Investigating how different pathways correlate with phenotype of interest may help unravel novel drug targets and discover a possible cure. Many pathway-based methods have been developed to incorporate biological knowledge into the study of microarray data. Most of these methods can only analyze individual pathways but cannot deal with two or more pathways in a model based framework. This represents a serious limitation because, like genes, individual pathways do not work in isolation, and joint modeling may enable researchers to uncover patterns not seen in individual pathway-based analysis. In this paper, we propose a random effects model to analyze two or more pathways. We also derive score test statistics for significance of pathway effects. We apply our method to a microarray study of Type II diabetes. Our method may eludicate how pathways crosstalk with each other and facilitate the investigation of pathway crosstalks. Further hypothesis on the biological mechanisms underlying the disease and traits of interest may be generated and tested based on this method. PMID- 26640602 TI - An Adaptive Genetic Association Test Using Double Kernel Machines. AB - Recently, gene set-based approaches have become very popular in gene expression profiling studies for assessing how genetic variants are related to disease outcomes. Since most genes are not differentially expressed, existing pathway tests considering all genes within a pathway suffer from considerable noise and power loss. Moreover, for a differentially expressed pathway, it is of interest to select important genes that drive the effect of the pathway. In this article, we propose an adaptive association test using double kernel machines (DKM), which can both select important genes within the pathway as well as test for the overall genetic pathway effect. This DKM procedure first uses the garrote kernel machines (GKM) test for the purposes of subset selection and then the least squares kernel machine (LSKM) test for testing the effect of the subset of genes. An appealing feature of the kernel machine framework is that it can provide a flexible and unified method for multi-dimensional modeling of the genetic pathway effect allowing for both parametric and nonparametric components. This DKM approach is illustrated with application to simulated data as well as to data from a neuroimaging genetics study. PMID- 26640603 TI - Performance assessment of Pulse Wave Imaging using conventional ultrasound in canine aortas ex vivo and normal human arteries in vivo. AB - The propagation behavior of the arterial pulse wave may provide valuable diagnostic information for cardiovascular pathology. Pulse Wave Imaging (PWI) is a noninvasive, ultrasound imaging-based technique capable of mapping multiple wall motion waveforms along a short arterial segment over a single cardiac cycle, allowing for the regional pulse wave velocity (PWV) and propagation uniformity to be evaluated. The purpose of this study was to improve the clinical utility of PWI using a conventional ultrasound system. The tradeoff between PWI spatial and temporal resolution was evaluated using an ex vivo canine aorta (n = 2) setup to assess the effects of varying image acquisition and signal processing parameters on the measurement of the PWV and the pulse wave propagation uniformity r2. PWI was also performed on the carotid arteries and abdominal aortas of 10 healthy volunteers (24.8 +/- 3.3 y.o.) to determine the waveform tracking feature that would yield the most precise PWV measurements and highest r2 values in vivo. The ex vivo results indicated that the highest precision for measuring PWVs ~ 2.5 - 3.5 m/s was achieved using 24-48 scan lines within a 38 mm image plane width (i.e. 0.63 - 1.26 lines/mm). The in vivo results indicated that tracking the 50% upstroke of the waveform would consistently yield the most precise PWV measurements and minimize the error in the propagation uniformity measurement. Such findings may help establish the optimal image acquisition and signal processing parameters that may improve the reliability of PWI as a clinical measurement tool. PMID- 26640604 TI - The Natural Emergence of (Bio)Semiosic Phenomena. AB - Biological organisms appear to have agency, goals, and meaningful behaviour. One possibility is that this is mere appearance, where such properties are not real, but only 'as if' consequences of the physiological structure of organisms. Another possibility is that these properties are real, as emerging from the organism's structure and from how the organism interacts with its environment. Here I will discuss a recent theory showing that the latter position is most likely correct, and argue that the theory is largely consistent with the basics of the field of biosemiotics. The theory can be represented as a triad that resembles the semiotic triad proposed by Peirce, which connects a sign with its object through a process of interpretation. In the theory presented, the sign is an internalized version of fitness (i.e., expected reproductive rate) which refers to the true fitness through a feedback loop that in effect produces interpretation. The feedback loop entangles deterministic and stochastic forms of causation in such a way that genuine agency, goal-directedness, and their associated meaning emerge. It produces a strong form of emergence not reducible to its constituents. The result is that novel phenomena arise that are real and necessary components for a complete understanding of living organisms. PMID- 26640605 TI - DNA Dispose, but Subjects Decide. Learning and the Extended Synthesis. AB - Adaptation by means of natural selection depends on the ability of populations to maintain variation in heritable traits. According to the Modern Synthesis this variation is sustained by mutations and genetic drift. Epigenetics, evodevo, niche construction and cultural factors have more recently been shown to contribute to heritable variation, however, leading an increasing number of biologists to call for an extended view of speciation and evolution. An additional common feature across the animal kingdom is learning, defined as the ability to change behavior according to novel experiences or skills. Learning constitutes an additional source for phenotypic variation, and change in behavior may induce long lasting shifts in fitness, and hence favor evolutionary novelties. Based on published studies, I demonstrate how learning about food, mate choice and habitats has contributed substantially to speciation in the canonical story of Darwin's finches on the Galapagos Islands. Learning cannot be reduced to genetics, because it demands decisions, which requires a subject. Evolutionary novelties may hence emerge both from shifts in allelic frequencies and from shifts in learned, subject driven behavior. The existence of two principally different sources of variation also prevents the Modern Synthesis from self-referring explanations. PMID- 26640606 TI - Virus is a Signal for the Host Cell. AB - Currently, the concept of the cell as a society or an ecosystem of molecular elements is gaining increasing acceptance. The basic idea arose in the 19th century, from the surmise that there is not just a single unit underlying an individual's appearance, but a plurality of entities with both collaborative and conflicting relationships. The following hypothesis is based around this model. The incompatible activities taking place between different original elements, which were subsumed into the first cell and could not be eliminated, had to be controlled very closely. Similarly, a strong level of control had to be developed over many cellular elements after the cell changed its genome to DNA. We assume that at least some of those original RNA agents and other biomolecules which carry incompatibilities and risks, are retained within current cells, although they are now under strict control. A virus functions as a signal informing these repressed cellular RNAs and other elements of ancient origin how to restore suppressed degrees of molecular freedom, favoring pre-existing molecular affinities and activities, re-establishing ancient molecular webs of interactions, and giving fragments of ancient coded information (mostly in the form of RNA structural motifs) the opportunity to be re-expressed. Collectively, these newly activated mechanisms lead to different possibilities for pathological cell states. All these processes are opposed by cell-control mechanisms. Thus, in this new scenario, the battle is considered intracellular rather than between the virus and the cell. And so the virus is treated as the signal that precipitates the cell's change from a latent to an active pathological state. PMID- 26640607 TI - A multiplex microsatellite set for non-invasive genotyping and sexing of the osprey (Pandion haliaetus). AB - During the 1950s and 1970s the osprey (Pandion haliaetus) experienced a dramatic population crash and remains of conservation concern in several parts of the world. We isolated 37 microsatellite loci and assessed these in ospreys sampled in the UK and Norway (using mouth swabs/feathers). From 26 loci variable in four ospreys, we selected 13, combined these into two multiplex-PCR sets and included a sex-typing marker. Additional markers confirmed sexes. In 17 ospreys, feather sampled in central Norway, we found 3-10 alleles per locus. The 13 loci are autosomal (heterozygotes were present in both sexes) and observed heterozygosities ranged from 0.24 to 0.94. The combined probability of identity for the 13 loci was 8.0 * 10-12. These microsatellite loci will be useful for genetic monitoring, parentage analysis and population genetic studies of the osprey. PMID- 26640608 TI - Cognitive Penetration and Predictive Coding: A Commentary on Lupyan. PMID- 26640609 TI - Immunogenicity in dogs and protection against visceral leishmaniasis induced by a 14kDa Leishmania infantum recombinant polypeptide. AB - In areas were human visceral leishmaniasis (VL) is endemic, the domestic dog is the main parasite reservoir in the infectious cycle of Leishmania infantum. Development of prophylactic strategies to lower the parasite burden in dogs would reduce sand fly transmission thus lowering the incidence of zoonotic VL. Here we demonstrate that vaccination of dogs with a recombinant 14kDa polypeptide of L. infantum nuclear transport factor 2 (Li-ntf2) mixed with adjuvant BpMPLA-SE resulted in the production of specific anti-Li-ntf2 IgG antibodies as well as IFN gamma release by the animals' peripheral blood mononuclear cells stimulated with the antigen. In addition, immunization with this single and small 14kDa poplypeptide resulted in protracted progression of the infection of the animals after challenging with a high dose of virulent L. infantum. Five months after challenge the parasite load was lower in the bone marrow of immunized dogs compared to non-immunized animals. The antibody response to K39, a marker of active VL, at ten months after challenge was strong and significantly higher in the control dogs than in vaccinated animals. At the study termination vaccinated animals showed significantly more liver granulomas and lymphoid hyperplasia than non-vaccinated animals, which are both histological markers of resistance to infection. Together, these results indicate that the 14kDa polypeptide is an attractive protective molecule that can be easily incorporated in a leishmanial polyprotein vaccine candidate to augment/complement the overall protective efficacy of the final product. PMID- 26640610 TI - Reasons to Use and Disclose Use of Complementary Medicine Use - An Insight from Cancer Patients. AB - Studies have shown a high prevalence (40-83%) of complementary and alternative medicine (CAM) use among cancer patients in the U.S.A cross-sectional, mixed methods pilot study was completed. This paper focuses on the quantitative analysis conducted on demographic predictors of complementary medicine (CM) use, reasons to use CM, and disclosure to healthcare provider data. Surveys were interview-administered at the Loma Linda University Medical Center Cancer Center. Participants, 18 years or older, were selected from a convenient sample. Eighty seven percent (87.9%) of participants reported to have used CM as a cancer treatment and most reported to have used it "to help fight the cancer." Women were eight-times more likely to use prayer. All non-Caucasian and Hispanic participants reported to use CM as a cancer therapy and none reported to use a CM provider. More women (72%) disclosed their CM use than men (53.3%). Different prevalences and predictors exist when differentiating CM modalities, reasons to use CM vary by gender, and disclosure proportions vary by gender. PMID- 26640611 TI - Role of the Charge-Transfer State in Reduced Langevin Recombination in Organic Solar Cells: A Theoretical Study. AB - Reduced Langevin recombination has been observed in organic solar cells (OSCs) for many years, but its origin is still unclear. A recent work by Burke et al. (Adv. Energy Mater.2015, 5, 1500123-1) was inspired by this reduced Langevin recombination, and they proposed an equilibrium model of charge-transfer (CT) states that correlates the open-circuit voltage of OSCs with experimentally available device parameters. In this work, we extend Burke et al.'s CT model further and for the first time directly correlate the reduced Langevin recombination with the energetic and dynamic behavior of the CT state. Recombination through CT states leads in a straightforward manner to a decrease in the Langevin reduction factor with increasing temperature, without explicit consideration of the temperature dependence of the mobility. To verify the correlation between the CT states and reduced Langevin recombination, we incorporated this CT model and the reduced Langevin model into drift-diffusion simulations of a bilayer OSC. The simulations not only successfully reproduced realistic current-voltage (J-V) characteristics of the bilayer OSC, but also demonstrate that the two models consistently lead to same value of the apparent Langevin reduction factor. PMID- 26640612 TI - Estrogen Replacement Reduces Oxidative Stress in the Rostral Ventrolateral Medulla of Ovariectomized Rats. AB - Cardiovascular disease prevalence rises rapidly after menopause, which is believed to be derived from the loss of estrogen. It is reported that sympathetic tone is increased in postmenopause. The high level of oxidative stress in the rostral ventrolateral medulla (RVLM) contributes to increased sympathetic outflow. The focus of this study was to determine if estrogen replacement reduces oxidative stress in the RVLM and sympathetic outflow in the ovariectomized (OVX) rats. The data of this study showed that OVX rat increased oxidative stress in the RVLM and sympathetic tone; estrogen replacement improved cardiovascular functions but also reduced the level of oxidative stress in the RVLM. These findings suggest that estrogen replacement decreases blood pressure and sympathoexcitation in the OVX rats, which may be associated with suppression in oxidative stress in the RVLM through downregulation of protein expression of NADPHase (NOX4) and upregulation of protein expression of SOD1. The data from this study is beneficial for our understanding of the mechanism of estrogen exerting cardiovascular protective effects on postmenopause. PMID- 26640613 TI - Markers of Antioxidant Defense in Patients with Type 2 Diabetes. AB - AIMS: Diabetes is considered a state of increased oxidative stress. This study evaluates blood concentrations of selected markers of antioxidant defense in patients with type 2 diabetes. METHODS: The study included 80 type 2 diabetes patients and 79 apparently healthy controls. Measured markers included ferric reducing ability of plasma (FRAP), reduced glutathione (GSH), glutathione peroxidase (GPx), glutathione reductase (GR), gamma-glutamyltransferase (GGT) and uric acid serum, and plasma and/or hemolysate levels. RESULTS: FRAP, uric acid, CRP, and GGT levels were significantly higher in patients with diabetes. Plasma and hemolysate GR was significantly higher whereas GPx activity was significantly lower in patients with diabetes. There were no significant differences in antioxidant defense markers between patients with and without chronic diabetes complications. Fasting serum glucose correlated with plasma GPx, plasma and hemolysate GR, FRAP, and serum GGT, and HbA1c correlated with serum GGT. Only FRAP and serum uric acid were significantly higher in obese (BMI > 30 kg/m(2)) patients with diabetes than in nonobese patients. CONCLUSIONS: Some components of antioxidant defense such as GR, uric acid, and GGT are increased in patients with type 2 diabetes. However, the whole system cannot compensate for an enhanced production of ROS as reflected by the trend toward decreased erythrocytes GSH. PMID- 26640614 TI - Redox Modulations, Antioxidants, and Neuropsychiatric Disorders. AB - Although antioxidants, redox modulations, and neuropsychiatric disorders have been widely studied for many years, the field would benefit from an integrative and corroborative review. Our primary objective is to delineate the biological significance of compounds that modulate our redox status (i.e., reactive species and antioxidants) as well as outline their current role in brain health and the impact of redox modulations on the severity of illnesses. Therefore, this review will not enter into the debate regarding the perceived medical legitimacy of antioxidants but rather seek to clarify their abilities and limitations. With this in mind, antioxidants may be interpreted as natural products with significant pharmacological actions in the body. A renewed understanding of these often overlooked compounds will allow us to critically appraise the current literature and provide an informed, novel perspective on an important healthcare issue. In this review, we will introduce the complex topics of redox modulations and their role in the development of select neuropsychiatric disorders. PMID- 26640615 TI - Curcumin Supplementation Decreases Intestinal Adiposity Accumulation, Serum Cholesterol Alterations, and Oxidative Stress in Ovariectomized Rats. AB - The aim of this study was to investigate the potential of curcumin oral supplementation (50 and 100 mg/Kg/day, for 30 days) in circumventing menopause associated oxidative stress and lipid profile dysfunctions in a rat ovariectomy (OVX) model. Female Wistar rats were operated and randomly divided into either sham-operated or OVX groups. Sham-operated group (n = 8) and one OVX group (n = 11) were treated with vehicle (refined olive oil), and the other two OVX groups received curcumin at 50 or 100 mg/Kg/day doses (n = 8/group). OVX vehicle-treated animals presented a higher deposition of intestinal adipose tissue as well as increased serum levels of IL-6, LDL, and total cholesterol when compared to sham operated rats. In addition, several oxidative stress markers in serum, blood, and liver (such as TBARS, carbonyl, reduced-sulphydryl, and nonenzymatic antioxidant defenses) were altered toward a prooxidant status by OVX. Interestingly, curcumin supplementation attenuated most of these parameters to sham comparable values. Thus, the herein presented results show that curcumin may be useful to ameliorate lipid metabolism alterations and oxidative damage associated with hormone deprivation in menopause. PMID- 26640617 TI - Induction of Expression of p75 Neurotrophin Receptor Intracellular Domain Does Not Induce Expression or Enhance Activity of Mitochondrial Complex II. AB - Fenretinide is a chemotherapeutic agent in clinical trials for the treatment of neuroblastoma, among the most common and most deadly cancers of childhood. Fenretinide induces apoptosis in neuroblastoma cells through accumulation of mitochondrial reactive oxygen species released from Complex II. The neurotrophin receptor, p75NTR, potentiates this effect. The signaling activity of p75NTR is dependent upon its cleavage to its intracellular domain, p75ICD, trafficking of p75ICD to the nucleus, and functioning of p75ICD as a transcription factor. Mitochondrial Complex II comprises 4 subunits, all of which are encoded by nuclear DNA. We therefore hypothesized that the fenretinide-potentiating effects of p75NTR are the result of transcriptional enrichment of Complex II by p75ICD. However, the present studies demonstrate that neither induced expression of p75ICD or its active fragments nor overexpression of p75NTR results in altered expression or activity of Complex II. PMID- 26640616 TI - Interaction of Hydrogen Sulfide with Nitric Oxide in the Cardiovascular System. AB - Historically acknowledged as toxic gases, hydrogen sulfide (H2S) and nitric oxide (NO) are now recognized as the predominant members of a new family of signaling molecules, "gasotransmitters" in mammals. While H2S is biosynthesized by three constitutively expressed enzymes (CBS, CSE, and 3-MST) from L-cysteine and homocysteine, NO is generated endogenously from L-arginine by the action of various isoforms of NOS. Both gases have been transpired as the key and independent regulators of many physiological functions in mammalian cardiovascular, nervous, gastrointestinal, respiratory, and immune systems. The analogy between these two gasotransmitters is evident not only from their paracrine mode of signaling, but also from the identical and/or shared signaling transduction pathways. With the plethora of research in the pathophysiological role of gasotransmitters in various systems, the existence of interplay between these gases is being widely accepted. Chemical interaction between NO and H2S may generate nitroxyl (HNO), which plays a specific effective role within the cardiovascular system. In this review article, we have attempted to provide current understanding of the individual and interactive roles of H2S and NO signaling in mammalian cardiovascular system, focusing particularly on heart contractility, cardioprotection, vascular tone, angiogenesis, and oxidative stress. PMID- 26640618 TI - Toll-Like Receptor 4 Reduces Oxidative Injury via Glutathione Activity in Sheep. AB - Toll-like receptor 4 (TLR4) is an important sensor of Gram-negative bacteria and can trigger activation of the innate immune system. Increased activation of TLR4 can lead to the induction of oxidative stress. Herein, the pathway whereby TLR4 affects antioxidant activity was studied. In TLR4-overexpressing sheep, TLR4 expression was found to be related to the integration copy number when monocytes were challenged with lipopolysaccharide (LPS). Consequently, production of malondialdehyde (MDA) was increased, which could increase the activation of prooxidative stress enzymes. Meanwhile, activation of an antioxidative enzyme, glutathione peroxidase (GSH-Px), was increased. Real-time PCR showed that expression of activating protein-1 (AP-1) and the antioxidative-related genes was increased. By contrast, the expression levels of superoxide dismutase 1 (SOD1) and catalase (CAT) were reduced. In transgenic sheep, glutathione (GSH) levels were dramatically reduced. Furthermore, transgenic sheep were intradermally injected with LPS in each ear. The amounts of inflammatory infiltrates were correlated with the number of TLR4 copies that were integrated in the genome. Additionally, the translation of gamma-glutamylcysteine synthetase (gamma-GCS) was increased. Our findings indicated that overexpression of TLR4 in sheep could ameliorate oxidative injury through GSH secretion that was induced by LPS stimulation. Furthermore, TLR4 promoted gamma-GCS translation through the AP-1 pathway, which was essential for GSH synthesis. PMID- 26640619 TI - PAN-811 Blocks Chemotherapy Drug-Induced In Vitro Neurotoxicity, While Not Affecting Suppression of Cancer Cell Growth. AB - Chemotherapy often results in cognitive impairment, and no neuroprotective drug is now available. This study aimed to understand underlying neurotoxicological mechanisms of anticancer drugs and to evaluate neuroprotective effects of PAN 811. Primary neurons in different concentrations of antioxidants (AOs) were insulted for 3 days with methotrexate (MTX), 5-fluorouracil (5-FU), or cisplatin (CDDP) in the absence or presence of PAN-811.Cl.H2O. The effect of PAN-811 on the anticancer activity of tested drugs was also examined using mouse and human cancer cells (BNLT3 and H460) to assess any negative interference. Cell membrane integrity, survival, and death and intramitochondrial reactive oxygen species (ROS) were measured. All tested anticancer drugs elicited neurotoxicity only under low levels of AO and elicited a ROS increase. These results suggested that ROS mediates neurotoxicity of tested anticancer drugs. PAN-811 dose-dependently suppressed increased ROS and blocked the neurotoxicity when neurons were insulted with a tested anticancer drug. PAN-811 did not interfere with anticancer activity of anticancer drugs against BNLT3 cells. PAN-811 did not inhibit MTX-induced death of H460 cells but, interestingly, demonstrated a synergistic effect with 5 FU or CDDP in reducing cancer cell viability. Thus, PAN-811 can be a potent drug candidate for chemotherapy-induced cognitive impairment. PMID- 26640621 TI - Polymeric vs hydroxyapatite-based scaffolds on dental pulp stem cell proliferation and differentiation. AB - AIM: To evaluate adhesion, proliferation and differentiation of human dental pulp stem cells (hDPSCs) on four commercially available scaffold biomaterials. METHODS: hDPSCs were isolated from human dental pulp tissues of extracted wisdom teeth and established in stem cell growth medium. hDPSCs at passage 3-5 were seeded on four commercially available scaffold biomaterials, SureOss (Allograft), Cerabone (Xenograft), PLLA (Synthetic), and OSTEON II Collagen (Composite), for 7 and 14 d in osteogenic medium. Cell adhesion and morphology to the scaffolds were evaluated by scanning electron microscopy (SEM). Cell proliferation and differentiation into osteogenic lineage were evaluated using DNA counting and alkaline phosphatase (ALP) activity assay, respectively. RESULTS: All scaffold biomaterials except SureOss (Allograft) supported hDPSC adhesion, proliferation and differentiation. hDPSCs seeded on PLLA (Synthetic) scaffold showed the highest cell proliferation and attachment as indicated with both SEM and DNA counting assay. Evaluating the osteogenic differentiation capability of hDPSCs on different scaffold biomaterials with ALP activity assay showed high level of ALP activity on cells cultured on PLLA (Synthetic) and OSTEON II Collagen (Composite) scaffolds. SEM micrographs also showed that in the presence of Cerabone (Xenograft) and OSTEON II Collagen (Composite) scaffolds, the hDPSCs demonstrated the fibroblastic phenotype with several cytoplasmic extension, while the cells on PLLA scaffold showed the osteoblastic-like morphology, round-like shape. CONCLUSION: PLLA scaffold supports adhesion, proliferation and osteogenic differentiation of hDPSCs. Hence, it may be useful in combination with hDPSCs for cell-based reconstructive therapy. PMID- 26640620 TI - Dedifferentiated fat cells: A cell source for regenerative medicine. AB - The identification of an ideal cell source for tissue regeneration remains a challenge in the stem cell field. The ability of progeny cells to differentiate into other cell types is important for the processes of tissue reconstruction and tissue engineering and has clinical, biochemical or molecular implications. The adaptation of stem cells from adipose tissue for use in regenerative medicine has created a new role for adipocytes. Mature adipocytes can easily be isolated from adipose cell suspensions and allowed to dedifferentiate into lipid-free multipotent cells, referred to as dedifferentiated fat (DFAT) cells. Compared to other adult stem cells, the DFAT cells have unique advantages in their abundance, ease of isolation and homogeneity. Under proper condition in vitro and in vivo, the DFAT cells have exhibited adipogenic, osteogenic, chondrogenic, cardiomyogenc, angiogenic, myogenic, and neurogenic potentials. In this review, we first discuss the phenomena of dedifferentiation and transdifferentiation of cells, and then dedifferentiation of adipocytes in particular. Understanding the dedifferentiation process itself may contribute to our knowledge of normal growth processes, as well as mechanisms of disease. Second, we highlight new developments in DFAT cell culture and summarize the current understanding of DFAT cell properties. The unique features of DFAT cells are promising for clinical applications such as tissue regeneration. PMID- 26640622 TI - Head Movement Dynamics During Play and Perturbed Mother-Infant Interaction. AB - We investigated the dynamics of head movement in mothers and infants during an age-appropriate, well-validated emotion induction, the Still Face paradigm. In this paradigm, mothers and infants play normally for 2 minutes (Play) followed by 2 minutes in which the mothers remain unresponsive (Still Face), and then two minutes in which they resume normal behavior (Reunion). Participants were 42 ethnically diverse 4-month-old infants and their mothers. Mother and infant angular displacement and angular velocity were measured using the CSIRO head tracker. In male but not female infants, angular displacement increased from Play to Still-Face and decreased from Still Face to Reunion. Infant angular velocity was higher during Still-Face than Reunion with no differences between male and female infants. Windowed cross-correlation suggested changes in how infant and mother head movements are associated, revealing dramatic changes in direction of association. Coordination between mother and infant head movement velocity was greater during Play compared with Reunion. Together, these findings suggest that angular displacement, angular velocity and their coordination between mothers and infants are strongly related to age-appropriate emotion challenge. Attention to head movement can deepen our understanding of emotion communication. PMID- 26640623 TI - Osseous Defects Seen in Patients with Anterior Shoulder Instability. AB - Shoulder surgeons need to be aware of the critical size of the glenoid or humeral osseous defects seen in patients with anterior shoulder instability, since the considerable size of osseous defect is reported to cause postoperative instability. Biomechanical studies have identified the size of the osseous defect which affects stability. Since engagement always occurs between a Hill-Sachs lesion and the glenoid rim, when considering the critical size of the Hill-Sachs lesion, we have to simultaneously consider the size of the glenoid osseous defect. With the newly developed concept of the glenoid track, we are able to evaluate whether a large Hill-Sachs lesion is an "on-track" or "off-track" lesion, and to consider both osseous defects together. In case of an off-track Hill-Sachs lesion, if the glenoid defect is less than 25%, no treatment is required. In this case, the Latarjet procedure or arthroscopic remplissage procedure can be a treatment option. However, if the glenoid defect is more than 25%, treatment such as bone grafting is required. This will convert an off-track lesion to an on-track lesion. After the bone graft or Latarjet procedure, if the Hill-Sachs lesion persists as off-track, then further treatment is necessitated. In case with an on-track Hill-Sachs lesion and a less than 25% glenoid defect, arthroscopic Bankart repair alone is enough. PMID- 26640624 TI - Carpometacarpal Joint Fracture Dislocation of Second to Fifth Finger. AB - BACKGROUND: Carpometacarpal joint fracture dislocation of the second to fifth finger is a rare hand injury associated with high energy trauma. Due to severe swelling and overlapping of bones on the radiograph of wrist-hand, dislocations are missed. We reported a series of six patients with rare carpometacarpal joint fracture dislocation treated with open reduction. METHODS: We retrospectively studied six cases of carpometacarpal joint fracture dislocation. All patients were treated with open reduction and internal fixation with Kirschner wire. Functional assessment was done with Quick Disabilities of the Arm, Shoulder and Hand score (Quick DASH score) at regular intervals. RESULTS: Average Quick DASH score was improved from 75.76 to 1.9 from 6 weeks to 18 months of duration. Of the six patients, three patients had a Quick DASH score of 0 at the end of 18 months. CONCLUSIONS: Careful hand examination and radiographic assessment is necessary to avoid missed diagnosis of carpometacarpal joint fracture dislocation. Early open reduction and internal fixation lead to excellent recovery of hand function. PMID- 26640625 TI - Calcar Preservation Arthroplasty for Unstable Intertrochanteric Femoral Fractures in Elderly. AB - BACKGROUND: The treatment of unstable intertrochanteric fractures in elderly is still controversial. The purpose of this study is to present treatment strategies for unstable intertrochanteric fractures with hemiarthroplasty using standard uncemented collared femoral stems and at the same time preserving the fractured calcar fragment. METHODS: Fifty-four patients aged 75 years or older with unstable intertrochanteric fractures were included in this prospective cohort study. All patients were treated with calcar preserving hemiarthroplasty using cementless collored femoral stems. Fractured calcar fragment was stabilized either by compaction between the implant and femur or fixed with cable grip system. Follow-up evaluations were performed at least 24 months and later. Palmer and Parker mobility score and visual analogue scale (VAS) pain score were assessed. We also analyzed radiographs of the operated hip at each follow-up visit. RESULTS: The patients were 15 males and 39 females with a mean age of 81.3 years (range, 75 to 93 years). The average operative time was 86.6 minutes. The mean transfused blood units were 1.2 units. The average duration of hospital stay was 5.3 days. The preoperative mean mobility score was 6.20. This score was found to be 4.96 on postoperative third day and 5.90 at 24 months postoperatively. The results of the statistical analysis revealed significant increase in the mobility scores at each follow-up after three days. Radiological interpretation revealed no loosening in the cable-grip systems, and no significant subsidence (> 5 mm) of prosthesis was observed. CONCLUSIONS: Calcar preservation arthroplasty is a good option for elderly patients with severe osteoporosis, frail constitution and the patients who are at higher risk for second operation due to unstable intertrochanteric fractures. PMID- 26640626 TI - Usefulness of Arthroscopic Treatment of Painful Hip after Acetabular Fracture or Hip Dislocation. AB - BACKGROUND: Painful hip following hip dislocation or acetabular fracture can be an important signal for early degeneration and progression to osteoarthritis due to intraarticular pathology. However, there is limited literature discussing the use of arthroscopy for the treatment of painful hip. The purpose of this retrospective study was to analyze the effectiveness and benefit of arthroscopic treatment for patients with a painful hip after major trauma. METHODS: From July 2003 to February 2013, we reviewed 13 patients who underwent arthroscopic treatment after acetabular fracture or hip dislocation and were followed up for a minimum of 2 postoperative years. The degree of osteoarthritis based on the Tonnis classification pre- and postoperatively at final follow-up was determined. Clinical outcomes were evaluated using visual analogue scale for pain (VAS) and modified Harris hip score (MHHS), and range of motion (ROM) of the hip pre- and postoperatively at final follow-up. RESULTS: There were nine male and four female patients with a mean age at surgery of 28 years (range, 20 to 50 years). The mean follow-up period of the patients was 59.8 months (range, 24 to 115 months), and the mean interval between initial trauma and arthroscopic treatment was 40.8 months (range, 1 to 144 months). At the final follow-up, VAS and MHHS improved significantly from 6.3 and 53.4 to 3.0 and 88.3, respectively (p = 0.002 and p < 0.001, respectively). However, there were no significant differences in hip flexion, abduction, adduction, external rotation, and internal rotation as minor improvements from 113.1 degrees , 38.5 degrees , 28.5 degrees , 36.5 degrees , and 22.7 degrees to 118.5 degrees , 39.0 degrees , 29.2 degrees , 38.9 degrees , and 26.5 degrees were observed, respectively (p = 0.070, p = 0.414, p = 0.317, p = 0.084, and p = 0.136, respectively). None of the patients exhibited progression of osteoarthritis of the hip at the final follow-up. CONCLUSIONS: Arthroscopic treatment after acetabular fracture or hip dislocation is effective and delays the progression of traumatic osteoarthritis. PMID- 26640627 TI - Analyzing the History of Falls in Patients with Severe Knee Osteoarthritis. AB - BACKGROUND: One out of three adults over the age of 65 years and one out of two over the age of 80 falls annually. Fall risk increases for older adults with severe knee osteoarthritis, a matter that should be further researched. The main purpose of this study was to investigate the history of falls including frequency, mechanism and location of falls, activity during falling and injuries sustained from falls examining at the same time their physical status. The secondary purpose was to determine the effect of age, gender, chronic diseases, social environment, pain elsewhere in the body and components of health related quality of life such as pain, stiffness, physical function, and dynamic stability on falls frequency in older adults aged 65 years and older with severe knee osteoarthritis. METHODS: An observational longitudinal study was conducted on 68 patients (11 males and 57 females) scheduled for total knee replacement due to severe knee osteoarthritis (grade 3 or 4) and knee pain lasting at least one year or more. Patients were personally interviewed for fall history and asked to complete self-administered questionnaires, such as the 36-item Short Form Health Survey (SF-36) and the Western Ontario and McMaster Universities Arthritis Index (WOMAC), and physical performance test was performed. RESULTS: The frequency of falls was 63.2% for the past year. The majority of falls took place during walking (89.23%). The main cause of falling was stumbling (41.54%). There was a high rate of injurious falling (29.3%). The time patients needed to complete the physical performance test implied the presence of disability and frailty. The high rates of fall risk, the high disability levels, and the low quality of life were confirmed by questionnaires and the mobility test. CONCLUSIONS: Patients with severe knee osteoarthritis were at greater risk of falling, as compared to healthy older adults. Pain, stiffness, limited physical ability, reduced muscle strength, all consequences of severe knee osteoarthritis, restricted patient's quality of life and increased the fall risk. Therefore, patients with severe knee osteoarthritis should not postpone having total knee replacement, since it was clear that they would face more complicated matters when combining with fractures other serious injuries and disability. PMID- 26640628 TI - Medial Patellofemoral Ligament Reconstruction for Recurrent Patellar Instability Using a Gracilis Autograft without Bone Tunnel. AB - BACKGROUND: Several tendon graft and fixation methods have been introduced in medial patellofemoral ligament (MPFL) reconstruction for recurrent patellar dislocation. The purpose of this study was to evaluate the results of MPFL reconstruction using a gracilis autograft fixation without bone tunnel in patients with recurrent patellar instability. METHODS: Nine patients (four males and five females) diagnosed with recurrent patellar instability from July 2009 to January 2013 and had MPFL reconstruction using a gracilis autograft were included. The average age of the patients was 24.6 years (range, 13 to 48 years), and the average follow-up period was 19.3 months (range, 12 to 30 months). For every patient, femoral attachment was fixed using suture anchors securing the patella by suturing the periosteum and surrounding soft tissue. Clinical evaluation included the Kujala, Lysholm, and Tegner scores; in addition, patients were examined for any complication including recurrent dislocation. The congruence angle and patella alta were assessed radiologically before and after surgery. RESULTS: The Kujala score improved from an average of 42.7 +/- 8.4 before surgery to 79.6 +/- 13.6 (p = 0.008) at final follow-up; the Lysholm score improved from 45.8 +/- 5.7 to 82.0 +/- 10.5 (p = 0.008); and the Tegner score improved from 2.8 +/- 0.8 to 5.6 +/- 1.5 (p = 0.007). The Insall-Salvati ratio changed from 1.16 +/- 0.1 (range, 0.94 to 1.35) before surgery to 1.14 +/- 0.1 (range, 0.96 to 1.29; p = 0.233) at the final follow-up without significance. The congruence angle significantly improved from 26.5 degrees +/- 10.6 degrees (range, 12 degrees to 43 degrees ) before surgery to -4.0 degrees +/- 4.3 degrees (range, -12 degrees to 5 degrees ; p = 0.008) at final follow-up. Subluxation was observed in one patient and hemarthrosis occurred in another patient 2 years after surgery, but these patients were asymptomatic. CONCLUSIONS: We achieved good results with a patellar fixation technique in MPFL reconstruction using a gracilis autograft employing soft tissue suturing in patients with recurrent patellar dislocation. PMID- 26640629 TI - Significance of Intramedullary High Signal Intensity on Magnetic Resonance Imaging in Patients with Cervical Ossification of the Posterior Longitudinal Ligament. AB - BACKGROUND: The purpose of this study was to analyze the relation between intramedullary high signal intensity (IMHS) on magnetic resonance imaging (MRI), radiographic parameters, and clinical symptoms in cervical ossification of the posterior longitudinal ligament (OPLL) patients. METHODS: Two hundred forty-one patients, who underwent simple radiography, computed tomography (CT), and MRI were included in the present study. As radiographic parameters, the OPLL occupying ratio and occupying area were measured on CT images. Dynamic factors were assessed by measuring cervical range of motion (ROM) on simple radiographs. Visual analog scale (VAS) for neck and arm pain, and Japanese Orthopaedic Association (JOA) scores were evaluated for clinical analysis. The differences in radiographic and clinical findings were assessed between patients with IMHS on T2 weighted MRI findings (group A) and patients without IMHS (group B). RESULTS: Eighty-one patients were assigned to group A and 160 patients to group B. The occupying ratios were found to be higher in group A than in group B on both sagittal and axial views (p < 0.01). Group A also showed a higher area occupying ratio (p < 0.01). The length and area of underlying spinal canal on the sagittal and cross-sectional planes were lower in group A than in group B (p < 0.01). No significant difference in ROM was observed (p = 0.63). On the clinical findings, group A had a lower JOA score (p < 0.001), and no intergroup differences in VAS scores were observed. CONCLUSIONS: In cervical OPLL cases, IMHS on MRI was associated with manifestation of myelopathic symptom. Occupying ratio was associated with high signal intensity on MRI, whereas no association was found with ROM. Occurrence of high signal intensity increased inversely with the length and area of underlying spinal canal. PMID- 26640630 TI - Semi-Circumferential Decompression: Microsurgical Total en-bloc Ligamentum Flavectomy to Treat Lumbar Spinal Stenosis with Grade I Degenerative Spondylolisthesis. AB - BACKGROUND: To describe and assess clinical outcomes of the semi-circumferential decompression technique for microsurgical en-bloc total ligamentum flavectomy with preservation of the facet joint to treat the patients who have a lumbar spinal stenosis with degenerative spondylolisthesis. METHODS: We retrospectively analyzed the clinical and radiologic outcomes of 19 patients who have a spinal stenosis with Meyerding grade I degenerative spondylolisthesis. They were treated using the "semi-circumferential decompression" method. We evaluated improvements in back and radiating pain using a visual analogue scale (VAS) and the Oswestry Disability Index (ODI). We also evaluated occurrence of spinal instability on radiological exam using percentage slip and slip angle. RESULTS: The mean VAS score for back pain decreased significantly from 6.3 to 4.3, although some patients had residual back pain. The mean VAS for radiating pain decreased significantly from 8.3 to 2.5. The ODI score improved significantly from 25.3 preoperatively to 10.8 postoperatively. No significant change in percentage slip was observed (10% preoperatively vs. 12.2% at the last follow-up). The dynamic percentage slip (gap in percentage slip between flexion and extension X-ray exams) did not change significantly (5.2% vs. 5.8%). Slip angle and dynamic slip angle did not change (3.2 degrees and 8.2 degrees vs. 3.6 degrees and 9.2 degrees , respectively). CONCLUSIONS: The results suggested that semi circumferential decompression is a clinically recommendable procedure that can improve pain. This procedure does not cause spinal instability when treating patients who have a spinal stenosis with degenerative spondylolisthesis. PMID- 26640631 TI - Patterns of Treatment for Metastatic Pathological Fractures of the Spine: The Efficacy of Each Treatment Modality. AB - BACKGROUND: Metastatic pathological fractures of the spine are a major problem for cancer patients; however, there is no consensus on treatment strategy. The purpose of this study was to evaluate various treatment options by analyzing their patterns for metastatic pathological fractures of the spine. METHODS: In this study, 54 patients (male:female = 36:18) who were diagnosed with metastatic pathological fractures of spine were recruited. Demographic data, origin of cancer, type of treatment, and results were obtained from electronic medical records. Treatment options were divided into radiotherapy (RT), vertebroplasty (VP) or kyphoplasty (KP), operation (OP), and other treatments. Treatment results were defined as aggravation, no response, fair response, good response, and unknown. The survival time after detection of pathologic fractures was analyzed with the Kaplan-Meier method. RESULTS: The mean age of the patients was 62.3 years. Hepatocellular carcinoma was the most common cancer of primary origin (n = 9), followed by multiple myeloma (n = 8). RT was the most common primary choice of treatment (n = 29, 53.7%), followed by OP (n = 13, 24.1%), and VP or KP (n = 10, 18.5%). Only 13 of 29 RT cases and 7 of 13 OP cases demonstrated a fair or good response. The mean survival time following detection of pathological spinal fractures was 11.1 months for 29 patients, who died during the study period. CONCLUSIONS: RT was the most common primary choice of treatment for metastatic pathological fractures of the spine. However, the response rate was suboptimal. Although OP should be considered for the relief of mechanical back pain or neurologic symptoms, care should be taken in determining the surgical indication. VP or KP could be considered for short-term control of localized pain, although the number of cases was too small to confirm the conclusion. It is difficult to determine the superiority of the treatment modalities, hence, a common guideline for the diagnosis and treatment of metastatic pathological fractures of the spine is required. PMID- 26640632 TI - Intraoperative Three-Dimensional Imaging in Calcaneal Fracture Treatment. AB - BACKGROUND: To compare the effectiveness of intraoperative three-dimensional (3D) image and conventional two-dimensional (2D) fluoroscopic images, which are used in the treatment of acute calcaneal fractures. METHODS: We retrospectively analyzed 40 patients who suffered calcaneal fracture and underwent surgery at Inje University Busan Paik Hospital. The patients were divided into two groups. Only 2D fluoroscopy was used to evaluate 20 patients of group 1. On the other hand, 3D fluoroscopy was performed on the remaining 20 patients of group 2; 3D fluoroscopy was performed on these patients after they were extensively evaluated by 2D fluoroscopy during surgery. We reviewed the radiographic and clinical outcomes of these patients, whose average follow-up period was 42.6 months. RESULTS: In group 2, 3D fluoroscopy detected four cases (20%) of articular incongruence and screw misplacement. All these complicated cases were corrected during surgery. At the final follow-up session, the mean American Orthopedic Foot and Ankle Society (AOFAS) hind foot score was 78.3 (range, 65 to 95) in group 1 and 82.3 (range, 68 to 95) in group 2. CONCLUSIONS: Intraoperative 3D imaging of calcaneal fractures is considered to be useful in evaluating the congruence of joints and the placement of implants. PMID- 26640634 TI - Outcomes of Combined Shelf Acetabuloplasty with Femoral Varus Osteotomy in Severe Legg-Calve-Perthes (LCP) Disease: Advanced Containment Method for Severe LCP Disease. AB - BACKGROUND: Standard treatments may provide adequate containment in mild to moderate Legg-Calve-Perthes disease (LCPD), but they can be problematic in more severe cases. The purpose of this study was to report the results of combined shelf acetabuloplasty with femoral varus osteotomy in severe LCPD. METHODS: We reviewed 12 patients who had undergone combined shelf acetabuloplasty with femoral varus osteotomy. The indications for this type of operation were: (1) above 8 years of age at clinical onset; (2) massive femoral epiphysis involvement (Catterall group 4, lateral pillar C); (3) femoral head lateral subluxation on the anteroposterior radiograph; and (4) impending hinged abduction on preoperative magnetic resonance imaging or arthrography. The mean age was 9.3 years (range, 8 to 10.8 years). The patients were clinically evaluated with Iowa hip score and leg length discrepancy at the final follow-up. Radiographic outcome was assessed using the Stulberg classification to evaluate femoral head sphericity. The presence of osteoarthritis was evaluated by the Tonnis classification. Correlation analysis was conducted to analyze the preoperative factors that were strongly associated with patients' outcomes. RESULTS: The mean follow-up period was 10.1 years (range, 7.1 to 13.2 years). Functional grade was excellent in all patients at last follow-up (mean, 92; range, 82 to 99). The mean leg length discrepancy after skeletal maturity was 0.9 cm (range, 0 to 1.7 cm). There were no significant complications or need for additional surgery. Radiographically, 92% of patients reached satisfactory outcomes: Stulberg grade I, 0 cases; Stulberg grade II, 4 cases (34%); Stulberg III, 7 cases (58%), Stulberg IV, 1 case (8%); and Stulberg V, 0 cases. There was no osteoarthritis by Tonnis classification. CONCLUSIONS: The surgical outcomes for combined shelf acetabuloplasty with femoral varus osteotomy in severe LCPD patients over 8 years old are comparable with other advanced surgical methods. In the cases of severe disease that match our inclusion criteria, our containment method could be another treatment option. PMID- 26640633 TI - Arthroscopic Assessment of Intra-Articular Lesion after Surgery for Rotational Ankle Fracture. AB - BACKGROUND: The purpose of this study was to report findings of exploratory arthroscopic assessment performed in conjunction with removal of internal fixation device placed in the initial surgery for rotational ankle fracture. METHODS: A total of 53 patients (33 male, 20 female) who underwent surgery for rotational ankle fracture between November 2002 and February 2008 were retrospectively reviewed. All patients gave consent to the exploratory arthroscopic surgery for the removal of internal fixation devices placed in the initial surgery. Lauge-Hansen classification system of ankle fractures was assessed for all patients. Intra-articular lesions (osteochondral lesion, loose body, and fibrosis) were evaluated via ankle arthroscopy. Comparative analysis was then performed between radiological classification of ankle fracture/patient's symptoms and arthroscopic findings. RESULTS: Lauge-Hansen classification system of ankle fractures included supination-external rotation type (n = 35), pronation-external rotation type (n = 9), and pronation-abduction type (n = 9). A total of 33 patients exhibited symptoms of pain or discomfort while walking whereas 20 exhibited no symptoms. Arthroscopic findings included abnormal findings around the syndesmosis area (n = 35), intra-articular fibrosis (n = 51), osteochondral lesions of the talus (n = 33), loose bodies (n = 6), synovitis (n = 13), and anterior bony impingement syndrome (n = 3). Intra articular fibrosis was seen in 31 of symptomatic patients (93.9%). Pain or discomfort with activity caused by soft tissue impingement with meniscus-like intra-articular fibrosis were found in 19 patients. There was statistical significance (p = 0.02) between symptoms (pain and discomfort) and the findings of meniscus-like fibrosis compared to the group without any symptom. CONCLUSIONS: Arthroscopic examination combined with treatment of intra-articular fibrosis arising from ankle fracture surgery may help improve surgical outcomes. PMID- 26640635 TI - Suture Bridge Fixation Technique for Posterior Cruciate Ligament Avulsion Fracture. AB - We presented a surgical technique including a suture bridge technique with relatively small incision for the reduction and fixation of posterior ligament avulsion fractures. A suture anchor was used to hold the avulsed fragment and a knotless anchor was used to continuously compress the bony fragment into the fracture site, thereby maintaining reduction during healing. PMID- 26640636 TI - Bilateral Total Hip Arthroplasty in a Rare Case of Multicentric Reticulohistiocytosis. AB - Multicentric reticulohistiocytosis (MRH) is a rare systemic disease, which commonly manifests as muco-cutaneous papulonodules and inflammatory erosive polyarthropathy. In this research, we report the clinical manifestations and management of a rare case of MRH with destructive arthropathy of bilateral hip joints and arthritis mutilans presenting with characteristic deformities. Disabling hip arthropathy that occurs secondary to MRH can be successfully managed with bilateral total hip arthroplasty (THA). Osteopenia and acetabular bone defects must be anticipated during THA. This case is reported due to its rare occurrence and because little literature has been published regarding THA in such patients. PMID- 26640637 TI - Unique Imaging Features of Spinal Neurenteric Cyst. AB - A 50-year-old male presented with acutely progressed paraplegia. His magnetic resonance imaging demonstrated two well-demarcated components with opposite signals in one cystic lesion between the T1- and T2-weighted images at the T1 spine level. The patient showed immediately improved neurological symptoms after surgical intervention and the histopathological exam was compatible with a neurenteric cyst. On operation, two different viscous drainages from the cyst were confirmed. A unique similarity of image findings was found from a review of the pertinent literature. The common findings of spinal neurenteric cyst include an isointense or mildly hyperintense signal relative to cerebrospinal fluid for both T1- and T2-weighted images. However, albeit rarer, the signals of some part of the cyst could change into brightly hyperintensity on T1-weighted images and hypointensity on T2-weighted images due to the differing sedimentation of the more viscous contents in the cyst. PMID- 26640638 TI - High Grade Infective Spondylolisthesis of Cervical Spine Secondary to Tuberculosis. AB - Spondylolisthesis coexisting with tuberculosis is rarely reported. There is a controversy whether spondylolisthesis coexists or precedes tuberculosis. Few cases of pathological spondylolisthesis secondary to tuberculous spondylodiscitis have been reported in the lumbar and lumbosacral spine. All cases in the literature presented as anterolisthesis, except one which presented as posterolisthesis of lumbar spine. Spondylolisthesis in the cervical spine is mainly degenerative and traumatic. Spondylolisthesis due to tuberculosis is not reported in the lower cervical spine. The exact mechanism of such an occurrence of spondylolisthesis with tuberculosis is sparsely reported in the literature and inadequately understood. We report a rare case of high grade pathological posterolisthesis of the lower cervical spine due to tubercular spondylodiscitis in a 67-year-old woman managed surgically with a three-year follow-up period. This case highlights the varied and complex presentation of tuberculosis of the lower cervical spine and gives insight into its pathogenesis, diagnosis, and management. PMID- 26640639 TI - Trigger Wrist. AB - Trigger wrist is a relatively rare disease compared to trigger finger, which is the most common disorder found in hands. Patients with trigger wrist usually complain about the following symptoms: snapping and clicking or triggering around carpal tunnel with or without mild to moderate median neuropathy. There are a total of five cases of trigger wrist: three cases of anomalous muscle belly of flexor digitorum superficialis and two cases of fibroma around flexor tendon sheath within carpal tunnel. This study reports on two of those cases: one with anomalous muscle and the other with fibroma of flexor tendon sheath. Accurate examination and proper diagnosis are mandatory to obviate improper and time wasting treatment for patients with trigger wrist. PMID- 26640640 TI - Acute Compartment Syndrome after Non-Contact Peroneus Longus Muscle Rupture. AB - This case demonstrates a rare variation in the pattern of injury and the presentation of acute lateral compartment syndrome of the leg. Although uncommon, lateral compartment syndrome of the leg after an ankle inversion leading to peroneus longus muscle rupture has been previously documented. This case was unusual because there was no overt ankle injury and the patient was able to continue physical activity, in spite of a significant rupture of the peroneus longus muscle that was determined later. This case highlights the necessary vigilance clinicians must maintain when assessing non-contact injuries in patients with possible compartment syndrome. PMID- 26640641 TI - Structure, phylogeny, and expression of the frizzled-related gene family in the lophotrochozoan annelid Platynereis dumerilii. AB - BACKGROUND: Wnt signaling pathways are highly conserved signal transduction pathways important for axis formation, cell fate specification, and organogenesis throughout metazoan development. Within the various Wnt pathways, the frizzled transmembrane receptors (Fzs) and secreted frizzled-related proteins (sFRPs) play central roles in receiving and antagonizing Wnt signals, respectively. Despite their importance, very little is known about the frizzled-related gene family (fzs & sfrps) in lophotrochozoans, especially during early stages of spiralian development. Here we ascertain the frizzled-related gene complement in six lophotrochozoan species, and determine their spatial and temporal expression pattern during early embryogenesis and larval stages of the marine annelid Platynereis dumerilii. RESULTS: Phylogenetic analyses confirm conserved homologs for four frizzled receptors (Fz1/2/7, Fz4, Fz5/8, Fz9/10) and sFRP1/2/5 in five of six lophotrochozoan species. The sfrp3/4 gene is conserved in one, divergent in two, and evidently lost in three lophotrochozoan species. Three novel fz related genes (fzCRD1-3) are unique to Platynereis. Transcriptional profiling and in situ hybridization identified high maternal expression of fz1/2/7, expression of fz9/10 and fz1/2/7 within animal and dorsal cell lineages after the 32-cell stage, localization of fz5/8, sfrp1/2/5, and fzCRD-1 to animal-pole cell lineages after the 80-cell stage, and no expression for fz4, sfrp3/4, and fzCRD-2, and -3 in early Platynereis embryos. In later larval stages, all frizzled-related genes are expressed in distinct patterns preferentially in the anterior hemisphere and less in the developing trunk. CONCLUSIONS: Lophotrochozoans have retained a generally conserved ancestral bilaterian frizzled-related gene complement (four Fzs and two sFRPs). Maternal expression of fz1/2/7, and animal lineage-specific expression of fz5/8 and sfrp1/2/5 in early embryos of Platynereis suggest evolutionary conserved roles of these genes to perform Wnt pathway functions during early cleavage stages, and the early establishment of a Wnt inhibitory center at the animal pole, respectively. Numerous frizzled receptor-expressing cells and embryonic territories were identified that might indicate competence to receive Wnt signals during annelid development. An anterior bias for frizzled related gene expression in embryos and larvae might point to a polarity of Wnt patterning systems along the anterior-posterior axis of this annelid. PMID- 26640642 TI - Sex differences in long-term outcomes among acute ischemic stroke patients with diabetes in China. AB - BACKGROUND: Diabetes has been shown to be significantly associated with poor outcome after stroke. However, the sex differences in stroke outcome among patients with diabetes are unknown. Therefore, we aimed to assess the sex differences in long-term prognosis among acute ischemic stroke patients with diabetes. METHODS: The ischemic stroke patients with diabetes were recruited to this study between May 2005 and September 2014 in Tianjin, China. Sex differences in mortality, dependency (modified rank scale > 2), and recurrence at 3, 12, and 36 months after stroke were analyzed. RESULTS: A total of 2360 patients were recruited in this study. The age of stroke onset, National Institute of Health stroke scale (NIHSS), and modified rank scale (mRS) on admission were greater in women than in men (P < 0.05). Women were more likely to have hypertension, obesity, atrial fibrillation, and dyslipidemias. In contrast, men were more likely to have artery stenosis, current smoking, and alcohol consumption (P < 0.001). There was higher mortality in women than in men at 3 months (7.9 % vs 5.2 %), 12 months (12.2 % vs 8.2 %), and 36 months (21.9 % vs 16.1 %) after stroke; but no differences were found in dependency and recurrence. Sex differences were found in associated factors of outcomes by time-point. Trial of Org 10172 in Acute Stroke Treatment (TOAST) of large artery atherothrombosis (LAA), cardioembolism (CE), and smoking were risk factors of outcomes in women at short term and medium term; but atrial fibrillation (AF), obesity, and alcohol were risk factors of outcomes in men at medium term and long term. CONCLUSIONS: These findings suggest that it is crucial to establish the individual scheme of therapy for every patient by different risk factors of stroke, strengthen the rehabilitation of stroke, and carry on the health education early for the secondary prevention of stroke in patients with diabetes mellitus (DM). PMID- 26640643 TI - Forbidden phenotypes and the limits of evolution. AB - Evolution has produced an astonishing array of organisms, but does it have limits and, if so, how are these overcome and how have they changed over the course of time? Here, I review models for describing and explaining existing diversity, and then explore parts of the evolutionary tree that remain empty. In an analysis of 32 forbidden states among eukaryotes, identified in major clades and in the three great habitat realms of water, land and air, I argue that no phenotypic constraint is absolute, that most constraints reflect a limited time-energy budget available to individual organisms, that natural selection is ultimately responsible for both imposing and overcoming constraints, including those normally ascribed to developmental patterns of construction and phylogenetic conservatism, and that increases in adaptive versatility in major clades together with accompanying new ecological opportunities have eliminated many constraints. Phenotypes that were inaccessible during the Early Palaeozoic era have evolved during later periods while very few adaptive states have disappeared. The filling of phenotypic space has proceeded cumulatively in three overlapping phases characterized by diversification at the biochemical, morphological and cultural levels. PMID- 26640645 TI - Limits in the evolution of biological form: a theoretical morphologic perspective. AB - Limits in the evolution of biological form can be empirically demonstrated by using theoretical morphospace analyses, and actual analytic examples are given for univalved ammonoid shell form, bivalved brachiopod shell form and helical bryozoan colony form. Limits in the evolution of form in these animal groups can be shown to be due to functional and developmental constraints on possible evolutionary trajectories in morphospace. Future evolutionary-limit research is needed to analyse the possible existence of temporal constraint in the evolution of biological form on Earth, and in the search for the possible existence of functional alien life forms on Titan and Triton that are developmentally impossible for Earth life. PMID- 26640644 TI - A new paradigm for animal symmetry. AB - My aim in this article is to soften certain rigid concepts concerning the radial and bilateral symmetry of the animal body plan, and to offer a more flexible framework of thinking for them, based on recent understandings of how morphogenesis is regulated by the mosaically acting gene regulatory networks. Based on general principles of the genetic regulation of morphogenesis, it can be seen that the difference between the symmetry of the whole body and that of minor anatomical structures is only a question of a diverse timing during development. I propose that the animal genome, as such, is capable of expressing both radial and bilateral symmetries, and deploys them according to the functional requirements which must be satisfied by both the anatomical structure and body as a whole. Although it may seem paradoxical, this flexible view of symmetry, together with the idea that symmetry is strongly determined by function, bolsters the concept that the presence of the two main symmetries in the animal world is not due to chance: they are necessary biological patterns emerging in evolution. PMID- 26640646 TI - What does convergent evolution mean? The interpretation of convergence and its implications in the search for limits to evolution. AB - Convergent evolution is central to the study of life's evolutionary history. Researchers have documented the ubiquity of convergence and have used this ubiquity to make inferences about the nature of limits on evolution. However, these inferences are compromised by unrecognized inconsistencies in the definitions, measures, significance tests and inferred causes of convergent evolution. I review these inconsistencies and provide recommendations for standardizing studies of convergence. A fundamental dichotomy exists between definitions that describe convergence as a pattern and those that describe it as a pattern caused by a particular process. When this distinction is not acknowledged it becomes easy to assume that a pattern of convergence indicates that a particular process has been active, leading researchers away from alternative explanations. Convergence is not necessarily caused by limits to evolution, either adaptation or constraint; even substantial amounts of convergent evolution can be generated by a purely stochastic process. In the absence of null models, long lists of examples of convergent events do not necessarily indicate that convergence or any evolutionary process is ubiquitous throughout the history of life. Pattern-based definitions of convergence, coupled with quantitative measures and null models, must be applied before drawing inferences regarding large-scale limits to evolution. PMID- 26640647 TI - Convergent evolution as natural experiment: the tape of life reconsidered. AB - Stephen Jay Gould argued that replaying the 'tape of life' would result in radically different evolutionary outcomes. Recently, biologists and philosophers of science have paid increasing attention to the theoretical importance of convergent evolution-the independent origination of similar biological forms and functions-which many interpret as evidence against Gould's thesis. In this paper, we examine the evidentiary relevance of convergent evolution for the radical contingency debate. We show that under the right conditions, episodes of convergent evolution can constitute valid natural experiments that support inferences regarding the deep counterfactual stability of macroevolutionary outcomes. However, we argue that proponents of convergence have problematically lumped causally heterogeneous phenomena into a single evidentiary basket, in effect treating all convergent events as if they are of equivalent theoretical import. As a result, the 'critique from convergent evolution' fails to engage with key claims of the radical contingency thesis. To remedy this, we develop ways to break down the heterogeneous set of convergent events based on the nature of the generalizations they support. Adopting this more nuanced approach to convergent evolution allows us to differentiate iterated evolutionary outcomes that are probably common among alternative evolutionary histories and subject to law-like generalizations, from those that do little to undermine and may even support, the Gouldian view of life. PMID- 26640648 TI - Are there ergodic limits to evolution? Ergodic exploration of genome space and convergence. AB - We examine the analogy between evolutionary dynamics and statistical mechanics to include the fundamental question of ergodicity-the representative exploration of the space of possible states (in the case of evolution this is genome space). Several properties of evolutionary dynamics are identified that allow a generalization of the ergodic dynamics, familiar in dynamical systems theory, to evolution. Two classes of evolved biological structure then arise, differentiated by the qualitative duration of their evolutionary time scales. The first class has an ergodicity time scale (the time required for representative genome exploration) longer than available evolutionary time, and has incompletely explored the genotypic and phenotypic space of its possibilities. This case generates no expectation of convergence to an optimal phenotype or possibility of its prediction. The second, more interesting, class exhibits an evolutionary form of ergodicity-essentially all of the structural space within the constraints of slower evolutionary variables have been sampled; the ergodicity time scale for the system evolution is less than the evolutionary time. In this case, some convergence towards similar optima may be expected for equivalent systems in different species where both possess ergodic evolutionary dynamics. When the fitness maximum is set by physical, rather than co-evolved, constraints, it is additionally possible to make predictions of some properties of the evolved structures and systems. We propose four structures that emerge from evolution within genotypes whose fitness is induced from their phenotypes. Together, these result in an exponential speeding up of evolution, when compared with complete exploration of genomic space. We illustrate a possible case of application and a prediction of convergence together with attaining a physical fitness optimum in the case of invertebrate compound eye resolution. PMID- 26640649 TI - What limits the morphological disparity of clades? AB - The morphological disparity of species within major clades shows a variety of trajectory patterns through evolutionary time. However, there is a significant tendency for groups to reach their maximum disparity relatively early in their histories, even while their species richness or diversity is comparatively low. This pattern of early high-disparity suggests that there are internal constraints (e.g. developmental pleiotropy) or external restrictions (e.g. ecological competition) upon the variety of morphologies that can subsequently evolve. It has also been demonstrated that the rate of evolution of new character states decreases in most clades through time (character saturation), as does the rate of origination of novel bodyplans and higher taxa. Here, we tested whether there was a simple relationship between the level or rate of character state exhaustion and the shape of a clade's disparity profile: specifically, its centre of gravity (CG). In a sample of 93 extinct major clades, most showed some degree of exhaustion, but all continued to evolve new states up until their extinction. Projection of states/steps curves suggested that clades realized an average of 60% of their inferred maximum numbers of states. Despite a weak but significant correlation between overall levels of homoplasy and the CG of clade disparity profiles, there were no significant relationships between any of our indices of exhaustion curve shape and the clade disparity CG. Clades showing early high disparity were no more likely to have early character saturation than those with maximum disparity late in their evolution. PMID- 26640650 TI - The morphological state space revisited: what do phylogenetic patterns in homoplasy tell us about the number of possible character states? AB - Biological variety and major evolutionary transitions suggest that the space of possible morphologies may have varied among lineages and through time. However, most models of phylogenetic character evolution assume that the potential state space is finite. Here, I explore what the morphological state space might be like, by analysing trends in homoplasy (repeated derivation of the same character state). Analyses of ten published character matrices are compared against computer simulations with different state space models: infinite states, finite states, ordered states and an 'inertial' model, simulating phylogenetic constraints. Of these, only the infinite states model results in evolution without homoplasy, a prediction which is not generally met by real phylogenies. Many authors have interpreted the ubiquity of homoplasy as evidence that the number of evolutionary alternatives is finite. However, homoplasy is also predicted by phylogenetic constraints on the morphological distance that can be traversed between ancestor and descendent. Phylogenetic rarefaction (sub sampling) shows that finite and inertial state spaces do produce contrasting trends in the distribution of homoplasy. Two clades show trends characteristic of phylogenetic inertia, with decreasing homoplasy (increasing consistency index) as we sub-sample more distantly related taxa. One clade shows increasing homoplasy, suggesting exhaustion of finite states. Different clades may, therefore, show different patterns of character evolution. However, when parsimony uninformative characters are excluded (which may occur without documentation in cladistic studies), it may no longer be possible to distinguish inertial and finite state spaces. Interestingly, inertial models predict that homoplasy should be clustered among comparatively close relatives (parallel evolution), whereas finite state models do not. If morphological evolution is often inertial in nature, then homoplasy (false homology) may primarily occur between close relatives, perhaps being replaced by functional analogy at higher taxonomic scales. PMID- 26640651 TI - The structure of the genotype-phenotype map strongly constrains the evolution of non-coding RNA. AB - The prevalence of neutral mutations implies that biological systems typically have many more genotypes than phenotypes. But, can the way that genotypes are distributed over phenotypes determine evolutionary outcomes? Answering such questions is difficult, in part because the number of genotypes can be hyper astronomically large. By solving the genotype-phenotype (GP) map for RNA secondary structure (SS) for systems up to length L = 126 nucleotides (where the set of all possible RNA strands would weigh more than the mass of the visible universe), we show that the GP map strongly constrains the evolution of non coding RNA (ncRNA). Simple random sampling over genotypes predicts the distribution of properties such as the mutational robustness or the number of stems per SS found in naturally occurring ncRNA with surprising accuracy. Because we ignore natural selection, this strikingly close correspondence with the mapping suggests that structures allowing for functionality are easily discovered, despite the enormous size of the genetic spaces. The mapping is extremely biased: the majority of genotypes map to an exponentially small portion of the morphospace of all biophysically possible structures. Such strong constraints provide a non-adaptive explanation for the convergent evolution of structures such as the hammerhead ribozyme. These results present a particularly clear example of bias in the arrival of variation strongly shaping evolutionary outcomes and may be relevant to Mayr's distinction between proximate and ultimate causes in evolutionary biology. PMID- 26640652 TI - Replaying the tape of life in the twenty-first century. AB - Should the tape of life be replayed, would it produce similar living beings? A classical answer has long been 'no', but accumulating data are now challenging this view. Repeatability in experimental evolution, in phenotypic evolution of diverse species and in the genes underlying phenotypic evolution indicates that despite unpredictability at the level of basic evolutionary processes (such as apparition of mutations), a certain kind of predictability can emerge at higher levels over long time periods. For instance, a survey of the alleles described in the literature that cause non-deleterious phenotypic differences among animals, plants and yeasts indicates that similar phenotypes have often evolved in distinct taxa through independent mutations in the same genes. Does this mean that the range of possibilities for evolution is limited? Does this mean that we can predict the outcomes of a replayed tape of life? Imagining other possible paths for evolution runs into four important issues: (i) resolving the influence of contingency, (ii) imagining living organisms that are different from the ones we know, (iii) finding the relevant concepts for predicting evolution, and (iv) estimating the probability of occurrence for complex evolutionary events that occurred only once during the evolution of life on earth. PMID- 26640653 TI - Neuronal boost to evolutionary dynamics. AB - Standard evolutionary dynamics is limited by the constraints of the genetic system. A central message of evolutionary neurodynamics is that evolutionary dynamics in the brain can happen in a neuronal niche in real time, despite the fact that neurons do not reproduce. We show that Hebbian learning and structural synaptic plasticity broaden the capacity for informational replication and guided variability provided a neuronally plausible mechanism of replication is in place. The synergy between learning and selection is more efficient than the equivalent search by mutation selection. We also consider asymmetric landscapes and show that the learning weights become correlated with the fitness gradient. That is, the neuronal complexes learn the local properties of the fitness landscape, resulting in the generation of variability directed towards the direction of fitness increase, as if mutations in a genetic pool were drawn such that they would increase reproductive success. Evolution might thus be more efficient within evolved brains than among organisms out in the wild. PMID- 26640654 TI - Identification of acetyltransferase genes (HAT1 and KAT8) regulating HBV replication by RNAi screening. AB - BACKGROUND: The initiation of hepatitis B virus (HBV) replication involves the formation of covalently closed circular DNA (cccDNA) and its transcription into pregenomic RNA (pgRNA) in hepatocyte nuclei. The regulatory mechanism of HBV replication by acetyltransferase is thus far not well understood, but human acetyltransferase has been reported as being involved in the regulation of HBV replication. RESULTS: Depletion of KAT8 or HAT1 via RNA interference (RNAi) markedly down-regulated HBV-DNA and pgRNA levels in HepG2.2.15 cells, with KAT8 knockdown reducing both HBsAg and HBeAg more than HAT1 knockdown. Consistent with these observations, HBV replication regulators hepatocyte nuclear factor-4-alpha (HNF4alpha) and peroxisome proliferator-activated receptor gamma coactivator- (PPARGC-) 1-alpha were decreased following knockdown of HAT1 or KAT8. CONCLUSIONS: These data suggest that KAT8 or HAT1 regulate HBV replication and may be potential drug targets of anti-HBV therapy. PMID- 26640655 TI - Estimating occupancy dynamics for large-scale monitoring networks: amphibian breeding occupancy across protected areas in the northeast United States. AB - Regional monitoring strategies frequently employ a nested sampling design where a finite set of study areas from throughout a region are selected and intensive sampling occurs within a subset of sites within the individual study areas. This sampling protocol naturally lends itself to a hierarchical analysis to account for dependence among subsamples. Implementing such an analysis using a classic likelihood framework is computationally challenging when accounting for detection errors in species occurrence models. Bayesian methods offer an alternative approach for fitting models that readily allows for spatial structure to be incorporated. We demonstrate a general approach for estimating occupancy when data come from a nested sampling design. We analyzed data from a regional monitoring program of wood frogs (Lithobates sylvaticus) and spotted salamanders (Ambystoma maculatum) in vernal pools using static and dynamic occupancy models. We analyzed observations from 2004 to 2013 that were collected within 14 protected areas located throughout the northeast United States. We use the data set to estimate trends in occupancy at both the regional and individual protected area levels. We show that occupancy at the regional level was relatively stable for both species. However, substantial variation occurred among study areas, with some populations declining and some increasing for both species. In addition, When the hierarchical study design is not accounted for, one would conclude stronger support for latitudinal gradient in trends than when using our approach that accounts for the nested design. In contrast to the model that does not account for nesting, the nested model did not include an effect of latitude in the 95% credible interval. These results shed light on the range-level population status of these pond-breeding amphibians, and our approach provides a framework that can be used to examine drivers of local and regional occurrence dynamics. PMID- 26640656 TI - Interactive effects of predation risk and conspecific density on the nutrient stoichiometry of prey. AB - The mere presence of predators (i.e., predation risk) can alter consumer physiology by restricting food intake and inducing stress, which can ultimately affect prey-mediated ecosystem processes such as nutrient cycling. However, many environmental factors, including conspecific density, can mediate the perception of risk by prey. Prey conspecific density has been defined as a fundamental feature that modulates perceived risk. In this study, we tested the effects of predation risk on prey nutrient stoichiometry (body and excretion). Using a constant predation risk, we also tested the effects of varying conspecific densities on prey responses to predation risk. To answer these questions, we conducted a mesocosm experiment using caged predators (Belostoma sp.), and small bullfrog tadpoles (Lithobates catesbeianus) as prey. We found that L. catesbeianus tadpoles adjust their body nutrient stoichiometry in response to predation risk, which is affected by conspecific density. We also found that the prey exhibited strong morphological responses to predation risk (i.e., an increase in tail muscle mass), which were positively correlated to body nitrogen content. Thus, we pose the notion that in risky situations, adaptive phenotypic responses rather than behavioral ones might partially explain why prey might have a higher nitrogen content under predation risk. In addition, the interactive roles of conspecific density and predation risk, which might result in reduced perceived risk and physiological restrictions in prey, also affected how prey stoichiometry responded to the fear of predation. PMID- 26640657 TI - Is a community still a community? Reviewing definitions of key terms in community ecology. AB - Community ecology is an inherently complicated field, confounded by the conflicting use of fundamental terms. Nearly two decades ago, Fauth et al. (1996) demonstrated that imprecise language led to the virtual synonymy of important terms and so attempted to clearly define four keywords in community ecology; "community," "assemblage," "guild," and "ensemble". We revisit Fauth et al.'s conclusion and discuss how the use of these terms has changed over time since their review. An updated analysis of term definition from a selection of popular ecological textbooks suggests that definitions have drifted away from those encountered pre-1996, and slightly disagreed with results from a survey of 100 ecology professionals (comprising of academic professors, nonacademic PhDs, graduate and undergraduate biology students). Results suggest that confusion about these terms is still widespread in ecology. We conclude with clear suggestions for definitions of each term to be adopted hereafter to provide greater cohesion among research groups. PMID- 26640658 TI - Asymmetrical nature of the Trollius-Chiastocheta interaction: insights into the evolution of nursery pollination systems. AB - The mutualistic versus antagonistic nature of an interaction is defined by costs and benefits of each partner, which may vary depending on the environment. Contrasting with this dynamic view, several pollination interactions are considered as strictly obligate and mutualistic. Here, we focus on the interaction between Trollius europaeus and Chiastocheta flies, considered as a specialized and obligate nursery pollination system - the flies are thought to be exclusive pollinators of the plant and their larvae develop only in T. europaeus fruits. In this system, features such as the globelike flower shape are claimed to have evolved in a coevolutionary context. We examine the specificity of this pollination system and measure traits related to offspring fitness in isolated T. europaeus populations, in some of which Chiastocheta flies have gone extinct. We hypothesize that if this interaction is specific and obligate, the plant should experience dramatic drop in its relative fitness in the absence of Chiastocheta. Contrasting with this hypothesis, T. europaeus populations without flies demonstrate a similar relative fitness to those with the flies present, contradicting the putative obligatory nature of this pollination system. It also agrees with our observation that many other insects also visit and carry pollen among T. europaeus flowers. We propose that the interaction could have evolved through maximization of by-product benefits of the Chiastocheta visits, through the male flower function, and selection on floral traits by the most effective pollinator. We argue this mechanism is also central in the evolution of other nursery pollination systems. PMID- 26640659 TI - Rainbow trout in seasonal environments: phenotypic trade-offs across a gradient in winter duration. AB - Survival through periods of resource scarcity depends on the balance between metabolic demands and energy storage. The opposing effects of predation and starvation mortality are predicted to result in trade-offs between traits that optimize fitness during periods of resource plenty (e.g., during the growing season) and those that optimize fitness during periods of resource scarcity (e.g., during the winter). We conducted a common environment experiment with two genetically distinct strains of rainbow trout to investigate trade-offs due to (1) the balance of growth and predation risk related to foraging rate during the growing season and (2) the allocation of energy to body size prior to the winter. Fry (age 0) from both strains were stocked into replicate natural lakes at low and high elevation that differed in winter duration (i.e., ice cover) by 59 days. Overwinter survival was lowest in the high-elevation lakes for both strains. Activity rate and growth rate were highest at high elevation, but growing season survival did not differ between strains or between environments. Hence, we did not observe a trade-off between growth and predation risk related to foraging rate. Growth rate also differed significantly between the strains across both environments, which suggests that growth rate is involved in local adaptation. There was not, however, a difference between strains or between environments in energy storage. Hence, we did not observe a trade-off between growth and storage. Our findings suggest that intrinsic metabolic rate, which affects a trade-off between growth rate and overwinter survival, may influence local adaptation in organisms that experience particularly harsh winter conditions (e.g., extended periods trapped beneath the ice in high-elevation lakes) in some parts of their range. PMID- 26640660 TI - The transcriptomic and evolutionary signature of social interactions regulating honey bee caste development. AB - The caste fate of developing female honey bee larvae is strictly socially regulated by adult nurse workers. As a result of this social regulation, nurse expressed genes as well as larval-expressed genes may affect caste expression and evolution. We used a novel transcriptomic approach to identify genes with putative direct and indirect effects on honey bee caste development, and we subsequently studied the relative rates of molecular evolution at these caste associated genes. We experimentally induced the production of new queens by removing the current colony queen, and we used RNA sequencing to study the gene expression profiles of both developing larvae and their caregiving nurses before and after queen removal. By comparing the gene expression profiles of queen destined versus worker-destined larvae as well as nurses observed feeding these two types of larvae, we identified larval and nurse genes associated with caste development. Of 950 differentially expressed genes associated with caste, 82% were expressed in larvae with putative direct effects on larval caste, and 18% were expressed in nurses with putative indirect effects on caste. Estimated selection coefficients suggest that both nurse and larval genes putatively associated with caste are rapidly evolving, especially those genes associated with worker development. Altogether, our results suggest that indirect effect genes play important roles in both the expression and evolution of socially influenced traits such as caste. PMID- 26640661 TI - Unmanned Aircraft Systems complement biologging in spatial ecology studies. AB - The knowledge about the spatial ecology and distribution of organisms is important for both basic and applied science. Biologging is one of the most popular methods for obtaining information about spatial distribution of animals, but requires capturing the animals and is often limited by costs and data retrieval. Unmanned Aircraft Systems (UAS) have proven their efficacy for wildlife surveillance and habitat monitoring, but their potential contribution to the prediction of animal distribution patterns and abundance has not been thoroughly evaluated. In this study, we assess the usefulness of UAS overflights to (1) get data to model the distribution of free-ranging cattle for a comparison with results obtained from biologged (GPS-GSM collared) cattle and (2) predict species densities for a comparison with actual density in a protected area. UAS and biologging derived data models provided similar distribution patterns. Predictions from the UAS model overestimated cattle densities, which may be associated with higher aggregated distributions of this species. Overall, while the particular researcher interests and species characteristics will influence the method of choice for each study, we demonstrate here that UAS constitute a noninvasive methodology able to provide accurate spatial data useful for ecological research, wildlife management and rangeland planning. PMID- 26640662 TI - A comparative approach to testing hypotheses for the evolution of sex-biased dispersal in bean beetles. AB - Understanding the selective forces that shape dispersal strategies is a fundamental goal of evolutionary ecology and is increasingly important in changing, human-altered environments. Sex-biased dispersal (SBD) is common in dioecious taxa, and understanding variation in the direction and magnitude of SBD across taxa has been a persistent challenge. We took a comparative, laboratory based approach using 16 groups (species or strains) of bean beetles (genera Acanthoscelides, Callosobruchus, and Zabrotes, including 10 strains of one species) to test two predictions that emerge from dominant hypotheses for the evolution of SBD: (1) groups that suffer greater costs of inbreeding should exhibit greater SBD in favor of either sex (inbreeding avoidance hypothesis) and (2) groups with stronger local mate competition should exhibit greater male bias in dispersal (kin competition avoidance hypothesis). We used laboratory experiments to quantify SBD in crawling dispersal, the fitness effects of inbreeding, and the degree of polygyny (number of female mates per male), a proxy for local mate competition. While we found that both polygyny and male-biased dispersal were common across bean beetle groups, consistent with the kin competition avoidance hypothesis, quantitative relationships between trait values did not support the predictions. Across groups, there was no significant association between SBD and effects of inbreeding nor SBD and degree of polygyny, using either raw values or phylogenetically independent contrasts. We discuss possible limitations of our experimental approach for detecting the predicted relationships, as well as reasons why single-factor hypotheses may be too simplistic to explain the evolution of SBD. PMID- 26640663 TI - Effects of fasting and nutritional restriction on the isotopic ratios of nitrogen and carbon: a meta-analysis. AB - Many organisms experience fasting in their life time, and this physiological process has the potential to alter stable isotope values of organisms, and confound interpretation of food web studies. However, previous studies on the effects of fasting and starvation on stable isotopes show disparate results, and have never been quantitatively synthesized. We performed a laboratory experiment and meta-analysis to determine how stable isotopes of delta (15)N and delta (13)C change with fasting, and we tested whether moderators such as taxa and tissue explain residual variation. We collected literature data from a wide variety of taxa and tissues. We surveyed over 2000 papers, and of these, 26 met our selection criteria, resulting in 51 data points for delta (15)N, and 43 data points for delta (13)C. We determine that fasting causes an average increase in the isotopic value of organisms of 0.50/00 for delta (15)N and that the only significant moderator is tissue type. We find that the overall effect size for delta (13)C is not significant, but when the significant moderator of tissue is considered, significant increases in blood and whole organisms are seen with fasting. Our results show that across tissues and taxa, the nutritional status of an organism must be considered when interpreting stable isotope data, as fasting can cause large differences in stable isotope values that would be otherwise attributed to other factors. PMID- 26640664 TI - Defoliation reduces soil biota - and modifies stimulating effects of elevated CO2. AB - To understand the responses to external disturbance such as defoliation and possible feedback mechanisms at global change in terrestrial ecosystems, it is necessary to examine the extent and nature of effects on aboveground-belowground interactions. We studied a temperate heathland system subjected to experimental climate and atmospheric factors based on prognoses for year 2075 and further exposed to defoliation. By defoliating plants, we were able to study how global change modifies the interactions of the plant-soil system. Shoot production, root biomass, microbial biomass, and nematode abundance were assessed in the rhizosphere of manually defoliated patches of Deschampsia flexuosa in June in a full-factorial FACE experiment with the treatments: increased atmospheric CO 2, increased nighttime temperatures, summer droughts, and all of their combinations. We found a negative effect of defoliation on microbial biomass that was not apparently affected by global change. The negative effect of defoliation cascades through to soil nematodes as dependent on CO 2 and drought. At ambient CO 2, drought and defoliation each reduced nematodes. In contrast, at elevated CO 2, a combination of drought and defoliation was needed to reduce nematodes. We found positive effects of CO 2 on root density and microbial biomass. Defoliation affected soil biota negatively, whereas elevated CO 2 stimulated the plant-soil system. This effect seen in June is contrasted by the effects seen in September at the same site. Late season defoliation increased activity and biomass of soil biota and more so at elevated CO 2. Based on soil biota responses, plants defoliated in active growth therefore conserve resources, whereas defoliation after termination of growth results in release of resources. This result challenges the idea that plants via exudation of organic carbon stimulate their rhizosphere biota when in apparent need of nutrients for growth. PMID- 26640665 TI - Evolution along the Great Rift Valley: phenotypic and genetic differentiation of East African white-eyes (Aves, Zosteropidae). AB - The moist and cool cloud forests of East Africa represent a network of isolated habitats that are separated by dry and warm lowland savannah, offering an opportunity to investigate how strikingly different selective regimes affect species diversification. Here, we used the passerine genus Zosterops (white-eyes) from this region as our model system. Species of the genus occur in contrasting distribution settings, with geographical mountain isolation driving diversification, and savannah interconnectivity preventing differentiation. We analyze (1) patterns of phenotypic and genetic differentiation in high- and lowland species (different distribution settings), (2) investigate the potential effects of natural selection and temporal and spatial isolation (evolutionary drivers), and (3) critically review the taxonomy of this species complex. We found strong phenotypic and genetic differentiation among and within the three focal species, both in the highland species complex and in the lowland taxa. Altitude was a stronger predictor of phenotypic patterns than the current taxonomic classification. We found longitudinal and latitudinal phenotypic gradients for all three species. Furthermore, wing length and body weight were significantly correlated with altitude and habitat type in the highland species Z. poliogaster. Genetic and phenotypic divergence showed contrasting inter- and intraspecific structures. We suggest that the evolution of phenotypic characters is mainly driven by natural selection due to differences in the two macro habitats, cloud forest and savannah. In contrast, patterns of neutral genetic variation appear to be rather driven by geographical isolation of the respective mountain massifs. Populations of the Z. poliogaster complex, as well as Z. senegalensis and Z. abyssinicus, are not monophyletic based on microsatellite data and have higher levels of intraspecific differentiation compared to the currently accepted species. PMID- 26640666 TI - Warning coloration can be disruptive: aposematic marginal wing patterning in the wood tiger moth. AB - Warning (aposematic) and cryptic colorations appear to be mutually incompatible because the primary function of the former is to increase detectability, whereas the function of the latter is to decrease it. Disruptive coloration is a type of crypsis in which the color pattern breaks up the outline of the prey, thus hindering its detection. This delusion can work even when the prey's pattern elements are highly contrasting; thus, it is possible for an animal's coloration to combine both warning and disruptive functions. The coloration of the wood tiger moth (Parasemia plantaginis) is such that the moth is conspicuous when it rests on vegetation, but when it feigns death and drops to the grass- and litter covered ground, it is hard to detect. This death-feigning behavior therefore immediately switches the function of its coloration from signaling to camouflage. We experimentally tested whether the forewing patterning of wood tiger moths could function as disruptive coloration against certain backgrounds. Using actual forewing patterns of wood tiger moths, we crafted artificial paper moths and placed them on a background image resembling a natural litter and grass background. We manipulated the disruptiveness of the wing pattern so that all (marginal pattern) or none (nonmarginal pattern) of the markings extended to the edge of the wing. Paper moths, each with a hidden palatable food item, were offered to great tits (Parus major) in a large aviary where the birds could search for and attack the "moths" according to their detectability. The results showed that prey items with the disruptive marginal pattern were attacked less often than prey without it. However, the disruptive function was apparent only when the prey was brighter than the background. These results suggest that warning coloration and disruptive coloration can work in concert and that the moth, by feigning death, can switch the function of its coloration from warning to disruptive. PMID- 26640667 TI - Ocean acidification and temperature increase impact mussel shell shape and thickness: problematic for protection? AB - Ocean acidification threatens organisms that produce calcium carbonate shells by potentially generating an under-saturated carbonate environment. Resultant reduced calcification and growth, and subsequent dissolution of exoskeletons, would raise concerns over the ability of the shell to provide protection for the marine organism under ocean acidification and increased temperatures. We examined the impact of combined ocean acidification and temperature increase on shell formation of the economically important edible mussel Mytilus edulis. Shell growth and thickness along with a shell thickness index and shape analysis were determined. The ability of M. edulis to produce a functional protective shell after 9 months of experimental culture under ocean acidification and increasing temperatures (380, 550, 750, 1000 MUatm pCO 2, and 750, 1000 MUatm pCO 2 + 2 degrees C) was assessed. Mussel shells grown under ocean acidification conditions displayed significant reductions in shell aragonite thickness, shell thickness index, and changes to shell shape (750, 1000 MUatm pCO 2) compared to those shells grown under ambient conditions (380 MUatm pCO 2). Ocean acidification resulted in rounder, flatter mussel shells with thinner aragonite layers likely to be more vulnerable to fracture under changing environments and predation. The changes in shape presented here could present a compensatory mechanism to enhance protection against predators and changing environments under ocean acidification when mussels are unable to grow thicker shells. Here, we present the first assessment of mussel shell shape to determine implications for functional protection under ocean acidification. PMID- 26640668 TI - Population and genetic outcomes 20 years after reintroducing bobcats (Lynx rufus) to Cumberland Island, Georgia USA. AB - In 1988-1989, 32 bobcats Lynx rufus were reintroduced to Cumberland Island (CUIS), Georgia, USA, from which they had previously been extirpated. They were monitored intensively for 3 years immediately post-reintroduction, but no estimation of the size or genetic diversity of the population had been conducted in over 20 years since reintroduction. We returned to CUIS in 2012 to estimate abundance and effective population size of the present-day population, as well as to quantify genetic diversity and inbreeding. We amplified 12 nuclear microsatellite loci from DNA isolated from scats to establish genetic profiles to identify individuals. We used spatially explicit capture-recapture population estimation to estimate abundance. From nine unique genetic profiles, we estimate a population size of 14.4 (SE = 3.052) bobcats, with an effective population size (N e) of 5-8 breeding individuals. This is consistent with predictions of a population viability analysis conducted at the time of reintroduction, which estimated the population would average 12-13 bobcats after 10 years. We identified several pairs of related bobcats (parent-offspring and full siblings), but ~75% of the pairwise comparisons were typical of unrelated individuals, and only one individual appeared inbred. Despite the small population size and other indications that it has likely experienced a genetic bottleneck, levels of genetic diversity in the CUIS bobcat population remain high compared to other mammalian carnivores. The reintroduction of bobcats to CUIS provides an opportunity to study changes in genetic diversity in an insular population without risk to this common species. Opportunities for natural immigration to the island are limited; therefore, continued monitoring and supplemental bobcat reintroductions could be used to evaluate the effect of different management strategies to maintain genetic diversity and population viability. The successful reintroduction and maintenance of a bobcat population on CUIS illustrates the suitability of translocation as a management tool for re-establishing felid populations. PMID- 26640669 TI - Priority effects of early successional insects influence late successional fungi in dead wood. AB - Community assembly is an integral process in all ecosystems, producing patterns of species distributions, biodiversity, and ecosystem functioning. Environmental filters and colonization history govern the assembly process, but their relative importance varies depending on the study system. Dead wood decomposition is a slow process, allowing decomposer communities to develop within a slowly changing substrate for decades. Despite this, there are few long-term studies of priority effects from colonization history in this ecosystem. In this study, we investigate the importance of insects in early succession of dead wood on the fungal community present one decade later. Sixty aspen trees were killed in two study landscapes, each tree producing one aspen high stump and log. Insects were sampled with flight interception traps during the first 4 years after tree death, and fungal fruiting bodies were registered in year twelve. We found positive priority effects of two fungivorous beetles, the sap beetle Glischrochilus quadripunctatus and the round fungus beetle Agathidium nigripenne, on the Artist's bracket (Ganoderma applanatum) and a positive priority effect of wood boring beetles on the ascomycete Yellow fairy cup (Bisporella citrina). The Aspen bracket (Phellinus tremulae) did not respond to insects in early succession of the dead wood. Our results suggest that early successional insects can have significant, long-lasting effects on the late successional fungal community in dead wood. Also, the effect can be specific, with one fungus species depending on one or a few fungivorous beetle species. This has implications for decomposition and biodiversity in dead wood, as loss of early colonizing beetles may also affect the successional pathways they seem to initiate. PMID- 26640670 TI - Population genetic structure of Bellamya aeruginosa (Mollusca: Gastropoda: Viviparidae) in China: weak divergence across large geographic distances. AB - Bellamya aeruginosa is a widely distributed Chinese freshwater snail that is heavily harvested, and its natural habitats are under severe threat due to fragmentation and loss. We were interested whether the large geographic distances between populations and habitat fragmentation have led to population differentiation and reduced genetic diversity in the species. To estimate the genetic diversity and population structure of B. aeruginosa, 277 individuals from 12 populations throughout its distribution range across China were sampled: two populations were sampled from the Yellow River system, eight populations from the Yangtze River system, and two populations from isolated plateau lakes. We used seven microsatellite loci and mitochondrial cytochrome oxidase I sequences to estimate population genetic parameters and test for demographic fluctuations. Our results showed that (1) the genetic diversity of B. aeruginosa was high for both markers in most of the studied populations and effective population sizes appear to be large, (2) only very low and mostly nonsignificant levels of genetic differentiation existed among the 12 populations, gene flow was generally high, and (3) relatively weak geographic structure was detected despite large geographic distances between populations. Further, no isolation by linear or stream distance was found among populations within the Yangtze River system and no signs of population bottlenecks were detected. Gene flow occurred even between far distant populations, possibly as a result of passive dispersal during flooding events, zoochoric dispersal, and/or anthropogenic translocations explaining the lack of stronger differentiation across large geographic distances. The high genetic diversity of B. aeruginosa and the weak population differentiation are likely the results of strong gene flow facilitated by passive dispersal and large population sizes suggesting that the species currently is not of conservation concern. PMID- 26640671 TI - multimark: an R package for analysis of capture-recapture data consisting of multiple "noninvasive" marks. AB - I describe an open-source R package, multimark, for estimation of survival and abundance from capture-mark-recapture data consisting of multiple "noninvasive" marks. Noninvasive marks include natural pelt or skin patterns, scars, and genetic markers that enable individual identification in lieu of physical capture. multimark provides a means for combining and jointly analyzing encounter histories from multiple noninvasive sources that otherwise cannot be reliably matched (e.g., left- and right-sided photographs of bilaterally asymmetrical individuals). The package is currently capable of fitting open population Cormack Jolly-Seber (CJS) and closed population abundance models with up to two mark types using Bayesian Markov chain Monte Carlo (MCMC) methods. multimark can also be used for Bayesian analyses of conventional capture-recapture data consisting of a single-mark type. Some package features include (1) general model specification using formulas already familiar to most R users, (2) ability to include temporal, behavioral, age, cohort, and individual heterogeneity effects in detection and survival probabilities, (3) improved MCMC algorithm that is computationally faster and more efficient than previously proposed methods, (4) Bayesian multimodel inference using reversible jump MCMC, and (5) data simulation capabilities for power analyses and assessing model performance. I demonstrate use of multimark using left- and right-sided encounter histories for bobcats (Lynx rufus) collected from remote single-camera stations in southern California. In this example, there is evidence of a behavioral effect (i.e., trap "happy" response) that is otherwise indiscernible using conventional single-sided analyses. The package will be most useful to ecologists seeking stronger inferences by combining different sources of mark-recapture data that are difficult (or impossible) to reliably reconcile, particularly with the sparse datasets typical of rare or elusive species for which noninvasive sampling techniques are most commonly employed. Addressing deficiencies in currently available software, multimark also provides a user-friendly interface for performing Bayesian multimodel inference using capture-recapture data consisting of a single conventional mark or multiple noninvasive marks. PMID- 26640672 TI - Spatial pattern of adaptive and neutral genetic diversity across different biomes in the lesser anteater (Tamandua tetradactyla). AB - The genes of the major histocompatibility complex (MHC) code for proteins involved in antigen recognition and activation of the adaptive immune response and are thought to be regulated by natural selection, especially due to pathogen driven selective pressure. In this study, we investigated the spatial distribution of MHC class II DRB exon 2 gene diversity of the lesser anteater (Tamandua tetradactyla) across five Brazilian biomes using next-generation sequencing and compared the MHC pattern with that of neutral markers (microsatellites). We found a noticeable high level of diversity in DRB (60 amino acid alleles in 65 individuals) and clear signatures of historical positive selection acting on this gene. Higher allelic richness and proportion of private alleles were found in rain forest biomes, especially Amazon forest, a megadiverse biome, possibly harboring greater pathogen richness as well. Neutral markers, however, showed a similar pattern to DRB, demonstrating the strength of demography as an additional force to pathogen-driven selection in shaping MHC diversity and structure. This is the first characterization and description of diversity of a MHC gene for any member of the magna-order Xenarthra, one of the basal lineages of placental mammals. PMID- 26640673 TI - Winners always win: growth of a wide range of plant species from low to future high CO2. AB - Evolutionary adaptation to variation in resource supply has resulted in plant strategies that are based on trade-offs in functional traits. Here, we investigate, for the first time across multiple species, whether such trade-offs are also apparent in growth and morphology responses to past low, current ambient, and future high CO 2 concentrations. We grew freshly germinated seedlings of up to 28 C3 species (16 forbs, 6 woody, and 6 grasses) in climate chambers at 160 ppm, 450 ppm, and 750 ppm CO 2. We determined biomass, allocation, SLA (specific leaf area), LAR (leaf area ratio), and RGR (relative growth rate), thereby doubling the available data on these plant responses to low CO 2. High CO 2 increased RGR by 8%; low CO 2 decreased RGR by 23%. Fast growers at ambient CO 2 had the greatest reduction in RGR at low CO 2 as they lost the benefits of a fast-growth morphology (decoupling of RGR and LAR [leaf area ratio]). Despite these shifts species ranking on biomass and RGR was unaffected by CO 2, winners continued to win, regardless of CO 2. Unlike for other plant resources we found no trade-offs in morphological and growth responses to CO 2 variation, changes in morphological traits were unrelated to changes in growth at low or high CO 2. Thus, changes in physiology may be more important than morphological changes in response to CO 2 variation. PMID- 26640674 TI - Ecological genetics of range size variation in Boechera spp. (Brassicaceae). AB - Many taxonomic groups contain both rare and widespread species, which indicates that range size can evolve quickly. Many studies have compared molecular genetic diversity, plasticity, or phenotypic traits between rare and widespread species; however, a suite of genetic attributes that unites rare species remains elusive. Here, using two rare and two widespread Boechera (Brassicaceae) species, we conduct a simultaneous comparison of quantitative trait diversity, genetic diversity, and population structure among species with highly divergent range sizes. Consistent with previous studies, we do not find strong associations between range size and within-population genetic diversity. In contrast, we find that both the degree of phenotypic plasticity and quantitative trait structure (Q ST) were positively correlated with range size. We also found higher F ST: Q ST ratios in rare species, indicative of either a greater response to stabilizing selection or a lack of additive genetic variation. While widespread species occupy more ecological and climactic space and have diverged at both traits and markers, rare species display constrained levels of population differentiation and phenotypic plasticity. Combined, our results provide evidence for a specialization-generalization trade-off across three orders of magnitude of range size variation in the ecological model genus, Boechera. PMID- 26640675 TI - Predator-driven elemental cycling: the impact of predation and risk effects on ecosystem stoichiometry. AB - Empirical evidence is beginning to show that predators can be important drivers of elemental cycling within ecosystems by propagating indirect effects that determine the distribution of elements among trophic levels as well as determine the chemical content of organic matter that becomes decomposed by microbes. These indirect effects can be propagated by predator consumptive effects on prey, nonconsumptive (risk) effects, or a combination of both. Currently, there is insufficient theory to predict how such predator effects should propagate throughout ecosystems. We present here a theoretical framework for exploring predator effects on ecosystem elemental cycling to encourage further empirical quantification. We use a classic ecosystem trophic compartment model as a basis for our analyses but infuse principles from ecological stoichiometry into the analyses of elemental cycling. Using a combined analytical-numerical approach, we compare how predators affect cycling through consumptive effects in which they control the flux of nutrients up trophic chains; through risk effects in which they change the homeostatic elemental balance of herbivore prey which accordingly changes the element ratio herbivores select from plants; and through a combination of both effects. Our analysis reveals that predators can have quantitatively important effects on elemental cycling, relative to a model formalism that excludes predator effects. Furthermore, the feedbacks due to predator nonconsumptive effects often have the quantitatively strongest impact on whole ecosystem elemental stocks, production and efficiency rates, and recycling fluxes by changing the stoichiometric balance of all trophic levels. Our modeling framework predictably shows how bottom-up control by microbes and top-down control by predators on ecosystems become interdependent when top predator effects permeate ecosystems. PMID- 26640676 TI - Effects of prolonged drought on the anatomy of sun and shade needles in young Norway spruce trees. AB - Predicted increases in the frequency and duration of drought are expected to negatively affect tree vitality, but we know little about how water shortage will influence needle anatomy and thereby the trees' photosynthetic and hydraulic capacity. In this study, we evaluated anatomical changes in sun and shade needles of 20-year-old Norway spruce trees exposed to artificial drought stress. Canopy position was found to be important for needle structure, as sun needles had significantly higher values than shade needles for all anatomical traits (i.e., cross-sectional needle area, number of tracheids in needle, needle hydraulic conductivity, and tracheid lumen area), except proportion of xylem area per cross sectional needle area. In sun needles, drought reduced all trait values by 10 40%, whereas in shade needles, only tracheid maximum diameter was reduced by drought. Due to the relatively weaker response of shade needles than sun needles in drought-stressed trees, the difference between the two needle types was reduced by 25% in the drought-stressed trees compared to the control trees. The observed changes in needle anatomy provide new understanding of how Norway spruce adapts to drought stress and may improve predictions of how forests will respond to global climate change. PMID- 26640677 TI - Predictors of male insemination success in the mosquitofish (Gambusia holbrooki). AB - Identifying targets of selection is key to understanding the evolution of sexually selected behavioral and morphological traits. Many animals have coercive mating, yet little is known about whether and how mate choice operates when these are the dominant mating tactic. Here, we use multivariate selection analysis to examine the direction and shape of selection on male insemination success in the mosquitofish (Gambusia holbrooki). We found direct selection on only one of five measured traits, but correlational selection involving all five traits. Larger males with longer gonopodia and with intermediate sperm counts were more likely to inseminate females than smaller males with shorter gonopodia and extreme sperm counts. Our results highlight the need to investigate sexual selection using a multivariate framework even in species that lack complex sexual signals. Further, female choice appears to be important in driving the evolution of male sexual traits in this species where sexual coercion is the dominant mating tactic. PMID- 26640678 TI - Screening of candidate genes and fine mapping of drought tolerance quantitative trait loci on chromosome 4 in rice (Oryza sativa L.) under drought stress. AB - Due to severe water resource shortage, genetics of and breeding for DT (drought tolerance) in rice (Oryza sativa L.) have become one of the hot research topics. Identification of grain yield QTLs (quantitative trait loci) directly related to the DT trait of rice can provide useful information for breeding new drought resistant and water-saving rice varieties via marker-assisted selection. A population of 105 advanced BILs (backcross introgression lines) derived from a cross between Zhenshan97B and IRAT109 in Zhenshan97B background were grown under drought stress in a field experiment and phenotypic traits were investigated. The results showed that in the target interval of RM273-RM255 on chromosome 4, three main-effect QTLs related to panicle length, panicle number, and spikelet number per panicle were identified (LOD [logarithm of the odds] > 2.0). The panicle length-related QTL had two loci located in the neighboring intervals of RM17308 RM17305 and RM17349-RM17190, which explained 18.80% and 20.42%, respectively, of the phenotypic variation, while the panicle number-related QTL was identified in the interval of RM1354-RM17308, explaining 11.47% of the phenotypic variation. As far as the spikelet number per panicle-related QTL was concerned, it was found to be located in the interval of RM17308-RM17305, which explained 28.08% of the phenotypic variation. Using the online Plant-GE query system, a total of 13 matched ESTs (expressed sequence tags) were found in the target region, and of the 13 ESTs, 12 had corresponding predicted genes. For instance, the two ESTs CB096766 and CA765747 were corresponded to the same predicted gene LOC_Os04g46370, while the other four ESTs, CA754286, CB000011, CX056247, and CX056240, were corresponded to the same predicted gene LOC_Os04g46390. PMID- 26640679 TI - Exceptional avian herbivores: multiple transitions toward herbivory in the bird order Anseriformes and its correlation with body mass. AB - Herbivory is rare among birds and is usually thought to have evolved predominately among large, flightless birds due to energetic constraints or an association with increased body mass. Nearly all members of the bird order Anseriformes, which includes ducks, geese, and swans, are flighted and many are predominately herbivorous. However, it is unknown whether herbivory represents a derived state for the order and how many times a predominately herbivorous diet may have evolved. Compiling data from over 200 published diet studies to create a continuous character for herbivory, models of trait evolution support at least five independent transitions toward a predominately herbivorous diet in Anseriformes. Although a nonphylogenetic correlation test recovers a significant positive correlation between herbivory and body mass, this correlation is not significant when accounting for phylogeny. These results indicate a lack of support for the hypothesis that a larger body mass confers an advantage in the digestion of low-quality diets but does not exclude the possibility that shifts to a more abundant food source have driven shifts toward herbivory in other bird lineages. The exceptional number of transitions toward a more herbivorous diet in Anseriformes and lack of correlation with body mass prompts a reinterpretation of the relatively infrequent origination of herbivory among flighted birds. PMID- 26640680 TI - Macroscale intraspecific variation and environmental heterogeneity: analysis of cold and warm zone abundance, mortality, and regeneration distributions of four eastern US tree species. AB - I test for macroscale intraspecific variation of abundance, mortality, and regeneration of four eastern US tree species (Tsuga canadensis,Betula lenta,Liriodendron tulipifera, and Quercus prinus) by splitting them into three climatic zones based on plant hardiness zones (PHZs). The primary goals of the analysis are to assess the differences in environmental heterogeneity and demographic responses among climatic zones, map regional species groups based on decision tree rules, and evaluate univariate and multivariate patterns of species demography with respect to environmental variables. I use the Forest Inventory Analysis (FIA) data to derive abundance, mortality, and regeneration indices and split the range into three climatic zones based on USDA PHZs: (1) cold adapted, leading region; (2) middle, well-adapted region; and (3) warm adapted, trailing region. I employ decision tree ensemble methods to assess the importance of environmental predictors on the abundance of the species between the cold and warm zones and map zonal variations in species groups. Multivariate regression trees are used to simultaneously explore abundance, mortality, and regeneration in tandem to assess species vulnerability. Analyses point to the relative importance of climate in the warm adapted, trailing zone (especially moisture) compared to the cold adapted, leading zone. Higher mortality and lower regeneration patterns in the warm trailing zone point to its vulnerability to growing season temperature and precipitation changes that could figure more prominently in the future. This study highlights the need to account for intraspecific variation of demography in order to understand environmental heterogeneity and differential adaptation. It provides a methodology for assessing the vulnerability of tree species by delineating climatic zones based on easily available PHZ data, and FIA derived abundance, mortality, and regeneration indices as a proxy for overall growth and fitness. Based on decision tree rules, ecologically meaningful variations in species abundance among the climatic zones can be related to environmental variability and mapped. PMID- 26640681 TI - Red mason bees cannot compete with honey bees for floral resources in a cage experiment. AB - Intensive beekeeping to mitigate crop pollination deficits and habitat loss may cause interspecific competition between bees. Studies show negative correlations between flower visitation of honey bees (Apis mellifera) and wild bees, but effects on the reproduction of wild bees were not proven. Likely reasons are that honey bees can hardly be excluded from controls and wild bee nests are generally difficult to detect in field experiments. The goal of this study was to investigate whether red mason bees (Osmia bicornis) compete with honey bees in cages in order to compare the reproduction of red mason bees under different honey bee densities. Three treatments were applied, each replicated in four cages of 18 m3 with 38 red mason bees in all treatments and 0, 100, and 300 honey bees per treatment with 10-20% being foragers. Within the cages, the flower visitation and interspecific displacements from flowers were observed. Niche breadths and resource overlaps of both bee species were calculated, and the reproduction of red mason bees was measured. Red mason bees visited fewer flowers when honey bees were present. Niche breadth of red mason bees decreased with increasing honey bee density while resource overlaps remained constant. The reproduction of red mason bees decreased in cages with honey bees. In conclusion, our experimental results show that in small and isolated flower patches, wild bees can temporarily suffer from competition with honey bees. Further research should aim to test for competition on small and isolated flower patches in real landscapes. PMID- 26640682 TI - Predicting bird phenology from space: satellite-derived vegetation green-up signal uncovers spatial variation in phenological synchrony between birds and their environment. AB - Population-level studies of how tit species (Parus spp.) track the changing phenology of their caterpillar food source have provided a model system allowing inference into how populations can adjust to changing climates, but are often limited because they implicitly assume all individuals experience similar environments. Ecologists are increasingly using satellite-derived data to quantify aspects of animals' environments, but so far studies examining phenology have generally done so at large spatial scales. Considering the scale at which individuals experience their environment is likely to be key if we are to understand the ecological and evolutionary processes acting on reproductive phenology within populations. Here, we use time series of satellite images, with a resolution of 240 m, to quantify spatial variation in vegetation green-up for a 385-ha mixed-deciduous woodland. Using data spanning 13 years, we demonstrate that annual population-level measures of the timing of peak abundance of winter moth larvae (Operophtera brumata) and the timing of egg laying in great tits (Parus major) and blue tits (Cyanistes caeruleus) is related to satellite-derived spring vegetation phenology. We go on to show that timing of local vegetation green-up significantly explained individual differences in tit reproductive phenology within the population, and that the degree of synchrony between bird and vegetation phenology showed marked spatial variation across the woodland. Areas of high oak tree (Quercus robur) and hazel (Corylus avellana) density showed the strongest match between remote-sensed vegetation phenology and reproductive phenology in both species. Marked within-population variation in the extent to which phenology of different trophic levels match suggests that more attention should be given to small-scale processes when exploring the causes and consequences of phenological matching. We discuss how use of remotely sensed data to study within-population variation could broaden the scale and scope of studies exploring phenological synchrony between organisms and their environment. PMID- 26640683 TI - A spatially explicit capture-recapture estimator for single-catch traps. AB - Single-catch traps are frequently used in live-trapping studies of small mammals. Thus far, a likelihood for single-catch traps has proven elusive and usually the likelihood for multicatch traps is used for spatially explicit capture-recapture (SECR) analyses of such data. Previous work found the multicatch likelihood to provide a robust estimator of average density. We build on a recently developed continuous-time model for SECR to derive a likelihood for single-catch traps. We use this to develop an estimator based on observed capture times and compare its performance by simulation to that of the multicatch estimator for various scenarios with nonconstant density surfaces. While the multicatch estimator is found to be a surprisingly robust estimator of average density, its performance deteriorates with high trap saturation and increasing density gradients. Moreover, it is found to be a poor estimator of the height of the detection function. By contrast, the single-catch estimators of density, distribution, and detection function parameters are found to be unbiased or nearly unbiased in all scenarios considered. This gain comes at the cost of higher variance. If there is no interest in interpreting the detection function parameters themselves, and if density is expected to be fairly constant over the survey region, then the multicatch estimator performs well with single-catch traps. However if accurate estimation of the detection function is of interest, or if density is expected to vary substantially in space, then there is merit in using the single-catch estimator when trap saturation is above about 60%. The estimator's performance is improved if care is taken to place traps so as to span the range of variables that affect animal distribution. As a single-catch likelihood with unknown capture times remains intractable for now, researchers using single-catch traps should aim to incorporate timing devices with their traps. PMID- 26640684 TI - Population genetic analyses are consistent with the introduction of Ceramium secundatum (Ceramiaceae, Rhodophyta) to Narragansett Bay, Rhode Island, USA. AB - During ongoing DNA barcode (COI-5P) surveys of the macroalgal flora along the northwest Atlantic coast, we discovered a population of Ceramium secundatum in Narragansett Bay, Rhode Island, USA. This species is regarded as common and widespread in the northeast Atlantic, ranging from Norway to Morocco, but until now has not been reported from the western Atlantic. Several lines of evidence suggest that C. secundatum may be introduced to Narragansett Bay: (1) despite extensive collecting, specimens have only been obtained from a limited geographic range in the northwest Atlantic; (2) three other nonindigenous seaweed species are reportedly introduced in this region, which is thought to be a consequence of shipping; and (3) this species is introduced to South Africa and New Zealand. To investigate this suspected introduction, we applied population genetic analyses (using the cox2-3 spacer) to compare the Narragansett Bay C. secundatum population to native populations in the Republic of Ireland and the United Kingdom. Collectively, analyses of biogeographical and molecular data indicate that C. secundatum is likely introduced to Narragansett Bay. The implications of this discovery are discussed. PMID- 26640686 TI - Experimental evidence of bark beetle adaptation to a fungal symbiont. AB - The importance of symbiotic microbes to insects cannot be overstated; however, we have a poor understanding of the evolutionary processes that shape most insect microbe interactions. Many bark beetle (Coleoptera: Curculionidae, Scolytinae) species are involved in what have been described as obligate mutualisms with symbiotic fungi. Beetles benefit through supplementing their nutrient-poor diet with fungi and the fungi benefit through gaining transportation to resources. However, only a few beetle-fungal symbioses have been experimentally manipulated to test whether the relationship is obligate. Furthermore, none have tested for adaptation of beetles to their specific symbionts, one of the requirements for coevolution. We experimentally manipulated the western pine beetle-fungus symbiosis to determine whether the beetle is obligately dependent upon fungi and to test for fine-scale adaptation of the beetle to one of its symbiotic fungi, Entomocorticium sp. B. We reared beetles from a single population with either a natal isolate of E. sp. B (isolated from the same population from which the beetles originated), a non-natal isolate (a genetically divergent isolate from a geographically distant beetle population), or with no fungi. We found that fungi were crucial for the successful development of western pine beetles. We also found no significant difference in the effects of the natal and non-natal isolate on beetle fitness parameters. However, brood adult beetles failed to incorporate the non-natal fungus into their fungal transport structure (mycangium) indicating adaption by the beetle to particular genotypes of symbiotic fungi. Our results suggest that beetle-fungus mutualisms and symbiont fidelity may be maintained via an undescribed recognition mechanism of the beetles for particular symbionts that may promote particular associations through time. PMID- 26640685 TI - Plasma markers of oxidative stress are uncorrelated in a wild mammal. AB - Oxidative stress, which results from an imbalance between the production of potentially damaging reactive oxygen species versus antioxidant defenses and repair mechanisms, has been proposed as an important mediator of life-history trade-offs. A plethora of biomarkers associated with oxidative stress exist, but few ecological studies have examined the relationships among different markers in organisms experiencing natural conditions or tested whether those relationships are stable across different environments and demographic groups. It is therefore not clear to what extent studies of different markers can be compared, or whether studies that focus on a single marker can draw general conclusions regarding oxidative stress. We measured widely used markers of oxidative damage (protein carbonyls and malondialdehyde) and antioxidant defense (superoxide dismutase and total antioxidant capacity) from 706 plasma samples collected over a 4-year period in a wild population of Soay sheep on St Kilda. We quantified the correlation structure among these four markers across the entire sample set and also within separate years, age groups (lambs and adults), and sexes. We found some moderately strong correlations between some pairs of markers when data from all 4 years were pooled. However, these correlations were caused by considerable among-year variation in mean marker values; correlation coefficients were small and not significantly different from zero after accounting for among-year variation. Furthermore, within each year, age, and sex subgroup, the pairwise correlation coefficients among the four markers were weak, nonsignificant, and distributed around zero. In addition, principal component analysis confirmed that the four markers represented four independent axes of variation. Our results suggest that plasma markers of oxidative stress may vary dramatically among years, presumably due to environmental conditions, and that this variation can induce population-level correlations among markers even in the absence of any correlations within contemporaneous subgroups. The absence of any consistent correlations within years or demographic subgroups implies that care must be taken when generalizing from observed relationships with oxidative stress markers, as each marker may reflect different and potentially uncoupled biochemical processes. PMID- 26640687 TI - Differential effects of climate and species interactions on range limits at a hybrid zone: potential direct and indirect impacts of climate change. AB - The relative contributions of climate versus interspecific interactions in shaping species distributions have important implications for closely related species at contact zones. When hybridization occurs within a contact zone, these factors regulate hybrid zone location and movement. While a hybrid zone's position may depend on both climate and interactions between the hybridizing species, little is known about how these factors interact to affect hybrid zone dynamics. Here, we utilize SDM (species distribution modeling) both to characterize the factors affecting the current location of a moving North American avian hybrid zone and to predict potential direct and indirect effects of climate change on future distributions. We focus on two passerine species that hybridize where their ranges meet, the Black-capped (Poecile atricapillus) and Carolina (P. carolinensis) chickadee. Our contemporary climate models predict the occurrence of climatically suitable habitat extending beyond the hybrid zone for P. atricapillus only, suggesting that interspecific interactions primarily regulate this range boundary in P. atricapillus, while climatic factors regulate P. carolinensis. Year 2050 climate models predict a drastic northward shift in suitable habitat for P. carolinensis. Because of the greater importance of interspecific interactions for regulating the southern range limit of P. atricapillus, these climate-mediated shifts in the distribution of P. carolinensis may indirectly lead to a range retraction in P. atricapillus. Together, our results highlight the ways climate change can both directly and indirectly affect species distributions and hybrid zone location. In addition, our study lends support to the longstanding hypothesis that abiotic factors regulate species' poleward range limits, while biotic factors shape equatorial range limits. PMID- 26640688 TI - An atypical reproductive cycle in a common viviparous Asia Agamid Phrynocephalus vlangalii. AB - Viviparous lizards living in cold climate of high altitude often exhibit atypical reproductive cycles, in which mating and fertilization occur synchronously and annually with parturition occurring at the end of the year. Nevertheless, detailed case studies on atypical reproductive cycles are few. Using anatomical data combined with behavioral observations, we examined the reproductive cycle of a common Asian agamid, Phrynocephalus vlangalii, from a high-elevation area in Sichuan, China. Male spermiation of P. vlangalii occurred in May, and spermatogenesis began in June and reached a maximum in October. For females, ovulation and fertilization occurred in May, and females developed gestation and pregnancy in 3 months from June to August, without vitellogenesis during this period. Females gave birth synchronously in late August, then vitellogenesis began and lasted until May of the next year. All adult males and females were synchronized in the same reproductive condition each month. The synchronous and annual reproductive cycle of P. vlangalii clearly represents an atypical cycle. The male courtship and mating behaviors were concordant with gonadal cycle and mainly happened in May and June. Despite the short growth period for neonates, they had a high over-winter survival rate of 84.4%, suggesting that autumn parturition did not generate high costs to this reproductive cycle. We propose that the high over-winter survival rate of neonates is likely linked with female delayed sexual maturity, female asynchronous vitellogenesis and gestation, large relative clutch mass (RCM), and adult-offspring burrow sharing behavior during hibernation. PMID- 26640689 TI - Click synthesis of a polyamidoamine dendrimer-based camptothecin prodrug. AB - In the present work we report on the click synthesis of a new camptothecin (CPT) prodrug based on anionic polyamidoamine (PAMAM) dendrimer intended for cancer therapy. We applied 'click' chemistry to improve polymer-drug coupling reaction efficiency. Specifically, CPT was functionalized with a spacer, 1-azido 3,6,9,12,15-pentaoxaoctadecan-18-oic acid (APO), via EDC/DMAP coupling reaction. In parallel, propargylamine (PPA) and methoxypoly(ethylene glycol) amine were conjugated to PAMAM dendrimer G4.5 in sequence using an effective coupling agent 4-(4,6-dimethoxy-(1,3,5)triazin-2-yl)-4-methyl-morpholinium chloride (DMTMM). CPT APO was then coupled to PEGylated PAMAM dendrimer G4.5-PPA via a click reaction using copper bromide/2,2'-bipyridine/ dimethyl sulfoxide (catalyst/ligand/solvent). Human glioma cells were exposed to the CPT-conjugate to determine toxicity and cell cycle effects using WST-1 assay and flow cytometry. The CPT-conjugate displayed a dose-dependent toxicity with an IC50 of 5 MUM, a 185-fold increase relative to free CPT, presumably as a result of slow release. As expected, conjugated CPT resulted in G2/M arrest and cell death while the dendrimer itself had little to no toxicity. Altogether, highly efficient click chemistry allows for the synthesis of multifunctional dendrimers for sustained drug delivery. PMID- 26640690 TI - GenomeTester4: a toolkit for performing basic set operations - union, intersection and complement on k-mer lists. AB - BACKGROUND: K-mer-based methods of genome analysis have attracted great interest because they do not require genome assembly and can be performed directly on sequencing reads. Many analysis tasks require one to compare k-mer lists from different sequences to find words that are either unique to a specific sequence or common to many sequences. However, no stand-alone k-mer analysis tool currently allows one to perform these algebraic set operations. FINDINGS: We have developed the GenomeTester4 toolkit, which contains a novel tool GListCompare for performing union, intersection and complement (difference) set operations on k mer lists. We provide examples of how these general operations can be combined to solve a variety of biological analysis tasks. CONCLUSIONS: GenomeTester4 can be used to simplify k-mer list manipulation for many biological analysis tasks. PMID- 26640691 TI - Enhanced reproducibility of SADI web service workflows with Galaxy and Docker. AB - BACKGROUND: Semantic Web technologies have been widely applied in the life sciences, for example by data providers such as OpenLifeData and through web services frameworks such as SADI. The recently reported OpenLifeData2SADI project offers access to the vast OpenLifeData data store through SADI services. FINDINGS: This article describes how to merge data retrieved from OpenLifeData2SADI with other SADI services using the Galaxy bioinformatics analysis platform, thus making this semantic data more amenable to complex analyses. This is demonstrated using a working example, which is made distributable and reproducible through a Docker image that includes SADI tools, along with the data and workflows that constitute the demonstration. CONCLUSIONS: The combination of Galaxy and Docker offers a solution for faithfully reproducing and sharing complex data retrieval and analysis workflows based on the SADI Semantic web service design patterns. PMID- 26640692 TI - A single chromosome assembly of Bacteroides fragilis strain BE1 from Illumina and MinION nanopore sequencing data. AB - BACKGROUND: Second and third generation sequencing technologies have revolutionised bacterial genomics. Short-read Illumina reads result in cheap but fragmented assemblies, whereas longer reads are more expensive but result in more complete genomes. The Oxford Nanopore MinION device is a revolutionary mobile sequencer that can produce thousands of long, single molecule reads. RESULTS: We sequenced Bacteroides fragilis strain BE1 using both the Illumina MiSeq and Oxford Nanopore MinION platforms. We were able to assemble a single chromosome of 5.18 Mb, with no gaps, using publicly available software and commodity computing hardware. We identified gene rearrangements and the state of invertible promoters in the strain. CONCLUSIONS: The single chromosome assembly of Bacteroides fragilis strain BE1 was achieved using only modest amounts of data, publicly available software and commodity computing hardware. This combination of technologies offers the possibility of ultra-cheap, high quality, finished bacterial genomes. PMID- 26640693 TI - Associated Anisotropy Decays of Ethidium Bromide Interacting with DNA. AB - Ethidium Bromide (EB) is a commonly used dye in a deoxyribonucleic acid (DNA) study. Upon an intercalation, this dye significantly increases its brightness and fluorescence lifetime. In this report we have studied the time-resolved fluorescence properties of EB existing simultaneously in free and DNA-bound forms in the solution. Fluorescence intensity decays were fitted globally to a double exponential model with lifetimes corresponding to free (1.6ns) and bound (22ns) forms, and molar fractions were determined for all used solutions. Anisotropy decays displayed characteristic time dependence with an initial rapid decline followed by recovery and slow decay. The short-lived fraction associated with free EB molecules decreases faster than long-lived fraction associated with EB bound to DNA. Consequently, contribution from fast rotation leads to initial rapid decay in anisotropy. On the other hand bound fraction, due to slow rotation helps recover anisotropy in time. This effect of associated anisotropy decays in systems such as EB free/EB-DNA is clearly visible in a wide range of concentrations, and should be taken into account in polarization assays and biomolecule dynamics studies. PMID- 26640694 TI - Effects of a home-exercise therapy programme on cervical and lumbar range of motion among nurses with neck and lower back pain: a quasi-experimental study. AB - BACKGROUND: Cervical and lumbar range of motion limitations are usually associated with musculoskeletal pain in the neck and lower back, and are a major health problem among nurses. Physical exercise has been evaluated as an effective intervention method for improving cervical and lumbar range of motion, and for preventing and reducing musculoskeletal pain. The purpose of this study was to investigate the effects of a home-exercise therapy programme on cervical and lumbar range of motion among intensive care unit nurses who had experienced mild to moderate musculoskeletal pain in the neck and or lower back during the previous six months. METHODS: A quasi-experimental study was conducted among intensive care unit nurses at Tartu University Hospital (Estonia) between May and July 2011. Thirteen nurses who had suffered musculoskeletal pain episodes in the neck and or lower back during the previous six months underwent an 8-week home exercise therapy programme. Eleven nurses without musculoskeletal pain formed a control group. Questions from the Nordic Musculoskeletal Questionnaire and the 11 point Visual Analogue Scale were used to select potential participants for the experimental group via an assessment of the prevalence and intensity of musculoskeletal pain. Cervical range of motion and lumbar range of motion in flexion, extension, lateral flexion and (cervical range of motion only) rotation were measured with a digital goniometer. A paired t-test was used to compare the measured parameters before and after the home-exercise therapy programme. A Student's t-test was used to analyse any differences between the experimental and control groups. RESULTS: After the home-exercise therapy, there was a significant increase (p < 0.05) in cervical range of motion in flexion, extension, lateral flexion and rotation, and in lumbar range of motion in lateral flexion. Cervical range of motion in flexion was significantly higher (p < 0.01) in the experimental group compared to the control group after therapy. CONCLUSIONS: Our results suggest an 8-week intensive home-exercise therapy programme may improve cervical and lumbar range of motion among intensive care nurses. Further studies are needed to develop this simple but effective home-exercise therapy programme to help motivate nurses to perform such exercises regularly. TRIAL REGISTRATION: Current Controlled Trials ISRCTN19278735. Registered 27 November 2015. PMID- 26640695 TI - Using Molecular Markers to Guide Therapy of Metastatic Colorectal Cancer. AB - Colorectal cancer remains one of the most commonly diagnosed cancers with almost one-fourth of patients presenting with metastatic disease at the time of diagnosis. As the repertoire of anticancer agents has expanded to treat colorectal patients with metastatic disease, life expectancies have increased and patients are remaining on therapy for longer periods of time. The exact way in which to combine chemotherapeutic and targeted agents remains a therapeutic challenge in an attempt to preserve efficacy while minimizing toxicity. A crucial need exists for reliable and reproducible biomarkers that can assist in personalizing the most advantageous therapy for patients based on the biology of their tumor that will prevent undue side effects and result in the longest duration of tumor stability. In this review, we discuss the completed studies for each agent currently approved for the treatment of metastatic colon cancer and emphasize a need for further prospective studies to solidify the use of biomarkers in this disease. PMID- 26640697 TI - Developing single nucleotide polymorphism markers for the identification of pineapple (Ananas comosus) germplasm. AB - Pineapple (Ananas comosus [L.] Merr.) is the third most important tropical fruit in the world after banana and mango. As a crop with vegetative propagation, genetic redundancy is a major challenge for efficient genebank management and in breeding. Using expressed sequence tag and nucleotide sequences from public databases, we developed 213 single nucleotide polymorphism (SNP) markers and validated 96 SNPs by genotyping the United States Department of Agriculture - Agricultural Research Service pineapple germplasm collection, maintained in Hilo, Hawaii. The validation resulted in designation of a set of 57 polymorphic SNP markers that revealed a high rate of duplicates in this pineapple collection. Twenty-four groups of duplicates were detected, encompassing 130 of the total 170 A cosmos accessions. The results show that somatic mutation has been the main source of intra-cultivar variations in pineapple. Multivariate clustering and a model-based population stratification suggest that the modern pineapple cultivars are comprised of progenies that are derived from different wild Ananas botanical varieties. Parentage analysis further revealed that both A. comosus var. bracteatus and A. comosus var. ananassoides are likely progenitors of pineapple cultivars. However, the traditional classification of cultivated pineapple into horticultural groups (e.g. 'Cayenne', 'Spanish', 'Queen') was not well supported by the present study. These SNP markers provide robust and universally comparable DNA fingerprints; thus, they can serve as an efficient genotyping tool to assist pineapple germplasm management, propagation of planting material, and pineapple cultivar protection. The high rate of genetic redundancy detected in this pineapple collection suggests the potential impact of applying this technology on other clonally propagated perennial crops. PMID- 26640696 TI - Elucidating the genetic basis of antioxidant status in lettuce (Lactuca sativa). AB - A diet rich in phytonutrients from fruit and vegetables has been acknowledged to afford protection against a range of human diseases, but many of the most popular vegetables are low in phytonutrients. Wild relatives of crops may contain allelic variation for genes determining the concentrations of these beneficial phytonutrients, and therefore understanding the genetic basis of this variation is important for breeding efforts to enhance nutritional quality. In this study, lettuce recombinant inbred lines, generated from a cross between wild and cultivated lettuce (Lactuca serriola and Lactuca sativa, respectively), were analysed for antioxidant (AO) potential and important phytonutrients including carotenoids, chlorophyll and phenolic compounds. When grown in two environments, 96 quantitative trait loci (QTL) were identified for these nutritional traits: 4 for AO potential, 2 for carotenoid content, 3 for total chlorophyll content and 87 for individual phenolic compounds (two per compound on average). Most often, the L. serriola alleles conferred an increase in total AOs and metabolites. Candidate genes underlying these QTL were identified by BLASTn searches; in several cases, these had functions suggesting involvement in phytonutrient biosynthetic pathways. Analysis of a QTL on linkage group 3, which accounted for >30% of the variation in AO potential, revealed several candidate genes encoding multiple MYB transcription factors which regulate flavonoid biosynthesis and flavanone 3-hydroxylase, an enzyme involved in the biosynthesis of the flavonoids quercetin and kaempferol, which are known to have powerful AO activity. Follow-up quantitative RT-PCR of these candidates revealed that 5 out of 10 genes investigated were significantly differentially expressed between the wild and cultivated parents, providing further evidence of their potential involvement in determining the contrasting phenotypes. These results offer exciting opportunities to improve the nutritional content and health benefits of lettuce through marker-assisted breeding. PMID- 26640698 TI - Mitochondrial pathology in progressive cerebellar ataxia. AB - BACKGROUND: Mitochondrial disease can manifest as multi-organ disorder, often with neurological dysfunction. Cerebellar ataxia in isolation or in combination with other features can result from mitochondrial disease yet genetic testing using blood DNA is not sufficient to exclude this as a cause of ataxia. Muscle biopsy is a useful diagnostic tool for patients with ataxia suspected of mitochondrial disease. Our aim was to determine specific patient selection criteria for muscle biopsy to see how frequent mitochondrial mutations are responsible for progressive ataxia. We performed a two centre retrospective review of patients with unexplained progressive ataxia who underwent muscle biopsy for suspected mitochondrial disease between 2004 and 2014 (Sheffield and Newcastle Ataxia Centres). RESULTS: A total of 126 patients were identified; 26 assessed in Newcastle and 100 in Sheffield. Twenty-four patients had pure ataxia and 102 had ataxia with additional features. The total number of patients with histologically suspected and/or genetically confirmed mitochondrial disease was 29/126 (23 %). CONCLUSIONS: A large proportion of patients (23 %) with progressive ataxia who underwent muscle biopsy were found to have features of mitochondrial dysfunction, with molecular confirmation in some. Muscle biopsy is a helpful diagnostic tool for mitochondrial disease in patients with progressive ataxia. PMID- 26640699 TI - Adult patients with supratentorial pilocytic astrocytoma: long-term follow-up of prospective multicenter clinical trial NCCTG-867251 (Alliance). AB - BACKGROUND: Pilocytic astrocytoma is a rare tumor in adults. This report is of a prospective clinical trial with long-term follow-up. METHODS: Between 1986 and 1994, 20 eligible adults with supratentorial pilocytic astrocytomas were enrolled in a prospective intergroup trial of radiotherapy (RT) after biopsy (3 patients) or observation after gross (11 patients) or subtotal (6 patients) resection. RESULTS: At the time of analysis (median follow-up, 20.8 years), 2 patients (10%) have died and 18 patients (90%) are alive. Neurologic and cognitive function were stable or improved over time for the majority of patients. No toxic effects of treatment or malignant transformations have been recorded at last follow-up. For the entire cohort the 20-year time to progression and overall survival rates are 95% and 90% respectively. The cause of death (2.2 and 16.1 years after enrollment) in both patients was unrelated to tumor although both were biopsy only patients. One subtotally resected tumor progressed 1 month after enrollment requiring P32 injection into an enlarging cyst. Because of further progression this patient required RT 18 months later. This patient is alive without evidence of progression 18 years after RT. CONCLUSION: The long-term follow-up results of this prospective trial confirm that adults with pilocytic astrocytomas have a favorable prognosis with regard to survival and neurologic function. Close observation is recommended for adults with pilocytic astrocytomas, reserving RT for salvage, as the majority remain stable after gross or subtotal resection and no adjuvant therapy. PMID- 26640700 TI - Assessment of the First Commercial ELISA Kit for the Diagnosis of Theileria annulata. AB - The present study assesses the efficacy of SVANOVIR Theileria annulata-Ab, the first commercial ELISA kit for the diagnosis of Theileria annulata infection in cattle based on a recombinant protein known as T. annulata surface protein (TaSp). As a reference test, a polymerase chain reaction (PCR) assay depending on T. annulata merozoite surface antigen (Tams-1) was applied. A total of 468 blood samples as well as serum samples were randomly collected from cattle and tested in the PCR as well as in the ELISA developed in this study. Moreover, all samples were also analyzed by conventional Giemsa-stained blood smear. The results of this study revealed a good correlation between the results obtained by PCR and the ELISA, whereas all PCR positive samples scored correctly positive in the ELISA and 73 of the 125 PCR negative samples scored correctly negative. Taken together, a sensitivity of 91.25% and a specificity of 78.4% were recorded, when compared to the PCR data. In conclusion, the SVANOVIR Theileria annulata-Ab is a suitable diagnostic assay for use in the diagnosis and epidemiological surveys of Theileria annulata infection in chronic and carrier animals. PMID- 26640701 TI - Larvicidal Activity of Nerium oleander against Larvae West Nile Vector Mosquito Culex pipiens (Diptera: Culicidae). AB - Background. Outbreaks of the West Nile virus infection were reported in Morocco in 1996, 2003, and 2010. Culex pipiens was strongly suspected as the vector responsible for transmission. In the North center of Morocco, this species has developed resistance to synthetic insecticides. There is an urgent need to find alternatives to the insecticides as natural biocides. Objective. In this work, the insecticidal activity of the extract of the local plant Nerium oleander, which has never been tested before in the North center of Morocco, was studied on larval stages 3 and 4 of Culex pipiens. Methods. Biological tests were realized according to a methodology inspired from standard World Health Organization protocol. The mortality values were determined after 24 h of exposure and LC50 and LC90 values were calculated. Results. The extract had toxic effects on the larvae of culicid mosquitoes. The ethanolic extract of Nerium oleander applied against the larvae of Culex pipiens has given the lethal concentrations LC50 and LC90 in the order of 57.57 mg/mL and 166.35 mg/mL, respectively. Conclusion. This investigation indicates that N. oleander could serve as a potential larvicidal, effective natural biocide against mosquito larvae, particularly Culex pipiens. PMID- 26640702 TI - The Effects of Hemodialysis on Tear Osmolarity. AB - Aim. To determine the effects of hemodialysis (HD) on tear osmolarity and to define the blood biochemical tests correlating with tear osmolarity among patients with end stage renal disease (ESRD). Material-Method. Tear osmolarity of ESRD patients before and after the hemodialysis program was determined as well as the blood biochemical data including glucose, sodium, potassium, calcium, urea, and creatinine levels. Results. Totally 43 eyes of 43 patients (20 females and 23 males) with a mean age of 53.98 +/- 18.06 years were included in the study. Tear osmolarity of patients was statistically significantly decreased after hemodialysis (314.06 +/- 17.77 versus 301.88 +/- 15.22 mOsm/L, p = 0.0001). In correlation analysis, pre-HD tear osmolarity was negatively correlated with pre HD blood creatinine level (r = -0.366, p = 0.016). Post-HD tear osmolarity was statistically significantly correlated with the post-HD glucose levels (r = 0.305 p = 0.047). Tear osmolarity alteration by HD was negatively correlated with creatinine alteration, body weight alteration, and ultrafiltration (r = -0.426, p = 0.004; r = -0.365, p = 0.016; and r = -0.320, p = 0.036, resp.). There was no correlation between tear osmolarity and Kt/V and URR values. Conclusion. HD effectively decreases tear osmolarity to normal values and corrects the volume and composition of the ocular fluid transiently. Tear osmolarity alteration induced by HD is correlated with body weight changes, creatinine alterations, and ultrafiltration. PMID- 26640703 TI - Superior Oblique Anterior Transposition with Horizontal Recti Recession-Resection for Total Third-Nerve Palsy. AB - Aims. To report the results of lateral rectus muscle recession, medial rectus muscle resection, and superior oblique muscle transposition in the restoration and maintenance of ocular alignment in primary position for patients with total third-nerve palsy. Methods. The medical records of patients who underwent surgery between March 2007 and September 2011 for total third-nerve palsy were reviewed. All patients underwent a preoperative assessment, including a detailed ophthalmologic examination. Results. A total of 6 patients (age range, 14-45 years) were included. The median preoperative horizontal deviation was 67.5 Prism Diopter (PD) (interquartile range [IQR] 57.5-70) and vertical deviation was 13.5 PD (IQR 10-20). The median postoperative horizontal residual exodeviation was 8.0 PD (IQR 1-16), and the vertical deviation was 0 PD (IQR 0-4). The median correction of hypotropia following superior oblique transposition was 13.5 +/- 2.9 PD (range, 10-16). All cases were vertically aligned within 5 PD. Four of the six cases were aligned within 10 PD of the horizontal deviation. Adduction and head posture were improved in all patients. All patients gained new area of binocular single vision in the primary position after the operation. Conclusion. Lateral rectus recession, medial rectus resection, and superior oblique transposition may be used to achieve satisfactory cosmetic and functional results in total third-nerve palsy. PMID- 26640704 TI - Loss of Visual Acuity after Successful Surgery for Macula-On Rhegmatogenous Retinal Detachment in a Prospective Multicentre Study. AB - Purpose. To quantify the frequency of visual loss after successful retinal detachment (RD) surgery in macula-on patients in a multicentric, prospective series of RD. Methods. Clinical variables from consecutive macula-on RD patients were collected in a prospective multicentric study. Visual loss was defined as at least a reduction in one line in best corrected visual acuity (VA) with Snellen chart. The series were divided into 4 subgroups: (1) all macula-on eyes (n = 357); (2) macula-on patients with visual loss at the third month of follow-up (n = 53) which were further subdivided in (3) phakic eyes (n = 39); and (4) pseudophakic eyes (n = 14). Results. Fifty-three eyes (14.9%) had visual loss three months after surgery (n = 39 phakic eyes; n = 14 pseudophakic eyes). There were no statistically significant differences between them regarding their clinical characteristics. Pars plana vitrectomy (PPV) was used in 67.2% of cases, scleral buckle in 57.7%, and scleral explant in 11.9% (36.1% were combined procedures). Conclusions. Around 15% of macula-on RD eyes lose VA after successful surgery. Development of cataracts may be one cause in phakic eyes, but vision loss in pseudophakic eyes could have other explanations such as the effect of released factors produced by retinal ischemia on the macula area. Further investigations are necessary to elucidate this hypothesis. PMID- 26640705 TI - Perceived and Ideal Body Image in Young Women in South Western Saudi Arabia. AB - OBJECTIVES: The aim of this study was to investigate perceived and ideal body image (BI) and associated factors among female university students in Saudi Arabia. METHODS: This cross-sectional study included 663 university female students. Anthropometric measurements including weight, height, BMI, and BI perception (the 9-figure silhouette) were obtained. Descriptive and logistic regression analysis were conducted. RESULTS: An agreement between actual, perceived, and ideal BI was found in 23% of the participants. Behavioral (activity levels), social (presence of obese parents and fathers' level of education), and economic factors (households' monthly income, number of cars in the household, and kind of residence) were positively and significantly associated with the desire to be thinner. Similarly, socioeconomic associations (number of sisters and number of cars in the household) correlated positively and significantly with the desire to be heavier. CONCLUSIONS: The whole family should rather be considered in interventions related to appearance concerns and BI discrepancies. Furthermore, campaigns targeting improvement of adolescents' physical self-image should be a major priority of the public health sector. PMID- 26640706 TI - Anemia in Patients with Type 2 Diabetes Mellitus. AB - The objective of this study was to evaluate the prevalence of anemia in DM2 patients and its correlation with demographic and lifestyle and laboratory variables. This is a descriptive and analytical study of the type of case studies in the urban area of the Ijui city, registered in programs of the Family Health Strategy, with a total sample of 146 patients with DM2. A semistructured questionnaire with sociodemographic and clinical variables and performed biochemical test was applied. Of the DM2 patients studied, 50 patients had anemia, and it was found that the body mass items and hypertension and hematological variables are significantly associated with anemia of chronic disease. So, the prevalence of anemia is high in patients with DM2. The set of observed changes characterizes the anemia of chronic disease, which affects quality of life of diabetic patients and is associated with disease progression, development, and comorbidities that contribute significantly to increasing the risk of cardiovascular diseases. PMID- 26640707 TI - Use of Lateral Calcaneal Flap for Coverage of Hindfoot Defects: An Anatomical Appraisal. AB - Lateral calcaneal flap is an established surgical option for coverage of lateral calcaneum and posterior heel defects. Lateral calcaneal flap vascularization and innervations are based on lateral calcaneal artery neurovascular bundle, that is, lateral calcaneal artery, small saphenous vein, and sural nerve. Anatomical research has allowed exploration of its many advantages but can also lead to its various modifications, permitting a wide variety of clinical applications. In this paper the authors report an anatomical and clinical study on lateral calcaneal artery course and lateral calcaneal flap clinical applications. Anatomic part of our study focused on lateral calcaneal artery course and optimization of surgical technique for flap harvesting. Data were used for design of lateral calcaneal flap in 5 patients. Our results were satisfactory in terms of coverage adequacy, perioperative morbidity, and functional and aesthetical outcome. PMID- 26640709 TI - Prevalence of Provocative Seizures in Persons with Epilepsy: A Longitudinal Study at Khon Kaen University Hospital, Thailand. AB - Background and Objective. Provocative factors are one causative factor of seizure attacks in persons with epilepsy (PWE). There are limited data of prevalence and major provocative factors in Asian populations. Methods. This study was performed at the Epilepsy Clinic, Khon Kaen University Hospital. The patients who aged 15 years or over, who had been treated at least 3 months with at least one antiepileptic drug, and who were followed up for at least one year were included. Data of seizure control and triggers were collected retrospectively from medical records. Data analysis was performed to identify independent provocative factors. Results. A total of 382 PWE met the study criteria. The mean age was 40.4 +/- 0.8 years. Approximately 44% of the patients had at least one provocative factor. By multivariate analysis, the independent provocative factors with the first three highest adjusted odds ratios were sleep deprivation (adjusted OR = 8.64, 95% CI 3.73-19.99), alcohol consumption (adjusted OR = 6.76, 95% CI 1.44-31.78), and feeling stressful (adjusted OR = 2.97, 95% CI 1.29-6.86). Conclusion. Almost half of seizure attacks may be caused by provocative factors in Thai PWEs and some factors may be preventable. Avoidance of these factors should be emphasized to epilepsy patients for improving clinical outcomes and quality of life. PMID- 26640708 TI - Comparison of Dry Needling versus Orthopedic Manual Therapy in Patients with Myofascial Chronic Neck Pain: A Single-Blind, Randomized Pilot Study. AB - Objective. The aim of this study was to compare the efficacy of three interventions for the treatment of myofascial chronic neck pain. Methods. Thirty six patients were randomly assigned to one of three intervention groups: orthopedic manual therapy (OMT), dry needling and stretching (DN-S), and soft tissue techniques (STT). All groups received two treatment sessions with a 48 h time interval. Outcome measures included neck pain intensity measured using a visual analogue scale, cervical range of motion (ROM), pressure pain threshold for measuring mechanical hyperalgesia, and two self-reported questionnaires (neck disability index and pain catastrophizing scale). Results. The ANOVA revealed significant differences for the group * time interaction for neck disability, neck pain intensity, and pain catastrophizing. The DN-S and OMT groups reduced neck disability. Only the OMT group showed decreases in mechanical hyperalgesia and pain catastrophizing. The cervical ROM increased in OMT (i.e., flexion, side bending, and rotation) and DN-S (i.e., side-bending and rotation) groups. Conclusions. The three interventions are all effective in reducing pain intensity. Reduction in mechanical hyperalgesia and pain catastrophizing was only observed in the OMT group. Cervical ROM improved in the DN-S and OMT groups and also neck disability being only clinically relevant for OMT group. PMID- 26640710 TI - Mechanical Recanalization following i.v. Thrombolysis: A Retrospective Analysis regarding Secondary Hemorrhagic Infarctions and Parenchymal Hematomas. AB - Introduction. In acute stroke by occlusion of the proximal medial cerebral artery (MCA) or the distal internal carotid artery, intravenous thrombolysis is an established treatment. Another option is mechanical recanalization. It remains unclear if the combination of both methods poses an additional bleeding risk. The aim of this retrospective analysis is to determine the proportion of hemorrhagic infarctions and parenchymal hematomas. Methods. Inclusion criteria were an occlusion of the carotid T or proximal MCA treated with full dose thrombolysis and mechanical recanalization. 31 patients were selected. Devices used were Trevo, Penumbra Aspiration system, Penumbra 3D Retriever, and Revive. The initial control by computed tomography was carried out with a mean delay to intervention of 10.9 hours (SD: 8.5 hours). Results. A slight hemorrhagic infarction (HI1) was observed in 2/31 patients, and a more severe HI2 occurred in two cases. A smaller parenchymal hematoma (PH1) was not seen and a space-occupying PH2 was seen in 2/31 cases. There was no significant difference in the probability of intracranial bleeding after successful (thrombolysis in cerebral infarctions 2b and 3) or unsuccessful recanalization. Conclusion. The proportion of intracranial bleeding using mechanical recanalization following intravenous thrombolysis appears comparable with reports using thrombolysis alone. PMID- 26640711 TI - Distal Insertional Footprint of the Brachialis Muscle: 3D Morphometric Study. AB - Objective. The purpose of this study is to describe the three-dimensional morphometry of the brachialis muscle at its distal attachment to the ulna. Methods. Fifty cadaveric elbows were dissected and the brachialis distal insertion was isolated on the ulna bone and probed with a three-dimensional digitizer, to create a three-dimensional model of the footprint. Measurements and analysis of each footprint shape were recorded and compared based on gender and size. Results. There was significant gender difference in the surface length (P= 0.002) and projected length (P= 0.001) of the brachialis footprint. The shapes of the footprint also differed among the specimens. Conclusion. The shape of the brachialis muscle insertion differed among all the specimens without significant variation in gender or sides. There was also a significant difference in muscle length between males and females with little difference in the width and surface area. Significance. The information obtained from this study is important for kinematic understanding and surgical procedures around the elbow joint as well as the understanding of the natural age related anatomy of the brachialis footprint morphology. PMID- 26640712 TI - Very Long Term Stability of Mixed Chimerism after Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Hematologic Malignancies. AB - The objective of this study is to analyze the evolution of chimerism of all patients transplanted for hematologic malignancies in our unit during a 20-year period, alive without relapse at 1 year after allogeneic hematopoietic stem cell transplantation (HSCT). Chimerism was tested using short tandem repeat polymorphisms after separation into mononuclear cells and granulocytes by Ficoll density gradient centrifugation. Of 155 patients studied, 89 had full chimerism (FC), 36 mononuclear cells mixed chimerism (MNC-MC), and 30 granulocytic MC with or without mononuclear cells MC (Gran-MC). Survival was significantly better in MNC-MC than in Gran-MC patients, with FC patients being intermediate. There was more disease relapse in the Gran-MC group but not in the MNC-MC group as compared to FC. MC was stable up to 21 years in the MNC-MC group and up to 19 years in the Gran-MC group. Of MC patients alive at 10 years, MC persisted in 83% in the MNC MC and 57% in the Gran-MC groups. In conclusion, mixed chimerism may remain stable over a very long time period. In survivors without relapse at 1 year after HSCT, determining lineage specific chimerism may be useful as outcome differs, MNC-MC being associated with better outcome than Gran-MC. PMID- 26640713 TI - Characterization and Compatibility Studies of Different Rate Retardant Polymer Loaded Microspheres by Solvent Evaporation Technique: In Vitro-In Vivo Study of Vildagliptin as a Model Drug. AB - The present study has been performed to microencapsulate the antidiabetic drug of Vildagliptin to get sustained release of drug. The attempt of this study was to formulate and evaluate the Vildagliptin loaded microspheres by emulsion solvent evaporation technique using different polymers like Eudragit RL100, Eudragit RS100, Ethyl cellulose, and Methocel K100M. In vitro dissolution studies were carried out in 0.1 N HCl for 8 hours according to USP paddle method. The maximum and minimum drug release were observed as 92.5% and 68.5% from microspheres, respectively, after 8 hours. Release kinetics were studied in different mathematical release models to find out the linear relationship and release rate of drug. The SEM, DSC, and FTIR studies have been done to confirm good spheres and smooth surface as well as interaction along with drug and polymer. In this experiment, it is difficult to explain the exact mechanism of drug release. But the drug might be released by both diffusion and erosion as the correlation coefficient (R (2)) best fitted with Korsmeyer model and release exponent (n) was 0.45-0.89. At last it can be concluded that all in vitro and in vivo experiments exhibited promising result to treat type II diabetes mellitus with Vildagliptin microspheres. PMID- 26640714 TI - Identification of Proximal and Distal 22q11.2 Microduplications among Patients with Cleft Lip and/or Palate: A Novel Inherited Atypical 0.6 Mb Duplication. AB - Misalignments of low-copy repeats (LCRs) located in chromosome 22, particularly band 22q11.2, predispose to rearrangements. A variety of phenotypic features are associated with 22q11.2 microduplication syndrome which makes it challenging for the genetic counselors to recommend appropriate genetic assessment and counseling for the patients. In this study, multiplex ligation probe dependent amplification (MLPA) analysis was performed on 378 patients with cleft lip and/or palate to characterize rearrangements in patients suspected of 22q11.2 microduplication and microdeletion syndromes. Of 378 cases, 15 were diagnosed with a microdeletion with various sizes and 3 with duplications. For the first time in this study an atypical 0.6 Mb duplication is reported. Illustration of the phenotypes associated with the microduplications increases the knowledge of phenotypes reported in the literature. PMID- 26640715 TI - Acalculous Acute Cholecystitis in Previously Healthy Children: General Overview and Analysis of Pediatric Infectious Cases. AB - Acute acalculous cholecystitis (AAC) is an inflammation of the gallbladder, which does not appear to be associated with the presence of gallstones. AAC is estimated to represent more than 50% of cases of acute cholecystitis in the pediatric population. Although this pathology was initially described in critically ill patients, actually most pediatric cases have been observed during several infectious diseases. Particularly, here we reviewed pediatric infectious acute acalculous cholecystitis and analyzed the pathophysiological and clinical aspects of bacterial and viral forms. PMID- 26640716 TI - Serum Adiponectin, Vitamin D, and Alpha-Fetoprotein in Children with Chronic Hepatitis C: Can They Predict Treatment Response? AB - Background & Aims. The currently available treatment for chronic hepatitis C (CHC) in children is costly and with much toxicity. So, predicting the likelihood of response before starting therapy is important. Methods. Serum adiponectin, vitamin D, and alpha-fetoprotein (AFP) were measured before starting pegylated interferon/ribavirin therapy for 50 children with CHC. Another 21 healthy children were recruited as controls. Results. Serum adiponectin, vitamin D, and AFP were higher in the CHC group than healthy controls (p < 0.0001, p = 0.071, and p = 0.87, resp.). In univariate analysis, serum adiponectin was significantly higher in responders than nonresponders (p < 0.0001) and at a cutoff value >=8.04 ng/mL it can predict treatment response by 77.8% sensitivity and 92.9% specificity, while both AFP and viremia were significantly lower in responders than nonresponders, p < 0.0001 and p = 0.0003, respectively, and at cutoff values <=3.265 ng/mL and <=235,384 IU/mL, respectively, they can predict treatment response with a sensitivity of 83.3% for both and specificity of 85.7% and 78.6%, respectively. In multivariate analysis, adiponectin was found to be the only independent predictor of treatment response (p = 0.044). Conclusions. The pretreatment serum level of adiponectin can predict the likelihood of treatment response, thus avoiding toxicities for those unlikely to respond to therapy. PMID- 26640718 TI - Multiple Coronary Artery Microfistulas Associated with Apical Hypertrophic Cardiomyopathy: Left and Right Coronary Artery to the Left Ventricle. AB - A 76-year-old woman underwent coronary angiography for chest pain. On the coronary angiogram, no significant coronary artery atherosclerotic stenosis was observed. Multiple coronary artery microfistulas, draining from the left anterior descending artery to the left ventricle and from the posterior descending artery of the right coronary artery to the left ventricle, were observed. Apical wall thickening and fistula flow from the left anterior descending artery were demonstrated by using transthoracic echocardiography. We describe a rare case of multiple coronary artery microfistulas from the left and right coronary artery to the left ventricle combined with apical hypertrophic cardiomyopathy. PMID- 26640719 TI - Insights into the Mechanism of Severe Mitral Regurgitation: RT-3D TEE Guided Management with Pathological Correlation. AB - Mitral valve perforation is an uncommon but important complication of infective endocarditis. We report a case of a 65-year-old man who was diagnosed to have infective endocarditis of his mitral valve. Through the course of his admission he had a rapid development of hemodynamic instability and pulmonary edema secondary to acutely worsening mitral regurgitation. While the TEE demonstrated an increase in the size of his bacterial vegetation, Real Time 3D TEE was ultimately the imaging modality through which the valve perforation was identified. Through this case report we discuss the advantages that RT-3D TEE has over traditional 2D TEE in the management of valve perforation. PMID- 26640717 TI - Brain Plasticity following Intensive Bimanual Therapy in Children with Hemiparesis: Preliminary Evidence. AB - Neuroplasticity studies examining children with hemiparesis (CH) have focused predominantly on unilateral interventions. CH also have bimanual coordination impairments with bimanual interventions showing benefits. We explored neuroplasticity following hand-arm bimanual intensive therapy (HABIT) of 60 hours in twelve CH (6 females, mean age 11 +/- 3.6 y). Serial behavioral evaluations and MR imaging including diffusion tensor (DTI) and functional (fMRI) imaging were performed before, immediately after, and at 6-week follow-up. Manual skills were assessed repeatedly with the Assisting Hand Assessment, Children's Hand Experience Questionnaire, and Jebsen-Taylor Test of Hand Function. Beta values, indicating the level of activation, and lateralization index (LI), indicating the pattern of brain activation, were computed from fMRI. White matter integrity of major fibers was assessed using DTI. 11/12 children showed improvement after intervention in at least one measure, with 8/12 improving on two or more tests. Changes were retained in 6/8 children at follow-up. Beta activation in the affected hemisphere increased at follow-up, and LI increased both after intervention and at follow-up. Correlations between LI and motor function emerged after intervention. Increased white matter integrity was detected in the corpus callosum and corticospinal tract after intervention in about half of the participants. Results provide first evidence for neuroplasticity changes following bimanual intervention in CH. PMID- 26640720 TI - Meningococcemia Presenting as a Myocardial Infarction. AB - Neisseria meningitidis is an encapsulated gram negative diplococcus that colonizes the nasopharynx and is transmitted by aerosol or secretions with the majority of cases occurring in infants and adolescents. Meningococcemia carries a high mortality which is in part due to myocarditis. Early recognition and prompt use of antibiotics improve morbidity and mortality. We report a 55-year-old male presenting to the emergency department with chest pain, shortness of breath, and electrocardiogram changes suggestive of ST elevation MI who developed cardiogenic shock and multisystem organ failure from N. meningitidis. We present this case to highlight the unique presentation of meningococcemia, the association with myocardial dysfunction, and the importance of early recognition and prompt use of antibiotics. PMID- 26640721 TI - Maxillary Swelling as the First Evidence of Multiple Myeloma. AB - Multiple myeloma is a malignant neoplasm of plasma cells characterized by proliferation of a single clone of abnormal immunoglobulin-secreting plasma cells. Since the amount of hemopoietic bone marrow is decreased in the maxilla, oral manifestations of multiple myeloma are less common in the maxilla than in the mandible. We report the case of 33-year-old Japanese man who presented with a mass in the right maxillary alveolar region. Computed tomography and magnetic resonance images showed a soft tissue mass in the right maxilla eroding the anterior and lateral walls of the maxillary sinus and extending into the buccal space. The biopsy results, imaging, and laboratory investigations led to the diagnosis of multiple myeloma. This case report suggests that oral surgeons and dentists should properly address oral manifestations as first indications of multiple myeloma. PMID- 26640722 TI - A Single Versatile Appliance for Habit Interception and Crossbite Correction. AB - Digit sucking is a common childhood behavior, which has an adaptive value for children up to the fourth year of life. It is usually associated with oral pleasure and self-comforting behavior. But chronic practice may produce deleterious effect in the form of dental and skeletal deformities. Adjunctive therapy using bluegrass appliance as a permanent reminder and quadhelix appliance as a reminder as well as a slow palatal expander has proven successful in intercepting digit-sucking habit and expanding the arch for crossbite correction. In the present case, a versatile modified quadhelix appliance incorporating a roller was designed to clinically correct the habit and its resulting dentofacial deformities. PMID- 26640723 TI - Incidental Finding of Inferior Vena Cava Atresia Presenting with Deep Venous Thrombosis following Physical Exertion. AB - Inferior vena cava atresia (IVCA) is a rare but well described vascular anomaly. It is a rare risk factor for deep venous thrombosis (DVT), found in approximately 5% of cases of unprovoked lower extremity (LE) DVT in patients <30 years of age. Affected population is in the early thirties, predominantly male, often with a history of major physical exertion and presents with extensive or bilateral DVTs. Patients with IVC anomalies usually develop compensatory circulation through the collateral veins with enlarged azygous/hemizygous veins. Despite the compensatory circulation, the venous drainage of the lower limbs is often insufficient leading to venous stasis and thrombosis. We describe a case of extensive and bilateral deep venous thrombosis following physical exertion in a thirty-six-year-old male patient with incidental finding of IVCA on imaging. PMID- 26640724 TI - Atypical Parathyroid Adenoma Complicated with Protracted Hungry Bone Syndrome after Surgery: A Case Report and Literature Review. AB - Hungry Bone Syndrome refers to the severe and prolonged hypocalcemia and hypophosphatemia, following parathyroidectomy in patients with hyperparathyroidism. We present the case of an eighteen-year-old woman with a four-year history of hyporexia, polydipsia, weight loss, growth retardation, and poor academic performance. The diagnostic work-up demonstrated primary hyperparathyroidism with hypercalcemia of 13.36 mg/dL, a PTH level of 2551 pg/mL, bone brown tumors, and microcalcifications within pancreas and kidneys. Neck ultrasonography revealed a parathyroid adenoma of 33 * 14 * 14 mm, also identified on (99)Tc-sestamibi scan. Bone densitometry showed decreased Z-Score values (total lumbar Z-Score of -4.2). A right hemithyroidectomy and right lower parathyroidectomy were performed. Pathological examination showed an atypical parathyroid adenoma, of 3.8 g of weight and 2.8 cm in diameter. After surgery she developed hypocalcemia with tetany and QTc interval prolongation. The patient required 3 months of oral and intravenous calcium supplementation due to Hungry Bone Syndrome (HBS). After 42 months, she is still under oral calcium. Usually HBS lasts less than 12 months. Therefore we propose the term "Protracted HBS" in patients with particularly long recovery of 1 year. We present a literature review of the diagnosis, pathophysiology, and treatment of HBS. PMID- 26640725 TI - Portal Vein Thrombosis due to Prothrombin Gene Mutation following Sleeve Gastrectomy. AB - Introduction. Portomesenteric thrombosis is increasingly recognized as a complication of laparoscopic sleeve gastrectomy (LSG). It often presents with abdominal pain. We present a mother and her son who both developed portal vein thrombosis (PVT) after LSG. Case Description. A 43-year-old woman presented complaining of sudden severe abdominal pain, two weeks after she had uncomplicated laparoscopic sleeve gastrectomy. CT scan of the abdomen and pelvis with IV contrast showed portal vein thrombosis and SMV thrombosis. Two weeks later her son had the same LSG for morbid obesity and presented with the same clinical picture. Thrombophilia workup showed heterozygous prothrombin gene mutation. Conclusions. A high index of suspicion is necessary to diagnose PVT; although rare, it can be potentially lethal. Anticoagulation therapy should be initiated immediately to limit the morbidities and improve the outcome. Patients with family history of thrombophilia should be investigated prior to any bariatric surgery and nonsurgical alternative treatments for morbid obesity should be strongly encouraged. PMID- 26640726 TI - Hereditary Neuropathy with Liability to Pressure Palsies Masked by Previous Gunshots and Tuberculosis. AB - Objectives. Although hereditary neuropathy with liability to pressure palsies (HNPP) presents with a distinct phenotype on history, clinical exam, and nerve conduction studies, it may be masked if diagnostic work-up suggests other causes. Case Report. In a 37-year-old male with pseudoradicular lumbar pain, neurological exam revealed sore neck muscles, peripheral facial nerve palsy, right anacusis and left hypoacusis, hemihypesthesia of the right face, mild distal quadriparesis, diffuse wasting, and generally reduced tendon reflexes. He had a history of skull fracture due to a gunshot behind the right ear and tuberculosis for which he had received adequate treatment for 3 years; MRI revealed a disc prolapse at C6/7 and Th11/12. Nerve conduction studies were indicative of demyelinating polyneuropathy with conduction blocks. Despite elevated antinuclear antibodies and elevated CSF-protein, HNPP was diagnosed genetically after having excluded vasculitis, CIDP, radiculopathy, and the side effects of antituberculous treatment. Conclusions. HNPP may manifest with mild, painless, distal quadriparesis. The diagnosis of HNPP may be blurred by a history of tuberculosis, tuberculostatic treatment, hepatitis, and the presence of elevated CSF-protein. PMID- 26640727 TI - Aspergillus Thyroiditis after Allogeneic Hematopoietic Stem Cell Transplantation. AB - Aspergillus thyroiditis is a rare disorder detected in immunocompromised patients during disseminated infections. Early management is essential to prevent high mortality. A 61-year-old allogeneic stem cell male recipient presented with painful thyroid nodular enlargement. He had low TSH and low free T4 levels. The thyroid ultrasound showed a hypoechoic nodule; biopsy indicated suppurative Aspergillus thyroiditis. He was successfully treated by amphotericin B. PMID- 26640728 TI - Aggressive FLC Escape in a Patient with IgD Myeloma. AB - Background. Some patients who are stable or in remission from a myeloma secreting intact monoclonal immunoglobulin (+/- associated free light-chains (FLCs)) relapse with production of FLC. This FLC escape is one of the illustrations of the intraclonal heterogeneity of multiple myeloma. Results. We report FLC escape in a patient with IgD myeloma characterized by a severe outcome. We discuss parameters that negatively impacted prognosis in this patient, including bone lesions, biochemical parameters, and genomic abnormalities. Conclusion. This case illustrates the selective pressure exerted by therapeutic drugs and the variable sensitivity of subclones to these drugs; it also highlights the importance of FLC monitoring in treated MM patients. PMID- 26640729 TI - Onychomycosis due to Cunninghamella bertholletiae in an Immunocompetent Male from Central India. AB - Onychomycosis is a fungal infection of nails seen frequently in immune competent and immune compromised patients due to dermatophytes, Candida spp., Fusarium spp., Scopulariopsis brevicaulis, Penicillium spp., and Aspergillus spp. We report a case of onychomycosis in a young immunocompetent male who presented onycholysis of a solitary nail without inflammation. The etiological agent was diagnosed to be Cunninghamella bertholletiae, a fungus pertaining to the order Mucorales (subdivision Mucoromycotina) and known for some of the invasive lesions among immunocompromised patients. This case demonstrates the association of onychomycosis with Cunninghamella bertholletiae in an immune competent individual, not reported so far. PMID- 26640730 TI - Changes over Time in Intracranial Air in Patients with Cerebral Air Embolism: Radiological Study in Two Cases. AB - Cerebral air embolism can be easily identified on computed tomography (CT) scans. However, changes in the distribution and amount of intracranial air are not well known. We report two patients with cerebral air embolism and present imaging findings on the serial changes in the intracranial air. We thought that the embolic source was venous in one patient because CT showed air inflow in cortical veins in the bilateral frontal areas, reflecting air buoyancy. In the other patient, CT showed air inflow into not only the cortical veins but also the bilateral cerebral hemispheres and we thought this to be a paradoxical cerebral air embolism. We found that intracranial air can be promptly absorbed and while cerebral infarcts due to air are clearly visualized on diffusion-weighted images (DWI), the air may rapidly disappear from images. In patients with suspected cerebral air embolism whose CT findings show no intracranial air, DWI should be performed because it may reveal cerebral infarction due to cerebral air embolism. PMID- 26640731 TI - Fatal Vertebral Artery Injury in Penetrating Cervical Spine Trauma. AB - Study Design. This case illustrates complications to a vertebral artery injury (VAI) resulting from penetrating cervical spine trauma. Objectives. To discuss the management of both VAI and cervical spine trauma after penetrating gunshot wound to the neck. Summary of Background Data. Vertebral artery injury following cervical spine trauma is infrequent, and a unilateral VAI often occurs without neurologic sequela. Nevertheless, devastating complications of stroke and death do occur. Methods. A gunshot wound to the neck resulted in a C6 vertebral body fracture and C5-C7 transverse foramina fractures. Neck CT angiogram identified a left vertebral artery occlusion. A cerebral angiography confirmed occlusion of the left extracranial vertebral artery and patency of the remaining cerebrovascular system. Following anterior cervical corpectomy and stabilization, brainstem infarction occurred and resulted in death. Results. A fatal outcome resulted from vertebral artery thrombus propagation with occlusion of the basilar artery triggering basilar ischemia and subsequent brainstem and cerebellar infarction. Conclusions. Vertebral artery injury secondary to cervical spine trauma can lead to potentially devastating neurologic sequela. Early surgical stabilization, along with anticoagulation therapy, contributes towards managing the combination of injuries. Unfortunately, despite efforts, a poor outcome is sometimes inevitable when cervical spine trauma is coupled with a VAI. PMID- 26640732 TI - Recurrent Renal Cell Carcinoma with Synchronous Tumor Growth in Azygoesophageal Recess and Duodenum: A Rare Cause of Anemia and Upper Gastrointestinal Bleeding. AB - Renal cell carcinoma (RCC) has potential to present with distant metastasis several years after complete resection. The common sites of metastases include the lungs, bones, liver, renal fossa, and brain. RCCs metastasize rarely to the duodenum, and duodenal metastasis presenting with acute gastrointestinal bleed is infrequently reported in literature. We present a case of synchronous presentation of duodenal and azygoesophageal metastasis manifesting as acute upper gastrointestinal bleeding, four years after undergoing nephrectomy for RCC. The patient underwent further workup and was treated with radiation. The synchronous presentation is rare and stresses the importance of searching for recurrence of RCC in patients presenting with acute gastrointestinal bleeding. PMID- 26640733 TI - A Case of Idiopathic Hypereosinophilic Syndrome Causing Mitral Valve Papillary Muscle Rupture. AB - Idiopathic Hypereosinophilic Syndrome (IHES) is a rare disease that can be difficult to diagnose as the differential is broad. This disease can cause significant morbidity and mortality if left untreated. Our patient is a 17-year old adolescent female who presented with nonspecific symptoms of abdominal pain and malaise. She was incidentally found to have hypereosinophilia of 16,000 on complete blood count and nonspecific colitis and pulmonary edema on computed tomography. She went into cardiogenic shock due to papillary rupture of her mitral valve requiring extreme life support measures including intubation and extracorporal membrane oxygenation (ECMO) as well as mitral valve replacement. Pathology of the valve showed eosinophilic infiltration as the underlying etiology. The patient was diagnosed with IHES after the exclusion of infectious, rheumatologic, and oncologic causes. She was treated with steroids with improvement of her symptoms and scheduled for close follow-up. In general patients with IHES that have cardiac involvement have poorer prognoses. PMID- 26640734 TI - Unusual Presentations of Focal Periphyseal Edema Zones: A Report of Bilateral Symmetric Presentation and Partial Physeal Closure. AB - Focal periphyseal edema (FOPE) zones are areas of periphyseal edema seen near the time of physeal closure which are believed to be a physiologic phenomenon related to changes in distribution of forces around the physis as it closes. Since the original case series describing these areas of periphyseal edema, there has been little published in regard to FOPE zone outside of review articles. We present a set of three patients identified with focal periphyseal edema zones around the knee and compare our findings with the initial case series. We include a patient presenting with bilateral, nearly symmetric, focal periphyseal edema zones of the proximal tibia physis and a patient with partial closure of the physis at time of presentation, which were not reported in the original case series. PMID- 26640735 TI - Dramatic Improvement of Subcutaneous Calcinosis by Intermittent, High-Dose Etidronate plus Cimetidine in a Patient with Juvenile Dermatomyositis. AB - A 17-year-old boy with juvenile dermatomyositis presented with typical skin symptoms, mild myositis, and bilateral lower limb calcinosis. His skin and muscle symptoms responded to treatment with prednisolone and azathioprine. However, calcinosis did not improve, and the patient had a limited range of knee joint motion and resultant disturbance of daily activities. Cimetidine was combined with intermittent administration of high-dose etidronate, leading to marked improvement of both subcutaneous and muscular calcinosis with no skeletal adverse reactions during a long treatment period exceeding 5 years. As a result, the range of knee joint motion has increased and performance of daily activities has improved. PMID- 26640736 TI - Open Reduction and Internal Fixation of the Isolated Tibial Lateral Plateau Posterior Fracture Using Direct Posterior Split Gastrocnemius Approach. AB - Open reduction and internal fixation of the isolated tibial lateral plateau posterior fractures using direct posterior split gastrocnemius approach is a safe and effective method. PMID- 26640737 TI - Amyand's Hernia with Appendicitis: A Case Report and Integrative Review. AB - Introduction. Inguinal hernia is a common disorder with an estimated prevalence of 1.2% of the entire population and it is 12 times more common in males. Objective. To describe a case of appendix with signs of inflammation in the hernia sac, condition that is rare and difficult to diagnose, and to perform literature review, describing the most relevant aspects and the main controversies. Method. Report of a case and search in PubMed on June 1, 2015, using the terms "Appendix" [MeSH term] AND "hernia, inguinal" [MeSH term]. Results. The search resulted in 38 articles in total, and after deleting the articles that were not part of the inclusion criteria, there were 26 case reports remaining. Discussion. The search resulted in a total of 38 articles and after deleting the articles that were not part of the inclusion criteria, there were 26 case reports remaining. Conclusion. Amyand's hernia is a rare and difficult to diagnose condition, being commonly found occasionally in surgical procedures. It should be remembered in the presence of cases of incarcerated hernia, due to its possible complications if not diagnosed. PMID- 26640738 TI - Impact of Deep Brain Stimulation on Daily Routine Driving Practice in Patients with Parkinson's Disease. AB - Objective. To determine the influence of deep brain stimulation (DBS) on daily routine driving behavior in Parkinson's disease (PD) patients. Methods. A cross sectional questionnaire survey was done in 121 DBS-PD patients. The influences of patient characteristics and DBS on current driving and driving at time of surgery and the predictive value of the preoperative levodopa-test on postoperative driving were evaluated. Results. 50% of 110 driving-license holders currently drove. 63.0% rated themselves as safe drivers, 39.4% reported improvement, and 10.9% noted deterioration in driving after DBS surgery. Inactive drivers had quit driving mainly due to disease burden (90.9%). Active drivers were younger, more often males, and less impaired according to H&Y and MMSE, had surgery more recently, and reported more often overall benefit from DBS. H&Y "on" and UPDRS III "off" scores at time of surgery were lower in pre- and postoperative active than in inactive drivers. Tremor and akinesia were less frequent reasons to quit driving after than before DBS surgery. Postoperatively, 22.7% (10/44) of patients restarted and 10.6% (7/66) of patients discontinued driving, independently of H&Y stage. The preoperative levodopa-test was not predictive for the postoperative driving outcome. Conclusion. 50% of PD patients with DBS drive. DBS surgery changes daily routine driving behavior. PMID- 26640739 TI - The Relationship between Clinical, Momentary, and Sensor-based Assessment of Depression. AB - The clinical assessment of severity of depressive symptoms is commonly performed with standardized self-report questionnaires, most notably the patient health questionnaire (PHQ-9), which are usually administered in a clinic. These questionnaires evaluate symptoms that are stable over time. Ecological momentary assessment (EMA) methods, on the other hand, acquire patient ratings of symptoms in the context of their lives. Today's smartphones allow us to also obtain objective contextual information, such as the GPS location, that may also be related to depression. Considering clinical PHQ-9 scores as ground truth, an interesting question is to what extent the EMA ratings and contextual sensor data can be used as potential predictors of depression. To answer this question, we obtained PHQ-9 scores from 18 participants with a variety of depressive symptoms in our lab, and then collected their EMA and GPS sensor data using their smartphones over a period of two weeks. We analyzed the relationship between GPS sensor features, EMA ratings, and the PHQ-9 scores. While we found a strong correlation between a number of sensor features extracted from the two-week period and the PHQ-9 scores, the other relationships remained non-significant. Our results suggest that depression is better evaluated using long-term sensor based measurements than the momentary ratings of mental state or short-term sensor information. PMID- 26640740 TI - MedLink: A Mobile Intervention to Address Failure Points in the Treatment of Depression in General Medicine. AB - Major depression is common, and imposes a high burden in terms of cost, morbidity, and suffering. Most people with depression are treated in general medicine using antidepressant medication. Outcomes are poor due to failure points across the care system, including patient non-adherence, failure of physicians to optimize the treatment regimens, and lack of patient-physician communication. This study reports on the 4-week pilot deployment of MedLink, a mobile intervention aimed at systemically addressing each of these failure points. A mobile app provides the patient with information and collects data on symptoms and side-effects. A cellularly enabled pill bottle monitors medication adherence. Data from these are provided to the physician and patient to foster communication and medication adjustments. Usability evaluation was generally favorable. Medication adherence rates in this first deployment were high with no patients discontinuing, and 84% of doses taken. Depressive symptom severity was significantly reduced. This study supports the use of a comprehensive, systemic approach to mHealth solutions to enhance processes of care for depression by general medicine physicians. PMID- 26640741 TI - Initial Field Trial of a Coach-Supported Web-Based Depression Treatment. AB - Early web-based depression treatments were often self-guided and included few interactive elements, instead focusing mostly on delivering informational content online. Newer programs include many more types of features. As such, trials should analyze the ways in which people use these sites in order to inform the design of subsequent sites and models of support. The current study describes of a field trial consisting of 9 patients with major depressive disorder who completed a 12-week program including weekly coach calls. Patients usage varied widely, however, patients who formed regular patterns tended to persist with the program for the longest. Future sites might be able to facilitate user engagement by designing features to support regular use and to use coaches to help establish patterns to increase long-term use and benefit. PMID- 26640742 TI - An open-label clinical trial of the effects of age and gender on the pharmacodynamics, pharmacokinetics and safety of the ghrelin receptor agonist anamorelin. AB - PURPOSE: To assess the effect of age and gender on the pharmacokinetics (PK) of the ghrelin receptor agonist anamorelin. METHODS: Three demographic cohorts of healthy subjects were enrolled in this single-center, open-label study. Subjects received a single oral dose (25 mg) of anamorelin HCl. Serial blood samples were collected over 24 hours to assess anamorelin PK and circulating growth hormone (GH) levels. Data were compared with a reference cohort. RESULTS: Anamorelin was rapidly absorbed in all cohorts; peak concentrations were observed 30-45 minutes and 2-4 hours post-dose, which declined biexponentially with mean terminal half lives of 6-7 hours. An age effect on Cmax and AUCinfinity was not apparent; however, mean AUCinfinity values were approximately 1.8-1.9-fold higher in the female cohorts than in the reference male cohort. GH increase was rapid and virtually identical in both sexes, though attenuated in elderly subjects. No clinically significant safety or tolerability findings were observed. CONCLUSIONS: While PK parameters do suggest higher exposure in females, this effect is considered to be modest given the variability of the 6-8 subjects per cohort. Moreover, no such effect was observed in the pharmacodynamic responses, thus, dose adjustment for age and gender is considered unnecessary. PMID- 26640743 TI - Mental Health Disorders and Treatment Seeking Among Veterans in Non-VA Facilities: Results and Implications from the Veterans' Health Study. AB - We surveyed 700 veterans who were outpatients in a non-Veterans Affairs (VA) multihospital system. Our objective was to assess the prevalence of mental disorders and service use among these veterans. The majority were Vietnam veterans (72.0%), and male (95.9%), and 40.4% reported recently using the VA for care. The prevalence of lifetime post-traumatic stress disorder (PTSD) was 9.6%, lifetime depression 18.4%, and lifetime mental health service use 50.1%. In multivariate analyses, significant factors associated with PTSD, depression, and mental health service use were low self-esteem, use of alcohol/drugs to cope, history of childhood adversity, high combat exposure, and low psychological resilience. VA service use was associated with greater mental health service use and combat exposure. With the exception of alcohol misuse, the mental health status of veterans seen in non-VA facilities appeared to be better than reported in past studies. Because most veterans have access to both VA and non-VA services, these findings have implications for veterans and outcomes research. PMID- 26640744 TI - Self-distancing from trauma memories reduces physiological but not subjective emotional reactivity among Veterans with posttraumatic stress disorder. AB - Self-distancing, or viewing oneself from a third-person perspective, reduces reactivity when analyzing one's feelings. Self-distancing may have important effects among individuals with posttraumatic stress disorder (PTSD), who have heightened emotional and physiological reactivity to trauma memories, but the effects of self-distancing in this group are unclear. We randomly assigned 48 Veterans diagnosed with PTSD to analyze their trauma-related feelings from an immersed (first-person) or distanced (third-person) perspective, and measured physiological and subjective emotional reactivity. Self-distancing during trauma analysis protected against increases in physiological reactivity, such that participants in the immersed condition showed a significant increase in heart rate and skin conductance responses not seen in the distanced condition. However, self-distancing had no effect on self-reported emotional reactivity. Our findings suggest that the effects of self-distancing on subjective emotions may not extend to trauma memories. However, self-distancing during trauma analysis did change physiological reactivity, suggesting at least a short-term benefit for individuals with PTSD. PMID- 26640745 TI - Power Loss Analysis and Comparison of Segmented and Unsegmented Energy Coupling Coils for Wireless Energy Transfer. AB - This paper investigated the power losses of unsegmented and segmented energy coupling coils for wireless energy transfer. Four 30-cm energy coupling coils with different winding separations, conductor cross-sectional areas, and number of turns were developed. The four coils were tested in both unsegmented and segmented configurations. The winding conduction and intrawinding dielectric losses of the coils were evaluated individually based on a well-established lumped circuit model. We found that the intrawinding dielectric loss can be as much as seven times higher than the winding conduction loss at 6.78 MHz when the unsegmented coil is tightly wound. The dielectric loss of an unsegmented coil can be reduced by increasing the winding separation or reducing the number of turns, but the power transfer capability is reduced because of the reduced magnetomotive force. Coil segmentation using resonant capacitors has recently been proposed to significantly reduce the operating voltage of a coil to a safe level in wireless energy transfer for medical implants. Here, we found that it can naturally eliminate the dielectric loss. The coil segmentation method and the power loss analysis used in this paper could be applied to the transmitting, receiving, and resonant coils in two- and four-coil energy transfer systems. PMID- 26640746 TI - Modeling of subglacial hydrological development following rapid supraglacial lake drainage. AB - : The rapid drainage of supraglacial lakes injects substantial volumes of water to the bed of the Greenland ice sheet over short timescales. The effect of these water pulses on the development of basal hydrological systems is largely unknown. To address this, we develop a lake drainage model incorporating both (1) a subglacial radial flux element driven by elastic hydraulic jacking and (2) downstream drainage through a linked channelized and distributed system. Here we present the model and examine whether substantial, efficient subglacial channels can form during or following lake drainage events and their effect on the water pressure in the surrounding distributed system. We force the model with field data from a lake drainage site, 70 km from the terminus of Russell Glacier in West Greenland. The model outputs suggest that efficient subglacial channels do not readily form in the vicinity of the lake during rapid drainage and instead water is evacuated primarily by a transient turbulent sheet and the distributed system. Following lake drainage, channels grow but are not large enough to reduce the water pressure in the surrounding distributed system, unless preexisting channels are present throughout the domain. Our results have implications for the analysis of subglacial hydrological systems in regions where rapid lake drainage provides the primary mechanism for surface-to-bed connections. KEY POINTS: Model for subglacial hydrological analysis of rapid lake drainage eventsLimited subglacial channel growth during and following rapid lake drainagePersistence of distributed drainage in inland areas where channel growth is limited. PMID- 26640748 TI - Joint line restoration during revision total knee arthroplasty: an accurate and reliable method. AB - During revision total knee arthroplasty, the joint line is frequently malpositioned, due to the disappearance of the anatomical landmarks following previous interventions. This leads to decreased clinical outcome and increased risk of re-intervention. Many methods have been proposed to restore the joint line, but none of them has shown itself to be reliable. We describe an accurate and precise method to localize the exact position of the joint line which guarantees a better clinical knee score. The adductor tubercle (AT) is recognized to be the most reliable landmark used to localize the knee joint line (JL). The distance from the AT to the JL on antero-posterior radiographs (ATJL) and the femoral diameter (FD) on true lateral views were measured on 200 randomly selected normal knees. These measurements were tested for intra- and inter observer differences. Then, the relationship between these two measurements was studied. A significant correlation and linear regression between FD and ATJL was found (p < 0.001), making the adductor tubercle a valid landmark to accurately position the prosthetic joint within 4 mm from the normal position. No significant difference was noted in the intra and inter-observer measurements (F test not significant). Sex was found to be an intervening variable (p ? 0.001). The correlation and regression between ATJL and FD had to be adjusted accordingly. Once the ATJL was determined preoperatively, the JL level is found during surgery by using a caliper that is held on the easily palpable AT. Knowing the femoral diameter, we can easily locate the joint line level surgically, using the adductor tubercle as a landmark. This method leads to better clinical outcomes and a reduced risk of re-intervention following revision total knee arthroplasty. PMID- 26640747 TI - Nanotechnology for photodynamic therapy: a perspective from the Laboratory of Dr. Michael R. Hamblin in the Wellman Center for Photomedicine at Massachusetts General Hospital and Harvard Medical School. AB - The research interests of the Hamblin Laboratory are broadly centered on the use of different kinds of light to treat many different diseases. Photodynamic therapy (PDT) uses the combination of dyes with visible light to produce reactive oxygen species and kill bacteria, cancer cells and destroy unwanted tissue. Likewise, UV light is also good at killing especially pathogens. By contrast, red or near-infrared light can have the opposite effect, to act to preserve tissue from dying and can stimulate healing and regeneration. In all these applications, nanotechnology is having an ever-growing impact. In PDT, self-assembled nano-drug carriers (micelles, liposomes, etc.) play a great role in solubilizing the photosensitizers, metal nanoparticles can carry out plasmon resonance enhancement, and fullerenes can act as photosensitizers, themselves. In the realm of healing, single-walled carbon nanotubes can be electrofocused to produce nano electonic biomedical devices, and nanomaterials will play a great role in restorative dentistry. PMID- 26640749 TI - Key information providers, channels, and characteristics of Japanese consumers' informed choices of over-the-counter medications. AB - People need reliable information regarding over-the-counter medications (OTCs), so that they can independently make appropriate informed choices. The study aimed to identify the information providers and channels that have an impact on the purchase of OTCs, and to demonstrate the information needs of OTC purchasers, using these providers and channels, from the viewpoint of information characteristics such as specialty, objectivity, concreteness, comprehensiveness, individuality, and availability, focusing on the efficacy of OTCs and related safety information. A questionnaire survey of randomly sampled adults aged >=20 was conducted at the Japan Drugstore Show 2012, hosted by the Japan Association of Chain Drug Stores. In this questionnaire, information was particularly limited to the efficacy and safety of OTCs. Multivariate logistic regression analysis was performed on data from 1743 respondents (1625 purchasers and 118 non-purchasers of OTCs) who obtained information on OTCs in their daily lives, to demonstrate the associations between the use of information providers and channels (predictor variables) and the purchase of OTCs (outcome variable), as well as between information characteristics valued by purchasers (predictor variables) and their use of these information providers or channels (outcome variables). Both the use of pharmacists as information providers and consultation at pharmacies as an information channel were positively associated with the purchase of OTCs (odds ratio [OR], 3.74; 95 % confidence interval [CI], 2.46-5.68; P < 0.001 and OR, 4.55; 95 % CI 2.92-7.11, P < 0.001, respectively), whereas both the use of family or friends using OTCs as information providers and family or friends as information channels were negatively associated with the purchase of OTCs (OR, 0.60; 95 % CI 0.40-0.90; P = 0.014 and OR, 0.55; 95 % CI 0.36-0.82; P = 0.004, respectively). OTC purchasers who valued individuality of information were more likely to use pharmacists (OR 2.00; 95 % CI 1.61-2.48; P < 0.001) and consultation at pharmacies (OR 1.98; 95 % CI 1.61-2.43; P < .001). In conclusion, individualized information provided by pharmacists on the efficacy and safety of OTCs during consultation at pharmacies can play the most important role in the informed choices of OTC purchasers. PMID- 26640750 TI - Assessing local vulnerability to climate change in Ecuador. AB - Vulnerability assessments have become necessary to increase the understanding of climate-sensitive systems and inform resource allocation in developing countries. Challenges arise when poor economic and social development combines with heterogeneous climatic conditions. Thus, finding and harmonizing good-quality data at local scale may be a significant hurdle for vulnerability research. In this paper we assess vulnerability to climate change at a local level in Ecuador. We take Ecuador as a case study as socioeconomic data are readily available. To incorporate the spatial and temporal pattern of the climatic variables we use reanalysis datasets and empirical orthogonal functions. Our assessment strategy relies on the statistical behavior of climatic and socioeconomic indicators for the weighting and aggregation mechanism into a composite vulnerability indicator. Rather than assuming equal contribution to the formation of the composite indicator, we assume that the weights of the indicators vary inversely as the variance over the cantons (administrative division of Ecuador). This approach captures the multi-dimensionality of vulnerability in a comprehensive form. We find that the least vulnerable cantons concentrate around Ecuador's largest cities (e.g. Quito and Guayaquil); however, approximately 20 % of the national population lives in other cantons that are categorized as highly and very highly vulnerable to climate change. Results also show that the main determinants of high vulnerability are the lack of land tenure in agricultural areas and the nonexistence of government-funded programs directed to environmental and climate change management. PMID- 26640751 TI - Brief report of the construction of infectious DNA clones of South African genetic variants of grapevine virus A and grapevine virus B. AB - BACKGROUND: Recent research results strongly suggest that certain genetic variants of grapevine virus A (GVA) and grapevine virus B (GVB), two members of the Vitivirus genus of the family Betaflexiviridae, are the cause of Shiraz disease and corky bark disease of grapevines in South Africa, respectively. To investigate this hypothesis, work was undertaken to construct DNA clones of these viruses. FINDINGS AND CONCLUSIONS: Biologically viable and stable DNA clones of genetic variants of GVA and GVB B from South Africa were constructed. The clones share 76.3, 73.2 and 85.2, 77.6 % nt sequence similarity with corresponding clones constructed in Italy and Israel. The results suggest that a derivative of a mini binary vector pCB302 is superior to pCAMBIA1305.1 for the construction of infectious and stable DNA clones of vitiviruses. Successful construction of such DNA clones of GVA and GVB reported in this study is a clear step towards fulfilling Koch's 3rd postulate in investigating the aetiology of Shiraz disease and corky bark disease. PMID- 26640752 TI - Bone-patellar tendon-bone allograft reconstruction for peri-patellar tendon sarcomas: case series. AB - INTRODUCTION: Reconstruction after wide resection for a sarcoma involving the knee extensor mechanism is challenging even if the tumor is small. CASE DESCRIPTION: We report on four consecutive peri-patellar tendon sarcomas treated similarly at a single institution. Histological diagnoses were synovial sarcoma (two cases), clear cell sarcoma and extraskeletal Ewing's sarcoma (one case each). Follow-up periods after surgery were 18-67 months. All cases underwent pre operative radiotherapy and subsequent surgery. After preoperative radiotherapy and wide resection including the patellar tendon, bone-patellar tendon-bone allograft was fixed to the residual patella and tibial tuberosity with screws and a cable wire. Soft tissue and skin defect over allograft was covered by free antero-lateral thigh flap. Post-operatively, the operated knee was splinted straight for at least 6 weeks, and then range-of-motion exercise was gradually introduced. Except for one case with a proximal tibial stress fracture 5 months post-operatively, no complication was observed. Both bone-bone junctions between allograft and residual bones were united within 1 year after surgery. At the latest clinical follow-up, all the patients had satisfactory functions with Musculoskeletal Tumor Society score of 28-30 out of 30 points and virtually full range of motion. DISCUSSION AND EVALUATION: This case series is the first to report bone-patellar tendon-bone allograft for reconstruction after tumor resection with joint preservation and with satisfactory clinical outcomes. CONCLUSIONS: Bone-patellar tendon-bone allograft reconstruction with vascularized flap reconstruction is a viable option for peri-patella tendon sarcomas. PMID- 26640753 TI - The development and validation of a test of science critical thinking for fifth graders. AB - The paper described the development and validation of the Test of Science Critical Thinking (TSCT) to measure the three critical thinking skill constructs: comparing and contrasting, sequencing, and identifying cause and effect. The initial TSCT consisted of 55 multiple choice test items, each of which required participants to select a correct response and a correct choice of critical thinking used for their response. Data were obtained from a purposive sampling of 30 fifth graders in a pilot study carried out in a primary school in Sabah, Malaysia. Students underwent the sessions of teaching and learning activities for 9 weeks using the Thinking Maps-aided Problem-Based Learning Module before they answered the TSCT test. Analyses were conducted to check on difficulty index (p) and discrimination index (d), internal consistency reliability, content validity, and face validity. Analysis of the test-retest reliability data was conducted separately for a group of fifth graders with similar ability. Findings of the pilot study showed that out of initial 55 administered items, only 30 items with relatively good difficulty index (p) ranged from 0.40 to 0.60 and with good discrimination index (d) ranged within 0.20-1.00 were selected. The Kuder Richardson reliability value was found to be appropriate and relatively high with 0.70, 0.73 and 0.92 for identifying cause and effect, sequencing, and comparing and contrasting respectively. The content validity index obtained from three expert judgments equalled or exceeded 0.95. In addition, test-retest reliability showed good, statistically significant correlations ([Formula: see text]). From the above results, the selected 30-item TSCT was found to have sufficient reliability and validity and would therefore represent a useful tool for measuring critical thinking ability among fifth graders in primary science. PMID- 26640754 TI - A model for delivering subspecialty pediatric surgical care in low- and middle income countries: one organization's early experience. AB - Delivery of humanitarian global surgical aid to low-middle income countries (LMICs) often occurs as a "fly-in, fly-out" marathon of operations. Unfortunately, the sustainability and efficacy of these missions remain questionable because they are difficult to reproduce and they have limited ability to provide peri-operative care. The goal of this project was to describe the Moore Pediatric Surgery Center (MPSC) in Guatemala City as an alternative model that provides a centralized structure to the interaction between surgical providers and patients in the operative and peri-operative periods. We also describe the Center's patient population and present feedback from surgical teams visiting the MPSC. A retrospective chart review was performed to quantify the number of patients, procedures, and post-operative complications at the MPSC between January 2011 and December 2014. We also performed a cross-sectional sociodemographic survey of MPSC patients and conducted a satisfaction survey of patients and surgical team members visiting the Center. Since 2011, the MPSC has hosted 42 surgical teams representing 7 different specialties. During its first four years, the surgery center hospital performed 2260 operations with a 1.07 % peri-operative complication rate and 0 % peri-operative mortality rate. All surgeries were performed free-of-charge to children from low-income households. Furthermore, the MPSC was rated highly among visiting team members (range 4.5-6 on a 7-point Likert scale) for quality metrics including organization, physical space, and collaboration with local staff. The MPSC represents a model for delivering multi-specialty surgical aid in low- and middle-income countries by providing modern surgical facilities with quality-assured post-operative care for the treatment of childhood surgical diseases. PMID- 26640755 TI - Complex Photonic Structures for Light Harvesting. AB - Over the last few years, micro- and nanophotonics have roused a strong interest in the scientific community for their promising impact on the development of novel kinds of solar cells. Certain thin- and ultrathin-film solar cells are made of innovative, often cheap, materials which suffer from a low energy conversion efficiency. Light-trapping mechanisms based on nanophotonics principles are particularly suited to enhance the absorption of electromagnetic waves in these thin media without changing the material composition. In this review, the latest results achieved in this field are reported, with particular attention to the realization of prototypes, spanning from deterministic to disordered photonic architectures, and from dielectric to metallic nanostructures. PMID- 26640756 TI - On the static structural design of climbing robots: part 2. AB - This manuscript is the second of two parts of a work investigating optimal configurations of legged climbing robots while loitering on vertical surfaces. In this Part 2, a structural analysis based on the finite element method, specifically the stiffness method, is performed to address the problem. Parameters that are investigated in this Part 2 include the inclination of both the body and the legs of the robot. Outcomes of the performed study are validated by analyzing the posture of 150 ants when loitering on vertical surfaces. The obtained validation ensures the predictions of the developed structural model are correct and can be used to identify optimal configurations of legged robots when loitering on vertical surfaces. PMID- 26640757 TI - Non-commutative holomorphic functions on operator domains. AB - We characterize functions of d-tuples of bounded operators on a Hilbert space that are uniformly approximable by free polynomials on balanced open sets. PMID- 26640758 TI - Effect of Acute and Chronic Exposure to High Altitude on the Aerobic and Anaerobic Metabolism in Rats. AB - In this study, we aimed to investigate the effect of acute and chronic exposure to HA on the aerobic and anaerobic metabolism in liver by determining the hepatic levels of ICDH and ATP. Lactate levels in liver and blood were also examined. Rats were exposed to an altitude of 4,300 m for 30 days, and those without HA exposure were used as controls. We observed an increased expression of liver ICDH following acute exposure (days 1, 3, and 7), whereas the liver ATP concentration was reduced on day 1. No changes in the hepatic expression of ICDH and ATP were found in rats chronically exposed to HA. Lactate concentrations of liver and blood did not show any significant changes following HA exposure. Thus, aerobic metabolism may be the major metabolic pathway in response to HA hypoxia in order to acclimatize themselves to the stressful environments. PMID- 26640759 TI - C1q Nephropathy: The Unique Underrecognized Pathological Entity. AB - C1q nephropathy is a rare glomerular disease with characteristic mesangial C1q deposition noted on immunofluorescence microscopy. It is histologically defined and poorly understood. Light microscopic features are heterogeneous and comprise minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), and proliferative glomerulonephritis. Clinical presentation is also diverse, and ranges from asymptomatic hematuria or proteinuria to frank nephritic or nephrotic syndrome in both children and adults. Hypertension and renal insufficiency at the time of diagnosis are common findings. Optimal treatment is not clear and is usually guided by the underlying light microscopic lesion. Corticosteroids are the mainstay of treatment, with immunosuppressive agents reserved for steroid resistant cases. The presence of nephrotic syndrome and FSGS appear to predict adverse outcomes as opposed to favorable outcomes in those with MCD. Further research is needed to establish C1q nephropathy as a universally recognized distinct clinical entity. In this paper, we discuss the current understanding of pathogenesis, histopathology, clinical features, therapeutic options, and outcomes of C1q nephropathy. PMID- 26640760 TI - Development and Validation of the Body-Focused Shame and Guilt Scale. AB - Body shame is described as central in clinical literature on body dysmorphic disorder (BDD). However, empirical investigations of body shame within BDD are rare. One potential reason for the scarcity of such research may be that existing measures of body shame focus on eating and weight-based content. Within BDD, however, body shame likely focuses more broadly on shame felt in response to perceived appearance flaws in one's body parts. We describe the development and validation of the Body-Focused Shame and Guilt Scale (BF-SGS), a measure of BDD relevant body shame, across two studies: a two time-point study of undergraduates, and a follow-up study in two Internet-recruited clinical samples (BDD, obsessive compulsive disorder) and healthy controls. Across both studies, the BF-SGS shame subscale demonstrated strong reliability and construct validity, with Study 2 providing initial clinical norms. PMID- 26640761 TI - Assessment of global proteome in LNCaP cells by 2D-RP/RP LC-MS/MS following sulforaphane exposure. AB - The phytochemical sulforaphane can induce cell cycle arrest and apoptosis in metastatic prostate cancer cells, though the mechanism of action is not fully known. We conducted a global proteome analysis in LNCaP metastatic prostate cancer cells to characterize how global protein signature responds to sulforaphane. We conducted parallel analyses to evaluate semi-quantitative 1 dimensional versus 2-dimensional liquid chromatography tandem mass spectrometry (LC-MS/MS) and their utility in characterizing whole cell lysate. We show that 2 dimensional LC-MS/MS can be a useful tool for characterizing global protein profiles and identify TRIAP1 as a novel regulator of cell proliferation in LNCaP metastatic prostate cancer cells. PMID- 26640762 TI - Structural connectivity of the anterior cingulate in children with unilateral cerebral palsy due to white matter lesions. AB - In this work we investigate the structural connectivity of the anterior cingulate cortex (ACC) and its link with impaired executive function in children with unilateral cerebral palsy (UCP) due to periventricular white matter lesions. Fifty two children with UCP and 17 children with typical development participated in the study, and underwent diffusion and structural MRI. Five brain regions were identified for their high connectivity with the ACC using diffusion MRI fibre tractography: the superior frontal gyrus, medial orbitofrontal cortex, rostral middle frontal gyrus, precuneus and isthmus cingulate. Structural connectivity was assessed in pathways connecting these regions to the ACC using three diffusion MRI derived measures: fractional anisotropy (FA), mean diffusivity (MD) and apparent fibre density (AFD), and compared between participant groups. Furthermore we investigated correlations of these measures with executive function as assessed by the Flanker task. The ACC-precuneus tract had significantly different MD (p < 0.0001) and AFD (p = 0.0072) between groups, with post-hoc analysis showing significantly increased MD in the right hemisphere of children with left hemiparesis compared with controls. The ACC-superior frontal gyrus tract had significantly different FA (p = 0.0049) and MD (p = 0.0031) between groups. AFD in this tract (contralateral to side of hemiparesis; right hemisphere in controls) showed a significant relationship with Flanker task performance (p = 0.0045, beta = -0.5856), suggesting that reduced connectivity correlates with executive dysfunction. Reduced structural integrity of ACC tracts appears to be important in UCP, in particular the connection to the superior frontal gyrus. Although damage to this area is heterogeneous it may be important in early identification of children with impaired executive function. PMID- 26640763 TI - Whole-brain structural topology in adult attention-deficit/hyperactivity disorder: Preserved global - disturbed local network organization. AB - Prior studies demonstrate altered organization of functional brain networks in attention-deficit/hyperactivity disorder (ADHD). However, the structural underpinnings of these functional disturbances are poorly understood. In the current study, we applied a graph-theoretic approach to whole-brain diffusion magnetic resonance imaging data to investigate the organization of structural brain networks in adults with ADHD and unaffected controls using deterministic fiber tractography. Groups did not differ in terms of global network metrics - small-worldness, global efficiency and clustering coefficient. However, there were widespread ADHD-related effects at the nodal level in relation to local efficiency and clustering. The affected nodes included superior occipital, supramarginal, superior temporal, inferior parietal, angular and inferior frontal gyri, as well as putamen, thalamus and posterior cerebellum. Lower local efficiency of left superior temporal and supramarginal gyri was associated with higher ADHD symptom scores. Also greater local clustering of right putamen and lower local clustering of left supramarginal gyrus correlated with ADHD symptom severity. Overall, the findings indicate preserved global but altered local network organization in adult ADHD implicating regions underpinning putative ADHD related neuropsychological deficits. PMID- 26640764 TI - Functional connectivity changes detected with magnetoencephalography after mild traumatic brain injury. AB - Mild traumatic brain injury (mTBI) may affect normal cognition and behavior by disrupting the functional connectivity networks that mediate efficient communication among brain regions. In this study, we analyzed brain connectivity profiles from resting state Magnetoencephalographic (MEG) recordings obtained from 31 mTBI patients and 55 normal controls. We used phase-locking value estimates to compute functional connectivity graphs to quantify frequency specific couplings between sensors at various frequency bands. Overall, normal controls showed a dense network of strong local connections and a limited number of long-range connections that accounted for approximately 20% of all connections, whereas mTBI patients showed networks characterized by weak local connections and strong long-range connections that accounted for more than 60% of all connections. Comparison of the two distinct general patterns at different frequencies using a tensor representation for the connectivity graphs and tensor subspace analysis for optimal feature extraction showed that mTBI patients could be separated from normal controls with 100% classification accuracy in the alpha band. These encouraging findings support the hypothesis that MEG-based functional connectivity patterns may be used as biomarkers that can provide more accurate diagnoses, help guide treatment, and monitor effectiveness of intervention in mTBI. PMID- 26640765 TI - Multivariate analyses applied to fetal, neonatal and pediatric MRI of neurodevelopmental disorders. AB - Multivariate analysis (MVA) is a class of statistical and pattern recognition methods that involve the processing of data that contains multiple measurements per sample. MVA can be used to address a wide variety of medical neuroimaging related challenges including identifying variables associated with a measure of clinical importance (i.e. patient outcome), creating diagnostic tests, assisting in characterizing developmental disorders, understanding disease etiology, development and progression, assisting in treatment monitoring and much more. Compared to adults, imaging of developing immature brains has attracted less attention from MVA researchers. However, remarkable MVA research growth has occurred in recent years. This paper presents the results of a systematic review of the literature focusing on MVA technologies applied to neurodevelopmental disorders in fetal, neonatal and pediatric magnetic resonance imaging (MRI) of the brain. The goal of this manuscript is to provide a concise review of the state of the scientific literature on studies employing brain MRI and MVA in a pre-adult population. Neurological developmental disorders addressed in the MVA research contained in this review include autism spectrum disorder, attention deficit hyperactivity disorder, epilepsy, schizophrenia and more. While the results of this review demonstrate considerable interest from the scientific community in applications of MVA technologies in pediatric/neonatal/fetal brain MRI, the field is still young and considerable research growth remains ahead of us. PMID- 26640766 TI - Executive attention control and emotional responding in attention deficit/hyperactivity disorder--A functional MRI study. AB - BACKGROUND: There are suggestions that patients with attention deficit/hyperactivity disorder (ADHD) show impairment in executive attention control and emotion regulation. This study investigated emotion regulation as a function of the recruitment of executive attention in patients with ADHD. METHODS: Thirty-five healthy children/adolescents (mean age = 13.91) and twenty six children/adolescents with ADHD (mean age = 14.53) participated in this fMRI study. They completed the affective Stroop paradigm viewing positive, neutral and negative images under varying cognitive loads. A 3-way ANOVA (diagnosis-by condition-by-emotion) was conducted on the BOLD response data. Following this, 2 3-way ANOVAs (diagnosis-by-condition-by-emotion) were applied to context dependent psychophysiological interaction (gPPI) analyses generated from a dorsomedial frontal cortex and an amygdala seed (identified from the BOLD response ANOVA main effects of condition and emotion respectively). RESULTS: A diagnosis-by-condition interaction within dorsomedial frontal cortex revealed reduced recruitment of dorsomedial frontal cortex as a function of increased task demands in the children/adolescents with ADHD relative to healthy children/adolescents. The level of reduction in recruitment of dorsomedial frontal cortex was significantly correlated with symptom severity (total and hyperactivity) measured by Conner's Parent Report Scale in the children/adolescents with ADHD. In addition, analysis of gPPI data from a dorsomedial frontal cortex seed revealed significant diagnosis-by-condition interactions within lateral frontal cortex; connectivity between dorsomedial frontal cortex and lateral frontal cortex was reduced in the patients with ADHD relative to comparison youth during congruent and incongruent task trials relative to view trials. There were no interactions of group, or main effect of group, within the amygdala in the BOLD response ANOVA (though children/adolescents with ADHD showed increased responses to positive images within temporal cortical regions during task trials; identified by the diagnosis by-condition-by-emotion interaction). However, analysis of gPPI data from an amygdala seed revealed decreased connectivity between amygdala and lentiform nucleus in the presence of emotional stimuli in children/adolescents with ADHD (diagnosis-by-emotion interaction). CONCLUSION: The current study demonstrated disrupted recruitment of regions implicated in executive function and impaired connectivity within those regions in children/adolescents with ADHD. There were also indications of heightened representation of emotional stimuli in patients with ADHD. However, as the findings were specific for positive stimuli, the suggestion of a general failure in emotion regulation in ADHD was not supported. PMID- 26640767 TI - Classifying individuals at high-risk for psychosis based on functional brain activity during working memory processing. AB - The psychosis high-risk state is accompanied by alterations in functional brain activity during working memory processing. We used binary automatic pattern classification to discriminate between the at-risk mental state (ARMS), first episode psychosis (FEP) and healthy controls (HCs) based on n-back WM-induced brain activity. Linear support vector machines and leave-one-out-cross-validation were applied to fMRI data of matched ARMS, FEP and HC (19 subjects/group). The HC and ARMS were correctly classified, with an accuracy of 76.2% (sensitivity 89.5%, specificity 63.2%, p = 0.01) using a verbal working memory network mask. Only 50% and 47.4% of individuals were classified correctly for HC vs. FEP (p = 0.46) or ARMS vs. FEP (p = 0.62), respectively. Without mask, accuracy was 65.8% for HC vs. ARMS (p = 0.03) and 65.8% for HC vs. FEP (p = 0.0047), and 57.9% for ARMS vs. FEP (p = 0.18). Regions in the medial frontal, paracingulate, cingulate, inferior frontal and superior frontal gyri, inferior and superior parietal lobules, and precuneus were particularly important for group separation. These results suggest that FEP and HC or FEP and ARMS cannot be accurately separated in small samples under these conditions. However, ARMS can be identified with very high sensitivity in comparison to HC. This might aid classification and help to predict transition in the ARMS. PMID- 26640768 TI - Mapping abnormal subcortical brain morphometry in an elderly HIV+ cohort. AB - Over 50% of HIV + individuals exhibit neurocognitive impairment and subcortical atrophy, but the profile of brain abnormalities associated with HIV is still poorly understood. Using surface-based shape analyses, we mapped the 3D profile of subcortical morphometry in 63 elderly HIV + participants and 31 uninfected controls. The thalamus, caudate, putamen, pallidum, hippocampus, amygdala, brainstem, accumbens, callosum and ventricles were segmented from high-resolution MRIs. To investigate shape-based morphometry, we analyzed the Jacobian determinant (JD) and radial distances (RD) defined on each region's surfaces. We also investigated effects of nadir CD4 + T-cell counts, viral load, time since diagnosis (TSD) and cognition on subcortical morphology. Lastly, we explored whether HIV + participants were distinguishable from unaffected controls in a machine learning context. All shape and volume features were included in a random forest (RF) model. The model was validated with 2-fold cross-validation. Volumes of HIV + participants' bilateral thalamus, left pallidum, left putamen and callosum were significantly reduced while ventricular spaces were enlarged. Significant shape variation was associated with HIV status, TSD and the Wechsler adult intelligence scale. HIV + people had diffuse atrophy, particularly in the caudate, putamen, hippocampus and thalamus. Unexpectedly, extended TSD was associated with increased thickness of the anterior right pallidum. In the classification of HIV + participants vs. controls, our RF model attained an area under the curve of 72%. PMID- 26640769 TI - Neural correlates of executive attention in adults born very preterm. AB - Very preterm birth is associated with an increased prevalence of attention problems and may especially impair executive attention, i.e., top-down control of attentional selection in situations where distracting information interferes with the processing of task-relevant stimuli. While there are initial findings linking structural brain alterations in preterm-born individuals with attention problems, the functional basis of these problems are not well understood. The present study used an fMRI adaptation of the Attentional Network Test to examine the neural correlates of executive attention in a large sample of N = 86 adults born very preterm and/or with very low birth weight (VP/VLBW), and N = 100 term-born controls. Executive attention was measured by comparing task behavior and brain activations associated with the processing of incongruent vs. congruent arrow flanker stimuli. Consistent with subtle impairments of executive attention, the VP/VLBW group showed lower accuracy and a tendency for increased response times during the processing of incongruent stimuli. Both groups showed similar activation patters, especially within expected fronto-cingulo-parietal areas, but no significant between-group differences. Our results argue for a maintained attention-relevant network organization in high-functioning preterm born adults in spite of subtle deficits in executive attention. Gestational age and neonatal treatment variables showed associations with task behavior, and brain activation in the dorsal ACC and lateral occipital areas, suggesting that the degree of prematurity (and related neonatal complications) has subtle modulatory influences on executive attention processing. PMID- 26640770 TI - Comparison of qualitative and quantitative imaging characteristics of [11C]PiB and [18F]flutemetamol in normal control and Alzheimer's subjects. AB - INTRODUCTION: Neuritic amyloid plaques and neurofibrillary tangles, the hallmark pathologic lesions of Alzheimer's disease, are thought to develop before the symptoms of brain failure are clinically detectable. Imaging methods capable of detecting the presence of neuritic amyloid plaques should improve a clinician's ability to identify Alzheimer's disease during the earliest symptomatic phase and to identify at-risk individuals presymptomatically. Currently the best studied amyloid imaging ligand is [(11)C]Pittsburgh Compound B ([(11)C]PiB). However, the 20-minute half-life of this radiotracer limits its use. This study is designed to evaluate the performance characteristics of [(18)F]flutemetamol and to independently compare results to [(11)C]PiB in the same subjects. METHODS: Twenty three subjects, 15 cognitively normal (NL) and 8 with a clinical diagnosis of Alzheimer's Dementia (AD), underwent [(11)C]PiB and [(18)F]flutemetamol PET scans within 28 days of study enrollment. We studied both normal and AD subjects to assess the uptake characteristics across a range of amyloid positivity. Blinded visual reads were conducted by five raters. Correlation analyses were performed between cortical SUVR for the two tracers and also between rater scores and SUVR for each tracer. Overall reader accuracy for classifying scans as amyloid positive or negative was determined for each tracer using SUVR classification as the standard. RESULTS: The linear correlation coefficient between global cortical SUVR for the two tracers was R(2) = 0.85, indicating that both tracers have similar retention characteristics. The two tracers were well correlated for rater determined AD-like positivity (Cohen kappa = 0.82). Averaged visual ratings and global cortical SUVR disagreed on their classification in 2/23 [(11)C]PiB scans and 4/23 [(18)F]flutemetamol scans. CONCLUSIONS: [(11)C]PiB and [(18)F]flutemetamol have similar retention characteristics across a range of amyloid negative to positive subjects. Both tracers performed similarly when a standardized visual read technique was used to classify scans as amyloid-positive or amyloid-negative and correlated well with SUVR classifications. However, care in visual interpretation of amyloid positive versus amyloid negative regions should be taken, particularly in the case of [(18)F]flutemetamol when considering cortical vs. white-matter retention. PMID- 26640772 TI - Real-time Near-infrared Virtual Intraoperative Surgical Photoacoustic Microscopy. AB - We developed a near infrared (NIR) virtual intraoperative surgical photoacoustic microscopy (NIR-VISPAM) system that combines a conventional surgical microscope and an NIR light photoacoustic microscopy (PAM) system. NIR-VISPAM can simultaneously visualize PA B-scan images at a maximum display rate of 45 Hz and display enlarged microscopic images on a surgeon's view plane through the ocular lenses of the surgical microscope as augmented reality. The use of the invisible NIR light eliminated the disturbance to the surgeon's vision caused by the visible PAM excitation laser in a previous report. Further, the maximum permissible laser pulse energy at this wavelength is approximately 5 times more than that at the visible spectral range. The use of a needle-type ultrasound transducer without any water bath for acoustic coupling can enhance convenience in an intraoperative environment. We successfully guided needle and injected carbon particles in biological tissues ex vivo and in melanoma-bearing mice in vivo. PMID- 26640771 TI - Review of photoacoustic flow imaging: its current state and its promises. AB - Flow imaging is an important method for quantification in many medical imaging modalities, with applications ranging from estimating wall shear rate to detecting angiogenesis. Modalities like ultrasound and optical coherence tomography both offer flow imaging capabilities, but suffer from low contrast to red blood cells and are sensitive to clutter artefacts. Photoacoustic imaging (PAI) is a relatively new field, with a recent interest in flow imaging. The recent enthusiasm for PA flow imaging is due to its intrinsic contrast to haemoglobin, which offers a new spin on existing methods of flow imaging, and some unique approaches in addition. This review article will delve into the research on photoacoustic flow imaging, explain the principles behind the many techniques and comment on their individual advantages and disadvantages. PMID- 26640773 TI - Sensing the delivery and endocytosis of nanoparticles using magneto-photo acoustic imaging. AB - Many biomedical applications necessitate a targeted intracellular delivery of the nanomaterial to specific cells. Therefore, a non-invasive and reliable imaging tool is required to detect both the delivery and cellular endocytosis of the nanoparticles. Herein, we demonstrate that magneto-photo-acoustic (MPA) imaging can be used to monitor the delivery and to identify endocytosis of magnetic and optically absorbing nanoparticles. The relationship between photoacoustic (PA) and magneto-motive ultrasound (MMUS) signals from the in vitro samples were analyzed to identify the delivery and endocytosis of nanoparticles. The results indicated that during the delivery of nanoparticles to the vicinity of the cells, both PA and MMUS signals are almost linearly proportional. However, accumulation of nanoparticles within the cells leads to nonlinear MMUS-PA relationship, due to non-linear MMUS signal amplification. Therefore, through longitudinal MPA imaging, it is possible to monitor the delivery of nanoparticles and identify the endocytosis of the nanoparticles by living cells. PMID- 26640774 TI - Design of optimal light delivery system for co-registered transvaginal ultrasound and photoacoustic imaging of ovarian tissue. AB - A hand-held transvaginal probe suitable for co-registered photoacoustic and ultrasound imaging of ovarian tissue was designed and evaluated. The imaging probe consists of an ultrasound transducer and four 1-mm-core multi-mode optical fibers both housed in a custom-made sheath. The probe was optimized for the highest light delivery output and best beam uniformity on tissue surface, by simulating the light fluence and power output for different design parameters. The laser fluence profiles were experimentally measured through chicken breast tissue and calibrated intralipid solution at various imaging depths. Polyethylene tubing filled with rat blood mimicking a blood vessel was successfully imaged up to ~30 mm depth through porcine vaginal tissue at 750 nm. This imaging depth was achieved with a laser fluence on the tissue surface of 20 mJ/cm(2), which is below the maximum permissible exposure (MPE) of 25 mJ/cm(2) recommended by the American National Standards Institute (ANSI). Furthermore, the probe imaging capability was verified with ex vivo imaging of benign and malignant human ovaries. The co-registered images clearly showed different vasculature distributions on the surface of the benign cyst and the malignant ovary. These results suggest that our imaging system has the clinical potential for in vivo imaging and characterization of ovarian tissues. PMID- 26640775 TI - A computational model to monitor and predict trends in bacterial resistance. AB - Current concern over the emergence of multidrug-resistant superbugs has renewed interest in approaches that can monitor existing trends in bacterial resistance and make predictions of future trends. Recent advances in bacterial surveillance and the development of online repositories of susceptibility tests across wide geographical areas provide an important new resource, yet there are only limited computational tools for its exploitation. Here we propose a hybrid computational model called BARDmaps for automated analysis of antibacterial susceptibility tests from surveillance records and for performing future predictions. BARDmaps was designed to include a structural computational model that can detect patterns among bacterial resistance changes as well as a behavioural computational model that can use the detected patterns to predict future changes in bacterial resistance. Data from the European Antimicrobial Resistance Surveillance Network (EARS-Net) were used to validate and apply the model. BARDmaps was compared with standard curve-fitting approaches used in epidemiological research. Here we show that BARDmaps can reliably predict future trends in bacterial resistance across Europe. BARDmaps performed better than other curve-fitting approaches for predicting future resistance levels. In addition, BARDmaps was also able to detect abrupt changes in bacterial resistance in response to outbreaks and interventions as well as to compare bacterial behaviour across countries and drugs. In conclusion, BARDmaps is a reliable tool to automatically predict and analyse changes in bacterial resistance across Europe. We anticipate that BARDmaps will become an invaluable tool both for clinical providers and governmental agencies to help combat the threat posed by antibiotic-resistant bacteria. PMID- 26640777 TI - Paving the Road for Modern Particle Therapy - What Can We Learn from the Experience Gained with Fast Neutron Therapy in Munich? AB - While neutron therapy was a highly topical subject in the 70s and 80s, today there are only a few remaining facilities offering fast neutron therapy (FNT). Nevertheless, up to today more than 30,000 patients were treated with neutron therapy. For some indications like salivary gland tumors and malignant melanoma, there is clinical evidence that the addition of FNT leads to superior local control compared to photon treatment alone. FNT was available in Munich from 1985 until 2000 at the Reactor Neutron Therapy (RENT) facility. Patient treatment continued at the new research reactor FRM II in 2007 under improved treatment conditions, and today it can still be offered to selected patients as an individual treatment option. As there is a growing interest in high-linear energy transfer (LET) therapy with new hadron therapy centers emerging around the globe, the clinical data generated by neutron therapy might help to develop biologically driven treatment planning algorithms. Also FNT might experience its resurgence as a combinational partner of modern immunotherapies. PMID- 26640778 TI - My 40-Year History with Cronobacter/Enterobacter sakazakii - Lessons Learned, Myths Debunked, and Recommendations. AB - Much has been learned about organism in the Cronobacter/Enterobacter sakazakii complex since I first named and described Enterobacter sakazakii in 1980. However, there are still wide knowledge gaps. One of the most serious is that are still many uncertainties associated with assessing the public health risk posed by these bacteria, particularly in neonatal meningitis. Over the last few decades, Cronobacter contamination of commercial powdered infant formula products has apparently been reduced, but it is still an ongoing problem. The powdered infant formula industry still cannot produce powdered formula that is free of bacterial contamination with Cronobacter, other Enterobacteriaceae, other pathogenic bacteria, and other microorganisms. Until this happens, infants and other will be at risk of becoming infected when they ingest contaminated formula. PMID- 26640776 TI - Development of an Internet Intervention to Address Behaviors Associated with Skin Cancer Risk among Young Adults. AB - PURPOSE: Skin cancer is the most common cancer in the US, and its incidence is increasing. The major risk factor for skin cancer is exposure to ultraviolet radiation (UV). Young adults tend to expose themselves to large amounts of UV and engage in minimal skin protection, which increases their skin cancer risk. Interventions are needed to address risk behaviors among young adults that may lead to skin cancer. The nternet offers a cost-effective way to widely disseminate efficacious interventions. The current paper describes the development of an online skin cancer risk reduction intervention (UV4.me) for young adults. PROCEDURES: The iterative development process for UV4.me followed best-practice guidelines and included the following activities: individual interviews, focus groups, content development by the expert team, acceptability testing, cognitive interviewing for questionnaires, quality control testing, usability testing, and a pilot randomized controlled trial. Participant acceptability and usability feedback was assessed. PRINCIPAL RESULTS: The development process produced an evidence-informed intervention that is individually-tailored, interactive, and multimedia in nature based on the Integrative Model of Behavior Prediction, a model for internet interventions, and other best-practice recommendations, expert input, as well as user acceptability and usability feedback gathered before, during, and after development. MAJOR CONCLUSIONS: Development of an acceptable intervention intended to have a significant public health impact requires a relatively large investment in time, money, expertise, and ongoing user input. Lessons learned and recommendations are discussed. The comprehensive process used may help prepare others interested in creating similar behavioral health interventions. PMID- 26640779 TI - Long-Term Outcomes in Children with Steroid-Resistant Nephrotic Syndrome Treated with Calcineurin Inhibitors. AB - BACKGROUND: Steroid-resistant nephrotic syndrome (SRNS) is an important cause of chronic kidney disease (CKD) in children that often progresses to end-stage renal disease (ESRD). Calcineurin inhibitors (CNIs) have been shown to be effective in inducing short-term remission in some patients with SRNS. However, there are little data examining their long-term impact on ESRD progression rates. METHODS: We performed a retrospective chart review of all patients treated for SRNS with CNIs at our institution from 1995 to 2013. Data collected including demographics, initial response to medical therapy, number of relapses, progression to ESRD, and treatment complications. RESULTS: A total of 16 patients met inclusion criteria with a mean follow-up of 6.6 years (range 0.6-17.6 years). Histopathological diagnoses were focal segmental glomerulosclerosis (8), mesangial proliferative glomerulonephritis (4), IgM nephropathy (3), and minimal change disease (1). Three patients (18.8%) were unresponsive to CNIs while the remaining 13 (81.2%) achieved remission with CNI therapy. Six patients (37.5%) progressed to ESRD during the study period, three of whom did so after initially responding to CNI therapy. Renal survival rates were 87, 71, and 57% at 2, 5, and 10 years, respectively. Non-Caucasian ethnicity was associated with progression to ESRD. Finally, a higher number of acute kidney injury (AKI) episodes were associated with a lower final estimated glomerular filtration rate. DISCUSSION: Despite the majority of SRNS patients initially responding to CNI therapy, a significant percentage still progressed to ESRD despite achieving short-term remission. Recurrent episodes of AKI may be associated with progression of CKD in patients with SRNS. PMID- 26640780 TI - Pharmacokinetics and Dosimetry Studies for Optimization of Pretargeted Radioimmunotherapy in CEA-Expressing Advanced Lung Cancer Patients. AB - OBJECTIVES: A phase I pretargeted radioimmunotherapy trial (EudractCT 200800603096) was designed in patients with metastatic lung cancer expressing carcinoembryonic antigen (CEA) to optimize bispecific antibody and labeled peptide doses, as well as the delay between their injections. METHODS: Three cohorts of three patients received the anti-CEA * anti-histamine-succinyl-glycine (HSG)-humanized trivalent bispecific antibody (TF2) and the IMP288 bivalent HSG peptide. Patients underwent a pretherapeutic imaging session S1 (44 or 88 nmol/m(2) of TF2 followed by 4.4 nmol/m(2), 185 MBq, of (111)In-labeled IMP288) and, 1-2 weeks later, a therapy session S2 (240 or 480 nmol/m(2) of TF2 followed by 24 nmol/m(2), 1.1 GBq/m(2), of (177)Lu-labeled IMP288). The pretargeting delay was 24 or 48 h. The dose schedule was defined based on preclinical TF2 pharmacokinetic (PK) studies, on our previous clinical data using the previous anti-CEA-pretargeting system, and on clinical results observed in the first patients injected using the same system in Netherlands. RESULTS: TF2 PK was represented by a two-compartment model in which the central compartment volume (Vc) was linearly dependent on the patient's surface area. PK was remarkably similar, with a clearance of 0.33 +/- 0.03 L/h/m(2). (111)In- and (177)Lu-IMP288 PK was also well represented by a two-compartment model. IMP288 PK was faster (clearance 1.4-3.3 L/h). The Vc was proportional to body surface area, and IMP288 clearance depended on the molar ratio of injected IMP288 to circulating TF2 at the time of IMP288 injection. Modeling of image quantification confirmed the dependence of IMP288 kinetics on circulating TF2, but tumor activity PK was variable. Organ-absorbed doses were not significantly different in the three cohorts, but the tumor dose was significantly higher with the higher molar doses of TF2 (p < 0.002). S1 imaging predicted absorbed doses calculated in S2. CONCLUSION: The best dosing parameters corresponded to the shorter pretargeting delay and to the highest TF2 molar doses. S1 imaging session accurately predicted PK as well as absorbed doses of S2, thus potentially allowing for patient selection and dose optimization. TRIAL REGISTRATION: ClinicalTrials.gov NCT01221675 (EudractCT 200800603096). PMID- 26640781 TI - Exploring Clinical and Epidemiological Characteristics of Interstitial Lung Diseases: Rationale, Aims, and Design of a Nationwide Prospective Registry--The EXCITING-ILD Registry. AB - Despite a number of prospective registries conducted in past years, the current epidemiology of interstitial lung diseases (ILD) is still not well defined, particularly regarding the prevalence and incidence, their management, healthcare utilisation needs, and healthcare-associated costs. To address these issues in Germany, a new prospective ILD registry, "Exploring Clinical and Epidemiological Characteristics of Interstitial Lung Diseases" (EXCITING-ILD), is being conducted by the German Centre for Lung Research in association with ambulatory, inpatient, scientific pulmonology organisations and patient support groups. This multicentre, noninterventional, prospective, and observational ILD registry aims to collect comprehensive and validated data from all healthcare institutions on the incidence, prevalence, characteristics, management, and outcomes regarding all ILD presentations in the real-world setting. Specifically, this registry will collect demographic data, disease-related data such as ILD subtype, treatments, diagnostic procedures (e.g., HRCT, surgical lung biopsy), risk factors (e.g., familial ILD), significant comorbidities, ILD managements, and disease outcomes as well as healthcare resource consumption. The EXCITING-ILD registry will include in-patient and out-patient ILD healthcare facilities in more than 100 sites. In summary, this registry will document comprehensive and current epidemiological data as well as important health economic data for ILDs in Germany. PMID- 26640782 TI - Increased Mesenchymal Stem Cell Response and Decreased Staphylococcus aureus Adhesion on Titania Nanotubes without Pharmaceuticals. AB - Titanium (Ti) implants with enhanced biocompatibility and antibacterial property are highly desirable and characterized by improved success rates. In this study, titania nanotubes (TNTs) with various tube diameters were fabricated on Ti surfaces through electrochemical anodization at 10, 30, and 60 V (denoted as NT10, NT30, and NT60, resp.). Ti was also investigated and used as a control. NT10 with a diameter of 30 nm could promote the adhesion and proliferation of bone marrow mesenchymal stem cells (BMSCs) without noticeable differentiation. NT30 with a diameter of 100 nm could support the adhesion and proliferation of BMSCs and induce osteogenesis. NT60 with a diameter of 200 nm demonstrated the best ability to promote cell spreading and osteogenic differentiation; however, it clearly impaired cell adhesion and proliferation. As the tube diameter increased, bacterial adhesion on the TNTs decreased and reached the lowest value on NT60. Therefore, NT30 without pharmaceuticals could be used to increase mesenchymal stem cell response and decrease Staphylococcus aureus adhesion and thus should be further studied for improving the efficacy of Ti-based orthopedic implants. PMID- 26640783 TI - A Novel Insight into Dehydroleucodine Mediated Attenuation of Pseudomonas aeruginosa Virulence Mechanism. AB - Increasing resistance of Pseudomonas aeruginosa (P. aeruginosa) to conventional treatments demands the search for novel therapeutic strategies. In this study, the antimicrobial activity of dehydroleucodine (DhL), a sesquiterpene lactone obtained from Artemisia (A.) douglasiana, was screened against several pathogenic virulence effectors of P. aeruginosa. In vitro, minimum inhibitory concentration of DhL was determined against P. aeruginosa strains PAO1, PA103, PA14, and multidrug resistant clinical strain, CDN118. Results showed that DhL was active against each strain where PAO1 and PA103 showed higher susceptibility (MIC 0.48 mg/mL) as compared to PA14 (MIC 0.96 mg/mL) and CDN118 (MIC 0.98 mg/mL). Also, when PAO1 strain was grown in the presence of DhL (MIC50, 0.12 mg/mL), a delay in the generation time was noticed along with significant inhibition of secretory protease and elastase activities, interruption in biofilm attachment phase in a stationary culture, and a significant decline in Type III effector ExoS. At MIC50, DhL treatment increased the sensitivity of P. aeruginosa towards potent antibiotics. Furthermore, treatment of P. aeruginosa with DhL prevented toxin induced apoptosis in macrophages. These observations suggest that DhL activity was at the bacterial transcriptional level. Hence, antimicrobial activity of DhL may serve as leads in the development of new anti-Pseudomonas pharmaceuticals. PMID- 26640784 TI - Selection of the Strain Lactobacillus acidophilus ATCC 43121 and Its Application to Brewers' Spent Grain Conversion into Lactic Acid. AB - Six Lactobacillus strains were analyzed to select a bacterium for conversion of brewers' spent grain (BSG) into lactic acid. Among the investigated strains, L. acidophilus ATCC 43121 showed the highest yield of lactic acid production (16.1 g/L after 48 hours) when grown in a synthetic medium. It was then analyzed for its ability to grow on the hydrolysates obtained from BSG after acid-alkaline (AAT) or aqueous ammonia soaking (AAS) pretreatment. The lactic acid production by L. acidophilus ATCC 43121 through fermentation of the hydrolysate from AAS treated BSG was 96% higher than that from the AAT treated one, although similar yields of lactic acid per consumed glucose were achieved due to a higher (46%) glucose consumption by L. acidophilus ATCC 43121 in the AAS BSG hydrolysate. It is worth noting that adding yeast extract to the BSG hydrolysates increased both the yield of lactic acid per substrate consumed and the volumetric productivity. The best results were obtained by fermentation of AAS BSG hydrolysate supplemented by yeast extract, in which the strain produced 22.16 g/L of lactic acid (yield of 0.61 g/g), 27% higher than the value (17.49 g/L) obtained in the absence of a nitrogen source. PMID- 26640785 TI - Three-Dimensional Analysis of the Curvature of the Femoral Canal in 426 Chinese Femurs. AB - PURPOSE: The human femur has long been considered to have an anatomical anterior curvature in the sagittal plane. We established a new method to evaluate the femoral curvature in three-dimensional (3D) space and reveal its influencing factors in Chinese population. METHODS: 3D models of 426 femurs and the medullary canal were constructed using Mimics software. We standardized the positions of all femurs using 3ds Max software. After measuring the anatomical parameters, including the radius of femoral curvature (RFC) and banking angle, of the femurs using the established femur-specific coordinate system, we analyzed and determined the relationships between the anatomical parameters of the femur and the general characteristics of the population. RESULTS: Pearson's correlation analyses showed that there were positive correlations between the RFC and height (r = 0.339, p < 0.001) and the femoral length and RFC (r = 0.369, p < 0.001) and a negative correlation between the femoral length and banking angle (r = -0.223, p < 0.001). Stepwise linear regression analyses showed that the most relevant factors for the RFC and banking angle were the femoral length and gender, respectively. CONCLUSIONS: This study concluded that the banking angle of the femur was significantly larger in female than in male. PMID- 26640786 TI - Senescence-Associated Changes in Proteome and O-GlcNAcylation Pattern in Human Peritoneal Mesothelial Cells. AB - INTRODUCTION: Senescence of peritoneal mesothelial cells represents a biological program defined by arrested cell growth and altered cell secretory phenotype with potential impact in peritoneal dialysis. This study aims to characterize cellular senescence at the level of global protein expression profiles and modification of proteins with O-linked N-acetylglucosamine (O-GlcNAcylation). METHODS: A comparative proteomics analysis between young and senescent human peritoneal mesothelial cells (HPMC) was performed using two-dimensional gel electrophoresis. O-GlcNAc status was assessed by Western blot under normal conditions and after modulation with 6-diazo-5-oxo-L-norleucine (DON) to decrease O-GlcNAcylation or O (2-acetamido-2-deoxy-D-glucopyranosylidene) amino N-phenyl carbamate (PUGNAc) to increase O-GlcNAcylation. RESULTS: Comparison of protein pattern of senescent and young HPMC revealed 29 differentially abundant protein spots, 11 of which were identified to be actin (cytoplasmic 1 and 2), cytokeratin-7, cofilin-2, transgelin-2, Hsp60, Hsc70, proteasome beta-subunits (type-2 and type-3), nucleoside diphosphate kinase A, and cytosolic 5'(3')-deoxyribonucleotidase. Although the global level of O-GlcNAcylation was comparable, senescent cells were not sensitive to modulation by PUGNAc. DISCUSSION: This study identified changes of the proteome and altered dynamics of O-GlcNAc regulation in senescent mesothelial cells. Whereas changes in cytoskeleton-associated proteins likely reflect altered cell morphology, changes in chaperoning and housekeeping proteins may have functional impact on cellular stress response in peritoneal dialysis. PMID- 26640787 TI - Overcoming the Underutilisation of Peritoneal Dialysis. AB - Peritoneal dialysis is troubled with declining utilisation as a form of renal replacement therapy in developed countries. We review key aspects of therapy evidenced to have a potential to increase its utilisation. The best evidence to repopulate PD programmes is provided for the positive impact of timely referral and systematic and motivational predialysis education: average odds ratio for instituting peritoneal dialysis versus haemodialysis was 2.6 across several retrospective studies on the impact of predialysis education. Utilisation of PD for unplanned acute dialysis starts facilitated by implantation of peritoneal catheters by interventional nephrologists may diminish the vast predominance of haemodialysis done by central venous catheters for unplanned dialysis start. Assisted peritoneal dialysis can improve accessibility of home based dialysis to elderly, frail, and dependant patients, whose quality of life on replacement therapy may benefit most from dialysis performed at home. Peritoneal dialysis providers should perform close monitoring, preventing measures, and timely prophylactic therapy in patients judged to be prone to EPS development. Each peritoneal dialysis programme should regularly monitor, report, and act on key quality indicators to manifest its ability of constant quality improvement and elevate the confidence of interested patients and financing bodies in the programme. PMID- 26640788 TI - The Ultrasonic Microsurgical Anatomical Comparative Study of the CHD Fetuses and Their Clinical Significance. AB - The aim of our study was to increase the detection rate of fetal cardiac malformations for congenital heart disease (CHD). The ultrasonic and microanatomical methods were combined to study the CHD cases firstly, which could provide the microsurgical anatomical basis to the prenatal ultrasonic diagnosis which was used in suspected CHD and help the sonographer to improve the quality of fetal cardiac diagnosis. We established the ultrasonic standard section of the 175 complex CHD cases and collected the fetal echocardiography image files. The induced/aborted fetuses were fixed by 4% paraformaldehyde and dissected by the ultrasonic microsurgical anatomy. This research could obtain the fetal cardiac anatomic cross-sectional images which was consistent with the ultrasonic standard section and could clearly show the internal structure of the vascular malformation that optimized the ultrasound examination individually. This method could directly display the variation of the CHD fetal heart clearly and comprehensively help us to understand the complex fetal cardiac malformation from the internal structure of the vascular malformation which was consolidated by the anatomical basis of the fetal heart. This study could improve the integrity and accuracy of the prenatal cardiac ultrasound examination tremendously. PMID- 26640790 TI - Simulations of Heart Function. PMID- 26640789 TI - Outcomes of Cryoballoon Ablation in High- and Low-Volume Atrial Fibrillation Ablation Centres: A Russian Pilot Survey. AB - PURPOSE: The results of cryoballoon ablation (CBA) procedure have been mainly derived from studies conducted in experienced atrial fibrillation (AF) ablation centres. Here, we report on CBA efficacy and complications resulting from real practice of this procedure at both high- and low-volume centres. METHODS: Among 62 Russian centres performing AF ablation, 15 (24%) used CBA technology for pulmonary vein isolation. The centres were asked to provide a detailed description of all CBA procedures performed and complications, if encountered. RESULTS: Thirteen sites completed interviews on all CBAs in their centres (>95% of CBAs in Russia). Six sites were high-volume AF ablation (>100 AF cases/year) centres, and 7 were low-volume AF ablation. There was no statistical difference in arrhythmia-free rates between high- and low-volume centres (64.6 versus 60.8% at 6 months). Major complications developed in 1.5% of patients and were equally distributed between high- and low-volume centres. Minor procedure-related events were encountered in 8% of patients and were more prevalent in high-volume centres. Total event and vascular access site event rates were higher in women than in men. CONCLUSIONS: CBA has an acceptable efficacy profile in real practice. In less experienced AF ablation centres, the major complication rate is equal to that in high-volume centres. PMID- 26640791 TI - Mechanistic Studies on the Use of Polygonum multiflorum for the Treatment of Hair Graying. AB - Polygonum multiflorum is a traditional Chinese medicine with a long history in hair growth promotion and hair blackening. The purpose of the study was to examine the effect and the mechanism of Polygonum multiflorum in hair blackening. C57BL/6 mice hair fade was induced with H2O2 and used in this research. Hair pigmentogenesis promotion activities of Polygonum Multiflorum Radix (PMR, raw crude drug), Polygonum Multiflorum Radix Preparata (PMRP, processed crude drug), and their major chemical constituent TSG were investigated. The regulation effects of several cytokines and enzymes such as POMC, alpha-MSH, MC1R, ASIP, MITF, TYR, TRP-1, and TRP-2 were investigated. PMR group gave out the most outstanding black hair among all groups with the highest contents of total melanin, alpha-MSH, MC1R, and TYR. Promotion of hair pigmentogenesis was slightly decreased after processing in the PMRP group. TSG as the major constituent of PMR showed weaker hair color regulation effects than both PMR and PMRP. PMR, but not PMRP, should be used to blacken hair. The alpha-MSH, MC1R, and TYR were the major targets in the medicinal use of PMR in hair graying. Chemical constituents other than TSG may contribute to the hair color regulation activity of PMR. PMID- 26640792 TI - Drug Delivery Using Novel Biological and Synthetic Materials. PMID- 26640793 TI - Rehabilitation and Improvement of the Postural Function. PMID- 26640794 TI - Protective Effect of Enalapril against Methionine-Enriched Diet-Induced Hypertension: Role of Endoplasmic Reticulum and Oxidative Stress. AB - In the present study, we investigated the effect of methionine-enriched diet (MED) on blood pressure in rats and examined the protective effect of enalapril, a widely used angiotensin converting enzyme inhibitors (ACEi) class antihypertensive drug. The results showed that MED induced significant increase of SBP and Ang II-induced contractile response in aortae of rats. MED significantly increased plasma levels of homocysteine (Hcy) and ACE. In addition, MED increased the phosphorylation of protein kinase R-like endoplasmic reticulum kinase (PERK) and eukaryotic initiation factor 2 (eIF2alpha) and expression of activating transcription factor 3 (ATF3) and ATF6 in aortae of rats, indicating the occurrence of endoplasmic reticulum (ER) stress. Moreover, MED resulted in oxidative stress as evidenced by significant increase of TBARS level and decrease of superoxide dismutase and catalase activities. Administration of enalapril could effectively inhibit these pathological changes induced by MED in rats. These results demonstrated that ACE-mediated ER stress and oxidative stress played an important role in high Hcy-induced hypertension and MED may exert a positive loop between the activation of ACE and accumulation of Hcy, aggravating the pathological condition of hypertension. The data provide novel insights into the mechanism of high Hcy-associated hypertension and the therapeutic efficiency of enalapril. PMID- 26640795 TI - Prevalence of Hyperuricemia and Gout in Mainland China from 2000 to 2014: A Systematic Review and Meta-Analysis. AB - We systematically identified the prevalence of hyperuricemia and gout in mainland China and provided informative data that can be used to create appropriate local public health policies. Relevant articles from 2000 to 2014 were identified by searching 5 electronic databases: PubMed, Google Scholar, Chinese Wanfang, CNKI, and Chongqing VIP. All of the calculations were performed using the Stata 11.0 and SPSS 20.0 software. The eligible articles (n = 36; 3 in English and 33 in Chinese) included 44 studies (38 regarding hyperuricemia and 6 regarding gout). The pooled prevalence of hyperuricemia and gout was 13.3% (95% CI: 11.9%, 14.6%) and 1.1% (95% CI: 0.7%, 1.5%), respectively. Although publication bias was observed, the results did not change after a trim and fill test, indicating that that impact of this bias was likely insignificant. The prevalence of hyperuricemia and gout was high in mainland China. The subgroup analysis suggested that the geographical region, whether the residents dwell in urban or rural and coastal or inland areas, the economic level, and sex may be associated with prevalence. PMID- 26640796 TI - Changes of Plantar Pressure and Gait Parameters in Children with Mild Cerebral Palsy Who Used a Customized External Strap Orthosis: A Crossover Study. AB - Toe-in gait and crouch gait can make children with mild cerebral palsy fall and suffer improper balance during walking or ambulation training. A customized external strap orthosis for correcting leg alignment was used to resolve this problem. The purpose of this study was to research the immediate effects while wearing the customized external strap orthosis. Pressure platform was used to assess the plantar pressure through static and dynamic assessments and to record the changes in path of pressure trajectory. Motion image analysis system was used to record the gait parameters, which included gait speed, stride length, and cadence. The influence of both wearing and removing the orthosis on the dominant leg of children with mild cerebral palsy was analyzed. Nine children with mild cerebral palsy, who all had a dominant right leg, were recruited. After wearing the orthosis, all gait parameters improved, and foot motion changed in the stance phase of the gait cycle. The path of pressure trajectory closing to the midline was also observed during dynamic assessment. Changes in plantar pressure and path of pressure trajectory were observed and the orthosis device could provide immediate assistance to correct the leg alignment and improve the gait performance in children with mild cerebral palsy. PMID- 26640797 TI - Docosahexaenoic Acid Modulates a HER2-Associated Lipogenic Phenotype, Induces Apoptosis, and Increases Trastuzumab Action in HER2-Overexpressing Breast Carcinoma Cells. AB - In breast cancer, lipid metabolic alterations have been recognized as potential oncogenic stimuli that may promote malignancy. To investigate whether the oncogenic nature of lipogenesis closely depends on the overexpression of HER2 protooncogene, the normal breast cell line, HB4a, was transfected with HER2 cDNA to obtain HER2-overexpressing HB4aC5.2 cells. Both cell lines were treated with trastuzumab and docosahexaenoic acid. HER2 overexpression was accompanied by an increase in the expression of lipogenic genes involved in uptake (CD36), transport (FABP4), and storage (DGAT) of exogenous fatty acids (FA), as well as increased activation of "de novo" FA synthesis (FASN). We further investigate whether this lipogenesis reprogramming might be regulated by mTOR/PPARgamma pathway. Inhibition of the mTORC1 pathway markers, p70S6 K1, SREBP1, and LIPIN1, as well as an increase in DEPTOR expression (the main inhibitor of the mTOR) was detected in HB4aC5.2. Based on these results, a PPARgamma selective antagonist, GW9662, was used to treat both cells lines, and the lipogenic genes remained overexpressed in the HB4aC5.2 but not HB4a cells. DHA treatment inhibited all lipogenic genes (except for FABP4) in both cell lines yet only induced death in the HB4aC5.2 cells, mainly when associated with trastuzumab. Neither trastuzumab nor GW9662 alone was able to induce cell death. In conclusion, oncogenic transformation of breast cells by HER2 overexpression may require a reprogramming of lipogenic genetic that is independent of mTORC1 pathway and PPARgamma activity. This reprogramming was inhibited by DHA. PMID- 26640798 TI - Autocrine Human Urotensin II Enhances Macrophage-Derived Foam Cell Formation in Transgenic Rabbits. AB - Circulating urotensin II (UII) is involved in the development of atherosclerosis. However, the role of autocrine UII in the development of atherosclerosis remains unclear. Here, we tested the hypothesis that autocrine UII would promote atherosclerosis. Transgenic rabbits were created as a model to study macrophage specific expressing human UII (hUII) and used to investigate the role of autocrine UII in the development of atherosclerosis. Transgenic rabbits and their nontransgenic littermates were fed a high cholesterol diet to induce atherosclerosis. Comparing the transgenic rabbits with their nontransgenic littermates, it was observed that hUII expression increased the macrophage positive area in the atherosclerotic lesions by 45% and the positive area ratio by 56% in the transgenic rabbits. Autocrine hUII significantly decreased the smooth muscle cell-positive area ratio in transgenic rabbits (by 54%), without affecting the plasma levels of total cholesterol, triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and glucose and adipose tissue contents. These results elucidated for the first time that autocrine UII plays an important role in the development of atherosclerosis by increasing the accumulation of macrophage-derived foam cell. PMID- 26640799 TI - The Applicability of the International Staging System in Chinese Patients with Multiple Myeloma Receiving Bortezomib or Thalidomide-Based Regimens as Induction Therapy: A Multicenter Analysis. AB - The International Staging System (ISS) is the most important prognostic system for multiple myeloma (MM). It was identified in the era of conventional agents. The outcome of MM has significantly changed by novel agents. Thus the applicability of ISS system in the era of novel agents in Chinese patients needs to be demonstrated. We retrospectively analyzed the clinical outcomes and prognostic significance of ISS system in 1016 patients with newly diagnosed multiple myeloma in Chinese patients between 2008 and 2012, who received bortezomib- or thalidomide-based regimens as first-line therapy. The median overall survival (OS) of patients for ISS stages I/II/III was not reached/55.4 months/41.7 months (p < 0.001), and the median progression-free survival (PFS) was 30/29.5/25 months (p = 0.072), respectively. Statistically significant difference in survival was confirmed among three ISS stages in thalidomide-based group, but not between ISS stages I and II in bortezomib-based group. These findings suggest that ISS system can predict the survival in the era of novel agents in Chinese MM patients, and bortezomib may have the potential to partially overcome adverse effect of risk factors on survival, especially in higher stage of ISS system. PMID- 26640801 TI - Optimization of Extraction Parameters for Enhanced Production of Ovotransferrin from Egg White for Antimicrobial Applications. AB - Ovotransferrin is the second most abundant protein (~12-13% of the total egg protein) in egg white after ovalbumin. Ovotransferrin is a potent natural antimicrobial agent as it possesses antibacterial, antifungal, and antiviral properties and is also the major metal binding protein found in egg, which makes it an industrially important protein. Ovotransferrin was extracted from egg white using its metal (iron) binding properties. In the present study, eggs from two different sources were used (fresh local eggs from domestic household source and poultry eggs from shops) to compare the results and Response Surface Methodology was used for the experiment design and data analysis. The following extraction conditions were optimized so as to maximize the yield of ovotransferrin from egg white: ethanol % (v/v) and pH and volume (mL) of 25 mM FeCl3/50 mL of egg white. A maximum yield of ~85 +/- 2.5% was obtained near the optimum extraction conditions. The yield was calculated based on the theoretical value (934 mg) of ovotransferrin in 100 mL of 1.5x diluted egg white solution. Our results suggest that efficient downstream processing may reduce the cost of overall production process of this promising enzyme, making it a natural and cost-effective alternative to the existing chemically synthesized antimicrobial agents. PMID- 26640802 TI - Corrigendum to "Information-Theoretical Quantifier of Brain Rhythm Based on Data Driven Multiscale Representation". PMID- 26640800 TI - Techniques and Methods for Testing the Postural Function in Healthy and Pathological Subjects. AB - The different techniques and methods employed as well as the different quantitative and qualitative variables measured in order to objectify postural control are often chosen without taking into account the population studied, the objective of the postural test, and the environmental conditions. For these reasons, the aim of this review was to present and justify the different testing techniques and methods with their different quantitative and qualitative variables to make it possible to precisely evaluate each sensory, central, and motor component of the postural function according to the experiment protocol under consideration. The main practical and technological methods and techniques used in evaluating postural control were explained and justified according to the experimental protocol defined. The main postural conditions (postural stance, visual condition, balance condition, and test duration) were also analyzed. Moreover, the mechanistic exploration of the postural function often requires implementing disturbing postural conditions by using motor disturbance (mechanical disturbance), sensory stimulation (sensory manipulation), and/or cognitive disturbance (cognitive task associated with maintaining postural balance) protocols. Each type of disturbance was tackled in order to facilitate understanding of subtle postural control mechanisms and the means to explore them. PMID- 26640803 TI - Improved Pre-miRNA Classification by Reducing the Effect of Class Imbalance. AB - MicroRNAs (miRNAs) play important roles in the diverse biological processes of animals and plants. Although the prediction methods based on machine learning can identify nonhomologous and species-specific miRNAs, they suffered from severe class imbalance on real and pseudo pre-miRNAs. We propose a pre-miRNA classification method based on cost-sensitive ensemble learning and refer to it as MiRNAClassify. Through a series of iterations, the information of all the positive and negative samples is completely exploited. In each iteration, a new classification instance is trained by the equal number of positive and negative samples. In this way, the negative effect of class imbalance is efficiently relieved. The new instance primarily focuses on those samples that are easy to be misclassified. In addition, the positive samples are assigned higher cost weight than the negative samples. MiRNAClassify is compared with several state-of-the art methods and some well-known classification models by testing the datasets about human, animal, and plant. The result of cross validation indicates that MiRNAClassify significantly outperforms other methods and models. In addition, the newly added pre-miRNAs are used to further evaluate the ability of these methods to discover novel pre-miRNAs. MiRNAClassify still achieves consistently superior performance and can discover more pre-miRNAs. PMID- 26640804 TI - Following "the Roots" of Kratom (Mitragyna speciosa): The Evolution of an Enhancer from a Traditional Use to Increase Work and Productivity in Southeast Asia to a Recreational Psychoactive Drug in Western Countries. AB - The use of substances to enhance human abilities is a constant and cross-cultural feature in the evolution of humanity. Although much has changed over time, the availability on the Internet, often supported by misleading marketing strategies, has made their use even more likely and risky. This paper will explore the case of Mitragyna speciosa Korth. (kratom), a tropical tree used traditionally to combat fatigue and improve work productivity among farm populations in Southeast Asia, which has recently become popular as novel psychoactive substance in Western countries. Specifically, it (i) reviews the state of the art on kratom pharmacology and identification; (ii) provides a comprehensive overview of kratom use cross-culturally; (iii) explores the subjective experiences of users; (iv) identifies potential risks and side-effects related to its consumption. Finally, it concludes that the use of kratom is not negligible, especially for self medication, and more clinical, pharmacological, and socioanthropological studies as well as a better international collaboration are needed to tackle this marginally explored phenomenon. PMID- 26640805 TI - Effects of Liraglutide Combined with Short-Term Continuous Subcutaneous Insulin Infusion on Glycemic Control and Beta Cell Function in Patients with Newly Diagnosed Type 2 Diabetes Mellitus: A Pilot Study. AB - The objective of this paper is to investigate the effects of liraglutide in combination with short-term continuous subcutaneous insulin infusion (CSII) therapy on glycemic control and beta cell function in patients with newly diagnosed type 2 diabetes mellitus (T2DM). Thirty-nine eligible newly diagnosed T2DM patients were recruited and randomized to receive either of two therapies: short-term CSII alone (CSII alone group) or CSII in combination with liraglutide (CSII + Lira group) for 12 weeks. Blood glucose control, homeostasis model assessment (HOMA) indices, and acute insulin response (AIR) were compared between the two groups. The patients in CSII + Lira group achieved euglycemia with equivalent insulin dosage in shorter time (1 (0) versus 2 (3) days, P = 0.039). HbA1c at the end of study was comparable between two groups (6.3 +/- 0.7% versus 6.0 +/- 0.5%, for CSII alone group and CSII + Lira group, resp., P = 0.325). The increment of AIR was higher in CSII + Lira group (177.58 (351.57) MUU . min/mL versus 58.15 (51.30) MUU . min/mL, P < 0.001). However, after stopping liraglutide, its effect on beta cell function disappeared completely. Liraglutide combined with short-term CSII was effective in further improving beta cell function, but the beneficial effects did not sustain after suspension of the therapy. PMID- 26640806 TI - Mannose-Binding Lectin Levels and Carotid Intima-Media Thickness in Type 2 Diabetic Patients. AB - INTRODUCTION: Mannose-binding lectin (MBL) activates complement system and has been suggested to play a role in vascular complications in diabetics. Carotid intima-media thickness (cIMT) detects subclinical atherosclerosis. We evaluated the association of MBL and IMT in type 2 diabetic (T2DM) patients. METHODS: Serum MBL levels and cIMT were measured in a total of 103 diabetics and in 98 age matched healthy controls. RESULTS: There was no significant difference in MBL level in T2DM versus controls. As expected, IMT was significantly higher in T2DM patients than in controls (P = 0.001). In T2DM, the lowest cIMT was seen in patients with normal MBL level (500-1000) while cIMT continuously increased with both high MBL and absolute MBL deficiency states. This was especially significant in high MBL versus normal MBL T2DM patients (P = 0.002). According to multiple regression analysis the main predictors of IMT in T2DM are age (P < 0.003), ApoA level (P = 0.023), and the MBL (P = 0.036). CONCLUSIONS: Our results suggest a dual role of MBL as a risk factor for cIMT in T2DM. MBL may also be used as a marker of macrovascular disease, as both low and high levels indicate the susceptibility for atherosclerosis in T2DM. PMID- 26640808 TI - The Effect of Tianmai Xiaoke Pian on Insulin Resistance through PI3-K/AKT Signal Pathway. AB - In the clinical setting, given the potential adverse effects of thiazolidinediones and biguanides, we often have difficulty in treatment that no other insulin sensitizers are available for use in type 2 diabetic mellitus (T2DM) patients. Tianmai Xiaoke Pian (TMXKP) is a traditional Chinese medicine tablet, which is comprised of chromium picolinate, Tianhuafen, Maidong, and Wuweizi. To understand its mechanism of action on insulin resistance, TMXKP (50 mg/kg orally) was tested in T2DM rats (induced by a high-fat diet and streptozotocin). Eight weeks later, fasting blood glucose (FBG) and oral glucose tolerance tests (OGTT) were performed. Area under the curve (AUC) and homeostatic model assessment of insulin resistance (HOMA-IR) were calculated, and PI3-K/AKT signal pathway-related genes and proteins were tested by reverse transcription polymerase chain reaction (RT-PCR) and western blot analysis in muscle, adipose, and liver tissues, respectively. TMXKP significantly reduced FBG, OGTT, AUC, and HOMA-IR in diabetic rats (P < 0.05). Furthermore, we also observed that TMXKP could significantly decrease IRS-1, IRS-2, PI3-K p85alpha, and AKT2 gene expression and also IRS-1, IRS-2, PI3-K, AKT2, and p-AKT2 protein expression levels (P < 0.05) in diabetic rats. These findings confirm that TMXKP can alleviate insulin resistance in T2DM rats through the PI3K/AKT pathway. Thus TMXKP appears to be a promising insulin sensitizer. PMID- 26640807 TI - Relationship of Hemoglobin A1c with beta Cell Function and Insulin Resistance in Newly Diagnosed and Drug Naive Type 2 Diabetes Patients. AB - OBJECTIVE: To investigate changes in the glycated hemoglobin A1c (A1c) level and those in beta cell function and insulin resistance in newly diagnosed and drug naive type 2 diabetes patients and to evaluate the relationship between them. DESIGN AND METHODS: A total of 818 newly diagnosed diabetic individuals who were >= 40 years of age were recruited. The subjects were grouped by A1c values (<6.5%, 6.5-7%, 7-8%, 8-9%, and >= 9%). The homeostasis model assessment (HOMA) was used to evaluate pancreatic beta cell function (HOMA-beta) and insulin resistance (HOMA-IR). ANOVA, t-tests, and binary logistic regression analysis were used for data analysis. RESULTS: Compared with subjects with A1c values <6.5%, individuals with an A1c of 6.5-7% exhibited an increased HOMA-beta index. However, the HOMA-beta index was significantly decreased at A1c values >= 7% and further decreased by 9.3% and by 23.7%, respectively, at A1c values of 7-8% and 8 9%. As A1c increased to >= 9%, a 62% reduction in beta cell function was observed, independently of age, gender, body mass index (BMI), blood pressure (BP), blood lipids, and hepatic enzyme levels. Meanwhile, insulin resistance was significantly increased with an increase in A1c values. CONCLUSIONS: Elevated A1c values (>= 7%) were associated with substantial reductions in beta cell function. PMID- 26640809 TI - Analysis of a Functional IL-6 Gene Polymorphism in HLAB27 Associated and Intermediate Uveitis Gives New Insight in Disease Pathogenesis and Commonality with Other Autoimmune Diseases. AB - PURPOSE: Interleukin 6 (IL-6) plays a crucial role in both adaptive and innate immunity. The rs1800795 gene polymorphism of IL-6 is associated with various autoimmune diseases, like multiple sclerosis. METHODS: 134 patients with HLAB27 positive iridocyclitis, 84 patients with intermediate uveitis, 132 controls, and 65 HLAB27 positive controls were recruited for the present case-control study. Main outcome measures were genotype distribution and allelic frequencies determined by polymerase chain reaction. RESULTS: The frequency of carriers of the minor allele for rs1800795 was significantly higher in patients with intermediate uveitis compared to controls (p = 0.04; OR: 1.46; CI: 1.02-2.11). Frequencies of the minor allele for rs1800795 did not differ significantly in patients with HLAB27 associated uveitis when compared to controls (p > 0.05). CONCLUSION: These findings further deepen our understanding of the commonality between multiple sclerosis and intermediate uveitis. Given the functionality of the investigated polymorphism, new pathophysiological insights are gained that help to evaluate possible therapeutic targets. PMID- 26640810 TI - Sexual Minority Stress and Suicide Risk: Identifying Resilience through Personality Profile Analysis. AB - BACKGROUND: Sexual minority-based victimization, which includes threats or enacted interpersonal violence, predicts elevated suicide risk among sexual minority individuals. However, research on personality factors that contribute to resilience among sexual minority populations is lacking. Using the Five-Factor Model, we hypothesized that individuals classified as adaptive (versus at-risk) would be at decreased risk for a suicide attempt in the context of reported lifetime victimization. METHOD: Sexual minority-identified young adults between the ages of 18 and 25 (N=412) were recruited nationally and asked to complete an online survey containing measures of personality, sexual minority stress, and lifetime suicide attempts. RESULTS: A two-stage cluster analytic method was used to empirically derive latent personality profiles and to classify respondents as adaptive (lower neuroticism and higher extroversion, agreeableness, conscientiousness, and openness) or at-risk (higher neuroticism, lower extroversion, agreeableness, conscientiousness, and openness) on the basis of their Five Factor Personality trait scores. Adaptive individuals were slightly older and less likely to conceal their sexual orientation, but reported similar rates of victimization, discrimination, and internalized heterosexism as their at risk counterparts. Logistic regression results indicate that despite reporting similar rates of victimization, which was a significant predictor of lifetime suicide attempt, adaptive individuals evidenced decreased risk for attempted suicide in the context of victimization, relative to at-risk individuals. DISCUSSION: These findings suggest that an adaptive personality profile may confer resilience in the face of sexual minority-based victimization. This study adds to our knowledge of sexual minority mental health and highlights new directions for future research. PMID- 26640811 TI - Advances in the understanding of Fanconi Anemia Complementation Group D2 Protein (FANCD2) in human cancer. AB - Fanconi anemia (FA) is a rare human genetic disease, resulting from dysfunction in any of 17 known complementation proteins: FANC-A, B, C, D1, D2, E, F, G, I, J, L, M, N, O, P, Q & S, and other unknowns. Besides the severe bone marrow failure, an extremely high incidence of cancer as well as many other clinic symptoms associated with FA patients, FA cells are known of insufficiency in homologous recombination, DNA mismatch repair, nucleotide excision repair, translesion DNA synthesis, and other molecular defects, leading to genome instability. Those similar molecular and cellular/tissue features show that all FA proteins function in one common signaling pathway, namely, the FA pathway. The monoubiquitination of FANCD2 is the central step of the FA pathway activation upon DNA damage or during DNA replication. The molecular functions of FANCD2 emerge as a very attractive filed of investigation in cancer research. Herein, we review the recent progresses in FANCD2 functions at these rapidly progressed aspects. PMID- 26640813 TI - Performance Evaluation of Multimodal Multifeature Authentication System Using KNN Classification. AB - This research proposes a multimodal multifeature biometric system for human recognition using two traits, that is, palmprint and iris. The purpose of this research is to analyse integration of multimodal and multifeature biometric system using feature level fusion to achieve better performance. The main aim of the proposed system is to increase the recognition accuracy using feature level fusion. The features at the feature level fusion are raw biometric data which contains rich information when compared to decision and matching score level fusion. Hence information fused at the feature level is expected to obtain improved recognition accuracy. However, information fused at feature level has the problem of curse in dimensionality; here PCA (principal component analysis) is used to diminish the dimensionality of the feature sets as they are high dimensional. The proposed multimodal results were compared with other multimodal and monomodal approaches. Out of these comparisons, the multimodal multifeature palmprint iris fusion offers significant improvements in the accuracy of the suggested multimodal biometric system. The proposed algorithm is tested using created virtual multimodal database using UPOL iris database and PolyU palmprint database. PMID- 26640812 TI - The Association of Patient Chronic Disease Burden and Self-Management Requirements With Shared Decision Making in Primary Care Visits. AB - BACKGROUND: Shared decision making (SDM) is associated with positive health outcomes and may be particularly relevant for patients with chronic disease. OBJECTIVES: To investigate whether (1) patients with chronic diseases, particularly those requiring self-management, are more likely to engage in SDM behaviors than patients without chronic diseases and (2) patients with chronic diseases are more likely to have their physicians engage them in SDM. DESIGN: A cross-sectional study of patients who were enrolled in a randomized controlled trial to improve patient-physician communication. PARTICIPANTS: Adult patients with hypertension at community health clinics in Baltimore, Maryland. APPROACH: We used multivariable regression models to examine the associations of the following predictor variables: (1) chronic disease burden and (2) diseases requiring self-management with the following outcome variables measuring SDM components: (1) patient information sharing, (2) patient decision making, and (3) physician SDM facilitation. KEY RESULTS: Patients with greater chronic disease burden and more diseases requiring self-management reported more information sharing (beta = .07, P = .03 and beta = .12, P = .046, respectively) and decision making (beta = .06, P = .02 and beta = .21, P < .001) as did patients who reported poor general health. Physician facilitation of SDM was not associated with chronic disease burden or with diseases requiring self-management but was associated with higher patient income. CONCLUSIONS: Patients with chronic diseases, particularly those requiring self-management, may be more likely to engage in SDM behaviors, but physicians may not be more likely to engage such patients in SDM. Targeting patients with chronic disease for SDM may improve health outcomes among the chronically ill, particularly among vulnerable patients (eg, minorities, low-income patients) who suffer disproportionately from such conditions. PMID- 26640814 TI - Women's Satisfaction of Maternity Care in Nepal and Its Correlation with Intended Future Utilization. AB - The impact of rapid increase in institutional birth rate in Nepal on women's satisfaction and planned future utilization of services is less well known. This study aimed to measure women's satisfaction with maternity care and its correlation with intended future utilisation. Data came from a nationally representative facility-based survey conducted across 13 districts in Nepal and included client exit interviews with 447 women who had either recently delivered or had experienced complications. An eight-item quality of care instrument was used to measure client satisfaction. Multivariate probit model was used to assess the attribution of different elements of client satisfaction with intended future utilization of services. Respondents were most likely to suggest maintaining clean/hygienic health facilities (42%), increased bed provision (26%), free services (24%), more helpful behaviour by health workers (18%), and better privacy (9%). Satisfaction with the information received showed a strong correlation with the politeness of staff, involvement in decision making, and overall satisfaction with the care received. Satisfaction with waiting time (p = 0.035), information received (p = 0.02), and overall care in the maternity care (<0.001) showed strong associations with willingness to return to facility. The findings suggest improving physical environment and interpersonal communication skills of service providers and reducing waiting time for improving client satisfaction and intention to return to the health facility. PMID- 26640817 TI - Multimorbidity in a Mexican Community: Secondary Analysis of Chronic Illness and Depression Outcomes. AB - The aims of this article are: 1) to examine the associations between health provider-diagnosed depression and multimorbidity, the condition of suffering from more than two chronic illnesses; 2) to assess the unique contribution of chronic illness in the prediction of depression; and 3) to suggest practice changes that would address risk of depression among individuals with chronic illnesses. Data collected in a cross-sectional community health study among adult Mexicans (n= 274) living in a low income neighborhood (colonia) in Ciudad Juarez, Chihuahua, Mexico, were examined. We tested the hypotheses that individuals who reported suffering chronic illnesses would also report higher rates of depression than healthy individuals; and having that two or more chronic illnesses further increased the risk of depression. PMID- 26640815 TI - Oncolysis by paramyxoviruses: preclinical and clinical studies. AB - Preclinical studies demonstrate that a broad spectrum of human malignant cells can be killed by oncolytic paramyxoviruses, which include cells of ecto-, endo-, and mesodermal origin. In clinical trials, significant reduction in size or even complete elimination of primary tumors and established metastases are reported. Different routes of viral administration (intratumoral, intravenous, intradermal, intraperitoneal, or intrapleural), and single- versus multiple-dose administration schemes have been explored. The reported side effects are grade 1 and 2, with the most common among them being mild fever. Some advantages in using para-myxoviruses as oncolytic agents versus representatives of other viral families exist. The cytoplasmic replication results in a lack of host genome integration and recombination, which makes paramyxoviruses safer and more attractive candidates for widely used therapeutic oncolysis in comparison with retroviruses or some DNA viruses. The list of oncolytic paramyxovirus representatives includes attenuated measles virus (MV), mumps virus (MuV), low pathogenic Newcastle disease (NDV), and Sendai (SeV) viruses. Metastatic cancer cells frequently overexpress on their surface some molecules that can serve as receptors for MV, MuV, NDV, and SeV. This promotes specific viral attachment to the malignant cell, which is frequently followed by specific viral replication. The paramyxoviruses are capable of inducing efficient syncytium-mediated lyses of cancer cells and elicit strong immunomodulatory effects that dramatically enforce anticancer immune surveillance. In general, preclinical studies and phase 1-3 clinical trials yield very encouraging results and warrant continued research of oncolytic paramyxoviruses as a particularly valuable addition to the existing panel of cancer-fighting approaches. PMID- 26640816 TI - Oncolysis by paramyxoviruses: multiple mechanisms contribute to therapeutic efficiency. AB - Oncolytic paramyxoviruses include some strains of Measles, Mumps, Newcastle disease, and Sendai viruses. All these viruses are well equipped for promoting highly specific and efficient malignant cell death, which can be direct and/or immuno-mediated. A number of proteins that serve as natural receptors for oncolytic paramyxoviruses are frequently overexpressed in malignant cells. Therefore, the preferential interaction of paramyxoviruses with malignant cells rather than with normal cells is promoted. Due to specific genetic defects of cancer cells in the interferon (IFN) and apoptotic pathways, viral replication has the potential to be promoted specifically in tumors. Viral mediation of syncytium formation (a polykaryonic structure) promotes intratumoral paramyxo virus replication and spreading, without exposure to host neutralizing antibodies. So, two related processes: efficient intratumoral infection spread as well as the consequent mass malignant cell death, both are enhanced. In general, the paramyxoviruses elicit strong anticancer innate and adaptive immune responses by triggering multiple danger signals. The paramyxoviruses are powerful inducers of IFN and other immuno-stimulating cytokines. These viruses efficiently promote anticancer activity of natural killer cells, dendritic cells, and cytotoxic T lymphocytes. Moreover, a neuraminidase (sialidase), a component of the viral envelope of Newcastle Disease, Mumps, and Sendai viruses, can cleave sialic acids on the surface of malignant cells thereby unmasking cancer antigens and exposing them to the immune system. These multiple mechanisms contribute to therapeutic efficacy of oncolytic paramyxovi-ruses and are responsible for encouraging results in preclinical and clinical studies. PMID- 26640818 TI - Modulation of Innate Immune Responses via Covalently Linked TLR Agonists. AB - We present the synthesis of novel adjuvants for vaccine development using multivalent scaffolds and bioconjugation chemistry to spatially manipulate Toll like receptor (TLR) agonists. TLRs are primary receptors for activation of the innate immune system during vaccination. Vaccines that contain a combination of small and macromolecule TLR agonists elicit more directed immune responses and prolong responses against foreign pathogens. In addition, immune activation is enhanced upon stimulation of two distinct TLRs. Here, we synthesized combinations of TLR agonists as spatially defined tri- and di-agonists to understand how specific TLR agonist combinations contribute to the overall immune response. We covalently conjugated three TLR agonists (TLR4, 7, and 9) to a small molecule core to probe the spatial arrangement of the agonists. Treating immune cells with the linked agonists increased activation of the transcription factor NF-kappaB and enhanced and directed immune related cytokine production and gene expression beyond cells treated with an unconjugated mixture of the same three agonists. The use of TLR signaling inhibitors and knockout studies confirmed that the tri agonist molecule activated multiple signaling pathways leading to the observed higher activity. To validate that the TLR4, 7, and 9 agonist combination would activate the immune response to a greater extent, we performed in vivo studies using a vaccinia vaccination model. Mice vaccinated with the linked TLR agonists showed an increase in antibody depth and breadth compared to mice vaccinated with the unconjugated mixture. These studies demonstrate how activation of multiple TLRs through chemically and spatially defined organization assists in guiding immune responses, providing the potential to use chemical tools to design and develop more effective vaccines. PMID- 26640819 TI - Mechanistic Insights into Two-Phase Radical C-H Arylations. AB - Kinetic, spectroscopic, and computational studies of radical C-H arylations highlight the interplay between chemical and physical rate processes in these multiphase reactions. Anomalous concentration dependences observed here may be reconciled by considering the role of phase transfer processes that mediate concentrations in each phase. In addition, understanding interactions through phase boundaries enables their use in optimization of reaction performance. PMID- 26640820 TI - Rural Student Voices to Improve Educational Attainment Oriented Programs. AB - The Health Sciences and Technology Academy (HSTA) strives to increase college going and completion rates for students in West Virginia (USA), a state with low educational attainment and the second most rural state in the country. The positive impact of HSTA on student academic trajectories has been documented, but student voices have not been represented. This qualitative study using Bronfenbrenner's ecological perspective explores student experiences through HSTA, with an eye toward how similar programs serving rural populations might improve while understanding student participant perspectives. Participants were 706 incoming 9th -12th graders from rural West Virginia who provided survey responses across two years. We address the organizational and individual considerations that were instrumental in creating a supportive learning environment for rural youth. PMID- 26640821 TI - Engineered Production of Tryprostatins in E. coli through Reconstitution of a Partial ftm Biosynthetic Gene Cluster from Aspergillus sp. AB - Tryprostatin A and B are indole alkaloid-based fungal products that inhibit mammalian cell cycle at the G2/M phase. They are biosynthetic intermediates of fumitremorgins produced by a complex pathway involving a nonribosomal peptide synthetase (FtmA), a prenyltransferase (FtmB), a cytochrome P450 hydroxylase (FtmC), an O-methyltransferase (FtmD), and several additional enzymes. A partial fumitremorgin biosynthetic gene cluster (ftmABCD) from Aspergillus sp. was reconstituted in Escherichia coli BL21(DE3) cells, with or without the co expression of an Sfp-type phosphopantetheinyltransferase gene (Cv_sfp) from Chromobacterium violaceum No. 968. Several recombinant E. coli strains produced tryprostatin B up to 106 mg/l or tryprostatin A up to 76 mg/l in the fermentation broth under aerobic condition, providing an effective way to prepare those pharmaceutically important natural products biologically. PMID- 26640822 TI - Towards a Role for Clinical Pathology Diagnostics for Childhood Maltreatment. AB - Recent reports from the Center for Disease Control and Kaiser Permanente demonstrate that early life adverse experience leads to morbidity and mortality in adulthood. To date there are no objective tests that help care-givers or local child protective services make informed decisions for children with a history of abuse, neglect or trauma. This is the first report from a new group of trans disciplinary investigators describing a new approach to identify the biological impact of childhood maltreatment using clinical pathology testing. Such new quantitative measurements will be useful to identify children at risk for poor mental and physical health outcomes and to follow response to interventions. PMID- 26640823 TI - The structure and timescales of heat perception in larval zebrafish. AB - Avoiding temperatures outside the physiological range is critical for animal survival, but how temperature dynamics are transformed into behavioral output is largely not understood. Here, we used an infrared laser to challenge freely swimming larval zebrafish with "white-noise" heat stimuli and built quantitative models relating external sensory information and internal state to behavioral output. These models revealed that larval zebrafish integrate temperature information over a time-window of 400 ms preceding a swimbout and that swimming is suppressed right after the end of a bout. Our results suggest that larval zebrafish compute both an integral and a derivative across heat in time to guide their next movement. Our models put important constraints on the type of computations that occur in the nervous system and reveal principles of how somatosensory temperature information is processed to guide behavioral decisions such as sensitivity to both absolute levels and changes in stimulation. PMID- 26640824 TI - Cost and cost-effectiveness analysis of a bundled intervention to enhance outcomes after stroke in Nigeria: Rationale and design. AB - The economic and social costs of stroke to the society can be enormous. These costs can cause serious economic damage to both the individual and the nation. It is thus important to conduct a cost effectiveness analysis to indicate whether an intervention provides high value where its health benefits justify its costs. This study will provide evidence based on the costs of stroke with a view of improving intervention and treatments of stoke survivors in Nigeria. This study utilizes two types of economic evaluation methods - cost-effectiveness analysis and cost-benefit analysis - to determine the economic impact of Tailored Hospital based Risk Reduction to Impede Vascular Events after Stroke (THRIVES) intervention. The study is conducted in four Nigerian hospitals where 400 patients are recruited to participate in the study. The cost-effectiveness of THRIVES post-discharge intervention is compared with the control Intervention scenario, which is the usual and customary care delivered at each health facility in terms of cost per quality adjusted life years (QALYs). It is expected that successful implementation of the project would serve as a model of cost-effective quality stroke care for implementation. PMID- 26640825 TI - Colposcopic Characteristics and Lugol's Staining Differentiate Anal High-Grade and Low-Grade Squamous Intraepithelial Lesions During High Resolution Anoscopy. PMID- 26640826 TI - Progesterone in Breast Cancer Angiogenesis. AB - The involvement of steroid hormones in breast carcinogenesis is well established. Recent evidence suggests that angiogenesis can be regulated by hormones. Both oestrogen and progesterone have been implicated in the angiogenic process of hormone-dependent cancers, such as breast cancer. Vascular Endothelial Growth Factor (VEGF) is a growth factor involved in angiogenesis in breast cancer that is up-regulated by estrogens. In our study we evaluated the role of progesterone in the expression of this angiogenic growth factor commonly up-regulated in breast cancer. Our findings indicate that progesterone activates an angiogenic pathway involving VEGF stimulation. The elucidation of specific angiogenic pathways promoted by progesterone can raise new therapeutic targets at least in a subset of breast cancers responsive to progesterone. PMID- 26640828 TI - A Biomedical Research Permissions Ontology: Cognitive and Knowledge Representation Considerations. AB - In designing a comprehensive mechanism for managing informed consents and permissions for biomedical research involving human participants, a significant effort is dedicated to the development of standardized classification of these consents and permissions. In this paper, we describe the considerations and implications of this effort that should be addressed during the development of a Biomedical Research Permissions Ontology (RPO). It is hoped that this standardization will allow disparate research institutions to pool research data and associated consents and permissions in order to facilitate collaborative translational research projects across multiple institutions and subsequent new breakthroughs in medicine while providing: 1) essential built in protections for privacy and confidentiality of research participants and 2) a mechanism for insuring that researchers adhere to patient's intent whether to participate in research or not. PMID- 26640827 TI - A Community-Based Exercise and Support Group Program Improves Quality of Life in African-American Breast Cancer Survivors: A Quantitative and Qualitative Analysis. AB - African-American (AA) breast cancer (BCa) survivors have higher mortality rates, more comorbidities and are less likely to meet national physical activity guidelines after diagnosis compared to Caucasian BCa survivors. We previously reported that a 20-week resistance exercise intervention coupled with a support group and home walking program, conducted using facilities and personnel at a community cancer support center, in Stage I-III AA BCa survivors improved strength, fitness and circulating C-peptide levels. Here, we report our findings on changes in quality of life (QoL) and other behavioral measures associated with this 20-week intervention and, discuss findings from a qualitative analysis of semi-structured patient interviews. We found a clinically relevant improvement in QoL using the Functional Assessment of Cancer Therapy for Breast Cancer (FACT-B) (Baseline, B: 101.1 +/- 21.5; End-of-Intervention, EOI: 108.5 +/- 21.6; p = 0.05) and, a significant decrease in depression using the Beck Depression Inventory-II (B: 11.9 +/- 8.1; EOI: 9.0 +/- 5.5; p = 0.03). Our analysis of the patient interviews support improvements in these behavioral measures in that participants stated that they "feel better", were "more motivated" and "uplifted" after the program. The patient interviews also provided insights to the primary motivators (e.g., social support, improvements in strength and function, weight loss) and barriers (e.g., family and health issues) in adhering to the program and provided suggestions for improving the program (e.g., incorporating nutritional and treatment related side-effect discussions). Our results suggest that community based lifestyle interventions may improve QoL and depression in AA BCa survivors and lend insights for improving future programs. PMID- 26640829 TI - HABs in a changing world: a perspective on harmful algal blooms, their impacts, and research and management in a dynamic era of climactic and environmental change. PMID- 26640830 TI - Algebraic connectivity of brain networks shows patterns of segregation leading to reduced network robustness in Alzheimer's disease. AB - Measures of network topology and connectivity aid the understanding of network breakdown as the brain degenerates in Alzheimer's disease (AD). We analyzed 3 Tesla diffusion-weighted images from 202 patients scanned by the Alzheimer's Disease Neuroimaging Initiative - 50 healthy controls, 72 with early- and 38 with late-stage mild cognitive impairment (eMCI/lMCI) and 42 with AD. Using whole brain tractography, we reconstructed structural connectivity networks representing connections between pairs of cortical regions. We examined, for the first time in this context, the network's Laplacian matrix and its Fiedler value, describing the network's algebraic connectivity, and the Fiedler vector, used to partition a graph. We assessed algebraic connectivity and four additional supporting metrics, revealing a decrease in network robustness and increasing disarray among nodes as dementia progressed. Network components became more disconnected and segregated, and their modularity increased. These measures are sensitive to diagnostic group differences, and may help understand the complex changes in AD. PMID- 26640831 TI - Characterizing Smoking and Drinking Abstinence from Social Media. AB - Social media has been established to bear signals relating to health and well being states. In this paper, we investigate the potential of social media in characterizing and understanding abstinence from tobacco or alcohol use. While the link between behavior and addiction has been explored in psychology literature, the lack of longitudinal self-reported data on long-term abstinence has challenged addiction research. We leverage the activity spanning almost eight years on two prominent communities on Reddit: StopSmoking and StopDrinking. We use the self-reported "badge" information of nearly a thousand users as gold standard information on their abstinence status to characterize long-term abstinence. We build supervised learning based statistical models that use the linguistic features of the content shared by the users as well as the network structure of their social interactions. Our findings indicate that long-term abstinence from smoking or drinking (~one year) can be distinguished from short term abstinence (~40 days) with 85% accuracy. We further show that language and interaction on social media offer powerful cues towards characterizing these addiction-related health outcomes. We discuss the implications of our findings in social media and health research, and in the role of social media as a platform for positive behavior change and therapy. PMID- 26640832 TI - Longitudinal Guided Super-Resolution Reconstruction of Neonatal Brain MR Images. AB - Neonatal images have low spatial resolution and insufficient tissue contrast. Generally, interpolation methods are used to upsample neonatal images to a higher resolution for more effective image analysis. However, the resulting images are often blurry and are susceptible to partial volume effect. In this paper, we propose an algorithm that utilizes longitudinal prior information for effective super-resolution reconstruction of neonatal images. We use a non-local approach to learn the spatial relationships of brain structures in high-resolution longitudinal images and apply this information to the super-resolution reconstruction of the neonatal image. In other words, the recurring patterns throughout the longitudinal scans are leveraged for reconstructing the neonatal image with high resolution. To solve this otherwise ill-posed inverse problem, low-rank and total-variation regularizations are enforced. Experiments performed on both T1- and T2-weighted MR images of 28 neonates demonstrate that the proposed method is capable of recovering more structural details and outperforms methods such as nearest neighbor interpolation, spline-based interpolation, non local means upsampling, and both low-rank and total variation based super resolution. PMID- 26640833 TI - Interaction Detection with Depth Sensing and Body Tracking Cameras in Physical Rehabilitation. AB - INTRODUCTION: This article is part of the Focus Theme of Methods of Information in Medicine on "Methodologies, Models and Algorithms for Patients Rehabilitation". OBJECTIVES: This paper presents a camera based method for identifying the patient and detecting interactions between the patient and the therapist during therapy. Detecting interactions helps to discriminate between active and passive motion of the patient as well as to estimate the accuracy of the skeletal data. METHODS: Continuous face recognition is used to detect, recognize and track the patient with other people in the scene (e.g. the therapist, or a clinician). We use a method based on local binary patterns (LBP). After identifying users in the scene we identify interactions between the patient and other people. We use a depth map/point cloud for estimating the distance between two people. Our method uses the association of depth regions to user identities and computes the minimal distance between the regions. RESULTS: Our results show state-of-the-art performance of real-time face recognition using low resolution images that is sufficient to use in adaptive systems. Our proposed approach for detecting interactions shows 91.9% overall recognition accuracy what is sufficient for applications in the context of serious games. We also discuss limitations of the proposed method as well as general limitations of using depth cameras for serious games. CONCLUSIONS: We introduced a new method for frame-by frame automated identification of the patient and labeling reliable sequences of the patient's data recorded during rehabilitation (games). Our method improves automated rehabilitation systems by detecting the identity of the patient as well as of the therapist and by detecting the distance between both over time. PMID- 26640834 TI - Eye Gaze Correlates of Motor Impairment in VR Observation of Motor Actions. AB - INTRODUCTION: This article is part of the Focus Theme of Methods of Information in Medicine on "Methodologies, Models and Algorithms for Patients Rehabilitation". OBJECTIVE: Identify eye gaze correlates of motor impairment in a virtual reality motor observation task in a study with healthy participants and stroke patients. METHODS: Participants consisted of a group of healthy subjects (N = 20) and a group of stroke survivors (N = 10). Both groups were required to observe a simple reach-and-grab and place-and-release task in a virtual environment. Additionally, healthy subjects were required to observe the task in a normal condition and a constrained movement condition. Eye movements were recorded during the observation task for later analysis. RESULTS: For healthy participants, results showed differences in gaze metrics when comparing the normal and arm-constrained conditions. Differences in gaze metrics were also found when comparing dominant and non-dominant arm for saccades and smooth pursuit events. For stroke patients, results showed longer smooth pursuit segments in action observation when observing the paretic arm, thus providing evidence that the affected circuitry may be activated for eye gaze control during observation of the simulated motor action. CONCLUSIONS: This study suggests that neural motor circuits are involved, at multiple levels, in observation of motor actions displayed in a virtual reality environment. Thus, eye tracking combined with action observation tasks in a virtual reality display can be used to monitor motor deficits derived from stroke, and consequently can also be used for rehabilitation of stroke patients. PMID- 26640835 TI - Quantitative Evaluation of Performance during Robot-assisted Treatment. AB - INTRODUCTION: This article is part of the Focus Theme of Methods of Information in Medicine on "Methodologies, Models and Algorithms for Patients Rehabilitation". OBJECTIVES: The great potential of robots in extracting quantitative and meaningful data is not always exploited in clinical practice. The aim of the present work is to describe a simple parameter to assess the performance of subjects during upper limb robotic training exploiting data automatically recorded by the robot, with no additional effort for patients and clinicians. METHODS: Fourteen children affected by cerebral palsy (CP) performed a training with Armeo(r)Spring. Each session was evaluated with P, a simple parameter that depends on the overall performance recorded, and median and interquartile values were computed to perform a group analysis. RESULTS: Median (interquartile) values of P significantly increased from 0.27 (0.21) at T0 to 0.55 (0.27) at T1 . This improvement was functionally validated by a significant increase of the Melbourne Assessment of Unilateral Upper Limb Function. CONCLUSIONS: The parameter described here was able to show variations in performance over time and enabled a quantitative evaluation of motion abilities in a way that is reliable with respect to a well-known clinical scale. PMID- 26640836 TI - Guiding Methods of Information in Medicine into the Next Generation: Welcome Note from the New Editor-in-Chief. PMID- 26640837 TI - Flexor digitorum lateralis tendon transposition for the repair of bilateral calcaneal tendon rupture in a cat with severe thermal injury. AB - OBJECTIVE: To describe a novel technique utilizing the flexor digitorum lateralis tendon to repair rupture of the common calcaneal tendon with a gap defect. CLINICAL REPORT: An eight-month-old male Domestic Shorthair cat with bilateral common calcaneal tendon rupture secondary to severe thermal injury underwent bilateral common calcaneal tendon repair performed in two stages. The first stage involved using the flexor digitorum lateralis tendon to reconstruct the common calcaneal tendon and a semitendinosus muscle flap for improved blood supply. A calcaneotibial screw was used for immobilization of the tarsocrural joint. The second surgery involved free skin grafting for complete wound closure. Twelve weeks after the calcaneotibial screws were placed, the calcaneotibial screws were removed and fibreglass splints were applied. The splints were removed after two weeks. RESULTS: Full recovery took five months between the surgery and the final follow-up examination. The cat had a functional gait with no lameness and was able to jump to a height of approximately 75 cm. CLINICAL SIGNIFICANCE: Use of the flexor digitorum lateralis tendon may be considered for repair of a common calcaneal tendon rupture when a gap exists and traditional tendon lengthening techniques are not feasible. PMID- 26640838 TI - Usefulness of multidetector computed tomography in the evaluation of spinal neuro musculoskeletal injuries. AB - Spinal trauma is commonly diagnosed in small animal practice. Although the first approach to the patient with spinal trauma includes survey spinal radiographs, an accurate evaluation of the injury often requires advanced imaging. Multidetector computed tomography has revolutionized computed tomography technology, providing near-isotropic volumetric representation of the complete body with exquisite anatomical detail in a brief scan time. This review aims to discuss the technical background, indications, and limitations of multidetector computed tomography in the assessment of spinal trauma with particular reference to skeletal, muscular and nervous spinal components. PMID- 26640839 TI - Retraction: Visualization of Lipid Metabolism in the Zebrafish Intestine Reveals a Relationship between NPC1L1-Mediated Cholesterol Uptake and Dietary Fatty Acid. PMID- 26640840 TI - Obituary: Professor Irena Hausmanowa-Petrusewicz (1917-2015). PMID- 26640841 TI - All around the circle: From patient to provider. PMID- 26640842 TI - [The neurovascular conflict of the vestibulocochlear nerve. Etiology, diagnostics, the methods for the surgical and conservative treatment]. AB - The present review of the current literature concerning pathogenesis, formation of neurovascular conflict of the vestibulocochlear nerve, its epidemiology, clinical manifestations, diagnostics, and the methods for the surgical and conservative treatment is focused on the indications for decompression of the vestibulocochlear nerve and its effectiveness in the patients presenting with the neurovascular conflict of the vestibulocochlear nerve. PMID- 26640843 TI - [The role of accessory ostia of the maxillary sinuses in pathogenesis of acute and chronic maxillary sinusitis]. AB - The objective of the present study was to analyze the literature publications concerning the problem of accessory ostia of the maxillary sinuses and their influence on the development and clinical course of acute and chronic maxillary sinusitis. It is concluded that, despite the conflicting opinions of different authors, accessory ostia appear to be involved in pathogenesis of maxillary sinusitis as the factors that provoke chronization of the inflammatory processes. PMID- 26640845 TI - TPPA needs health check. PMID- 26640844 TI - A History of Some Optometric Periodicals. PMID- 26640846 TI - Surgeons praised for tackling bullying. PMID- 26640847 TI - Waikato DHB must consult again on masks. PMID- 26640848 TI - Programme to develop aged-care workforce gets positive report. PMID- 26640849 TI - Informal equal pay talks held. PMID- 26640850 TI - Gender pay gap widens. PMID- 26640851 TI - Nursing workforce continues to grow. PMID- 26640852 TI - Nurse prescribing finalised by year's end? PMID- 26640853 TI - Standing order needed for students to administer vaccines. . PMID- 26640854 TI - Ethicist challenges nurses' thinking. PMID- 26640855 TI - Nursing in an isolated community. PMID- 26640856 TI - Chief executive issues a warning on the constitution. PMID- 26640857 TI - NZNO in strong position. PMID- 26640858 TI - More nurse prescribers - minister. PMID- 26640859 TI - Health targets should not be 'all consuming'. PMID- 26640861 TI - Health policy creating health inequities. PMID- 26640862 TI - Nursing was the winner on the night. PMID- 26640863 TI - Changing the guard at NZNO. PMID- 26640864 TI - Positive 'gang' fights war for better health. PMID- 26640865 TI - Nuku helps develop a smooth succession plan. PMID- 26640866 TI - Women MPs sign the equal pay pledge. PMID- 26640868 TI - Panel calls for stronger nursing voice. PMID- 26640867 TI - Nurses challenged to change. PMID- 26640869 TI - Uptake of CCDM 'slow'. PMID- 26640870 TI - #Robandme. PMID- 26640871 TI - Special Needs Patients on the 25th Anniversary of the Americans with Disabilities Act: 10 Things Florida Dentists Need to Know. PMID- 26640872 TI - Beam Me Up, Scotty! What Can Technology Help You with Today? PMID- 26640873 TI - A LECOM Student's Perspective in Reply to "Is Dentistry Already Succumbing to the "New Normal"? PMID- 26640874 TI - LECOM: A Breath of Fresh Air. PMID- 26640875 TI - Letter to the Editor. PMID- 26640876 TI - Letter to the Editor. PMID- 26640877 TI - Letter to the Editor. PMID- 26640878 TI - An Unfortunate Step Backwards. PMID- 26640879 TI - Board of Dentistry Meets in Safety Harbor. PMID- 26640880 TI - I'm Just a Regular Guy Treating Special Children. PMID- 26640881 TI - Can Your Landlord Relocate Your Dental Practice? PMID- 26640882 TI - Corporations and the Future of Dentistry. PMID- 26640884 TI - Organized Dentistry ... Can Take You Places You Never Expected. PMID- 26640883 TI - A Successful Disability Insurance Claim Begins with the Application for Benefits. PMID- 26640885 TI - Wheelchair Transfer: A Health Care Provider's Guide. PMID- 26640886 TI - 5 Important Steps to Purchasing Disability Insurance. PMID- 26640887 TI - Diagnostic Discussion. Langerhans Cell Histiocytosis. PMID- 26640888 TI - Practical Oral Care for People with an Intellectual Disability. PMID- 26640889 TI - Embracing Variety: Helping Our Patients with Special Needs Do Better in the Dental Chair. PMID- 26640890 TI - Isn't That Special? PMID- 26640891 TI - The High Prevalence of Low HDL-Cholesterol Levels and Dyslipidemia in Rural Populations in Northwestern China. AB - BACKGROUND: Dyslipidemia is a major health problem in China and an important modifiable cardiovascular disease (CVD) risk factor. This study aimed to describe the prevalence of dyslipidemia and low high density lipoprotein cholesterol (HDL cholesterol) and associated risk factors among adults in rural northwest China. METHODS: In a cross-sectional analyses involving 2,980 adults aged >18 years, information on the demographics, cigarette smoking, alcohol consumption, education, and medical history was collected via face-to-face interviews. Blood samples were collected to determine total cholesterol (TC), low-density lipoprotein cholesterol (LDL-cholesterol), and HDL-cholesterol, and triglycerides (TG) levels. RESULTS: The prevalence of high TC, high LDL-cholesterol, low HDL cholesterol, and high TG were 1.0%, 0.6%, 60.9%, and 13.7%, respectively. TC, LDL cholesterol, and TG increased with age in females. Elevated TC was more common in females than in males. The prevalence of low HDL-cholesterol was 67.6% in males and 55.4% in females. Current smokers, those with less education, those who were overweight or obese, and those with large waist circumference were more likely to have low HDL-cholesterol (p<0.05). Multivariable regression showed that male gender showed an association with low HDL-cholesterol (OR 2.10, 95%CI 1.68-2.61), age >=60 years (OR 0.80, 95% CI 0.64-0.99), BMI (BMI = 24-27.9, OR 1.27, 95%CI 1.04-1.54, p = 0.02 and BMI>=28, OR 1.56, 95%CI 1.10-2.20, p = 0.01) and enlarged waist circumference (OR 2.10, 95%CI 1.51-2.92). Non-alcohol drinker was associated with low HDL-cholesterol levels (OR 0.72, 95%CI 0.53-0.99, p = 0.04). CONCLUSIONS: This study found that the prevalence of low HDL-cholesterol was 67.6% and 55.4% for males and females. Male gender, non-alcohol drinker, BMI and central obesity were important risk factors for low HDL-cholesterol in Chinese adults. PMID- 26640892 TI - Cooperation and Shared Beliefs about Trust in the Assurance Game. AB - Determinants of cooperation include ingroup vs. outgroup membership, and individual traits, such as prosociality and trust. We investigated whether these factors can be overridden by beliefs about people's trust. We manipulated the information players received about each other's level of general trust, "high" or "low". These levels were either measured (Experiment 1) or just arbitrarily assigned labels (Experiment 2). Players' choices whether to cooperate or defect in a stag hunt (or an assurance game)--where it is mutually beneficial to cooperate, but costly if the partner should fail to do so--were strongly predicted by what they were told about the other player's trust label, as well as by what they were told that the other player was told about their own label. Our findings demonstrate the importance for cooperation in a risky coordination game of both first- and second-order beliefs about how much people trust each other. This supports the idea that institutions can influence cooperation simply by influencing beliefs. PMID- 26640893 TI - Association between Sarcopenic Obesity and Bone Mineral Density in Middle-Aged and Elderly Korean. AB - OBJECTIVES: To identify the prevalence of osteosarcopenic obesity and to evaluate the association between sarcopenic obesity and bone mineral density in middle aged and elderly Korean. METHODS: This study included 3,385 males and 4,064 females (age >=50 years and in the stage of menopause) who participated in the Korean National Health and Nutrition Examination Survey (KNHANES) from 2008 to 2011. The cutoff value for sarcopenia was 7.26 kg/m2 for men and 5.45 kg/m2 for female. The fat mass was >30% for men and 40% for female; these values were used to define obesity. Based on the combination of sarcopenia and obesity status, all subjects were classified as sarcopenic obese (SO), sarcopenic nonobese (SNO), nonsarcopenic obese (NSO), or nonsarcopenic nonobese. RESULTS: The incidence rates of sarcopenia, sarcopenic obesity, and osteosarcopenic obesity were 31.5, 5.1, and 4.1%, respectively. Following adjustment, the ORs for osteoporosis were 8.67 in the SO group (95% CI 4.19-17.94), 3.85 in the SNO group (95% CI 2.61 5.67), and 1.88 in the NSO group (95% CI 0.72-4.91) in men and 2.93 in the SO group (95% CI 1.99-4.32), 1.71 in the SNO group (95% CI 1.31-2.23), and 0.58 in the NSO group (95% CI 0.43-0.78) in women. CONCLUSIONS: Sarcopenic obesity is associated with the development of osteoporosis among the middle-aged and elderly Korean population. PMID- 26640895 TI - Disproportionate Declines in Ground-Foraging Insectivorous Birds after Mistletoe Removal. AB - Insectivorous birds have been recognized as disproportionately sensitive to land use intensification and habitat loss, with those species feeding primarily on the ground exhibiting some of the most dramatic declines. Altered litter inputs and availability of epigeic arthropods have been suggested to underlie reduced abundances and shrinking distributions but direct evidence is lacking. I used a patch-scale removal experiment in southern Australia to evaluate whether ground feeding insectivores are especially vulnerable to altered litter-fall. Building on work demonstrating the importance of mistletoe litter to nutrient dynamics, litter was reduced by removing mistletoe (Loranthaceae) from one set of eucalypt woodlands, responses of birds three years after mistletoe removal compared with otherwise similar control woodlands containing mistletoe. Despite not feeding on mistletoes directly, insectivores exhibited the greatest response to mistletoe removal. Among woodland residents, ground-foraging insectivores showed the most dramatic response; treatment woodlands losing an average of 37.4% of their pre treatment species richness. Once these 19 species of ground-foraging insectivores were excluded, remaining woodland species showed no significant effect of mistletoe removal. This response reflects greater initial losses in treatment woodlands during the study (which coincided with a severe drought) and double the number of species returning to control woodlands (where mistletoe numbers and litter were not manipulated) post-drought. These findings support the productivity-based explanation of declining insectivores, suggesting diminished litter-fall reduced habitat quality for these birds via decreased availability of their preferred prey. In addition to altered prey availability, interactions between litter-fall and epigeic arthropods exemplify the importance of below ground / above-ground linkages driving ecosystem function. PMID- 26640894 TI - Early Loss of Splenic Tfh Cells in SIV-Infected Rhesus Macaques. AB - Follicular T helper cells (Tfh), a subset of CD4 T lymphocytes, provide crucial help to B cells in the production of antigen-specific antibodies. Although several studies have analyzed the dynamics of Tfh cells in peripheral blood and lymph nodes (LNs) during Aids, none has yet addressed the impact of SIV infection on the dynamics of Tfh cells in the spleen, the primary organ of B cell activation. We show here a significant decrease in splenic Tfh cells in SIVmac251 infected rhesus macaques (RMs) during the acute phase of infection, which persists thereafter. This profound loss is associated with lack of sustained expression of the Tfh-defining transcription factors, Bcl-6 and c-Maf but with higher expression of the repressors KLF2 and Foxo1. In this context of Tfh abortive differentiation and loss, we found decreased percentages of memory B cell subsets and lower titers of SIV-specific IgG. We further demonstrate a drastic remodeling of the lymphoid architecture of the spleen and LNs, which disrupts the crucial cell-cell interactions necessary to maintain memory B cells and Tfh cells. Finally, our data demonstrated the early infection of Tfh cells. Paradoxically, the frequencies of SIV DNA were higher in splenic Tfh cells of RMs progressing more slowly suggesting sanctuaries for SIV in the spleen. Our findings provide important information regarding the impact of HIV/SIV infection on Tfh cells, and provide new clues for future vaccine strategies. PMID- 26640897 TI - Dimensions of Delusions and Attribution Biases along the Continuum of Psychosis. AB - This study compared delusional dimensions and attribution biases along the continuum of psychosis. Participants completed questionnaires on delusion-like beliefs and attributions. Although patients with first-episode psychosis (N = 70) endorsed fewer delusion-like beliefs than non-clinical individuals with psychotic like experiences (N = 12), they scored highest on delusional conviction, distress and preoccupation, followed by non-clinical individuals with psychotic-like experiences, and then healthy controls (N = 642). Self-serving bias was found in patients and non-clinical individuals with psychotic-like experiences, but not in healthy controls. Personalizing bias for negative events was not significantly different across the three groups. When compared with healthy controls, non clinical individuals with psychotic-like experiences had an exaggerated self serving bias, but were not more marked in personalizing bias. Self-serving bias and personalizing bias were both associated with delusional dimensions. However, the association between self-serving bias and number of delusion-like beliefs was stronger among patients than non-clinical participants. Future research could investigate the extent to which self-serving bias, in combination with an appraisal of delusional ideation as convincing, distress, and preoccupying, contributes to the development of clinical delusions. PMID- 26640899 TI - Organ Donation From Deceased Donors: A Proactive Detection Program in Saudi Arabia. AB - Several challenging obstacles remain to increasing the number of organ donations from deceased patients in a hospital setting. These include medical, administrative, and ethical issues. Possible medical obstacles include the failure of early recognition of possible donors and inadequate care of potential and actual donors. To maximize the use of donated organs, proper care of the donors and expedited donor consent cannot be overemphasized. The care rendered to patients should ensure appropriate perfusion and nutrition of the organs, with meticulous follow-up until organ recovery. For example, patients involved in accidents are presumed to be healthy, but many have no available medical history on file. At the time of organ recovery, unexpected infections or malignancies can be minimized by raising the index of suspicion of the presence of serious conditions in donors, especially in donors with unknown medical history. A careful physical examination and an appropriate and aggressive laboratory investigation may disclose the cause of suspected clinical conditions in these potential donors. Individuals who work in intensive care units are the main group of health care providers directly involved in the process of organ donation. Appointing a donor coordinator in each intensive care unit could improve all aspects of organ donation. Such coordination could harmonize efforts toward the goals mentioned above and surmount the obstacles encountered during deceased donor organ donation. Here, we describe the preliminary results of the Proactive Detection Program, a collaboration between the Saudi Center for Organ Transplantation (the national organ donation and transplant supervising center) and intensive care units of donating hospitals. With its success in Saudi Arabia, it is hoped that it will be widely adopted in other regions. PMID- 26640898 TI - Cloning and Functional Characterization of Two BTB Genes in the Predatory Mite Metaseiulus occidentalis. AB - Proteins containing the BTB (Bric-a-brac, tramtrack, and Broad Complex) domain typically share low sequence similarities and are involved in a wide range of cellular functions. We previously identified two putative and closely related BTB genes, BTB1 and BTB2, in the genome of the predatory mite Metaseiulus occidentalis. In the current study, full-length BTB1 and BTB2 cDNAs were cloned and sequenced. BTB1 and BTB2 encode proteins of 380 and 401 amino acids, respectively. BTB1 and BTB2 proteins each contain an N-terminal BTB domain and no other identifiable domains. Thus, they belong to a large category of BTB-domain proteins that are widely distributed in eukaryotes, yet with largely unknown function(s). BTB1 and BTB2 gene knockdowns in M. occidentalis females using RNAi reduced their fecundity by approximately 40% and 73%, respectively, whereas knockdown had no impact on their survival or the development of their offspring. These findings suggest these two proteins may be involved in processes related to egg production in this predatory mite, expanding the list of functions attributed to these diverse proteins. PMID- 26640900 TI - Organ Transplants in Kazakhstan. AB - The Republic of Kazakhstan is one of the fastest developing countries in the world and has a health care system that is unique in Central Asia. Its organ transplant services are also developing rapidly. We aimed to analyze and briefly report on the current status of organ transplant in the Republic of Kazakhstan. We analyzed organ transplant activities in that country for the period 2012 to 2014. All data were collected from the official database of the National Transplant Coordinating Center of the Republic of Kazakhstan. At the end of 2014, the number of transplant centers had increased to 10, three of which could perform multiorgan transplants; during the same period, the number of deceased donor organ-donating hospitals increased up to 37. By 2013, the transplant activity rate for all centers had reached 9.22 per million population. During the previous 3 years (2012-2014), there was a 3-fold increase in the number of living donors and an 18-fold increase in the number of kidney transplants. Between 2012 and 2014, the number of living-donor liver transplants increased from 17 to 25, and the number of deceased-donor transplants increased from 3 to 7. During the last 3 years (2012-2014), the number of heart transplants increased to 7 cases. During the last 3 years (2012-2014), Kazakhstan achieved a significant improvement in the organization of its transplant services, and a noticeable upward trend in the system continues. PMID- 26640901 TI - Implications of Treating Hepatitis C Virus Infection Among Patients Awaiting Cadaveric Liver Transplant: A Single-Center Experience. AB - OBJECTIVES: We examined hepatitis C virus positivity among the donors in our center to investigate whether hepatitis C treatment affected liver transplant Model for End-Stage Liver Disease. MATERIALS AND METHODS: We retrospectively reviewed all deceased-donor liver transplants performed between January 2013 and December 2014 at our center, with the primary indication of hepatitis C virus. Baseline demographic and laboratory characteristics of recipients and donors were collected. Statistical analyses were done with P values <= .05 considered significant. RESULTS: Seventy-five liver transplants were performed, and 62 of them were hepatitis C virus RNA-positive at the time of liver transplant donor offer. In 2013, during the Pre-Direct Antiviral Agents era, 14 of 33 hepatitis C virus RNA-positive recipients (42%) were matched to hepatitis C virus-positive donors. During the Direct Antiviral Agents era in 2014, this ratio was 38% (11/29) (P = .72). The mean Model for End-Stage Liver Disease at transplant of the 62 hepatitis C virus RNA-positive recipients was 29, whereas the mean Model for End-Stage Liver Disease of 13 hepatitis C virus RNA-negative recipients was 31. This was not statistically significant (P = .25). CONCLUSIONS: Although hepatitis C virus treatment before liver transplant is an attractive option to eliminate the risk of complications because of recurrent hepatitis C virus after liver transplant, its potential effect on limiting the donor pool for the recipient must also be considered. In our observation, 40% of our donor pool consists of hepatitis C virus-positive donors. Further multiregional studies are warranted to verify this observation and to see the potential effect of direct antiviral agent treatment into waiting times and the Model for End-Stage Liver Disease at organ allocation. PMID- 26640902 TI - Early Infections in Renal Transplant Recipients: Incidence, Risk Factors, and Causative Microorganisms. AB - OBJECTIVES: This study aimed to compare renal transplant recipients with and without infection with respect to demographic and clinical characteristics as well as risk factors; to determine the incidence of posttransplant infections; and to study the antibiotic resistance patterns of bacterial species identified as the causative organisms in posttransplant infections. MATERIALS AND METHODS: This study included a total of 136 patients undergoing renal transplant in a 4 year period. The patients were categorized into 2 groups. The 2 groups were compared with each other with respect to general clinical and demographic variables and the number and frequency of infectious attacks within a 1-year follow-up, infection type, and antibiotic resistance patterns. RESULTS: Ninety two (67.6%) of the subjects were male and 44 (32.4%) were female. A total of 57 (41.9%) patients developed 128 infectious attacks. Urinary tract infections were the most common infections (42.1%). There was a significant correlation between a clinically relevant urinary culture proliferation and postoperative infection rate (P = .002). There was a significant correlation between antimicrobial resistance and the number of infectious attacks (P = .023). There was a significant correlation between the proliferation of Extended Spectrum Beta Lactamase-positive Enterobactericeae species and the number of infectious attacks (P = .000). CONCLUSIONS: Presence of a clinically relevant proliferation in the preoperative urinary culture, which was identified as a risk factor for infection, increased the number of infectious attacks. Moreover, Extended Spectrum Beta Lactamase-positive Enterobactericeae species increased the number of infections. These 2 principle results should be taken into account in patient management. PMID- 26640903 TI - Late Intensive Care Unit Admission in Liver Transplant Recipients: 10-Year Experience. AB - OBJECTIVES: We evaluated late intensive care unit admission in liver transplant recipients to identify incidences and causes of acute respiratory failure in the postoperative period and to compare these results with results in patients who did not have acute respiratory failure. MATERIALS AND METHODS: We retrospectively screened the data of 173 consecutive adult liver transplant recipients from January 2005 through March 2015 to identify patients with late admission (> 30 d posttransplant) to an intensive care unit. Patients were divided into 2 groups: patients with and without acute respiratory failure. Acute respiratory failure was defined as severe dyspnea, respiratory distress, decreased oxygen saturation, hypoxemia or hypercapnia on room air, or need for noninvasive or invasive mechanical ventilation. Demographic, laboratory, clinical, and respiratory data were collected. Model for End-Stage Liver Disease, Acute Physiology and Chronic Health Evaluation II, and Sequential Organ Failure Assessment scores; lengths of intensive care unit and hospital stays; and hospital mortality were assessed. RESULTS: Among 173 patients, 37 (21.4%) were admitted to an intensive care unit, including 22 (59.5%) with acute respiratory failure. The leading cause of acute respiratory failure was pneumonia (n = 19, 86.4%). Patients with acute respiratory failure had significantly lower levels of albumin before intensive care unit admission (P = .003). In patients with acute respiratory failure, severe sepsis and septic shock were more frequently observed and tracheotomy was more frequently performed (P = .041). CONCLUSIONS: Acute respiratory failure developed in 59.5% of liver transplant recipients with late intensive care unit admission. The leading cause was pneumonia, with this group of patients having higher requirements for invasive mechanical ventilation and tracheotomy, longer stays in an intensive care unit, and higher mortality. PMID- 26640904 TI - Acute Respiratory Failure in Cardiac Transplant Recipients. AB - OBJECTIVES: This study sought to evaluate the incidence, risk factors, and outcomes of acute respiratory failure in cardiac transplant recipients. MATERIALS AND METHODS: Cardiac transplant recipients >15 years of age and readmitted to the intensive care unit after cardiac transplant between 2005 and 2015 were included. RESULTS: Thirty-nine patients were included in the final analyses. Patients with acute respiratory failure and without acute respiratory failure were compared. The most frequent causes of readmission were routine intensive care unit follow up after endomyocardial biopsy, heart failure, sepsis, and pneumonia. Patients who were readmitted to the intensive care unit were further divided into 2 groups based on presence of acute respiratory failure. Patients' ages and body weights did not differ between groups. The groups were not different in terms of comorbidities. The admission sequential organ failure assessment scores were higher in patients with acute respiratory failure. Patients with acute respiratory failure were more likely to use bronchodilators and n-acetylcysteine before readmission. Mean peak inspiratory pressures were higher in patients in acute respiratory failure. Patients with acute respiratory failure developed sepsis more frequently and they were more likely to have hypotension. Patients with acute respiratory failure had higher values of serum creatinine before admission to intensive care unit and in the first day of intensive care unit. Patients with acute respiratory failure had more frequent bilateral opacities on chest radiographs and positive blood and urine cultures. Duration of intensive care unit and hospital stays were not statistically different between groups. Mortality in patients with acute respiratory failure was 76.5% compared with 0% in patients without acute respiratory failure. CONCLUSIONS: A significant number of cardiac transplant recipients were readmitted to the intensive care unit. Patients presenting with acute respiratory failure on readmission more frequently developed sepsis and hypotension, suggesting a poorer prognosis. PMID- 26640906 TI - Outcomes of Patients With Hepatocellular Carcinoma After Liver Transplant. AB - OBJECTIVES: Liver transplant is one of the few effective treatments for hepatocellular carcinoma. Our aim in this study was to evaluate the risk factors for hepatocellular carcinoma recurrence after liver transplant. MATERIALS AND METHODS: In this retrospective study, conducted between October 1988 and March 2015, four hundred seventy-three liver transplants were performed at our institution. Of these, 231 were pediatric and 242 were adult. Among these patients, liver transplant was performed in 58 patients (12.3%) for treatment of hepatocellular carcinoma. RESULTS: Hepatocellular carcinoma recurrence was detected in 14 patients (24.1%). Overall 5-year and 10-year survival rates of patients underwent liver transplant beyond the Milan criteria for hepatocellular carcinoma were 50.3% and 43.1%. Overall, 5- and 10-year survival rates of patients underwent liver transplant within the Milan criteria for hepatocellular carcinoma were 78.4% and 72.6%. The main predictive variable was whether the tumor had expensed beyond the Milan criteria. CONCLUSIONS: As expected, outcomes were significantly better in the Milan criteria group. Although the overall- and disease-free survival rates were promising in such a group of patients who had no better chance, it could be asserted that liver transplant is a safe and effective treatment option with promising results, even if the tumor expanse is beyond the Milan criteria. PMID- 26640905 TI - Incidence and Outcomes of Acute Kidney Injury After Orthotopic Cardiac Transplant: A Population-Based Cohort. AB - OBJECTIVES: Acute kidney injury is a frequent complication after orthotopic cardiac transplant. We aimed to describe the risk factors for acute kidney injury after cardiac transplant according to Kidney Disease: Improving Global Outcomes criteria. MATERIALS AND METHODS: We retrospectively studied a population-based cohort of cardiac transplant recipients (aged > 12 y) at Baskent University between February 2003 and January 2015. Of 94 patients, 64 were evaluated and included in the study. The main outcome was acute kidney injury, defined and classified according to Kidney Disease: Improving Global Outcomes criteria, during 7 postoperative days. Other outcomes included risk factors, use of renal replacement therapy, postoperative complications, mortality, and kidney recovery. RESULTS: Mean age at transplant was 34.14 +/- 16.30 years, and 45 patients (70.32%) were men. Acute kidney injury developed in 34 (53.12%) of 64 cardiac transplant recipients, with severity classified as stage 1 in 10 (15.62%), stage 2 in 14 (21.87%), and stage 3 in 10 (15.62%). Renal replacement therapy was given to 25 patients (39.06%). Patients with acute kidney injury were significantly older (40.41 +/- 15.85 y vs 27.03 +/- 13.91 y; P = .001), had larger body surface area (1.78 +/- 0.28 m2 vs 1.61 +/- 0.31 m2; P = .033), and more frequently had a history of hypertension (P = .011) and smoking (P = .007) than did patients without acute kidney injury. They also had lower intraoperative urine output (453.380 +/- 266.85 mL) than did patients who did not develop acute kidney injury (632.33 +/- 430.94 mL (P = .01). CONCLUSIONS: According to the Kidney Disease: Improving Global Outcomes criteria, acute kidney injury occurs in more than 50% of heart transplant patients postoperatively. Older age, larger body surface area, and history of hypertension and smoking are associated with acute kidney dysfunction following orthotopic heart transplant. PMID- 26640907 TI - Pathologic Criteria to Estimate the State of the Liver in Potential Donors. AB - OBJECTIVES: The pathologic evaluation of the liver is one of the most important issues in liver transplants. We evaluated the histopathological condition of livers in potential donors. MATERIALS AND METHODS: After liver biopsy, 37 potential donor livers were histologically studied. Liver tissue was stained by hematoxylin and eosin as well as Masson Trichrome. RESULTS: The results of the study showed the morphologic criteria used to estimate the state of the liver in potential donors is not only steatosis and fibrosis, but other important histologic criteria, such as proteinosis, necrosis of hepatocytes, endotheliitis of central veins, inflammatory infiltration, endarteritis in portal tracts and phlebitis in portal tracts, proliferation of the bile ducts, and cholestasis. CONCLUSIONS: Results of the study showed that the morphologic criteria to estimate the state of the liver in potential donors includes not only steatosis and fibrosis, but other important histologic criteria as well. PMID- 26640908 TI - The Effect of Hepatitis B Virus on Graft and Overall Survival in Kidney Transplant Patients. AB - OBJECTIVES: We investigated the effect of hepatitis B virus in kidney transplant patients in terms of patient care and survival. MATERIALS AND METHODS: We retrospectively analyzed kidney transplant patients from 1993 to 2013. A control group with negative serology was selected. The hepatitis B virus-positive group was divided into 2 subgroups based on serologic status, treatments, and treatment responses. Group A had viral suppression, and group B had hepatitis B virus DNA persistence. Overall and allograft survival rates were compared. RESULTS: We identified 32 hepatitis B virus-positive and 74 hepatitis B virus-negative patients. Positive group was treated with lamivudine (n = 23), lamivudine plus entecavir (n = 4), lamivudine plus tenofovir (n = 4), or lamivudine plus entecavir and tenofovir (n = 1). In group A (n = 15), antiviral treatment was given based on the presence of either hepatitis B surface antigen with negative hepatitis B virus DNA (n = 11) or hepatitis B virus DNA positivity (n = 4). Group B patients (n = 17) received antiviral treatment for persistence of hepatitis B virus DNA (n = 7) or for viral reactivation (ie, recurrence of hepatitis B virus DNA) (n = 10). Groups A and B did not differ significantly in terms of graft or overall survival. Liver biopsy was performed in 17 patients; 3 patients had high grade fibrosis or cirrhosis, and 14 patients had normal histology or mild hepatitis. Median graft survival time was longer in positive group (69.5 mo vs 54 mo; P = .007). Five- and 10-year overall survival rates were comparable (89%-84% vs 96%-96%; P = .107). CONCLUSIONS: Hepatitis B virus-positive kidney transplant patients have increased liver transaminase levels, longer graft survival times, and similar median overall survival rates compared with hepatitis B virus negative patients. PMID- 26640909 TI - Liver Transplant Experience in Syzganov's National Scientific Center of Surgery. AB - OBJECTIVES: Patients with chronic end-stage liver disease present a significant problem in the Republic of Kazakhstan. The liver transplant program was started in December 2011 and for May 2015, more than 80 liver transplant operations have been performed in 7 different hospitals of the country. MATERIALS AND METHODS: The main problem that hinders the wide implementation of liver transplant in our country is poor development of regularity of deceased-organ donation system. This is because of the specific mentality of the population and imperfect legislation. RESULTS: From 26 operated recipients, 19 lead a normal life (73.1%), receiving a minimal immunosuppressive therapy. In patients with cirrhosis of viral cause, there are no cases of viral hepatitis reinfection. CONCLUSIONS: Preliminary findings based on a small experience showed a good perceptiveness of developing of Liver Transplant program in Kazakhstan. PMID- 26640910 TI - Acute Respiratory Failure in Renal Transplant Recipients: A Single Intensive Care Unit Experience. AB - OBJECTIVES: Frequency of pulmonary complications after renal transplant has been reported to range from 3% to 17%. The objective of this study was to evaluate renal transplant recipients admitted to an intensive care unit to identify incidence and cause of acute respiratory failure in the postoperative period and compare clinical features and outcomes between those with and without acute respiratory failure. MATERIALS AND METHODS: We retrospectively screened the data of 540 consecutive adult renal transplant recipients who received their grafts at a single transplant center and included those patients admitted to an intensive care unit during this period for this study. Acute respiratory failure was defined as severe dyspnea, respiratory distress, decreased oxygen saturation, hypoxemia or hypercapnia on room air, or requirement of noninvasive or invasive mechanical ventilation. RESULTS: Among the 540 adult renal transplant recipients, 55 (10.7%) were admitted to an intensive care unit, including 26 (47.3%) admitted for acute respiratory failure. Median time from transplant to intensive care unit admission was 10 months (range, 0-67 mo). The leading causes of acute respiratory failure were bacterial pneumonia (56%) and cardiogenic pulmonary edema (44%). Mean partial pressure of arterial oxygen to fractional inspired oxygen ratio was 174 +/- 59, invasive mechanical ventilation was used in 13 patients (50%), and noninvasive mechanical ventilation was used in 8 patients (31%). The overall mortality was 16.4%. CONCLUSIONS: Acute respiratory failure was the reason for intensive care unit admission in almost half of our renal transplant recipients. Main causes of acute respiratory failure were bacterial pneumonia and cardiogenic pulmonary edema. Mortality of patients admitted for acute respiratory failure was similar to those without acute respiratory failure. PMID- 26640911 TI - Percutaneous Dilational Tracheotomy in Solid-Organ Transplant Recipients. AB - OBJECTIVES: Solid-organ transplant recipients may require percutaneous dilational tracheotomy because of prolonged mechanical ventilation or airway issues, but data regarding its safety and effectiveness in solid-organ transplant recipients are scarce. Here, we evaluated the safety, effectiveness, and benefits in terms of lung mechanics, complications, and patient comfort of percutaneous dilational tracheotomy in solid-organ transplant recipients. MATERIALS AND METHODS: Medical records from 31 solid-organ transplant recipients (median age of 41.0 years [interquartile range, 18.0-53.0 y]) who underwent percutaneous dilational tracheotomy at our hospital between January 2010 and March 2015 were analyzed, including primary diagnosis, comorbidities, duration of orotracheal intubation and mechanical ventilation, length of intensive care unit and hospital stays, the time interval between transplant to percutaneous dilational tracheotomy, Acute Physiology and Chronic Health Evaluation II score, tracheotomy-related complications, and pulmonary compliance and ratio of partial pressure of arterial oxygen to fraction of inspired oxygen. RESULTS: The median Acute Physiology and Chronic Health Evaluation II score on admission was 24.0 (interquartile range, 18.0-29.0). The median interval from transplant to percutaneous dilational tracheotomy was 105.5 days (interquartile range, 13.0-2165.0 d). The only major complication noted was left-sided pneumothorax in 1 patient. There were no significant differences in ratio of partial pressure of arterial oxygen to fraction of inspired oxygen before and after procedure (170.0 [interquartile range, 102.2-302.0] vs 210.0 [interquartile range, 178.5-345.5]; P = .052). However, pulmonary compliance results preprocedure and postprocedure were significantly different (0.020 L/cm H2O [interquartile range, 0.015-0.030 L/cm H2O] vs 0.030 L/cm H2O [interquartile range, 0.020-0.041 L/cm H2O); P = .001]). Need for sedation significantly decreased after tracheotomy (from 17 patients [54.8%] to 8 patients [25.8%]; P = .004]). CONCLUSIONS: Percutaneous dilational tracheotomy with bronchoscopic guidance is an efficacious and safe technique for maintaining airways in solidorgan transplant recipients who require prolonged mechanical ventilation, resulting in possible improvements in ventilatory mechanics and patient comfort. PMID- 26640912 TI - Splenic Artery Embolization in Patients After Orthotopic Liver Transplant. AB - OBJECTIVES: Hypersplenism (thrombocytopenia, leukopenia, anemia) syndrome and ascites occur after orthotopic liver transplant. These conditions can be treated by open splenectomy. Splenic artery embolization has been practiced as an alternative surgical method. MATERIALS AND METHODS: Between January 2013 and January 2015, twenty-one orthotopic liver transplants were performed at the National Scientific Medical Research Center, Astana, Kazakhstan. Of these patients, 3 subsequently received splenic artery embolization 12, 8, and 6 months after transplant: 2 patients who had been diagnosed with primary biliary cirrhosis and 1 patient with hepatitis B virus -related liver cirrhosis. Two patients received a right-lobe living orthotopic liver transplant, and 1 patient received a deceased donor transplant. Indications for splenic artery embolization (ascites, splenomegaly) were based on clinical and ultrasonographic investigation and laboratory findings (thrombocytopenia, platelet count < 60 * 109/L, leukocytopenia, and white blood cell count < 2 * 109/L). Two recipients had leukothrombocytopenia and refractory ascites, and 1 had only thrombocytopenia. Splenic artery embolization was performed via a percutaneous femoral artery approach under local anesthesia. Transcatheter splenic artery branch occlusion was performed by deploying occlusion material. Preoperative spleen size ranged from 17.5 * 8.0 cm to 22.0 * 12.5 cm; ascites volumes were > 1000 mL. RESULTS: In all patients, ascites and platelet levels decreased after splenic artery embolization. In 1 patient with leukopenia, white blood cell count normalized. After embolization, 1 patient had severe abdominal pain requiring analgesia medication, and 2 patients had fever that lasted 3 days. Patients were discharged 6 to 9 days after embolization. One patient developed a perisplenic abscess without fever 1 month after discharge, and the abscess was drained using an ultrasound-guided percutaneous procedure. CONCLUSIONS: Splenic artery embolization is a safe and effective minimally invasive method for treating hypersplenism and ascites in orthotopic liver transplant recipients and an alternative to open splenectomy. PMID- 26640913 TI - Significance of Colonoscopic Findings in Patients After Kidney Graft. AB - OBJECTIVES: We aimed to investigate the colonoscopy findings in patients after kidney transplant. MATERIALS AND METHODS: We retrospectively analyzed kidney transplant patients who had colonoscopy examinations for various indications between 2011 and 2015. RESULTS: Eighty-one patients (25 women and 56 men) with a mean age of 39 years (range, 18-64 y) were identified. Mean follow-up after transplant was 9 years (range, 1-29 y). The most common indications for colonoscopy were diarrhea (41%), anemia (29%), gastrointestinal bleeding (12%), abdominal pain (12%), and unexplained weight loss (6%). Either colitis or ileitis or both were diagnosed in 20 patients (25%), whereas polyps were found in 9 patients (11%). One patient presented with hematochezia, which was diagnosed as cytomegalovirus colitis. The remaining cases of colitis or ileitis were diagnosed as nonspecific inflammation. Indications for colonoscopy were not correlated with age, duration after transplant, or use of immunosuppressive drugs. A subgroup analysis for mycophenolate-induced colitis found that 88% of patients used mycophenolate, but presence of colitis or ileitis had no statistical correlation with its use. In patients with poor gastrointestinal symptoms, the only significant predictor of presence of colitis or ileitis was a high C-reactive protein value (> 5 mg/dL; P = .02). CONCLUSIONS: Incidence of colitis and/or ileitis is a relatively common finding in patients after kidney transplant. Opportunistic infections, mycophenolate use, and mild degree of indeterminate colitis or ileitis disease may be the underlying condition. Cytomegalovirus infection should be screened in all recipients because it may cause serious complications or death in chronically immunocompromised patients. PMID- 26640914 TI - Development of an Information Model for Kidney Transplant Wait List. AB - OBJECTIVES: Deceased-donor kidney transplant is unique among surgical procedures that are an urgent procedure performed in an elective population. It has not been possible to accurately determine when a given patient will be called for transplant. Patients on the active transplant list can be called for a transplant at any time. As a result, every effort must be made to optimize their health according to best practices and published clinical practice guidelines. MATERIALS AND METHODS: Once the patient is placed on the transplant wait list after undergoing an initial extensive evaluation, continued surveillance is required. Therefore, we developed a kidney transplant wait list surveillance software program that alerts organ transplant coordinator on time regarding which patients need a work-up. RESULTS: The new designed software has a database of our waiting patients with their completed and pending controls. The software also has built in functions to warn the responsible staff with an E-mail. If one of the controls of a recipient delayed, the software sends an automated E-mail to the staff regarding the patients delayed controls. The software is a Web application that works on any platform with a Web browser and Internet connection and allows access by multiple users. The software has been developed with NET platform. The database is SQL server. The software has the following functions: patient communication info, search, alert list, alert E-mail, control entry, and system management. CONCLUSIONS: As of January 2014, a total of 21 000 patients were registered on the National Kidney Transplant wait list in Turkey and the kidney transplant wait list had been expanding by 2000 to 3000 patients each year. Therefore computerized wait list programs are crucial to help to transplant centers to keep their patients up-to-date on time. PMID- 26640915 TI - Evaluation of Kidney Allograft in the Early Posttransplant Period Using Ultrasonography. AB - OBJECTIVES: The aim of this study was to evaluate the kidney allograft after transplant to assess restoration of blood flow, the time required to functionally recovery after surgery, and the ability to differentiate normal from pathologic grafts using color Doppler ultrasonography in the early posttransplant period. MATERIALS AND METHODS: Sixteen kidney recipients underwent renal color Doppler ultrasonography examinations 1, 2, 3, 7, 15, and 30 days after transplant. We evaluated the clinical and biochemical test results of recipients and the functioning allografts and evaluated the acute pathology. Results of resistive index in color Doppler ultrasonography were compared with blood test results. RESULTS: During the early postoperative period after kidney transplant, the average size of the kidney was 10.7 * 5.1 cm, with parenchyma at 1.7 cm. The structure of the parenchyma was nonhomogeneous in 14 patients and homogeneous in 2 patients. The medullary pyramid layer was prominent in 6 patients, moderately prominent in 7 patients, and not prominent in 3 patients. The pyelocaliceal system was condensed in 1 patient. Hematoma in the perinephrium was found in 5 patients, and free fluid was found in 5 patients. Satisfactory vascularization of allografts occurred in 14 patients, with resistive index sensitivity of 93% and specificity of 83%. CONCLUSIONS: Color Doppler ultrasonography and resistive index results were useful in evaluating kidney allografts during the early postoperative period and in confirming their condition despite excessive blood parameter values. PMID- 26640916 TI - Liver Metabolic Function of Hemodialysis Patients With Surface Antigen-Positive Hepatitis B. AB - OBJECTIVES: Hepatitis B virus remains a serious problem, particularly for patients with end-stage renal disease on maintenance hemodialysis. This study sought to investigate the levels of serum cholestasis markers in hepatitis B virus-positive patients on maintenance hemodialysis. MATERIALS AND METHODS: This study included 50 hepatitis B virus-positive hemodialysis patients (aged 45.4 +/- 4.1 years). All patients had been receiving hemodialysis (because of end-stage renal disease) from 2008 to 2009 at the "MedServis" Private Medical Center in Baku, Azerbaijan. We studied serum gamma-glutamyl transpeptidase and alkaline phosphatase levels after the admission (baseline levels) and after 1, 3, and 6 months of beginning of hemodialysis (or observation for control groups-2). The control groups consisted of hepatitis B virus-negative hemodialysis patients (control group-1) and hepatitis B virus-positive patients with end-stage renal disease not requiring hemodialysis (control group-2). RESULTS: After 1 and 3 months of hemodialysis, serum gamma-glutamyl transpeptidase and alkaline phosphatase levels gradually declined but remained elevated in hepatitis B virus positive hemodialysis patients compared to control group-1 and control group-2 patients. After 1 month gamma-glutamyl transpeptidase levels in hepatitis B virus positive hemodialysis patients were 67.9% lower than baseline levels (P0 < .05), were 51.6% higher compared to control group-2 patients (P1 < .05) and did not differ from control group-1 patients (at the same time points). By month 6, serum alkaline phosphatase levels in hepatitis B virus-positive hemodialysis patients had become 53.9% lower than baseline (P < .01), and did not differ from control group-1 and control group-2 patients. CONCLUSIONS: The data obtained in this study suggest that hemodialysis may have a positive effect on cholestasis in end stage renal disease patients with hepatitis B virus infection, and may increase immune response and improve liver function in this group of patients. PMID- 26640917 TI - Kidney Function Evaluation According to Percentage of Technetium-99m Capture With Addition of Correcting Factor for Technetium-99mm Decay. AB - OBJECTIVES: Assess the safety and accuracy of renal static scintigraphy with introduction of the amendment coefficient for decay of 99m metastable (Tc-99m) at the calculation formula of capture percent Technemec 99m. MATERIALS AND METHODS: This study analyzes retrospectively the results of renal static scanning of 44 patients. Of this group of patients, 21 are Chornobyl Nuclear Power Station accident liquid ators who have arterial hypertension and chronic pyelonephritis. Renal scanning was carried out with Genesys EPIC single-photon emission computed tomography system. Calculation of the capture percent of the radiopharmaceutical Technemec 99m was executed in the standard way with introduction of the amendment coefficient Tc-99m to decay at the calculation formula of capture percentage Technemec. RESULTS: Significant differences by standard calculation method took place in the both the Chornobyl Nuclear Power Station accident liquidators and persons who were not subjected to the influence of a small radiation dosage (P < .05). CONCLUSIONS: A small radiation dose did not affect kidney function (P > .05) with introduction of the amendment coefficient for decay of technetium 99m; therefore, static scintigraphy is a safe method for assessing kidney structure and morphology. Introduction of amendment for decay of Tc-99m allowed false positive results in 11.9% of renal function assessments for patients with arterial hypertension and kidney dysfunction (P < .05). Calculation of the specific capture percent of radiopharmaceutical on 1 cm2 of visualization of renal parenchyma enabled a 29% increase in renal function identification accuracy. PMID- 26640918 TI - Delaying Renal Transplant after Radical Prostatectomy for Low-Risk Prostate Cancer. AB - To minimize the recurrence of a previously treated neoplasm in organ recipients, a period of 2 to 5 years without recurrence is advocated for most malignancies. However, prostate cancer is different because of its biological properties, diagnosis, and treatment. Most prostate cancers are detected at a low stage and demonstrate slow growth after detection. Definitive treatment with radical prostatectomy affords excellent results. Renal transplant candidates with early stage prostate cancer have a higher risk of dying on dialysis than dying from prostate cancer; therefore, renal transplant candidates with organ-confined prostate cancer should be immediately considered for transplant. PMID- 26640919 TI - Multiple Brain Abscesses Due to Phialemonium in a Renal Transplant Recipient: First Case Report in the Literature. AB - Fungal brain abscesses are a rare but serious complication in transplant recipients. Phialemonium organisms are rare causes of invasive mold infections. Here, we present the first case of a renal transplant recipient with multiple brain abscesses caused by Phialemonium infection A. A 51-year-old female kidney transplant recipient was admitted with pneumonia of an unknown cause and treated with empiric intravenous antibiotics. Her treatment was uneventful, and she was discharged 1010 days later. After 5 days, she was readmitted with fever, cerebral palsy, and speech disorder. The patient had undergone living-donor renal transplant 7 months earlier. A cranial computed tomography and magnetic resonance imaging were performed for a possible cerebrovascular pathology. The magnetic resonance imaging scan showed multiple brain abscesses located at the left parietal, frontal and occipital lobes; right parietal and occipital lobes; right basal ganglia; and left cerebellum. The patient received meropenem, linezolid, sulfamethoxazole and trimethoprim, and AmBisome for probable pathogenic infection, and immunosuppressive agents dosage was reduced increasingly immunosuppressed. We identified Phialemonium in cerebrospinal fluid culture. The patient received voriconazole 200 mg twice daily. Lesions could not be drained due to lack of capsula formation. The patient died on the 30th day of antifungal therapy. Phialemonium organisms, although a rare cause of fungal infections, are associated with a high mortality rate in immunocompromised patients. To our knowledge, this is the first case report in the literature describing multiple brain abscesses due to Phialemonium in a transplant recipient. Clinicians recipient should be alert about these rare opportunistic fungi in the differential diagnosis of brain abscess, and bronchoscopy and bronchoalveolar lavage are recommended for transplant patients when they are admitted with pneumonia exclude fungal infections. PMID- 26640920 TI - Malposition of a Peripherally Inserted Central Venous Catheter in the Graft Hepatic Vein. AB - Central venous catheters are used for delivering medications and parenteral nutrition, measuring hemodynamic variations, and providing long-term intravenous access. In our clinic, during liver transection using a living-liver donor, peripherally inserted central venous catheters are generally preferred because they involve a less invasive technique with a lower risk of complications. In this report, we present the case of a 36-year-old male liver donor into whom we peripherally inserted a central venous catheter from his left basilic vein. After transecting the hepatic vein, the surgeon found foreign material inside the venous lumen, which turned out to be the distal segment of the catheter. PMID- 26640921 TI - Preservation Solution Effluent Osmolality as a Predictor of Initial Kidney Transplant Dysfunction. AB - OBJECTIVES: The aim of this study was to identify new predictors of kidney graft primary dysfunction from results of metabolic, electrolyte composition, and preservation solution effluent osmolality analyses of kidneys from deceased donors. MATERIALS AND METHODS: Samples of left renal veins in Custodiol preservation solution (produced by Dr. F. Kohler, Chemie, Bensheim, Germany) from kidney explants and from back table surgical procedures were obtained from 55 deceased donors. We compared metabolic parameters (glucose and lactate levels), electrolyte composition (potassium, sodium, calcium, chlorine), and effluent osmolality of kidney samples from donors whose recipients had satisfactory initial graft function (n = 44) and dysfunction (n = 22). Values are shown as median and interquartile ranges between the 25th and 75th percentiles. We used the Mann-Whitney U test to compare quantitative variables. RESULTS: Statistically significant differences were observed in effluent osmolality results between kidneys that resulted in satisfactory graft function (median, 85; interquartile range, 65.5-97.1) and those that did not result in satisfactory graft function (median, 103.25; interquartile range, 78.7-125.75) (P = .045). We also observed a trend toward significance in sodium ion levels (P = .073) and lactate levels (P = .09). No statistically significant differences were shown in samples obtained from the back table surgical procedure. CONCLUSIONS: As a predictor of an initially satisfactory functioning deceased-donor kidney graft, it is possible to use the level of osmolality in Custodiol solution effluent obtained at explant. PMID- 26640922 TI - Computed Tomography in the Preoperative and Postoperative Evaluation of Kidney Transplant Patients. AB - OBJECTIVES: Computed tomography is required for selection of living donors for kidney transplant. We assessed the diagnostic relevance and effectiveness of multiphase contrast-enhanced computed tomography angiography for evaluating patients before and after transplant. MATERIALS AND METHODS: Thirty-two potentially living kidney donors (15 men and 17 women) underwent multiphase computed tomography angiography for evaluation before kidney transplant and 2 posttransplant recipients under went this test owing to abnormal vascularization. Computed tomography angio graphy was used to determine parenchymal blood-flow conditions and vascular architecture of the kidney grafts. All of the 34 patients underwent prestudy Doppler ultrasonography. RESULTS: Additional renal arteries were found in 11 patients (32.3%). From them, a single additional renal artery, situated from the aorta to the lower segment of the kidney, was observed in 8 (72.7%) patients; dual additional renal arteries with equivalent caliber trunks were observed in 3 (27.3%) patients. An additional renal artery occurred more often in women in 6 (54.5%) donors. Concomitant renal pathology was detected in 3 (9.3%) of 32 donors: simple cysts in 2 donors and hydro nephrosis transformation in 1 donor. These 3 cases represented an accidental discovery and were therefore excluded from the list of donors. In addition, all donors underwent excretory phase computed tomography, and their renal function and urinary collecting system results were evaluated. Two recipients with graft dysfunction presented with decreased venous return and delayed arterial filling of the renal arteries that manifested as delayed contrast in the kidney graft medulla. Renal parenchymal ischemic zones were consistent with microvasculature thrombosis, the most common cause of vascular complications in these recipients. CONCLUSIONS: Multiphase computed tomography angiography is a necessary tool for assessing the structure and condition of vascular architecture in kidney donors and recipients. Individuals with ambiguous Doppler results, this test should be required; it is also warranted when renal graft vascular complications are suspected. PMID- 26640923 TI - Microbiologic Monitoring of Patients Before and After Living-Donor Kidney Transplant. AB - OBJECTIVES: The aim of this study was to analyze microbiologic screening results of the respiratory tract and urine of patients before and after livingdonor kidney transplant. MATERIALS AND METHODS: We analyzed the clinical screening results of 30 patients before and after living-donor kidney transplant who were treated in the Department of Transplantology at the National Scientific Medical Research Center from 2013 to 2014. Microbiologic screening results from urine, sputum, nasal, and throat tests were included: diagnostically significant concentration of isolates measured 105 colony-forming units/1 mL and above. Identification of isolates and antibiotic susceptibility testing were performed with the Vitek 2 Automated System (BioMerieux, 673 620 399 RCS LYON, 69280 Marcy I 'Etoile / France). RESULTS: Results of routine microbiologic screening before living-donor kidney transplant showed that 29 of 30 patients had isolates at 105 colony-forming units /1 mL and above. In 10 patients (34.4%) isolates were obtained from throat swabs, with Streptococcus pneumoniae being the most frequent infection (37.9%). Results from nasal swabs showed Staphylococcus aureus (10.3%) and Staphylococcus epidermidis (17.2%). Sputum results showed that 15 patients had positive cultures (as monoculture in 11 patients and in microbial association in 4 patients). Bacteriuria was found in 4 patients. After transplant, only 6 patients showed isolates at infectious concentrations in microbiologic screening. CONCLUSIONS: Microbiologic screening showed a decreased frequency of pathogenic and conditionally pathogenic isolates in patients after living-donor kidney transplant therefore, it is possible to significantly reduce septic complications. PMID- 26640924 TI - Endoscopic Retrograde Cholangiopancreatography in Kidney Transplant Patients: Results From a Single Center. AB - OBJECTIVES: We report the outcomes of endoscopic retrograde cholangiopancreatography procedures performed for diagnostic and therapeutic purposes in patients who had undergone kidney transplant. MATERIALS AND METHODS: We retrospectively evaluated the records of kidney transplant patients for January 1993 to December 2014. Endoscopic retrograde cholangiopancreatography was carried out using an Olympus JF240 duodenoscope (tip outer diameter 12.6 mm, working channel diameter 3.2 mm). The procedures were performed by Department of Anesthesiology staff while the patients were deeply sedated, given a combination of midazolam plus propofol. RESULTS: Data from 21 kidney transplant patients (16 men and 5 women; mean age at endoscopic retrograde cholangiopancreatography 42.6 +/- 23.4 y) were evaluated. A total of 23 endoscopic retrograde cholangiopancreatography procedures were performed. The indications were choledocholithiasis in 6 patients (28.6%), common bile duct dilatation plus liver enzyme elevations in 4 patients (19%), liver enzyme elevation alone in 4 (19%), biliary necrotizing pancreatitis in 2 (9.6%), and cholangitis in 5 (23.8%). Hepatobiliary ultrasonography findings showed that 3 patients (14.3%) had absence of gallbladder owing to cholecystectomy, 14 (66.7%) had gallstones, 1 (4.7%) had gallstones with cholecystitis findings, and 3 (14.3%) were normal. Endoscopic retrograde cholangiopancreatography findings were normal in 4 patients (19%), showed cholangitis in 2 (9.6%), choledocholithiasis in 10 (47.6%), bile duct wall irregularities in 2 (9.6%), dilated common bile duct in 2 (9.6%), and cholangiocarcinoma in 1 (4.7%). Sphincterotomy was performed in 16 patients. None of the patients who underwent endoscopic retrograde cholangiopancreatography developed any complications, for example, acute pancreatitis, bleeding, duodenal, or bile duct perforation. CONCLUSIONS: In kidney transplant patients, endoscopic retrograde cholangiopancreatography is safe and able to provide substantial information for managing biliopancreatic diseases. PMID- 26640925 TI - Anesthesia Management of a Deceased Cadaveric-Donor Combined Liver and Kidney Transplant for Primary Hyperoxaluria Type 1: Report of a Case. AB - Primary hyperoxaluria type 1 is an autosomal recessive disorder that is responsible for the overproduction of oxalate and has an incidence of 1 in 120 000 live births. Indications for combined liver and kidney transplant are still debated. However, combined liver and kidney transplant is preferred in various conditions, including primary hyperoxaluria, liver-based metabolic abnormalities affecting the kidney, and structural diseases affecting both the liver and the kidney, such as congenital hepatic fibrosis and polycystic kidney disease. When compared with sequential liver and kidney transplant, the rejection rate of both liver and kidney allografts was reported to be lower than with combined liver and kidney transplant. With proper anesthesia management, the probable increased complications with combined liver and kidney transplant can be prevented. In this report, we present the anesthesia care of a 22-year-old patient with primary hyperoxaluria type 1 who had deceased-donor combined liver and kidney transplant. PMID- 26640926 TI - Perioperative Characteristics of Siblings Undergoing Liver or Kidney Transplant. AB - OBJECTIVES: Reasons for chronic liver and kidney failure may vary; sometimes more than 1 family member may be affected, and may require a transplant. The aim of this study was to examine the similarities or differences between the perioperative characteristics of siblings undergoing liver or kidney transplant. MATERIALS AND METHODS: The medical records of 6 pairs of siblings who underwent liver transplant and 4 pairs of siblings who underwent kidney transplant at Baskent University Hospital between 1989 and 2014 were retrospectively analyzed. Collected data included demographic features; comorbidities; reasons for liver and kidney failure; perioperative laboratory values; intraoperative hemodynamic parameters; use and volume of crystalloids, colloids, blood products, cell saver system, and albumin; duration of anesthesia; urine output; and postoperative follow-up data. RESULTS: The mean age of the 6 sibling pairs who underwent liver transplant was 16.3 +/- 12.2 years. All 12 patients had Child-Pugh grade B cirrhosis, with mean disease duration of 7.8 +/- 3.9 years. There were no significant differences between siblings with respect to intraoperative blood product transfusion, crystalloid and colloid fluid replacements, hypotension frequency, blood gas analyses, urinary output, duration of anhepatic phase, inotropic agent administration, postoperative laboratory values, need for mechanical ventilation and vasopressors, occurrence of acute renal failure and infections, and duration intensive care unit stay (P > .05). The mean age of the 4 sibling pairs who underwent kidney transplant was 21.3 +/- 6.4 years, with mean duration of renal insufficiency of 2.2 +/- 1.6 years. There were no significant differences between siblings with respect to intraoperative crystalloid and colloid fluid administration, duration of anesthesia, intraoperative mannitol and furosemide administration, and postoperative laboratory values (P > .05). CONSLUSIONS: In conclusion, the 6 sibling pairs who underwent liver transplant and 4 sibling pairs who underwent kidney transplant in our cohort had similar perioperative characteristics. PMID- 26640927 TI - Late-Onset Drug-Induced Cholestasis in a Living-Related Liver Transplant Donor With Progressive Familial Intrahepatic Cholestasis. AB - We present a rare case of progressive familial intrahepatic cholestasis within a family. A 34-yearold female became a living-related liver transplant donor for her son, who had the disease. Nine years after the transplant, the mother developed severe intrahepatic cholestasis, for which she was evaluated after using an oral contraceptive drug. She presented with jaundice, pruritus, and increased bilirubin levels, together with elevated gamma glutamyl transferase and alkaline phosphatase levels. A liver biopsy revealed findings consistent with intrahepatic cholestasis. However, despite follow-up management and cessation of the insulting drug, her total bilirubin count continuously increased to 20 mg/dL and was accompanied by intractable pruritus. A total of 9 plasmapheresis sessions were performed, and she was started on a regimen of ursodeoxycholic acid (13 mg/kg/d) and cholestyramine (4 g, 3 times daily). The clinical and laboratory picture dramatically improved following cessation of the oral contraceptive, plasmapheresis sessions, and drug treatment. The patient's cholestasis normalized within 3 months, and she recovered uneventfully. A genetic analysis of the whole family revealed that both parents were heterozygous for the mutation c.124G>A in ABCB11, and the son was homozygous for this mutation. These findings supported varying degrees of bile salt export pump deficiency in the family members. Defective bile salt excretory system function can result in a wide spectrum of clinical presentations, ranging from progressive familial intrahepatic cholestasis requiring liver transplant to late-onset drug-induced cholestasis. Our findings suggest that, in a heterozygous carrier of a progressive familial intrahepatic cholestasis mutation, drug-induced cholestasis is responsive to treatment, after which the clinical picture can normalize within 3 months. PMID- 26640928 TI - Awareness of Respiratory Failure Can Predict Early Postoperative Pulmonary Complications in Liver Transplant Recipients. AB - OBJECTIVES: Cardiovascular and respiratory system complications are the most common causes of early mortality after liver transplant. We evaluated the causes of respiratory failure as an early postoperative pulmonary complication in liver transplant recipients. MATERIALS AND METHODS: Patients who underwent orthotropic liver transplant between 2001 and 2014 were retrospectively evaluated. Clinical and demographic variables and pulmonary complications at the first and second visit after transplant were noted. The first visit was within the first week and the second was between 1 and 4 weeks after transplant. An arterial oxygen saturation value below 90% in room air for at least 1 day was considered a medically significant respiratory failure. RESULTS: Our study included 204 (148 men and 56 women; mean age 43.0.4 +/- 13.06 y) adult liver transplant recipients (46 from deceased and 158 from living donors). At the first visit after transplant, 161 patients (79%) had postoperative pulmonary complications, including pleural effusion accompanied by atelectasis (47.1%), only atelectasis (17.2%), and only pleural effusion (10.3%). At the second visit, complications included atelectasis associated with pleural effusion (12.3%) and pneumonia (12.3%). All patients had documented respiratory failure at the first visit, and 92 patients (45.1%) had respiratory failure at the second visit. Causes of respiratory failure at the first visit included atelectasis in 35 patients (17.2%) and atelectasis accompanied by pleural effusion in 96 patients (47.1%). At the second visit, 25 of 161 patients (25.3%) had respiratory failure due to pneumonia. Other causes included atelectasis accompanied by pleural effusion (24.2%) and pleural effusion (23.2%). Ninety-seven patients had no pulmonary complications. The mortality rate was 6.4% within the first visit and 8.7% within the second visit. CONCLUSIONS: Pneumonia, atelectasis, and pleural effusion can cause respiratory failure within the first month after liver transplant. Early pulmonary examination, diagnosis, and treatment can improve patient survival. PMID- 26640929 TI - Pulmonary Hypertension Improves After Orthotopic Liver Transplant in Patients With Chronic Liver Disease. AB - OBJECTIVES: Pulmonary hypertension is a common finding in chronic liver disease patients that has prognostic significance. In this study, we aimed to evaluate the prevalence and severity of pulmonary hypertension in patients undergoing orthotopic liver transplant. We also evaluated pulmonary artery pressure changes after transplant surgery. MATERIALS AND METHODS: The records of adult patients with chronic liver disease who underwent orthotopic liver transplant at our center between 2004 and 2015 were retrospectively evaluated. Clinical and demographic variables and laboratory data were noted. Transthoracic Doppler echocardiographic examination reports were obtained. Using continuous-wave Doppler examination, systolic pulmonary artery pressure values were calculated. Pulmonary hypertension was defined as systolic pulmonary artery pressure >= 30 mm Hg. Among 208 adult patients who underwent orthotopic liver transplant, 203 who had Doppler echocardiographic examination were enrolled. RESULTS: The mean age of patients was 42.1 +/- 14.1 years (range, 16-67 y), and 143 (70.4%) were men. During preoperative assessment, pulmonary hypertension was identified in 47 patients (23.2%), of whom 10 displayed systolic pulmonary artery pressure > 50 mm Hg. Compared with preoperative values of systolic pulmonary artery pressure (46.8 +/- 8.4 mm Hg), a significant reduction in mean values (to 39.3 +/- 13.3 mm Hg) was observed postoperatively (P = .007). CONCLUSIONS: The findings of this study indicate that pulmonary hypertension is a common finding in adult chronic liver disease patients undergoing orthotopic liver transplant. A significant improvement occurs in systolic pulmonary artery pressure values following transplant surgery. Regarding the prevalence and prognostic significance of pulmonary hypertension, all patients with chronic liver disease should be evaluated with transthoracic Doppler echocardiography before transplant. PMID- 26640930 TI - Liver Transplant Outcomes in a Newly Started Program. AB - OBJECTIVES: Kazakhstan is experiencing a high demand for liver transplants. More than 1000 patients have end-stage liver disease in the country, and liver transplant is the only viable option for their treatment. MATERIALS AND METHODS: Liver transplant patients, treated from February 2013 to December 2014, were included in this retrospective analysis. RESULTS: From February 2013 to December 2014, seven patients received a liver transplant in our center (1 pediatric patient was excluded). Deceased liver recipients' (n = 3) median age was 52 years and median Model for End-Stage Liver Disease score 9. The indication for transplant was uncontrolled portal hypertension due to autoimmune liver disease. Cadaveric donors' median age was 45 years. Recipients' intensive care unit stay was > 5 days, time on inotropic support was > 3 days. Mean cold ischemic time was > 6 hours, and secondary ischemic time was 67 minutes. One patient in the deceased donor transplant group died during postoperative week 1 from hepatic artery thrombosis. Living donor liver recipients' (n = 3) median age was 47 years (43-48 y) and median Model for End-Stage Liver Disease score was 17 (range 14 20). Liver disease was hepatitis virus related (hepatitis C virus in 1 patient and hepatitis B and D virus in 2 patients). Mean cold ischemic time was 0.43 hours, and mean secondary ischemic time was 64 minutes. One recipient in the living donor liver group died early in the postoperative period from hemorrhage. CONCLUSIONS: Our experience was insufficient to adequately assess morbidity and survival rates in patients for whom the longest follow-up was 25 months. However, no episodes of rejection were observed. Survival rates between living and deceased donor recipients were equivalent, although cadaveric-donor liver conditions were imperfect. This analysis demonstrates the necessity for timely diagnosis of surgical complications, which accounted for all mortality incidence in our series. PMID- 26640931 TI - Microbiologic Analyses of Patients Before and After Liver Transplant. AB - OBJECTIVES: The aim of this study was to analyze microbiologic screening results of patients before and after liver transplant. MATERIALS AND METHODS: We analyzed the microbiologic screening results (throat and nasal swabs and sputum samples) before and after liver transplant of 16 patients who were treated in the Department of Transplantation at the National Scientific Medical Research Center during 2013 and 2014. Identification of isolates and antibiotic susceptibility testing were performed with the Vitek 2 Automated System (bioMerieux, Chemin de l'Orme 69280 Marcy l'Etoile France). RESULTS: Microbiologic screening results of the respiratory tract before liver transplant showed that 10 of 15 patients (66.6%) had isolates at concentrations of 105 colony-forming units/mL and above. One patient did not receive microbiologic screening. In throat and nasal swabs, 8 patients (53.3%) displayed association of isolates. Throat swab results showed Streptococcus pneumoniae in 6 patients from this group at a concentration of 105 to 106 colony-forming units/mL and above. Enterococcus durans and Enterobacter aerogenes were identified in 1 patient at a concentration of 105 colony-forming units/mL. In nasal swabs, 5 patients (33.3%) showed Staphylococcus aureus and 3 patients (20%) showed Staphylococcus epidermidis (20%) infections. Sputum samples revealed isolates at infectious concentrations in 33.3% of patients. After transplant, microbiologic screening results showed qualitative and quantitative changes in the microbial spectrum of patients. The proportion of patients who had infectious levels of isolates increased to 66.6%. In throat and nasal swabs, isolates were identified as Streptococcus pneumoniae (44.4%), Streptococcus pyogenes (22.2%), Klebsiella pneumoniae (22.2%), and Enterobacter aerogenes (11.1%). CONCLUSIONS: Before transplant, 66.6% of patients showed Streptococcus pneumoniae and Staphylococcus aureus in their respiratory tract. After transplant, there were qualitative and quantitative changes in the microbial spectrum of patients. We found that 40.0% of patients had multidrug-resistant gram-negative isolates. PMID- 26640932 TI - Report of 3 Patients With Urea Cycle Defects Treated With Related Living-Donor Liver Transplant. AB - Urea cycle defects are a group of metabolic disorders caused by enzymatic disruption of the urea cycle pathway, transforming nitrogen to urea for excretion from the body. Severe cases present in early infancy with life-threatening metabolic decompensation, and these episodes of hyperammonemia can be fatal or result in permanent neurologic damage. Despite the progress in pharmacologic treatment, long-term survival is poor especially for severe cases. Liver transplant is an alternative treatment option, providing sufficient enzymatic activity and decreasing the risk of metabolic decompensation. Three patients with urea cycle defects received related living-donor liver transplants at our hospital. Patients presented with late-onset ornithine transcarbamylase deficiency, argininosuccinate lyase deficiency, and citrullinemia. Maximum pretransplant ammonia levels were between 232 and 400 MUmol/L (normal range is 18 72 MUmol/L), and maximum posttransplant values were 52 to 94 MUmol/L. All patients stopped medical treatment and dietary protein restriction for urea cycle defects after transplant. The patient with late-onset ornithine transcarbamylase deficiency already had motor deficits related to recurrent hyperammonemia attacks pretransplant. A major improvement could not be achieved, and he is wheelchair dependent at the age of 6 years. The other 2 patients had normal motor and mental skills before transplant, which have continued 12 and 14 months after transplant. Hepatic artery thrombosis in the patient with the ornithine transcarbamylase deficiency, intraabdominal infection in the patient with argininosuccinate lyase deficiency, and posterior reversible encephalopathy syndrome in the patient with citrullinemia were early postoperative complications. Histopathologic changes in livers explanted from patients with ornithine transcarbamylase deficiency and citrullinemia were nonspecific. The argininosuccinate lyase-deficient patient had portoportal fibrosis and cirrhotic nodule formation. In conclusion, liver transplant was a lifesaving procedure for our patients. Proper timing for transplant is important because high ammonia levels may result in permanent neurologic damage; however, transplant at younger ages also may increase morbidity. PMID- 26640933 TI - Factors Affecting Mortality and Morbidity of Patients With Cirrhosis Hospitalized for Spontaneous Bacterial Peritonitis. AB - OBJECTIVES: Spontaneous bacterial peritonitis, unless originating from surgery or an intra-abdominal source, is an infection diagnosed by neutrophil counts greater than 250/mm3 in ascites. Spontaneous bacterial peritonitis is the most common infection among patients hospitalized with cirrhosis, with a prevalence of 9% and a risk of development among all patients with cirrhosis within 1 year of 10%. No valid parameters have been defined to predict the mortality related to spontaneous bacterial peritonitis. Unless it is treated, the mortality rate as a result of spontaneous bacterial peritonitis is 50%, and serious complications may arise. MATERIALS AND METHODS: Medical records from 29 patients on the deceased donor transplant waiting list and receiving treatment at the Baskent University Hospital Gastroenterology Clinic for cirrhotic ascites infection between 1996 and 2013 were analyzed. Demographic information, paracentesis findings, clinical follow-up, and treatment results were reviewed and collected from patient medical records, with data recorded to the research form. RESULTS: In our patient group, 72.4% were men and the average age was 46.6 years. Most of our patients were at advanced stage, with 55.2% having a Child-Pugh score of C and an average Model for End-Stage Liver Disease score of 17 +/- 4.1. We found that 34.5% of the patients received prophylactic treatment for spontaneous bacterial peritonitis, 72.4% received a proton pump inhibitor, and 82.8% had treatment with intravenous albumin support at the time of diagnosis. Albumin treatment showed no effect on mortality. Mortality rate among patients with Child-Pugh score of C was 81.3%. CONCLUSIONS: Existence of chronic renal failure, liver graft surgery, and hepatocellular cancer did not seem to have a significant effect on patient mortality. The albumin treatment protocol showed no significant difference despite common belief among physicians. PMID- 26640934 TI - Effect of Left Ventricular Assist Devices on Red Blood Cell Distribution Width. AB - OBJECTIVES: Red blood cell distribution width is a measure of the variability in the size of circulating erythrocytes, which is calculated by automated blood cell counters as part of a routine blood cell count analysis. Our aim was to examine whether continuous flow left ventricular assist devices affected red blood cell distribution width. MATERIALS AND METHODS: Our study included 16 of 24 patients who received a HeartWare HVAD Pump (HeartWare Inc, Framingham, MA, USA) implant (continuous flow left ventricular assist device) between April 2012 and February 2015 at our institution. The mean age of the patients was 46.6 years. We compared patient erythrocyte, leucocyte, and platelet counts, hemoglobin and hematocrit levels, mean corpuscular volume, and red blood cell distribution width values before and 6 months after implant. RESULTS: Hemoglobin level (P = .008), hematocrit level (P = .027), and mean corpuscular volume (P = .003) were significantly decreased; however, we observed no significant change in red blood cell distribution width. CONCLUSIONS: Although we did not find significant results in our group of patients with left ventricular assist device implant, a larger group of patients may show more significant results, and an increase in red blood cell distribution width can be used as an indicator of a negative prognosis in these patients. PMID- 26640935 TI - Prevalence, Cause, and Treatment of Respiratory Insufficiency After Orthotopic Heart Transplant. AB - OBJECTIVES: Heart transplant is the best treatment for end-stage heart failure. Respiratory insufficiency after heart transplant is a potentially serious complication. Pulmonary complications, pulmonary hypertension, allograft failure or rejection, and structural heart defects in the donor heart are among the causes of hypoxemia after transplant. In this study, we evaluated the prevalence of hypoxemia and respiratory insufficiency in patients with orthotopic heart transplant during the early postoperative period. MATERIALS AND METHODS: We retrospectively evaluated the medical records of 45 patients who had received orthotopic heart transplant at our center. Clinical and demographic variables and laboratory data were noted. Oxygen saturation values from patients in the first week and the first month after transplant were analyzed. We also documented the cause of respiratory insufficiency and the type of treatment. RESULTS: Mean age was 35.3 +/- 15.3 years (range, 12-61 y), with males comprising 32 of 45 patients (71.1%). Two patients had mild chronic obstructive pulmonary disease and 1 had asthma. Twenty-five patients (55.6%) had a history of smoking. Respiratory insufficiency was noted in 9 patients (20%) during the first postoperative week. Regarding cause, 5 of these patients (11.1%) had pleural effusion, 2 (4.4%) had atelectasis, 1 (2.2%) had pneumonia, and 1 (2.2%) had acute renal failure. Therapies administered to patients with respiratory insufficiency were as follows: 5 patients had oxygen therapy with nasal canula/mask, 3 patients had continuous positive airway pressure, and 1 patient had mechanical ventilation. One month after transplant, 2 patients (4.4%) had respiratory insufficiency 1 (2.2%) due to pleural effusion and 1 (2.2%) due to atelectasis. CONCLUSIONS: Respiratory insufficiency is a common complication in the first week after orthotopic heart transplant. Identification of the underlying cause is an important indicator for therapy. With appropriate care, respiratory insufficiency can be treated successfully. PMID- 26640936 TI - Catamenial Pneumothorax. AB - The Spanish congress of the European association of pulmonologists and thoracic surgeons, held in 2009, confirmed the international classification of spontaneous pneumothorax in which catamenial (menstrual) pneumothorax was identified. Different from usual pneumothorax, its reason is not because of bleb disease in the lungs, but rather, caused by menstrual cycle in women. The cause was partly studied and explained by several theories. By the first of them, congenital defects (holes, fenestrations) in the diaphragm allow air to get into pleural space because of increased permeability of the fallopian tubes during menstruation. The second hypothesis, the same mechanism is considered, but it has been supposed that a hole in the diaphragm can be caused by endometriosis. The third theory, endometriosis of a pulmonary parenchyma can create leak of air during menstruation. The fourth theory, significance is attached to production of F2 prostaglandin, which is a powerful broncho- and vasoconstriction agent, causing ruptures of alveoli in women in the period of the woman's menstrual cycle. Two groups of patients were identified: with a defect in the diaphragm and without. Existence of such defects is described in 50% of cases. Having a wide clinical experience in the field of thoracic surgery, we, for the first time in practice, diagnosed catamenial pneumothorax in patients with the recurrence course of the disease. PMID- 26640937 TI - Predictive Value of Hematologic Parameters for Detecting Asymptomatic Graft Rejection After Heart Transplant: Preliminary Results. AB - OBJECTIVES: Hematologic parameters, such as mean platelet volume, red-cell distribution width, and neutrophil-to-lymphocyte ratio, have prognostic value in multiple cardiac conditions such as stable angina pectoris, acute coronary syndromes, and heart failure. However, no previous studies have evaluated the association between hematologic parameters and asymptomatic graft rejection after heart transplant. We evaluated the role of hematologic parameters for detecting asymptomatic graft rejection after heart transplant. MATERIALS AND METHODS: We retrospectively evaluated medical records of 47 adult patients who underwent orthotopic heart transplant between February 25, 2005, and July 6, 2014, in our hospital, noting their hematologic parameters before each biopsy. Two groups were created according to biopsy results: rejection and no-rejection. RESULTS: We excluded 4 patients who died during the first month posttransplant owing to early complications. We evaluated 422 endomyocardial biopsy results of 43 adult patients (mean age, 43.4 +/- 11.4 y; 14 women). Mean follow-up was 33 months. A total of 109 biopsies performed because of clinical suspicion of rejection were excluded. Red-cell distribution width levels were similar between groups (17.2% +/- 2.6% in the rejection group and 17.1% +/- 2.5% in the no-rejection group; P = .856). Neutrophil-to-lymphocyte ratio was similar between groups (7.8 +/- 9.9 in the rejection group and 8.2 +/- 9.7 in the no-rejection group; P = .791). Mean platelet volume levels were significantly lower in the rejection group (8.3 +/- 1.3 fL) than in the no-rejection group (8.8 +/- 1.8 fL) (P = .037) (Table 1). CONCLUSIONS: According to our results, only lower mean platelet volume levels were significantly associated with asymptomatic graft rejection in patients with a transplanted heart. More detailed analyses are needed to exclude the effects of immunosuppressant drugs, and further studies are needed to clarify the exact role of hematologic parameters for detecting asymptomatic rejection after heart transplant. PMID- 26640938 TI - Left Ventricular Assist Device Results: Single Center Experience. AB - OBJECTIVES: The number of patients with end-stage cardiac failure who are waiting for transplant has been increasing, although number of heart donations stays limited. This has resulted in an increased use of left ventricular assist devices. Here, we present results of patients who received left ventricular assist device implants at Baskent University Ankara Hospital. MATERIALS AND METHODS: We retrospectively evaluated 24 patients who received a HeartWare left ventricular assist device (HeartWare Inc, Framingham, MA, USA) between April 2012 and February 2015; 2 patients (8.33%) were female. RESULTS: Patients had end stage heart failure as a result of the following causes: 11 patients (45%) had ischemic cardiomyopathy, 12 patients (50%) had dilated cardiomyopathy, and 1 patient (4.1%) had acute myocarditis. Regarding use of the left ventricular assist device, 10 patients (41.6%) had the device as destination therapy, and the remaining 14 patients (48.6%) had it as bridge to transplant. The Interagency Registry for Mechanically Assisted Circulatory Support Profile was 1 for 3 patients (12.5%), 2 for 9 patients (37.5%), and 3 for 12 patients (50%). Mean follow-up was 239.8 days, and the mortality rate was 33.3% (8 patients died). During follow-up, we found that 3 patients (12.5%) had received a heart transplant and 1 patient (4.1%) eventually recovered, with the device extracted. Six patients had driveline infections, and 3 patients had cerebrovascular events. CONCLUSIONS: With the insufficient number of cardiac donors, use of a left ventricular assist device for patients with end-stage cardiac failure who are awaiting transplant may be the best option. PMID- 26640939 TI - Valve Repair: A "Bridge" to Heart Transplant. AB - Cardiac transplants are limited because of a deficiency of donor organs. Most recipients with severe chronic heart failure are on a waiting list. Therefore, palliative surgical treatment of chronic heart failure is widely used. We report a case of successful application of palliative surgical approach for a patient with decompensated heart failure. PMID- 26640940 TI - Fetal Renal Stem Cell Transplant in Nephrotic and Nonnephrotic Glomerulonephritis with Stage 2-4 Chronic Kidney Disease: Potential Effect on Proteinuria and Glomerular Filtration Rate. AB - OBJECTIVES: Proteinuria is a major cause of glomerulosclerosis progression in glomerular diseases, and the development of end-stage renal disease is more rapid in nephrotic patients than in nonnephrotic ones. The renal parenchyma is less regenerable because it is a tissue consisting of renal cells. Thus, stem cells obtained from fetal kidney tissue might be effective for reducing proteinuria and delaying glomerulosclerosis in these patients. MATERIALS AND METHODS: This report presents preliminary data from a prospective cohort study that included 17 patients with chronic glomerulonephritis in stage 2 to 4 chronic kidney disease who completed 3 visits during 1 year of follow-up. Fetal renal stem cells (multiple cells in suspension) were injected into the patient every 6 months. Patients were divided into 2 groups according to their nephrotic status, and 24 hour maximal proteinuria was recorded for at least 6 months (first group with proteinuria < 3.5 g/24 h, and second group with proteinuria > 3.5 g/24 h). RESULTS: During follow-up, group 1 was observed to have stable hemoglobin and total protein levels but significantly decreased albumin levels and glomerular filtration rates. In group 2, total protein with serum albumin significantly increased, and proteinuria and glomerular filtration rates significantly decreased. There was no significant difference in glomerular filtration rate decline between groups. CONCLUSIONS: Treatment with fetal renal stem cells significantly decreased proteinuria in nephrotic patients. However, this outcome also might have resulted from a reduction in glomerular filtration rate. Further studies with a larger number of patients and a control group would help to achieve better results that measure the efficacy of this treatment. PMID- 26640941 TI - Fetal Pancreatic Stem-Cell Transplant in Patients With Diabetes Mellitus. AB - OBJECTIVES: To determine the efficacy of fetal stem cell transplant for treating patients with diabetes mellitus types 1 and 2. MATERIALS AND METHODS: Five patients with diabetes mellitus type 1 and 5 patients with diabetes mellitus type 2 (aged 18-56 years) received a fetal pancreatic stem-cell transplant (cells were 16-18 wk gestation) performed by intravenous infusion at 50 mL/hour. The quantity of fetal stem cells infused was >= 5-8*106. We analyzed the patients' C-peptide and glycated hemoglobin levels both before and 3 months after fetal stem cell transplant. RESULTS: In patients with diabetes mellitus type 1, fetal stem-cell transplant led to a significant increase in C-peptide levels, from 0.09 +/- 0.01 ng/mL to 0.20 +/- 0.07 ng/mL, after 3 months (P < .008). CONCLUSIONS: Treatment with fetal pancreatic stem cells may be beneficial for treating patients with type 1 or type 2 diabetes. PMID- 26640942 TI - Standard Treatment in Adults: Which Steroid? Or without Steroids? AB - KEY MESSAGES: (1) Standard treatment of autoimmune hepatitis in adults should be steroid based. In early trials, prednisolone +/- azathioprine was superior to the azathioprine mono-therapy (which was not significantly better than placebo). Prednisolone plus azathioprine has similar efficacy to, but is better tolerated than a higher-dose of prednisolone alone and therefore has become standard therapy. (2) In most treated patients, serum transaminases and globulin/IgG fall, but percentage attaining normal values within 6 months varies between 10 and 90%. Patients failing to do so have a worse longer-term outcome. (3) A higher initial prednisolone dose (1 mg/kg/day) plus azathioprine achieved 76% serum transaminase normalisation after 6 months but needs longer-term evaluation. (4) Histological remission (minimal hepatitis on re-biopsy) lags behind transaminase normalisation by 6-12 months and is achieved in 55-70% of patients after 24-36 months prednisolone. This lag and the inefficacy of azathioprine mono-therapy justifies continuing prednisolone (5-10 mg/day), even after transaminase normalisation, for a total of >2 years. (5) Repeat biopsy should be considered because 40-60% of patients still have (usually mild) persisting inflammation, despite normal serum transaminases and IgG. In such patients, fibrosis is less likely to regress and long-term mortality is higher. (6) In a large trial, non-cirrhotic treatment naive patients given budesonide (9 mg/day) plus azathioprine were more likely to achieve normal serum ALT after 6 months than those receiving prednisolone plus azathioprine and had less side effects. This trial was short term in nature and lacked follow-up histology. Budesonide is recommended in non-cirrhotic patients who develop prednisolone-related side effects. In an open study of mycophenolate plus prednisolone, 88% of treatment-naive patients achieved normal serum transaminases. However, half relapsed during or after steroid withdrawal and only one of eight re-biopsied patients achieved histological remission. Mycophenolate is teratogenic, limiting its use in younger women. CONCLUSION: Despite its limitations, no regime has yet been shown clearly to be better than prednisolone and azathioprine-based therapy. PMID- 26640943 TI - Diagnosis, Differential Diagnosis, and Epidemiology of Primary Sclerosing Cholangitis. AB - According to recent guidelines, primary sclerosing cholangitis (PSC) is diagnosed when a patient has a cholestatic liver enzyme profile, characteristic bile duct changes on imaging, and when secondary causes of sclerosing cholangitis are excluded. In patients with a clinical suspicion but normal cholangiography, a liver biopsy is indicated to establish a diagnosis of small duct PSC. Several other disease entities such as IgG4-associated cholangitis (IAC), cholangiocarcinoma (CCA), and secondary causes of sclerosing cholangitis such as choledocholithiasis, AIDS-cholangiopathy, ischemia, surgical bile duct trauma, or mast cell cholangiopathy can mimic PSC. IAC can be differentiated from PSC by applying the HISORt criteria including the serum IgG4 level. In cases where serum IgG4 is less than 2 * ULN, the ratio of IgG4/IgG1 >0.24 is indicative for IAC. Choledocholithiasis with recurrent cholangitis as a cause of sclerosing cholangitis can pose a conundrum, since PSC itself is associated with an increased prevalence of gallstones. The epidemiology of PSC worldwide has been poorly described. Incidence and prevalence rates vary from 0-1.3 and 0-16.2 per 100,000 inhabitants respectively. However, these figures are not based on population-based cohorts. A recent large population-based cohort from the Netherlands reported an incidence of 0.5 and a prevalence of 6/100,000. Approximately 10% fulfil the criteria for small duct PSC. At diagnosis of PSC, concurrent inflammatory bowel disease (IBD), primarily ulcerative colitis or Crohn's colitis is present in 50%, but increasing to 80%, 10 years or more after diagnosis. Conversely, 3% of IBD patients will develop PSC. PSC predisposes to malignancy. The estimated cumulative risk of developing CCA after 30 years is 20%. For colorectal carcinoma in PSC/colitis patients, the estimated cumulative risk at 30 years is 13%. PMID- 26640944 TI - Transcriptomic Analysis and the Expression of Disease-Resistant Genes in Oryza meyeriana under Native Condition. AB - Oryza meyeriana (O. meyeriana), with a GG genome type (2n = 24), accumulated plentiful excellent characteristics with respect to resistance to many diseases such as rice shade and blast, even immunity to bacterial blight. It is very important to know if the diseases-resistant genes exist and express in this wild rice under native conditions. However, limited genomic or transcriptomic data of O. meyeriana are currently available. In this study, we present the first comprehensive characterization of the O. meyeriana transcriptome using RNA-seq and obtained 185,323 contigs with an average length of 1,692 bp and an N50 of 2,391 bp. Through differential expression analysis, it was found that there were most tissue-specifically expressed genes in roots, and next to stems and leaves. By similarity search against protein databases, 146,450 had at least a significant alignment to existed gene models. Comparison with the Oryza sativa (japonica-type Nipponbare and indica-type 93-11) genomes revealed that 13% of the O. meyeriana contigs had not been detected in O. sativa. Many diseases-resistant genes, such as bacterial blight resistant, blast resistant, rust resistant, fusarium resistant, cyst nematode resistant and downy mildew gene, were mined from the transcriptomic database. There are two kinds of rice bacterial blight resistant genes (Xa1 and Xa26) differentially or specifically expressed in O. meyeriana. The 4 Xa1 contigs were all only expressed in root, while three of Xa26 contigs have the highest expression level in leaves, two of Xa26 contigs have the highest expression profile in stems and one of Xa26 contigs was expressed dominantly in roots. The transcriptomic database of O. meyeriana has been constructed and many diseases-resistant genes were found to express under native condition, which provides a foundation for future discovery of a number of novel genes and provides a basis for studying the molecular mechanisms associated with disease resistance in O. meyeriana. PMID- 26640945 TI - Tissue-Specific Contributions of Paternally Expressed Gene 3 in Lactation and Maternal Care of Mus musculus. AB - Paternally Expressed Gene 3 (Peg3) is an imprinted gene that controls milk letdown and maternal-caring behaviors. In this study, a conditional knockout allele has been developed in Mus musculus to further characterize these known functions of Peg3 in a tissue-specific manner. The mutant line was first crossed with a germline Cre. The progeny of this cross displayed growth retardation phenotypes. This is consistent with those seen in the previous mutant lines of Peg3, confirming the usefulness of the new mutant allele. The mutant line was subsequently crossed individually with MMTV- and Nkx2.1-Cre lines to test Peg3's roles in the mammary gland and hypothalamus, respectively. According to the results, the milk letdown process was impaired in the nursing females with the Peg3 mutation in the mammary gland, but not in the hypothalamus. This suggests that Peg3's roles in the milk letdown process are more critical in the mammary gland than in the hypothalamus. In contrast, one of the maternal-caring behaviors, nest-building, was interrupted in the females with the mutation in both MMTV- and Nkx2.1-driven lines. Overall, this is the first study to introduce a conditional knockout allele of Peg3 and to further dissect its contribution to mammalian reproduction in a tissue-specific manner. PMID- 26640946 TI - Fine Dissection of Human Mitochondrial DNA Haplogroup HV Lineages Reveals Paleolithic Signatures from European Glacial Refugia. AB - Genetic signatures from the Paleolithic inhabitants of Eurasia can be traced from the early divergent mitochondrial DNA lineages still present in contemporary human populations. Previous studies already suggested a pre-Neolithic diffusion of mitochondrial haplogroup HV*(xH,V) lineages, a relatively rare class of mtDNA types that includes parallel branches mainly distributed across Europe and West Asia with a certain degree of structure. Up till now, variation within haplogroup HV was addressed mainly by analyzing sequence data from the mtDNA control region, except for specific sub-branches, such as HV4 or the widely distributed haplogroups H and V. In this study, we present a revised HV topology based on full mtDNA genome data, and we include a comprehensive dataset consisting of 316 complete mtDNA sequences including 60 new samples from the Italian peninsula, a previously underrepresented geographic area. We highlight points of instability in the particular topology of this haplogroup, reconstructed with BEAST-generated trees and networks. We also confirm a major lineage expansion that probably followed the Late Glacial Maximum and preceded Neolithic population movements. We finally observe that Italy harbors a reservoir of mtDNA diversity, with deep rooting HV lineages often related to sequences present in the Caucasus and the Middle East. The resulting hypothesis of a glacial refugium in Southern Italy has implications for the understanding of late Paleolithic population movements and is discussed within the archaeological cultural shifts occurred over the entire continent. PMID- 26640947 TI - Construction of a Genome-Scale Metabolic Model of Arthrospira platensis NIES-39 and Metabolic Design for Cyanobacterial Bioproduction. AB - Arthrospira (Spirulina) platensis is a promising feedstock and host strain for bioproduction because of its high accumulation of glycogen and superior characteristics for industrial production. Metabolic simulation using a genome scale metabolic model and flux balance analysis is a powerful method that can be used to design metabolic engineering strategies for the improvement of target molecule production. In this study, we constructed a genome-scale metabolic model of A. platensis NIES-39 including 746 metabolic reactions and 673 metabolites, and developed novel strategies to improve the production of valuable metabolites, such as glycogen and ethanol. The simulation results obtained using the metabolic model showed high consistency with experimental results for growth rates under several trophic conditions and growth capabilities on various organic substrates. The metabolic model was further applied to design a metabolic network to improve the autotrophic production of glycogen and ethanol. Decreased flux of reactions related to the TCA cycle and phosphoenolpyruvate reaction were found to improve glycogen production. Furthermore, in silico knockout simulation indicated that deletion of genes related to the respiratory chain, such as NAD(P)H dehydrogenase and cytochrome-c oxidase, could enhance ethanol production by using ammonium as a nitrogen source. PMID- 26640948 TI - Performance of the Interferon Gamma Release Assays in Tuberculosis Disease in Children Five Years Old or Less. AB - Interferon Gamma Release Assays (IGRAs) were developed for the indirect or immunologic diagnosis of tuberculosis infection; however, they have also been used to assist in difficult to diagnose cases of tuberculosis disease in adults, and to a lesser extent, in children, especially in those under 5 years old. We evaluated the utility of using an IGRA in pediatric tuberculosis in younger children in a hospital setting. The diagnostic accuracy of T-SPOT.TB and TST was assessed in 117 children with active tuberculosis and 413 children with respiratory tract infection. Sensitivity and specificity were calculated for the tests used individually and together. Concordance was also calculated. Sensitivity of T-SPOT.TB (82.9%) was higher than TST (78.6% using a 5mm cut-off), especially in children confirmed to have TB. T-SPOT.TB was more specific than TST using a 5mm cut-off (96.1% vs. 70.9%). Combining T-SPOT.TB and TST results improved the sensitivity to 96.6%. In conclusion, the results of the current study indicate that T-SPOT.TB has good sensitivity and specificity, supporting its use among patients of this age. A combination of IGRA and TST would be useful additions to assist in the diagnosis of childhood TB. PMID- 26640949 TI - Cholera Toxin B Subunit Shows Transneuronal Tracing after Injection in an Injured Sciatic Nerve. AB - Cholera toxin B subunit (CTB) has been extensively used in the past for monosynaptic mapping. For decades, it was thought to lack the ability of transneuronal tracing. In order to investigate whether biotin conjugates of CTB (b-CTB) would pass through transneurons in the rat spinal cord, it was injected into the crushed left sciatic nerve. For experimental control, the first order afferent neuronal projections were defined by retrograde transport of fluorogold (FG, a non-transneuronal labeling marker as an experimental control) injected into the crushed right sciatic nerve in the same rat. Neurons containing b-CTB or FG were observed in the dorsal root ganglia (DRG) at the L4-L6 levels ipsilateral to the tracer injection. In the spinal cord, b-CTB labeled neurons were distributed in all laminae ipsilaterally between C7 and S1 segments, but labeling of neurons at the cervical segment was abolished when the T10 segment was transected completely. The interneurons, distributed in the intermediate gray matter and identified as gamma-aminobutyric acid-ergic (GABAergic), were labeled by b-CTB. In contrast, FG labeling was confined to the ventral horn neurons at L4 L6 spinal segments ipsilateral to the injection. b-CTB immunoreactivity remained to be restricted to the soma of neurons and often appeared as irregular patches detected by light and electron microscopy. Detection of monosialoganglioside (GM1) in b-CTB labeled neurons suggests that GM1 ganglioside may specifically enhance the uptake and transneuronal passage of b-CTB, thus supporting the notion that it may be used as a novel transneuronal tracer. PMID- 26640950 TI - Investigation of FOXM1 as a Potential New Target for Melanoma. AB - Recent studies have shown that immunotherapies and molecular targeted therapies are effective for advanced melanoma. Non-antigen-specific immunotherapies such as immunocheckpoint blockades have been shown to be effective in the treatment of advanced melanoma. However, the response rates remain low. To improve their efficacy, they should be combined with antigen-specific immunotherapy. Elevated expression of the transcription factor, Forkhead box M1 (FOXM1), has been reported in various human cancers, and it has been shown to have potential as a target for immunotherapy. The purpose of this study was to investigate the FOXM1 expression in human melanoma samples and cell lines, to evaluate the relationship between the FOXM1 expression and the clinical features of melanoma patients and to investigate the association between the FOXM1 and MAPK and PI3K/AKT pathways in melanoma cell lines. We conducted the quantitative reverse transcription PCR (qRT-PCR) and Western blotting analyses of melanoma cell lines, and investigated melanoma and nevus tissue samples by qRT-PCR and immunohistochemistry. We performed MEK siRNA and PI3K/AKT inhibitor studies and FOXM1 siRNA studies in melanoma cell lines. We found that FOXM1 was expressed in all of the melanoma cell lines, and was expressed in 49% of primary melanomas, 67% of metastatic melanomas and 10% of nevi by performing immunohistochemical staining. Metastatic melanoma samples exhibited significantly higher mRNA levels of FOXM1 (p = 0.004). Primary melanomas thicker than 2 mm were also more likely to express FOXM1. Patients whose primary melanoma expressed FOXM1 had a significantly poorer overall survival compared to patients without FOXM1 expression (p = 0.024). Downregulation of FOXM1 by siRNA significantly inhibited the proliferation of melanoma cells, and blockade of the MAPK and PI3K/AKT pathways decreased the FOXM1 expression in melanoma cell lines. In conclusion, FOXM1 is considered to be a new therapeutic target for melanoma. PMID- 26640951 TI - Allergic Non-Asthmatic Adults Have Regional Pulmonary Responses to Segmental Allergen Challenge. AB - BACKGROUND: Allergic non-asthmatic (ANA) adults experience upper airway symptoms of allergic disease such as rhinorrhea, congestion and sneezing without symptoms of asthma. The aim of this study was to utilize PET-CT functional imaging to determine whether allergen challenge elicits a pulmonary response in ANA subjects or whether their allergic disease is truly isolated to the upper airways. METHODS: In 6 ANA subjects, bronchoalveolar lavages (BAL) were performed at baseline and 24h after instillation of an allergen and a diluent in separate lung lobes. After instillation (10h), functional imaging was performed to quantify and compare regional perfusion, ventilation, fractional gas content (Fgas), and glucose uptake rate (Ki) between the baseline, diluent and allergen lobes. BAL cell counts were also compared. RESULTS: In ANA subjects, compared to the baseline and diluent lobes, perfusion and ventilation were significantly lower in the allergen lobe (median [inter-quartile range], baseline vs. diluent vs. allergen: Mean-normalized perfusion; 0.87 [0.85-0.97] vs. 0.90 [0.86-0.98] vs. 0.59 [0.55-0.67]; p<0.05. Mean-normalized ventilation 0.89 [0.88-0.98] vs. 0.95 [0.89-1.02] vs. 0.63 [0.52-0.67], p<0.05). In contrast, no significant differences were found in Fgas between baseline, diluent and allergen lobes or in Ki. Total cell counts, eosinophil and neutrophil cell counts (cells/ml BAL) were significantly greater in the allergen lobe compared to the baseline lobe (all P<0.05). CONCLUSIONS: Despite having no clinical symptoms of a lower airway allergic response (cough and wheeze) allergic non-asthmatic subjects have a pulmonary response to allergen exposure which manifests as reduced ventilation and perfusion. PMID- 26640952 TI - The Isoquinolone Derived Prolyl Hydroxylase Inhibitor ICA Is a Potent Substrate of the Organic Anion Transporters 1 and 3. AB - OBJECTIVE: Many cellular responses to hypoxia are mediated by the transcription factor complex hypoxia-inducible factor (HIF). HIF stability is governed by a family of dioxygenases called HIF prolyl hydroxylases (PHDs). Isoquinolone derived PHD inhibitors, like 2-(1-chloro-4-hydroxyisoquinoline-3-carboxamido) acetate (ICA), which stabilize the intracellular HIF-alpha have been suggested as a potentially beneficial therapeutic strategy for the treatment of disorders associated with ischemia. To stabilize HIF-alpha, ICA has to be taken up into proximal tubule cells (PCTs) across the basolateral membrane by one of the organic anion transporters 1, 2 or 3 (OAT1, OAT2 or OAT3). The release into the urine across the luminal membrane may be mediated by OAT4. METHOD: To demonstrate interaction of ICA with human OAT1, OAT2, OAT3 and OAT4, ICA was tested on these transporters stably transfected in HEK293 cells by using p-aminohippurate (PAH), cGMP and estrone-3-sulfate (ES) as reference substrates, respectively. RESULTS: Uptakes of PAH and ES in OAT1- and OAT3-transfected HEK293 cells were inhibited by ICA with half-maximal inhibition values of 0.29 +/- 0.05 and 2.58 +/- 0.16 uM, respectively. OAT2 was less sensitive to ICA. Efflux experiments identified ICA as an OAT1 and OAT3 substrate. Preloading OAT4-transfected HEK293 cells with ICA stimulated ES uptake by 18.3 +/- 3.8%. CONCLUSION: The uptake of ICA across the basolateral membrane of PCTs occurs mainly by OAT1 and the efflux into the tubular lumen by OAT4. PMID- 26640954 TI - Collective Motion in a Network of Self-Propelled Agent Systems. AB - Collective motions of animals that move towards the same direction is a conspicuous feature in nature. Such groups of animals are called a self-propelled agent (SPA) systems. Many studies have been focused on the synchronization of isolated SPA systems. In real scenarios, different SPA systems are coupled with each other forming a network of SPA systems. For example, a flock of birds and a school of fish show predator-prey relationships and different groups of birds may compete for food. In this work, we propose a general framework to study the collective motion of coupled self-propelled agent systems. Especially, we study how three different connections between SPA systems: symbiosis, predator-prey, and competition influence the synchronization of the network of SPA systems. We find that a network of SPA systems coupled with symbiosis relationship arrive at a complete synchronization as all its subsystems showing a complete synchronization; a network of SPA systems coupled by predator-prey relationship can not reach a complete synchronization and its subsystems converges to different synchronized directions; and the competitive relationship between SPA systems could increase the synchronization of each SPA systems, while the network of SPA systems coupled by competitive relationships shows an optimal synchronization for small coupling strength, indicating that small competition promotes the synchronization of the entire system. PMID- 26640955 TI - Stable Pseudohyphal Growth in Budding Yeast Induced by Synergism between Septin Defects and Altered MAP-kinase Signaling. AB - Upon nutrient limitation, budding yeasts like Saccharomyces cerevisiae can be induced to adopt alternate filament-like growth patterns called diploid pseudohyphal or invasive haploid growth. Here, we report a novel constitutive pseudohyphal growth state, sharing some characteristics with classic forms of filamentous growth, but differing in crucial aspects of morphology, growth conditions and genetic regulation. The constitutive pseudohyphal state is observed in fus3 mutants containing various septin assembly defects, which we refer to as sadF growth (septin assembly defect induced filamentation) to distinguish it from classic filamentation pathways. Similar to other filamentous states, sadF cultures comprise aggregated chains of highly elongated cells. Unlike the classic pathways, sadF growth occurs in liquid rich media, requiring neither starvation nor the key pseudohyphal proteins, Flo8p and Flo11p. Moreover sadF growth occurs in haploid strains of S288C genetic background, which normally cannot undergo pseudohyphal growth. The sadF cells undergo highly polarized bud growth during prolonged G2 delays dependent on Swe1p. They contain septin structures distinct from classical pseudo-hyphae and FM4-64 labeling at actively growing tips similar to the Spitzenkorper observed in true hyphal growth. The sadF growth state is induced by synergism between Kss1p-dependent signaling and septin assembly defects; mild disruption of mitotic septins activates Kss1p dependent gene expression, which exacerbates the septin defects, leading to hyper activation of Kss1p. Unlike classical pseudo-hyphal growth, sadF signaling requires Ste5, Ste4 and Ste18, the scaffold protein and G-protein beta and gamma subunits from the pheromone response pathway, respectively. A swe1 mutation largely abolished signaling, breaking the positive feedback that leads to amplification of sadF signaling. Taken together, our findings show that budding yeast can access a stable constitutive pseudohyphal growth state with very few genetic and regulatory changes. PMID- 26640953 TI - Prognostic Value of the Fibrosis-4 Index in Human Immunodeficiency Virus Type-1 Infected Patients Initiating Antiretroviral Therapy with or without Hepatitis C Virus. AB - OBJECTIVE: To evaluate the Fibrosis (FIB)-4 index as a predictor of major liver related events (LRE) and liver-related death (LRD) in human immunodeficiency virus (HIV) type-1 patients initiating combination antiretroviral therapy (cART). DESIGN: Retrospective analysis of a prospective cohort study. SETTING: Italian HIV care centers participating to the ICONA Foundation cohort. PARTICIPANTS: Treatment-naive patients enrolled in ICONA were selected who: initiated cART, had hepatitis C virus (HCV) serology results, were HBsAg negative, had an available FIB-4 index at cART start and during follow up. METHODS: Cox regression models were used to determine the association of FIB4 with the risk of major LRE (gastrointestinal bleeding, ascites, hepatic encephalopathy, hepato-renal syndrome or hepatocellular carcinoma) or LRD. RESULTS: Three-thousand four hundred seventy-five patients were enrolled: 73.3% were males, 27.2% HCV seropositive. At baseline (time of cART initiation) their median age was 39 years, had a median CD4+ T cell count of 260 cells/uL, and median HIV RNA 4.9 log copies/mL, 65.9% had a FIB-4 <1.45, 26.4% 1.45-3.25 and 7.7% >3.25. Over a follow up of 18,662 person-years, 41 events were observed: 25 major LRE and 16 LRD (incidence rate, IR, 2.2 per 1,000 PYFU [95% confidence interval, CI 1.6-3.0]). IR was higher in HCV seropositives as compared to negatives (5.9 vs 0.5 per 1,000 PYFU). Higher baseline FIB-4 category as compared to <1.45 (FIB-4 1.45-3.25: HR 3.55, 95% CI 1.09-11.58; FIB-4>3.25: HR 4.25, 1.21-14.92) and time-updated FIB-4 (FIB-4 1.45-3.25: HR 3.40, 1.02-11.40; FIB-4>3.25: HR 21.24, 6.75-66.84) were independently predictive of major LRE/LRD, after adjusting for HIV- and HCV related variables, alcohol consumption and type of cART. CONCLUSIONS: The FIB-4 index at cART initiation, and its modification over time are risk factors for major LRE or LRD, independently of infection with HCV and could be used to monitor patients on cART. PMID- 26640956 TI - Low Efficacy of Pegylated Interferon plus Ribavirin plus Nitazoxanide for HCV Genotype 4 and HIV Coinfection. AB - BACKGROUND: Nitazoxanide (NTZ) plus pegylated interferon and ribavirin (Peg IFN/RBV) improved the sustained virological response (SVR) achieved with Peg IFN/RBV in hepatitis C virus genotype 4 (HCV-4)-monoinfected patients. There are no data currently on the efficacy of Peg-IFN/RBV plus NTZ for human immunodeficiency virus (HIV)/HCV-4 coinfection. Therefore, the objectives of this clinical trial were to assess the efficacy and to evaluate the safety of Peg IFN/RBV plus NTZ in HIV/HCV-4-coinfected patients. PATIENTS AND METHODS: This was an open-label, single arm, multicenter phase II pilot clinical trial (NCT01529073) enrolling HIV-infected individuals with HCV-4 chronic infection, naive to HCV therapy. Patients were treated with NTZ 500 mg bid for 4 weeks, followed by NTZ 500 mg bid plus Peg-IFN alpha-2b 1.5 MUg/kg/week plus weight adjusted RBV during 48 weeks. Analyses were done by intention-to-treat (ITT, missing = failure). A historical cohort of HIV/HCV-4-infected patients treated with Peg-IFN alpha-2b and RBV at the same area was used as control. RESULTS: Two (9.5%) of 21 patients included in the trial compared with 5 (21.7%) of 23 patients included in the historical cohort achieved SVR (SVR risk difference, 12.2%; 95% confidence interval, -33.2% to 8.8%; p = 0.416). Virological failure was due to lack of response in 13 (62%) individuals recruited in the trial. Two (9.5%) patients included in the trial and two (9.5%) individuals from the historical cohort discontinued permanently due to adverse events. CONCLUSIONS: No increase in SVR was observed among HIV/HCV-4-coinfected patients receiving Peg IFN/RBV plus NTZ compared with a historical cohort treated with Peg-IFN/RBV. Interruptions due to adverse events of Peg-IFN/RBV plus NTZ were similar to those of dual therapy. TRIAL REGISTRATION: ClinicalTrials.gov NCT01529073. PMID- 26640958 TI - One-Pot Synthesis of Strained Macrocyclic Pyridone Hexamers and Their High Selectivity toward Cu(2+) Recognition. AB - The removal of Cu(2+) ions is relevant to environmental pollution control and neurodegenerative disease treatment. A novel family of strained macrocyclic pyridone hexamers, which exhibit highly selective recognition of Cu(2+) ions and reduce copper content in artificial seawater by 97% at a very low [host]:[CuCl2] molar ratio of 2:1, is documented. PMID- 26640957 TI - Comparison of Gene Expression by Sheep and Human Blood Stimulated with the TLR4 Agonists Lipopolysaccharide and Monophosphoryl Lipid A. AB - BACKGROUND: Animal models that mimic human biology are important for successful translation of basic science discoveries into the clinical practice. Recent studies in rodents have demonstrated the efficacy of TLR4 agonists as immunomodulators in models of infection. However, rodent models have been criticized for not mimicking important characteristics of the human immune response to microbial products. The goal of this study was to compare genomic responses of human and sheep blood to the TLR4 agonists lipopolysaccharide (LPS) and monophosphoryl lipid A (MPLA). METHODS: Venous blood, withdrawn from six healthy human adult volunteers (~ 28 years old) and six healthy adult female sheep (~3 years old), was mixed with 30 MUL of PBS, LPS (1MUg/mL) or MPLA (10MUg/mL) and incubated at room temperature for 90 minutes on a rolling rocker. After incubation, 2.5 mL of blood was transferred to Paxgene Blood RNA tubes. Gene expression analysis was performed using an Agilent Bioanalyzer with the RNA6000 Nano Lab Chip. Agilent gene expression microarrays were scanned with a G2565 Microarray Scanner. Differentially expressed genes were identified. RESULTS: 11,431 human and 4,992 sheep probes were detected above background. Among them 1,029 human and 175 sheep genes were differentially expressed at a stringency of 1.5-fold change (p<0.05). Of the 175 sheep genes, 54 had a known human orthologue. Among those genes, 22 had > 1.5-fold changes in human samples. Genes of major inflammatory mediators, such as IL-1, IL-6 and IL-8, TNF alpha, NF kappaB, ETS2, PTGS2, PTX3, CXCL16, KYNU, and CLEC4E were similarly (>2-fold) upregulated by LPS and MPLA in both species. CONCLUSION: The genomic responses of peripheral blood to LPS and MPLA in sheep are quite similar to those observed in humans, supporting the use of the ovine model for translational studies that mimic human inflammatory diseases and the study of TLR-based immunomodulators. PMID- 26640959 TI - Probing the Photodynamics of Rhodopsins with Reduced Retinal Chromophores. AB - While the light-induced population dynamics of different photoresponsive proteins has been investigated spectroscopically, systematic computational studies have not yet been possible due to the phenomenally high cost of suitable high level quantum chemical methods and the need of propagating hundreds, if not thousands, of nonadiabatic trajectories. Here we explore the possibility of studying the photodynamics of rhodopsins by constructing and investigating quantum mechanics/molecular mechanics (QM/MM) models featuring reduced retinal chromophores. In order to do so we use the sensory rhodopsin found in the cyanobacterium Anabaena PCC7120 (ASR) as a benchmark system. We find that the basic mechanistic features associated with the excited state dynamics of ASR QM/MM models are reproduced using models incorporating a minimal (i.e., three double-bond) chromophore. Furthermore, we show that ensembles of nonadiabatic ASR trajectories computed using the same abridged models replicate, at both the CASPT2 and CASSCF levels of theory, the trends in spectroscopy and lifetimes estimated using unabridged models and observed experimentally at room temperature. We conclude that a further expansion of these studies may lead to low-cost QM/MM rhodopsin models that may be used as effective tools in high throughput in silico mutant screening. PMID- 26640960 TI - Capillary Electrophoresis. PMID- 26640961 TI - Sensitivity and Reliability of a Specific Test of Stroke Performance in Table Tennis. AB - PURPOSE: To develop a simple, reliable, and sensitive test to measure stroke performance (ball speed and accuracy) in table tennis. METHODS: Fifty-two players were divided into 3 groups in accordance with their level: expert (EG), advanced (AG), and inexperienced (IG). The test consisted of 45 forehand shots where players were asked to reach 3 targets. The test was performed 2 times (separated by 8 min) during the first session (n = 52) to assess intrasession reliability. A second session (n = 28), at least 3 d later, was performed to test intersession reliability. Both speed and accuracy of the ball were measured to evaluate the absolute sensitivity and reliability of the specific test. RESULTS: This study showed good reliability of the specific test for both ball speed and accuracy of EG and AG (ICC range .42-.96, CV range 2.0-9.0%). However, the reliability is low for IG. Ball speed and accuracy were greater in EG than in the other groups, and both variables were correlated with the level of the players. CONCLUSION: Results suggest that the specific test appears to be a simple and sensitive procedure to assess stroke performance in table tennis and that this test could be a relevant tool for coaches in table tennis. PMID- 26640963 TI - Expanding Phenotypic Spectrum of NKX2-1-Related Disorders-Mitochondrial and Immunologic Dysfunction. PMID- 26640962 TI - Aptamer-Enabled Manipulation of the Hsp70 Chaperone System Suggests a Novel Strategy for Targeted Ubiquitination. AB - The Hsp70 chaperone system plays an important role in protein quality control by assisting in the folding and clearance of misfolded proteins. However, the mechanism by which it chooses between folding and degradation pathways is not fully understood. In this study, we used an RNA aptamer for Hsp70 to perturb the function of Hsp70 in cell-free systems. We found that the aptamer inhibited both Hsp70-mediated folding and Hsp70-CHIP-mediated ubiquitination/degradation of a misfolded protein substrate. Based on these results, we explored a novel strategy for targeted protein ubiquitination, using an engineered bifunctional aptamer to tether a protein substrate to Hsp70. We demonstrated that increased Hsp70-CHIP mediated ubiquitination of the tethered protein substrate can be specifically induced by this bifunctional aptamer. This strategy may be useful in selective degradation of disease-causing proteins for therapeutic purposes. In addition, these studies provide insight into the mechanism of Hsp70-mediated protein triage. PMID- 26640964 TI - [Asthma Update 2015--What Cell Biology in Basic Pulmonary Research Can Offer to the Pneumologist]. AB - Bronchial asthma is one of the most common chronic inflammatory diseases world wide causing an enormous socio-economic burden especially in industrialized countries. Currently, asthma is increasingly considered to be a poly-symptomatic disease comprising a variety of different asthma phenotypes and endotypes. This heterogeneity of asthma explains why the standard treatment with corticosteroids and beta-agonists cannot achieve full symptom control in all cases, especially not during acute exacerbations. Therefore, current asthma research focuses on primary prevention of asthma as well as on novel approaches towards a phenotype- and endotype-specific asthma therapy. PMID- 26640965 TI - Anti-inflammatory properties of tianeptine on lipopolysaccharide-induced changes in microglial cells involve toll-like receptor-related pathways. AB - Accumulating evidence suggests that activation of microglia plays a key role in the pathogenesis of depression. Activated microglia produce a wide range of factors whose prolonged or excessive release may lead to brain disorders. Thus, the inhibition of microglial cells may be beneficial in the treatment of depressive diseases. Tianeptine is an atypical antidepressant drug with proven clinical efficacy, but its mechanism of action remains still not fully understood. In the present study, using microglial cultures we investigated whether tianeptine modifies microglial activation after lipopolysaccharide (LPS) stimulation and which intracellular pathways are involved in the activity of this antidepressant. Our study shows that tianeptine attenuated the LPS-evoked inflammatory activation of microglia by decreasing the expression of proinflammatory cytokines such as IL-1beta, IL-18, IL-6 and tumor necrosis factor alpha (TNF-alpha), the release of nitric oxide (NO) and reactive oxygen species (ROS) as well as the expression of inducible nitric oxide synthase. Analyses of signaling pathways demonstrate that tianeptine led to the suppression of LPS induced TLR4 expression and ERK1/2 phosphorylation. Furthermore, our study reveals the inhibitory impact of tianeptine on caspase-3-induced PKCdelta degradation and consequently on the activation of NF-kappaB factor in microglial cells. Taken together, present results show anti-inflammatory properties of tianeptine in microglial cultures stimulated by LPS. This study provides evidence that the inhibition of microglial activation may underlie the therapeutic activity of tianeptine. Our findings show the anti-inflammatory effect of tianeptine (TIA) in lipopolisaccharide (LPS)-stimulated microglial cells. The beneficial tianeptine action is mediated through the inhibition of Toll-like receptor 4 (TLR4) expression as well as the TLR4-related pathways: extracellular signal-regulated kinase 1/2 (ERK1/2), caspase-3-dependent protein kinase delta (PKCdelta) cleavage and the expression of nuclear factor kappa-light-chain enhancer of activated B cells (NF-kappaB). These findings may provide a new therapeutic strategy for treatment of disorders based on neuroinflammation, including depression. PMID- 26640966 TI - Modulation of Photocatalytic Properties by Strain in 2D BiOBr Nanosheets. AB - BiOBr nanosheets with highly reactive {001} facets exposed were selectively synthesized by a facile hydrothermal method. The inner strain in the BiOBr nanosheets has been tuned continuously by the pH value. The photocatalytic performance of BiOBr in dye degradation can be manipulated by the strain effect. The low-strain BiOBr nanosheets show improved photocatalytic activity. Density functional calculations suggest that strain can modify the band structure and symmetry in BiOBr. The enhanced photocatalytic activity in low-strain BiOBr nanosheets is due to improved charge separation attributable to a highly dispersive band structure with an indirect band gap. PMID- 26640967 TI - Resolving the paradox of suboptimal choice. AB - When humans engage in commercial (totally probabilistic) gambling they are making suboptimal choices because the return is generally less than the investment. This review (a) examines the literature on pigeon suboptimal choice, (b) describes the conditions under which it occurs, (c) identifies the mechanisms that appear to be responsible for the effect, and (d) suggests that similar processes may be able to account for analogous suboptimal choice when humans engage in commercial gambling. Pigeons show suboptimal choice when they choose between 1 alternative that 20% of the time provides them with a signal that they will always get fed or 80% of the time with a signal that they will not get fed (overall 20% reinforcement) and a second alternative that 100% of the time provides them with a signal that they will get fed 50% of the time (overall 50% reinforcement). The pigeons' strong preference for the suboptimal choice was investigated in a series of experiments that found the preference for the suboptimal alternative was determined by the value of the signal that predicted reinforcement, rather its frequency and that the frequency of the signal that predicted nonreinforcement had little effect on the suboptimal choice. Paradoxically, this account makes the prediction that pigeons will be indifferent between an alternative that 50% of the time provides a fully predictive stimulus for reinforcement and an alternative that 100% of the time provides a fully predictive stimulus for reinforcement. The similarities and differences of this suboptimal choice task to human gambling are discussed. PMID- 26640968 TI - An Isochemogenic Set of Inhibitors To Define the Therapeutic Potential of Histone Deacetylases in beta-Cell Protection. AB - Modulation of histone deacetylase (HDAC) activity has been implicated as a potential therapeutic strategy for multiple diseases. However, it has been difficult to dissect the role of individual HDACs due to a lack of selective small-molecule inhibitors. Here, we report the synthesis of a series of highly potent and isoform-selective class I HDAC inhibitors, rationally designed by exploiting minimal structural changes to the clinically experienced HDAC inhibitor CI-994. We used this toolkit of isochemogenic or chemically matched inhibitors to probe the role of class I HDACs in beta-cell pathobiology and demonstrate for the first time that selective inhibition of an individual HDAC isoform retains beneficial biological activity and mitigates mechanism-based toxicities. The highly selective HDAC3 inhibitor BRD3308 suppressed pancreatic beta-cell apoptosis induced by inflammatory cytokines, as expected, or now glucolipotoxic stress, and increased functional insulin release. In addition, BRD3308 had no effect on human megakaryocyte differentiation, while inhibitors of HDAC1 and 2 were toxic. Our findings demonstrate that the selective inhibition of HDAC3 represents a potential path forward as a therapy to protect pancreatic beta cells from inflammatory cytokines and nutrient overload in diabetes. PMID- 26640969 TI - Reaction of 2H-Azirine-Phosphine Oxides and -Phosphonates with Enolates Derived from beta-Keto Esters. AB - Cyclopenta[b]-pyrrole-2-phosphine oxides 4a and -phosphonates 4b,c are generated by the addition of cyclic enolates derived from ethyl 2-oxo cyclopentanecarboxylate 2 to phosphorated 2H-azirines 1. However, the addition of enolate derived from acyclic 2-oxo-butanoate 10 to 2H-azirine phosphine oxide 1 led to vinylogous N-acyl-alpha-aminoalkyl phosphine oxides 12, involving the carbonyl group and the Calpha of the keto ester 10. Ring closure of vinylogous derivative 12 in the presence of base afforded pyrrole-2-phosphine oxide 11. The addition of enolates derived from indenone-carboxylate 15 to 2H-azirines 1 led to the formation of functionalized N-substituted 1H-benzo[d]azepine derivatives 17. PMID- 26640970 TI - Video-based respiration monitoring with automatic region of interest detection. AB - Vital signs monitoring is ubiquitous in clinical environments and emerging in home-based healthcare applications. Still, since current monitoring methods require uncomfortable sensors, respiration rate remains the least measured vital sign. In this paper, we propose a video-based respiration monitoring method that automatically detects a respiratory region of interest (RoI) and signal using a camera. Based on the observation that respiration induced chest/abdomen motion is an independent motion system in a video, our basic idea is to exploit the intrinsic properties of respiration to find the respiratory RoI and extract the respiratory signal via motion factorization. We created a benchmark dataset containing 148 video sequences obtained on adults under challenging conditions and also neonates in the neonatal intensive care unit (NICU). The measurements obtained by the proposed video respiration monitoring (VRM) method are not significantly different from the reference methods (guided breathing or contact based ECG; p-value = 0.6), and explain more than 99% of the variance of the reference values with low limits of agreement (-2.67 to 2.81 bpm). VRM seems to provide a valid solution to ECG in confined motion scenarios, though precision may be reduced for neonates. More studies are needed to validate VRM under challenging recording conditions, including upper-body motion types. PMID- 26640971 TI - Standard Reduction Potentials for Oxygen and Carbon Dioxide Couples in Acetonitrile and N,N-Dimethylformamide. AB - A variety of next-generation energy processes utilize the electrochemical interconversions of dioxygen and water as the oxygen reduction reaction (ORR) and the oxygen evolution reaction (OER). Reported here are the first estimates of the standard reduction potential of the O2 + 4e(-) + 4H(+) ? 2H2O couple in organic solvents. The values are +1.21 V in acetonitrile (MeCN) and +0.60 V in N,N dimethylformamide (DMF), each versus the ferrocenium/ferrocene couple (Fc(+/0)) in the respective solvent (as are all of the potentials reported here). The potentials have been determined using a thermochemical cycle that combines the free energy for transferring water from aqueous solution to organic solvent, 0.43 kcal mol(-1) for MeCN and -1.47 kcal mol(-1) for DMF, and the potential of the H(+)/H2 couple, - 0.028 V in MeCN and -0.662 V in DMF. The H(+)/H2 couple in DMF has been directly measured electrochemically using the previously reported procedure for the MeCN value. The thermochemical approach used for the O2/H2O couple has been extended to the CO2/CO and CO2/CH4 couples to give values of 0.12 and +0.15 V in MeCN and -0.73 and -0.48 V in DMF, respectively. Extensions to other reduction potentials are discussed. Additionally, the free energy for transfer of protons from water to organic solvent is estimated as +14 kcal mol( 1) for acetonitrile and +0.6 kcal mol(-1) for DMF. PMID- 26640972 TI - Critical Undercooling in DNA-Mediated Nanoparticle Crystallization. AB - The nucleation of DNA-functionalized nanoparticle superlattices is observed to exhibit a temperature hysteresis between melting (superlattice dissociation) and freezing (particle association) transitions that allows for the study of nucleation thermodynamics. Through detailed study of the assembly of these particles, which can be considered programmable atom equivalents (PAEs), we identify this hysteresis as critical undercooling-a phase transition phenomenon related to a thermodynamic barrier to nucleation. The separable nature of the DNA bonding elements and nanoparticle core enables the PAE platform to pose unique questions about the microscopic dependencies of critical undercooling and, ultimately, to control the nucleation pathway. Specifically, we find that the undercooling required to initiate nucleation increases as the nanoparticle coordination number increases (number of particles to which a single particle can bind). PMID- 26640973 TI - Promoting Patient-Centered Counseling to Reduce Use of Low-Value Diagnostic Tests: A Randomized Clinical Trial. AB - IMPORTANCE: Low-value diagnostic tests have been included on primary care specialty societies' "Choosing Wisely" Top Five lists. OBJECTIVE: To evaluate the effectiveness of a standardized patient (SP)-based intervention designed to enhance primary care physician (PCP) patient-centeredness and skill in handling patient requests for low-value diagnostic tests. DESIGN, SETTING, AND PARTICIPANTS: Randomized clinical trial of 61 general internal medicine or family medicine residents at 2 residency-affiliated primary care clinics at an academic medical center in California. INTERVENTIONS: Two simulated visits with SP instructors portraying patients requesting inappropriate spinal magnetic resonance imaging for low back pain or screening dual-energy x-ray absorptiometry. The SP instructors provided personalized feedback to residents regarding use of 6 patient-centered techniques to address patient concerns without ordering low-value tests. Control group physicians received SP visits without feedback and were emailed relevant clinical guidelines. MAIN OUTCOMES AND MEASURES: The primary outcome was whether resident PCPs ordered SP-requested low value tests during up to 3 unannounced SP clinic visits over 3 to 12 months follow-up, with patients requesting spinal magnetic resonance imaging, screening dual-energy x-ray absorptiometry, or headache neuroimaging. Secondary outcomes included PCP patient-centeredness and use of targeted techniques (both coded from visit audiorecordings), and SP satisfaction with the visit (0-10 scale). RESULTS: Of 61 randomized resident PCPs (31 control group and 30 intervention group), 59 had encounters with 155 SPs during follow-up. Compared with control PCPs, intervention PCPs had similar patient-centeredness (Measure of Patient-Centered Communication, 43.9 [95% CI, 42.0 to 45.7] vs 43.7 [95% CI, 41.8 to 45.6], adjusted mean difference, -0.2 [95% CI, -2.9 to 2.5]; P = .90) and used a similar number of targeted techniques (5.4 [95% CI, 4.9 to 5.8] vs 5.4 [95% CI, 4.9 to 5.8] on a 0-9 scale, adjusted mean difference, 0 [95% CI, -0.7 to 0.6]; P = .96). Residents ordered low-value tests in 41 SP encounters (26.5% [95% CI, 19.7% 34.1%]) with no significant difference in the odds of test ordering in intervention PCPs relative to control group PCPs (adjusted odds ratio, 1.07 [95% CI, 0.49-2.32]). Rates of test ordering among intervention and control PCPs were similar for all 3 SP cases. The SPs rated visit satisfaction higher among intervention than control PCPs (8.5 [95% CI, 8.1-8.8] vs 7.8 [95% CI, 7.5-8.2], adjusted mean difference, 0.6 [95% CI, 0.1-1.1]). CONCLUSIONS AND RELEVANCE: An SP-based intervention did not improve the patient-centeredness of SP encounters, use of targeted interactional techniques, or rates of low-value test ordering, although SPs were more satisfied with intervention than control residents. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01808664. PMID- 26640974 TI - The processing of singular and plural nouns in English, French, and Dutch: New insights from megastudies. AB - In this study, we explored the processing of singular and plural word forms, using megastudies in French, English, and Dutch. For singulars, we observed a base frequency effect but no surface frequency effect. For plurals, the effect depended on the frequency of the word form. When the word form had a frequency above a threshold value, we observed both surface and base frequency effects; for the frequencies below the threshold, we found a base frequency effect only, suggesting full decomposition for these words. The threshold differed between the languages, suggesting that more plurals are decomposed in French than in Dutch and more in Dutch than in English. In contrast, for all languages the singular form seems to be coactivated whenever the plural form is processed. These results are interpreted in light of some of the main models of morphological processing. (PsycINFO Database Record PMID- 26640975 TI - Abstracts of the 2015 CSBBCS Annual Meeting: Resumes du congres annuel 2015 de la SCCCSC. AB - Provides a collection of abstracts from the 2015 CSBBCS Annual Meeting. PMID- 26640976 TI - Ernest Becker and Stanley Milgram: Twentieth-century students of evil. AB - Both Stanley Milgram and Ernest Becker studied and theorized human evil and offered explanations for evil acts, such as those constituting the Holocaust. Yet the explanations offered by Becker and Milgram are strikingly different. In this essay, brief biographical records of their lives are provided. Differences in their research methods and theories are then examined and traced to relevant differences in their lives, education, and careers. Especially important in this regard were their personal experiences of evil and the scholarly practices and traditions of social scientific and humanities scholarship that characterized their graduate education and scholarly work. The final parts of the essay are devoted to a comparative and integrative analysis of their respective approaches to the question of evil, especially as manifest during the Holocaust, and a brief exegesis of their disciplinary commitments. PMID- 26640977 TI - Moving forward in uveitis therapy: preclinical to phase II clinical trial drug development. AB - INTRODUCTION: Several advances have been made in the diagnostic approach and therapeutic management of patients with immune-mediated uveitis over the last few decades, which have to lead to an improvement in the visual prognosis of patients. However, the use of available therapies, including steroids and immunosuppressive drugs, is still associated with limited efficacy and potentially serious side effects. Consequently, efforts have been made to develop novel therapeutic alternatives including new molecules and innovative therapeutic approaches. AREAS COVERED: Herein, the authors provide an updated review of those drugs in the initial phases of evaluation for the treatment of immune-mediated uveitides as well as the latest evidence from basic research. EXPERT OPINION: Enhanced understanding of the pathogenic mechanisms leading to immune-mediated uveitis has led to the identification of new therapeutic targets and thus to the development of more specific drugs. In addition, considering that the eye is a semi-enclosed chamber and that local therapy has the benefit of sparing the rest of the body from potentially toxic exposure, several attempts of establishing direct ophthalmologic avenues for delivery of the established and emerging drugs have also been made. All these advances have been an unquestionable step forward in the challenging management of uveitis patients. PMID- 26640978 TI - Alzheimer's disease lymphocytes: potential for biomarkers? PMID- 26640979 TI - Surgical and Patient Risk Factors for Severe Arterial Line Complications in Adults. AB - BACKGROUND: Prior research has provided inconsistent data regarding the risk factors associated with complications from arterial cannulation. The goal of this study was to clearly define the incidence and risks factors associated with arterial cannulation complications. METHODS: After obtaining institutional review board approval, all patients requiring arterial line placement with documentation were included in this retrospective study between January 1, 2006, and December 31, 2012. Leveraging two robust data warehouses, the Perioperative DataMart and the Mayo Clinic Life Silences System, the authors cross-matched arterial line cannulation with a documented vascular consult, neurologic consult, infection, or return to surgery within 30 days in order to identify the initial patient population. RESULTS: A total of 62,626 arterial lines were placed in 57,787 patients, and 90.1% of the catheters placed were 20-gauge catheters. The radial artery was cannulated in 94.5% of patients. A total of 21 patients were identified as having experienced vascular complications or nerve injuries, resulting in a complication rate of 3.4 per 10,000 (95% CI, 2.1 to 5.1). Cardiac surgery had the largest number of catheters placed (n = 15,419) with 12 complications (complication rate = 7.8 per 10,000; 95% CI, 4.0 to 13.6). The rate of complications differed significantly (P < 0.001) across the three most common catheter sizes (2.7 per 10,000 [95% CI, 1.5 to 4.4] for 20 gauge, 17.2 per 10,000 [95% CI, 4.7 to 43.9] for 18 gauge, and 9.4 per 10,000 [95% CI, 1.1 to 34.1] for 5 French). CONCLUSION: In a large retrospective study, the authors document a very low rate of complications with arterial line placement. PMID- 26640980 TI - Persistence, adherence, and all-cause healthcare costs in atazanavir- and darunavir-treated patients with human immunodeficiency virus in a real-world setting. AB - OBJECTIVES: Atazanavir (ATV) and darunavir (DRV) are protease inhibitors approved for HIV treatment in combination with ritonavir (/r). The objectives of this study were to compare persistence (time to treatment discontinuation/modification), adherence, and healthcare costs among patients with human immunodeficiency virus (HIV) initiating ATV/r or DRV/r. METHODS: This retrospective cohort study used commercial and Medicaid administrative insurance claims data. Patients initiating ATV/r or DRV/r from 2006-2013 with continuous enrollment for >=6 months before and >=3 months after initiation were included. Patients were followed from initiation until discontinuation/modification (>=30 day gap in ATV or DRV or initiation of a new antiretroviral medication), during which time adherence (proportion of days covered [PDC], with PDC >=80% or 95% considered adherent) and per-patient per-month (PPPM) total healthcare costs were measured. DRV/r patients were propensity score matched to ATV/r patients at a 1:1 ratio to achieve balance on potentially confounding demographic and clinical factors. Commercial and Medicaid samples were analyzed separately, as were antiretroviral (ART)-naive and experienced patients. RESULTS: The final samples comprised 2988 commercially-insured and 1158 Medicaid-insured patients. There were no significant differences in hazards of discontinuation/modification between the ATV/r or DRV/r cohorts. With respect to odds of being adherent, the only marginally significant result was comparing odds of achieving PDC >=80% among ART-naive Medicaid patients, which favored ATV/r. All other adherence comparisons were not significant. Although ATV/r cohorts tended to have lower PPPM costs, the majority of these differences were not statistically significant. CONCLUSIONS: Patients with HIV treated with either ATV/r or DRV/r had similar time to treatment discontinuation/modification, adherence, and monthly healthcare costs. Results were similar across the pre-specified sub-groups. These findings are useful not only as an insight into clinical practice, but also as a resource for healthcare providers and payers evaluating treatment options for HIV+ individuals. PMID- 26640981 TI - Reinvestigating Old Pharmacophores: Are 4-Aminoquinolines and Tetraoxanes Potential Two-Stage Antimalarials? AB - The syntheses and antiplasmodial activities of various substituted aminoquinolines coupled to an adamantane carrier are described. The compounds exhibited pronounced in vitro and in vivo activity against Plasmodium berghei in the Thompson test. Tethering a fluorine atom to the aminoquinoline C(3) position afforded fluoroaminoquinolines that act as intrahepatocytic parasite inhibitors, with compound 25 having an IC50 = 0.31 MUM and reducing the liver load in mice by up to 92% at 80 mg/kg dose. Screening our peroxides as inhibitors of liver stage infection revealed that the tetraoxane pharmacophore itself is also an excellent liver stage P. berghei inhibitor (78: IC50 = 0.33 MUM). Up to 91% reduction of the parasite liver load in mice was achieved at 100 mg/kg. Examination of tetraoxane 78 against the transgenic 3D7 strain expressing luciferase under a gametocyte-specific promoter revealed its activity against stage IV-V Plasmodium falciparum gametocytes (IC50 = 1.16 +/- 0.37 MUM). To the best of our knowledge, compounds 25 and 78 are the first examples of either an 4-aminoquinoline or a tetraoxane liver stage inhibitors. PMID- 26640982 TI - Versatile Method for Coating Surfaces with Functional and Responsive Polymer Based Films. AB - A versatile surface modification technique was developed to yield poly(N isopropylacrylamide) (pNIPAm) microgel-based thin films on a variety of substrates, e.g., metals, nonmetals, and polymers. Because the chemistry, and hence functionality and responsivity, of the pNIPAm-based microgels is easily tuned, multifunctional and responsive thin films could be generated on many different surfaces without varying the coating conditions. In one case, we showed that fluorescent/light emitting thin films could be generated using crystal violet-modified microgels. Antibacterial films could be obtained using silver nanoparticle-modified pNIPAm-based microgels. Finally, we show that thin films fabricated via the methods here could be used as a component in optical sensors. Although we show only a few examples of the utility of this approach, we feel that the apparent universality of the technique can be extended to countless other applications. PMID- 26641009 TI - Inherited mutations in cancer susceptibility genes are common among survivors of breast cancer who develop therapy-related leukemia. AB - BACKGROUND: Risk factors for the development of therapy-related leukemia (TRL), an often lethal late complication of cytotoxic therapy, remain poorly understood and may differ for survivors of different malignancies. Survivors of breast cancer (BC) now account for the majority of TRL cases, making the study of TRL risk factors in this population a priority. METHODS: Subjects with TRL after cytotoxic therapy for a primary BC were identified from the TRL registry at The University of Chicago. Those with an available germline DNA sample were screened with a comprehensive gene panel covering known inherited BC susceptibility genes. Clinical and TRL characteristics of all subjects and those with identified germline mutations were described. RESULTS: Nineteen of 88 survivors of BC with TRL (22%) had an additional primary cancer and 40 of the 70 survivors with an available family history (57%) had a close relative with breast, ovarian, or pancreatic cancer. Of the 47 subjects with available DNA, 10 (21%) were found to carry a deleterious inherited mutation in BRCA1 (3 subjects; 6%), BRCA2 (2 subjects; 4%), TP53 (tumor protein p53) (3 subjects; 6%), CHEK2 (checkpoint kinase 2) (1 subject; 2%), and PALB2 (partner and localizer of BRCA2) (1 subject; 2%). CONCLUSIONS: Survivors of BC with TRL have personal and family histories suggestive of inherited cancer susceptibility and frequently carry germline mutations in BC susceptibility genes. The data from the current study support the role of these genes in TRL risk and suggest that long-term follow-up studies of women with germline mutations who are treated for BC and functional studies of the effects of heterozygous mutations in these genes on bone marrow function after cytotoxic exposures are warranted. Cancer 2016;122:304-311. (c) 2015 American Cancer Society. PMID- 26641010 TI - The persistence of maternal vitamin D deficiency and insufficiency during pregnancy and lactation irrespective of season and supplementation. AB - BACKGROUND: Pregnancy and lactation comprise a critical window spanning all seasons during which maternal vitamin D status potentially may influence the long term health of the newborn. Women typically receive calcium/vitamin D supplementation through antenatal vitamins, but there has been limited serial evaluation of maternal vitamin D status across this critical window. DESIGN/PATIENTS/MEASUREMENTS: In this prospective observational cohort study, 467 women in Toronto, Canada, underwent measurement of serum 25-hydroxy vitamin D (25 OH-D) at mean 29.7 +/- 2.9 weeks' gestation, 3 months postpartum and 12 months postpartum, enabling serial assessment across 3 seasons. At each assessment, vitamin D status was classified as deficiency (25-OH-D<50 nmol/l), insufficiency (25-OH-D>=50 nmol/l and <75 nmol/l) or sufficiency (25-OH-D>=75 nmol/l). RESULTS: The prevalence rates of vitamin D deficiency and insufficiency were 31.5% and 35.1% in pregnancy, 33.4% and 35.3% at 3 months, and 35.6% and 33.8% at 12 months postpartum, respectively. These high rates remained stable over time (P = 0.49) despite declining usage of antenatal calcium/vitamin D supplementation from pregnancy to 3 months to 12 months postpartum (P < 0.001). Indeed, on mixed model analyses, vitamin D deficiency and insufficiency in pregnancy were independently associated with decrements in average 25-OH-D over time of 49.6 nmol/l and 26.4 nmol/l, respectively (both P < 0.001). In contrast, season of baseline assessment and use of calcium/vitamin D supplements were independently associated with changes in 25-OH-D in the range of 3-5 nmol/l (both P < 0.008). CONCLUSIONS: The persistence of vitamin D deficiency/insufficiency during pregnancy and lactation, irrespective of season and supplementation, supports the emerging concept that current vitamin D supplementation in antenatal care is likely inadequate. PMID- 26641011 TI - CrossTalk opposing view: High intensity interval training does not have a role in risk reduction or treatment of disease. PMID- 26641012 TI - Complete mitochondrial genome of Motacilla alba and implications for Motacillidae taxonomy. AB - Motacilla alba is a species of small and passerine songbird in the Family Motacillidae, which is widely distributed. In this study, we determined the complete mitochondrial genome of M. alba. The result showed that the total length of the mitogenome was 16 826 bp and contained 2 ribosomal RNA genes, 22 transfer RNA genes, 13 protein-coding genes, and one control region. All the genes in M. alba were distributed on the H-strand, except for the ND6 subunit gene and eight tRNA genes which were encoded on the L-strand. The phylogenetic tree was reconstructed using maximum-likelihood analysis and divided into three major clades. The species from genus Anthus were clustered into clade A. The clade B contained M. alba and other seven Motacilla species. Dendronanthus indicus as one species from Dendronanthus comprised the clade C, and received strong support. PMID- 26641013 TI - A mesocosm experiment of suspended particulate matter dynamics in nutrient- and biomass-affected waters. AB - An experimental study was conducted to test the hypothesis that the biomass growing after an increase in available nutrient in an aquatic ecosystem affects the flocculation dynamics of suspended particulate matter (SPM). The experiment was carried out in a settling column equipped with a turbulence generating system, a water quality monitoring system, and an automated MUPIV system to acquire micro photographs of SPM. Three SPM types were tested combinatorially at five turbulence shear rates, three nutrient concentrations, and three mineral concentrations. Analyses of experimental data showed that nutrient availability together with the presence of biomass increased the SPM size by about 60% at low shear as compared to nutrient- and biomass-free conditions; a lower increase was observed at higher shears. In contrast, only 2% lower fractal (capacity) dimension and nearly invariant settling velocity were observed than in nutrient- and biomass-free conditions. Likewise, SPM size and capacity dimension were found to be insensitive to the SPM concentration. Although limited to nearly homogeneous mineral mixes (kaolinite), these experimental findings not only reject the hypothesis that SPM in natural waters can be dealt with as purely mineral systems in all instances, but also anticipate that SPM dynamics in natural waters increasingly exposed to the threat of anthropogenic nutrient discharge would lead to an increased advective flow of adsorbed chemicals and organic carbon. PMID- 26641014 TI - Desalination and sustainability - An appraisal and current perspective. AB - Desalination technologies have evolved and advanced rapidly along with increasing water demands around the world since 1950s. Many reviews have focused on the techno-economic and environmental and ecological issues of the desalination technologies and emphasized the feasibility of desalination industry as an alternative to meet the water demands in many water scarce regions. Despite these efforts, many perceptions about desalination processes hinder their applications for potential water supplies. This article has two specific aims: 1) provide an overview of the desalination trends around the world and discuss the sustainability components of desalination processes in comparison with other water supply alternatives; and 2) discuss case studies for desalination, and drivers and factors that influence sustainable desalination and other alternative water sources for desalination to increase our current understanding on the sensitive and futuristic issues of water supply and resource management options for drought facing regions. Although some of the facts and recent developments discussed here show that desalination can be affordable and potentially sustainable, contributions that meaningfully address socio-economic and ecological and environmental issues of desalination processes are urgently required in this critical era of severe water stress for the present context and the future development of desalination technologies. PMID- 26641015 TI - Water quality modeling in the dead end sections of drinking water distribution networks. AB - Dead-end sections of drinking water distribution networks are known to be problematic zones in terms of water quality degradation. Extended residence time due to water stagnation leads to rapid reduction of disinfectant residuals allowing the regrowth of microbial pathogens. Water quality models developed so far apply spatial aggregation and temporal averaging techniques for hydraulic parameters by assigning hourly averaged water demands to the main nodes of the network. Although this practice has generally resulted in minimal loss of accuracy for the predicted disinfectant concentrations in main water transmission lines, this is not the case for the peripheries of the distribution network. This study proposes a new approach for simulating disinfectant residuals in dead end pipes while accounting for both spatial and temporal variability in hydraulic and transport parameters. A stochastic demand generator was developed to represent residential water pulses based on a non-homogenous Poisson process. Dispersive solute transport was considered using highly dynamic dispersion rates. A genetic algorithm was used to calibrate the axial hydraulic profile of the dead-end pipe based on the different demand shares of the withdrawal nodes. A parametric sensitivity analysis was done to assess the model performance under variation of different simulation parameters. A group of Monte-Carlo ensembles was carried out to investigate the influence of spatial and temporal variations in flow demands on the simulation accuracy. A set of three correction factors were analytically derived to adjust residence time, dispersion rate and wall demand to overcome simulation error caused by spatial aggregation approximation. The current model results show better agreement with field-measured concentrations of conservative fluoride tracer and free chlorine disinfectant than the simulations of recent advection dispersion reaction models published in the literature. Accuracy of the simulated concentration profiles showed significant dependence on the spatial distribution of the flow demands compared to temporal variation. PMID- 26641016 TI - Self-assembled RNA-triple-helix hydrogel scaffold for microRNA modulation in the tumour microenvironment. AB - The therapeutic potential of miRNA (miR) in cancer is limited by the lack of efficient delivery vehicles. Here, we show that a self-assembled dual-colour RNA triple-helix structure comprising two miRNAs-a miR mimic (tumour suppressor miRNA) and an antagomiR (oncomiR inhibitor)-provides outstanding capability to synergistically abrogate tumours. Conjugation of RNA triple helices to dendrimers allows the formation of stable triplex nanoparticles, which form an RNA-triple helix adhesive scaffold upon interaction with dextran aldehyde, the latter able to chemically interact and adhere to natural tissue amines in the tumour. We also show that the self-assembled RNA-triple-helix conjugates remain functional in vitro and in vivo, and that they lead to nearly 90% levels of tumour shrinkage two weeks post-gel implantation in a triple-negative breast cancer mouse model. Our findings suggest that the RNA-triple-helix hydrogels can be used as an efficient anticancer platform to locally modulate the expression of endogenous miRs in cancer. PMID- 26641017 TI - Molecular design and control of fullerene-based bi-thermoelectric materials. AB - Molecular junctions are a versatile test bed for investigating nanoscale thermoelectricity and contribute to the design of new cost-effective environmentally friendly organic thermoelectric materials. It was suggested that transport resonances associated with discrete molecular levels could play a key role in thermoelectric performance, but no direct experimental evidence has been reported. Here we study single-molecule junctions of the endohedral fullerene Sc3N@C80 connected to gold electrodes using a scanning tunnelling microscope. We find that the magnitude and sign of the thermopower depend strongly on the orientation of the molecule and on applied pressure. Our calculations show that Sc3N inside the fullerene cage creates a sharp resonance near the Fermi level, whose energetic location, and hence the thermopower, can be tuned by applying pressure. These results reveal that Sc3N@C80 is a bi-thermoelectric material, exhibiting both positive and negative thermopower, and provide an unambiguous demonstration of the importance of transport resonances in molecular junctions. PMID- 26641018 TI - Strong interplay between stripe spin fluctuations, nematicity and superconductivity in FeSe. AB - In iron-based superconductors the interactions driving the nematic order (that breaks four-fold rotational symmetry in the iron plane) may also mediate the Cooper pairing. The experimental determination of these interactions, which are believed to depend on the orbital or the spin degrees of freedom, is challenging because nematic order occurs at, or slightly above, the ordering temperature of a stripe magnetic phase. Here, we study FeSe (ref. )-which exhibits a nematic (orthorhombic) phase transition at Ts = 90 K without antiferromagnetic ordering by neutron scattering, finding substantial stripe spin fluctuations coupled with the nematicity that are enhanced abruptly on cooling through Ts. A sharp spin resonance develops in the superconducting state, whose energy (~4 meV) is consistent with an electron-boson coupling mode revealed by scanning tunnelling spectroscopy. The magnetic spectral weight in FeSe is found to be comparable to that of the iron arsenides. Our results support recent theoretical proposals that both nematicity and superconductivity are driven by spin fluctuations. PMID- 26641019 TI - The classical and quantum dynamics of molecular spins on graphene. AB - Controlling the dynamics of spins on surfaces is pivotal to the design of spintronic and quantum computing devices. Proposed schemes involve the interaction of spins with graphene to enable surface-state spintronics and electrical spin manipulation. However, the influence of the graphene environment on the spin systems has yet to be unravelled. Here we explore the spin-graphene interaction by studying the classical and quantum dynamics of molecular magnets on graphene. Whereas the static spin response remains unaltered, the quantum spin dynamics and associated selection rules are profoundly modulated. The couplings to graphene phonons, to other spins, and to Dirac fermions are quantified using a newly developed model. Coupling to Dirac electrons introduces a dominant quantum relaxation channel that, by driving the spins over Villain's threshold, gives rise to fully coherent, resonant spin tunnelling. Our findings provide fundamental insight into the interaction between spins and graphene, establishing the basis for electrical spin manipulation in graphene nanodevices. PMID- 26641021 TI - Ciprofloxacin-Loaded Inorganic-Organic Composite Microparticles To Treat Bacterial Lung Infection. AB - Ciprofloxacin (CIP) is an antibiotic that has been clinically trialed for the treatment of lung infections by aerosolization. However, CIP is rapidly systemically absorbed after lung administration, increasing the risk for subtherapeutic pulmonary concentrations and resistant bacteria selection. In the presence of calcium, CIP forms complexes that reduce its oral absorption. Such complexation may slow down CIP absorption from the lung thereby maintaining high concentration in this tissue. Thus, we developed inhalable calcium-based inorganic-organic composite microparticles to sustain CIP within the lung. The aerodynamics and micromeritic properties of the microparticles were characterized. FTIR and XRD analysis suggest that the inorganic component of the particles comprised amorphous calcium carbonate and amorphous calcium formate, and that CIP and calcium interact in a 1:1 stoichiometry in the particles. CIP was completely released from the microparticles within 7 h, with profiles showing a slight dependence on pH (5 and 7.4) compared to the dissolution of pure CIP. Transport studies of CIP across Calu-3 cell monolayers, in the presence of various calcium concentrations, showed a decrease of up to 84% in CIP apparent permeability. The apparent minimum inhibitory concentration of CIP against Pseudomonas aeruginosa and Staphylococcus aureus was not changed in the presence of the same calcium concentration. These results indicate that the designed particles should provide sustained levels of CIP with therapeutic effect in the lung. With these microparticles, it should be possible to control CIP pharmacokinetics within the lung, based on controlled CIP release from the particles and reduced apparent permeability across the epithelial barrier due to the cation-CIP interaction. PMID- 26641020 TI - Tunable spin polarization and superconductivity in engineered oxide interfaces. AB - Advances in growth technology of oxide materials allow single atomic layer control of heterostructures. In particular delta doping, a key materials' engineering tool in today's semiconductor technology, is now also available for oxides. Here we show that a fully electric-field-tunable spin-polarized and superconducting quasi-2D electron system (q2DES) can be artificially created by inserting a few unit cells of delta doping EuTiO3 at the interface between LaAlO3 and SrTiO3 oxides. Spin polarization emerges below the ferromagnetic transition temperature of the EuTiO3 layer (TFM = 6-8 K) and is due to the exchange interaction between the magnetic moments of Eu-4f and of Ti-3d electrons. Moreover, in a large region of the phase diagram, superconductivity sets in from a ferromagnetic normal state. The occurrence of magnetic interactions, superconductivity and spin-orbit coupling in the same q2DES makes the LaAlO3/EuTiO3/SrTiO3 system an intriguing platform for the emergence of novel quantum phases in low-dimensional materials. PMID- 26641022 TI - Release of Fluconazole from Contact Lenses Using a Novel In Vitro Eye Model. AB - PURPOSE: Rapid drug release followed by a plateau phase is a common observation with drug delivery from contact lenses (CLs) when evaluated in a vial. The aim of this study was to compare the release of fluconazole from seven commercially available daily disposable CLs using a conventional vial-based method with a novel in vitro eye model. METHODS: An eye model was created using two 3 dimensional printed molds, which were filled with polydimethylsiloxane to obtain an inexpensive model that would mimic the eyeball and eyelid. The model was integrated with a microfluidic syringe pump, and the flow-through was collected in a 12-well microliter plate. Four commercial daily disposable conventional hydrogels (nelfilcon A, omafilcon A, etafilcon A, ocufilcon B) and three silicone hydrogels (somofilcon A, narafilcon A, delefilcon A) were evaluated. These CLs were incubated with fluconazole for 24 h. The drug release was measured in a vial containing 4.8 mL of phosphate-buffered saline and in the polydimethylsiloxane eye model with a 4.8-mL tear flow across 24 h. RESULTS: Overall, conventional hydrogel CLs had a higher uptake and release of fluconazole than silicone hydrogel CLs (p < 0.05). A higher drug release was observed in the vial condition compared with the eye model (p < 0.001). In the vial system, the drugs were rapidly released from the CL within the first 2 h, followed by a plateau phase. In contrast, drug release in the eye model under low tear volume was sustained and did not reach a plateau across 24 h (p < 0.05). CONCLUSIONS: Rapid drug release results from using a vial as the release system. Under low tear volume at physiological tear flow, commercial CLs can maintain a sustained drug release profile for up to 24 h. However, eyes with fungal keratitis may have increased tearing, which would significantly accelerate drug release. PMID- 26641023 TI - Relenza-Induced Acute Myopia Change. AB - PURPOSE: To report a case of a patient with a notable side effect to Relenza, an anti-influenza virus medication, who also developed acute transient myopia. CASE REPORT: A 31-year-old woman was diagnosed as having seasonal influenza and treated with Relenza. However, an allergic reaction and blurred vision caused by a transient myopic change were noted after she received Relenza treatment. Relenza-induced acute transient myopia had never been reported. The possible mechanisms include (1) ciliary spasm, (2) lens edema, (3) ciliary body and/or choroidal effusion. Fortunately, the drug-induced myopic change mostly resolved spontaneously after discontinuation of the drug and had a benign course. CONCLUSIONS: Patients suspected of having drug-induced myopia should be examined by an internist for a systemic allergic reaction and referred to an optometrist or an ophthalmologist for further special examinations such as A-scan, B-scan, and ultrasound biomicroscopy. Optometrists and ophthalmologists should keep in mind and be aware of the possible ocular side effect (myopic change) of Relenza and warn patients of this potential condition. PMID- 26641024 TI - Aqueous Solutions of Ionic Liquids: Microscopic Assembly. AB - Aqueous solutions of ionic liquids are of special interest, due to the distinctive properties of ionic liquids, in particular, their amphiphilic character. A better understanding of the structure-property relationships of such systems is hence desirable. One of the crucial molecular-level interactions that influences the macroscopic behavior is hydrogen bonding. In this work, we conduct molecular dynamics simulations to investigate the effects of ionic liquids on the hydrogen-bond network of water in dilute aqueous solutions of ionic liquids with various combinations of cations and anions. Calculations are performed for imidazolium-based cations with alkyl chains of different lengths and for a variety of anions, namely, [Br](-), [NO3](-), [SCN](-) [BF4](-), [PF6](-), and [Tf2N](-). The structure of water and the water-ionic liquid interactions involved in the formation of a heterogeneous network are analyzed by using radial distribution functions and hydrogen-bond statistics. To this end, we employ the geometric criterion of the hydrogen-bond definition and it is shown that the structure of water is sensitive to the amount of ionic liquid and to the anion type. In particular, [SCN](-) and [Tf2N](-) were found to be the most hydrophilic and hydrophobic anions, respectively. Conversely, the cation chain length did not influence the results. PMID- 26641025 TI - Management of T1 colorectal cancers after endoscopic treatment based on the risk stratification of lymph node metastasis. AB - BACKGROUND AND AIM: Recent advances in endoscopic technology have allowed many T1 colorectal carcinomas to be resected endoscopically with negative margins. However, the criteria for curative endoscopic resection remain unclear. We aimed to identify risk factors for nodal metastasis in T1 carcinoma patients and hence establish the indication for additional surgery with lymph node dissection. METHODS: Initial or additional surgery with nodal dissection was performed in 653 T1 carcinoma cases. Clinicopathological factors were retrospectively analyzed with respect to nodal metastasis. The status of the muscularis mucosae (MM grade) was defined as grade 1 (maintenance) or grade 2 (fragmentation or disappearance). The lesions were then stratified based on the risk of nodal metastasis. RESULTS: Muscularis mucosae grade was associated with nodal metastasis (P = 0.026), and no patients with MM grade 1 lesions had nodal metastasis. Significant risk factors for nodal metastasis in patients with MM grade 2 lesions were attribution of women (P = 0.006), lymphovascular infiltration (P < 0.001), tumor budding (P = 0.045), and poorly differentiated adenocarcinoma or mucinous carcinoma (P = 0.007). Nodal metastasis occurred in 1.06% of lesions without any of these pathological factors, but in 10.3% and 20.1% of lesions with at least one factor in male and female patients, respectively. There was good inter-observer agreement for MM grade evaluation, with a kappa value of 0.67. CONCLUSIONS: Stratification using MM grade, pathological factors, and patient sex provided more appropriate indication for additional surgery with lymph node dissection after endoscopic treatment for T1 colorectal carcinomas. PMID- 26641026 TI - From Korotkoff and Marey to automatic non-invasive oscillometric blood pressure measurement: does easiness come with reliability? AB - The auscultatory technique remains the point of reference for the validation of non-invasive blood pressure measurement devices, although the exact origin of the Korotkoff sounds is still debated and comparison with intra-arterial measurement shows limits and pitfalls. Automatic oscillometric devices are now widely used by nurses, physicians, and patients. However, many available devices have not been duly validated. Moreover, they calculate systolic and diastolic blood pressures using undisclosed algorithms. Therefore, these devices are not interchangeable, and their reliability may be questionable in some clinical situations. Nevertheless, oscillometry is increasingly used, beside NIBP, for the assessment of central blood pressure and systemic arterial wall stiffness. Awareness of its limits and causes of error is all the more necessary. PMID- 26641027 TI - The Triumph of Innovation and the Hard Work of Caring for Patients With Diabetes. PMID- 26641028 TI - Full-Color Emissive Poly(Ethylene Oxide) Electrospun Nanofibers Containing a Single Hyperbranched Conjugated Polymer for Large-Scale, Flexible Light-Emitting Sheets. AB - White-light-emitting protocols based on organic materials have received much attention in the academic and industrial fields because of their potential applications in full-color displays and back-lighting units for liquid crystal displays. Here, the attempt is made to fabricate white-light-emitting, electrospun poly(ethylene oxide) (PEO) sheets containing controlled concentrations of a single light-emitting material composed of a type of hyperbranched conjugated polymer (HCP). The HCPs used here have the unique property of exhibiting a variety of fluorescence colors in the electrospun matrix that is caused by the different distances between HCP chains depending on their concentrations, leading to different degrees of intermolecular energy transfer. Therefore, the emission colors of the PEO sheets can be easily manipulated by simply varying the HCP concentrations in the PEO matrix. The resulting method for fabricating nanofibers comprising light-emitting materials in the polymer matrix has great potential for easy fabrication of cost-effective, flexible light emitting system. PMID- 26641030 TI - Blown Bubble Assembly of Graphene Oxide Patches for Transparent Electrodes in Carbon-Silicon Solar Cells. AB - Graphene oxide (GO) sheets have a strong tendency to aggregate, and their interfaces can impose limitations on the electrical conductivity, which would hinder practical applications. Here, we present a blown bubble film method to assemble GO sheets with a uniform distribution over a large area and further interconnect individual GO sheets by transforming the bubble film into graphitized carbon. A conventional polymer was used to facilitate the bubble blowing process and disperse GO sheets in the bubble. Then, the bubble film was annealed on a Cu substrate, resulting in a highly transparent reduced GO (RGO) carbon hybrid structure consisting of RGO patches well adhered to the carbon film. We fabricated RGO-carbon/Si solar cells with power conversion efficiencies up to 6.42%, and the assembled RGO patches hybridized with carbon film can form an effective junction with Si, indicating potential applications in thin film electronic devices and photovoltaics. PMID- 26641031 TI - Assessment of the economic impacts of porcine epidemic diarrhea virus in the United States. AB - Porcine epidemic diarrhea virus (PEDV), which first emerged in the United States in 2013, spread throughout the U.S. hog population. Limited preemptive knowledge impeded the understanding of PEDV introduction, spread, and prospective economic impacts in the United States. To assess these impacts, this article reviews the timeline of PEDV in the United States and the corresponding impacts. PEDV is a supply-impacting disease and is not demand inhibiting, as pork demand remained strong since PEDV first appeared. Pig losses reached significant levels during September 2013 through August 2014, with the majority of pork production impacts occurring in 2014. PEDV had differing impacts for subsectors of the pork industry. A budget model demonstrates that producers could have had pig losses and decreases in productivity proportionally smaller than price increases, resulting in net returns above what was expected before the major outbreak of PEDV. Previous literature is reviewed to identify the potential main industry beneficiaries of the PEDV outbreaks in the United States. As a result of reduced volumes of available pig and hog supplies, reductions in annual returns likely occurred for packers, processors, distributors, and retailers. In addition, pork consumers who experienced reduced-supply-induced pork-price increases were likely harmed directly by higher prices paid for pork and indirectly as prices of competing meats were also likely strengthened by PEDV. This article also identifies future considerations motivated by the appearance of PEDV in the United States, such as discussions of industry-wide efficiency and competitive advantage, the future role of PEDV vaccines, enhancement in biosecurity measures, and consumer perceptions of food safety and insecurity. PMID- 26641029 TI - Iron-Oxide-Based Nanovector for Tumor Targeted siRNA Delivery in an Orthotopic Hepatocellular Carcinoma Xenograft Mouse Model. AB - Hepatocellular carcinoma (HCC) is one of the deadliest cancers worldwide. Small interfering RNA (siRNA) holds promise as a new class of therapeutics for HCC, as it can achieve sequence-specific gene knockdown with low cytotoxicity. However, the main challenge in the clinical application of siRNA lies in the lack of effective delivery approaches that need to be highly specific and thus incur low or no systemic toxicity. Here, a nonviral nanoparticle-based gene carrier is presented that can specifically deliver siRNA to HCC. The nanovector (NP-siRNA GPC3 Ab) is made of an iron oxide core coated with chitosan-polyethylene glycol (PEG) grafted polyethyleneimine copolymer, which is further functionalized with siRNA and conjugated with a monoclonal antibody (Ab) against human glypican-3 (GPC3) receptor highly expressed in HCC. A rat RH7777 HCC cell line that coexpresses human GPC3 and firefly luciferase (Luc) is established to evaluate the nanovector. The nanoparticle-mediated delivery of siRNA against Luc effectively suppresses Luc expression in vitro without notable cytotoxicity. Significantly, NP-siLuc-GPC3 Ab administered intravenously in an orthotopic model of HCC is able to specifically bound to tumor and induce remarkable inhibition of Luc expression. The findings demonstrate the potential of using this nanovector for targeted delivery of therapeutic siRNA to HCC. PMID- 26641032 TI - Genome-wide association for the outcome of fixed-time artificial insemination of Brahman heifers in northern Australia. AB - Fixed-time AI (FTAI) is a powerful tool for genetic improvement of extensively managed beef cattle. A genomewide association study (GWAS) was conducted to investigate genes and genetic markers associated with the outcome (pregnant or not pregnant) of FTAI in 614 commercial Brahman heifers genotyped for 18,895 SNP and imputed to 51,588 SNP. The likelihood of Brahman heifers becoming pregnant after hormonal treatment to synchronize ovulation followed by FTAI was influenced by the content of their genomes, as determined by a principal component analysis. The principal component analysis involved comparisons between the studied heifers and populations of known and ancestry. The heritability of FTAI outcome was = 0.18, which is higher than for most other reproductive outcome traits. The number of SNP associated with FTAI outcome was 101 ( < 0.001, false discovery rate = 0.53). Compared with all SNP tested, associated SNP had a tendency for highly divergent allelic frequencies between and . Associated SNP were located in nearly all chromosomes, a result that shows a complex genetic architecture that is typical of highly complex traits with low heritability. Considering this and previous GWAS that examined Brahman heifer puberty and postpartum anestrus interval, 3 genomic regions emerge as important for overall Brahman heifer fertility, which mapped to chromosomes 1, 7, and 9. Further analyses, including improved genome annotation, are required to elucidate the link between these regions and heifer fertility. Additional studies are needed to confirm SNP and gene associations reported herein and further elucidate the genetics of FTAI outcome. Future GWAS should target other Braham populations and additional cattle breeds with FTAI records, including breeds with higher ancestry. PMID- 26641033 TI - A survey of polymorphisms detected from sequences of popular beef breeds. AB - The genome sequence was obtained from 270 sires used in the Germplasm Evaluation (GPE) project. These bulls included 154 purebred AI sires from GPE Cycle VII breeds (Hereford, Angus, Simmental, Limousin, Charolais, Gelbvieh, and Red Angus), 83 F crosses of those breeds, and 33 AI sires from 8 other breeds. The exome capture sequence targeting coding regions of the genome was obtained from 176 of these bulls. Sequence reads were mapped to the UMD 3.1 bovine genome assembly; a mean of 2.5-fold (x) coverage per bull was obtained from the genomic sequence, and the targeted exons were covered at a mean of 20.0x. Over 28.8 million biallelic sequence variants were detected where each allele was present in at least 3 different bulls. These included 22.0 million previously reported variants and 94.1% of the 774,660 autosomal and BTA X SNP on the BovineHD BeadChip assay (HD). More than 92% of the variants detected in targeted exons were also detected from the low-coverage genome sequence. Less than 1% of the variants detected from the combined genome and exome sequence occurred in annotated protein-coding sequences and 5' and 3' untranslated regions (UTR) surrounding the 19,994 annotated protein coding regions. Variation was detected in the coding sequence or UTR of 96.8% of the genes: loss-of-function variants were predicted for 3,298 genes, 14,973 contained nonsynonymous variants, 11,276 had variation in UTR, and 17,721 genes contained synonymous variants. Minor allele frequencies (MAF) were <0.05 for 47.8% of the coding sequence and UTR variants, and MAF distributions were skewed toward low MAF. In contrast, 11.1% of the HD SNP detected in these bulls had MAF < 0.05, and the distribution was skewed toward higher MAF. Genes involved in immune system processes and immune response were overrepresented among those genes containing high MAF loss-of function and nonsynonymous polymorphisms. Detected variants were submitted to the National Center for Biotechnology Information genetic variation database (dbSNP) under the handle MARC, batch GPE_Bull_GenEx. PMID- 26641034 TI - Tissue expression analysis, cloning, and characterization of the 5'-regulatory region of the bovine fatty acid binding protein 4 gene. AB - Fatty acid binding protein 4 (FABP4) is a member of the FABP family of proteins that bind fatty acids and play important roles in fatty acid uptake and intracellular transport. In the present study, we cloned the 5'-regulatory region of bovine and identified its transcription initiation sites. Sequence comparative analysis demonstrated amino acids and promoter sequences of were highly conservative in mammals. Real-time PCR analysis revealed the products of bovine were very highly expressed in subcutaneous adipose tissue. Serial deletion constructs of the bovine 5'-regulatory region evaluated in a dual-luciferase reporter assay showed that 209 bp upstream from the transcription initiation site was its core promoter. An electrophoretic mobility shift assay combined with a site-directed mutation experiment indicated that peroxisome proliferator activated receptor gamma (PPARgamma), CCAAT/enhancer-binding protein beta (C/EBPbeta), and sterol regulatory element-binding protein (SREBP) were important transcription factors for bovine . These results provide an important basis for further understanding the regulation of bovine . PMID- 26641035 TI - Variance component estimates for alternative litter size traits in swine. AB - Litter size at d 5 (LS5) has been shown to be an effective trait to increase total number born (TNB) while simultaneously decreasing preweaning mortality. The objective of this study was to determine the optimal litter size day for selection (i.e., other than d 5). Traits included TNB, number born alive (NBA), litter size at d 2, 5, 10, 30 (LS2, LS5, LS10, LS30, respectively), litter size at weaning (LSW), number weaned (NW), piglet mortality at d 30 (MortD30), and average piglet birth weight (BirthWt). Litter size traits were assigned to biological litters and treated as a trait of the sow. In contrast, NW was the number of piglets weaned by the nurse dam. Bivariate animal models included farm, year-season, and parity as fixed effects. Number born alive was fit as a covariate for BirthWt. Random effects included additive genetics and the permanent environment of the sow. Variance components were plotted for TNB, NBA, and LS2 to LS30 using univariate animal models to determine how variances changed over time. Additive genetic variance was minimized at d 7 in Large White and at d 14 in Landrace pigs. Total phenotypic variance for litter size traits decreased over the first 10 d and then stabilized. Heritability estimates increased between TNB and LS30. Genetic correlations between TNB, NBA, and LS2 to LS29 with LS30 plateaued within the first 10 d. A genetic correlation with LS30 of 0.95 was reached at d 4 for Large White and at d 8 for Landrace pigs. Heritability estimates ranged from 0.07 to 0.13 for litter size traits and MortD30. Birth weight had an h of 0.24 and 0.26 for Large White and Landrace pigs, respectively. Genetic correlations among LS30, LSW, and NW ranged from 0.97 to 1.00. In the Large White breed, genetic correlations between MortD30 with TNB and LS30 were 0.23 and -0.64, respectively. These correlations were 0.10 and -0.61 in the Landrace breed. A high genetic correlation of 0.98 and 0.97 was observed between LS10 and NW for Large White and Landrace breeds, respectively. This would indicate that NW could possibly be used as an effective maternal trait, given a low level of cross-fostering, to avoid back calculating litter size traits from piglet records. Litter size at d 10 would be a compromise between gain in litter size at weaning and minimizing the potentially negative effects of the nurse dam and direct additive genetics of the piglets, as they are expected to increase throughout lactation. PMID- 26641036 TI - Genetic diversity and divergence among Spanish beef cattle breeds assessed by a bovine high-density SNP chip. AB - The availability of SNP chips for massive genotyping has proven to be useful to genetically characterize populations of domestic cattle and to assess their degree of divergence. In this study, the Illumina BovineHD BeadChip genotyping array was used to describe the genetic variability and divergence among 7 important autochthonous Spanish beef cattle breeds. The within-breed genetic diversity, measured as the marker expected heterozygosity, was around 0.30, similar to other European cattle breeds. The analysis of molecular variance revealed that 94.22% of the total variance was explained by differences within individuals whereas only 4.46% was the result of differences among populations. The degree of genetic differentiation was small to moderate as the pairwise fixation index of genetic differentiation among breeds (F) estimates ranged from 0.026 to 0.068 and the Nei's D genetic distances ranged from 0.009 to 0.016. A neighbor joining (N-J) phylogenetic tree showed 2 main groups of breeds: Pirenaica, Bruna dels Pirineus, and Rubia Gallega on the one hand and Avilena Negra Iberica, Morucha, and Retinta on the other. In turn, Asturiana de los Valles occupied an independent and intermediate position. A principal component analysis (PCA) applied to a distance matrix based on marker identity by state, in which the first 2 axes explained up to 17.3% of the variance, showed a grouping of animals that was similar to the one observed in the N-J tree. Finally, a cluster analysis for ancestries allowed assigning all the individuals to the breed they belong to, although it revealed some degree of admixture among breeds. Our results indicate large within-breed diversity and a low degree of divergence among the autochthonous Spanish beef cattle breeds studied. Both N-J and PCA groupings fit quite well to the ancestral trunks from which the Spanish beef cattle breeds were supposed to derive. PMID- 26641037 TI - Estimates of genetic parameters and genetic trends for reproductive traits and weaning weight in Tabapua cattle. AB - The Tabapua breed is a beef cattle Brazilian breed known for its sexual precocity and desirable characteristics for tropical conditions. However, this is a newly formed breed and few studies have been conducted regarding genetic parameters and genetic trends for its reproductive traits. The objective of the present study was to estimate the genetic parameters, genetic trends, and relative selection efficiency for weaning weight adjusted to 210 d of age (W210), age at first calving (AFC), average calving interval (ACI), first calving interval (CI1), and accumulated productivity (ACP) among Tabapua beef cattle. Pedigree data on 15,241 Tabapua animals born between 1958 and 2011 and phenotype records from 7,340 cows born between 1970 and 2011 were supplied by the National Association of Breeders and Researchers (Associacao Nacional de Criadores e Pesquisadores). Analysis through the least squares method assisted in defining the fixed effects that were considered within the models. The estimates for the genetic parameters were obtained through the REML, using a multitrait animal model. The likelihood ratio test applied for W210 was significant ( < 0.05) for the inclusion of maternal additive genetic and permanent environmental effects in the model. Genetic trends were calculated through linear regression of the EBV of the animals, according to the year of birth. The heritability estimates obtained ranged from 0.04 +/- 0.03 for CI1 to 0.25 +/- 0.05 for W210. The genetic correlations ranged from 0.004 +/- 0.19 for W210-AFC and 0.93 +/- 0.12 for ACI-CI1. The genetic trend was significant ( < 0.05) and favorable for CI1 and the maternal genetic effect of W210 and was significant ( < 0.05) and unfavorable for AFC, ACI, and ACP. The ACP could be used in the selection index to assist the breeding goal of improved productive and reproductive performance. The genetic trends indicated small and unfavorable genetic changes for AFC, ACI, and ACP in light of the recent implementation of a genetic breeding program for this breed. PMID- 26641038 TI - Technical note: Isolation and characterization of porcine mammary epithelial cells. AB - Within the mammary gland, functional synthesis of milk is performed by its epithelial (alveolar) cells. The availability of a stable mammary epithelial cell line is essential for biochemical studies to elucidate cellular and molecular mechanisms responsible for nutritional regulation of lactation. Therefore, porcine mammary epithelial cells (PMEC) were isolated from mammary glands of a 9 mo-old nonpregnant and nonlactating gilt and cultured to establish a nonimmortalized cell line. These cells were characterized by expression of cytokeratin-18 (an intermediate filament specific for epithelial cells), beta casein (a specific marker for mammary epithelial cells), and alpha-lactalbumin. In culture, the PMEC doubled in number every 24 h and maintained a cobblestone morphology, typical for cultured epithelial cells, for at least 15 passages. Addition of 0.2 to 2 MUg/mL prolactin to culture medium for 3 d induced the production of beta-casein and alpha-lactalbumin by PMEC in a dose-dependent manner. Thus, we have successfully developed a useful PMEC line for future studies of cellular and molecular regulation of milk synthesis by mammary epithelial cells of the sow. PMID- 26641040 TI - Effects of administration of prostaglandin F at initiation of the seven-day CO Synch+controlled internal drug release ovulation synchronization protocol for suckled beef cows and replacement beef heifers. AB - Two experiments were conducted to determine the effect of administering PGF at the initiation of the 7-d CO-Synch+controlled internal drug release (CIDR) fixed timed AI (TAI) protocol on pregnancy rates of suckled beef cows and replacement heifers. Within location, cows were stratified by days postpartum (DPP), BCS, and parity (Exp. 1; = 1,551) and heifers were stratified by BCS (Exp. 2; = 999) and randomly assigned to 1 of 2 treatments: 1) CO-Synch+CIDR (100-MUg injection of GnRH at CIDR insertion [d -10] with a 25-mg injection of PGF at CIDR removal [d 3] followed by injection of GnRH and TAI on d 0) or 2) PG-CO-Synch+CIDR (a 25-mg injection of PGF on d -10 of the CO-Synch+CIDR protocol). Follicle diameter and corpus luteum (CL) development were assessed on d -10 and -3, and pregnancy status was determined on d 30 to 35. Blood was collected on d -20, -10, -3, and 0 relative to TAI to determine concentrations of progesterone (P4). In Exp. 1, TAI pregnancy rates did not differ ( = 0.667) between treatments and were affected by BCS ( = 0.003) and DPP ( = 0.006). Concentrations of P4 were greater ( < 0.0001) on d -3 for CO-Synch+CIDR than for PG-CO-Synch+CIDR (4.1 +/- 0.2 and 3.4 +/- 0.2 ng/mL, respectively). Follicle diameter on d -3 differed ( = 0.05) between PG-CO Synch+CIDR (13.4 +/- 0.3 mm) and CO-Synch+CIDR (12.5 +/- 0.3 mm) treatments. Cows with P4 > 2.5 ng/mL on d -10 had greater ( = 0.024) pregnancy rate to TAI (56.5%) compared with cows with 2.5 ng/mL < P4 > 1 (43.0%), whereas cows with P4 < 1 ng/mL were intermediate (51.6%). Cows with a CL on d -10 had greater ( = 0.012) pregnancy rates to TAI than cows without a CL (66.3 vs. 39.4%, respectively). In Exp. 2, TAI pregnancy rates did not differ ( = 0.316) between treatments. Concentrations of P4 differed ( < 0.0001) on d -3 with greater concentrations of P4 for CO-Synch+CIDR than for PG-CO-Synch+CIDR (3.75 +/- 0.20 ng/mL and 3.60 +/- 0.21 ng/mL, respectively). Follicle diameter was similar ( = 0.749) between treatments on d -10 and -3. Regardless of treatment, cyclic status tended ( = 0.062) to improve pregnancy rates to TAI (55 vs. 45%, for cycling and noncycling heifers, respectively). We concluded that addition of PGF to the 7-d CO Synch+CIDR protocol decreased concentrations of P4 in cows and heifers and increased follicle diameter at CIDR removal in cows but failed to increase TAI pregnancy rates. PMID- 26641039 TI - Effects of immunological challenge induced by lipopolysaccharide on skeletal muscle fiber type conversion of piglets. AB - The objective of this study was to investigate the effects of immunological challenge on the skeletal muscle fiber type conversion of piglets. Sixteen Large White weaned barrows (28 +/- 3 d, 8.22 +/- 0.89 kg BW) were allotted by weight and litter to 2 groups: the control group and the lipopolysaccharide (LPS) group. Saline (control) or LPS was injected intravenously via a jugular catheter on d 1, 3, 5, 7, 9, 11, 13, and 15 at an initial dosage of 80 MUg/kg BW, which was increased by 30% at each subsequent injection. Blood samples were collected via the jugular catheter 3 h after the LPS challenge on d -1, 1, 5, 9, and 13. Muscle tissue samples were collected from the LM after exsanguination on d 15. The LPS challenge increased the plasma IL-6, tumor necrosis factor-alpha (TNF-alpha), cortisol, IL-1beta, and haptoglobin concentrations on d 1 and 5 ( < 0.01) and increased the plasma IL-6 ( < 0.05), TNF-alpha ( < 0.05), and haptoglobin ( < 0.01) levels on d 9. Compared with that of the control group, the ADG of the LPS group decreased by 40.00% ( < 0.01), 29.52% ( < 0.05), and 19.30% ( < 0.05), and the ADFI decreased by 25.09% ( < 0.01), 23.15% ( < 0.05), and 19.47% ( < 0.05) during d 1 to 4, d 5 to 8, and d 9 to 15, respectively. In the LM of LPS challenged piglets, myosin heavy chain 1 (MyHC1) mRNA and protein expression tended to be reduced ( = 0.08, 0.09), whereas mRNA, mRNA, and MyHC2 protein expression increased ( < 0.05). The LPS challenge reduced succinic dehydrogenase (SDH) activity ( < 0.05) and increased lactate dehydrogenase (LDH) activity ( < 0.05) in the LM of piglets. Compared with those in the control group, transcriptional peroxisome proliferator-activated receptor coactivator-alpha () mRNA ( < 0.05), calcineurin (CaN) mRNA, and protein expression were reduced ( < 0.05), and PGC-alpha protein expression tended to be reduced ( = 0.08) in the LM of LPS-challenged piglets. These results show that immunological challenge induced by LPS resulted in a shift from type I to type II fibers in the LM of piglets, which may be mediated by the downregulation of the CaN/PGC-alpha signaling pathway. PMID- 26641041 TI - Quantification of adenosine triphosphate, adenosine diphosphate, and creatine phosphate in sterlet spermatozoa during maturation. AB - Sturgeon spermatozoa maturation during their passage through the kidney is a prerequisite for initiation of motility. Samples of sterlet () testicular sperm (TS) were matured in vitro by incubation in seminal fluid (SF) or in SF supplemented with carbonyl cyanide -chlorophenyl hydrazone (CCCP; a respiration uncoupling agent). Sperm was diluted in activation medium (AM) containing 10 m Tris-HCl buffer (pH 8.5) and 0.25% Pluronic, and spermatozoon motility was assessed. Samples were taken and fixed in 3 perchloric acid at 3 points in the incubation process. Quantification of ATP, ADP, and creatine phosphate (CrP) was conducted using liquid chromatography/high-resolution mass spectrometry. We observed a significant decrease in CrP during artificial maturation of TS in SF. In contrast, ATP and ADP were not significantly affected. Addition of CCCP to SF halted maturation and led to significantly lower CrP whereas ADP significantly increased and ATP was unaffected. Dilution of matured and immature TS with AM led to a significant decrease of ATP and CrP and an increase of ADP compared with their levels before dilution, although immature TS were not motile. Energy dependency of TS maturation in sturgeon was confirmed, which suggests that mitochondrial oxidative phosphorylation is needed for maturation of sturgeon TS. PMID- 26641042 TI - Preimplantation genetic diagnosis in Welsh pony embryos after biopsy and cryopreservation. AB - Preimplantation genetic diagnosis and embryo cryopreservation are important tools to improve genetic management in equine species with marked consequences on the economic value, health, biodiversity, and preservation of the animals. This study aimed to develop a biopsy method at the blastocyst stage that provides viable genotyped cryopreserved Welsh pony embryos. Embryos were collected at d 6.75 to 7 after ovulation. Biopsies were performed with either a microblade or a micropipette. After biopsy, embryos were cryopreserved. The survival rate of biopsied embryos was evaluated on fresh and cryopreserved embryos either 24 h after in vitro culture or after transfer to recipients. Fresh and nonbiopsied embryos were used as controls. Sex, coat color genes, myotony (neuromuscular disorder) diagnosis, and markers of parentage were investigated using PCR on biopsied cells after whole-genome amplification and on remaining embryos. The embryo survival rate after transfer was not affected by the micropipette biopsy (50%, = 8; 43%, = 7; and 50%, = 12, at d 30 for fresh biopsied embryos, vitrified biopsied embryos, and control embryos, respectively) but was significantly reduced by the use of microblade biopsy: 9 ( = 11) vs. 67% ( = 12) for control embryos. Successful sex determination was achieved for 82% ( = 28) of the micropipette biopsies and 100% ( = 50) of the microblade biopsies. Sex determined on biopsied cells was found to correspond completely (100%) with that determined on the remaining embryo ( = 37). More than 90% of the parentage checking markers, coat color, and myotony diagnosis were successfully determined on biopsies obtained with either a micropipette or a microblade. Mendelian incompatibility (7.5 and 5.5%) and embryo genotyping errors (6.6 and 8.6%) were low and not significantly different between the 2 methods. In conclusion, for the first time, pregnancy at Day 30 was obtained after transfer of Welsh pony biopsied and vitrified embryos >300 MUm in diameter to recipient pony mares. The biopsied cells collected enabled multigenetic embryo diagnoses to be performed to a high degree of accuracy. The micropipette biopsy is the better method to apply on Welsh pony embryos. PMID- 26641043 TI - Postweaning nutritional programming of ovarian development in beef heifers. AB - Peripubertal caloric restriction increases primordial follicle numbers at breeding, which may improve reproductive potential. Our hypothesis was that feed restriction was changing primordial follicle number through stimulation of follicle formation via leptin, roundabout axon guidance receptor, homolog 4 (), or or through inhibition of follicle activation via anti-Mullerian hormone (). Heifers ( = 30) were fed a ration consisting of 30% alfalfa hay, 69.8% corn silage, and 0.2% salt as DM. Heifers received the control diet for 42 d before an initial 6 heifers were ovariectomized at 8 mo of age. The remaining 24 heifers were divided into 2 treatment groups. Controls were offered 97.9 g DM/kg BW over the entire feeding period. Stair-step heifers received 67.4 g DM/kg BW for 84 d. Following the 84-d restriction, heifers were stepped up to receive 118.9 g DM/kg BW over a 15-d period and were held at this feeding level 68 d. At the end of the feed restriction (11 mo of age), ovaries were collected from 6 heifers per treatment, and at the end of the refeeding period (13 mo of age), ovaries were collected from 6 heifers per treatment. Plasma leptin concentrations were greater in control heifers than in stair-step heifers at 11 mo of age ( < 0.0001). In histological sections, stair-step heifers had more primordial follicles ( = 0.03) than control heifers at 13 mo of age. There was no difference in secondary or antral follicle numbers between dietary treatment groups or ages. Relative abundance of mRNA in ovarian cortex of control heifers was greater at 13 mo than at 11 mo or before feed restriction (8 mo; = 0.01). Relative abundance of mRNA in stair-step heifers at 13 mo was greater than before feed restriction ( = 0.02) and at 11 mo did not differ from 8 or 13 mo ( = 0.70). Relative abundance of mRNA in the ovarian cortex followed a similar pattern, being greater in stair-step heifers at 11 mo compared with control heifers ( = 0.001). At 13 mo, mRNA did not differ between treatments ( = 0.30). Abundance of mRNA in the ovarian cortex did not change due to dietary treatment or age ( > 0.10). In conclusion, developing heifers on a stair-step compensatory growth scheme resulted in larger ovarian reserve before the onset of breeding, which may have beneficial effects on increasing reproductive lifespan. PMID- 26641044 TI - Impact of cryopreservation on bull () semen proteome. AB - Cryopreservation of bull spermatozoa is a well-established technique, allowing artificial insemination of cattle on a commercial scale. However, the extent of proteome changes in seminal plasma and spermatozoa during cryopreservation are not yet fully known. The objective of this study was to compare the proteomes of fresh, equilibrated, and cryopreserved bull semen (spermatozoa and seminal plasma) to establish the changes in semen proteins during the cryopreservation process. Semen was collected from 6 mature Holstein Friesian bulls. After sample processing, comparative analysis and identification of proteins was performed using 2-dimensional difference in-gel electrophoresis coupled with matrix assisted laser desorption/ionization mass spectrometry. Analysis of spermatozoa extracts revealed that 25 identified protein spots, representing 16 proteins, underwent significant ( < 0.05) changes in abundance due to equilibration and cryopreservation. Eighteen protein spots decreased in abundance, 5 protein spots increased in abundance, and 2 protein spots showed different, specific patterns of abundance changes. Analysis of seminal fluid containing seminal plasma showed that 6 identified protein spots, representing 4 proteins, underwent significant ( < 0.05) changes in abundance due to equilibration and cryopreservation. Two protein spots increased in abundance and 4 decreased in abundance. Semen extending and equilibration seems to be responsible for a significant portion of the proteome changes related to cryopreservation technology. Most sperm proteins affected by equilibration and cryopreservation are membrane bound, and loss of those proteins may reduce natural spermatozoa coating. Further research is needed to unravel the mechanisms of the particular protein changes described in this study and establish the relationship between those changes and sperm quality. PMID- 26641045 TI - Impact of feeding reduced crude protein diets to lactating sows on nitrogen utilization. AB - Forty lactating multiparous Yorkshire sows were used to test the hypothesis that reducing dietary CP and supplementing with crystalline amino acids (CAA) increases dietary N utilization for milk production during early and peak lactation. Sows were assigned to 1 of 4 diets: 1) 16.0% CP (as-fed; analyzed contents; HCP); 2) 15.7% CP (MHCP); 3) 14.3% CP (MLCP); 4) 13.2% CP (LCP); diet HCP was formulated using soybean meal and corn as the only Lys sources. The reduced CP diets contained CAA to meet requirements of the limiting AA. Sow and piglet BW were measured on d 1, 3, 7, 14, 18, and 21 of lactation. Nitrogen retention was measured on sows between d 3 and 7 (early) and d 14 and 18 (peak) of lactation. Milk true protein output was calculated from estimated milk yield and analyzed true protein concentration. Sow BW change (overall mean: -4.2 +/- 3.37 kg over the 21-d lactation period) and average daily DM intake (overall mean: 4.05 +/- 0.18 and 6.12 +/- 0.20 kg/d, early and peak lactation, respectively) did not differ between diets. Nitrogen intake decreased as dietary CP concentration decreased (114.3, 106.0, 107.4, and 99.0 +/- 5.29 g/d and 169.5, 168.3, 161.2, and 145.1 +/- 5.29 g/d for HCP, MHCP, MLCP, and LCP in early and peak lactation, respectively; L: < 0.05). Sow loin eye area loss tended to increase as dietary CP concentration decreased (Linear (): = 0.082). Litter growth rate (LGR) over the 21-d lactation period tended to increase with decreasing dietary CP concentration (L: = 0.084). In early lactation, N retention (N intake- fecal and urinary N) and milk true protein and casein output were not affected by dietary treatment. In early lactation, as dietary CP decreased, N retained as percentage of N intake tended to increase (L: = 0.093) and estimated efficiency of using retained N for milk N output was not influenced by dietary CP concentration. In peak lactation, N retention (122.5, 123.8, 121.2, and 109.0 +/- 4.88 g/d for HCP, MHCP, MLCP, and LCP, respectively) decreased (L: < 0.05), N retained as percentage of N absorbed (N intake - fecal N) increased (L: < 0.05), milk casein yield increased ( = 0.051), and estimated efficiency of using retained N for milk N output (44.5, 51.0, 54.9, and 62.9 +/- 5.9% for HCP, MHCP, MLCP, and LCP, respectively) increased (L: < 0.05). Feeding lactating diets reduced in CP from 16.0% to 14.3% with CAA inclusion as partial replacement for limiting AA improved N retention and N utilization efficiency for milk protein production in peak lactation, while these effects were less pronounced in early lactation. PMID- 26641046 TI - Effects of high levels of dietary zinc oxide on ex vivo epithelial histamine response and investigations on histamine receptor action in the proximal colon of weaned piglets. AB - The aim of the study was to identify the effect of high dietary zinc oxide (ZnO) levels on the histamine-induced secretory-type response and histamine metabolism in the porcine proximal colon. After weaning at d 26, 3 diets with low (LZn), normal (NZn), and high (HZn) concentrations of zinc (57, 164, or 2,425 mg/kg) were fed to a total of 120 piglets. Digesta and tissue samples were taken from the ascending colon after 7 +/- 1, 14 +/- 1, 21 +/- 1, and 28 +/- 1 d. Partially stripped tissue was mounted in Ussing chambers, and histamine was applied either to the serosal or mucosal compartments. Tissue was pretreated with or without aminoguanidine and amodiaquine to block the histamine-degrading enzymes diamine oxidase (DAO) and histamine -methyltransferase (HMT), respectively. Gene expression and catalytic activity of DAO and HMT in the tissue were analyzed. The numbers of mast cells were determined in tissue samples, and histamine concentration was measured in the colon digesta. Colon tissue from another 12 piglets was used for functional studies on histamine H and H receptors by using the neuronal conduction blocker tetrodotoxin (TTX) and the H and H receptor blocker chloropyramine and famotidine, respectively. After serosal histamine application to colonic tissue in Ussing chambers, the change of short-circuit current (Delta) was not affected by pretreatment and was not different between Zn feeding groups. The Delta after mucosal histamine application was numerically lower ( = 0.168) in HZn compared to LZn and NZn pigs. Mast cell numbers increased from 32 to 46 d of life ( < 0.05). Further studies elucidated that the serosal histamine response was partly inhibited by chloropyramine or famotidine ( < 0.01). The response to mucosal histamine tended to be decreased when chloropyramine but not famotidine was applied from either the serosal or the mucosal side ( = 0.055). Tetrodotoxin alone or in combination with chloropyramine resulted in a similar reduction in the mucosal histamine response ( < 0.01). In conclusion, the present study could not identify marked changes in colonic histamine metabolism on dietary ZnO oversupplementation. For the first time, however, H receptors were functionally identified in the pig colon that are localized either on neurons or on cells that activate secretion via neurons. Luminal histamine can elicit a secretory-type response via these receptors. PMID- 26641047 TI - Temporal plasma vitamin concentrations are altered by fat-soluble vitamin administration in suckling pigs. AB - Piglets are born with purportedly low plasma vitamin D levels. The objective of this study was to investigate the effect of fat-soluble vitamin administration, primarily vitamin D, by different administration routes on plasma vitamin concentrations in suckling pigs. A total of 45 pigs from 5 litters were allotted at birth to 3 treatments within each litter. Pigs were administered 400 IU of alpha-tocopherol, 40,000 IU of retinyl palmitate, and 40,000 IU of vitamin D at d 1 of age either orally or by i.m. injection and compared with control pigs with no supplemental vitamin administration. Blood samples were collected at d 0 (initial), 1, 2, 3, 4, 6, 9, 14, and 20 after administration. Plasma 25 hydroxycholecalciferol (25OHD), alpha-tocopherol, retinyl palmitate, and retinol concentrations were analyzed. Except for retinol, the effects of treatment, day, and day * treatment interaction ( < 0.01) were observed on plasma vitamin concentrations. Plasma concentrations of 25OHD and alpha-tocopherol increased immediately regardless of administration routes to peak at d 2 and 1 after administration, respectively. Plasma retinyl palmitate concentrations increased only with the injection treatment, with the peak at d 1 after administration. Plasma concentrations of 25OHD in both administration treatments and alpha tocopherol in the injection treatment were maintained at greater levels than those in the control treatment until d 20 after administration. With regard to the pharmacokinetic parameters for plasma 25OHD concentrations, the injection treatment had greater elimination half-life ( < 0.01), maximum plasma concentrations ( < 0.05), and all area under the curve parameters ( < 0.01) but a lower elimination rate constant ( < 0.01) than the oral treatment. Relative bioavailability of oral administration compared with injection administration was 55.26%. These results indicate that plasma status of 25OHD,alpha-tocopherol, and retinyl palmitate are differentially changed between types of vitamins administered and between administration routes and that the injection route had a greater increase and slower disappearance of plasma vitamin levels than the oral route during the suckling period. PMID- 26641048 TI - The addition of a Buttiauxella sp. phytase to lactating sow diets deficient in phosphorus and calcium reduces weight loss and improves nutrient digestibility. AB - Improving the efficiency of P use by pigs is especially important for lactating sows, whose metabolic requirements for P and Ca are high. The effect of a sp. phytase on lactating sow performance and nutrient digestibility was investigated using the combined data set for 6 studies. Treatments included a nutritionally adequate positive control diet (PC), a negative control diet (NC; with an average reduction of 0.16% available phosphorous and 0.15% Ca vs. PC), and NC supplemented with a sp. phytase at 250, 500, 1,000 or 2,000 phytase unit (FTU)/kg, respectively. Phosphorus and Ca deficiency in the NC resulted in significantly higher BW loss compared with the PC. All phytase treatments maintained BW loss at the same level as the PC. Increasing doses of phytase significantly ( < 0.05) reduced sow BW loss and increased energy intake, with improvements most apparent in sows older than parity 5. The positive effects on BW and energy intake were not observed in first-parity sows. This may be a consequence of fewer first parity sows in the data set. The apparent total tract digestibility of DM, OM, and CP were not affected by phytase supplementation. Digestible P and Ca were significantly improved (linear, < 0.0001; quadratic, < 0.0001) by increasing the dose of phytase supplementation. Significantly lower apparent total tract digestibility of energy, Ca, and P was found in the NC treatment vs. the PC treatment, whereas no significant differences were found between phytase treatment and the PC treatment. In conclusion, phytase supplementation at a level of 250 FTU/kg can replace 0.16% available phosphorous and 0.15% Ca; however, increasing the phytase dose can further reduce BW loss in sows fed P- and Ca- deficient diets. PMID- 26641049 TI - Effects of arginine supplementation during early gestation (day 1 to 30) on litter size and plasma metabolites in gilts and sows. AB - Two experiments were conducted, under typical commercial swine production conditions, to determine effects of dietary arginine supplementation during early gestation on the performance of gilts and sows. In Exp. 1, between d 1 and 30 of gestation, 62 Landrace gilts and 113 sows consumed a corn- and soybean meal-based diet supplemented with 1.3% -arginine HCl or 2.2% -alanine. Total numbers of piglets born ( < 0.05) and born alive ( < 0.01) per litter and litter birth weights of piglets born ( < 0.05) and born alive ( < 0.05) were increased in the arginine group compared with the control. In Exp. 2, 155 multiparous Landrace sows received 1.3% -arginine HCl supplementation between d 1 and 14 (T2; = 41), d 15 and 30 (T3; = 40), or d 1 and 30 (T4; = 37), whereas the control group received 2.2% -alanine supplementation between d 1 and 30 (T1; = 37). Blood samples were randomly obtained from 6 sows per group on d 1, 14, and 28 of gestation to determine plasma concentrations of AA and related metabolites. Total numbers of piglets born ( = 0.084) and born alive ( = 0.080) per litter tended to be higher for sows supplemented with arginine between d 1 and 14 of gestation (T2) than for control sows (T1). Concentrations of arginine and nitric oxide metabolites were greater ( < 0.05) in T4 compared with T1 and T3 on d 14 of gestation and were also greater in T4 compared with T1 and T2 on d 28 of gestation. Plasma concentrations of spermidine ( < 0.001) were increased in T3 and T4 compared with T1 and T2 on d 28. These results indicate that dietary arginine supplementation during early gestation improves the reproductive performance of gilts and sows, possibly via nitric oxide and polyamine-dependent mechanisms. PMID- 26641050 TI - Efficacy of a supplemental candy coproduct as an alternative carbohydrate source to lactose on growth performance of newly weaned pigs in a commercial farm condition. AB - The experiment investigated the effects of a supplemental candy coproduct (Chocolate Candy Feed [CCF]; International Ingredient Corp., St. Louis, MO), an alternative carbohydrate source to dietary lactose, on growth performance and on health status of nursery pigs. Crossbred pigs ( = 1,408; 21 d of age and 7.1 +/- 0.3 kg BW; Smithfield Premium Genetics, Rose Hill, NC) were randomly assigned to 4 treatments (16 pens/treatment and 22 pigs/pen) in a randomized complete block design: 0, 15, 30, and 45% of lactose replaced by CCF based on equal amounts of total sugars. The experimental period was divided into 3 phases: phase I (1.8 kg diet/pig for 11 +/- 1 d), phase II (6.8 kg diet/pig for 17 +/- 2 d), and phase III (until 49 d after weaning). Pigs received a common phase III diet. The levels of lactose, supplied by whey permeate (79.3 +/- 0.8% lactose), were 20, 8, and 0% in phase I, II, and III, respectively. All experimental diets contained the same levels of essential AA and energy (ME) for each phase. Fecal scores were observed on d 5, 7, and 9 after weaning. Blood samples were taken at the end of phase I and II to measure blood urea N. The duration of phase I tended to linearly decrease ( = 0.063) with increasing CCF. In phase I, the ADFI increased ( < 0.05) with increasing CCF whereas ADG and G:F did not change. In phase II, the duration and ADFI did not change whereas ADG linearly decreased ( < 0.05) with increasing CCF. However, the G:F was not changed as CCF increased. During phase I and II together, the duration was linearly decreased ( < 0.05) as CCF increased, whereas no difference in growth performance was observed. Overall, ADFI, ADG, and G:F were not affected by replacing whey permeate with CCF in diets, indicating no adverse effects of a candy coproduct as a carbohydrate substitute to lactose on growth performance of nursery pigs. Blood urea N did not change in phase I but tended to linearly increase ( = 0.088) in phase II as CCF increased. There were no differences in fecal scores and mortality as CCF increased. However, increasing CCF tended to linearly decrease ( = 0.083) morbidity, which implies no adverse effects of a candy coproduct replacement on health status of nursery pigs. In conclusion, a candy coproduct can be used to replace up to 45% of dietary lactose for nursery pigs without negative effects on growth performance or health status. A candy coproduct could be an economical alternative to partly replace the use of lactose in swine production. PMID- 26641051 TI - Effects of probiotics Pediococcus acidilactici strain MA18/5M and Saccharomyces cerevisiae subsp. boulardii strain SB-CNCM I-1079 on fecal and intestinal microbiota of nursing and weanling piglets. AB - In this study, the influence of (PA) and subsp. (SCB) on fecal and intestinal microbiota of piglets during lactation and after weaning was monitored. Forty sows and their litters were used and allocated to the following dietary treatments: 1) PA, 2) SCB, 3) a mixture of the 2 probiotics (PA+SCB), 4) antibiotics (ATB), and 5) control (CTRL). Four weeks before parturition, probiotic-treated sows started receiving a daily probiotic dose of at least 2.5 * 10 cfu mixed in 500 g of feed until the end of lactation. The other groups were fed a diet without probiotics and ATB. Two days after birth, piglets received, daily, 1 * 10 cfu of the same probiotics as their mother. At weaning (d 21), these piglets were fed a basal diet enriched with the same probiotics whereas piglets from untreated litters were fed the basal diet with or without ATB. Two piglets per litter were randomly chosen to evaluate the influence of treatments on fecal microbial composition (d 10 and 28) and on ileum and colon microbiota at d 37. The microbiota was characterized by culture on selective media and by 16S rRNA gene diversity assessment using the terminal RFLP technique and clone library analysis to evaluate diversity index and phylum affiliation. Terminal RFLP profiles were also analyzed to determine differences in microbial composition between animals receiving different treatments and to identify diet specific terminal restriction fragments (TRF) using pairwise multiresponse permutation procedures (MRPP) and indicator species analysis. Before weaning, administration of probiotics to sows and piglets had minor effect on fecal microbiota of piglets. Most modulatory effects of probiotics on ileum and colon microbiota were observed on d 37. Results revealed that PA or ATB treatments reduced ileal microbiota diversity compared with the CTRL ( < 0.05) and promoted the establishment of Firmicutes whereas SCB consumption positively influenced the establishment of the Porphyromonadaceae and Ruminococcaceae bacterial families in the colon. Moreover, pairwise MRPP analysis indicated that ileum bacterial communities of pigs treated with PA or ATB differed from those of CTRL pigs ( < 0.05). In conclusion, PA and SCB supplements, respectively, influenced, in a strain-dependent manner, the ileum and colon microbiota of weaned piglets. Results also suggest that PA and SCB have the potential as feed additives to modulate bacterial populations associated with gut health. PMID- 26641052 TI - Cecum microbial communities from steers differing in feed efficiency. AB - Apart from the rumen, limited knowledge exists regarding the structure and function of bacterial communities within the gastrointestinal tract and their association with beef cattle feed efficiency. The objective of this study was to characterize the microbial communities of the cecum among steers differing in feed efficiency. Within 2 contemporary groups of steers, individual feed intake and BW gain were determined from animals fed the same diet. Within both of 2 contemporary groups, BW was regressed on feed intake and 4 steers within each Cartesian quadrant were sampled ( = 16/group). Bacterial 16S rRNA gene amplicons were sequenced from the cecal content using next-generation sequencing technology. No significant changes in diversity or richness were detected among quadrants, and UniFrac principal coordinate analysis did not show any differences among quadrants for microbial communities within the cecum. The relative abundances of microbial populations and operational taxonomic units revealed significant differences among feed efficiency groups ( < 0.05). Firmicutes was the dominant cecal phylum in all groups and accounted for up to 81% of the populations among samples. Populations were also dominated by families Ruminococcaceae, Lachnospiraceae, and Clostridiaceae, with significant shifts in the relative abundance of taxa among feed efficiency groups, including families Ruminococcaceae ( = 0.040), Lachnospiraceae ( = 0.020), Erysipelotrichaceae ( = 0.046), and Clostridiaceae ( = 0.043) and genera ( = 0.049), ( = 0.044), ( = 0.042), ( = 0.040), ( = 0.042), and ( = 0.042). The study identified cecal microbial associations with feed efficiency, ADG, and ADFI. This study suggests an association of the cecum microbial community with bovine feed efficiency at the 16S level. PMID- 26641053 TI - Technical Note: Predicting ruminal methane inhibition by condensed tannins using nonlinear exponential decay regression analysis. AB - Methane (CH) is a potent greenhouse gas that is normally produced by microbial fermentation in the rumen and released to the environment mainly during eructation. Prediction of ruminal CH production is important for ruminant nutrition, especially for the determination of ME intake to assess the amount of total GE available for metabolism by an animal. Equations have been developed to predict ruminal CH production based on dietary constituents, but none have considered condensed tannins (CT), which are known to impact CH production by ruminants. The objective was to develop an equation to predict ruminal CH, accounting for CT effects. Methane production data were acquired from 48-h in vitro fermentation of a diverse group of warm-season perennial forage legumes containing different concentrations of CT over the course of 3 yr ( = 113). The following nonlinear exponential decay regression equation was developed: CH4 = 113.6 * exp (-0.1751 x CT) - 2.18), [corrected] in which CH is expressed in grams per kilogram of fermentable organic matter and CT is in percentage of the DM. This equation predicted that CH production could be reduced by approximately 50% when CT is 3.9% DM. This equation is likely more accurate when screening CT containing forages for their potential ability to mitigate in vitro CH production by ruminants when the CT concentration is greater than 3% DM. Therefore, despite the degree of variability in ruminal CH production, this equation could be used as a tool for screening CT-containing forages for their potential to inhibit ruminal CH. Future research should focus on the development of predictive equations when other potential reducers of ruminal CH are used in conjunction with CT. PMID- 26641054 TI - Mitigation of in vitro hydrogen sulfide production using bismuth subsalicylate with and without monensin in beef feedlot diets. AB - The objective of this study was to determine if a sulfur binder, bismuth subsalicylate (BSS), alone or combined with monensin (MON) could decrease the production of HS by rumen microbes. In Exp. 1, two 24-h batch culture incubations were conducted using a substrate consisting of 50% corn, 40% distillers grains, 9.75% hay, and 0.25% mineral premix, on a DM basis. Five treatments including BSS concentrations of 0% (control), 0.5%, 1%, 2%, and 4% of DM were assigned in 5 replicates to 120-mL serum bottles containing rumen fluid, buffer, and 0.5 g of dietary substrate. Addition of 2% and 4% BSS decreased ( < 0.05) gas production, whereas all concentrations of BSS reduced ( < 0.05) HS production by 18%, 24%, 82%, and 99% for 0.5%, 1%, 2%, and 4% BSS, respectively. Final pH increased ( < 0.05) with 2% and 4% BSS treatments. At 4% of DM, BSS decreased ( < 0.05) total VFA concentration (m) and propionate (mol/100 mol) but increased acetate (mol/100 mol) and acetate to propionate ratio. Concentration of branched-chain VFA increased ( < 0.05) with the addition of 0.5% BSS, compared with the control. On the basis of these results, addition of BSS (1% of DM) and MON (5 mg/kg) were used to assess their effects on metabolism and HS release by rumen microbes in 8 dual flow continuous culture fermenters during two 10-d periods (Exp. 2). Treatments were arranged in a 2 * 2 factorial design. Substrate similar to that used in Exp. 1 was provided at 75 g DM/fermenter daily. Headspace HS concentration was reduced ( < 0.05) by 99% with BSS treatment but was not affected ( = 0.21) by MON. An overall increase ( < 0.05) in fermentation pH was found following addition of BSS. Addition of BSS increased ( < 0.05) digestion of NDF and ADF but decreased ( < 0.05) nonfiber carbohydrate digestion and total VFA concentration. Acetate and propionate (mol/100 mol) increased ( < 0.05) with BSS, whereas butyrate (mol/100 mol) and branched-chain VFA (m) decreased ( < 0.05). Addition of BSS increased ( < 0.05) NH-N concentration and NH-N outflow but decreased ( < 0.05) microbial N outflow. Results from this study showed no response to monensin addition, but BSS markedly reduced HS production and altered microbial fermentation during in vitro rumen fluid incubations. PMID- 26641055 TI - Effects of grain source, grain processing, and protein degradability on rumen kinetics and microbial protein synthesis in Boer kids. AB - Microbial protein synthesis in the rumen would be optimized when dietary carbohydrates and proteins have synchronized rates and extent of degradation. The aim of this study was to evaluate the effect of varying ruminal degradation rate of energy and nitrogen sources on intake, nitrogen balance, microbial protein yield, and kinetics of nutrients in the rumen of growing kids. Eight Boer goats (38.2 +/- 3.0 kg) were used. The treatments were arranged in a split-plot Latin square design with grain sources (barley or corn) forming the main plots (squares). Grain processing methods and levels of protein degradability formed the subplots in a 2 * 2 factorial arrangement for a total of 8 dietary treatments. The grain processing method was rolling for barley and cracking for corn. Levels of protein degradability were obtained by feeding untreated soybean meal (SBM) or heat-treated soybean meal (HSBM). Each experimental period lasted 21 d, consisting of a 10-d adaptation period, a 7-d digestibility determination period, and a 4-d rumen evacuation and sampling period. Kids fed with corn had higher purine derivatives (PD) excretion when coupled with SBM compared with HSBM and the opposite occurred with barley-fed kids ( <= 0.01). Unprocessed grain offered with SBM led to higher PD excretion than with HSBM whereas protein degradability had no effect when processed grain was fed ( <= 0.03). Results of the current experiment with high-concentrate diets showed that microbial N synthesis could be maximized in goat kids by combining slowly fermented grains (corn or unprocessed grains) with a highly degradable protein supplement (SBM). With barley, a more rapidly fermented grain, a greater microbial N synthesis was observed when supplementing a low-degradable protein (HSBM). PMID- 26641056 TI - Nitrate but not tea saponin feed additives decreased enteric methane emissions in nonlactating cows. AB - Tea saponin is considered a promising natural compound for reducing enteric methane emissions in ruminants. A trial was conducted to study the effect of this plant extract fed alone or in combination with nitrate on methane emissions, total tract digestive processes, and ruminal characteristics in cattle. The experiment was conducted as a 2 * 2 factorial design with 4 ruminally cannulated nonlactating dairy cows. Feed offer was restricted to 90% of voluntary intake and diets consisted of (DM basis): 1) control (CON; 50% hay and 50% pelleted concentrates), 2) CON with 0.5% tea saponin (TEA), 3) CON with 2.3% nitrate (NIT), and 4) CON with 0.5% tea saponin and 2.3% nitrate (TEA+NIT). Tea saponin and nitrate were included in pelleted concentrates. Diets contained similar amounts of CP (12.2%), starch (26.0%), and NDF (40.1%). Experimental periods lasted 5 wk including 2 wk of measurement (wk 4 and 5), during which intake was measured daily. In wk 4, daily methane emissions were quantified for 4 d using open circuit respiratory chambers. In wk 5, total tract digestibility, N balance, and urinary excretion of purine derivatives were determined from total feces and urine collected separately for 6 d. Ruminal fermentation products and protozoa concentration were analyzed from samples taken after morning feeding for 2 nonconsecutive days in wk 5. Tea saponin and nitrate supplementation decreased feed intake ( < 0.05), with an additive effect when fed in combination. Compared with CON, tea saponin did not modify methane emissions (g/kg DMI; > 0.05), whereas nitrate-containing diets (NIT and TEA+NIT) decreased methanogenesis by 28%, on average ( < 0.001). Total tract digestibility, N balance, and urinary excretion of purine derivatives were similar among diets. Ruminal fermentation products were not affected by tea saponin, whereas nitrate-containing diets increased acetate proportion and decreased butyrate proportion and ammonia concentration ( < 0.05). Under the experimental conditions tested, we confirmed the antimethanogenic effect of nitrate, whereas tea saponin alone included in pelleted concentrates failed to decrease enteric methane emissions in nonlactating dairy cows. PMID- 26641058 TI - Assessment of algae meal as a ruminant feedstuff: Nutrient digestibility in sheep as a model species. AB - Heterotrophic microalgae combined with soyhulls forms an algae meal (ALG), which contains partially deoiled microalgae (PDM; 57% DM basis) and soyhulls (43%). Two experiments were conducted to evaluate the effects of PDM and ALG on lamb digestibility. In Exp. 1, 8 wethers (23.02 +/- 0.54 kg) were used in a 4 * 4 Latin square design to determine the effect of the PDM portion of ALG on total tract nutrient digestibility. Diets included a soyhull-based control (CON; 53% soyhulls), 10% PDM from ALG, 20% PDM from ALG (PDM20), and 30% PDM from ALG. Dry matter and OM intake and fecal DM and OM output were similar ( >= 0.11) between CON- and ALG-fed lambs. Urine output linearly increased ( = 0.02) as PDM increased in diets. Dry matter, OM, NDF, and ADF digestibility linearly decreased ( < 0.01) as PDM increased in diets. Ether extract digestibility did not differ ( = 0.24) between CON- and PDM-fed lambs. Nitrogen digestibility and N retention linearly decreased ( <= 0.05) as PDM increased in the diet. In Exp. 2, to determine the effects of ALG on diet and nutrient digestibility and N retention, 10 whiteface cross wethers (33.71 +/- 0.55 kg) were used in a replicated 5 * 5 Latin square. Diets included a cracked corn-based control (CORN), 15% ALG, 30% ALG, 45% ALG (ALG45), and 60% ALG (ALG60). Dry matter and OM digestibility linearly ( < 0.001) decreased as ALG inclusion increased. Digestibility of NDF and ADF were lesser ( <= 0.03) for CORN-fed sheep than for ALG-fed sheep and linearly ( <= 0.03) increased as ALG increased in the diet. Ether extract digestibility was lesser ( = 0.002) for CORN than ALG, with a linear ( = 0.002) increase as ALG inclusion increased. There was a cubic ( = 0.03) effect for N digestibility with ALG45 and ALG60 being lesser and CORN being greater than all other treatments. Retention of N and plasma urea N concentration did not differ ( >= 0.22) between CORN and ALG. Nonfibrous carbohydrate digestibility linearly ( < 0.001) decreased as ALG increased in the diet. These results suggest that the PDM portion of ALG may be less digestible than soyhulls in ruminants, and differences in N retention in Exp. 1 may suggest an effect on growth in lambs. Furthermore, changes in digestibility of specific nutrients suggest that ALG is more characteristic of a concentrate rather than a fibrous feedstuff. However, lambs will readily consume ALG and this novel feedstuff could potentially serve as a viable component of ruminant diets. PMID- 26641057 TI - Diets of differentially processed wheat alter ruminal fermentation parameters and microbial populations in beef cattle. AB - The influences of differently processed wheat products on rumen fermentation, microbial populations, and serum biochemistry profiles in beef cattle were studied. Four ruminally cannulated Limousin * Luxi beef cattle (400 +/- 10 kg) were used in the experiment with a 4 * 4 Latin square design. The experimental diets contained (on a DM basis) 60% corn silage as a forage source and 40% concentrate with 4 differently processed wheat products (extruded, pulverized, crushed, and rolled wheat). Concentrations of ruminal NH-N and microbial protein (MCP) in cattle fed crushed and rolled wheat were greater ( < 0.05) than the corresponding values in cattle fed pulverized and extruded wheat. Ruminal concentrations of total VFA and acetate and the ratio of acetate to propionate decreased ( < 0.05) with increased geometric mean particle size (geometric mean diameter) of processed wheat, except for extruded wheat; cattle fed extruded wheat had the lowest concentrations of total VFA and acetate among all treatments. The relative abundance of , , ciliated protozoa, and was lower in cattle fed the pulverized wheat diet than in the other 3 diets ( < 0.05), whereas the relative abundance of was decreased in cattle fed extruded wheat compared with cattle fed crushed and rolled wheat ( < 0.05). No treatment effect was obtained for serum enzyme activity and protein concentration ( > 0.05). Our findings suggest that the method of wheat processing could have a significant effect on ruminal fermentation parameters and microbial populations in beef cattle and that crushed and rolled processing is better in terms of ruminal NH-N and MCP content, acetate-to-propionate ratio, and relative abundance of rumen microorganisms. PMID- 26641059 TI - Evaluating equations estimating change in swine feed intake during heat and cold stress. AB - The objectives of this study were to evaluate heat stress feed intake models for growing swine using a data set assembled from the literature and to develop a series of new equations modeling the influence of the thermal environment and interactions between the thermal environmental and other factors on feed intake. A literature survey was conducted to identify studies assessing intake responses to temperature. The resulting data set comprised 35 studies containing 120 comparisons to thermoneutral intake. Intake as a fraction of thermoneutral intake (FFI) was the primary response variable, where a value of 1 represented no change from thermoneutral intake. The FFI predicted by NRC and a recent model from a meta-analysis (Renaudeau et al.,) were compared to observed values. New parameters for the NRC equation (NRCmod) were derived, and a series of new equations incorporating duration of exposure (TD), temperature cycling (TC), and floor type (TH) were also derived. Root-mean-square prediction error (RMSPE) and concordance correlation coefficients were used to evaluate all models. The RMSPE for the NRC model was 23.6 with mean and slope bias accounting for 12.6% and 51.1% of prediction error, respectively. The TD, TC, and TH models had reduced RMSPE compared with NRC: 12.9 for TD, 12.6 for TC, and 12.9 for TS. Substantial improvements were also made by refitting parameters (NRCmod; RMSPE 13.0%). In NRCmod, TD, TC, and TH, random error was the predominant source, accounting for over 97% of prediction error. The Renaudeau et al. model was also evaluated. Renaudeau et al. had relatively low RMSPE (22.3) for intake but higher RMSPE for FFI (22.6) than NRC, NRCmod, TD, TC, or TH. Additional parameters were derived for the Renaudeau et al. equation to account for housing system and diet characteristics. This adjustment reduced RMSPE of predicting feed intake (16.0) and FFI (16.3) and reduced systematic bias in the equation. This evaluation of equations highlights the effects of novel explanatory variables on feed intake during heat stress, and the comparison can be useful when selecting a model that best explains variability in feed intake responses to heat stress given available input data. PMID- 26641060 TI - Evaluation of implant strategies in Angus-sired steers with high or low genetic potential for marbling and gain. AB - Sixty-nine Angus-sired steer calves (332.3 kg initial BW) were used to determine the effects of single or double implant strategies on steers of high or low genetic potential (GP) determined by the GeneMax (Zoetis, Florham Park, NJ) genetic profiling test. Steers were assigned to treatments in a 2 * 2 factorial design with factors of 1) composite GP score (high, mean GP score of 86.5 [HI]; low, mean GP score of 25.3[LO]) and 2) implant strategy (single, steers implanted on d 70 [1X], or double, steers implanted d 0 and 70 [2X]). All steers were given the same implant (Revalor-S; Merck Animal Health, Summit, NJ), with the 2X group implanted on d 0 and 70 and the 1X group implanted only on d 70. A diet containing 1.38 Mcal NEg/kg DM was fed ad libitum, once daily. Ultrasound was used to measure body composition characteristics on d 0 and 70. Steers were harvested after 140 d on feed. At both the d-0 and d-70 ultrasound, HI steers had greater ( < 0.001) percent intramuscular fat (IMF) than LO steers, but no differences ( >= 0.24) were observed in LM area (LMA), rib fat thickness (RF), or rump fat thickness (RMFT). Steers in the 2X group had larger ( = 0.02) LMA and less ( = 0.03) IMF on d 70 than 1X steers and no differences ( >= 0.50) in RF or RMFT were observed. From d 0 to 70, HI steers had ADG, DMI, and G:F ( >= 0.60) similar to LO steers; however, 2X steers had greater ( < 0.001) ADG and were more ( < 0.001) feed efficient compared with 1X steers during the same interval. Over the entire 140-d feeding period, there were no differences ( >= 0.6) in BW, ADG, DMI, or G:F between GP groups; however, 2X steers had greater ( = 0.03) ADG compared with 1X steers and still had similar ( >= 0.12) DMI and G:F. Upon slaughter, marbling score tended to be impacted by a GP * implant interaction (499.9 +/- 18.5, 545.6 +/- 18.5, 487.1 +/- 18.5, and 469.8 +/- 18.5 for HI and 2X, HI and 1X, LO and 2X, and LO and 1X, respectively; = 0.06). No differences ( >= 0.7) were observed between GP groups for HCW, LMA, RF, KPH, or yield grade (YG). Steers in the 1X group had less ( = 0.003) RF than 2X steers but similar ( >= 0.14) HCW, marbling, LMA, KPH, and YG. A greater proportion ( = 0.03) of HI steers had choice carcasses (100 +/- 0.0%) compared with LO steers (87.8 +/- 3.9%). Results of this study indicate that the GP test used in the current study predicted differences in IMF, carcass marbling, and percent carcasses graded as choice. PMID- 26641061 TI - Impacts of temperament on Nellore cattle: physiological responses, feedlot performance, and carcass characteristics. AB - Forty-four feedlot-finished Nellore cattle were used to evaluate the impacts of temperament on performance, meat and carcass traits, and serum concentrations of hormones, proteins, enzymes, and immunoglobulins. Individual temperament was assessed at feedlot entry (d 0), 67 d, and 109 d, utilizing chute score (CS; 5 point scale) and exit velocity (EV). Temperament scores were calculated averaging CS and EV scores, and cattle were subsequently classified according to their temperament (an average of <=3 = adequate temperament [ADQ], or an average of >3 = excitable temperament [EXC]). At the end of the experiment (d 109), all 44 animals were slaughtered, and 16 were randomly selected for final empty body weight (EBW) estimation. Blood samples were collected at 0, 67, and 109 d and analyzed for serum variables (cortisol, insulin, haptoglobin, total protein, lactate, creatinine kinase [CK], lactate dehydrogenase [LDH], and IgA). The incidence of carcass bruises was verified immediately after the hide was removed. Carcass pH was obtained at 0 and 24 h postmortem. Samples of the LM were collected for meat quality analyses. Cattle classified as ADQ had greater final BW ( = 0.03), final EBW ( = 0.02), metabolic weight ( = 0.03), ADG ( = 0.02), feed efficiency ( = 0.03), HCW ( = 0.02), cold carcass weight ( = 0.02), and LM area ( < 0.01) compared to that of the EXC cohorts. Cattle classified as ADQ tended to have a lower percentage of cooler shrink ( = 0.06) compared to that of EXC cattle. No temperament effects were detected for initial BW ( = 0.70), DMI ( = 0.14), cold dressing percentage ( = 0.98), or backfat thickness ( = 0.29). Cattle classified as ADQ had greater marbling ( = 0.02) and meat fat content ( = 0.05) compared with that of EXC cattle. No temperament effects ( > 0.05) were detected for unsaturated fatty acid (UFA), SFA, MUFA, PUFA, and n-6:n-3 ratio. For blood parameters, EXC cattle had greater values of cortisol ( = 0.04) and haptoglobin ( = 0.05) and tended ( = 0.06) to have reduced serum insulin concentration compared with ADQ cattle. Both temperament groups had similar serum concentrations of IgA ( = 0.25) and total protein ( = 0.84). Cattle classified as EXC presented greater amounts ( = 0.05) of carcass bruises. In conclusion, an EXC temperament impaired feedlot performance, carcass characteristics, and meat quality traits in finishing Nellore cattle. PMID- 26641062 TI - Decreasing the frequency of energy supplementation from daily to three times weekly impairs growth and humoral immune response of preconditioning beef steers. AB - We evaluated the effects of frequency of energy supplementation on growth and measurements of innate and humoral immune responses of preconditioning beef steers following vaccination. Angus steers ( = 24; 221 +/- 6.3 kg; 177 +/- 4 d of age) were weaned on d -7 and kept in a single drylot pen with free access to tall fescue hay and concentrate DMI at 0.5% of BW (50:50 mix of soyhulls and corn gluten pellets; DM basis) from d -7 to 0. On d 0, steers were stratified by BW and age and randomly assigned to 1 of 8 feedlot pens (3 steers/pen). Treatments were randomly assigned to pens (4 pens/treatment) and consisted of steers provided daily free access to ground tall fescue hay and similar weekly concentrate DMI (1% of BW times 7 d), which was divided and offered either daily (S7) or 3 times weekly (S3; Monday, Wednesday, and Friday) from d 0 to 42. Individual BW was measured before feeding on d 0 and 42, after 12 h of feed and water withdrawal. Steers were vaccinated against infectious bovine rhinotracheitis, bovine viral diarrhea virus (BVDV), and clostridium on d 7 and 21. Blood samples were collected from the jugular vein on d -7 and 4 h after concentrate supplementation on d 0, 7, 8, 9, 10, 14, 21, 22, 23, 24, 28, 35, and 42. Steers offered concentrate daily had greater ( <= 0.02) BW on d 42, overall ADG, and total DMI, but similar ( = 0.14) G:F, than S3 steers. On days that S7 and S3 steers were offered concentrate, total DMI was greater and hay DMI was less for S3 vs. S7 steers ( <= 0.05). On days that only S7 steers were supplemented, hay DMI was greater, but total DMI was less for S3 vs. S7 steers ( <= 0.05). Mean CP and NEg intake were greater ( <= 0.03) for S7 vs. S3 steers. Plasma cortisol concentrations on d 7 and 28, and mean plasma haptoglobin concentrations, but not liver mRNA expression of haptoglobin ( = 0.75), were greater for S3 vs. S7 steers ( <= 0.03). Plasma IGF-1 concentrations on d 0 and urea nitrogen on d 1 and 3, relative to vaccination, were greater for S7 vs. S3 steers ( <= 0.008). Positive seroconversion to BVDV-1b on d 42 and mean serum BVDV-1b titers were greater for S7 vs. S3 steers ( <= 0.05). In summary, decreasing the frequency of concentrate supplementation from daily to three times weekly, during a 42-d preconditioning period, decreased growth performance, increased plasma concentrations of haptoglobin and cortisol, and decreased vaccine-induced antibody production against BVDV-1b of beef steers. PMID- 26641063 TI - Development of piglets raised in a new multi-litter housing system vs. conventional single-litter housing until 9 weeks of age. AB - This study compared the development until 9 wk of age of piglets raised in either a multi-litter (ML) system or a conventional single-litter (SL) system. The ML system consisted of a multi-suckling system with 5 sows and their litters before weaning, followed by housing in a pen with enrichment in a group of 40 piglets after weaning. In the SL system, piglets were housed with a crated sow before weaning, followed by postweaning housing in groups of 10 littermates in a standard pen. Fifty litters were used in 5 batches and piglets were weaned at 4 wk of age. Preweaning mortality was higher in the ML system than in the SL system (3.22 +/- 0.42 vs. 1.52 +/- 0.25 piglets per litter, < 0.01), mainly due to crushing before grouping of litters. Litter size at grouping did not differ between systems. ML piglets showed more feed-directed behavior at 2 wk of age (6.80 +/- 0.96 vs. 2.35 +/- 0.59, < 0.01), suggesting an earlier start of feed exploration, possibly due to social learning from the floor-fed sows and other piglets. Moreover, before weaning, ML piglets showed less damaging oral manipulation (e.g., tail biting) than SL piglets (1.4 +/- 0.2 vs. 3.6 +/- 0.3 freq/h, < 0.001), which was likely related to the more enriched environment in the ML system. After weaning, ML piglets ate 81% more feed between d 1 and 2 (0.29 +/- 0.02 vs. 0.16 +/- 0.03 kg/piglet, < 0.01) and had an 82% higher weight gain until d 5 than SL piglets (1.35 +/- 0.21 vs. 0.75 +/- 0.17 kg, < 0.05) despite a similar weaning weight (ML: 8.4 +/- 0.2 kg, SL: 8.3 +/- 0.2 kg). Within the first 2 wk after weaning, ML piglets had a lower fecal consistency score (0.27 +/- 0.03 vs. 0.39 +/- 0.03, < 0.05), indicating a lower occurrence of diarrhea compared with SL piglets. Over the entire 5-wk postweaning phase, ML piglets had a 24% higher weight gain ( < 0.05) and showed more play behavior (4.0 +/- 0.3 vs. 2.8 +/- 0.3 freq/h, < 0.05) and less damaging oral manipulation (1.8 +/- 0.3 vs. 3.5 +/- 0.4 freq/h, < 0.01) than SL piglets. These results are probably explained by a combination of the differences in preweaning development, early postweaning performance, and postweaning environment, with a larger and more diverse social group and more physical enrichment in the ML pen. To summarize, provided that preweaning mortality can be reduced, the ML system seems promising for raising robust piglets with better welfare, indicated by a better preweaning behavioral development, improved transition to the postweaning phase, and better postweaning performance. PMID- 26641064 TI - Shade use by small groups of domestic horses in a hot, sunny environment. AB - Horses in the United States are commonly managed in outside pens or pastures in small groups. Limited research on shade use by domestic horses housed singly in individual pens has shown benefits and a preference for using available shade. The objective of this study was to examine the amount of shade use and the behavioral and physiological responses of small groups of horses when housed with access to shade (SH) and without access to shade (SUN). Thirty-six horses were randomized into 3 consecutive trials using 3 horses per group and 4 groups per trial. Groups experienced 5 d in each treatment in a crossover design. Weather factors were measured with automated sensors 24 h/d throughout the study. The mean afternoon ambient temperature was 31.0 degrees C with relative humidity of 32%. Rectal temperature, respiration rate, and skin temperature were recorded at 1000, 1330, and 1900 h daily. Venous blood samples were obtained on Days 0 and 5 to measure serum cortisol, the neutrophil:lymphocyte ratio, and hematocrit. Behavioral observations for presence in shade, standing near or away from water, locomotion, and foraging were recorded at 5-min intervals from 1400 to 1900 h daily. Insect avoidance behaviors were recorded hourly during that same time period for 1 min/horse. Horses in the SH treatment were observed using shade in 7.1% of observations between 1400 and 1900 h, and behavioral differences were observed between the SH and SUN treatments. When in the SUN treatment, horses stood near the water troughs more (18.5 vs. 14.2% of observations; = 0.029) and foraged less (29.3 vs. 33.8% of observations; < 0.001) than when in the SH treatment. There were no treatment differences for other behaviors or for physiological measures ( > 0.05). Provision of shade structures accessible to groups of mature, healthy horses in hot, sunny environments should be considered in developing future guidelines for best management practices for horses. PMID- 26641066 TI - Errata. PMID- 26641065 TI - Pregnancy disruption in artificially inseminated domestic horse mares as a counterstrategy against potential infanticide. AB - In a previous study, we suggested that the common practice of transporting a mare for mating and then bringing her back to an environment that also contains males that did not sire the fetus may be a major cause of high percentages of pregnancy disruption in domestic horses. In this study, we tested whether disruption of pregnancies induced by AI occurs as frequently as after mating with a strange stallion away from home and is affected by the same factors in the home social environment. Based on 77 records, the probability of pregnancy disruption after AI depended on the social environment in which the mare was maintained after mating and the number of foals the mare had delivered in the past. Also after AI, as with natural matings away from home, the probability of pregnancy disruption was higher when the mare had no male company in her enclosure but stallions or geldings were present in an adjacent enclosure than when the mare was sharing the enclosure with geldings (generalized linear mixed model = 8.68, = 0.007, odds ratio = 8.17). These data support the prediction that the mare perceives conception after AI equally to natural mating with a strange stallion. The results suggested pregnancy disruption may be stimulated by the social circumstances of the home environment in mares artificially inseminated as in mares mated naturally away from home. The practical implications of this result is that after AI, to reduce risk of pregnancy disruption and improve welfare, horse breeders should place the pregnant mare into an environment with no stallion or stallions/gelding or geldings or to an enclosure together with the male or males. PMID- 26641067 TI - Fibroblasts prolong serum prostate-specific antigen decline after androgen deprivation therapy in prostate cancer. AB - In patients with prostate cancer (PCa), serum prostate-specific antigen (PSA) is a useful marker for evaluating the effects of androgen deprivation therapy (ADT). Intuitively, most urologists expect that a more rapid PSA decline in response to ADT would be positively associated with extended survival. Recently, we have reported that prolonged gradual serum PSA decline after ADT is strongly associated with favorable prognosis in PCa patients, however, the mechanism remains unknown. We investigated the role of fibroblasts in serum PSA decline after ADT. We performed in vitro experiments using androgen-sensitive, androgen receptor (AR)-positive prostate epithelial cell lines (LNCaP, 22Rv1, and RWPE-1 cells), commercially available prostate stromal cells (PrSC), and primary cultures of prostate fibroblasts (pcPrFs). In LNCaP and 22Rv1 cells, PSA production was increased by co-culture with fibroblasts under androgen-deprived conditions. In an in vivo model using LNCaP cells, serum PSA declined rapidly after ADT becoming undetectable within 14 days in mice inoculated with LNCaP cells alone. In contrast, when LNCaP cells were co-inoculated with fibroblasts, serum PSA levels were still high on 14 days post ADT and did not drop to undetectable levels until 21 days post ADT. Tumor volumes and Ki67 labeling indices were not altered between days 14 and 21 post ADT in mice inoculated with LNCaP cells; however, those in mice inoculated with LNCaP cells plus fibroblasts decreased gradually. PSA protein was detected in all tumors on 21 days post ADT by immunohistochemical staining. Microvessel densities were higher on 14 days post ADT for tumors from mice inoculated with LNCaP cells plus fibroblasts as compared with LNCaP cells alone. In summary, co-inoculation of fibroblasts with LNCaP cells prolonged serum PSA decline after ADT and enhanced the efficacy of ADT. Prolonged serum PSA decline may indicate the presence of protective fibroblasts that preserve the AR dependence of PCa cells, improving treatment efficacy. PMID- 26641069 TI - Dkk3 prevents familial dilated cardiomyopathy development through Wnt pathway. AB - To date, the role of Dickkopf 3 (Dkk3) on the pathogenesis of familial dilated cardiomyopathy (FDCM), and whether and how Dkk3 interferes with Wnt signaling in heart tissues remains unknown. Here, we demonstrate that strong Dkk3 expression was markedly downregulated in adult hearts from WT mice, and Dkk3 expression was upregulated suddenly in hearts from DCM mouse models. Using Dkk3 transgenic and knockout mice, as well as cTnT(R141W) transgenic mice, which manifests progressive chamber dilation and contractile dysfunction and has pathologic phenotypes similar to human DCM patients, we determined that transgenic expression of Dkk3 increased survival rate, improved cardiac morphology breakage and dysfunction, and ameliorated cardiac pathological changes in the cTnT(R141W) mice. In contrast, Dkk3 knockout reduced the survival rate and aggravated the pathological phenotypes of the cTnT(R141W) mice. The protective effects of Dkk3 appeared clearly at 3 months of age, peaked at 6 months of age, and decreased at 10 months of age in the cTnT(R141W) mice. Furthermore, we determined that Dkk3 upregulated Dvl1 (Dishevelled 1) and key proteins of the canonical Wnt pathway (cytoplasmic and nuclear beta-catenin, c-Myc, and Axin2) and downregulated key proteins of the noncanonical Wnt pathway (c-Jun N-terminal kinase (JNK), Ca(2+)/calmodulin-dependent protein kinase II (CAMKII), and histone deacetylase 4 (HDAC4)). In contrast, Dkk3 knockout reversed these changes in the cTnT(R141W) mice. In summary, Dkk3 could prevent FDCM development in mice, especially in the compensatory stage, and probably through activation of the canonical and inhibition of the noncanonical Wnt pathway, which suggested that Dkk3 could serve as a therapeutic target for the treatment of cardiomyopathy and heart failure. PMID- 26641068 TI - WNT signaling in glioblastoma and therapeutic opportunities. AB - WNTs and their downstream effectors regulate proliferation, death, and migration and cell fate decision. Deregulation of WNT signaling is associated with various cancers including GBM, which is the most malignant primary brain cancer. In this review, we will summarize the experimental evidence supporting oncogenic roles of WNT signaling in GBM and discuss current progress in the targeting of WNT signaling as an anti-cancer approach. In particular, we will focus on (1) genetic and epigenetic alterations that lead to aberrant WNT pathway activation in GBM, (2) WNT-mediated control of GBM stem cell maintenance and invasion, and (3) cross talk between WNT and other signaling pathways in GBM. We will then review the discovery of agents that can inhibit WNT signaling in preclinical models and the current status of human clinical trials. PMID- 26641071 TI - The Fundamentals of Laparoscopic Surgery and LapVR evaluation metrics may not correlate with operative performance in a novice cohort. AB - BACKGROUND: Considerable resources have been invested in both low- and high fidelity simulators in surgical training. The purpose of this study was to investigate if the Fundamentals of Laparoscopic Surgery (FLS, low-fidelity box trainer) and LapVR (high-fidelity virtual reality) training systems correlate with operative performance on the Global Operative Assessment of Laparoscopic Skills (GOALS) global rating scale using a porcine cholecystectomy model in a novice surgical group with minimal laparoscopic experience. METHODS: Fourteen postgraduate year 1 surgical residents with minimal laparoscopic experience performed tasks from the FLS program and the LapVR simulator as well as a live porcine laparoscopic cholecystectomy. Performance was evaluated using standardized FLS metrics, automatic computer evaluations, and a validated global rating scale. RESULTS: Overall, FLS score did not show an association with GOALS global rating scale score on the porcine cholecystectomy. None of the five LapVR task scores were significantly associated with GOALS score on the porcine cholecystectomy. CONCLUSIONS: Neither the low-fidelity box trainer or the high fidelity virtual simulator demonstrated significant correlation with GOALS operative scores. These findings offer caution against the use of these modalities for brief assessments of novice surgical trainees, especially for predictive or selection purposes. PMID- 26641070 TI - Wnt signaling in cartilage development and diseases: lessons from animal studies. AB - Cartilage not only plays essential roles in skeletal development and growth during pre- and postnatal stages but also serves to provide smooth movement of skeletons throughout life. Thus, dysfunction of cartilage causes a variety of skeletal disorders. Results from animal studies reveal that beta-catenin dependent canonical and independent non-canonical Wnt signaling pathways have multiple roles in regulation of cartilage development, growth, and maintenance. beta-Catenin-dependent signaling is required for progression of endochondral ossification and growth of axial and appendicular skeletons, while excessive activation of this signaling can cause severe inhibition of initial cartilage formation and growth plate organization and function in mice. In contrast, non canonical Wnt signaling is important in columnar organization of growth plate chondrocytes. Manipulation of Wnt signaling causes or ameliorates articular cartilage degeneration in rodent osteoarthritis models. Human genetic studies indicate that Wnt/beta-catenin signaling is a risk factor for osteoarthritis. Accumulative findings from analysis of expression of Wnt signaling molecules and in vivo and in vitro functional experiments suggest that Wnt signaling is a therapeutic target for osteoarthritis. The target tissues of Wnt signaling may be not only articular cartilage but also synovium and subchondral bone. PMID- 26641072 TI - Apoptotic vesicles as tumor vaccine. PMID- 26641073 TI - Psychological essentialism, gender, and parenthood: Physical transformation leads to heightened essentialist conceptions. AB - Psychological essentialism is the tendency to view entities as if they have an underlying, often invisible essence that makes them what they are (Medin & Ortony, 1989), and the presence of a genetic basis for group membership contributes to such conceptions (Dar-Nimrod & Heine, 2011; Keller, 2005). We argue that undergoing visually salient physical transformations in the process of becoming a group member leads to particularly heightened essentialist conceptions. We test this idea in the context of parenthood. Public discourse suggests the category mother is imbued with special properties and is viewed as a deeper, more lasting, and real category than father. Such perceptions may contribute to unequal work outcomes for women relative to men. Collectively, the 5 studies reported show that mothers are perceived in more essentialist terms than fathers, and that physical changes women undergo in the process of becoming mothers play a substantial role in producing this difference. Moreover, viewing mothers as a particularly natural and real category predicted judgments that women struggle to successfully manage their roles as mothers and professionals, but only when motherhood was biological in nature. The role that observable physical transformations may play in the reification of categories is discussed. PMID- 26641074 TI - When is shame linked to constructive approach orientation? A meta-analysis. AB - Despite recent evidence that episodic shame can be linked to the constructive approach of failure (i.e., prosociality, self-improvement), the prevailing view is that shame is neither constructive nor approach-oriented. To integrate these opposing views, we conducted a theory-driven meta-analysis of 90 samples from the published literature (N = 12,364). As expected, shame had a positive link to constructive approach when failure (g = .47, 95% confidence interval [CI] [.37, .55]) or social image (g = .37, 95% CI [.06, .68]) was more reparable. In contrast, shame had a negative link to constructive approach when failure was less reparable (g = -.34, 95% CI [-.53, -.14]). A supplemental meta-analysis of 42 samples showed shame and guilt to have a similar positive link to constructive approach orientation when failure was more reparable (g = .44 and .43), but not when it was less reparable (g = -.08 and .27). PMID- 26641075 TI - Brief Morning Light Exposure, Visuomotor Performance, and Biochemistry in Sport Shooters. AB - CONTEXT: Demands on concentrative and cognitive performance are high in sport shooting and vary in a circadian pattern, aroused by internal and external stimuli. The most prominent external stimulus is light. Bright light (BL) has been shown to have a certain impact on cognitive and physical performance. PURPOSE: To evaluate the impact of a single half hour of BL exposure in the morning hours on physical and cognitive performance in 15 sport shooters. In addition, courses of sulfateoxymelatonin (aMT6s), tryptophan (TRP), and kynurenine (KYN) were monitored. METHODS: In a crossover design, 15 sport shooters were exposed to 30 min of BL and dim light (DL) in the early-morning hours. Shooting performance, balance, visuomotor performance, and courses of aMT6s, TRP, and KYN were evaluated. RESULTS: Shooting performance was 365.4 (349.7-381.0) and 368.5 (353.9-383.1), identical in both light setups. Numbers of right reactions (sustained attention) and deviations from the horizontal plane (balance-related measure) were higher after BL. TRP concentrations decreased from 77.5 (73.5-81.4) to 66.9 (60.7-67.0) in the DL setup only. CONCLUSIONS: The 2 light conditions generated heterogeneous visuomotor and physiological effects in sport shooters. The authors therefore suggest that a single half hour of BL exposure is effective in improving cognitive aspects of performance, but not physical performance. Further research is needed to evaluate BL's impact on biochemical parameters. PMID- 26641076 TI - Association between Hyaluronic Acid Injections and Time-to-Total Knee Replacement Surgery. AB - This study assessed the association between hyaluronic acid (HA) injections and time-to-total knee replacement (TKR) surgery for patients with knee osteoarthritis (OA). Patients 18 to 64 years of age who had TKR surgery between January 1, 2006 and December 31, 2011 were identified from the MarketScan Commercial claims database. All patients had 6 years or more of continuous enrollment prior to TKR surgery. There were two cohorts (1) patients with HA injections prior to TKR surgery and (2) patients who did not have HA injections prior to TKR surgery. Time-to-TKR was defined as the total days from the date of diagnosis of knee OA on the patient's first visit to an orthopedic surgeon to the date of TKR surgery. Results included 22,555 patients who had TKR surgery: 14,132 in the non-HA and 8,423 in the HA cohort. In this retrospective analysis of patients undergoing TKR, the median Time-to-TKR surgery was 326 days for the non HA and 908 days for the HA cohort, a difference of 582 days. Those receiving HA injections had a median 1.6-year longer Time-to-TKR surgery versus those who did not receive HA injections. These results have both clinical and economic implications. PMID- 26641077 TI - Subchondroplasty for Treating Bone Marrow Lesions. AB - The prognosis of osteoarthritis (OA) is worsened by persistent subchondral defects known as bone marrow lesions (BMLs), which herald severe joint degeneration and the need for joint replacement. Joint-preserving treatments that reverse the progression of pain and immobility are limited. Subchondroplasty is a procedure developed to treat BMLs by injecting a calcium phosphate bone substitute into compromised subchondral bone, under fluoroscopic guidance. Here we evaluate the effectiveness of this approach for relieving pain and improving function in patients with documented BMLs and advanced knee OA, in a retrospective study. Data were collected from a consecutive patient series (n = 66) who underwent subchondroplasty combined with arthroscopy, performed at a single center by one surgeon. We observed significant improvements in both pain and function following subchondroplasty with arthroscopic debridement, as measured by the visual analog scale (VAS) and the International Knee Documentation Committee (IKDC) Subjective Knee Evaluation Form, through 2 years postoperative follow-up. Given that arthroscopic debridement alone has been previously shown to yield insignificant pain relief beyond 6 months postoperatively, our results suggest that subchondroplasty may be a promising approach for the treatment of OA with BMLs. PMID- 26641078 TI - Biphasic Analysis of Cartilage Stresses in the Patellofemoral Joint. AB - The objective of this study was to examine the state of stress within the solid matrix of articular cartilage in the patellofemoral joint, using anatomically faithful biphasic models of the articular layers, with the joint subjected to physiologic muscle force magnitudes. Finite element models of five joints were created from human cadaver knees. Biphasic sliding contact analyses were performed using FEBio software to analyze the response of the joint from 30 to 60 degrees of knee flexion. Results demonstrated that the collagen matrix always sustains tensile stresses, despite the fact that the articular layers are loaded in compression. The principal direction of maximum solid stresses was consistent with the known orientation of collagen fibrils in cartilage. The magnitudes of these tensile stresses under muscle forces representative of activities of daily living were well below tensile failure stresses reported in the prior literature. Results also hinted that solid matrix stresses were higher in the patellar versus femoral superficial zone. These anatomically correct finite element models predicted outcomes consistent with our understanding of structure-function relationships in articular cartilage, while also producing solid matrix stress estimates not observable from experiments alone, yet highly relevant to our understanding of tissue degeneration. PMID- 26641079 TI - Malignancies in Primary Sclerosing Cholangitis--A Continuing Threat. AB - Primary sclerosing cholangitis (PSC) is a chronic inflammatory liver disease of unknown etiology, primarily targeting cholangiocytes at any portion of the biliary tree. No effective medical treatments are currently available. A unique feature of PSC is its close association (about 80%) with inflammatory bowel disease (IBD), mainly ulcerative colitis (UC). As in many chronic inflammatory conditions, cancer development can complicate PSC, accounting for >40% of deaths. Cholangiocarcinoma (CCA), gallbladder carcinoma (GBC) and colorectal carcinoma (CRC) have been variably associated to PSC, with a prevalence up to 13-14%. The risk of cancer is one of the most challenging issues in the management of PSC; it raises several questions about cancer surveillance, early diagnosis, prevention and treatment. KEY MESSAGES: Among the different cancers complicating PSC, CCA is the most relevant, because it is more frequent (incidence of 0.5-1.5%) and because the prognosis is poor (5-year survival <10%). Early diagnosis of CCA in PSC can be difficult because lesions may not be evident in radiological studies. Surgical resection provides disappointing results; liver transplantation combined with neoadjuvant chemoradiotherapy is being proposed, but this approach is limited to a highly selected group of patients and is available only in a few specialized centers. Similar to CCA, GBC carries a dismal prognosis. Since it is difficult to discriminate GBC from other gallbladder abnormalities, cholecystectomy has been proposed in all gallbladder lesions detected in PSC, regardless of their size. CRC is a frequent complication of PSC associated to UC; its incidence steadily increases with time of colitis, reaching up to 20-30% of the patients after 20 years. Colonoscopy with extensive histologic sampling at an annual/biannual interval is an effective surveillance strategy. However, when dysplastic lesions are detected, preemptive proctocolectomy should be considered. CONCLUSIONS: PSC may be regarded as paradigmatic of the sequence leading from chronic inflammatory epithelial damage to neoplastic transformation. Understanding the molecular mechanisms regulating this pathogenetic sequence, may improve strategies of disease surveillance and cancer prevention and treatment. PSC is a chronic inflammatory cholangiopathy of unknown etiology but likely immune-mediated, characterized by peribiliary inflammation and fibrosis leading to strictures in any portion (intra- and/or extrahepatic) of the bile duct system. No effective medical treatments are currently available. A unique feature of PSC is the close association (about 80%) with IBD, mainly UC, often diagnosed before PSC (PSC/UC). As in other chronic inflammatory diseases, development of malignancies is a feared complication of PSC. PMID- 26641080 TI - Children Born Preterm at the Turn of the Millennium Had Better Lung Function Than Children Born Similarly Preterm in the Early 1990s. AB - OBJECTIVE: Compare respiratory health in children born extremely preterm (EP) or with extremely low birthweight (ELBW) nearly one decade apart, hypothesizing that better perinatal management has led to better outcome. DESIGN: Fifty-seven (93%) of 61 eligible 11-year old children born in Western Norway in 1999-2000 with gestational age (GA) <28 weeks or birthweight <1000 gram (EP1999-2000) and matched term-controls were assessed with comprehensive lung function tests and standardized questionnaires. Outcome was compared with data obtained at 10 years of age from all (n = 35) subjects born at GA <29 weeks or birthweight <1001 gram within a part of the same region in 1991-92 (EP1991-1992) and their matched term controls. RESULTS: EP1999-2000 had significantly reduced forced expiratory flow in 1 second (FEV1), FEV1 to forced vital capacity (FEV1/FVC) and forced expiratory flow between 25-75% of FVC (FEF25-75), with z-scores respectively 0.34, -0.50 and -0.61 below those of the term-control group, and more bronchial hyperresponsiveness to methacholine (dose-response-slope 13.2 vs. 3.5; p<0.001), whereas other outcomes did not differ. Low birthweight z-scores, but not neonatal bronchopulmonary dysplasia (BPD) or low GA, predicted poor outcome. For children with neonatal BPD, important lung-function variables were better in EP1999-2000 compared to EP1991-1992. In regression models, improvements were related to more use of antenatal corticosteroids and surfactant treatment in the EP1999-2000. CONCLUSIONS: Small airway obstruction and bronchial hyperresponsiveness were still present in children born preterm in 1999-2000, but outcome was better than for children born similarly preterm in 1991-92, particularly after neonatal BPD. The findings suggest that better neonatal management not only improves survival, but also long-term pulmonary outcome. PMID- 26641081 TI - Kinetics of Respiratory Syncytial Virus (RSV) Memphis Strain 37 (M37) Infection in the Respiratory Tract of Newborn Lambs as an RSV Infection Model for Human Infants. AB - RATIONALE: Respiratory syncytial virus (RSV) infection in preterm and newborn infants can result in severe bronchiolitis and hospitalization. The lamb lung has several key features conducive to modeling RSV infection in human infants, including susceptibility to human strains of RSV such as the A2, Long, and Memphis Strain 37 (M37). In this study, the kinetics of M37 infection was investigated in newborn lambs in order to better define clinical, viral, physiological, and immunological parameters as well as the pathology and lesions. METHODS: Newborn lambs were nebulized with M37 hRSV (6 mL of 1.27 x 10(7) FFU/mL), monitored daily for clinical responses, and respiratory tissues were collected from groups of lambs at days 1, 3, 4, 6, and 8 post-inoculation for the assessment of viral replication parameters, lesions and also cellular, immunologic and inflammatory responses. RESULTS: Lambs had increased expiratory effort (forced expiration) at days 4, 6, and 8 post-inoculation. Nasal wash lacked RSV titers at day 1, but titers were present at low levels at days 3 (peak), 4, and 8. Viral titers in bronchoalveolar lavage fluid (BALF) reached a plateau at day 3 (4.6 Log10 FFU/mL), which was maintained until day 6 (4.83 Log10 FFU/mL), and were markedly reduced or absent at day 8. Viral RNA levels (detected by RT-qPCR) in BALF were indistinguishable at days 3 (6.22 +/- 0.08 Log10 M37 RNA copies/mL; mean +/- se) and 4 (6.20 +/- 0.16 Log10 M37 RNA copies/mL; mean +/- se) and increased slightly on day 6 (7.15 +/- 0.2 Log10 M37 RNA copies/mL; mean +/- se). Viral antigen in lung tissue as detected by immunohistochemistry was not seen at day 1, was present at days 3 and 4 before reaching a peak by day 6, and was markedly reduced by day 8. Viral antigen was mainly present in airways (bronchi, bronchioles) at day 3 and was increasingly present in alveolar cells at days 4 and 6, with reduction at day 8. Histopathologic lesions such as bronchitis/bronchiolitis, epithelial necrosis and hyperplasia, peribronchial lymphocyte infiltration, and syncytial cells, were consistent with those described previously for lambs and infants. CONCLUSION: This work demonstrates that M37 hRSV replication in the lower airways of newborn lambs is robust with peak replication on day 3 and sustained until day 6. These findings, along with the similarities of lamb lung to those of infants in terms of alveolar development, airway branching and epithelium, susceptibility to human RSV strains, lesion characteristics (bronchiolitis), lung size, clinical parameters, and immunity, further establish the neonatal lamb as a model with key features that mimic RSV infection in infants. PMID- 26641082 TI - Molecular Genotyping of Giardia duodenalis Isolates from Symptomatic Individuals Attending Two Major Public Hospitals in Madrid, Spain. AB - BACKGROUND: The flagellate protozoan Giardia duodenalis is an enteric parasite causing human giardiasis, a major gastrointestinal disease of global distribution affecting both developing and industrialised countries. In Spain, sporadic cases of giardiasis have been regularly identified, particularly in pediatric and immigrant populations. However, there is limited information on the genetic variability of circulating G. duodenalis isolates in the country. METHODS: In this longitudinal molecular epidemiological study we report the diversity and frequency of the G. duodenalis assemblages and sub-assemblages identified in 199 stool samples collected from 184 individual with symptoms compatible with giardiasis presenting to two major public hospitals in Madrid for the period December 2013-January 2015. G. duodenalis cysts were initially detected by conventional microscopy and/or immunochomatography on stool samples. Confirmation of the infection was performed by direct immunofluorescence and real-time PCR methods. G. duodenalis assemblages and sub-assemblages were determined by multi locus genotyping of the glutamate dehydrogenase (GDH) and beta-giardin (BG) genes of the parasite. Sociodemographic and clinical features of patients infected with G. duodenalis were also analysed. PRINCIPAL FINDINGS: Of 188 confirmed positive samples from 178 giardiasis cases a total of 124 G. duodenalis isolates were successfully typed at the GDH and/or the BG loci, revealing the presence of sub assemblages BIV (62.1%), AII (15.3%), BIII (4.0%), AI (0.8%), and AIII (0.8%). Additionally, 6.5% of the isolates were only characterised at the assemblage level, being all of them assigned to assemblage B. Discordant genotype results AII/AIII or BIII/BIV were also observed in 10.5% of DNA isolates. A large number of multi-locus genotypes were identified in G. duodenalis assemblage B, but not assemblage A, isolates at both the GDH and BG loci, confirming the high degree of genetic variability observed in other molecular surveys. BIV was the most prevalent genetic variant of G. duodenalis found in individuals with symptomatic giardiasis in the population under study. CONCLUSIONS: Human giardiasis is an ongoing public health problem in Spain affecting primarily young children under four years of age but also individuals of all age groups. Our typing and sub typing results demonstrate that assemblage B is the most prevalent G. duodenalis assemblage circulating in patients with clinical giardiasis in Central Spain. Our analyses also revealed a large genetic variability in assemblage B (but not assemblage A) isolates of the parasite, corroborating the information obtained in similar studies in other geographical regions. We believe that molecular data presented here provide epidemiological evidence at the population level in support of the existence of genetic exchange within assemblages of G. duodenalis. PMID- 26641083 TI - No Reef Is an Island: Integrating Coral Reef Connectivity Data into the Design of Regional-Scale Marine Protected Area Networks. AB - We integrated coral reef connectivity data for the Caribbean and Gulf of Mexico into a conservation decision-making framework for designing a regional scale marine protected area (MPA) network that provides insight into ecological and political contexts. We used an ocean circulation model and regional coral reef data to simulate eight spawning events from 2008-2011, applying a maximum 30-day pelagic larval duration and 20% mortality rate. Coral larval dispersal patterns were analyzed between coral reefs across jurisdictional marine zones to identify spatial relationships between larval sources and destinations within countries and territories across the region. We applied our results in Marxan, a conservation planning software tool, to identify a regional coral reef MPA network design that meets conservation goals, minimizes underlying threats, and maintains coral reef connectivity. Our results suggest that approximately 77% of coral reefs identified as having a high regional connectivity value are not included in the existing MPA network. This research is unique because we quantify and report coral larval connectivity data by marine ecoregions and Exclusive Economic Zones (EZZ) and use this information to identify gaps in the current Caribbean-wide MPA network by integrating asymmetric connectivity information in Marxan to design a regional MPA network that includes important reef network connections. The identification of important reef connectivity metrics guides the selection of priority conservation areas and supports resilience at the whole system level into the future. PMID- 26641085 TI - Glomerular Hypertrophy Is a Risk Factor for Relapse in Minimal Change Disease Patients. AB - BACKGROUND/AIMS: Patients with minimal change disease (MCD) have a high relapse rate, which results in many complications. Identifying the risk factors for relapse is crucial, but little is known about these factors. Therefore, we performed the current study to determine the factors related to relapse in this patient population. METHODS: We retrospectively analyzed 51 adult patients with biopsy-proven primary MCD treated between 2003 and 2013. The demographic, physiologic, laboratory and therapeutic data were gathered from the electronic medical records database. Lesions of the glomerulus, tubulointerstitium and vasculature were analyzed for associations with relapse. RESULTS: During a median 50.9 months, 96.1% (49 of 51) of patients had achieved complete remission, and the rest ultimately achieved at least partial remission. A total of 56.9% (29 of 51) patients experienced at least 1 episode of relapse after the first remission. Patients with relapse had a higher rate of glomerular hypertrophy (GH; 34.5%) than those without relapse (9.1%; p < 0.05). After adjusting for confounders, GH was associated with increased odds of relapse (OR 15.992; 95% CI 1.537-166.362; p = 0.02). In a subgroup analysis according to median age, sex and tubulointerstitial (TI) lesions, the association between GH and relapse was evident only in men and in the group with TI lesions. CONCLUSION: GH is associated with relapse in adult patients with MCD, particularly in men and in those with TI lesions. Frequent monitoring and early intervention are needed in these groups. Future large prospective cohort studies are needed to confirm the study results. PMID- 26641084 TI - Generation of Triple-Transgenic Forsythia Cell Cultures as a Platform for the Efficient, Stable, and Sustainable Production of Lignans. AB - Sesamin is a furofuran lignan biosynthesized from the precursor lignan pinoresinol specifically in sesame seeds. This lignan is shown to exhibit anti hypertensive activity, protect the liver from damages by ethanol and lipid oxidation, and reduce lung tumor growth. Despite rapidly elevating demand, plant sources of lignans are frequently limited because of the high cost of locating and collecting plants. Indeed, the acquisition of sesamin exclusively depends on the conventional extraction of particular Sesamum seeds. In this study, we have created the efficient, stable and sustainable sesamin production system using triple-transgenic Forsythia koreana cell suspension cultures, U18i-CPi-Fk. These transgenic cell cultures were generated by stably introducing an RNAi sequence against the pinoresinol-glucosylating enzyme, UGT71A18, into existing CPi-Fk cells, which had been created by introducing Sesamum indicum sesamin synthase (CYP81Q1) and an RNA interference (RNAi) sequence against pinoresinol/lariciresinol reductase (PLR) into F. koreanna cells. Compared to its transgenic prototype, U18i-CPi-Fk displayed 5-fold higher production of pinoresinol aglycone and 1.4-fold higher production of sesamin, respectively, while the wildtype cannot produce sesamin due to a lack of any intrinsic sesamin synthase. Moreover, red LED irradiation of U18i-CPi-Fk specifically resulted in 3.0-fold greater production in both pinoresinol aglycone and sesamin than production of these lignans under the dark condition, whereas pinoresinol production was decreased in the wildtype under red LED. Moreover, we developed a procedure for sodium alginate-based long-term storage of U18i-CPi-Fk in liquid nitrogen. Production of sesamin in U18i-CPi-Fk re-thawed after six-month cryopreservation was equivalent to that of non-cryopreserved U18i-CPi-Fk. These data warrant on-demand production of sesamin anytime and anywhere. Collectively, the present study provides evidence that U18i-CP-Fk is an unprecedented platform for efficient, stable, and sustainable production of sesamin, and shows that a transgenic and specific light-regulated Forsythia cell-based metabolic engineering is a promising strategy for the acquisition of rare and beneficial lignans. PMID- 26641086 TI - Homocysteine Level Is Associated with White Matter Hyperintensity Locations in Patients with Acute Ischemic Stroke. AB - BACKGROUND AND PURPOSE: The relationship between plasma level of total homocysteine (tHcy) and white matter hyperintensities (WMHs), especially in patients with acute ischemic stroke (AIS), is controversial. The present study investigated the association between these two as well as WMH locations in a large cohort of patients with AIS. METHODS: Consecutive patients were reviewed from a prospective ischemic stroke database. Clinical data, including tHcy level and WMHs, were assessed. WMHs were assessed using the Fazekas scale and Age Related White Matter Changes (ARWMC) visual grading scale. The association between tHcy and WMH locations was investigated by using multivariate logistic regression analyses. RESULTS: A total of 923 out of 1,205 patients were examined. The average age was 58.9 +/- 11.9 years; 31.6% were female. Elevated tHcy level was significantly associated with WMHs. For the highest tHcy quartile, the odds ratio (OR) (95% confidence interval; CI) was 1.891 (1.257; 2.843) according to the Fazekas scale and 1.781 (1.185; 2.767) according to the ARWMC scale when compared to the lowest quartile. However, in a subgroup analysis, only WMHs in the periventricular area and left or right frontal areas were found to be independently associated with tHcy level. For the highest tHcy quartile, the OR (95% CI) was 1.761 (1.172; 2.648) for the periventricular WMHs, 1.768 (1.134; 2.756)for the left frontal WMHs, and 1.890 (1.206; 2.960)for the right frontal WMHs. CONCLUSIONS: In patients with AIS, plasma tHcy level is related to WMHs, especially WMHs distributed within the periventricular and frontal areas. PMID- 26641088 TI - Amastin Knockdown in Leishmania braziliensis Affects Parasite-Macrophage Interaction and Results in Impaired Viability of Intracellular Amastigotes. AB - Leishmaniasis, a human parasitic disease with manifestations ranging from cutaneous ulcerations to fatal visceral infection, is caused by several Leishmania species. These protozoan parasites replicate as extracellular, flagellated promastigotes in the gut of a sandfly vector and as amastigotes inside the parasitophorous vacuole of vertebrate host macrophages. Amastins are surface glycoproteins encoded by large gene families present in the genomes of several trypanosomatids and highly expressed in the intracellular amastigote stages of Trypanosoma cruzi and Leishmania spp. Here, we showed that the genome of L. braziliensis contains 52 amastin genes belonging to all four previously described amastin subfamilies and that the expression of members of all subfamilies is upregulated in L. braziliensis amastigotes. Although primary sequence alignments showed no homology to any known protein sequence, homology searches based on secondary structure predictions indicate that amastins are related to claudins, a group of proteins that are components of eukaryotic tight junction complexes. By knocking-down the expression of delta-amastins in L. braziliensis, their essential role during infection became evident. delta-amastin knockdown parasites showed impaired growth after in vitro infection of mouse macrophages and completely failed to produce infection when inoculated in BALB/c mice, an attenuated phenotype that was reverted by the re-expression of an RNAi resistant amastin gene. Further highlighting their essential role in host parasite interactions, electron microscopy analyses of macrophages infected with amastin knockdown parasites showed significant alterations in the tight contact that is normally observed between the surface of wild type amastigotes and the membrane of the parasitophorous vacuole. PMID- 26641089 TI - Comparative Genomic Analyses of the Human NPHP1 Locus Reveal Complex Genomic Architecture and Its Regional Evolution in Primates. AB - Many loci in the human genome harbor complex genomic structures that can result in susceptibility to genomic rearrangements leading to various genomic disorders. Nephronophthisis 1 (NPHP1, MIM# 256100) is an autosomal recessive disorder that can be caused by defects of NPHP1; the gene maps within the human 2q13 region where low copy repeats (LCRs) are abundant. Loss of function of NPHP1 is responsible for approximately 85% of the NPHP1 cases-about 80% of such individuals carry a large recurrent homozygous NPHP1 deletion that occurs via nonallelic homologous recombination (NAHR) between two flanking directly oriented ~45 kb LCRs. Published data revealed a non-pathogenic inversion polymorphism involving the NPHP1 gene flanked by two inverted ~358 kb LCRs. Using optical mapping and array-comparative genomic hybridization, we identified three potential novel structural variant (SV) haplotypes at the NPHP1 locus that may protect a haploid genome from the NPHP1 deletion. Inter-species comparative genomic analyses among primate genomes revealed massive genomic changes during evolution. The aggregated data suggest that dynamic genomic rearrangements occurred historically within the NPHP1 locus and generated SV haplotypes observed in the human population today, which may confer differential susceptibility to genomic instability and the NPHP1 deletion within a personal genome. Our study documents diverse SV haplotypes at a complex LCR-laden human genomic region. Comparative analyses provide a model for how this complex region arose during primate evolution, and studies among humans suggest that intra-species polymorphism may potentially modulate an individual's susceptibility to acquiring disease-associated alleles. PMID- 26641090 TI - Characterization of VAMP2 in Schistosoma japonicum and the Evaluation of Protective Efficacy Induced by Recombinant SjVAMP2 in Mice. AB - BACKGROUND: The outer-tegument membrane covering the schistosome is believed to maintain via the fusion of membranous vesicles. Fusion of biological membranes is a fundamental process in all eukaryotic cells driven by formation of trans-SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) complexes through pairing of vesicle associated v-SNAREs (VAMP) with complementary t-SNAREs on target membranes. The purpose of this study was to characterize Schistosoma japonicum vesicle-associated membrane protein 2 (SjVAMP2) and to investigate its potential as a candidate vaccine against schistosomiasis. METHODOLOGY/PRINCIPAL FINDINGS: The sequence of SjVAMP2 was analyzed, cloned, expressed and characterized. SjVAMP2 is a member of the synaptobrevin superfamily harboring the v-SNARE coiled-coil homology domain. RT-PCR analysis revealed that significantly higher SjVAMP2 levels were observed in 14-, 28- and 42-day-old worms, and SjVAMP2 expression was much higher in 42-day-old female worms than in those male worms. Additionally, the expression of SjVAMP2 was associated with membrane recovery in PZQ-treated worms. Immunostaining assay showed that SjVAMP2 was mainly distributed in the sub-tegument of the worms. Western blotting revealed that rSjVAMP2 showed strong immunogenicity. Purified rSjVAMP2 emulsified with ISA206 adjuvant induced 41.5% and 27.3% reductions in worm burden, and 36.8% and 23.3% reductions in hepatic eggs in two independent trials. Besides, significantly higher rSjVAMP2-specific IgG, IgG1, IgG2a levels were detected in rSjVAMP2 vaccinated mice. CONCLUSION: Our study indicated that SjVAMP2 is a potential vaccine candidate against S. japonicum and provided the basis for further investigations into the biological function of SjVAMP2. PMID- 26641091 TI - Semi-Supervised Multi-View Learning for Gene Network Reconstruction. AB - The task of gene regulatory network reconstruction from high-throughput data is receiving increasing attention in recent years. As a consequence, many inference methods for solving this task have been proposed in the literature. It has been recently observed, however, that no single inference method performs optimally across all datasets. It has also been shown that the integration of predictions from multiple inference methods is more robust and shows high performance across diverse datasets. Inspired by this research, in this paper, we propose a machine learning solution which learns to combine predictions from multiple inference methods. While this approach adds additional complexity to the inference process, we expect it would also carry substantial benefits. These would come from the automatic adaptation to patterns on the outputs of individual inference methods, so that it is possible to identify regulatory interactions more reliably when these patterns occur. This article demonstrates the benefits (in terms of accuracy of the reconstructed networks) of the proposed method, which exploits an iterative, semi-supervised ensemble-based algorithm. The algorithm learns to combine the interactions predicted by many different inference methods in the multi-view learning setting. The empirical evaluation of the proposed algorithm on a prokaryotic model organism (E. coli) and on a eukaryotic model organism (S. cerevisiae) clearly shows improved performance over the state of the art methods. The results indicate that gene regulatory network reconstruction for the real datasets is more difficult for S. cerevisiae than for E. coli. The software, all the datasets used in the experiments and all the results are available for download at the following link: http://figshare.com/articles/Semi_supervised_Multi_View_Learning_for_Gene_Network Reconstruction/1604827. PMID- 26641093 TI - Sentiment of Emojis. AB - There is a new generation of emoticons, called emojis, that is increasingly being used in mobile communications and social media. In the past two years, over ten billion emojis were used on Twitter. Emojis are Unicode graphic symbols, used as a shorthand to express concepts and ideas. In contrast to the small number of well-known emoticons that carry clear emotional contents, there are hundreds of emojis. But what are their emotional contents? We provide the first emoji sentiment lexicon, called the Emoji Sentiment Ranking, and draw a sentiment map of the 751 most frequently used emojis. The sentiment of the emojis is computed from the sentiment of the tweets in which they occur. We engaged 83 human annotators to label over 1.6 million tweets in 13 European languages by the sentiment polarity (negative, neutral, or positive). About 4% of the annotated tweets contain emojis. The sentiment analysis of the emojis allows us to draw several interesting conclusions. It turns out that most of the emojis are positive, especially the most popular ones. The sentiment distribution of the tweets with and without emojis is significantly different. The inter-annotator agreement on the tweets with emojis is higher. Emojis tend to occur at the end of the tweets, and their sentiment polarity increases with the distance. We observe no significant differences in the emoji rankings between the 13 languages and the Emoji Sentiment Ranking. Consequently, we propose our Emoji Sentiment Ranking as a European language-independent resource for automated sentiment analysis. Finally, the paper provides a formalization of sentiment and a novel visualization in the form of a sentiment bar. PMID- 26641092 TI - The Activation-Induced Assembly of an RNA/Protein Interactome Centered on the Splicing Factor U2AF2 Regulates Gene Expression in Human CD4 T Cells. AB - Activation of CD4 T cells is a reaction to challenges such as microbial pathogens, cancer and toxins that defines adaptive immune responses. The roles of T cell receptor crosslinking, intracellular signaling, and transcription factor activation are well described, but the importance of post-transcriptional regulation by RNA-binding proteins (RBPs) has not been considered in depth. We describe a new model expanding and activating primary human CD4 T cells and applied this to characterizing activation-induced assembly of splicing factors centered on U2AF2. We immunoprecipitated U2AF2 to identify what mRNA transcripts were bound as a function of activation by TCR crosslinking and costimulation. In parallel, mass spectrometry revealed the proteins incorporated into the U2AF2 centered RNA/protein interactome. Molecules that retained interaction with the U2AF2 complex after RNAse treatment were designated as "central" interactome members (CIMs). Mass spectrometry also identified a second class of activation induced proteins, "peripheral" interactome members (PIMs), that bound to the same transcripts but were not in physical association with U2AF2 or its partners. siRNA knockdown of two CIMs and two PIMs caused changes in activation marker expression, cytokine secretion, and gene expression that were unique to each protein and mapped to pathways associated with key aspects of T cell activation. While knocking down the PIM, SYNCRIP, impacts a limited but immunologically important set of U2AF2-bound transcripts, knockdown of U2AF1 significantly impairs assembly of the majority of protein and mRNA components in the activation induced interactome. These results demonstrated that CIMs and PIMs, either directly or indirectly through RNA, assembled into activation-induced U2AF2 complexes and play roles in post-transcriptional regulation of genes related to cytokine secretion. These data suggest an additional layer of regulation mediated by the activation-induced assembly of RNA splicing interactomes that is important for understanding T cell activation. PMID- 26641095 TI - Two Monthly Continuous Dynamic Model Based on Nash Bargaining Theory for Conflict Resolution in Reservoir System. AB - So far many optimization models based on Nash Bargaining Theory associated with reservoir operation have been developed. Most of them have aimed to provide practical and efficient solutions for water allocation in order to alleviate conflicts among water users. These models can be discussed from two viewpoints: (i) having a discrete nature; and (ii) working on an annual basis. Although discrete dynamic game models provide appropriate reservoir operator policies, their discretization of variables increases the run time and causes dimensionality problems. In this study, two monthly based non-discrete optimization models based on the Nash Bargaining Solution are developed for a reservoir system. In the first model, based on constrained state formulation, the first and second moments (mean and variance) of the state variable (water level in the reservoir) is calculated. Using moment equations as the constraint, the long-term utility of the reservoir manager and water users are optimized. The second model is a dynamic approach structured based on continuous state Markov decision models. The corresponding solution based on the collocation method is structured for a reservoir system. In this model, the reward function is defined based on the Nash Bargaining Solution. Indeed, it is used to yield equilibrium in every proper sub-game, thereby satisfying the Markov perfect equilibrium. Both approaches are applicable for water allocation in arid and semi-arid regions. A case study was carried out at the Zayandeh-Rud river basin located in central Iran to identify the effectiveness of the presented methods. The results are compared with the results of an annual form of dynamic game, a classical stochastic dynamic programming model (e.g. Bayesian Stochastic Dynamic Programming model, BSDP), and a discrete stochastic dynamic game model (PSDNG). By comparing the results of alternative methods, it is shown that both models are capable of tackling conflict issues in water allocation in situations of water scarcity properly. Also, comparing the annual dynamic game models, the presented models result in superior results in practice. Furthermore, unlike discrete dynamic game models, the presented models can significantly reduce the runtime thereby avoiding dimensionality problems. PMID- 26641096 TI - AIH: Which Alternative for Difficult-to-Treat Patients? AB - BACKGROUND: Oftentimes we are expected to make difficult decision when patients with autoimmune hepatitis (AIH) present themselves before us. Among these cases, advanced liver cirrhosis, fulminant AIH with hepatic failure or pregnancy with highly active AIH will pose challenges on their own. In patients where standard treatment has failed, the risk of disease progression including liver transplantation has to be weighed against the risk of drug-related side effects, including infectious complications. KEY MESSAGES: Standard treatment of AIH includes the use of drugs like corticosteroids and usually azathioprine. However, up to 15% of patients will require second-line treatment. There are no prospective studies evaluating second- or third-line treatment regimens in AIH. In our opinion, it is essential to differentiate between those patients who are intolerant and those who do not respond sufficiently to standard treatment. For patients intolerant to prednisolone due to steroid-induced side effects, budesonide may be a feasible alternative, unless liver cirrhosis forbids its use. Our experience indicates that 6-mercaptopurine may be given as an alternative to azathioprine, especially in cases of gastrointestinal side effects, with good tolerance and response rates of up to 70%. As a more expensive alternative, mycophenolat mofetil (MMF) has been shown to effectively suppress disease activity in a majority of patients intolerant to azathioprine. Of note, MMF is contraindicated in pregnancy. In patients with insufficient response to azathioprine, the dose should be increased up to 2.5 mg/kg of body weight, and measurement of azathioprine metabolites (6TGN and MMP) may aid the optimal dosage. Several other immunosuppressive treatment strategies have been tested and published in small case series. These include the calcineurin inhibitors cyclosporine A and tacrolimus, mTOR inhibitors, anti-tumor necrosis factor alpha treatment with infliximab, rituximab as well as cyclophosphamide. CONCLUSIONS: It is difficult to tell whether 1 strategy is superior to another in the case of difficult-to-treat AIH patients. Intolerance should be differentiated from insufficient response to standard treatment. The choice of second- and third-line treatment will depend on the comorbidities, patient's choice after informed consent and also local expertise. PMID- 26641097 TI - Distribution and Availability of Essential Tuberculosis Diagnostic Items in Amhara Region, Ethiopia. AB - Adequate supplies of tuberculosis laboratory reagents and consumables are necessary for tuberculosis diagnosis and monitoring of treatment response. This study assessed the distribution and stock levels of laboratory commodities used in tuberculosis control in health centers of Amhara region, Ethiopia. A cross sectional study was conducted in 82 health centers, among 801, providing sputum microscopy services. Stock levels were calculated, and distribution of reagents and consumables assessed. Thirty three (40.2%) health centers were under stocked for at least one of the key items for tuberculosis diagnosis at the time of visit. Fifteen (18.3%) health centers had no stocks of at least one of the key items (methylene blue (11%), carbol fuchsin (11%), acid alcohol (8.5%) and sputum cups (3.7%)). Of the 82 health centers, 77 (93.9%) did not fulfill the criteria for effective distribution of tuberculosis laboratory reagents and consumables. There were many health centers that had no or only low stocks of key tuberculosis laboratory reagents and consumables as a result of ineffective distribution system. It is necessary to strengthen supply chain management to ensure uninterrupted TB diagnostic service. PMID- 26641094 TI - Integrating Diverse Types of Genomic Data to Identify Genes that Underlie Adverse Pregnancy Phenotypes. AB - Progress in understanding complex genetic diseases has been bolstered by synthetic approaches that overlay diverse data types and analyses to identify functionally important genes. Pre-term birth (PTB), a major complication of pregnancy, is a leading cause of infant mortality worldwide. A major obstacle in addressing PTB is that the mechanisms controlling parturition and birth timing remain poorly understood. Integrative approaches that overlay datasets derived from comparative genomics with function-derived ones have potential to advance our understanding of the genetics of birth timing, and thus provide insights into the genes that may contribute to PTB. We intersected data from fast evolving coding and non-coding gene regions in the human and primate lineage with data from genes expressed in the placenta, from genes that show enriched expression only in the placenta, as well as from genes that are differentially expressed in four distinct PTB clinical subtypes. A large fraction of genes that are expressed in placenta, and differentially expressed in PTB clinical subtypes (23-34%) are fast evolving, and are associated with functions that include adhesion neurodevelopmental and immune processes. Functional categories of genes that express fast evolution in coding regions differ from those linked to fast evolution in non-coding regions. Finally, there is a surprising lack of overlap between fast evolving genes that are differentially expressed in four PTB clinical subtypes. Integrative approaches, especially those that incorporate evolutionary perspectives, can be successful in identifying potential genetic contributions to complex genetic diseases, such as PTB. PMID- 26641098 TI - Phosphoethanolamine Modification of Neisseria gonorrhoeae Lipid A Reduces Autophagy Flux in Macrophages. AB - Autophagy, an ancient homeostasis mechanism for macromolecule degradation, performs an important role in host defense by facilitating pathogen elimination. To counteract this host defense strategy, bacterial pathogens have evolved a variety of mechanisms to avoid or otherwise dysregulate autophagy by phagocytic cells so as to enhance their survival during infection. Neisseria gonorrhoeae is a strictly human pathogen that causes the sexually transmitted infection, gonorrhea. Phosphoethanolamine (PEA) addition to the 4' position of the lipid A (PEA-lipid A) moiety of the lipooligosaccharide (LOS) produced by gonococci performs a critical role in this pathogen's ability to evade innate defenses by conferring decreased susceptibility to cationic antimicrobial (or host-defense) peptides, complement-mediated killing by human serum and intraleukocytic killing by human neutrophils compared to strains lacking this PEA decoration. Heretofore, however, it was not known if gonococci can evade autophagy and if so, whether PEA lipid A contributes to this ability. Accordingly, by using murine macrophages and human macrophage-like phagocytic cell lines we investigated if PEA decoration of gonococcal lipid A modulates autophagy formation. We report that infection with PEA-lipid A-producing gonococci significantly reduced autophagy flux in murine and human macrophages and enhanced gonococcal survival during their association with macrophages compared to a PEA-deficient lipid A mutant. Our results provide further evidence that PEA-lipid A produced by gonococci is a critical component in the ability of this human pathogen to evade host defenses. PMID- 26641099 TI - Web-Based Mindfulness Intervention in Heart Disease: A Randomized Controlled Trial. AB - BACKGROUND: Evidence is accumulating that mindfulness training has favorable effects on psychological outcomes, but studies on physiological outcomes are limited. Patients with heart disease have a high incidence of physiological and psychological problems and may benefit from mindfulness training. Our aim was to determine the beneficial physiological and psychological effects of online mindfulness training in patients with heart disease. METHODS: The study was a pragmatic randomized controlled single-blind trial. Between June 2012 and April 2014 we randomized 324 patients (mean age 43.2 years, 53.7% male) with heart disease in a 2:1 ratio (n = 215 versus n = 109) to a 12-week online mindfulness training in addition to usual care (UC) compared to UC alone. The primary outcome was exercise capacity measured with the 6 minute walk test (6MWT). Secondary outcomes were other physiological parameters (heart rate, blood pressure, respiratory rate, and NT-proBNP), subjective health status (SF-36), perceived stress (PSS), psychological well-being (HADS), social support (PSSS12) and a composite endpoint (all-cause mortality, heart failure, symptomatic arrhythmia, cardiac surgery, and percutaneous cardiac intervention). Linear mixed models were used to evaluate differences between groups on the repeated outcome measures. RESULTS: Compared to UC, mindfulness showed a borderline significant improved 6MWT (effect size, meters: 13.2, 95%CI: -0.02; 26.4, p = 0.050). There was also a significant lower heart rate in favor of the mindfulness group (effect size, beats per minute: -2.8, 95%CI: -5.4;-0.2, p = 0.033). No significant differences were seen on other outcomes. CONCLUSIONS: Mindfulness training showed positive effects on the physiological parameters exercise capacity and heart rate and it might therefore be a useful adjunct to current clinical therapy in patients with heart disease. TRIAL REGISTRATION: Dutch Trial Register 3453. PMID- 26641101 TI - How Do Changes to the Railroad Causeway in Utah's Great Salt Lake Affect Water and Salt Flow? AB - Managing terminal lake elevation and salinity are emerging problems worldwide. We contribute to terminal lake management research by quantitatively assessing water and salt flow for Utah's Great Salt Lake. In 1959, Union Pacific Railroad constructed a rock-filled causeway across the Great Salt Lake, separating the lake into a north and south arm. Flow between the two arms was limited to two 4.6 meter wide rectangular culverts installed during construction, an 88 meter opening (referred to locally as a breach) installed in 1984, and the semi porous material of the causeway. A salinity gradient developed between the two arms of the lake over time because the south arm receives approximately 95% of the incoming streamflow entering Great Salt Lake. The north arm is often at, or near, salinity saturation, averaging 317 g/L since 1966, while the south is considerably less saline, averaging 142 g/L since 1966. Ecological and industrial uses of the lake are dependent on long-term salinity remaining within physiological and economic thresholds, although optimal salinity varies for the ecosystem and between diverse stakeholders. In 2013, Union Pacific Railroad closed causeway culverts amid structural safety concerns and proposed to replace them with a bridge, offering four different bridge designs. As of summer 2015, no bridge design has been decided upon. We investigated the effect that each of the proposed bridge designs would have on north and south arm Great Salt Lake elevation and salinity by updating and applying US Geological Survey's Great Salt Lake Fortran Model. Overall, we found that salinity is sensitive to bridge size and depth, with larger designs increasing salinity in the south arm and decreasing salinity in the north arm. This research illustrates that flow modifications within terminal lakes cannot be separated from lake salinity, ecology, management, and economic uses. PMID- 26641100 TI - Necrosis-Induced Sterile Inflammation Mediated by Interleukin-1alpha in Retinal Pigment Epithelial Cells. AB - Endogenous danger signals released from necrotic cells contribute to retinal inflammation. We have now investigated the effects of necrotic cell extracts prepared from ARPE-19 human retinal pigment epithelial cells (ANCE) on the release of proinflammatory cytokines and chemokines by healthy ARPE-19 cells. ANCE were prepared by subjection of ARPE-19 cells to freeze-thaw cycles. The release of various cytokines and chemokines from ARPE-19 cells was measured with a multiplex assay system or enzyme-linked immunosorbent assays. The expression of interleukin (IL)-1alpha and the phosphorylation and degradation of the endogenous nuclear factor-kappaB (NF-kappaB) inhibitor IkappaB-alpha were examined by immunoblot analysis. Among the various cytokines and chemokines examined, we found that ANCE markedly stimulated the release of the proinflammatory cytokine IL-6 and the chemokines IL-8 and monocyte chemoattractant protein (MCP)-1 by ARPE 19 cells. ANCE-induced IL-6, IL-8, and MCP-1 release was inhibited by IL-1 receptor antagonist and by an IKK2 inhibitor (a blocker of NF-kappaB signaling) in a concentration-dependent manner, but was not affected by a pan-caspase inhibitor (Z-VAD-FMK). Recombinant IL-1alpha also induced the secretion of IL-6, IL-8, and MCP-1 from ARPE-19 cells, and IL-1alpha was detected in ANCE. Furthermore, ANCE induced the phosphorylation and degradation of IkappaB-alpha in ARPE-19 cells. Our findings thus suggest that IL-1alpha is an important danger signal that is released from necrotic retinal pigment epithelial cells and triggers proinflammatory cytokine and chemokine secretion from intact cells in a manner dependent on NF-kappaB signaling. IL-1alpha is therefore a potential therapeutic target for amelioration of sterile inflammation in the retina. PMID- 26641102 TI - Worldwide Incidence of Autoimmune Liver Disease. AB - BACKGROUND: The variation that occurs in the incidence patterns of autoimmune liver diseases may provide insight into the risk factors causing the diseases. We systematically reviewed studies on the incidence of autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), and immunoglobulin G4-associated cholangitis (IAC) in general populations. KEY MESSAGES: We found relevant studies through Medline and Scopus, and we examined whether they were population-based; the way they found cases for inclusion and which diagnostic criteria they used; and whether they used standardization to facilitate comparison with other studies. The 55 identified studies varied greatly in their case-finding methods, and only 14 (25%) of them used a standard population. Reported incidence rates of AIH were around 1 per 100,000 population per year, possibly higher in Scandinavia than in other countries, and a Danish study of the 1994-2012 period found an increasing incidence. A majority of PBC studies found incidence rates of 1-2 per 100,000 population per year and an increasing time trend, but incidence was lower in the Netherlands and New Zealand and higher in North East England. Most studies of PSC found incidence rates around 1 per 100,000 population per year, but there were no incident cases among 100,000 Alaska natives during the period 1984-2000. The incidence of IAC remains unknown. CONCLUSIONS: The incidence of the autoimmune liver diseases is around 1 2 per 100,000 population per year for each disease. The variation in incidence over time and place suggests that there are differences in the prevalence of risk factors for the diseases, but the studies used different methods and so it is difficult to draw firm conclusions. We recommend that groups of investigators conduct multisite studies with identical case-finding methods, and that they use a standard population to account for differences in demographics. PMID- 26641103 TI - Pre-eclampsia: reducing the risk with calcium supplements. AB - INTRODUCTION: Pre-eclampsia (raised blood pressure and proteinuria) complicates 2% to 8% of pregnancies, and increases morbidity and mortality in the mother and child. Pre-eclampsia is more common in older women, women with a high body mass index, and women with multiple pregnancy. Pre-eclampsia risk is also increased in women with underlying medical conditions, particularly conditions associated with microvascular disease. METHODS AND OUTCOMES: We conducted a systematic overview, aiming to answer the following clinical questions: Does oral calcium supplementation during pregnancy reduce the risk and/or severity of pre eclampsia? What are the effects of preventive calcium supplements pre-conception in women at risk of pre-eclampsia? We searched: Medline, Embase, The Cochrane Library, and other important databases up to November 2014 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to date version of this review). RESULTS: At this update, searching of electronic databases retrieved 109 studies. After deduplication and removal of conference abstracts, 55 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 30 studies and the further review of 25 full publications. Of the 25 full articles evaluated, one update of a previously included systematic review was added. We performed a GRADE evaluation for seven PICO combinations. CONCLUSIONS: In this systematic overview, we categorised the efficacy for three interventions based on information about the effectiveness and safety of calcium supplementation used to prevent pre eclampsia, both during pregnancy and pre-conception, and different doses of calcium supplementation versus each other during pregnancy. PMID- 26641104 TI - Temporal associations between arousal and body/limb movement in children with suspected obstructed sleep apnoea. AB - The inter-relationship between arousal events and body and/or limb movements during sleep may significantly impact the performance and clinical interpretation of actigraphy. As such, the objective of this study was to quantify the temporal association between arousals and body/limb movement. From this, we aim to determine whether actigraphy can predict arousal events in children, and identify the impact of arousal-related movements on estimates of sleep/wake periods. Thirty otherwise healthy children (5-16 years, median 9 years, 21 male) with suspected sleep apnoea were studied using full polysomnography and customised raw tri-axial accelerometry measured at the left fingertip, left wrist, upper thorax, left ankle and left great toe. Raw data were synchronised to within 0.1 s of the polysomnogram. Movements were then identified using a custom algorithm. On average 67.5% of arousals were associated with wrist movement. Arousals associated with movement were longer than those without movement (mean duration: 12.2 s versus 7.9 s respectively, p < 0.01); movements during wake and arousal were longer than other sleep movements (wrist duration: 6.26 s and 9.89 s versus 2.35 s respectively, p < 0.01); and the movement index (movements/h) did not predict apnoea-hypopnoea index (rho = -0.11). Movements associated with arousals are likely to unavoidably contribute to actigraphy's poor sensitivity for wake. However, as sleep-related movements tend to be shorter than those during wake or arousal, incorporating movement duration into the actigraphy scoring algorithm may improve sleep staging performance. Although actigraphy based measurements cannot reliably predict all arousal events, actigraphy can likely identify longer events that may have the greatest impact on sleep quality. PMID- 26641106 TI - Stereoselective Allylstannane Addition for a Convergent Synthesis of a Complex Molecule. AB - A convergent methodology with 13 lineal steps for the synthesis of phormidolides B and C macrocyclic core is described. Stereoselective formation of the tetrahydrofuran (THF) core was achieved using a stereocontrolled allylation reaction. The key step of the synthesis is a (Z)-1,5-anti stereoselective allylstannane addition where a new stereocenter and a trisubstituted double bond are formed simultaneously. Finally, Shiina macrolactonization conditions improved the yield of the final cyclization. PMID- 26641107 TI - Molecular Dynamics Simulation for the Dynamics and Kinetics of Folding Peptides in the Gas Phase. AB - The conformations of flexible molecular species, such as oligomers and oligopeptides, and their interconversion in the gas phase have been probed by ion mobility spectrometry measurements. The ion motion is interpreted through the calculation of effective cross sections in the case of stable conformations of the macromolecules. However, when the molecular structures transform to each other as the ions collide with gas atoms during their flight through the drift tube, the introduction of an average cross section is required. To provide a direct way for the reproduction of the ion motion, we employ a nonequilibrium molecular dynamics simulation method and consider a molecular model that consists of two connected stiff cylindrical bodies interacting through an intramolecular model potential. With this procedure we have calculated the ion mobility as a function of temperature for a prototype peptide that converts between a helical and an extended globular form. The results are in good agreement with ion mobility spectrometry data confirming that an angular vibration coordinate can be used for the interpretation of the shifting of the drift-time distributions at high temperatures. The approach produces mean kinetic energies as well as various combined distributions of the ion degrees of freedom. It is easily applied to flexible macromolecular ions and can be extended to include additional degrees of freedom. PMID- 26641105 TI - Base-Displaced Intercalated Structure of the N-(2'-Deoxyguanosin-8-yl)-3 aminobenzanthrone DNA Adduct. AB - 3-Nitrobenzanthrone (3-NBA), an environmental mutagen found in diesel exhaust and a suspected carcinogen, undergoes metabolic reduction followed by reaction with DNA to form aminobenzanthrone (ABA) adducts, with the major alkylation product being N-(2'-deoxyguanosin-8-yl)-3-aminobenzanthrone (C8-dG-ABA). Site-specific synthesis of the C8-dG-ABA adduct in the oligodeoxynucleotide 5'-d(GTGCXTGTTTGT) 3':5'-d(ACAAACACGCAC)-3'; X = C8-dG-ABA adduct, including codons 272-275 of the p53 gene, has allowed for investigation into the structural and thermodynamic properties of this adduct. The conformation of the C8-dG-ABA adduct was determined using NMR spectroscopy and was refined using molecular dynamics (MD) calculations restrained by experimentally determined interproton distance restraints obtained from NOE experiments. The refined structure revealed that the C8-dG-ABA adduct formed a base-displaced intercalated conformation. The adducted guanine was shifted into the syn conformation about the glycosidic bond. The 5'- and 3'-neighboring base pairs remained intact. While this facilitated pi-stacking interactions between the ABA moiety and neighboring bases, the thermal melting temperature (Tm) of the adduct-containing duplex showed a decrease of 11 degrees C as compared to the corresponding unmodified oligodeoxynucleotide duplex. Overall, in this sequence, the base-displaced intercalated conformation of the C8 dG-ABA lesion bears similarity to structures of other arylamine C8-dG adducts. However, in this sequence, the base-displaced intercalated conformation for the C8-dG-ABA adduct differs from the conformation of the N(2)-dG-ABA adduct reported by de los Santos and co-workers, in which it is oriented in the minor groove toward the 5' end of the duplex, with the modified guanine remaining in the anti conformation about the glyosidic torsion angle, and the complementary base remaining within the duplex. The results are discussed in relationship to differences between the C8-dG-ABA and N(2)-dG-ABA adducts with respect to susceptibility to nucleotide excision repair (NER). PMID- 26641109 TI - Introducing the Journal of Chemical Theory and Computation. PMID- 26641108 TI - Dual Recognition Strategy for Specific and Sensitive Detection of Bacteria Using Aptamer-Coated Magnetic Beads and Antibiotic-Capped Gold Nanoclusters. AB - Food poisoning and infectious diseases caused by pathogenic bacteria such as Staphylococcus aureus (SA) are serious public health concerns. A method of specific, sensitive, and rapid detection of such bacteria is essential and important. This study presents a strategy that combines aptamer and antibiotic based dual recognition units with magnetic enrichment and fluorescent detection to achieve specific and sensitive quantification of SA in authentic specimens and in the presence of much higher concentrations of other bacteria. Aptamer-coated magnetic beads (Apt-MB) were employed for specific capture of SA. Vancomycin stabilized fluorescent gold nanoclusters (AuNCs@Van) were prepared by a simple one-step process and used for sensitive quantification of SA in the range of 32 10(8) cfu/mL with the detection limit of 16 cfu/mL via a fluorescence intensity measurement. And using this strategy, about 70 cfu/mL of SA in complex samples (containing 3 * 10(8) cfu/mL of other different contaminated bacteria) could be successfully detected. In comparison to prior studies, the developed strategy here not only simplifies the preparation procedure of the fluorescent probes (AuNCs@Van) to a great extent but also could sensitively quantify SA in the presence of much higher concentrations of other bacteria directly with good accuracy. Moreover, the aptamer and antibiotic used in this strategy are much less expensive and widely available compared to common-used antibodies, making it cost-effective. This general aptamer- and antibiotic-based dual recognition strategy, combined with magnetic enrichment and fluorescent detection of trace bacteria, shows great potential application in monitoring bacterial food contamination and infectious diseases. PMID- 26641110 TI - An Efficient Linear-Scaling Ewald Method for Long-Range Electrostatic Interactions in Combined QM/MM Calculations. AB - A method is presented for the efficient evaluation of long-range electrostatic forces in combined quantum mechanical and molecular mechanical (QM/MM) calculations of periodic systems. The QM/MM-Ewald method is a linear-scaling electrostatic method that utilizes the particle mesh Ewald algorithm for calculation of point charge interactions of molecular mechanical atoms and a real space multipolar expansion for the quantum mechanical electrostatic terms plus a pairwise periodic correction factor for the QM and QM/MM interactions that does not need to be re-evaluated during the self-consistent field procedure. The method is tested in a series of molecular dynamics simulations of the ion-ion association of ammonium chloride and ammonium metaphosphate and the dissociative phosphoryl transfer of methyl phosphate and acetyl phosphate. Results from periodic boundary molecular dynamics (PBMD) simulations employing the QM/MM-Ewald method are compared with corresponding PBMD simulations using electrostatic cutoffs and with results from nonperiodic stochastic boundary molecular dynamics (SBMD) simulations, with cutoffs and with full electrostatics (no cutoff). The present method allows extension of linear-scaling Ewald methods to molecular simulations of enzyme and ribozyme reactions that use combined QM/MM potentials. PMID- 26641111 TI - Neural Network Models of Potential Energy Surfaces: Prototypical Examples. AB - Neural networks can be used generate potential energy hypersurfaces by fitting to a data set of energies at discrete geometries, as might be obtained from ab initio calculations. Prior work has shown that this method can generate accurate fits in complex systems of several dimensions. The present paper explores fundamental properties of neural network potential representations in some simple prototypes of one, two, and three dimensions. Optimal fits to the data are achieved by adjusting the network parameters using an extended Kalman filtering algorithm, which is described in detail. The examples provide insight into the relationships between the form of the function being fit, the amount of data needed for an adequate fit, and the optimal network configuration and number of neurons needed. The quality of the network interpolation is substantially improved if gradients as well as the energy are available for fitting. The fitting algorithm is effective in providing an accurate interpolation of the underlying potential function even when random noise is added to the data used in the fit. PMID- 26641112 TI - Parametrization of Reversible Digitally Filtered Molecular Dynamics Simulations. AB - Reversible Digitally Filtered Molecular Dynamics (RDFMD) is a method of amplifying or suppressing motions in a molecular dynamics simulation, through the application of a digital filter to the simulation velocities. RDFMD and its derivatives have been previously used to promote conformational motions in liquid phase butane, the Syrian hamster prion protein, alanine dipeptide, and the pentapeptide, YPGDV. The RDFMD method has associated with it a number of parameters that require specification to optimize the desired response. In this paper methods for the systematic analysis of these parameters are presented and applied to YPGDV with the specific emphasis of ensuring a gentle and progressive method that produces maximum conformation change from the energy put into the system. The portability of the new parameter set is then shown with an application to the M20 loop of E-coli dihydrofolate reductase. A conformational change is induced from a closed to an open structure similar to that seen in the DHFR-NADP(+) complex. PMID- 26641113 TI - Superposition State Molecular Dynamics. AB - The ergodic sampling of rough energy landscapes is crucial for understanding phenomena like protein folding, peptide aggregation, polymer dynamics, and the glass transition. These rough energy landscapes are characterized by the presence of many local minima separated by high energy barriers, where Molecular Dynamics (MD) fails to satisfy ergodicity. To enhance ergodic behavior, we have developed the Superposition State Molecular Dynamics (SSMD) method, which uses a superposition of energy states to obtain an effective potential for the MD simulation. In turn, the dynamics on this effective potential can be used to sample the configurational free energy of the real potential. The effectiveness of the SSMD method for a one-dimensional rough potential energy landscape is presented as a test case. PMID- 26641114 TI - New Effective Core Method (Effective Core Potential and Valence Basis Set) for Al Clusters and Nanoparticles and Heteronuclear Al-Containing Molecules. AB - In previous work we have shown that the PBE0 hybrid density functional method with the MG3 all-electron basis set is an accurate method for calculating the atomization energies of small aluminum clusters (Al2-Al7). However, the MG3 basis set is very expensive for molecules much larger than Al13; therefore, we have developed a new effective core potential (ECP) method for aluminum to reduce the cost of obtaining accurate results for nanoparticles. Our method involves a hybrid of the Stuttgart semiempirical effective core potential and the compact effective potential (CEP) potential, and it uses a newly optimized polarized valence triple-zeta basis set. The combination of the new ECP and the new polarized valence triple-zeta basis set for Al is called the Minnesota effective core (MEC) method for Al. The method was optimized with a training set of atomization energies and geometries for AlH, AlC, AlO, AlCCH, Al2H, Al2C, Al2O, and Al3 and atomization energies of three Al13 structures, and we tested it on six test sets composed of 20 atomization energies for systems as large as Al13. We also present an improved all-electron polarized triple split basis set for oxygen, called 6-311+G(d*,p). For the test sets, the mean unsigned error (MUE) of the new method with respect to PBE0/MG3 is 0.06 eV for atomization energies and 0.007 A for bond lengths, which constitutes a very significant improvement over the quality of the results that can be obtained with effective core potentials and valence basis sets in the literature (of the eight methods in the literature, the best previous method had average errors of 0.63 eV and 0.036 A). We have also tested the MEC method with a variety of hybrid density functional theory, hybrid meta density functional theory, and pure GGA and meta GGA functionals and found that the average MUE, relative to each functional with all-electron basis sets, is 0.04 eV for atomization energies and 0.009 A for bond lengths for the new effective core method and 0.16-0.20 eV and 0.013-0.033 A for effective core potential and valence basis sets in the literature. PMID- 26641115 TI - Use of Block Hessians for the Optimization of Molecular Geometries. AB - We test a strategy for using block Hessians for transition state geometry optimizations. The block Hessian matrix is constructed by mixing a small critical block of the accurate Hessian for key atoms involved in bond breaking and forming with large noncritical blocks of the low-level Hessian. The method is tested for transition state optimizations at the MC-QCISD/3 level for five reactive systems: H + CH3OH, O + CH4, OH + CH4, NH2 + CH4, and H + C2H5OH. When the entire low level Hessian was used, significant oscillations were observed during the optimizations for the first four systems, whereas the transition state for the last system was optimized to a wrong structure. The block Hessian strategy efficiently removed these pathological effects of using low-level Hessians, and therefore it provides a highly reliable method for optimizing transition state structures with reduced computational cost. The method is very general, and it is especially well suited for optimizing transition state structures and equilibrium structures of large systems at very high levels of theory. PMID- 26641116 TI - Using Hessian Updating To Increase the Efficiency of a Hessian Based Predictor Corrector Reaction Path Following Method. AB - The reaction path is a key concept in the theoretical description of a chemical reaction. The intrinsic reaction coordinate is defined as the steepest descent path in mass-weighted Cartesian coordinates that connects the transition state to reactants and products on the potential energy surface. Recently, a new Hessian based predictor-corrector reaction path following algorithm was presented that is comparable to a fourth-order algorithm developed earlier. Although the method is very accurate, it is costly because second derivatives of the energy are required at each step. In this work, the efficiency of the method is greatly enhanced by employing Hessian updating. Three different updating schemes have been tested: Murtagh and Sargent, Powell-symmetric Broyden, and Bofill. Bofill's update performs the best and yields excellent speed-up. PMID- 26641117 TI - Benchmarking the Conductor-like Polarizable Continuum Model (CPCM) for Aqueous Solvation Free Energies of Neutral and Ionic Organic Molecules. AB - The conductor-like polarizable continuum model (CPCM) using several cavity models is applied to compute aqueous solvation free energies for a number of organic molecules (30 neutral molecules, 21 anions, and 19 cations). The calculated solvation free energies are compared to the available experimental data from the viewpoint of cavity models, computational methods, calculation time, and aqueous pKa values. The HF/6-31+G(d)//HF/6-31+G(d) and the HF/6-31+G(d)//B3LYP/6-31+G(d) with the UAKS cavities, in which radii are optimized with PBE0/6-31G(d), provide aqueous solvation effects in best agreement with available experimental data. The mean absolute deviations from experiment are 2.6 kcal/mol. The MP2/6 31++G(d,p)//HF/6-31+G(d) with the CPCM-UAKS(HF/6-31+G(d)) calculation is also performed for the base-catalyzed hydrolysis of methyl acetate in water. PMID- 26641118 TI - Adsorption of Water Molecules on Flat and Stepped Nickel Surfaces from First Principles. AB - We present an ab initio density functional study of the adsorption of a series of water oligomers (molecule, dimer and trimer) on nickel surfaces with and without step defects. We investigate the preferred adsorption geometries and adsorption energies and analyze the binding mechanisms by means of electronic density difference maps. Special attention is devoted to the incremental adsorption process, i.e., the way additional molecules attaches to an already adsorbed water. In agreement with recent findings, we show that the first water molecule is bound to the surface with an energy of about 0.2-0.4 eV, i.e., with up to twice the strength of a hydrogen bond. In contrast to this, subsequent water molecules increase the total adsorption energy by typically 0.5 eV. However, electron density difference considerations indicate that this additional attraction is not due to the interaction of the new molecule with the surface but mediated by the first water molecule. The interaction of the additional molecule with the surface appears even to be repulsive. We discuss the implications of these findings for the wetting properties of transition metal surfaces. PMID- 26641119 TI - An Aromaticity Scale Based on the Topological Analysis of the Electron Localization Function Including sigma and pi Contributions. AB - In this work, the average bifurcation value of the electron localization function (ELF) of both sigma (ELFsigma) and pi (ELFpi) contributions was used to construct an aromaticity scale for chemical compounds. We have validated the scale with a series of well-known molecules and then used it to evaluate global aromaticity on aluminum based clusters, which present sigma aromaticity and pi antiaromaticity. The proposed scaled predicts an overall antiaromatic character for the Al4(4)(-) moiety. PMID- 26641120 TI - A Simple Mathematical Model for the Cooperative and Competitive Substituent Effects Found in the Cope Rearrangements of Phenyl-Substituted 1,5-Hexadienes. AB - A simple mathematical model is derived for the dependence of the substituent effects in the Cope rearrangements of substituted 1,5-hexadienes on the interallylic bond lengths in the transition structures. The model qualitatively reproduces the cooperative substituent effects that have been found in the Cope rearrangements of 2,5-diphenyl- and 1,3,4,6-tetraphenyl-1,5-hexadiene and the competitive substituent effects that have been found in the Cope rearrangement of 1,3,5-triphenyl-1,5-hexadiene. B3LYP/6-31G* calculations have been performed in order to assess more quantitatively the performance of the model, and the results of these calculations are discussed. PMID- 26641121 TI - Computational and Spectroscopic Studies of Re(I) Bipyridyl Complexes Containing 2,6-Dimethylphenylisocyanide (CNx) Ligand. AB - Density Functional Theory (DFT) calculations produce optimized geometries of the complexes [Re(CO)3(bpy)Cl] (1), [Re(CO)3(bpy)(py)](CF3SO3) (2), [Re(CO)3(bpy)(CNx)](CF3SO3) (3), and [Re(CO)(bpy)(CNx)3](CF3SO3) (4), where bpy = 2,2'-bipyridine, py = pyridine, and CNx = 2,6-dimethylphenylisocyanide in their ground and lowest-lying triplet states. The ground-state optimized geometry for the cation of [Re(CO)3(bpy)(CNx)](CF3SO3) (3) results in a Re-C (CNx) bond length of 2.10 A, a Re-C (CO) bond length trans to CNx of 2.01 A, and a Re-C (CO) bond length cis to CNx of 1.96 A which compares favorably to the single-crystal analysis of a Re-C (CNx) bond length of 2.074(4) A, a Re-C (CO) bond length trans to CNx of 1.971(4) A, and Re-C (CO) bond length cis to CNx of 1.932(4) A. The majority of the singlet excited-state energies calculated using Time-dependent Density Functional Theory (TDDFT) and Conductor-like Polarizable Continuum Model (CPCM) are metal-ligand-to-ligand charge transfer (MLLCT) states and are in good agreement with the UV-vis spectral energies for the complexes in ethanol. The complexes exhibit emission both at room temperature and at 77 K except 4 which is only emissive at 77 K. The 77 K emission lifetimes range from 3.9 MUs for 1 to 8.8 MUs for 3. The emissive lowest-lying triplet state is a (3)MLLCT state for complexes 1-3 but a triplet ligand-to-metal charge transfer ((3)LMCT) state for complex 4. The electronic, electrochemical, thermodynamic, HOMO-LUMO, and emitting-state energy gaps as well as the emission lifetimes increase in the order 1 < 2 < 3. A (3)d-d excited- state, which is located above the (3)LMCT state, accounts for the loss of room-temperature emission for complex 4. PMID- 26641122 TI - Modeling the Morphology and Phase Stability of TiO2 Nanocrystals in Water. AB - The potential of titanium dioxide nanoparticles for advanced photochemical applications has prompted a number of studies to analyze the size, phase, and morphology dependent properties. Previously we have used a thermodynamic model of nanoparticles as a function of size and shape to predict the phase stability of titanium dioxide nanoparticles, with particular attention given to the crossover of stability between the anatase and rutile phases. This work has now been extended to titanium dioxide nanoparticles in water, to examine the effects of various adsorption configurations on the equilibrium shape and the phase transition. Density functional calculations have been used to accurately determine surface energies and surface tension of low index hydrated stoichiometric surfaces of anatase and rutile, which are presented along with a brief outline of the surface structure. We have shown that morphology of TiO2 nanocrystals is affected by the presence of water, resulting in variations in the size of the (001) and (001) truncation facets in anatase, and a reduction in the aspect ratio of rutile nanocrystals. Our results also highlight that the consideration of hydrated nanocrystal surfaces is necessary to accurately predict the correct size dependence of the anatase to rutile phase transition. PMID- 26641123 TI - Normal-Mode Analysis of Circular DNA at the Base-Pair Level. 1. Comparison of Computed Motions with the Predicted Behavior of an Ideal Elastic Rod. AB - We have extended a newly developed approach to study the low-frequency normal modes of mesoscopic fragments of linear DNA in order to investigate the dynamics of closed circular molecules of comparable size, i.e., a few hundred base pairs. We have added restraint energy terms and a global minimization step to treat the more complicated, spatially constrained duplex in terms of the intrinsic conformation and flexibility of the constituent base-pair "step" parameters. Initial application of the methodology to the normal modes of an ideal closed circular DNA molecule [Formula: see text] which is naturally straight in its relaxed open linear state, inextensible, and capable of isotropic bending and independent twisting at the base-pair level [Formula: see text] matches theoretical predictions of elastic rod dynamics. The energy-optimized closed circular states and the types of low frequency motions follow expected behavior, with (1) uniform twist density and uniform energy density in the minimum energy state; (2) a near-zero frequency torsional mode with "free" rotation about the global helical axis; (3) higher-order torsional modes accompanied by global rocking motions and pure in-plane and out-of-plane bending motions in the torsionally relaxed circle; and (4) mixed modes of bending when the chain is supercoiled (over- or undertwisted). Furthermore, the computed changes in normal mode frequencies with imposed supercoiling or with variation of chain length are virtually identical to theoretically predicted values. PMID- 26641124 TI - Normal-Mode Analysis of Circular DNA at the Base-Pair Level. 2. Large-Scale Configurational Transformation of a Naturally Curved Molecule. AB - Fine structural and energetic details embedded in the DNA base sequence, such as intrinsic curvature, are important to the packaging and processing of the genetic material. Here we investigate the internal dynamics of a 200 bp closed circular molecule with natural curvature using a newly developed normal-mode treatment of DNA in terms of neighboring base-pair "step" parameters. The intrinsic curvature of the DNA is described by a 10 bp repeating pattern of bending distortions at successive base-pair steps. We vary the degree of intrinsic curvature and the superhelical stress on the molecule and consider the normal-mode fluctuations of both the circle and the stable figure-8 configuration under conditions where the energies of the two states are similar. To extract the properties due solely to curvature, we ignore other important features of the double helix, such as the extensibility of the chain, the anisotropy of local bending, and the coupling of step parameters. We compare the computed normal modes of the curved DNA model with the corresponding dynamical features of a covalently closed duplex of the same chain length constructed from naturally straight DNA and with the theoretically predicted dynamical properties of a naturally circular, inextensible elastic rod, i.e., an O-ring. The cyclic molecules with intrinsic curvature are found to be more deformable under superhelical stress than rings formed from naturally straight DNA. As superhelical stress is accumulated in the DNA, the frequency, i.e., energy, of the dominant bending mode decreases in value, and if the imposed stress is sufficiently large, a global configurational rearrangement of the circle to the figure-8 form takes place. We combine energy minimization with normal-mode calculations of the two states to decipher the configurational pathway between the two states. We also describe and make use of a general analytical treatment of the thermal fluctuations of an elastic rod to characterize the motions of the minicircle as a whole from knowledge of the full set of normal modes. The remarkable agreement between computed and theoretically predicted values of the average deviation and dispersion of the writhe of the circular configuration adds to the reliability in the computational approach. Application of the new formalism to the computed modes of the figure-8 provides insights into macromolecular motions which are beyond the scope of current theoretical treatments. PMID- 26641125 TI - Rapid Estimation of Solvation Energy for Simulations of Protein-Protein Association. AB - We have formulated the Energy by Linear Superposition of Corrections Approximation (ELSCA) for estimating the electrostatic and apolar solvation energy of bringing two proteins into close proximity or into contact as defined by the linearized Poisson-Boltzmann model and a linear function of the solvent accessible surface area. ELSCA utilizes potentials of mean force between atom types found in the AMBER ff99 force field, a uniform distance-dependent dielectric, and a potential that mimics the change in solvent accessible surface area for bringing two solvated spheres into contact. ELSCA was trained by a linear least-squares fit on more than 39 000 putative complexes, each formed from pairs of nonhomologous proteins with a range of shapes, sizes, and charges. The training set was also designed to capture various stages of complex formation. ELSCA was tested against over 8000 non-native complexes of 45 enzyme/inhibitor, antibody/antigen, and other systems that are known to form complexes and gives an overall correlation of 0.962 with PBSA-derived energies for these complexes. The predictions have a slope of 0.89 on the actual values with a bias of 11.1 kcal/mol. When applied to native complexes of these 45 protein systems, ELSCA reproduces PBSA results with a correlation of 0.787, a slope of 1.13, and a bias of 13.0 kcal/mol. We report parameters for ELSCA in the context of the AMBER ff99 parameter set. Our model is most useful in macromolecular docking and protein association simulations, where large portions of each molecule may be considered rigid. PMID- 26641126 TI - Determination of Electrostatic Parameters for a Polarizable Force Field Based on the Classical Drude Oscillator. AB - A procedure to determine the electrostatic parameters has been developed for a polarizable empirical force field based on the classical Drude oscillator model. Atomic charges and polarizabilities for a given molecule of interest were derived from restrained fitting to quantum-mechanical electrostatic potentials (ESP) calculated at the B3LYP/ cc-pVDZ or B3LYP/aug-cc-pVDZ levels on grid points located on concentric Connolly surfaces. The determination of the atomic polarizabilities requires a series of perturbed ESP maps, each one representing the electronic response of the molecule in the presence of a background charge placed on Connolly surfaces primarily along chemical bonds and lone pairs. Reference values for the partial atomic charges were taken from the CHARMM27 additive all-atom force field, and those for the polarizabilities were based on adjusted Miller's ahp atomic polarizability values. The fitted values of atomic polarizabilities were scaled to reflect the reduced polarization expected for the condensed media and/or to correct for the systematic underestimation of experimental molecular polarizabilities by B3LYP calculations. Following correction of the polarizabilities, the atomic charges were adjusted to reproduce gas-phase dipole moments. The developed scheme has been tested on a set of small molecules representing functional moieties of nucleic acids. The derived electrostatic parameters have been successfully applied in a preliminary polarizable molecular dynamics simulation of a DNA octamer in a box of water with sodium counterions. Thus, this study confirms the feasibility of the use of a polarizable force field based on a classical Drude model for simulations of biomolecules in the condensed phase. PMID- 26641127 TI - Efficient Simulation Method for Polarizable Protein Force Fields: Application to the Simulation of BPTI in Liquid Water. AB - A methodology for large scale molecular dynamics simulation of a solvated polarizable protein, using a combination of permanent and inducible point dipoles with fluctuating and fixed charges, is discussed and applied to the simulation of water solvated bovine pancreatic trypsin inhibitor (BPTI). The electrostatic forces are evaluated using a generalized form of the P3M Ewald method which includes point dipoles in addition to point charge sites. The electrostatic configuration is propagated along with the nuclei during the course of the simulation using an extended Lagrangian formalism. For the system size studied, 20000 atoms, this method gives only a marginal computational overhead relative to nonpolarizable potential models (1.23-1.45) per time step of simulation. The models employ a newly developed polarizable dipole force field for the protein(1) with two commonly used water models TIP4P-FQ and RPOL. Performed at constant energy and constant volume (NVE) using the velocity Verlet algorithm, the simulations show excellent energy conservation and run stably for their 2 ns duration. To characterize the accuracy of the solvation models the protein structure is analyzed. The simulated structures remain within 1 A of the experimental crystal structure for the duration of the simulation in line with the nonpolarizable OPLS-AA model. PMID- 26641128 TI - An Investigation of (Diacetoxyiodo)arenes as Precursors for Preparing No-Carrier Added [(18)F]Fluoroarenes from Cyclotron-Produced [(18)F]Fluoride Ion. AB - Treatment of (diacetoxyiodo)arenes (1a-1u) with cyclotron-produced [(18)F]fluoride ion rapidly affords no-carrier-added [(18)F]fluoroarenes (2a-2u) in useful yields and constitutes a new method for converting substituted iodoarenes into substituted [(18)F]fluoroarenes in just two steps. PMID- 26641129 TI - High Performance Shape Memory Epoxy/Carbon Nanotube Nanocomposites. AB - A series of shape memory nanocomposites based on diglycidyl ether of bisphenol A (DGEBA) E51/methylhexahydrophthalic anhydride (MHHPA)/multiwalled carbon nanotube (MWCNT) with various stoichiometric ratios (rs) of DGEBA/MHHPA from 0.5 to 1.2 and filler contents of 0.25 and 0.75 wt % are fabricated. Their morphology, curing kinetics, phase transition, mechanical properties, thermal conduction, and shape memory behaviors are systematically investigated. The prepared materials show a wide range of glass transition temperatures (Tg) of ca. 65-140 degrees C, high flexural modulus (E) at room temperature up to ca. 3.0 GPa, high maximum stress (sigmam) up to ca. 30 MPa, high strain at break (epsilonb) above 10%, and a fast recovery of 32 s. The results indicate that a small amount of MWCNT fillers (0.75 wt %) can significantly increase all three key mechanical properties (E, sigmam, and epsilonb) at temperatures close to Tg, the recovery rate, and the repetition stability of the shape memory cycles. All of these remarkable advantages make the materials good candidates for the applications in aerospace and other important fields. PMID- 26641130 TI - Restoring Resolution in Biological Solid-State NMR under Conditions of Off-Magic Angle Spinning. AB - Spin-state-selective excitation (S3E) experiments allow the selection of individual transitions in a coupled two spin system. We show that in the solid state, the dipole-dipole interaction (DD) between (15)N and (1)H in a (1)H-(15)N bond and the chemical shift anisotropy (CSA) of (15)N in an amide moiety mutually cancel each other for a particular multiplet component at high field, when the sample is spun off the magic angle (Arctan [?2] = 54.74 degrees ). The accuracy of the adjustment of the spinning angle is crucial in conventional experiments. We demonstrate that for S3E experiments, the requirement to spin the sample exactly at the magic angle is not mandatory. Applications of solid state NMR in narrow bore magnets will be facilitated where the adjustment of the magic angle is often difficult. The method opens new perspectives for the development of schemes to determine distances and to quantify dynamics in the solid state. PMID- 26641131 TI - Remarkable Lattice Shrinkage in Highly Oriented Crystalline Three-Dimensional Metal-Organic Framework Thin Films. AB - Highly oriented crystalline thin films of metal-organic frameworks (MOFs) have promising practical applications, such as in gas separation, catalysis, and sensing. We report on the successful fabrication of highly oriented crystalline thin films of three-dimensional porous MOFs, Fe(pz)[M(CN)4] (M = Ni, Pd; pz = pyrazine). Synchrotron X-ray diffraction studies reveal not only the highly oriented crystalline nature but also the remarkable shrunken structure of the thin films (~3-7% volume shrinkage) compared with bulk samples. Furthermore, because of lattice shrinkage, these films exhibit large lattice expansions upon guest adsorption, in marked contrast to the almost unchanged lattice in the bulk samples. PMID- 26641132 TI - Novel Microtubule-Targeting 7-Deazahypoxanthines Derived from Marine Alkaloid Rigidins with Potent in Vitro and in Vivo Anticancer Activities. AB - Docking studies of tubulin-targeting C2-substituted 7-deazahypoxanthine analogues of marine alkaloid rigidins led to the design and synthesis of compounds containing linear C2-substituents. The C2-alkynyl analogue was found to have double- to single-digit nanomolar antiproliferative IC50 values and showed statistically significant tumor size reduction in a colon cancer mouse model at nontoxic concentrations. These results provide impetus and further guidance for the development of these rigidin analogues as anticancer agents. PMID- 26641133 TI - Particle Trajectory-Dependent Ionic Current Blockade in Low-Aspect-Ratio Pores. AB - Resistive pulse sensing with nanopores having a low thickness-to-diameter aspect ratio structure is expected to enable high-spatial-resolution analysis of nanoscale objects in a liquid. Here we investigated the sensing capability of low aspect-ratio pore sensors by monitoring the ionic current blockades during translocation of polymeric nanobeads. We detected numerous small current spikes due to partial occlusion of the pore orifice by particles diffusing therein reflecting the expansive electrical sensing zone of the low-aspect-ratio pores. We also found wide variations in the ion current line-shapes in the particle capture stage suggesting random incident angle of the particles drawn into the pore. In sharp contrast, the ionic profiles were highly reproducible in the post translocation regime by virtue of the spatial confinement in the pore that effectively constricts the stochastic capture dynamics into a well-defined ballistic motion. These results, together with multiphysics simulations, indicate that the resistive pulse height is highly dependent on the nanoscopic single particle trajectories involved in ultrathin pore sensors. The present finding indicates the importance of regulating the translocation pathways of analytes in low-aspect-ratio pores for improving the discriminability toward single bioparticle tomography in liquid. PMID- 26641134 TI - Efficient and Tumor Targeted siRNA Delivery by Polyethylenimine-graft polycaprolactone-block-poly(ethylene glycol)-folate (PEI-PCL-PEG-Fol). AB - Efficient delivery of functional nucleic acids into specific cells or tissues is still a challenge for gene therapy and largely depends on targeted delivery strategies. The folate receptor (FR) is known to be overexpressed extracellularly on a variety of human cancers and is therefore an outstanding gate for tumor targeted Trojan horse-like delivery of therapeutics. In this study, an amphiphilic and biodegradable ternary copolymer conjugated with folate as ligand, polyethylenimine-graft-polycaprolactone-block-poly(ethylene glycol)-folate (PEI PCL-PEG-Fol) was synthesized and evaluated for targeted siRNA delivery via folate FR recognition. The amphiphilic character of similar polymers was shown previously to support endosomal release of endocytosed nanocarriers and to promote formation of long circulating micelles. The obtained PEI-PCL-PEG-Fol exhibited less cytotoxicity in comparison with the corresponding ternary copolymer without folate (PEI-PCL-PEG) and with unmodified PEI25kDa. Stable micelle-like polyplexes with hydrodynamic diameters about 100 nm were found to have a zeta potential of +8.6 mV, which was lower than that of micelleplexes without folate-conjugation (+13-16 mV). Nonetheless, increased cellular uptake and in vitro gene knockdown of PEI-PCL-PEG-Fol/siRNA micelleplexes were observed in SKOV-3 cells, an FR overexpressing cell line, in comparison with the nonfolate conjugated ones. Moreover, PEI-PCL-PEG-Fol/siRNA micelleplexes exhibited excellent stability in vivo during the analysis of 120 min and a longer circulation half life than hyPEI25kDa/siRNA polyplexes. Most interestingly, the targeted delivery system yielded 17% deposition of the i.v. injected siRNA per gram in the tumor after 24 h due to the effective folate targeting and the prolonged circulation. PMID- 26641135 TI - Dosing of antifungal agents in obese people. AB - Obesity is a worldwide epidemic associated with multiple comorbidities that increase the risk of hospitalization. Very little pharmacokinetic data are available for antifungal agents in obesity, as this population is often excluded from drug development studies and these agents are less commonly used than other antimicrobials. Systemic antifungal therapy for invasive candidiasis continues to have a high failure rate, and dose optimization in obesity provides an opportunity for improvement. Based on currently available data, some antifungals should be dosed based on total body weight (i.e. fluconazole), while others should not be adjusted for increased body weight (i.e. posaconazole). More studies are needed to determine if and when dosing changes are needed for many of the antifungal agents. Therefore, drug therapy regimens should be individually evaluated for dose optimization due to body weight. PMID- 26641136 TI - A pharmacological treatment algorithm for localized neuropathic pain. AB - Neuropathic pain is caused by a lesion or disease affecting the somatosensory system and is difficult to manage, often proving refractory to existing treatments. In more than half of cases, it is localized and affects a specific, clearly circumscribed area of the body (localized neuropathic pain, or LNP). A recently developed screening tool enables patients with probable neuropathic pain/LNP to be identified quickly and easily. In view of the conflicting current treatment recommendations, an advisory board of pain specialists met in June 2015 to develop a complementary treatment guidance algorithm, for use in the primary care setting and by non-pain specialists. The starting point of the algorithm is a diagnosis of LNP and there was consensus that first-line treatment should be a topical analgesic agent, because the benefit/risk ratios are far better than for systemic agents. Topical application offers site-specific delivery, a lower total systemic dose and avoidance of first-pass metabolism, reducing the risk of adverse events and drug/drug interactions. The 5% lidocaine medicated plaster has most evidence supporting its use in LNP, producing effective analgesia and reducing the associated area of allodynia, but other topical agents include capsaicin, clonidine and botulinum toxin type A. Treatment should be commenced with the topical agent of choice, and the patient re-assessed after an appropriate period. Where the response is good the topical agent is continued, with a re-evaluation after 3-6 months. A systemic agent (e.g. gabapentin, pregabalin, duloxetine, venlafaxine) is added if there is only a partial response, or substituted if there is no response, and the patient re-assessed after a month. If there is poor or no response to the systemic agent the patient should be switched to an alternative one and, if this also proves ineffective, referred to a pain specialist. PMID- 26641138 TI - The complete chloroplast genome sequences of Iris sanguinea donn ex Hornem. AB - The complete chloroplast genome of Iris sanguinea was sequenced newly in this study. The total chloroplast genome size of I. sanguinea was 152 408 bp, its structure and gene contents were well conserved as typical chloroplast characteristics. Large single copy (LSC) and small single copy (SSC) of 82 340 bp and 18 016 bp, respectively, were separated from a pair of inverted repeats (IRA and IRB) of 26 026 bp. A total of 112 genes, i.e. 78 protein-coding genes, 30 tRNA genes, and four rRNA genes, were encoded in the chloroplast genome of I. sanguinea. Overall GC content of I. sanguinea was 36.83%. Phylogenetic analysis with the reported chloroplast genomes revealed that I. sanguinea is most closely related to I. gatesii. PMID- 26641137 TI - Acalabrutinib (ACP-196) in Relapsed Chronic Lymphocytic Leukemia. AB - BACKGROUND: Irreversible inhibition of Bruton's tyrosine kinase (BTK) by ibrutinib represents an important therapeutic advance for the treatment of chronic lymphocytic leukemia (CLL). However, ibrutinib also irreversibly inhibits alternative kinase targets, which potentially compromises its therapeutic index. Acalabrutinib (ACP-196) is a more selective, irreversible BTK inhibitor that is specifically designed to improve on the safety and efficacy of first-generation BTK inhibitors. METHODS: In this uncontrolled, phase 1-2, multicenter study, we administered oral acalabrutinib to 61 patients who had relapsed CLL to assess the safety, efficacy, pharmacokinetics, and pharmacodynamics of acalabrutinib. Patients were treated with acalabrutinib at a dose of 100 to 400 mg once daily in the dose-escalation (phase 1) portion of the study and 100 mg twice daily in the expansion (phase 2) portion. RESULTS: The median age of the patients was 62 years, and patients had received a median of three previous therapies for CLL; 31% had chromosome 17p13.1 deletion, and 75% had unmutated immunoglobulin heavy chain variable genes. No dose-limiting toxic effects occurred during the dose escalation portion of the study. The most common adverse events observed were headache (in 43% of the patients), diarrhea (in 39%), and increased weight (in 26%). Most adverse events were of grade 1 or 2. At a median follow-up of 14.3 months, the overall response rate was 95%, including 85% with a partial response and 10% with a partial response with lymphocytosis; the remaining 5% of patients had stable disease. Among patients with chromosome 17p13.1 deletion, the overall response rate was 100%. No cases of Richter's transformation (CLL that has evolved into large-cell lymphoma) and only one case of CLL progression have occurred. CONCLUSIONS: In this study, the selective BTK inhibitor acalabrutinib had promising safety and efficacy profiles in patients with relapsed CLL, including those with chromosome 17p13.1 deletion. (Funded by the Acerta Pharma and others; ClinicalTrials.gov number, NCT02029443.). PMID- 26641140 TI - The complete mitochondrial genome of Mastacembelus aculeatus (Cypriniformes, Mastacembelidae) from the Pearl River, China. AB - In this paper, the complete mitochondrial DNA (mtDNA) sequence of Mastacembelus aculeatus was determined. The mitochondrial genome is 16 543 bp in length, including 13 protein-coding genes, 2 ribosomal RNAs (rRNAs), 22 transfer RNAs (tRNAs), and a non-coding control region as those found in other vertebrates, with the gene identical to that of typical vertebrates. The overall base composition of the heavy strand is 30.0% A, 26.4% T, 14.8% C, and 28.7% G, with an AT bias of 56.49%. Phylogeny of M. aculeatus suggested more close relationship with Mastacembelus armatus and Mastacembelus favus. The complete mitogenome may add new information to existing mitogenome data for Mastacembelidae, providing further information that may contribute to their taxonomy, evolution, and phylogeny. PMID- 26641141 TI - Epitaxial Stabilization between Intermetallic and Carbide Domains in the Structures of Mn16SiC4 and Mn17Si2C4. AB - The concept of frustration between competing geometrical or bonding motifs is frequently evoked in explaining complex phenomena in the structures and properties of materials. This idea is of particular importance for metallic systems, where frustration forms the basis for the design of metallic glasses, a source of diverse magnetic phenomena, and a rationale for the existence of intermetallics with giant unit cells containing thousands of atoms. Unlike soft materials, however, where conflicts can be synthetically encoded in the molecular structure, staging frustration in the metallic state is challenging due to the ease of macroscopic segregation of incompatible components. In this Article, we illustrate one approach for inducing the intergrowth of incompatible bonding motifs with the synthesis and characterization of two new intermetallic carbides: Mn16SiC4 (mC42) and Mn17Si2C4 (mP46). Similar to the phases Mn5SiC and Mn8Si2C in the Mn-Si-C system, these compounds appear as intergrowths of Mn3C and tetrahedrally close-packed (TCP) regions reminiscent of Mn-rich Mn-Si phases. The nearly complete spatial segregation of Mn-Si (intermetallic) and Mn-C (carbide) interactions in these structures can be understood from the differing geometrical requirements of C and Si. Rather than macroscopically separating into distinct phases, though, the two bonding types are tightly interwoven, with most Mn atoms being on the interfaces. DFT chemical pressure analysis reveals a driving force stabilizing these interfaces: the major local pressures acting between the Mn atoms in the Mn-Si and Mn-C systems are of opposite signs. Joining the intermetallic and carbide domains together then provides substantial relief to these local pressures, an effect we term epitaxial stabilization. PMID- 26641139 TI - Factors associated with antiretroviral treatment uptake and adherence: a review. Perspectives from Australia, Canada, and the United Kingdom. AB - International focus on reducing onward HIV transmission emphasizes the need for routine HIV testing and early uptake of antiretroviral treatment (ART). Strategic targets have been set for 2020 to achieve the goal of 90% of people infected with HIV diagnosed, 90% of identified cases on treatment, and 90% of persons on treatment virally suppressed (90-90-90). It is vital to understand the complexity of factors influencing a person's treatment decisions over time and the context which may enable better adherence. In this paper we present findings from the review of published and gray literature (2003-2013) on the documented factors associated with treatment initiation and adherence in the general adult population of Australia, Canada, and the UK. A framework developed by Begley, McLaws, Ross, and Gold [2008. Cognitive and behavioural correlates of non adherence to HIV anti-retroviral therapy: Theoretical and practical insight for clinical psychology and health psychology. Clinical Psychologist, 12(1), 9-17] in Australia was adapted to summarize the findings. A systematic database search using keywords and a set of inclusion criteria yielded 17 studies (Australia = 6; Canada = 8; UK = 3). In addition 11 reports were included in the review. We found that a person's abilities and motivations (intrapersonal factors, reported in 7 studies) to start and continue ART are influenced by a host of interconnected factors spanning relationship (interpersonal, 3 studies) and broader structural (extrapersonal, 15 studies) factors that are situated within social determinants of health. People therefore evaluate various costs and benefits of starting and staying on treatment, in which biomedical concerns play an important yet often subsidiary role. In this review the economic barriers to care were found to be significant and under-reported, highlighting the persistent health inequities in terms of access to services. Our understanding of the context around people's use of ART remains poor. Qualitative social research within HIV-positive communities is urgently needed to capture people's lived experiences and may address some of this deficit in understanding. PMID- 26641142 TI - Cost-effectiveness of vortioxetine versus venlafaxine (extended release) in the treatment of major depressive disorder in South Korea. AB - OBJECTIVE: To assess the cost-effectiveness of vortioxetine versus venlafaxine XR (extended-release) in major depressive disorder (MDD) patients in South Korea. METHODS: A 1-year cost-effectiveness analysis from a limited societal perspective was performed using a combined model consisting of a decision-tree and a Markov model. Patients entered the model when initiating or switching antidepressant treatment following inadequate response to previous treatment. Remission, relapse and recovery were the main health states. RESULTS: Vortioxetine dominated venlafaxine XR, with quality-adjusted life year (QALY) gains of 0.0131 and cost savings of KRW 623,229/year [US$530/year] from a limited societal perspective. Safety contributed more than efficacy to the incremental QALY gains. More patients were in recovery after initial treatment and after 1 year with vortioxetine (31%, 40%) compared to venlafaxine XR (23%, 36%). Vortioxetine remained dominant in 98% of probabilistic simulations. CONCLUSION: Vortioxetine dominated venlafaxine XR in South Korea and is a relevant treatment option for MDD patients initiating or switching therapy. PMID- 26641143 TI - The role of insulin resistance in nonalcoholic steatohepatitis and liver disease development--a potential therapeutic target? AB - Insulin resistance (IR) is defined by the inability of insulin to exert its metabolic actions, due to impaired activation of intracellular insulin signaling. This condition is caused by genetic defects or by environmental conditions, among which the most common is obesity. Systemic IR determines the development of hepatic fat accumulation, which can progress to nonalcoholic steatohepatitis, cirrhosis and hepatocellular carcinoma, and is a major determinant of liver disease independently of coexisting factors. Therefore, insulin-sensitizing drugs are currently under evaluation to improve steatohepatitis. Indeed, manipulation of nuclear hormone receptors is already under scrutiny for liver disease prevention by amelioration of IR, whereas NOTCH signaling inhibition represents a novel approach. Nevertheless, further research is warranted to better understand the mechanism linking IR to progressive fibrogenesis in the absence of inflammation and to identify novel drug targets. PMID- 26641144 TI - Quantification of microRNA by DNA-Peptide Probe and Liquid Chromatography-Tandem Mass Spectrometry-Based Quasi-Targeted Proteomics. AB - The distorted and unique expression of microRNAs (miRNAs) in cancer makes them an attractive source of biomarkers. However, one of prerequisites for the application of miRNAs in clinical practice is to accurately profile their expression. Currently available assays normally require pre-enrichment, amplification, and labeling steps, and most of them are semiquantitative. In this study, we converted the signal of target miR-21 into reporter peptide by a DNA peptide probe and the reporter peptide was ultimately quantified using LC-MS/MS based targeted proteomics. Specifically, substrate peptide GDKAVLGVDPFR containing reporter peptide AVLGVDPFR and tryptic cleavage site (lysine at position 3) was first designed, followed by the conjugation with DNA sequence that was complementary to miR-21. The newly formed DNA-peptide probe was then hybridized with miR-21, which was biotinylated and attached to streptavidin agarose in advance. After trypsin digestion, the reporter peptide was released and monitored by a targeted proteomics assay. The obtained limit of quantification (LOQ) was 1 pM, and the detection dynamic range spanned ~5 orders of magnitude. Using this assay, the developed quasi-targeted proteomics approach was applied to determine miR-21 level in breast cells and tissue samples. Finally, qRT-PCR was also performed for a comparison. This report grafted the strategy of targeted proteomics into miRNA quantification. PMID- 26641145 TI - Patient Complaints: Not Ours to Own, But Ours to Fix. PMID- 26641146 TI - Evaluation of Work Stress, Turnover Intention, Work Experience, and Satisfaction with Preceptors of New Graduate Nurses Using a 10-Minute Preceptor Model. PMID- 26641147 TI - Enhancing Trifocal Leadership Practices Using Simulation in a Pediatric Charge Nurse Orientation Program. PMID- 26641148 TI - Combining Evidence-Based Practice, Learner-Guided Education, and Continuing Education. AB - Personal interest and investment in a topic can bring learning to life and affect real change in nursing practice. This article explains an innovative approach to combining learner-guided education and continuing education credit through a three-part approach to implementing evidence-based practice. This method can be used for nurses in any practice setting to generate learner interest and participation, while improving patient care. PMID- 26641149 TI - Improving Quality Outcomes Using a Champion Model for Ancillary Nursing Staff. AB - The goal of this article is to describe the implementation of a champion model for ancillary nursing staff. As Quality Champions, nursing assistants attended specialized education classes to promote improvement in quality outcomes related to skin care, diabetes care, and prevention of catheter-associated urinary tract infections. PMID- 26641150 TI - Tips for Working With External Reviewers. AB - Leaders are responsible for creating a culture of quality and safety within a highly regulated industry. Five tips for working with regulators are presented from a leadership coaching framework. PMID- 26641151 TI - Charting the Course for a Nursing Online Journal Club: Part I. AB - In a pediatric inpatient setting, an interdisciplinary team designed and implemented an online journal club to discuss current nursing trends and research and to foster evidence-based practice. This article is Part I of a two-part series in which the process will be described. PMID- 26641152 TI - Impact of Nurse Certification Rates on Patient Satisfaction and Outcomes: A Literature Review. AB - The Institute of Medicine's report The Future of Nursing: Leading Change, Advancing Health states that continued competence requires lifelong learning. Certification measures lifelong learning by validating the expertise of nurses in specialty areas beyond those required by licensure examinations. Current research provides limited quantitative evidence to support a positive correlation between nurse certification rates and patient satisfaction and outcomes. The health care industry and affiliated professionals are experiencing increased public scrutiny and accountability through mandated quality of care measures that impact monetary reimbursement. Increased public scrutiny and accountability highlights the need for research to substantiate the quantitative benefits of nurse certification on patient satisfaction and outcomes. The Hospital Consumer Assessment of Healthcare Providers and Systems Survey scores, the Hospital Value-Based Purchasing program, and the National Database of Nursing Quality Indicators((r)) are potential sources for producing the reliable and valid evidence needed to convince RNs, hospital administrators, and all other stakeholders that nurse certification has a quantifiable correlation with patient satisfaction and outcomes. PMID- 26641153 TI - Personal Information Management for Nurses Returning to School. AB - Registered nurses with a diploma or an associate's degree are encouraged to return to school to earn a Bachelor of Science in Nursing degree. Until they return to school, many RNs have little need to regularly write, store, and retrieve work-related papers, but they are expected to complete the majority of assignments using a computer when in the student role. Personal information management (PIM) is a system of organizing and managing electronic information that will reduce computer clutter, while enhancing time use, task management, and productivity. This article introduces three PIM strategies for managing school work. Nesting is the creation of a system of folders to form a hierarchy for storing and retrieving electronic documents. Each folder, subfolder, and document must be given a meaningful unique name. Numbering is used to create different versions of the same paper, while preserving the original document. PMID- 26641154 TI - Evaluating the Clinical Judgment of Newly Hired Staff Nurses. AB - Assessing newly hired nurses' readiness for practice is critical for safe practice and the quality care of patients; therefore, hospitals need effective assessment strategies to promote clinical judgment development. One large medical center hospital developed a process to assess new hires' clinical judgment, using case studies. This article describes the assessment process and reports findings from a retrospective analysis of the clinical judgment competency of the participants. The findings suggest that more orientation time and experience are needed for less-experienced nurses (<3 years) and experienced nurses who have not practiced in acute care. The research concludes that practice and academic educators must work more closely for a smoother transition of novice nurses into practice. PMID- 26641155 TI - Team-Based Learning in a Graduate Nurse Residency Program. AB - Nurse residency programs have become a standard of practice for transitioning nurses into the workforce. Resources and support determine the length and structure of these programs. New content and information is often delivered by the traditional lecture style. The organization described in this article implemented an innovative framework, derived from team-based learning, that facilitated learner engagement, interprofessional communication and patient care, enhanced critical thinking, problem solving, and knowledge development. PMID- 26641156 TI - Branched Hydrocarbon Low Surface Energy Materials for Superhydrophobic Nanoparticle Derived Surfaces. AB - We present a new class of superhydrophobic surfaces created from low-cost and easily synthesized aluminum oxide nanoparticles functionalized carboxylic acids having highly branched hydrocarbon (HC) chains. These branched chains are new low surface energy materials (LSEMs) which can replace environmentally hazardous and expensive fluorocarbons (FCs). Regardless of coating method and curing temperature, the resulting textured surfaces develop water contact angles (theta) of ~155 degrees and root-mean-square roughnesses (Rq) ~ 85 nm, being comparable with equivalent FC functionalized surfaces (theta = 157 degrees and Rq = 100 nm). The functionalized nanoparticles may be coated onto a variety of substrates to generate different superhydrophobic materials. PMID- 26641157 TI - BILL E. KUNKLE INTERDISCIPLINARY BEEF SYMPOSIUM: Tall fescue toxicosis update. PMID- 26641158 TI - BILL E. KUNKLE INTERDISCIPLINARY BEEF SYMPOSIUM: Coping with tall fescue toxicosis: Solutions and realities. AB - Beef cattle consume more tall fescue [ (Schreb.) Darbysh.] than any other perennial cool-season grass in North America. Tall fescue forms a mutualistic relationship with the fungus (Morgan-Jones and W. Cams) C.W. Bacon & Schardl, comb. nov.; these plants are often referred to as endophyte-infected tall fescue. Agronomically, endophyte infection is good; endophyte-infected plants resist biotic and abiotic stresses better than do endophyte-free plants. However, tall fescue plants infected with a common toxic endophyte produce the ergot alkaloids that cause tall fescue toxicosis. Several agronomic practices can eliminate or reduce the effects of tall fescue toxicosis. Renovating tall fescue fields infected with a common toxic endophyte to new cultivars infected with a novel (or nontoxic) endophyte eliminates the problem for that field. Although the cost to renovate currently exceeds US$600/ha, most economic analyses show it to be a good long-term investment, especially on fields with high forage production potential. Less effective, but popular, methods of dealing with tall fescue toxicosis include adding clovers ( spp.) or other forage species to the pastures to dilute the effects of the toxins, avoiding the use of high rates of nitrogen fertilizers, feeding supplements, and rotating cattle to warm-season forages in summer. Also, the alkaloid concentration in forage can be reduced by making it (drying) into hay. Recent research shows that animal tolerance to tall fescue toxicosis is possible, although there is still much to learn about this topic. Tall fescue toxicosis is likely a reality in the beef industry for some time to come. We contend that renovation of the most productive fields to cultivars infected with a novel endophyte coupled with the prospect of using tolerant livestock in scenarios where renovation is not possible will give innovative producers a competitive edge. PMID- 26641159 TI - BILL E. KUNKLE INTERDISCIPLINARY BEEF SYMPOSIUM: A meta-analysis of research efforts aimed at reducing the impact of fescue toxicosis on cattle weight gain and feed intake. AB - The objective of this paper is to present a systematic review and meta-analysis of research efforts aimed at recovering cattle production losses attributed to toxic endophyte-infected [ (Morgan-Jones & Gams.) Glenn, Bacon, & Hanlin comb. Nov.] tall fescue [ (Schreb.) Darbysh.]. The strategies presented include those 1) applied with forage systems, 2) based on pharmacological compounds and functional foods, and 3) based on supplemental dietary nutrients. Cattle BW gain and DM intake was the dependent response evaluated. Among the forage systems reviewed, studies with nontoxic, endophyte-infected tall fescue as a total replacement forage system demonstrated the greatest improvement in per-hectare (152 +/- 27.5 kg/ha) and per-animal (0.29 +/- 0.03 kg/d) BW gain. Studies with interseeded legumes have exhibited a small and highly variable BW gain effect size per hectare (52 +/- 24.1 kg/ha) and per animal (0.11 +/- 0.03 kg/d). The legume response was seasonal, with summer exhibiting the greatest benefit. Studies with chemicals that suppress plant growth demonstrated BW gain responses (0.17 +/- 0.06 kg/d) equal to or greater than the response observed with legume studies. Cattle grazing toxic tall fescue responded well to anthelmentics, antimicrobial feed additives, and steroid implants, and the use of these technologies may additively help recover production losses. As a group, functional foods have not improved BW gain ( = 0.85). Studies with cattle supplemented with highly digestible fiber supplements observed a 0.15 kg greater BW gain compared with studies using starch- and sugar-based supplements ( < 0.05). Weight gain was positively impacted by the level of supplementation (0.06 kg/DM intake as percent BW). Supplement feed conversion was estimated at 6:1 for the highly digestible fiber supplements compared with 11:1 for starch-based supplements. Tall fescue forage DM intake was predicted to maximize at a supplemental feeding rate of 0.24% BW with a breakpoint at 0.5% BW, and total maximum DM intake (forage plus supplement) occurred at 2.7% BW when supplemental feeding approached 0.9% BW. Results from this meta-analysis should be useful for 1) establishing and comparing measured responses to theoretical improvements in BW gain when additive strategies are considered, 2) research planning, and 3) producer education. PMID- 26641160 TI - BILL E. KUNKLE INTERDISCIPLINARY BEEF SYMPOSIUM: Genetic resistance to the effects of grazing endophyte-infected tall fescue. AB - Forages are the base source of nutrition for any cow-calf operation. Forage types vary based on soil type and climate. Tall fescue () is the most commonly used cultivated grass for grazing beef cattle in the United States. This cool-season perennial is easily established; is resistant to drought, insects, and nematodes; and has the ability to withstand heavy grazing pressure. Most tall fescue varieties are infected with the endophyte fungus () that is essential for the plant's survival but detrimental to cattle performance. Ergot alkaloids are the generally accepted toxic agents produced by the fescue endophyte. Cattle that consume forages infected with this endophyte can develop fescue foot, fat necrosis, or fescue toxicosis. It is estimated that the beef industry loses over US$500 million annually due to fescue toxicosis through heat stress, reduced weight gain, suppressed appetite, and decreased reproductive performance. Other symptoms include a retained or rough hair coat and increased body temperature, which can be detrimental when animals are located in hot and or humid environments. Different forages and forage systems, feed additives, and animal management strategies have been tested through the years allowing the use of tall fescue in beef production systems while minimizing the adverse effects. An animal genetics approach needs to identify and select animals less susceptible to the ergot alkaloids. Research in this area reports that different cattle within the same herd can respond differently when grazing tall fescue, and evidence exists that breed type may also play a role in genetic tolerance to the negative effects on performance. Some studies have looked at the potential of identifying genetic markers that may assist in the selection of more resistant animals. From these studies, there is evidence that genetic variation does exist for resistance to the ergot alkaloids present when grazing endophyte-infected tall fescue. Forage management coupled with animal genetic selection could allow for more efficient use of tall fescue as a significant forage source in beef cattle systems. These would allow producing more beef per hectare in the United States in response to an increasing population combined with decreasing resources. PMID- 26641161 TI - BILL E. KUNKLE INTERDISCIPLINARY BEEF SYMPOSIUM: Physiologic effects of ergot alkaloids: What happens when excretion does not equal consumption? AB - Increased persistence of tall fescue () infested with an endophytic fungus, (formerly ), in forage-based agriculture has led to increased effort in understanding the negative effects caused by consumption of ergot alkaloids by animals consuming this forage. Ergot alkaloids have been shown to have an extremely short plasma half-life, but this does not necessarily equate to total clearance. Studies that measured consumption and excretion of alkaloids have demonstrated that in the case of ergovaline, less is excreted than is consumed. The fate of ergot alkaloids that leave circulation but are not excreted is not well understood. Consequently, these "alkaloid balance studies" have led to speculation that ergovaline might bioaccumulate in the animal. Unfortunately, few data indisputably support this outcome. Progress has been slowed by the fact that the fungus produces a multitude of different ergot alkaloids that can bind to a variety of different receptors. Binding studies have shown that ergot alkaloids have unusually slow receptor dissociation rates that have been described as irreversible and contribute to a persistent signaling effect. In vitro analyses have revealed a potential for accumulation of ergot alkaloids through repetitive exposures to low concentrations creating a "depot" of alkaloids available to interact with receptors. The specific high binding affinity of ergot alkaloids combined with the potential turnover of alkaloids bound nonspecifically could extend residual effects of these compounds. Interestingly, cattle exposed to ergot alkaloids in vivo have a consistently lower vascular response to agonists that target receptors known to bind ergot alkaloids. If these same receptors are blocked with an antagonist, contractile response to ergopeptine alkaloids is also reduced significantly (>60% reduction). This observation that alkaloid exposure interrupts normal function of a receptor can persist 5 to 6 wk after animals have been removed from an ergot alkaloid source (and prolactin levels have long since returned to normal). Thus, clearance of ergot alkaloids from cattle grazing pasture with ergot alkaloid-producing endophytes may occur in a similar gradual manner. Studies that improve the understanding of how cattle process ergot alkaloids will help answer the question of whether ergot alkaloids bioaccumulate. PMID- 26641162 TI - BILL E. KUNKLE INTERDISCIPLINARY BEEF SYMPOSIUM: Does tall fescue toxicosis negatively impact bull growth and breeding potential? AB - The predominant cool-season forage in the southeastern United States is the tall fescue cultivar Kentucky 31 (KY31). Kentucky 31 possesses an endophyte (), which produces a family of toxins called ergot alkaloids. These toxins negatively affect the physiology of animals on consumption and result in the syndrome known as fescue toxicosis. Currently, the United States annually produces approximately 11.4 billion kg of beef, of which 25% originates in the southeastern region of the United States where forage systems frequently are tall fescue based. Cattle within this forage system exhibit reduced gains and reproductive performance. The result is a reduction in the nation's beef supply with annual revenue losses recently estimated at approximately US$1 billion. Our hypothesis is that exposure to these ergot alkaloids in conjunction with limited availability of nutrients decreases bull semen quality and fertility. Although the literature is clear that these toxins affect BW, body temperature, blood flow, hair growth, and female reproduction in cattle, their effect on bull reproduction and the mechanisms through which the toxins act are not well defined. Six studies published from 2004 to 2015 assessed bull growth, body composition, and semen quality of young beef bulls exposed to ergot alkaloids. If semen quality or fertility is altered, the mechanisms involved may be either direct effects of ergot alkaloids through neurotransmitter receptors or indirect effects such as inhibiting the release of prolactin (PRL). The possible effects of ergot alkaloids or PRL require establishing the presence or absence of dopamine, adrenergic, serotonin, or PRL receptors in the testis, epididymis, and sperm cell of the bull. The objective of this review is to relate our findings to the few previous studies conducted that evaluated the impact of fescue toxicosis on bull reproduction and to propose possible mechanisms of action for lowered semen quality. PMID- 26641163 TI - TRIENNIAL LACTATION SYMPOSIUM: Nutrigenomics in dairy cows. PMID- 26641164 TI - TRIENNIAL LACTATION SYMPOSIUM: Nutrigenomics in dairy cows: Nutrients, transcription factors, and techniques. AB - Nutrigenomics in dairy cows is a relatively new area of research. It is defined as the study of the genomewide influences of nutrition altering the expression of genes. Dietary compounds affect gene expression directly or indirectly via interactions with transcription factors. Among those, the most relevant for nutrigenomics are ligand-dependent nuclear receptors, especially peroxisome proliferator-activated receptors (PPAR) and liver X receptor. Among other transcription factors, a prominent nutrigenomic role is played by the sterol regulatory element-binding protein 1 (SREBP1). Data from studies on dairy cows using gene expression and gene reporters among the main molecular methods used to study nutrigenomics in dairy cows are indicative of a network of multiple transcription factors at play in controlling the nutrigenomic responses. Fatty acids, AA, and level of feed and energy intake have the strongest nutrigenomic potential. The effect of 10,12 CLA on depressing milk fat synthesis via inhibition of SREBP1 was among the first and likely the best-known nutrigenomic example in dairy cows. Although long-chain fatty acids (LCFA) are clearly the most potent, a nutrigenomic role for short-chain fatty acids is emerging. Available data indicate that saturated compared with unsaturated LCFA have a more potent nutrigenomic effect in vitro, likely through PPAR. In vivo, the effect of saturated LCFA is more modest, with contrasting effects among tissues. Nutrigenomic effects of AA are emerging, particularly for the regulation of milk protein synthesis-associated genes. The level of energy in the diet has a strong and broad nutrigenomic effect and appears to "prime" tissue metabolism, particularly liver. We are at the frontier of the nutrigenomics era in ruminants and initial data strongly indicate that this scientific branch (and spinoffs such as nutriepigenomics) can play a critical role in future strategies to better feed dairy cattle. PMID- 26641165 TI - TRIENNIAL LACTATION SYMPOSIUM: Nutrigenomics in livestock: Systems biology meets nutrition. AB - The advent of high-throughput technologies to study an animal's genome, proteome, and metabolome (i.e., "omics" tools) constituted a setback to the use of reductionism in livestock research. More recent development of "next-generation sequencing" tools was instrumental in allowing in-depth studies of the microbiome in the rumen and other sections of the gastrointestinal tract. Omics, along with bioinformatics, constitutes the foundation of modern systems biology, a field of study widely used in model organisms (e.g., rodents, yeast, humans) to enhance understanding of the complex biological interactions occurring within cells and tissues at the gene, protein, and metabolite level. Application of systems biology concepts is ideal for the study of interactions between nutrition and physiological state with tissue and cell metabolism and function during key life stages of livestock species, including the transition from pregnancy to lactation, in utero development, or postnatal growth. Modern bioinformatic tools capable of discerning functional outcomes and biologically meaningful networks complement the ever-increasing ability to generate large molecular, microbial, and metabolite data sets. Simultaneous visualization of the complex intertissue adaptations to physiological state and nutrition can now be discerned. Studies to understand the linkages between the microbiome and the absorptive epithelium using the integrative approach are emerging. We present examples of new knowledge generated through the application of functional analyses of transcriptomic, proteomic, and metabolomic data sets encompassing nutritional management of dairy cows, pigs, and poultry. Published work to date underscores that the integrative approach across and within tissues may prove useful for fine-tuning nutritional management of livestock. An important goal during this process is to uncover key molecular players involved in the organismal adaptations to nutrition. PMID- 26641166 TI - TRIENNIAL LACTATION SYMPOSIUM: Systems biology of regulatory mechanisms of nutrient metabolism in lactation. AB - A major role of the dairy cow is to convert low-quality plant materials into high quality protein and other nutrients for humans. We must select and manage cows with the goal of having animals of the greatest efficiency matched to their environment. We have increased efficiency tremendously over the years, yet the variation in productive and reproductive efficiency among animals is still large. In part, this is because of a lack of full integration of genetic, nutritional, and reproductive biology into management decisions. However, integration across these disciplines is increasing as the biological research findings show specific control points at which genetics, nutrition, and reproduction interact. An ordered systems biology approach that focuses on why and how cells regulate energy and N use and on how and why organs interact through endocrine and neurocrine mechanisms will speed improvements in efficiency. More sophisticated dairy managers will demand better information to improve the efficiency of their animals. Using genetic improvement and animal management to improve milk productive and reproductive efficiency requires a deeper understanding of metabolic processes throughout the life cycle. Using existing metabolic models, we can design experiments specifically to integrate data from global transcriptional profiling into models that describe nutrient use in farm animals. A systems modeling approach can help focus our research to make faster and larger advances in efficiency and determine how this knowledge can be applied on the farms. PMID- 26641167 TI - TRIENNIAL LACTATION SYMPOSIUM: Nutrient partitioning during intramammary inflammation: A key to severity of mastitis and risk of subsequent diseases? AB - In early lactation, susceptibility to disease is greatest, impacting cow health and productivity and leading to economic losses. Mastitis is the most economically costly disease to the dairy industry and is most frequent at this time. The objective of this paper is to discuss the energetic fuels used by leukocytes in the metabolic response during mastitis that may reveal potential mechanisms linking mastitis with the development of subsequent metabolic diseases for dairy cows during lactation. Glucose and glutamine are the primary fuels used by leukocytes and are essential substrates for optimal leukocyte function. Yet because these substrates are in high demand to support milk synthesis during early lactation, their supply to leukocytes may be compromised and may partly contribute to immunosuppression observed at this time. Production-related metabolic diseases during early lactation, such as ketosis and hepatic lipidosis, can also adversely affect health and productivity. Risk of subsequent disease for cows during mastitis has not been fully elucidated. Regardless of stage of lactation and physiological state, increases in circulating NEFA and glucose and decreases in ketones during an intramammary inflammation in dairy cows have been reported. In addition, previous work indicates that hepatic metabolism may be impaired during inflammation. These results indicate a potential link between mastitis and the risk of subsequent metabolic disease for dairy cows during lactation. This paper will discuss the complex relationships between metabolism and immune function and how these immunometabolic interactions relate mastitis with increased risk of subsequent disease during early lactation. PMID- 26641168 TI - 2014 H. Allen Tucker Lactation and Endocrinology Award Graduate education: Lessons from my mentor. PMID- 26641169 TI - Visual body-scores selection and its influence on body size and ultrasound carcass traits in Nellore cattle. AB - Genetic parameters, genetic trends, and genetic progress of carcass traits were estimated for 12,447 Nellore individuals from different Brazilian herds. The following carcass traits were analyzed: visual body scores of conformation (CONF), precocity (PREC), and muscularity (MUSC); rump width (RW) and rump length (RL), body size (frame); and ultrasound evaluation of ribeye area (REA), backfat thickness (BFT), and rump fat thickness (RFT). Heritability estimates (+/- SE) for CONF, PREC, and MUSC were 0.23 +/- 0.02, 0.33 +/- 0.03, and 0.31 +/- 0.02, respectively. The heritability estimates (+/- SE) for RW, RL, and frame were 0.25 +/- 0.05, 0.16 +/- 0.04, and 0.31 +/- 0.03, respectively. Ultrasound of the REA, BFT, and RFT presented mean heritability estimates (+/- SE) of 0.38 +/- 0.03, 0.44 +/- 0.04, and 0.47 +/- 0.04, respectively. The visual body score of CONF had high genetic correlations with RW, RL, and frame (0.74 +/- 0.09, 0.82 +/- 0.08, and 0.83 +/- 0.04, respectively), indicating a high association of CONF with the measurements related to body structure. The REA had no correlation with BFT and RFT (-0.09 +/- 0.04 and -0.03 +/- 0.04, respectively) and showed only a moderate genetic correlation with MUSC (0.39 +/- 0.05). The BFT and RFT had moderate genetic correlations with PREC (0.36 +/- 0.07 and 0.29 +/- 0.07, respectively) and no correlation with frame (-0.02 +/- 0.03 and 0.05 +/- 0.05, respectively), suggesting that selection for frame had no effect on the subcutaneous fat content of the carcass. Low genetic trends and low genetic progress were obtained for REA (0.026 cm, 0.02%), BFT (0.0031 mm, 0.05%), and RFT (0.0013 mm, 0.02%), with no significant values of genetic progress detected throughout the studied period. The CONF, PREC, and MUSC presented high genetic trends (0.030 points, 0.030 points, and 0.029 points, respectively) and high genetic progress (0.60%, 0.56%, and 0.59%, respectively), indicating a significant genetic progress for these traits throughout the evaluated period. Carcass traits evaluated by ultrasound and visual body scores are eligible for selection and can be used in genetic improvement programs in Nellore cattle; however, visual body score selection for carcass traits can result in slower genetic progress for carcass quality when compared to selection performed by ultrasound. PMID- 26641170 TI - Implementing meta-analysis from genome-wide association studies for pork quality traits. AB - Pork quality plays an important role in the meat processing industry. Thus, different methodologies have been implemented to elucidate the genetic architecture of traits affecting meat quality. One of the most common and widely used approaches is to perform genome-wide association (GWA) studies. However, a limitation of many GWA in animal breeding is the limited power due to small sample sizes in animal populations. One alternative is to implement a meta analysis of GWA (MA-GWA) combining results from independent association studies. The objective of this study was to identify significant genomic regions associated with meat quality traits by performing MA-GWA for 8 different traits in 3 independent pig populations. Results from MA-GWA were used to search for genes possibly associated with the set of evaluated traits. Data from 3 pig data sets (U.S. Meat Animal Research Center, commercial, and Michigan State University Pig Resource Population) were used. A MA was implemented by combining -scores derived for each SNP in every population and then weighting them using the inverse of estimated variance of SNP effects. A search for annotated genes retrieved genes previously reported as candidates for shear force (calpain-1 catalytic subunit [] and calpastatin []), as well as for ultimate pH, purge loss, and cook loss (protein kinase, AMP-activated, gamma 3 noncatalytic subunit []). In addition, novel candidate genes were identified for intramuscular fat and cook loss (acyl-CoA synthetase family member 3 mitochondrial []) and for the objective measure of muscle redness, CIE a* (glycogen synthase 1, muscle [] and ferritin, light polypeptide []). Thus, implementation of MA-GWA allowed integration of results for economically relevant traits and identified novel genes to be tested as candidates for meat quality traits in pig populations. PMID- 26641171 TI - Can multi-subpopulation reference sets improve the genomic predictive ability for pigs? AB - In most countries and for most livestock species, genomic evaluations are obtained from within-breed analyses. To achieve reliable breeding values, however, a sufficient reference sample size is essential. To increase this size, the use of multibreed reference populations for small populations is considered a suitable option in other species. Over decades, the separate breeding work of different pig breeding organizations in Germany has led to stratified subpopulations in the breed German Large White. Due to this fact and the limited number of Large White animals available in each organization, there was a pressing need for ascertaining if multi-subpopulation genomic prediction is superior compared with within-subpopulation prediction in pigs. Direct genomic breeding values were estimated with genomic BLUP for the trait "number of piglets born alive" using genotype data (Illumina Porcine 60K SNP BeadChip) from 2,053 German Large White animals from five different commercial pig breeding companies. To assess the prediction accuracy of within- and multi-subpopulation reference sets, a random 5-fold cross-validation with 20 replications was performed. The five subpopulations considered were only slightly differentiated from each other. However, the prediction accuracy of the multi-subpopulations approach was not better than that of the within-subpopulation evaluation, for which the predictive ability was already high. Reference sets composed of closely related multi subpopulation sets performed better than sets of distantly related subpopulations but not better than the within-subpopulation approach. Despite the low differentiation of the five subpopulations, the genetic connectedness between these different subpopulations seems to be too small to improve the prediction accuracy by applying multi-subpopulation reference sets. Consequently, resources should be used for enlarging the reference population within subpopulation, for example, by adding genotyped females. PMID- 26641172 TI - Resistance to infectious diseases is a heritable trait in rabbits. AB - Selection for disease resistance is a powerful way to improve the health status of herds and to reduce the use of antibiotics. The objectives of this study were to estimate 1) the genetic parameters for simple visually assessed disease syndromes and for a composite trait of resistance to infectious disease including all syndromes and 2) their genetic correlations with production traits in a rabbit population. Disease symptoms were recorded in the selection herds of 2 commercial paternal rabbit lines during weighing at the end of the test (63 and 70 d of age, respectively). Causes of mortality occurring before these dates were also recorded. Seven disease traits were analyzed: 3 elementary traits visually assessed by technicians on farm (diarrhea, various digestive syndromes, and respiratory syndromes), 2 composite traits (all digestive syndromes and all infectious syndromes), and 2 mortality traits (digestive mortality and infectious mortality). Each animal was assigned only 1 disease trait, corresponding to the main syndrome ( = 153,400). Four production traits were also recorded: live weight the day before the end of test on most animals ( = 137,860) and cold carcass weight, carcass yield, and perirenal fat percentage of the carcass on a subset of slaughtered animals ( = 13,765). Records on both lines were analyzed simultaneously using bivariate linear animal models after validation of consistency with threshold models applied to logit-transformed traits. The heritabilities were low for disease traits, from 0.01 +/- 0.002 for various digestive syndromes to 0.04 +/- 0.004 for infectious mortality, and moderate to high for production traits. The genetic correlations between digestive syndromes were high and positive, whereas digestive and respiratory syndromes were slightly negatively correlated. The genetic correlations between the composite infectious disease trait and digestive or respiratory syndromes were moderate. Genetic correlations between disease and production traits were favorable. Our results indicate that it is possible to select rabbits using visually assessed disease syndromes without the need for a trade-off between health and production traits. Using a composite criterion that includes all infectious syndromes is easy to implement and heritable and is, therefore, a promising way to improve the general disease resistance in livestock species. PMID- 26641173 TI - The direct-maternal genetic correlation has little impact on genetic evaluations. AB - Obtaining unbiased estimates of the direct-maternal genetic correlation proves far from straightforward for several reasons. Consequently, the use of such over- or underestimated correlations may introduce errors in genetic evaluation models. The objective of our study was to evaluate how the value of the direct-maternal genetic correlation affects EBV. Direct, maternal, and total breeding values were predicted for the ADG or weight at weaning for 3 different species (sheep, rabbits, and pigs) using models that differ depending on the fixed value of the direct-maternal genetic correlation (ranging from -0.9 to 0.9) as well as a model in which the correlation was estimated. The results were consistent between species. The direct-maternal genetic correlation had a greater impact on the estimated maternal genetic effects than on direct effects. The lowest correlations between maternal breeding values obtained with different models were -0.20, -0.01, and -0.72 in pigs, sheep, and rabbits, respectively, whereas for the direct breeding value, the lowest correlations were 0.45, 0.90, and 0.95 in pigs, sheep, and rabbits, respectively. The total EBV, calculated as the unweighted sum of direct and maternal genetic effects, did not differ greatly between the models, the lowest correlations between total breeding values being 0.93, 0.98, and 0.97 for pigs, sheep, and rabbits, respectively. Given the uncertainty associated with estimating the direct-maternal genetic correlation, setting its value to 0 in genetic evaluation models appears to be a good compromise. PMID- 26641174 TI - The developmental transcriptome landscape of bovine skeletal muscle defined by Ribo-Zero ribonucleic acid sequencing. AB - Ribonucleic acid sequencing (RNA-Seq) libraries are normally prepared with oligo(dT) selection of poly(A)+ mRNA, but it depends on intact total RNA samples. Recent studies have described Ribo-Zero technology, a novel method that can capture both poly(A)+ and poly(A)- transcripts from intact or fragmented RNA samples. We report here the first application of Ribo-Zero RNA-Seq for the analysis of the bovine embryonic, neonatal, and adult skeletal muscle whole transcriptome at an unprecedented depth. Overall, 19,893 genes were found to be expressed, with a high correlation of expression levels between the calf and the adult. Hundreds of genes were found to be highly expressed in the embryo and decreased at least 10-fold after birth, indicating their potential roles in embryonic muscle development. In addition, we present for the first time the analysis of global transcript isoform discovery in bovine skeletal muscle and identified 36,694 transcript isoforms. Transcriptomic data were also analyzed to unravel sequence variations; 185,036 putative SNP and 12,428 putative short insertions-deletions (InDel) were detected. Specifically, many stop-gain, stop loss, and frameshift mutations were identified that probably change the relative protein production and sequentially affect the gene function. Notably, the numbers of stage-specific transcripts, alternative splicing events, SNP, and InDel were greater in the embryo than in the calf and the adult, suggesting that gene expression is most active in the embryo. The resulting view of the transcriptome at a single-base resolution greatly enhances the comprehensive transcript catalog and uncovers the global trends in gene expression during bovine skeletal muscle development. PMID- 26641175 TI - Gene expression profiling indicates an increased capacity for proline, serine, and ATP synthesis and mitochondrial mass by the liver of steers grazing high vs. low endophyte-infected tall fescue. AB - Grazing -infected forages results in a variety of reduced animal performance parameters, collectively known as "fescue toxicosis." The initial, limited evaluations of hepatic mechanisms affected by fescue toxicosis have used transcriptomic expression profiling of experimental phenotypes developed by short term feeding of concentrated ergot alkaloids or fescue seeds to rodents and steers. To assess the effects of fescue toxicosis in growing cattle using a commercially relevant phenotype, we induced fescue toxicosis in beef steers by summer-long grazing (89 to 105 d) of a single high toxic endophyte-infected tall fescue pasture (HE; 0.746 MUg/g ergot alkaloids; 5.7 ha; = 10; BW = 267 +/- 14.5 kg) vs. a low toxic endophyte tall fescue-mixed pasture (LE; 0.023 MUg/g ergot alkaloids; 5.7 ha; = 9; BW = 266 +/- 10.9 kg). High toxic endophyte tall fescue mixed pasture steers had decreased BW (313 vs. 338 kg) and an increased potential for hepatic gluconeogenesis from AA-derived carbons. To gain a greater perspective into fescue toxicosis-induced hepatic metabolism and identify candidate regulatory mechanisms, the goal of the current research was to examine liver samples for changes in gene (mRNA) expression profiles using a Bovine Affymetrix microarray and selected reverse-transcription PCR and immunoblot analyses. The expression (false discovery rate < 10%; < 0.01) of 147 genes was increased (7 to 268%) and that of 227 was decreased (4 to 87%) in livers of HE vs. LE steers. The top (1) functional gene category was cell-mediated immune response (33 genes; <= 0.012), (2) canonical cell signaling pathway was primary immunodeficiency signaling (8 genes; <= 0.0003), and (3) canonical metabolic pathways were oxidative phosphorylation (5 genes; <= 0.016) and purine metabolism (8 genes; <= 0.029). High toxic endophyte tall fescue-mixed pasture steers had increased ( <= 0.022) expression of genes critical for increased (1) Pro () and Ser () synthesis, (2) shunting of AA carbons into pyruvate () and ATP synthesis (, , , COX4, , and ), and (3) mitochondrial mass (COX4). Targeted reverse transcribed PCR or immunoblot assays corroborated ( <= 0.035) these latter microarray findings for , , , , and COX4. Moreover, network analysis identified glucocorticoid receptor-mediated signaling as the most probable mechanism to coordinate the above findings. These results greatly extend our knowledge of the consequences of summer-long grazing of endophyte-infected tall fescue to the hepatic metabolism of growing steers. PMID- 26641176 TI - Muscle growth in young horses: Effects of age, cytokines, and growth factors. AB - Success as equine athletes requires proper muscle growth in young horses. Muscle hypertrophy occurs through protein synthesis and the contribution of muscle satellite cells, which can be stimulated or inhibited by cytokines and growth factors present during exercise and growth. The hypotheses of this study were that 1) the LM area in young horses would increase over 1 yr, and 2) specific cytokines and growth factors (IL-1beta, IL-6, tumor necrosis factor [TNF]-alpha, IGF-I, and fibroblast growth factor [FGF]-2) would alter proliferation and differentiation of satellite cells isolated from young horses. Fourteen horses were divided into 3 age groups: weanlings ( = 5), yearlings to 2 yr olds ( = 4), and 3 to 4 yr olds ( = 5). The area, height, and subcutaneous fat depth of the LM were measured using ultrasonography, and BW and BCS were taken in October (Fall1), April (Spring), and October of the following year (Fall2). Satellite cells obtained from 10-d-old foals ( = 4) were cultured in the presence of IL-6, IL-1beta, TNF-alpha, IGF-I, or FGF-2 before evaluation of proliferation and differentiation. Data were analyzed using PROC MIXED in SAS. Body weight increased from Fall1 to Spring in weanlings ( < 0.001) and increased in all horses from Spring to Fall2 ( <= 0.02). Area and height of the LM increased over time ( < 0.001) and with increasing age group of horse ( <= 0.03), although there was no interaction of time and age ( > 0.61). There was a significant increase in LM area in all animals from Spring to Fall2 ( < 0.001) but not from Fall1 to Spring. Interleukin-6 and TNF-alpha decreased satellite cell proliferation by 14.9 and 11.5%, respectively ( <= 0.01). Interleukin-6 increased fusion 6.2%, whereas TNF-alpha decreased fusion 8.7% compared with control cells ( <= 0.001). Interleukin-1beta had no effect on proliferation ( = 0.32) but tended to decrease fusion ( = 0.06). Satellite cell proliferation was increased 28.8 and 73.0% by IGF-I and FGF-2, respectively ( < 0.0001). Differentiation was decreased 13.1% in the presence of FGF-2 but increased 3.5% in the presence of IGF-I ( <= 0.01). In summary, the LM area increases over the course of a year in young horses with the most growth occurring in summer. By stimulating or inhibiting proliferation and differentiation of satellite cells, IL-6, TNF-alpha, IL-1beta, IGF-I, and FGF-2 may alter muscle growth in young horses, thereby impacting athletic potential. PMID- 26641177 TI - Deconstructing the pig sex metabolome: Targeted metabolomics in heavy pigs revealed sexual dimorphisms in plasma biomarkers and metabolic pathways. AB - Metabolomics has opened new possibilities to investigate metabolic differences among animals. In this study, we applied a targeted metabolomic approach to deconstruct the pig sex metabolome as defined by castrated males and entire gilts. Plasma from 545 performance-tested Italian Large White pigs (172 castrated males and 373 females) sampled at about 160 kg live weight were analyzed for 186 metabolites using the Biocrates AbsoluteIDQ p180 Kit. After filtering, 132 metabolites (20 AA, 11 biogenic amines, 1 hexose, 13 acylcarnitines, 11 sphingomyelins, 67 phosphatidylcholines, and 9 lysophosphatidylcholines) were retained for further analyses. The multivariate approach of the sparse partial least squares discriminant analysis was applied, together with a specifically designed statistical pipeline, that included a permutation test and a 10 cross fold validation procedure that produced stability and effect size statistics for each metabolite. Using this approach, we identified 85 biomarkers (with metabolites from all analyzed chemical families) that contributed to the differences between the 2 groups of pigs ( < 0.05 at the stability statistic test). All acylcarnitines and almost all biogenic amines were higher in castrated males than in gilts. Metabolites involved in tryptophan catabolism had the largest differences (i.e., delta = 20% for serotonin) between castrated males (higher) and gilts (lower). The level of several AA (Ala, Arg, Gly, His, Lys, Ser, Thr, and Trp) was higher in gilts (delta was from approximately 1.0 to approximately 4.8%) whereas products of AA catabolism (taurine, 2-aminoadipic acid, and methionine sulfoxide) were higher in castrated males (delta was approximately 5.0-6.0%), suggesting a metabolic shift in castrated males toward energy storage and lipid production. Similar general patterns were observed for most sphingomyelins, phosphatidylcholines, and lysophosphatidylcholines. Metabolomic pathway analysis and pathway enrichment identified several differences between the 2 sexes. This metabolomic overview opened new clues on the biochemical mechanisms underlying sexual dimorphism that, on one hand, might explain differences in terms of economic traits between castrated male pigs and entire gilts and, on the other hand, could strengthen the pig as a model to define metabolic mechanisms related to fat deposition. PMID- 26641178 TI - Concentrations of digestible, metabolizable, and net energy in soybean meal produced in different areas of the United States and fed to pigs. AB - An experiment was conducted to determine concentrations of DE, ME, and NE in soybean meal (SBM) produced in different areas of the United States if fed to growing pigs. Twenty-two sources of SBM were procured from crushing facilities located throughout the soybean growing area of the United States. For analysis, crushing plant locations were separated into 4 zones: 1) MI, MN, and SD ( = 4); 2) GA, IN, and OH ( = 6); 3) IA, MO, and NE ( = 7), and 4) IL ( = 5). Dietary treatments included a corn-based diet and 22 diets based on a mixture of corn and each source of SBM. Twenty-three growing barrows (initial BW: 26.4 +/- 1.8 kg) were allotted to a 23 * 8 Youden square design with 23 diets and 8 periods. Pigs were placed in individual metabolism crates that were equipped with a feeder, a cup waterer, slatted floors, and a urine tray. Feces and urine were collected for 5 d after a 7-d adaptation period. The GE was 4,165, 4,209, 4,162, and 4,198 kcal/kg (as-fed) for SBM from Zones 1, 2, 3, and 4, respectively, and the GE in SBM from Zone 2 tended ( = 0.08) to be greater than the GE in SBM from Zones 1 and 3. The apparent total tract digestibility (ATTD) of GE for SBM was not different among zones. The DE and ME were 4,343 and 4,098; 4,319 and 4,117; 4,135 and 3,926; and 4,248 and 4,039 kcal/kg DM for SBM from Zones 1, 2, 3, and 4, respectively. The DE and ME of SBM from Zones 1 and 2 were greater ( < 0.05) than the DE and ME of SBM from Zone 3, but the DE and ME of SBM from Zone 4 were not different from that of the other zones. Net energy was calculated for each source of SBM using a published prediction equation based on DE, ether extract, starch, CP, and ADF. The NE of SBM from Zones 1 and 2 (2,534 and 2,497 kcal/kg DM) was greater ( < 0.05) than the NE of SBM from Zone 3 (2391 kcal/kg DM), but the NE of SBM from Zone 4 (2448 kcal/kg DM) was not different from the NE of SBM from the other zones. Regardless of growing area, values for DE, ME, and NE of SBM determined in this experiment are greater than values published by and indicate that DE, ME, and NE values for SBM may be underestimated by . In conclusion, regardless of growing area, GE, DE, ME, and NE were not different for SBM from the northern or eastern growing area or from Illinois, but DE, ME, and NE were less in SBM from the western growing area. PMID- 26641179 TI - Comparison among gilts, physical castrates, entire males, and immunological castrates in terms of growth performance, nitrogen and phosphorus retention, and carcass fat iodine value. AB - The main objective was to determine the nitrogen and P retention and energy digestibility of immunological castrates (IC), entire males (EM), physical castrates (PC), and gilts (G) during 3 growth phases. A second objective was to compare growth performance among the sexes. The final objective was to determine the carcass iodine value (IV) among the sexes. Twelve individually housed pigs (PIC 337 * C22/29) of each sex with an initial mean BW of 35.7 +/- 0.6 kg and a final BW of 145.0 +/- 1.3 kg were evaluated. Anti-gonadotropin-releasing factor injections were administered at d 23 and 15 for groups 1 and 2, respectively. The second injection was given on d 56 of the 98-d experiment. Nitrogen, P, and energy digestibility were measured the last 3 d of the 10-d metabolism period starting at mean BW of 39.5 +/- 0.6, 73.7 +/- 0.8, and 105.5 +/- 0.9 kg for periods 1, 2, and 3, respectively. The third collection started 14 d after the second injection. Entire males and IC had superior overall ADG compared to PC and G ( < 0.05). Entire males and G had the lowest overall ADFI, and PC had the greatest, with IC being intermediate ( < 0.05). Entire males were overall the most efficient, followed by IC, with PC and G being the least efficient ( < 0.05). Immunological castrates and EM had similar nitrogen retention (g/d) for the first 2 collection periods ( > 0.05). In the third collection period, nitrogen retention of IC was similar to that of both EM and PC ( < 0.05). Phosphorus retained (g/d) was not different among the sexes in the first collection; during the second collection, EM retained the greatest amount of P, G and PC retained the lowest, with IC being similar to all sexes. For the third collection, IC had P retention similar to that of EM, EM had retention similar to that of PC, and PC had retention similar to that of G ( > 0.05). However, G retained less P than EM or IC ( < 0.05). Apparent total tract digestibility of DM and GE and the DE of the diet did not differ among the sexes in any of the collection periods ( > 0.05). The jowl IV was the lowest in IC and PC and highest in EM, with G being similar to all sexes ( < 0.05). For the belly, EM had the highest IV, with the other 3 sexes being similar. In conclusion, 2 wk after the second injection, IC transition to become more similar to PC in terms of nitrogen utilization but are still similar to EM in P utilization. These data suggest a feeding program for IC that is intermediate between EM and PC is required to meet their nutritional requirements. PMID- 26641180 TI - True digestible phosphorus requirement for forty- to eighty-kilogram pigs. AB - The objective of this study was to determine the true digestible P requirement of 40- to 60-kg (Exp. 1) and 60- to 80-kg (Exp. 2) pigs by broken-line analysis of growth performance data using 6 levels of true digestible P. In each 3-wk experiment, 108 barrows and gilts were used, and 6 levels of monocalcium phosphate were added to a corn-soybean meal-based diet to establish 6 graded levels of true total tract digestible P ranging from 1.26 to 3.98 g/kg of diet in Exp. 1 or from 1.21 to 3.31 g/kg in Exp. 2. The true digestible P content was calculated using true total tract digestibility of 40.53%, 35.96%, and 84.31% for P in corn, soybean meal, and monocalcium phosphate, respectively. Limestone was added accordingly to maintain a constant Ca level across all diets of each experiment. The results of Exp. 1 showed that with graded supplementation of monocalcium phosphate, ADG linearly increased ( < 0.001) in wk 1 and both linearly and quadratically increased ( < 0.01) in wk 2, wk 3, and wk 0 to 3, and G:F linearly improved ( < 0.001) in wk 1, quadratically improved ( < 0.05) in wk 3, and both linearly and quadratically improved ( < 0.05) in wk 2 and wk 0 to 3 ( < 0.05). In Exp. 2, ADG linearly increased ( < 0.001) in wk 1 and both linearly and quadratically increased ( < 0.05) in wk 2, wk 3, and wk 0 to 3, with the graded supplementation of monocalcium phosphate, and G:F linearly improved ( < 0.01) in wk 1 and wk 3 and both linearly and quadratically improved ( < 0.001) in wk 2 and wk 0 to 3. In Exp. 1, the true digestible P requirement was estimated to be 2.66, 2.79, and 2.51 g/kg of diet (884 g DM/kg) for pigs of mixed sex, barrows, and gilts, respectively, on the basis of broken-line regression of ADG data for wk 0 to 3 against 6 true digestible P levels. Using G:F, the P requirement estimate was correspondingly 2.67, 2.51, and 2.93 g/kg of diet. In Exp. 2, the true digestible P requirement was estimated to be 2.29, 2.20, and 2.39 g/kg of diet (884 g DM/kg) using ADG data for wk 0 to 3 as the response variable and to be 2.33, 2.19, and 2.47 g/kg using wk 0 to 3 G:F data for pigs of mixed sex, barrows, and gilts, respectively. In conclusion, the mean TTTD-based P requirement was 2.66 and 2.31 g/kg of diet (884 g DM/kg) for 40- to 60-kg and 60- to 80-kg pigs, respectively. PMID- 26641181 TI - The feeding of dried distillers' grains with solubles to lactating sows. AB - Three experiments were conducted to evaluate the feeding of dried distillers' grains with solubles (DDGS) in sow lactation diets. In Exp. 1, 168 multiparous sows (PIC, Camborough 22) were fed a 10% DDGS diet throughout gestation. Sows were randomly allotted to 1 of 4 corn-soybean meal lactation diets formulated to contain different levels of DDGS (0, 10, 20, and 30%, respectively). All diets were formulated to be isocaloric (3.46 Mcal ME/kg) and all other nutrients exceeded NRC (1998) nutrient recommendations. Sow ADFI was not different ( > 0.10) as DDGS level increased. Increasing DDGS resulted in a linear ( < 0.03) increase in sow weight gain (7.5, 11.3, 20.3, and 17.2 kg, respectively) and a reduction in wean-to-first-service interval (7.1, 5.2, 5.0, and 4.9 d, respectively). Increasing DDGS did not affect subsequent total born per litter (13.7, 12.8, 13.3, and 12.3, respectively; > 0.10). In Exp. 2 and 3, lactation diets consisted of corn and 20, 30, 40, or 50% DDGS. Diets were formulated at 3.25 Mcal ME/kg, 1.05% standardized ileal digestible lysine, and all other nutrients to exceed NRC (1998) nutrient recommendations. In both experiments, sows (PIC, Camborough) were fed 40% DDGS in gestation and allocated to a randomized complete block based on the parity of the sow at the time of entry into the farrowing house. In Exp. 2, 256 gilts and multiparous sows were fed the randomly assigned diets. As DDGS inclusion increased, sow feed intake (6.2, 6.2, 6.0, and 5.9 kg/d, respectively) and sow weight gain (10.5, 10.3, 8.2, and 6.2 kg, respectively) tended to linearly decrease ( < 0.06). Sow wean to estrus differed between 20 and 30% DDGS inclusion (4.9 vs. 6.9 d; < 0.01). Litter gain was not different (2.55, 2.53, 2.51, and 2.59 kg/d, respectively; > 0.10) as DDGS inclusion increased. In Exp. 3, 98 multiparous sows were randomly allotted to 1 of the 4 experimental diets during the summer months. Sow feed intake, sow weight gain, and litter gain were not different ( > 0.10) between treatments. The data suggest that feeding high levels of DDGS of 40 to 50% may reduce sow feed intake and litter performance. These results demonstrate that feeding up to 30% DDGS in lactation diets can be done without adversely influencing sow or litter performance. PMID- 26641182 TI - Effects of maternal dietary manganese and incubation temperature on hatchability, antioxidant status, and expression of heat shock proteins in chick embryos. AB - To investigate whether supplementing manganese (Mn) to the maternal diet could reduce the deleterious effect of heat stress on the developing embryo, the hatchability, antioxidant status, and expression of heat shock proteins (HSP) were evaluated in chick embryos under normal and high incubation temperatures. A completely randomized design ( = 6) with 2 maternal dietary Mn treatments (unsupplemented control basal diet versus the basal diet + 120 mg Mn/kg as inorganic Mn) * 2 incubation temperatures (normal, 37.8 degrees C, versus high, 39.0 degrees C) was used. High incubation temperature did not affect ( > 0.19) hatchability and embryo mortality and development but did increase ( < 0.05) activities of heart manganese superoxide dismutase (MnSOD) and liver copper zinc superoxide dismutase and liver MnSOD mRNA and protein levels in embryos. High incubation temperature also decreased ( < 0.003) HSP70 protein level in the heart but had no effects ( > 0.07) in the liver of embryos. Maternal diet with Mn supplementation not only increased ( < 0.05) the hatchability and Mn content ( < 0.001) in the yolk and embryonic tissues and the activity of MnSOD in the heart ( < 0.004) as well as relative liver weight ( < 0.05) under normal incubation temperature but also decreased ( <= 0.05) embryo mortality and HSP90 mRNA level in the liver and heart of embryos. Furthermore, under high incubation temperature, maternal diet Mn supplementation increased ( < 0.002) MnSOD protein expression in the liver of embryos but had no effect ( > 0.43) under normal incubation temperature. These results indicated that high incubation temperature induced self-protective responses of chick embryos with a modification of antioxidant status and a depression of HSP70 protein level. Maternal dietary supplementation of Mn could improve the hatchability as well as antioxidant ability to protect against heat challenge in embryos during incubation. PMID- 26641183 TI - Phosphorus digestibility and phytate degradation by yearlings and mature horses. AB - Inorganic P is often added to growing horse diets because organic P, or phytate P, is believed to have lower digestibility. If horses can efficiently digest organic P, then the need for inorganic P may be reduced. Much of the P in grain based concentrates fed to growing horses is in the form of phytate-P. Little is known about the ability of growing horses to degrade phytate-P or whether horse age affects mineral digestion in horses. The objective of this study was to examine the effect of age on P, Ca, and Mg digestibility as well as phytate-P degradation. Four yearling geldings and 4 mature geldings were fed a diet of alfalfa cubes, timothy cubes, and a pelleted concentrate. The diet contained 0.28% total P and 17.4% of that P was in the phytate form. There was a 14-d diet adaptation period followed by a 4-d fecal collection period. Apparent total tract P digestibility was higher for yearlings than mature geldings ( = 0.036; 7.7 and 6.6% for yearlings and mature geldings, respectively). Phytate-P disappearance was 94.8% and did not differ between ages ( = 0.190). Apparent Ca digestibility was lower in mature geldings ( = 0.043), but apparent Mg digestibility did not differ between ages ( = 0.414). Phytate is broken down in the gastrointestinal tract, but the low P digestibilities suggest that either degradation occurs after the site of P absorption or liberated P is recycled back into the gastrointestinal tract. Yearlings can utilize organic P as well as mature horses; therefore, diets without inorganic P are acceptable for growing horses. PMID- 26641184 TI - A cooperative study on the standardized total-tract digestible phosphorus requirement of twenty-kilogram pigs. AB - A cooperative study comprising growth performance, bone mineralization, and nutrient balance experiments was conducted at 11 stations to determine the standardized total-tract digestible (STTD) P requirement of 20-kg pigs using broken-line regression analysis. Monocalcium phosphate and limestone were added to a corn-soybean meal-based diet at the expense of cornstarch to establish 6 concentrations of STTD P from 1.54 to 5.15 g/kg in increments of 0.62 g/kg at a constant Ca:total P of 1.52:1.0. Diets were fed to 936 pigs (average initial BW of 19 kg) in 240 pens for 20 replicate pens of barrows and 20 replicate pens of gilts per diet. As STTD P increased from 1.54 to 5.15 g/kg of the diet for d 0 to 14, 14 to 28, and 0 to 28, the ADG, ADFI, and G:F increased ( < 0.01). Barrows gained and ate more ( < 0.05) than gilts during d 14 to 28 and 0 to 28. There was no interaction between sex and STTD P concentration for any of the growth performance response criteria. There were both linear and quadratic increases ( < 0.05) in mineral density and content of ash, Ca, and P in the femur expressed as a percentage of dry, fat-free metacarpal as dietary STTD P increased. Furthermore, the maximum load of the femur and mineral density and content and maximum load as well as the Ca and P expressed as a percentage of metacarpal ash linearly increased ( < 0.01) with increasing dietary concentrations of STTD P. There were both linear and quadratic increases ( < 0.01) in apparent digestibility and retention of P with increasing concentrations of STTD P in the diets. Digestibility and retention of Ca linearly ( < 0.01) increased with increasing dietary concentrations of STTD P. Breakpoints determined from nonlinear broken-line regression analyses revealed estimates of 4.20 +/- 0.102, 3.20 +/- 0.036, or 3.87 +/- 0.090 g/kg for ADG during d 0 to 14, 14 to 28, or 0 to 28, respectively. Corresponding estimates using G:F as the response criterion were 4.34 +/- 0.146, 3.38 +/- 0.139, or 4.08 +/- 0.195 g/kg. When mineralization of the femur was used as criteria of response, estimates of STTD P requirement were 4.28, 4.28, or 4.34, g/kg for mineral density, mineral content, or maximum load, respectively. Using mineralization of the metacarpal as criteria of response, estimates of STTD P requirement ranged from 3.5 to 5.0 g/kg depending on the metacarpal response criteria. The study provided empirical estimates of STTD P requirements of 20- to 40-kg pigs. PMID- 26641185 TI - Plasma metabolomics indicates metabolic perturbations in low birth weight piglets supplemented with arginine. AB - Large profit losses in the swine industry can be attributed to morbidity and mortality of piglets before weaning, especially in the low birth weight (LBW) piglet. Recent evidence suggests sow's milk contains insufficient concentrations of Arg to support optimal growth and health of piglets. Therefore, our objective was to assess global metabolomic profiles and the potential for Arg supplementation to promote growth of LBW (<=0.9 kg BW) and average birth weight (ABW; 1.3 to 1.5 kg BW) piglets. Piglets were selected in littermate pairs at processing to receive either Arg or an isonitrogenous control (Ala) and weighed daily to assess growth rate, and blood was collected at approximately 16 d of age for metabolomics analysis. In terms of growth, LBW and ABW piglets supplemented with Arg weighed 22.3 and 12.7% less, respectively, at d 16 compared with Ala supplemented piglets of the same birth weight group. Overall, differences ( < 0.05) were observed among treatments for metabolic pathways involving energy (i.e., tricarboxylic acid cycle intermediates), AA, nucleotides, and fatty acids. Increased nucleotide turnover, indicative of an increase in DNA damage and cell death, was particularly noted in the LBW piglet. However, Arg supplementation reduced these effects to levels comparable to those observed in ABW piglets. Moreover, changes in glucose metabolism suggested a compromised ability to extract energy from dietary sources may have occurred in the LBW piglet, but these effects were partially recovered by Arg supplementation. We conclude that a reduction in the growth potential of LBW piglets may be associated with alterations in multiple metabolic pathways, and further reduction due to Arg supplementation may have resulted from perturbations in multiple metabolic pathways. PMID- 26641187 TI - Technical Note: Collection and preparation techniques change nutrient composition of masticate collected from esophageally fistulated cattle. AB - Two experiments determined effects of collection and preparation techniques on nutrient composition of masticate samples from esophageally fistulated cattle. In Exp. 1, 12 esophageally fistulated cattle were maintained on 2 precollection diets, high CP (24% CP; = 6) or low CP (7.7% CP; = 6), for 8 d. On d 9, the esophageal plug was removed, screen bottom bags were attached, and each cow was offered fresh grass. Immediately after fresh grass sample collection was complete, dry grass (hay) was offered and a sample was collected. Blood samples were collected and analyzed for serum urea nitrogen concentration. Masticate samples of both fresh and dry grass were divided and each was either squeezed by hand until no more saliva could be removed or remained unsqueezed. In Exp. 2, 10 esophageally fistulated cattle were fitted with either screen ( = 5) or solid ( = 5) bottom collection bags after removal of the esophageal plug and presented grass hay, fresh grass, alfalfa hay, or fresh alfalfa. In Exp. 1, the precollection diet did not affect ( = 0.49) CP content of masticate even though serum urea nitrogen tended to be greater ( = 0.08) for high- vs. low-CP precollection diets. Forage harvest type offered (fresh vs. hay) interacted ( = 0.01) with preparation technique (squeezed vs. unsqueezed) for CP, where CP decreased in squeezed fresh samples ( < 0.001) but not in squeezed grass hay samples ( = 0.98). In Exp. 2, ingestion greatly increased levels of ash ( < 0.001). Crude protein was greater ( < 0.004) before ingestion for all samples except grass hay ( = 0.43). Levels of NDF were similar before and after ingestion ( > 0.15) for all samples except fresh alfalfa, which was greater after ingestion ( = 0.002). Ingestion status did not affect in vitro OM disappearance (IVOMD; > 0.34) except for grass hay, which was greater after ingestion ( < 0.001). Bag type (screen vs. solid) did not affect ash and NDF ( > 0.31), except for fresh alfalfa, which were greater ( < 0.03) for solid bottom bags. Bag type did not affect alfalfa CP ( = 0.71) but did affect grass CP, which was lower ( = 0.02) for solid bottom bags. Bag type did not affect IVOMD ( > 0.33). More ( = 0.01) fresh forage than hay was recovered through the esophageal opening. Previous diet did not impact masticate samples but squeezing impacted CP levels of high-quality forage and therefore should not be performed. Nutrient values should be reported on an OM basis. PMID- 26641186 TI - Effects of breed, sex, and concentrate supplementation on digestibility, enteric methane emissions, and nitrogen utilization efficiency in growing lambs offered fresh grass. AB - Forty-eight lowland lambs were used in a completely randomized design (23-d period) with a factorial arrangement of treatments: 2 breeds (Highlander vs. Texel) * 3 sexes (female vs. intact male vs. wether) * 2 diets (fresh grass vs. fresh grass plus 0.5 kg/d pelleted concentrate). Animals ( = 48) were approximately 5 mo old and 36 +/- 5.0 kg BW at the commencement of the study with 4 lambs for each breed-sex-diet combination. Fresh grass was harvested daily from the first regrowth of perennial ryegrass sward and offered ad libitum with a similar growth stage throughout the experiment. The animals were individually housed in pens and fed experimental diets for 19 d before being transferred to individual calorimeter chambers for a further 4 d with feed intake, fecal and urine outputs, and methane (CH) emissions measured. Lambs offered 0.5 kg/d concentrate had greater DM and energy (i.e., GE, DE and ME) intake, BW, and CH production (g/d) and greater N intake, fecal and manure N outputs, and fecal N per N intake than those given only fresh grass ( < 0.05). However, diets had no effect on CH emission rates (i.e., CH/DMI [ = 0.408] and CH energy/GE intake [ = 0.821]). Texels produced more CH/DMI (g/kg) than Highlanders ( = 0.044), and sex had no effect on CH/DMI (g/kg; = 0.101). Neither breed nor sex had an effect on N utilization efficiency ( > 0.05). The results reflected that high-quality forages may play a role similar to concentrate in mitigation of enteric CH emissions. The effects of sex and breed on rumen function require further investigation to understand relationships with CH emissions and N excretion in sheep. PMID- 26641188 TI - Chemical composition, fermentation characteristics, digestibility, and degradability of silages from two amaranth varieties (Kharkovskiy and Sem), corn, and an amaranth-corn combination. AB - Amaranth ( sp.) is a C plant adapted to poor soils and regions with limited rainfall and high temperatures. The plant is characterized by a yield of up to 85 t/ha, CP concentration of up to 28.5% of DM, and DM digestibility of 59 to 79%, which may vary depending on the species and variety. The potential of this plant as a forage source for ruminants has not been completely considered. This study aimed at assessing the nutritive value of silages from corn (), 2 amaranth () varieties (var. Kharkovskiy and Sem), and an amaranth-corn combination by chemical composition, silage fermentation characteristics, in vivo digestibility, and in situ DM degradability. Treatments evaluated were ensiled corn var. hybrid SC 704 (EC), ensiled amaranth var. Kharkovskiy (EK), ensiled amaranth var. Sem (ES), ensiled corn-amaranth var. Kharkovskiy mixture, and ensiled corn-amaranth var. Sem mixture. Five sheep were used in a 5 * 5 Latin square design experiment to determine in vivo digestibility. The nylon bag technique was used to determine the in situ DM degradability using 3 ruminally fistulated sheep. Compared with EK, ES had greater ash-free NDF (NDFom) and CP concentrations. In comparison with EC, the ensiled amaranths and corn-amaranth mixtures had a greater ( < 0.001) concentration of CP but less concentrations of NDFom, ADL ( < 0.001), and water soluble carbohydrates ( = 0.034). Silage pH and ammonia-N concentration were the least ( < 0.001) for EC and greatest for ES. The EC had greater ( < 0.001) concentrations of lactic and acetic acids but less ( < 0.001) concentrations of propionic and butyric acids compared with the other silages. The in vivo DM digestibility ( = 0.035) and ME ( = 0.030) of EK and ES were greater than those of EC. Effective degradability of DM in EK and ES was less ( < 0.001) than with the other silages. Overall, mixing amaranth with corn improved concentration of CP and digestibility of the mixed corn-amaranth silages and has the potential of completing corn in ruminant diets. PMID- 26641189 TI - Dehydrated citrus pulp alters feedlot performance of crossbred heifers during the receiving period and modulates serum metabolite concentrations before and after an endotoxin challenge. AB - English * Continental heifers ( = 180) were sourced in 2 loads (219.3 +/- 16.0 and 221.4 +/- 16.4 kg, respectively) from commercial auction barns to study the effects of feeding dehydrated citrus pulp (DCP) on feedlot performance of newly received heifers. A completely randomized block design was used with BW nested within arrival load and blocked by BW into 3 dietary treatments (36 pens, 5 heifers/pen, 12 blocks, 3 pens/block, and 12 pens/treatment). Treatment diets contained 1) 0% DCP (control diet [CON]), 2) 10% DCP, or 3) 20% DCP on a DM basis. Diets containing DCP were exchanged with steam-flaked corn on a 1:1 basis. Cattle were fed a 63, 73, and 83% concentrate diet from d 0 to 28, d 28 to 42, and d 42 to 56, respectively. Over the 56-d trial period, as the amount of dietary DCP increased, DMI decreased ( = 0.01), ADG decreased ( < 0.01), and G:F decreased ( = 0.02). From d 0 to 28, there was no difference in the observed minus the predicted NEg of the diet ( = 0.73); from d 28 to 42, there was a linear increase in NEg favoring DCP treatments ( < 0.01); and from d 42 to 56, there was a linear decrease in NEg against the DCP treatments ( < 0.01). At the conclusion of the trial, a subset of heifers ( = 22; 307.89 +/- 3.32 kg on d 63) were used to evaluate blood metabolite concentrations before and after a lipopolysaccharide (LPS) challenge. On d 63, heifers were fitted with jugular catheters and moved into individual stalls. On d 64, heifers were intravenously challenged with LPS (0.5 MUg/kg BW), and blood samples were collected every 0.5 h from -2 to 8 h and at 24 h relative to the LPS challenge (0 h). Serum glucose, serum urea nitrogen (SUN), and NEFA concentrations were determined. Cattle lost less weight at both 24 and 72 h after the LPS challenge with increasing DCP percentage ( < 0.01). Glucose ( = 0.12) and NEFA ( = 0.13) concentrations did not differ before the LPS challenge; however, there was a treatment effect for SUN, with elevated concentrations of SUN in CON cattle ( < 0.01). After the LPS challenge, DCP-fed cattle had reduced glucose, elevated NEFA, and reduced SUN concentrations ( <= 0.01). Results indicate that dietary DCP modulated metabolite concentrations in heifers following an endotoxin challenge and affected feedlot performance when incorporated in receiving diets in replacement of corn. Future studies will need to address strategies to increase DMI or explore levels of DCP less than 10% in the diet of newly received heifer calves. PMID- 26641191 TI - Effect of steam-flaked corn and soybeans on muscle and intramuscular fatty acid composition in Holstein calves. AB - This study aimed to evaluate the effects of steam-flaked corn grains and soybeans on muscle fatty acid composition. Thirty Holstein bull calves (21 +/- 3 d) were divided into 3 groups according to birth date and BW and were randomly assigned to receive fresh milk and a commercial pelleted starter diet containing extruded corn and soybean (ECS), steam-flaked corn and soybean (SFCS), or ground corn and raw soybean (GCS). The calves were fed the designated diet from 3 to 13 wk of age, after which they were slaughtered. The supraspinatus (CTM), longissimus lumborum (RLM), and spinalis dorsi (ERM) were analyzed to determine the chemical and intramuscular fatty acid composition. The fatty acid composition of muscle and its deposition differed among calves fed different starter feeds. Medium chain fatty acid levels of the RLM and CTM were greater in GCS-fed calves than in ECS- and SFCS-fed calves ( < 0.05). Extruded processing increased the content of linoleic, linolenic, and arachidonic acids of the RLM ( < 0.05). The palmitoleic and -vaccenic acid content of the ERM were greater in GCS-fed calves than in ECS- or SFCS-fed calves ( < 0.05). No significant differences were observed among the 3 diets with respect to the stearic, oleic, linoleic, -9 -11 CLA, or arachidonic acid content of the ERM ( > 0.05). The levels of -3 and -6 fatty acids were similar among the 3 groups; a lower -6:-3 PUFA ratio was observed in GCS-fed calves ( < 0.05). The cereal processing method of the calf starter feed had no significant effect on the chemical composition of the CTM, RLM, or ERM. Therefore, different methods of processing corn and soybean in calf starter feeds had no effect on the chemical composition of the RLM, CTM, or ERM but had a significant effect on the intramuscular fatty acid composition. PMID- 26641190 TI - Effects of shade and feeding zilpaterol hydrochloride to finishing steers on performance, carcass quality, heat stress, mobility, and body temperature. AB - Steers ( = 480; 22% with black hides and 78% with red hides) were used to study the effects of shade and feeding zilpaterol hydrochloride (ZH) on performance, carcass quality, heat stress, mobility, and body temperature (BT). A randomized block design with a 2 * 2 factorial treatment arrangement was used with 4 replicates per treatment. Factors included housing type (open or shaded pens) and the feeding of ZH (0 or 8.33 mg/kg DM) the last 21 d on feed with a 3-d withdrawal. Cattle were blocked by BW into a heavy or light block and randomly assigned to pen within each block. Rumen boluses to record BT were inserted before ZH feeding. Respiration rate and panting scores were recorded daily during the ZH feeding period. Mobility scores were collected at various time points from before ZH feeding through harvest. Interactions between ZH and housing type were not significant ( > 0.26) for animal performance, carcass characteristics, and respiration or panting score. No differences ( > 0.44) were observed for DMI, ADG, or G:F on a live basis due to ZH; however, cattle fed in open pens tended ( = 0.08) to have a greater ADG than cattle in shaded pens. Cattle fed ZH had 14 kg heavier carcasses with larger LM area ( < 0.01) than control cattle. Respiration rates for cattle fed ZH were greater ( = 0.05) with no differences ( = 0.88) due to housing. Time affected ( < 0.01) mobility scores, with observations on the morning of harvest at the abattoir being the worst for all groups of cattle. An interaction ( < 0.01) was observed between ZH and housing type for BT. Cattle fed ZH, in both shaded and open pens, had lower ( < 0.05) average, maximum, and area under the curve BT than control cattle fed in the same housing type. However, the observed reduction in BT due to ZH was greater for cattle fed ZH in open pens than for cattle fed ZH in shaded pens. From these results, we conclude that ZH improved HCW with little impact on heat stress or mobility, suggesting that animal welfare was not affected by feeding ZH for 21 d at the end of the feeding period. PMID- 26641192 TI - Influence of late gestation drylot rations differing in protein degradability and fat content on beef cow and subsequent calf performance. AB - Spring-calving, mature cows ( = 191 total) and their progeny were used to evaluate the effects of late gestation drylot rations differing in RUP and fat content on cow performance as well as performance and carcass characteristics of subsequent progeny. Cows were blocked by BW and anticipated calving date and assigned to 16 pens. Pens were randomly allotted to 1 of 2 treatments: limit-fed corn coproducts and ground cornstalks (COP; TDN = 64.4%, CP = 11.1%, RDP = 60.2% of CP, and fat = 5.1%) or limit-fed ground mixed, cool-season grass hay (HY; TDN = 55.7%, CP = 9.5%, RDP = 86.0% of CP, and fat = 2.3%). Treatments were limit fed as isocaloric, isonitrogenous rations from 88 +/- 11 d prepartum to calving. All cows were fed a common diet postpartum. Cow BW and BCS were collected at the beginning of the feeding period, within 48 h after calving, and at breeding. Calf BW was collected at birth and at 64 +/- 11 and 124 +/- 11 d of age. Milk production was determined using the weigh-suckle-weigh technique at 64 +/- 11 and 124 +/- 11 d postpartum. At 124 +/- 11 d of age, steers ( = 68) and nonreplacement heifer calves ( = 25) were weaned and placed on a common feedlot diet with individual feed intake monitored using GrowSafe. Feedlot calves were slaughtered at a commercial facility 35 +/- 10 d after a minimum ultrasound 12 rib fat thickness estimation of 0.9 cm. After calving, cow BW was greater ( < 0.01) and BCS was greater ( < 0.01) for cows fed COP than for cows fed HY. Calf birth BW was greater ( = 0.04) for those born to cows fed COP with no difference ( = 0.43) in percentage of unassisted births across treatment. Cows fed HY were lighter ( < 0.01) at breeding with lower BCS ( = 0.03); nevertheless, overall pregnancy rate was not different ( = 0.80). No differences ( >= 0.22) in milk production were detected. For feedlot progeny, initial feedlot BW, final BW, and days on feed were not different ( >= 0.23), and as a result, no difference ( = 0.21) in feedlot ADG was detected. Feedlot DMI and G:F were not different ( >= 0.19) across treatments. Feedlot calf health was monitored with no differences ( >= 0.68) in morbidity and mortality observed. No differences ( >= 0.27) were detected for HCW, LM area, backfat, marbling score, yield grade, or KPH. Increased dietary RUP and fat content during late gestation increased cow BW and BCS but did not alter milk production, subsequent reproduction, or subsequent calf performance or carcass characteristics. PMID- 26641193 TI - Drought effect on weaning weight and efficiency relative to cow size in semiarid rangeland. AB - Cow size has been suggested to be an important consideration for selecting cattle to match their production environment. Over the last several decades, the trend in genetic selection for maximum growth has led to gradual increases in beef cow size. An unrelated trend during this same period in the western United States has been an increase in temperature, drought frequency, and drought severity. Due to the potential influence of the increasing cow size trend on nutritional maintenance costs and production, we assessed the effect of cow size on weaning weight and efficiency in relation to drought on a semiarid high-elevation ranch in Wyoming. This study addresses a lack of empirical studies on the interaction between cow size and drought. We measured calf weaning weights of 80 Angus * Gelbvieh cows from 2011 to 2014 and assessed how drought affected weaning weights, efficiency (considered as calf weight relative to cow weight), intake requirements, and potential herd sizes relative to cow size. We stratified cows into 5 weight classes (453, 498, 544, 589, and 634 kg) as a proxy for cow size and adjusted weaning weights to a 210-d calf sex adjusted value. Cow size was a significant factor every year, with different cow sizes having advantages or disadvantages different years relative to weaning weight. However, efficiency for the smallest cows (453 kg) was always greater than efficiency for largest cows (634 kg; < 0.001). Efficiency for the smallest cows was greater in the driest year (0.41 +/- 0.02) than efficiency of the largest cows in the wettest years (0.37 +/- 0.01). The change in efficiency (DeltaE) between wet and dry years was 0.18 for the smallest cow size and 0.02 for the largest cow size, and DeltaE decreased as cow size increased. This is an indication of the ability of smaller cows to lower maintenance requirements in response to changes in the production environment but with optimal upside potential when conditions are favorable. These results indicate large cows (589 to 634 kg) do not maximize genetic potential in this production environment when conditions are optimum or provide any advantage over small or moderate size cows (453 to 544 kg) across the drought gradient. PMID- 26641194 TI - Effects of season, truck type, and location within truck on gastrointestinal tract temperature of market-weight pigs during transport. AB - Two experiments were done to assess the effects of season, truck type, and location in the truck on the gastrointestinal tract temperature (GTT) of market weight pigs during transport. In Exp. 1, a total of 504 sentinel pigs were selected from a total load of 3,756 pigs over 12 wk in summer or winter and transported in either a double-decked (DD) hydraulic truck or a pot-belly (PB) trailer for 2 h. In Exp. 2, a total of 330 sentinel pigs were selected from a total load of 2,145 pigs over 11 wk in summer or winter and transported in a PB trailer for 8 h. In both experiments, sentinel pigs were equipped with a temperature data logger for the real-time GTT recording from the farm to slaughter. Transport was divided into 8 periods in Exp. 1 (rest, pretravel, initial travel, prearrival 1, prearrival 2, unloading, lairage 1, and lairage 2) and in Exp. 2 (rest, pretravel 1, pretravel 2, travel, prearrival 1, prearrival 2, lairage 1, and lairage 2). A delta GTT (DeltaGTT) was calculated as the difference between the measured GTT at any determined event and the GTT measured at rest. In Exp. 1, the DeltaGTT of pigs was greater ( < 0.001) in summer than in winter and only during the pretravel and initial travel periods. No difference was observed in the DeltaGTT between the 2 truck types ( > 0.10). In summer, pigs located in the front top and rear top compartments of the PB trailer presented greater ( < 0.05) DeltaGTT values than those transported in the middle top and front belly compartments during initial travel. In summer, during prearrival 1 and 2, a greater ( < 0.05) loss of GTT was found in pigs located in the rear top compartment of the DD truck compared with the rear lower compartment and in the front middle compartment compared with the rear middle compartment of the PB trailer. In Exp. 2, the DeltaGTT of pigs was greater ( = 0.03) in summer than in winter during pretravel 2. Pigs in the front top compartment had a greater ( < 0.05) DeltaGTT compared with pigs in the middle top, lower deck, and front belly compartments during the pretravel periods. Based on the results of the 2 experiments, modifications of the PB trailer model are recommended to limit body temperature increase due to physical stress at loading and unloading, and during transport due to inconsistent ventilation rate across vehicle locations. PMID- 26641195 TI - Effects of feed intake and genetics on tissue nitrogen-15 enrichment and feed conversion efficiency in sheep. AB - This study investigated the effects of sheep genetics and feed intake on nitrogen isotopic fractionation (DeltaN) and feed conversion efficiency (FCE; live weight gain/DMI), using a 2 * 2 factorial design, with 2 levels of genetic merit for growth (high vs. low) and 2 levels of feed intake (110 vs. 170% of ME for maintenance [MEm]). No effect of genetic merit was detected for live weight gain ( = 0.64), FCE ( = 0.46), plasma urea nitrogen ( = 0.52), plasma glucose ( = 0.78), and DeltaN of wool ( = 0.45), blood ( = 0.09), and plasma ( = 0.51). Sheep receiving 170% of MEm had 175% higher live weight gain ( < 0.001) and 77% higher FCE ( < 0.001) than sheep receiving 110% of MEm. There was no difference among treatments at the beginning of the study for either blood or plasma ?N, but the treatment groups started to diverge in blood and plasma ?N at 21 and 7 d, respectively. Blood, plasma, and wool samples were enriched in N compared with feed. There was a higher blood, plasma, and wool ?N for the low feed intake group than the high feed intake group ( < 0.001 in all cases). Across the 4 treatment groups, higher FCE in sheep was associated with lower ?N for plasma, blood, and wool. Overall, the results are consistent with the potential of ?N as a rapid, low-cost biomarker of FCE in sheep, despite there being no effects of genetic treatment on FCE and ?N. PMID- 26641196 TI - Relationships among temperament, behavior, and growth during performance testing of bulls. AB - Excitable cattle are dangerous to personnel and have reduced individual performance. The aim of this study was to 1) identify objective criteria for evaluating bull temperament and 2) examine relationships among temperament, behavior, and performance of bulls during an 84-d performance test. Angus bulls ( = 60) were reared in 6 pens based on BW and age. Pen scores (PS; 1 = docile and 5 = very aggressive) were assigned on d -1, 27, 55, and 83. Exit velocity (EV), BW, time to exit the chute, and order through the chute were recorded on d 0, 28, 56, and 84. The ADG was calculated for the 84-d test period, and ultrasound data and frame score calculations were recorded on d 84. Dataloggers measured steps taken, lying time, number of lying bouts, and lying bout duration of bulls ( = 27; 3 pens) from d 3 to 28 and d 59 to 84. Bulls with a d -1 PS of 1 or 2 were categorized as calm (PScalm; = 40), whereas bulls with a PS of 3 or 4 were categorized as excitable (PSexcitable; = 20). Bulls were separated into 2 groups based on the bottom 20 EV (EVcalm) and top 20 EV (EVexcitable) on d 0. Mixed model ANOVA (SAS 9.3) was used to compare groups for the two temperament assessment methods, behavior, and growth performance. Mean EV decreased ( < 0.05) by d 84. Total lying time from d 3 to 28 was greater ( < 0.05) for PScalm bulls when compared with PSexcitable bulls. However, total lying time from d 59 to 84 was greater ( < 0.05) for EVexcitable bulls when compared with EVcalm bulls. Regardless of initial contemporary group assignment, all bulls exited the chute slower ( < 0.001) on d 84 than on d 0. The PSexcitable bulls had greater ( < 0.01) frame scores and greater ADG than PScalm bulls. The PSexcitable bulls had more ( < 0.01) backfat than PScalm bulls. However, ribeye area was smaller ( < 0.01) in EVexcitable bulls than EVcalm bulls. Based on these results, bulls appeared to have habituated over the testing period. Additionally, the potential lack of innate temperament variation may have attributed to the little difference seen among the behavioral and performance data. Therefore, temperament should be reassessed within a novel environment with new handlers to differentiate between the bull's true temperament and its ability to habituate. PMID- 26641197 TI - Aging implications on fresh muscle traits of Certified Angus Beef steaks. AB - Vacuum-packaged Certified Angus Beef (CAB) subprimals ( = 72) that included the longissimus thoracis (LT), longissimus lumborum (LL), gluteus medius (GM), and infraspinatus (IF) muscles were purchased from a major beef packing facility. Subprimals were allocated to 1 of 3 aging periods (14, 28, or 42 d) and aged at 2 degrees C. After aging, 5 steaks were cut from each subprimal and assigned to pH, water-holding capacity, Warner-Bratzler shear force (WBSF), cooked color, cooking yield, cooking loss, and sensory panel analysis. Infraspinatus steaks were more tender ( < 0.05) than all other steaks, and subprimals aged 14 d had greater ( < 0.05) WBSF values than the other 2 aging periods, regardless of muscle. Water holding capacity and cook yield were greater ( < 0.05) for LL and LT than IF and GM steaks, whereas purge loss was greater ( < 0.05) for IF and GM than LL and LT steaks. Throughout the aging periods, pH declined for all muscle groups, with IF steaks having the greatest ( < 0.05) pH values among all muscles. Among IF steaks, sensory evaluations of all attributes did not ( >= 0.26) differ across aging periods; yet among LT steaks, consumers rated those aged 14 d greater ( < 0.05) in overall impression than LT steaks aged 28 and 42 d. Among LT steaks, those aged 14 d received greater ( < 0.05) flavor ratings than LT steaks subjected to longer aging periods, and LT steaks aged 14 d received the greatest ( < 0.05) overall impression, with consumers giving greater ( < 0.05) overall impression scores to LT steaks aged 42 d over those aged 28 d. Aging period had no effect ( >= 0.017) on consumer ratings for flavor, tenderness, juiciness, or overall impression of LL steaks. Among GM steaks, consumers rated steaks aged 14 and 28 d more ( < 0.05) flavorful than those aged 42 d, and consumer ratings for overall impression were greater ( < 0.05) for GM steaks aged 28 d than for GM steaks aged 42 d; however, consumers failed ( = 0.035) to note differences in tenderness scores of GM steaks in response to aging period. Furthermore, consumers indicated a greater ( < 0.05) likelihood to purchase LT steaks aged 14 d over LT steaks aged 28 d, LL steaks aged 42 d over LL steaks aged 14 d, and GM steaks aged 14 and 28 d over GM steaks aged 42 d. These results indicate that consumers struggled to identify steak flavor attributes and suggest that the benefit of aging for premium beef products does not offer a tremendous sensory advantage to the consumer. PMID- 26641198 TI - Sub-40 fs, 1060-nm Yb-fiber laser enhances penetration depth in nonlinear optical microscopy of human skin. AB - Advancing the practical utility of nonlinear optical microscopy requires continued improvement in imaging depth and contrast. We evaluated second-harmonic generation (SHG) and third-harmonic generation images from ex vivo human skin and showed that a sub-40 fs, 1060-nm Yb-fiber laser can enhance SHG penetration depth by up to 80% compared to a >100 fs, 800 nm Ti:sapphire source. These results demonstrate the potential of fiber-based laser systems to address a key performance limitation related to nonlinear optical microscopy (NLOM) technology while providing a low-barrier-to-access alternative to Ti:sapphire sources that could help accelerate the movement of NLOM into clinical practice. PMID- 26641199 TI - Optical coherence tomography spectral analysis for detecting apoptosis in vitro and in vivo. AB - Apoptosis is a form of programmed cell death characterized by a series of predictable morphological changes at the subcellular level, which modify the light-scattering properties of cells. We present a spectroscopic optical coherence tomography (OCT) technique to detect changes in subcellular morphology related to apoptosis in vitro and in vivo. OCT data were acquired from acute myeloid leukemia (AML) cells treated with cisplatin over a 48-h period. The backscatter spectrum of the OCT signal acquired from the cell samples was characterized by calculating its in vitro integrated backscatter (IB) and spectral slope (SS). The IB increased with treatment duration, while the SS decreased, with the most significant changes occurring after 24 to 48 h of treatment. These changes coincided with striking morphological transformations in the cells and their nuclei. Similar trends in the spectral parameter values were observed in vivo in solid tumors grown from AML cells in mice, which were treated with chemotherapy and radiation. Our results provide a strong foundation from which future experiments may be designed to further understand the effect of cellular morphology and kinetics of apoptosis on the OCT signal and demonstrate the feasibility of using this technique in vivo. PMID- 26641200 TI - Novel immunotherapeutic strategies for pyelonephritis. AB - Acute pyelonephritis is an infection of the renal parenchyma and renal pelvis. When it is caused by a typical pathogen in an immunocompetent female patient with normal urinary tract, it is considered uncomplicated. In all other cases, sepsis is the most worrisome complication. In the event of sepsis, patients should be hospitalized and treated aggressively with antibiotics, intravenous fluids and agents that enhance the immune response of the host. In this review, we summarize findings from immunomodulatory interventions in experimental studies of acute pyelonephritis and the application of these interventions into clinical practice. Vaccine against bacterial virulence factors and agents aiming to modulate the immune response of the host belong to these interventions and they are discussed. PMID- 26641201 TI - Definition and Implications of the Preventable Stroke. AB - IMPORTANCE: Although patients with acute stroke are routinely evaluated for potential treatment (ie, treatability of the stroke), preventability of the presenting stroke is generally not seriously considered. OBJECTIVE: To systematically analyze stroke preventability. DESIGN, SETTING, AND PARTICIPANTS: We evaluated medical records of 274 consecutive patients discharged with a diagnosis of ischemic stroke between December 2, 2010, and June 11, 2012, at the University of California Irvine Medical Center. Mean (SE) patient age was 67.2 (0.8) years. Data analysis was conducted from July 3, 2014, to August 4, 2015. EXPOSURES: Medical records were systematically examined for demographic information, stroke risk factors, stroke severity, and acute stroke treatment. MAIN OUTCOMES AND MEASURES: We defined stroke preventability as the degree to which the patient's presenting stroke was preventable. Using variables easily determined at onset of stroke, we developed a 10-point scale (0, not preventable; 10, most preventable) to classify the degree of stroke preventability. Our focus was effectiveness of treatment of hypertension (0-2 points), hyperlipidemia (0-2 points), and atrial fibrillation (0-4 points), as well as use of antithrombotic treatment for known prior cerebrovascular and cardiovascular disease (0-2 points). RESULTS: Total risk scores ranged from 0 to 8 (mean [SE], 2.2 [0.1]), with 207 patients (75.5%) exhibiting some degree of preventability (score of 1 or higher). Seventy-one patients (25.9%) had scores of 4 or higher, indicating that the stroke was highly preventable. Severity of stroke as determined by the National Institutes of Health Stroke Scale score was not related to preventability of stroke. However, 21 of 71 patients (29.6%) whose stroke was highly preventable were treated with intravenous or intra-arterial acute stroke therapy while these treatments were provided for only 13 of 67 patients (19.4%) with scores of 0 (no preventability) and 19 of 136 patients (14.0%) with scores of 1 to 3 (low preventability) (P = .03). CONCLUSIONS AND RELEVANCE: Most patients with acute stroke exhibited some degree of preventability. Preventability and treatment of stroke were significantly associated, indicating that the most preventable strokes paradoxically were more likely to receive acute treatment. PMID- 26641202 TI - A New Era for Residency Training in Internal Medicine. PMID- 26641203 TI - Becoming a normal guy: Men making sense of long-term bodily changes following bariatric surgery. AB - BACKGROUND: To date, research on bodily changes following bariatric surgery has focused predominantly on women, leaving the long-term experience of men relatively unexplored. In this paper, we draw on interviews with men who have undergone an irreversible gastric bypass procedure to explore their bodily changes more than 4 years post-surgery. We apply a phenomenological framework that draws on Leder's perspectives on the "disappearing" and "dys-appearing" body, combined with a gender-sensitive lens that draws on Connell's theory of hegemonic masculinity and Robertson's conceptions of embodied masculinity. FINDINGS: Our principal finding was that the men negotiated their bodily changes following bariatric surgery in profoundly ambivalent ways. Although they enthusiastically praised the surgery for improving their health, self-esteem, and social functioning, they also emphasized their efforts to cope with post-surgical side effects and life-threatening complications. Our analysis elaborates on their efforts to adjust to and come to terms with these changes, focusing on episodes of hypoglycemia, severe pain and internal herniation, and the significance of physical activity and exercise. CONCLUSIONS: Our findings point to the need to acknowledge men's ways of making sense of profound and ongoing bodily changes following bariatric surgery and how these negotiations are closely intertwined with masculine ideals of embodiment and social value. PMID- 26641204 TI - Pacing Behavior and Tactical Positioning in 500- and 1000-m Short-Track Speed Skating. AB - PURPOSE: To explore pacing behavior and tactical positioning during the shorter 500- and 1000-m short-track competitions. METHODS: Lap times and intermediate rankings of elite 500- and 1000-m short-track-skating competitors were collected over the 2012-13 season. First, lap times were analyzed using a MANOVA, and for each lap, differences between sex, race type, final ranking, and stage of competition were determined. Second, Kendall tau-b correlations were used to assess relationships between intermediate and final rankings. In addition, intermediate rankings of the winner of each race were examined. RESULTS: Top placed athletes appeared faster than bottom-placed athletes in every lap in the 500-m, while in the 1000-m no differences were found until the final 4 laps (P < .05). Correlations between intermediate and final rankings were already high at the beginning stages of the 50-m (lap 1: r = .59) but not for the 1000-m (lap 1: r = .21). CONCLUSIONS: Although 500- and 1000-m short-track races are both relatively short, fundamental differences in pacing behavior and tactical positioning were found. A fast-start strategy seems to be optimal for 500-m races, while the crucial segment in 1000-m races seems to be from the 6th lap to the finish line (ie, after +/- 650 m). These findings provide evidence to suggest that athletes balance between choosing an energetically optimal profile and the tactical and positional benefits that play a role when riding against an opponent, as well as contributing to developing novel insights in exploring athletic behavior when racing against opponents. PMID- 26641205 TI - WITHDRAWN: Interventions for replacing missing teeth: preprosthetic surgery versus dental implants. PMID- 26641206 TI - Pharmacokinetic investigation of sildenafil using positron emission tomography and determination of its effect on cerebrospinal fluid cGMP levels. AB - Sildenafil (Viagra) is a selective inhibitor of phosphodiesterase type 5 (PDE5), which degrades cyclic guanosine monophosphate to the linear nucleotide. Sildenafil is acutely used in erectile dysfunction and chronically in pulmonary hypertension. Evidence in the last decade shows that sildenafil may have potential as a therapeutic option for Alzheimer's disease or other neurodegenerative disorders. The purpose of this work was to explore whether sildenafil crosses the blood-brain barrier. Pharmacokinetic properties of sildenafil in rodents were investigated using (11) C-radiolabeling followed by in vivo positron emission tomography (PET) and ex vivo tissue dissection and gamma counting. PET results in rats suggest penetration into the central nervous system. Ex vivo data in perfused animals suggest that trapping of [(11) C]sildenafil within the cerebral vascular endothelium limits accumulation in the central nervous system parenchyma. Peroral sildenafil administration to Macaca fascicularis and subsequent chemical analysis of plasma and cerebrospinal fluid (CSF) using liquid chromatography coupled with tandem mass spectrometry showed that drug content in the CSF was high enough to achieve PDE5 inhibition, which was also demonstrated by the significant increases in CSF cyclic guanosine monophosphate levels. Central actions of sildenafil include both relaxation of the cerebral vasculature and inhibition of PDE5 in neurons and glia. This central action of sildenafil may underlie its efficacy in neuroprotection models, and may justify the continued search for a PDE5 ligand suitable for PET imaging. Sildenafil interacts with phosphodiesterase type 5 (PDE5) expressed in the endothelium and/or smooth muscle cells of brain vessels and also crosses the blood-brain barrier to interact with PDE5 expressed in brain cells. At therapeutic doses, the concentration of sildenafil in the cerebrospinal fluid (CSF) is high enough to inhibit PDE5 in the neural cells (neurons and glia). In turn, the concentration of cGMP likely increases in parenchymal cells and, as shown in this report, in the CSF. Read the Editorial Highlight for this article on page 220. Cover Image for this issue: doi: 10.1111/jnc.13302. PMID- 26641207 TI - Assessment of endothelin and copeptin as biomarkers for vasovagal syncope. AB - BACKGROUND: The diagnosis of vasovagal syncope continues to be difficult despite the use of accurate histories, tilt testing and implantable loop recorders. A circulating biomarker might be useful to facilitate diagnoses. Both endothelin-1 and vasopressin are increased during positive tilt tests resulting in syncope. Copeptin is a stable cleavage product of vasopressin formation. We conducted a pilot study to assess the utility of endothelin-1 and copeptin as circulating biomarkers of vasovagal syncope. METHODS: Three populations were studied: syncope patients, epilepsy patients and controls. Vasovagal syncope diagnosis was ascertained with the Calgary Syncope Score and epilepsy diagnosis was confirmed with EEG. Plasma levels of endothelin-1 were measured using by ELISA and copeptin levels were determined using an EIA kit. RESULTS: Asymptomatic control subjects had mean age 35 +/- 11 years (7/22 male); epileptic subjects had mean age 32 +/- 7 years (4/15 male); and syncope subjects had mean age 33 +/- 16 years (4 of 21 male). Circulating plasma levels of endothelin-1 and copeptin were no different among the three groups. Mean concentrations of endothelin-1 were as follows: syncope, 23 +/- 32 pg/mL; controls, 21 +/- 17 pg/mL; and epileptics, 18 +/- 12 pg/mL. Mean concentrations of copeptin were as follows: syncope, 1.29 +/- 0.79 ng/mL; controls, 1.25 +/- 0.79 ng/mL; and seizures, 1.23 +/- 0.45 ng/mL. There were no significant correlations between syncope frequency and copeptin or endothelin-1 levels. CONCLUSION: Circulating plasma endothelin-1 and copeptin levels are not significantly different among populations of controls, syncope patients and seizure patients. PMID- 26641208 TI - Broadening the spectrum of photosynthesis in the grass, Alloteropsis semialata. AB - This article comments on: Evolutionary implications of C3 -C4 intermediates in the grass Alloteropsis semialata. PMID- 26641209 TI - Graphene Oxide-Assisted Synthesis of Pt-Co Alloy Nanocrystals with High-Index Facets and Enhanced Electrocatalytic Properties. AB - Metal nanocrystals (NCs) are grown directly on the surface of reduced graphene oxide (rGO), which can maximize the rGO-NCs contact/interaction to achieve the enhanced catalytic activity. However, it is difficult to control the size and morphology of metal NCs by in situ method due to the effects of functional groups on the surface of GO, and as a result, the metal NCs/rGO hybrids are conventionally synthesized by two-step method. Herein, one-pot synthesis of Pt-Co alloy NCs is demonstrated with concave-polyhedrons and concave-nanocubes bounded by {hkl} and {hk0} high-index facets (HIFs) distributed on rGO. GO can affect the geometry and electronic structure of Pt-Co NCs. Thanks to the synergy of the HIFs and the electronic effect of the intimate contact/interaction between Pt-Co alloy and rGO, these as-prepared Pt-Co NCs/rGO hybrids presents enhanced catalytic properties for the electrooxidation of formic acid, as well as for the oxygen reduction reaction. PMID- 26641210 TI - Traumatic tracheal diverticulum corrected with resection and anastomosis during one-lung ventilation and total intravenous anesthesia in a cat. AB - OBJECTIVE: This report describes the clinical findings and diagnostic images of a traumatic intrathoracic tracheal avulsion with a tracheal diverticulum in a cat. Furthermore, a complete description of the tracheal resection and anastomosis using one-lung ventilation (OLV) with total and partial intravenous anesthesia is made. CASE SUMMARY: A 3-year-old neutered male domestic shorthair cat weighing 6.8 kg was presented to the University Teaching Hospital for evaluation of increased respiratory noise 3 months following unknown trauma. Approximately 12 weeks prior to presentation, the cat had been seen by the primary care veterinarian for respiratory distress. At that time, the cat had undergone a tracheal ballooning procedure for a distal tracheal stricture diagnosed by tracheoscopy. The tracheal ballooning had provided only temporary relief. At presentation to our institution, the cat had increased respiratory effort with harsh upper airway noise auscultated during thoracic examination. The remainder of the physical examination was normal. Diagnostics included a tracheoscopy and a thoracic computed tomographic examination. The cat was diagnosed with tracheal avulsion, pseudotrachea with a tracheal diverticulum, and stenosis of the avulsed tracheal ends. Surgical correction of the tracheal stricture via a thoracotomy was performed using OLV with total and partial intravenous anesthesia. The cat recovered uneventfully and at last follow-up was active and doing well. UNIQUE INFORMATION PROVIDED: This case report describes OLV using standard anesthesia equipment that is available at most private practices. Furthermore, this case describes the computed tomographic images of the intrathoracic tracheal avulsion and offers a positive outcome for tracheal resection and anastomosis. PMID- 26641211 TI - Triblock Terpolymers by Simultaneous Tandem Block Polymerization (STBP). AB - A route of synthesizing triblock terpolymers in a one-pot, "one-step" polymerization approach is presented. The combination of two distinct polymerization techniques through orthogonal catalyst/initiator functionalities attached to a polymeric linker furnishes novel pathways to ABC-terpolymers. Both polymerizations have to be compatible regarding mechanisms, chosen monomers, and solvents. Here, an alpha,omega-heterobifunctional poly(ethylene glycol) serves as poly-meric catalyst/initiator to obtain triblock terpolymers of poly(norbornene) b-poly(ethylene glycol)-b-poly(L-lactic acid) PNB-PEG-PLLA via simultaneous ring opening metathesis poly-merization and ring opening polymerization in a fast one pot polymerization. Structural characterization of the polymers is provided via (1)H-, DOSY-, and (1)H,(1)H-COSY-NMR, while solution and thin film self-assembly are investigated by dynamic light scattering and atomic force microscopy. PMID- 26641239 TI - Body-Attachable and Stretchable Multisensors Integrated with Wirelessly Rechargeable Energy Storage Devices. AB - A stretchable multisensor system is successfully demonstrated with an integrated energy-storage device, an array of microsupercapacitors that can be repeatedly charged via a wireless radio-frequency power receiver on the same stretchable polymer substrate. The integrated devices are interconnected by a liquid-metal interconnection and operate stably without noticeable performance degradation under strain due to the skin attachment, and a uniaxial strain up to 50%. PMID- 26641212 TI - Testosterone and cardiac mass and function in men with type 1 diabetes in the Epidemiology of Diabetes Interventions and Complications Study (EDIC). AB - OBJECTIVE: Low testosterone concentrations have been reported to be associated with increased risk of congestive heart failure, but the mechanisms are unclear. Our objective was to examine the relationship between endogenous testosterone and measures of cardiac mass and function among men with type 1 diabetes. DESIGN: Secondary analysis of a prospective observational study. PARTICIPANTS: Men (n = 508) in the Epidemiology of Diabetes Interventions and Complications (EDIC) study, the observational follow-up of the Diabetes Control and Complications Trial (DCCT). MEASUREMENTS: Testosterone assessed by liquid chromatography mass spectrometry at EDIC year 10 and cardiac magnetic resonance imaging (CMR) measures at EDIC years 14/15. Linear regression models were used to assess the relationship between testosterone, sex hormone binding globulin (SHBG) and left ventricular (LV) mass, volume, ejection fraction and cardiac index before and after adjustment for age, randomization arm, alcohol and cigarette use, macroalbuminuria, haemoglobin A1c, insulin dose, body mass index, lipids, blood pressure, use of antihypertensive medications and microvascular complications. RESULTS: In fully adjusted models, total testosterone concentrations were significantly associated with LV mass (P = 0.014), end-diastolic volume (P = 0.002), end-systolic volume (P = 0.012) and stroke volume (P = 0.022), but not measures of LV function after adjustment for cardiac risk factors. Bioavailable testosterone was associated with LV mass, but not volume or function, while SHBG was associated with volume, but not mass or function. CONCLUSIONS: Among men with type 1 diabetes, higher total testosterone was associated with higher LV mass and volume, but not with function. The clinical significance of this association remains to be established. PMID- 26641240 TI - Recombinant Passenger Proteins Can Be Conveniently Purified by One-Step Affinity Chromatography. AB - Fusion tag is one of the best available tools to date for enhancement of the solubility or improvement of the expression level of recombinant proteins in Escherichia coli. Typically, two consecutive affinity purification steps are often necessitated for the purification of passenger proteins. As a fusion tag, acyl carrier protein (ACP) could greatly increase the soluble expression level of Glucokinase (GlcK), alpha-Amylase (Amy) and GFP. When fusion protein ACP-G2-GlcK Histag and ACP-G2-Amy-Histag, in which a protease TEV recognition site was inserted between the fusion tag and passenger protein, were coexpressed with protease TEV respectively in E. coli, the efficient intracellular processing of fusion proteins was achieved. The resulting passenger protein GlcK-Histag and Amy Histag accumulated predominantly in a soluble form, and could be conveniently purified by one-step Ni-chelating chromatography. However, the fusion protein ACP GFP-Histag was processed incompletely by the protease TEV coexpressed in vivo, and a large portion of the resulting target protein GFP-Histag aggregated in insoluble form, indicating that the intracellular processing may affect the solubility of cleaved passenger protein. In this context, the soluble fusion protein ACP-GFP-Histag, contained in the supernatant of E. coli cell lysate, was directly subjected to cleavage in vitro by mixing it with the clarified cell lysate of E. coli overexpressing protease TEV. Consequently, the resulting target protein GFP-Histag could accumulate predominantly in a soluble form, and be purified conveniently by one-step Ni-chelating chromatography. The approaches presented here greatly simplify the purification process of passenger proteins, and eliminate the use of large amounts of pure site-specific proteases. PMID- 26641241 TI - The Study of Object-Oriented Motor Imagery Based on EEG Suppression. AB - Motor imagery is a conventional method for brain computer interface and motor learning. To avoid the great individual difference of the motor imagery ability, object-oriented motor imagery was applied, and the effects were studied. Kinesthetic motor imagery and visual observation were administered to 15 healthy volunteers. The EEG during cue-based simple imagery (SI), object-oriented motor imagery (OI), non-object-oriented motor imagery (NI) and visual observation (VO) was recorded. Study results showed that OI and NI presented significant contralateral suppression in mu rhythm (p < 0.05). Besides, OI exhibited significant contralateral suppression in beta rhythm (p < 0.05). While no significant mu or beta contralateral suppression could be found during VO or SI (p > 0.05). Compared with NI, OI showed significant difference (p < 0.05) in mu rhythm and weak significant difference (p = 0.0612) in beta rhythm over the contralateral hemisphere. The ability of motor imagery can be reflected by the suppression degree of mu and beta frequencies which are the motor related rhythms. Thus, greater enhancement of activation in mirror neuron system is involved in response to object-oriented motor imagery. The object-oriented motor imagery is favorable for improvement of motor imagery ability. PMID- 26641242 TI - Therapy of Primary Sclerosing Cholangitis--Today and Tomorrow. AB - Primary sclerosing cholangitis (PSC) represents a fibro-obliterative bile duct disease with unpredictable individual clinical course that may progress to liver cirrhosis and malignancy. Due to our incomplete understanding of the etiology and pathogenesis of this disease, the therapeutic options are still rather limited. Bile acids play a key role in mediating cholangiocellular and hepatocellular injury in cholangiopathies such as PSC. Therefore, strategies targeting bile composition and homeostasis are valid approaches in PSC. Ursodeoxycholic acid (UDCA) is the paradigm therapeutic bile acid and its role in medical therapy of PSC is still under debate. Promising novel bile acid-based therapeutic options include 24-norursodeoxycholic acid (norUDCA), a side chain-shortened C23 homologue of UDCA, and bile acid receptor/farnesoid X receptor agonists (e.g. obeticholic acid). Other nuclear receptors such as fatty acid-activated peroxisome proliferator-activated receptors, vitamin D receptor and vitamin A receptors (retinoic acid receptor, retinoid X receptor) are also of potential interest and can be targeted by already available drugs. Furthermore, drugs targeting the gut-liver axis (e.g. intregrin blockers such as vedolizumab, antibiotics) appear promising, based on the close link of PSC to inflammatory bowel disease and the emerging relevance of the gut microbiome for the development of PSC. Finally, fibrosis represents a valid therapeutic target for anti-fibrotic drugs (e.g. simtuzumab) in PSC as paradigm fibro-obliterative disease. This review summarizes the current status and recent progress in the development of targeted therapeutic approaches based on increasing knowledge about the pathogenesis of this disease. PMID- 26641243 TI - Influence of Granulocyte-Macrophage Colony-Stimulating Factor or Influenza Vaccination on HLA-DR, Infection and Delirium Days in Immunosuppressed Surgical Patients: Double Blind, Randomised Controlled Trial. AB - PURPOSE: Surgical patients are at high risk for developing infectious complications and postoperative delirium. Prolonged infections and delirium result in worse outcome. Granulocyte-macrophage colony-stimulating factor (GM CSF) and influenza vaccination are known to increase HLA-DR on monocytes and improve immune reactivity. This study aimed to investigate whether GM-CSF or vaccination reverses monocyte deactivation. Secondary aims were whether it decreases infection and delirium days after esophageal or pancreatic resection over time. METHODS: In this prospective, randomized, placebo-controlled, double blind, double dummy trial setting on an interdisciplinary ICU of a university hospital 61 patients with immunosuppression (monocytic HLA-DR [mHLA-DR] <10,000 monoclonal antibodies [mAb] per cell) on the first day after esophageal or pancreatic resection were treated with either GM-CSF (250 MUg/m2/d), influenza vaccination (Mutagrip 0.5 ml/d) or placebo for a maximum of 3 consecutive days if mHLA-DR remained below 10,000 mAb per cell. HLA-DR on monocytes was measured daily until day 5 after surgery. Infections and delirium were followed up for 9 days after surgery. Primary outcome was HLA-DR on monocytes, and secondary outcomes were duration of infection and delirium. RESULTS: mHLA-DR was significantly increased compared to placebo (p < 0.001) and influenza vaccination (p < 0.001) on the second postoperative day. Compared with placebo, GM-CSF treated patients revealed shorter duration of infection (p < 0.001); the duration of delirium was increased after vaccination (p = 0.003). CONCLUSION: Treatment with GM-CSF in patients with postoperative immune suppression was safe and effective in restoring monocytic immune competence. Furthermore, therapy with GM CSF reduced duration of infection in immune compromised patients. However, influenza vaccination increased duration of delirium after major surgery. TRIAL REGISTRATION: www.controlled-trials.com ISRCTN27114642. PMID- 26641244 TI - Frequency of Extreme Heat Event as a Surrogate Exposure Metric for Examining the Human Health Effects of Climate Change. AB - Epidemiological investigation of the impact of climate change on human health, particularly chronic diseases, is hindered by the lack of exposure metrics that can be used as a marker of climate change that are compatible with health data. Here, we present a surrogate exposure metric created using a 30-year baseline (1960-1989) that allows users to quantify long-term changes in exposure to frequency of extreme heat events with near unabridged spatial coverage in a scale that is compatible with national/state health outcome data. We evaluate the exposure metric by decade, seasonality, area of the country, and its ability to capture long-term changes in weather (climate), including natural climate modes. Our findings show that this generic exposure metric is potentially useful to monitor trends in the frequency of extreme heat events across varying regions because it captures long-term changes; is sensitive to the natural climate modes (ENSO events); responds well to spatial variability, and; is amenable to spatial/temporal aggregation, making it useful for epidemiological studies. PMID- 26641245 TI - "Healthy Men" and High Mortality: Contributions from a Population-Based Study for the Gender Paradox Discussion. AB - BACKGROUND: Inequalities between men and women in morbidity and mortality show a contrast, which has been called gender paradox. Most studies evaluating this paradox were conducted in high-income countries and, until now, few investigations have been performed in Brazil. This study aims to estimate the magnitude of inequalities between adult men and women in several dimensions: demographic and socioeconomic, health behaviors, morbidity, use of health services and mortality. METHODS: The data were obtained from population-based household survey carried out in Campinas (Campinas Health Survey 2008/09) corresponding to 957 people, and data from the Mortality Information System (MIS) between 2009 and 2011. Prevalences and prevalence ratios were analyzed in order to verify the differences between men and women regarding socioeconomic and demographic variables, health behaviors, morbidities and consultations in the last two weeks. Mortality rates and the ratio between coefficients considering the underlying causes of death were calculated. RESULTS: Women had a greater disadvantage in socioeconomic indicators, chronic diseases diagnosed by a health professional and referred health problems as well as make more use of health services, while men presented higher frequency of most unhealthy behaviors and excessive mortality for all causes investigated. CONCLUSIONS: The findings contribute to the discussion of gender paradox and demonstrate the need to employ health actions that consider the differences between men and women in the various health dimensions analyzed. The premature male mortality from preventable causes was outstanding, making clear the need for more effective prevention and health promotion directed to this segment of the population. PMID- 26641246 TI - Germline Prolactin Receptor Mutation Is Not a Major Cause of Sporadic Prolactinoma in Humans. AB - BACKGROUND/AIMS: No genetic anomalies specifically predisposing humans to prolactinomas have so far been identified. The prolactin receptor (PRLR) is a good candidate, however, as Prlr knockout mice develop prolactinomas, and a case of familial hyperprolactinemia has been linked to PRLR mutation. The main objective of this study was to detect germline PRLR mutations in patients with sporadic prolactinomas unrelated to AIP or MEN1 mutation. METHODS: We sequenced all PRLR exons and intron-exon junctions on genomic DNA from 88 patients with a median age of 24 years. RESULTS: We identified 4 PRLR variations (p.Ile76Val, p.Ile146Leu, p.Glu108Lys and p.Glu554Gln) in 16 patients. One patient had the rare variant p.Glu554Gln in the heterozygous state. Another patient had the extremely rare p.Glu108Lys variant described here for the first time. The other 2 variants (p.Ile76Val and p.Ile146Leu) are relatively common in the general population. All these 4 variants have been functionally tested in vitro and have no effect on PRLR expression, localization and signaling after prolactin stimulation. CONCLUSION: Inactivating germline variations of PRLR are not associated with sporadic prolactinoma in this series. Nevertheless, somatic disruption of PRLR has not been excluded in this subset of pituitary tumors. PMID- 26641247 TI - TcCYPR04, a Cacao Papain-Like Cysteine-Protease Detected in Senescent and Necrotic Tissues Interacts with a Cystatin TcCYS4. AB - The interaction amongst papain-like cysteine-proteases (PLCP) and their substrates and inhibitors, such as cystatins, can be perceived as part of the molecular battlefield in plant-pathogen interaction. In cacao, four cystatins were identified and characterized by our group. We identified 448 proteases in cacao genome, whereof 134 were cysteine-proteases. We expressed in Escherichia coli a PLCP from cacao, named TcCYSPR04. Immunoblottings with anti-TcCYSPR04 exhibited protein increases during leaf development. Additional isoforms of TcCYSPR04 appeared in senescent leaves and cacao tissues infected by Moniliophthora perniciosa during the transition from the biotrophic to the saprophytic phase. TcCYSPR04 was induced in the apoplastic fluid of Catongo and TSH1188 cacao genotypes, susceptible and resistant to M. perniciosa, respectively, but greater intensity and additional isoforms were observed in TSH1188. The fungal protein MpNEP induced PLCP isoform expression in tobacco leaves, according to the cross reaction with anti-TcCYSPR04. Several protein isoforms were detected at 72 hours after treatment with MpNEP. We captured an active PLCP from cacao tissues, using a recombinant cacao cystatin immobilized in CNBr-Sepharose. Mass spectrometry showed that this protein corresponds to TcCYSPR04. A homology modeling was obtained for both proteins. In order to become active, TcCYSPR04 needs to lose its inhibitory domain. Molecular docking showed the physical-chemical complementarities of the interaction between the cacao enzyme and its inhibitor. We propose that TcCYSPR04 and its interactions with cacao cystatins are involved in the senescence and necrosis events related to witches' broom symptoms. This molecular interaction may be the target for future interventions to control witches' broom disease. PMID- 26641248 TI - Developmental Dynamics of X-Chromosome Dosage Compensation by the DCC and H4K20me1 in C. elegans. AB - In Caenorhabditis elegans, the dosage compensation complex (DCC) specifically binds to and represses transcription from both X chromosomes in hermaphrodites. The DCC is composed of an X-specific condensin complex that interacts with several proteins. During embryogenesis, DCC starts localizing to the X chromosomes around the 40-cell stage, and is followed by X-enrichment of H4K20me1 between 100-cell to comma stage. Here, we analyzed dosage compensation of the X chromosome between sexes, and the roles of dpy-27 (condensin subunit), dpy-21 (non-condensin DCC member), set-1 (H4K20 monomethylase) and set-4 (H4K20 di-/tri methylase) in X chromosome repression using mRNA-seq and ChIP-seq analyses across several developmental time points. We found that the DCC starts repressing the X chromosomes by the 40-cell stage, but X-linked transcript levels remain significantly higher in hermaphrodites compared to males through the comma stage of embryogenesis. Dpy-27 and dpy-21 are required for X chromosome repression throughout development, but particularly in early embryos dpy-27 and dpy-21 mutations produced distinct expression changes, suggesting a DCC independent role for dpy-21. We previously hypothesized that the DCC increases H4K20me1 by reducing set-4 activity on the X chromosomes. Accordingly, in the set-4 mutant, H4K20me1 increased more from the autosomes compared to the X, equalizing H4K20me1 level between X and autosomes. H4K20me1 increase on the autosomes led to a slight repression, resulting in a relative effect of X derepression. H4K20me1 depletion in the set-1 mutant showed greater X derepression compared to equalization of H4K20me1 levels between X and autosomes in the set-4 mutant, indicating that H4K20me1 level is important, but X to autosomal balance of H4K20me1 contributes slightly to X-repression. Thus H4K20me1 is not only a downstream effector of the DCC [corrected].In summary, X chromosome dosage compensation starts in early embryos as the DCC localizes to the X, and is strengthened in later embryogenesis by H4K20me1. PMID- 26641250 TI - Pain in the Early Phase of Pediatric Pancreatitis (PINEAPPLE Trial): Pre-Study Protocol of a Multinational Prospective Clinical Trial. AB - BACKGROUND: There are unexpectedly large differences between the incidences of acute pancreatitis (AP) as indicated by different hospitals. Retrospective studies suggest that the reason behind this is the large differences that exist between the local managements of abdominal pain at emergency units. Unfortunately, no evidence-based medicine (EBM) guidelines are available to give proper instruction concerning the necessity of serum pancreatic enzyme measurement during abdominal pain. SUMMARY: Pain in Early Phase of Pediatric Pancreatitis (PINEAPPLE) is an observational, multinational observational clinical trial to explore the route from the first sign of abdominal pain to the diagnosis of pancreatitis (PINEAPPLE trial). The PINEAPPLE-R subtrial is a retrospective review on the records of children (patients under 18) appearing at emergency units - a review of their clinical symptoms, results of imaging examinations and laboratory parameters. The PINEAPPLE-P subtrial is a prospective trial designed to develop a fast and simple EBM guideline that helps to evaluate (in a reliable and cost-efficient way) the necessity of pancreatic enzyme test and abdominal ultrasonography (or even computed tomography) when a child has abdominal pain. The trial has been registered at the ISRCTN registry and has received the relevant ethical approval. KEY MESSAGE: The PINEAPPLE trial will help to recognize AP in children in a highly efficient manner. PMID- 26641251 TI - Assessment of Filtration Bleb and Endplate Positioning Using Magnetic Resonance Imaging in Eyes Implanted with Long-Tube Glaucoma Drainage Devices. AB - BACKGROUND: To evaluate ocular fluid filtration and endplate positioning in glaucomatous eyes with long-tube glaucoma drainage devices (GDDs) using magnetic resonance imaging (MRI) and the effects of various factors on postoperative intraocular pressure (IOP). METHODS: This observational case series included 27 consecutive glaucomatous eyes (18 men, 7 women; mean age +/- standard error, 63.0+/-2.0 years) who underwent GDD implantation (n = 8 Ahmed Glaucoma Valves [AGV] and n = 19 Baerveldt Glaucoma Implants [BGI]). Tubes were inserted into the pars plana in 23 eyes and anterior chamber in 4 eyes. Six months postoperatively, high-resolution orbital images were obtained using 3-Tesla MRI with head-array coils, and the filtering bleb volume, bleb height, and distances between the anterior endplate edge and corneal center or limbus or between the endplate and orbital wall were measured. RESULTS: In MR images obtained by three-dimensional fast imaging employing steady-state acquisition (3D-FIESTA) sequences, the shunt endplate was identified as low-intensity signal, and the filtering bleb was identified as high-intensity signals above and below the endplate in all eyes. The 6-month-postoperative IOP level was correlated negatively with bleb volume (r = -0.4510, P = 0.0182) and bleb height (r = -0.3954, P = 0.0412). The postoperative IOP was significantly (P = 0.0026) lower in BGI-implanted eyes (12.2+/-0.7 mmHg) than AGV-implanted eyes (16.7+/-1.2 mmHg); bleb volume was significantly (P = 0.0093) larger in BGI-implanted eyes (478.8+/-84.2 mm3) than AGV-implanted eyes (161.1+/-52.3 mm3). Other parameters did not differ. CONCLUSIONS: The presence of intraorbital/periocular accumulation of ocular fluid affects postoperative IOP levels in eyes implanted with long-tube GDDs. Larger filtering blebs after BGI than AGI implantations explain lower postoperative IOP levels achieved with BGI than AGV. The findings will contribute to better understanding of IOP reducing mechanism of long-tube GDDs. PMID- 26641249 TI - Evolution of Helicobacter: Acquisition by Gastric Species of Two Histidine-Rich Proteins Essential for Colonization. AB - Metal acquisition and intracellular trafficking are crucial for all cells and metal ions have been recognized as virulence determinants in bacterial pathogens. Virulence of the human gastric pathogen Helicobacter pylori is dependent on nickel, cofactor of two enzymes essential for in vivo colonization, urease and [NiFe] hydrogenase. We found that two small paralogous nickel-binding proteins with high content in Histidine (Hpn and Hpn-2) play a central role in maintaining non-toxic intracellular nickel content and in controlling its intracellular trafficking. Measurements of metal resistance, intracellular nickel contents, urease activities and interactomic analysis were performed. We observed that Hpn acts as a nickel-sequestration protein, while Hpn-2 is not. In vivo, Hpn and Hpn 2 form homo-multimers, interact with each other, Hpn interacts with the UreA urease subunit while Hpn and Hpn-2 interact with the HypAB hydrogenase maturation proteins. In addition, Hpn-2 is directly or indirectly restricting urease activity while Hpn is required for full urease activation. Based on these data, we present a model where Hpn and Hpn-2 participate in a common pathway of controlled nickel transfer to urease. Using bioinformatics and top-down proteomics to identify the predicted proteins, we established that Hpn-2 is only expressed by H. pylori and its closely related species Helicobacter acinonychis. Hpn was detected in every gastric Helicobacter species tested and is absent from the enterohepatic Helicobacter species. Our phylogenomic analysis revealed that Hpn acquisition was concomitant with the specialization of Helicobacter to colonization of the gastric environment and the duplication at the origin of hpn 2 occurred in the common ancestor of H. pylori and H. acinonychis. Finally, Hpn and Hpn-2 were found to be required for colonization of the mouse model by H. pylori. Our data show that during evolution of the Helicobacter genus, acquisition of Hpn and Hpn-2 by gastric Helicobacter species constituted a decisive evolutionary event to allow Helicobacter to colonize the hostile gastric environment, in which no other bacteria persistently thrives. This acquisition was key for the emergence of one of the most successful bacterial pathogens, H. pylori. PMID- 26641252 TI - Psychosocial Predictors and Outcomes of Delayed Breast Reconstruction in Mastectomized Women in Mainland China: An Observational Study. AB - BACKGROUND: The aim of the present study was to evaluate potential psychosocial factors that impact Chinese female breast cancer patients to select breast reconstruction (BR), and potential connection of psychosocial outcomes with their satisfaction with BR. METHODS: A total of 264 female breast cancer patients with mastectomy were recruited from 2012 to 2014. All patients were informed with BR options at their first visit. Personal and medical profiles were collected. Body image, self-esteem, depression and anxiety were assessed using validated scales. Patients who were selected to undergo BR after the first visit were followed up for six months. The same assessment was performed at 6 months post BR, and their satisfaction with BR was evaluated using the Alderman scale. Multivariate linear and logistic regressions were performed. RESULTS: Forty-seven percent of the patients (126/264) opted to undergo BR within six months after the initial visit. Multivariate logistic regression analysis revealed that self-esteem (P < 0.05), body image (P < 0.01), education level (P < 0.05), and their husband's recommendation (P < 0.05) were highly related to the patients' decision to undergo BR. In addition, multivariate linear regression analysis showed that patient satisfaction with BR was significantly associated with preoperative body image (P < 0.01), postoperative improvement in self-esteem (P < 0.01), improvement in body image (P < 0.01), reduction in depression (P < 0.05), pain (P < 0.05), and scarring (P < 0.01). CONCLUSIONS: The psychosocial factors including self-esteem and body image are highly related to selecting the BR option and post BR satisfaction in Chinese female breast cancer patients. PMID- 26641253 TI - Adjunctive Corticotherapy for Community Acquired Pneumonia: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Community-acquired pneumonia (CAP) induces lung and systemic inflammation, leading to high morbidity and mortality. We systematically reviewed the risks and benefits of adjunctive corticotherapy in the management of patients with CAP. METHODS: We systematically searched Pubmed, Embase and the Cochrane Library for randomized controlled trials comparing adjunctive corticotherapy and antimicrobial therapy with antimicrobial therapy alone in patients with CAP. The primary outcome was 30-day mortality. Secondary outcomes were length of hospital stay, time to clinical stability and severe complications. RESULTS: 14 trials (2077 patients) were included. The reported 30-day mortality was 7.9% (80/1018) among patients treated with adjunctive corticotherapy versus 8.3% (85/1028) among patients treated with antimicrobial therapy alone (RR 0.84; 95%CI 0.55 to1.29). Adjunctive corticotherapy was associated with a reduction of severe complications (RR 0.36; 95%CI 0.23 to 0.56), a shorter length of stay (9.0 days; 95%CI 7.6 to 10.7 vs 10.6 days; 95%CI 7.4 to 15.3) and a shorter time to clinical stability (3.3 days; 95% CI 2.8 to 4.1 vs 4.3 days; 95%CI 3.6 to 5.1). The risk of hyperglycemia was higher among patients treated with adjunctive corticotherapy (RR 1.59; 95%CI 1.06 to 2.38), whereas the risk of gastro-intestinal bleeding was similar (RR 0.83; 95%CI 0.35 to 1.93). In the subgroup analysis based on CAP severity, a survival benefit was found among patients with severe CAP (RR 0.47; 95%CI 0.23 to 0.96). CONCLUSION: Adjunctive corticotherapy is associated with a reduction of length of stay, time to clinical stability, and severe complications among patients with CAP, but the effect on mortality remains uncertain. PMID- 26641255 TI - Second and Third Laparoscopic Liver Resection for Patients With Recurrent Colorectal Liver Metastases. PMID- 26641254 TI - Association between Single-Nucleotide Polymorphisms of the Tyrosine Kinase Receptor B (TrkB) and Post-Stroke Depression in China. AB - BACKGROUND: Polymorphisms of the brain-derived neurotrophic factor (BDNF) have been investigated as candidate genes for post-stroke depression (PSD), and its receptor, neurotrophic tyrosine kinase receptor B (TrkB), has been associated with depression. However, no further data have yet reported the association between PSD and polymorphisms in TrkB. This study aims to investigate whether a relationship exists between TrkB polymorphisms and PSD. METHODS: A total of 312 depression patients (PSD patients) and 472 non-depression patient controls (NPSD patients) were recruited. All patients were evaluated using the Hamilton Rating Scale for Depression (HAMD) to determine depression severity, and PSD patients were diagnosed in accordance with DSM-V criteria. Three single-nucleotide polymorphisms (SNPs), namely, rs1187323, rs1212171, and rs1778929, in the TrkB gene were genotyped by high-resolution melt analysis. RESULTS: The SNP rs1778929 was significantly more associated with incident PSD in participants with the TT genotype than in those with CC (OR 0.482, 95% CI: 0.313-0.744). In terms of rs1187323, stroke was significantly more associated with incident depression in participants with the AC genotype than in those with AA (OR 0.500, 95% CI: 0.368 0.680). The minor allele (T) of rs1778929 (P = 0.024, OR = 0.725, 95% CI = 0.590 0.890) and the minor allele (C) of rs1187323 (P = 0.000, OR = 0.598, 95% CI = 0.466-0.767) were found to be significantly associated with PSD. Neither genotype nor allele frequencies of rs1212171 showed statistically significant differences between PSD and NPSD patients. CONCLUSIONS: The results suggest that rs1778929 and rs1187323 in the TrkB gene are significantly associated with post-stroke depression in the Chinese population. Further studies are necessary to confirm our findings. PMID- 26641256 TI - Expression of MAGE-A and NY-ESO-1 in Primary and Metastatic Cancers. AB - Melanoma-associated antigen-A (MAGE-A) and New York esophageal squamous cell cancer-1 (NY-ESO-1) are 2 cancer testis antigens (CTA) demonstrating potential for use in targeted immunotherapy. Clinical trials in melanoma and synovial sarcomas targeting these antigens in immune-based therapies have demonstrated durable tumor regression. Although protein expression of NY-ESO-1 has been assessed in a variety of cancer types, the expression of MAGE-A has not been studied in depth. In this study we analyzed MAGE-A and NY-ESO-1 expression in 314 melanoma specimens from 301 melanoma patients, 38 patients with squamous cell cancers and 111 patients with adenocarcinomas. Our results demonstrated higher expression of MAGE-A compared with NY-ESO-1 in melanomas (32% vs. 13%) and squamous cell carcinomas (45% vs. 7.9%), and higher expression of both CTAs in metastatic versus primary tumors. CTA expression in adenocarcinomas was low (MAGE A: 10%, NY-ESO-1: 0.9%). In addition, we looked at concordance of expression among metastatic melanoma lesions within the same patient and found concordant expression in 38 of 47 patients for MAGE-A and 43 of 47 patients for NY-ESO-1. Our study demonstrated that the MAGE-A family may be of greater utility than NY ESO-1 for targeted immunotherapy in a variety of cancer histologies, in particular metastatic melanomas and squamous cell carcinomas. PMID- 26641257 TI - Differential Expression of Bcl-2 Family Proteins Determines the Sensitivity of Human Follicular Lymphoma Cells to Dexamethasone-mediated and Anti-BCR-mediated Apoptosis. AB - Bcl-2 family comprises proapoptotic and antiapoptotic proteins. The balance between these proteins is critical for the survival of the cells. Overexpression of the antiapoptotic protein, Bcl-2, is the hallmark of follicular lymphoma (FL). High expression of Bcl-2 provides survival advantage and may facilitate chemotherapeutic resistance in FL. In the present study, we examined expression profile of Bcl-2 family proteins such as Bcl-2, Bcl-xL, and Bim in human FL cell lines, HF1A3 and HF28. We assessed the correlation between the expression levels of these proteins and cells' sensitivity to dexamethasone (Dex)-mediated and B cell receptor (BCR)-mediated apoptosis. Here, we show that Dex and anti-BCR induced synergistic apoptosis which correlated with significant downregulation of Bcl-xL, inhibition of ERK1/2 phosphorylation and accumulation of nonphosphorylated Bim. However, HF28 cells were less sensitive than HF1A3 cells to Dex-induced and anti-BCR-induced apoptosis due to high Bcl-2 protein level. It is interesting to note that, a Bcl-2-specific inhibitor, ABT-199, sensitized HF28 cells to Dex-induced or anti-BCR-induced apoptosis. In addition, overexpression of Bcl-xL prevented Dex-mediated, anti-BCR-mediated, and ABT-199-mediated apoptosis, indicating that mitochondria were involved. In conclusion, these data show that the expression levels of Bcl-2 family proteins may serve to predict tumor response to BH3 mimetics and the sensitivity of FL cells to Dex-induced and anti-BCR-induced apoptosis. Moreover, our results show that BCR-targeted apoptosis might have therapeutic benefit against FL and B-cell lymphomas. PMID- 26641258 TI - Identification of Melanoma-reactive CD4+ T-Cell Subsets From Human Melanoma Draining Lymph Nodes. AB - Our laboratory has previously demonstrated that melanoma draining lymph node (MDLN) samples from stage III patients contained both CD4 and CD8 T cells that can be readily expanded to mediate tumor cell apoptosis in vitro and improve survival in mice bearing human melanoma xenografts. In this study, we investigated whether MDLN T cells contain melanoma-reactive CD4 T-cell compartment and what they are. To test this, we performed multiparametric (11 color and 6-color) fluorescence-activated cell sorting analyses to monitor phenotypic and functional property of CD4 T cells in response to melanoma cell antigen reexposure. Our results have demonstrated that the antigen reexposure could result in a generation of CD4CCR7CD62LCD27 T-cell subsets with various effector cell-like properties. Within the CD4CCR7CD62LCD27 T-cell compartment, in response to antigen reexposure, some of the cells expressed significantly upregulated CD40L and/or CXCR5, and some of them expressed significantly upregulated interleukin-2 and/or tumor necrosis factor-alpha. This may suggest the existence of melanoma-reactive CD4 "effector-precursor" cells within the expanded MDLN cells and their differentiation into various effector lineages in response to antigen restimulation. Recent clinical trials have demonstrated that effective adoptive cellular immunotherapy maybe enhanced by antigen-specific CD4 T cells. Therefore, results of this study may significantly benefit innovative design of +adoptive cellular immunotherapy that can potentially mediate enhanced and durable clinical responses. PMID- 26641259 TI - Adenovirus-specific T-cell Subsets in Human Peripheral Blood and After IFN-gamma Immunomagnetic Selection. AB - Adoptive antiviral cellular immunotherapy by infusion of virus-specific T cells (VSTs) is becoming an alternative treatment for viral infection after hematopoietic stem cell transplantation. The T memory stem cell (TSCM) subset was recently described as exhibiting self-renewal and multipotency properties which are required for sustained efficacy in vivo. We wondered if such a crucial subset for immunotherapy was present in VSTs. We identified, by flow cytometry, TSCM in adenovirus (ADV)-specific interferon (IFN)-gamma+ T cells before and after IFN gamma-based immunomagnetic selection, and analyzed the distribution of the main T cell subsets in VSTs: naive T cells (TN), TSCM, T central memory cells (TCM), T effector memory cell (TEM), and effector T cells (TEFF). In this study all of the different T-cell subsets were observed in the blood sample from healthy donor ADV VSTs, both before and after IFN-gamma-based immunomagnetic selection. As the IFN gamma-based immunomagnetic selection system sorts mainly the most differentiated T-cell subsets, we observed that TEM was always the major T-cell subset of ADV specific T cells after immunomagnetic isolation and especially after expansion in vitro. Comparing T-cell subpopulation profiles before and after in vitro expansion, we observed that in vitro cell culture with interleukin-2 resulted in a significant expansion of TN-like, TCM, TEM, and TEFF subsets in CD4IFN-gamma T cells and of TCM and TEM subsets only in CD8IFN-gamma T cells. We demonstrated the presence of all T-cell subsets in IFN-gamma VSTs including the TSCM subpopulation, although this was weakly selected by the IFN-gamma-based immunomagnetic selection system. PMID- 26641260 TI - Prognostic Role of Immune Cells in Hepatitis B-associated Hepatocellular Carcinoma Following Surgical Resection Depends on Their Localization and Tumor Size. AB - This study aims to evaluate localized expression of CD4, interleukin (IL)-17, Foxp3, and CD8 in hepatitis B-associated hepatocellular carcinoma (HBV-HCC) and to explore their potential effects on outcome following surgical resection. This prospective study includes 66 HBV-HCC surgical resection patients enrolled from 2008 to 2013. CD4, IL-17, Foxp3, and CD8 mRNA in 4 regions of the resection specimens (center of the tumor, periphery of the tumor, non-neoplastic liver bordering tumor, non-neoplastic liver distant from tumor) was quantitated using real-time polymerase chain reaction. The tumoral regions had lower CD4 and CD8 expression as compared with paired non-neoplastic regions, whereas the expression of IL-17 and Foxp3 did not differ. High Foxp3 in all regions except non neoplastic liver distant from tumor was associated with poor overall survival, whereas low CD8 expression in distant non-neoplastic liver may be associated with high HCC recurrence rate. Although the expression of almost all molecules did not differ between small (<=3 cm) and large HCC (>3 cm), high IL-17 in periphery of tumor, high CD8 in center of tumor, or low CD8 in distant non-neoplastic liver was associated with high HCC recurrence rate in patients with small HCC, but not in those with large HCC. The effect of immune cells on HCC progression therefore depends on the expression level, localization, and tumor size, and an imbalance toward regulatory T cells is associated with poor outcome. PMID- 26641261 TI - Mastoid Dimensions in Children and Young Adults: Consequences for the Geometry of Transcutaneous Bone-Conduction Implants. AB - OBJECTIVES: Bone-conduction implants (BCI) are available for adults and children who are aged 5 years or more. Because a transcutaneous bone-conduction implant introduced in 2013 does not completely fit into all adult mastoids, we investigated mastoid dimensions and the possibility of fitting the implant in children. DESIGN: Computed tomography scans of 151 mastoids from 80 children and young adolescents from the age of 5 months to 20 years and 52 control mastoids from 33 adults were retrospectively analyzed. After three-dimensional reconstruction, mastoid volume was measured. The chances of fitting the Bonebridge or a novel BCI were determined as a function of age. Implant diameter and implantation depths were virtually varied to identify the most advantageous dimensions for reducing the minimum age for implantation. RESULTS: Mastoid volume increased to 13.8 ml in female and 16.4 ml in male adult mastoids at ages 18.9 years (male) and 19.0 years (female). Without compromising the middle fossa dura or the sinus and without lifts, the Bonebridge implant fit in 81% of male adult mastoids and 77% of the female adult mastoids. For children, the 50% chance of fitting a Bonebridge in the mastoids was reached at age 12 years; with a protrusion of 4 mm (4-mm lifts), this age was reduced to >6 years. The novel BCI fit in 100% of male and 94% of female adult mastoids. CONCLUSIONS: Casing diameter is the most limiting factor for Bonebridge implantation in children. A modified implant casing with a truncated cone and reduced diameter and volume would increase the number of hearing impaired children who can be rehabilitated with a Bonebridge implant. Radiological planning for Bonebridge implantation is necessary in all children. PMID- 26641262 TI - From the Macro to the Micro: Gel Mapping to Differentiate between Sporozoites of Two Immunologically Distinct Strains of Eimeria maxima (Strains M6 and Guelph). AB - Two immunologically distinct strains of E. maxima were examined in this study: the M6 strain and the Guelph strain. The differential expression between the sporozoites of the two strains of E. maxima was determined by image analysis of 100 MUg of protein from each strain separated by standard one- and conventional two-dimensional polyacrylamide gel electrophoresis. In addition to differences in both molecular weight and the electrophoretic mobility, differences in the intensity of polypeptide bands for example, GS 136.4 and M6 169 were explored. Pooled gels were prepared from each strain. A representative 2D-PAGE gel spanning a non-linear pH range of 3-10 of E. maxima strain M6 consisted of approximately 694 polypeptide spots with about 67 (9.6%) of the polypeptide spots being unique relative to the other strain. E. maxima strain GS had about 696 discernable polypeptide spots with 69 spots (9.9%) that differed from those of the M6 strain. In-depth characterization of the variable polypeptide spots; unique polypeptide spots (absence or presence) and shared polypeptide spots with modifications may lead to novel vaccine target in the form of multi-component, multi-stage, multi immunovariant strains, multi-species subunit vaccine, and diagnostic probe for E. maxima. PMID- 26641264 TI - Geoepidemiology, Genetic and Environmental Risk Factors for PBC. AB - Primary biliary cirrhosis (PBC) is the most paradigmatic autoimmune liver disease with still several controversial issues in epidemiology, diagnosis, causation, and therapy. Although we are witnessing an enormous increase in the quantum of our basic knowledge of the disease with an initial translation in clinical practice, there are still a number of key open questions in PBC. Among them are the following questions: Why are there vast geographical variations in disease frequency? What are the reasons for female preponderance? Why do only small-size bile ducts get affected: What is the real role of genetics and epigenetics in its development? In particular, the prevalence of PBC is known to vary both on an international and a regional level, suggesting the existence of substantive geographical differences in terms of genetic susceptibility and environmental factors. New theories on potential environmental triggers, such as chemical xenobiotics, which lead to the breaking of self-tolerance within a unique immunological milieu of the liver, have been suggested. On the other hand, new and solid data on the genetic architecture of PBC are now obtained from recent high-throughput studies, together with data on sex chromosomes defects, and epigenetic abnormalities, thus strongly suggesting a role of genetic and epigenetic factors in the triggering and perpetuation of the autoimmune aggression in PBC. Based on these evidences, a number of novel drugs directed against specific immune-related molecules are currently under development. In this paper, we review a comprehensive collection of current epidemiological reports from various world regions. We also discuss here the most recent data regarding candidate genetic and environmental risk factors for PBC. PMID- 26641263 TI - Photoperiodic Modulation of Circadian Clock and Reproductive Axis Gene Expression in the Pre-Pubertal European Sea Bass Brain. AB - The acquisition of reproductive competence requires the activation of the brain pituitary-gonad (BPG) axis, which in most vertebrates, including fishes, is initiated by changes in photoperiod. In the European sea bass long-term exposure to continuous light (LL) alters the rhythm of reproductive hormones, delays spermatogenesis and reduces the incidence of precocious males. In contrast, an early shift from long to short photoperiod (AP) accelerates spermatogenesis. However, how photoperiod affects key genes in the brain to trigger the onset of puberty is still largely unknown. Here, we investigated if the integration of the light stimulus by clock proteins is sufficient to activate key genes that trigger the BPG axis in the European sea bass. We found that the clock genes clock, npas2, bmal1 and the BPG genes gnrh, kiss and kissr share conserved transcription factor frameworks in their promoters, suggesting co-regulation. Other gene promoters of the BGP axis were also predicted to be co-regulated by the same frameworks. Co-regulation was confirmed through gene expression analysis of brains from males exposed to LL or AP photoperiod compared to natural conditions: LL fish had suppressed gnrh1, kiss2, galr1b and esr1, while AP fish had stimulated npas2, gnrh1, gnrh2, kiss2, kiss1rb and galr1b compared to NP. It is concluded that fish exposed to different photoperiods present significant expression differences in some clock and reproductive axis related genes well before the first detectable endocrine and morphological responses of the BPG axis. PMID- 26641265 TI - Use of power-line interference for adaptive motion artifact removal in biopotential measurements. AB - Motion artifacts (MA) have long been a problem in biopotential measurements. Adaptive filtering is widely used for optimal noise removal in many biomedical applications. However, the existing adaptive filtering methods involve the use of additional sensors, limiting the applicability of adaptive filtering for MA reduction. In the present study, a novel adaptive filtering method without need for additional sensors is proposed. In biopotential measurements, movement of the electrodes and their leads may cause variations not only in the skin and half cell potential (motion artifacts), but also in the electrode-skin impedance. Such impedance variations may also cause power-line interference modulation (PLIM), resulting in additional spectral components around the power-line interference (PLI) in the frequency domain. Demodulation of the PLI may reflect the movement induced electrode-skin impedance variation, and can therefore represent a reference signal for the adaptive filter. Preliminary validation on ECG measurements with seven volunteers showed a high correlation coefficient (R = 0.97) between MA and PLIM, and excellent MA removal by the proposed adaptive filter, possibly leading to improved analysis of biopotential signals. PMID- 26641267 TI - Current Capabilities and Capacity of Ebola Treatment Centers in the United States. AB - OBJECTIVE: To describe current Ebola treatment center (ETC) locations, their capacity to care for Ebola virus disease patients, and infection control infrastructure features. DESIGN: A 19-question survey was distributed electronically in April 2015. Responses were collected via email by June 2015 and analyzed in an electronic spreadsheet. SETTING: The survey was sent to and completed by site representatives of each ETC. PARTICIPANTS: The survey was sent to all 55 ETCs; 47 (85%) responded. RESULTS: Of the 47 responding ETCs, there are 84 isolation beds available for adults and 91 for children; of these pediatric beds, 35 (38%) are in children's hospitals. In total, the simultaneous capacity of the 47 reporting ETCs is 121 beds. On the basis of the current US census, there are 0.38 beds per million population. Most ETCs have negative pressure isolation rooms, anterooms, and a process for category A waste sterilization, although only 11 facilities (23%) have the capability to sterilize infectious waste on site. CONCLUSIONS: Facilities developed ETCs on the basis of Centers for Disease Control and Prevention guidance, but specific capabilities are not mandated at this present time. Owing to the complex and costly nature of Ebola virus disease treatment and variability in capabilities from facility to facility, in conjunction with the lack of regulations, nationwide capacity in specialized facilities is limited. Further assessments should determine whether ETCs can adapt to safely manage other highly infectious disease threats. PMID- 26641266 TI - Metformin Reduces Desmoplasia in Pancreatic Cancer by Reprogramming Stellate Cells and Tumor-Associated Macrophages. AB - BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a highly desmoplastic tumor with a dismal prognosis for most patients. Fibrosis and inflammation are hallmarks of tumor desmoplasia. We have previously demonstrated that preventing the activation of pancreatic stellate cells (PSCs) and alleviating desmoplasia are beneficial strategies in treating PDAC. Metformin is a widely used glucose lowering drug. It is also frequently prescribed to diabetic pancreatic cancer patients and has been shown to associate with a better outcome. However, the underlying mechanisms of this benefit remain unclear. Metformin has been found to modulate the activity of stellate cells in other disease settings. In this study, we examine the effect of metformin on PSC activity, fibrosis and inflammation in PDACs. METHODS/RESULTS: In overweight, diabetic PDAC patients and pre-clinical mouse models, treatment with metformin reduced levels of tumor extracellular matrix (ECM) components, in particular hyaluronan (HA). In vitro, we found that metformin reduced TGF-beta signaling and the production of HA and collagen-I in cultured PSCs. Furthermore, we found that metformin alleviates tumor inflammation by reducing the expression of inflammatory cytokines including IL-1beta as well as infiltration and M2 polarization of tumor-associated macrophages (TAMs) in vitro and in vivo. These effects on macrophages in vitro appear to be associated with a modulation of the AMPK/STAT3 pathway by metformin. Finally, we found in our preclinical models that the alleviation of desmoplasia by metformin was associated with a reduction in ECM remodeling, epithelial-to-mesenchymal transition (EMT) and ultimately systemic metastasis. CONCLUSION: Metformin alleviates the fibro-inflammatory microenvironment in obese/diabetic individuals with pancreatic cancer by reprogramming PSCs and TAMs, which correlates with reduced disease progression. Metformin should be tested/explored as part of the treatment strategy in overweight diabetic PDAC patients. PMID- 26641269 TI - Maternal emotion socialization differentially predicts third-grade children's emotion regulation and lability. AB - Numerous parental emotion socialization factors have been implicated as direct and indirect contributors to the development of children's emotional competence. To date, however, no study has combined parents' emotion-related beliefs, behaviors, and regulation strategies in one model to assess their cumulative-as well as unique-contributions to children's emotion regulation. We considered the 2 components that have recently been distinguished: emotion regulation and emotional lability. We predicted that mothers' beliefs about the value of and contempt for children's emotions, mothers' supportive and nonsupportive reactions to their children's emotions, as well as mothers' use of cognitive reappraisal and suppression of their own emotions would each contribute unique variance to their children's emotion regulation and lability, as assessed by children's teachers. The study sample consisted of an ethnically and socioeconomically diverse group of 165 mothers and their third-grade children. Different patterns emerged for regulation and lability: Controlling for family income, child gender, and ethnicity, only mothers' lack of suppression as a regulatory strategy predicted greater emotion regulation in children, whereas mothers' valuing of children's emotions, mothers' lack of contempt for children's emotions, mothers' use of cognitive reappraisal to reinterpret events, and mothers' lack of emotional suppression predicted less lability in children. These findings support the divergence of emotion regulation and lability as constructs and indicate that, during middle childhood, children's lability may be substantially and uniquely affected by multiple forms of parental socialization. PMID- 26641268 TI - Analysis of Genetic and Non-Genetic Factors Influencing Timing and Time Perception. AB - Performance on different psychophysical tasks measuring the sense of time indicates a large amount of individual variation in the accuracy and precision of timing in the hundredths of milliseconds-to-minutes range. Quantifying factors with an influence on timing is essential to isolating a biological (genetic) contribution to the perception and estimation of time. In the largest timing study to date, 647 participants completed a duration-discrimination task in the sub-second range and a time-production task in the supra-second range. We confirm the stability of a participant's time sense across multiple sessions and substantiate a modest sex difference on time production. Moreover, we demonstrate a strong correlation between performance on a standardized cognitive battery and performance in both duration-discrimination and time-production tasks; we further show that performance is uncorrelated with age after controlling for general intelligence. Additionally, we find an effect of ethnicity on time sense, with African Americans and possibly Hispanics in our cohort differing in accuracy and precision from other ethnic groups. Finally, a preliminary genome-wide association and exome chip study was performed on 148 of the participants, ruling out the possibility for a single common variant or groups of low-frequency coding variants within a single gene to explain more than ~18% of the variation in the sense of time. PMID- 26641270 TI - Differential effects of self- and situation-focused reappraisal. AB - In the present research, we investigated the effects of self- and situation focused reappraisal, which are 2 distinct types of cognitive reappraisal, on emotion experiences, memory, and electrocortical responses to unpleasant pictures. In Study 1, situation-focused reappraisal was found to improve recall accuracy, whereas self-focused reappraisal had no effect. Both strategy types were associated with reductions in self-reported negative emotion, with larger reductions during situation-focused reappraisal. In Study 2, event-related potentials (ERPs) were measured while participants engaged in the 2 strategy types. Situation-focused, but not self-focused, reappraisal was associated with reductions in the late positive potential, an ERP that reflects facilitated attention to emotional stimuli. Taken together, these findings suggest that reappraisal is not a homogenous regulation strategy; on the contrary, subtypes of reappraisal elicit distinct consequence profiles. (PsycINFO Database Record PMID- 26641271 TI - Blushing in early childhood: Feeling coy or socially anxious? AB - Blushing has adaptive social functions. However, blushing is also assumed to be a hallmark of social anxiety and shyness. For the first time, blushing and its relation to the expressions of shyness and social anxiety was examined in early childhood. Four-and-a-half-year-old children (N = 102) were asked to perform (singing in front of an audience) and watched back their performance in the presence of that audience. Physiological blushing (blood volume pulse, blood volume, and cheek temperature) was measured, and positive (gaze and/or head aversion with smiling) and negative expressions of shyness (gaze and/or head aversion with negative facial expressions) were observed. In addition, both parents reported their child's social anxiety level. A higher level of blushing response was related to greater social anxiety in children who displayed few positive shy expressions, but not in children who displayed many positive shy expressions during the performance. Moreover, children who expressed many negative shy expressions were highly socially anxious, no matter their blushing. Our findings suggest that blushing appears to be an early indicator of social anxiety in children who are not able to successfully cope with fearful social situations. In contrast, blushing, in combination with positive shy behaviors, appears to be an adaptive social mechanism that may protect from heightened social anxiety. (PsycINFO Database Record PMID- 26641273 TI - A flexible full-information approach to the modeling of response styles. AB - We present a flexible full-information approach to modeling multiple user-defined response styles across multiple constructs of interest. The model is based on a novel parameterization of the multidimensional nominal response model that separates estimation of overall item slopes from the scoring functions (indicating the order of categories) for each item and latent trait. This feature allows the definition of response styles to vary across items as well as overall item slopes that vary across items for both substantive and response style dimensions. We compared the model with similar approaches using examples from the smoking initiative of the Patient-Reported Outcomes Measurement Information System. A small set of simulations showed that the estimation approach is able to recover model parameters, factor scores, and reasonable estimates of standard errors. Furthermore, these simulations suggest that failing to include response style factors (when present in the data generating model) has adverse consequences for substantive trait factor score recovery. (PsycINFO Database Record PMID- 26641272 TI - Interactive Effects of Early Exclusive Breastfeeding and Pre-Pregnancy Maternal Weight Status on Young Children's BMI - A Chinese Birth Cohort. AB - OBJECTIVES: To assess if the maternal pre-pregnancy weight status (MPWS) alters the association of early infant feeding pattern (at one and third months) with infant body mass index (BMI) in the first two years of life. METHODS: A cohort of 2,220 neonates were recruited in a community-based study conducted in China. Body weight and length were measured at birth, at age one and two, with BMI calculated accordingly. The BMI z-scores (BMI-Z) were computed according to the World Health Organization Growth Standard (2006). Feeding patterns were classified as exclusive breastfeeding (EBF), mixed feeding (MF), and formula feeding (FF). General linear models (GLM) were employed to estimate main and interaction effects of EBF and MPWS on children's BMI-Z. RESULTS: No main effect of MPWS was found on child BMI-Z at ages one and two, nor the feeding patterns. An interaction between MPWS and feeding patterns was detected (p<0.05). For children who were formula fed during the first month, those who were born to overweight/obesity (OW/OB) mothers had a significantly greater BMI-Z at ages one and two, compared with those with underweight/normal weight (UW/NW) mothers. FF children had greater BMI-Z at ages one and two compared with their EBF and MF counterparts, when they were born to OW/OB mothers. CONCLUSIONS: Maternal pre pregnancy weight control and early initiation of EBF for children are essential for healthy development in children's BMI, hence the prevention of early life obesity. PMID- 26641274 TI - Weakened N3 Hydrogen Bonding by 5-Formylcytosine and 5-Carboxylcytosine Reduces Their Base-Pairing Stability. AB - In the active cytosine demethylation pathway, 5-methylcytosine (5mC) is oxidized sequentially to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5 carboxylcytosine (5caC). Thymine DNA glycosylase (TDG) selectively excises 5fC and 5caC but not cytosine (C), 5mC, and 5hmC. We propose that the electron withdrawing properties of -CHO and -COOH in 5fC and 5caC increase N3 acidity, leading to weakened hydrogen bonding and reduced base pair stability relative to C, 5mC, and 5hmC, thereby facilitating the selective recognition of 5fC and 5caC by TDG. Through (13)C NMR, we measured the pKa at N3 of 5fC as 2.4 and the two pKa's of 5caC as 2.1 and 4.2. We used isotope-edited IR spectroscopy coupled with density functional theory (DFT) calculations to site-specifically assign the more acidic pKa of 5caC to protonation at N3, indicating that N3 acidity is increased in 5fC and 5caC relative to C. IR and UV melting studies of self-complementary DNA oligomers confirm reduced stability for 5fC-G and 5caC-G base pairs. Furthermore, while the 5fC-G base pair stability is insensitive to pH, the 5caC-G stability is reduced as pH decreases and the carboxyl group is increasingly protonated. Despite suggestions that 5fC and 5caC may exist in rare tautomeric structures which form wobble GC base pairs, our two-dimensional infrared (2D IR) spectroscopy of 5fC and 5caC free nucleosides confirms that both bases are predominantly in the canonical amino-keto form. Taken together, these findings support our model that weakened base pairing ability for 5fC and 5caC in dsDNA contributes to their selective recognition by TDG. PMID- 26641275 TI - Developing Universal Genetic Tools for Rapid and Efficient Deletion Mutation in Vibrio Species Based on Suicide T-Vectors Carrying a Novel Counterselectable Marker, vmi480. AB - Despite that Vibrio spp. have a significant impact on the health of humans and aquatic animals, the molecular basis of their pathogenesis is little known, mainly due to the limited genetic tools for the functional research of genes in Vibrio. In some cases, deletion of target DNAs in Vibrio can be achieved through the use of suicide vectors. However, these strategies are time-consuming and lack universality, and the widely used counterselectable gene sacB does not work well in Vibrio cells. In this study, we developed universal genetic tools for rapid and efficient deletion mutations in Vibrio species based on suicide T-Vectors carrying a novel counterselectable marker, vmi480. We explored two uncharacterized genes, vmi480 and vmi470, in a genomic island from Vibrio mimicus VM573 and confirmed that vmi480 and vmi470 constitute a two-component toxin antitoxin system through deletion and expression of vmi480 and vmi470. The product of vmi480 exhibited strong toxicity to Escherichia coli cells. Based on vmi480 and the PBAD or PTAC promoter system, we constructed two suicide T vectors, pLP11 and pLP12, and each of these vectors contained a multiple cloning region with two AhdI sites. Both vectors linearized by AhdI digestion could be stored and directly ligated with purified PCR products without a digestion step. By using pLP11 and pLP12 coupled with a highly efficient conjugation system provided by E. coli beta2163, six genes from four representative Vibrio species were easily deleted. By using the counterselective marker vmi480, we obtained 3 12 positive colonies (deletion mutants) among no more than 20 colonies randomly selected on counterselection plates. The strategy does not require the digestion of PCR products and suicide vectors every time, and it avoids large-scale screening colonies on counterselective plates. These results demonstrate that we successfully developed universal genetic tools for rapid and efficient gene deletion in Vibrio species. PMID- 26641276 TI - Distillation Time as Tool for Improved Antimalarial Activity and Differential Oil Composition of Cumin Seed Oil. AB - A steam distillation extraction kinetics experiment was conducted to estimate essential oil yield, composition, antimalarial, and antioxidant capacity of cumin (Cuminum cyminum L.) seed (fruits). Furthermore, regression models were developed to predict essential oil yield and composition for a given duration of the steam distillation time (DT). Ten DT durations were tested in this study: 5, 7.5, 15, 30, 60, 120, 240, 360, 480, and 600 min. Oil yields increased with an increase in the DT. Maximum oil yield (content, 2.3 g/100 seed), was achieved at 480 min; longer DT did not increase oil yields. The concentrations of the major oil constituents alpha-pinene (0.14-0.5% concentration range), beta-pinene (3.7-10.3% range), gamma-cymene (5-7.3% range), gamma-terpinene (1.8-7.2% range), cumin aldehyde (50-66% range), alpha-terpinen-7-al (3.8-16% range), and beta-terpinen-7 al (12-20% range) varied as a function of the DT. The concentrations of alpha pinene, beta-pinene, gamma-cymene, gamma-terpinene in the oil increased with the increase of the duration of the DT; alpha-pinene was highest in the oil obtained at 600 min DT, beta-pinene and gamma-terpinene reached maximum concentrations in the oil at 360 min DT; gamma-cymene reached a maximum in the oil at 60 min DT, cumin aldehyde was high in the oils obtained at 5-60 min DT, and low in the oils obtained at 240-600 min DT, alpha-terpinen-7-al reached maximum in the oils obtained at 480 or 600 min DT, whereas beta-terpinen-7-al reached a maximum concentration in the oil at 60 min DT. The yield of individual oil constituents (calculated from the oil yields and the concentration of a given compound at a particular DT) increased and reached a maximum at 480 or 600 min DT. The antimalarial activity of the cumin seed oil obtained during the 0-5 and at 5-7.5 min DT timeframes was twice higher than the antimalarial activity of the oils obtained at the other DT. This study opens the possibility for distinct marketing and utilization for these improved oils. The antioxidant capacity of the oil was highest in the oil obtained at 30 min DT and lowest in the oil from 360 min DT. The Michaelis-Menton and the Power nonlinear regression models developed in this study can be utilized to predict essential oil yield and composition of cumin seed at any given duration of DT and may also be useful to compare previous reports on cumin oil yield and composition. DT can be utilized to obtain cumin seed oil with improved antimalarial activity, improved antioxidant capacity, and with various compositions. PMID- 26641277 TI - Genetic Risk and the Development of Autoimmune Liver Disease. AB - Primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH) have collectively been recognized as autoimmune liver diseases. They have all been subjected to genome-wide association studies (GWAS) and several dozens susceptibility loci have been determined. The predominant feature of the genetic findings is that of a strong association with the human leukocyte antigen (HLA) and numerous weak associations scattered throughout the remainder of the genome. The non-HLA associations show some degree of overlap, not only between PBC, PSC and AIH, but also with other autoimmune and immune mediated diseases. Mathematical modelling shows that the main fraction of autoimmune disease risk (including that of autoimmune liver diseases) is not explained by GWAS, proposing a major role of environmental factors. The HLA associations and autoantibodies observed in these conditions may hold clues as to the nature of such factors, which are exceedingly difficult to map by means of epidemiological study designs. The present review article explores the potential relationship between genetic risk as determined by GWAS and environmental risk in autoimmune liver diseases, and proposes a model for relevant thinking on the susceptibility genes in PBC, PSC and AIH. PMID- 26641278 TI - Hydrazonyl Radical-Participated Tandem Reaction: A Strategy for the Synthesis of Pyrazoline-Functionalized Oxindoles. AB - An efficient and practical tandem cyclization/addition/cyclization strategy is developed for the initial generated hydrazonyl radicals derived from the oxidation of beta,gamma-unsaturated hydrazones. By using this protocol, structurally novel pyrazoline-functionalized oxindoles are prepared by the reaction of easily accessible beta,gamma-unsaturated hydrazones with N-aryl acrylamides under the metal- and solvent-free conditions of DTBP (di-tert-butyl peroxide) via a tandem intra/intermolecular C-N/C-C/C-C bond formation. PMID- 26641279 TI - Enthalpy-Entropy Compensation (EEC) Effect: A Revisit. AB - A short account of the developments and perspectives of IKR (iso-kinetic relation) and EEC (enthalpy (H) - entropy (S) compensation) has been presented. The IKR and EEC are known to be extra thermodynamic or empirical correlations though linear H-S correlation can be thermodynamically deduced. Attempt has also been made to explain the phenomena in terms of statistical thermodynamics. In this study, we have briefly revisited the fundamentals of both IKR and EEC from kinetic and thermodynamic grounds. A detailed revisit of the EEC phenomenon on varied kinetic and equilibrium processes has been also presented. Possible correlations among the free energy (DeltaG), enthalpy (DeltaH), and entropy (DeltaS) changes of different similar and nonsimilar chemical processes under varied conditions have been discussed with possible future projections. PMID- 26641280 TI - Effects of the sugarcane dietary fiber and pre-emulsified sesame oil on low-fat meat batter physicochemical property, texture, and microstructure. AB - The purpose of this study was to evaluate the effects of sugarcane dietary fiber (SDF) and pre-emulsified sesame oil for pork fat replacement on batter characteristics. Replacing pork fat with SDF and pre-emulsified sesame oil significantly affected color, water- and fat-binding properties, texture, dynamic rheology, microstructure and sensory analysis. With SDF and pre-emulsified sesame oil, the batters had improved textures and gave good sensory scores. These batters containing SDF had reduced the cholesterol and fat contents. With increasing levels of SDF, the batters had higher water- and fat-binding properties, improved texture (hardness, gumminess and chewiness), dynamic rheology and a more balanced nutritional composition. However, when the level of SDF reached 3%, the pores formed by SDF in batter were too large to hinder aggregation and the hardness of batter was unacceptable, which result the allover acceptability to be unsatisfactory. The sample 2% SDF had comparable overall acceptability to the control batter. PMID- 26641281 TI - A novel fluorescent probe for Cr(3+) based on rhodamine-crown ether conjugate and its application to drinking water examination and bioimaging. AB - A trivalent chromium (Cr(3+)) fluorescence probe (RhC) was designed and synthesized via Schiff base reaction based on rhodamine-crown ether conjugate. This probe displayed a favorable selectivity for Cr(3+) over a range of other common metal ions in DMF/H2O (3:7, v/v; PBS buffer 50 mmol L(-1); pH=6.8) solution, leading to prominent fluorescence "OFF-ON" switching of the rhodamine fluorophore. The limit of detection was calculated to be 1.5 MUmol L(-1) (S/N=3). The binding ratio of RhC-Cr(3+) complex was determined to be 1:2 according to the Job's plot and HR-MS. The probe was successfully applied to examination of Cr(3+) in drinking water spiked samples. The average recoveries ranged from 104.9% to 106.9% at spiked concentration level of 10.00 MUmol L(-1), and the obtained results were consistent with those obtained using atomic absorption spectrometry (AAS). Moreover, bioimaging experiments showed that RhC can sense the Cr(3+) in living cells with a fluorescence enhancement signal. PMID- 26641282 TI - A simple and rapid method for direct determination of Al(III) based on the enhanced resonance Rayleigh scattering of hemin-functionalized graphene-Al(III) system. AB - A novel method for direct determination of Al(III) by using hemin-functionalized graphene (H-GO) has been established based on the enhancement of resonance Rayleigh scattering (RRS) intensity. The characteristics of RRS spectra, the optimum reaction conditions, and the reaction mechanism have been investigated. In this experiment, the Al(III) would exist in sol-gel Al(OH)3 species under the condition of pH5.9 in aqueous solutions. When H-GO existed in the solution, the sol-gel Al(OH)3 would react with H-GO and result in enhancement of RRS intensity, owing to the enhanced hydrophobicity of H-GO surface. Therefore, a simple and rapid sensor for Al(III) was developed. The increased intensity of RRS is directly proportional to the concentration of Al(III) in the range of 10 nM-6 MUM, along with a detection limit of 0.87 nM. Moreover, the sensor has been applied to determination of Al(III) concentration in real water and aspirin tablet samples with satisfactory results. Therefore, the proposed method is promising as an effective means for selective and sensitive determination of Al(III). PMID- 26641283 TI - Aggregation of Congo red with surfactants and Ag-nanoparticles in an aqueous solution. AB - Self aggregation, sorption, and interaction of Congo red, with cetyltrimethylammonium bromide (CTAB), sodium dodecylsulfate (SDS), Ag(+) ions and silver nanoparticles have been determined spectrophotometrically. Congo red self-aggregation was identified from UV-visible spectra due to the shrinkage in an absorption band at 495 nm. The shape of the absorbance spectrum changed entirely with increasing [Congo red] but wavelength maxima remain unchanged. The molar absorptivity was found to be 9804 mol(-1) dm(3) cm(-1) at 495 nm. Absorption spectra of Congo red with Ag(+) ions show an isosbestic point. The complex formation constant and difference in absorption coefficients were found to be 8.5 * 10(4) mol(-1) dm(3) and 11,764 mol(-1) dm(3) cm(-1), respectively. Silver nano-particles could not be used for the catalytic degradation of Congo red because it results in the formation of a strong complex with them. Sodium dodecylsulfate did not show any significant interaction with this dye. Congo red was also used as a probe to determine the critical micellar concentration of CTAB. PMID- 26641284 TI - The efficiency of micro-Raman spectroscopy in the analysis of complicated mixtures in modern paints: Munch's and Kupka's paintings under study. AB - Twenty one mock-up samples containing inorganic pigments primarily used at the turn of the 19th and 20th century were selected for comparative study and measured by micro-Raman and portable Raman spectrometers. They included pure grounds (chalk-based, earth-based and lithopone-based), grounds covered by resin based varnish, and different paint layers containing mixtures of white, yellow, orange, red, green, blue and black pigments, usually in combination with white pigments (titanium, zinc and barium whites or chalk). In addition, ten micro samples obtained from seven paintings of two world-famous modern painters Edvard Munch and Frantisek Kupka have been investigated. Infrared reflection spectroscopy (FTIR), portable X-ray fluorescence (XRF) and scanning electron microscopy with energy dispersive spectroscopy (SEM-EDS) were used as supplementary methods. The measurements showed that blue pigments (ultramarine, Prussian blue and azurite), vermilion and ivory black in mixture with whites provided characteristic Raman spectra, while Co-, Cd- and Cr- pigments' bands were suppressed by fluorescence. The best success rate of micro-Raman spectroscopy has been achieved using the 780 nm excitation, however, the sensitivity of this excitation laser in a portable Raman instrument significantly decreased. The analyses of micro-samples of paintings by E. Munch and F. Kupka showed that micro-Raman spectroscopy identified pigments which would remain unidentified if analyzed only by SEM-EDS (zinc yellow, Prussian blue). On the other hand, chromium oxide green and ultramarine were not detected together in a sample due to overlap of their main bands. In those cases, it is always necessary to complement Raman analysis with other analytical methods. PMID- 26641285 TI - Raman, SEM-EDS and XRPD investigations on pre-Columbian Central America "estucado" pottery. AB - Seventeen different colored fragments from six selected pre-Columbian estucado ceramics from El Salvador have been investigated by Raman spectroscopy, scanning electron microscope coupled to an energy dispersive spectrometer (SEM/EDS) and X ray powder diffraction (XRPD). The peculiarity of this kind of ceramics consist of the unusual presence of a white engobe, traditionally termed stucco, between the ceramic body and the decoration elements, hence the name estucado ceramics. The aim of this work was to study the unusual manufacturing technique and to identify the chemical composition of the engobe and of the pigment palette. The results showed that the stucco layer is made of clay (kaolinite) with traces of titanium oxide (anatase). Remarkably, this is the same composition of the white pigments used for the decoration layer, thus excluding an early use of natural titanium oxide as a white pigment in the estucado productions as suggested in previous investigations. Moreover, the presence of kaolinite and anatase both in the stucco and in the decoration layer suggests a cold-working or low temperature technique. The red, yellow and green decorations were realized by the use of natural ochre, while in all the blue and gray decorations Maya blue pigment was identified. Finally, an amorphous carbon pigment of vegetal origin and manganese oxide were used to obtain black pigments. PMID- 26641286 TI - Effect of genetic algorithm as a variable selection method on different chemometric models applied for the analysis of binary mixture of amoxicillin and flucloxacillin: A comparative study. AB - Different chemometric models were applied for the quantitative analysis of amoxicillin (AMX), and flucloxacillin (FLX) in their binary mixtures, namely, partial least squares (PLS), spectral residual augmented classical least squares (SRACLS), concentration residual augmented classical least squares (CRACLS) and artificial neural networks (ANNs). All methods were applied with and without variable selection procedure (genetic algorithm GA). The methods were used for the quantitative analysis of the drugs in laboratory prepared mixtures and real market sample via handling the UV spectral data. Robust and simpler models were obtained by applying GA. The proposed methods were found to be rapid, simple and required no preliminary separation steps. PMID- 26641287 TI - Importance of Ion Packing on the Dynamics of Ionic Liquids during Micropore Charging. AB - Molecular simulations of the diffusion of EMIM(+) and TFSI(-) ions in slit-shaped micropores under conditions similar to those during charging show that in pores that accommodate only a single layer of ions, ions diffuse increasingly faster as the pore becomes charged (with diffusion coefficients even reaching ~5 * 10(-9) m(2)/s), unless the pore becomes very highly charged. In pores wide enough to fit more than one layer of ions, ion diffusion is slower than in the bulk and changes modestly as the pore becomes charged. Analysis of these results revealed that the fast (or slow) diffusion of ions inside a micropore during charging is correlated most strongly with the dense (or loose) ion packing inside the pore. The molecular details of the ions and the precise width of the pores modify these trends weakly, except when the pore is so narrow that the ion conformation relaxation is strongly constrained by the pore walls. PMID- 26641288 TI - Computational (59)Co NMR Spectroscopy: Beyond Static Molecules. AB - GIAO-B3LYP computations of (59)Co NMR chemical shifts are reported for CoH(CO)4, Co(CO)4(-), CoCp(C2H4)2, Co(CN)6(3)(-), Co(NH3)3(CN)3, Co(NH3)6(3+), Co(NH3)4(CO3)(+), Co(acac)3, and Co(H2O)6(3+), employing both static calculations for equilibrium geometries as well as methods which include zero-point and classical thermal effects. The zero-point effects were computed by applying a perturbational approach, and the classical thermal effects were evaluated using Car-Parrinello molecular dynamics simulations. Both methods lead to a downfield shift of delta((59)Co) with respect to the equilibrium values, which can be attributed to a large extent to cobalt-ligand bond elongation. In some cases the zero-point and classical thermal corrections improve the agreement between computed and experimental values, but especially for complexes where the experimental NMR data were obtained in aqueous solution, the error increases somewhat. Mean absolute deviations between averaged and experimental delta((59)Co) values are on the order of 500-760 ppm over a chemical shift range of almost 20 000 ppm. The computed structures and properties of three Co2(CO)8 tautomers reproduce the experimental data very well. Two transition states for interconversion of these tautormers were located: low barriers are obtained, consistent with the observed fluxionality on the NMR time scale. Two model cobaloximes were taken as test cases to study the change of delta((59)Co) upon deuteration three bonds away from the metal. The sizable downfield shift of delta((59)Co) observed on going from H to D is attributed to a changed vibrational wave function, which causes a noticeable cobalt-ligand bond elongation. PMID- 26641289 TI - Understanding the Cosolvation Effect of Dendrimers. AB - Molecules that are virtually insoluble in certain solvents may be uploaded to "hostile" phases by dendrimers. Prime examples of this phenomenon are Eosin Y, EY, and Rose Bengal, RB, that are not soluble in CH2Cl2 where they can, however, be solvated through the interaction with a fourth generation dendrimer of polypropylene amine, POPAM-4D. The two dyes share the same carbon framework and differ for the pattern of halogenation, and yet their cosolvation varies over a factor of 4: six Eosin Y and ~25 Rose Bengals are solvated by the macromolecule. Leveraging on a previous report where molecular dynamics simulations of 12 EY@POPAM-4D in CH2Cl2 showed a reduction to the experimental limit of 6, we now perform similar calculations with an excess, i.e., 40, of RB@POPAM-4D. The simulations quantitatively reproduce the cosolvation effect. They also provide a microscopic understanding of its origin and of motions-interactions of the macromolecule and both of its guests. PMID- 26641290 TI - Direct Dynamics Studies on the Hydrogen Abstraction Reactions of an F Atom with CH3X (X = F, Cl, and Br). AB - The hydrogen abstraction reactions of F + CH3F (R1), F + CH3Cl (R2), and F + CH3Br (R3) are investigated by the dual-level direct dynamics method. Optimized geometries and frequencies of all the stationary points and extra points along the minimum-energy path (MEP) are obtained at the MP2/6-311G(d, p) level of theory, and then the energy profiles are refined at the CCSD(T)/6-311++G(3df, 2pd) level of theory. The basis set superposition error (BSSE) on the energy changes is corrected by means of the counterpoise method. Using the variational transition state theory (VTST) with the inclusion of the small-curvature tunneling correction, the rate constants are calculated over a wide temperature range of 189-2000 K. It is found that the activation energies for the title reactions are on the order of R1 > R2 > R3 and the rate constants exhibit just the opposite order of k3 > k2 > k1. Both the activation energies and the rate constants show the clear-cut linear correlations with the hardness eta of the halomethane molecules. Good agreement between the calculated and experimental rate constants is obtained at the measured temperatures. Furthermore, we hope that the theoretical studies for these compounds can give further information concerning the effects of halogen substitution on the rate constants of this class of hydrogen abstraction reactions. PMID- 26641291 TI - Hierarchical Numerical Solution of Smoluchowski Equations with Rough Potentials. AB - We present an efficient and numerically robust algorithm to follow diffusive processes on rough potential energy surfaces. The hierarchical nature of the algorithm (hierarchical discrete approximation or HDA) fully explores the fine- and coarse-grained structure of the underlying interaction potential. The present approach does not impose any restriction on the topology of the potential. The hierarchical grid allows to capture the roughness of the potential and achieve significant reduction of computational time using fewer grid points compared to other DA methods. HDA is shown to be accurate and efficient by comparing with results from the conventional DA and from the "mean first passage time" (MFPT) method. Using potential-optimized grids HDA monotonically converges to results from an analytical treatment for a very rough interaction potential (107 minima). Contrary to MFPT the solution from HDA is numerically stable. Because of the hierarchical structure of the method HDA can be extended to multidimensional problems. PMID- 26641292 TI - A Theoretical Study on the Factors Influencing Cyanine Photoisomerization: The Case of Thiacyanine in Gas Phase and in Methanol. AB - The effects influencing cyanine photoisomerization on the S1 surface in the condensed phase have been investigated by an integrated quantum mechanical approach, focused mainly on 3,3'-diEt-2,2'-thiacyanine. After excitation, a barrierless motion, involving the torsion coupled to bond skeletal deformation, leads to a slightly nonplanar local C2 minimum, which we propose to be the fluorescent state. Crossed a barrier of ~120 cm(-)(1), a steeper path drives to a more stable C1 minimum S1-Min, corresponding to a pseudoperpendicular twisted intramolecular charge transfer (TICT) state. CAS(6,6) optimization allows for locating the lowest energy S1/S0 conical intersection in the isomerization path which is reached from S1-Min by an increased asymmetry of the two rings and a marked pyramidalization at one N center. The S1 surface is rather flat in the Franck-Condon region and suggests that other paths can be competitive with the minimum energy one. The comparison among different cyanines shows how variation of the molecular scaffold and/or of its substituents modulate the dynamics of the photoisomerization. All the indications coming from our computations are in line with and provide an explanation to the available experimental results. PMID- 26641293 TI - Ab Initio and DFT Conformational Studies of Propanal, 2-Butanone, and Analogous Imines and Enamines. AB - The potential energy surfaces (PES) of 2-butanone, 2-butanimine, 1-butenamine, propanal, and propanimine have been explored with ab initio and DFT calculations at the RHF/6-311G**, MP2/6-311G**, and B3LYP/6-311G** levels of theory. In agreement with previous experimental and computational results, the PES provides two minima for each of the above molecules with the exception of 2-butanone, which clearly shows three distinct minima. Factors influencing the conformational preferences are also elaborated. Our calculations suggest that for 2-butanone and propanal, the steric and the bond dipole interactions are primarily responsible for the conformational preferences of these compounds. Additional charge-charge interactions might also play an important role in determining the imine conformations. For enamines, however, steric interactions play a critical role, with bond dipole interactions exerting some influence. Our results also suggest that for imine formation from butanone and/or propanal, the imine is the predominant product, not the enamine, which is consistent with experimental observations. Therefore, these calculations should provide a better understanding of the ketone/aldehyde to imine and enamine transformations. This transformation may introduce an important imine moiety for the analogues of trans-N-methyl-4-(1 naphthylvinyl)pyridine (NVP), a choline acetyltransferase (ChAT) inhibitor. PMID- 26641294 TI - Theoretical Surface Spectroscopy of NO on the Pt(111) Surface with the DAM (Dipped Adcluster Model) and the SAC-CI (Symmetry-Adapted-Cluster Configuration Interaction) Method. AB - Theoretical surface spectroscopy for NO on the Pt(111) surface is carried out and combined with the experimentally known facts to elucidate the structures, absorption sites, absorption energies and K-shell binding energies of NO adsorbates on the surface. The electronic structures were studied by using the dipped adcluster model (DAM) for chemisorptions on a metal surface proposed previously and the symmetry-adapted-cluster configuration-interaction (SAC-CI) method, which is an established method for studying molecular spectroscopy. The natures of the two different adsorption species suggested experimentally have clearly been identified based on the studies on the geometries, vibrational frequencies, adsorption energies, and the N and O K-shell binding energies. The PES (potential energy surface) of NO on the metal surface was also calculated. The most stable adsorption species was on the fcc or the hcp hollow site, and the on-top one was less stable. The 2-fold bridge site did not have a minimum on the PES and therefore was only transient. The inter NO interactions at higher densities were shown to be rather weak. We examined the cluster model (CM) vs the DAM as a model of the surface adsorption on a metal surface. The CM was shown to be unable to describe the adsorption of NO on a metal surface, demonstrating the importance of the electron transfer between the NO and Pt surfaces included in the DAM. The DAM and the SAC-CI methods proved to be a useful tool for studying the nature, electronic structure, and the spectroscopic properties of the adsorbates on a metal surface. PMID- 26641295 TI - Pseudospectral Local Second-Order Moller-Plesset Methods for Computation of Hydrogen Bonding Energies of Molecular Pairs. AB - We present a methodology for computing the binding energy of molecular dimers based on extrapolation of pseudospectral local second-order Moller-Plesset (MP2), or PS-LMP2, energies to the basis set limit. The extrapolation protocol is based on carrying out PS-LMP2 calculations with the Dunning cc-pVTZ (-f) and cc-pVQZ ( g) basis sets and then using a simple two-parameter function to compute the final basis set limit results. The function is parametrized to ultralarge basis set MP2 calculations for 5 molecular pairs taken from the literature and then tested by calculating results for a set of formamide dimers for which such calculations have also been carried out. The results agree to within ca. 0.2 kcal/mol with the conventional MP2 large basis set calculations. A specialized, but relatively simple, protocol is described for eliminating noise due to overcompleteness of the basis set. Timing results are presented for the LMP2 calculations, and comparisons are made with the LMP2 methodology of the QChem program. CPU time required by each of the methods scales as N(3), where N is the number of the basis functions, with the PS-LMP2 approach displaying a 2- to 3-fold advantage in the prefactor. We also discuss one set of test cases for which the PS-LMP2 results disagree with those obtained from an alternative type of MP2 calculation, N-methyl acetamide (NMA) dimers, and show that the results for liquid-state simulations using polarizable parameters derived by fitting to the PS-LMP2 binding energies appear to produce better results when compared with experimental data. The convergence issues associated with the alternative MP2 formulation remain to be investigated. PMID- 26641296 TI - Connecting Pauling and Mulliken Electronegativities. AB - A conversion formula between Pauling and Mulliken electronegativities is derived from a new analytic treatment of the classic valence bond model for a single bond A-B in terms of Mulliken-Jaffe "a and b" parameters for the atomic valence states. The new formula works better than the traditional linear and half-power empirical formulas. The results are consistent with an absolute Pauling scale in which both electronegativities approach zero simultaneously. PMID- 26641297 TI - An Examination of Basis Set Superposition Error at the Correlated Level: Illuminating the Role of the Exchange Repulsion. AB - A reformulated 'virtuals-only' counterpoise procedure for the correction of basis set superposition error is introduced and applied to an examination of the interaction energy of the helium dimer. This method allows a direct calculation of the exchange (Pauli) repulsion at the correlated level. Our findings suggest that at the correlated level the Pauli repulsion may be interpreted as a decrease in the monomer correlation energy calculated using the dimer virtual space relative to that with a monomer-only virtual space. This observation provides further theoretical justification for the Full Counterpoise procedure in preference to any virtuals-only counterpoise procedure. PMID- 26641298 TI - Functional Group Basis Sets. AB - The electronic properties of molecular functional groups (methyl, benzyl, etc.) are generally conserved across different molecules. However, atomic basis sets use the same electronic variational space on an element regardless of the functional group it is in. The computational expense of ab initio calculations on molecules may be reduced by constructing functional-group-specific basis sets. Our functional group (FG) basis functions are contractions over a "parent" atomic basis on all atoms in the functional group of interest. Contraction coefficients are obtained by calculating the functional group's electron density in a set of representative molecules and performing principle component analysis of the results. When the functional group's chemical identity is maintained (e.g. no bonds are broken in the group), FG basis sets provide accuracies similar to the parent basis while using a smaller number of basis functions. We demonstrate our methods by parametrizing FG basis sets for the -OH and -CH- functional groups and testing them in DFT calculations on several molecules. The results suggest that FG basis sets may be useful in many contexts, especially for treating spectator groups in mixed basis calculations. PMID- 26641299 TI - The Perfluoroadamantyl Radicals C10F15 and Their Anions. AB - The optimized geometries, electron affinities, and harmonic vibrational frequencies of perfluoroadamantyl radicals (C10F15) have been obtained using four carefully calibrated density functional theory methods in conjunction with diffuse function augmented double-zeta plus polarization (DZP++) basis sets. There are two C10F15 isomers with close energies. With the DZP++ B3LYP method, the C3v isomer (1-C10F15) lies energetically above the Cs isomer (2-C10F15) by 0.086 eV (2.0 kcal/mol), while the anionic 1-C10F15(-) isomer is predicted to lie below 2-C10F15(-) anion by 1.00 eV (23.0 kcal/mol). The DZP++ B3LYP method predicts the ZPVE-corrected adiabatic electron affinity for the C3v isomer (1 C10F15) to be 4.16 eV, and that for the Cs isomer (2-C10F15) is 3.10 eV. These EAad values are significantly larger than that (1.31 eV) of the parent molecule perfluoroadamantane (C10F16). For the 1-C10F15 radical, the C*-C bond length is shortened by 0.043 A upon removal of F from the C10F16 molecule. The C*-C bond distance for the 1-C10F15(-) anion is 0.068 A shorter than that for C10F16. Similarly, for 2-C10F15 the C*-C distance is 0.053 A shorter than for C10F16, while re(C*-C) for the anion is 0.061 A shorter than for C10F16. PMID- 26641300 TI - Activation of H-H, C-H, C-C and C-Cl Bonds by Pd and PdCl(-). Understanding Anion Assistance in C-X Bond Activation. AB - To understand the mechanism of anion assistance in palladium-catalyzed H-H, C-H, C-C and C-Cl bond activation, several mechanistic pathways for oxidative addition of Pd and PdCl(-) to H2 (H-H), CH4 (C-H), C2H6 (C-C and C-H) and CH3Cl (C-Cl) were studied uniformly at the ZORA-BP86/TZ(2)P level of relativistic nonlocal density functional theory (DFT). Oxidative addition of the neutral, uncoordinated Pd atom proceeds, as reported earlier, via direct oxidative insertion (DeltaH(?)298 is -22 to 10 kcal/mol), whereas straight SN2 substitution (yielding, e.g., PdCH3(+) + X(-)) is highly endothermic (144-237 kcal/mol) and thus not competitive. Anion assistance (i.e., going from Pd to PdCl(-)) lowers all activation barriers and increases the exothermicity of all model reactions studied. The effect is however selective: it favors the highly endothermic SN2 mechanism over direct oxidative insertion (OxIn). Activation enthalpies DeltaH(?)298 for oxidative insertion of PdCl(-) increase along C-H (-14.0 and 13.5 kcal/mol for CH4 and C2H6) ~ C-Cl (-11.2 kcal/mol) < C-C (6.4 kcal/mol), i.e., essentially in the same order as for neutral Pd. Interestingly, in case of PdCl(-) + CH3Cl, the two-step mechanism of SN2 substitution followed by leaving group rearrangement becomes the preferred mechanism for oxidative addition. The highest overall barrier of this pathway (-20.2 kcal/mol) drops below the barrier for direct oxidative insertion (-11.2 kcal/mol). The effect of anion assistance is analyzed using the Activation Strain model in which activation energies DeltaE(?) are decomposed into the activation strain DeltaE(?)strain of and the stabilizing transition state (TS) interaction DeltaE(?)int between the reactants in the activated complex: DeltaE(?) = DeltaE(?)strain + DeltaE(?)int. For each type of activated bond and reaction mechanism, the activation strain DeltaE(?)strain adopts characteristic values which differ only moderately, within a relatively narrow range, between corresponding reactions of Pd and PdCl(-). The lowering of activation barriers through anion assistance is caused by the TS interaction DeltaE(?)int becoming more stabilizing. PMID- 26641301 TI - Melting-like Transition in a Ternary Alkali Nanoalloy: Li13Na30Cs12. AB - A theoretical analysis of the equilibrium geometry and thermal behavior of the ternary Li13Na30Cs12 alkali nanoalloy is presented. The calculations are based on the orbital-free approach to density functional theory and the classical Newtonian equations to deal with the electronic and atomic subsystems, respectively. An onion-like polyicosahedral structure is found to have the lowest energy, with a core shell formed by Li atoms and an external (incomplete) surface shell formed by Cs atoms, the remaining Na atoms forming an intermediate shell. In a narrow range of 10 meV/atom above the ground-state energy, we identify several other isomers, with varying compositional and structural disorder, but all of them based on a polyicosahedral growing pattern. The most important result extracted from an analysis of thermal properties is that diffusion of Cs atoms at the surface starts at ~140 K, which is 50 K above typical surface melting temperatures of homogeneous Cs clusters. Thus we conclude that alloying may be useful in enlarging the thermodynamic stability of solid surfaces of clusters beyond its homogeneous limit. As the chemical reactivity of a cluster is known to be highly structure dependent, this observation may be especially relevant to heterogeneous catalysis and related applications. We also analyze the dynamical melting behavior of one of the higher-energy isomers and compare it to that of the ground-state structure. PMID- 26641302 TI - Linear and Nonlinear Optics Properties of Polyphosphazene/Polynitrile Alternating Copolymers. AB - The linear and nonlinear optical properties of polyphosphazene/polynitrile alternating copolymers, -(PH2 = N - CH = N)-N, are studied, at the MP2/6-31G(d) level of approximation, by using an oligomeric approach. We report the evolution with the chain length of the geometry, charges, dipole moments, polarizabilities, and first hyperpolarizabilities of two conformers (trans-transoid and trans cisoid). Comparisons with the polyphosphazene/polyacetylene and poly(thiophosphazene) structures are performed. It turns out that the polyphosphazene/polynitrile copolymers present dipole moment and polarizabilities comparable to polyphosphazene but larger (+50%) first hyperpolarizabilities. The relative response of these copolymers is comparable to the one of standard push pull systems. PMID- 26641303 TI - Molecular Dynamics Simulations of HIV-1 Protease Suggest Different Mechanisms Contributing to Drug Resistance. AB - A major problem in the antiretroviral treatment of HIV-infections with protease inhibitors is the emergence of resistance, resulting from the occurrence of distinct mutations within the protease molecule. In the present work molecular dynamics simulations of an active-site mutation (D30N) and a nonactive-site mutation (N88S) of HIV-1 protease that both directly confer resistance to the protease inhibitor Nelfinavir but not to Amprenavir were performed and compared to wild-type HIV-protease. A decreased interaction energy between protease and Nelfinavir was observed for the D30N mutant giving a plausible explanation for resistance, while the N88S mutation did not significantly affect the interaction energies in the bound form. Structural analysis including both ligand-bound and unliganded HIV-1 proteases revealed that the free N88S mutant protease shows significant differences in its hydrogen bonding pattern compared to free or Nelfinavir-bound wild-type protease. In particular, Asp30 forms more frequently a hydrogen bond with Ser88 in the unbound N88S mutant thus interfering with the Asp30-Nelfinavir interaction. These findings suggest that different molecular mechanisms contribute to resistance in active-site and nonactive-site mutants and propose a mechanism for the N88S mutant that is based on a shift of the conformational equilibrium of the unbound protease. PMID- 26641304 TI - Electrostatic Polymer Condensation and the A/B Polymorphism in DNA: Sequence Effects. AB - Dynamics of the polymorphic A<->B transitions in DNA is compared for two polypurine sequences, poly(dA).poly(dT) and poly(dG).poly(dC), long known to exhibit contrasting properties in experiments. In free molecular dynamics simulations reversible transitions are induced by changing the size of a water drop around DNA neutralized by sodium ions. In poly(dG).poly(dC) the B<->A transitions are easy, smooth and perfectly reversible. In contrast, a B->A transition in a poly(dA).poly(dT) dodecamer fragment could not be obtained even though its A-form is stable under low hydration. An intermediate range of hydration numbers is identified where opposite transitions are observed, namely, A->B in poly(dA).poly(dT) and B->A in poly(dG).poly(dC). The two sequences exhibit qualitatively different counterion distributions, with a characteristic accumulation of sodium in the major groove of poly(dG).poly(dC) and the B->A transition driven by the electrostatic condensation mechanism. The resistance of the poly(dA).poly(dT) sequence to adopting the A-form is traced to the specific steric interactions of thymine methyl groups in the major groove. With these methyls replaced by hydrogens, reversible B<->A transitions become possible and the difference between the two molecules is significantly reduced. The good overall agreement with experimental data corroborates the general role of the electrostatic condensation mechanism in the A/B polymorphism in DNA. PMID- 26641305 TI - Theoretical Study of the Antioxidant Activity of Vitamin E: Reactions of alpha Tocopherol with the Hydroperoxy Radical. AB - The reactivity of the hydroperoxy radical with alpha-tocopherol [Formula: see text] a prototype of the chemical reactions involved in biological antioxidant actions [Formula: see text] was studied theoretically. Two pathways were analyzed: hydrogen abstraction from the phenolic hydrogen and hydroperoxy addition to the aromatic ring. The reaction paths for the two mechanisms were traced independently, and the respective thermal rate constants were calculated using variational transition-state theory with multidimensional small-curvature tunneling. The reactivity of the hydroperoxy radical was found to be dominated by the hydrogen abstraction mechanism on alpha-tocopherol, with a rate constant of 1.5 * 10(5) M(-1) s(-1) at 298 K. It was also found that the mechanism of the reaction is not direct but passes through two intermediates, one of which may have a significant role in preventing the pro-oxidant effects of alpha tocopherol. PMID- 26641306 TI - Biosynthetic Studies of 13-Desmethylspirolide C Produced by Alexandrium ostenfeldii (= A. peruvianum): Rationalization of the Biosynthetic Pathway Following Incorporation of (13)C-Labeled Methionine and Application of the Odd Even Rule of Methylation. AB - Understanding the biosynthesis of dinoflagellate polyketides presents many unique challenges. Because of the remaining hurdles to dinoflagellate genome sequencing, precursor labeling studies remain the only viable way to investigate dinoflagellate biosynthesis. However, prior studies have shown that polyketide chain assembly does not follow any of the established processes. Additionally, acetate, the common precursor for polyketides, is frequently scrambled, thus compromising interpretation. These factors are further compounded by low production yields of the compounds of interest. A recent report on the biosynthesis of spirolides, a group belonging to the growing class of toxic spiroimines, provided some insight into the polyketide assembly process based on acetate labeling studies, but many details were left uncertain. By feeding (13)C methyl-labeled methionine to cultures of Alexandrium ostenfeldii, the producing organism of 13-desmethylspirolide C, and application of the odd-even methylation rule, the complete biosynthetic pathway has been established. PMID- 26641307 TI - Longitudinal relations between parental media monitoring and adolescent aggression, prosocial behavior, and externalizing problems. AB - The current study examined longitudinal relations between parental media monitoring and adolescent behavior, and explored indirect effects via sympathy and self-regulation. A sample of adolescents and their mothers from Northwestern and Mountain West cities in the USA participated in a study at three time points, approximately one year apart (N = 681; M age of child at Time 3 = 13.33, SD = 1.06; 51% female; 73% European American, 9% African American, 17% Multi-ethnic). Though findings varied by reporter, results suggested that restrictive and active media monitoring were indirectly associated with adolescents' prosocial behavior, aggression, and externalizing behavior, with restrictive monitoring being somewhat maladaptive and active monitoring adaptive. The discussion focuses on the need to examine multiple aspects of media monitoring, and highlights implications of findings for parents. PMID- 26641308 TI - Toward Infection-Resistant Surfaces: Achieving High Antimicrobial Peptide Potency by Modulating the Functionality of Polymer Brush and Peptide. AB - Bacterial infection associated with indwelling medical devices and implants is a major clinical issue, and the prevention or treatment of such infections is challenging. Antimicrobial coatings offer a significant step toward addressing this important clinical problem. Antimicrobial coatings based on tethered antimicrobial peptides (AMPs) on hydrophilic polymer brushes have been shown to be one of the most promising strategies to avoid bacterial colonization and have demonstrated broad spectrum activity. Optimal combinations of the functionality of the polymer-brush-tethered AMPs are essential to maintaining long-term AMP activity on the surface. However, there is limited knowledge currently available on this topic. Here we report the development of potent antimicrobial coatings on implant surfaces by elucidating the roles of polymer brush chemistry and peptide structure on the overall antimicrobial activity of the coatings. We screened several combinations of polymer brush coatings and AMPs constructed on nanoparticles, titanium surfaces, and quartz slides on their antimicrobial activity and bacterial adhesion against Gram-positive and Gram-negative bacteria. Highly efficient killing of planktonic bacteria by the antimicrobial coatings on nanoparticle surfaces, as well as potent killing of adhered bacteria in the case of coatings on titanium surfaces, was observed. Remarkably, the antimicrobial activity of AMP-conjugated brush coatings demonstrated a clear dependence on the polymer brush chemistry and peptide structure, and optimization of these parameters is critical to achieving infection-resistant surfaces. By analyzing the interaction of polymer-brush-tethered AMPs with model lipid membranes using circular dichroism spectroscopy, we determined that the polymer brush chemistry has an influence on the extent of secondary structure change of tethered peptides before and after interaction with biomembranes. The peptide structure also has an influence on the density of conjugated peptides on polymer brush coatings and the resultant wettability of the coatings, and both of these factors contributed to the antimicrobial activity and bacterial adhesion of the coatings. Overall, this work highlights the importance of optimizing the functionality of the polymer brush to achieve infection-resistant surfaces and presents important insight into the design criteria for the selection of polymers and AMPs toward the development of potent antimicrobial coating on implants. PMID- 26641309 TI - Structural Properties of the Acidification Products of Scandium Hydroxy Chloride Hydrate. AB - The structural properties of a series of scandium inorganic acid derivatives were determined. The reaction of Sc(0) with concentrated aqueous hydrochloric acid led to the isolation of [(H2O)5Sc(MU-OH)]24Cl.2H2O (1). Compound 1 was modified with a series of inorganic acids (i.e., HNO3, H3PO4, and H2SO4) at room temperature and found to form {[(H2O)4Sc(kappa(2)-NO3)(MU-OH)]NO3}2 (2a), [(H2O)4Sc(kappa(2) NO3)2]NO3.H2O (2b) (at reflux temperatures), {6[H][Sc(MU-PO4)(PO4)]6}n (3), and [H][Sc(MU3-SO4)2].2H2O (4a). Additional organosulfonic acid derivatives were investigated, including tosylic acid (H-OTs) to yield {[(H2O)4Sc(OTs)2]OTs}.2H2O (4b) in H2O and [(DMSO)3Sc(OTs)3] (4c) in dimethyl sulfoxide and triflic acid (H OTf) to form [Sc(H2O)8]OTf3 (4d). Other organic acid modifications of 1 were also investigated, and the final structures were determined to be {([(H2O)2Sc(MU OAc)2]Cl)6}n (5) from acetic acid (H-OAc) and [Sc(MU-TFA)3Sc(MU-TFA)3]n (6) from trifluoroacetic acid (H-TFA). In addition to single-crystal X-ray structures, the compounds were identified by solid-state and solution-state (45)Sc nuclear magnetic resonance spectroscopic studies. PMID- 26641310 TI - Antimicrobial therapy of acute diarrhoea: a clinical review. AB - Diarrhoea is one of the most commonly occurring diseases. This article presents a review of the current state of the treatment of acute infectious diarrhoea, as well as of the most important pathogens. The general principles of the therapy of diarrhoea are exemplified, followed by a description of the targeted antimicrobial therapy of the most important bacterial gastrointestinal infections, including salmonellosis, shigellosis and Campylobacter infections, as well as infections with pathogenic Escherichia coli strains, yersiniosis and cholera. Diarrhoea caused by toxigenic Clostridium difficile strains has increased in incidence and in severity. These infections will therefore be described in detail, including important new aspects of treatment. Symptomatic therapy is still the most important component of the treatment of infectious diarrhoea. However, empirical antibiotic therapy should be considered for severely ill patients with a high frequency of stools, fever, bloody diarrhoea, underlying immune deficiency, advanced age or significant comorbidities. Increasing resistance, in particular against fluoroquinolones, must be taken into consideration. Therapy with motility inhibitors is not recommended for Shiga toxin-producing Escherichia coli (STEC) infections, Clostridium difficile infections (CDI), and severe colitis. The macrocyclic antibiotic fidaxomicin can reduce the rate of recurrent disease in CDI. Furthermore, evidence for the benefits of faecal microbiota transplantation as a treatment option for multiple recurrences of CDI is increasing. In conclusion, the treatment of acute diarrhoea is still primarily supportive. General empirical antibiotic therapy for acute diarrhoea is not evidence-based. PMID- 26641311 TI - Three-dimensional force microscopy of cells in biopolymer networks. AB - We describe a technique for the quantitative measurement of cell-generated forces in highly nonlinear three-dimensional biopolymer networks that mimic the physiological situation of living cells. We computed forces of MDA-MB-231 breast carcinoma cells from the measured network deformations around the cells using a finite-element approach based on a constitutive equation that captures the complex mechanical properties of diverse biopolymers such as collagen gels, fibrin gels and Matrigel. Our measurements show that breast carcinoma cells cultured in collagen gels generated nearly constant forces regardless of the collagen concentration and matrix stiffness. Furthermore, time-lapse force measurements showed that these cells migrated in a gliding motion with alternating phases of high and low contractility, elongation, migratory speed and persistence. PMID- 26641312 TI - Radiative heat transfer in the extreme near field. AB - Radiative transfer of energy at the nanometre length scale is of great importance to a variety of technologies including heat-assisted magnetic recording, near field thermophotovoltaics and lithography. Although experimental advances have enabled elucidation of near-field radiative heat transfer in gaps as small as 20 30 nanometres (refs 4-6), quantitative analysis in the extreme near field (less than 10 nanometres) has been greatly limited by experimental challenges. Moreover, the results of pioneering measurements differed from theoretical predictions by orders of magnitude. Here we use custom-fabricated scanning probes with embedded thermocouples, in conjunction with new microdevices capable of periodic temperature modulation, to measure radiative heat transfer down to gaps as small as two nanometres. For our experiments we deposited suitably chosen metal or dielectric layers on the scanning probes and microdevices, enabling direct study of extreme near-field radiation between silica-silica, silicon nitride-silicon nitride and gold-gold surfaces to reveal marked, gap-size dependent enhancements of radiative heat transfer. Furthermore, our state-of-the art calculations of radiative heat transfer, performed within the theoretical framework of fluctuational electrodynamics, are in excellent agreement with our experimental results, providing unambiguous evidence that confirms the validity of this theory for modelling radiative heat transfer in gaps as small as a few nanometres. This work lays the foundations required for the rational design of novel technologies that leverage nanoscale radiative heat transfer. PMID- 26641314 TI - The complete mitochondrial genome of the Ptychobarbus kaznakovi (Cyprinidae: Schizothoracinae). AB - Ptychobarbus kaznakovi is endemic to the Qinghai-Tibet Plateau in China. The complete mitochondrial genome of P. kaznakovi was sequenced and characterized. The genome is 16 700 bp in length and contains 13 protein-coding genes, 2 ribosomal RNAs, 22 transfer RNAs, and a non-coding control region. The gene arrangement and nucleotide composition of the mitochondrial genome are similar to those of Cyprinidae fish. A 2 bp tandem repeat was identified in the control region. We conclude that the control region is variable in length between and within species. The complete mitochondrial DNA in this study should be used in the studies on population genetics and phylogeny of P. kaznakovi. PMID- 26641313 TI - Repairing oxidized proteins in the bacterial envelope using respiratory chain electrons. AB - The reactive species of oxygen and chlorine damage cellular components, potentially leading to cell death. In proteins, the sulfur-containing amino acid methionine is converted to methionine sulfoxide, which can cause a loss of biological activity. To rescue proteins with methionine sulfoxide residues, living cells express methionine sulfoxide reductases (Msrs) in most subcellular compartments, including the cytosol, mitochondria and chloroplasts. Here we report the identification of an enzymatic system, MsrPQ, repairing proteins containing methionine sulfoxide in the bacterial cell envelope, a compartment particularly exposed to the reactive species of oxygen and chlorine generated by the host defence mechanisms. MsrP, a molybdo-enzyme, and MsrQ, a haem-binding membrane protein, are widely conserved throughout Gram-negative bacteria, including major human pathogens. MsrPQ synthesis is induced by hypochlorous acid, a powerful antimicrobial released by neutrophils. Consistently, MsrPQ is essential for the maintenance of envelope integrity under bleach stress, rescuing a wide series of structurally unrelated periplasmic proteins from methionine oxidation, including the primary periplasmic chaperone SurA. For this activity, MsrPQ uses electrons from the respiratory chain, which represents a novel mechanism to import reducing equivalents into the bacterial cell envelope. A remarkable feature of MsrPQ is its capacity to reduce both rectus (R-) and sinister (S-) diastereoisomers of methionine sulfoxide, making this oxidoreductase complex functionally different from previously identified Msrs. The discovery that a large class of bacteria contain a single, non-stereospecific enzymatic complex fully protecting methionine residues from oxidation should prompt a search for similar systems in eukaryotic subcellular oxidizing compartments, including the endoplasmic reticulum. PMID- 26641317 TI - Studies of the Mechanism and Origins of Enantioselectivity for the Chiral Phosphoric Acid-Catalyzed Stereoselective Spiroketalization Reactions. AB - Mechanistic and computational studies were conducted to elucidate the mechanism and the origins of enantiocontrol for asymmetric chiral phosphoric acid-catalyzed spiroketalization reactions. These studies were designed to differentiate between the S(N)1-like, S(N)2-like, and covalent phosphate intermediate-based mechanisms. The chiral phosphoric acid-catalyzed spiroketalization of deuterium-labeled cyclic enol ethers revealed a highly diastereoselective syn-selective protonation/nucleophile addition, thus ruling out long-lived oxocarbenium intermediates. Hammett analysis of the reaction kinetics revealed positive charge accumulation in the transition state (rho = -2.9). A new computational reaction exploration method along with dynamics simulations supported an asynchronous concerted mechanism with a relatively short-lived polar transition state (average lifetime = 519 +/- 240 fs), which is consistent with the observed inverse secondary kinetic isotope effect of 0.85. On the basis of these studies, a transition state model explaining the observed stereochemical outcome has been proposed. This model predicts the enantioselective formation of the observed enantiomer of the product with 92% ee, which matches the experimentally observed value. PMID- 26641316 TI - Complete mitochondrial genome of Skeletonema marinoi (Mediophyceae, Bacillariophyta), a clonal chain forming diatom in the west coast of Korea. AB - The complete mitochondrial DNA of common planktonic diatom, Skeletonema marinoi JK029 was sequenced and characterized. The circular mitogenome contains 62 genes in 38 515 bp (29.7% GC), including 35 protein-coding, 2 rRNA, and 25 tRNA genes. Total 80% of protein-coding genes have usual ATG start codon and 20% have alternative start codons. The GC content of tRNA genes (39.8%) is relatively higher than those of the rRNA (32.9%) and CDS (29.3%). There are four cases of gene overlapping between neighboring genes, i.e., rrs-trnM, rps2-rps4, nad1-tatC, and rps11-trnY. Newly determined mitogenome of S. marinoi was compared with available seven diatoms and eight stramenopiles by using the maximum-likelihood analysis. The 34-CDS concatenated data (8528 amino acids) support the monophyly of Bacillariophyta. However, mitogenome data showed different higher class-levels clustering with previous study. These results suggested that additional mitogenome data will provide useful information for mitochondrial genome diversity and evolution of the diatoms and stramenopiles. PMID- 26641318 TI - Understanding respiratory syncytial virus (RSV) vaccine development and aspects of disease pathogenesis. AB - Respiratory syncytial virus (RSV) is the most important cause of lower respiratory tract infections causing bronchiolitis and some mortality in young children and the elderly. Despite decades of research there is no licensed RSV vaccine. Although significant advances have been made in understanding the immune factors responsible for inducing vaccine-enhanced disease in animal models, less information is available for humans. In this review, we discuss the different types of RSV vaccines and their target population, the need for establishing immune correlates for vaccine efficacy, and how the use of different animal models can help predict vaccine efficacy and clinical outcomes in humans. PMID- 26641319 TI - Pediatric liver diseases: current challenges and future perspectives. AB - Chronic liver diseases in children represent a rising problem with significant effects on public health. In fact, several pediatric liver diseases are precursors of adult chronic hepatopathies, cirrhosis and hepatocellular carcinoma. The prevalence of liver diseases in children is unknown. In the USA, every year, 15,000 children are hospitalized for liver diseases, but these disorders continue to be under-recognized or diagnosed late. The main reason is due to the frequent absence of symptoms in the vast majority of liver diseases, especially in the early stages. In the last few decades several advances have been made in understanding the pathogenesis of liver diseases, permitting the discovery of new therapeutic targets to treat liver diseases, thus improving the natural history of these disorders. In this article we discuss the most recent advances in the understanding of the pathogenesis, diagnosis and treatment of the most frequent pediatric liver diseases. PMID- 26641321 TI - Impacts of Enhanced-Efficiency Nitrogen Fertilizers on Greenhouse Gas Emissions in a Coastal Plain Soil under Cotton. AB - Enhanced-efficiency N fertilizers (EENFs) have the potential to increase crop yield while decreasing soil N loss. However, the effect of EENFs on greenhouse gas (GHG) emissions from different agricultural systems is not well understood. Thus, studies from a variety of locations and cropping systems are needed to evaluate their impact. An experiment was initiated on a Coastal Plain soil under cotton ( L.) production for comparing EENFs to traditional sources. Nitrogen sources included urea, ammonia sulfate (AS), urea-ammonia sulfate (UAS), controlled-release, polymer-coated urea (Environmental Smart Nitrogen [ESN]), stabilized granular urea (SuperU), poultry litter (PL), poultry litter plus AgrotainPlus (PLA), and an unfertilized control. Carbon dioxide (CO), nitrous oxide (NO), and methane (CH) fluxes were monitored regularly after fertilization through harvest from 2009 to 2011 using a closed-chamber method. Poultry litter and PLA had higher CO flux than other N treatments, while ESN and SU were generally lowest following fertilization. Nitrous oxide fluxes were highly variable and rarely affected by N treatments; PL and PLA were higher but only during the few samplings in 2010 and 2011. Methane fluxes were higher in 2009 (wet year) than 2010 or 2011, and N treatments had minimal impact. Global warming potential (GWP), calculated from cumulative GHG fluxes, was highest with PL and PLA and lowest for control, UAS, ESN, and SU. Results suggest that PL application to cotton increases GHG flux, but GHG flux reductions from EENFs were infrequently different from standard inorganic fertilizers, suggesting their higher cost may render them presently impractical. PMID- 26641322 TI - Yearlong Impact of Buried Organic Carbon on Nitrate Retention in Stream Sediments. AB - Carbon supply influences nitrogen transformation in ecosystems, but the longer term effects of buried organic carbon on nitrogen processing in stream sediments have been rarely addressed. The effects of buried particulate organic carbon (red maple leaves) on net nitrogen retention, net dissolved organic carbon (DOC) production, and pore water dissolved oxygen concentration were assessed for 1 yr in a nitrogen-rich gaining stream (Emmons Creek, WI). Retention of nitrate and total dissolved nitrogen (TDN) and production of DOC were measured by comparing groundwater fluxes of nutrients at shallow and deeper depths in mesocosms inserted in the sediments. Buried leaves caused large increases in nitrate and TDN retention and DOC production relative to the control (combusted sand) that decreased in magnitude throughout the year. Nitrate and TDN retention occurred throughout the year in unmanipulated (ambient) sediments. Dissolved oxygen approached anoxia in most mesocosms containing buried leaves and ambient sediments, particularly early in the experiment. Collectively, these results indicate that buried leaves had persistent, diminishing effects on nitrate and TDN retention throughout a 1-yr period. The TDN retention in the ambient sediments throughout the year suggests that the deep sediments in Emmons Creek are a nitrogen sink. PMID- 26641320 TI - Biocompatible, Biodegradable, and Electroactive Polyurethane-Urea Elastomers with Tunable Hydrophilicity for Skeletal Muscle Tissue Engineering. AB - It remains a challenge to develop electroactive and elastic biomaterials to mimic the elasticity of soft tissue and to regulate the cell behavior during tissue regeneration. We designed and synthesized a series of novel electroactive and biodegradable polyurethane-urea (PUU) copolymers with elastomeric property by combining the properties of polyurethanes and conducting polymers. The electroactive PUU copolymers were synthesized from amine capped aniline trimer (ACAT), dimethylol propionic acid (DMPA), polylactide, and hexamethylene diisocyanate. The electroactivity of the PUU copolymers were studied by UV-vis spectroscopy and cyclic voltammetry. Elasticity and Young's modulus were tailored by the polylactide segment length and ACAT content. Hydrophilicity of the copolymer films was tuned by changing DMPA content and doping of the copolymer. Cytotoxicity of the PUU copolymers was evaluated by mouse C2C12 myoblast cells. The myogenic differentiation of C2C12 myoblasts on copolymer films was also studied by analyzing the morphology of myotubes and relative gene expression during myogenic differentiation. The chemical structure, thermal properties, surface morphology, and processability of the PUU copolymers were characterized by NMR, FT-IR, gel permeation chromatography (GPC), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray diffraction (XRD), scanning electron microscopy (SEM), atomic force microscopy (AFM), and solubility testing, respectively. Those biodegradable electroactive elastic PUU copolymers are promising materials for repair of soft tissues such as skeletal muscle, cardiac muscle, and nerve. PMID- 26641323 TI - Effect of Wood Biochar in Manure-Applied Sand Columns on Leachate Quality. AB - Agricultural operations can pose a threat to the quality of nearby water sources particularly from nitrogen (N) and phosphorus (P) losses following land application of manure. Biochar application to soils has the potential to ameliorate degraded soils and reduce nutrient leaching to groundwater. The effects of amending sand soil columns with hybrid poplar biochar ( spp.) made by a slow-pyrolysis process at 450 degrees C at varying rates (0, 1, 2, and 5% by weight) with repeated dairy manure applications over a 56-wk period was examined to evaluate the impact to leachate water quality. Increasing levels of biochar decreased cumulative levels of total N (TN) by 21 to 59%, nitrate (NO-N) by 17 to 46%, and ammonia (NH-N + NH-N) by 46 to 90% in leachate but increased cumulative leaching of total P (TP). Overall leachate pH was increased and peak levels of 5 d biological oxygen demand (BOD) in leachate after manure application were decreased with increasing levels of biochar amendment. The results from this study indicate that biochar amendments could be effective in reducing nitrogen leaching from soils, though further study is needed to determine practical application in a field setting. PMID- 26641324 TI - Adsorption of Arsenate on Iron Oxides as Influenced by Humic Acids. AB - Humic acid (HA) and iron oxides (FeOs) commonly coexist, and their interactions alter their ability to adsorb pollutants in the environment. The influences of HA on arsenate [As(V)] adsorption on FeOs were investigated on the preformation of complexes and their coexistence with As(V) in solution. The results indicated that HA could be strongly adsorbed on FeOs, and the adsorption capacity (, mg g HA-C) followed the sequence goethite (7.73) > ferrihydrite (3.14) > hematite (2.25) with a desorption rate <1%. The HA adsorbed existed uniformly on the FeOs surfaces in spot form and did not change the x-ray diffraction (XRD) patterns of FeOs. The formation of FeOs-HA complexes altered As(V) adsorption with a reduced adsorption capacity, prolonged reaction kinetics, and enhanced adsorption strength. The As(V) adsorption on both FeOs and FeOs-HA complexes decreased with increasing pH (2.5-9) or decreasing ionic strength (0.2-0 M). The coexistence of HA in solution linearly decreased the As(V) adsorption on FeOs. Thus, our results demonstrated two impact pathways of HA on As(V) adsorption on FeOs: (i) blockage or occupation in the surface sites of FeOs if HA preformed complexes with FeOs and (ii) a competition to the surface sites of FeOs when HA coexisted with As(V) in the solution. PMID- 26641325 TI - Interactive Effects of Metal Mixtures on Seed Germination and Bioluminescence Activities based on the Theory of Probabilities. AB - The interactive effects of metal mixtures on seed germination (36 combinations) and bacterial bioluminescence (60 combinations) activities were investigated based on the theory of probabilities. Observed effects were compared with expected effects, which were calculated based on single metal activities. Different responses and sensitivities were observed depending on the types and concentrations of mixture metals as well as the organisms tested. In general, an additive mode of action (observed and expected effects are nearly same) was mostly common in the bioluminescence assay, whereas synergistic and additive inhibition modes were mostly observed in seed germination. Therefore, the mixture effects of the different bioassays could not be generalized because they were dependent on the types and concentrations of chemicals and organisms used. The results indicated that mixture, rather than single, effects by various bioassays and wide ranges of concentration combinations may comprise a better strategy for the bioassessment of contaminated environments. PMID- 26641326 TI - Phosphorus Characterization and Contribution from Eroding Streambank Soils of Vermont's Lake Champlain Basin. AB - Streambank erosion is an important contributor to sediment and nutrient export. This study determined total P (TP), soil-test P (Modified Morgan's, MM-P), and the degree of P saturation (DPS) in eroding riparian soils along four Lake Champlain Basin stream corridors. We investigated the relationship between these data and soil texture and with a series of GIS-derived landscape metrics. We also quantified the potential P load from eroding streambanks using remote sensing. Soil samples were taken from 76 erosion features to a depth of 90 cm on four streams in Chittenden County, Vermont. Mean concentrations of TP and MM-P were similar among the watersheds and through depth. Neither TP, MM-P, nor DPS were well related to texture. Metrics from available spatial databases for parent material, soil series, and landscape position were somewhat useful in predicting TP and MM-P. Eroding streambank soil from 2004 through 2007 in the four streams was estimated to contain from 0.5 to 3.9 Mg of TP and 1.4 to 10.9 kg MM-P. The mean DPS in each watershed was <18% and, along with low MM-P concentrations, suggests that eroded streambanks may act as sinks rather than sources of P. The portion of total nonpoint P export potentially contributed by streambank erosion ranged from 6% in the stream with the lowest erosion rate to 30% in the stream with the highest erosion rate. Based on TP values, the P contribution of these streambanks could be considerable, and more information is needed on their actual contribution to bioavailable P in receiving waters. PMID- 26641327 TI - Tile Drainage Density Reduces Groundwater Travel Times and Compromises Riparian Buffer Effectiveness. AB - Strategies to reduce nitrate-nitrogen (nitrate) pollution delivered to streams often seek to increase groundwater residence time to achieve measureable results, yet the effects of tile drainage on residence time have not been well documented. In this study, we used a geographic information system groundwater travel time model to quantify the effects of artificial subsurface drainage on groundwater travel times in the 7443-ha Bear Creek watershed in north-central Iowa. Our objectives were to evaluate how mean groundwater travel times changed with increasing drainage intensity and to assess how tile drainage density reduces groundwater contributions to riparian buffers. Results indicate that mean groundwater travel times are reduced with increasing degrees of tile drainage. Mean groundwater travel times decreased from 5.6 to 1.1 yr, with drainage densities ranging from 0.005 m (7.6 mi) to 0.04 m (62 mi), respectively. Model simulations indicate that mean travel times with tile drainage are more than 150 times faster than those that existed before settlement. With intensive drainage, less than 2% of the groundwater in the basin appears to flow through a perennial stream buffer, thereby reducing the effectiveness of this practice to reduce stream nitrate loads. Hence, strategies, such as reconnecting tile drainage to buffers, are promising because they increase groundwater residence times in tile drained watersheds. PMID- 26641328 TI - Remediation of Hydrocarbon-Contaminated Soil by Washing with Novel Chemically Modified Humic Substances. AB - In this work, humic (HA) and fulvic acid (FA) were chemically modified by esterification and etherification with alkanes under microwave (MW) irradiation to improve their surfactant properties for the remediation of total petroleum hydrocarbons (TPHs)-contaminated soil. Humic acid and FA were evaluated as surfactant for the remediation of soil by means of washing an aged highly TPH contaminated soil (50,000 mg TPH kg) sampled from a Mexican petrochemical area. The efficiency of chemical modification of HA and FA was increased and accelerated under MW irradiation with respect to that of conventional heating. Results showed that modified HA and FA were able to considerably reduce the contamination of TPH-polluted soils. The best results were obtained with HA modified by esterification with -dodecanol and FA modified with -decanol, which increased the hydrocarbon removal by 24 and 18%, respectively, with respect to amounts removed by the unmodified derivatives. PMID- 26641329 TI - Phosphorus Containing Water Dispersible Nanoparticles in Arable Soil. AB - Due to the limited solubility of phosphorus (P) in soil, understanding its binding in fine colloids is vital to better forecast P dynamics and losses in agricultural systems. We hypothesized that water-dispersible P is present as nanoparticles and that iron (Fe) plays a crucial role for P binding to these nanoparticles. To test this, we isolated water-dispersible fine colloids (WDFC) from an arable topsoil (Haplic Luvisol, Germany) and assessed colloidal P forms after asymmetric flow field-flow fractionation coupled with ultraviolet and an inductively coupled plasma mass spectrometer, with and without removal of amorphous and crystalline Fe oxides using oxalate and dithionite, respectively. We found that fine colloidal P was present in two dominant sizes: (i) in associations of organic matter and amorphous Fe (Al) oxides in nanoparticles <20 nm, and (ii) in aggregates of fine clay, organic matter and Fe oxides (more crystalline Fe oxides) with a mean diameter of 170 to 225 nm. Solution P-nuclear magnetic resonance spectra indicated that the organically bound P predominantly comprised orthophosphate-monoesters. Approximately 65% of P in the WDFC was liberated after the removal of Fe oxides (especially amorphous Fe oxides). The remaining P was bound to larger-sized WDFC particles and Fe bearing phyllosilicate minerals. Intriguingly, the removal of Fe by dithionite resulted in a disaggregation of the nanoparticles, evident in higher portions of organically bound P in the <20 nm nanoparticle fraction, and a widening of size distribution pattern in larger-sized WDFC fraction. We conclude that the crystalline Fe oxides contributed to soil P sequestration by (i) acting as cementing agents contributing to soil fine colloid aggregation, and (ii) binding not only inorganic but also organic P in larger soil WDFC particles. PMID- 26641330 TI - Measuring Leaf Penetration and Volatilization of Chlorothalonil and Epoxiconazole Applied on Wheat Leaves in a Laboratory-Scale Experiment. AB - Estimation of pesticide volatilization from plants is difficult because of our poor understanding of foliar penetration by pesticides, which governs the amount of pesticide available for volatilization from the leaf surface. The description of foliar penetration is still incomplete because experimental measurements of this complex process are difficult. In this study, the dynamics of leaf penetration of C-chlorothalonil and C-epoxiconazole applied to wheat leaves were measured in a volatilization chamber, which allowed us to simultaneously measure pesticide volatilization. Fungicide penetration into leaves was characterized using a well-defined sequential extraction procedure distinguishing pesticide fractions residing at different foliar compartments; this enabled us to accurately measure the penetration rate constant into the leaves. The effect of pesticide formulation was also examined by comparing formulated and pure epoxiconazole. We observed a strong effect of formulation on leaf penetration in the case of a systemic product. Furthermore, the penetration rate constant of formulated epoxiconazole was almost three times that of pure epoxiconazole (0.47 +/- 0.20 and 0.17 +/- 0.07, respectively). Our experimental results showed high recovery rates of the radioactivity applied within the range of 90.5 to 105.2%. Moreover, our results confirm that pesticide physicochemical properties are key factors in understanding leaf penetration of pesticide and its volatilization. This study provides important and useful parameters for mechanistic models describing volatilization of fungicides applied to plants, which are scarce in the literature. PMID- 26641331 TI - Bluejoint Is an Effective Bio-Barrier Species on Mine Covers. AB - Covers with capillary barrier effects (CCBE) are used to prevent acid mine drainage from mine wastes in the short term. However, the long-term efficiency of CCBE can be affected by trees because their roots may reduce the ability of covers to limit oxygen migration and also physically damage the CCBE. Two plant species that are native to boreal Canada, bluejoint () and sheep laurel (, were selected as bio-barrier species (BBS) to test if they reduce the growth and root system architecture of trees established on mine covers (balsam poplar [], willow [ spp], and black spruce []). The experiment was established in 2008 on a mine tailings impoundment located in northwestern Quebec, Canada. Trees were measured for height, diameter, and biomass. Coarse roots were excavated from the plots and digitized in three dimensions. Compared with the control (no BBS), bluejoint strongly decreased tree height and diameter increment, biomass, maximum root depth and radial extension, total root length and volume, and number of second- and third-order tree roots. Height and diameter increment, biomass, maximum root depth and volume, and number of second-order roots of balsam poplar increased with sheep laurel compared with control conditions, whereas willow showed no response to this treatment. Most characteristics of black spruce (except root-to shoot ratio and number of second-order roots) improved in the presence of sheep laurel compared with the control. Thus, bluejoint was a more efficient BBS than sheep laurel. Bio-barriers comprised of bluejoint can be used as a countermeasure for controlling tree invasion of CCBE. PMID- 26641332 TI - Quantitative Reconstruction of Sulfur Deposition Using a Mixing Model Based on Sulfur Isotope Ratios in Tree Rings. AB - Quantification of sulfur (S) deposition is critical to deciphering the environmental archive of S in terrestrial ecosystems. Here we propose a mixing model that quantifies S deposition based on the S isotope ratio (deltaS) in tree rings. We collected samples from Japanese cedar ( D. Don) stumps from two sites: one near Yokkaichi City (YOK), which is well known for having the heaviest S air pollution in the world, and one at Inabu-cho (INA) in central Japan, which has been much less affected by air pollution. The deltaS profiles at both sites are consistent with S air pollution and contributions of anthropogenic S. The minimum value in YOK is lower than the deltaS values of anthropogenic S or any other possible source. Because the deltaS in the tree rings is affected by fractionation in the forest ecosystems, we used a mixing model to account for the isotope effects and to distinguish the sources of S. Based on the model results, we infer that the peak of S emissions at YOK occurred sometime between the late 1960s and early 1970s (489 mmol m yr). This estimated value is comparable with the highest reported values in Europe. This is the first quantitative estimate of anthropogenic input of S in forest systems based on deltaS in tree rings. Our results suggest that tree ring data can be used when monitoring stations of atmospheric S are lacking and that estimates of S deposition using deltaS in tree rings will advance our understanding of the local-scale S dynamics and the effect of human activities on it. PMID- 26641333 TI - Evaluation of Three Models for Simulating Pesticide Runoff from Irrigated Agricultural Fields. AB - Three models were evaluated for their accuracy in simulating pesticide runoff at the edge of agricultural fields: Pesticide Root Zone Model (PRZM), Root Zone Water Quality Model (RZWQM), and OpusCZ. Modeling results on runoff volume, sediment erosion, and pesticide loss were compared with measurements taken from field studies. Models were also compared on their theoretical foundations and ease of use. For runoff events generated by sprinkler irrigation and rainfall, all models performed equally well with small errors in simulating water, sediment, and pesticide runoff. The mean absolute percentage errors (MAPEs) were between 3 and 161%. For flood irrigation, OpusCZ simulated runoff and pesticide mass with the highest accuracy, followed by RZWQM and PRZM, likely owning to its unique hydrological algorithm for runoff simulations during flood irrigation. Simulation results from cold model runs by OpusCZ and RZWQM using measured values for model inputs matched closely to the observed values. The MAPE ranged from 28 to 384 and 42 to 168% for OpusCZ and RZWQM, respectively. These satisfactory model outputs showed the models' abilities in mimicking reality. Theoretical evaluations indicated that OpusCZ and RZWQM use mechanistic approaches for hydrology simulation, output data on a subdaily time-step, and were able to simulate management practices and subsurface flow via tile drainage. In contrast, PRZM operates at daily time-step and simulates surface runoff using the USDA Soil Conservation Service's curve number method. Among the three models, OpusCZ and RZWQM were suitable for simulating pesticide runoff in semiarid areas where agriculture is heavily dependent on irrigation. PMID- 26641334 TI - Measuring the Contribution of Agricultural Conservation Practices to Observed Trends and Recent Condition in Water Quality Indicators in Ohio, USA. AB - Over the last three decades, significant investments made to upgrade wastewater infrastructure and manage pollution from diffuse sources have resulted in measurably improved water quality and biological conditions in Ohio's rivers and streams. Conservation measures to reduce soil loss appear to have contributed significantly to the improvement witnessed over the last two decades and should therefore be continued. Within the most recent timeframe examined, little difference was found in either total phosphorus or suspended sediment concentration in relation to conservation measures, indicating that the environmental benefits of measures targeting soil loss may be approaching an asymptote. Conservation measures targeting livestock and forage management, however, appear to have reduced nitrogen concentrations within the recent time frame. An examination of the interrelationships between habitat quality, conservation measures, and land use indicated that water quality was generally mediated by interactions with stream habitat quality. However, the positive effect of habitat quality was reduced in catchments draining fine-textured soils. The implication of these latter two findings suggest that proscriptively adding natural function to the large network of ditched and maintained conveyances draining agricultural lands would substantially improve water quality, but management at the field level is necessary to minimize phosphorus losses. PMID- 26641335 TI - Impacts of Lithological and Anthropogenic Factors Affecting Water Chemistry in the Upper Paraguay River Basin. AB - Located in the Upper Paraguay River Basin (UPRB), the Pantanal is considered the world's largest wetland, being rather pristine although increasingly threatened by development programs. The main objective of this paper is to provide a baseline of water chemistry for this region, which is largely unknown as a result of poor accessibility. We used two datasets (70 and 122 water samples) collected in the Pantanal floodplain and surrounding uplands during the wet season occurring from November to March. From the major-ion mineral chemistry, dissolved silica, pH, electrical conductivity (EC), and the ionic forms of N, principal components analysis (PCA) treatments were used to identify and rank the main factors of variability and decipher the associated processes affecting the water chemistry. The results revealed that the water mineral concentration was a major factor of variability and it must be attributed first to lithology and second to agricultural inputs from extensive crop cultivation areas that mainly affects sulfate (SO) concentration on the eastern edge of the Pantanal. These processes influence the floodplain, where (i) the mixing of waters remains the main process, (ii) the weight of the biological and redox processes increased, and (iii) the chemical signature of the extensive cropping is transferred along the Sao Lourenco Basin down to its confluence with the Cuiaba River. Optimized parameters based on projections in the main factorial score plots were used for the mapping of lithological and agricultural impacts on water chemistry. PMID- 26641336 TI - Analysis for Regression Model Behavior by Sampling Strategy for Annual Pollutant Load Estimation. AB - Water quality data are typically collected less frequently than streamflow data due to the cost of collection and analysis, and therefore water quality data may need to be estimated for additional days. Regression models are applicable to interpolate water quality data associated with streamflow data and have come to be extensively used, requiring relatively small amounts of data. There is a need to evaluate how well the regression models represent pollutant loads from intermittent water quality data sets. Both the specific regression model and water quality data frequency are important factors in pollutant load estimation. In this study, nine regression models from the Load Estimator (LOADEST) and one regression model from the Web-based Load Interpolation Tool (LOADIN) were evaluated with subsampled water quality data sets from daily measured water quality data sets for N, P, and sediment. Each water quality parameter had different correlations with streamflow, and the subsampled water quality data sets had various proportions of storm samples. The behaviors of the regression models differed not only by water quality parameter but also by proportion of storm samples. The regression models from LOADEST provided accurate and precise annual sediment and P load estimates using the water quality data of 20 to 40% storm samples. LOADIN provided more accurate and precise annual N load estimates than LOADEST. In addition, the results indicate that avoidance of water quality data extrapolation and availability of water quality data from storm events were crucial in annual pollutant load estimation using pollutant regression models. PMID- 26641337 TI - 4R Water Quality Impacts: An Assessment and Synthesis of Forty Years of Drainage Nitrogen Losses. AB - The intersection of agricultural drainage and nutrient mobility in the environment has led to multiscale water quality concerns. This work reviewed and quantitatively analyzed nearly 1,000 site-years of subsurface tile drainage nitrogen (N) load data to develop a more comprehensive understanding of the impacts of 4R practices (application of the right source of nutrients, at the right rate and time, and in the right place) within drained landscapes across North America. Using drainage data newly compiled in the "Measured Annual Nutrient loads from AGricultural Environments" (MANAGE) database, relationships were developed across N application rates for nitrate N drainage loads and corn ( L.) yields. The lack of significant differences between N application timing or application method was inconsistent with the current emphasis placed on application timing, in particular, as a water quality improvement strategy ( = 0.934 and 0.916, respectively). Broad-scale analyses such as this can help identify major trends for water quality, but accurate implementation of the 4R approach will require site-specific knowledge to balance agronomic and environmental goals. PMID- 26641338 TI - Comparison of Surface Water Quality and Yields from Organically and Conventionally Produced Sweet Corn Plots with Conservation and Conventional Tillage. AB - Organic agricultural systems are often assumed to be more sustainable than conventional farming, yet there has been little work comparing surface water quality from organic and conventional production, especially under the same cropping sequence. Our objective was to compare nutrient and sediment losses, as well as sweet corn ( L. var. ) yield, from organic and conventional production with conventional and conservation tillage. The experiment was located in the Appalachian Mountains of North Carolina. Four treatments, replicated four times, had been in place for over 18 yr and consisted of conventional tillage (chisel plow and disk) with conventional production (CT/Conven), conservation no-till with conventional production (NT/Conven), conventional tillage with organic production (CT/Org), and conservation no-till with organic production (NT/Org). Water quality (surface flow volume; nitrogen, phosphorus, and sediment concentrations) and sweet corn yield data were collected in 2011 and 2012. Sediment and sediment-attached nutrient losses were influenced by tillage and cropping system in 2011, due to higher rainfall, and tillage in 2012. Soluble nutrients were affected by the nutrient source and rate, which are a function of the cropping system. Sweet corn marketable yields were greater in conventional systems due to high weed competition and reduced total nitrogen availability in organic treatments. When comparing treatment efficiency (yield kg ha /nutrient loss kg ha ), the NT/Conven treatment had the greatest sweet corn yield per unit of nutrient and sediment loss. Other treatment ratios were similar to each other; thus, it appears the most sustainably productive treatment was NT/Conven. PMID- 26641339 TI - Approximating Phosphorus Leaching from Agricultural Organic Soils by Soil Testing. AB - Phosphorus applied to soils in excess of crop requirement could create situations favorable to P enrichment in subsurface flow that contributes to eutrophication of surface water. This pathway of P loss can be more severe in muck (i.e., organic) soils where agricultural production is intensive. This study evaluated the suitability of various environmental and agronomic soil P tests initially designed for mineral soils to predict dissolved reactive P (DRP) in subsurface flow from organic soils. Intact soil columns were collected from 44 muck soils in Ontario to provide a wide range of soil test P levels. A lysimeter leaching study was conducted by evenly adding water in an amount equivalent to 5 mm of rainfall. The leachate DRP concentration was linearly related to soil water-extractable P and CaCl-extractable P with values of 0.90 and 0.93, respectively, and to Bray-1 P and FeO-impregnated filter paper extractable P in a split-line model with a change point. Mehlich-3 P and Olsen P, a method recommended for agronomic P calibration in Ontario, were not related to leachate DRP concentration. All P sorption index (PSI) based degree of P saturation (DPS) values were closely related to leachate DRP in split-line models, with the DPS indices expressed as Bray-1 P/PSI and FeO-P/PSI having the highest correlation with leachate DRP concentration. Because it is desirable from practical and economic standpoints that the environmental risk assessment shares the same soil test with agronomic P calibration, the two PSI-based DPS indices as presented can be considered as environmental risk indicators of DRP subsurface loss from organic soils. PMID- 26641340 TI - Moisture Effects on Nitrogen Availability in Municipal Biosolids from End-of-Life Municipal Lagoons. AB - Nitrogen (N) availability affects plant biomass yield and, hence, phytoextraction of contaminants during phytoremediation of end-of-life municipal lagoons. End-of life lagoons are characterized by fluctuating moisture conditions, but the effects on biosolid N dynamics have not been adequately characterized. This 130-d laboratory incubation investigated effects of three moisture levels (30, 60, and 90% water-filled pore space [WFPS]) on N mineralization (N) in biosolids from a primary (PB) and a secondary (SB) municipal lagoon cell. Results showed a net increase in N with time at 60% WFPS and a net decrease at 90% WFPS in PB, while N at 30% WFPS did not change significantly. Moisture level and incubation time had no significant effect on N in SB. Nitrogen mineralization rate in PB followed three-half-order kinetics. Potentially mineralizable N (N) in PB was significantly greater at 60% WFPS (222 mg kg) than at 30% WFPS (30 mg kg), but rate constants did not differ significantly between the moisture levels. Nitrogen mineralization in SB followed first-order kinetics, with N significantly greater at 60% WFPS (68.4 mg kg) and 90% WFPS (94.1 mg kg) than at 30% WFPS (32 mg kg). Low N in SB suggests high-N-demanding plants may eventually have limited effectiveness to remediate biosolids in the secondary cell. While high N in PB would provide sufficient N to support high biomass yield, phytoextraction potential is reduced under dry and near-saturated conditions. These results have important implications on the management of moisture during phytoextraction of contaminants in end-of-life municipal lagoons. PMID- 26641341 TI - Management Practices Affect Soil Nutrients and Bacterial Populations in Backgrounding Beef Feedlot. AB - Contaminants associated with manure in animal production sites are of significant concern. Unless properly managed, manure-derived soil nutrients in livestock production sites can deteriorate soil and water quality. This 3-yr study evaluated a soil nutrient management strategy with four sequentially imposed management practices: 12-mo backgrounding (BG), manure removal from the feeder area (FD), 12-mo destocking (DS), and 12-mo grass hay harvesting (H) in a small backgrounding feedlot. Resulting soil nutrient levels, total (), and N cycling bacterial ( and ) populations after each management practice in feedlot feeder and grazing (GR) areas and in crop grown at the control location (CT) were measured. Irrespective of management practice, FD contained greater soil nutrient concentrations than the GR and CT. Regardless of management practice, total bacteria cells (1.4 * 10 cells g soil) and nitrate reducers (5.2 * 10 cells g soil) were an order of magnitude higher in the FD than in the GR and CT, whereas nitrifying bacteria concentrations (1.4 * 10 cells g soil) were higher in the GR. Manure removal from the feeder area reduced M3-P (39%), total C (21%), total N (23%), NH-N (47%), and NO-N (93%) levels established in the FD during BG. Destocking lowered total C and N (45%) in the FD and NH-N (47%), NO-N (76%), and Zn (16%) in the GR. Hay harvesting reduced all soil nutrients in the FD and GR marginally. The management strategy has potential to lower soil nutrient concentrations, control soil nutrient buildup, and limit nutrient spread within the feedlot. PMID- 26641342 TI - Multiple Applications of Sodium Bisulfate to Broiler Litter Affect Ammonia Release and Litter Properties. AB - Ammonia (NH) emissions from animal manures can cause air and water quality problems. Poultry litter treatment (PLT, sodium bisulfate; Jones-Hamilton Co.) is an acidic amendment that is applied to litter in poultry houses to decrease NH emissions, but currently it can only be applied once before birds are placed in the houses. This project analyzed the effect of multiple PLT applications on litter properties and NH release. Volatility chambers were used to compare multiple, single, and no application of PLT to poultry litter, all with and without fresh manure applications. A field component consisted of two commercial broiler houses: one had a single, preflock PLT application, while the other received PLT reapplications during the flock using an overhead application system. In the volatility chambers, single and reapplied PLT caused greater litter moisture and lower litter pH and , relative to no PLT. After 14 d, NH released from litter treated with reapplied PLT was significantly less than litter with both single and no applications. Furthermore, total N in litter was greatest in litter treated with reapplied PLT, increasing its fertilizer value. In the commercial poultry houses, PLT reapplication led to a temporary decrease in litter pH and , but these effects did not last because of continued bird excretion. Although one preflock PLT application is currently used as a successful strategy to control NH during early flock growth, repeat PLT application using the overhead reapplication system was not successful because of problems with the reapplication system and litter moisture concerns. PMID- 26641343 TI - Evaluation of Soil Manipulation to Prepare Engineered Earthen Waste Covers for Revegetation. AB - Seven ripping treatments designed to improve soil physical conditions for revegetation were compared on a test pad simulating an earthen cover for a waste disposal cell. The field test was part of study of methods to convert compacted soil waste covers into evapotranspiration covers. The test pad consisted of a compacted layer of fine-textured soil simulating a barrier protection layer overlain by a gravelly sand bedding layer and a cobble armor layer. Treatments included combinations of soil-ripping implements (conventional shank [CS], wing tipped shank [WTS], and parabolic oscillating shank with wings [POS]), ripping depths, and number of passes. Dimensions, dry density, moisture content, and particle size distribution of disturbance zones were determined in two trenches excavated across rip rows. The goal was to create a root-zone dry density between 1.2 and 1.6 Mg m and a seedbed soil texture ranging from clay loam to sandy loam with low rock content. All treatments created V-shaped disturbance zones as measured on trench faces. Disturbance zone size was most influenced by ripping depth. Winged implements created larger disturbance zones. All treatments lifted fines into the bedding layer, moved gravel and cobble down into the fine-textured protection layer, and thereby disrupted the capillary barrier at the interface. Changes in dry density within disturbance zones were comparable for the CS and WTS treatments but were highly variable among POS treatments. Water content increased in the bedding layer and decreased in the protection layer after ripping. The POS at 1.2-m depth and two passes created the largest zone with a low dry density (1.24 Mg m) and the most favorable seedbed soil texture (gravely silt loam). However, ripping also created large soil aggregates and voids in the protection layer that may produce preferential flow paths and reduce water storage capacity. PMID- 26641344 TI - Stacking Time and Aluminum Sulfate Effects on Polyether Ionophores in Broiler Litter. AB - The use of ionophores as antiparasitic drugs plays an important role in US poultry production, especially in the broiler () industry. However, administered ionophores can pass through the bird's digestive system and appear in broiler litter, which, when applied to agricultural fields, can present an environmental hazard. Stacking (storing or stockpiling) broiler litter for some time might decrease the litter ionophore concentrations before land application. Because ionophores undergo abiotic hydrolysis at low pH, decreasing litter pH with acidic aluminum sulfate (alum) might also decrease ionophore concentrations. We assessed the change in ionophore concentrations in broiler litter in response to the length of time broiler litter was stored (stacking time) and alum addition. We spiked broiler litter with monensin and salinomycin, placed alum-amended litter (~pH 4-5) and unamended litter (~pH 8-9) into 1.8-m bins, and repeatedly sampled each bin for 112 d. Our findings showed that stacking broiler litter alone did not have an impact on monensin concentration, but it did slowly reduce salinomycin concentration by 55%. Adding alum to broiler litter reduced monensin concentration by approximately 20% relative to unamended litter, but it did not change salinomycin concentration. These results call for continued search for alternative strategies that could potentially reduce the concentration of ionophores in broiler litter before their application to agricultural soils. PMID- 26641345 TI - Subsurface Band Application of Poultry Litter and Its Influence on Phosphorus Concentration and Retention after Runoff from Permanent Pastures. AB - Excessive phosphorus (P) loss from agricultural fields is a major cause of eutrophication to rivers, lakes, and streams. To mitigate P loss after poultry litter (PL) applications, technology is being developed to apply litter below the soil surface. Thus, research was conducted to evaluate the effects of subsurface PL banding on soil P under pasture management. Treatments consisted of surface broadcasted or subsurface-banded PL (38 cm apart) at 9 Mg ha, surface-broadcasted commercial fertilizer (CF; urea and triple superphosphate blend) at N (330 kg N ha) and P (315 kg N ha) application rates equivalent to PL, and a nonfertilized control. Runoff events lasting 40 min were simulated in bermudagrass ( L.) pastures on common soil types of the Coastal Plain and Piedmont regions. One day later, Mehlich-1 and water-soluble P concentrations in soil were measured at depths of 0 to 5 cm and 5 to 10 cm to determine P distribution and movement. The greatest P concentrations were observed at the shallow depth for all treatments. Phosphorus measurements at the point of application for PL bands were greater than for the surface-applied treatments (PL and CF) and control. Measurements between subsurface PL bands were slightly higher than the control but were statistically similar, suggesting that this application method can abate short term P movement. Results obtained from this study show that subsurface band applying PL could increase P retention and reduce movement by precluding contact between surface water and litter nutrients. PMID- 26641346 TI - Effects of Produced Water on Soil Characteristics, Plant Biomass, and Secondary Metabolites. AB - The Powder River Basin in Wyoming and Montana contains the United States' largest coal reserve. The area produces large amounts of natural gas through extraction from water-saturated coalbeds. Determining the impacts of coalbed natural gas produced efflux water on crops is important when considering its potential use as supplemental irrigation water. We hypothesized that coalbed natural gas water, because of its high salinity and sodicity, would affect plant secondary metabolism (essential oils) and biomass accumulation. A 2-yr field study was conducted in Wyoming to investigate the effects of produced water on two traditional bioenergy feedstocks-corn ( L.) and switchgrass ( L.)-and four novel biofuel feedstock species-spearmint ( L.), Japanese cornmint ( L.), lemongrass [ (Nees ex Steud.) J.F. Watson]), and common wormwood ( L.). The four nontraditional feedstock species were chosen because they contain high-value plant chemicals that can offset production costs. Essential oil content was significantly affected by coalbed natural gas water in lemongrass and spearmint. Oil content differences between two spearmint harvests in the same year indicated that there were significant changes between the growth stage of the plant and essential oil content; the first harvest averaged 0.42 g of oil per 100 g biomass while the second harvest (harvested before flowering) yielded only 0.19 g oil per 100 g dry biomass. Results indicated that produced water can be used for short period (2 yr) irrigation of crops. However, prolonged use of untreated produced water for irrigation would likely have deleterious long-term effects on the soil and plants unless the water was treated or diluted (mixed) with good-quality water. PMID- 26641347 TI - Persistence of the Sulfonylurea Herbicides Sulfosulfuron, Rimsulfuron, and Nicosulfuron in Farm Dugouts (Ponds). AB - Sulfonylurea herbicides are applied at relatively low rates (3-40 g ha) to control weeds in a variety of crops grown in the prairie pothole region of south central Canada. Because of their high phytotoxicity and the likelihood of their transport in surface runoff, there is concern about impacts of sulfonylurea herbicides to wetland ecosystems embedded in agricultural landscapes. In a previous study, dissipation half-lives (DT values) were determined for three sulfonylurea herbicides (thifensulfuron-methyl, ethametsulfuron-methyl, and metsulfuron-methyl), each possessing a hydrolyzable methyl ester linkage. In the current study, persistence of three sulfonylurea herbicides without a methyl ester linkage was determined in prairie farm dugouts (ponds). The dugouts were fortified with environmentally relevant concentrations (3.3-6.5 MUg L) of either sulfosulfuron, rimsulfuron, or nicosulfuron. The order of persistence of these herbicides in dugout water from May and June to November and December was nicosulfuron > sulfosulfuron > rimsulfuron, with DT values of 75, 44, and 10 d, respectively. The lack of a methyl ester linkage in these herbicides did not significantly affect their overall persistence relative to those with the ester linkage. In all three dugouts, the decrease in herbicide mass in the water column from water loss via hydrological discharge to groundwater was minimal. The relatively long persistence of these herbicides in the water column of the dugouts reflects the stability of the sulfonylurea linkage to hydrolysis in weakly alkaline waters and indicates not only that microbial and photolytic degradation were low but also that there was little partitioning into sediments. PMID- 26641348 TI - Evaluation of Legacy Phosphorus Storage and Release from Wetland Soils. AB - To better manage legacy phosphorus (P) in watersheds, reliable techniques to predict P storage and release from uplands, ditches, streams, and wetlands must be developed. Techniques such as the P saturation ratio (PSR) and the soil P storage capacity (SPSC), originally developed for upland soils, are hypothesized to be applicable to wetland soils as well. Surface soils were collected from eight beef ranches within the Lake Okeechobee Watershed, FL, to obtain a threshold PSR value and to evaluate the use of PSR and SPSC for identifying legacy P storage and release from wetland soils. Water-soluble P (WSP) was determined for all soils; the equilibrium P concentration (EPC) was determined for selected soils through the generation of Langmuir isotherms. The threshold PSR for wetland soils, calculated from P, Fe, and Al in a Mehlich 1 solution, was determined to be 0.1; SPSC, calculated using the threshold PSR, was found to be related to WSP. When SPSC was positive, WSP and EPC were minimal. However, both WSP and EPC increased once SPSC became negative. Organic matter (OM) varied from 0.4 to 90 g kg for both positive and negative SPSC, suggesting that OM in wetland soils does not have any effect on P retention and release below the threshold PSR. Moreover, when a wetland or drainage ditch is heavily P impacted, it could be a P source; wetland vegetation may no longer be able to assimilate additional P, resulting in P loss from the soil. This study suggests that the PSR-SPSC concept could be a valuable tool for evaluating legacy P release from wetlands. PMID- 26641349 TI - Performance of Seasonally and Continuously Loaded Constructed Wetlands Treating Dairy Farm Wastewater. AB - A 2-yr study compared the performance of seasonally and continuously loaded constructed wetlands treating dairy farm wastewater. One wetland was loaded during the growing season (GS) periods only, while the other was continuously loaded. Weekly samples were analyzed for 5-d biochemical oxygen demand (BOD), total suspended solids (TSS), total Kjeldahl N (TKN), total ammoniacal N (TAN), total P (TP), and . Annual average daily mass removal rates (kg ha) were similar for both wetlands in both years; however, seasonal differences were observed. With the exception of BOD in Year 2, average daily GS areal mass removal rates were higher for the seasonal wetland. However, GS mass exports from the seasonal wetland were higher by 28 to 94%, with the exception of BOD in Year 1. Annual mass reductions (MRs; %) for nutrients were higher for the continuous wetland in both years. Annual MRs were similar for in both years and for TSS in Year 2. Annual mass exports from the seasonal wetland were higher for nutrients and by 14 to 77% in both years. Pollutant MRs generally decreased during the nongrowing season (NGS) for the continuous wetland; however, in Year 2 when lower loading rates were used, the wetland still removed 84 to 99% of the pollutant masses. The continuous wetland also performed better during periods of high flow that occurred during the GS. Although there were minimal differences in annual treatment performance, continuously loaded systems require less additional infrastructure and should require less maintenance and may, therefore, be more attractive for agricultural applications. PMID- 26641350 TI - A Snapshot of Greenhouse Gas Emissions from a Cattle Feedlot. AB - Beef cattle feedlots emit large amounts of the greenhouse gases (GHG) methane (CH) and nitrous oxide (NO), as well as ammonia (NH), which contributes to NO emission when NH is deposited to land. However, there is a lack of simultaneous, in situ, and nondisturbed measurements of the major GHG gas components from beef cattle feedlots, or measurements from different feedlot sources. A short-term campaign at a beef cattle feedlot in Victoria, Australia, quantified CH, NO, and NH emissions from the feedlot pens, manure stockpiles, and surface run-off pond. Open-path Fourier transform infrared (OP-FTIR) spectrometers and open-path lasers (OP-Laser) were used with an inverse-dispersion technique to estimate emissions. Daily average emissions of CH, NO, and NH were 132 (+/- 2.3 SE), 0, and 117 (+/- 4.5 SE) g animal d from the pens and 22 (+/- 0.7 SE), 2 (+/- 0.2 SE), and 9 (+/- 0.6 SE) g animal d from the manure stockpiles. Emissions of CH and NH from the run-off pond were less than 0.5 g animal d. Extrapolating these results to the feedlot population of cattle across Australia would mean that feedlots contribute approximately 2% of the agricultural GHG emissions and 2.7% of livestock sector emissions, lower than a previous estimate of 3.5%. PMID- 26641354 TI - Communicating With Patients--The Other Side of the Conversation. PMID- 26641355 TI - Appropriate Screening for Substance Use vs Disorder. PMID- 26641356 TI - Communicating With Patients--The Other Side of the Conversation--Reply. PMID- 26641357 TI - Appropriate Screening for Substance Use vs Disorder--Reply. PMID- 26641358 TI - Distinguishing Between Substance Use and Substance Use Disorder. PMID- 26641359 TI - Organ Donation and New Policies: Do We Need to Act Less Generally and More Locally? PMID- 26641360 TI - Organ Donation and New Policies: Do We Need to Act Less Generally and More Locally? PMID- 26641361 TI - Demographic Prevalence of Class III Obesity. PMID- 26641362 TI - Organ Donation and New Policies--Reply: Do We Need to Act Less Generally and More Locally? PMID- 26641363 TI - Demographic Prevalence of Class III Obesity--Reply. PMID- 26641364 TI - Neighborhoods and Risk of Diabetes Mellitus: Person and Place or Person in Place? PMID- 26641365 TI - Neighborhoods and Risk of Diabetes Mellitus--Reply: Person and Place or Person in Place? PMID- 26641366 TI - Telemedicine in Prehospital Stroke Evaluation and Thrombolysis: Taking Stroke Treatment to the Doorstep. AB - IMPORTANCE: Mobile stroke treatment units (MSTUs) with on-site treatment teams that include a vascular neurologist can provide thrombolysis in the prehospital setting faster than treatment in the hospital. These units can be made more resource efficient if the need for an on-site neurologist can be eliminated by relying solely on telemedicine for physician presence. OBJECTIVE: To test whether telemedicine is reliable and remote physician presence is adequate for acute stroke treatment using an MSTU. DESIGN, SETTING, AND PARTICIPANTS: Prospective observational study conducted between July 18 and November 1, 2014. The dates of the study analysis were November 1, 2014, to March 30, 2015. The setting was a community-based study assessing telemedicine success of the MSTU in Cleveland, Ohio. Participants were the first 100 residents of Cleveland who had an acute onset of stroke-like symptoms between 8 am and 8 pm and were evaluated by the MSTU after the implementation of the MSTU program at the Cleveland Clinic. A vascular neurologist evaluated the first 100 patients via telemedicine, and a neuroradiologist remotely assessed images obtained by mobile computed tomography (CT). Data were entered into the medical record and a prospective registry. MAIN OUTCOMES AND MEASURES: The study compared the evaluation and treatment of patients on the MSTU with a control group of patients brought to the emergency department via ambulance during the same year. Process times were measured from the time the patient entered the door of the MSTU or emergency department, and any problems encountered during his or her evaluation were recorded. RESULTS: Ninety-nine of 100 patients were evaluated successfully. The median duration of telemedicine evaluation was 20 minutes (interquartile range [IQR], 14-27 minutes). One connection failure was due to crew error, and the patient was transported to the nearest emergency department. There were 6 telemedicine disconnections, none of which lasted longer than 60 seconds or affected clinical care. Times from the door to CT completion (13 minutes [IQR, 9-21 minutes]) and from the door to intravenous thrombolysis (32 minutes [IQR, 24-47 minutes]) were significantly shorter in the MSTU group compared with the control group (18 minutes [IQR, 12-26 minutes] and 58 minutes [IQR, 53-68 minutes], respectively). Times to CT interpretation did not differ significantly between the groups. CONCLUSIONS AND RELEVANCE: An MSTU using telemedicine is feasible, with a low rate of technical failure, and may provide an avenue for reducing the high cost of such systems. PMID- 26641368 TI - Progress feedback and the OQ-system: The past and the future. AB - A serious problem in routine clinical practice is clinician optimism about the benefit clients derive from the therapy that they offer compared to measured benefits. The consequence of seeing the silver lining is a failure to identify cases that, in the end, leave treatment worse-off than when they started or are simply unaffected. It has become clear that some methods of measuring, monitoring, and providing feedback to clinicians about client mental health status over the course of routine care improves treatment outcomes for clients at risk of treatment failure (Shimokawa, Lambert, & Smart, 2010) and thus is a remedy for therapist optimism by identifying cases at risk for poor outcomes. The current article presents research findings related to use of the Outcome Questionnaire-45 and Clinical Support Tools for this purpose. The necessary characteristics of feedback systems that work to benefit client's well-being are identified. In addition, suggestions for future research and use in routine care are presented. PMID- 26641367 TI - Sexual Risk Behavior Among Virologically Detectable Human Immunodeficiency Virus Infected Young Men Who Have Sex With Men. AB - IMPORTANCE: Human immunodeficiency virus (HIV) diagnoses continue to increase among young men who have sex with men (YMSM). Many YMSM living with HIV engage in sexual risk behaviors, and those who have a detectable viral load can transmit HIV to sex partners. Understanding factors that are related to sexual risk taking among virologically detectable (VL+) YMSM can inform prevention and treatment efforts. OBJECTIVES: To describe differences between virologically suppressed (VL ) and VL+ YMSM living with HIV and to identify correlates of condomless anal intercourse (CAI) and serodiscordant CAI among VL+ YMSM. DESIGN, SETTING, AND PARTICIPANTS: In this cross-sectional survey conducted from December 1, 2009, through June 30, 2012, we studied 991 HIV-infected YMSM 15 to 26 years of age at 20 adolescent HIV clinics in the United States. Data analysis was conducted December 1, 2013, through July 31, 2015. MAIN OUTCOMES AND MEASURES: Demographic, behavioral, and psychosocial assessments obtained using audio computer-assisted self-interviews. Viral load information was obtained via blood draw or medical record abstraction. RESULTS: Of the 991 participants, 688 (69.4%) were VL+ and 458 (46.2%) reported CAI, with 310 (31.3%) reporting serodiscordant CAI in the past 3 months. The VL+ YMSM were more likely than the VL- YMSM to report CAI (detectable, 266 [54.7%]; suppressed, 91 [44.4%]; P = .01) and serodiscordant CAI (detectable, 187 [34.9%]; suppressed, 57 [25.0%]; P < .01). Multivariable analyses indicated that among VL+ YMSM, those reporting problematic substance use were more likely to report CAI (adjusted odds ratio [AOR], 1.46; 95% CI, 1.02 2.10) and serodiscordant CAI (AOR, 1.45; 95% CI, 1.06-1.99). Black VL+ YMSM were less likely to report CAI (AOR, 0.63; 95% CI, 0.44-0.90) or serodiscordant CAI (AOR, 0.66; 95% CI, 0.46-0.94) compared with other VL+ YMSM. In addition, VL+ YMSM who disclosed their HIV status to sex partners were more likely to report CAI compared with nondisclosing YMSM (AOR, 1.35; 95% CI, 1.01-1.81). Transgender participants were less likely to report CAI than cisgender participants (AOR, 0.35; 95% CI, 0.14-0.85). Last, VL+ YMSM who reported currently being employed were less likely to report serodiscordant CAI than those who were unemployed (AOR, 0.74; 95% CI, 0.55-0.99). CONCLUSIONS AND RELEVANCE: Targeted multilevel interventions are needed to reduce HIV transmission risk behaviors among YMSM living with HIV, particularly among those who are VL+. PMID- 26641369 TI - The Partners for Change Outcome Management System (PCOMS) revisiting the client's frame of reference. AB - Despite overall psychotherapy efficacy (Lambert, 2013), many clients do not benefit (Reese, Duncan, Bohanske, Owen, & Minami, 2014), dropouts are a problem (Swift & Greenberg, 2012), and therapists vary significantly in success rates (Baldwin & Imel, 2013), are poor judges of negative outcomes (Chapman et al., 2012), and grossly overestimate their effectiveness (Walfish, McAlister, O'Donnell, & Lambert, 2012). Systematic client feedback offers 1 solution (Duncan, 2014). Several feedback systems have emerged (Castonguay, Barkham, Lutz, & McAleavey, 2013), but only 2 have randomized clinical trial support and are included in the Substance Abuse and Mental Health Administration's National Registry of Evidence-Based Programs and Practices: The Outcome Questionnaire-45.2 System (Lambert, 2010) and the Partners for Change Outcome Management System (PCOMS; Duncan, 2012). This article presents the current status of PCOMS, the psychometrics of the PCOMS measures, its empirical support, and its clinical and training applications. Future directions and implications of PCOMS research, training, and practice are detailed. Finally, we propose that systematic feedback offers a way, via large-scale data collection, to reprioritize what matters to psychotherapy outcome, reclaim our empirically validated core values and identity, and change the conversation from a medical model dominated discourse to a more scientific, relational perspective. PMID- 26641370 TI - A CORE approach to progress monitoring and feedback: Enhancing evidence and improving practice. AB - This article describes the Clinical Outcomes in Routine Evaluation (CORE) System and reports on its scientific yield and practice impact. First, we describe the suite of CORE measures, including the centerpiece CORE-Outcome Measure (CORE-OM), its short forms, special purpose forms, translations, and psychometric properties, along with the pretreatment CORE Therapy Assessment Form and the CORE End of Therapy Form. Second, we provide an overview of the scientific yield arising from analyses of large CORE data sets collected in routine practice. Third, we describe the use of CORE measures for feedback in practice settings. Finally, we consider future directions for monitoring and feedback in research and practice. PMID- 26641371 TI - A collaborative outcome resource network (ACORN): Tools for increasing the value of psychotherapy. AB - The authors describe a collaborative outcomes resource network (ACORN) and the suite of measurement and decision support tools (ACORN Toolkit) that have emerged from this collaboration for the purpose of providing clinical feedback to therapists. The ACORN Toolkit is most accurately described as a comprehensive clinical information system designed to increase the value of mental health services across large systems of care. It was built to integrate large datasets from multiple sources including outcome data, client demographics and diagnostic data, therapist credentialing information, pharmacy data, and service claims data. For the limited purposes of this article, the authors focus on the ACORN Toolkit for measuring and how it has contributed to improving outcomes in psychotherapy. Implications to current practice and future training are provided. PMID- 26641372 TI - Treatment Outcome Package: Measuring and facilitating multidimensional change. AB - The Treatment Outcome Package (TOP; D. R. Kraus, Seligman, & Jordan, 2005) is a multidimensional routine progress and outcome measure developed for use in diverse naturalistic practice settings. In this article, we (a) provide a brief review and summary of the extant psychometric and research support for the TOP, (b) provide examples of the TOP's use in clinical training and practice, and (c) discuss the implications of the TOP for future psychotherapy training, research, and practice. In particular, we focus on the implications of risk-adjusted progress monitoring for systems of care and mental health care decision making. PMID- 26641373 TI - The Counseling Center Assessment of Psychological Symptoms (CCAPS): Merging clinical practice, training, and research. AB - The goal of this article is to present information about a standardized multidimensional measure of psychological symptoms, the Counseling Center Assessment of Psychological Symptoms (CCAPS; Locke et al., 2011; Locke, McAleavey, et al., 2012; McAleavey, Nordberg, Hayes, et al., 2012), developed to assess difficulties specific to college students' mental health. We provide (a) a brief review and summary of the psychometric and research support for the CCAPS; (b) examples of the use of the CCAPS for various purposes, including clinical, training, policy, and counseling center advocacy; and (c) implications of the integration of routine outcome monitoring and feedback for the future of training, research, and clinical practice. In particular, the article emphasizes how the assimilation of and symbiotic relationship between research and practice can address the scientist-practitioner gap. PMID- 26641374 TI - Measuring psychotherapy outcomes with the Behavioral Health Measure-20: Efficient and comprehensive. AB - The Behavioral Health Measure-20 (BHM-20; Kopta & Lowry, 2002) through the computer-based CelestHealth System-MH (CHS-MH) has proven to be an effective and efficient instrument for assessing psychotherapy outcomes and providing feedback to psychotherapists. This article describes its features, the psychometric and research support of the measure, as well as its use in clinical training and practice. Additionally, we offer some hopes and possibilities for the future of clinical feedback systems. PMID- 26641375 TI - Beyond measures and monitoring: Realizing the potential of feedback-informed treatment. AB - More than a dozen randomized controlled trials and several meta-analyses have provided strong empirical support for routine outcome monitoring (ROM) in clinical practice. Despite current enthusiasm, advances in implementation, and the growing belief among some proponents and policymakers that ROM represents a major revolution in the practice of psychotherapy, other research has suggested that the focus on measurement and monitoring is in danger of missing the point. Any clinical tool or technology is only as good as the therapist who uses it. Failing to attend to the therapist's contribution, the long neglected variable in psychotherapy outcome, ensures that efforts to create, research, and refine new outcome measurement systems will inevitably fall short. Research from the field of expertise and expert performance provides guidance for realizing the full potential of ROM. PMID- 26641376 TI - Routine outcome monitoring: Coming of age--With the usual developmental challenges. AB - The articles in this series present a variety of systems that involve routine outcome monitoring and the provision of feedback to therapists and/or patients with the goal of improving the quality of mental health care. Sufficient evidence exists for the adopting 1 of these systems (or 1 that was not discussed in this series); nevertheless, a number of challenges exist. Issues related to identifying the efficacious components, implementation, utilization, scientific inquiry, and the next generation are discussed. PMID- 26641377 TI - Striatal dynamics explain duration judgments. AB - The striatum is an input structure of the basal ganglia implicated in several time-dependent functions including reinforcement learning, decision making, and interval timing. To determine whether striatal ensembles drive subjects' judgments of duration, we manipulated and recorded from striatal neurons in rats performing a duration categorization psychophysical task. We found that the dynamics of striatal neurons predicted duration judgments, and that simultaneously recorded ensembles could judge duration as well as the animal. Furthermore, striatal neurons were necessary for duration judgments, as muscimol infusions produced a specific impairment in animals' duration sensitivity. Lastly, we show that time as encoded by striatal populations ran faster or slower when rats judged a duration as longer or shorter, respectively. These results demonstrate that the speed with which striatal population state changes supports the fundamental ability of animals to judge the passage of time. PMID- 26641378 TI - Intraoperative use of low volume ventilation to decrease postoperative mortality, mechanical ventilation, lengths of stay and lung injury in patients without acute lung injury. AB - BACKGROUND: During the last decade, there has been a trend towards decreasing tidal volumes for positive pressure ventilation during surgery. It is not known whether this new trend is beneficial or harmful for patients. OBJECTIVES: To assess the benefit of intraoperative use of low tidal volume ventilation (< 10 mL/kg of predicted body weight) to decrease postoperative complications. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL 2014, Issue 9), MEDLINE (OvidSP) (from 1946 to 5 September 2014) and EMBASE (OvidSP) (from 1974 to 5 September 2014). SELECTION CRITERIA: We included all parallel randomized controlled trials (RCTs) that evaluated the effect of low tidal volumes (defined as < 10 mL/kg) on any of our selected outcomes in adult participants undergoing any type of surgery. We did not retain studies with participants requiring one-lung ventilation. DATA COLLECTION AND ANALYSIS: Two authors independently assessed the quality of the retained studies with the Cochrane 'Risk of bias' tool. We analysed data with both fixed-effect (I(2) statistic < 25%) or random-effects (I(2) statistic > 25%) models based on the degree of heterogeneity. When there was an effect, we calculated a number needed to treat for an additional beneficial outcome (NNTB) using the odds ratio. When there was no effect, we calculated the optimal size information. MAIN RESULTS: We included 12 studies in the review. In total these studies detailed 1012 participants (499 participants in the low tidal volume group and 513 in the high volume group). All studies included were at risk of bias as defined by the Cochrane tool. Based on nine studies including 899 participants, we found no difference in 0- to 30-day mortality between low and high tidal volume groups (risk ratio (RR) 0.79, 95% confidence interval (CI) 0.40 to 1.54; I(2) statistic 0%; low quality evidence). Based on four studies including 601 participants undergoing abdominal or spinal surgery, we found a lower incidence of postoperative pneumonia in the lower tidal volume group (RR 0.44, 95% CI 0.20 to 0.99; I(2) statistic 19%; moderate quality evidence; NNTB 19, 95% CI 14 to 169). Based on two studies including 428 participants, low tidal volumes decreased the need for non-invasive postoperative ventilatory support (RR 0.31, 95% CI 0.15 to 0.64; moderate quality evidence; NNTB 11, 95% CI 9 to 19). Based on eight studies including 814 participants, low tidal volumes during surgery decreased the need for postoperative invasive ventilatory support (RR 0.33, 95% CI 0.14 to 0.80; I(2) statistic 0%; NNTB 36, 95% CI 27 to 202; moderate quality evidence). Based on three studies including 650 participants, we found no difference in the intensive care unit length of stay (standardized mean difference (SMD) -0.01, 95% CI -0.22 to 0.20; I(2) statistic = 42%; moderate quality evidence). Based on eight studies including 846 participants, we did not find a difference in hospital length of stay (SMD -0.16, 95% CI -0.40 to 0.07; I(2) statistic 52%; moderate quality evidence). A meta-regression showed that the effect size increased proportionally to the peak pressure measured at the end of surgery in the high volume group. We did not find a difference in the risk of pneumothorax (RR 2.01, 95% CI 0.51 to 7.95; I(2) statistic 0%; low quality evidence). AUTHORS' CONCLUSIONS: Low tidal volumes (defined as < 10 mL/kg) should be used preferentially during surgery. They decrease the need for postoperative ventilatory support (invasive and non-invasive). Further research is required to determine the maximum peak pressure of ventilation that should be allowed during surgery. PMID- 26641411 TI - Integrative Psychotherapy for Schizophrenia: Its Potential for a Central Role in Recovery Oriented Treatment. AB - Research has affirmed that recovery from serious mental illnesses (SMI), such as schizophrenia, is a common outcome and often involves subjective changes in the experience of self, one's identity, and one's sense of agency in the world. Although many different interventions have been developed and validated, efforts to consider how those interventions should be integrated to assist people to direct their own recovery have been limited. This article considers the 5 case reports of psychotherapy presented in this special issue that have sought to integrate scientifically valid approaches within a recovery frame work. Exploring shared themes, this article suggests that a common set of processes exists between these examples of integrative work. These include therapist acceptance of a vulnerable stance in the face of uncertainty, which rejects stigma and remains open to knowing the person. This ultimately allows the kinds of meaning to be made jointly between the therapist and client that promote recovery. PMID- 26641379 TI - Increase in Maximal Cycling Power With Acute Dietary Nitrate Supplementation. AB - : Muscle-shortening velocity and hence power have been shown to increase in the presence of nitric oxide (NO). NO availability increases after consuming nitrate (NO3-). Ingestion of NO3-rich beetroot juice (BRJ) has increased muscle power in untrained adults. PURPOSE: This study determined whether NO3- supplementation could acutely enhance maximal power in trained athletes. METHODS: In this double blind, crossover study, 13 trained athletes performed maximal inertial-load cycling trials (3-4 s) immediately before (PRE) and after (POST) consuming either NO3-rich (NO3) or NO3-depleted (PLA) BRJ to assess acute changes (ie, within the same day) in maximal power (PMAX) and optimal pedaling rate (RPMopt). Participants also performed maximal isokinetic cycling (30 s) to assess performance differences after supplementation. RESULTS: 2 x 2 repeated-measures ANOVA indicated a greater increase in PMAX from PRE to POST NO3 (PRE 1160 +/- 301 W to POST 1229 +/- 317 W) than with PLA (PRE 1191 +/- 298 W to POST 1213 +/- 300 W) (P = .009; etap2 = 0.45). A paired t-test verified a greater relative change in PMAX after NO3 (6.0% +/- 2.6%) than with PLA (2.0% +/- 3.8%) (P = .014; d = 1.21). RPMopt remained unchanged from PRE (123 +/- 14 rpm) to POST PLA (122 +/- 14 rpm) but increased from PRE (120 +/- 14 rpm) to POST NO3 (127 +/- 13 rpm) (P = .043; etap2 = 0.30). There was no relative change in RPMopt after PLA (-0.3% +/- 4.1%), but there was an increase after NO3 (6.5% +/- 11.4%) (P = .049; d = 0.79). No differences were observed between the 30-s isokinetic trials. CONCLUSIONS: Acute NO3- supplementation can enhance maximal muscle power in trained athletes. These findings may particularly benefit power-sport athletes who perform brief explosive actions. PMID- 26641412 TI - Petrus van Musschenbroek and Newton's 'vera stabilisque Philosophandi methodus'. AB - According to a dominant view in the scholarly literature, Musschenbroek is to be considered a follower of Newton's methodology, i.e. as a natural philosopher who, although he occasionally departed from Newton's doctrines, aligned himself to Newton's methodological views. Few scholars have, however, explained in full detail what it means to claim that Musschenbroek followed Newton's method. The purpose of this essay is to get more grip on this matter. PMID- 26641414 TI - [How to do Things with Metaphors: Reflections on the Role of Metaphors and Metaphor Theory for the History of Science Using the Example of Shock Metaphors in Medicine]. AB - In recent decades, metaphors have attracted a great deal of interest within the history, philosophy, and sociology of science. The article takes the growing interest in epistemic metaphors as the starting point of a discussion of two conflicting motives prevalent in theories of metaphor and metaphoricity: On the one hand, metaphors are associated with the indeterminacy of scientific discovery and the emergence of new epistemic objects; and on the other hand, metaphors are said to provide a filter of possible meanings and vantage-points. It is argued that an approach, which aims to do justice to both tendencies, cannot exclusively rely on linguistic models but must expand its scope of inquiry to include the practical trajectories of a metaphor's usage as well as the problematizations to which they respond, since both engender metaphorical meaning, albeit at the cost of semantic precision. The exemplary case discussed in the article, the psychologization of nervous shock in nineteenth century medical discourse, demonstrates that the incremental process of shock's shifting semantics would be inadequately characterized as a metaphorical transfer. Instead, it is shown how the actualization of earlier meanings, in particular of shock as a state of altered consciousness, in novel professional and cultural contexts acted as a catalyst for the psychologization of shock and related nascent concepts such as psychic trauma. As a possible, and methodologically fruitful way of overcoming the one-sidedness of linguistic notions of metaphor, a combination of Jirgen Link's concept of inter-discourse with a philosophical metaphorology (Blumenberg) is discussed in the final section of the paper. PMID- 26641413 TI - [Focal Point "Reading Animal". Hermann Cohn and the Emergence of the Fin de Siecle Hygiene of Reading]. AB - From the 1860s onward, 'eye experts' increasingly fretted the alleged surge of myopia attributed to an increase of reading matter circulating in schools. In order to avert the inauspicious prospects, revised school desks designed to prevent children from becoming myopic were introduced. During the 1880s, said experts turned to printed matter, maintaining that books must become more reader friendly. Along with the turn to books, a peculiar shift within the hygiene discourse occurred: While the ill addressed by school desk-revisions was myopia, the goal of revising book design was to make reading less tiring. This paper explores both the shift from the hygiene of the eye to the hygiene of reading as well as the materialization of the stipulations and claims made by reading hygienists. In doing so, the paper demonstrates that optimizing the reading process was closely linked to a fear of overburdening and fatigue which expressed itself in the psychopathological discourse of the time. PMID- 26641415 TI - Rational Integration of Polypropylene/Graphene Oxide/Nafion as Ternary-Layered Separator to Retard the Shuttle of Polysulfides for Lithium-Sulfur Batteries. AB - The reversible electrochemical transformation from lithium (Li) and sulfur (S) into Li2 S through multielectron reactions can be utilized in secondary Li-S batteries with very high energy density. However, both the low Coulombic efficiency and severe capacity degradation limits the full utilization of active sulfur, which hinders the practical applications of Li-S battery system. The present study reports a ternary-layered separator with a macroporous polypropylene (PP) matrix layer, graphene oxide (GO) barrier layer, and Nafion retarding layer as the separator for Li-S batteries with high Coulombic efficiency and superior cyclic stability. In the ternary-layered separator, ultrathin layer of GO (0.0032 mg cm(-2) , estimated to be around 40 layers) blocks the macropores of PP matrix, and a dense ion selective Nafion layer with a very low loading amount of 0.05 mg cm(-2) is attached as a retarding layer to suppress the crossover of sulfur-containing species. The ternary-layered separators are effective in improving the initial capacity and the Coulombic efficiency of Li-S cells from 969 to 1057 mAh g(-1) , and from 80% to over 95% with an LiNO3 -free electrolyte, respectively. The capacity degradation is reduced from 0.34% to 0.18% per cycle within 200 cycles when the PP separator is replaced by the ternary-layered separators. This work provides the rational design strategy for multifunctional separators at cell scale to effective utilizing of active sulfur and retarding of polysulfides, which offers the possibility of high energy density Li-S cells with long cycling life. PMID- 26641416 TI - Prevalence and risk factors for development of hemorrhagic gastro-intestinal disease in veterinary intensive care units in the United Kingdom. AB - OBJECTIVE: To determine the prevalence of hemorrhagic gastro-intestinal (GI) disease developing in dogs and cats admitted for management of non-GI disease in veterinary intensive care units (ICUs). DESIGN: Retrospective study of animals presented between October 2012 and July 2013. SETTING: Three ICUs located in veterinary teaching hospitals in the United Kingdom. ANIMALS: Dogs (n = 272) and cats (n = 94) were consecutively enrolled from 3 ICUs if they were hospitalized in the unit for at least 24 hours. Cases were excluded if they had hemorrhagic GI disease in the 48-hour period before presentation or in the 24-hour period after admission. Cases were also excluded if they suffered skull fracture, epistaxis, or hemoptysis, if they underwent surgical procedures of the GI or upper respiratory tracts, or if they were presented for management of GI disease. MEASUREMENTS AND MAIN RESULTS: Hemorrhagic GI disease was observed in dogs at all 3 units, but at different rates (Center 1: 10.3%, Center 2: 4.8%, Center 3: 2.2%). Hemorrhagic GI disease was not observed in cats at any of the participating centers. Construction of a multivariable logistic regression model revealed that serum albumin concentration, administration of prophylactic gastro protectant drugs, and institution were significantly associated with the development of hemorrhagic GI disease in dogs. Development of hemorrhagic GI disease and placement of a feeding tube were significantly associated with mortality during the period of hospitalization in dogs. Thirty-seven (13.6%) dogs and 12 (12.8%) cats died or were euthanized while hospitalized, with a higher mortality rate (42.1%) in dogs with hemorrhagic GI disease. CONCLUSIONS: Hemorrhagic GI disease does develop in dogs hospitalized for management of non-GI disease, but this phenomenon was not observed in cats. Development of hemorrhagic GI disease appeared to have a significant impact on survival in veterinary ICUs. PMID- 26641417 TI - Effect of Supramolecular Interchain Sticking on the Low-Frequency Relaxation of Transient Polymer Networks. AB - Supramolecular polymer networks and gels often exhibit three effects in rheology as a function of increasing strength and extent of transient chain interlinkage: (i) the longest relaxation time increases, (ii) the elastic part of the complex shear modulus on timescales longer than that increases, and (iii) the frequency dependent power-law scaling of this modulus gets shallower in this regime. In a recent report, these effects have been systematically assessed by comparing transient polymer networks derived from a common precursor modified with different extents of a common hydrogen-bonding supramolecular sticker. In this communication, complementary studies are discussed that are based on a set of polymers also derived from a common precursor but all modified with the same extent (4.8%) of very different supramolecular crosslinking motifs. This comparison reveals that effect (iii) can be rationalized by exacerbation of polydispersity effects to the relaxation time spectrum if supramolecular interchain sticking is present. In addition, effect (ii) is addressable to a simple thermodynamic argument that appraises the supramolecular sticking contribution to the elastic part of the shear modulus in the relaxation regime. PMID- 26641418 TI - Glucocorticoid therapy for adrenal insufficiency: nonadherence, concerns and dissatisfaction with information. AB - OBJECTIVE: Appropriate self-management of glucocorticoid therapy (GC) is crucial for patients with adrenal insufficiency (AI). We aimed to describe patients' self reported nonadherence to GC, evaluate perceived doubts about need for GC, concerns about adverse effects, and dissatisfaction with information received about GC. DESIGN: Cross-sectional survey. PATIENTS: Patients prescribed GC for AI (n = 81) from five European countries. MEASUREMENTS: Online survey including the Medication Adherence Report Scale (MARS), Beliefs about Medicines Questionnaire((c)) (BMQ Specific, adapted for AI) and Satisfaction with Information about Medicines Scale((c)) (Prof Rob Horne; SIMS). RESULTS: Most patients (85.2%) reported a degree of nonadherence to GC. The most frequent types of nonadherence concerned changing the timing of GC doses, for example taking a dose later in the day than advised (37.0%). Few patients doubted their personal need for daily GC, but most reported high concerns about GC including potential weight gain (50.6%), osteoporosis (53.6%) and the continuing risk of adrenal crisis (50.6%). Dissatisfaction with information about GC was frequent, with participants particularly dissatisfied with the amount of information they had received about potential problems with GC. People who expressed dissatisfaction with information about GC, and concerns about its adverse effects were also more likely to report nonadherence (P < 0.05). CONCLUSIONS: Nonadherence to treatment, concerns about potential adverse effects and dissatisfaction with the information provided about treatment were frequently reported by this European sample of AI patients. Many AI patients may need additional information about their GC and support to address concerns about GC and facilitate adherence. PMID- 26641445 TI - Photolithographic Micropatterning of Conducting Polymers on Flexible Silk Matrices. AB - High-resolution micropatterning of a PEDOT: PSS conducting-polymer-silksericin composite is presented using a water-based, benchtop photolithographic process. Conducting microstructures formed on a flexible silk fibroin sheet allow a fully organic, flexible bioelectronic device. Large-area microfabricated devices such as biosensors that are biocompatible and degradable over a controlled period of time can be formed. PMID- 26641446 TI - Do participants differ in their cognitive abilities, task motivation, or personality characteristics as a function of time of participation? AB - Four experiments tested the conventional wisdom in experimental psychology that participants who complete laboratory tasks systematically differ in their cognitive abilities, motivational levels, and personality characteristics as a function of the time at which they participate during an academic term. Across 4 experiments with over 2,900 participants from 2 different universities with 2 different academic schedules, no convincing evidence suggested that individuals differ in cognitive abilities (working memory capacity, fluid intelligence, crystallized intelligence, long-term memory, and attention control). Similarly, no evidence suggested participants' task motivation varies systematically with time of participation, nor do any of the Big Five personality traits. The present study concludes that researchers need not be overly concerned with time of participation effects as a potential confound in individual differences or experimental psychology. (PsycINFO Database Record PMID- 26641447 TI - Is VIRTU4L larger than VIR7UAL? Automatic processing of number quantity and lexical representations in leet words. AB - Recent research has shown that leet words (i.e., words in which some of the letters are replaced by visually similar digits; e.g., VIRTU4L) can be processed as their base words without much cost. However, it remains unclear whether the digits inserted in leet words are simply processed as letters or whether they are simultaneously processed as numbers (i.e., in terms of access to their quantity representation). To address this question, we conducted 2 experiments that examined the size congruity effect (i.e., when comparisons of the physical size of numbers are affected by their numerical magnitudes) in a physical-size judgment task. Participants were presented with pairs of leet words that were nominally identical except for the embedded digit (e.g., VIR7UAL-VIRTU4L) and were asked to decide as quickly and accurately as possible which word in the pair appeared in a bigger font. In Experiment 1, we examined the congruity effect (congruent: VIRTU4L-VIR7UAL vs. incongruent: VIR7UAL-VIRTU4L vs. neutral: VIR7UAL VIR7UAL) and the numerical distance effect (distance 1: PAN3L-P4NEL vs. distance 3: VIRTU4L-VIR7UAL). To examine whether the meaning of these words was accessed, we also manipulated word frequency (i.e., a marker of lexical access) in Experiment 2. Results revealed effects of congruity, distance, and word frequency, thus suggesting automatic access to both number quantity and word representations for leet words. These findings favor multidimensional accounts of number/word recognition. (PsycINFO Database Record PMID- 26641448 TI - Spatial processes in linear ordering. AB - Memory performance in linear order reasoning tasks (A > B, B > C, C > D, etc.) shows quicker, and more accurate responses to queries on wider (AD) than narrower (AB) pairs on a hypothetical linear mental model (A - B - C - D). While indicative of an analogue representation, research so far did not provide positive evidence for spatial processes in the construction of such models. In a series of 7 experiments we report such evidence. Participants respond quicker when the dominant element in a pair is presented on the left (or top) rather than on the right (or bottom). The left-anchoring tendency reverses in a sample with Farsi background (reading/writing from right to left). Alternative explanations and confounds are tested. A theoretical model is proposed that integrates basic assumptions about acquired reading/writing habits as a scaffold for spatial simulation, and primacy/dominance representation within such spatial simulations. (PsycINFO Database Record PMID- 26641449 TI - Phonotactic constraints: Implications for models of oral reading in Russian. AB - The present article investigates how phonotactic rules constrain oral reading in the Russian language. The pronunciation of letters in Russian is regular and consistent, but it is subject to substantial phonotactic influence: the position of a phoneme and its phonological context within a word can alter its pronunciation. In Part 1 of the article, we analyze the orthography-to-phonology and phonology-to-phonology (i.e., phonotactic) relationships in Russian monosyllabic words. In Part 2 of the article, we report empirical data from an oral word reading task that show an effect of phonotactic dependencies on skilled reading in Russian: humans are slower when reading words where letter-phoneme correspondences are highly constrained by phonotactic rules compared with those where there are few or no such constraints present. A further question of interest in this article is how computational models of oral reading deal with the phonotactics of the Russian language. To answer this question, in Part 3, we report simulations from the Russian dual-route cascaded model (DRC) and the Russian connectionist dual-process model (CDP++) and assess the performance of the 2 models by testing them against human data. PMID- 26641450 TI - Unconscious cross-modal priming of auditory sound localization by visual words. AB - Little is known about the cross-modal integration of unconscious and conscious information. In the current study, we therefore tested whether the spatial meaning of an unconscious visual word, such as up, influences the perceived location of a subsequently presented auditory target. Although cross-modal integration of unconscious information is generally rare, unconscious meaning stemming from only 1 particular modality could, in principle, be available for other modalities. Also, on the basis of known influences and dependencies of meaning on sensory information processing, such an unconscious meaning-based effect could impact sensory processing in a different modality. In 3 experiments, this prediction was confirmed. We found that an unconscious spatial word, such as up, facilitated position discrimination of a spatially congruent sound (here, a sound from above) as compared to a spatially incongruent sound (here, from below). This was found even though participants did not recognize the meaning of the primes. The results show that unconscious processing extends to semantic sensory connections between different modalities. (PsycINFO Database Record PMID- 26641452 TI - Pathogenesis and Management of Pruritus in PBC and PSC. AB - Pruritus is a preeminent symptom in patients with chronic cholestatic liver disorders such as primary biliary cirrhosis and primary sclerosing cholangitis. More than two-thirds of these patients experience itching during the course of their disease. This symptom is also frequently observed in patients with other causes of cholestasis such as cholangiocarcinoma, inherited forms of cholestasis and intrahepatic cholestasis of pregnancy, but may accompany almost any other liver disease. The pathogenesis of pruritus of cholestasis remains largely elusive. Increased concentrations of bile salts, histamine, serotonin, progesterone metabolites and endogenous opioids have been controversially discussed as potential pruritogens. However, for these molecules, neither a correlation with itch intensity nor a causative link could be established. The G protein-coupled receptor for bile salts, TGR5, has been shown to be expressed in dorsal root ganglia and give rise to itch in rodents, albeit upon stimuli with suprapathological concentrations of bile salts. The potent neuronal activator lysophosphatidic acid (LPA) and its forming enzyme, autotaxin (ATX), could be identified in the serum of patients with cholestatic pruritus. ATX activity correlated with itch severity and effectiveness of several anti-pruritic therapeutic interventions in cholestatic patients. Thus, the ATX-LPA-axis may represent a key element in the pathogenesis of this agonizing symptom. Treatment options for pruritus of cholestasis remain limited to a few evidence-based and several experimental medical and interventional therapies. The current guideline based recommendations include the anion exchange resins colestyramine, the pregnane X receptor-agonist and enzyme inducer rifampicin, the MU-opioid antagonist naltrexone, and the selective serotonin reuptake inhibitors sertraline. Still, a considerable part of patients is unresponsive to these drugs and requires experimental approaches including phototherapy, plasmapheresis, albumin dialysis or nasobiliary drainage. This review outlines the current knowledge on pathogenesis of cholestatic pruritus and summarizes evidence-based and experimental therapeutic interventions for cholestatic patients with itch. PMID- 26641451 TI - Oral Microbiota and Risk for Esophageal Squamous Cell Carcinoma in a High-Risk Area of China. AB - Poor oral health has been linked with an increased risk of esophageal squamous cell carcinoma (ESCC). We investigated whether alteration of oral microbiota is associated with ESCC risk. Fasting saliva samples were collected from 87 incident and histopathologicallly diagnosed ESCC cases, 63 subjects with dysplasia and 85 healthy controls. All subjects were also interviewed with a questionnaire. V3-V4 region of 16S rRNA was amplified and sequenced by 454-pyrosequencing platform. Carriage of each genus was compared by means of multivariate-adjusted odds ratios derived from logistic regression model. Relative abundance was compared using Metastats method. Beta diversity was estimated using Unifrac and weighted Unifrac distances. Principal coordinate analysis (PCoA) was applied to ordinate dissimilarity matrices. Multinomial logistic regression was used to compare the coordinates between different groups. ESCC subjects had an overall decreased microbial diversity compared to control and dysplasia subjects (P<0.001). Decreased carriage of genera Lautropia, Bulleidia, Catonella, Corynebacterium, Moryella, Peptococcus and Cardiobacterium were found in ESCC subjects compared to non-ESCC subjects. Multinomial logistic regression analyses on PCoA coordinates also revealed that ESCC subjects had significantly different levels for several coordinates compared to non-ESCC subjects. In conclusion, we observed a correlation between altered salivary bacterial microbiota and ESCC risk. The results of our study on the saliva microbiome are of particular interest as it reflects the shift in microbial communities. Further studies are warranted to verify this finding, and if being verified, to explore the underlying mechanisms. PMID- 26641453 TI - In Vivo Fate Imaging of Intracerebral Stem Cell Grafts in Mouse Brain. AB - We generated transgenic human neural stem cells (hNSCs) stably expressing the reporter genes Luciferase for bioluminescence imaging (BLI) and GFP for fluorescence imaging, for multimodal imaging investigations. These transgenic hNSCs were further labeled with a clinically approved perfluoropolyether to perform parallel 19F MRI studies. In vitro validation demonstrated normal cell proliferation and differentiation of the transgenic and additionally labeled hNSCs, closely the same as the wild type cell line, making them suitable for in vivo application. Labeled and unlabeled transgenic hNSCs were implanted into the striatum of mouse brain. The time profile of their cell fate after intracerebral grafting was monitored during nine days following implantation with our multimodal imaging approach, assessing both functional and anatomical condition. The 19F MRI demarcated the graft location and permitted to estimate the cell number in the graft. BLI showed a pronounce cell loss during this monitoring period, indicated by the decrease of the viability signal. The in vivo obtained cell fate results were further validated and confirmed by immunohistochemistry. We could show that the surviving cells of the graft continued to differentiate into early neurons, while the severe cell loss could be explained by an inflammatory reaction to the graft, showing the graft being surrounded by activated microglia and macrophages. These results are different from earlier cell survival studies of our group where we had implanted the identical cells into the same mouse strain but in the cortex and not in the striatum. The cortical transplanted cells did not show any loss in viability but only pronounced and continuous neuronal differentiation. PMID- 26641454 TI - Teaching and Learning with Mobile Technology: A Qualitative Explorative Study about the Introduction of Tablet Devices in Secondary Education. AB - This paper investigates teachers' and students' perceptions concerning the impact of using tablet devices for teaching and learning purposes. An explorative focus group study was conducted with teachers (n = 18) and students (n = 39) in a secondary school that has implemented tablet devices since 2012. The general finding of this study shows that the use of tablet devices in the classroom setting has an impact on both teaching and learning practices. The results suggest that teachers can be divided into two categories: the innovative teachers and the instrumental teachers. Innovative teachers attempt to shift from a teacher-centered to a learning-centered approach. They have changed their teaching style by transforming lessons in accordance with the advantages tablet computers can offer. Instrumental teachers seem to use the device as a 'book behind glass'. The distinction between the two groups has consequences for both the way courses are given and how students experience them. In general, the introduction of tablet devices entails a shift in the way students learn, as the devices provide interactive, media-rich, and exciting new environments. The results of this study indicate that policy makers should consider introducing technical and pedagogical support in order to facilitate both teachers' and students' understanding of the full potential of this kind of technology in education. PMID- 26641455 TI - Metabolomic Responses of Guard Cells and Mesophyll Cells to Bicarbonate. AB - Anthropogenic CO2 presently at 400 ppm is expected to reach 550 ppm in 2050, an increment expected to affect plant growth and productivity. Paired stomatal guard cells (GCs) are the gate-way for water, CO2, and pathogen, while mesophyll cells (MCs) represent the bulk cell-type of green leaves mainly for photosynthesis. We used the two different cell types, i.e., GCs and MCs from canola (Brassica napus) to profile metabolomic changes upon increased CO2 through supplementation with bicarbonate (HCO3-). Two metabolomics platforms enabled quantification of 268 metabolites in a time-course study to reveal short-term responses. The HCO3- responsive metabolomes of the cell types differed in their responsiveness. The MCs demonstrated increased amino acids, phenylpropanoids, redox metabolites, auxins and cytokinins, all of which were decreased in GCs in response to HCO3-. In addition, the GCs showed differential increases of primary C-metabolites, N metabolites (e.g., purines and amino acids), and defense-responsive pathways (e.g., alkaloids, phenolics, and flavonoids) as compared to the MCs, indicating differential C/N homeostasis in the cell-types. The metabolomics results provide insights into plant responses and crop productivity under future climatic changes where elevated CO2 conditions are to take center-stage. PMID- 26641456 TI - Collagen Type III and VI Turnover in Response to Long-Term Immobilization. AB - BACKGROUND: Muscle mass and function are perturbed by immobilization and remobilization. When muscle mass changes, the quality and quantity of the extracellular matrix protein, particularly the collagens, change with it. In this study, we investigated the temporal profile of three peptide biomarkers derived from turnover of collagen type III and type VI in a long-term immobilization and remobilization study. We also compared individual biomarker levels with Lean body Mass (LBM) and changes therein, hypothesizing that these biomarkers would be biomarkers of the remodeling processes associated with immobilization and/or remobilization. METHODS: In the Berlin bed rest study, 20 young men were recruited and randomly assigned to 8-week's strict bed rest with or without resistive vibration exercise countermeasure. We measured three neo-epitope ELISA kits in the serum samples of this study: Pro-C3, measured the synthesis of collagen type III; Pro-C6, measured the synthesis of collagen type VI; and C6M measured the degradation of collagen type VI induced by MMP-2 and MMP-9 cleavage. RESULTS: Pro-C3 and Pro-C6 biomarkers are up-regulated with both immobilization and remobilization, whereas C6M is hardly affected at all. We found that Pro-C3 and C6M levels are related to LBM at baseline and that high levels of Pro-C6 are associated with smaller changes in muscle mass during both immobilization and remobilization. CONCLUSION: The Pro-C3 and-C6 biomarkers change likely reflect remodeling changes in response to unloading or reloading, whereas C6M does not appear to respond to unloading. Pro-C3 and C6M levels correlate with LBM at baseline, while Pro-C6 is related to the anabolic and catabolic responses to unloading and reloading. PMID- 26641457 TI - Malnutrition Predicts Clinical Outcome in Patients with Neuroendocrine Neoplasia. AB - Malnutrition is a common problem in oncological diseases, influencing treatment outcomes, treatment complications, quality of life and survival. The potential role of malnutrition has not yet been studied systematically in neuroendocrine neoplasms (NEN), which, due to their growing prevalence and additional therapeutic options, provide an increasing clinical challenge to diagnosis and management. The aim of this cross-sectional observational study, which included a long-term follow-up, was therefore to define the prevalence of malnutrition in 203 patients with NEN using various methodological approaches, and to analyse the short- and long-term outcome of malnourished patients. A detailed subgroup analysis was also performed to define risk factors for poorer outcome. When applying malnutrition screening scores, 21-25% of the NEN patients were at risk of or demonstrated manifest malnutrition. This was confirmed by anthropometric measurements, by determination of serum surrogate parameters such as albumin as well as by bioelectrical impedance analysis (BIA), particularly phase angle alpha. The length of hospital stay was significantly longer in malnourished NEN patients, while long-term overall survival was highly significantly reduced. Patients with high-grade (G3) neuroendocrine carcinomas, progressive disease and undergoing chemotherapy were at particular risk of malnutrition associated with a poorer outcome. Multivariate analysis confirmed the important and highly significant role of malnutrition as an independent prognostic factor for NEN besides proliferative capacity (G3 NEC). Malnutrition is therefore an underrecognized problem in NEN patients which should systematically be diagnosed by widely available standard methods such as Nutritional Risk Screening (NRS), serum albumin assessment and BIA, and treated to improve both short- and long term outcomes. PMID- 26641458 TI - Down-Regulation of NDUFB9 Promotes Breast Cancer Cell Proliferation, Metastasis by Mediating Mitochondrial Metabolism. AB - Despite advances in basic and clinical research, metastasis remains the leading cause of death in breast cancer patients. Genetic abnormalities in mitochondria, including mutations affecting complex I and oxidative phosphorylation, are found in breast cancers and might facilitate metastasis. Genes encoding complex I components have significant breast cancer prognostic value. In this study, we used quantitative proteomic analyses to compare a highly metastatic cancer cell line and a parental breast cancer cell line; and observed that NDUFB9, an accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (complex I), was down-regulated in highly metastatic breast cancer cells. Furthermore, we demonstrated that loss of NDUFB9 promotes MDA-MB-231 cells proliferation, migration, and invasion because of elevated levels of mtROS, disturbance of the NAD+/NADH balance, and depletion of mtDNA. We also showed that, the Akt/mTOR/p70S6K signaling pathway and EMT might be involved in this mechanism. Thus, our findings contribute novel data to support the hypothesis that misregulation of mitochondrial complex I NADH dehydrogenase activity can profoundly enhance the aggressiveness of human breast cancer cells, suggesting that complex I deficiency is a potential and important biomarker for further basic research or clinical application. PMID- 26641459 TI - The Influence of Socio-economic, Behavioural and Environmental Factors on Taenia spp. Transmission in Western Kenya: Evidence from a Cross-Sectional Survey in Humans and Pigs. AB - Taenia spp. infections, particularly cysticercosis, cause considerable health impacts in endemic countries. Despite previous evidence of spatial clustering in cysticercosis and the role of environmental factors (e.g. temperature and humidity) in the survival of eggs, little research has explored these aspects of Taenia spp. EPIDEMIOLOGY: In addition, there are significant gaps in our understanding of risk factors for infection in humans and pigs. This study aimed to assess the influence of socio-economic, behavioural and environmental variables on human and porcine cysticercosis. A cross-sectional survey for human taeniasis (T. solium and T. saginata), human cysticercosis (T. solium) and pig cysticercosis (T. solium) in 416 households in western Kenya was carried out. These data were linked to questionnaire responses and environmental datasets. Multi-level regression was used to examine the relationships between covariates and human and porcine cysticercosis. The HP10 Ag-ELISA sero-prevalence (suggestive of cysticercosis) was 6.6% for humans (95% CI 5.6%-7.7%), and 17.2% for pigs (95% CI 10.2%-26.4%). Human taeniasis prevalence, based on direct microscopic observation of Taenia spp. eggs (i.e. via microscopy results only) was 0.2% (95% CI 0.05%-0.5%). Presence of Taenia spp. antigen in both humans and pigs was significantly associated with a range of factors, including positive correlations with land cover. The presence of HP10 antigen in humans was correlated (non-linearly) with the proportion of land within a 1 km buffer that was flooding agricultural land and grassland (odds ratio [OR] = 1.09 and 0.998; p = 0.03 and 0.03 for the linear and quadratic terms respectively), gender (OR = 0.58 for males compared to females, p = 0.02), level of education (OR = 0.62 for primary level education versus no formal education, p = 0.09), use of well water for drinking (OR = 2.76 for those who use well water versus those who do not, p = 0.02) and precipitation (OR = 0.998, p = 0.02). Presence of Taenia spp. antigen in pigs was significantly correlated with gender and breeding status of the pig (OR = 10.35 for breeding sows compared to boars, p = 0.01), and the proportion of land within a 1 km buffer that was flooding agricultural land and grassland (OR = 1.04, p = 0.004). These results highlight the role of multiple socio-economic, behavioural and environmental factors in Taenia spp. transmission patterns. Environmental contamination with Taenia spp. eggs is a key issue, with landscape factors influencing presence of Taenia spp. antigens in both pigs and humans. PMID- 26641460 TI - Formation of Potato Virus A-Induced RNA Granules and Viral Translation Are Interrelated Processes Required for Optimal Virus Accumulation. AB - RNA granules are cellular structures, which play an important role in mRNA translation, storage, and degradation. Animal (+)RNA viruses often co-opt RNA granule proteins for viral reproduction. However, the role of RNA granules in plant viral infections is poorly understood. Here we use Potato virus A (PVA) as a model potyvirus and demonstrate that the helper component-proteinase (HCpro), the potyviral suppressor of RNA silencing, induces the formation of RNA granules. We used confocal microscopy to demonstrate the presence of host RNA binding proteins including acidic ribosomal protein P0, argonaute 1 (AGO1), oligouridylate-binding protein 1 (UBP1), varicose (VCS) and eukaryotic initiation factor iso4E (eIF(iso)4E) in these potyvirus-induced RNA granules. We show that the number of potyviral RNA granules is down-regulated by the genome-linked viral protein (VPg). We demonstrated previously that VPg is a virus-specific translational regulator that co-operates with potyviral RNA granule components P0 and eIF(iso)4E in PVA translation. In this study we show that HCpro and varicose, components of potyviral RNA granules, stimulate VPg-promoted translation of the PVA, whereas UBP1 inhibits this process. Hence, we propose that PVA translation operates via a pathway that is interrelated with potyviral RNA granules in PVA infection. The importance of these granules is evident from the strong reduction in viral RNA and coat protein amounts that follows knock down of potyviral RNA granule components. HCpro suppresses antiviral RNA silencing during infection, and our results allow us to propose that this is also the functional context of the potyviral RNA granules we describe in this study. PMID- 26641461 TI - Two novel mutations in RNU4ATAC in two siblings with an atypical mild phenotype of microcephalic osteodysplastic primordial dwarfism type 1. PMID- 26641462 TI - The Role of Toll-Like Receptors and Myeloid Differentiation Factor 88 in Bjerkandera adusta-Induced Lung Inflammation. AB - BACKGROUND: Recently, a cluster of patients with an intractable allergic fungal cough who were characterized by sensitization to Bjerkandera adusta was reported. In the present study, the role of Toll-like receptors and myeloid differentiation factor 88 (MyD88) in B. adusta-induced lung inflammation was investigated. METHODS: Wild-type (WT), TLR2-/-,TLR4-/-, and MyD88-/- BALB/c mice were intratracheally challenged with B. adusta 4 times at 2-week intervals. Lung pathology, bronchoalveolar lavage fluid (BALF) cytological profiles, and inflammatory mediators in BALF were investigated. Bone marrow-derived macrophages (BMDM) from TLR2-/-,TLR4-/-, TLR2/4-/-, TLR7/9-/-,MyD88-/-, and WT C57BL/6J mice were stimulated with B. adusta for 12 h, and inflammatory mediators in the culture medium were measured. RESULTS: B. adusta caused lung inflammation along with Th2 cytokine [interleukin (IL)-5 and IL-13] and eosinophil-related chemokine [eotaxin and monocyte chemotactic protein (MCP-3)] production, an increase in eosinophils in BALF, and eosinophil infiltration in the airways in WT and TLR4-/- mice. However, Th2 and eosinophil-related responses in TLR2-/- and MyD88-/- mice were low or undetectable. The induction of neutrophils and IL-6, IL-12, IL-17A, and MCP-1 in the BALF of MyD88-/- mice was attenuated compared to that in WT mice. The induction of IL-6, TNF-alpha, MCP-1, and macrophage inflammatory protein-1alpha was reduced or undetectable in B. adusta-stimulated BMDM from TLR7/9-/- and MyD88-/- mice compared to WT mice. CONCLUSIONS: These results suggest that TLR2 and the adapter protein MyD88 may play an important role in the induction of eosinophils by B. adusta. However, TLR7/9-MyD88 might be important in the induction of neutrophils and the relevant inflammatory mediators, especially IL-17A. PMID- 26641464 TI - The Clinical Learning Environment: Improving the Education Experience and Patient Outcomes Within Magnet(r) Organizations. AB - Creating a safe and supportive clinical learning environment where students can learn collaboratively with each other and with practicing healthcare providers is the responsibility of Magnet(r) leaders. In this month's Magnet Perspectives, the Vice President of the ANCC Accreditation Program and Institute for Credentialing Research discusses the imperative for interprofessional learning environments. PMID- 26641463 TI - Expression of the Troponin C at 41C Gene in Adult Drosophila Tubular Muscles Depends upon Both Positive and Negative Regulatory Inputs. AB - Most animals express multiple isoforms of structural muscle proteins to produce tissues with different physiological properties. In Drosophila, the adult muscles include tubular-type muscles and the fibrillar indirect flight muscles. Regulatory processes specifying tubular muscle fate remain incompletely understood, therefore we chose to analyze the transcriptional regulation of TpnC41C, a Troponin C gene expressed in the tubular jump muscles, but not in the fibrillar flight muscles. We identified a 300-bp promoter fragment of TpnC41C sufficient for the fiber-specific reporter expression. Through an analysis of this regulatory element, we identified two sites necessary for the activation of the enhancer. Mutations in each of these sites resulted in 70% reduction of enhancer activity. One site was characterized as a binding site for Myocyte Enhancer Factor-2. In addition, we identified a repressive element that prevents activation of the enhancer in other muscle fiber types. Mutation of this site increased jump muscle-specific expression of the reporter, but more importantly reporter expression expanded into the indirect flight muscles. Our findings demonstrate that expression of the TpnC41C gene in jump muscles requires integration of multiple positive and negative transcriptional inputs. Identification of the transcriptional regulators binding the cis-elements that we identified will reveal the regulatory pathways controlling muscle fiber differentiation. PMID- 26641465 TI - The Influence of Emerging Nursing Administrative and Leadership Researchers: An Interview With Dr Nora Warshawsky, RN. PMID- 26641466 TI - The Strategic Plan for Cross-Continuum Nursing. PMID- 26641467 TI - Building a Culture of Inclusion: Disability as Opportunity for Organizational Growth and Improving Patient Care. AB - Administrators at Rush University Medical Center have made a commitment to diversity, including accommodating disabilities in the workplace and for students. This article explains extensive multilevel accommodations instituted by Rush University Medical Center that promote organizational growth and a healthier work environment and improve patient care. PMID- 26641468 TI - Creating a Culture of Safety Around Bar-Code Medication Administration: An Evidence-Based Evaluation Framework. AB - Bar-code medication administration (BCMA) effectiveness is contingent upon compliance with best-practice protocols. We developed a 4-phased BCMA evaluation program to evaluate the degree of integration of current evidence into BCMA policies, procedures, and practices; identify barriers to best-practice BCMA use; and modify BCMA practice in concert with changes to the practice environment. This program provides an infrastructure for frontline nurses to partner with hospital leaders to continually evaluate and improve BCMA using a systematic process. PMID- 26641469 TI - Transforming Practice Through Publication: A Community Hospital Approach to the Creation of a Research-Intensive Environment. AB - Publication of 28 data-based articles in peer-reviewed journals over a 4-year period is the result of a commitment to conducting and publishing research at a 383-bed Magnet(r)-redesignated community hospital. The research-intensive environment in nursing at this institution supports publication as the desired outcome of all projects. The provision of appropriate resources, the development of 2 models to guide the conduct of research and nursing leadership that encourages and supports research activities enables nurses to submit manuscripts describing their work. Steps taken to support the publication of findings can be adapted for other practice settings. PMID- 26641470 TI - Using a Lean Six Sigma Approach to Yield Sustained Pressure Ulcer Prevention for Complex Critical Care Patients. AB - BACKGROUND: Under value-based purchasing, Medicare withholds reimbursements for hospital-acquired pressure ulcer occurrence and rewards hospitals that meet performance standards. With little evidence of a validated prevention process, nurse managers are challenged to find evidence-based interventions. OBJECTIVE: The aim of this study was to reduce the unit-acquired pressure ulcer (UAPU) rate on targeted intensive care and step-down units by 15% using Lean Six Sigma (LSS) methodology. METHODS: An interdisciplinary team designed a pilot program using LSS methodology to test 4 interventions: standardized documentation, equipment monitoring, patient out-of-bed-to-chair monitoring, and a rounding checklist. RESULTS: During the pilot, the UAPU rate decreased from 4.4% to 2.8%, exceeding the goal of a 15% reduction. The rate remained below the goal through the program control phase at 2.9%, demonstrating a statistically significant reduction after intervention implementation. CONCLUSIONS: The program significantly reduced UAPU rates in high-risk populations. LSS methodologies are a sustainable approach to reducing hospital-acquired conditions that should be broadly tested and implemented. PMID- 26641471 TI - Employee Engagement and a Culture of Safety in the Intensive Care Unit. AB - A descriptive, retrospective design was used to explore the relationship between employee engagement and culture of safety in ICUs within a large Midwestern healthcare system. Results demonstrated a strong positive relationship between total engagement score and total patient safety score (r = 0.645, P < .01) and positive relationships between total engagement score and the 12 safety culture dimensions. These findings have implications for improving managerial strategies relative to employee engagement that may ultimately impact perceptions of a safety culture. PMID- 26641472 TI - Acoustic-Emergent Phonology in the Amplitude Envelope of Child-Directed Speech. AB - When acquiring language, young children may use acoustic spectro-temporal patterns in speech to derive phonological units in spoken language (e.g., prosodic stress patterns, syllables, phonemes). Children appear to learn acoustic phonological mappings rapidly, without direct instruction, yet the underlying developmental mechanisms remain unclear. Across different languages, a relationship between amplitude envelope sensitivity and phonological development has been found, suggesting that children may make use of amplitude modulation (AM) patterns within the envelope to develop a phonological system. Here we present the Spectral Amplitude Modulation Phase Hierarchy (S-AMPH) model, a set of algorithms for deriving the dominant AM patterns in child-directed speech (CDS). Using Principal Components Analysis, we show that rhythmic CDS contains an AM hierarchy comprising 3 core modulation timescales. These timescales correspond to key phonological units: prosodic stress (Stress AM, ~2 Hz), syllables (Syllable AM, ~5 Hz) and onset-rime units (Phoneme AM, ~20 Hz). We argue that these AM patterns could in principle be used by naive listeners to compute acoustic-phonological mappings without lexical knowledge. We then demonstrate that the modulation statistics within this AM hierarchy indeed parse the speech signal into a primitive hierarchically-organised phonological system comprising stress feet (proto-words), syllables and onset-rime units. We apply the S-AMPH model to two other CDS corpora, one spontaneous and one deliberately-timed. The model accurately identified 72-82% (freely-read CDS) and 90-98% (rhythmically regular CDS) stress patterns, syllables and onset-rime units. This in-principle demonstration that primitive phonology can be extracted from speech AMs is termed Acoustic-Emergent Phonology (AEP) theory. AEP theory provides a set of methods for examining how early phonological development is shaped by the temporal modulation structure of speech across languages. The S-AMPH model reveals a crucial developmental role for stress feet (AMs ~2 Hz). Stress feet underpin different linguistic rhythm typologies, and speech rhythm underpins language acquisition by infants in all languages. PMID- 26641473 TI - The Combination of Vitamin K3 and Vitamin C Has Synergic Activity against Forms of Trypanosoma cruzi through a Redox Imbalance Process. AB - Chagas' disease is an infection that is caused by the protozoan Trypanosoma cruzi, affecting millions of people worldwide. Because of severe side effects and variable efficacy, the current treatments for Chagas' disease are unsatisfactory, making the search for new chemotherapeutic agents essential. Previous studies have reported various biological activities of naphthoquinones, such as the trypanocidal and antitumor activity of vitamin K3. The combination of this vitamin with vitamin C exerted better effects against various cancer cells than when used alone. These effects have been attributed to an increase in reactive oxygen species generation. In the present study, we evaluated the activity of vitamin K3 and vitamin C, alone and in combination, against T. cruzi. The vitamin K3 + vitamin C combination exerted synergistic effects against three forms of T. cruzi, leading to morphological, ultrastructural, and functional changes by producing reactive species, decreasing reduced thiol groups, altering the cell cycle, causing lipid peroxidation, and forming autophagic vacuoles. Our hypothesis is that the vitamin K3 + vitamin C combination induces oxidative imbalance in T. cruzi, probably started by a redox cycling process that leads to parasite cell death. PMID- 26641474 TI - Pharmacogenetic analysis of advanced non-small-cell lung cancer patients treated with first-line paclitaxel and carboplatin chemotherapy. AB - BACKGROUND: Genetic polymorphisms contribute toward interindividual variations in drug response. We investigated the effects of genetic polymorphisms on the clinical outcome of advanced non-small-cell lung cancer patients with first-line paclitaxel and carboplatin. MATERIALS AND METHODS: A total of 194 non-small-cell lung cancer patients were prospectively enrolled from January 2010 to January 2013. We genotyped 11 polymorphisms in seven genes involved in the glycolysis pathway and the related pharmacokinetic/pharmacodynamic pathway. Genetic associations with PET-SUV, survival outcome, and toxicity were analyzed, and in vitro drug transport activity was measured in the oocyte system. RESULTS: Patients with the c.334 T>G and c.699 G>A homozygous variant in SLCO1B3 showed a higher incidence of grade 3/4 anemia (P=0.002). Transport activities of oocyte that overexpress the SLCO1B3 c.699 G>A variant showed a significantly decreased uptake of paclitaxel compared with the wild-type expressing oocytes. In addition, patients with GG/GA/AA genotypes of ABCB1, c.2677 T>G/A locus showed inferior progression-free survival (hazard ratio=1.49, P=0.017) compared with other genotypes. The GA genotype of HIF1A, c.1834 G>A locus was associated with inferior progression-free survival compared with the GG genotype (hazard ratio=2.47, P=0.008). CONCLUSION: This study showed that the SLCO1B3 c.699 G>A polymorphism may predict anemia and ABCB1, HIF1A polymorphism are highly predictive for worse survival in advanced NSCLC with first-line paclitaxel and carboplatin. PMID- 26641475 TI - Evaluation and Validation of Assembling Corrected PacBio Long Reads for Microbial Genome Completion via Hybrid Approaches. AB - Despite the ever-increasing output of next-generation sequencing data along with developing assemblers, dozens to hundreds of gaps still exist in de novo microbial assemblies due to uneven coverage and large genomic repeats. Third generation single-molecule, real-time (SMRT) sequencing technology avoids amplification artifacts and generates kilobase-long reads with the potential to complete microbial genome assembly. However, due to the low accuracy (~85%) of third-generation sequences, a considerable amount of long reads (>50X) are required for self-correction and for subsequent de novo assembly. Recently developed hybrid approaches, using next-generation sequencing data and as few as 5X long reads, have been proposed to improve the completeness of microbial assembly. In this study we have evaluated the contemporary hybrid approaches and demonstrated that assembling corrected long reads (by runCA) produced the best assembly compared to long-read scaffolding (e.g., AHA, Cerulean and SSPACE LongRead) and gap-filling (SPAdes). For generating corrected long reads, we further examined long-read correction tools, such as ECTools, LSC, LoRDEC, PBcR pipeline and proovread. We have demonstrated that three microbial genomes including Escherichia coli K12 MG1655, Meiothermus ruber DSM1279 and Pdeobacter heparinus DSM2366 were successfully hybrid assembled by runCA into near-perfect assemblies using ECTools-corrected long reads. In addition, we developed a tool, Patch, which implements corrected long reads and pre-assembled contigs as inputs, to enhance microbial genome assemblies. With the additional 20X long reads, short reads of S. cerevisiae W303 were hybrid assembled into 115 contigs using the verified strategy, ECTools + runCA. Patch was subsequently applied to upgrade the assembly to a 35-contig draft genome. Our evaluation of the hybrid approaches shows that assembling the ECTools-corrected long reads via runCA generates near complete microbial genomes, suggesting that genome assembly could benefit from re analyzing the available hybrid datasets that were not assembled in an optimal fashion. PMID- 26641478 TI - Robust off-line heartbeat detection using ECG and pressure-signals. AB - Artefacts in pressure- and ECG-signals generally arise due to different causes. Therefore, the combined analysis of both signals can increase the effectiveness of heartbeat detection compared to analysis using solely ECG-signals. In this paper, we present an algorithm for heartbeat annotation by combining the analysis of both the pressure- and ECG-signals. The novelties of our algorithm are as follows: (1) development of a new approach for annotating heartbeats using pressure-signals, (2) development of a mechanism that identifies and corrects paced rhythms, and (3) development of a noise detection approach. Our algorithm is tested on the datasets from the extended phase of the Physionet CINC-2014 challenge and produces an overall score of 87.31%. Finally, we put forth several recommendations that could further improve our algorithm. PMID- 26641477 TI - Elevational Ranges of Montane Birds and Deforestation in the Western Andes of Colombia. AB - Deforestation causes habitat loss, fragmentation, degradation, and can ultimately cause extinction of the remnant species. Tropical montane birds face these threats with the added natural vulnerability of narrower elevational ranges and higher specialization than lowland species. Recent studies assess the impact of present and future global climate change on species' ranges, but only a few of these evaluate the potentially confounding effect of lowland deforestation on species elevational distributions. In the Western Andes of Colombia, an important biodiversity hotspot, we evaluated the effects of deforestation on the elevational ranges of montane birds along altitudinal transects. Using point counts and mist-nets, we surveyed six altitudinal transects spanning 2200 to 2800 m. Three transects were forested from 2200 to 2800 m, and three were partially deforested with forest cover only above 2400 m. We compared abundance-weighted mean elevation, minimum elevation, and elevational range width. In addition to analysing the effect of deforestation on 134 species, we tested its impact within trophic guilds and habitat preference groups. Abundance-weighted mean and minimum elevations were not significantly different between forested and partially deforested transects. Range width was marginally different: as expected, ranges were larger in forested transects. Species in different trophic guilds and habitat preference categories showed different trends. These results suggest that deforestation may affect species' elevational ranges, even within the forest that remains. Climate change will likely exacerbate harmful impacts of deforestation on species' elevational distributions. Future conservation strategies need to account for this by protecting connected forest tracts across a wide range of elevations. PMID- 26641480 TI - Stress in nonregular work arrangements: A longitudinal study of task- and employment-related aspects of stress. AB - In nonregular forms of employment, such as fixed-term or temporary agency work, 2 sources of stress must be distinguished: task-related stress components (e.g., time pressure) and employment-related stress components (e.g., effort to maintain employment). The present study investigated the relationship between task- and employment-related demands and resources and indicators of strain, well-being, work engagement, and self-rated performance in a sample of nonregular employed workers. Using a 2-wave longitudinal design, the results of autoregressive cross lagged structural equation models demonstrated that time pressure, as a task related demand, is positively related to strain and negatively related to well being and self-rated performance. Autonomy, as a task-related resource, exhibited no significant relationships in the current study. Employment-related demands exhibited negative relationships with well-being and work engagement as well as negative and positive relationships with self-rated performance over time. Employment-related resources were primarily positive predictors of well-being and self-rated performance. Fit indices of comparative models indicated that reciprocal effect models (which enable causal and reverse effects) best fit the data. Accordingly, demands and resources predicted strain, well-being, work engagement, and self-rated performance over time and vice versa. (PsycINFO Database Record PMID- 26641479 TI - Comparison of Accuracy of Whole-Exome Sequencing with Formalin-Fixed Paraffin Embedded and Fresh Frozen Tissue Samples. AB - Formalin fixing with paraffin embedding (FFPE) has been a standard sample preparation method for decades, and archival FFPE samples are still very useful resources. Nonetheless, the use of FFPE samples in cancer genome analysis using next-generation sequencing, which is a powerful technique for the identification of genomic alterations at the nucleotide level, has been challenging due to poor DNA quality and artificial sequence alterations. In this study, we performed whole-exome sequencing of matched frozen samples and FFPE samples of tissues from 4 cancer patients and compared the next-generation sequencing data obtained from these samples. The major differences between data obtained from the 2 types of sample were the shorter insert size and artificial base alterations in the FFPE samples. A high proportion of short inserts in the FFPE samples resulted in overlapping paired reads, which could lead to overestimation of certain variants; >20% of the inserts in the FFPE samples were double sequenced. A large number of soft clipped reads was found in the sequencing data of the FFPE samples, and about 30% of total bases were soft clipped. The artificial base alterations, C>T and G>A, were observed in FFPE samples only, and the alteration rate ranged from 200 to 1,200 per 1M bases when sequencing errors were removed. Although high confidence mutation calls in the FFPE samples were compatible to that in the frozen samples, caution should be exercised in terms of the artifacts, especially for low-confidence calls. Despite the clearly observed artifacts, archival FFPE samples can be a good resource for discovery or validation of biomarkers in cancer research based on whole-exome sequencing. PMID- 26641481 TI - What happens at work stays at work? Workplace supervisory social interactions and blood pressure outcomes. AB - We investigated the relationship between workplace supervisory social interactions and blood pressure outcomes using hourly diary entries and ambulatory blood pressure data from an experience sampling study of 55 long-term care employees. After accounting for relevant cardiovascular controls, significant effects of supervisory interactions on cardiovascular reactivity and recovery were found. Multilevel analyses revealed that negatively perceived supervisory interactions predicted higher systolic blood pressure at work (B = 1.59, p < .05, N observations = 422). Using time-lagged hierarchical regression analyses, the average perceived valence of supervisory interactions at work predicted average systolic blood pressure recovery after work (B = -14.52, p < .05, N = 33). Specifically, negatively perceived supervisory interactions at work predicted poorer cardiovascular recovery after work. Suggestions for improving practices in organizations and in experience sampling research are discussed. PMID- 26641482 TI - Can job redesign interventions influence a broad range of employee outcomes by changing multiple job characteristics? A quasi-experimental study. AB - Many job redesign interventions are based on a multiple mediator-multiple outcome model in which the job redesign intervention indirectly influences a broad range of employee outcomes by changing multiple job characteristics. As this model remains untested, the aim of this study is to test a multiple mediator-multiple outcome model of job redesign. Multilevel analysis of data from a quasi experimental job redesign intervention in a call center confirmed the hypothesized model and showed that the job redesign intervention affected a broad range of employee outcomes (i.e., employee well-being, psychological contract fulfillment, and supervisor-rated job performance) through changes in 2 job characteristics (i.e., job control and feedback). The results provide further evidence for the efficacy and mechanisms of job redesign interventions. (PsycINFO Database Record PMID- 26641484 TI - A qualitative and quantitative examination of the antecedents of customer incivility. AB - Customer incivility is known to have a negative impact on employees working in service jobs. Despite an understanding of the negative outcomes of customer incivility (e.g., burnout, disengagement, absenteeism), little research has investigated antecedents of this low-intensity deviant behavior. This is a clear oversight, given that understanding antecedents of customer incivility is essential for determining methods for reducing this stressor. As such, we conducted 2 studies examining these antecedents. For Study 1, we used a qualitative approach, assessing customer incivility from the perspective of the customer. Three overall themes (with 13 subthemes) emerged that could potentially lead to customer incivility: characteristics of the customer, characteristics of the organization/environment, and characteristics of the service employee. In Study 2, we conducted a quantitative study to investigate-from the perspective of the service employee-customer incivility antecedents that could be potentially controlled by the organization, either through changing the work environment or the employee (through training and selection). The results of a 2 time-point survey study showed that the service environment, service rep incivility, service orientation, agreeableness, and neuroticism served as antecedents to customer incivility. Practical implications are discussed, identifying options for organizational leaders interested in reducing customer incivility, and advice is provided for researchers seeking to further examine the antecedents of customer incivility. PMID- 26641483 TI - Family, employment, and individual resource-based antecedents of maternal work family enrichment from infancy through middle childhood. AB - This study used data from the National Institute of Child Health and Human Development (NICHD) Study of Early Child Care and Youth Development (N = 1,019) to examine family, employment, and individual antecedents of maternal work-family enrichment from infancy through middle childhood. Work-family conflict and important confounding factors were controlled. From the family domain, higher income-to-needs ratio and social support were associated with higher work-family enrichment. From the employment domain, greater job rewards, benefits of employment for children, and work commitment were associated with higher work family enrichment. From the individual domain, higher maternal education and extroversion were associated with higher work-family enrichment. No family, employment, and individual characteristics were associated with work-family conflict across time except for partner intimacy. In general, the results supported antecedents of work-family enrichment that supply needed resources. The present study contributed to the literature by identifying antecedents of maternal work-family enrichment across early child developmental stages, which goes beyond examinations of particular life stages and a work-family conflict perspective. Implications for theory and practice are discussed. (PsycINFO Database Record PMID- 26641485 TI - Abusive supervision, psychosomatic symptoms, and deviance: Can job autonomy make a difference? AB - Recently, interest in abusive supervision has grown (Tepper, 2000). However, little is still known about organizational factors that can reduce its adverse effects on employee behavior. Based on the Job Demands-Resources Model (Demerouti, Bakker, Nachreiner, & Schaufeli, 2001), we predict that job autonomy acts as a buffer of the positive relationship between abusive supervision, psychosomatic symptoms and deviance. Therefore, when job autonomy is low, a higher level of abusive supervision should be accompanied by increased psychosomatic symptoms and thus lead to higher production deviance. When job autonomy is high, abusive supervision should fail to produce increased psychosomatic symptoms and thus should not lead to higher production deviance. Our model was explored among a sample of 170 supervisor-subordinate dyads from 4 organizations. The results of the moderated mediation analysis supported our hypotheses. That is, abusive supervision was significantly related to production deviance via psychosomatic symptoms when job autonomy was low, but not when job autonomy was high. These findings suggest that job autonomy buffers the impact of abusive supervision perceptions on psychosomatic symptoms, with consequences for production deviance. (PsycINFO Database Record PMID- 26641486 TI - Effective and ineffective coping strategies in a low-autonomy work environment. AB - The authors examined the effectiveness of different coping strategies in buffering the negative effects of uncontrollable stressors and predicting mental health symptoms in a low-autonomy work environment using a longitudinal design. Soldiers in training indicated the extent to which they engaged in various coping strategies to deal with stressors related to the training environment at 4 different points in time. Factor analyses of soldiers in 2 different countries (i.e., United States and Australia) yielded 5 coping dimensions: active coping, acceptance of demands, seeking social support, humor, and denial/self-criticism. Among U.S. soldiers in basic training, acceptance of demands and denial/self criticism interacted with the magnitude of basic-training stressors to predict mental health symptoms (depression and anxiety) at 3 different points during training while controlling for symptoms at the immediate prior time period. Acceptance buffered soldiers from the negative effects of the stressors, whereas denial/self-criticism exacerbated the effects of the stressors. The results of LGC models also indicated that the slopes of acceptance and active coping were negatively related to the slope of mental health symptoms across training, whereas the slope for denial/self-criticism was positively related to the slope of symptoms. Active coping was less predictive of functioning in the face of stressors and in the prediction of symptoms over time. The results demonstrated that in a low-autonomy occupational setting, acceptance coping was more effective in facilitating good mental health outcomes compared with other coping strategies considered important in prior research (e.g., active coping). PMID- 26641487 TI - Aspects of the Pathophysiology of Primary Biliary Cirrhosis. AB - Primary biliary cirrhosis is a classical autoimmune liver disease and is present in around 1 in 1,000 women over the age of 40. It has a number of diagnostic characteristics consistent with autoimmune liver injury, in particular, the high specificity of circulating anti-mitochondrial antibodies. Histologically, the disease is reflected as a granulomatous lymphocytic cholangitis that consequently leads to small bile duct loss and cholestasis. Progressive disease is characterised by the development of a biliary cirrhosis, with end-stage features of liver disease ultimately impacting patient outcomes. Studies support a combination of environmental and genetic risk factors that coalesce to lead to loss of immunological tolerance and persistent biliary inflammation. Significant advances have occurred recently in understanding the genetic risk factors for disease, as well as utilising human and murine studies to characterise the nature of the biliary injury and cholestatic response. PMID- 26641488 TI - Application of Brown Planthopper Salivary Gland Extract to Rice Plants Induces Systemic Host mRNA Patterns Associated with Nutrient Remobilization. AB - Insect saliva plays an important role in modulation of plant-insect interactions. Although this area of research has generated much attention in recent years, mechanisms of how saliva affects plant responses remain poorly understood. To address this void, the present study investigated the impact of the brown planthopper (Nilaparvata lugens, Stal; hereafter BPH) salivary gland extract (SGE) on rice (Oryza sativa) systemic responses at the mRNA level. Differentially expressed rice mRNAs were generated through suppression subtractive hybridization (SSH) and classified into six functional groups. Those with the most representatives were from the primary metabolism (28%), signaling-defense (22%) and transcription-translation-regulation group (16%). To validate SSH library results, six genes were further analyzed by One-Step Real-Time Reverse Transcriptase-PCR. Five of these genes exhibited up-regulation levels of more than 150% of those in the control group in at least one post-application time point. Results of this study allow assignment of at least two putative roles of BPH saliva: First, application of SGE induces immediate systemic responses at the mRNA level, suggesting that altering of the rice transcriptome at sites distant to hoppers feeding locations may play an important role in BPH-rice interactions. Second, 58% of SGE-responsive up-regulated genes have a secondary function associated with senescence, a process characterized by remobilization of nutrients. This suggests that BPH salivary secretions may reprogram the rice transcriptome for nutritional enhancement. When these findings are translated onto 'whole plant' scale, they indicate that BPH saliva may play the 'wise investment' role of 'minimum input today, maximum output tomorrow'. PMID- 26641489 TI - Production of Abundant Hydroxyl Radicals from Oxygenation of Subsurface Sediments. AB - Hydroxyl radicals (*OH) play a crucial role in the fate of redox-active substances in the environment. Studies of the *OH production in nature has been constrained to surface environments exposed to light irradiation, but is overlooked in the subsurface under dark. Results of this study demonstrate that abundant *OH is produced when subsurface sediments are oxygenated under fluctuating redox conditions at neutral pH values. The cumulative concentrations of *OH produced within 24 h upon oxygenation of 33 sediments sampled from different redox conditions are 2-670 MUmol *OH per kg dry sediment or 6.7-2521 MUM *OH in sediment pore water. Fe(II)-containing minerals, particularly phyllosilicates, are the predominant contributor to *OH production. This production could be sustainable when sediment Fe(II) is regenerated by the biological reduction of Fe(III) during redox cycles. Production of *OH is further evident in a field injection-extraction test through injecting oxygenated water into a 23-m depth aquifer. The *OH produced can oxidize pollutants such as arsenic and tetracycline and contribute to CO2 emissions at levels that are comparable with soil respiration. These findings indicate that oxygenation of subsurface sediments is an important source of *OH in nature that has not been previously identified, and *OH-mediated oxidation represents an overlooked process for substance transformations at the oxic/anoxic interface. PMID- 26641490 TI - Monitoring Ultrafast Chemical Dynamics by Time-Domain X-ray Photo- and Auger Electron Spectroscopy. AB - The directed flow of charge and energy is at the heart of all chemical processes. Extraordinary efforts are underway to monitor and understand the concerted motion of electrons and nuclei with ever increasing spatial and temporal sensitivity. The element specificity, chemical sensitivity, and temporal resolution of ultrafast X-ray spectroscopy techniques hold great promise to provide new insight into the fundamental interactions underlying chemical dynamics in systems ranging from isolated molecules to application-like devices. Here, we focus on the potential of ultrafast X-ray spectroscopy techniques based on the detection of photo- and Auger electrons to provide new fundamental insight into photochemical processes of systems with various degrees of complexity. Isolated nucleobases provide an excellent testing ground for our most fundamental understanding of intramolecular coupling between electrons and nuclei beyond the traditionally applied Born-Oppenheimer approximation. Ultrafast electronic relaxation dynamics enabled by the breakdown of this approximation is the major component of the nucleobase photoprotection mechanisms. Transient X-ray induced Auger electron spectroscopy on photoexcited thymine molecules provides atomic-site specific details of the extremely efficient coupling that converts potentially bond changing ultraviolet photon energy into benign heat. In particular, the time dependent spectral shift of a specific Auger band is sensitive to the length of a single bond within the molecule. The X-ray induced Auger transients show evidence for an electronic transition out of the initially excited state within only ~200 fs in contrast to theoretically predicted picosecond population trapping behind a reaction barrier. Photoinduced charge transfer dynamics between transition metal complexes and semiconductor nanostructures are of central importance for many emerging energy and climate relevant technologies. Numerous demonstrations of photovoltaic and photocatalytic activity have been performed based on the combination of strong light absorption in dye molecules with charge separation and transport in adjacent semiconductor nanostructures. However, a fundamental understanding of the enabling and limiting dynamics on critical atomic length- and time scales is often still lacking. Femtosecond time-resolved X-ray photoelectron spectroscopy is employed to gain a better understanding of a short lived intermediate that may be linked to the unexpectedly limited performance of ZnO based dye-sensitized solar cells by delaying the generation of free charge carriers. The transient spectra strongly suggest that photoexcited dye molecules attached to ZnO nanocrystals inject their charges into the substrate within less than 1 ps but the electrons are then temporarily trapped at the surface of the semiconductor in direct vicinity of the injecting molecules. The experiments are extended to monitor the electronic response of the semiconductor substrate to the collective injection from a monolayer of dye molecules and the subsequent electron-ion recombination dynamics. The results indicate some qualitative similarities but quantitative differences between the recombination dynamics at molecule-semiconductor interfaces and previously studied bulk-surface electron hole recombination dynamics in photoexcited semiconductors. PMID- 26641491 TI - The Willingness to Pay for Vaccination against Tick-Borne Encephalitis and Implications for Public Health Policy: Evidence from Sweden. AB - The increasing incidence of tick-borne encephalitis (TBE) in Sweden and several other European countries has sparked a discussion about the need for a public vaccination strategy. However, TBE vaccination coverage is incomplete and there is little knowledge about the factors influencing vaccination behavior. Based on a survey of 1,500 randomly selected respondents in Sweden, we estimate vaccination coverage in areas with different TBE risk levels and analyze the role of vaccine price and other factors influencing the demand for vaccination. First, we find that the average rate of TBE vaccination in Sweden is 33% in TBE risk areas and 18% elsewhere. Income, age and risk-related factors such as incidence of TBE in the area of residence, frequency of visits to areas with TBE risk, and experience with tick bites are positively associated with demand for TBE vaccine. Next, using contingent valuation methodology, we estimate the willingness to pay for TBE vaccination among the unvaccinated respondents and the effect of a possible subsidy. Among the unvaccinated respondents in TBE risk areas, we estimate the mean willingness to pay for the recommended three doses of TBE vaccine to be 465 SEK (approximately 46 euros or 40% of the current market price). We project that a subsidy making TBE vaccines free of charge could increase the vaccination rate in TBE risk areas to around 78%, with a larger effect on low-income households, whose current vaccination rate is only 15% in risk areas. However, price is not the only factor affecting demand. We find significant effects on vaccination behavior associated with trust in vaccine recommendations, perceptions about tick bite-related health risks and knowledge about ticks and tick-borne diseases. Hence, increasing knowledge and trust, as well as ease of access to vaccinations, can also be important measures for public health agencies that want to increase the vaccination rate. PMID- 26641492 TI - Gait in Very Preterm School-Aged Children in Dual-Task Paradigms. AB - OBJECTIVE: The control of gait requires executive and attentional functions. As preterm children show executive and attentional deficits compared to full-term children, performing concurrent tasks that impose additional cognitive load may lead to poorer walking performance in preterm compared to full-term children. Knowledge regarding gait in preterm children after early childhood is scarce. We examined straight walking and if it is more affected in very preterm than in full term children in dual-task paradigms. STUDY DESIGN: Twenty preterm children with very low birth-weight (<= 1500 g), 24 preterm children with birth-weight > 1500 g, and 44 full-term children, born between 2001 and 2006, were investigated. Gait was assessed using an electronic walkway system (GAITRite) while walking without a concurrent task (single-task) and while performing one concurrent (dual-task) or two concurrent (triple-task) tasks. Spatio-temporal gait parameters (gait velocity, cadence, stride length, single support time, double support time), normalized gait parameters (normalized velocity, normalized cadence, normalized stride length) and gait variability parameters (stride velocity variability, stride length variability) were analyzed. RESULTS: In dual- and triple-task conditions children showed decreased gait velocity, cadence, stride length, as well as increased single support time, double support time and gait variability compared to single-task walking. Further, results showed systematic decreases in stride velocity variability from preterm children with very low birth weight (<= 1500 g) to preterm children with birth weight > 1500 g to full-term children. There were no significant interactions between walking conditions and prematurity status. CONCLUSIONS: Dual and triple tasking affects gait of preterm and full term children, confirming previous results that walking requires executive and attentional functions. Birth-weight dependent systematic changes in stride velocity variability indicate poorer walking performance in preterm children who were less mature at birth. PMID- 26641493 TI - Light-Mediated Sulfenic Acid Generation from Photocaged Cysteine Sulfoxide. AB - S-Sulfenylation is a post-translational modification with a crucial role in regulating protein function. However, its analysis has remained challenging due to the lack of facile sulfenic acid models. We report the first photocaged cysteine sulfenic acid with efficient photodeprotection and demonstrate its utility by generating sulfenic acid in a thiol peroxidase after illumination in vitro. These caged sulfoxides should be promising for site-specific incorporation of Cys sulfenic acid in living cells via genetic code expansion. PMID- 26641495 TI - Effects of the Terminal Aromatic Residues on Polyproline Conformation: Thermodynamic and Kinetic Studies. AB - In a peptide or protein, the sequence of aromatic residue-proline or proline aromatic residue shows a high propensity in forming cis prolyl bonds due to aromatic-proline interactions. In this work, we designed and prepared the polyproline peptides with aromatic amino acids (F, Y, W) incorporated into their N-terminal or C-terminal end to investigate the effects of a terminal aromatic residue on polyproline conformation and the transition kinetics of polyproline I (PPI) to polyproline II (PPII) helices. Circular dichroism measurements reveal that the N-terminal aromatic-proline interaction imposes a more pronounced consequence on the forming propensity of PPI conformation than does the C terminal aromatic-proline interaction in n-propanol. The propensity of forming PPI is correlated with the strength of aromatic-proline interactions in the order of Tyr-Pro > Trp-Pro > Phe-Pro. In aqueous solution, kinetic studies indicate that aromatic-substitution effects are nondirectional and indistinct on the PPI > PPII conversion rates, suggesting that aromatic-proline interactions may not be an important factor in this process. In addition, the temperature-dependent kinetics shows that the hydrophobicity of aromatic side chain may play a critical role affecting the activation enthalpy and entropy of the conversion of PPI to PPII, providing new insights into the folding of polyproline helices. PMID- 26641494 TI - Physio-Biochemical Composition and Untargeted Metabolomics of Cumin (Cuminum cyminum L.) Make It Promising Functional Food and Help in Mitigating Salinity Stress. AB - Cumin is an annual, aromatic, herbaceous, medicinal, spice plant, most widely used as a food additive and flavoring agent in different cuisines. The study is intended to comprehensively analyse physiological parameters, biochemical composition and metabolites under salinity stress. Seed germination index, rate of seed emergence, rate of seed germination, mean germination time, plant biomass, total chlorophyll and carotenoid contents decreased concomitantly with salinity. In contrast, total antioxidant activity, H2O2, proline and MDA contents increased concurrently with stress treatments. Total phenolic and flavonoid contents were decreased initially about 1.4-fold at 50 mM, and thereafter increased about 1.2-fold at 100 mM NaCl stress. Relative water content remained unchanged up to 50 mM NaCl stress, and thereafter decreased significantly. About 2.8-fold electrolyte leakage was found in 50 mM, which increases further 4-fold at 100 mM NaCl stress. Saturated fatty acids (FAs) increased gradually with salinity, whereas unsaturation index and degree of unsaturation change arbitrarily along with the percent quantity of unsaturated FAs. Total lipid and fatty acid composition were significantly influenced by salinity stress. A total of 45 differentially expressed metabolites were identified, including luteolin, salvianolic acid, kaempferol and quercetin, which are phenolic, flavonoid or alkaloids in nature and contain antioxidant activities. Additionally, metabolites with bioactivity such as anticancerous (docetaxel) and antimicrobial (megalomicin) properties were also identified. The study evidenced that plant shoots are a rich source of metabolites, essential amino acids, phenolic compounds and fatty acids, which unveil the medicinal potential of this plant, and also provide useful insight about metabolic responses under salinity stress. PMID- 26641496 TI - Two Distinct Cyclodipeptide Synthases from a Marine Actinomycete Catalyze Biosynthesis of the Same Diketopiperazine Natural Product. AB - Diketopiperazine natural products are structurally diverse and offer many biological activities. Cyclodipeptide synthases (CDPSs) were recently unveiled as a novel enzyme family that employs aminoacyl-tRNAs as substrates for 2,5 diketopiperazine assembly. Here, the Nocardiopsis sp. CMB-M0232 genome is predicted to encode two CDPSs, NozA and NcdA. Metabolite profiles from E. coli expressing these genes and assays with purified recombinant enzymes revealed that NozA and NcdA catalyze cyclo(l-Trp-l-Trp) (1) biosynthesis from tryptophanyl-tRNA and do not accept other aromatic aminoacyl-tRNA substrates. Fidelity is uncommon among characterized CDPSs, making NozA and NcdA important CDPS family additions. Further, 1 was previously supported as a biosynthetic precursor of the nocardioazines; the current study suggests that Nocardiopsis sp. may derive this precursor from both NozA and NcdA. This study offers a rare example of a single bacterium encoding multiple phylogenetically distinct enzymes that yield the same secondary metabolite and provides tools for chemoenzymatic syntheses of indole alkaloid diketopiperazines. PMID- 26641498 TI - Association of Extrahepatic Manifestations with Autoimmune Hepatitis. AB - For many patients with autoimmune hepatitis (AIH), the presence of extrahepatic features is well recognised both at the time of presentation and during long-term follow-up. Concomitant 'autoimmune disorders' have been described in 20-50% of patients with AIH, both in adults and children. Indeed, the presence of these associated phenomena has been incorporated into both the original and revised International AIH group scoring systems as an aid to codifying the diagnosis. In acute index presentations, non-specific joint pains sometimes flitting in nature have been reported in 10-60% of patients, and while joint swelling is uncommon, rheumatoid arthritis and mixed connective tissue disease have been reported in 2 4% of patients with AIH. For a majority of patients, these joint symptoms resolve within days of the introduction of immunosuppressive therapy. Rarer features at index presentation include a maculopapular skin rash and unexplained fever, which are features that tend to resolve quickly with treatment. Interestingly, joint pain and stiffness are also well recognised in the context of steroid withdrawal and cessation in AIH. The occasional co-presentation of AIH with coeliac disease is clinically important (1-6%), since for some patients, there is a risk of immunosuppression malabsorption, thus delaying effective treatment. Similarly, the co-existence of selective IgA deficiency (IgAD) can occur in patients with coeliac disease or in isolation. Selective IgAD as a co-existing extraheaptic feature seems to be more common in paediatric patients with AIH. For these patients, they are at an increased risk of respiratory and sinus infections. Although, typically associated with primary sclerosing cholangitis, the presence of inflammatory bowel disease (IBD; both Crohn's disease and ulcerative colitis) has been described in 2-8% of patients with AIH. Interestingly, for patients with autoimmune sclerosing cholangitis, a distinct pattern of IBD has been recently described. Other conditions have been reported at a lower frequency, including Sjogren's syndrome 1-7%, systemic lupus erythematosus 1-3% and glomerulonephritis 1%. Rarer still and at a frequency of <1% include fibrosing alveolitis, haemolytic anaemia, uveitis, mononeuritis multiplex, polymyositis and multiple sclerosis. In contrast, the reported associations between AIH and thyroiditis 8 23%, diabetes 1-10% and psoriasis 3% are commonly seen and notable in clinical practice. PMID- 26641497 TI - TGF-beta Controls miR-181/ERK Regulatory Network during Retinal Axon Specification and Growth. AB - Retinal axon specification and growth are critically sensitive to the dosage of numerous signaling molecules and transcription factors. Subtle variations in the expression levels of key molecules may result in a variety of axonal growth anomalies. miR-181a and miR-181b are two eye-enriched microRNAs whose inactivation in medaka fish leads to alterations of the proper establishment of connectivity and function in the visual system. miR-181a/b are fundamental regulators of MAPK signaling and their role in retinal axon growth and specification is just beginning to be elucidated. Here we demonstrate that miR 181a/b are key nodes in the interplay between TGF-beta and MAPK/ERK within the functional pathways that control retinal axon specification and growth. Using a variety of in vivo and in vitro approaches in medaka fish, we demonstrate that TGF-beta signaling controls the miR-181/ERK regulatory network, which in turn strengthens the TGF-beta-mediated regulation of RhoA degradation. Significantly, these data uncover the role of TGF-beta signaling in vivo, for the first time, in defining the correct wiring and assembly of functional retina neural circuits and further highlight miR-181a/b as key factors in axon specification and growth. PMID- 26641499 TI - Rtt107 BRCT domains act as a targeting module in the DNA damage response. AB - Cells are constantly exposed to assaults that cause DNA damage, which must be detected and repaired to prevent genome instability. The DNA damage response is mediated by key kinases that activate various signaling pathways. In Saccharomyces cerevisiae, one of these kinases is Mec1, which phosphorylates numerous targets, including H2A and the DNA damage protein Rtt107. In addition to being phosphorylated, Rtt107 contains six BRCA1 C-terminal (BRCT) domains, which typically recognize phospho-peptides. Thus Rtt107 represented an opportunity to study complementary aspects of the phosphorylation cascades within one protein. Here we sought to describe the functional roles of the multiple BRCT domains in Rtt107. Rtt107 BRCT5/6 facilitated recruitment to sites of DNA lesions via its interaction with phosphorylated H2A. Rtt107 BRCT3/4 also contributed to Rtt107 recruitment, but BRCT3/4 was not sufficient for recruitment when BRCT5/6 was absent. Intriguingly, both mutations that affected Rtt107 recruitment also abrogated its phosphorylation. Pointing to its modular nature, replacing Rtt107 BRCT5/6 with the BRCT domains from the checkpoint protein Rad9 was able to sustain Rtt107 function. Although Rtt107 physically interacts with both the endonuclease Slx4 and the DNA replication and repair protein Dpb11, only Slx4 was dependent on Rtt107 for its recruitment to DNA lesions. Fusing Rtt107 BRCT5/6 to Slx4, which presumably allows artificial recruitment of Slx4 to DNA lesions, alleviated some phenotypes of rtt107Delta mutants, indicating the functional importance of Slx4 recruitment. Together this data revealed a key function of the Rtt107 BRCT domains for targeting of both itself and its interaction partners to DNA lesions. PMID- 26641500 TI - Source of Electrofreezing of Supercooled Water by Polar Crystals. AB - Polar crystals, which display pyroelectricity, have a propensity to elevate, in a heterogeneous nucleation, without epitaxy, the freezing temperature of supercooled water (SCW). Upon cooling, such crystals accumulate an electric charge at their surfaces, which creates weak electric fields, sigma* negative hyperconjugation effect and destabilizing repulsion among lone pairs, complicates the conformational analysis. In this work, the modern ab initio valence bond (VB) method is employed to quantitatively investigate the torsional energy curves of hydrogen peroxide and hydrazine in terms of hyperconjugative stabilization, steric repulsion, and structural and electronic relaxations. It is found that if the hyperconjugation effect is completely quenched, the trans conformers will be favored, while the cis conformers are the only transition state pertaining to the torsional motion in the potential energy surfaces of H2O2 and N2H4. Although usually the steric effect includes the contributions from the electronic and geometric changes, our energy decomposition analysis shows that even the steric effect favors the skew conformers, while the electronic and geometric changes stabilize the trans conformers. Thus, we conclude that both the hyperconjugative and steric interactions lower the energy of skew conformers and eventually form low barriers from skew to trans conformers and high barriers from skew to cis conformers in both H2O2 and N2H4. Comparison between the VB and the natural bond orbital (NBO) results show similarities and discrepancies between the two methods. PMID- 26641507 TI - Properties of Atoms in Molecules: Caged Atoms and the Ehrenfest Force. AB - This paper uses the properties of atom X enclosed within an adamantane cage, denoted by X@C10H16, as a vehicle to introduce the Ehrenfest force into the discussion of bonding, the properties being determined by the physics of an open system. This is the force acting on an atom in a molecule and determining the potential energy appearing in Slater's molecular virial theorem. The Ehrenfest force acting across the interatomic surface of a bonded pair atoms [Formula: see text] atoms linked by a bond path [Formula: see text] is attractive, each atom being drawn toward the other, and the associated surface virial that measures the contribution to the energy arising from the formation of the surface is stabilizing. It is the Ehrenfest force that determines the adhesive properties of surfaces. The endothermicity of formation for X = He or Ne is not a result of instabilities incurred in the interaction of X with the four methine carbons to which it is bonded, interactions that are stabilizing both in terms of the changes in the atomic energies and in the surface virials. The exothermicity for X = Be(2+), B(3+), and Al(3+) is a consequence of the transfer of electron density from the hydrogen atoms to the carbon and X atoms, the exothermicity increasing with charge transfer despite an increase in the contained volume of X. PMID- 26641508 TI - Benchmark Databases for Nonbonded Interactions and Their Use To Test Density Functional Theory. AB - We present four benchmark databases of binding energies for nonbonded complexes. Four types of nonbonded interactions are considered: hydrogen bonding, charge transfer, dipole interactions, and weak interactions. We tested 44 DFT methods and 1 WFT method against the new databases; one of the DFT methods (PBE1KCIS) is new, and all of the other methods are from the literature. Among the tested methods, the PBE, PBE1PBE, B3P86, MPW1K, B97-1, and BHandHLYP functionals give the best performance for hydrogen bonding. MPWB1K, MP2, MPW1B95, MPW1K, and BHandHLYP give the best performances for charge-transfer interactions, and MPW3LYP, B97-1, PBE1KCIS, B98, and PBE1PBE give the best performance for dipole interactions. Finally, MP2, B97-1, MPWB1K, PBE1KCIS, and MPW1B95 give the best performance for weak interactions. Overall, MPWB1K is the best of all the tested DFT methods, with a relative error (highly averaged) of only 11%, and MPW1K, PBE1PBE, and B98 are the best of the tested DFT methods that do not contain kinetic energy density. Moving up the rungs of Jacob's ladder for nonempirical DFT, PBE improves significantly over the LSDA, and TPSS improve slightly over PBE (on average) for nonbonded interactions. PMID- 26641509 TI - Tetrahedral Sulfur-Based Dianions Stable in the Gas Phase: Application of the Cederbaum-Dreuw Design Principles. AB - Cederbaum and Dreuw [Chem. Rev. 2002, 102, 181-200] developed an extensive set of examples of small dianions generally stable to autoionization and in some cases to dissociation as well. Their design principles include arranging alternating positive and negative charges in roughly spherical shells, as in the alkaline earth tetrahalides MX4(2)(-). This principle embraces a series of surprising tetrahedral oxygen-centered dianions of O(C2)4, O(BN)4, and O(BeO)4. These systems are stable with respect to autoionization (their vertical ionization energy is positive) but are metastable with respect to dissociation into monoanions. We present a family of dianions with sulfur cores which are stable both with respect to autoionization and dissociation. The shell charge alternation still contributes to stability, but these systems have a positive core in contrast to the oxo systems' negative core. PMID- 26641510 TI - Variational Iterative Time Dependent Method for Eigenvalues and Eigenfunctions of the Hamiltonian. AB - Short time information on the time evolution of wave packets is combined with the variational theorem to determine eigenvalues and eigenfunctions. As in the Filter Diagonalization Method the input that is needed is a correlation function and its time derivative. The method is iterative and convergent. The time interval needed is short, for example, the determination of tunneling splitting energies DeltaE is obtained in a time interval which is substantially shorter than the Fourier time 2pih/DeltaE. The method is applied to some model problems including determining the ground tunneling state in a quartic double well potential using numerically exact short time results obtained from the semiclassical initial value representation series of the exact propagator. This is another example in which tunneling is obtained using only coherent classical paths. Implications of the method for ab initio computation of molecular electronic energies is discussed. PMID- 26641511 TI - TDHF Evaluation of the Dipole-Quadrupole Polarizability and Its Geometrical Derivatives. AB - Analytical procedures based on the time-dependent Hartree-Fock (TDHF) scheme are elaborated to evaluate the frequency-dependent electric dipole-electric quadrupole polarizability and its derivatives with respect to atomic Cartesian coordinates. On one hand, the mixed second-order TDHF equations are solved iteratively to obtain the second-order derivatives of the linear combination of atomic orbitals coefficients, once with respect to atomic Cartesian coordinates and once with respect to external dynamic electric fields or electric field gradients. On the other hand, taking advantage of the 2n + 1 rule, the first order derivatives of A are expressed with respect to atomic Cartesian coordinates in terms of lower-order derivatives. These procedures have been implemented in the GAMESS quantum chemistry package and have been illustrated in the case of several small molecules as well as adamantane. PMID- 26641512 TI - Monte Carlo Simulations of Water Adsorption Isotherms in Silicalite and Dealuminated Zeolite Y. AB - The affinity that adsorbents have for water can influence their effectiveness in organics removal from drinking water due to competitive adsorption. The extent of the affinity of microporous zeolites for water is determined, in part, by AlO4(-) tetrahedral sites (T-sites) in the crystal lattice and lattice defects in the form of silanol nests. In this study, water adsorption isotherms in silicalite and in dealuminated zeolite Y (DAY) were simulated using the Compass force-field. The results show that the simulations can predict the shape of water adsorption isotherms and predict adsorption levels comparable to literature results. Moreover, simulations revealed that the results are influenced significantly by the presence of AlO4(-) T-sites. The results confirm the capacity of the Compass force-field to predict water sorption properties in silicalite and in DAY. PMID- 26641513 TI - Effects of the Aluminum Content of a Zeolite Framework: A DFT/MM Hybrid Approach Based on Cluster Models Embedded in an Elastic Polarizable Environment. AB - We report the first computational study with a sophisticated quantum mechanics/molecular mechanics (QM/MM) technique that addresses the effect of the aluminum content on the properties of acidic zeolites. To account for both electrostatic and mechanical interaction between the QM cluster and its MM environment, we used cluster models embedded in the covalent variant of the elastic polarizable environment (covEPE) [Nasluzov, V. A.; Ivanova, E. A.; Shor, A. M.; Vayssilov, G. N.; Birkenheuer, U.; Rosch, N. J. Phys. Chem. B 2003, 107, 2228]. For the practical application of the covEPE method, it was necessary to develop a new force field for Al containing zeolites. Two types of zeolite materials, FAU and MFI, were employed as examples. We modeled the variation of the Al content both in the MM environment and in the QM cluster, and we studied pertinent properties of bridging OH groups of the zeolite frameworks, OH vibrational frequencies, and deprotonation energies. The computational results suggest that the local structure and the location of the OH groups exert a stronger effect than the variation of the Al content of the framework. PMID- 26641514 TI - Histidine-Aromatic Interactions in Proteins and Protein-Ligand Complexes: Quantum Chemical Study of X-ray and Model Structures. AB - His-aromatic complexes, with the His located above the aromatic plane, are stabilized by pi-pi, delta(+)-pi and/or cation-pi interactions according to whether the His is neutral or protonated and the partners are in stacked or T shape conformations. Here we attempt to probe the relative strength of these interactions as a function of the geometry and protonation state, in gas phase, in water and protein-like environments (acetone, THF and CCl4), by means of quantum chemistry calculations performed up to second order of the Moller-Plesset pertubation theory. Two sets of conformations are considered for that purpose. The first set contains 89 interactions between His and Phe, Tyr, Trp, or Ade, observed in X-ray structures of proteins and protein-ligand complexes. The second set contains model structures obtained by moving an imidazolium/imidazole moiety above a benzene ring or an adenine moiety. We found that the protonated complexes are much more stable than the neutral ones in gas phase. This higher stability is due to the electrostatic contributions, the electron correlation contributions being equally important in the two forms. Thus, pi-pi and delta(+)-pi interactions present essentially favorable electron correlation energy terms, whereas cation-pi interactions feature in addition favorable electrostatic energies. The protonated complexes remain more stable than the neutral ones in protein-like environments, but the difference is drastically reduced. Furthermore, the T-shape conformation is undoubtedly more favorable than the stacked one in gas phase. This advantage decreases in the solvents, and the stacked conformation becomes even slightly more favorable in water. The frequent occurrence of His-aromatic interactions in catalytic sites, at protein-DNA or protein-ligand interfaces and in 3D domain swapping proteins emphasize their importance in biological processes. PMID- 26641515 TI - Optimized Radii for Poisson-Boltzmann Calculations with the AMBER Force Field. AB - Implicit solvent models are a standard tool for assessing the electrostatics of biomolecular systems. The accuracy of quantitative predictions, such as pKa values, transfer free energies, binding energies, and solvation forces, is strongly dependent on one's choice of continuum parameters: the solute charges, dielectric coefficient, and radii, which define the dielectric boundary. To ensure quantitative accuracy, these parameters can be benchmarked against explicit solvent simulations. Here we present two sets of optimized radii to define either abrupt or cubic-spline smoothed dielectric boundaries in Poisson Boltzmann calculations of protein systems with AMBER (parm99) charges. Spline smoothing stabilizes the electrostatic potential at the molecular surface, allowing for continuum force calculations. Most implementations, however, require significantly different radii than the abrupt boundary surfaces. The optimal continuum radii are initially approximated from the solvent radial charge distribution surrounding each atom type. A genetic algorithm is then used to fine tune the starting values to reproduce charging free energies measured from explicit solvent simulations. The optimized radii are tested on four protein-like polypeptides. The results show increased accuracy of molecular solvation energies and atomic forces relative to commonly used continuum parameter sets. These radii are suitable for Poisson-Boltzmann calculations with the AMBER force field and offer energetic congruence to any model that combines molecular mechanics and Poisson-Boltzmann solvation energies. PMID- 26641516 TI - Enzymatic Hydroxylation in p-Hydroxybenzoate Hydroxylase: A Case Study for QM/MM Molecular Dynamics. AB - We investigate the OH transfer step of the hydroxylation reaction of p hydroxybenzoate in the enzyme p-hydroxybenzoate hydroxylase (PHBH) using QM/MM molecular dynamics methods. The QM region (49 atoms) is treated at the AM1 level, while the MM part (ca. 23 000 atoms) is described by the GROMOS force field. Performing pointwise thermodynamic integration from 10 starting structures, we have obtained an average value of the free-energy barrier for this reaction of 101 kJ mol(-)(1). The simulations provide insight into the dynamics of the hydrogen bonding network in the active site along the course of the reaction. In addition, we describe statistical techniques to analyze molecular dynamics data that assess the convergence of averages and yield an error measure. We discuss the effect of different error sources on the free energy. PMID- 26641517 TI - Determination of Intermolecular Hydrogen Bonded Conformers of alpha Aryloxypropanoic Acids Using Density Functional Theory Predictions of Vibrational Absorption and Vibrational Circular Dichroism Spectra. AB - The density functional theoretical predictions of vibrational absorption (VA) and vibrational circular dichroism (VCD) spectra for monomeric chiral alpha aryloxypropanoic acids are found to be in serious disagreement with corresponding experimental spectra. This disagreement made it difficult to establish the predominant conformations and absolute configuration of chiral alpha aryloxypropanoic acids. Since carboxylic acids tend to form dimers through intermolecular hydrogen bonding in solution, such hydrogen bonding should be either eliminated in the experimental measurements or modeled properly in the theoretical calculations for achieving agreement between theoretical predictions and experimental observations. Esterification eliminates hydrogen bonding in solution, but this approach does not provide information about the conformations of the acids. As a consequence, the option to properly model the dimers of alpha aryloxypropanoic acids and to evaluate the dimer conformations in reproducing the experimental spectra becomes important. Here we report a method for obtaining the dimer conformations of alpha-aryloxypropanoic acids using density functional theory and evaluate their reliability by comparing the predicted and experimental VA and VCD spectra. The population weighted predicted VA and VCD spectra of dimers matched well with the corresponding experimental spectra in solution, thereby indicating the predominant dimer conformers and absolute configuration of alpha-aryloxypropanoic acids. PMID- 26641518 TI - A multilevel analysis of the relationship between parental migration and left behind children's macronutrient intakes in rural China. AB - OBJECTIVE: China's internal migration has left 61 million children living apart from their parent(s) in rural areas. The present study aimed to examine whether the relative contributions of macronutrients (protein, fat and carbohydrate) to total energy intake differ between children left behind by the father or mother, compared with children from intact families. DESIGN: Drawing on a longitudinal study, the China Health and Nutrition Survey (1997-2009), multilevel modelling analyses (level 1: occasions; level 2: children; level 3: villages) were performed. SETTING: Data from rural communities in nine provinces in China. SUBJECTS: Rural children (n 975; 555 boys and 420 girls) from 140 villages. RESULTS: Among boys of school age, being left behind by the father tended to reduce the relative protein intake by 0.70 % (P<0.01) compared with boys from intact families. Being left behind by at least the mother was more detrimental for young boys under the age of 6 years than paternal migration, reducing relative protein intake by 1.14 % (P<0.05). Parental migration was associated with a significant increase in young boys' relative fat intake by 2.60 % (P<0.05). No significant associations were found for girls. Results suggest left behind boys, especially in early life, are subject to a higher-fat and lower protein diet compared with non-left-behind boys. This may put them at increased risk of being overweight or obese, or of suffering from stunted growth, when they grow up. CONCLUSIONS: Public health policies should recognise the influences of parental migration on boys, especially maternal migration, and encourage a more balanced diet for children in rural China. PMID- 26641519 TI - Health risk assessment of migrant workers' exposure to polychlorinated biphenyls in air and dust in an e-waste recycling area in China: Indication for a new wealth gap in environmental rights. AB - Migrant workers who work and live in polluted environment are a special vulnerable group in the accelerating pace of urbanization and industrialization in China. In the electronic waste (e-waste) recycling area, for example, migrant workers' exposure to pollutants, such as PCBs (polychlorinated biphenyls), is the result of an informal e-waste recycling process. A village in an electronic waste recycling area where migrant workers gather was surveyed. The migrant workers' daily routines were simulated according to the three-space transition: work place on the road-home. Indoor air and dust in the migrant workers' houses and workplaces and the ambient air on the roads were sampled. The PCB levels of the air and dust in the places corresponding to the migrant workers are higher than those for local residents. The migrant workers have health risks from PCBs that are 3.8 times greater than those of local residents. This is not only caused by the exposure at work but also by their activity patterns and the environmental conditions of their dwellings. These results revealed the reason for the health risk difference between the migrant workers and local residents, and it also indicated that lifestyle and economic status are important factors that are often ignored compared to occupational exposure. PMID- 26641520 TI - Prenatal particulate air pollution and neurodevelopment in urban children: Examining sensitive windows and sex-specific associations. AB - BACKGROUND: Brain growth and structural organization occurs in stages beginning prenatally. Toxicants may impact neurodevelopment differently dependent upon exposure timing and fetal sex. OBJECTIVES: We implemented innovative methodology to identify sensitive windows for the associations between prenatal particulate matter with diameter <= 2.5 MUm (PM2.5) and children's neurodevelopment. METHODS: We assessed 267 full-term urban children's prenatal daily PM2.5 exposure using a validated satellite-based spatio-temporally resolved prediction model. Outcomes included IQ (WISC-IV), attention (omission errors [OEs], commission errors [CEs], hit reaction time [HRT], and HRT standard error [HRT-SE] on the Conners' CPT-II), and memory (general memory [GM] index and its components - verbal [VEM] and visual [VIM] memory, and attention-concentration [AC] indices on the WRAML-2) assessed at age 6.5+/-0.98 years. To identify the role of exposure timing, we used distributed lag models to examine associations between weekly prenatal PM2.5 exposure and neurodevelopment. Sex-specific associations were also examined. RESULTS: Mothers were primarily minorities (60% Hispanic, 25% black); 69% had <=12 years of education. Adjusting for maternal age, education, race, and smoking, we found associations between higher PM2.5 levels at 31-38 weeks with lower IQ, at 20-26 weeks gestation with increased OEs, at 32-36 weeks with slower HRT, and at 22-40 weeks with increased HRT-SE among boys, while significant associations were found in memory domains in girls (higher PM2.5 exposure at 18 26 weeks with reduced VIM, at 12-20 weeks with reduced GM). CONCLUSIONS: Increased PM2.5 exposure in specific prenatal windows may be associated with poorer function across memory and attention domains with variable associations based on sex. Refined determination of time window- and sex-specific associations may enhance insight into underlying mechanisms and identification of vulnerable subgroups. PMID- 26641522 TI - Pollutant exposures and health symptoms in aircrew and office workers: Is there a link? AB - Sensory effects in eyes and airways are common symptoms reported by aircraft crew and office workers. Neurological symptoms, such as headache, have also been reported. To assess the commonality and differences in exposures and health symptoms, a literature search of aircraft cabin and office air concentrations of non-reactive volatile organic compounds (VOCs) and ozone-initiated terpene reaction products were compiled and assessed. Data for tricresyl phosphates, in particular tri-ortho-cresyl phosphate (ToCP), were also compiled, as well as information on other risk factors such as low relative humidity. A conservative health risk assessment for eye, airway and neurological effects was undertaken based on a "worst-case scenario" which assumed a simultaneous constant exposure for 8h to identified maximum concentrations in aircraft and offices. This used guidelines and reference values for sensory irritation for eyes and upper airways and airflow limitation; a tolerable daily intake value was used for ToCP. The assessment involved the use of hazard quotients or indexes, defined as the summed ratio(s) (%) of compound concentration(s) divided by their guideline value(s). The concentration data suggest that, under the assumption of a conservative "worst-case scenario", aircraft air and office concentrations of the compounds in question are not likely to be associated with sensory symptoms in eyes and airways. This is supported by the fact that maximum concentrations are, in general, associated with infrequent incidents and brief exposures. Sensory symptoms, in particular in eyes, appear to be exacerbated by environmental and occupational conditions that differ in aircraft and offices, e.g., ozone incidents, low relative humidity, low cabin pressure, and visual display unit work. The data do not support airflow limitation effects. For ToCP, in view of the conservative approach adopted here and the rareness of reported incidents, the health risk of exposure to this compound in aircraft is considered negligible. PMID- 26641521 TI - Particulate matter air pollution components and risk for lung cancer. AB - BACKGROUND: Particulate matter (PM) air pollution is a human lung carcinogen; however, the components responsible have not been identified. We assessed the associations between PM components and lung cancer incidence. METHODS: We used data from 14 cohort studies in eight European countries. We geocoded baseline addresses and assessed air pollution with land-use regression models for eight elements (Cu, Fe, K, Ni, S, Si, V and Zn) in size fractions of PM2.5 and PM10. We used Cox regression models with adjustment for potential confounders for cohort specific analyses and random effect models for meta-analysis. RESULTS: The 245,782 cohort members contributed 3,229,220 person-years at risk. During follow up (mean, 13.1 years), 1878 incident cases of lung cancer were diagnosed. In the meta-analyses, elevated hazard ratios (HRs) for lung cancer were associated with all elements except V; none was statistically significant. In analyses restricted to participants who did not change residence during follow-up, statistically significant associations were found for PM2.5 Cu (HR, 1.25; 95% CI, 1.01-1.53 per 5 ng/m(3)), PM10 Zn (1.28; 1.02-1.59 per 20 ng/m(3)), PM10 S (1.58; 1.03-2.44 per 200 ng/m(3)), PM10 Ni (1.59; 1.12-2.26 per 2 ng/m(3)) and PM10 K (1.17; 1.02-1.33 per 100 ng/m(3)). In two-pollutant models, associations between PM10 and PM2.5 and lung cancer were largely explained by PM2.5 S. CONCLUSIONS: This study indicates that the association between PM in air pollution and lung cancer can be attributed to various PM components and sources. PM containing S and Ni might be particularly important. PMID- 26641523 TI - The mortality effect of ship-related fine particulate matter in the Sydney greater metropolitan region of NSW, Australia. AB - This study investigates the mortality effect of primary and secondary PM2.5 related to ship exhaust in the Sydney greater metropolitan region of Australia. A detailed inventory of ship exhaust emissions was used to model a) the 2010/11 concentration of ship-related PM2.5 across the region, and b) the reduction in PM2.5 concentration that would occur if ships used distillate fuel with a 0.1% sulfur content at berth or within 300 km of Sydney. The annual loss of life attributable to 2010/11 levels of ship-related PM2.5 and the improvement in survival associated with use of low-sulfur fuel were estimated from the modelled concentrations. In 2010/11, approximately 1.9% of the region-wide annual average population weighted-mean concentration of all natural and human-made PM2.5 was attributable to ship exhaust, and up to 9.4% at suburbs close to ports. An estimated 220 years of life were lost by people who died in 2010/11 as a result of ship exhaust-related exposure (95% CIbeta: 140-290, where CIbeta is the uncertainty in the concentration-response coefficient only). Use of 0.1% sulfur fuel at berth would reduce the population weighted-mean concentration of PM2.5 related to ship exhaust by 25% and result in a gain of 390 life-years over a twenty year period (95% CIbeta: 260-520). Use of 0.1% sulfur fuel within 300 km of Sydney would reduce the concentration by 56% and result in a gain of 920 life years over twenty years (95% CIbeta: 600-1200). Ship exhaust is an important source of human exposure to PM2.5 in the Sydney greater metropolitan region. This assessment supports intervention to reduce ship emissions in the GMR. Local strategies to limit the sulfur content of fuel would reduce exposure and will become increasingly beneficial as the shipping industry expands. A requirement for use of 0.1% sulfur fuel by ships within 300 km of Sydney would provide more than twice the mortality benefit of a requirement for ships to use 0.1% sulfur fuel at berth. PMID- 26641524 TI - Phase-Controlled Electrochemical Activity of Epitaxial Mg-Spinel Thin Films. AB - We report an approach to control the reversible electrochemical activity (i.e., extraction/insertion) of Mg(2+) in a cathode host through the use of phase-pure epitaxially stabilized thin film structures. The epitaxially stabilized MgMn2O4 (MMO) thin films in the distinct tetragonal and cubic phases are shown to exhibit dramatically different properties (in a nonaqueous electrolyte, Mg(TFSI)2 in propylene carbonate): tetragonal MMO shows negligible activity while the cubic MMO (normally found as polymorph at high temperature or high pressure) exhibits reversible Mg(2+) activity with associated changes in film structure and Mn oxidation state. These results demonstrate a novel strategy for identifying the factors that control multivalent cation mobility in next-generation battery materials. PMID- 26641526 TI - Electrochemistry of Simple Organometallic Models of Iron-Iron Hydrogenases in Organic Solvent and Water. AB - Synthetic models of the active site of iron-iron hydrogenases are currently the subjects of numerous studies aimed at developing H2-production catalysts based on cheap and abundant materials. In this context, the present report offers an electrochemist's view of the catalysis of proton reduction by simple binuclear iron(I) thiolate complexes. Although these complexes probably do not follow a biocatalytic pathway, we analyze and discuss the interplay between the reduction potential and basicity and how these antagonist properties impact the mechanisms of proton-coupled electron transfer to the metal centers. This question is central to any consideration of the activity at the molecular level of hydrogenases and related enzymes. In a second part, special attention is paid to iron thiolate complexes holding rigid and unsaturated bridging ligands. The complexes that enjoy mild reduction potentials and stabilized reduced forms are promising iron-based catalysts for the photodriven evolution of H2 in organic solvents and, more importantly, in water. PMID- 26641525 TI - Azaphilones from an Acid Mine Extremophile Strain of a Pleurostomophora sp. AB - An extremophilic fungus identified as a Pleurostomophora sp. was isolated from the Berkeley Pit, an acid mine waste lake. When grown in liquid culture, the fungus produced berkchaetoazaphilones A-C (1, 2, and 5), the red pigment berkchaetorubramine (6), and the known compound 4-(hydroxymethyl)quinoline. These compounds were evaluated as inhibitors of matrix metalloproteinase-3, caspase-1, and proinflammatory cytokine production in induced THP-1 cells. Berkchaetoazaphilone B (2) inhibited IL-1beta, TNFalpha, and IL-6 production in the induced inflammasome assay and was cytotoxic toward human retinoblastoma cell line Y79 (IC50 = 1.1 MUM), leukemia cell lines CCRF-CEM and SR, and the melanoma cell line LOX IMVI (IC50 = 10 MUM). PMID- 26641527 TI - Should we refrain from antibiotic use in hospice patients? PMID- 26641528 TI - Stable and Size-Tunable Aggregation-Induced Emission Nanoparticles Encapsulated with Nanographene Oxide and Applications in Three-Photon Fluorescence Bioimaging. AB - Organic fluorescent dyes with high quantum yield are widely applied in bioimaging and biosensing. However, most of them suffer from a severe effect called aggregation-caused quenching (ACQ), which means that their fluorescence is quenched at high molecular concentrations or in the aggregation state. Aggregation-induced emission (AIE) is a diametrically opposite phenomenon to ACQ, and luminogens with this feature can effectively solve this problem. Graphene oxide has been utilized as a quencher for many fluorescent dyes, based on which biosensing can be achieved. However, using graphene oxide as a surface modification agent of fluorescent nanoparticles is seldom reported. In this article, we used nanographene oxide (NGO) to encapsulate fluorescent nanoparticles, which consisted of a type of AIE dye named TPE-TPA-FN (TTF). NGO significantly improved the stability of nanoparticles in aqueous dispersion. In addition, this method could control the size of nanoparticles' flexibly as well as increase their emission efficiency. We then used the NGO-modified TTF nanoparticles to achieve three-photon fluorescence bioimaging. The architecture of ear blood vessels in mice and the distribution of nanoparticles in zebrafish could be observed clearly. Furthermore, we extended this method to other AIE luminogens and showed it was widely feasible. PMID- 26641529 TI - Ultralow effective work function surfaces using diamondoid monolayers. AB - Electron emission is critical for a host of modern fabrication and analysis applications including mass spectrometry, electron imaging and nanopatterning. Here, we report that monolayers of diamondoids effectively confer dramatically enhanced field emission properties to metal surfaces. We attribute the improved emission to a significant reduction of the work function rather than a geometric enhancement. This effect depends on the particular diamondoid isomer, with [121]tetramantane-2-thiol reducing gold's work function from ~ 5.1 eV to 1.60 +/- 0.3 eV, corresponding to an increase in current by a factor of over 13,000. This reduction in work function is the largest reported for any organic species and also the largest for any air-stable compound. This effect was not observed for sp(3)-hybridized alkanes, nor for smaller diamondoid molecules. The magnitude of the enhancement, molecule specificity and elimination of gold metal rearrangement precludes geometric factors as the dominant contribution. Instead, we attribute this effect to the stable radical cation of diamondoids. Our computed enhancement due to a positively charged radical cation was in agreement with the measured work functions to within +/- 0.3 eV, suggesting a new paradigm for low-work function coatings based on the design of nanoparticles with stable radical cations. PMID- 26641530 TI - Nanoscale phase engineering of thermal transport with a Josephson heat modulator. AB - Macroscopic quantum phase coherence has one of its pivotal expressions in the Josephson effect, which manifests itself both in charge and energy transport. The ability to master the amount of heat transferred through two tunnel-coupled superconductors by tuning their phase difference is the core of coherent caloritronics, and is expected to be a key tool in a number of nanoscience fields, including solid-state cooling, thermal isolation, radiation detection, quantum information and thermal logic. Here, we show the realization of the first balanced Josephson heat modulator designed to offer full control at the nanoscale over the phase-coherent component of thermal currents. Our device provides magnetic-flux-dependent temperature modulations up to 40 mK in amplitude with a maximum of the flux-to-temperature transfer coefficient reaching 200 mK per flux quantum at a bath temperature of 25 mK. Foremost, it demonstrates the exact correspondence in the phase engineering of charge and heat currents, breaking ground for advanced caloritronic nanodevices such as thermal splitters, heat pumps and time-dependent electronic engines. PMID- 26641531 TI - A CRISPR-Cas9 gene drive system targeting female reproduction in the malaria mosquito vector Anopheles gambiae. AB - Gene drive systems that enable super-Mendelian inheritance of a transgene have the potential to modify insect populations over a timeframe of a few years. We describe CRISPR-Cas9 endonuclease constructs that function as gene drive systems in Anopheles gambiae, the main vector for malaria. We identified three genes (AGAP005958, AGAP011377 and AGAP007280) that confer a recessive female-sterility phenotype upon disruption, and inserted into each locus CRISPR-Cas9 gene drive constructs designed to target and edit each gene. For each targeted locus we observed a strong gene drive at the molecular level, with transmission rates to progeny of 91.4 to 99.6%. Population modeling and cage experiments indicate that a CRISPR-Cas9 construct targeting one of these loci, AGAP007280, meets the minimum requirement for a gene drive targeting female reproduction in an insect population. These findings could expedite the development of gene drives to suppress mosquito populations to levels that do not support malaria transmission. PMID- 26641533 TI - Gene-edited pigs are protected from porcine reproductive and respiratory syndrome virus. PMID- 26641532 TI - The quantitative and condition-dependent Escherichia coli proteome. AB - Measuring precise concentrations of proteins can provide insights into biological processes. Here we use efficient protein extraction and sample fractionation, as well as state-of-the-art quantitative mass spectrometry techniques to generate a comprehensive, condition-dependent protein-abundance map for Escherichia coli. We measure cellular protein concentrations for 55% of predicted E. coli genes (>2,300 proteins) under 22 different experimental conditions and identify methylation and N-terminal protein acetylations previously not known to be prevalent in bacteria. We uncover system-wide proteome allocation, expression regulation and post-translational adaptations. These data provide a valuable resource for the systems biology and broader E. coli research communities. PMID- 26641534 TI - Mitochondrial genome of one kind of giant Asian mantis, Hierodula formosana (Mantodea: Mantidae). AB - The giant Asian mantis Hierodula formosana (Mantodea: Mantidae) is widely distributed in Taiwan. In the present study, we investigated the complete mitochondrial genome of H. formosana and the mitogenome is 16 266 bp in length. The circular molecule consists of 13 protein-coding genes, 2 ribosomal RNA genes, 22 transfer RNA genes, and a non-coding control region, with an AT content of 75.8%. An extra non-coding region is inserted between trnM and ND2, similar to the other Mantidae species T. tamolana. A preliminary phylogenetic analysis has been carried out with 11 related species and the status of Hierodula formosana is further confirmed. PMID- 26641535 TI - Once-daily glycopyrronium bromide (Seebri Breezhaler((r))) for the treatment of chronic obstructive pulmonary disease (COPD). AB - INTRODUCTION: Long-acting bronchodilators are the mainstay of pharmacological therapy for patients with chronic obstructive pulmonary disease (COPD). The choice of optimal bronchodilator therapy for COPD is increasingly difficult for clinicians as new treatments are marketed. AREAS COVERED: Inhaled glycopyrronium bromide (Seebri Breezhaler(r)) is a well-tolerated long-acting anti-muscarinic agent (LAMA) with a fast onset of action. In patients with moderate to severe COPD, glycopyrronium bromide has clinically important effects on level of FEV1, use of relief medication, day-time dyspnea scores, and probably also on health status. Furthermore, glycopyrronium bromide also has beneficial effects on dynamic hyperinflation and, probably by that, exercise tolerance. Glycopyrronium bromide has been shown to reduce the rate of exacerbations in patients with moderate to severe COPD, although as a secondary outcome only. EXPERT OPINION: Once-daily inhaled glycopyrronium bromide has positive impact on important COPD outcomes, comparable to the effects of other marketed LAMAs. Once-daily administration may improve adherence, and glycopyrronium bromide has the potential for a role in the future management of COPD similar to that of other long-acting anti-muscarinic agents, including tiotropium. Studies of glycopyrronium bromide with exacerbation rate as the primary outcome of interest is needed. PMID- 26641536 TI - The complete mitochondrial genome sequence of White-collared Yuhina (Yuhina diademata). AB - We sequenced the complete mitochondrial DNA genome of Yuhina diademata by means of polymerase chain reaction. The circle genome (17 834 bp in length) contained 13 protein-coding genes (PCGs), 2 rRNA genes, 22 tRNA genes, and 2 control regions (Dloop1 and Dloop2), which was similar to the other published mitogenome of Timaliidae species. Most PCGs began with ATG, while COI and ND2 genes started with GTG. Nine of the PCGs used complete (TAA) or incomplete (TA- or T--) stop codon, while ND1 and ND6 genes ended with AGA, COI gene ended with AGG, and ND6 gene with TAG. Overall base composition of the complete mtDNA was 30.30% A, 23.81% T, 31.72% C, and 14.17% G. All the PCGs in Y. diademata were distributed on the H-strand, except for the ND6 gene and eight tRNA genes which were encoded on the L-strand. PMID- 26641537 TI - High-fat diet differentially regulates metabolic parameters in obesity-resistant S5B/Pl rats and obesity-prone Osborne-Mendel rats. AB - The current experiment tested the hypothesis that consumption of a high-fat diet (HFD) would differentially affect metabolic parameters in obesity-prone Osborne Mendel (OM) and obesity-resistant S5B/Pl (S5B) rats. In OM rats consuming a HFD, an increase in HFD intake, body mass, and percent fat mass, and a HFD-induced decrease in metabolic rate and energy expenditure were demonstrated. In S5B rats consuming a HFD, no change in percent body fat or HFD intake was demonstrated and HFD increased metabolic rate and energy expenditure. To assess whether HFD differentially altered skeletal muscle markers of metabolism in OM and S5B rats, the expression of the transporters, CD36 and GLUT4, and the energy sensors, AMPK and PPARgamma, in the gastrocnemius muscle was measured. Oxidation and lipid accumulation in the gastrocnemius muscle was histologically determined. Consumption of a HFD decreased phosphorylated AMPK and PPARgamma expression in the skeletal muscle of obesity-prone OM rats. Lipid accumulation in skeletal muscle was significantly higher in OM rats fed a HFD. Overall, these data suggest that the differential response to HFD on metabolic rate, energy expenditure, and phosphorylated AMPK and PPARgamma in OM and S5B rats, may partially account for differences in the susceptibility to develop obesity. PMID- 26641538 TI - Elucidating Electrostatic Self-Assembly: Molecular Parameters as Key to Thermodynamics and Nanoparticle Shape. AB - The rational design of supramolecular nanoparticles by self-assembly is a crucial field of research due to the wide applications and the possibility of control through external triggers. Understanding the shape-determining factors is the key for tailoring nanoparticles with desired properties. Here, we show how the thermodynamics of the interaction control the shape of the nanoparticle. We highlight the connection between the molecular structure of building blocks, the interaction strength, and the nanoassembly shape. Nanoparticles are prepared by electrostatic self-assembly of cationic polyelectrolyte dendrimers of different generations and oppositely charged multivalent organic dyes relying on the combination of electrostatic and pi-pi interactions. Different building blocks have been used to vary interaction strength, geometric constraints, and charge ratio, providing insights into the assembly process. The nanoassembly structure has been characterized using atomic force microscopy, static light scattering, small angle neutron scattering, and UV-vis spectroscopy. We show that the isotropy/anisotropy of the nanoassemblies is related to the dye valency. Isothermal titration calorimetry has been used to investigate both dye-dye and dye-dendrimer interaction. The existence of a threshold value in entropy and enthalpy change separating isotropic and anisotropic shapes for both interactions has been demonstrated. The effects of the dye molecular structure on the interaction thermodynamics and therefore on the nanoparticle structure have been revealed using molecular modeling. The polar surface area of the dye molecule takes a key role in the dye self-interaction. This study opens the possibility for a priori shape determination knowing the building blocks structure and their interactions. PMID- 26641539 TI - Evidence update: GlaxoSmithKline's inactivated quadrivalent influenza vaccines. AB - Inactivated trivalent influenza vaccines (IIV3s) are designed to protect against illness caused by two influenza A virus subtypes and one influenza B virus lineage. They may provide inadequate protection due to the co-circulation of viruses from two antigenically distinct influenza B lineages. Incorporating strains from both B lineages as in inactivated quadrivalent influenza vaccines (IIV4s) reduces this risk. We summarize the evidence supporting two IIV4s manufactured by GSK Vaccines. Compared to IIV3s, these two IIV4s demonstrated noninferior immunogenicity against the shared influenza strains and superior immunogenicity for the strain of the additional B lineage, particularly in subjects who were seronegative for that B strain. One IIV4's efficacy in children aged 3-8 years was 55.4% against influenza of any severity and 73.1% against moderate-to-severe influenza. Both IIV4s were well-tolerated with a similar safety profile to IIV3s. These IIV4s are more likely than IIV3s to protect against the added influenza B strain. PMID- 26641540 TI - The efficacy of standard laxative use for the prevention and treatment of opioid induced constipation during oxycodone use: a small Dutch observational pilot study. AB - BACKGROUND: Dutch clinical guidelines recommend that a standard laxative treatment (SLT) should be prescribed concomitantly when starting opioid treatment to prevent opioid-induced constipation (OIC). METHODS: Clinical evidence for SLT in the treatment of OIC is lacking, therefore an observational pilot study was performed to explore the efficacy and tolerability of SLT on OIC in patients treated with the opioid oxycodone. RESULTS: Twenty-four patients (58% female, median (range) age 65 (39-92)) were included in this pilot study. The analysis showed that 9 out of 21 patients (43%) were non-responders to SLT. When also taking into consideration patients tending to develop diarrhea 75% of patients are non-responsive to SLT. CONCLUSION: This pilot study indicates that optimal laxative therapy (SLT) might not be effective and feasible for the prevention and treatment of OIC. PMID- 26641541 TI - Rapid Screening of Glycerol Ether Lipid Biomarkers in Recent Marine Sediment Using Atmospheric Pressure Photoionization in Positive Mode Fourier Transform Ion Cyclotron Resonance Mass Spectrometry. AB - Many of the molecular proxies commonly used for paleoenvironmental reconstruction are focused on a limited set of glycerol ether lipids, mainly due to the lack of more comprehensive analytical methods and instrumentation able to deal with a more diverse range of species. In this study, we describe an FTICR-MS-based method for rapid, nontargeted screening of ether lipid biomarkers in recent marine sediments. This method involves simplified sample preparation and enables rapid identification of known and novel ether lipid species. Using this method, we were able to identify complete series of core glycerol dialkyl glycerol tetraethers (GDGTs with 0 to 8 alicyclic rings), including the complete resolution of GDGT-4 and the unexpected detection of GDGTs with more than 5 rings, in sediments from mesophilic marine environments (sea surface temperature, SST, of 24-25 degrees C). Additionally, mono- and dihydroxy-GDGT analogs (including novel species with >2 rings), as well as glycerol dialkanol diethers, GDDs (including novel species with >5 rings) were detected. Finally, we putatively identified other, previously unreported groups of glycerol ether lipid species. Adequacy of the APPI-P FTICR-MS data for the determination of commonly used GDGT-based proxy indices was demonstrated. The results of this study show great potential for the use of FTICR-MS as both a rapid method for determining existing proxy indices and, perhaps more importantly, as a tool for the early detection of possible new biomarkers and proxies that may establish novel geochemical relationships between archaeal ether lipids and key environmental-, energy-, and climate-related system variables. PMID- 26641542 TI - Association Mapping of Quantitative Trait Loci for Mineral Element Contents in Whole Grain Rice (Oryza sativa L.). AB - Mineral elements in brown rice grain play an important role in human health. In this study, variations in the content of iron (Fe), zinc (Zn), selenium (Se), cadmium (Cd), and lead (Pb) in 378 accessions of brown rice were investigated, and association mapping was used to detect the quantitative trait loci (QTLs) responsible for the variation. Among seven subpopulations, the mean values of Zn and Cd in the japonica group were significantly higher than in the indica groups. The population structure accounted for from 5.7% (Se) to 22.1% (Pb) of the total variation. Correlation analyses showed that Pb was positively correlated with the other minerals (P < 0.001) except for Se. For the five mineral elements investigated, 20 QTLs, including some previously reported and new candidate loci, were identified. Particularly, three cases of QTL colocalization, i.e. Cd and Pb on chromosome 5, Zn and Pb on chromosome 7, and Se and Pb on chromosome 11, were observed. This study suggested that the identified markers could feasibly be used to enhance desired micronutrients while reducing the heavy metal content in whole rice grain by marker-assisted selection (MAS). PMID- 26641543 TI - Highly Photoluminescent Nitrogen-Doped Carbon Nanodots and Their Protective Effects against Oxidative Stress on Cells. AB - Highly photoluminescent (PL) (quantum yield = 54%) nitrogen doped carbon nanodots (C-dots) have been prepared through one-step carbonizing citric acid and tris(hydroxymethyl)aminomethane and using oleic acid as solvent. The synthesized C-dots are monodisperse with narrow size distribution (average 1.7 nm). The PL properties of C-dots are pH dependent, and hence, using C-dots as sophisticated pH sensor to detect pH values between 7 and 9 can be expected. In addition, the PL intensity of C-dots remains stable under high ionic strength. The C-dots can protect cells from oxidative stress, which shows potential to expand the biological application of C-dots, especially in medical treatment. The protective mechanism is associated with intracellular reactive oxygen species elimination and the intracellular superoxide dismutase production. PMID- 26641544 TI - Research in Medical Education and Patient-Centered Outcomes: Shall Ever the Twain Meet? PMID- 26641546 TI - Variant c.2262A>C in DOCK9 Leads to Exon Skipping in Keratoconus Family. AB - PURPOSE: Keratoconus (KTCN) is a degenerative disorder of the eye that is characterized by a conical shape and thinning of the cornea, resulting in impaired visual function. Previously, we identified heterozygous single base-pair substitutions in DOCK9, IPO5, and STK24, showing concurrent 100% segregation with the affected phenotype in an Ecuadorian family. As the pathogenic consequences of these variants were not obvious, we performed in vitro splicing analyses to determine their functional significance. METHODS: We generated expression constructs using patient DNA as a template corresponding to the wild-type and mutant alleles of DOCK9, IPO5, and STK24. After transfecting HeLa cells with each construct, total RNA samples were extracted, reverse transcribed, and amplified using specific primers. RESULTS: In vitro splicing analysis revealed that only c.2262A>C in exon 20 of DOCK9 led to aberrant splicing, resulting in the changed ratio between two protein isoforms: a normal transcript and a transcript with exon skipping. The exon skipping causes a premature stop codon, disrupting the functional domains of DOCK9 protein, which may alter the biological role of DOCK9 as a Cdc42 activator. CONCLUSIONS: Based on in vitro results, we demonstrated that c.2262A>C substitution in DOCK9, previously identified in KTCN-affected members of an Ecuadorian family, leads to a splicing aberration. However, because the mutation effect was observed in vitro, a definitive relationship between DOCK9 and KTCN phenotype could not be established. Our results indicate that further elucidation of the causes of KTCN is needed. PMID- 26641545 TI - The Connective Tissue Components of Optic Nerve Head Cupping in Monkey Experimental Glaucoma Part 1: Global Change. AB - PURPOSE: To characterize optic nerve head (ONH) connective tissue change within 21 monkey experimental glaucoma (EG) eyes, so as to identify its principal components. METHODS: Animals were imaged three to five times at baseline then every 2 weeks following chronic unilateral IOP elevation, and euthanized early through end-stage confocal scanning laser tomographic change. Optic nerve heads were serial-sectioned, three-dimensionally (3D) reconstructed, delineated, and quantified. Overall EG versus control eye differences were assessed by general estimating equations (GEE). Significant, animal-specific, EG eye change was required to exceed the maximum physiologic intereye differences in six healthy animals. RESULTS: Overall EG eye change was significant (P < 0.0026) and animal specific EG eye change most frequent, for five phenomena (number of EG eyes and range of animal-specific change): posterior laminar deformation (21, -29 to -437 MUm), laminar thickening (11, 20-73 MUm) and thinning (3, -23 to -31 MUm), scleral canal expansion (17, 20-139 MUm), outward anterior (16, -16 to -124 MUm) and posterior (17, -22 to -279 MUm) laminar insertion migration, and peripapillary scleral bowing (11, 21-77 MUm). Experimental glaucoma versus control eye laminar thickness differences were bimodal in behavior, being thickened in most EG eyes demonstrating the least deformation and less thickened or thinned in most EG eyes demonstrating the greatest deformation. CONCLUSIONS: Our postmortem studies retrospectively identify five connective tissue components of ONH "cupping" in monkey EG which serve as targets for longitudinally staging and phenotyping ONH connective tissue alteration within all forms of monkey and human optic neuropathy. PMID- 26641547 TI - Ciliary Muscle Cell Changes During Guinea Pig Development. AB - PURPOSE: Guinea pig ciliary muscle (CM) increases robustly in volume, length, and thickness with age. We wanted to characterize CM cells during development to determine the contributions of hypertrophy (cell size increase) and hyperplasia (cell number increase) during development. METHODS: Six pigmented guinea pig eyes were collected at each of five ages: 1, 10, 20, 30, and 90 days. Refractive errors and axial lengths were determined. Eyes were temporally marked, enucleated, hemisected, and fixed. Nasal and temporal eye segments were embedded and 30-MUm serial sections were collected; the two most central slides from each hemisection were analyzed with an epifluorescence microscope and Stereo Investigator software to determine normal morphologic parameters. RESULTS: Refractive errors became less hyperopic (P = 0.0001) while axial lengths and CM lengths, cross-sectional areas, volumes, and cell sizes all increased linearly with log age (all P < 0.00001). Ciliary muscle cell numbers increased only during the first 20 days of life (P = 0.02). Nasal and temporal CM lengths (P = 0.07), cross-sectional areas (P = 0.18), and cell numbers (P = 0.70) were not different, but CM cell sizes were initially larger temporally and became larger nasally after age 30 days. CONCLUSIONS: The mechanism of guinea pig CM cell growth during the first 90 days of life was characterized by early hyperplasia combined with hypertrophic cell growth throughout development that results in larger CM lengths, cross-sectional areas, and volumes. Nasal-temporal CM development was generally symmetric, but there was more CM hypertrophy nasally at older ages. PMID- 26641548 TI - The Ability of 10-2 Short-Wavelength Perimetry in Detecting Functional Loss of the Macular Area in Preperimetric Glaucoma Patients. AB - PURPOSE: To better understand functional loss in the macular area of preperimetric glaucoma patients exhibiting structural loss by exploring correlations between parameters of the ganglion cell-inner plexiform layer (GCIPL) and 10-2 short-wavelength perimetry (SWAP). METHODS: One hundred thirty four patients underwent 10-2 SWAP and conventional 24-2 visual field (VF) testing using a Humphrey field analyzer and macular scanning via Cirrus optical coherence tomography (OCT). Correlations between GCIPL thickness (GCIPLT) and the mean sensitivity (MS) of topographically corresponding areas explored in various VF tests were calculated. Correlations between GCIPL parameters and MS of the VF, in terms of the asymmetries of various VF sectors, were also determined. RESULTS: Glaucoma patients, preperimetric by standard 24-2 VF analysis but exhibiting GCIPL thinning, had lower MS in 10-2 SWAP and central 24-2 VF analyses. The correlations between average GCIPLT and the corresponding MS were significant for both 10-2 SWAP (r = 0.291, P = 0.018) and 24-2 standard automated perimetry (r = 0.235, P = 0.029). The associations between sectoral GCIPLT and the corresponding 10-2 SWAP MS were significant for all sectors, with the highest correlation evident in the inferotemporal (r = 0.324, P = 0.009) and the lowest in the superonasal GCIPL sectors (r = 0.214, P = 0.043). Asymmetric relationships between GCIPLT and 10-2 SWAP MS exhibited similar yet stronger correlations. CONCLUSIONS: Preperimetric glaucoma patients exhibiting structural loss in the macula also had functional loss revealed by 10-2 SWAP, which was less prominent in conventional 24-2 VF. Therefore, if structural abnormality is evident in the macular area, the central VF areas should be further examined even if the standard 24-2 data appear to be normal. PMID- 26641550 TI - A2E Suppresses Regulatory Function of RPE Cells in Th1 Cell Differentiation Via Production of IL-1beta and Inhibition of PGE2. AB - PURPOSE: Inflammatory status of RPE cells induced by A2E is essential in the development of AMD. Recent research indicated T-cell immunity was involved in the pathological progression of AMD. This study was designed to investigate how A2E suppresses immunoregulatory function of RPE cells in T-cell immunity in vitro. METHODS: Mouse RPE cells or human ARPE19 cells were stimulated with A2E, and co cultured with naive T cells under Th1, Th2, Th17, and regulatory T cell (Treg) polarization conditions. The intracellular cytokines or transcript factors of the induced T-cells subset were detected with flow cytometer and qRT-PCR. The ROS levels were detected, and the factors and possible pathways involved in the A2E laden RPE cells were analyzed through neutralization antibody of IL-1beta and inhibitors of related pathways. RESULTS: The A2E reduced regulatory function of RPE cells in Treg differentiation. The A2E-laden RPE cells promoted polarization of Th1 cells in vitro, but not Th2 or Th17 differentiation. The A2E induced RPE cells to release inflammatory cytokines and ROS, but PGE2 production was inhibited. Through neutralization of IL-1beta or inhibition of COX2-PGE2 pathways, A2E-laden RPE cells expressed reduced effect in inducing Th1 cells. CONCLUSIONS: The A2E inhibited regulatory function of RPE cells in suppressing Th1 cell immunity in vitro through production of IL-1beta and inhibition of PGE2. Our data indicate that A2E could suppress immunoregulatory function of RPE cells and adaptive immunity might play a role in the immune pathogenesis of AMD. PMID- 26641549 TI - Vitamin D Activation and Function in Human Corneal Epithelial Cells During TLR Induced Inflammation. AB - PURPOSE: Vitamin D is recognized to be an important modulator of the immune system. In the eye, studies have shown that deficiencies and genetic differences in vitamin D-related genes have a significant impact on the development of various ocular diseases. Our current study examines the ability of human corneal epithelial cells (HCEC) to activate vitamin D and the effect of vitamin D treatment on antimicrobial peptide production and cytokine modulation during inflammation, with the ultimate goal of using vitamin D therapeutically for corneal inflammation. METHODS: Human corneal epithelial cells were treated with 10-7M vitamin D3 (D3) or 25-hydroxyvitamin D3 (25D3) for 24 hours and 1,25 dihydroxyvitamin D3 (1,25D3) detected by immunoassay. Human cathelicidin (LL-37) expression was examined by RT-PCR, immunoblot, and immunostaining following 1,25D3 treatment and antimicrobial activity of 1,25D3-treated cells was determined. Cells were stimulated with TLR3 agonist polyinosinic-polycytidylic acid (Poly[I:C]) for 24 hours and cytokine levels measured by RT-PCR, ELISA, and Luminex. Immunostaining determined expression of vitamin D receptor (VDR) and retinoic acid inducible gene-1 receptor (RIG-1) as well as NF-kappaB nuclear translocation. RESULTS: When treated with inactive vitamin D metabolites, HCEC produced active 1,25D3, leading to enhanced expression of the antimicrobial peptide, LL-37, dependent on VDR. 1,25-D3 decreased the expression of proinflammatory cytokines (IL-1beta, IL-6, TNFalpha, and CCL20) and MMP-9 induced by Poly(I:C) as well as pattern recognition receptor expression (TLR3, RIG-1, MDA5). However, early activation of NF-kappaB was not affected. CONCLUSIONS: These studies demonstrate the protective ability of vitamin D to attenuate proinflammatory mediators while increasing antimicrobial peptides and antipseudomonas activity in corneal cells, and further our knowledge on the immunomodulatory functions of the hormone. PMID- 26641551 TI - High Throughput Assay Identifies Glafenine as a Corrector for the Folding Defect in Corneal Dystrophy-Causing Mutants of SLC4A11. AB - PURPOSE: Protein misfolding, causing retention of nascent protein in the endoplasmic reticulum (ER), is the most common molecular phenotype for disease alleles of membrane proteins. Strategies are needed to identify therapeutics able to correct such folding/trafficking defects. Mutations of SLC4A11, a plasma membrane transport protein of the human corneal endothelial cell layer, cause cases of congenital hereditary endothelial dystrophy, Harboyan syndrome, and Fuchs' endothelial corneal dystrophy. Most SLC4A11 mutations induce SLC4A11 misfolding and retention in the ER. METHODS: An assay amenable to high-throughput screening was developed to quantify SLC4A11 at the plasma membrane, enabling a search for potential traffic-correcting small molecules. The assay was validated by comparing cell surface abundance of SLC4A11 mutants measured in the assay to observations from confocal immunofluorescence and values from cell surface biotinylation. Functionality of mutant proteins was assessed, using a confocal microscopic green fluorescent protein (GFP) water flux assay where relative rates of cell swelling are compared. RESULTS: A small-scale screen revealed that the nonsteroidal anti-inflammatory drugs (NSAIDs), glafenine, ibuprofen, and acetylsalicylic acid dissolved in 0.2% dimethyl sulfoxide (DMSO), partially rescued the trafficking defect in some SLC4A11 mutants, expressed in HEK293 cells. These SLC4A11 mutants retained functional activity when rescued to the plasma membrane by glafenine treatment. Glafenine was effective with an EC50 of 1.5 +/- 0.7 MUM. CONCLUSIONS: These data suggest that glafenine, and perhaps other NSAIDs, hold potential as therapeutics for misfolded membrane proteins, like SLC4A11. The high throughput approach described here can be modified to identify correctors of other misfolded plasma membrane proteins that cause eye disease. PMID- 26641552 TI - Neuropeptide FF Promotes Recovery of Corneal Nerve Injury Associated With Hyperglycemia. AB - PURPOSE: To investigate how the neuropeptide FF (NPFF) promotes the recovery of corneal nerve injury associated with hyperglycemia. METHODS: Gene expression was analyzed using neurotrophin and receptor RT2 profiler polymerase chain reaction arrays in trigeminal (TG) sensory neurons. The role of NPFF in the regeneration of diabetic TG nerves was investigated in vitro by using cultured TG neurons from diabetic BKS.Cg-m+/+Leprdb/J (db/db) mice and in vivo by following corneal injury healing responses. RF9, a selective NPFF receptor (NPFF2R) antagonist, was used to prevent the interactions between NPFF and NPFF2R. RESULTS: Using a mRNA real time PCR array, NPFF was found to be significantly lower in diabetic TG sensory neurons. Hyperglycemia induced the deficiency of ocular properties in db/db mice. The application of NPFF enhanced neurite elongation in diabetic TG neurons. Through subconjunctival injection, NPFF promoted corneal nerve injury recovery and epithelial wound healing in db/db mice. Furthermore, the application of NPFF rescued the activation of SIRT1 and PPAR-gamma, and downregulated the expression of PTEN and Rb in diabetic TG neurons. The promotion of NPFF on diabetic corneal epithelial healing and corneal innervations was completely abolished by RF9. Moreover, subconjunctivally injected NPFF accelerated the reinnervation of corneal nerves via the ERK1/2 pathway. CONCLUSIONS: These results indicate that NPFF signaling through NPFFR2 contributes to diabetic corneal nerve injury recovery and epithelial wound healing. Neuropeptide FF is a potential neuroregenerative factor for diabetic sensory nerve injury. Chinese Abstract. PMID- 26641553 TI - Genetic Variants and Systemic Complement Activation Levels Are Associated With Serum Lipoprotein Levels in Age-Related Macular Degeneration. AB - PURPOSE: Genetic variants in genes encoding components of lipid metabolism have been associated with AMD. The aims of this study were to evaluate the relation of these genetic variants with serum lipid levels in AMD in a large case-control cohort (n = 3070) and to test for correlations between lipids and complement activation. METHODS: Single nucleotide polymorphisms (SNPs) in eight lipid metabolism genes, previously described to be associated with AMD, were genotyped and tested for their association in our case-control cohort. Serum apolipoprotein B (ApoB), apolipoprotein AI (Apo-AI), cholesterol, triglycerides (TG), high density lipoprotein-cholesterol (HDLC), and complement activation levels (C3d/C3) were measured and tested for association with AMD. Non-HDL cholesterol and LDL were inferred based on the measurements of the other lipids and lipoproteins. General linear models and chi2 tests were used to evaluate the relation of SNPs and lipids/lipoproteins to the disease as well as their interrelations. RESULTS: Significant genotypic associations with AMD were observed for SNPs in CETP, APOE, and FADS1. The serum levels of Apo-AI and HDLC were significantly higher in patients compared with controls. Triglycerides (TG) levels were lower in AMD compared with controls. A cumulative effect was observed for APOE and CETP genotypes on HDLC and Apo-AI levels. Complement activation levels correlated positively with HDLC and Apo-AI, and negatively with TG. Both the lipids/lipoproteins and the complement activation levels associate independently to AMD. CONCLUSIONS: This study bridges the gap between genetic associations and physiological lipid levels in AMD. Additionally, the observed correlations between complement activation and lipid levels link two major systems that previously were always assessed independently. PMID- 26641554 TI - Tear Production After Bilateral Main Lacrimal Gland Resection in Rabbits. AB - PURPOSE: This study reports tear compensation observed in rabbits with bilateral resection of main lacrimal gland (LG) and explored the potential mechanisms. METHODS: Dry eye conditions were created by resection of nictitating membrane (NM), Harderian gland (HG), and main LG in eight (16 eyes) male New Zealand White rabbits. In addition to Schirmer test, Periodic acid-Schiff (PAS) staining, and ocular surface staining with fluorescein and rose Bengal, conjunctival impression cytology was employed before and up to 4 months after excision (AE). Using reverse transcription-quantitative polymerase chain reaction (RT-qPCR), expression of inflammatory biomarkers (IL-1beta, TNF-alpha, and matrix metalloproteinase-9) were monitored. Further, involvement of ionic and water transporters were investigated in conjunctival epithelium. RESULTS: Significant dry eye phenotypes in rabbits were observed 1 month AE, which corroborated with elevated biomarker mRNA expression. However, Schirmer test score and goblet cell numbers never decreased AE in conjunctival epithelium. Moreover, ocular surface staining, and biomarker expression declined to baseline in over 4 months AE. No upregulation was observed of the following conjunctival ionic transporters: cystic fibrosis transmembrane conductance regulator, sodium potassium chloride cotransporters, sodium potassium ATPase, and epithelial sodium channels. Instead, aquaporin (AQP) 4 and AQP5 were upregulated. Immunolocalization and immune blotting of AQP4 was demonstrated in rabbit conjunctival epithelium. CONCLUSIONS: In the absence of NM, HG, and main LG in rabbits, tear secretion was not decreased and significant improvement of dry eye phenotypes observed with time AE. Conjunctival AQPs are possibly involved in a compensatory tear fluid production. PMID- 26641555 TI - Multidisciplinary COPD disease management program: impact on clinical outcomes. AB - OBJECTIVES: We hypothesized performance improvement interventions would improve COPD guideline-recommended care and decrease COPD exacerbations in primary care clinic practices. METHODS: We initiated a performance improvement project in 12 clinics to improve COPD outcomes incorporating physician education, case management, web-based decision support (CareManager(TM)), and performance feedback. We collected baseline and one-year follow up data on 242 patients who had COPD with acute exacerbations. We analyzed data by two methods. First, the 12 clinics were cluster randomized to 4 intervention (117 patients) and 8 control (125 patients) clinics which all had access to CareManager(TM) but only intervention clinic physicians received case management, academic detailing, and decision support assistance. Exacerbation rates and guideline adherence were compared. Second, data from all 12 clinics were pooled in a quasi-experimental design comparing baseline and post-implementation of CareManager(TM) to determine the value of system-wide performance improvement during the study period. RESULTS: In the randomized analysis, baseline demographics were similar. No differences (p = 0.79) occurred in exacerbation rates between intervention and control clinics although both groups had decreased numbers of exacerbations from baseline to follow up (p < 0.05). The pooled data from all 12 clinics demonstrated a reduction (p < 0.05) in mean exacerbations/patient from 2.3 (CI 2.0-2.6) during baseline to 1.4 (CI 1.1-1.7) at one-year follow up. Emergency department visits and hospitalizations/patient decreased (p = 0.003). Patients naive at study start to depression screening, pneumococcal vaccination, inhaled control medications or smoking cessation had fewer (p < 0.05) exacerbations after these interventions. CONCLUSION: We observed no difference in exacerbation rates between clinics receiving case management, academic detailing, and ongoing assistance with decision support and controls. Implementation of a web-based disease management system (CareManager(TM)) along with health system-wide COPD performance improvement efforts was associated with fewer COPD exacerbations and increased adherence to guideline recommendations. PMID- 26641556 TI - Neuroprotection After Traumatic Brain Injury. PMID- 26641557 TI - Promoting Physical Activity With the Out of School Nutrition and Physical Activity (OSNAP) Initiative: A Cluster-Randomized Controlled Trial. AB - IMPORTANCE: Millions of children attend after-school programs in the United States. Increasing physical activity levels of program participants could have a broad effect on children's health. OBJECTIVE: To test the effectiveness of the Out of School Nutrition and Physical Activity (OSNAP) Initiative in increasing children's physical activity levels in existing after-school programs. DESIGN, SETTING, AND PARTICIPANTS: Cluster-randomized controlled trial with matched program pairs. Baseline data were collected September 27 through November 12, 2010, with follow-up data collected April 25 through May 27, 2011. The dates of our analysis were March 11, 2014, through August 18, 2015. The setting was 20 after-school programs in Boston, Massachusetts. All children 5 to 12 years old in participating programs were eligible for study inclusion. INTERVENTIONS: Ten programs participated in a series of three 3-hour learning collaborative workshops, with additional optional opportunities for training and technical assistance. MAIN OUTCOMES AND MEASURES: Change in number of minutes and bouts of moderate to vigorous physical activity, vigorous physical activity, and sedentary activity and change in total accelerometer counts between baseline and follow-up. RESULTS: Participants with complete data were 402 racially/ethnically diverse children, with a mean age of 7.7 years. Change in the duration of physical activity opportunities offered to children during program time did not differ between conditions (-1.2 minutes; 95% CI, -14.2 to 12.4 minutes; P = .87). Change in moderate to vigorous physical activity minutes accumulated by children during program time did not differ significantly by intervention status (-1.0; 95% CI, 3.3 to 1.3; P = .40). Total minutes per day of vigorous physical activity (3.2; 95% CI, 1.8-4.7; P < .001), vigorous physical activity minutes in bouts (4.1; 95% CI, 2.7-5.6; P < .001), and total accelerometer counts per day (16,894; 95% CI, 5101-28,686; P = .01) increased significantly during program time among intervention participants compared with control participants. CONCLUSIONS AND RELEVANCE: Although programs participating in the OSNAP Initiative did not allot significantly more time for physical activity, they successfully made existing time more vigorously active for children receiving the intervention. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01396473. PMID- 26641558 TI - Factoring out nondecision time in choice reaction time data: Theory and implications. AB - Choice reaction time (RT) experiments are an invaluable tool in psychology and neuroscience. A common assumption is that the total choice response time is the sum of a decision and a nondecision part (time spent on perceptual and motor processes). While the decision part is typically modeled very carefully (commonly with diffusion models), a simple and ad hoc distribution (mostly uniform) is assumed for the nondecision component. Nevertheless, it has been shown that the misspecification of the nondecision time can severely distort the decision model parameter estimates. In this article, we propose an alternative approach to the estimation of choice RT models that elegantly bypasses the specification of the nondecision time distribution by means of an unconventional convolution of data and decision model distributions (hence called the D*M approach). Once the decision model parameters have been estimated, it is possible to compute a nonparametric estimate of the nondecision time distribution. The technique is tested on simulated data, and is shown to systematically remove traditional estimation bias related to misspecified nondecision time, even for a relatively small number of observations. The shape of the actual underlying nondecision time distribution can also be recovered. Next, the D*M approach is applied to a selection of existing diffusion model application articles. For all of these studies, substantial quantitative differences with the original analyses are found. For one study, these differences radically alter its final conclusions, underlining the importance of our approach. Additionally, we find that strongly right skewed nondecision time distributions are not at all uncommon. PMID- 26641559 TI - Layer by layer assembly of albumin nanoparticles with selective recognition of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). AB - Crosslinked albumin nanoparticles which loaded with doxorubicin (DOX) were fabricated with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and biocompatible polysaccharide, alginate (ALG), using layer-by-layer technique. Albumin nanoparticles exhibited narrow size distribution and fluorescent property. The assembled core/shell structure of the nanoparticles can be internalized more easily with the cancer cells, which attributes to TRAIL binding with death receptors. TRAIL still hold bioactive properties after assembled onto the particles. In addition, after loaded into the albumin core nanoparticles, DOX (as the chemotherapeutics) display a synergistic cytotoxic effect on cytotoxicity in combination with TRAIL in vitro. The core/shell nanostructured nanoparticles realized in this study would be used as a promising candidate for novel drug carriers. PMID- 26641560 TI - Preparation of nano/macroporous polycaprolactone microspheres for an injectable cell delivery system using room temperature ionic liquid and camphene. AB - The nano/macroporous polycaprolactone (PCL) microspheres with cell active surfaces were developed as an injectable cell delivery system. Room temperature ionic liquid (RTIL) and camphene were used as a liquid mold and a porogen, respectively. Various-sized spheres of 244-601MUm with pores of various size and shape of 0.02-100MUm, were formed depending on the camphene/RTIL ratio (0.8-2.6). To give cell activity, the surface of porous microspheres were further modified with nerve growth factors (NGF) containing gelatin to give a thin NGF/gelatin layer, to which the neural progenitor cells (PC-12) attached and extended their neurites on to the surface layers of the microspheres. The developed microspheres may be potentially applicable as a neuronal cell delivery scaffold for neuron tissue engineering. PMID- 26641561 TI - Acoustically-controlled Leidenfrost droplets. AB - Suppressing the Leidenfrost effect can significantly improve heat transfer from a heated substrate to a droplet above it. In this work, we demonstrate that by generating high frequency acoustic wave in the droplet, at sufficient vibration displacement amplitudes, the Leidenfrost effect can be suppressed due to the acoustic radiation pressure exerted on the liquid-vapor interface; strong capillary waves are observed at the liquid-vapor interface and subsequently leads to contact between the liquid and the heated substrate. Using this technique, with 10(5)Hz vibration frequency and 10(-6)m displacement amplitude of the acoustic transducer, a maximum of 45% reduction of the initial temperature (T0~200-300 degrees C) of the heated substrate can be achieved with a single droplet of volume 10(-5)l. PMID- 26641562 TI - Effects of surface charge on interfacial interactions related to membrane fouling in a submerged membrane bioreactor based on thermodynamic analysis. AB - Effects of both membrane and sludge foulant surface zeta potentials on interfacial interactions between membrane and sludge foulant in different interaction scenarios were systematically investigated based on thermodynamic methods. Under conditions in this study, it was found that zeta potential had marginal effects on total interfacial interaction between two infinite planar surfaces, and the total interfacial interaction between foulant particles and membrane would be more repulsive with increase of absolute value of zeta potential. Adhesion of foulant particles on membrane surface should overcome an energy barrier. There exists a critical zeta potential below which energy barrier would disappear. Results also showed that rough surface membrane corresponded to significantly low strength of interfacial interactions. This study not only provided a series of methods to quantitatively assess the interfacial interactions between membrane and sludge foulants, but also reconciled the contradictory conclusions regarding effects of zeta potential in literature, giving important implications for membrane fouling mitigation. PMID- 26641563 TI - Enhanced light extraction by heterostructure photonic crystals toward white-light emission. AB - In this work, we present a novel approach on the simultaneous enhancement of intensity of red, green, and blue (RGB) emission by heterostructure colloidal photonic crystals (PCs) with tri-stopbands. The intensity of RGB emission on heterostructure PCs with tri-stopbands overlapping emission wavelengths of RGB QDs can be up to about 8-fold enhancement in comparison to that on the control sample. Furthermore, CIE diagrams show the chromaticity parameters approaching that of white light. The method will be favorable for developing optical devices of high performance. PMID- 26641564 TI - Robust surface patterning by parylene-reinforced breath figures: An enabling tool for liquid crystal microcell arrays. AB - We propose a novel fabrication method for realizing robust and solvent resistant honeycomb films by combining parylene deposition with the polymer auto organization phenomenon leading to breath figures. Parylene CVD process is suitable for producing a conformal protective layer on the honeycomb surface, reinforcing and stabilizing this structure. We demonstrate that the stabilized porous films can be filled with chloroform solution of fluorescent materials, without losing the integrity of their microstructure. In addition, liquid crystals can be encapsulated inside the patterned surface between two layers of parylene, showing interesting organization features dictated by the spatial constrains. This is the first reported application of breath figures with liquid crystals, suggesting a new approach for the development of honeycomb-based liquid crystal cells for flexible displays. PMID- 26641565 TI - Diffusiophoresis of a charged, rigid sphere in a Carreau fluid. AB - Since non-Newtonian fluid behavior are not uncommon in practice, especially in modern applications of colloid and interface science, assessment of how serious is the deviation of the existing results for Newtonian fluids due to fluid nature is highly desirable and necessary. Here, we extend previous analyses for the diffusiophoresis of a particle in a Newtonian fluid to that in a non-Newtonian fluid choosing Carreau fluids as an example. Results gathered reveal that due to the shear-thinning property of the fluid considered, the difference between the particle mobility in a Carreau fluid and that in the corresponding Newtonian fluid can be on the order of 100%. In addition, this difference has a local minimum as the thickness of double layer varies. PMID- 26641566 TI - The structure of montmorillonite gels revealed by sequential cryo-XHR-SEM imaging. AB - Imaging by extreme high resolution-scanning electron microscopy (XHR-SEM) with a monochromated and decelerated beam was applied on 5% (wt/wt) Na and Ca montmorillonite gels frozen by high pressure freezing (HPF). In order to visualize the three-dimensional structure and the contacts between clay platelets, a new approach was developed. It consists in recording a sequence of micrographs on a region of interest during controlled sublimation. This simple method allows to rewind and to relate the instantaneous configuration between several particles to their original position in the hydrated state. Consequently, aggregates of parallel platelets (i.e. curved tactoids) were present in the Ca sample and the instantaneous position of these aggregates in the course of sedimentation was revealed. The Na-sample consisted of a continuous network of flexible platelets sharing mostly face-to-face (FF) contacts caused by jamming at the relatively high concentration of the suspension (5% (wt/wt)), which was above the gel transition. Yet individual platelets belonging to the smallest size fraction were observed to be fully dispersed within the entangled structure, which confirmed the repulsive character of the gel. Substructures consisting of several platelets connected by FF-associations were also evidenced. The origin and potential impact of such substructures on the occurrence of the sol-gel transition and birefringence are discussed. PMID- 26641567 TI - Hofmeister effect on thermo-responsive poly(propylene oxide): Role of polymer molecular weight and concentration. AB - Although a vast amount of research has been dedicated to investigate the Hofmeister effect on the stability of polymer solutions, a clear understanding of the role of polymer properties in this phenomenon is still missing. Here, the Hofmeister effect of NaCl (destabilizing) and NaSCN (stabilizing) salts on aqueous solutions of poly(propylene oxide) (PPO) is studied. Four different molecular weights of PPO were investigated, to determine how the variation in the polymer coil size affects the Hofmeister effect. The investigation was further conducted for different PPO concentrations, in order to understand the effect of inter-chain interactions on the response to addition of salt. The temperature driven phase separation of the solutions was monitored by differential scanning calorimetry, which provides the precise value of the phase separation temperature, as well as the enthalpy change accompanied with the transition. It was observed that increasing the molecular weight weakens the effect of the both salts, which is interpreted in terms of a scaling law between the molecular weight and the accessible surface area of the polymers. Increasing the PPO concentration further diminished the NaCl effect, but amplified the NaSCN effect. This difference is attributed to an electrostatic stabilization mechanism in the case of NaSCN. PMID- 26641568 TI - Adsorption of phosphate from water by easily separable Fe3O4@SiO2 core/shell magnetic nanoparticles functionalized with hydrous lanthanum oxide. AB - Hydrous lanthanum oxide was loaded onto the surface of Fe3O4@SiO2 core/shell magnetic nanoparticles to obtain an easily separable adsorbent (abbreviated as Fe Si-La) for efficient separation of phosphate from water. Fe-Si-La was characterized with XRF, XRD, TEM, specific surface area and magnetization and their performance for phosphate removal was investigated. The Fe3O4@SiO2 core/shell structure was confirmed and the hydrous lanthanum oxide was successfully loaded onto its surface. The newly developed adsorbent had magnetization of 51.27emu/g. The Langmuir adsorption capacity of phosphate by Fe Si-La reached 27.8mg/g by loading only 1mmol lanthanum per gram of magnetite. The adsorption was fast; nearly 99% of phosphate could be removed within 10min. The removal of phosphate was favored within the pH range 5.0-9.0. The adsorption on Fe-Si-La was not significantly influenced by ionic strength and by the coexistence of the anions of chloride and nitrate but sulfate, bicarbonate and humic acid showed slightly greater negative effects. Phosphate removal efficiency of higher than 95% was attained for real effluent of a wastewater treatment plant when the dose of adsorbent was >0.2kg/ton. The results showed that adsorbed phosphate could be nearly completely desorbed with NaOH solution for further use. In conclusion, Fe-Si-La is a promising adsorbent for the removal and recovery of phosphate from water. PMID- 26641569 TI - Impairment of Performance Variables After In-Season Strength-Training Cessation in Elite Cyclists. AB - The current study investigated the effects of 8 wk of strength-training cessation after 25 wk of strength training on strength- and cycling-performance characteristics. Elite cyclists were randomly assigned to either 25 wk of endurance training combined with heavy strength training (EXP, n = 7, maximal oxygen uptake [VO2max] 77 +/- 6 mL . kg-1 . min-1; 3 * 4-10 RM, 1 to 2 d/wk) or to endurance training only (CON, n = 7, VO2max 73 +/- 5 mL . kg-1 . min-1). Thereafter, both groups performed endurance training only for 8 wk, coinciding with the initial part of the competition season. Data were assessed for practical significance using magnitude-based inferences. During the 25-wk preparatory period, EXP had a larger positive impact on maximal isometric half-squat force, squat jump (SJ), maximal aerobic power (Wmax), power output at 4 mmol/L [La], and mean power in 30-s Wingate test than did CON (ES = 0.46-0.74). Conversely, during the 8-wk competition period EXP had a reduction in SJ, Wmax, and mean power in the 30-s Wingate test compared with CON (ES = 0.49-0.84). The present findings suggest rapid decline of adaptations on termination of strength training during the first 8 wk of the competition period in elite cyclists. PMID- 26641596 TI - Are Front of Pack Claims Indicators of Nutrition Quality? Evidence from 2 Product Categories. AB - American grocery shoppers face an array of front of pack (FOP) nutrition and health claims when making food selections. Such systems have been categorized as summary or nutrient specific. Either type should help consumers make judgments about the nutrition quality of a product. This research tests if the type or quantity of FOP claims are indeed good indicators of objective nutrition quality. Claim and nutrition information from more than 2200 breakfast cereals and prepared meals launched between 2006 and 2010 were analyzed using binary and multinomial logistic regression models. Results suggest that no type or number of front of pack claims could distinguish "healthy" foods. However, some types and frequencies of FOP claims were significant predictors of higher or lower levels of certain key nutrients. Given the complex and crowded label environment in which these FOP claims reside, one may be concerned that such cues are not closely related to objective measures of nutrition quality. PMID- 26641597 TI - Correlates of Physical Activity Among Middle-Aged and Older Korean Americans at Risk for Diabetes. AB - PURPOSE: To explore correlates of meeting recommended physical activity (PA) goals among middle-aged and older Korean Americans at risk for diabetes mellitus (DM). DESIGN AND METHODS: PA patterns and their correlates were assessed among 292 middle-aged and older Korean Americans at risk for DM living in New York City using cross-sectional design of baseline information from a diabetes prevention intervention. PA was assessed by self-report of moderate and vigorous activity, results were stratified by age group (45-64 and 65-75 years), and bivariate analyses compared individuals performing less than sufficient PA and individuals performing sufficient PA. Logistic regression was used to calculate adjusted odds ratios predicting sufficient PA. FINDINGS: After adjusting for sex, age group, years lived in the United States, marital status, health insurance, and body mass index (BMI), sufficient PA was associated with male sex, older age, lower BMI, eating vegetables daily, and many PA-specific questions (lack of barriers, confidence, and engagement). When stratified by age group, male sex and eating vegetables daily was no longer significant among Koreans 65 to 75 years of age, and BMI was not significant for either age group. CONCLUSIONS: PA interventions targeting this population may be beneficial and should consider the roles of sex, age, physical and social environment, motivation, and self-efficacy. CLINICAL RELEVANCE: Clinical providers should understand the unique motivations for PA among Korean Americans and recognize the importance of culturally driven strategies to enable lifestyle changes and support successful aging for diverse populations. PMID- 26641598 TI - Flexible Hierarchical TiO2/Fe2O3 Composite Membrane with High Separation Efficiency for Surfactant-Stabilized Oil-Water Emulsions. AB - Globally, efficient oil-water separation for surfactant-stabilized oil-water emulsions has been in urgent demand. The current options available for separation are neither sustainable nor resistant to fouling. Herein, we introduce a hierarchically nanostructured TiO2/Fe2O3 composite membrane, which is capable of separating surfactant-stabilized oil-water emulsions with high separation efficiency. The high oil rejection rate is contributed by the acquisition of an interconnected delicate network and underwater superoleophobic interface. Meanwhile, its self-cleaning function promote the facile recovery of the contaminated membrane. Furthermore, the mechanical flexible characteristic of the TiO2/Fe2O3 composite membrane widens its applicability in industrial employment. Thanks to these properties, this novel membrane can be considered as a practical option for treating surfactant-stabilized oil-water emulsions. PMID- 26641599 TI - Facile Synthesis of Novel Polyethylene-Based A-B-C Block Copolymers Containing Poly(methyl methacrylate) Using a Living Polymerization System. AB - Ethylene-propylene-methyl methacrylate (MMA) and ethylene-hexene-MMA A-B-C block copolymers with high molecular weight (>100,000) are synthesized using fluorenylamide-ligated titanium complex activated by modified methylaluminoxane and 2,6-di-tert-butyl-4-methylphenol for the first time. After diblock copolymerization of olefin is conducted completely, MMA is added and activated by aluminum Lewis acid to promote anionic polymerization. The length of polyolefin and poly (methyl methacrylate) (PMMA) is controllable precisely by the change of the additive amount of olefin and polymerization time, respectively. A soft amorphous polypropylene or polyhexene segment is located between two hard segments of semicrystalline polyethylene and glassy PMMA blocks. PMID- 26641600 TI - Effects of nitrogen sources and metal ions on ethanol fermentation with cadmium containing medium. AB - This study evaluated ethanol fermentation and its correlation with glutathione (GSH) synthesis under various cadmium-conditions with different metal ions and nitrogen sources. We found that corn steep liquor (CSL) and yeast extract have differential roles to play in GSH accumulation in cell even though both of them could alleviate the inhibition by cadmium. The different GSH accumulation in cell resulted from the different contents of metal ions in CSL and yeast extract. Intracellular GSH decreased with increasing calcium concentrations, and high calcium concentrations rendered the yeast more tolerant to cadmium stress than the nitrogen sources did. When the mole ratio of calcium to cadmium was 100:1, yeast tolerated 1000 umol/L cadmium with no decrease in efficiency in ethanol production. As a result, the use of calcium allowed a significant saving of high cost nutrient yeast extract with an efficient ethanol production, making the bioconversion of cadmium-containing biomass into ethanol possible. PMID- 26641629 TI - Synthesis, In Vitro Biological Evaluation, and Molecular Docking of New Triazoles as Potent Antifungal Agents. AB - Based on the structure of the active site of CYP51 and the structure-activity relationships of azole antifungal compounds that we designed in a previous study, a series of 1-{1-[2-(substitutedbenzyloxy)ethyl]-1H-1,2,3-triazol-4-yl}-2-(2,4 difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ols (6a-n) were designed and synthesized utilizing copper-catalyzed azide-alkyne cycloaddition. Preliminary antifungal tests against eight human pathogenic fungi in vitro showed that all the title compounds exhibited excellent antifungal activities with a broad spectrum in vitro. Molecular docking results indicated that the interaction between the title compounds and CYP51 comprised pi-pi interactions, hydrophobic interactions, and the narrow hydrophobic cleft. PMID- 26641630 TI - Targeting Innate Immunity with dsRNA-Conjugated Mesoporous Silica Nanoparticles Promotes Antitumor Effects on Breast Cancer Cells. AB - We describe herein a Toll-like receptor 3 (TLR3) targeting delivery system based on mesoporous silica nanoparticles capped with the synthetic double stranded RNA polyinosinic-polycytidylic acid (poly(I:C)) for controlled cargo delivery in SK BR-3 breast carcinoma cells. Our results show that poly(I:C)-conjugated nanoparticles efficiently targeted breast cancer cells due to dsRNA-TLR3 interaction. Such interaction also triggered apoptotic pathways in SK-BR-3, significantly decreasing cells viability. Poly(I:C) cytotoxic effect in breast carcinoma cells was enhanced by loading nanoparticles' mesopores with the anthracyclinic antibiotic doxorubicin, a commonly used chemotherapeutic agent. PMID- 26641631 TI - Blood Eosinophils and Exacerbations in Chronic Obstructive Pulmonary Disease. The Copenhagen General Population Study. AB - RATIONALE: Whether high blood eosinophils are associated with chronic obstructive pulmonary disease (COPD) exacerbations among individuals with COPD in the general population is largely unknown. OBJECTIVES: To test the hypothesis that high blood eosinophils predict COPD exacerbations. METHODS: Among 81,668 individuals in the Copenhagen General Population Study, we examined 7,225 with COPD based on spirometry. We recorded blood eosinophils at baseline and future COPD exacerbations longitudinally, defined as moderate (short-course treatment with systemic corticosteroids) or severe (hospitalization). We also assessed exacerbation risk in a subgroup of 203 individuals with clinical COPD, defined as participants with a smoking history of at least 10 pack-years, FEV1 less than 70% of predicted value, and at least one moderate or severe exacerbation in the year before baseline. MEASUREMENTS AND MAIN RESULTS: During a median of 3.3 years of follow-up (range, 0.03-8.1), 1,439 severe and 2,864 moderate COPD exacerbations were recorded. Among all participants with COPD, blood eosinophils above versus below 0.34 * 10(9) cells per liter had multivariable-adjusted incidence rate ratios of 1.76 (95% confidence interval, 1.56-1.99) for severe exacerbations and 1.15 (1.05-1.27) for moderate exacerbations. Corresponding values in those with clinical COPD were 3.21 (2.49-4.14) and 1.69 (1.40-2.04). In contrast, using a cutpoint of 2% for blood eosinophils, the risk of exacerbations was increased for severe exacerbations only among individuals with clinical COPD and not in individuals in the broader population. CONCLUSIONS: Among individuals with COPD in the general population, increased blood eosinophil levels above 0.34 * 10(9) cells per liter were associated with a 1.76-fold increased risk of severe exacerbations. PMID- 26641632 TI - Introducing Computer-Based Testing in High-Stakes Exams in Higher Education: Results of a Field Experiment. AB - The introduction of computer-based testing in high-stakes examining in higher education is developing rather slowly due to institutional barriers (the need of extra facilities, ensuring test security) and teacher and student acceptance. From the existing literature it is unclear whether computer-based exams will result in similar results as paper-based exams and whether student acceptance can change as a result of administering computer-based exams. In this study, we compared results from a computer-based and paper-based exam in a sample of psychology students and found no differences in total scores across the two modes. Furthermore, we investigated student acceptance and change in acceptance of computer-based examining. After taking the computer-based exam, fifty percent of the students preferred paper-and-pencil exams over computer-based exams and about a quarter preferred a computer-based exam. We conclude that computer-based exam total scores are similar as paper-based exam scores, but that for the acceptance of high-stakes computer-based exams it is important that students practice and get familiar with this new mode of test administration. PMID- 26641633 TI - IgG4-Associated Cholangitis--A Mimic of PSC. AB - IgG4-associated cholangitis (IAC) is an inflammatory disorder of the biliary tract representing a major manifestation of IgG4-related disease (IgG4-RD) often with elevation of serum IgG4 levels, infiltration of IgG4+ plasma cells in the affected tissue and good response to immunosuppressive treatment. Its first description may go back to 150 years ago. The clinical presentation of IAC is often misleading, mimicking other biliary diseases such as primary sclerosing cholangitis (PSC) or cholangiocarcinoma. The HISORt criteria--histopathological, imaging, and serological features (sIgG4), other organ manifestations of IgG4-RD and response to treatment--are the standard for the diagnosis of IAC. In this overview of a recent lecture, we summarize our original findings on IgG4-RD that (i) dominant IgG4+ B-cell clones identified by advanced next generation sequencing (NGS) are highly specific for IgG4-RD (meanwhile confirmed by others), are a highly accurate diagnostic marker to distinguish IgG4-RD from PSC and biliary/pancreatic malignancies and may be crucial in unravelling the pathophysiology of IgG4-RD; (ii) sIgG4/sIgG1 >0.24 have additional diagnostic value in comparison to sIgG4 in differentiating IAC from PSC; (iii) blood IgG4 mRNA is a highly accurate diagnostic marker comparable to NGS and may become an easily available and affordable diagnostic standard for distinguishing IgG4-RD from PSC and biliary/pancreatic malignancies; and (iv) 'blue collar work' with long-term exposure to solvents, paints, oil products or industrial gases may be a risk factor for development of IgG4-RD. These findings may contribute to the understanding of the pathophysiology and to the early diagnosis and adequate treatment of IgG4-RD. PMID- 26641634 TI - Factors Affecting the Timing of Signal Detection of Adverse Drug Reactions. AB - We investigated factors affecting the timing of signal detection by comparing variations in reporting time of known and unknown ADRs after initial drug release in the USA. Data on adverse event reactions (AERs) submitted to U.S. FDA was used. Six ADRs associated with 6 drugs (rosuvastatin, aripiprazole, teriparatide, telithromycin, exenatide, varenicline) were investigated: Changes in the proportional reporting ratio, reporting odds ratio, and information component as indexes of signal detection were followed every 3 months after each drugs release, and the time for detection of signals was investigated. The time for the detection of signal to be detected after drug release in the USA was 2-10 months for known ADRs and 19-44 months for unknown ones. The median lag time for known and unknown ADRs was 99.0-122.5 days and 185.5-306.0 days, respectively. When the FDA released advisory information on rare but potentially serious health risks of an unknown ADR, the time lag to report from the onset of ADRs to the FDA was shorter. This study suggested that one factor affecting signal detection time is whether an ADR was known or unknown at release. PMID- 26641636 TI - Monomeric and gemini surfactants as antimicrobial agents - influence on environmental and reference strains. AB - Quaternary ammonium salts (QAS) belong to surfactant commonly used both, in the household and in different branches of industry, primarily in the process of cleaning and disinfection. They have several positive features inter alia effectively limiting the development of microorganisms on many surfaces. In the present work, two compounds were used as biocides: hexamethylene-1,6-bis-(N,N dimethyl-N-dodecylammonium bromide) that belongs to the gemini surfactant (GS), and its single analogue - dodecyl(trimethyl)ammonium bromide (DTAB). Two fold dilution method was used to determine the minimum concentration of compounds (MIC) which inhibit the growth of bacteria: Staphylococcus aureus (ATCC 6538 and an environmental strain), Pseudomonas aeruginosa (ATCC 85327 and an environmental strain), and yeast Candida albicans (ATCC 11509 and an environmental strain). The viability of cells in liquid cultures with addition of these substances at 1/4 MIC, 1/2 MIC and MIC concentrations were also determined. The obtained results show that DTAB inhibits the growth of bacteria at the concentration of 0.126 1.010 uM/ml, and gemini surfactant is active at 0.036-0.029 uM/ml. Therefore, GS is active at more than 17-70-fold lower concentrations than its monomeric analogue. Strains isolated from natural environment are less sensitive upon testing biocides than the references strains. Both compounds at the MIC value reduced the number of cells of all strains. The use of too low concentration of biocides can limit the growth of microorganisms, but often only for a short period of time in case of special environmental strains. Later on, they can adapt to adverse environmental conditions and begin to evolve defence mechanisms. PMID- 26641635 TI - Phylogenetic relationship of the stringent response-related genes of marine bacteria. AB - Bacteria living in marine environment encounter various challenges and limitations, thus in order to survive, they need to employ efficient stress response mechanisms. One of these mechanisms is the stringent response, where unusual nucleotides, guanosine tetra- and pentaphosphates, herald starvation and physico-chemical stresses. All so far sequenced free-living bacteria contain the gene(s) responsible for (p)ppGpp synthesis - rsh (named after Escherichia coli genes, relA and spoT). Two similar genes were identified mostly in beta- and gamma-proteobacteria while other bacteria have only one gene coding the dual function of (p)ppGpp synthesis and degradation. Although the presence of (p)ppGpp mediated response to the stress conditions has been shown for a few, and predicted for some other marine microorganisms, the (p)ppGpp effects may vary among different organisms. Thus, in this work we asked whether marine bacteria could have evolved a genetic adaptation specifically suited to adapt to environment with limited resources. The phylogenetic analyses of SpoT, RelA and RSH proteins from organisms associated with marine environment showed, however, that the evolutionary correlations obtained for these proteins are congruent with those constructed for 16S rRNA sequences and reflect taxonomical relationships of these organisms. Likewise, the similarity of specific amino acid residues indispensable for catalytic activity of these enzymes is very high, and any observed changes parallel with the taxonomical and evolutionary relationships. However, potential homologs of Mesh1 enzyme (metazoan SpoT homologs) that occur in both eukaryotic and prokaryotic organisms and contain the hydrolytic domain orthologous to SpoT were identified in Cellulophaga, Erythrobacter and Flavobacterium genera for the first time, as well as in soil bacterium Cytophaga hutchinsonii and freshwater Rhodothermus marinus. PMID- 26641637 TI - The balance between pro- and anti-inflammatory cytokines in the immune responses to BCG and DTwP vaccines. AB - Bacillus Calmette-Guerin (BCG) and pertussis vaccines have been found to be insufficient and their further improvement is required. In order to develop improved vaccines, a better understanding of the main pathways involved in the host's protective immunity to the pathogens is crucial. We address the question as to whether the balance between pro- and anti-inflammatory cytokine production might affect the host responses to BCG and diphtheria-tetanus toxoids-whole cell pertussis (DTwP) vaccines. The study population consisted of 118 healthy people, age range 18-30 years, who had been subjected to BCG and DTwP vaccination according to the state policy. Tuberculin skin testing (TST) revealed a delayed type hypersensitivity (DTH) to PPD (purified protein derivative) in 53% volunteers. The variability in development of the BCG-driven DTH to tuberculin prompted us to address a question as to whether Th1/Th2 polarization is involved in the lack of skin responsiveness to PPD. PPD-stimulated blood lymphocytes from TST(+) participants produced significantly more IFN-gamma and less IL-10 than lymphocytes from TST(-) volunteers. However, TST(-) volunteers' sera contained more anti-pertussis IgG but not anti-diphtheria toxin IgG. Mycobacterial antigens and particularly PPD induced a higher expression of HLA-DR and co-stimulatory CD80 receptors on DCs from TST(+) than TST(-) participants. BCG but not PPD pulsed DCs from TST(-) volunteers produced significantly more IL-10. Mycobacterial antigen stimulated DCs from TST(+) volunteers induced a more intense IFN-gamma production in co-cultures with autologous lymphocytes than the cells from TST(-) participants. Differences among the types of dendritic cell activities contribute to development of tuberculin reactivity in BCG vaccinated volunteers. PMID- 26641638 TI - Physical state of human papillomavirus type 16 in cervical intraepithelial lesions and cancers determined by two different quantitative real-time PCR methods. AB - The aim of this study was to analyse the correlation between a new multiplex qPCR assay and a reference qPCR assay for assessment of the human papillomavirus (HPV16) load and the viral genome status. The study was performed on 100 HPV16 positive samples containing premalignant lesions and carcinomas. HPV16 E2 and E6 gene loads were assessed by two PCR methods. The load of E2 and E6 was normalized to the cell number by qPCR targeting the RNase P open reading frame. The physical state of the viral genome was determined as a ratio of E2/E6 copies number per cell. Among 100 samples analysed, there were no statistically significant differences in the E2 and E6 viral load evaluated by multiplex qPCR and qPCR, the correlation coefficients were 0.98 and 0.97, respectively. There were 19% of samples with the integrated, 73% with mixed and 8% with episomal state of viral genome detected by multiplex qPCR and 17%, 79%, 4%, respectively, found by qPCR. Prevalence of integrated and episomal forms estimated by multiplex qPCR was higher than the one obtained by qPCR (Chi2, p < 0.0001), but in samples with premalignant and malignant diagnoses no significant differences were demonstrated regardless of the methods used. Sensitivity and specificity of multiplex qPCR were 93.7% and 100% as compared with qPCR, the positive predictive value was 100%. In summary, the multiplex qPCR assay in respect of HPV16 load and the frequency of viral genome status was shown to be a sensitive and specific reference method. Simultaneous estimation of E2 and E6 genes in one reaction tube reduces the cost of testing. PMID- 26641639 TI - Inactivation of alpha1-proteinase inhibitor by Candida albicans aspartic proteases favors the epithelial and endothelial cell colonization in the presence of neutrophil extracellular traps. AB - Candida albicans, a causative agent of opportunistic fungal infections in immunocompromised patients, uses ten secreted aspartic proteases (SAPs) to deregulate the homeostasis of the host organism on many levels. One of these deregulation mechanisms involves a SAP-dependent disturbance of the control over proteolytic enzymes of the host by a system of dedicated proteinase inhibitors, with one important example being the neutrophil elastase and alpha1-proteinase inhibitor (A1PI). In this study, we found that soluble SAPs 1-4 and the cell membrane-anchored SAP9 efficiently cleaved A1PI, with the major cleavage points located at the C-terminal part of A1PI in a close vicinity to the reactive-site loop that plays a critical role in the inhibition mechanism. Elastase is released by neutrophils to the environment during fungal infection through two major processes, a degranulation or formation of neutrophil extracellular traps (NET). Both, free and NET-embedded elastase forms, were found to be controlled by A1PI. A local acidosis, resulting from the neutrophil activity at the infection sites, favors A1PI degradation by SAPs. The deregulation of NET-connected elastase affected a NET-dependent damage of epithelial and endothelial cells, resulting in the increased susceptibility of these host cells to candidal colonization. Moreover, the SAP-catalyzed cleavage of A1PI was found to decrease its binding affinity to a proinflammatory cytokine, interleukin-8. The findings presented here suggest a novel strategy used by C. albicans for the colonization of host tissues and overcoming the host defense. PMID- 26641640 TI - Qualitative variability in microbial community of constructed wetlands used for purifying wastewater contaminated with pharmaceutical substances. AB - Pharmaceutical substances and their residues are increasingly present in the environment. Therefore, attempts at their removal are made by using different processes. Increasingly important among these processes are those modeled on natural phenomena which occur in wetland ecosystems, called technical scale constructed wetlands. Microbial degradation is an important process in these constructed wetlands. The biodegradation of chemicals often involves a complex series of biochemical reactions and usually varies with the microorganisms involved. The objectives of this study were to determine the impact of sulfamethoxazole and diclofenac on ammonia oxidizing bacteria and other parameters of wastewater in the microcosm of down-flow constructed wetlands. The Spearman correlation coefficient attained negative values in the case of comparison of the Shannon biodiversity index and the parameters of purified wastewater. This dependence was pronounced. In the case of pharmaceutical substances dosed with wastewater, the Spearman correlation coefficient assumed positive values. The highest value assumed by the Spearman correlation coefficient (0.9) was for the removal of diclofenac and Shannon index values for the planted columns, with a very high relationship. For unplanted columns, this value equaled 0.6. For sulfamethoxazole, the value for planted columns was 0.7, and for unplanted -0.7. The presence of plants did not have an impact on the Shannon biodiversity index. PMID- 26641641 TI - Identification of selected microorganisms from activated sludge capable of benzothiazole and benzotriazole transformation. AB - Benzothiazole (BT) and benzotriazole (BTA) are present in the environment - especially in urban and industrial areas, usually as anthropogenic micropollutants. BT and BTA have been found in the municipal and industrial wastewater, rivers, soil, groundwater, sediments and sludge. The origins of those substances' presence in the environment are various industry branches (food, chemical, metallurgical, electrical), households and surface runoff from industrial areas. Increasingly strict regulations on water quality and the fact that the discussed compounds are poorly biodegradable, make them a serious problem in the environment. Considering this, it is important to look for environmentally friendly and socially acceptable ways to remove BT and BTA. The aim of this study was to identify microorganisms capable of BT and BTA transformation or/and degradation in aquatic environment. Selected microorganisms were isolated from activated sludge. The identification of microorganisms capable of BT and BTA removal was possible using molecular biology techniques (PCR, DNA sequencing). Among isolated microorganisms of activated sludge are bacteria potentially capable of BT and BTA biotransformation and/or removal. The most common bacteria capable of BT and BTA transformation were Rhodococcus sp., Enterobacter sp., Arthrobacter sp. They can grow in a medium with BT and BTA as the only carbon source. Microorganisms previously adapted to the presence of the studied substances at a concentration of 10 mg/l, showed a greater rate of growth of colonies on media than microorganisms unconditioned to the presence of such compounds. Results of the biodegradation test suggest that BT was degraded to a greater extent than BTA, 98-100% and 11-19%, respectively. PMID- 26641642 TI - Socio-Demographic Predictors and Distribution of Pulmonary Tuberculosis (TB) in Xinjiang, China: A Spatial Analysis. AB - OBJECTIVES: Xinjiang is one of the high TB burden provinces of China. A spatial analysis was conducted using geographical information system (GIS) technology to improve the understanding of geographic variation of the pulmonary TB occurrence in Xinjiang, its predictors, and to search for targeted interventions. METHODS: Numbers of reported pulmonary TB cases were collected at county/district level from TB surveillance system database. Population data were extracted from Xinjiang Statistical Yearbook (2006~2014). Spatial autocorrelation (or dependency) was assessed using global Moran's I statistic. Anselin's local Moran's I and local Getis-Ord statistics were used to detect local spatial clusters. Ordinary least squares (OLS) regression, spatial lag model (SLM) and geographically-weighted regression (GWR) models were used to explore the socio demographic predictors of pulmonary TB incidence from global and local perspectives. SPSS17.0, ArcGIS10.2.2, and GeoDA software were used for data analysis. RESULTS: Incidence of sputum smear positive (SS+) TB and new SS+TB showed a declining trend from 2005 to 2013. Pulmonary TB incidence showed a declining trend from 2005 to 2010 and a rising trend since 2011 mainly caused by the rising trend of sputum smear negative (SS-) TB incidence (p<0.0001). Spatial autocorrelation analysis showed the presence of positive spatial autocorrelation for pulmonary TB incidence, SS+TB incidence and SS-TB incidence from 2005 to 2013 (P <0.0001). The Anselin's Local Moran's I identified the "hotspots" which were consistently located in the southwest regions composed of 20 to 28 districts, and the "coldspots" which were consistently located in the north central regions consisting of 21 to 27 districts. Analysis with the Getis-Ord Gi* statistic expanded the scope of "hotspots" and "coldspots" with different intensity; 30 county/districts clustered as "hotspots", while 47 county/districts clustered as "coldspots". OLS regression model included the "proportion of minorities" and the "per capita GDP" as explanatory variables that explained 64% the variation in pulmonary TB incidence (adjR2 = 0.64). The SLM model improved the fit of the OLS model with a decrease in AIC value from 883 to 864, suggesting "proportion of minorities" to be the only statistically significant predictor. GWR model also improved the fitness of regression (adj R2 = 0.68, AIC = 871), which revealed that "proportion of minorities" was a strong predictor in the south central regions while "per capita GDP" was a strong predictor for the southwest regions. CONCLUSION: The SS+TB incidence of Xinjiang had a decreasing trend during 2005 2013, but it still remained higher than the national average in China. Spatial analysis showed significant spatial autocorrelation in pulmonary TB incidence. Cluster analysis detected two clusters-the "hotspots", which were consistently located in the southwest regions, and the "coldspots", which were consistently located in the north central regions. The exploration of socio-demographic predictors identified the "proportion of minorities" and the "per capita GDP" as predictors and may help to guide TB control programs and targeting intervention. PMID- 26641643 TI - Women's Barriers to Prevention of Lymphedema After Breast Surgery and Home Care Needs: A Qualitative Study. AB - BACKGROUND: The incidence of lymphedema occurring after breast surgery poses a high risk of public health. Women undergoing breast surgery have been shown to experience an uncertainty about the prognosis and outcomes of the treatment of lymphedema. OBJECTIVE: The aim of this study was to determine women's barriers to prevention of lymphedema after breast surgery and home care needs. METHODS: In this qualitative study using semistructured in-depth interviews, 14 women with lymphedema selected through purposeful sampling were interviewed. Data were analyzed using inductive content analysis techniques. RESULTS: The following themes were identified and defined: "lymphedema development," "coping with lymphedema," and effects of lymphedema on life." Subthemes were also identified. CONCLUSION: This study revealed physical, psychological, and social difficulties in the consistent use of behaviors to manage lymphedema. It turned out that the women were not provided with sufficient information and counseling before lymphedema development. Familial support and meeting with women experiencing the same disease were found to have a positive effect on management of lymphedema. IMPLICATIONS FOR PRACTICE: Management of lymphedema should be initiated before surgery and continued even when treatment for the cancer is concluded. Patients should be offered information and monitored throughout their life. Individual methods of managing lymphedema should be determined in patients' own home environments at the time of home visits. Families and social networks of women should also be involved. Support groups including patients with similar problems are recommended to create awareness and motivation. PMID- 26641644 TI - Living in Heterogeneous Woodlands - Are Habitat Continuity or Quality Drivers of Genetic Variability in a Flightless Ground Beetle? AB - Although genetic diversity is one of the key components of biodiversity, its drivers are still not fully understood. While it is known that genetic diversity is affected both by environmental parameters as well as habitat history, these factors are not often tested together. Therefore, we analyzed 14 microsatellite loci in Abax parallelepipedus, a flightless, forest dwelling ground beetle, from 88 plots in two study regions in Germany. We modeled the effects of historical and environmental variables on allelic richness, and found for one of the regions, the Schorfheide-Chorin, a significant effect of the depth of the litter layer, which is a main component of habitat quality, and of the sampling effort, which serves as an inverse proxy for local population size. For the other region, the Schwabische Alb, none of the potential drivers showed a significant effect on allelic richness. We conclude that the genetic diversity in our study species is being driven by current local population sizes via environmental variables and not by historical processes in the studied regions. This is also supported by lack of genetic differentiation between local populations sampled from ancient and from recent woodlands. We suggest that the potential effects of former fragmentation and recolonization processes have been mitigated by the large and stable local populations of Abax parallelepipedus in combination with the proximity of the ancient and recent woodlands in the studied landscapes. PMID- 26641645 TI - Clinical Correlates of Mass Effect in Autosomal Dominant Polycystic Kidney Disease. AB - Mass effect from polycystic kidney and liver enlargement can result in significant clinical complications and symptoms in autosomal dominant polycystic kidney disease (ADPKD). In this single-center study, we examined the correlation of height-adjusted total liver volume (htTLV) and total kidney volume (htTKV) by CT imaging with hepatic complications (n = 461) and abdominal symptoms (n = 253) in patients with ADPKD. "Mass-effect" complications were assessed by review of medical records and abdominal symptoms, by a standardized research questionnaire. Overall, 91.8% of patients had 4 or more liver cysts on CT scans. Polycystic liver disease (PLD) was classified as none or mild (htTLV < 1,600 mL/m); moderate (1,600 <= htTLV <3,200 mL/m); and severe (htTLV >= 3,200 mL/m). The prevalence of moderate and severe PLD in our patient cohort was 11.7% (n = 54/461) and 4.8% (n = 22/461), respectively, with a female predominance in both the moderate (61.1%) and severe (95.5%) PLD groups. Pressure-related complications such as leg edema (20.4%), ascites (16.6%), and hernia (3.6%) were common, and patients with moderate to severe PLD exhibited a 6-fold increased risk (compared to no or mild PLD) for these complications in multivariate analysis. Similarly, abdominal symptoms including back pain (58.8%), flank pain (53.1%), abdominal fullness (46.5%), and dyspnea/chest-discomfort (44.3%) were very common, and patients with moderate to severe PLD exhibited a 5-fold increased risk for these symptoms. Moderate to severe PLD is a common and clinically important problem in ~16% of patients with ADPKD who may benefit from referral to specialized centers for further management. PMID- 26641646 TI - European Guidelines for Obesity Management in Adults. AB - Obesity is a chronic metabolic disease characterised by an increase of body fat stores. It is a gateway to ill health, and it has become one of the leading causes of disability and death, affecting not only adults but also children and adolescents worldwide. In clinical practice, the body fatness is estimated by BMI, and the accumulation of intra-abdominal fat (marker for higher metabolic and cardiovascular disease risk) can be assessed by waist circumference. Complex interactions between biological, behavioural, social and environmental factors are involved in regulation of energy balance and fat stores. A comprehensive history, physical examination and laboratory assessment relevant to the patient's obesity should be obtained. Appropriate goals of weight management emphasise realistic weight loss to achieve a reduction in health risks and should include promotion of weight loss, maintenance and prevention of weight regain. Management of co-morbidities and improving quality of life of obese patients are also included in treatment aims. Balanced hypocaloric diets result in clinically meaningful weight loss regardless of which macronutrients they emphasise. Aerobic training is the optimal mode of exercise for reducing fat mass while a programme including resistance training is needed for increasing lean mass in middle-aged and overweight/obese individuals. Cognitive behavioural therapy directly addresses behaviours that require change for successful weight loss and weight loss maintenance. Pharmacotherapy can help patients to maintain compliance and ameliorate obesity-related health risks. Surgery is the most effective treatment for morbid obesity in terms of long-term weight loss. A comprehensive obesity management can only be accomplished by a multidisciplinary obesity management team. We conclude that physicians have a responsibility to recognise obesity as a disease and help obese patients with appropriate prevention and treatment. Treatment should be based on good clinical care, and evidence-based interventions; should focus on realistic goals and lifelong multidisciplinary management. PMID- 26641647 TI - Association of Hematological Variables with Team-Sport Specific Fitness Performance. AB - PURPOSE: We investigated association of hematological variables with specific fitness performance in elite team-sport players. METHODS: Hemoglobin mass (Hbmass) was measured in 25 elite field hockey players using the optimized (2 min) CO-rebreathing method. Hemoglobin concentration ([Hb]), hematocrit and mean corpuscular hemoglobin concentration (MCHC) were analyzed in venous blood. Fitness performance evaluation included a repeated-sprint ability (RSA) test (8 x 20 m sprints, 20 s of rest) and the Yo-Yo intermittent recovery level 2 (YYIR2). RESULTS: Hbmass was largely correlated (r = 0.62, P<0.01) with YYIR2 total distance covered (YYIR2TD) but not with any RSA-derived parameters (r ranging from -0.06 to -0.32; all P>0.05). [Hb] and MCHC displayed moderate correlations with both YYIR2TD (r = 0.44 and 0.41; both P<0.01) and RSA sprint decrement score (r = -0.41 and -0.44; both P<0.05). YYIR2TD correlated with RSA best and total sprint times (r = -0.46, P<0.05 and -0.60, P<0.01; respectively), but not with RSA sprint decrement score (r = -0.19, P>0.05). CONCLUSION: Hbmass is positively correlated with specific aerobic fitness, but not with RSA, in elite team-sport players. Additionally, the negative relationships between YYIR2 and RSA tests performance imply that different hematological mechanisms may be at play. Overall, these results indicate that these two fitness tests should not be used interchangeably as they reflect different hematological mechanisms. PMID- 26641648 TI - Use of Dexmedetomidine for Prophylactic Analgesia and Sedation in Patients With Delayed Extubation After Craniotomy: A Randomized Controlled Trial. AB - BACKGROUND: We conducted a randomized trial to evaluate the efficacy and safety of dexmedetomidine for prophylactic analgesia and sedation in patients with delayed extubation after craniotomy. METHODS: From June 2012 to July 2014, 150 patients with delayed extubation after craniotomy were randomized 1:1 and were assigned to the dexmedetomidine group that received a continuous infusion of 0.6 MUg/kg/h (10 MUg/mL) or the control group that received a maintenance infusion of 0.9% sodium chloride for injection. The mean percentage of time under optimal sedation (SAS3-4), the percentage of patients who required rescue with propofol/fentanyl, and the total dose of propofol/fentanyl required throughout the course of drug infusion, as well as VAS, HR, MAP, and SpO2 were recorded. RESULTS: The percentage of time under optimal sedation was significantly higher in the dexmedetomidine group than in the control group (98.4%+/-6.7% vs. 93.0%+/ 16.2%, P=0.008). The VAS was significantly lower in the dexmedetomidine group than in the control group (1.0 vs. 4.0, P=0.000). The HR and mean BP were significantly lower in the dexmedetomidine group than in the control group at all 3 time points (before endotracheal suctioning, immediately after extubation, and 30 min after extubation). No significant difference in SpO2 was observed between the 2 groups. For hemodynamic adverse events, patients in the dexmedetomidine group were more likely to develop bradycardia (5.3% vs. 0%, P=0.043) but had a lower likelihood of tachycardia (2.7% vs. 18.7%, P=0.002). CONCLUSIONS: Dexmedetomidine may be an effective prophylactic agent to induce sedation and analgesia in patients with delayed extubation after craniotomy. The use of dexmedetomidine (0.6 MUg/kg/h) infusion does not produce respiratory depression, but may increase the incidence of bradycardia. PMID- 26641649 TI - Tracking Cholera through Surveillance of Oral Rehydration Solution Sales at Pharmacies: Insights from Urban Bangladesh. AB - BACKGROUND: In Bangladesh, pharmacy-purchased oral rehydration solution (ORS) is often used to treat diarrhea, including cholera. Over-the-counter sales have been used for epidemiologic surveillance in the past, but rarely, if ever, in low income countries. With few early indicators for cholera outbreaks in endemic areas, diarrhea-related product sales may serve as a useful surveillance tool. METHODOLOGY/PRINCIPAL FINDINGS: We tracked daily ORS sales at 50 pharmacies and drug-sellers in an urban Bangladesh community of 129,000 for 6-months while simultaneously conducting surveillance for diarrhea hospitalizations among residents. We developed a mobile phone based system to track the sales of ORS and deployed it in parallel with a paper-based system. Our objectives were to determine if the mobile phone system was practical and acceptable to pharmacists and drug sellers, whether data were reported accurately compared to a paper-based system, and whether ORS sales were associated with future incidence of cholera hospitalizations within the community. We recorded 47,215 customers purchasing ORS, and 315 hospitalized diarrhea cases, 22% of which had culture-confirmed cholera. ORS sales and diarrhea incidence were independently associated with the mean daily temperature; therefore both unadjusted and adjusted models were explored. Through unadjusted cross-correlation statistics and generalized linear models, we found increases in ORS sales were significantly associated with increases in hospitalized diarrhea cases up to 9-days later and hospitalized cholera cases up to one day later. After adjusting for mean daily temperature, ORS was significantly associated with hospitalized diarrhea two days later and hospitalized cholera one day later. CONCLUSIONS/SIGNIFICANCE: Pharmacy sales data may serve as a feasible and useful surveillance tool. Given the relatively short lagged correlation between ORS sales and diarrhea, rapid and accurate sales data are key. More work is needed in creating actionable algorithms that make use of this data and in understanding the generalizability of our findings to other settings. PMID- 26641651 TI - Investigation of Embedded Si/C System Exposed to a Hybrid Reaction of Centrifugal Assisted Thermite Method. AB - A novel method is proposed to study the behavior and phase formation of a Si+C compacted pellet under centrifugal acceleration in a hybrid reaction. Si+C as elemental mixture in the form of a pellet is embedded in a centrifugal tube. The pellet assembly and tube are exposed to the sudden thermal energy of a thermite reaction resulted in a hybrid reaction. The hybrid reaction of thermite and Si+C produced unique phases. X-ray diffraction pattern (XRD) as well as microstructural and elemental analyses are then investigated. XRD pattern showed formation of materials with possible electronic and magnetic properties. The cooling rate and the molten particle viscosity mathematical model of the process are meant to assist in understanding the physical and chemical phenomena took place during and after reaction. The results analysis revealed that up to 85% of materials converted into secondary products as ceramics-matrix composite. PMID- 26641652 TI - Effects of Sublethal Concentrations of Insecticides on the Functional Response of Two Mirid Generalist Predators. AB - The use of agrochemicals particularly pesticides, can hamper the effectiveness of natural enemies, causing disruption in the ecosystem service of biological control. In the current study, the effects of the insecticides thiacloprid and chlorantraniliprole on the functional response curves were assessed for two mirid predator nymphs, Macrolophus pygmaeus Rambur and Nesidiocoris tenuis Reuter. In the absence of insecticides, both predators exhibited a type II functional response when feeding on eggs of the moth Ephestia kuehniella. N. tenuis seems to be a more efficient predator than M. pygmaeus, as model estimated handling time was significantly lower for the former than for the latter. Residual exposure of M. pygmaeus to sublethal concentrations of either insecticide was associated with a change in the asymptote but not the type of the functional response curve. Thiacloprid seems to be the least compatible with M. pygmaeus, as it led to both a significant reduction of the attack rate and an increase in handling time. In contrast, chlorantraniliprole exposure significantly increased the handling time, but not the attack rate of the predator. Residual exposure of N. tenuis to sublethal concentrations of either insecticide did not have a significant effect on the type nor the parameters of the functional response model. The results show that pesticide residues that do not have lethal effects on beneficial arthropods can reduce prey consumption depending on predator species and on likely risks associated with toxicity. PMID- 26641654 TI - Prevalence of Pulmonary Tuberculosis among Prison Inmates in Ethiopia, a Cross Sectional Study. AB - SETTING: Tuberculosis (TB) is one of the major health problems in prisons. OBJECTIVE: This study was done to assess the prevalence and determinants of active tuberculosis in Ethiopian prisons. DESIGN: A cross-sectional study was conducted from January 2013 to December 2013 in 13 zonal prisons. All incarcerated inmates underwent TB symptom screening according to WHO criteria. From identified TB-suspects two sputum samples were analyzed using smear microscopy and solid culture. A standardized questionnaire assessing TB risk factors was completed for each TB suspect. RESULTS: 765 (4.9%) TB suspects were identified among 15,495 inmates. 51 suspects were already on anti-TB treatment (6.67%) and 20 (2.8%) new culture-confirmed TB cases were identified in the study, resulting in an overall TB prevalence of 458.1/100,000 (95%CI: 350 560/100,000). Risk factors for active TB were alcohol consumption, contact with a TB case before incarceration and no window in prison cell. HIV prevalence was not different between TB suspects and active TB cases. Further, the TB burden in prisons increased with advancing distance from the capital Addis Ababa. CONCLUSIONS: The overall TB prevalence in Ethiopian prisons was high and extremely variable among different prisons. TB risk factors related to conditions of prison facilities and the impact of implemented TB control measures need to be further studied in order to improve TB control among inmates. PMID- 26641655 TI - Elevated Biomarkers of Inflammation and Coagulation in Patients with HIV Are Associated with Higher Framingham and VACS Risk Index Scores. AB - BACKGROUND: Biomarkers of inflammation and altered coagulation are of increasing interest as predictors of chronic disease and mortality in HIV patients, as well as the use of risk stratification scores such as the Framingham index and the Veterans Aging Cohort Study (VACS) score. METHODS: Demographic and laboratory data for 252 HIV patients were assessed for their relationship with 5 biomarkers: hsCRP, D-dimer, Cystatin C, IL-6 and TNF-alpha. Analysis of variance was used to model the association between the number of elevated biomarkers patients had and their Framingham 10 year cardiovascular risk and VACS scores. RESULTS: 87% of patients were male and 75.7% were virally suppressed (HIV RNA <48 copies/ml). The median and interquartile ranges for each biomarker were: hsCRP 1.65 ug/mL (0.73, 3.89), D-dimer 0.17 ug/mL (0.09, 0.31), Cystatin C 0.87 mg/L (0.78, 1.01), IL-6 2.13 pg/mL (1.3, 3.59), TNF-alpha 4.65 pg/mL (3.5, 5.97). 62.6% of patients had more than one biomarker >75th percentile, while 18.6% had three or more elevated biomarkers. Increased age, cigarette smoking, CD4 counts of <200 cells/mm3, Framingham scores and VACS scores were most strongly associated with elevations in biomarkers. When biomarkers were used to predict the Framingham and VACS scores, those with a higher number of elevated biomarkers had higher mean VACS scores, with a similar but less robust finding for Framingham scores. CONCLUSIONS: Despite viral suppression and immunological stability, biomarkers of inflammation and coagulation remain elevated in a significant number of patients with HIV and are associated with higher scores on risk stratification indices. PMID- 26641656 TI - Effect of heat-induced pain stimuli on pulse transit time and pulse wave amplitude in healthy volunteers. AB - Pain is commonly assessed subjectively by interpretations of patient behaviour and/or reports from patients. When this is impossible the availability of a quantitative objective pain assessment tool based on objective physiological parameters would greatly benefit clinical practice and research beside the standard self-report tests. Vasoconstriction is one of the physiological responses to pain. The aim of this study was to investigate whether pulse transit time (PTT) and pulse wave amplitude (PWA) decrease in response to this vasoconstriction when caused by heat-induced pain. The PTT and PWA were measured in healthy volunteers, on both index fingers using photoplethysmography and electrocardiography. Each subject received 3 heat-induced pain stimuli using a Temperature-Sensory Analyzer thermode block to apply a controlled, increasing temperature from 32.0 degrees C to 50.0 degrees C to the skin. After reaching 50.0 degrees C, the thermode was immediately cooled down to 32.0 degrees C. The study population was divided into 2 groups with a time-interval between the stimuli 20s or 60s. The results showed a significant (p < 0.05) decrease of both PTT and PWA on the stimulated and contralateral side. Moreover, there was no significant difference between the stimulated and contralateral side. The time interval of 20s was too short to allow PTT and PWA to return to baseline values and should exceed 40s in future studies. Heat-induced pain causes a decrease of PTT and PWA. Consequently, it is expected that, in the future, PTT and PWA may be applied as objective indicators of pain, either beside the standard self-report test, or when self-report testing is impossible. PMID- 26641657 TI - In Vitro Morphogenesis of Arabidopsis to Search for Novel Endophytic Fungi Modulating Plant Growth. AB - Fungal endophytes have shown to affect plant growth and to confer stress tolerance to the host; however, effects of endophytes isolated from water plants have been poorly investigated. In this study, fungi isolated from stems (stem-E) and roots (root-E) of Mentha aquatica L. (water mint) were identified, and their morphogenetic properties analysed on in vitro cultured Arabidopsis (L.) Heynh., 14 and 21 days after inoculation (DAI). Nineteen fungi were analysed and, based on ITS analysis, 17 isolates showed to be genetically distinct. The overall effect of water mint endophytes on Arabidopsis fresh (FW) and dry weight (DW) was neutral and positive, respectively, and the increased DW, mainly occurring 14 DAI, was possibly related to plant defence mechanism. Only three fungi increased both FW and DW of Arabidopsis at 14 and 21 DAI, thus behaving as plant growth promoting (PGP) fungi. E-treatment caused a reduction of root depth and primary root length in most cases and inhibition-to-promotion of root area and lateral root length, from 14 DAI. Only Phoma macrostoma, among the water mint PGP fungi, increased both root area and depth, 21 DAI. Root depth and area 14 DAI were shown to influence DWs, indicating that the extension of the root system, and thus nutrient uptake, was an important determinant of plant dry biomass. Reduction of Arabidopsis root depth occurred to a great extent when plants where treated with stem-E while root area decreased or increased under the effects of stem-E and root-E, respectively, pointing to an influence of the endophyte origin on root extension. M. aquatica and many other perennial hydrophytes have growing worldwide application in water pollution remediation. The present study provided a model for directed screening of endophytes able to modulate plant growth in the perspective of future field applications of these fungi. PMID- 26641658 TI - Congener Patterns of Persistent Organic Pollutants Establish the Extent of Contaminant Biotransport by Pacific Salmon in the Great Lakes. AB - In the Great Lakes, introduced Pacific salmon (Oncorhynchus spp.) can transport persistent organic pollutants (POPs), such as polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs), to new environments during their spawning migrations. To explore the nature and extent of POP biotransport by salmon, we compared 58 PCB and 6 PBDE congeners found in spawning salmon directly to those in resident stream fish. We hypothesized that stream fish exposed to salmon spawners would have congener patterns similar to those of salmon, the presumed contaminant source. Using permutational multivariate analysis of variance (PERMANOVA) and nonmetric multidimensional scaling (NMDS), we found that POP congener patterns of Pacific salmon varied among regions in the Great Lakes basin (i.e., Lake Huron, Lake Michigan, or Lake Superior), tissue type (whole fish or eggs), and contaminant type (PCB or PBDE). For stream-resident fish, POP congener pattern was influenced by the presence of salmon, location (i.e., Great Lakes Basin), and species identity (i.e., brook trout [Salvelinus fontinalis] or mottled sculpin [Cottus bairdii]). Similarity in congener patterns indicated that salmon are a source of POPs to brook trout in stream reaches receiving salmon spawners from Lake Michigan and Lake Huron but not from Lake Superior. Congener patterns of mottled sculpin differed from those of brook trout and salmon, suggesting that brook trout and mottled sculpin either use salmon tissue to differing degrees, acquire POPs from different dietary sources, or bioaccumulate or metabolize POPs differently. Overall, our analyses identified the important role of salmon in contaminant biotransport but also demonstrated that the extent of salmon-mediated POP transfer and uptake in Great Lakes tributaries is location and species-specific. PMID- 26641659 TI - How Lipid Membranes Affect Pore Forming Toxin Activity. AB - Pore forming toxins (PFTs) evolved to permeate the plasma membrane of target cells. This is achieved in a multistep mechanism that usually involves binding of soluble protein monomer to the lipid membrane, oligomerization at the plane of the membrane, and insertion of part of the polypeptide chain across the lipid membrane to form a conductive channel. Introduced pores allow uncontrolled transport of solutes across the membrane, inflicting damage to the target cell. PFTs are usually studied from the perspective of structure-function relationships, often neglecting the important role of the bulk membrane properties on the PFT mechanism of action. In this Account, we discuss how membrane lateral heterogeneity, thickness, and fluidity influence the pore forming process of PFTs. In general, lipid molecules are more accessible for binding in fluid membranes due to steric reasons. When PFT specifically binds ordered domains, it usually recognizes a specific lipid distribution pattern, like sphingomyelin (SM) clusters or SM/cholesterol complexes, and not individual lipid species. Lipid domains were also suggested to act as an additional concentration platform facilitating PFT oligomerization, but this is yet to be shown. The last stage in PFT action is the insertion of the transmembrane segment across the membranes to build the transmembrane pore walls. Conformational changes are a spontaneous process, and sufficient free energy has to be available for efficient membrane penetration. Therefore, fluid bilayers are permeabilized more readily in comparison to highly ordered and thicker liquid ordered lipid phase (Lo). Energetically more costly insertion into the Lo phase can be driven by the hydrophobic mismatch between the thinner liquid disordered phase (Ld) and large protein complexes, which are unable to tilt like single transmembrane segments. In the case of proteolipid pores, membrane properties can directly modulate pore size, stability, and even selectivity. Finally, events associated with pore formation can modulate properties of the lipid membrane and affect its organization. Model membranes do not necessarily reproduce the physicochemical properties of the native cellular membrane, and caution is needed when transferring results from model to native lipid membranes. In this context, the utilization of novel approaches that enable studying PFTs on living cells at a single molecule level should reveal complex protein-lipid membrane interactions in greater detail. PMID- 26641661 TI - Treatment Withdrawal in Autoimmune Hepatitis. AB - BACKGROUND: Autoimmune hepatitis (AIH) is a chronic inflammatory liver disorder of unknown aetiology, which when left untreated can lead to liver cirrhosis and hepatic failure. Current treatment strategies include long-term treatment with corticosteroids and/or azathioprine. Most patients respond well to immunosuppressive therapy and treatment usually results in an asymptomatic course of AIH in remission. Nevertheless, both drugs are associated with serious side effects that can sometimes be severe and may necessitate drug withdrawal. Whether or not treatment in patients who are in longstanding remission can be discontinued is unknown. KEY MESSAGES: Available data rely on retrospective data sets and are not conclusive. Some studies indicate that a sustained remission after treatment withdrawal is feasible, whereas other studies have found relapse rates in up to 90% of patients, even in patients with established histological remission. Patients who relapse after drug withdrawal have a high probability for a re-relapse to occur. Life-long maintenance therapy should be strongly considered in these patients, since patients who have multiple relapses are more likely to progress to cirrhosis, liver transplantation and death from liver failure. CONCLUSION: For a majority of patients, AIH is a lifelong disease requiring permanent treatment. Patients in longstanding clinical remission on monotherapy, with complete normalisation of aminotransferases and IgG could be offered one attempt of drug withdrawal. The risk of disease progression after a single relapse appears low, while a patient's realization that infinite maintenance therapy is mandatory may improve drug adherence. PMID- 26641660 TI - Detecting Protein Complexes in Protein Interaction Networks Modeled as Gene Expression Biclusters. AB - Developing suitable methods for the detection of protein complexes in protein interaction networks continues to be an intriguing area of research. The importance of this objective originates from the fact that protein complexes are key players in most cellular processes. The more complexes we identify, the better we can understand normal as well as abnormal molecular events. Up till now, various computational methods were designed for this purpose. However, despite their notable performance, questions arise regarding potential ways to improve them, in addition to ameliorative guidelines to introduce novel approaches. A close interpretation leads to the assent that the way in which protein interaction networks are initially viewed should be adjusted. These networks are dynamic in reality and it is necessary to consider this fact to enhance the detection of protein complexes. In this paper, we present "DyCluster", a framework to model the dynamic aspect of protein interaction networks by incorporating gene expression data, through biclustering techniques, prior to applying complex-detection algorithms. The experimental results show that DyCluster leads to higher numbers of correctly-detected complexes with better evaluation scores. The high accuracy achieved by DyCluster in detecting protein complexes is a valid argument in favor of the proposed method. DyCluster is also able to detect biologically meaningful protein groups. The code and datasets used in the study are downloadable from https://github.com/emhanna/DyCluster. PMID- 26641663 TI - Deciphering Time Scale Hierarchy in Reaction Networks. AB - Markovian dynamics on complex reaction networks are one of the most intriguing subjects in a wide range of research fields including chemical reactions, biological physics, and ecology. To represent the global kinetics from one node (corresponding to a basin on an energy landscape) to another requires information on multiple pathways that directly or indirectly connect these two nodes through the entire network. In this paper we present a scheme to extract a hierarchical set of global transition states (TSs) over a discrete-time Markov chain derived from first-order rate equations. The TSs can naturally take into account the multiple pathways connecting any pair of nodes. We also propose a new type of disconnectivity graph (DG) to capture the hierarchical organization of different time scales of reactions that can capture changes in the network due to changes in the time scale of observation. The crux is the introduction of the minimum conductance cut (MCC) in graph clustering, corresponding to the dividing surface across the network having the "smallest" transition probability between two disjoint subnetworks (superbasins on the energy landscape) in the network. We present a new combinatorial search algorithm for finding this MCC. We apply our method to a reaction network of Claisen rearrangement of allyl vinyl ether that consists of 23 nodes and 66 links (saddles on the energy landscape) connecting them. We compare the kinetic properties of our DG to those of the transition matrix of the rate equations and show that our graph can properly reveal the hierarchical organization of time scales in a network. PMID- 26641662 TI - Surface Modification of Biodegradable Polymers towards Better Biocompatibility and Lower Thrombogenicity. AB - PURPOSE: Drug-eluting stents (DES) based on permanent polymeric coating matrices have been introduced to overcome the in stent restenosis associated with bare metal stents (BMS). A further step was the development of DES with biodegradable polymeric coatings to address the risk of thrombosis associated with first generation DES. In this study we evaluate the biocompatibility of biodegradable polymer materials for their potential use as coating matrices for DES or as materials for fully bioabsorbable vascular stents. MATERIALS AND METHODS: Five different polymers, poly(L-lactide) PLLA, poly(D,L-lactide) PDLLA, poly(L-lactide co-glycolide) P(LLA-co-GA), poly(D,L-lactide-co-glycolide) P(DLLA-co-GA) and poly(L-lactide-co-epsilon-caprolactone), P(LLA-co-CL) were examined in vitro without and with surface modification. The surface modification of polymers was performed by means of wet-chemical (NaOH and ethylenediamine (EDA)) and plasma chemical (O2 and NH3) processes. The biocompatibility studies were performed on three different cell types: immortalized mouse fibroblasts (cell line L929), human coronary artery endothelial cells (HCAEC) and human umbilical vein endothelial cells (HUVEC). The biocompatibility was examined quantitatively using in vitro cytotoxicity assay. Cells were investigated immunocytochemically for expression of specific markers, and morphology was visualized using confocal laser scanning (CLSM) and scanning electron (SEM) microscopy. Additionally, polymer surfaces were examined for their thrombogenicity using an established hemocompatibility test. RESULTS: Both endothelial cell types exhibited poor viability and adhesion on all five unmodified polymer surfaces. The biocompatibility of the polymers could be influenced positively by surface modifications. In particular, a reproducible effect was observed for NH3-plasma treatment, which enhanced the cell viability, adhesion and morphology on all five polymeric surfaces. CONCLUSION: Surface modification of polymers can provide a useful approach to enhance their biocompatibility. For clinical application, attempts should be made to stabilize the plasma modification and use it for coupling of biomolecules to accelerate the re-endothelialization of stent surfaces in vivo. PMID- 26641664 TI - An Effective Bifunctional Aldehyde Linchpin for Type II Anion Relay Chemistry: Development and Application to the Synthesis of a C16-C29 Fragment of Rhizopodin. AB - The design, synthesis, and validation of a new bifunctional aldehyde linchpin for Type II anion relay chemistry have been achieved. For this linchpin, the initial nucleophilic addition proceeds under Felkin-Anh control to generate the syn alkoxide, which undergoes a 1,4-Brook rearrangement to relay the negative charge, thus leading to the formation of a dithiane-stabilized carbanion. Subsequent trapping with an electrophile furnishes a tricomponent adduct with an embedded propionate subunit, a ubiquitous structural motif found in polyketides. The utility of this new linchpin is demonstrated with the construction of a potential C16-C29 fragment for the synthesis of rhizopodin, an actin-binding macrolide. PMID- 26641665 TI - Crocodilian Nest in a Late Cretaceous Sauropod Hatchery from the Type Lameta Ghat Locality, Jabalpur, India. AB - The well-known Late Cretaceous Lameta Ghat locality (Jabalpur, India) provides a window of opportunity to study a large stable, near shore sandy beach, which was widely used by sauropod dinosaurs as a hatchery. In this paper, we revisit the eggs and eggshell fragments previously assigned to lizards from this locality and reassign them to crocodylomorphs. Several features point to a crocodilian affinity, including a subspherical to ellipsoidal shape, smooth, uneven external surface, discrete trapezoid shaped shell units with wide top and narrow base, basal knobs and wedge shaped crystallites showing typical inverted triangular extinction under crossed nicols. The crocodylomorph eggshell material presented in this paper adds to the skeletal data of these most probably Cretaceous-Eocene dryosaurid crocodiles. PMID- 26641667 TI - Evidence and Model for Strain-Driven Release of Metal Nanocatalysts from Perovskites during Exsolution. AB - The evolution of the surface morphology during exsolution of Ni from the perovskite La0.4Sr0.4Ti0.97Ni0.03O3-delta under reducing conditions was determined using atomic force microscopy. The exsolution process was found to initially induce the formation of a 20-30 nm deep pit on the oxide surface followed by the emergence of a Ni particle at the bottom of the pit. Continued emergence of the particle results in it nearly filling the pit, producing a unique structure in which the Ni particle is socketed into the oxide surface. We also show that this morphological evolution can be explained using a simple energy-based model that accounts for the interplay between the surface free energy and the strain energy induced by the included metal nucleate. The unique socketed structure results in strong anchorage between the exsolved particles and the oxide host lattice, which imparts both high thermal stability and unique catalytic activity. PMID- 26641666 TI - TALEN-Based Mutagenesis of Lipoxygenase LOX3 Enhances the Storage Tolerance of Rice (Oryza sativa) Seeds. AB - The deterioration of rice grain reduces the quality of rice, resulting in serious economic losses for farmers. Lipoxygenases (LOXs) catalyze the dioxygenation of polyunsaturated fatty acids with at least one cis,cis-1,4-pentadiene to form hydroperoxide, which is a major factor influencing seed longevity and viability. Recently, genome editing, an essential tool employed in reverse genetics, has been used experimentally to investigate basic plant biology or to modify crop plants for the improvement of important agricultural traits. In this study, we performed targeted mutagenesis in rice using transcription activator-like effector nucleases (TALENs) to improve seed storability. A modified ligation independent cloning method (LIC) was employed to allow for the quick and efficient directional insertion of TALEN monomer modules into destination vectors used in plants. We demonstrated the feasibility and flexibility of the technology by developing a set of modular vectors for genome editing. After construction and validation, the TALEN pairs were used to create stable transgenic rice lines via Agrobacterium-mediated transformation. One heterozygous mutant (4%) was recovered from 25 transgenic NPTII-resistant lines, and the mutation was transmitted to the next generation. Further molecular and protein level experiments verified LOX3 deficiency and demonstrated the improvement of seed storability. Our work provides a flexible genome editing tool for improving important agronomic traits, as well as direct evidence that Lox3 has only a limited impact on seed longevity. PMID- 26641668 TI - How the Sequence of a Gene Specifies Structural Symmetry in Proteins. AB - Internal symmetry is commonly observed in the majority of fundamental protein folds. Meanwhile, sufficient evidence suggests that nascent polypeptide chains of proteins have the potential to start the co-translational folding process and this process allows mRNA to contain additional information on protein structure. In this paper, we study the relationship between gene sequences and protein structures from the viewpoint of symmetry to explore how gene sequences code for structural symmetry in proteins. We found that, for a set of two-fold symmetric proteins from left-handed beta-helix fold, intragenic symmetry always exists in their corresponding gene sequences. Meanwhile, codon usage bias and local mRNA structure might be involved in modulating translation speed for the formation of structural symmetry: a major decrease of local codon usage bias in the middle of the codon sequence can be identified as a common feature; and major or consecutive decreases in local mRNA folding energy near the boundaries of the symmetric substructures can also be observed. The results suggest that gene duplication and fusion may be an evolutionarily conserved process for this protein fold. In addition, the usage of rare codons and the formation of higher order of secondary structure near the boundaries of symmetric substructures might have coevolved as conserved mechanisms to slow down translation elongation and to facilitate effective folding of symmetric substructures. These findings provide valuable insights into our understanding of the mechanisms of translation and its evolution, as well as the design of proteins via symmetric modules. PMID- 26641670 TI - Paediatric Autoimmune Liver Disease. AB - In paediatrics, there are 2 liver disorders in which liver damage most likely stems from an autoimmune attack: 'classical' autoimmune hepatitis (AIH) and the AIH/sclerosing cholangitis overlap syndrome (also known as autoimmune sclerosing cholangitis, ASC). The presentation of childhood autoimmune liver disease (AILD) is non-specific and can mimic most other liver disorders. AIH is exquisitely responsive to immunosuppressive treatment, which should be instituted promptly to prevent rapid deterioration and promote remission and long-term survival. Difficult-to-treat or non-responsive patients should be treated with mycophenolate mofetil; if this fails then calcineurin inhibitors can be tried. Persistent failure to respond or lack of adherence to treatment result in end stage liver disease. These patients, and those with fulminant liver failure at diagnosis, will require liver transplantation. ASC responds to the same immunosuppressive treatment used for AIH when treatment is initiated early. Abnormal liver function tests often resolve within a few months of treatment, although medium- to long-term prognosis is worse than that of AIH because bile duct disease continues to progress despite treatment in approximately 50% of patients. Ursodeoxycholic acid is usually added to conventional treatment regimen in ASC, but whether this actually helps arrest the progression of bile duct disease remains to be established. The pathogenesis of paediatric-onset AILD is not fully understood, although there is mounting evidence that genetic susceptibility, molecular mimicry and impaired immunoregulatory networks contribute to the initiation and perpetuation of the autoimmune attack. Liver damage is thought to be mediated primarily by CD4pos T-cells. While Th1 effector cells are associated with hepatocyte damage in both AIH and ASC, Th17 immune responses predominate in the latter where they correlate with biochemical indices of cholestasis, indicating that IL-17 is involved in the bile duct damage characteristic of this condition. Since a substantial difference between these 2 pathologies is the frequent association of ASC with inflammatory bowel disease, it can be speculated that lymphocytes of intestinal origin are present in patients with a diagnosis of ASC rather than in those with AIH. Animal models faithfully representing the human conditions are needed to unravel the contribution of innate and adaptive, effector and regulatory immune responses. A deeper understanding of the pathogenesis of AILD is likely to contribute to the development of novel treatments, such as the adoptive transfer of autologous expanded antigen-specific regulatory T-cells, which ultimately aim at restoring tolerance to liver-derived antigens. PMID- 26641671 TI - Extracting Markov Models of Peptide Conformational Dynamics from Simulation Data. AB - A high-dimensional time series obtained by simulating a complex and stochastic dynamical system (like a peptide in solution) may code an underlying multiple state Markov process. We present a computational approach to most plausibly identify and reconstruct this process from the simulated trajectory. Using a mixture of normal distributions we first construct a maximum likelihood estimate of the point density associated with this time series and thus obtain a density oriented partition of the data space. This discretization allows us to estimate the transfer operator as a matrix of moderate dimension at sufficient statistics. A nonlinear dynamics involving that matrix and, alternatively, a deterministic coarse-graining procedure are employed to construct respective hierarchies of Markov models, from which the model most plausibly mapping the generating stochastic process is selected by consideration of certain observables. Within both procedures the data are classified in terms of prototypical points, the conformations, marking the various Markov states. As a typical example, the approach is applied to analyze the conformational dynamics of a tripeptide in solution. The corresponding high-dimensional time series has been obtained from an extended molecular dynamics simulation. PMID- 26641669 TI - Changes of 25-OH-Vitamin D during Overwintering at the German Antarctic Stations Neumayer II and III. AB - PURPOSE: Humans in Antarctica face different environmental challenges, such as low ultra-violet radiation, which is crucial for vitamin D production in humans. Therefore we assessed changes in 25-OH-vitamin D serum concentration during 13 months of overwintering at the German Stations Neumayer II and III (2007-2012). We hypothesized that (i) 25-OH-vitamin D serum concentration would significantly decrease, (ii) changes would be affected by age, gender, baseline (i.e. pre overwintering) fat mass, baseline 25-OH-vitamin D serum concentration, and station residence, and (iii) our results would not differ from similar previous studies in comparable high latitudes. MATERIALS & METHODS: 25-OH-vitamin D serum concentrations were determined before, after, and monthly during the campaigns from venous blood samples of n = 43 participants (28 men, 15 women). Baseline fat mass was determined via bio impedance analysis and body plethysmography. Data were analyzed for change over time, dependency on independent parameters, and after categorization for sufficiency (>50nmol/l), insufficiency (25-50nmol/l), and deficiency (<25nmol/l). Results were compared with data from similar previous studies. RESULTS: We found a significant decrease of 25-OH-vitamin D with dependency on month. Age, gender, fat mass, and station residence had no influence. Only baseline 25-OH-vitamin D serum concentrations significantly affected subsequent 25-OH-vitamin D values. CONCLUSIONS: Overwinterings at the Antarctic German research stations Neumayer II and III are associated with a decrease in 25-OH-vitamin D serum concentrations, unaffected by age, gender, baseline fat mass, and station residence. Higher baseline vitamin D serum concentrations might protect from subsequent deficiencies. Residence at the Neumayer Stations may lead to lower vitamin D serum concentrations than found in other comparable high latitudes. PMID- 26641672 TI - Non-Born-Oppenheimer Liouville-von Neumann Dynamics. Evolution of a Subsystem Controlled by Linear and Population-Driven Decay of Mixing with Decoherent and Coherent Switching. AB - Electronic energy flow in an isolated molecular system involves coupling between the electronic and nuclear subsystems, and the coupled system evolves to a statistical mixture of pure states. In semiclassical theories, nuclear motion is treated using classical mechanics, and electronic motion is treated as an open quantal system coupled to a "bath" of nuclear coordinates. We have previously shown how this can be simulated by a time-dependent Schrodinger equation with coherent switching and decay of mixing, where the decay of mixing terms model the dissipative effect of the environment on the electronic subdynamics (i.e., on the reduced dynamics of the electronic subsystem). In the present paper we reformulate the problem as a Liouville-von Neumann equation of motion (i.e., we propagate the reduced density matrix of the electronic subsystem), and we introduce the assumption of first-order linear decay. We specifically examine the cases of equal relaxation times for both longitudinal (i.e., population) decay and transverse decay (i.e., dephasing) and of longitudinal relaxation only, yielding the linear decay of mixing (LDM) and the population-driven decay of mixing (PDDM) schemes, respectively. Because we do not generally know the basis in which coherence decays, that is, the pointer basis, we judge the semiclassical methods in part by their ability to give good results in both the adiabatic and diabatic bases. The accuracy in the prediction of physical observables is shown to be robust not only with respect to basis but also with respect to the way in which demixing is incorporated into the master equation for the density matrix. The success of the PDDM scheme is particularly interesting because it incorporates the least amount of decoherence (i.e., the PDDM scheme is the most similar of the methods discussed to the fully coherent semiclassical Ehrenfest method). For both the new and previous decay of mixing schemes, four kinds of decoherent state switching algorithms are analyzed and compared to one another: natural switching (NS), self-consistent switching (SCS), coherent switching (CS), and globally coherent switching (GCS). The CS formulations are examples of a non Markovian method, in which the system retains some memory of its history, whereas the GCS, SCS, and NS schemes are Markovian (time local). These methods are tested against accurate quantum mechanical results using 17 multidimensional atom-diatom test cases. The test cases include avoided crossings, conical interactions, and systems with noncrossing diabatic potential energy surfaces. The CS switching algorithm, in which the state populations are controlled by a coherent stochastic algorithm for each complete passage through a strong interaction region, but successive strong-interaction regions are not mutually coherent, is shown to be the most accurate of the switching algorithms tested for the LDM and PDDM methods as well as for the previous decay of mixing methods, which are reformulated here as Liouville-von Neumann equations with nonlinear decay of mixing (NLDM). We also demonstrate that one variant of the PDDM method with CS performs almost equally well in the adiabatic and diabatic representations, which is a difficult objective for semiclassical methods. Thus decay of mixing methods provides powerful mixed quantum-classical methods for modeling non-Born-Oppenheimer polyatomic dynamics including photochemistry, charge-transfer, and other electronically nonadiabatic processes. PMID- 26641673 TI - Assessment of Density Functionals for Predicting One-Bond Carbon-Hydrogen NMR Spin-Spin Coupling Constants. AB - We benchmark the performance of 20 approximate density functionals for the calculation of one-bond carbon-hydrogen NMR spin-spin coupling constants (SSCCs). These functionals range from the simplest local-spin density approximation to novel meta-generalized gradient approximation and hybrid density functionals. Our testing set consists of 72 diverse molecules that represent multiple types of hybridization of the carbon atom corresponding to 96 experimentally measured one bond carbon-hydrogen SSCCs. Our results indicate that generalized gradient approximations perform best for this type of coupling. PMID- 26641674 TI - Accurate Atomic and Molecular Calculations without Gradient Corrections: Scaled SVWNV Density Functional. AB - The local spin density approximation (LSDA) approximation was one of the first density functional theory (DFT) methods employed to calculate atomic and molecular properties. As newer, more sophisticated methods, such as BLYP and B3LYP, were developed, the LSDA approximation has grown less popular for molecular systems. In this paper we revisit the LSDA method and investigate a simple way to improve the results that can be obtained using this approximation. By scaling the contribution of the local correlation to the SVWNV functional, improved results can be obtained for heats of formation, ionization potentials, electron affinities, bond angles, bond distances, vibrational frequencies, conformational energies, interaction energies, and barrier heights. The results of our studies show that scaling the SVWNV functional yields heats of formations with average unsigned errors up to about nine times smaller than those of the standard SVWNV functional. The decreases in the errors of other properties studied in this work were not as dramatic as those of the heat of formation but were, in most cases, significant. There is a notable time saving in this density only functional. For a 9-alanine system SVWNV is 55% faster than B3LYP and 40% faster than BLYP at a 3-21G* basis set. Based on our observations we propose an improved SVWNV density functional that is suitable for the study of molecular systems at a fraction of the cost of more sophisticated DFT methods, which also produces reasonable accuracy at small basis sets. One type of application for which the improved SVWNV functional would be extremely well suited is QM/QM methods where a fairly inexpensive method is needed for the larger part of a system that is treated at a lower level of theory. PMID- 26641675 TI - Scanning Reactive Pathways with Orbital Biased Molecular Dynamics. AB - To accelerate reactive events in molecular dynamics simulations we introduce a general bias potential scheme which depends only on the electronic degrees of freedom of the reactive system. This electronic reaction coordinate, which is expressed in terms of a penalty function of the one-electron orbital energies, has been applied to study different reaction pathways of s-cis-butadiene. Three different reactive channels have been identified: the cis/trans isomerization, the s-cis/s-trans isomerization, and the symmetry allowed cyclization. For the latter, despite the fact that the Woodward-Hoffmann rules are guided by the butadiene frontier orbitals, biasing only these orbitals is not enough to drive the system toward cyclization, but a low-lying valence shell orbital needs to be included. PMID- 26641676 TI - Stabilization of Cylindrical N12 and N18 by Phosphorus Substitution. AB - Molecules consisting entirely or predominantly of nitrogen are the subject of much research for their potential as high energy density materials (HEDM). The problem with many such HEDM candidates is their instability with respect to dissociation. For example, a low-energy dissociation path has been shown for a cylindrical cage isomer of N12. The instability is at least partially due to the ease of ring opening at triangles on either end of the molecule. In the current study, nitrogen cage molecules are examined to determine the stabilizing effect of substituting the triangle nitrogens with an element that more naturally forms triangles, namely phosphorus, which is valence isoelectronic with nitrogen. The cylindrical N12, and a larger analogue N18, form the structural basis for cage molecules of N6P6 and N12P6. Theoretical calculations using Hartree-Fock theory and perturbation theory (MP2 and MP4), along with the correlation-consistent basis sets of Dunning, have been carried out to determine dissociation energies along various pathways. The energies are discussed in terms of low-energy dissociation and the ability of the molecules to resist dissociation. PMID- 26641677 TI - Search for the Lin(0/+1/-1) (n = 5-7) Lowest-Energy Structures Using the ab Initio Gradient Embedded Genetic Algorithm (GEGA). Elucidation of the Chemical Bonding in the Lithium Clusters. AB - We report the study of small lithium clusters Lin(0/+1/)(-)(1) (n = 5-7), performed via the novel Gradient Embedded Genetic Algorithm (GEGA) technique and molecular orbital analysis. GEGA was developed for searching of the lowest-energy structures of clusters. Results of our search, obtained using this program, have been compared with the previous ab initio calculations, and the efficiency of the developed GEGA method has thus been confirmed. The molecular orbital analysis of the found Lin(0/+1/)(-)(1) (n = 5-7) clusters showed the presence of multiple (sigma and pi) aromatic character in their chemical bonding, which governs their preferable shapes and special stability. PMID- 26641678 TI - Anchoring the Torsional Potential of Biphenyl at the ab Initio Level: The Role of Basis Set versus Correlation Effects. AB - The torsional profile of biphenyl has been calculated by means of quantum chemical perturbations and coupled-cluster methods of increasing accuracy. The performance of the various theoretical approaches has been assessed through a critical comparison with experimental barrier heights. The theoretical data indicate that the basis set effects become more critical than the correlation effects beyond the perturbational MP4 or variational CCSD(T) levels of theory to obtain the most accurate results. We also discuss the various additional corrections that would be required beyond the scope of our study to provide the best match to the experimental results. PMID- 26641679 TI - Density-Functional-Based Determination of Vibrational Polarizabilities in Molecules within the Double-Harmonic Approximation: Derivation and Application. AB - We present a nonperturbative derivation for the primary contribution to the vibrational polarizability for molecules, clusters, and other finite systems. Using a double-harmonic approximation and a finite-field approach the vibrational polarizability is calculated within the generalized gradient approximation to the density functional theory for a variety of molecules and clusters. The agreement between theory and experiment is quite good. The results show that for small ionic molecules and clusters, inclusion of the vibrational polarizability is necessary to achieve agreement with experiment. PMID- 26641680 TI - Iron(IV) Porphyrin Difluoride Does Not Exist: Implications for DFT Calculations on Heme Protein Reaction Pathways. AB - DFT (B3LYP as well as a number of common exchange-correlation functionals) predicts a low-spin Fe(IV) ground state for Fe(P)F2 (P = porphyrinato), whereas electrochemical evidence has apparently indicated an Fe(III) porphyrin pi-cation radical formulation for such a species. Ab initio CASPT2 calculations favor a high-spin porphyrin pi-cation radical as the ground state by a significant energetic margin, thus dramatically overturning the DFT results. In contrast, both DFT and CASPT2 calculations correctly indicate a true Mn(IV) ground state for Mn(P)F2. The remarkable failure of DFT to correctly predict the metal- versus ligand-oxidized nature of Fe(P)F2 may have significant ramifications for the theoretical modeling of heme protein reaction pathways where until now the performance of DFT has raised little concern. PMID- 26641681 TI - Density Functional Study of H-D Coupling Constants in Heavy Metal Dihydrogen and Dihydride Complexes: The Role of Geometry, Spin-Orbit Coupling, and Gradient Corrections in the Exchange-Correlation Kernel. AB - The H-D nuclear spin-spin coupling constants J(H-D) of 14 heavy transition-metal dihydrogen and dihydride complexes were calculated with density functional theory using the "zeroth-order regular approximation" (ZORA) for the one-electron operators. The applied gradient-corrected density functional was able to achieve an average agreement with experimental data that is almost comparable to what has been obtained recently with hybrid functionals [J. Am. Chem. Soc. 2004, 126, 14249]. However, a systematic overestimation of J(H-D) for complexes with short H D distances was obtained, which could be traced back to problems of the gradient functional to describe the H-D coupling in free dihydrogen well. We implemented gradient corrections for the exchange-correlation (XC) kernel and employed a basis sets with high-exponent 1s function for the coupled hydrogens. The gradient terms in the XC kernel turned out to be very important in order to achieve reasonable agreement with experimental coupling constants. On the other hand, our study reveals that spin-orbit relativistic corrections on the H-D coupling constants are comparatively small and need not to be considered at the accuracy level of currently available "standard" density functionals. The discussion of the results highlights the strong dependence of the coupling constants on the H-D distance and the possibility of large vibrational contributions to them. We also discuss the coupling constant for the hydrogen molecule in detail because of its relevance to the coupling in dihydrogen and dihydride complexes. PMID- 26641682 TI - All-Electron Hybrid Density Functional Calculations on UFn and UCln (n = 1-6). AB - We calculate the bond dissociation energies of the series UFn and UCln (n = 1-6) using the all-electron third-order Douglas-Kroll-Hess approximation in combination with hybrid density functionals. The spin-orbit (SO) operator is included self-consistently using the nuclear-only SO and the screened-nuclear SO approximations. Results are in very good agreement with experimental values, with the exception of the smallest molecules of each series, UF and UCl. By shifting the one-electron orbital energies of UF6 and UCl6 to match the HOMO level with the DeltaSCF calculated value of the first ionization energy, we are able to reproduce the main features of the photoelectron spectrum of these two molecules. PMID- 26641683 TI - Effects of Arg90 Neutralization on the Enzyme-Catalyzed Rearrangement of Chorismate to Prephenate. AB - Chorismate mutase (CM) is an enzyme that catalyzes the Claisen rearrangement of chorismate to prephenate. In a recent effort to understand the basis for catalysis by CM, Kienhofer and co-workers (J. Am. Chem. Soc. 2003, 125, 3206 3207) reported results on the mutation of Arg90 in Bacillus subtilis CM (BsCM) to citrulline (Cit), an isosteric but neutral arginine analogue. An ca. 10(4)-fold decrease in kcat or 5.9 kcal/mol increase in the free-energy barrier (DeltaG(?)) for the overall catalysis was observed upon mutation. In this work, attention is turned to determining the key factors that contribute to the reduced catalytic efficiency of Arg90Cit BsCM. Using a combined QM/MM Monte Carlo/Free-Energy Perturbation method, a DeltaDeltaG(?) value of 3.3 kcal/mol is obtained. The higher free-energy barrier for the mutant is exclusively related to inferior stabilization of the TS, particularly one of its carboxylate groups, by neutral Cit. In addition, the reaction becomes 2.0 kcal/mol more exergonic. As BsCM is limited by product release, this step contributes to the remainder of the 10(4) fold decrease in the rate constant in going from Arg90 to Cit. PMID- 26641684 TI - Frequency-Dependent Polarizabilities of Amino Acids as Calculated by an Electrostatic Interaction Model. AB - The frequency-dependent polarizability of the 20 essential amino acids has been calculated by an electrostatic interaction model where an Unsold-type of model has been adopted for the frequency dependence. The interaction model has previously been parametrized from Hartree-Fock calculations on a set of molecules, and the model is in this work extended by sulfur parameters by including a set of 18 small sulfur compounds. The results for the amino acids by using the interaction model compare well with Hartree-Fock calculations with deviations of around 5% for the isotropic polarizability. Furthermore, the intrinsic (or optical) dielectric constant related to the polarizability has been calculated for three small proteins, ribonuclease inhibitor, lysozyme, and green fluorescent protein, adopting the interaction model. The results are consistent with the intrinsic dielectric constants found for proteins in the literature. PMID- 26641685 TI - A Simple Method for Improving Torsion Optimization of Ligand Molecules in Receptor Binding Sites. AB - A simple but effective method is introduced for optimizing ligand molecules in torsion space within receptor binding sites. The algorithm makes use of geometric constraints of ligand molecules to search for energetically favorable conformations. It is applied to a conjugate gradient (CG) method as an example. During conformational energy optimization, new line search directions are modified according to the spatial span of rotational groups in ligand molecules. Significant improvements were observed in terms of the abilities both to recover global optimal structures and to obtain lower energy ensembles. This simple algorithm allows rapid implementation and can be incorporated into other conformational energy optimization techniques. PMID- 26641686 TI - From Hydrophobic to Hydrophilic Solvation: An Application to Hydration of Benzene. AB - We report a computer simulation study on the hydration of benzene, which, despite being hydrophobic, is a weak hydrogen bond acceptor. The effect of benzene-water hydrogen bonding on the hydration free energy has been analyzed in terms of solute-solvent energies and entropies. Our calculations show that benzene-water hydrogen bonding restricts the number of arrangements possible for the water molecules resulting in a more unfavorable (negative) solute-solvent entropy change than observed for a 'nonpolar benzene' not capable of accepting water hydrogen bonds. More favorable hydration free energies of aromatic hydrocarbons in comparison with aliphatic hydrocarbons observed experimentally as well as in our calculations must therefore be a result of more favorable solute-solvent interaction energies. This result supports the view that lower aqueous solubilities of nonpolar molecules compared to polar molecules are due to a lack of favorable electrostatic interactions with water molecules. The calculated hydration free energy, enthalpy, entropy, and hydration heat capacity of benzene are in good agreement with experimentally reported values. PMID- 26641687 TI - Modeling Nitrogen Adsorption in Spherical Pores of Siliceous Materials by Density Functional Theory. AB - Adsorption of nitrogen in spherical pores of FDU-1 silica at 77 K is considered by means of a nonlocal density functional theory (NLDFT) accounting for a disordered structure of pore walls. Pore size distribution analysis of various FDU-1 samples subject to different temperatures of calcination revealed three distinct groups of pores. The principal group of pores is identified as ordered spherical mesopores connected with each other by smaller interconnecting pores and irregular micropores present in the mesopore walls. To account for the entrances (connecting pores) into spherical mesopores, a concept of solid mass distribution with respect to the apparent density was introduced. It is shown that the introduction of the aforementioned distribution was sufficient to quantitatively describe experimental adsorption isotherms over the entire range of relative pressures spanning six decades. PMID- 26641688 TI - Computational Free Energy Studies of a New Ice Polymorph Which Exhibits Greater Stability than Ice Ih. AB - The absolute free energies of several ice polymorphs were calculated using thermodynamic integration. These polymorphs are predicted by computer simulations using a variety of common water models to be stable at low pressures. A recently discovered ice polymorph that has as yet only been observed in computer simulations (Ice-i) was determined to be the stable crystalline state for all the water models investigated. Phase diagrams were generated, and phase coexistence lines were determined for all of the known low-pressure ice structures. Additionally, potential truncation was shown to play a role in the resulting shape of the free energy landscape. PMID- 26641689 TI - Control of the Barrier in Cyanide Based Single Molecule Magnets Mn(III)2Mn(II)3: Theoretical Analysis. AB - The aim of this communication is to probe the possibility of increasing the barrier for reversal of magnetization in the family of new cyano-bridged pentanuclear Mn(III)2Mn(II)3 clusters in which single molecule magnet behavior has been recently discovered. In this context, we analyze the global magnetic anisotropy arising from the unquenched orbital angular momenta of ground terms (3)T1(t2(4)) of the two apical Mn(III) ions. The model takes into account the trigonal component of the crystal field, spin-orbit interaction in (3)T1(t2(4)), and an isotropic exchange interaction between Mn(III) and Mn(II) ions. The height of the barrier is shown to be sensitive to the change of the trigonal field stabilizing orbital doublet (3)E, which carries the first-order orbital magnetic contribution and enhances with an increase of the trigonal field. This result is expected to be useful for the more rational design of new cyano-bridged SMMs with high blocking temperatures. PMID- 26641690 TI - QM/MM Study of the NMR Spectroscopy of the Retinyl Chromophore in Visual Rhodopsin. AB - The (1)H and (13)C nuclear magnetic resonance (NMR) spectra of the retinyl chromophore in rhodopsin are investigated by using quantum mechanics/molecular mechanics (QM/MM) hybrid methods at the density functional theory (DFT) B3LYP/6 31G*:Amber level of theory, in conjunction with the gauge independent atomic orbital (GIAO) method for the ab initio self-consistent-field (SCF) calculation of NMR chemical shifts. The study provides a first-principle interpretation of solid-state NMR experiments based on recently developed QM/MM computational models of rhodopsin and bathorhodopsin [Gascon, J. A.; Batista, V. S. Biophys. J. 2004, 87, 2931-2941]. The reported results are particularly relevant to the development and validation of atomistic models of prototypical G-protein-coupled receptors which regulate signal transduction across plasma membranes. PMID- 26641691 TI - Catalytic Reaction Mechanism of Oxalate Oxidase (Germin). A Hybrid DFT Study. AB - The mechanism of the catalytic reaction for oxalate oxidase has been investigated with the hybrid density functional method B3LYP. The models used in the calculations comprise of the manganese ion, three imidazoles, and one acetate, which model the active-site Mn(II) and its first-shell protein ligands. Moreover, the reactants, i.e., singly protonated oxalate and dioxygen, have been explicitly considered. The computational results suggest that the enzyme-oxalate complex can adopt two conformations, one with bidentate oxalate and 6-coordinate manganese and the second one with monodentate substrate and coordinatively unsaturated Mn(II). This second species reacts with dioxygen on the quartet potential energy surface, and in a rate-limiting step yields one CO2 molecule and a reactive intermediate, in which Mn(III) is coordinated by HOO(-) and a formyl radical anion. A subsequent fast spin transition, from the quartet to the sextet spin state, allows an electron transfer from the formyl radical anion to Mn(III) and leads to the product-enzyme complexes. It is proposed that the final step of the catalytic cycle involves protonation of these species and release of products. Taken together, the mechanistic proposal presented in this work agrees well with the available experimental data and provides an explanation for the very efficient coupling between the two-electron dioxygen reduction and oxalate oxidation performed by oxalate oxidase. PMID- 26641692 TI - A Polarizable Force Field and Continuum Solvation Methodology for Modeling of Protein-Ligand Interactions. AB - A polarizable force field, and associated continuum solvation model, have been developed for the explicit purpose of computing and studying the energetics and structural features of protein binding to the wide range of ligands with potential for medicinal applications. Parameters for the polarizable force field (PFF) are derived from gas-phase ab initio calculations and then utilized for applications in which the protein binding to ligands occurs in aqueous solvents, wherein the charge distributions of proteins and ligands can be dramatically altered. The continuum solvation model is based on a self-consistent reaction field description of solvation, incorporating an analytical gradient, that allows energy minimizations (and, potentially, molecular dynamics simulations) of protein/ligand systems in continuum solvent. This technology includes a nonpolar model describing the cost of cavity formation, and van der Waals interactions, between the continuum solvent and protein/ligand solutes. Tests of the structural accuracy and computational stability of the methodology, and timings for energy minimizations of proteins and protein/ligand systems in the condensed phase, are reported. In addition, the derivation of polarizability, electrostatic, exchange repulsion, and torsion parameters from ab initio data is described, along with the use of experimental solvation energies for determining parameters for the solvation model. PMID- 26641693 TI - Structural Determinants of Transmembrane beta-Barrels. AB - The recognition of beta-barrel membrane proteins based on their sequence is more challenging than the recognition of alpha-helical membrane proteins. This goal could benefit from a better understanding of the physical determinants of transmembrane beta-barrel structure. To that end, we first extend the IMM1 implicit membrane model in a way that allows the modeling of membrane proteins with an internal aqueous pore. The new model (IMM1-pore) gives stable molecular dynamics trajectories for three beta-barrel membrane proteins of different sizes and negative water-to-membrane transfer energies of reasonable magnitude. It also discriminates the correct fold for a pair of 10-stranded and 12-stranded transmembrane beta-barrels. We then consider a pair of beta-barrel proteins: OmpA, which is a membrane beta-barrel with hydrophobic residues on the exterior and polar residues in the interior, and retinol binding protein, which is a water soluble protein with polar residues on the exterior and hydrophobic residues in the interior. By threading the sequence of one onto the structure of the other we make two pairs of structures for each sequence, one native and the other a decoy, and evaluate their energy. The energy function discriminates the correct structure. By decomposing the energy into residue contributions we examine which features of each sequence make it fold into one or the other structure. It is found that for the OmpA sequence the largest contribution to stability comes from interactions between polar residues in the interior of the barrel. The major factor that prevents the retinol binding protein sequence from adopting a transmembrane fold is the presence of polar/charged residues at the edges of the putative transmembrane beta-strands as well as the less favorable interior polar residue interactions. These results could help design simplified scoring functions for fold recognition and structure prediction of transmembrane beta barrels. PMID- 26641694 TI - Free Energy Landscape of Protein-Protein Encounter Resulting from Brownian Dynamics Simulations of Barnase:Barstar. AB - Over the past years Brownian dynamics (BD) simulations have been proven to be a suitable tool for the analysis of protein-protein association. The computed rates and relative trends for protein mutants and different ionic strength are generally in good agreement with experimental results, e.g. see ref 1. By design, BD simulations correspond to an intensive sampling over energetically favorable states, rather than to a systematic sampling over all possible states which is feasible only at rather low resolution. On the example of barnase and barstar, a well characterized model system of electrostatically steered diffusional encounter, we report here the computation of the 6-dimensional free energy landscape for the encounter process of two proteins by a novel, careful analysis of the trajectories from BD simulations. The aim of these studies was the clarification of the encounter state. Along the trajectories, the individual positions and orientations of one protein (relative to the other) are recorded and stored in so-called occupancy maps. Since the number of simulated trajectories is sufficiently high, these occupancy maps can be interpreted as a probability distribution which allows the calculation of the entropy landscape by the use of a locally defined entropy function. Additionally, the configuration dependent electrostatic and desolvation energies are recorded in separate maps. The free energy landscape of protein-protein encounter is finally obtained by summing the energy and entropy contributions. In the free energy profile along the reaction path, which is defined as the path along the minima in the free energy landscape, a minimum shows up suggesting this to be used as the definition of the encounter state. This minimum describes a state of reduced diffusion velocity where the electrostatic attraction is compensated by the repulsion due to the unfavorable desolvation of the charged residues and the entropy loss due to the increasing restriction of the motional freedom. In the simulations the orientational degrees of freedom at the encounter state are found to be less restricted than the translational degrees of freedom. Therefore, the orientational alignment of the two binding partners seems to take place beyond this free energy minimum. The free energy profiles along the reaction pathway are compared for different ionic strength and temperature. This novel analysis technique facilitates mechanistic interpretation of protein-protein encounter pathways which should be useful for interpretation of experimental results as well. PMID- 26641695 TI - A Molecular Dynamics Simulation of the Binding Modes of d-Glutamate and d Glutamine to Glutamate Racemase. AB - Classical molecular dynamics simulations of the d-Gln/Aquifex pyrophilus MurI and d-Glu/Aquifex pyrophilus MurI complexes have been carried out. Since the active site of the enzyme contains many charged and polar residues, several binding modes are possible. Thus, three very different stable conformations of the substrate analogue d-Gln have been found, and at least three binding modes are possible for the substrate d-Glu. These qualitative results give an explanation for the apparent disagreement between the d-Gln bound MurI X-ray crystal structure and the expected position and orientation of the substrate d-Glu in order to make it possible the assumed Calpha deprotonation (by Cys70)/reprotonation (by Cys178) racemization mechanism. PMID- 26641697 TI - Structural Optimization of Silver Clusters up to 80 Atoms with Gupta and Sutton Chen Potentials. AB - The structure of silver clusters containing up to 80 atoms is optimized by using a random tunneling algorithm (RTA). The Gupta-type many-body potential and the Sutton-Chen (SC) many-body potential are used to account for the interactions among the atoms in the cluster, respectively. It is found that many of the structural configurations optimized with the two potentials are different, especially at a small size, and the structures with the Gupta potential are highly strained and apt to be the disordered motifs, whereas the structures with the SC potential are less-strained and the ordered morphologies are more favorable. Due to the difference of long-range interaction and pair contribution between two potentials, the assignment of outermost-shell atoms in decahedron and the missing atoms on the surface of the icosahedral motifs are also different for the two potentials. Furthermore, a new global minimum of the 68-atom silver cluster with the decahedral motif is found for both two potential models. PMID- 26641696 TI - A QM/MM Exploration of the Potential Energy Surface of Pyruvate to Lactate Transformation Catalyzed by LDH. Improving the Accuracy of Semiempirical Descriptions. AB - We present a QM/MM study of the potential energy surface of the pyruvate to lactate transformation catalyzed by L-lactate dehydrogenase. The transformation involves a hydride and a proton transfer which are followed by means of the corresponding antisymmetric combination of the distances from the hydrogen atom to the donor and the acceptor atoms. To discriminate among the possible reaction mechanisms we have considered different improvements of the AM1/MM description: reoptimization of the van der Waals parameters and inclusion of corrections to the QM energy associated with both transfer coordinates. The QM subsystem has been also enlarged to include charge-transfer effects from the substrate to some specific residues. In our best treatment, the transformation is described as a concerted process through a single transition structure in which the hydride transfer is more advanced than the proton transfer. From the methodological point of view, the correction schemes tested here improve the quality of the semiempirical potential energy surface although they also present deficiencies attributed to consideration of the proton and hydride transfer corrections as separable ones. PMID- 26641698 TI - Current advances in ant venom proteins causing hypersensitivity reactions in the Asia-Pacific region. AB - The main insects causing allergy reactions to stinging insect in humans are Apidae (bees), Vespidae (wasps, yellow jackets and hornets) and Formicidae (ants). Their venom stings are composed of various biologically active peptides and protein components, some of which can cause toxicity or anaphylaxis in humans. The protein venom demonstrate some common allergenic activity such as for fire ants and vespids, which have two common allergens that are phospholipase A1 (enzymatic activity) and antigen 5 with unknown biological activity. The common allergens seem to share some degree of immunological cross-reactivity, particularly when the sequence homology is above 70%. Therefore immunotherapeutic approaches targeting more than one specific species are of interest. Recent widespread increases of various ant species in many countries have resulted in higher number of reported about serious allergic reactions to stings. Most insect allergy related cases have been reported for species from Solenopsis, Myrmecia and Pachycondyla genera, and their stings can often result in human fatalities. In addition, stinging ants can have serious health effects on livestock, agricultural damage adversely affecting the biodiversity of the region. This review discusses the impact of important ant species on human health in the Asia Pacific region along with the molecular immunological aspects of the identified venoms and current status of diagnostics and therapeutics. PMID- 26641699 TI - Tuning Structural Changes in Glucose Oxidase for Enzyme Fuel Cell Applications. AB - Stabilization and electrical contacting of redox enzymes with electrodes are fundamental requirements for bioelectronics devices, including biosensors and enzyme fuel cells (EFCs). In this study, we show increased glucose oxidase (GOx) stability by immobilization with Nafion. The immobilization process affected GOx conformation but was not detrimental to its activity, which was maintained for more than 120 days. The GOx/Nafion system was interfaced to a carbon cloth electrode and assembled in a prototypal EFC fed with glucose. Polarization and power density curves demonstrated that GOx/Nafion system was able to generate power, exploiting a Nafion-assisted electron transfer process to the electrode. Our findings are consistent with the onset of pH-dependent conformational equilibrium for the enzyme secondary structure and its active site. Significantly, the protective effect exerted by Nafion on the enzyme structure may be tuned by varying parameters such as the pH to fabricate durable EFCs with good electrocatalytic performance. PMID- 26641700 TI - Suture Button Fixation Treatment of Chronic Lisfranc Injury in Professional Dancers and High-Level Athletes. AB - Chronic Lisfranc injury is a subtle and severe injury in high-level athletes, including dancers. This patient population is generally intolerant of intra articular screw fixation and can develop significant post-traumatic arthritis with potentially career ending complications. Flexible fixation with suture button devices provides potential restoration of physiologic motion at the joint, with appropriate support for healing that may facilitate return to en pointe activities for dancers. We hypothesized that the suture-button device would restore motion at the Lisfranc joint and allow for return to activities in this particular population without the limitations and complications of rigid fixation. We operated on seven dancers and high-level athletes with diagnosed Lisfranc injuries by installing a suture-button device. All patients had failed conservative management after late presentation. They were allowed to return to sport in 6 months, preoperative and postoperative American Orthopaedic Foot and Ankle Score (AOFAS) foot scores were obtained, and patients were followed for a minimum of 15 months. All seven returned to full activities in 6 months, with radiographic evidence of fixation and no complications to date. AOFAS foot scores improved from an average of 65 preoperatively to an average of 97 postoperatively at latest follow-up. It is concluded that flexible fixation with suture-button type device represents a viable alternative to screw fixation or fusion that may allow dancers and athletes to return to previous levels of activity after Lisfranc injury. This case series represents to our knowledge the first application of this device to a unique population that requires flexibility at the Lisfranc joint for performance. PMID- 26641701 TI - Epidemiological Review of Injury in Pre-Professional Ballet Dancers. AB - The objective of this study was to provide an epidemiological review of the literature concerning ballet injuries affecting pre-professional ballet dancers. The literature search was limited to published peer-reviewed reports and involved an extensive examination of Scopus, SPORTDiscus, and CINAHL. The following search terms were used in various combinations: ballet, injury, epidemiology, risk factor, pre-professional, and intervention. Additional citations were located using the ancestry approach. Unlike some other athletic activities that have been the focus of recent intervention research, there is a paucity of intervention and translational research in pre-professional ballet, and sample sizes have often been small and have not accounted for the multivariate nature of ballet injury. Exposure-based injury rates in this population appear similar to those reported for professional ballet dancers and female gymnasts. A preponderance of injuries affect the lower extremity of these dancers, with sprains and strains being the most frequent type of injury reported. The majority of injuries appear to be overuse in nature. Injury risk factors have been tested in multiple studies and indicate a variety of potential injury predictors that may provide useful guidance for future research. PMID- 26641702 TI - Suitability of the Perceived Motivational Climate in Sport Questionnaire-2 for Dance Research: A Think Aloud Approach. AB - The Perceived Motivational Climate in Sport Questionnaire-2 (PMCSQ-2) adapted for dance has been employed in a variety of dance settings. However, the content validity of the measure and the relevance of particular subscales (e.g., Intra Team Member Rivalry) have been questioned. Thus, the aims of this study were twofold: first, to examine the content validity of the PMCSQ-2 and identify problematic items and the nature and frequency of such problems experienced by dancers completing the measure; and second, to determine whether the content of task-involving and ego-involving climates, as captured in the subscales of the PMCSQ-2, are relevant and meaningful in dance contexts. Think aloud interviews were conducted with 21 dancers (10 male, 11 female) representing diverse types and levels of dance experience. The interviews were transcribed verbatim and segmented into text related to each item in the PMCSQ-2. Each participant's responses were individually analyzed, with the nature and frequency of problems encountered recorded in relation to five potential causes: errors in understanding, interpretation, retrieval, judgment, and responding. Think aloud interviews revealed that 72% of the participant responses presented no problem, indicating that the measure has an acceptable degree of content validity. However, the findings highlight a number of potentially problematic areas that warrant further attention. Implications for the interpretation of previous research and the conduct of future research employing the PMCSQ-2 in dance as well as other achievement contexts (e.g., sport) are discussed. PMID- 26641703 TI - Trunk Muscle Activation and Estimating Spinal Compressive Force in Rope and Harness Vertical Dance. AB - Rope and harness vertical dance takes place off the floor with the dancer suspended from his or her center of mass in a harness attached to a rope from a point overhead. Vertical dance represents a novel environment for training and performing in which expected stresses on the dancer's body are different from those that take place during dance on the floor. Two male and eleven female dancers with training in vertical dance performed six typical vertical dance movements with electromyography (EMG) electrodes placed bilaterally on rectus abdominus, external oblique, erector spinae, and latissimus dorsi. EMG data were expressed as a percentage of maximum voluntary isometric contraction (MVIC). A simplified musculoskeletal model based on muscle activation for these four muscle groups was used to estimate the compressive force on the spine. The greatest muscle activation for erector spinae and latissimus dorsi and the greatest trunk compressive forces were seen in vertical axis positions where the dancer was moving the trunk into a hyper-extended position. The greatest muscle activation for rectus abdominus and external oblique and the second highest compressive force were seen in a supine position with the arms and legs extended away from the center of mass (COM). The least muscle activation occurred in positions where the limbs were hanging below the torso. These movements also showed relatively low muscle activation compression forces. Post-test survey results revealed that dancers felt comfortable in these positions; however, observation of some positions indicated insufficient muscular control. Computing the relative contribution of muscles, expressed as muscle activation and estimated spinal compression, provided a measure of how much the muscle groups were working to support the spine and the rest of the dancer's body in the different movements tested. Additionally, identifying typical muscle recruitment patterns in each movement will help identify key exercises for training that should promote injury prevention. PMID- 26641704 TI - Efficient Determination of the Enantiomeric Purity and Absolute Configuration of Flavanones by Using (S)-3,3'-Dibromo-1,1'-bi-2-naphthol as a Chiral Solvating Agent. AB - The enantiomeric purity and absolute configuration of flavanones were first determined using (S)-3,3'-dibromo-1,1'-bi-2-naphthol as a chiral solvating agent by means of (1)H NMR spectroscopy. The enantiomeric purity results closely matched those based on chiral HPLC analysis. PMID- 26641705 TI - A versatile, quantitative analytical method for pharmaceutical relevant lipids in drug delivery systems. AB - Over the past few years, liposomal formulations as drug carrier systems have markedly advanced in pharmaceutical research and development. Therefore, analytical methods to characterize liposome-based formulations are required. One particular issue in liposome analysis is the imbalance of lipid ratios within the vesicle formulations and the detectability of degradation products such as lysophospholipids and fatty acids caused by hydrolysis, especially in low molar ranges. Here, a highly sensitive and selective reversed-phase high-performance liquid chromatography (rp-HPLC) method is described by the combination of an organic solvent/trifluoroacetic acid (TFA) triggered gradient and the application of an evaporative light scattering detector (ELSD). Gain setting adjustments of the ELSD were applied to obtain an optimal detection profile of the analyzed substances. This optimization provides simultaneous separation and quantification of 16 components, including different phosphatidylcholines, phosphatidylglycerols and their degradation products, as well as cholesterol. Parameters such as limit of detection (LOD) and limit of quantification (LOQ) were determined for each of the components and had ranges from 0.25-1.00mg/mL (LOD) and 0.50-2.50MUg/mL (LOQ), respectively. The intra-day precision for all analytes is less than 3% (RSD) and inter-day precision is about 8%. The applicability of the method was verified by analyzing two different liposome formulations consisting of DSPC:DPPC:DSPG:Chol (35:35:20:10) and DSPC:DPPC:DSPG (38:38:24). For degradation studies, both formulations were stored at 4 degrees C and at ambient temperature. Additionally, forced degradation experiments were performed to determine hydrolysis mass balances. A total recovery of 96-102% for phospholipid compounds was found. Analytical data revealed that the sensitivity, selectivity, accuracy, and resolution are appropriate for the detection and quantification of phospholipids and their hydrolysis products. These results as well as additional preliminary analyses of other relevant components used in liposomal formulations indicate that the developed method is suitable for the development, characterization, and stability testing of liposomal based biopharmaceuticals. PMID- 26641706 TI - Development and validation of a sensitive UPLC-MS/MS method for the simultaneous determination of dapoxetine and its two metabolites in human plasma. AB - A sensitive and rapid ultra performance liquid chromatography tandem mass spectroscopy (UPLC-MS/MS) method was developed to determine dapoxetine and its two major metabolites (dapoxetine-N-oxide and desmethyldapoxetine) in human plasma simultaneously. After a simple protein precipitation, the analytes and the combined internal standard (carbamazepine) were separated on an Acquity UPLC BEH C18 column using a mobile phase of acetonitrile and 0.1% formic acid in water with gradient elution. Mass spectrometric analysis was performed using a XEVO TQD triple quadruple mass spectrometer coupled with an electro-spray ionization (ESI) source in the positive ion mode. The MRM transitions are of m/z 306.3->261.2, m/z 322.2->261.2, m/z 292.2->261.2 and m/z 237.1->194.2 for dapoxetine, dapoxetine-N oxide, desmethyldapoxetine and IS, respectively. The linearity of this method was found to be within the concentration range of 1.0-200ng/mL for dapoxetine; 0.5 100ng/mL for dapoxetine-N-oxide; and 0.1-5.0ng/mL for desmethyldapoxetine in human plasma, respectively. Only 4.0min was needed for an analytical run. Intra day and inter-day accuracy and precision were within the acceptable limits of +/ 15% at all of the concentrations. This assay was successfully used to support a clinical pharmacokinetic study following oral administration of dapoxetine tablets in healthy Chinese subjects. PMID- 26641707 TI - In vitro metabolism of a novel synthetic cannabinoid, EAM-2201, in human liver microsomes and human recombinant cytochrome P450s. AB - In vitro metabolism of a new synthetic cannabinoid, EAM-2201, has been investigated with human liver microsomes and major cDNA-expressed cytochrome P450 (CYP) isozymes using liquid chromatography-high resolution mass spectrometry (LC HRMS). Incubation of EAM-2201 with human liver microsomes in the presence of NADPH resulted in the formation of 37 metabolites, including nine hydroxy-EAM 2201 (M1-M9), five dihydroxy-EAM-2201 (M10-M14), dihydrodiol-EAM-2201 (M15), oxidative defluorinated EAM-2201 (M16), two hydroxy-M16 (M17 and M18), three dihydroxy-M16 (M19-M21), N-dealkyl-EAM-2201 (M22), two hydroxy-M22 (M23 and M24), dihydroxy-M22 (M25), EAM-2201 N-pentanoic acid (M26), hydroxy-M26 (M27), dehydro EAM-2201 (M28), hydroxy-M28 (M29), seven dihydroxy-M28 (M30-M36), and oxidative defluorinated hydroxy-M28 (M37). Multiple CYPs, including CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2J2, 3A4, and 3A5, were involved in the metabolism of EAM-2201. In conclusion, EAM-2201 is extensively metabolized by CYPs and its metabolites can be used as an indicator of EAM-2201 abuse. PMID- 26641708 TI - Alternative determination of blood alcohol concentration by (1)H NMR spectroscopy. AB - A rapid, accurate and specific proton nuclear magnetic resonance ((1)H NMR) spectroscopic method is developed to determine ethanol in blood, known as the blood alcohol concentration (BAC). The limits of detection and quantification are 0.02g/L and 0.07g/L, respectively. The (1)H NMR spectra show linearity for whole blood and serum samples of a concentration range of 0.00-3.00g/L (R(2)>0.9995). The (1)H NMR method is applied and validated for whole blood as the sample media. Real driving under influence case samples are analyzed with the reference enzyme based alcohol dehydrogenase and headspace gas chromatography techniques by the Forensic Medicine in Bonn. The reference results are compared with the (1)H NMR spectroscopic results. The validation and comparison indicate that (1)H NMR is suitable for the quantification of BAC in whole blood. This technique has the advantages of automated analysis with good measurement precision and fast sample throughput. A drop of blood (V=20MUL) is adequate for an analysis leading to a possible simplification of the sample collection. Due to the non-destructive method, follow-up examinations by (1)H NMR spectroscopy or DNA determinations by different techniques (PCR, in situ hybridization) are possible in resolving legal disputes. PMID- 26641709 TI - New Graphene Form of Nanoporous Monolith for Excellent Energy Storage. AB - Extraordinary tubular graphene cellular material of a tetrahedrally connected covalent structure was very recently discovered as a new supermaterial with ultralight, ultrastiff, superelastic, and excellent conductive characteristics, but no high specific surface area will keep it from any next-generation energy storage applications. Herein, we prepare another new graphene monolith of mesoporous graphene-filled tubes instead of hollow tubes in the reported cellular structure. This graphene nanoporous monolith is also composed of covalently bonded carbon network possessing high specific surface area of ~1590 m(2) g(-1) and electrical conductivity of ~32 S cm(-1), superior to graphene aerogels and porous graphene forms self-assembled by graphene oxide. This 3D graphene monolith can support over 10 000 times its own weight, significantly superior to CNT and graphene cellular materials with a similar density. Furthermore, pseudocapacitance-active functional groups are introduced into the new nanoporous graphene monolith as an electrode material in electrochemical capacitors. Surprisingly, the electrode of 3D mesoporous graphene has a specific capacitance of 303 F g(-1) and maintains over 98% retention after 10 000 cycles, belonging to the list for the best carbon-based active materials. The macroscopic mesoporous graphene monolith suggests the great potential as an electrode for supercapacitors in energy storage areas. PMID- 26641710 TI - Chiral Porous Metacrystals: Employing Liquid-Phase Epitaxy to Assemble Enantiopure Metal-Organic Nanoclusters into Molecular Framework Pores. AB - We describe the fabrication of hybrid yet well-ordered porous nanoparticle (NP) arrays with full three-dimensional periodicity by embedding nanometer-sized metal organic clusters (MOCs) into metal-organic frameworks (MOFs). Although conventional NP@MOF encapsulation procedures failed for these fairly large (1.66 nm diameter) NPs, we achieved maximum loading efficiency (one NP per pore) by using a modified liquid phase epitaxy (LPE) layer-by-layer approach to grow and load the MOF. The preformed NPs, homochiral Ti4(OH)4(R/S-BINOL)6 clusters (Ti MOC, BINOL = 1,1'-bi-2-naphthol), formed a regular lattice inside the pores of an achiral HKUST-1 (or Cu3(BTC)2, BTC = 1,3,5-benzenetricarboxylate) MOF thin film. Exposure to the different enantiomers of methyl lactate revealed that the NP@MOF metacrystal is quite efficient regarding enantiomer recognition and separation. The approach presented here is also suited for other MOF types and expected to provide a substantial stimulus for the fabrication of metacrystals, crystalline solids made from nanoparticles instead of atoms. PMID- 26641711 TI - Atomic model of a nonenveloped virus reveals pH sensors for a coordinated process of cell entry. AB - Viruses sense environmental cues such as pH to engage in membrane interactions for cell entry during infection, but how nonenveloped viruses sense pH is largely undefined. Here, we report both high- and low-pH structures of bluetongue virus (BTV), which enters cells via a two-stage endosomal process. The receptor-binding protein VP2 possesses a zinc finger that may function to maintain VP2 in a metastable state and a conserved His866, which senses early-endosomal pH. The membrane-penetration protein VP5 has three domains: dagger, unfurling and anchoring. Notably, the beta-meander motif of the anchoring domain contains a histidine cluster that can sense late-endosomal pH and also possesses four putative membrane-interaction elements. Exposing BTV to low pH detaches VP2 and dramatically refolds the dagger and unfurling domains of VP5. Our biochemical and structure-guided-mutagenesis studies support these coordinated pH-sensing mechanisms. PMID- 26641712 TI - Recognition of distinct RNA motifs by the clustered CCCH zinc fingers of neuronal protein Unkempt. AB - Unkempt is an evolutionarily conserved RNA-binding protein that regulates translation of its target genes and is required for the establishment of the early bipolar neuronal morphology. Here we determined the X-ray crystal structure of mouse Unkempt and show that its six CCCH zinc fingers (ZnFs) form two compact clusters, ZnF1-3 and ZnF4-6, that recognize distinct trinucleotide RNA substrates. Both ZnF clusters adopt a similar overall topology and use distinct recognition principles to target specific RNA sequences. Structure-guided point mutations reduce the RNA binding affinity of Unkempt both in vitro and in vivo, ablate Unkempt's translational control and impair the ability of Unkempt to induce a bipolar cellular morphology. Our study unravels a new mode of RNA sequence recognition by clusters of CCCH ZnFs that is critical for post transcriptional control of neuronal morphology. PMID- 26641713 TI - Structural dynamics of potassium-channel gating revealed by single-molecule FRET. AB - Crystallography has provided invaluable insights regarding ion-channel selectivity and gating, but to advance understanding to a new level, dynamic views of channel structures within membranes are essential. We labeled tetrameric KirBac1.1 potassium channels with single donor and acceptor fluorophores at different sites and then examined structural dynamics within lipid membranes by single-molecule fluorescence resonance energy transfer (FRET). We found that the extracellular region is structurally rigid in both closed and open states, whereas the N-terminal slide helix undergoes marked conformational fluctuations. The cytoplasmic C-terminal domain fluctuates between two major structural states, both of which become less dynamic and move away from the pore axis and away from the membrane in closed channels. Our results reveal mobile and rigid conformations of functionally relevant KirBac1.1 channel motifs, implying similar dynamics for similar motifs in eukaryotic Kir channels and in cation channels in general. PMID- 26641714 TI - The complete mitochondrial genome sequence of Sphyraena jello (Perciformes: Sphyraenidae) and its phylogenetic position. AB - In this study, we obtained the complete mitochondrial genome sequence of Sphyraena jello and analyzed its phylogenetic position. The complete mitogenome of S. jello is 16 699 bp in length, consisting of 13 protein-coding genes, 22 transfer RNA genes, 2 ribosomal RNA genes, and a control region. Among the 37 genes, 28 were encoded on heavy strand, while 9 were encoded on light strand. The overall base composition was 28.97% for A, 16.14% for G, 29.64% for C, and 25.25% for T, with a higher A + T content (54.22%). The phylogenetic analysis based on 13 concatenated protein-coding genes suggested that S. jello is a sister species to Sphyraena barracuda in the family Sphyraenidae. This result should be useful for understanding the genetic structure, molecular evolution, and phylogeny of S. jello and related species. PMID- 26641716 TI - Orchestrated content release from Drosophila glue-protein vesicles by a contractile actomyosin network. AB - Releasing content from large vesicles measuring several micrometres in diameter poses exceptional challenges to the secretory system. An actomyosin network commonly coats these vesicles, and is thought to provide the necessary force mediating efficient cargo release. Here we describe the spatial and temporal dynamics of the formation of this actomyosin coat around large vesicles and the resulting vesicle collapse, in live Drosophila melanogaster salivary glands. We identify the Formin family protein Diaphanous (Dia) as the main actin nucleator involved in generating this structure, and uncover Rho as an integrator of actin assembly and contractile machinery activation comprising this actomyosin network. High-resolution imaging reveals a unique cage-like organization of myosin II on the actin coat. This myosin arrangement requires branched-actin polymerization, and is critical for exerting a non-isotropic force, mediating efficient vesicle contraction. PMID- 26641717 TI - Persistent cell migration and adhesion rely on retrograde transport of beta(1) integrin. AB - Integrins have key functions in cell adhesion and migration. How integrins are dynamically relocalized to the leading edge in highly polarized migratory cells has remained unexplored. Here, we demonstrate that beta1 integrin (known as PAT-3 in Caenorhabditis elegans), but not beta3, is transported from the plasma membrane to the trans-Golgi network, to be resecreted in a polarized manner. This retrograde trafficking is restricted to the non-ligand-bound conformation of beta1 integrin. Retrograde trafficking inhibition abrogates several beta1 integrin-specific functions such as cell adhesion in early embryonic development of mice, and persistent cell migration in the developing posterior gonad arm of C. elegans. Our results establish a paradigm according to which retrograde trafficking, and not endosomal recycling, is the key driver for beta1 integrin function in highly polarized cells. These data more generally suggest that the retrograde route is used to relocalize plasma membrane machinery from previous sites of function to the leading edge of migratory cells. PMID- 26641715 TI - Sequential Notch activation regulates ventricular chamber development. AB - Ventricular chambers are essential for the rhythmic contraction and relaxation occurring in every heartbeat throughout life. Congenital abnormalities in ventricular chamber formation cause severe human heart defects. How the early trabecular meshwork of myocardial fibres forms and subsequently develops into mature chambers is poorly understood. We show that Notch signalling first connects chamber endocardium and myocardium to sustain trabeculation, and later coordinates ventricular patterning and compaction with coronary vessel development to generate the mature chamber, through a temporal sequence of ligand signalling determined by the glycosyltransferase manic fringe (MFng). Early endocardial expression of MFng promotes Dll4-Notch1 signalling, which induces trabeculation in the developing ventricle. Ventricular maturation and compaction require MFng and Dll4 downregulation in the endocardium, which allows myocardial Jag1 and Jag2 signalling to Notch1 in this tissue. Perturbation of this signalling equilibrium severely disrupts heart chamber formation. Our results open a new research avenue into the pathogenesis of cardiomyopathies. PMID- 26641718 TI - Innate control of actin nucleation determines two distinct migration behaviours in dendritic cells. AB - Dendritic cell (DC) migration in peripheral tissues serves two main functions: antigen sampling by immature DCs, and chemokine-guided migration towards lymphatic vessels (LVs) on maturation. These migratory events determine the efficiency of the adaptive immune response. Their regulation by the core cell locomotion machinery has not been determined. Here, we show that the migration of immature DCs depends on two main actin pools: a RhoA-mDia1-dependent actin pool located at their rear, which facilitates forward locomotion; and a Cdc42-Arp2/3 dependent actin pool present at their front, which limits migration but promotes antigen capture. Following TLR4-MyD88-induced maturation, Arp2/3-dependent actin enrichment at the cell front is markedly reduced. Consequently, mature DCs switch to a faster and more persistent mDia1-dependent locomotion mode that facilitates chemotactic migration to LVs and lymph nodes. Thus, the differential use of actin nucleating machineries optimizes the migration of immature and mature DCs according to their specific function. PMID- 26641719 TI - Human keratinocytes have two interconvertible modes of proliferation. AB - Single stem cells, including those in human epidermis, have a remarkable ability to reconstitute tissues in vitro, but the cellular mechanisms that enable this are ill-defined. Here we used live imaging to track the outcome of thousands of divisions in clonal cultures of primary human epidermal keratinocytes. Two modes of proliferation were seen. In 'balanced' mode, similar proportions of proliferating and differentiating cells were generated, achieving the 'population asymmetry' that sustains epidermal homeostasis in vivo. In 'expanding' mode, an excess of cycling cells was produced, generating large expanding colonies. Cells in expanding mode switched their behaviour to balanced mode once local confluence was attained. However, when a confluent area was wounded in a scratch assay, cells near the scratch switched back to expanding mode until the defect was closed. We conclude that the ability of a single epidermal stem cell to reconstitute an epithelium is explained by two interconvertible modes of proliferation regulated by confluence. PMID- 26641720 TI - Evidence of Helminth Infection in Guanche Mummies: Integrating Paleoparasitological and Paleogenetic Investigations. AB - The Guanches, ancient inhabitants of the Canary Islands, Spain, practiced mummification of their dead. A paleoparasitological and paleogenetic analysis was conducted on mummified bodies (n = 6) (AD 1200, Cal BP 750) belonging to the Guanche culture from Gran Canaria Island. Coprolite and sediment samples (n = 19) were removed from below the abdominal region or sacral foramina. The samples were rehydrated in 0.5% trisodium phosphate solution for 72 hr at 4 C, and the paleoparasitological investigation was conducted by spontaneous sedimentation method and microscopic examination. The results revealed the presence of well preserved eggs of Ascaris sp., Trichuris trichiura , Enterobius vermicularis , and hookworms. Ancient DNA was extracted from sediment samples to elucidate the ancestry of the mummies and for molecular detection of Ascaris sp. infection. Results of paleogenetic analysis demonstrated Ascaris sp. infection using 2 molecular targets, cytb and nad1. The mtDNA haplotypes U6b, U6b1, and HV were identified, which confirmed records of Guanche ancestry. The excellent preservation of Guanche mummies facilitated the paleoparasitological and paleogenetic study, the results of which contribute to our knowledge of Guanche culture and their health status. PMID- 26641721 TI - Complete mitochondrial genome of Plodia interpunctella (Lepidoptera: Pyralidae). AB - The complete mitochondrial genome sequence of Plodia Interpunctella (Lepidoptera: Pyralidae) was determined. The circular genome has a size of 15 733 base pairs, containing 36 gene protein-coding genes, two rRNA genes, and 21 tRNA genes. The overall base composition was 41.37% of A, 37.99% of T, 12.54% of G, and 8.10% of C. Furthermore, a phylogenetic tree was constructed based on complete mitogenomes of Plodia interpunctella and 11 closely related Pyralidae species to validate the taxonomy relationship. The complete mitochondrial genome of the P. interpunctella would provide more information for the evolution of Pyralidae family. PMID- 26641722 TI - Relationship between male hormonal status, Bezold-Jarisch reflex function, and ACE activity (cardiac and plasmatic). AB - The negative relationship between androgens and the Bezold-Jarisch reflex (BJR) has been demonstrated, but no studies evaluated the physiological influence of testosterone on this reflex. We evaluated the influence of male rat castration on the BJR, cardiac morphometric parameters, and the plasmatic and the cardiac angiotensin converting enzyme (ACE) activity. After castration (CAS), the rats were divided into 24 and 72 h (CAS24H, CAS72H), and 7 and 21 days (CAS7D, CAS21D) groups. The BJR was studied by administering increasing doses of phenylbiguanide (PBG; 1.5-24 MUg/kg) at different times after castration. Castration results in the following: (i) reduction in testosterone levels (SHAM: 238.7 +/- 15.1; CAS24H: 9.0 +/- 0.5; CAS72H: 6.7 +/- 0.4; CAS7D: 5.2 +/- 0.2; and CAS21D: 2.2 +/- 0.3 ng/dL; p < 0.05); (ii) no changes in 17beta-estradiol; (iii) a reduced BJR sensitivity (PBG 6 MUg/kg; SHAM: 77 +/- 7; CAS24H: 63 +/- 10; CAS72H: 55 +/- 6; CAS7D: 54 +/- 4; and CAS21D: 35 +/- 2%; p < 0.01); (iv) a decrease in cardiac (SHAM: 107 +/- 6; CAS24H: 92 +/- 2; CAS72H: 82 +/- 3; CAS7D: 54 +/- 3; and CAS21D: 43 +/- 4%; p < 0.05) and plasmatic (SHAM: 135 +/- 8; CAS24H: 102 +/- 5; CAS72H: 99 +/- 3; CAS7D: 89 +/- 4; and CAS21D: 56 +/- 6%; p < 0.05) ACE activity. No changes were observed in cardiac morphometry and hemodynamic parameters. Therefore, castration leads to decrease in testosterone levels as early as 24 h, reduction in ACE activity and loss of BJR sensitivity 7 days after castration. The loss of BJR sensitivity was not related to cardiac morphometric changes and cardiovascular hemodynamics. PMID- 26641723 TI - A Model of a Closed Cycle of Water Splitting Using ansa-Titanocene(III/IV) Triflate Complexes. AB - A series of ansa-titanocene triflate complexes are described as model compounds for the elementary steps of light-driven overall water splitting. Titanocene(III) triflate complexes are readily obtained by reaction of a titanocene source with Yb(OTf)3. Subsequent reactions with water and with/without TEMPO as hydrogen scavenger are studied. The as-obtained titanocene(IV) compounds can be photoreduced to give titanocene(III) triflate complexes, which can undergo further hydrolysis to form a closed catalytic cycle of water splitting. No further degradation of the photoreduced species was observed because of the presence of the OTf group. The stability of the system was evaluated in an experiment with high concentrations of water and TEMPO. X-ray crystallography on all titanocene complexes, EPR and NMR spectroscopy, and DFT were used to support our observations. PMID- 26641724 TI - Strategies towards universal pandemic influenza vaccines. AB - Vaccination is considered to be the most effective and economical strategy against pandemic influenza. Vaccine development for multiple highly pathogenic avian influenza viruses, for example, H5N1, is hindered by antigenic drift, especially in the hemagglutinin (HA) sequence, as well as the antigenic shift. Growing efforts have been made to generate universal pandemic influenza vaccines. As mainly shown in animal trials, cross-clade and heterosubtypic protection by these universal vaccines are generally elicited by either a broad antigen specific antibody response or influenza-specific CD4+ and CD8+ T-cell responses. Strain selection, HA engineering and broad neutralizing antigen determination are major strategies to achieve universal and specific antibody response, while studies on other factors including vectors, adjuvants and administration routes aim for enhanced T-cell responses against diverse influenza subtypes. Prospectively, cost-effective universal vaccines developed based on these combined technologies are promising solutions for broad protection against influenza. PMID- 26641725 TI - Statin therapy across the lifespan: evidence in major age groups. AB - This review provides needed perspective on statin efficacy and safety in individuals under 40, 40-75, and > 75 years of age. Starting with the 2013 ACC AHA cholesterol guidelines extensive evidence base on randomized controlled trials (RCTs) we added references in the past 5 years that discussed statin efficacy and safety over the life span. In those under 40, statins are primarily used for treatment of severe hypercholesterolemia, often familial, and they are well tolerated. In middle-aged adults, statins have strong evidence for benefit in primary and secondary prevention trials; however, in primary prevention, a clinician-patient risk discussion should precede statin prescription in order to determine appropriate treatment. In those over 75, issues of statin intensity and net benefit loom large as associated comorbidity, polypharmacy, and potential for adverse effects impact the decision to use statins with RCT data strongest in support of use in secondary prevention. Statin drugs have been studied by RCTs in a large number of individuals. In those groups shown to benefit, statins have reduced the risk of atherosclerotic cardiovascular disease with few side effects as compared to controls. This review has detailed considerations that should occur when statins are given to individuals in different age groups. PMID- 26641726 TI - A Constrained Variable Projection Reconstruction Method for Photoacoustic Computed Tomography Without Accurate Knowledge of Transducer Responses. AB - Photoacoustic computed tomography (PACT) is an emerging computed imaging modality that exploits optical contrast and ultrasonic detection principles to form images of the absorbed optical energy density within tissue. When the imaging system employs conventional piezoelectric ultrasonic transducers, the ideal photoacoustic (PA) signals are degraded by the transducers' acousto-electric impulse responses (EIRs) during the measurement process. If unaccounted for, this can degrade the accuracy of the reconstructed image. In principle, the effect of the EIRs on the measured PA signals can be ameliorated via deconvolution; images can be reconstructed subsequently by application of a reconstruction method that assumes an idealized EIR. Alternatively, the effect of the EIR can be incorporated into an imaging model and implicitly compensated for during reconstruction. In either case, the efficacy of the correction can be limited by errors in the assumed EIRs. In this work, a joint optimization approach to PACT image reconstruction is proposed for mitigating errors in reconstructed images that are caused by use of an inaccurate EIR. The method exploits the bi-linear nature of the imaging model and seeks to refine the measured EIR during the process of reconstructing the sought-after absorbed optical energy density. Computer-simulation and experimental studies are conducted to investigate the numerical properties of the method and demonstrate its value for mitigating image distortions and enhancing the visibility of fine structures. PMID- 26641727 TI - LRTV: MR Image Super-Resolution With Low-Rank and Total Variation Regularizations. AB - Image super-resolution (SR) aims to recover high-resolution images from their low resolution counterparts for improving image analysis and visualization. Interpolation methods, widely used for this purpose, often result in images with blurred edges and blocking effects. More advanced methods such as total variation (TV) retain edge sharpness during image recovery. However, these methods only utilize information from local neighborhoods, neglecting useful information from remote voxels. In this paper, we propose a novel image SR method that integrates both local and global information for effective image recovery. This is achieved by, in addition to TV, low-rank regularization that enables utilization of information throughout the image. The optimization problem can be solved effectively via alternating direction method of multipliers (ADMM). Experiments on MR images of both adult and pediatric subjects demonstrate that the proposed method enhances the details in the recovered high-resolution images, and outperforms methods such as the nearest-neighbor interpolation, cubic interpolation, iterative back projection (IBP), non-local means (NLM), and TV based up-sampling. PMID- 26641728 TI - Cramer-Rao Lower Bound for Point Based Image Registration With Heteroscedastic Error Model for Application in Single Molecule Microscopy. AB - The Cramer-Rao lower bound for the estimation of the affine transformation parameters in a multivariate heteroscedastic errors-in-variables model is derived. The model is suitable for feature-based image registration in which both sets of control points are localized with errors whose covariance matrices vary from point to point. With focus given to the registration of fluorescence microscopy images, the Cramer-Rao lower bound for the estimation of a feature's position (e.g., of a single molecule) in a registered image is also derived. In the particular case where all covariance matrices for the localization errors are scalar multiples of a common positive definite matrix (e.g., the identity matrix), as can be assumed in fluorescence microscopy, then simplified expressions for the Cramer-Rao lower bound are given. Under certain simplifying assumptions these expressions are shown to match asymptotic distributions for a previously presented set of estimators. Theoretical results are verified with simulations and experimental data. PMID- 26641729 TI - Erratum to "Noise Suppression for Dual-Energy CT Through Entropy Minimization". PMID- 26641730 TI - Extended Gas-Phase Trapping Followed by Surface-Induced Dissociation of Noncovalent Protein Complexes. AB - Mass spectrometry has emerged as a useful tool in the study of proteins and protein complexes. It is of fundamental interest to explore how the structures of proteins and protein complexes are affected by the absence of solvent and how this alters with increasing time in the gas phase. Here we demonstrate that a range of protein and protein complexes can be confined within the Trap T-wave region of a modified Waters Synapt G2S instrument, including monomeric (beta lactoglobulin), dimeric (beta-lactoglobulin and enolase), tetrameric (streptavidin, concanavalin A, and pyruvate kinase), and pentameric (C-reactive protein) complexes, ranging in size up to 237 kDa. We demonstrate that complexes can be confined within the Trap region for varying lengths of time over the range 1-60 s and with up to 86% trapping efficiency for 1 s trapping. Furthermore, using model systems, we show that these noncovalent complexes can also be fragmented by surface-induced dissociation (SID) following trapping. SID reveals similar dissociation patterns over all trapping times studied for unactivated protein complexes, suggesting that any conformational changes occurring over this time scale are insufficient to cause substantial differences in the SID spectra of these complexes. Intentional alteration of structure by cone activation produces a distinct SID spectrum, with the differences observed being conserved, in comparison to unactivated complex, after trapping. However, subtle differences in the SID spectra of the activated complex are also observed as a function of trapping time. PMID- 26641731 TI - Concentrations of Inorganic Arsenic in Milled Rice from China and Associated Dietary Exposure Assessment. AB - Total arsenic (As) and inorganic As (Asi) in milled rice (n = 1653) collected from China were studied to evaluate the contamination level, distribution, and health risks. The mean concentrations of the total As and Asi were 116.5 and 90.9 MUg/kg, respectively. There were significant differences (P < 0.01) between the 11 provinces, and 1.1% of samples exceeded the maximum contaminant level established by Chinese legislation. According to the exposure assessment method of probabilistic simulation, all values of the target hazard quotients (THQs) for chronic noncarcinogenic risks (skin lesions as the point of departure) were below 1, suggesting that the Chinese population will not encounter a significant noncarcinogenic risk. However, the mean values of margin of exposure (MOE) for lung cancer risks ranging from 3.86 to 8.54 were under 100 for all age groups and genders of the Chinese population; moreover, MOE values for some major rice producing and -consuming countries, such as Japan, Thailand, Bangladesh, and the United States, were all also below 100. More attention should be paid to carcinogenic risks from rice Asi intake, and some control measures to reduce rice Asi intake should be taken. PMID- 26641732 TI - Heptazine-Based Porous Framework for Selective CO2 Sorption and Organocatalytic Performances. AB - A new heptazine-based polymer network (Cy-pip) with highly rich nitrogen sites has been synthesized via catalyst-free direct coupling of cyameluric chloride (Cy) and piperazine (Pip). Cy-pip exhibits large CO2 uptake capacity (103.4 mg/g, 9.4 wt %, 1 bar/273 K) with high selectivity (117) toward CO2 over N2. Furthermore, this framework with high Lewis basic nitrogen sites has also been exploited as heterogeneous catalyst for Knoevenagel reaction of aromatic and heterocyclic aldehydes with active methylene compounds. Moreover, the catalyst can recycle up to four times with only a minor loss of activity. PMID- 26641733 TI - Amphiphilic Polymer Micellar Disruption Based on Main-Chain Photodegradation. AB - The amphiphilic block copolymer poly(ethylene oxide)-b-poly(N,N' dihydroxypyromellitimide-hexamethylene diisocyanate) (PEO-b-PNH) with photocleavable N-O urethanes has been prepared to investigate the photodegradation of the hydrophobic main chain and therefore the disruption of copolymer micelles. Measurements of absorption and emission spectra, optical transmittance, DLS analysis, and TEM observations were applied. It was shown that PEO-b-PNH could self-assemble into flower compound micelles in water. The photodegradation of the hydrophobic polyurethane within the micellar core upon irradiation with 365 nm light could be conveniently controlled by changing the irradiation intensity; furthermore, complete micellar disruption could be achieved when 42% of N-O urethanes were photocleaved. By using DOX as the hydrophobic guest, the drug release profile showed a linear leakage of DOX out of the swelling polymer micelles in the initial stage and thereafter a much more quick exponential decay of DOX precipitation because of the micellar disruption upon further irradiation. The diffusion experiment of the leaked DOX into buffer solution (pH 7.4) showed that the DOX leakage could be prominently accelerated by a very short time of 365 nm irradiation, indicating that the N-O photocleavage can serve as a "turn-on" switch for the release of DOX in aqueous media. PMID- 26641734 TI - An Intervention to Reduce Use of Low-Value Imaging Tests. PMID- 26641735 TI - Erythrina excelsa exhibits estrogenic effects in vivo and in vitro and is cytotoxic on breast and colon cancer cell lines. AB - CONTEXT: Eythrina excelsa Baker (Fabaceae) is a medicinal plant used to treat various ailments including those of the female genital tract. OBJECTIVE: The objective of this study is to investigate the estrogenic and cytotoxic effects of the ethanol extract of the stem bark of E. excelsa. MATERIALS AND METHODS: Erythrina excelsa was evaluated in vitro using the yeast estrogen screen (YES). The extract was then tested in a 3-day uterotrophic assay on ovariectomised Wistar rats at doses of 50 and 100 mg/kg BW/d. Cytotoxic effects were assessed on breast (MCF-7) and colon (HT-29) cancer cell lines using the MTT cell viability assay. Additionally, a LC-PDA-ESI (+)-HRMS and HRMS/MS method was developed and applied for the identification of representative secondary metabolites scaffolds in the extract. RESULTS: In the YES, the extract stimulated the transactivation of the estrogen receptor in a dose-dependent manner with an EC50 value of 1.8 MUg/mL. In rats, E. excelsa increased uterine wet weight, uterine epithelial height, and the mRNA expression of estrogen-responsive genes in the uterus and liver at 50 whereas at 100 mg/kg BW/d anti-estrogenic effects were observed. In the MTT-assay, a dose-dependent decrease of the viability of both cell lines was observed with EC50 values of 13.6 MUg/mL (MCF-7) and 27.7 MUg/mL (HT-29). The phytochemical analysis revealed that the extract is rich in isoflavonoids, mainly prenylated and pyran-derivatives thereof. CONCLUSION: Erythrina excelsa is rich in prenylated and pyran-substituted isoflavonoids, exhibits estrogenic/anti estrogenic and cytotoxic effects and warrant sufficient interest for deeper investigations. PMID- 26641736 TI - Valsartan/Sacubitril for Heart Failure: Reconciling Disparities Between Preclinical and Clinical Investigations. PMID- 26641737 TI - Balancing Service and Education in Residency Training: A Logical Fallacy. PMID- 26641738 TI - "Preliminary data suggest rates of male military sexual trauma may be higher than previously reported": Retraction of Sheppard et al. (2015). AB - Reports the retraction of "Preliminary data suggest rates of male military sexual trauma may be higher than previously reported" by Sean C. Sheppard, Edward J. Hickling, Mitch Earleywine, Tim Hoyt, Amanda R. Russo, Matthew R. Donati and Kevin E. Kip (Psychological Services, 2015[Nov], Vol 12[4], 344-347). The following article from the November 2015 issue is being retracted. The retraction is at the request of the authors. The data analysis was flawed due to the method used to test for statistical significance which was not consistent with modern methods. This compromised the study findings. Thus, the conclusions about statistical significance drawn in the paper were not consistent with the data. The statistical testing error that occurred was unintentional and acknowledged by the authors when pointed out by external scholars. All authors of the article joined in the request for the retraction. (The following abstract of the original article appeared in record 2015-49326-002.) Stigma associated with disclosing military sexual trauma (MST) makes estimating an accurate base rate difficult. Anonymous assessment may help alleviate stigma. Although anonymous research has found higher rates of male MST, no study has evaluated whether providing anonymity sufficiently mitigates the impact of stigma on accurate reporting. This study used the unmatched count technique (UCT), a form of randomized response techniques, to gain information about the accuracy of base rate estimates of male MST derived via anonymous assessment of Operation Enduring Freedom (OEF)/Operation Iraqi Freedom (OIF) combat veterans. A cross-sectional convenience sample of 180 OEF/OIF male combat veterans, recruited via online websites for military populations, provided data about history of MST via traditional anonymous self-report and the UCT. The UCT revealed a rate of male MST more than 15 times higher than the rate derived via traditional anonymous assessment (1.1% vs. 17.2%). These data suggest that anonymity does not adequately mitigate the impact of stigma on disclosure of male MST. Results, though preliminary, suggest that published rates of male MST may substantially underestimate the true rate of this problem. The UCT has significant potential to improve base rate estimation of sensitive behaviors in the military. PMID- 26641739 TI - Ustekinumab in hidradenitis suppurativa: clinical results and a search for potential biomarkers in serum. AB - BACKGROUND: Treatment of hidradenitis suppurativa (HS) is difficult and the search for effective therapies continues. OBJECTIVES: To evaluate the efficacy of ustekinumab and to discover a potential biomarker for HS. METHODS: Seventeen patients were included in this open-label study and treated with 45 or 90 mg ustekinumab at weeks 0, 4, 16 and 28. Proteomic technology and enzyme-linked assay analysis was applied to sera. RESULTS: Twelve patients completed the protocol. Moderate-to-marked improvement of the modified Sartorius score was achieved in 82% of patients at week 40 and the Hidradenitis Suppurativa Clinical Response 50 in 47%. With regard to the expression of 54 serum proteins, at baseline, a significant difference was observed between patients and healthy controls. Involved pathways were related to inflammation, immune cell signalling and tissue morphology/development. Good responders had milder disease and lower expression of leukotriene A4-hydrolase (LTA4H). Interleukin (IL)-2R, tumour necrosis factor-alpha, IL-17A and IL-17F were not elevated and did not change during treatment. CONCLUSIONS: The majority of patients improved with ustekinumab. Although no biomarker was discovered, low LTA4H concentrations with mild disease severity may be predictive of the effectiveness of ustekinumab. PMID- 26641740 TI - Influence of an Enforced Fast Start on 10-km-Running Performance. AB - The effects of an enforced fast start on long-distance performance are controversial and seem to depend on the athlete's capacity to delay and tolerate metabolic disruption. The aim of this study was to investigate the effects of an enforced start on 10-km-running performance and the influence of the some physiological and performance variables on the ability to tolerate an enforced fast start during the running. Fifteen moderately trained runners performed two 10-km time trials (TTs): free pacing (FP-TT) and fast start (FS-TT). During FS TT, speed during the first kilometer was 6% higher than in FP-TT. Maximal oxygen uptake (VO2max), peak velocity (PV), velocity associated with VO2max (vVO2max), ventilatory threshold, and running economy at 10 and 12 km/h and FP-TT average velocity (AV-10 km) were individually determined. There were no differences between FP-TT and FS-TT performance (45:01 +/- 4:08 vs 45:11 +/- 4:46 min:s, respectively, P = .4). Eight participants improved (+2.2%) their performance and were classified as positive responders (PR) and 7 decreased (-3.3%) performance and were classified as negative responders (NR). Running speed was significantly higher for PR between 6 and 9.2 km (P < .05) during FS-TT. In addition, PR presented higher PV (P = .02) and vVO2max (P = .01) than NR, suggesting that PV and vVO2max might influence the ability to tolerate a fast-start strategy. In conclusion, there was an individual response to the enforced fast-start strategy during 10-km running, and those who improved performance also presented higher vVO2max and PV, suggesting a possible association between these variables and response to the strategy adopted. PMID- 26641741 TI - Variations in U.S. Consumers' Acceptability of Korean Rice Cake, Seolgitteok, with respect to Sensory Attributes and Nonsensory Factors. AB - Because the Korean rice cake, Seolgitteok, is mainly prepared with rice flour containing no gluten-protein associated with celiac disease, it can be considered for inclusion in a gluten-free diet. However, Western consumers may be unlikely to enjoy the plain flavor and chewy texture of Seolgitteok. This study aimed to determine both sensory and nonsensory factors that might affect U.S. consumers' acceptability of Seolgitteok. A total of 119 U.S. consumers rated 5 Seolgitteok samples, differentiated by descriptive sensory analysis, with respect to hedonic impression and just-about-right aspects of sensory attributes. Nonsensory factors such as demographic profile, innovativeness, social representation, sensation seeking, and personality traits were also assessed. Addition levels of brown rice flour (0% to 100%) and sugar (5% to 20%) not only enriched flavor, but also lessened chewiness of Seolgitteok, thereby increasing an overall hedonic impression. Moreover, consumer acceptability of Seolgitteok varied with respect to nonsensory factors. Seolgitteok was more appreciated by males, sensation seekers, and individuals constrained by social desirability than by other groups. In conclusion, these findings demonstrate that U.S. consumers' acceptability of Seolgitteok varies not only by sensory attributes such as rice flavor, sweetness, and chewiness, but also by nonsensory factors such as gender, sensation-seeking characteristics, and personality traits. PMID- 26641770 TI - The Influence of Work-Related Fatigue, Work Conditions, and Personal Characteristics on Intent to Leave Among New Nurses. AB - PURPOSE: This study aimed to (a) test the fit of the hypothesized model for new nurses' intent to leave and (b) determine the extent to which personal characteristics, work conditions, and work-related fatigue predict intent to leave among new nurses. DESIGN AND METHODS: This study was a cross-sectional survey study. A total of 162 new nurses were recruited. A hypothesized model was proposed for model testing. Structural equation modelling was used for data analysis. FINDINGS: Work conditions only had an effect through work-related fatigue on new nurses' intent to leave. Personal characteristics did not have a significant effect on new nurses' intent to leave. The final model showed a good fit. Work-related fatigue, work conditions, and health explained 65% of the variance in new nurses' intent to leave. CONCLUSIONS: Work-related fatigue was a major determinant of new nurses' intent to leave. More attention should be paid to fatigue reduction strategies among new nurses. CLINICAL RELEVANCE: Work related fatigue should be monitored, particularly for new nurses who work more than 10 hr per day and who have greater workloads. PMID- 26641771 TI - An emerging role for cytopathology in precision oncology. AB - Precision medicine is an emerging field in medicine for disease prevention and treatment that takes into account the individual variability in genes, environment, and lifestyle for each individual patient. The authors have developed a special program as part of the Englander Institute for Precision Medicine to grow patient-derived, 3-dimensional tumor organoids for tumor specific drug testing, tailoring treatment strategies, and as models for studying drug resistance. Routine cytology preparations represent a cost-effective and powerful tool to aid in performing molecular testing in the age of personalized medicine. In this commentary, the platforms used for the characterization and validation of patient-derived, 3-dimensional tumor organoids are outlined and discussed, and the role of cytology as a cost-effective and powerful quality control measure is illustrated. PMID- 26641772 TI - COMPARISON OF TWO COARSE FRACTIONATED RADIATION PROTOCOLS FOR THE MANAGEMENT OF CANINE PITUITARY MACROTUMOR: AN OBSERVATIONAL STUDY OF 24 DOGS, MARCINOWSKA ET AL., DOI: 10.1111/VRU.12270. PMID- 26641773 TI - Allopurinol induces innate immune responses through mitogen-activated protein kinase signaling pathways in HL-60 cells. AB - Allopurinol, an inhibitor of xanthine oxidase, is a frequent cause of severe cutaneous adverse reactions (SCARs) in humans, including drug rash with eosinophilia and systemic symptoms, Stevens-Johnson syndrome and toxic epidermal necrolysis. Although SCARs have been suspected to be immune-mediated, the mechanisms of allopurinol-induced SCARs remain unclear. In this study, we examined whether allopurinol has the ability to induce innate immune responses in vitro using human dendritic cell (DC)-like cell lines, including HL-60, THP-1 and K562, and a human keratinocyte cell line, HaCaT. In this study, we demonstrate that treatment of HL-60 cells with allopurinol significantly increased the mRNA expression levels of interleukin-8, monocyte chemotactic protein-1 and tumor necrosis factor alpha in a time- and concentration-dependent manner. Furthermore, allopurinol induced the phosphorylation of mitogen-activated protein kinases (MAPK), such as c-Jun N-terminal kinase and extracellular signal-regulated kinase, which regulate cytokine production in DC. In addition, allopurinol induced increases in cytokine expression were inhibited by co-treatment with the MAPK inhibitors. Collectively, these results suggest that allopurinol has the ability to induce innate immune responses in a DC-like cell line through activation of the MAPK signaling pathways. These results indicate that innate immune responses induced by allopurinol might be involved in the development of allopurinol-induced SCARs. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26641800 TI - Substantial proportion of MODY among multiplex families participating in a Type 1 diabetes prediction programme. AB - AIMS: Patients with maturity-onset diabetes of the young (MODY) might be over represented in families with histories of Type 1 diabetes. Our aim was to re evaluate families participating in the Czech T1D Prediction Programme (PREDIA.CZ) with at least two members affected with diabetes to assess the proportion of MODY among these families and determine its most significant clinical predictors. METHODS: Of the 557 families followed up by the PREDIA.CZ, 53 (9.5%) had two or more family members with diabetes. One proband with diabetes from these families was chosen for direct sequencing of the GCK, HNF1A, HNF4A and INS genes. Non parametric tests and a linear logistic regression model were used to evaluate differences between MODY and non-MODY families. RESULTS: MODY was genetically diagnosed in 24 of the 53 families with multiple occurrences of diabetes (45%). Mutations were detected most frequently in GCK (58%), followed by HNF1A (38%) and INS (4%). MODY families were more likely to have a parent with diabetes and had a higher proportion of females with diabetes than non-MODY families. Higher age (P < 0.001), a lower level of HbA1c (P < 0.001) at clinical onset and at least two generations affected by diabetes were the variables most predictive for probands of MODY families already presenting with diabetes. CONCLUSIONS: A prediction programme for Type 1 diabetes would provide a useful new source of patients with MODY most likely to benefit from an accurate diagnosis. This identification has implications for patient treatment and disease prognosis. PMID- 26641801 TI - A Fluorination/Aryl Migration/Cyclization Cascade for the Metal-Free Synthesis of Fluoro-Benzoxazepines. AB - Fluorinated organic molecules are of high interest for many applications across chemical and medical disciplines. Efficient methods for the synthesis of such compounds are thus needed. Within this work, application of the bench-stable cyclic hypervalent iodine(III) fluoro reagent 1 facilitated the development of an efficient, metal-free method for the preparation of the novel class of 4-fluoro 1,3-benzoxazepines starting from readily available styrenes. The efficacy and broad applicability of this concept is demonstrated by the synthesis of 20 structurally diverse congeners in high yields, regio-, and diastereoselectivities. The presented method provides complementary chemoselectivity when compared to the common, commercially available electrophilic fluorination reagents, such as selectfluor. First mechanistic investigations with isotopically labeled substrates reveal a complex reaction mechanism, proceeding via an unusual fluorination/1,2-aryl migration/cyclization cascade. PMID- 26641802 TI - Elevated MicroRNA-33 in Sarcoidosis and a Carbon Nanotube Model of Chronic Granulomatous Disease. AB - We established a murine model of multiwall carbon nanotube (MWCNT)-induced chronic granulomatous disease, which resembles human sarcoidosis pathology. At 60 days after oropharyngeal MWCNT instillation, bronchoalveolar lavage (BAL) cells from wild-type mice exhibit an M1 phenotype with elevated proinflammatory cytokines and reduced peroxisome proliferator-activated receptor gamma (PPARgamma)-characteristics also present in human sarcoidosis. Based upon MWCNT associated PPARgamma deficiency, we hypothesized that the PPARgamma target gene, ATP-binding cassette (ABC) G1, a lipid transporter with antiinflammatory properties, might also be repressed. Results after MWCNT instillation indicated significantly repressed ABCG1, but, surprisingly, lipid transporter ABCA1 was also repressed, suggesting a possible second pathway. Exploration of potential regulators revealed that microRNA (miR)-33, a lipid transporter regulator, was strikingly elevated (13.9 fold) in BAL cells from MWCNT-instilled mice but not sham control mice. Elevated miR-33 was also detected in murine granulomatous lung tissue. In vitro studies confirmed that lentivirus-miR-33 overexpression repressed both ABCA1 and ABCG1 (but not PPARgamma) in cultured murine alveolar macrophages. BAL cells of patients with sarcoidosis also displayed elevated miR 33 together with reduced ABCA1 and ABCG1 messenger RNA and protein compared with healthy control subjects. Moreover, miR-33 was elevated within sarcoidosis granulomatous tissue. The findings suggest that alveolar macrophage miR-33 is up regulated by proinflammatory cytokines and may perpetuate chronic inflammatory granulomatous disease by repressing antiinflammatory functions of ABCA1 and ABCG1 lipid transporters. The results also suggest two possible pathways for transporter dysregulation in granulomatous disease-one associated with intrinsic PPARgamma status and the other with miR-33 up-regulation triggered by environmental challenges, such as MWCNT. PMID- 26641803 TI - Living in three dimensions. PMID- 26641805 TI - The medical life of Henry Norman Bethune. PMID- 26641806 TI - The role and interpretation of specific inhalation challenges in the diagnosis of occupational asthma. PMID- 26641807 TI - Corrigendum Re: FM Ducharme, SD Dell, D Radhakrishnan, et al. Diagnosis and management of asthma in preschoolers: A Canadian Thoracic Society and Canadian Paediatric Society position paper. Can Respir J 2015;22(3):135-143. PMID- 26641808 TI - Difficult situations in anticoagulation after stroke: between Scylla and Charybdis. AB - PURPOSE OF REVIEW: A significant proportion of stroke patients is treated with anticoagulants for secondary stroke prevention. Often, in such patients, stroke physicians are required to make difficult clinical decisions when confronted with the dilemma to choose between the risk of thromboembolism and the risk of bleeding. This article focuses on three common anticoagulant-related situations, where the stroke physician needs to find the delicate balance between the two risks. RECENT FINDINGS: Three typical case vignettes are presented and the associated dilemmas are discussed: a patient with an anticoagulant-related intracranial hemorrhage: would you restart anticoagulation?, an anticoagulated patient with a previous stroke because of atrial fibrillation is scheduled for an elective polyp removal: how would you handle anticoagulation perioperatively?, and a patient presents with an ischemic stroke because of atrial fibrillation: how soon would you start anticoagulation for secondary stroke prevention? The article summarizes the related literature and discusses the pros and cons of each choice. SUMMARY: The available evidence is limited; we need to individualize our approach according to the specific characteristics of our patients, and share the decision process with our patients and their proxies, taking strongly into consideration their values and preferences. PMID- 26641809 TI - Current concepts in pseudotumor cerebri. AB - PURPOSE OF REVIEW: Idiopathic intracranial hypertension (IIH) is a potentially blinding disorder of unknown cause, characterized by elevated intracranial pressure in the absence of a mass lesion, venous sinus thrombosis, or meningitis. This review summarizes recent developments and insights from leading treatment trials, emerging treatment options, and evolving ways to evaluate IIH. RECENT FINDINGS: The Idiopathic Intracranial Hypertension Treatment Trial is the first large-scale, randomized, prospective study to evaluate medical treatment of patients with mild vision loss. These data have facilitated our understanding of baseline clinical manifestations, including impact on quality of life and treatment outcomes. Recent hypotheses and studies evaluating the role of cerebral venous sinus stenosis and stenting are discussed. Technological advances in optical coherence tomography are emerging to provide novel ways of evaluating and tracking optic disc swelling in IIH. SUMMARY: Recent changes in defining IIH, understanding the impact and treatment of mild visual loss, and the roles that cerebral venous stenting and optical coherence tomography might have in clinical practice provide the framework to better treat patients with IIH. PMID- 26641810 TI - Mechanisms of cell death in neurodegenerative and retinal diseases: common pathway? AB - The review intends to draw the attention of researchers working in retinal degenerations on the fact that classical apoptosis, for example, apoptosis triggering caspase activation, may not be the main pathway of cellular demise in this tissue.Former work already showed the difficulty of proving the activation of apoptosis effectors in different models of retinal degeneration. However, these results were not really considered because of the lack of an alternative explanation for cell death. Nowadays, the description of many pathways of cellular demise is filling the gap and other forms of cell death are now described in the retina.The knowledge on the molecular mechanisms of cell death is very important for the development of new therapeutic strategies, as well as for the evaluation of cell death onset in retinal degeneration. PMID- 26641811 TI - Imaging-based selection for revascularization in acute ischemic stroke. AB - PURPOSE OF REVIEW: With the positive results of recent endovascular thrombectomy (EVT) trials, intravenous thrombolysis (IVT) and EVT provide physicians with two majorly effective acute treatment options for patients with acute ischemic stroke. IVT and EVT can be used as a single treatment or as a combined IVT/EVT treatment approach. This review summarizes how imaging findings can help in selecting stroke patients who are likely to benefit from these revascularization therapies. RECENT FINDINGS: IVT applied within 4.5 h from symptom onset remains the mainstay of acute stroke therapy and was also applied to most patients in the randomized EVT trials. Recent studies have failed to demonstrate the effectiveness of IVT in later time windows. Vascular imaging is crucial to identify patients with a target intracranial occlusion prior to EVT. Patients with a small ischemic core, with good leptomeningeal collaterals or with evidence of penumbral tissue may particularly benefit from EVT. These imaging findings may also identify patients who benefit from EVT if applied more than 6 h from symptom onset. SUMMARY: Pretherapeutic imaging findings help in identifying stroke patients who are likely to benefit from endovascular stroke therapies, and may identify patients who benefit from revascularization therapies in later time windows. PMID- 26641812 TI - Eye movements and deep brain stimulation. AB - PURPOSE OF REVIEW: Deep brain stimulation (DBS) is an established treatment for several neurological conditions, and is most commonly used to treat Parkinson's disease by implanting electrodes in the basal ganglia. Despite the fact that circuits involved in eye movement control traverse the basal ganglia and are thus likely to be affected by DBS, studies combining DBS with eye movement analysis have been infrequent. This review focuses on recent research studies that examine the relationship between DBS and various types of eye movements and which highlight the potential of this approach. RECENT FINDINGS: Recent work shows that DBS in the subthalamic nucleus (STN) can improve smooth pursuit in Parkinson's disease. STN DBS has also been shown to modulate visuospatial attention, and has provided experimental evidence backing a Bayesian model of basal ganglia function. DBS in the pallidum can improve antisaccadic performance in Parkinson's disease, suggesting improvement in higher control of oculomotor function, and implying retrograde striatal stimulation as part of the mechanism of action. SUMMARY: These studies show that the combination of DBS with eye movement analysis is a powerful research tool. It may be used to study oculomotor physiology, basal ganglia pathophysiology, and the mechanism of action of DBS. PMID- 26641813 TI - Stroke of undetermined cause: workup and secondary prevention. AB - PURPOSE OF REVIEW: The purpose of this review is to update the reader on current concepts of workup and secondary prevention in patients with stroke of undetermined cause. RECENT FINDINGS: Clinical research in patients with cryptogenic stroke has been hampered by the lack of standardized, widely accepted diagnostic criteria. The new definition of 'Embolic stroke of undetermined etiology' postulates an embolic mechanism of ischemic stroke. It is based on the exclusion of lacunar infarction by brain imaging, arterial stenosis more than 50% or dissection of the respective brain-supplying artery by computed tomography/magnetic resonance-angiography or ultrasound, atrial fibrillation by at least 24 h EKG monitoring, as well as some rare etiologies such as vasculitis, drug abuse, or coagulopathies. However, it still comprises many patients with atherosclerotic etiologies (but <50% stenosis) as well as covert paroxysmal atrial fibrillation which can be detected by repeated Holter EKG or an implantable device. A patent foramen ovale can be found in up to 58% of cryptogenic stroke patients, but causality in an individual patient remains uncertain and can only be statistically inferred. SUMMARY: The new concept of embolic stroke of undetermined etiology enabled three ongoing randomized controlled trials which investigate oral anticoagulation versus aspirin for secondary stroke prevention. PMID- 26641814 TI - Abnormal head oscillations in neuro-ophthalmology and neuro-otology. AB - PURPOSE OF REVIEW: The study describes the clinical phenomenology and contemporary pathophysiology of concurrent oscillations of the eyes and the head that are present in neurological conditions with diverse causes. RECENT FINDINGS: One classic example is spasmus nutans in which the eye oscillations are the primary cause, whereas head nodding is thought to be an operant conditional response that suppresses the eye oscillations to facilitate clear vision. The second example is a combination of head tremor and inadequate compensatory eye movements because of vestibular hypofunction leading to the illusion of pendular nystagmus - hence, the condition is called pseudonystagmus. Cerebellar degeneration in ataxia-telangiectasia or synchronized spontaneous discharge from the inferior olive and cerebellum in the syndrome of ocular palatal tremor with dystonia are examples of eye and head oscillations because of the impairment in cerebellar outflow. Infantile nystagmus syndrome also presents with eye and head oscillations, but here the relationship between the two types of oscillations differs among patients and is still unclear. SUMMARY: The clinical features and putative pathophysiology of diverse disorders of the eyes and head that produce unwanted oscillations are reviewed. Key clinical pearls that are essential to separate these disorders at the bedside are also emphasized. PMID- 26641815 TI - Pre and intrahospital workflow for acute stroke treatment. AB - PURPOSE OF REVIEW: With the recent demonstration of the effectiveness of rapid recanalization of large vessel occlusions in acute ischemic stroke, it is important to assess the current status of pre and intrahospital workflow for acute stroke. RECENT FINDINGS: We will review trends in the evaluation and treatment of acute stroke and offer suggestions for how best to advance the workflow for acute stroke care in the coming years. SUMMARY: Future research is needed for: field use of clinical scores for predicting large vessel occlusions, telemedicine to facilitate prehospital triage, and pre and intrahospital processes for optimizing stroke care delivery. PMID- 26641816 TI - Management of patients with aneurysmal subarachnoid haemorrhage. AB - PURPOSE OF REVIEW: Outcome of patients with aneurysmal subarachnoid haemorrhage (ASAH) has improved, but is still poor. After the introduction of endovascular treatment of intracranial aneurysms, much attention has been given to indications for and advances in endovascular and microneurosurgical techniques to occlude aneurysms, but management of patients with ASAH encompasses much more than occluding the aneurysm. RECENT FINDINGS: This review describes recent advances in diagnosis and general management of ASAH and in knowledge and medical treatment of delayed cerebral ischaemia and rebleeding. SUMMARY: In patients with a head computed tomography scan performed less than 6 h after headache onset and reported negative by a staff radiologist, lumbar puncture can be withheld. Patients with ASAH should preferably be treated in a tertiary care centre that treats more than 100 ASAH patients per year. Currently, the only treatment strategy to reduce the risk of delayed cerebral ischaemia remains nimodipine; there is no place for statins or magnesium sulphate, nor for lumbar drainage. Hypervolaemia and induced hypertension may be less beneficial than presumed, and further trials are urgently needed. Very early and short treatment with antifibrinolytic drugs may also be beneficial, but data from ongoing trials should be awaited before this treatment strategy can be implemented. PMID- 26641817 TI - Eye movements in neurodegenerative diseases. AB - PURPOSE OF REVIEW: Abnormalities of oculomotor control accompany the pathological changes underlying many neurodegenerative diseases. Clinical examination of eye movements can contribute to differential diagnosis, whereas quantitative laboratory measures can provide detailed insight into the disease process. In this review of eye movements in neurodegenerative disease, we summarise recent empirical findings and conceptual advances. RECENT FINDINGS: Oculomotor researchers continue to be particularly prolific in studying Parkinson's disease but there is also substantial activity in Alzheimer's disease and spinocerebellar ataxia. Interesting findings have been reported in Huntington's, motor neuron disease, and glaucoma. Most studies report laboratory-based investigations but useful progress in clinical description continues to be made. SUMMARY: Eye movements remain an active field of investigation across a variety of neurodegenerative conditions. Progress continues to be made at the clinical level as well by using laboratory techniques. PMID- 26641818 TI - Ecologically-Relevant Maps of Landforms and Physiographic Diversity for Climate Adaptation Planning. AB - Key to understanding the implications of climate and land use change on biodiversity and natural resources is to incorporate the physiographic platform on which changes in ecological systems unfold. Here, we advance a detailed classification and high-resolution map of physiography, built by combining landforms and lithology (soil parent material) at multiple spatial scales. We used only relatively static abiotic variables (i.e., excluded climatic and biotic factors) to prevent confounding current ecological patterns and processes with enduring landscape features, and to make the physiographic classification more interpretable for climate adaptation planning. We generated novel spatial databases for 15 landform and 269 physiographic types across the conterminous United States of America. We examined their potential use by natural resource managers by placing them within a contemporary climate change adaptation framework, and found our physiographic databases could play key roles in four of seven general adaptation strategies. We also calculated correlations with common empirical measures of biodiversity to examine the degree to which the physiographic setting explains various aspects of current biodiversity patterns. Additionally, we evaluated the relationship between landform diversity and measures of climate change to explore how changes may unfold across a geophysical template. We found landform types are particularly sensitive to spatial scale, and so we recommend using high-resolution datasets when possible, as well as generating metrics using multiple neighborhood sizes to both minimize and characterize potential unknown biases. We illustrate how our work can inform current strategies for climate change adaptation. The analytical framework and classification of landforms and parent material are easily extendable to other geographies and may be used to promote climate change adaptation in other settings. PMID- 26641819 TI - Overlap Syndromes. AB - BACKGROUND: Some patients present with features of both primary biliary cirrhosis (PBC) or primary sclerosing cholangitis (PSC) on the one hand and autoimmune hepatitis (AIH) on the other hand, either simultaneously or consecutively. The term 'overlap syndrome (OS)' is used to describe these settings, but lack of universal agreement on what precisely constitutes an OS has generated considerable confusion. The low prevalence of OS (roughly 10% of PBC or PSC) has made it impracticable to perform randomized controlled trials. It remains unclear whether this syndrome forms a distinct entity or is a variant of PBC, PSC or AIH. KEY MESSAGES: Moderate to severe interface hepatitis is a fundamental component and histology is vital in evaluating patients with overlap presentation. Use of the International Autoimmune Hepatitis Group criteria for the diagnosis of OS is not recommended. For PBC-AIH OS, EASL has provided diagnostic criteria and, in most cases, it is possible to define one primary disorder ('dominant' disease), usually PBC. Patients with OS seem to have a more severe disease compared to conventional PBC. PSC-AIH OS is assumed to exist in a considerable part of mainly young patients with autoimmune liver disease and long-term progression towards cirrhosis seems to occur in the majority of cases. In children, the hepatitic feature can be very dominant, and up to 50% of pediatric AIH have cholangiographic abnormalities suggestive of PSC (autoimmune sclerosing cholangitis). Treatment of OS is empiric and includes ursodeoxycholic acid for the cholestatic component (depending on local policy for PSC) and immunosuppressive agents for the hepatitic component, either simultaneously or sequentially. The dominant clinical feature should be treated first and therapy adjusted according to the response. CONCLUSIONS: OS is not uncommon but should not be over-diagnosed in order not to expose unnecessarily PBC or PSC patients to the risk of steroid side effects. Therapy has to be individualized and not be static. PMID- 26641820 TI - Ear Mite Removal in the Santa Catalina Island Fox (Urocyon littoralis catalinae): Controlling Risk Factors for Cancer Development. AB - Ear mites (Otodectes cynotis) and ear canal tumors are highly prevalent among federally endangered Island foxes (Urocyon littoralis catalinae) living on Santa Catalina Island off the coast of Southern California. Since studies began in the 1990s, nearly all foxes examined were found to be infected with ear mites, and ceruminous gland tumors (carcinomas and adenomas) were detected in approximately half of all foxes >= 4 years of age. We hypothesized that reduction of ear mite infection would reduce otitis externa and ceruminous gland hyperplasia, a risk factor for tumor development. In this study, we conducted a randomized field trial to assess the impact of acaricide treatment on ear mite prevalence and intensity of infection, otitis externa, ceruminous gland hyperplasia, and mite specific IgG and IgE antibody levels. Treatment was highly effective at eliminating mites and reducing otitis externa and ceruminous gland hyperplasia, and mite-specific IgG antibody levels were significantly lower among uninfected foxes. Ceruminous gland hyperplasia increased in the chronically infected, untreated foxes during the six month study. Our results provide compelling evidence that acaricide treatment is an effective means of reducing ear mites, and that mite removal in turn reduces ear lesions and mite-specific IgG antibody levels in Santa Catalina Island foxes. This study has advanced our understanding of the underlying pathogenesis which results in ceruminous gland tumors, and has helped inform management decisions that impact species conservation. PMID- 26641821 TI - Does Targeting Higher Health Risk Employees or Increasing Intervention Intensity Yield Savings in a Workplace Wellness Program? AB - OBJECTIVE: This article aims to test whether a workplace wellness program reduces health care cost for higher risk employees or employees with greater participation. METHODS: The program effect on costs was estimated using a generalized linear model with a log-link function using a difference-in difference framework with a propensity score matched sample of employees using claims and program data from a large US firm from 2003 to 2011. RESULTS: The program targeting higher risk employees did not yield cost savings. Employees participating in five or more sessions aimed at encouraging more healthful living had about $20 lower per member per month costs relative to matched comparisons (P = 0.002). CONCLUSIONS: Our results add to the growing evidence base that workplace wellness programs aimed at primary prevention do not reduce health care cost, with the exception of those employees who choose to participate more actively. PMID- 26641822 TI - Long-Lasting Obesity Predicts Poor Work Ability at Midlife: A 15-Year Follow-Up of the Northern Finland 1966 Birth Cohort Study. AB - OBJECTIVE: To investigate the effect of adulthood obesity on work ability in early midlife during a 15-year follow-up. METHODS: The study population included men and women (n = 5470), born in northern Finland in 1966. Participants evaluated their current perceived work ability compared with their lifetime best at the age of 46. Participants' weight and height were measured at 31 years and self-reported at 46 years, and body mass indexes were calculated. RESULTS: Obesity at both ages, and developing obesity between the ages of 31 and 46 increased the relative risk of poor work ability at 46 years among sexes, and among those in both low and high physically strenuous work. CONCLUSIONS: Long term obesity and developing obesity in mid-adulthood increase the risk of poor work ability. Thus, the promotion of healthy behaviors by policies, healthcare services, and at workplaces is important. PMID- 26641823 TI - The Portion of Health Care Costs Associated With Lifestyle-Related Modifiable Health Risks Based on a Sample of 223,461 Employees in Seven Industries: The UM HMRC Study. AB - OBJECTIVE: This study estimates the percent of health care costs associated with employees' modifiable health risks. METHODS: Cross-sectional multivariate analysis of 223,461 employees from seven industries who completed a health risk assessment during 2007 to 2012. RESULTS: Modifiable health risks were associated with 26.0% of health care costs ($761/person) among employees with no self reported medical conditions and 25.4% among employees with a medical condition ($2598/person). The prevalence and relative costs of each of the 10 risks were different for those without and with medical conditions, but high body mass index was the most prevalent risk for both groups (41.0% and 63.9%) and also contributed the largest percentage of excess costs (7.2% and 7.3%). CONCLUSIONS: This study, coupled with past work, gives an employer a sense of the magnitude that might be saved if modifiable health risks could be eliminated. PMID- 26641824 TI - Maternal Exposure to Air Pollution and Adverse Birth Outcomes in Halifax, Nova Scotia. AB - OBJECTIVE: We aimed to examine the associations between exposure to air pollution exposure and the outcomes of preterm birth (PTB), term low birth weight (TLBW), and small for gestational age. METHODS: We conducted a population-based cohort study using a perinatal database linked to land-use regression-modeled air pollution data. RESULTS: Compared with women in the lowest quartile of toluene exposure, those in the second lowest quartile showed a positive association with PTB (odds ratio = 1.35, 95% confidence interval: 1.12, 1.63). A piecewise logistic regression breakpoint analysis identified a cut point (identifying a change in the slope) of 0.36 MUg/m for toluene and the risk of PTB. There was also some evidence to suggest an association between sulfur dioxide and TLBW. CONCLUSIONS: This study provides some evidence to suggest that in an area of relatively low air pollution concentration, maternal exposure to some air pollutants may be associated with adverse birth outcomes. PMID- 26641825 TI - Heat Illness Among North Carolina Latino Farmworkers. AB - OBJECTIVE: Heat exposure is an important hazard for workers in manual occupations, including farmworkers. This analysis delineates the prevalence of heat illness among farmworkers, and the factors associated with heat illness. METHODS: North Carolina Latino male farmworkers completed interviews in August, 2013. They reported on heat exposure and behaviors over the previous 3 months while working both outdoors and indoors. RESULTS: A third (35.6%) of the participants reported heat illness while working outside, and 13.9% while working inside. Factors associated with heat illness while working outside included working in wet clothes and shoes, harvesting and topping tobacco, and spending after-work time in an extremely hot house. CONCLUSIONS: Policy addressing heat illness is needed, as is more detailed research on occupational heat exposure that uses common measures. PMID- 26641826 TI - Injury and Illness Data for Illinois Mining Industry Employees, 1990 to 2012. AB - OBJECTIVE: This study identifies and evaluates injury types associated with distribution of cause of injuries and compensation among Illinois miners. METHODS: Cases were selected from the Illinois Workers' Compensation database from 1990 to 2012 to determine injury distributions and compensation among miners and non-miners. Logistic models were used to analyze total monetary compensation, temporary total disability (TTD), and permanent partial disability as primary outcomes. RESULTS: The major predictors of total monetary compensation in both miners and non-miners were TTD, permanent partial disability, average weekly wage, and age at the time of filing. Systemic injuries were an additional driver of final monetary compensation among miners. Miners were compensated $618 less (total monetary compensation; confidence interval 95%: -971, -266; P < 0.001), had 2.1 more weeks away from work (TTD; confidence interval 95%: 1.58, 2.63; P < 0.001), and had higher numbers of systemic injuries than non-miners. CONCLUSIONS: Systemic injuries are important drivers for TWC in miners in terms of median compensation and TTD. PMID- 26641827 TI - Bayesian Approach to "Healthy Worker Hire Effect" in Standardized Mortality Ratio Analysis. AB - OBJECTIVES: In this study, we address the healthy worker hire effect that arises when people with greater than average health are recruited to work in industrial jobs. METHODS: Epidemiologists have used both general and working population reference rates to gauge influence of healthy worker hire effect on the standardized mortality ratio. We propose a Bayesian procedure that uses information derived from general and working population reference rates to calculate standardized mortality ratio. RESULTS: The procedure is illustrated in the context of heart disease and lung cancer mortality analyses of a cohort of workers from a fluoropolymer production facility. CONCLUSIONS: Application of our method should allow for fuller discussions of the healthy worker effect when one of its components, the healthy worker hire effect, is evaluated quantitatively. Our method can be utilized to improve risk estimates for a cohort with occupational exposure. PMID- 26641828 TI - Is Early Prescribing of Opioid and Psychotropic Medications Associated With Delayed Return to Work and Increased Final Workers' Compensation Cost? AB - OBJECTIVE: To explore the association between the initial 60 days of prescriptions for psychotropic medications and final workers' compensation claim outcomes. METHODS: A cohort of 11,394 claimants involved in lost time injuries between 1999 and 2002 were followed through December 31, 2009. Logistic regressions and Cox Proportional Hazard Models were used in the analysis. RESULTS: The initial 60 days of prescriptions for psychotropic medications were significantly associated with a final claim cost at least $100,000. Odds ratios were 1.88 for short-acting opioids, 2.14 for hypnotics, antianxiety agents, or antidepressants, and 3.91 for long-acting opioids, respectively. Significant associations were also found between decreased time lost from work and decreased claim closures during the study period. CONCLUSIONS: Early prescription of opioids and other psychotropic drugs may be useful predictors of high claim costs and time lost from work. PMID- 26641829 TI - Health Status After Job Loss: Does the Reason for Job Change Matter? AB - OBJECTIVE: This study examines health status of the recently but no longer employed population by reason for job loss. METHODS: Using the Medical Expenditure Panel Survey 2008 to 2012, a sample of 8807 respondents experiencing job loss during the survey year was evaluated by reason for job loss. Multivariate regressions and ordered probit models were used to estimate the association between unemployment reasons and SF-12v2 physical, mental, and self rated health outcomes post-unemployment, controlling for demographic, socioeconomic, and prior health factors. RESULTS: Health status was significantly worse among those who passively lost employment from layoffs or jobs ending, compared with health status of the recently employed population who left jobs for maternity, family care, or pursuing education. The negative associations between jobs lost and health outcomes were more substantial among respondents with better prior health status. CONCLUSIONS: Results support investigation into policy alternatives for comprehensive unemployment assistance. PMID- 26641830 TI - Fish Consumption and Hair Mercury Among Asians in Chicago. AB - OBJECTIVES: The aim of the study was to characterize the risk for elevated mercury (Hg) from fish consumption among Asians in Chicago. Consumption of fish contaminated with methyl Hg (MeHg) can affect the neurodevelopment in children and cardiovascular disease risk in adults. METHODS: We collected fish consumption information and hair samples for Hg at two health fairs. We purchased fish from Asian fish markets. RESULTS: Geometric mean hair Hg from 71 participants was 0.58 MUg/g, with 28% overall and 29% of women of childbearing age having hair Hg levels at least 1 MUg/g; 20% ate fish 4 or more times/wk. Tuna consumption and non-Chinese Asian ethnicity were associated with elevated Hg. Hg levels in purchased fish were generally low. CONCLUSIONS: Our study confirms other findings that, compared with estimates of the general US population, Asians are at higher risk of elevated MeHg because of frequent fish consumption. PMID- 26641832 TI - Provision Increases Reported PPE Use for Mexican Immigrant Farmworkers: An mHealth Pilot Study. AB - OBJECTIVE: Personal protective equipment (PPE) reduces pesticide exposures, but many farmworkers complain that it is difficult to obtain. We examined if PPE provision increased usage. We also delivered motivational messaging aimed to promote PPE use. METHODS: First, we delivered a daily survey through a mobile phone app to assess PPE use. Farmworkers subsequently received a daily, individualized motivational message based on their PPE use and reported difficulties. PPE use was evaluated at baseline and at the close of the study. RESULTS: PPE behaviors improved for gloves (P <= 0.01) and safety glasses (P <= 0.001). Use of long-sleeved shirts, hats, and long pants were already consistently used at baseline and did not exhibit significant change. CONCLUSIONS: Our findings demonstrate that PPE provision and delivery of motivational messaging through mobile phones may increase PPE usage for farmworkers. PMID- 26641831 TI - N-Acetyltransferase 2 Genotypes Are Associated With Diisocyanate-Induced Asthma. AB - OBJECTIVE: To investigate whether genetic variants of N-acetyltransferase (NAT) genes are associated with diisocyanate asthma (DA). METHODS: The study population consisted of 354 diisocyanate-exposed workers. Genotyping was performed using a 5'-nuclease polymerase chain reaction assay. RESULTS: The NAT2 rs2410556 and NAT2 rs4271002 variants were significantly associated with DA in the univariate analysis. In the first logistic regression model comparing DA+ and asymptomatic worker groups, the rs2410556 (P = 0.004) and rs4271002 (P < 0.001) single nucleotide polymorphisms and the genotype combination, NAT2 rs4271002*NAT1 rs11777998, showed associations with DA risk (P = 0.014). In the second model comparing DA+ and DA- groups, NAT2 rs4271002 variant and the combined genotype, NAT1 rs8190845*NAT2 rs13277605, were significantly associated with DA risk (P = 0.022, P = 0.036, respectively). CONCLUSIONS: These findings suggest that variations in the NAT2 gene and their interactions contribute to DA susceptibility. PMID- 26641833 TI - Feasibility and Implementation of Musculoskeletal Ultrasound Training in Occupational Medicine Residency Education. AB - OBJECTIVE: This article aims to present the musculoskeletal (MSK) ultrasound (US) course, the objective measures of occupational medicine (OM) resident skill, and subjective opinions of OM residents regarding the MSK US course and MSK US in general. Also, to provide other OM residency programs information to help them develop this skill for their programs. METHODS: Didactic sessions based on American Institute of Ultrasound in Medicine (AIUM) guidelines were taught in modular format with subsequent practice-based workshops. A practical examination was given at the completion of the workshop and a survey of the residents experience during the workshop. RESULTS: The average score on the practical examination among residents was 92.5%. The survey indicated that the residents felt like they learned from this course and increased their knowledge of MSK US. CONCLUSIONS: The findings suggest that a course in MSK US for OM residents can feasibly be implemented in an OM residency curriculum. PMID- 26641834 TI - Worksite Prevalence of (un)Diagnosed Cardiovascular Risk Factors From a Health Check-Program in An Austrian Company. AB - OBJECTIVE: This investigation aims to determine cardiovascular disease risk profile in a cohort of employees. METHODS: In 704 participants, within the Special Institute for Preventive Cardiology And Nutrition health-check-program, body mass index, waist circumference, blood pressure (BP), lipids, glucose, and 10-year cardiovascular disease risk were assessed. RESULTS: Mean age was 37 (10) years (20% women) with 25.5 (3.9) kg/m. A total of 38% demonstrated overweight, 44% abdominal obesity, 12% obesity, and 19% metabolic syndrome. We found a significant difference in increased BP versus diagnosed hypertension (47% vs. 14%; P < 0.001). Increasing age was a significant predictor of metabolic syndrome (odds ratio [95% confidence interval] = 1.08 [1.06 to 1.10]; P < 0.001). Ten percent had intermediate and 8% high cardiovascular disease risk. A total of 79% demonstrated at least one risk factor. CONCLUSIONS: We detected high prevalence of risk factors particularly increased BP and abdominal obesity. Workplace prevention programs should aim in initially identifying risk factors and subsequently improving lifestyle. PMID- 26641835 TI - Matching Work Capacity and Job Demands: Toward an Enhanced Measure of Work Ability. AB - OBJECTIVE: The Work Ability Index (WAI), the dominant measure of work ability, provides little information for targeting workplace interventions. There are benefits of developing new measures that focus on self-rated capacity to meet job demands rather than on health subscales of the WAI. METHODS: Structural equation modeling with cross-sectional data from 186 underground coal miners aged 18 to 64 years was used to model multivariate relationships between the WAI subscales, worker autonomy, and relationships with management. RESULTS: The results show differential associations between workplace factors and the WAI subscales, particularly self-rated capacity, highlighting potential intervention avenues not identifiable using traditional composite WAI scoring. CONCLUSIONS: Focusing on self-rated work ability could be beneficial in clinical settings, provided measures are enhanced to capture a sufficient array of job demands. PMID- 26641838 TI - Sickness Presenteeism Among Health Care Workers and the Effect of BMI, Cardiorespiratory Fitness, and Muscle Strength. AB - OBJECTIVES: The primary objective of this study was to assess the relationship between sickness presenteeism and body mass index (BMI), cardiorespiratory fitness (CRF), and maximal voluntary contraction (MVC). METHODS: Female health care workers (n = 139) were analyzed cross-sectional as well as longitudinal after 3 and 12-month follow-up. Sickness presenteeism was assessed as a summed score using validated questions from three questionnaires: Health and Work Performance Questionnaire, Work Ability Index, and Quantity and Quality Method. CRF was assessed by a maximal cycling test and MVC from four muscle groups. RESULTS: Significant relationships were found between sickness presenteeism and BMI as well as MVC both cross-sectional and as changes over 3 months. Participants with BMI more than 30 kg/m had significantly higher sickness presenteeism than those with BMI less than 25 kg/m. CONCLUSIONS: This study suggests that actions that decrease BMI and increase MVC decrease the amount of sickness presenteeism. PMID- 26641839 TI - Evaluating Endocrine Disruption Activity of Deposits on Firefighting Gear Using a Sensitive and High Throughput Screening Method. AB - OBJECTIVE: Adverse health outcomes related to exposure to endocrine disrupting chemicals, including increased incidences of coronary heart disease, prostate and testicular cancers, and congenital disabilities, have been reported in firefighters or their offspring. We, therefore, measured the estrogenic and antiestrogenic activity of extracts of used firefighter gear to assess exposure to these agents. METHODS: Extracts and known chemical contaminants were examined for estrogenicity and antiestrogenicity in yeast cells expressing the estrogen receptor. RESULTS: Most extracts of used gear and phthalate diesters detectable on this gear displayed strong antiestrogenic effects. Notably, new glove and hood extracts showed significant estrogenic activity. CONCLUSIONS: Overall, our data suggest that firefighters are exposed to both estrogenic and antiestrogenic agents, possibly phthalates that may lead to health risks observed in this occupation as a result of perturbation of hormone homeostasis. PMID- 26641840 TI - The Utility of an Online Convenience Panel for Reaching Rare and Dispersed Populations. AB - Gaps in data collection systems, as well as challenges associated with gathering data from rare and dispersed populations, render current health surveillance systems inadequate to identify and monitor efforts to reduce health disparities. Using sexual and gender minorities we investigated the utility of using a large nonprobability online panel to conduct rapid population assessments of such populations using brief surveys. Surveys of the Google Android Panel (four assessing sexual orientation and one assessing gender identity and sex assigned at birth) were conducted resulting in invitation of 53,739 application users (37,505 of whom viewed the invitation) to generate a total of 34,759 who completed screening questions indicating their sexual orientation, or gender identity and sex at birth. Where possible we make comparisons to similar data from two population-based surveys (NHIS and NESARC). We found that 99.4% to 100.0% of respondents across our Google Android panel samples completed the screening questions and 97.8% to 99.2% of those that consented to participate in our surveys indicated they were "OK" with the content of surveys that assessed sexual orientation and sex/gender. In our Google Android panel samples there was a higher percentage of sexual minority respondents than in either NHIS or NESARC with 7.4% of men and 12.4% of women reporting gay, lesbian or bisexual identities. The proportion sexual minority was 2.8 to 5.6 times higher in the Google Android panel samples than was found in the 2012 NHIS sample, for men and women, respectively. The percentage of "transgender" identified individuals in the Google sample was 0.7%, which is similar to 0.5% transgender identified through the Massachusetts BRFSS, and using a transgender status item we found that 2.0% of the overall sample fit could be classified as transgender. The Google samples sometimes more closely approximated national averages for ethnicity and race than NHIS. PMID- 26641841 TI - Bone Marrow Edema and Low Back Pain in Elderly Degenerative Lumbar Scoliosis: A Cross-Sectional Study. AB - STUDY DESIGN: Cross-sectional study. OBJECTIVE: To examine whether bone marrow edema is associated with low back pain in elderly patients with degenerative lumbar scoliosis. SUMMARY OF BACKGROUND DATA: The cause of low back pain in degenerative lumbar scoliosis is unclear. METHODS: A total of 120 degenerative lumbar scoliosis patients 65 years of age or older were evaluated. Radiography, computed tomography (CT), magnetic resonance imaging (MRI), and tender point examination in the lumbar spine were performed. On MRI, coronal gadolinium contrasted T1- or T2-weighed fat-saturated images were used to score the size of bone marrow edema. The prevalence of bone marrow edema in patients with and without low back pain was compared; in patients with low back pain, we tested whether the locations of lumbar tender point were consistent with that of bone marrow edema. RESULTS: Bone marrow edema was found in 62 of 64 (96.9%) patients with low back pain compared with 21 of 56 (37.5%) patients without it (P < 0.001). Bone marrow edema located more frequently on the concave side than on the convex side of scoliosis (P < 0.001). Among patients with low back pain, bone marrow edema score was associated with low back pain severity (r = 0.724; P < 0.001), and the location of lumbar tender point were consistent with that of bone marrow edema (kappa value = 0.745; P < 0.001). CONCLUSION: Bone marrow edema on MRI was closely associated with the presence of low back pain in elderly degenerative lumbar scoliosis. LEVEL OF EVIDENCE: 4. PMID- 26641842 TI - The Clinical Correlation of the Hart-ISSG Proximal Junctional Kyphosis Severity Scale With Health-Related Quality-of-life Outcomes and Need for Revision Surgery. AB - STUDY DESIGN: Retrospective analysis of prospective data. OBJECTIVE: Evaluate the utility of the Hart-International Spine Study Group proximal junctional kyphosis severity scale (Hart-ISSG PJKSS). SUMMARY OF BACKGROUND DATA: Proximal junctional kyphosis (PJK) and failure (PJF) are well-described complications after long segment instrumentation. The Hart-ISSG PJKSS was recently developed and incorporates neurological deficit, pain, instrumentation issues, degree of kyphosis, presence of fracture, and level of upper-most instrumented vertebrae. METHODS: All adult spinal deformity patients with PJK or PJF were identified from two academic centers over a 7-year period. Health-related quality-of-life (HRQOL) outcomes were prospectively collected: Oswestry Disability Index (ODI), visual analogue scale (VAS) pain, SF-36 questionnaire, and SRS-30 questionnaire. Patients were retrospectively assigned Hart-ISSG PJKSS scores. Correlation between the Hart-ISSG PJKSS and outcomes was assessed with linear regression, Pearson correlation coefficients, and chi2 analysis. RESULTS: A total of 184 cases were included; 21.2% were men and mean age was 65.0 years. Weakness and/or myelopathy were present in 11.4% of patients and 88.6% had pain. Instrumentation issues occurred in 44.0% and 64.1% had PJK-associated fractures. PJK occurred in the upper thoracic spine in 21.7% of cases. Mean PJKSS score was 5.9. The Hart ISSG PJKSS was significantly and strongly associated with ODI (P < 0.001, r = 0.611), VAS pain (P < 0.001, r = 0.676), SRS-30 function (P < 0.001, r = -0.401), SRS-30 mental health (P < 0.001, r = -0.592), SRS-30 self-image (P < 0.001, r = 0.511), SRS-30 satisfaction (P < 0.001, r = -0.531), and SRS-30 pain (P < 0.001, r = -0.445). Higher scores were associated with higher proportion of patients undergoing revision surgery (P < 0.001); scores of 9 to 11 and 12 to 15 underwent revision 96.0% and 100.0% of the time, respectively. CONCLUSION: The Hart-ISSG PJKSS was strongly correlated with validated functional outcomes and higher scores were associated with higher rates of revision surgery. The Hart-ISSG PJKSS may be a useful clinical tool in the treatment of patient with PJK. LEVEL OF EVIDENCE: 3. PMID- 26641843 TI - Bioinformatics Analysis of microRNA Time-Course Expression in Brown Rat (Rattus norvegicus): Spinal Cord Injury Self-Repair. AB - STUDY DESIGN: This is a bioinformatic study designed to investigate the time course expression changes of microRNAs (miRNAs) after spinal cord injury (SCI). OBJECTIVE: To investigate the mechanism of SCI self-repair at miRNAs level and target genes level. SUMMARY OF BACKGROUND DATA: SCI results in loss of sensory and locomotor function, and SCI self-repair might provide clinical therapies; however, the mechanism of SCI self-repair remains unclear. METHODS: The miRNA expression profile (GSE19890) of adult female Wistar brown rats (Rattus norvegicus) in SCI (laminectony and contusion), sham (laminectony but no contusion), and control (untreated) groups was downloaded from Gene Expression Omnibus. Totally, 35 chips were available, including five controls, five SCI-1 day, five SCI-3-day, five SCI-7-day, five sham-1-day, five sham-3-day, and five sham-7-day. Betr and limma package were used to screen time-course differentially expressed miRNAs (DEmiRNAs), followed by Bayesian hierarchical clustering (BHC), synergetic and functional enrichment analysis through BHC and cluster Profiler packages, respectively. Furthermore, STRING database and Cytoscape software were used to construct interaction networks between time-course DEmiRNAs, and GenCLip2.0 software was applied to pathway enrichment for key genes associated with nervous system. RESULTS: Totally, 68 time-course DEmiRNAs were identified and divided into 15 BHC clusters. Then, 100 time-course DEmiRNA pairs with synergetic function were identified, and time-course DEmiRNAs and target genes interaction networks were constructed, in which 10 genes (AKT1, VEGFA, CTNNB1, IGF1, APP, PTEN, CDC42, BDNF, SOD2, and IFNG) with highest degrees were found. Furthermore, key genes were significantly enriched in neurotrophin signaling pathway. CONCLUSION: After SCI, miRNAs might collectively regulate target genes, facilitating or inhibiting self-repair. Modulation of these miRNAs might provide novel therapies for SCI treatment. LEVEL OF EVIDENCE: N/A. PMID- 26641844 TI - Surgical Morbidity and Mortality Associated With Transoral Approach to the Cervical Spine. AB - STUDY DESIGN: A retrospective cohort analysis of prospectively collected data. OBJECTIVE: The aim of this study was to analyze morbidity and mortality in adult patients undergoing transoral approach using a large national database. SUMMARY OF BACKGROUND DATA: The transoral approach to the anterior skull base and atlanto axial cervical spine provides a direct corridor to the lower clivus, C1, C2, and occasionally C3. Due to the rarity of this approach and the unfamiliar anatomy, there is potential for significant morbidity and mortality. METHODS: Adult patients undergoing transoral approach to the cervical spine from 2008 to 2012 were identified by the Current Procedural Terminology (CPT) code 22548 in the ACS NSQIP database. Cases with missing preoperative information were excluded. Univariate and multivariate analyses were performed to assess associated morbidity and mortality. RESULTS: One hundred twenty-six patients underwent cervical spine and clival surgery via the transoral approach. There were a total of 27 (21.4%) postoperative complications with three (2.4%) mortalities. On multivariate analysis, there was an increased risk of complications with operative time >4 hours [odds ratio (OR) 7.8, 95% confidence interval (95% CI) 1.8-33.1, P = 0.0054] and total length of stay >5 days (OR 7.5, 95% CI 2.4-23.4, P = 0.0006). CONCLUSION: The transoral approach carries significant risks of morbidity and mortality. Maintaining operative time <4 hours and LOS <5 days may decrease morbidity and mortality. LEVEL OF EVIDENCE: 4. PMID- 26641845 TI - Readability of Spine-Related Patient Education Materials From Leading Orthopedic Academic Centers. AB - STUDY DESIGN: Cross-sectional analysis of online spine-related patient education materials from leading academic centers. OBJECTIVE: To assess the readability levels of spine surgery-related patient education materials available on the websites of academic orthopedic surgery departments. SUMMARY OF BACKGROUND DATA: The Internet is becoming an increasingly popular resource for patient education. Yet many previous studies have found that Internet-based orthopedic-related patient education materials from subspecialty societies are written at a level too difficult for the average American; however, no prior study has assessed the readability of spine surgery-related patient educational materials from leading academic centers. METHODS: All spine surgery-related articles from the online patient education libraries of the top five US News & World Report-ranked orthopedic institutions were assessed for readability using the Flesch-Kincaid (FK) readability test. Mean readability levels of articles amongst the five academic institutions and articles were compared. We also determined the number of articles with readability levels at or below the recommended sixth- or eight grade levels. Intraobserver and interobserver reliability of readability assessment were assessed. RESULTS: A total of 122 articles were reviewed. The mean overall FK grade level was 11.4; the difference in mean FK grade level between each department varied significantly (range, 9.3-13.4; P < 0.0001). Twenty-three articles (18.9%) had a readability level at or below the eighth grade level, and only one (0.8%) was at or below the sixth grade level. Intraobserver and interobserver reliability were both excellent (intraclass correlation coefficient of 1 for both). CONCLUSION: Online patient education materials related to spine from academic orthopedic centers are written at a level too high for the average patient, consistent with spine surgery-related patient education materials provided by the American Academy of Orthopaedic Surgeons and spine subspecialty societies. This study highlights the potential difficulties patients might have in reading and comprehending the information in publicly available education materials related to spine. LEVEL OF EVIDENCE: N/A. PMID- 26641846 TI - Reliability and Validity of the Adapted Spanish Version of the Early-onset Scoliosis-24 Questionnaire. AB - STUDY DESIGN: Translation and validation of the Early Onset Scoliosis-24 Questionnaire (EOSQ-24). OBJECTIVE: To cross-culturally adapt the American English version of the EOSQ-24 into Spanish language, and to assess its reliability and discriminative validity. SUMMARY OF BACKGROUND DATA: Treatment of early-onset scoliosis (EOS) seeks to improve natural history and health-related quality of life in children, but radiographic parameters are insufficient to evaluate the severity and efficacy of treatment in these patients. EOSQ-24 was developed to assess the health-related quality of life of EOS children; however, it has not been transculturally adapted and validated for Spanish subjects. METHODS: Translation and cross-cultural adaptation of the original EOSQ-24 was performed according to published guidelines by an expert committee. The Spanish version of the EOSQ-24 was applied to 44 EOS patients. Reliability was assessed by internal consistency using Cronbach alpha, item-total correlations, and inter item correlations. Data quality was assessed by mean, median, percentage of missing data, and ceiling and floor effects. For discriminative validity, comparisons between categorical variables were made by using non-parametric (Kruskal-Wallis and/or Mann Whitney U) tests, and Spearman correlation coefficients were used for continuous variables. RESULTS: In our study, all items and domains showed very good global internal consistencies (Cronbach alpha 0.897 and 0.836, respectively). Corrected item-total correlations were good for all domains (>0.3). Two of 24 items showed low corrected item-total correlations (r = 0.179 and r = 0.254), but Cronbach alpha did not increase when these items were removed. Inter-item correlations were acceptable (>0.2). EOSQ-24 was found capable to discriminate patients with different curves severity (P = 0.001), diagnosis (P = 0.006), and ambulatory status (P = 0.053). CONCLUSION: The Spanish version of the EOSQ-24 is reliable and a valid tool for the psychometric assessment of children with EOS, and can be applied in routine clinical practice and for research purposes. LEVEL OF EVIDENCE: 2. PMID- 26641847 TI - Return to Play in Elite Athletes After Lumbar Microdiscectomy: A Meta-analysis. AB - STUDY DESIGN: Systematic literature review and meta-analysis of English language studies. OBJECTIVE: This study is a meta-analysis assessing elite athlete's return-to-play (RTP) rates after a lumbar herniated nucleus pulposus (HNP) treated with microdiscectomy. Additionally, we compare RTP rates of those treated operatively versus nonoperatively. SUMMARY OF BACKGROUND DATA: Microdiscectomy for a lumbar HNP in elite athletes remains a controversial subject with no consensus in the literature regarding true RTP. METHODS: A literature search of Medline, Embase, and Cochrane Reviews was performed. The pooled results were analyzed by calculating the effect size based on the logit event rate. Studies were weighted by the inverse of the variance, which included both within and between study errors. Confidence intervals (CIs) were reported at 95%. Heterogeneity was assessed using the Q statistic and I. RESULTS: The initial literature search resulted in 547 articles, of which 14 were determined relevant on abstract review. Overall, nine studies provided data for 558 patients who underwent a lumbar microdiscectomy. The pooled clinical success rate was 83.5% (CI: 79.7%, 88.0%), which was statistically significant (P < 0.0001). The studies demonstrated minimal heterogeneity Q value of 7.41 and I value of 5.53. Four studies included operative and nonoperative cohorts. The odds ratio of RTP with a symptomatic lumbar disc herniation was 1.13 (CI: 0.37-5.90). There was no statistical difference in RTP between the two groups (P = 0.59). CONCLUSION: Elite athletes return to competition 83.5% of the time after undergoing a single level lumbar microdiscectomy. Additionally, when comparing lumbar microdiscectomy to non-operative treatment, there is no difference in RTP rates, suggesting that a more aggressive approach to managing a symptomatic HNP in this population with earlier surgical intervention may be employed judiciously if timing necessitates for the athlete's benefit. LEVEL OF EVIDENCE: 3. PMID- 26641848 TI - Obesity Is an Independent Risk Factor of Early Complications After Revision Spine Surgery. AB - STUDY DESIGN: Retrospective cohort analysis of risk factors in revision spine surgery using a prospectively collected database. OBJECTIVE: To examine the risk of developing early (30-day) complications across obesity level after adjusting for comorbidities in patients undergoing revision spine surgery. SUMMARY OF BACKGROUND DATA: Prior studies suggest obesity influences early complications after primary surgery. The association between obesity and early complications after revision surgery remains to be characterized. METHODS: Data were abstracted from the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database from 2005 to 2012. Adult Caucasian patients undergoing removal/revision of instrumentation or exploration of fusion were included. Patients were categorized by WHO body mass index (BMI, kg/m): Non-Obese (18.5-29.9), Obese Class I (30-34.9), and Obese Class II/III (>=35). Univariate regression was performed to assess the predictive value of obesity level and baseline risk factors in the presence of at least one early complication, and significant predictors were entered into the multivariable model. RESULTS: Of 2538 patients, 57.6% were nonobese, 23% Obese Class I, and 19.4% Obese Class II/III. Obesity was associated with diabetes, hypertension, respiratory disease, and American Society of Anesthesiologists (ASA) score of 3-4 (all P < 0.001). BMI group (P = 0.01), older age (P = 0.008), functional dependence (P < 0.001), ASA 3 4 (P = 0.008), bleeding disorder (P = 0.04), and diabetes (P = 0.016) were identified as univariate predictors for early complications. In the multivariable model, higher BMI (P = 0.04), older age (P = 0.014), and functional dependence (P < 0.001) remained significant predictors for early complications. Notably, patients who were Obese Class II/III (OR 1.66, 95% CI [1.12-2.45]), age >=75 (OR 1.83, [1.20-2.81]), and functionally dependent (OR 3.02 [1.85-4.94]) had significantly higher risk compared with their reference groups. CONCLUSION: Obesity is an independent risk factor for early complications after revision spine surgery. Although obesity may not contraindicate revision surgery, its status as a modifiable risk factor warrants disclosure and preoperative counseling to optimize outcomes. LEVEL OF EVIDENCE: 3. PMID- 26641849 TI - Association Between Intercellular Adhesion Molecule-1, -2, -3 Plasma Levels and Disease Activity of Ankylosing Spondylitis in the Chinese Han Population. AB - STUDY DESIGN: We investigated the association between ICAM-1, -2, -3 plasma levels and ankylosing spondylitis (AS) disease activity. OBJECTIVE: In the present study, we aimed to investigate the association between ICAM-1, -2, -3 plasma levels and AS disease activity in the Chinese Han population. SUMMARY OF BACKGROUND DATA: AS is a chronic inflammatory rheumatic disease that effects the sacroiliac joints and axial skeleton. The intercellular adhesion molecules (ICAMs) are members of the immunoglobulin superfamily and have been identified to play major roles in inflammation and immune responses. METHODS: A total of 60 patients with AS and 60 healthy individuals were selected. The plasma levels of proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and ICAM-1, -2, -3, were analyzed by ELISA. Disease severity-related indexes, including the Bath ankylosing spondylitis disease activity index (BASDAI), Bath ankylosing spondylitis functional index (BASFI), and ankylosing spondylitis disease activity score (ASDAS), were assessed, along with the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level. RESULTS: Both ICAM-1 and ICAM-2 levels in plasma were markedly increased in AS patients compared with levels in the plasma of controls. There was no difference between controls and patients in term of ICAM-3 levels. Furthermore, in patients, correlation analysis showed that TNF-alpha and IL-6 production, as well as the ESR and CRP levels, have positive relationships with ICAM-1 and ICAM-2 plasma levels; the BASDAI, BASFI, and ASDAS scores were also found to be positively correlated with ICAM-2. However, no significant correlations between ICAM-1 levels and BASDAI, BASFI, or ASDAS were detected in our study. CONCLUSION: The current findings suggest that ICAM-2 may be a potential biomarker reflecting disease activity and functional ability in AS patients. LEVEL OF EVIDENCE: 5. PMID- 26641850 TI - Povidone-Iodine Has a Profound Effect on In Vitro Osteoblast Proliferation and Metabolic Function and Inhibits Their Ability to Mineralize and Form Bone. AB - STUDY DESIGN: A study examining the clinical protocol of scoliosis wound irrigation, demonstrating povidone-iodine's (PVI) effect on human osteoblast cells. Primary and immortal cell line osteoblasts were treated with 0.35% PVI for 3 minutes, and analyzed for proliferation rate, oxidative capacity, and mineralization. OBJECTIVE: To model spinal wound irrigation with dilute PVI in vitro, in order to investigate the effect of PVI on osteoblast proliferation, metabolism, and bone mineralization. SUMMARY OF BACKGROUND DATA: Previously PVI irrigation has been proposed as a safe and effective practice to avoid bacterial growth after spinal surgery. However, recent evidence in multiple cell types suggests that PVI has a deleterious effect on cellular viability and cellular function. METHODS: Primary and immortal human osteoblast cells were exposed to either phosphate buffered saline control or with 0.35% PVI for 3 minutes. Cellular proliferation was measured over the duration of 7 days by MTS assay. Oxygen consumption rate, extracellular acidification rate, and proton production rate were analyzed using a Seahorse XF24 Bioanalyzer. Protein expression of the electron transport chain subunits CII-SDHB, CIII-UQRCR2, and CV-ATP5A was measured via Western blotting. Mineralized bone nodules were stained with alizarin red. RESULTS: Expressed as a percentage of normal osteoblast proliferation, osteoblasts exposed to 0.35% PVI exhibited a significant 24% decrease in proliferation after 24 hours. This was a sustained response, resulting in a 72% decline in cellular proliferation at 1 week. There was a significant reduction in oxygen consumption rate, extracellular acidification rate, and proton production rate (P < 0.05), in osteoblasts that had been exposed to 0.35% PVI for 3 minutes, coupled with a marked reduction in the protein expression of CII-SDHB. Osteoblasts exposed to 0.35% PVI exhibited reduced bone nodule mineralization compared to control phosphate buffered saline exposed osteoblasts (P < 0.01). CONCLUSION: PVI has a rapid and detrimental effect on human osteoblast cellular proliferation, metabolic function, and bone nodule mineralization. LEVEL OF EVIDENCE: NA. PMID- 26641851 TI - The Impact of Commercial Health Plan Prior Authorization Programs on the Utilization of Services for Low Back Pain. AB - STUDY DESIGN: An observational study. OBJECTIVE: The aim of this study was to evaluate the impact of a health plan's prior authorization (PA) programs for low back pain (LBP) in a non-Medicare population by assessing changes in pre-surgical nonoperative care; lumbar fusion trends; and overall back surgery rates compared with another health plan with a similar program and national benchmarks. The PA programs require mandatory physiatrist consultation before surgical evaluation, with subsequent additional LBP surgery PA. SUMMARY OF BACKGROUND DATA: LBP is prevalent and concern exists that spinal fusion is overutilized for LBP. METHODS: Annual rates of lumbar fusion trended over 6 years, and analysis of changes in standardized costs for LBP-related services among a 501-member subset who underwent lumbar fusion before and after program implementations, during the period January 1, 2008, through December 31, 2013, among commercial members aged 18 and 65 years enrolled in a health maintenance organization with commercial membership averaging >500,000 annually. RESULTS: After initiation of the physiatrist PA in December 2010, lumbar fusions decreased from 76.27/100,000 in 2010 to 62.63/100,000 in 2011 with subsequent increases to 64.24/100,000 and 73.84/100,000 in years 2012 and 2013. For members who had lumbar fusion, per member, pre-surgical costs increased by $2,233 with the physiatrist PA and an additional $1,370 with implementation of the LBP surgery PA (March 2013). Spinal injections and inpatient admissions were the greatest contributors to the overall increase in costs. The physiatrist and LBP surgery PA programs were also associated with lengthening of LBP episodes ending in surgery by 309 and 198 days. CONCLUSION: Mandatory referral to a physiatrist before surgical evaluation did not result in persistent reduction in lumbar fusions. Instead, these programs were associated with the unintended consequence of increased costs from more nonoperative care for only a transitory change in the lumbar fusion rate, likely from delays due to the introduction of both PA programs. LEVEL OF EVIDENCE: 3. PMID- 26641852 TI - Magnetic Resonance Imaging of the Codman Microsensor Transducer Used for Intraspinal Pressure Monitoring: Findings From the Injured Spinal Cord Pressure Evaluation Study. AB - STUDY DESIGN: Laboratory and human study. OBJECTIVE: To test the Codman Microsensor Transducer (CMT) in a cervical gel phantom. To test the CMT inserted to monitor intraspinal pressure in a patient with spinal cord injury. SUMMARY OF BACKGROUND DATA: We recently introduced the technique of intraspinal pressure monitoring using the CMT to guide management of traumatic spinal cord injury [Werndle et al. Crit Care Med 2014;42:646]. This is analogous to intracranial pressure monitoring to guide management of patients with traumatic brain injury. It is unclear whether magnetic resonance imaging (MRI) of patients with spinal cord injury is safe with the intraspinal pressure CMT in situ. METHODS: We measured the heating produced by the CMT placed in a gel phantom in various configurations. A 3-T MRI system was used with the body transmit coil and the spine array receive coil. A CMT was then inserted subdurally at the injury site in a patient who had traumatic spinal cord injury and MRI was performed at 1.5 T. RESULTS: In the gel phantom, heating of up to 5 degrees C occurred with the transducer wire placed straight through the magnet bore. The heating was abolished when the CMT wire was coiled and passed away from the bore. We then tested the CMT in a patient with an American Spinal Injuries Association grade C cervical cord injury. The CMT wire was placed in the configuration that abolished heating in the gel phantom. Good-quality T1 and T2 images of the cord were obtained without neurological deterioration. The transducer remained functional after the MRI. CONCLUSION: Our data suggest that the CMT is MR conditional when used in the spinal configuration in humans. Data from a large patient group are required to confirm these findings. LEVEL OF EVIDENCE: N/A. PMID- 26641853 TI - Effect of Expectations on Treatment Outcome for Lumbar Intervertebral Disc Herniation. AB - STUDY DESIGN: Secondary analysis of randomized and nonrandomized prospective cohorts. OBJECTIVE: To examine the effect of patient treatment expectations on treatment outcomes for patients with intervertebral disc herniation. SUMMARY OF BACKGROUND DATA: Patient expectations about treatment effectiveness may have important relationships with clinical outcomes. METHODS: Subgroup and reanalysis of the Spine Patient Outcomes Research Trial, a randomized trial and comprehensive cohort study enrolling patients between March 2000 and November 2004 from 13 multidisciplinary spine clinics in 11 US states. Overall, 501 randomized and 744 observational patients (1244 total) who were surgical candidates with radiculopathy and imaging confirmed lumbar intervertebral disc herniation were enrolled. The primary study compared surgical discectomy to usual nonoperative care; this subgroup analysis reassessed outcomes on the basis of treatment expectations at baseline. Expectations about symptomatic and functional improvement for both surgery and nonoperative care were assessed on 5-point scales (1="No Chance (0%)" to 5="Certain (100%)"). Outcomes were assessed using longitudinal regression models analyzed by treatment received. RESULTS: Among 1244 IDH SPORT participants, 1168 provided data on both outcomes and baseline expectations and were included in the current analysis: 467 from the randomized and 701 from the observational cohort. Low expectations of outcomes with surgery predicted poorer outcome regardless of treatment. High expectations of outcomes with nonoperative care predicted better nonoperative outcomes but did not affect surgical results. These differences were of similar magnitude to the difference in outcomes between surgery and nonoperative care. CONCLUSION: High expectations of treatment benefit had clinically significant positive associations with outcomes. LEVEL OF EVIDENCE: 2. PMID- 26641854 TI - Dissonance-Based Eating Disorder Prevention Program Reduces Reward Region Response to Thin Models; How Actions Shape Valuation. AB - Research supports the effectiveness of a dissonance-based eating disorder prevention program wherein high-risk young women with body dissatisfaction critique the thin ideal, which reduces pursuit of this ideal, and the theory that dissonance induction contributes to these effects. Based on evidence that dissonance produces attitudinal change by altering neural representation of valuation, we tested whether completing the Body Project would reduce response of brain regions implicated in reward valuation to thin models. Young women with body dissatisfaction were randomized to this intervention or an educational control condition, completing assessments and fMRI scans while viewing images of thin versus average-weight female models at pre and post. Whole brain analyses indicated that, compared to controls, Body Project participants showed greater reductions in caudate response to images of thin versus average-weight models, though participants in the two conditions showed pretest differences in responsivity of other brain regions that might have contributed to this effect. Greater pre-post reductions in caudate and putamen response to thin models correlated with greater reductions in body dissatisfaction. The finding that the Body Project reduces caudate response to thin models provides novel preliminary evidence that this intervention reduces valuation of media images thought to contribute to body dissatisfaction and eating disorders, providing support for the intervention theory by documenting that this intervention alters an objective biological outcome. PMID- 26641856 TI - Angiotensin-(1-7)/Mas Signaling Inhibits Lipopolysaccharide-Induced ADAM17 Shedding Activity and Apoptosis in Alveolar Epithelial Cells. AB - A disintegrin and metalloproteinase (ADAM) 17, constitutively expressed in alveolar epithelium, is the pivotal shedding enzyme mediating acute lung inflammation. On the other hand, angiotensin (Ang)-(1-7)/Mas signaling has been shown to improve acute respiratory distress syndrome and protect alveolar epithelial cells from apoptosis. In this study, we explored the effect of Ang-(1 7)/Mas signaling on the expression and activity of ADAM17 and assessed its impact on apoptosis in lipopolysaccharide (LPS)-treated human alveolar epithelial cells. LPS markedly induced the shedding activity of ADAM17 in alveolar epithelial cells, which was blocked by selective c-Jun N-terminal kinase (JNK) inhibitor SP600125. Ang-(1-7) concentration-dependently inhibited LPS-induced ADAM17 shedding activity, which was abolished by selective Mas blocker A779 and Mas shRNA. LPS and Ang-(1-7) showed no significant effect on the expression of ADAM17. Overexpression of ADAM17 synergized with LPS on increasing the shedding activity of ADAM17 and apoptosis in alveolar epithelial cells, counteracting the inhibitory effects of Ang-(1-7). In addition, LPS significantly increased the JNK activity in alveolar epithelial cells; Ang-(1-7) concentration-dependently inhibited LPS-induced JNK activity, which was abolished by A779 and Mas shRNA. In conclusion, this study suggests that Ang-(1-7)/Mas signaling inhibits LPS-induced alveolar epithelial cell apoptosis by inhibiting LPS-induced shedding activity of ADAM17, likely by a JNK-dependent mechanism. PMID- 26641855 TI - DYRK1A Controls HIV-1 Replication at a Transcriptional Level in an NFAT Dependent Manner. AB - BACKGROUND: Transcription of the HIV-1 provirus is regulated by both viral and host proteins and is very important in the context of viral latency. In latently infected cells, viral gene expression is inhibited as a result of the sequestration of host transcription factors and epigenetic modifications. RESULTS: In our present study we analyzed the effect of host factor dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) on HIV-1 replication. We show that DYRK1A controls HIV-1 replication by regulating provirus transcription. Downregulation or inhibition of DYRK1A increased LTR driven transcription and viral replication in cell lines and primary PBMC. Furthermore, inhibition of DYRK1A resulted in reactivation of latent HIV-1 provirus to a similar extent as two commonly used broad-spectrum HDAC inhibitors. We observed that DYRK1A regulates HIV-1 transcription via the Nuclear Factor of Activated T-cells (NFAT) by promoting its translocation from the nucleus to the cytoplasm. Therefore, inhibition of DYRK1A results in increased nuclear levels of NFAT and increased NFAT binding to the viral LTR and thus increasing viral transcription. CONCLUSIONS: Our data indicate that host factor DYRK1A plays a role in the regulation of viral transcription and latency. Therefore, DYRK1A might be an attractive candidate for therapeutic strategies targeting the viral reservoir. PMID- 26641857 TI - Rheological and Performance Research on a Regenerable Polyvinyl Alcohol Fracturing Fluid. AB - A regenerable polyvinyl alcohol/organic boron fracturing fluid system with 1.6 wt% polyvinyl alcohol (PVOH) and 1.2 wt% organic boron (OBT) was studied, and its main regeneration mechanism is the reversible cross-linking reaction between B(OH)4- and hydroxyl groups of PVOH as the change of pH. Results of rheology evaluations show that both the apparent viscosity and the thermal stability of the fracturing fluid decreased with the regeneration number of times increasing. In addition, the apparent viscosity of the fluid which was without regeneration was more sensitive to the shear action compared with that of the fluid with regeneration once or twice. When the fracturing fluid was without regeneration, the elasticity was dominating due to the three-dimensional network structure of the formed gel; the viscosity gradually occupied the advantage when the fracturing fluid was regenerated once or twice. The settling velocity of proppant was accelerated by both the regeneration process and the increasing temperature, but it was decelerated when the proppant ratio increased. Results of core damage tests indicate that less permeability damage was caused by the PVOH/OBT fracturing fluid compared with that caused by the guar gum fracturing fluid after gel breaking. PMID- 26641860 TI - Theoretical Basis for Dynamic Label Propagation in Stationary Metabolic Networks under Step and Periodic Inputs. AB - The dynamics of label propagation in a stationary metabolic network during an isotope labeling experiment can provide highly valuable information on the network topology, metabolic fluxes, and on the size of metabolite pools. However, major issues, both in the experimental set-up and in the accompanying numerical methods currently limit the application of this approach. Here, we propose a method to apply novel types of label inputs, sinusoidal or more generally periodic label inputs, to address both the practical and numerical challenges of dynamic labeling experiments. By considering a simple metabolic system, i.e. a linear, non-reversible pathway of arbitrary length, we develop mathematical descriptions of label propagation for both classical and novel label inputs. Theoretical developments and computer simulations show that the application of rectangular periodic pulses has both numerical and practical advantages over other approaches. We applied the strategy to estimate fluxes in a simulated experiment performed on a complex metabolic network (the central carbon metabolism of Escherichia coli), to further demonstrate its value in conditions which are close to those in real experiments. This study provides a theoretical basis for the rational interpretation of label propagation curves in real experiments, and will help identify the strengths, pitfalls and limitations of such experiments. The cases described here can also be used as test cases for more general numerical methods aimed at identifying network topology, analyzing metabolic fluxes or measuring concentrations of metabolites. PMID- 26641861 TI - LL-37 Triggers Formation of Streptococcus pyogenes Extracellular Vesicle-Like Structures with Immune Stimulatory Properties. AB - Reports have shown that the antimicrobial peptide LL-37 is abundantly expressed but has limited bactericidal effect in Streptococcus pyogenes infections. At sub inhibitory concentrations, LL-37 has been reported to alter virulence gene expression. Here, we explored the interaction of S. pyogenes strains with LL-37, focusing on bacterial growth, cell surface alterations and pro-inflammatory responses. Bioscreen turbidity measurements of strain 5448 cultured in the presence or absence of LL-37 confirmed the poor antimicrobial effect, and revealed a significant increase in turbidity of bacterial cultures exposed to sub inhibitory concentrations of LL-37. However, this was not linked to increased bacterial counts. Electron microscopy of LL-37-exposed bacteria revealed the presence of vesicle-like structures on the bacterial surface. The vesicles stained positive for LL-37 and were released from the bacterial surface. Concentrated supernatants enriched in these structures had a broader protein content, including several virulence factors, compared to supernatants from untreated bacteria. The supernatants from LL-37-exposed bacteria were pro inflammatory and elicited resistin and myeloperoxidase release from neutrophils. This is the first report on S. pyogenes extracellular vesicle-like structures formed at the bacterial surface in response to LL-37. The associated increased pro-inflammatory activity further implicates LL-37 as a potential factor involved in S. pyogenes pathogenesis. PMID- 26641858 TI - Molecular Differentiation of the African Yellow Fever Vector Aedes bromeliae (Diptera: Culicidae) from Its Sympatric Non-vector Sister Species, Aedes lilii. AB - INTRODUCTION: Yellow fever continues to be a problem in sub-Saharan Africa with repeated epidemics occurring. The mosquito Aedes bromeliae is a major vector of yellow fever, but it cannot be readily differentiated from its non-vector zoophilic sister species Ae. lilii using morphological characters. Genetic differences have been reported between anthropophilic Ae. bromeliae and zoophilic Ae. lilii and between forest and domestic populations. However, due to the application of different molecular markers and non-overlapping populations employed in previous studies, interpretation of species delimitation is unclear. METHODOLOGY/PRINCIPLE FINDINGS: DNA sequences were generated from specimens of Ae. simpsoni s.l. from the Republic of Benin, Tanzania and Uganda for two nuclear genes apolipophorin 2 (apoLp2) and cytochrome p450 (CYPJ92), the ribosomal internal transcribed spacer region (ITS) and the mitochondrial cytochrome c oxidase (COI) barcoding region. Nuclear genes apoLp2 and CYPJ92 were unable to differentiate between species Ae. bromeliae and Ae. lilii due to ancestral lineage sorting, while ITS sequence data provided clear topological separation on a phylogeny. The standard COI barcoding region was shown to be subject to species introgression and unable to clearly distinguish the two taxa. Here we present a reliable direct PCR-based method for differentiation of the vector species Ae. bromeliae from its isomorphic, sympatric and non-biomedically important sister taxon, Ae. lilii, based on the ITS region. Using molecular species verification, we describe novel immature habitats for Ae. lilii and report both sympatric and allopatric populations. Whereas only Ae. lilii is found in the Republic of Benin and only Ae. bromeliae in Tanzania, both species are sympatric in Uganda. CONCLUSIONS/SIGNIFICANCE: Our accurate identification method will allow informed distribution and detailed ecological studies that will facilitate assessment of arboviral disease risk and development of future targeted vector control. PMID- 26641862 TI - Learning-Dependent Plasticity of the Barrel Cortex Is Impaired by Restricting GABA-Ergic Transmission. AB - Experience-induced plastic changes in the cerebral cortex are accompanied by alterations in excitatory and inhibitory transmission. Increased excitatory drive, necessary for plasticity, precedes the occurrence of plastic change, while decreased inhibitory signaling often facilitates plasticity. However, an increase of inhibitory interactions was noted in some instances of experience-dependent changes. We previously reported an increase in the number of inhibitory markers in the barrel cortex of mice after fear conditioning engaging vibrissae, observed concurrently with enlargement of the cortical representational area of the row of vibrissae receiving conditioned stimulus (CS). We also observed that an increase of GABA level accompanied the conditioning. Here, to find whether unaltered GABAergic signaling is necessary for learning-dependent rewiring in the murine barrel cortex, we locally decreased GABA production in the barrel cortex or reduced transmission through GABAA receptors (GABAARs) at the time of the conditioning. Injections of 3-mercaptopropionic acid (3-MPA), an inhibitor of glutamic acid decarboxylase (GAD), into the barrel cortex prevented learning induced enlargement of the conditioned vibrissae representation. A similar effect was observed after injection of gabazine, an antagonist of GABAARs. At the behavioral level, consistent conditioned response (cessation of head movements in response to CS) was impaired. These results show that appropriate functioning of the GABAergic system is required for both manifestation of functional cortical representation plasticity and for the development of a conditioned response. PMID- 26641863 TI - Estimating actigraphy from motion artifacts in ECG and respiratory effort signals. AB - Recent work in unobtrusive sleep/wake classification has shown that cardiac and respiratory features can help improve classification performance. Nevertheless, actigraphy remains the single most discriminative modality for this task. Unfortunately, it requires the use of dedicated devices in addition to the sensors used to measure electrocardiogram (ECG) or respiratory effort. This paper proposes a method to estimate actigraphy from the body movement artifacts present in the ECG and respiratory inductance plethysmography (RIP) based on the time frequency analysis of those signals. Using a continuous wavelet transform to analyze RIP, and ECG and RIP combined, it provides a surrogate measure of actigraphy with moderate correlation (for ECG+RIP, rho = 0.74, p < 0.001) and agreement (mean bias ratio of 0.94 and 95% agreement ratios of 0.11 and 8.45) with reference actigraphy. More important, it can be used as a replacement of actigraphy in sleep/wake classification: after cross-validation with a data set comprising polysomnographic (PSG) recordings of 15 healthy subjects and 25 insomniacs annotated by an external sleep technician, it achieves a statistically non-inferior classification performance when used together with respiratory features (average kappa of 0.64 for 15 healthy subjects, and 0.50 for a dataset with 40 healthy and insomniac subjects), and when used together with respiratory and cardiac features (average kappa of 0.66 for 15 healthy subjects, and 0.56 for 40 healthy and insomniac subjects). Since this method eliminates the need for a dedicated actigraphy device, it reduces the number of sensors needed for sleep/wake classification to a single sensor when using respiratory features, and to two sensors when using respiratory and cardiac features without any loss in performance. It offers a major benefit in terms of comfort for long-term home monitoring and is immediately applicable for legacy ECG and RIP monitoring devices already used in clinical practice and which do not have an accelerometer built-in. PMID- 26641864 TI - Empiric and creative: Are these opposed? AB - We feel proud that Families, Systems, and Health disseminates different ways of knowing, and different ways of influencing thought: empiric work such as research papers and conceptual papers in contrast to creative work such as personal narrative, poetry, and 55-word stories. In this issue, we feature an interview with Dr. Julie Phillips, a family physician, scholar, and poet, who has contributed both research papers and creative manuscripts to the medical literature. Our commitment to publishing creative writing is balanced by our longstanding pursuit of scientific knowledge, which also requires creative thinking. In this issue, three knowledgeable scholars and members of our discipline set forth a call for papers for a special issue. Jodi Polaha, Ph.D., Jennifer S. Funderburk, Ph.D., and Deborah Cohen, Ph.D. will be the guest editors of a future issue blending two goals. We want to help our readers learn how to study their innovations and describe their learning so others can benefit. This special issue of Families, Systems, and Health seeks contributions from authors willing to help others learn to generate generalizable learning. In the process of doing this, we hope they will share the results of their studies to improve, implement, and disseminate integrated health care. (PsycINFO Database Record PMID- 26641865 TI - A call to engage youth in health research. AB - Community-based participatory research (CBPR) is characterized by its collaborative efforts between professional researchers and lay community members to design, implement, and iteratively evaluate interventions. This approach creates knowledge and improves practice in ways that reflect the collective wisdom and expertise of all involved stakeholders. It represents a significant departure from conventional "top down" methods that define "collaboration" as professionals working with each other-but not with patients and families. It is our position, however, that these exciting developments are only most visible in adult medicine. We believe that it is important to engage youth in health-related CBPR for three primary reasons which are provided in this article. Examples of youth-engagement in health research are also provided. It is important that we do not leave our youth on the sidelines as we advance health care research. During this critical time in health care, we must endeavor to engage our youth as active stakeholders. As we use methods that bridge our professional expertise with teens' lived experience and wisdom, we can create sustainable interventions that are effective in preventing or mitigating the conditions that weigh most heavily on us all. (PsycINFO Database Record PMID- 26641866 TI - Profile of Julie Phillips, MD, MPH: Family physician, medical educator, researcher, poet. AB - Dr. Julie Phillips, an Associate Professor of Family Medicine at Michigan State University College of Human Medicine, has contributed several poems to Families, Systems, and Health over the last 2 years. This month's issue features her fourth poem in this journal, titled "Autumn Chores" (Phillips, 2015). We were interested in learning more about Julie's creative writing, why she writes poetry, how she balances writing and a demanding academic medical career, and what she hopes her poems might contribute to clinical practice and medical education. Colleen Fogarty interviewed her to find out the answers in this article. Julie's poems are indeed, as she says, carved from small moments in time, but they have a disproportionately large emotional impact. Her poems tackle issues such as the tension between medical and parental authority; professional boundaries; worklife balance; the still-gaping holes in our health care system; and what it means to care for others. To read her work, please search the journal index. (PsycINFO Database Record PMID- 26641867 TI - Autumn chores. AB - The author presents a poem about serving her patients. (PsycINFO Database Record PMID- 26641871 TI - Transparency. AB - This poem focuses on a patient who was suffering but whose physicians were optimistic for recovery. The author-physician saw the degree of suffering and made the patient's DNR, ending the suffering. The author expresses the need for complete honesty. (PsycINFO Database Record PMID- 26641872 TI - No, thank YOU. AB - This poem focuses on the positive outcome of saying no to a patient regarding her controlled refill request. (PsycINFO Database Record PMID- 26641873 TI - "It's just one of those things that happens". AB - I thought this prenatal visit would be like any other. But then I read the patient's name-Rosa. Six months earlier, Rosa had left Minnesota with her husband and kids to visit their home and family in Mexico. Their 18-month-old, Manuelo, had been dying. He was diagnosed with the neurodegenerative condition Tay-Sachs disease. She had a second pregnancy that developed normally and I worried. Two days later, her baby, Luz was in my clinic and a blood test showed she had Tay Sachs disease. Luz died on the way home after two days after Rosa' delivered her next baby. Rosa believed U.S. doctors were wrong. Manuelo didn't have Tay-Sachs. Manuelo's difficulties were from mal de ojo-the evil eye. Rosa told me that they had stopped Manuelo's antiseizure medications a month before his death, and he had seemed better, almost rolling over again. This improvement was strong evidence that mal de ojo had caused his problems. But it had been discovered too late, so Manuelo had died. Caught between wanting to respect their beliefs and worrying about the baby, I probed for any doubt in Rosa's thinking. During their last clinic visit, I asked Rosa how she understood what had happened to Manuelo and Luz. She still believed mal de ojo was responsible. It has been 9 years since that farewell. Recently, I heard from Rosa's extended family in Minnesota that Rosa, Pedro, and their kids are well and plan to return to Minnesota this year. I am looking forward to seeing them. My existence as a physician is dependent on and continually shaped by the patients and families that come to me for care. There is a lot in that process that is not in my control. For me, caring for Rosa and her family was "one of those things that happens," and something that has sculpted me into the physician that I am. (PsycINFO Database Record PMID- 26641875 TI - The next frontier: Bringing collaborative care to scale. AB - In my position as CEO of the Health Federation of Philadelphia (HFP), I am acutely aware of the effort required to implement practice transformation, including fully integrated behavioral health (IBH) and primary care. We integrate knowledge of our marketplace, best practices from the field, and the wisdom of our providers to achieve our practice goals. We have found this to be a key to the success of our advocacy, efficient replication, and rapid regional spread of IBH. Even when payment models, the other driving barrier to IBH, catch up and reflect a better fit with the demands of efficiently integrated, whole-person, teambased care, the challenges resulting from lack of implementation support will still exist. That's where the Collaborative Family Healthcare Association (CFHA) comes in. CFHA can be that centralized and reliable structure to help guide the planning and application of the essential core elements of integrated care: aligned systems, metrics and operations; patient and family centered approaches; workforce competencies; and strategies for stakeholder engagement. In spite of its influence, integrity, and accomplishments, CFHA is still a "too-well-kept secret." By embracing a focused approach, strategic partnerships, clear communication of our unique strengths and capabilities, and the collective might that exists within our own CFHA family, CFHA can grow and thrive and continue to lead the field of collaborative family health care. (PsycINFO Database Record PMID- 26641876 TI - Development and Psychometric Evaluation of an Instrument to Assess Cross-Cultural Competence of Healthcare Professionals (CCCHP). AB - BACKGROUND: Cultural competence of healthcare professionals (HCPs) is recognized as a strategy to reduce cultural disparities in healthcare. However, standardised, valid and reliable instruments to assess HCPs' cultural competence are notably lacking. The present study aims to 1) identify the core components of cultural competence from a healthcare perspective, 2) to develop a self-report instrument to assess cultural competence of HCPs and 3) to evaluate the psychometric properties of the new instrument. METHODS: The conceptual model and initial item pool, which were applied to the cross-cultural competence instrument for the healthcare profession (CCCHP), were derived from an expert survey (n = 23), interviews with HCPs (n = 12), and a broad narrative review on assessment instruments and conceptual models of cultural competence. The item pool was reduced systematically, which resulted in a 59-item instrument. A sample of 336 psychologists, in advanced psychotherapeutic training, and 409 medical students participated, in order to evaluate the construct validity and reliability of the CCCHP. RESULTS: Construct validity was supported by principal component analysis, which led to a 32-item six-component solution with 50% of the total variance explained. The different dimensions of HCPs' cultural competence are: Cross Cultural Motivation/Curiosity, Cross-Cultural Attitudes, Cross-Cultural Skills, Cross-Cultural Knowledge/Awareness and Cross-Cultural Emotions/Empathy. For the total instrument, the internal consistency reliability was .87 and the dimension's Cronbach's alpha ranged from .54 to .84. The discriminating power of the CCCHP was indicated by statistically significant mean differences in CCCHP subscale scores between predefined groups. CONCLUSIONS: The 32-item CCCHP exhibits acceptable psychometric properties, particularly content and construct validity to examine HCPs' cultural competence. The CCCHP with its five dimensions offers a comprehensive assessment of HCPs' cultural competence, and has the ability to distinguish between groups that are expected to differ in cultural competence. This instrument can foster professional development through systematic self-assessment and thus contributes to improve the quality of patient care. PMID- 26641878 TI - Climate Impact and Economic Feasibility of Solar Thermochemical Jet Fuel Production. AB - Solar thermochemistry presents a promising option for the efficient conversion of H2O and CO2 into liquid hydrocarbon fuels using concentrated solar energy. To explore the potential of this fuel production pathway, the climate impact and economic performance are analyzed. Key drivers for the economic and ecological performance are thermochemical energy conversion efficiency, the level of solar irradiation, operation and maintenance, and the initial investment in the fuel production plant. For the baseline case of a solar tower concentrator with CO2 capture from air, jet fuel production costs of 2.23 ?/L and life cycle greenhouse gas (LC GHG) emissions of 0.49 kgCO2-equiv/L are estimated. Capturing CO2 from a natural gas combined cycle power plant instead of the air reduces the production costs by 15% but leads to LC GHG emissions higher than that of conventional jet fuel. Favorable assumptions for all involved process steps (30% thermochemical energy conversion efficiency, 3000 kWh/(m(2) a) solar irradiation, low CO2 and heliostat costs) result in jet fuel production costs of 1.28 ?/L at LC GHG emissions close to zero. Even lower production costs may be achieved if the commercial value of oxygen as a byproduct is considered. PMID- 26641877 TI - A culture-brain link: Negative age stereotypes predict Alzheimer's disease biomarkers. AB - Although negative age stereotypes have been found to predict adverse outcomes among older individuals, it was unknown whether the influence of stereotypes extends to brain changes associated with Alzheimer's disease. To consider this possibility, we drew on dementia-free participants, in the Baltimore Longitudinal Study of Aging, whose age stereotypes were assessed decades before yearly magnetic resonance images and brain autopsies were performed. Those holding more negative age stereotypes earlier in life had significantly steeper hippocampal volume loss and significantly greater accumulation of neurofibrillary tangles and amyloid plaques, adjusting for relevant covariates. These findings suggest a new pathway to identifying mechanisms and potential interventions related to the pathology of Alzheimer's disease. PMID- 26641880 TI - Multifunctional Pt(II) Reagents: Covalent Modifications of Pt Complexes Enable Diverse Structural Variation and In-Cell Detection. AB - To enhance the functionality of Pt-based reagents, several strategies have been developed that utilize Pt compounds modified with small, reactive handles. This Account encapsulates work done by us and other groups regarding the use of Pt(II) compounds with reactive handles for subsequent elaboration with fluorophores or other functional moieties. Described strategies include the incorporation of substituents for well-known condensation or nucleophilic displacement-type reactions and their use, for example, to tether spectroscopic handles to Pt reagents for in vivo investigation. Other chief uses of displacement-type reactions have included tethering various small molecules exhibiting pharmacological activity directly to Pt, thus adding synergistic effects. Click chemistry-based ligation techniques have also been applied, primarily with azide- and alkyne-appended Pt complexes. Orthogonally reactive click chemistry reactions have proven invaluable when more traditional nucleophilic displacement reactions induce side-reactivity with the Pt center or when systematic functionalization of a larger number of Pt complexes is desired. Additionally, a diverse assortment of Pt-fluorophore conjugates have been tethered via click chemistry conjugation. In addition to providing a convenient synthetic path for diversifying Pt compounds, the use of click-capable Pt complexes has proved a powerful strategy for postbinding covalent modification and detection with fluorescent probes. This strategy bypasses undesirable influences of the fluorophore camouflaged as reactivity due to Pt that may be present when detecting preattached Pt fluorophore conjugates. Using postbinding strategies, Pt reagent distributions in HeLa and lung carcinoma (NCI-H460) cell cultures were observed with two different azide-modified Pt compounds, a monofunctional Pt(II)-acridine type and a difunctional Pt(II)-neutral complex. In addition, cellular distribution was observed with an alkyne-appended difunctional Pt(II)-neutral complex analogous in structure to the aforementioned difunctional azide-Pt(II) reagent. In all cases, significant accumulation of Pt in the nucleolus of cells was observed, in addition to broader localization in the nucleus and cytoplasm of the cell. Using the same strategy of postbinding click modification with fluorescent probes, Pt adducts were detected and roughly quantified on rRNA and tRNA from Pt-treated Saccharomyces cerevisiae; rRNA adducts were found to be relatively long-lived and not targeted for immediate degradation. Finally, the utility and feasibility of the alkyne-appended Pt(II) compound has been further demonstrated with a turn-on fluorophore, dansyl azide, in fluorescent detection of DNA in vitro. In all, these modifications utilizing reactive handles have allowed for the diversification of new Pt reagents, as well as providing cellular localization information on the modified Pt compounds. PMID- 26641879 TI - Work Stress and Metabolic Syndrome in Police Officers. A Prospective Study. AB - OBJECTIVE: The aim of this longitudinal study was to evaluate the association between occupational stress and metabolic syndrome (MetS) in a rapid response police unit. METHOD: Work-related stress was continuously monitored during the 5 year period with both the Demand-Control-Support (DCS) and the Effort-Reward Imbalance (ERI) models. Blood pressure, body mass index (BMI), waist circumference, triglycerides, HDL-cholesterol, and fasting blood glucose were measured at baseline in January 2009, and in January 2014. 234 out of 290 police officers (81%) completed the follow-up. RESULTS: The majority of police officers had high stress levels. At follow-up, police officers in the highest quartile of stress had significantly higher mean levels of triglycerides, and lower levels of HDL-cholesterol than their colleagues in the lowest quartile. Police officers with high stress had an increased adjusted risk of developing MetS (aOR = 2.68; CI95% = 1.08-6.70), and hypertriglyceridemia (aOR = 7.86; CI95 = 1.29-48.04). Demand and Effort were significant predictors of MetS. CONCLUSION: Our study supports the hypothesis that work-related stress induces MetS, particularly through its effects on blood lipids. Future longitudinal studies with continuous monitoring of stress levels will definitively confirm this hypothesis. PMID- 26641882 TI - Structure and Dynamics of NaCl Ion Pairing in Solutions of Water and Methanol. AB - Ion pairing can have profound effects upon the ionic strength of electrolyte solutions but is poorly understood in solutions containing more than one solvent. Herein a combined density functional theory and molecular dynamics approach is used to examine the effect of both methanol concentration and interionic distance upon the structure and dynamics within successive solvation shells of Na(+) and Cl(-) in water/methanol binary solutions. The structure and dynamics of the first and second solvation shells were studied along a reaction coordinate associated with ion pair formation using potential of mean force simulations. The lifetimes of the solvent-solvent hydrogen bonds become perturbed when the second solvation shells of the ions begin to interact. In contrast, the structural properties within the first and second solvation shells of the ions were found to be largely independent of both methanol concentration and interionic distance until a contact ion pair is formed. Thus, as the ions are brought together, the effect of the opposing ion manifests itself in the solvation dynamics before any structural changes are observed. As anticipated based upon the decreased dielectric constant of the binary solution, ion pair formation becomes energetically more favorable as the concentration of methanol increases. PMID- 26641881 TI - Surfactant Proteins SP-A and SP-D Modulate Uterine Contractile Events in ULTR Myometrial Cell Line. AB - Pulmonary surfactant proteins SP-A and SP-D are pattern recognition innate immune molecules. However, there is extrapulmonary existence, especially in the amniotic fluid and at the feto-maternal interface. There is sufficient evidence to suggest that SP-A and SP-D are involved in the initiation of labour. This is of great importance given that preterm birth is associated with increased mortality and morbidity. In this study, we investigated the effects of recombinant forms of SP A and SP-D (rhSP-A and rhSP-D, the comprising of trimeric lectin domain) on contractile events in vitro, using a human myometrial cell line (ULTR) as an experimental model. Treatment with rhSP-A or rhSP-D increased the cell velocity, distance travelled and displacement by ULTR cells. rhSP-A and rhSP-D also affected the contractile response of ULTRs when grown on collagen matrices showing reduced surface area. We investigated this effect further by measuring contractility-associated protein (CAP) genes. Treatment with rhSP-A and rhSP-D induced expression of oxytocin receptor (OXTR) and connexin 43 (CX43). In addition, rhSP-A and rhSP-D were able to induce secretion of GROalpha and IL-8. rhSP-D also induced the expression of IL-6 and IL-6 Ra. We provide evidence that SP-A and SP-D play a key role in modulating events prior to labour by reconditioning the human myometrium and in inducing CAP genes and pro inflammatory cytokines thus shifting the uterus from a quiescent state to a contractile one. PMID- 26641883 TI - Free Form Deformation-Based Image Registration Improves Accuracy of Traction Force Microscopy. AB - Traction Force Microscopy (TFM) is a widespread method used to recover cellular tractions from the deformation that they cause in their surrounding substrate. Particle Image Velocimetry (PIV) is commonly used to quantify the substrate's deformations, due to its simplicity and efficiency. However, PIV relies on a block-matching scheme that easily underestimates the deformations. This is especially relevant in the case of large, locally non-uniform deformations as those usually found in the vicinity of a cell's adhesions to the substrate. To overcome these limitations, we formulate the calculation of the deformation of the substrate in TFM as a non-rigid image registration process that warps the image of the unstressed material to match the image of the stressed one. In particular, we propose to use a B-spline -based Free Form Deformation (FFD) algorithm that uses a connected deformable mesh to model a wide range of flexible deformations caused by cellular tractions. Our FFD approach is validated in 3D fields using synthetic (simulated) data as well as with experimental data obtained using isolated endothelial cells lying on a deformable, polyacrylamide substrate. Our results show that FFD outperforms PIV providing a deformation field that allows a better recovery of the magnitude and orientation of tractions. Together, these results demonstrate the added value of the FFD algorithm for improving the accuracy of traction recovery. PMID- 26641884 TI - Fatigue in Primary Biliary Cirrhosis: Prevalence, Pathogenesis and Management. AB - Fatigue is a significant problem in approximately 50% of primary biliary cirrhosis (PBC) patients, with 20% of all patients experiencing significant or life-altering fatigue. Large-scale population studies show that fatigue has a major impact on quality of life (QoL) in PBC, and that it disproportionately affects younger patients. The presence of social dysfunction that accompanies fatigue appears to be a major factor in determining whether fatigue of a particular severity impacts on QoL. The pathogenesis of fatigue in PBC remains unclear, although it is unrelated to the severity of underlying disease and is unresponsive to ursodeoxycholic acid. Perhaps, unsurprisingly, it appears to be complex in origin, probably multifactorial in the majority of patients and associated with depression, autonomic dysfunction and sleep disturbance. Clinically, fatigue has both central and peripheral components. The central component is associated with cognitive impairment and sleep disturbance and characterised by neurophysiological abnormalities of activation and facilitation, together with CNS changes. Peripheral fatigue is associated with muscle dysfunction and an inability to sustain exercise. One hypothesis is that the central processes result directly from cholestasis, which impacts autonomic centres in the brain; these processes then regulate peripheral muscle perfusion, leading to systemic peripheral effects. At present, there is no specific drug therapy for fatigue in PBC and no significant improvement following transplantation. In managing patients with fatigue, understanding their situation is crucial and advice regarding pacing and maintaining social interactions is critical. Most important of all is an understanding of the impact this symptom has on patients' lives and an empathetic clinical interaction. PMID- 26641885 TI - Baseline Assessment of Net Calcium Carbonate Accretion Rates on U.S. Pacific Reefs. AB - This paper presents a comprehensive quantitative baseline assessment of in situ net calcium carbonate accretion rates (g CaCO3 cm(-2) yr(-1)) of early successional recruitment communities on Calcification Accretion Unit (CAU) plates deployed on coral reefs at 78 discrete sites, across 11 islands in the central and south Pacific Oceans. Accretion rates varied substantially within and between islands, reef zones, levels of wave exposure, and island geomorphology. For forereef sites, mean accretion rates were the highest at Rose Atoll, Jarvis, and Swains Islands, and the lowest at Johnston Atoll and Tutuila. A comparison between reef zones showed higher accretion rates on forereefs compared to lagoon sites; mean accretion rates were also higher on windward than leeward sites but only for a subset of islands. High levels of spatial variability in net carbonate accretion rates reported herein draw attention to the heterogeneity of the community assemblages. Percent cover of key early successional taxa on CAU plates did not reflect that of the mature communities present on surrounding benthos, possibly due to the short deployment period (2 years) of the experimental units. Yet, net CaCO3 accretion rates were positively correlated with crustose coralline algae (CCA) percent cover on the surrounding benthos and on the CAU plates, which on average represented >70% of the accreted material. For foreeefs and lagoon sites combined CaCO3 accretion rates were statistically correlated with total alkalinity and Chlorophyll-a; a GAM analysis indicated that SiOH and Halimeda were the best predictor variables of accretion rates on lagoon sites, and total alkalinity and Chlorophyll-a for forereef sites, demonstrating the utility of CAUs as a tool to monitor changes in reef accretion rates as they relate to ocean acidification. This study underscores the pivotal role CCA play as a key benthic component and supporting actively calcifying reefs; high Mg-calcite exoskeletons makes CCA extremely susceptible changes in ocean water pH, emphasizing the far reaching threat that ocean acidification poses to the ecological function and persistence of coral reefs worldwide. PMID- 26641887 TI - Lyme disease in Poland - A serious problem? AB - PURPOSE: We evaluated the clinical picture of patients hospitalized with Lyme disease (LD). Additionally, we analyzed the possible cause of sudden rise in LD incidence in Poland. MATERIALS AND METHODS: We retrospectively analyzed medical documentation of patients admitted to the Department of Infectious Diseases and Neuroinfections, Medical University in Bialystok in 2013 with suspicion of LD. The collected data featured patients' age, gender, occupation, symptoms, clinical form of LD and final diagnosis. Additionally 38 patients with diagnosed LD and chronic joint pain, with no improvement after previous antibiotic treatment, completed the survey. RESULTS: In 2013 overall 378 patients were admitted to our Department with suspicion of LD. Neuroborreliosis (NB) was confirmed in 10 out of 42 patients. Acrodermatitis chronica atrophicans (ACA) was confirmed in 5 cases. As far as patients with joint pains are concerned - in 4 cases Lyme arthritis (LA) was diagnosed, in 174 the serology and clinical symptoms indicated possibility of active infection, in 153 patients no features of active infection were found. The majority of surveyed patients had BMI over 25, they suffered from many chronic diseases, e.g. osteoarthrosis, hypertension, diabetes. CONCLUSIONS: The reported incidence of LD in Poland, in our opinion, may be biased by overreporting and overdiagnosis. Nonspecific musculoskeletal and joint pain are the most frequent cause of LD suspicion and hospitalization. There is a necessity of better tests for active LD confirmation (especially in patients with musculoskeletal pain) as seroprevalence of anti Borrelia burgdorferi antibodies is high in endemic regions. PMID- 26641886 TI - Stable Evans Blue Derived Exendin-4 Peptide for Type 2 Diabetes Treatment. AB - In the treatment of type 2 diabetes mellitus, it is very important to develop therapeutics with prolonged circulation half-life. Exendin-4 is a glucagon like peptide-1 receptor (GLP-1R) agonist that has been modified in different ways for imaging insulinoma and for treating type-2 diabetes. In this work, we synthesized a maleimide derivative of truncated Evans blue dye (MEB-C3-Mal) to conjugate with (Cys(40))exendin-4 to obtain a highly stable MEB-C3-(Cys(40))exendin-4 (denoted as Abextide II). Through in situ binding with endogenous albumin, Abextide II lowers blood glucose level and prolongs the hypoglycemic effect in a type 2 diabetes mouse model more than the FDA approved Albiglutide. PMID- 26641888 TI - Elevation of CA19-9-Related Novel Marker, Core 1 Sialyl Lewis A, in Sera of Adenocarcinoma Patients Verified by a SRM-Based Method. AB - We have attempted to identify a novel glycan tumor marker. Pyridylaminated (PA) O glycans were prepared from sera, and the corresponding O-glycan profiles were constructed by HPLC separation. By comparing the serum O-glycan profiles from healthy controls with those of cancer patients, we identified a marker candidate, core 1 sialyl Lewis A (NeuAcalpha2-3Galbeta1-3(Fucalpha1-4)GlcNAcbeta1-3Gal) (abbreviated C1SLA), whose concentration appeared to be weakly correlated with CA19-9 values. To quantify this glycan, we developed a selected reaction monitoring (SRM) assay that used a stable isotope, tetradeuterium-labeled pyridylamino (d4-PA) glycan, as an internal standard. The analyte (d0-PA-C1SLA) and the internal standard (d4-PA-C1SLA) were subjected to SRM analyses after two types of HPLC separation. Serum levels of C1SLA, determined as the relative ratio to total O-glycans, were then measured. These analyses revealed that (i) C1SLA is a CA19-9-related glycan, (ii) the mean value of C1SLA in normal controls is 3.41 ppm, (iii) the level of C1SLA was significantly higher in samples of stages II-IV stomach cancers (P = 0.0036) as well as pancreatic cancers (P < 0.0001) compared to that of normal controls, (iv) the relationship between C1SLA and CA19-9 varies from poor to weak depending on the cancer, and (v) C1SLA could be valuable as a diagnostic adjunct for cancer. PMID- 26641889 TI - Gemini Surfactants Based on Bis-Imidazolium Alkoxy Derivatives as Effective Agents for Delivery of Nucleic Acids: A Structural and Spectroscopic Study. AB - The success rate of gene therapy depends on the efficient transfection of genetic material into cells. The golden mean between harmlessness and high effectiveness can be provided by synthetic lipid-like molecules that are similar to the components of biological membranes. Cationic gemini surfactants are one such moiety and because of their favourable physicochemical properties (double positive electric charge, reduced toxicity, low values of critical micelle concentration), they show great potential as delivery system components for genetic material in gene therapy. The aim of this study was to investigate the process of the complexation of cationic gemini surfactants with nucleic acids: double-stranded DNA of different sizes (21 bp, ~185 bp, ~20 kbp) and siRNA (21 bp). The tested series of dicationic surfactants consists of bis-imidazolium quaternary salts with varying lengths of hydrophobic side chains (m = 5, 6, 7, 8, 9, 11, 12, 14, 16). On the basis of the data obtained by circular dichroism spectroscopy and electrophoresis, we concluded that the studied gemini surfactants with long side chains effectively bind nucleic acids at low concentrations, which leads to the formation of stable lipoplexes. Images obtained by atomic force microscopy also confirmed the formation of vesicular structures, i.e., complexes between DNA and surfactants. The cytotoxicity of selected surfactants was also tested on HeLa cells. The surfactant toxicity significantly depends on surfactant geometry (the length of hydrophobic chain). PMID- 26641890 TI - Energetics of an rf SQUID Coupled to Two Thermal Reservoirs. AB - We study energetics of a Josephson tunnel junction connecting a superconducting loop pierced by an external magnetic flux (an rf SQUID) and coupled to two independent thermal reservoirs of different temperature. In the framework of the theory of quantum dissipative systems, we analyze energy currents in stationary states. The stationary energy flow can be periodically modulated by the external magnetic flux exemplifying the rf SQUID as a quantum heat interferometer. We also consider the transient regime and identify three distinct regimes: monotonic decay, damped oscillations and pulse-type behavior of energy currents. The first two regimes can be controlled by the external magnetic flux while the last regime is robust against its variation. PMID- 26641891 TI - Are Husbands Involving in Their Spouses' Utilization of Maternal Care Services?: A Cross-Sectional Study in Yangon, Myanmar. AB - INTRODUCTION: Husbands can play a crucial role in pregnancy and childbirth, especially in patriarchal societies of developing countries. In Myanmar, despite the critical influence of husbands on the health of mothers and newborns, their roles in maternal health have not been well explored. Therefore, the aim of this study was to identify the factors associated with husbands' involvement in maternal health in Myanmar. This study also examined the associations between husbands' involvement and their spouses' utilization of maternal care services during antenatal, delivery and postnatal periods. METHODS: A community-based, cross sectional study was conducted with 426 husbands in Thingangyun Township, Yangon, Myanmar. Participants were husbands aged 18 years or older who had at least one child within two years at the time of interview. Face to face interviews were conducted using a pretested structured questionnaire. Factors associated with the characteristics of husband's involvement as well as their spouses' utilization of maternal care services were analyzed by multivariable logistic regression models. RESULTS: Of 426 husbands, 64.8% accompanied their spouses for an antenatal visit more than once while 51.6% accompanied them for a postnatal visit. Husbands were major financial supporters for both antenatal (95.8%) and postnatal care (68.5%). Overall, 69.7% were involved in decision making about the place of delivery. Regarding birth preparedness, the majority of husbands prepared for skilled birth attendance (91.1%), delivery place (83.6%), and money saving (81.7%) before their spouses gave birth. In contrast, fewer planned for a potential blood donor (15.5%) and a safe delivery kit (21.1%). In the context of maternal health, predictors of husband's involvement were parity, educational level, type of marriage, decision making level in family, exposure to maternal health education and perception of risk during pregnancy and childbirth. Increased utilization of maternal health services was found among spouses of husbands who accompanied them to antenatal visits (AOR 5.82, 95% CI, 3.34-10.15) and those who had a well birth plan (AOR 2.42, 95% CI, 1.34-4.39 for antenatal visit and AOR 2.88, 95% CI, 1.52-5.47 for postnatal visit). CONCLUSION: The majority of husbands supported their spouses' maternal care services use financially; however, they were less involved in birth preparedness and postnatal care. Exposure to maternal health education and their maternal health knowledge were main predictors of their involvement. Women were more likely to use maternal care services when their husbands company them for ANC visits and had a well birth plan in advance. PMID- 26641893 TI - Wavelet Transforms for Determining Time-Dependent Vibrational Frequencies. AB - Fourier transforms of autocorrelation functions are typically used to calculate spectra and transport properties, but they require oscillations periodic in time (a stationary time series). The time-scale relation revealed by a wavelet transform (WT), on the other hand, gives a relation between time and pseudo frequency that is used here to calculate vibrational frequencies for HONO and to detect the molecule's trans-cis conformational change in ab initio molecular dynamics simulations. Thus, the WT shows potential for giving new insights into nonstationary time series frequently encountered in chemistry and physics. PMID- 26641892 TI - Epitope-Based Vaccine Target Screening against Highly Pathogenic MERS-CoV: An In Silico Approach Applied to Emerging Infectious Diseases. AB - Middle East respiratory syndrome coronavirus (MERS-CoV) with pandemic potential is a major worldwide threat to public health. However, vaccine development for this pathogen lags behind as immunity associated with protection is currently largely unknown. In this study, an immunoinformatics-driven genome-wide screening strategy of vaccine targets was performed to thoroughly screen the vital and effective dominant immunogens against MERS-CoV. Conservancy and population coverage analysis of the epitopes were done by the Immune Epitope Database. The results showed that the nucleocapsid (N) protein of MERS-CoV might be a better protective immunogen with high conservancy and potential eliciting both neutralizing antibodies and T-cell responses compared with spike (S) protein. Further, the B-cell, helper T-cell and cytotoxic T lymphocyte (CTL) epitopes were screened and mapped to the N protein. A total of 15 linear and 10 conformal B cell epitopes that may induce protective neutralizing antibodies were obtained. Additionally, a total of 71 peptides with 9-mer core sequence were identified as helper T-cell epitopes, and 34 peptides were identified as CTL epitopes. Based on the maximum HLA binding alleles, top 10 helper T-cell epitopes and CTL epitopes that may elicit protective cellular immune responses against MERS-CoV were selected as MERS vaccine candidates. Population coverage analysis showed that the putative helper T-cell epitopes and CTL epitopes could cover the vast majority of the population in 15 geographic regions considered where vaccine would be employed. The B- and T-cell stimulation potentials of the screened epitopes is to be further validated for their efficient use as vaccines against MERS-CoV. Collectively, this study provides novel vaccine target candidates and may prompt further development of vaccines against MERS-CoV and other emerging infectious diseases. PMID- 26641894 TI - Infrared Spectroscopy of N-Methylacetamide Revisited by ab Initio Molecular Dynamics Simulations. AB - The density functional theory based molecular dynamics simulation method ("Car Parrinello") was applied in a numerical study of the electronic properties, hydrogen bonding, and infrared spectroscopy of the trans and cis isomer of N methylacetamide in aqueous solution. A detailed analysis of the electronic structure of the solvated molecules, in terms of localized Wannier functions and Born atomic charges, is presented. Two schemes for the computation of the solute infrared absorption spectrum are investigated: In the first method the spectrum is determined by Fourier transforming the time correlation function of the solute dipole as determined from the Wannier function analysis. The second method uses instead the molecular current-current correlation function computed from the Born charges and atomic velocities. The resulting spectral properties of trans- and cis-NMA are carefully compared to each other and to experimental results. We find that the two solvated isomers can be clearly distinguished by their infrared spectral profile in the 1000-2000 cm(-)(1) range. PMID- 26641895 TI - Exploring the Essential Dynamics of B-DNA. AB - The essential dynamics of different normal and chemically modified DNA duplexes pertaining to the B family have been extensively explored from molecular dynamics simulations using powerful data mining techniques. Some of them, which are presented here for the first time, might become standard, powerful tools to characterize the dynamical behavior of complex biomolecular structures such as nucleic acids. Their potential impact is illustrated by examining the extended trajectories sampled for the set of DNA duplexes considered in this study, which allows us to discuss the degree of conservation of the natural flexibility pattern of the different DNAs, which in specific cases contain severe chemical modifications. PMID- 26641896 TI - Theoretical Conformational Analysis for Neurotransmitters in the Gas Phase and in Aqueous Solution. Serotonin. AB - Conformational analyses have been performed for protonated serotonin in the gas phase, aqueous solution, and in the binding cavity of a 5-HT2A receptor model. DFT geometry optimizations have been performed in the gas phase at the B3LYP/6 31G* levels. Optimized calculations up to the B3LYP/6-311++G** level find two low energy gauche conformations separated by 8-10 kcal/mol barriers from a trans conformation with relative energy of about 6 kcal/mol. In aqueous solution as concluded from IEF-PCM/B3LYP/6-31G* and IEF-PCM/MP2/6-31G*//IEF-PCM/B3LYP/6-31G* continuum solvent calculations as well as Monte Carlo free energy perturbation simulations with explicit solvent molecules, those barriers decrease to 2-7 kcal/mol, while the two gauche and one trans conformers are within a 3 kcal/mol relative free energy range. The solute is strongly hydrated by about three water molecules around the -NH3(+) group and by one water molecule for each of the pyrrole and phenolic hydrogen atoms. Docking studies of the protonated ligand predicted both gauche and trans ligand conformers to favorably interact with the 5-HT2A receptor in its hypothesized binding cavity. The theoretical studies confirm the experimental results regarding strong interactions with the Asp155 and Ser159 residues (TM helix III) and the interactions of the indole ring with Phe, Trp, and Tyr side chains in TM V, VI, and VII helices within a 24 kcal/mol range for the relative interaction energies. PMID- 26641897 TI - Rationalization of the pi-sigma (Anti)aromaticity in All Metal Molecular Clusters. AB - A sigma-pi separation analysis of the energies in Al4Li4 reveals that the system is more pi-antiaromatic than the sigma-aromaticity in it. This is true also for C4H4 and Ga4Li4. Unlike C4H4 that has a very large component of pi antiaromaticity, for these all-metal clusters, these energy scales are comparable though pi-antiaromaticity is the major driving force for the distortion of the molecules from the square (sigma-aromatic) structure to the rectangular (pi antiaromatic) architecture. For the dianion Al4Li4(2)(-), the sigma-equalization prevails over the pi-distortion in Al4Li4, and for the dication Al4Li4(2+), pi equalization is the driving force for the square symmetric structure. PMID- 26641898 TI - Quantum Chemical Characterization of the Structural and Energetic Properties of HCN-BF3. AB - The structure, dipole moment, binding energy, and vibrational frequencies of HCN BF3 are investigated via 12 DFT methods as well as MP2, MC-QCISD, and MCG3 calculations. By comparing the DFT results to both experimental data and results from post-Hartree-Fock molecular orbital methods, we gauge the effectiveness of various density functionals in modeling this fairly weak donor-acceptor system. For structural data, B3PW91, B98, and mPWPW91 provide results that compare favorably with experiment. All DFT methods that yield a reasonable structure predict dipole moments that are only slightly larger than the experimental value by 0.1 to 0.2 D. Moreover, to ensure that a comparison of calculated (equilibrium) and experimental (vibrationally averaged) data is indeed valid for this system, the B-N distance potential is calculated using B3PW91, MP2, and MCG3, and the one-dimensional Schrodinger equation for motion along this bond stretching coordinate is solved to obtain vibrational energy levels, wave functions, and expectation values of the B-N distance and dipole moment. In every instance, average bond lengths differ by only a few thousandths of an angstrom from the corresponding equilibrium values, and dipole moments are unchanged to within hundredths of a debye. For vibrational frequencies, B3PW91 agrees most closely with gas-phase experimental data for BF3 and also with MP2 calculations of the BF3-localized modes in the complex; mPW1PW91 and B3LYP agree nearly as well. However, despite the effectiveness of DFT for structure, dipole moment, and vibrational frequencies, all DFT methods fail to predict a binding energy that compares favorably to the MCG3//MC-QCISD result of -5.7 kcal/mol. PMID- 26641899 TI - Quantitative Ranking of Crystal Packing Modes by Systematic Calculations on Potential Energies and Vibrational Amplitudes of Molecular Dimers. AB - Quantum chemical calculations including electron correlation and calculations with the density sums (Pixel) method have been performed on a variety of molecular dimers representing some frequently observed recognition modes in molecular condensed phases. Notwithstanding some individual fluctuations when different computational methods are used, there is a general agreement for the relative orders of magnitude. The results have been collected in a table that ranks the interaction energies and amplitudes of the energy wells for the recognition between molecular fragments, providing a quantitative guideline to assess the relative importance of hydrogen bonding, aromatic ring stacking, antiparallel arrangements of polar moieties, weak Coulombic C-H...X interactions, and dispersive interactions between nonpolar groups. Since the Pixel method naturally allows for a separation between Coulombic, dispersion, polarization, and repulsion energy contributions, their relative importance can be analyzed with respect to the chemical constitution of the interacting partners. The relevance of these results to the current ideas and methods of "crystal engineering" is discussed. PMID- 26641900 TI - An Efficient a Posteriori Treatment for Dispersion Interaction in Density Functional-Based Tight Binding. AB - The performance of density functional theory (DFT) (VWN-LDA, PBE-GGA, and B3LYP hybrid functionals), density-functional-based tight binding (DFTB), and ab initio methods [HF, MP2, CCSD, and CCSD(T)] for the treatment of London dispersion is investigated. Although highly correlated ab initio methods are capable of describing this phenomenon, if they are used with rather large basis sets, DFT methods are found to be inadequate for the description of H2/PAH (polycyclic aromatic hydrocarbon) interactions. As an alternative approach, an a posteriori addition of a van der Waals term to DFTB is proposed. This method provides results for H2/PAH interactions in close agreement with MP2 and higher-level ab initio methods. Bulk properties of graphite also compare well with the experimental data. PMID- 26641901 TI - Evaluation of Functionals O3LYP, KMLYP, and MPW1K in Comparison to B3LYP for Selected Transition-Metal Compounds. AB - We have investigated the performance of the hybrid density functionals O3LYP, KMLYP, and MPW1K in comparison to B3LYP for predicting geometrical parameters of selected transition-metal compounds. We used different combinations of ECPs and basis sets (Stuttgart/Dresden 1997, LANL2DZ, 6-31G(d), 6-311++G(d,p)) to analyze the effect on selected transition-metal compounds. B3LYP is superior to the other three density functionals for the split valence double-zeta basis set 6-31G(d), contrary to what was reported for organic reactions. But in combination with the split valence triple-zeta basis set 6-311++G(d,p) O3LYP was clearly superior to all the other functionals. LANL2DZ performed worse in every case. PMID- 26641902 TI - Highly Reduced Polyoxometalates: Ab Initio and DFT Study of [PMo8V4O40(VO)4](5)(.). AB - DFT and post Hartree-Fock calculations were carried out to characterize the electronic structure of the 10-electron-reduced [PMo8V4O40(VO)4](5)(-) polyoxometalate. This molecule may be viewed as a mixed-metal PMo8V4O40 Keggin structure capped with four VO units, in which the eight vanadiums form a ring. In mixed V/Mo clusters it is accepted that the first reductions occur at the V(5+) ions. The BP86 calculations on this modified Keggin anion reveal that the ground state is a septet with the six unpaired electrons delocalized over the eight V centers. The B3LYP calculations and especially the CASSCF technique modify the tendency of the BP86 method, thus reproducing the expected 8/2 distribution. The unpaired electrons residing in the eight vanadiums are antiferromagnetically coupled. PMID- 26641903 TI - A Resolution-Of-The-Identity Implementation of the Local Triatomics-In-Molecules Model for Second-Order Moller-Plesset Perturbation Theory with Application to Alanine Tetrapeptide Conformational Energies. AB - In this work, we incorporate the resolution-of-the-identity (RI) approximation into the theoretical framework of the local triatomics-in-molecules (TRIM) second order Moller-Plesset (MP2) perturbation theory model. The resultant model, RI TRIM MP2, emerges as a robust fourth-order methodology that extends the regime of practical MP2 calculations. With RI-TRIM MP2, correlation energy corrections can easily be obtained for systems that contain more than 125 heavy atoms with a computational timing cost less than those of the prerequisite self-consistent field procedure and popular density functional theory (DFT) alternatives. In this work, the chemical performance of RI-TRIM MP2 is numerically assessed against untruncated RI-MP2 and DFT (B3LYP) in determining the relative energies of 27 different alanine tetrapeptide conformations at the cc-pVXZ (X = D, T, and Q) levels and the results are T -> Q extrapolated to the complete basis set limit. As the quality of the basis set employed increases, we report a significant reduction in the error introduced by the RI-TRIM approximation; at the cc-pVDZ level, the root mean-square (RMS) relative error was found as 0.192 kcal/mol and is decreased to an almost negligible 0.040 kcal/mol at the T -> Q extrapolated complete basis set limit. Basis set dependence was investigated by computing the RMS (max) deviations from the extrapolated RI-MP2/cc-pV(TQ)Z data set found as 0.377 (0.944) kcal/mol (MP2/cc-pVTZ) and 0.250 (0.591) kcal/mol (TRIM MP2/cc pVTZ). These deviations are chemically significant when compared against the conformer energy differences, suggesting that to obtain reliably converged relative conformational energies, computations must be done using the cc-pVTZ and cc-pVQZ basis sets followed by extrapolation to the cc-pV(TQ)Z limit. The findings reported herein also provide the first computational evidence demonstrating that the TRIM model approaches exactness as the one-particle basis approaches completeness. PMID- 26641904 TI - The Rotational g Tensor as a Benchmark for Density-Functional Theory Calculations of Molecular Magnetic Properties. AB - The rotational g factor for a large number of organic compounds has been investigated with density-functional theory. Rapid convergence toward the basis set limit is ensured by the use of London atomic orbitals. A statistical analysis of the results has been carried out in comparison with accurate experimental data. It is shown that gradient-corrected and hybrid functionals reproduce experimental results most closely, with the Keal-Tozer KT2 functional being the most accurate. PMID- 26641905 TI - Modeling beta-Scission Reactions of Peptide Backbone Alkoxy Radicals: Backbone C C Bond Fission. AB - To model the C-C beta-scission reactions of backbone peptide alkoxy radicals, enthalpies and barriers for the fragmentation of four substituted alkoxy radicals have been calculated with a variety of ab initio molecular orbital theory and density functional theory procedures. The high-level methods examined include CBS QB3, variants of the G3 family, and W1. Simpler methods include HF, MP2, QCISD, B3-LYP, BMK, and MPW1K with a range of basis sets. We find that good accuracy can be achieved with the G3(MP2)//B3-LYP and G3X(MP2)-RAD methods. Lower-cost methods producing reasonable results are single-point energy calculations with UB3-LYP/6 311+G(3df,2p), RB3-LYP/6-311+G(3df,2p), UBMK/6-311+G(3df,2p), and RBMK/6 311+G(3df,2p) on geometries optimized with UB3-LYP/6-31G(d) or UBMK/6-31G(d). Heats of formation at 0 K for the alkoxy radicals and their fragmentation products were also calculated. We predict DeltafH0 values for the alkoxy radicals of -71.4 ((*)OCH2CH [Formula: see text] O), -102.5 ((*)OCH(CH3)CH [Formula: see text] O), -176.6 ((*)OCH(CH3)C(NH2) [Formula: see text] O), and -264.6 ((*)OC(CH3)(NHCH [Formula: see text] O)CH [Formula: see text] O) kJ mol(-)(1). For the fragmentation products NH2C((*)) [Formula: see text] O and CH( [Formula: see text] O)NHC(CH3) [Formula: see text] O, we predict DeltafH0 values of -5.9 kJ mol(-)(1) and -352.8 kJ mol(-)(1). PMID- 26641906 TI - Basis Set Requirements for Sulfur Compounds in Density Functional Theory: a Comparison between Correlation-Consistent, Polarized-Consistent, and Pople-Type Basis Sets. AB - We have investigated the SX (X = first- or second-row atom), SO2, and SO3 molecules employing the correlation-consistent (cc), the recently developed polarization-consistent (pc), and three Pople-type basis sets, in conjunction with the B3LYP functional. The results confirmed that the aug-pc basis sets represent a great contribution in terms of cost-benefits. In the case of the B3LYP functional, when employing the aug-pc-3 and aug-pc-4 basis sets, it is possible to obtain results that are of aug-cc-pV(5+d)Z and aug-cc-pV(6+d)Z quality, respectively, at a much lower cost. The estimations obtained employing smaller members of the family are of nearly double-zeta quality and do not provide reliable results. There is no basis set of quadruple-zeta quality among the polarized-consistent basis sets, although in terms of composition, the aug-pc 3 basis set is a QZ basis set. A precise estimation of the Kohn-Sham complete basis set (CBS) limit with the aug-pc-X basis sets is too difficult for the B3LYP functional because the infinity(aug-pc-4, aug-pc-3, aug-pc-2) extrapolation gives the same results as those of the aug-pc-4 basis set. This is in contrast with the results observed for ab initio methodologies for which the largest basis sets provided the best estimation of the CBS limit. In our opinion, the closest results to the B3LYP/CBS limit are expected to be those obtained with a two-point extrapolation employing the aug-cc-pV(X+d)Z (X = 5, 6) basis sets. The results obtained with this extrapolation are very close to those predicted by the infinity(aug-pc-3, aug-pc-2, aug-pc-1) extrapolation, and that provides a cheaper but more inaccurate alternative to estimate the CBS limit. Minor problems were found for the aug-pc-X basis sets and the B3LYP functional for molecules in which sulfur is bound to a very electronegative element, such as SO, SF, SO2, and SO3. For these molecules, the cc basis sets were demonstrated to be more useful. The importance of tight d functions was observed; the total atomization energy of SO2 employing the cc-pV6Z basis set is 1 kcal/mol lower than that obtained with the aug-cc-pV(6+d)Z basis set. PMID- 26641907 TI - Hydrogen Abstraction Acetylene Addition and Diels-Alder Mechanisms of PAH Formation: A Detailed Study Using First Principles Calculations. AB - Extensive ab initio Gaussian-3-type calculations of potential energy surfaces (PES), which are expected to be accurate within 1-2 kcal/mol, combined with statistical theory calculations of reaction rate constants have been applied to study various possible pathways in the hydrogen abstraction acetylene addition (HACA) mechanism of naphthalene and acenaphthalene formation as well as Diels Alder pathways to acenaphthalene, phenanthrene, and pyrene. The barrier heights; reaction energies; and molecular parameters of the reactants, products, intermediates, and transition states have been generated for all types of reactions involved in the HACA and Diels-Alder mechanisms, including H abstraction from various aromatic intermediates, acetylene addition to radical sites, ring closures leading to the formation of additional aromatic rings, elimination of hydrogen atoms, H disproportionation, C2H2 cycloaddition, and H2 loss. The reactions participating in various HACA sequences (e.g., Frenklach's, alternative Frenklach's, and Bittner and Howard's routes) are demonstrated to have relatively low barriers and high rate constants under combustion conditions. A comparison of the significance of different HACA mechanisms in PAH growth can be made in the future using PES and molecular parameters obtained in the present work. The results show that the Diels-Alder mechanism cannot compete with the HACA pathways even at high combustion temperatures, because of high barriers and consequently low reaction rate constants. The calculated energetic parameters and rate constants have been compared with experimental and theoretical data available in the literature. PMID- 26641908 TI - Double-Metal-Ion/Single-Metal-Ion Mechanisms of the Cleavage Reaction of Ribozymes: First-Principles Molecular Dynamics Simulations of a Fully Hydrated Model System. AB - The role of metal cations (Mg(2+)) in the cleavage reaction of fully hydrated RNA enzymes is investigated via Car-Parrinello calculations. We find that the action of two metal catalysts is the most efficient way to promote, on one hand, the proton abstraction from O(2)(')-H that triggers the nucleophilic attack and, on the other hand, the weakening and subsequent cleavage of the P-O(5)(') bond. The elimination of one of the two metal cations is shown to lead to an increase in the activation energy. Furthermore, we also find that an OH(-) included in the coordination shell of the Mg(2+) close to O(2)(') promotes the initial proton abstraction and prevents its transfer to the ribozyme in both single- and double metal-ion pathways, consistently with the experiment. This suggests that in real ribozyme systems, the double-metal-ion reaction mechanism in the presence of an OH(-) anion is favored with respect to single-metal-ion mechanisms. PMID- 26641909 TI - Potential Energy Surface Profile of the Oxygen Reduction Reaction on a Pt Cluster: Adsorption and Decomposition of OOH and H2O2. AB - Because of their essential roles on determining pathways of the oxygen reduction reaction (ORR), the adsorption behavior and decomposition of the radical OOH and hydrogen peroxide on Pt clusters (Ptn, n = 3, 6, and 10) are extensively investigated using density functional theory. Two types of adsorption of the radical OOH on Pt clusters are found. One-end adsorbed hydrogen peroxide H2O2, arising from reduction of adsorbed OOH, is also located on Pt3, with an adsorption energy of -0.63 eV, suggesting that the ORR may proceed via a series pathway generating H2O2 as an intermediate. However, since OOH readily decomposes on Pt3 into atop adsorbed atomic oxygen and hydroxyl with an activation energy of only ~0.25 eV, the OOR may take place preferentially via a direct pathway without H2O2 produced. A potential energy surface profile for the ORR is proposed, and the adsorption properties of other involved oxide species are characterized. PMID- 26641910 TI - Revisiting Hydrogen [1,5] Shifts in Cyclopentadiene and Cycloheptatriene as Bimolecular Reactions. AB - Hydrogen [1,5] shifts are pericyclic reactions and take place typically in 1,3 pentadiene. However, because of structure restriction, the symmetry-allowed thermal reactions of 1,3-cyclopentadiene (CPD) and 1,3,5-cycloheptatriene (CHT) suffer large energy barriers, DeltaU(?) = +26.9 kcal/mol and DeltaU(?) = +37.5 kcal/mol by density-functional theory (B3LYP/6-31G*) calculations, respectively. This theoretical study has shown that exo [4+2] and [6+4] cycloadduct dimers involve novel hydrogen-shift channels. After hydrogen migration, one-center adducts are obtained, which undergo Cope rearrangements leading to the second one center adducts. From the intermediates, reverse routes lead to CPD and CHT with [1,5] migrated hydrogens. A correlation between cycloadditions and [1,5] and [3,3] sigmatropic rearrangements in pericyclic reactions is also discussed. PMID- 26641911 TI - Predictions of Optical Excitations in Transition-Metal Complexes with Time Dependent-Density Functional Theory: Influence of Basis Sets. AB - The calculation of the absorption spectra of four families of transition-metal complexes (Ni(CO)4, MnO4(-), MF6 (M = Cr, Mo, W) and CpM(CO)2 (M = Rh, Ir)) has been undertaken to unravel the influence of basis sets onto excitation energies, oscillator strengths, and assignments. Three among the most common pseudopotentials, with the corresponding valence basis sets, and two all-electron basis sets have been used for the metal center description in the framework of the time dependent Density Functional Theory (TD-DFT). Our results show that this approach does not particularly depend on the basis set used on the metal atoms. Furthermore, the chosen functional PBE0 provides transitions in good agreement with experiments, and it provides an accuracy of about 0.3 eV, comparable to that of refined post-Hartree-Fock methods. PMID- 26641912 TI - Molecular Dynamics Study of a Surfactant Monolayer Adsorbed at the Air/Water Interface. AB - A constant volume and temperature (NVT) molecular dynamics (MD) simulation has been carried out to investigate the properties of a monolayer of monododecyl hexaethylene glycol (C12E6) adsorbed at the air/water interface at a surface coverage corresponding to that at its critical micelle concentration (55 A(2) per molecule). The simulated results have been found to agree reasonably well with available experimental data and with other simulation studies. The study shows that the long polar headgroups of the surfactants are more tilted toward the aqueous layer due to strong interaction between them and water. It has been shown that the surfactant monolayer strongly influences the translational and rotational mobility of interfacial water molecules. A drastic change in the dipolar reorientational motion of water molecules in the aqueous layer is observed with a small variation of distance from the surfactant headgroups. PMID- 26641913 TI - The Interaction of Coinage Metal Clusters with the MgO(100) Surface. AB - The results of a systematic study of the interaction of small coinage metal clusters (Mn, n = 1-3) and extended deposition (one and two MLs; ML = monolayer) with the regular and locally defected (Fs center and divacancy) neutral MgO(100) surface are presented. The calculations have been performed at the DFT level employing plane waves as a basis set and using a gradient-corrected exchange correlation functional (PW91). The adhesion energy along the group follows a trend that can be rationalized in terms of the strength and "stickiness" of the metallic bond, electrostatic polarization effects, and chemical interactions. Coinage metal dimers and trimers are absorbed on the regular surface in an upright position with little modification with respect to the gas-phase structure and can easily diffuse from site to site (in the case of trimers, also because of their fluxional character). In the case of extended deposition, the adhesion energy increases when passing from one to two MLs because of a "metal-on-top" stabilization mechanism. Neutral localized defects on the surface such as the Fs center (generated by a missing O atom) and the double vacancy (generated by a missing MgO dimer) act as strong trapping centers for small clusters and remarkably increase the adhesion of metal slabs to the surface in the case of extended deposition. At variance with the Fs center, the double vacancy induces a strong structural and energetic modification of the surrounding oxide lattice, varying also as a function of the metal deposition. A peculiar structural rearrangement consisting of the segregation of the metal slab into "islands" on the surface is observed in the case of one ML Cu and (to a lesser extent) Au. PMID- 26641914 TI - Intrinsic Relative Stabilities of the Neutral Tautomers of Arginine Side-Chain Models. AB - The specific protonation state of amino acids is crucial for the physicochemical properties of proteins and their biological functions. These protonation states influence, for instance, properties related to hydrogen bonding, solubility, and folding. pKa calculations for proteins are, therefore, important and require, in principle, a specification of the most stable protonated and deprotonated forms of each titratable group. This is complicated by the existence of multiple tautomers, like the five neutral tautomers of the guanidine moiety in arginine. In this study, the compounds N-methyl-guanidine and N-ethyl-guanidine were used to model the charged and all neutral protonation states of the arginine side chain. The relative stabilities of all five neutral tautomers were investigated systematically for the first time, using quantum-mechanical calculations. These relative stabilities were obtained in vacuo, water and chloroform, by combining the quantum-mechanical calculations with a continuum solvation model. The water model was used to represent arginines exposed to an aqueous solution, whereas the chloroform model has a polarity representative of a protein core or a membrane. This allowed determining the relative pKa's associated with each neutral tautomer in these environments. A key result is that significant differences in stability are found between the neutral tautomers, in both water and chloroform. Some tautomers are consistently found to be the most stable. These findings will be helpful to refine pKa calculations in proteins. PMID- 26641915 TI - Intrinsic Carbon-Carbon Bond Reactivity at the Manganese Center of Oxalate Decarboxylase from Density Functional Theory. AB - The detailed manganese-dependent chemistry employed by oxalate decarboxylase (OxDC) to catalyze the nonoxidative decarboxylation of oxalic acid remains poorly understood. For example, enzyme activity requires the presence of dioxygen even though this compound is not a formal substrate in the reaction. We now report density functional theory (DFT) calculations upon a series of hypothetical OxDC active site model structures. Our results suggest that the function of the metal ion may be to position dioxygen and oxalate such that electrons can be shuttled directly between these species, thereby removing the need for the existence of Mn(III) as an intermediate in the mechanism. These calculations also indicate that the intrinsic, gas-phase reactivity of the Bacillus subtilis oxalate decarboxylase active center is to oxidize oxalate. Since this reactivity is not observed for OxDC, our DFT results suggest that protein environment modulates the intrinsic metallocenter reactivity, presumably by affecting the electronic distribution at the manganese center during catalysis. PMID- 26641916 TI - Improving the QM/MM Description of Chemical Processes: A Dual Level Strategy To Explore the Potential Energy Surface in Very Large Systems. AB - Potential energy surfaces are fundamental tools for the analysis of reaction mechanisms. The accuracy of these surfaces for reactions in very large systems is often limited by the size of the system even if hybrid quantum mechanics/molecular mechanics (QM/MM) strategies are employed. The large number of degrees of freedom of the system requires hundreds or even thousands of optimization steps to reach convergence. Reactions in condensed media (such as enzymes or solutions) are thus usually restricted to be analyzed using low level quantum mechanical methods, thus introducing a source of error in the description of the QM region. In this paper, an alternative method is proposed, coupled to the use of a micro/macroiteration algorithm during the optimization. In these algorithms, the number of microsteps involved in the QM region optimization is usually much smaller than the number of macrosteps required to optimize the MM region. Thus, we define a new potential energy surface in which the gas-phase energy of the QM subsystem and the interaction energy with the MM subsystem are calculated at different computational levels. The high computational level is restricted to the gas-phase energy, which is only requested during the microsteps. The dual level strategy is tested for two reactions in solution (the Menshutkin and the oxy-Cope reactions) and an enzymatic one (the nucleophilic substitution of 1,2-dichloroethane in DhlA). The performance of the proposed computational scheme seems to be quite promising for future applications in other systems. PMID- 26641917 TI - Evaluating the Accuracy of the Quasiharmonic Approximation. AB - The quasiharmonic approximation (QH) allows the configurational entropy of a molecule to be estimated on the basis of a molecular dynamics simulation, through construction of a Gaussian probability distribution of conformations with variances equal to those provided by the simulation. At its introduction in 1981, the QH method was successfully applied to simple molecular systems with only one highly occupied energy well, and fluctuations were analyzed in a system of internal bond-angle-torsion coordinates. However, more recent studies have applied the QH method to complex biomolecular systems and have relied upon Cartesian coordinates. The present study evaluates the accuracy of the QH method through comparisons with more detailed methods. The chief findings are that the QH method can markedly overestimate the configurational entropy for systems with multiple occupied energy wells and that such errors tend to be magnified by the use of Cartesian coordinates instead of bond-angle-torsion coordinates. PMID- 26641918 TI - New General Tools for Constrained Geometry Optimizations. AB - A modification of the constrained geometry optimization method by Anglada and Bofill (Anglada, J. M.; Bofill, J. M. J. Comput. Chem. 1997, 18, 992-1003) is designed and implemented. The changes include the choice of projection, quasi line-search, and the use of a Rational Function optimization approach rather than a reduced-restricted-quasi-Newton-Raphson method in the optimization step. Furthermore, we show how geometrical constrains can be implemented in an approach based on nonredundant curvilinear coordinates avoiding the inclusion of the constraints in the set of redundant coordinates used to define the internal coordinates. The behavior of the new implementation is demonstrated in geometry optimizations featuring single or multiple geometrical constraints (bond lengths, angles, etc.), optimizations on hyperspherical cross sections (as in the computation of steepest descent paths), and location of energy minima on the intersection subspace of two potential energy surfaces (i.e. minimum energy crossing points). In addition, a novel scheme to determine the crossing point geometrically nearest to a given molecular structure is proposed. PMID- 26641919 TI - Open Shell Dianions Likely To Be Stable in the Gas Phase with Respect to Autoionization. AB - We address the challenge set by Dreuw and Cederbaum [Dreuw, A.; Cederbaum, L. S. Chem. Rev. 2002, 102, 181-200] to develop a set of "small" open shell stable dianions. We offer two families of such species, based on a central diradical center with attached anionic sites. Both families achieve dianion stabilization through alternating zones of positive and negative charge. First, quasi-linear systems such as NB(C2)n-Q-(C2)nBN become diradical dianions stable to autoionization in two cases: (a) for Q a divalent (carbene) carbon when n is two or greater and (b) for Q a C4 ring diradical when n is one or greater. Second, carbenes with certain anionic aromatic substituents can be stable with respect to autoionization. pi-Acid substituted carbenes (A2Q) have triplet ground states generally. If A is cyclopentadienyl anion stabilized by cyano substitution, the resulting triplet dianion is stable with respect to autoionization. In bisphenyl carbenes the triplet is relatively stabilized when ortho substituents force the system toward D2d symmetry. The dianion of bis(orthochlorophenyl) carbene produced by para-substitution with BN retains the triplet preference and is stable with respect to autoionization. These results obtained first by density functional calculations in a small basis, B3LYP/6-31G(d), are confirmed and extended by ROMP2 and CCSD calculations in a more flexible basis, 6-31+G(d). DFT has a systematic bias against systems with excess electrons, which is paradoxically a virtue in the screening of candidate dianions since the DFT calculation does not make false predictions of stability. PMID- 26641920 TI - Microsolvation of Li(+) in Small He Clusters. Li(+)Hen Species from Classical and Quantum Calculations. AB - A structural study of the smaller Li(+)Hen clusters with n <= 30 has been carried out using different theoretical methods. The structures and the energetics of the clusters have been obtained using both classical energy minimization methods and quantum Diffusion Monte Carlo. The total interaction acting within the clusters has been obtained as a sum of pairwise potentials: Li(+)-He and He-He. This approximation had been shown in our earlier study to give substantially correct results for energies and geometries once compared to full ab initio calculations. The general features of the spatial structures, and their energetics, are discussed in details for the clusters up to n = 30, and the first solvation shell is shown to be essentially completed by the first 8-10 helium atoms. PMID- 26641921 TI - Theoretical Study of the Interaction between the Guanidinium Cation and Chloride and Sulfate Anions. AB - The interactions between the guanidinium cation and the chloride and sulfate anions have been explored theoretically. As a basis for this study, the structure of the guanidinium cation has been reexamined and confirmed to possess a nonplanar propeller structure. Thus, computations at the MP2/6-31+G* level yielded several guanidinium-chloride complexes in 1:1 and 2:1 stoichiometry, with the most stable being those in which the guanidinium cation(s) interact in pincerlike form with the spherical chloride anion. In the case of guanidinium sulfate complexes, a large number of stable 1:1 dimers and 2:1 trimers were found at the same level of computation. The nature of all the interactions established has been analyzed by means of the AIMs and NBO approaches, and several correlations have been found between electron density at the bond critical points, hydrogen bond distances, and orbital interaction energies. The guanidinium moiety has been widely exploited as an anion receptor in supramolecular chemistry and bears relation to the arginine amino acid, which interacts with anionic substrates within proteins. Thus, the current study provides insight into the nature of the interactions involving the guanidinium cation within both abiotic and natural systems. PMID- 26641922 TI - Development of a Graphene Oxide Nanocarrier for Dual-Drug Chemo-phototherapy to Overcome Drug Resistance in Cancer. AB - Despite tremendous progress in chemotherapy, drug resistance remains a major challenge for anticancer treatment. The combinations of chemo-photothermal and chemo-chemo treatments have been reported to be potential solutions to overcome drug resistance. In this study, we developed a dual-in-dual synergistic therapy based on the use of dual anticancer drug-loaded graphene oxide (GO) stabilized with poloxamer 188 for generating heat and delivering drugs to kill cancer cells under near-infrared (NIR) laser irradiation. The nanocomparable system is stable and uniform in size, generating sufficient heat to induce cell death. Dual drugs (doxorubicin and irinotecan)-loaded GO (GO-DI) in combination with laser irradiation caused higher cytotoxicity than that caused by the administration of a free single drug as well as a combination of drugs and blank GO in various cancer cells, especially in MDA-MB-231 resistant breast cancer cells. Exposure to "hot" NIR and GO-DI activated the intrinsic apoptosis pathway, which was confirmed based on changes in the morphology of cell nuclei and overexpression of apoptosis-related proteins. On the basis of the results, the combined treatment showed a synergistic effect compared to the effect of chemotherapy or photothermal treatment alone, demonstrating higher therapeutic efficacy to overcome one of the most severe problem in anticancer therapy, that of intrinsic resistance to chemotherapeutics. PMID- 26641924 TI - Diagnostic Criteria for Autoimmune Hepatitis: Scores and More. AB - The diagnosis of autoimmune hepatitis is a clinical diagnosis that combines the patient's history, clinical examination, laboratory and serological markers and the results of a liver biopsy. As the clinical spectrum of autoimmune hepatitis is very wide, making the diagnosis can sometimes be difficult, especially in non expert hands. Diagnostic scores can help in making the diagnosis, and the simplified diagnostic score of the International Autoimmune Hepatitis Group has a sensitivity and specificity of around 90% in the different populations that have been studied. Therefore, it can be very helpful in everyday use, but nonetheless for some patients the score is not good enough. Limitations are patients with very acute presentations as well as atypical cases. In such cases, a trial of monotherapy with steroids and quick tapering of the steroids is recommended. If the disease responds well to treatment, but recurs after tapering the steroids, the diagnosis of autoimmune hepatitis is confirmed. In addition to its clinical use, diagnostic scores can also be helpful in defining the unified criteria in order to make scientific studies comparable. PMID- 26641923 TI - Disseminins and Spiciferone Analogues: Polyketide-Derived Metabolites from a Fungicolous Isolate of Pestalotiopsis disseminata. AB - Seven new polyketide metabolites (disseminins A-E, 1-5, and spiciferones D and E, 7 and 8) were obtained from cultures of a fungicolous isolate of Pestalotiopsis disseminata (NRRL 62562), together with a related compound (6) previously known only as a semisynthetic product. Structures were determined mainly by analysis of HRMS and NMR data. Biogenetically related compounds 1 and 2 possess uncommon bis tetrahydrofuran and dioxabicyclo[3.2.1]octane ring systems, respectively. X-ray crystallographic analysis of the p-bromobenzoate derivative of 1 confirmed the structure and enabled assignment of its absolute configuration. PMID- 26641925 TI - Dietary melatonin alters uterine artery hemodynamics in pregnant Holstein heifers. AB - The objective was to examine uterine artery hemodynamics and maternal serum profiles in pregnant heifers supplemented with dietary melatonin (MEL) or no supplementation (CON). In addition, melatonin receptor-mediated responses in steroid metabolism were examined using a bovine endometrial epithelial culture system. Twenty singleton pregnant Holstein heifers were supplemented with 20 mg of melatonin (n = 10) or no melatonin supplementation (control; n = 10) from days 190 to 262 of gestation. Maternal measurements were recorded on days 180 (baseline), 210, 240, and 262 of gestation. Total uterine blood flow was increased by 25% in the MEL-treated heifers compared with the CON. Concentrations of progesterone were decreased in MEL vs CON heifers. Total serum antioxidant capacity was increased by 43% in MEL-treated heifers when compared with CON. Activity of cytochrome P450 1A, 2C, and superoxide dismutase was increased in bovine endometrial epithelial cells treated with melatonin, whereas the melatonin receptor antagonist, luzindole, negated the increase in cytochrome P450 2C activity. Moreover, estradiol or progesterone treatment altered bovine uterine melatonin receptor expression, which could potentiate the melatonin-mediated responses during late gestation. The observed increase in total uterine blood flow during melatonin supplementation could be related to its antioxidant properties. Compromised pregnancies are typically accompanied by increased oxidative stress; therefore, melatonin could serve as a therapeutic supplementation strategy. This could lead to further fetal programming implications in conjunction with offspring growth and development postnatally. PMID- 26641926 TI - A Two-Photon Ratiometric Fluorescent Probe for Imaging Carboxylesterase 2 in Living Cells and Tissues. AB - In this study, a two-photon ratiometric fluorescent probe NCEN has been designed and developed for highly selective and sensitive sensing of human carboxylesterase 2 (hCE2) based on the catalytic properties and substrate preference of hCE2. Upon addition of hCE2, the probe could be readily hydrolyzed to release 4-amino-1,8-naphthalimide (NAH), which brings remarkable red-shift in fluorescence (90 nm) spectrum. The newly developed probe exhibits good specificity, ultrahigh sensitivity, and has been successfully applied to determine the real activities of hCE2 in complex biological samples such as cell and tissue preparations. NCEN has also been used for two-photon imaging of intracellular hCE2 in living cells as well as in deep-tissues for the first time, and the results showed that the probe exhibited high ratiometric imaging resolution and deep-tissue imaging depth. All these findings suggested that this probe holds great promise for applications in bioimaging of endogenous hCE2 in living cells and in exploring the biological functions of hCE2 in complex biological systems. PMID- 26641927 TI - Anatomy and Giant Enhancement of the Perpendicular Magnetic Anisotropy of Cobalt Graphene Heterostructures. AB - We report strongly enhanced perpendicular magnetic anisotropy (PMA) of Co films by graphene coating from both first-principles and experiments. Our calculations show that graphene can dramatically boost the surface anisotropy of Co films up to twice the value of its pristine counterpart and can extend the out-of-plane effective anisotropy up to unprecedented thickness of 25 A. These findings are supported by our experiments on graphene coating on Co films grown on Ir substrate. Furthermore, we report layer-resolved and orbital-hybridization resolved anisotropy analysis, which help understanding of the physical mechanisms of PMA and more practically can help design structures with giant PMA. As an example, we propose superexchange stabilized Co-graphene heterostructures with a robust constant effective PMA and linearly increasing interfacial anisotropy as a function of film thickness. These findings point toward possibilities to engineer graphene/ferromagnetic metal heterostructures with giant magnetic anisotropy more than 20-times larger compared to conventional multilayers, which constitutes a hallmark for future graphene and traditional spintronic technologies. PMID- 26641928 TI - The potential of oxytocin as a therapeutic target for psychiatric disorders. PMID- 26641929 TI - Strategies for improving the efficacy of donor lymphocyte infusion following stem cell transplantation. AB - Donor lymphocyte infusion (DLI) is an effective immunotherapeutic approach with significant activity in the treatment and prevention of relapse after allogeneic stem cell transplantation. DLI is associated with significant toxicity mainly due to graft-versus-host disease. Moreover, DLI does not produce durable responses in aggressive malignancies like acute leukemia. Improvement in DLI efficacy requires dissociation of graft-versus-leukemia effect from graft-versus-host disease. Minor histocompatibility antigens with tissue restriction and leukemia or tumor associated antigens represent ideal antigenic targets. A brief overview of the existing methods of DLI administration is the topic of this article. T cells transduced with genes encoding for T-cell receptors with reactivity against minor histocompatibility antigens or leukemia-associated antigens is a promising option. PMID- 26641930 TI - Formulation and characterization of taste masked ondansetron-magnesium aluminum silicate adsorption systems. AB - CONTEXT: Taste masking greatly influences the acceptability of bitter tasting formulation; moreover, it governs the commercial and therapeutic success of drug products. OBJECTIVE: This work is directed toward masking the bitter taste of ondansetron HCl (ONS) utilizing the excipient, which can delay the reach of drug to the taste buds. MATERIAL AND METHODS: Magnesium aluminum silicate (Veegum F), a clay material having capability to adsorb the drugs onto it, was used. The adsorption systems of ONS with Veegum were obtained by dynamic adsorption technique and examined by scanning electron microscopy, differential scanning calorimetry, Fourier transform infrared (FTIR) spectroscopy, and X-ray diffraction (XRD) for morphology, thermal behavior, and interactions. The taste assessment of prepared systems was done by in vitro method based on drug release. RESULTS: The molecular interaction between ONS and Veegum in the system was revealed by FTIR spectroscopy. A change in thermal behavior of the system was observed owing to interaction or replacement of the cationic groups of Veegum with that of ONS. XRD studies revealed that the prepared system was having lower crystallinity as compared to ONS. The in vitro drug release study showed that ONS release from the system was relatively slow in basic environment than the acidic one. DISCUSSION: Adsorption of ONS on the surface of Veegum was mainly due to electrostatic interactions and hydrogen bonding. CONCLUSION: The experimental results reveal the successful intercalation of ONS into the space available between the layers of Veegum. Furthermore, this resulted in a control on drug release in salivary pH resulting in a concentration lower than bitterness threshold. PMID- 26641931 TI - Protein engineering: Beating the odds. PMID- 26641932 TI - High-throughput analysis and protein engineering using microcapillary arrays. AB - We describe a multipurpose technology platform, termed MUSCALE (microcapillary single-cell analysis and laser extraction), that enables massively parallel, quantitative biochemical and biophysical measurements on millions of protein variants expressed from yeast or bacteria. MUSCALE spatially segregates single cells within a microcapillary array, enabling repeated imaging, cell growth and protein expression. We performed high-throughput analysis of cells and their protein products using a range of fluorescent assays, including binding-affinity measurements and dynamic enzymatic assays. A precise laser-based extraction method allows rapid recovery of live clones and their genetic material from microcapillaries for further study. With MUSCALE, we discovered a new antibody against a clinical cancer target, evolved a fluorescent protein biosensor and engineered an enzyme to reduce its sensitivity to its inhibitor. These protein analysis and engineering applications each have unique assay requirements and different host organisms, highlighting the flexibility and technical capabilities of the MUSCALE platform. PMID- 26641933 TI - Molecular mechanism of respiratory syncytial virus fusion inhibitors. AB - Respiratory syncytial virus (RSV) is a leading cause of pneumonia and bronchiolitis in young children and the elderly. Therapeutic small molecules have been developed that bind the RSV F glycoprotein and inhibit membrane fusion, yet their binding sites and molecular mechanisms of action remain largely unknown. Here we show that these inhibitors bind to a three-fold-symmetric pocket within the central cavity of the metastable prefusion conformation of RSV F. Inhibitor binding stabilizes this conformation by tethering two regions that must undergo a structural rearrangement to facilitate membrane fusion. Inhibitor-escape mutations occur in residues that directly contact the inhibitors or are involved in the conformational rearrangements required to accommodate inhibitor binding. Resistant viruses do not propagate as well as wild-type RSV in vitro, indicating a fitness cost for inhibitor escape. Collectively, these findings provide new insight into class I viral fusion proteins and should facilitate development of optimal RSV fusion inhibitors. PMID- 26641935 TI - Perceived environment in relation to objective and self-reported physical activity in Spanish youth. The UP&DOWN study. AB - The aims of the present study were to assess the association of environmental perception with objective and self-reported physical activity (PA) and the relation between environmental perception and meeting PA recommendations on children and adolescents. A sample of 1520 youth (770 boys) aged 8-18 years (12.1 +/- 2.5 years) from the UP&DOWN study were included in the data analyses. Environmental perception was assessed with the short adapted version of the ALPHA environmental questionnaire. PA was objectively (accelerometers) and self reported measured (PA Questionnaire for Children, Patient-centered Assessment and Counseling for Exercise Questionnaire and Finnish PA Index). Linear regression models were used to assess the association of environmental perception with PA. Bivariate logistic regression models were used to assess differences between environmental perception and meeting PA recommendations. Environmental perception was positively associated with both objective and self-reported PA. Some differences were found in the association of environmental perception and PA between sex- and age-specific groups. Youth who perceived a more favourable environment were more likely to meet PA recommendations (at least 60 min . day( 1) of moderate to vigorous PA (MVPA)). Results suggest that environmental perceptions of children and adolescents may play an important role in achieving higher levels of PA. PMID- 26641936 TI - Impact and management of depression in psoriasis patients. PMID- 26641934 TI - 'Deadman' and 'Passcode' microbial kill switches for bacterial containment. AB - Biocontainment systems that couple environmental sensing with circuit-based control of cell viability could be used to prevent escape of genetically modified microbes into the environment. Here we present two engineered safeguard systems known as the 'Deadman' and 'Passcode' kill switches. The Deadman kill switch uses unbalanced reciprocal transcriptional repression to couple a specific input signal with cell survival. The Passcode kill switch uses a similar two-layered transcription design and incorporates hybrid LacI-GalR family transcription factors to provide diverse and complex environmental inputs to control circuit function. These synthetic gene circuits efficiently kill Escherichia coli and can be readily reprogrammed to change their environmental inputs, regulatory architecture and killing mechanism. PMID- 26641937 TI - Agmatine improves renal function in gentamicin-induced nephrotoxicity in rats. AB - The present study was designed to explore the possible protective effects of agmatine, a known nitric oxide (NO) synthase inhibitor, against gentamicin induced nephrotoxicity in rats. For this purpose, we quantitatively evaluated gentamicin-induced renal structural and functional alterations using histopathological and biochemical approaches. Furthermore, the effect of agmatine on gentamicin-induced hypersensitivity of urinary bladder rings to acetylcholine (ACh) was evaluated. Twenty-four male Wistar albino rats were randomly divided into 3 groups, namely control, gentamicin (100 mg/kg, i.p.), and gentamicin plus agmatine (40 mg/kg, orally). At the end of the study, all rats were sacrificed and then blood and urine samples and kidneys were taken. Administration of agmatine significantly decreased kidney/body mass ratio, serum creatinine, lactate dehydrogenase (LDH), renal malondialdehyde (MDA), myeloperoxidase (MPO), NO, and tumor necrosis factor-alpha (TNF-alpha) while it significantly increased creatinine clearance and renal superoxide dismutase (SOD) activity when compared with the gentamicin-treated group. Additionally, agmatine ameliorated tissue morphology as evidenced by histological evaluation and reduced the responses of isolated bladder rings to ACh. Our study indicates that agmatine administration with gentamicin attenuates oxidative-stress associated renal injury by reducing oxygen free radicals and lipid peroxidation, restoring NO level and inhibiting inflammatory mediators such as TNF-alpha. PMID- 26641939 TI - Transition Metal-Free Visible Light-Driven Photoredox Oxidative Annulation of Arylamidines. AB - A fast catalytic synthesis of multisubstituted quinazolines from readily available amidines via visible light-mediated oxidative C(sp(3))-C(sp(2)) bond formation has been established. This reaction is a metal-free oxidative coupling catalyzed by a photoredox organocatalyst. The protocol features low catalyst loading (1 mol %). PMID- 26641938 TI - Exceptional Antibodies Produced by Successive Immunizations. AB - Antibodies stand between us and pathogens. Viruses mutate quickly to avoid detection, and antibodies mutate at similar rates to hunt them down. This death spiral is fueled by specialized proteins and error-prone polymerases that change DNA sequences. Here, we explore how B lymphocytes stay in the race by expressing activation-induced deaminase, which unleashes a tsunami of mutations in the immunoglobulin loci. This produces random DNA substitutions, followed by selection for the highest affinity antibodies. We may be able to manipulate the process to produce better antibodies by expanding the repertoire of specific B cells through successive vaccinations. PMID- 26641940 TI - The complete mitogenome of brown trout (Salmo trutta fario) and its phylogeny. AB - The complete mitochondrial genome of Salmo trutta fario, commonly known as brown trout, was sequenced using NGS technology. The mitochondrial genome size was determined to be 16 677 bp and composed of 13 protein-coding gene (PCG), 22 tRNAs, 2 rRNA genes, and 1 putative control region. The overall mitogenome composition of S. trutta fario is A: 28.13%, G: 16.44%, C: 29.47%, and T: 25.96% with A + T content of 54.09% and G + C content of 45.91%. The gene arrangement and the order are similar to other vertebrates. The phylogenetic tree constructed using 42 complete mitogenomes of Salmonidae fishes confirmed the position of the present species under the genus Salmo of subfamily Salmoninae. NGS platform was proved to be a rapid and time-saving technology to reveal complete mitogenomes. PMID- 26641941 TI - A Stable Coordination Complex of Rh(IV) in an N,O-Donor Environment. AB - We describe facial and meridional isomers of [Rh(III)(pyalk)3], as well as meridional [Rh(IV)(pyalk)3](+) {pyalk =2-(2-pyridyl)-2-propanoate}, the first coordination complex in an N,O-donor environment to show a clean, reversible Rh(III/IV) redox couple and to have a stable Rh(IV) form, which we characterize by EPR and UV-visible spectroscopy as well as X-ray crystallography. The unprecedented stability of the Rh(IV) species is ascribed to the exceptional donor strength of the ligands, their oxidation resistance, and the meridional coordination geometry. PMID- 26641942 TI - Cerebral microbleeds as a biomarker in Alzheimer's disease? A review in the field. AB - Cerebral microbleeds (CMBs) are a marker of small vessel disease, increasingly recognized as being of importance in the Alzheimer's disease (AD) process. CMBs influence in AD, and its longitudinal impact on disease progression is however still unknown. CMBs show several associations with AD across studies, are associated with decreased cerebrospinal fluid amyloid levels and are related with the ApoE epsilon4 allele, as well as other imaging manifestations typical for small vessel disease. CMBs, in addition to other markers of small vessel disease, are important to discover further in order to discern possible AD phenotypes. PMID- 26641944 TI - A focus on inflammation as a major risk factor for atherosclerotic cardiovascular diseases. AB - Atherosclerosis is a dynamic, pathogenic process in the artery wall, with potential adverse outcome for the host. Acute events such as myocardial infarction and ischemic stroke often result from rupture of unstable atherosclerotic lesions. Understanding the underlying pathology of such lesions and why and when they rupture, is therefore of great interest for the development of new diagnostics and treatment. Inflammation is one of the key drivers of atherosclerotic plaque development and the interplay between inflammation and lipids constitutes the hallmark of atherosclerotic disease. This review summarizes the role of inflammation in atherosclerosis and presents some of the latest discoveries as well as unmet needs regarding the role of inflammation as major risk factor in atherosclerotic disease. PMID- 26641943 TI - How to assess the binding strength of antibodies elicited by vaccination against HIV and other viruses. AB - Vaccines that protect against viral infections generally induce neutralizing antibodies. When vaccines are evaluated, the need arises to assess the affinity maturation of the antibody responses. Binding titers of polyclonal sera depend not only on the affinities of the constituent antibodies but also on their individual concentrations, which are difficult to ascertain. Therefore an assay based on chaotrope disruption of antibody-antigen complexes was designed for measuring binding strength. This assay works well with many viral antigens but gives differential results depending on the conformational dependence of epitopes on complex antigens such as the envelope glycoprotein of HIV-1. Kinetic binding assays might offer alternatives, since they can measure average off-rate constants for polyclonal antibodies in a serum. Here, potentials and fallacies of these techniques are discussed. PMID- 26641945 TI - Short UV-B Exposure Stimulated Enzymatic and Nonenzymatic Antioxidants and Reduced Oxidative Stress of Cold-Stored Mangoes. AB - The effects of UV-B irradiation on reactive oxygen species (ROS) levels, antioxidant compound contents, antioxidative enzyme activities, and oxidative damage of cold-stored mangoes were examined. Superoxide anion production rate, hydrogen peroxide concentration, ion leakage level and malondialdehyde content of the cold-stored fruit preradiated with 5 KJ m(-2) UV-B for 4 h were significantly decreased as compared with control fruit. The activities of ROS generating enzymes remained unchanged in UV-B-irradiated mangoes as compared to the control, but superoxide dismutase and catalase activities, ascorbate and polyphenol contents and antioxidant capacities of the cold-stored mangoes were significantly enhanced by UV-B. The UV-B-enhanced antioxidant compounds and antioxidative enzymes were highly correlated with the reduced-ROS levels in UV-B-irradiated mangoes. The data indicated that a short UV-B exposure reduced oxidative stress and alleviated oxidative damage of the cold-stored mangoes by triggering both enzymatic and nonenzymatic antioxidant systems although ROS generation in the fruit was not affected. PMID- 26641946 TI - Multimap formation in visual cortex. AB - An extrastriate visual area such as V2 or V4 contains neurons selective for a multitude of complex shapes, all sharing a common topographic organization. Simultaneously developing multiple interdigitated maps--hereafter a "multimap"- is challenging in that neurons must compete to generate a diversity of response types locally, while cooperating with their dispersed same-type neighbors to achieve uniform visual field coverage for their response type at all orientations, scales, etc. Previously proposed map development schemes have relied on smooth spatial interaction functions to establish both topography and columnar organization, but by locally homogenizing cells' response properties, local smoothing mechanisms effectively rule out multimap formation. We found in computer simulations that the key requirements for multimap development are that neurons are enabled for plasticity only within highly active regions of cortex designated "learning eligibility regions" (LERs), but within an LER, each cell's learning rate is determined only by its activity level with no dependence on location. We show that a hybrid developmental rule that combines spatial and activity-dependent learning criteria in this way successfully produces multimaps when the input stream contains multiple distinct feature types, or in the degenerate case of a single feature type, produces a V1-like map with "salt-and pepper" structure. Our results support the hypothesis that cortical maps containing a fine mixture of different response types, whether in monkey extrastriate cortex, mouse V1 or elsewhere in the cortex, rather than signaling a breakdown of map formation mechanisms at the fine scale, are a product of a generic cortical developmental scheme designed to map cells with a diversity of response properties across a shared topographic space. PMID- 26641947 TI - Chronic and acute biases in perceptual stabilization. AB - When perceptually ambiguous stimuli are presented intermittently, the percept on one presentation tends to be the same as that on the previous presentation. The role of short-term, acute biases in the production of this perceptual stability is relatively well understood. In addition, however, long-lasting, chronic bias may also contribute to stability. In this paper we develop indices for both biases and for stability, and show that stability can be expressed as a sum of contributions from the two types of bias. We then apply this analytical procedure to binocular rivalry, showing that adjustment of the monocular contrasts can alter the relative contributions of the two biases. Stability is mainly determined by chronic bias when the contrasts are equal, but acute bias dominates stability when right-eye contrast is set lower than left-eye contrast. Finally, we show that the right-eye bias persists in continuous binocular rivalry. Our findings reveal a previously unappreciated contribution of chronic bias to stable perception. PMID- 26641949 TI - Probability, not linear summation, mediates the detection of concentric orientation-defined textures. AB - Previous studies investigating signal integration in circular Glass patterns have concluded that the information in these patterns is linearly summed across the entire display for detection. Here we test whether an alternative form of summation, probability summation (PS), modeled under the assumptions of Signal Detection Theory (SDT), can be rejected as a model of Glass pattern detection. PS under SDT alone predicts that the exponent beta of the Quick- (or Weibull-) fitted psychometric function should decrease with increasing signal area. We measured spatial integration in circular, radial, spiral, and parallel Glass patterns, as well as comparable patterns composed of Gabors instead of dot pairs. We measured the signal-to-noise ratio required for detection as a function of the size of the area containing signal, with the remaining area containing dot-pair or Gabor-orientation noise. Contrary to some previous studies, we found that the strength of summation never reached values close to linear summation for any stimuli. More importantly, the exponent beta systematically decreased with signal area, as predicted by PS under SDT. We applied a model for PS under SDT and found that it gave a good account of the data. We conclude that probability summation is the most likely basis for the detection of circular, radial, spiral, and parallel orientation-defined textures. PMID- 26641948 TI - What is white? AB - To shed light on the perceptual basis of the color white, we measured settings of unique white in a dark surround. We find that settings reliably show more variability in an oblique (blue-yellow) direction in color space than along the cardinal axes of the cone-opponent mechanisms. This is against the idea that white perception arises at the null point of the cone-opponent mechanisms, but one alternative possibility is that it occurs through calibration to the visual environment. We found that the locus of maximum variability in settings lies close to the locus of natural daylights, suggesting that variability may result from uncertainty about the color of the illuminant. We tested this by manipulating uncertainty. First, we altered the extent to which the task was absolute (requiring knowledge of the illumination) or relative. We found no clear effect of this factor on the reduction in sensitivity in the blue-yellow direction. Second, we provided a white surround as a cue to the illumination or left the surround dark. Sensitivity was selectively worse in the blue-yellow direction when the surround was black than when it was white. Our results can be functionally related to the statistics of natural images, where a greater blue yellow dispersion is characteristic of both reflectances (where anisotropy is weak) and illuminants (where it is very pronounced). Mechanistically, the results could suggest a neural signal responsive to deviations from the blue-yellow locus or an adaptively matched range of contrast response functions for signals that encode different directions in color space. PMID- 26641950 TI - High Resolution CZE-MS Quantitative Characterization of Intact Biopharmaceutical Proteins: Proteoforms of Interferon-beta1. AB - New and improved methods are required for the enhanced characterization of complex biopharmaceuticals, especially those with charge and glycan heterogeneity. High resolution separation and mass spectrometry (MS) analysis of intact proteoforms can contribute significantly to the characterization of such proteins, many of which are glycoproteins. Here, we report on capillary zone electrophoresis (CZE) coupled via a commercial CESI sheathless interface to an Orbitrap ELITE MS for the intact analysis of recombinant human interferon-beta1 (Avonex, rhIFN-beta1), a biopharmaceutical with complex glycosylation at a single N-linked site. Using a cross-linked polyethylenimine coating, column efficiencies between 350,000 and 450,000 plates were produced, allowing separation based on charge and subtle hydrodynamic volume differences. A total of 138 proteoforms were found, and 55 were quantitated. Charge species due to deamidation and sialylation were separated by CZE. Given the high column efficiency, isobaric positional isomers of a single sialic acid on biantennary glycan antennae were resolved. Further, triantennary isomers (antenna on alpha(1-3) or alpha(1-6) arms) were separated and confirmed by exoglycosidase digestion. Proteoforms of the N-terminal cleavage of methionine were detected by precursor molecular weight and top-down ETD and HCD analysis of the reduced protein. Quantitative analysis suggested potential correlations between the methionine loss with the relative amount of the deamidation, as well as the level of deamidation with glycan structure. We demonstrate that high resolution CZE separation of intact glycoprotein species coupled to MS has significant potential for the in-depth characterization and quantitative analysis of biopharmaceutical proteoforms. PMID- 26641951 TI - Liquid-Phase Epitaxy Effective Encapsulation of Lanthanide Coordination Compounds into MOF Film with Homogeneous and Tunable White-Light Emission. AB - As a new family of hybrid inorganic-organic materials with large porosity, metal organic frameworks (MOFs) have received attractive attention recently on encapsulating functional guest species. Although the encapsulation of luminescent guest into bulk MOFs can tune the luminescent property, the powder composite materials are limited to the application in optical sensors and devices. In the present work, we use a modified liquid-phase epitaxial (LPE) pump method for the fabrication of lanthanide coordination compounds (LCCs)-encapsulated MOF thin film on substrate with high encapsulation efficiency. The resultant composite film reveals an oriented and homogeneous composite film, in which a white light emission by tuning the LCCs of red, blue and green emission can be obtained. This strategy may open new perspectives for developing high-encapsulation-efficiency, oriented, and homogeneous solid-state lighting composite films in the application of optical sensors and devices. PMID- 26641952 TI - Health Policy and Medical Training: Breaking Down Barriers Between the Wards and the World. PMID- 26641954 TI - Fast Electrically Driven Capillary Rise Using Overdrive Voltage. AB - Enhancement of response speed (or reduction of response time) is crucial for the commercialization of devices based on electrowetting (EW), such as liquid lenses and reflective displays, and presents one of the main challenges in EW research studies. We demonstrate here that an overdrive EW actuation gives rise to a faster rise of a liquid column between parallel electrodes, compared to a DC EW actuation. Here, DC actuation is actually a simple applied step function, and overdrive is an applied step followed by reduction to a lower voltage. Transient behaviors and response time (i.e., the time required to reach the equilibrium height) of the rising liquid column are explored under different DC and overdrive EW actuations. When the liquid column rises up to a target height by means of an overdrive EW, the response time is reduced to as low as 1/6 of the response time using DC EW. We develop a theoretical model to simulate the EW-driven capillary rise by combining the kinetic equation of capillary flow (i.e., Lucas-Washburn equation) and the dynamic contact angle model considering contact line friction, contact angle hysteresis, contact angle saturation, and the EW effect. This theoretical model accurately predicts the outcome to within a +/- 5% error in regard to the rising behaviors of the liquid column with a low viscosity, under both DC EW and overdrive actuation conditions, except for the early stage (95 percentile for age and sex). CONCLUSIONS: Undiagnosed CAH is an uncommon cause of PA, and therefore routine screening for NC-CAH in every case of PA may not be justified, although, perhaps, should still be considered in high risk ethnicities. Obesity does not appear to exclude the possibility of being affected with mild or NC-CAH. PMID- 26641962 TI - Functional outcome after intracerebral haemorrhage - a review of the potential role of antiapoptotic agents. AB - Intracerebral haemorrhage (ICH) is the second most common form of stroke and is associated with greater mortality and morbidity compared with ischaemic stroke. The current ICH management strategies, which mainly target primary injury mechanisms, have not been shown to improve patient's functional outcome. Consequently, multimodality treatment approaches that will focus on both primary and secondary pathophysiology have been suggested. During the last decade, a proliferation of experimental studies has demonstrated the role of apoptosis in secondary neuronal loss at the periphery of the clot after ICH. Subsequently, the value of certain antiapoptotic agents in reducing neuronal death and improving functional outcome following ICH was evaluated in animal models. Preliminary evidence from those studies strongly supports the potential role of antiapoptotic agents in reducing neuronal death and improving functional outcome after intracerebral haemorrhage. Expectedly, the ongoing and subsequent clinical trials will substantiate these findings and provide clear information on the most potent and safe antiapoptotic agents, their appropriate dosage, and temporal window of action, thereby making them suitable for the multimodality treatment approach. PMID- 26641963 TI - Current advances in cell electrophysiology: applications for the analysis of intercellular communications within the neurovascular unit. AB - Patch clamp is a golden standard for studying (patho)physiological processes affecting membranes of excitable cells. This method is rather labor-intensive and requires well-trained professionals and long-lasting experimental procedures; therefore, accurate designing of the experiments with patch clamp methodology as well as collecting and analyzing the data obtained are essential for the widely spread implementation of this method into the routine research practice. Recently, the method became very prospective not only for the characterization of single excitable cells but also for the detailed assessment of intercellular communication, i.e. within the neurovascular unit. Here, we analyze the main advantages and disadvantages of patch clamp method, with special focus on the tendencies in clamping technique improvement with the help of patch electrodes for the assessment of intercellular communication in the brain. PMID- 26641964 TI - Leaching from the stratum corneum does not explain the previously reported elevated potassium ion concentration in sweat. AB - BACKGROUND: The purpose of this study was to determine if K+ is leached from the stratum corneum when sweat is present on the skin's surface. The results will help address whether sweat [K+] previously reported in the literature are artifactually elevated as a result of K+ leaching. METHODS: Twelve (six female, six male) healthy volunteers participated in this study. After thorough skin cleansing and preparation with isopropyl alcohol and high-performance liquid chromatography-grade distilled water, three sites were chosen and a 50 MUL drop of artificial sweat was pipetted directly onto the skin. The artificial sweat had a [K+] of 4 mEq.L-1, an osmolality of 120 mosm.L-1, and a pH of 6.0. Immediately following, a clear plastic cover slip (~6 cm2) with a shallow 0.8 cm2 convex impression in the center was applied over each drop, preventing evaporation. Each sample was allowed to sit on the forearm, under the plastic cover slip, for 10 min. RESULTS: The mean (+/-SD) [K+] in 'artificial' sweat not exposed to the skin was measured to be 4.2+/-0.4 mEq.L-1. After 10 min of exposure to the stratum corneum of the forearm, the artificial sweat had a mean (+/-SD) [K+] of 3.9+/-0.3 mEq.L-1. There was no significant difference (p>0.05) in the [K+] between the control artificial sweat and the samples collected after 10 min of exposure to forearm skin. CONCLUSIONS: These results do not support the hypothesis that significant K+ leaching from the stratum corneum into standing sweat is the cause for the previously reported elevated sweat [K+]. PMID- 26641965 TI - Signaling pathways regulating Homer1a expression: implications for antidepressant therapy. AB - Homer1a is upregulated by several different antidepressant measures, including non-pharmacological treatments, like sleep deprivation (SD) and electroconvulsive therapy (ECT) and antidepressant drugs, such as imipramine, fluoxetine and ketamine. Homer1a induction might thus be a crucial joint mechanism for antidepressant therapy in general. However, the upstream signaling pathways that regulate or induce Homer1a expression are still not well understood. The main focus of the present review is to offer an overview of the current knowledge about the potential role of Homer1a in depression and the signaling pathways responsible for Homer1a regulation. It is suggested here that a detailed characterization of the signaling mechanisms leading to Homer1a expression might provide novel therapeutic targets for antidepressant drug development. PMID- 26641966 TI - TSH and fT4 during pregnancy: an observational study and a review of the literature. AB - BACKGROUND: Trimester-specific reference intervals for TSH are recommended to assess thyroid function during pregnancy due to changes in thyroid physiology. Laboratories should verify reference intervals for their population and assay used. No consistent upper reference limit (URL) for TSH during pregnancy is reported in literature. We investigated the use of non-pregnant reference intervals for TSH, recommended during pregnancy by current Dutch guidelines, by deriving trimester-specific reference intervals in disease-free Dutch pregnant women as these are not available. METHODS: Apparently healthy low risk pregnant women were recruited via midwifery practices. Exclusion criteria included current or past history of thyroid or other endocrine disease, multiple pregnancy, use of medication known to influence thyroid function and current pregnancy as a result of hormonal stimulation. Women who were TPO-antibody positive, miscarried, developed hyperemesis gravidarum, hypertension, pre-eclampsia, HELLP, diabetes or other disease, delivered prematurely or had a small for gestational age neonate were excluded. Blood samples were collected at 9-13 weeks (n=99), 27-29 weeks (n=96) and 36-39 weeks (n=96) of gestation and at 4-13 weeks post-partum (n=95). Sixty women had complete data during pregnancy and post-partum. All analyses were performed on a Roche Cobas e601 analyser. RESULTS AND CONCLUSIONS: In contrast to current Dutch guidelines, the 97.5th percentiles of TSH in the first (3.39 mIU/L) and second trimesters (3.38 mIU/L) are well under the non-pregnant URL of 4.0 mIU/L. The higher TSH in the third trimester (97.5th percentile 3.85 mIU/L) is close to the current non-pregnant URL of 4.0 mIU/L. Absolute intra-individual TSH is relatively stable during pregnancy and post-partum as individuals tracked within the tertile assigned in trimester 1. Even small deviations within the population reference interval may indicate subtle thyroid dysfunction. PMID- 26641967 TI - Use of isoelectric focusing to discriminate transient oligoclonal bands from monoclonal protein in treated myeloma. AB - A 62-year-old diabetic man with prostate cancer first presented to our clinical laboratory in 2003 with a normal serum protein electrophoresis and immunofixation. In March 2009 he was diagnosed with an IgG kappa myeloma. He underwent treatment and went into remission with the original paraprotein band being undetectable. Over the following 5 years, he developed oligoclonal bands and then eventually relapsed. Serum protein electrophoresis and immunofixation were inconclusive, however, isoelectrofocusing identified the oligoclonal pattern then the return of the original band, indicating relapse. This case illustrates the usefulness of an isoelectric focusing method to correctly determine clonality of small abnormal protein bands. It also highlights the need for appropriate commenting on reported results so that they are not confusing for clinicians. PMID- 26641968 TI - Substrate-zymography: a still worthwhile method for gelatinases analysis in biological samples. AB - Matrix metallo-proteinases (MMPs) are a family of zinc-dependent endopeptidases, capable of degrading all the molecular components of extracellular matrix. A class of MMPs is gelatinases which includes gelatinase A or MMP-2 (72 kDa) and gelatinase B or MMP-9 (92 kDa), which have been shown to play critical roles in pathophysiology of many human disease and, in particular, cancer progression. For these reasons they obtained a great interest as potential non-invasive biomarker in providing useful clinical information in cancer diagnosis and therapy. A sensitive and unexpensive method for analysis of gelatinases is the gelatine zymography, which allows to measure the relative amounts of active and inactive enzymes in body fluids and tissue extracts. The procedure involves the electrophoretic separation of proteins under denaturing but non reducing conditions through a polyacrylamide gel containing a synthetic substrate (gelatin). The aim of this mini-review has been to describe the general principles of gelatine zymography technique, underling the main advantages and disadvantages. Even though an improvement of this method is necessary for a better applicability in laboratory medicine, gelatine zymography represents the most convenient method to detect the activity of the different gelatinases from a wide range of biological samples. PMID- 26641969 TI - Quantitative determination of four immunosuppressants by high resolution mass spectrometry (HRMS). AB - BACKGROUND: Liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) utilizing triple-quadrupole instruments has been widely used for quantification of endogenous compounds, drugs or metabolites in clinical laboratories. In contrast, high-resolution mass spectrometry (HRMS) is typically used for compound identification due to its limited dynamic range. Recently HRMS instruments with enhanced linear dynamic range have become available. The aim of this study was to evaluate HRMS for fast quantitative applications in a clinical laboratory. METHODS: A high throughput UPLC-TOF-MS assay for simultaneous quantification of cyclosporin A, tacrolimus, sirolimus and everolimus was developed. All immunosuppressants were analyzed as sodium adducts in TOF-only mode using an Agilent 6540 Q-TOF system. Extracted ion chromatograms of analytes and internal standards were created from full-scan data. The assay was evaluated and compared to an established LC-MS/MS assay according to CLSI recommendations. RESULTS: The novel HRMS assay has a total run time of 3 min. The assay is linear in a clinical relevant concentration range for all four immunosupressants. Method correlations vs. established LC-MS/MS assay were between R2=0.99 and R2=0.97. Total coefficients of variation (CVT) ranges were 4.5%-6.4% (tacrolimus), 7.4%-8.0% (sirolimus), 8.0%-8.8% (everolimus) and 6.1%-7.4% (cyclosporine A) for three relevant concentration levels each. CONCLUSIONS: High resolution TOF-MS and LC MS/MS show equivalent quantitative performance for monitoring of cyclosporin A, tacrolimus, sirolimus and everolimus. HRMS has the potential to replace conventional LC-MS/MS in clinical laboratories because it simplifies assay development (no optimization of fragmentations and product ions necessary) and its full-scan data can provide additional information. PMID- 26641970 TI - Is accuracy of serum free light chain measurement achievable? AB - The serum free light chain (FLC) assay has proven to be an important complementary test in the management of patients with monoclonal gammopathies. The serum FLC assay has value for patients with plasma cell disorders in the context of screening and diagnosis, prognostic stratification, and quantitative monitoring. Nonetheless, serum FLC measurements have analytical limitations which give rise to differences in FLC reporting depending on which FLC assay and analytical platform is used. As the FLC measurements are incorporated in the International Myeloma Working Group guidelines for the evaluation and management of plasma cell dyscrasias, this may directly affect clinical decisions. As new certified methods for serum FLC assays emerge, the need to harmonise patient FLC results becomes increasingly important. In this opinion paper we provide an overview of the current lack of accuracy and harmonisation in serum FLC measurements. The clinical consequence of non-harmonized FLC measurements is that an individual patient may or may not meet certain diagnostic, prognostic, or response criteria, depending on which FLC assay and platform is used. We further discuss whether standardisation of serum FLC measurements is feasible and provide an overview of the steps needed to be taken towards harmonisation of FLC measurements. PMID- 26641971 TI - The quality indicator paradox. PMID- 26641973 TI - A Binomial Integer-Valued ARCH Model. AB - We present an integer-valued ARCH model which can be used for modeling time series of counts with under-, equi-, or overdispersion. The introduced model has a conditional binomial distribution, and it is shown to be strictly stationary and ergodic. The unknown parameters are estimated by three methods: conditional maximum likelihood, conditional least squares and maximum likelihood type penalty function estimation. The asymptotic distributions of the estimators are derived. A real application of the novel model to epidemic surveillance is briefly discussed. Finally, a generalization of the introduced model is considered by introducing an integer-valued GARCH model. PMID- 26641972 TI - Addressing Confounding in Predictive Models with an Application to Neuroimaging. AB - Understanding structural changes in the brain that are caused by a particular disease is a major goal of neuroimaging research. Multivariate pattern analysis (MVPA) comprises a collection of tools that can be used to understand complex disease efxcfects across the brain. We discuss several important issues that must be considered when analyzing data from neuroimaging studies using MVPA. In particular, we focus on the consequences of confounding by non-imaging variables such as age and sex on the results of MVPA. After reviewing current practice to address confounding in neuroimaging studies, we propose an alternative approach based on inverse probability weighting. Although the proposed method is motivated by neuroimaging applications, it is broadly applicable to many problems in machine learning and predictive modeling. We demonstrate the advantages of our approach on simulated and real data examples. PMID- 26641974 TI - An Empirical Bayes risk prediction model using multiple traits for sequencing data. AB - The rapidly developing sequencing technologies have led to improved disease risk prediction through identifying many novel genes. Many prediction methods have been proposed to use rich genomic information to predict binary disease outcomes. It is intuitive that these methods can be further improved by making efficient use of the rich information in measured quantitative traits that are correlated with binary outcomes. In this article, we propose a novel Empirical Bayes prediction model that uses information from both quantitative traits and binary disease status to improve risk prediction. Our method is built on a new statistic that better infers the gene effect on multiple traits, and it also enjoys the good theoretical properties. We then consider using sequencing data by combining information from multiple rare variants in individual genes to strengthen the signals of causal genetic effects. In simulation study, we find that our proposed Empirical Bayes approach is superior to other existing methods in terms of feature selection and risk prediction. We further evaluate the effectiveness of our proposed method through its application to the sequencing data provided by the Genetic Analysis Workshop 18. PMID- 26641975 TI - Exploring the awareness of research among registered massage therapists in Ontario. AB - BACKGROUND: An increase in available research has highlighted that knowledge changes over time as theories are challenged and adjusted or dismissed. This is particularly important to healthcare practitioners, including massage therapists, who need to frequently review current research and adjust practice accordingly. However, when research findings related to practice are generated, there is considerable delay in implementation. Few studies measure actual knowledge of current evidence for practice. The objectives of the study reported here were to (a) describe current awareness of evidence for practice among registered massage therapists (RMTs) in Ontario and (b) identify the sources of information RMTs use to inform their awareness of current evidence and the reported importance and frequency of use for each source. METHODS: An online questionnaire-based mixed methods cross-sectional study was conducted. Ontario RMTs were invited to participate. This report focuses on the quantitative analysis. RESULTS: In total, 1,762 questionnaires were included. Of seven sources of information provided, respondents rated cumulative professional experience as most important, followed by recent research studies and education. Cumulative professional experience also rated as most frequently used, followed by other RMTs and education. CONCLUSIONS: There was a tendency for respondents to agree with positive statements about MT, or disagree with negative statements, regardless of correctness. The results suggest that RMTs need to improve their awareness of the current evidence for practice. Furthermore, cumulative professional experience was ranked most frequently used. This has the potential to not include the most current research. Improving communication of research findings to RMTs might improve awareness. PMID- 26641976 TI - Evaluation of the antioxidant properties of tryptophan and its metabolites in in vitro assay. AB - BACKGROUND: Human milk contains a number of nutrients and bioactive ingredients which play an important role in the growth and development of infants. One important nutrient and bioactive ingredient of human milk is L-tryptophan. L Tryptophan is an essential aromatic alpha-amino acid and is required in the diet of children and adult humans. As an essential amino acid, it is needed for protein synthesis and as a precursor of key biomolecules such as serotonin, melatonin, tryptamine, niacin, quinolinic acid and kynurenic acid, nicotinamide adenine dinucleotide. The aim of the study was to evaluate the antioxidant, anti inflammatory and antiproliferative properties of tryptophan isolated from enzymatic hydrolysates from human milk and its metabolites on human glioma U251 cells and to evaluate the effects of human recombinant (hrIFNgamma) on molecular ions of tryptophan and its metabolites in human glial U251 cells. METHODS: The cytotoxicity was determined by MTT (3-(4, 5-dimethylthiazolyl-2)-2, 5 diphenyltetrazolium bromide) assay. The antioxidant property was assessed by the oxygen radical scavenging capacity (ORAC) method. The anti-inflammatory effect was determined by the enzyme-linked immunosorbent assay (ELISA) against cytokines IL-6 and TNF-alpha. The effects of recombinant human (rhIFNgamma) on molecular ions of tryptophan and its catabolites were evaluated by mass spectrometry. The tryptophan was isolated from milk peptides following enzymatic digestion, followed by separation by chromatographic and mass spectrometric methods. RESULTS: Tryptophan from human milk exhibited profoundly higher oxygen radical absorption capacity (7,986+/-468 um Trolox equivalent (TE)/g) than that of whole human milk (80.4+/-13.3 um TE/g). Tryptophan showed a moderate degree of anti inflammatory activity against TNF-alpha and IL-6. rhIFNgamma inhibited tryptophan metabolism. A low concentration of L-tryptophan (10-25 MUg/mL) inhibited nearly 25% of cell growth. When U251 cells were treated with 25 MUg/mL L-tryptophan and subsequently challenged with 30 ng/mL of human recombinant IFNgamma, a significant inhibitory effect on cell growth was observed. Low concentrations of Xanthurenic acid, L-kynurenine, and 3-OH DL kynurenine were found to inhibit cell growth except melatonin and 3-OH anthranilic acid. Melatonin was a strong inducer of TNF-alpha in RAW cells, whereas 3-OH kynurenine at 25, 50 and 100 ug/mL inhibited IL-6 in RAW cells. No significant change was observed in the IL-8 profile in tryptophan-treated U251 cells except that L-kynurenine at 10 ug/mL produced significantly high level of an inflammatory cytokine IL-8. Melatonin, 3 OH, DL kynurenine at high concentrations (100 ug/mL) induced proliferation of U251 cells. Melatonin seemed to show synergistic effects with recombinant human IFNgamma (rhINFgamma) in promoting growth of human glioma cells. While treatment of U251 cells with tryptophan alone and subsequent treatment with rhIFNgamma inhibited the growth of human cancer glioma cells, and conversely melatonin combined with rhIFNgamma promoted growth of the U251 cells. CONCLUSIONS: The findings from this study suggest that human milk-derived tryptophan and its metabolites possess strong antioxidant properties. Such effects might play a significant role in regulating the cell proliferation and growth of human cancer cells in a concentration-dependent manner. PMID- 26641977 TI - The role of pharmacogenetics and pharmacogenomics in 21st-century medicine: state of the art and new challenges discussed in the VII Conference of the Spanish Pharmacogenetics and Pharmacogenomics Society (SEFF). PMID- 26641978 TI - Antioxidant Properties of Caffeic acid Phenethyl Ester and 4-Vinylcatechol in Stripped Soybean Oil. AB - Caffeic acid was used to synthesize 4-vinylcatechol (4-VC) by thermal decarboxylation and to prepare caffeic acid phenethyl ester (CAPE) by esterification reaction. The identities of synthesized products were confirmed by (1)H NMR. Antioxidative activities of 4-VC and CAPE were compared with alpha tocopherol and BHT in stripped soybean oil at 60 degrees C under the dark. To evaluate the degrees of oxidation at different concentrations and combinations, peroxide value (PV) and (1)H NMR were performed. From the results of PV, the formation of primary oxidation products (i.e., hydroperoxides) in stripped soybean oil containing 200 ppm CAPE was the slowest. The relative oxidation degree of 200 ppm CAPE (9.5%) was lower than other samples on 9 d. Similar results were obtained by (1)H NMR analysis. After 15 d of storage, levels of conjugated diene forms and aldehydes of 200 ppm CAPE sample (57.3 and 0.9 mmol/mol oil) were also lower than other treatments. In addition, 4-VC and alpha tocopherol were found to have a synergistic antioxidant effect. PMID- 26642005 TI - Public Understanding of the Role of Nurses During Ebola. AB - PURPOSE: To examine media portrayals of nurses and their roles during the 2014 2015 Ebola epidemic in western Africa. METHODS: The study used document analysis and in-depth content analysis to review and assess literature on the Ebola epidemic. A total of 234 potentially relevant articles were identified; 109 were excluded and 125 were included in the analysis. FINDINGS: The analysis revealed a gap in system preparedness for global health events and a lack of public awareness of the critical role of nurses. Little attention was paid to nurses and their knowledge and expertise as they worked through the Ebola event. The perception of nurses evolved over the epidemic. CONCLUSIONS: Portrayals of nurses and their work during the Ebola epidemic evolved over the epidemic, from positive to negative, and health systems were shown to be unprepared for a major epidemic. CLINICAL RELEVANCE: Media coverage of major health events can demonstrate system inadequacies, but inaccurate and misleading portrayals of nurses and the nursing profession can undermine and diminish the image of the nursing profession. PMID- 26642007 TI - Exacerbations in neuroendocrine cell hyperplasia of infancy are characterized by increased air trapping. AB - Neuroendocrine cell Hyperplasia of Infancy (NEHI) presents with tachypnea, retractions, hypoxemia, and often failure to thrive. The radiologic and physiologic findings in infants with NEHI have been well described with a distinct geographic pattern of ground-glass opacities on chest computerized tomography imaging and profound air-trapping on infant pulmonary function testing. Despite gradual improvement over time, unexplained exacerbation has been observed but not well characterized. We present physiological and radiological changes of increased air-trapping during acute exacerbations in two older children with NEHI who had previously experienced significant clinical improvement. These cases illustrate previously undescribed manifestations of NEHI in older children. PMID- 26642006 TI - Genomic divergence and brain evolution: How regulatory DNA influences development of the cerebral cortex. AB - The cerebral cortex controls our most distinguishing higher cognitive functions. Human-specific gene expression differences are abundant in the cerebral cortex, yet we have only begun to understand how these variations impact brain function. This review discusses the current evidence linking non-coding regulatory DNA changes, including enhancers, with neocortical evolution. Functional interrogation using animal models reveals converging roles for our genome in key aspects of cortical development including progenitor cell cycle and neuronal signaling. New technologies, including iPS cells and organoids, offer potential alternatives to modeling evolutionary modifications in a relevant species context. Several diseases rooted in the cerebral cortex uniquely manifest in humans compared to other primates, thus highlighting the importance of understanding human brain differences. Future studies of regulatory loci, including those implicated in disease, will collectively help elucidate key cellular and genetic mechanisms underlying our distinguishing cognitive traits. PMID- 26642039 TI - Towards an inpatient diabetes curriculum: medical student-generated aims, objectives and methods for ward-based learning of non-critical, non-perioperative inpatient diabetes care. AB - AIMS: To create a summative document containing aims, objectives and methods that can be used for the training of healthcare professionals in inpatient diabetes care. METHODS: A four-stage approach was introduced for the ward-based teaching of inpatient diabetes care at the University of the West Indies, Cave Hill over the 2014-2015 academic year. Within this approach, 55 students (100%) submitted aims, objectives and methods to support two 2-h, ward-based sessions. This was guided by brief instructions and access to a copy of the Endocrine Society Clinical Practice Guideline on the management of non-critical, non-perioperative inpatient diabetes. Conceptual content analysis was used to convert submissions into a unifying document. RESULTS: Six themes emerged from students' submissions: diagnosis; assessment and investigation of diabetes and its complications; planning individualized care and pharmacological management; hypoglycaemia management, including severe hypoglycaemia; patient education; discharge planning; and multidisciplinary teamwork. Students were primarily interested in patient management and treatment using higher-level objectives and active learning methods. CONCLUSIONS: This study produced comprehensive, student generated, and hence student-centred, aims, objectives and methods for inpatient diabetes care with objectives appropriately set for higher cognitive levels of learning. This material can be used to guide teaching or for further development into a curriculum. This is the first known publication of content that could be used in a ward-based inpatient diabetes curriculum. PMID- 26642008 TI - AUTHOR RESPONSE. PMID- 26642040 TI - A New Family of Anionic Fe(III) Spin Crossover Complexes Featuring a Weak-Field N2O4 Coordination Octahedron. AB - Unprecedented anionic Fe(III) spin crossover (SCO) complexes involving a weak field O,N,O-tridentate ligand were discovered. The SCO transition was evidenced by the temperature variations in magnetic susceptibility, Mossbauer spectrum, and coordination structure. The DFT calculations suggested that larger coefficients on the azo group in the HOMO-1 of a ligand might contribute to the enhancement of a ligand-field splitting energy. The present anionic SCO complex also exhibited the light- induced excited-spin-state trapping effect. PMID- 26642041 TI - Accuracy of Urine Color to Detect Equal to or Greater Than 2% Body Mass Loss in Men. AB - CONTEXT: Clinicians and athletes can benefit from field-expedient measurement tools, such as urine color, to assess hydration state; however, the diagnostic efficacy of this tool has not been established. OBJECTIVE: To determine the diagnostic accuracy of urine color assessment to distinguish a hypohydrated state (>=2% body mass loss [BML]) from a euhydrated state (<2% BML) after exercise in a hot environment. DESIGN: Controlled laboratory study. SETTING: Environmental chamber in a laboratory. PATIENTS OR OTHER PARTICIPANTS: Twenty-two healthy men (age = 22 +/- 3 years, height = 180.4 +/- 8.7 cm, mass = 77.9 +/- 12.8 kg, body fat = 10.6% +/- 4.6%). INTERVENTION(S): Participants cycled at 68% +/- 6% of their maximal heart rates in a hot environment (36 degrees C +/- 1 degrees C) for 5 hours or until 5% BML was achieved. At the point of each 1% BML, we assessed urine color. MAIN OUTCOME MEASURE(S): Diagnostic efficacy of urine color was assessed using receiver operating characteristic curve analysis, sensitivity, specificity, and likelihood ratios. RESULTS: Urine color was useful as a diagnostic tool to identify hypohydration after exercise in the heat (area under the curve = 0.951, standard error = 0.022; P < .001). A urine color of 5 or greater identified BML >=2% with 88.9% sensitivity and 84.8% specificity (positive likelihood ratio = 5.87, negative likelihood ratio = 0.13). CONCLUSIONS: Under the conditions of acute dehydration due to exercise in a hot environment, urine color assessment can be a valid, practical, inexpensive tool for assessing hydration status. Researchers should examine the utility of urine color to identify a hypohydrated state under different BML conditions. PMID- 26642042 TI - Preface. PMID- 26642044 TI - Effect of alpha-Amylase Degradation on Physicochemical Properties of Pre-High Hydrostatic Pressure-Treated Potato Starch. AB - The effect of high hydrostatic pressure (HHP) on the susceptibility of potato starch (25%, w/v) suspended in water to degradation by exposure to bacterial alpha-amylase (0.02%, 0.04% and 0.06%, w/v) for 40 min at 25 degrees C was investigated. Significant differences (p < 0.05) in the structure, morphology and physicochemical properties were observed. HHP-treated potato starch (PS) exposed to alpha-amylase (0.06%, w/v) showed a significantly greater degree of hydrolysis and amount of reducing sugar released compared to alpha-amylase at a concentration of 0.04% (w/v) or 0.02% (w/v). Native PS (NPS) granules have a spherical and elliptical form with a smooth surface, whereas the hydrolyzed NPS (hNPS) and hydrolyzed HHP-treated PS granules showed irregular and ruptured forms with several cracks and holes on the surface. Hydrolysis of HHP-treated PS by alpha-amylase could decrease the average granule size significantly (p <0.05) from 29.43 to 20.03 MUm. Swelling power decreased and solubility increased with increasing enzyme concentration and increasing pressure from 200-600 MPa, with the exception of the solubility of HHP-treated PS at 600 MPa (HHP600 PS). Fourier transform infrared spectroscopy (FTIR) showed extensive degradation of the starch in both the ordered and the amorphous structure, especially in hydrolyzed HHP600 PS. The B-type of hydrolyzed HHP600 PS with alpha-amylase at a concentration 0.06% (w/v) changed to a B+V type with an additional peak at 2theta = 19.36 degrees . The HHP600 starch with 0.06% (w/v) alpha-amylase displayed the lowest value of To (onset temperature), Tc (conclusion temperature) and DeltaHgel (enthalpies of gelatinization). These results indicate the pre-HHP treatment of NPS leads to increased susceptibility of the granules to enzymatic degradation and eventually changes of both the amorphous and the crystalline structures. PMID- 26642043 TI - Defective Expression of the Mitochondrial-tRNA Modifying Enzyme GTPBP3 Triggers AMPK-Mediated Adaptive Responses Involving Complex I Assembly Factors, Uncoupling Protein 2, and the Mitochondrial Pyruvate Carrier. AB - GTPBP3 is an evolutionary conserved protein presumably involved in mitochondrial tRNA (mt-tRNA) modification. In humans, GTPBP3 mutations cause hypertrophic cardiomyopathy with lactic acidosis, and have been associated with a defect in mitochondrial translation, yet the pathomechanism remains unclear. Here we use a GTPBP3 stable-silencing model (shGTPBP3 cells) for a further characterization of the phenotype conferred by the GTPBP3 defect. We experimentally show for the first time that GTPBP3 depletion is associated with an mt-tRNA hypomodification status, as mt-tRNAs from shGTPBP3 cells were more sensitive to digestion by angiogenin than tRNAs from control cells. Despite the effect of stable silencing of GTPBP3 on global mitochondrial translation being rather mild, the steady-state levels and activity of Complex I, and cellular ATP levels were 50% of those found in the controls. Notably, the ATPase activity of Complex V increased by about 40% in GTPBP3 depleted cells suggesting that mitochondria consume ATP to maintain the membrane potential. Moreover, shGTPBP3 cells exhibited enhanced antioxidant capacity and a nearly 2-fold increase in the uncoupling protein UCP2 levels. Our data indicate that stable silencing of GTPBP3 triggers an AMPK-dependent retrograde signaling pathway that down-regulates the expression of the NDUFAF3 and NDUFAF4 Complex I assembly factors and the mitochondrial pyruvate carrier (MPC), while up-regulating the expression of UCP2. We also found that genes involved in glycolysis and oxidation of fatty acids are up-regulated. These data are compatible with a model in which high UCP2 levels, together with a reduction in pyruvate transport due to the down-regulation of MPC, promote a shift from pyruvate to fatty acid oxidation, and to an uncoupling of glycolysis and oxidative phosphorylation. These metabolic alterations, and the low ATP levels, may negatively affect heart function. PMID- 26642045 TI - The Effect of Temperature on Kinetics and Diffusion Coefficients of Metallocene Derivatives in Polyol-Based Deep Eutectic Solvents. AB - The temperature dependence of the density, dynamic viscosity and ionic conductivity of several deep eutectic solvents (DESs) containing ammonium-based salts and hydrogen bond donvnors (polyol type) are investigated. The temperature dependent electrolyte viscosity as a function of molar conductivity is correlated by means of Walden's rule. The oxidation of ferrocene (Fc/Fc+) and reduction of cobaltocenium (Cc+/Cc) at different temperatures are studied by cyclic voltammetry and potential-step chronoamperometry in DESs. For most DESs, chronoamperometric transients are demonstrated to fit an Arrhenius-type relation to give activation energies for the diffusion of redox couples at different temperatures. The temperature dependence of the measured conductivities of DES1 and DES2 are better correlated with the Vogel-Tamman-Fulcher equation. The kinetics of the Fc/Fc+ and Cc+/Cc electrochemical systems have been investigated over a temperature range from 298 to 338 K. The heterogeneous electron transfer rate constant is then calculated at different temperatures by means of a logarithmic analysis. The glycerol-based DES (DES5) appears suitable for further testing in electrochemical energy storage devices. PMID- 26642046 TI - The Effects of Potassium Channels in Human Internal Mammary Artery. AB - BACKGROUND: Structural and functional changes in potassium channels of vascular smooth muscle cells may contribute to the development of diseases such as hypertension. We aim to investigate the vascular effects of potassium channel openers and blockers in human internal mammary artery (HIMA). METHODS: Remaining segments of HIMA from 18 consecutive patients undergoing coronary artery bypass surgery were obtained to examine the vascular effects of various potassium channel openers (staurosporine, hydrochlorothiazide and cromakalim) and potassium channel blockers (4-aminopyridin [4-AP], charybdotoxin [CTX] and glibenclamide [GLBC]). RESULTS: Noradrenaline (NA)-induced maximal contractions were inhibited by all 3 K+-channel blockers but only fully inhibited by 4-AP (95.6%). Only NA induced contractions were reversed by CTX. Only K+-induced maximal contractions were significantly inhibited by 4-AP (95.6%, p < 0.05). Only acetylcholine induced relaxation was fully inhibited by CTX. Only sodium nitroprusside-induced relaxations in potassium chloride-precontracted strips could be reversed by GLBC. CONCLUSIONS: Drugs affecting potassium channels may be useful in the treatment of hypertension and management of perioperative vasospasm during the coronary artery bypass surgery. PMID- 26642047 TI - Applications of Light Amplification by Stimulated Emission of Radiation (Lasers) for Restorative Dentistry. AB - Light amplification by stimulated emission of radiation (laser) has been used widely in a range of biomedical and dental applications in recent years. In the field of restorative dentistry, various kinds of lasers have been developed for diagnostic (e.g. caries detection) and operative applications (e.g. tooth ablation, cavity preparation, restorations, bleaching). The main benefits for laser applications are patient comfort, pain relief and better results for specific applications. Major concerns for using dental lasers frequently are high cost, need for specialized training and sensitivity of the technique, thereby compromising its usefulness particularly in developing countries. The main aim of this paper is to evaluate and summarize the applications of lasers in restorative dentistry, including a comparison of the applications of lasers for major restorative dental procedures and conventional clinical approaches. A remarkable increase in the use of lasers for dental application is expected in the near future. PMID- 26642048 TI - Complement Effectors of Inflammation in Cystic Fibrosis Lung Fluid Correlate with Clinical Measures of Disease. AB - In cystic fibrosis (CF), lung damage is mediated by a cycle of obstruction, infection, and inflammation. Here we explored complement inflammatory effectors in CF lung fluid. In this study soluble fractions (sols) from sputum samples of 15 CF patients were assayed for complement effectors and analyzed with clinical measurements. The pro-inflammatory peptide C5a was increased 4.8-fold (P = 0.04) in CF sols compared with controls. Incubation of CF sols with P. aeruginosa or S. aureus increased C5a concentration 2.3-fold (P = 0.02). A peptide inhibitor of complement C1 (PIC1) completely blocked the increase in C5a concentration from P. aeruginosa in CF sol in vitro (P = 0.001). C5a concentration in CF sol correlated inversely with body mass index (BMI) percentile in children (r = -0.77, P = 0.04). C3a, which has anti-inflammatory effects, correlated positively with FEV1% predicted (rs = 0.63, P = 0.02). These results suggest that complement effectors may significantly impact inflammation in CF lung fluid. PMID- 26642049 TI - Very-Heavy Precipitation in the Greater New York City Region and Widespread Drought Alleviation Tied to Western US Agriculture. AB - Observed intensification of precipitation extremes, responsible for extensive societal impacts, are widely attributed to anthropogenic sources, which may include indirect effects of agricultural irrigation. However quantifying the effects of irrigation on far-downstream climate remains a challenge. We use three paired Community Earth System Model simulations to assess mechanisms of irrigation-induced precipitation trends and extremes in the conterminous US and the effect on the terrestrial carbon sink. Results suggest precipitation enhancement in the central US reduced drought conditions and increased regional carbon uptake, while further downstream, the heaviest precipitation events were more frequent and intense. Specifically, moisture advection from irrigation in the western U.S. and recycling of enhanced local convective precipitation produced very-heavy storm events that were 11% more intense and occurred 23% more frequently in the densely populated greater New York City region. PMID- 26642050 TI - Colour Association with Music Is Mediated by Emotion: Evidence from an Experiment Using a CIE Lab Interface and Interviews. AB - Crossmodal associations may arise at neurological, perceptual, cognitive, or emotional levels of brain processing. Higher-level modal correspondences between musical timbre and visual colour have been previously investigated, though with limited sets of colour. We developed a novel response method that employs a tablet interface to navigate the CIE Lab colour space. The method was used in an experiment where 27 film music excerpts were presented to participants (n = 22) who continuously manipulated the colour and size of an on-screen patch to match the music. Analysis of the data replicated and extended earlier research, for example, that happy music was associated with yellow, music expressing anger with large red colour patches, and sad music with smaller patches towards dark blue. Correlation analysis suggested patterns of relationships between audio features and colour patch parameters. Using partial least squares regression, we tested models for predicting colour patch responses from audio features and ratings of perceived emotion in the music. Parsimonious models that included emotion robustly explained between 60% and 75% of the variation in each of the colour patch parameters, as measured by cross-validated R2. To illuminate the quantitative findings, we performed a content analysis of structured spoken interviews with the participants. This provided further evidence of a significant emotion mediation mechanism, whereby people tended to match colour association with the perceived emotion in the music. The mixed method approach of our study gives strong evidence that emotion can mediate crossmodal association between music and visual colour. The CIE Lab interface promises to be a useful tool in perceptual ratings of music and other sounds. PMID- 26642051 TI - The Effect of Disease Modifying Therapies on Disease Progression in Patients with Relapsing-Remitting Multiple Sclerosis: A Systematic Review and Meta-Analysis. AB - IMPORTANCE: A number of officially approved disease-modifying drugs (DMD) are currently available for the early intervention in patients with relapsing remitting multiple sclerosis (RRMS). The aim of the present study was to systematically evaluate the effect of DMDs on disability progression in RRMS. METHODS: We performed a systematic review on MEDLINE and SCOPUS databases to include all available placebo-controlled randomized clinical trials (RCTs) of RRMS patients that reported absolute numbers or percentages of disability progression during each study period. Observational studies, case series, case reports, RCTs without placebo subgroups and studies reporting the use of RRMS therapies that are not still officially approved were excluded. Risk ratios (RRs) were calculated in each study protocol to express the comparison of disability progression in RRMS patients treated with a DMD and those RRMS patients receiving placebo. The mixed-effects model was used to calculate both the pooled point estimate in each subgroup and the overall estimates. RESULTS: DMDs for RRMS were found to have a significantly lower risk of disability progression compared to placebo (RR = 0.72, 95%CI: 0.66-0.79; p<0.001), with no evidence of heterogeneity or publication bias. In subsequent subgroup analyses, neither dichotomization of DMDs as "first" and "second" line RRMS therapies [(RR = 0.72, 95% CI = 0.65-0.80) vs. (RR = 0.72, 95% = 0.57-0.91); p = 0.96] nor the route of administration (injectable or oral) [RR = 0.75 (95% CI = 0.64-0.87) vs. RR = 0.74 (95% CI = 0.66 0.83); p = 0.92] had a differential effect on the risk of disability progression. Either considerable (5-20%) or significant (>20%) rates of loss to follow-up were reported in many study protocols, while financial and/or other support from pharmaceutical industries with a clear conflict of interest on the study outcomes was documented in all included studies. CONCLUSIONS: Available DMD are effective in reducing disability progression in patients with RRMS, independently of the route of administration and their classification as "first" or "second" line therapies. Attrition bias needs to be taken into account in the interpretation of these findings. PMID- 26642052 TI - Predictors of Outcome and Hemorrhage in Patients Undergoing Endovascular Therapy with Solitaire Stent for Acute Ischemic Stroke. AB - BACKGROUND: Endovascular mechanical thrombectomy is emerging as a promising therapeutic approach for acute ischemic stroke and show some advantages. However, the data of predicting clinical outcome after thrombectomy with Solitaire retriever were limited. We attempt to identify prognostic factors of clinical outcome in patients with acute ischemic stroke undergoing thrombectomy with Solitaire retriever. METHODS: We conducted a retrospective analysis of consecutive acute ischemic strokes cases treated between December 2010 and December2013 where the Solitaire stent retriever was used for acute ischemic stroke. We assessed the effect of selected demographic characteristics, clinical factors on poor outcome at 3 months (modified Rankin score 3-6), mortality at 3 months, and hemorrhage within 24 h (symptomatic and asymptomatic). Clinical, imaging and logistic variables were analyzed. A multivariate logistic regression analysis was used to identify variables influencing clinical outcome, based on discharge NIHSS score change and mRS at 3 months. RESULTS: Eighty nine consecutive patients with acute ischemic stroke underwent mechanical thrombectomy. Multivariate analysis revealed that admission NIHSS score, Serum glucose and endovascular procedure duration were independently associated with clinical outcome. Sex, NIHSS score at admission, diabetes and time of operation were associated with sICH in 1 day. NIHSS score >=20 (OR 9.38; 95% CI 2.41 36.50), onset to reperfusion >5 hours (OR 5.23; 95% CI1.34,20.41) and symptomatic intracranial hemorrhage (OR 10.19; 95% CI1.80,57.83) were potential predictive factors of mortality at 3 months. CONCLUSION: Multiple pre- and intra-procedural factors can be used to predict clinical outcome, symptomatic intracranial hemorrhage and mortality in acute ischemic stroke patients undergoing endovascular therapy. This knowledge is helpful for patients selection for endovascular mechanical thrombectomy. PMID- 26642053 TI - The Schistosome Esophagus Is a 'Hotspot' for Microexon and Lysosomal Hydrolase Gene Expression: Implications for Blood Processing. AB - BACKGROUND: The schistosome esophagus is divided into anterior and posterior compartments, each surrounded by a dense cluster of gland cell bodies, the source of distinct secretory vesicles discharged into the lumen to initiate the processing of ingested blood. Erythrocytes are lysed in the lumen, leucocytes are tethered and killed and platelets are eliminated. We know little about the proteins secreted from the two glands that mediate these biological processes. METHODOLOGY/PRINCIPAL FINDINGS: We have used subtractive RNA-Seq to characterise the complement of genes that are differentially expressed in a head preparation, compared to matched tissues from worm tails. The expression site of representative highlighted genes was then validated using whole munt in situ hybridisation (WISH). Mapping of transcript reads to the S. mansoni genome assembly using Cufflinks identified ~90 genes that were differentially expressed >fourfold in the head preparation; ~50 novel transcripts were also identified by de novo assembly using Trinity. The largest subset (27) of secreted proteins was encoded by microexon genes (MEGs), the most intense focus identified to date. Expression of three (MEGs 12, 16, 17) was confirmed in the anterior gland and five (MEGs 8.1, 9, 11, 15 and 22) in the posterior gland. The other major subset comprised nine lysosomal hydrolases (aspartyl proteases, phospholipases and palmitoyl thioesterase), again localised to the glands. CONCLUSIONS: A proportion of the MEG-encoded secretory proteins can be classified by their primary structure. We have suggested testable hypotheses about how they might function, in conjunction with the lysosomal hydrolases, to mediate the biological processes that occur in the esophagus lumen. Antibodies bind to the esophageal secretions in both permissive and self-curing hosts, suggesting that the proteins represent a novel panel of untested vaccine candidates. A second major task is to identify which of them can serve as immune targets. PMID- 26642054 TI - Growth Simulation and Discrimination of Botrytis cinerea, Rhizopus stolonifer and Colletotrichum acutatum Using Hyperspectral Reflectance Imaging. AB - This research aimed to develop a rapid and nondestructive method to model the growth and discrimination of spoilage fungi, like Botrytis cinerea, Rhizopus stolonifer and Colletotrichum acutatum, based on hyperspectral imaging system (HIS). A hyperspectral imaging system was used to measure the spectral response of fungi inoculated on potato dextrose agar plates and stored at 28 degrees C and 85% RH. The fungi were analyzed every 12 h over two days during growth, and optimal simulation models were built based on HIS parameters. The results showed that the coefficients of determination (R2) of simulation models for testing datasets were 0.7223 to 0.9914, and the sum square error (SSE) and root mean square error (RMSE) were in a range of 2.03-53.40*10(-4) and 0.011-0.756, respectively. The correlation coefficients between the HIS parameters and colony forming units of fungi were high from 0.887 to 0.957. In addition, fungi species was discriminated by partial least squares discrimination analysis (PLSDA), with the classification accuracy of 97.5% for the test dataset at 36 h. The application of this method in real food has been addressed through the analysis of Botrytis cinerea, Rhizopus stolonifer and Colletotrichum acutatum inoculated in peaches, demonstrating that the HIS technique was effective for simulation of fungal infection in real food. This paper supplied a new technique and useful information for further study into modeling the growth of fungi and detecting fruit spoilage caused by fungi based on HIS. PMID- 26642055 TI - The Burden of Influenza-Associated Hospitalizations in Oman, January 2008-June 2013. AB - INTRODUCTION: Acute respiratory infections (ARI), including influenza, comprise a leading cause of morbidity and mortality worldwide. Influenza surveillance provides important information to inform policy on influenza control and vaccination. While the epidemiology of influenza has been well characterized in western countries, few data exist on influenza epidemiology in the Eastern Mediterranean Region. We describe the epidemiology of influenza virus in Oman. METHODS: Using syndromic case definitions and protocols, patients from four regional hospitals in Oman were enrolled in a descriptive prospective study to characterize the burden of severe acute respiratory infections (SARI) and influenza. Eligible patients provided demographic information as well as oropharyngeal (OP) and nasopharyngeal (NP) swabs. Specimens were tested for influenza A and influenza B; influenza A viruses were subtyped using RT-PCR. RESULTS: From January 2008 through June 2013, a total of 5,147 cases were enrolled and tested for influenza. Influenza strains were detected in 8% of cases for whom samples were available. Annual incidence rates ranged from 0.5 to 15.4 cases of influenza-associated SARI per 100,000 population. The median age of influenza patients was 6 years with children 0-2 years accounting for 34% of all influenza-associated hospitalizations. By contrast, the median age of non influenza SARI cases was 1 year with children 0-2 years comprising 59% of SARI. Compared to non-influenza SARI cases, a greater proportion of influenza cases had pre-existing chronic conditions and underwent ventilation during hospitalization. CONCLUSIONS: Influenza virus is associated with a substantial proportion of SARI in Oman. Influenza in Oman approximately follows northern hemisphere seasonality, with major peaks in October to December and a lesser peak around April. The burden of influenza was greatest in children and the elderly. Future efforts should examine the burden of influenza in other potential risk groups such as pregnant women to inform interventions including targeted vaccination. PMID- 26642056 TI - In Utero Cigarette Smoke Affects Allergic Airway Disease But Does Not Alter the Lung Methylome. AB - Prenatal and postnatal cigarette smoke exposure enhances the risk of developing asthma. Despite this as well as other smoking related risks, 11% of women still smoke during pregnancy. We hypothesized that cigarette smoke exposure during prenatal development generates long lasting differential methylation altering transcriptional activity that correlates with disease. In a house dust mite (HDM) model of allergic airway disease, we measured airway hyperresponsiveness (AHR) and airway inflammation between mice exposed prenatally to cigarette smoke (CS) or filtered air (FA). DNA methylation and gene expression were then measured in lung tissue. We demonstrate that HDM-treated CS mice develop a more severe allergic airway disease compared to HDM-treated FA mice including increased AHR and airway inflammation. While DNA methylation changes between the two HDM treated groups failed to reach genome-wide significance, 99 DMRs had an uncorrected p-value < 0.001. 6 of these 99 DMRs were selected for validation, based on the immune function of adjacent genes, and only 2 of the 6 DMRs confirmed the bisulfite sequencing data. Additionally, genes near these 6 DMRs (Lif, Il27ra, Tle4, Ptk7, Nfatc2, and Runx3) are differentially expressed between HDM-treated CS mice and HDM-treated FA mice. Our findings confirm that prenatal exposure to cigarette smoke is sufficient to modify allergic airway disease; however, it is unlikely that specific methylation changes account for the exposure-response relationship. These findings highlight the important role in utero cigarette smoke exposure plays in the development of allergic airway disease. PMID- 26642057 TI - Altered T Lymphocyte Proliferation upon Lipopolysaccharide Challenge Ex Vivo. AB - CONTEXT: Sepsis is characterized by the development of adaptive immune cell alterations, which intensity and duration are associated with increased risk of health-care associated infections and mortality. However, pathophysiological mechanisms leading to such lymphocyte dysfunctions are not completely understood, although both intrinsic lymphocyte alterations and antigen-presenting cells (APCs) dysfunctions are most likely involved. STUDY: The aim of the current study was to evaluate whether lipopolysaccharide (LPS, mimicking initial Gram negative bacterial challenge) could directly impact lymphocyte function after sepsis. Therefore, we explored ex-vivo the effect of LPS priming on human T lymphocyte proliferation induced by different stimuli. RESULTS: We showed that LPS priming of PBMCs reduced T cell proliferative response and altered IFNgamma secretion after stimulation with OKT3 but not with phytohaemagglutinin or anti-CD2/CD3/CD28 coated beads stimulations. Interestingly only LPS priming of monocytes led to decreased T cell proliferative response as opposed to LPS priming of lymphocytes. Importantly, LPS priming was associated with reduced expression of HLA-DR, CD86 and CD64 on monocytes but not with the modification of CD3, CTLA4, PD-1 and CD28 expressions on lymphocytes. Finally, IFNgamma stimulation restored monocytes accessory functions and T cell proliferative response to OKT3. CONCLUSION: We conclude that LPS priming does not directly impact lymphocyte functions but reduces APC's capacity to activate T cells. This recapitulates ex vivo indirect mechanisms participating in sepsis-induced lymphocyte alterations and suggests that monocyte-targeting immunoadjuvant therapies in sepsis may also help to improve adaptive immune dysfunctions. Direct mechanisms impacting lymphocytes being also at play during sepsis, the respective parts of direct versus indirect sepsis-induced lymphocyte alterations remain to be evaluated in clinic. PMID- 26642059 TI - Successful Wide Hybridization and Introgression Breeding in a Diverse Set of Common Peppers (Capsicum annuum) Using Different Cultivated Aji (C. baccatum) Accessions as Donor Parents. AB - Capsicum baccatum, commonly known as aji, has been reported as a source of variation for many different traits to improve common pepper (C. annuum), one of the most important vegetables in the world. However, strong interspecific hybridization barriers exist between them. A comparative study of two wide hybridization approaches for introgressing C. baccatum genes into C. annuum was performed: i) genetic bridge (GB) using C. chinense and C. frutescens as bridge species; and, ii) direct cross between C. annuum and C. baccatum combined with in vitro embryo rescue (ER). A diverse and representative collection of 18 accessions from four cultivated species of Capsicum was used, including C. annuum (12), C. baccatum (3), C. chinense (2), and C. frutescens (1). More than 5000 crosses were made and over 1000 embryos were rescued in the present study. C. chinense performed as a good bridge species between C. annuum and C. baccatum, with the best results being obtained with the cross combination [C. baccatum (?) * C. chinense (?)] (?) * C. annuum (?), while C. frutescens gave poor results as bridge species due to strong prezygotic and postzygotic barriers. Virus-like syndrome or dwarfism was observed in F1 hybrids when both C. chinense and C. frutescens were used as female parents. Regarding the ER strategy, the best response was found in C. annuum (?) * C. baccatum (?) crosses. First backcrosses to C. annuum (BC1s) were obtained according to the crossing scheme [C. annuum (?) * C. baccatum (?)] (?) * C. annuum (?) using ER. Advantages and disadvantages of each strategy are discussed in relation to their application to breeding programmes. These results provide breeders with useful practical information for the regular utilization of the C. baccatum gene pool in C. annuum breeding. PMID- 26642058 TI - Rare Variants in Transcript and Potential Regulatory Regions Explain a Small Percentage of the Missing Heritability of Complex Traits in Cattle. AB - The proportion of genetic variation in complex traits explained by rare variants is a key question for genomic prediction, and for identifying the basis of "missing heritability"--the proportion of additive genetic variation not captured by common variants on SNP arrays. Sequence variants in transcript and regulatory regions from 429 sequenced animals were used to impute high density SNP genotypes of 3311 Holstein sires to sequence. There were 675,062 common variants (MAF>0.05), 102,549 uncommon variants (0.0150% stenosis, but the relationship between PCOS and actual cardiovascular events remains unclear. Therapies for PCOS are varied in their effects and targets and include both nonpharmacologic as well as pharmacologic approaches. Weight loss is the primary therapy in PCOS--reduction in weight of as little as 5% can restore regular menses and improve response to ovulation- inducing and fertility medications. Metformin in premenopausal PCOS women has been associated with a reduction in features of MetS. Clamp studies using ethinyl estradiol/drosperinone combination failed to reveal evidence of an increase in either peripheral or hepatic insulin resistance. Subjects with PCOS have a 1.5-times higher baseline risk of venous thromboembolic disease and a 3.7-fold greater effect with OCP use compared with non-PCOS subjects. There is currently no genetic test to screen for or diagnose PCOS, and there is no test to assist in the choice of treatment strategies. Persistent bleeding should always be investigated for pregnancy and/or uterine pathology--including transvaginal ultrasound exam and endometrial biopsy--in women with PCOS. PCOS women can have difficulty conceiving. Those who become pregnant are at risk for gestational diabetes (which should be evaluated and managed appropriately) and the microvascular complications of diabetes. Assessment of a woman with PCOS for infertility involves evaluating for preconceptional issues that may affect response to therapy or lead to adverse pregnancy outcomes and evaluating the couple for other common infertility issues that may affect the choice of therapy, such as a semen analysis. Women with PCOS have multiple factors that may lead to an elevated risk of pregnancy, including a high prevalence of IGT--a clear risk factor for gestational diabetes--and MetS with hypertension, which increases the risk for pre-eclampsia and placental abruption. Women should be screened and treated for hypertension and diabetes prior to attempting conception. Women should be counseled about weight loss prior to attempting conception, although there are limited clinical trial data demonstrating a benefit to this recommendation. Treatment for women with PCOS and anovulatory infertility should begin with an oral agent such as clomiphene citrate or letrozole, an aromatase inhibitor. PMID- 26642103 TI - AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS, AMERICAN COLLEGE OF ENDOCRINOLOGY DISEASE STATE CLINICAL REVIEW: CLINICAL RELEVANCE OF MACROPROLACTIN IN THE ABSENCE OR PRESENCE OF TRUE HYPERPROLACTINEMIA. AB - OBJECTIVE: To review the current literature regarding the prevalence of macroprolactin (macroPRL) in hyperprolactinemic patients and determine recommendations for testing. METHODS: An electronic United States National Library of Medicine PubMed search (through October, 2014) was conducted for search term "macroprolactin." Only English-language articles were considered. RESULTS: MacroPRL is an under-recognized cause of elevated prolactin (PRL) and is present in approximately 4% to 40% of hyperprolactinemic patients depending on the referral population. Clinical findings which could be due to hyperprolactinemia are the impetus for testing for PRL. Because of this there is significant overlap in the clinical presentation of patients with true hyperprolactinemia and those with macroPRL, differentiation cannot always be made on the basis of symptoms. A lack of recognition of the presence of macroPRL can lead to unnecessary laboratory investigations, imaging, and pharmacologic or surgical treatment. CONCLUSION: Until there is a commercially available PRL assay that is not subject to interference by macroPRL, clinicians should consider the possibility of macroPRL, especially if the clinical presentation, imaging findings, and/or response to therapy reveal inconsistencies. PMID- 26642104 TI - Correction. PMID- 26642105 TI - Breast Cancer Survivorship Guidelines. PMID- 26642107 TI - 2-Acrylamido-2-methyl-1-propanesulfonic Acid Grafted Poly(vinylidene fluoride-co hexafluoropropylene)-Based Acid-/Oxidative-Resistant Cation Exchange for Membrane Electrolysis. AB - For developing acid-/oxidative-resistant aliphatic-polymer-based cation-exchange membrane (CEM), macromolecular modification of poly(vinylidene fluoride-co hexafluoropropylene) (PVDF-co-HFP) was carried out by controlled chemical grafting of 2-acrylamido-2-methyl-1-propanesulfonic acid (AMPS). To introduce the unsaturation suitable for chemical grafting, dehydrofluorination of commercially available PVDF-co-HFP was achieved under alkaline medium. Sulfonated copolymer (SCP) was prepared by the free radical copolymerization of dehydofluorinated PVDF co-HFP (DHPVDF-co-HFP) and AMPS in the presence of free radical initiator. Prepared SCP-based CEMs were analyzed for their morphological characteristics, ion-exchange capacity (IEC), water uptake, conductivity, and stabilities (mechanical, chemical, and thermal) in comparison with state-of-art Nafion117 membrane. High bound water content avoids the membrane dehydration, and most optimal (SCP-1.33) membrane exhibited about ~2.5-fold high bound water content in comparison with that of Nafion117 membrane. Bunsen reaction of iodine-sulfur (I S) was successfully performed by direct-contact-mode membrane electrolysis in a two-compartment electrolytic cell using different SCP membranes. High current efficiency (83-99%) confirmed absence of any side reaction and 328.05 kJ mol-H2( 1) energy was required for to produce 1 mol of H2 by electrolytic cell with SCP 1.33 membrane. In spite of low conductivity for reported SCP membrane in comparison with that of Nafion117 membrane, SCP-1.33 membrane was assessed as suitable candidate for electrolysis because of its low-cost nature and excellent stabilities in highly acidic environment may be due to partial fluorinated segments in the membrane structure. PMID- 26642108 TI - Patterns of Needlestick and Sharps Injuries Among Training Residents. PMID- 26642106 TI - Fabrication of High-Performance Magnetic Lysozyme-Imprinted Microsphere and Its NIR-Responsive Controlled Release Property. AB - The preparation of efficient and practical biomacromolecules imprinted polymer materials is still a challenging task because of the spatial hindrance caused by the large size of template and target molecules in the imprinting and recognition process. Herein, we provided a novel pathway to coat a NIR-light responsive lysozyme-imprinted polydopamine (PDA) layer on a fibrous SiO2 (F-SiO2) microsphere grown up from a magnetic Fe3O4 core nanoparticle. The magnetic core shell structured lysozyme-imprinted Fe3O4@F-SiO2@PDA microspheres (MIP-lysozyme) can be easily separated by a magnet and have a high saturation adsorption capacity of lysozyme of 700 mg/g within 30 min because of the high surface area of 570 m(2)/g and the mesopore size of 12 nm of the Fe3O4@F-SiO2 support. The MIP lysozyme microspheres also show an excellent selective adsorption of lysozyme (IF > 4). The binding thermodynamic parameters studied by ITC proves that the lysozyme should be restricted by the well-defined 3D structure of MIP-lysozyme microspheres. The MIP-lysozyme can extract lysozyme efficiently from real egg white. Owing to the efficient NIR light photothermal effect of PDA layer, the MIP lysozyme microspheres show the controlled release property triggered by NIR laser. The released lysozyme molecules still maintain good bioactivity, which can efficiently decompose E. coli. Therefore, this work provides a novel strategy to build practical NIR-light-responsive MIPs for the extraction and application of biomacromolecules. PMID- 26642109 TI - Thermal Processing Alters the Chemical Quality and Sensory Characteristics of Sweetsop (Annona squamosa L.) and Soursop (Annona muricata L.) Pulp and Nectar. AB - The objective of this study was to investigate the effect of thermal processing on the chemical quality and sensory characteristics of Annona squamosa L. and Annona muricata L. fruit pulps and nectar. The fruit pulps were pasteurized at 85 degrees C for 20 min and nectar prepared as per Food Safety and Standards Authority of India (FSSAI) specifications. The chemical composition of fresh and heated pulps of A. squamosa and A. muricata showed that compared to fresh, the chemical profile and sensory profile changed in heated samples and nectar. The free and bound phenolics of A. squamosa increased in heated pulp (127.61 to 217.22 mg/100 g and 150.34 to 239.74 mg/100 g, respectively), while in A. muricata, free phenolics increased very marginally from 31.73 to 33.74 mg/100 g and bound phenolics decreased from 111.11 to 86.91 mg/100 g. This increase in phenolic content may be attributed to the perception of bitterness and astringency in A. squamosa pulp on heating. In electronic tongue studies, principal component analysis (PCA) confirmed that the fresh and heated pulps had different scores, as indicated by sensory analysis using qualitative descriptive analysis (QDA). E-tongue analysis of samples discriminated the volatile compounds released from the heated A. squamosa and A. muricata fruit pulps and nectar in their respective PCA plots by forming different clusters. PMID- 26642112 TI - A Crusted Papule in a Premature Neonate. Cutaneous fungal infection. PMID- 26642113 TI - Patent Ductus Arteriosus in Preterm Neonates--Concerns With Some Recommendations. PMID- 26642115 TI - Reducing Weight Stigma in the Health Care Setting: Important Considerations for Medical Education. PMID- 26642114 TI - In Reply. PMID- 26642116 TI - Sexual Assault and Rape Among College Students. PMID- 26642117 TI - Infant Growth and Risk of Childhood-Onset Type 1 Diabetes in Children From 2 Scandinavian Birth Cohorts. AB - IMPORTANCE: Type 1 diabetes mellitus is one of the most common chronic diseases with onset in childhood, but environmental risk factors have not been convincingly established. OBJECTIVE: To test whether increased growth during the first year of life is associated with higher risk of childhood-onset type 1 diabetes. DESIGN, SETTING, AND PARTICIPANTS: This is a cohort study using information from 2 population-based cohort studies in Norway and Denmark, the Norwegian Mother and Child Cohort Study (MoBa) and the Danish National Birth Cohort (DNBC), of children born between February 1998 and July 2009. The current study was conducted between November 2014 and June 2015. EXPOSURES: Change in weight and length from birth to age 12 months. MAIN OUTCOMES AND MEASURES: Unadjusted and adjusted hazard ratios (HRs) of type 1 diabetes, classified based on nationwide childhood diabetes registers, obtained using Cox proportional hazards regression. RESULTS: A total of 99,832 children were included in the study, with 59,221 in MoBa (51.2% boys and 48.8% girls; mean age at end of follow up, 8.6 years [range, 4.6-14.2 years]) and 40,611 in DNBC (50.6% boys and 49.4% girls; mean age at end of follow-up, 13.0 years [range, 10.4-15.7 years]). The incidence rate of type 1 diabetes from age 12 months to the end of follow-up was 25 cases per 100,000 person-years in DNBC and 31 cases per 100,000 person-years in MoBa. The change in weight from birth to 12 months was positively associated with type 1 diabetes (pooled unadjusted HR = 1.24 per 1-SD increase; 95% CI, 1.11 1.39; pooled adjusted HR = 1.24 per 1-SD increase; 95% CI, 1.09-1.41). There was no significant association between length increase from birth to 12 months and type 1 diabetes (pooled unadjusted HR = 1.06 per 1-SD increase; 95% CI, 0.93 1.22; pooled adjusted HR = 1.06 per 1-SD increase; 95% CI, 0.86-1.32). The associations were similar in both sexes. CONCLUSIONS AND RELEVANCE: This is the first prospective population-based study, to our knowledge, providing evidence that weight increase during the first year of life is positively associated with type 1 diabetes. This supports the early environmental origins of type 1 diabetes. PMID- 26642119 TI - Sequelae Following Postnatally Acquired Cytomegalovirus Infection in Very Low Birth-Weight Neonates: Back to the Future. PMID- 26642118 TI - Postnatal Cytomegalovirus Infection and the Risk for Bronchopulmonary Dysplasia. AB - IMPORTANCE: Postnatally acquired cytomegalovirus (CMV) is typically benign in term infants but in very low-birth-weight (VLBW) infants can cause pneumonitis and sepsislike illness. Whether postnatal CMV infection results in long-term pulmonary sequelae in these infants is unknown. OBJECTIVE: To investigate the association between postnatal CMV infection and bronchopulmonary dysplasia (BPD) and mortality in a large multicenter cohort of VLBW infants. DESIGN, SETTING, AND PARTICIPANTS: Conducted between October 2014 and June 2015, this propensity matched retrospective cohort study involved 101,111 hospitalized VLBW (<1500 g) infants at 348 neonatal intensive care units in the United States from 1997 to 2012. We matched infants with postnatal CMV infection 1:1 to comparison infants using propensity scores, and we used Poisson regression to examine the effect of postnatal CMV on the combined risk for death or BPD at 36 weeks' postmenstrual age. To describe features of postnatal CMV infection, we extracted clinical and laboratory data from 7 days before until 7 days after infants met criteria for postnatal CMV. EXPOSURES: Postnatal CMV infection was defined as a diagnosis of CMV or detection of CMV from blood, urine, cerebrospinal fluid, or respiratory secretions on or after day of life 21. Infants with a CMV diagnosis or virologic detection of CMV prior to day of life 21 were not considered to have postnatal infection. MAIN OUTCOMES AND MEASURES: The primary outcome was death or BPD at 36 weeks' postmenstrual age. RESULTS: Of 101,111 infants, 328 (0.3%) had postnatal CMV infection. We matched a comparison infant to 303 CMV-infected infants (92%) for a final cohort of 606 infants. The median gestational age and birth weight of this cohort were 25 weeks and 730 g, respectively. Postnatal CMV infection was associated with an increased risk for death or BPD at 36 weeks' postmenstrual age (risk ratio, 1.21; 95% CI, 1.10-1.32) and BPD (risk ratio, 1.33; 95% CI, 1.19 1.50). Changes in cardiorespiratory status associated with postnatal CMV infection included a new requirement for vasopressor medications (9%; n = 29), intubation for mechanical ventilation (15%; n = 49), a new oxygen requirement (28%; n = 91), and death (1.2%; n = 4). CONCLUSIONS AND RELEVANCE: In VLBW infants, postnatal CMV infection was associated with increased risk for BPD. Further studies are needed to determine the role of preventive measures against CMV in this population. PMID- 26642121 TI - Tailoring the Valence Band Offset of Al2O3 on Epitaxial GaAs(1-y)Sb(y) with Tunable Antimony Composition. AB - Mixed-anion, GaAs1-ySby metamorphic materials with tunable antimony (Sb) compositions extending from 0 to 100%, grown by solid source molecular beam epitaxy (MBE), were used to investigate the evolution of interfacial chemistry under different passivation conditions. X-ray photoelectron spectroscopy (XPS) was used to determine the change in chemical state progression as a function of surface preclean and passivation, as well as the valence band offsets, conduction band offsets, energy band parameters, and bandgap of atomic layer deposited Al2O3 on GaAs1-ySby for the first time, which is further corroborated by X-ray analysis and cross-sectional transmission electron microscopy. Detailed XPS analysis revealed that the near midpoint composition, GaAs0.45Sb0.55, passivation scheme exhibits a GaAs-like surface, and that precleaning by HCl and (NH4)2S passivation are mandatory to remove native oxides from the surface of GaAsSb. The valence band offsets, DeltaEv, were determined from the difference in the core level to the valence band maximum binding energy of GaAs1-ySby. A valence band offset of >2 eV for all Sb compositions was found, indicating the potential of utilizing Al2O3 on GaAs1-ySby (0 <= y <= 1) for p-type metal-oxide-semiconductor (MOS) applications. Moreover, Al2O3 showed conduction band offset of ~2 eV on GaAs1 ySby (0 <= y <= 1), suggesting Al2O3 dielectric can also be used for n-type MOS applications. The surface passivation of GaAs0.45Sb0.55 materials and the detailed band alignment analysis of Al2O3 high-kappa dielectrics on tunable Sb composition, GaAs1-ySby materials, provides a pathway to utilize GaAsSb materials in future microelectronic and optoelectronic applications. PMID- 26642120 TI - Ovine rumen papillae biopsy via oral endoscopy; a rapid and repeatable method for serial sampling. AB - AIMS: To explore and validate the utility of rumen endoscopy for collection of rumen papillae for gene expression measurement. METHODS: Four adult Coopworth ewes were fasted for either 4 or 24 hours. Animals were sedated, placed in a dorsally recumbent position at 45 degrees with the head upright, and an endoscope inserted via a tube inserted into the mouth. Biopsies of rumen papillae were taken from the ventral surface of the rumen atrium under visual guidance. Two biopsies were collected from one of the animals that had been fasted for 4 hours, and three from one of the animals that had been fasted for 24 hours. Video of the rumen atrium and reticulum was also collected. The animals recovered uneventfully. Biopsies were subsequently used for extraction and sequencing of mRNA. RESULTS: The ventral surface of the rumen atrium was accessible after 4 hours off pasture, but a larger region was accessible after 24 hours of fasting. Sedation allowed access for endoscope use for around 5 to 10 minutes after which increased saliva flow was noted. Rumen papillae biopsies were easily collected, with samples from a variety of sites collected in the ~10 minute time window. High quality RNA was obtained for stranded mRNA sequencing. Of the resulting reads, 69-70% mapped uniquely to version 3.1 of the ovine genome, and 48-49% to a known gene. The rumen mRNA profiles were consistent with a previously reported study. CONCLUSIONS: This method for obtaining rumenal tissue was found to be rapid and resulted in no apparent short or long term effects on the animal. High quality RNA was successfully extracted and amplified from the rumen papillae biopsies, indicating that this technique could be used for future gene expression studies. The use of rumen endoscopy could be extended to collection of a variety of rumen and reticulum anatomical measurements and deposition and retrieval of small sensors from the rumen. Rumen endoscopy offers an attractive and cost effective approach to repeated rumen biopsies compared with serial slaughter or use of cannulated animals. PMID- 26642122 TI - Identifying Opportunities for Alignment in Pediatric Residency Training. PMID- 26642125 TI - Student loans assist with living expenses. PMID- 26642126 TI - How can veterinarians be reporters of animal abuse when they are not taught to recognize it? PMID- 26642127 TI - What Is Your Diagnosis? Intracavity lipomas. PMID- 26642128 TI - Theriogenology Question of the Month. Vulvovaginitis or uterine, cervical, or vaginal neoplasia. PMID- 26642129 TI - Pathology in Practice. Esophageal lesions. PMID- 26642130 TI - Pathology in Practice. Canine Morbillivirus infection. PMID- 26642131 TI - Epizootiological investigation of a Q fever outbreak and implications for future control strategies. AB - OBJECTIVE: To describe the epizootiological investigation of an outbreak of Q fever (Coxiella burnetii infection). DESIGN: Epidemiological study. ANIMALS: 17 goat herds in Washington, Montana, and Oregon. PROCEDURES: In April 2011, an abortion storm at a commercial goat farm in Washington was determined to be caused by C burnetii. A joint epidemiological investigation by public health and veterinary professionals was subsequently performed to assess the extent of the outbreak by performing a trace-forward of goats sold from the index farm, to determine risk factors associated with infection, and to implement control measures. A herd management plan was developed to control the outbreak and reduce risk of human exposure. Quarantine and temporary holds preventing the sale or movement of goats allowed time for trace-forward investigation, education of farmers regarding disease risk, and testing to determine the scope of the outbreak. RESULTS: 17 farms were affected; 21 human Q fever cases were identified. Bacterial shedding in feces, vaginal fluid, or milk was confirmed in 156 of 629 (25%) goats tested by PCR assay. Seroprevalence of antibodies against C burnetii in goats, determined by ELISA, was 12%. The risk for C burnetii infection in goats was highest among females, those on farms associated with human Q fever, and those on Washington farms. A protective effect was observed for goats at farms where the primary form of goat carcass disposal was burial. CONCLUSIONS AND CLINICAL RELEVANCE: This outbreak illustrated the importance of a joint investigation for zoonotic pathogens and the need to expand and strengthen relationships between medical, public health, and veterinary partners. Heightened awareness and enhanced veterinary diagnostic capabilities for C burnetii are needed to identify and control outbreaks expediently. PMID- 26642132 TI - Egg residue considerations during the treatment of backyard poultry. AB - The purpose of this digest was to provide US veterinarians guidance on the responsible treatment of backyard poultry flocks. The treatment of backyard poultry can be a daunting task for veterinarians because only limited resources are available; however, it is likely to become an increasingly common task owing to the increasing popularity of backyard poultry throughout the United States, especially in urban and suburban areas. Although backyard poultry flock owners may consider their birds pets, the FDA considers them food-producing animals, and veterinarians should follow all regulations that pertain to food-producing animals when administering or prescribing drugs to those birds. The lack of FDA approved drugs for use in laying hens frequently necessitates the use of drugs in an extralabel manner in backyard poultry. Unfortunately, information regarding the depletion of drug residues in eggs from hens treated with various drugs in an extralabel manner is sparse or lacking, and veterinarians need to be cognizant of this issue, especially when the eggs from treated hens are intended for human consumption. PMID- 26642134 TI - Splenic liposarcoma in dogs: 13 cases (2002-2012). AB - OBJECTIVE: To describe the clinical signs, diagnostic findings, surgical management, and outcome in dogs with splenic liposarcoma. DESIGN: Retrospective case series. ANIMALS: 13 client-owned dogs with splenic liposarcoma. PROCEDURES: Medical and pathology records of dogs with a histopathologic diagnosis of splenic liposarcoma from 2002 to 2012 were reviewed for the following data: clinical signs, CBC, biochemical profile, thoracic and abdominal imaging, surgical management, histologic grade, and outcome (local recurrence, distant metastasis, and survival time). Telephone interviews were conducted with referring veterinarians. RESULTS: The median survival time (MST) was 623 days (range, 1 to 1,283 days). In 5 dogs that died of splenic liposarcoma, survival times ranged from 42 to 369 days. Metastasis at the time of surgery was a negative prognostic indicator: the MST was 45 days for dogs with metastasis and 767 days for dogs without metastasis. Dogs with grade 1 splenic liposarcoma had a significantly greater MST (1,009 days), compared with dogs with grade 2 or 3 splenic liposarcoma (MST, 206 and 74 days, respectively). CONCLUSIONS AND CLINICAL RELEVANCE: Results confirmed that splenic liposarcoma is a rare differential diagnosis in dogs with a splenic mass. Survival time was influenced by preoperative clinical stage and histologic grade. PMID- 26642135 TI - Cervical intervertebral disk herniation in chondrodystrophoid and nonchondrodystrophoid small-breed dogs: 187 cases (1993-2013). AB - OBJECTIVE: To identify characteristics of chondrodystrophoid and nonchondrodystrophoid small-breed dogs with cervical intervertebral disk herniation (IVDH). DESIGN: Retrospective case series. ANIMALS: 187 small-breed (<= 15 kg [33 lb]) dogs that underwent surgery because of cervical IVDH. PROCEDURES: Medical records were reviewed for information on breed, sex, age, weight, location of affected intervertebral disks, duration and severity of neurologic signs, and recovery time. RESULTS: 55 of the 187 (29.4%) dogs were Beagles. The most frequently affected intervertebral disk was C2-3 (81/253 [32.0%]), and this was the more frequently affected intervertebral disk in dogs of several chondrodystrophoid breeds, including Beagles (29/66 [43.9%]), Dachshunds (13/37 [35.1%]), Shih Tzus (16/41 [39.0%]), and Pekingese (3/10 [30.0%]). However, caudal disks (C5-6 or C6-7) were more frequently affected in Yorkshire Terriers (13/24 [54.2%]) and Chihuahuas (9/13 [69%]). Shih Tzus and Yorkshire Terriers were significantly older at the time of surgery (mean +/- SD age, 9.6 +/- 2.3 years and 9.5 +/- 2.5 years, respectively) than were Pomeranians (6.2 +/- 2.3 years), and Yorkshire Terriers had a significantly higher number of affected disks (2.0 +/- 0.9) than did Dachshunds (1.1 +/- 0.3). Mean recovery time was significantly longer in Yorkshire Terriers (36.7 +/- 13.0 days) than in Beagles (16.5 +/- 17.1 days), Shih Tzus (17.8 +/- 14.5 days), or Chihuahuas (12.2 +/- 7. 2 days). CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that there may be breed-specific differences in the characteristics of cervical IVDH in small-breed dogs. PMID- 26642136 TI - Anicteric gallbladder rupture in dogs: 5 cases (2007-2013). AB - OBJECTIVE: To describe clinical, laboratory, and surgical findings in dogs with confirmed gallbladder rupture and in which serum total bilirubin concentration was within reference limits. DESIGN: Retrospective case series. ANIMALS: 5 dogs. PROCEDURES: Medical records were searched to identify dogs with gallbladder rupture that underwent treatment at the Kansas State University Veterinary Health Center from November 2007 through November 2013. Dogs were included if they had undergone abdominal ultrasonography, serum total bilirubin concentration was <= 0.4 mg/dL, and abdominal exploratory surgery confirmed the presence of gallbladder upture. RESULTS: An exploratory celotomy was performed in all dogs because of ultrasonographic findings of mild to marked abdominal effusion and either an unidentifiable gallbladder (n = 1 dog) or a distended gallbladder with a suspected gallbladder mucocele (4 dogs). Serum total bilirubin concentration was within reference limits (median, 0.2 mg/dL; range, 0.1 to 0.4 mg/dL; reference range, 0.1 to 0.4 mg/dL) in all dogs before surgery. In 1 dog, bile acids concentrations in serum and in peritoneal fluid were compared and the results (48 MUmol/L and 1,070 MUmol/L, respectively) were supportive of the diagnosis of gallbladder rupture. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that even when serum total bilirubin concentration is within reference limits, gallbladder rupture should be considered in dogs with acute signs of abdominal pain when a mucocele is suspected on abdominal imaging and free abdominal fluid is present. Results suggested that a comparison of serum to peritoneal fluid bile acids concentrations may provide additional support for a diagnosis of gallbladder rupture. PMID- 26642137 TI - Assessment of dexmedetomidine and other agents for emesis induction in cats: 43 cases (2009-2014). AB - OBJECTIVE: To compare the use of dexmedetomidine hydrochloride, xylazine hydrochloride, and hydrogen peroxide for emesis induction in cats. DESIGN: Retrospective case series. ANIMALS: 43 client-owned cats for which emesis induction was attempted because of known or suspected toxicant ingestion or recent ingestion of a string foreign body. PROCEDURES: Data collected from the cats' medical records included type, dose, and route of administration of emetic agent; outcome of attempted emesis induction; time until emesis or postemesis administration of a reversal agent (to counter sedative effects of the emetic agent); and adverse events. RESULTS: Emesis induction was attempted by oral administration of hydrogen peroxide (n = 3) or IM or IV administration of xylazine (25 [including 1 cat that had already received hydrogen peroxide]) or dexmedetomidine (16). No cat that received hydrogen peroxide vomited. Emesis was induced in 11 of 25 xylazine-treated cats and in 13 of 16 dexmedetomidine-treated cats. Dexmedetomidine was more likely to cause vomiting than xylazine (OR, 5.5; 95% confidence interval, 1.1 to 36). The median dose of dexmedetomidine that caused emesis was 7.0 MUg/kg (3.2 MUg/lb; range, 0.96 to 10.0 MUg/kg [0.44 to 4.55 MUg/lb]). The elapsed time until emesis or postemesis reversal agent administration was recorded for 5 xylazine-treated cats (median interval, 10 minutes [range, 5 to 175 minutes]) and 10 dexmedetomidine-treated cats (median interval, 5 minutes [range, 1 to 12 minutes]). Sedation was the only adverse effect, occurring in 2 xylazine-treated cats and 1 dexmedetomidine-treated cat. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that dexmedetomidine can be used successfully to induce emesis in cats. PMID- 26642138 TI - Keratitis in six dogs after topical treatment with carbonic anhydrase inhibitors for glaucoma. AB - CASE DESCRIPTION: 6 dogs (10 eyes) with keratitis following long-term topical treatment with a carbonic anhydrase inhibitor (CAI) were evaluated. In 4 dogs (6 eyes), CAI treatment was discontinued. Three dogs (4 eyes) underwent enucleation because of end-stage corneal disease. One dog was treated differently in each eye and thus was represented in both aforementioned groups. CLINICAL FINDINGS: Following initiation of treatment with a CAI (ie, brinzolamide or dorzolamide), the median time to development of severe ocular signs was 266 days (range, 133 to 679 days). Clinically severe ocular signs included ulcerative and nonulcerative perilimbal keratitis or severe diffuse keratitis with marked vascularization. The keratitis was refractory to treatment with anti-inflammatory medications. Histologic and immunohistochemical examination of enucleated globes was performed in 3 affected dogs and in 1 dog with keratitis that recovered. Corneal lesions included 2 distinct inflammatory infiltrates with plasma cells predominating in the anterior stroma and both T cells and neutrophils in the epithelium. Stromal plasma cells and overlying epithelium exhibited strong positive immunoreactivity for IgG. TREATMENT AND OUTCOME: Topical CAI treatment was discontinued in 4 dogs after a median of 209 days (range, 44 to 433 days), and in these dogs, clinical improvement was evident within 2 to 4 days of CAI treatment cessation. Signs of keratitis resolved in 12 to 25 days in these 4 dogs, and median follow-up time after CAI discontinuation was 25.5 months (range, 6 to 42 months), during which time signs of corneal disease did not recur. CLINICAL RELEVANCE: On the basis of this small series, presumed topical CAI-associated keratitis in dogs appeared to be an uncommon immune-mediated disease that was not responsive to corticosteroid treatment. Affected patients improved rapidly, but only after discontinuation of CAI treatment. In dogs with glaucoma, clinicians should consider the development of punctate keratopathy and severe diffuse keratitis as potential adverse effects related to topical administration of CAIs, even after previously uneventful long term use. PMID- 26642166 TI - Editorial. PMID- 26642139 TI - Potential for iatrogenic coil embolization of the caudal cerebellar artery during treatment of internal carotid artery bifurcation in two horses with guttural pouch mycosis. AB - CASE DESCRIPTION: 2 horses were examined for chronic nasal discharge secondary to unilateral guttural pouch mycosis. CLINICAL FINDINGS: Initial endoscopic examination of both horses confirmed the presence of a fungal plaque on the dorsomedial aspect of the medial compartment of the guttural pouch (auditory tube diverticulum) involving the internal carotid artery (ICA). No signs of hemorrhage or neurologic deficits were present at admission. TREATMENT AND OUTCOME: Transarterial stainless steel coil embolization of the affected ICA was performed under general anesthesia, with fluoroscopic guidance. During treatment, an aberrant branch of the ICA, or a proposed bifid ICA, that anastomosed with the caudal cerebellar artery was identified. Occlusion of the distal (noncardiac) side of the aberrant branch was performed in both horses because of potential mycotic involvement at that level. Following treatment, resolution of the mycotic infection was observed in both horses; however, 1 horse developed neurologic signs compatible with unilateral caudal cerebellar artery ischemia on recovery from anesthesia; these signs resolved over the following 2 months. CLINICAL RELEVANCE: Findings highlighted variability of the anatomy of the ICA in 2 horses that was identified during treatment for guttural pouch mycosis and identified caudal cerebellar artery infarction as a potential complication of treatment. Because of the size and pathway of both arterial branches, we suggest that the term bifurcation of the ICA is more appropriate than aberrant branching, as has been previously described in the literature. The information in this report may be of value to clinicians performing procedures involving the vasculature of the head and neck in horses. PMID- 26642167 TI - Talking about a (business continuity) revolution: Why best practices are wrong and possible solutions for getting them right. AB - The business continuity profession has been following a methodology that has barely evolved since its inception. Unfortunately, the stodgy, labour-intensive practices of the past are poorly suited to today's fast-paced and ever-changing work environments. Proposed herein is a new approach to the discipline. Just as agile methodology revolutionised project management, new tactics in preparedness can drastically change how this profession is practised. That is the hope. If there is to be any significant change in business continuity ahead, it may just take a revolution. PMID- 26642168 TI - Disaster prepared: How federal funding in the USA supports health system and public health readiness. AB - Federal funding for health and medical preparedness in the USA has created an important foundation for preparing the health and medical systems to respond to a wide range of hazards. A declining trend in funding for these preparedness activities threatens to undo the progress that has been made over the last decade and reduce the state of readiness to respond to the health and medical impacts of disasters. PMID- 26642169 TI - An academic approach to climate change emergency preparedness. AB - To achieve effective emergency management and business continuity, all hazards should be considered during the planning and preparedness process. In recent years, several new hazards have attracted the attention of Emergency Management and Business Continuity practitioners. Climate change presents a unique challenge. Practitioners must rely on historical data combined with scientific projections to guide their planning and preparedness efforts. This article examines how an academic institution's emergency management programme can plan successfully for this hazard by focusing on best practices in the area of building cross-departmental and cross-jurisdictional relationships. Examples of scientific data related to the hazard of climate change will be presented along with the latest guidance from the Federal Emergency Management Agency encouraging the planning for future hazards. The article presents a functional exercise in which this hazard was prominently featured, and presents testimony from subject matter experts. Recommendations for emergency management and business continuity programmes are so provided. PMID- 26642170 TI - Municipal resilience: A paradigm shift in emergency and continuity management. AB - More than a decade of emergency and continuity management vision was instrumental in providing the unprecedented level of response and recovery from the great flood of 2013. Earlier assessments, planning and validation promulgated development of corporate continuity, emergency and contingency plans along with tactical, strategic and recovery operations centres that all led to a reliable emergency management model that will continue to provide the backbone for municipal resilience. PMID- 26642171 TI - Building the bridge between healthcare emergency management and daily operations. AB - Healthcare emergency management continues to suffer from not being part of daily organisational operations. The aim of this paper is to shed light on a new paradigm for healthcare emergency management by viewing it in a distilled way: incidents that negatively affect the environment of care are simply deviations from normal. Doing so simplifies the approach and enables such work to meld more easily into the already complex healthcare clinical, operational and financial environs. Readers will take away knowledge on healthcare emergency management as deviations from normal operations, the goal being to aid in improving understanding and integrating such work into daily operations. The scope of this paper is a descriptive one of healthcare facilities, be they inpatient or outpatient, urban or rural and any combination of each. PMID- 26642172 TI - International employees' concerns during serious disease outbreaks and the potential impact on business continuity: Lessons identified from the 2014-15 West African Ebola outbreak. AB - This paper presents the findings of research carried out into the information seeking behaviour, and information requirements of a small sample of international workers stationed in West Africa during the Zaire Ebola virus outbreak of 2014-15. The research study under which these results were obtained was part of exploratory research for a PhD focused on the use, and potential uses, of social media platforms during serious disease outbreaks that might be used to inform policy planning for public health and emergency response interventions. Thus, the findings from this study may provide valuable insights to business continuity managers and emergency planners in making future decisions about information exchange and crisis decision-making during future serious disease outbreaks. PMID- 26642173 TI - Resilience and 21st century malicious attacks. PMID- 26642174 TI - Resilience and legislation: Will IT security legislation boost critical infrastructure resilience in Germany? AB - The German government is seeking to enhance the resilience of critical national infrastructures via its new IT Security Law. This paper analyses the content of the law, as well as the limitations and constraints arising from the conflicting interests of affected stakeholders. The paper also offers solutions to help the IT Security Law fulfil its potential despite the constraints. PMID- 26642175 TI - Shaken but prepared: Analysis of disaster response at an academic medical centre following the Boston Marathon bombings. AB - Over the last decade, there has been a rise in the number of mass casualty incidences (MCIs) and their subsequent effect on hospital systems. While there has been much discussion over improving procedures to treat victims of MCIs, there has not been a thorough, systems-based analysis concerning the costs incurred by hospitals during such events. Here the authors examine the history of the Hospital Incident Command Center and how its evolution at Tufts Medical Center helped mitigate the damage following the Boston Marathon Bombings. Tufts' unique variations to the Hospital Incident Command Center include strategic communication hierarchies and a 'zero cost centre' financial system which both provided for a quick and adaptive response. Operating in collaboration with the Conference of Boston Teaching Hospitals encouraged coordination and preparation during emergency situations such as mass casualty events. The direct and indirect effects on Tufts Medical Center stemming from the Boston Marathon Bombings were analysed. Tufts MC treated 36 victims immediately following the MCI. The estimated total cost during the week of April 15 to April 19, 2013 was $776,051. The cost was primarily comprised of lost revenue from cancelled outpatient and inpatient hospital services, as well as expenses incurred due to overtime pay, salary expenses, PPE kits and hospitality services. Finally, the authors examine ways to reduce the future costs during emergency situations through increasing communication with employees, understanding the source of all direct expenses, and mitigating excess risk by developing partnerships with other hospital systems. PMID- 26642176 TI - Building organisational cyber resilience: A strategic knowledge-based view of cyber security management. AB - The concept of cyber resilience has emerged in recent years in response to the recognition that cyber security is more than just risk management. Cyber resilience is the goal of organisations, institutions and governments across the world and yet the emerging literature is somewhat fragmented due to the lack of a common approach to the subject. This limits the possibility of effective collaboration across public, private and governmental actors in their efforts to build and maintain cyber resilience. In response to this limitation, and to calls for a more strategically focused approach, this paper offers a knowledge-based view of cyber security management that explains how an organisation can build, assess, and maintain cyber resilience. PMID- 26642177 TI - The Relationships of Nurse Staffing Level and Work Environment With Patient Adverse Events. AB - PURPOSE: The purpose of this study was to examine the relationships of nurse staffing level and work environment with patient adverse events. DESIGN: This cross-sectional study used a combination of nurse survey data (N = 4,864 nurses), facility data (N = 58 hospitals), and patient hospital discharge data (N = 113,426 patients) in South Korea. METHODS: The three most commonly nurse-reported adverse events included administration of the wrong medication or dose to a patient, pressure ulcers, and injury from a fall after admission. Multilevel ordinal logistic regression was employed to explore the relationships of nurse staffing level (number of patients assigned to a nurse) and work environment (Practice Environment Scale of the Nursing Work Index) with patient adverse events after controlling for nurse, hospital, and patient characteristics. FINDINGS: A larger number of patients per nurse was significantly associated with a greater incidence of administration of the wrong medication or dose (odds ratio [OR] = 1.01, 95% confidence interval [CI] = 1.007-1.016), pressure ulcer (OR = 1.01, 95% CI = 1.007-1.016), and patient falls with injury (OR = 1.02, 95% CI = 1.013-1.022). A better work environment had a significant inverse relationship with adverse events; the odds of reporting a higher incidence of adverse events were 45% lower for administration of the wrong medication or dose (OR = 0.55, 95% CI = 0.400-0.758), followed by 39% lower for pressure ulcer (OR = 0.61, 95% CI = 0.449-0.834) and 32% lower for falls with injury after admission (OR = 0.68, 95% CI = 0.490-0.939). CONCLUSIONS: This study found that a larger number of patients per nurse and poor work environment increase the incidence of patient adverse events, such as administration of the wrong medication or dose to a patient, pressure ulcers, and injury from falling after admission. The findings suggest that South Korean hospitals could prevent patient adverse events by improving nurse staffing and work environment. CLINICAL RELEVANCE: Healthcare strategies and efforts to modify adequate nurse staffing levels and better work environments for nurses are needed to improve patient outcomes. PMID- 26642178 TI - Exploration of a potential difluoromethyl-nucleoside substrate with the fluorinase enzyme. AB - The investigation of a difluoromethyl-bearing nucleoside with the fluorinase enzyme is described. 5',5'-Difluoro-5'-deoxyadenosine 7 (F2DA) was synthesised from adenosine, and found to bind to the fluorinase enzyme by isothermal titration calorimetry with similar affinity compared to 5'-fluoro-5' deoxyadenosine 2 (FDA), the natural product of the enzymatic reaction. F2DA7 was found, however, not to undergo the enzyme catalysed reaction with L selenomethionine, unlike FDA 2, which undergoes reaction with L-selenomethionine to generate Se-adenosylselenomethionine. A co-crystal structure of the fluorinase and F2DA7 and tartrate was solved to 1.8A, and revealed that the difluoromethyl group bridges interactions known to be essential for activation of the single fluorine in FDA 2. An unusual hydrogen bonding interaction between the hydrogen of the difluoromethyl group and one of the hydroxyl oxygens of the tartrate ligand was also observed. The bridging interactions, coupled with the inherently stronger C-F bond in the difluoromethyl group, offers an explanation for why no reaction is observed. PMID- 26642179 TI - Correlates of family involvement before and during medical visits among older adults with high-risk diabetes. AB - AIMS: To examine the characteristics of patients with diabetes who regularly receive help from a supporter in preparing for and attending medical visits, and the association between this help and clinical risk factors for diabetes complications. METHODS: We linked survey data about family involvement for patients in the Veterans Health Administration system with poorly controlled Type 2 diabetes (n = 588; mean 67 years; 97% male) with health record data on blood pressure, glycaemic control and prescription-fill gaps. We used multivariable regression to assess whether supporter presence and, among patients with supporters, supporter role (visit preparation, accompaniment to medical visit or no involvement) were associated with concurrent trends in clinical risk factors over 2 years, adjusting for sociodemographic and health characteristics. RESULTS: Most patients (78%) had a main health supporter; of these, more had regular support for preparing for appointments (69%) than were regularly accompanied to them (45%). Patients with preparation help only were younger and more educated than accompanied patients. Support presence and type was not significantly associated with clinical risk factors. CONCLUSIONS: Family help preparing for appointments was common among these patients with high-risk diabetes. In its current form, family support for medical visits may not affect clinical factors in the short term. Supporters helping patients engage in medical visits may need training and assistance to have an impact on the clinical trajectory of patients with diabetes. PMID- 26642180 TI - Effect of lipopolysaccharide on the hemocyte apoptosis of Eriocheir sinensis. AB - In the present study, we investigated the possible toxicity mechanism of lipopolysaccharide (LPS) extracted from Gram-negative bacteria in Eriocheir sinensis hemocytes. Apoptotic hemocytes and reactive oxygen species (ROS) production induced by the LPS were monitored by the combination of flow cytometry and microscope observation. It was shown that LPS induced serious damage on the DNA and morphological changes in hemocytes, including cell shrinkage, fracture of nucleus membrane, margination, condensation and fragmentation of chromatin, and formation of apoptotic bodies indicating obvious hemocyte apoptosis. As compared with the control group, the apoptotic cell ratio increased to 30.61% and 39.01% after 1-h exposure and 57.72% and 75.01% after 2-h exposure to 1 and 10 MUg/ml LPS, respectively (P<0.05). Significant outburst of ROS production was observed in LPS-treated hemocytes with approximately 176.6% of relative dichlorofluorescein mean fluorescence at 1-h exposure, followed by a drastic decline (P<0.05). These results indicated that LPS would induce oxidative stress on hemocytes from E. sinensis and cause ROS burst, DNA damage, and subsequently apoptosis. The process of ROS-mediated apoptosis might be one of the potential toxicity mechanisms of LPS on crustacean hemocytes. PMID- 26642181 TI - Induction of follicular luteinization by equine chorionic gonadotropin in cyclic guinea pigs. AB - The effects of equine chorionic gonadotropin (eCG) on follicular development and ovulation in cyclic guinea pigs were investigated by histological and immunohistochemical analyses. Three groups of guinea pigs (n=12) were administrated subcutaneously with saline, 20 or 50 IU of eCG, respectively, on cyclic Day 12 (Day 1=vaginal openings). Ovaries were collected at 4 and 8 d after administration (6 animals per group each time). The eCG administration induced significant and distinct morphological changes in the ovaries, as it promoted the luteinization of granulosa cells, but not follicular development. In addition, proliferating cell nuclear antigen (PCNA) and steroidogenic acute regulatory protein (StAR) were immunolocalized specifically in luteinized follicles. Our experiments together indicate that eCG administration can induce follicular luteinization but not superovulation in guinea pigs. The eCG in cyclic guinea pigs functions similar to that of luteinizing hormone (LH), but not follicle stimulating hormone (FSH). PMID- 26642182 TI - Construction and analysis of the cDNA subtraction library of yeast and mycelial phases of Sporothrix globosa isolated in China: identification of differentially expressed genes. AB - Species included in the Sporothrix schenckii complex are temperature-dependent with dimorphic growth and cause sporotrichosis that is characterized by chronic and fatal lymphocutaneous lesions. The putative species included in the Sporothrix complex are S. brasiliensis, S. globosa, S. mexicana, S. pallida, S. schenckii, and S. lurei. S. globosa is the causal agent of sporotrichosis in China, and its pathogenicity appears to be closely related to the dimorphic transition, i.e. from the mycelial to the yeast phase, it adapts to changing environmental conditions. To determine the molecular mechanisms of the switching process that mediates the dimorphic transition of S. globosa, suppression subtractive hybridization (SSH) was used to prepare a complementary DNA (cDNA) subtraction library from the yeast and mycelial phases. Bioinformatics analysis was performed to profile the relationship between differently expressed genes and the dimorphic transition. Two genes that were expressed at higher levels by the yeast form were selected, and their differential expression levels were verified using a quantitative real-time reverse transcriptase polymerase chain reaction (qRT-PCR). It is believed that these differently expressed genes are involved in the pathogenesis of S. globosa infection in China. PMID- 26642183 TI - Submerged fermentation production and characterization of intracellular triterpenoids from Ganoderma lucidum using HPLC-ESI-MS. AB - As the main bioactive metabolites of Ganoderma lucidum, triterpenoids have various pharmacological effects. In this paper, the nutritional requirements and culture conditions of a submerged culture of G. lucidum were optimized using the response surface methodology; maximum mycelia biomass and intracellular triterpenoid production reached 1.87 g/100 ml and 93.21 mg/100 ml, respectively, for a culture consisting of wort 4.10% (0.041 g/ml) and yeast extract 1.89% (0.0189 g/ml), pH 5.40. For the first time, we established that wort, which is cheap and abundant, can replace the more commonly used glucose as the sole source of carbohydrate. Using high-performance liquid chromatography-electrospray ionization-mass spectrometry (HPLC-ESI-MS), 10 major ganoderic acids were tentatively identified based on the predominant fragmentation pathways with the elimination of H2O and CO2, as well as cleavage of the D-ring. PMID- 26642184 TI - Mutualistic fungal endophytes produce phytohormones and organic acids that promote japonica rice plant growth under prolonged heat stress. AB - This study identifies the potential role in heat-stress mitigation of phytohormones and other secondary metabolites produced by the endophytic fungus Paecilomyces formosus LWL1 in japonica rice cultivar Dongjin. The japonica rice was grown in controlled chamber conditions with and without P. formosus LWL1 under no stress (NS) and prolonged heat stress (HS) conditions. Endophytic association under NS and HS conditions significantly improved plant growth attributes, such as plant height, fresh weight, dry weight, and chlorophyll content. Furthermore, P. formosus LWL1 protected the rice plants from HS compared with controls, indicated by the lower endogenous level of stress-signaling compounds such as abscisic acid (25.71%) and jasmonic acid (34.57%) and the increase in total protein content (18.76%-33.22%). Such fungal endophytes may be helpful for sustainable crop production under high environmental temperatures. PMID- 26642185 TI - Long-term effects of oral tea polyphenols and Lactobacillus brevis M8 on biochemical parameters, digestive enzymes, and cytokines expression in broilers. AB - This study investigates the long-term effects of oral tea polyphenols (TPs) and Lactobacillus brevis M8 (LB) on biochemical parameters, digestive enzymes, and cytokines expression in broilers. In experiment 1, 240 broiler chickens were selected to investigate the effects of 0.06 g/kg body weight (BW) TP and 1.0 ml/kg BW LB on broilers; in experiment 2, 180 broiler chickens were assigned randomly to three groups to investigate the effects of different dosages of TP (0.03, 0.06, and 0.09 g/kg BW) combined with 1.0 ml/kg BW LB on broilers; in experiment 3, 180 broiler chickens were assigned randomly to three groups to investigate the effects of different dosages of LB (0.5, 1.0, and 1.5 ml/kg BW) combined with 0.06 g/kg BW TP on broilers. The results showed that TP and LB affected serum biochemical parameters, and TP reduced serum cholesterol (CHO) and low-density lipoprotein cholesterol (LDL-C) abundances in a dosage-dependent manner (P<0.05) on Day 84. Meanwhile, broilers fed a diet supplemented with TP or LB had a lower intestinal lipase activity on Day 84 compared with the control group (P<0.05). Middle and high dosages of TP increased pancreatic lipase and proventriculus pepsin activities (P<0.05). Also middle and high dosages of LB significantly enhanced pancreatic lipase activity (P<0.05), while high LB supplementation inhibited intestinal trypsase (P<0.05) on Day 84. Furthermore, both TP and LB reduced intestinal cytokine expression and nuclear factor-kappa B (NF-kappaB) mRNA level on Days 56 and 84. In conclusion, long-term treatment of TP and LB improved lipid metabolism and digestive enzymes activities, and affected intestinal inflammatory status, which may be associated with the NF kappaB signal. PMID- 26642186 TI - Transcriptome changes in Polygonum multiflorum Thunb. roots induced by methyl jasmonate. AB - Transcriptome profiling has been widely used to analyze transcriptomic variation in plants subjected to abiotic or biotic stresses. Although gene expression changes induced by methyl jasmonate (MeJA) have been profiled in several plant species, no information is available on the MeJA-triggered transcriptome response of Polygonum multiflorum Thunb., a species with highly valuable medicinal properties. In this study, we used transcriptome profiling to investigate transcriptome changes in roots of P. multiflorum seedlings subjected to a 0.25 mmol/L-MeJA root-irrigation treatment. A total of 18 677 differentially expressed genes (DEGs) were induced by MeJA treatment, of which 4535 were up-regulated and 14 142 were down-regulated compared with controls. These DEGs were associated with 125 metabolic pathways. In addition to various common primary and secondary metabolic pathways, several secondary metabolic pathways related to components with significant pharmacological effects were enriched by MeJA, including arachidonic acid metabolism, linoleic acid metabolism, and stilbenoid biosynthesis. The MeJA-induced transcriptome changes uncovered in this study provide a solid foundation for future study of functional genes controlling effective components in secondary metabolic pathways of P. multiflorum. PMID- 26642187 TI - Investigation of one-lung ventilation postoperative cognitive dysfunction and regional cerebral oxygen saturation relations. AB - OBJECTIVE: To explore the relationship of postoperative cognitive dysfunction (POCD) in one-lung ventilation (OLV) patients and regional cerebral oxygen saturation (rSO2). METHODS: Twenty-nine male and twenty-one female cases of OLV received thoracic surgery, with American Standards Association (ASA) physical status being at Grades I-III. Neuropsychological tests were performed on the day before operation and 7 d after operation, and there was an intraoperative continuous monitoring of rSO2. The values of rSO2 before anesthesia induction (t1), at the beginning of OLV (t2), and at the time of OLV 30 min (t3), OLV 60 min (t4), the end of OLV (t5), and the end of surgery (t6) were recorded. The intraoperative average of rSO2 , the intraoperative minimum value of rSO2 (rSO(2, min)), and the reduced maximum percentage of rSO2 (rSO(2, %max)) when compared with the baseline value were calculated. The volume of blood loss, urine output, and the amount of fluid infusion was recorded. RESULTS: A total of 14 patients (28%) in the 50 cases suffered from POCD. The values of mini-mental state examination (MMSE), the digit span and the digit symbol on the 7th day after the operation for POCD in OLV patients were found to be significantly lower than those before the operation (P<0.05). The values of MMSE and vocabulary fluency scores were significantly lower than those in the non-POCD group (P<0.05). The values of rSO2 in the POCD group of OLV patients at t2 and t3 and the values of rSO2 in the non-POCD group at t2 were found to be significantly higher than those at t1 (P<0.05). The values of rSO(2, %max) in the POCD group were significantly higher than those in the non-POCD group (P<0.05). When the value of rSO(2, %max) is more than 10.1%, it may act as an early warning index for cognitive function changes. CONCLUSIONS: POCD after OLV may be associated with a decline in rSO2. PMID- 26642188 TI - Development and application of multiple immunofluorescence staining for diagnostic cytology of canine and feline lymphoma. AB - BACKGROUND: Immunophenotyping of canine and feline lymphoma to determine B-cell or T-cell origin is important for predicting prognosis and for development of treatment protocols. For advanced diagnostic cytology tests that can be performed on smears are required to predict the immunophenotype of lymphomas. OBJECTIVES: The aim of this study was to develop a multiple immunofluorescence (MIF) staining method for the determination of lymphocyte immunophenotype in cytologic specimens, and to evaluate its clinical utility. METHODS: B cells and T cells were detected using anti-CD79alpha and anti-CD3 antibodies, respectively, followed by specific fluorescence-labeled secondary antibodies. The MIF staining method was first developed using fresh-frozen sections of normal canine lymph nodes. The optimal fixative, the necessity of antigen retrieval (AR), and the optimal concentration of the antibodies were determined. The MIF method was then applied to smears of normal lymph nodes, and to clinical samples from dogs and cats with lymphoma. The MIF results were compared to genetic clonality results. RESULTS: B and T cells were detected based on specific fluorescence in frozen sections, using formalin fixation without AR. Specific fluorescence was also detected in smears from normal lymph nodes and lymphomas, and the immunophenotypes predicted from this MIF staining method completely corresponded to those from genetic clonality analysis. CONCLUSIONS: The MIF staining method that we developed in this study effectively distinguished lymphocyte immunophenotypes with high specificity and sensitivity using a single smear sample, and was useful as a diagnostic tool for canine and feline lymphoma. PMID- 26642189 TI - Into and out of the tropics: global diversification patterns in a hyperdiverse clade of ectomycorrhizal fungi. AB - Ectomycorrhizal (ECM) fungi, symbiotic mutualists of many dominant tree and shrub species, exhibit a biogeographic pattern counter to the established latitudinal diversity gradient of most macroflora and fauna. However, an evolutionary basis for this pattern has not been explicitly tested in a diverse lineage. In this study, we reconstructed a mega-phylogeny of a cosmopolitan and hyperdiverse genus of ECM fungi, Russula, sampling from annotated collections and utilizing publically available sequences deposited in GenBank. Metadata from molecular operational taxonomic unit cluster sets were examined to infer the distribution and plant association of the genus. This allowed us to test for differences in patterns of diversification between tropical and extratropical taxa, as well as how their associations with different plant lineages may be a driver of diversification. Results show that Russula is most species-rich at temperate latitudes and ancestral state reconstruction shows that the genus initially diversified in temperate areas. Migration into and out of the tropics characterizes the early evolution of the genus, and these transitions have been frequent since this time. We propose the 'generalized diversification rate' hypothesis to explain the reversed latitudinal diversity gradient pattern in Russula as we detect a higher net diversification rate in extratropical lineages. Patterns of diversification with plant associates support host switching and host expansion as driving diversification, with a higher diversification rate in lineages associated with Pinaceae and frequent transitions to association with angiosperms. PMID- 26642190 TI - CrossTalk proposal: High intensity interval training does have a role in risk reduction or treatment of disease. PMID- 26642191 TI - Applying a PCR-based open-reading frame typing method for easy genotyping and molecular epidemiological analysis of Pseudomonas aeruginosa. AB - AIMS: Molecular epidemiological techniques, such as pulsed-field gel electrophoresis (PFGE), or multilocus sequence typing (MLST) have facilitated our understanding of the transmission routes of nosocomial infections by Pseudomonas aeruginosa. However, they are time consuming and technically demanding. To perform molecular epidemiological analysis in a standard microbiology laboratory, we aimed to develop a simpler and effective molecular epidemiological technique based on the open-reading frame (ORF) distribution patterns detected by PCR, which we call PCR-based ORF typing (POT). METHODS AND RESULTS: Ten ORFs from genomic islets, five ORFs from genomic islands, and the metallo-beta-lactamases (MBLs) blaIMP and blaVIM were selected by comparing the whole-genome sequences of different Ps. aeruginosa strains (PAO1, PA7, UCBPP-PA14 and LESB58). These 17 ORFs were detected, along with a Ps. aeruginosa marker, using 9-plex and 10-plex PCR systems. The genotypes in the POT were compared to those obtained by using PFGE and MLST. CONCLUSIONS: Using the POT method, molecular epidemiological analyses of Ps. aeruginosa can be completed in 4 h. SIGNIFICANCE AND IMPACT OF THE STUDY: Since this method is very easy to perform, even in standard clinical laboratories, it could be a valuable tool for monitoring daily infection control measures. PMID- 26642193 TI - Behavior of Tilted Angle Shear Connectors. AB - According to recent researches, angle shear connectors are appropriate to transfer longitudinal shear forces across the steel-concrete interface. Angle steel profile has been used in different positions as L-shaped or C-shaped shear connectors. The application of angle shear connectors in tilted positions is of interest in this study. This study investigates the behaviour of tilted-shaped angle shear connectors under monotonic loading using experimental push out tests. Eight push-out specimens are tested to investigate the effects of different angle parameters on the ultimate load capacity of connectors. Two different tilted angles of 112.5 and 135 degrees between the angle leg and steel beam are considered. In addition, angle sizes and lengths are varied. Two different failure modes were observed consisting of concrete crushing-splitting and connector fracture. By increasing the size of connector, the maximum load increased for most cases. In general, the 135 degrees tilted angle shear connectors have a higher strength and stiffness than the 112.5 degrees type. PMID- 26642194 TI - Mouse Sphingosine Kinase 1a Is Negatively Regulated through Conventional PKC Dependent Phosphorylation at S373 Residue. AB - Sphingosine kinase is a lipid kinase that converts sphingosine into sphingosine-1 phosphate, an important signaling molecule with intracellular and extracellular functions. Although diverse extracellular stimuli influence cellular sphingosine kinase activity, the molecular mechanisms underlying its regulation remain to be clarified. In this study, we investigated the phosphorylation-dependent regulation of mouse sphingosine kinase (mSK) isoforms 1 and 2. mSK1a was robustly phosphorylated in response to extracellular stimuli such as phorbol ester, whereas mSK2 exhibited a high basal level of phosphorylation in quiescent cells regardless of agonist stimulation. Interestingly, phorbol ester-induced phosphorylation of mSK1a correlated with suppression of its activity. Chemical inhibition of conventional PKCs (cPKCs) abolished mSK1a phosphorylation, while overexpression of PKCalpha, a cPKC isoform, potentiated the phosphorylation, in response to phorbol ester. Furthermore, an in vitro kinase assay showed that PKCalpha directly phosphorylated mSK1a. In addition, phosphopeptide mapping analysis determined that the S373 residue of mSK1a was the only site phosphorylated by cPKC. Interestingly, alanine substitution of S373 made mSK1a refractory to the inhibitory effect of phorbol esters, whereas glutamate substitution of the same residue resulted in a significant reduction in mSK1a activity, suggesting the significant role of this phosphorylation event. Taken together, we propose that mSK1a is negatively regulated through cPKC-dependent phosphorylation at S373 residue. PMID- 26642195 TI - Functional Limitations, Medication Support, and Responses to Drug Costs among Medicare Beneficiaries. AB - OBJECTIVE: Standard Medicare Part D prescription drug benefits include substantial and complex cost-sharing. Many beneficiaries also have functional limitations that could affect self-care capabilities, including managing medications, but also have varying levels of social support to help with these activities. We examined the associations between drug cost responses, functional limitations, and social support. DATA SOURCES AND STUDY SETTING: We conducted telephone interviews in a stratified random sample of community-dwelling Medicare Advantage beneficiaries (N = 1,201, response rate = 70.0%). Participants reported their functional status (i.e., difficulty with activities of daily living) and social support (i.e., receiving help with medications). Drug cost responses included cost-reducing behaviors, cost-related non-adherence, and financial stress. STUDY DESIGN: We used multivariate logistic regression to assess associations among functional status, help with medications, and drug cost responses, adjusting for patient characteristics. PRINCIPAL FINDINGS: Respondents with multiple limitations who did not receive help with their medications were more likely to report cost-related non-adherence (OR = 3.2, 95% CI: 1.2-8.5) and financial stress (OR = 2.4, 95% CI: 1.3-4.5) compared to subjects with fewer limitations and no help; however, those with multiple limitations and with medication help had similar odds of unfavorable cost responses as those with fewer limitations. CONCLUSION: The majority of beneficiaries with functional limitations did not receive help with medications. Support with medication management for beneficiaries who have functional limitations could improve adherence and outcomes. PMID- 26642196 TI - Molecular Pathology of Cryptorchidism-Induced Infertility. AB - Cryptorchidism is the most common cause of non-obstructive azoospermia in man. In contrast to the general belief that temperature-dependent effects on the undescended gonad damage cryptorchid testes before sexual maturation is complete, molecular pathology strongly supports the theory that impaired mini-puberty is responsible for azoospermia and infertility in cryptorchidism. Molecular biological observations favor LH deficiency, with EGR4 as a master regulatory gene in Leydig cell dysgenesis, as the reason for impaired mini-puberty, and recent evidence supports the idea that infertility in cryptorchidism is a consequence of alterations in the Piwi pathway. PMID- 26642197 TI - New Predictive Equations for Serum Ionized Calcium in Hospitalized Patients. AB - OBJECTIVE: To study a new and easy way to calculate equations to predict ionized calcium (Ca2+) for adult hospitalized patients with the usual laboratory and clinical parameters. SUBJECTS AND METHODS: This retrospective observational study was conducted in a third-level university hospital. An initial learning cohort (cohort L: 269 patients) was selected to derive the new equations. These equations were tested in a validation of another cohort (cohort V: 146 patients). Patients selected were hospitalized adults who had simultaneous determinations of Ca2+ and serum total calcium (CaTot). They were classified using their estimated glomerular filtration rate (GFRe) into normal function, moderate and severe kidney dysfunction. Demographic and biochemical parameters, in addition to comorbidities, were collected from hospital databases. Nine published equations to predict Ca2+ and 2 widely used equations to predict corrected CaTot were also selected to be compared to newer equations for accuracy in detecting serum calcium alterations. New equations were derived by a multiple linear-regression analysis from patients in cohort L. RESULTS: Three equations were derived containing the CaTot square root as the main independent variable. Equation 1: Ca2+ = 0.815 * CaTot(0.5). Equation 2: Ca2+ = 0.826 * CaTot(0.5) - 0.023 * renal function. Equation 3: Ca2+ = 0.813 * CaTot(0.5) - 0.006 * albumin(0.75) + 0.079. These equations performed better than published equations to predict Ca2+ when their error measures were analyzed in cohort V, even in special populations such as critically ill and very old patients. CONCLUSIONS: Three new equations predicting Ca2+ were derived requiring easily available clinical and laboratory parameters. They could be valuable in predicting hypocalcemia but are of limited use in hypercalcemia. PMID- 26642198 TI - Correction: Modulating the Structure of EGFR with UV Light: New Possibilities in Cancer Therapy. PMID- 26642199 TI - Clinicopathological Characteristics and Survival Outcomes of Primary Signet Ring Cell Carcinoma in the Stomach: Retrospective Analysis of Single Center Database. AB - PURPOSE: To investigate the clinicopathological features and prognosis of signet ring cell carcinoma of the stomach (SRC). METHODS: A total of 1464 gastric cancer patients who underwent curative gastrectomy from 2000 to 2008 at a single center were evaluated. Signet ring cell carcinoma (SRC) was defined as the presence of at least 50% signet ring cells in the pathologic specimen. The clinicopathological parameters and prognosis of SRC were analyzed by comparing with non-signet ring cell carcinoma (NSRC). RESULTS: Of 1464 patients, 138 patients (9.4%) were classified as SRC. There were significant differences in gender, age, tumor location, TNM stage, p21 expression, and p53 expression between SRC and NSRC. The 5-year survival rates of SRC and NSRC were 36.2% and 49.5%, respectively. The prognosis of SRC was poorer than that of NSRC (P <0.001). Multivariate analysis showed that SRC histology was an independent factor for poor prognosis (P <0.001). CONCLUSION: Patients with SRC tend to present with a more advanced stage and poorer prognosis than patients with other types of gastric carcinoma. PMID- 26642200 TI - Identification of New Molecular Entities (NMEs) as Potential Leads against Tuberculosis from Open Source Compound Repository. AB - The purpose of this study was to provide a number of diverse and promising early lead compounds that will feed into the drug discovery pipeline for developing new antitubercular agents. The results from the phenotypic screening of the open source compound library against Mycobacterium smegmatis and Mycobacterium bovis (BCG) with hit validation against M. tuberculosis (H37Rv) have identified novel potent hit compounds. To determine their druglikeness, a systematic analysis of physicochemical properties of the hit compounds has been performed using cheminformatics tools. The hit molecules were analysed by clustering based on their chemical finger prints and structural similarity determining their chemical diversity. The hit compound library is also filtered for druglikeness based on the physicochemical descriptors following Lipinski filters. The robust filtration of hits followed by secondary screening against BCG, H37Rv and cytotoxicity evaluation has identified 12 compounds with potential against H37Rv (MIC range 0.4 to 12.5 MUM). Furthermore in cytotoxicity assays, 12 compounds displayed low cytotoxicity against liver and lung cells providing high therapeutic index > 50. To avoid any variations in activity due to the route of chemical synthesis, the hit compounds were re synthesized independently and confirmed for their potential against H37Rv. Taken together, the hits reported here provides copious potential starting points for generation of new leads eventually adds to drug discovery pipeline against tuberculosis. PMID- 26642201 TI - The Cut-Off Point and Boundary Values of Waist-to-Height Ratio as an Indicator for Cardiovascular Risk Factors in Chinese Adults from the PURE Study. AB - To explore a scientific boundary of WHtR to evaluate central obesity and CVD risk factors in a Chinese adult population. The data are from the Prospective Urban Rural Epidemiology (PURE) China study that was conducted from 2005-2007. The final study sample consisted of 43 841 participants (18 019 men and 25 822 women) aged 35-70 years. According to the group of CVD risk factors proposed by Joint National Committee 7 version and the clustering of risk factors, some diagnosis parameters, such as sensitivity, specificity and receiver operating characteristic (ROC) curve least distance were calculated for hypertension, diabetes, high serum triglyceride (TG), high serum low density lipoprotein cholesterol (LDL-C), low serum high density lipoprotein cholesterol (HDL-C) and clustering of risk factors (number>=2) to evaluate the efficacy at each value of the WHtR cut-off point. The upper boundary value for severity was fixed on the point where the specificity was above 90%. The lower boundary value, which indicated above underweight, was determined by the percentile distribution of WHtR, specifically the 5th percentile (P5) for both males and females population. Then, based on convenience and practical use, the optimal boundary values of WHtR for underweight and obvious central obesity were determined. For the whole study population, the optimal WHtR cut-off point for the CVD risk factor cluster was 0.50. The cut-off points for severe central obesity were 0.57 in the whole population. The upper boundary values of WHtR to detect the risk factor cluster with specificity above 90% were 0.55 and 0.58 for men and women, respectively. Additionally, the cut-off points of WHtR for each of four cardiovascular risk factors with specificity above 90% in males ranged from 0.55 to 0.56, whereas in females, it ranged from 0.57 to 0.58. The P5 of WHtR, which represents the lower boundary values of WHtR that indicates above underweight, was 0.40 in the whole population. WHtR 0.50 was an optimal cut-off point for evaluating CVD risks in Chinese adults of both genders. The optimal boundaries of WHtR were 0.40 and 0.57, indicating low body weight and severe risk for CVD, respectively, in Chinese adults. PMID- 26642203 TI - Correction: Decline in Clinical Efficacy of Oral Miltefosine in Treatment of Post Kala-azar Dermal Leishmaniasis (PKDL) in India. PMID- 26642202 TI - Inequalities in Global Trade: A Cross-Country Comparison of Trade Network Position, Economic Wealth, Pollution and Mortality. AB - In this paper we investigate how structural patterns of international trade give rise to emissions inequalities across countries, and how such inequality in turn impact countries' mortality rates. We employ Multi-regional Input-Output analysis to distinguish between sulfur-dioxide (SO2) emissions produced within a country's boarders (production-based emissions) and emissions triggered by consumption in other countries (consumption-based emissions). We use social network analysis to capture countries' level of integration within the global trade network. We then apply the Prais-Winsten panel estimation technique to a panel data set across 172 countries over 20 years (1990-2010) to estimate the relationships between countries' level of integration and SO2 emissions, and the impact of trade integration and SO2 emission on mortality rates. Our findings suggest a positive, (log-) linear relationship between a country's level of integration and both kinds of emissions. In addition, although more integrated countries are mainly responsible for both forms of emissions, our findings indicate that they also tend to experience lower mortality rates. Our approach offers a unique combination of social network analysis with multiregional input-output analysis, which better operationalizes intuitive concepts about global trade and trade structure. PMID- 26642204 TI - Clues on Syntenic Relationship among Some Species of Oryzomyini and Akodontini Tribes (Rodentia: Sigmodontinae). AB - Sigmodontinae rodents represent one of the most diverse and complex components of the mammalian fauna of South America. Among them most species belongs to Oryzomyini and Akodontini tribes. The highly specific diversification observed in both tribes is characterized by diploid complements, which vary from 2n = 10 to 86. Given this diversity, a consistent hypothesis about the origin and evolution of chromosomes depends on the correct establishment of synteny analyzed in a suitable phylogenetic framework. The chromosome painting technique has been particularly useful for identifying chromosomal synteny. In order to extend our knowledge of the homeological relationships between Akodontini and Oryzomyini species, we analyzed the species Akodon montensis (2n = 24) and Thaptomys nigrita (2n = 52) both from the tribe Akodontini, with chromosome probes of Hylaeamys megacephalus (2n = 54) of the tribe Oryzomyini. The results indicate that at least 12 of the 26 autosomes of H. megacephalus show conserved synteny in A. montensis and 14 in T. nigrita. The karyotype of Akodon montensis, as well as some species of the Akodon cursor species group, results from many chromosomal fusions and therefore the syntenic associations observed probably represent synapomorphies. Our finding of a set of such associations revealed by H. megacephalus chromosome probes (6/21; 3/25; 11/16/17; and, 14/19) provides phylogenetic information for both tribes. An extension of these observations to other members of Akodontini and Oryzomyini tribes should improve our knowledge about chromosome evolution in both these groups. PMID- 26642205 TI - The Expression of miR-375 Is Associated with Carcinogenesis in Three Subtypes of Lung Cancer. AB - Many studies demonstrated unique microRNA profiles in lung cancer. Nonetheless, the role and related signal pathways of miR-375 in lung cancer are largely unknown. Our study investigated relationships between carcinogenesis and miR-375 in adenocarcinoma, squamous cell carcinoma and small cell lung carcinoma to identify new molecular targets for treatment. We evaluated 723 microRNAs in microdissected cancerous cells and adjacent normal cells from 126 snap-frozen lung specimens using microarrays. We validated the expression profiles of miR-375 and its 22 putative target mRNAs in an independent cohort of 78 snap-frozen lung cancer tissues using quantitative reverse-transcriptase PCR. Moreover, we performed dual luciferase reporter assay and Western blot on 6 targeted genes (FZD8, ITGA10, ITPKB, LRP5, PIAS1 andRUNX1) in small cell lung carcinoma cell line NCI-H82. We also detected the effect of miR-375 on cell proliferation in NCI H82. We found that miR-375 expression was significantly up-regulated in adenocarcinoma and small cell lung carcinoma but down-regulated in squamous cell carcinoma. Among the 22 putative target genes, 11 showed significantly different expression levels in at least 2 of 3 pair-wise comparisons (adenocarcinoma vs. normal, squamous cell carcinoma vs. normal or small cell lung carcinoma vs. normal). Six targeted genes had strong negative correlation with the expression level of miR-375 in small cell lung carcinoma. Further investigation revealed that miR-375 directly targeted the 3'UTR of ITPKB mRNA and over-expression of miR 375 led to significantly decreased ITPKB protein level and promoted cell growth. Thus, our study demonstrates the differential expression profiles of miR-375 in 3 subtypes of lung carcinomas and finds thatmiR-375 directly targets ITPKB and promoted cell growth in SCLC cell line. PMID- 26642206 TI - Crowding and Follicular Fate: Spatial Determinants of Follicular Reserve and Activation of Follicular Growth in the Mammalian Ovary. AB - Initiation of growth of resting ovarian follicles is a key phenomenon for providing an adequate number of mature oocytes in each ovulation, while preventing premature exhaustion of primordial follicle reserve during the reproductive lifespan. Resting follicle dynamics strongly suggest that primordial follicles are under constant inhibitory influences, by mechanisms and factors whose nature remains ill defined. In this work, we aimed to assess the influence of spatial determinants, with special attention to clustering patterns and crowding, on the fate of early follicles in the adult mouse and human ovary. To this end, detailed histological and morphometric analyses, targeting resting and early growing follicles, were conducted in ovaries from mice, either wild type (WT) or genetically modified to lack kisspeptin receptor expression (Kiss1r KO), and healthy adult women. Kiss1r KO mice were studied as model of persistent hypogonadotropism and anovulation. Different qualitative and quantitative indices of the patterns of spatial distribution of resting and early growing follicles in the mouse and human ovary, including the Morisita's index of clustering, were obtained. Our results show that resting primordial follicles display a clear-cut clustered pattern of spatial distribution in adult mouse and human ovaries, and that resting follicle aggrupation is inversely correlated with the proportion of follicles initiating growth and entering into the growing pool. As a whole, our data suggest that resting follicle crowding, defined by changes in density and clustered pattern of distribution, is a major determinant of follicular activation and the fate of ovarian reserve. Uneven follicle crowding would constitute the structural counterpart of the major humoral regulators of early follicular growth, with potential implications in ovarian ageing and pathophysiology. PMID- 26642207 TI - Multiple Genes in a Single Host: Cost-Effective Production of Bacterial Laccase (cotA), Pectate Lyase (pel), and Endoxylanase (xyl) by Simultaneous Expression and Cloning in Single Vector in E. coli. AB - This study attempted to reduce the enzyme production cost for exploiting lignocellulosic materials by expression of multiple genes in a single host. Genes for bacterial laccase (CotA), pectate lyase (Pel) and endoxylanase (Xyl), which hold significance in lignocellulose degradation, were cloned in pETDuet-1 vector containing two independent cloning sites (MCS). CotA and xyl genes were cloned in MCS1 and MCS 2, respectively. Pel gene was cloned by inserting complete cassette (T7 promoter, ribosome binding site, pel gene, His tag and complete gene ORF) preceded by cotA open reading frame in the MCS1. IPTG induction of CPXpDuet-1 construct in E. coli BL21(DE3) resulted in expression of all three heterologous proteins of ~65 kDa (CotA), ~45 kDa (Pel) and ~25 kDa (Xyl), confirmed by SDS PAGE and western blotting. Significant portions of the enzymes were also found in culture supernatant (~16, ~720 and ~370 IU/ml activities of CotA, Pel and Xyl, respectively). Culture media optimization resulted in 2, 3 and 7 fold increased secretion of recombinant CotA, Pel and Xyl, respectively. Bioreactor level optimization of the recombinant cocktail expression resulted in production of 19 g/L dry cell biomass at OD600nm 74 from 1 L induced culture after 15 h of cultivation, from which 9, 627 and 1090 IU/ml secretory enzyme activities of CotA, Xyl and Pel were obtained, respectively. The cocktail was also found to increase the saccharification of orange peel in comparison to the xylanase alone. Thus, simultaneous expression as well as extra cellular secretion of these enzymes as cocktail can reduce the enzyme production cost which increases their applicability specially for exploiting lignocellulosic materials for their conversion to value added products like alcohol and animal feed. PMID- 26642208 TI - Gene Delivery by Subconjunctival Injection of Adenovirus in Rats: A Study of Local Distribution, Transgene Duration and Safety. AB - Subconjunctival injection is a minimally invasive route for gene delivery to ocular tissues, but has traditionally been limited to use in the cornea. The accurate ocular distribution of virus has not, however, been previously investigated. Adenovirus is an attractive gene vector as it can deliver large genes and allow for short-term gene expression, but how safe it is when delivered via subconjunctival injection remains to be established. We have characterized the bio-distribution and safety of subconjunctivally administered adenovirus in Brown Norway rats. The bio-distribution and transgene duration of adenovirus carrying luciferase gene (Ad-Luci) at various time intervals were evaluated via bioluminescence imaging after subconjunctival injection. Adenovirus carrying a reporter gene, beta-galactosidase (Ad-LacZ) or hrGFP (Ad-hrGFP) was administered subconjunctivally and the viral distribution in various ocular tissues was assessed by histological analysis and quantitative PCR (qPCR). Hepatic damage was assessed by biochemical and immunohistological analysis with TUNEL stain. Systemic immunogenicity was assessed by measuring serum level of TNF-alpha via ELISA, 2 hours and 14 days after administration of adenovirus. Retinal function was examined by electroretinography. Subconjunctival injection of Ad-Luci induced luciferase expression in the injected eyes within 24 hours, for at least 64 days. Histological analysis showed adenovirus distributed across anterior and posterior ocular tissues. qPCR demonstrated different amounts of adenovirus in different ocular tissues, with the highest amounts closest to the injection site Unlike the intravenous route, subconjunctivally delivered adenovirus did not elicit any detectable hepatic injury or systemic immunogenicity. Retinal function was unaffected by adenovirus irrespective of administration route. In conclusion, an adenoviral vector administered subconjunctivally can infiltrate into different ocular tissues and lead to short-term ocular transgene expression, without causing hepatic injury and immune activation. Therefore, subconjunctivally administered adenovirus may be a promising gene delivery approach for managing anterior and posterior segment eye diseases requiring short-term therapy. PMID- 26642210 TI - Discordance between Prevalent Vertebral Fracture and Vertebral Strength Estimated by the Finite Element Method Based on Quantitative Computed Tomography in Patients with Type 2 Diabetes Mellitus. AB - BACKGROUND: Bone fragility is increased in patients with type 2 diabetes mellitus (T2DM), but a useful method to estimate bone fragility in T2DM patients is lacking because bone mineral density alone is not sufficient to assess the risk of fracture. This study investigated the association between prevalent vertebral fractures (VFs) and the vertebral strength index estimated by the quantitative computed tomography-based nonlinear finite element method (QCT-based nonlinear FEM) using multi-detector computed tomography (MDCT) for clinical practice use. RESEARCH DESIGN AND METHODS: A cross-sectional observational study was conducted on 54 postmenopausal women and 92 men over 50 years of age, all of whom had T2DM. The vertebral strength index was compared in patients with and without VFs confirmed by spinal radiographs. A standard FEM procedure was performed with the application of known parameters for the bone material properties obtained from nondiabetic subjects. RESULTS: A total of 20 women (37.0%) and 39 men (42.4%) with VFs were identified. The vertebral strength index was significantly higher in the men than in the women (P<0.01). Multiple regression analysis demonstrated that the vertebral strength index was significantly and positively correlated with the spinal bone mineral density (BMD) and inversely associated with age in both genders. There were no significant differences in the parameters, including the vertebral strength index, between patients with and without VFs. Logistic regression analysis adjusted for age, spine BMD, BMI, HbA1c, and duration of T2DM did not indicate a significant relationship between the vertebral strength index and the presence of VFs. CONCLUSION: The vertebral strength index calculated by QCT-based nonlinear FEM using material property parameters obtained from nondiabetic subjects, whose risk of fracture is lower than that of T2DM patients, was not significantly associated with bone fragility in patients with T2DM. This discordance may indirectly suggest that patients with T2DM have deteriorated bone material compared with nondiabetic subjects, a potential cause of bone fragility in T2DM patients. PMID- 26642209 TI - Nuclear Receptor-Like Structure and Interaction of Congenital Heart Disease Associated Factors GATA4 and NKX2-5. AB - AIMS: Transcription factor GATA4 is a dosage sensitive regulator of heart development and alterations in its level or activity lead to congenital heart disease (CHD). GATA4 has also been implicated in cardiac regeneration and repair. GATA4 action involves combinatorial interaction with other cofactors such as NKX2 5, another critical cardiac regulator whose mutations also cause CHD. Despite its critical importance to the heart and its evolutionary conservation across species, the structural basis of the GATA4-NKX2-5 interaction remains incompletely understood. METHODS AND RESULTS: A homology model was constructed and used to identify surface amino acids important for the interaction of GATA4 and NKX2-5. These residues were subjected to site-directed mutagenesis, and the mutant proteins were characterized for their ability to bind DNA and to physically and functionally interact with NKX2-5. The studies identify 5 highly conserved amino acids in the second zinc finger (N272, R283, Q274, K299) and its C-terminal extension (R319) that are critical for physical and functional interaction with the third alpha helix of NKX2-5 homeodomain. Integration of the experimental data with computational modeling suggests that the structural arrangement of the zinc finger-homeodomain resembles the architecture of the conserved DNA binding domain of nuclear receptors. CONCLUSIONS: The results provide novel insight into the structural basis for protein-protein interactions between two important classes of transcription factors. The model proposed will help to elucidate the molecular basis for disease causing mutations in GATA4 and NKX2-5 and may be relevant to other members of the GATA and NK classes of transcription factors. PMID- 26642212 TI - Adverse Effects of Cholinesterase Inhibitors in Dementia, According to the Pharmacovigilance Databases of the United-States and Canada. AB - This survey analyzes two national pharmacovigilance databases in order to determine the major adverse reactions observed with the use of cholinesterase inhibitors in dementia. We conducted a statistical analysis of the Food and Drug Administration Adverse Event Reporting System (FAERS) and the Canada Vigilance Adverse Reaction Database (CVARD) concerning the side effects of cholinesterase inhibitors. The statistics calculated for each adverse event were the frequency and the reporting odds ratios (ROR). A total of 9877 and 2247 reports were extracted from the FAERS and CVARD databases, respectively. A disproportionately higher frequency of reports of death as an adverse event for rivastigmine, compared to the other acetylcholinesterase inhibiting drugs, was observed in both the FAERS (ROR = 3.42; CI95% = 2.94-3.98; P<0.0001) and CVARD (ROR = 3.67; CI95% = 1.92-7.00; P = 0.001) databases. While cholinesterase inhibitors remain to be an important therapeutic tool against Alzheimer's disease, the disproportionate prevalence of fatal outcomes with rivastigmine compared with alternatives should be taken into consideration. PMID- 26642213 TI - Autoantibodies in Autoimmune Hepatitis. AB - BACKGROUND: The detection of diagnostic autoantibodies such as antinuclear antibodies (ANA), anti-smooth muscle antibodies (SMA), anti-liver/kidney microsomal type 1 (anti-LKM1), anti-liver cytosol type 1 (anti-LC1) and anti soluble liver antigen (anti-SLA) is historically associated with the diagnosis of autoimmune hepatitis. KEY MESSAGES: When autoimmune hepatitis is suspected, the detection of one or any combination of diagnostic autoantibodies, by indirect immunofluorescence or immuno-enzymatic techniques with recombinant antigens, is a pivotal step to reach a diagnostic score of probable or definite autoimmune hepatitis. CONCLUSIONS: Diagnostic autoantibodies (ANA, SMA, anti-LKM1, anti-LC1, anti-SLA) are a cornerstone in the diagnosis of autoimmune hepatitis. Other ancillary autoantibodies, associated with peculiar clinical correlations, appear to be assay-dependent and institution-specific, and validation studies are needed. PMID- 26642214 TI - Outcomes in a Cohort of Patients Started on Antiretroviral Treatment and Followed up for a Decade in an Urban Clinic in Uganda. AB - BACKGROUND: Short-medium term studies from sub-Saharan Africa show that, despite high early mortality, substantial loss to program, and high rates toxicity, patients on antiretroviral treatment have achieved outcomes comparable to those in developed settings. However, these studies were unable to account for long term outcomes of patients as they stayed longer on treatment. OBJECTIVES: We aim to describe ten years outcomes of one of the first cohort of HIV positive patients started on antiretroviral treatment (ART) in Sub-Saharan Africa. METHODS: We report 10-years outcomes including mortality, retention, CD4-count response, virological outcomes, ART regimens change from a prospective cohort of 559 patients initiating ART and followed up for 10 years Uganda. RESULTS: Of 559 patients, 69.1% were female, median age (IQR) was 38 (33-44) years, median CD4 count (IQR) 98 (21-163) cell/MUL; 74% were started on stavudine, lamivudine and nevirapine, 26% on zidovudine, lamivudine and efavirenz. After 10 years 361 (65%) patients were still in the study; 127 (22.7%) had died; 30 (5%) were lost to follow-up; 27 (5%) transferred; 18 (3%) withdrew consent. The probability of death was high in the first year (0.15, 95%, CI 0.12-0.18). The median CD4 count increased from 98 to 589 cell/MUL (IQR: 450-739 cell/MUL) with a median increase of 357 cells/MUL (IQR: 128-600 cells/MUL); 7.4% never attained initial viral suppression and of those who did 31.7% experienced viral failure. Three hundred and two patients had at least one drug substitution while on first line after a median of 40 months; 66 (11.9%) of the patients were switched to a second line PI based regimen due to confirmed treatment failure. CONCLUSIONS: Despite the high rate of early mortality due to advanced disease at presentation the outcomes from this cohort are encouraging, particularly the remarkable and incremental immune recovery and a satisfactory rate of virologic suppression. PMID- 26642216 TI - Effects of various organic carbon sources on simultaneous V(V) reduction and bioelectricity generation in single chamber microbial fuel cells. AB - Four ordinary carbon sources affecting V(V) reduction and bioelectricity generation in single chamber microbial fuel cells (MFCs) were investigated. Acetate supported highest maximum power density of 589.1mW/m(2), with highest V(V) removal efficiency of 77.6% during 12h operation, compared with glucose, citrate and soluble starch. Exorbitant initial V(V) concentration led to lower V(V) removal efficiencies and power outputs. Extra addition of organics had little effect on the improvement of MFCs performance. V(V) reduction and bioelectricity generation were enhanced and then suppressed by the increase of conductivity. The larger the external resistance, the higher the V(V) removal efficiencies and voltage outputs. High-throughput 16S rRNA gene pyrosequencing analysis implied the accumulation of Enterobacter which had the capabilities of V(V) reduction, electrochemical activity and fermentation, accompanied with other functional species as Pseudomonas, Spirochaeta, Sedimentibacter and Dysgonomonas. This study steps forward to remediate V(V) contaminated environment based on MFC technology. PMID- 26642215 TI - Comparison of 3 ABR Methods for Diagnosis of Retrocochlear Hearing Impairment. AB - BACKGROUND The purpose of this study was to compare the effectiveness of methods for screening for retrocochlear pathologies based on auditory evoked brainstem responses (ABRs). The study compared the sensitivity, specificity, and effectiveness of these 3 techniques. MATERIAL AND METHODS The methods were: (i) standard ABR utilizing click-evoked responses, (ii) stacked ABR based on derived band responses, and (iii) ABRs evoked by tone-pips (ABR TP). The methods were tested on patients with retrocochlear pathologies confirmed by MRI-Gd, normal hearing subjects, and patients with cochlear hearing loss. The system and software used in the tests was NavPro AEP v.6.2.0 (BioLogic - Natus). Prior to testing, all subjects were given comprehensive audiologic and otologic examinations, including MR imaging. Sensitivity and specificity functions and predictive values of methods were determined. RESULTS The stacked ABR method as realized in the NavPro system exhibited high sensitivity but specificity was very low, due to the high variability of stacked ABR amplitudes. The standard ABR method had good specificity, but low sensitivity in cases of small tumors (below 1 cm in diameter). Best sensitivity and specificity was obtained with the ABR TP method. CONCLUSIONS The stacked ABR method allows small acoustic tumors to be detected, but produces high percentage of false positive results. The ABR TP method offers good sensitivity and specificity, and relatively high predictive value. The best option would be to use a two-stage screening, consisting of a standard ABR in the first stage and an ABR TP test in the second. PMID- 26642217 TI - Microwave-assisted catalytic pyrolysis of switchgrass for improving bio-oil and biochar properties. AB - Solid additives were used as a microwave absorber to improve the low microwave absorption rate of switchgrass going through pyrolysis, and as a catalyst to improve the bio-oil and biochar characteristics. The synergistic effects were manifested in the presence of a mixture of K3PO4 and clinoptilolite or bentonite compared with single catalyst, resulting in increased microwave absorption rate, and improved bio-oil and biochar quality. The sample of microwave heating switchgrass with 10wt.% K3PO4+10wt.% bentonite reached 400 degrees C after 2.8min, compared with 28.8min through conventional heating, producing biochar with increase in BET surface area from 0.33m(2)/g to 76.3m(2)/g compared with conventional heating. Furthermore, water content of the bio-oil reduced from 22.7 to 15.0wt.% compared with biomass mixed with 20wt.% SiC, a chemically-inert microwave absorbing material used to increase microwave heating. Introducing catalysts showed a great potential for accelerating microwave heating and improving bio-oil and biochar qualities. PMID- 26642218 TI - Enzymatic in situ saccharification of chestnut shell with high ionic liquid tolerant cellulases from Galactomyces sp. CCZU11-1 in a biocompatible ionic liquid-cellulase media. AB - In this study, it was the first time to report that the cellulases of Galactomyces sp. CCZU11-1 showed high activity and stability in the culture and reaction media containing IL [Mmim]DMP. Using untreated chestnut shell (CNS) as carbon source in the culture media containing IL [Mmim]DMP (5%, w/v), high activity of FPA (28.6U/mL), xylanase (186.2U/mL), and CMCase (107.3U/mL) were obtained, and 184.9mg/L of total protein was achieved. Furthermore, the changes in the structural features (crystallinity, morphology, and porosity) of the solid residue of CNS utilized with Galactomyces sp. CCZU11-1 were characterized with Fourier transform infrared spectroscopy, scanning electron microscopy, and X-ray diffraction. After was enzymatically hydrolyzed with the prepared crude enzymes in IL diluted to 20% (w/v), a high yield of reducing sugars, 62.1%, was obtained. Significantly, Galactomyces sp. CCZU11-1 showed high potential for the efficient transformation of lignocellulosic materials to glucose in a single-step process. PMID- 26642219 TI - Role of aeration intensity on performance and microbial community profiles in a sequencing batch reaction kettle (SBRK) for wastewater nutrients rapid removal. AB - A lab-scale SBRK was operated to investigate the effects of aeration intensity on the system performance and microbial community dynamics within it. Results showed that the sewage nutrients was removed rapidly (just about 3-6h) with the aeration intensity increasing from 0 to 0.6MPa. Average effluent parameters were: COD below 50mg/L, NH4(+)-N less than 1mg/L, 1.5-4.5mg/L for nitrate and TP below 0.5mg/L. The highest community similarity and diversity emerged simultaneously with the aeration pressure rising from 0.2 to 0.4MPa, which was regarded as the optimal aeration intensity range. Microbial community shifted obviously and the function species of Comamonadaceae, Dechloromonas, Flavobacterium and Nitrospira dominated in the corresponding communities. RDA indicated that aeration intensity was the main factor for regulating system communities to optimize the system performance. It inferred that high aeration pressure played a key role on sewage nutrients rapid removal. PMID- 26642220 TI - Enhancement of butanol production in Clostridium acetobutylicum SE25 through accelerating phase shift by different phases pH regulation from cassava flour. AB - A prominent delay with 12h was encountered in the phase shift from acidogenesis to solventogenesis in butanol production when the substrate-glucose was replaced by cassava flour. To solve this problem, different phase of pH regulation strategies were performed to shorten this delay time. With this effort, the phase shift occurred smoothly and the fermentation time was shortened. Under the optimal conditions, 16.24g/L butanol and 72h fermentation time were achieved, which were 25.3% higher and 14.3% shorter than those in the case of without pH regulation. Additionally, the effect of CaCO3 on "acid crash" and butanol production was also investigated. It was found that organic acids reassimilation would be of benefit to enhance butanol production. These results indicated that the simple but effective approach for acceleration of phase shift is a promising technique for shortening the fermentation time and improvement of butanol production. PMID- 26642221 TI - Development of a bi-equilibrium model for biomass gasification in a downdraft bed reactor. AB - This work proposes a simple and accurate tool for predicting the main parameters of biomass gasification (syngas composition, heating value, flow rate), suitable for process study and system analysis. A multizonal model based on non stoichiometric equilibrium models and a repartition factor, simulating the bypass of pyrolysis products through the oxidant zone, was developed. The results of tests with different feedstocks (corn cobs, wood pellets, rice husks and vine pruning) in a demonstrative downdraft gasifier (350kW) were used for validation. The average discrepancy between model and experimental results was up to 8 times less than the one with the simple equilibrium model. The repartition factor was successfully related to the operating conditions and characteristics of the biomass to simulate different conditions of the gasifier (variation in potentiality, densification and mixing of feedstock) and analyze the model sensitivity. PMID- 26642222 TI - Improving CO2 fixation with microalgae by bubble breakage in raceway ponds with up-down chute baffles. AB - The aeration gas was broken into smaller bubbles with enhanced local solution velocity to improve CO2 fixation with microalgae in raceway ponds with up-down chute baffles. A high-speed photography system and online precise pH probes were used to measure bubble generation and residence times, which were affected by paddlewheel speed, aerator orifice diameter, gas flow rate, and solution depth. Bubble generation time (from gas reaching aerator orifice surface to completely escaping from the aerator) decreased because of the enhanced local solution velocity, whereas bubble residence time increased because of the vortex flow field produced by up-down chute baffles. Bubble generation time decreased by 27% and bubble residence time increased by 27% when paddlewheel speed was 10r/min with an aeration gas rate of 0.03vvm. The decreased generation time and increased residence time of aeration bubbles promoted microalgae biomass yield by 29% in optimized flow fields in raceway ponds. PMID- 26642223 TI - Effect of thermal, acid, alkaline and alkaline-peroxide pretreatments on the biochemical methane potential and kinetics of the anaerobic digestion of wheat straw and sugarcane bagasse. AB - The effect of thermal, acid, alkaline and alkaline-peroxide pretreatments on the methane produced by the anaerobic digestion of wheat straw (WS) and sugarcane bagasse (SCB) was studied, using whole slurry and solid fraction. All the pretreatments released formic and acetic acids and phenolic compounds, while 5 hydroxymetilfurfural (HMF) and furfural were generated only by acid pretreatment. A remarkable inhibition was found in most of the whole slurry experiments, except in thermal pretreatment which improved methane production compared to the raw materials (29% for WS and 11% for SCB). The alkaline pretreatment increased biodegradability (around 30%) and methane production rate of the solid fraction of both pretreated substrates. Methane production results were fitted using first order or modified Gompertz equations, or a novel model combining both equations. The model parameters provided information about substrate availability, controlling step and inhibitory effect of compounds generated by each pretreatment. PMID- 26642224 TI - A new approach for hydrogen generation from sewage sludge. AB - A new process to produce hydrogen efficiently from sewage sludge (SWS) was developed with co-grinding operation of the dried SWS with calcium and nickel hydroxides (Ca(OH)2 and Ni(OH)2) and subsequent heating of the ground mixture at relatively low temperature below 600 degrees C. A set of analytical methods were used to characterize the ground samples before heating and the gaseous and solid products after heating. Thermo-mass spectroscopic (TG-MS) analysis showed hydrogen occurrence around 450 degrees C. Hydrogen yield over 70g per kg SWS with concentration of 93.6% was obtained with the hydroxide additions of Ca to C from SWS at 1:1 and Ni to C at 1:6, respectively. X-ray diffraction (XRD) analysis of the solid residues after heating confirmed the existences of calcium carbonate and nickel metal. Based on the obtained results, possible reaction pathway was proposed. PMID- 26642225 TI - Surrogate Endpoints for Optimal Therapeutic Response to UDCA in Primary Biliary Cholangitis. AB - BACKGROUND: Ursodeoxycholic acid (UDCA) is the standard treatment for primary biliary cholangitis (PBC), as it can delay histological progression, improve long term outcome and is extremely safe and well tolerated. However, UDCA is not always sufficient and the prognosis of patients inadequately responding to treatment is worse compared with the general population. Reliable identification of so-called non-responders is of key importance, not only for selecting patients who could benefit from additional, second-line therapy, but also for identifying those individuals who are at low risk of developing end-stage disease and in whom UDCA mono-therapy can be safely continued. Several laboratory surrogate endpoints for the long-term response to UDCA have been proposed, including the Barcelona, Paris, Toronto and Rotterdam criteria. All these criteria have limitations and the superiority of one over the other has not been firmly established. KEY MESSAGES: Recently the Global PBC Study Group developed a new prognostic tool by studying a large, representative and multinational cohort of 4,119 UDCA-treated patients. In a random sample of 2,488 cases, a risk score--the GLOBE score--was developed, predictive of transplantation-free survival. This risk score comprises age, and bilirubin, albumin, alkaline phosphatase and platelet count obtained after 1 year therapy, and has a performance (C statistic 0.81, 95% CI 0.79-0.83) that is markedly better than that of previously proposed response criteria. Comparable performance was found in an independent validation cohort of 1,631 cases (C statistic 0.82, 95% CI 0.79-0.84). A web app will allow the easy use of the score in clinical practice. PMID- 26642226 TI - Cost of Operating Central Cancer Registries and Factors That Affect Cost: Findings From an Economic Evaluation of Centers for Disease Control and Prevention National Program of Cancer Registries. AB - CONTEXT: The Centers for Disease Control and Prevention (CDC) evaluated the economics of the National Program of Cancer Registries to provide the CDC, the registries, and policy makers with the economics evidence-base to make optimal decisions about resource allocation. Cancer registry budgets are under increasing threat, and, therefore, systematic assessment of the cost will identify approaches to improve the efficiencies of this vital data collection operation and also justify the funding required to sustain registry operations. OBJECTIVES: To estimate the cost of cancer registry operations and to assess the factors affecting the cost per case reported by National Program of Cancer Registries funded central cancer registries. METHODS: We developed a Web-based cost assessment tool to collect 3 years of data (2009-2011) from each National Program of Cancer Registries-funded registry for all actual expenditures for registry activities (including those funded by other sources) and factors affecting registry operations. We used a random-effects regression model to estimate the impact of various factors on cost per cancer case reported. RESULTS: The cost of reporting a cancer case varied across the registries. Central cancer registries that receive high-quality data from reporting sources (as measured by the percentage of records passing automatic edits) and electronic data submissions, and those that collect and report on a large volume of cases had significantly lower cost per case. The volume of cases reported had a large effect, with low volume registries experiencing much higher cost per case than medium- or high volume registries. CONCLUSIONS: Our results suggest that registries operate with substantial fixed or semivariable costs. Therefore, sharing fixed costs among low volume contiguous state registries, whenever possible, and centralization of certain processes can result in economies of scale. Approaches to improve quality of data submitted and increasing electronic reporting can also reduce cost. PMID- 26642227 TI - When do fearful faces override inhibition of return? AB - Inhibition of return (IOR) occurs when more than about 300 ms elapses between the cue and the target in atypical peripheral cueing task: reaction times (RTs) become longer when the cue and target locations are the same versus different. IOR could serve the adaptive role of optimizing visual search by discouraging the re-inspection of previously attended locations. As such, IOR should not reduce our chances of noticing relevant event information and emotional stimuli, in particular. However, previous studies have led to inconsistent results. The present study offers a systematic investigation of the conditions under which target fearful faces can modulate either the magnitude or the time course of the IOR effect. Notably, we manipulated the depth of facial processing required to perform the task and/or the task relevance of the facial expressions. When participants localized target faces (Experiment 1) or discriminated them from non face stimuli (Experiment 2), their emotional expression had no impact on IOR whatsoever. However, IOR occurred later for fearful versus neutral faces when the participants performed emotion (Experiment 3) or gender (Experiment 4) discrimination tasks. These findings are discussed with regard to the mechanisms responsible for IOR and to the processing of emotional facial expressions. PMID- 26642229 TI - The alternative DSM-5 personality disorder traits criterion: A comparative examination of three self-report forms in a Danish population. AB - The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5; American Psychiatric Association, 2013a) offers an alternative model for Personality Disorders (PDs) in Section III, which consists in part of a pathological personality traits criterion measured with the Personality Inventory for DSM-5 (PID-5). The PID-5 selfreport instrument currently exists in the original 220-item form, a short 100-item form, and a brief 25-item form. For clinicians and researchers, the choice of a particular PID- 5 form depends on feasibility, but also reliability and validity. The goal of the present study was to examine the psychometric qualities of all 3 PID-5 forms, simultaneously, based on a Danish sample (N = 1376) of 451 psychiatric outpatients and 925 community dwelling participants. Scale reliability and factorial validity were satisfactory across all 3 PID-5 forms. The correlational profiles of the short and brief PID-5 forms with clinician-rated PD dimensions were nearly identical with that of the original PID-5 (rICC = .99 and .95, respectively). All 3 forms discriminated appropriately between psychiatric patients and community-dwelling individuals. This supports that all 3 PID-5 forms can be used to reliably and validly assess PD traits and provides initial support for the use of the abbreviated PID-5 forms in a European population. However, only the original 220-item form and the short 100-item form capture all 25 trait facets, and the brief 25-item form may be ideally limited to preliminary screening or situations with substantial time restrictions. PMID- 26642228 TI - The Characteristics of Heterozygous Protein Truncating Variants in the Human Genome. AB - Sequencing projects have identified large numbers of rare stop-gain and frameshift variants in the human genome. As most of these are observed in the heterozygous state, they test a gene's tolerance to haploinsufficiency and dominant loss of function. We analyzed the distribution of truncating variants across 16,260 autosomal protein coding genes in 11,546 individuals. We observed 39,893 truncating variants affecting 12,062 genes, which significantly differed from an expectation of 12,916 genes under a model of neutral de novo mutation (p<10-4). Extrapolating this to increasing numbers of sequenced individuals, we estimate that 10.8% of human genes do not tolerate heterozygous truncating variants. An additional 10 to 15% of truncated genes may be rescued by incomplete penetrance or compensatory mutations, or because the truncating variants are of limited functional impact. The study of protein truncating variants delineates the essential genome and, more generally, identifies rare heterozygous variants as an unexplored source of diversity of phenotypic traits and diseases. PMID- 26642230 TI - The relevance of schizotypal traits for understanding interpersonal functioning in adolescents with psychiatric problems. AB - Social relationships are considered highly important throughout adolescence (Kenny et al., 2013), both for the further development and consolidation of identity, social roles, and skills. The schizotypal personality disorder (STPD) has a strong negative impact on these relationships with both parents and peers (Cramer et al., 2006; Hengartner et al., 2014), and can thus be considered as a risk factor for early maladaptive social functioning. The current study focuses on the relevance of different dimensional STPD traits for understanding social functioning, by examining their unique associations with global and more specific parental and peer relationship characteristics in a group of referred late adolescents (N = 205, mean age = 20.27). Negative schizotypal traits, assessed by the Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM-5; American Psychiatric Association, 2013) STPD traits Restricted Affectivity, Withdrawal, and Suspiciousness (Krueger et al., 2012) appeared to be a unique predictor for less maternal and peer social support. Positive schizotypal traits were measured with the age-specific Oddity trait scale (Verbeke & De Clercq, 2014) and proved to be a unique predictor beyond negative schizotypal traits for negative interactions with adolescents' mother and a best friend. These results highlight the heterogeneous nature of the STPD construct and suggest that a dimensional description may contribute to a more detailed understanding of how the STPD relates to poor interpersonal relationship quality in vulnerable adolescents. (PsycINFO Database Record PMID- 26642231 TI - Arrhythmia diagnosis and management throughout life in congenital heart disease. AB - Arrhythmias, covering bradycardia and tachycardia, occur in association with congenital heart disease (CHD) and as a consequence of surgical repair. Symptomatic bradycardia can occur due to sinus node dysfunction or atrioventricular block secondary to either unrepaired CHD or surgical repair in the area of the conduction system. Tachyarrhythmias are common in repaired CHD due to scar formation, chamber distension or increased chamber pressure, all potentially leading to abnormal automaticity and heterogeneous conduction properties as a substrate for re-entry. Atrial arrhythmias occur more frequently, but ventricular tachyarrhythmias may be associated with an increased risk of sudden cardiac death, notably in patients with repaired tetralogy of Fallot or aortic stenosis. Defibrillator implantation provides life-saving electrical therapy for hemodynamically unstable arrhythmias. Ablation procedures with 3D electroanatomic mapping technology offer a viable alternative to pharmacologic or device therapy. Advances in electrophysiology have allowed for successful management of arrhythmias in patients with congenital heart disease. PMID- 26642232 TI - Anacetrapib for the treatment of dyslipidaemia: the last bastion of the cholesteryl ester transfer protein inhibitors? AB - INTRODUCTION: Inhibition of cholesteryl ester transfer protein (CETP) has emerged as a potential way to decrease cardiovascular risk by raising high density lipoprotein (HDL) cholesterol and lowering low density lipoprotein (LDL) cholesterol concentrations. However, high profile withdrawals of several CETP inhibitors have cast doubt over this hypothesis. Despite this concern, anacetrapib appears to be safe, well-tolerated and delivers a substantial increases in HDL cholesterol and reductions in LDL cholesterol as monotherapy and when combined with a statin. AREAS COVERED: We discuss the role of CETP and HDL cholesterol as therapeutic targets, describe the pharmacokinetics and pharmacodynamics of anacetrapib, as well as report on the recent clinical trials. EXPERT OPINION: The focus of CETP inhibition has shifted from HDL cholesterol raising to LDL cholesterol-lowering. Although anacetrapib appears to be safe and is effective in altering lipid-related biochemical parameters of interest, its effect on cardiovascular outcomes remains unknown. Extrapolation of LDL cholesterol lowering to improved cardiovascular outcomes is not possible, because LDL and HDL functionality in the setting of anacetrapib treatment is unclear. The results of the phase III REVEAL randomised controlled trial will be critical for anacetrapib to establish a place in clinical care. PMID- 26642234 TI - Single versus combination immunotherapy drug treatment in melanoma. AB - INTRODUCTION: The advent of new immunotherapies for the treatment of metastatic melanoma has resulted in various novel combination strategies. Because of their distinct modes of action, different immunotherapies have been investigated in combination with one another, as well as combined with targeted therapies and other treatment modalities. AREAS COVERED: Anti-CTLA-4 and anti-PD-1 treatments enhance antitumor immunity through complementary and non-redundant mechanisms. The combination of the anti-CTLA-4 agent ipilimumab and the anti-PD-1 agent nivolumab has been shown to improve progression-free survival and objective response rate compared with either agent alone as monotherapy in patients with advanced melanoma. However, the combination was associated with significant toxicity, with around one-third of patients discontinuing treatment as a result. The sequential use of nivolumab and ipilimumab was associated with similar outcomes and comparable toxicity to concurrent therapy. Clinical trials assessing various combinations of immunomodulating antibodies are ongoing or planned. Ipilimumab and pembrolizumab have also been investigated in combination with the oncolytic virus, talimogene laherparepvec (T-VEC), with promising results. In addition, immunotherapies have also been combined with chemotherapy, radiotherapy and electrochemotherapy. EXPERT OPINION: Investigation of combination approaches represents the start of a new story that begins with melanoma treatment and expands to embrace other solid and hematological cancers. PMID- 26642233 TI - Benefits and Harms of Once-Weekly Glucagon-like Peptide-1 Receptor Agonist Treatments: A Systematic Review and Network Meta-analysis. AB - BACKGROUND: Once-weekly glucagon-like peptide-1 receptor agonists (GLP-1RAs) are new drugs for the treatment of type 2 diabetes. PURPOSE: To summarize evidence for the cardiometabolic efficacy and adverse effects of once-weekly GLP-1RAs in adults with type 2 diabetes. DATA SOURCES: Electronic databases (PubMed, Web of Science, Cochrane Central Register of Controlled Trials, U.S. Food and Drug Administration, European Medicines Agency, ClinicalTrials.gov) and congress abstracts from inception through 26 September 2015. STUDY SELECTION: Randomized, controlled trials (>= 24 weeks of follow-up) studying albiglutide, dulaglutide, once-weekly exenatide, semaglutide, and taspoglutide and reporting a cardiometabolic (primary outcome, hemoglobin A1c [HbA1c]) or safety outcome. DATA EXTRACTION: Extraction was done in duplicate, and risk of bias was assessed. No language restriction was applied. DATA SYNTHESIS: 34 trials (21,126 participants) were included. Compared with placebo, all once-weekly GLP-1RAs reduced HbA1c and fasting plasma glucose; taspoglutide, 20 mg, once-weekly exenatide, and dulaglutide, 1.5 mg, reduced body weight. Among once-weekly GLP-1RAs, the greatest differences were found between dulaglutide, 1.5 mg, and taspoglutide, 10 mg, for HbA1c (-0.4% [95% CI, -0.7% to -0.2%]), once-weekly exenatide and albiglutide for fasting plasma glucose (-0.7 mmol/L [CI, -1.1 to -0.2 mmol/L]; 12.6 mg/dL [CI, -19.8 to -3.6 mg/dL]), and taspoglutide, 20 mg, and dulaglutide, 0.75 mg, for body weight (-1.5 kg [CI, -2.2 to -0.8]). Clinically marginal or no differences were found for blood pressure, blood lipid levels, and C-reactive protein levels. Once-weekly exenatide increased heart rate compared with albiglutide and dulaglutide (1.4 to 3.2 beats/min). Among once-weekly GLP-1RAs, the risk for hypoglycemia was similar, whereas taspoglutide, 20 mg, had the greatest risk for nausea (odds ratios, 1.9 to 5.9). LIMITATION: Data were unavailable for semaglutide, definitions of outcomes were heterogeneous, the last observation-carried-forward imputation method was used in 73% of trials, and publication bias is possible. CONCLUSION: Compared with other once-weekly GLP 1RAs, dulaglutide, 1.5 mg; once-weekly exenatide; and taspoglutide, 20 mg, showed a greater reduction of HbA1c, fasting plasma glucose, and body weight. Taspoglutide, 20 mg, had the highest risk for nausea; risk for hypoglycemia among once-weekly GLP-1RAs was similar. PRIMARY FUNDING SOURCE: Sanofi Aventis (grant to the University of Leicester). PMID- 26642235 TI - HDL signaling and protection against coronary artery atherosclerosis in mice. AB - Atherosclerosis is a leading underlying factor in cardiovascular disease and stroke, important causes of morbidity and mortality across the globe. Abundant epidemiological studies demonstrate that high levels of high density lipoprotein (HDL) are associated with reduced risk of atherosclerosis and preclinical, animal model studies demonstrate that this association is causative. Understanding the molecular mechanisms underlying the protective effects of HDL will allow more strategic approaches to development of HDL based therapeutics. Recent evidence suggests that an important aspect of the ability of HDL to protect against atherosclerosis is its ability to trigger signaling responses in a variety of target cells including endothelial cells and macrophages in the vessel wall. These signaling responses require the HDL receptor, scavenger receptor class B type 1 (SR-B1), an adaptor protein (PDZK1) that binds to the cytosolic C terminus of SR-B1, Akt1 activation and (at least in endothelial cells) activation of endothelial NO synthase (eNOS). Mouse models of atherosclerosis, exemplified by apolipoprotein E or low density lipoprotein receptor gene inactivated mice (apoE or LDLR KO) develop atherosclerosis in their aortas but appear generally resistant to coronary artery atherosclerosis. On the other hand, inactivation of each of the components of HDL signaling (above) in either apoE or LDLR KO mice renders them susceptible to extensive coronary artery atherosclerosis suggesting that HDL signaling may play an important role in protection against coronary artery disease. PMID- 26642236 TI - Bone site-specific delivery of siRNA. AB - Small interfering RNAs (siRNA) have enormous potential as therapeutics to target and treat various bone disorders such as osteoporosis and cancer bone metastases. However, effective and specific delivery of siRNA therapeutics to bone and bone specific cells in vivo is very challenging. To realize the full therapeutic potential of siRNA in treating bone disorders, a safe and efficient, tissue- and cell-specific delivery system must be developed. This review focuses on recent advances in bone site-specific delivery of siRNA at the tissue or cellular level. Bone-targeted nanoparticulate siRNA carriers and various bone-targeted moieties such as bisphosphonates, oligopeptides (Asp)8 and (AspSerSer)6, and aptamers are highlighted. Incorporation of these bone-seeking targeting moieties into siRNA carriers allows for recognition of different sub-tissue functional domains of bone and also specific cell types residing in bone tissue. It also provides a means for bone-formation surface-, bone-resorption surface-, or osteoblast specific targeting and transportation of siRNA therapeutics. The discussion mainly focuses on systemic and local bone-specific delivery of siRNA in osteoporosis and bone metastasis preclinical models. PMID- 26642237 TI - A Decade of Change in NO2 and SO2 over the Canadian Oil Sands As Seen from Space. AB - A decade (2005-2014) of observations from the Ozone Monitoring Instrument (OMI) were used to examine trends in nitrogen dioxide (NO2) and sulfur dioxide (SO2) over a large region of western Canada and the northern United States, with a focus on the Canadian oil sands. In the oil sands, primarily over an area of intensive surface mining, NO2 tropospheric vertical column densities (VCDs) are seen to be increasing by as much as 10%/year, with the location of the largest trends in a newly developing NO2 "lobe" well removed from surface monitoring stations. SO2 VCDs in the oil sands have remained approximately constant. The only other significant increase in the region was seen in NO2 over Bakken gas fields in North Dakota which showed increases of up to 5%/yr. By contrast, other locations in the region show substantial declines in both pollutants, providing strong evidence to the efficacy of environmental pollution control measures implemented by both nations. The OMI-derived trends were found to be consistent with those from the Canadian surface monitoring network, although in the case of SO2, it was necessary to apply a correction in order to remove the residual signal from volcanic eruptions present in the OMI data. PMID- 26642238 TI - Correction to Surface-Bubble-Modulated Liquid Chromatography: A New Approach for Manipulation of Chromatographic Retention and Investigation of Solute Distribution at Water/Hydrophobic Interfaces. PMID- 26642239 TI - Multidimensional Mass Spectrometry Coupled with Separation by Polarity or Shape for the Characterization of Sugar-Based Nonionic Surfactants. AB - Mass spectrometry (MS) and tandem mass spectrometry (MS/MS) were interfaced with ultra-performance liquid chromatography (UPLC) and ion mobility (IM) separation to characterize a complex nonionic surfactant, consisting of a methylated glucose core (glucam) conjugated with poly(ethylene oxide) (PEO(n)) branches that were partially esterified with stearic acid to form ethoxylated glucam (PEO(n)-glucam) stearates. Reverse-phase LC-MS afforded fast separation according to polarity into five major fractions. Accurate mass measurements of the ions in the mass spectra extracted from these fractions enabled conclusive identification of six components in the surfactant, including PEO(n)-glucam mono-, di-, and tristearates as well as free and esterified PEO(n) as byproducts. MS/MS experiments provided corroborating evidence for the fatty acid content in each fraction based on the number of stearic acid losses observed. With IM-MS, the total surfactant ions were separated according to charge and shape into four distinct bands. Extracted mass spectra confirmed the presence of two disaccharide stearates in the surfactant, which were undetectable by LC-MS. PEO(n)-glucam tristearates were, however, not observed upon IM-MS. Hence, LC-MS and IM-MS unveiled complementary compositional insight. With each method, certain components were particularly well separated from other ingredients (by either polarity or shape), to be detected with confidence. Consequently, combined LC-MS and IM-MS offer a superior approach for the characterization of surfactants and other amphiphilic polymers and for the differentiation of similarly composed amphiphilic blends. It is finally noteworthy that NH4(+) charges minimized chemical noise in MS mode and Li(+) charges maximized the fragmentation efficiency in MS/MS mode. PMID- 26642240 TI - A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency. AB - Patients with a combined immunodeficiency characterized by normal numbers but impaired function of T and B cells had a homozygous p.Tyr20His substitution in transferrin receptor 1 (TfR1), encoded by TFRC. The substitution disrupts the TfR1 internalization motif, resulting in defective receptor endocytosis and markedly increased TfR1 expression on the cell surface. Iron citrate rescued the lymphocyte defects, and expression of wild-type but not mutant TfR1 rescued impaired transferrin uptake in patient-derived fibroblasts. Tfrc(Y20H/Y20H) mice recapitulated the immunological defects of patients. Despite the critical role of TfR1 in erythrocyte development and function, patients had only mild anemia and only slightly increased TfR1 expression in erythroid precursors. We show that STEAP3, a metalloreductase expressed in erythroblasts, associates with TfR1 and partially rescues transferrin uptake in patient-derived fibroblasts, suggesting that STEAP3 may provide an accessory TfR1 endocytosis signal that spares patients from severe anemia. These findings demonstrate the importance of TfR1 in adaptive immunity. PMID- 26642241 TI - Abundant contribution of short tandem repeats to gene expression variation in humans. AB - The contribution of repetitive elements to quantitative human traits is largely unknown. Here we report a genome-wide survey of the contribution of short tandem repeats (STRs), which constitute one of the most polymorphic and abundant repeat classes, to gene expression in humans. Our survey identified 2,060 significant expression STRs (eSTRs). These eSTRs were replicable in orthogonal populations and expression assays. We used variance partitioning to disentangle the contribution of eSTRs from that of linked SNPs and indels and found that eSTRs contribute 10-15% of the cis heritability mediated by all common variants. Further functional genomic analyses showed that eSTRs are enriched in conserved regions, colocalize with regulatory elements and may modulate certain histone modifications. By analyzing known genome-wide association study (GWAS) signals and searching for new associations in 1,685 whole genomes from deeply phenotyped individuals, we found that eSTRs are enriched in various clinically relevant conditions. These results highlight the contribution of STRs to the genetic architecture of quantitative human traits. PMID- 26642242 TI - Visualizing spatial population structure with estimated effective migration surfaces. AB - Genetic data often exhibit patterns broadly consistent with 'isolation by distance'-a phenomenon where genetic similarity decays with geographic distance. In a heterogeneous habitat, this may occur more quickly in some regions than in others: for example, barriers to gene flow can accelerate differentiation between neighboring groups. We use the concept of 'effective migration' to model the relationship between genetics and geography. In this paradigm, effective migration is low in regions where genetic similarity decays quickly. We present a method to visualize variation in effective migration across a habitat from geographically indexed genetic data. Our approach uses a population genetic model to relate effective migration rates to expected genetic dissimilarities. We illustrate its potential and limitations using simulations and data from elephant, human and Arabidopsis thaliana populations. The resulting visualizations highlight important spatial features of population structure that are difficult to discern using existing methods for summarizing genetic variation. PMID- 26642244 TI - A prospective randomised study of dense Infinity cytological brush versus regularly used brush in pancreaticobiliary malignancy. AB - BACKGROUND AND STUDY AIMS: Endoscopic retrograde cholangiopancreatography (ERCP) with a cytological sample is a valuable tool in the diagnosis of the aetiology of biliary stricture. Our aim was to evaluate whether a more dense Infinity(r) cytological brush is more sensitive in diagnosing malignancy than the regularly used brush. PATIENTS AND METHODS: We recruited 60 patients with a biliary stricture suspicious for malignancy for a randomised controlled trial. Patients were randomly assigned to an Infinity(r) brush group (n = 30) and a regularly used cytology brush group (n = 30). All the patients had verified cancer during follow-up. RESULTS: Crossing the brush over the stricture was possible in each case without dilatation of the biliary duct. Brush cytology yield was good or excellent in 86.7% of cases with the Infinity(r) brush and 96.7% with the regular brush (p = 0.161). The cytological sample showed clear malignancy in three patients (10.0%) in the Infinity(r) group and in 12 (40.0%) patients of the regular brush group (p = 0.007). The cytological diagnosis was highly suspicious for malignancy or malignant in 14 patients (46.7%) in the Infinity(r) group and in 23 patients (76.7%) in the regular brush group (p = 0.017). The result was benign in 10 patients (33.3%) in the Infinity(r) group and in four patients (13.6%) in the regular brush group (p = 0.067). CONCLUSIONS: With the standardised technique, the sensitivity of brush cytology is fairly good. The dense Infinity(r) brush does not show any advantage regarding sensitivity compared with the conventional cytology brush. PMID- 26642245 TI - Isomers of Pyrene-Imidazole Compounds: Synthesis and Configuration Effect on Optical Properties. AB - Two pyrene-imidazole-based structural isomers, axisymmetric syn-PyDTI and centrosymmetric anti-PyDTI, have been easily produced and successfully separated in a one-pot reaction. Crystalline syn-PyDTI exhibited a 2-fold higher quantum efficiency than anti-PyDTI and displayed a much better performance in OLEDs with a etac.max of 11.4 cd A(-1) (8.8 cd A(-1) for anti-PyDTI), although they possess the same apparent electronic structure. Observations revealed that the molecular excited-state properties are derived from distinct structural symmetries. PMID- 26642246 TI - Iodine-Promoted Radical Cyclization in Water: A Selective Reaction of 1,6-Enynes with Sulfonyl Hydrazides. AB - An iodine-promoted one-pot radical cyclization reaction of 1,6-enynes with sulfonyl hydrazides to provide five-membered and hexatomic ring sulfonylated products under the same conditions is established. This reaction proceeded smoothly in water and gave the corresponding products by using I2/TBHP instead of expensive and toxic catalysts with C-S and C-I bond formed in one step. This method also allowed easy access to significant functional sulfones for potential applications in medicinal and organic chemistry. PMID- 26642243 TI - Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early-onset autoinflammatory disease. AB - Systemic autoinflammatory diseases are driven by abnormal activation of innate immunity. Herein we describe a new disease caused by high-penetrance heterozygous germline mutations in TNFAIP3, which encodes the NF-kappaB regulatory protein A20, in six unrelated families with early-onset systemic inflammation. The disorder resembles Behcet's disease, which is typically considered a polygenic disorder with onset in early adulthood. A20 is a potent inhibitor of the NF kappaB signaling pathway. Mutant, truncated A20 proteins are likely to act through haploinsufficiency because they do not exert a dominant-negative effect in overexpression experiments. Patient-derived cells show increased degradation of IkappaBalpha and nuclear translocation of the NF-kappaB p65 subunit together with increased expression of NF-kappaB-mediated proinflammatory cytokines. A20 restricts NF-kappaB signals via its deubiquitinase activity. In cells expressing mutant A20 protein, there is defective removal of Lys63-linked ubiquitin from TRAF6, NEMO and RIP1 after stimulation with tumor necrosis factor (TNF). NF kappaB-dependent proinflammatory cytokines are potential therapeutic targets for the patients with this disease. PMID- 26642247 TI - The complete mitochondrial genome of Sinilabeo rendahli (Cypriniformes: Cyprinidae). AB - The Sinilabeo rendahli (S. rendahli) belongs to the family Cyprinidae and the order Cypriniformes, which is an economic fish species in southern China. In this study, the complete mitochondrial genome of S. rendahli was determined (the GenBank accession number is KT336714). The mitochondrial genome sequence of S. rendahli was a circular molecule with 16 586 bp in length, and it contained 37 typical animal mitochondrial genes including 2 ribosomal RNA genes, 13 protein coding genes, 22 transfer RNA genes and a control region (D-loop). Four nucleotide compositions and their relative proportions of the entire mitogenome were, 26.62% C, 15.29% G, 32.31% A and 25.78% T, with an A + T and G + C contents being 58.09 and 41.91%, respectively. PMID- 26642248 TI - Prognostic use of soluble fms-like tyrosine kinase-1 and placental growth factor in patients with coronary artery disease. AB - BACKGROUND: Intention of the study is to assess the cardiovascular mortality of patients with coronary artery disease (CAD) with the biomarkers of angiogenesis PlGF and its endogenous inhibitor sFlt-1. METHODS: The cohort included n = 1848 patients with CAD and 282 subjects without CAD. In 85 patients cardiovascular mortality, as combination of fatal myocardial infarction or any cardiac death, during a median follow-up duration of 3.9 years was reported. RESULTS: In Kaplan Meier curve analysis PlGF in rising thirds was not predictive regarding outcome (p = 0.54), the same was shown for sFlt-1 (p = 0.44). Cox regression for the fully adjusted model provided a hazard ratio (HR) of 0.8 (p = 0.18) for PlGF and for sFlt-1 a HR = 1.0 (p = 0.8). CONCLUSION: Our results point out that these biomarkers reflecting angiogenesis might not be suited to establish prognosis in CAD. PMID- 26642249 TI - Novel targets for natural killer/T-cell lymphoma immunotherapy. AB - Extranodal natural killer/T-cell lymphoma, nasal type (NKTL) is a rare but highly aggressive Epstein-Barr virus-related malignancy, which mainly occurs in nasopharyngeal and nasal/paranasal areas. In addition to its high prevalence in Asian, Central American and South American populations, its incidence rate has been gradually increasing in Western countries. The current mainstay of treatment is a combination of multiple chemotherapies and irradiation. Although chemoradiotherapy can cure NKTL, it often causes severe and fatal adverse events. Because a growing body of evidence suggests that immunotherapy is effective against hematological malignancies, this treatment could provide an alternative to chemoradiotherapy for treatment of NKTL. In this review, we focus on how recent findings could be used to develop efficient immunotherapies against NKTL. PMID- 26642255 TI - Genomics: the Power and the Promise. PMID- 26642251 TI - Increasing global participation in genetics research through DNA barcoding. AB - DNA barcoding--the sequencing of short, standardized DNA regions for specimen identification and species discovery--has promised to facilitate rapid access to biodiversity knowledge by diverse users. Here, we advance our opinion that increased global participation in genetics research is beneficial, both to scientists and for science, and explore the premise that DNA barcoding can help to democratize participation in genetics research. We examine publication patterns (2003-2014) in the DNA barcoding literature and compare trends with those in the broader, related domain of genomics. While genomics is the older and much larger field, the number of nations contributing to the published literature is similar between disciplines. Meanwhile, DNA barcoding exhibits a higher pace of growth in the number of publications as well as greater evenness among nations in their proportional contribution to total authorships. This exploration revealed DNA barcoding to be a highly international discipline, with growing participation by researchers in especially biodiverse nations. We briefly consider several of the challenges that may hinder further participation in genetics research, including access to training and molecular facilities as well as policy relating to the movement of genetic resources. PMID- 26642256 TI - Cancer susceptibility genes and their potential implication regarding systemic therapy for early-stage breast cancer. PMID- 26642257 TI - Ultrafine CoP Nanoparticles Supported on Carbon Nanotubes as Highly Active Electrocatalyst for Both Oxygen and Hydrogen Evolution in Basic Media. AB - The development of low-cost and highly active electrocatalysts for two half reactions: H2 and O2 evolution reactions (HER and OER), is still a huge challenge to realize water splitting. Herein, we report that CoP nanoparticles (NPs) can act as a bifunctional catalyst for both HER and OER. Particularly, ultrafine CoP NPs decorated on N-doped multiwalled carbon nanotube (MWCNT) exhibit remarkable catalytic performance for OER in 0.1 M NaOH aqueous solution, with a low onset overpotential of 290 mV, a Tafel slope of 50 mV dec(-1), an overpotential (eta) of 330 mV at 10 mA cm(-2), and approximately 100% Faradaic efficiency, paralleling the performance of state-of-the-art Co-based OER catalysts including Co3O4, CoSe2, and Co-Pi. The hybrid catalyst is capable of maintaining a high catalytic current density for at least 10 h without any loss of catalytic activity. Meanwhile, the noble-metal-free catalyst also shows good activity and duarability for HER under the same basic condition. PMID- 26642258 TI - The Fragment Molecular Orbital Method Reveals New Insight into the Chemical Nature of GPCR-Ligand Interactions. AB - Our interpretation of ligand-protein interactions is often informed by high resolution structures, which represent the cornerstone of structure-based drug design. However, visual inspection and molecular mechanics approaches cannot explain the full complexity of molecular interactions. Quantum Mechanics approaches are often too computationally expensive, but one method, Fragment Molecular Orbital (FMO), offers an excellent compromise and has the potential to reveal key interactions that would otherwise be hard to detect. To illustrate this, we have applied the FMO method to 18 Class A GPCR-ligand crystal structures, representing different branches of the GPCR genome. Our work reveals key interactions that are often omitted from structure-based descriptions, including hydrophobic interactions, nonclassical hydrogen bonds, and the involvement of backbone atoms. This approach provides a more comprehensive picture of receptor-ligand interactions than is currently used and should prove useful for evaluation of the chemical nature of ligand binding and to support structure-based drug design. PMID- 26642259 TI - Simultaneously Enhancing the Cohesion and Electrical Conductivity of PEDOT:PSS Conductive Polymer Films using DMSO Additives. AB - Conductive polymer poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) ( PEDOT: PSS) has attracted significant attention as a hole transport and electrode layer that substitutes metal electrodes in flexible organic devices. However, its weak cohesion critically limits the reliable integration of PEDOT: PSS in flexible electronics, which highlights the importance of further investigation of the cohesion of PEDOT: PSS. Furthermore, the electrical conductivity of PEDOT: PSS is insufficient for high current-carrying devices such as organic photovoltaics (OPVs) and organic light emitting diodes (OLEDs). In this study, we improve the cohesion and electrical conductivity through adding dimethyl sulfoxide (DMSO), and we demonstrate the significant changes in the properties that are dependent on the wt % of DMSO. In particular, with the addition of 3 wt % DMSO, the maximum enhancements for cohesion and electrical conductivity are observed where the values increase by 470% and 6050%, respectively, due to the inter-PEDOT bridging mechanism. Furthermore, when OLED devices using the PEDOT: PSS films are fabricated using the 3 wt % DMSO, the display exhibits 18% increased current efficiency. PMID- 26642260 TI - Kinetics of Thermal Inactivation of Peroxidase and Color Degradation of African Cowpea (Vigna unguiculata) Leaves. AB - Cowpea leaves form an important part of the diet for many Kenyans, and they are normally consumed after a lengthy cooking process leading to the inactivation of peroxidase (POD) that could be used as an indicator for the potential shelf life of the vegetables. However, color degradation can simultaneously occur, leading to poor consumer acceptance of the product. The kinetics of POD in situ thermal (for thermal treatments in the range of 75 to 100 degrees C/120 min) inactivation showed a biphasic first-order model, with Arrhenius temperature dependence of the rate constant. The kinetic parameters using a reference temperature (Tref ) of 80 degrees C were determined for both the heat-labile phase (kref = 11.52 +/- 0.95 * 10(-2) min(-1) and Ea of 109.67 +/- 6.20 kJ/mol) and the heat-stable isoenzyme fraction (kref = 0.29 +/- 0.07 * 10(-2) min(-1) and Ea of 256.93 +/- 15.27 kJ/mol). Color degradation (L*, a*, and b* value) during thermal treatment was investigated, in particular as the "a*" value (the value of green color). Thermal degradation (thermal treatments between 55 and 80 degrees C per 90 min) of the green color of the leaves followed a fractional conversion model and the temperature dependence of the inactivation rate constant can be described using the Arrhenius law. The kinetic parameters using a reference temperature (TrefC = 70 degrees C) were determined as krefC = 13.53 +/- 0.01 * 10(-2) min(-1) and EaC = 88.78 +/- 3.21 kJ/mol. The results indicate that severe inactivation of POD (as an indicator for improved shelf life of the cooked vegetables) is accompanied by severe color degradation and that conventional cooking methods (typically 10 min/100 degrees C) lead to a high residual POD activity suggesting a limited shelf life of the cooked vegetables. PMID- 26642261 TI - Internal Medicine Resident Computer Usage: An Electronic Audit of an Inpatient Service. PMID- 26642262 TI - Corrosion and Tribological Behavior of ZrO2 Films Prepared on Stainless Steel Surface by the Sol-Gel Method. AB - ZrO2 films with one, two, and three layers were prepared on a 304 stainless steel surface through the sol-gel method, followed by sintering at 500, 600, and 700 degrees C. The crystal structure and the surface morphology of the films were characterized by X-ray diffraction and atomic force microscopy. The corrosion resistances of uncoated and coated specimens were studied by electrochemical corrosion tests in a 5% NaCl solution at room temperature. The tribological properties of ZrO2 films were investigated using a tribometer. The results showed that the crystal structure of ZrO2 partially transformed from the tetragonal phase to the monoclinic phase with a rise in sintering temperature. The grain size of the ZrO2 films grew, and the surface roughness of the films increased. However, with an increase in the number of film layers, the grain size and the surface roughness of the ZrO2 films decreased and the films became more uniform and denser. ZrO2 films effectively enhanced the corrosion and wear resistances of the stainless steel surface. With the increase of the sintering temperature and the number of layers in the film, the corrosion resistance of the ZrO2 films increased gradually, but the wear resistance of the films slowly decreased. The film with three layers, which was sintered at 700 degrees C, had the highest corrosion resistance. Nevertheless, the film with one layer, which was sintered at 500 degrees C, exhibited relatively well wear resistance. PMID- 26642264 TI - Corrigenda. PMID- 26642263 TI - Switched On-Expert Advice in Prehospital Thrombolysis via Telemedicine. PMID- 26642265 TI - Erratum. PMID- 26642268 TI - Letter to the Editor: Comment on Statistical Adjustment in "DDT Exposure in Utero and Breast Cancer" By Cohn B.A., et al. PMID- 26642269 TI - Response to the Letter by Stoop, P. PMID- 26642270 TI - Letter to the Editor: Comments on "LGR5 Activates Noncanonical Wnt Signaling and Inhibits Aldosterone Production in the Human Adrenal" by Shaikh L.H., et al. PMID- 26642271 TI - Letter to the Editor: "Steroid Sex Hormones, Sex Hormone-Binding Globulin, and Diabetes Incidence in the Diabetes Prevention Program" by Mather K.J., et al. PMID- 26642272 TI - Letter to the Editor: Possible Decrease in GIP Levels May Explain Increased Plasma Dipeptidyl Peptidase-4 Activity-Associated Osteoporosis. PMID- 26642273 TI - Letter to the Editor: Potential Role for FGF21 as a Mediator of Thyroid Hormone Effects on Metabolic Regulation. PMID- 26642274 TI - Contrast enhancement in EIT imaging of the brain. AB - We consider electrical impedance tomography (EIT) imaging of the brain. The brain is surrounded by the poorly conducting skull which has low conductivity compared to the brain. The skull layer causes a partial shielding effect which leads to weak sensitivity for the imaging of the brain tissue. In this paper we propose an approach based on the Bayesian approximation error approach, to enhance the contrast in brain imaging. With this approach, both the (uninteresting) geometry and the conductivity of the skull are embedded in the approximation error statistics, which leads to a computationally efficient algorithm that is able to detect features such as internal haemorrhage with significantly increased sensitivity and specificity. We evaluate the approach with simulations and phantom data. PMID- 26642299 TI - Interprofessional Education: A Summary of Reports and Barriers to Recommendations. AB - PURPOSE: Effective, quality care to achieve the newly developed sustainable development goals requires the development of collaborative teams and is predicated on implementing transformative interprofessional education and on team members who are equally empowered. This is a report on The Lancet commission on transformative education for health professionals and the National Academy of Medicine's dialogues on developing and implementing innovations to enhance collaborations and to facilitate the effectiveness of healthcare teams. METHODS: Using postcolonial feminist theory for critical analysis and integrations of findings from both reports, as well as for identification of barriers to achieving equity in team functioning. FINDINGS: The global Lancet commission and the National Academy of Medicine/Institute of Medicine forum developed frameworks that could be used to educate the next generation of professionals based on identifying the local needs of communities within a global context. Recommendations included breaking down silos that exists between schools and using an equity and justice framework in developing educational programs; utilizing contemporary innovations in teaching that correspond with innovations in healthcare systems; and insuring investments in time, energy, and resources in interprofessional education. However, without addressing the silos created through professional identities and power differentials, goals of interprofessional education and collaborative practice may not be achieved. CONCLUSIONS: While a great deal has been written about interprofessional education, it is imperative for faculty in the different professional schools and for members of healthcare teams to engage in dialogues that address the fundamental and most obstinate barriers to forming equitable teams, which is the consistent narrative of medical privilege and centrism. CLINICAL RELEVANCE: The dialogues about medical privilege and physician centrism in education and health care could drive the development of programmatic approaches to enhancing interprofessional education and teamwork based on justice and equity frameworks. PMID- 26642300 TI - N-Acetylneuraminic acid attenuates hypercoagulation on high fat diet-induced hyperlipidemic rats. AB - BACKGROUND AND OBJECTIVE: N-Acetylneuraminic acid (Neu5Ac), a type of sialic acid, has close links with cholesterol metabolism and is often used as a biomarker in evaluating the risk of cardiovascular diseases. However, most studies on the health implications of Neu5Ac have focused on its effects on the nervous system, while its effects on cardiovascular risk factors have largely been unreported. Thus, the effects of Neu5Ac on coagulation status in high fat diet (HFD)-induced hyperlipidemic rats were evaluated in this study. METHODS: Sprague Dawley male rats were divided into five different groups and fed with HFD alone, HFD low-dose Neu5Ac, HFD high-dose Neu5Ac, HFD simvastatin (10 mg/kg day), and normal pellet alone. Food was given ad libitum while body weight of rats was measured weekly. After 12 weeks of intervention, rats were sacrificed and serum and tissue samples were collected for biochemistry and gene expression analysis, respectively. RESULTS: The results showed that Neu5Ac could improve lipid metabolism and hyperlipidemia-associated coagulation. Neu5Ac exerted comparable or sometimes better physiological effects than simvastatin, at biochemical and gene expression levels. CONCLUSIONS: The data indicated that Neu5Ac prevented HFD induced hyperlipidemia and associated hypercoagulation in rats through regulation of lipid-related and coagulation-related genes and, by extension, induced metabolite and protein changes. The implications of the present findings are that Neu5Ac may be used to prevent coagulation-related cardiovascular events in hyperlipidemic conditions. These findings are worth studying further. PMID- 26642301 TI - Saxagliptin co-therapy in C-peptide negative Type 1 diabetes does not improve counter-regulatory responses to hypoglycaemia. AB - AIMS: To test the hypothesis that dipeptidyl peptidase-4 inhibition in C-peptide negative Type 1 diabetes would reduce glucose variability and exposure to hypoglycaemia and therefore may indirectly enhance counter-regulatory responses to subsequent hypoglycaemia. METHODS: We conducted a 12-week double-blind, randomized, placebo-controlled crossover study. The study was conducted in a tertiary hospital outpatient clinic, with additional studies performed in a clinical research centre. After obtaining informed consent, we recruited 14 subjects with moderately well controlled Type 1 diabetes (HbA1c 64 +/- 2 mmol/mol) of long duration (20.5 +/- 2.7 years). The subjects received 12 weeks' therapy with oral saxagliptin (5 mg) or placebo. Glucose variability, assessed via continuous glucose monitoring, together with frequency of hypoglycaemia, hypoglycaemia awareness and symptomatic, cognitive and counter-regulatory hormone responses to experimental hypoglycaemia, were assessed. Additional outcome measures included HbA1c level, weight, total daily insulin dose and adverse events. RESULTS: Saxagliptin co-therapy did not reduce glucose variability (low blood glucose index, average daily risk range), hypoglycaemia frequency or awareness and did not improve counter-regulatory hormonal responses during experimental hypoglycaemia (area under the curve for adrenaline 25 775 vs. 24 454, for placebo vs saxagliptin, respectively; P = 0.76). CONCLUSIONS: No additional benefit of dipeptidyl peptidase-4 inhibition co-therapy with saxagliptin in the management of Type 1 diabetes was observed. PMID- 26642302 TI - Rebuttal from Tanya M. Holloway and Lawrence L. Spriet. PMID- 26642303 TI - Evaluation of the genes encoding CD39/NTPDase-1 and CD39L1/NTPDase-2 in horses with and without abnormal hemorrhage and in horses with pathologic evidence of exercise-induced pulmonary hemorrhage. AB - BACKGROUND: Exercise-induced pulmonary hemorrhage (EIPH) is a common disorder of equine athletes. The role of polymorphisms in genes encoding hemostasis regulatory proteins in horses with abnormal hemorrhage is unknown. OBJECTIVES: The goal of this study was to evaluate the genes encoding 2 ectonucleotidases, CD39/NTPDase-1 and CD39L1/NTPDase-2, and one ecto-5' nucleotidase, CD73, in horses with abnormal hemorrhage or pathologic changes consistent with EIPH. METHODS: Twenty-three horses with histories of abnormal hemorrhage, 8 horses with gastrointestinal signs, and 45 healthy horses were evaluated using polymerase chain reaction-based techniques. Formalin-fixed tissues from 21 horses with pathologic changes consistent with EIPH were also evaluated. RESULTS: Three single nucleotide polymorphisms (SNPs) were identified in the gene encoding CD39 and one SNP was identified in the gene encoding CD39L1. No SNPs were identified in the gene encoding CD73. CD39 SNPs were identified in 19 of 20 (95%) horses with unexplained hemorrhage and 20 of 21 (95%) horses with pathologic features consistent with EIPH. CD39L1 SNPs were identified in 6 of 20 (30%) horses with unexplained hemorrhage and 8 of 21 (38%) horses with pathologic features consistent with EIPH. CD39 and CD39L1 SNPs were identified in 5 of 8 (62.5%) and one of 8 (12.5%) horses, respectively, presenting with colic or weight loss. CD39 and CD39L1 SNPs were identified in 28 of 45 (62%) and 13 of 45 (28.8%) healthy horses, respectively. CONCLUSIONS: CD39 and CD39L1 are critically important in maintaining normal hemostasis and limiting inflammation. Further studies are needed to evaluate their role in the pathogenesis of equine EIPH. PMID- 26642304 TI - Strategies for the Controlled Electronic Doping of Colloidal Quantum Dot Solids. AB - Over the last several years tremendous progress has been made in incorporating colloidal quantum dot (CQD) solids as photoactive components in optoelectronic devices. A large part of this progress is associated with significant advancements made in controlling the electronic doping of CQD solids. Today, a variety of strategies exists towards that purpose; this Minireview aims to survey the major published works in this subject. Additional attention is given to the many challenges associated with the task of doping CQDs, as well as to the realization of optoelectronic functionalities and applications upon successful light and heavy electronic doping of CQD solids. PMID- 26642305 TI - Nanoscale radiation transport and clinical beam modeling for gold nanoparticle dose enhanced radiotherapy (GNPT) using X-rays. AB - We review radiation transport and clinical beam modelling for gold nanoparticle dose-enhanced radiotherapy using X-rays. We focus on the nanoscale radiation transport and its relation to macroscopic dosimetry for monoenergetic and clinical beams. Among other aspects, we discuss Monte Carlo and deterministic methods and their applications to predicting dose enhancement using various metrics. PMID- 26642306 TI - Detection of bladder cancer: comparison of low-dose scans with AIDR 3D and routine-dose scans with FBP on the excretory phase in CT urography. AB - OBJECTIVE: To prospectively compare the detection of bladder cancer between low dose scans with adaptive iterative dose reduction three dimensional projection (AIDR 3D) and routine-dose scans with filtered back projection (FBP) on the excretory phase (EP) in CT urography. METHODS: 42 patients were included. Routine and low-dose EP were performed in each patient. Routine-dose images were reconstructed with FBP, and low-dose images were reconstructed with AIDR 3D. Two radiologists scored confidence levels for the presence or absence of bladder cancer using a 5-point scale. The CT dose index of each EP was measured, and the dose reduction was calculated. RESULTS: Sensitivity, specificity and accuracy were 86.4%, 95.0% and 90.5% on routine-dose scans and were 86.4%, 90.0% and 88.1% on low-dose scans, respectively. There was no significant difference (p; not significant, 1.00 and 1.00, respectively). The average CT dose index was 8.07 and 2.63 mGy on routine- and low-dose scans, and the ratio of dose reduction was 67.6%. CONCLUSION: The detection of bladder cancer on low-dose scans with AIDR 3D is almost equal to that on routine-dose scans with FBP on the EP, with nearly 70% dose reduction. ADVANCES IN KNOWLEDGE: Using AIDR 3D, the radiation dose may be reduced on the EP in CT urography for the detection of bladder cancer. PMID- 26642307 TI - Functional imaging of interstitial brachytherapy in pancreatic carcinoma xenografts using spectral CT: how does iodine concentration correlate with standardized uptake value of (18)FDG-PET-CT? AB - OBJECTIVE: This study aimed to investigate the correlation between iodine concentration (IC) for the quantitative analysis of spectral CT and maximum standardized uptake value (SUVmax) of 18 fludeoxyglucose positron emission tomography-CT ((18)FDG PET-CT) as an indicator of therapeutic response to interstitial brachytherapy in transplanted human pancreatic carcinomas in BALB/c nu mice. METHODS: Xenograft models were created by subcutaneous injection of SW1990 human pancreatic cancer cell suspensions into immunodeficient BALB/c-nu mice. 30 mice bearing SW1990 human pancreatic cancer cell xenografts were randomly separated into two groups: experimental (n = 15; 1.0 mCi) and control (n = 15, 0 mCi). After 2 weeks of treatment, spectral CT and (18)FDG micro-PET-CT scan were performed. IC values and SUVmax in the lesions were measured. IC normalized to the muscle tissue is indicated as nIC. The relationships between the nIC and SUVmax of the transplantation tumours were analysed. RESULTS: 2 weeks after treatment, the nIC in three-phase scans and SUVmax of the experimental group were significantly lower than those of the control group. The nIC values of the three-phase scans have certain positive correlation with the SUVmax values (r = 0.69, p < 0.05; r = 0.73 and p < 0.05; r = 0.80, p < 0.05 in the 10-, 25- and 60-s phase, respectively). CONCLUSION: Spectral CT could serve as a valuable imaging modality, as our results suggest that nIC correlates with SUVmax of (18)FDG PET-CT for evaluating the therapeutic effect of (125)I interstitial brachytherapy in a pancreatic carcinoma xenograft. ADVANCES IN KNOWLEDGE: Spectral CT offers opportunities to assess the therapeutic response of pancreatic cancer. This study supports the conclusion that nIC values in spectral CT could also serve as a valuable functional imaging parameter for early monitoring and evaluation of the therapeutic response of (125)I interstitial brachytherapy mouse models because the nIC correlates with the SUVmax of (18)FDG PET-CT. PMID- 26642308 TI - A diffusion-based quantification technique for assessment of sacroiliitis in adolescents with enthesitis-related arthritis. AB - OBJECTIVE: To investigate the use of a quantitative diffusion-weighted imaging (DWI) tool for measuring inflammation of the sacroiliac joints (SIJs) in enthesitis-related arthritis (ERA). METHODS: A retrospective study was performed with institutional review board approval. Subjects were adolescents who had undergone MRI of the SIJs since January 2010. 10 patients with a clinical diagnosis of ERA and 10 controls with a clinical diagnosis of mechanical back pain were assessed. Axial T1 weighted, short tau inversion recovery (STIR) and DWI (b-values 0, 50, 100, 300 and 600 mm(2) s(-1)) images were acquired. Apparent diffusion coefficient (ADC) maps were generated using a monoexponential fit. On each of four slices, two to three linear regions-of-interest were placed on each joint. Normalized ADC (nADC) values were defined as joint ADC divided by a reference ADC derived from normal sacral bone. STIR images were scored using a modification of an established technique. The correlation between nADC values and STIR scores was evaluated using Spearman's rank correlation. RESULTS: Mean nADC values were significantly higher in cases than in controls (p = 0.0015). There was a strong correlation between STIR scores and nADC values (R = 0.85). CONCLUSION: ADC values are significantly increased in inflamed SIJs compared with controls. There is a good correlation between this diffusion-based method and STIR scores of inflammation. ADVANCES IN KNOWLEDGE: We have described and provisionally validated a method for quantifying the severity of inflammation in the SIJs in ERA using ADC measurements. This method is quick, is reproducible and could potentially be automated. PMID- 26642309 TI - Paediatric femur fractures at the emergency department: accidental or not? AB - Only a small proportion of all paediatric fractures is caused by child abuse or neglect, especially in highly prevalent long bone fractures. It can be difficult to differentiate abusive fractures from non-abusive fractures. This article focuses on femoral fractures in young children. Based on three cases, this article presents a forensic evidence-based approach to differentiate between accidental and non-accidental causes of femoral fractures. We describe three cases of young children who were presented to the emergency department because of a suspected femur fracture. Although in all cases, the fracture had a similar location and appearance, the clinical history and developmental stage of the child led to three different conclusions. In the first two cases, an accidental mechanism was a plausible conclusion, although in the second case, neglect of parental supervision was the cause for concern. In the third case, a non accidental injury was diagnosed and appropriate legal prosecution followed. Any doctor treating children should always be aware of the possibility of child abuse and neglect in children with injuries, especially in young and non-mobile children presenting with an unknown trauma mechanism. If a suspicion of child abuse or neglect arises, a thorough diagnostic work-up should be performed, including a full skeletal survey according to the guidelines of the Royal College of Radiologists and the Royal College of Paediatrics and Child Health. In order to make a good assessment, the radiologist reviewing the skeletal survey needs access to all relevant clinical and social information. PMID- 26642310 TI - The role of interventional radiology in abdominopelvic trauma. AB - The management of trauma patients has evolved in recent decades owing to increasing availability of advanced imaging modalities such as CT. Nowadays, CT has replaced the diagnostic function of angiography. The latter is considered when a therapeutic option is hypothesized. Arterial embolization is a life-saving procedure in abdominopelvic haemorrhagic patients, reducing relevant mortality rates and ensuring haemodynamic stabilization of the patient. Percutaneous transarterial embolization has been shown to be effective for controlling ongoing bleeding for patients with high-grade abdominopelvic injuries, thereby reducing the failure rate of non-operative management, preserving maximal organ function. Surgery is not always the optimal solution for stabilization of a patient with polytrauma. Mini-invasivity and repeatability may be considered as relevant advantages. We review technical considerations, efficacy and complication rates of hepatic, splenic, renal and pelvic embolization to extrapolate current evidence about transarterial embolization in traumatic patients. PMID- 26642312 TI - Identification and Structural Analysis of Amino Acid Substitutions that Increase the Stability and Activity of Aspergillus niger Glucose Oxidase. AB - Glucose oxidase is one of the most conspicuous commercial enzymes due to its many different applications in diverse industries such as food, chemical, energy and textile. Among these applications, the most remarkable is the manufacture of glucose biosensors and in particular sensor strips used to measure glucose levels in serum. The generation of ameliorated versions of glucose oxidase is therefore a significant biotechnological objective. We have used a strategy that combined random and rational approaches to isolate uncharacterized mutations of Aspergillus niger glucose oxidase with improved properties. As a result, we have identified two changes that increase significantly the enzyme's thermal stability. One (T554M) generates a sulfur-pi interaction and the other (Q90R/Y509E) introduces a new salt bridge near the interphase of the dimeric protein structure. An additional double substitution (Q124R/L569E) has no significant effect on stability but causes a twofold increase of the enzyme's specific activity. Our results disclose structural motifs of the protein which are critical for its stability. The combination of mutations in the Q90R/Y509E/T554M triple mutant yielded a version of A. niger glucose oxidase with higher stability than those previously described. PMID- 26642314 TI - Bladder Cancer in HIV-infected Adults: An Emerging Issue? Case-Reports and Systematic Review. AB - OBJECTIVES: Non-AIDS-related malignancies now represent a frequent cause of death among HIV-infected patients. Albeit bladder cancer is one of the most common malignancies worldwide, it has been rarely reported among HIV-infected patients. We wished to assess the prevalence and characteristics of bladder cancer in HIV infected patients. METHODS: We conducted a single center retrospective study from 1998 to 2013 in a university hospital in Paris. Cases of bladder cancer among HIV infected patients were identified using the electronic records of the hospital database and of the HIV-infected cohort. Patient characteristics and outcomes were retrieved from patients charts. A systematic review of published cases of bladder cancers in patients with HIV-infection was also performed. RESULTS: During the study period we identified 15 HIV-infected patients (0.2% of the cohort) with a bladder cancer. Patients were mostly men (73%) and smokers (67%), with a median age of 56 years at cancer diagnosis. Bladder cancer was diagnosed a median of 14 years after HIV-infection. Most patients were on ART (86%) with median current and nadir CD4 cell counts of 506 and 195 cells/mm3, respectively. Haematuria (73%) was the most frequent presenting symptom and HPV-associated lesions were seen in 6/10 (60%) patients. Histopathology showed transitional cell carcinoma in 80% and a high proportion of tumors with muscle invasion (47%) and high histologic grade (73%). One-year survival rate was 74.6%. The systematic review identified 13 additional cases of urothelial bladder cancers which shared similar features. CONCLUSIONS: Bladder cancers in HIV-infected patients remain rare but may occur in relatively young patients with a low nadir CD4 cell count, have aggressive pathological features and can be fatal. PMID- 26642313 TI - Studies on the Coordination of Ribosomal Protein Assembly Events Involved in Processing and Stabilization of Yeast Early Large Ribosomal Subunit Precursors. AB - Cellular production of ribosomes involves the formation of highly defined interactions between ribosomal proteins (r-proteins) and ribosomal RNAs (rRNAs). Moreover in eukaryotic cells, efficient ribosome maturation requires the transient association of a large number of ribosome biogenesis factors (RBFs) with newly forming ribosomal subunits. Here, we investigated how r-protein assembly events in the large ribosomal subunit (LSU) rRNA domain II are coordinated with each other and with the association of RBFs in early LSU precursors of the yeast Saccharomyces cerevisiae. Specific effects on the pre ribosomal association of RBFs could be observed in yeast mutants blocked in LSU rRNA domain II assembly. Moreover, formation of a cluster of r-proteins was identified as a downstream event in LSU rRNA domain II assembly. We analyzed in more detail the functional relevance of eukaryote specific bridges established by this r-protein cluster between LSU rRNA domain II and VI and discuss how they can support the stabilization and efficient processing of yeast early LSU precursor RNAs. PMID- 26642315 TI - Wearable ECG Based on Impulse-Radio-Type Human Body Communication. AB - Human body communication (HBC) provides a promising physical layer for wireless body area networks (BANs) in healthcare and medical applications, because of its low propagation loss and high security characteristics. In this study, we have developed a wearable electrocardiogram (ECG) which employs impulse radio (IR) type HBC technology for transmitting vital signals on the human body in a wearable BAN scenario. The HBC-based wearable ECG has two excellent features. First, the wideband performance of the IR scheme contributed to very low radiation power so that the transceiver is easy to satisfy the extremely weak radio laws, which does not need a license. This feature can provide big convenience in the use and spread of the wearable ECG. Second, the realization of common use of sensing and transmitting electrodes based on time sharing and capacitive coupling largely simplified the HBC-based ECG structure and contributed to its miniaturization. To verify the validity of the HBC-based ECG, we evaluated its communication performance and ECG acquisition performance. The measured bit error rate, smaller than 10 -3 at 1.25 Mb/s, showed a good physical layer communication performance, and the acquired ECG waveform and various heart rate variability parameters in time and frequency domains exhibited good agreement with a commercially available radio-frequency ECG and a Holter ECG. These results sufficiently showed the validity and feasibility of the HBC-based ECG for healthcare applications. This should be the first time to have realized a real-time ECG transmission by using the HBC technology. PMID- 26642316 TI - Oxidized Docosahexaenoic Acid Species and Lipid Peroxidation Products Increase Amyloidogenic Amyloid Precursor Protein Processing. AB - One of the main characteristics of Alzheimer's disease (AD) is the beta-amyloid peptide (Abeta) generated by beta- and gamma-secretase processing of the amyloid precursor protein (APP). Previously it has been demonstrated that polyunsaturated fatty acids (PUFAs), especially docosahexaenoic acid (DHA), are associated with a reduced risk of AD caused by decreased Abeta production. However, in epidemiological studies and nutritional approaches, the outcomes of DHA-dependent treatment were partially controversial. PUFAs are very susceptible to reactive oxygen species and lipid peroxidation, which are increased during disease pathology. In line with published results, lipid peroxidation was elevated in human postmortem AD brains; especially 4-hydroxy-nonenal (HNE) was increased. To investigate whether lipid peroxidation is only a consequence or might also influence the processes leading to AD, we analyzed 7 different oxidized lipid species including 5 oxidized DHA derivatives and the lipid peroxidation products of omega-3 and omega-6 PUFAs, HNE and 4-hydroxy-hexenal, in human neuroblastoma cells and mouse mixed cortical neurons. In the presence of oxidized lipids Abeta and soluble beta-secreted APP levels were elevated, whereas soluble alpha secreted APP was decreased, suggesting a shift from the nonamyloidogenic to the amyloidogenic pathway of APP processing. Furthermore, beta- and gamma-secretase activity was increased by oxidized lipids via increased gene expression and additionally by a direct effect on beta-secretase activity. Importantly, only 1% oxidized DHA was sufficient to revert the protective effect of DHA and to significantly increase Abeta production. Therefore, our results emphasize the need to prevent DHA from oxidation in nutritional approaches and might help explain the divergent results of clinical DHA studies. PMID- 26642317 TI - Correction: Collagen Sequence Analysis of the Extinct Giant Ground Sloths Lestodon and Megatherium. PMID- 26642318 TI - Impacts of Interannual Ocean Circulation Variability on Japanese Eel Larval Migration in the Western North Pacific Ocean. AB - The Japanese eel larvae hatch near the West Mariana Ridge seamount chain and travel through the North Equatorial Current (NEC), the Kuroshio, and the Subtropical Countercurrent (STCC) region during their shoreward migration toward East Asia. The interannual variability of circulation over the subtropical and tropical regions of the western North Pacific Ocean is affected by the Philippines-Taiwan Oscillation (PTO). This study examines the effect of the PTO on the Japanese eel larval migration routes using a three-dimensional (3D) particle tracking method, including vertical and horizontal swimming behavior. The 3D circulation and hydrography used for particle tracking are from the ocean circulation reanalysis produced by the Japan Coastal Ocean Predictability Experiment 2 (JCOPE2). Our results demonstrate that bifurcation of the NEC and the strength and spatial variation of the Kuroshio affect the distribution and migration of eel larvae. During the positive phase of PTO, more virtual eels ("v eels") can enter the Kuroshio to reach the south coast of Japan and more v-eels reach the South China Sea through the Luzon Strait; the stronger and more offshore swing of the Kuroshio in the East China Sea leads to fewer eels entering the East China Sea and the onshore movement of the Kuroshio to the south of Japan brings the eels closer to the Japanese coast. Significant differences in eel migration routes and distributions regulated by ocean circulation in different PTO phases can also affect the otolith increment. The estimated otolith increment suggests that eel age tends to be underestimated after six months of simulation due to the cooler lower layer temperature. Underestimation is more significant in the positive PTO years due to the wide distribution in higher latitudes than in the negative PTO years. PMID- 26642320 TI - Activity Profiles and Physiological Responses of Representative Tag Football Players in Relation to Playing Position and Physical Fitness. AB - This study determined the physical fitness, match-activity profiles and physiological responses of representative tag football players and examined the relationship between physical fitness and the match-activity profile. Microtechnology devices and heart rate (HR) chest straps were used to determine the match-activity profiles of sixteen tag football players for five matches during the 2014 Australian National Championships. The relationships between lower body muscular power, straight line running speed and Yo-Yo intermittent recovery test level 2 (Yo-Yo IR2) and the match-activity profile were examined using Pearson's correlation coefficients. Outside players had greater lower body muscular power (ES = 0.98) and straight line running speed (ES = 1.03-1.18) than inside players, and also covered greater very high-speed running (VHSR) distance/min (ES = 0.67) and reached higher peak running speeds (ES = 0.95) during matches. Inside and outside players performed a similar number of repeated high-intensity effort (RHIE) bouts and reported similar mean and maximum efforts per RHIE bout. However, there were differences between playing positions for mean and maximal RHIE effort durations (ES = 0.69-1.15) and mean RHIE bout recovery (ES = 0.56). Inside and outside players also reported small to moderate differences (ES = 0.43-0.80) for times spent in each HR zone. There were a number of moderate to very large correlations between physical fitness measures and match-activity profile variables. This study found lower body muscular power, straight line running speed and Yo-Yo IR2 to be related to the match-activities of representative tag football players, although differences between inside and outside players suggest that athlete testing and training practices should be modified for different playing positions. PMID- 26642319 TI - Overexpression of Catalase Diminishes Oxidative Cysteine Modifications of Cardiac Proteins. AB - Reactive protein cysteine thiolates are instrumental in redox regulation. Oxidants, such as hydrogen peroxide (H2O2), react with thiolates to form oxidative post-translational modifications, enabling physiological redox signaling. Cardiac disease and aging are associated with oxidative stress which can impair redox signaling by altering essential cysteine thiolates. We previously found that cardiac-specific overexpression of catalase (Cat), an enzyme that detoxifies excess H2O2, protected from oxidative stress and delayed cardiac aging in mice. Using redox proteomics and systems biology, we sought to identify the cysteines that could play a key role in cardiac disease and aging. With a 'Tandem Mass Tag' (TMT) labeling strategy and mass spectrometry, we investigated differential reversible cysteine oxidation in the cardiac proteome of wild type and Cat transgenic (Tg) mice. Reversible cysteine oxidation was measured as thiol occupancy, the ratio of total available versus reversibly oxidized cysteine thiols. Catalase overexpression globally decreased thiol occupancy by >=1.3 fold in 82 proteins, including numerous mitochondrial and contractile proteins. Systems biology analysis assigned the majority of proteins with differentially modified thiols in Cat Tg mice to pathways of aging and cardiac disease, including cellular stress response, proteostasis, and apoptosis. In addition, Cat Tg mice exhibited diminished protein glutathione adducts and decreased H2O2 production from mitochondrial complex I and II, suggesting improved function of cardiac mitochondria. In conclusion, our data suggest that catalase may alleviate cardiac disease and aging by moderating global protein cysteine thiol oxidation. PMID- 26642321 TI - Intervention trial of previous nonattender invitation for breast screening. AB - BreastCheck, the National Breast Screening Programme in the Republic of Ireland, invites women aged between 50 and 64 years biennially. A pilot intervention trial of invitation for screening of women not attending the previous appointment [previous nonattender (PNA)] was carried out that aimed at maximizing the efficiency of resources in terms of radiographer workload and scheduled appointment slots. The trial was conducted during screening round 5 at two of the regional units. The intervention arm implemented an alternative process for inviting PNA women, in which they were sent a letter inviting them to phone their screening unit to make an appointment at a convenient date/time. The control arm continued usual practice - that is, all PNA women were sent a single invitation letter with a scheduled appointment slot at a predetermined date/time. In the intervention arm, fewer PNAs took up their appointments (15.5%) compared with the control arm (18.3%; P<0.001). Uptake among PNAs fell in both arms between screening rounds 4 and 5 (intervention arm: 22.0% OSR 4, 15.5% OSR 5; control arm: 21.4% OSR 4, 18.3% OSR 5). There was a significant increase in mobile unit screening days saved because of the intervention and a significant improvement in the percentage of women reinvited for screening within 27 months in the intervention arm (85.5%). PNA recall and cancer detection rates were significantly higher compared with the general screened population. This trial showed an improvement in the efficiency of resource use. However, there was a higher cancer detection rate in PNA women. This trial provides important evidence for invitation policy for screening. PMID- 26642322 TI - Scenario-Based Multi-Objective Optimum Allocation Model for Earthquake Emergency Shelters Using a Modified Particle Swarm Optimization Algorithm: A Case Study in Chaoyang District, Beijing, China. AB - The correct location of earthquake emergency shelters and their allocation to residents can effectively reduce the number of casualties by providing safe havens and efficient evacuation routes during the chaotic period of the unfolding disaster. However, diverse and strict constraints and the discrete feasible domain of the required models make the problem of shelter location and allocation more difficult. A number of models have been developed to solve this problem, but there are still large differences between the models and the actual situation because the characteristics of the evacuees and the construction costs of the shelters have been excessively simplified. We report here the development of a multi-objective model for the allocation of residents to earthquake shelters by considering these factors using the Chaoyang district, Beijing, China as a case study. The two objectives of this model were to minimize the total weighted evacuation time from residential areas to a specified shelter and to minimize the total area of all the shelters. The two constraints were the shelter capacity and the service radius. Three scenarios were considered to estimate the number of people who would need to be evacuated. The particle swarm optimization algorithm was first modified by applying the von Neumann structure in former loops and global structure in later loops, and then used to solve this problem. The results show that increasing the shelter area can result in a large decrease in the total weighted evacuation time from scheme 1 to scheme 9 in scenario A, from scheme 1 to scheme 9 in scenario B, from scheme 1 to scheme 19 in scenario C. If the funding were not a limitation, then the final schemes of each scenario are the best solutions, otherwise the earlier schemes are more reasonable. The modified model proved to be useful for the optimization of shelter allocation, and the result can be used as a scientific reference for planning shelters in the Chaoyang district, Beijing. PMID- 26642323 TI - "I Feel Contaminated in My Fake Hand": Obsessive-Compulsive-Disorder like Disgust Sensations Arise from Dummy during Rubber Hand Illusion. AB - Despite its theoretical and clinical interest, there are no experimental studies exploring obsessive-compulsive disorder (OCD)-like disgust sensations through using somatosensory illusions. Such illusions provide important clues to the nature and limits of multisensory integration and how the brain constructs body image; and may potentially inform novel therapies. One such effect is the rubber hand illusion (RHI) in which tactile sensations are referred to a rubber hand; if the experimenter simultaneously strokes a subject's occluded hand together with a visible fake hand, the subject starts experiencing the touch sensations as arising from the dummy. In this study, we explore whether OCD-like disgust may result from contamination of a dummy hand during the RHI; suggesting a possible integration of somatosensory and limbic inputs in the construction of body image. We predicted that participants would experience sensations of disgust, when placing a disgust stimulus (fake feces, vomit or blood) on the dummy hand after establishing the RHI. We found that 9 out of 11 participants experienced greater disgust during the synchronous condition (real hidden hand and fake hand are stroked in synchrony) compared to the asynchronous control condition (real hidden hand and fake hand are stroked in asynchrony); and on average such disgust was significantly greater during the synchronous condition compared to the asynchronous control condition, Z = 2.7, p = .008. These results argue against a strictly hierarchical modular approach to brain function and suggest that a four way multisensory interaction occurs between vision, touch, proprioception on the one hand and primal emotions like disgust on the other. These findings may inform novel clinical approaches for OCD; that is, contaminating a dummy during the RHI could possibly be used as part of an in-vivo exposure-intervention for OCD. PMID- 26642324 TI - Size Dependent Male Reproductive Tactic in the Two-Spotted Goby (Gobiusculus flavescens). AB - Male investment in testes and sperm duct gland in the polygamous nest breeding two-spotted goby Gobiusculus flavescens (Fabricius) was investigated in relation to time in reproductive season and individual physical parameters. This small teleost fish is most likely the most abundant species found along the rocky shores of the North East Atlantic. The two-spotted goby has a single reproductive season, during which nest-caring males can raise several clutches of offspring. According to the literature the males are on average larger than the females. Here we report for the first time a population showing a reversal of this trend, with males on average being smaller than females, a difference likely caused by a large proportion of small males. Early in the breeding season these small males have typical sneaker characters, with relatively large testes and small seminal duct glands compared to the larger dominant territorial males. The presence of these two alternative male reproductive tactics is confirmed by histological studies, which shows the presence of sperm in the sperm duct glands (SDG) of smaller males, but not in the SDG of intermediate and larger males. To our knowledge, males with typical sneaker characters have not been reported in earlier studied populations of two-spotted goby. Interestingly we found that testes investment declined significantly over the course of the breeding season, and that this reduction was significantly more pronounced in small compared to the large males. Further, a significant increase in seminal duct gland (SDG) mass was observed for the smaller males over the breeding season. We propose that this indicates a possible shift in mating tactic by smaller males from a parasitic to a nest-holding tactic over the course of the breeding season. Thus, the observed size dependent plasticity in investment in SDG over time suggests that the reproductive tactic of G. flavescens is conditional, and possibly influenced by mate availability and male--male competition. PMID- 26642325 TI - Use of FabV-Triclosan Plasmid Selection System for Efficient Expression and Production of Recombinant Proteins in Escherichia coli. AB - Maintenance of recombinant plasmid vectors in host bacteria relies on the presence of selection antibiotics in the growth media to suppress plasmid -free segregants. However, presence of antibiotic resistance genes and antibiotics themselves is not acceptable in several applications of biotechnology. Previously, we have shown that FabV-Triclosan selection system can be used to select high and medium copy number plasmid vectors in E. coli. Here, we have extended our previous work and demonstrated that expression vectors containing FabV can be used efficiently to express heterologous recombinant proteins in similar or better amounts in E. coli host when compared with expression vectors containing beta-lactamase. Use of small amount of non-antibiotic Triclosan as selection agent in growth medium, enhanced plasmid stability, applicability in various culture media, and compatibility with other selection systems for multiple plasmid maintenance are noteworthy features of FabV-Triclosan selection system. PMID- 26642326 TI - Addition of Berberine to 5-Aminosalicylic Acid for Treatment of Dextran Sulfate Sodium-Induced Chronic Colitis in C57BL/6 Mice. AB - Ulcerative colitis (UC) is a common chronic remitting disease but without satisfactory treatment. Alternative medicine berberine has received massive attention for its potential in UC treatment. Conventional therapies with the addition of berberine are becoming attractive as novel therapies in UC. In the present study, we investigated the preclinical activity of a conventional oral 5 aminosalicylic acid (5-ASA) therapy plus berberine in experimental colitis. A subclinical dose of 5-ASA (200 mg/kg/day) alone or 5-ASA plus berberine (20 mg/kg/day) was orally administered for 30 days to C57BL/6 mice with colitis induced by three cycles of 2% dextran sulfate sodium (DSS). The disease severity, inflammatory responses, drug accumulation and potential toxicity of colitis mice were examined. The results showed that comparing to 5-ASA alone, 5-ASA plus berberine more potently ameliorated DSS-induced disease severity, colon shortening, and colon histological injury. Further, the up-regulation in mRNA level of colonic TNF-alpha as well as NFkappaB and JAK2 phosphorylation caused by DSS were more pronouncedly reversed in animals treated with the combination therapy than those treated with 5-ASA alone. Moreover, the addition of berberine to 5-ASA more significantly inhibited lymphocyte TNF-alpha secretion of DSS mice than 5-ASA alone. In the meanwhile, no extra drug accumulation or potential toxicity to major organs of colitis mice was observed with this combination treatment. In summary, our studies provide preclinical rationale for the addition of berberine to 5-ASA as a promising therapeutic strategy in clinic by reducing dose of standard therapy. PMID- 26642328 TI - Stress "Deafness" Reveals Absence of Lexical Marking of Stress or Tone in the Adult Grammar. AB - A Sequence Recall Task with disyllabic stimuli contrasting either for the location of prosodic prominence or for the medial consonant was administered to 150 subjects equally divided over five language groups. Scores showed a significant interaction between type of contrast and language group, such that groups did not differ on their performance on the consonant contrast, while two language groups, Dutch and Japanese, significantly outperformed the three other language groups (French, Indonesian and Persian) on the prosodic contrast. Since only Dutch and Japanese words have unpredictable stress or accent locations, the results are interpreted to mean that stress "deafness" is a property of speakers of languages without lexical stress or tone markings, as opposed to the presence of stress or accent contrasts in phrasal (post-lexical) constructions. Moreover, the degree of transparency between the locations of stress/tone and word boundaries did not appear to affect our results, despite earlier claims that this should have an effect. This finding is of significance for speech processing, language acquisition and phonological theory. PMID- 26642327 TI - Correlated Evolution of Nucleotide Positions within Splice Sites in Mammals. AB - Splice sites (SSs)--short nucleotide sequences flanking introns--are under selection for spliceosome binding, and adhere to consensus sequences. However, non-consensus nucleotides, many of which probably reduce SS performance, are frequent. Little is known about the mechanisms maintaining such apparently suboptimal SSs. Here, we study the correlations between strengths of nucleotides occupying different positions of the same SS. Such correlations may arise due to epistatic interactions between positions (i.e., a situation when the fitness effect of a nucleotide in one position depends on the nucleotide in another position), their evolutionary history, or to other reasons. Within both the intronic and the exonic parts of donor SSs, nucleotides that increase (decrease) SS strength tend to co-occur with other nucleotides increasing (respectively, decreasing) it, consistent with positive epistasis. Between the intronic and exonic parts of donor SSs, the correlations of nucleotide strengths tend to be negative, consistent with negative epistasis. In the course of evolution, substitutions at a donor SS tend to decrease the strength of its exonic part, and either increase or do not change the strength of its intronic part. In acceptor SSs, the situation is more complicated; the correlations between adjacent positions appear to be driven mainly by avoidance of the AG dinucleotide which may cause aberrant splicing. In summary, both the content and the evolution of SSs is shaped by a complex network of interdependences between adjacent nucleotides that respond to a range of sometimes conflicting selective constraints. PMID- 26642329 TI - Internet-Based Brief Intervention to Prevent Unhealthy Alcohol Use among Young Men: A Randomized Controlled Trial. AB - INTRODUCTION: Alcohol use is one of the leading modifiable morbidity and mortality risk factors among young adults. STUDY DESIGN: 2 parallel-group randomized controlled trial with follow-up at 1 and 6 months. SETTING/PARTICIPANTS: Internet based study in a general population sample of young men with low-risk drinking, recruited between June 2012 and February 2013. Intervention: Internet-based brief alcohol primary prevention intervention (IBI). The IBI aims at preventing an increase in alcohol use: it consists of normative feedback, feedback on consequences, calorific value alcohol, computed blood alcohol concentration, indication that the reported alcohol use is associated with no or limited risks for health. Intervention group participants received the IBI. Control group (CG) participants completed only an assessment. MAIN OUTCOME MEASURES: Alcohol use (number of drinks per week), binge drinking prevalence. Analyses were conducted in 2014-2015. RESULTS: Of 4365 men invited to participate, 1633 did so; 896 reported low-risk drinking and were randomized (IBI: n = 451; CG: n = 445). At baseline, 1 and 6 months, the mean (SD) number of drinks/week was 2.4(2.2), 2.3(2.6), 2.5(3.0) for IBI, and 2.4(2.3), 2.8(3.7), 2.7(3.9) for CG. Binge drinking, absent at baseline, was reported by 14.4% (IBI) and 19.0% (CG) at 1 month and by 13.3% (IBI) and 13.0% (CG) at 6 months. At 1 month, beneficial intervention effects were observed on the number of drinks/week (p = 0.05). No significant differences were observed at 6 months. CONCLUSION: We found protective short term effects of a primary prevention IBI. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN55991918. PMID- 26642330 TI - Molecular Characterization and Functional Analysis of Annulate Lamellae Pore Complexes in Nuclear Transport in Mammalian Cells. AB - Annulate lamellae are cytoplasmic organelles containing stacked sheets of membranes embedded with pore complexes. These cytoplasmic pore complexes at annulate lamellae are morphologically similar to nuclear pore complexes at the nuclear envelope. Although annulate lamellae has been observed in nearly all types of cells, their biological functions are still largely unknown. Here we show that SUMO1-modification of the Ran GTPase-activating protein RanGAP1 not only target RanGAP1 to its known sites at nuclear pore complexes but also to annulate lamellae pore complexes through interactions with the Ran-binding protein RanBP2 and the SUMO-conjugating enzyme Ubc9 in mammalian cells. Furthermore, upregulation of annulate lamellae, which decreases the number of nuclear pore complexes and concurrently increases that of annulate lamellae pore complexes, causes a redistribution of nuclear transport receptors including importin alpha/beta and the exportin CRM1 from nuclear pore complexes to annulate lamellae pore complexes and also reduces the rates of nuclear import and export. Moreover, our results reveal that importin alpha/beta-mediated import complexes initially accumulate at annulate lamellae pore complexes upon the activation of nuclear import and subsequently disassociate for nuclear import through nuclear pore complexes in cells with upregulation of annulate lamellae. Lastly, CRM1 mediated export complexes are concentrated at both nuclear pore complexes and annulate lamellae pore complexes when the disassembly of these export complexes is inhibited by transient expression of a Ran GTPase mutant arrested in its GTP bound form, suggesting that RanGAP1/RanBP2-activated RanGTP hydrolysis at these pore complexes is required for the dissociation of the export complexes. Hence, our findings provide a foundation for further investigation of how upregulation of annulate lamellae decreases the rates of nuclear transport and also for elucidation of the biological significance of the interaction between annulate lamellae pore complexes and nuclear transport complexes in mammalian cells. PMID- 26642331 TI - Longitudinal qPCR monitoring of nucleophosmin 1 mutations after allogeneic hematopoietic stem cell transplantation to predict AML relapse. PMID- 26642332 TI - Does ex vivo CD34+ positive selection influence outcome after autologous hematopoietic stem cell transplantation in systemic sclerosis patients? AB - This EBMT Autoimmune Disease Working Party study aimed to evaluate the influence of CD34+ positive graft selection (CD34+) on the outcome of systemic sclerosis (SSc) patients after autologous hematopoietic stem cell transplantation (AHSCT). Clinical and laboratory data from 138 SSc patients at diagnosis, before and after AHSCT were retrospectively analyzed. CD34+ selection was performed in 47.1% (n=65) patients. By multivariate analysis adjusting for all factors differing between the two groups (without or with CD34+), there was no statistically significant difference in terms of overall survival (hazard ratio (HR): 0.98, 95% confidence interval (CI) 0.40-2.39, P=0.96), PFS (HR: 1.55, 95% CI 0.83-2.88, P=0.17) and incidence of relapse or progression (HR: 1.70, 95% CI 0.85-3.38, P=0.13). We demonstrate that CD34+ does not add benefit to the outcome of SSc patient treated with AHSCT. These findings should be further confirmed by prospective randomized trials. PMID- 26642335 TI - When is second allogeneic HSCT for relapse of acute leukaemia an option? PMID- 26642336 TI - HLA-identical siblings versus haploidentical donors: full match still beats half match. PMID- 26642334 TI - Prognostic impact of progression to induction chemotherapy and prior paclitaxel therapy in patients with germ cell tumors receiving salvage high-dose chemotherapy in the last 10 years: a study of the European Society for Blood and Marrow Transplantation Solid Tumors Working Party. AB - Little is known about the prognostic impact of prior paclitaxel therapy and response to induction chemotherapy defined as the regimen preceding high-dose chemotherapy (HDCT) for the salvage therapy of advanced germ cell tumors. Twenty European Society for Blood and Marrow Transplantation centers contributed data on patients treated between 2002 and 2012. Paclitaxel used in either prior lines of therapy or in induction-mobilization regimens was considered. Multivariable Cox analyses of prespecified factors were undertaken on PFS and overall survival (OS). As of October 2013, data for 324 patients had been contributed to this study. One hundred and ninety-two patients (59.3%) had received paclitaxel. Sixty one patients (19%) had a progression to induction chemotherapy, 234 (72%) a response (29 (9%) missing or granulocyte colony-stimulating factor without chemotherapy). Both progression to induction chemotherapy and prior paclitaxel were significantly associated with shorter OS univariably (P<0.001 and P=0.032). On multivariable analysis from the model with fully available data (N=216) progression to induction was significantly prognostic for PFS and OS (P=0.003), but prior paclitaxel was not (P=0.674 and P=0.739). These results were confirmed after multiple imputation of missing data. Progression to induction chemotherapy could be demonstrated as an independent prognostic factor, in contrast to prior paclitaxel. PMID- 26642338 TI - Monitoring the kinetics of B-cell recovery following rituximab may guide the management of steroid-refractory chronic GvHD. PMID- 26642337 TI - Improvement of overall survival after allogeneic hematopoietic stem cell transplantation for children and adolescents: a three-decade experience of a single institution. AB - Allogeneic stem cell transplantation (allo-SCT) has become an essential component of the treatment for a variety of diseases in pediatric patients. During the past decades, advances in the transplant technology, availability of hematopoietic stem cells and supportive care not only have resulted in improved outcomes, but also have expanded the transplant options. However, these features have been studied mainly in adult populations. This investigation analyzed changes in patient profile, transplantation, graft characteristics and outcome among 250 children and adolescent patients who received allo-SCT in a single center between 1983 and 2010. In the 2000-2010, compared with the 1983-1999 period, a significantly higher 5-year overall survival (64% versus 52%, P=0.03) was observed together with a significant decrease of non-relapse mortality (27% versus 9%, P=0.0002). The progression-free survival was comparable between the two periods (49% versus 57%; P=0.17). The 5-year cumulative incidence of relapse was 24% between 1983 and 1999, and 34% between 2000 and 2010 (P=0.08). Major advances in supportive care practice have been made over the past decade, resulting in a significant survival benefit for the pediatric population undergoing allo-SCT. However, post-transplant relapse remains the leading cause of failure of this therapeutic approach, and preventing relapse represents a major challenge today. PMID- 26642333 TI - Plasmacytoid dendritic cells in allogeneic hematopoietic cell transplantation: benefit or burden? AB - Plasmacytoid dendritic cells (pDCs) bridge innate and adaptive immune responses and have important roles in hematopoietic engraftment, GvHD and graft-versus leukemia responses following allogeneic hematopoietic cell transplantation (HCT). In addition, pDCs mediate antiviral immunity, particularly as they are the body's primary cellular source of type I interferon. Given their pleiotropic roles, pDCs have emerged as cells that critically impact transplant outcomes, including overall survival. In this article, we will review the pre-clinical and clinical literature, supporting the crucial roles that pDCs assume as key immune effector cells during HCT. PMID- 26642339 TI - Preemptive antiviral therapy for CMV infection in allogeneic stem cell transplant recipients guided by the viral doubling time in the blood. PMID- 26642341 TI - Post-transplantation-emerging anti-HLA DQA1/DQB1 antibody possibly responsible for graft rejection after myeloablative-unrelated marrow grafting. PMID- 26642340 TI - Childhood to adult transition and long-term follow-up after blood and marrow transplantation. AB - The use of hematopoietic stem cell transplantation or blood and marrow transplantation (BMT) is on the increase worldwide. With BMT's increasing utilization and increasing success, the number of BMT survivors in the United States alone is expected to surpass 500 000 by the year 2030. BMT survivors are susceptible to a host of long-term side effects and complications. The pediatric and adolescent and young adult (AYA) populations comprise an increasing proportion of BMT survivors. Though these populations are both at risk of a specific set of sequelae and faced with the additional challenge of transitioning to adult care, no previous literature has addressed their specific challenges. In this review, we illustrate with clinical vignettes the need for focused and specific survivorship clinics for pediatric/AYA BMT survivors. We then focus on the following areas pertaining to pediatric BMT survivorship and care: (1) psychological health, (2) neurocognition, (3) endocrine health, (4) infertility resources, (5) issues in transition from pediatric to adult clinicians, (6) preventative services and (7) cost of care issues. PMID- 26642342 TI - Immunoablation and autologous hematopoietic stem cell transplantation in the treatment of new-onset type 1 diabetes mellitus: long-term observations. AB - The activity of the autoimmune mechanism underlying type 1 diabetes mellitus (T1DM) can be suppressed when immunoablation and autologous hematopoietic stem cell transplantation (AHSCT) are applied early in the course of the disease. We report here a single centre experience with this treatment modality. Twenty-four patients underwent a AHSCT preceded by immunoablative conditioning with high-dose cyclophosphamide and anti-thymocyte globulin. During the 52-month median time of follow-up 20 out of 23 patients (87%) remained for at least 9.5 months without the use of exogenous insulin. The median time of T1DM remission for these patients was 31 months (range of 9.5-80 months). Among the patients available for follow-up (n=20), four remain insulin free (for 80, 61, 42 and 34 months). The average glycated hemoglobin (HbA1c) concentrations were 10.9% at diagnosis, 5.9% at 1 year, 6.4% at 2 years, 6.8% at 3 years and 7.1% at 4 years after AHSCT. No severe complications of diabetes were seen, however one of the patients died of pseudomonas sepsis in the course of neutropenia after AHSCT. AHSCT leads to a remission of T1DM with good glycemic control in the vast majority of patients, with the period of remission lasting over 5 years in some patients. PMID- 26642343 TI - Impact of low-dose TBI on outcomes of reduced intensity conditioning allogeneic hematopoietic stem cell transplantation for AML. PMID- 26642344 TI - Correlative microscopy of a carbide-free bainitic steel. AB - In this work a carbide-free bainitic steel was examined by a novel correlative microscopy approach using transmission Kikuchi diffraction (TKD) and transmission electron microscopy (TEM). The individual microstructural constituents could be identified by TKD based on their different crystal structure for bainitic ferrite and retained austenite and by image quality for the martensite-austenite (M-A) constituent. Subsequently, the same area was investigated in the TEM and a good match of these two techniques regarding the identification of the area position and crystal orientation could be proven. Additionally, the M-A constituent was examined in the TEM for the first time after preceded unambiguous identification using a correlative microscopy approach. The selected area diffraction pattern showed satellites around the main reflexes which might indicate a structural modulation. PMID- 26642345 TI - Biotrophic interaction of Sporisorium scitamineum on a new host--Saccharum spontaneum. AB - Sporisorium scitamineum is a biotrophic smut fungus harbored inside the smut gall on the top internodal region of Saccharum spontaneum, a wild relative of sugarcane (Saccharum officinarum). The interactions of spined conidia of S. scitamineum with S. spontaneum were examined during the different stages of plant growth starting from the bud stage to the decaying stage. The spores in the soil from the polyetic inocula grew into confined epidermal cells of the buds and finally sporulated in the topmost internodal region. Hyphae invasion of the plant tissues were restricted to the point of infection. Culms of infected plants in late October sporulated, notably; hyphal sporulation produced shorter hyphal stolons. Remarkably, the nodal regions of infected plants had no spores and fragmented hyphae. On the basis of microscopic analyses, hyphae and spores were absent in all internodes above the ground till the topmost smut gall region. This result indicated that, S. scitamineum undergoes tissue-confined invasion of S. spontaneum. By associating culture medium method with polymerase chain reaction (PCR) on plant portions void of smut gall, S. scitamineum was not detected, indicating that colonization was not systemic. It was observed that the biotrophic interaction resulted in structural reorganization in the restricted region of infection forming erect cylindrical structure, in which the fungus was sandwiched between the central stalk and sheath, and possibly played a key role in preventing inflorescence. Comparatively, a significant difference in the rate of teliospores germination between reference Ustilago esculenta (26.6%, P<0.05) and S. scitamineum (62.9%, P<0.05) at 20 degrees C was observed. This study also provides insights on the effect of different temperature regimes on the germination of S. scitamineum teliospores in vitro. PMID- 26642346 TI - Regulatory T Cells in Hepatic Immune Tolerance and Autoimmune Liver Diseases. AB - Regulatory T cells (Tregs) have a profound ability to control immune responses. A majority of Tregs are derived from the thymus; yet a substantial Treg fraction is derived from the periphery. The liver seems to be an important source of peripherally derived Tregs. Indeed, the liver's well-known ability to induce immune tolerance is at least partly based on hepatic Treg generation. With recently developed tools to deliver antigens to tolerance-inducing liver cells, it is now possible to harness liver-derived Tregs for specific control of unwanted immune responses. Indeed, the selective delivery of autoantigens to liver sinusoidal endothelial cells could induce autoantigen-specific Tregs in vivo, providing effective treatment of autoimmune disease. Owing to the fundamental role Tregs play in controlling immune responses, an impairment of Tregs seems to be a plausible explanation for the development of autoimmune diseases, for example, in the liver. However, the actual role of Treg impairment in autoimmune liver diseases, such as autoimmune hepatitis (AIH), remains controversial. Major obstacles for clarifying the role of Tregs in autoimmune liver diseases are related to the difficulty to identify human Tregs unambiguously and to the difficulty to identify those Tregs and effector T cells that specifically recognize disease-driving autoantigens. However, even if AIH turned out to be a disease that is not driven by Treg impairment, Treg-based therapies for autoimmune liver diseases might still be effective, provided the Tregs for therapeutic use recognize the relevant antigens. PMID- 26642347 TI - Validity of Estimation of Pelvic Floor Muscle Activity from Transperineal Ultrasound Imaging in Men. AB - PURPOSE: To investigate the relationship between displacement of pelvic floor landmarks observed with transperineal ultrasound imaging and electromyography of the muscles hypothesised to cause the displacements. MATERIALS AND METHODS: Three healthy men participated in this study, which included ultrasound imaging of the mid-urethra, urethra-vesical junction, ano-rectal junction and bulb of the penis. Fine-wire electromyography electrodes were inserted into the puborectalis and bulbocavernosus muscles and a transurethral catheter electrode recorded striated urethral sphincter electromyography. A nasogastric sensor recorded intra abdominal pressure. Tasks included submaximal and maximal voluntary contractions, and Valsalva. The relationship between each of the parameters measured from ultrasound images and electromyography or intra-abdominal pressure amplitudes was described with nonlinear regression. RESULTS: Strong, non-linear relationships were calculated for each predicted landmark/muscle pair for submaximal contractions (R2-0.87-0.95). The relationships between mid-urethral displacement and striated urethral sphincter electromyography, and bulb of the penis displacement and bulbocavernosus electromyography were strong during maximal contractions (R2-0.74-0.88). Increased intra-abdominal pressure prevented shortening of puborectalis, which resulted in weak relationships between electromyography and anorectal and urethravesical junction displacement during all tasks. CONCLUSIONS: Displacement of landmarks in transperineal ultrasound imaging provides meaningful measures of activation of individual pelvic floor muscles in men during voluntary contractions. This method may aid assessment of muscle function or feedback for training. PMID- 26642348 TI - Treating co-occurring chronic low back pain & generalized anxiety disorder. AB - The complex, bidirectional correlation between chronic low back pain (CLBP) and generalized anxiety disorder (GAD), common ailments in primary care, can increase the risk of inadequate treatment. This article will review the relationship between CLBP and GAD and provide optimal management strategies for NPs caring for individuals with this dyad. PMID- 26642350 TI - Therapy of Primary Biliary Cirrhosis: Novel Approaches for Patients with Suboptimal Response to Ursodeoxycholic Acid. AB - Primary biliary cirrhosis (PBC) is a chronic cholestatic disease of presumed autoimmune pathogenesis, characterized by the inflammation and damage of the intrahepatic intermediate and small bile ducts, which eventually results in cirrhosis. A number of randomized and observational and pilot studies using several agents were carried out in the 80s, but no clear results or even harmful effects were reported. Over the past 2 decades, increasing evidence indicates that ursodeoxycholic acid (UDCA) - 13 to 16 mg/kg/day--is the treatment of choice for patients with PBC. Biochemical response to UDCA, assessed at 1 year, clearly predicts the long-term outcome, since in UDCA, responders survival is similar to that estimated for the matched control population. However, about 40% of patients have incomplete biochemical response and increased risk of progression and decreased survival free of transplantation. Patients with suboptimal biochemical response to UDCA outline the group in whom further single or combined treatments with UDCA are needed. Accordingly, data on the effect of fibrates alone or in combination with UDCA, and budesonide in combination with UDCA have been reported. The combined treatment of UDCA and fibrates in patients without optimal biochemical response to UDCA improves the degree of cholestasis and may minimize the long-term management of these patients. The results of the combined therapy of UDCA with budesonide are appealing but they should be established in large randomized trials. The effect of new agents such obeticholic acid are promising, since the addition of this farnesoide-X-receptor agonist bile acid in patients with stable UDCA dosage and increased alkaline phosphatase levels results in an improvement of cholestasis as compared to placebo, with a parallel decrease of aminotransferases and immunoglobulin M, as well as one surrogate marker of bile acid synthesis. New molecular therapies are currently being investigated. PMID- 26642349 TI - Inhibition of Cell Proliferation and Growth of Pancreatic Cancer by Silencing of Carbohydrate Sulfotransferase 15 In Vitro and in a Xenograft Model. AB - Chondroitin sulfate E (CS-E), a highly sulfated glycosaminoglycan, is known to promote tumor invasion and metastasis. Because the presence of CS-E is detected in both tumor and stromal cells in pancreatic ductal adenocarcinoma (PDAC), multistage involvement of CS-E in the development of PDAC has been considered. However, its involvement in the early stage of PDAC progression is still not fully understood. In this study, to clarify the direct role of CS-E in tumor, but not stromal, cells of PDAC, we focused on carbohydrate sulfotransferase 15 (CHST15), a specific enzyme that biosynthesizes CS-E, and investigated the effects of the CHST15 siRNA on tumor cell proliferation in vitro and growth in vivo. CHST15 mRNA is highly expressed in the human pancreatic cancer cell lines PANC-1, MIA PaCa-2, Capan-1 and Capan-2. CHST15 siRNA significantly inhibited the expression of CHST15 mRNA in these four cells in vitro. Silencing of the CHST15 gene in the cells was associated with significant reduction of proliferation and up-regulation of the cell cycle inhibitor-related gene p21CIP1/WAF1. In a subcutaneous xenograft tumor model of PANC-1 in nude mice, a single intratumoral injection of CHST15 siRNA almost completely suppressed tumor growth. Reduced CHST15 protein signals associated with tumor necrosis were observed with the treatment with CHST15 siRNA. These results provide evidence of the direct action of CHST15 on the proliferation of pancreatic tumor cells partly through the p21CIP1/WAF1 pathway. Thus, CHST15-CS-E axis-mediated tumor cell proliferation could be a novel therapeutic target in the early stage of PDAC progression. PMID- 26642351 TI - Complications of Guillain-Barre syndrome. AB - Guillain-Barre syndrome (GBS) is an immune-mediated disorder in the peripheral nervous system with a wide spectrum of complications. A good understanding of the complications of GBS assists clinicians to recognize and manage the complications properly thereby reducing the mortality and morbidity of GBS patients. Herein, we systemically review the literature on complications of GBS, including short-term complications and long-term complications. We summarize the frequency, severity, clinical manifestations, managements and possible mechanisms of different kinds of complications, and point out the flaws of current studies as well as demonstrate the further investigations needed. PMID- 26642353 TI - Sludge-Drying Lagoons: a Potential Significant Methane Source in Wastewater Treatment Plants. AB - "Sludge-drying lagoons" are a preferred sludge treatment and drying method in tropical and subtropical areas due to the low construction and operational costs. However, this method may be a potential significant source of methane (CH4) because some of the organic matter would be microbially metabolized under anaerobic conditions in the lagoon. The quantification of CH4 emissions from lagoons is difficult due to the expected temporal and spatial variations over a lagoon maturing cycle of several years. Sporadic ebullition of CH4, which cannot be easily quantified by conventional methods such as floating hoods, is also expected. In this study, a novel method based on mass balances was developed to estimate the CH4 emissions and was applied to a full-scale sludge-drying lagoon over a three year operational cycle. The results revealed that processes in a sludge-drying lagoon would emit 6.5 kg CO2-e per megaliter of treated sewage. This would represent a quarter to two-thirds of the overall greenhouse gas (GHG) emissions from wastewater-treatment plants (WWTPs). This work highlights the fact that sludge-drying lagoons are a significant source of CH4 that adds substantially to the overall GHG footprint of WWTPs despite being recognized as a cheap and energy-efficient means of drying sludge. PMID- 26642352 TI - MiR-192-Mediated Positive Feedback Loop Controls the Robustness of Stress-Induced p53 Oscillations in Breast Cancer Cells. AB - The p53 tumor suppressor protein plays a critical role in cellular stress and cancer prevention. A number of post-transcriptional regulators, termed microRNAs, are closely connected with the p53-mediated cellular networks. While the molecular interactions among p53 and microRNAs have emerged, a systems-level understanding of the regulatory mechanism and the role of microRNAs-forming feedback loops with the p53 core remains elusive. Here we have identified from literature that there exist three classes of microRNA-mediated feedback loops revolving around p53, all with the nature of positive feedback coincidentally. To explore the relationship between the cellular performance of p53 with the microRNA feedback pathways, we developed a mathematical model of the core p53 MDM2 module coupled with three microRNA-mediated positive feedback loops involving miR-192, miR-34a, and miR-29a. Simulations and bifurcation analysis in relationship to extrinsic noise reproduce the oscillatory behavior of p53 under DNA damage in single cells, and notably show that specific microRNA abrogation can disrupt the wild-type cellular phenotype when the ubiquitous cell-to-cell variability is taken into account. To assess these in silico results we conducted microRNA-perturbation experiments in MCF7 breast cancer cells. Time-lapse microscopy of cell-population behavior in response to DNA double-strand breaks, together with image classification of single-cell phenotypes across a population, confirmed that the cellular p53 oscillations are compromised after miR-192 perturbations, matching well with the model predictions. Our study via modeling in combination with quantitative experiments provides new evidence on the role of microRNA-mediated positive feedback loops in conferring robustness to the system performance of stress-induced response of p53. PMID- 26642354 TI - Diagnosis of Latent Tuberculosis Infection: Too Soon to Pull the Plug on the Tuberculin Skin Test. PMID- 26642355 TI - Interfacing Microfluidics with Negative Stain Transmission Electron Microscopy. AB - A microfluidic platform is presented for preparing negatively stained grids for use in transmission electron microscopy (EM). The microfluidic device is composed of glass etched with readily fabricated features that facilitate the extraction of the grid poststaining and maintains the integrity of the sample. Utilization of this device simultaneously reduced environmental contamination on the grids and improved the homogeneity of the heavy metal stain needed to enhance visualization of biological specimens as compared to conventionally prepared EM grids. This easy-to-use EM grid preparation device provides the basis for future developments of systems with more integrated features, which will allow for high throughput and dynamic structural biology studies. PMID- 26642356 TI - NLRP3 activation and mitosis are mutually exclusive events coordinated by NEK7, a new inflammasome component. AB - The NLRP3 inflammasome responds to microbes and danger signals by processing and activating proinflammatory cytokines, including interleukin 1beta (IL-1beta) and IL-18. We found here that activation of the NLRP3 inflammasome was restricted to interphase of the cell cycle by NEK7, a serine-threonine kinase previously linked to mitosis. Activation of the NLRP3 inflammasome required NEK7, which bound to the leucine-rich repeat domain of NLRP3 in a kinase-independent manner downstream of the induction of mitochondrial reactive oxygen species (ROS). This interaction was necessary for the formation of a complex containing NLRP3 and the adaptor ASC, oligomerization of ASC and activation of caspase-1. NEK7 promoted the NLRP3 dependent cellular inflammatory response to intraperitoneal challenge with monosodium urate and the development of experimental autoimmune encephalitis in mice. Our findings suggest that NEK7 serves as a cellular switch that enforces mutual exclusivity of the inflammasome response and cell division. PMID- 26642358 TI - Diversity and evolution of the envelope gene of dengue virus type 1 circulating in India in recent times. AB - Dengue viral attacks have been reported in various parts of India in recent years. In this paper we report on our studies of the characterisation and evolutionary aspects of gene sequences of the envelope glycoprotein of the prevalent Indian dengue virus type 1. Comparison with sequences from other countries shows that the envelope genes identified in India are closely related to strains from Malaysia. From the evolutionary point of view the envelope gene sequences of this dengue virus of India for past few years show that a marked mutational shift in the nucleotide sequences of the envelope gene have taken place from around the year 2000. Also, phylogenetic relationship with other three sera of dengue virus reported in India from 2005 shows that the dengue virus 1 is more closely related to dengue viruses 3 and 4 and relatively distantly to dengue virus 2. PMID- 26642359 TI - On the interconnection of stable protein complexes: inter-complex hubs and their conservation in Saccharomyces cerevisiae and Homo sapiens networks. AB - Protein complexes are key molecular entities that perform a variety of essential cellular functions. The connectivity of proteins within a complex has been widely investigated with both experimental and computational techniques. We developed a computational approach to identify and characterise proteins that play a role in interconnecting complexes. We computed a measure of inter-complex centrality, the crossroad index, based on disjoint paths connecting proteins in distinct complexes and identified inter-complex hubs as proteins with a high value of the crossroad index. We applied the approach to a set of stable complexes in Saccharomyces cerevisiae and in Homo sapiens. Just as done for hubs, we evaluated the topological and biological properties of inter-complex hubs addressing the following questions. Do inter-complex hubs tend to be evolutionary conserved? What is the relation between crossroad index and essentiality? We found a good correlation between inter-complex hubs and both evolutionary conservation and essentiality. PMID- 26642360 TI - Neural network and rough set hybrid scheme for prediction of missing associations. AB - Currently, internet is the best tool for distributed computing, which involves spreading of data geographically. But, retrieving information from huge data is critical and has no relevance unless it provides certain information. Prediction of missing associations can be viewed as fundamental problems in machine learning where the main objective is to determine decisions for the missing associations. Mathematical models such as naive Bayes structure, human composed network structure, Bayesian network modelling, etc., were developed to this end. But, it has certain limitations and failed to include uncertainties. Therefore, effort has been made to process inconsistencies in the data with the introduction of rough set theory. This paper uses two processes, pre-process and post-process, to predict the decisions for the missing associations in the attribute values. In preprocess, rough set is used to reduce the dimensionality, whereas neural network is used in postprocess to explore the decision for the missing associations. A real-life example is provided to show the viability of the proposed research. PMID- 26642357 TI - Self-renewing resident arterial macrophages arise from embryonic CX3CR1(+) precursors and circulating monocytes immediately after birth. AB - Resident macrophages densely populate the normal arterial wall, yet their origins and the mechanisms that sustain them are poorly understood. Here we use gene expression profiling to show that arterial macrophages constitute a distinct population among macrophages. Using multiple fate-mapping approaches, we show that arterial macrophages arise embryonically from CX3CR1(+) precursors and postnatally from bone marrow-derived monocytes that colonize the tissue immediately after birth. In adulthood, proliferation (rather than monocyte recruitment) sustains arterial macrophages in the steady state and after severe depletion following sepsis. After infection, arterial macrophages return rapidly to functional homeostasis. Finally, survival of resident arterial macrophages depends on a CX3CR1-CX3CL1 axis within the vascular niche. PMID- 26642361 TI - Automatic segmentation of Potyviridae family polyproteins. AB - We describe an automatic segmentation method for polyproteins of the viruses belonging to the Potyviridae family. It uses machine learning techniques in order to predict the cleavage site which define the segments in which said polyproteins are cut in their process of functional maturation. The segmentation application is publicly available for use on a website and it can be accessed through the web service interface too. The prediction models have an average sensitivity of 0.79 and a Matthews correlation coefficient average of 0.23. This method is capable of predicting correctly (coinciding with previously published segmentation) the segmentation of sequences which come from Potyvirus and Rymovirus, genera. However accurate prediction capabilities are affected when faced with either atypical sequences or viruses belonging to less common genera in the Potyviridae family. Future work will focus on establishing greater flexibility in this sense. PMID- 26642362 TI - Docking analysis of gallic acid derivatives as HIV-1 protease inhibitors. AB - HIV-1 Protease (HIV-1 PR) enzymes are essential for accurate assembly and maturation of infectious HIV retroviruses. The significant role of HIV-1 protease in viral replication has made it a potential drug target. In the recent past, phytochemical Gallic Acid (GA) derivatives have been screened for protease inhibitor activity. The present work aims to design and evaluate potential GA based HIV-1 PR phytoinhibitors by docking approach. The ligands were prepared by ChemDraw and docking was performed in HEX software. In this present study, one of the GA analogues (GA4) emerged as a potent drug candidate for HIV-1 PR inhibition, and docking results showed it to be comparable with anti-HIV drugs, darunavir and amprenavir. The GA4 derivative provided a lead for designing more effective HIV-1 PR inhibitors. PMID- 26642363 TI - In silico analysis, annotation and characterisation of putative ESTs from Sorghum bicolor associated with heat stress. AB - Owing to their sessile nature, plants experience a variety of environmental stresses, but tolerance to these adverse conditions is a very complex phenomenon. Among all stresses, heat stress is the most important constraint that affects plant yield in rain-fed areas. To shed some light on candidate genes involved in heat stress, sequences potentially associated with heat shock resistance were retrieved and identified by in silico analysis using the public sequence database of various plants. A total of 30,000 EST sequences were mined and 24 putative ESTs associated with heat stress were picked up for further studies. In silico analysis revealed that all ESTs were linked with the HSP family. Gene Ontology (GO) analysis revealed that the deduced protein sequences of the heat-linked 24 ESTs were involved in various biological pathways regulating heat stress response. Hydropathy analysis revealed that all protein sequences were hydrophilic in nature. Based on the phylogenetic analysis, all HSP-related protein sequences were divided into seven groups. Analysis of cis-elements provides molecular evidence for the possible involvement of hydrophilic ESTs in the process of abiotic stress tolerance in sorghum. Based on these results, it was suggested that putative ESTs may play an important role in heat stress tolerance. PMID- 26642364 TI - POPDC1(S201F) causes muscular dystrophy and arrhythmia by affecting protein trafficking. AB - The Popeye domain-containing 1 (POPDC1) gene encodes a plasma membrane-localized cAMP-binding protein that is abundantly expressed in striated muscle. In animal models, POPDC1 is an essential regulator of structure and function of cardiac and skeletal muscle; however, POPDC1 mutations have not been associated with human cardiac and muscular diseases. Here, we have described a homozygous missense variant (c.602C>T, p.S201F) in POPDC1, identified by whole-exome sequencing, in a family of 4 with cardiac arrhythmia and limb-girdle muscular dystrophy (LGMD). This allele was absent in known databases and segregated with the pathological phenotype in this family. We did not find the allele in a further screen of 104 patients with a similar phenotype, suggesting this mutation to be family specific. Compared with WT protein, POPDC1(S201F) displayed a 50% reduction in cAMP affinity, and in skeletal muscle from patients, both POPDC1(S201F) and WT POPDC2 displayed impaired membrane trafficking. Forced expression of POPDC1(S201F) in a murine cardiac muscle cell line (HL-1) increased hyperpolarization and upstroke velocity of the action potential. In zebrafish, expression of the homologous mutation (popdc1(S191F)) caused heart and skeletal muscle phenotypes that resembled those observed in patients. Our study therefore identifies POPDC1 as a disease gene causing a very rare autosomal recessive cardiac arrhythmia and LGMD, expanding the genetic causes of this heterogeneous group of inherited rare diseases. PMID- 26642365 TI - Serum amyloid A impairs the antiinflammatory properties of HDL. AB - HDL from healthy humans and lean mice inhibits palmitate-induced adipocyte inflammation; however, the effect of the inflammatory state on the functional properties of HDL on adipocytes is unknown. Here, we found that HDL from mice injected with AgNO3 fails to inhibit palmitate-induced inflammation and reduces cholesterol efflux from 3T3-L1 adipocytes. Moreover, HDL isolated from obese mice with moderate inflammation and humans with systemic lupus erythematosus had similar effects. Since serum amyloid A (SAA) concentrations in HDL increase with inflammation, we investigated whether elevated SAA is a causal factor in HDL dysfunction. HDL from AgNO3-injected mice lacking Saa1.1 and Saa2.1 exhibited a partial restoration of antiinflammatory and cholesterol efflux properties in adipocytes. Conversely, incorporation of SAA into HDL preparations reduced antiinflammatory properties but not to the same extent as HDL from AgNO3-injected mice. SAA-enriched HDL colocalized with cell surface-associated extracellular matrix (ECM) of adipocytes, suggesting impaired access to the plasma membrane. Enzymatic digestion of proteoglycans in the ECM restored the ability of SAA containing HDL to inhibit palmitate-induced inflammation and cholesterol efflux. Collectively, these findings indicate that inflammation results in a loss of the antiinflammatory properties of HDL on adipocytes, which appears to partially result from the SAA component of HDL binding to cell-surface proteoglycans, thereby preventing access of HDL to the plasma membrane. PMID- 26642366 TI - Rituximab does not reset defective early B cell tolerance checkpoints. AB - Type 1 diabetes (T1D) patients show abnormalities in early B cell tolerance checkpoints, resulting in the accumulation of large numbers of autoreactive B cells in their blood. Treatment with rituximab, an anti-CD20 mAb that depletes B cells, has been shown to preserve beta cell function in T1D patients and improve other autoimmune diseases, including rheumatoid arthritis and multiple sclerosis. However, it remains largely unknown how anti-B cell therapy thwarts autoimmunity in these pathologies. Here, we analyzed the reactivity of Abs expressed by single, mature naive B cells from 4 patients with T1D before and 52 weeks after treatment to determine whether rituximab resets early B cell tolerance checkpoints. We found that anti-B cell therapy did not alter the frequencies of autoreactive and polyreactive B cells, which remained elevated in the blood of all patients after rituximab treatment. Moreover, the limited proliferative history of autoreactive B cells after treatment revealed that these clones were newly generated B cells and not self-reactive B cells that had escaped depletion and repopulated the periphery through homeostatic expansion. We conclude that anti-B cell therapy may provide a temporary dampening of autoimmune processes through B cell depletion. However, repletion with autoreactive B cells may explain the relapse that occurs in many autoimmune patients after anti-B cell therapy. PMID- 26642368 TI - Copper-Catalyzed Domino Synthesis of 2-Arylthiochromanones through Concomitant C S Bond Formations Using Xanthate as Sulfur Source. AB - An efficient domino process for the synthesis of thioflavanones has been described using a copper catalyst without addition of any external ligand. A variety of thioflavanones have been synthesized from easily accessible 2' iodochalcones or 2'-bromochalcones in excellent yield through in situ incorporation of sulfur using xanthate as an odorless sulfur source. This domino process proceeds through Cu-catalyzed C(aryl)-S bond formation by the coupling reaction of xanthate with 2'-halochalcones followed by C-S bond cleavage of thioester then S-C bond formation by intramolecular Michael addition. PMID- 26642369 TI - Bioinspired Syntheses of the Pyridoacridine Marine Alkaloids Demethyldeoxyamphimedine, Deoxyamphimedine, and Amphimedine. AB - Efficient bioinspired syntheses of the biologically active pyridoacridine marine alkaloids demethyldeoxyamphimedine, deoxyamphimedine, and amphimedine are reported. Reaction of styelsamine D, prepared via an optimized route starting from Boc-dopamine, with paraformaldehyde afforded demethyldeoxyamphimedine and deoxyamphimedine. Oxidation of the latter using either K3[Fe(CN)6] or DMSO/conc. HCl gave amphimedine in 8 steps from tryptamine with an overall yield of 14%. The versatility of the method was demonstrated by the synthesis of non-natural ethyl and benzyl congeners of deoxyamphimedine and amphimedine. PMID- 26642371 TI - In vitro hemodynamic testing of Amplatzer plugs for paravalvular leak occlusion after transcatheter aortic valve implantation. AB - OBJECTIVE: We aimed to in-vitro test Amplatzer devices (Amplatzer Vascular Plug II and Amplatzer Vascular Plug III, SJM, St. Paul, MN) in closing PVL generated by transcatheter balloon expandable aortic valve prosthesis in order to quantify the effective treatment of PVL. BACKGROUND: Transcatheter aortic valve implantation (TAVI) procedures represent the treatment of choice for high risk patients. Despite evolving technologies paravalvular leak (PVL) is still a major unaddressed issue. This severe complication significantly impairs long-term survival. Percutaneous treatment of this complication is usually performed with the implantation of not specifically designed and not approved vascular devices. METHODS: A 26 mm Sapien XT (Edwards Lifesciences, Irvine, CA) was implanted in a rubber aortic root and a semi-elliptical shape PVL was created. The vascular occluder devices were implanted in the PVL and hemodynamic performance was tested in a pulse duplicator according to international standard ISO 5840-3:2013. Different type of comparison tests together with high speed camera recording allowed us to define the global efficiency of the occluders and their interaction with the transcatheter prosthesis. RESULTS: The results revealed that the use of vascular plugs was not per se sufficient to produce an effective or substantial reduction of PVL with a maximum efficiency of less than 50%. Recorded video showed clearly that the vascular plug always interfered with the leaflet of the prosthetic valve. CONCLUSIONS: Currently used devices do not guarantee effective treatment of PVL and may otherwise compromise the structural integrity of the prosthetic valve implanted. Specifically designed devices are required. CONDENSED ABSTRACT: Despite evolving technologies, paravalvular leak (PVL) is still a major unaddressed issue after transcatheter aortic valve implantation. Percutaneous treatment of this complication is usually performed with the implantation of Amplatzer devices not specifically designed and not approved for this specific use. We tested Amplatzer devices in a pulse duplicator to occlude PVL generated after implantation of a 26 mm SAPIENT XT prosthesis. The results revealed that the use of vascular plugs was not per se sufficient to produce an effective or substantial reduction of PVL. The video showed clearly that the vascular plug always interfered with the leaflet of the prosthetic valve. PMID- 26642367 TI - Loss of CD73-mediated actin polymerization promotes endometrial tumor progression. AB - Ecto-5'-nucleotidase (CD73) is central to the generation of extracellular adenosine. Previous studies have highlighted a detrimental role for extracellular adenosine in cancer, as it dampens T cell-mediated immune responses. Here, we determined that, in contrast to other cancers, CD73 is markedly downregulated in poorly differentiated and advanced-stage endometrial carcinoma compared with levels in normal endometrium and low-grade tumors. In murine models, CD73 deficiency led to a loss of endometrial epithelial barrier function, and pharmacological CD73 inhibition increased in vitro migration and invasion of endometrial carcinoma cells. Given that CD73-generated adenosine is central to regulating tissue protection and physiology in normal tissues, we hypothesized that CD73-generated adenosine in endometrial carcinoma induces an innate reflex to protect epithelial integrity. CD73 associated with cell-cell contacts, filopodia, and membrane zippers, indicative of involvement in cell-cell adhesion and actin polymerization-dependent processes. We determined that CD73-generated adenosine induces cortical actin polymerization via adenosine A1 receptor (A1R) induction of a Rho GTPase CDC42-dependent conformational change of the actin related proteins 2 and 3 (ARP2/3) actin polymerization complex member N-WASP. Cortical F-actin elevation increased membrane E-cadherin, beta-catenin, and Na(+)K(+) ATPase. Together, these findings reveal that CD73-generated adenosine promotes epithelial integrity and suggest why loss of CD73 in endometrial cancer allows for tumor progression. Moreover, our data indicate that the role of CD73 in cancer is more complex than previously described. PMID- 26642372 TI - One-shot 86-mm slender transradial bifurcation stenting. PMID- 26642370 TI - Pharmacological treatment with L-DOPA may reduce striatal dopamine transporter binding in in vivo imaging studies. AB - Numerous neurologic and psychiatric conditions are treated with pharmacological compounds, which lead to an increase of synaptic dopamine (DA) levels. One example is the DA precursor L-3,4-dihydroxyphenylalanine (L-DOPA), which is converted to DA in the presynaptic terminal. If the increase of DA concentrations in the synaptic cleft leads to competition with exogenous radioligands for presynaptic binding sites, this may have implications for DA transporter (DAT) imaging studies in patients under DAergic medication. This paper gives an overview on those findings, which, so far, have been obtained on DAT binding in human Parkinson's disease after treatment with L-DOPA. Findings, moreover, are related to results obtained on rats, mice or non-human primates. Results indicate that DAT imaging may be reduced in the striata of healthy animals, in the unlesioned striata of animal models of unilateral Parkinson's disease and in less severly impaired striata of Parkinsonian patients, if animal or human subjects are under acute or subchronic treatment with L-DOPA. If also striatal DAT binding is susceptible to alterations of synaptic DA levels, this may allow to quantify DA reuptake in analogy to DA release by assessing the competition between endogenous DA and the administered exogenous DAT radioligand. PMID- 26642373 TI - Patient selection for cardiac surgery: Time to consider subgroups within risk categories? AB - BACKGROUND: Medical guidelines increasingly use risk stratification and implicitly assume that individuals classified in the same risk category form a homogeneous group, while individuals with similar, or even identical, predicted risks can still be very different. We evaluate a strategy to identify homogeneous subgroups typically comprising predicted risk categories to allow further tailoring of treatment allocation and illustrate this strategy empirically for cardiac surgery patients with high postoperative mortality risk. METHODS: Using a dataset of cardiac surgery patients (n=6517) we applied cluster analysis to identify homogenous subgroups of patients comprising the high postoperative mortality risk group (EuroSCORE >= 15%). Cluster analyses were performed separately within younger (<75 years) and older (>= 75 years) patients. Validity measures were calculated to evaluate quality and robustness of the identified subgroups. RESULTS: Within younger patients two distinct and robust subgroups were identified, differing mainly in preoperative state and indication of recent myocardial infarction or unstable angina. In older patients, two distinct and robust subgroups were identified as well, differing mainly in preoperative state, presence of chronic pulmonary disease, previous cardiac surgery, neurological dysfunction disease and pulmonary hypertension. CONCLUSIONS: We illustrated a feasible method to identify homogeneous subgroups of individuals typically comprising risk categories. This allows a single treatment strategy--optimal only on average, across all individuals in a risk category--to be replaced by subgroup specific treatment strategies, bringing us another step closer to individualized care. Discussions on allocation of cardiac surgery patients to different interventions may benefit from focusing on such specific subgroups. PMID- 26642375 TI - The complete mitochondria genome of Parasarcophaga albiceps (Diptera: Sarcophagidae). AB - Parasarcophaga albiceps is one of the forensically important fly species which belongs to the family Sarcophagidae. In this study, we report the complete mitochondrial genome of P. albiceps to provide a supplemental data for species identification. The 14 935 bp-long mitogenome is composed of 13 protein-encoding genes, 22 transfer RNA genes, 2 ribosomal RNA genes, and a non-coding AT-rich region. The permutation of the genes is in conformity with that observed in the ancestral arthropod. The overall base compositions of A, G, C and T are 39.24%, 9.70%, 14.44%, and 36.62%, respectively. Phylogenetic analysis shows the composition of the P. albiceps mitochondrial genome, which is very similar to that of another eight species of Sarcophagidae. The monophyletic branches of the phylogenetic tree reveal that complete mitochondrial genome is suitable for discrimination between these species, providing high support for separation on congeneric species. Therefore, the molecular method applied to the sarcophagid species identification is feasible. The complete mitochondrial genome of P. albiceps is supposed to make contributions to enriching the dipteran mitochondrial genomes and provide a potential tool for species identification. PMID- 26642376 TI - Paradigm shift: semantic memory decline as a biomarker of preclinical Alzheimer's disease. PMID- 26642374 TI - Layer-by-Layer Assembly of Supported Lipid Bilayer Poly-L-Lysine Multilayers. AB - Multilayer lipid membranes perform many important functions in biology, such as electrical isolation (myelination of axons), increased surface area for biocatalytic purposes (thylakoid grana and mitochondrial cristae), and sequential processing (golgi cisternae). Here we develop a simple layer-by-layer methodology to form lipid multilayers via vesicle rupture onto existing supported lipid bilayers (SLBs) using poly l-lysine (PLL) as an electrostatic polymer linker. The assembly process was monitored at the macroscale by quartz crystal microbalance with dissipation (QCM-D) and the nanoscale by atomic force microscopy (AFM) for up to six lipid bilayers. By varying buffer pH and PLL chain length, we show that longer chains (>=300 kDa) at pH 9.0 form thicker polymer supported multilayers, while at low pH and shorter length PLL, we create close packed layers (average lipid bilayers separations of 2.8 and 0.8 nm, respectively). Fluorescence recovery after photobleaching (FRAP) and AFM were used to show that the diffusion of lipid and three different membrane proteins in the multilayered membranes has little dependence on lipid stack number or separation between membranes. These approaches provide a straightforward route to creating the complex membrane structures that are found throughout nature, allowing possible applications in areas such as energy production and biosensing while developing our understanding of the biological processes at play. PMID- 26642377 TI - Important Hydrogen Bond Networks in Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitor Design Revealed by Crystal Structures of Imidazoleisoindole Derivatives with IDO1. AB - Indoleamine 2,3-dioxygenase 1 (IDO1), promoting immune escape of tumors, is a therapeutic target for the cancer immunotherapy. A number of IDO1 inhibitors have been identified, but only limited structural biology studies of IDO1 inhibitors are available to provide insights on the binding mechanism of IDO1. In this study, we present the structure of IDO1 in complex with 24, a NLG919 analogue with potent activity. The complex structure revealed the imidazole nitrogen atom of 24 to coordinate with the heme iron, and the imidazoleisoindole core situated in pocket A with the 1-cyclohexylethanol moiety extended to pocket B to interact with the surrounding residues. Most interestingly, 24 formed an extensive hydrogen bond network with IDO1, which is a distinct feature of IDO1/24 complex structure and is not observed in the other IDO1 complex structures. Further structure-activity relationship, UV spectra, and structural biology studies of several analogues of 24 demonstrated that extensive hydrophobic interactions and the unique hydrogen bonding network contribute to the great potency of imidazoleisoindole derivatives. These results are expected to facilitate the structure-based drug design of new IDO inhibitors. PMID- 26642378 TI - IL-6 blockers in systemic onset juvenile idiopathic arthritis. AB - IL-6 has a key role in the pathogenesis, clinical manifestations and activity of Systemic Onset Idiopathic Arthritis (sJIA). Tocilizumab (TCZ), the first humanized antihuman IL-6 receptor antibody, inhibits the activity of IL-6. In this review, we summarize the main studies performed, to date, about the use of TCZ in children affected by sJIA refractory to conventional treatment. Nowadays TCZ can be used, alone or in association with Metotrexate, in children older than 2 years. Its use in children younger than 2 years is being investigated. Further study about its use in sJIA and other type of idiopathic arthritis should be done. PMID- 26642379 TI - A Stability Study of Ni/Yttria-Stabilized Zirconia Anode for Direct Ammonia Solid Oxide Fuel Cells. AB - In recent years, solid oxide fuel cells fueled with ammonia have been attracting intensive attention. In this work, ammonia fuel was supplied to the Ni/yttria stabilized zirconia (YSZ) cermet anode at 600 and 700 degrees C, and the change of electrochemical performance and microstructure under the open-circuit state was studied in detail. The influence of ammonia exposure on the microstructure of Ni was also investigated by using Ni/YSZ powder and Ni film deposited on a YSZ disk. The obtained results demonstrated that Ni in the cermet anode was partially nitrided under an ammonia atmosphere, which considerably roughened the Ni surface. Moreover, the destruction of the anode support layer was confirmed for the anode-supported cell upon the temperature cycling test between 600 and 700 degrees C because of the nitriding phenomenon of Ni, resulting in severe performance degradation. PMID- 26642380 TI - Combination of Ambiguous and Unambiguous Data in the Restraint-driven Docking of Flexible Peptides with HADDOCK: The Binding of the Spider Toxin PcTx1 to the Acid Sensing Ion Channel (ASIC) 1a. AB - Peptides that bind to ion channels have attracted much interest as potential lead molecules for the development of new drugs and insecticides. However, the structure determination of large peptide-channel complexes using experimental methods is challenging. Thus structural models are often derived from combining experimental information with restraint-driven docking approaches. Using the complex formed by the venom peptide PcTx1 and the acid sensing ion channel (ASIC) 1a as a case study, we have examined the effect of different combinations of restraints and input structures on the statistical likelihood of (a) correctly predicting the structure of the binding interface and (b) the ability to predict which residues are involved in specific pairwise peptide-channel interactions. For this, we have analyzed over 200,000 water-refined docked structures obtained with various amounts and types of restraints of the peptide-channel complex predicted using the docking program HADDOCK. We found that increasing the number of restraints or even the use of pairwise interaction data resulted in only a modest improvement in the likelihood of finding a structure within a given accuracy. This suggests that shape complementarity and the force field make a large contribution to the accuracy of the predicted structure. The results also showed that there are large variations in the accuracy of the predicted structure depending on the precise combination of residues used as restraints. Finally, we reflect on the limitations of relying on geometric criteria such as root-mean square deviations to assess the accuracy of docking procedures. We propose that in addition to currently used measures, the likelihood of finding a structure within a given level of accuracy should be also used to evaluate docking methods. PMID- 26642381 TI - Effects of Electrolyzed Oxidizing Water on Inactivation of Bacillus subtilis and Bacillus cereus Spores in Suspension and on Carriers. AB - Spores of some Bacillus species are responsible for food spoilage and foodborne disease. These spores are highly resistant to various interventions and cooking processes. In this study, the sporicidal efficacy of acidic electrolyzed oxidizing (EO) water (AEW) and slightly acidic EO water (SAEW) with available chlorine concentration (ACC) of 40, 60, 80, 100, and 120 mg/L and treatment time for 1, 2, 3, 4, 5, and 6 min were tested on Bacillus subtilis and Bacillus cereus spores in suspension and on carrier with or without organics. The reduction of spore significantly increased with increasing ACC and treatment time (P < 0.05). Nondetectable level of B. cereus spore in suspension occurred within 2 min after exposure to both EO waters containing 120 mg/L ACC, while only SAEW at 120 mg/L and 2 min treatment achieved >6 log reductions of B. subtilis spore. Both types of EO water with ACC of 60 mg/L and 6 min treatment achieved a reduction of B. subtilis and B. cereus spores to nondetectable level. EO water with ACC of 80 mg/L and treatment time of 3 min on carrier test without organics addition resulted in reductions of B. subtilis spore to nondetectable level. But, addition of 0.3% organics on carrier decreased the inactivation effect of EO water. This study indicated that EO water was highly effective in inactivation of B. subtilis and B. cereus spores in suspension or on carrier, and therefore, rendered it as a promising disinfectant to be applied in food industry. PMID- 26642382 TI - Southern Medical Students' Views on Medicaid Expansion. PMID- 26642383 TI - The Canadian Pediatric Surgery Network (CAPSNet): Lessons Learned from a National Registry Devoted to the Study of Congenital Diaphragmatic Hernia and Gastroschisis. AB - The Canadian Pediatric Surgery Network (CAPSNet) was created in 2005 by a geographically representative, multidisciplinary group of clinicians and researchers with the intent of establishing a national research registry for gastroschisis (GS) and congenital diaphragmatic hernia (CDH). Since then, CAPSNet has used this registry and its 16-center network to make contributions to the knowledge base informing best practices for GS and CDH care. More recently, CAPSNet has expanded its focus to include quality assurance and improvement at each of its sites, by issuing a benchmarked outcomes "report card" with its annual report. Finally, a major objective of CAPSNet has been to establish and adopt standardized, evidence-based practice guidelines for GS and CDH across all Canadian perinatal centers. PMID- 26642384 TI - The Challenges of the European Anorectal Malformations-Net Registry. AB - Anorectal malformations (ARM) have a low prevalence, patients need specialized surgical care, and in many cases, patients born with ARM even need life-long aftercare. Due to its low prevalence most patients are still treated in low volume pediatric surgical centers without any adequate monitoring of the outcome. Data on prevalence, comparison of different surgical techniques, and prospective outcome measurements are still scarce and difficult to interpret. In 2010, a consortium was founded (ARM-Net consortium) including several European pediatric surgical centers to collaborate more in research and share knowledge on ARM. One of the structures started by the consortium was an ARM-Net registry for the inclusion of all future patients treated in these centers. With this review, we report the structure of the ARM-Net registry, some of the results, and discuss the challenges we faced and still face after its introduction in 2010. PMID- 26642385 TI - The Congenital Diaphragmatic Hernia Study Group Registry. AB - Congenital diaphragmatic hernia (CDH) is a rare anomaly with an incidence between 1/2,500 and 1/3,000 live births. The rarity of the disease makes it difficult to design powerful studies leading to accurate and meaningful evidence. For rare diseases, the development of multicenter international registries may help in collecting data and give an overall picture of the disease. In this review, we will describe the development of the CDH study group, we will describe its work methodology, and the results obtained since its birth in 1995. PMID- 26642386 TI - Registries for Biliary Atresia and Related Disorders. AB - Most neonatal cholestatic disorders are rare diseases (RD), but they represent the leading indication for pediatric liver transplantation. From the pediatric surgical point of view, biliary atresia (BA) and choledochal cyst are from particular interest because diagnostic pathways and therapeutic algorithms are diverging as well as outcome parameters of follow-up studies. In addition, screening programs for BA are still at an early stage while transition of those patients with and without liver transplantation is not established yet. The newly created Web site www.bard-online.com focuses on BA and related diseases and includes decentralized online registries, information for patients and health workers, as well as a platform for interdisciplinary communication and service offerings. This initiative was started to compensate for disadvantages for patients with RD and to help unifying the community of clinicians and researchers in this field. PMID- 26642387 TI - National Esophageal Atresia Register. AB - National Esophageal Atresia was created in 2008 by the National Reference Center for Esophageal Congenital Abnormalities created in 2006. Primary goal was estimation of live birth prevalence in France. A national network of surgeons and pediatricians was initiated and entire teams dealing with esophageal atresia accepted to participate in an exhaustive national register. A questionnaire was validated by a national committee and data were centralized in our center. Scientific exploitation showed that such database is useful for health authorities as for medical professionals. Live birth prevalence in France is at 1.9/10,000 births. Prenatal diagnosis is more common but its effect on prevalence is not yet fully understood. Associated congenital abnormalities are frequent and major malformations with termination of pregnancy can influence prevalence. PMID- 26642388 TI - The Value of Trainee Networks in Pediatric Surgical Research. AB - In 2007, the first trainee-led surgical research network was founded in the United Kingdom (UK). The West Midlands Research Collaborative was started by a group of enthusiastic adult surgical trainees who saw the benefits of altruistic collaboration to generate high quality, multicenter research. Seeing the success of their research projects, including randomized controlled trials, trainees in other regions and specialties were spurred on to founding their own research collaboratives. The Pediatric Surgical Trainee Research Network was started in 2011 by a group of UK trainees with the aim to promote, facilitate, and encourage trainee-led research in pediatric surgery. This article summarizes the history and evolution of the trainee collaborative surgical research. It examines the challenges which multicenter research entails and the steps the collaboratives have taken to overcome them. We describe some of the projects which have been successfully completed and the benefits that the trainee networks have for patients and surgeons alike. PMID- 26642389 TI - The Value of Surveys in Pediatric Surgery. AB - Surveys are an important research tool to evaluate the practice patterns of physicians. In the medical literature, practice surveys are increasingly used in specialties, such as pediatric surgery, characterized by the lack of sufficient evidence-based literature due to the rarity of the conditions treated. To maintain a level that yields to a meaningful scientific contribution the design, data collection and analysis of the survey have to be rigorous. Herein, we describe the general principles of survey methodology, we report the benefits and limitations of this statistical method, and we discuss the value of surveys in pediatric surgery. PMID- 26642390 TI - Recent Advances in Controlling the Depositing Morphologies of Inkjet Droplets. AB - Inkjet printing has been widely used in functional material patterning for fabrication of optical/electrical devices. The depositing morphologies of inkjet droplets are critical to the resolution and performance of resulted functional patterns. This review summarizes various strategies to control the depositing morphologies of inkjet droplets, including suppressing and utilizing coffee-ring effect, employing liquid substrates, developing patterned substrates and controlling droplets coalescence. Moreover, the remaining challenges in controlling inkjet droplets are presented, and the broad research and application prospects of controlling nanomaterial patterning by inkjet printing are proposed. PMID- 26642392 TI - Reversible Cerebral Vasoconstriction Syndrome. PMID- 26642391 TI - Selective Intracellular Delivery of Recombinant Arginine Deiminase (ADI) Using pH Sensitive Cell Penetrating Peptides To Overcome ADI Resistance in Hypoxic Breast Cancer Cells. AB - Arginine depletion strategies, such as pegylated recombinant arginine deiminase (ADI-PEG20), offer a promising anticancer treatment. Many tumor cells have suppressed expression of a key enzyme, argininosuccinate synthetase 1 (ASS1), which converts citrulline to arginine. These tumor cells become arginine auxotrophic, as they can no longer synthesize endogenous arginine intracellularly from citrulline, and are therefore sensitive to arginine depletion therapy. However, since ADI-PEG20 only depletes extracellular arginine due to low internalization, ASS1-expressing cells are not susceptible to treatment since they can synthesize arginine intracellularly. Recent studies have found that several factors influence ASS1 expression. In this study, we evaluated the effect of hypoxia, frequently encountered in many solid tumors, on ASS1 expression and its relationship to ADI-resistance in human MDA-MB-231 breast cancer cells. It was found that MDA-MB-231 cells developed ADI resistance in hypoxic conditions with increased ASS1 expression. To restore ADI sensitivity as well as achieve tumor-selective delivery under hypoxia, we constructed a pH-sensitive cell penetrating peptide (CPP)-based delivery system to carry ADI inside cells to deplete both intra- and extracellular arginine. The delivery system was designed to activate the CPP-mediated internalization only at the mildly acidic pH (6.5-7) associated with the microenvironment of hypoxic tumors, thus achieving better selectivity toward tumor cells. The pH sensitivity of the CPP HBHAc was controlled by recombinant fusion to a histidine-glutamine (HE) oligopeptide, generating HBHAc-HE-ADI. The tumor distribution of HBHAc-HE-ADI was comparable to ADI-PEG20 in a mouse xenograft model of human breast cancer cells in vivo. In addition, HBHAc-HE-ADI showed increased in vitro cellular uptake in cells incubated in a mildly acidic pH (hypoxic conditions) compared to normal pH (normoxic conditions), which correlated with pH-sensitive in vitro cytotoxicity in hypoxic MDA-MB-231 and human prostate cancer PC3 cells. Together, we conclude that the HBHAc-HE-based peptide delivery offers a useful means to overcome hypoxia-induced resistance to ADI in breast cancer cells, and to target the mildly acidic tumor microenvironment. PMID- 26642422 TI - Correction: Corrigendum. PMID- 26642423 TI - The value of (18) F-fluorodeoxyglucose positron emission tomography for prediction of treatment response in gastrointestinal stromal tumors: a systematic review and meta-analysis. AB - BACKGROUND: Early detection of response to treatment is critically important in gastrointestinal stromal tumors (GIST). Therefore, the present systematic review and meta-analysis assessed the value of (18) f-fluorodeoxyglucose positron emission tomography ((18) FDG-PET) on prediction of therapeutic response of GIST patients to systemic treatments. METHODS: The literature search was conducted using PubMed, SCOPUS, Cochrane, and Google Scholar databases, and review article references. Eligible articles were defined as studies included confirmed GIST patients who underwent (18) FDG-PET as well as assessing the screening role of it. RESULTS: Finally, 21 relevant articles were included. The analysis showed the pooled sensitivity and specificity of 18FDG-PET in evaluation of response to treatment of GIST patient were 0.90 (95% CI: 0.85-0.94; I(2) = 52.59, P = 0.001) and 0.62 (95% CI: 0.49-0.75; I(2) = 69.7, P = 0.001), respectively. In addition, the pooled prognostic odds ratio of (18) FDG-PET for was 14.99 (95% CI, 6.42 34.99; I(2) = 100.0, P < 0.001). The Meta regression showed that sensitivity of (18) FDG-PET was higher if the sample size of study was equal or more than 30 cases (sensitivity = 0.93; 95% CI: 0.89-0.97), when using PET/CT (sensitivity = 0.92; 95% CI: 0.89-0.97), and self-design criteria (sensitivity = 0.93; 95% CI: 0.87-1.0). CONCLUSION: The present meta-analysis showed (18) FDG-PET has a significant value in predicting treatment response in GIST patients. PMID- 26642425 TI - Thyrotoxicosis associated with the use of amiodarone: the utility of ultrasound in patient management. AB - Amiodarone is an anti-arrhythmic drug that commonly affects the thyroid, causing hypothyroidism or thyrotoxicosis. Amiodarone-induced thyrotoxicosis (AIT) is caused by excessive thyroid hormone biosynthesis in response to iodine load in autonomously functioning thyroid glands with pre-existing nodular goitre or underlying Graves' disease (type 1 or AIT 1), or by a destructive thyroiditis typically occurring in normal glands (type 2 or AIT 2). Indeterminate or mixed forms are also recognized. The distinction is clinically useful as AIT 1 is treated predominantly with thionamides, whereas AIT 2 is managed with glucocorticoids. We review the tools used to differentiate type 1 from type 2 thyrotoxicosis, with specific reference to the imaging modalities used. PMID- 26642426 TI - Well-Ordered Nanoporous ABA Copolymer Thin Films via Solvent Vapor Annealing, Homopolymer Blending, and Selective Etching of ABAC Tetrablock Terpolymers. AB - Solvent vapor annealing treatments are used to control the orientation of nanostructures produced in thin films of a poly(styrene)-block-poly(isoprene) block-poly(styrene)-block-poly((+/-)-lactide) (PS-PI-PS-PLA) and its blends with PLA homopolymer. The PS-PI-PS-PLA tetrablock terpolymer, previously determined to adopt a core(PLA)-shell(PS) cylindrical morphology in the bulk, gave perpendicular alignment of PLA cylinders over a limited range of thicknesses using a mixed solvent environment of tetrahydrofuran and acetone. On the other hand, perpendicular alignment was achieved regardless of film thickness by inclusion of 5 wt % homopolymer PLA in the PS-PI-PS-PLA tetrablock. Tapping mode atomic force microscopy (AFM) was used to visualize film surface morphologies. Subsequent reactive ion etching (RIE) and basic hydrolysis of PLA produced 15 nm pores in a PS-PI-PS triblock thin film matrix. Nanoporosity was confirmed by scanning electron microscopy (SEM) images and the vertical continuity of pores was confirmed by cross-sectional SEM analysis. PMID- 26642424 TI - Effectiveness of Scotland's National Naloxone Programme for reducing opioid related deaths: a before (2006-10) versus after (2011-13) comparison. AB - AIMS: To assess the effectiveness for Scotland's National Naloxone Programme (NNP) by comparison between 2006-10 (before) and 2011-13 (after NNP started in January 2011) and to assess cost-effectiveness. DESIGN: This was a pre-post evaluation of a national policy. Cost-effectiveness was assessed by prescription costs against life-years gained per opioid-related death (ORD) averted. SETTING: Scotland, in community settings and all prisons. INTERVENTION: Brief training and standardized naloxone supply became available to individuals at risk of opioid overdose. MEASUREMENTS: ORDs as identified by National Records of Scotland. Look back determined the proportion of ORDs who, in the 4 weeks before ORD, had been (i) released from prison (primary outcome) and (ii) released from prison or discharged from hospital (secondary). We report 95% confidence intervals for effectiveness in reducing the primary (and secondary) outcome in 2011-13 versus 2006-10. Prescription costs were assessed against 1 or 10 life-years gained per averted ORD. FINDINGS: In 2006-10, 9.8% of ORDs (193 of 1970) were in people released from prison within 4 weeks of death, whereas only 6.3% of ORDs in 2011 13 followed prison release (76 of 1212, P < 0.001; this represented a difference of 3.5% [95% confidence interval (CI) = 1.6-5.4%)]. This reduction in the proportion of prison release ORDs translates into 42 fewer prison release ORDs (95% CI = 19-65) during 2011-13, when 12,000 naloxone kits were issued at current prescription cost of L225,000. Scotland's secondary outcome reduced from 19.0 to 14.9%, a difference of 4.1% (95% CI = 1.4-6.7%). CONCLUSIONS: Scotland's National Naloxone Programme, which started in 2011, was associated with a 36% reduction in the proportion of opioid-related deaths that occurred in the 4 weeks following release from prison. PMID- 26642427 TI - Rebuttal from Ulrik Wisloff, Jeff Coombes and Oivind Rognmo. PMID- 26642428 TI - Use of Lanthanide-Containing Polyoxometalates to Sensitise the Emission of Fluorescent Labelled Serum Albumin. AB - Monitoring the interaction of biomolecules is important, and the use of energy transfer is a principal technique in elucidating nanoscale interactions. Lanthanide compounds are promising luminescent probes for biological samples as their emission is longer-lived than any native autofluorescence. Polyoxometalates (POMs) are interesting structural motifs to incorporate lanthanides, offering low toxicity and a size pertinent for biological applications. Here, we employ iso structured POMs containing either terbium or europium and assess their interaction with serum albumin by sensitisation of a fluorescent tag on the protein via LRET (luminescence resonance energy transfer) by exciting the lanthanide. Time-resolved measurements showed energy transfer with an efficiency of over 90% for the POM-protein systems. The Tb-POM results were relatively straightforward, while those with the iso-structured Eu-POM were complicated by the effect of protein shielding from the aqueous environment. PMID- 26642429 TI - Phase-Contrast Micro-Computed Tomography Measurements of the Intraocular Pressure Induced Deformation of the Porcine Lamina Cribrosa. AB - The lamina cribrosa (LC) is a complex mesh-like tissue in the posterior eye. Its biomechanical environment is thought to play a major role in glaucoma, the second most common cause of blindness. Due to its small size and relative inaccessibility, high-resolution measurements of LC deformation, important in characterizing LC biomechanics, are challenging. Here we present a novel noninvasive imaging method, which enables measurement of the three-dimensional deformation of the LC caused by acute elevation of intraocular pressure (IOP). Posterior segments of porcine eyes were imaged using synchrotron radiation phase contrast micro-computed tomography (PC MUCT) at IOPs between 6 and 37 mmHg. The complex trabecular architecture of the LC was reconstructed with an isotropic spatial resolution of 3.2 MUm. Scans acquired at different IOPs were analyzed with digital volume correlation (DVC) to compute full-field deformation within the LC. IOP elevation caused substantial tensile, shearing and compressive devformation within the LC, with maximum tensile strains at 30 mmHg averaging 5.5%, and compressive strains reaching 20%. We conclude that PC MUCT provides a novel high-resolution method for imaging the LC, and when combined with DVC, allows for full-field 3D measurement of ex vivo LC biomechanics at high spatial resolution. PMID- 26642430 TI - Examining predictors of healthcare utilization in youth with inflammatory bowel disease. AB - BACKGROUND AND AIMS: Traditional definitions of healthcare utilization (HCU) emphasize clinical visits and procedures. Clinic calls, an understudied form of HCU, occur with high frequency. Understanding and examining predictors of HCU, such as disease activity and parent distress, may help reduce overutilization. METHODS: A total of 68 adolescents with inflammatory bowel disease [IBD; mean (SD) =14.18 (1.92) years] and their parents participated. Parent distress was assessed through parent report on the PedsQL Family Impact Module, and physicians provided ratings of patient disease activity using the Physician's Global Assessment index. Medical record reviews yielded HCU and clinic call information for 12 months after enrollment. HCU was operationalized as the total number of routine and sick gastrointestinal clinic visits, Emergency room visits, and IBD related hospitalizations. A call composite reflected the total number of calls related to IBD symptoms/illness. RESULTS: Disease activity and parent distress predicted 12% of the variance in calls and 12% of the variance in HCU. Disease activity was the only significant predictor of clinic calls after accounting for the impact of other predictors; however, parent distress was the only individual variable that contributed significant variance to the prediction of HCU after accounting for other predictors. CONCLUSION: Greater parent distress and disease activity together predicted HCU and clinic calls. Disease activity was the most salient predictor of calls, whereas parent distress was the most salient predictor of in-person HCU. Clinic calls should not be overlooked as a form of HCU, as communication that takes place outside of scheduled appointments utilizes resources and may indicate poorer disease control. PMID- 26642432 TI - Adseverin mediates RANKL-induced osteoclastogenesis by regulating NFATc1. AB - Adseverin is a Ca2+-dependent actin filament-severing protein that has been reported to regulate exocytosis via rearrangements of the actin cytoskeleton in secretory cells. However, the role of adseverin in bone cells has not yet been well characterized. Here, we investigated the role of adseverin in osteoclastogenesis using primary osteoclast precursor cells. Adseverin expression was upregulated during RANKL (receptor activator of nuclear factor-kappaB ligand) induced osteoclast differentiation. Moreover, genetic silencing of adseverin decreased the number of osteoclasts generated by RANKL. Adseverin knockdown also suppressed the RANKL-mediated induction of nuclear factor of activated T-cell c1 (NFATc1), which is a key transcription factor in osteoclastogenesis. In addition, adseverin knockdown impaired bone resorption and the secretion of bone-degrading enzymes from osteoclasts. These effects were accompanied by decreased NFATc1 expression and the activation of nuclear factor-kappaB. Collectively, our results indicate that adseverin has a crucial role in osteoclastogenesis by regulating NFATc1. PMID- 26642431 TI - Crosstalk between FLS and chondrocytes is regulated by HIF-2alpha-mediated cytokines in arthritis. AB - Rheumatoid arthritis (RA) and osteoarthritis (OA), two common types of arthritis, affect the joints mainly by targeting the synovium and cartilage. Increasing evidence indicates that a significant network connects synovitis and cartilage destruction during the progression of arthritis. We recently demonstrated that hypoxia-inducible factor (HIF)-2alpha causes RA and OA by regulating the expression of catabolic factors in fibroblast-like synoviocytes (FLS) or chondrocytes. To address the reciprocal influences of HIF-2alpha on FLS and chondrocytes, we applied an in vitro co-culture system using a transwell apparatus. When co-cultured with HIF-2alpha-overexpressing chondrocytes, FLS exhibited increased expression of matrix metalloproteinases and inflammatory mediators, similar to the effects induced by tumor-necrosis factor (TNF)-alpha treatment of FLS. Moreover, chondrocytes co-cultured with HIF-2alpha overexpressing FLS exhibited upregulation of Mmp3 and Mmp13, which is similar to the effects induced by interleukin (IL)-6 treatment of chondrocytes. We confirmed these differential HIF-2alpha-induced effects via distinct secretory mediators using Il6-knockout cells and a TNF-alpha-blocking antibody. The FLS-co-culture induced gene expression changes in chondrocytes were significantly abrogated by IL-6 deficiency, whereas TNF-alpha neutralization blocked the alterations in gene expression associated with co-culture of FLS with chondrocytes. Our results further suggested that the observed changes might reflect the HIF-2alpha-induced upregulation of specific receptors for TNF-alpha (in FLS) and IL-6 (in chondrocytes). This study broadens our understanding of the possible regulatory mechanisms underlying the crosstalk between the synovium and cartilage in the presence of HIF-2alpha, and may suggest potential new anti-arthritis therapies. PMID- 26642433 TI - Conformational analysis of champedak galactose-binding lectin under different urea concentrations. AB - Conformational analysis of champedak galactose-binding (CGB) lectin under different urea concentrations was studied in phosphate-buffered saline (pH 7.2) using far-ultraviolet circular dichroism (far-UV CD), tryptophan (Trp) fluorescence and ANS fluorescence. In all cases, CGB lectin displayed a two-step, three-state transition. The first transition (from the native state to the intermediate state) started at ~2.0 M urea and ended at ~4.5 M urea, while the second transition (from the intermediate state to the completely denatured state) was characterized by the start- and end-points at ~5.75 M and ~7.5 M urea, respectively, when analyzed by the emission maximum of Trp fluorescence. A marked increase in the Trp fluorescence, ANS fluorescence and -CD values at 218 nm ( CD218 nm) represented the first transition, whereas a decrease in these parameters defined the second transition. On the other hand, emission maximum of the Trp fluorescence showed a continuous increase throughout the urea concentration range. Transformation of tetramer into monomer represented the first transition, whereas the second transition reflected the unfolding of monomer. Far-UV CD, Trp fluorescence and ANS fluorescence spectra were used to characterize the native, the intermediate and the completely denatured states of CGB lectin, obtained at 0.0 M, 5.0 M and 9.0 M urea, respectively. The intermediate state was characterized by the presence of higher secondary structures, increased ANS binding as well as increased Trp fluorescence intensity. A gradual decrease in the hemagglutination activity of CGB lectin was observed with increasing urea concentrations, showing complete loss at 4.0 M urea. PMID- 26642434 TI - 20-Hydroxyecdysone protects wheat seedlings (Triticum aestivum L.) against lead stress. AB - 20-Hydroxyecdysone (20E) is the most abundant phytoecdysteroid (PE) produced by plants, where it represents a protective molecule against insect attack. The aim of the present study was to assess the effects of 20E on the growth, metabolic enzymes and antioxidant systems of wheat seedlings under lead stress induced by Pb(NO3)2 (3 mM). Pre-treatment concentrations (0, 1, 3 and 5 MUM) of 20E were applied for two days, then wheat seedlings were transferred for 5 days to a treatment solution containing lead nitrate. When plants were grown without pre treatment, germination and growth were impaired, while signs of oxidative stress were observed. 20E pre-treatment (3 or 5 MUM) was able to efficiently protect seedlings from Pb toxicity by reducing Pb uptake and Pb-induced oxidative stress, as well by enhancing Pb excretion. Thus, 20E pre-treatment maintains normal germination, elongation, biomass, and metabolism in spite of the presence of Pb. Our results show that 20E protects oxidative balance and enhances the anti oxidative systems, and more specifically the ascorbate-glutathione system. To our knowledge, this study shows for the first time that 20E treatment induces metabolic changes that allow the plants to resist heavy metal stress. PMID- 26642435 TI - Pairwise comparison of 18F-FDG and 18F-FCH PET/CT in prostate cancer patients with rising PSA and known or suspected second malignancy. AB - OBJECTIVE: This study aimed to evaluate the usefulness of combining fluorine-18 choline (F-FCH) and fluorine-18 fluorodeoxyglucose (F-FDG) PET/computed tomography (CT) in patients with rising prostate-specific antigen and known or suspected second malignancy. MATERIALS AND METHODS: F-FCH and F-FDG PET/CT were performed 15+/-9 days apart on the same PET/CT system and acquisition and reconstruction parameters. A mean standardized uptake value (SUVmean) was computed for every lesion that could be discriminated with both tracers. PET results were confirmed by histology (eight patients) and clinical and imaging follow-up (mean+/-SD: 15+/-9 months). RESULTS: Of 77 consecutive patients who underwent F-FCH PET/CT scans for suspected prostate cancer recurrence, 10 (13%) were suspected to have a second malignancy because of F-FCH PET pattern inconsistency with that of prostate cancer (n=6), because of a history of a second malignancy with similar metastatic patterns (n=2) or inconsistency between disease burden and prostate-specific antigen value (n=2). Seventy lesions were studied, with a final diagnosis of prostate cancer, other cancers and benign disease in 55, nine and six lesions, respectively. F-FCH SUVmean and F-FCH/F-FDG SUVmean ratios were significantly different between prostate cancer, nonprostate cancer and benign disease (P<0.0001 and P=0.04, respectively). Receiving operating characteristic analysis showed that the F-FCH/F-FDG ratios were not better than F-FCH SUVmean in discriminating prostate cancer from nonprostate cancer and benign diseases (sensitivity, specificity and area under the curve were 69%, 80%, 0.71 and 84%, 80% and 0.89, respectively). CONCLUSION: We found that F-FCH/F-FDG SUVmean ratios cannot differentiate prostate cancer recurrences from other cancer types when both diagnoses are suspected. Doubtful lesions should be biopsied. PMID- 26642436 TI - Kicking against the PRCs - A Domesticated Transposase Antagonises Silencing Mediated by Polycomb Group Proteins and Is an Accessory Component of Polycomb Repressive Complex 2. AB - The Polycomb group (PcG) and trithorax group (trxG) genes play crucial roles in development by regulating expression of homeotic and other genes controlling cell fate. Both groups catalyse modifications of chromatin, particularly histone methylation, leading to epigenetic changes that affect gene activity. The trxG antagonizes the function of PcG genes by activating PcG target genes, and consequently trxG mutants suppress PcG mutant phenotypes. We previously identified the ANTAGONIST OF LIKE HETEROCHROMATIN PROTEIN1 (ALP1) gene as a genetic suppressor of mutants in the Arabidopsis PcG gene LIKE HETEROCHROMATIN PROTEIN1 (LHP1). Here, we show that ALP1 interacts genetically with several other PcG and trxG components and that it antagonizes PcG silencing. Transcriptional profiling reveals that when PcG activity is compromised numerous target genes are hyper-activated in seedlings and that in most cases this requires ALP1. Furthermore, when PcG activity is present ALP1 is needed for full activation of several floral homeotic genes that are repressed by the PcG. Strikingly, ALP1 does not encode a known chromatin protein but rather a protein related to PIF/Harbinger class transposases. Phylogenetic analysis indicates that ALP1 is broadly conserved in land plants and likely lost transposase activity and acquired a novel function during angiosperm evolution. Consistent with this, immunoprecipitation and mass spectrometry (IP-MS) show that ALP1 associates, in vivo, with core components of POLYCOMB REPRESSIVE COMPLEX 2 (PRC2), a widely conserved PcG protein complex which functions as a H3K27me3 histone methyltransferase. Furthermore, in reciprocal pulldowns using the histone methyltransferase CURLY LEAF (CLF), we identify not only ALP1 and the core PRC2 components but also plant-specific accessory components including EMBRYONIC FLOWER 1 (EMF1), a transcriptional repressor previously associated with PRC1-like complexes. Taken together our data suggest that ALP1 inhibits PcG silencing by blocking the interaction of the core PRC2 with accessory components that promote its HMTase activity or its role in inhibiting transcription. ALP1 is the first example of a domesticated transposase acquiring a novel function as a PcG component. The antagonistic interaction of a modified transposase with the PcG machinery is novel and may have arisen as a means for the cognate transposon to evade host surveillance or for the host to exploit features of the transposition machinery beneficial for epigenetic regulation of gene activity. PMID- 26642437 TI - TCF1 links GIPR signaling to the control of beta cell function and survival. AB - The glucagon-like peptide-1 (GLP-1) receptor and the glucose-dependent insulinotropic polypeptide (GIP) receptor transduce nutrient-stimulated signals to control beta cell function. Although the GLP-1 receptor (GLP-1R) is a validated drug target for diabetes, the importance of the GIP receptor (GIPR) for the function of beta cells remains uncertain. We demonstrate that mice with selective ablation of GIPR in beta cells (MIP-Cre:Gipr(Flox/Flox); Gipr(-/ betaCell)) exhibit lower levels of meal-stimulated insulin secretion, decreased expansion of adipose tissue mass and preservation of insulin sensitivity when compared to MIP-Cre controls. Beta cells from Gipr(-/-betaCell) mice display greater sensitivity to apoptosis and markedly lower islet expression of T cell specific transcription factor-1 (TCF1, encoded by Tcf7), a protein not previously characterized in beta cells. GIP, but not GLP-1, promotes beta cell Tcf7 expression via a cyclic adenosine monophosphate (cAMP)-independent and extracellular signal-regulated kinase (ERK)-dependent pathway. Tcf7 (in mice) or TCF7 (in humans) levels are lower in islets taken from diabetic mice and in humans with type 2 diabetes; knockdown of TCF7 in human and mouse islets impairs the cytoprotective responsiveness to GIP and enhances the magnitude of apoptotic injury, whereas restoring TCF1 levels in beta cells from Gipr(-/-betaCell) mice lowers the number of apoptotic cells compared to that seen in MIP-Cre controls. Tcf7(-/-) mice show impaired insulin secretion, deterioration of glucose tolerance with either aging and/or high-fat feeding and increased sensitivity to beta cell injury relative to wild-type (WT) controls. Hence the GIPR-TCF1 axis represents a potential therapeutic target for preserving both the function and survival of vulnerable, diabetic beta cells. PMID- 26642439 TI - The effect of beta blocker withdrawal on myocardial SPECT modeled from adenosine 13N-ammonia PET. AB - AIM: The effect of beta blockers (BB) on myocardial imaging has been studied in several SPECT and PET studies with divergent results concerning perfusion and impact on diagnostic accuracy. The present study evaluated the effect of BB withdrawal on virtual SPECT studies modeled from quantitative PET perfusion scans. PATIENTS, METHODS: Data from 20 CAD patients scheduled for adenosine 13N ammonia imaging with and without BB were considered. Modeling the uptake characteristics of 99mTc-MIBI, all parametric stress PET polarmaps were transferred to virtual 20-segment SPECT polarmaps. The SPECT studies were categorized with a 5-point score and read to assess the effect of the BB withdrawal on scan result and interpretation. RESULTS: The SPECT analysis revealed a mean score of 6.0 +/- 4.7 with, and of 5.9 +/- 4.5 without BB (p = 0.84). In 260 (74.9%) segments the scores were equal in both conditions. Without BB a downstaging was recorded in 44 segments (12.7%), an upstaging in 43 segments (12.4%). An essentially different interpretation (shift from medical therapy recommendation to angiography) was recorded in one patient. In six cases the interpretation differed mildly. CONCLUSION: In the majority of patients studied, scan results and interpretation remain unchanged after discontinuation of the BB. Nevertheless, the segmental scan results are not uniformly affected. The recommendation to stop BBs prior to stress testing in order to ensure the highest MBF remains advisable. If temporary BB withdrawal is unfeasible due to contraindications, a tight clinical schedule, or because a patient forgot to withhold the BB, it is appropriate to perform adenosine stress testing according to the results of this study. PMID- 26642440 TI - Highly porous oil sorbent based on hollow fibers as the interceptor for oil on static and running water. AB - Highly porous fibrous assembly made by kapok and hollow PET fibers was prepared by the air-laying-bonding method, and used as the interceptor for oils on static and running water. SEM showed that the vast majority of kapok and PET fibers in the assembly was intact and retained their hollow lumens, with the assembly's porosity high to 98.03%. Oil sorption tests exhibited that kapok/PET assembly could absorb 63.00g/g of vegetable oil and 58.50g/g of used motor oil, with high oil retention after 24h dripping. In static condition of oil interception, the two oils started to leak at around 20min for 10-mm thick kapok/PET wall. The time for that was prolonged with increasing the thickness of kapok/PET wall. After oil breakthrough, continuous oil leaking took place. The typical leakage was divided into three stages in which oils leaked separately in sharply increased rate, reduced rate and finally gently. In running condition, oils leaked in markedly quicker way than that in static condition, with initial leakage of oils shortened to less 6min when the water ran at 60.35ml/s. The leakage of oils was considerably accelerated with increasing running rates. PMID- 26642441 TI - Adsorption of quinolone antibiotics in spherical mesoporous silica: Effects of the retained template and its alkyl chain length. AB - In this study, mesoporous silica (meso-silica) MCM-41 and those with the templates retained were synthesized and characterized. Adsorption capacities of the synthesized materials towards typical quinolone antibiotic pollutants, enrofloxacin and norfloxacin as representative, were investigated, and effects of the alkyl chain length of the templates on the adsorption capacity were evaluated. The results of this study indicated that the retained templates enhanced the adsorption capacities (Qmax) of the meso-silica MCM-41 toward hydrophobic enrofloxacin, but had an inhibitory effect on that towards hydrophilic norfloxacin, which were attributed to the hydrophobic inter environment created by the long alkyl chains of the retained templates. Importantly, the adsorption capacity increased with the increase of the alkyl chain length of the retained templates. PMID- 26642438 TI - PPAR-delta is repressed in Huntington's disease, is required for normal neuronal function and can be targeted therapeutically. AB - Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the huntingtin (HTT) gene, which encodes a polyglutamine tract in the HTT protein. We found that peroxisome proliferator activated receptor delta (PPAR-delta) interacts with HTT and that mutant HTT represses PPAR-delta-mediated transactivation. Increased PPAR-delta transactivation ameliorated mitochondrial dysfunction and improved cell survival of neurons from mouse models of HD. Expression of dominant-negative PPAR-delta in the central nervous system of mice was sufficient to induce motor dysfunction, neurodegeneration, mitochondrial abnormalities and transcriptional alterations that recapitulated HD-like phenotypes. Expression of dominant-negative PPAR-delta specifically in the striatum of medium spiny neurons in mice yielded HD-like motor phenotypes, accompanied by striatal neuron loss. In mouse models of HD, pharmacologic activation of PPAR-delta using the agonist KD3010 improved motor function, reduced neurodegeneration and increased survival. PPAR-delta activation also reduced HTT-induced neurotoxicity in vitro and in medium spiny-like neurons generated from stem cells derived from individuals with HD, indicating that PPAR delta activation may be beneficial in HD and related disorders. PMID- 26642442 TI - Highly efficient degradation of 4-nitrophenol over the catalyst of Mn2O3/AC by microwave catalytic oxidation degradation method. AB - A new microwave catalytic oxidation process based on two kinds of catalysts, the commercially available activated carbon (AC) and Mn2O3 nanoparticle modified AC (Mn2O3/AC), was reported for the degradation of 4-nitrophenol (4-NP) without adding any oxidant. Effects of microwave power, catalyst dosage, irradiation time, and initial concentration for the degradation efficiency were studied. Results indicated that catalyst of Mn2O3/AC showed much higher catalytic activity than pure AC and Mn2O3 particles. Significantly, 4-NP degradation efficiency reached 99.6%, corresponding to 93.5% TOC removal under optimal conditions with microwave power of 400W, Mn2O3/AC dosage of 2g, reaction time of 5min, and initial concentration of 100mg/L. Hydroxyl radicals (OH) generated during catalytic reaction is the main oxidant, and O2 can not effectively improve removal rate. We proposed the microwave 'photoelectric effect' to interpret the generation of OH in view that microwave irradiation can directly excite the catalyst to produce electron-hole pairs and then transform H2O into OH on the surface of catalyst in solution. The obtained kinetic equation for microwave catalytic oxidation degradation of 4-NP was in line with pseudo-first-order kinetic model, that is, apparent rate constant increased as microwave power density increase. PMID- 26642443 TI - Solubility constraints affecting the migration of selenium through the cementitious backfill of a geological disposal facility. AB - This work presents the study of the solubility of selenium under cementitious conditions and its diffusion, as SeO3(2-), through monolithic cement samples. The solubility studies were carried out under alkaline conditions similar to those anticipated in the near-field of a cement-based repository for low- and intermediate-level radioactive waste. Experiments were conducted in NaOH solution, 95%-saturated Ca(OH)2, water equilibrated with a potential backfill material (Nirex reference vault backfill, NRVB) and in solutions containing cellulose degradation products, with and without reducing agents. The highest selenium concentrations were found in NaOH solution. In the calcium-containing solutions, analysis of the precipitates suggests that the solubility controlling phase is Ca2SeO3(OH)2.2H2O, which appears as euhedral rhombic crystals. The presence of cellulose degradation products caused an increase in selenium concentration, possibly due to competitive complexation, thereby, limiting the amount of calcium available for precipitation. Iron coupons had a minor effect on selenium solubility in contrast to Na2S2O4, suggesting that effective reduction of Se(IV) occurs only at Eh values below -300mV. Radial through-diffusion experiments on NRVB and in a fly ash cement showed no evidence of selenium breakthrough after one year. However, autoradiography of the exposed surfaces indicated that some migration had occurred and that selenium was more mobile in the higher porosity backfill than in the fly ash cement. PMID- 26642444 TI - Evaluation of in vivo graphene oxide toxicity for Acheta domesticus in relation to nanomaterial purity and time passed from the exposure. AB - Graphene and its oxidized form-graphene oxide (GO) have become exceptionally popular in industry and medicine due to their unique properties. However, there are suspicions that GO can cause adverse effects. Therefore, comprehensive knowledge on its potential toxicity is essential. This research assesses the in vivo toxicity of pure and manganese ion contaminated GO, which were injected into the hemolymph of Acheta domesticus. The activity of catalase (CAT) and gluthiathione peroxidases (GSTPx) as well as heat shock protein (HSP 70) and total antioxidant capacity (TAC) levels were measured at consecutive time points 1h, 24h, 48h and 72h after injection. Neither pure GO nor GO contaminated with manganese were neutral to the organism. The results proved the intensification of oxidative stress after GO injection, which was confirmed by increased enzyme activity. The organism seems to cope with this stress, especially in the first 24h after injection. In the following days, increasing HSP 70 levels were observed, which might suggest the synthesis of new proteins and the removal of old and damaged ones. With that in mind, the potential toxicity of the studied material, which could lead to serious and permanent damage to the organism, should still be taken into consideration. PMID- 26642445 TI - Electrochemically induced oxidative removal of As(III) from groundwater in a dual anode sand column. AB - In situ treatment of high-arsenic groundwater cost-effectively is still challenging. We proposed an in situ treatment approach which utilizes O2 produced from groundwater electrolysis to increase the redox potential for oxidative removal of arsenic. A sand column was configured to simulate groundwater flow in an aquifer, and a stable anode, a stable cathode and an iron anode were arrayed in an upward mode in the column to evaluate the performance on arsenic removal from the groundwater induced by the oxidative precipitation of Fe(2+) by O2. As(III) at 500MUg/L was efficiently oxidized to As(V) by the stable anode followed by the reactive oxidants produced from Fe(II)-O2, and total As were completely removed by the newly formed amorphous iron hydroxides. Quantitative models for the dependence of As(III) oxidation, total As removal and Fe(II) oxidative precipitation on the flow rate and the current density applied to Fe anode were developed. The presence of humic substance promoted the oxidation of As(III) on the stable anode but inhibited the oxidation and removal induced by Fe(II) oxidative precipitation. A stable performance on As(III) oxidation and removal was observed in a 10-day continuous operation. Results from this study prove that groundwater electrolysis could be applicable for oxidative removal of As(III) in porous media, with a controllable and lasting treatment efficiency. PMID- 26642446 TI - Lead recovery and glass microspheres synthesis from waste CRT funnel glasses through carbon thermal reduction enhanced acid leaching process. AB - In this study, a novel process for detoxification and reutilization of waste cathode ray tube (CRT) funnel glass was developed by carbon thermal reduction enhanced acid leaching process. The key to this process is removal of lead from the CRT funnel glass and synchronous preparation of glass microspheres. Carbon powder was used as an isolation agent and a reducing agent. Under the isolation of the carbon powder, the funnel glass powder was sintered into glass microspheres. In thermal reduction, PbO in the funnel glass was first reduced to elemental Pb by carbon monoxide and then located on the surface of glass microspheres which can be removed easily by acid leaching. Experimental results showed that temperature, carbon adding amount and holding time were the major parameters that controlled lead removal rate. The maximum lead removal rate was 94.80% and glass microspheres that measured 0.73-14.74MUm were obtained successfully by setting the temperature, carbon adding amount and holding time at 1200 degrees C, 10% and 30min, respectively. The prepared glass microspheres may be used as fillers in polymer materials and abrasive materials, among others. Accordingly, this study proposed a practical and economical process for detoxification and recycling of waste lead-containing glass. PMID- 26642447 TI - Impact of activator type on the immobilisation of lead in fly ash-based geopolymer. AB - Immobilisation of heavy metals in geopolymers has attracted attention as a potential means of treating toxic wastes. Lead is known to be effectively immobilised in a geopolymer matrix, but detailed explanation for the mechanisms involved and the specific chemical form of lead are not fully understood. To reveal the effect of the activator types on the immobilisation of lead in geopolymers, 0.5 and 1.0wt% lead in the form of lead nitrate was mixed with fly ash and alkaline activators. Different alkaline activators (either combined sodium hydroxide and sodium silicate or sodium aluminate) were used to achieve the target Si:Al ratios 2.0 and 5.0 in geopolymers. Zeolite was formed in aluminate-activated geopolymers having a Si:Al ratio of 2.0, but the zeolite crystallization was suppressed as lead content increased. No specific crystalline phase of lead was detected by X-ray diffraction, electron diffraction or FT-IR spectrometry. In fact, double Cs corrected TEM analysis revealed that lead was evenly distributed with no evidence of formation of a specific lead compound. A sequential extraction procedure for fractionation of lead showed that lead did not exist as an exchangeable ion in geopolymers, regardless of activator type used. Aluminate activation is shown to be superior in the immobilisation of lead because about 99% of extracted lead existed in the oxidizing and residual fractions. PMID- 26642448 TI - Wide-area decontamination in an urban environment after radiological dispersion: A review and perspectives. AB - Nuclear or radiological terrorism in the form of uncontrolled radioactive contamination presents a unique challenge in the field of nuclear decontamination. Potential targets require an immediate decontamination response, or mitigation plan to limit the social and economic impact. To date, experience with urban decontamination of building materials - specifically hard, porous, external surfaces - is limited to nuclear weapon fallout and nuclear reactor accidents. Methods are lacking for performing wide-area decontamination in an urban environment so that in all release scenarios the area may be re-occupied without evaluation and/or restriction. Also lacking is experience in developing mitigation strategies, that is, methods of mitigating contamination and its resultant radiation dose in key areas during the immediate aftermath of an event and after lifesaving operations. To date, the tremendous strategy development effort primarily by the European community has focused on the recovery phase, which extends years beyond the release event. In this review, we summarize the methods and data collected over the past 70 years in the field of hard, external surface decontamination of radionuclide contaminations, with emphasis on methods suitable for response to radiological dispersal devices and their potentially unique physico-chemical characteristics. This review concludes that although a tremendous amount of work has been completed primarily by the European Community (EU) and the United Kingdom (UK), the few studies existing on each technique permit only very preliminary estimates of decontamination factors for various building materials and methods and extrapolation of those values for use in environments outside the EU and UK. This data shortage prevents us from developing an effective and detailed mitigation response plan and remediation effort. Perhaps most importantly, while the data available does include valuable information on the practical aspects of performing the various remediation methods including costs, coverage rates, manpower, pitfalls, etc., it lacks the details on lessons learned, best practices, and standard procedures, for instance, that would be required to develop a mitigation strategy. While the urban decontamination problem is difficult and there is much more research to do, the existing literature provides a framework for a response plan. Using this framework, in conjunction with computer modeling and relevant data collection, can lead to development of appropriate plans and exercises that would permit development of a mitigation and remediation response. PMID- 26642450 TI - Electrostatic Generation of Bulk Acoustic Waves and Electrical Parameters of Si MEMS Resonators. AB - This paper proposes an analytical approach to model the generation of bulk acoustic waves in an electrostatically excited silicon MEMS structure, as well as its electromechanical response in terms of static and dynamic displacements, electromechanical coupling, and motional current. The analysis pertains to the single-port electrostatic drive of trapped-energy thickness-extensional (TE) modes in thin plates. Both asymmetric single-side and symmetric double-side electrostatic gap configurations are modeled. Green's function is used to describe the characteristic of the static displacement of the driven surface of the structure versus the dc bias voltage, which allows us to determine the electrical response of the resonator. Optical and electrical characterizations have been performed on resonator samples operating at 10.3 MHz on the fundamental of TE mode under single-side electrostatic excitation. The various figures of merit depend on the dc bias voltage. Typical values of 9000 for the Q-factor, and of 10(-5) for the electromechanical coupling factor k(2) have been obtained with [Formula: see text] for [Formula: see text]-thick gaps. Here-considered modes have a typical temperature coefficients of frequency (TCF) close to -30 ppm/( degrees )C. We conclude that the practical usability of such electrostatically excited bulk acoustic waves (BAW) resonators essentially depends on the efficiency of the compensation of feed-through capacitance. PMID- 26642449 TI - Thermal decomposition of nano-enabled thermoplastics: Possible environmental health and safety implications. AB - Nano-enabled products (NEPs) are currently part of our life prompting for detailed investigation of potential nano-release across their life-cycle. Particularly interesting is their end-of-life thermal decomposition scenario. Here, we examine the thermal decomposition of widely used NEPs, namely thermoplastic nanocomposites, and assess the properties of the byproducts (released aerosol and residual ash) and possible environmental health and safety implications. We focus on establishing a fundamental understanding on the effect of thermal decomposition parameters, such as polymer matrix, nanofiller properties, decomposition temperature, on the properties of byproducts using a recently-developed lab-based experimental integrated platform. Our results indicate that thermoplastic polymer matrix strongly influences size and morphology of released aerosol, while there was minimal but detectable nano release, especially when inorganic nanofillers were used. The chemical composition of the released aerosol was found not to be strongly influenced by the presence of nanofiller at least for the low, industry-relevant loadings assessed here. Furthermore, the morphology and composition of residual ash was found to be strongly influenced by the presence of nanofiller. The findings presented here on thermal decomposition/incineration of NEPs raise important questions and concerns regarding the potential fate and transport of released engineered nanomaterials in environmental media and potential environmental health and safety implications. PMID- 26642451 TI - Detection of Contrast Agents: Plane Wave Versus Focused Transmission. AB - Ultrasound contrast agent (UCA) imaging provides a cost-effective diagnostic tool to assess tissue perfusion and vascular pathologies. However, excessive transmission (TX) levels may negatively impact both uniform diffusion and survival rates of contrast agents, limiting their density and thus their echogenicity. Contrast detection methods with both high sensitivity and low contrast destruction rate are thus essential to maintain diagnostic capabilities. Plane-wave TX with a high number of compounding angles has been suggested to produce good quality images at pressure levels that do not destroy UCA. In this paper, we performed a quantitative evaluation of detection efficacy of flowing UCA with either traditional focused scanning or ultrafast plane-wave imaging. Amplitude modulation (AM) at nondestructive pressure levels was implemented in the ULA-OP ultrasound research platform. The influence of the number of compounding angles, peak-negative pressure, and flow speed on the final image quality was investigated. Results show that the images obtained by compounding multiple angled plane waves offer a greater contrast (up to a 12-dB increase) with respect to focused AM. This increase is attributed mainly to noise reduction caused by the coherent summation in the compounding step. Additionally, we show that highly sensitive detection is already achieved with a limited compounding number ( ), thus suggesting the feasibility of continuous contrast monitoring at a high frame rate. This capability is essential to properly detect contrast agents flowing at high speed, as an excessive angle compounding is shown to be destructive for the contrast signal, as the UCA motion quickly causes loss of correlation between consecutive echoes. PMID- 26642452 TI - Implications for the future of the HIV epidemic if drug resistance against dolutegravir cannot occur in first-line therapy. PMID- 26642453 TI - TVR-DART: A More Robust Algorithm for Discrete Tomography From Limited Projection Data With Automated Gray Value Estimation. AB - In this paper, we present a novel iterative reconstruction algorithm for discrete tomography (DT) named total variation regularized discrete algebraic reconstruction technique (TVR-DART) with automated gray value estimation. This algorithm is more robust and automated than the original DART algorithm, and is aimed at imaging of objects consisting of only a few different material compositions, each corresponding to a different gray value in the reconstruction. By exploiting two types of prior knowledge of the scanned object simultaneously, TVR-DART solves the discrete reconstruction problem within an optimization framework inspired by compressive sensing to steer the current reconstruction toward a solution with the specified number of discrete gray values. The gray values and the thresholds are estimated as the reconstruction improves through iterations. Extensive experiments from simulated data, experimental MUCT, and electron tomography data sets show that TVR-DART is capable of providing more accurate reconstruction than existing algorithms under noisy conditions from a small number of projection images and/or from a small angular range. Furthermore, the new algorithm requires less effort on parameter tuning compared with the original DART algorithm. With TVR-DART, we aim to provide the tomography society with an easy-to-use and robust algorithm for DT. PMID- 26642454 TI - Analysis of Crosstalk in 3D Circularly Polarized LCDs Depending on the Vertical Viewing Location. AB - Crosstalk in circularly polarized (CP) liquid crystal display (LCD) with polarized glasses (passive 3D glasses) is mainly caused by two factors: 1) the polarizing system including wave retarders and 2) the vertical misalignment (VM) of light between the LC module and the patterned retarder. We show that the latter, which is highly dependent on the vertical viewing location, is a much more significant factor of crosstalk in CP LCD than the former. There are three contributions in this paper. Initially, a display model for CP LCD, which accurately characterizes VM, is proposed. A novel display calibration method for the VM characterization that only requires pictures of the screen taken at four viewing locations. In addition, we prove that the VM-based crosstalk cannot be efficiently reduced by either preprocessing the input images or optimizing the polarizing system. Furthermore, we derive the analytic solution for the viewing zone, where the entire screen does not have the VM-based crosstalk. PMID- 26642455 TI - On Counting Metamers. AB - Objects reflecting lights, which invoke the identical responses of the photoreceptors, are called metameric. Metameric objects match each other in color. Assuming all the reflecting objects equiprobable, the probability density distribution on the set of all the classes of mutually metameric objects is evaluated. Metamerism depends on illumination. Objects metameric under one illumination might produce different photoreceptor responses (i.e., mismatch each other) under the other illumination. In particular, objects mapping to a single point in the photoreceptor response space under one illumination map to a volume (referred to as the metamer mismatch volume) in the photoreceptor response space under the second illumination. The probability density distribution in the metamer mismatch volume is also evaluated. Its center is expressed as a function of the photoreceptor spectral sensitivities and the spectral power distributions of the illuminants. Potential application of the obtained results to color management is discussed. PMID- 26642456 TI - Removal of Vesicle Structures From Transmission Electron Microscope Images. AB - In this paper, we address the problem of imaging membrane proteins for single particle cryo-electron microscopy reconstruction of the isolated protein structure. More precisely, we propose a method for learning and removing the interfering vesicle signals from the micrograph, prior to reconstruction. In our approach, we estimate the subspace of the vesicle structures and project the micrographs onto the orthogonal complement of this subspace. We construct a 2D statistical model of the vesicle structure, based on higher order singular value decomposition (HOSVD), by considering the structural symmetries of the vesicles in the polar coordinate plane. We then propose to lift the HOSVD model to a novel hierarchical model by summarizing the multidimensional HOSVD coefficients by their principal components. Along with the model, a solid vesicle normalization scheme and model selection criterion are proposed to make a compact and general model. The results show that the vesicle structures are accurately separated from the background by the HOSVD model that is also able to adapt to the asymmetries of the vesicles. This is a promising result and suggests even wider applicability of the proposed approach in learning and removal of statistical structures. PMID- 26642457 TI - Desktop Haptic Interface for Simulation of Hand-Tremor. AB - This paper presents a haptic system that is conceived to support the design process of a class of products or services in order to make them more accessible to people affected by hand tremor diseases. The main aim is to foster the designer empathy allowing her/him to directly feel the effect of the impairment in first person. Specifically, a desktop haptic device is employed to induce a programmable hand-tremor, that is typically observed in people affected by some kind of neurological diseases, on healthy subjects (i.e., the designers). The developed tool is based on a wrist-attached haptic interface with a workspace that is comparable to that of the arm of the user. Such device is able to exert controlled forces on the user's wrist and induces a hand-tremor whose frequency and amplitude are correlated with those measured on impaired people. The control of the device is based on a custom trajectory-tracking algorithm that takes as input tremor signals that are acquired on patients using an optical motion tracking system. In this paper, we present the employed haptic system, the structure of the control system and the experimental validation of the controller done through the acquisition of data on six patients affected by Parkinson's disease. PMID- 26642458 TI - Adaptive Scaling of Cluster Boundaries for Large-Scale Social Media Data Clustering. AB - The large scale and complex nature of social media data raises the need to scale clustering techniques to big data and make them capable of automatically identifying data clusters with few empirical settings. In this paper, we present our investigation and three algorithms based on the fuzzy adaptive resonance theory (Fuzzy ART) that have linear computational complexity, use a single parameter, i.e., the vigilance parameter to identify data clusters, and are robust to modest parameter settings. The contribution of this paper lies in two aspects. First, we theoretically demonstrate how complement coding, commonly known as a normalization method, changes the clustering mechanism of Fuzzy ART, and discover the vigilance region (VR) that essentially determines how a cluster in the Fuzzy ART system recognizes similar patterns in the feature space. The VR gives an intrinsic interpretation of the clustering mechanism and limitations of Fuzzy ART. Second, we introduce the idea of allowing different clusters in the Fuzzy ART system to have different vigilance levels in order to meet the diverse nature of the pattern distribution of social media data. To this end, we propose three vigilance adaptation methods, namely, the activation maximization (AM) rule, the confliction minimization (CM) rule, and the hybrid integration (HI) rule. With an initial vigilance value, the resulting clustering algorithms, namely, the AM-ART, CM-ART, and HI-ART, can automatically adapt the vigilance values of all clusters during the learning epochs in order to produce better cluster boundaries. Experiments on four social media data sets show that AM-ART, CM-ART, and HI-ART are more robust than Fuzzy ART to the initial vigilance value, and they usually achieve better or comparable performance and much faster speed than the state-of-the-art clustering algorithms that also do not require a predefined number of clusters. PMID- 26642459 TI - Information Theoretic Subspace Clustering. AB - This paper addresses the problem of grouping the data points sampled from a union of multiple subspaces in the presence of outliers. Information theoretic objective functions are proposed to combine structured low-rank representations (LRRs) to capture the global structure of data and information theoretic measures to handle outliers. In theoretical part, we point out that group sparsity-induced measures ( l2,1 -norm, lalpha -norm, and correntropy) can be justified from the viewpoint of half-quadratic (HQ) optimization, which facilitates both convergence study and algorithmic development. In particular, a general formulation is accordingly proposed to unify HQ-based group sparsity methods into a common framework. In algorithmic part, we develop information theoretic subspace clustering methods via correntropy. With the help of Parzen window estimation, correntropy is used to handle either outliers under any distributions or sample specific errors in data. Pairwise link constraints are further treated as a prior structure of LRRs. Based on the HQ framework, iterative algorithms are developed to solve the nonconvex information theoretic loss functions. Experimental results on three benchmark databases show that our methods can further improve the robustness of LRR subspace clustering and outperform other state-of-the-art subspace clustering methods. PMID- 26642460 TI - SpikeTemp: An Enhanced Rank-Order-Based Learning Approach for Spiking Neural Networks With Adaptive Structure. AB - This paper presents an enhanced rank-order-based learning algorithm, called SpikeTemp, for spiking neural networks (SNNs) with a dynamically adaptive structure. The trained feed-forward SNN consists of two layers of spiking neurons: 1) an encoding layer which temporally encodes real-valued features into spatio-temporal spike patterns and 2) an output layer of dynamically grown neurons which perform spatio-temporal classification. Both Gaussian receptive fields and square cosine population encoding schemes are employed to encode real valued features into spatio-temporal spike patterns. Unlike the rank-order-based learning approach, SpikeTemp uses the precise times of the incoming spikes for adjusting the synaptic weights such that early spikes result in a large weight change and late spikes lead to a smaller weight change. This removes the need to rank all the incoming spikes and, thus, reduces the computational cost of SpikeTemp. The proposed SpikeTemp algorithm is demonstrated on several benchmark data sets and on an image recognition task. The results show that SpikeTemp can achieve better classification performance and is much faster than the existing rank-order-based learning approach. In addition, the number of output neurons is much smaller when the square cosine encoding scheme is employed. Furthermore, SpikeTemp is benchmarked against a selection of existing machine learning algorithms, and the results demonstrate the ability of SpikeTemp to classify different data sets after just one presentation of the training samples with comparable classification performance. PMID- 26642461 TI - Boundary-to-Marker Evidence-Controlled Segmentation and MDL-Based Contour Inference for Overlapping Nuclei. AB - This paper presents a novel method for automated morphology delineation and analysis of cell nuclei in histopathology images. Combining the initial segmentation information and concavity measurement, the proposed method first segments clusters of nuclei into individual pieces, avoiding segmentation errors introduced by the scale-constrained Laplacian-of-Gaussian filtering. After that a nuclear boundary-to-marker evidence computing is introduced to delineate individual objects after the refined segmentation process. The obtained evidence set is then modeled by the periodic B-splines with the minimum description length principle, which achieves a practical compromise between the complexity of the nuclear structure and its coverage of the fluorescence signal to avoid the underfitting and overfitting results. The algorithm is computationally efficient and has been tested on the synthetic database as well as 45 real histopathology images. By comparing the proposed method with several state-of-the-art methods, experimental results show the superior recognition performance of our method and indicate the potential applications of analyzing the intrinsic features of nuclei morphology. PMID- 26642462 TI - Near-Optimal Tracking Control of Mobile Robots Via Receding-Horizon Dual Heuristic Programming. AB - Trajectory tracking control of wheeled mobile robots (WMRs) has been an important research topic in control theory and robotics. Although various tracking control methods with stability have been developed for WMRs, it is still difficult to design optimal or near-optimal tracking controller under uncertainties and disturbances. In this paper, a near-optimal tracking control method is presented for WMRs based on receding-horizon dual heuristic programming (RHDHP). In the proposed method, a backstepping kinematic controller is designed to generate desired velocity profiles and the receding horizon strategy is used to decompose the infinite-horizon optimal control problem into a series of finite-horizon optimal control problems. In each horizon, a closed-loop tracking control policy is successively updated using a class of approximate dynamic programming algorithms called finite-horizon dual heuristic programming (DHP). The convergence property of the proposed method is analyzed and it is shown that the tracking control system based on RHDHP is asymptotically stable by using the Lyapunov approach. Simulation results on three tracking control problems demonstrate that the proposed method has improved control performance when compared with conventional model predictive control (MPC) and DHP. It is also illustrated that the proposed method has lower computational burden than conventional MPC, which is very beneficial for real-time tracking control. PMID- 26642463 TI - A Variational Bayesian Approach to Robust Identification of Switched ARX Models. AB - A variational Bayesian approach to robust identification of switched auto regressive exogenous models is developed in this paper. By formulating the problem of interest under a full Bayesian identification framework, the number of local-models can be determined automatically, while accounting for the uncertainty of parameter estimates in the overall identification procedure. A set of significance coefficients is used to assign proper importance weights to local models. By maximizing the marginal likelihood of the identification data, insignificant local-models will be suppressed and the optimal number of local models can be determined. Considering the fact that the identification data may be contaminated with outliers, t distributions with adjustable tails are utilized to model the contaminating noise so that the proposed identification algorithm is robust. The effectiveness of the proposed Bayesian approach is demonstrated through a simulated example as well as a detailed industrial application. PMID- 26642464 TI - Optimal Decision-Making in an Opportunistic Sensing Problem. AB - In this paper, we consider the problem of sensing a finite set of (moving) objects over a finite planning horizon using a set of sensors in prefixed locations that vary with respect to time over a discretized space. Control in this situation is limited and the problem considered is one of opportunistic sensing. We formulate an integer program that maximizes the quality of sensor return given either deterministic or probabilistic (i.e., forecasted) object routes. We examine the computational complexity of the problem and show it is non deterministic polynomial-hard. We theoretically and numerically illustrate subclasses of the problem that are computationally simpler, ultimately deriving a heuristic that is strongly polynomial. Real-world and constructed data sets are used in our analysis. PMID- 26642465 TI - Cardioprotective effect of metformin against doxorubicin cardiotoxicity in rats. AB - OBJECTIVE: The clinical use of doxorubicin, which is a strong antineoplastic agent, is limited due to its cardiotoxic side effects. Metformin is a drug with antihyperglycemic effects, and it has been shown to have a cardioprotective effect on left ventricular function in experimental animal models of myocardial ischemia. The present study investigated the cardioprotective effect of metformin in rats with doxorubicin cardiotoxicity. METHODS: Wistar albino rats were used in the study. Forty male, 10-week-old Wistar albino rats were randomly divided four groups. The control group rats were intraperitoneally administered saline solution twice a week, four doses in total. The doxorubicin group rats received doxorubicin (4 mg/kg, twice a week, cumulative dose: 16 mg/kg) intraperitoneally. The metformin group rats received metformin (250 mg/kg/day, every day for 14 days) via gavage. The doxorubicin + metformin group rats received doxorubicin and metformin at the same dose. Left ventricular functions were evaluated by using M mode echocardiography one day after the last dose of doxorubicin. Heart tissue samples were histopathologically examined. Cardiomyocyte apoptosis was detected using in situ terminal deoxynucleotide transferase assay (TUNEL). Serum brain natriuretic peptide and C-type natriuretic peptide levels were measured. Catalase, superoxide dismutase, glutathione peroxidase, and tumor necrosis factor alpha levels were analyzed in the heart tissue. The assumptions of equality of variances and normal distribution were checked for all variables (Shapiro-Wilk test and Q-Q graphics).To identify intergroup differences, one-way variant analysis or the Kruskal-Wallis test was used. A p<0.05 value was accepted as statistically significant. RESULTS: Our results showed that doxorubicin treatment caused significant deterioration in left ventricular functions by echocardiography, histological heart tissue damage, and increase in cardiomyocyte apoptosis. Doxorubicin + metformin group showed protection in left ventricular function, elimination of histopathologic change, and reduced of cardiomyocyte apoptosis. CONCLUSION: The present study provided evidence that metformin has cardioprotective effects against doxorubicin cardiotoxicity. PMID- 26642466 TI - The value of coronary artery calcium score in the early diagnosis of coronary artery disease in patients with stable chronic obstructive pulmonary disease. AB - OBJECTIVE: Our aim was to assess the value of coronary artery calcium score (CACS) in the early diagnosis of coronary artery disease in Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage II chronic obstructive pulmonary disease (COPD) patients and to identify high-risk patients. METHODS: Forty-two patients with GOLD stage II COPD and 31 healthy control subjects were enrolled in the study. This study was designed as a prospective observational cross-sectional study. Pearson's correlation coefficient was used for comparisons between groups. Criteria for stage II COPD diagnosis were forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) of <70% and 50%<=FEV1<80%. Excluded from the study were individuals who had a previous diagnosis of coronary artery disease, GOLD stage I-III-IV COPD, or left ventricular systolic dysfunction. RESULTS: As compared with the control group, CACS values were significantly higher in the patient group (p=0.030 and 0.001, respectively). CACS was significantly higher in male patients with a positive family history, physical inactivity, long duration of disease, and low FEV1 (0.027, 0.008; 0.001 and 0.001; 0.001, respectively). Logistical regression analysis of sex, age, diabetes mellitus, hypertension, cigarette smoking, family history, physical inactivity, and FEV1 values showed that physical inactivity was independently correlated with high CACS [odds ratio (OR): 7; confidence interval (CI): 3-20; p=0.001]. CONCLUSION: The value of CACS is high in stage II COPD patients. Male stage II COPD patients with a disease duration of 10 years, physical inactivity, and/or a positive family history should be monitored for early stage coronary artery disease and coronary events, regardless of risk factors such as diabetes, hypertension, and hyperlipidemia. PMID- 26642467 TI - Computed tomography pulmonary embolism residua index (CTPER-index): a simple tool for pulmonary embolism residua description. AB - OBJECTIVE: Chronic thromboembolic pulmonary hypertension (CTEPH) is a relatively common long-term complication of acute pulmonary embolism (PE) with severely negative impact on the patient's quality of life and prognosis. The aim of our study was to assess morphological changes, with respect to CTEPH development, in the pulmonary artery vascular bed 6 months after diagnosis of acute PE as the first thromboembolic event in the patient's history. METHODS: Our prospective study included a population of 87 consecutive patients with proven PE. Multidetector computer tomography pulmonary arteriography (CTA) was performed 6 months after acute PE to assess residua of thrombi and abnormalities supporting the presence of pulmonary hypertension. To quantify the individual totality of morphological abnormalities, a computer tomography pulmonary embolism residua index (CTPER-index) was constructed and groups of patients with and without CTEPH were compared. The study follow-up was 24 months, with echocardiography performed 6, 12, and 24 months after PE. RESULTS: Morphological abnormalities corresponding to thrombi residua or pulmonary hypertension on CTA were found in 68% of patients. The CTPER-index reached significantly higher values in patients with CTEPH during a 2-year follow-up. A CTPER-index value >=4 equates to a 12-fold higher risk of CTEPH development (p=0.013) with sensitivity 0.80 (95% CI 0.31; 0.989) and specificity 0.79 (95% CI 0.754; 0.799). CONCLUSION: Our CTPER-index may provide useful information for a clinician performing CTA for differential diagnosis of dyspnea in a patient with a history of PE. PMID- 26642468 TI - Heart rate recovery, cardiac rehabilitation and erectile dysfunction in males with ischaemic heart disease. AB - OBJECTIVE: Heart rate recovery (HRR) is a recognised marker used in clinical practice for assessing the risk of sudden cardiac death. Physical exercise leads to an improvement in HRR and has a proven beneficial effect on erection quality (EQ) related to the activity of the autonomic nervous system in men with ischaemic heart disease (IHD). This paper evaluates the relationship between HRR and EQ in patients with IHD and erectile dysfunction (ED) who underwent cardiac rehabilitation. METHODS: The main analysis was based on the Mann-Whitney U test, Wilcoxon signed-rank test, Spearman correlation coefficient, Pearson's chi-square test, chi-square test, with the Yates correction and (if possible) parametric tests were used. This prospective, non-randomised intervention study included 124 men with IHD and ED [International Index of Erectile Function (IIEF-5) scores of <=21]. Of these, 89 patients underwent a 6-month cardiac rehabilitation phase III programme, whereas 35 did not. The results of the participants' total IIEF-5 scores and their HRR, demographic and clinical data were analysed. RESULTS: The results of the 89 rehabilitated patients (mean age: 60.44+/-9.29 years) and 35 controls (mean age: 61.43+/-8.81 years) were analysed. In the rehabilitated patients, the mean baseline IIEF-5 score was 13.15+/-5.76 (95% CI: 11.93-14.36) and HRR was 16.49+/-7.68/min (95% CI: 14.88-18.11). After cardiac rehabilitation, the parameters of ED and HRR improved significantly and were significantly higher than those of the controls; the mean IIEF-5 score of the rehabilitated group increased to 15.36+/-6.51 (95% CI: 13.99-16.73), while HRR increased to 21.40+/ 7.25/min (95% CI: 19.88-22.93). A significant correlation was found between ?HRR and ?EQ (r=0.409791) as a result of the 6-month cardiac training programme. CONCLUSION: Cardiac rehabilitation assessed by HRR has a sizable effect on autonomic balance in patients with IHD and ED, which plays a significant role in the mechanism of erection improvement. PMID- 26642469 TI - Deterioration of heart rate recovery index in patients with erectile dysfunction. AB - OBJECTIVE: Heart rate recovery (HHR) after exercise is a function of vagal reactivation. This study aimed to evaluate HHR index in patients with erectile dysfunction. METHODS: Men over the age of 18 years who were diagnosed with erectile dysfunction were included in the study. Ninety patients with erectile dysfunction (mean age=56.1+/-8.3 years) and 50 healthy subjects as controls (mean age=53.1+/-10.4 years) were compared. The erectile status of patients was evaluated using the sexual health inventory for men questionnaire. Basal electrocardiography, echocardiography, and treadmill exercise testing were performed in all patients and controls. The HHR index was defined as the reduction in heart rate from the rate at peak exercise to the rate at the first minute (HRR1), second minute (HRR2), third minute (HRR3), and fifth minute (HRR5) after terminating exercise stress testing. An independent sample t-test, Pearson correlation coefficient test, linear multivariate regression analysis, and receiver operating characteristic curve analysis were used for statistical assessment. RESULTS: All HHR indices were found to be significantly decreased in patients with erectile dysfunction (p<0.001). Effort capacity was markedly lower (9.1+/-2.3 vs. 10.4+/-2.3 METs, p=0.002) among patients with erectile dysfunction. HRR1 and HRR3 were found to be an independent risk factor for erectile dysfunction (Beta=0.462, p<0.001; Beta=0.403, p<0.001; respectively) in linear regression analysis. CONCLUSION: Decreased HHR index may be considered as one of the independent predictors of impaired autonomic function in patients with erectile dysfunction. PMID- 26642470 TI - What is better for predilatation in bioresorbable vascular scaffold implantation: a non-compliant or a compliant balloon? AB - OBJECTIVE: The bioresorbable vascular scaffold system (BVS) is a fully absorbable vascular treatment system. In this study, we aimed to compare the periprocedural effectiveness and long term results of non-compliant balloon (NCB) and compliant balloon (CB) systems, which are used for predilatation before BVS implantation. METHODS: One hundred forty-six BVS-treated lesions from 119 patients were retrospectively analyzed in the study. Patients with acute coronary syndrome, stable angina and silent ischemia were included in the study. Lesions and patients were categorized into the NCB and CB groups according to the type of balloon used for predilatation. NCB was implemented on 72 lesions (59 patients) and CB was implemented on 74 lesions (60 patients). The two groups were compared on terms of procedural features and both in-hospital and 1-year clinical follow up results. Chi-square and independent sample t test were performed for statistical analysis. RESULTS: There was no significant difference between the two groups in terms of patient characteristics and lesion properties. The number of postdilated lesions was significantly higher in the CB group. Procedure time, fluoroscopy time, and contrast volume were significantly lower in the NCB group. At follow-up, one patient had myocardial infarction in the CB group because of scaffold thrombosis and no mortality was observed. CONCLUSION: Predilatation with NCB before BVS implantation reduces the need for postdilatation. In addition, use of NCB reduces the procedure time, fluoroscopy time, and contrast volume but had no effect on 1 year clinical follow-up results compared with CB. PMID- 26642471 TI - Heart rate variability improvement in children using transcatheter atrial septal defect closure. AB - OBJECTIVE: We evaluated autonomic behavior by examining heart rate variability (HRV) in the time domain and frequency domain in pediatric patients who underwent transcatheter closure of atrial septal defect (ASD). METHODS: A prospective study design was used. Holter ECG was performed in a control group of 30 healthy subjects and a group of 47 patients who underwent transcatheter ASD closure. ECG was taken one day before, one day after, and six months after the procedure to evaluate changes in the time domain [SDNN, rMSSD, NN, pNN50(%), and SDANN] and frequency domain (VLF, LF, HF, VHF, and LF/HF) in the patient group. Student's t test was used to evaluate changes prior to and after the procedure. RESULTS: There were 28 females (60%) in the patient group and 21 females (70%) in the control group. The mean age and weight of the participants in the patient group were 9.61+/-4.72 years and 32.40+/-19.60 kg, respectively; the mean age and weight of the control subjects were 10.43+/-5.31 years and 32.83+/-13.00 kg, respectively. In both the time domain and frequency domain analyses, the patient group values were found to be lower than those in the control group prior to the procedure; the values in the patient group were found to approach the values in the control group following the procedure. By the sixth month, the values in the patient group reached the control levels with no statistically significant difference (SDNN: 145+/-0.84, 137.50+/-42.50; rMSSD: 72.18+/-48.22, 58.14+/ 28.49; SDANN: 125.13+/-13.50, 122.40+/-41.06; VLF: 112.85+/-29.07, 114.41+/ 98.39; LF: 50.40+/-24.09, 45.69+/-15.13; HF: 39.28+/-19.86, 44.29+/-13.14; VHF: 10.29+/-4.24, 9.99+/-6.47; LF/HF: 1.90+/-1.44, 1.24+/-0.81; p>0.05). CONCLUSION: The transcatheter closure of secundum ASDs was found to have a positive effect on HRV. Consequently, it may contribute to reduced mortality and morbidity. We can conclude that in children, HRV recovers approximately six months after transcatheter ASD closure. PMID- 26642472 TI - Neuromuscular Activation During Short-Track Speed Skating in Young Athletes. AB - PURPOSE: To investigate differences in muscle activation of both legs between the straight and the curve and changes in muscle activity during a 1000-m time trial (TT) and their relationship to the change in skating velocity in 9 young short track speed skaters. The authors recorded skating times and EMG data from different leg muscles during maximum-effort skating trials on the straight and in the curve, as well as during a 1000-m TT. RESULTS: Muscle activation differs between the straight and the curves and between legs; ie, average activities of selected muscles of the right leg were significantly higher during skating through the curves than in the straights. This could not be observed for the left leg. The reduction in speed during the 1000-m TT highly correlates with the decrease in the muscle activity of both the tibialis anterior and the rectus femoris of the right leg. Muscle recruitment is different in relation to lap section (straight vs curve) and leg (right vs left leg). The decreased muscle activity of the tibialis anterior and rectus femoris of the right leg showed the highest relationships with the reduction in skating speed during the 1000-m TT. PMID- 26642473 TI - Ecological Validity and Reliability of the Rugby Sevens Simulation Protocol. AB - PURPOSE: To assess the ecological validity of the Rugby Sevens Simulation Protocol (R7SP) and to evaluate its interday reliability. METHODS: Ten male participants (20 +/- 2 y, 74 +/- 11 kg) completed 2 trials of the R7SP, separated by 7 d. The R7SP comprised typical running and collision activities, based on data recorded during international rugby sevens match play. Heart rate (HR) was monitored continuously during the R7SP, and the participants' movements were recorded through a 20-Hz global positioning system unit. Blood lactate and rating of perceived exertion were collected before and immediately after the 1st and 2nd halves of the R7SP. RESULTS: The average activity profile was 117 +/- 5 m/min, of which 27 +/- 2 m/min was covered at high speed, with a calculated energetic demand of 1037 +/- 581 J/kg, of which ~40% was expended at a rate above 19 W/kg. Mean HR was 88% +/- 4% of maximal HR. Participants spent ~45% +/- 27% of time above 90% of maximal HR (t >90%HRmax). There were no significant differences between trials, except for lactate between the halves of the R7SP. The majority of the measured variables demonstrated a between-trials coefficient of variation (CV%) lower than 5%. Blood lactate measurements (14-20% CV) and t >90%HRmax (26% CV) were less reliable variables. In most cases, the calculated moderate worthwhile change was higher than the CV%. CONCLUSIONS: The R7SP replicates the activity profile and HR responses of rugby sevens match play. It is a reliable simulation protocol that can be used in a research environment to detect systematic worthwhile changes in selected performance variables. PMID- 26642474 TI - CMMS helps to build maintenance efficiency at hospital. PMID- 26642475 TI - [Abstracts of the 37th Annual Meeting of the Japanese Society of Clinical Toxicology. July 17-18, 2015. Wakayama, Japan]. PMID- 26642476 TI - Editorial. PMID- 26642477 TI - [Recent Advances in Management of Acute Pancreatitis]. AB - Acute pancreatitis is common but remains a condition with significant morbidity and mortality. Despite a better understanding of the pathophysiology of acute pancreatitis achieved during the past few decades, there is no specific pharmacologic entity available. Therefore, supportive care is still the mainstay of treatment. Recently, novel interventions for increasing survival and minimizing morbidity have been investigated, which are highlighted in this review. PMID- 26642478 TI - [The Life Cycle of Early Gastric Cancer]. PMID- 26642479 TI - [Effect of Roux-en-Y Gastric Bypass Surgery on Plasma Motilin Levels and Hunger in Obese Patients]. PMID- 26642480 TI - Modeling and Simulation of Road Traffic Noise Using Artificial Neural Network and Regression. AB - Modeling and simulation of noise pollution has been done in a large city, where the population is over 2 millions. Two models of artificial neural network and regression were developed to predict in-city road traffic noise pollution with using the data of noise measurements and vehicle counts at three points of the city for a period of 12 hours. The MATLAB and DATAFIT softwares were used for simulation. The predicted results of noise level were compared with the measured noise levels in three stations. The values of normalized bias, sum of squared errors, mean of squared errors, root mean of squared errors, and squared correlation coefficient calculated for each model show the results of two models are suitable, and the predictions of artificial neural network are closer to the experimental data. PMID- 26642481 TI - Biological membranes are unique material in terms of surface and mechanical properties. Introduction. PMID- 26642482 TI - Meaningful Use of Health Information Technology: Proving Its Worth? AB - Health policymakers in recent years have looked to the implementation of health information technology (IT)--electronic health records and the like--as a means to improve quality, reduce costs, and achieve better health outcomes across populations. But implementing health IT in a meaningful way must go beyond purchasing medical records software. The U.S. Department of Health and Human Services (HHS) devised a set of measures and incentives for hospitals and eligible medical professionals within Medicare or Medicaid to mark successive stages of effective IT implementation. This issue brief discusses the history of meaningful use, the measures used to evaluate effectiveness, and the policy implications of the HHS requirements. PMID- 26642484 TI - ON INNOVATION. Make the NHS the hotbed for innovation. PMID- 26642483 TI - Contamination Nation. PMID- 26642485 TI - KEOGH HAS CUT THE MOST GLARING TARGET PERVERSITIES. PMID- 26642486 TI - WE NEED A CLEARER PLAN FOR CANCER SURVIVORS. PMID- 26642487 TI - WORKFORCE. Tap into your staff talent. PMID- 26642489 TI - Editorial. PMID- 26642488 TI - WHAT DO WE GET FOR L14.5BN? PMID- 26642490 TI - Protecting yourself from scam artistry in the publishing world. PMID- 26642491 TI - Evaluating the outcomes of complex nursing initiatives: Insights from the CANO/ACIO National Strategy for Chemotherapy Administration Project. AB - Because nursing interventions are typically complex and dynamic, evaluating their impact upon care and care systems is a notoriously daunting challenge. Nursing organizations seeking to evaluate the impact of their efforts are frequently frustrated by the gap between the evaluation research ideal and their available resources. In this paper, we describe a practical and manageable process developed to address such an evaluation challenge. Using a three-step inquiry approach, supported by modest organizational funding and a realistic level of voluntary member time, we were able to generate a meaningful understanding of intersecting outcomes arising from the implementation of CANO/ACIO's National Strategy for Chemotherapy Administration. On the basis of our experience, we see considerable merit in both process and outcomes of this form of targeted evaluation. PMID- 26642492 TI - The care continuum with interprofessional oncology teams: Perspectives of patients and family. AB - To accompany the individual diagnosed with cancer along the care continuum, teams of professionals have been created based on integrating an interprofessional patient-centred (IPPC) practice. The goal of this article is to present some of the results of a case study documenting IPPC practice carried on by teams within the oncology care continuum. Observations and interviews with patients and their family were conducted. The results suggest that IPPC practice is variable within teams, but optimal at the beginning of treatments or cancer recurrence. However, patients can experience breakdowns in the continuity of care and more difficult transitions between oncology continuum periods (diagnosis, treatment, follow-up). PMID- 26642493 TI - Physical activity and cancer: A cross-sectional study on the barriers and facilitators to exercise during cancer treatment. AB - The purpose of this investigation was to explore the barriers and facilitators to exercise in individuals with cancer in Ontario. A cross-sectional study using an online survey was used to collect qualitative and quantitative data. A convenience sample was used to recruit individuals with a current or previous diagnosis of any type of cancer. Percentages and themes were obtained from the data. Data were collected from 30 participants of which 63.3% reported infrequent, low intensity physical activity during treatment. Barriers to exercise during treatment included physical symptoms and lack of awareness of exercise programs. Facilitators for exercise were past positive experience with exercise and accessibility. More than 80% of participants did not receive education on the importance of exercise. PMID- 26642494 TI - Loss, adaptation and new directions: The impact of arm morbidity on leisure activities following breast cancer. AB - The impact of arm morbidity on leisure and quality of life is an understudied area in cancer survivorship. The purpose of this study was to qualitatively describe the impact of breast cancer-related arm morbidity on leisure participation in Canadian women. A grounded theory approach was used to generate thematic categories and a model. Drawing on participants from a larger cohort study (n = 740), 40 women with arm morbidity symptoms were purposively sampled and interviewed. Three themes emerged: a sense of loss, adapting participation, and new directions. Women with arm morbidity may experience an abrupt loss of previously enjoyed leisure activities and engage in a process of adapting to discover new meanings and directions. Comprehensive, person-centred cancer survivorship programs may assist with adaptation to arm morbidity. PMID- 26642495 TI - Investigating coping strategies and social support among Canadian melanoma patients: A survey approach. AB - Complex support needs are involved in coping with a diagnosis of melanoma. The purpose of this study was to determine the perceived social support levels and utilization of adaptive and maladaptive coping strategies by Canadian melanoma patients. The impact of social support level on coping strategy utilization was also examined. Social support and coping strategies were assessed using the Medical Outcomes Study Social Support Survey (MOS-SSS) and the 28-item Brief COPE, respectively. Perceived levels of emotional/informational support were significantly lower than affectionate support and positive social interaction. Acceptance, active coping, and use of emotional support were the most frequently utilized coping strategies. Patients with higher perceived levels of social support had significantly higher adaptive coping scores than patients with lower levels of social support. Health care professionals have an important role in promoting awareness of and access to emotional and informational support resources in order to improve perceived social support levels. PMID- 26642496 TI - Health disparities in cancer care: Exploring Canadian, American and international perspectives. PMID- 26642497 TI - Broken telephone? Being out of the loop? Or Houston--we have a problem! PMID- 26642498 TI - Does feeling part of the team affect other characteristics of nursing teamwork? PMID- 26642499 TI - Leadership Special Interest Group: What is leadership? PMID- 26642500 TI - Special Interest Group Report: Surgical Oncology. PMID- 26642501 TI - Nurse to Know: Terra Thibault. PMID- 26642502 TI - Nurse to Know: Amenudzie Yayra. PMID- 26642503 TI - ON PARTY LEADERSHIP ELECTIONS. Cameron and Sturgeon need stronger rivals. PMID- 26642504 TI - MORECAMBE BAY FAILINGS COULD HAPPEN AGAIN. PMID- 26642505 TI - THE BUDGET POSES FOUR BIG QUESTIONS. PMID- 26642506 TI - A confidence booster. PMID- 26642507 TI - Leadership is all about nurturing. PMID- 26642508 TI - ON DEVOVING HEALTH AND SOCIAL CARE. Don't let devolution become yet another fad. PMID- 26642509 TI - THE NHS CAPACITY MYTH HAS BEEN SHATTERED. PMID- 26642510 TI - THE NHS NEEDS A TRANSFORMATION FUND. PMID- 26642511 TI - LONG TERM CONDITIONS. For patients, by patients. PMID- 26642512 TI - ELECTIVE CARE. Time to get back on the target track. PMID- 26642513 TI - Why chasing happiness might be making you miserable. PMID- 26642514 TI - WHY DOCTORS ARE RETHINKING BREAST-CANCER TREATMENT. PMID- 26642515 TI - Virginia elections could signal future of Medicaid expansion. PMID- 26642516 TI - Longer lives, falling rates put pressure on hospital pension plans. PMID- 26642517 TI - Justice Department scrutinizing individual execs' role in fraud. PMID- 26642518 TI - Millennial challenge. PMID- 26642519 TI - EXPANDING VIP CARE. New concierge doc models focus on employers, with some offering specialists. PMID- 26642520 TI - CMS' PET peeve. PMID- 26642521 TI - Care delivery innovations must be combined to reduce waste and boost value. PMID- 26642522 TI - Organizing systems to demand IT interoperability. PMID- 26642523 TI - Harmed patients 'keep me from being pulled into the providers' excuses'. PMID- 26642524 TI - By the numbers. Largest professional liability carriers. Ranked by direct premiums written for medical professional liability in the U.S., 2014. PMID- 26642525 TI - Gauging the impact of health care codes. PMID- 26642526 TI - Medical center finds efficient path to meeting fire safety requirements. PMID- 26642528 TI - Building a brand. PMID- 26642527 TI - 2015 Sustainable Operations Survey. Managers dig deeper for saving as easy fixes become routine. PMID- 26642529 TI - Durable designs. Interior considerations for behavioral health facilities. PMID- 26642530 TI - Finding common ground. Flooring manufacturers catch up to the demands of today's health facilities. PMID- 26642531 TI - Centering compliance efforts on frequently cited concerns. PMID- 26642532 TI - Becoming a future-focused strategic health care leader. PMID- 26642533 TI - Design requirements for HVAC systems. Considering different codes during engineering projects. PMID- 26642534 TI - The ES department's role in construction. PMID- 26642535 TI - How drug prices and payment reform are changing the pharmacy benefit business. PMID- 26642536 TI - Municipal IDs help prevent medical mishaps, provide access to care. PMID- 26642537 TI - LEARNING to be LEAN. One hospital's staff discovers improving efficiency isn't easy. PMID- 26642538 TI - Healthcare data mining. OptumLabs collaborative begins to offer insights about what works. PMID- 26642539 TI - Diagnosing Wisely. PMID- 26642540 TI - Hospitals redesigning care delivery to best serve changing needs of their communities. PMID- 26642541 TI - Building better supports for dementia. PMID- 26642542 TI - 'We were one of the catalysts to get Detroit going again'. PMID- 26642543 TI - By the numbers. Health systems with highest ratio of unfunded pension liabilities. Ranked by organizaton's ratio of unfunded pension liabilities in 2014. PMID- 26642544 TI - Readmission penalties have experts queasy about quality measures. PMID- 26642545 TI - Boeing's direct contracting strategy may spread to other large employers. PMID- 26642546 TI - Disclosure of CEO pay ratios could stoke healthcare industry tensions. PMID- 26642547 TI - CHS set to leave the country for the city. PMID- 26642548 TI - NURSING HOMES' USE OF BINDING ARBITRATION UNDER FIRE. PMID- 26642549 TI - CEO PAY SOARS AT TOP NOT-FOR-PROFITS. PMID- 26642550 TI - GOING UP. Surge in exec comp driven by pay-for-performance bonuses. PMID- 26642551 TI - The world isn't waiting for better quality measures. PMID- 26642552 TI - Realizing the promise of 'big data' requires the right culture, leadership strategy. PMID- 26642553 TI - Moving wearables into wellness. PMID- 26642555 TI - By the numbers. Highest-paid executives at not-for-profit healthcare organizations. Ranked by total compensation for 2013 as reported in available IRS Form 990 filings. PMID- 26642554 TI - Cassel discusses NQF's search for better quality metrics. PMID- 26642556 TI - ON JEREMY HUNT'S FUTURE. Hunt could be all at sea unless he takes a risk. PMID- 26642557 TI - WHY THE NHS MUST EVALUATE COMPLEX SERVICE CHANGES. PMID- 26642558 TI - REVIEW MUST ACCOUNT FOR SEVEN DAY NHS. PMID- 26642559 TI - SERVICE REDESIGN. Needed: A recipe for NHS success. PMID- 26642561 TI - TECHNOLOGY: CASE STUDY. 'WHY NOT HERE'? PMID- 26642560 TI - TECHNOLOGY ADOPT TEAM TACTICS. PMID- 26642562 TI - Semantics matter. PMID- 26642563 TI - Time for change: Sustainability for MSSP-ACOs in question. MGMA recommends changes to CMS program. PMID- 26642564 TI - First two vendors achieve PMS accreditation. Vendors evaluated on key performance standards of quality, privacy and security as well as ICD-10 readiness. PMID- 26642565 TI - Practices move toward value-based compensation. PMID- 26642566 TI - Will ICD-10 be delayed again? Recent federal action suggests Oct. 1, 2015, date will stand. PMID- 26642567 TI - ACCOUNTING WITH 'LIFO' VS. 'FIFO': THE DEVIL IS IN THE DETAIL. PMID- 26642568 TI - Provider compensation: Getting your money's worth. PMID- 26642569 TI - ARE YOU ELIGIBLE? Small businesses offset cost of health insurance premiums with tax credits. PMID- 26642570 TI - 4 steps to move from a fee-for-service to a value-based world. PMID- 26642572 TI - Interviewing for success: Tools help ID the best candidate. PMID- 26642571 TI - Staying ahead of the curve: Practices of better-performers. PMID- 26642573 TI - A matter of perspective: Commonalities between wildlife photography and practice management. PMID- 26642574 TI - Unpredictable virus means no one can promise last year's flu season won't happen again. PMID- 26642575 TI - More hospitals require workers to get flu shots, but resistance persists. PMID- 26642576 TI - ICD-10 earthquake caused barely a shake. PMID- 26642577 TI - Contraception, data-sharing among issues expected on Supreme Court docket. PMID- 26642578 TI - Rehabilitation care reimbursement under renewed fire from OIG. PMID- 26642579 TI - GIVING SHELTER CARE. Some health systems serve the homeless where they stay. PMID- 26642581 TI - Toward a revolution in physician training. PMID- 26642580 TI - LEGISLATION LANGUISHES as rural hospitals struggle. PMID- 26642582 TI - Clinicians must push back against critics challenging the role of quality measures. PMID- 26642583 TI - While Ebola has faded from the headlines, cost of preparedness still weighs on hospitals. PMID- 26642584 TI - An app to fill the care instruction gap. PMID- 26642585 TI - The centrality of health IT to ACO success. PMID- 26642586 TI - By the numbers. Critical-access hospitals by state. Ranked by total number of CAHs. PMID- 26642587 TI - ON ERROR REPORTING. Why the gap between anecdote and fact? PMID- 26642588 TI - THE NHS HAS A BLIND SPOT ON DRUG ACCESS FOR RARE CONDITIONS. PMID- 26642589 TI - COMPETITIVE TENDER MAY NOT BE NECESSARY. PMID- 26642590 TI - Linked data is key to understanding. PMID- 26642591 TI - PATIENT EXPERIENCE. A personalised approach to care. PMID- 26642592 TI - MENTAL HEALTH. An appetite for service change. PMID- 26642593 TI - [Scientific and complementary medicine. Irreconcilable differences or mutually supportive systems]. PMID- 26642594 TI - [Hungarian health policy]. PMID- 26642595 TI - MALOCCLUSIONS AND QUALITY OF LIFE. Cross-sectional and longitudinal studies in children. AB - There are few longitudinal studies of the prevalence of malocclusions and possible self-correction of malocclusions during the development of the dentition. Early intervention might be unnecessary if self-correction of the malocclusion occurs during the transition from the primary to the permanent dentition. Most studies are cross-sectional and in those of longitudinal design, the results are inconsistent and difficult to interpret. Malocclusions may or may not influence the quality of life in children and adolescents. Thus, evaluations of the influence of different malocclusions on quality of life will certainly underpin a broader understanding and knowledge about how malocclusions affect the daily life of young patients. This information may also be important when it comes to assessing the most appropriate time for starting orthodontic treatment, not only from a professional point of view, but also, most importantly, from the patients' perspective. The overall aim of this thesis was therefore to evaluate the prevalence of malocclusions, and to document changes occurring during the development of the dentition, from the primary dentition stage at age 3, through the mixed dentition at age 7, to the early permanent dentition at age 11.5 years. Further aims were to review the current state of knowledge about the impact of malocclusions on oral health related quality of life (OHRQoL) and to investigate how malocclusions affect the quality of life in a cohort of children, aged 11.5 years, whose dental care is provided by the Swedish Public Dental Service. PMID- 26642596 TI - Sources of Health Insurance Coverage: A Look at Changes Between 2013 and 2014 from the March 2014 and 2015 Current Population Survey. PMID- 26642597 TI - Medicaid expansion: How to make it work for physicians. Despite some progress, the program still does not work for many physicians. PMID- 26642598 TI - Disconnected. How stalled interoperability hurts patient care. PMID- 26642600 TI - How patient portals can help you build a PCMH. PMID- 26642599 TI - DISCONNECTED, PART 2: New interoperability approaches offer promise and challenges. PMID- 26642601 TI - New Career Directions. Financial factors and practice models to consider. PMID- 26642602 TI - INCIDENT-TO BILLING CLARIFICATION: A PHYSICIAN AS AN EXTENDER. PMID- 26642603 TI - Implementing a strategic plan in five steps. PMID- 26642604 TI - Why malpractice coverage is still needed when practicing ends. PMID- 26642605 TI - The last words you should say to any patient. PMID- 26642606 TI - Easy physician credentialing for medical practices. PMID- 26642607 TI - The guide for physicians to remain independent. PMID- 26642608 TI - The right interoperability must become reality. PMID- 26642609 TI - To prevent readmissions, think outside the hospital walls. AB - Initiatives from the Centers for Medicare & Medicaid Services (CMS) and commercial payers that penalize hospitals when patients are readmitted make it necessary for providers throughout the continuum to collaborate and ensure that patients get the care they need. Create discharge plans that go beyond the hospital walls and coordinate with the post-acute providers to ensure that they have the information they need to help the patient follow the plan. Develop close relationships with post-acute providers by meeting with them face to face and discussing ways to improve transitions and solve problems. Track quality metrics, such as readmission rates, and share them with the providers. When patterns occur, alert the group to work on solutions. PMID- 26642610 TI - IMPACT Act levels the playing field on healthcare performance. AB - The Improving Medicare Post-Acute Care Transformation Act (IMPACT), which requires post-acute providers to compile and submit quality, performance, and resource use data, gives hospitals an opportunity to work closely with the providers to which they discharge patients. The Act standardizes data collection and data sharing among post-acute providers. The data will eventually be reported publicly. The IMPACT Act is part of the CMS emphasis on basing reimbursement on quality. Currently, post-acute providers are paid on a fee-for-service basis. The Act gives post-acute providers an incentive to work on initiatives to reduce readmissions to collaborate with hospitals on improving transitions. PMID- 26642611 TI - Bed leasing program helps hospitals discharge hard-to-place patients. AB - UCLA Health's program that pays a negotiated daily rate to skilled nursing facilities to hold beds for patients who otherwise would stay in an acute care bed saved a total of 2,516 acute care days from June 2014 to July 2015. UCLA Health pays a negotiated daily rate if the beds are occupied or not. The rate covers boarding, nursing care, medications, and physical therapy and occupational therapy Nurse practitioners are embedded in the participating nursing homes and provide care for UCLA Health's patients every day, often treating problems that might cause a readmission. The program helps with emergency department throughput and frees up acute care beds for patients who need them. PMID- 26642612 TI - Interdisciplinary Walking Rounds: A Key Strategy for Improving Case Management Outcomes--Part 1. AB - This month, we began our discussion of walking rounds with an overview of why rounds are important and how you might begin to structure rounds in your organization. Because IHI and TJC both identify walking rounds as best practice, we have focused our discussion on the elements needed for a successful walking rounds process. Next month, we will continue our discussion of walking rounds with strategies for preparing for rounds, as well as how to engage the patient and family in the rounding process. PMID- 26642613 TI - Video handoffs cut readmissions from post-acute providers. AB - When Oregon Health & Science University Hospital began video handoffs when patients were being discharged to a skilled nursing facility, readmission rates dropped. The hospital nurse goes to the bedside and connects with the nurse who will be caring for the patient at the receiving facility. The program makes patients feel more comfortable about the new facility and gives the nurse a chance to meet his or her patient. The hospital also conducts educational sessions via videoconferencing for the staff at the skilled nursing facilities. PMID- 26642614 TI - Do your duty: Report all infections. PMID- 26642615 TI - Preventing Healthcare's Top Four Documentation Disasters. PMID- 26642616 TI - Reinvigorating YOUR CDI PROGRAM. PMID- 26642617 TI - CLOSING THE LOOP ON QUALITY AND CDI. PMID- 26642618 TI - Survey Predicts Future HIM Workforce Shifts. PMID- 26642619 TI - ONC Targets Information Blocking. PMID- 26642620 TI - Clinical Documentation Improvement's Main Ingredient: 'Physicians First'. PMID- 26642621 TI - Clinical Definition Standards Case Study. PMID- 26642622 TI - The New CDI Challenge: Adjusting to Quality, Not Quantity. PMID- 26642623 TI - Best Practices in the Art and Science of Clinical Documentation Improvement. PMID- 26642625 TI - DRG Grouping and ICD-10-CM/PCS. PMID- 26642624 TI - Clinical Documentation Improvement in the Outpatient Setting. PMID- 26642626 TI - ON NEW CARE MODELS. NHS must shift focus to adapt to care models. PMID- 26642627 TI - BOLD TARIFF REFORM COULD TRANSFORM THE NHS. PMID- 26642628 TI - WORKFORCE. NURTURING TALENT. PMID- 26642629 TI - DATA. THE COMPLETE PICTURE. PMID- 26642630 TI - VANGUARDS WON'T FIX SHORT-TERM ISSUES. PMID- 26642631 TI - INTEGRATED CARE. Knit services together. PMID- 26642632 TI - SORTING WORKFORCE WOES. PMID- 26642633 TI - ICD-10: Ready or not, here it comes. PMID- 26642634 TI - CODE IT RIGHT. Get paid the first time. PMID- 26642635 TI - INCIDENT-TO BILLING GUIDELINES. PMID- 26642636 TI - Payer negotiating tips for small practices. PMID- 26642637 TI - 4 financial reports physicians must see monthly. PMID- 26642638 TI - Video in the exam room. Should you allow patients to record visits? PMID- 26642639 TI - Getting in front of healthcare's connectivity curve. PMID- 26642640 TI - Manage the complexity of practicing medicine. PMID- 26642641 TI - HIPAA investigations: How to protect your practice. PMID- 26642642 TI - Treating LGBT patients. PMID- 26642644 TI - MIPS vs. APM: 4 things physicians need to consider. PMID- 26642643 TI - Emma. PMID- 26642645 TI - Exam room today, YouTube tomorrow? PMID- 26642646 TI - [The effect of generic price competition on drug consumption and health insurance pharmaceutical expenditures in Hungary]. AB - AIM: The aim of our study was to analyze the Hungarian montelukast sodium drug market. We examined the effect of the appearance of generic drugs on the price and turnover of the brand-name drug, Singulair. DATA AND METHODS: Data derived from the nationwide pharmaceutical database of Hungarian National Health Insurance Fund Administration (2007-2014). We analized the turnover and price of the medicaments containing the active substance montelukast sodium. Accordingly our indicators were: consumer price, social insurance subsidy, patients' co payment and days of treatment (DOT). RESULTS: First the generics started from a significantly lower price of 18 USD which was lower than the price of brand-name Singulair (32 USD). Then the prices of the generics started to diminish. While in 2007 the DOT was below 2 million, it increased over 10 million days by 2014. The increase of DOT was followed by the increase of health insurance subsidy until 2011. Then the amount of health insurance subsidy decreased from 10,5 million USD to 7 million USD in 2012. In 2013 and 2014 there was a further reduction, the amount of the health insurance subsidy decreased to 4,1 million USD in 2013, and in 2014 it was reduced to 2.2 million USD. CONCLUSIONS: Following the introduction of generic drugs, the price of the medicaments containing montelukast sodium was significantly reduced, while the days on treatment (DOT) increased. The patients' access to drugs containing montelukast sodium increased significantly. The annual health insurance subsidy was significantly reduced as well. PMID- 26642648 TI - [Introduction of Functional Foods--Types, Manufacturing Methods and Quality Assurance]. AB - Because of the beneficial effects to health functional foods are important elements of health promotion. The positive effect of the functional components should be based on scientific evidence-based. In addition to the traditional food processing technology new technologies have appeared, e.g. microencapsulation, edible coatings and orodispersible films, nano-technology, vacuum impregnation. In the present study, probiotics and the structure, the production and the impact of prebiotic functional cereals are discussed in more detail. In addition to their numerous advantages in connection with the safe application, several questions arise because of inadequate quality control measures prior to coming onto the market. PMID- 26642647 TI - [Pharmacognosy study of Verbascum species]. AB - The mullein (Verbascum phlomoides L., V thapsus L., V. thapsiforme Schrad., V. speciosum L.) is a medicinal herb known and used for a long time, especially in traditional Turkish medicine. The aims of our study were to identify the species and study the plant's major active substances both qualitatively and quantitatively, comparing it to data found in scientific literature. The plants were identified as probable hybrids of V. phlomoides and V. thapsiforme. Microscopic analysis of the flowers showed no major difference between the specimens. The diameter of both stomata and pollen we observed was around 15-20 MUm. Important flavonoids like rutin and quercetin were identified. Dosage resulted in a 0.135% total flavonoid aglycone content. (expressed as hypericin) and a 1.3% total flavonoid glycoside content (expressed as rutoside). Thin layer chromatography from saponines revealed two spots. A hemolytic index of 13095 was also determined. Repeating the dosage experiment a year later resulted in significantly lower flavonoid aglycone and glycoside content (0.006% and 0.95% respectively) as well as a hemolytic index of approximately 4000. PMID- 26642649 TI - THERMOSENSITIVE MICROGELS OF POLY-N-ISOPROPYLACRYLAMIDE FOR DRUG CARRIERS- PRACTICAL APPROACH TO SYNTHESIS. AB - The aim of the work is to present the main actual information on the preparation of polymers, derivatives of N-isopropylacrylamide, formed into microgels. The most often used comonomers, crosslinkers, and initiator systems are gathered herein. The known methods of emulsion polymerization and precipitation polymerization are also described, including the application of the surfactants, as well as the surfactant free emul- sion polymerization. Finally, the procedures of lab-scale production of microgel were evaluated in the paper, with special intact on the thermosensitive N-isopropylacrylamide derivatives for application in biomedical field. PMID- 26642650 TI - DEVELOPMENT AND VALIDATION OF THE STABILITY-INDICATING LC-UV METHOD FOR DETERMINATION OF CEFOZOPRAN HYDROCHLORIDE. AB - The stability-indicating LC assay method was developed and validated for quantitative determination of cefozopran hydrochloride (CZH) in the presence of degradation products formed during the forced degradation studies. An isocratic, RP-HPLC method was developed with C-18 (250 mm x 4.6 mm, 5 um) column and 12 mM ammonium acetate-acetonitrile (92:8, v/v) as a mobile phase. The flow rate of the mobile phase was 1.0 mL/min. Detection wavelength was 260 not and temperature was 30 degrees C. Cefozopran hydrochloride as other cephalosporins was subjected to stress conditions of degradation in aqueous solutions including hydrolysis, oxidation, photolysis and thermal degradation. The developed method was validated with regard to linearity, accuracy, precision, selectivity and robustness. The method was applied successfully for identification and determination of cefozopran hydrochloride in pharmaceuticals and during kinetic studies. PMID- 26642651 TI - DEVELOPMENT OF CHROMATOGRAPHIC METHOD FOR DETERMINATION OF DRUGS REDUCING CHOLESTEROL LEVEL--STATINS AND EZETIMIBE. AB - The presented developed HPLC method and GC method may be used to separate and determine all analyzed 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) and ezetimibe using a single columns and a uniform methodology. In order to perform qualitative and quantitative tests of statins and ezetimibe the Symmetry C18 column 250 mm x 4.6 mm, 5 um, the mobile phase: acetonitrile:water (70:30, v/v), adjusted to pH = 2.5 and a spectrophotometric detector for the HPLC method were used. For GC method column HP-1; 30 m x 0.25 mm x 0.25 um and FID detector were selected. All results and statistical data obtained indicate good method sensitivity and precision. The RSD values are appropriate for both newly developed methods. PMID- 26642652 TI - DIFFERENT RESPONSE OF ANTIOXIDANT DEFENSE SYSTEM TO ACAMPROSATE IN ETHANOL PREFERRING AND NON-PREFERRING RATS. AB - The aim of the study was to investigate whether acamprosate, an agent attenuating relapse in human alcoholics, might modulate antioxidant status in rats chronically administered ethanol. Male Wistar rats were presented with a free choice paradigm between tap water and ethanol solution for three month to distinguish two groups of animals, preferring (PRF) and non-preferring (NPF) ethanol. Then, rats were administered acamprosate, 500 mg/kg/day, per os, for 21 days. The hepatic level of enzymatically-driven lipid peroxidation was enhanced by ethanol in PRF and NPF rats by 67 and 82%, respectively. Unstimulated microsomal lipid peroxidation was increased solely in NPF rats by 33%. Acamprosate caused 36% increase in stimulated lipid peroxidation only in NPF animals. The activities of all hepatic antioxidant enzymes examined: superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glutathione S-transferase were decreased in rats treated with ethanol by 30 to 64% as compared to controls, however, this decrease was more distinct in ethanol preferring rats. Administration of acamprosate further reduced the activity of antioxidant enzymes only in NPF rats: catalase by 47%, glutathione peroxidase and glutathione S-transferase by 37% and glutathione reductase by 33%. No effect of acamprosate on 4-nitrophenol hydroxylase, a marker of CYP2E1 activity, was observed. As acamprosate enhanced oxidative stress only in the rats non preferring ethanol, it could be expected that these adverse effects are not demonstrated in alcohol-dependent humans treated with acamprosate. PMID- 26642653 TI - IMPACT OF GENTAMICIN ON ANTIOXIDANT ENZYMES ACTIVITY IN HEMn-DP CELLS. AB - Aminoglycoside antibiotics, including gentamicin, are widely used clinically in treatment of bacterial infections. Unfortunately, their side effects, especially nephrotoxicity and ototoxicity remain a problem. It is known that aminoglycoside antibiotics bind well to melanin biopolymer, but the relation between their affinity to melanin and ototoxicity is not well documented. The aim of this work was to examine the impact of gentamicin on antioxidant enzymes activity in cultured dark pigmented normal human melanocytes (HEMn-DP). The WST-1 assay was used to detect gentamicin cytotoxic effect. The analyzed antibiotic induced concentration-dependent loss in melanocytes viability. The value of EC50 was found to be 7.5 mM. Significant changes in the cellular antioxidant enzymes: SOD, CAT and GPx were stated in melanocytes exposed to gentamicin, what may indicate the depletion of antioxidant defense system. It is concluded, that the results obtained in vitro may explain a potential role of melanocytes and melanin in the causative mechanisms of aminoglycosides ototoxic effects in vivo. PMID- 26642654 TI - METHOTREXATE AND MYOTREXATE INDUCE APOPTOSIS IN HUMAN MYOMA FIBROBLASTS (T hES CELL LINE) VIA MITOCHONDRIAL PATHWAY. AB - Uterine leiomyomas (fibroids) are the most common benign tumors in women of reproductive age. Although the local application of low doses of methotrexate (MTX) is used as an effective treatment of the myomas, myotrexate could be a promising new drug. This study investigated the cytotoxic and apoptotic effects of both MTX and myotrexate in human fibroblasts derived from the uterine fibroids (T hES cell line). The myotrexate adduct is an aqueous solution of MTX and L arginine. Cells were treated with a graded concentrations of both MTX and myothrexate (0.1-16 uM) for 24 h. The cytotoxicity was assayed by MTT test, apoptosis was evaluated by Annexin V-FITC assay and their possible role in apoptosis was determined by immnu- flourescence. Both MTX and myotrexate induced apoptosis in T hES cells in a dose dependent manner (p < 0.001). Myotrexate significantly increased the percentage of AnnexinV positive cells, BAX/Bcl-2 ratio and subsequent caspase-3 activation compared to the MTX treated cells (p < 0.05). Both MTX or myotrexate treatment showed a diffuse staining of cytochrome c indicating its release from mitochondria to the cytosol, suggesting that their mechanisms of action most likely involves the mitochondrial apoptotic pathway. PMID- 26642655 TI - SYNTHESIS AND IN VITRO ANTIMICROBIAL ACTIVITY OF NOVEL SERIES OF 3,5 DIACETYLPYRIDINE COMPOUNDS. AB - Bis diacetylpyridine derivative (1) was prepared and reacted with different halo compounds, namely: epichlorohydrine and dichloroethyl ethyl ether to give 2a,b, respectively, and reacted with morpholine and piperidine to afford Mannich products 3a,b, successively. Compound 4 was synthesized by reaction of 1 with potassium thiocyanate. Reaction of 4 with 4-chlorobenzaldehyde, glucose and phthalic or maleic anhydrides produced 5, 6 and 7a,b. Compound 1 reacted with 4 chlorobenzaldehyde to give bisanylmethylene derivative 8. Also some new compounds 9-11 were prepared from the reaction of compound 8 with nucleophiles, namely: hydrazine hydrate, thiosemicarbazide and hydroxylamine via Michael condensation reaction. On the other hand, compound 8 was reacted with cyclohexanone and cyclopentanone to give 12a,b. The structures of newly synthesized products have been deduced on the basis of elemental analysis and spectral data. Some synthesized compounds were screened for their antimicrobial evaluation. Among the assayed compounds, derivatives 3b and 12a showed the highest antimicrobial activities. PMID- 26642656 TI - SYNTHESIS AND ANTIMICROBIAL EVALUATION OF CYANOPYRIDINYL TETRAHYDRONAPHTHALENE DERIVATIVES. AB - A novel series of cyanopyridinyl tetrahydronaphthalene incorporated with different heterocycles were synthesized. The key compounds 2a,b were condensed with chloroacetone and ethyl chloroacetate to give 3a,b and 4a,b, respectively. Also condensation of 4a,b with hydrazine hydrate gave the corresponding hydrazide 5a,b. Reaction of 5b with different isothiocyanates gave the corresponding thiosemicarbazide derivatives 6a-c. Also, condensation of 5a with chloroacetic acid, methyl iodide and/or acetic anhydride yielded 7- 9, respectively. Moreover, reaction of 5a with acetylacetone, ethyl acetoacetate, diethylmalonate, ethyl cyanoacetate, chloroacetone, ethyl chloroacetate, urea, phthalic anhydride, malic anhydride and/ or different aldehydes yielded the corresponding derivatives 10 18, respectively. Newly synthesized compounds were screened for their antibacterial (Staphylococcus aureus, Bacillus subtilis, Bacillus megaterium, Sarcina lutea, Klebsiella pneumoniae, Pseudomonas aeruginosa, Escherichia coli) and antifungal (Saccharomyces cerevisiae and Candida albicans) activity. The results revealed that some of novel compounds have exhibited significant biological activity against the tested microorganisms. PMID- 26642657 TI - SYNTHESIS AND STUDY OF HALOGENATED BENZYLAMIDES OF SOME ISOCYCLIC AND HETEROCYCLIC ACIDS AS POTENTIAL ANTICONVULSANTS. AB - A series of potential anticonvulsants have been synthesized. There are eight fluorobenzylamides and three chlorobenzylamides of isocyclic or heterocyclic acids. Two not halogenated benzylamides were also synthesized to compare the effect of halogenation. The aim of the research performed was to evaluate whether halogenation of the mother structure is able to improve its anticonvulsant activity. The compounds were tested in Anticonvulsant Screening Project (ASP) of Antiepileptic Drug Development Program (ADDP) of NIH. Compound 1 showed MES ED50 = 80.32 mg/kg, PI = 3.16. Compound 7 showed CKM ED50 = 56.72 mg/kg. Compound 8 showed MES ED50 = 34.23 mg/kg and scPTZ ED50 > 300 mg/kg, PI = 8.53.Compound 13 showed 6Hz ED50 = 78.96, PI = 3.37. The results indicate that fluorination does not improve activity, whereas chlorination in our experiment even reduces it. PMID- 26642658 TI - HEMATOLOGICAL AND IMMUNOBIOCHEMICAL STUDY OF GREEN TEA AND GINGER EXTRACTS IN EXPERIMENTALLY INDUCED DIABETIC RABBITS. AB - The present study was designed to investigate the effects of the extract of green tea and/or ginger on some hematological and immunobiochemical profiles in alloxan induced diabetic rabbits. The results revealed that treatment of diabetic animals with extract of green tea and/or ginger elevated the decreased HDL-c and LDL-c but significantly decreased triglycerides, the elevated glucose and GOT concentrations. The result also displayed a non-significant increase in the levels of CRP and fibrinogen. The experiment also revealed that the elevated MDA and GSH level fell down to the normal control group. The result also showed that after green tea and/or ginger extract treatment, the lowered RBC, WBC counts, PCV, percentage of neutrophils were increased and the elevated MCV, MCH, and MCHC of diabetic rabbits were decreased to normal levels. Thus, the overall results may indicate that green tea and/or ginger extracts have a significant hypoglycemic effect in diabetic rabbits. In addition, the extracts may be capable of improving hyperlipidemia, the impaired kidney function and hemogram in alloxan induced diabetic rabbits. PMID- 26642659 TI - EFFECTIVENESS OF THE DERYNG AND CLEVENGER-TYPE APPARATUS IN ISOLATION OF VARIOUS TYPES OF COMPONENTS OF ESSENTIAL OIL FROM THE MUTELINA PURPUREA THELL. FLOWERS. AB - In this study, both qualitative and quantitative analyses of chemical composition of M. purpurea essential oil obtained in the Deryng and Clevenger-type apparatuses were compared. As a result, content of volatile compounds were: 785.67 mg/mL and 833.33 mg/mL in the oil obtained in the Deryng (D-EO) and Clevenger-type apparatuses (C-EO), respectively. The major components of both essential oils from M. purpurea were: a-pinene, sabinene, myrcene, (Z) sesquisabinene hydrate, (E)-sesquisabinene hydrate, and a-bis-abolol. The correlation coefficients values are not determined by the differences in the concentrations of the components resulting from the application of two different methods of distillation. PMID- 26642660 TI - APPLICATION OF CHEMOMETRICS FOR IDENTIFICATION OF PSYCHOACTIVE PLANTS. AB - Drug market changes dynamically causing many analytical challenges for police experts. Among illicit substances there are synthetic designer products but also herbal material. Plant material is usually in fine-cut or powdered form, thus difficult to identify. For such fragmented material classic taxonomical identification methods using anatomical and morphological features of the plant cannot be employed. The aim of the study was to develop an identification method of the powdered material with employment of multidimensional data analysis techniques. Principal Component Analysis (PCA) was chosen as a method of data exploration. The study was conducted on four plants controlled in Poland: Salvia divinorum, Mitragyna speciosa, Psychotria viridis and Calea zacatechichi. The compatibility of grouping features of selected species was compared in two variants: chemical and elemental composition. In a first variant, GC-MS chromatograms of extracts were analyzed and in the second, elements composition with the AAS and the ICP-MS techniques. The GC-MS method, based on the qualitative interpretation of results, allows for clear differentiation of samples with regard to their species affiliation. Even the plants belonging to the same family Rubiaceae, P. viridis and M. speciosa formed homogeneous and clearly separated clusters. Additionally, the cluster analysis was performed, as a method confirming sample grouping. PMID- 26642661 TI - PHARMACOKINETICS OF DICLOFENAC SODIUM AND PAPAVERINE HYDROCHLORIDE AFTER ORAL ADMINISTRATION OF TABLETS TO RABBITS. AB - Non-compartmental pharmacokinetic analysis of diclofenac sodium (DIC) and papaverine hydrochloride (PAP) after oral administration of composed tablets to rabbits was developed. HPLC method for determination of DIC and PAP in rabbit plasma was developed and validated. Chromatographic separation of DIC, PAP and the IS was achieved on a Zorbax SB C18 5-um column (150 mm x 4.6 mm) using methanol-water (55:45, v/v) as mobile phase at a flow rate of 0.8 mL/min. Pharmacokinetic analysis showed that oral administration of a tablet composed of DIC and PAP do not change the pharmacokinetic parameters such as MRT, MAT, Cl and bioavailability of the active substances compared with single administration of DIC and PAP after single dose. PMID- 26642662 TI - EVALUATION OF SORPTIVE PROPERTIES OF VARIOUS CARRIERS AND COATING MATERIALS FOR LIQUISOLID SYSTEMS. AB - The basic principle of liquisolid systems formulation lies in the conversion of the drug in a liquid state into an apparently dry, free-flowing and readily compressible powder by its blending (or spraying) with specific carriers and coating materials. The selection of the most suitable carrier and coating material depends especially on their values of flowable liquid retention potential (Phi), which is defined as the maximum mass of liquid that can be retained per unit mass of powder material, while maintaining an acceptable flowability. The presented work focused on the determination of the maximum amount of propylene glycol (PG), which can be retained by several selected carriers and coating materials while maintaining acceptable flow properties of the liquisolid powder blend. Granulated forms of magnesium aluminometasilicates (Neusilin(r) US2 and Neusilin(r) NS2N), dibasic calcium phosphate (Fujicalin(r)) and microcrystalline cellulose (Avicel(r) PH 101) were tested due to their frequent use. Powdered forms of magnesium aluminometasilicate (Neusilin(r) UFL2) and colloidal silica (Aerosil(r) 200) were used as common coating materials. From the evaluation of liquisolid mixtures with different amounts of liquid, it could be observed that 1 g of Neusilin(r) US2, Neusilin(r) UFL2, Neusilin(r) NS2N, Aerosil(r) 200, Fujicalin(r) and Avicel(r) PH 101 can retain 1.00, 0.97, 0.54, 0.04, 0.25 and 0.12 g of propylene glycol, respectively, while maintaining acceptable flowing properties for further processing. PMID- 26642663 TI - EVALUATION OF CASES WITH THE USAGE OF COMMERCIALLY AVAILABLE TABLETS IN THE PEDIATRIC FORMULA. AB - Lack of availability, of either the medicinal product intended to be used for children, or such in a dose which is fitting for the individual child's needs, results in physicians administering medicines meant for the adult. The target of the thesis was to evaluate the cases with the usage of commercially avaible conventional tablet-formulated medicinal products intended for the adult in the pediatric formula. The subjects of the evaluation were the form of the pediatric drug, prepared from commercially available tablets and capsules, as well as the legitimacy of their usage in the treatment of the pediatric population. One hundred and fifty-four prescriptions filled in community pharmacies of Warminsko Mazurskie Voivodeship in 2011 were chosen. A total of 5805 divided powders in starch capsules were prepared. The prescribing practice included 6 groups of manufactured medicinal products in the form of conventional tablets, containing as follows: anti-hypertensive medicines (ACE inhibitors--enalapril, captopril, ramipril, loop diuretics--furosemide, potassium sparing diuretics- spironolactone, beta-adrenolytics--propranolol, alpha- and beta-adrenolytics- carvedilol), medicines for heart failure (foxglove glycosides--digoxin, methyldigoxin), anti-clotting medicines (acetylsalicylic acid), peristalsis stimulating agents (metoclopramide), antibacterial medicines (furagin), and dopaminergic (carbidopa-levodopa). The only compounded forms ordered by the physicians were divided powders for an internal use. Starch capsules for powder preparation provided the only 'package' for the dose of the compounded powder, which after pouring, solving or suspending in water was administered to children. Such a shift of the form, between an oral tablet and divided powder for an internal use, did not cause a change in the method of administration. The information on indications and the way of dosage for children, inserted in the Summary of Product Characteristics, enables the administration which follows the registered indications, despite the shortage of an appropriate dose in the pharmaceutical market. In contrast, an absence of the information regarding the indications and a dosage for children in the Summary of Product Characteristic, results in an off-label administration, in case of a child. PMID- 26642664 TI - RELEASE AND MUCOADHESION PROPERTIES OF DICLOFENAC MATRIX TABLETS FROM NATURAL AND SYNTHETIC POLYMER BLENDS. AB - The delayed release and mucoadhesive properties of Cedrela gum and hydroxypropylmethylcellulose blend in diclofenac sodium tablet formulations were evaluated. Tablets were prepared by direct compression and the crushing strength and detachment force were found to increase from 74.49 +/- 1.22 to 147.25 +/- 2.57 N and 0.302 +/- 0.36 to 1.141 +/- 0.05 N from low to high level of polymers, respectively. The release kinetics followed Korsmeyer-Peppas release and the n varied between 0.834 and 1.273, indicating that the release mechanism shifts from Fickian to super case I (anomalous release). The drug release profile fits a pulsatile-release pattern characterized by a lag time followed by a more or less rapid and complete drug release. The Cedrela gum-hydroxypropylmethylcelluse blend tablets delayed diclofenac release for 2 h and sustained the release for 12 h. The polymer blend delayed drug release in the 0.1 M HCl simulating gastric environment and subsequent release pH 6.8 phosphate buffer. PMID- 26642665 TI - EVALUATION OF ALGINATE MICROSPHERES WITH METRONIDAZOLE OBTAINED BY THE SPRAY DRYING TECHNIQUE. AB - In the present study, nine formulations (F1-F9) of alginate microspheres with metronidazole were prepared by the spray drying technique with using different drug:polymer ratio (1:2, 1:1, 2:1) and different sodium alginate concentration (1, 2, 3%). The obtained microspheres were characterized for size, morphology, drug loading, (potential and swelling degree. Mucoadhesive properties were examined using texture analyzer and three different models of adhesive layers- gelatin discs, mucin gel and porcine vaginal mucosa. In vitro drug release, mathematical release profile and physical state of microspheres were also evaluated. The obtained results indicate that sodium alginate is a suitable polymer for developing mucoadhesive dosage forms of metronidazole. The optimal formulation F3 (drug:polymer ratio 1:2 and 1% alginate solution) was characterized by the highest metronidazole loading and sustained drug release. The results of this study indicate promising potential of ALG microspheres as alternative dosage forms for metronidazole delivery. PMID- 26642666 TI - THE EFFECT OF SEROTONIN 5-HT1A, 5-HT2 RECEPTOR LIGANDS, KETOPROFEN AND THEIR COMBINATION IN MODELS OF INDUCED PAIN IN MICE. AB - The present study was carried out to investigate the effects of the 7-(3 chlorophenyl)piperazinylalkyl derivatives of 8-alkoxypurine-2,6-dione (compounds 1-4) in two animal models of induced pain and to compare their effects with ketoprofen and with their combination. All experiments were performed on albino mice. Mice were evaluated for their responsiveness to noxious stimuli using: the hot-plate test and the phenylbenzo-quinone-induced writhing test. All compounds showed analgesic activity only in the writhing test. The analgesic activities of compounds 3 and 4 were similar to ketoprofen. The compounds slightly increased the analgesic effect of ketoprofen when used in combination in the visceral type of pain. The possible mechanisms of the antinociceptive effect of these compounds are thought to involve the activation of analgesic effect mediated by the serotonergic pathways or combination of this mechanism with other important mediators playing a role in pain modulation. PMID- 26642667 TI - BIOCHANIN A SHOWS NO EFFECT ON SKELETAL SYSTEM IN OVARIECTOMIZED RATS, WHEN ADMINISTERED IN MODERATE DOSE. AB - Biochanin A is a naturally occurring isoflavone. Its main sources are clover species such as Trifolium pretense, Trifolium subterraneum or Trifolium incarnatum. Phytoestrogens, including isoflavones, are plant-derived substances, which exhibit estrogen-like properties, thus they may be used as an alternative for hormonal replacement therapies and prevent postmenopausal osteoporosis. Therefore, the aim of the presented study, was to investigate the effect of biochanin A on chemistry and mechanical properties of skeletal system in rats with ovariectomy-induced osteoporosis. The animals were divided into 4 groups- (I) sham-operated rats, (II) ovariectomized rats, (III) ovariectomized rats receiving estradiol at a dose of 0.2 mg/kg p.o., which were a positive control, and (IV) ovariectomized rats receiving biochanin A at a dose of 5 mg/kg p.o. for four weeks. The administered dose of biochanin A is considered as moderate for human, which can be received in the dietary supplements, and was established using ten-fold conversion rate resulting from faster metabolism in rats. Obtained results showed that ovariectomy induced harmful changes in bone tissue, causing worsening in both chemistry and mechanical parameters in bones. Administration of biochanin A to ovariectomized rats did not affect any changes in bone tissue in comparison to the bones of untreated ovariectomized rats. There was neither improvement nor deterioration noted in chemical composition and mechanical properties in all analyzed bones. Basing on the results, it could be concluded, that biochanin A administered in a moderate dose shows no influence on bone tissue of rats with ovariectomy-induced osteoporosis. PMID- 26642668 TI - CLINICAL EXPERIENCE OF LONG-TERM TREATMENT WITH ARIPIPRAZOLE (ABILIFY) IN CHILDREN AND ADOLESCENTS AT THE CHILD AND ADOLESCENT PSYCHIATRIC CLINIC 1 IN ROSKILDE, DENMARK. AB - The aim of this paper is to share the clinical experience of the treatment of aripiprazole (Abilify) in children and adolescents. The authors have done a cross sectional study about Abilify's treatment in children and adolescents with severe conduct problems (high impulsivity, aggression, outward reaction, physical cross border behavior), high restlessness with ADHD, psychotic and psychosis-like symptoms with autistic disorders, psychosis, and intensive tics with Tourette's syndrome. The authors studied and described patients at the Child and Adolescent Psychiatric Clinic 1 in Roskilde, Denmark, who were treated with Abilify and were patients of the clinic in June 2013. The target group consisted of 33 patients, aged 9-18 years, which were in Abilify treatment during this time. Indications for the treatment and effectiveness of Abilify, Abilify's common doses used in children and adolescents, and the most common adverse effects of Abilify are presented. Abilify was found to be effective, well tolerated and safe for children and adolescents. The dose depends on the complexity of diagnosis (higher doses used in cases of complex diagnosis), on the age (higher doses used in older children, but only in the case of noncomplex diagnoses). Statistical analysis shows that in cases of complex diagnoses, dosage does not depend on age but depends on other factors. It also shows that the effect of treatment is better for those who did not gain weight. PMID- 26642669 TI - RATIONALIZED AND COMPLEMENTARY FINDINGS OF SILYMARIN (MILK THISTLE) IN PAKISTANI HEALTHY VOLUNTEERS. AB - The aim of the work was to examine the influence of gender on pharmacokinetics of silymarin; a basic constituent of medicinal herb "milk thistle" (Silybum marianum). The presented work is the extension of published work of Usman et al. (16). The comparative parallel design pharmacokinetic study was conducted in Pakistani healthy volunteers (male and female) receiving a single 200 mg oral dose of silymarin. Sixteen subjects (8 males and 8 females) were enrolled and completed the 12 h study. Blood screening was done on HPLC and the pharmacokinetic parameters were calculated by APO, 3.2 Ver. software using non compartmental and two compartment model approaches. A significant difference (p < 0.05) was observed in almost all calculated pharmacokinetic parameters of silymarin in male and female. Clinically, the silymarin has been underestimated in the previous study. Gender based clinical investigations should be directed in the future on other flavono-lignans of 'milk thistle' as well. PMID- 26642670 TI - KAP AMONG DOCTORS WORKING IN HOSPITALS, REGARDING HALAL PHARMACEUTICALS; A CROSS SECTIONAL ASSESSMENT. AB - There is a growing awareness amongst Muslims to avoid all items containing non Halal ingredients. This sentiment has now progressed into the field of various medications. It therefore, required a study to assess the knowledge, attitude and perception (KAP) relating to pharmaceuticals containing non-Halal ingredients among doctors working in various hospitals of Malaysia. This was a cross sectional study, carried out in January 2013-February 2013 period, using a structured, self-administered questionnaires. Study settings included various government hospitals in Malaysia. Data were collected by distributing questionnaires through respective heads of the departments. Study was conducted on a sample of 243 participants. Inclusion criterion was a registered medical doctor working in a government hospital. Descriptive statistics (mean, standard deviation, frequency, percentage, median, inter quartile range) was applied to summarize the data, non-parametric tests were applied. chi2 Test and Fisher's Exact Test were applied to assess the association between demographic characteristics and knowledge, attitude and perception scores. Results revealed that the hospital doctors had a good and positive attitude and perception about Halal pharmaceuticals. Mean knowledge score out of maximum possible 9 score was 7.67 +/- 1.68. Mean attitude score out of maximum possible 45 score was 34.10 +/- 5.35 while mean perception score out of maximum possible 55 score was 45.73 +/- 5.44. Mean overall KAP score out of maximum possible 109 was 87.60 +/- 10.37. There was a significant, positive and weak correlation (0.20-0.29) between knowledge and attitude (r = 0.231, p < 0.001) as well as between knowledge and perception (r = 0.209, p = 0.001) while there was good correlation (0.5-0.75) between attitude and perception (r = 0.588, p < 0.001). It is concluded from the results that the better knowledge the respondents have on Halal pharmaceuticals the better is their perception and attitude towards Halal pharmaceuticals. PMID- 26642671 TI - IMPACT OF STRESS FACTORS ON OPTICAL ISOMERISM OF BENAZEPRIL HYDROCHLORIDE. AB - Benazepril hydrochloride contains two stereogenic centers, but is currently available as single enantiomer (S,S configuration) for the treatment of hypertension. Its enantiomer (R,R configuration) and the diastereoisomeric pair (R,S and S,R) can be regarded as impurities. Stereochemical stability of S,S isomer of benazepril hydrochloride and its potential susceptibility to conversion in the.active substance and in Lisonid tablets were examinated. The separation with the use of the TLC method with the following system: chromatographic plates Chiralplate and a mobile phase: methanol - acetonitrile - 1 mM copper(II) acetate (4 : 2 : 4, v/v/v) with saturation of glacial acetic acid for 1 h and the HPLC method system: Chiral AGP column (150 x 4.0 man x 5 um) and a mobile phase: phosphate buffer pH = 6.0 - methanol (80 : 20, v/v) were obtained. Active substance - benazepril hydrochloride and Lisonid tablets 20 mg were subjected to the impact of different stress factors. Samples were examined after 1 and 6 weeks. It was found that none of the applied stress factors caused the transformation of the S,S enantiomer of benazepril hydrochloride in the substance and tablets to other identified stereoisomers - only the compound decomposition has occurred. PMID- 26642672 TI - DETERMINATION OF FLUCONAZOLE IN HUMAN PLASMA BY REVERSE PHASE HIGH PERFORMANCE LIQUID CHROMATOGRAPHY. AB - A rapid, simple and reproducible high performance liquid chromatographic method was developed and validated for determination of fluconazole in human plasma. The separation was performed on MZ C8 column (125 x 4 mm, 5 um) using acetonitrile - potassium dihydrogen phosphate buffer (15 : 85, v/v), pH 3.0, as the mobile phase at a flow rate of 1.5 mL/min. The wavelength was set at 261 nm. The assay enables the measurement of fluconazole for therapeutic drug monitoring with a minimum quantification limit of 20 ng/mL. The method involves simple, protein precipitation procedure and analytical recovery was complete. The calibration curve was linear over the concentration range 0.1-4 ug/mL. The coefficients of variation for inter-day and intra-day assay were found to be less than 10%. PMID- 26642673 TI - LIPOPHILICITY ASSESSMENT OF SPIRONOLACTONE BY MEANS OF REVERSED PHASE LIQUID CHROMATOGRAPHY AND BY NEWLY DEVELOPED CALCULATION PROCEDURES. AB - The parameters of lipophilicity of spironolactone (a single member of steroids group), which is widely applied as diuretic and antihypertensive agent, were experimentally determined by reversed-phase TLC and HPLC methods as well as calculated using different computer programs and also by a novel mode based on topological indices. Various stationary phases, such as RP-18WFA4254, RP-2F254, RP-18F254 and also different binary solvent systems composed of organic modifier (e.g., methanol, dioxane, acetone) and water were used as mobile phases in order to predict the following chromatographic parameters: Rm, and logkw, respectively. LogP of examined spironolactone calculated with respective theoretical procedures: AlogPs, logPKOWWIN, xlogP2, xlogP3, AClogP, AlogP, MlogP and also logPaverage were obtained from online package software. The partition coefficients expressed as logP1, logP2 and logP3 were calculated by means of the formulae based on the numerical values of the following topological indices: , 0B, 1B, W, 0chiv and IB, which was novelty of this study. A good agreement between logP calculated by new method and experimentally estimated lipophilicity parameters (by chromatography and by shake flask method) was found. The results confirmed applicability of the topological indices for calculating lipophilicity of spironolactone as alternative procedure to the experimental and other computed logP values. PMID- 26642674 TI - ANTIOXIDANT ACTIVITY AND FREE RADICAL SCAVENGING CAPACITY OF L-ARGININE AND NAHS: A COMPARATIVE IN VITRO STUDY. AB - In the family of gaseous transmitters, hydrogen sulfide (H2S) is considered as third member beside nitric oxide (NO) and carbon monoxide (CO), which can play physiological role in different organs. The present study was designed to elucidate the antioxidant and free radical scavenging potentials of L-arginnine (a source for endogenous production of NO in vivo) and NaHS (a source H2S) individually and in combination. Different assays like 2,2-diphenyl-1 picrylhydrazyl (DPPH) free radical scavenging, percent inhibition of linoleic acid peroxidation and reducing power assays were used to evaluate the free radical scavenging capacity and antioxidant activity of L-arginine and NaHS. Furthermore, study was aimed to know the antioxidant potential of both compounds at their effective doses in human body, which is 56 uM for H2S and 1.2 g/mL for L arginine. The study also aimed to clear whether either NaHS, L-arginine or the mixture of NaHS and L-arginine in vitio (in the form of new compounds) is responsible for their therapeutic action. Results showed that NaHS, L-arginine and combination of NaHS + L-arginine showed good radical scavenging activity i.e., 55.60%, 52.10% and 52.32%, respectively. Moreover, NaHS was found to have ability to inhibit linoleic acid peroxidation by 53.98% at effective dose while L arginine did not show inhibition of linoleic acid peroxidation. Combination of NaHS + L-arginine showed 54.15% inhibition of linoleic acid peroxidation, which is similar to that of H2S. Reducing power of NaHS was 0.073 and L-arginine showed 0.037, combination of NaHS + L-arginine showed 0.063. It can be concluded that NaHS showed better antioxidant potential in vitio as compared to L-arginine and the antioxidant activity of the mixture of NaHS + L-arginine is closed to the antioxidant activity of NaHS, which reflects that NaHS is a dominant factor in combination mixture that is responsible for antioxidant activity. PMID- 26642675 TI - CLINDAMYCIN: EFFECTS ON PLASMA LIPID PROFILE AND PEROXIDATION PARAMETERS IN RABBIT BLOOD PLASMA. AB - Alteration of plasma lipid profile and induction of lipid peroxidation may take place due to drug effect, which may be correlated with adverse drug reactions and drug-induced toxicity. Considering this fact, the present in vivo study was carried out to evaluate the effect of clindamycin on plasma lipid profile and peroxidation parameters alone and in combination with ascorbic acid, a promising antioxidant. After administering drug and antioxidant alone and in combination in rabbit, it was found that clindamycin had mild lipid peroxidation induction and profile alteration capacity, which can be arrested on co-administration of ascorbic acid. PMID- 26642676 TI - EVALUATION OF SELECTED BIOCHEMICAL PARAMETERS OF OXIDATIVE STRESS IN RATS PRETREATED WITH ROSUVASTATIN AND FLUOXETINE. AB - The aim of this study was to assess the effect of a combined 14-day treatment with rosuvastatin (10 mg/kg) and fluoxetine (10 mg/kg) on selected biochemical parameters of oxidative stress in the blood of rats. The activity of glutathione peroxidase (GPX), glutathione reductase (GR) and the total antioxidant status (TAS) were determined. A combined 14-day treatment with rosuvastatin and fluoxetine significantly increases glutathione peroxidase and glutathione reductase activity and decreases the level of TAS. Rosuvastatin administered to rats caused a decrease in the glutathione peroxidase activity and an increase in the glutathione reductase activity but did not affect the level of TAS. A 14-day treatment with fluoxetine exerted practically no effect on the investigated parameters of oxidative stress in rats. The abovementioned changes in the biochemical parameters after the combined treatment with rosuvastatin and fluoxetine may imply an imbalance in prooxidant and antioxidant levels in the combined treatment with rosuvastatin and fluoxetine. PMID- 26642677 TI - INFLUENCE OF CLOUDY APPLE JUICE ON N-NITROSODIETHYLAMINE- INDUCED LIVER INJURY AND PHASES I AND II BIOTRANSFORMATION ENZYMES IN RAT LIVER. AB - Cloudy apple juice (CAJ) is a rich source of nutrients as well as non-nutrient components including high quantity of polyphenols, particularly oligomeric procyanidins, which are considered as potential chemopreventive agents that protect against the action of chemical carcinogens. The aim of this study was to examine the effect of CAJ alone or in combination with hepatocarcinogenic N nitrosodiethylamine (NDEA) on liver damage biomarkers, including DNA damage, and the phase I and II enzymes in rat. The forced feeding with CAJ alone for 28 days, has slightly reduced the activities of phase I enzymes, MROD (CYP1A2 biomarker) and PNPH (CYP2El biomarker), while phase II enzymes, glutathione S-transferase (GST) and NAD(P)H: quinone oxidoreductase-1 (NQO1), were elevated. Combined treatment of rats with CAJ and NDEA significantly reduced the levels of hepatic ALT and SDH (by ~100%) as compared to values from NDEA-treated animals. CAJ pretreatment further increased the PROD (CYP2B biomarker) and NQO1 activities increased by NDEA administration. Modulation of enzymes activities was accompanied by the changes in the proteins levels. These results indicate that CAJ may protect liver against damage induced by NDEA. Moreover, a significant decrease of SDH activity by CAJ may confirm its potential anti-diabetic activity. PMID- 26642678 TI - 1-[(IMIDAZOLIN-2-YL)AMINO]INDOLINE AND 1-[(IMIDAZOLIN-2 YL)AMINO] 1,2,3,4 TETRAHYDROQUINOLINE DERIVATIVES: NEW INSIGHTS INTO THEIR CIRCULATORY ACTIVITIES. AB - N-[(Imidazolin-2-yl)amino]indolines and N-[(imidazolin-2-yl)amino]-1,2,3,4 tetrahydroquinolines, previously described in patent literature as hypertensive agents, were synthesized and tested in viny for their affinities to alpha1- and alpha2-adrenoceptors as well as imidazoline I, and I2 receptors. The compounds most potent at either alpha1- or alpha2-adrenoceptors were administered intravenously to normotensive Wistar rats to determine their effects on mean arterial blood pressure and heart rate. Upon intravenous administration at dose of 0.1 mg/kg to normotensive male Wistar rats, the initial transient pressor effect was followed by long-lasting hypotension and bradycardia. In view of the above results the 1-[(imidazolin-2-yl)amino]indolines and [(imidazolin-2 yl)amino]-1,2,3,4-tetrahydroquinolines are now found to possess circulatory profile characteristic of the centrally acting clonidine-like hypotensive imidazolines. PMID- 26642679 TI - NEW HETEROCYCLIC OXIME ETHERS OF 1-(BENZOFURAN-2-YL)ETHAN- 1-ONE AND THEIR ANTIMICROBIAL ACTIVITY. AB - In this study, some O-benzyl (benzofuran-2-yl)ethan-1-one ether oximes were synthesized starting from 2-acetylbenzofuran. The structure elucidation of the compounds was performed by IR, 1H-NMR and 13C-NMR spectra. Antimicrobial activities of the compounds were examined and notable activity was observed. PMID- 26642680 TI - SYNTHESIS AND IN VITRO ANTIPROLIFERATIVE SCREENING OF NEW 2,7-NAPHTHYRIDINE-3 CARBOXYLIC ACID HYDRAZIDE DERIVATIVES. AB - The new pyrrolo[3,4-c]pyridines and 2,7-naphthyridine derivatives have been synthesized. 4-Hydroxy-8-methyl-l-oxo-6-phenyl-1,2-dihydro-2,7-naphthyridine-3 carboxylic acid hydrazide (4) was the key intermediate for the synthesis of the novel derivatives of various chemical structures: Schiff bases, 1,3,4 oxadiazoles, pyrazoles, carbohydrazides, semi- and thiosemicarbazides. The structures of these new compounds were confirmed by elemental analysis and IR, NMR and MS spectra. The antitumor activities of the obtained derivatives were examined. Eight of the twenty one newly synthesized compounds were qualified by the NCI (Bethesda, MD, USA) for in vito screening against 60 different human tumor cell lines. The most active proved to be the Schiff bases. PMID- 26642681 TI - ANTICANCER ACTIVITY OF NEWLY SYNTHESIZED TRIAZOLOPYRIMIDINE DERIVATIVES AND THEIR NUCLEOSIDE ANALOGS. AB - New substituted triazolopyrimidne derivatives were synthesized starting from 1,2,3-triazolo-4-carboxamide derivative. The N- and S-glycoside derivatives of the synthesized triazolopyrimidine ring system as well as their acyclic sugar analogs were also synthesized. The cytotoxicity and in vito anticancer evaluation of the prepared compounds have been assessed against three different human tumor cell lines including human breast MCF-7, lung A549 and colon HCT116 cancer cell lines. The results revealed that the prepared compounds exert their actions in MCF-7 and A549. MCF-7 cells are more sensitive to the tested compounds than the other cell lines. Compounds 2, 3, 9 and 10 revealed promising anticancer activities compared to the activity of the commonly used anticancer drug, doxorubicin in both MCF-7 and A549 cell lines. PMID- 26642682 TI - BIOASSAY-GUIDED FRACTIONATION AND ANTIHYPERTENSIVE PROPERTIES OF FRACTIONS AND CRUDE EXTRACTS OF PERISTROPHE BICALYCULATA (RETZ) NEES. AB - Hypertension is an important public health issue in both developed and developing countries due to its high incidence and morbidity. This has motivated researchers especially in developing countries to search for strategies for the treatment using different plant parts. The use of the aqueous decoction of the leaves of Peristiophe bicalyculata in the treatment of hypertension has been documented. This study was designed to carry out a bioassay-guided isolation of the antihypertensive components of the leaves of Peristrophe bicalyculata in L-NAME hypertensive rats, determine the angiotensin-converting enzyme inhibitory activity of the extracts and fractions obtained and identify the constituent(s) present. From our results, L-NAME hypertensive rats given the cold water extract had significantly (p < 0.05) lower mean arterial blood pressure (MABP) with longer duration of action than other extracts. Also, the angiotensin-converting enzyme inhibitory activity of the cold water extract was significantly (p < 0.05) higher than that of other extracts. From the GC-MS analysis of the most effective fraction (fraction 4), P,P,P-triphenyl-imino(triphenyl)phosphorane and andrographolide 2(3H)-furanone were identified among others. The present work demonstrates the hypotensive effect of the cold water extract of Peiistiophe bicalyculata on L-NAME hypertensive rats, which further justifies the folkloric application of extracts of the plant in the management as well as treatment of hypertension. PMID- 26642683 TI - PRELIMIARY PHYTOCHEMICAL ANALYSIS AND ANTIFUNGAL ACTIVITIES OF CRUDE EXTRACTS OF ZALEYA PENTANDRA AND CORCHORUS DEPRESSUS LINN. AB - Zaleya pentandra (Zp) and Cochoms depressus Linn. (Cd) have been considered as herbs with potential therapeutic benefits. Zp and Cd belong to the important family Aizoaceae and Tiliaceae, respectively. The extractions were carried out successively with methanol and dichloromethane at room temperature for 24 h. Preliminary phytochemical screening of Zp and Cd revealed the presence of steroids, alkaloids, saponins, and anthraquinones. The methanolic and dichloromethane extracts of selected plants were subjected to examination of antifungal activity by using agar tube dilution. The extracts were tested against different fungi such as A. nigeir, A. flavus, F. solani, A. funigatis and Mucor. The dichloromethane extract of aerial parts of Cd showed high antifungal activity against A. niger as compared to all other tested extracts. PMID- 26642684 TI - RAPESEED PHOSPHATIDYLCHOLINE HYDROLYSIS TO PHOSPHATIDIC ACID USING PLANT EXTRACTS WITH PHOPSPHOLIPASE D. AB - Phosphatidic acid (PA) has a crucial role in cell membrane structure and function. For that reason it has a possible application in the treatment of some health disorders in humans, can be used as a natural and non toxic emulsifier and the component of drug carriers in pharmaceuticals and cosmetics as well as a component for synthesis of some new phospholipids. PA is short-lived in the cell and is difficult to extract directly from the biological material. PA may be easily prepared by hydrolysis of phospholipids, especially phosphatidylcholine (PC), using cabbage phospholipase D (PLD). Hydrolytic activity of purified by us PLD extracts from cabbage towards rapeseed phosphatidylcholine (RPC) was investigated. Hydrolysis was carried out in the biphasic system (water/diethyl ether) at pH 6,5 and temp 30 degrees C. Influence of enzymatic extracts from three cabbage varieties, reaction time, Ca2+ concentration and enzyme extracts/PC ratio, on activity towards RPC resulting in rapeseed phosphatidic acid (RPA) formation were examined. Our study shows that the PLD extracts from savoy cabbage (PLDsc), white cabbage (PLDwc) and brussels sprouts (PLDbs) used in experiments exhibit hydrolytic activity towards RPC resulting in rapeseed RPA with different yield. The highest activity towards RPC shows PLD extract from PLDsc with the RPC conversion degree to RPA (90%) was observed at 120 mM Ca2+ concentration, reaction time 60 min and ratio of PLD extract to RPC 6 : 1 (w/w). Our study shows that purified by us PLDsc extracts exhibit hydrolytic activity towards RPC giving new RPA with satisfying conversion degree for use in pharmacy, cosmetics and as a standard in analytical chemistry. PMID- 26642685 TI - TOTAL PHENOLIC CONTENT, ANTIOXIDANT AND ANTIBACTERIAL ACTIVITIES OF THE EXTRACT OF EPHEDRA PROCERA FISCH. ET MEY. AB - Ephedra prcera belonging to the family Ephedraceae is a poison and medicinal plant. The main aim of present study was to determine total phenolic content and antioxidant and antibacterial activities of ethanolic extract from the aerial parts of E. procera collected from a natural habitat in Chaharmahal va Bakhtiari province, Southwestern Iran. The total phenolic content of the extract by Folin Ciocalteu method and the antioxidant activity using DPPH assay were determined. The antibacterial activity, minimum inhibitory concentration (MIC), and minimum bactericidal concentration (MBC) of the extract were evaluated against five bacteria, including Proteus vulgaris, Pseudomonas aeruginosa, Enteobacter aeogenes, Bacillus ceirus and Staphylococcus aureus. Total phenolic content in the extract of E. procera was 0.718 mg tannic acid/g dry weight extract. The results indicated that the ethanolic extract of E. piocera exhibited radical scavenging activity. In addition, the results of this study confirmed that the ethanolic extract of E. procera exhibited antibacterial activity. In conclusion, the extract of E. piocera could be an important source of phenolic components with antioxidant capacity and antibacterial activity. PMID- 26642686 TI - DISSOLUTION PROPERTIES AND KINETIC STUDY OF SULFADIMIDINE AND TRIMETHOPRIM TABLETS CONTAINING FOUR DIFFERENT SUPERDISINTEGRANTS. AB - The objective of this study was to evaluate and compare the effect of four superdisintegrants such as croscarmellose sodium (Ac-Di-Sol), crospovidone (Kollidon CL and with smaller particle sizes Kollidon CL-F), sodium starch glycolate (Explotab) in combination with beta-lactose and microcrystalline cellulose (Avicel PH-102) as base excipients exhibiting properties of directly compressed tablets and increasing the disintegration and the dissolution rate of sulfadimidine sodium (SDD-Na) and trimethoprim (TMP). All tablets were prepared by direct compression method and superdisintegrants were used at 2% for all formulations. The tablets were evaluated with regard to uniformity of weight, hardness, friability, drug content, disintegration time and dissolution properties. Dissolution properties such as t50% and t80% (time to release 50 and 80% of drug), DP3045 (percent of drug dissolved in 30 and 45 min) and the dissolution rate constant value (K) were considered in comparing the dissolution results. The results showed that crospovidone (Kollidon CL) provides the shortest disintegration time and the fastest rate of dissolution for both TMP and SDD-Na. The kinetic study of the dissolution data reveals that in vitro release profiles of TMP and SDD-Na can be best explained by first order model or by Higuchi model. The obtained data were plotted into Korsmeyer-Peppas equation to find out the confirmed diffusion mechanism. For TMP release, the values of the release exponent are beyond the limits of Korsmeyer model, so-called, power law. For SDD Na release, exponent values are characteristic for anomalous transport (non Fickian) or the value of the release exponent is beyond the limits of Korsmeyer model. PMID- 26642687 TI - EFFECT OF FORMULATION AND PROCESS VARIABLES ON THE RELEASE, MECHANICAL AND MUCOADHESIVE PROPERTIES OF IBUPROFEN TABLET FORMULATIONS. AB - A 2(4) full factorial analysis was used to study the individual and interactive effects of binder type, X1; binder concentration, X2; relative density, X3 and tabletting technique, X4, on disintegration time (DT), brittle fracture index (BFI), tensile strength (TS) and mucoadhesion time (MT) of ibuprofen tablets formulated by direct compression (DC) and wet granulation (WG), and containing Entandophragnia angolense gum (ENTA) as binder, in comparison with hydroxypropylcellulose. The result of the FTIR and UV peaks suggests the absence of any interaction between ENTA and ibuprofen. Interactions between the polymers and ibuprofen were determined using FTIR and UV determinations. The ranking of the individual effects on DT and BFI was X2 > X3 > X1 > X4, on TS; X3 > X2> X1 > X4 and on MT; X2> X > X4 > X3. The effects of changing the binder from hydroxypropylcellulose to ENTA led to an increase in DT and decrease in TS, BFI and MT. Changing X2 and X3 to higher values increased the DT and TS. The interaction between X1 and X2 had the highest influence on BEI and MT, while interaction between "X3 and X4", and "X2 and X3" had the highest influence on DT and TS, respectively. Ibuprofen tablets prepared by wet granulation method and containing Entandophragma angolense gum showed lower capping/lamination tendencies and better mucoadhesive drug release profiles. PMID- 26642688 TI - IN-VITRO ANTIMICROBIAL ACTIVITY OF BRONCHOSOL. AB - Bronchosol is a traditional medicinal product in the form of syrup used in cough and impeded expectoration. The active ingredients that it contains include extracts from the herb of thyme, the root of primrose and thymol. It is recommended in disorders of the respiratory tract when expectoration is impeded and secretion of liquid mucus in bronchi is insufficient. Antimicrobial activity of the components of Bronchosol, especially thyme and thymol, has frequently been reported in the literature. To date, there have not been any studies to confirm such activity of Bronchosol, though. The results of our research are the first one to point to the great activity of Bronchosol against microorganisms causing infections of the respiratory tract. It has been demonstrated that this product displayed antimicrobial activity against reference strains as well as strains of anaerobic and aerobic bacteria and fungi isolated from patients. The confirmation of the antimicrobial activity of Bronchosol provides an explanation of its effectiveness in the therapy of the respiratory tract infections. PMID- 26642689 TI - PERCEPTION OF ACADEMIC PHARMACISTS TOWARDS THEIR ROLE IN HEALTHCARE SYSTEM OF A DEVELOPING COUNTRY, PAKISTAN: A QUANTITATIVE SIGHT. AB - To investigate perception of academic pharmacists towards their role in healthcare system of a developing country, Pakistan, was the aim of this study. The study participants consisted of academic pharmacists from the government and private universities of Pakistan. Study was conducted for a period of three months, from January to March 2011, in Pakistan. Academic pharmacists were informed regarding the aim, objective and nature of the study. Verbal consent was given and execution of the study took place. Main sections of the questionnaire were comprised of series of statements pertaining to pharmacist perception and experience with the pharmacists. During the period, of January to April, the total number of questionnaires received from different government and private universities was 113. The response rate based on the 205 academic pharmacists working in universities during the study period was 63.9%. A majority (93.9%) of the respondents were satisfied working as academic pharmacist, 68.7% expressed that their interest in research is the reason to embark carrier as an academic pharmacist. Only half (55.7%) of the respondents agreed about pharmacy curriculum standard in Pakistan, and their satisfaction towards curriculum is less, as after the implementation of Pharm. D. (Doctor of Pharmacy). In the country, the curriculum is still focusing more towards theoretical knowledge rather than practical. In this case significant difference was noted with respect to university (p = 0.012). Academic pharmacists do have concern about the pharmacy profession in Pakistan. They ascertain the key issues facing the profession and its educators. Recommendations have been made to improve the current pharmacy curricula in order that future pharmacists in Pakistan practice effectively with the collaboration of other healthcare professionals. PMID- 26642690 TI - MICROBIOLOGICAL QUALITY OF FOOD SUPPLEMENTS. AB - Many specialists note that the food offered today - as a result of very complex technological processing - is devoid of many components that are important for the organism and the shortages have to be supplemented. The simplest for it is to consume diet supplements that provide the missing element in a concentrated form. In accordance with the applicable law, medicinal products include all substances or mixtures of substances that are attributed with properties of preventing or treating diseases with humans or animals. Permits to admit supplements to the market are issued by the Chief Sanitary Inspector and the related authorities; permits for medicines are issued by the Chief Pharmaceutical Inspector and the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products. Therefore, admittance of a supplement to the market is less costly and time consuming_than admittance of a medicine. Supplements and medicines may contain the same component but medicines will have a larger concentration than supplements. Sale of supplements at drug stores and in the form of tablets, capsules, liquids or powders makes consumer often confusing supplements with medicines. Now there are no normative documents specifying limits of microbiological impurities in diet supplements. In Polish legislation, diet supplements are subject to legal acts concerning food. Medicines have to comply with microbiological purity requirements specified in the Polish Pharmacopeia. As evidenced with the completed tests, the proportion of diet supplement samples with microbiological impurities is 6.5%. Sales of diet supplements have been growing each year, they are consumed by healthy people but also people with immunology deficiencies and by children and therefore consumers must be certain that they buy safe products. PMID- 26642691 TI - USE OF MEDICINES AMONG STUDENTS OF HIGH SCHOOLS IN THE CZECH REPUBLIC. AB - The aim of the study was to examine the prevalence and type of medicines used by high school students in the Czech Republic and to analyze association between use of medicines during last 6 months and self medication with different socio demographic and lifestyle aspects. A cross-sectional study was conducted in high schools from two regions and three towns in the Czech Republic. The study sample was a student population of nine selected high schools. The study was approved by the local Ethics Committees and school board and was conducted in compliance with the ethical principles of the Declaration of Helsinki. Questionnaires respecting anonymity were distributed to the students during the regular class period. Students answered closed and open questions divided into six sections focussing on their experience with chronic and irregular use of medicines, medicines use during last six months, conditions treated, type and source of used medicines. A modified log-linear Poisson regression model with a robust variance estimator (sandwich) was used for statistical analysis. In total, 979 students, aged 14-21 years (mean age 17 years) participated in the study: 32% were male and 68% female; 19% of students reported regular use of medicines for chronic disease. The use of medicines during the last 6 months was reported by 83% of students; 42% of them reported the use of both prescription and over the counter (OTC) medicines; 22% the use only of OTC, and 31% only prescription medicines. Allergy, asthma, disorders of the thyroid gland, atopic dermatitis, and hypertensive diseases were among the most frequent long-term diseases. The most frequent groups of medicines used for the treatment of long-term diseases were systemic antihistamines, thyroid preparations, and respiratory drugs. Nonsteroidal anti inflammatory medicines, ibuprofen and paracetamol were the most frequently used medicines during last six months. The study results showed quite extensive use of both prescription and OTC medicines in students of high schools between 14-21 years of age in the Czech Republic. Statistically significant associations were found between use of medicines during last 6 months and type of school, sex and chronic diseases, and between self-medication and sex. PMID- 26642692 TI - CYTOTOXICITY AND ANTIGLUCOSIDASE POTENTIAL OF SIX SELECTED EDIBLE AND MEDICINAL FERNS. PMID- 26642693 TI - FLUORESCENCE SPECTROSCOPY STUDY OF THE INTERACTION BETWEEN OCHRATOXIN A AND HUMAN SERUM ALBUMIN IN THE PRESENCE OF FLURBIPROFEN. PMID- 26642694 TI - Changes of Lymphocyte Subgroups in Non-Small Cell Lung Cancer Patients Before and During Chemotherapy. AB - BACKGROUND: The aim of this study was to analyse changes in the lymphocyte subgroups of non-small cell lung cancer (NSCLC) patients before and during four cycles of chemotherapy. METHODS: NSCLC patients (n = 32) who were undergoing their initial chemotherapy or had finished their final chemotherapy >= three months ago were enrolled. The patients were divided into demographic subgroups. Lymphocyte subgroups (n = 13) were examined via flow cytometry before and during chemotherapy (9 time points). RESULTS: NSCLC patients exhibited overall decreases in lymphocyte subgroups during chemotherapy. Most of the subgroups increased slightly before the second cycle of chemotherapy but decreased afterwards compared with pre-chemotherapy levels. Significant decreases (p < 0.05) were observed in lymphocyte subgroups starting at the third cycle of chemotherapy. In the first efficacy assessment, CD4+ and CD8+CD28+ levels in the tumour control group were significantly higher compared with the tumour progression group (p < 0.05). The first and second efficacy assessments revealed that the DC1/DC2 levels in the tumour progression group on the last day of the first cycle and the ninth day of the second cycle were significantly higher compared with the tumour control group (p < 0.05), and the CD4+/CD8+ level in the non-surgery group was significantly higher compared with the surgery group (p < 0.05). CONCLUSIONS: The immune functions of NSCLC patients began to decrease beginning in the second cycle of chemotherapy. During the third and fourth cycles of chemotherapy, immune function was decreased significantly compared with pre-chemotherapy levels. CD4+, CD8+CD28+, and DC1/DC2 cells were associated with tumour progression, representing new biomarkers for chemotherapeutic efficacy in NSCLC. PMID- 26642695 TI - The Synergistic Mechanism of Pemetrexed Followed by Kanglaite was due to KLT Subsequently Inhibiting the Pemetrexed-Activated MAPK Signaling Pathway. AB - BACKGROUND: Kanglaite (KLT) can enhance the cytotoxic effects of chemotherapy; however, the underlying mechanism remains unclear. We investigated the mechanism underlying the cytotoxic synergy between KLT and pemetrexed in NSCLC cell lines. METHODS: A549 and H1975 cell lines were treated with pemetrexed and/or KLT in vitro. IC50 values, the combination index, cell cycle distribution, and signaling pathway analysis were assessed. RESULTS: Cytotoxic interactions between KLT and pemetrexed were dose-dependent in A549 and H1975 NSCLC cell lines. The administration of pemetrexed followed by KLT had a synergistic effect and an advantage over KLT followed by pemetrexed. Concomitant administration in both cell lines indicated that the cytotoxic interactions between KLT and pemetrexed were schedule-dependent. Cell cycle analysis showed that KLT arrested cells mainly in the G2/M phase, whereas pemetrexed arrested cells mainly in the S phase. Exposure to KLT first induced G2/M arrest and subsequently prevented the cytotoxicity of the S phase-specific drug pemetrexed. Signaling pathway analysis showed that exposure to pemetrexed resulted in increased phospho-p44/42MAPK levels which were inhibited by subsequent exposure to KLT. Thus pemetrexed followed by KLT inhibited the MAPK signaling pathway more obviously than KLT followed by pemetrexed. CONCLUSIONS: Pemetrexed followed by KLT had a synergistic effect and an advantage over other sequences in NSCLC cell lines. The synergistic mechanism was due to KLT subsequently inhibiting the pemetrexed-activated MAPK signaling pathway. These findings may provide molecular evidence to support clinical treatment strategies for patients with NSCLC. PMID- 26642696 TI - Autophagy Blockage Enhances Radiosensitivity of Osteosarcoma MG-63 Cells In Vitro. AB - BACKGROUND: Osteosarcoma is the most prevalent malignant neoplasm in children and young adults with a very high propensity for local invasion and early systemic metastases. Radiotherapy has been widely used in metastatic and recurrent osteosarcoma, particularly with chemoresistance. METHODS: To determine whether autophagy is induced by radiation therapy and contributes to cell death of osteosarcoma, we investigated the influence of autophagy blockage on the radiosensitivity of osteosarcoma MG-63 cells in vitro. Firstly, autophagy in the MG-63 osteosarcoma cells after radiation treatment was determined by quantitative GFP-LC3 analysis and autophagy-related molecules analysis by western blotting. Then the viability and death of cells post-blockage of autophagy was determined by MTT assay and flow cytometry. RESULTS: It was demonstrated that autophagy was involved in MG-63 cells subject to radiation. Significantly up-regulated autophagic vesicles in MG-63 cells were subject to radiation. The transformation of LC-3 I to LC-3 II and the expression of autophagy-associated molecules were promoted in the radiation-treated MG-63 cells. Moreover, autophagy could ameliorate the cell viability post radiation. On the other hand, the chemical blockage of autophagy by 3MA not only could downregulate the level of autophagy, but also could reduce cell viability and accelerate apoptosis in the radiation treated MG-63 cells. CONCLUSIONS: Autophagy was involved in the radiation treatment of MG-63 osteosarcoma cells, and autophagy blockage enhances the radiosensitivity of the osteosarcoma cell line MG-63 in vitro. PMID- 26642697 TI - Genetic and Epigenetic Biomarkers of Molecular Alterations in Oral Carcinogenesis. AB - Worldwide, oral cancers represent the 6th most common type of cancer. Oral squamous cell carcinoma (OSCC), which is the most common type of oral cancer, is present in about 90% of the patients with this malignancy. OSCC presents a survival rate up to 80%, if it is detected in an early stage (T1), but if detected at later stages (T3 - T4) the survival rate decreases to 20 - 30%. Due to these survival rates, it is obvious that there is an urgent need to introduce new molecular biomarkers for the early, noninvasive diagnosis of oral cancers from saliva. These biomarkers will aid in increasing the survival rate of the patients for the long-term. MicroRNAs are part of a class of small, non-coding RNAs that contain 19 - 23 nucleotides. MicroRNAs play an important role in the regulation of biochemical mechanisms, cell proliferation, and other cellular mechanisms in the human body. Recently, due to the developments in the field of molecular genetics, salivary microRNAs became important biomarkers in early detection and monitoring of oral cancers by noninvasive methods. We want to present in this review the most important genetic and epigenetic biomarkers involved in oral carcinogenesis, focusing especially on the salivary microRNAs as biomarkers in early diagnosis of OSCC. PMID- 26642698 TI - Status of External Quality Assessment on Tumor Markers in China. AB - BACKGROUND: The nationwide external quality assessment (EQA) of tumor markers in China has been launched for years. The quality of the performance of Chinese clinical laboratories on tumor markers is partly reflected through analysis of EQA results. This report presents an 8-year EQA result of the six most common tumor markers from 2006 to 2013. METHODS: Ten freeze-dried EQA samples were distributed to participants every year. Satisfactory performance was defined as scores of more than 80% of acceptable responses with the evaluation criterion of +/- 25%. The robust coefficient of variability (CV) between laboratories and percentage difference against the target value of each sample were also calculated by year. RESULTS: A total number of 1154 laboratories submitted results in 2013, which was more than threefold of 2006. The proportion of laboratories with satisfactory performance showed an overall rising trend over the years and was up to 95% for the second survey in 2013. The overall decrease of robust CV was observed for all analytes including alpha fetoprotein (AFP), carcinoembryonic antigen (CEA), total prostate specific antigen (t-PSA), cancer antigen 125 (CA 125), cancer antigen 15-3 (CA 15-3), and cancer antigen 19-9 (CA 19-9) except for CEA, which exhibited a rise followed by a flat trend. The percentage difference narrowed gradually and was less than 2% in 2013. CONCLUSIONS: The 8-year EQA results showed a significant enhancement of degree of harmonization of tumor markers in China. However, standardization among various testing systems and improvement of harmonization has yet to be achieved. PMID- 26642699 TI - Genetic Polymorphisms of Toll-like Receptor 4 are Associated with Respiratory Syncytial Virus Infection in a Chinese Infant Population. AB - BACKGROUND: While genetic polymorphisms in Toll-like Receptor 4 (TLR4) have been demonstrated to play an important role in respiratory syncytial virus (RSV) infections in Western populations, the association between TLR4 polymorphisms and RSV infections has not been investigated in Chinese patient populations. The study presented here identifies TLR4 polymorphisms and investigates the association of TLR4 genetic polymorphism with RSV infection in a Chinese infant patient population. METHODS: One-hundred and ninety-six infants hospitalized with RSV infections and 311 healthy control subjects were enrolled in this study. Genetic polymorphisms in the 5' untranslated region (5'UTR), exons, and 3' untranslated region (3'UTR) of the TLR4 gene were screened using PCR and sequencing analysis. The association between the genetic polymorphisms in TLR4, RSV infection risk, and the related disease severity was investigated using Fisher's Exact Test and the Chi-square test. RESULTS: Fourteen different genetic polymorphisms within the TLR4 gene, including two in the 5'UTR, four in the exons, and eight in the 3'UTR were found in the study population. Two polymorphisms, Asp299Gly and Thr399Ile, typically associated with RSV in Caucasian infants were not observed in the Chinese infants. Of the 14 polymorphisms, only rs41426344 (G/C) in the 3'UTR of the TLR4 gene was found to be associated with RSV infection risk and disease severity. CONCLUSIONS: The TLR4 genetic polymorphism rs41426344 may be a specific genetic risk factor in Chinese infants associated with RSV infection and disease severity. PMID- 26642700 TI - Association Between Serum Cystatin C and High Blood Pressure (HBP): A Cross Sectional Study of an Elder Chinese Type 2 Diabetic Population. AB - BACKGROUND: The aim of this study was to investigate the relationship between serum CysC levels and high blood pressure (HBP) and to explore its diagnostic value for HBP in elder type 2 diabetic (T2D) population. METHODS: A total of 369 elder T2D patients (age > 60) were included in this cross-sectional study. Their clinical and biochemical characteristics were detected. Patients were divided into two groups: with HBP and without. The risk factors of HBP were explored by binary logistic regression analysis. RESULTS: The serum concentrations of CysC were 1.08 +/- 0.42 and 0.90 +/- 0.21 mg/L in patients with and without HBP, respectively. Binary logistic regression analysis showed that the significant risk factors were CysC (p = 0.000, OR = 16.977), systolic blood pressure (p = 0.000, OR = 1.087), and diabetes duration (p = 0.000, OR = 1.289). The prevalence of HBP increased with CysC (p < 0.05), and the prevalence of HBP in patients with CysC >= 1.2 mg/L was much higher than the other three quartile groups. The risk of HBP dramatically increased in patients with cystatin C >= 1.2 mg/L (OR = 1.601, 95% confidence interval 1.239 - 2.069, p = 0.000). After adjusting for gender, age, and diabetes duration, its OR still remained 1.633 (95% confidence interval 1.181 - 2.257, p = 0.003). CONCLUSIONS: There was a strong and independent association between CysC and HBP in elder diabetic population, and cystatin C >= 1.2 mg/L indicated a great increased risk of HBP. PMID- 26642701 TI - Therapeutic Effect of Metformin on Chemerin in Non-Obese Patients with Non Alcoholic Fatty Liver Disease (NAFLD). AB - BACKGROUND: Chemerin is an important risk factor of insulin resistance. Non alcoholic fatty liver has typical characteristics of insulin resistance. The aim of this study was to explore the potential role of chemerin in NAFLD. METHODS: 45 subjects included 22 control subjects (A group) and 23 subjects diagnosed with non-alcoholic fatty liver disease (B group) participated in the study. 23 patients in the NAFLD group received oral daily metformin at a dose of 20 mg/kg/day for 24 weeks follow-up. Chemerin and insulin resistance markers were determined at baseline and 24 weeks. RESULTS: The levels of WHR, BMI, FINS, HOMA IR, TG, ALT, AST, and Chemerin in B group were significantly higher than A group. After 24 weeks of metformin treatment, the levels of WHR, AST, ALT, TG, chemerin and HOMA-IR were significantly reduced (p < 0.05) and other indexes were not changed significantly. Correlation analysis indicated that serum chemerin concentrations were positively correlated with BMI, WHR, HOMA-IR, FINS, TG, ALT, and AST levels. Logistic regression analysis showed chemerin, TG, and ALT were independent variables associated with NAFLD. CONCLUSIONS: These findings showed a significant increase of chemerin level in NAFLD patients. Metformin treatment can improve NAFLD and decrease the level of chemerin. Chemerin, TG, and ALT were independent variables associated with NAFLD. PMID- 26642702 TI - The Serum Value of NO and IL-17 were Increased in Children with Influenza A Viral Pneumonia. AB - BACKGROUND: Influenza A virus can cause severe respiratory infection in children and even result in immune system dysfunction. The aim of this study is to examine the clinical value of peripheral blood lymphocytes and serum nitric oxide (NO) and cytokines in children with influenza A viral pneumonia. METHODS: Thirty children hospitalized with confirmed influenza A viral pneumonia and 30 healthy controls were enrolled in this study. The blood samples were collected from all the children and anti-coagulated with EDTA. The peripheral blood lymphocyte subsets were analyzed by flow cytometry. Griess assay were performed to calculate serum NO and nitrite (NO2-) levels. The serum concentrations of IFN-gamma and IL 17 were measured by ELISA. RESULTS: The serum levels of NO, NO2-, and IL-17 were significantly higher in children with influenza A viral pneumonia than controls (p < 0.01), while the level of IFN-gamma had no significant difference (p = 0.515). Additionally, the patients had significantly lower percentages of peripheral blood CD3+, CD3+CD4+ T lymphocytes, and CD56+CD16+ natural killer (NK) cells than controls (p < 0.05), while CD3+CD8+ and CD4-CD8- (double negative, DN) T lymphocytes did not differ significantly (p > 0.05). Correlation analysis suggests that the serum NO level is positively correlated with IL-17 (p < 0.05). Conclusions: The increased levels of NO and IL-17 may be related to dysregulated lymphocytes' immune response in children with influenza A viral pneumonia. These abnormalities may be the main cause of inflammatory lung damage, and thus have significant prognostic value. PMID- 26642703 TI - Low Serum Amylase is Associated with Gestational Diabetes Mellitus in Chinese Pregnant Women. AB - BACKGROUND: The association between low serum amylase levels and type 2 diabetes mellitus and metabolic syndrome has been clearly disclosed. However, the relationship between serum amylase levels and gestational diabetes mellitus (GDM) has not been extensively studied. This study aimed to assess the association of serum amylase with GDM. METHODS: A cross-sectional study was performed among 878 Chinese pregnant women who underwent detailed prenatal visits in Hangzhou, China. RESULTS: A total of 108 (12.30%) subjects fulfilled the diagnostic criteria of GDM. Patients with GDM had significantly lower levels of serum amylase than those without GDM. The prevalence rate of GDM decreased across serum amylase increasing tertiles (p for trend < 0.001). Correlation analysis showed that serum amylase level was negatively correlated with fasting plasma glucose, 1hPG, 2hPG, HOMA-IR, triglyceride, free fatty acid, and thyroid stimulating hormone (all with p < 0.05). Multiple logistic regression showed that low serum amylase level predicted increased risk of GDM. CONCLUSIONS: Our findings suggest that low serum amylase level is significantly associated with increased risk of GDM. PMID- 26642704 TI - Expressions of CD96 and CD123 in Bone Marrow Cells of Patients with Myelodysplastic Syndromes. AB - BACKGROUND: Our goal was to detect the expression of CD96 and CD123 in myelodysplastic syndromes (MDS) and their proliferation and differentiation characteristics. METHODS: Forty-three patients with MDS, thirteen AML patients diagnosed in the Hematology Department of General Hospital of Tianjin Medical University, and sixteen healthy controls were enrolled in this study. The expressions of CD96 and CD123 on CD34+CD38- bone marrow cells (BMC) of these patients and controls were measured by FACS. CD114 (GCSFR), EPOR, and CD110 (TPOR) expression on their CD34+CD38-CD96+ and CD34+CD38-CD96- BMC and these cells' apoptosis (Annexin V) were also detected by FACS. RESULTS: MDS patients had a significantly higher proportion of CD34+CD38-/CD34+ BMC (22.72 +/- 23.91%) than normal controls (8.63 +/- 9.35%) (p < 0.01). The expressions of CD34+CD38 CD96+/CD34+CD38- BMC and CD34+ CD38-CD123+/CD34+CD38- BMC of MDS patients (21.18 +/- 24.06%, 31.62 +/- 28.42%, respectively) were significantly higher than those of normal controls (11.23 +/- 17.91%, 9.29 +/- 12.63%) (p < 0.01). The expressions of CD34+CD38-CD96+/CD34+CD38- BMC and CD34+CD38-CD123+/CD34+CD38- BMC in the high-risk MDS group (26.25 +/- 27.64%, 37.56 +/- 31.01%) was significantly higher than those in the low-risk group (11.44 +/- 10.88, 15.53 +/- 10.96%) (p < 0.05). The expression levels of CD123 and CD96 were significantly correlated with the proportion of bone marrow blasts (r = 0.384, p < 0.05; r = 0.625, p < 0.05). The expressions of CD114, CD110, and Annexin V in CD34+CD38-CD96+ BMC (7.23 +/- 10.25%, 0.52 +/- 1.23%, 2.96 +/- 3.84%, respectively) were significantly lower than those in CD34+CD38-CD96- BMC (24.35 +/- 21.74%, 12.03 +/- 10.91%, 13.69 +/- 17.98%, respectively) of MDS patients (p < 0.05). CONCLUSIONS: There was a higher proportion of CD34+CD38-CD96+ and CD34+CD38-CD123+ cells in bone marrow of MDS patients. Those cells expressed lower cytokine receptors and displayed lower apoptosis. Leukemia stem cells (LSC) in MDS might be contained in those cells. PMID- 26642705 TI - Adenovirus-Mediated E2F-1 Gene Transfer Augments Gemcitabine-Induced Apoptosis in Human Colon Cancer Cells. AB - BACKGROUND: E2F-1 is a transcription factor that stimulates cellular proliferation and cell cycle progression. E2F-1 alone is sufficient to stimulate cells to initiate DNA synthesis, and this unscheduled entry into S phase is a potent trigger of apoptosis. Gemcitabine, a novel pyrimidine analogue with structural and metabolic similarities to cytarabine, also can efficiently induce apoptosis, especially for cancer cells that are already in S phase. Gemcitabine has established antitumor activity against solid tumors, including head and neck, ovarian, and non-small cell lung cancers. Therefore, we hypothesized that exogenous E2F-1 expression could accumulate cells in the S phase and thus sensitize them to gemcitabine. METHODS: We constructed an adenoviral vector (AdCMVE2F-1) to transduce the exogenous E2F-1 gene into human cancer cells. Infection of human colon cancer cells with AdCMVE2F-1 resulted in the overexpression of E2F-1 mRNA and protein in a dose-dependent manner and consequently induced accumulation in S phase as measured by FACS analysis. To assess the synergistic antitumor effect of AdCMVE2F-1 and gemcitabine, the human colon cancer cel lines SW620, DLD-1, and LoVo were infected with AdCMVE2F-1 at various multiplicities of infection and then exposed to various concentrations of gemcitabine 24 hours after infection. RESULT: Isobologram analysis showed that E2F-1-transduced cancer cells exhibited higher sensitivity to gemcitabine treatment compared to control virus-infected cells. Treatment with AdCMVE2F-1 plus gemcitabine enhanced endogenous p53 expression in LoVo cells, which contain wild-type p53; however, the finding that the synergistic effect can also be observed in mutant p53-expressing SW620 and DLD-1 cells suggests that wild-type p53 function may not be necessary for the therapeutic effects of this drug combination. Conclusions: Our data demonstrate that overexpression of ectopic E2F 1 protein may render cels more sensitive to gemcitabine-mediated apoptosis, an outcome that has important general implications for the treatment of human cancer. PMID- 26642706 TI - Prokaryotic Expression of Bioactive Zinc Transporter 8 Antigens and Detection of Diabetes Specific Autoantibodies in a Single Dot Immunogold Filtration Assay. AB - BACKGROUND: Type 1 diabetes mellitus is an autoimmune disease, and islet autoantibodies secreted by auto-reactive plasma cells are diagnostic indicators of the immune processes. Autoantibodies to zinc transporter 8 (ZnT8) have been identified as a novel reliable biomarker for the prediction, diagnosis, monitoring, and prognosis of autoimmune diabetes, complementing the panel of existing diagnostic autoantibodies. Although the enzyme-linked immunosorbent assay (ELISA) and radioimmunoassay are the most frequently used testing methods, they do not allow simultaneous detection of multiple autoantibodies. Another obstacle is the cost of ZnT8 production for antibody assays. This study aimed to develop a cost-effective expression system for the production of two ZnT8 C terminal fragments containing main ZnT8 antigen epitopes and establish an improved reliable and rapid assay for the detection of anti-ZnT8 antibodies with a potential to simultaneously measure multiple autoantibodies. METHODS: The coding codons of the human ZnT8 were optimized for prokaryotic expression and the mutation was achieved using site-directed mutagenesis. A total of 42 newly diagnosed type 1 diabetes patients (16 males and 26 females) and 100 healthy controls (57 males and 43 females) were enrolled for sera. The dot immunogold filtration assay (DIGFA) was evaluated by comparing with ELISA as the "gold standard". RESULTS: Two ZnT8 antigens (arginine and tryptophan ZnT8 at position 325) were successfully produced. We established a rapid DIGFA method for the simultaneous detection of anti-ZnT8 antibodies, with the sensitivity, specificity, accuracy, Youden index, and positive and negative likelihood ratio being 64.3%, 96.4%, 85.7%, 0.607, 18.0, and 0.370, respectively, and the results did not significantly differ from those for ELISA (p = 0.22). CONCLUSIONS: These results demonstrate that the pColdII expression system is suitable for the production of bioactive ZnT8 antigens and that DIGFA can be a rapid, reliable, and highly specific method for the detection of ZnT8 antibodies, which can be potentially applied to identify a panel of diabetes-specific autoantibodies simultaneously. PMID- 26642707 TI - Influence of Duration and Temperature of Transport and Storage Prior to Processing on Cell Quality of Cord Blood Units--A German. Experience. AB - BACKGROUND: In Germany, cord blood needs to be transported to the processing facility to be processed and cryopreserved within 48 hours after collection according to national guidelines. During that time, a temperature of 22 +/- 4 degrees C must be maintained. The purpose of this study was to analyse the influence of temperature during transport and storage prior to processing and cryopreservation on stem cells in 2460 both autologous and allogeneic umbilical cord blood samples. METHODS: Total and viable CD45+ cells, total and viable CD34+ cells, and mononuclear cells (MNC) of cord blood and resulting leucocyte concentrate both before and after freezing were analysed by flow cytometry. Transport protocols and the records of temperature measuring chips used in transport were evaluated in order to analyse how long each unit was exposed to which temperature ranges. RESULTS: On average, the cord blood preparations were delivered within 16.4 +/- 6.3 hours. No cord blood was delivered and processed later than 48 hours after donation. Temperature of transport and storage before processing had minor but sometimes significant effects on cell viability. A temperature range of 20 - 24 degrees C showed best survival rates for CD34+ cells and highest colony forming potential. CONCLUSIONS: The temperature prior to processing has little yet sometimes significant effects on cell viability in stem cell concentrates prepared from cord blood. However, the absolute differences in cell viabilities are quite small. Therefore, the effect is clinically negligible in a range from 4 degrees C to 28 degrees C if cryopreservation is done within 48 hours. PMID- 26642708 TI - The Relationship Between Lipoprotein-Associated Phospholipase A(2), Cholesteryl Ester Transfer Protein and Lipid Profile and Risk of Atherosclerosis in Women with Iron Deficiency Anaemia. AB - BACKGROUND: The relationship between lipoprotein-associated phospholipase A2 (Lp PLA2), cholesteryl ester transfer protein (CETP), and risk of atherosclerosis in IDA women has not been fully clarified. The objective of this study was to investigate lipid-related atherogenic risk factors in women with IDA. METHODS: Eighty women with IDA and 80 age-matched healthy women as the control group were enrolled in the study. Serum lipid profile, Lp-PLA2, and CETP were determined. Correlations between lipid-related atherogenic risk factors were analyzed by Pearson's correlation analyses. RESULTS: TG levels were higher and HDL-C levels were lower in the IDA women. Lp-PLA2 activity, Lp-PLA2 concentration, and CETP concentration were higher in the IDA women. There were negative correlations between activity or concentration of Lp-PLA2 and hemoglobin level (r = -0.29 or r = -0.33, p < 0.05), as well as HDL-C level (r = -0.38 or r = -0.35, p < 0.05). Positive correlations were observed between Lp-PLA2 activity and Lp-PLA2 concentration and low-density lipoprotein cholesterol (LDL-C) level (r = 0.41 or r = 0.36 respectively, p < 0.05). CETP concentration was negatively correlated with hemoglobin (r = -0.56, p < 0.01) and HDL-C level (r = -0.35, p < 0.05) and positively correlated with triglyceride level (r = 0.34, p < 0.05). CONCLUSIONS: Increases in the levels of circulating CETP and Lp-PLA2 might partly play a role in the atherogenic disturbances in patients with IDA through increased susceptibility to lipid peroxidation. PMID- 26642709 TI - PAX1 Methylation Hallmarks Promising Accuracy for Cervical Cancer Screening in Asians: Results from a Meta-Analysis. AB - BACKGROUND: DNA methylation has been proposed as a potential biomarker for cervical cancer detection. This study aimed to evaluate the diagnostic role of paired boxed gene 1 (PAX1) methylation for cervical cancer screening in Asians. METHODS: Eligible studies were retrieved by searching the electronic databases, and the quality of the enrolled studies was assessed via the quality assessment for studies of diagnostic accuracy (QUADAS) tool. The bivariate meta-analysis model was employed to generate the summary receiver operator characteristic (SROC) curve using Stata 12.0 software. Cochran's Q test and I2 statistics were applied to assess heterogeneity among studies. Publication bias was evaluated by the Deeks' funnel plot asymmetry test. RESULTS: A total of 9 articles containing 15 individual studies were included. The SROC analysis showed that single PAX1 methylation allowed for the discrimination between cancer/high-grade squamous intraepithelial lesion (HSIL) patients and normal individuals with a sensitivity (95% confidence interval) of 0.80 (0.70 - 0.87) and specificity of 0.89 (0.86 - 0.92), corresponding to an area under curve (AUC) of 0.92. Notably, our subgroup analysis suggested that combing parallel testing of PAX1 methylation and HPV DNA (AUC, sensitivity, and specificity of 0.90, 0.82, and 0.84, respectively) seemed to harbor higher accuracy than single HPV DNA testing (AUC, sensitivity, and specificity of 0.81, 0.86, and 0.67, respectively). CONCLUSIONS: PAX1 methylation hallmarks a potential diagnostic value for cervical cancer screening in Asians, and parallel testing of PAX1 methylation and HPV in cervical scrapings confers an improved accuracy than single HPV DNA testing. PMID- 26642710 TI - Proteomic Analysis of Plasma in Adult Active Pulmonary Tuberculosis Patients with Diabetes Mellitus. AB - BACKGROUND: There is a high burden of both diabetes and tuberculosis in China. Diabetes depresses the immunologic response that facilitates the development of infectious diseases, including infection by Mycobacterium tuberculosis, the agent of tuberculosis. Tuberculosis is the third cause of death among subjects with non communicable diseases, and among the non-communicable diseases, diabetes is one of the most important. The relationship between diabetes and tuberculosis has already been object of many investigations but the association between these two diseases is not fully understood. The aim of this study was to determine whether relative qualitative and quantitative differences in protein expression of plasma could be related to active pulmonary tuberculosis complicated with diabetes. METHODS: Biological parameters are useful tools for understanding and monitoring complicated disease processes. Our study employed two-dimensional gel electrophoresis and mass spectrometry to analyze the proteins associated with active pulmonary tuberculosis complicated with diabetes. RESULTS: Under the baseline condition, we found that the levels of alpha-1 antitrypsin precursor, vitamin D-binding protein precursor, CD5 antigen like precursor, clusterin precursor, apolipoprotein A-I precursor, haptoglobin, and fibrinogen gamma-chain differed between patients with active pulmonary tuberculosis and active pulmonary tuberculosis complicated with diabetes subjects. Western blotting results confirmed differential expression of clusterin. CONCLUSIONS: We identified active pulmonary tuberculosis complicated with diabetes-associated proteins in plasma. C terminal haptoglobin is a possible candidate protein of interest, which might be a link between active pulmonary tuberculosis and diabetes. The dynamics of protein expression during disease progression may improve our understanding of the pathogenesis of active pulmonary tuberculosis complicated with diabetes. PMID- 26642711 TI - Association of FOXP4 Gene with Prostate Cancer and the Cumulative Effects of rs4714476 and 8q24 in Chinese Men. AB - BACKGROUND: The tumor suppressor forkhead box P4 (FOXP4) plays important roles in oncogenesis, and the FOXP4 variant rs1983891 is associated with prostate cancer (PCa) in several studies. However, association studies conducted in Northern and Southern Chinese have provided conflicting results. Therefore, here we performed fine mapping of FOXP4 to identify the association with PCa and the potential application in Chinese men. METHODS: We examined 11 variants spaced approximately 55 kb apart spanning FOXP4 using high-resolution melting-curve analysis and sequencing methods in 286 PCa patients and 630 controls, and the association between these variants and PCa risk was evaluated. Additionally, we evaluated the cumulative effect of rs4714476 and 2 variants in 8q24 (rs16901966, rs10090154) confirmed in our previous study. RESULTS: Of 11 SNPs, only rs4714476-C at the 5' near gene of FOXP4 was associated with increased age-adjusted PCa risk (p = 0.012, OR = 1.32, 95% CI = 1.06 - 1.63) and aggressive PCa (p = 0.026). The CG haplotype covering rs4714476-C demonstrated significant differences between PCa cases and controls (p = 0.009). The cumulative effect analysis showed men who carried any combination of 1, 2, or 3 risk genotypes had a gradually increased PCa risk (age-adjusted OR is from 1.244 to 3.312). CONCLUSIONS: These data suggest that rs4714476 at the 5' near gene of FOXP4 potentially contributes to the susceptibility of PCa in Chinese men. The cumulative effect of rs4714476 at FOXP4 and 8q24 could increase PCa risk. PMID- 26642712 TI - Phospholipid Scramblase 1 Interacts with Midkine and Regulates Hepatic Cancer Cell Proliferation and Migration. AB - BACKGROUND: Mounting evidence indicates that nuclear targeting by growth factors plays an indispensable role on their biological activities. Midkine (MK) is a multifunctional growth factor and has been discovered to play important roles in carcinogenesis. MK has been reported to localize to the nucleus and nucleolus of HepG2 cells and is involved in cell proliferation and apoptosis. METHODS: The interaction was reconfirmed by in vitro pull down and in vivo coimmunoprecipitation (Co-IP), also by the colocalization in the HepG2 cells. The proliferation and migration was determined by MTT and trans-well assay. RESULTS: PLSCR1 was identified as a novel MK-interacting protein. Notably, PLSCR1 interacted with MK in the cell nucleus and regulated hepatic carcinoma cell proliferation and migration. CONCLUSIONS: This study suggests that PLSCR1 positively regulates hepatic carcinoma cell proliferation and migration through interacting with MK, thus deepening our understanding on the regulation of midkine during hepatic carcinoma growth and metastasis. PMID- 26642713 TI - Variance of Serum Lipid Levels in Stroke Subtypes. AB - BACKGROUND: An increasing number of epidemiological studies have identified a close relationship between dyslipidemia and atherosclerotic stroke. Indeed, lipid metabolism is significantly different among the different ischemic stroke subtypes. There are few studies available regarding risk factors for specific subtypes of ischemic stroke, and in particular, there is little evidence about the role of dyslipidemia. The aim of this study is to determine the relationship between acute ischemic stroke subtype and serum lipid level. METHODS: The levels of serum lipid including TC, TG, LDL-C, HDL-C, apoA, apoB, apoE, and LP (a) were tested in 362 ischemic stroke patients and 181 healthy controls. Lipid levels were analyzed in stroke subtypes according to the TOAST classification. RESULTS: Levels of TC, TG, LDL-C, apoA, apoB, apoE, and LP (a) were significantly higher and HDL-C levels were significantly lower in the patient group relative to control. The TC/HDL-C ratio, TG/HDL-C ratio, and LDL-C/HDL-C ratio were remarkably higher in the patient group. The levels of TC, TG, LDL-C, apoA, apoB, apoE, and LP(a) were markedly higher and HDL-C was markedly lower in the large artery atherosclerosis stroke subtype relative to the cardioembolism subtype. Compared with the small-vessel occlusion group, the level of LP(a), TC, and TC/HDL-C were strikingly higher in the cardioembolism group. The TC/HDL-C ratio was different among subgroups, with the large-artery atherosclerosis group exhibiting the highest value. For TC, TG, LDL-C, apoA, apoB, apoE, LP(a), TC/HDL C, TG/HDL-C, and LDL-C/HDL-C levels a statistically significant difference was found between the large-artery atherosclerosis group and the small-vessel occlusion group. CONCLUSIONS: We found that LDL-C and TC levels may be independent predictors for the occurrence of large-artery atherosclerotic stroke. PMID- 26642714 TI - Genome-Wide Analysis of Long Noncoding RNA Expression Profiles in Human Xuanwei Lung Cancer. AB - BACKGROUND: Long noncoding RNAs (lncRNAs) play an important role in various biological processes involved the development and progression of lung cancer. However, their expression signature in Xuanwei lung cancer (XWLC) remains unknown. METHODS: High throughput microarray assay was performed to detect lncRNA and mRNA expression profiles in five paired human XWLC and adjacent normal tissues. Bioinformatic analyses (gene ontology, pathway, and net-work analysis) were applied for further study of these differentially expressed mRNAs. An additional 33 paired XWLC samples were collected to verify the expression levels of 6 candidate lncRNAs using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). RESULTS: Using abundant and varied probes, about 37,000 lncRNAs and 34,000 mRNAs were assessed in our micro-array. 1,484 lncRNAs and 1,997 mRNAs were differentially expressed in XWLC and adjacent normal samples (fold change >= 2.0). Using qRT-PCR validation, six candidate lncRNAs were differentially expressed in XWLC and adjacent normal tissues. The qRT-PCR results were consistent with the microarray data. Among these, FENDRR and SGOL1-AS1 were the most aberrantly expressed lncRNAs. CONCLUSIONS: This study firstly ascertained the expression profile of lncRNAs in XWLC by microarray. The results revealed that many lncRNAs were differentially expressed in XWLC and adjacent normal tissues. Further investigation of the differentially expressed lncRNAs may serve as new biomarkers for diagnosis of XWLC or novel therapeutic targets. PMID- 26642715 TI - The Cutoff Level for Urine Protein in Urine Immunofixation Electrophoresis. AB - BACKGROUND: Immunofixation electrophoresis (IFE) maintains its importance in diagnosing monoclonal gammopathies. In particular, urine IFE detects free light chains (FLC) in urine samples even at low concentrations and offers higher sensitivity compared to serum electrophoresis and serum IFE. The aim of the present study was to determine the place and significance of quantitative urinary protein measurement before IFE in interpreting the results of subsequent IFE and to determine the most appropriate protein concentrations for the appearance of bands. METHODS: The records of a total of 600 patients, who underwent screening for Bence Jones proteinuria using IFE on 24-hour urine, were retrospectively reviewed. Urine IFE was performed using Helena SAS-I and SAS-I devices. The total protein concentration in the urine was quantitatively determined by the Pyrogallol red method, and the urine albumin level was determined using the immunoturbidimetric method. These analyses were measured on an Olympus/Beckmann AU5800. RESULTS: The evaluation of IFE results revealed that 311 patients had normal results, 108 patients had monoclonal bands, five patients had biclonal bands, 28 had polyclonal bands, and 148 patients had various degrees of proteinuria. ROC curves were created in order to determine the most appropriate urinary protein and albumin levels to observe bands in IFE. Accordingly, urine baseline protein level (mg/dL) showed the highest AUC value (cutoff value: 19.4 mg/dL, sensitivity: 92%, specificity: 98.2%, AUC: 0.972). CONCLUSIONS: The present study showed that quantitative protein measurement before IFE eliminated the disadvantages associated with the IFE method and its interpretation. PMID- 26642717 TI - Multiplex PCR for Diagnosis of Salmonella enterica Serovar Typhi. AB - BACKGROUND: Typhoid fever caused by Salmonella enterica serovar Typhi is endemic in developing countries. Its detection by culturing on specific media or serological methods like the Widal test is time consuming and/or less sensitive than the PCR technique. Here we apply a multiplex PCR dependent detection for S. Typhi using two specific primers for invA and fliC genes. METHODS: 76 patients with clinical suspicion of typhoid fever were examined. Two sets of primers derived from invA and fliC genes specific for Salmonella spp. and S. Typhi were used as multiplex PCR in order to detect the pathogen in their blood samples. This was compared with traditional culturing methods on two different chromogenic media [Melibiose, mannitol, and sorbitol (MMS) agar media specific for S. Typhi and Salmonella-Shigella (SS) agar media]. Also, the suspected typhoid samples were tested by Widal O antigen. RESULTS: The sensitivities of culturing, Widal test, and multiplex PCR were 61.36%, 88.64%, and 100%, respectively, while their specificities were 100%, 62.50%, and 86.49%, respectively. The multiplex PCR showed higher efficiency reaching 93.42% compared to culturing and Widal test which was 77.63%. CONCLUSIONS: The high sensitivity, specificity, and efficiency of the studied multiplex PCR encourage us to recommend it as a useful tool for S. Typhi detection not only in clinically suspected negative culture individuals, but also for the false positive Widal test cases of typhoid fever in endemic regions. PMID- 26642716 TI - X-linked Adrenoleukodystrophy, The Tunisian Experience. AB - BACKGROUND: X-linked adrenoleukodystrophy is a genetic disease affecting the degradation of very long chain fatty acids. This study aims to describe the clinical phenotype and biochemical feature of Tunisian patients; it also seeks to describe recognition of pattern analysis on the level of very long chain fatty acids in plasma for the visual discrimination of X-linked patients from a healthy group. METHODS: During the last 21 years, 19 patients were diagnosed with X linked adrenoleukodystrophy based on the clinical features combined with the area percentage of hexacosanoic acid (C26:0) as well as the ratio of C26:0 and lignoceric acid (C24:0) relative to behenic acid (C22:0) by gas chromatography. For the biochemical diagnosis of X-ALD with better accuracy, it has been desired to transform the numerical values of these biochemical markers into visually discriminating patterns. RESULTS: The clinical features of 19 patients aged between 4 to 47 years were classified into cerebral form (57.8%), adrenomyeloneuropathic (26.3%), and a few patients were asymptomatic. The ratio C24:0/C22:0 ranged from 1.12 to 2.41 (normal value: 0.46 - 0.9) and C26:0/C22:0 ratio ranged from 0.03 to 0.36 (normal value: 0.003 - 0.009). The concentration of fatty acids with 22 or more carbons in body fluid did not change with age in control subjects and patients. For the visual diagnostic of patients, the Scatter plot was a reliable method for the diagnostic patterns of very long chain fatty acids of patients with X-linked adrenoleukodystrophy disorders. CONCLUSIONS: The incidence of X-linked adrenoleukodystrophy disorders is under diagnosed in Tunisia. The diagnosis was confirmed by enzymatic activity study and molecular analysis but the analysis of very long chain fatty acids by gas chromatography remains a reliable tool for the diagnosis and early initiation of the treatment. PMID- 26642718 TI - Metabolic Syndrome, Independent Predictor for Coronary Artery Disease. AB - BACKGROUND: Metabolic syndrome (MS) was reported to be associated with coronary artery disease (CAD). The aim of the present study was to assess the association between MS and CAD angiographic severity and to search the predictive value of MS and its individual components for CAD. METHODS: 428 patients who underwent elective coronary angiography at the Cardiology Department were included in the study. MS was defined according to National Cholesterol Education Program (NCEP) Adult Treatment Panel III criteria. CAD severity was determined by Gensini scors. RESULTS: The proportion of CAD (+) who had MS was significantly higher compared to CAD (-) (63.6% vs. 48.6%, p = 0.020). Gensini score and number of MS components were positively correlated (r = 0.144, p = 0.019). The adjusted predictive abilities for angiographic CAD of MS and its individual components showed that high FBG and high TG are predictive factors for CAD in binary logistic regression analysis (OR = 2.238, 95% CI 1.111 - 4.508, p = 0.024 vs. OR = 2.200, 95% CI 1.078 - 4.492, p = 0.030). The OR for CAD risk of different phenotypes in high FBG and/or HTG shows that this combination increased the OR significantly to 2.307. Among the quartets, the cluster with high BP and low HDL C was the highest risk (OR = 4.879). However, the combination including all components of MS was a significant contributor to CAD risk. CONCLUSIONS: The MS score correlates with the angiographic severity of CAD. The predictive ability for CAD was stronger with high FBG and high TG and associated low HDL-C and high BP, which seem to act synergistically as risk factors for CAD. Therefore, to prevent or decrease this risk of CAD, clinicians should screen for individual abnormalities of MS, mainly elevated blood glucose level and TG. PMID- 26642719 TI - Antitumor Effect of C21 Steroidal Glycosides on Adenoid Cystic Carcinoma Cell Line SACC83. AB - BACKGROUND: To observe the anti-tumor effects and possible mechanism of C21 steroidal glycoside (17-beta-Marsdenia tenacissima glycoside B (17-beta tenacigenin B)) and Xiaoaiping injection in the adenoid cystic carcinoma cell line SACC83. METHODS: We used the salivary adenoid cystic carcinoma cell line SACC83 for the study and used MTT, flow cytometry, and Western-blot (WB) to study the anti-tumor efficacy and mechanism of 17-beta-tenacigenin B and Xiaoaiping injection. Three groups were divided as follows: group 1: control group (without drug treatment), group 2: SACC83 treated with 17-beta-Marsdenia tenacissima glycoside B, group 3: SACC83 treated with Xiaoaiping injec- tion. RESULTS: The 17 beta-tenacigenin B had no significant anti-tumor effect while the Xiaoaiping injection had a dosage-dependent growth inhibition effect on the adenoid cystic carcinoma cell line SACC83. According to WB, after the administration of the 17-p tenacigenin B, the expression of apoptosis-related protein was not very significant; however, after the administration of the Xiaoaiping injection, the expression of apoptosis inhibition protein bcl-2 decreased while the expression of apoptosis promotion protein bax increased. CONCLUSIONS: The 17-beta tenacigenin B had no obvious anti-tumor effects while the Xiaoaiping injection had good anti-tumor effects. Even though the 17-beta-tenacigenin B is an important component of the Xiaoaiping injection, in the in vitro experiment, compared with the Xiaoaiping injection, the 17-beta-tenacigenin B showed no good anti-tumor effects. However, we need further studies on in vivo experiments of 17 beta-tenacigenin B and the anti-tumor effect of other C21 steroidal glycoside monomers in the Xiaoaiping injection. PMID- 26642720 TI - Neuroprotection by Carbenoxolone Against Ischemia Injury Involves PI3K/Akt Pathway. AB - BACKGROUND: Previous experimental studies have shown some protective effects on brain ischemic injures in vivo and in vitro models. However, cotreatment with carbenoxolone (Cbx) and phosatidylinositol 3-kinase (PI3K) inhibitor LY 294002 to a focal cerebral ischemia and reperfusion rat model has not been studied yet. Here we investigate their protective effects on neural cells and examine the function of PI3K/Akt pathway in this protection. METHODS: Both flow cytometry and western blot were used quantitatively and qualitatively to determine cell apoptosis. RESULTS: The neural cell apoptosis is related with Cx43, and Bcl-2/Bax and caspase 3 pathways. The percentage of apoptosis cells following transient middle cerebral artery occlusion (MCAO) in mice decrease with the treatment of Cbx. Our data demonstrated that treatment with Cbx reduced cerebral injury in rats exposed to transient focal ischemia and reperfusion (I/R), and this was mediated by the activation of the PI3K/Akt pathways as well as by blocking the caspase 3 apoptosis pathway. LY294002 blocked the increase in phospho-AKT evoked by Cbx and abolished the associated protective effect. CONCLUSIONS: Taken together, these findings provide evidence that Cbx protects neurons against ischemia injury and this neuroprotective effect involves the PI3K/Akt pathway. PMID- 26642721 TI - Tetrandrine Inhibits the Intracellular Calcium Ion Level and Upregulates the Expression of Brg1 and AHNAK in Hep-2 Cells. AB - BACKGROUND: Tetrandrine has been found to inhibit the growth of various types of tumor cells, but the underlying molecular mechanism remains to be determined. We aimed to investigate the effects of tetrandrine on human laryngeal carcinoma Hep 2 cells. METHODS: Cell viability was tested using the 3-(4,5-dimethylthiazol-2 yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The cell cycle was analyzed using flow cytometric analysis. The intracellular Ca2+ concentration was monitored using the membrane-permeable Ca(2+)-sensitive fluorescent probe fluo-3 acetoxymethyl ester-AM (Fluo3-AM). The mRNA and protein expression of Brgl and AHNAK were evaluated by real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and immunocytochemistry, respectively. RESULTS: Tetrandrine significantly inhibited the proliferation of Hep-2 cells as indicated by an IC50 value of 13.28 MUg/mL. Tetrandrine induced cell cycle arrest at the G1 phase and decreased the intracellular concentration of Ca2+ in a concentration dependent manner. Intriguingly, tetrandrine upregulated Brg1 expression in a dose and time-dependent pattern and elevated the expression of AHNAK in Hep-2 cells. CONCLUSIONS: Our results suggest that tetrandrine may inhibit the growth of Hep-2 cells by decreasing the intracellular concentration of Ca2+ and upregulating the expressions of Brg1 and AHNAK. PMID- 26642722 TI - CCL28 Cannot Replace IgE for Severity by Objective SCORAD Index in Atopic Dermatitis in Children. AB - BACKGROUND: Recently, CC chemokine ligand28 (CCL28) has been reported as a severity marker in atopic dermatitis. We studied the association between objectively observed lesions and the level of CCL28 in children patients. METHODS: A total of 105 children patients were grouped by the objective Scoring Atopic Dermatitis index (SCORAD). Total IgE, specific IgE, complete blood count, and serum level of CCL28 were evaluated. RESULTS: The mean age of the subjects was 5.3 (range, 0 - 12 years). The median SCORAD was 21.4 and consisted of mild 70%, moderate 25%, and severe 6% disease. There were no statistical differences among severity groups for CCL28 or for total IgE. Total IgE showed positive correlation with eosinophil count (r = 0.429, p < 0.01), and SCORAD (r = 0.210, p < 0.05). CONCLUSIONS: The disease severity of atopic dermatitis in children is not correlated to the level of CCL28, but rather related to that of total IgE. PMID- 26642723 TI - Highly Sensitive and Efficient Screening of Streptococcus Agalactiae Through Improved Real-Time PCR Protocols and Optimized Analytical Parameters. AB - BACKGROUND: The detection of Streptococcus agalactiae colonization during pregnancy is important in order to prevent neonatal infections and reduce mortality rates. METHODS: A highly sensitive (up to 1,000 UFC/mL), fully automated, and cost effective cylB specific real-time PCR protocol was developed for the detection of S. agalactiae in anal and vaginal swabs of pregnant women. RESULTS: From the 62 test subjects, 24 were considered positive by PCR (38%) and 14 by culture (24%; p = 0.0015). CONCLUSIONS: The observed discrepancies and the reduced turnaround time justifies molecular screening for S. agalactiae. PMID- 26642724 TI - Comparison of a Point-Of-Care Test for High-Sensitivity C-Reactive Protein with an Established Immuno-Nephelometric Method. AB - BACKGROUND: High-sensitivity C-reactive protein (hsCRP) is an established marker of cardiovascular risk particularly in primary prevention. For years, it was exclusively measured using automated methods in clinical laboratories, but point of-care tests (POCT) are urgently needed to simplify and hasten the determination of hsCRP. METHODS: This study compared a novel hsCRP POCT with an established nephelometric method in 104 patients showing a broad spectrum of cardiovascular risk. RESULTS: The results indicated a moderate agreement of the POCT with the standard method, with a sensitivity of 87% and a specificity of 80% to detect elevated hsCRP (> 1 mg/L). CONCLUSIONS: The minimization of sample volume appears to be the most promising strategy for future test improvement. PMID- 26642725 TI - [Cancer-related Cognitive Impairment: Current Knowledge and Future Challenges]. AB - Cancer patients often suffer from various distresses, including cognitive impairment. Cognitive impairment during and after cancer diagnosis and treatment are collectively called "Cancer-related cognitive impairment (CRCI)". The number of publications about cognitive impairment due to cancer therapy, especially chemotherapy, hormonal therapy, and radiotherapy, has been growing. Patients often worry not only about their disease condition and therapies, but also experience concerns regarding their memory, attention, and ability to concentrate. Even subtle CRCI can have a significant impact on social relationships, the ability to work, undergo treatment, accomplish meaningful goals, and the quality of life. Longitudinal studies of cancer patients indicated that up to 75% experience CRCI during treatment. Furthermore, CRCI may persist for many years following treatment. However, it is not well understood by most physicians and medical staff. CRCI can be mediated through increased inflammatory cytokines and hormonal changes. In addition, the biology of the cancer, stress, and attentional fatigue can also contribute to CRCI. Genetic factors and co occurring symptoms may explain some of the inter-individual variability in CRCI. Researchers and patients are actively trying to identify effective interventional methods and useful coping strategies. Many patients are willing to discuss their disease condition and future treatment with medical staff and/or their families. Some patients also hope to discuss their end-of-life care. However, it is difficult to express their will after developing cognitive impairment. Advance care planning (ACP) can help in such situations. This process involves discussion between a patient, their family, and clinicians to clarify and reflect on values, treatment preferences, and goals to develop a shared understanding of how end-of life care should proceed. The number of cancer patients with cognitive impairment has been increasing owing to the super-aging of society. Psychiatrists need to develop appropriate care for them and understand the value of ACP. In this review, an outline of CRCI is given, especially related to cancer therapy such as chemotherapy, hormonal therapy, and radiation therapy. In addition, the importance of ACP to facilitate a living will for patients likely to develop impaired cognitive functions in the future is described. PMID- 26642726 TI - [A Clinical Case of Grief Hallucination through the Mourning Work Normal Grief and Spiritual Care]. AB - Auditory or visual hallucinations of a deceased person are well known in the normal course of the bereavement process. According to DSM-5, this symptom is included in the associated features supporting diagnosis of persistent complex bereavement disorder. In Japan, however, little is known about these hallucinatory experiences during grieving, and few reports on their prevalence are available. Here, we have reported a clinical case of such experiences following the loss of a spouse. A 66-year-old patient presented to the outpatient department with insomnia after her husband's death. She was preoccupied with a sense of loss and absolute loneliness. One day, she confessed to regularly encountering her husband's ghost at night; the ghost was distinguishable from a dream and provided the bereaved wife with some degree of comfort. The appearances lasted for 15 months and occurred several times a week without disturbing her social functioning. She gradually became aware that her husband was returning from the spirit world to give her solace. Her treatment was focused on resolving her conflicting feelings concerning her grief at his death and her relief at his no longer suffering from disease. While accepting her experiences, she started to review the days they spent together and appreciated his attachment. Therefore she completed the work of mourning and the ghost no longer appeared. One year after the departure of the ghost, she still attends the hospital regularly and there has been no recurrence. A reconstruction of her internal world leads us to conclude that the support of normal grief with such hallucinations prevents the intense experience of loss from generating pathological grief. Furthermore, we suggest reconsidering the importance of the mourning work and the inclusion of both the bereaved and deceased person in the medical context. PMID- 26642727 TI - [Spirituality and Resilience in Psychiatric Medicine]. AB - At the end of the twentieth century, the WHO tried to change the definition of health. Until then, the health of a person comprised biological, psychological, and social aspects. At the conclusion of the twentieth century, we understood that happiness required more than just these 3 aspects of health. So, the WHO discussed the addition of a spiritual aspect for the new definition of health. It is difficult to translate spirituality into Japanese. However, spirituality is very important in psychiatric care. For example, people who have spiritual pain or grief of loss experience a need for spiritual care. In the recovery process, the importance of resilience has been reported numerous times. Doctor Mieko Kamiya was an excellent psychiatrist and poet. After she contracted tuberculosis and recuperated alone, she fell into a deep depressive state and spent days of distress. In extreme situations, she had the mysterious experience of having her whole body bathed in light. She felt the presence of a great, natural power. Her spirituality and resilience awakened. So, she recovered to strong health through resilience and spirituality. Strong resilience was induced by spirituality. Spiritual care is important in disasters. PMID- 26642728 TI - [Resilience and the Role of Spiritual Care]. AB - One of the main goals of spiritual care is to elicit the patient's own power. Previously, religious professionals encouraged people to believe in God, Buddha, or spiritual beings and helped those who were suffering. The power to recover was believed to come from outside human beings. For example, the foremost role of hospital chaplains in the past was to pray to a transcendental being (s) with those who were suffering. When resilience was expected, the first thing to do was to rely on the transcendental being (s). In contrast, the priority in contemporary spiritual care is to trust the resilience of those with difficulties, even when the concerned believe in a transcendental power. The emphasis is on human beings and things which can be seen, rather than transcendental beings. Through this kind of expectation, resilience is to be expected and becomes a source of hope. However, there may be cases in which resilience does not grow. On caring for the dying or those with marked grief, just facing spiritual pain may be the prevalent situation. Care workers need to accept the reality that overcoming spiritual pain is not easy. Then, the paradox is that facing weakness itself can become a source of power. This may be experienced in spiritual care, and it helps elucidate an aspect of resilience. The author's position is that there are many cases in which power is elicited from weakness. Examples are found through the activities to provide aid following the Great East Japan Earthquake, in the spiritual care of dying persons at home, as well as in the care of psychiatric patients who are liberated from the obsession that they must be cured. PMID- 26642729 TI - [Resilience and Spirituality Considered from Viewpoint of Existential Philosophy of Karl Jaspers]. AB - After publishing "General Psychopathology" in 1913, Jaspers turned his attention to serious philosophical contemplation. Using the term grenzsituation (limit situation) as a key concept, he first presented a framework to shed light on the pathology of both individuals and groups, and this led on to include the perspective of resilience. He then used three more key concepts, transzendenz (transcendence), chiffer (cipher), and unverstadliche (unintelligible) to offer a framework to focus on the possibilities of human existence. In the field of medicine, this is useful to support a spiritual approach which is discussed in palliative treatment. The philosophy developed by Jaspers can be considered as indicating a practical form of guidance for people to find self-support from a limit situation where they have lost their own support, and finally, come to a degree of mutual acceptance. Mutual acceptance is made possible at the level of ciphers, in which specific meaning remains undefined, by directing both the self and the other toward a state of "transcendence". Nowadays there is a trend for those chaplains involved in spiritual care from a specialist point of view to be trained to effectively transcend any difference in religious belief. As a basic premise, the author considers there is a need to once again return to a state before the start of individual religions, and stand on a cross-sectional ground level, an area which could be regarded as common to all religions. When conducting such a task, in the author's view, the restrained spirituality that Jaspers expounded is thought-provoking. PMID- 26642730 TI - [Knowledge of Man Returns: Some Considerations on Spirituality and Resilience]. AB - Over the last decade,"spirituality" and "resilience" have jointly become a topic in psychiatry. The aim of this paper is to discuss the future of psychiatry suggested by this topic. It may be related to what Jaspers, K. called "Knowledge of Man (die Erkenntnis des Menschen)". Knowledge of man in psychiatry can be learned only through clinical experince: e. g., clinical observations and case studies. Modern academic psychiatry seems to be suffering a loss of knowledge of man, which returns periodically in clinical practice. Hence, I will call the re discovery of the topic in psychiatry as "Return of Man". Since WW II, there have been three eras in which psychiatrists showed deep concern regarding knowledge of man. Firstly, psychopathology and psychotherapy widely developed, when the destructive impulses of mankind were revealed in the nuclear weapons of WW II. Secondly, in the 1970's, the reforms of psychiatric services and legal systems took place somewhat successfully, when social reforms were concerns of the younger generations. Lastly, over the last decade, the topic again returned as spirituality and resilience, when scientists seemed to be powerless in the aftermath of the West Japan Earthquake. Regarding the definition of health made by the WHO in 1946, I further discuss that "Return of Man" in psychiatry is the necessary dynamism between negative and positive health, or between disease control and health promotion. There is an underlying dynamism between "Knowledge of Man" and natural sciences, which is constantly changing. So long as any theory can exist only as a part of dynamism, the Return of Man may re-surface whenever clinical theories do not fit with clinical realities. PMID- 26642731 TI - [Three Essential Shared Capabilities for Young Psychiatrists: Brain, Real-world, and Life-course Principles toward Values-based Psychiatry]. AB - The discipline of psychiatry promotes well-being and recovery based on a comprehensive understanding of the patient from the perspectives of the brain, real-world, and life-course. Pursuant to efforts toward addressing social issues at a regional and national level, it is assumed that the psychiatrist can assist individuals based on an understanding of these three perspectives. This tripartite relationship goes beyond the history of extreme reductionism in neuroscience and the aftermath resulting from the anti-psychiatry movement to provide a foundation for the development of psychiatry and a theoretical groundwork for such basic psychiatric issues as what role pharmacotherapy plays in psychiatric treatment, just why the lives of people living in the community are thought to be important to an individual's well-being, and just what constitutes recovery. Humans have come to possess highly developed brain and mental functions as a result of the adaptation to the social environment that takes place as part of the evolutionary process. While mental functions are thus dictated in large part by evolution of the brain, they also consist of important features that are not attributable to reductionist models of the brain. That is, human mental functioning forms a foundation for metacognition and sophisticated language functions, and through interactions with others and society, one's mental functioning allows for further brain transformation and development (self regulation of mental functions). Humans develop their own brain and mental functions through mutual exchanges with others, and their dealings with other people and society form their individual modes of living in the real-world. The human brain and mental functions have evolved in such a way as to provide for a better mode of living. Accordingly, for the individual, the makeup of his or her mode of living in the real-world is the source of the well-being that serves to support that individual's values. The scientific background that the human recovery process for those suffering from mental disease involves the combined support of work, school, marriage, and childrearing stems from this fact. Humans develop their own mental capital over their life-courses and utilize it in an effort to realize their well-beings. Humans utilize mental function self regulation based on the emotional and interpersonal functions developed during childhood in order to formulate an image of themselves (the ego) as well as the type of person they want to become (values/needs). This is indeed the true essence of adolescence. The values that drive an individual's behavior by their very nature exist in the outside world and are shared by others as well as society. These are internalized as individual characteristics through the self regulation process of adolescence. Regardless of life stage or type of mental illness, individual reflection, verbalization, and reorganization of adolescent ego and values formation are essential to the recovery process. Humans are born with both bodies and brains, and throughout the courses of their lives, they formulate and develop values. Based on an understanding of the tripartite relationship between the brain, real-world, and life courses, it can be argued that the supporting of individual values is the scientific basis for the so called "patient-centered care" and "needs-based support" that serve as a psychiatrist's essential capabilities. Along with the patient's recovery, which is based on this values-based psychiatry, professional growth is the privilege enjoyed by those in the psychiatric field. Beginning with a foundation based on assisted recovery at the individual level, the psychiatrist can produce mental health changes at the regional level. The psychiatrist consequently possesses the national-level vision necessary to implement a community design model that combines mental health and preventive medicine. PMID- 26642732 TI - [The Basic Act on Measures against Alcohol-related Health Harm and Role of General Psychiatrists--With focus on SBRIT and Deadly Triangle]. AB - Japan has just enacted a national law for alcohol, that named "Basic Act on Measures Against Alcohol-related Health Harm". This article includes 5 topics; i) General psychiatrists have the roles and responsibilities in this law, ii) All psychiatrists need to know about alcohol-related health harm and alcohol-related problem, iii) Alcohol dependence is attributed to change of neurotransmitter in the brain, iv) Mood disorder is more likely to be complicated by alcohol dependence and/or hazardous drinking. Some of the patients with the above mentioned complicated disease have alcohol-induced mood disorder, v) If the patient has alcohol-induced mood disorder, it will place priority on alcoholism treatment and will be important to quickly resolve with abstinence. Finally, the proposals are made as follows; i) Making a guideline, ii) Physicians skilled at SBIRT (Screening, Brief Intervention, and Referral to Treatment) should be qualified as a certifying physician, and having the qualification should allow reimbursing medical institutions for the alcohol related service provided. PMID- 26642733 TI - [A Treatment for Drug Dependence not Requiring Specialists: A Treatment Program based on a Workbook, the "SMARPP"]. AB - In Japan, few psychiatric institutions provide rehabilitation for drug dependence, since dependence on illicit drugs including methamphetamine has generally been regarded as a crime and not an illness by Japanese psychiatrists. However, partial revisions of the Penal Code (the Partial Stays of Execution System) are going to be enforced in 2016, and it has been predicted that many illicit drug-dependent convicts will be treated in the community. Accordingly, the expansion of support resources in the community, including psychiatric institutions, is an urgent requirement. The Serigaya Methamphetamine Relapse Prevention Program ("SMARPP"), which consists of once-a-week groups sessions including motivational interviewing attitudes, and cognitive behavioral therapy for relapse prevention following the Matrix model, is expected to be one of the community resources for drug-dependent convicts. This paper introduces the principle and contents of the "SMARPP". PMID- 26642734 TI - [Higher Brain Dysfunction]. AB - The technical term "higher brain dysfunction" is used widely in Japan. However, it is not always clear what "higher" means. The author thinks that the term "higher" is understood as being associated with a meaning. In this article, the differences between higher brain dysfunctions and elementary brain dysfunctions are discussed from the point of view of lesion localization and the consistency of symptoms. The psychiatric approach is indispensable for the assessment of higher brain dysfunction. A simple test for mild Alzheimer-type dementia is also introduced. PMID- 26642735 TI - [What are the Specific Characteristics of Clinical Trials for Neuropsychiatric Disorders?]. AB - To increase medical standards, not only the establishment of therapeutic strategies to accumulate evidence for existing therapies but also the development of new therapies are required. In recent years, as a number of new drugs have been approved, treatment options for neuropsychiatric disorders have expanded. It is significant for clinicians to interpret the evidence adequately in order to select the optimal therapeutic method. This paper aims to describe the important points in interpreting the results of clinical trials, which involve direct evidence for efficacy and safety. There are several specific characteristics of clinical trials for neuropsychiatric disorders. As typical features, the following can be mentioned: 1) a high and variable response in placebo groups, 2) impact on the effect size of the baseline severity of disorders, 3) high dropout rates, and 4) biases related to subjective measures of clinical symptoms. In this paper, the key points to be evaluated in the results of clinical trials for neuropsychiatric disorders are discussed based on these features. PMID- 26642736 TI - On the relationship between subjective and objective measures of fatigue. AB - OBJECTIVE: Objective and subjective methods have been used in the past to assess workplace fatigue, but little is known about correlations between them. We examine correlations between subjective and objective measures, including measures collected in a workplace scenario. METHODS: 15 young and 17 older participants were assessed before and after work with four types of fatigue measure: objective physical (posturography), objective mental (psychomotor vigilance task), subjective physical and mental (self-assessment), objective and subjective realistic (oculomotor behaviour, observer-rated facial expression, typing performance). RESULTS: Pre- and post-test scores were analysed with an ANOVA, significant differences were submitted to a factor analysis. It yielded three factors: one representing posturography, the second self-rated mental and physical fatigue and the third observer-rated facial expression. CONCLUSIONS: Results advocate the existence of three independent fatigue components: Objective physical fatigue, introspective and extrospective fatigue. Practitioner Summary: This study analyses correlations between different subjective and objective fatigue markers to better understand the complex nature of workplace fatigue. Measurements were conducted directly at the workplace. Results reveal that fatigue comprises three independent fatigue components: Objective physical fatigue, introspective and extrospective fatigue. PMID- 26642737 TI - The complete mitochondrial DNA sequence of the cape hare Lepus capensis pamirensis. AB - Lepus capensis pamirensis is a specific cape hare species that is only distributed in the Pamirs, with a cruel natural environment. The complete mitochondrial genome of the cape hare L. c. pamirensis was first determined (accession number LC073697), in a total length of 17 597 nucleotides, of which 15 310 nucleotides are coding DNA and 2287 nucleotides are non-coding DNA. It has the common feature with those of other hares with respect to genome structure and gene arrangement. It contained 13 protein-coding genes, 2 ribosomal RNA genes, 22 transfer tRNA genes and 1 control region (D-loop region). The complete mitochondrial genome of the cape hare L. c. pamirensis provides an important data set for further study on its classification. PMID- 26642740 TI - Are animacy effects in episodic memory independent of encoding instructions? AB - The adaptive view of human memory [Nairne, J. S. 2010. Adaptive memory: Evolutionary constraints on remembering. In B. H. Ross (Ed.), The psychology of learning and motivation (Vol. 53 pp. 1-32). Burlington: Academic Press; Nairne, J. S., & Pandeirada, J. N. S. 2010a. Adaptive memory: Ancestral priorities and the mnemonic value of survival processing. Cognitive Psychology, 61, 1-22, 2010b; Memory functions. In The Corsini encyclopedia of psychology and behavioral science, (Vol 3, 4th ed. pp. 977-979). Hokoben, NJ: John Wiley & Sons] assumes that animates (e.g., baby, rabbit presented as words or pictures) are better remembered than inanimates (e.g., bottle, mountain) because animates are more important for fitness than inanimates. In four studies, we investigated whether the animacy effect in episodic memory (i.e., the better remembering of animates over inanimates) is independent of encoding instructions. Using both a factorial (Studies 1 and 3) and a multiple regression approach (Study 2), three studies tested whether certain contexts drive people to attend to inanimate more than to animate things (or the reverse), and therefore lead to differential animacy effects. The findings showed that animacy effects on recall performance were observed in the grassland-survival scenario used by Nairne, Thompson, and Pandeirada (2007. Adaptive memory: Survival processing enhances retention. Journal of Experimental Psychology: Learning, Memory, & Cognition, 33, 263-273) (Studies 1-3), when words were rated for their pleasantness (Study 2), and in explicit learning (Study 3). In the non-survival scenario of moving to a foreign land (Studies 1-2), animacy effects on recall rates were not reliable in Study 1, but were significant in Study 2, whereas these effects were reliable in the non survival scenario of planning a trip as a tour guide (Study 3). A final (control) study (Study 4) was conducted to test specifically whether animacy effects are related to the more organised nature of animates than inanimates. Overall, the findings suggest that animacy effects are robust since they do not vary across different sets of encoding instructions (e.g., encoding for survival, preparing a trip and pleasantness). PMID- 26642738 TI - Progesterone Receptor Membrane Component 1 (PGRMC1) Expression in Murine Retina. AB - PURPOSE: Sigma receptors 1 (sigmaR1) and 2 (sigmaR2) are thought to be two distinct proteins which share the ability to bind multiple ligands, several of which are common to both receptors. Whether sigmaR1 and sigmaR2 share overlapping biological functions is unknown. Recently, progesterone receptor membrane component 1 (PGRMC1) was shown to contain the putative sigmaR2 binding site. PGRMC1 has not been studied in retina. We hypothesize that biological interactions between sigmaR1 and PGRMC1 will be evidenced by compensatory upregulation of PGRMC1 in sigmaR1-/- mice. METHODS: Immunofluorescence, RT-PCR, and immunoblotting methods were used to analyze expression of PGRMC1 in wild-type mouse retina. Tissues from sigmaR1-/- mice were used to investigate whether a biological interaction exists between sigmaR1 and PGRMC1. RESULTS: In the eye, PGRMC1 is expressed in corneal epithelium, lens, ciliary body epithelium, and retina. In retina, PGRMC1 is present in Muller cells and retinal pigment epithelium. This expression pattern is similar, but not identical to sigmaR1. PGRMC1 protein levels in neural retina and eye cup from sigmaR1-/- mice did not differ from wild-type mice. Nonocular tissues, lung, heart, and kidney showed similar Pgrmc1 gene expression in wild-type and sigmaR1-/- mice. In contrast, liver, brain, and intestine showed increased Pgrmc1 gene expression in sigmaR1-/- mice. CONCLUSION: Despite potential biological overlap, deletion of sigmaR1 did not result in a compensatory change in PGRMC1 protein levels in sigmaR1-/- mouse retina. Increased Pgrmc1 gene expression in organs with high lipid content such as liver, brain, and intestine indicates a possible tissue-specific interaction between sigmaR1 and PGRMC1. The current studies establish the presence of PGRMC1 in retina and lay the foundation for analysis of its biological function. PMID- 26642739 TI - Postnatal Loss of Mef2c Results in Dissociation of Effects on Synapse Number and Learning and Memory. AB - BACKGROUND: Myocyte enhancer factor 2 (MEF2) transcription factors play critical roles in diverse cellular processes during central nervous system development. Studies attempting to address the role of MEF2 in brain have largely relied on overexpression of a constitutive MEF2 construct that impairs memory formation or knockdown of MEF2 function that increases spine numbers and enhances memory formation. Genetic deletion of individual MEF2 isoforms in brain during embryogenesis demonstrated that Mef2c loss negatively regulates spine numbers resulting in learning and memory deficits, possibly as a result of its essential role in development. METHODS: To investigate MEF2C function in brain further, we genetically deleted Mef2c during postnatal development in mice. We characterized these conditional Mef2c knockout mice in an array of behavioral paradigms and examined the impact of postnatal loss of Mef2c on long-term potentiation. RESULTS: We observed increased spine numbers in hippocampus of the conditional Mef2c knockout mice. However, the postnatal loss of Mef2c did not impact learning and memory, long-term potentiation, or social and repetitive behaviors. CONCLUSIONS: Our findings demonstrate a critical role for MEF2C in the regulation of spine numbers with a dissociation of learning and memory, synaptic plasticity, and measures of autism-related behaviors in postnatal brain. PMID- 26642741 TI - Estimation of the sensitivity of various environmental sampling methods for detection of Salmonella in duck flocks. AB - Reports of Salmonella in ducks in the UK currently rely upon voluntary submissions from the industry, and as there is no harmonized statutory monitoring and control programme, it is difficult to compare data from different years in order to evaluate any trends in Salmonella prevalence in relation to sampling methodology. Therefore, the aim of this project was to assess the sensitivity of a selection of environmental sampling methods, including the sampling of faeces, dust and water troughs or bowls for the detection of Salmonella in duck flocks, and a range of sampling methods were applied to 67 duck flocks. Bayesian methods in the absence of a gold standard were used to provide estimates of the sensitivity of each of the sampling methods relative to the within-flock prevalence. There was a large influence of the within-flock prevalence on the sensitivity of all sample types, with sensitivity reducing as the within-flock prevalence reduced. Boot swabs (individual and pool of four), swabs of faecally contaminated areas and whole house hand-held fabric swabs showed the overall highest sensitivity for low-prevalence flocks and are recommended for use to detect Salmonella in duck flocks. The sample type with the highest proportion positive was a pool of four hair nets used as boot swabs, but this was not the most sensitive sample for low-prevalence flocks. All the environmental sampling types (faeces swabs, litter pinches, drag swabs, water trough samples and dust) had higher sensitivity than individual faeces sampling. None of the methods consistently identified all the positive flocks, and at least 10 samples would be required for even the most sensitive method (pool of four boot swabs) to detect a 5% prevalence. The sampling of dust had a low sensitivity and is not recommended for ducks. PMID- 26642742 TI - The effect of cold stress on the pathogenesis of necrotic enteritis in broiler chicks. AB - Cold stress is a physical environmental stressor with significant effect on the poultry industry. The aim of the present study was to investigate the effect of cold stress as a predisposing factor for necrotic enteritis in broiler chicks. The experimental challenge model included an oral inoculation with 10-fold dose of attenuated anticoccidial vaccine and multiple oral inoculations with a specific strain of Clostridium perfringens. Birds were either challenged or not as described above, and either exposed or not to repeated cold stress (15 degrees C for 12 h/day for 4 days). From each bird, intestinal gross lesions were scored and intestinal digesta pH and viscosity were measured. C. perfringens was counted in the caecum. The statistical analysis and evaluation of the experimental data revealed that the cold stress in challenged birds significantly increased the incidence and the severity of necrotic enteritis lesions (Rho <= 0.05), while causing no lesions in unchallenged birds. Moreover, the cold stress caused a significant increase (Rho <= 0.05) in the pH and C. perfringens counts in the caeca. The study provides evidence that cold stress increased the susceptibility to necrotic enteritis in a subclinical experimental model and thus should be regarded as a physical environmental stressor that could significantly affect the welfare, health and intestinal ecosystem of broiler chicks. PMID- 26642748 TI - The relationship between oxygen consumption rate and viability of in vivo-derived pig embryos vitrified by the micro volume air cooling method. AB - The aim of this study was to assess the viability of vitrified-warmed in vivo derived pig embryos after measuring the oxygen consumption rate. Six days after artificial insemination, blastocysts were collected from gilts and vitrified by the micro volume air cooling method. The oxygen consumption rate was measured in 60 vitrified-warmed embryos, which were then cultured for 48h to assess the viability. The survival (re-expansion) rate of embryos after warming was 85.0%. The average oxygen consumption rate of embryos immediately after warming was greater in embryos which could re-expand during subsequent culture (F=0.75+/ 0.04) than that in those which failed to re-expand (F=0.33+/-0.05). Moreover, the oxygen consumption rate of vitrified-warmed embryos was greater in the hatched (F=0.88+/-0.06) than that in the not-hatched group (F=0.53+/-0.04). When the oxygen consumption rate of the vitrified-warmed embryos and the numbers of viable and dead cells in embryos were determined, there was a positive correlation between the oxygen consumption rate and the number of live cells (P<0.01, r=0.538). A total of 29 vitrified embryos after warming and measuring the oxygen consumption rate were surgically transferred into uterine horns of two recipients. Both of the recipients become pregnant and farrowed 12 healthy piglets. These results demonstrate that the oxygen consumption rate of vitrified warmed pig embryos can be related to the number of live cells and that the measurement of oxygen consumption of embryos after cryopreservation may be useful for estimating embryo survivability. PMID- 26642749 TI - Effects of estradiol on uterine perfusion in anesthetized cyclic mares affected with uterine vascular elastosis. AB - Uterine vascular elastosis in mares is characterized by degeneration of uterine vasculature through thickening of the elastin layers. Factors commonly associated with this degeneration include age, parity, and chronic uterine endometritis. Affected mares have also been shown to exhibit decreases in uterine blood flow and perfusion of the uterus. Due to the increased thickness of the elastin layers, we hypothesize that vasodilatation of the uterine vasculature is also impaired. To test the functionality of these vessels, we evaluated the vasodilatory effects of estradiol on the uterine vascular bed in mares with normal vasculature and mares with severe elastosis. Both groups were tested in estrus and diestrus. Fluorescent microspheres were used to determine basal blood perfusion, followed by the intravenous administration of 1.0 MUg/kg of 17beta estradiol. After 90 min, perfusion was measured once again to determine the vascular response to estradiol. Control mares in estrus displayed a significant increase in total uterine blood flow after the administration of estradiol when compared to baseline levels. No other group had a significant increase in total blood flow and perfusion after estradiol administration. The administration of estradiol in control mares induced regional increases in perfusion in the uterine horns and uterine body during estrus and only in the uterine horns during diestrus. Mares affected by elastosis exhibited no regional differences in perfusion levels post-estradiol administration. The difference in the vasodilatory response induced by estradiol between reproductively healthy mares and mares affected with elastosis indicates that the functionality of the affected vessels is compromised. PMID- 26642750 TI - Effect of the novel DNA vaccine fusing inhibin alpha (1-32) and the RF-amide related peptide-3 genes on immune response, hormone levels and fertility in Tan sheep. AB - The objective of the present study was to evaluate the effects of novel DNA vaccines fusing inhibin (INH) alpha (1-32) and RFamide-related peptide-3 (RFRP-3) genes on the immune response, reproductive hormone levels, and fertility of Tan sheep. Thirty-two female Tan sheep were divided into four groups (groups A, B, C, and D with 8 sheep per group) and respectively immunized (thrice, 20 d apart) with 0.6mg of p-TPA-SINH/TPA-SRFRP (group A), p-SINH/SRFRP (group B), p-SINH (group C) or 0.4ml saline (group D). Twenty days after primary immunization, all vaccines elicited significant immune responses, and the antibody levels of anti INH and anti-RFRP-3 in the vaccinated groups were significantly higher (p<0.05) than that of the control group. Immunization with p-TPA-SINH/TPA-SRFRP induced higher antibodies against INH and RFRP-3. Hormone levels of FSH and LH in group A immunized with p-TPA-SINH/TPA-SRFRP were significantly higher (p<0.05) than those in group C, which are immunized with p-SINH and the control group 20 d after the third immunization. Additionally, the p-TPA-SINH/TPA-SRFRP, p-SINH/SRFRP, p-SINH and saline vaccine induced different twinning rate of ewes (37.5%, 37.5%, 12.5%, and 0, respectively), but no significant differences were found in improving twinning rate of ewes among four groups. These results suggested that neutralization of endogenous INH and RFRP-3 with novel DNA vaccine fusing INH alpha (1-32) and RFRP-3 genes successfully elicited a humoral immune response, increased reproductive hormone levels, but it did not significantly improve litter sizes and twinning rate of ewes in the present study. PMID- 26642751 TI - Age and gender differences in children and adolescents' attitudes toward noise. AB - OBJECTIVE: Most school-aged children experience exposure to hazardous sound levels via high-risk noise activities (e.g. loud music/concerts, firearms). Little information exists regarding factors influencing pediatric engagement in these activities and use of hearing protection devices. This study explores effects of age, gender, and attitudes toward noise on participation in acoustic risk-taking behaviors and hearing conservation practices in children and adolescents. DESIGN: Cross-sectional. STUDY SAMPLE: Children and adolescents (10 19 years) with normal hearing. RESULTS: Most children and adolescents (86.5%) participate in at least one potentially high-risk noise behavior. The most frequently cited activities include sporting events, concerts, and playing a musical instrument. Use of hearing protection devices varies by activity, with consistent wear while using firearms but inconsistent application during all other activities. Gender, but not age, influences acoustic risk-taking behaviors: Boys engage in significantly more high-risk noise activities than girls. Participants expressed a neutral attitude toward noise that persisted across age and gender, but a trend shifting toward a pro-noise attitude emerges in later adolescence. CONCLUSIONS: The proliferation of acoustic risk-taking behaviors and lack of hearing conservation practices in children and adolescents requires attention at an early age to prevent future noise-induced hearing loss and subsequent quality of life effects. PMID- 26642752 TI - Transcanal endoscopic myringoplasty: a case series in a university center. AB - INTRODUCTION: Transcanal myringoplasty has the advantages of demanding lower operative time and minimal external incisions. It can be performed using the microscopic or endoscopic approach. In the last decade, the use of endoscopes in ear surgery has increased significantly. This technique may allow "around the corner" visualization of small recesses, through narrow spaces, without the aid of canalplasty in unfavorable ear canals. OBJECTIVE: To describe a case series of transcanal endoscopic myringoplasty performed in a university service. The characteristics, advantages, and disadvantages of this technique are also discussed. METHODS: A case series study, based on the chart review of patients submitted to transcanal endoscopic myringoplasty in the period from January of 2012 to October of 2014. RESULTS: Data from 22 patients were analyzed. Tympanic perforation closure three months after surgery was observed in 86.4% of all patients. There was statistically significant improvement in pure tone average thresholds after surgery (p<0.001). CONCLUSION: Transcanal endoscopic myringoplasty is a feasible, safe, and effective procedure; it can be an alternative to microscopic surgery. PMID- 26642753 TI - Temporal processing in postlingual adult users of cochlear implant. AB - INTRODUCTION: Postlingual adults demonstrate impressive performance in speech recognition in silence after cochlear implant (CI) surgery. However, problems in central hearing abilities remain, which complicates understanding in certain situations, such as in competitive listening and in the perception of suprasegmental aspects of speech. OBJECTIVE: To assess the temporal processing abilities in postlingual adult users of CI. METHODS: Cross-sectional and descriptive study, with a non-probabilistic sample for convenience. The population was divided into two groups. The study group consisted of 12 postlingual adult users of cochlear implants and the control group consisted of 12 adults with normal hearing, matched for age and gender with the control group. The Frequency Pattern Test and the Gaps in Noise test were selected to assess temporal processing. Free-field testing was applied at 50dB SL. RESULTS: Adult users of cochlear implant attained a mean temporal threshold of 16.33ms and scored 47.7% in the pattern frequency test; the difference was statistically significant in comparison with the control group. CONCLUSION: It was verified that postlingual adult users of cochlear implants have significant alterations in temporal processing abilities in comparison to adults with normal hearing. PMID- 26642754 TI - Increased sliding of transverse abdominis during contraction after myofascial release in patients with chronic low back pain. AB - PURPOSE: Recent evidence suggested the significance of integrity of the tension balance of the muscle-fascia corset system in spinal stability, particularly the posterior musculofascial junction which is adjacent to dorsal located paraspinal muscles joining each other at lateral raphe (LR). The purpose of this study was to compare the contraction of the transversus abdominis (TrA) at both anterior and posterior musculofascial muscle-fascia junctions in patients with low back pain (LBP) and asymptomatic participants before and immediately after a sustained manual pressure to LR. METHODS: The present observational cohort study used a single-instance, test-retest design. The outcome variables included the resting thickness (Tr), the thickness during contraction (Tc), change in thickness (DeltaT), sliding of musculofascial junction (DeltaX), muscle length at rest (L) and displacement pattern (DeltaD) of the TrA using ultrasonography. Vertical tolerable pressure at the LR was applied manual for 1 min. Tr, Tc, DeltaT, and DeltaX were analyzed by three-way ANOVA (musculofascial junction sites*group* pre post manual release). DeltaL and DeltaD were analyzed by two-way ANOVA (group* pre-post manual release). RESULTS: Participants with LBP revealed less Tc, DeltaT and DeltaX at both sites (p < 0.005). After myofascial release, LBP group demonstrated a positive DeltaD of the musculofascial junctions at both end (p < 0.001). Nevertheless, both groups increased the DeltaT and DeltaX at both sites (p < 0.001 and 0.001, respectively). CONCLUSION: The result indicated immediately effect of sustained manual pressure on musculofascial junction of TrA and supported the concept that the possible imbalanced tension of the myofascia corset of TrA in patients with LBP. PMID- 26642755 TI - The role of rice fields, fish ponds and water canals for transmission of fish borne zoonotic trematodes in aquaculture ponds in Nam Dinh Province, Vietnam. AB - BACKGROUND: Fish-borne zoonotic trematodes (FZT), such as Clonorchis sinensis, Opistorchis viverini (Opisthorchiidae) and intestinal trematodes of the family Heterophyidae, constitute a public health hazard in Vietnam and infections with these trematodes has been linked to consumption of raw or undercooked fish from aquaculture. The FZT transmission pathways, however, are more complicated than just the presence of intermediate snail hosts in aquaculture ponds as ponds may exchange water with surrounding habitats such as rice fields and irrigation canals and thereby these surrounding habitats may be a source of snails and cercariae and contribute to FZT infection in cultured fish. METHODS: This is a longitudinal descriptive study on selected farms (n = 30) in Nam Dinh Province which is endemic for FZT. At each farm, we sampled one pond, a small irrigation canal used to supply the pond with water, and a nearby rice field. At each of these three sites, we estimated the density of the FZT intermediate snail hosts and determined their trematode infection status. Comparative analysis was performed for the prevalence and density of FZT infections in fish and snails. RESULTS: Species of the Thiaridae, and most notably Melanoides tuberculata, the most important host species for FZT belonging to the Heterophyidae, were particularly abundant in ponds and small canals, i.e. M. tuberculata was found in 27 ponds and 13 small canals. Bithynia fuchsiana, a potential host for both Heterophyidae and Opisthorchiidae, was rarely found in fish ponds but common in rice fields. A total of 12 types of cercariae were found in the snails and pleurolophocercous cercariae, primarily FZT, constituted about 40 % of all cercarial infections. The fish species cultured were mainly carp species and Haplorchis pumilio was the dominating trematode species infecting fish. Clonorchis spp. were not recorded in any of the ponds. FZT transmission to fish was intense during the summer period (May-June to November) but less intense during the winter months (December-January) partly because cercarial emergence ceases due to the low temperature. CONCLUSION: Our findings highlight the complexity of FZT transmission within aquaculture farm settings and suggest that efforts to control these infections must take a holistic approach using interventions against all stages of the transmission cycle. PMID- 26642756 TI - Pedicle screw-rod fixation: a feasible treatment for dogs with severe degenerative lumbosacral stenosis. AB - BACKGROUND: Degenerative lumbosacral stenosis is a common problem in large breed dogs. For severe degenerative lumbosacral stenosis, conservative treatment is often not effective and surgical intervention remains as the last treatment option. The objective of this retrospective study was to assess the middle to long term outcome of treatment of severe degenerative lumbosacral stenosis with pedicle screw-rod fixation with or without evidence of radiological discospondylitis. RESULTS: Twelve client-owned dogs with severe degenerative lumbosacral stenosis underwent pedicle screw-rod fixation of the lumbosacral junction. During long term follow-up, dogs were monitored by clinical evaluation, diagnostic imaging, force plate analysis, and by using questionnaires to owners. Clinical evaluation, force plate data, and responses to questionnaires completed by the owners showed resolution (n = 8) or improvement (n = 4) of clinical signs after pedicle screw-rod fixation in 12 dogs. There were no implant failures, however, no interbody vertebral bone fusion of the lumbosacral junction was observed in the follow-up period. Four dogs developed mild recurrent low back pain that could easily be controlled by pain medication and an altered exercise regime. CONCLUSIONS: Pedicle screw-rod fixation offers a surgical treatment option for large breed dogs with severe degenerative lumbosacral stenosis with or without evidence of radiological discospondylitis in which no other treatment is available. Pedicle screw-rod fixation alone does not result in interbody vertebral bone fusion between L7 and S1. PMID- 26642757 TI - Qualitative and semi-quantitative evaluation of myocardium perfusion with 3 T stress cardiac MRI. AB - BACKGROUND: 3 T MRI has been adopted by some centers as the primary choice for assessment of myocardial perfusion over conventional 1.5 T MRI. However, there is no data published on the potential additional value of incorporating semi quantitative data from 3 T MRI. This study sought to determine the performance of qualitative 3 T stress magnetic resonance myocardial perfusion imaging (3 T MRMPI) and the potential incremental benefit of using a semi-quantitative perfusion technique in patients with suspected coronary artery disease (CAD). METHODS: Fifty eight patients (41 men; mean age: 59 years) referred for elective diagnostic angiography underwent stress 3 T MRMPI with a 32-channel cardiac receiver coil. The MR protocol included gadolinium-enhanced stress first-pass perfusion (0.56 mg/kg, dipyridamole), rest perfusion, and delayed enhancement (DE). Visual analysis was performed in two steps. Ischemia was defined as a territory with perfusion defect at stress study but no DE or a territory with DE but additional peri-infarcted perfusion defect at stress study. Semi-quantitative analysis was calculated by using the upslope of the signal intensity-time curve during the first pass of contrast medium during dipyridamole stress and at rest. ROC analysis was used to determine the MPRI threshold that maximized sensitivity. Quantitative coronary angiography served as the reference standard with significant stenosis defined as >70 % diameter stenosis. Diagnostic performance was determined on a per-patient and per-vessel basis. RESULTS: Qualitative assessment had an overall sensitivity and specificity for detecting significant stenoses of 77 % and 80 %, respectively. By adding MPRI analysis, in cases with negative qualitative assessment, the overall sensitivity increased to 83 %. The impact of MPRI differed depending on the territory; with the sensitivity for detection of left circumflex (LCx) stenosis improving the most after semi quantification analysis, (66 % versus 83 %). CONCLUSIONS: Pure qualitative assessment of 3 T MRI had acceptable performance in detecting severe CAD. There is no overall benefit of incorporating semi-quantitative data; however a higher sensitivity can be obtained by adding MPRI, especially in the detection of LCx lesions. PMID- 26642758 TI - Burkholderia cepacia complex: clinical course in cystic fibrosis patients. AB - BACKGROUND: Pulmonary deterioration after B.cepacia complex (BCC) colonization has a heterogeneous pattern. The aim was to investigate the clinical outcome of BCC colonization in CF patients chronically colonized with P. aeruginosa. METHODS: CF patients chronically colonized with P. aeruginosa were divided into three groups: intermittent (I), chronic (II) and no colonization (III) with BCC. Body mass index (BMI) percentile and spirometric parameters were analyzed at three different times in each group. RESULTS: Fifty-six patients chronically colonized with P. aeruginosa were included. Of these, 27 also had evidence of BCC colonization (13 intermittent and 14 chronic). BMI percentile was significantly lower among patients chronically colonized by both P. aeruginosa and BCC. Mean values of FEV1 and FVC % were also significantly lower in these patients, both at the time of chronic BCC colonization and 24 months forward. CONCLUSIONS: Chronic BCC colonization is associated with significant loss of lung function. Lower BMI might be a risk factor for chronic BCC colonization, preceding these events. PMID- 26642759 TI - Height and skeletal morphology in relation to modern life style. AB - Height and skeletal morphology strongly relate to life style. Parallel to the decrease in physical activity and locomotion, modern people are slimmer in skeletal proportions. In German children and adolescents, elbow breadth and particularly relative pelvic breadth (50th centile of bicristal distance divided by body height) have significantly decreased in recent years. Even more evident than the changes in pelvic morphology are the rapid changes in body height in most modern countries since the end-19th and particularly since the mid-20th century. Modern Japanese mature earlier; the age at take-off (ATO, the age at which the adolescent growth spurt starts) decreases, and they are taller at all ages. Preece-Baines modelling of six national samples of Japanese children and adolescents, surveyed between 1955 and 2000, shows that this gain in height is largely an adolescent trend, whereas height at take-off (HTO) increased by less than 3 cm since 1955; adolescent growth (height gain between ATO and adult age) increased by 6 cm. The effect of globalization on the modern post-war Japanese society ("community effect in height") on adolescent growth is discussed. PMID- 26642760 TI - Commentary on 'Operative Factors Associated with the Development of New Brain Lesions During Awake Carotid Endarterectomy'. PMID- 26642761 TI - Biological significance of co- and post-translational modifications of the yeast 26S proteasome. AB - In yeast (Saccharomyces cerevisiae), co- and post-translational modifications of the 26S proteasome, a large protein complex, were comprehensively detected by proteomic techniques, and their functions were investigated. The presence, number, site, and state of co- and post-translational modifications of the 26S proteasome differ considerably among yeast, human, and mouse. The roles of phosphorylation, N(alpha)-acetylation, N(alpha)-myristoylation, N(alpha) methylation, and N-terminal truncation in the yeast 26S proteasome were investigated. Although there is only one modification site for either N(alpha) acetylation, N(alpha)-myristoylation, or N(alpha)-methylation, these modifications play an important role in the functions of the yeast proteasome. In contrast, there are many phosphorylation sites in the yeast 26S proteasome. However, the phosphorylation patterns might be a few, suggesting that tiny modifications exert considerable effects on the function of the proteasome. BIOLOGICAL SIGNIFICANCE: Protein co- and post-translational modifications produce different protein species which often have different functions. The yeast 26S proteasome, a large protein complex, consisting of many subunits has a number of co- and post-translational modification sites. This review describes the effects of the modifications on the function of the protein complex. This article is part of a Special Issue entitled: Protein species. Guest Editors: Peter Jungblut, Hartmut Schluter and Bernd Thiede. PMID- 26642762 TI - Quantitative tissue proteomic investigation of invasive ductal carcinoma of breast with luminal B HER2 positive and HER2 enriched subtypes towards potential diagnostic and therapeutic biomarkers. AB - Worldwide, breast cancer is one of the frequently diagnosed cancers in women with high mortality if not diagnosed at early stage. Although biomarker discoveries through various proteomic approaches have been studied in breast cancer, a limited number of studies have explored the invasive ductal carcinoma with Luminal B HER2 positive (LB) and HER2 enriched (HE) subtypes. The present study employed the complementary quantitative proteomic approaches to find a panel of markers that could discriminate LB and HE subtypes as well as early (ES) and late stages (LS) of these subtypes. A total of 67 and 68 differentially expressed proteins were identified by DIGE for the subtype and stage wise categories, respectively. Multivariate statistical analysis was employed to identify the set of most significant proteins, which could discriminate between these two subtypes and also early and late stages under study. Immunoblotting and MRM based validation in a separate cohort of samples confirmed that panel of biosignatures for LB are APOA1, GELS, HS90B, EF1A1, NHRF1 and PRDX3 and for HE are PRDX1, CATD, CALR, ATPB and CH60. For the diagnosis of early and late stages the potential markers are TPM4, CATD, PRDX3, ANXA3, HSPB1 and CALR, TRFE, GELS, CH60, CAPG, NHRF1, 1433G, GRP78 respectively. PMID- 26642763 TI - [Improved prognosis for symptom-free older women with mammography-detected breast cancer?]. PMID- 26642764 TI - Gene expression changes triggered by end-of-day far-red light treatment on early developmental stages of Eustoma grandiflorum (Raf.) Shinn. AB - To better understand the molecular mechanisms related to growth promotion in the early developmental stages of Eustoma grandiflorum (Raf.) Shinn. under end-of-day far-red light (EOD-FR) treatment, we analyzed the leaf transcriptome of treated (EOD) and untreated plants (Cont) by using RNA-seq technology. EOD-FR treatment for only about 2 weeks in regions with limited sunshine during winter resulted in significantly higher internode length between the 3rd and 4th nodes on the main stem in EOD than in Cont. Among the differentially expressed genes (DEGs) related to synthesis or transport of auxin, higher levels of YUCCA (CL6581) and PIN4 (CL6181) were noted after treatment in EOD than in Cont in the leaf. In addition, high expression levels of GA20ox (Unigene11862) related to gibberellin (GA) synthesis and transcription factor bHLH 135 (CL7761) were observed in the stem of EOD, 3 h after treatment. A vertical section of the stem showed that the pith length of cells at the 4th node was longer in EOD than in Cont. Collectively, these results suggested that EOD-FR treatment increased the expression of DEGs related to GA and auxin biosynthesis, bHLH transcription factor, and internodal cell elongation along the longitudinal axis of Eustoma plants. PMID- 26642765 TI - Synthesis of a new inhibitor of breast cancer resistance protein with significantly improved pharmacokinetic profiles. AB - The design, synthesis, in vitro inhibitory potency, and pharmacokinetic (PK) profiles of Ko143 analogs are described. Compared to commonly used Ko143, the new breast cancer resistance protein (BCRP) inhibitor (compound A) showed the same potency and a significantly improved PK profile in rats (lower clearance [1.54L/h/kg] and higher bioavailability [123%]). Ko143 on the other hand suffers from poor bioavailability. Compared to Ko143, compound A would be a useful probe for delineating the role of BCRP during in vivo studies in animals. PMID- 26642766 TI - Promising applications in drug delivery systems of a novel beta-cyclodextrin derivative obtained by green synthesis. AB - An efficient and green method has been developed for the synthesis of succinyl beta-cyclodextrin in aqueous media obtaining very good yield. Acidic groups have been introduced in the synthesized carrier molecule to improve the guest-host affinity. To evaluate the suitability of the novel excipient focused to develop oral dosage forms, albendazole, a BSC class II compound, was chosen as a model drug. The beta-cyclodextrin derivative and the inclusion complex were thoroughly characterized in solution and solid state by phase solubility studies, FT-IR spectroscopy, SEM, XRD, ESI-MS, DSC, 1D (1)H NMR, 1D (13)C NMR, selective 1D TOCSY, 2D COSY, 2D HSQC, 2D HMBC and ROESY NMR spectroscopy. Phase solubility studies indicated that both of them beta-cyclodextrin and succinyl-beta cyclodextrin formed 1:1 inclusion complexes with albendazole, and the stability constants were 68M(-1) (beta-cyclodextrin), 437M(-1) (succinyl-beta cyclodextrin), respectively. Water solubility and dissolution rate of albendazole were significantly improved in complex forms. Thus, the succinyl-beta cyclodextrin derivative could be a promising excipient to design oral dosage forms. PMID- 26642767 TI - Development of a novel sulfonate ester-based prodrug strategy. AB - A self-immolative gamma-aminopropylsulfonate linker was investigated for use in the development of prodrugs that are reactive to various chemical or biological stimuli. To demonstrate their utility, a leucine-conjugated prodrug of 5 chloroquinolin-8-ol (5-Cl-8-HQ), which is a potent inhibitor against aminopeptidase from Aeromonas proteolytica (AAP), was synthesized. The sulfonate prodrug was considerably stable under physiological conditions, with only enzyme mediated hydrolysis of leucine triggering the subsequent intramolecular cyclization to simultaneously release 5-Cl-8-HQ and form gamma-sultam. It was also confirmed that this gamma-aminopropylsulfonate linker was applicable for prodrugs of not only 8-HQ derivatives but also other drugs bearing a phenolic hydroxy group. PMID- 26642768 TI - Synthesis and bioactivity of novel triazole incorporated benzothiazinone derivatives as antitubercular and antioxidant agent. AB - In search of new active molecules against Mycobacterium tuberculosis (MTB) H37Ra and M. bovis BCG, a small focused library of benzothiazinone based 1,2,3 triazoles has been efficiently prepared via click chemistry approach. Several derivatives were found to be promising inhibitors of MTB and M. bovis BCG characterized by lower MIC values (27.34-29.37MUg/mL). Among all the synthesized compounds, 6c and 6e is the most active compound against MTB and M. bovis BCG. The compounds were further tested for anti-proliferative activity against HeLa, A549 and A431 cell lines using MTT assay and showed no significant cytotoxic activity at the maximum concentration evaluated. Further, the synthesized compounds were found to have potential antioxidant activity with IC50 range=14.14 47.11MUg/mL. Furthermore, to rationalize the observed biological activity data, the molecular docking study also been carried out against a potential target MTB DprE1, which revealed a significant correlation between the binding score and biological activity for these compounds. The results of the in vitro and in silico study suggest that the triazole incorporated benzothiazinone may possess the ideal structural requirements for further development of novel therapeutic agents. PMID- 26642769 TI - Identification and characterization of natural microbial products that alter the free d-aspartate content of mammalian cells. AB - Mammalian cells possess the molecular apparatus necessary to take up, degrade, synthesize, and release free d-aspartate, which plays an important role in physiological functions within the body. Here, biologically active microbial compounds and pre-existing drugs were screened for their ability to alter the intracellular d-aspartate level in mammalian cells, and several candidate compounds were identified. Detailed analytical studies suggested that two of these compounds, mithramycin A and geldanamycin, suppress the biosynthesis of d aspartate in cells. Further studies suggested that these compounds act at distinct sites within the cell. These compounds may advance our current understanding of biosynthesis of d-aspartate in mammals, a whole picture of which remains to be disclosed. PMID- 26642770 TI - Antioxidant C-glycosylflavones of Drymaria cordata (Linn.) Willd. AB - A new C-glycosylflavone, drymaritin E (6-C-(3-keto-beta-digitoxopyranosyl)-4'-O (beta-D-glucopyranosyl)-7-methoxyl-5,4'-dihydroxylflavone) 1 was isolated from the oily upper phase (SU) of the MeOH extract from aerial parts of Drymaria cordata together with two known compounds (cassiaoccidentalin A 2 and anemonin 3) and an inseparable mixture of two known C-glycosylflavones 5,4'-dihydroxy-7 methoxyflavone-6-C-(2''-O-alpha-L-rhamnopyranosyl)-beta-D-glucopyranoside 4a and 5,7,3',4'-tetrahydroxyflavone-6-C-(2''-O-alpha-L-rhamnopyranosyl)-beta-D glucopyranoside 4b. The alkaline hydrolysis of 3 led to a new hemisynthetic derivative, sodium anemonate (sodium 2-((1'E) 2'-sodium-carboxylate-vinyl)-5-oxo cyclohex-1-ene carboxylate) 3a. The chemical structures were determined by spectroscopic methods ((1)H NMR, (13)C NMR, (1)H-(1)H COSY, HMBC, HSQC, and NOESY) and mass spectrometry (ESI-MS). C-glycosylflavones had significant free radical-scavenging activities on the radical 2,2-diphenyl-1-picrylhydrazyl (DPPH). However, SU and compounds 3 and 3a exhibited no activity. In particular, compound 1 exhibited a concentration-dependent radical scavenging activity on DPPH with EC50 of 31.43 ug/mL. PMID- 26642771 TI - The Determining Risk of Vascular Events by Apnea Monitoring (DREAM) study: design, rationale, and methods. AB - PURPOSE: The goal of the Determining Risk of Vascular Events by Apnea Monitoring (DREAM) study is to develop a prognostic model for cardiovascular outcomes, based on physiologic variables-related to breathing, sleep architecture, and oxygenation-measured during polysomnography in US veterans. METHODS: The DREAM study is a multi-site, retrospective observational cohort study conducted at three Veterans Affairs (VA) centers (West Haven, CT; Indianapolis, IN; Cleveland, OH). Veterans undergoing polysomnography between January 1, 2000 and December 31, 2004 were included based on referral for evaluation of sleep-disordered breathing, documented history and physical prior to sleep testing, and >=2-h sleep monitoring. Demographic, anthropomorphic, medical, medication, and social history factors were recorded. Measures to determine sleep apnea, sleep architecture, and oxygenation were recorded from polysomnography. VA Patient Treatment File, VA-Medicare Data, Vista Computerized Patient Record System, and VA Vital Status File were reviewed on dates subsequent to polysomnography, ranging from 0.06 to 8.8 years (5.5 +/- 1.3 years; mean +/- SD). RESULTS: The study population includes 1840 predominantly male, middle-aged veterans. As designed, the main primary outcome is the composite endpoint of acute coronary syndrome, stroke, transient ischemic attack, or death. Secondary outcomes include incidents of neoplasm, congestive heart failure, cardiac arrhythmia, diabetes, depression, and post-traumatic stress disorder. Laboratory outcomes include measures of glycemic control, cholesterol, and kidney function. (Actual results are pending.) CONCLUSIONS: This manuscript provides the rationale for the inclusion of veterans in a study to determine the association between physiologic sleep measures and cardiovascular outcomes and specifically the development of a corresponding outcome-based prognostic model. PMID- 26642773 TI - Atrial Fibrillation During or After TAVI: Incidence, Implications and Therapeutical Considerations. AB - INTRODUCTION: Aortic stenosis is one of the most frequent valvulopathy of modern time necessitating interventional therapy when symptoms arise and stenosis becomes severe. First line treatment has traditionally been surgical aortic valve replacement (SAVR). However in the last decade transcatheter aortic valve implantation (TAVI) with bioprosthetic valves has proved to be a sound solution for high-risk for SAVR or inoperable patients. As expected implantation of the bioprosthetic device requires administration of antiplatelet regimen to the patients for a certain period. Atrial fibrillation (AF) may occur frequently during the peri-procedural period. In this background, the occurrence of AF after device implantation may be a challenging issue. METHODS: We performed a literature search of PubMed and Embase database. Published articles reporting the incidence, clinical implications and description of antithrombotic regimen of New onset atrial fibrillation (NOAF) in individuals undergoing TAVI were considered eligible. Incidence, Implications and Antithrombotic Regimen: The overall occurrence of NOAF is reported to be 1%-32% after TAVI. Left atrial enlargement and transapical approach constitute independent predictors for NOAF. Additionally it has been shown that patients with AF face an increased risk of death irrespective of the type of AF. Patients, with a history of AF, present greater rate of death than individuals with NOAF. NOAF is responsible for cerebrovascular events (CVE) occurring in the subacute phase (days 1-30) after the procedure. The risk of stroke/transient ischemic attack after TAVI is increased at least two fold by the presence of atrial fibrillation. Empirically, a dual antiplatelet strategy has been used for patients undergoing TAVR, including aspirin and a thienopyridine. In cases where patients are in need of oral anticoagulation after TAVI a combination of aspirin or thienopyridine with acenocoumarol has been the preferred regimen. DISCUSSION: Despite the continuously crescent use of TAVI for patients with symptomatic severe aortic stenosis, there are still many aspects of this procedure to be clarified. A lack of data exists from the available clinical trials regarding the appropriate anticoagulation therapy for patients with greater risk for thromboembolic events. As a result, patient's treatment remains at the discretion of the physician. CONCLUSION: Limited data are available regarding the optimal therapeutic regimen in patients undergoing TAVI who need therapy for AF. Carefully designed clinical studies might further clarify the incidence and interrelation between atrial fibrillation and TAVI. The balance between the efficacy and risk of anticoagulation needs to be further clarified in patients undergoing TAVI. PMID- 26642772 TI - Contribution of synovial lining cells to synovial vascularization of the rat temporomandibular joint. AB - The lining layer of the synovial membrane in the temporomandibular joint (TMJ) contains two types of lining cells: macrophage-like type A and fibroblast-like type B cells. The type B cells are particularly heterogeneous in their morphology and immunoreactivity, so that details of their functions remain unclear. Some of the type B cells exhibit certain resemblances in their ultrastructure to those of an activated capillary pericyte at the initial stage of the angiogenesis. The articular surface, composed of cartilage and the disc in the TMJ, has few vasculatures, whereas the synovial lining layer is richly equipped with blood capillaries to produce the constituent of synovial fluid. The present study investigated at both the light and electron microscopic levels the immunocytochemical characteristics of the synovial lining cells in the adult rat TMJ, focusing on their contribution to the synovial vascularization. It also employed an intravascular perfusion with Lycopersicon esculentum (tomato) lectin to identify functional vessels in vivo. Results showed that several type B cells expressed desmin, a muscle-specific intermediate filament which is known as the earliest protein to appear during myogenesis as well as being a marker for the immature capillary pericyte. These desmin-positive type B cells showed immunoreactions for vimentin and pericyte markers (neuron-glial 2; NG2 and PDGFRbeta) but not for the other markers of myogenic cells (MyoD and myogenin) or a contractile apparatus (alphaSMA and caldesmon). Immunoreactivity for RECA-1, an endothelial marker, was observed in the macrophage-like type A cells. The arterioles and venules inside the synovial folds extended numerous capillaries with RECA-1-positive endothelial cells and desmin-positive pericytes to distribute densely in the lining layer. The distal portion of these capillaries showing RECA-1-immunoreactivity lacked lectin-staining, indicating a loss of blood-circulation due to sprouting or termination in the lining layer. The desmin positive type B and RECA-1-positive type A cells attached to this portion of the capillaries. Some capillaries in the lining layer also expressed ninein, a marker for sprouting endothelial cells, called tip cells. Since an activated pericyte, macrophage and tip cell are known to act together at the forefront of the vessel sprout during angiogenesis, the desmin-positive type B cell and RECA-1-positive type A cell might serve as these angiogenic cells in the synovial lining layer. Tomato lectin perfusion following decalcification would be a highly useful tool for research on the vasculature of the mineralized tissue. Use of this technique combined with immunohistochemistry should permit future extensive investigations on the presence of the physiological angiogenesis and on the function of the lining cells in the synovial membrane. PMID- 26642774 TI - Pharmacogenomics of Oral Antithrombotic Drugs. AB - Pharmacogenomics is a relatively recent yet rapidly expanding field of study examining how genetic variations influence responses to drugs. Antithrombotic drugs include the anticoagulant and antiplatelet compounds widely prescribed for the treatment and prevention of cardiovascular diseases. However, there is a large variability in response to antithrombotics, and this can modify the benefit/risk ratio of taking such medications. This variability can be explained by clinical factors such as age, sex, and drug-drug interactions, but also by genetic variants. In recent years, several genetic polymorphisms have been associated with variable biological responses to antithrombotics. Relevant polymorphisms related to antithrombotics have included target genes and genes that participate in the drugs' pharmacokinetics. This article provides a comprehensive review of the published literature about the pharmacogenomics of antithrombotic drugs, including well-studied compounds such as vitamin K antagonists (e.g., warfarin, acenocoumarol, and phenprocoumon), aspirin, and clopidogrel, as well as more recently approved compounds such as prasugrel, ticagrelor, and direct oral anticoagulants. PMID- 26642775 TI - Balancing the Risks of Thrombosis and Bleeding Following Transcatheter Aortic Valve Implantation: Current State-of-Evidence. AB - While transcatheter aortic valve implantation (TAVI) has rapidly evolved as an acceptable alternative to conventional surgical aortic valve replacement in elderly, high-risk surgical candidates with critical aortic stenosis, thrombotic and bleeding complications remain relatively frequent and potentially life threatening. Thrombotic events during and following TAVI relate to the dynamic interplay between the systemic burden of atherosclerotic disease, atrial arrhythmias, device and native aortic valve interactions, as well as platelet and coagulation cascade activation. Bleeding in the acute setting relates primarily to access site vascular complications, but also appears related to pre-existing renal impairment and anemia. Current pre-, peri- and post-procedural anti thrombotic regimens are empirical, based on expert consensus following extrapolation from the wealth of experience gleaned following percutaneous coronary intervention. However the complexities of the TAVI procedure, the high risk clinical substrate and competing effects of anti-thrombotic regimens and bleeding risk are yet to be prospectively assessed in randomized clinical trials for defining evidence-based anti-thrombotic strategies. PMID- 26642776 TI - Bivalirudin or Heparin Treatment During Transcatheter Valve Interventions: Where are we Now? AB - While the main gist of research pertaining to TAVR procedure involves improvement of existing valve technologies, lower size delivery systems and post-procedure antithrombotic therapy, the optimal intra-procedure anticoagulation has not been sufficiently defined. Peri-procedural complications such as cerebrovascular events and bleeding are largely associated with the safety and efficacy of anticoagulation regimen. Current guidelines advocate the use of heparin for anticoagulation with a target activated clotting time >=300 seconds and careful protamine infusion in patients with high estimated bleeding risk. In this setting bivalirudin, devoid of all undesirable properties of unfractionated heparin such as highly variable elimination time and heparin-induced thrombocytopenia, may represent an alternative option in the interventionist's armamentarium. Initial experience with bivalirudin has been encouraging as shown in two observational studies in the context of TAVR and balloon aortic valvuloplasty. The need for bleeding events reduction is particularly pronounced in this population that exhibits an inherent high bleeding risk due to platelet and von Willebrand factor dysfunction. Nevertheless, data from randomized studies are needed to establish bivalirudin role during TAVR procedure. PMID- 26642777 TI - General or Local Anesthesia for TAVI? A Systematic Review of the Literature and Meta-Analysis. AB - BACKGROUND: Transcatheter aortic valve implantation (TAVI) is becoming a valuable alternative to surgical aortic valve replacement in patients with severe aortic stenosis that are at high surgical risk or deemed inoperable. The optimal anesthesia technique for TAVI is still undecided. We performed a systematic review and metaanalysis to compare the safety of locoregional anesthesia (LRA) with or without conscious sedation and general anesthesia (GA) for the TAVI procedure. METHODS: We searched PUBMED, MEDLINE, EMBASE and the Cochrane central register of controlled trials from January 1st 2002 to February 15th 2015. The primary outcome parameters searched were 30-days mortality, hospital length of stay, procedure time, use of adrenergic support, stroke rate, incidence of myocardial infarction, incidence of acute kidney injury, rate of procedural succes. RESULTS: Ten studies, including 5919 patients, fulfilled the inclusion criteria. None of these studies was randomized resulting in a considerable risk of bias. The choice for a specific anesthesia technique did neither affect the average 30-day mortality rate [RR 0.91 (95% CI: 0.53 to 1.56), p=0.72] nor a wide variety of safety endpoints. LRA for TAVI was associated with a significantly shorter procedure time when compared to GA, and a reduction in hospital length of stay. However, LRA significantly increased the risk for implantation of a permanent pacemaker (RR 1.23, p=0.02) and for paravalvular leakage (RR 1.31, p=0.006.). CONCLUSION: Neither mortality nor the incidence of major adverse cardiac and cerebrovascular events after TAVI is affected by the choice for either LRA or GA. PMID- 26642778 TI - Algorithms and Criteria for Transcatheter Aortic Valve Replacement Patient Selection: Current Status and Future Trends. AB - The advent of transcatheter aortic valve replacement (TAVR) has revolutionized the treatment of aortic stenosis and established a life-prolonging therapy in patients that are not operative candidates. It is also approved for high-risk surgical candidates and shows effectiveness comparable to surgical aortic valve replacement (SAVR). The inoperable and high-risk groups represent two parallel but partly divergent populations. In those deemed inoperable, decisions revolve around offering TAVR, palliation, or rehabilitation. These are based primarily on the likelihood of procedural success and clinical benefit, with a careful assessment of the source of their debility and features that underlie extreme surgical risk. In patients that are at high-risk for SAVR, determination of the most favorable route of valve replacement is guided by comparative procedural characteristics, the need for coincident interventions, and presumed ability for rehabilitation. These decisions are inherently difficult and currently rely on imperfect but developing risk assessment systems. Given the complexity of these decisions and patient population, the TAVR experience has underscored the value of a multi-disciplinary approach to advanced cardiovascular disease. PMID- 26642779 TI - Jean-Baptiste de Senac's (1693-1770) Important Work on Cardiology and Valvular Disorders. AB - In the 18(th) century clinical cardiology was based on pulse examination and auscultation by placing the ear directly on the patient's chest, while diagnosis of heart diseases was done in postmortem examination. In 1749, Jean-Baptiste de Senac, physician of King Louis XV, published his work on the heart Traite de la structure du coeur, de son action et de ses maladies. It was the result of years of anatomical and physiological study, in an attempt to illuminate heart and its functions. Senac recognized among several heart disorders, aortic regurgitation, mitral calcification, and mitral regurgitation. His work remained a landmark in valvular pathology and cardiology until the early 19(th) century. PMID- 26642780 TI - Strategies to Avoid TAVI-related Acute Kidney Injury. AB - Acute kidney injury (AKI) is relatively common in patients undergoing transcatheter aortic valve implantation (TAVI) and has been associated with increased mortality and worse outcomes. The administration of iodinated contrast media in an elderly population with increased rates of chronic kidney injury and heart failure, the risk of hemodynamic compromise and the use of large catheters intra-procedurally make patients undergoing TAVI particularly vulnerable to renal insults and AKI. Furthermore, these patients are commonly exposed to iodinated contrast media during diagnostic and possible interventional procedures pre-TAVI. While risk factors such as baseline comorbidities are non-modifiable, others such as administration of nephrotoxic medications, the type and amount of contrast medium and the catheters size can be avoided, modified and improved. In addition, numerous other interventions such as volume expansion and possibly medications can prevent contrast related kidney injury. In this review, we sought to focus on strategies aiming at reducing the incidence of TAVI-related AKI. PMID- 26642781 TI - Antiplatelet Agents in Cardiology: A Report on Aspirin, Clopidogrel, Prasugrel, and Ticagrelor. AB - Antiplatelet drugs are the cornerstone of therapy in many cardiovascular conditions. With the current success and increased use of transcatheter aortic valve implantation (TAVI), the use of antiplatelet therapy is considered part of the medical therapy for these patients. Clinicians caring for these patients need to have a thorough understanding of the pharmacology, pharmacokinetics, pharmacodynamic, and clinical efficacy and safety of commonly used antiplatelet therapy. While aspirin therapy is widely used, dual antiplatelet therapy with clopidogrel has become part of standard of care. Despite the extensive experience with clopidogrel, there are limitations such as drug interactions, metabolism genetic polymorphisms, and variability in the antiplatelet response. More predictable and more potent antiplatelet agents, prasugrel and ticagrelor, have demonstrated superior reductions in ischemic endpoints as part of dual antiplatelet therapy compared to clopidogrel, but at the cost of more major bleeding in patients with an acute coronary syndrome. Significant research needs to be conducted in the setting of TAVI to help define the optimal antiplatelet regimen. PMID- 26642782 TI - Alcohol Misuse Among Female Veterans: Exploring Associations With Interpersonal Violence and Mental Health. AB - BACKGROUND: The correlates of alcohol misuse among female Veterans are not well understood. The present study explored associations among alcohol misuse, demographic/military-related characteristics, interpersonal violence exposure, and posttraumatic stress disorder (PTSD) and depression symptom severity. METHOD: Participants were 369 female Veteran patients of the VA New England Healthcare System. Participants completed a paper-and-pencil mail survey that included validated assessments of alcohol misuse, interpersonal violence, and psychological distress. RESULTS: Younger age, adulthood physical abuse, military sexual trauma, past-year psychological aggression by an intimate partner, and PTSD and depression symptom severity showed significant univariate associations with alcohol misuse (as indicated by unsafe drinking levels, presence or incipience of an alcohol use disorder, intrapersonal alcohol-related concerns, and/or interpersonal alcohol-related concerns). A couple of these associations remained significant when examined in logistic regression models. CONCLUSIONS: Findings suggest that female Veterans who are at risk for alcohol use disorders and/or are experiencing alcohol-related problems may benefit from screening and intervention efforts that take into account interpersonal violence exposures and mental health symptoms on a case-by-case basis. Results also suggest the importance of future research examining correlates and risk factors for substance misuse among female Veterans. PMID- 26642783 TI - Evidence-informed policy formulation and implementation: a comparative case study of two national policies for improving health and social care in Sweden. AB - BACKGROUND: Evidence has come to play a central role in health policymaking. However, policymakers tend to use other types of information besides research evidence. Most prior studies on evidence-informed policy have focused on the policy formulation phase without a systematic analysis of its implementation. It has been suggested that in order to fully understand the policy process, the analysis should include both policy formulation and implementation. The purpose of the study was to explore and compare two policies aiming to improve health and social care in Sweden and to empirically test a new conceptual model for evidence informed policy formulation and implementation. METHODS: Two concurrent national policies were studied during the entire policy process using a longitudinal, comparative case study approach. Data was collected through interviews, observations, and documents. A Conceptual Model for Evidence-Informed Policy Formulation and Implementation was developed based on prior frameworks for evidence-informed policymaking and policy dissemination and implementation. The conceptual model was used to organize and analyze the data. RESULTS: The policies differed regarding the use of evidence in the policy formulation and the extent to which the policy formulation and implementation phases overlapped. Similarities between the cases were an emphasis on capacity assessment, modified activities based on the assessment, and a highly active implementation approach relying on networks of stakeholders. The Conceptual Model for Evidence-Informed Policy Formulation and Implementation was empirically useful to organize the data. CONCLUSIONS: The policy actors' roles and functions were found to have a great influence on the choices of strategies and collaborators in all policy phases. The Conceptual Model for Evidence-Informed Policy Formulation and Implementation was found to be useful. However, it provided insufficient guidance for analyzing actors involved in the policy process, capacity-building strategies, and overlapping policy phases. A revised version of the model that includes these aspects is suggested. PMID- 26642784 TI - Erratum to: CORR ((r)) Curriculum--Orthopaedic Education: Developing Safe, Independent Practitioners. PMID- 26642785 TI - CORR((r)) Tumor Board: Sacral Insufficiency Fractures are Common After High-dose Radiation for Sacral Chordomas Treated With or Without Surgery. PMID- 26642786 TI - Pearls: How I Create the Tibial Socket for PCL Reconstruction. PMID- 26642787 TI - Letter to the Editor: Low Albumin Levels, More Than Morbid Obesity, Are Associated With Complications After TKA. PMID- 26642788 TI - Smoking is Associated with Increased Blood Loss and Transfusion Use After Lumbar Spinal Surgery. AB - BACKGROUND: Little is known about the association between smoking and intraoperative blood loss and perioperative transfusion use in patients undergoing spinal surgery. However, we found that although many of the common complications and deleterious effects of smoking on surgical patients had been well documented, the aspect of blood loss seemingly had been overlooked despite data reported in nonorthopaedic sources to suggest a possible connection. QUESTIONS/PURPOSES: We asked: (1) Is smoking associated with increased estimated blood loss during surgery in patients undergoing lumbar spine surgery? (2) Is smoking associated with increased perioperative transfusion usage? METHODS: Between 2005 and 2009, 581 lumbar decompression procedures (with or without fusion) were performed at one academic spine center. Of those, 559 (96%) had sufficient chart documentation to categorize patients by smoking status, necessary intra- and postoperative data to allow analysis with respect to bleeding and transfusion-related endpoints, and who did not meet exclusion criteria. Exclusion criteria included: patients whose smoking status did not fit in our two categories, patients with underlying coagulopathy, patients receiving anticoagulants (including aspirin and platelet inhibitors), history of hepatic disease, history of platelet disorder or other blood dyscrasias, and patient or family history of any other known bleeding disorder. Smoking history in packs per day was obtained for all subjects. We defined someone as a smoker if the patient reported smoking up until the day of their surgical procedure; nonsmokers were patients who quit smoking at least 6 weeks before surgery or had no history of smoking. We used a binomial grouping for whether patients did or did not receive a transfusion perioperatively. Age, sex, number of levels of discectomies, number of levels decompressed, number of levels fused, and use of instrumentation were recorded. The same approaches were used for transfusions in all patients regardless of smoking history; decisions were made in consultation between the surgeon and the anesthesia team. Absolute indications for transfusion postoperatively were: a hemoglobin less than 7 g/dL, continued symptoms of dizziness, tachycardia, decreased exertional tolerance, or hypotension that failed to respond to fluid resuscitation. Multiple linear regression analyses correcting for the above variables were performed to determine associations with intraoperative blood loss, while logistic regression was used to analyze perioperative transfusion use. RESULTS: After controlling for potentially relevant confounding variables noted earlier, we found smokers had increased estimated blood loss compared with nonsmokers (mean, 328 mL more for each pack per day smoked; 95% CI, 249-407 mL; p < 0.001). We also found that again correcting for confounders, smokers had increased perioperative transfusion use compared with nonsmokers (odds ratio, 13.8; 95% CI, 4.59-42.52). CONCLUSIONS: Smoking is associated with increased estimated surgical blood loss and transfusion use in patients undergoing lumbar spine surgery. Patients who smoke should be counseled regarding these risks and on smoking cessation before undergoing lumbar surgery. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 26642790 TI - Development of role-differentiated bimanual manipulation in infancy: Part 3. Its relation to the development of bimanual object acquisition and bimanual non differentiated manipulation. AB - This third paper in a series of three related developmental trajectories of bimanual object acquisition and non-differentiated bimanual manipulation (NDBM) to patterns of role-differentiated bimanual manipulation (RDBM) development to help identify the sequence of events that might predict (and potentially facilitate) the development of RDBM skill. Ninety infants were tested monthly from 6 to 14 months of age for object acquisition, and from 9 to 14 months for NDBM and RDBM. The results did not support the hypothesis proposing that the onset of RDBM would require decoupling of the hands in unimanual acquisition, but supported the prediction that coupling of the hands in bimanual acquisition would predict increasing expertise in the RDBM skill. The relation between the bimanual object acquisition and RDBM was found to be mediated by NDBM, which prompts the hypothesis that bimanual acquisition of objects facilitates the development of NDBM, which, in its turn, facilitates the development of the RDBM skill. PMID- 26642789 TI - What Are the Biomechanical Effects of Half-pin and Fine-wire Configurations on Fracture Site Movement in Circular Frames? AB - BACKGROUND: Fine-wire circular frame (Ilizarov) fixators are hypothesized to generate favorable biomechanical conditions for fracture healing, allowing axial micromotion while limiting interfragmentary shear. Use of half-pins increases fixation options and may improve patient comfort by reducing muscle irritation, but they are thought to induce interfragmentary shear, converting beam-to cantilever loading. Little evidence exists regarding the magnitude and type of strain in such constructs during weightbearing. QUESTIONS/PURPOSES: This biomechanical study was designed to investigate the levels of interfragmentary strain occurring during physiologic loading of an Ilizarov frame and the effect on this of substituting half-pins for fine-wires. METHODS: The "control" construct was comprised of a four-ring all fine-wire construct with plain wires at 90 degrees -crossing angles in an entirely unstable acrylic pipe synthetic fracture model. Various configurations, substituting half-pins for wires, were tested under levels of axial compression, cantilever bending, and rotational torque simulating loading during gait. In total three frames were tested for each of five constructs, from all fine-wire to all half-pin. RESULTS: Substitution of half-pins for wires was associated with increased overall construct rigidity and reduced planar interfragmentary motion, most markedly between all-wire and all pin frames (axial: 5.9 mm +/- 0.7 vs 4.2 mm +/- 0.1, mean difference, 1.7 mm, 95% CI, 0.8-2.6 mm, p < 0.001; torsional: 1.4% +/- 0.1 vs 1.1% +/- 0.0 rotational shear, mean difference, 0.3%, 95% CI, 0.1%-0.5%, p = 0.011; bending: 7.5 degrees +/- 0.1 vs 3.4 degrees +/- 0.1, mean difference, -4.1 degrees , 95% CI, -4.4 degrees to -3.8 degrees , p < 0.001). Although greater transverse shear strain was observed during axial loading (0.4% +/- 0.2 vs 1.9% +/- 0.1, mean difference, 1.4%, 95% CI, 1.0%-1.9%, p < 0.001), this increase is unlikely to be of clinical relevance given the current body of evidence showing bone healing under shear strains of up to 25%. The greatest transverse shear was observed under bending loads in all fine-wire frames, approaching 30% (29% +/- 1.9). This was reduced to 8% (+/-0.2) by incorporation of sagittal plane half-pins and 7% (+/-0.2) in all half-pin frames (mean difference, -13.2% and -14.0%, 95% CI, -16.6% to 9.7% and 17.5% to -10.6%, both p < 0.001). CONCLUSIONS: Appropriate use of half-pins may reduce levels of shear strain on physiologic loading of circular frames without otherwise altering the fracture site mechanical environment at levels likely to be clinically important. Given the limitations of a biomechanical study using a symmetric and uniform synthetic bone model, further clinical studies are needed to confirm these conclusions in vivo. CLINICAL RELEVANCE: The findings of this study add to the overall understanding of the mechanics of circular frame fixation and, if replicated in the clinical setting, may be applied to the preoperative planning of frame treatment, particularly in unstable fractures or bone transport where control of shear strain is a priority. PMID- 26642791 TI - Lipid Status and Predisposing Genes in Patients with Diabetes Mellitus Type 1 from Various Ethnic Groups. AB - The peculiarities of HLA class II profile and lipid metabolism were examined in Buryat and Russian ethnic groups of patients with diabetes mellitus type 1. The incidence of type 1 haplotypes in HLA class II gene family was lower in Buryats than that in Russians. In comparison with Russians, the course of diabetes mellitus type 1 in Buryat patients was characterized with a lower content of total lipids, triacylglycerols, total cholesterol, and LDL, which probably explains a more favorable course of the disease in Buryat population. PMID- 26642792 TI - Expression of B23/Nucleophosphamine Nonribosomal Nucleolar Protein in Smooth Muscle Tumors of the Corpus Uteri. AB - Immunohistochemical study of B23/nucleophosmine (NPM), the key argyrophilic nonribosomal protein associated with the nucleolus-producing regions, in smooth muscle formations of the body of the uterus and myometrium was carried out. The uterus index, number of positively stained nucleoli in the nucleus, integral optical density, and area of positively stained nucleoli were studied by computer aided image analysis. The results indicated significant differences in the integral optical density and less so in the areas of NPM+ nucleoli in leiomyosarcomas, but not in intact myometrium and leiomyomas. Coefficients of variations in the integral optical density and NPM area proved to be significant parameters for differentiating leiomyosarcomas by size (<=7 cm or larger), evaluating the malignancy grade and stage of the process. NPM parameters in leiomyomas and leiomyosarcomas differed significantly, depending on the levels of Ki-67 and p53 expression and the receptor status of leiomyosarcoma. The index of area and the integral optical density of NPM could serve a accessory objective differential diagnostic criteria in cellular and mitotically active liomyomas and well-differentiated leiomyosarcoma of the corpus uteri. PMID- 26642793 TI - Role of Interleukin-10 Gene Promoter Region Polymorphism in the Development of Chronic Lymphoid Leukemia. AB - Relationship between interleukin-10 (IL-10) gene G-1082A (rs1800896) polymorphism and the risk of development and stages of chronic lymphoid leukemia is studied in ethnic Russian residents of the Kirov region of Russia. Associations of allele 1082A and genotypes (-1082AA/-1082AG) with the risk of chronic lymphoid leukemia are detected (OR=1.39, 95%CI=1.09-1.78 and OR=1.66, 95%CI=1.09-2.54, respectively). In addition, association of 1082AA genotype with late stages of the disease by the moment of diagnosis is detected. These data indicate that IL 10 polymorphism G-1082A may be involved in the pathogenesis of chronic lymphoid leukemia. PMID- 26642794 TI - Aberrant demethylation and expression of MAGEB2 in a subset of malignant peripheral nerve sheath tumors from neurofibromatosis type 1. AB - BACKGROUND: Malignant peripheral nerve sheath tumors (MPNSTs) occur in several percent of neurofibromatosis type 1 (NF-1) patients. When a CpG island (CGI) in the 5' region of a gene is methylated, transcription of that gene may be suppressed. Although cancer-testis antigens, including MAGEB2, are potential therapeutic targets for cancer in medical practice, information on MAGEB2 in MPNST is scarce. OBJECTIVE: The purpose is to clarify the methylation status and expression of MAGEB2 in MPNSTs derived from patients with NF-1. METHODS: Quantitative real-time methylation-specific PCR (RT-MSP) and quantitative real time reverse transcription-PCR (RT-PCR) were performed to measure methylation and mRNA expression, respectively, in MPNST cell lines and in MPNST and neurofibroma samples from patients with NF-1. Immunohistochemical analysis was also performed to assess MAGEB2 protein expression. RESULTS: RT-MSP and RT-PCR data showed low methylation levels and detectable mRNA expression of MAGEB2, respectively, in one MPNST cell line, but high methylation level and absence of expression in each other cell line and in normal cells. Based on RT-MSP data, 3 of 18 MPNST clinical samples exhibited low methylation levels; in contrast, all cutaneous and plexiform neurofibroma samples and normal cells exhibited high methylation levels. Methylation levels were not significantly associated with any clinical parameters. Immunohistochemical analysis revealed expression of MAGEB2 protein in MPNST clinical samples with the low methylation level. CONCLUSIONS: MAGEB2 can be aberrantly demethylated and expressed in MPNSTs. Conversely, the gene may not be demethylated in any types of neurofibroma, suggesting that the demethylation does not occur before malignant transformation. PMID- 26642795 TI - Percutaneous exposure to high-dose hapten induces systemic immunosuppression through the inhibition of dendritic cell migration. PMID- 26642796 TI - Exposure to a mildly aversive early life experience leads to prefrontal cortex deficits in the rat. AB - Aversive early life experiences in humans have been shown to result in deficits in the function of the prefrontal cortex (PFC). In an effort to elucidate possible neurobiological mechanisms involved, we investigated in rats, the effects of a mildly aversive early experience on PFC structure and function. The early experience involved exposure of rat pups during postnatal days (PND) 10-13 to a T-maze in which they search for their mother, but upon finding her are prohibited contact with her, thus being denied the expected reward (DER). We found that the DER experience resulted in adulthood in impaired PFC function, as assessed by two PFC-dependent behavioral tests [attention set-shifting task (ASST) and fear extinction]. In the ASST, DER animals showed deficits specifically in the intra-dimensional reversal shifts and a lower activation-as determined by c-Fos immunohistochemistry-of the medial orbital cortex (MO), a PFC subregion involved in this aspect of the task. Furthermore, the DER experience resulted in decreased glutamatergic neuron and dendritic spine density in the MO and infralimbic cortex (IL) in the adult brain. The decreased neuronal density was detected as early as PND12 and was accompanied by increased micro- and astroglia-density in the MO/IL. PMID- 26642797 TI - A single-neuron tracing study of arkypallidal and prototypic neurons in healthy rats. AB - The external globus pallidus (GP) is known as a relay nucleus of the indirect pathway of the basal ganglia. Recent studies in dopamine-depleted and healthy rats indicate that the GP comprises two main types of pallidofugal neurons: the so-called "prototypic" and "arkypallidal" neurons. However, the reconstruction of complete arkypallidal neurons in healthy rats has not been reported. Here we visualized the entire axonal arborization of four single arkypallidal neurons and six single prototypic neurons in rat brain using labeling with a viral vector expressing membrane-targeted green fluorescent protein and examined the distribution of axon boutons in the target nuclei. Results revealed that not only the arkypallidal neurons but nearly all of the prototypic neurons projected to the striatum with numerous axon varicosities. Thus, the striatum is a major target nucleus for pallidal neurons. Arkypallidal and prototypic GP neurons located in the calbindin-positive and calbindin-negative regions mainly projected to the corresponding positive and negative regions in the striatum. Because the GP and striatum calbindin staining patterns reflect the topographic organization of the striatopallidal projection, the striatal neurons in the sensorimotor and associative regions constitute the reciprocal connection with the GP neurons in the corresponding regions. PMID- 26642798 TI - AFAST - Adult Female Acne Scoring Tool: an easy-to-use tool for scoring acne in adult females. AB - BACKGROUND: Acne is a concern in adults, especially in women. The specifications in current acne grading systems are not applicable to this particular population. OBJECTIVE: To develop and validate a measurement tool (AFAST: adult female acne scoring tool) for acne in women by taking into account the specific locations of adult female acne, and to evaluate the impact of the photographic modalities on rating reproducibility. METHODS: Six experts in dermatology rated pictures of 54 women with a phototype from I to IV during two sessions, with an interval of 24 h. They rated the acne severity on the face using the GEA scale (Score 1) together with a new scale to assess acne on the mandibular zone (Score 2). Pictures of 30 women were taken using a standardized photographic device; pictures of the other 24 women were taken by their own dermatologists during daily practice. RESULTS: At session 1, the inter-rater's reproducibility was good for Score 1 with an ICC of 0.77 [0.72-0.83], and excellent for Score 2 with an ICC of 0.87 [0.82-0.91]. Between sessions 1 and 2, the mean intra-rater's reproducibility was excellent for both scores with an ICC of 0.88 [0.84-0.92] for Score 1, and an ICC of 0.87 [0.78-0.92] for Score 2. Photographic modalities had no significant effect on the inter- and intra-rater's reproducibility. CONCLUSION: For the first time, it has been demonstrated that AFAST can accurately rate acne severity in women. It is a promising, easy-to-use tool for both daily practice and clinical investigation. PMID- 26642799 TI - Patient characteristics associated with treatment choice for pelvic organ prolapse and urinary incontinence. AB - INTRODUCTION AND HYPOTHESIS: Women with pelvic organ prolapse (POP) and stress urinary incontinence (SUI) frequently undergo more than one treatment prior to settling on their final strategy. We hypothesize that women who are younger, with worse POP and SUI symptoms will desire and choose surgical treatment. METHODS: A retrospective cohort study was performed over 1 year identifying new patients presenting with POP and/or SUI at a university hospital. Our aim was to determine patient desire for either surgical or conservative treatment, as well as the actual treatment chosen and received after the first visit and 1 year later. To identify predictors of choice, baseline demographic characteristics were obtained. RESULTS: Of the 203 women who met the inclusion criteria, 44.3 % (90/203) desired surgery and 55.7 % (113/203) desired conservative treatment at their first visit. Women who desired surgery were more likely to be younger (p = 0.003), sexually active (p = 0.001), have more advanced prolapse (p = 0.006), and have more bothersome symptoms (p = 0.05). Of the women who desired surgery at their first visit, 12.2 % (11/90) actually chose conservative treatment. These women were less likely to be insured (p = 0.01). By 1 year, of the women who initially desired and subsequently chose conservative treatment, 26.5 % (30/113) had undergone surgery. The women who changed from conservative to surgical treatment were more likely to be younger (p = 0.01), non-White (p = 0.03), and sexually active (p = 0.04). CONCLUSIONS: In this study, younger, sexually active women were more likely to either opt for surgery initially or to change their treatment plan from conservative to surgical. PMID- 26642800 TI - Complementary therapies for bladder pain syndrome: a systematic review. AB - INTRODUCTION AND HYPOTHESIS: Bladder pain syndrome is a difficult condition to treat. The purpose of this systematic review is to assess the effectiveness of various complementary therapies available for treatment. METHODS: This review was conducted in adherence with Preferred Reporting Items for Systematic Reviews. Citations were retrieved using a comprehensive database search (from inception to July 2014: CINAHL, Cochrane, EMBASE, Medline and SIGEL and grey literature). Studies that fulfilled the inclusion criteria were selected. Eligibility consisted of women with bladder pain syndrome, an intervention of alternative/complementary therapies and an outcome of improvement of symptoms. Information regarding study characteristics and primary outcomes was collated. The Cochrane risk of bias scale was used to evaluate the quality of the studies included. RESULTS: A total of 1,454 citations were identified, 11 studies fulfilled the inclusion criteria (4 randomised control trials [RCTs] and 7 prospective studies). The key interventions studied were acupuncture, relaxation therapy, physical therapy, hydrogen-rich therapy, diet and nitric oxide synthetase. CONCLUSION: Therapies with the potential for benefit in patients with bladder pain syndrome are dietary management, acupuncture and physical therapy. These findings were obtained from small studies and hence caution is advised. Robustly designed multicentre RCTs on these complementary therapies are needed to guide patients and clinicians. PMID- 26642801 TI - Dry eye findings worsen with anticholinergic therapy in patients with urge incontinence. AB - INTRODUCTION AND HYPOTHESIS: To evaluate the effects of oral anticholinergic (OAC) drugs on tear secretion in women with overactive bladder over a 3-month follow-up period. METHODS: In this prospective study, 108 women with a diagnosis of overactive bladder were evaluated. All patients were examined ophthalmologically at baseline (day 0), and after 1 month (day 30) and 3 months (day 90) of OAC treatment. Tear film break-up time (BUT) and Schirmer 1 test results were recorded. The subjective complaints of the patients including dry mouth, and burning, dryness and foreign body sensation in the eyes, were also recorded. The chi-squared test or the paired sample t test as appropriate, was used for statistical analysis. RESULTS: The mean age of the patients was 51.8 +/- 9.2 years (30 - 69 years). The most frequent subjective complaints were dry mouth and dry eyes and both complaints were significant on both day 30 and day 90. Both tear film BUT and Schirmer 1 test results were significantly lower on day 30 and day 90. Dry eye measurement values worsened with prolongation of OAC treatment (p = 0.037 and p = 0.012 for BUT, and p = 0.046 and p = 0.035 for Schirmer 1 test, on day 30 and day 90, respectively). CONCLUSIONS: OAC treatment in women with overactive bladder significantly and progressively affects tear secretion. PMID- 26642802 TI - The impact of agglomeration economies on hospital input prices. AB - This paper examines the extent to which agglomeration of the hospital service industry enhances the productivity of producing health care. Specifically, we use a large set of private insurance claims from the FAIR Health database to show that an increasing spatial concentration of hospital services results in a decreased cost of obtaining intermediate medical services. We explicitly test whether the reduced cost at concentrated locations arises from the ability to share intermediate service providers. The identification relies on state variation in medical lab technician licensure requirements, which influence the cost of intermediate services only through the cost of running a lab. Our findings suggest that agglomeration of the hospital service industry attracts specialized medical labs, which in turn help to reduce the cost of producing laboratory tests. PMID- 26642803 TI - Additional heritable virus in the parasitic wasp Leptopilina boulardi: prevalence, transmission and phenotypic effects. AB - Parasitoid wasps can be found in association with heritable viruses. Although some viruses have been shown to profoundly affect the biology and evolution of parasitoid wasps, the genetic and phenotypic diversity of parasitoid-associated viruses remains largely unexplored. We previously discovered a behaviour manipulating DNA virus in the parasitoid wasp Leptopilina boulardi. In this species, which lays its eggs inside Drosophila larvae, Leptopilina boulardi filamentous virus (LbFV) forces the females to lay their eggs in already parasitized Drosophila larvae. This behavioural manipulation increases the chances for the horizontal transmission of the virus. Here, we describe in the same parasitoid species another virus, which we propose to call Leptopilina boulardi toti-like virus (LbTV). This double-stranded RNA virus is highly prevalent in insect laboratory lines as well as in parasitoids caught in the field. In some cases, LbTV was found in coinfection with LbFV, but did not affect the behaviour of the wasp. Instead we found that the presence of LbTV correlates with an increase in the number of offspring, mostly due to increased survival of parasitoid larvae. LbTV is vertically transmitted mostly through the maternal lineage even if frequent paternal transmission also occurs. Unlike LbFV, LbTV is not horizontally transmitted. Its genome encodes a putative RNA-dependent RNA polymerase (RdRp) showing similarities with RdRps of Totiviridae. These results underline the high incidence and diversity of inherited viruses in parasitoids as well as their potential impact on the phenotype of their hosts. PMID- 26642804 TI - High Sensitivity Bacillus thuringiensis Cry1Ac Protein Detections Using Fluorescein Diacetate Nanoparticles. AB - A highly sensitive transgenic protein analysis method was proposed here based on fluorescein diacetate (FDA). First, FDA was prepared by the ball mill to harvest the nano-sized organic particles. Further examines showed that the FDA size can be controlled by the speed of centrifugation which can obtain FDA in well distributed size. Cy3 antibody immobilization tests showed that the proteins can attach onto the FDA particles while keep bioactivities. FDA and Cry1Ac antibody immunoassay tests showed that when the FDA particle was in 150 nm, the linear range was 0.01 ng/L-30 MUg/mL. And it has the lower detection limitation of 0.01 ng/L, which is 100 times more sensitive than the ELISA methods. These results indicate that the FDA related immunoassays are the promising approach in the transgenic analysis. PMID- 26642805 TI - Transcranial magnetic stimulation intensity affects exercise-induced changes in corticomotoneuronal excitability and inhibition and voluntary activation. AB - Transcranial magnetic stimulation (TMS) of the motor cortex during voluntary contractions elicits electrophysiological and mechanical responses in the target muscle. The effect of different TMS intensities on exercise-induced changes in TMS-elicited variables is unknown, impairing data interpretation. This study aimed to investigate TMS intensity effects on maximal voluntary activation (VATMS), motor-evoked potentials (MEPs), and silent periods (SPs) in the quadriceps muscles before, during, and after exhaustive isometric exercise. Eleven subjects performed sets of ten 5-s submaximal isometric quadriceps contractions at 40% of maximal voluntary contraction (MVC) strength until task failure. Three different TMS intensities (I100, I75, I50) eliciting MEPs of 53 +/ 6%, 38 +/- 5% and 25 +/- 3% of maximal compound action potential (Mmax) at 20% MVC were used. MEPs and SPs were assessed at both absolute (40% baseline MVC) and relative (50%, 75%, and 100% MVC) force levels. VATMS was assessed with I100 and I75. When measured at absolute force level, MEP/Mmax increased during exercise at I50, decreased at I100 and remained unchanged at I75. No TMS intensity effect was observed at relative force levels. At both absolute and relative force levels, SPs increased at I100 and remained stable at I75 and I50. VATMS assessed at I75 tended to be lower than at I100. TMS intensity affects exercise-induced changes in MEP/Mmax (only when measured at absolute force level), SPs, and VATMS. These results indicate a single TMS intensity assessing maximal voluntary activation and exercise-induced changes in corticomotoneuronal excitability/inhibition may be inappropriate. PMID- 26642806 TI - Role of adenosine A2A receptor in cerebral ischemia reperfusion injury: Signaling to phosphorylated extracellular signal-regulated protein kinase (pERK1/2). AB - Following brain ischemia reperfusion (IR), the dramatic increase in adenosine activates A2AR to induce further neuronal damage. Noteworthy, A2A antagonists have proven efficacious in halting IR injury, however, the detailed downstream signaling remains elusive. To this end, the present study aimed to investigate the possible involvement of phospho-extracellular signal-regulated kinase (pERK1/2) pathway in mediating protection afforded by the central A2A blockade. Male Wistar rats (250-270 g) subjected to bilateral carotid occlusion for 45 min followed by a 24-h reperfusion period showed increased infarct size corroborating histopathological damage, memory impairment and motor incoordination as well as increased locomotor activity. Those events were mitigated by the unilateral intrahippocampal administration of the selective A2A antagonist SCH58261 via a decrease in pERK1/2 downstream from diacyl glycerol (DAG) signaling. Consequent to pERK1/2 inhibition, reduced hippocampal microglial activation, glial tumor necrosis factor-alpha (TNF-alpha) and brain-derived neurotropic factor (BDNF) expression, glutamate (Glu), inducible nitric oxide synthase (iNOS) and thiobarbituric acid reactive substances (TBARS) were evident in animals receiving SCH58261. Additionally, the anti-inflammatory cytokine interleukin-10 (IL-10) increased following nuclear factor (erythroid-derived 2)-like 2 (Nrf-2). Taken all together, these events suppressed apoptotic pathways via a reduction in cytochrome c (Cyt. c) as well as caspase-3 supporting a crucial role for pERK1/2 inhibition in consequent reduction of inflammatory and excitotoxic cascades as well as correction of the redox imbalance. PMID- 26642807 TI - Annexin A2 in primary afferents contributes to neuropathic pain associated with tissue type plasminogen activator. AB - Annexin A2 (ANX2) is a calcium (Ca(2+))-binding protein that binds to acidic phospholipids and is known to play a crucial role in many cellular regulatory processes. In particular, ANX2 has been described as a crucial receptor for thrombolysis by the tissue-type plasminogen activator (tPA) and plasmin system. In the nervous system, tPA is involved in processes of neuronal plasticity such as hippocampal long-term potentiation (LTP) and in the dorsal horn pain in several pain models. We investigated detailed changes in expression of ANX2 after nerve injury and evaluated the interaction with tPA using the rat spared nerve injury (SNI) model. SNI-induced the expression of ANX2 in L4/5 dorsal root ganglia (DRG) neurons. In the spinal cord, constitutive ANX2-immunoreactivity was expressed in laminae I-II. Peripheral nerve injury increased the ANX2 immunoreactive terminals mainly in laminae I-V of the dorsal horn on the side ipsilateral to the nerve injury. Double-labeling analysis revealed the co localization of ANX2 with tPA in the axons of primary afferents in the dorsal horn. Experimental inhibition of ANX2 and tPA interaction by intrathecal administration of homocysteine significantly prevented and reversed SNI-induced mechanical allodynia. Thus, alterations of ANX2 may be involved in tPA-dependent plasticity after peripheral nerve injury and have an important role in neuropathic pain. PMID- 26642808 TI - Increased innervation of forebrain targets by midbrain dopaminergic neurons in the absence of FGF-2. AB - Fibroblast growth factors (FGFs) regulate development and maintenance, and reduce vulnerability of neurons. FGF-2 is essential for survival of midbrain dopaminergic (DA) neurons and is responsible for their dysplasia and disease related degeneration. We previously reported that FGF-2 is involved in adequate forebrain (FB) target innervation by these neurons in an organotypic co-culture model. It remains unclear, how this ex-vivo phenotype relates to the in vivo situation, and which FGF-related signaling pathway is involved in this process. Here, we demonstrate that lack of FGF-2 results in an increased volume of the striatal target area in mice. We further add evidence that the low molecular weight (LMW) FGF-2 isoform is responsible for this phenotype, as this isoform is predominantly expressed in the embryonic ventral midbrain (VM) as well as in postnatal striatum (STR) and known to act via canonical transmembrane FGF receptor (FGFR) activation. Additionally, we confirm that the phenotype with an enlarged FB-target area by DA neurons can be mimicked in an ex-vivo explant model by inhibiting the canonical FGFR signaling, which resulted in decreased extracellular signal-regulated kinase (ERK) activation, while AKT activation remained unchanged. PMID- 26642809 TI - Scientists call for moratorium on clinical use of human germline editing. PMID- 26642810 TI - A Phase II Randomized Study of Lapatinib Combined With Capecitabine, Vinorelbine, or Gemcitabine in Patients With HER2-Positive Metastatic Breast Cancer With Progression After a Taxane (Latin American Cooperative Oncology Group 0801 Study). AB - BACKGROUND: Novel targeted agents and combinations have become available in multiple lines of treatment for human epidermal growth factor receptor 2-positive (HER2(+)) metastatic breast cancer (MBC). In this context, alternatives to the lapatinib (L) and capecitabine (C) regimen, evaluating L combined with other cytotoxic drugs, are warranted. PATIENTS AND METHODS: In the present phase II, multicenter study, patients with HER2(+) MBC with progression after taxane were randomized between L, 1250 mg, combined with C, 2000 mg/m(2) on days 1 to 14 (LC), vinorelbine (V), 25 mg/m(2) on days 1 and 8 (LV), or gemcitabine (G), 1000 mg/m(2) on days 1 and 8 (LG), every 21 days. The primary endpoint was the overall response rate. RESULTS: A total of 142 patients were included from 2009 to 2012. No differences were found in the patient baseline characteristics. The median age was 51 years, 69% were postmenopausal, 32% had liver metastasis, 57% were hormone receptor negative, and 48% had been previously treated with trastuzumab. The overall response rate was 49% (95% confidence interval [CI], 34.8%-63.4%), 56% (95% CI, 40%-70.4%), and 41% (95% CI, 27%-56.8%) in the LC, LV, and LG groups, respectively. The median progression-free survival was 9 months in the LC arm and 7 months in the other 2 arms (P = .28). The most common grade 3 and 4 adverse events were hand-foot syndrome (18%), diarrhea (6%), and increased alanine aminotransferase/aspartate aminotransferase (4%) in the LC arm; neutropenia (36%), diarrhea (9%), and febrile neutropenia (6%) in the LV arm; and neutropenia (47%), alanine aminotransferase/aspartate aminotransferase (13%), and rash (4%) in the LG arm. CONCLUSION: LV and LG seem to be active combinations in patients with HER2(+) MBC after taxane failure. The overall toxicity was manageable in all regimens. PMID- 26642811 TI - Physicians' Considerations for Repeat Biopsy in Patients With Recurrent Metastatic Breast Cancer. AB - BACKGROUND: A strong recommendation has been made to perform repeat biopsy for recurrent metastatic breast cancer (RMBC), to reconfirm the histologic features, and to assess for possible changes in hormone receptors (HRs) or human epidermal growth factor receptor 2 (HER2) status. The present study was undertaken to assess the documented and nondocumented factors affecting physicians' decisions to perform a repeat biopsy in patients with RMBC. PATIENTS AND METHODS: We reviewed the medical records of 410 patients with RMBC for whom recurrence had developed between January 2000 and August 2014. The demographic data and characteristics regarding early and metastatic disease were recorded. The written follow-up records were examined, seeking considerations for or against repeat biopsy. Multivariate analysis was performed using logistic regression to determine the nondocumented reasons for repeat biopsy. RESULTS: A new biopsy was performed in 295 of 410 patients (72%). However, only 88 of the 295 patients (30%) had a documented reason for rebiopsy. The reason for not performing repeat biopsy was documented for only 1 of the 115 patients. The main documented consideration for rebiopsy was to obtain a new receptor status (recorded in 47 of 88 patients; 53%). The other recorded reasons were suspicion of a second primary, differential diagnosis of metastasis from a second primary, the time from early diagnosis, and patient desire. Significant, but undocumented, considerations for repeat biopsy were low stage at early diagnosis, year of recurrence, interval to recurrence, and site of recurrence. Only for 165 of 295 patients (56%) was the full HR and HER2 status from the new biopsy specimen obtained. CONCLUSION: Nondocumented factors influence physicians' decisions for referring patients for rebiopsy. This might reflect a low rate of patient involvement in their disease management and decision making. PMID- 26642812 TI - Complete mitochondrial genome of the Antarctic midge Parochlus steinenii (Diptera: Chironomidae). AB - Parochlus steinenii is a winged midge found in the Antarctic Peninsula and its offshore islands. We determined the complete mitochondrial genome sequence of P. steinenii, which is comprised of 16 803 nucleotides and contains 13 protein coding genes (PCGs), 22 tRNA genes, and the large (rrnL) and small (rrnS) rRNA genes. Its total A + T content is 72.5%. The PCG arrangement of P. steinenii is identical to that of the ancestral Diptera ground pattern. This is the first report on the mitogenome sequence of an Antarctic midge, and provides insights into the evolution of dipterans in Antarctica. PMID- 26642814 TI - Reactivity and Selectivity of Bowl-Shaped Polycyclic Aromatic Hydrocarbons: Relationship to C60. AB - The Diels-Alder reactivity of different bowl-shaped polycyclic aromatic hydrocarbons (namely, corannulene, cyclopentacorannulene, diindenochrysene, hemifullerene, and circumtrindene) has been explored computationally within the DFT framework. To this end, both the increase in reactivity with the size of the buckybowl and complete [6,6]-regioselectivity in the process have been analyzed in detail by using the activation strain model of reactivity in combination with the energy decomposition analysis method. These results have been compared with the parent C60 fullerene, which also produces the corresponding [6,6]-cycloadduct exclusively. The behavior of the buckybowls considered herein resembles, in general, that of C60 . Whereas the interaction energy between the deformed reactants along the reaction coordinate mainly controls the regioselectivity of the process, it is the interplay between the activation strain energy and the transition-state interaction that governs the reactivity of the system. PMID- 26642813 TI - Dicer-independent RNA-directed DNA methylation in Arabidopsis. AB - RNA-directed DNA methylation (RdDM) is an important de novo DNA methylation pathway in plants. Small interfering RNAs (siRNAs) generated by Dicers from RNA polymerase IV (Pol IV) transcripts are thought to guide sequence-specific DNA methylation. To gain insight into the mechanism of RdDM, we performed whole genome bisulfite sequencing of a collection of Arabidopsis mutants, including plants deficient in Pol IV (nrpd1) or Dicer (dcl1/2/3/4) activity. Unexpectedly, of the RdDM target loci that required Pol IV and/or Pol V, only 16% were fully dependent on Dicer activity. DNA methylation was partly or completely independent of Dicer activity at the remaining Pol IV- and/or Pol V-dependent loci, despite the loss of 24-nt siRNAs. Instead, DNA methylation levels correlated with the accumulation of Pol IV-dependent 25-50 nt RNAs at most loci in Dicer mutant plants. Our results suggest that RdDM in plants is largely guided by a previously unappreciated class of Dicer-independent non-coding RNAs, and that siRNAs are required to maintain DNA methylation at only a subset of loci. PMID- 26642815 TI - Large Stokes Shift and High Efficiency Luminescent Solar Concentrator Incorporated with CuInS2/ZnS Quantum Dots. AB - Luminescent solar concentrator (LSC) incorporated with quantum dots (QDs) have been widely regarded as one of the most important development trends of cost effective solar energy. In this study, for the first time we report a new QDs-LSC integrated with heavy metal free CuInS2/ZnS core/shell QDs with large Stokes shift and high optical efficiency. The as-prepared CuInS2/ZnS QDs possess advantages of high photoluminescence quantum yield of 81% and large Stocks shift more than 150 nm. The optical efficiency of CuInS2/ZnS QDs-LSC reaches as high as 26.5%. Moreover, the power conversion efficiency of the QDs-LSC-PV device reaches more than 3 folds to that of pure PMMA-PV device. Furthermore, the PV device is able to harvest 4.91 folds solar energy with the assistance of this new CuInS2/ZnS QDs-LSC for the same size c-Si PV cell. The results demonstrate that this new CuInS2/ZnS QDs-LSC provides a promising way for the high efficiency, nonhazardous and low cost solar energy. PMID- 26642816 TI - Is ischemia modified albumin a disease activity marker for inflammatory bowel diseases? AB - BACKGROUND AND AIM: We aimed to identify ischemia-modified albumin (IMA) levels in inflammatory bowel disease (IBD) and IBD subgroups, and to examine its relation with disease activity index. METHODS: Sixty-eight patients with IBD (35 ulcerative colitis [UC] and 33 crohn disease [CD]) and 65 healthy volunteers were included in the study. Rachmilewitz scoring system (endoscopic activity index [EAI]) was used to determine UC activity, and as for CD activity, CD activity index (CDAI) scoring was used. IMA measurement was performed with ELISA kit. RESULTS: Ischemia-modified albumin levels in IBD, UC, and CD groups were comparably higher than the control group (37.7 ng/mL vs 42.4 ng/mL vs 36.4 ng/mL vs 21.8 ng/mL, respectively; P < 0.05). In IBD group, a positive correlation was identified between IMA level and CRP (r = 0.325, P = 0.011), EAI(r = 0.302, P = 0.020), and CDAI (r = 0.311, P = 0.013). In stepwise regression model; it was identified that IMA(OR = 1.496; P = 0.016) and CRP(OR = 3.457; P = 0.015) are predictors of IBD in comparison with the control group. In linear regression model, it was identified that risk factors such as log(IMA) and log(CRP) were independent predictors of log(CDAI) and log(EAI) levels. CONCLUSION: This is the first study showing that IMA levels in IBD were determined higher in comparison with the control group. Moreover, IMA being a predictor for IBD and being positively correlated with disease activity indexes were determined for the first time in the study. In accordance with these results, it is possible to say that IMA in IBD might be related with the pathogenesis of disease and correlated with the severity of the disease. PMID- 26642817 TI - Public Education Campaigns to Transform Perceptions of Pharmacists: Are They Worth the Investment? AB - Recent public opinion polls consistently rank pharmacists as highly trusted health care professionals, but the reasoning for this ranking continues to remain vague and inconclusive. One possible explanation for this high ranking is that it is due in part to the limited expectations the public has of the profession. To gather comparative "before" and "after" data for this study, a self-administered, 33-item paper questionnaire was disseminated to 382 postsecondary (undergraduate) business students in a classroom setting. The questionnaire was designed to assess respondents' baseline perceptions toward (1) the pharmacy profession, in general, and (2) a prerecorded video of a simulated patient-pharmacist counseling session. Most respondents initially reported a "Poor/Fair" understanding of pharmacist education and training (52.1%), what to expect when having a prescription dispensed (55.5%), the content of a counseling session (49.7%), and pharmacist scope of practice (55.5%). After viewing the educational video, the number of respondents who reported a "Poor/Fair" understanding dropped to less than 5%; the majority of respondents reported a "Very Good/Excellent" understanding of pharmacist education and training (63.1%), what to expect when having a prescription dispensed (56.0%), the content of a counseling session (66.4%), and pharmacist scope of practice (60.5%). Results of this study demonstrated that using a public education-type video to increase public awareness for the pharmacy profession and pharmacist counseling duties significantly impacted respondents' knowledge and perception of value toward the profession and of pharmacist counseling. PMID- 26642818 TI - Similar local, but different systemic, metabolomic responses of closely related pine subspecies to folivory by caterpillars of the processionary moth. AB - Plants respond locally and systemically to herbivore attack. Most of the research conducted on plant-herbivore relationships at element and molecular levels have focused on the elemental composition or/and certain molecular compounds or specific families of defence metabolites showing that herbivores tend to select plant individuals or species with higher nutrient concentrations and avoid those with higher levels of defence compounds. We performed stoichiometric and metabolomics, both local and systemic, analyses in two subspecies of Pinus sylvestris under attack from caterpillars of the pine processionary moth, an important pest in the Mediterranean Basin. Both pine subspecies responded locally to folivory mainly by increasing relative concentrations of terpenes and some phenolics. Systemic responses differed between pine subspecies, and most of the metabolites presented intermediate concentrations between those of the affected parts and unattacked trees. Our results support the hypothesis that foliar nutrient concentrations are not a key factor for plant selection by adult female processionary moths for oviposition, since folivory was not associated with any of the elements analysed. Phenolic compounds generally did not increase in the attacked trees, questioning the suggestion of induction of phenolics following folivory attack and the anti-feeding properties of phenolics. Herbivory attack produced a general systemic shift in pines, in both primary and secondary metabolism, which was less intense and chemically different from the local responses. Local pine responses were similar between pine subspecies, while systemic responses were more distant. PMID- 26642819 TI - [A sarcophagus with a surprise: computed tomography of a mummy from the Late Period of ancient Egypt]. AB - INTRODUCTION: Diagnostic imaging techniques, at present especially computed tomography (CT), have become the most important noninvasive method for the study of mummies because they enable high resolution images and three-dimensional reconstructions without damaging the mummified subject. We present a sarcophagus with a mummy hidden inside that was acquired by a gallery in Barcelona. MATERIAL AND METHODS: The sarcophagus and mummy were examined by CT at the Hospital Universitari Sagrat Cor in Barcelona. A flexible clamp was used to obtain tissue samples for further study. RESULTS: The results showed the presence of an anatomically intact female human subject albeit with a destructured thorax and upper abdomen. Various metal objects were detected, corresponding to amulets, artificial eyes, and an external wooden brace. CONCLUSION: CT is an excellent noninvasive imaging technique for the detailed study of mummies, as it enables not only the anatomic identification of the mummified subject but also the obtainment of tissue samples for complementary analyses. The description of these findings enables us to know the major radiologic landmarks for the paleopathologic study of mummies. PMID- 26642820 TI - Proteomics and glomerulonephritis: A complementary approach in renal pathology for the identification of chronic kidney disease related markers. AB - Glomerulonephritis (GN) is one of the most common origins of chronic kidney disease and its careful evaluation is crucial for prognostic and therapeutic purposes, with the renal biopsy still playing a central role for the diagnosis. However, due to its invasiveness, it is not devoid of complications and many investigations have focused on identifying biomarkers for chronic kidney diseases using less-invasive and easy-to-collect samples, such as urine and blood. In this context, proteomics has played a crucial role in determining the molecular changes related to disease progression and early pathological glomerular modifications. Here, we report a review of selected literature for each GN, based on selected works published in the last 10 years, showing how these approaches have generated clinically relevant findings in the study of glomerulonephritis. We also describe several proteomic strategies, highlighting their technical advantages and limitations, future perspectives for proteomic applications in the study of GNs, and their possible application in routine practice. PMID- 26642821 TI - In through the backdoor: surgical considerations for the morbidly adherent placenta. PMID- 26642822 TI - Detection of airborne viruses using electro-aerodynamic deposition and a field effect transistor. AB - We report a technique for the detection of aerosolized viruses. Conventional field-effect-transistor (FET)-based techniques use solution-based processes, thus require antibody binding to the detection region of the FET prior to the supply of the analyte. With the method described here, virus-antibody-bound particles are delivered to the FET during detection; therefore, neither a pre-treatment antibody binding step on the FET channel nor washing process for virus-antibody binding are necessary. Our method is based on the concept that virus-antibody bound particles are larger than the virus or antibody alone, and thus have larger charge numbers following aerosol charging. When these particles are charged by negative ions and electro-aerodynamically deposited on a substrate, there exists a location on the substrate where neither lone virus nor antibody particles land, and where only virus-antibody-bound particles are deposited. If this location coincides with the channel of the FET, the resulting variation in the current can be used to indicate the existence of a virus. By aerosolizing a mixed solution of the virus and the antibody, only the virus-antibody-bound particles were transported to the swCNT-FET, and the electric current in the swCNT-FET decreased to 30% of that measured with no deposited particles. PMID- 26642823 TI - Bodies on Display: Queer Biopolitics in Popular Culture. AB - For this contribution to the special issue on "Mapping Queer Bioethics," the author undertakes the curatorial spaces of the library, the museum, the textbook, and the public exhibition. With showcases such as natural history museums and the recent Bodyworlds traveling exhibit as touchstones, the author argues that distinctions between medical and popular visual culture in pedagogical contexts are porous, such that the study of sensational body types (queer, anatomically atypical, and otherwise) are couched in culturally problematic appreciations of the agency of certain bodies to speak for and/or about themselves. By extension, how and where certain bodies are viewed represent vital, bioethical dilemmas on the nature of corporeal viability. PMID- 26642824 TI - Where do the Neotropical Empidini lineages (Diptera: Empididae: Empidinae) fit in a worldwide context? AB - The tribe Empidini (Diptera: Empididae: Empidinae) is a diverse group with fourteen genera, seven of which are exclusive to the Neotropical region: Bolrhamphomyia Rafael, Chilerhamphomyia Rafael, Hystrichonotus Collin, Lamprempis Wheeler and Melander, Macrostomus Wiedemann, Opeatocerata Melander and Porphyrochroa Melander. Although Empidini itself is likely paraphyletic, many presumably monophyletic genera and species groups are recognized. Here, we apply DNA sequences from multiple genes to infer the phylogeny of Empidini, focusing on placing the Neotropical lineages within the entire tribe and identifying monophyletic groups. We included 98 Empidini taxa along with 18 outgrous terminals, spanning the diversity within the group. The results from the analyses performed are largely similar, with major groupings of genera in common. Specifically, the analyses recovered a monophyletic Hilarini and a paraphyletic Empidini. Most species from Chile and Argentina (Andean region) are found to belong to an early branching lineage within Empidinae, and are not monophyletic with other Empidini. A large portion of the remaining Neotropical Empidini (not Andean) comprises a single clade that includes four endemic genera and a number of Neotropical Empis Linneaus species. Macrostomus and Porphyrochroa each recovered as monophyletic and sister to one another, although generic placement of a few taxa remains uncertain due to conflicting morphological features. Lamprempis+Opeatocerata are also found to be sister-taxa in most analyses. Several large genera were found to be polyphyletic or paraphyletic including Empis and Rhamphomyia Meigen. We evaluate our findings and discuss them in light of current Empidinae taxonomy. PMID- 26642825 TI - Molecular phylogeny and evolution of internal fertilization in South American seasonal cynopoeciline killifishes. AB - Internal fertilization is a widespread mode of reproduction in chondrichthyans and tetrapods, but uncommon in actinopterygian fishes. In killifishes of the suborder Aplocheiloidei, internal fertilization is restricted to two genera, Campellolebias and Cynopoecilus, both containing species adapted to life in seasonal pools of subtropical South America and exhibiting elaborated inseminating structures. Phylogenetic studies involving these genera are scarce and limited to morphological characters and fragments of mitochondrial DNA sequences available for a few taxa, providing incongruent results and thus impeding hypotheses on the evolution of insemination and related morphological traits. We analyzed three nuclear loci (GLYT1, ENC1, Rho) for 13 aplocheiloid taxa obtaining the first well-supported phylogeny for cynopoecilines, thus providing a significant background to interpret evolutionary changes within the group. Like in killifishes of the suborder Cyprinodontoidei, the evolution of internal fertilization in aplocheiloids is associated with deep changes in the structure of male anal fin. The phylogenetic analyses indicate that internal fertilization corresponds to a single evolutionary event during the evolution of aplocheiloid killifishes. The analyses also indicate that male specialized muscle characters, comprising a muscular ejaculatory pump in the urogenital region and hypertrophied inclinatores and depressores anales, arose in the ancestor of the clade comprising Campellolebias and Cynopoecilus. On the other hand, anal fin specialized structures including the male inseminating tube of Campellolebias and the male inseminating fan of Cynopoecilus evolved independently in each genus. PMID- 26642827 TI - An event-based architecture for solving constraint satisfaction problems. AB - Constraint satisfaction problems are ubiquitous in many domains. They are typically solved using conventional digital computing architectures that do not reflect the distributed nature of many of these problems, and are thus ill-suited for solving them. Here we present a parallel analogue/digital hardware architecture specifically designed to solve such problems. We cast constraint satisfaction problems as networks of stereotyped nodes that communicate using digital pulses, or events. Each node contains an oscillator implemented using analogue circuits. The non-repeating phase relations among the oscillators drive the exploration of the solution space. We show that this hardware architecture can yield state-of-the-art performance on random SAT problems under reasonable assumptions on the implementation. We present measurements from a prototype electronic chip to demonstrate that a physical implementation of the proposed architecture is robust to practical non-idealities and to validate the theory proposed. PMID- 26642826 TI - Network-Dependent Modulation of COMT and DRD2 Polymorphisms in Healthy Young Adults. AB - Nonlinear modulation of the dopamine signaling on brain functions can be estimated by the interaction effects of dopamine-related genetic variations. We aimed to explore the interaction effects of COMT rs4680 and DRD2 rs1076560 on intra-network connectivity using independent component analysis. In 250 young healthy adults, we identified 11 meaningful resting-state networks (RSNs), including the salience, visual, auditory, default-mode, sensorimotor, attention and frontoparietal networks. A two-way analysis of covariance was used to investigate COMT*DRD2 interactions on intra-network connectivity in each network, controlling for age, gender and education. Significant COMT*DRD2 interaction was found in intra-network connectivity in the left medial prefrontal cortex of the anterior default-mode network, in the right dorsolateral frontal cortex of the right dorsal attention network, and in the left dorsal anterior cingulate cortex of the salience network. Post hoc tests revealed that these interactions were driven by the differential effects of DRD2 genotypes on intra-network connectivity in different COMT genotypic subgroups. Moreover, even in the same COMT subgroup, the modulation effects of DRD2 on intra-network connectivity were different across RSNs. These findings suggest a network-dependent modulation of the DA-related genetic variations on intra-network connectivity. PMID- 26642828 TI - A survey of UK services for younger people living with dementia. PMID- 26642829 TI - Synthesis of 4-[2-(3,4-dimethoxybenzyl)cyclopentyl]-1,2-dimethoxybenzene Derivatives and Evaluations of Their Carbonic Anhydrase Isoenzymes Inhibitory Effects. AB - Rearrangement of 1,6-bis(3,4-dimethoxyphenyl)hexane-1,6-dione (8) gave two isomeric products having cyclopentene moiety. Starting from the major product (3,4-dimethoxyphenyl)[2-(3,4-dimethoxyphenyl)cyclopent-1-en-1-yl]methanone (11), eight new compounds (16-23) were obtained by the reactions such as reduction (by catalytic hydrogenation and NaBH4 ), nitration, 1,4-addition, bromination, and esterification reactions. Carbonic anhydrases (CA, E.C.4.2.1.1) are ubiquitous metalloenzymes present in almost all living organism that catalyze a simple reaction, the conversion of carbon dioxide (CO2 ) and water (H2 O) to bicarbonate ion (HCO3 (-) ) and a proton (H(+) ). CA isoenzymes I and II (hCA I and II) inhibition effects of synthesized eleven new and four known compounds (8-13 and 15-23) were investigated. Inhibition studies of the hCA I and II with 4-[2-(3,4 dimethoxybenzyl)cyclopentyl]-1,2-dimethoxybenzene derivatives revealed that they possess effective inhibitory potency. Cytosolic hCA I and II isoenzymes were potently inhibited by new synthesized 4-[2-(3,4-dimethoxybenzyl)cyclopentyl]-1,2 dimethoxybenzene derivatives with Ki s in the range of 313.16-1537.00 nm against hCA I and in the range of 228.31-1927.31 nm against hCA II, respectively. PMID- 26642830 TI - Adolescent Obesity Risk Knowledge (AORK): Let the Discussion Begin. AB - PURPOSE: This study aims to examine adolescent level of knowledge concerning obesity risk. DESIGN AND METHODS: Qualitative and quantitative data were collected using a staged process. Data collected with (a) Obesity Risk Knowledge Scale (ORK-10), (b) focus groups, (c) scientific advisory group input, and (d) the Adolescent Obesity Risk Knowledge Scale (AORK). RESULTS: The AORK is tailored from the ORK-10 (alpha = .53) to capture adolescents' knowledge of obesity complications and/or risks (alpha = .68). PRACTICE IMPLICATIONS: The AORK integrates questions for assisting practitioners to initiate discussions about obesity and lifestyle choices with adolescents and their families. PMID- 26642831 TI - Impacts of impervious surface expansion on soil organic carbon--a spatially explicit study. AB - The rapid expansion of impervious surface areas (ISA) threatens soil organic carbon (SOC) pools in urbanized areas globally. The paucity of field observations on SOC under ISA (SOCISA), especially in dryland areas has limited our ability to assess the ecological impacts of ISA expansion. Based on systematically measured SOCISA (0-80 cm depth) of a dryland city, and land-use and land-cover change data derived from remotely sensed data, we investigated the magnitude and vertical/horizontal patterns of SOCISA and mapped the impact of ISA expansion on SOC storage. The mean SOCISA in the city was 5.36 +/- 0.51 kg C m(-2), lower than that observed in humid cities but much higher than that assumed in many regional carbon assessments. SOCISA decreased linearly as the soil depth or the horizontal distance from the open area increased. SOCISA accounted for over half of the city's SOC stock, which decreased by 16% (primarily in the converted croplands) because of ISA expansion from 1990 to 2010. The impacts of the ISA expansion varied spatially, depending on the land- use and converted land-cover type. PMID- 26642832 TI - First report and description of a Cyrilia sp. (Apicomplexa: Haemogregarinidae) from a freshwater Cururu Stingray Potamotrygon cf. histrix (Elasmobranchii: Potamotrygonidae), from the Amazon Region, Brazil. AB - A haemogregarine is described in 12 cururu stingray (Potamotrygon cf. histrix), from Mariua Archipelago, Negro River, in the Brazilian Amazon Basin. All animals, both male and female, were parasitized by the haemogregarine and parasitaemia varied between 0.8% and 10% of erythrocytes. The stages observed included trophozoites or merozoites, suspected meronts, and gamonts presumed to be of two types, macrogamonts and microgamonts. Most stages were observed inside mature erythrocytes, while others were extracellular. The stages observed were most similar to those characteristics of the genus Cyrilia, than to any other fish haemogregarine and may represent a new Cyrilia species. PMID- 26642833 TI - Effects of Mini-Volume Priming During Cardiopulmonary Bypass on Clinical Outcomes in Low-Bodyweight Neonates: Less Transfusion and Postoperative Extracorporeal Membrane Oxygenation Support. AB - Mixing of autologous blood with priming volume has relatively significant effects on blood composition, especially in low-bodyweight neonates. In an effort to reduce these effects, mini-volume priming (MP) has been applied in cardiopulmonary bypass (CPB). The present study was designed to examine the effect of MP on clinical outcomes of low-bodyweight neonates undergoing open heart surgery.We retrospectively reviewed medical records of low-bodyweight (2.5 kg or less) neonates who underwent open heart surgery in our center from January 2000 to December 2014. A total of 64 patients were included. MP was introduced in 2007, and became a routine protocol in 2009. Preoperative and intraoperative characteristics included age, bodyweight, RACHS-1, priming volume, CPB time, and aortic cross-clamp time, transfusion, and hematocrit during CPB. Clinical outcomes included 30-day mortality, postoperative extracorporeal membrane oxygenation (ECMO) support, open sternum status, prolonged mechanical ventilation care (>7 days), and acute renal failure. MP was utilized in 39 patients and conventional priming (CP) was used in 25 patients. The priming volume decreased to 126.0 mL in the MP group compared with 321.6 mL in the CP group. Transfusion volume during CPB was 87.3 mL in the MP group versus 226.8 mL in the CP group, and the difference was statistically significant (P < 0.001). Hematocrit at the end of the CPB and maximal decrease of hematocrit during CPB were not significantly different between the two groups. The 30-day mortality rate was 12.8% in the MP group versus 20.0% in the CP group. Postoperative ECMO support was performed in 5.1% of patients in the MP group versus 17.4% of patients in the CP group. Open sternum status was required in 20.8% of patients in the MP group versus 10.3% of patients in the CP group, and prolonged ventilator care was required in 54.2% of patients in the MP group versus 38.5% of patients in the CP group. However, no statistical significance was measured in any of the clinical outcome measures. Larger priming volume and higher RACHS-1 were significant risk factors of postoperative ECMO support in univariate and multivariate analysis. The results of the present study suggest that MP may be beneficial in avoiding transfusion without having a significant effect on the hematocrit. Clinical outcomes did not differ between the two groups. However, larger priming volume was a significant risk factor for postoperative ECMO support with RACHS-1 category. PMID- 26642835 TI - Searching for new thermoelectric materials: some examples among oxides, sulfides and selenides. AB - Different families of thermoelectric materials have been investigated since the discovery of thermoelectric effects in the mid-19th century, materials mostly belonging to the family of degenerate semi-conductors. In the last 20 years, new thermoelectric materials have been investigated following different theoretical proposals, showing that nanostructuration, electronic correlations and complex crystallographic structures (low dimensional structures, large number of atoms per lattice, presence of 'rattlers'...) could enhance the thermoelectric properties by enhancing the Seebeck coefficient and/or reducing the thermal conductivity. In this review, the different strategies used to optimize the thermoelectric properties of oxides and chalcogenides will be presented, starting with a review on thermoelectric oxides. The thermoelectric properties of sulfides and selenides will then be discussed, focusing on layered materials and low dimensional structures (TiS2 and pseudo-hollandites). Some sulfides with promising ZT values will also be presented (tetrahedrites and chalcopyrites). PMID- 26642836 TI - Highly Efficient Simplified Single-Emitting-Layer Hybrid WOLEDs with Low Roll-off and Good Color Stability through Enhanced Forster Energy Transfer. AB - Single-emitting layer hybrid white organic light-emitting diodes (SEL-hybrid WOLEDs) usually suffer from low efficiency, significant roll-off, and poor color stability, attributed to the incomplete energy transfer from the triplet states of the blue fluorophores to the phosphors. Here, we demonstrate highly efficient SEL-hybrid-WOLEDs with low roll-off and good color-stability utilizing blue thermally activated delayed fluorescence (TADF) materials as the host emitters. The triplet states of the blue TADF host emitter can be up-converted into its singlet states, and then the energy is transferred to the complementary phosphors through the long-range Forster energy transfer, enhancing the energy transfer from the host to the dopant. Simplified SEL-hybrid-WOLEDs achieve the highest forward-viewing external quantum efficiency (EQE) of 20.8% and power efficiency of 51.2 lm/W with CIE coordinates of (0.398, 0.456) at a luminance of 500 cd/m(2). The device EQE only slightly drops to 19.6% at a practical luminance of 1000 cd/m(2) with a power efficiency of 38.7 lm/W. Furthermore, the spectra of the device are rather stable with the raising voltage. The reason can be assigned to the enhanced Forster energy transfer, wide charge recombination zone, as well as the bipolar charge transporting ability of the host emitter. We believe that our work may shed light on the future development of highly efficient SEL-hybrid WOLEDs with simultaneous low roll-off and good color stability. PMID- 26642834 TI - Magnetic resonance imaging spectrum of succinate dehydrogenase-related infantile leukoencephalopathy. AB - OBJECTIVE: Succinate dehydrogenase-deficient leukoencephalopathy is a complex II related mitochondrial disorder for which the clinical phenotype, neuroimaging pattern, and genetic findings have not been comprehensively reviewed. METHODS: Nineteen individuals with succinate dehydrogenase deficiency-related leukoencephalopathy were reviewed for neuroradiological, clinical, and genetic findings as part of institutional review board-approved studies at Children's National Health System (Washington, DC) and VU University Medical Center (Amsterdam, the Netherlands). RESULTS: All individuals had signal abnormalities in the central corticospinal tracts and spinal cord where imaging was available. Other typical findings were involvement of the cerebral hemispheric white matter with sparing of the U fibers, the corpus callosum with sparing of the outer blades, the basis pontis, middle cerebellar peduncles, and cerebellar white matter, and elevated succinate on magnetic resonance spectroscopy (MRS). The thalamus was involved in most studies, with a predilection for the anterior nucleus, pulvinar, and geniculate bodies. Clinically, infantile onset neurological regression with partial recovery and subsequent stabilization was typical. All individuals had mutations in SDHA, SDHB, or SDHAF1, or proven biochemical defect. INTERPRETATION: Succinate dehydrogenase deficiency is a rare leukoencephalopathy, for which improved recognition by magnetic resonance imaging (MRI) in combination with advanced sequencing technologies allows noninvasive diagnostic confirmation. The MRI pattern is characterized by cerebral hemispheric white matter abnormalities with sparing of the U fibers, corpus callosum involvement with sparing of the outer blades, and involvement of corticospinal tracts, thalami, and spinal cord. In individuals with infantile regression and this pattern of MRI abnormalities, the differential diagnosis should include succinate dehydrogenase deficiency, in particular if MRS shows elevated succinate. PMID- 26642837 TI - Metastatic phenotype in CWR22 prostate cancer xenograft following castration. AB - BACKGROUND: CWR22 is a human xenograft model of primary prostate cancer (PCa) that is often utilized to study castration recurrent (CR) PCa. CWR22 recapitulates clinical response to androgen deprivation therapy (ADT), in that tumors regress in response to castration, but can recur after a period of time. METHODS: Two cohorts of mice, totaling 117 mice were implanted with CWR22, allowed to develop tumors, castrated by pellet removal and followed for a period of 32 and 50 weeks. Mice presenting with tumors >2.0 cm(3) at the primary site, moribund appearance, or palpable masses other than the primary tumor were sacrificed prior to the endpoint of the study. Tumor tissue, serum, and abnormal lesions were collected upon necropsy and analyzed by IHC, H&E, and PCR for presence of metastatic lesions arising from CWR22. RESULTS: Herein, we report that CWR22 progresses after castration from a primary, hormonal therapy-naive tumor to metastatic disease in 20% of castrated nude mice. Histological examination of CWR22 primary tumors revealed distinct pathologies that correlated with metastatic outcome after castration. CONCLUSION: This is the first report and characterization of spontaneous metastasis in the CWR22 model, thus, CWR22 is a bona-fide model of clinical PCa representing the full progression from androgen sensitive, primary PCa to metastatic CR-PCa. PMID- 26642838 TI - Effect of poly and mono-unsaturated fatty acids on stability and structure of recombinant S100A8/A9. AB - Recombinant pET 15b vectors containing the coding sequences S100A8 and S100A9 are expressed in Escherichia coli BL21 (DE3) and purified using Ni-NTA affinity chromatography. The structural changes of S100A8/A9 complex are analyzed upon interaction with poly/mono-unsaturated fatty acids (UFAs). The thermodynamic values, Gibbs free energy and the protein melting point, are obtained through thermal denaturation of protein both with and without UFAs by thermal scanning of protein emission using the fluorescence spectroscopy technique. The far ultraviolet circular dichroism spectra show that all studied unsaturated fatty acids, including arachidonic, linoleic, alpha-linolenic and oleic acids, induce changes in the secondary structure of S100A8/A9 by reducing the alpha-helix and beta-sheet structures. The tertiary structure of S100A8/A9 has fluctuations in the fluorescence emission spectra after the incubation of protein with UFAs. The blue-shift of emission maximum wavelength and the increase in fluorescence intensity of anilino naphthalene-8-sulfonic acid confirm that the partial unfolding is caused by the conformational changes in the tertiary structure in the presence of UFAs. The structural changes in S100A8/A9 and its lower stability in the presence of UFAs may be necessary for S100A8/A9 to play a biological role in the inflammatory milieu. PMID- 26642839 TI - Improved oral absorption of tacrolimus by a solid dispersion with hypromellose and sodium lauryl sulfate. AB - A novel surfactant-incorporated hydroxypropyl methylcellulose (HPMC) solid dispersion (SD) system was constructed in order to facilitate the release rate and oral absorption of tacrolimus (FK506), a poorly water-soluble immunosuppressant. Several emulsifiers including sodium lauryl sulfate (SLS), as drug release promotors, were employed with HPMC to fabricate SD using the solvent wetting method. The solid state characteristics using differential scanning calorimetry and X-ray powder diffraction, revealed that FK506 was molecularly distributed within all dispersions in amorphous form. The dissolution rates of FK506 in SLS-incorporated SDs were much higher than those in SDs prepared with HPMC alone, and even with stearoyl polyoxyl-32 glycerides or tocopheryl polyethylene glycol 1000 succinate. In particular, the greatest dissolution enhancement was obtained from the SD consisting of the drug, HPMC, and SLS in a weight ratio of 1:1:3, providing a 50-fold higher drug concentration within 15 min, compared with HPMC SD. In vivo absorption study in rats demonstrates that the optimized formula remarkably increased the oral absorption of FK506, providing about 4.0-fold greater bioavailability (p<0.05) compared with the marketed product (Prograf(r), Astellas Pharma). These data suggest that a novel SLS/HPMC SD may be an advantageous dosage form of FK506, boosting the dissolution and absorption in gastrointestinal tract. PMID- 26642840 TI - Effect of Cd2+ on muscle type of creatine kinase: Inhibition kinetics integrating computational simulations. AB - Creatine kinase (EC 2.7.3.2, CK) plays an important role in cellular energy metabolism and homeostasis by catalyzing the transfer of phosphate between ATP and creatine phosphate. We investigated the effects of Cd2+ on muscle type of creatine kinase from Pelodiscus sinensis (PSCKM). Cd2+ conspicuously inactivated the activity of PSCKM (IC50=0.062 mM) in a first-order kinetic process and exhibited non-competitive inhibition with creatine and ATP. A conformational study showed that Cd2+ induced tertiary structure changes in PSCKM with exposure of hydrophobic surfaces. The addition of osmolytes, such as glycine and proline, partially reactivated the Cd2+-mediated inactive PSCKM. Additionally, molecular dynamics and docking simulations between PSCKM and Cd2+ were conducted to show that Cd2+ blocked the entrance of ATP to the active site, and this result is consistent with the experimental results showing Cd2+-induced inactivation of PSCKM. Our study demonstrates the effect of Cd2+ on PSCKM enzymatic function and unfolding, including the protective effects of osmolytes on PSCKM inactivation. This study provides important insights into the changes in the PSCKM metabolic enzyme of ectothermic animals in response to the environment. PMID- 26642841 TI - Recrystallization characteristics of high hydrostatic pressure gelatinized normal and waxy corn starch. AB - High hydrostatic pressure (HHP) can lead to starch gelatinization at room temperature, while the retrogradation mechanism of HHP gelatinized starch is not well known. HHP gelatinized normal and waxy corn starches were stored at room temperature for 192 h in order to investigate the retrogradation characteristics. The scanning electron microscopy (SEM), polarised light microscopy and differential scanning calorimetric (DSC) analysis showed that the pressurization of normal and waxy corn starch suspensions with concentration of 30% (w/v) at 600 MPa for 15 min resulted in a complete gelatinization. In addition, the pressure gelatinized normal and waxy corn starch gels were stored and subjected to X-ray diffraction (XRD) analysis, resistant starch content determination, swelling power and pasting behavior. The retrograded normal maize and waxy maize starch showed a substantial loss of A-type crystallinity. Both pressure-gelatinized normal and waxy corn starches showed an increase in resistant starch content and relative crystallinity degree with the increase of storage time. In addition, restricted starch swelling power and lower pasting viscosities were observed for these two retrograded starches. The amylose molecule within starch granules has been regarded as the main factor to affect the structural and physicochemical properties during the retrogradation process of HHP-gelatinized starch granules. PMID- 26642842 TI - Antihypertensive activity of polysaccharide from Crassostrea gigas. AB - Water-soluble polysaccharide was extracted from Crassostrea gigas by hydrolysis with flavourzyme and filtered, ultrafiltered and precipitated using absolute ethanol. Sugar composition analysis performed on the C. gigas polysaccharide (CGP) by high performance liquid chromatography indicated that it was comprised primarily of glucose, and its molecular weight was determined using a TSK-GEL G5000PW column to be ~3.413*10(6) Da. Next, the antihypertensive activity of CGP was evaluated in rats. Hypertension model Wistar rats were divided into three groups and intragastrically treated with physiological saline (negative control group), CGP (treatment group), and captopril (positive control group). CGP treatment led to significant decrease in both systolic and diastolic pressures in the hypertension model Wistar rats. Furthermore, the antihypertensive effect of CGP was comparable with that of captopril. Thus, CGP has antihypertensive effects and can potentially be used as a therapeutic agent for hypertension. PMID- 26642843 TI - We have to become more specific: A reply to Morrison et al. PMID- 26642844 TI - Assessment of practical tasks in the Phantom course of Conservative Dentistry by pre-defined criteria: a comparison between self-assessment by students and assessment by instructors. AB - INTRODUCTION: Assessment of practical skills in undergraduate dental education has difficulties, including a lack of transparency/objectivity in student evaluations. This prospective study investigated whether agreement between student- and faculty-based assessments increased when students were trained to use the assessment criteria. MATERIALS AND METHODS: Assessment criteria were available for 6 tasks in the Phantom course of Conservative Dentistry: Class II cavity preparation, composite restoration, gold and ceramic partial crown preparation, trepanation and access cavity preparation, and root canal filling. Forty-two students were allocated to three different assessment training groups. Students' self-assessments of practical tests were compared with instructors' assessments, depending on training intensity and task type (Pearson's rho, ANOVA, Tukey's post hoc test, Kruskal-Wallis test). Students/instructors were questioned regarding benefits/drawbacks of the criteria. RESULTS: Student self-assessments showed either consent (24.2%), overestimation (31%) or underestimation (44.8%). Gender differences were negligible. Regarding passing/failing grades, more intensive training yielded significantly increased agreement only for preparation of gold partial crowns (rho = +0.313, P = 0.044). Ratings exhibited significant differences amongst tasks (P = 0.002), for example, trepanation assessment had significantly lower differences than gold or ceramic preparation assessments. These discrepancies decreased with increased training. Students consistently reported benefitting most from learning the criteria for gold preparations, followed by composite and ceramic preparations. They also reported that learning the criteria was beneficial for knowledge transfer/feedback. Instructors rated the criteria as helpful for task evaluation and feedback efficiency. CONCLUSIONS: Pre-defined assessment criteria may increase consistency between student self assessment and instructor assessment depending on the task, improving transparency and feedback in dental education. PMID- 26642845 TI - Tumor islands and spread through air spaces: Distinct patterns of invasion in lung adenocarcinoma. AB - Lung adenocarcinoma is a highly heterogeneous disease and the heterogeneity is associated with various patient outcomes even in early-stage tumors. In order to improve prognostic and predictive values, the IASLC/ATS/ERS international multidisciplinary lung adenocarcinoma classification was put forth in 2011 and it has been adopted in the recently published World Health Organization (WHO) classification of Tumours of the Lung, Pleura, Thymus and Heart 4th edition 2015, and lung adenocarcinomas are classified based on the predominant pattern. The performance of the classification in stratifying patient outcomes after resection of Stage I tumors and predicting molecular alterations has been confirmed by several studies. It also includes the category of minimally invasive adenocarcinoma (MIA) that predicts 100% 5-year recurrence free survival after curative resection similar to adenocarcinoma in situ. The diagnosis of MIA is based on not only size of the invasive component but also the absence of aggressive morphologic features such as pleural and/or lymphovascular invasion. Importantly, the WHO 2015 classification has introduced the concept of air space invasion and includes it as the exclusion criteria for MIA. The air space invasion consists of tumor islands and spread through air spaces (STAS). In this review, we will discuss the two entities and their clinical implications. PMID- 26642846 TI - DNA double-strand breaks disrupted the spindle assembly in porcine oocytes. AB - We used etoposide (25-100 ug/mL) to induce DNA double-strand breaks (DSBs) in porcine oocytes at the germinal vesicle (GV) stage to determine how such damage affects oocyte maturation. We observed that DNA damage did not delay the rate of germinal vesicle breakdown (GVBD), but did inhibit the final stages of maturation, as indicated by the failure to extrude the first polar body. Oocytes with low levels of DSBs failed to effectively activate ataxia telangiectasia mutated (ATM) kinase, while those with severe DNA DSBs failed to activate checkpoint kinase 1 (CHK1)--the two regulators of the DNA damage response pathway -indicating that porcine oocytes lack an efficient G2/M phase checkpoint. DSBs induced spindle defects and chromosomal misalignments, leading to the arrest of these oocytes at meiotic metaphase I. The activity of maturation-promoting factor also did not increase appropriately in oocytes with DNA DSBs, although its abundance was sufficient to promote GVBD and chromosomal condensation. Following parthenogenetic activation, embryos from etoposide-treated oocytes formed numerous micronuclei. Thus, our results indicate that DNA DSBs do not efficiently activate the ATM/CHK1-dependent DNA-damage checkpoint in porcine oocytes, allowing these DNA-impaired oocytes to enter M phase. Oocytes with DNA damage did, however, arrest at metaphase I in response to spindle defects and chromosomal misalignments, which limited the ability of these oocytes to reach meiotic metaphase II. PMID- 26642847 TI - Elective colectomy for severe ulcerative colitis may reduce mortality more than medical therapy. PMID- 26642848 TI - The effectiveness of a single dose of oral ibuprofen plus caffeine in acute postoperative pain in adults. PMID- 26642849 TI - An adnexal tumour masquerading as a distal interphalangeal joint ganglion. PMID- 26642850 TI - Motorcyclist's thumb: carpometacarpal injuries of the thumb sustained in motorcycle crashes. AB - The purpose of this study was to investigate motorcycle crash thumb injury patterns. We hypothesized that ulnar collateral ligament injuries at the thumb metacarpophalangeal joint would be most common and there would be a side predilection due to the clutch and brake positions. Motorcyclist admissions following injury between 2002 and 2013 were reviewed, and phalangeal and metacarpal injuries treated acutely identified. Demographics, injury, and treatment characteristics were recorded. Association between laterality and injury type was assessed. Of 128 patients, 59 underwent acute treatment for thumb injuries. Eleven patients sustained thumb ulnar collateral ligament injuries; 27 sustained thumb carpometacarpal injuries. Most carpometacarpal injuries were fracture-dislocations (19/27). Thumb carpometacarpal injuries had no overall side predilection; ulnar collateral ligament injuries occurred more on the right. Carpometacarpal fractures and dislocations are the most frequent motorcycle crash thumb injury, probably due to the mechanics of gripping handlebars and the high energy force directed into the palm and against the metacarpal base. LEVEL OF EVIDENCE: Level IV. PMID- 26642851 TI - Interfering with VE-PTP stabilizes endothelial junctions in vivo via Tie-2 in the absence of VE-cadherin. AB - Vascular endothelial (VE)-protein tyrosine phosphatase (PTP) associates with VE cadherin, thereby supporting its adhesive activity and endothelial junction integrity. VE-PTP also associates with Tie-2, dampening the tyrosine kinase activity of this receptor that can support stabilization of endothelial junctions. Here, we have analyzed how interference with VE-PTP affects the stability of endothelial junctions in vivo. Blocking VE-PTP by antibodies, a specific pharmacological inhibitor (AKB-9778), and gene ablation counteracted vascular leak induction by inflammatory mediators. In addition, leukocyte transmigration through the endothelial barrier was attenuated. Interference with Tie-2 expression in vivo reversed junction-stabilizing effects of AKB-9778 into junction-destabilizing effects. Furthermore, lack of Tie-2 was sufficient to weaken the vessel barrier. Mechanistically, inhibition of VE-PTP stabilized endothelial junctions via Tie-2, which triggered activation of Rap1, which then caused the dissolution of radial stress fibers via Rac1 and suppression of nonmuscle myosin II. Remarkably, VE-cadherin gene ablation did not abolish the junction-stabilizing effect of the VE-PTP inhibitor. Collectively, we conclude that inhibition of VE-PTP stabilizes challenged endothelial junctions in vivo via Tie-2 by a VE-cadherin-independent mechanism. In the absence of Tie-2, however, VE-PTP inhibition destabilizes endothelial barrier integrity in agreement with the VE-cadherin-supportive effect of VE-PTP. PMID- 26642853 TI - Correction: CLEC-2 in megakaryocytes is critical for maintenance of hematopoietic stem cells in the bone marrow. PMID- 26642852 TI - Hif-1alpha and Hif-2alpha synergize to suppress AML development but are dispensable for disease maintenance. AB - Leukemogenesis occurs under hypoxic conditions within the bone marrow (BM). Knockdown of key mediators of cellular responses to hypoxia with shRNA, namely hypoxia-inducible factor-1alpha (HIF-1alpha) or HIF-2alpha, in human acute myeloid leukemia (AML) samples results in their apoptosis and inability to engraft, implicating HIF-1alpha or HIF-2alpha as therapeutic targets. However, genetic deletion of Hif-1alpha has no effect on mouse AML maintenance and may accelerate disease development. Here, we report the impact of conditional genetic deletion of Hif-2alpha or both Hif-1alpha and Hif-2alpha at different stages of leukemogenesis in mice. Deletion of Hif-2alpha accelerates development of leukemic stem cells (LSCs) and shortens AML latency initiated by Mll-AF9 and its downstream effectors Meis1 and Hoxa9. Notably, the accelerated initiation of AML caused by Hif-2alpha deletion is further potentiated by Hif-1alpha codeletion. However, established LSCs lacking Hif-2alpha or both Hif-1alpha and Hif-2alpha propagate AML with the same latency as wild-type LSCs. Furthermore, pharmacological inhibition of the HIF pathway or HIF-2alpha knockout using the lentiviral CRISPR-Cas9 system in human established leukemic cells with MLL-AF9 translocation have no impact on their functions. We therefore conclude that although Hif-1alpha and Hif-2alpha synergize to suppress the development of AML, they are not required for LSC maintenance. PMID- 26642855 TI - Mechanism and Reconstitution In Vitro of Germ Cell Development in Mammals. AB - The germ cell lineage creates new individuals, perpetuating/diversifying the genetic and epigenetic information across generations. Based on the knowledge obtained through investigations into the mechanisms of germ cell specification and development in mice, we have succeeded in precisely reconstituting the specification and subsequent development of germ cells in culture in both males and females: Embryonic stem cells (ESCs)/induced pluripotent stem cells (iPSCs) are induced into epiblast-like cells (EpiLCs) and then into primordial germ cell like cells (PGCLCs), which robustly contribute to spermatogenesis and oogenesis and to fertile offspring. This in vitro mouse PGC specification/development system has led to the elucidation of signaling, transcriptional, and epigenetic regulation during germ cell development in a detailed fashion. More recently, based on this system, we and others have demonstrated the induction of human PGCLCs from human ESCs/iPSCs, creating an opportunity for understanding the mechanism of human germ cell development in vitro. PMID- 26642854 TI - The Evolution of Tumors in Mice and Humans with Germline p53 Mutations. AB - Mice with a homozygous p53 gene deletion develop thymic lymphomas by 9 wk of age. Using the sequence of the rearranged T-cell receptor gene from each clone of cells in the thymus, one can determine the number of independent transformation events. These tumors are oligoclonal, occurring at a frequency of 0.13-0.8 new cancer clones per day. By 20 wk only a few clones are detected, indicating competition among transformed cell clones. DNA sequencing of these tumors demonstrates a point mutation frequency of one per megabase and many genes that are consistently amplified or deleted in independent tumors. The tumors begin with an inherited p53 gene deletion. Next is a PTEN mutation in a stem cell or progenitor cell, before the rearrangement of the T-cell receptor. After that, the T-cell clone selects gene amplifications in cyclin D and cdk-6, and in Ikaros in the Notch pathway. Humans heterozygous for the p53 mutant gene in the germline (Li-Fraumeni syndrome) develop cancers at an early age. The penetrance of heterozygous p53 mutations is ~93% of individuals developing tumors over their lives. At older ages the remaining 7% of this Li-Fraumeni population actually have a lower risk of developing tumors than the population at large with wild type p53 genes. PMID- 26642856 TI - The African Turquoise Killifish: A Model for Exploring Vertebrate Aging and Diseases in the Fast Lane. AB - Why and how organisms age remains a mystery, and it defines one of the biggest challenges in biology. Aging is also the primary risk factor for many human pathologies, such as cancer, diabetes, cardiovascular diseases, and neurodegenerative diseases. Thus, manipulating the aging rate and potentially postponing the onset of these devastating diseases could have a tremendous impact on human health. Recent studies, relying primarily on nonvertebrate short-lived model systems, have shown the importance of both genetic and environmental factors in modulating the aging rate. However, relatively little is known about aging in vertebrates or what processes may be unique and specific to these complex organisms. Here we discuss how advances in genomics and genome editing have significantly expanded our ability to probe the aging process in a vertebrate system. We highlight recent findings from a naturally short-lived vertebrate, the African turquoise killifish, which provides an attractive platform for exploring mechanisms underlying vertebrate aging and age-related diseases. PMID- 26642857 TI - Flavoring Chemicals in E-Cigarettes: Diacetyl, 2,3-Pentanedione, and Acetoin in a Sample of 51 Products, Including Fruit-, Candy-, and Cocktail-Flavored E Cigarettes. AB - BACKGROUND: There are > 7,000 e-cigarette flavors currently marketed. Flavoring chemicals gained notoriety in the early 2000s when inhalation exposure of the flavoring chemical diacetyl was found to be associated with a disease that became known as "popcorn lung." There has been limited research on flavoring chemicals in e-cigarettes. OBJECTIVE: We aimed to determine if the flavoring chemical diacetyl and two other high-priority flavoring chemicals, 2,3-pentanedione and acetoin, are present in a convenience sample of flavored e-cigarettes. METHODS: We selected 51 types of flavored e-cigarettes sold by leading e-cigarette brands and flavors we deemed were appealing to youth. E-cigarette contents were fully discharged and the air stream was captured and analyzed for total mass of diacetyl, 2,3-pentanedione, and acetoin, according to OSHA method 1012. RESULTS: At least one flavoring chemical was detected in 47 of 51 unique flavors tested. Diacetyl was detected above the laboratory limit of detection in 39 of the 51 flavors tested, ranging from below the limit of quantification to 239 MUg/e cigarette. 2,3-Pentanedione and acetoin were detected in 23 and 46 of the 51 flavors tested at concentrations up to 64 and 529 MUg/e-cigarette, respectively. CONCLUSION: Because of the associations between diacetyl and bronchiolitis obliterans and other severe respiratory diseases observed in workers, urgent action is recommended to further evaluate this potentially widespread exposure via flavored e-cigarettes. CITATION: Allen JG, Flanigan SS, LeBlanc M, Vallarino J, MacNaughton P, Stewart JH, Christiani DC. 2016. Flavoring chemicals in e cigarettes: diacetyl, 2,3-pentanedione, and acetoin in a sample of 51 products, including fruit-, candy-, and cocktail-flavored e-cigarettes. Environ Health Perspect 124:733-739; http://dx.doi.org/10.1289/ehp.1510185. PMID- 26642858 TI - Isolation and characterization of the complete mitochondrial genome of Taenioides anguillaris (Gobiidae: Amblyopinae) with phylogenetic consideration. AB - Here we first isolated and characterized the complete mitochondrial genome DNA of Taenioides anguillaris. It was 16 974 bp in length, and contained 13 protein coding genes, 22 tRNA genes, two rRNA genes, and a putative control region. The structure and the gene arrangement of this genome were identical to those isolated from other Gobiidae fishes. Twenty-eight genes were encoded by heavy strand, while nine genes were encoded by light strand. The total nucleotide composition of this genome was 28.7% for A, 15.6% for G, 28.6% for C, and 27.1% for T, with a high A + T content of 55.8%. From the neighbor-joining (NJ) phylogenetic tree, we can find that T. anguillaris was genetically closest to species Odontamblyopus rubicundus among 20 species within suborder Gobioidei. This work should be helpful for the studies on population genetic diversity and molecular evolution in T. anguillaris and related fish species. PMID- 26642859 TI - Intestinal microbiota contributes to individual susceptibility to alcoholic liver disease. AB - OBJECTIVE: There is substantial inter-individual diversity in the susceptibility of alcoholics to liver injury. Alterations of intestinal microbiota (IM) have been reported in alcoholic liver disease (ALD), but the extent to which they are merely a consequence or a cause is unknown. We aimed to demonstrate that a specific dysbiosis contributes to the development of alcoholic hepatitis (AH). DESIGN: We humanised germ-free and conventional mice using human IM transplant from alcoholic patients with or without AH. The consequences on alcohol-fed recipient mice were studied. RESULTS: A specific dysbiosis was associated with ALD severity in patients. Mice harbouring the IM from a patient with severe AH (sAH) developed more severe liver inflammation with an increased number of liver T lymphocyte subsets and Natural Killer T (NKT) lymphocytes, higher liver necrosis, greater intestinal permeability and higher translocation of bacteria than mice harbouring the IM from an alcoholic patient without AH (noAH). Similarly, CD45+ lymphocyte subsets were increased in visceral adipose tissue, and CD4(+)T and NKT lymphocytes in mesenteric lymph nodes. The IM associated with sAH and noAH could be distinguished by differences in bacterial abundance and composition. Key deleterious species were associated with sAH while the Faecalibacterium genus was associated with noAH. Ursodeoxycholic acid was more abundant in faeces from noAH mice. Additionally, in conventional mice humanised with the IM from an sAH patient, a second subsequent transfer of IM from an noAH patient improved alcohol-induced liver lesions. CONCLUSIONS: Individual susceptibility to ALD is substantially driven by IM. It may, therefore, be possible to prevent and manage ALD by IM manipulation. PMID- 26642861 TI - The rs2296651 (S267F) variant on NTCP (SLC10A1) is inversely associated with chronic hepatitis B and progression to cirrhosis and hepatocellular carcinoma in patients with chronic hepatitis B. AB - OBJECTIVE: The sodium taurocholate co-transporting polypeptide (NTCP), encoded by SLC10A1, was recently identified as a receptor for HBV. We assessed the association of the p.Ser267Phe variant (rs2296651) with chronic hepatitis B (CHB) serostatus, cirrhosis and hepatocellular carcinoma (HCC) in patients with CHB. DESIGN: The variant was genotyped in 3801 patients with CHB and 3801 matched hepatitis B surface antigen (HBsAg) seronegative individuals. ORs with 95% CIs for the variant's association with CHB, cirrhosis and HCC were estimated using logistic regression. RESULTS: In patients with CHB, the S267F variant was observed in 515 (18.5%) controls, 40 (17.2%) cirrhosis only cases, 49 (13.2%) non cirrhotic HCC cases, and 52 (12.7%) cirrhotic-HCC cases. After adjustment for known risk factors, S267F was significantly associated with decreased risk for cirrhosis (OR 0.65 (95% CI 0.49 to 0.86), p=0.002) and HCC (OR 0.55 (95% CI 0.42 to 0.72), p<0.001). This association persisted for non-cirrhotic and cirrhotic HCC. Compared with patients with HBV DNA levels greater than 10(5) copies/mL who carried the GG genotype, patients who had undetectable HBV DNA and the GA or AA genotypes had a 25-fold decreased risk of developing HCC (OR 0.04 (95% CI 0.02 to 0.11), p<0.001). The AA genotype was also associated with HBsAg seronegativity (OR 0.13 (95% CI 0.05 to 0.34), p<0.001). CONCLUSIONS: The SLC10A1 (NTCP) S267F variant is independently associated with decreased risk of cirrhosis and HCC, and resistance to CHB infection. Together with serum HBV DNA levels, S267F may help to identify patients with CHB with very low risk of HCC. PMID- 26642862 TI - The Role of Health Anxiety and Depressive Symptoms in Dry Eye Disease. AB - PURPOSE: To investigate the associations between health anxiety, depressive and anxiety symptoms, and the severity of the subjective and objective symptoms of dry eye disease (DED). METHODS: Participants completed the following psychological questionnaires: Shortened Health Anxiety Inventory, Shortened Beck Depression Inventory, and Beck Anxiety Inventory. Dry eye symptoms were evaluated using the ocular surface disease index (OSDI). Bilateral tear osmolarity measurement, tear film break-up time (TBUT), ocular surface staining, Schirmer 1 test, and meibomian gland dysfunction assessment were performed. RESULTS: Based on the OSDI score, 56 of the 84 participants enrolled were symptomatic and 28 asymptomatic. According to the objective parameters, 48/56 (85.7%) in the symptomatic group and 23/28 (82.1%) in the asymptomatic group were diagnosed with DED. In terms of the objective parameters, except for TBUT, there were no statistically significant differences between the symptomatic and asymptomatic group (p > 0.108), or between the subgroups with objectively proven dry eye (p > 0.233). The results of the psychological questionnaires were significantly worse in the symptomatic group (p < 0.01) and the symptomatic subgroup with objective dry eye (p < 0.05), than in the asymptomatic groups. In the overall study population the scores of the psychological questionnaires demonstrated significant positive correlations with the OSDI scores (r > 0.306, p < 0.01). CONCLUSIONS: These results support the role of health anxiety and of depressive and anxiety symptoms in DED, and may serve as an explanation for the lack of correlation between subjective symptoms and objective signs of the disease. PMID- 26642860 TI - Caffeine protects against experimental acute pancreatitis by inhibition of inositol 1,4,5-trisphosphate receptor-mediated Ca2+ release. AB - OBJECTIVE: Caffeine reduces toxic Ca2+ signals in pancreatic acinar cells via inhibition of inositol 1,4,5-trisphosphate receptor (IP3R)-mediated signalling, but effects of other xanthines have not been evaluated, nor effects of xanthines on experimental acute pancreatitis (AP). We have determined effects of caffeine and its xanthine metabolites on pancreatic acinar IP3R-mediated Ca2+ signalling and experimental AP. DESIGN: Isolated pancreatic acinar cells were exposed to secretagogues, uncaged IP3 or toxins that induce AP and effects of xanthines, non xanthine phosphodiesterase (PDE) inhibitors and cyclic adenosine monophosphate and cyclic guanosine monophosphate (cAMP/cGMP) determined. The intracellular cytosolic calcium concentration ([Ca2+]C), mitochondrial depolarisation and necrosis were assessed by confocal microscopy. Effects of xanthines were evaluated in caerulein-induced AP (CER-AP), taurolithocholic acid 3-sulfate induced AP (TLCS-AP) or palmitoleic acid plus ethanol-induced AP (fatty acid ethyl ester AP (FAEE-AP)). Serum xanthines were measured by liquid chromatography mass spectrometry. RESULTS: Caffeine, dimethylxanthines and non-xanthine PDE inhibitors blocked IP3-mediated Ca2+ oscillations, while monomethylxanthines had little effect. Caffeine and dimethylxanthines inhibited uncaged IP3-induced Ca2+ rises, toxin-induced Ca2+ release, mitochondrial depolarisation and necrotic cell death pathway activation; cAMP/cGMP did not inhibit toxin-induced Ca2+ rises. Caffeine significantly ameliorated CER-AP with most effect at 25 mg/kg (seven injections hourly); paraxanthine or theophylline did not. Caffeine at 25 mg/kg significantly ameliorated TLCS-AP and FAEE-AP. Mean total serum levels of dimethylxanthines and trimethylxanthines peaked at >2 mM with 25 mg/kg caffeine but at <100 uM with 25 mg/kg paraxanthine or theophylline. CONCLUSIONS: Caffeine and its dimethylxanthine metabolites reduced pathological IP3R-mediated pancreatic acinar Ca2+ signals but only caffeine ameliorated experimental AP. Caffeine is a suitable starting point for medicinal chemistry. PMID- 26642863 TI - Collaborating with cardiac sonographers to develop work-related musculoskeletal disorder interventions. AB - For more than two decades, surveys of imaging technologists, including cardiac sonographers, diagnostic medical sonographers and vascular technologists, have consistently reported high prevalence of work-related musculoskeletal discomfort (WRMSD). Yet, intervention research involving sonographers is limited. In this study, we used a participatory approach to identifying needs and opportunities for developing interventions to reduce sonographers' exposures to WRMSD risk factors. In this paper, we present some of those needs. We include descriptions of two interventions, targeted for cardiac sonographers, that were developed, through an iterative process, into functional prototypes that were evaluated in pilot tests by practicing sonographers. One of these interventions is now in daily use. We would like other engineers and ergonomists to recognise this area of opportunity to apply their knowledge of biomechanics and design in order to begin to address the high prevalence of WRMSDs in sonographers, by working with sonographers to develop useful and usable interventions. Practitioner Summary: This paper discusses needs, opportunities and methods for working with sonographers in order to develop interventions to reduce their exposure to risk factors for work-related musculoskeletal discomfort. Results from field tests of two novel interventions targeting cardiac sonographers are also presented. PMID- 26642864 TI - Epidemiological aspects of lice (Menacanthus species) infections in laying hen flocks from the State of Minas Gerais, Brazil. AB - The epidemiology of chicken lice species such as Menacanthus stramineus, M. cornutus and M. pallidulus were studied during an observational, analytical and sectional survey, to determine predisposing factors for their occurrence in laying hen farms in the State of Minas Gerais, Brazil. A total of 431 houses on 43 farms were visited in 2012. M. cornutus, M. stramineus and M. pallidulus occurred in 20.9%, 11.6% and 11.6% of farms, respectively. The frequencies of occurrence of M. cornutus, M. stramineus and M.pallidulus in poultry houses were 10.4%, 8.8% and 3.7%, respectively. The epidemiological determinants for the occurrence of these species were investigated using Poisson or logistic regression models. The region of the farm, the recent use of acaricides and the presence of birds, such as saffron finch (Sicalis flaveola), feral pigeon (Columba livia) and Guira cuckoo (Guira guira) around the farms were related to the epidemiology of M. cornutus. Infestation by M. stramineus was associated with age of birds, number of birds per cage and the presence of Guira cuckoo and Chopi blackbird (Gnorimopsar chopi) near the poultry houses. The occurrence of M. pallidulus was influenced by the type of facilities, presence of cattle egret (Bubulcus ibis) and free-range domestic hens around the farm. The use of wire mesh nets in the houses and of forced moulting did not influence lice infestation. PMID- 26642865 TI - Parents' Experiences of Health and Needs When Supporting Their Adolescents With Cerebral Palsy During Transition to Adulthood. AB - AIMS: Parents are the primary support providers for adolescents with disabilities, their health and wellbeing is therefore of great importance when planning for youths' transition into adulthood. The aim of this study was to gain a deeper understanding of how parents of adolescents with cerebral palsy (CP) experience their own health and wellbeing and their needs for support during the adolescent's transition to adulthood. METHODS: An inductive qualitative approach was used, including interviews with 15 mothers and fathers to 10 adolescents with CP aged 17-18 years. Latent content analysis was used for analyzing the data. RESULTS: The main theme "Friction blisters chafing and healing during transition" illustrates the parents' experiences. Five sub-themes formed the parents' experiences of concerns along with sorrow and stress in life, worries about what was to come, their need for support, strategies for coping, and experiences of cohesion. CONCLUSIONS: Knowledge of parents' experiences of their health, wellbeing, and needs provide valuable information for the planning of transition for adolescents with disabilities. Help with parents' sorrow, stress, and worry in daily life might be facilitated and parental health safeguarded by a navigator who can both guide and give hands-on support. PMID- 26642866 TI - Prevalence and risk factors for reduced sound tolerance (hyperacusis) in children. AB - OBJECTIVE: To estimate the prevalence of reduced sound tolerance (hyperacusis) in a UK population of 11-year-old children and examine the association of early life and auditory risk factors with report of hyperacusis. DESIGN: A prospective UK population-based study. STUDY SAMPLE: A total of 7097 eleven-year-old children within the Avon longitudinal study of parents and children (ALSPAC) were asked about sound tolerance; hearing and middle-ear function was measured using audiometry, otoacoustic emissions, and tympanometry. Information on neonatal risk factors and socioeconomic factors were obtained through parental questionnaires. RESULTS: 3.7% (95% CI 3.25, 4.14) children reported hyperacusis. Hyperacusis report was less likely in females (adj OR 0.64, 95% CI 0.49, 0.85), and was more likely with higher maternal education level (adj OR 1.72, 95% CI 1.08, 2.72) and with readmission to hospital in first four weeks (adj OR 1.98, 95% CI 1.20, 3.25). Report of hyperacusis was associated with larger amplitude otoacoustic emissions but with no other auditory factors. CONCLUSIONS: The prevalence of hyperacusis in the population of 11-year-old UK children is estimated to be 3.7%. It is more common in boys. PMID- 26642867 TI - Challenges in vaccinating infants born to mothers taking immunoglobulin biologicals during pregnancy. AB - While immunoglobulin biologicals are increasingly used during pregnancy, there have been concerns on the immune function and vaccination of infants born to mothers taking immunoglobulin biologicals. In addition to the detection of biologicals in cord blood, cases of severe neonatal neutropenia and fatal dissemination of Bacillus Calmette-Guerin (BCG) have been reported. With increasing number of infants exposed to immunoglobulin biologicals in utero, there is a need to address the challenges in vaccinating these infants. This review summarizes the available evidence to discuss the issues of immunoglobulin biological exposure in utero, neonatal immune function, long-term immune development, and the challenges and strategies of vaccinating newborns and infants who were born to mothers taking biologicals during pregnancy. PMID- 26642868 TI - Retrieval-practice task affects relationship between working memory capacity and retrieval-induced forgetting. AB - Retrieving a subset of items from memory can cause forgetting of other items in memory, a phenomenon referred to as retrieval-induced forgetting (RIF). Individuals who exhibit greater amounts of RIF have been shown to also exhibit superior working memory capacity (WMC) and faster stop-signal reaction times (SSRTs), results which have been interpreted as suggesting that RIF reflects an inhibitory process that is mediated by the processes of executive control. Across four experiments, we sought to further elucidate this issue by manipulating the way in which participants retrieved items during retrieval practice and examining how the resulting effects of forgetting correlated with WMC (Experiments 1-3) and SSRT (Experiment 4). Significant correlations were observed when participants retrieved items from an earlier study phase (within-list retrieval practice), but not when participants generated items from semantic memory (extra-list retrieval practice). These results provide important new insight into the role of executive control processes in RIF. PMID- 26642869 TI - Flagging Drugs That Inhibit the Bile Salt Export Pump. AB - The bile salt export pump (BSEP) is an ABC-transporter expressed at the canalicular membrane of hepatocytes. Its physiological role is to expel bile salts into the canaliculi from where they drain into the bile duct. Inhibition of this transporter may lead to intrahepatic cholestasis. Predictive computational models of BSEP inhibition may allow for fast identification of potentially harmful compounds in large databases. This article presents a predictive in silico model based on physicochemical descriptors that is able to flag compounds as potential BSEP inhibitors. This model was built using a training set of 670 compounds with available BSEP inhibition potencies. It successfully predicted BSEP inhibition for two independent test sets and was in a further step used for a virtual screening experiment. After in vitro testing of selected candidates, a marketed drug, bromocriptin, was identified for the first time as BSEP inhibitor. This demonstrates the usefulness of the model to identify new BSEP inhibitors and therefore potential cholestasis perpetrators. PMID- 26642871 TI - Thematic Issue: Pharmacologic Strategies with Afterload Reduction in Low Cardiac Output Syndrome After Pediatric Cardiac Surgery. PMID- 26642870 TI - High-Intensity Drug Use and Health Service Access Among Street-Involved Youth in a Canadian Setting. AB - BACKGROUND/OBJECTIVES: Addiction severity has been associated with numerous social- and health-related harms. This study sought to examine the prevalence and correlates of high-intensity drug use among street-involved youth in a Canadian setting with a focus on high-risk drug use practices and health service access. METHODS: Data were derived from the At-Risk Youth Study, a Vancouver-based prospective cohort of street-involved youth aged 14-26. We used generalized estimating equations to examine variables associated with high-intensity drug use, defined as daily use of crack cocaine, cocaine, heroin, or crystal methamphetamine. RESULTS: From September 2005 to November 2012, of 1017 youth included in the analyses, 529 (52%) reported high-intensity drug use as defined above at least once during the study period. In a multivariate analysis, older age (Adjusted Odds Ratio [AOR] = 1.47); residing in the Downtown Eastside of Vancouver (AOR = 1.46); homelessness (AOR = 1.30); recent incarceration (AOR = 1.25); inability to access addiction treatment (AOR = 1.42); and crack pipe sharing and/or used syringe injecting (AOR = 2.64), were all positively and independently associated with high-intensity drug use (p < 0.05). The most common barrier to accessing addiction treatment reported by these youth was long waiting lists. CONCLUSIONS: High-intensity drug use among street-involved youth was prevalent and associated with structural and geographical disadvantages in addition to high-risk drug administration practices. Youth reporting more frequent drug use also reported barriers to accessing addiction treatment, highlighting the need to expand addiction services tailored to youth at greatest risk of harm from illicit drug use and street-involvement. PMID- 26642872 TI - Bivalirudin and the Matrix Trial: The End of the Story? PMID- 26642873 TI - Liraglutide and Cardiometabolic Effects: More than Just Another Antiobesity Drug? PMID- 26642874 TI - Effect of alginate microencapsulation on the catalytic efficiency and in vitro enzyme-prodrug therapeutic efficacy of cytosine deaminase and of recombinant E. coli expressing cytosine deaminase. AB - Cytosine deaminase (CD) catalyses the enzymatic conversion of the non-toxic prodrug 5-fluorocytosine (5-FC) to the potent chemotherapeutic form, 5 fluorouracil (5-FU). Intratumoral delivery of CD localises chemotherapy dose while reducing systemic toxicity. Encapsulation in biocompatible microcapsules immunoisolates CD and protects it from degradation. We report on the effect of alginate encapsulation on the catalytic and functional activity of isolated CD and recombinant E. coli engineered to express CD (E. coli(CD)). Alginate microcapsules containing either CD or Escherichia coli(CD) were prepared using ionotropic gelation. Conversion of 5-FC to 5-FU was quantitated in unencapsulated and encapsulated CD/E. coli(CD) using spectrophotometry, with a slower rate of conversion observed following encapsulation. Both encapsulated CD/5-FC and E. coli(CD)/5-FC resulted in cell kill and reduced proliferation of 9 L rat glioma cells, which was comparable to direct 5-FU treatment. Our results show that encapsulation preserves the therapeutic potential of CD and E. coli(CD) is equally effective for enzyme-prodrug therapy. PMID- 26642875 TI - Influences of Mental Illness Stigma on Perceptions of and Responses to Requests for Favors. AB - This article examines mental illness stigma effects on a request for a favor from a mentally ill individual. Four hundred and fourteen participants interacted with a hypothetical target on Facebook who was believed to have schizophrenia, depression, or a tooth cavity (i.e., the control group). Participants were asked to rate the favor request in terms of face threat, in addition to writing a response, which was then coded using message design logics. Results indicated that a request by a schizophrenic target threatened participants' positive face more significantly than that of a target with depression or without any mental illness. Participants' responses to the schizophrenic target were more likely to be conventional messages, whereas responses to the depressed target were more likely to be rhetorical messages. Theoretical and practical contributions are considered. PMID- 26642876 TI - Learning From Philadelphia: Topographies of HIV/AIDS Media Assemblages. AB - For this contribution to the special issue on "Mapping Queer Bioethics," the author employs an array of public health and popular media texts (especially Jonathan Demme's film Philadelphia) to challenge the construction and reconstruction of HIV-positive bodies as sites of bioethical concern. In outlining notions of "digital restoration," the author argues that there has been of late a remapping of the first decade of the HIV/AIDS pandemic through media projects assembled from archived materials. Accordingly, the author suggests that in the first decades of the 2000s, we have witnessed a media-archaeological turn, whereby old materials have been reassembled for commemorative purposes that oftentimes perform a reshaping of the topography of the first decade of the AIDS pandemic. PMID- 26642877 TI - Consecutive magnetic resonance imaging during brachytherapy for cervical carcinoma: predictive value of volume measurements with respect to persistent disease and prognosis. AB - BACKGROUND: Cervical cancer is associated with a high yearly mortality. The presence of persistent disease after radiotherapy is a significant predictor of patient survival. The aim of our study was to assess if tumor volume regression measured with MR imaging at the time of brachytherapy can discriminate between patients who eventually will achieve a complete response to radiotherapy from those who will not. The second objective was to evaluate whether tumor volume regression predicts overall treatment failure. METHODS: MRI was evaluated quantitatively in 35 patients; by means of tumor volumetry on T2-weighted MR images before treatment, at the first BCT application, and at the final BCT. The MR images were independently analyzed by two investigators. As a reference standard histopathologic confirmation of residual tumor and/or clinical exam during follow-up > 1 year were used. Area under the curve were compared, P-values <0.05 were considered significant. RESULTS: There was a good correlation between volume measurements made by the two observers. A residual tumor volume >9.4 cm(3) at final BCT and tumor volume regression < 77 % of the pre-treatment volume were significantly associated with local residual tumor after completion of therapy (p < 0.02) (AUC, 0.98-1.00). A volume >2.8 cm(3) at final BCT was associated with overall treatment failure (p < 0.03). CONCLUSION: Our study shows that volume analysis during BCT is a predictive tool for local tumor response and overall treatment outcome. The potential of local response assessment to identify patients at high risk of overall treatment failure is promising. PMID- 26642878 TI - A viability-linked metagenomic analysis of cleanroom environments: eukarya, prokaryotes, and viruses. AB - BACKGROUND: Recent studies posit a reciprocal dependency between the microbiomes associated with humans and indoor environments. However, none of these metagenome surveys has considered the viability of constituent microorganisms when inferring impact on human health. RESULTS: Reported here are the results of a viability linked metagenomics assay, which (1) unveil a remarkably complex community profile for bacteria, fungi, and viruses and (2) bolster the detection of underrepresented taxa by eliminating biases resulting from extraneous DNA. This approach enabled, for the first time ever, the elucidation of viral genomes from a cleanroom environment. Upon comparing the viable biomes and distribution of phylotypes within a cleanroom and adjoining (uncontrolled) gowning enclosure, the rigorous cleaning and stringent control countermeasures of the former were observed to select for a greater presence of anaerobes and spore-forming microflora. Sequence abundance and correlation analyses suggest that the viable indoor microbiome is influenced by both the human microbiome and the surrounding ecosystem(s). CONCLUSIONS: The findings of this investigation constitute the literature's first ever account of the indoor metagenome derived from DNA originating solely from the potential viable microbial population. Results presented in this study should prove valuable to the conceptualization and experimental design of future studies on indoor microbiomes aimed at inferring impact on human health. PMID- 26642879 TI - Risk of exacerbation in chronic obstructive pulmonary disease: a primary care retrospective cohort study. AB - BACKGROUND: The risk of exacerbation in chronic obstructive pulmonary disease (COPD) depends on the severity of disease and other less well known factors. Predictive models of exacerbation are more accurate than the forced expiratory volume in one second (FEV1). The objective was to design a model that predicts the risk of exacerbation in COPD. METHODS: Retrospective cohort study with data from the electronic medical records of patients diagnosed with COPD in the province of Lleida (Spain). A total of 2501 patients were followed during 3 years. The dependent variable was acute exacerbation; independent variables were: clinical parameters, spirometry results, severity of disease, influenza and 23 valent pneumococcal immunisation, comorbidities, smoking and history of exacerbation. The association of these variables with disease exacerbation was measured by the adjusted odds ratio using a logistic regression model. RESULTS: Mean age at the start of the study was 68.38 years (SD = 11.60) and 74.97% patients were men; severity of disease was considered mild in 50.82% of patients, moderate in 35.31%, severe in 9.44% and very severe in 4.44%. During the three year study period up to 83.17% of patients experienced at least one exacerbation. Predictive factors in the model were age, gender, previous exacerbations, influenza and 23-valent pneumococcal immunisations, number of previous visits to the General Practice and severity (GOLD), with an area under the ROC curve (AUROC) of 0.70. CONCLUSIONS: This model can identify patients at high risk of acute exacerbation. Preventive measures and modification of treatment in these high-risk patients would improve survival. PMID- 26642880 TI - Erratum: Universal conventional and real-time PCR diagnosis tools for Sarcoptes scabiei. PMID- 26642881 TI - Haemophilus influenzae induces steroid-resistant inflammatory responses in COPD. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is an inflammatory disorder partially resistant to glucocorticoids. A reduced histone deacetylase (HDAC) activity has been proposed to explain this resistance. Haemophilus influenzae frequently colonizes the airways of COPD patients, where it enhances inflammation. The effects of Haemophilus influenzae on HDAC activity have not been investigated before. METHODS: The effects of the presence or absence of Haemophilus influenzae ex-vivo and in vitro were studied. To this end, we determined: (1) cytokine release in alveolar macrophages (AM) from 7 patients with COPD, 5 healthy smokers, 6 healthy non-smokers and (2) HDAC activity, nuclear factor kappa B (NF-kappaB) activation in a macrophage-like cell line (PMA transformed U937 cells) co-cultured with epithelial cells. Experiments were repeated with dexamethasone (1 MUM) and/or the HDAC enhancer theophylline (10 MUM). RESULTS: Haemophilus influenzae induced a steroid-resistant inflammatory response in AM from COPD and controls and decreased HDAC activity, activated NF kappaB and induced the secretion of several cytokines (IL-6, IL-8, IL-1beta, IL 10 and TNF-alpha) (p < 0.001 for all comparisons) in the macrophage-like cell line. Dexamethasone reduced NF-kappaB activation but it did not modify HDAC activity. The addition of theophylline to dexamethasone increased HDAC activity and suppressed cytokine release completely, without modifying NF-kappaB activation. CONCLUSIONS: These results indicate that Haemophilus influenzae reduces HDAC activity and induces a NF-kappaB mediated inflammatory response that is only partially suppressed by glucocorticoids irrespective of having COPD. Yet, the latter can be fully restored by targeting HDAC activity. PMID- 26642883 TI - Large-Scale, Highly Efficient, and Green Liquid-Exfoliation of Black Phosphorus in Ionic Liquids. AB - We developed a facile, large-scale, and environmentally friendly liquid exfoliation method to produce stable and high-concentration dispersions of mono- to few-layer black phosphorus (BP) nanosheets from bulk BP using nine ionic liquids. The prepared suspensions can stabilize without any obvious sedimentation and aggregation in ambient air for one month. In particular, the concentration (up to 0.95 mg mL(-1)) of BP nanoflakes obtained in 1-hydroxyethyl-3 methylimidazolium trifluoromethansulfonate ([HOEMIM][TfO]) is the highest reported for BP nanosheets dispersions. This work provides new opportunities for preparing atomically thin BP nanosheets in green, large-scale, and highly concentrated processes and achieving its in situ application. PMID- 26642882 TI - Cellular automaton-based model for radiation-induced bystander effects. AB - BACKGROUND: The radiation-induced bystander effect is a biological response observed in non-irradiated cells surrounding an irradiated cell. The bystander effect is known to be induced by two intercellular signaling pathways, the medium mediated pathway (MDP) and the gap junctional pathway (GJP). To investigate the relative contribution of each signaling pathway, we have developed a mathematical model of the cellular response through these two pathways, with a particular focus on cell-cycle modification. METHODS: The model is based on a cellular automaton and consists of four components: (1) irradiation, (2) generation and diffusion of intercellular signals, (3) induction of DNA double-strand breaks (DSBs), and (4) cell-cycle modification or cell death. The intercellular signals are generated in and released from irradiated cells. The signals through the MDP and the GJP are modeled independently based on diffusion equations. The irradiation and both signals raise the number of DSBs, which determines transitions of cellular states, such as cell-cycle arrest or cell death. RESULTS: Our model reproduced fairly well previously reported experimental data on the number of DSBs and cell survival curves. We examined how radiation dose and intercellular signaling dynamically affect the cell cycle. The analysis of model dynamics for the bystander cells revealed that the number of arrested cells did not increase linearly with dose. Arrested cells were more efficiently accumulated by the GJP than by the MDP. CONCLUSIONS: We present here a mathematical model that integrates various bystander responses, such as MDP and GJP signaling, DSB induction, cell-cycle arrest, and cell death. Because it simulates spatial and temporal conditions of irradiation and cellular characteristics, our model will be a powerful tool to predict dynamical radiobiological responses of a cellular population in which irradiated and non-irradiated cells co-exist. PMID- 26642884 TI - Glass polymorphism in amorphous germanium probed by first-principles computer simulations. AB - The low-density (LDA) to high-density (HDA) transformation in amorphous Ge at high pressure is studied by first-principles molecular dynamics simulations in the framework of density functional theory. Previous experiments are accurately reproduced, including the presence of a well-defined LDA-HDA transition above 8 GPa. The LDA-HDA density increase is found to be about 14%. Pair and bond-angle distributions are obtained in the 0-16 GPa pressure range and allowed us a detailed analysis of the transition. The local fourfold coordination is transformed in an average HDA sixfold coordination associated with different local geometries as confirmed by coordination number analysis and shape of the bond-angle distributions. PMID- 26642885 TI - Dengue haemorrhagic fever with Roth's spot. PMID- 26642886 TI - The complete mitochondrial genome sequence of the wild Huoba Tibetan sheep of the Qinghai-Tibetan Plateau in China. AB - The wild Huoba Tibetan sheep belongs to the subfamily Caprinae, which distributes in Huoba Town of Tibet Autonomous Region, China. In the present work, we report the complete mitochondrial genome sequence of wild Huoba Tibetan sheep for the first time. The total length of the mitogenome is 16 621 bp, consisting of 13 protein-coding genes, 22 transfer RNA (tRNA) genes, two ribosomal RNA (rRNA) genes, and a non-coding control region (D-loop region). As in other mammals, most mitochondrial genes are encoded on the heavy strand. Its overall base composition is A: 33.64%, T: 27.32%, C: 25.90%, and G: 13.14%, A + T (61.96%) was higher than G + C (39.04%). The phylogenetic relationships was analyzed using the complete mitogenome sequence, results show that wild Huoba Tibetan sheep should be a different species differ from the Ovis aries. These information provide an important data for further study on protection of genetic resources and the taxonomy of Caprinae. PMID- 26642887 TI - Prevalence of hypoglycemia among diabetic old age home residents in South India. AB - AIM: To assess the prevalence of diabetes among inmates at old age care homes in south India and scrutinize their therapy, glycemic levels and burden of hypoglycemic episodes. MATERIALS AND METHODS: The medication record based observational study was conducted in 9 old-age care facilities across south India from February to September 2015. The cognitive and functional status were analysed and the prevalence of hypoglycemia estimated. Descriptive analysis was performed using SPSS 18.0 for windows. RESULTS: The prevalence, predisposing variables and therapeutic modalities used in 189 inmates of 9 old-age homes in Kerala. The mean age of the sample was estimated to be 71.3+/-3.4 years. 67.2% of the total inmates were found to be diabetic and met the inclusion criteria. Of the total patients, 72.44% had co-existence of both cognitive and functional impairment.86% patients developed hypoglycemia at least at some point during the therapy and insulin was found to be the drug used in majority of patients with the condition indicating that aggressive therapies can increase fatality due to hypoglycemia. CONCLUSIONS: Most guidelines call for an individualized therapeutic approach suing less aggressive strategies for patients vulnerable to hypoglycemia and geriatric population form such a substantial group. The current study highlights the necessity for special attention when considering therapeutic regimen among such patients. PMID- 26642888 TI - Assessment of clinical pharmacist interventions in drug therapy in patients with diabetes mellitus in a tertiary care teaching hospital. AB - AIM: To assess the impact of clinical pharmacist interventions in drug therapy in hospitalized patients with diabetes mellitus. METHODS: A Prospective interventional study was carried out in the medicine wards of a tertiary care teaching hospital over a period of 10 months from September 2013 to June 2014. The drug therapy details of the patients were collected from inpatient case records in the respective clinical wards. Clinical pharmacist reviewed the drug therapy, identified the drug related problems during ward rounds and discussed with the physicians and suitable suggestions was provided which had been documented. RESULTS: A total of 189 drug therapy problems were identified from 151 patient case records. The number of drug related problems was found to more in males than females. Drug related problems were commonly seen in patients aged between 61 and 70 years of age. The most common drug related problems was found to be drug use without indication (17.98%) followed by improper drug selection (16.40%). The most frequent suggestions by the clinical pharmacist were on cessation of drug (30.68%). The acceptance rate of suggestions and the changes in drug therapy was found to be high (58.20%). The majority of the level of significance of drug related problems was seen to have moderate significance in grade. CONCLUSION: Involvement of clinical pharmacist as a member of healthcare team during ward rounds in hospitalized patients with diabetes mellitus helps in identification and prevention of drug related problems which will helps to rationalize drug therapy, achieve better therapeutic outcomes and improved patient care. PMID- 26642889 TI - Molecular Insights into the Enigmatic Metabolic Regulator, SnRK1. AB - Sucrose non-fermenting-1 (SNF1)-related kinase 1 (SnRK1) lies at the heart of metabolic homeostasis in plants and is crucial for normal development and response to stress. Evolutionarily related to SNF1 in yeast and AMP-activated kinase (AMPK) in mammals, SnRK1 acts protectively to maintain homeostasis in the face of fluctuations in energy status. Despite a conserved function, the structure and regulation of the plant kinase differ considerably from its relatively well-understood opisthokont orthologues. In this review, we highlight the known plant-specific modes of regulation involving SnRK1 together with new insights based on a 3D molecular model of the kinase. We also summarise how these differences from other orthologues may be specific adaptations to plant metabolism, and offer insights into possible avenues of future inquiry into this enigmatic enzyme. PMID- 26642890 TI - Age-Related Changes in Murine Corneal Nerves. AB - PURPOSE: The aim of this study is to determine age-related morphological changes in the corneal subbasal nerve plexus (SNP) in two inbred mouse strains. MATERIALS AND METHODS: The corneal SNP was investigated by in vivo confocal laser scanning microscopy (CLSM) in 0.5-, 1-, 1.5-, and 2-year-old C57BL/6J mice and in 0.5- and 1-year-old BALB/c mice (n = 4 per age category and strain; 10 images per mouse). Fixed corneal samples from C57BL/6J mice were also analyzed after PGP9.5 staining. Nerve fiber density (NFD) was determined using the semi-automated NeuronJ program. In addition, a new custom-designed, fully automated computerized technique based on oriented multiscale matched filtering was tested to objectify and accelerate image analysis. RESULTS: C57BL/6J mice showed low NFD (11.7 +/- 0.5 mm/mm2). Aging from 0.5 to 1, 1.5, and 2 years resulted in significant reductions in subbasal NFD by 34%, 49%, and 66%, respectively. The decline in nerve fibers revealed by in vivo CLSM together with NeuronJ quantification was confirmed by ex vivo immunohistochemical analyses. Subbasal NFD in BALB/c mice (30.0 +/- 1.4 mm/mm2) was 3-fold higher than in C57BL/6J mice. Aging from 0.5 to 1 year resulted in a significant 17% reduction in NFD. With the automated approach, NFD of 22.6 +/- 2.9 mm/mm2 and a 45% reduction during aging was determined from the same images. CONCLUSIONS: An age-related reduction in subbasal corneal nerve fibers was observed. The differing extent of reduction in the two mouse strains may be accounted for by genetic factors. Automated NFD quantification of corneal nerve fibers in mice appears to be a useful, reliable, objective, and time-saving tool. PMID- 26642891 TI - Establishing the Cultural Equivalence of the Young Children's Participation and Environment Measure (YC-PEM) for Use in Singapore. AB - AIMS: Establishing the cultural equivalence of clinical assessments is critical to ensuring culturally competent care. Developed in North America, the Young Children's Participation and Environment Measure (YC-PEM) is a caregiver questionnaire of participation in home, preschool, and community activities and perceptions of environmental impact on participation. The purpose of this study is to establish the cultural equivalence of YC-PEM content for use in Singapore. METHODS: We conducted semi-structured interviews with ten early childhood and healthcare providers and cognitive interviews with ten parents in Singapore to examine the relevance of original YC-PEM content (activities, environmental factors, item wording). Interviews were transcribed, summarized, and categorized according to item, semantic, conceptual, and operational dimensions of the Applied Cultural Framework that served as a decision-making guide to keep, modify, or delete the items. RESULTS: Providers and parents agreed on conceptual, item and semantic changes but less on operational changes. Significant changes were made to improve comprehension of the YC-PEM. CONCLUSIONS: Despite using the same language, the majority of the YC-PEM items needed modification to be relevant to the Singapore culture. Cultural adaptation of the YC-PEM is important because there are cultural differences in children's participation and their environments, as well as the way people understand words. PMID- 26642893 TI - Cardiovascular risk factors and hearing loss: The HUNT study. AB - OBJECTIVE: The purpose of the present paper was to examine the association between prospectively and cross-sectionally assessed cardiovascular risk factors and hearing loss. DESIGN: Hearing was assessed by pure-tone average thresholds at low (0.25-0.5 kHz), middle (1-2 kHz), and high (3-8 kHz) frequencies. Self reported or measured cardiovascular risk factors were assessed both 11 years before and simultaneously with the audiometric assessment. Cardiovascular risk factors were smoking, alcohol use, physical inactivity, waist circumference, body mass index, resting heart rate, blood pressure, triglycerides, total serum cholesterol, LDL cholesterol, HDL cholesterol, and diabetes. STUDY SAMPLE: A population-based cohort of 31 547 subjects. RESULTS: After adjustment for age, sex, level of education, income, recurrent ear infections, and noise exposure, risk factors associated with poorer hearing sensitivity were smoking, diabetes, physical inactivity, resting heart rate, and waist circumference. Smoking was only associated with hearing loss at high frequencies. The effects were very small, in combination explaining only 0.2-0.4% of the variance in addition to the component explained by age and the other cofactors. CONCLUSION: This cohort study indicates that, although many cardiovascular risk factors are associated with hearing loss, the effects are small and of doubtful clinical relevance. PMID- 26642892 TI - Prevalence of various etiologies of hearing loss among cochlear implant recipients: Systematic review and meta-analysis. AB - OBJECTIVE: To investigate the etiology of deafness in cochlear implanted children and to address the question whether there is a need for more thorough diagnostics, especially concerning genetics. DESIGN: Systematic review. Four databases were searched for studies (year 2000-2014) on cochlear implanted children (n > 100). Studies were excluded if etiology had influenced their inclusion criteria. Eligibility and methodological quality were assessed independently by three authors. The studies' description of diagnostic evaluation was categorized in three groups. STUDY SAMPLE: Sixteen studies were included (5069 children). RESULTS: The most common etiological categories were 'Unknown' 40.3% (95% CI 32.8 to 48.0), 'Non-syndromic' 22.4% (95% CI 17.1 to 28.2), and 'Postnatal' 11.3% (95% CI 7.2 to 16.2). Studies published after 2006 had a lower proportion of 'Unknown' etiology 35.3% (95% CI 28.0 to 42.8) than older 45.5% (95% CI 31.0 to 60.4). Important information was missing from several studies: 11 (69%) studies did not provide detailed description on diagnostic evaluation of the etiology of deafness and had a higher proportion of 'Unknown' etiology. CONCLUSIONS: In order to ensure a higher level of comparability in future studies, we recommend agreement upon an international standard of diagnostics and the introduction of an international standard for reporting etiology. PMID- 26642894 TI - Dichotic listening training in children with autism spectrum disorder: A single subject design. AB - OBJECTIVE: Previous research has shown that dichotic listening training has improved auditory and language processing for individuals with large interaural asymmetries on dichotic listening tasks. This training can be a useful treatment for children with autism spectrum disorder (ASD). DESIGN: A single subject, multiple baseline across subjects study was utilized. STUDY SAMPLE: Three children with ASD, between the ages of 8-12, participated in the study. RESULTS: This training demonstrated improvement in language and auditory processing tasks following completion of up to twelve weeks of auditory training. CONCLUSION: This study supports the idea that deficit specific, dichotic auditory training can remediate auditory and language deficits for children with ASD. More research is needed, with a group design and controls, in order to generalize these results to the larger ASD population. PMID- 26642896 TI - Red meat consumption and healthy ageing: A review. AB - According to World Health Organization older individuals is the fastest growing age-group around the globe, thanks to the tremendous improvements in medical and pharmaceutical therapies, as well as in quality of life. Unfortunately, this raise in life span is accompanied by significant increase in disease burden, and consequent economical costs. Lifestyle modifications and effective prevention strategies have shown considerable benefits as regards the development of age oriented chronic diseases. Among lifestyle factors, nutrition is a key component for achieving good health. Nevertheless, this parameter has insufficiently been investigated in older people. This is a rather important scientific gap, considering the westernization of nutritional habits observed the last few decades, with high red meat consumption and its processed products being an indispensable part. Moreover, its adverse impact in cardiovascular disease and cancer has been extensively investigated, while in recent literature, interest has been remarkably oriented towards its subtypes (i.e., fresh and processed); however, outcomes as regards the older population are controversial with a variety of them proposing moderation of red meat mainly the processed type, whilst others recognizing fresh red meat, especially the lean type, an important source of high quality protein so as to manage muscle tissue loss, a common implication of advanced-age discount. The aim of the present review was to present an overview of studies which have investigated the association between red meat and its subtypes, with chronic diseases, in middle and advanced age individuals. PMID- 26642897 TI - Two lung development-related microRNAs, miR-134 and miR-187, are differentially expressed in lung tumors. AB - INTRODUCTION: MicroRNAs (miRNAs) are involved in various cellular events needed for embryonic development and tumorigenesis. As some of the development-specific gene expression patterns could be observed in cancers, we speculated that the expression pattern of lung development-specific miRNAs miR-134 and miR-187 might be altered in lung tumor samples. Lung cancer is the first cause of cancer related deaths worldwide, mostly due to its late diagnosis. Therefore, finding a reliable diagnostic tumor marker, based on molecular profile of tumorigenesis, would be critical in lowering lung cancer mortality. METHODS: We employed a real time RT-PCR approach to evaluate the expression alteration of two lung development-related miRNAs in lung tumor tissues. The suitability of miRs expression alterations as lung tumor biomarkers was tested by receiver operating characteristic (ROC) curve analysis. The effect of miR-187 overexpression on a lung carcinoma cell cycle was assessed using flow cytometry analysis. RESULTS: Our data revealed a significant upregulation (7.8 times, p<0.02) of miR-134 in lung tumors. However, its expression level failed to discriminate different tumor types and grades of malignancies from each other. Moreover, the ROC curves analysis did not give it a good score as a reliable biomarker (AUC=0.522, P=0.729). In contrast, miR-187 showed a significant down-regulation (P=0.008) in lung tumors. Similarly, its expression level failed to differentiate different tumor types or grades of malignancies. Nevertheless, ROC curve analysis gave it an AUC score of 0.669 (P=0.012), which suggests its suitability as a potential biomarker for lung cancer. Furthermore, ectopic expression of miR-187 in A549 cells caused a cell cycle arrest in G1 phase (P=0.013). CONCLUSION: Altogether, our data demonstrated an altered expression of two development-related miRNAs namely miR-134 and miR-187 in lung tumors for the first time. Moreover we have shown that miR-134 and miR-187 expression alternation were in accordance with their approved regulatory roles, therefore these miRNAs could serve as new biomarkers with potential usefulness in lung cancer diagnosis and treatments. In addition, miR-187 expression in tumor cells could perturb cell cycle which supported its possible role as tumor suppressor. PMID- 26642898 TI - BmRobo1a and BmRobo1b control axon repulsion in the silkworm Bombyx mori. AB - The development of the nervous system is based on the growth and connection of axons, and axon guidance molecules are the dominant regulators during this course. Robo, as the receptor of axon guidance molecule Slit, plays a key role as a conserved repellent cue for axon guidance during the development of the central nervous system. However, the function of Robo in the silkworm Bombyx mori is unknown. In this study, we cloned two novel robo genes in B. mori (Bmrobo1a and Bmrobo1b). BmRobo1a and BmRobo1b lack an Ig and a FNIII domain in the extracellular region and the CC0 and CC2 motifs in the intracellular region. BmRobo1a and BmRobo1b were colocalized with BmSlit in the neuropil. Knock-down of Bmrobo1a and Bmrobo1b by RNA interference (RNAi) resulted in abnormal development of axons. Our results suggest that BmRobo1a and BmRobo1b have repulsive function in axon guidance, even though their structures are different from Robo1 of other species. PMID- 26642899 TI - Cochlear implantees: Analysis of behavioral and objective measures for a clinical population of various age groups. AB - INTRODUCTION: As of 2014 more than 1200 patients have received a cochlear implant (CI) at Oslo University Hospital (OUS) and approximately half of them have been children. The data obtained from these patients have been used to develop a comprehensive database for a systematic analysis of several objective measurements and programming measurements. During the past 10 years, we have used an objective measurements protocol for our CI surgeries. Our intra-operative protocol includes: Evoked Compound Action Potentials (ECAP), visually observed Electrically evoked Stapedius Reflex Threshold (ESRT), and electrode impedances. Post-operative (Post-OP) programming sessions typically begin 4-6 weeks after surgery and continue on a scheduled basis. The initial programming data include threshold levels (T-levels) and comfortable levels (C-levels) for the different patient age groups. In this study, we compared initial stimulation levels and stimulation levels after at least 1 year of CI with objective measurements obtained intra-operatively. METHOD: This study focused on the development of a comprehensive database of detailed intra-operative objective measures and post-OP programming measurements from a group of 296 CI patients who received the same type of CI and electrode configuration (Cochlear Corporation CI with Contour electrode). This group included 92 bilateral CI patients. Measurements from 388 CI devices were studied. Patients were divided into 5 different age groups at the age of implantation: 0-2, 2-5, 5-10, 10-20, and above 20 years in order to investigate age-related differences in programming levels and objective measurements. For the comparison analysis we used T- and C-levels obtained after the last day of initial programming and also after at least 1 year implant use. These programming levels were then correlated with some of the intra-operative objective measurements. RESULTS: T-levels were found to be the lowest for the youngest patient group and increased with age. C-levels varied within age groups and frequency range. Patients above 20 years of age had the highest comfort levels in the low to mid-frequencies (electrodes 22-8) and the lowest comfort levels in the high-frequency range (electrodes 1-7). Correlation coefficients between intra-operative objective measurements and programming levels were found to be in the range of no correlation to moderate correlation. Adult patients had the most significant correlation coefficients between ECAP thresholds and T levels in the low frequencies. The younger patients aged 10-20 years and 5-10 years had more significant correlations in the higher frequency channels compared to the other age groups. Intra-operative visually observed ESRTs and electrode impedances were not significantly correlated with initial or stable programming levels for the children or adults. CONCLUSION: Analyzing initial and follow-up mapping levels from previous patients is very important for a CI Center in terms of quality control. The mean T/C-levels reported in this study can provide guidance to our programming audiologists and help them determine the initial programming levels to be stored in the speech processor, especially for very young patients. Unfortunately intra-operative objective measures in our study, such as ECAP, ESRT, and electrode impedances did not provide statistically significant correlations that may help to predict the programming T- and C-levels for all patients. However, we have observed cases where the intra-operative objective measures of ESRT and TECAP profiles were very similar to an individual's MAP profile. It was not possible, however, to determine why some patients did not have an objective measures profile that was similar to their programming levels profile. PMID- 26642900 TI - Clues to long noncoding RNA taxonomy. PMID- 26642901 TI - Towards Multidisciplinary HIV-Cure Research: Integrating Social Science with Biomedical Research. AB - The quest for a cure for HIV remains a timely and key challenge for the HIV research community. Despite significant scientific advances, current HIV therapy regimens do not completely eliminate the negative impact of HIV on the immune system; and the economic impact of treating all people infected with HIV globally, for the duration of their lifetimes, presents significant challenges. This article discusses, from a multidisciplinary approach, critical social, behavioral, ethical, and economic issues permeating the HIV-cure research agenda. As part of a search for an HIV cure, both the perspective of patients/participants and clinical researchers should be taken into account. In addition, continued efforts should be made to involve and educate the broader community. PMID- 26642902 TI - [Teaching practices of thoracic epidural catheterizations in different grade of anesthesia residents]. AB - BACKGROUND AND OBJECTIVES: In this study, we aimed to clarify the importance of residency grade and other factors which influence the success of thoracic epidural catheterization in thoracotomy patients. METHODS: After the ethical committee approval, data were recorded retrospectively from the charts of 415 patients. All patients had given written informed consent. The thoracic epidural catheterization attempts were divided into two groups as second-third year (Group I) and fourth year (Group II) according to residency grade. We retrospectively collected demographic data, characteristics of thoracic epidural catheterization attempts, and all difficulties and complications during thoracic epidural catheterization. RESULTS: Overall success rate of thoracic epidural catheterization was similar between the groups. Levels of catheter placement, number and duration of thoracic epidural catheterization attempts were not different between the groups (p>0.05). Change of needle insertion level was statistically higher in Group II (p=0.008), whereas paresthesia was significantly higher in Group I (p=0.007). Dural puncture and postdural puncture headache rates were higher in Group I. Higher body mass index and level of the insertion site were significant factors for thoracic epidural catheterization failure and postoperative complication rate and those were independence from residents' experience (p<0.001, 0.005). CONCLUSION: Body mass index and level of insertion site were significant on thoracic epidural catheterization failure and postoperative complication rate. We think that residents' grade is not a significant factor in terms overall success rate of thoracic epidural catheterization, but it is important for outcome of these procedures. PMID- 26642903 TI - [Comparative effects of vitamin C on the effects of local anesthetics ropivacaine, bupivacaine, and lidocaine on human chondrocytes]. AB - BACKGROUND: Intra-articular injections of local anesthetics are commonly used to enhance post-operative analgesia following orthopedic surgery as arthroscopic surgeries. Nevertheless, recent reports of severe complications due to the use of intra-articular local anesthetic have raised concerns. OBJECTIVES: The study aims to assess use of vitamin C in reducing adverse effects of the most commonly employed anesthetics - ropivacaine, bupivacaine and lidocaine - on human chondrocytes. METHODS: The chondrocyte viability following exposure to 0.5% bupivacaine or 0.75% ropivacaine or 1.0% lidocaine and/or vitamin C at doses 125, 250 and 500MUM was determined by Live/Dead assay and annexin V staining. Expression levels of caspases 3 and 9 were assessed using antibodies by Western blotting. Flow cytometry was performed to analyze the generation of reactive oxygen species. RESULTS: On exposure to the local anesthetics, chondrotoxicity was found in the order ropivacaine=90 cm had 95% (hazard ratio [HR], 1.95; 95% confidence interval [CI], 1.34-2.83) and 163% (HR, 2.63; 95% CI, 1.58 4.40) higher mortality risk than men who were fit, respectively (P <.05). Men who were unfit and overweight had 41% (HR, 1.41; 95% CI, 1.04-1.90) higher mortality risk with a waist circumference <100 cm (P <.05), but were at no greater risk (HR, 1.30; 95% CI, 0.92-1.84) if their waist circumference was >=100 cm (P = .14). Men who were unfit and obese were not at increased mortality risk (HR, 1.37; 95% CI, 0.90-2.09) with a waist circumference <110 cm (P = .14), but were at 111% (HR, 2.11; 95% CI, 1.31-3.42) increased risk with a waist circumference >=110 cm (P <.05). CONCLUSIONS: For most of the body mass index and waist circumference categories, inclusion of cardiorespiratory fitness allowed for improved identification of men at increased mortality risk. PMID- 26642908 TI - Can We Get There From Here? PMID- 26642907 TI - Warfarin Dosing Algorithms and the Need for Human Intervention. AB - BACKGROUND: Dosing algorithms for warfarin incorporate clinical and genetic factors, but human intervention to overrule algorithm-based dosing may occasionally be required. The frequency and reasons for varying from algorithmic warfarin management have not been well studied. METHODS: We analyzed a prospective cohort of 1015 participants from the Clarification of Optimal Anticoagulation through Genetics trial who were randomized to either pharmacogenetic- or clinically-guided warfarin dosing algorithms. Clinicians and participants were blinded to dose but not international normalized ratio (INR) during the first 28 days. If an issue arose that raised concern for clinicians but might not be adequately accounted for by the protocol, then clinicians contacted the unblinded medical monitor who could approve exceptions if clinically justified. All granted exceptions were logged and categorized. We analyzed the relationships between dosing exceptions and both baseline characteristics and the outcome of percentage of time in the therapeutic INR range during the first 4 weeks. RESULTS: Sixteen percent of participants required at least one exception to the protocol-defined warfarin dose (15% in the genotype arm and 17% in the clinical arm). Ninety percent of dose exceptions occurred after the first 5 days of dosing. The only baseline characteristic associated with dose exceptions was congestive heart failure (odds ratio 2.12, 95% confidence interval, 1.49-3.02, P <.001). Neither study arm nor genotype was associated with dose exceptions. CONCLUSION: Despite rigorous algorithms, human intervention is frequently employed in the early management of warfarin dosing. Congestive heart failure at baseline appears to predict early exceptions to standardized protocol management. PMID- 26642909 TI - Epidemiological Trends in Search and Rescue Incidents Documented by the Alpine Club of Canada From 1970 to 2005. AB - OBJECTIVE: To provide a descriptive review of the epidemiology of search and rescue (SAR) incidents across Canada as documented in the Alpine Club of Canada (ACC) database. METHODS: A retrospective, cross-sectional review of SAR reports collected by the ACC with incidents dating from January 1, 1970 to June 12, 2005, was analyzed. RESULTS: The ACC database contained 1088 incidents with 1377 casualties. Casualties had 944 (68.6%; 95% CI, 64.2 to 73.1) injuries or illness, and 433 (31.4%; 95% CI, 28.6 34.6) fatalities. Males accounted for 76.1% of all casualties and 82.3% of the fatalities when sex was reported. A bimodal distribution of casualties was seen, with the peaks around February and August. Hiking and mountaineering resulted in more than half of all casualties that yielded any type of morbidity, whereas mountaineering and skiing, ski mountaineering, or snowboarding accounted for almost two thirds of all fatalities. Human error and slips and falls were the major contributors to the presumptive cause of incidents. The lower limb was the most common anatomic location of traumatic injury, accounting for 41.6% (95% CI, 37.6 to 45.9) of these injuries. Hypothermia, exhaustion, frostbite, and dehydration represented the majority of all nontraumatic conditions. British Columbia and Alberta accounted for 91.6% (95% CI, 86.0 to 97.5) of the incidents in the database. CONCLUSIONS: The study serves to illustrate trends in SAR epidemiology that may be encountered by SAR personnel within British Columbia and Alberta. Furthermore, it highlights the need for additional Canadian-based studies to better understand this area of prehospital medical encounters. PMID- 26642912 TI - WITHDRAWN: Novel opportunities for computational biology and sociology in drug discovery. AB - The Publisher regrets that this article is an accidental duplication of an article that has already been published, DOI of original article: http://dx.doi.org/10.1016/j.tibtech.2010.01.004. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 26642913 TI - Take-the-best and the influence of decision-inconsistent attributes on decision confidence and choices in memory-based decisions. AB - Take-the-best (TTB) is a decision strategy according to which attributes about choice options are sequentially processed in descending order of validity, and attribute processing is stopped once an attribute discriminates between options. Consequently, TTB-decisions rely on only one, the best discriminating, attribute, and lower-valid attributes need not be processed because they are TTB-irrelevant. Recent research suggests, however, that when attribute information is visually present during decision-making, TTB-irrelevant attributes are processed and integrated into decisions nonetheless. To examine whether TTB-irrelevant attributes are retrieved and integrated when decisions are made memory-based, we tested whether the consistency of a TTB-irrelevant attribute affects TTB-users' decision behaviour in a memory-based decision task. Participants first learned attribute configurations of several options. Afterwards, they made several decisions between two of the options, and we manipulated conflict between the second-best attribute and the TTB-decision. We assessed participants' decision confidence and the proportion of TTB-inconsistent choices. According to TTB, TTB irrelevant attributes should not affect confidence and choices, because these attributes should not be retrieved. Results showed, however, that TTB-users were less confident and made more TTB-inconsistent choices when TTB-irrelevant information was in conflict with the TTB-decision than when it was not, suggesting that TTB-users retrieved and integrated TTB-irrelevant information. PMID- 26642914 TI - Crystal Structure of the Glycophorin A Transmembrane Dimer in Lipidic Cubic Phase. AB - The mechanisms of assembly and function for many important type I/II (single pass) transmembrane (TM) receptors are proposed to involve the formation and/or alteration of specific interfaces among their membrane-embedded alpha-helical TM domains. The application of lipidic cubic phase (LCP) bilayer media for crystallization of single-alpha-helical TM complexes has the potential to provide valuable structural and mechanistic insights into many such systems. However, the fidelity of the interfaces observed in crowded crystalline arrays has been difficult to establish from the very limited number of such structures determined using X-ray diffraction data. Here we examine this issue using the glycophorin A (GpA) model system, whose homodimeric TM helix interface has been characterized by solution and solid-state NMR and biochemical techniques but never crystallographically. We report that a GpA-TM peptide readily crystallized in a monoolein cubic phase bilayer, yielding a dimeric alpha-helical structure that is in excellent agreement with previously reported NMR measurements made in several different types of host media. These results provide compelling support for the wider application of LCP techniques to enable X-ray crystallographic analysis of single-pass TM interactions. PMID- 26642910 TI - Decreased anxiety in juvenile rats following exposure to low levels of chlorpyrifos during development. AB - Exposure to chlorpyrifos (CPF) during the late preweanling period in rats inhibits the endocannabinoid metabolizing enzymes fatty acid hydrolase (FAAH) and monoacylglycerol lipase (MAGL), resulting in accumulation of their respective substrates anandamide (AEA) and 2-arachidonylglycerol (2-AG). This occurs at 1.0mg/kg, but at a lower dosage (0.5mg/kg) only FAAH and AEA are affected with no measurable inhibition of either cholinesterase (ChE) or MAGL. The endocannabinoid system plays a vital role in nervous system development and may be an important developmental target for CPF. The endocannabinoid system plays an important role in the regulation of anxiety and, at higher dosages, developmental exposure to CPF alters anxiety-like behavior. However, it is not clear whether exposure to low dosages of CPF that do not inhibit ChE will cause any persistent effects on anxiety-like behavior. To determine if this occurs, 10-day old rat pups were exposed daily for 7 days to either corn oil or 0.5, 0.75, or 1.0mg/kg CPF by oral gavage. At 12h following the last CPF administration, 1.0mg/kg resulted in significant inhibition of FAAH, MAGL, and ChE, whereas 0.5 and 0.75mg/kg resulted in significant inhibition of only FAAH. AEA levels were significantly elevated in all three treatment groups as were palmitoylethanolamide and oleoylethanolamide, which are also substrates for FAAH. 2-AG levels were significantly elevated by 0.75 and 1.0mg/kg but not 0.5mg/kg. On day 25, the latency to emerge from a dark container into a highly illuminated novel open field was measured as an indicator of anxiety. All three CPF treatment groups spent significantly less time in the dark container prior to emerging as compared to the control group, suggesting a decreased level of anxiety. This demonstrates that repeated preweanling exposure to dosages of CPF that do not inhibit brain ChE can induce a decline in the level of anxiety that is detectable during the early postweanling period. PMID- 26642915 TI - Acute effects of muscle stretching on physical performance, range of motion, and injury incidence in healthy active individuals: a systematic review. AB - Recently, there has been a shift from static stretching (SS) or proprioceptive neuromuscular facilitation (PNF) stretching within a warm-up to a greater emphasis on dynamic stretching (DS). The objective of this review was to compare the effects of SS, DS, and PNF on performance, range of motion (ROM), and injury prevention. The data indicated that SS- (-3.7%), DS- (+1.3%), and PNF- (-4.4%) induced performance changes were small to moderate with testing performed immediately after stretching, possibly because of reduced muscle activation after SS and PNF. A dose-response relationship illustrated greater performance deficits with >=60 s (-4.6%) than with <60 s (-1.1%) SS per muscle group. Conversely, SS demonstrated a moderate (2.2%) performance benefit at longer muscle lengths. Testing was performed on average 3-5 min after stretching, and most studies did not include poststretching dynamic activities; when these activities were included, no clear performance effect was observed. DS produced small-to-moderate performance improvements when completed within minutes of physical activity. SS and PNF stretching had no clear effect on all-cause or overuse injuries; no data are available for DS. All forms of training induced ROM improvements, typically lasting <30 min. Changes may result from acute reductions in muscle and tendon stiffness or from neural adaptations causing an improved stretch tolerance. Considering the small-to-moderate changes immediately after stretching and the study limitations, stretching within a warm-up that includes additional poststretching dynamic activity is recommended for reducing muscle injuries and increasing joint ROM with inconsequential effects on subsequent athletic performance. PMID- 26642916 TI - Teaching diversity to medical undergraduates: Curriculum development, delivery and assessment. AMEE GUIDE No. 103. AB - The aim of this Guide is to support teacher with the responsibility of designing, delivering and/or assessing diversity education. Although, the focus is on medical education, the guidance is relevant to all healthcare professionals. The Guide begins by providing an overview of the definitions used and the principles that underpin the teaching of diversity as advocated by Diversity and Medicine in Health (DIMAH). Following an outline of these principles we highlight the difference between equality and diversity education. The Guide then covers diversity education throughout the educational process from the philosophical stance of educators and how this influences the approaches used through to curriculum development, delivery and assessment. Appendices contain practical examples from across the UK, covering lesson plans and specific exercises to deliver teaching. Although, diversity education remains variable and fragmented there is now some momentum to ensure that the principles of good educational practice are applied to diversity education. The nature of this topic means that there are a range of different professions and medical disciplines involved which leads to a great necessity for greater collaboration and sharing of effective practice. PMID- 26642917 TI - A Psychophysiological Study of Processing HIV/AIDS Public Service Announcements: The Effects of Novelty Appeals, Sexual Appeals, Narrative Versus Statistical Evidence, and Viewer's Sex. AB - This study used self-reports and physiological measures-heart rate (HR) and skin conductance level (SCL)-to examine the effects of novelty appeals, sexual appeals, narrative versus statistical evidence, and viewer's sex on cognitive and emotional processing of HIV/AIDS public service announcements (PSAs) among heterosexually active single college students. Novelty or sexual appeals differently affected self-reported attention and cognitive effort as measured by HR. High- rather than low-novelty HIV/AIDS PSAs, perceived as more attention eliciting, did not lead to more cognitive effort. High- rather than low-sex HIV/AIDS PSAs, not perceived as more attention-eliciting, led to more cognitive effort as reflected by greater HR deceleration. Novelty or sexual appeals also affected self-reported emotional arousal and SCL differently. HIV/AIDS PSAs with high rather than low levels of novelty or sexual appeals led to greater self reported arousal, but not greater SCL. Message evidence interacted with message appeals to affect cognitive effort. Participants exerted greater cognitive effort during high- rather than low-novelty narrative HIV/AIDS PSAs, and during low- rather than high-novelty statistical ones. The advantage of high over low sexual appeals was more obvious in statistical than in narrative HIV/AIDS PSAs. Males reported greater emotional arousal than females during high- rather than low-sex HIV/AIDS PSAs. PMID- 26642919 TI - A dendritic organization of lateral amygdala neurons in fear susceptible and resistant mice. AB - Subtle differences in neuronal microanatomy may be coded in individuals with genetic susceptibility for neuropsychiatric disorders. Genetic susceptibility is a significant risk factor in the development of anxiety disorders, including post traumatic stress disorder (PTSD). Pavlovian fear conditioning has been proposed to model key aspects of PTSD. According to this theory, PTSD begins with the formation of a traumatic memory which connects relevant environmental stimuli to significant threats to life. The lateral amygdala (LA) is considered to be a key network hub for the establishment of Pavlovian fear conditioning. Substantial research has also linked the LA to PTSD. Here we used a genetic mouse model of fear susceptibility (F-S) and resistance (F-R) to investigate the dendritic and spine structure of principal neurons located in the LA. F-S and F-R lines were bi directionally selected based on divergent levels of contextual and cued conditioned freezing in response to fear-evoking footshocks. We examined LA principal neuron dendritic and spine morphology in the offspring of experimentally naive F-S and F-R mice. We found differences in the spatial distribution of dendritic branch points across the length of the dendrite tree, with a significant increase in branch points at more distal locations in the F-S compared with F-R line. These results suggest a genetic predisposition toward differences in fear memory strength associated with a dendritic branch point organization of principal neurons in the LA. These micro-anatomical differences in neuron structure in a genetic mouse model of fear susceptibility and resistance provide important insights into the cellular mechanisms of pathophysiology underlying genetic predispositions to anxiety and PTSD. PMID- 26642920 TI - Angiotensin-(1-7)/Mas axis modulates fear memory and extinction in mice. AB - Inappropriate defense-alerting reaction to fear is a common feature of neuropsychiatric diseases. Therefore, impairments in brain circuits, as well as in molecular pathways underlying the neurovegetative adjustments to fear may play an essential role on developing neuropsychiatric disorders. Here we tested the hypothesis that interfering with angiotensin-(1-7) [Ang-(1-7)]/Mas receptor axis homeostasis, which appears to be essential to arterial pressure control, would affect fear memory and extinction. Mas knockout (MasKO) mice, in FVB/N background, showed normal cued fear memory and extinction, but increased freezing in response to context. Next, as FVB/N has poor performance in contextual fear memory, we tested MasKO in mixed 129xC57BL/6 background. MasKO mice behaved similarly to wild-type (WT), but memory extinction was slower in contextual fear conditioning to a weak protocol (1CS/US). In addition, delayed extinction in MasKO mice was even more pronounced after a stronger protocol (3CS/US). We showed previously that Angiotensin II receptor AT1 antagonist, losantan, rescued object recognition memory deficit in MasKO mice. Here, losartan was also effective. Memory extinction was accelerated in MasKO mice after treatment with losartan. In conclusion, we showed for the first time that Ang-(1-7)/Mas axis may modulate fear memory extinction. Furthermore, we suggest MasKO mice as an animal model to study post-traumatic stress disorder (PTSD). PMID- 26642918 TI - Prefrontal-hippocampal pathways underlying inhibitory control over memory. AB - A key function of the prefrontal cortex is to support inhibitory control over behavior. It is widely believed that this function extends to stopping cognitive processes as well. Consistent with this, mounting evidence establishes the role of the right lateral prefrontal cortex in a clear case of cognitive control: retrieval suppression. Retrieval suppression refers to the ability to intentionally stop the retrieval process that arises when a reminder to a memory appears. Functional imaging data indicate that retrieval suppression involves top down modulation of hippocampal activity by the dorsolateral prefrontal cortex, but the anatomical pathways supporting this inhibitory modulation remain unclear. Here we bridge this gap by integrating key findings about retrieval suppression observed through functional imaging with a detailed consideration of relevant anatomical pathways observed in non-human primates. Focusing selectively on the potential role of the anterior cingulate cortex, we develop two hypotheses about the pathways mediating interactions between lateral prefrontal cortex and the medial temporal lobes during suppression, and their cellular targets: the entorhinal gating hypothesis, and thalamo-hippocampal modulation via the nucleus reuniens. We hypothesize that whereas entorhinal gating is well situated to stop retrieval proactively, thalamo-hippocampal modulation may interrupt an ongoing act of retrieval reactively. Isolating the pathways that underlie retrieval suppression holds the potential to advance our understanding of a range of psychiatric disorders characterized by persistent intrusive thoughts. More broadly, an anatomical account of retrieval suppression would provide a key model system for understanding inhibitory control over cognition. PMID- 26642921 TI - MicroRNAs: Regulators of TLR2-Mediated Probiotic Immune Responses. AB - MicroRNAs (miRNAs) are similar in importance to transcription factors and critical to confer accuracy and robustness in gene expression programs and consequently, have emerged as controllers of the immune response. On the other hand, probiotic influence over immune responses against a wide spectrum of health conditions are widely studied but the mechanism for this modulation has not yet completely elucidated. One proposed mechanism involves the receptor-mediated interaction of dendritic cells with components of the cellular membrane and/or secreted peptides of probiotics ending with the production of cytokines. However, the cytokine response elicited by dendritic cells is largely strain-dependent, and not to the same extent. The signaling pathway involved must be tightly regulated in order to be precise and effective; proteins as TNF receptor associated factor 6 (TRAF6), Interleukin-1 receptor-associated kinase 4 (IRAK4) and Interleukin-1 receptor-associated kinase 3 (IRAK3 or IRAKM) participate in an important way in the nuclear factor kappa B (NF-kappaB) signaling pathway, which is the main cascade activated in response to probiotics. These proteins can be regulated by miRNAs and alter the immune outcome. This review discusses the current understanding on the participation of miRNAs modulating the TLR2/NF kappaB pathway in the innate immune response mediated by probiotics. PMID- 26642922 TI - "Requestioning" AIDS: An Ethical Reflection From 1993 to Today. Reflections on Claude Vandevyer's "Homosexuals and AIDS: A New Approach to the Illness" from Journal of Homosexuality 25(3). AB - This article serves as one of the supplementary pieces of this special issue on "Mapping Queer Bioethics," in which we take a solipsistic turn to "map" the Journal of Homosexuality itself. Here, the author examines the first feature length article to address the relationship between HIV status and homosexuality. Lingering on both the temporal gap between the dawn of AIDS in American discourse and its inclusion in this journal, the author asks us to consider (in hindsight) such a delay bearing in mind queer theoretical projects of the present such as gay shame, stigma, and queer biopolitics. PMID- 26642923 TI - Moisture parameters and fungal communities associated with gypsum drywall in buildings. AB - Uncontrolled excess moisture in buildings is a common problem that can lead to changes in fungal communities. In buildings, moisture parameters can be classified by location and include assessments of moisture in the air, at a surface, or within a material. These parameters are not equivalent in dynamic indoor environments, which makes moisture-induced fungal growth in buildings a complex occurrence. In order to determine the circumstances that lead to such growth, it is essential to have a thorough understanding of in situ moisture measurement, the influence of building factors on moisture parameters, and the levels of these moisture parameters that lead to indoor fungal growth. Currently, there are disagreements in the literature on this topic. A literature review was conducted specifically on moisture-induced fungal growth on gypsum drywall. This review revealed that there is no consistent measurement approach used to characterize moisture in laboratory and field studies, with relative humidity measurements being most common. Additionally, many studies identify a critical moisture value, below which fungal growth will not occur. The values defined by relative humidity encompassed the largest range, while those defined by moisture content exhibited the highest variation. Critical values defined by equilibrium relative humidity were most consistent, and this is likely due to equilibrium relative humidity being the most relevant moisture parameter to microbial growth, since it is a reasonable measure of moisture available at surfaces, where fungi often proliferate. Several sources concur that surface moisture, particularly liquid water, is the prominent factor influencing microbial changes and that moisture in the air and within a material are of lesser importance. However, even if surface moisture is assessed, a single critical moisture level to prevent fungal growth cannot be defined, due to a number of factors, including variations in fungal genera and/or species, temperature, and nutrient availability. Despite these complexities, meaningful measurements can still be made to inform fungal growth by making localised, long-term, and continuous measurements of surface moisture. Such an approach will capture variations in a material's surface moisture, which could provide insight on a number of conditions that could lead to fungal proliferation. PMID- 26642924 TI - Aortic root remodeling and external aortic annuloplasty to treat sinus of Valsalva aneurysm in a patient with complete situs inversus. AB - BACKGROUND: Sinus of Valsalva aneurysm is an uncommon anomaly of the aorta. It occurs most frequently in the right sinus of Valsalva. Complications depend on its size and location. Situs inversus totalis is a rare condition wherein organs are reversed from their normal positions (mirror image). CASE PRESENTATION: We report the case of a 69-year-old man who presented situs inversus totalis known since his childhood and a sinus of Valsalva aneurysm in the right coronary sinus discovered by echocardiography following a history of infection. This was confirmed by CT-scan and MRI. Valve sparing surgery was performed using the remodeling technique associated with external aortic annuloplasty CONCLUSIONS: The remodeling technique with exteranl aortic annuloplasty is usual technique to treat SVA. PMID- 26642926 TI - Comparison between Na-Ion and Li-Ion Cells: Understanding the Critical Role of the Cathodes Stability and the Anodes Pretreatment on the Cells Behavior. AB - The electrochemical behavior of Na-ion and Li-ion full cells was investigated, using hard carbon as the anode material, and NaNi0.5Mn0.5O2 and LiNi0.5Mn0.5O2 as the cathodes. A detailed description of the structure, phase transition, electrochemical behavior and kinetics of the NaNi0.5Mn0.5O2 cathodes is presented, including interesting comparison with their lithium analogue. The critical effect of the hard carbon anodes pretreatment in the total capacity and stability of full cells is clearly demonstrated. Using impedance spectroscopy in three electrodes cells, we show that the full cell impedance is dominated by the contribution of the cathode side. We discuss possible reasons for capacity fading of these systems, its connection to the cathode structure and relevant surface phenomena. PMID- 26642925 TI - Complete re-sequencing of a 2Mb topological domain encompassing the FTO/IRXB genes identifies a novel obesity-associated region upstream of IRX5. AB - BACKGROUND: Association studies have identified a number of loci that contribute to an increased body mass index (BMI), the strongest of which is in the first intron of the FTO gene on human chromosome 16q12.2. However, this region is both non-coding and under strong linkage disequilibrium, making it recalcitrant to functional interpretation. Furthermore, the FTO gene is located within a complex cis-regulatory landscape defined by a topologically associated domain that includes the IRXB gene cluster, a trio of developmental regulators. Consequently, at least three genes in this interval have been implicated in the aetiology of obesity. METHODS: Here, we sequence a 2 Mb region encompassing the FTO, RPGRIP1L and IRXB cluster genes in 284 individuals from a well-characterised study group of Danish men containing extremely overweight young adults and controls. We further replicate our findings both in an expanded male cohort and an independent female study group. Finally, we compare our variant data with a previous study describing IRX3 and FTO interactions in this region. RESULTS: We obtain deep coverage across the entire region, allowing accurate and unequivocal determination of almost every single nucleotide polymorphism and short insertion/deletion. As well as confirming previous findings across the interval, we identify a further novel age-dependent association upstream of IRX5 that imposes a similar burden on BMI to the FTO locus. CONCLUSIONS: Our findings are consistent with the hypothesis that chromatin architectures play a role in regulating gene expression levels across topological domains while our targeted sequence approach represents a widely applicable methodology for high-resolution analysis of regional variation across candidate genomic loci. PMID- 26642927 TI - A case of rosacea fulminans staining negative for LL-37. PMID- 26642928 TI - Influence of defects and domain walls on dielectric and mechanical resonances in LiNbO3. AB - Monodomain and periodically poled LiNbO3 crystals (congruent composition) show dielectric and piezoelectric resonances between 100 K and 900 K. Dielectric measurements show resonances in some samples between 10-100 kHz. These resonances vanish under thermal anneal in monodomain crystals while they remain stable in periodically poled samples with high domain wall densities. The low activation energy of 0.18 eV suggests their electronic (bi-polaronic) origin. Resonant piezoelectric spectroscopy, RPS, shows two features in virgin samples: a relaxation peak at 420 K and a rapid hardening when the sample was slowly heated to ~500 K. The dynamic relaxation and the hardening are related to excitations and reorientations of Li defects. The relaxations and hardening are irreversibly suppressed by high temperature anneal. We do not observe domain wall related RPS resonances in annealed samples, which excludes the existence of highly charged walls. We suggest that domain walls stabilize polaronic states with (bi-)polarons located inside or near to the ferroelectric domain walls. PMID- 26642929 TI - Erratum to: Macroscopic and microscopic assessments of the glenohumeral and subacromial synovitis in rotator cuff disease. PMID- 26642930 TI - Dimeric dipeptide mimetics of the nerve growth factor Loop 4 and Loop 1 activate TRKA with different patterns of intracellular signal transduction. AB - BACKGROUND: This study aimed at developing nerve growth factor (NGF) mimetics that selectively activate specific biological signals and, as a result, lack the side effects of the full-length protein. Two dimeric dipeptides, bis-(N aminocaproyl-glycyl-L-lysine) hexamethylenediamide (GK-6) and bis(N-succinyl-L glutamyl-L-lysine) hexamethylenediamide (GK-2), were designed based on the most exposed outside fragments of NGF, namely, the loop 1 and loop 4 beta-turn sequences, respectively. These dipeptides exhibited neuroprotective activity in vitro at micro-nanomolar concentrations. RESULTS: Studies on the mechanism of action revealed that both compounds elevate the level of tyrosine kinase A (TrkA) receptor phosphorylation and that they each have different postreceptor signaling patterns. GK-6 increases the levels of extracellular signal-regulated kinase (ERK) and AKT kinase phosphorylation, whereas GK-2 only increases the level of AKT phosphorylation. Apart from the neuroprotective activity, GK-6 promoted differentiation in PC12 cells, whereas GK-2 did not. Furthermore, it was established that the neuroprotective activity of GK-2 was completely abolished by a selective inhibitor of phosphatidylinositol 3-kinase (LY294002) but not by a specific inhibitor of mitogen-activated protein kinases MEK1 and MEK2 (PD98059). In vivo experiments demonstrated that GK-2 did not induce hyperalgesia, which is one of the primary adverse effects of NGF. By contrast, GK-6 produced a significant decrease in the pain threshold of rats as determined by the tail flick test. CONCLUSION: The data obtained suggest that dimeric dipeptide NGF mimetics are promising candidates in the development of pharmacological agents with NGF-like activity that are free of the main side effect of NGF. PMID- 26642931 TI - A snapshot of the nutritional status of Crohn's disease among adolescents in Brazil: a prospective cross-sectional study. AB - BACKGROUND: The relationship between nutrition and Crohn's disease (CD) is complex and involves several therapeutic possibilities including: nutrition treatment for malnourished patients, optimization of growth and development, prevention of osteoporosis, first-line therapy for active disease, and maintenance of disease remission. In children and adolescents with CD, malnutrition is a common problem that adversely affects the prognosis. In at-risk adolescent CD patients, it is important to assess body composition, food intake, energy expenditure, nutrient balance and serum levels of nutrients before planning interventions for this population. The aim of this study was to provide a snapshot of the nutritional status of adolescents with CD in Brazil. METHODS: We prospectively selected 22 patients with mildly to moderately active CD, 29 patients with inactive CD and 35 controls (first-degree relatives of and in the same age bracket as the CD patients). The age range of participants was between 13.2 and 19.4 years old. We collected anthropometric data including weight, height, and body mass index (BMI), which were expressed as Z scores: weight-for age, height-for-age and BMI-for-age, respectively, as well as using bioimpedance to determine body composition and assessing the Tanner stage. We also assessed macronutrients and micronutrients (serum levels and dietary intake of both). We used the chi-square test to determine whether any of the studied variables were associated with inactive or active CD. The level of significance was set at 5 % (p < 0.05). We have written informed parental consent for participation for any minors and written informed consent for any participants that were adults. RESULTS: The mean values for lean body mass, Tanner stage, height-for-age Z score and BMI-for-age Z score were lower in the active CD group than in the inactive CD and control groups (p < 0.05 for both). Compared with the controls, the CD patients showed significant differences in terms of the quality of dietary intake (particularly in caloric intake, dietary protein intake, dietary fiber intake, and micronutrient intake), which were reflected in the serum levels of nutrients, mainly vitamins A and E (p < 0.05). CONCLUSIONS: Adolescents with CD (including those with mildly to moderately active or inactive disease) have a nutritional risk, which makes it important to conduct nutritional assessments in such patients. PMID- 26642932 TI - Bio-inspired heterogeneous composites for broadband vibration mitigation. AB - Structural biological materials have developed heterogeneous and hierarchical architectures that are responsible for the outstanding performance to provide protection against environmental threats including static and dynamic loading. Inspired by this observation, this research aims to develop new material and structural concepts for broadband vibration mitigation. The proposed composite materials possess a two-layered heterogeneous architecture where both layers consist of high-volume platelet-shape reinforcements and low-volume matrix, similar to the well-known "brick and mortar" microstructure of biological composites. Using finite element method, we numerically demonstrated that broadband wave attenuation zones can be achieved by tailoring the geometric features of the heterogeneous architecture. We reveal that the resulting broadband attenuation zones are gained by directly superimposing the attenuation zones in each constituent layer. This mechanism is further confirmed by the investigation into the phonon dispersion relation of each layer. Importantly, the broadband wave attenuation capability will be maintained when the mineral platelet orientation is locally manipulated, yet a contrast between the mineral platelet concentrations of the two constituent layers is essential. The findings of this work will provide new opportunities to design heterogeneous composites for broadband vibration mitigation and impact resistance under mechanically challenging environmental conditions. PMID- 26642933 TI - Variability in Postarrest Targeted Temperature Management Practice: Implications of the 2015 Guidelines. AB - In 2002 postarrest care was significantly altered when multiple randomized controlled trials found that therapeutic hypothermia at a goal temperature of 32 34 degrees C significantly improved survival and neurologic outcomes. In 2013, targeted temperature management (TTM) was reexamined via a randomized controlled trial between 33 degrees C and 36 degrees C in post-cardiac arrest patients and found similar outcomes in both cohorts. Before the release of the 2015 American Heart Association (AHA) Guidelines, our group found that across hospitals in the United States, and even within the same institution, TTM protocol variability existed. After the 2013 TTM trial, it was anticipated that the 2015 Guidelines would clarify which target temperature should be used during postarrest care. The AHA released their updates for post-cardiac arrest TTM recently and, based on the literature available, have recommended the use of TTM at a goal temperature between 32 degrees C and 36 degrees C. Whether this variability has an effect on TTM implementation or patient outcomes is unknown. PMID- 26642934 TI - Early apoptosis of porcine alveolar macrophages limits avian influenza virus replication and pro-inflammatory dysregulation. AB - Pigs are evidently more resistant to avian than swine influenza A viruses, mediated in part through frontline epithelial cells and alveolar macrophages (AM). Although porcine AM (PAM) are crucial in influenza virus control, their mode of control is unclear. To gain insight into the possible role of PAM in the mediation of avian influenza virus resistance, we compared the host effects and replication of two avian (H2N3 and H6N1) and three mammalian (swine H1N1, human H1N1 and pandemic H1N1) influenza viruses in PAM. We found that PAM were readily susceptible to initial infection with all five avian and mammalian influenza viruses but only avian viruses caused early and extensive apoptosis (by 6 h of infection) resulting in reduced virus progeny and moderated pro-inflammation. Full length viral PB1-F2 present only in avian influenza viruses is a virulence factor that targets AM for mitochondrial-associated apoptotic cell death. With the use of reverse genetics on an avian H5N1 virus, we found that full length PB1 F2 contributed to increased apoptosis and pro-inflammation but not to reduced virus replication. Taken together, we propose that early apoptosis of PAM limits the spread of avian influenza viruses and that PB1-F2 could play a contributory role in the process. PMID- 26642935 TI - Double-way spectral tunability for the control of optical nanocavity resonance. AB - Scanning Near-field Optical Microscopy (SNOM) has been successful in finely tuning the optical properties of photonic crystal (PC) nanocavities. The SNOM nanoprobes proposed so far allowed for either redshifting or blueshifting the resonance peak of the PC structures. In this paper, we theoretically demonstrate the possibility of a redshifting (up to +0.65 nm) and a blueshifting (up to -5 nm) the PC cavity resonance wavelength with a single perturbation element. As an example, a fiber bowtie-aperture nano-antenna (BNA) engraved at the apex of a SNOM tip is proposed to play this role. The double-way tunability is the result of a competition between an induced electric dipole (BNA at resonance) leading to a redshift and an induced magnetic dipole (the tip metalcoating) giving rise to a blueshift of the resonance wavelength. We demonstrate that the sign of the spectral shift can be simply controlled through the tip-to-cavity distance. This study opens the way to the full postproduction control of the resonance wavelength of high quality-factor optical cavities. PMID- 26642936 TI - Magnetic microscopy and topological stability of homochiral Neel domain walls in a Pt/Co/AlOx trilayer. AB - The microscopic magnetization variation in magnetic domain walls in thin films is a crucial property when considering the torques driving their dynamic behaviour. For films possessing out-of-plane anisotropy normally the presence of Neel walls is not favoured due to magnetostatic considerations. However, they have the right structure to respond to the torques exerted by the spin Hall effect. Their existence is an indicator of the interfacial Dzyaloshinskii-Moriya interaction (DMI). Here we present direct imaging of Neel domain walls with a fixed chirality in device-ready Pt/Co/AlOx films using Lorentz transmission electron and Kerr microscopies. It is shown that any independently nucleated pair of walls in our films form winding pairs when they meet that are difficult to annihilate with field, confirming that they all possess the same topological winding number. The latter is enforced by the DMI. The field required to annihilate these winding wall pairs is used to give a measure of the DMI strength. Such domain walls, which are robust against collisions with each other, are good candidates for dense data storage. PMID- 26642937 TI - Phylogenetics reveals the crustacean order Amphionidacea to be larval shrimps (Decapoda: Caridea). AB - We present evidence that the single representative of the crustacean order Amphionidacea is a decapod shrimp and not a distinct order. After reviewing available morphological evidence, it is concluded that Amphionides is a larval form, but with an as yet unknown parentage. Although the most likely adult form is in the family Pandalidae, the limited molecular data available cannot fully resolve its affinity. We therefore propose to treat Amphionides reynaudii as incertae sedis within Caridea, rather than a separate family. In view of the large scale, tropical and subtropical distribution of the taxon, the possibility is discussed that Amphionides is more likely to be a composite taxon at generic level, rather than larvae of a single shrimp species. PMID- 26642938 TI - Strategies Identified as Effective by Mothers During Occupational Performance Coaching. AB - AIMS: This study examined strategies mothers reported as effective in facilitating children's successful performance in activities they identified as goals during Occupational Performance Coaching (OPC). METHODS: Twenty-nine mothers of children with occupational performance issues engaged in OPC. A random sample of 44 /157 (28%) coaching sessions were video-recorded from which the audio recording was analyzed using a general inductive approach to explore the nature of strategies reported as effective by mothers. RESULTS: Two major themes emerged: (1) Context-focused; or (2) Child-focused. Context-focused strategies were characterized by mothers' actions that made the performance context more conducive to children's success. The emphasis of mothers' intention in Context focused strategies was achievement of the task with minimal stress. Context focused strategies included subthemes of Adjust Manner, Create Distance, Add Structure and Routine, and Teach. Child-focused strategies required higher levels of engagement with children in the application of strategies and were focused on children's skill development. Subthemes included Collaboration and Offer Choice. CONCLUSIONS: Mothers engaged in coaching identified strategies which they found supported children's performance, attesting to the existing capacity of mothers in identifying and evaluating effective ways of enhancing children's performance. Findings suggest the potential of coaching as a capacity-building, context-based intervention to improve children's performance. PMID- 26642939 TI - Physician perspectives of CYP2C19 and clopidogrel drug-gene interaction active clinical decision support alerts. AB - OBJECTIVE: To determine if physicians find clinical decision support alerts for pharmacogenomic drug-gene interactions useful and assess their perceptions of usability aspects that impact usefulness. MATERIALS AND METHODS: 52 physicians participated in an online simulation and questionnaire involving a prototype alert for the clopidogrel and CYP2C19 drug-gene interaction. RESULTS: Only 4% of participants stated they would override the alert. 92% agreed that the alerts were useful. 87% found the visual interface appropriate, 91% felt the timing of the alert was appropriate and 75% were unfamiliar with the specific drug-gene interaction. 80% of providers preferred the ability to order the recommended medication within the alert. Qualitative responses suggested that supplementary information is important, but should be provided as external links, and that the utility of pharmacogenomic alerts depends on the broader ecosystem of alerts. PRINCIPAL CONCLUSIONS: Pharmacogenomic alerts would be welcomed by many physicians, can be built with minimalist design principles, and are appropriately placed at the end of the prescribing process. Since many physicians lack familiarity with pharmacogenomics but have limited time, information and educational resources within the alert should be carefully selected and presented in concise ways. PMID- 26642940 TI - Heat shock protein 90 inhibitors induce functional inhibition of human natural killer cells in a dose-dependent manner. AB - Heat shock protein 90 (Hsp90) is a ubiquitously expressed ATP-dependent molecular chaperone across all species that helps to the correct the folding of many proteins related to important signaling pathways. Tumor cells expressing Hsp90 have more ATP-binding affinity than normal cells. Many correlative inhibitors have been developed to promising anti-tumor strategies and have been evaluated in clinical trials. However, the effect of Hsp90 inhibitors on immunocytes cannot be ignored. Natural killer (NK) cells are key components of the innate immune system that play a pivotal role in tumor surveillance. The present study has investigated the potential effect of four Hsp90 inhibitors (NVP-AUY922, BIIB021, 17-DMAG, and SNX-2112) on human primary NK cells. The viability, cytotoxicity, apoptosis, phenotype, and cytokine secretion of NK cells after inhibitor treatment were assessed. The results of this study demonstrated that the inhibitors had negative effects on NK cell activity in a dose-dependent manner. The four inhibitors significantly reduced the cytotoxicity of the NK cells by decreasing viability, inducing apoptosis and down-regulating the expression of cytokines and functional receptors. These findings suggest that more attention should be given to the effect of Hsp90 inhibitors on NK cell function during clinical trials and also represent a potential immunosuppressant strategy. PMID- 26642941 TI - Genetic variability among Hymenolepis nana isolates from different geographical regions in China revealed by sequence analysis of three mitochondrial genes. AB - Hymenolepis nana is a common tapeworm that parasitizes in the small intestine of rodent animals and humans. The present study examined the sequence diversity of three mitochondrial (mt) genes namely NADH dehydrogenase subunits 5 (nad5), small subunit ribosomal RNA (rrnS), and ATPase subunit 6 (atp6) of H. nana from mice in different geographical regions of China. A part of the nad5 (pnad5), complete rrnS and atp6 genes were amplified separately from individual H. nana isolates using polymerase chain reaction (PCR) and then sequenced. The sequences of pnad5, rrnS, and atp6 were 710 bp, 704-711 bp, and 516 bp in length, respectively. The A + T contents of the sequences were 70.1-73.5% (pnad5), 70.1-71.7% (rrnS), and 76.6-77.9% (atp6). Sequence variation within H. nana was 0-1.4% for atp6, 0-1.7% for rrnS, and 0-0.7% for pnad5. The inter-specific sequence differences between H. nana and Hymenolepis diminuta were significantly higher, which was 31.6-31.7% (pnad5), 16.1-17.6% (rrnS), and 26.5-27.1% (atp6). Phylogenetic analysis based on the combined three sequences using the maximum parsimony (MP) method supported that H. nana is a species complex or "cryptic" species. These findings demonstrated clearly the usefulness of the three mtDNA sequences for population genetics and systematic studies of H. nana of human and animal health significance. PMID- 26642942 TI - Comparison of different comorbidity measures for oral cancer patients with surgical intervention: A longitudinal study from a single cancer center. AB - OBJECTIVE: Several comorbid measures have been developed and demonstrated the predictive ability for cancer mortality. We conducted a retrospective study on oral squamous cell carcinoma (OSCC) patients to compare the Charlson comorbidity index score (CCIS) to the Elixhauser comorbidity index score (ECIS). METHODS: Newly diagnosed OSCC patients (n=232) post major surgery with or without adjuvant therapy were identified from the cancer registry database between 2006 and 2011. Comorbidities present prior to the cancer diagnosis were obtained and adapted to the CCIS and ECIS. The prevalence of comorbid conditions and the influence on disease-specific survival (DSS) rate were calculated and analyzed by Cox regression model. The discriminatory ability of these two comorbid measures was evaluated by using the adjusted hazard ratio and Akaike information criterion (AIC) in a multivariate regression model. The prediction accuracy was assessed using Harrell's c-statistic. RESULTS: Most of the patients (93.5%) were male with a mean age of 54 +/- 11 years and 77 of them (33.1%) had at least one comorbid condition. The ECIS was associated DSS, with an additional 10% increased risk observed for mortality for each increased score (HR, 1.10; 95% confidence interval [CI], 1.03-1.18) after adjusting with pathological risk features. However, the CCIS was not an independent prognostic factor for these patients. The ECIS increased discriminatory ability but the CCIS did not improve discrimination. CONCLUSIONS: Comorbid conditions significantly influenced the clinical outcomes of patient with OSCC post major surgery. A higher ECIS was associated with worse disease specific survival indicative of a valuable prognostic indicator. The ECIS may be considered in further clinical trials for a variety of cancers, including head and neck cancers. PMID- 26642943 TI - Endoscopic transnasal approach for orbital tumors: A report of four cases. AB - Endoscopic transnasal approach is an excellent technique for resecting orbital tumors located inferiorly and/or medially to the optic nerve. The aim of this study was to present four cases of orbital tumor which were, at least in part, resected by an endoscopic transnasal approach and to discuss both indications and limitations of this approach through a comparison of the location and tumor status, including the pathology, of these cases. In two cases with orbital tumor located in a medial-inferior quadrant, we were able to resect it only by an endoscopic transnasal approach. Because we experienced transient diplopia and dyschromatopsia after resecting intraconal tumors, a careful choice for the best approach is suggested in view of the location, size and properties of the tumor. In the third case, with tumor located in an inferior-lateral quadrant, it was eventually resected using a frontal-zygomatic approach because the medial and inferior borders of the tumor could not be identified and the lateral border was beyond the limits of manipulation by an endoscopic transnasal approach. In the last case with possible malignant tumor adhered to the lateral vital, the tumor was resected using a transantral approach. Based on these experiences, we introduce the indications for an endoscopic transnasal resection of orbital tumors. PMID- 26642944 TI - Drug-Drug Interaction Potentials of Tyrosine Kinase Inhibitors via Inhibition of UDP-Glucuronosyltransferases. AB - Tyrosine kinase inhibitors (TKIs) are anticancer drugs that may be co administered with other drugs. The aims of this study are to investigate the inhibitory effects of TKIs on UDP-glucuronosyltransferase (UGT) activities, and to quantitatively evaluate their potential to cause drug-drug interactions (DDIs). Inhibition kinetic profiles of a panel of UGT enzymes (UGT1A1, 1A3, 1A4, 1A6, 1A7, 1A8, 1A9, 1A10, 2B4, 2B7, 2B15, and 2B17) by four TKIs (axitinib, imatinib, lapatinib and vandetanib) were characterized by using hepatic microsomes and recombinant proteins. Lapatinib exhibited potent competitive inhibition against UGT1A1 activity with a Ki of 0.5 MUM. Imatinib was found to exhibit broad inhibition on several UGTs, particularly potent competitive inhibition against UGT2B17 with a Ki of 0.4 MUM. The TKIs also exerted intermediate inhibition against several UGTs (i.e., UGT1A7 by lapatinib; UGT1A1 by imatinib; UGT1A4, 1A7 and 1A9 by axitinib; and UGT1A9 by vandetanib). Results from modeling for the quantitative prediction of DDI risk indicated that the coadministration of lapatinib or imatinib at clinical doses could result in a significant increase in AUC of drugs primarily cleared by UGT1A1 or 2B17. Lapatinib and imatinib may cause clinically significant DDIs when co-administered UGT1A1 or 2B17 substrates. PMID- 26642945 TI - Simple low-cost miniaturization approach for pharmaceutical nanocrystals production. AB - Systematic screening for optimal formulation composition and production parameters for nanosuspensions consumes a lot of time and also drug material when performed at lab scale. Therefore, a cost-effective miniaturized scale top down approach for nanocrystals production by wet bead milling was developed. The final set-up consisted of 3 magnetic stirring bars placed vertically one over the other in a 2 mL glass vial and agitated by a common magnetic stirring plate. All of the tested actives (cyclosporin A, resveratrol, hesperitin, ascorbyl palmitate, apigenin and hesperidin) could be converted to nanosuspensions. For 4 of them, the particles sizes achieved were smaller than previously reported on the literature (around 90 nm for cyclosporin A; 50 nm for hesperitin; 160 nm for ascorbyl palmitate and 80 nm for apigenin). The "transferability" of the data collect by the miniaturized method was evaluated comparing the production at larger scale using both wet bead milling and high pressure homogenization. Transferable information obtained from the miniaturized scale is minimum achievable size, improvements in size reduction by reduction of beads size, diminution kinetics and potentially occurring instabilities during processing. The small scale batches also allow identification of optimal stabilizer types and concentrations. The batch size is 0.5 mL, requiring approximately 50 mg or 5 mg of drug (5% and 1% suspension, respectively). Thus, a simple, accessible, low cost miniaturized scale method for the production of pharmaceutical nanocrystals was established. PMID- 26642946 TI - Nanoemulsion formulations for anti-cancer agent piplartine--Characterization, toxicological, pharmacokinetics and efficacy studies. AB - Piplartine (PL) is an alkaloid found in black-pepper and known for its anticancer activity, however, due to poor solubility and lack of proper formulation, its use for oral administration is a challenge. The objective of this study was to formulate PL into nanoemulsion drug delivery system for oral delivery and thereafter evaluate toxicity, pharmacokinetics and therapeutic efficacy. Optimized nanoemulsions were formulated by self-emulsification as well as by homogenization-sonication method. Two nanoemulsions enhanced the solubility of PL with low polydispersity index and high stability. Both PL loaded nanoemulsions exhibited enhanced dissolution, cellular permeability and cytotoxic effects as compared to pure PL. Formulation of PL into nanoemulsions did not obstruct its cellular uptake in cancer cells. Blank or PL loaded nanoemulsions did not exhibited toxicity in mice upon daily oral administration for 60 days. Pharmacokinetics of PL followed a two-compartment model after intravenous administration. PL loaded nanoemulsions showed 1.5-fold increase in oral bioavailability as compared to free PL. Finally, PL loaded nanoemulsions showed marked anti-tumor activity at a dose of 10mg/kg in melanoma tumor bearing mice. In conclusion, for the first time we have developed a stable nanoemulsion delivery system for oral administration of PL, which enhanced its solubility, oral bioavailability and anti-tumor efficacy. PMID- 26642948 TI - Studying epigenomics in single cells: what is feasible and what can we learn? PMID- 26642947 TI - Ethambutol plasma and intracellular pharmacokinetics: A pharmacogenetic study. AB - We evaluated ethambutol plasma and intracellular pharmacokinetic according to single nucleotide polymorphisms in ABCB1, OATP1B1, PXR, VDR, CYP24A1 and CYP27B1 genes. Mycobacterium tubercolosis infected patients were enrolled. Standard weight-adjusted antitubercular treatment was administered intravenously for 2 weeks and then orally. Allelic discrimination was performed by real-time PCR. Ethambutol plasma and intracellular concentrations were measured by UPLC-MS/MS methods. Twenty-four patients were included. Considering weeks 2 and 4, median plasma Ctrough were 73 ng/mL and 247 ng/mL, intracellular Ctrough were 16,863 ng/mL and 13,535 ng/mL, plasma Cmax were 5627 ng/mL and 2229 ng/mL, intracellular Cmax were 133,830 ng/mL and 78,544 ng/mL. At week 2, ABCB1 3435 CT/TT (p=0.023) and CYP24A1 8620 AG/GG (p=0.030) genotypes for plasma Ctrough, BsmI AA (p=0.036) for intracellular Ctrough and BsmI AA (p<0.001) and ApaI AA (p=0.048) for intracellular Cmax, remained in linear regression analysis as predictive factors. Concerning week 4 only ABCB1 3435 CT/TT (p=0.035) and Cdx2 AG/GG (p=0.004) genotypes for plasma Ctrough and BsmI AA (p=0.028) for plasma Cmax were retained in final regression model. We reveal, for the first time, the possible role of single nucleotide polymorphisms on ethambutol plasma and intracellular concentrations; this may further the potential use of pharmacogenetic for tailoring antitubercular treatment. PMID- 26642949 TI - Sacroiliac joint pain: Prospective, randomised, experimental and comparative study of thermal radiofrequency with sacroiliac joint block. AB - OBJECTIVE: To compare the analgesic effects between the blockade and bipolar thermal radiofrequency in the treatment of sacroiliac joint pain. METHOD: Prospective, randomised and experimental study conducted on 60 patients selected in the two hospitals over a period of nine months, who had intense sacroiliac joint pain (Visual Analogue Scale [VAS]>6) that lasted more than 3 months. Patients were randomised into three groups (n=20): Group A (two intra-articular sacroiliac injections of local anaesthetic/corticosteroid guided by ultrasound in 7 days). Group B: conventional bipolar radiofrequency "palisade". Target points were the lateral branch nerves of S1, S2, and S3, distance needles 1cm. Group C: modified bipolar radiofrequency "palisade" (needle distance >1cm). Patients were evaluated at one month, three months, and one year. Demographic data, VAS reduction, and side effects of the techniques were assessed. RESULTS: One month after the treatment, pain reduction was >50% in the three groups P<.001. Three and 12 months after the technique, the patients of the group A did not have a significant reduction in pain. At 3 months, almost 50% patients of the group B referred to improvement of the pain (P=.03), and <25% at 12 months, and those results were statistically significant (P=.01) compared to the baseline. Group C showed an improvement of 50% at 3 and 12 months (P<.001). All patients completed the study. CONCLUSIONS: Bipolar radiofrequency "palisade", especially when the distance between the needles was increased, was more effective and lasted longer, compared to join block and steroids, in relieving pain sacroiliac joint. PMID- 26642950 TI - [Advances in airway management: The future is here]. PMID- 26642951 TI - Germinoma recurrence in the conus medullaris 12 years after remission of primary intracranial lesion in the pituitary. AB - Intracranial germinomas are rare primary central nervous system tumours that are highly sensitive to radiotherapy and chemotherapy. Recurrences are infrequent, with the majority occurring within 5 years. Although multidisciplinary treatments have resulted in good event-free survival, long-term outcomes, over decades, are relatively poorly reported. We present a rare case of a recurrence in the conus medullaris 12 years after complete remission of the primary pituitary germinoma. To the best of our knowledge, this represents the first case of a significantly delayed spinal recurrence, occurring at a very distant and uncommon site, from the primary tumour. This case highlights the importance of long-term follow-up, even after complete remission, in order to identify and limit disability from late spinal recurrences in a relatively young patient population. We consider the literature regarding identifying high risk patients, and the role of craniospinal irradiation in limiting late spinal recurrences. PMID- 26642952 TI - Use of frameless neuronavigation for bedside placement of external ventricular catheters. AB - Neuronavigation for placement of ventricular catheters has been described. At our institution, electromagnetic neuronavigation is frequently utilized for difficult ventricular catheter placement. In patients who develop a trapped ventricle as a result of an intraparenchymal or intraventricular mass lesion, successful catheter placement may be difficult, as the location and trajectory are unfamiliar. The authors report their experience using electromagnetic neuronavigation for bedside placement of external ventricular catheters in patients with trapped ventricles. The technique for bedside placement of external ventricular catheters utilizing electromagnetic neuronavigation is reviewed. The benefits of this technique and those patients in whom it may be most useful are discussed. Utilization of bedside electromagnetic neuronavigation for placement of difficult external ventricular catheters into trapped ventricles is an option for accurate navigated catheter placement. Bedside electromagnetic neuronavigation offers accurate catheter placement in awake patients. This technique may be utilized in patients with high perioperative risk factors as it does not require general anesthesia. The procedure is well tolerated as it does not require rigid head fixation. PMID- 26642953 TI - Traumatic anterior cerebral artery aneurysms and management options in the endovascular era. AB - Traumatic anterior cerebral artery (ACA) pseudoaneurysms are a challenge to manage. Difficult diagnosis, delayed presentation and catastrophic outcomes contribute to the overall prognosis of traumatic intracranial aneurysms. Clipping or coiling of the aneurysm and/or parent vessel occlusion are the treatment options. However, surgery and coiling both may be difficult due to limited access and the need for parent vessel preservation. Rarely, these aneurysms must be managed conservatively. We present four patients with traumatic ACA aneurysms admitted to our center in the last 10 months. Three patients had pseudoaneurysms of the distal ACA and one had an aneurysm arising from a cortical branch of the ACA. Their clinical presentations and management, along with outcomes, are discussed as well as the dilemmas associated with them. Three patients were managed by clipping and coiling while one was managed conservatively. The diagnosis was made relatively early in three patients while delayed subarachnoid hemorrhage led to diagnosis in the fourth. Although the overall prognosis remains grim, with high mortality and morbidity rates, both microsurgical and interventional management of these traumatic aneurysms may be useful, if detected early before rupture. Expectant management and surveillance may be required in a select group of patients. PMID- 26642954 TI - Probing the biophysical interaction between Neocarzinostatin toxin and EpCAM RNA aptamer. AB - Neocarzinostatin (NCS) a potent DNA-damaging, anti-tumor toxin extracted from Streptomyces carzinostaticus that recognizes double-stranded DNA bulge and induces DNA damage. 2 Fluoro (2F) Modified EpCAM RNA aptamer is a 23-mer that targets EpCAM protein, expressed on the surface of epithelial tumor cells. Understanding the interaction between NCS and the ligand is important for carrying out the targeted tumor therapy. In this study, we have investigated the biophysical interactions between NCS and 2-fluro Modified EpCAM RNA aptamer using Circular Dichroism (CD) and Infra-Red (IR) spectroscopy. The aromatic amino acid residues spanning the beta sheets of NCS are found to participate in intermolecular interactions with 2 F Modified EpCAM RNA aptamer. In-silico modeling and simulation studies corroborate with CD spectra data. Furthermore, it reinforces the involvement of C and D1 strand of NCS in intermolecular interactions with EpCAM RNA aptamer. This the first report on interactions involved in the stabilization of NCS-EpCAM aptamer complex and will aid in the development of therapeutic modalities towards targeted cancer therapy. PMID- 26642955 TI - CREB is activated by ER stress and modulates the unfolded protein response by regulating the expression of IRE1alpha and PERK. AB - Living cells are frequently exposed to various stresses. Hypoxic conditions induce endoplasmic reticulum (ER) stress, and activate the unfolded protein response (UPR) to maintain homeostasis. We previously reported that CREB has an important role in the proper response to prolonged hypoxia. To further understand the role of CREB in the hypoxic response, CREB stable knock-down (CREB-KD) cells were established from breast cancer MDA-MB231 cells and analyzed. CREB was activated by ER stress, and activation of CREB and the UPR pathway occurred in a coordinated manner in response to different stimuli, including ER stress-inducing chemicals, prolonged hypoxia, and oxygen-glucose deprivation (OGD). Depletion of CREB decreased the expression of IRE1alpha and PERK, two critical UPR signaling molecules. Promoter analysis and a chromatin immunoprecipitation assay indicated that CREB binds to the promoter region of these genes and regulates their expression. ER stress induced by hypoxia was reduced in CREB-KD cells, leading to reduced tumor metastasis to the lung. Finally, OGD strongly activated the UPR and induced cell death in control cells, whereas the UPR was moderately activated in CREB-KD cells, which were more resistant to cell death. This study demonstrates a new role for CREB as a regulator of ER stress, which is required to properly respond to stressful conditions, such as hypoxia. PMID- 26642956 TI - [Social inequalities in nutrition: Evidence, causes and interventions]. AB - Malnutrition is unhealthy: obesity, type 2 diabetes, cardiovascular diseases, some cancers, and premature mortality are reliably associated with poor nutrition. However, literature reveals that some population groups are at higher risk of poor nutrition than others. More specifically, evidence shows that people with low social status are more likely to have poor nutrition than those with higher status, what may contribute to health inequalities. In this article, selected reviews and meta-analyses on social inequalities in nutrition are presented. By showing current data from the Second National Food Consumption Study, the situation in Germany is highlighted. Further, potential causes of social inequalities in nutrition are discussed, drawing on the results of current research. More specifically, socioeconomic and structural deprivation (e.g., poverty, living in deprived neighborhoods) in addition to unfavorable psychosocial (e.g., poor knowledge of nutrition, low levels of social support) and sociocultural factors (e.g., unfavorable nutritional traditions) might be associated with poor nutrition in people with low social status. Interventions promoting nutritional quality in disadvantaged groups should take into account the various influences on nutrition and meet good practice criteria for health promotion. Using three examples of interventions, conceivable concrete measures that can reduce social inequalities in nutrition are presented. PMID- 26642958 TI - [Not Available]. PMID- 26642957 TI - [Release of antibiotics into urban wastewater: A secondary-data based analysis for the input assessment using the city of Dresden as an example]. AB - Antibiotics are essential for the successful treatment of bacterial infections. Recently, the increasing number of resistant bacteria and the occurrence of residues of antibiotics in the environment has become the focus of scientific interest. The aim of the cooperative project ANTI-Resist was to investigate the release of antibiotics and the occurrence and distribution of antibiotic resistance in the urban waste water system of the city of Dresden.This article presents the main results of the secondary data analysis for the determination of outpatient and inpatient antibiotic consumption and provides an insight into the complexity of the topic antibiotics in waste water.Based on the data of outpatient prescriptions provided by the AOK PLUS for the period 2005 to 2013, thirteen focus substances were identified to estimate antibiotic consumption. Furthermore, delivery data from the pharmacies of three hospitals in Dresden were available.Depending on the substances investigated, seasonality and age dependency were determined. The results at a regional level were mostly in good accordance with general trends throughout Germany. It should be noted that the total amount of antibiotics used remained nearly constant over the whole period investigated, but the prescription of fluoroquinolones increased. This must be questioned when taking into account the increasingly critical situation in the treatment of Gram-negative bacteria in particular. Examinations of waste water conducted indicated that sewage treatment plants are not able to remove antibiotics or their metabolites completely from waste water. The residues are released into surface waters via the treatment plants. The impact cannot be assessed at the moment and further investigations are necessary. PMID- 26642959 TI - Erratum to: Overdose the addiction--A new strategy to ablate cancer cells. PMID- 26642960 TI - HER2 mutation status in Japanese HER2-positive breast cancer patients. AB - BACKGROUND: Human epidermal growth factor receptor 2 (HER2) gene amplification/overexpression is a major therapeutic target in breast cancer, and has been introduced as a predictive biomarker to identify patients who may benefit from therapy with anti-HER2 agents. HER2 somatic mutations have been reported, and these may influence the effect of HER2-targeted drugs. METHODS: Here, we sought HER2 mutations in a group of 135 Japanese breast cancer patients with HER2-positive tumors. We analyzed HER2 mutations by direct Sanger sequencing of two major areas, the extracellular domain at position 309-310 and the kinase domain between 755 and 781. RESULTS: Two patients with the HER2 somatic mutation S310F in the extracellular domain were found in this series. One patient with the S310F mutation had a node-negative invasive ductal carcinoma classified as HER2 2+ by the HercepTest and fluorescence in situ hybridization (FISH) positive, and which was estrogen receptor (ER)-negative and progesterone receptor (PgR) negative. Another patient with the S310F mutation had an apocrine carcinoma with seven lymph nodes positive for metastasis, classified as HER2 3+ by the HercepTest, but which was FISH-negative, as well as ER-negative and PgR-negative. Both patients had received adjuvant single-agent trastuzumab therapy, and had no local recurrence or distant metastasis for five and three years after surgery, respectively. CONCLUSIONS: Our data show that HER2 mutations are rare in HER2 positive Japanese breast cancer patients. The two mutations found in this study were identical, S310F. We suggest that in vitro experiments to determine whether the S310F mutation could be involved in resistance to anti-HER2 drugs are worthwhile in future. PMID- 26642961 TI - Restructuring supervision and reconfiguration of skill mix in community pharmacy: Classification of perceived safety and risk. AB - BACKGROUND: Broadening the range of services provided through community pharmacy increases workloads for pharmacists that could be alleviated by reconfiguring roles within the pharmacy team. OBJECTIVES: To examine pharmacists' and pharmacy technicians (PTs)' perceptions of how safe it would be for support staff to undertake a range of pharmacy activities during a pharmacist's absence. Views on supervision, support staff roles, competency and responsibility were also sought. METHODS: Informed by nominal group discussions, a questionnaire was developed and distributed to a random sample of 1500 pharmacists and 1500 PTs registered in England. Whilst focused on community pharmacy practice, hospital pharmacy respondents were included, as more advanced skill mix models may provide valuable insights. Respondents were asked to rank a list of 22 pharmacy activities in terms of perceived risk and safety of these activities being performed by support staff during a pharmacist's absence. Descriptive and comparative statistic analyses were conducted. RESULTS: Six-hundred-and-forty-two pharmacists (43.2%) and 854 PTs (57.3%) responded; the majority worked in community pharmacy. Dependent on agreement levels with perceived safety, from community pharmacists and PTs, and hospital pharmacists and PTs, the 22 activities were grouped into 'safe' (n = 7), 'borderline' (n = 9) and 'unsafe' (n = 6). Activities such as assembly and labeling were considered 'safe,' clinical activities were considered 'unsafe.' There were clear differences between pharmacists and PTs, and sectors (community pharmacy vs. hospital). Community pharmacists were most cautious (particularly mobile and portfolio pharmacists) about which activities they felt support staff could safely perform; PTs in both sectors felt significantly more confident performing particularly technical activities than pharmacists. CONCLUSION: This paper presents novel empirical evidence informing the categorization of pharmacy activities into 'safe,' 'borderline' or 'unsafe.' 'Borderline' activities will deserve particular attention, especially where they are part of processes, e.g. dispensing. This categorization could help inform reconfiguration of skill mix in community pharmacy and thus make an important contribution to the rebalancing medicines legislation agenda and pharmacist supervision. PMID- 26642962 TI - Skin cancer prevention practices among malignant melanoma survivors: a systematic review. AB - PURPOSE: This systematic review was conducted to evaluate and summarize the existing literature on prevalence of ultraviolet radiation (UVR) exposure, sun protection, and screening behaviors among individuals diagnosed with malignant melanoma (MM). METHODS: The search was performed in PubMed, CINAHL, PsycINFO, ScienceDirect, EMBASE, and ERIC from inception of each database through July 2014. Studies were included if (1) individuals diagnosed with MM were the primary sample, (2) measured UVR exposure, primary and secondary preventive behaviors, (3) original research communication that constitutes an entire set of empirical data, (4) observational design, and (5) English peer-reviewed. Studies were excluded if (1) all of the inclusion criteria were not met and (2) duplicates, conference abstracts, editorials, news, letters to the editor, comments, reviews, feature articles, white papers, and guidelines. RESULTS: The search resulted in 255 articles that were screened for relevance; however, only 15 articles met all of the inclusion criteria. Most of the studies were cross-sectional (n = 10), used self-administered surveys (n = 8), and were conducted in North America (n = 10). The sample sizes ranged considerably, but were mostly Caucasian (n = 6) and included a higher proportion of women (n = 8). Evidence demonstrated that individuals with MM still engaged in sunbathing, indoor tanning, and reported sunburns. Moreover, survivors reported inadequate levels of both sun protection and skin self-examinations. CONCLUSIONS: The findings highlight the need for intensifying intervention strategies to reduce the risk of new primary MMs in this group. Future research should increase in rigor and include more diverse populations and regions. PMID- 26642963 TI - Determinants of change in bone mineral density and fracture risk during bisphosphonate holiday. AB - In a retrospective analysis of 208 osteoporotic patients followed during a bisphosphonate holiday, lower body weight and risedronate use were associated with a more rapid decline in bone mineral density during the bisphosphonate holiday, while bone mineral density (BMD) trends were similar in patients who sustained vs. did not sustain a fracture. INTRODUCTION: A drug holiday has been suggested for some bisphosphonate-treated patients with osteoporosis to minimize potential side effects from prolonged use. However, there is limited information on the evolution of BMD during a bisphosphonate holiday. Our study analyzed the longitudinal course of BMD following bisphosphonate discontinuation and assessed its determinants. METHODS: Retrospective single-center cohort study of osteoporosis patients treated with alendronate or risedronate for at least 2 years and then discontinued their bisphosphonate for a drug holiday. Patients were stratified by bisphosphonate type and by fracture occurrence during drug holiday. RESULTS: A total of 208 patients were included in this analysis (87.5 % female). At the time of bisphosphonate cessation, mean +/- SD age was 66.9 +/- 8.9 years and BMI 24.5 +/- 4.4 kg/m(2). Duration of bisphosphonate treatment was 5.2 +/- 2.3 years, and follow-up during holiday was 3.3 +/- 1.7 years. During the first 2 years of the holiday, BMD remained stable at the lumbar spine and femoral neck, but declined significantly at the total hip. BMD declined significantly at all sites thereafter. Significant predictors of BMD decline during bisphosphonate holiday included lower BMI at the start of the holiday and change in body weight during the holiday. BMD decline was more pronounced in former risedronate compared to former alendronate users. BMD trends were similar in patients who sustained vs. did not sustain a fracture during the holiday. CONCLUSIONS: BMD at the total hip declines significantly within 1 year of bisphosphonate discontinuation, particularly in lean patients. Additional studies are needed to identify predictors of fracture incidence during a bisphosphonate holiday. PMID- 26642964 TI - The Moral Reasoning of Genetic Dilemmas Amongst Jewish Israeli Undergraduate Students with Different Religious Affiliations and Scientific Backgrounds. AB - The main objective of this study was to shed light on the moral reasoning of undergraduate Israeli students towards genetic dilemmas, and on how these are affected by their religious affiliation, by the field they study and by their gender. An open ended questionnaire was distributed among 449 undergraduate students in institutions of higher education in Israel, and their answers were analyzed according to the framework described by Sadler and Zeidler (Science Education, 88(1), 4-27, 2004). They were divided into two major categories: those whose reasoning was based on the consideration of moral consequences (MC), and those who supported their opinion by citing non-consequentialist moral principles (MP). Students' elaborations to questions dealing with values towards genetic testing showed a correlation between the students' religious affiliation and their reasoning, with religious students' elaborations tending to be more principle based than those of secular ones. Overall, the students' elaborations indicate that their main concern is the possibility that their personal genetic information will be exposed, and that their body's personal rights will be violated. We conclude the paper by offering several practical recommendations based on our findings for genetic counseling that is specifically tailored to fit different patients according to their background. PMID- 26642965 TI - [Choking games among 2nd and 3rd graders]. AB - It is suspected that elementary school age children engage in "the choking game" or other asphyxial practices, but the prevalence is unknown. OBJECTIVE: This study was conducted to determine the prevalence among 2nd and 3rd graders. METHODS: Twenty-five schools in a region in Southeastern France were sampled on the following criteria: school size, rural/urban location, underprivileged neighborhood or not, and private/public school. Second and third grade classes were randomly sampled in each school. Another sample of 25 schools was selected in case a school refused to participate. A self-administered questionnaire, previously validated in two nonsampled schools, was administered in selected classes by the pediatrician leading the project. RESULTS: A total of 1125 questionnaires were distributed and 95% were completed. The mean (SD) age of children was 8.3 (0.7) years. Forty percent of children reported they had already played choking games. Among all the declared players (n=401), the male to female ratio was 1.4; 13% of them played this game every day or several times a day (91% were male). This prevalence varied between schools (16-75%) and games and was significantly higher among children schooled in underprivileged neighborhoods. Seventy-six percent of non-players and 48% of players were aware of the potential life-threatening risk. CONCLUSIONS: The mean prevalence in elementary school (40%) appears to be higher compared to middle and high schools (5-10%). Motivation differs in elementary school children compared to older children and teenagers. Prevention of choking games should start at elementary school and determinants leading to the continuation of such practices from elementary school to high school need to be explored. PMID- 26642966 TI - Functional connectivity change as shared signal dynamics. AB - BACKGROUND: An increasing number of neuroscientific studies gain insights by focusing on differences in functional connectivity-between groups, individuals, temporal windows, or task conditions. We found using simulations that additional insights into such differences can be gained by forgoing variance normalization, a procedure used by most functional connectivity measures. Simulations indicated that these functional connectivity measures are sensitive to increases in independent fluctuations (unshared signal) in time series, consistently reducing functional connectivity estimates (e.g., correlations) even though such changes are unrelated to corresponding fluctuations (shared signal) between those time series. This is inconsistent with the common notion of functional connectivity as the amount of inter-region interaction. NEW METHOD: Simulations revealed that a version of correlation without variance normalization - covariance - was able to isolate differences in shared signal, increasing interpretability of observed functional connectivity change. Simulations also revealed cases problematic for non-normalized methods, leading to a "covariance conjunction" method combining the benefits of both normalized and non-normalized approaches. RESULTS: We found that covariance and covariance conjunction methods can detect functional connectivity changes across a variety of tasks and rest in both clinical and non clinical functional MRI datasets. COMPARISON WITH EXISTING METHOD(S): We verified using a variety of tasks and rest in both clinical and non-clinical functional MRI datasets that it matters in practice whether correlation, covariance, or covariance conjunction methods are used. CONCLUSIONS: These results demonstrate the practical and theoretical utility of isolating changes in shared signal, improving the ability to interpret observed functional connectivity change. PMID- 26642967 TI - Automatic detection of rapid eye movements (REMs): A machine learning approach. AB - BACKGROUND: Rapid eye movements (REMs) are a defining feature of REM sleep. The number of discrete REMs over time, or REM density, has been investigated as a marker of clinical psychopathology and memory consolidation. However, human detection of REMs is a time-consuming and subjective process. Therefore, reliable, automated REM detection software is a valuable research tool. NEW METHOD: We developed an automatic REM detection algorithm combining a novel set of extracted features and the 'AdaBoost' classification algorithm to detect the presence of REMs in Electrooculogram data collected from the right and left outer canthi (ROC/LOC). Algorithm performance measures of Recall (percentage of REMs detected) and Precision (percentage of REMs detected that are true REMs) were calculated and compared to the gold standard of human detection by three expert sleep scorers. REM detection by four non-experts were also investigated and compared to expert raters and the algorithm. RESULTS: The algorithm performance (78.1% Recall, 82.6% Precision) surpassed that of the average (expert & non expert) single human detection performance (76% Recall, 83% Precision). Agreement between non-experts (Cronbach Alpha=0.65) is markedly lower than experts (Cronbach Alpha=0.80). COMPARISON WITH EXISTING METHOD(S): By following reported methods, we implemented all previously published LOC and ROC based detection algorithms on our dataset. Our algorithm performance exceeded all others. CONCLUSIONS: The automatic detection algorithm presented is a viable and efficient method of REM detection as it reliably matches the performance of human scorers and outperforms all other known LOC- and ROC-based detection algorithms. PMID- 26642968 TI - Non-invasive brain mapping in epilepsy: Applications from magnetoencephalography. AB - BACKGROUND: Non-invasive in vivo neurophysiological recordings with EEG/MEG are key to the diagnosis, classification, and further understanding of epilepsy. Historically the emphasis of these recordings has been the localisation of the putative sources of epileptic discharges. More recent developments see new techniques studying oscillatory dynamics, connectivity and network properties. NEW METHOD: New analysis strategies for whole head MEG include the development of spatial filters or beamformers for source localisation, time-frequency analysis for cortical dynamics and graph theory applications for connectivity. RESULTS: The idea of epilepsy as a network disorder is not new, and new applications of structural and functional brain imaging show differences in cortical and subcortical networks in patients with epilepsy compared to controls. Concepts of 'focal' and 'generalised' are challenged by evidence of focal onsets in generalised epileptic discharges, and widespread network changes in focal epilepsy. Spectral analyses can show differences in induced cortical response profiles, particularly in photosensitive epilepsy. COMPARISON WITH EXISTING METHOD: This review focuses on the application of MEG in the study of epilepsy, starting with a brief historical perspective, followed by novel applications of source localisation, time-frequency and connectivity analyses. CONCLUSION: Novel MEG analyses approaches show altered cortical dynamics and widespread network alterations in focal and generalised epilepsies, and identification of regional network abnormalities may have a role in epilepsy surgery evaluation. PMID- 26642969 TI - Preface for methods and models in epilepsy research. PMID- 26642970 TI - The accuracy of presepsin for the diagnosis of sepsis from SIRS: a systematic review and meta-analysis. AB - BACKGROUND: Sepsis is a common condition that has a high mortality and morbidity that need prompt diagnosis and treatment. Biomarkers like Soluble CD14 subtype (sCD14-ST, presepsin) may be useful in identifying patients with sepsis and its diagnostic superiority has been confirmed by several preliminary studies. The aim of this study was systematically and quantitatively to evaluate the value of presepsin for the diagnosis of sepsis through the method of meta-analysis. METHODS: Four major databases, including MEDLINE, EMBASE, ISI Web of Knowledge, and the Cochrane Library were systematically searched from inception to March 2015. Two investigators conducted the processes of literature search, study selection, data extraction, and quality evaluation independently. And the original data were extracted from all eligible individual studies to construct two-by-two tables. RESULTS: A total of eight studies comprising 1757 patients were included in this meta-analysis. The pooled sensitivity, specificity, and diagnostic odds ratio were 0.77 (95 % confidence interval [CI]: 0.75-0.80), 0.73 (95 % CI 0.69-0.77), and 14.25 (95 % CI 8.66-23.42), respectively. The summary receiver operating characteristic curve (SROC) area under the curve (AUC) was 0.8598. The subgroup analysis based on excluding the outliers showed that the pooled sensitivity and specificity were 0.85 (95 % CI 0.81-0.89) and 0.65 (95 % CI 0.59-0.70), respectively. The AUC was 0.8213 with no significant heterogeneity. CONCLUSIONS: Presepsin has moderate diagnostic capacity for the detection of sepsis. Further research of presepsin is needed before widespread use in emergency department. And presepsin in combination with other laboratory biomarkers in diagnosing sepsis may be the focus of future studies. PMID- 26642972 TI - Executive functions in obsessive-compulsive disorder: An activation likelihood estimate meta-analysis of fMRI studies. AB - OBJECTIVES: To identify activation changes assessed in functional magnetic resonance imaging (fMRI) studies of obsessive-compulsive disorder (OCD) through Activation Likelihood Estimate meta-analysis. METHODS: We included 28 peer reviewed standard stereotactic space studies assessing adult OCD patients (OCDpts) vs. healthy controls (HCs) with fMRI during executive task performance. RESULTS: In within-group analyses, HCs showed task-related activations in bilateral inferior frontal gyri, right middle frontal gyrus, right inferior parietal lobule, right claustrum, bilateral cingulate gyri, and left caudate body. OCDpts showed task-related left-sided activations in the superior, medial, and inferior frontal gyri, and thalamus, and bilateral activations in the middle frontal gyri, inferior parietal lobule, and insular cortices. Subtraction analysis showed increased left middle frontal gyrus activation in OCDpts. In between-groups analyses, OCDpts hypoactivated the right caudate body, left putamen, left ACC, and right medial and middle frontal gyri. Right caudate hypoactivation persisted also after applying Family-wise error algorithms. CONCLUSIONS: This meta-analysis confirms that during executive functioning OCDpts show a functional deficit of the right caudate body, which could represent a major neural functional correlate of their illness. PMID- 26642971 TI - Adenosine kinase deficiency: expanding the clinical spectrum and evaluating therapeutic options. AB - BACKGROUND: Adenosine kinase deficiency is a recently described defect affecting methionine metabolism with a severe clinical phenotype comprising mainly neurological and hepatic impairment and dysmorphism. METHODS: Clinical data of 11 additional patients from eight families with adenosine kinase deficiency were gathered through a retrospective questionnaire. Two liver biopsies of one patient were systematically evaluated. RESULTS: The main clinical symptoms are mild to severe liver dysfunction with neonatal onset, muscular hypotonia, global developmental retardation and dysmorphism (especially frontal bossing). Hepatic involvement is not a constant finding. Most patients have epilepsy and recurrent hypoglycemia due to hyperinsulinism. Major biochemical findings are intermittent hypermethioninemia, increased S-adenosylmethionine and S-adenosylhomocysteine in plasma and increased adenosine in urine. S-adenosylmethionine and S adenosylhomocysteine are the most reliable biochemical markers. The major histological finding was pronounced microvesicular hepatic steatosis. Therapeutic trials with a methionine restricted diet indicate a potential beneficial effect on biochemical and clinical parameters in four patients and hyperinsulinism was responsive to diazoxide in two patients. CONCLUSION: Adenosine kinase deficiency is a severe inborn error at the cross-road of methionine and adenosine metabolism that mainly causes dysmorphism, brain and liver symptoms, but also recurrent hypoglycemia. The clinical phenotype varies from an exclusively neurological to a multi-organ manifestation. Methionine-restricted diet should be considered as a therapeutic option. PMID- 26642973 TI - Selective impairment of sensorimotor representations following short-term upper limb immobilization. AB - In the present experiment, we examined whether short-term upper-limb immobilization would selectively affect the representation of the immobilized limb (using a hand laterality task) or whether the effect of immobilization would extend to another body part (using a foot laterality task). A rigid splint placed on the participants' left hand was used for immobilization. A control group did not undergo the immobilization procedure. We compared the participants' performances on the hand and foot laterality tasks before (T1) and after (T2) a 48-hour delay, corresponding to the immobilization period. For controls, response time analysis indicated a benefit of task repetition for the recognition of both hand and foot images. For the immobilized group, a slowdown of performance appeared in T2 for hand images, but not for foot images. The reduced benefit of task repetition following left-hand immobilization appeared for both the immobilized and non-immobilized hand images. These findings revealed that the general cognitive representation of upper-limb movements is affected by the decrease in input/output signal processing due to the left-hand immobilization, while the cognitive representation of lower-limb movements is not. PMID- 26642974 TI - Randomized crossover sham-controlled clinical trial of targeted low-frequency transcranial magnetic stimulation comparing a figure-8 and a round coil to treat refractory neocortical epilepsy. AB - OBJECTIVE: Determine the efficacy and side effects of low-frequency repetitive transcranial magnetic stimulation (rTMS) to treat refractory neocortical epilepsy and study differences in effect between a figure-8 and round coil type. METHODS: This single-center randomized sham-controlled crossover trial (NCT01745952 on ClinicalTrials.gov) included 11 patients with well-defined focal epilepsy. rTMS (0.5 Hz) was targeted to the focus during three treatment conditions consisting of 1,500 stimulations/day for 10 weekdays at 90% of resting motor threshold (rMT) followed by a 10-week observation period. Patients were randomized for the order in which the figure-8, round, and sham coil were used. Outcome assessors and patients were blinded to the type of coil used. The primary outcome measure was the percentage of seizure reduction after active rTMS treatment. Other outcome measures were responder rate, quality of life, and side effects. RESULTS: There was no difference between a figure-8 and round coil. None of the patients achieved an overall 50% seizure reduction. One patient responded during 1 month after treatment with either active coil, followed by a significant increase in seizure frequency. Another patient had a fourfold increase in seizure frequency during rTMS treatment. SIGNIFICANCE: This study provides evidence that rTMS is on average not effective for reducing seizure frequency. No difference in effectiveness between the different coil types was observed. It can, however, exacerbate seizures during treatment and lead to a rebound in seizure frequency after an initial reduction. PMID- 26642975 TI - Trinuclear Cage-Like Zn(II) Macrocyclic Complexes: Enantiomeric Recognition and Gas Adsorption Properties. AB - Three zinc(II) ions in combination with two units of enantiopure [3+3] triphenolic Schiff-base macrocycles 1, 2, 3, or 4 form cage-like chiral complexes. The formation of these complexes is accompanied by the enantioselective self-recognition of chiral macrocyclic units. The X-ray crystal structures of these trinuclear complexes show hollow metal-organic molecules. In some crystal forms, these barrel-shaped complexes are arranged in a window-to window fashion, which results in the formation of 1D channels and a combination of both intrinsic and extrinsic porosity. The microporous nature of the [Zn3 12 ] complex is reflected in its N2 , Ar, H2 , and CO2 adsorption properties. The N2 and Ar adsorption isotherms show pressure-gating behavior, which is without precedent for any noncovalent porous material. A comparison of the structures of the [Zn3 12 ] and [Zn3 32 ] complexes with that of the free macrocycle H3 1 reveals a striking structural similarity. In H3 1, two macrocyclic units are stitched together by hydrogen bonds to form a cage very similar to that formed by two macrocyclic units stitched together by Zn(II) ions. This structural similarity is manifested also by the gas adsorption properties of the free H3 1 macrocycle. Recrystallization of [Zn3 12 ] in the presence of racemic 2-butanol resulted in the enantioselective binding of (S)-2-butanol inside the cage through the coordination to one of the Zn(II) ions. PMID- 26642976 TI - Therapy-related cutaneous adverse effects in an Indian cohort of adult leukaemia patients. PMID- 26642978 TI - Quantum Derivative Fitting and Biomolecular Force Fields: Functional Form, Coupling Terms, Charge Flux, Nonbond Anharmonicity, and Individual Dihedral Potentials. AB - Computer simulations are increasingly prevalent, complementing experimental studies in all fields of biophysics, chemistry, and materials. Their utility, however, is critically dependent on the validity of the underlying force fields employed. In this Perspective we review the ability of quantum mechanics, and in particular analytical ab initio derivatives, to inform on the nature of intra- and intermolecular interactions. The power inherent in the exploitation of forces and second derivatives (Hessians) to derive force fields for a variety of compound types, including inorganic, organic, and biomolecules, is explored. We discuss the use of these quantities along with QM energies and geometries to determine force constants, including nonbond and electrostatic parameters, and to assess the functional form of the energy surface. The latter includes the optimal form of out-of-plane interactions and the necessity for anharmonicity, and terms to account for coupling between internals, to adequately represent the energy of intramolecular deformations. In addition, individual second derivatives of the energy with respect to selected interaction coordinates, such as interatomic distances or individual dihedral angles, have been shown to select out for the corresponding interactions, annihilating other interactions in the potential expression. Exploitation of these quantities allows one to probe the individual interaction and explore phenomena such as, for example, anisotropy of atom-atom nonbonded interactions, charge flux, or the functional form of isolated dihedral angles, e.g., a single dihedral X-C-C-Y about a tetrahedral C-C bond. PMID- 26642977 TI - The benefit of paracentesis on hospitalized adults with cirrhosis and ascites. AB - BACKGROUND AND AIM: The aim of this study is to assess paracentesis utilization and outcomes in hospitalized adults with cirrhosis and ascites. METHODS: The 2011 Nationwide Inpatient Sample was used to identify adults, non-electively admitted with diagnoses of cirrhosis and ascites. The primary endpoint was in-hospital mortality. Variables included patient and hospital demographics, early (Day 0 or 1) or late (Day 2 or later) paracentesis, hepatic decompensation, and spontaneous bacterial peritonitis. RESULTS: Out of 8 023 590 admissions, 31 614 met inclusion criteria. Among these hospitalizations, approximately 51% (16 133) underwent paracentesis. The overall in-hospital mortality rate was 7.6%. There was a significantly increased mortality among patients who did not undergo paracentesis (8.9% vs 6.3%, P < 0.001). Patients who did not receive paracentesis died 1.83 times more often in the hospital than those patients who did receive paracentesis (95% confidence interval 1.66-2.02). Patients undergoing early paracentesis showed a trend towards reduction in mortality (5.5% vs 7.5%) compared with those undergoing late paracentesis. Patients admitted on a weekend demonstrated less frequent use of early paracentesis (50% weekend vs 62% weekday) and demonstrated increased mortality (adjusted odds ratio 1.12 95% confidence interval 1.01-1.25). Among patients diagnosed with spontaneous bacterial peritonitis, early paracentesis was associated with shorter length of stay (7.55 vs 11.45 days, P < 0.001) and decreased hospitalization cost ($61 624 vs $107 484, P < 0.001). CONCLUSION: Paracentesis is under-utilized among cirrhotic patients presenting with ascites and is associated with decreased in-hospital mortality. These data support the use of paracentesis as a key inpatient quality measure among hospitalized adults with cirrhosis. Future studies are needed to investigate the barriers to paracentesis use on admission. PMID- 26642979 TI - Recovering Protein Thermal Stability Using All-Atom Hamiltonian Replica-Exchange Simulations in Explicit Solvent. AB - The REST2 method is successfully applied to investigate the thermal stability of chignolin CLN025 and of Trp-cage. As opposed to temperature replica exchange, REST2 relies on the rescaling of the protein potential energy, which allows a smaller number of replicas. The shape of the stability curve reconstructed on the basis of the corresponding-state principle is in very good agreement with experimental data; for chignolin, the effect of mutations is also recovered. PMID- 26642980 TI - Coupling an Ensemble of Homologues Improves Refinement of Protein Homology Models. AB - Atomic models of proteins built by homology modeling or from low-resolution experimental data may contain considerable local errors. The refinement success of molecular dynamics simulations is usually limited by both force field accuracy and by the substantial width of the conformational distribution at physiological temperatures. We propose a method to overcome both these problems by coupling homologous replicas during a molecular dynamics simulation, which narrows the conformational distribution, and smoothens and even improves the energy landscape by adding evolutionary information. PMID- 26642981 TI - A Comparison of Barostats for the Mechanical Characterization of Metal-Organic Frameworks. AB - In this paper, three barostat coupling schemes for pressure control, which are commonly used in molecular dynamics simulations, are critically compared to characterize the rigid MOF-5 and flexible MIL-53(Al) metal-organic frameworks. We investigate the performance of the three barostats, the Berendsen, the Martyna Tuckerman-Tobias-Klein (MTTK), and the Langevin coupling methods, in reproducing the cell parameters and the pressure versus volume behavior in isothermal isobaric simulations. A thermodynamic integration method is used to construct the free energy profiles as a function of volume at finite temperature. It is observed that the aforementioned static properties are well-reproduced with the three barostats. However, for static properties depending nonlinearly on the pressure, the Berendsen barostat might give deviating results as it suppresses pressure fluctuations more drastically. Finally, dynamic properties, which are directly related to the fluctuations of the cell, such as the time to transition from the large-pore to the closed-pore phase, cannot be well-reproduced by any of the coupling schemes. PMID- 26642982 TI - New Monte Carlo Based Technique To Study DNA-Ligand Interactions. AB - We present a new all-atom Monte Carlo technique capable of performing quick and accurate DNA-ligand conformational sampling. In particular, and using the PELE software as a frame, we have introduced an additional force field, an implicit solvent, and an anisotropic network model to effectively map the DNA energy landscape. With these additions, we successfully generated DNA conformations for a test set composed of six DNA fragments of A-DNA and B-DNA. Moreover, trajectories generated for cisplatin and its hydrolysis products identified the best interacting compound and binding site, producing analogous results to microsecond molecular dynamics simulations. Furthermore, a combination of the Monte Carlo trajectories with Markov State Models produced noncovalent binding free energies in good agreement with the published molecular dynamics results, at a significantly lower computational cost. Overall our approach will allow a quick but accurate sampling of DNA-ligand interactions. PMID- 26642983 TI - Water Freezing and Ice Melting. AB - The generalized replica exchange method (gREM) is designed to sample states with coexisting phases and thereby to describe strong first order phase transitions. The isobaric MD version of the gREM is presented and applied to the freezing of liquid water and the melting of hexagonal and cubic ice. It is confirmed that coexisting states are well-sampled. The statistical temperature as a function of enthalpy, TS(H), is obtained. Hysteresis between freezing and melting is observed and discussed. The entropic analysis of phase transitions is applied and equilibrium transition temperatures, latent heats, and surface tensions are obtained for hexagonal ice <-> liquid and cubic ice <-> liquid with excellent agreement with published values. A new method is given to assign water molecules among various symmetry types. Pathways for water freezing, ultimately leading to hexagonal ice, are found to contain intermediate layered structures built from hexagonal and cubic ice. PMID- 26642984 TI - GW100: Benchmarking G0W0 for Molecular Systems. AB - We present the GW100 set. GW100 is a benchmark set of the ionization potentials and electron affinities of 100 molecules computed with the GW method using three independent GW codes and different GW methodologies. The quasi-particle energies of the highest-occupied molecular orbitals (HOMO) and lowest-unoccupied molecular orbitals (LUMO) are calculated for the GW100 set at the G0W0@PBE level using the software packages TURBOMOLE, FHI-aims, and BerkeleyGW. The use of these three codes allows for a quantitative comparison of the type of basis set (plane wave or local orbital) and handling of unoccupied states, the treatment of core and valence electrons (all electron or pseudopotentials), the treatment of the frequency dependence of the self-energy (full frequency or more approximate plasmon-pole models), and the algorithm for solving the quasi-particle equation. Primary results include reference values for future benchmarks, best practices for convergence within a particular approach, and average error bars for the most common approximations. PMID- 26642985 TI - Large-Scale First-Principles Molecular Dynamics Simulations with Electrostatic Embedding: Application to Acetylcholinesterase Catalysis. AB - Enzymes are complicated solvated systems that typically require many atoms to simulate their function with any degree of accuracy. We have recently developed numerical techniques for large scale first-principles molecular dynamics simulations and applied them to the study of the enzymatic reaction catalyzed by acetylcholinesterase. We carried out density functional theory calculations for a quantum-mechanical (QM) subsystem consisting of 612 atoms with an O(N) complexity finite-difference approach. The QM subsystem is embedded inside an external potential field representing the electrostatic effect due to the environment. We obtained finite-temperature sampling by first-principles molecular dynamics for the acylation reaction of acetylcholine catalyzed by acetylcholinesterase. Our calculations show two energy barriers along the reaction coordinate for the enzyme-catalyzed acylation of acetylcholine. The second barrier (8.5 kcal/mol) is rate-limiting for the acylation reaction and in good agreement with experiment. PMID- 26642986 TI - Investigating Disjoint Non-Kekule Diradicals with Quantum Monte Carlo: The Tetramethyleneethane Molecule through the Jastrow Antisymmetrized Geminal Power Wave Function. AB - Disjoint non-Kekule molecules are diradicals that present two independent radical centers and can violate Hund's rule, according to which the ground state should have triplet spin symmetry. The prototype of this class of systems is the tetramethyleneethane (TME) molecule for which indeed ion photoelectron spectroscopy (IPS) experiments revealed the singlet (1)A state to be more stable than the triplet (3)Bu. In this work we investigate the potential energy curves of the two spin states of TME and of the two anionic states of TME(-) ((2)A and (2)B1) as a function of the torsion of the central dihedral angle, with quantum Monte Carlo methods and a Jastrow Antisymmetrized Geminal Power wave function. Through ab initio geometrical optimizations we study the possible structural interconversions between the states, finding results which are in full agreement with the IPS experimental data. PMID- 26642987 TI - Improving the Accuracy of the Charge Transfer Integrals Obtained by Coupled Cluster Theory, MBPT(2), and TDDFT. AB - Theoretical modeling of the charge transport in organic materials in the diabatic representation requires an accurate evaluation of the charge transfer integrals. In this paper, we show that the coupled cluster and MBPT(2) approaches are the methods of choice for performing the benchmark calculations of this quantity, in contrast to some recently published results. We demonstrate that a proper treatment of the involved ionized states, achieved by applying the continuum orbital strategy, reduces the error of the transfer integrals by one order of magnitude, which in the case of the CC2 method corresponds to a lowering of the mean relative unsigned error (MRUE) from 39.9 to 3.8%. Moreover, we extend the application of the continuum-orbital strategy to the TDDFT method, and show that it leads to a dramatic improvement of the description of ionized states compared to the conventional TDDFT approach, characterized by lowering of MRUE from 209.0 to 24.5%. PMID- 26642988 TI - Heuristics-Guided Exploration of Reaction Mechanisms. AB - For the investigation of chemical reaction networks, the efficient and accurate determination of all relevant intermediates and elementary reactions is mandatory. The complexity of such a network may grow rapidly, in particular if reactive species are involved that might cause a myriad of side reactions. Without automation, a complete investigation of complex reaction mechanisms is tedious and possibly unfeasible. Therefore, only the expected dominant reaction paths of a chemical reaction network (e.g., a catalytic cycle or an enzymatic cascade) are usually explored in practice. Here, we present a computational protocol that constructs such networks in a parallelized and automated manner. Molecular structures of reactive complexes are generated based on heuristic rules derived from conceptual electronic-structure theory and subsequently optimized by quantum-chemical methods to produce stable intermediates of an emerging reaction network. Pairs of intermediates in this network that might be related by an elementary reaction according to some structural similarity measure are then automatically detected and subjected to an automated search for the connecting transition state. The results are visualized as an automatically generated network graph, from which a comprehensive picture of the mechanism of a complex chemical process can be obtained that greatly facilitates the analysis of the whole network. We apply our protocol to the Schrock dinitrogen-fixation catalyst to study alternative pathways of catalytic ammonia production. PMID- 26642989 TI - Assessment of Approximate Coupled-Cluster and Algebraic-Diagrammatic-Construction Methods for Ground- and Excited-State Reaction Paths and the Conical-Intersection Seam of a Retinal-Chromophore Model. AB - As a minimal model of the chromophore of rhodopsin proteins, the penta-2,4 dieniminium cation (PSB3) poses a challenging test system for the assessment of electronic-structure methods for the exploration of ground- and excited-state potential-energy surfaces, the topography of conical intersections, and the dimensionality (topology) of the branching space. Herein, we report on the performance of the approximate linear-response coupled-cluster method of second order (CC2) and the algebraic-diagrammatic-construction scheme of the polarization propagator of second and third orders (ADC(2) and ADC(3)). For the ADC(2) method, we considered both the strict and extended variants (ADC(2)-s and ADC(2)-x). For both CC2 and ADC methods, we also tested the spin-component-scaled (SCS) and spin-opposite-scaled (SOS) variants. We have explored several ground- and excited-state reaction paths, a circular path centered around the S1/S0 surface crossing, and a 2D scan of the potential-energy surfaces along the branching space. We find that the CC2 and ADC methods yield a different dimensionality of the intersection space. While the ADC methods yield a linear intersection topology, we find a conical intersection topology for the CC2 method. We present computational evidence showing that the linear-response CC2 method yields a surface crossing between the reference state and the first response state featuring characteristics that are expected for a true conical intersection. Finally, we test the performance of these methods for the approximate geometry optimization of the S1/S0 minimum-energy conical intersection and compare the geometries with available data from multireference methods. The present study provides new insight into the performance of linear response CC2 and polarization-propagator ADC methods for molecular electronic spectroscopy and applications in computational photochemistry. PMID- 26642990 TI - Electronic Excitations in Solution: The Interplay between State Specific Approaches and a Time-Dependent Density Functional Theory Description. AB - We critically analyze the performances of continuum solvation models when coupled to time-dependent density functional theory (TD-DFT) to predict solvent effects on both absorption and emission energies of chromophores in solution. Different polarization schemes of the polarizable continuum model (PCM), such as linear response (LR) and three different state specific (SS) approaches, are considered and compared. We show the necessity of introducing a SS model in cases where large electron density rearrangements are involved in the excitations, such as charge-transfer transitions in both twisted and quadrupolar compounds, and underline the very delicate interplay between the selected polarization method and the chosen exchange-correlation functional. This interplay originates in the different descriptions of the transition and ground/excited state multipolar moments by the different functionals. As a result, the choice of both the DFT functional and the solvent polarization scheme has to be consistent with the nature of the studied electronic excitation. PMID- 26642991 TI - Multireference Character for 4d Transition Metal-Containing Molecules. AB - Four diagnostic criteria have been examined to identify the suitability of single reference wave function-based quantum chemistry methods for a set of 118 4d transition metal species. These diagnostics include the weight of the leading configuration of the CASSCF wave function, C0(2); the Frobenius norm of the coupled cluster amplitude vector related to single excitations, T1; the matrix 2 norm of the coupled cluster T1 amplitude vector arising from coupled cluster calculations, D1; and the percent total atomization energy, %TAE, corresponding to a relationship between energies determined with CCSD and CCSD(T) calculations. New criteria, namely, T1 >= 0.045, D1 >= 0.120, and %TAE >= 10%, are herein proposed as a gauge for 4d transition metal-containing molecules to predict the possible need to employ multireference (MR) wave function-based methods to describe energetic and spectroscopic properties. PMID- 26642992 TI - Computational Design of Intrinsic Molecular Rectifiers Based on Asymmetric Functionalization of N-Phenylbenzamide. AB - We report a systematic computational search of molecular frameworks for intrinsic rectification of electron transport. The screening of molecular rectifiers includes 52 molecules and conformers spanning over 9 series of structural motifs. N-Phenylbenzamide is found to be a promising framework with both suitable conductance and rectification properties. A targeted screening performed on 30 additional derivatives and conformers of N-phenylbenzamide yielded enhanced rectification based on asymmetric functionalization. We demonstrate that electron donating substituent groups that maintain an asymmetric distribution of charge in the dominant transport channel (e.g., HOMO) enhance rectification by raising the channel closer to the Fermi level. These findings are particularly valuable for the design of molecular assemblies that could ensure directionality of electron transport in a wide range of applications, from molecular electronics to catalytic reactions. PMID- 26642993 TI - Quantum Fragment Based ab Initio Molecular Dynamics for Proteins. AB - Developing ab initio molecular dynamics (AIMD) methods for practical application in protein dynamics is of significant interest. Due to the large size of biomolecules, applying standard quantum chemical methods to compute energies for dynamic simulation is computationally prohibitive. In this work, a fragment based ab initio molecular dynamics approach is presented for practical application in protein dynamics study. In this approach, the energy and forces of the protein are calculated by a recently developed electrostatically embedded generalized molecular fractionation with conjugate caps (EE-GMFCC) method. For simulation in explicit solvent, mechanical embedding is introduced to treat protein interaction with explicit water molecules. This AIMD approach has been applied to MD simulations of a small benchmark protein Trpcage (with 20 residues and 304 atoms) in both the gas phase and in solution. Comparison to the simulation result using the AMBER force field shows that the AIMD gives a more stable protein structure in the simulation, indicating that quantum chemical energy is more reliable. Importantly, the present fragment-based AIMD simulation captures quantum effects including electrostatic polarization and charge transfer that are missing in standard classical MD simulations. The current approach is linear-scaling, trivially parallel, and applicable to performing the AIMD simulation of proteins with a large size. PMID- 26642994 TI - Searching the Sequence Space for Potent Aptamers Using SELEX in Silico. AB - To isolate functional nucleic acids that bind to defined targets with high affinity and specificity, which are known as aptamers, the systematic evolution of ligands by exponential enrichment (SELEX) methodology has emerged as the preferred approach. Here, we propose a computational approach, SELEX in silico, that allows the sequence space to be more thoroughly explored regarding binding of a certain target. Our approach consists of two steps: (i) secondary structure based sequence screening, which aims to collect the sequences that can form a desired RNA motif as an enhanced initial library, followed by (ii) sequence enrichment regarding target binding by molecular dynamics simulation-based virtual screening. Our SELEX in silico method provided a practical computational solution to three key problems in aptamer sequence searching: design of nucleic acid libraries, knowledge of sequence enrichment, and identification of potent aptamers. Six potent theophylline-binding aptamers, which were isolated by SELEX in silico from a sequence space containing 4(13) sequences, were experimentally verified to bind theophylline with high affinity: Kd ranging from 0.16 to 0.52 MUM, compared with the dissociation constant of the original aptamer theophylline, 0.32 MUM. These results demonstrate the significant potential of SELEX in silico as a new method for aptamer discovery and optimization. PMID- 26642995 TI - Prediction of Water Binding to Protein Hydration Sites with a Discrete, Semiexplicit Solvent Model. AB - Buried water molecules are ubiquitous in protein structures and are found at the interface of most protein-ligand complexes. Determining their distribution and thermodynamic effect is a challenging yet important task, of great of practical value for the modeling of biomolecular structures and their interactions. In this study, we present a novel method aimed at the prediction of buried water molecules in protein structures and estimation of their binding free energies. It is based on a semiexplicit, discrete solvation model, which we previously introduced in the context of small molecule hydration. The method is applicable to all macromolecular structures described by a standard all-atom force field, and predicts complete solvent distribution within a single run with modest computational cost. We demonstrate that it indicates positions of buried hydration sites, including those filled by more than one water molecule, and accurately differentiates them from sterically accessible to water but void regions. The obtained estimates of water binding free energies are in fair agreement with reference results determined with the double decoupling method. PMID- 26642996 TI - Correction to Comprehensive Benchmark of Association (Free) Energies of Realistic Host-Guest Complexes. PMID- 26642997 TI - Caesarean hysterectomy for placenta praevia/accreta using an approach via the pouch of Douglas. AB - Placenta praevia/accreta is associated with significant maternal morbidity and mortality and is a common cause of obstetric hysterectomy. This paper describes posterior retrograde abdominal hysterectomy, a new surgical technique for caesarean hysterectomy, in 11 women with placenta percreta, increta or accreta There were no intraoperative or postoperative maternal complications, and only one fetus required admission to the neonatal unit, for prematurity. Our technique in placenta praevia/accreta allows easy identification of the vagina and early uterine devascularisation, as well as safe resection of the involved urinary bladder in women with placenta percreta showing bladder penetration. Analytical studies are needed to confirm our findings. TWEETABLE ABSTRACT: Posterior retrograde abdominal hysterectomy in women with placenta praevia/accreta may enable safer surgery. PMID- 26642998 TI - Capitate glandular trichomes in Aldama discolor (Heliantheae - Asteraceae): morphology, metabolite profile and sesquiterpene biosynthesis. AB - The capitate glandular trichome is the most common type described in Asteraceae species. It is known for its ability to produce various plant metabolites of ecological and economic importance, among which sesquiterpene lactones are predominant. In this paper, we applied microscopy, phytochemical and molecular genetics techniques to characterise the capitate glandular trichome in Aldama discolor, a native Brazilian species of Asteraceae, with pharmacological potential. It was found that formation of trichomes on leaf primordia of germinating seeds starts between 24 h and 48 h after radicle growth indicates germination. The start of metabolic activity of trichomes was indicated by separation of the cuticle from the cell wall of secretory cells at the trichome tip after 72 h. This coincided with the accumulation of budlein A, the major sesquiterpene lactone of A. discolor capitate glandular trichomes, in extracts of leaf primordia after 96 h. In the same timeframe of 72-96 h post-germination, gene expression studies showed up-regulation of the putative germacrene A synthase (pGAS2) and putative germacrene A oxidase (pGAO) of A. discolor in the transcriptome of these samples, indicating the start of sesquiterpene lactone biosynthesis. Sequencing of the two genes revealed high similarity to HaGAS and HaGAO from sunflower, which shows that key steps of this pathway are highly conserved. The processes of trichome differentiation, metabolic activity and genetic regulation in A. discolor and in sunflower appear to be typical for other species of the subtribe Helianthinae. PMID- 26642999 TI - Aspiration Thrombectomy in Patients Undergoing Primary Angioplasty for ST Elevation Myocardial Infarction: An Updated Meta-Analysis. AB - BACKGROUND: The Trial of Routine Aspiration Thrombectomy with PCI versus PCI alone in patients with STEMI (TOTAL trial) refuted the salutary effect of routine aspiration thrombectomy (AT) in PPCI for patients with ST-elevation myocardial infarction (STEMI). OBJECTIVES: We performed an updated meta-analysis to assess clinical outcomes with AT prior to PPCI compared with conventional PPCI alone including the additional trial data. METHODS AND RESULTS: Clinical trials (n = 20) that randomized patients (n = 21,281) with STEMI between Routine AT (n = 10,619) and PPCI (n = 10,662) were pooled. There was no difference in all-cause mortality between the 2 groups (RR: 0.89, 95%CI: 0.78-1.01, P = 0.08). Stratifying by follow up at 1-month (RR: 0.87, 95%CI: 0.69-1.10, P = 0.25), up to 6 months (RR: 0.91, 95%CI: 0.74-1.13, P = 0.39 and beyond 6 months (RR: 0.88, 95%CI: 0.74-1.05, P = 0.16) yielded similar results. There was a statistically significant increase risk of stoke rate in the AT arm (RR: 1.51, 95%CI: 1.01 2.25, P = 0.04). The 2 groups were similar with regards to target vessel revascularization (0.94, 95%CI: 0.83-1.06, P = 0.28) recurrent MI (RR: 0.96, 95%CI: 0.80-1.16, P = 0.68, MACE events (RR: 0.91 95%CI: 0.81-1.02, P = 0.11), early (0.59, 95%CI: 0.23-1.50, P = 0.27) and late (RR: 0.91, 95%CI: 0.69-1.18, P = 0.47) stent thrombosis and net clinical benefit (RR 0.99, 95%CI: 0.91-1.07, P = 0.76). CONCLUSION: Routine AT prior to PPCI in STEMI is associated with higher risk of stroke. There is no statistical difference in clinical outcome parameters of mortality, major adverse cardiac events, target vessel revascularization, stent thrombosis, and net clinical benefit between AT and PCI alone. PMID- 26643000 TI - Recurrent Myocardial Infarction After Primary Percutaneous Coronary Intervention in Multivessel Coronary Disease Is Primarily Related to Stent Failure: Post-Hoc Analysis of the PASSION Trial. AB - OBJECTIVES: Our aim was to investigate the risk of events related to non-culprit lesions after primary percutaneous coronary intervention (PCI) in patients with multivessel coronary disease (MVD). BACKGROUND: In patients undergoing primary PCI for ST-elevation myocardial infarction (STEMI) who are diagnosed with MVD, the optimal treatment strategy is currently under debate. Although observational data exposed an increased risk of multivessel PCI in the acute phase of STEMI, 2 recently published randomized controlled trials showed a reduction of death or recurrent myocardial infarction (MI) after preventive PCI of non-culprit lesions when compared with culprit-lesion PCI only. METHODS: We performed a post-hoc analysis of 279 patients with MVD included in the Paclitaxel-Eluting Stent versus Conventional Stent in Myocardial Infarction with ST-Segment Elevation (PASSION) trial. We analyzed the incidence and cause of recurrent MI. Recurrent MI due to stent failure was assumed in the event of definite or probable stent thrombosis. RESULTS: After 5 years, 14 patients (5.7%) with MVD had a recurrent MI versus 17 (5.4%) patients with 1-vessel disease (HR 1.06, 95%CI 0.52-2.15, P = 0.87). The majority of events was attributable to stent failure, while of the remaining 6 events, only 1 was proven to originate from a lesion that was judged significant at enrolment. CONCLUSIONS: In this post-hoc analysis of the PASSION trial, recurrent MI in patients with MVD was mainly related to stent failure rather than a new event originating from a significant stenosis in a non-culprit coronary artery. PMID- 26643001 TI - Low On-Treatment Platelet Reactivity Predicts Long-Term Risk of Bleeding After Elective PCI. AB - BACKGROUND: Bleeding after percutaneous coronary interventions (PCI) is an important complication with impact on prognosis. AIM: To evaluate the predictive value of enhanced platelet responsiveness to dual antiplatelet therapy with aspirin and clopidogrel, for bleeding, after elective PCI. METHODS AND RESULTS: We performed multiple electrode aggregometry (MAE) platelet functional tests induced by arachidonic acid (ASPI) and adenosine-diphosphate (ADP) before PCI, and 24 hours after PCI, in 481 elective PCI patients who were followed-up for an average of 15.34 +/- 7.19 months. Primary end point was the occurrence of any bleeding, while ischemic major adverse cardiovascular event (MACE) was a secondary endpoint. The incidence of total, BARC <= 2, and BARC >= 3 bleeding, according to BARC classification, was 19, 18, and 1%, respectively. Groups with any, and BARC <= 2 bleeding, had a lower average value of MAE ADP test after 24 hours, compared to the group without bleeding: 45.30 +/- 18.63 U versus 50.99 +/- 19.01 U; P = 0.005; and 45.75 +/- 18.96 U versus 50.99 +/- 18.99 U; P = 0.01; respectively. Female gender (HR 2.11; CI 1.37-3.25; P = 0.001), previous myocardial infarction (HR 0.56; CI 0.37-0.85; P = 0.006), lower body mass (HR 0.78; CI 0.62-0.98; P = 0.03), and MAE ADP test after 24 hours (HR 0.75; CI 0.61 0.93; P = 0.009) were the independent predictors for any bleeding by Cox univariate analysis. After adjustment, MAE ADP test after 24 hours, was the only independent predictor for any (HR 0.7; CI 0.56-0.87; P = 0.002), and BARC <= 2 (HR 0.71; CI 0.56-0.89; P = 0.003) bleeding, by Cox multivariate analysis. CONCLUSION: MAE ADP test before and after PCI, was associated with any, and BARC <= 2 bleeding after elective PCI. PMID- 26643002 TI - Practical Usefulness of Dual Lumen Catheter-Facilitated Reverse Wire Technique for Markedly Angulated Bifurcated Lesions. AB - OBJECTIVES: This study aimed to investigate the practical usefulness of dual lumen catheter-facilitated reverse wire technique. BACKGROUND: We sometimes encounter difficulty in introducing a guidewire to the highly angulated side branch. In those cases, the reverse wire technique is considered as a last resort to overcome the situation. METHODS: Between January 2013 and June 2015, we performed the reverse wire technique for guidewire crossing into an extremely angulated side branch in consecutive seven cases with true bifurcated lesions. We retrospectively evaluated patients' backgrounds, lesion characteristics, and details of the percutaneous coronary intervention (PCI) procedures. RESULTS: Three interventional cardiologists with various levels of experience in coronary intervention performed this technique. A polymer-jacket hydrophilic-coated guidewire was used for the reverse wire system excluding in one case, and we adopted a sharp curve for the tip shape in all cases. After crossing the reverse wire into a highly angulated side branch, we usually deliver a flexible micro catheter over the guidewire for the purpose of guidewire exchange. We deployed a stent in the side branch in three cases. We successfully performed all PCI procedures without any complications and no major adverse cardiac event was observed during hospitalization. CONCLUSIONS: We could safely and effectively perform the reverse wire technique for guidewire crossing into a markedly angulated side branch. We recommend a polymer-jacket hydrophilic-coated guidewire with a sharp curve in the tip shape for this technique. All interventional cardiologists should acquire knowledge and skills regarding this guidewire manipulation technique. PMID- 26643003 TI - Percutaneous Coronary Interventions and Hemodynamic Support in the USA: A 5 Year Experience. AB - OBJECTIVES: To compare the utilization and outcomes in patients who had percutaneous coronary interventions (PCIs) performed with intra-aortic balloon pump (IABP) versus percutaneous ventricular assist devices (PVADs) such as Impella and TandemHeart and identify a sub-group of patient population who may derive the most benefit from the use of PVADs over IABP. BACKGROUND: Despite the lack of clear benefit, the use of PVADs has increased substantially in the last decade when compared to IABP. METHODS: We performed a cross sectional study including using the Nationwide Inpatient Sample. Procedures performed with hemodynamic support were identified through appropriate ICD-9-CM codes. RESULTS: We identified 18,094 PCIs performed with hemodynamic support. IABP was the most commonly utilized hemodynamic support device (93%, n = 16, 803) whereas 6% (n = 1069) were performed with PVADs and 1% (n = 222) utilized both IABP and PVAD. Patients in the PVAD group were older in age and had greater burden of co morbidities whereas IABP group had higher percentage of patients with cardiac arrest. On multivariable analysis, the use of PVAD was a significant predictor of reduced mortality (OR 0.55, 0.36-0.83, P = 0.004). This was particularly evident in sub-group of patients without acute MI or cardiogenic shock. The propensity score matched analysis also showed a significantly lower mortality (9.9% vs 15.1%; OR 0.62, 0.55-0.71, P < 0.001) rate associated with PVADs when compared to IABP. CONCLUSION: This largest and the most contemporary study on the use of hemodynamic support demonstrates significantly reduced mortality with PVADs when compared to IABP in patients undergoing PCI. The results are largely driven by the improved outcomes in non-AMI and non-cardiogenic shock patients. PMID- 26643004 TI - Real Time Intraprocedural Ultrasound Measurements of the Radial and Ulnar Arteries in 565 Consecutive Patients Undergoing Cardiac Catheterization and/or Percutaneous Coronary Intervention via the Wrist: Understanding Anatomy and Anomalies May Improve Access Success. AB - OBJECTIVES: Ultrasound evaluation of both the radial artery (RA) and ulnar artery (UA) in patients undergoing cardiac catheterization/percutaneous coronary intervention. BACKGROUND: Arterial access from the wrist is almost exclusively obtained from the RA. Crossover to secondary femoral arterial access was observed in up to 7.6% in randomized multicenter trials utilizing palpation guided RA access. METHODS: Intraprocedural ultrasound evaluation of the RA and UA was performed in a consecutive series of patients. A difference of >=20% in diameter was defined as significant. In the case of a dual artery, measurements of the dual arteries and the proximal confluens were obtained. RESULTS: A total of 566 RA/UA measurements were analysed (patients: n = 565, female: n = 201 [35.5%], mean age: 66.5 years). Overall, the RA measured 3.03 +/- 0.57 mm and the UA 2.70 +/- 0.57 mm (P < 0.01). The RA was larger in 210 (37.1%) and the UA in 37 (6.5%) measurements. A dual RA was present in 25 (4.4%) measurements. The mean diameters of the smaller and larger of the dual RAs were 1.82 +/- 0.37 and 2.59 +/- 0.36 mm (P < 0.01). The corresponding proximal confluens measured 3.10 +/- 0.40 mm. No dual UA was observed. CONCLUSION: In 10.9 % of patients, a larger UA or a dual RA with a more accessible confluens was observed. This information can only be obtained using ultrasound and may improve arterial access from the wrist if the larger UA or RA confluens is accessed instead of blind palpation guided RA access. PMID- 26643005 TI - Benefits of Balloon-Dilatable Bilateral Pulmonary Artery Banding in Patients With Hypoplastic Left Heart Syndrome and Other Complex Cardiac Anomalies. AB - OBJECTIVES: The purpose of this study was to evaluate the potential of balloon dilatable bilateral pulmonary artery banding (b-PAB) and its impact on the configuration of the pulmonary artery (PA). BACKGROUND: We have previously used balloon-dilatable b-PAB as first-stage palliation for patients with hypoplastic left heart syndrome (HLHS) and other complex cardiac anomalies. METHODS: Two pliable tapes were placed around each branch of the PA and tightened with 7-0 polypropylene sutures in a manner that allowed for the subsequent adjustment of PA diameters. We retrospectively examined the adjustability of PA diameters by balloon dilation and the need for surgical PA angioplasty at later stages. RESULTS: From January 2010 to October 2013, we performed b-PAB in 8 patients, including 3 borderline cases between biventricular repair (BVR) and univentricular repair (UVR). The b-PAB procedures were performed at a median age of 6.5 days (range, 2-10 days). Balloon dilations were performed in 10 lesions in 4 patients. All of the procedures were performed safely. Two patients reached definite BVR. The remaining 6 patients underwent open palliative procedures with univentricular physiologies that resulted in 2 deaths unrelated to the initial b PAB. In all but 1 of the patients, the PA configuration was properly maintained and did not require surgical pulmonary angioplasty. CONCLUSIONS: Balloon dilatable b-PAB can be performed safely and prevents PA distortion at later stages. This technique should be considered for patients with complex cardiac anomalies if uncertainty exists regarding the optimal surgical strategy (BVR or UVR) in early infancy. PMID- 26643006 TI - Recurrent and Residual Shunts After Patent Foramen Ovale Closure: Results From a Long-Term Transcranial Doppler Study. AB - OBJECTIVES: Assess the evolution of right-to-left shunt (RLS) after transcatheter patent foramen ovale (PFO) closure. BACKGROUND: Despite the high number of interventional procedures performed worldwide, limited systematic data on the long-term abolition of RLS after percutaneous closure are available. METHODS: All patients treated at our Institution between February 2001 and July 2009 were included in this single center, prospective study, and were asked to repeat late contrast transcranial Doppler (cTCD). Rate of complete closure, residual RLS (i.e., a shunt that persists after closure), and recurrent RLS (i.e., a shunt that reappears after a previous negative cTCD) was assessed. RESULTS: Long-term follow-up was completed in 120 patients (56% male). RLS was still detectable 4.9 +/- 2.3 years (range 1.3-10.3) after the procedure in 55 patients; 20 (17%) had residual RLS and 35 (29%) had recurrent RLS. Multivariate analysis revealed that significant predictors of residual RLS included post-procedural shunt at transesophageal echocardiography (OR 3.07, 95%CI 0.97-9.7), use of a bigger device (35 vs 25 mm, OR 3.85, 95%CI 1.22-12.2) and length of follow-up (OR 0.75, 95%CI 0.57-0.98), while only length of follow-up (OR 0.77, 95%CI 0.62-0.95) was associated with recurrent RLS. Neurological recurrences (1 stroke, 6 transient ischemic attacks) were equally distributed between the groups. CONCLUSION: A significant number of recurrent and residual shunts may be observed by cTCD up to 5 years after PFO closure. Management of late RLSs includes periodic re evaluation, exclusion of device-induced complications or secondary sources of RLS, and optimization of antithrombotic treatment with or without a second intervention. PMID- 26643007 TI - Severe Dorsal Hand Laceration Secondary to Compartment Syndrome Following Transradial Coronary Intervention. PMID- 26643008 TI - "Treatment of Small Vessel Disease With the Paclitaxel Drug-Eluting Balloon" Is the Target Lesion the Culprit One? PMID- 26643009 TI - The trout farm effect on Dinocras megacephala (Plecoptera: Perlidae) larvae: Antioxidative defense. AB - Trout production represents a major agricultural activity in Serbia. Organic compounds are drained into the environment, usually without previous sedimentation, thus affecting the stream biota. Considering that biological monitoring is commonly based on aquatic macroinvertebrates as target organisms, the authors used larvae of Dinocras megacephala to estimate trout farm effects on the mass of the larvae and their antioxidative defense in pollution stress conditions. Four locations were chosen along the channel of the Raska River, 2 upstream (L1, L2) and 2 downstream (L3, L4) from the trout farm outlet. Basic physical and chemical water parameters were measured. Superoxide dismutase (SOD) and catalase (CAT) activity changes were analyzed to determine the level of oxidative stress caused by the increase of organic compounds originating from the trout farm. Dissolved oxygen concentration decreased from the upstream to downstream locations. Furthermore, the concentration of ionized ammonia was almost 10 times higher at the downstream locations than at the upstream locations. Larval mass, as well as CAT activity, was significantly higher at L3 compared with the other 3 locations. Activity of SOD was significantly higher at L3 than at L1. The results indicate that higher concentrations of organic compounds from the trout farm induce clear changes in the status of the antioxidant defense of D. megacephala larvae. Environ Toxicol Chem 2016;35:1775 1782. (c) 2015 SETAC. PMID- 26643010 TI - Electromagnetic Contact-Force Sensing Electrophysiological Catheters: How Accurate is the Technology? AB - BACKGROUND: Contact-force (CF) sensing catheters are increasingly used in clinical electrophysiological practice due to their efficacy and safety profile. As data about the accuracy of this technology are scarce, we sought to quantify accuracy based on in vitro experiments. METHODS AND RESULTS: A custom-made force sensor was constructed that allowed exact force reference measurements registered via a flexible membrane. A Smarttouch Surround Flow (ST SF) ablation catheter (Biosense Webster, Diamond Bar, CA, USA) was brought in contact with the membrane of the force sensor in order to compare the ST SF force measurements to force sensor reference measurements. ST SF force sensing technology is based on deflection registration between the distal and proximal catheter tip. The experiment was repeated for n = 10 ST SF catheters, which showed no significant difference in accuracy levels. A series of measurements (n = 1200) was carried out for different angles of force acting to the catheter tip (0 degrees /perpendicular contact, 30 degrees , 60 degrees , 90 degrees /parallel contact). The mean absolute differences between reference and ST SF measurements were 1.7 +/- 1.8 g (0 degrees ), 1.6 +/- 1.2 g (30 degrees ), 1.4 +/- 1.3 g (60 degrees ), and 6.6 +/- 5.9 g (90 degrees ). Measurement accuracy was significantly higher in non-parallel contact when compared with parallel contact (P < 0.01). CONCLUSIONS: Catheter force measurements using the ST SF catheters show a high level of accuracy regarding differences to reference measurements and reproducibility. The reduced accuracy in measurements of 90 degrees acting forces (parallel contact) might be clinically important when creating, for example, linear lesions. PMID- 26643011 TI - Histopathological features of intra-ductal carcinoma of prostatic and high grade prostatic intraepithelialneoplasia and correlation with PTEN and P63. AB - BACKGROUND: The main morphologic differential diagnosis of intra-ductal carcinoma of prostate (IDC-P) is high grade prostatic intraepithelialneoplasia (HGPIN). Since IDC-P, unlike PIN, was strongly correlated with aggressive prostate cancer, differentiation of these is too necessary. So we evaluated immunohistopathological patterns and the prognostic factors of IDC-P and HGPIN, in radical prostatectomy samples. METHODS: We evaluated 250 radical prostatectomy and detected 210 cases of prostatic adenocarcinoma without IDC-P foci, 40 cases with adenocarcinoma concomitant IDC-P, and 40 cases HGPIN; therefore, we evaluated immunohistopathological criteria in these groups. Data were analyzed using SPSS and P-value <0.05 was considered as the statistical significant level. RESULTS: PSA level was significantly higher in IDC-P compared with non-IDC-P patients (15.7 +/- 3.1 vs. 10.2 +/- 4.3, P = 0.041). All pathological and morphologic features, also invasions factors were higher in IDC-P compared to non IDC-P groups (P < 0.001). P63 was positive expressed in all IDC-P and HGPIN specimen. PTEN protein was diffusely expressed in the cytoplasm of all HGPIN but in 4 (11.1%) of IDC-P. PTEN and P63 were negative in adenocarcinoma foci. CONCLUSION: We found that IDC-P had a unique histoclinical feature and was strongly associated with poor prognostic factors. Diagnosis and report of IDC-P should be considered in all prostate specimens. Also, we recommend PTEN IHC application for differentiated IDC-P from HGPIN in biopsies. PMID- 26643013 TI - An empirical analysis of Moscovitch's reconceptualised model of social anxiety: How is it different from fear of negative evaluation? AB - Cognitive-behavioural models propose that excessive fear of negative evaluation is central to social anxiety. Moscovitch (2009) instead proposes that perceived deficiencies in three self attributes: fears of showing signs of anxiety, deficits in physical appearance, or deficits in social competence are at the core of social anxiety. However, these attributes are likely to overlap with fear of negative evaluation. Responses to an online survey of 286 participants with a range of social anxiety severity were analysed using hierarchical multiple regression to identify the overall unique predictive value of Moscovitch's model. Altogether, Moscovitch's model provided improvements in the prediction of safety behaviours, types of fears and cognitions; however only the fear of showing anxiety subscale provided unique information. This research supports further investigations into the utility of this revised model, particularly related to utility of explicitly assessing and addressing fears of showing anxiety. PMID- 26643012 TI - Continuous event monitoring via a Bayesian predictive approach. AB - In clinical trials, continuous monitoring of event incidence rate plays a critical role in making timely decisions affecting trial outcome. For example, continuous monitoring of adverse events protects the safety of trial participants, while continuous monitoring of efficacy events helps identify early signals of efficacy or futility. Because the endpoint of interest is often the event incidence associated with a given length of treatment duration (e.g., incidence proportion of an adverse event with 2 years of dosing), assessing the event proportion before reaching the intended treatment duration becomes challenging, especially when the event onset profile evolves over time with accumulated exposure. In particular, in the earlier part of the study, ignoring censored subjects may result in significant bias in estimating the cumulative event incidence rate. Such a problem is addressed using a predictive approach in the Bayesian framework. In the proposed approach, experts' prior knowledge about both the frequency and timing of the event occurrence is combined with observed data. More specifically, during any interim look, each event-free subject will be counted with a probability that is derived using prior knowledge. The proposed approach is particularly useful in early stage studies for signal detection based on limited information. But it can also be used as a tool for safety monitoring (e.g., data monitoring committee) during later stage trials. Application of the approach is illustrated using a case study where the incidence rate of an adverse event is continuously monitored during an Alzheimer's disease clinical trial. The performance of the proposed approach is also assessed and compared with other Bayesian and frequentist methods via simulation. PMID- 26643014 TI - Catatonia in 26 patients with bipolar disorder: clinical features and response to electroconvulsive therapy. AB - OBJECTIVES: We describe the clinical characteristics and short-term outcomes of a sample of inpatients with bipolar disorder with severe catatonic features resistant to pharmacological treatment. METHODS: The study involved 26 catatonic patients, resistant to a trial of benzodiazepines, and then treated with electroconvulsive therapy (ECT). All patients were evaluated prior to and one week following the ECT course using the Bush-Francis Catatonia Rating Scale (BFCRS) and the Clinical Global Impression (CGI). RESULTS: In our sample, women were over-represented (n = 23, 88.5%), the mean (+/- standard deviation) age was 49.5 +/- 12.5 years, the mean age at onset was 28.1 +/- 12.8 years, and the mean number of previous mood episodes was 5.3 +/- 2.9. The mean duration of catatonic symptoms was 16.7 +/- 11.8 (range: 3-50) weeks, and personal history of previous catatonic episodes was present in 10 patients (38.5%). Seventeen (65.4%) patients showed abnormalities at cerebral computerized tomography and/or magnetic resonance imaging and neurological comorbidities were observed in 15.4% of the sample. Stupor, rigidity, staring, negativism, withdrawal, and mutism were observed in more than 90% of patients. At the end of the ECT course, 21 patients (80.8%) were classified as responders. The BFCRS showed the largest percentage of improvement, with an 82% reduction of the initial score. The number of previous mood episodes was significantly lower and the use of anticholinergic and dopamine agonist medications was significantly more frequent in non-responders than in responders. CONCLUSIONS: Our patients with bipolar disorder had predominantly retarded catatonia, frequent previous catatonic episodes, indicating a recurrent course, and high rates of concomitant brain structure alterations. However, ECT was a very effective treatment for catatonia in this patient group that was resistant to benzodiazepines. PMID- 26643015 TI - Mortality risk in a cohort of Italian alcoholic individuals treated for alcohol dependence. AB - INTRODUCTION AND AIMS: The aim of this study was to investigate the mortality risk and to explore the presence of subjects more at risk of dying in a cohort of alcoholic individuals treated for alcohol dependence over a lengthy follow-up period. DESIGN AND METHODS: A total of 2363 subjects attending 10 centres for addiction treatment for alcohol dependence were recruited. RESULTS: During the 17 year follow-up period, 14.7% of the entire cohort died. Total standardised mortality rates (SMR) were higher in women (SMR = 5.94) as compared with men (SMR = 4.65). Higher SMRs were found for several diseases, for traumatic episodes (SMR = 6.65) and in younger patients (18-44 age group) (SMR = 8.16). Alcoholic women showed a higher survival rate as compared with men. In addition, a higher risk of death for men and unemployed subjects, with a progressive increase of risk in line with the increase of the age of admission to treatment, and with a progressive decrease of risk after 1 year from the beginning of the treatment, was also found. DISCUSSION AND CONCLUSIONS: This study confirms that mortality risk in alcoholic individuals in treatment is higher in comparison with the general population. Moreover, alcoholics men, unemployed, >40 years at time of admission and during the first year of treatment are more at risk to die. Thus, much more attention to patients with these characteristics should be planned by the professional staff working in centres for addiction treatment. [ Pavarin R M, Caputo F, Zoli G, Domenicali M, Bernardi M, Gambini D. Mortality risk in a cohort of Italian alcoholic individuals treated for alcohol dependence Drug Alcohol Rev 2017;36:186-191]. PMID- 26643016 TI - Efficacy of PD-1 blockade in tumors with MMR deficiency. PMID- 26643017 TI - Synthesis, in Vitro, and in Vivo Biological Evaluation and Molecular Docking Analysis of Novel 3-(3-oxo-substitutedphenyl-3-)4-(2 (piperidinyl)ethoxy)phenyl)propyl)-2H-chromen-2-one Derivatives as Anti-breast Cancer Agents. AB - The analogs of coumarin-chalcones have been reported to exhibit antineoplastic, anti-allergic, antihepatoprotective, and estrogenic activity. Herein, we have reported 3-(3-oxo-substitutedphenyl-3-)4-(2-(piperidinyl)ethoxy)phenyl)propyl)-2H chromen-2-one derivatives as a new class of compounds that exhibit selectivity for ER-alpha binding along with antiproliferative and cytotoxic activity on human breast cancer cell line. The active compounds which show prominent activity against estrogen receptor-alpha-positive (ER+) human breast cancer cell lines MCF 7 and Zr-75-1 are subjected to in vivo screening. The Glide XP docking was performed for designed scaffold to optimize its structural requirement for ER alpha inhibition. PMID- 26643018 TI - Viral Vectors for Gene Therapy: Translational and Clinical Outlook. AB - In a range of human trials, viral vectors have emerged as safe and effective delivery vehicles for clinical gene therapy, particularly for monogenic recessive disorders, but there has also been early work on some idiopathic diseases. These successes have been enabled by research and development efforts focusing on vectors that combine low genotoxicity and immunogenicity with highly efficient delivery, including vehicles based on adeno-associated virus and lentivirus, which are increasingly enabling clinical success. However, numerous delivery challenges must be overcome to extend this success to many diseases; these challenges include developing techniques to evade preexisting immunity, to ensure more efficient transduction of therapeutically relevant cell types, to target delivery, and to ensure genomic maintenance. Fortunately, vector-engineering efforts are demonstrating promise in the development of next-generation gene therapy vectors that can overcome these barriers. This review highlights key historical trends in clinical gene therapy, the recent clinical successes of viral-based gene therapy, and current research that may enable future clinical application. PMID- 26643019 TI - Digital Microfluidic Cell Culture. AB - Digital microfluidics (DMF) is a droplet-based liquid-handling technology that has recently become popular for cell culture and analysis. In DMF, picoliter- to microliter-sized droplets are manipulated on a planar surface using electric fields, thus enabling software-reconfigurable operations on individual droplets, such as move, merge, split, and dispense from reservoirs. Using this technique, multistep cell-based processes can be carried out using simple and compact instrumentation, making DMF an attractive platform for eventual integration into routine biology workflows. In this review, we summarize the state-of-the-art in DMF cell culture, and describe design considerations, types of DMF cell culture, and cell-based applications of DMF. PMID- 26643022 TI - Biological Soft Robotics. AB - In nature, nanometer-scale molecular motors are used to generate force within cells for diverse processes from transcription and transport to muscle contraction. This adaptability and scalability across wide temporal, spatial, and force regimes have spurred the development of biological soft robotic systems that seek to mimic and extend these capabilities. This review describes how molecular motors are hierarchically organized into larger-scale structures in order to provide a basic understanding of how these systems work in nature and the complexity and functionality we hope to replicate in biological soft robotics. These span the subcellular scale to macroscale, and this article focuses on the integration of biological components with synthetic materials, coupled with bioinspired robotic design. Key examples include nanoscale molecular motor-powered actuators, microscale bacteria-controlled devices, and macroscale muscle-powered robots that grasp, walk, and swim. Finally, the current challenges and future opportunities in the field are addressed. PMID- 26643023 TI - Image-Based Predictive Modeling of Heart Mechanics. AB - Personalized biophysical modeling of the heart is a useful approach for noninvasively analyzing and predicting in vivo cardiac mechanics. Three main developments support this style of analysis: state-of-the-art cardiac imaging technologies, modern computational infrastructure, and advanced mathematical modeling techniques. In vivo measurements of cardiac structure and function can be integrated using sophisticated computational methods to investigate mechanisms of myocardial function and dysfunction, and can aid in clinical diagnosis and developing personalized treatment. In this article, we review the state-of-the art in cardiac imaging modalities, model-based interpretation of 3D images of cardiac structure and function, and recent advances in modeling that allow personalized predictions of heart mechanics. We discuss how using such image based modeling frameworks can increase the understanding of the fundamental biophysics behind cardiac mechanics, and assist with diagnosis, surgical guidance, and treatment planning. Addressing the challenges in this field will require a coordinated effort from both the clinical-imaging and modeling communities. We also discuss future directions that can be taken to bridge the gap between basic science and clinical translation. PMID- 26643020 TI - The Mechanobiology of Aging. AB - Aging is a complex, multifaceted process that induces a myriad of physiological changes over an extended period of time. Aging is accompanied by major biochemical and biomechanical changes at macroscopic and microscopic length scales that affect not only tissues and organs but also cells and subcellular organelles. These changes include transcriptional and epigenetic modifications; changes in energy production within mitochondria; and alterations in the overall mechanics of cells, their nuclei, and their surrounding extracellular matrix. In addition, aging influences the ability of cells to sense changes in extracellular matrix compliance (mechanosensation) and to transduce these changes into biochemical signals (mechanotransduction). Moreover, following a complex positive feedback loop, aging is accompanied by changes in the composition and structure of the extracellular matrix, resulting in changes in the mechanics of connective tissues in older individuals. Consequently, these progressive dysfunctions facilitate many human pathologies and deficits that are associated with aging, including cardiovascular, musculoskeletal, and neurodegenerative disorders and diseases. Here, we critically review recent work highlighting some of the primary biophysical changes occurring in cells and tissues that accompany the aging process. PMID- 26643021 TI - Synergizing Engineering and Biology to Treat and Model Skeletal Muscle Injury and Disease. AB - Although skeletal muscle is one of the most regenerative organs in our body, various genetic defects, alterations in extrinsic signaling, or substantial tissue damage can impair muscle function and the capacity for self-repair. The diversity and complexity of muscle disorders have attracted much interest from both cell biologists and, more recently, bioengineers, leading to concentrated efforts to better understand muscle pathology and develop more efficient therapies. This review describes the biological underpinnings of muscle development, repair, and disease, and discusses recent bioengineering efforts to design and control myomimetic environments, both to study muscle biology and function and to aid in the development of new drug, cell, and gene therapies for muscle disorders. The synergy between engineering-aided biological discovery and biology-inspired engineering solutions will be the path forward for translating laboratory results into clinical practice. PMID- 26643025 TI - Hamiltonian Systems and Optimal Control in Computational Anatomy: 100 Years Since D'Arcy Thompson. AB - The Computational Anatomy project is the morphome-scale study of shape and form, which we model as an orbit under diffeomorphic group action. Metric comparison calculates the geodesic length of the diffeomorphic flow connecting one form to another. Geodesic connection provides a positioning system for coordinatizing the forms and positioning their associated functional information. This article reviews progress since the Euler-Lagrange characterization of the geodesics a decade ago. Geodesic positioning is posed as a series of problems in Hamiltonian control, which emphasize the key reduction from the Eulerian momentum with dimension of the flow of the group, to the parametric coordinates appropriate to the dimension of the submanifolds being positioned. The Hamiltonian viewpoint provides important extensions of the core setting to new, object-informed positioning systems. Several submanifold mapping problems are discussed as they apply to metamorphosis, multiple shape spaces, and longitudinal time series studies of growth and atrophy via shape splines. PMID- 26643026 TI - Inflammatory myofibroblastic tumor-like stromal proliferation within gastric inverted hyperplastic polyp. PMID- 26643024 TI - Positron Emission Tomography: Current Challenges and Opportunities for Technological Advances in Clinical and Preclinical Imaging Systems. AB - Positron emission tomography (PET) imaging is based on detecting two time coincident high-energy photons from the emission of a positron-emitting radioisotope. The physics of the emission, and the detection of the coincident photons, give PET imaging unique capabilities for both very high sensitivity and accurate estimation of the in vivo concentration of the radiotracer. PET imaging has been widely adopted as an important clinical modality for oncological, cardiovascular, and neurological applications. PET imaging has also become an important tool in preclinical studies, particularly for investigating murine models of disease and other small-animal models. However, there are several challenges to using PET imaging systems. These include the fundamental trade-offs between resolution and noise, the quantitative accuracy of the measurements, and integration with X-ray computed tomography and magnetic resonance imaging. In this article, we review how researchers and industry are addressing these challenges. PMID- 26643027 TI - The Effects of Expressing Religious Support Online for Breast Cancer Patients. AB - The growth of online support groups has led to an expression effects paradigm within the health communication literature. Although religious support expression is characterized as a typical subdimension of emotional support, we argue that in the context of a life-threatening illness, the inclusion of a religious component creates a unique communication process. Using data from an online group for women with breast cancer, we test a theoretical expression effects model. Results demonstrate that for breast cancer patients, religious support expression has distinct effects from general emotional support messages, which highlights the need to further theorize expression effects along these lines. PMID- 26643028 TI - Dynamic drag force based on iterative density mapping: A new numerical tool for three-dimensional analysis of particle trajectories in a dielectrophoretic system. AB - Dielectrophoresis is a widely used means of manipulating suspended particles within microfluidic systems. In order to efficiently design such systems for a desired application, various numerical methods exist that enable particle trajectory plotting in two or three dimensions based on the interplay of hydrodynamic and dielectrophoretic forces. While various models are described in the literature, few are capable of modeling interactions between particles as well as their surrounding environment as these interactions are complex, multifaceted, and computationally expensive to the point of being prohibitive when considering a large number of particles. In this paper, we present a numerical model designed to enable spatial analysis of the physical effects exerted upon particles within microfluidic systems employing dielectrophoresis. The model presents a means of approximating the effects of the presence of large numbers of particles through dynamically adjusting hydrodynamic drag force based on particle density, thereby introducing a measure of emulated particle-particle and particle-liquid interactions. This model is referred to as "dynamic drag force based on iterative density mapping." The resultant numerical model is used to simulate and predict particle trajectory and velocity profiles within a microfluidic system incorporating curved dielectrophoretic microelectrodes. The simulated data are compared favorably with experimental data gathered using microparticle image velocimetry, and is contrasted against simulated data generated using traditional "effective moment Stokes-drag method," showing more accurate particle velocity profiles for areas of high particle density. PMID- 26643029 TI - Incarcerated women's relationship-based strategies to avoid drug use after community re-entry. AB - While recent research has stressed the supportive role that family and friends play for incarcerated persons as they re-enter the community, drug-using incarcerated women re-entering the community often have to rely on family, community, and intimate relationships that have played a role in their substance abuse and criminalization. In this study the authors conducted qualitative analysis of clinical sessions with rural, drug-using women (N = 20) in a larger prison-based HIV risk reduction intervention in Kentucky during 2012-2014 to examine incarcerated women's perceptions of the role of their family, community, and intimate relationships in their plans to decrease their substance abuse upon community re-entry. Women stressed the obstacles to receiving support in many of their family and drug-using relationships after community re-entry. Nonetheless, they asserted that changes in their relationships could support their desires to end their substance abuse by setting limits on and using their positive relationships, particularly with their children, to motivate them to change. Interventions to promote incarcerated women's health behavior changes-including substance abuse-must acknowledge the complex social environments in which they live. PMID- 26643030 TI - Improved Prediction of CD34+ Cell Yield before Peripheral Blood Hematopoietic Progenitor Cell Collection Using a Modified Target Value-Tailored Approach. AB - The most commonly used stem cell source for both autologous and allogeneic transplantation is mobilized peripheral blood hematopoietic progenitor cells collected by apheresis. In the 1990s, an Italian group used the correlation between the preapheresis peripheral blood CD34+ cell count and the final number of CD34+ cells collected to devise a formula for "target value-tailored" (TVT) apheresis. Using local patient data, the Canadian Blood Services Stem Cell Laboratory created a similar model to determine the blood volume to process during apheresis collection. The objectives of this study were to determine the correlation between the number of CD34+ cells predicted by the TVT formula and the actual number of CD34+ cells collected and to determine whether the TVT formula remains predictive when applied to an external data set. All apheresis collections performed at the Ottawa Hospital between January 1, 2003 and October 2, 2013 were reviewed. The primary outcome was the correlation between the number of CD34+ cells predicted by the TVT formula and the actual number of CD34+ cells collected on day 1 of apheresis. For the external data set, all autologous collections performed at the London Health Sciences Centre between December 1, 2008 and December 1, 2013 were reviewed. The external data set was divided into test and validation sets to determine whether a model could be created to predict the final number of CD34+ cells collected on day 1 based on the preapheresis CD34+ count. A total of 1252 collections were included in the analysis. The Ottawa data set included 1012 collections, 836 of which were autologous and 176 of which were from donors. Of the autologous collections in Ottawa, 764 (92.5%) were first collections. In 759 (91%) collections, chemotherapy plus granulocyte colony-stimulating factor (G-CSF) was used as the mobilization regimen. In 747 collections (89%), only 1 collection day was required to achieve the desired number of CD34+ cells. The TVT estimate was highly predictive of the number of CD34+ cells * 10(6)/kg actually collected on apheresis day 1 (r = .90, P < .0001). The London data set included 240 autologous collections. All mobilizations were with G-CSF alone. For the test set, the precollection CD34+ count was highly predictive of the number of CD34+ cells * 10(6)/kg collected on day 1 of apheresis. Applying this model to the validation set, the correlation between the predicted and final and day 1 CD34+ cells * 10(6)/kg count was .9186 (P < .0001). Using a modified TVT approach, the preapheresis CD34+ count can be used to accurately predict the number of CD34+ cells * 10(6)/kg collected on day 1. This approach can be applied at other centers and for different diseases and mobilization regimens. This method can be used to individualize the blood volume processed and, thus, optimize resource utilization. PMID- 26643031 TI - A Genetic Modifier of the Gut Microbiome Influences the Risk of Graft-versus-Host Disease and Bacteremia After Hematopoietic Stem Cell Transplantation. AB - The human gut microbiome is involved in vital biological functions, such as maintenance of immune homeostasis and modulation of intestinal development and enhanced metabolic capabilities. Disturbances of the intestinal microbiota have been associated with development and progression of inflammatory conditions, including graft-versus-host disease (GVHD). The fucosyltransferase 2 (FUT2) gene produces an enzyme that is responsible for the synthesis of the H antigen in body fluids and on the intestinal mucosa. FUT2 genotype has been shown to modify the gut microbiome. We hypothesized that FUT2 genotype influences risk of GVHD and bacterial translocation after allogeneic hematopoietic stem cell transplantation (HSCT). FUT2 genotype was determined in 150 consecutive patients receiving allogeneic HSCT at our center. We abstracted clinical characteristics and outcomes from the transplantation database. Cumulative risk of any acute GVHD varied by FUT2 genotype, with decreased risk in those with A/A genotype and increased risk in those with G/G genotype. In contrast, the cumulative incidence of bacteremia was increased in those with A/A genotype. We conclude that the FUT2 genotype influences risk of acute GVHD and bacteremia after HSCT. We hypothesize that the mechanisms involve altered intestinal surface glycosylation and microbial composition but this requires additional study. PMID- 26643032 TI - Mapping Queer Bioethics: Space, Place, and Locality. AB - This article, which introduces the special issue of the Journal of Homosexuality on "Mapping Queer Bioethics," begins by offering an overview of the analytical scope of the issue. Specifically, the first half of this essay raises critical questions central to the concept of a space-related queer bioethics, such as: How do we appreciate and understand the special needs of queer parties given the constraints of location, space, and geography? The second half of this article describes each feature article in the issue, as well as the subsequent special sections on the ethics of reading literal, health-related maps ("Cartographies") and scrutinizing the history of this journal as concerns LGBT health ("Mapping the Journal of Homosexuality"). PMID- 26643033 TI - Tuning Equilibrium Compositions in Colloidal Cd1-xMnxSe Nanocrystals Using Diffusion Doping and Cation Exchange. AB - The physical properties of semiconductor nanocrystals can be tuned dramatically via composition control. Here, we report a detailed investigation of the synthesis of high-quality colloidal Cd1-xMnxSe nanocrystals by diffusion doping of preformed CdSe nanocrystals. Until recently, Cd1-xMnxSe nanocrystals proved elusive because of kinetic incompatibilities between Mn(2+) and Cd(2+) chemistries. Diffusion doping allows Cd1-xMnxSe nanocrystals to be prepared under thermodynamic rather than kinetic control, allowing access to broader composition ranges. We now investigate this chemistry as a model system for understanding the characteristics of nanocrystal diffusion doping more deeply. From the present work, a Se(2-)-limited reaction regime is identified, in which Mn(2+) diffusion into CdSe nanocrystals is gated by added Se(2-), and equilibrium compositions are proportional to the amount of added Se(2-). At large added Se(2-) concentrations, a solubility-limited regime is also identified, in which x = xmax = ~0.31, independent of the amount of added Se(2-). We further demonstrate that Mn(2+) in diffusion can be reversed by cation exchange with Cd(2+) under exactly the same reaction conditions, purifying Cd1-xMnxSe nanocrystals back to CdSe nanocrystals with fine tunability. These chemistries offer exceptional composition control in Cd1-xMnxSe NCs, providing opportunities for fundamental studies of impurity diffusion in nanocrystals and for development of compositionally tuned nanocrystals with diverse applications ranging from solar energy conversion to spin-based photonics. PMID- 26643034 TI - Annular pustular psoriasis associated with colon cancer. PMID- 26643035 TI - Ground state magnetic response of two coupled dodecahedra. AB - The antiferromagnetic Heisenberg model on the dodecahedron possesses a number of ground state magnetization discontinuities in a field at the classical and quantum level, even though it lacks magnetic anisotropy. Here the model is considered for two dodecahedra coupled antiferromagnetically along one of their faces, as a first step to determine the magnetic response of collections of fullerene molecules. The magnetic response is determined from the competition among the intra-, interdodecahedral exchange and magnetic field energies. At the classical level the discontinuities of the isolated dodecahedron are renormalized by the interdodecahedral coupling, while new ones show up, with the maximum number of ground state discontinuities being six for a specific range of the coupling. In the full quantum limit where the individual spin magnitude [Formula: see text], there are two ground state discontinuities originating in the single discontinuity of the isolated dodecahedron, and another one due to the intermolecular coupling, generating a total of three discontinuities which come one right after the other. These results show that the magnetic response of more than one dodecahedra interacting together is quite richer than the one of a single dodecahedron. PMID- 26643036 TI - Use of prescription medicines in Australian women of child-bearing age. AB - BACKGROUND: This study aimed to examine current utilisation of prescribed medicines amongst Australian women of child-bearing age, with a particular focus on the extent of use of medicines in Category D and X risk groups, which are moderate and high risk teratogens, respectively. The use of those medicines may pose risk of birth defects in pregnant women. METHODS: A retrospective cross sectional study was undertaken involving all women of child-bearing age (15 to 44 years) who were dispensed medicines in 2013 using the 10% random sample of dispensing data from the Australian Government Department of Human Services. Dispensing patterns were reported by medicine, therapeutic class, pregnancy risk category and women's age. RESULTS: Over one-third of women aged 15 to 44 years received at least one prescribed medicine in 2013. Psychoanaleptics, antibiotics and analgesics were the top three classes. Around 9% of all dispensings were for medicines from risk category D, with statins, agents acting on renin-angiotensin system, and some anti-epileptic agents being the most commonly used. Both statins and agents acting on renin-angiotensin system showed increasing use with age, estimated to be 35,600 women nationally for each group. Collectively between 2% and 4% of women used anti-epileptics from risk category D in each year of age, with overall use estimated to be 51,000 women nationally. Below 1% of all dispensings were for category X medicines, mainly isotretinoin. CONCLUSIONS: It is important for medical practitioners to offer counselling around pregnancy planning and the risk of birth defects when prescribing moderate or high risk teratogens to women in child-bearing age. For the antihypertensives and some anti epileptics, alternative medicines with lower risk categorization are available. PMID- 26643037 TI - Comparative transcriptomic analysis of silkworm Bmovo-1 and wild type silkworm ovary. AB - The detailed molecular mechanism of Bmovo-1 regulation of ovary size is unclear. To uncover the mechanism of Bmovo-1 regulation of ovarian development and oogenesis using RNA-Seq, we compared the transcriptomes of wild type (WT) and Bmovo-1-overexpressing silkworm (silkworm(+Bmovo-1)) ovaries. Using a pair-end Illumina Solexa sequencing strategy, 5,296,942 total reads were obtained from silkworm(+Bmovo-1) ovaries and 6,306,078 from WT ovaries. The average read length was about 100 bp. Clean read ratios were 98.79% for silkworm(+Bmovo-1) and 98.87% for WT silkworm ovaries. Comparative transcriptome analysis showed 123 upregulated and 111 downregulated genes in silkworm(+Bmovo-1) ovaries. These differentially expressed genes were enriched in the extracellular and extracellular spaces and involved in metabolism, genetic information processing, environmental information processing, cellular processes and organismal systems. Bmovo-1 overexpression in silkworm ovaries might promote anabolism for ovarian development and oogenesis and oocyte proliferation and transport of nutrients to ovaries by altering nutrient partitioning, which would support ovary development. Excessive consumption of nutrients for ovary development alters nutrient partitioning and deters silk protein synthesis. PMID- 26643038 TI - Early and long-term outcomes of minimally invasive mitral valve surgery through right minithoracotomy: a 10-year experience in 1604 patients. AB - BACKGROUND: To report early and long-term outcomes of patients undergoing minimally invasive mitral valve surgery (MIMVS) through right mini-thoracotomy (RT) over a 10-year period. METHODS: From September 2003 to December 2013, a total of 1604 consecutive patients underwent MIMVS through RT. RESULTS: The mean age was 63 +/- 13 years, 770 (48 %) patients were female and 218 (13.6 %) had previous cardiac operations. The most predominant pathology was degenerative disease (70 %), followed by functional mitral valve regurgitation (12 %), rheumatic disease (9.4 %), endocarditis (5 %) and prosthetic dysfunction (3.2 %). Mitral valve repair was performed in 1137 (71 %) patients and 476 (29 %) had mitral valve replacement. Direct aortic cannulation was achieved in 1325 (83 %) patients. Among patients with degenerative disease candidate for repair (n = 958), rate of mitral valve repair was 95 %. Repair techniques included annuloplasty (95 %), leafleat resection (63 %), neochordae implantation (16 %) and sliding plasty (11 %). Concomitant procedures included tricuspid valve repair (14.6 %), atrial fibrillation ablation (9.5 %) and atrial septal defect closure (3.2 %). Overall in-hospital mortality was 1.1 %. Thirty-four patients (2.1 %) had conversion to sternotomy. Incidence of stroke was 2 %. Overall survival at 10 years was 88 +/- 2 %. Freedom from reoperation at 10 years was 94 +/- 2 % for repair and 80 +/- 6 % for replacement. Freedom from recurrent mitral regurgitation >3+ at 10 years was 90 +/- 3 %. CONCLUSIONS: Minimally invasive mitral valve surgery is a safe and reproducible approach associated with low mortality and morbidity, high rate of mitral valve repair and excellent late results. PMID- 26643039 TI - ScanIndel: a hybrid framework for indel detection via gapped alignment, split reads and de novo assembly. AB - Comprehensive identification of insertions/deletions (indels) across the full size spectrum from second generation sequencing is challenging due to the relatively short read length inherent in the technology. Different indel calling methods exist but are limited in detection to specific sizes with varying accuracy and resolution. We present ScanIndel, an integrated framework for detecting indels with multiple heuristics including gapped alignment, split reads and de novo assembly. Using simulation data, we demonstrate ScanIndel's superior sensitivity and specificity relative to several state-of-the-art indel callers across various coverage levels and indel sizes. ScanIndel yields higher predictive accuracy with lower computational cost compared with existing tools for both targeted resequencing data from tumor specimens and high coverage whole genome sequencing data from the human NIST standard NA12878. Thus, we anticipate ScanIndel will improve indel analysis in both clinical and research settings. ScanIndel is implemented in Python, and is freely available for academic use at https://github.com/cauyrd/ScanIndel. PMID- 26643040 TI - Screening for early breast cancer reduces invasive cancer, study finds. PMID- 26643041 TI - Haptic perception of force magnitude and its relation to postural arm dynamics in 3D. AB - In a previous study, we found the perception of force magnitude to be anisotropic in the horizontal plane. In the current study, we investigated this anisotropy in three dimensional space. In addition, we tested our previous hypothesis that the perceptual anisotropy was directly related to anisotropies in arm dynamics. In experiment 1, static force magnitude perception was studied using a free magnitude estimation paradigm. This experiment revealed a significant and consistent anisotropy in force magnitude perception, with forces exerted perpendicular to the line between hand and shoulder being perceived as 50% larger than forces exerted along this line. In experiment 2, postural arm dynamics were measured using stochastic position perturbations exerted by a haptic device and quantified through system identification. By fitting a mass-damper-spring model to the data, the stiffness, damping and inertia parameters could be characterized in all the directions in which perception was also measured. These results show that none of the arm dynamics parameters were oriented either exactly perpendicular or parallel to the perceptual anisotropy. This means that endpoint stiffness, damping or inertia alone cannot explain the consistent anisotropy in force magnitude perception. PMID- 26643042 TI - Gut Microbiota Modulation and Mucosal Immunity: Focus on Rifaximin. AB - The gastrointestinal tract is a complex and dynamic network where an intricate and mutualistic symbiosis modulates the relationship between the host and the microbiota in order to establish and ensure gut homeostasis. Every day, thousands of compounds derived from food and microorganisms come in contact with the intestinal mucosa. This interaction requires a complex defense system that separates intestinal contents from the host tissues, regulates nutrient absorption, and allows tolerance between the resident bacterial flora and the mucosal immune system, while inhibiting translocation of infectious agents to the inner tissues. Unfavorable alteration of microbiota composition has been implicated in hepatic, gastrointestinal, and perhaps also systemic disorders. In this scenario, gut microbiota modulation represents an intriguing field and can be obtained by several approaches, including antibiotics, pro- and pre-biotics supplementation. Among antibiotics, Rifaximin seems to be a promising antibiotic to treat conditions related to gut microbiota imbalance and to potentially modulate intestinal homeostasis. This review focuses on what is currently known regarding the possible role of Rifaximin in restoring normal gut immune physiology and a healthy gut-liver axis. Detailed mechanistic studies will improve the development of targeted therapies that may shape gut microflora composition with the end goal of promoting gut health. PMID- 26643043 TI - Successful correction of tibial bone deformity through multiple surgical procedures, liquid nitrogen-pretreated bone tumor autograft, three-dimensional external fixation, and internal fixation in a patient with primary osteosarcoma: a case report. AB - BACKGROUND: In a previous report, we described a method of reconstruction using tumor-bearing autograft treated by liquid nitrogen for malignant bone tumor. Here we present the first case of bone deformity correction following a tumor-bearing frozen autograft via three-dimensional computerized reconstruction after multiple surgeries. CASE PRESENTATION: A 16-year-old female student presented with pain in the left lower leg and was diagnosed with a low-grade central tibial osteosarcoma. Surgical bone reconstruction was performed using a tumor-bearing frozen autograft. Bone union was achieved at 7 months after the first surgical procedure. However, local tumor recurrence and lung metastases occurred 2 years later, at which time a second surgical procedure was performed. Five years later, the patient developed a 19 degrees varus deformity and underwent a third surgical procedure, during which an osteotomy was performed using the Taylor Spatial Frame three-dimensional external fixation technique. A fourth corrective surgical procedure was performed in which internal fixation was achieved with a locking plate. Two years later, and 10 years after the initial diagnosis of tibial osteosarcoma, the bone deformity was completely corrected, and the patient's limb function was good. CONCLUSION: We present the first report in which a bone deformity due to a primary osteosarcoma was corrected using a tumor bearing frozen autograft, followed by multiple corrective surgical procedures that included osteotomy, three-dimensional external fixation, and internal fixation. PMID- 26643044 TI - A novel consortium of Lactobacillus rhamnosus and Streptococcus thermophilus for increased access to functional fermented foods. AB - BACKGROUND: The lactic acid bacterium Lactobacillus rhamnosus GG is the most studied probiotic bacterium with proven health benefits upon oral intake, including the alleviation of diarrhea. The mission of the Yoba for Life foundation is to provide impoverished communities in Africa increased access to Lactobacillus rhamnosus GG under the name Lactobacillus rhamnosus yoba 2012, world's first generic probiotic strain. We have been able to overcome the strain's limitations to grow in food matrices like milk, by formulating a dried starter consortium with Streptococcus thermophilus that enables the propagation of both strains in milk and other food matrices. The affordable seed culture is used by people in resource-poor communities. RESULTS: We used S. thermophilus C106 as an adjuvant culture for the propagation of L. rhamnosus yoba 2012 in a variety of fermented foods up to concentrations, because of its endogenous proteolytic activity, ability to degrade lactose and other synergistic effects. Subsequently, L. rhamnosus could reach final titers of 1E+09 CFU ml(-1), which is sufficient to comply with the recommended daily dose for probiotics. The specific metabolic interactions between the two strains were derived from the full genome sequences of L. rhamnosus GG and S. thermophilus C106. The piliation of the L. rhamnosus yoba 2012, required for epithelial adhesion and inflammatory signaling in the human host, was stable during growth in milk for two rounds of fermentation. Sachets prepared with the two strains, yoba 2012 and C106, retained viability for at least 2 years. CONCLUSIONS: A stable dried seed culture has been developed which facilitates local and low-cost production of a wide range of fermented foods that subsequently act as delivery vehicles for beneficial bacteria to communities in east Africa. PMID- 26643045 TI - APA-style human milk fat analogue from silkworm pupae oil: Enzymatic production and improving storage stability using alkyl caffeates. AB - Silkworm pupae oil derived from reeling waste is a rich source of alpha-linolenic acid (ALA), which has multipal applications. ALAs were added in sn-1, 3 positions in a triacylglycerol (TAG) to produce an APA-human milk fat analogues (APA-HMFAs, A: alpha-linolenic acid, P: palmitic acid). The optimum condition is that tripalmitin to free fatty acids of 1:12 (mole ratio) at 65 degrees C for 48 h using lipase Lipozyme RM IM. Results show that, the major TAG species that comprised APA-HMFAs were rich in ALA and palmitic acid, which contained 64.52% total unsaturated fatty acids (UFAs) and 97.05% PA at the sn-2 position. The melting point of APA was -27.5 degrees C which is much lower than tripalmitin (40.5 degrees C) indicating more plastic character. In addition, the practical application of alkyl caffeates as liposoluble antioxidants in APA was developed. Alkyl caffeate showed a superior IC50 (1.25-1.66 MUg/mL) compared to butyl hydroxy anisd (1.67 MUg/mL) and L-ascorbic acid-6-palmitate (L-AP) (1.87 MUg/mL) in DPPH analysis. The addition of ethyl caffeate to oil achieved a higher UFAs content (73.58%) at high temperatures. Overall, APA was obtained from silkworm pupae oil successfully, and the addition of caffeates extended storage ranges for APA-HMFAs. PMID- 26643046 TI - Balance control in aging: improvements in anticipatory postural adjustments and updating of internal models. AB - Postural stability of older subjects can be estimated during orthostatic equilibrium. However, dynamic equilibrium is also important to investigate risks of fall. It implies different interpretations of measures given by force plates. Same dependant variables (e.g. center of pressure displacement) cannot be interpreted the same ways depending of the type of equilibrium that is investigated. In particular, sways increases during dynamic equilibrium and before movement execution may reflect an improvement of feedforward control. PMID- 26643047 TI - Current and emerging therapies in the management of diabetic foot ulcers. AB - BACKGROUND: Diabetic foot ulcers are one of the major causes of mortality in diabetic patients. Very few drugs and therapies have regulatory approval for this indication and several agents from diverse pharmacological classes are currently in various phases of clinical trials for the management of diabetic foot ulcers. SCOPE: The purpose of this review is to provide concise information of the drugs and therapies which are approved and present in clinical trials. REVIEW METHODS: This review was carried out by systematic searches of relevant guidelines, patents, published articles, reviews and abstracts in PubMed/Medline, Web of Science, clinicaltrials.gov, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews and Google Scholar of all English language articles up to 1 March 2015. The following search terms were used: diabetes, diabetic foot, diabetic foot ulcer, diabetic wound, diabetic foot infections, wound management, randomized controlled trials, approved treatments, new treatments and clinical trials. CONCLUSIONS: The various drugs and therapies for the management of diabetic foot ulcers comprise antibiotics, neuropathic drugs, wound dressings, skin substitutes, growth factors and inflammatory modulators. The majority of these therapies target the treatment of diabetic foot ulcers to address the altered biochemical composition of the diabetic wound. However, no single treatment can be definitively recommended for the treatment of diabetic foot ulcers. PMID- 26643048 TI - Magneto-optical investigation of spin-orbit torques in metallic and insulating magnetic heterostructures. AB - Manipulating magnetism by electric current is of great interest for both fundamental and technological reasons. Much effort has been dedicated to spin orbit torques (SOTs) in metallic structures, while quantitative investigation of analogous phenomena in magnetic insulators remains challenging due to their low electrical conductivity. Here we address this challenge by exploiting the interaction of light with magnetic order, to directly measure SOTs in both metallic and insulating structures. The equivalency of optical and transport measurements is established by investigating a heavy-metal/ferromagnetic-metal device (Ta/CoFeB/MgO). Subsequently, SOTs are measured optically in the contrasting case of a magnetic-insulator/heavy-metal (YIG/Pt) heterostructure, where analogous transport measurements are not viable. We observe a large anti damping torque in the YIG/Pt system, revealing its promise for spintronic device applications. Moreover, our results demonstrate that SOT physics is directly accessible by optical means in a range of materials, where transport measurements may not be possible. PMID- 26643049 TI - The hematopoietic regulator, ELF-1, enhances the transcriptional response to Interferon-beta of the OAS1 anti-viral gene. AB - Interferon (IFN) therapy is effective in treating cancers, haematological and virus induced diseases. The classical Jak/Stat pathway of IFN signal transduction leading to changes in transcriptional activity is well established but alone does not explain the whole spectrum of cellular responses to IFN. Gene promoters contain cis-acting sequences that allow precise and contextual binding of transcription factors, which control gene expression. Using the transcriptional response to IFN as a starting point we report a high frequency of tandem GGAA motifs in the proximal promoters of Interferon stimulated genes, suggesting a key regulatory action. Utilizing the well-characterized anti-viral gene, OAS1, as an example Interferon stimulated gene promoter containing such a duplicated GGAA motif, we have demonstrated a regulatory role of this promoter in response to IFN by mutation analysis. Furthermore, we identified ELF-1 as a direct binding factor at this motif. Additionally, recruitment of RB1 and SP1 factors to the promoter following IFN stimulation is shown. ELF-1 overexpression enhanced and knockdown of ELF-1 inhibited full activation of OAS1 by IFN stimulation. Collectively, ELF 1 binds an important duplicated GGAA cis-acting element at the OAS1 promoter and in cooperation with RB1 and SP1 recruitment contributes to regulation in response to IFN stimulation. PMID- 26643050 TI - Triage of HPV positive women in cervical cancer screening. AB - Despite HPV vaccines, screening will remain central for decades to control cervical cancer. Recently, HPV testing alone or with cytology was introduced as an alternative to cytology screening. However, most HPV infections are harmless and additional tests are required to identify women with progressing infections or precancer. With three options for primary screening, and without clear strategies for triage of screen-positive women, there is great confusion about the best approach. Also, increasing HPV vaccination coverage will lead to lower disease prevalence, and force new screening approaches. Currently recommended triage strategies for primary HPV screening include HPV genotyping for HPV16 and HPV18 and cytology. Other alternatives that are currently evaluated include p16/Ki-67 dual stain cytology, host methylation, and viral methylation testing. Clinical management of women with cervical cancer screening results is moving to use risk thresholds rather than individual test results. Specific risk thresholds have been defined for return to primary screening, repeat testing, referral to colposcopy, and immediate treatment. Choice of test algorithms is based on comparison of absolute risk estimates from triage tests with established clinical thresholds. Importantly, triage tests need to be evaluated together with the primary screening test and the downstream clinical management. An optimal integrated screening and triage strategy should reassure the vast majority of women that they are at very low risk of cervical cancer, send the women at highest risk to colposcopy at the right time, when disease can be colposcopically detected, and minimize the intermediate risk group that requires continued surveillance. PMID- 26643051 TI - Three-year longitudinal data on the clinical performance of the Abbott RealTime High Risk HPV test in a cervical cancer screening setting. AB - BACKGROUND: Testing cervical smears for the presence of high-risk human papillomaviruses (hrHPV) increases the sensitivity for detecting women with underlying high-grade cervical intraepithelial neoplasia (CIN) and provides better and longer protection against invasive cervical cancer compared to cytology testing alone. The Abbott RealTime High Risk HPV test (RealTime) is a hrHPV DNA test with concurrent partial genotyping for HPV16 and HPV18 and aggregate detection of 12 other hrHPV types that have been extensively analytically and clinically evaluated over the last 6 years. OBJECTIVES AND STUDY DESIGN: To provide the first 3-year longitudinal data regarding the clinical performance of RealTime, the risk of CIN2+ according to various negative baseline characteristics, and baseline and future risk for CIN2+ at 3 years for women with baseline infection with various hrHPV types were assessed in a cohort of 3,920 Slovenian women that had hrHPV DNA and/or cytology in 36- to 48-month follow-up results after a baseline screening round in 2009/2010. RESULTS: A total of 36 CIN2+ cases were identified in the second screening round. Of these, 17 CIN2+ cases were identified passively through questionnaires/data registries and 19 cases actively as the result of actions triggered by second-round cytology and/or HPV test results. Accumulation of CIN2+ cases during follow-up occurred predominantly in woman with normal cytology at baseline. Among women >30 years old, significantly better protection against CIN2+ at 3 years was associated with a negative hrHPV DNA result at baseline (risk for CIN2+ 0.04% [95 CI, 0.00 0.22%]) than by normal cytology at baseline (risk for CIN2+ 0.68% [95 CI, 0.40 1.08%]). Women with baseline HPV16 infection had a significantly higher risk of CIN2+ at baseline (21.9% [95 CI, 15.2-30.4%]) and baseline plus future risk at 3 years for CIN2+ (33.3% [95 CI, 24.7-44.0%]) in comparison to women with baseline non-HPV16/18 hrHPV infection (7.0% [95 CI, 4.6-10.2%]) or those that were hrHPV positive (11.7% [95 CI, 9.1-14.9%]). CONCLUSIONS: 3-year longitudinal data reinforce evidence from previous studies that RealTime can be safely used in primary HPV-based cervical cancer screening. Concurrent partial genotyping for HPV16/18 should be strongly considered as a triage method for HPV screen-positive women. PMID- 26643052 TI - Younger Children with Cerebral Palsy Respond Better Than Older Ones to Therapist Based Constraint-Induced Therapy at Home on Functional Outcomes and Motor Control. AB - AIMS: To examine the differences in efficacy of home-based constraint-induced therapy (CIT) on functional outcomes and motor control in two age groups of children with cerebral palsy (CP). METHODS: Twenty-three children with spastic unilateral CP receiving 4-week home-based CIT by a therapist were divided into younger (6-8 years; n = 11) and older (9-12 years; n = 12) groups. The home-based CIT involved intensive functional training of the more affected upper-limb while restraining the less affected upper-limb. The outcome measures were Peabody Developmental Motor Scale-2nd edition (PDMS-2) that was being used in a modified way, Functional Independence Measure for Children (WeeFIM), and reach-to-grasp kinematic parameters, including reaction time (RT), normalized movement time (MT), normalized movement units (MUs), peak velocity (PV), and maximum grip aperture (MGA). The outcome measures were assessed at baseline, 4-weeks (post treatment), 3- and 6-months (follow-up). RESULTS: The younger group showed greater changes in visual motor integration skills and RT at all post-tests after intervention than the older group. Groups had comparable changes on any other measures. CONCLUSIONS: Younger children with CP responded better to home-based CIT on some areas of upper-limb functions and reach-to-grasp motor control strategies than older children. PMID- 26643053 TI - In the mood. PMID- 26643054 TI - Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for mood disorders. AB - OBJECTIVES: To provide guidance for the management of mood disorders, based on scientific evidence supplemented by expert clinical consensus and formulate recommendations to maximise clinical salience and utility. METHODS: Articles and information sourced from search engines including PubMed and EMBASE, MEDLINE, PsycINFO and Google Scholar were supplemented by literature known to the mood disorders committee (MDC) (e.g., books, book chapters and government reports) and from published depression and bipolar disorder guidelines. Information was reviewed and discussed by members of the MDC and findings were then formulated into consensus-based recommendations and clinical guidance. The guidelines were subjected to rigorous successive consultation and external review involving: expert and clinical advisors, the public, key stakeholders, professional bodies and specialist groups with interest in mood disorders. RESULTS: The Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for mood disorders (Mood Disorders CPG) provide up-to-date guidance and advice regarding the management of mood disorders that is informed by evidence and clinical experience. The Mood Disorders CPG is intended for clinical use by psychiatrists, psychologists, physicians and others with an interest in mental health care. CONCLUSIONS: The Mood Disorder CPG is the first Clinical Practice Guideline to address both depressive and bipolar disorders. It provides up-to date recommendations and guidance within an evidence-based framework, supplemented by expert clinical consensus. MOOD DISORDERS COMMITTEE: Professor Gin Malhi (Chair), Professor Darryl Bassett, Professor Philip Boyce, Professor Richard Bryant, Professor Paul Fitzgerald, Dr Kristina Fritz, Professor Malcolm Hopwood, Dr Bill Lyndon, Professor Roger Mulder, Professor Greg Murray, Professor Richard Porter and Associate Professor Ajeet Singh. INTERNATIONAL EXPERT ADVISORS: Professor Carlo Altamura, Dr Francesco Colom, Professor Mark George, Professor Guy Goodwin, Professor Roger McIntyre, Dr Roger Ng, Professor John O'Brien, Professor Harold Sackeim, Professor Jan Scott, Dr Nobuhiro Sugiyama, Professor Eduard Vieta, Professor Lakshmi Yatham. AUSTRALIAN AND NEW ZEALAND EXPERT ADVISORS: Professor Marie-Paule Austin, Professor Michael Berk, Dr Yulisha Byrow, Professor Helen Christensen, Dr Nick De Felice, A/Professor Seetal Dodd, A/Professor Megan Galbally, Dr Josh Geffen, Professor Philip Hazell, A/Professor David Horgan, A/Professor Felice Jacka, Professor Gordon Johnson, Professor Anthony Jorm, Dr Jon-Paul Khoo, Professor Jayashri Kulkarni, Dr Cameron Lacey, Dr Noeline Latt, Professor Florence Levy, A/Professor Andrew Lewis, Professor Colleen Loo, Dr Thomas Mayze, Dr Linton Meagher, Professor Philip Mitchell, Professor Daniel O'Connor, Dr Nick O'Connor, Dr Tim Outhred, Dr Mark Rowe, Dr Narelle Shadbolt, Dr Martien Snellen, Professor John Tiller, Dr Bill Watkins, Dr Raymond Wu. PMID- 26643055 TI - Thomas Hodgkin (1798-1866). AB - Thomas Hodgkin was a diligent, selfless and benevolent man whose name is instantly recognisable in the medical field due to his description of a type of the lymphoma that is named after him, 'Hodgkin's Lymphoma'. Based at Guy's Hospital, London, he created a vast catalogue of specimens in their Medical Museum and facilitated teaching at the establishment. He was dedicated to education, public health and social reform in the 19th century. PMID- 26643056 TI - The Wesselhoefts: A medical dynasty from the age of Goethe to the era of nuclear medicine. AB - For six generations, members of the Wesselhoeft family have practiced medicine in Germany, Denmark, Switzerland, Canada and/or the USA. In the early decades of the 19th century, two Wesselhoeft brothers left Europe to eventually settle in New England, where they and their progeny gave rise to a regional medical dynasty. The Wesselhoeft doctors became well-known practitioners of homeopathy, hydropathy, conventional medicine and surgery, in academic and general clinical settings. An additional connection was established to the literary worlds of Germany and the USA, either through friendships or as personal physicians. PMID- 26643058 TI - The complete mitochondrial genome of the citrus long-horned beetle, Anoplophora chinensis (Coleoptera: Cerambycidae). AB - In this paper, the complete mitochondrial genome of Anoplophora chinensis is sequenced and reported for the first time. The mitochondrial genome is a circular molecule of 15 805 bp, 13 protein-coding genes (PCGs), 22 transfer RNA genes, 2 ribosomal RNA genes, and 1 control region. Nine protein-coding genes and 14 tRNA genes are encoded on the H strand, and the other four protein-coding genes and eight tRNA genes are encoded on the L strand. The arrangement of genes is identical to all know long-horn beetles mitochondrial genomes. The nucleotide composition of the A. chinensis mitogenome is strongly biased toward A + T nucleotides (77.65%). Finally, the phylogenetic relationships of 12 Lamiinae species were reconstructed based on nucleotide sequences of COI using the Bayesian inference method. These molecular-based phylogenies support the traditional morphologically based view of relationships within the Lamiinae. PMID- 26643059 TI - How experienced intensive care nurses communicate with families about shift to end-of-life care. PMID- 26643060 TI - Optimising palliative and end-of-life care within care home settings. PMID- 26643057 TI - Iron acquisition in the cystic fibrosis lung and potential for novel therapeutic strategies. AB - Iron acquisition is vital to microbial survival and is implicated in the virulence of many of the pathogens that reside in the cystic fibrosis (CF) lung. The multifaceted nature of iron acquisition by both bacterial and fungal pathogens encompasses a range of conserved and species-specific mechanisms, including secretion of iron-binding siderophores, utilization of siderophores from other species, release of iron from host iron-binding proteins and haemoproteins, and ferrous iron uptake. Pathogens adapt and deploy specific systems depending on iron availability, bioavailability of the iron pool, stage of infection and presence of competing pathogens. Understanding the dynamics of pathogen iron acquisition has the potential to unveil new avenues for therapeutic intervention to treat both acute and chronic CF infections. Here, we examine the range of strategies utilized by the primary CF pathogens to acquire iron and discuss the different approaches to targeting iron acquisition systems as an antimicrobial strategy. PMID- 26643061 TI - Immunoglobulin G response in patients with Campylobacter concisus diarrhea. AB - Limited information is available on the systemic immunoglobulin response in patients infected with the emerging pathogen Campylobacter concisus. The aim of the present study was to detect anti-C. concisus antibodies in serum of 88 patients with C. concisus gastroenteritis. Specific IgG antibodies to C. concisus were measured in serum using an in-house enzyme-linked immunosorbent assay, and pooled donor serum was used as a control. The mean optical density was 0.135 (SEM: 0.020) for the 88 adult patients and 0.100 (SEM: 0.011) in controls. When using an optical density value equal to the mean +3 SEM for the control serum, 22 (25%) C. concisus-positive patients had increased IgG antibodies. Patients with high IgG levels more often reported headache, and they had a trend toward more mucus in stools, whereas IgG levels were unrelated to age, duration of diarrhea, number of stools per day, and weight loss. PMID- 26643062 TI - Prevalence and characteristics of Escherichia coli sequence type 131 and its H30 and H30Rx subclones: a multicenter study from Korea. AB - We investigated the prevalence and characteristics of Escherichia coli sequence type 131 (ST131) and its subclones among 268 E. coli isolates. The isolates were collected from 21 Korean hospitals without use of selection criteria and were screened for ST131 status by PCR. ST131 isolates were characterized for extended spectrum beta-lactamase variants, fluoroquinolone resistance genes, plasmid addiction systems, and replicon types. The collection's 57 identified ST131 isolates (21% of 268) were distributed disproportionately by clonal subset, as follows: 21 (37%) H30Rx, 27 (47%) H30 non-Rx, and 8 (14%) non-H30. Most (93%) ST131 isolates were ciprofloxacin resistant, and all H30 isolates had the same 5 nonsynonymous mutations in gyrA, parC, and parE. Twenty (95%) of H30Rx isolates harbored CTX-M-15, whereas only 14 (52%) of H30 non-Rx isolates harbored CTX-M-14 or CTX-M-27. Most (97%) ST131 isolates harbored IncF plasmids, but vagCD was confined exclusively to H30Rx. Our findings suggest that the distinctive characteristics of H30Rx isolates could have contributed to this subclone's recent epidemiologic success. PMID- 26643063 TI - Enterovirus meningitis in Tunisia (Monastir, Mahdia, 2011-2013): identification of virus variants cocirculating in France. AB - Acute enterovirus (EV) meningitis is a frequent cause of hospitalisation, and over 100 EV serotypes may be involved. A total of 215 patients of all ages with meningitis signs were investigated in 2 Tunisian hospitals. Their cerebrospinal fluid (CSF) was analysed retrospectively for EVs with a TaqMan real-time RT-qPCR. The virus strains were typed, and their evolutionary relationships were determined by Bayesian phylogenetic methods. An EV genome was detected in 21/215 patients (9.8%). The CSF viral loads ranged from 3.27 to 5.63 log10 genome copies/mL. The strains were identified in 13/21 patients and assigned to EV-B types. Viruses identified in Tunisian patients were genetically related to variants detected in France. The viral loads were similar in Tunisian and French patients for most EV types. The phylogenetic data and viral loads determined in Tunisian and French patients suggest that close EV variants were involved in aseptic meningitis in the 2 countries over a same period. PMID- 26643064 TI - Effects of sample storage and shell orientation on LA-ICPMS trace element measurements on deep-sea mussels. AB - Geochemical markers are being increasingly applied to fundamental questions in population and community ecology in marine habitats because they allow inferences on individuals dispersal, but vital effects, small sample size and instrumental limitation are still challenging particularly in deep-sea studies. Here we use shells of the deep-sea bivalve Idas modiolaeformis to assess potential effects of sample storage, mineralogy, and valve orientation on LA-ICPMS measurements. Trace element concentrations of (24)Mg, (43)Ca, (88)Sr, (137)Ba, (208)Pb, and (238)U are not affected by the two most commonly used storage methods of biologic deep sea samples (frozen at -20 degrees C and fixed in 95% ethanol); thus combined analysis of differently preserved specimens is possible when the number of individuals is insufficient and distinct sample fixation is needed for multiple purposes. Valve orientation had a strong impact on quantification of trace elements in the calcitic but not in the aragonitic layer of adult shells. Hence, to enable comparisons between adult shells and entirely aragonitic embryonic shells, a reference map of site-specific signatures can potentially be generated using the aragonitic layer of the adult shells. Understanding ontogenetic changes and environmental effects in trace element incorporation is critical before geochemical fingerprinting can be used as a tool for larval dispersal studies in the deep-sea. PMID- 26643065 TI - Gleditsia species: An ethnomedical, phytochemical and pharmacological review. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The plants in the genus Gleditsia, mainly distributed in central and Southeast Asia and North and South America, have been used as local and traditional medicines in many regions, especially in China, for the treatment of measles, indigestion, whooping, smallpox, arthrolithiasis, constipation, diarrhea, hematochezia, dysentery, carbuncle, etc. This present paper systemically reviews the miscellaneous information surrounding its traditional use, phytochemistry and pharmacology to provide opportunities and recommendations for the future research. MATERIALS AND METHODS: The scientific literatures were systematically searched from scientific databases (PubMed, Scopus, Elsevier, SpringerLink, SciFinder, Google Scholar and others). In addition, the ethnopharmacological information on this genus was mainly acquired from Chinese and Korean herbal classics, and library catalogs. RESULTS: More than 60 compounds including triterpenes, sterols, flavonoids, alkaloids, phenolics and their derivatives were isolated from Gleditsia japonica Miq., Gleditsia sinensis Lam., Gleditsia caspica Desf. and Gleditsia triacanthos L. Among these compounds, triterpenoid saponins were the main constituents of Gleditsia species. Moreover, the crude extracts and purified molecules were tested, revealing diverse biological activities such as anti-tumor, anti-inflammatory, anti-allergic, anti hyperlipidemic, analgesic, antimutagenic, antioxidant, anti-HIV, antibacterial, antifungal activities, etc. Among these biological studies, the possible mechanisms of antitumor action are stressed in this review, and these include causing cytotoxicity to cancer cells, inhibition of proliferation of cancer cells by affecting their growth, regeneration and apoptosis, inhibition of basic fibroblast growth factor (bFGF) and nitric oxide (NO), modulation of the oncogenic expression and telomerase activity results, inhibition of the expression of pro-angiogenic proteins, as well as down-regulation of intra/extracellular proangiogenic modulators, etc. CONCLUSIONS: On the basis of preliminary research on Gleditsia genus it could be stated that saponins investigations may be more promising in future. Although 32 compounds of 67 identified compounds were saponins, modern pharmacological research on saponins were not a priority in Gleditsia species. Therefore, more bioactive experiments and in-depth mechanisms of action are required for elucidating their roles in physiological systems. Moreover, the present review also highlights that analgesic, anti-tumor and anti-HIV activities should have priority in saponins research. Additionally, it is imperative to explore more structure-activity relationships and possible synergistic actions of triterpenoid saponins for revaluating their pharmacological activities. PMID- 26643066 TI - Use of a checklist to improve pain control in hospitalized cancer patients: the 38Checkpain project. AB - AIM: Checklists may improve management of patients in different settings. However, no studies have been conducted to investigate the use of this tool to improve inpatient pain control. This study, conducted in Italy, aims to describe the experience, in terms of pain control, of the widespread introduction of a checklist for pain control in oncological patients, according to current Italian legislation. MATERIALS & METHODS: In total, 92 Italian centers were randomly assigned to the use of the 38Checkpain to monitor pain management or to continue their standard practice without the use of this tool. RESULTS: The 38Checkpain improved the control of pain compared with centers who did not use this tool. CONCLUSION: Overall, the findings of this study suggest that the application of the 38Checkpain may help improve control of pain of hospitalized oncological patients. PMID- 26643067 TI - TUBB4A-related hypomyelinating leukodystrophy: New insights from a series of 12 patients. AB - BACKGROUND: Hypomyelination with atrophy of the basal ganglia and cerebellum (H ABC) was first described in 2002. After the recent identification of TUBB4A mutation as the genetic basis of the disease, the clinical and neuroimaging phenotype related to TUBB4A mutations expanded, ranging from primary dystonia type 4 with normal MRI to severe H-ABC cases. PATIENTS AND METHODS: The study included patients referred to us for an unclassified hypomyelinating leukodystrophy. We selected patients with deleterious heterozygous TUBB4A mutations. Molecular analysis of TUBB4A was performed on genomic DNA extracted from peripheral blood. RESULTS: The series included 12 patients (5 females and 7 males). Five patients carried the common mutation c.745G > A (p.Asp249Asn), while the remaining harbored different mutations. Three new mutations were found in 5 patients. Clinical and neuroimaging observations are described. A clear correlation between the clinical presentation and the genotype seems to be absent in our group of 12 patients. CONCLUSIONS: TUBB4A-mutated patients manifest a comparable clinical and neuroimaging picture but they can differ from each other in terms of rate of disease progression. Extrapyramidal signs can be absent in the first stages of the disease, and a careful evaluation of MRI is fundamental to obtain the final diagnosis. From a therapeutic perspective a trial with l-dopa should be considered in all patients presenting extrapyramidal symptoms. PMID- 26643068 TI - Dispersion relations of elastic waves in one-dimensional piezoelectric/piezomagnetic phononic crystal with initial stresses. AB - The dispersion relations of elastic waves in a one-dimensional phononic crystal formed by periodically repeating of a pre-stressed piezoelectric slab and a pre stressed piezomagnetic slab are studied in this paper. The influences of initial stress on the dispersive relation are considered based on the incremental stress theory. First, the incremental stress theory of elastic solid is extended to the magneto-electro-elasto solid. The governing equations, constitutive equations, and boundary conditions of the incremental stresses in a magneto-electro-elasto solid are derived with consideration of the existence of initial stresses. Then, the transfer matrices of a pre-stressed piezoelectric slab and a pre-stressed piezomagnetic slab are formulated, respectively. The total transfer matrix of a single cell in the phononic crystal is obtained by the multiplication of two transfer matrixes related with two adjacent slabs. Furthermore, the Bloch theorem is used to obtain the dispersive equations of in-plane and anti-plane Bloch waves. The dispersive equations are solved numerically and the numerical results are shown graphically. The oblique propagation and the normal propagation situations are both considered. In the case of normal propagation of elastic waves, the analytical expressions of the dispersion equation are derived and compared with other literatures. The influences of initial stresses, including the normal initial stresses and shear initial stresses, on the dispersive relations are both discussed based on the numerical results. PMID- 26643071 TI - Acute stent thrombosis due to stent underexpansion managed with rotational atherectomy. AB - Stent underexpansion is a well known risk factor for stent thrombosis. We report a case of acute stent thrombosis which occurred after primary percutaneous coronary intervention to the right coronary artery for an inferior ST-elevation myocardial infarction. Minutes after completion of the procedure, the patient had acute stent thrombosis, manifested by new chest pain and new ST-elevation. IVUS showed the stent to be underexpanded. Despite high pressure balloon inflation, the stent remained underexpanded. This was then managed with rotational atherectomy within the underexpanded stent, followed by high-pressure balloon dilatation and deployment of another stent within it. PMID- 26643070 TI - Pioglitazone, a PPARgamma agonist, attenuates PDGF-induced vascular smooth muscle cell proliferation through AMPK-dependent and AMPK-independent inhibition of mTOR/p70S6K and ERK signaling. AB - Pioglitazone (PIO), a PPARgamma agonist that improves glycemic control in type 2 diabetes through its insulin-sensitizing action, has been shown to exhibit beneficial effects in the vessel wall. For instance, it inhibits vascular smooth muscle cell (VSMC) proliferation, a major event in atherosclerosis and restenosis after angioplasty. Although PPARgamma-dependent and PPARgamma-independent mechanisms have been attributed to its vasoprotective effects, the signaling events associated with PIO action in VSMCs are not fully understood. To date, the likely intermediary role of AMP-activated protein kinase (AMPK) toward PIO inhibition of VSMC proliferation has not been examined. Using human aortic VSMCs, the present study demonstrates that PIO activates AMPK in a sustained manner thereby contributing in part to inhibition of key proliferative signaling events. In particular, PIO at 30MUM concentration activates AMPK to induce raptor phosphorylation, which diminishes PDGF-induced mTOR activity as evidenced by decreased phosphorylation of p70S6K, 4E-BP1, and S6 and increased accumulation of p27(kip1), a cell cycle inhibitor. In addition, PIO inhibits the basal phosphorylation of ERK in VSMCs. Downregulation of endogenous AMPK by target specific siRNA reveals an AMPK-independent effect for PIO inhibition of ERK, which contributes in part to diminutions in cyclin D1 expression and Rb phosphorylation and the suppression of VSMC proliferation. Furthermore, AMPK dependent inhibition of mTOR/p70S6K and AMPK-independent inhibition of ERK signaling occur regardless of PPARgamma expression/activation in VSMCs as evidenced by gene silencing and pharmacological inhibition of PPARgamma. Strategies that utilize nanoparticle-mediated PIO delivery at the lesion site may limit restenosis after angioplasty without inducing PPARgamma-mediated systemic adverse effects. PMID- 26643069 TI - Gates, Channels, and Switches: Elements of the Proteasome Machine. AB - The proteasome has emerged as an intricate machine that has dynamic mechanisms to regulate the timing of its activity, its selection of substrates, and its processivity. The 19-subunit regulatory particle (RP) recognizes ubiquitinated proteins, removes ubiquitin, and injects the target protein into the proteolytic chamber of the core particle (CP) via a narrow channel. Translocation into the CP requires substrate unfolding, which is achieved through mechanical force applied by a hexameric ATPase ring of the RP. Recent cryoelectron microscopy (cryoEM) studies have defined distinct conformational states of the RP, providing illustrative snapshots of what appear to be progressive steps of substrate engagement. Here, we bring together this new information with molecular analyses to describe the principles of proteasome activity and regulation. PMID- 26643072 TI - A web-based intervention (RESTORE) to support self-management of cancer-related fatigue following primary cancer treatment: a multi-centre proof of concept randomised controlled trial. AB - PURPOSE: Cancer-related fatigue (CRF) is a frequent and distressing symptom experienced after cancer treatment. RESTORE is the first web-based resource designed to enhance self-efficacy to manage CRF following curative-intent treatment. The aim of this study is to test the proof of concept and inform the design of an effectiveness trial. METHODS: A multi-centre parallel-group two armed (1:1) exploratory randomised controlled trial (RCT) with qualitative process evaluation was employed in the study. Participants (>=18 years; <=5 years post treatment with moderate to severe fatigue) were recruited and randomly assigned to RESTORE or a leaflet. Feasibility and acceptability were measured by recruitment, attrition, intervention adherence, completion of outcome measures and process evaluation. Change in self-efficacy to manage CRF was also explored. Outcome measures were completed at baseline (T0), 6 weeks (T1) and 12 weeks (T2). Data were analysed using mixed-effects linear regression and directed content analysis. RESULTS: One hundred and sixty-three people participated in the trial and 19 in the process evaluation. The intervention was feasible (39 % of eligible patients consented) and acceptable (attrition rate 36 %). There was evidence of higher fatigue self-efficacy at T1 in the intervention group vs comparator (mean difference 0.51 [-0.08 to 1.11]), though the difference in groups decreased by 12 weeks. Time since diagnosis influenced perceived usefulness of the intervention. Modifications were suggested. CONCLUSION: Proof of concept was achieved. The RESTORE intervention should be subject to a definitive trial with some adjustments. Provision of an effective supportive resource would empower cancer survivors to manage CRF after treatment completion. TRIAL REGISTRATION: ISRCTN67521059. PMID- 26643073 TI - Down-Regulation of Cytokinin Oxidase 2 Expression Increases Tiller Number and Improves Rice Yield. AB - BACKGROUND: Cytokinins are plant-specific hormones that affect plant growth and development. The endogenous level of cytokinins in plant cells is regulated in part by irreversible degradation via cytokinin oxidase/dehydrogenase (CKX). Among the 11 rice CKXs, CKX2 has been implicated in regulation of rice grain yield. RESULTS: To specifically down-regulate OsCKX2 expression, we have chosen two conserved glycosylation regions of OsCKX2 for designing artificial short hairpin RNA interference genes (shRNA-CX3 and -CX5, representing the 5' and 3' glycosylation region sequences, respectively) for transformation by the Agrobacterium-mediated method. For each construct, 5 independent transgenic lines were obtained for detailed analysis. Southern blot analysis confirmed the integration of the shRNA genes into the rice genome, and quantitative real time RT-PCR and northern blot analyses showed reduced OsCKX2 expression in the young stem of transgenic rice at varying degrees. However, the expression of other rice CKX genes, such as CKX1 and CKX3, in these transgenic lines was not altered. Transgenic rice plants grown in the greenhouse were greener and more vigorous with delayed senescence, compared to the wild type. In field experiments, both CX3 and CX5 transgenic rice plants produced more tillers (27-81 %) and grains (24 67 %) per plant and had a heavier 1000 grain weight (5-15 %) than the wild type. The increases in grain yield were highly correlated with increased tiller numbers. Consistently, insertional activation of OsCKX2 led to increased expression of CKX2 and reduced tiller number and growth in a gene-dosage dependant manner. CONCLUSIONS: Taken together, these results demonstrate that specific suppression of OsCKX2 expression through shRNA-mediated gene silencing leads to enhanced growth and productivity in rice by increasing tiller number and grain weight. PMID- 26643075 TI - Real-Time Management of Multimodal Streaming Data for Monitoring of Epileptic Patients. AB - New generation of healthcare is represented by wearable health monitoring systems, which provide real-time monitoring of patient's physiological parameters. It is expected that continuous ambulatory monitoring of vital signals will improve treatment of patients and enable proactive personal health management. In this paper, we present the implementation of a multimodal real time system for epilepsy management. The proposed methodology is based on a data streaming architecture and efficient management of a big flow of physiological parameters. The performance of this architecture is examined for varying spatial resolution of the recorded data. PMID- 26643074 TI - A method for rapid quantitative assessment of biofilms with biomolecular staining and image analysis. AB - The accumulation of bacteria in surface-attached biofilms can be detrimental to human health, dental hygiene, and many industrial processes. Natural biofilms are soft and often transparent, and they have heterogeneous biological composition and structure over micro- and macroscales. As a result, it is challenging to quantify the spatial distribution and overall intensity of biofilms. In this work, a new method was developed to enhance the visibility and quantification of bacterial biofilms. First, broad-spectrum biomolecular staining was used to enhance the visibility of the cells, nucleic acids, and proteins that make up biofilms. Then, an image analysis algorithm was developed to objectively and quantitatively measure biofilm accumulation from digital photographs and results were compared to independent measurements of cell density. This new method was used to quantify the growth intensity of Pseudomonas putida biofilms as they grew over time. This method is simple and fast, and can quantify biofilm growth over a large area with approximately the same precision as the more laborious cell counting method. Stained and processed images facilitate assessment of spatial heterogeneity of a biofilm across a surface. This new approach to biofilm analysis could be applied in studies of natural, industrial, and environmental biofilms. PMID- 26643076 TI - Evaluation of Electromagnetic Fields in a Hospital for Safe Use of Electronic Medical Equipment. AB - Establishment of electromagnetic compatibility is important in use of electronic medical equipment in hospitals. To evaluate the electromagnetic environment, the electric field intensity induced by electromagnetic radiation in broadcasting spectra coming from outside the hospital was measured in a new hospital building before any patients visited the hospital and 6 months after the opening of the hospital. Various incoming radio waves were detected on the upper floors, with no significant difference in measured levels before and after opening of the hospital. There were no cellphone terminal signals before the hospital opened, but these signals were strongly detected at 6 months thereafter. Cellphone base stations signals were strongly detected on the upper floors, but there were no signals at most locations in the basement and in the center of the building on the lower floors. A maximum electrical intensity of 0.28 V/m from cellphone base stations (2.1 GHz) was detected at the south end of the 2nd floor before the hospital opened. This value is lower than the EMC marginal value for general electronic medical equipment specified in IEC 60601-1-2 (3 V/m). Therefore, electromagnetic interference with electronic medical equipment is unlikely in this situation. However, cellphone terminal signals were frequently detected in non-base station signal areas. This is a concern, and understanding signal strength from cellphone base stations at a hospital is important for promotion of greater safety. PMID- 26643077 TI - Importance of Statistical Evidence in Estimating Valid DEA Scores. AB - Data Envelopment Analysis (DEA) allows healthcare scholars to measure productivity in a holistic manner. It combines a production unit's multiple outputs and multiple inputs into a single measure of its overall performance relative to other units in the sample being analyzed. It accomplishes this task by aggregating a unit's weighted outputs and dividing the output sum by the unit's aggregated weighted inputs, choosing output and input weights that maximize its output/input ratio when the same weights are applied to other units in the sample. Conventional DEA assumes that inputs and outputs are used in different proportions by the units in the sample. So, for the sample as a whole, inputs have been substituted for each other and outputs have been transformed into each other. Variables are assigned different weights based on their marginal rates of substitution and marginal rates of transformation. If in truth inputs have not been substituted nor outputs transformed, then there will be no marginal rates and therefore no valid basis for differential weights. This paper explains how to statistically test for the presence of substitutions among inputs and transformations among outputs. Then, it applies these tests to the input and output data from three healthcare DEA articles, in order to identify the effects on DEA scores when input substitutions and output transformations are absent in the sample data. It finds that DEA scores are badly biased when substitution and transformation are absent and conventional DEA models are used. PMID- 26643078 TI - Using a Calculated Pulse Rate with an Artificial Neural Network to Detect Irregular Interbeats. AB - Heart rate is an important clinical measure that is often used in pathological diagnosis and prognosis. Valid detection of irregular heartbeats is crucial in the clinical practice. We propose an artificial neural network using the calculated pulse rate to detect irregular interbeats. The proposed system measures the calculated pulse rate to determine an "irregular interbeat on" or "irregular interbeat off" event. If an irregular interbeat is detected, the proposed system produces a danger warning, which is helpful for clinicians. If a non-irregular interbeat is detected, the proposed system displays the calculated pulse rate. We include a flow chart of the proposed software. In an experiment, we measure the calculated pulse rates and achieve an error percentage of < 3% in 20 participants with a wide age range. When we use the calculated pulse rates to detect irregular interbeats, we find such irregular interbeats in eight participants. PMID- 26643079 TI - FPGA Implementation of Heart Rate Monitoring System. AB - This paper describes a field programmable gate array (FPGA) implementation of a system that calculates the heart rate from Electrocardiogram (ECG) signal. After heart rate calculation, tachycardia, bradycardia or normal heart rate can easily be detected. ECG is a diagnosis tool routinely used to access the electrical activities and muscular function of the heart. Heart rate is calculated by detecting the R peaks from the ECG signal. To provide a portable and the continuous heart rate monitoring system for patients using ECG, needs a dedicated hardware. FPGA provides easy testability, allows faster implementation and verification option for implementing a new design. We have proposed a five-stage based methodology by using basic VHDL blocks like addition, multiplication and data conversion (real to the fixed point and vice-versa). Our proposed heart rate calculation (R-peak detection) method has been validated, using 48 first channel ECG records of the MIT-BIH arrhythmia database. It shows an accuracy of 99.84%, the sensitivity of 99.94% and the positive predictive value of 99.89%. Our proposed method outperforms other well-known methods in case of pathological ECG signals and successfully implemented in FPGA. PMID- 26643080 TI - A Framework for Evaluating the Software Product Quality of Pregnancy Monitoring Mobile Personal Health Records. AB - Stakeholders' needs and expectations are identified by means of software quality requirements, which have an impact on software product quality. In this paper, we present a set of requirements for mobile personal health records (mPHRs) for pregnancy monitoring, which have been extracted from literature and existing mobile apps on the market. We also use the ISO/IEC 25030 standard to suggest the requirements that should be considered during the quality evaluation of these mPHRs. We then go on to design a checklist in which we contrast the mPHRs for pregnancy monitoring requirements with software product quality characteristics and sub-characteristics in order to calculate the impact of these requirements on software product quality, using the ISO/IEC 25010 software product quality standard. The results obtained show that the requirements related to the user's actions and the app's features have the most impact on the external sub characteristics of the software product quality model. The only sub characteristic affected by all the requirements is Appropriateness of Functional suitability. The characteristic Operability is affected by 95% of the requirements while the lowest degrees of impact were identified for Compatibility (15%) and Transferability (6%). Lastly, the degrees of the impact of the mPHRs for pregnancy monitoring requirements are discussed in order to provide appropriate recommendations for the developers and stakeholders of mPHRs for pregnancy monitoring. PMID- 26643081 TI - Reliable and Accurate Calcium Volume Measurement in Coronary Artery Using Intravascular Ultrasound Videos. AB - Quantitative assessment of calcified atherosclerotic volume within the coronary artery wall is vital for cardiac interventional procedures. The goal of this study is to automatically measure the calcium volume, given the borders of coronary vessel wall for all the frames of the intravascular ultrasound (IVUS) video. Three soft computing fuzzy classification techniques were adapted namely Fuzzy c-Means (FCM), K-means, and Hidden Markov Random Field (HMRF) for automated segmentation of calcium regions and volume computation. These methods were benchmarked against previously developed threshold-based method. IVUS image data sets (around 30,600 IVUS frames) from 15 patients were collected using 40 MHz IVUS catheter (Atlantis(r) SR Pro, Boston Scientific(r), pullback speed of 0.5 mm/s). Calcium mean volume for FCM, K-means, HMRF and threshold-based method were 37.84 +/- 17.38 mm(3), 27.79 +/- 10.94 mm(3), 46.44 +/- 19.13 mm(3) and 35.92 +/- 16.44 mm(3) respectively. Cross-correlation, Jaccard Index and Dice Similarity were highest between FCM and threshold-based method: 0.99, 0.92 +/- 0.02 and 0.95 + 0.02 respectively. Student's t-test, z-test and Wilcoxon-test are also performed to demonstrate consistency, reliability and accuracy of the results. Given the vessel wall region, the system reliably and automatically measures the calcium volume in IVUS videos. Further, we validated our system against a trained expert using scoring: K-means showed the best performance with an accuracy of 92.80%. Out procedure and protocol is along the line with method previously published clinically. PMID- 26643082 TI - Molecular Cloning, Expression Analysis, and Functional Characterization of the H(+)-Pyrophosphatase from Jatropha curcas. AB - H(+)-pyrophosphatase (H(+)-PPase) is a primary pyrophosphate (PPi)-energized proton pump to generate electrochemical H(+) gradient for ATP production and substance translocations across membranes. It plays an important role in stress adaptation that was intensively substantiated by numerous transgenic plants overexpressing H(+)-PPases yet devoid of any correlated studies pointing to the elite energy plant, Jatropha curcas. Herein, we cloned the full length of J. curcas H(+)-PPase (JcVP1) complementary DNA (cDNA) by reverse transcription PCR, based on the assembled sequence of its ESTs highly matched to Hevea brasiliensis H(+)-PPase. This gene encodes a polypeptide of 765 amino acids that was predicted as a K(+)-dependent H(+)-PPase evolutionarily closest to those of other Euphorbiaceae plants. Many cis-regulatory elements relevant to environmental stresses, molecular signals, or tissue-specificity were identified by promoter prediction within the 1.5-kb region upstream of JcVP1 coding sequence. Meanwhile, the responses of JcVP1 expression to several common abiotic stresses (salt, drought, heat, cold) were characterized with a considerable accordance with the inherent stress tolerance of J. curcas. Moreover, we found that the heterologous expression of JcVP1 could significantly improve the salt tolerance in both recombinant Escherichia coli and Saccharomyces cerevisiae, and this effect could be further fortified in yeast by N-terminal addition of a vacuole-targeting signal peptide from the H(+)-PPase of Trypanosoma cruzi. PMID- 26643083 TI - Terson's syndrome in aneurysmal subarachnoid haemorrhage. PMID- 26643084 TI - Transient global amnesia like syndrome associated with acute infarction of the corpus callosum: a case report. PMID- 26643085 TI - A randomized, double-blind, phase II, exploratory trial evaluating the palliative benefit of either continuing pamidronate or switching to zoledronic acid in patients with high-risk bone metastases from breast cancer. AB - Previous studies suggest switching from pamidronate to a more potent bone targeted agent is associated with biomarker and palliative response in breast cancer patients with bone metastases. Until now, this has not been addressed in a double-blind, randomized trial. Breast cancer patients with high-risk bone metastases, despite >3 months of pamidronate, were randomized to either continue pamidronate or switch to zoledronic acid every 4 weeks for 12 weeks. Primary outcome was the proportion of patients achieving a fall in serum C-telopeptide (sCTx) at 12 weeks. Secondary outcomes included difference in mean sCTx, pain scores, quality of life, toxicity, and skeletal-related events (SREs). Seventy three patients entered the study; median age 61 years (range 37-87). Proportion of patients achieving a fall in sCTx over the 12-week evaluation period was 26/32 (81 %) with zoledronic acid and 18/29 (62 %) with pamidronate (p = 0.095). Mean decrease in sCTx (mean difference between groups = 50 ng/L, 95 % CI 18-84; p = 0.003) was significantly greater in patients who received zoledronic acid. Quality of life, pain scores, toxicity, and frequency of new SREs were comparable between the two arms. While a switch from pamidronate to zoledronic acid resulted in reduction in mean sCTx, there were no significant differences between the arms for proportion of patients achieving a reduction in sCTx, quality of life, pain scores, toxicity or SREs. Given the lack of palliative improvement, the current data do not support a switching strategy. PMID- 26643086 TI - Impact of guideline-based use of uPA/PAI-1 on patient outcome in intermediate risk early breast cancer. AB - The purpose of this study was to evaluate the influence of guideline-based prospective use of uPA/PAI-1 on clinical outcome in an intermediate-risk cohort of breast cancer patients. We analyzed 381 consecutive primary breast cancer patients (2003-2011) at the breast center Ostbayern meeting the following criteria: M0/N0/estrogen receptor (ER)+/G2. Clinical-pathological data, uPA/PAI 1, and follow-up data were collected. Decisions for adjuvant chemotherapy were made upon consideration of prospectively measured uPA/PAI-1. Observed disease free survival (DFS) and overall survival (OS) were calculated by Kaplan-Meier estimates. Using guideline-based analysis of uPA/PAI-1, treatment with adjuvant chemotherapy was avoided in 86.5 % of patients with low uPA/PAI-1, i.e., 38.8 % of the total patient collective. Median follow-up was 52.5 months. Five-year relapse-free survival in intermediate-risk patients (N0, G2) without chemotherapy was 99 %. Five-year overall survival including all causes of death was 95 %. By using uPA/PAI-1, adjuvant chemotherapy can be avoided in a major part of patients with intermediate-risk breast cancer. Nevertheless, DFS and OS of these patients at 5 years remain excellent. The potential, but hardly measurable, benefit of adjuvant chemotherapy has to be set in contrast with its associated side effects and increased morbidity. Patients with high uPA/PAI-1 show benefit from chemotherapy. In this subgroup, a very good OS was observed as well. These findings strongly support the use of uPA/PAI-1 together with clinic-pathological parameters as an evidence-based, clinically relevant and inexpensive decision tool in the routine of a breast center. PMID- 26643087 TI - Minimizing the cost of locomotion with inclined trunk predicts crouched leg kinematics of small birds at realistic levels of elastic recoil. AB - Small birds move with pronograde trunk orientation and crouched legs. Although the pronograde trunk has been suggested to be beneficial for grounded running, the cause(s) of the specific leg kinematics are unknown. Here we show that three charadriiform bird species (northern lapwing, oystercatcher, and avocet; great examples of closely related species that differ remarkably in their hind limb design) move their leg segments during stance in a way that minimizes the cost of locomotion. We imposed measured trunk motions and ground reaction forces on a kinematic model of the birds. The model was used to search for leg configurations that minimize leg work that accounts for two factors: elastic recoil in the intertarsal joint, and cheaper negative muscle work relative to positive muscle work. A physiological level of elasticity (~ 0.6) yielded segment motions that match the experimental data best, with a root mean square of angular deviations of ~ 2.1 deg. This finding suggests that the exploitation of elastic recoil shapes the crouched leg kinematics of small birds under the constraint of pronograde trunk motion. Considering that an upright trunk and more extended legs likely decrease the cost of locomotion, our results imply that the cost of locomotion is a secondary movement criterion for small birds. Scaling arguments suggest that our approach may be utilized to provide new insights into the motion of extinct species such as dinosaurs. PMID- 26643088 TI - Volumetric flow imaging reveals the importance of vortex ring formation in squid swimming tail-first and arms-first. AB - Squids use a pulsed jet and fin movements to swim both arms-first (forward) and tail-first (backward). Given the complexity of the squid multi-propulsor system, 3D velocimetry techniques are required for the comprehensive study of wake dynamics. Defocusing digital particle tracking velocimetry, a volumetric velocimetry technique, and high-speed videography were used to study arms-first and tail-first swimming of brief squid Lolliguncula brevis over a broad range of speeds [0-10 dorsal mantle lengths (DML) s(-1)] in a swim tunnel. Although there was considerable complexity in the wakes of these multi-propulsor swimmers, 3D vortex rings and their derivatives were prominent reoccurring features during both tail-first and arms-first swimming, with the greatest jet and fin flow complexity occurring at intermediate speeds (1.5-3.0 DML s(-1)). The jet generally produced the majority of thrust during rectilinear swimming, increasing in relative importance with speed, and the fins provided no thrust at speeds >4.5 DML s(-1). For both swimming orientations, the fins sometimes acted as stabilizers, producing negative thrust (drag), and consistently provided lift at low/intermediate speeds (<2.0 DML s(-1)) to counteract negative buoyancy. Propulsive efficiency (eta) increased with speed irrespective of swimming orientation, and eta for swimming sequences with clear isolated jet vortex rings was significantly greater (eta=78.6+/-7.6%, mean+/-s.d.) than that for swimming sequences with clear elongated regions of concentrated jet vorticity (eta=67.9+/ 19.2%). This study reveals the complexity of 3D vortex wake flows produced by nekton with hydrodynamically distinct propulsors. PMID- 26643089 TI - Cold-hardening during long-term acclimation in a freeze-tolerant woolly bear caterpillar, Pyrrharctia isabella. AB - The banded woolly bear caterpillar, Pyrrharctia isabella (Lepidoptera: Erebidae), overwinters in leaf litter and survives freezing under natural conditions. Following 18 weeks of cold acclimation at 5 degrees C, all caterpillars could survive 1 week of continuous freezing at -20 degrees C or seven cycles of freezing-thawing at -20 degrees C, but none survived freezing at -80 degrees C. Field-collected caterpillars had a temperature of crystallization of -7.7+/-0.5 degrees C that decreased significantly to -9.5+/-0.6 degrees C after 12 weeks of acclimation at 5 degrees C. Hemolymph levels of free proline, total amino acids and proteins reached a peak during the first 4 weeks of acclimation; concomitantly, hemolymph osmolality increased markedly during this interval (from 364 to 1282 mosmol kg(-1)). In contrast, hemolymph pH decreased during the first 4 weeks of acclimation before this trend reversed and pH values gradually returned to initial values. However, pH reached its peak value following 1 week at -20 degrees C, but decreased after longer periods of freezing. During cold acclimation, cholesterol levels decreased in the hemolymph and the membrane fraction of fat body but not in other tissues. Lethal freezing at -80 degrees C reduced cell survival in foregut tissue and caused leakage of free proline, total amino acids and proteins from tissues into the hemolymph. The addition of glycerol to the bathing medium reduced freezing injury in fat body cells, as evidenced by reduced leakage of amino acids and proteins. PMID- 26643090 TI - The thick left ventricular wall of the giraffe heart normalises wall tension, but limits stroke volume and cardiac output. AB - Giraffes--the tallest extant animals on Earth--are renowned for their high central arterial blood pressure, which is necessary to secure brain perfusion. Arterial pressure may exceed 300 mmHg and has historically been attributed to an exceptionally large heart. Recently, this has been refuted by several studies demonstrating that the mass of giraffe heart is similar to that of other mammals when expressed relative to body mass. It thus remains unexplained how the normal sized giraffe heart generates such massive arterial pressures. We hypothesized that giraffe hearts have a small intraventricular cavity and a relatively thick ventricular wall, allowing for generation of high arterial pressures at normal left ventricular wall tension. In nine anaesthetized giraffes (495+/-38 kg), we determined in vivo ventricular dimensions using echocardiography along with intraventricular and aortic pressures to calculate left ventricular wall stress. Cardiac output was also determined by inert gas rebreathing to provide an additional and independent estimate of stroke volume. Echocardiography and inert gas-rebreathing yielded similar cardiac outputs of 16.1+/-2.5 and 16.4+/-1.4 l min(-1), respectively. End-diastolic and end-systolic volumes were 521+/-61 ml and 228+/-42 ml, respectively, yielding an ejection fraction of 56+/-4% and a stroke volume of 0.59 ml kg(-1). Left ventricular circumferential wall stress was 7.83+/-1.76 kPa. We conclude that, relative to body mass, a small left ventricular cavity and a low stroke volume characterizes the giraffe heart. The adaptations result in typical mammalian left ventricular wall tensions, but produce a lowered cardiac output. PMID- 26643091 TI - Feed-forward motor control of ultrafast, ballistic movements. AB - To circumvent the limits of muscle, ultrafast movements achieve high power through the use of springs and latches. The time scale of these movements is too short for control through typical neuromuscular mechanisms, thus ultrafast movements are either invariant or controlled prior to movement. We tested whether mantis shrimp (Stomatopoda: Neogonodactylus bredini) vary their ultrafast smashing strikes and, if so, how this control is achieved prior to movement. We collected high-speed images of strike mechanics and electromyograms of the extensor and flexor muscles that control spring compression and latch release. During spring compression, lateral extensor and flexor units were co-activated. The strike initiated several milliseconds after the flexor units ceased, suggesting that flexor activity prevents spring release and determines the timing of strike initiation. We used linear mixed models and Akaike's information criterion to serially evaluate multiple hypotheses for control mechanisms. We found that variation in spring compression and strike angular velocity were statistically explained by spike activity of the extensor muscle. The results show that mantis shrimp can generate kinematically variable strikes and that their kinematics can be changed through adjustments to motor activity prior to the movement, thus supporting an upstream, central-nervous-system-based control of ultrafast movement. Based on these and other findings, we present a shishiodoshi model that illustrates alternative models of control in biological ballistic systems. The discovery of feed-forward control in mantis shrimp sets the stage for the assessment of targets, strategic variation in kinematics and the role of learning in ultrafast animals. PMID- 26643092 TI - Rectal Radiotherapy--Intensity-modulated Radiotherapy Delivery, Delineation and Doses. AB - The use of intensity-modulated radiotherapy in rectal cancer is attractive in that it may reduce acute and late toxicities and potentially facilitate dose escalation. Intensity-modulated radiotherapy probably has a role in selected patients, but further investigation is required to identify the parameters for selection. Delineation of specific nodal groups allows maximal sparing of bladder and small bowel. In locally advanced tumours a simultaneous integrated boost allows dose escalation incorporating hypofractionation and a shorter overall treatment time. However, due to a sparsity of data on late toxicity in doses >= 60 Gy, doses at this level should be used with caution, ideally within prospective trials. Future studies investigating dose escalation must ascertain late toxicity as well as local control, as both can significantly affect quality of life and without both, the risk-benefit ratio cannot be calculated. PMID- 26643093 TI - "Why, sometimes I've believed as many as six impossible things before breakfast." Lewis Carroll, In "Through the looking-glass, and what Alice found there". PMID- 26643094 TI - Effects of anesthesia on the respiratory system. AB - Most anesthetics cause a loss of muscle tone that is accompanied by a fall in the resting lung volume. The lowered lung volume promotes cyclic (tidal) or continuous airway closure. High inspired oxygen fractions cause rapid absorption of gas behind closed airways, resulting in atelectasis. This chapter deals with these mechanisms in more detail, and it addresses possible measures to keep the lung open with the use of recruitment maneuvers, continuous and/or end-expiratory positive pressure, as well as the interaction with different oxygen concentrations. The effects on ventilation/perfusion matching and pulmonary gas exchange are also discussed. PMID- 26643095 TI - Modes of mechanical ventilation for the operating room. AB - Most patients undergoing surgical procedures need to be mechanically ventilated, because of the impact of several drugs administered at induction and during maintenance of general anaesthesia on respiratory function. Optimization of intraoperative mechanical ventilation can reduce the incidence of post-operative pulmonary complications and improve the patient's outcome. Preoxygenation at induction of general anaesthesia prolongs the time window for safe intubation, reducing the risk of hypoxia and overweighs the potential risk of reabsorption atelectasis. Non-invasive positive pressure ventilation delivered through different interfaces should be considered at the induction of anaesthesia morbidly obese patients. Anaesthesia ventilators are becoming increasingly sophisticated, integrating many functions that were once exclusive to intensive care. Modern anaesthesia machines provide high performances in delivering the desired volumes and pressures accurately and precisely, including assisted ventilation modes. Therefore, the physicians should be familiar with the potential and pitfalls of the most commonly used intraoperative ventilation modes: volume-controlled, pressure-controlled, dual-controlled and assisted ventilation. Although there is no clear evidence to support the advantage of any one of these ventilation modes over the others, protective mechanical ventilation with low tidal volume and low levels of positive end-expiratory pressure (PEEP) should be considered in patients undergoing surgery. The target tidal volume should be calculated based on the predicted or ideal body weight rather than on the actual body weight. To optimize ventilation monitoring, anaesthesia machines should include end-inspiratory and end-expiratory pause as well as flow-volume loop curves. The routine administration of high PEEP levels should be avoided, as this may lead to haemodynamic impairment and fluid overload. Higher PEEP might be considered during surgery longer than 3 h, laparoscopy in the Trendelenburg position and in patients with body mass index >35 kg/m(2). Large randomized trials are warranted to identify subgroups of patients and the type of surgery that can potentially benefit from specific ventilation modes or ventilation settings. PMID- 26643096 TI - Mechanisms of ventilator-induced lung injury in healthy lungs. AB - Mechanical ventilation is an essential method of patient support, but it may induce lung damage, leading to ventilator-induced lung injury (VILI). VILI is the result of a complex interplay among various mechanical forces that act on lung structures, such as type I and II epithelial cells, endothelial cells, macrophages, peripheral airways, and the extracellular matrix (ECM), during mechanical ventilation. This article discusses ongoing research focusing on mechanisms of VILI in previously healthy lungs, such as in the perioperative period, and the development of new ventilator strategies for surgical patients. Several experimental and clinical studies have been conducted to evaluate the mechanisms of mechanotransduction in each cell type and in the ECM, as well as the role of different ventilator parameters in inducing or preventing VILI. VILI may be attenuated by reducing the tidal volume; however, the use of higher or lower levels of positive end-expiratory pressure (PEEP) and recruitment maneuvers during the perioperative period is a matter of debate. Many questions concerning the mechanisms of VILI in surgical patients remain unanswered. The optimal threshold value of each ventilator parameter to reduce VILI is also unclear. Further experimental and clinical studies are necessary to better evaluate ventilator settings during the perioperative period in different types of surgery. PMID- 26643097 TI - Post-operative pulmonary complications: Understanding definitions and risk assessment. AB - Post-operative pulmonary complications (PPCs) can have severe consequences and their incidence is high. In recent years, PPCs have been the subject of numerous studies and articles, which have provided a great deal of information that is beneficial but that can cause confusion on a practical level. This review focusses on three main points: (1) the definitions of PPCs, which are heterogeneous and often vary from one report to another, despite emerging consensus; (2) the risk as reflected in the pool of PPC predictors, with each study identifying some but leaving us with a myriad of combinations; and (3) the many PPC prediction scores proposed, each with its strengths and limitations. We attempt to clarify the practical and research implications of the current situation. PMID- 26643098 TI - Intraoperative ventilation strategies to prevent postoperative pulmonary complications: Systematic review, meta-analysis, and trial sequential analysis. AB - For many years, mechanical ventilation with high tidal volumes (V(T)) was common practice in operating theaters because this strategy recruits collapsed lung tissue, improves ventilation-perfusion mismatch, and thus decreases the need for high oxygen fractions. Positive end-expiratory pressure (PEEP) was seldom used because it could cause cardiac compromise. Increasing advances in the understanding of the mechanisms of ventilator-induced lung injury from animal studies and randomized controlled trials in patients with uninjured lungs in intensive care unit and operation room have pushed anesthesiologists to consider lung-protective strategies during intraoperative ventilation. These strategies at least include the use of low V(T), and perhaps also the use of PEEP, which when compared to high V(T) with low PEEP may prevent the occurrence of postoperative pulmonary complications (PPCs). Such protective effects, however, are likely ascribed to low V(T) rather than to PEEP. In fact, at least in nonobese patients undergoing open abdominal surgery, high PEEP does not protect against PPCs, and it can impair the hemodynamics. Further studies shall determine whether a strategy consisting of low V(T) combined with PEEP and recruitment maneuvers reduces PPCs in obese patients and other types of surgery (e.g., laparoscopic and thoracic), compared to low V(T) with low PEEP. Furthermore, the role of driving pressure for titrating ventilation settings in patients with uninjured lungs shall be investigated. PMID- 26643099 TI - Intraoperative mechanical ventilation strategies to prevent postoperative pulmonary complications in patients with pulmonary and extrapulmonary comorbidities. AB - A variety of patient characteristics and comorbidities have been identified, which increase the risk of postoperative pulmonary complications (PPCs), including smoking, age, chronic obstructive pulmonary disease, pulmonary hypertension, obstructive sleep apnea, cardiac and neurologic diseases as well as critical illness. In contrast to the variety of conditions, evidence for specific intraoperative ventilation strategies to reduce PPC is very limited for most comorbidities. Here, we provide an overview of and discuss possible implications for the intraoperative ventilatory management of patients with comorbidities. PMID- 26643100 TI - Intraoperative mechanical ventilation strategies for one-lung ventilation. AB - One-lung ventilation (OLV) has two major challenges: oxygenation and lung protection. The former is mainly because the ventilation of one lung is stopped while the perfusion continues; the latter is mainly because the whole ventilation is applied to only one lung. Recommendations for maintaining the oxygenation and methods of lung protection can contradict each other (such as high vs. low inspiratory oxygen fraction (FiO2), high vs. low tidal volume (TV), etc.). In light of the (very few) randomized clinical trials, this review focuses on a recent strategy for OLV, which includes a possible decrease in FiO2, lower TVs, positive end-expiratory pressure (PEEP) to the dependent lung, continuous positive airway pressure (CPAP) to the non-dependent lung and recruitment manoeuvres. Other applications such as anaesthetic choice and fluid management can affect the success of ventilatory strategy; new developments have changed the classical approach in this respect. PMID- 26643101 TI - Intraoperative mechanical ventilation for the pediatric patient. AB - Invasive mechanical ventilation is required when children undergo general anesthesia for any procedure. It is remarkable that one of the most practiced interventions such as pediatric mechanical ventilation is hardly supported by any scientific evidence but rather based on personal experience and data from adults, especially as ventilation itself is increasingly recognized as a harmful intervention that causes ventilator-induced lung injury. The use of low tidal volume and higher levels of positive end-expiratory pressure became an integral part of lung-protective ventilation following the outcomes of clinical trials in critically ill adults. This approach has been readily adopted in pediatric ventilation. However, a clear association between tidal volume and mortality has not been ascertained in pediatrics. In fact, experimental studies have suggested that young children might be less susceptible to ventilator-induced lung injury. As such, no recommendations on optimal lung-protective ventilation strategy in children with or without lung injury can be made. PMID- 26643102 TI - Perioperative ventilatory strategies in cardiac surgery. AB - Recent data promote the utilization of prophylactic protective ventilation even in patients without acute respiratory distress syndrome (ARDS), and especially after cardiac surgery. The implementation of specific perioperative ventilatory strategies in patients undergoing cardiac surgery can improve both respiratory and extra-pulmonary outcomes. Protective ventilation is not limited to tidal volume reduction. The major components of ventilatory management include assist controlled mechanical ventilation with low tidal volumes (6-8 mL kg(-1) of predicted body weight) associated with higher positive end-expiratory pressure (PEEP), limitation of fraction of inspired oxygen (FiO2), ventilation maintenance during cardiopulmonary bypass, and finally recruitment maneuvers. In order for such strategies to be fully effective, they should be integrated into a multimodal approach beginning from the induction and continuing over the postoperative period. PMID- 26643103 TI - Non-ventilatory approaches to prevent postoperative pulmonary complications. AB - This educational narrative review provides a summary of non-ventilatory strategies to prevent postoperative pulmonary complications (PPCs). It highlights patient- and procedure-related risk factors for PPCs that are non-modifiable, potentially modifiable, or well modifiable. Non-ventilatory strategies, mainly based on the modification of risk factors, play a key role in reducing PPCs. Non modifiable risk factors, most importantly age, American Society of Anesthesiologists (ASA) class, and risk of the procedure, should be recognized and patients intensively screened for the potential to optimize other, potentially or well-modifiable, risk factors. Potentially modifiable risk factors, mainly comorbidities and the surgical approach, increase the risk of PPCs. Patient-related factors can be improved while procedure-related factors may be adapted in high-risk patients. Well-modifiable risk factors, mainly certain anesthesia techniques, for example, general anesthesia, intravenous opioids or liberal fluid management, and smoking or alcohol abuse, should be avoided as far as possible in order to prevent PPCs. PMID- 26643104 TI - Development and Evaluation of a Training Program for Organ Procurement Coordinators Using Standardized Patient Methodology. AB - OBJECTIVES: The low rate of consent by next of kin of donor-eligible patients is a major limiting factor in organ transplant. Educating health care professionals about their role may lead to measurable improvements in the process. Our aim was to describe the developmental steps of a communication skills training program for health care professionals using standardized patients and to evaluate the results. MATERIALS AND METHODS: We developed a rubric and 5 cases for standardized family interviews. The 20 participants interviewed standardized families at the beginning and at the end of the training course, with interviews followed by debriefing sessions. Participants also provided feedback before and after the course. The performance of each participant was assessed by his or her peers using the rubric. We calculated the generalizability coefficient to measure the reliability of the rubric and used the Wilcoxon signed rank test to compare achievement among participants. Statistical analyses were performed with SPSS software (SPSS: An IBM Company, version 17.0, IBM Corporation, Armonk, NY, USA). RESULTS: All participants received higher scores in their second interview, including novice participants who expressed great discomfort during their first interview. The participants rated the scenarios and the standardized patients as very representative of real-life situations, with feedback forms showing that the interviews, the video recording sessions, and the debriefing sessions contributed to their learning. CONCLUSIONS: Our program was designed to meet the current expectations and implications in the field of donor consent from next of kin. Results showed that our training program developed using standardized patient methodology was effective in obtaining the communication skills needed for family interviews during the consent process. The rubric developed during the study was a valid and reliable assessment tool that could be used in further educational activities. The participants showed significant improvements in communication skills. PMID- 26643106 TI - A generalized birth and death process for modeling the fates of gene duplication. AB - BACKGROUND: Accurately estimating the timing and mode of gene duplications along the evolutionary history of species can provide invaluable information about underlying mechanisms by which the genomes of organisms evolved and the genes with novel functions arose. Mechanistic models have previously been introduced that allow for probabilistic inference of the evolutionary mechanism for duplicate gene retention based upon the average rate of loss over time of the duplicate. However, there is currently no probabilistic model embedded in a birth death modeling framework that can take into account the effects of different evolutionary mechanisms of gene retention when analyzing gene family data. RESULTS: In this study, we describe a generalized birth-death process for modeling the fates of gene duplication. Use of mechanistic models in a phylogenetic framework requires an age-dependent birth-death process. Starting with a single population corresponding to the lineage of a phylogenetic tree and with an assumption of a clock that starts ticking for each duplicate at its birth, an age-dependent birth-death process is developed by extending the results from the time-dependent birth-death process. The implementation of such models in a full phylogenetic framework is expected to enable large scale probabilistic analysis of duplicates in comparative genomic studies. CONCLUSIONS: We develop an age-dependent birth-death model for understanding the mechanisms of gene retention, which allows a gene loss rate dependent on each duplication event. Simulation results indicate that different mechanisms of gene retentions produce distinct likelihood functions, which can be used with genomic data to quantitatively distinguish those mechanisms. PMID- 26643105 TI - The interaction of lubricin/proteoglycan 4 (PRG4) with toll-like receptors 2 and 4: an anti-inflammatory role of PRG4 in synovial fluid. AB - BACKGROUND: Lubricin/proteoglycan-4 (PRG4) is a mucinous glycoprotein secreted by synovial fibroblasts and superficial zone chondrocytes. PRG4 has a homeostatic multifaceted role in the joint. PRG4 intra-articular treatment retards progression of cartilage degeneration in pre-clinical posttraumatic osteoarthritis models. The objective of this study is to evaluate the binding of recombinant human PRG4 (rhPRG4) and native human PRG4 (nhPRG4) to toll-like receptors 2 and 4 (TLR2 and TLR4) and whether this interaction underpins a PRG4 anti-inflammatory role in synovial fluid (SF) from patients with osteoarthritis (OA) and rheumatoid arthritis (RA). METHODS: rhPRG4 and nhPRG4 binding to TLR2 and TLR4 was evaluated using a direct enzyme linked immunosorbent assay (ELISA). Association of rhPRG4 with TLR2 and TLR4 overexpressing human embryonic kidney (HEK) cells was studied by flow cytometry. Activation of TLR2 and TLR4 on HEK cells by agonists Pam3CSK4 and lipopolysaccharide (LPS) was studied in the absence or presence of nhPRG4 at 50, 100 and 150 MUg/ml. Activation of TLR2 and TLR4 by OA SF and RA SF and the effect of nhPRG4 SF treatment on receptor activation was assessed. PRG4 was immunoprecipitated from pooled OA and RA SF. TLR2 and TLR4 activation by pooled OA and RA SF with or without PRG4 immunoprecipitation was compared. RESULTS: rhPRG4 and nhPRG4 exhibited concentration-dependent binding to TLR2 and TLR4. rhPRG4 associated with TLR2- and TLR4-HEK cells in a time-dependent manner. Co-incubation of nhPRG4 (50, 100 and 150 MUg/ml) and Pam3CSK4 or LPS reduced TLR2 or TLR4 activation compared to Pam3CSK4 or LPS alone (p <0.05). OA SF and RA SF activated TLR2 and TLR4 and nhPRG4 treatment reduced SF-induced receptor activation (p <0.001). PRG4 depletion by immunoprecipitation significantly increased TLR2 activation by OA SF and RA SF (p <0.001). CONCLUSION: PRG4 binds to TLR2 and TLR4 and this binding mediates a novel anti-inflammatory role for PRG4. PMID- 26643107 TI - Inverse association between microRNA-124a and ABCC4 in HepG2 cells treated with antiretroviral drugs. AB - The ATP-binding cassette (ABC) super-family of drug transporters regulates efflux of xenobiotic compounds. The subfamily, multi-drug resistance proteins (MRPs) transports cyclic nucleotides and xenobiotics. Epigenetic modulation of drug transporters is scarcely described. The regulatory role of microRNA (miR)-124a on drug transporter gene ABCC4 was only recently reported. Our study investigated the differential regulation of miR-124a by nucleoside reverse transcriptase inhibitors (NRTIs): Zidovudine (AZT), Stavudine (d4T) and Tenofovir (TFV); at 24 h and 120 h treatments in HepG2 cells. ABCC4 mRNA (qPCR) and ABCC4 protein (western blot) were quantified. Cytotoxicity was evaluated by lactate dehydrogenase (LDH) levels. All NRTIs elevated miR-124a levels at 24 h, with a concomitant decline in ABCC4 mRNA levels (p<0.05). At 120 h, d4T and TFV elevated miR-124a and depleted ABCC4 mRNA levels (p<0.0001), while the inverse was observed with AZT (p<0.005). ABCC4 protein was increased by d4T and TFV at 24h. A significant reduction in protein levels was observed at 120 h in all three treatments (p<0.005). The disjoint in mRNA and protein levels is likely due to ABCC4 being a membrane bound protein. Following prolonged exposure, membrane integrity was compromised as evidenced by increased LDH leakage (p<0.005). We conclude antiretroviral drugs have varying effects on miR-124a and ABCC4. PMID- 26643108 TI - Association between use of warfarin with common sulfonylureas and serious hypoglycemic events: retrospective cohort analysis. AB - STUDY QUESTION: Is warfarin use associated with an increased risk of serious hypoglycemic events among older people treated with the sulfonylureas glipizide and glimepiride? METHODS: This was a retrospective cohort analysis of pharmacy and medical claims from a 20% random sample of Medicare fee for service beneficiaries aged 65 years or older. It included 465,918 beneficiaries with diabetes who filled a prescription for glipizide or glimepiride between 2006 and 2011 (4,355,418 person quarters); 71,895 (15.4%) patients also filled a prescription for warfarin (416,479 person quarters with warfarin use). The main outcome measure was emergency department visit or hospital admission with a primary diagnosis of hypoglycemia in person quarters with concurrent fills of warfarin and glipizide/glimepiride compared with the rates in quarters with glipizide/glimepiride fills only, Multivariable logistic regression was used to adjust for individual characteristics. Secondary outcomes included fall related fracture and altered consciousness/mental status. SUMMARY ANSWER AND LIMITATIONS: In quarters with glipizide/glimepiride use, hospital admissions or emergency department visits for hypoglycemia were more common in person quarters with concurrent warfarin use compared with quarters without warfarin use (294/416,479 v 1903/3,938,939; adjusted odds ratio 1.22, 95% confidence interval 1.05 to 1.42). The risk of hypoglycemia associated with concurrent use was higher among people using warfarin for the first time, as well as in those aged 65-74 years. Concurrent use of warfarin and glipizide/glimepiride was also associated with hospital admission or emergency department visit for fall related fractures (3919/416,479 v 20,759/3,938,939; adjusted odds ratio 1.47, 1.41 to 1.54) and altered consciousness/mental status (2490/416,479 v 14,414/3,938,939; adjusted odds ratio 1.22, 1.16 to 1.29). Unmeasured factors could be correlated with both warfarin use and serious hypoglycemic events, leading to confounding. The findings may not generalize beyond the elderly Medicare population. WHAT THIS STUDY ADDS: A substantial positive association was seen between use of warfarin with glipizide/glimepiride and hospital admission/emergency department visits for hypoglycemia and related diagnoses, particularly in patients starting warfarin. The findings suggest the possibility of a significant drug interaction between these medications. FUNDING, COMPETING INTERESTS, DATA SHARING: JAR and DPG receive support from the National Institute on Aging, the Commonwealth Fund, and the Leonard D. Schaeffer Center for Health Policy and Economics at the University of Southern California. ABJ receives support from the NIH Office of the Director. No additional data are available. PMID- 26643109 TI - Eviprostat has an identical effect compared to pollen extract (Cernilton) in patients with chronic prostatitis/chronic pelvic pain syndrome: a randomized, prospective study. AB - BACKGROUND: Previously reported results of a prospective, randomized placebo controlled study showed that the pollen extract (Cernilton) significantly improved total symptoms, pain, and quality of life in patients with inflammatory prostatitis/chronic pelvic pain syndrome (CP/CPPS) without severe side effects. A phytotherapeutic agent, Eviprostat, is reportedly effective in a rat model of nonbacterial prostatitis. The aim of the present study was to compare the efficacy and safety of Eviprostat to that of the pollen extract in the management of CP/CPPS. METHODS: The patients with category III CP/CPPS were randomized to receive either oral capsules of Eviprostat (two capsules, q 8 h) or the pollen extract (two capsules, q 8 h) for 8 weeks. The primary endpoint of the study was symptomatic improvement in the NIH Chronic Prostatitis Symptom Index (NIH-CPSI). Participants were evaluated using the NIH-CPSI and the International Prostate Symptom Score (IPSS) at baseline and after 4 and 8 weeks. RESULTS: In the intention-to-treat analysis, 100 men were randomly allocated to Eviprostat (n = 50) or the pollen extract (n = 50). Response (defined as a decrease in the NIH CPSI total score by at least 25 %) in the Eviprostat group and the pollen extract group was 88.2 and 78.1 %, respectively. There was no significant difference in the total, pain, urinary, and quality of life (QOL) scores of the NIH-CPSI between the two groups at 8 weeks. This was also the case with the total, voiding, and storage symptoms of the IPSS. There were no severe adverse events observed in any patients in this study. CONCLUSION: Both the pollen extract and Eviprostat significantly reduced the symptoms of category III CP/CPPS without any adverse events. Eviprostat may have an identical effect on category III CP/CPPS compared the pollen extract. TRIAL REGISTRATION: The study was registered with the University Hospital Medical Information Network Clinical Trials Registry in Japan (UMIN000019618); registration date: 3 November 2015. PMID- 26643111 TI - The Role of Order in the Amplification of Light-Energy Conversion in a Dye Sensitized Solar Cell Coupled to a Photonic Crystal. AB - We investigate the cause of amplification of light-energy conversion when coupling a nc-TiO2 film to a TiO2 inverse opal by comparing it to an inverse TiO2 glass (i-TiO2 -g) fabricated with the exact monodisperse air-hole size as an inverse opal with a stop band at 600 nm (600-i-TiO2 -o). A significant twofold average gain in the photon-to-current conversion efficiency is measured to the red of the stop band at the 600-i-TiO2 -o/nc-TiO2 bilayer under front-wall and back-wall illumination, greater than the gain within the stop band. A smaller amplification is measured under front-wall illumination-and no gain is measured under back-wall illumination-for i-TiO2 -g/nc-TiO2 at these energies. The photonic crystal therefore causes trapping of light through the bilayer, not only within the gap but also to the red, at frequencies within its dielectric band. This light-trapping effect is found to be dependent on structural order, as a highly disordered inverse glass film with the same air-hole size and thickness does not yield the same gain. A drop in the transmission of light is measured within the same frequencies to the red of the stop band upon adding nc-TiO2 to 600-i-TiO2 -o, consistent with light trapping in the bilayer. PMID- 26643110 TI - Modelling optimum use of attractive toxic sugar bait stations for effective malaria vector control in Africa. AB - BACKGROUND: The development of insecticide resistance and the increased outdoor biting behaviour of malaria vectors reduce the efficiency of indoor vector control methods. Attractive toxic sugar baits (ATSBs), a method targeting the sugar-feeding behaviours of vectors both indoors and outdoors, is a promising supplement to indoor tools. The number and configuration of these ATSB stations needed for malaria control in a community needs to be determined. METHODS: A hypothetical village, typical of those in sub-Saharan Africa, 600 * 600 m, consisting of houses, humans and essential resource requirements of Anopheles gambiae (sugar sources, outdoor resting sites, larval habitats) was simulated in a spatial individual-based model. Resource-rich and resource-poor environments were simulated separately. Eight types of configurations and different densities of ATSB stations were tested. Anopheles gambiae population size, human biting rate (HBR) and entomological inoculation rates (EIR) were compared between different ATSB configurations and densities. Each simulated scenario was run 50 times. RESULTS: Compared to the outcomes not altered by ATSB treatment in the control scenario, in resource-rich and resource-poor environments, respectively, the optimum ATSB treatment reduced female abundance by 98.22 and 91.80 %, reduced HBR by 99.52 and 98.15 %, and reduced EIR by 99.99 and 100 %. In resource-rich environments, n * n grid design, stations at sugar sources, resting sites, larval habitats, and random locations worked better in reducing vector population and HBRs than other configurations (P < 0.0001). However, there was no significant difference of EIR reductions between all ATSB configurations (P > 0.05). In resource-poor environments, there was no significant difference of female abundances, HBRs and EIRs between all ATSB configurations (P > 0.05). The optimum number of ATSB stations was about 25 for resource-rich environments and nine for resource-poor environments. CONCLUSIONS: ATSB treatment reduced An. gambiae population substantially and reduced EIR to near zero regardless of environmental resource availability. In resource-rich environments, dispersive configurations worked better in reducing vector population, and stations at or around houses worked better in preventing biting and parasite transmission. In resource-poor environments, all configurations worked similarly. Optimum numbers of bait stations should be adjusted according to seasonality when resource availability changes. PMID- 26643112 TI - Examining systemic steroid Use in older inflammatory bowel disease patients using hurdle models: a cohort study. AB - BACKGROUND: Interpreting clinical guideline adherence and the appropriateness of medication regimens requires consideration of individual patient and caregiver factors. Factors leading to initiation of a medication may differ from those determining continued use. We believe this is the case for systemic steroid therapy in inflammatory bowel disease (IBD), resulting in a need to apply methods that separately consider factors associated with initiation and duration of therapy. To evaluate the relationship between patient characteristics and the frequency and duration of incident steroid use we apply a 2-part hurdle model to Medicare data. We do so in older patients with tumor necrosis factor antagonist (anti-TNFs) contraindications, as they are of special interest for compliance with Medicare-adopted, quality metrics calling for anti-TNFs and nonbiologic immune therapies to reduce steroid utilization. Many older patients have contraindications to anti-TNFs. However, nonbiologics cause adverse events that are concerning in older adults, limiting their use in this population and increasing reliance on systemic steroids. METHODS: We used a national Medicare sample for 2006-2009 including patients with 12 months or greater of Parts A and B and 6 months or greater of Part D coverage, IBD confirmed with at least 2 claims for ICD-9CM 555.xx or 556.xx, anti-TNF contraindications and without contraindications to nonbiologic agents. We applied a negative binomial-logit hurdle model to examine patient characteristics associated with systemic steroid utilization. RESULTS: Among the 1,216 IBD patients without baseline steroid use, 21% used systemic steroids. Odds of receiving systemic steroids were greater in those younger, rural, and those receiving other agents. Available patient characteristics failed to predict longer steroid treatment duration. CONCLUSIONS: Our study identified differences in predictors of frequency and duration of medication use and suggests the utility of two-part models to examine drug utilization patterns. Applying such a model to Medicare data, we determined that despite medical consensus that systemic steroid use should be minimized, its use was substantial. Findings indicate anticipated difficulties in implementing recently adopted quality measures to avoid systemic steroids. PMID- 26643114 TI - Endobronchial metastasised endometrial stromal sarcoma. PMID- 26643113 TI - alpha-synuclein interacts with SOD1 and promotes its oligomerization. AB - BACKGROUND: Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS) are both neurodegenerative diseases leading to impaired execution of movement. alpha Synuclein plays a central role in the pathogenesis of PD whereas Cu, Zn superoxide dismutase (SOD1) is a key player in a subset of familial ALS cases. Under pathological conditions both alpha-synuclein and SOD1 form oligomers and fibrils. In this study we investigated the possible molecular interaction of alpha-synuclein and SOD1 and its functional and pathological relevance. RESULTS: Using a protein-fragment complementation approach and co-IP, we found that alpha synuclein and SOD1 physically interact in living cells, human erythrocytes and mouse brain tissue. Additionally, our data show that disease related mutations in alpha-synuclein (A30P, A53T) and SOD1 (G85R, G93A) modify the binding of alpha synuclein to SOD1. Notably, alpha-synuclein accelerates SOD1 oligomerization independent of SOD1 activity. CONCLUSION: This study provides evidence for a novel interaction of alpha-synuclein and SOD1 that might be relevant for neurodegenerative diseases. PMID- 26643115 TI - Tuning Endothelial Permeability with Functionalized Nanodiamonds. AB - Cancer nanomedicine vehicles are required to cross the vascular barrier to reach the tumor site in order to ensure the successful delivery of their therapeutic load. Here, nanodiamond (ND) variants were shown to induce surface dependent vascular barrier leakiness. The ND-induced leakiness was found to be mediated by the increase in intracellular reactive oxygen species (ROS) and Ca(2+). These then in turn triggered the loss in endothelial cell-endothelial cell connections of the vascular barrier and also triggered their quasi-stable cytoskeletal remodelling. This ND driven increase in leakiness allowed more doxorubicin drug to penetrate through the vascular barrier to reach the cancer cells. This increase in the doxorubicin penetration subsequently led to an increase in the cancer killing effect. Overall, tuning the vascular barrier leakiness through ND surface group functionalization could provide an alternative strategy for the cancer nanomedicine to traverse across the vascular barrier. PMID- 26643116 TI - Improving the radical cure of vivax malaria (IMPROV): a study protocol for a multicentre randomised, placebo-controlled comparison of short and long course primaquine regimens. AB - BACKGROUND: Plasmodium vivax malaria is a major cause of morbidity and recognised as an important contributor to mortality in some endemic areas. The current recommended treatment regimen for the radical cure of P. vivax includes a schizontocidal antimalarial, usually chloroquine, combined with a 14 day regimen of primaquine. The long treatment course frequently results in poor adherence and effectiveness. Shorter courses of higher daily doses of primaquine have the potential to improve adherence and thus effectiveness without compromising safety. The proposed multicentre randomised clinical trial aims to provide evidence across a variety of endemic settings on the safety and efficacy of high dose short course primaquine in glucose-6-phosphate-dehydrogenase (G6PD) normal patients. DESIGN: This study is designed as a placebo controlled, double blinded, randomized trial in four countries: Indonesia, Vietnam, Afghanistan and Ethiopia. G6PD normal patients diagnosed with vivax malaria are randomized to receive either 7 or 14 days high dose primaquine or placebo. G6PD deficient (G6PDd) patients are allocated to weekly primaquine doses for 8weeks. All treatment is directly observed and recurrent episodes are treated with the same treatment than allocated at the enrolment episode. Patients are followed daily until completion of treatment, weekly until 8 weeks and then monthly until 1 year after initiation of the treatment. The primary endpoint is the incidence rate (per person year) of symptomatic recurrent P. vivax parasitaemia over 12 months of follow-up, for all individuals, controlling for site, comparing the 7 versus 14-day primaquine treatment arms. Secondary endpoints are other efficacy measures such as incidence risk at different time points. Further endpoints are risks of haemolysis and severe adverse events. DISCUSSION: This study has been approved by relevant institutional ethics committees in the UK and Australia, and all participating countries. Results will be disseminated to inform P. vivax malaria treatment policy through peer-reviewed publications and academic presentations. Findings will contribute to a better understanding of the risks and benefits of primaquine which is crucial in persuading policy makers as well as clinicians of the importance of radical cure of vivax malaria, contributing to decreased transmission and a reduce parasite reservoir. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01814683 . Registered March 18, 2013. PMID- 26643118 TI - Effects of growth conditions on archaellation and N-glycosylation in Methanococcus maripaludis. AB - In this study, the effects of growth conditions on archaellation in Methanococcus maripaludis were examined. Cells were grown in a variety of media, including complex, minimal and with formate as the electron donor, with different nitrogen sources, varied salinities and at a variety of growth temperatures. Of the conditions tested, Western blot results showed that major archaellin FlaB2 levels only varied detectably as a result of growth temperature. Whilst the amount of FlaB2 was similar for cells grown at < 35 degrees C, protein levels decreased at 38 degrees C and were barely detectable at 42 degrees C. Quantitative reverse transcription PCR experiments demonstrated that the flaB2 transcript levels were almost undetectable at 42 degrees C. Electron microscopy confirmed that the FlaB2 levels detected by Western blots corresponded to the state of archaellation, with cells grown at 42 degrees C being mostly non-archaellated. Unexpectedly, a lower apparent molecular mass for FlaB2 was observed in Western blots of cells grown at temperatures >38 degrees C, suggestive of a truncation in the attached N-linked tetrasaccharide at higher growth temperatures. MS analysis of archaella isolated from cells grown at 40 degrees C confirmed that FlaB2 was now decorated with a trisaccharide in which the third sugar was also lacking the attached threonine and acetamidino modifications found in the WT glycan. PMID- 26643117 TI - Sexual Orientation Self-Concept Ambiguity: Scale Adaptation and Validation. AB - The current article describes the adaptation of a measure of sexual orientation self-concept ambiguity (SSA) from an existing measure of general self-concept clarity. Latent "trait" scores of SSA reflect the extent to which a person's beliefs about their own sexual orientation are perceived as inconsistent, unreliable, or incongruent. Sexual minority and heterosexual women ( n = 348), ages 18 to 30, completed a cross-sectional survey. Categorical confirmatory factor analysis guided the selection of items to form a 10-item, self-report measure of SSA. In the current report, we also examine (a) reliability of the 10 item scale score, (b) measurement invariance based on respondents' sexual identity status and age group, and (c) correlations with preexisting surveys that purport to measure similar constructs and theoretical correlates. Evidence for internal reliability, measurement invariance (based on respondent sex), and convergent validity was also investigated in an independent, validation sample. The lowest SSA scores were reported by women who self-ascribed an exclusively heterosexual or exclusively lesbian/gay sexual identity, whereas those who reported a bisexual, mostly lesbian/gay, or mostly heterosexual identity, reported relatively higher SSA scores. PMID- 26643119 TI - No single electrophysiological marker for facilitation and inhibition of return: A review. AB - Different electrophysiological components have been associated with behavioural facilitation and inhibition of return (IOR), although there is no consensus about which of these components are essential to the mechanism/s underlying the cueing effects. Different spatial attention hypotheses propound different roles for these components. In this review, we try and describe these inconsistencies by first presenting the electrophysiological component modulations of exogenous spatial attention as predicted by different attentional hypotheses. We then review and quantitatively analyze data from the existing electrophysiological studies trying to accommodate their findings. Variables such as the task at hand, the temporal properties and interactions between cues and targets, the presence/absence of intervening events, or stimuli arrangement in the visual field, might critically explain the discrepancies between the theoretical predictions and the electrophysiological modulations that both facilitation and IOR produce. We conclude that there is no single neural marker for facilitation and IOR because the behavioural effect that is observed depends on the contribution of several components: perceptual (P1), late-perceptual (N1, Nd), spatial selection (N2pc), and decision processes (P3). Many variables determine the electrophysiological modulations of different attentional orienting mechanisms, which jointly define the observed spatial cueing effects. PMID- 26643120 TI - Internet-Based Information on Long-Acting Reversible Contraception for Adolescents. AB - BACKGROUND: Long-acting reversible contraception (LARC) is safe, effective, and recommended as first-line contraception for adolescents. Despite clear medical recommendations, the type and quality of Internet information regarding LARC for teenagers is unknown. METHODS: Data were collected through web queries. Resulting websites were assessed for quality criteria and a priori content themes based on the leading medical societies' recommendations for adolescent LARC. RESULTS: Of the 238 websites evaluated, 77% made no recommendation of LARC for adolescent females. Of the 55 websites that did recommend LARC, only 40% specifically discussed its use in the adolescent population. Of note, 16% of websites recommending LARC discouraged their use in adolescents. Quality varied among LARC discussing websites, ranging from 3 to 13 of the 15 criteria assessed. DISCUSSION: Few websites offer up-to-date information regarding the use of LARC, and most fail to discuss LARC use at all. As LARC is highly effective in preventing unplanned pregnancies in adolescents, incomplete or inaccurate information on the Internet present a barrier to promoting its utilization in this at-risk population. PMID- 26643121 TI - Lichen sclerosus associated with urinary contamination. PMID- 26643122 TI - A Comparative Morphometric Analysis of Three Cranial Nerves in Two Phocids: The Hooded Seal (Cystophora cristata) and the Harbor Seal (Phoca vitulina). AB - While our knowledge about the senses of pinnipeds has increased over the last decades almost nothing is known about the organization of the neuroanatomical pathways. In a first approach to this field of research, we assessed the total number of myelinated axons of three cranial nerves (CNs) in the harbor (Phoca vitulina, Pv) and hooded seal (Cystophora cristata, Cc). Axons were counted in semithin sections of the nerves embedded in Epon and stained with toluidine blue. In both species, the highest axon number was found within the optic nerve (Pv 187,000 +/- 8,000 axons, Cc 481,600 +/- 1,300 axons). Generally, considering absolute axon numbers, far more axons were counted within the optic and trigmenial nerve (Pv 136,700 +/- 2,500 axons, Cc 179,300 +/- 6,900 axons) in hooded in comparison to harbor seals. The axon counts of the vestibulocochlear nerve are nearly identical for both species (Pv 87,100 +/- 8,100 axons, Cc 86,600 +/- 2,700 axons). However, when comparing cell density, the cell density is almost equal for all nerves for both species except for the optic nerve in which cell density was particularly higher than in the other nerves and higher in hooded in comparison to harbor seals. We here present the first comparative analysis of three CNs in two phocid seals. While the CNs of these closely related species share some general characteristics, pronounced differences in axon numbers/densities are apparent. These differences seem to reflect differences in e.g. size, habitat, and/or functional significance of the innervated sensory systems. PMID- 26643123 TI - Combining Taxonomic and Functional Approaches to Unravel the Spatial Distribution of an Amazonian Butterfly Community. AB - This study investigated the spatial distribution of an Amazonian fruit-feeding butterfly assemblage by linking species taxonomic and functional approaches. We hypothesized that: 1) vegetation richness (i.e., resources) and abundance of insectivorous birds (i.e., predators) should drive changes in butterfly taxonomic composition, 2) larval diet breadth should decrease with increase of plant species richness, 3) small-sized adults should be favored by higher abundance of birds, and 4) communities with eyespot markings should be able to exploit areas with higher predation pressure. Fruit-feeding butterflies were sampled with bait traps and insect nets across 25 km(2) of an Amazonian ombrophilous forest in Brazil. We measured larval diet breadth, adult body size, and wing marking of all butterflies. Our results showed that plant species richness explained most of the variation in butterfly taxonomic turnover. Also, community average diet breadth decreased with increase of plant species richness, which supports our expectations. In contrast, community average body size increased with the abundance of birds, refuting our hypothesis. We detected no influence of environmental gradients on the occurrence of species with eyespot markings. The association between butterfly taxonomic and functional composition points to a mediator role of the functional traits in the environmental filtering of butterflies. The incorporation of the functional approach into the analyses allowed for the detection of relationships that were not observed using a strictly taxonomic perspective and provided an extra insight into comprehending the potential adaptive strategies of butterflies. PMID- 26643124 TI - Subdivision of the lateral plate mesoderm and specification of the forelimb and hindlimb forming domains. AB - The limbs are a significant evolutionary innovation that enabled vertebrates to diversify and colonise new environments. Tetrapods have two pairs of limbs, forelimbs in the upper body and hindlimbs in the lower body. The morphologies of the forelimbs and hindlimbs are distinct, reflecting their specific locomotory functions although they share many common signalling networks that regulate their development. The paired appendages in vertebrates form at fixed positions along the rostral-caudal axis and this occurs as a consequence of earlier subdivision of the lateral plate mesoderm (LPM) into regions with distinct limb forming potential. In this review, we discuss the molecular mechanisms that confer a broad region of the flank with limb-forming potential and its subsequent refinement into distinct forelimb-forming, hindlimb-forming and interlimb territories. PMID- 26643125 TI - Back massage intervention for relieving lower back pain in puerperal women. PMID- 26643126 TI - Creating Welcoming Spaces for Lesbian, Gay, Bisexual, and Transgender (LGBT) Patients: An Evaluation of the Health Care Environment. AB - Health outcomes are affected by patient, provider, and environmental factors. Previous studies have evaluated patient-level factors; few focusing on environment. Safe clinical spaces are important for lesbian, gay, bisexual, and transgender (LGBT) communities. This study evaluates current models of LGBT health care delivery, identifies strengths and weaknesses, and makes recommendations for LGBT spaces. Models are divided into LGBT-specific and LGBT embedded care delivery. Advantages to both models exist, and they provide LGBT patients different options of healthcare. Yet certain commonalities must be met: a clean and confidential system. Once met, LGBT-competent environments and providers can advocate for appropriate care for LGBT communities, creating environments where they would want to seek care. PMID- 26643127 TI - Ultra-sensitive speciation analysis of mercury by CE-ICP-MS together with field amplified sample stacking injection and dispersive solid-phase extraction. AB - A simple dispersive solid-phase extraction (DSPE) used to extract and preconcentrate ultra-trace MeHg, EtHg and Hg(2+) from water sample, and a sensitive method for the simultaneous analysis of MeHg, EtHg and Hg(2+) by using capillary electrophoresis-inductively coupled plasma mass spectrometry (CE-ICP MS) with field-amplified sample stacking injection (FASI) were first reported in this study. The DSPE used thiol cotton particles as adsorbent, and is simple and effective. It can be used to extract and preconcentrate ultra-trace mercury compounds in water samples within 30 min with a satisfied recovery and no mercury species alteration during the process. The FASI enhanced the sensitivity of CE ICP-MS with 25-fold, 29-fold and 27-fold for MeHg, EtHg and Hg(2+) , respectively. Using FASI-CE-ICP-MS together with DSPE, we have successfully determined ultra-trace MeHg, EtHg and Hg(2+) in tap water with a limits of quantification (LOQs) of 0.26-0.45 pg/mL, an RSD (n = 3) < 6% and a recovery of 92-108%. Ultra-high sensitivity, as well as much less sample and reagent consumption and low operating cost, make our method a valuable technique to the speciation analysis of ultra-trace mercury. PMID- 26643128 TI - Incretin-based therapies are associated with acute pancreatitis: Meta-analysis of large randomized controlled trials. AB - Previous studies have offered weak and conflicting evidence regarding the impact of incretin-based oral antihyperglycemic agents on risk of acute pancreatitis. This meta-analysis of three recent mega-trials found an 82% increase in the odds of acute pancreatitis with the use of these agents compared to usual care (95% CI, 1.17-2.82). PMID- 26643129 TI - Full genome analysis of enterovirus D-68 strains circulating in Alberta, Canada. AB - A widespread outbreak of enterovirus (EV)-D68 that started in the summer of 2014 has been reported in the USA and Canada. During the course of this outbreak, EV D68 was identified as a possible cause of acute, unexplained severe respiratory illness and a temporal association was observed between acute flaccid paralysis with anterior myelitis and EV-D68 detection in the upper respiratory tract. In this study, four nasopharyngeal samples collected from patients in Alberta, Canada with a laboratory diagnosis of EV-D68 were used to determine the near full length genome sequence directly from the specimens. Phylogenetic analysis was performed to study the genotypes and pathogenesis of the circulating strains. Our results support the contention that mutations in the VP1 gene and other regions of the genome causing altered antigenicity, as well as lack of immunity in the younger population, may be responsible for the increased severe respiratory disease outbreaks of EV-D68 worldwide. PMID- 26643130 TI - Association of BRCA1 promoter methylation with sporadic breast cancers: Evidence from 40 studies. AB - Breast cancer susceptibility gene 1 (BRCA1) located at chromosome 17q12-21 is a classic tumor suppressor gene, and has been considered as a significant role in hereditary breast cancers. Moreover, numerous studies demonstrated the methylation status of CpG islands in the promoter regions of BRCA1 gene was aberrant in patients with sporadic breast tumors compared with healthy females or patients with benign diseases. However, these conclusions were not always consistent. Hence, a meta-analysis was performed to get a more precise estimate for these associations. Crude odds ratio with 95% confidence interval were used to assess the association of BRCA1 promoter methylation and the risk or clinicopathologic characteristics of breast cancers under fixed or random effect model. A total of 40 studies were eligible for this present study. We observed the frequency of BRCA1 promoter methylation was statistically significant higher in breast cancers than non-cancer controls. Furthermore, BRCA1 methylation was statistically associated with lymph node metastasis, histological grade 3, ER(-), PR(-), triple-negative phenotype, and decreased or lack levels of BRCA1 protein expression. In conclusion, this study indicated that BRCA1 promoter methylation appeared to be a useful predictive or prognostic biomarker for breast cancers in clinical assessment. PMID- 26643131 TI - WRKY71 accelerates flowering via the direct activation of FLOWERING LOCUS T and LEAFY in Arabidopsis thaliana. AB - Flowering is crucial for achieving reproductive success. A large number of well delineated factors affecting flowering are involved in complex genetic networks in Arabidopsis thaliana. However, the underlying part played by the WRKY transcription factors in this process is not yet clear. Here, we report that WRKY71 is able to accelerate flowering in Arabidopsis. An activation-tagged mutant WRKY71-1D and a constitutive over-expresser of WRKY71 both flowered earlier than the wild type (WT). In contrast, both the RNA interference-based multiple WRKY knock-out mutant (w71w8 + 28RNAi) and the dominant repression line (W71-SRDX) flowered later. Gene expression analysis showed that the transcript abundance of the flowering time integrator gene FLOWERING LOCUS T (FT) and the floral meristem identity genes LEAFY (LFY), APETALA1 (AP1) and FRUITFULL (FUL) were greater in WRKY71-1D than in the WT, but lower in w71w8 + 28RNAi and W71 SRDX. Further, WRKY71 was shown to bind to the W-boxes in the FT and LFY promoters in vitro and in vivo. The suggestion is that WRKY71 activity hastens flowering via the direct activation of FT and LFY. PMID- 26643133 TI - Optimizing prevention programs and maximizing public health impact are not the same thing. PMID- 26643132 TI - "I just use it for weed": The modification of little cigars and cigarillos by young adult African American male users. AB - Little cigar and cigarillo (LCC) use has received increased attention, but research on their modification is limited. Qualitative interviews with 17 young adult African American male LCC users investigated tobacco use behaviors and patterns, including LCC modification. The modification of LCCs for use as blunts emerged as a very prominent aspect of LCC users' tobacco use. Four subthemes regarding marijuana and blunt use are explored in this article, including participants' explanations of how blunts are made and used, concurrent use of marijuana and tobacco, perceptions and reasons for smoking marijuana and blunts, and perceptions of the risks of blunt use. PMID- 26643137 TI - Shimon Sakaguchi - Canada Gairdner International Award 2015. PMID- 26643138 TI - Switching on the Aire conditioner. AB - Aire has been cloned as the gene responsible for a hereditary type of organ specific autoimmune disease. Aire controls the expression of a wide array of tissue-restricted Ags by medullary thymic epithelial cells (mTECs), thereby leading to clonal deletion and Treg-cell production, and ultimately to the establishment of self-tolerance. However, relatively little is known about the mechanism responsible for the control of Aire expression itself. In this issue of the European Journal of Immunology, Haljasorg et al. [Eur. J. Immunol. 2015. 45: 3246-3256] have reported the presence of an enhancer element for Aire that binds with NF-kappaB components downstream of the TNF receptor family member, RANK (receptor activator of NF-kappaB). The results suggest that RANK has a dual mode of action in Aire expression: one involving the promotion of mTEC differentiation and the other involving activation of the molecular switch for Aire within mature mTECs. PMID- 26643141 TI - Time for a Change. PMID- 26643143 TI - PICH promotes sister chromatid disjunction and co-operates with topoisomerase II in mitosis. AB - PICH is a SNF2 family DNA translocase that binds to ultra-fine DNA bridges (UFBs) in mitosis. Numerous roles for PICH have been proposed from protein depletion experiments, but a consensus has failed to emerge. Here, we report that deletion of PICH in avian cells causes chromosome structural abnormalities, and hypersensitivity to an inhibitor of Topoisomerase II (Topo II), ICRF-193. ICRF 193-treated PICH(-/-) cells undergo sister chromatid non-disjunction in anaphase, and frequently abort cytokinesis. PICH co-localizes with Topo IIalpha on UFBs and at the ribosomal DNA locus, and the timely resolution of both structures depends on the ATPase activity of PICH. Purified PICH protein strongly stimulates the catalytic activity of Topo II in vitro. Consistent with this, a human PICH(-/-) cell line exhibits chromosome instability and chromosome condensation and decatenation defects similar to those of ICRF-193-treated cells. We propose that PICH and Topo II cooperate to prevent chromosome missegregation events in mitosis. PMID- 26643144 TI - Metal-Organic Frameworks Containing Missing-Linker Defects Leading to High Hydroxide-Ion Conductivity. AB - The ionic conductivity properties of the face-centered cubic [Ni8 (OH)4 (H2O)2 (BDP_X)6] (H2 BDP_X=1,4-bis(pyrazol-4-yl)benzene-4-X with X=H (1), OH (2), NH2 (3)) metal-organic framework (MOF) systems as well as their post-synthetically modified materials K[Ni8 (OH)5 (EtO)(BDP_X)5.5] (1@KOH, 3@KOH) and K3 [Ni8 (OH)3 (EtO)(BDP_O)5] (2@KOH), which contain missing-linker defects, have been studied by variable temperature AC impedance spectroscopy. It should be noted that these modified materials exhibit up to four orders of magnitude increase in conductivity (-) values in comparison to pristine 1-3 systems. As an example, the conductivity value of 5.86 * 10(-9) S cm(-1) (activation energy Ea of 0.60 eV) for 2 at 313 K and 22% relative humidity (RH) increases up to 2.75 * 10(-5) S cm( 1) (Ea of 0.40 eV) for 2@KOH. Moreover, a further increase of conductivity values up to 1.16 * 10(-2) S cm(-1) and diminution of Ea down to 0.20 eV is achieved at 100% RH for 2@KOH. The increased porosity, basicity and hydrophilicity of the 1@KOH-3@KOH materials compared to the pristine 1-3 systems should explain the better performance of the KOH-modified materials. PMID- 26643145 TI - Developmental effects of two different copper oxide nanomaterials in sea urchin (Lytechinus pictus) embryos. AB - Copper oxide nanomaterials (nano-CuOs) are widely used and can be inadvertently introduced into estuarine and marine environments. We analyzed the effects of different nano-CuOs (a synthesized and a less-pure commercial form), as well as ionic copper (CuSO4) on embryo development in the white sea urchin, a well-known marine model. After 96 h of development with both nano-CuO exposures, we did not detect significant oxidative damage to proteins but did detect decreases in total antioxidant capacity. We show that the physicochemical characteristics of the two nano-CuOs play an essential role in their toxicities. Both nano-CuOs were internalized by embryos and their differential dissolution was the most important toxicological parameter. The synthesized nano-CuO showed greater toxicity (EC50 = 450 ppb of copper) and had increased dissolution (2.5% by weight over 96 h) as compared with the less-pure commercial nano-CuO (EC50 = 5395 ppb of copper, 0.73% dissolution by weight over 96 h). Copper caused specific developmental abnormalities in sea urchin embryos including disruption of the aboral-oral axis as a result in changes to the redox environment caused by dissolution of internalized nano-CuO. Abnormal skeleton formation also occurred. PMID- 26643146 TI - Cognitive caching promotes flexibility in task switching: evidence from event related potentials. AB - Time-consuming processes of task-set reconfiguration have been shown to contribute to the costs of switching between cognitive tasks. We describe and probe a novel mechanism serving to reduce the costs of task-set reconfiguration. We propose that when individuals are uncertain about the currently valid task, one task set is activated for execution while other task sets are maintained at a pre-active state in cognitive cache. We tested this idea by assessing an event related potential (ERP) index of task-set reconfiguration in a three-rule task switching paradigm involving varying degrees of task uncertainty. In high uncertainty conditions, two viable tasks were equally likely to be correct whereas in low-uncertainty conditions, one task was more likely than the other. ERP and performance measures indicated substantial costs of task-set reconfiguration when participants were required to switch away from a task that had been likely to be correct. In contrast, task-set-reconfiguration costs were markedly reduced when the previous task set was chosen under high task uncertainty. These results suggest that cognitive caching of alternative task sets adds to human cognitive flexibility under high task uncertainty. PMID- 26643148 TI - In the Eye of the Beholder: Exploring Variations in the Perceptions of Pornography. AB - While many studies have explored the correlates and outcomes associated with pornography use, the measurement of such use has relied heavily on self definitions of pornography from research participants, and little is known regarding how individuals define pornography for themselves. Using a diverse sample of 2,089 individuals sampled from the online MTurk Web site, participants were asked to rate whether they felt 20 different examples of sexual media were pornography. Differences by gender, religious attendance, marital status, and pornography use patterns were explored. Results suggested significant variation across the sample in how specific examples of sexual media were perceived. In addition, response profiles significantly differed by gender, religious attendance, marital status, and use of pornography. Implications for the measurement of pornography are discussed. PMID- 26643149 TI - CML - we are not there yet. PMID- 26643150 TI - Stroke Risk Stratification in Atrial Fibrillation: Bridging the Evidence Gaps. PMID- 26643151 TI - Beyond the Capture of Circulating Tumor Cells: Next-Generation Devices and Materials. AB - Over the last decade, significant progress has been made towards the development of approaches that enable the capture of rare circulating tumor cells (CTCs) from the blood of cancer patients, a critical capability for noninvasive tumor profiling. These advances have leveraged new insights in materials chemistry and microfluidics and allowed the capture and enumeration of CTCs with unprecedented sensitivity. However, it has become increasingly clear that simply capturing and counting tumor cells launched into the bloodstream may not provide the information needed to advance our understanding of the biology of these rare cells, or to allow us to better exploit them in medicine. A variety of advances have now emerged demonstrating that more information can be extracted from CTCs with next-generation devices and materials featuring tailored physical and chemical properties. In this Minireview, the last ten years of work in this area will be discussed, with an emphasis on the groundbreaking work of the last five years, during which the focus has moved beyond the simple capture of CTCs and gravitated towards approaches that enable in-depth analysis. PMID- 26643152 TI - Why food policy and obesity policy are not synonymous: the need to establish clear obesity policy in the United States. PMID- 26643147 TI - RNA-binding proteins, neural development and the addictions. AB - Transcriptional and post-transcriptional regulation of gene expression defines the neurobiological mechanisms that bridge genetic and environmental risk factors with neurobehavioral dysfunction underlying the addictions. More than 1000 genes in the eukaryotic genome code for multifunctional RNA-binding proteins (RBPs) that can regulate all levels of RNA biogenesis. More than 50% of these RBPs are expressed in the brain where they regulate alternative splicing, transport, localization, stability and translation of RNAs during development and adulthood. Dysfunction of RBPs can exert global effects on their targetomes that underlie neurodegenerative disorders such as Alzheimer's and Parkinson's diseases as well as neurodevelopmental disorders, including autism and schizophrenia. Here, we consider the evidence that RBPs influence key molecular targets, neurodevelopment, synaptic plasticity and neurobehavioral dysfunction underlying the addictions. Increasingly well-powered genome-wide association studies in humans and mammalian model organisms combined with ever more precise transcriptomic and proteomic approaches will continue to uncover novel and possibly selective roles for RBPs in the addictions. Key challenges include identifying the biological functions of the dynamic RBP targetomes from specific cell types throughout subcellular space (e.g. the nuclear spliceome vs. the synaptic translatome) and time and manipulating RBP programs through post transcriptional modifications to prevent or reverse aberrant neurodevelopment and plasticity underlying the addictions. PMID- 26643153 TI - Cortical auditory evoked responses of older adults with and without probable mild cognitive impairment. AB - OBJECTIVE: Hearing loss has been well-documented as a risk factor for cognitive impairment, but the simple presence of hearing loss is not a sufficient predictor of cognitive decline. Although auditory behavioral research has not revealed an effective indicator of early cognitive impairment, a limited number of studies using cortical auditory evoked potentials (CAEPs) have shown promising evidence of an auditory neurophysiological indicator of early-stage cognitive impairment. The purpose of this study was to examine the P1-N1-P2 complex for indicators of cognitive impairment. METHODS: The latency and amplitude of the P1-N1-P2 complex was measured for two stimuli (pure tone, speech) in two groups: cognitively normal older adults (CNOAs) and older adults with probable mild cognitive impairment (MCI), based on the Montreal Cognitive Assessment. RESULTS: Significantly smaller P2 amplitudes were found for those with probable MCI compared to CNOA across stimulus conditions. Stimulus effects were found for P1 and P2 latency. CONCLUSION: P2 amplitude may be a useful indicator of early-stage cognitive impairment. SIGNIFICANCE: As effective treatments become available, early identification of cognitive impairment can facilitate the prescription of treatment at the earliest juncture. CAEPs have the potential to serve as efficient, non-invasive, cost-effective indicators of future cognitive decline and impairment. PMID- 26643154 TI - Exosomal particles secreted by prostate cancer cells are potent mRNA and protein vehicles for the interference of tumor and tumor environment. AB - BACKGROUND: Remodeling of the tumor environment and the modulation of tumor associated non-malignant cells are essential events in tumor progression. Exosomes are small membranous vesicles of 50-150 nm in diameter, which are secreted into the extracellular space and supposedly serve as vehicles for signal and effector molecules to modulate adjacent target cells. We characterized the mRNA and protein composition as well as cellular functions of prostate cancer cell-derived exosomes. METHODS: Exosomes were prepared from prostate cancer cell culture supernatant by ultracentrifugation and subsequently characterized by dynamic light scattering and electron microscopy. Exosomal mRNA and protein composition were analyzed by DNA microarrays and gel electrophoresis coupled with mass spectrometry. Physiological effects of exosomes were studied by means of 3 (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and lactate dehydrogenase release cell assays. Using a SILAC approach, putative uptake of exosomal human proteins in canine cells and canine de novo synthesis of proteins specified by exosome-transferred human mRNA was analyzed in MDCK cells via mass spectrometry. RESULTS: Preparations of exosomes revealed typical cup shaped particles of 150 nm in diameter. Analysis of mRNA and protein composition of exosomes exhibited a wide range of mRNA and protein species. Interestingly, the packaging of at least small proteins into exosomes was apparently unspecific, as shown with the example of two model proteins. In cell culture incubation experiments exosomal preparations of prostate cancer cells caused anti proliferative effects. MS analysis revealed the uptake of exosomal human proteins into canine cells after 6 hr of incubation. CONCLUSIONS: The results reveal a distinct exosomal functionality in the modulation of the prostatic tumor adjacent environment. The multitude of translocated factors implies the induction of numerous effects in tumor-associated target cells, including impact on cellular growth. PMID- 26643155 TI - [Tracheostomy techniques]. AB - Due to the comprehensive establishment of modern techniques, tracheostomy has become a routine procedure in intensive care units (ICU). The negative effects of prolonged translaryngeal intubation on the laryngeal and tracheal mucosa up to tracheal stenosis can be reduced by tracheostomy. Furthermore, long-term ventilation is facilitated; however, there is no clear evidence on the optimal timing of tracheostomy in critically ill patients. The specific indications and contraindications of surgical as well as percutaneous tracheostomy must be strictly observed for a safe and successful intervention. Exchanging the tracheostomy tube may lead to potentially dangerous situations especially after percutaneous tracheostomy. A standardized and structured approach is therefore recommended. PMID- 26643156 TI - Activated charcoal may not be necessary in all oral overdoses of medication. PMID- 26643157 TI - Fragmented QRS complexes have predictive value of imperfect ST-segment resolution in patients with STEMI after primary percutaneous coronary intervention. AB - OBJECTIVES: To investigate the clinical characteristics of patients with the fragmented QRS complexes (fQRS) and the predictive value of fQRS in patients undergoing primary percutaneous coronary intervention (p-PCI). METHODS: The study enrolled 227 consecutive patients with ST-elevation myocardial infarction who underwent p-PCI. Baseline clinical characteristics, the percentage of ST-segment resolution, and parameters of electrocardiography and coronary angiography were investigated. The relationship between fQRS on pre-PCI and post-PCI electrocardiogram and the percentage of ST-segment resolution after PCI were studied. RESULTS: Patients with fQRS have higher troponin I, creatine kinase-MB levels, prolonged QRS duration, higher Gensini score, lower percentage of total ST-segment resolution, and left ventricular ejection fraction compared with patients without fQRS. Gensini score (odds ratio [OR], 1.013; 95% confidence interval [CI], 1.002-1.024; P < .006) and percentage of total ST-segment resolution (OR, 0.384; 95% CI, 0.186-0.795; P = .01) were independently associated with the presence of fQRS. A multivariate logistic regression analysis selected presence of fQRS pre-PCI (OR, 2.908; 95% CI, 1.095-7.723; P = .032) and the number of leads with fQRS before PCI (OR, 1.582; 95% CI, 1.250-2.002; P < .001) as independent predictors of imperfect ST-segment resolution. CONCLUSIONS: The presence of fQRS is a predictor in ST-elevation myocardial infarction patients undergoing p-PCI. The occurrence of fQRS is beneficial to identify the patients with severe coronary lesion, left ventricular contraction dysfunction, and larger areas of ischemic injury. PMID- 26643158 TI - Ibuprofen-induced thrombotic thrombocytopenic purpura. PMID- 26643159 TI - Is the neutrophil-to-lymphocyte ratio a potential diagnostic marker for peptic ulcer perforation? A retrospective cohort study. AB - OBJECTIVES: Peptic ulcer perforation (PUP) accounts for 5% of all abdominal emergencies and is recognized as a gastrointestinal emergency requiring rapid and efficient clinical evaluation and treatment. The mortality rate ranges from 10% to 40% among patients with perforation. In the present retrospective study, we examined the potential utility of the neutrophil-to-lymphocyte ratio (NLR) in early diagnosis of PUP; we asked whether this ratio allowed PUP and peptic ulcer disease to be distinguished. METHODS: We enrolled the following patients: 58 with PUP, 62 with noncomplicated peptic ulcer diseases (NCPU), and 62 controls, between May 2010 and 2015. Patients who underwent surgical repair to treat PUP were included in the study group. Another group consisted of NCPU patients who had a noncomplicated peptic ulcer. The control group consisted of patients presenting with nonspecific abdominal pain to the emergency department. RESULTS: The mortality rate was 5.2% in the PUP group. The white blood cell count, C reactive protein, and NLRs were higher in the PUP compared to the other groups (P<.001 for all). The white blood cell count and NLR did not differ between the NCPU and control groups. The sensitivities, specificities, positive predictive values, and negative predictive values of the NLRs were 68.0%, 88.0%, 82.9%, and 72.9%, respectively. CONCLUSIONS: We suggest that preoperative NLR aids in the diagnosis of PUP and can be used to distinguish this condition from peptic ulcer disease. Thus, the NLR should be calculated in addition to the clinical examination. PMID- 26643160 TI - Inborn errors of metabolism: an emergency medicine approach. PMID- 26643161 TI - The simultaneous recording of right- and left-sided electrocardiogram in acute pulmonary embolism. PMID- 26643162 TI - On the pathways of an imperfect chameleon: posterior reversible encephalopathy syndrome. PMID- 26643163 TI - Ectopic pregnancy causing splenic rupture. PMID- 26643164 TI - The intraosseous access devices as a method of vascular access during cardiopulmonary resuscitation. PMID- 26643165 TI - Closed traumatic finger tip injuries in patients with artificial nails: removal of UV gel and acrylic nails. PMID- 26643167 TI - A New, Improved Hybrid Scoring Function for Molecular Docking and Scoring Based on AutoDock and AutoDock Vina. AB - Automated docking is one of the most important tools for structure-based drug design that allows prediction of ligand binding poses and also provides an estimate of how well small molecules fit in the binding site of a protein. A new scoring function based on AutoDock and AutoDock Vina has been introduced. The new hybrid scoring function is a linear combination of the two scoring function components derived from a multiple linear regression fitting procedure. The scoring function was built on a training set of 2412 protein-ligand complexes from pdbbind database (www.pdbbind.org.cn, version 2012). A test set of 313 complexes that appeared in the 2013 version was used for validation purposes. The new hybrid scoring function performed better than the original functions, both on training and test sets of protein-ligand complexes, as measured by the non parametric Pearson correlation coefficient, R, mean absolute error (MAE), and root-mean-square error (RMSE) between the experimental binding affinities and the docking scores. The function also gave one of the best results among more than 20 scoring functions tested on the core set of the pdbbind database. The new AutoDock hybrid scoring function will be implemented in modified version of AutoDock. PMID- 26643166 TI - MR imaging of perianal fistulas in Crohn's disease: sensitivity and specificity of STIR sequences. AB - INTRODUCTION: Although some studies proved the role of STIR sequences in the evaluation of perianal fistulas in Crohn's Disease (CD), contrast medium is still injected in many institutions since there is not a validated reference MR protocol. Our purpose was to evaluate the role of the STIR sequence in the detection and characterization of perianal fistulae comparing it to the post contrast T1 sequence and correlating it with rectal examination under anesthesia. MATERIALS AND METHODS: We retrospectively reviewed all clinical records of 31 CD patients, suspected of having perianal fistulas, who had been submitted to an MR study before and after contrast medium injection and surgical exploration under anesthesia within the same month. Perianal fistulas were classified according to the Parks' criteria. Finally, comparison between STIR and post-contrast T1 weighted fat saturated sequences was done. RESULTS: 29 fistulas were detected in 25 patients who underwent an MR study. There was no significant difference between MR imaging and exploration under anesthesia. For the detection of perianal fistulas of any type, there was a perfect statistical agreement between gadolinium-enhanced and STIR sequences (kappa value = 1). CONCLUSION: STIR sequences represent a valid alternative to the T1-weighted sequences acquired after the injection of contrast medium, allowing the identification of the primary fistula, any secondary ramification, and complications of the disease. PMID- 26643168 TI - Quercetin phospholipid complex significantly protects against oxidative injury in ARPE-19 cells associated with activation of Nrf2 pathway. AB - Age-related macular degeneration (AMD) is a major cause of blindness worldwide. Oxidative stress plays a crucial role in the pathogenesis of dry AMD. Quercetin has potent anti-oxidative activities, but poor bioavailability limits its therapeutic application. Herein, we prepared the phospholipid complex of quercetin (quercetin-PC), characterized its structure by differential scanning calorimetry, infrared spectrum and x-ray diffraction. Quercetin-PC had equilibrium solubility of 38.36 and 1351.27MUg/ml in water and chloroform, respectively, which was remarkably higher than those of quercetin alone. Then we established hydrogen peroxide (H2O2)-induced oxidative injury model in human ARPE 19 cells to examine the effects of quercetin-PC. Quercetin-PC, stronger than quercetin, promoted cell proliferation, and the proliferation rate was increased to be 78.89% when treated with Quercetin-PC at 400MUM. Moreover, quercetin-PC effectively prevented ARPE-19 cells from apoptosis, and the apoptotic rate was reduced to be 3.1% when treated with Quercetin-PC at 200MUM. In addition, quercetin-PC at 200MUM significantly increased the activities of SOD, CAT and GSH PX, and reduced the levels of reactive oxygen species and MDA in H2O2-treated ARPE-19 cells, but quercetin at 200MUM failed to do so. Molecular examinations revealed that quercetin-PC at 200MUM significantly activated Nrf2 nuclear translocation and significantly enhanced the expression of target genes HO-1, NQO 1 and GCL by different folds at both mRNA and protein levels. Our current data collectively indicated that quercetin-PC had stronger protective effects against oxidative-induced damages in ARPE-19 cells, which was associated with activation of Nrf2 pathway and its target genes implicated in antioxidant defense. PMID- 26643169 TI - Epigallocatechin gallate attenuates amyloid beta-induced inflammation and neurotoxicity in EOC 13.31 microglia. AB - Microglia are the primary immune cells that contribute to neuroinflammation by releasing various proinflammatory cytokines and neurotoxins in the brain. Microglia-mediated neuroinflammation is one of the key characteristics of Alzheimer's disease (AD). Therefore, inhibitory reagents that prevent microglial activation may be used as potential therapeutic agents for treating AD. Recently, many studies have been performed to determine the bioactivities of green tea polyphenol epigallocatechin-3-gallate (EGCG), an efficient antioxidant that prevents neuroinflammation. However, limited information is available on the effects of EGCG on microglia-mediated neuroinflammation. In this study, we investigated the inhibitory effects of EGCG on amyloid beta (Abeta)-induced microglial activation and neurotoxicity. Our results indicated that EGCG significantly suppressed the expression of tumor necrosis factor alpha (TNFalpha), interleukin-1beta, interleukin-6, and inducible nitric oxide synthase (iNOS) in Abeta-stimulated EOC 13.31 microglia. EGCG also restored the levels of intracellular antioxidants nuclear erythroid-2 related factor 2 (Nrf2) and heme oxygenase-1 (HO-1), thus inhibiting reactive oxygen species-induced nuclear factor-kappaB (NF-kappaB) activation after Abeta treatment. Furthermore, EGCG effectively protected neuro-2a neuronal cells from Abeta-mediated, microglia induced cytotoxicity by inhibiting mitogen-activated protein kinase-dependent, Abeta-induced release of TNFalpha. Taken together, our findings suggested that EGCG suppressed Abeta-induced neuroinflammatory response of microglia and protected against indirect neurotoxicity. These results suggest that EGCG is a possible therapeutic agent for preventing Abeta-induced inflammatory neurodegeneration. PMID- 26643170 TI - Studies on the reproductive effects of chronic treatment with agomelatine in the rat. AB - Agomelatine is an antidepressant with a novel mechanism of action. It is a melatonergic agonist for MT1 and MT2 receptors and a serotonin (5-HT2C) receptor antagonist. Agomelatine has been suggested not to have adverse effects on sexual functions. However, the effects of chronic agomelatine administration on reproductive functions have not been sufficiently studied in animal models. We mainly aimed to explore the effects of agomelatine on reproductive functions in the male and female rats. For the experimental studies, Sprague Dawley rats were used. The animals started to receive daily oral agomelatine (10mg/kg) on post natal day 21. Agomelatine advanced vaginal opening in the female rats whereas it delayed puberty onset in the male rats. Agomelatine treatment significantly decreased intromission frequencies, which indicates a facilitator role of this antidepressant on male sexual behavior. In the forced swimming test (FST) used for assessing antidepressant efficacy, agomelatine induced a significant decrease in duration of immobility, and an increase in the swimming time, respectively, which confirms the antidepressant-like activity of agomelatine. The present findings suggest that agomelatine shows a strong antidepressant effect in the male rats without any adverse influences on sexual behavior, and its effects on pubertal maturation seem to show sex-dependent differences. PMID- 26643171 TI - Pharmacological evidence that NaHS inhibits the vasopressor responses induced by stimulation of the preganglionic sympathetic outflow in pithed rats. AB - It has been reported that i.v. administration of NaHS, a donor of H2S, elicited dose-dependent hypotension although the mechanisms are not completely understood. In this regard, several mechanisms could be involved including the inhibition of the vasopressor sympathetic outflow. Thus, this study was designed to determine the potential capability of NaHS to mediate inhibition of the vasopressor responses induced by preganglionic sympathetic stimulation. For this purpose, Wistar rats were anaesthetised, pithed and cannulated for drug administration. In animals pre-treated with gallamine, the effect of i.v. infusion of NaHS (310 and 560MUg/kgmin) or its vehicle (phosphate buffer) was determined on the vasopressor responses induced by: (1) sympathetic stimulation (0.03-10Hz); (2) i.v. bolus injections of exogenous noradrenaline (0.03-3MUg/kg); or (3) methoxamine (1 100MUg/kg). The vasopressor responses induced by preganglionic sympathetic stimulation were dose-dependently inhibited by i.v. infusion of NaHS (310 and 560MUg/kgmin), but not by vehicle, particularly at high frequencies. In marked contrast, the vasopressor responses to exogenous noradrenaline or methoxamine were not inhibited by the above doses of NaHS or its vehicle. The above results, taken together, demonstrate that NaHS inhibited the vasopressor responses induced by preganglionic sympathetic outflow by a prejunctional mechanism. This is the first evidence demonstrating this effect by NaHS that may contribute, at least in part, to the hypotension induced by NaHS. PMID- 26643173 TI - Cardiac 123I-MIBG scintigraphy: A window into the brain in Parkinsonism? PMID- 26643174 TI - PTH-Induced Osteoblast Proliferation Requires Upregulation of the Ubiquitin Specific Peptidase 2 (Usp2) Expression. AB - Osteoporosis is a common disease that increases individual's fragility fracture risk. PTH is the only therapeutic agent for severe osteoporosis that requires anabolic action of bone formation. Although a part of the PTH actions is explained by increased proliferation of osteoblastic precursor cells, the mechanisms involved in the proliferation of osteoblastic cells by PTH have not been clarified yet. Therefore, in this study, we investigated the effects of PTH on gene expression in the cultured osteoblastic MC3T3-E1 cells, and found that the ubiquitin-specific peptidase 2 (Usp2) may be one of the direct target genes of PTHR signaling. Usp2 is a deubiquitination enzyme targeting various factors including CyclinD1 in cancer cells and PTH receptor 1 in osteoblasts. We confirmed that consistent induction of Usp2 expression peaked at 1 h by PTH1-34 (teriparatide) in MC3T3-E1 cells and primary calvarial osteoblasts. Among the three known splicing variants of the Usp2, we found the isoforms 1 and 2 are predominantly expressed in osteoblasts. Live-imaging analysis of the Fucci transgenic mouse-derived primary osteoblasts indeed demonstrated that Usp2 is required for the PTH1-34-induced osteoblast proliferation. Western blotting analysis of the CyclinD1 indicated that Usp2 knock-down influences the paradoxical changes of CyclinD1 protein levels in this condition. Our data indicate that Usp2 is required for the PTH1-34-induced proliferation of osteoblasts. PMID- 26643176 TI - [In Process Citation]. PMID- 26643175 TI - Peroxidase Enzymes Regulate Collagen Biosynthesis and Matrix Mineralization by Cultured Human Osteoblasts. AB - The early recruitment of inflammatory cells to sites of bone fracture and trauma is a critical determinant in successful fracture healing. Released by infiltrating inflammatory cells, myeloperoxidase (MPO) and eosinophil peroxidase (EPO) are heme-containing enzymes, whose functional involvement in bone repair has mainly been studied in the context of providing a mechanism for oxidative defense against invading microorganisms. We report here novel findings that show peroxidase enzymes have the capacity to stimulate osteoblastic cells to secrete collagen I protein and generate a mineralized extracellular matrix in vitro. Mechanistic studies conducted using cultured osteoblasts show that peroxidase enzymes stimulate collagen biosynthesis at a post-translational level in a prolyl hydroxylase-dependent manner, which does not require ascorbic acid. Our studies demonstrate that osteoblasts rapidly bind and internalize both MPO and EPO, and the catalytic activity of these peroxidase enzymes is essential to support collagen I biosynthesis and subsequent release of collagen by osteoblasts. We show that EPO is capable of regulating osteogenic gene expression and matrix mineralization in culture, suggesting that peroxidase enzymes may play an important role not only in normal bone repair, but also in the progression of pathological states where infiltrating inflammatory cells are known to deposit peroxidases. PMID- 26643177 TI - [In Process Citation]. PMID- 26643178 TI - SRPX2 Enhances the Epithelial-Mesenchymal Transition and Temozolomide Resistance in Glioblastoma Cells. AB - Glioblastoma (GBM) is the most common and most aggressive central nervous system tumor in adults. Due to GBM cell invasiveness and resistance to chemotherapy, current medical interventions are not satisfactory, and the prognosis for GBM is poor. It is necessary to investigate the underlying mechanism of GBM metastasis and drug resistance so that more effective treatments can be developed for GBM patients. sushi repeat-containing protein, X-linked 2 (SRPX2) is a prognostic biomarker in many different cancer cell lines and is associated with poor prognosis in cancer patients. SRPX2 overexpression promotes interactions between tumor and endothelial cells, leading to tumor progression and metastasis. We hypothesize that SRPX2 also contributes to GBM chemotherapy resistance and metastasis. Our results revealed that GBM tumor samples from 42 patients expressed higher levels of SRPX2 than the control normal brain tissue samples. High-SRPX2 expression levels are correlated with poor prognosis in those patients, as well as resistance to temozolomide in cultured GBM cells. Up regulating SRPX2 expression in cultured GBM cell lines facilitated invasiveness and migration of GBM cells, while down-regulating SRPX2 through RNA interference was inhibitory. These results suggest that SRPX2 plays an important role in GBM metastasis. Epithelial to mesenchymal transition (EMT) is one of the processes that facilitate GBM metastasis and resistance to chemotherapy. EMT marker expression was decreased in SRPX2 down-regulated GBM cells, and MAPK signaling pathway marker expression was also decreased when SRPX2 is knocked down in GBM cultured cells. Blocking the MAPK signaling pathway inhibited GBM metastasis but did not inhibit cell invasion and migration in SRPX2 down-regulated cells. Our results indicate that SRPX2 facilitates GBM metastasis by enhancing the EMT process via the MAPK signaling pathway. PMID- 26643179 TI - Effects of Dietary Selenium Against Lead Toxicity on mRNA Levels of 25 Selenoprotein Genes in the Cartilage Tissue of Broiler Chicken. AB - The interactions between the essential element selenium (Se) and the toxic element lead (Pb) have been reported extensively; however, little is known about the effect of Se on Pb toxicity and the expression pattern of selenoproteins in the cartilage of chicken. To investigate the effects of Se on Pb toxicity and the messenger RNA (mRNA) expressions of selenoproteins in cartilage tissue, an in vitro study was performed on 1-day-old broiler chickens (randomly allocated into four groups) with diet of different concentration of Se and Pb. After 90 days, the meniscus cartilage and sword cartilage tissue were examined for the mRNA levels of 25 selenoprotein genes. The results showed that Se and Pb influenced the expression of selenoprotein genes in the chicken cartilage tissue. In detail, Se could alleviate the downtrend of the expression of Gpx1, Gpx2, Gpx4, Txnrd2, Txnrd3, Dio1, Dio2, Seli, Selu, Sepx1, Selk, Selw, Selo, Selm, Sep15, Sepnn1, Sels, and Selt induced by Pb exposure in the meniscus cartilage. In the sword cartilage, Se alleviated the downtrend of the expression of Gpx2, Gpx3, Gpx4, Txnrd1, Txnrd2, Dio2, Dio3, Seli, Selh, SPS2, Sepx1, Selk, Selw, Selo, Selm, Sep15, Selpb, Sepn1, and Selt induced by Pb exposure. The present study provided some compensated data about the roles of Se against Pb toxicity in the regulation of selenoprotein expression. PMID- 26643180 TI - Radical-mediated ring contraction in the biosynthesis of 7-deazapurines. AB - Pyrrolopyrimidine containing natural products are widely distributed in Nature. The biosynthesis of the 7-deazapurine moiety that is common to all pyrrolopyrimidines entails multiple steps, one of which is a complex radical mediated ring contraction reaction catalyzed by CDG synthase. Herein we review the biosynthetic pathways of deazapurines, focusing on the biochemical and structural insights into CDG synthase. PMID- 26643182 TI - Tinea nigra on the fingers. PMID- 26643181 TI - Neonatal complications associated with use of fetal scalp electrode: a retrospective study. AB - OBJECTIVES: To estimate the incidence and risk of complications associated with a fetal scalp electrode and to determine whether its application in the setting of operative vaginal delivery was associated with increased neonatal morbidity. DESIGN: Retrospective cohort study. SETTING: Twelve clinical centers with 19 hospitals across nine American Congress of Obstetricians and Gynecologists US districts. POPULATION: Women in the USA. METHODS: We evaluated 171 698 women with singleton deliveries >= 23 weeks of gestation in a secondary analysis of the Consortium on Safe Labor study between 2002 and 2008, after excluding conditions that precluded fetal scalp electrode application such as prelabour caesarean delivery. Secondary analysis limited to operative vaginal deliveries >= 34 weeks of gestation was also performed. MAIN OUTCOME MEASURES: Incidences and adjusted odds ratios with 95% confidence intervals of neonatal complications were calculated, controlling for maternal characteristics, delivery mode and pregnancy complications. RESULTS: Fetal scalp electrode was used in 37 492 (22%) of deliveries. In non-operative vaginal delivery, fetal scalp electrode was associated with increased risk of injury to scalp due to birth trauma (1.2% versus 0.9%; adjusted odds ratios 1.62; 95% confidence intervals 1.41-1.86) and cephalohaematoma (1.0% versus 0.9%; adjusted odds ratios 1.57; 95% confidence intervals 1.36-1.83). Neonatal complications were not significantly different comparing fetal scalp electrode with vacuum-assisted vaginal delivery and vacuum assisted vaginal delivery alone or comparing fetal scalp electrode with forceps assisted vaginal delivery and forceps-assisted vaginal delivery alone. CONCLUSIONS: We found increased neonatal morbidity with fetal scalp electrode though the absolute risk was very low. It is possible that these findings reflect an underlying indication for its use. Our findings support the use of fetal scalp electrodes when clinically indicated. TWEETABLE ABSTRACT: Neonatal risks associated with fetal scalp electrode use were low (injury to scalp 1.2% and cephalohaematoma 1.0%). PMID- 26643183 TI - Obstruction of the external auditory meatus secondary to a giant pyogenic granuloma. AB - Pyogenic granuloma is a benign lesion of the skin and mucosa commonly known to occur in the head and neck region. The current literature has not yet identified its occurrence within the conchal bowl, a condition that leads to obstruction of the external auditory meatus. We present the case of a 28-year-old man who presented with a history of 3-4 weeks of a rapidly enlarging pedunculated lesion within the conchal bowl of the right ear and conductive hearing loss. Initial management included excision under local anaesthesia. The histological report concluded that it was a pyogenic granuloma. Later, reoccurrence was treated with a more definitive excision under general anaesthesia. During follow-up, the operative site was seen to have healed by secondary intention without reoccurrence. Although a pyogenic granuloma within the conchal bowl is benign, early therapeutic excision is important for histological diagnosis as much as to relieve consequential secondary obstruction and conductive hearing loss. PMID- 26643184 TI - From bone to heart: a case of MRSA osteomyelitis with haematogenous spread to the pericardium. AB - We report a case of a 55-year-old woman with a history of type 2 diabetes mellitus, Charcot arthropathy and end-stage renal disease, who presented with a syncopal episode after undergoing haemodialysis. She had a history of methicillin resistant Staphylococcus aureus (MRSA) bacteraemia from an unknown source 3 months earlier, which was treated with an 8-week course of intravenous antibiotics. At the time of presentation to the emergency room, she was found to be in refractory shock. Bedside echocardiogram was performed, which showed moderate pericardial effusion. The effusion was later found to be due to MRSA, which was identified in blood and in pericardial fluid cultures. The patient was successfully treated with intravenous daptomycin for 6 weeks. Acute osteomyelitis of her right foot was the source of the MRSA, for which a right below-knee amputation was ultimately performed. PMID- 26643185 TI - Intravenous leiomyomatosis with intracardiac extension: an unusual presentation of uterine leiomyoma and evaluation with 256-slice dual-source multidetector CT and cardiac MRI. AB - We report a case of a 40-year-old woman who presented with breathlessness, palpitations and vague pelvic pain for 6 months. The dyspnoea was non-exertional and episodic. She was a non-diabetic, non-hypertensive and had no history of prior surgeries. ECG and chest radiograph were normal. Cardiac MRI and 256-slice dual-source multidetector CT evaluation revealed the presence of a uterine and left adnexal mass with intravenous extension into the inferior vena cava via the gonadal veins, and further cephalad extension into the right atrium and ventricle. The patient was referred to the cardiothoracic surgery department and underwent two-stage surgical procedures. The first stage consisted of thoracotomy and tumour removal from the right atrium and inferior vena cava. In the second stage, hysterectomy and bilateral salpingo-oophorectomy was performed. The histological analysis of the excised specimen was consistent with an intravascular leiomyoma. PMID- 26643186 TI - Drug-induced elastosis perforans serpiginosa. PMID- 26643187 TI - Erythema migrans associated with partial Horner's syndrome. AB - Lyme disease is a tick-borne illness caused mainly by three species of spirochaete Borrelia--B. burgdorferi, B. afzelii and B. garinii. It has three stages of presentation--early localised, early-disseminated and late Lyme. Erythema migrans is the most common manifestation of Lyme disease, and is usually seen 7-14 days after the tick bite. Patients seldom remember the tick bite. Patients may often present with neurological manifestations indicating neuroborreliosis. These manifestations range from a simple nerve palsy to severe complications such as papilloedema, myelitis or meningitis. We present a case of a 37-year-old woman who presented with partial Horner's syndrome, which was associated with erythema migrans, and other signs of Lyme disease. PMID- 26643188 TI - A rare case of pulmonary alveolar microlithiasis. PMID- 26643189 TI - Epidermal inclusion cyst in a male breast: parallel linear echoes (tram-track appearance) on sonography as a diagnostic clue. PMID- 26643190 TI - Antenatal diagnosis of aneurysmal malformation of the vein of Galen. AB - Vein of Galen malformation (VGAM) results from an aneurysmal aberration with an arteriovenous shunting of blood. Vein of Galen aneurysmal malformations are the most frequent arteriovenous malformations in infants and fetuses. The congenital malformation develops during weeks 6-11 of fetal development. Infants often die from high-output congestive heart failure. PMID- 26643191 TI - The Role of Computer-Assisted Technology in Post-Traumatic Orbital Reconstruction: A PRISMA-driven Systematic Review. AB - Post-traumatic orbital reconstruction remains a surgical challenge and requires careful preoperative planning, sound anatomical knowledge and good intraoperative judgment. Computer-assisted technology has the potential to reduce error and subjectivity in the management of these complex injuries. A systematic review of the literature was conducted to explore the emerging role of computer-assisted technologies in post-traumatic orbital reconstruction, in terms of functional and safety outcomes. We searched for articles comparing computer-assisted procedures with conventional surgery and studied outcomes on diplopia, enophthalmos, or procedure-related complications. Six observational studies with 273 orbits at a mean follow-up of 13 months were included. Three out of 4 studies reported significantly fewer patients with residual diplopia in the computer-assisted group, while only 1 of the 5 studies reported better improvement in enophthalmos in the assisted group. Types and incidence of complications were comparable. Study heterogeneities limiting statistical comparison by meta-analysis will be discussed. This review highlights the scarcity of data on computer-assisted technology in orbital reconstruction. The result suggests that computer-assisted technology may offer potential advantage in treating diplopia while its role remains to be confirmed in enophthalmos. Additional well-designed and powered randomized controlled trials are much needed. PMID- 26643192 TI - Two 6-minute Walk Tests Are Required During Hospitalisation for Acute Exacerbation of COPD. AB - The 6-minute walk test (6MWT) is recommended to be performed twice to accurately assess exercise performance in stable chronic obstructive pulmonary disease (COPD) due to the presence of a learning effect. It is unknown whether a learning effect exists when the 6MWT is performed during hospitalisation for acute exacerbation of COPD (AECOPD). This study investigated whether repeat 6MWTs are necessary when conducted in inpatients with AECOPD. Pooled analysis was undertaken of data from two studies (Australia and Brazil) involving 46 participants (25 males, mean age 67.2 years, FEV1 43% predicted) admitted with AECOPD. Two 6MWTs, separated by >=20 minutes, were performed on the day of discharge. Six-minute walk distance (6MWD; primary outcome), perceived dyspnoea (Borg scale), heart rate and oxyhaemoglobin saturation were recorded. 6MWD data from tests one (T1) and two (T2) were analysed via visual inspection of Bland Altman plots. Factors associated with test improvement or decline were explored. Mean 6MWD difference between T1 and T2 was 6.2 m, however limits of agreement were wide (-92.2 m to 104.5 m). 32 (70%) participants improved (by any distance) from T1 to T2 by a mean (+/- standard deviation) of 32 m +/- 28 m. Of these, 14 (30%) improved by a distance > 30 m. Fourteen (30%) participants recorded poorer 6MWD at T2 by a mean of 52 m +/- 36 m. No factors were able to identify participants who improved or declined upon repeat testing. When performed in patients admitted to hospital with AECOPD, the 6MWT needs to be conducted twice in order to better estimate 6MWD. PMID- 26643193 TI - Cell culture-derived HCV cannot infect synovial fibroblasts. AB - Worldwide 170 million individuals are infected with hepatitis C virus (HCV), up to 45 million of whom are affected by arthropathy. It is unclear whether this is due to viral infection of synovial cells or immune-mediated mechanisms. We tested the capacity of primary synovial fibroblasts to support HCV propagation. Out of the four critical HCV receptors, only CD81 was expressed to any significant extent in OASF and RASF. Consistent with this, pseudotyped HCV particles were unable to infect these cells. Permissiveness for HCV replication was investigated by transfecting cells with a subgenomic replicon of HCV encoding a luciferase reporter. OASF and RASF did not support replication of HCV, possibly due to low expression levels of miR-122. In conclusion, primary human synovial fibroblasts are unable to support propagation of HCV in vitro. HCV-related arthropathy is unlikely due to direct infection of these cells. PMID- 26643194 TI - Classification of Pelteobagrus fish in Poyang Lake based on mitochondrial COI gene sequence. AB - We use DNA molecular marker technology to correct the deficiency of traditional morphological taxonomy. Totality 770 Pelteobagrus fish from Poyang Lake were collected. After preliminary morphological classification, random selected eight samples in each species for DNA extraction. Mitochondrial COI gene sequence was cloned with universal primers and sequenced. The results showed that there are four species of Pelteobagrus living in Poyang Lake. The average of intraspecific genetic distance value was 0.003, while the average interspecific genetic distance was 0.128. The interspecific genetic distance is far more than intraspecific genetic distance. Besides, phylogenetic tree analysis revealed that molecular systematics was in accord with morphological classification. It indicated that COI gene is an effective DNA molecular marker in Pelteobagrus classification. Surprisingly, the intraspecific difference of some individuals (P. e6, P. n6, P. e5, and P. v4) from their original named exceeded species threshold (2%), which should be renewedly classified into Pelteobagrus fulvidraco. However, another individual P. v3 was very different, because its genetic distance was over 8.4% difference from original named Pelteobagrus vachelli. Its taxonomic status remained to be further studied. PMID- 26643195 TI - Functional characterization and hormonal regulation of the PHEOPHYTINASE gene LpPPH controlling leaf senescence in perennial ryegrass. AB - Chlorophyll (Chl) degradation occurs naturally during leaf maturation and senescence, and can be induced by stresses, both processes involving the regulation of plant hormones. The objective of this study was to determine the functional roles and hormonal regulation of a gene encoding pheophytin pheophorbide hydrolyase (PPH) that catabolizes Chl degradation during leaf senescence in perennial grass species. A PPH gene, LpPPH, was cloned from perennial ryegrass (Lolium perenne L.). LpPPH was localized in the chloroplast. Overexpressing LpPPH accelerated Chl degradation in wild tobacco, and rescued the stay-green phenotype of the Arabidopsis pph null mutant. The expression level of LpPPH was positively related to the extent of leaf senescence. Exogenous application of abscisic acid (ABA) and ethephon (an ethylene-releasing agent) accelerated the decline in Chl content in leaves of perennial ryegrass, whereas cytokinin (CK) and aminoethoxyvinylglycine (AVG; an ethylene biosynthesis inhibitor) treatments suppressed leaf senescence, corresponding to the up- or down-regulation of LpPPH expression. The promoters of five orthologous PPH genes were predicted to share conserved cis-elements potentially recognized by transcription factors in the ABA and CK pathways. Taken together, the results suggested that LpPPH-mediated Chl breakdown could be regulated positively by ABA and ethylene, and negatively by CK, and LpPPH could be a direct downstream target gene of transcription factors in the ABA and CK signaling pathways. PMID- 26643196 TI - What a difference a CRP makes. A prospective observational study on how point-of care C-reactive protein testing influences antibiotic prescription for respiratory tract infections in Swedish primary health care. AB - OBJECTIVE: To explore how C-reactive protein (CRP) tests serve to support physicians in decisions concerning antibiotic prescription to patients with respiratory tract infections (RTI). DESIGN: Prospective observational study. SETTING: Primary health care centres in western Sweden. SUBJECTS: Physicians in primary health care. Patients with acute RTI. MAIN OUTCOME MEASURES: Physician willingness to measure CRP, their ability to estimate CRP, and changes in decision-making concerning antibiotic treatment based on error estimate and the physician's opinion of whether CRP measurement was crucial. RESULTS: Data from 340 consultations were gathered. CRP testing was found to be crucial in 130 cases. In 86% of visits decisions regarding antibiotic prescription were unchanged. Physicians considering CRP crucial and physicians making an error estimate of CRP altered their decisions concerning antibiotic prescription after CRP testing more often than those who considered CRP unnecessary, and those making a more accurate estimate. Physicians changed their decision on antibiotic prescription in 49 cases. In the majority of these 49 cases physicians underestimated CRP levels, and the majority of changes were from "no" to "yes" as to whether to prescribe antibiotics. CONCLUSION: CRP is an important factor in the decision on whether to prescribe antibiotics for RTIs. Error estimates of CRP and willingness to measure CRP are important factors leading to physicians changing decisions on antibiotic treatment. Key points There is a generally low antibiotic prescription rate and a high frequency of C-reactive protein (CRP) testing for respiratory tract infections (RTIs) in Sweden. CRP testing was considered essential to further management in 38% of cases. In 86% of visits decisions concerning antibiotic prescription were unchanged. The strongest predictors for revised decisions on antibiotic treatment were error estimates of CRP and the physician's opinion that CRP measurement was crucial. PMID- 26643197 TI - A Brazilian report using serological and molecular diagnosis to monitoring acute ocular toxoplasmosis. AB - BACKGROUND: Toxoplasmosis was recently included as a neglected disease by the Center for Disease Control. Ocular toxoplasmosis is one clinical presentation of congenital or acquired infection. The laboratory diagnosis is being used worldwide to support the clinical diagnosis and imaging. The aim of this study was to evaluate the use of serology and molecular methods to monitor acute OT in immunocompetent patients during treatment. METHODS: Five immunocompetent patients were clinically diagnosed with acute OT. The clinical evaluation was performed by ophthalmologic examination using the Early Treatment Diabetic Retinopathy Study, best-corrected visual acuity, slit lamp biomicroscopy, fundoscopic examination with indirect binocular ophthalmoscopy color fundus photography, fluorescein angiography and spectral optical coherence tomography (OCT). Serology were performed by ELISA (IgA, IgM, IgG) and confirmed by ELFA (IgG, IgM). Molecular diagnoses were performed in peripheral blood by cPCR using the Toxoplasma gondii B1 gene as the marker. Follow-up exams were performed on day +15 and day +45. RESULTS: Only five non-immunocompromised male patients completed the follow up and their data were used for analysis. The mean age was 41.2 +/- 11.3 years (median: 35; range 31-54 years). All of them were positive for IgG antibodies but with different profiles for IgM and IgA, as well as PCR. For all patients the OCT exam showed active lesions with the inner retinal layers being abnormally hyper reflective with full-thickness disorganization of the retinal reflective layers, which assumed a blurred reflective appearance and the retina was thickened. CONCLUSIONS: The presence of IgA and IgM confirmed the acute infection and thus was in agreement with the clinical evaluation. Our results show the adopted treatment modified the serological profile of IgM antibodies and the PCR results, but not the IgG and IgA antibodies and that imaging is a good tool to follow-up patients. PMID- 26643198 TI - Novel, More Accurate Assessments of Renal Function in Heart Transplant Patients [corrected]. PMID- 26643199 TI - The emergence of DNA in the RNA world: an in silico simulation study of genetic takeover. AB - BACKGROUND: It is now popularly accepted that there was an "RNA world" in early evolution of life. This idea has a direct consequence that later on there should have been a takeover of genetic material - RNA by DNA. However, since genetic material carries genetic information, the "source code" of all living activities, it is actually reasonable to question the plausibility of such a "revolutionary" transition. Due to our inability to model relevant "primitive living systems" in reality, it is as yet impossible to explore the plausibility and mechanisms of the "genetic takeover" by experiments. RESULTS: Here we investigated this issue by computer simulation using a Monte-Carlo method. It shows that an RNA-by-DNA genetic takeover may be triggered by the emergence of a nucleotide reductase ribozyme with a moderate activity in a pure RNA system. The transition is unstable and limited in scale (i.e., cannot spread in the population), but can get strengthened and globalized if certain parameters are changed against RNA (i.e., in favor of DNA). In relation to the subsequent evolution, an advanced system with a larger genome, which uses DNA as genetic material and RNA as functional material, is modeled - the system cannot sustain if the nucleotide reductase ribozyme is "turned off" (thus, DNA cannot be synthesized). Moreover, the advanced system cannot sustain if only DNA's stability, template suitability or replication fidelity (any of the three) is turned down to the level of RNA's. CONCLUSIONS: Genetic takeover should be plausible. In the RNA world, such a takeover may have been triggered by the emergence of some ribozyme favoring the formation of deoxynucleotides. The transition may initially have been "weak", but could have been reinforced by environmental changes unfavorable to RNA (such as temperature or pH rise), and would have ultimately become irreversible accompanying the genome's enlargement. Several virtues of DNA (versus RNA) - higher stability against hydrolysis, greater suitability as template and higher fidelity in replication, should have, each in its own way, all been significant for the genetic takeover in evolution. This study enhances our understandings of the relationship between information and material in the living world. PMID- 26643200 TI - Citrus medica L. cv Diamante (Rutaceae) peel extract improves glycaemic status of Zucker diabetic fatty (ZDF) rats and protects against oxidative stress. AB - This study aimed to investigate the antidiabetic, antilipidaemic and antioxidant activities of Citrus medica cv Diamante (Rutaceae) hydroalcoholic (CD) peel extract in Zucker diabetic fatty (ZDF) rats. The ability of CD to protect against oxidative stress was investigated by using different in vitro assays and in vivo by using the reactive oxygen metabolites-derived compounds (d-ROMs) test and the biological antioxidant potential test (BAP). Two different doses of CD extract (300 and 600 mg/kg/die) were administered at ZDF rats for 4 weeks. CD reduced cholesterol and triglycerides levels. A dose-dependent effect on body weight and serum glucose levels was observed. A decrease of d-ROMs and an increase of BAP were recorded by using the dose of 600 mg/kg. The extract inhibited lipid peroxidation (IC50 value of 0.23 mg/ml). These findings suggest as an efficient phytotherapeutic approach in combating hyperlipidaemic and hyperglycaemic disorders. PMID- 26643201 TI - Dedicated to Professor Peter Krumbiegel on the occasion of his 80th birthday. PMID- 26643202 TI - The 13C bicarbonate method: an inverse end product method for measuring CO2 production and energy expenditure. AB - We reconsider the principle of the (13)C bicarbonate (NaH(13)CO3) method ((13)C BM) for the determination of the CO2 production to obtain an estimate of energy expenditure (EE). Its mathematical concept based on a three-compartmental model is related to the [(15)N]glycine end product method. The CO2 production calculated by the (13)C-BM, RaCO2((13)C) is compared to the result from the indirect calorimetry, RCO2(IC). In an interspecies comparison (dog, goat, horse, cattle, children, adult human; body mass ranging from 15 to 350 kg, resting and fasting conditions) we found an excellent correlation between the results of (13)C-BM and IC with RCO2(IC) = 0.703 * RaCO2((13)C), (R(2) = 0.99). The slope of this correlation corresponds to the fractional (13)C recovery (RF((13)C)) of (13)C in breath CO2 after administration of NaH(13)CO3. Significant increase in RF((13)C) was found in physically active dogs (0.95 +/- 0.14; n = 5) vs. resting dogs (0.71 +/- 0.10, n = 17; p = .015). The (13)C recovery in young bulls was greater in blood CO2 (0.81 +/- 0.05) vs. breath CO2 (0.73 +/- 0.05, n = 12, p < .001) and in ponies with oral (0.76 +/- 0.03, n = 8) vs. intravenous administration of NaH(13)CO3 (0.69 +/- 0.07; n = 8; p = .026). We suggest considering the (13)C-BM as a 'stand-alone' method to provide information on the total CO2 production as an index of EE. PMID- 26643204 TI - Measurement of occupational doses of ionising radiation to the lens of the eyes of interventional radiologists. AB - Currently, there exists no standardised method for monitoring radiation doses to the eye lens. This investigation aimed to determine the optimum method for monitoring the eye doses for interventional radiologists. Three interventional radiologists were issued with a series of dosimeters to wear during their routine work. These dosimeters were worn at defined positions on the body and the absorbed dose to each position was measured. It was confirmed that the dose received to the thyroid collar followed an apparently well-defined relationship to the dose recorded on the forehead, which is representative of the dose to the lens of the eye. It was also confirmed that, as hypothesised, the dose to the left eye was universally greater than to the right, although by varying factors. It was concluded that the use of dosimeters attached to the inside arms of protective eyewear is the optimum solution for eye lens dosimetry. It was also concluded that, when used with a dose conversion factor which corroborates existing literature, dosimeters attached to the outside of a thyroid collar yield sufficiently accurate results for use in routine dosimetry programmes. PMID- 26643206 TI - Low bone mineral density is a common feature of Zellweger spectrum disorders. AB - Patients with Zellweger Spectrum Disorders (ZSDs) have impaired peroxisome biogenesis and severe, multisystem disease. Although the neurologic symptoms of ZSD tend to be the most prominent, patients also have hepatic, renal and adrenal impairment. Little is known about bone health in patients with ZSD, particularly those with mild or moderate presentation. We investigated 13 ZSD patients who had strikingly abnormal bone mineral density for age. DXA scans showed mean lumbar and femoral neck Z-scores of -3.2. There were no major differences between ambulatory and nonambulatory patients, and no biochemical abnormalities consistent with rickets or vitamin D deficiency were seen. Cyclic bisphosphonate therapy in one ZSD patient was successfully used to increase in bone mineral density. Although the etiology of bone disease in this condition is unknown, we speculate that altered signaling through the PPARgamma pathway or deficient plasmalogens in patients with ZSD disrupts osteogenesis, resulting in poor bone formation and poor mineralization. Further investigation into the pathogenic mechanisms of bone disease in ZSD and the role of peroxisomal metabolism in osteogenesis may yield insights into the pathology of bone disease and suggest novel treatment options. PMID- 26643205 TI - Xanthurenic Acid Activates mGlu2/3 Metabotropic Glutamate Receptors and is a Potential Trait Marker for Schizophrenia. AB - The kynurenine pathway of tryptophan metabolism has been implicated in the pathophysiology of psychiatric disorders, including schizophrenia. We report here that the kynurenine metabolite, xanturenic acid (XA), interacts with, and activates mGlu2 and mGlu3 metabotropic glutamate receptors in heterologous expression systems. However, the molecular nature of this interaction is unknown, and our data cannot exclude that XA acts primarily on other targets, such as the vesicular glutamate transporter, in the CNS. Systemic administration of XA in mice produced antipsychotic-like effects in the MK-801-induced model of hyperactivity. This effect required the presence of mGlu2 receptors and was abrogated by the preferential mGlu2/3 receptor antagonist, LY341495. Because the mGlu2 receptor is a potential drug target in the treatment of schizophrenia, we decided to measure serum levels of XA and other kynurenine metabolites in patients affected by schizophrenia. Serum XA levels were largely reduced in a large cohort of patients affected by schizophrenia, and, in patients with first episode schizophrenia, levels remained low after 12 months of antipsychotic medication. As opposed to other kynurenine metabolites, XA levels were also significantly reduced in first-degree relatives of patients affected by schizophrenia. We suggest that lowered serum XA levels might represent a novel trait marker for schizophrenia. PMID- 26643207 TI - Apparent underdiagnosis of Cerebrotendinous Xanthomatosis revealed by analysis of ~60,000 human exomes. AB - Cerebrotendinous Xanthomatosis (CTX) is a treatable inborn error of metabolism caused by recessive variants in CYP27A1. Clinical presentation varies, but typically includes infant-onset chronic diarrhea, juvenile-onset bilateral cataracts, and later-onset tendinous xanthomas and progressive neurological dysfunction. CYP27A1 plays an essential role in side-chain oxidation of cholesterol necessary for the synthesis of the bile acid, chenodeoxycholic acid, and perturbations in this gene that reduce enzyme activity result in elevations of cholestanol. It is commonly held that CTX is exceedingly rare, but epidemiological studies are lacking. In order to provide an accurate incidence estimate of CTX, we studied the ExAC cohort of ~60,000 unrelated adults from global populations to determine the allele frequency of the 57 variants in CYP27A1 reported pathogenic for CTX. In addition, we conducted bioinformatics analyses on these CTX-causing variants and determined a bioinformatics profile to predict variants that may be pathogenic but have not yet been reported in the CTX patient literature. An additional 29 variants were identified that met bioinformatics criteria for being potentially pathogenic. Incidence was estimated based allele frequencies of pathogenic CTX variants plus those determined to be potentially pathogenic. One variant, p.P384L, previously reported in three unrelated CTX families had an allele frequency >= 1% in European, Latino and Asian populations. Three additional mutations had a frequency of >= 0.1% in Asian populations. CTX disease incidence was calculated excluding the high frequency p.P384L and separately using a genetic paradigm where this high frequency variant only causes classic CTX when paired in trans with a null variant. These calculations place CTX incidence ranging from 1:134,970 to 1:461,358 in Europeans, 1:263,222 to 1:468,624 in Africans, 1:71,677 to 1:148,914 in Americans, 1:64,267 to 1:64,712 in East Asians and 1:36,072 to 1:75,601 in South Asians. This work indicates CTX is under-diagnosed and improved patient screening is needed as early intervention prevents disease progression. PMID- 26643208 TI - High serum uric acid levels increase the risk of metabolic syndrome in elderly women: The PRO.V.A study. AB - BACKGROUND AND AIMS: Serum uric acid (SUA) is the end-product of purine metabolism in humans, and its levels often increase in subjects with metabolic syndrome (MetS). Despite several studies demonstrating a relationship between increased SUA levels and the prevalence of MetS, prospective data on SUA as a predictor of the incidence of MetS in the elderly are limited. Our aim was to conduct a prospective study on the association between SUA concentrations and the onset of MetS in an elderly Italian cohort. METHODS AND RESULTS: This is a cohort study (Progetto Veneto Anziani; Pro.V.A.) involving community-dwelling subjects aged >=65 years and followed up for a mean 4.4 years. We included 1128 participants (aged 74.7 +/- 7.1 years) without MetS at the baseline. Gender specific SUA groups according to the standard deviation (SD) from the mean were considered, taking the incidence of MetS as the main outcome. The mean SUA level was significantly higher in men than in women (5.4 +/- 1.2 vs. 4.5 +/- 1.2 mg/dl; p < 0.0001). Over the 4.4-year follow-up, 496 individuals developed MetS. After adjusting for potential confounders, Cox's regression analysis revealed no relationship between higher baseline SUA concentrations and the incidence of MetS in men or in the sample as whole, while women with SUA levels more than 1 SD above the mean (>=5.7 mg/dl) carried a 58% higher risk (95%CI: 1.03-2.40; p = 0.03) of being newly diagnosed with MetS during the follow-up. CONCLUSION: High SUA levels significantly and independently predicted MetS in older women, but not in men, over a 4.4-year follow-up. PMID- 26643209 TI - Influence of the hypothalamic-pituitary-adrenal axis dysregulation on the metabolic profile of patients affected by diabetes mellitus-associated late onset hypogonadism. AB - BACKGROUND AND AIMS: Functional hypercortisolism (FH) is generated by clinical states able to chronically activate the hypothalamic-pituitary-adrenal (HPA) axis [e.g. diabetes mellitus (DM)]. No study has evaluated FH influence in worsening the metabolic profile of male patients affected by DM-associated hypogonadism. In this retrospective work, we assess the possible association between HPA axis dysregulation and cardiovascular risk factors in men simultaneously affected by DM and late-onset hypogonadism (LOH). METHODS AND RESULTS: Fourteen DM and LOH subjects affected by FH (Hypercort-DM-LOH) and fourteen DM and LOH subjects who were not suffering from FH (Normocort-DM-LOH) were retrospectively considered. Clinical, hormonal and metabolic parameters were retrieved. All metabolic parameters, except for systolic blood pressure, were significantly worse in Hypercort-DM-LOH than in Normocort-DM-LOH. After adjustment for body mass index, waist and total testosterone, Hypercort-DM-LOH subjects showed significantly worse metabolic parameters than Normocort-DM-LOH ones. In Normocort-DM-LOH, no significant correlation between general/hormonal parameters and metabolic variables was present. In Hypercort-DM-LOH, positive and significant correlations of cortisol area under the curve (AUC) after corticotropin releasing hormone with glycemia, triglycerides and blood pressure were evident; on the other hand, negative and significant correlation was present between cortisol AUC and high density lipoprotein (HDL) cholesterol. The associations of AUC cortisol with glycemia, HDL cholesterol and diastolic blood pressure (DBP) were further confirmed at quantile regression after adjustment for therapy. CONCLUSIONS: FH may determine a worsening of the metabolic profile in DM-associated hypogonadism. PMID- 26643210 TI - Hyponatremia in the general population. What does it mean? AB - Hyponatremia is a frequent problem in clinical practice and is known to be associated with a variety of serious adverse outcomes. Estimates from the US general population and several community-based cohorts indicate that hyponatremia is also relatively common in these settings, especially among seniors, individuals with underlying disease, and those taking a variety of prescription medications. Prevalence is greatly increased when persons with a "low normal" level of serum sodium are considered. Population-based studies have identified a U-shaped relationship between serum sodium and all-cause mortality, with the increased risk at the lower end of the distribution being seen in persons with a "low normal" level of serum sodium as well as those meeting the traditional definition of hyponatremia. The hyponatremia associated risk in epidemiologic studies is of lesser magnitude than in hospital-based studies but of great potential importance give the much larger number of persons with a low serum sodium in the general population. An important challenge for the research community is to determine whether low levels of serum sodium are a direct cause of increased risk. Population-based studies are likely to provide the best opportunity to resolve this question. PMID- 26643211 TI - Hemodynamic overload and intra-abdominal adiposity in obese children: Relationships with cardiovascular structure and function. AB - BACKGROUND AND AIMS: Childhood obesity promotes adverse changes in cardiovascular structure and function. This study evaluated whether these changes are related to intra-abdominal adiposity and associated cardiometabolic risk or to body-size induced hemodynamic overload. METHODS AND RESULTS: 55 obese children/adolescents and 35 healthy-weight controls underwent carotid, cardiac and abdominal ultrasound to assess carotid artery intima-media thickness (IMT), diameter, distension and stiffness, left ventricular (LV) dimension, mass and function and extent of intra-abdominal adiposity. As compared to controls with healthy BMI, obese children had higher systolic blood pressure (BP), stroke volume and lower total peripheral resistance (P < 0.001-0.0001), higher plasma triglycerides, glycated hemoglobin, insulin and HOMA-IR index (P = 0.01-<0.0001), higher carotid IMT, diameter and distension (P < 0.005-0.0005), higher LV diameter, wall thickness and mass (P < 0.001-0.0001), and impaired LV diastolic function assessed by myocardial longitudinal performance (P < 0.005). In entire population, independent determinants of carotid diameter, LV diameter, wall thickness and mass were fat-free mass (or stroke volume, respectively) and BP. Carotid distension was determined by carotid diameter and BP, and carotid IMT by carotid diameter, BP, HDL-cholesterol and glycated hemoglobin. LV diastolic performance was inversely related to preperitoneal fat thickness and plasma insulin levels. CONCLUSIONS: Obese youths present signs of impaired lipid and glucose metabolism, hyperdynamic circulation and cardiovascular changes. Increase in LV dimensions and mass and in carotid diameter and distension seems to reflect adaptation to body-size induced increase in hemodynamic load, changes in LV diastolic performance a negative impact of intra-abdominal adiposity and associated metabolic risk, and increase in IMT both adaptive remodeling and metabolic risk. PMID- 26643213 TI - Juvenile zebrafish in the vitellogenin blank period as an alternative test organism for evaluation of estrogenic activity of chemicals. AB - The present study aimed to determine the suitable development period for zebrafish to evaluate estrogenic activities accurately. An enzyme-linked immunosorbent assay was developed and used to detect the vitellogenin (Vtg) derived yolk proteins and newly produced Vtg, and 9 d to 56 d posthatching was determined as the Vtg-blank period. Juveniles in this period were found to have lower baseline Vtg levels than adult males and were considered an alternative test organism for detecting environmental estrogens. Environ Toxicol Chem 2016;35:1783-1787. (c) 2015 SETAC. PMID- 26643214 TI - Framing health policy in the context of Saudi Arabia. PMID- 26643212 TI - Endoplasmic reticulum pathology and stress response in neurons precede programmed necrosis after neonatal hypoxia-ischemia. AB - The endoplasmic reticulum (ER) is tasked, among many other functions, with preventing excitotoxicity from killing neurons following neonatal hypoxia ischemia (HI). With the search for delayed therapies to treat neonatal HI, the study of delayed ER responses becomes relevant. We hypothesized that ER stress is a prominent feature of delayed neuronal death via programmed necrosis after neonatal HI. Since necrostatin-1 (Nec-1), an inhibitor of programmed necrosis, provides delayed neuroprotection against neonatal HI in male mice, Nec-1 is an ideal tool to study delayed ER responses. C57B6 male mice were exposed to right carotid ligation followed by exposure to FiO2=0.08 for 45 min at p7. Mice were treated with vehicle or Nec-1 (0.1 MUl of 8 MUmol) intracerebroventricularly with age-matched littermates as controls. Biochemistry assays at 3 and 24h and electron microscopy (EM) and immunohistochemistry at 96 h after HI were performed. EM showed ER dilation and mitochondrial swelling as apparent early changes in neurons. With advanced neurodegeneration, large cytoplasmic fragments containing dilated ER "shed" into the surrounding neuropil and calreticulin immunoreactivity was lost concurrent with nuclear features suggestive of programmed necrosis. Nec-1 attenuated biochemical markers of ER stress after neonatal HI, including PERK and eIF2alpha phosphorylation, and unconventional XBP 1 splicing, consistent with the mitigation of later ER pathology. ER pathology may be an indicator of severity of neuronal injury and potential for recovery characterized by cytoplasmic shedding, distinct from apoptotic blebbing, that we term neuronal macrozeiosis. Therapies to attenuate ER stress applied at delayed stages may rescue stressed neurons after neonatal HI. PMID- 26643215 TI - Acetylation of histones in neocortex and hippocampus of rats exposed to different modes of hypobaric hypoxia: Implications for brain hypoxic injury and tolerance. AB - Acetylation of nucleosome histones results in relaxation of DNA and its availability for the transcriptional regulators, and is generally associated with the enhancement of gene expression. Although it is well known that activation of a variety of pro-adaptive genes represents a key event in the development of brain hypoxic/ischemic tolerance, the role of epigenetic mechanisms, in particular histone acetylation, in this process is still unexplored. The aim of the present study was to investigate changes in acetylation of histones in vulnerable brain neurons using original well-standardized model of hypobaric hypoxia and preconditioning-induced tolerance of the brain. Using quantitative immunohistochemistry and Western blot, effects of severe injurious hypobaric hypoxia (SH, 180mm Hg, 3h) and neuroprotective preconditioning mode (three episodes of 360mm Hg for 2h spaced at 24h) on the levels of the acetylated proteins and acetylated H3 Lys24 (H3K24ac) in the neocortex and hippocampus of rats were studied. SH caused global repression of the acetylation processes in the neocortex (layers II-III, V) and hippocampus (CA1, CA3) by 3-24h, and this effect was prevented by the preconditioning. Moreover, hypoxic preconditioning remarkably increased the acetylation of H3K24 in response to SH in the brain areas examined. The preconditioning hypoxia without subsequent SH also stimulated acetylation processes in the neocortex and hippocampus. The moderately enhanced expression of the acetylated proteins in the preconditioned rats was maintained for 24h, whereas acetylation of H3K24 was intense but transient, peaked at 3h. The novel data obtained in the present study indicate that large activation of the acetylation processes, in particular acetylation of histones might be essential for the development of brain hypoxic tolerance. PMID- 26643216 TI - Developmental expression and distribution of nesfatin-1/NUCB2 in the canine digestive system. AB - Nesfatin-1/NUCB2 is a neuropeptide that plays important roles in regulating food intake and energy homeostasis. The distribution of nesfatin-1/NUCB2 protein and mRNA has not been investigated in the canine digestive system. The present study was conducted to evaluate the expression of nesfatin-1/NUCB2 protein and NUCB2 mRNA in the canine digestive organs (esophagus, stomach, duodenum, jejunum, ileum, cecum, colon, rectum, liver and pancreas). The tissues of the digestive system were collected from dogs at different developmental stages (infantile, juvenile, pubertal and adult). Nesfatin-1/NUCB2 protein localization in the organs of adult dogs was detected by immunohistochemistry. The expression of NUCB2 mRNA at the four developmental stages was analyzed by real-time fluorescence quantitative PCR (qRT-PCR). Nesfatin-1/NUCB2 protein was distributed in the fundic gland region of the stomach, and the islet area and exocrine portions of the pancreas. However, NUCB2 mRNA was found in all digestive organs, although the expression levels in the pancreas and stomach were higher than those in liver, duodenum and other digestive tract tissues (P<0.05) at the four different developmental stages of the dogs. In this study, nesfatin-1/NUCB2 was found to be present at high levels in the stomach and pancreas at both the protein and mRNA levels; however, NUCB2 expression was found at lower levels in all of the digestive organs. These findings provide the basis of further investigations to elucidate the functions of nefatin-1 in the canine digestive system. PMID- 26643217 TI - Development of (68)Ga-labeled multivalent nitroimidazole derivatives for hypoxia imaging. AB - Radiolabeled nitroimidazole (NI) derivatives have been extensively studied for imaging hypoxia. To increase the hypoxic tissue uptake, we developed (68)Ga labeled agents based on mono-, bis-, and trisnitroimidazole conjugates with the chelating agent 1,4,7-triazacyclononane-1,4,7-tris[methyl(2 carboxyethyl)phosphinic acid] (TRAP). All the three agents showed high radiolabeling yields (>96%) and were found to be stable up to 4h in prepared medium at room temperature and in human serum at 37 degrees C. The trivalent agent showed a significant increase in hypoxic to normoxic uptake ratio (p <0.005) according to the in vitro cell uptake experiments. Immunohistochemical analysis confirmed the presence of hypoxia in xenografted CT26 tumor tissue. The trivalent derivative ((68)Ga-3: 0.17+/-0.04, (68)Ga-4: 0.33+/-0.04, (68)Ga-5: 0.45+/-0.09, and (68)Ga-6: 0.47+/-0.05% ID/g) showed the highest uptake by tumor cells according to the biodistribution studies in CT-26 xenografted mice. All the nitroimidazole derivatives showed significantly higher uptake by tumor cells than the control agent (p <0.05) at 1h post-injection. The trivalent derivative ((68)Ga-3: 0.10+/-0.06; (68)Ga-4: 0.20+/-0.06; (68)Ga-5: 0.33+/-0.08; (68)Ga-6: 0.59+/-0.09) also showed the highest standard uptake value for tumor cells at 1h post-injection in animal PET studies using CT-26 xenografted mice. In conclusion, we successfully synthesized multivalent (68)Ga-labeled NI derivatives for imaging hypoxia. Among them, the trivalent agent showed the highest tumor uptake in biodistribution and animal PET studies. PMID- 26643218 TI - Discovery of benzothiazoles as antimycobacterial agents: Synthesis, structure activity relationships and binding studies with Mycobacterium tuberculosis decaprenylphosphoryl-beta-D-ribose 2'-oxidase. AB - We report the discovery of benzothiazoles, a novel anti-mycobacterial series, identified from a whole cell based screening campaign. Benzothiazoles exert their bactericidal activity against Mycobacterium tuberculosis (Mtb) through potent inhibition of decaprenylphosphoryl-beta-d-ribose 2'-oxidase (DprE1), the key enzyme involved in arabinogalactan synthesis. Specific target linkage and mode of binding were established using co-crystallization and protein mass spectrometry studies. Most importantly, the current study provides insights on the utilization of systematic medicinal chemistry approaches to mitigate safety liabilities while improving potency during progression from an initial genotoxic hit, the benzothiazole N-oxides (BTOs) to the lead-like AMES negative, crowded benzothiazoles (cBTs). These findings offer opportunities for development of safe clinical candidates against tuberculosis. The design strategy adopted could find potential application in discovery of safe drugs in other therapy areas too. PMID- 26643219 TI - Synthesis, structure-activity relationship and biological evaluation of novel arylpiperzines as alpha1A/1D-AR subselective antagonists for BPH. AB - A series of novel arylpiperazine derivatives as alpha1A/1D-adrenergic receptors (AR) subtype selective antagonists were designed, synthesized and evaluated for their antagonistic activities towards alpha1-ARs (alpha1A, alpha1B, and alpha1D). Compounds 9, 12, 13, 15, 17, 18, 21, 22, 25 and 26 exerted strong antagonistic effects on alpha1A and/or alpha1D subtypes over alpha1B in vitro. SAR analysis indicated that chloride at the ortho-phenyl position for compound 17 was beneficial for the highest alpha1A/D-AR sub-selectivity. Moreover, molecular docking study of compound 17 with the homology-modeled alpha1-ARs (alpha1A, alpha1B, and alpha1D) structures exhibited differences of key amino resides in the docking pocket which may influence the subtype selectivity. ILE 193 of alpha1A was validated as the key residues for binding ligand. This work provides useful information for finding more new potential drugs in clinic in treating benign prostatic hyperplasia (BPH). PMID- 26643220 TI - 1,2,3-Triazolyl-4-oxoquinolines: A feasible beginning for promising chemical structures to inhibit oseltamivir-resistant influenza A and B viruses. AB - We described the synthesis of a new congener series of 1,2,3-triazolyl-4 oxoquinolines and evaluated their ability to inhibit oseltamivir (OST)-resistant influenza strains. Oxoquinoline derivative 1i was the most potent compound within this series, inhibiting 94% of wild-type (WT) influenza neuraminidase (NA) activity. Compound 1i inhibited influenza virus replication with an EC50 of 0.2MUM with less cytotoxicity than OST, and also inhibited different OST resistant NAs. These results suggest that 1,2,3-triazolyl-4-oxoquinolines represent promising lead molecules for further anti-influenza drug design. PMID- 26643221 TI - In Vitro Evaluation of Dentin Hydraulic Conductance After 980 nm Diode Laser Irradiation. AB - BACKGROUND: Dentin hypersensitivity treatments are based on the physical obliteration of the dentinal tubules to reduce hydraulic conductance. The aim of the present study is to evaluate the hydraulic conductance of bovine root dentin after irradiation with a 980-nm diode laser, with or without associated fluoride varnish. METHODS: Sixty bovine root dentin specimens were divided into six groups (n = 10 in each group): G1, G3, and G5 (0.5 W, 0.7 W, and 1 W diode laser, respectively); G2, G4, and G6 (fluoride varnish application + 0.5 W, 0.7 W, and 1 W diode laser, respectively). The dentin hydraulic conductance was evaluated at four time periods with a fluxmeter: 1) with smear layer, 2) after 37% phosphoric acid etching, 3) after the treatments, and 4) after 6% citric acid challenge. After the dentinal fluid flow measurements, specimens were also evaluated for mineral composition using energy dispersive X-ray spectroscopy (EDS). RESULTS: Analysis demonstrated a better result with increased irradiation power (P < 0.001), especially if the diode laser irradiation was associated with the application of fluoride varnish (P < 0.001), ensuring a greater reduction in permeability. Considering the groups treated only with laser irradiation, the 1 W group was superior when compared with the 0.5 W and 0.7 W irradiated groups immediately after treatment (P < 0.001). After citric acid testing, all groups showed similar results, except when comparing the 1 W groups with the 0.5 W groups (P = 0.04). EDS results of the irradiated groups showed an increase in the proportion of calcium and phosphorus ions, which demonstrates a superficial composition modification after laser treatments. CONCLUSION: Laser irradiation of exposed dentin promoted significant reduction in the dentin hydraulic conductance, mainly with higher energy densities and association with fluoride varnish. PMID- 26643222 TI - Prevalence, Etiology and Treatment of Peri-Implant Mucositis and Peri Implantitis: A Survey of Periodontists in the United States. AB - BACKGROUND: Currently, information available on the exact prevalence and standard therapeutic protocol of peri-implant diseases is insufficient. The aim of this survey was to investigate the perceived prevalence, etiology, and management of peri-implant mucositis and peri-implantitis by periodontists in the United States. METHODS: A twenty-question survey was developed. Periodontists currently practicing in the United States were contacted by an e-mail that contained a link to access the survey. RESULTS: Two hundred eighty periodontists (79.3% males; 62.9% with >10 years in practice, 75.7% in private practice) completed the survey. Most (96.1%) of the participants were placing implants (58.3% for >10 years and 32.4% >150 implants/year). The majority reported that the prevalence of peri-implant mucositis and peri-implantitis in their practices is up to 25% but is higher in the general US population and that up to 10% of implants must be removed due to peri-implantitis. There was agreement among contributing etiologic factors such as: 1) plaque; 2) smoking; 3) adverse loading; 4) oral hygiene; 5) use of antimicrobial gel/mouthrinse; 6) non-surgical debridement; 7) use of systemic antibiotics; and 8) 3-month supportive care for treatment of peri implantitis. Significant heterogeneity was recorded in relation to the instruments used for debridement, use and type of surgical treatment, and materials used for regeneration. Only 5.1% believed that treatment is very effective. CONCLUSIONS: This survey indicates that peri-implant diseases are a frequently encountered problem in periodontal practices and that the absence of a standard therapeutic protocol results in significant empirical use of therapeutic modalities and a moderately effective treatment outcome. PMID- 26643223 TI - Prediabetes Enhances Periodontal Inflammation Consistent With Activation of Toll Like Receptor-Mediated Nuclear Factor-kappaB Pathway in Rats. AB - BACKGROUND: Clinical studies have showed that prediabetes (preDM) is a predisposing factor for periodontitis. However, the pathogenic mechanism involved is unclear. Because it is known that the activation of Toll-like receptor (TLR) mediated nuclear factor-kappa B (NF-kappaB) signaling pathway plays a crucial role in periodontitis, it is hypothesized that preDM enhances periodontal inflammation by activation of the TLR-mediated NF-kappaB pathway. METHODS: In this study, a preDM rat model is established by feeding a high-fat diet (HFD). HFD-induced rats with preDM (n = 7) and normal chow-fed rats (n = 7) were studied. The animal model was characterized in terms of body weight and the glycemic and insulinemic profiles. The following parameters were assessed to evaluate possible early periodontal alterations and underlying mechanisms: 1) histology analysis of periodontal tissue; and 2) serum and mRNA levels and/or the tissue protein expression of TLRs, myeloid differentiation factor 88 (MyD88), tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6), NF-kappaB, cytokines, advanced glucose ends (AGEs), and free fatty acids (FFAs). RESULTS: Rats with preDM presented higher expression of TLR2 and TLR4 in periodontal tissue in the HFD group compared with the control group. The TLR2 and TLR4 was mostly expressed in gingiva, and TLR4 was expressed in periodontal ligament in rats. Furthermore, the MyD88 and TRAF6 protein levels were significantly increased in gingiva in rats with preDM compared with normal rats. The activity of NF-kappaB signals was higher in rats with preDM than in normal rats. Regarding cytokines expression, the TNF-alpha protein levels and interleukin-1beta mRNA levels were significantly increased in the HFD group compared with the control group. In the serum, AGEs levels were significantly increased in the rats with preDM. Mean FFAs concentrations were increased in rats with preDM compared with normal rats, but it did not reach statistical significance. CONCLUSION: In rats with preDM, TLR2 and TLR4 gene and protein levels were higher in periodontal tissue, and the activation of NF-kappaB may, through TLRs/MyD88, cause more cytokine secretion, which is associated with the onset or development of periodontal disease. PMID- 26643224 TI - Insight into species diversity of the Trichostrongylidae Leiper, 1912 (Nematoda: Strongylida) in ruminants. AB - This paper focuses on the species diversity among the Trichostrongylidae Leiper, 1912 (Nematoda: Strongylida), and complexity of the family systematics. Polymorphism (subfamilies: Ostertagiinae, Cooperiinae and Haemonchinae), the presence of cryptic species (genus: Teladorsagia) and hybridization (genera: Cooperia, Haemonchus and Ostertagia) are presented and discussed, considering both morphological and molecular evidence. Some of these phenomena are common, nevertheless not sufficiently understood, which indicates the need for expanding the current state of knowledge thereof. Within the Trichostrongylidae, species distinction supported merely by morphological features is difficult, and requires confirmation by means of molecular methods. The parasitic nematode taxonomy is complicated mainly by the genus Teladorsagia, but complexity may also be expected among other Ostertagiinae (e.g. in the genera Ostertagia and Marshallagia). The data presented here show that the members of the Trichostrongylidae can significantly complicate unambiguous species identification. Hence, it is essential to consider the phenomena mentioned, to gather valid and comparable data on the biodiversity of this family. PMID- 26643225 TI - Correlation Between Liver Volumetric Computed Tomography Results and Measured Liver Weight: A Tool for Preoperative Planning of Liver Transplant. AB - OBJECTIVES: Before liver transplant, it is necessary to know the size of the organ in advance of the procedure. We studied the correlation between liver volumetric computed tomography results and liver weight. MATERIALS AND METHODS: Postmortem volumetric computed tomography was conducted on cadavers before autopsy, and 3-dimensional liver volume was estimated with semiautomated software. Liver weight was then determined at autopsy. Linear regression and univariate analysis of variance results were used to determine the accuracy of volumetric 3-dimensional computed tomography in estimating liver weight. We also used 2-dimensional liver sizes to design a 2-dimensional formula to estimate liver volume. RESULTS: We found that 3-dimensional volumetric computed tomography was able to accurately estimate liver weight (standard error = 157 g) with a liver density of 0.99 g/mL. Intraobserver and interobserver variabilities were small. The 2-dimensional formula estimated liver weight slightly less accurately (standard error = 212 g). CONCLUSIONS: We conclude that liver weight can be estimated accurately with 3-dimensional volumetric computed tomography; estimates were more precise than with the 2-dimensional formula-based liver volume estimation. Volumetric computed tomography can be an important tool during preoperative workup before transplant surgery. PMID- 26643227 TI - Intergenerational report misses the point on health spending. PMID- 26643228 TI - Intergenerational Report 2015: A limited and political view of our future. PMID- 26643229 TI - Mental health and well-being in older people. PMID- 26643230 TI - Management of urinary catheters following hip fracture. AB - AIM: To examine current practices and factors associated with outcomes of urinary catheter removal ('trial of void' or TOV) in patients following hip fracture. METHOD: Retrospective file audit of patients discharged over a three-year period with a diagnosis of recent hip fracture. RESULTS: There were 133 TOVs in 310 patients. Of the 78 TOVs occurring in the aged care rehabilitation hospital, 50% were successful. Adherence to the hospital's TOV guideline was documented infrequently. TOV outcome was not related to interval since catheter insertion, constipation or inability to mobilise. Multivariate analysis showed that dementia was independently associated with the presence of an in-dwelling catheter (IDC) on discharge and that patients discharged with an IDC had a higher probability of residential care placement. CONCLUSIONS: Practices in managing TOVs are inconsistent. No potentially modifiable predictors of TOV success were identified. The presence of an IDC has implications for discharge destination. PMID- 26643231 TI - Innovation and Consumer Directed Care: Identifying the challenges. AB - Our aim was to report clinician and researcher observations about the practical difficulties with achieving the articulated objectives of Consumer Directed Care (CDC). The methods used were as follows: identification of key client community services issues through analysis of qualitative data related to a PhD project; review of the summary of these issues by the supervising academic; presentation of the issues to five clinicians involved with a community service clinical trial; verification of the findings through discussions with a senior community service provider. There is anecdotal evidence that the current overlay of CDC in the existing community-based home services sector for people who are older will continue to prevent its effective implementation. The existing culture and underlying philosophies related to this sector maybe unable to support the level of innovative change required. Research is needed into how the stated objectives of CDC can be achieved in Australia and how this can best be managed. PMID- 26643232 TI - On the advantages and dangers of specialisation. PMID- 26643233 TI - Sleep disturbance in people with dementia and its effect on caregivers. PMID- 26643235 TI - Using the International Classification of Functioning, Disability and Health framework to categorise goals and assess goal attainment for transition care clients. AB - AIM: To classify goals according to the International Classification of Functioning, Disability and Health (ICF) and to examine factors associated with goal attainment for transition care program (TCP) clients. METHODS: Recorded goals at admission were rated at discharge as achieved, partially achieved or not achieved. Two researchers independently linked each statement to the most closely corresponding ICF categories. RESULTS: Of 268 TCP clients, 215 had 851 goal statements recorded. Of these, 794 (93%) statements were linked to 12 different ICF categories. A total of 515 (61.4%) were attained at discharge, 117 (14%) were partially attained and 207 (24.6%) were not attained. Multivariate analysis identified number of goals, TCP length of stay and high or very high case manager perception of goal attainment to be significant predictors for goal attainment. CONCLUSIONS: The ICF framework can be used to identify and structure clients' goals in transitional care. Goal attainment can be used to determine overall functional improvement. PMID- 26643236 TI - Prehospital care for multiple trauma patients in Germany. AB - For the German speaking countries, Tscherne's definition of "polytrauma" which represents an injury of at least two body regions with one or a combination being life-threatening is still valid. The timely and adequate management including quick referral of the trauma patient into a designated trauma center may limit secondary injury and may thus improve outcomes already during the prehospital phase of care. The professional treatment of multiple injured trauma patients begins at the scene in the context of a well structured prehospital emergency medical system. The "Primary Survey" is performed by the emergency physician at the scene according to the Prehospital Trauma Life Support (PHTLS)-concept. The overall aim is to rapidly assess and treat life-threatening conditions even in the absence of patient history and diagnosis ("treat-first-what-kills-first"). If no immediate treatment is necessary, a "Secondary Sur- vey" follows with careful and structured body examination and detailed assessment of the trauma mechanism. Massive and life-threatening states of hemorrhage should be addressed immediately even disregarding the ABCDE-scheme. Critical trauma patients should be referred without any delay ("work and go")toTR-DGU(r) certified trauma centers of the local trauma networks. Due to the difficult pre- hospital environment the number of quality studies in the field is low and, as consequence, the level of evidence for most recommendations is also low. Much information has been obtained from different care systems and the interchangeability of results is limited. The present article provides a synopsis of rec- ommendations for early prehospital care for the severely injured based upon the 2011 updated multi- disciplinary S3 Guideline "Polytrauma/Schwerstverletzten Behandlung", the most recently updated European Trauma guideline and the current PHTLS-algorithms including grades of recommendation whenever possible. PMID- 26643237 TI - Current status and development of traumatic brain injury treatments in China. AB - Due to its high incidence, high disability rate, and high mortality rate, traumatic brain injury (TBI) poses a serious threat to human health. This manuscript describes the urgent problems currently existing in China's TBI treatment and proposes a scheme of a nationwide collaboration platform for the treatment of TBI so as to improve the overall level of TBI treatment in China, and reduce disability and mortality rates in TBI patients. PMID- 26643238 TI - Performance of a prehospital trauma diversion system in Hong Kong, China. AB - PURPOSE: To evaluate the performance of a prehospital trauma diversion system in Hong Kong, China. METHODS: A retrospective analysis of prospectively collected data in the trauma registry of Queen Mary Hospital, Hong Kong from 1 January 2009 to 31 December 2013 was done. All adult patients aged 18 years or above, either primarily or secondarily diverted to Queen Mary Hospital according to the trauma patient diversion protocol, were recruited. Need for trauma center level of care was based on a consensus-based criterion standard published in 2014. Performance of the protocol in terms of over- diversion and under-diversion was determined. RESULTS: A total of 209 patients were included for analysis. About 30% of the patients required trauma center level of care. The most common reason was the need for vascular, neurologic, abdominal, thoracic, pelvic, spine or limb conserving surgery within 24 h of presentation. The over-diversion rate and under diversion rate were 69.6% and 19.7% respectively. CONCLUSION: The trauma patient diversion protocol currently in use in Hong Kong is not accurate enough. Further revision and refinement is needed. PMID- 26643239 TI - Impact of subtropical climate on frequency of ambulance use for trauma patients in a coastal area of China. AB - PURPOSE: To explore the impact of subtropical maritime monsoon climate on the frequency of ambulance use for trauma patients in a coastal region in China. METHOD: Statistical analysis of data on ambulance use from the 120 Emergency Command Center in Shantou City, Guangdong Province, from January to December 2012 as well as daily meteorological data from a Shantou observatory was performed to determine how climatic factors (seasons, time, and weather) affect the frequency of ambulance use for trauma patients. RESULTS: The daily ambulance use for trauma patients differed between spring and summer or autumn (p<0.05), between sunny and rainy days (p<0.05), and between cloudy and lightly or moderately rainy days (p<0.05).We found a linear correlation between daily maximum temperature and daily ambulance use for trauma patients (R2 =0.103, p<0.05). In addition, there was significant difference in ambulance use between good and bad weather (p<0.05). CONCLUSION: Frequency of ambulance use for trauma patients is affected by the subtropical maritime monsoon climate in the coastal region. Better weather contributes to increased daily frequency of ambulance use, which is the highest in autumn and lowest in spring. PMID- 26643240 TI - Comparison of fondaparinux sodium and low molecular weight heparin in the treatment of hypercoagulability secondary to traumatic infection. AB - PURPOSE: To compare the effects and side-effects of fondaparinux sodium and low molecular weight heparin in patients with hypercoagulability accompanied with traumatic infection. METHODS: Thirty-six patients with post-traumatic infections in our hospital intensive care center were diagnosed with hypercoagulability from February 2012 to February 2013. These patients were randomly divided into 2 groups. In group F (18 patients), the patients were treated with fondaparinux sodium, 2.5 mg, 1/d for 11 d. In group L (18 patients), the patients were treated with low molecular weight heparin, 4100 U, 1/12 h for 11 d. The incidence of deep vein thrombosis, bleeding events and multiple organ dysfunction syndrome (MODS) and mortality of two groups after anticoagulation therapy were analyzed. Fibrinogen, D-dimer level and activity of antithrombin III were measured by the coagulation analyzer. RESULTS: The incidence of deep vein thrombosis, MODS incidence and mortality were not significantly different between the two groups. The rate of bleeding evens in group F was lower than group L (p < 0.05). Antithrombin III got an upward trend after anticoagulant therapy, in which it was higher in group F than in group L on the 5th d and 11th d (p<0.05). Fibrinogen levels were gradually increased, and there was no significant difference between two groups (p>0.05). D-dimer was significantly decreased after anticoagulant therapy for 5 d (p<0.01), and there were significant differences between two groups on the 5th d and 7th d (p<0.05). It showed no significant difference on the 11th d (p>0.05). CONCLUSION: Fondaparinux sodium and low molecular weight heparin can effectively improve coagulopathy in patients with traumatic infection. Compared with low molecular weight heparin, fondaparinux sodium may reduce the risk of bleeding events in patients with hypercoagulability accompanied by traumatic infection. PMID- 26643241 TI - Effect of the same mechanical loading on osteogenesis and osteoclastogenesis in vitro. AB - PURPOSE: To investigate the influence of the same mechanical loading on osteogenesis and osteoclastogenesis in vitro. METHODS: Primary osteoblasts, bone marrow-derived mesenchymal stem cells (BMSCs, cultured in osteoinductive medium) and RAW264.7 cells cultured in osteoclast inductive medium were all subjected to a 1000 MUstrain (MUs) at 1 Hz cyclic mechanical stretch for 30 min (twice a day). RESULTS: After mechanical stimulation, the alkaline phosphatase (ALP) activity, osteocalcin protein level of the osteoblasts and BMSCs were all enhanced, and the mRNA levels of ALP and collagen type I increased. Additionally, extracellular deposited calcium of both osteoblasts and BMSCs increased. At the same time, the activity of secreted tartrate-resistant acid phosphatase, the number of tartrate resistant acid phosphatase-positive multinucleated cells, matrix metalloproteinase-9 protein levels of RAW264.7 cells and the extracellular calcium solvency all decreased. CONCLUSION: The results demonstrated that 1000 MUs cyclic mechanical loading enhanced osteoblasts activity, promoted osteoblastic differentiation of BMSCs and restrained osteoclastogenesis of RAW264.7 cells in vitro. PMID- 26643242 TI - A contrast study of the traumatic condition between the wounded in 5.12 Wenchuan earthquake and 4.25 Nepal earthquake. AB - PURPOSE: 5.12 Wenchuan earthquake and 4.25 Nepal earthquake are of the similar magnitude, but the climate and geographic environment are totally different. Our team carried out medical rescue in both disasters, so we would like to compare the different traumatic conditions of the wounded in two earthquakes. METHODS: The clinical data of the wounded respectively in 5.12 Wenchuan earthquake and 4.25 Nepal earthquake rescued by Chengdu Military General Hospital were retrospectively analyzed. Then a contrast study between the wounded was conducted in terms of age, sex, injury mechanisms, traumatic conditions, complications and prognosis. RESULTS: Three days after 5.12 Wenchuan earthquake, 465 cases of the wounded were hospitalized in Chengdu Military General Hospital, including 245 males (52.7%) and 220 females (47.3%) with the average age of (47.6+/-22.7) years. Our team carried out humanitarian relief in Katmandu after 4.25 Nepal earthquake. Three days after this disaster, 71 cases were treated in our field hospital, including 37 males (52.1%) and 34 females (47.9%) with the mean age of (44.8+/-22.9) years. There was no obvious difference in sex and mean age between two groups, but the age distribution was a little different: there were more wounded people at the age over 60 years in 4.25 Nepal earthquake (p<0.01) while more wounded people at the age between 21 and 60 years in 5.12 Wenchuan earthquake (p<0.05). The main cause of injury in both disasters was bruise by heavy drops but 5.12 Wenchuan earthquake had a higher rate of bruise injury and crush injury (p<0.05) while 4.25 Nepal earthquake had a higher rate of falling injury (p<0.01). Limb fracture was the most common injury type in both disasters. However, compared with 5.12 Wenchuan earthquake, 4.25 Nepal earthquake has a much higher incidence of limb fractures (p<0.01), lung infection (p<0.01) and malnutrition (p<0.05), but a lower incidence of thoracic injury (p<0.05) and multiple injury (p<0.05). The other complications and death rate showed no significant differences. CONCLUSION: Major earthquakes of the similar magnitude can cause different injury mechanisms, traumatic conditions and complications in the wounded under different climate and geographic environment.When an earthquake occurs in a poor traffic area of high altitude and large temperature difference, early medical rescue, injury control and wounded evacuation as well as sufficient warmth retention and food supply are of vital significance. PMID- 26643243 TI - Pattern of bony injuries among civilian gunshot victims at tertiary care hospital in Karachi, Pakistan. AB - PURPOSE: Firearm injuries impose a continuous economic burden on society and hospital resources. The aim of this study was to assess the pattern of bony injuries among victims of gunshots. METHODS: A retrospective study was conducted in the Department of Orthopedics, Dow University of Health Sciences and Civil Hospital Karachi from January 2011 to December 2012. Patients with isolated bony injuries were included while patients with other systemic injuries were excluded. RESULTS: There were 90 cases and the majority of them were male (84.4%). Mean age was (32.52 +/- 10.27) years. Most of the patients (72.2%) belong to the younger age group. A low velocity weapon was used in 61 (67.8%) cases and a high velocity weapon was used in 29 (32.2%) cases. Armed robbery (64.4%) was the cause of conflict in more than half of the cases. Lower limb was involved in 72.2%. Fifty eight (64.4%) patients remained hospitalized for 15-20 days and others for more than 20 days. Internal fixation with intramedullary nailing was done in 35 patients while K-wire was used in 5 patients. Fifty patients were managed with external fixation, either uniplanar or multiplanar ilizarov. Deep wound infection and nonunion were observed more often in high velocity injuries. CONCLUSION: Armed robbery was the leading cause of gunshot bony injuries in our hospital. Young males were victimized in a majority of cases. High velocity injuries were associated with more complications. PMID- 26643244 TI - Heel pain: A systematic review. AB - Heel pain is a very common foot disease. Varieties of names such as plantar fasciitis, jogger's heel, tennis heal, policeman's heel are used to describe it. Mechanical factors are the most common etiology of heel pain. Common causes of hell pain includes: Plantar Fasciitis, Heel Spur, Sever's Disease, Heel bump, Achilles Tendinopathy, Heel neuritis, Heel bursitis. The diagnosis is mostly based on clinical examination. Normally, the location of the pain and the absence of associated symptoms indicating a systemic disease strongly suggest the diagnosis. Several therapies exist including rest, physical therapy, stretching, and change in footwear, arch supports, orthotics, night splints, anti inflammatory agents, and surgery. Almost all patients respond to conservative nonsurgical therapy. Surgery is the last treatment option if all other treatments had failed. Rest, ice, massage, the use of correct exercise and complying with a doctor's advice all play important part in helping to recover from this hell pain condition, but getting good quality, suitable shoes with the appropriate amount of support for the whole foot is the most important. PMID- 26643245 TI - Cosmetic arm lengthening with monorail fixator. AB - Upper limb length discrepancy is a rare occurrence. Humerus shortening may need specialized treatment to restore the functional and cosmetic status of upper limb. We report a case of humerus lengthening of 9 cm with a monorail external fixator and the result was observed during a 2-year follow-up. Humerus lengthening needs specialized focus as it is not only a cosmetic issue but also a functional demand. The monorail unilateral fixator is more functional and cosmetically acceptable, and thus becomes an effective treatment option. PMID- 26643246 TI - Functional thenar eminence myocutaneous flap for reconstruction of thumb volar defect. AB - This case report describes the use of a Functional Thenar Eminence myocutaneous flap for reconstruction of volar defect of distal right thumb of a 25-year-old male who sustained a twisting injury while working. Part of bone and tendon were exposed and the tip of the distal phalanx was crushed, with bony defect. PMID- 26643247 TI - Hoffa's fracture with ipsilateral fibular fracture in a 16-year-old girl: An approach to a rare injury. AB - Hoffa's fracture is an uncommon fracture of the femoral condyle with coronal orientation of the fracture line. The mechanism of injury in pediatric Hoffa's fracture is road traffic accident, sports injury, and trivial injury. Clinical examination and proper imaging is important for diagnosis of pediatric Hoffa's fracture because of high chances of missing these injuries which can lead to nonunion and malunion at the fracture site. Open reduction and anatomical reduction of intraarticular fragment is the gold standard treatment of these fractures. We present a rare case of Hoffa's fracture in a 16-year-old girl with asso ciated ipsilateral fibular fracture. PMID- 26643248 TI - Inferior glenohumeral joint dislocation with greater tuberosity avulsion. AB - Inferior glenohumeral dislocation is the least common type of glenohumeral dislocations. It may be associated with fractures of the adjacent bones and neurovascular compromise. It should be treated immediately by close reduction. The associated neuropraxia usually recovers with time. Traction-counter traction method is commonly used for reduction followed by immobilization of the shoulder for three weeks. Here, we report a case of inferior glenohumeral joint dislocation with greater tuberosity fracture with transient neurovascular compromise and present a brief review of the literature. PMID- 26643249 TI - Posttraumatic tuberculous osteomyelitis of the foot--A rare case report. AB - Skeletal tuberculosis developing after trauma is a rare occurrence.We report a rare case of posttraumatic tubercular osteomyelitis of mid-tarsal bone of the right foot. Patient was treated with regular dressing and anti-tubercular drugs. Posttraumatic skeletal tuberculosis should be considered in patient with non healing ulcer. PMID- 26643250 TI - Comparison of waist to height ratio and body indices for prediction of metabolic disturbances in the Korean population: the Korean National Health and Nutrition Examination Survey 2008-2011. AB - BACKGROUND: The aim of the present study of the general population was to identify the best predictor of metabolic risk among the body index variables evaluated with dual-energy X-ray absorptiometry (DEXA) or anthropometric indices including the waist to height ratio (WHtR). PATIENTS AND METHODS: Data from the Korean National Health and Nutrition Examination Survey 2008-2011 were used for the analyses. As a result, 15,965 participants were included in this study. The body mass (BM) index was calculated as the body weight divided by the height squared. The WHtR was calculated as the waist circumference divided by height. Body composition indices such as lean mass (LM), fat mass (FM), trunk fat mass (TFM), and bone mineral content (BMC) were determined by using DEXA. Skeletal muscle mass (SM) was defined as the sum of the lean soft masses of both extremities. The LM, FM, BMC, TFM, and SM indices were calculated by dividing the total LM, total FM, total BMC, TFM, or SM by the height squared. RESULTS: The WHtR had the highest area under the curve (AUC) and was the best predictor of metabolic syndrome for both sexes. In addition, the WHtR had the highest AUCs for components of metabolic syndrome (male: AUC 0.823, 95 % confidence interval [CI] 0.814-0.832; female: AUC 0.870, 95 % CI 0.863-0.877). There was a small statistically significant difference in AUC between WHtR and the other indices. Multivariate logistic regression showed that male participants in the second, third, and fourth quartiles had a 4.0 (95 % CI, 3.1-5.2), 9.6 (95 % CI, 7.5 12.3), and 36.1 (95 % CI, 28.0-46.4) times increased risk of metabolic syndrome compared with patients in the first quartile and female participants in the second, third, and fourth quartiles had a 4.3 (95 % CI, 3.1-6.0), 18.0 (95 % CI, 13.3-24.5), and 58.5 (95 % CI, 42.9-79.9) times increased risk of metabolic syndrome compared with patients in the first quartile. CONCLUSION: Among the BM, FM, LM, SM, TFM, and WHtR indices, WHtR is most useful to predict the presence of metabolic syndrome and insulin resistance in the Korean population. PMID- 26643251 TI - Nanoscale Electric Permittivity of Single Bacterial Cells at Gigahertz Frequencies by Scanning Microwave Microscopy. AB - We quantified the electric permittivity of single bacterial cells at microwave frequencies and nanoscale spatial resolution by means of near-field scanning microwave microscopy. To this end, calibrated complex admittance images have been obtained at ~19 GHz and analyzed with a methodology that removes the nonlocal topographic cross-talk contributions and thus provides quantifiable intrinsic dielectric images of the bacterial cells. Results for single Escherichia coli cells provide a relative electric permittivity of ~4 in dry conditions and ~20 in humid conditions, with no significant loss contributions. Present findings, together with the ability of microwaves to penetrate the cell membrane, open an important avenue in the microwave label-free imaging of single cells with nanoscale spatial resolution. PMID- 26643253 TI - Emerging roles of A-kinase anchoring proteins in cardiovascular pathophysiology. AB - Heart and blood vessels ensure adequate perfusion of peripheral organs with blood and nutrients. Alteration of the homeostatic functions of the cardiovascular system can cause hypertension, atherosclerosis, and coronary artery disease leading to heart injury and failure. A-kinase anchoring proteins (AKAPs) constitute a family of scaffolding proteins that are crucially involved in modulating the function of the cardiovascular system both under physiological and pathological conditions. AKAPs assemble multifunctional signaling complexes that ensure correct targeting of the cAMP-dependent protein kinase (PKA) as well as other signaling enzymes to precise subcellular compartments. This allows local regulation of specific effector proteins that control the function of vascular and cardiac cells. This review will focus on recent advances illustrating the role of AKAPs in cardiovascular pathophysiology. The accent will be mainly placed on the molecular events linked to the control of vascular integrity and blood pressure as well as on the cardiac remodeling process associated with heart failure. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Integration of Developmental and Environmental Cues in the Heart edited by Marcus Schaub and Hughes Abriel. PMID- 26643254 TI - The store-operated Ca(2+) entry-mediated signaling is important for cancer spread. AB - Tumor cell migration and invasion are essential steps in the metastatic cascade that has great impact on patient outcomes. Spatial and temporal organization of Ca(2+) signaling regulates the multiple aspects of migration machinery, including cytoskeletal reorganization, traction force generation, and focal adhesion dynamics. Stromal interaction molecules (STIM) and Orai proteins, recently identified as critical constituents of store-operated Ca(2+) entry (SOCE), have been implicated in cancer cell migration and tumor metastasis. The clinical significance of STIM proteins and Orai Ca(2+) channels in tumor progression and their diagnostic and prognostic potentials have also been demonstrated in different types of cancers. Here we review the recent advances in understanding the important roles and regulatory mechanisms of STIM/Orai-mediated SOCE in cancer spread. The clinical implications and the emergence as a selective target for cancer therapeutics are also discussed. This article is part of a Special Issue entitled: Calcium and Cell Fate. Guest Editors: Jacques Haiech, Claus Heizmann, Joachim Krebs, Thierry Capiod and Olivier Mignen. PMID- 26643252 TI - A functional connectome: regulation of Wnt/TCF-dependent transcription by pairs of pathway activators. AB - BACKGROUND: Wnt/beta-catenin signaling is often portrayed as a simple pathway that is initiated by Wnt ligand at the cell surface leading, via linear series of interactions between 'core pathway' members, to the induction of nuclear transcription from genes flanked by beta-catenin/TCF transcription factor binding sites. Wnt/beta-catenin signaling is also regulated by a much larger set of 'non core regulators'. However the relationship between 'non-core regulators' is currently not well understood. Aberrant activation of the pathway has been shown to drive tumorgenesis in a number of different tissues. METHODS: Mammalian cells engineered to have a partially-active level of Wnt/beta-catenin signaling were screened by transfection for proteins that up or down-regulated a mid-level of TCF-dependent transcription induced by transient expression of an activated LRP6 Wnt co-receptor (?NLRP). RESULTS: 141 novel regulators of TCF-dependent transcription were identified. Surprisingly, when tested without ?NLRP activation, most up-regulators failed to alter TCF-dependent transcription. However, when expressed in pairs, 27 % (466/1170) functionally interacted to alter levels of TCF-dependent transcription. When proteins were displayed as nodes connected by their ability to co-operate in the regulation of TCF-dependent transcription, a network of functional interactions was revealed. In this network, 'core pathway' components (Eg. beta-catenin, GSK-3, Dsh) were found to be the most highly connected nodes. Activation of different nodes in this network impacted on the sensitivity to Wnt pathway small molecule antagonists. CONCLUSIONS: The 'functional connectome' identified here strongly supports an alternative model of the Wnt pathway as a complex context-dependent network. The network further suggests that mutational activation of highly connected Wnt signaling nodes predisposed cells to further context-dependent alterations in levels of TCF-dependent transcription that may be important during tumor progression and treatment. PMID- 26643255 TI - Weight increase in first year of life linked to type 1 diabetes. PMID- 26643256 TI - Forkhead Box Transcription Factor (FOXO3a) mediates the cytotoxic effect of vernodalin in vitro and inhibits the breast tumor growth in vivo. AB - BACKGROUND: Natural compounds have been demonstrated to lower breast cancer risk and sensitize tumor cells to anticancer therapies. Recently, we demonstrated that vernodalin (the active constituent of the medicinal herb Centratherum anthelminticum seeds) induces apoptosis in breast cancer cell-lines. The aim of this work was to gain an insight into the underlying anticancer mechanism of vernodalin using in vitro and in vivo model. METHODS: Vernodalin was isolated through the bioassay guided fractionation from the seeds. The protein expression of p-Akt, PI3K, FOXO3a, Bim, p27kip1, cyclinD1, and cyclinE was examined by the Western blot analysis. Immunoprecipitation assays were performed to analyse Akt kinase activity. Small interfering RNA (siRNA) was used to study the role of FOXO3a upregulation and their targets during vernodalin treatment. Immunofluorescence, subcellular localisation of FOXO3a by Western blot was performed to analyse FOXO3a localisation in nucleus of breast cancer cells. Immunohistochemical analysis of PCNA, Ki67, p27kip1, FOXO3a and p-FOXO3a in the LA7-induced mammary gland tumor model was performed. RESULTS: Our results showed that vernodalin regulates cancer cell apoptosis through activation of FOXO transcription factors and its downstream targets (Bim, p27Kip1, p21Waf1/cip1, cyclin D1, cyclin E) as examined by Western blots. Furthermore, we showed that FOXO3a/PI3K-Akt played a significant role in vernodalin induced apoptosis in breast cancer cells. Immunoprecipitation assays showed Akt kinase activity was downregulated. Immunofluorescence, subcellular fractionation and Western blot showed FOXO3a accumulation in the nucleus of breast cancer cells after vernodalin treatment. Silencing of FOXO3a protected breast cancer cells against vernodalin induced apoptosis. The anti-tumor action of vernodalin was further confirmed by examining cell proliferative markers, PCNA and Ki67 in the LA7-induced mammary gland tumor model. We also corroborated our findings in vivo by showing upregulation of p27Kip1, FOXO3a and decrease in the p-FOXO3a level in vernodalin treated breast tumor tissue. CONCLUSIONS: Our results suggest that PI3K-Akt/FOXOa pathway is a critical mediator of vernodalin-induced cytotoxicity and this compound could be further developed as a potential chemopreventive or chemotherapeutic agent for breast cancer therapy. PMID- 26643257 TI - Progression of liver stiffness predicts clinical events in HIV/HCV-coinfected patients with compensated cirrhosis. AB - BACKGROUND: Our objective was to assess the predictive value of the changes of liver stiffness (LS) for clinical outcome in HIV/HCV-coinfected patients with compensated liver cirrhosis and a LS value < 40 kPa. METHODS: Prospective cohort of 275 HIV/HCV-coinfected patients with cirrhosis, no previous liver decompensation (LD) and LS < 40 kPa. The time from diagnosis to LD and/or hepatocellular carcinoma (HCC) and the predictors of this outcome were evaluated. Significant progression of LS was defined as an increase >= 30 % over the baseline value at any time during the follow-up. RESULTS: After a median (Q1-Q3) follow-up of 32 (20-48) months, 19 (6.9 %, 95 % CI: 3.8 %-9.9 %) patients developed a first LD and/or HCC. At the end of the follow-up, 247 (90 %) patients had undergone a further LS examination. Of them, 77 (31 %) patients had a significant progression of LS. The mean (SD) survival time free of LD and/or HCC was 67 (3) and 77 (1) months in patients with or without significant progression of LS (p = 0.01). Significant progression of LS was an independent predictor of LD and/or HCC (Adjusted Hazard Ratio 4.63; 95 % confidence interval: 1.34-16.02; p = 0.015). CONCLUSIONS: Significant progression of LS is associated with a higher risk of clinical events in HIV/HCV-coinfected patients with compensated cirrhosis and LS < 40 kPa. PMID- 26643258 TI - Detachment-Based Equilibrium of Anoikic Cell Death and Autophagic Cell Survival Through Adaptor Protein p66(Shc). AB - Anoikis (detachment-induced cell death) confers a tumor-suppressive function in metastatic cancer cells. Autophagy, a conserved self-degradative process, enhances the anoikis resistance of detached cancer cells by maintaining cellular homeostasis. However, the mechanism of regulating cell fate-decision by balancing anoikis and autophagy has been poorly understood. Our previous studies have shown that the adaptor protein p66(Shc) mediates anoikis through RhoA activation and inhibits tumor metastasis in vivo. We also found that p66(Shc) depletion mitigates nutrient-deprivation-induced autophagy. These findings suggest p66(Shc) may coordinately regulate these two processes. To verify this hypothesis, we investigated the effect of p66(Shc) on the cell death of detached lung cancer cells, and measured autophagy markers and autophagic flux. Results showed that p66(Shc) depletion significantly inhibited anoikis, and reduced the formation of LC3B-II and the degradation of Sequestosome 1 (SQSTM1, p62) in detachment-induced cells. Using monodansylcadaverine (MDC)-LysoTracker double staining and monomeric Cherry (mCherry)-GFP-LC3 assay, we found that the autophagic flux was also mitigated by p66(Shc) depletion. In addition, p66(Shc) knockdown increased the formation of full-length X-linked inhibitor of apoptosis (XIAP)-associated factor 1 (XAF1), which enhances anoikis sensitivity. In conclusion, p66(Shc) plays an essential role in detachment-based equilibrium of anoikic cell death and autophagic cell survival. PMID- 26643260 TI - Safety of ustekinumab for the treatment of psoriasis vulgaris with myotonic dystrophy. PMID- 26643259 TI - Multiple vitellogenins and product yolk proteins in European sea bass (Dicentrarchus labrax): Molecular characterization, quantification in plasma, liver and ovary, and maturational proteolysis. AB - Three complete vitellogenin (Vtg) polypeptides of European sea bass (Dicentrarchus labrax), an acanthomorph teleost spawning pelagic eggs in seawater, were deduced from cDNA and identified as VtgAa, VtgAb and VtgC based on current Vtg nomenclature and phylogeny. Label free quantitative mass spectrometry verified the presence of the three sea bass Vtgs or their product yolk proteins (YPs) in liver, plasma and ovary of postvitellogenic females. As evidenced by normalized spectral counts, VtgAb-derived protein was 2- to 5-fold more abundant, depending on sample type, than for VtgAa, while VtgC-derived protein was less abundant, albeit only 3-fold lower than for VtgAb in the ovary. Western blotting with Vtg type-specific antisera raised against corresponding gray mullet (Mugil cephalus) lipovitellins (Lvs) detected all three types of sea bass Vtg in the blood plasma of gravid females and/or estrogenized males and showed that all three forms of sea bass Lv undergo limited partial degradation during oocyte maturation. The comparatively high levels of VtgC-derived YPs in fully-grown oocytes and the maturational proteolysis of all three types of Lv differ from what has been reported for other teleosts spawning pelagic eggs in seawater but are similar to recent findings for two species of North American Moronidae, the striped bass (Morone saxatilis) and white perch (Morone americana), which spawn pelagic and demersal eggs, respectively in fresh water. Together with the high Vtg sequence homologies and virtually identical structural features of each type of Vtg between species, these findings indicate that the moronid multiple Vtg systems do not substantially vary with reproductive environment. PMID- 26643261 TI - Discovery of Transcriptional Targets Regulated by Nuclear Receptors Using a Probabilistic Graphical Model. AB - Nuclear receptors (NRs) are ligand-activated transcriptional regulators that play vital roles in key biological processes such as growth, differentiation, metabolism, reproduction, and morphogenesis. Disruption of NRs can result in adverse health effects such as NR-mediated endocrine disruption. A comprehensive understanding of core transcriptional targets regulated by NRs helps to elucidate their key biological processes in both toxicological and therapeutic aspects. In this study, we applied a probabilistic graphical model to identify the transcriptional targets of NRs and the biological processes they govern. The Tox21 program profiled a collection of approximate 10 000 environmental chemicals and drugs against a panel of human NRs in a quantitative high-throughput screening format for their NR disruption potential. The Japanese Toxicogenomics Project, one of the most comprehensive efforts in the field of toxicogenomics, generated large-scale gene expression profiles on the effect of 131 compounds (in its first phase of study) at various doses, and different durations, and their combinations. We applied author-topic model to these 2 toxicological datasets, which consists of 11 NRs run in either agonist and/or antagonist mode (18 assays total) and 203 in vitro human gene expression profiles connected by 52 shared drugs. As a result, a set of clusters (topics), which consists of a set of NRs and their associated target genes were determined. Various transcriptional targets of the NRs were identified by assays run in either agonist or antagonist mode. Our results were validated by functional analysis and compared with TRANSFAC data. In summary, our approach resulted in effective identification of associated/affected NRs and their target genes, providing biologically meaningful hypothesis embedded in their relationships. PMID- 26643262 TI - Chronic hepatitis B virus in the Philippines. AB - Multiple studies have shown a high prevalence of chronic hepatitis B (CHB) infection in the Philippines, not only in high-risk populations but also in the general population. The most recent national study estimated HBsAg seroprevalence to be 16.7%, corresponding to an estimated 7.3 million CHB adults. The factors underlying the high prevalence of CHB and its sequelae include the inadequate use of vaccination for prevention and the lack of treatment for many Filipinos. Because without medical monitoring and treatment of CHB the risk of progression to liver failure and death is 25-30%, the ultimate medical and societal costs will be very high if the Philippines fails to properly address hepatitis B infection. It will be very important to move forward with programs that can help to ensure universal vaccination of newborns, screening and vaccination nationwide, and monitoring and treatment for CHB persons. It will also be crucial to address transmission of HBV in the health-care setting (via contaminated needles and syringes and inadequately sterilized hospital equipment) and via injection drug use and tattooing. Because of the relatively low average per capita income and the lack of coverage by PhilHealth of outpatient visits and medications, there is an urgent need to move forward with a nationally supported program that includes education for both the general public and health-care workers on liver disease and screening for hepatitis viruses, followed by, as appropriate, vaccination or treatment, with expanded government coverage for these for all those who could not otherwise afford it. PMID- 26643263 TI - Between Legal Recognition and Moral Policing: Mapping the Queer Subject in India. AB - With the decriminalization of homosexuality in India in 2009, Indian queer subjects have become visible in various ways. Where Indian queer identities have asserted their public presence through Pride marches and protests, incidents of moral policing and surveillance, especially after decriminalization, have highlighted the broader social and religious attitudes that continue to pathologize homosexuality with grave outcomes. This article argues that debates around access to health care of Indian queer subjects must be framed against the social and religious pathologization of homosexuality in various contexts, which remains a primary bioethical dilemma, particularly in relation to legal change. PMID- 26643264 TI - A self-directed home yoga programme for women with breast cancer during chemotherapy: A feasibility study. AB - Recent studies suggest yoga as a promising approach for improving the cognitive function of cancer survivors. We studied whether a self-directed home yoga programme was feasible for patients with breast cancer who were undergoing chemotherapy. Participants' preferences for the type of yoga course and the clinical effects of the programme were also assessed. In this study, 18 women (mean age, 43.9 years) were enrolled (44.7% recruitment rate). Of the participants, 63.6% had stage II cancer and 71.4% received adjuvant chemotherapy. Favourable retention (86%), adherence (94.4%) and acceptability (96.5%) rates were determined. Most (94.4%) of the women practiced the home programme more than twice a week on average. The participants preferred to gradually increase the intensity of the exercises. We only observed improvements in the cognitive aspects of fatigue. No serious adverse events were encountered during the programme. This self-directed home yoga programme was safe and feasible for patients with breast cancer undergoing chemotherapy. PMID- 26643265 TI - Electrophoretic separation techniques and their hyphenation to mass spectrometry in biological inorganic chemistry. AB - Electrophoretic methods have been widely applied in research on the roles of metal complexes in biological systems. In particular, CE, often hyphenated to a sensitive MS detector, has provided valuable information on the modes of action of metal-based pharmaceuticals, and more recently new methods have been added to the electrophoretic toolbox. The range of applications continues to expand as a result of enhanced CE-to-MS interfacing, with sensitivity often at picomolar level, and evolved separation modes allowing for innovative sample analysis. This article is a followup to previous reviews about CE methods in metallodrug research (Electrophoresis, 2003, 24, 2023-2037; Electrophoresis, 2007, 28, 3436 3446; Electrophoresis, 2012, 33, 622-634), also providing a comprehensive overview of metal species studied by electrophoretic methods hyphenated to MS. It highlights the latest CE developments, takes a sneak peek into gel electrophoresis, traces biomolecule labeling, and focuses on the importance of early-stage drug development. PMID- 26643266 TI - Negative statin-related news stories decrease statin persistence and increase myocardial infarction and cardiovascular mortality: a nationwide prospective cohort study. AB - AIM: We tested the hypothesis that statin-related news stories, cardiovascular disease, diabetes, statin dose, calendar year, and socio-demographic status are associated with early statin discontinuation. We also examined frequency and consequences of early statin discontinuation. METHODS AND RESULTS: From the entire Danish population, we studied 674 900 individuals aged 40 or older who were initiated on statin therapy in 1995-2010, and followed them until 31 December 2011. Individuals on statins increased from <1% in 1995 to 11% in 2010, while early statin discontinuation increased from 6% in 1995 to 18% in 2010. The odds ratios for early statin discontinuation vs. continued use were 1.09 (95% confidence interval, 1.06-1.12) for negative statin-related news stories, 1.04 (1.02-1.07) per increasing calendar year, 1.04 (1.02-1.06) per increasing defined daily dose of statin, 1.05 (1.03-1.06) for male sex, 1.13 (1.11-1.15) for living in cities, 1.67 (1.63-1.71) for other ethnicity than Danish, 0.92 (0.90-0.94) for positive statin-related news stories, 0.73 (0.72-0.74) for baseline cardiovascular disease, and 0.91 (0.90-0.93) for baseline diabetes. During follow up, the hazard ratios for individuals with vs. without early statin discontinuation were 1.26 (1.21-1.30) for myocardial infarction and 1.18 (1.14 1.23) for death from cardiovascular disease. CONCLUSION: Early statin discontinuation increased with negative statin-related news stories, calendar year, statin dose, male sex, living in cities, and with other ethnicity than Danish, while the opposite was true for positive statin-related news stories and for baseline cardiovascular disease and diabetes. Early statin discontinuation was also associated with increased risk of myocardial infarction and death from cardiovascular disease. PMID- 26643267 TI - Differential expression of two C-type lectins in grass carp Ctenopharyngodon idella and their response to grass carp reovirus. AB - The cDNAs of two C-type lectins in grass carp Ctenopharyngodon idella, galactose binding lectin (galbl) and mannose-binding lectin (mbl), were cloned and analysed in this study. Both of them exhibited the highest expression level in liver, whereas their expression pattern differed in early phase of embryonic development. Following exposure to grass carp reovirus (GCRV), the mRNA expression level of galbl and mbl was significantly up-regulated in liver and intestine. PMID- 26643269 TI - Reply to Cronin et al., Iatrogenic Atrial Septal Defect after Radiofrequency or Cryoablation of Atrial Fibrillation. PMID- 26643268 TI - The PPR-SMR protein PPR53 enhances the stability and translation of specific chloroplast RNAs in maize. AB - Pentatricopeptide repeat (PPR) proteins are helical repeat proteins that bind RNA and influence gene expression in mitochondria and chloroplasts. Several PPR proteins in plants harbor a carboxy-terminal small-MutS-related (SMR) domain, but the functions of the SMR appendage are unknown. To address this issue, we studied a maize PPR-SMR protein denoted PPR53 (GRMZM2G438524), which is orthologous to the Arabidopsis protein SOT1 (AT5G46580). Null ppr53 alleles condition a chlorotic, seedling-lethal phenotype and a reduction in plastid ribosome content. Plastome-wide transcriptome and translatome analyses revealed strong defects in the expression of the ndhA and rrn23 genes, which were superimposed on secondary effects resulting from a decrease in plastid ribosome content. Transcripts with processed 5'-ends mapping approximately 70 nucleotides upstream of rrn23 and ndhA are absent in ppr53 mutants, and the translational efficiency of the residual ndhA mRNAs is reduced. Recombinant PPR53 binds with high affinity and specificity to the 5' proximal region of the PPR53-dependent 23S rRNA, suggesting that PPR53 protects this RNA via a barrier mechanism similar to that described for several PPR proteins lacking SMR motifs. However, recombinant PPR53 did not bind with high affinity to the ndhA 5' untranslated region, suggesting that PPR53's RNA stabilization and translation-enhancing effects at the ndhA locus involve the participation of other factors. PMID- 26643270 TI - Seven gene deletions in seven days: Fast generation of Escherichia coli strains tolerant to acetate and osmotic stress. AB - Generation of multiple genomic alterations is currently a time consuming process. Here, a method was established that enables highly efficient and simultaneous deletion of multiple genes in Escherichia coli. A temperature sensitive plasmid containing arabinose inducible lambda Red recombineering genes and a rhamnose inducible flippase recombinase was constructed to facilitate fast marker-free deletions. To further speed up the procedure, we integrated the arabinose inducible lambda Red recombineering genes and the rhamnose inducible FLP into the genome of E. coli K-12 MG1655. This system enables growth at 37 degrees C, thereby facilitating removal of integrated antibiotic cassettes and deletion of additional genes in the same day. Phosphorothioated primers were demonstrated to enable simultaneous deletions during one round of electroporation. Utilizing these methods, we constructed strains in which four to seven genes were deleted in E. coli W and E. coli K-12. The growth rate of an E. coli K-12 quintuple deletion strain was significantly improved in the presence of high concentrations of acetate and NaCl. In conclusion, we have generated a method that enables efficient and simultaneous deletion of multiple genes in several E. coli variants. The method enables deletion of up to seven genes in as little as seven days. PMID- 26643271 TI - A qualitative analysis of emerging adult black men's sexual decision-making behavior and substance use. AB - Emerging adult Black men and substance users may have an increased risk for compromised sexual health. This study qualitatively investigated how substance use affects the sexual decision-making of emerging adult Black men. Nineteen Black men in college (18-24 years) completed a semi-structured interview about their sexual attitudes, behaviors, and perceptions and their substance use. Results show that substance use may not independently affect sexual risk behavior among emerging adult Black men. Findings highlight the importance of using approaches that incorporate structural and sociocultural factors when framing research and interventions related to substance use, sexual decision making, and Black men. PMID- 26643272 TI - The role of protective factors in the prevention of negative body image and disordered eating. PMID- 26643273 TI - Gx-50 reduces beta-amyloid-induced TNF-alpha, IL-1beta, NO, and PGE2 expression and inhibits NF-kappaB signaling in a mouse model of Alzheimer's disease. AB - Chronic inflammation, which is regulated by overactivated microglia in the brain, accelerates the occurrence and development of Alzheimer's disease (AD). Gx-50 has been investigated as a novel drug for the treatment of AD in our previous studies. Here, we investigated whether gx-50 possesses anti-inflammatory effects in primary rat microglia and a mouse model of AD, amyloid precursor protein (APP) Tg mice. The expression of TNF-alpha, IL-1beta, NO, prostaglandin E2, and the expression of iNOS and COX2 were inhibited by gx-50 in amyloid beta (Abeta) treated rat microglia; additionally, microglial activation and the expression of IL-1beta, iNOS, and COX2 were also significantly suppressed by gx-50 in APP(+) transgenic mice. Furthermore, gx-50 inhibited the activation of NF-kappaB and MAPK cascades in vitro and in vivo in APP-Tg mice. Moreover, the expression of TLR4 and its downstream signaling proteins MyD88 and tumor necrosis factor receptor associated factor 6 (TRAF6) was reduced by gx-50 in vitro and in vivo. Interestingly, silencing of TLR4 reduced Abeta-induced upregulation of IL-1beta and TRAF6 to levels similar to gx-50 inhibition; moreover, overexpression of TLR4 increased the expression of MyD88 and TRAF6, which was significantly reduced by gx-50. These findings provide strong evidence that gx-50 has anti-inflammatory effects against Abeta-triggered microglial overactivation via a mechanism that involves the TLR4-mediated NF-kappaBB/MAPK signaling cascade. PMID- 26643274 TI - Liquid Nickel Salts: Synthesis, Crystal Structure Determination, and Electrochemical Synthesis of Nickel Nanoparticles. AB - New nickel-containing ionic liquids were synthesized, characterized and their electrochemistry was investigated. In addition, a mechanism for the electrochemical synthesis of nanoparticles from these compounds is proposed. In these so-called liquid metal salts, the nickel(II) cation is octahedrally coordinated by six N-alkylimidazole ligands. The different counter anions that were used are bis(trifluoromethanesulfonyl)imide (Tf2 N(-) ), trifluoromethanesulfonate (OTf(-) ) and methanesulfonate (OMs(-) ). Several different N-alkylimidazoles were considered, with the alkyl sidechain ranging in length from methyl to dodecyl. The newly synthesized liquid metal salts were characterized by CHN analysis, FTIR, DSC, TGA and viscosity measurements. An odd even effect was observed for the melting temperatures and viscosities of the ionic liquids, with the complexes with an even number of carbon atoms in the alkyl chain of the imidazole having a higher melting temperature and a lower viscosity than the complexes with an odd number of carbons. The crystal structures of several of the nickel(II) complexes that are not liquid at room temperature were determined. The electrochemistry of the compounds with the lowest viscosities was investigated. The nickel(II) cation could be reduced but surprisingly no nickel deposits were obtained on the electrode. Instead, nickel nanoparticles were formed at 100 % selectivity, as confirmed by TEM. The magnetic properties of these nanoparticles were investigated by SQUID measurements. PMID- 26643276 TI - Comprehensive Behavioral Treatment of Trichotillomania: A Treatment Development Study. AB - This study aimed to concretize and pilot test comprehensive behavioral (ComB) treatment of trichotillomania (TTM), to facilitate rigorous testing of its efficacy. ComB provides a conceptualization to develop individualized treatment and choose interventions for managing distinct factors that maintain the individual's hair pulling. It has been used by clinicians for almost three decades, yet was not previously manualized or studied empirically. A manual was drafted and revised based on patient (N= 16) and therapist feedback, an intervention choice study demonstrated therapists reliably selected model consistent interventions, and a therapist adherence measure was developed and tested. Uncontrolled preliminary data showed ComB to be highly acceptable, and it led to reduced TTM symptom severity and impairment, with large effects. Quality of life and disability also improved, with effects maintained at follow-up. This study resulted in the development of a manual and measures to be used in a randomized controlled trial (RCT) of ComB for TTM. PMID- 26643275 TI - The Notch and Wnt pathways regulate stemness and differentiation in human fallopian tube organoids. AB - The epithelial lining of the fallopian tube is of critical importance for human reproduction and has been implicated as a site of origin of high-grade serous ovarian cancer. Here we report on the establishment of long-term, stable 3D organoid cultures from human fallopian tubes, indicative of the presence of adult stem cells. We show that single epithelial stem cells in vitro can give rise to differentiated organoids containing ciliated and secretory cells. Continuous growth and differentiation of organoids depend on both Wnt and Notch paracrine signalling. Microarray analysis reveals that inhibition of Notch signalling causes downregulation of stem cell-associated genes in parallel with decreased proliferation and increased numbers of ciliated cells and that organoids also respond to oestradiol and progesterone treatment in a physiological manner. Thus, our organoid model provides a much-needed basis for future investigations of signalling routes involved in health and disease of the fallopian tube. PMID- 26643277 TI - Depression and Rural Environment are Associated With Poor Oral Health Among Pregnant Women in Northern Appalachia. AB - Both oral health problems and depression among pregnant women contribute to maternal-infant health outcomes. Little is known, however, about the potential effects of clinically significant depression on the oral health status of pregnant women. The purpose of the present study was to determine the influence of clinically significant depression and rural- or urban-dwelling status on oral health outcomes among pregnant women. Pregnant women (N = 685) in rural (i.e., West Virginia) and urban (i.e., Pittsburgh, PA) areas of northern Appalachia were assessed by calibrated examiners regarding gingivitis, oral hygiene, and DMFT (decayed, missing, and filled teeth), completed the Center for Epidemiologic Studies-Depression Scale (CES-D) and provided demographics. Participants were categorized based on clinically significant depressive symptoms (CES-D >= 16) and rural/urban domicile. Women with depression and those living in rural areas had worse oral health on all three indices than their non-depressed and urban counterparts. Depression, particularly among women in rural areas, affects certain oral health indices and represents a modifiable target for intervention. Moreover, treatments designed specifically for rural populations may be of particular utility. Women who are pregnant or planning to become pregnant may benefit from regular depression screenings from their dental and medical health care providers. PMID- 26643278 TI - Intracellular accumulation and dissolution of silver nanoparticles in L-929 fibroblast cells using live cell time-lapse microscopy. AB - Cytotoxicity assessments of nanomaterials, such as silver nanoparticles, are challenging due to interferences with test reagents and indicators as well uncertainties in dosing as a result of the complex nature of nanoparticle intracellular accumulation. Furthermore, current theories suggest that silver nanoparticle cytotoxicity is a result of silver nanoparticle dissolution and subsequent ion release. This study introduces a novel technique, nanoparticle associated cytotoxicity microscopy analysis (NACMA), which combines fluorescence microscopy detection using ethidium homodimer-1, a cell permeability marker that binds to DNA after a cell membrane is compromised (a classical dead-cell indicator dye), with live cell time-lapse microscopy and image analysis to simultaneously investigate silver nanoparticle accumulation and cytotoxicity in L 929 fibroblast cells. Results of this method are consistent with traditional methods of assessing cytotoxicity and nanoparticle accumulation. Studies conducted on 10, 50, 100 and 200 nm silver nanoparticles reveal size dependent cytotoxicity with particularly high cytotoxicity from 10 nm particles. In addition, NACMA results, when combined with transmission electron microscopy imaging, reveal direct evidence of intracellular silver ion dissolution and possible nanoparticle reformation within cells for all silver nanoparticle sizes. PMID- 26643279 TI - Microwave-Assisted Synthesis of Highly-Crumpled, Few-Layered Graphene and Nitrogen-Doped Graphene for Use as High-Performance Electrodes in Capacitive Deionization. AB - Capacitive deionization (CDI) is a promising procedure for removing various charged ionic species from brackish water. The performance of graphene-based material in capacitive deionization is lower than the expectation of the industry, so highly-crumpled, few-layered graphene (HCG) and highly-crumpled nitrogen-doped graphene (HCNDG) with high surface area have been introduced as promising candidates for CDI electrodes. Thus, HCG and HCNDG were prepared by exfoliation of graphite in the presence of liquid-phase, microwave-assisted methods. An industrially-scalable, cost-effective, and simple approach was employed to synthesize HCG and HCNDG, resulting in few-layered graphene and nitrogen-doped graphene with large specific surface area. Then, HCG and HCNDG were utilized for manufacturing a new class of carbon nanostructure-based electrodes for use in large-scale CDI equipment. The electrosorption results indicated that both the HCG and HCNDG have fairly large specific surface areas, indicating their huge potential for capacitive deionization applications. PMID- 26643280 TI - Human fear acquisition deficits in relation to genetic variants of the corticotropin-releasing hormone receptor 1 and the serotonin transporter- revisited. AB - We recently showed that a genetic polymorphism (rs878886) in the human corticotropin-releasing hormone receptor 1 (CRHR1) is associated with reduced fear-conditioned responses to a threat cue. This is a potentially important finding considering that the failure to acquire fear contingencies can leave an individual in a maladaptive state of more generalized anxiety. Consistent with that idea, the CRHR1-dependent fear acquisition deficit translated into heightened contextual anxiety when taking genetic variability within the serotonin transporter long polymorphic region (5-HTTLPR) into account. To replicate our previous findings, we conducted a replication study in 224 healthy medication-free human subjects using the exact same cue and context virtual reality fear-conditioning procedure as in study by Heitland et al. (2013). In the replication study, consistent with the original findings, CRHR1 rs878886 G-allele carriers showed reduced acquisition of cue-specific fear-conditioned responses compared with C/C homozygotes. Also, in this larger sample the cue acquisition deficit of G-allele carriers translated into heightened contextual anxiety, even independent of 5-HTT gene variation. In contrast to our earlier findings, there was an additional interaction effect of CRHR1 rs878886 and the triallelic 5 HTTLPR/rs25531 variant on cued fear acquisition. In summary, this study replicated the initially reported association of the CRHR1 rs878886 G-allele with cued fear acquisition deficits, albeit with a different pattern of results regarding the interaction with 5-HTT variation. This further supports the notion that the human corticotropin-releasing hormone plays a role in the acquisition of fears. PMID- 26643281 TI - A new non-craniotomy model of subarachnoid hemorrhage in the pig: a pilot study. AB - Subarachnoid hemorrhage (SAH) from rupture of an intracranial arterial aneurysm is a devastating disease affecting young people, with serious lifelong disability or death as a frequent outcome. Large animal models that exhibit all the cardinal clinical features of human SAH are highly warranted. In this pilot study we aimed to develop a non-craniotomy model of SAH in pigs suitable for acute intervention studies. Six Norwegian Landrace pigs received advanced invasive hemodynamic and intracranial pressure (ICP) monitoring. The subarachnoid space, confirmed by a clear cerebrospinal fluid (CSF) tap, was reached by advancing a needle below the ocular bulb through the superior orbital fissure and into the interpeduncular cistern. SAH was induced by injecting 15 mL of autologous arterial blood into the subarachnoid space. Macro- and microanatomical investigations of the pig brain showed a typical blood distribution consistent with human aneurysmal SAH (aSAH) autopsy data. Immediately after SAH induction ICP sharply increased with a concomitant reduction in cerebral perfusion pressure (CPP). ICP returned to near normal values after 30 min, but increased subsequently during the experimental period. Signs of brain edema were confirmed by light microscopy post-mortem. None of the animals died during the experimental period. This new transorbital injection model of SAH in the pig mimics human aSAH and may be suitable for acute intervention studies. However, the model is technically challenging and needs further validation. PMID- 26643282 TI - Evaluation of clinical chemistry analytes from a single mouse using diluted plasma: effective way to reduce the number of animals in toxicity studies. AB - Clinical chemistry is an essential analytical tool in many areas of research, drug assessment and development, and in the evaluation of general health. A certain amount of blood is required to evaluate all blood analytes. Experiments where mice are used, it is difficult to measure all analytes due to the small amount of blood that can be obtained from a single animal. To overcome this problem, separate cohorts of animals are used in toxicity studies for hematology and biochemistry analysis. This requires the use of extra animals and additional resources. Hence interpretation of results derived from using these different animals can be unreliable. This study was undertaken to explore the possibility of using diluted plasma for measuring various biochemistry analytes. Plasma from mice was diluted to 3, 5 and 10-fold with Water for Injection, and various biochemistry analytes were analyzed using an automated analyzer. Results of diluted and undiluted plasma from the same mouse were compared. Most of the analytes from the diluted plasma were found to be well within the ranges of the undiluted plasma except for sodium, potassium and chloride. Diluting plasma to analyze some analytes also freed up undiluted plasma for analyzing electrolytes. In conclusion, in order to obtain reliable and interpretable data from a single mouse it is worthwhile considering diluting the plasma, which should reduce the number of animals used in an experiment. PMID- 26643283 TI - Molecular physiopathology of obesity-related diseases: multi-organ integration by GRK2. AB - Obesity is a worldwide problem that has reached epidemic proportions both in developed and developing countries. The excessive accumulation of fat poses a risk to health since it favours the development of metabolic alterations including insulin resistance and tissue inflammation, which further contribute to the progress of the complex pathological scenario observed in the obese. In this review we put together the different outcomes of fat accumulation and insulin resistance in the main insulin-responsive tissues, and discuss the role of some of the key molecular routes that control disease progression both in an organ specific and also in a more systemic manner. In particular, we focus on the importance of studying the integrated regulation of different organs and pathways that contribute to the global pathophysiology of this condition with a specific emphasis on the role of emerging key molecular nodes such as the G protein coupled receptor kinase 2 (GRK2) signalling hub. PMID- 26643284 TI - The ability of multipotent mesenchymal stromal cells from the bone marrow of patients with leukemia to maintain normal hematopoietic progenitor cells. AB - BACKGROUND: The development of leukemia impairs normal hematopoiesis and marrow stromal microenvironment. The aim of the investigation was to study the ability of multipotent mesenchymal stromal cells (MSCs) derived from the bone marrow of patients with leukemia to maintain normal hematopoietic progenitor cells. METHODS: MSCs were obtained from the bone marrow of 14 patients with acute lymphoblastic (ALL), 25 with myeloid (AML), and 15 with chronic myeloid (CML) leukemia. As a control, MSCs from 22 healthy donors were used. The incidence of cobblestone area forming cells (CAFC 7-8 d) in the bone marrow of healthy donor cultivated on the supportive layer of patients MSCs was measured. RESULTS: The ability of MSCs from AML and ALL patients at the moment of diagnosis to maintain normal CAFC was significantly decreased when compared to donors. After chemotherapy, the restoration of ALL patients' MSCs functions was slower than that of AML. CML MSCs maintained CAFC better than donors' at the moment of diagnosis and this ability increased with treatment. CONCLUSIONS: The ability of patients' MSCs to maintain normal hematopoietic progenitor cells was shown to change in comparison with MSCs from healthy donors and depended on nosology. During treatment, the functional capacity of patients' MSCs had been partially restored. PMID- 26643286 TI - A Rhodium-Mediated Contraction of Benzene to Cyclopentadiene: Transformations of Rhodium(III) m-Benziporphyrin. AB - The contraction of benzene is one of an exclusive group of reactions where the cleavage of aromatic structure is of fundamental importance. Rhodium(III) m benziporphyrin undergoes an unprecedented transformation of the built-in m phenylene in which a perimeter carbon atom is extruded to form rhodium(III) 21 carbaporphyrin, stabilizing the formyl-unit-substituted rhodacyclopropane motif. PMID- 26643285 TI - Ventricular Tachycardia Ablation in the Presence of Left Ventricular Thrombus: Safety and Efficacy. AB - INTRODUCTION: The safety of ventricular tachycardia (VT) ablation in patients with laminated left ventricular (LV) thrombus has not been examined. METHODS: Patients with laminated LV thrombus on transthoracic echocardiogram who underwent scar-mediated VT ablation at two centers from 2010 to 2013 were retrospectively analyzed. All patients had failed medical therapy. Acute procedural outcomes, complications, and clinical outcomes at 1 year were assessed. RESULTS: Eight patients (four ischemic, four nonischemic cardiomyopathy) underwent VT ablation in the presence of laminated intracavitary thrombus. Six out of eight (75%) had electrical storm (ES). The mapping and ablation approach was LV endocardial-only in three patients, epicardial-only in two, combined epicardial-RV endocardial in two, and combined epicardial-LV endocardial in one. Major complication (ischemic stroke) occurred in one patient 9 days post-procedure. There was no procedural mortality. Complete acute procedural success (noninducibility of any VT after ablation) was achieved in five (63%), and partial success (ablation of only clinical VT) in an additional three (37%). At 1 year, freedom from VT and survival were achieved in six (75%) and seven (88%) patients, respectively. CONCLUSION: Initial data suggest that ablation of VT in the presence of intracavitary thrombus is feasible, is associated with a similar success rate to historical studies in patients without thrombus, and has an acceptable risk of complications given the high-risk nature of patients with ES. Further data are needed; however, the presence of a laminated thrombus should not necessarily preclude ablation in patients who have failed medical therapy for VT in whom ablation is otherwise indicated. PMID- 26643287 TI - Bayesian inference for generalized linear mixed models with predictors subject to detection limits: an approach that leverages information from auxiliary variables. AB - This paper is motivated from a retrospective study of the impact of vitamin D deficiency on the clinical outcomes for critically ill patients in multi-center critical care units. The primary predictors of interest, vitamin D2 and D3 levels, are censored at a known detection limit. Within the context of generalized linear mixed models, we investigate statistical methods to handle multiple censored predictors in the presence of auxiliary variables. A Bayesian joint modeling approach is proposed to fit the complex heterogeneous multi-center data, in which the data information is fully used to estimate parameters of interest. Efficient Monte Carlo Markov chain algorithms are specifically developed depending on the nature of the response. Simulation studies demonstrate the outperformance of the proposed Bayesian approach over other existing methods. An application to the data set from the vitamin D deficiency study is presented. Possible extensions of the method regarding the absence of auxiliary variables, semiparametric models, as well as the type of censoring are also discussed. PMID- 26643288 TI - Spontaneous Coronary Artery Dissection: Case Series from a Tertiary Centre. AB - Spontaneous coronary artery dissection (SCAD) is a rare cause of non atherosclerotic acute coronary syndrome (ACS). As it is more commonly seen in young women, the diagnosis can be missed. Current evidence is based on case reports and retrospective studies with no consensus recommendations on immediate management and long-term follow-up. We present a case series of four patients to outline clinical presentation, prognosis and long-term management of this rare clinical entity. PMID- 26643290 TI - Quality assurance of lymphadenectomy for melanoma: Why and how? PMID- 26643289 TI - The Management of Supraventricular Tachyarrhythmias in Patients with Pulmonary Arterial Hypertension. AB - BACKGROUND: Atrial remodelling in pulmonary arterial hypertension (PAH) may lead to higher incidence of supraventricular arrhythmias (SVA). The purpose of this study was to evaluate the efficiency and safety of various methods for treatment of SVA in this group. METHODS: This was a single centre study. Forty-eight patients (33 women and 15 men) aged 19-77 years (median 49 years) were enrolled. There were 30 patients with idiopathic PAH, 10 had PAH associated with connective tissue disease, and eight with congenital heart disease. A retrospective analysis was performed to estimate the prevalence and type of supraventricular arrhythmias, as well as efficiency and safety of treatment methods. Mean follow up period was 28.8+/-17.7 months. RESULTS: Supraventricular arrhythmias occurred in 17 patients (35%) and appeared to be atrial fibrillation, flutter or tachycardia. Supraventricular arrhythmias coexisted with elevated mean right atrial pressure in 75%. Four patients had more than one type of SVA. A flutter like macro-reentrant form of atrial tachycardia dependent on cavo-tricuspid isthmus was found in four cases. The treatment of SVA included typical methods: antiarrhythmic drugs, direct current cardioversion (DCC), and radiofrequency (RF) ablation. All of the therapeutic methods were effective in managing acute arrhythmia. Three patients required re-ablation. Overall mortality: 14 patients (29%) in the whole study group, including six in SVA group (35%) and eight without SVA (26%). CONCLUSIONS: In patients with PAH DCC, pharmacological cardioversion and RF ablation can be applied safely and effectively. Flutter-like macro-reentrant atrial tachycardia dependent on cavo-tricuspid isthmus is observed in this group. It is more challenging, but possible, to successfully treat this arrhythmia with RF ablation. PMID- 26643291 TI - Cerebellar neurophysiology in Gilles de la Tourette syndrome and its role as a target for therapeutic intervention. AB - Therapy resistance of approximately one-third of patients with Gilles de la Tourette syndrome (GTS) requires consideration of alternative therapeutic interventions. The article demonstrates the role of the cerebellum in neuropsychiatric disorders and GTS in particular, specifically its role in functions relating to motor and cognitive symptoms. Certain circuits in the cerebellum have been shown to undergo learning-induced changes during conditioning, with cells in the cortex of the cerebellum appearing to decrease their activity whilst those in deep nuclei seem to do the inverse. Evidence exists showing that abnormal excitability of the motor cortex via the cerebellum could be expected to participate in motor tics in GTS possibly due to aberrations in certain structures of involved circuits. The role of the cerebellum in learning and plasticity processes renders it a strategic and valuable structure to consider for brain stimulation when investigating potential treatment options for neuropsychiatric disorders such as GTS. This article puts forth the concept of using non-invasive and invasive brain stimulation techniques as a novel platform for non-pharmacological neuromodulation of GTS symptoms. PMID- 26643292 TI - [Adverse drug reactions in the elderly: What dermatologists should know]. AB - Pharmacotherapy in the elderly represents a challenge for dermatologists in regard to comorbidities, drug interactions, and compliance. Age-associated multimorbidity often results in polypharmacy and elevates the risk of adverse drug reactions. Crucial age-related alterations in pharmacokinetics must be considered when selecting drugs, particularly decreased total body water, altered proportion between muscle mass and adipose tissue, as well as decreased renal function. The purpose of this review is to help the reader identify relevant adverse drug reactions of often prescribed systemic dermatological pharmacons in geriatric patients and makes recommendations for their adequate application. PMID- 26643293 TI - Wnt3a suppresses Wnt/beta-catenin signaling and cancer cell proliferation following serum deprivation. AB - Canonical Wnt/beta-catenin signaling is often aberrantly activated in tumor cells and required for tumor growth. The internalization of Wnt co-receptor low-density lipoprotein receptor-related protein 6 (LRP6) induced by Wnt ligands is commonly thought to be critical for Wnt/beta-catenin signaling activation. However, in contrast to theses previous studies, we here show that persistent excessive stimulation with a canonical Wnt ligand Wnt3a could induce a long-term decreased expression level of membrane LRP6, which prevented nuclear beta-catenin accumulation and tumor cell;proliferation. Importantly, Wnt3a was robustly upregulated following serum deprivation. The upregulated Wnt3a under serum deprivation was responsible for LRP6 internalization, decreased accumulation of nuclear beta-catenin, and further inhibition of tumor cell proliferation. It has well been known that insufficient blood supply during tumor development occurs frequently, causing a worsening environment for tumor growth. Therefore, these results reveal a novel inhibitory role of Wnt3a on canonical Wnt/beta-catenin signaling and cancer cell proliferation when there is an insufficient blood supply during tumor development, which might be a potential mechanism for tumor evasion within a worsening environment. PMID- 26643294 TI - Authorship, credit, contribution and problems. PMID- 26643297 TI - Ileal J-Pouch Volvulus Following Total Proctocolectomy for Ulcerative Colitis. AB - Total proctocolectomy with ileal pouch-anal anastomosis (IPAA) allows restoration of continence in select patients with ulcerative colitis but is associated with significant morbidity. Well-known complications following IPAA include pouchitis, anastomotic leak, and small bowel obstruction. Obstruction secondary to ileal pouch volvulus is exceedingly rare. We report a case of ileal pouch volvulus, which occurred secondary to internal hernia. Radiographic and endoscopic identification of volvulus allowed for early operative management and pouch salvage. PMID- 26643296 TI - Surgical Endoscopic Vacuum Therapy for Defects of the Upper Gastrointestinal Tract. AB - INTRODUCTION: Intraluminal therapy used in the gastrointestinal (GI) tract was first shown for anastomotic leaks after rectal resection. Since a few years vacuum sponge therapy is increasingly being recognized as a new promising method for repairing upper GI defects of different etiology. The principles of vacuum assisted closure (VAC) therapy remain the same no matter of localization: Continuous or intermittent suction and drainage decrease bacterial contamination, secretion, and local edema. At the same time, perfusion and granulation is promoted. However, data for endoscopic vacuum therapy (EVT) of the upper intestinal tract are still scarce and consist of only a few case reports and small series with low number of patients. OBJECTIVES: Here, we present a single center experience of EVT for substantial wall defects in the upper GI tract. METHODS: Retrospective single-center analysis of EVT for various defects of the upper GI tract over a time period of 4 years (2011-2015) with a mean follow-up of 17 (2-45) months was used. If necessary, initial endoscopic sponge placement was performed in combination with open surgical revision. RESULTS: In total, 126 polyurethane sponges were placed in upper gastrointestinal defects of 21 patients with a median age of 72 years (range, 49-80). Most frequent indication for EVT was anastomotic leakage after esophageal or gastric resection (n = 11) and iatrogenic esophageal perforation (n = 8). The median number of sponge insertions was five (range, 1-14) with a mean changing interval of 3 days (range, 2-4). Median time of therapy was 15 days (range, 3-46). EVT in combination with surgery took place in nine of 21 patients (43 %). A successful vacuum therapy for upper intestinal defects with local control of the septic focus was achieved in 19 of 21 patients (90.5 %). CONCLUSION: EVT is a promising approach for postoperative, iatrogenic, or spontaneous lesions of the upper GI tract. In this series, EVT was combined with operative revision in a relevant proportion of patients. PMID- 26643298 TI - Circular Stapler-Assisted Extraperitoneal Colostomy in Laparoscopic Abdominoperineal Resection: a Single Surgeon Experience. AB - BACKGROUND: Nowadays, laparoscopic abdominoperineal resection (LAPR) not only has the same oncologic safety of open surgery and but also has the common advantages of laparoscopic surgery. However, given the difficulty in operation and long operative time, laparoscopic extraperitoneal colostomy construction is rarely practiced and reported. In this study, we describe technique of extraperitoneal colostomy using circular stapler following LAPR and demonstrate its efficacy and safety. METHODS: This is a retrospective analysis of prospectively maintained data of 42 patients who underwent LAPR with circular stapler-assisted extraperitoneal colostomy in our department between July 2011 and June 2014. RESULTS: The mean time for extraperitoneal colostomy construction was 25 min (18 33 min). The mean operative time, estimated blood loss, postoperative gastrointestinal function recovery time, and duration of postoperative hospital stay were 160 min (115-225 min), 45 ml (10-250 ml), 33 h (26-45 h), and 8.6 days (6-13 days), respectively; 4.8 % of the patients had postoperative short-term complications. There were no stenosis, prolapse, and parastomal hernia observed in follow-up period. At 6 months after operation, 26 patients (62 %) claimed to be satisfied with their postoperative stool habits, 29 patients (69 %) had sensation to defecate per stoma, and 11 (26.2 %) patients had the ability to defer defecation for solid or liquid stool per stoma. CONCLUSION: Circular stapler-assisted extraperitoneal colostomy is an easy, effective, and safe technique following LAPR and appears to minimize the occurrence of stomal complications and improve the quality of life for patients. PMID- 26643299 TI - Antroduodenectomy with Gastroduodenal Anastomosis: Salvage Emergency Surgery for Complicated Peptic Ulcer Disease--Results of a Double Institution Study of 35 Patients. AB - BACKGROUND: Endoscopic and interventional techniques are currently the mainstay of management of bleeding duodenal ulcer. As well, for patients with perforated duodenal ulcer, laparoscopic simple closure is nowadays usually performed. Although indications for emergency antroduodenectomy have declined, this procedure is still necessary as a salvage option when conservative management has failed or is not practicable. Our study aimed to evaluate indications and results of antroduodenectomy with gastroduodenal anastomosis in current practice and to examine the factors that predict operative outcomes. METHODS: All patients who underwent emergency antroduodenectomy with gastroduodenal anastomosis in two surgical care departments specialized in emergency digestive surgery were studied from 2000 to 2015. RESULTS: Thirty-five patients (27 males, 77 %) with a median age of 68 years (20-90) underwent emergency antroduodenectomy with gastroduodenal anastomosis. Indications were bleeding and perforated duodenal ulcer in 24 and 11 patients, respectively. The overall complication rate was 69 %, especially because of a high rate of medical complications (57 %). Only two patients (6 %) required reoperation for anastomotic leakage. The overall mortality rate was 40 % (n = 14). According to the univariate analysis, age >70, >3 comorbidities, ASA score >2, and postoperative medical complications were associated with an increased risk of in-hospital mortality. In the multivariate analysis, age and ASA score remained independent risk factors. No recurrence of complicated duodenal disease was observed. CONCLUSION: Antroduodenectomy with gastroduodenal anastomosis is a safe and effective long-term strategy, with a low and acceptable rate of surgical complications, for complicated duodenal ulcer not responding to conservative measures. PMID- 26643301 TI - Administering human chorionic gonadotropin injections for triggering follicle maturation could impact fertility during the subsequent menstrual cycle. AB - OBJECTIVE: To determine whether the use of a human chorionic gonadotropin (hCG) injection as a follicle-maturation trigger affects a patient's reproductive ability during their subsequent menstrual cycle. METHODS: Patients that were infertile undergoing natural-cycle in vitro fertilization at Kato Ladies Clinic, Japan, between March and June 2012 were enrolled in a prospective cohort study. Patients who had received fertility treatments other than hCG injections were excluded from the study. The remaining patients were divided into two cohorts; patients who had received injection-administered hCG (study group) and patients who had not received any fertility treatment (control group) during their preceding menstrual cycle. The rates of oocyte retrieval, fertilization, clinical pregnancy, and live deliveries were analyzed using a Fisher exact test. RESULTS: The rate of successful oocyte-retrieval (P<0.001) and the delivery-rate (P=0.002) were significantly lower in the study group in comparison with the control group. Additionally, the incidence of empty follicles (P<0.001) and degenerated oocytes (P=0.002) was significantly higher in the exposure group. CONCLUSION: Triggering follicle maturation with hCG during in vitro fertilization could impact patient fertility during their next cycle. Treatment with hCG injection has the potential to influence not only the cycle during which it is administered, but also the subsequent menstrual cycle. PMID- 26643300 TI - Symptomatic Perihepatic Fluid Collections After Hepatic Resection in the Modern Era. AB - BACKGROUND: Improvements in liver surgery have led to decreased mortality rates. Symptomatic perihepatic collections (SPHCs) requiring percutaneous drainage remain a significant source of morbidity. STUDY DESIGN: A single institution's prospectively maintained hepatic resection database was reviewed to identify patients who underwent hepatectomy between January 2004 and February 2012. RESULTS: Data from 2173 hepatectomies performed in 2040 patients were reviewed. Overall, 200 (9%) patients developed an SPHC, the majority non-bilious (75.5%) and infected (54%). Major hepatic resections, larger than median blood loss (>=360 ml), use of surgical drains, and simultaneous performance of a colorectal procedure were associated with an SPHC on multivariate analysis. Non-bilious, non infected (NBNI) collections were associated with lower white blood cell (WBC) counts, absence of a bilio-enteric anastomosis, use of hepatic arterial infusion pump (HAIP), and presence of metastatic disease, and resolved more frequently with a single interventional radiology (IR) procedure (85 vs. 46.5%, p < 0.001) more quickly (15 vs. 30 days, p = 0.001). CONCLUSIONS: SPHCs developed in 9% of patients in a modern series of hepatic resections, and in one third were non bilious and non-infected. In the era of modern interventional radiology, the need for re-operation for SPHC is exceedingly rare. A significant proportion of minimally symptomatic SPHC patients may not require drainage, and strategies to avoid unnecessary drainage are warranted. PMID- 26643302 TI - Systematic reviews and meta-analyses of benefits and harms of cryotherapy, LEEP, and cold knife conization to treat cervical intraepithelial neoplasia. AB - BACKGROUND: Cervical intraepithelial neoplasia (CIN) stage 2-3 is a premalignant lesion that can progress to cervical cancer in 10-20 years if untreated. OBJECTIVES: To conduct systematic reviews of randomized and nonrandomized studies for effects of cryotherapy, loop electrosurgical excision procedure (LEEP), and cold knife conization (CKC) as treatment for CIN 2-3. SEARCH STRATEGY: Medline, Embase, and other databases were searched to February 2012 for benefits, and to July 2012 for harms. Additionally, experts were contacted. Keywords for CIN, cervical cancer, and the treatments were used. SELECTION CRITERIA: Studies of nonpregnant women 18 years or older not previously treated for CIN were included. DATA COLLECTION AND ANALYSIS: Two investigators independently screened and collected data. Relative risks and proportions were calculated and evidence assessed using GRADE (Grading of Recommendations Assessment, Development and Evaluation). MAIN RESULTS: Recurrence rate was 5.3% 12 months after cryotherapy or LEEP, and 1.4% after CKC. There seemed to be little or no differences in frequency of complications after LEEP or cryotherapy, but they occurred more often after CKC. Evidence suggests premature delivery is most common with CKC, but it also occurs after LEEP and cryotherapy. CONCLUSIONS: Despite a comprehensive search, there is very low quality evidence and often no evidence for important outcomes, including reproductive outcomes and complications. Studies assessing these outcomes are needed. PMID- 26643304 TI - Upgrading and replacement in CRT devices: experience counts. PMID- 26643303 TI - Echo response and clinical outcome in CRT patients. AB - BACKGROUND: Change in left ventricular end-systolic volume (?LVESV) is the most frequently used surrogate marker in measuring response to cardiac resynchronisation therapy (CRT). We investigated whether ?LVESV is the best measure to discriminate between a favourable and unfavourable outcome and whether this is equally applicable to non-ischaemic and ischaemic cardiomyopathy. METHODS: 205 CRT patients (age 65 +/- 12 years, 69 % men) were included. At baseline and 6 months echocardiographic studies, exercise testing and laboratory measurements were performed. CRT response was assessed by: ?LVESV, ?LV ejection fraction (LVEF), ? interventricular mechanical delay, ?VO2 peak, ?VE/VCO2, ?BNP, ?creatinine, ?NYHA, and ?QRS. These were correlated to the occurrence of major adverse cardiac events (MACE) between 6 and 24 months. RESULTS: MACE occurred in 19 % of the patients (non-ischaemic: 13 %, ischaemic: 24 %). ?LVESV remained the only surrogate marker for CRT response for the total population and patients with non-ischaemic cardiomyopathy, showing areas under the curve (AUC) of 0.69 and 0.850, respectively. For ischaemic cardiomyopathy, ?BNP was the best surrogate marker showing an AUC of 0.66. CONCLUSION: ?LVESV is an excellent surrogate marker measuring CRT response concerning long-term outcome for non-ischaemic cardiomyopathy. ?LVESV is not suitable for ischaemic cardiomyopathy in which measuring CRT response remains difficult. PMID- 26643305 TI - "Are CRT upgrade procedures more complex and associated with more complications than de novo CRT implantations?" A single centre experience. AB - OBJECTIVE: The objective of the study was to examine whether cardiac resynchronisation therapy upgrade procedures are more complex and associated with more complications than de novo implantations. METHOD: We retrospectively compared 134 upgrade procedures performed between 2006-2012 with a random, equally sized, sample of de novo CRT device implantations in the same period. Procedural data and the occurrence of periprocedural (<= 30 days) and long-term device-related (<= 1 year) complications were analysed. Complications with consequences were defined as those in need of adjustment of standard care. RESULTS: Median time to upgrade was 57 (31-115) months. There were no significant differences in procedure duration, radiation time or total hospitalisation between upgrades and de novo implantations. Perioperative complications occurred in 6.7 % of upgrade patients and in 9.0 % of de novo patients. The most frequently seen complications were phrenic nerve stimulation, coronary sinus dissection and pocket haematoma. Procedure success was comparable (upgrade: 98.5 % versus de novo: 96.3 %). A total of 236 patients completed 1 year of follow-up. Ten (4.2 %) patients had a long-term device-related complication with consequences including phrenic nerve stimulation, lead dislodgement/dysfunction, and infection (upgrade: 3.5 % versus de novo: 4.9 %). CONCLUSION: Upgrade procedures are not more complex nor associated with more complications than de novo CRT implantations. PMID- 26643306 TI - Current aspects of cardiac resynchronisation therapy. PMID- 26643307 TI - Spatiotemporal Trends Analysis of Pyrethroid Sediment Concentrations Spanning 10 Years in a Residential Creek in California. AB - The objective of this study was to assess temporal and spatial trends for eight pyrethroids monitored in sediment spanning 10 years from 2006 to 2015 in a residential stream in California (Pleasant Grove Creek). The timeframe for this study included sampling 3 years during a somewhat normal non-drought period (2006 2008) and 3 years during a severe drought period (2013-2015). Regression analysis of pyrethroid concentrations in Pleasant Grove Creek for 2006, 2007, 2008, 2012, 2013, 2014, and 2015 using 1/2 the detection limit for nondetected concentrations showed statistically significant declining trends for cyfluthrin, cypermethrin, deltamethrin, permethrin, and total pyrethoids. Additional trends analysis of the Pleasant Grove Creek pyrethroid data using only measured concentrations, without nondetected values, showed similar statistically significant declining trends for cyfluthrin, cypermethrin, deltamethrin, esfenvalerate, fenpropathrin, permethrin, and total pyrethroids. Spatial trends analysis for the specific creek sites showed that six of the eight pyrethroids had a greater number of sites with statistically significant declining concentrations. Possible reasons for reduced pyrethroid concentrations in the stream bed in Pleasant Grove Creek during this 10-year period are label changes in 2012 that reduced residential use and lack of precipitation during the later severe drought years of 2013-2015. PMID- 26643308 TI - Evolocumab: A Review in Hyperlipidemia. AB - Evolocumab (Repatha((r))) is a monoclonal antibody targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) that is administered subcutaneously at a dosage of 140 mg every 2 weeks or 420 mg once monthly. Across 12-week phase III trials in patients with primary hypercholesterolemia or mixed dyslipidemia, evolocumab was more effective than placebo (treatment difference -54.8 to -76.3%) and/or ezetimibe (treatment difference -36.9 to -47.2%) at reducing low-density lipoprotein cholesterol (LDL-C) levels, including when added to statin therapy, when administered to statin-intolerant patients, when administered as monotherapy, and in patients with heterozygous familial hypercholesterolemia who were receiving statins with or without other lipid-lowering drugs. Evolocumab also significantly lowered LDL-C levels (treatment difference of ~30% vs. placebo) in patients with homozygous familial hypercholesterolemia when added to statins with or without ezetimibe in a 12-week phase III trial. The efficacy of evolocumab was maintained in the longer term, and it was well tolerated. In conclusion, subcutaneous evolocumab is a valuable new treatment for use in primary hypercholesterolemia or mixed dyslipidemia and homozygous familial hypercholesterolemia, particularly in patients unable to reach LDL-C goals despite treatment with statins with or without other lipid-lowering therapies and in patients who do not tolerate or are not able to receive statins. PMID- 26643309 TI - L1 and L2 Spoken Word Processing: Evidence from Divided Attention Paradigm. AB - The present study aims to reveal some facts concerning first language (L1) and second language (L2) spoken-word processing in unbalanced proficient bilinguals using behavioral measures. The intention here is to examine the effects of auditory repetition word priming and semantic priming in first and second languages of these bilinguals. The other goal is to explore the effects of attention manipulation on implicit retrieval of perceptual and conceptual properties of spoken L1 and L2 words. In so doing, the participants performed auditory word priming and semantic priming as memory tests in their L1 and L2. In a half of the trials of each experiment, they carried out the memory test while simultaneously performing a secondary task in visual modality. The results revealed that effects of auditory word priming and semantic priming were present when participants processed L1 and L2 words in full attention condition. Attention manipulation could reduce priming magnitude in both experiments in L2. Moreover, L2 word retrieval increases the reaction times and reduces accuracy on the simultaneous secondary task to protect its own accuracy and speed. PMID- 26643310 TI - The Janus soul of centrosomes: a paradoxical role in disease? AB - The centrosome is the main microtubule organizing center of animal cells. It contributes to spindle assembly and orientation during mitosis and to ciliogenesis in interphase. Numerical and structural defects in this organelle are known to be associated with developmental disorders such as dwarfism and microcephaly, but only recently, the molecular mechanisms linking centrosome aberrations to altered physiology are being elucidated. Defects in centrosome number or structure have also been described in cancer. These opposite clinical outcomes--arising from reduced proliferation and overproliferation respectively- can be explained in light of the tissue- and developmental-specific requirements for centrosome functions. The pathological outcomes of centrosome deficiencies have become clearer when considering its consequences. Among them, there are genetic instability (mainly aneuploidy, a defect in chromosome number), defects in the symmetry of cell division (important for cell fate specification and tissue architecture) and impaired ciliogenesis. In this review, we discuss the origins and the consequences of centrosome flaws, with particular attention on how they contribute to developmental diseases. PMID- 26643311 TI - Centrosomes in spindle organization and chromosome segregation: a mechanistic view. AB - Centrosomes are complex structures, which are embedded into the opposite poles of the mitotic spindle of most animals, acting as microtubule organizing centres. Surprisingly, in several biological systems, such as flies, chicken, or human cells, centrosomes are not essential for cell division. Nonetheless, they ensure faithful chromosome segregation. Moreover, mis-functioning centrosomes can act in a dominant-negative manner, resulting in erroneous mitotic progression. Here, I review the mechanisms by which centrosomes contribute to proper spindle organization and faithful chromosome segregation under physiological conditions and discuss how errors in centrosome function impair transmission of the genomic material in a pathological setting. PMID- 26643312 TI - Sexual dysfunction in women with cancer: a systematic review with meta-analysis of studies using the Female Sexual Function Index. AB - Cancer may impair sexual function in women. We provide an overview of studies that address Female Sexual Dysfunction (FSD) in women with cancer with a meta analysis of observational studies that used a validated diagnostic tool. Searches included MEDLINE, Scopus, and Google Scholar for studies published from January 2000 to 31 December 2014. Every included study had to involve at least 30 cancer patients, to investigate FSD based on the Female Sexual Function Index (FSFI), and to have been published in peer-review journals. Duplicate independent data extraction and quality assessment were performed. Data were pooled using a random effects model if statistical heterogeneity was present. The main outcomes were FSFI total score and FSD prevalence. FSFI is a 19-item self-report instrument for assessing key dimensions of female sexual function. A value less than 26.55 is consistent with FSD. Thirty-five studies met the inclusion criteria. Among these, 27 reported FSFI scores, and 16 FSD prevalence. Most studies (56 %) had low to moderate quality. The mean value of FSFI was lower than 20 at all cancer sites: 16.25 (pooled random effect, 95 % CI 14.91-17.58, I 2 = 14.5 %) for colorectal cancer, 18.11 (95 % CI 14.45-21.77, I 2 = 97.8 %) for gynecological cancer, and 19.58 (95 % CI 17.64-21.53, I 2 = 90.9 %) for breast cancer. FSD prevalence was higher than 60 % at all cancer sites, with the highest value for gynecological cancer (78.44 %, 95 % CI 68.36-88.52 %, I 2 = 94.1 %). Women with cancer showed low FSFI scores with a high prevalence of FSD. PMID- 26643315 TI - A germ cell tumor in a patient with Swyer syndrome with ambiguous genitalia. AB - BACKGROUND: Swyer syndrome is a rare manifestation of disorders of sex development in which the individual is 46, XY in genotype but phenotypically a female. They have normal female external genitalia with under developed female internal genitalia. They usually present with primary amenorrhoea and delayed puberty but also can present with gonadal tumors in adult life. CASE PRESENTATION: A 25-year-old Sri Lankan phenotypically female having 46 XY karyotype with a history of primary amenorrhoea, presented with left loin pain associated with fever. General examination revealed a tall stature, scanty axillary and pubic hair, small breasts and clitoromegally. A tender ill-defined mass was detected in the left hypochondrial region. She had high erythrocyte sedimentation rate with elevated alkaline phosphatase and lactate dehydrogenase levels. Her serum hormonal assay revealed a low estradiol level with elevated luteinizing hormone and follicular stimulating hormone levels with normal progesterone and testosterone levels. Computerized tomography of abdomen showed a large complex mass lesion in relation to antero-medial aspect of the lower pole of the left kidney with para-aortic and left common iliac lymph nodes. The diagnostic laparoscopy confirmed the presence of internal female genitalia and the mass lesion was seen in left para-aortic region. The histology revealed a germ cell tumor compatible with a dysgerminoma. CONCLUSION: Patients with Swyer syndrome can present with gonadal tumors, typically a dysgerminoma in their adult life. PMID- 26643313 TI - Exercise and diabetes: relevance and causes for response variability. AB - Exercise as a key prevention strategy for diabetes and obesity is commonly accepted and recommended throughout the world. Unfortunately, not all individuals profit to the same extent, some exhibit exercise resistance. This phenomenon of non-response to exercise is found for several endpoints, including glucose tolerance and insulin sensitivity. Since these non-responders are of notable quantity, there is the need to understand the underlying mechanisms and to identify predictors of response. This displays the basis to develop personalized training intervention regimes. In this review, we summarize the current knowledge on response variability, with focus on human studies and improvement of glucose homeostasis as outcome. PMID- 26643316 TI - Larval nutrition-induced plasticity affects reproduction and gene expression of the ladybeetle, Cryptolaemus montrouzieri. AB - BACKGROUND: Organisms may develop into multiple phenotypes under different nutritional environments by developmental plasticity, whereas the potential costs and mechanisms of such plasticity are poorly understood. Here we examined the fitness and gene expression of nutrition-induced phenotypes in the ladybeetle, Cryptolaemus montrouzieri after having experienced varying larval food regimes. RESULTS: We found that C. montrouzieri adults undergoing a variable larval food regime achieved a similar developmental time, survival, body mass and egg production as those undergoing a high larval food regime. The survival, developmental time, body mass and fecundity of the adults from a restricted larval food regime were inferior to those from the high and variable larval food regimes. However, the adults from this restricted larval food regime had a higher expression level of genes encoding immune- and antioxidant-related enzymes than those from the high and variable larval food regimes when exposed to starvation and pesticide conditions in adult life. CONCLUSIONS: These results suggest that larval food availability in C. montrouzieri not only triggers adult phenotypic differences but also affects reproduction and expression level of genes in adult life, indicating that the larval nutritional conditions can affect adult fitness and resistance to stressful conditions through developmental plasticity. PMID- 26643314 TI - Long live FOXO: unraveling the role of FOXO proteins in aging and longevity. AB - Aging constitutes the key risk factor for age-related diseases such as cancer and cardiovascular and neurodegenerative disorders. Human longevity and healthy aging are complex phenotypes influenced by both environmental and genetic factors. The fact that genetic contribution to lifespan strongly increases with greater age provides basis for research on which "protective genes" are carried by long-lived individuals. Studies have consistently revealed FOXO (Forkhead box O) transcription factors as important determinants in aging and longevity. FOXO proteins represent a subfamily of transcription factors conserved from Caenorhabditis elegans to mammals that act as key regulators of longevity downstream of insulin and insulin-like growth factor signaling. Invertebrate genomes have one FOXO gene, while mammals have four FOXO genes: FOXO1, FOXO3, FOXO4, and FOXO6. In mammals, this subfamily is involved in a wide range of crucial cellular processes regulating stress resistance, metabolism, cell cycle arrest, and apoptosis. Their role in longevity determination is complex and remains to be fully elucidated. Throughout this review, the mechanisms by which FOXO factors contribute to longevity will be discussed in diverse animal models, from Hydra to mammals. Moreover, compelling evidence of FOXOs as contributors for extreme longevity and health span in humans will be addressed. PMID- 26643317 TI - Transcription Factor Runx3 Is Induced by Influenza A Virus and Double-Strand RNA and Mediates Airway Epithelial Cell Apoptosis. AB - Influenza A virus (IAV) targets airway epithelial cells and exploits the host cell machinery to replicate, causing respiratory illness in annual epidemics and pandemics of variable severity. The high rate of antigenic drift (viral mutation) and the putative antigenic shift (reassortant strains) have raised the need to find the host cell inducible factors modulating IAV replication and its pathogenesis to develop more effective antiviral treatment. In this study, we found for the first time that transcription factor Runx3, a developmental regulator and tumor suppressor, was induced by IAV H1N1 and H3N2, viral RNA, a synthetic analog of viral double-stranded RNA (dsRNA) polyinosinic-polycytidylic acid, and type-II interferon-gamma (IFNgamma) in human airway epithelial cells. Whereas Runx3 was essentially not induced by type-I IFNalpha and type-III IFNlambda, we show that Runx3 induction by IAV infection and viral RNA is mediated through the innate immune receptor MDA5 and the IkappaB kinase-beta-NF kappaB pathway. Moreover, we provide substantial evidence indicating that Runx3 plays a crucial role in airway epithelial cell apoptosis induced by IAV infection and dsRNA through the activation of extrinsic and intrinsic apoptosis pathways. Thus, we have identified Runx3 as an inducible and important transcription factor modulating IAV-induced host epithelial cell apoptosis. PMID- 26643318 TI - Two Cases With Developing Neurologic Complications After Liver Transplant. AB - The widespread use of immunosuppressive agents has significantly increased the rates of successful solid-organ and stem cell transplants, especially with liver and kidney. Cyclosporine and tacrolimus are most commonly used for this purpose. Although these agents have different mechanisms of action, both have various adverse effects, including nausea, vomiting, headache, hypertension, nephrotoxicity, and rarely epileptic seizures. In our first case, a patient presented with epileptic seizures and hemiparesis after a liver transplant, and posterior reversible encephalopathy syndrome related to cyclosporine toxicity was considered. Once cyclosporine levels in the blood decreased, the patient had both clinical and radiologic improvements. In our second case, a patient presented with delirium after a liver transplant. Again, when cyclosporine levels in the blood decreased, the patient showed improvement in clinical findings. Neurologic complications may develop after liver transplant, and these complications are encountered most frequently within the first postoperative month. Neurologic complications are multifactorial; insufficient graft function, intracranial bleeding, cerebral infarcts, infections, and immunosuppressive drug toxicity (tacrolimus and cyclosporine) may be considered among these factors. As shown in our presented cases, most neurologic complications can be successfully treated by correcting the underlying factor. PMID- 26643319 TI - Loss of PIM2 enhances the anti-proliferative effect of the pan-PIM kinase inhibitor AZD1208 in non-Hodgkin lymphomas. AB - BACKGROUND: A promising therapeutic approach for aggressive B-cell Non-Hodgkin lymphoma (NHL), including diffuse large B-cell lymphoma (DLBCL), and Burkitt lymphoma (BL) is to target kinases involved in signal transduction and gene regulation. PIM1/2 serine/threonine kinases are highly expressed in activated B cell-like DLBCL (ABC-DLBCL) with poor prognosis. In addition, both PIM kinases have a reported synergistic effect with c-MYC in mediating tumour development in several cancers, c-MYC gene being translocated to one of the immunoglobulin loci in nearly all BLs. METHODS: For these reasons, we tested the efficiency of several PIM kinase inhibitors (AZD1208, SMI4a, PIM1/2 inhibitor VI and Quercetagetin) in preventing proliferation of aggressive NHL-derived cell lines and compared their efficiency with PIM1 and/or PIM2 knockdown. RESULTS: We observed that most of the anti-proliferative potential of these inhibitors in NHL was due to an off-target effect. Interestingly, we present evidence of a kinase independent function of PIM2 in regulating cell cycle. Moreover, combining AZD1208 treatment and PIM2 knockdown additively repressed cell proliferation. CONCLUSION: Taken together, this study suggests that at least a part of PIM1/2 oncogenic potential could be independent of their kinase activity, justifying the limited anti-tumorigenic outcome of PIM-kinase inhibitors in NHL. PMID- 26643320 TI - Sensitization pattern to inhalant and food allergens in symptomatic children at first evaluation. AB - BACKGROUND: Data on specific IgE sensitization prevalence in children with allergy-like symptoms seen in the primary care setting are rare. Early diagnosis of allergic diseases is important to prevent clinical manifestations, exacerbations or expansion of allergic diseases to other organ systems. The present study aims to assess the usefulness of early serological diagnosis in children with common allergic symptoms. METHODS: 532 children (<15 years of age), with at least one of ten allergy-like symptoms, from 21 primary care centers in two geographic areas of Italy and Spain were included in the study. Patients were tested with, either Phadiatop(r) Infant (0-5 years of age) or Phadiatop(r) and food mix (fx5e) (>5 years of age) to discriminate atopic from non-atopic subjects. A blood sample of atopic subjects was taken for additional 6-26 specific IgE antibody determinations from a predefined panel using the ImmunoCAP(r) System. RESULTS: 267 children (50.2 %) were positive in the initial test and were classified as atopic. 14 % were mono-sensitized, 37 % were sensitized to 2-3 allergens and 49 % to more than 3 allergens. The average number of symptoms in the atopic group was 3.3 vs 2.8 in the non-atopic group. The prevalence of sensitization to single allergens was highest for grass and ragweed pollen and house-dust mites (19-28 %). Sensitization to tree allergens was highest for olive tree (16.5 %). Cow's milk and egg white were the most sensitizing foods (~15 %). Food allergen sensitization predominated in younger children (OR = 2.8) whereas the inverse occurred with inhalant allergens (OR = 2.5 to 5.6). A significant positive correlation between patient age and the number of sensitizations was found. CONCLUSIONS: Specific IgE sensitization in children with allergy-like symptoms is common. Multiple sensitization is predominating. Number of clinical symptoms was higher in the atopic group compared to the non-atopic without a correlation with the number of positive allergens. Age seems to play a crucial role in the development of sensitization with a significant positive correlation between patient age and the number of sensitizations. PMID- 26643321 TI - Five minutes with . . . Stephen Duffy. PMID- 26643322 TI - New quantitative classification of the anatomical relationship between impacted third molars and the inferior alveolar nerve. AB - BACKGROUND: Before extracting impacted lower third molars, dentists must first identify the spatial relationship between the inferior alveolar nerve (IAN) and an impacted lower third molar to prevent nerve injury from the extraction. Nevertheless, the current method for describing the spatial relationship between the IAN and an impacted lower third molar is deficient. Therefore, the objectives of this study were to: (1) evaluate the relative position between impacted lower third molars and the IAN; and (2) investigate the relative position between impacted lower third molars and the IAN by using a cylindrical coordinate system. METHODS: From the radiology department's database, we selected computed tomography images of 137 lower third molars (from 75 patients) requiring removal and applied a Cartesian coordinate system by using Mimics, a medical imaging software application, to measure the distribution between impacted mandibular third molars and the IAN. In addition, the orientation of the lower third molar to the IAN was also measured, but by using a cylindrical coordinate system with the IAN as the origin. RESULTS: According to the Cartesian coordinate system, most of the IAN runs through the inferior side of the third molar (78.6 %), followed by the lingual side (11.8 %), and the buccal side (8.9 %); only 0.7 % is positioned between the roots. Unlike the Cartesian coordinate system, the cylindrical coordinate system clearly identified the relative position, r and theta, between the IAN and lower third molar. CONCLUSIONS: Using the cylindrical coordinate system to present the relationship between the IAN and lower third molar as (r, theta) might provide clinical practitioners with a more explicit and objective description of the relative position of both sites. However, comprehensive research and cautious application of this system remain necessary. PMID- 26643324 TI - Complete Sequence of blaKPC-2-Harboring Plasmid with a Mosaic of IncN1- and IncN3 Type Plasmids in a Klebsiella pneumoniae Isolate from South Korea. PMID- 26643323 TI - The Cholestanol-Conjugated Sulfated Oligosaccharide PG545 Disrupts the Lipid Envelope of Herpes Simplex Virus Particles. AB - Herpes simplex virus (HSV) and many other viruses, including HIV, initiate infection of host cells by binding to glycosaminoglycan (GAG) chains of cell surface proteoglycans. Although GAG mimetics, such as sulfated oligo- and polysaccharides, exhibit potent antiviral activities in cultured cells, the prophylactic application of these inhibitors as vaginal microbicides failed to protect women upon their exposure to HIV. A possible explanation for this failure is that sulfated oligo- and polysaccharides exhibit no typical virucidal activity, as their interaction with viral particles is largely electrostatic and reversible and thereby vulnerable to competition with GAG-binding proteins of the genital tract. Here we report that the cholestanol-conjugated sulfated oligosaccharide PG545, but not several other sulfated oligosaccharides lacking this modification, exhibited virucidal activity manifested as disruption of the lipid envelope of HSV-2 particles. The significance of the virus particle disrupting activity of PG545 was also demonstrated in experimental animals, as this compound, in contrast to unmodified sulfated oligosaccharide, protected mice against genital infection with HSV-2. Thus, PG545 offers a novel prophylaxis option against infections caused by GAG-binding viruses. PMID- 26643325 TI - New Verapamil Analogs Inhibit Intracellular Mycobacteria without Affecting the Functions of Mycobacterium-Specific T Cells. AB - There is a growing interest in repurposing mycobacterial efflux pump inhibitors, such as verapamil, for tuberculosis (TB) treatment. To aid in the design of better analogs, we studied the effects of verapamil on macrophages and Mycobacterium tuberculosis-specific T cells. Macrophage activation was evaluated by measuring levels of nitric oxide, tumor necrosis factor alpha (TNF-alpha), interleukin-1 beta (IL-1beta), and gamma interferon (IFN-gamma). Since verapamil is a known autophagy inducer, the roles of autophagy induction in the antimycobacterial activities of verapamil and norverapamil were studied using bone marrow-derived macrophages from ATG5(flox/flox) (control) and ATG5(flox/flox) Lyz-Cre mice. Our results showed that despite the well-recognized effects of verapamil on calcium channels and autophagy, its action on intracellular M. tuberculosis does not involve macrophage activation or autophagy induction. Next, the effects of verapamil and norverapamil on M. tuberculosis specific T cells were assessed using flow cytometry following the stimulation of peripheral blood mononuclear cells from TB-skin-test-positive donors with M. tuberculosis whole-cell lysate for 7 days in the presence or absence of drugs. We found that verapamil and norverapamil inhibit the expansion of M. tuberculosis specific T cells. Additionally, three new verapamil analogs were found to inhibit intracellular Mycobacterium bovis BCG, and one of the three analogs (KSV21) inhibited intracellular M. tuberculosis replication at concentrations that did not inhibit M. tuberculosis-specific T cell expansion. KSV21 also inhibited mycobacterial efflux pumps to the same degree as verapamil. More interestingly, the new analog enhances the inhibitory activities of isoniazid and rifampin on intracellular M. tuberculosis. In conclusion, KSV21 is a promising verapamil analog on which to base structure-activity relationship studies aimed at identifying more effective analogs. PMID- 26643326 TI - Analysis of Hepatitis C Virus Genotype 1b Resistance Variants in Japanese Patients Treated with Paritaprevir-Ritonavir and Ombitasvir. AB - Treatment of HCV genotype 1b (GT1b)-infected Japanese patients with paritaprevir (NS3/4A inhibitor boosted with ritonavir) and ombitasvir (NS5A inhibitor) in studies M12-536 and GIFT-I demonstrated high sustained virologic response (SVR) rates. The virologic failure rate was 3% (13/436) across the two studies. Analyses were conducted to evaluate the impact of baseline resistance-associated variants (RAVs) on treatment outcome and the emergence and persistence of RAVs in patients experiencing virologic failure. Baseline paritaprevir resistance conferring variants in NS3 were infrequent, while Y93H in NS5A was the most prevalent ombitasvir resistance-conferring variant at baseline. A comparison of baseline prevalence of polymorphisms in Japanese and western patients showed that Q80L and S122G in NS3 and L28M, R30Q, and Y93H in NS5A were significantly more prevalent in Japanese patients. In the GIFT-I study, the prevalence of Y93H in NS5A varied between 13% and 21% depending on the deep-sequencing detection threshold. Among patients with Y93H comprising <1%, 1 to 40%, or >40% of their preexisting viral population, the 24-week SVR (SVR24) rates were >99% (276/277), 93% (38/41), and 76% (25/33), respectively, indicating that the prevalence of Y93H within a patient's viral population is a good predictor of treatment response. The predominant RAVs at the time of virologic failure were D168A/V in NS3 and Y93H alone or in combination with other variants in NS5A. While levels of NS3 RAVs declined over time, NS5A RAVs persisted through posttreatment week 48. Results from these analyses are informative in understanding the resistance profile of an ombitasvir- plus paritaprevir/ritonavir-based regimen in Japanese GT1b-infected patients. PMID- 26643327 TI - IncI1 Plasmids Carrying Various blaCTX-M Genes Contribute to Ceftriaxone Resistance in Salmonella enterica Serovar Enteritidis in China. AB - Resistance to extended-spectrum beta-lactams in Salmonella, in particular, in serotypes such as Salmonella enterica serovar Enteritidis that are frequently associated with clinical infections, is a serious public health concern. In this study, phenotypic characterization of 433 clinical S. Enteritidis strains obtained from a nationwide collection of the Chinese Center for Disease Control and Prevention during the period from 2005 to 2010 depicted a trend of increasing resistance to ceftriaxone from 2008 onwards. Seventeen (4%) of the strains were found to be resistant to ceftriaxone, 7% were found to be resistant to ciprofloxacin, and 0.7% were found to be resistant to both ciprofloxacin and ceftriaxone. Most of the ceftriaxone-resistant S. Enteritidis strains (15/17) were genetically unrelated and originated from Henan Province. The complete sequence of an IncI1 plasmid, pSE115, which belonged to a novel sequence type, was obtained. This 87,255-bp IncI1 plasmid was found to harbor a blaCTX-M-14 gene in a novel multidrug resistance region (MRR) within the tra locus. Although the majority of strains were also found to contain conjugative IncI1 plasmids with a size similar to that of pSE115 (~90 kb) and harbor a variety of blaCTX-M group 1 and group 9 elements, the novel MRR site at the tra locus in pSE115 was not detectable in the other IncI1 plasmids. The findings from this study show that cephalosporin resistance in S. Enteritidis strains collected in China was mainly due to the dissemination of IncI1 plasmids carrying blaCTX-M, resembling the situation in which IncI1 plasmids serve as major vectors of blaCTX-M variants in other members of the Enterobacteriaceae. PMID- 26643328 TI - Searching for the Optimal Predictor of Ciprofloxacin Resistance in Klebsiella pneumoniae by Using In Vitro Dynamic Models. AB - There is growing evidence of applicability of the hypothesis of the mutant selection window (MSW), i.e., the range between the MIC and the mutant prevention concentration (MPC), within which the enrichment of resistant mutants is most probable. However, it is not clear if MPC-based pharmacokinetic variables are preferable to the respective MIC-based variables as interstrain predictors of resistance. To examine the predictive power of the ratios of the area under the curve (AUC24) to the MPC and to the MIC, the selection of ciprofloxacin-resistant mutants of three Klebsiella pneumoniae strains with different MPC/MIC ratios was studied. Each organism was exposed to twice-daily ciprofloxacin for 3 days at AUC24/MIC ratios that provide peak antibiotic concentrations close to the MIC, between the MIC and the MPC, and above the MPC. Resistant K. pneumoniae mutants were intensively enriched at an AUC24/MIC ratio of 60 to 360 h (AUC24/MPC ratio from 2.5 to 15 h) but not at the lower or higher AUC24/MIC and AUC24/MPC ratios, in accordance with the MSW hypothesis. AUC24/MPC and AUC24/MIC relationships with areas under the time courses of ciprofloxacin-resistant K. pneumoniae (AUBCM) were bell shaped. These relationships predict highly variable "antimutant" AUC24/MPC ratios (20 to 290 h) compared to AUC24/MIC ratios (1,310 to 2,610 h). These findings suggest that the potential of the AUC24/MPC ratio as an interstrain predictor of K. pneumoniae resistance is lower than that of the AUC24/MIC ratio. PMID- 26643329 TI - Albumin Enhances Caspofungin Activity against Aspergillus Species by Facilitating Drug Delivery to Germinating Hyphae. AB - The modest in vitro activity of echinocandins against Aspergillus implies that host-related factors augment the action of these antifungal agents in vivo. We found that, in contrast to the other antifungal agents (voriconazole, amphotericin B) tested, caspofungin exhibited a profound increase in activity against various Aspergillus species under conditions of cell culture growth, as evidenced by a >=4-fold decrease in minimum effective concentrations (MECs) (P = 0. 0005). Importantly, the enhanced activity of caspofungin against Aspergillus spp. under cell culture conditions was strictly dependent on serum albumin and was not observed with the other two echinocandins, micafungin and anidulafungin. Of interest, fluorescently labeled albumin bound preferentially on the surface of germinating Aspergillus hyphae, and this interaction was further enhanced upon treatment with caspofungin. In addition, supplementation of cell culture medium with albumin resulted in a significant, 5-fold increase in association of fluorescently labeled caspofungin with Aspergillus hyphae (P < 0.0001). Collectively, we found a novel synergistic interaction between albumin and caspofungin, with albumin acting as a potential carrier molecule to facilitate antifungal drug delivery to Aspergillus hyphae. PMID- 26643330 TI - Fluconazole Susceptibility in Cryptococcus gattii Is Dependent on the ABC Transporter Pdr11. AB - Cryptococcus gattii isolates from the Pacific Northwest have exhibited higher fluconazole MICs than isolates from other sites. The mechanism of fluconazole resistance in C. gattii is unknown. We sought to determine the role of the efflux pumps Mdr1 and Pdr11 in fluconazole susceptibility. Using biolistic transformation of the parent isolate, we created a strain lacking Mdr1 (mdr1Delta) and another strain lacking Pdr11 (pdr11Delta). Phenotypic virulence factors were assessed by standard methods (capsule size, melanin production, growth at 30 and 37 degrees C). Survival was assessed in an intranasal murine model of cryptococcosis. Antifungal MICs were determined by the M27-A3 methodology. No differences in key virulence phenotypic components were identified. Fluconazole susceptibility was unchanged in the Mdr1 knockout or reconstituted isolates. However, fluconazole MICs decreased from 32 MUg/ml for the wild-type isolate to <0.03 MUg/ml for the pdr11Delta strain and reverted to 32 MUg/ml for the reconstituted strain. In murine models, no difference in virulence was observed between wild-type, knockout, or reconstituted isolates. We conclude that Pdr11 plays an essential role in fluconazole susceptibility in C. gattii. Genomic and expression differences between resistant and susceptible C. gattii clinical isolates should be assessed further in order to identify other potential mechanisms of resistance. PMID- 26643331 TI - Clinical Candidate VT-1161's Antiparasitic Effect In Vitro, Activity in a Murine Model of Chagas Disease, and Structural Characterization in Complex with the Target Enzyme CYP51 from Trypanosoma cruzi. AB - A novel antifungal drug candidate, the 1-tetrazole-based agent VT-1161 [(R)-2 (2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-{5-[4-(2,2,2 trifluoroethoxy)phenyl]pyridin-2-yl}propan-2-ol], which is currently in two phase 2b antifungal clinical trials, was found to be a tight-binding ligand (apparent dissociation constant [Kd], 24 nM) and a potent inhibitor of cytochrome P450 sterol 14alpha-demethylase (CYP51) from the protozoan pathogen Trypanosoma cruzi. Moreover, VT-1161 revealed a high level of antiparasitic activity against amastigotes of the Tulahuen strain of T. cruzi in cellular experiments (50% effective concentration, 2.5 nM) and was active in vivo, causing >99.8% suppression of peak parasitemia in a mouse model of infection with the naturally drug-resistant Y strain of the parasite. The data strongly support the potential utility of VT-1161 in the treatment of Chagas disease. The structural characterization of T. cruzi CYP51 in complex with VT-1161 provides insights into the molecular basis for the compound's inhibitory potency and paves the way for the further rational development of this novel, tetrazole-based inhibitory chemotype both for antiprotozoan chemotherapy and for antifungal chemotherapy. PMID- 26643332 TI - Role of Residues W228 and Y233 in the Structure and Activity of Metallo-beta Lactamase GIM-1. AB - Metallo-beta-lactamases (MBLs) hydrolyze virtually all beta-lactam antibiotics, including penicillins, cephalosporins, and carbapenems. The worldwide emergence of antibiotic-resistant bacteria harboring MBLs poses an increasing clinical threat. The MBL German imipenemase-1 (GIM-1) possesses an active site that is narrower and more hydrophobic than the active sites of other MBLs. The GIM-1 active-site groove is shaped by the presence of the aromatic side chains of tryptophan at residue 228 and tyrosine at residue 233, positions where other MBLs harbor hydrophilic residues. To investigate the importance of these two residues, eight site-directed mutants of GIM-1, W228R/A/Y/S and Y233N/A/I/S, were generated and characterized using enzyme kinetics, thermostability assays, and determination of the MICs of representative beta-lactams. The structures of selected mutants were obtained by X-ray crystallography, and their interactions with beta-lactam substrates were modeled in silico. Steady-state kinetics revealed that both positions are important to GIM-1 activity but that the effects of individual mutations vary depending on the beta-lactam substrate. Activity against type 1 substrates bearing electron-donating C-3/C-4 substituents (cefoxitin, meropenem) could be enhanced by mutations at position 228, whereas hydrolysis of type 2 substrates (benzylpenicillin, ampicillin, ceftazidime, imipenem) with methyl or positively charged substituents was favored by mutations at position 233. The crystal structures showed that mutations at position 228 or the Y233A variant alters the conformation of GIM-1 loop L1 rather than that of loop L3, on which the mutations are located. Taken together, these data show that point mutations at both positions 228 and 233 can influence the catalytic properties and the structure of GIM-1. PMID- 26643333 TI - Characterization of Antifungal Activity and Nail Penetration of ME1111, a New Antifungal Agent for Topical Treatment of Onychomycosis. AB - Fungal nail infection (onychomycosis) is a prevalent disease in many areas of the world, with a high incidence approaching 23%. Available antifungals to treat the disease suffer from a number of disadvantages, necessitating the discovery of new efficacious and safe antifungals. Here, we evaluate the in vitro antifungal activity and nail penetration ability of ME1111, a novel antifungal agent, along with comparator drugs, including ciclopirox, amorolfine, terbinafine, and itraconazole. ME1111 showed potent antifungal activity against Trichophyton rubrum and Trichophyton mentagrophytes (the major etiologic agents of onychomycosis) strains isolated in Japan and reference fungal strains with an MIC range of 0.12 to 0.5 mg/liter and an MIC50 and MIC90 of 0.5 mg/liter for both. Importantly, none of the tested isolates showed an elevated ME1111 MIC. Moreover, the antifungal activity of ME1111 was minimally affected by 5% wool keratin powder in comparison to the other antifungals tested. The ME1111 solution was able to penetrate human nails and inhibit fungal growth in a dose-dependent manner according to the TurChub assay. In contrast, 8% ciclopirox and 5% amorolfine nail lacquers showed no activity under the same conditions. ME1111 demonstrated approximately 60-fold-greater selectivity in inhibition of Trichophyton spp. than of human cell lines. Our findings demonstrate that ME1111 possesses potent antidermatophyte activity, maintains this activity in the presence of keratin, and possesses excellent human nail permeability. These results suggest that ME1111 is a promising topical medication for the treatment of onychomycosis and therefore warrants further clinical evaluation. PMID- 26643335 TI - Clofazimine Prevents the Regrowth of Mycobacterium abscessus and Mycobacterium avium Type Strains Exposed to Amikacin and Clarithromycin. AB - Multidrug therapy is a standard practice when treating infections by nontuberculous mycobacteria (NTM), but few treatment options exist. We conducted this study to define the drug-drug interaction between clofazimine and both amikacin and clarithromycin and its contribution to NTM treatment. Mycobacterium abscessus and Mycobacterium avium type strains were used. Time-kill assays for clofazimine alone and combined with amikacin or clarithromycin were performed at concentrations of 0.25* to 2* MIC. Pharmacodynamic interactions were assessed by response surface model of Bliss independence (RSBI) and isobolographic analysis of Loewe additivity (ISLA), calculating the percentage of statistically significant Bliss interactions and interaction indices (I), respectively. Monte Carlo simulations with predicted human lung concentrations were used to calculate target attainment rates for combination and monotherapy regimens. Clofazimine alone was bacteriostatic for both NTM. Clofazimine-amikacin was synergistic against M. abscessus (I = 0.41; 95% confidence interval [CI], 0.29 to 0.55) and M. avium (I = 0.027; 95% CI, 0.007 to 0.048). Based on RSBI analysis, synergistic interactions of 28.4 to 29.0% and 23.2 to 56.7% were observed at 1* to 2* MIC and 0.25* to 2* MIC for M. abscessus and M. avium, respectively. Clofazimine clarithromycin was also synergistic against M. abscessus (I = 0.53; 95% CI, 0.35 to 0.72) and M. avium (I = 0.16; 95% CI, 0.04 to 0.35), RSBI analysis showed 23.5% and 23.3 to 53.3% at 2* MIC and 0.25* to 0.5* MIC for M. abscessus and M. avium, respectively. Clofazimine prevented the regrowth observed with amikacin or clarithromycin alone. Target attainment rates of combination regimens were >60% higher than those of monotherapy regimens for M. abscessus and M. avium. The combination of clofazimine with amikacin or clarithromycin was synergistic in vitro. This suggests a potential role for clofazimine in treatment regimens that warrants further evaluation. PMID- 26643334 TI - International Evaluation of MIC Distributions and Epidemiological Cutoff Value (ECV) Definitions for Fusarium Species Identified by Molecular Methods for the CLSI Broth Microdilution Method. AB - The CLSI epidemiological cutoff values (ECVs) of antifungal agents are available for various Candida spp., Aspergillus spp., and the Mucorales. However, those categorical endpoints have not been established for Fusarium spp., mostly due to the difficulties associated with collecting sufficient CLSI MICs for clinical isolates identified according to the currently recommended molecular DNA-PCR based identification methodologies. CLSI MIC distributions were established for 53 Fusarium dimerum species complex (SC), 10 F. fujikuroi, 82 F. proliferatum, 20 F. incarnatum-F. equiseti SC, 226 F. oxysporum SC, 608 F. solani SC, and 151 F. verticillioides isolates originating in 17 laboratories (in Argentina, Australia, Brazil, Canada, Europe, Mexico, and the United States). According to the CLSI guidelines for ECV setting, ECVs encompassing >=97.5% of pooled statistically modeled MIC distributions were as follows: for amphotericin B, 4 MUg/ml (F. verticillioides) and 8 MUg/ml (F. oxysporum SC and F. solani SC); for posaconazole, 2 MUg/ml (F. verticillioides), 8 MUg/ml (F. oxysporum SC), and 32 MUg/ml (F. solani SC); for voriconazole, 4 MUg/ml (F. verticillioides), 16 MUg/ml (F. oxysporum SC), and 32 MUg/ml (F. solani SC); and for itraconazole, 32 MUg/ml (F. oxysporum SC and F. solani SC). Insufficient data precluded ECV definition for the other species. Although these ECVs could aid in detecting non-wild-type isolates with reduced susceptibility to the agents evaluated, the relationship between molecular mechanisms of resistance (gene mutations) and MICs still needs to be investigated for Fusarium spp. PMID- 26643336 TI - Abalone Hemocyanin Blocks the Entry of Herpes Simplex Virus 1 into Cells: a Potential New Antiviral Strategy. AB - A marine-derived compound, abalone hemocyanin, from Haliotis rubra was shown to have a unique mechanism of antiviral activity against herpes simplex virus 1 (HSV 1) infections. In vitro assays demonstrated the dose-dependent and inhibitory effect of purified hemocyanin against HSV-1 infection in Vero cells with a 50% effective dose (ED50) of 40 to 50 nM and no significant toxicity. In addition, hemocyanin specifically inhibited viral attachment and entry by binding selectively to the viral surface glycoproteins gD, gB, and gC, probably by mimicking their receptors. However, hemocyanin had no effect on postentry events and did not block infection by binding to cellular receptors for HSV. By the use of different mutants of gD and gB and a competitive heparin binding assay, both protein charge and conformation were shown to be the driving forces of the interaction between hemocyanin and viral glycoproteins. These findings also suggested that hemocyanin may have different motifs for binding to each of the viral glycoproteins B and D. The dimer subunit of hemocyanin with a 10-fold smaller molecular mass exhibited similar binding to viral surface glycoproteins, showing that the observed inhibition did not require the entire multimer. Therefore, a small hemocyanin analogue could serve as a new antiviral candidate for HSV infections. PMID- 26643337 TI - Towards Rational Dosing Algorithms for Vancomycin in Neonates and Infants Based on Population Pharmacokinetic Modeling. AB - Because of the recent awareness that vancomycin doses should aim to meet a target area under the concentration-time curve (AUC) instead of trough concentrations, more aggressive dosing regimens are warranted also in the pediatric population. In this study, both neonatal and pediatric pharmacokinetic models for vancomycin were externally evaluated and subsequently used to derive model-based dosing algorithms for neonates, infants, and children. For the external validation, predictions from previously published pharmacokinetic models were compared to new data. Simulations were performed in order to evaluate current dosing regimens and to propose a model-based dosing algorithm. The AUC/MIC over 24 h (AUC24/MIC) was evaluated for all investigated dosing schedules (target of >400), without any concentration exceeding 40 mg/liter. Both the neonatal and pediatric models of vancomycin performed well in the external data sets, resulting in concentrations that were predicted correctly and without bias. For neonates, a dosing algorithm based on body weight at birth and postnatal age is proposed, with daily doses divided over three to four doses. For infants aged <1 year, doses between 32 and 60 mg/kg/day over four doses are proposed, while above 1 year of age, 60 mg/kg/day seems appropriate. As the time to reach steady-state concentrations varies from 155 h in preterm infants to 36 h in children aged >1 year, an initial loading dose is proposed. Based on the externally validated neonatal and pediatric vancomycin models, novel dosing algorithms are proposed for neonates and children aged <1 year. For children aged 1 year and older, the currently advised maintenance dose of 60 mg/kg/day seems appropriate. PMID- 26643339 TI - Amikacin Pharmacokinetics/Pharmacodynamics in a Novel Hollow-Fiber Mycobacterium abscessus Disease Model. AB - The treatment of pulmonary Mycobacterium abscessus disease is associated with very high failure rates and easily acquired drug resistance. Amikacin is the key drug in treatment regimens, but the optimal doses are unknown. No good preclinical model exists to perform formal pharmacokinetics/pharmacodynamics experiments to determine these optimal doses. We developed a hollow-fiber system model of M. abscessus disease and studied amikacin exposure effects and dose scheduling. We mimicked amikacin human pulmonary pharmacokinetics. Both amikacin microbial kill and acquired drug resistance were linked to the peak concentration to-MIC ratios; the peak/MIC ratio associated with 80% of maximal kill (EC80) was 3.20. However, on the day of the most extensive microbial kill, the bacillary burden did not fall below the starting inoculum. We performed Monte Carlo simulations of 10,000 patients with pulmonary M. abscessus infection and examined the probability that patients treated with one of 6 doses from 750 mg to 4,000 mg would achieve or exceed the EC80. We also examined these doses for the ability to achieve a cumulative area under the concentration-time curve of 82,232 mg . h/liter * days, which is associated with ototoxicity. The standard amikacin doses of 750 to 1,500 mg a day achieved the EC80 in <= 21% of the patients, while a dose of 4 g/day achieved this in 70% of the patients but at the cost of high rates of ototoxicity within a month or two. The susceptibility breakpoint was an MIC of 8 to 16 mg/liter. Thus, amikacin, as currently dosed, has limited efficacy against M. abscessus. It is urgent that different antibiotics be tested using our preclinical model and new regimens developed. PMID- 26643338 TI - Immunomodulatory Role of Clarithromycin in Acinetobacter baumannii Infection via Formation of Neutrophil Extracellular Traps. AB - Macrolide antibiotics have been shown to act as immunomodulatory molecules in various immune cells. However, their effect on neutrophils has not been extensively investigated. In this study, we investigated the role of macrolide antibiotics in the generation of neutrophil extracellular traps (NETs). By assessing ex vivo and in vivo NET formation, we demonstrated that clarithromycin is able to induce NET generation both in vitro and in vivo. Clarithromycin utilizes autophagy in order to form NETs, and these NETs are decorated with antimicrobial peptide LL-37. Clarithromycin-induced NETs are able to inhibit Acinetobacter baumannii growth and biofilm formation in an LL-37-dependent manner. Additionally, LL-37 antimicrobial function depends on NET scaffold integrity. Collectively, these data expand the knowledge on the immunomodulatory role of macrolide antibiotics via the generation of LL-37-bearing NETs, which demonstrate LL-37-dependent antimicrobial activity and biofilm inhibition against A. baumannii. PMID- 26643340 TI - Characterization of Polymyxin B Biodistribution and Disposition in an Animal Model. AB - Despite dose-limiting nephrotoxicity concerns, polymyxin B has resurged as the treatment of last resort for multidrug-resistant Gram-negative bacterial infections. However, the pharmacokinetic, pharmacodynamic, and nephrotoxic properties of polymyxin B still are not thoroughly understood. The objective of this study was to provide additional insights into the overall biodistribution and disposition of polymyxin B in an animal model. Sprague-Dawley rats were dosed with intravenous polymyxin B (3 mg/kg of body weight). Drug concentrations in the serum, urine, bile, and tissue (brain, heart, lungs, liver, spleen, kidneys, and skeletal muscle) samples over time were assayed by a validated methodology. Among all the organs evaluated, polymyxin B distribution was highest in the kidneys. The mean renal tissue/serum polymyxin B concentration ratios were 7.45 (95% confidence interval [CI], 4.63 to 10.27) at 3 h and 19.62 (95% CI, 5.02 to 34.22) at 6 h postdose. Intrarenal drug distribution was examined by immunostaining. Using a ratiometric analysis, proximal tubular cells showed the highest accumulation of polymyxin B (Mander's overlap coefficient, 0.998) among all cell types evaluated. Less than 5% of the administered dose was recovered in urine over 48 h, but all 4 major polymyxin B components were detected in the bile over 4 h. These findings corroborate previous results that polymyxin B is highly accumulated in the kidneys, but the elimination likely is via a nonrenal route. Biliary excretion could be one of the routes of polymyxin B elimination, and this should be further explored. The elucidation of mechanism(s) of drug uptake in proximal tubular cells is ongoing. PMID- 26643341 TI - Is a New Standard Needed for Diffusion Methods for In Vitro Susceptibility Testing of Fosfomycin against Pseudomonas aeruginosa? AB - We analyzed fosfomycin susceptibility results in Pseudomonas aeruginosa clinical isolates obtained by MIC gradient strips and disk diffusion methods using two different inocula, 10(8) and 10(6) CFU/ml, and compared them to the agar dilution reference method. Essential and categorical agreements were 93.6% and 95%, respectively, for the 10(6) CFU/ml alternative inoculum, and they were 67.6% and 78.2%, respectively, for the standard inoculum (10(8) CFU/ml). The use of the 10(6) CFU/ml inoculum improves the agreement values and inhibition zone readings. PMID- 26643342 TI - Inhibition of Efavirenz Metabolism by Sertraline and Nortriptyline and Their Effect on Efavirenz Plasma Concentrations. AB - Between 22 and 45% of HIV-positive subjects are likely to report symptoms of depression. Considering this background, a potential pharmacokinetic interaction between the nonnucleoside reverse transcriptase inhibitor efavirenz (EFV) and two antidepressants, sertraline (SRT) and nortriptyline (NT), was studied. Rats were administered EFV alone or together with the antidepressants, and changes in the plasma levels and pharmacokinetic parameters of EFV were analyzed. Additional in vitro experiments with rat and human hepatic microsomes were carried out to evaluate the inhibitory effect of SRT and NT on EFV metabolism by determining the formation rate of the major EFV metabolite (8-OH-EFV). In vivo studies showed similar increases in the plasma levels of EFV when it was coadministered with SRT or NT. However, the studies using rat hepatic microsomes showed a more potent inhibitory effect of NT than of SRT on the metabolism of EFV, with values for the 50% inhibition constant (IC50) and inhibitory constant (Ki) for NT about 9-fold lower than those for SRT. An equation was deduced that explains the similar in vivo effects of SRT and NT in spite of the different in vitro performance data. Using human hepatic microsomes, the strongest inhibitory effect was observed with SRT. In summary, pharmacokinetic interactions between EFV, SRT, and NT, associated with the inhibition of hepatic metabolism of EFV, have been detected in rats. Both antidepressants also inhibit EFV metabolism in human hepatic microsomes, but additional in vivo studies in humans are required to evaluate the clinical implication of this interaction. PMID- 26643343 TI - Visual Hallucinations Associated with High Posaconazole Concentrations in Serum. PMID- 26643344 TI - High Prevalence of SXT/R391-Related Integrative and Conjugative Elements Carrying blaCMY-2 in Proteus mirabilis Isolates from Gulls in the South of France. AB - The genetic structures involved in the dissemination of blaCMY-2 carried by Proteus mirabilis isolates recovered from different gull species in the South of France were characterized and compared to clinical isolates. blaCMY-2 was identified in P. mirabilis isolates from 27/93 yellow-legged gulls and from 37/65 slender-billed gulls. It was carried by a conjugative SXT/R391-like integrative and conjugative element (ICE) in all avian strains and in 3/7 human strains. Two clinical isolates had the same genetic background as six avian isolates. PMID- 26643345 TI - Population Pharmacokinetics of Rifampin in Pregnant Women with Tuberculosis and HIV Coinfection in Soweto, South Africa. AB - Effective treatment of tuberculosis during pregnancy is essential for preventing maternal and fetal mortality, but little is known about the effects of pregnancy on the disposition of antituberculosis drugs. We explored the effects of pregnancy on the pharmacokinetics of rifampin, the key sterilizing drug in tuberculosis treatment, in Tshepiso, a prospective cohort study involving pregnant HIV-infected women with or without tuberculosis in Soweto, South Africa. Participants receiving standard first-line tuberculosis treatment underwent sparse sampling for rifampin at 37 weeks' gestation or delivery and then postpartum. Cord blood was collected when possible. A population pharmacokinetic model was developed to investigate the effects of pregnancy on rifampin pharmacokinetics. Among the 48 participants, median age and weight were 28 years and 67 kg, respectively. A one-compartment model with first-order elimination, transit compartment absorption, and allometric scaling described the data well. Pregnancy reduced rifampin clearance by 14%. The median (interquartile range) model-estimated rifampin area under the concentration-time curve over 24 h (AUC0 24) during pregnancy or intrapartum was 40.8 h . mg/liter (27.1 to 54.2 h . mg/liter) compared to 37.4 h . mg/liter (26.8 to 50.3 h . mg/liter) postpartum. The maximum concentrations were similar during pregnancy and postpartum. Rifampin was detectable in 36% (8/22) of cord blood samples, and 88% (42/48) of the women had successful treatment outcomes. There was one case of perinatal tuberculosis. In conclusion, rifampin clearance is modestly reduced during the last trimester of pregnancy. Exposures are only slightly increased, so dose adjustment during pregnancy is not needed. Rifampin was detected in cord blood samples when delivery occurred soon after dosing. The consequences of exposure to this potent inducer of metabolizing enzymes among HIV-exposed infants are unclear. PMID- 26643346 TI - Molecular Characterization by Using Next-Generation Sequencing of Plasmids Containing blaNDM-7 in Enterobacteriaceae from Calgary, Canada. AB - Enterobacteriaceae with blaNDM-7 are relatively uncommon and had previously been described in Europe, India, the United States, and Japan. This study describes the characteristics of Enterobacteriaceae (Klebsiella pneumoniae [n = 2], Escherichia coli [n = 2], Serratia marcescens [n = 1], and Enterobacter hormaechei [n = 1] isolates) with blaNDM-7 obtained from 4 patients from Calgary, Canada, from 2013 to 2014. The 46,161-bp IncX3 plasmids with blaNDM-7 are highly similar to other blaNDM-harboring IncX3 plasmids and, interestingly, showed identical structures within the different isolates. This finding may indicate horizontal transmission within our health region, or it may indicate contact with individuals from areas of endemicity within the hospital setting. Patients infected or colonized with bacteria containing blaNDM-7 IncX3 plasmids generate infection control challenges. Epidemiological and molecular studies are required to better understand the dynamics of transmission, the risk factors, and the reservoirs for bacteria harboring blaNDM-7. To the best of our knowledge, this is the first report of S. marcescens and E. hormaechei with blaNDM-7. PMID- 26643347 TI - The Asp20-to-Asn Substitution in the Response Regulator AdeR Leads to Enhanced Efflux Activity of AdeB in Acinetobacter baumannii. AB - Overexpression of the resistance-nodulation-cell division-type efflux pump AdeABC is often associated with multidrug resistance in Acinetobacter baumannii and has been linked to mutations in the genes encoding the AdeRS two-component system. In a previous study, we reported that the Asp20->Asn amino acid substitution in the response regulator AdeR is associated with adeB overexpression and reduced susceptibility to the antimicrobials levofloxacin, tigecycline, and trimethoprim sulfamethoxazole. To further characterize the effect of the Asp20->Asn substitution on antimicrobial susceptibility, the expression of the efflux genes adeB, adeJ, and adeG, and substrate accumulation, four plasmid constructs [containing adeR(Asp20)S, adeR(Asn20)S, adeR(Asp20)SABC, and adeR(Asn20)SABC] were introduced into the adeRSABC-deficient A. baumannii isolate NIPH 60. Neither adeRS construct induced changes in antimicrobial susceptibility or substrate accumulation from that for the vector-only control. The adeR(Asp20)SABC transformant showed reduced susceptibility to 6 antimicrobials and accumulated 12% less ethidium than the control, whereas the Asn20 variant showed reduced susceptibility to 6 of 8 antimicrobial classes tested, and its ethidium accumulation was only 72% of that observed for the vector-only construct. adeB expression was 7-fold higher in the adeR(Asn20)SABC transformant than in its Asp20 variant. No changes in adeG or adeJ expression or in acriflavine or rhodamine 6G accumulation were detected. The antimicrobial susceptibility data suggest that AdeRS does not regulate any resistance determinants other than AdeABC. Furthermore, the characterization of the Asp20->Asn20 substitution proves that the reduced antimicrobial susceptibility previously associated with this substitution was indeed caused by enhanced efflux activity of AdeB. PMID- 26643348 TI - Bacteriophage Combinations Significantly Reduce Clostridium difficile Growth In Vitro and Proliferation In Vivo. AB - The microbiome dysbiosis caused by antibiotic treatment has been associated with both susceptibility to and relapse of Clostridium difficile infection (CDI). Bacteriophage (phage) therapy offers target specificity and dose amplification in situ, but few studies have focused on its use in CDI treatment. This mainly reflects the lack of strictly virulent phages that target this pathogen. While it is widely accepted that temperate phages are unsuitable for therapeutic purposes due to their transduction potential, analysis of seven C. difficile phages confirmed that this impact could be curtailed by the application of multiple phage types. Here, host range analysis of six myoviruses and one siphovirus was conducted on 80 strains representing 21 major epidemic and clinically severe ribotypes. The phages had complementary coverage, lysing 18 and 62 of the ribotypes and strains tested, respectively. Single-phage treatments of ribotype 076, 014/020, and 027 strains showed an initial reduction in the bacterial load followed by the emergence of phage-resistant colonies. However, these colonies remained susceptible to infection with an unrelated phage. In contrast, specific phage combinations caused the complete lysis of C. difficile in vitro and prevented the appearance of resistant/lysogenic clones. Using a hamster model, the oral delivery of optimized phage combinations resulted in reduced C. difficile colonization at 36 h postinfection. Interestingly, free phages were recovered from the bowel at this time. In a challenge model of the disease, phage treatment delayed the onset of symptoms by 33 h compared to the time of onset of symptoms in untreated animals. These data demonstrate the therapeutic potential of phage combinations to treat CDI. PMID- 26643349 TI - Multiyear, Multinational Survey of the Incidence and Global Distribution of Metallo-beta-Lactamase-Producing Enterobacteriaceae and Pseudomonas aeruginosa. AB - Metallo-beta-lactamases (MBLs) hydrolyze all classes of beta-lactams except monobactams and are not inhibited by classic serine beta-lactamase inhibitors. Gram-negative pathogens isolated from patient infections were collected from 202 medical centers in 40 countries as part of a global surveillance study from 2012 to 2014. Carbapenem-nonsusceptible Enterobacteriaceae and Pseudomonas aeruginosa were characterized for bla genes encoding VIM, IMP, NDM, SPM, and GIM variants using PCR and sequencing. A total of 471 MBL-positive isolates included the following species (numbers of isolates are in parentheses): P. aeruginosa (308), Klebsiella spp. (85), Enterobacter spp. (39), Proteeae (16), Citrobacter freundii (12), Escherichia coli (6), and Serratia marcescens (5) and were submitted by sites from 34 countries. Of these, 69.6% were collected in 9 countries (numbers of isolates are in parentheses): Russia (72), Greece (61), Philippines (54), Venezuela (29), and Kuwait, Nigeria, Romania, South Africa, and Thailand (20 to 25 isolates each). Thirty-two different MBL variants were detected (14 VIM, 14 IMP, and 4 NDM enzymes). Seven novel MBL variants were encountered in the study, each differing from a previously reported variant by one amino acid substitution: VIM-42 (VIM-1 [V223I]), VIM-43 (VIM-4 [A24V]), VIM-44 (VIM-2 [K257N]), VIM-45 (VIM-2 [T35I]), IMP-48 (IMP-14 [I69T]), IMP-49 (IMP-18 [V49F]), and NDM-16 (NDM-1 [R264H]). The in vitro activities of all tested antibiotics against MBL-positive Enterobacteriaceae were significantly reduced with the exception of that of aztreonam-avibactam (MIC90, 0.5 to 1 MUg/ml), whereas colistin was the most effective agent against MBL-positive P. aeruginosa isolates (>97% susceptible). Although the global percentage of isolates encoding MBLs remains relatively low, their detection in 12 species, 34 countries, and all regions participating in this surveillance study is concerning. PMID- 26643350 TI - Characterization of a Novel Composite Staphylococcal Cassette Chromosome mec in Methicillin-Resistant Staphylococcus pseudintermedius from Thailand. AB - A novel staphylococcal cassette chromosome mec (SCCmec) composite island (SCCmecAI16-SCCczrAI16-CI) was identified in Staphylococcus pseudintermedius. Four integration site sequences for SCC subdivided the 60,734-bp island into 41,232-bp SCCmecAI16, 19,400-bp SCCczrAI16, and 102-bp SCC-likeAI16 elements. SCCmecAI16 represents a new combination of ccrA1B3 genes with a class A mec complex. SCCczrAI16 contains ccrA1B6 and genes related to restriction modification and heavy metal resistance. SCCmecAI16-SCCczrAI16-CI was found in methicillin-resistant S. pseudintermedius sequence type 112 (ST112) and ST111 isolated from dogs and veterinarians in Thailand. PMID- 26643351 TI - Next-Generation Sequencing and Comparative Analysis of Sequential Outbreaks Caused by Multidrug-Resistant Acinetobacter baumannii at a Large Academic Burn Center. AB - Next-generation sequencing (NGS) analysis has emerged as a promising molecular epidemiological method for investigating health care-associated outbreaks. Here, we used NGS to investigate a 3-year outbreak of multidrug-resistant Acinetobacter baumannii (MDRAB) at a large academic burn center. A reference genome from the index case was generated using de novo assembly of PacBio reads. Forty-six MDRAB isolates were analyzed by pulsed-field gel electrophoresis (PFGE) and sequenced using an Illumina platform. After mapping to the index case reference genome, four samples were excluded due to low coverage, leaving 42 samples for further analysis. Multilocus sequence types (MLST) and the presence of acquired resistance genes were also determined from the sequencing data. A transmission network was inferred from genomic and epidemiological data using a Bayesian framework. Based on single-nucleotide variant (SNV) differences, this MDRAB outbreak represented three sequential outbreaks caused by distinct clones. The first and second outbreaks were caused by sequence type 2 (ST2), while the third outbreak was caused by ST79. For the second outbreak, the MLST and PFGE results were discordant. However, NGS-based SNV typing detected a recombination event and consequently enabled a more accurate phylogenetic analysis. The distribution of resistance genes varied among the three outbreaks. The first- and second-outbreak strains possessed a blaOXA-23-like group, while the third-outbreak strains harbored a blaOXA-40-like group. NGS-based analysis demonstrated the superior resolution of outbreak transmission networks for MDRAB and provided insight into the mechanisms of strain diversification between sequential outbreaks through recombination. PMID- 26643352 TI - Sterilizing Activity of Pyrazinamide in Combination with First-Line Drugs in a C3HeB/FeJ Mouse Model of Tuberculosis. AB - Pyrazinamide (PZA) is a key sterilizing drug in first-line tuberculosis (TB) regimens and exerts its activity entirely during the first 2 months in human infections. We recently described the reduced activity of PZA in C3HeB/FeJ mice with large caseous tubercles due to neutral pH. Here, we aimed to determine the contribution of PZA to the sterilizing activity of the first-line TB regimen in C3HeB/FeJ and BALB/c mice. Three regimens were compared (in combinations: R, rifampin; H, isoniazid; E, ethambutol; Z, pyrazinamide; with numbers indicating the treatment duration, in months): 2RHEZ/4RH, 2RHE/4RH, and 2RHEZ/4RHZ. Lung CFU counts were assessed after 0 and 2 months of treatment, and relapse rates were assessed 3 months after 3, 4.5, and 6 months of treatment. The relapse rates after 3 months of treatment were 53% and 95% in C3HeB/FeJ mice receiving 2RHEZ/1RH and 2RHE/1RH, respectively, and 67%, 100%, and 80% in BALB/c receiving 2RHEZ/1RH, 2RHE/1RH, and 2RHEZ/1RHZ, respectively. The relapse rates after 4.5 months of treatment were 32%, 20%, and 0% in C3HeB/FeJ mice receiving 2RHEZ/2.5RH, 2RHE/2.5RH, and 2RHEZ/2.5RHZ, respectively, and 0% and 67% in BALB/c receiving 2RHEZ/2.5RH and 2RHE/2.5RH, respectively. The month-6 relapse rates were 0%, 13%, and 0% in C3HeB/FeJ mice given 2RHEZ/4RH, 2RHE/4RH, and 2RHEZ/4RHZ, respectively, and 7% in BALB/c mice receiving 2RHE/4RH. The addition of PZA shortens the duration of treatment needed to prevent relapse in both mouse strains. However, while its contribution is limited to the first 2 months of treatment in BALB/c mice, continuing PZA beyond the first 2 months is beneficial in C3HeB/FeJ mice by preventing relapse among those with the highest disease burden. PMID- 26643353 TI - White Matter Alterations in Infants at Risk for Developmental Dyslexia. AB - Developmental dyslexia (DD) is a heritable condition characterized by persistent difficulties in learning to read. White matter alterations in left-lateralized language areas, particularly in the arcuate fasciculus (AF), have been observed in DD, and diffusion properties within the AF correlate with (pre-)reading skills as early as kindergarten. However, it is unclear how early these alterations can be observed. We investigated white matter structure in 14 infants with (FHD+; ages 6.6-17.6 months) and 18 without (FHD-; ages 5.1-17.6 months) familial risk for DD. Diffusion scans were acquired during natural sleep, and early language skills were assessed. Tractography for bilateral AF was reconstructed using manual and automated methods, allowing for independent validation of results. Fractional anisotropy (FA) was calculated at multiple nodes along the tracts for more precise localization of group differences. The analyses revealed significantly lower FA in the left AF for FHD+ compared with FHD- infants, particularly in the central portion of the tract. Moreover, expressive language positively correlated with FA across groups. Our results demonstrate that atypical brain development associated with DD is already present within the first 18 months of life, suggesting that the deficits associated with DD may result from altered structural connectivity in left-hemispheric regions. PMID- 26643354 TI - Is There a Nonadditive Interaction Between Spontaneous and Evoked Activity? Phase Dependence and Its Relation to the Temporal Structure of Scale-Free Brain Activity. AB - The aim of our study was to use functional magnetic resonance imaging to investigate how spontaneous activity interacts with evoked activity, as well as how the temporal structure of spontaneous activity, that is, long-range temporal correlations, relate to this interaction. Using an extremely sparse event-related design (intertrial intervals: 52-60 s), a novel blood oxygen level-dependent signal correction approach (accounting for spontaneous fluctuations using pseudotrials) and phase analysis, we provided direct evidence for a nonadditive interaction between spontaneous and evoked activity. We demonstrated the discrepancy between the present and previous observations on why a linear superposition between spontaneous and evoked activity can be seen by using co occurring signals from homologous brain regions. Importantly, we further demonstrated that the nonadditive interaction can be characterized by phase dependent effects of spontaneous activity, which is closely related to the degree of long-range temporal correlations in spontaneous activity as indexed by both power-law exponent and phase-amplitude coupling. Our findings not only contribute to the understanding of spontaneous brain activity and its scale-free properties, but also bear important implications for our understanding of neural activity in general. PMID- 26643355 TI - 5-Aminolevulinic acid regulates the inflammatory response and alloimmune reaction. AB - 5-Aminolevulinic acid (5-ALA) is a naturally occurring amino acid and precursor of heme and protoporphyrin IX (PpIX). Exogenously administrated 5-ALA increases the accumulation of PpIX in tumor cells specifically due to the compromised metabolism of 5-ALA to heme in mitochondria. PpIX emits red fluorescence by the irradiation of blue light and the formation of reactive oxygen species and singlet oxygen. Thus, performing a photodynamic diagnosis (PDD) and photodynamic therapy (PDT) using 5-ALA have given rise to a new strategy for tumor diagnosis and therapy. In addition to the field of tumor therapy, 5-ALA has been implicated in the treatment of inflammatory disease, autoimmune disease and transplantation due to the anti-inflammation and immunoregulation properties that are elicited with the expression of heme oxygenase (HO)-1, an inducible enzyme that catalyzes the rate-limiting step in the oxidative degradation of heme to free iron, biliverdin and carbon monoxide (CO), in combination with sodium ferrous citrate (SFC), because an inhibitor of HO-1 abolishes the effects of 5-ALA. Furthermore, NF-E2-related factor 2 (Nrf2), mitogen-activated protein kinase (MAPK), and heme are involved in the HO-1 expression. Biliverdin and CO are also known to have anti-apoptotic, anti-inflammatory and immunoregulatory functions. We herein review the current use of 5-ALA in inflammatory diseases, transplantation medicine, and tumor therapy. PMID- 26643356 TI - Fabrication of Transparent Multilayer Circuits by Inkjet Printing. AB - Conductive microcables embedded in a transparent film are fabricated by inkjet printing silver-nanoparticle ink into a liquid poly(dimethylsiloxane) (PDMS) precursor substrate. By controlling the spreading of the ink droplet and the rheological properties of the liquid substrate, transparent multilayer circuits composed of high-resolution embedded cables are achieved using a commercial inkjet printer. This facile strategy provides a new avenue for inkjet printing of highly integrated and transparent electronics. PMID- 26643357 TI - Relationship between cardiac autonomic function and cognitive function in Alzheimer's disease. AB - AIM: Alzheimer's disease (AD) affects many central nervous structures and neurotransmitter systems. These changes affect not only cognitive function, but also cardiac autonomic function. However, the functional relationship between cardiac autonomic function and cognition in AD has not yet been investigated. The objective of the present study was to evaluate the association between cardiac autonomic function measured by heart rate variability and cognitive function in AD. METHODS: A total of 78 AD patients were recruited for this study. Cardiac autonomic function was evaluated using heart rate variability analysis. Multiple linear regression analysis was used to model the association between heart rate variability and cognitive function (global cognitive function, memory, executive function and processing speed), after adjustment for covariates. RESULTS: Global cognitive function was negatively associated with sympathetic modulation (low-to high frequency power ratio). Memory performance was positively associated with parasympathetic modulation (high frequency power) and negatively associated with sympathetic modulation (low-to-high frequency power ratio). These associations were independent of age, sex, educational years, diabetes, hypertension and cholinesterase inhibitor use. CONCLUSIONS: Cognitive function, especially in the areas of memory, is associated with cardiac autonomic function in AD. Specifically, lower cognitive performance was found to be associated with significantly higher cardiac sympathetic and lower parasympathetic function in AD. Geriatr Gerontol Int 2017; 17: 92-98. PMID- 26643358 TI - Description of total population hospital admissions for cleft lip and/or palate in Australia. AB - BACKGROUND: Orofacial clefts are a group of frequently observed congenital malformations often requiring multiple hospital admissions over the lifespan of affected individuals. The aim of this study was to describe the total-population hospital admissions with principal diagnosis of cleft lip and/or palate in Australia over a 10 year period. METHODS: Data for admissions to hospitals were obtained from the Australian Institute of Health and Welfare National Hospital Morbidity Database (July 2000 to June 2010). The outcome variable was a hospital separation with the principal diagnosis of cleft palate, cleft lip or cleft lip and palate (ICD-10-AM diagnosis codes Q35-Q37 respectively). Trends in rates of admission and length of stay by age, gender and cleft type were investigated. RESULTS: A total of 11, 618 admissions were identified; cleft palate (4,454; 0.22 per 10,000 people per year), cleft lip (2,251; 0.11) and cleft lip and palate (4,913; 0.25). Admission age ranged from birth to 79 years with males more frequently admitted. Most admissions occurred prior to adolescence in cleft palate and cleft lip and through to late teens in cleft lip and palate, declining for all groups after 25 years. CONCLUSIONS: This study identified population level trends in hospital separations for orofacial cleft diagnosis in Australia. PMID- 26643359 TI - How mental health literacy and experience of mental illness relate to stigmatizing attitudes and social distance towards people with depression or psychosis: A cross-sectional study. AB - Background Evidence suggests that mental health literacy among the public is low, and stigmatizing attitudes are widespread. So far the effects of anti-stigma campaigns are small, and studies demonstrate that negative attitudes have been quite stable through recent decades. Aims To investigate the relationships between mental health literacy, experience of mental illness and stigmatizing attitudes/social distance towards people with depression or psychosis. Methods A cross-sectional study in which staff members from public services in Sweden (n = 1027) completed questionnaires covering demographic data, self-reported experience of mental illness, identification of a vignette for depression or psychosis, beliefs about helpful interventions for the illness presented in the vignette, and attitudes and social distance towards people with the illness. Results About 50% of participants could identify depression and less than 40% psychosis. A higher degree of mental health literacy was related to less stigma and social distance but mainly towards people with depression. A similar relationship was shown for having personal or family experience of mental illness and attitudes/social distance. Negative attitudes and social distance were significantly higher in all aspects measured towards a person with psychosis than a person with depression. Conclusions A higher degree of mental health literacy relates to more positive attitudes and less desire for social distance towards people with depression. The differences between depression and psychosis should be taken into account in anti-stigma interventions. PMID- 26643360 TI - Reprogramming mitochondrial metabolism in macrophages as an anti-inflammatory signal. AB - Mitochondria are master regulators of metabolism. Mitochondria generate ATP by oxidative phosphorylation using pyruvate (derived from glucose and glycolysis) and fatty acids (FAs), both of which are oxidized in the Krebs cycle, as fuel sources. Mitochondria are also an important source of reactive oxygen species (ROS), creating oxidative stress in various contexts, including in the response to bacterial infection. Recently, complex changes in mitochondrial metabolism have been characterized in mouse macrophages in response to varying stimuli in vitro. In LPS and IFN-gamma-activated macrophages (M1 macrophages), there is decreased respiration and a broken Krebs cycle, leading to accumulation of succinate and citrate, which act as signals to alter immune function. In IL-4 activated macrophages (M2 macrophages), the Krebs cycle and oxidative phosphorylation are intact and fatty acid oxidation (FAO) is also utilized. These metabolic alterations in response to the nature of the stimulus are proving to be determinants of the effector functions of M1 and M2 macrophages. Furthermore, reprogramming of macrophages from M1 to M2 can be achieved by targeting metabolic events. Here, we describe the role that metabolism plays in macrophage function in infection and immunity, and propose that reprogramming with metabolic inhibitors might be a novel therapeutic approach for the treatment of inflammatory diseases. PMID- 26643361 TI - Reliability, Agreement and Minimal Detectable Change of the Timed Up & Go and the 10-Meter Walk Tests in Older Patients with COPD. AB - This study aimed to determine the interrater and intrarater reliability and agreement and the minimal detectable change (MDC) of the Timed Up & Go (TUG) test and the 10-Meter Walk Test (10MWT) in older patients with Chronic Obstructive Pulmonary Disease (COPD). Patients (>= 60 years old) living in the community were asked to attend 2 sessions with 48-72-hour interval. In session 1, participants completed the TUG and 10MWT twice (2 trials) and were assessed by 2 raters. In session 2, they repeated the tests twice and were assessed by 1 rater. Interrater and intrarater reliability were calculated for the exact scores (using data from trial 1) and mean scores (mean of 2 trials) using Intraclass Correlation Coefficients (ICC2,1 and ICC2,2, respectively). Interrater and intrarater agreement were explored with the Bland & Altman method. The MDC95 was calculated from the standard error of measurement. Sixty participants (72.43 +/- 6.90 years old) completed session 1 and 41 participants session 2. Excellent ICC values were found for the TUG test (interrater: ICC2,1 = 0.997 ICC2,2 = 0.999; intrarater: ICC2,1 = 0.921 ICC2,2 = 0.964) and 10MWT (interrater: ICC2,1 = 0.992 ICC2,2 = 0.997; intrarater: ICC2,1 = 0.903 ICC2,2 = 0.946). Good interrater and intrarater agreement was also found for both tests. The MDC95 was 2.68 s and 1.84 s for the TUG and 0.40 m/s and 0.30 m/s for the 10MWT considering the exact and mean scores, respectively. Findings suggest that the TUG test and the 10MWT are reliable and have acceptable measurement error. Therefore, these measures may be used to assess functional balance (TUG) and gait (10MWT) deficits in older patients with COPD. PMID- 26643362 TI - [The Ulm trauma track : Trauma care and research as focal points for medical students]. AB - BACKGROUNDS AND OBJECTIVES: As part of the expansion of the site-specific education profile of the medical curriculum MED@ULM of the University of Ulm, a new track "trauma care and trauma research" was established in the winter semester 2012/2013. The acceptance of the track was evaluated during the winter semester 2013/2014. MATERIAL AND METHODS: The 6-semester track extends the existing curriculum by offering subjects in trauma management and trauma research to students of human medicine. A central aim of the track is to promote medical professional competence, expertise in emergency care and competence in trauma related scientific work and research. Central learning contents could be intensified in newly established emergency simulation training. Additionally, participating students have to perform a doctoral thesis on an obligatory trauma related experimental subject. A first analysis study focusing on the learning style of the participating students (n = 17) and a control group consisting of members of the same semester (n = 20) was performed using the Kolb learning style inventory. In a validated evaluation in the winter semesters 2013/2014 and 2014/2015, the students were asked about their expectations and experience with the track, criticisms, suggestions and satisfaction with the study conditions. The data were analyzed using descriptive statistics. RESULTS: The analysis of the students' preferred learning styles revealed no differences between track students and the control group. Most of the students considered the track as a form of personal further education. The students had high expectations of practical skills with relevance to the clinical daily routine, learning scientific methods and preparing their thesis. The track students were more critical with regard to the study conditions than the control group students, although the track students of the third semester still judged their studies to be more interesting than the track students of the first semester and the control group. CONCLUSION: With the introduction of the new trauma track into the curriculum of the medical curriculum MED@ULM of the University of Ulm, a further possibility for medical students to focus on their own individual options was established. At least half of the track students wanted to be later active in the triad of patient care, teaching and research. Further investigations are necessary to determine whether the establishment of the trauma track has a positive influence on the number of new recruits in trauma surgery and anesthesiology. PMID- 26643363 TI - [Comprehensive certification in the TraumaNetwork DGU. Milestones achieved and new challenges]. PMID- 26643364 TI - How to block the ways to eating disorders. PMID- 26643365 TI - Structural polymorphisms and distinct genomic composition suggest recurrent origin and ongoing evolution of B chromosomes in the Prospero autumnale complex (Hyacinthaceae). AB - Supernumerary B chromosomes (Bs) are genomic parasitic components, originating from the A complement via chromosomal rearrangements, which follow their own evolutionary trajectories. They often contain repetitive DNAs, some shared with regular chromosomes and some newly evolved. Genomic composition, origin and evolution of Bs have been analysed in the chromosomally variable Prospero autumnale complex. Two rDNAs and a satellite DNA (PaB6) from regular chromosomes were mapped to Bs of 26 plants from three diploid cytotypes, their hybrids and polyploid derivatives. In homoploid diploid hybrids, genomic in situ hybridization (GISH) allowed B painting with the parental DNAs. Bs were structurally variable and highly enriched in 5S rDNA and satDNA PaB6, and rarely in 35S rDNA. Eleven combinations of rDNA and PaB6 localization were observed. The quantities of PaB6 in Bs and regular chromosomes were not correlated, suggesting amplification mechanisms other than recombination. PaB6 and 5S rDNA amounts increased with increasing ploidy level. GISH revealed two independent origins of Bs. The structural variation, repeat content, repeat-type fluctuations and differing genomic affinities of Bs in different cytotypes suggest that they represent young proto-B chromosomes. Bs in P. autumnale probably form recurrently as by-products of the extensive genome restructuring within this chromosomally variable species complex. PMID- 26643366 TI - Increasing access to Cognitive Behaviour Therapy in Low and Middle Income Countries: A strategic framework. AB - Cognitive Behaviour Therapy has been demonstrated to be an effective intervention in outpatient and inpatient settings for a wide range of presenting mental health problems including depression, Obsessive Compulsive Disorder, Post traumatic Stress Disorder, Social Anxiety Disorder, Panic Disorder and Somatorform Disorder. There is likely to be an unmet need for this therapeutic approach in most Low and Middle Income Countries (LMIC). However, the training of therapists to deliver this intervention has historically been a lengthy and expensive process, with already highly trained staff such as psychiatrists and psychologists undertaking additional training of up to one year duration in order to develop expertise in this area. This paper proposes that a model where training, supervision, leadership and service evaluation is provided by a small number of highly trained staff to front-line non-specialist staff who will then deliver manualised therapy. These front-line staff may also be conceptualised as part of a stepped care model where self-help and manualised therapy approaches are used in the first instance. Where patient functioning does not improve there is then the possibility of being stepped-up for treatment by a more specialised and highly trained therapist. This approach may help in meeting the huge mental health treatment gap in LMIC. This paper also suggests that lessons learnt from the dissemination of behaviourally informed parenting interventions internationally can be applied to the dissemination of this therapeutic approach. PMID- 26643368 TI - Exome capture sequencing identifies a novel CCM1 mutation in a Chinese family with multiple cerebral cavernous malformations. AB - PURPOSE: Cerebral cavernous malformations (CCMs) are vascular anomalies predominantly in the central nervous system but may include lesions in other tissues, such as the retina, skin and liver. The main clinical manifestations include seizures, hemorrhage, recurrent headaches and focal neurological deficits. Previous studies of familial CCMs (FCCMs) have mainly reported in Hispanic and Caucasian cases. Here, we report on FCCMs in a Chinese family further characterized by a novel CCM1 gene mutation. MATERIALS AND METHODS: We investigated clinical and neuroradiological features of a Chinese family of 30 members. Furthermore, we used exome capture sequencing to identify the causing gene. The CCM1 mRNA expression level in three patients of the family and 10 wild type healthy individuals were detected by real-time quantitative polymerase chain reaction (real-time RT-PCR). RESULTS: Brain magnetic resonance imaging demonstrated multiple intracranial lesions in seven members. The clinical manifestation of CCM was found in five of these cases, including recurrent headaches, weakness, hemorrhage and seizures. Moreover, we identified a novel nonsense mutation c.1159G>T (p. E387*) in the CCM1 gene in the pedigree. Based on real-time RT-PCR results, we have found that the CCM1 mRNA expression level in three patients was reduced by 35% than that in wild-type healthy individuals. CONCLUSIONS: Our finding suggests that the novel nonsense mutation c.1159G>T in CCM1 gene is associated with FCCM, and that CCM1 haploinsufficiency may be the underlying mechanism of CCMs. Furthermore, it also demonstrates that exome capture sequencing is an efficient and direct diagnostic tool to identify causes of genetically heterogeneous diseases. PMID- 26643367 TI - Erythropoietin alleviates hepatic insulin resistance via PPARgamma-dependent AKT activation. AB - Erythropoietin (EPO) has beneficial effects on glucose metabolism and insulin resistance. However, the mechanism underlying these effects has not yet been elucidated. This study aimed to investigate how EPO affects hepatic glucose metabolism. Here, we report that EPO administration promoted phosphatidylinositol 3-kinase (PI3K)/AKT pathway activation in palmitic acid (PA)-treated HepG2 cells and in the liver of high-fat diet (HFD)-fed mice, whereas adenovirus-mediated silencing of the erythropoietin receptor (EPOR) blocked EPO-induced AKT signalling in HepG2 cells. Importantly, a peroxisome proliferator-activated receptor gamma (PPARgamma) antagonist and PPARgamma small interfering RNA (siRNA) abrogated the EPO-induced increase in p-AKT in HepG2 cells. Lentiviral vector mediated hepatic PPARgamma silencing in HFD-fed C57BL/6 mice impaired EPO mediated increases in glucose tolerance, insulin sensitivity and hepatic AKT activation. Furthermore, EPO activated the AMP-activated protein kinase (AMPK)/sirtuin 1 (SIRT1) signalling pathway, and AMPKalpha and SIRT1 knockdown each attenuated the EPO-induced PPARgamma expression and deacetylation and PPARgamma-dependent AKT activation in HepG2 cells. In summary, these findings suggest that PPARgamma is involved in EPO/EPOR-induced AKT activation, and targeting the PPARgamma/AKT pathway via EPO may have therapeutic implications for hepatic insulin resistance and type 2 diabetes. PMID- 26643369 TI - The role of red meat in the diet: nutrition and health benefits. AB - Red meat has been an important part of the human diet throughout human evolution. When included as part of a healthy, varied diet, red meat provides a rich source of high biological value protein and essential nutrients, some of which are more bioavailable than in alternative food sources. Particular nutrients in red meat have been identified as being in short supply in the diets of some groups of the population. The present paper discusses the role of red meat in the diets of young infants, adolescents, women of childbearing age and older adults and highlights key nutrients red meat can provide for these groups. The role of red meat in relation to satiety and weight control is discussed as the inclusion of lean red meat in a healthy, varied diet may help weight loss as part of an energy reduced diet. A summary of the UK advice on the amount of red meat that can be consumed as part of a healthy, varied diet is also provided. PMID- 26643370 TI - Quantification of the boron speciation in alkali borosilicate glasses by electron energy loss spectroscopy. AB - Transmission electron microscopy and related analytical techniques have been widely used to study the microstructure of different materials. However, few research works have been performed in the field of glasses, possibly due to the electron-beam irradiation damage. In this paper, we have developed a method based on electron energy loss spectroscopy (EELS) data acquisition and analyses, which enables determination of the boron speciation in a series of ternary alkali borosilicate glasses with constant molar ratios. A script for the fast acquisition of EELS has been designed, from which the fraction of BO4 tetrahedra can be obtained by fitting the experimental data with linear combinations of the reference spectra. The BO4 fractions (N4) obtained by EELS are consistent with those from (11)B MAS NMR spectra, suggesting that EELS can be an alternative and convenient way to determine the N4 fraction in glasses. In addition, the boron speciation of a CeO2 doped potassium borosilicate glass has been analyzed by using the time-resolved EELS spectra. The results clearly demonstrate that the BO4 to BO3 transformation induced by the electron beam irradiation can be efficiently suppressed by doping CeO2 to the borosilicate glasses. PMID- 26643371 TI - Factors confounding fluorescein-guided malignant glioma resections: edema bulk flow, dose, timing, and now: imaging hardware? PMID- 26643372 TI - Wide variation in activity of antibiotic discs from nine manufacturers. PMID- 26643373 TI - Thermal catalytic oxidation of octachloronaphthalene over anatase TiO2 nanomaterial and its hypothesized mechanism. AB - As an environmentally-green technology, thermal catalytic oxidation of octachloronaphthalene (CN-75) over anatase TiO2 nanomaterials was investigated at 300 degrees C. A wide range of oxidation intermediates, which were investigated using various techniques, could be of three types: naphthalene-ring, single benzene-ring, and completely ring-opened products. Reactive oxygen species on anatase TiO2 surface, such as O2(-*) and O(2-), contributed to oxidative degradation. Based on these findings, a novel oxidation degradation mechanism was proposed. The reaction at (101) surface of anatase TiO2 was used as a model. The naphthalene-ring oxidative products with chloronaphthols and hydroxyl pentachloronaphthalene-dione, could be formed via attacking the carbon of naphthalene ring at one or more positions by nucleophilic O(2-). Lateral cleavage of the naphthalene ring at different C1-C10 and C4-C9, C1-C2 and C4-C9, C1-C2 or and C3-C4 bond positions by electrophilic O2(-*) could occur. This will lead to the formation of tetrachlorophenol, tetrachloro-benzoic acid, tetrachloro phthalaldehyde, and tetrachloro-acrolein-benzoic acid, partially with further transformation into tetrachlorobenzene-dihydrodiol and tetrachloro-salicylic acid. Unexpectedly, the symmetric half section of CN-75 could be completely remained with generating the intricate oxidative intermediates characteristically containing tetrachlorobenzene structure. Complete cleavage of naphthalene ring could produce the ring-opened products, such as formic and acetic acids. PMID- 26643374 TI - Epileptic auras: phenomenology and neurophysiology. AB - This review discusses the phenomenology, neurophysiology, and localization of epileptic auras with particular emphasis on how auras can manifest as part of an epileptic network. Epileptic auras, as the first clinical symptom of a seizure, may lead us to infer the site of seizure onset. At the same time, auras can also be a result of activation or alteration in an epileptic network. They can be highly specific or ill-defined in symptomatology. They occur as a result of limited seizure activation, allowing access of the neural signal to the conscious brain. An understanding of epileptic auras offers a window into understanding fundamental brain functions, and helps the clinician at the bedside to make appropriate diagnostic and therapeutic choices. PMID- 26643375 TI - Aqueous Sulfate Separation by Sequestration of [(SO4 )2 (H2 O)4 ]4- Clusters within Highly Insoluble Imine-Linked Bis-Guanidinium Crystals. AB - Selective crystallization of sulfate with a simple bis-guanidinium ligand, self assembled in situ from terephthalaldehyde and aminoguanidinium chloride, was employed as an effective way to separate the highly hydrophilic sulfate anion from aqueous solutions. The resulting bis-iminoguanidinium sulfate salt has exceptionally low aqueous solubility (Ksp =2.4*10-10 ), comparable to that of BaSO4 . Single-crystal X-ray diffraction analysis showed the sulfate anions are sequestered as [(SO4 )2 (H2 O)4 ]4- clusters within the crystals. Variable temperature solubility measurements indicated the sulfate crystallization is slightly endothermic (DeltaHcryst =3.7 kJ mol-1 ), thus entropy driven. The real world utility of this crystallization-based approach for sulfate separation was demonstrated by removing up to 99 % of sulfate from seawater in a single step. PMID- 26643376 TI - Risking Life and Limb: A Case of Spontaneous Diabetic Muscle Infarction (Diabetic Myonecrosis). AB - Diabetic muscle infarction, also known as diabetic myonecrosis, is a microvascular complication of poorly controlled diabetes mellitus characterized by unilateral limb pain and swelling. Because these symptoms closely mimic cellulitis and thromboembolism, diagnosis is often delayed or missed altogether, leading to increased morbidity and inappropriate treatment. We describe a case of unilateral limb pain and swelling due to diabetic muscle infarction in a 36-year old patient with poorly controlled diabetes mellitus. We also review the literature on the diagnosis, prognosis, and management of this under-recognized condition. PMID- 26643377 TI - Susceptible genes of restless legs syndrome in migraine. AB - Objective Several genetic variants have been found to increase the risk of restless legs syndrome (RLS). The aim of the present study was to determine if these genetic variants were also associated with the comorbidity of RLS and migraine in patients. Methods Thirteen single-nucleotide polymorphisms (SNPs) at six RLS risk loci ( MEIS1, BTBD9, MAP2K5, PTPRD, TOX3, and an intergenic region on chromosome 2p14) were genotyped in 211 migraine patients with RLS and 781 migraine patients without RLS. Association analyses were performed for the overall cohort, as well as for the subgroups of patients who experienced migraines with and without aura and episodic migraines (EMs) vs. chronic migraines (CMs). In order to verify which genetic markers were potentially related to the incidence of RLS in migraine patients, multivariate regression analyses were also performed. Results Among the six tested loci, only MEIS1 was significantly associated with RLS. The most significant SNP of MEIS1, rs2300478, increased the risk of RLS by 1.42-fold in the overall cohort ( p = 0.0047). In the subgroup analyses, MEIS1 augmented the risk of RLS only in the patients who experienced EMs (odds ratio (OR) = 1.99, p = 0.0004) and not those experiencing CMs. Multivariate regression analyses further showed that rs2300478 in MEIS1 (OR = 1.39, p = 0.018), a CM diagnosis (OR = 1.52, p = 0.022), and depression (OR = 1.86, p = 0.005) were independent predictors of RLS in migraine. Conclusions MEIS1 variants were associated with an increased risk of RLS in migraine patients. It is possible that an imbalance in iron homeostasis and the dopaminergic system may represent a link between RLS incidence and migraines. PMID- 26643378 TI - Premonitory symptoms in migraine: A cross-sectional study in 2714 persons. AB - AIM: To describe the frequency and number of premonitory symptoms (PS) in migraine, the co-occurrence of different PS, and their association with migraine related factors. METHODS: In this cross-sectional study, a validated questionnaire was sent to Finnish migraine families between 2002 and 2013 to obtain data on 14 predefined PS, migraine diagnoses, demographic factors, and migraine characteristics. The estimated response rate was 80%. RESULTS: Out of 2714 persons, 2223 were diagnosed with migraine. Among these, 77% reported PS, with a mean number of 3.0 symptoms compared to 30% (p < 0.001) and 0.5 symptoms (p < 0.001) among 491 persons with non-migraine headaches. Yawning was the most commonly reported symptom (34%) among migraineurs. Females reported PS more frequently than males (81 versus 64%, p < 0.001) and experienced a higher number of different symptoms (mean 3.3 versus 1.8, p < 0.001). All measures of migraine severity were associated with a higher burden of PS. Light and sound sensitivity showed the highest co-occurrence (kappa = 0.51, 95% CI 0.47-0.55). In a generalized linear model, age, gender, higher frequency, duration and intensity of headache, reduced working capacity, most aura symptoms, and associated symptoms of the headache phase were significantly associated with an increased in the number of PS. CONCLUSION: PS are experienced by a majority of migraineurs. More severe migraine is associated with a higher burden of PS. Since the material was not entirely representative of the general population of migraineurs, caution should be exercised in generalizing the results. PMID- 26643379 TI - AMP-Activated Protein Kinase Mediates the Antiplatelet Effects of the Thiazolidinediones Rosiglitazone and Pioglitazone. AB - The thiazolidinedione antidiabetic drugs rosiglitazone and pioglitazone exert antiplatelet effects. Such effects are known to be mediated by the peroxisome proliferator-activated receptor gamma (PPARgamma), an acknowledged target of the thiazolidinediones, although the molecular mechanism is elusive. Recently, AMP activated protein kinase (AMPK) signaling was reported to inhibit platelet aggregation. Because AMPK is another target of the thiazolidinediones, the impact of rosiglitazone and pioglitazone on platelet AMPK and its involvement in aggregation were investigated to assess the contribution of AMPK to the antiplatelet activity of these agents. Treatment with rosiglitazone stimulated both AMPK and PPARgamma in isolated rat platelets. However, the concentration and the treatment time required for activation were distinct from each other. Indeed, stimulation of AMPK and PPARgamma were discrete events without any cross activation in platelets. Activation of AMPK or PPARgamma by rosiglitazone rendered platelets less responsive to aggregatory stimuli such as collagen, ADP, and thrombin. However, the resultant efficacy caused by activating AMPK was higher than that attributable to PPARgamma stimulation. Similar results were obtained with pioglitazone. Taken together, rosiglitazone and pioglitazone inhibit platelet aggregation by activating AMPK. AMPK functions as a potential target of rosiglitazone and pioglitazone for their antiplatelet activity, although the in vivo or clinical relevance remains to be assessed. PMID- 26643380 TI - Histogenesis of the stomach of the pre-hatching quail: a light microscopic study. AB - The current study conducted a careful description of the histological events during the embryonic development of quail stomach. Daily histological specimens from the quail stomach from day 4 to day 17 post incubation were examined by light microscopy. The primitive gut tube of the embryonic quail appeared at day 4 post incubation. The gut tube consisted of an endodermal epithelium of pseudostratified type, surrounded by splanchnic mesenchyme. The prospective glandular epithelium invaginated at day 5 in the proventriculus and gradually developed to prospective proventricular glands. The muscular coat became distinguished at day 7 and day 8 in the proventriculus and gizzard, respectively. Transformation into simple columnar epithelium occurred in both proventriculus and the gizzard at day 12. The gizzard epithelium gave rise to tubular invaginations also at day 12. Canalization of the gizzard tubular glands was recognized at day 14. By day 15, the proventricular surface epithelium invaginated in a concentric manner around a central cavity to form immature secretory units that contained inactive oxyntico-peptic cells. The mucosal folding in the gizzard appeared at day 15 to form plicae and sulci. The wall of the proventriculus and gizzard at day 17 acquired histological features of post hatching birds. PMID- 26643381 TI - Glutamic acid decarboxylase isoform distribution in transgenic mouse septum: an anti-GFP immunofluorescence study. AB - The septum is a basal forebrain region located between the lateral ventricles in rodents. It consists of lateral and medial divisions. Medial septal projections regulate hippocampal theta rhythm whereas lateral septal projections are involved in processes such as affective functions, memory formation, and behavioral responses. Gamma-aminobutyric acidergic neurons of the septal region possess the 65 and 67 isoforms of the enzyme glutamic acid decarboxylase. Although data on the glutamic acid decarboxylase isoform distribution in the septal region generally appears to indicate glutamic acid decarboxylase 67 dominance, different studies have given inconsistent results in this regard. The aim of this study was therefore to obtain information on the distributions of both of these glutamic acid decarboxylase isoforms in the septal region in transgenic mice. Two animal groups of glutamic acid decarboxylase-green fluorescent protein knock-in transgenic mice were utilized in the experiment. Brain sections from the region were taken for anti-green fluorescent protein immunohistochemistry in order to obtain estimated quantitative data on the number of gamma-aminobutyric acidergic neurons. Following the immunohistochemical procedures, the mean numbers of labeled cells in the lateral and medial septal nuclei were obtained for the two isoform groups. Statistical analysis yielded significant results which indicated that the 65 isoform of glutamic acid decarboxylase predominates in both lateral and medial septal nuclei (unpaired two-tailed t-test p < 0.0001 for LS, p < 0.01 for MS). This study is the first to reveal the dominance of glutamic acid decarboxylase isoform 65 in the septal region in glutamic acid decarboxylase green fluorescent protein transgenic mice. PMID- 26643383 TI - alpha-Synuclein aggregation in the olfactory bulb of middle-aged common marmoset. AB - The synaptic protein alpha-synuclein has been identified as a major component of Lewy bodies, a pathological hallmark of Parkinson's disease (PD). Prior to the formation of Lewy bodies, mislocalization and aggregation of the alpha-synuclein in brain tissue is frequently observed in various neurodegenerative diseases. Aberrant accumulation and localization of alpha-synuclein are also observed in the aging human brain, for which reason aging is regarded as a risk factor for neurodegenerative disease. To investigate changes in alpha-synuclein properties in the aging brain, we compared alpha-synuclein immunoreactivity in brain tissue of young (2-years-old) and middle-aged (6-years-old) common marmoset (Callithrix jacchus). Our analyses revealed marked changes in alpha-synuclein immunoreactivity in the olfactory bulb of common marmosets of these age cohorts. Perikaryal alpha-synuclein aggregations were formed in the olfactory bulb in middle-aged animals. We also observed signals of alpha-synuclein accumulation in hippocampus in this cohort; however, unlike in the olfactory bulb, hippocampal alpha-synuclein signals were localized in the synaptic terminals. We did not observe either of these features in younger marmosets, which suggest that aging may play a role in these phenomena. Our results using common marmoset brain corresponded with the observation that the alpha-synuclein aggregations were first occurred from olfactory bulb in human normal aged and PD brain. Therefore, common marmoset is expected as useful model for alpha-synuclein pathology. PMID- 26643384 TI - Slow dynamics perspectives on the Embodied-Brain Systems Science. AB - Recent researches point out the importance of the fast-slow cognitive process and learning process of self-body. Bayesian perspectives on the cognitive system also attract research attentions. The view of fast-slow dynamical system has long attracted wide range of attentions from physics to the neurobiology. In many research fields, there is a vast well-organized and coherent behavior in the multi degrees-of-freedom. This behavior matches the mathematical fact that fast slow system is essentially described with a few variables. In this paper, we review the mathematical basis for understanding the fast-slow dynamical systems. Additionally, we review the basis of Bayesian statistics and provide a fast-slow perspective on the Bayesian inference. PMID- 26643386 TI - Characteristics and phylogenetic studies of Acrossocheilus parallens (Cypriniformes, Barbinae) complete mitochondrial genome. AB - In this paper, the complete mitochondrial genome sequence of Acrossocheilus parallens was determined. The circle genome (16 591 bp) comprises 13 protein coding genes, 22 tRNA genes, two rRNA genes, and one control region. The overall base composition of A. parallens is 30.9% for A, 28.1% for C, 24.6% for T, and 16.4% for G, with a higher AT content of 55.5%. Only ND6 and other eight tRNA genes are encoded on the L-strand while most of these genes are located in the H strand. It has the typical vertebrate mitochondrial gene arrangement. The phylogenetic trees showed that A. parallens was clustered with other species of Acrossocheilus. The complete mitochondrial genomic sequence of A. parallens would contribute for the better understanding of genetic structure, identification, evolution and phylogeny of this species. PMID- 26643387 TI - Atomic Structures of CH3NH3PbI3 (001) Surfaces. AB - We report on the atomic structures of methylammonium (MA) lead iodide (CH3NH3PbI3) perovskite surfaces, based on a combined scanning tunneling microscopy and density functional theory calculation study. A reconstructed surface phase with iodine dimers, coexisting with the pristine zigzag phase, was found at the MA-iodine-terminated (001) surfaces of the orthorhombic perovskite films grown on Au(111) surfaces. The reorientation of surface MA dipoles, which strengthens the interactions with surface iodine anions, resulting in a slight energy reduction of 34 meV per unit cell, is responsible for the surface iodine dimerization. According to our calculation, the surface MA dipoles weaken the surface polarity and are therefore considered to be stabilizing the surface structures. PMID- 26643385 TI - In-vivo T2-relaxation times of asymptomatic cervical intervertebral discs. AB - Limited research exists on T2-mapping techniques for cervical intervertebral discs and its potential clinical utility. The objective of this research was to investigate the in-vivo T2-relaxation times of cervical discs, including C2-C3 through C7-T1. Ten asymptomatic subjects were imaged using a 3.0 T MR scanner and a sagittal multi-slice multi-echo sequence. Using the mid-sagittal image, intervertebral discs were divided into five regions-of-interest (ROIs), centered along the mid-line of the disc. Average T2 relaxation time values were calculated for each ROI using a mono-exponential fit. Differences in T2 values between disc levels and across ROIs of the same disc were examined. For a given ROI, the results showed a trend of increasing relaxation times moving down the spinal column, particularly in the middle regions (ROIs 2, 3 and 4). The C6-C7 and C7-T1 discs had significantly greater T2 values compared to superior discs (discs between C2 and C6). The results also showed spatial homogeneity of T2 values in the C3-C4, C4-C5, and C5-C6 discs, while C2-C3, C6-C7, and C7-T1 showed significant differences between ROIs. The findings indicate there may be inherent differences in T2-relaxation time properties between different cervical discs. Clinical evaluations utilizing T2-mapping techniques in the cervical spine may need to be level-dependent. PMID- 26643388 TI - An international comparison of the management of the neck in early oral squamous cell carcinoma in the Netherlands, UK, and USA. AB - BACKGROUND: Early oral cavity squamous cell carcinoma (OCSCC) management appears to vary both within and between countries. Variation in practice can be an indicator of absence of evidence-based management and may negatively influence survival and morbidity. The exact variation and the relationship to differences in guidelines are unknown. This study aimed to report on these variations in the Netherlands, UK, and USA, and to evaluate them. METHODS: Information regarding the variation in OCSCC management strategies was obtained from a questionnaire sent to representatives of head and neck cancer centers in the Netherlands, UK, and USA. Within-country and between-country variations were also assessed in light of the different guidelines. RESULTS: In total, representatives of 45 centers completed the questionnaire; 10 from the Netherlands, 26 from the UK and 9 from the USA. Our results demonstrate a distinct variation in the diagnoses, treatment and follow-up of OCSCC, both within and between countries. Only a small amount of variation between countries could be linked to differences in guidelines. CONCLUSIONS: There is high variation in the management of the neck in OCSCC. There seem to be a need for direct evidence about optimal management decisions to establish more evidence-based management and uniform practice. PMID- 26643389 TI - Health-related quality of life in patients with nasal prosthesis. AB - OBJECTIVE: To evaluate the health-related quality of life (QOL) in patients with nasal prosthesis after tumour resection with partial or total rhinectomy. MATERIAL AND METHODS: Patients with nasal prosthesis were asked to complete a quality of life questionnaire. 43 patients with prosthesis after partial or total rhinectomy completed the University of Washington quality of life questionnaire. Answers were systematically analysed. RESULTS: 27 patients were male, 16 were female. Mean age was 62 years, and the mean interval between tumour resection and date of study inclusion was 45.3 months. There are gender-specific differences for the QOL domain 'recreation' and age-specific differences for the domains 'appearance' and 'saliva'. The fields 'activity', 'mood' and 'appearance' are the most severely affected QOL domains in patients with nasal prosthesis. CONCLUSION: Similar to other head and neck cancers there is a need and a deficiency in psycho oncological support after partial or total rhinectomy, the influence on QOL however was much lower than initially expected. This should be considered with regard to the oncological benefits of this surgical procedure. Compared to the results of other head and neck malignancies the 'appearance' is only slightly affected. A stable prosthesis is needed to enable the maintenance of the accustomed activities. PMID- 26643390 TI - Minimal impact of maternal intravenous immunoglobulin infusion on cell-free DNA sequencing for fetal aneuploidy. PMID- 26643391 TI - [Update on the management of trigeminal neuralgia]. AB - Trigeminal neuralgia is one of the most severe facial pain syndromes. The annual incidence varies between 4-13% and has a significant effect on patient quality of life. The initial treatment of trigeminal neuralgia is pharmacological, and although other drugs have demonstrated efficacy, albeit in more limited form, carbamazepine is the only drug with sufficient level of evidence. When medical treatment fails, surgery should be considered and can opt for open surgery or minimally invasive percutaneous techniques. This paper reviews the medical and surgical therapeutic options for the treatment of trigeminal neuralgia, based on current available evidence. PMID- 26643392 TI - [Useful diagnostic tools for early recognition of necrotising soft tissue infections]. PMID- 26643393 TI - [Chagasic dolicho-megacolon]. PMID- 26643394 TI - [Mayer-Rokitansky-Kuster-Hauser syndrome: A case report]. PMID- 26643395 TI - [Granuloma fissuratum: A little known, but easily identifiable, entity]. PMID- 26643396 TI - [Prevalence and features of coeliac disease in the Mediterranean area of Spain]. AB - INTRODUCTION: The aim of this study is to determine the prevalence of coeliac disease in patients of a basic health area in Valencia, on the Mediterranean coast, and describe their sociodemographic and clinical features. MATERIAL AND METHODS: A descriptive, cross-sectional, observational study was conducted on a target population of the inhabitants of the Basic Health Area 14th, Health Department Xativa-Ontinyent, in Valencia, comprising the municipalities of Ontinyent, Aielo de Malferit, and Fontanars dels Alforins. INCLUSION CRITERIA: the patient belongs to a quota of Primary Care in the basic health area and the diagnosis of coeliac disease was active in the computerised medical records. EXCLUSION CRITERIA: the patient did not have any serology or intestinal biopsy compatible with coeliac disease. The study included 115 patients, selected to complete an interviewer-administered questionnaire. As 9 patients did not respond, the study was performed with 106 people. RESULTS: The prevalence of coeliac disease is 0.26%, and higher among women than among men (2.31: 1), with a statistically significant difference. The mean age of the patients was 29.71 years. The mean diagnostic delay was 5.15 years, and among the paediatric population it was 0.68 years. There were no statistically significant differences between patients (60) born in spring and summer, and the 46 born in autumn and winter. The prevalence of coeliac disease among first-degree relatives was 7.06%. CONCLUSIONS: Coeliac disease is an underdiagnosed condition in our environment, especially among adults, so knowledge and awareness about this disease by general practitioners is necessary. PMID- 26643397 TI - [An unusual cause of dysphagia in the family doctor clinic]. PMID- 26643398 TI - [Erythema multiforme of unusual origin: Topical ketoprofen and varicella zoster virus]. PMID- 26643399 TI - Shared recovery: Couples' experiences after treatment for colorectal cancer. AB - PURPOSE: Completing cancer treatment involves significant challenges for patients as well as their families. This study aimed to explore couples' experiences of colorectal (bowel) cancer, focusing on the transition after treatment. METHOD: Separate, semi-structured interviews were conducted within 12 months of completing treatment with a purposeful sample of ten participants, comprising five patient-partner dyads. Data were analysed using the Framework approach, incorporating dyadic analysis to compare narratives within as well as between couples. RESULTS: Three main themes were elaborated: the process of recovery, the relationship dynamics, and the mixed experiences of healthcare services. The lasting impact of cancer following completion of treatment was evident for patients as well as their partners, and was shaped by their reciprocal influence on each other. CONCLUSIONS: The findings underscore the value of a systemic approach for supporting couples during recovery from colorectal cancer and demonstrate the need for consistency of healthcare provision across the cancer trajectory, including post-treatment. PMID- 26643400 TI - Effects of a psycho-educational programme on health-related quality of life in patients treated for colorectal and anal cancer: A feasibility trial. AB - PURPOSE: Colorectal cancer (CRC) may have a negative impact on a person's quality of life. Psycho-educational interventions for patients with CRC are rarely studied. The purpose of this feasibility trial was to evaluate the effect of a psycho-educational programme (PEP) on the health-related quality of life (HRQL) of patients treated for CRC and anal cancer. METHODS: Patients with CRC and anal cancer were randomly assigned to a PEP (n = 47) or standard treatment (n = 39). The PEP included informative lectures, discussion, and reflection. HRQL was evaluated using the SF-36 at baseline and 1, 6, and 12 months after the end of the PEP. RESULTS: Patients in the PEP group had significantly better Mental Health scores after 1 month and significantly better Bodily Pain scores after 6 months compared with patients who received standard care. CONCLUSION: The results of this study indicate that a PEP can have a short-term effect on the mental health and bodily pain of patients treated for CRC and anal cancer when comparing with a control group. The article discusses the methodological difficulties of evaluating an intervention such as this PEP in a clinical setting. PMID- 26643401 TI - Effects of community-based exercise in children with severe burns: A randomized trial. AB - OBJECTIVE: To counteract long-lasting muscle break down, muscle weakness, and poor physical fitness resulting from severe burns, we recommend a 12-week in hospital exercise training rehabilitation program. Unfortunately, this in hospital training program requires time away from home, family, school or work. This study was undertaken to evaluate an alternative exercise rehabilitation strategy involving a 12-week community-based exercise training rehabilitation program (COMBEX) carried out at or near the patient and caretaker's home. STUDY DESIGN AND PARTICIPANTS: Pediatric patients (7-18 years) with >= 30% of total body surface area (TBSA) burns were randomized to participate in COMBEX (N=12) or an outpatient exercise program (EX) at the hospital (N=22). Both programs were started after hospital discharge and consisted of 12 weeks of progressive resistive and aerobic exercise. COMBEX was performed in community fitness centers near the patients' home. Endpoints were assessed at discharge (pre-exercise) and after the 12-week program. Primary endpoints were lean body mass (dual energy X ray absorptiometry), muscle strength (isokinetic dynamometry), and peak aerobic capacity (indirect calorimetry). RESULTS: Demographics, length of hospitalization, and TBSA burned were comparable between groups (P>0.05). Both groups exhibited a significant (P <= 0.01 for all) increase (mean +/- SEM) in lean muscle mass (EX: 6.9 +/- 1.7%; COMBEX: 6.5 +/- 1.1%), muscle strength (EX: 67.1 +/- 7.0%; COMBEX: 49.9 +/- 6.8%), and peak aerobic capacity (EX: 35.5 +/- 4.0%; COMBEX: 46.9 +/- 7.7%). Furthermore, the magnitude of these increases were not different between groups (P>0.12). CONCLUSIONS: Both EX and COMBEX are efficacious in improving lean mass, strength, and cardiopulmonary capacity in severely burned children. PMID- 26643402 TI - Myths and Misconceptions of Within-Cycle Correction: A Guide for Modelers and Decision Makers. AB - Commonly used decision-analytic models for cost-effectiveness analysis simulate time in discrete steps. Use of discrete-time steps can introduce errors when calculating cumulative outcomes such as costs and quality-adjusted life-years. There are a number of myths or misconceptions concerning how to correct these errors and the need to do so. This tutorial shows that, by neglecting to apply within-cycle (sometimes referred to as half-cycle or continuity) correction methods to the results of discrete-time models, the analyst may arrive at the wrong recommendation regarding the use of a technology. We show that the standard half-cycle correction method results in the same cumulative outcome as the trapezoidal rule and life-table method. However, the trapezoidal rule has the added advantage of applying the correction at each cycle, not just the initial and final cycle. We further show that the Simpson's 1/3 rule is more accurate than the trapezoidal rule. We recommend using the Simpson's 1/3 rule in the base case analysis and, if needed, showing the results with other methods in the sensitivity analysis. We also demonstrate that both the trapezoidal and Simpson's rules can easily be implemented in commonly used software. PMID- 26643403 TI - Breakdown of interlocking domains may contribute to formation of membranous globules and lens opacity in ephrin-A5(-/-) mice. AB - Ephrin-A5, a ligand of the Eph family of receptor tyrosine kinases, plays a key role in lens fiber cell packing and cell-cell adhesion, with approximately 87% of ephrin-A5(-/-) mice develop nuclear cataracts. Here, we investigated the extensive formation of light-scattering globules associated with breakdown of interlocking protrusions during lens opacification in ephrin-A5(-/-) mice. Lenses from wild-type (WT) and ephrin-A5(-/-) mice between 2 and 21 weeks old were studied with light and electron microscopy, immunofluorescence labeling, freeze fracture TEM and filipin cytochemistry for membrane cholesterol detection. Lens opacities with various densities were first observed in ephrin-A5(-/-) mice at around 60 days old. Dense cataracts in the mutant lenses were seen primarily in the nuclear region surrounded by transparent cortices from all eyes examined. We confirmed that a majority of nuclear cataracts were dislocated posteriorly and ruptured the thinner posterior lens capsule. SEM analysis indicated that numerous interlocking protrusions and wavy ridge-and-valley membrane surfaces in deep cortical and nuclear fibers did not cause lens opacity in both transparent ephrin A5(-/-) and WT mice. In contrast, abundant isolated membranous globules of approximately 1000 nm in size were distributed randomly along the intact fiber cells during early stage of all ephrin-A5(-/-) cataracts examined. A further examination using both SEM and TEM revealed that isolated globules were generated from the disintegrated interlocking protrusions originally located along the corners of hexagonal fiber cells. Freeze-fracture TEM further revealed the association of square-array aquaporin junctions with both isolated globules and interlocking membrane domains. This study reports for the first time that disrupted interlocking protrusions are the source of numerous large membranous globules that contribute to light scattering and nuclear cataracts in the ephrin A5(-/-) mice. Our results further suggest that dissociations of N-cadherin and adherens junctions in the associated interlocking domains may result in the formation of isolated globules and nuclear opacities in the ephrin-A5(-/-) mice. PMID- 26643404 TI - Comparison of continuous positive airway pressure and bosentan effect in mildly hypertensive patients with obstructive sleep apnoea: A randomized controlled pilot study. AB - BACKGROUND AND OBJECTIVE: Randomized controlled trials (RCT) have shown that continuous positive airway pressure (CPAP) has only limited impact on blood pressure (BP). Alternative strategies for obstructive sleep apnoea (OSA) associated hypertension are therefore needed. Endothelin-1 has been demonstrated a key player in the deleterious cardiovascular consequences of OSA. In OSA, CPAP treatment has never been compared with endothelin receptor antagonist medications. Thus, we assessed the respective efficacy of CPAP and bosentan in reducing 24-h diastolic BP (DBP) in patients with OSA never treated by either therapy. METHODS: In a crossover pilot study, 16 mildly hypertensive patients (office systolic BP (SBP)/DBP: 142 +/- 7/85 +/- 8 mm Hg) with severe OSA (55 +/- 8 years; body mass index, 29.6 +/- 4.2 kg/m(2) ; apnoea-hypopnoea index, 40.8 +/- 20.2/h) were randomized to either CPAP (n = 7) or bosentan (125 mg/day, n = 9) first for 4 weeks. After 2-weeks of washout, the second 4-week period consisted of the alternative treatment (in crossover). The primary outcome was the 24-h mean DBP change after treatment. RESULTS: In intention-to-treat analysis, the mean difference in 24-h DBP measurements between treatments was -3.1 (-6.9/0.7) mm Hg (median, 25th/75th percentiles) (P = 0.101) with bosentan having a greater effect. CONCLUSION: In this RCT, in mildly hypertensive patients with OSA, bosentan did not modify 24-h DBP but only reduced office BP suggesting that Endothelin-1 blockade does not play a major role in treatment of OSA-related hypertension. PMID- 26643405 TI - Acute Appendicitis Is Associated with Peptic Ulcers: A Population-based Study. AB - Despite some studies having indicated a possible association between appendicitis and duodenal ulcers, this association was mainly based on regional samples or limited clinician experiences, and as such, did not permit unequivocal conclusions. In this case-control study, we examined the association of acute appendicitis with peptic ulcers using a population-based database. We included 3574 patients with acute appendicitis as cases and 3574 sex- and age-matched controls. A Chi-squared test showed that there was a significant difference in the prevalences of prior peptic ulcers between cases and controls (21.7% vs. 16.8%, p < 0.001). The adjusted odds ratio (OR) of prior peptic ulcers for cases was 1.40 (95% confidence interval [CI]: 1.24~1.54, p < 0.001) compared to controls. The results further revealed that younger groups demonstrated higher ORs for prior peptic ulcers among cases than controls. In particular, the adjusted OR for cases < 30 years old was as high as 1.65 (95% CI = 1.25~2.19; p < 0.001) compared to controls. However, we failed to observe an association of acute appendicitis with peptic ulcers in the >= 60-year age group (OR = 1.19, 95% CI = 0.93~1.52). We concluded that there is an association between acute appendicitis and a previous diagnosis of peptic ulcers. PMID- 26643406 TI - An Anatomical and Morphometric Study of the Coccyx Using Three-Dimensional Reconstruction. AB - To provide anatomical and morphological data regarding the coccyx using three dimensional images, with a view to aiding the diagnosis of idiopathic coccydynia, one hundred and thirty-six normal adult pelvises were investigated. Three dimensional models of the pelvis were reconstructed using software from computed tomography images of whole specimens. The following six coccyx parameters were measured: (1) width, (2) straight length, (3) thickness, (4) sacrococcygeal angle, (5) intercoccygeal angle, and (6) angle of lateral deviation of the coccyx. The presence of fusion between the sacral and coccygeal cornua, and between the sacrum and the transverse process of the coccyx was also investigated, and lateral deviations of the coccyx were classified and analyzed. Most of the measured coccyx parameters were larger in males than in females, with the exception of the sacrococcygeal and intercoccygeal angles. Unilateral or bilateral fusion of the sacral cornu and the coccygeal cornu was not a rare finding. With respect to the sacrum and the transverse process of coccyx, the separated type was more common than the fused type. The incidence and angle of lateral deviation of the coccyx varied widely between individuals. The present detailed description of the gross anatomy of the coccyx obtained using three dimensional modeling will help toward understanding the mechanism underlying the development of idiopathic coccydynia. Fusion of the sacrum and coccyx or lateral deviation of the coccyx may cause coccydynia by compressing the coccygeal nerves. PMID- 26643408 TI - Evaluation of Entrance Skin Dose during Catheter Ablation Procedures by Use of Reference Air-Kerma Displayed on Angiography Systems. AB - BACKGROUND: Our aim in this study was to estimate entrance skin doses (ESDs) to patients who underwent catheter ablation procedures, by using a reference air kerma (RAK) displayed on the monitor of an angiography system (displayed RAK). METHODS: The displayed RAK was calibrated with use of an air-kerma value measured on a 20-cm-thick acrylic plate at the interventional reference point for the inclusion of backscattered x-rays (calibrated RAK). The ESD evaluated from the calibrated RAK (evaluated ESD) was verified through direct ESD measurements on an anthropomorphic phantom. The values of the evaluated ESD agreed with those of the measured ESD within a statistical error of 10% for both fluoroscopy and digital cine. The patient population included 356 consecutive patients (108 female and 248 male) who underwent catheter ablation procedures in the catheter laboratory of the Nagoya Daini Red-Cross Hospital from January 2013 to February 2014, where ablation procedures were performed for seven types of arrhythmias, i.e., atrial fibrillation (AF), atrial flutter (AFL), atrial tachycardia (AT), atrioventricular nodal reentrant tachycardia (AVNRT), ventricular premature contraction (VPC), ventricular tachycardia (VT), and Wolff-Parkinson-White syndrome (WPW). RESULTS: Patients who had arrhythmias that received the highest evaluated ESD were those for AF, followed by those for VPC, AT, WPW, AFL, VT, and AVNRT. CONCLUSIONS: Despite extremely long fluoroscopy times of up to 66.6 minutes in left anterior oblique projection, only one patient was considered to exceed a threshold dose of 2 Gy for the onset of radiation-induced skin injuries. PMID- 26643407 TI - Studying mechanisms of cAMP and cyclic nucleotide phosphodiesterase signaling in Leydig cell function with phosphoproteomics. AB - Many cellular processes are modulated by cyclic AMP and nucleotide phosphodiesterases (PDEs) regulate this second messenger by catalyzing its breakdown. The major unique function of testicular Leydig cells is to produce testosterone in response to luteinizing hormone (LH). Treatment of Leydig cells with PDE inhibitors increases cAMP levels and the activity of its downstream effector, cAMP-dependent protein kinase (PKA), leading to a series of kinase dependent signaling and transcription events that ultimately increase testosterone release. We have recently shown that PDE4B and PDE4C as well as PDE8A and PDE8B are expressed in rodent Leydig cells and that combined inhibition of PDE4 and PDE8 leads to dramatically increased steroid biosynthesis. Here we investigated the effect of PDE4 and PDE8 inhibition on the molecular mechanisms of cAMP actions in a mouse MA10 Leydig cell line model with SILAC mass spectrometry-based phosphoproteomics. We treated MA10 cells either with PDE4 family specific inhibitor (Rolipram) and PDE8 family specific inhibitor (PF 04957325) alone or in combination and quantified the resulting phosphorylation changes at five different time points between 0 and 180min. We identified 28,336 phosphosites from 4837 proteins and observed significant regulation of 749 sites in response to PDE4 and PDE8 inhibitor treatment. Of these, 132 phosphosites were consensus PKA sites. Our data strongly suggest that PDE4 and PDE8 inhibitors synergistically regulate phosphorylation of proteins required for many different cellular processes, including cell cycle progression, lipid and glucose metabolism, transcription, endocytosis and vesicle transport. Our data suggests that cAMP, PDE4 and PDE8 coordinate steroidogenesis by acting on not one rate limiting step but rather multiple pathways. Moreover, the pools of cAMP controlled by these PDEs also coordinate many other metabolic processes that may be regulated to assure timely and sufficient testosterone secretion in response to LH. PMID- 26643409 TI - Astaxanthin supplementation enhances adult hippocampal neurogenesis and spatial memory in mice. AB - SCOPE: There is a growing necessity for efficacious natural supplements with antioxidant effects on the brain, in particular, hippocampal function. One such compound, which also has a neuroprotective effect, is the carotenoid astaxanthin (ASX). Despite ASX's potential benefit to the brain, very little is known about its effect on hippocampal plasticity and cognition. Thus, we investigated the effect of ASX on adult hippocampal neurogenesis (AHN) and spatial memory using a mouse model. METHODS AND RESULTS: Dose-response was examined in mice fed ASX supplemented diets (0, 0.02, 0.1, and 0.5%) to define the effect of ASX on AHN. In conjunction with AHN results, hippocampus-dependent cognitive function was assessed. We delineated molecular mechanisms associated with ASX-enhanced AHN using DNA microarray analysis. Results revealed that ASX enhanced cell proliferation and survival at 0.1% and 0.5% doses. Newborn mature neurons were higher only with 0.5% ASX, which also enhanced spatial memory. Transcriptomic profiling revealed potential AHN-associated molecules (Prl, Itga4, and Il4) that were ASX induced. Their downstream factors, identified through Ingenuity Pathway Analysis, were positively correlated with ASX-induced increases in spatial memory. CONCLUSION: ASX supplementation enhanced AHN and spatial memory, and a DNA microarray approach provided, for the first time, novel molecular insights into ASX action. PMID- 26643410 TI - Erratum to: Reduced expression of MyHC slow isoform in rat soleus during unloading is accompanied by alterations of endogenous inhibitors of calcineurin/NFAT signaling pathway. PMID- 26643411 TI - Power and sample size calculations for interval-censored survival analysis. AB - We propose a method for calculating power and sample size for studies involving interval-censored failure time data that only involves standard software required for fitting the appropriate parametric survival model. We use the framework of a longitudinal study where patients are assessed periodically for a response and the only resultant information available to the investigators is the failure window: the time between the last negative and first positive test results. The survival model is fit to an expanded data set using easily computed weights. We illustrate with a Weibull survival model and a two-group comparison. The investigator can specify a group difference in terms of a hazards ratio. Our simulation results demonstrate the merits of these proposed power calculations. We also explore how the number of assessments (visits), and thus the corresponding lengths of the failure intervals, affect study power. The proposed method can be easily extended to more complex study designs and a variety of survival and censoring distributions. PMID- 26643412 TI - Synergistic anti-pancreatic cancer immunological effects by treatment with reduced expression in immortalized cells/dickkopf-3 protein and peripheral blood mononuclear cells. AB - BACKGROUND AND AIM: Reduced expression in immortalized cells/dickkopf-3 (REIC/DKK3) is a reported tumor suppressor gene and has potential to become an innovative therapy for various cancers. We examined the antitumor immunological effects of human REIC/DKK3 protein against pancreatic cancer. METHODS: Activation of extracellular signal-regulated kinases 1 and 2, mammalian target of rapamycin, and signal transducer and activator of transcription 3 by REIC/DKK3 protein was assessed in human peripheral blood mononuclear cells using immunoblotting. Pancreatic cancer cell lines (AsPC-1 and MIA Paca-2) were cocultured with peripheral blood mononuclear cells, and the anticancer effects of REIC/DKK3 protein were assessed using the methyl thiazole tetrazolium, cytotoxicity, and enzyme-linked immunospot assays. The antitumor immunological effects of the combined treatment with REIC/DKK3 protein and peripheral blood mononuclear cells were also assessed in a pancreatic cancer model using non-obese diabetic/severe combined immunodeficiency mice. RESULTS: The REIC/DKK3 protein activated extracellular signal-regulated kinases 1 and 2, mammalian target of rapamycin, and signal transducer and activator of transcription 3 in peripheral blood mononuclear cells. REIC/DKK3 protein inhibited in vitro cancer cell viability and enhanced cytotoxicity when incubated with peripheral blood mononuclear cells. REIC/DKK3 protein induced significant production of interferon gamma from lymphocytes incubated with pancreatic cancer cells, indicating that CD8+ T cells were activated in the peripheral blood mononuclear cells when cocultured with AsPC-1 and MIA Paca-2 in the presence of REIC/DKK3 protein. Combined treatment with REIC/DKK3 protein and peripheral blood mononuclear cells produced in vivo anticancer immunostimulatory effects on pancreatic cancer cells. CONCLUSIONS: The REIC/DKK3 protein and peripheral blood mononuclear cells synergistically enhanced anticancer immunological effects against pancreatic cancer cells. The observed immunomodulatory effect of combined treatment likely occurs in adenovirus mediated REIC/DKK3 gene therapy and provides important clues to the therapeutic mechanisms involving immune cells. PMID- 26643413 TI - Research START: A Multimethod Study of Barriers and Accelerators of Recruiting Research Participants. AB - Under-recruitment into clinical trials is a common and costly problem that undermines medical research. To better understand barriers to recruitment into clinical trials in our region, we conducted a multimethod descriptive study. We initially surveyed investigators who had conducted or were currently conducting studies that utilized an adult or pediatric clinical research center (n = 92). We then conducted focus groups and key informant interviews with investigators, coordinators, and other stakeholders in clinical and translational research (n = 32 individuals). Only 41% of respondents reported that they had or were successfully meeting recruitment goals and 24% of the closed studies actually met their targeted recruitment goals. Varied reasons were identified for poor recruitment but there was not a single investigator or study "phenotype" that predicted enrollment outcome. Investigators commonly recruited from their own practice or clinic, and 29% used a manual electronic medical record search. The majority of investigators would utilize a service that provides recruitment advice, including feasibility assessment and consultation, easier access to the electronic health record and assistance with institutional review board and other regulatory requirements. Our findings suggest potential benefits providing assistance across a range of services that can be individualized to the varied needs of clinical and translational investigators. PMID- 26643414 TI - Psychosocial determinants of marijuana use among African American youth. AB - This study examines the psychosocial determinants of marijuana use among youth. A total of 7,488 African American middle and high school students from 133 metropolitan private and public schools completed a survey assessing psychosocial factors associated with annual marijuana use. The PRIDE survey, a nationally recognized survey on substance use, was used to assess the frequency of marijuana use and the influence of psychosocial factors on marijuana use among African American students. Results indicated that 18.5% of African American youth used marijuana in the past year. Males were significantly more likely than females to report using marijuana. Engaging in risky behaviors, such as getting in trouble at school and with police and attending a party with alcohol and other drugs, were significantly correlated with annual marijuana use. Conversely, having multiple parent, teacher, and school protective factors reduced annual marijuana use in this population. Such findings may assist prevention specialists in developing interventions to reduce and prevent marijuana use. PMID- 26643415 TI - A chronic toxicity test for the tropical marine snail Nassarius dorsatus to assess the toxicity of copper, aluminium, gallium, and molybdenum. AB - Chronic toxicity test methods for assessing the toxicity of contaminants to tropical marine organisms are generally lacking. A 96-h chronic growth rate toxicity test was developed for the larval stage of the tropical dogwhelk, Nassarius dorsatus. Growth rates of N. dorsatus larvae were assessed following exposures to copper (Cu), aluminium (Al), gallium (Ga), and molybdenum (Mo). Exposure to Cu at 28 degrees C validated the sensitivity of the test method, with 10% (EC10) and 50% (EC50) effect concentrations of 4.2 MUg/L and 7.3 MUg/L Cu, respectively. The EC10 and EC50 values for Al (<0.45-MUm filtered fraction) at 28 degrees C were 115 MUg/L and 185 MUg/L, respectively. The toxicity of Cu and Al was also assessed at 24 degrees C and 31 degrees C, representing average year-round water temperatures for subtropical and tropical Australian coastal environments. At 24 degrees C, the growth rate of control larvae was reduced by 52% compared with the growth rate at 28 degrees C and there was an increase in sensitivity to Cu (EC50 = 4.7 MUg/L) but a similar sensitivity to Al (EC50 = 180 MUg/L). At 31 degrees C the control growth rate increased by 35% from that measured at 28 degrees C and there was reduced sensitivity to both Cu and Al (EC50s = 8.5 MUg/L and 642 MUg/L, respectively). There was minimal toxicity resulting from Ga (EC50 = 4560 MUg/L) and Mo (no effect at <=7000 MUg/L Mo). Environ Toxicol Chem 2016;35:1788-1795. (c) 2015 SETAC. PMID- 26643417 TI - [Tauroursodeoxycholic acid suppresses endoplasmic reticulum stress in pulmonary tissues of intermittent hypoxia mice]. AB - OBJECTIVE: To explore the mechanism of tauroursodeoxycholic acid (TUDCA) in suppressing apoptosis in pulmonary tissues of intermittent hypoxia (IH) mice model.? METHODS: A total of 32 C57 mice were randomly divided into a control group, a TUDCA group, an IH group and an IH+TUDCA group (8 mice per group). The mice were put in specially designed chambers and exposed to IH treatment for 4 weeks. In the chambers, oxygen levels repeatedly decreased from 21% to 10% and recovered from 10% to 21%, lasting for 8 hours in every day. After 4 weeks of IH exposure, the expression levels of caspase-12 and cleaved caspase-3 in pulmonary tissues were detected by Western blot. Meanwhile, the expression levels of glucose regulated protein-78 (GRP78) and CCAAT/enhancer-binding protein homologous protein (CHOP) were quantified by Western blot, immunochemistry and real-time PCR.? RESULTS: Compared with the control group, the expression levels of caspase-12, cleaved caspase-3, GRP78 and CHOP were increased in the IH group (all P<0.01). TUDCA treatment could reduce these proteins expression (all P<0.05).? CONCLUSION: Endoplasmic reticulum stress-mediated apoptosis can be activated in pulmonary tissues after chronic IH exposure, and TUDCA can reduce the cellular apoptosis via suppressing endoplasmic reticulum stress. PMID- 26643416 TI - Risk Factors for Seclusion and Restraint in a Pediatric Psychiatry Day Hospital. AB - The use of seclusion and restraints (SR) in acute hospital settings remains a controversial practice. Despite the focus on SR in the psychiatric services literature, data on SR use in pediatric day hospital settings is lacking. A case control retrospective analysis for children admitted into a pediatric psychiatry day hospital in a 2-year span examined predictors of SR use. Demographic and clinical descriptors were examined in relation to SR events using univariate and multivariate regression models. Significant univariate risk factors for SR use were psychiatric morbidity, history of physical abuse, post-traumatic stress disorder, having any anxiety disorder, and younger age. Knowledge of risk factors for SR use in pediatric psychiatric day hospitals can avert use of SR and lead to improved safety in a trauma-informed care model. PMID- 26643418 TI - [Protective effects of hydrogen sulfide on diaphragmatic muscle of Type 1 diabetic rats and its anti-apoptotic mechanisms]. AB - OBJECTIVE: To explore the protective effects of hydrogen sulfide (H2S) on diaphragmatic muscle of Type 1 diabetic rats and its anti-apoptotic mechanism.? METHODS: Thirty male Sprague Dawley rats were randomly divided into a control group, a diabetes group and a treatment group (n=10 per group). Streptozotocin (i.p.) was utilized to establish a rat model of Type 1 diabetes mellitus (DM). The DM rats were treated with NaHS solution (i.p.). After 8 weeks, the diaphragmatic muscle contractility was assessed by isolated diaphragmatic strips experiments. The peak twitch tension (Pt), maximum tetanic tension (Po), time to peak contraction (CT), half relaxation time (1/2RT) and maximal rates of contraction/relaxation (+/-dT/dtmax) were measured. The alterations of diaphragmtic ultrastructure were observed by electron microscopy. The content of malondialdehyde (MDA), the activities of superoxide dismutase (SOD) and caspase-3 were analyzed by spectrophotometric method. The expressions levels of Bcl-2 and Bax mRNA in diaphragmatic muscle were detected by RT-PCR.? RESULTS: Compared with the control group, in the diabetic group, the Pt, Po and +/-dT/dtmax were significantly reduced (all P<0.01), while CT and 1/2RT were significantly increased (both P<0.01); ultrastructure in the diaphragmatic muscle were obviously changed; the content of MDA and the activity of caspase-3 were increased (both P<0.01), while the activity of SOD was decreased (P<0.01); the ratio of Bcl-2/Bax at mRNA level was decreased (P<0.01). Compared with the diabetes group, in the treatment group, the diaphragm contractility and ultrastructural damage were improved; the content of MDA and the activity of caspase-3 were decreased (P<0.05, P<0.01 respectively), while the activity of SOD was increased (P<0.01), the ratio of Bcl-2/Bax at mRNA level was also increased (P<0.01). ? CONCLUSION: The exogenous H2S can protect diaphragmatic muscle of Type 1 diabetic rats, which is related to reducing oxidative damage and suppressing cell apoptosis. PMID- 26643419 TI - [Injection of submandibular gland with recombinant Exendin-4 and adeno-associated virus for the treatment of diabetic rats]. AB - OBJECTIVE: To evaluate the therapeutic effects of recombinant Exendin-4 and double-stranded adeno-associated virus (Exendin-4/dsAAV) on SD rats with type 2 diabetes (T2DM) through injecting it into submandibular gland (SG).? METHODS: The Exendin-4/dsAAV was injected into submandibular gland of diabetic rat. The insulin and alpha-amylase were detected by real-time PCR at the 2nd, 4th and 8th weeks. The immunohistochemisty was used to detect the insulin contents in SG at the 8th week. The concentration of blood glucose and levels of insulin secretion were detected after pancreatectomy.? RESULTS: The SG gland was bigger in Exendin 4/dsAAV group than that in the control group, but the changes in alpha-amylase were not significant. The Exendin-4 and insulin gene expression was increased in the Exendin-4/dsAAV group (P<0.05). The Exendin-4 and insulin were positive in the SG. The blood glucose was lower and insulin concentration was higher in the Exendin-4/dsAAV group than those in the control group after pancreatectomy (P<0.05), and the insulin content was also increased in the dsAAV groups.? CONCLUSION: Continuous expression of Exendin-4 in SG may improve glucose control and insulin secretion in T2DM rats through inducing expression of insulin. PMID- 26643420 TI - [Impact of sitagliptin on aspirin resistance in patients with Type 2 diabetes mellitus]. AB - OBJECTIVE: To explore the impact of sitagliptin on aspirin resistance (AR) in patients with Type 2 diabetes mellitus (T2DM).? METHODS: A total of 68 cases of AR were chosen from 136 cases of T2DM patients. The clinical data, including blood samples, fasting plasma glucose (FPG), glycosylated hemoglobin (HbAlc), and high sensitive C reactive protein (hs-CRP) were collected. Aenosine diphosphate (ADP) and arachidonic acid (AA) -induced platelet aggregation rate (PAG) were detected in 1, 3, 6 and 12 months after the treatment to evaluate the impact of sitagliptin on AR. ? RESULTS: After 6 months of hypoglycemic treatment, FPG and HbAlc in two groups were at the normal level. The hypoglycemic effect was not obviously different (P>0.05), but the hsCRP and ADP or AA-induced PAG were decreased in the sitagliptin group with statistical significance when compared with the metformin group (P<0.05).? CONCLUSION: Sitagliptin can significantly improve the oxidative stress inflammatory state in T2DM patients and AR, which is independent on blood glucose control. PMID- 26643421 TI - [Vitamin E prevents the toxic effect of benzo(a)pryene on reproductive system in male SD rats]. AB - OBJECTIVE: To investigate the protective effects and the potential mechanisms of vitamin E (VE) on benzo(a)pryene (B[a]P)-induced toxicity in the reproductive system of male rats. ? METHODS: A total of 60 male Sprague Dawley (SD) rats, weighted 70-90 g, were randomly assigned to 6 groups: a control group, a vehicle group, a B[a]P group (5 mg/kg), a VE (10 mg/kg)+ B[a]P (5 mg/kg) group, a VE (50 mg/kg) + B[a]P (5 mg/kg) group and a VE (100 mg/kg)+B[a]P (5 mg/kg) group (n=10 per group). The rats were treated with B[a]P and/or VE once a day for 30 days via intragastric administration. The sperm quality and the levels of SOD, GSH-Px, 8 OHdG and MDA were detected, respectively. The testicular tissue morphology and DNA damage were observed by HE staining and comet assay.? RESULTS: The sperm count, the rate of sperm deformation, the content of MDA and 8-OHdG were all significantly increased in single B[a]P-treated group in comparison to the control groups. The activities of SOD and GSH-Px were markedly decreased by B[a]P as compared with the control groups (P<0.05). The injury of testicular tissue in B[a]P-treated rats was remarkably improved after VE treatment. The levels of oxidative stress and DNA damage indicators in the B[a]P-treated group were all attenuated by VE. These protective effects of VE were in a dose-dependent manner (P<0.05).? CONCLUSION: Vitamin E can protect the male SD rats against the B[a]P induced reproductive toxicity. PMID- 26643422 TI - [Association of VEGFR2 gene polymorphisms with the effect of L-dopa and dyskinesia complications]. AB - OBJECTIVE: To explore the association of VEGFR2 gene polymorphisms (rs2305948 and rs1870377) with the effect of levodopa (L-dopa) and dyskinesia in Chinese population and to provide theoretical basis for clinical treatment.? METHODS: By using Taqman MGB analysis and gene sequencing, the rs2305948 and rs1870377 polymorphisms of 69 enrolled Parkinson's disease (PD) patients were detected. Among them, 32 cases developed dyskinesia during 5 years and 37 cases did not develop dyskinesia during 8 years (as the control).? RESULTS: There was no significant association between the occurrence of dyskinesia and VEGFR2 polymorphisms at rs2305948 and rs1870377. However, rs1870377 polymorphism of AA showed greater maximum L-dopa dose [(565.00+/-163.55) mg/d vs (396.88+/-200.39) mg/d, (300.00+/-80.18) mg/d, P=0.038] and higher value of Modified Abnormal Involuntary Movement Scale (mAIMS) compared with that with polymorphisms of AT and TT [17.00+/-5.24 vs 8.94+/-6.53, 7.86+/-4.45, P=0.026]. ? CONCLUSION: VEGFR2 genes polymorphism (rs1870377) is associated with maximum L-dopa dose and mAIMS value in PD patients. PMID- 26643423 TI - [Association between CCND1 G870A polymorphism and radiotherapy response in high risk human papillomavirus-related cervical cancer]. AB - OBJECTIVE: To investigate the correlation of cyclin D1 (CCND1) G870A single nucleotide polymorphism (SNP) with radiotherapy response in patients with high risk human papillomavirus (HR-HPV) related cervical cancer.? METHODS: A total of 273 patients with cervical cancer, who were confirmed by histopathology and hybrid capture 2 (HC-2) assay and treated by radiotherapy, were enrolled for this study. The correlation of CCND1 G870A polymorphism with tumor response in patients was assessed.? RESULTS: Compared with patients with AA genotype, the patients with GG genotype and AA genotype showed lower sensitivity to radio therapy treatment (adjusted ORGA=2.69, 95% CI 1.28-5.67 and adjusted ORGG=3.28, 95% CI 1.47-7.29, respectively), an increase in risks of recurrence/metastasis (adjusted ORGA=2.52, 95% CI 1.12-5.63 and adjusted ORGG=3.95, 95% CI 1.68-9.26, respectively), and shorter recurrence/metastasis-free survival (PGA=0.010 and PGG=0.045).? CONCLUSION: G870A polymorphism is a frequent variation that could be used for evaluate the radio-sensitivity and prognosis for patients with HR-HPV related cervical cancer. PMID- 26643424 TI - [Effects of tanshinone IIA on the expressions of p53, pp53 and apoptosis in the rats with Alzheimer's disease]. AB - OBJECTIVE: To observe effects of tanshinone (Tan) IIA on the apoptosis and expressions of p53 and pp53 in brain tissues of rats with Alzheimer's disease (AD).? METHODS: Thirty male Sprague-Dawley rats were randomized into 3 groups: Sham, AD, and Tan IIA groups. The AD models were established by injecting Abeta into the hippocampus of rats. Brain tissues were collected and paraffin sections were prepared to assess pathological changes. The expression of p53 and pp53 was detected by immunohistochemical staining and Western blot. Apoptosis was detected by TUNEL assay.? RESULTS: There was no Abeta staining in the sham group, and the difference of Abeta staining between the AD group and the Tan IIA group was not significant (P>0.05). The expressions of p53 and pp53 were significantly higher in the AD group than those in the control group (P<0.05). The number of apoptotic cells in the AD group was significantly higher than that in the sham groups (P<0.05). Treatment of Tan IIA for AD rats significantly reduced the numbers of apoptotic cells (P<0.05).? CONCLUSION: Abeta can increase the expression of p53 and pp53, and the number of apoptotic cells. Tan IIA treatment may inhibit apoptosis by down-regulation of p53 and pp53 in rats, and in turn to protect neurons. PMID- 26643425 TI - [Significance of P53 and high mobility group box 1 protein in different levels of liver fibrosis in chronic hepatitis B]. AB - OBJECTIVE: To investigate the role of P53 and high mobility group protein 1 (HMGB1) protein expression in liver fibrosis stages in chronic hepatitis B patients.? METHODS: According to the pathological grades, 103 patients were divided into 3 groups: no fibrosis group (n=18), low fibrosis group (n=49) or high fibrosis group (n=36). Serum HMGB1 levels were determined and receiver operating characteristic (ROC) curve was made based on the HMGB1 level and liver fibrosis score. Liver fibrosis model was developed by CCl4 in 60 male SD rats, which were sacrificed 6 or 12 weeks later. The degree of fibrosis was examined by Masson staining; HMGB1 and P53 protein expression were analyzed by Western blot; histone deacetylase (HDAC) activity, TNF-alpha, IL-1beta and IL-6 levels in serum were measured.? RESULTS: The serum levels of HMGB1 level in low and high fibrosis groups were significantly higher than that in no fibrosis group (P<0.01, respectively). ROC curve showed that serum HMGB1 in the diagnosis of hepatic fibrosis with cut off at 74 pg/mL, specificity at 65% and sensitivity at 87%. Compared with the control group, HMGB1 expression in both low and high fibrosis group was decreased in nucleus but was increased in cytoplasm, accompanied by the elevated P53 expression, increased HDAC activity and inflammatory cytokine levels (all P<0.01, respectively).? CONCLUSION: P53 and HMGB1 expression was significantly increased in chronic hepatitis B patients with liver fibrosis; serum HMGB1 level was positively correlated with the degree of liver cirrhosis and HMGB1 could be used as a sensitive and specific index for liver fibrosis prognosis. PMID- 26643427 TI - [Multivariate analysis for pelvic floor dysfunction]. AB - OBJECTIVE: To investigate the risky factors for pelvic floor functional disorder.? METHODS: A total of 346 patients, who undergone surgery for pelvic floor reconstruction from January 2007 to December 2013 in the Third Affiliated Hospital of Zhengzhou University, were enrolled for this study and served as an experimental group. Meanwhile, 349 female healthy subjects were selected as a control group. The data including the times of gestation and parity, history of menopause, hysterectomy surgery, uterine fibroid and leucorrhea were recorded.? RESULTS: Compared with the controls, the numbers of people with hysterectomy, menopause and clean vagina>=III degree, lack of lactobacillus as well as the times of gestation and parity in the experimental group were significantly increased (P<0.05). The history of hysterectomy, the times of gestation and parity and lack of lactobacillus in vagina were the independent risk factors of pelvic floor dysfunction.? CONCLUSION: The history of hysterectomy, the times of gestation and parity, and clean vagina may involve in the occurrence and development of pelvic floor functional disorder, and the existence of lactobacillus in the vagina might be a protective factor. PMID- 26643426 TI - [Risk factors for the formation of aberrant artery collaterals in the uterus with scar in pregnancy womenunderwent cesarean]. AB - OBJECTIVE: To evaluate the prevalence and risk factors for the formation of aberrant artery collaterals in the uterus during uterine artery embolization (UAE).? METHODS: The data of 144 women with scar in the uterus due to cesarean were retrospectively analyzed. They underwent UAE in the period of 2009-2014 and were divided into two groups according to a standard with or without the aberrant artery collaterals in the uterus. The risk factors were analyzed.? RESULTS: Aberrant artery collaterals were found in thirty-four patients. According to multiple logistic regression analysis, the presence of placenta previa (RR=78.556, 95% CI: 2.869-2 150.651, P=0.010), pelvic inflammatory disease (RR=6.633, 95% CI: 1.595-27.592, P=0.009), pregnancy complications (RR=7.264, 95% CI: 1.622-32.531, P=0.010), abortions (RR=18.381, 95% CI: 1.683-200.752, P=0.017) and uterine fibroids or adenomyosis (RR=12.580, 95% CI: 1.004-157.550, P=0.050) were the factors for the presence of aberrant artery collaterals.? CONCLUSION: Aberrant artery collaterals were more frequent in patients with pelvic inflammatory disease, pregnancy complications, abortions and uterine fibroids or adenomyosis. PMID- 26643428 TI - [Perioperative anesthetic exposure and the neurodevelopmental status of 1 year old baby underwent neonatal cardiac surgery]. AB - OBJECTIVE: To determine the association between perioperative anesthetic exposure and neurodevelopmental status at age 1 year old baby underwent complex cardiac surgery.? METHODS: One hundred and fifteen infants were selected from Sichuan People's Hospital. A cohort study was conducted on neonates who underwent complex cardiac surgery. The babies were performed brain MRI before the operation and 7 days after the operation, and 12-month neurodevelopmental testing was carried out with Bayley Scales of Infant and Toddler Development (the third Edition, Bayley III). Doses of volatile anesthetics (VAA), benzodiazepines, and opioids were determined during the 12 months. The association between peri-operative anesthetic exposure and 12-month neurodevelopmental status were analyzed.? RESULTS: A total of 92 infants were enrolled for the final analysis. Their Bayley III scores of cognitive, language, and movement were as follows: 104.2 +/- 14.7, 85.6 +/- 11.3, and 86.9 +/- 13.5, respectively. MRI results showed that 17 infants showed pre-operative brain injury and 25 infants showed new post operative injury. After performing the analysis of stepwise multivariable linear regression, MRI showed the factors affecting neurodevelopment of newborn include the new post-operative injury, higher VAA exposure, fentanyl dose, benzodiazepine dose, ICU length of stay, pre-operative mean regional cerebral oxygen saturation (rSO2), and abnormal chromosomes.? CONCLUSION: VAA exposure and ICU length of stay are associated with poor neurodevelopmental scores at 12 months of age. Further studies need to identify the potential modifiable factors in the peri operative care of neonates to improve neurodevelopmental outcomes. PMID- 26643429 TI - [Arthroscopic anatomical medical patellofemoral ligament reconstruction to treat recurrent patellar dislocation]. AB - OBJECTIVE: To investigate the procedure and efficacy of anatomical medial patellofemoral ligament (MPFL) reconstruction for the treatment of recurrent patellar dislocation assisted with arthroscopy.? METHODS: Between January, 2010 and December 2012, 13 patients with recurrent patellar dislocation, who underwent anatomical MPFL reconstruction and the grafts of operation, were all adopted with autograft semitendinosus. The patellar side used the modified double bone tunnels and the minimally invasive percutaneous grafts through double patellar bone tunnels, and then fixed in the femoral tunnel with absorbable interference screw. Follow-up included the records of the subjective feeling, patellar apprehension test, recurrent dislocation, CT evaluation of bone tunnel position and patellar tilt angle. Knee function was evaluated by the Lysholm score and Kujala score. ? RESULTS: Twelve patients were followed up for 36 months (range 24-60 months). All patients were satisfied with the treatment. No recurrent dislocation occurred. All the patients showed negative apprehension test. Two patients felt uncomfortable after excessive activity in the knee. Another 2 cases lost 10 degrees flexion than the healthy knee. CT showed that the bone tunnel position were all well. The patellar tilt angle was decreased from 20.52 degrees +/-1.48 degrees preoperative to 13.52 degrees +/-1.32 degrees postoperative, with significant difference (t=14.88, P<0. 05); the Kujala score was improved from 55.2+/-4.51 preoperative to 93.8+/-3.87 postoperative, with significant difference (t=-36.238, P<0.05); and the Lysholm score was improved from 56.68+/ 5.52 to 93.08+/-4.68, with significant difference (t=-33.382, P<0.05). ? CONCLUSION: MPFL reconstruction assisted with arthroscopy is an effective surgical procedure for the treatment of recurrent patellar dislocation, which can improve the knee function with little trauma and complications. PMID- 26643430 TI - [Clinical value of virtual touch tissue quantification and PGA index in evaluation of alcoholic liver fibrosis]. AB - OBJECTIVE: To explore the clinical value of virtual touch tissue quantification (VTQ) technique and the PGA index [prothrombin time (P), gamma-glutamyl transpeptadase (GG) and apolipoprotein A1 (ApoAl)] in evaluating the degree of liver fibrosis in alcoholic patients.? METHODS: A total of 64 patients with long term alcohol history were enrolled for this study. The liver ultrasonography elasticity was examined by VTQ techniques, the VTQ value was assessed in the liver target region, and then the PGA index was calculated. According the liver biopsy biological results, a golden standard, the patients were divided into a non-fibrosis group (n=11), a fibrosis group (n=10), a significant fibrosis group (n=14) and a cirrhosis group (n=29). The diagnostic value of VTQ and PGA index were compared in alcoholic patients following the classification of liver fibrosis.? RESULTS: The elastography VTQ values were (1.38+/-0.33), (1.49+/ 0.30), (1.76+/-0.22) and (2.28+/-0.53) m/s; while the PGA indexes were 2.09+/ 0.94, 2.30+/-1.06, 3.57+/-1.09, and 2.21+/-1.99 in the non-fibrosis group, the fibrosis group, the significant fibrosis group and the cirrhosis group, respectively. The VTQ value and PGA index were positively correlated with the classification of liver fibrosis (VTG: r=0.719, PGA: r=0.683; both P<0.01).? CONCLUSION: The alcoholic liver fibrosis can be assessed by noninvasive VTQ technology and PGA index. As a real-time ultrasound elastography technique, VTQ is more accurate than the PGA index. Combination of the two methods is helpful for early diagnosis and treatment in the patients with alcoholic liver fibrosis. PMID- 26643431 TI - [Bacterial culture analysis for patients with chronic rhinosinusitis with or without polyps]. AB - OBJECTIVE: To determine the distribution of bacteria in patients with chronic rhinosinusitis, and to compare the bacteriologic features in middle meatus specimens between patients with nasal polyps (CRSwNP) and patients without nasal polyps (CRSsNP). ? METHODS: We retrospectively analyzed the positive rate and types of bacterial culture in middle meatus specimens from 40 controls, 65 patients with CRSwNP, and 72 patients of CRSsNP. The specimens from the middle meatus were obtained during endoscopic sinus surgery.? RESULTS: The positive rates of bacteria for CRSwNP, CRSsNP and the controls 81.9%, 80.0% and 82.5%, respectively, with no significant difference among the 3 groups. The common aerobe bacteria found in the specimens was Coagulase-negative staphylococci, Staphylococcus aureus, Streptococcus and Corynebacterium. The common anaerobe was Fusobacterium. The positive rates for aerobic and anaerobic bacteria showed no significant differences among the 3 groups.? CONCLUSION: The distribution of bacteria in middle meatus specimens is not significantly different among CRSwNP, CRSsNP and the controls. Therefore, bacterial infection may not play a key role in the pathogenesis of CRS patients with and without nasal polyos. PMID- 26643432 TI - [Effect of the integration pattern of hospital-community on the grade-based management for hypertension in elders]. AB - OBJECTIVE: To investigate the effect of the integration pattern of hospital community on the grade-based management for hypertension in elders.? METHODS: We randomly chosen 218 (male, n=121; female, n=97) primary senile hypertension patients from a Community Health Service Center of District in Changsha City, from June, 2013 to December, 2013. Based on the risky factors, the subjects were divided into three groups and every group received grade-based management on blood pressure with a integration pattern of hospital-community for six months. According to the HILL-BONE high blood pressure compliance scale and the self- designed blood pressure monitoring form, we assessed the effect of compliance and blood pressure control on senile hypertension patient. ? RESULTS: Hypertension treatment rate for the elders ranged from 22.9% to 88.1% (P<0.01). The levels of blood pressure of the subjects were significantly decreased compared with baseline. The level of diastolic blood pressure in the low, average, high and very high-risk group was decreased by 17, 20 and 23 mmHg, respectively (P<0.01). The level of systolic blood in the low, average, high and very high-risk group was decreased by 6, 5 and 7 mmHg, respectively (P<0.01). The compliance rate of HILL-BONE hypertension rose from 54.5% to 87.4% (P<0.01).? CONCLUSION: The integration pattern of hospital-community with the grade-based management for hypertension significantly improved the senile hypertension control rate and compliance of drug treatment. The rational for drug usage rate rose obviously. The integration pattern of hospital-community with the grade-based management for elders deserves to spread. PMID- 26643433 TI - [Progress in research on the relationship between NGAL and metabolic syndrome]. AB - Neutrophil gelatinase-associated lipocalin (NGAL) is a member of the lipocalin family. As a novel adipokine, it widely presents in the tissues under the condition of metabolic disorders. More and more studies suggest that NGAL might be a marker for a variety of diseases associated with lipid metabolism. It is likely that NGAL plays an important role in obese-inflammation-induced metabolic syndrome,insulin resistance, glucose and lipid metabolism, endothelial dysfunction and atherosclerosis pathway. PMID- 26643434 TI - [Progress in study on the role of exosome-derived microRNA in diagnosis and treatment of diseases]. AB - Exosome is a kind of biological membrane structure at nanometer level. It is secreted by various cells in the body and widely distributed in most body fluids, such as saliva, blood, and milk. Biological active substances, including mRNAs, microRNAs, cytokines, and transcription factor, have been identified in the exosomes. MiRNAs are short and non-coding RNAs that modulate gene expression at the posttranscriptional level. MiRNAs extensively involves in henogenesis, cell proliferation and apoptosis. With various biological functions, exosome-derived miRNAs can not only be served as biomarkers to diagnose tumor, neurological diseases and mental disorders, but also possess potential as therapeutic targets. PMID- 26643435 TI - [Clinical value in detection of blood miRNAs in patients with colorectal cancer]. AB - Colorectal cancer (CRC) is the most common cancer in digestive system, with the highest mortality rate. Its pathogenesis, diagnosis and treatment have been studied extensively. With the deepening of the investigations, more and more studies show that miRNA is closely related with the carcinogenesis, diagnosis and treatment of CRC. The abnormal expression of blood miRNA is expected to become the biomarkers for early diagnosis of CRC and prognostic evaluation, and it may provide a new strategy for clinical treatment. PMID- 26643436 TI - [Diagnostic experience in 3 cases of cardiac occupying lesion]. AB - The clinic symptoms of cardiac occupying lesions are complex and difficult to diagnose currently. In this study, three cases of atrial angiosarcoma, left ventricular aneurysm and left ventricular diverticulum were selected, respectively. The clinical characteristics, imaging features (echocardiogram, cardiac CT and MRI) and the postoperative and pathological results for patients were studied. We compared the differences in clinical symptoms, morphology, histology and haemodynamics among the three patients. The diagnosis were confirmed by intraoperative and postoperative pathological examination. We conclude that proper imaging approaches would be beneficial to diagnose the cardiac occupying lesions. Accurate preoperative diagnosis is beneficial to preoperative preparation as well as the decrease in operative risks. PMID- 26643437 TI - Hospital merger control in Germany, the Netherlands and England: Experiences and challenges. AB - Aiming at the efficiency enhancing and quality improving effects of competition, various steps have been undertaken to foster competition in hospital markets. For these mechanisms to work, robust competition policy needs to be enacted and enforced. We compare the hospital markets in Germany, the Netherlands and England regarding their experience with competition and put a special focus on merger control and the stringency of its implementation. Elaborating on the differences in merger control practice we find that despite very similar goals the respective agencies apply very different approaches and take fundamentally different routes when balancing proclaimed benefits of mergers with potential risks of consolidated markets. While the German competition authority has a strong focus on maintaining the preconditions for competition, in the Netherlands we find over the past decade a much stronger focus on hypothesized countervailing buyer power, accepting in turn highly concentrated markets. In England we find the currently most comprehensive analysis of proposed mergers in combination with a clearly positive assessment of the effects of patient choice and competition on prices and quality. All agencies are still reluctant to implement merger simulation models or similarly advanced econometric methods in their appraisal. One very likely reason is a lack of country specific empirical evidence on these matters. PMID- 26643438 TI - Benign and pathological electrocardiographic changes in athletes. AB - Sudden cardiac death is the leading cause of death in athletes during sport. It is a tragic event that generates significant media attention and discussion throughout society as to whether everything possible had been done to prevent it. Regular physical exercise causes cardiac remodeling at both the mechanical and electrical level, known as athlete's heart, resulting in an electrocardiogram (ECG) considered abnormal compared with the ECGs of the general population. Some of these electrocardiographic changes are considered normal or physiological in athletes, while others suggest underlying cardiac disease with the potential to cause sudden cardiac death. There is thus an urgent need to define the electrocardiographic patterns that allow or prohibit participation in sports, and to differentiate them in terms of gender, ethnicity and age. The purpose of this review is to present the latest data on the electrocardiographic changes considered benign or pathological that are typically found in athletes and to critically analyze the most recent criteria for classifying ECGs in this population (the Seattle criteria), comparing them with previous guidelines and with the latest studies on the subject. This article also examines the question of including ECGs in pre-participation screening programs, the US and European approaches to the subject, and the most up-to-date data on the sensitivity, specificity and cost-effectiveness of the ECG in athletes. PMID- 26643439 TI - The structural origin of anomalous properties of liquid water. AB - Water is unique in its number of unusual, often called anomalous, properties. When hot it is a normal simple liquid; however, close to ambient temperatures properties, such as the compressibility, begin to deviate and do so increasingly on further cooling. Clearly, these emerging properties are connected to its ability to form up to four well-defined hydrogen bonds allowing for different local structural arrangements. A wealth of new data from various experiments and simulations has recently become available. When taken together they point to a heterogeneous picture with fluctuations between two classes of local structural environments developing on temperature-dependent length scales. PMID- 26643440 TI - Choice of reference-guided sequence assembler and SNP caller for analysis of Listeria monocytogenes short-read sequence data greatly influences rates of error. AB - BACKGROUND: The influences that different programs and conditions have on error rates of single-nucleotide polymorphism (SNP) analyses are poorly understood. Using Illumina short-read sequence data generated from Listeria monocytogenes strain HPB5622, we assessed the performance of four SNP callers (BCFtools, FreeBayes, UnifiedGenotyper, VarScan) under a variety of conditions, including: (1) a range of sequencing coverages; (2) use of four popular reference-guided assemblers (Burrows-Wheeler Aligner, Novoalign, MOSAIK, SMALT); (3) with and without read quality trimming and filtering; and (4) use of different reference sequences. RESULTS: At 8-fold coverage the proportions of true positive calls ranged from 0.22 to 25.00 % when reads were aligned to a nearly identical reference (0.000096 % distant). Calls made when reads were aligned to a non identical reference (0.85 % distant) were from 92.54 to 98.88 % accurate. At 79 fold coverage accuracies ranged from 3.95 to 20.00 % with the nearly identical reference and 93.80-98.75 % with the non-identical reference. Read preprocessing significantly changed the numbers of false positive calls made, from a 65.24 % decrease to a 54.55 % increase. CONCLUSIONS: The combinations of reference-guided sequence assemblers and SNP callers greatly influenced not only the numbers of true and false positive sites but also the proportions of true positive calls relative to the total numbers of calls made. Furthermore, the efficacy of different assembler and caller combinations changed dramatically with the different conditions tested. Researchers should consider whether identifying the greatest numbers of true positive sites, reducing the numbers of false positive calls, or achieving the highest accuracies are desired. PMID- 26643441 TI - Saprophytic and pathogenic fungi in the Ceratocystidaceae differ in their ability to metabolize plant-derived sucrose. AB - BACKGROUND: Proteins in the Glycoside Hydrolase family 32 (GH32) are carbohydrate active enzymes known as invertases that hydrolyse the glycosidic bonds of complex saccharides. Fungi rely on these enzymes to gain access to and utilize plant derived sucrose. In fungi, GH32 invertase genes are found in higher copy numbers in the genomes of pathogens when compared to closely related saprophytes, suggesting an association between invertases and ecological strategy. The aim of this study was to investigate the distribution and evolution of GH32 invertases in the Ceratocystidaceae using a comparative genomics approach. This fungal family provides an interesting model to study the evolution of these genes, because it includes economically important pathogenic species such as Ceratocystis fimbriata, C. manginecans and C. albifundus, as well as saprophytic species such as Huntiella moniliformis, H. omanensis and H. savannae. RESULTS: The publicly available Ceratocystidaceae genome sequences, as well as the H. savannae genome sequenced here, allowed for the identification of novel GH32-like sequences. The de novo assembly of the H. savannae draft genome consisted of 28.54 megabases that coded for 7 687 putative genes of which one represented a GH32 family member. The number of GH32 gene family members appeared to be related to the ecological adaptations of these fungi. The pathogenic Ceratocystis species all contained two GH32 family genes (a putative cell wall and a putative vacuolar invertase), while the saprophytic Huntiella species had only one of these genes (a putative cell wall invertase). Further analysis showed that the evolution of the GH32 gene family in the Ceratocystidaceae involved transposable element-based retro-transposition and translocation. As an example, the activity of a Fot5-like element likely facilitated the assembly of the genomic regions harbouring the GH32 family genes in Ceratocystis. CONCLUSIONS: This study provides insight into the evolutionary history of the GH32 gene family in Ceratocystidaceae. Our findings suggest that transposable elements shaped the evolution of the GH32 gene family, which in turn determines the sucrolytic activities and related ecological strategies of the Ceratocystidaceae species that harbour them. The study also provides insights into the role of carbohydrate-active enzymes in plant-fungal interactions and adds to our understanding of the evolution of these enzymes and their role in the life style of these fungi. PMID- 26643442 TI - Multi-Atlas Library for Eliminating Normalization Failures in Non-Human Primates. AB - Current tools for automated skull stripping, normalization, and segmentation of non-human primate (NHP) brain MRI studies typically demonstrate high failure rates. Many of these failures are due to a poor initial estimate for the affine component of the transformation. The purpose of this study is to introduce a multi-atlas approach to overcome these limitations and drive the failure rate to near zero. A library of study-specific templates (SST) spanning three Old World primate species (Macaca fascicularis, M. mulatta, Chlorocebus aethiops) was created using a previously described unbiased automated approach. Several modifications were introduced to the methodology to improve initial affine estimation at the study-specific template level, and at the individual subject level. These involve performing multiple separate normalizations to a multi-atlas library of templates and selecting the best performing template on the basis of a covariance similarity metric. This template was then used as an initialization for the affine component of subsequent skull stripping and normalization procedures. Normalization failure rate for SST generation and individual-subject segmentation on a set of 150 NHP was evaluated on the basis of visual inspection. The previous automated template creation procedure results in excellent skull stripping, segmentation, and atlas labeling across species. Failure rate at the individual-subject level was approximately 1%, however at the SST generation level it was 17%. Using the new multi-atlas approach, failure rate was further reduced to zero for both SST generation and individual subject processing. We describe a multi-atlas library registration approach for driving normalization failures in NHP to zero. It is straightforward to implement, and can have application to a wide variety of existing tools, as well as in difficult populations including neonates and the elderly. This approach is also an important step towards developing fully automated high-throughput processing pipelines that are critical for future high volume multi-center NHP imaging studies for studies of drug abuse and brain health. PMID- 26643443 TI - Mapping the Journal of Homosexuality: A Preface. AB - This article serves as a Preface to the supplementary section of this special issue on "Mapping Queer Bioethics," in which we take a solipsistic turn to "map" the Journal of Homosexuality itself. Born contemporaneously with the depathologization of "homosexuality" in the early 1970s, how does the Journal of Homosexuality's commitment to LGBT health issues the past four decades reveal longstanding tensions between medical pathology, cultural appropriation, and political progress? Introducing the articles that follow (each of which examines a seminal medical-themed subject from the journal's history), this article asks how LGBT-sensitive academic texts play complicit roles in both the reinforcement and the liberation of queer subjects in biomedical discourse. PMID- 26643444 TI - Fever phobia: The impact of time and mortality--a systematic review and meta analysis. AB - BACKGROUND: Fever phobia is a term that has been used to describe the exaggerated and unrealistic fear of fever expressed by parents and carers. Since the term was first used in the early 1980s, there have been numerous publications and guidelines stating that fever is not, in itself dangerous, however these fears persist. OBJECTIVES: Investigate the extent of fever phobia and to explore potential associations with time, under-5 mortality rate and geography. DATA SOURCES: Embase (1980 to week 1 2015) and Medline (1946 to week 1 2015) were searched using the terms 'fever' and 'phobia'; and 'fever phobia' as a free text term. One additional paper was published during the review period. STUDY ELIGIBILITY CRITERIA: Studies giving proportion of parents, carers or professionals expressing fear of fever. STUDY APPRAISAL AND SYNTHESIS METHODS: Meta-analysis and cluster analysis using metafor, meta and Cluster in R. RESULTS: Fear of brain damage, coma, convulsions, death and dehydration was high across many of the studies; however there was significant variation as shown by the high I(2) scores which exceeded 95%. This was not explained by the two predictive variables of year of publication, or background mortality apart from a reduction in the fear of brain damage (-0.0185, CI -0.0313 to -0.0057, p=0.0046) and dehydration (-0.0831, -0.1477 to -0.0184, p=0.0118) associated with increased child mortality. LIMITATIONS: Studies were all cross-sectional surveys with a high risk of bias. The pooled estimate, although statistically significant is not the outcome of interest and so should be interpreted with caution. CONCLUSIONS AND IMPLICATIONS: Fever phobia is common and has not significantly declined over time. This may suggest that it is a cultural, rather than individually learned trait and that individual educational programmes are unlikely to be successful in the face of widespread cultural transmission. PMID- 26643445 TI - Structure and processes of interdisciplinary geriatric consultation teams in acute care hospitals: A scoping review. AB - BACKGROUND AND OBJECTIVES: Interdisciplinary geriatric consultation teams are implemented in the acute hospital setting in several high-income countries to provide comprehensive geriatric assessment for the increasing numbers of older patients with a geriatric profile hospitalized on non-geriatric units. Given the inconclusive evidence on this care model's effectiveness to improve patient outcomes, health care policy and practice oriented recommendations to redesign the structure and process of care provided by interdisciplinary geriatric consultation teams are needed. A scoping review was conducted to explore the structure and processes of interdisciplinary geriatric consultation teams in an international context. As nurses are considered key members of these teams, their roles and responsibilities were specifically explored. DESIGN: The revised scoping methodology framework of Arksey and O'Malley was applied. DATA SOURCES: An electronic database search in Ovid MEDLINE, CINAHL and EMBASE and a hand search were performed for the identification of descriptive and experimental studies published in English, French or Dutch until April 2014. REVIEW METHODS: Thematic reporting with descriptive statistics was performed and study findings were validated through interdisciplinary expert meetings. RESULTS: Forty-six papers reporting on 25 distinct interdisciplinary geriatric consultation teams in eight countries across three continents were included. Eight of the 12 teams (67%) reporting on their composition, stated that nurses and physicians were the main core members with head counts varying from 1 to 4 members per profession. In 80% of these teams nurses were required to have completed training in geriatrics. Advanced practice nurses were integrated in eleven out of fourteen interdisciplinary geriatric consultation teams from the USA. Only 32% of teams used formal screening to identify patients most likely to benefit from their intervention, using heterogeneous screening methods, and scarcely providing information on the responsibilities of nurses. Nurses were involved in the medical, functional, psychological and social assessment of patients in 68% of teams, either in a leading role or in collaboration with other professions. Responsibilities of interdisciplinary geriatric consultation teams' nurses regarding in-hospital follow-up or transitional care at hospital discharge were infrequently specified (16% of teams). CONCLUSIONS: This scoping review identified that the structure and processes of care provided to geriatric patients by interdisciplinary geriatric consultation teams are highly heterogeneous. Despite nurses being key team members, only limited information on their specific roles and responsibilities was identified. More research in this area is required in order to inform health care policy and to formulate practice oriented recommendations to redesign the interdisciplinary geriatric consultation team care model aiming to improve its effectiveness. PMID- 26643446 TI - Links between recognition and degradation of cytoplasmic viral RNA in innate immune response. AB - Recognition and degradation of viral RNA are essential for antiviral innate immune responses. Cytoplasmic viral RNA is recognized by retinoic acid-inducible gene I (RIG-I)-like receptors, which trigger type I interferon (IFN) production. Secreted type I IFN activates ubiquitously expressed type I IFN receptor and induces IFN-stimulated genes (ISGs). To suppress viral replication, several nucleases degrade viral RNA. RNase L is an ISG with endonuclease activity that degrades viral RNA, producing small RNA that activates RIG-I, resulting in the amplification of type I IFN production. Moreover, recent studies have elucidated novel links between viral RNA recognition and degradation. The RNA exosome is a protein complex that includes nucleases and is essential for host and viral RNA decay. Although the small RNAs produced by the RNA exosome do not activate RIG-I, several accessory factors of the RNA exosome promote RIG-I activation. Zinc finger antiviral protein (ZAP) is an accessory factor that recognizes viral RNA and promotes viral RNA degradation via the RNA exosome. ZAPS is an alternative splicing form of ZAP and promotes RIG-I oligomerization and ATPase activity, resulting in RIG-I activation. DDX60 is another cofactor involved in the viral RNA degradation via the RNA exosome. The DDX60 protein promotes RIG-I signaling in a cell-type specific manner. These observations imply that viral RNA degradation and recognition are linked to each other. In this review, I discuss the links between recognition and degradation of viral RNA. PMID- 26643447 TI - Simulation of enamel wear for reconstruction of diet and feeding behavior in fossil animals: A micromechanics approach. AB - The deformation and wear events that underlie microwear and macrowear signals commonly used for dietary reconstruction in fossil animals can be replicated and quantified by controlled laboratory tests on extracted tooth specimens in conjunction with fundamental micromechanics analysis. Key variables governing wear relations include angularity, stiffness (modulus), and size of the contacting particle, along with material properties of enamel. Both axial and sliding contacts can result in the removal of tooth enamel. The degree of removal, characterized by a "wear coefficient," varies strongly with particle content at the occlusal interface. Conditions leading to a transition from mild to severe wear are discussed. Measurements of wear traces can provide information about contact force and particle shape. The potential utility of the micromechanics methodology as an adjunct for investigating tooth durability and reconstructing diet is explored. PMID- 26643449 TI - Bendamustine and rituximab in combination with lenalidomide in patients with chronic lymphocytic leukemia. AB - PURPOSE: A phase I/II trial to assess safety and efficacy of the combination bendamustine, rituximab, and lenalidomide (BRL) in patients with chronic lymphocytic leukemia (CLL). PATIENTS AND METHODS: Seventeen relapsed or refractory (R/R) and five previously untreated (FL) CLL patients were enrolled in the trial. In the R/R cohort, four different dose levels of lenalidomide (maximum 15 mg/d) were used. In the FL cohort, lenalidomide was dose escalated from 5 mg/d to 15 mg/d. Bendamustine was used at doses of 50 or 90 mg/m(2) for R/R or FL treatment, respectively. 375 mg/m(2) Rituximab were used for the first and 500 mg/m(2) for subsequent treatment courses. Treatment consisted of up to six courses of 28 d. RESULTS: The maximal tolerable dose of lenalidomide was 5 mg/d. The response rate was 47.1% in R/R and 60% in FL patients. Median progression free survival was 8.0 months. Median overall survival was 22.9 and 12.3 months, respectively, in R/R and FL patients. Grade 3/4 hematological toxicity was observed in 71.4%, and severe infections in 47.6% of patients. Due to high toxicity and low response rate of BRL, the trial was closed prematurely. CONCLUSION: BRL was associated with a high toxicity rate, a high number of treatment interruptions, and a low remission rate. Therefore, BRL cannot be considered an appropriate treatment option for patients with CLL. PMID- 26643451 TI - Post-traumatic stress disorder and depression co-occurrence: Structural relations among disorder constructs and trait and symptom dimensions. AB - OBJECTIVES: Post-traumatic stress disorder (PTSD) and major depressive disorder (MDD) in response to trauma co-occur at high rates. A better understanding of the nature of this co-occurrence is critical to developing an accurate conceptualization of the disorders. This study examined structural relations among the PTSD and MDD constructs and trait and symptom dimensions within the framework of the integrative hierarchical model of anxiety and depression. DESIGN: Study participants completed clinician-rated and self-report measures during a pre-treatment assessment. METHODS: The sample consisted of 200 treatment seeking individuals with a primary DSM-IV PTSD diagnosis. Structural equation modelling was used to examine the relationship between the constructs. RESULTS: The trait negative affect/neuroticism construct had a direct effect on both PTSD and MDD. The trait positive affect/extraversion construct had a unique, negative direct effect on MDD, and PTSD had a unique, direct effect on the physical concerns symptoms construct. An alternative model with the PTSD and MDD constructs combined into an overall general traumatic stress construct produced a decrement in model fit. CONCLUSIONS: These findings provide a clearer understanding of the relationship between co-occurring PTSD and MDD as disorders with shared trait negative affect/neuroticism contributing to the overlap between them and unique trait positive affect/extraversion and physical concerns differentiating them. Therefore, PTSD and MDD in response to trauma may be best represented as two distinct, yet strongly related constructs. PRACTITIONER POINTS: In assessing individuals who have been exposed to trauma, practitioners should recognize that co-occurring PTSD and MDD appears to be best represented as two distinct, yet strongly related constructs. Negative affect may be the shared vulnerability directly influencing both PTSD and MDD; however, in the presence of both PTSD and MDD, low positive affect appears to be more specifically related to MDD and fear of physical sensations to PTSD, which is information that could be used by practitioners in the determination of treatment approach. Overall, these findings are clinically relevant in that they may inform assessment, treatment planning, and ultimately diagnostic classification. PMID- 26643452 TI - Value of cerebrospinal fluid alpha-synuclein species as biomarker in Parkinson's diagnosis and prognosis. AB - Since diagnosis of Parkinson's disease (PD) is mostly based on clinical criteria, it is almost impossible to formulate an early diagnosis, as well as a timely differential diagnosis versus other parkinsonisms. A great effort in searching reliable biomarkers both for early diagnosis and prognosis in PD is currently ongoing. Cerebrospinal fluid has been widely investigated as potential source for such biomarkers, with particular emphasis on alpha-synuclein (alpha-syn) species. We reviewed all the clinical studies carried out so far on cerebrospinal fluid quantification of alpha-syn species in PD. Current evidence supports the value of total and oligomeric alpha-syn in PD diagnosis and in the differential diagnosis of PD and other parkinsonisms. Conversely, the role of alpha-syn species in PD prognosis remains unsatisfactory. PMID- 26643453 TI - Discriminating Active Tuberculosis from Latent Tuberculosis Infection by flow cytometric measurement of CD161-expressing T cells. AB - Interferon-gamma Release Assays (IGRAs) significantly increases the possibility for early diagnosis of tuberculosis, but IGRAs alone cannot discriminate active TB from LTBI. Therefore, fast and reliable discrimination of active tuberculosis, especially bacteriology negative tuberculosis, from LTBI is a great necessity. Here we established an assay based on flow cytometric multiparameter assay assessing expression of CD161 along with CD3, CD4, and CD8, whereby a set of indices formulated by the percentages of CD3(+)CD161(+), CD3(+)CD4(+)CD161(+) and CD3(+)CD8(+)CD161(+) T cells multiplied with lymphocyte/monocyte ratio were established. Application of the CD3(+)CD8(+)CD161(+) index to compare a cohort of active tuberculosis with a cohort of LTBI or health control yielded 0.7662 (95% confidence interval [CI] 0.6559-0.8552) or 0.7922 (95% CI 0.6846-0.8763) for sensitivity and 0.9048 (95% CI 0.8209-0.9580) or 0.8939 (95% CI 0.8392-0.9349) for specificity when the TB cohort was AFB(+); the corresponding results were 0.7481 (95% CI 0.6648-0.8198) or 0.7557 (95% CI 0.6730-0.8265) for sensitivity and 0.8571 (95% CI 0.7637-0.9239) or 0.8603 (95% CI 0.8008-0.9075) for specificity when the TB cohort was AFB(-). Our results reveal that in combination with IGRAs, CD161-based indices provide a novel, fast diagnostic solution addressing the limitation of current tuberculosis diagnostics. PMID- 26643454 TI - A discussion of key values to inform the design and delivery of services for HIV affected women and couples attempting pregnancy in resource-constrained settings. AB - INTRODUCTION: HIV-affected women and couples often desire children and many accept HIV risk in order to attempt pregnancy and satisfy goals for a family. Risk reduction strategies to mitigate sexual and perinatal HIV transmission include biomedical and behavioural approaches. Current efforts to integrate HIV and reproductive health services offer prime opportunities to incorporate strategies for HIV risk reduction during pregnancy attempts. Key client and provider values about services to optimize pregnancy in the context of HIV risk provide insights for the design and implementation of large-scale "safer conception" programmes. DISCUSSION: Through our collective experience and discussions at a multi-disciplinary international World Health Organization convened workshop to initiate the development of guidelines and an algorithm of care to support the delivery of services for HIV-affected women and couples attempting pregnancy, we identified four values that are key to the implementation of these programmes: (1) understanding fertility care and an ability to identify potential fertility problems; (2) providing equity of access to resources enabling informed decision-making about reproductive choices; (3) creating enabling environments that reduce stigma associated with HIV and infertility; and (4) creating enabling environments that encourage disclosure of HIV status and fertility status to partners. Based on these values, recommendations for programmes serving HIV-affected women and couples attempting pregnancy include the following: incorporation of comprehensive reproductive health counselling; training to support the transfer and exchange of knowledge between providers and clients; care environments that reduce the stigma of childbearing among HIV-affected women and couples; support for safe and voluntary disclosure of HIV and fertility status; and increased efforts to engage men in reproductive decision-making at times that align with women's desires. CONCLUSIONS: Programmes, policies and guidelines that integrate HIV treatment and prevention, sexual and reproductive health and fertility care services in a manner responsive to user values and preferences offer opportunities to maximize demand for and use of these services. For HIV-affected women and couples attempting pregnancy, the provision of comprehensive services using available tools - and the development of new tools that are adaptable to many settings and follow consensus recommendations - is a public health imperative. The impetus now is to design and deliver value-driven inclusive programming to achieve the greatest coverage and impact to reduce HIV transmission during pregnancy attempts. PMID- 26643455 TI - Advancing the sexual and reproductive health and human rights of women living with HIV: a review of UN, regional and national human rights norms and standards. AB - INTRODUCTION: The right to sexual and reproductive health (SRH) is an essential part of the right to health and is dependent upon substantive equality, including freedom from multiple and intersecting forms of discrimination that result in exclusion in both law and practice. Nonetheless, general and specific SRH needs of women living with HIV are often not adequately addressed. For example, services that women living with HIV need may not be available or may have multiple barriers, in particular stigma and discrimination. This study was conducted to review United Nations Human Rights Council, Treaty Monitoring Bodies and Special Rapporteur reports and regional and national mechanisms regarding SRH issues of women living with HIV. The objective is to assess areas of progress, as well as gaps, in relation to health and human rights considerations in the work of these normative bodies on health and human rights. METHODS: The review was done using keywords of international, regional and national jurisprudence on findings covering the 2000 to 2014 period for documents in English; searches for the Inter-American Commission on Human Rights and national judgments were also conducted in Spanish. Jurisprudence of UN Treaty Monitoring Bodies, regional mechanisms and national bodies was considered in this regard. RESULTS AND DISCUSSION: In total, 236 findings were identified using the search strategy, and of these 129 were selected for review based on the inclusion criteria. The results highlight that while jurisprudence from international, regional and national bodies reflects consideration of some health and human rights issues related to women living with HIV and SRH, the approach of these bodies has been largely ad hoc and lacks a systematic integration of human rights concerns of women living with HIV in relation to SRH. Most findings relate to non discrimination, accessibility, informed decision-making and accountability. There are critical gaps on normative standards regarding the human rights of women living with HIV in relation to SRH. CONCLUSIONS: A systematic approach to health and human rights considerations related to women living with HIV and SRH by international, regional and national bodies is needed to advance the agenda and ensure that policies and programmes related to SRH systematically take into account the health and human rights of women living with HIV. PMID- 26643456 TI - The time has come to make cervical cancer prevention an essential part of comprehensive sexual and reproductive health services for HIV-positive women in low-income countries. AB - INTRODUCTION: HIV and cervical cancer are intersecting epidemics that disproportionately affect one of the most vulnerable populations in the world: women in low- and middle-income countries (LMICs). Historically, the disparity in cervical cancer risk for women in LMICs has been due to the lack of organized screening and prevention programmes. In recent years, this risk has been augmented by the severity of the HIV epidemic in LMICs. HIV-positive women are at increased risk for developing cervical precancer and cancer, and while the introduction of antiretroviral therapy has dramatically improved life expectancies among HIV-positive women it has not been shown to improve cancer related outcomes. Therefore, an increasing number of HIV-positive women are living in LMICs with limited or no access to cervical cancer screening programmes. In this commentary, we describe the gaps in cervical cancer prevention, the state of evidence for integrating cervical cancer prevention into HIV programmes and future directions for programme implementation and research. DISCUSSION: Despite the biologic, behavioural and demographic overlap between HIV and cervical cancer, cervical cancer prevention has for the most part been left out of sexual and reproductive health (SRH) services for HIV-positive women. Lower cost primary and secondary prevention strategies for cervical cancer are becoming more widely available in LMICs, with increasing evidence for their efficacy and cost-effectiveness. Going forward, cervical cancer prevention must be considered a part of the essential package of SRH services for HIV-positive women. Effective cervical cancer prevention programmes will require a coordinated response from international policymakers and funders, national governments and community leaders. Leveraging the improvements in healthcare infrastructure created by the response to the global HIV epidemic through integration of services may be an effective way to make an impact to prevent cervical cancer among HIV-positive women, but more work remains to determine optimal approaches. CONCLUSIONS: Cervical cancer prevention is an essential part of comprehensive HIV care. In order to ensure maximal impact and cost-effectiveness, implementation strategies for screening programmes must be adapted and rigorously evaluated through a framework that includes equal participation with policymakers, programme planners and key stakeholders in the target communities. PMID- 26643458 TI - "Violence. Enough already": findings from a global participatory survey among women living with HIV. AB - INTRODUCTION: Women living with HIV are vulnerable to gender-based violence (GBV) before and after diagnosis, in multiple settings. This study's aim was to explore how GBV is experienced by women living with HIV, how this affects women's sexual and reproductive health (SRH) and human rights (HR), and the implications for policymakers. METHODS: A community-based, participatory, user-led, mixed-methods study was conducted, with women living with HIV from key affected populations. Simple descriptive frequencies were used for quantitative data. Thematic coding of open qualitative responses was performed and validated with key respondents. RESULTS: In total, 945 women living with HIV from 94 countries participated in the study. Eighty-nine percent of 480 respondents to an optional section on GBV reported having experienced or feared violence, either before, since and/or because of their HIV diagnosis. GBV reporting was higher after HIV diagnosis (intimate partner, family/neighbours, community and health settings). Women described a complex and iterative relationship between GBV and HIV occurring throughout their lives, including breaches of confidentiality and lack of SRH choice in healthcare settings, forced/coerced treatments, HR abuses, moralistic and judgemental attitudes (including towards women from key populations), and fear of losing child custody. Respondents recommended healthcare practitioners and policymakers address stigma and discrimination, training, awareness-raising, and HR abuses in healthcare settings. CONCLUSIONS: Respondents reported increased GBV with partners and in families, communities and healthcare settings after their HIV diagnosis and across the life-cycle. Measures of GBV must be sought and monitored, particularly within healthcare settings that should be safe. Respondents offered policymakers a comprehensive range of recommendations to achieve their SRH and HR goals. Global guidance documents and policies are more likely to succeed for the end-users if lived experiences are used. PMID- 26643457 TI - Sexual inactivity and sexual satisfaction among women living with HIV in Canada in the context of growing social, legal and public health surveillance. AB - INTRODUCTION: Women represent nearly one-quarter of the 71,300 people living with HIV in Canada. Within a context of widespread HIV-related stigma and discrimination and on-going risks to HIV disclosure, little is known about the influence of growing social, legal and public health surveillance of HIV on sexual activity and satisfaction of women living with HIV (WLWH). METHODS: We analyzed baseline cross-sectional survey data for WLWH (>=16 years, self identifying as women) enrolled in the Canadian HIV Women's Sexual and Reproductive Health Cohort Study (CHIWOS), a multisite, longitudinal, community based research study in British Columbia (BC), Ontario (ON) and Quebec (QC). Sexual inactivity was defined as no consensual sex (oral or penetrative) in the prior six months, excluding recently postpartum women (<=6 months). Satisfaction was assessed using an item from the Sexual Satisfaction Scale for Women. Multivariable logistic regression analysis examined independent correlates of sexual inactivity. RESULTS: Of 1213 participants (26% BC, 50% ON, 24% QC), median age was 43 years (IQR: 35, 50). 23% identified as Aboriginal, 28% as African, Caribbean and Black, 41% as White and 8% as other ethnicities. Heterosexual orientation was reported by 87% of participants and LGBTQ by 13%. In total, 82% were currently taking antiretroviral therapy (ART), and 77% reported an undetectable viral load (VL<40 copies/mL). Overall, 49% were sexually inactive and 64% reported being satisfied with their current sex lives, including 49% of sexually inactive and 79% of sexually active women (p<0.001). Sexually inactive women had significantly higher odds of being older (AOR=1.06 per year increase; 95% CI=1.05-1.08), not being in a marital or committed relationship (AOR=4.34; 95% CI=3.13-5.88), having an annual household income below $20,000 CAD (AOR: 1.44; 95% CI=1.08-1.92), and reporting high (vs. low) HIV-related stigma (AOR=1.81; 95% CI=1.09-3.03). No independent association was found with ART use or undetectable VL. CONCLUSIONS: Approximately half of WLWH in this study reported being sexually inactive. Associations with sexual dissatisfaction and high HIV-related stigma suggest that WLWH face challenges navigating healthy and satisfying sexual lives, despite good HIV treatment outcomes. As half of sexually inactive women reported being satisfied with their sex lives, additional research is required to determine whether WLWH are deliberately choosing abstinence as a means of resisting surveillance and disclosure expectations associated with sexual activity. Findings underscore a need for interventions to de-stigmatize HIV, support safe disclosure and re-appropriate the sexual rights of WLWH. PMID- 26643459 TI - Fundamental concerns of women living with HIV around the implementation of Option B+. AB - INTRODUCTION: In 2011, the Global Plan towards the Elimination of New HIV Infections among Children by 2015 and Keeping Their Mothers Alive was launched to scale up efforts to comprehensively end vertical HIV transmission and support mothers living with HIV in remaining healthy. Amidst excitement around using treatment as prevention, Malawi's Ministry of Health conceived Option B+, a strategy used to prevent vertical transmission by initiating all pregnant and breastfeeding women living with HIV on lifelong antiretroviral therapy, irrespective of CD4 count. In 2013, for programmatic and operational reasons, the WHO officially recommended Option B+ to countries with generalized epidemics, limited access to CD4 testing, limited partner testing, long breastfeeding duration or high fertility rates. DISCUSSION: While acknowledging the opportunity to increase treatment access globally and its potential, this commentary reviews the concerns of women living with HIV about human rights, community-based support and other barriers to service uptake and retention in the Option B+ context. Option B+ intensifies many of the pre-existing challenges of HIV prevention and treatment programmes. As women seek comprehensive services to prevent vertical transmission, they can experience various human rights violations, including lack of informed consent, involuntary or coercive HIV testing, limited treatment options, termination of pregnancy or coerced sterilization and pressure to start treatment. Yet, peer and community support strategies can promote treatment readiness, uptake, adherence and lifelong retention in care; reduce stigma and discrimination; and mitigate potential violence stemming from HIV disclosure. Ensuring available and accessible quality care, offering food support and improving linkages to care could increase service uptake and retention. With the heightened focus on interventions to reach pregnant and breastfeeding women living with HIV, a parallel increase in vigilance to secure their health and rights is critical. CONCLUSION: The authors conclude that real progress towards reducing vertical transmission and achieving viral load suppression can only be made by upholding the human rights of women living with HIV, investing in community-based responses, and ensuring universal access to quality healthcare. Only then will the opportunity of accessing lifelong treatment result in improving the health, dignity and lives of women living with HIV, their children and families. PMID- 26643460 TI - How does living with HIV impact on women's mental health? Voices from a global survey. AB - INTRODUCTION: Women living with HIV experience a disproportionate burden of mental health issues. To date, global guidelines contain insufficient guidance on mental health support, particularly regarding perinatal care. The aim of this article is to describe the extent and impact of mental health issues as experienced by women living with HIV on their sexual and reproductive health and human rights (SRH&HR). METHODS: A global, mixed-methods, user-led and designed survey on SRH&HR of women living with HIV was conducted using snowball sampling, containing an optional section exploring mental health issues. Statistical quantitative data analysis included descriptive statistics, correlation and multiple linear regression analysis for the mental health responses. Thematic analysis of open free-text responses was performed for qualitative data. RESULTS: A total of 832 respondents from 94 countries participated in the online survey with 489 responses to the optional mental health section. Of the respondents, 82% reported depression symptoms and 78% rejection. One-fifth reported mental health issues before HIV diagnosis. Respondents reported experiencing a 3.5-fold higher number of mental health issues after diagnosis (8.71 vs 2.48, t[488]=23.00, p<0.001). Nearly half (n=224; 45.8%) had multiple socially disadvantaged identities (SDIs). The number of SDIs was positively correlated with experiencing mental health issues (p<0.05). Women described how mental health issues affected their ability to enjoy their right to sexual and reproductive health and to access services. These included depression, rejection and social exclusion, sleep problems, intersectional stigma, challenges with sexual and intimate relationships, substance use and sexual risk, reproductive health barriers and human rights (HR) violations. Respondents recommended that policymakers and clinicians provide psychological support and counselling, funding for peer support and interventions to challenge gender-based violence and to promote HR. CONCLUSIONS: Interventions addressing intersecting stigmas and any especial impacts of diagnosis during pregnancy are required to ensure women's SRH&HR. Global policy guidelines regarding women living with HIV must incorporate mental health considerations. PMID- 26643461 TI - Human rights and the sexual and reproductive health of women living with HIV--a literature review. AB - INTRODUCTION: Even as the number of women living with HIV around the globe continues to grow, realization of their sexual and reproductive health and human rights remains compromised. The objective of this study was to review the current state of knowledge on the sexual and reproductive health and human rights of women living with HIV to assess evidence and gaps. METHODS: Relevant databases were searched for peer-reviewed and grey literature. Search terms included a combination of MeSH terms and keywords representing women, HIV/AIDS, ART, human rights, sexual and reproductive health. We included both qualitative and quantitative literature published in English, French, or Spanish between July 2011 and December 2014. RESULTS AND DISCUSSION: The search yielded 2228 peer reviewed articles, of which 40 met the inclusion criteria in the final review. The grey literature search yielded 2186 documents of which seven met the inclusion criteria in the final review. Of the articles and documents reviewed, not a single peer-reviewed article described the explicit implementation of rights in programming, and only two documents from the grey literature did so. With one possible exception, no articles or documents were found which addressed rights comprehensively, or addressed the majority of relevant rights (i.e. equality; non-discrimination; participation; privacy and confidentiality; informed decision making; availability, accessibility, acceptability and quality (3AQ) of services individually or in their totality; and accountability). Additional findings indicate that the language of rights is used most often to describe the apparent neglect or violation of human rights and what does exist only addresses a few rights in the context of a few areas within sexual and reproductive health. CONCLUSIONS: Findings from this review suggest the need to better integrate rights into interventions, particularly with attention to provider training, service delivery, raising awareness and capacity building among the community of women living with HIV. Further research is urgently needed to support the sexual and reproductive health and rights of women living with HIV, to identify what works and to inform future programming and policies to improve care, treatment and support for women living with HIV. PMID- 26643462 TI - Safer disclosure of HIV serostatus for women living with HIV who experience or fear violence: a systematic review. AB - INTRODUCTION: Supporting individuals as they disclose their HIV serostatus may lead to a variety of individual and public health benefits. However, many women living with HIV are hesitant to disclose their HIV status due to fear of negative outcomes such as violence, abandonment, relationship dissolution and stigma. METHODS: We conducted a systematic review of studies evaluating interventions to facilitate safer disclosure of HIV status for women living with HIV who experience or fear violence. Articles, conference abstracts and programme reports were included if they reported post-intervention evaluation results and were published before 1 April 2015. Searching was conducted through electronic databases for peer-reviewed articles and conference abstracts, reviewing websites of relevant organizations for grey literature, hand searching reference lists of included studies and contacting experts. Systematic methods were used for screening and data abstraction, which was conducted in duplicate. Study quality (rigor) was assessed with the Cochrane risk of bias tool. RESULTS: Two interventions met the inclusion criteria: the Safe Homes and Respect for Everyone cluster-randomized trial of combination HIV and intimate partner violence (IPV) services in Rakai, Uganda, and the South Africa HIV/AIDS Antenatal Post-Test Support study individual randomized trial of an enhanced counselling intervention for pregnant women undergoing HIV testing and counselling. Both programmes integrated screening for IPV into HIV testing services and trained counsellors to facilitate discussions about disclosure based on a woman's risk of violence. However, both were implemented as part of multiple-component interventions, making it impossible to isolate the impact of the safer disclosure components. CONCLUSIONS: The existing evidence base for interventions to facilitate safe HIV serostatus disclosure for women who experience or fear violence is limited. Development and implementation of new approaches and rigorous evaluation of safe disclosure outcomes is needed to guide programme planners and policy makers. PMID- 26643463 TI - A pressing need to respond to the needs and sexual and reproductive health problems of adolescent girls living with HIV in low- and middle-income countries. AB - INTRODUCTION: This commentary provides the rationale and makes a call for greater investment and effort to meet the sexual and reproductive health (SRH) problems of adolescent girls living with HIV in low- and middle-income countries (LMIC). DISCUSSION: Adolescent girls in LMIC are at a greater risk of acquiring HIV infection than their male peers. They also face a number of other serious SRH problems--early pregnancy, pregnancy- and childbirth-related complications, unsafe abortions, sexual abuse and intimate partner violence and sexually transmitted infections. While many LMIC have made notable progress in preventing HIV in children and adults and in improving the access of these population groups to HIV treatment and care, adolescents in general and adolescent girls in particular have not received the same effort and investment. CONCLUSIONS: Much more needs to be done to implement proven approaches to prevent new HIV infections in adolescent girls in LMIC and to meet the needs of those living with HIV. PMID- 26643465 TI - Advancing the sexual and reproductive health and human rights of women living with HIV. AB - INTRODUCTION: Many women living with HIV can have safe, healthy and satisfying sexual and reproductive health, but there is still a long way to go for this to be a reality, especially for the most vulnerable amongst them who face repeated violations of their rights. DISCUSSION: The contributions in this Supplement from researchers, clinicians, programme managers, policy makers, and women living with HIV demands an important appreciation that the field of sexual and reproductive health and human rights for women living with HIV is complex on many levels, and women living with HIV form a very diverse community. CONCLUSIONS: The manuscripts emphasize that attention must be paid to the following critical dimensions: 1) Placing human rights and gender equality at the centre of a comprehensive approach to health programming, in particular in relation to sexuality and sexual health; 2) Ensuring health systems responsiveness to minimizing inequalities in access to health care and quality of care that often do not meet the needs of women living with HIV; 3) Engaging and empowering women living with HIV in the development of policies and programmes that affect them; and 4) Strengthening monitoring, evaluation and accountability procedures to provide good quality data and ensuring remedies for violations of health and human rights of women living with HIV. PMID- 26643464 TI - Addressing gender inequalities to improve the sexual and reproductive health and wellbeing of women living with HIV. AB - INTRODUCTION: Globally, women constitute 50% of all persons living with HIV. Gender inequalities are a key driver of women's vulnerabilities to HIV. This paper looks at how these structural factors shape specific behaviours and outcomes related to the sexual and reproductive health of women living with HIV. DISCUSSION: There are several pathways by which gender inequalities shape the sexual and reproductive health and wellbeing of women living with HIV. First, gender norms that privilege men's control over women and violence against women inhibit women's ability to practice safer sex, make reproductive decisions based on their own fertility preferences and disclose their HIV status. Second, women's lack of property and inheritance rights and limited access to formal employment makes them disproportionately vulnerable to food insecurity and its consequences. This includes compromising their adherence to antiretroviral therapy and increasing their vulnerability to transactional sex. Third, with respect to stigma and discrimination, women are more likely to be blamed for bringing HIV into the family, as they are often tested before men. In several settings, healthcare providers violate the reproductive rights of women living with HIV in relation to family planning and in denying them care. Lastly, a number of countries have laws that criminalize HIV transmission, which specifically impact women living with HIV who may be reluctant to disclose because of fears of violence and other negative consequences. CONCLUSIONS: Addressing gender inequalities is central to improving the sexual and reproductive health outcomes and more broadly the wellbeing of women living with HIV. Programmes that go beyond a narrow biomedical/clinical approach and address the social and structural context of women's lives can also maximize the benefits of HIV prevention, treatment, care and support. PMID- 26643467 TI - Advances in Wearable Fiber-Shaped Lithium-Ion Batteries. AB - It is highly desirable to develop flexible and efficient energy-storage systems for widely used wearable electronic products. To this end, fiber-shaped lithium ion batteries (LIBs) attract increasing interest due to their combined superiorities of miniaturization, adaptability, and weavability, compared with conventional bulky and planar structures. Recent advances in the fabrication, structure, mechanism, and properties of fiber-shaped LIBs are summarized here, with a focus on the electrode material. Remaining challenges and future directions are also highlighted to provide some useful insights from the viewpoint of practical applications. PMID- 26643469 TI - Malignancies After Heart Transplant. AB - Along with graft vasculopathy, malignancies comprise a major complication after heart transplant, with a rate of occurrence of 39.1% in 10 years. Skin cancers and posttransplant lymphoproliferative disorder are more common in adults, whereas lymphoma is more often shown in children. A major cause of malignancies after heart transplant is the use of increased doses of prophylactics needed during immunosuppressive therapy. Data, however, are scarce regarding the association between a particular immunosuppressive drug and a posttransplant malignancy. Compared with the general population, recipients have a higher incidence of malignancies after heart transplant, with an early onset and more aggressive disease. Solid tumors known to occur in heart transplant recipients include lung cancer, bladder and prostate carcinoma, adenocarcinoma of the oral cavity, stomach cancer, and bowel cancer, although the incidence is rare. The risk factors for development of a malignancy after heart transplant are the same as for the nontransplant population. PMID- 26643468 TI - An adhesin from hydrogen-utilizing rumen methanogen Methanobrevibacter ruminantium M1 binds a broad range of hydrogen-producing microorganisms. AB - Symbiotic associations are ubiquitous in the microbial world and have a major role in shaping the evolution of both partners. One of the most interesting mutualistic relationships exists between protozoa and methanogenic archaea in the fermentative forestomach (rumen) of ruminant animals. Methanogens reside within and on the surface of protozoa as symbionts, and interspecies hydrogen transfer is speculated to be the main driver for physical associations observed between the two groups. In silico analyses of several rumen methanogen genomes have previously shown that up to 5% of genes encode adhesin-like proteins, which may be central to rumen interspecies attachment. We hypothesized that adhesin-like proteins on methanogen cell surfaces facilitate attachment to protozoal hosts. Using phage display technology, we have identified a protein (Mru_1499) from Methanobrevibacter ruminantium M1 as an adhesin that binds to a broad range of rumen protozoa (including the genera Epidinium and Entodinium). This unique adhesin also binds the cell surface of the bacterium Butyrivibrio proteoclasticus, suggesting a broad adhesion spectrum for this protein. PMID- 26643470 TI - Relationship between phosphoinositide-3-kinase genetic polymorphism and schizophrenia. AB - Schizophrenia, with incidence of 1% worldwide, is a common mental disorder. Phosphoinositide-3-kinases (PI3Ks) are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, intracellular trafficking, and survival. These enzymes play an important role in the PI3K/AKT signalling pathway. The PIK3CA gene encodes the alpha catalytic subunit of the PI3K enzyme. The present study analysed the role of three SNPs of the PIK3CA gene (rs6443624 (A/C), rs7640662(C/G) and rs7621329(C/T)) in the development of schizophrenia. METHODS: In this case-controlled study, DNA was extracted from blood samples from 108 patients with schizophrenia and 108 healthy patients as controls. Genotypic analyses of PIK3CA SNPs rs6443624 (A/C), rs7640662(C/G) and rs7621329(C/T) were made using the tetra primer ARMS-PCR technique. RESULTS: The outcome shows significant difference between CT and the combined genotype (CT + TT) of rs7621329 and the risk of schizophrenia (OR = 6.4, 95% CI = 3.023-14.23, p < 0.0001). Outcome showed no significant difference for were for analyses of the rs6443624 and rs7640662 genotypes. CONCLUSIONS: These results indicate an association between PIK3CA gene polymorphism on the rs7621329(C/T) site and the risk of schizophrenia. Further study of the genetic population using a larger sample size is necessary in order to validate these present findings. PMID- 26643472 TI - Bursectomy and non-bursectomy D2 gastrectomy for advanced gastric cancer, initial experience from a single institution in China. AB - BACKGROUND: The aim of this study is to evaluate the safety and efficacy of bursectomy of D2 gastrectomy in terms of postoperative complications and short term survival outcomes. METHODS: From January 2012 to December 2013, data of 406 gastric cancer patients with advanced tumor stages and who underwent D2 radical gastrectomy and were grouped according to whether bursectomy was performed or not in West China Hospital, Sichuan University, were analyzed. RESULTS: Finally, 159 patients were in bursectomy group and 247 patients in non-bursectomy group. Surgical duration was 260.1 +/- 43.4 min in the bursectomy group, compared to 227.9 +/- 48.6 min in the non-bursectomy group (p < 0.001). The intraoperative blood loss was comparable between the bursectomy group and the non-bursectomy group (198.9 +/- 63.5 vs. 201.1 +/- 53.7 ml, p = 0.729). Postoperative morbidity rate showed no significant difference between the two groups, which were 23.3 % in the bursectomy group and 17.8 % in the non-bursectomy group, p = 0.179. The overall survival outcomes of patients were compared between the two groups of all patients (p = 0.055): patients who underwent distal gastrectomy (p = 0.129) and total gastrectomy (p = 0.016) and pT2-3 stage patients (p = 0.117) and pT4a stage patients (p = 0.128). The multivariate survival analysis identified that bursectomy or not, pT stage and pN stage were independent prognostic risk factors for the overall survival. CONCLUSIONS: The bursectomy might increase the surgical duration when the D2 gastrectomy was done. Experienced surgeons can perform it safely. However, for the survival benefits of bursectomy, long-term, large sample sized, and high-quality randomized controlled trials are expected. PMID- 26643471 TI - European trauma guideline compliance assessment: the ETRAUSS study. AB - INTRODUCTION: Haemorrhagic shock is the leading cause of preventable death in trauma patients. The 2013 European trauma guidelines emphasise a comprehensive, multidisciplinary, protocol-based approach to trauma care. The aim of the present Europe-wide survey was to compare 2015 practice with the 2013 guidelines. METHODS: A group of members of the Trauma and Emergency Medicine section of the European Society of Intensive Care Medicine developed a 50-item questionnaire based upon the core recommendations of the 2013 guidelines, employing a multistep approach. The questionnaire covered five fields: care structure and organisation, haemodynamic resuscitation targets, fluid management, transfusion and coagulopathy, and haemorrhage control. The sampling used a two-step approach comprising initial purposive sampling of eminent trauma care providers in each European country, followed by snowball sampling of a maximum number of trauma care providers. RESULTS: A total of 296 responses were collected, 243 (81 %) from European countries. Those from outside the European Union were excluded from the analysis. Approximately three-fourths (74 %) of responders were working in a designated trauma centre. Blunt trauma predominated, accounting for more than 90 % of trauma cases. Considerable heterogeneity was observed in all five core aspects of trauma care, along with frequent deviations from the 2013 guidelines. Only 92 (38 %) of responders claimed to comply with the recommended systolic blood pressure target, and only 81 (33 %) responded that they complied with the target pressure in patients with traumatic brain injury. Crystalloid use was predominant (n = 209; 86 %), and vasopressor use was frequent (n = 171, 76 %) but remained controversial. Only 160 respondents (66 %) declared that they used tranexamic acid always or often. CONCLUSIONS: This is the first European trauma survey, to our knowledge. Heterogeneity is significant across centres with regard to the clinical protocols for trauma patients and as to locally available resources. Deviations from guidelines are frequent, differ from region to region and are dependent upon specialty training. Further efforts are required to provide consensus guidelines and to improve their implementation across European countries. PMID- 26643473 TI - Clinical and radiologic rebound after discontinuation of natalizumab therapy in a highly active multiple sclerosis patient was not halted by dimethyl-fumarate: a case report. AB - BACKGROUND: The evidence on the use of the oral dimethyl-fumarate after the discontinuation of treatment with natalizumab in people with Multiple Sclerosis is still little. Natalizumab discontinuation may induce the recurrence or rebound of the clinical and neuroradiological disease activity. Currently no therapeutic approach has been established to abolish disease reactivation and rebound after natalizumab interruption. CASE PRESENTATION: We describe a case of a 21-year-old woman affected from a highly active relapsing-remitting Multiple Sclerosis who developed a clinical and radiological rebound 5 months after the last infusion of natalizumab, while she was being treated with dimethyl-fumarate 240 mg twice daily. She had received a bridge "therapy" with Cyclophosphamide before staring dimethyl-fumarate. CONCLUSION: We report on this case to stimulate further research to establish whether new current and future drugs available for multiple sclerosis are able to halt the disease rebound after the natalizumab interruption. PMID- 26643474 TI - Case Report: Secondary SUNCT After Radiation Therapy--A Novel Presentation. PMID- 26643475 TI - The device industry and payments to doctors. PMID- 26643476 TI - Regulatory T Cells Orchestrate Similar Immune Evasion of Fetuses and Tumors in Mice. AB - Embryos and tumors are both masses of dividing cells expressing foreign Ags, but they are not rejected by the immune system. We hypothesized that similar tolerogenic mechanisms prevent their rejection. Global comparison of fetal and tumor microenvironments through transcriptomics in mice revealed strikingly similar and dramatic decreases in expression of numerous immune-related pathways, including Ag presentation and T cell signaling. Unsupervised analyses highlighted the parallel kinetics and similarities of immune signature downregulation, from the very first days after tumor or embryo implantation. Besides upregulated signatures related to cell proliferation, the only significant signatures shared by the two conditions across all biological processes and all time points studied were downmodulated immune response signatures. Regulatory T cell depletion completely reverses this immune downmodulation to an immune upregulation that leads to fetal or tumor immune rejection. We propose that evolutionarily selected mechanisms that protect mammalian fetuses from immune attack are hijacked to license tumor development. PMID- 26643477 TI - Cutting Edge: IL-1 Receptor Signaling is Critical for the Development of Autoimmune Uveitis. AB - IL-1beta is a proinflammatory cytokine important for local and systemic immunity. However, aberrant production of this cytokine is implicated in pathogenic mechanisms of a number of inflammatory diseases, including Behcet's disease and age-related macular degeneration. In this study, we report the increased secretion of IL-1beta in the retina by neutrophils, macrophages, and dendritic cells during ocular inflammation and show that loss of IL-1R signaling confers protection from experimental autoimmune uveitis. Moreover, the amelioration of experimental autoimmune uveitis in Il1r-deficient mice was associated with reduced infiltration of inflammatory cells into the retina and decreased numbers of uveitogenic Th17 cells that mediate uveitis. These findings indicate the possible utility of IL-1R-blocking agents for the treatment of ocular inflammatory diseases. PMID- 26643478 TI - Comparative Analysis of Novel Complement-Targeted Inhibitors, MiniFH, and the Natural Regulators Factor H and Factor H-like Protein 1 Reveal Functional Determinants of Complement Regulation. AB - The serum proteins factor H (FH), consisting of 20 complement control protein modules (CCPs), and its splice product FH-like protein 1 (FHL-1; consisting of CCPs 1-7) are major regulators of the alternative pathway (AP) of complement activation. The engineered version of FH, miniFH, contains only the N- and C terminal portions of FH linked by an optimized peptide and shows ~ 10-fold higher ex vivo potency. We explored the hypothesis that regulatory potency is enhanced by unmasking of a ligand-binding site in the C-terminal CCPs 19-20 that is cryptic in full-length native FH. Therefore, we produced an FH variant lacking the central domains 10-15 (FHDelta10-15). To explore how avidity affects regulatory strength, we generated a duplicated version of miniFH, termed midiFH. We compared activities of FHDelta10-15 and midiFH to miniFH, FH, and FHL-1. Relative to FH, FHDelta10-15 exhibited an altered binding profile toward C3 activation products and a 5-fold-enhanced complement regulation on a paroxysmal nocturnal hemoglobinuria patient's erythrocytes. Contrary to dogma, FHL-1 and FH exhibited equal regulatory activity, suggesting that the role of FHL-1 in AP regulation has been underestimated. Unexpectedly, a substantially increased avidity for complement opsonins, as seen in midiFH, did not potentiate the inhibitory potential on host cells. In conclusion, comparisons of engineered and native FH-based regulators have identified features that determine high AP regulatory activity on host cells. Unrestricted availability of FH CCPs 19-20 and an optimal spatial orientation between the N- and C-terminal FH regions are key. PMID- 26643479 TI - Naturally Occurring Subclinical Endotoxemia in Humans Alters Adaptive and Innate Immune Functions through Reduced MAPK and Increased STAT1 Phosphorylation. AB - Multiple studies have shown correlates of immune activation with microbial translocation and plasma LPS during HIV infection. It is unclear whether this activation is due to LPS, residual viral replication, or both. Few studies have addressed the effects of persistent in vivo levels of LPS on specific immune functions in humans in the absence of chronic viral infection or pathological settings such as sepsis. We previously reported on a cohort of HIV-negative men with subclinical endotoxemia linked to alterations in CD4/CD8 T cell ratio and plasma cytokine levels. This HIV-negative cohort allowed us to assess cellular immune functions in the context of different subclinical plasma LPS levels ex vivo without confounding viral effects. By comparing two samples of differing plasma LPS levels from each individual, we now show that subclinical levels of plasma LPS in vivo significantly alter T cell proliferative capacity, monocyte cytokine release, and HLA-DR expression, and induce TLR cross-tolerance by decreased phosphorylation of MAPK pathway components. Using this human in vivo model of subclinical endotoxemia, we furthermore show that plasma LPS leads to constitutive activation of STAT1 through autocrine cytokine signaling, suggesting that subclinical endotoxemia in healthy individuals might lead to significant changes in immune function that have thus far not been appreciated. PMID- 26643481 TI - Search for Rare Copy-Number Variants in Congenital Heart Defects Identifies Novel Candidate Genes and a Potential Role for FOXC1 in Patients With Coarctation of the Aorta. AB - BACKGROUND: Congenital heart defects are the most frequent malformations among newborns and a frequent cause of morbidity and mortality. Although genetic variation contributes to congenital heart defects, their precise molecular bases remain unknown in the majority of patients. METHODS AND RESULTS: We analyzed, by high-resolution array comparative genomic hybridization, 316 children with sporadic, nonsyndromic congenital heart defects, including 76 coarctation of the aorta, 159 transposition of the great arteries, and 81 tetralogy of Fallot, as well as their unaffected parents. We identified by array comparative genomic hybridization, and validated by quantitative real-time polymerase chain reaction, 71 rare de novo (n=8) or inherited (n=63) copy-number variants (CNVs; 50 duplications and 21 deletions) in patients. We identified 113 candidate genes for congenital heart defects within these CNVs, including BTRC, CHRNB3, CSRP2BP, ERBB2, ERMARD, GLIS3, PLN, PTPRJ, RLN3, and TCTE3. No de novo CNVs were identified in patients with transposition of the great arteries in contrast to coarctation of the aorta and tetralogy of Fallot (P=0.002; Fisher exact test). A search for transcription factor binding sites showed that 93% of the rare CNVs identified in patients with coarctation of the aorta contained at least 1 gene with FOXC1-binding sites. This significant enrichment (P<0.0001; permutation test) was not observed for the CNVs identified in patients with transposition of the great arteries and tetralogy of Fallot. We hypothesize that these CNVs may alter the expression of genes regulated by FOXC1. Foxc1 belongs to the forkhead transcription factors family, which plays a critical role in cardiovascular development in mice. CONCLUSIONS: These data suggest that deregulation of FOXC1 or its downstream genes play a major role in the pathogenesis of coarctation of the aorta in humans. PMID- 26643480 TI - Identification of Drosophila Zfh2 as a Mediator of Hypercapnic Immune Regulation by a Genome-Wide RNA Interference Screen. AB - Hypercapnia, elevated partial pressure of CO2 in blood and tissue, develops in many patients with chronic severe obstructive pulmonary disease and other advanced lung disorders. Patients with advanced disease frequently develop bacterial lung infections, and hypercapnia is a risk factor for mortality in such individuals. We previously demonstrated that hypercapnia suppresses induction of NF-kappaB-regulated innate immune response genes required for host defense in human, mouse, and Drosophila cells, and it increases mortality from bacterial infections in both mice and Drosophila. However, the molecular mediators of hypercapnic immune suppression are undefined. In this study, we report a genome wide RNA interference screen in Drosophila S2* cells stimulated with bacterial peptidoglycan. The screen identified 16 genes with human orthologs whose knockdown reduced hypercapnic suppression of the gene encoding the antimicrobial peptide Diptericin (Dipt), but did not increase Dipt mRNA levels in air. In vivo tests of one of the strongest screen hits, zinc finger homeodomain 2 (Zfh2; mammalian orthologs ZFHX3/ATBF1 and ZFHX4), demonstrate that reducing zfh2 function using a mutation or RNA interference improves survival of flies exposed to elevated CO2 and infected with Staphylococcus aureus. Tissue-specific knockdown of zfh2 in the fat body, the major immune and metabolic organ of the fly, mitigates hypercapnia-induced reductions in Dipt and other antimicrobial peptides and improves resistance of CO2-exposed flies to infection. Zfh2 mutations also partially rescue hypercapnia-induced delays in egg hatching, suggesting that Zfh2's role in mediating responses to hypercapnia extends beyond the immune system. Taken together, to our knowledge, these results identify Zfh2 as the first in vivo mediator of hypercapnic immune suppression. PMID- 26643482 TI - The prevalence in the general population of advance directives on euthanasia and discussion of end-of-life wishes: a nationwide survey. AB - BACKGROUND: To determine the extent to which members of the general population have talked to their physician about their wishes regarding medical treatment at the end of life, to describe the prevalence of advance directives on euthanasia, and to identify associated factors. METHOD: This study used data from the cross sectional Health Interview Study (HIS) 2008 that collected data from a representative sample (N = 9651) of the Belgian population. RESULTS: Of all respondents, 4.4 % had spoken to their physician about their wishes regarding medical treatment at the end of life, while 1.8 % had an advance directive on euthanasia. Factors positively associated with discussions regarding wishes for medical treatment at the end of life were being female, being older in age, having poorer health status and having more GP contacts. People older than 55 years and living in Flanders or Brussels were more likely than the youngest age categories to have an advance directive on euthanasia. CONCLUSION: Younger people, men, people living in the Walloon region of Belgium, people without a longstanding illness, chronic condition or disability and people with few GP contacts could represent a target group for education regarding advance care planning. Public information campaigns and education of physicians may help to enable the public and physicians to engage more in advance care planning. PMID- 26643483 TI - Drugs down the drain: When nurses object. AB - The authors examine the nursing practice of disposing unaltered controlled substances into public water systems as an issue for nurses concerned with the environmental harm it can cause. A summary of the history of controlled substance management reveals inconsistencies in the interpretation of current regulations that have led to disposal policies that vary by institution, according to a benchmarking survey of regional hospitals. Much attention has been given to the phenomenon of conscientious objection in the context of patient care that conflicts with a nurse's moral integrity. Nurses who are compelled to dispose narcotics down drains may also face this struggle. The authors submit that this disposal method is based on a type of double effect logic where preventing diversion is viewed as a good effect of flushing unused controlled substances that outweighs any harm it may cause, though there is little evidence to support this conclusion. Consequently, the topic deserves further study so that nurse managers and administrators can support and offer alternatives to nurses who object to flushing drugs down the drain. PMID- 26643485 TI - Sexual Enhancement Treatment for Sexually Violent Predators: Ethical and Legal Implications. AB - The treatment of sexually violent predators (SVPs) has been controversial since the implementation of sexual predator laws and statutes that seek to balance the civil rights of SVPs and the protection of potential victims. In this paper, we will present the case of an SVP who sought sexual enhancement surgery in order to perform intercourse with his wife. We will also discuss the conflicting legal and ethical issues affecting a decision to implement sexual enhancement therapy for SVPs in an effort to reconcile these divergent positions. PMID- 26643484 TI - Crucial contextual attributes of nursing leadership towards a care ethics. AB - BACKGROUND: It is of importance to understand and communicate caring ethics as a ground for qualitative caring environments. Research is needed on nursing attributes that are visible in nursing leadership since it may give bases for reflections related to the patterns of specific contexts. AIM: The aim of this study was to illuminate the meaning of crucial attributes in nursing leadership toward an ethical care of patients in psychiatric in-patient settings. RESEARCH DESIGN: The design of the study was descriptive and qualitative with a phenomenological hermeneutical approach. Participants and research context: The study comprised focus group interviews with nurses working in indoor psychiatric care who participated after giving informed consent. Ethical considerations: Since the topic and informants are not labeled as sensitive and subject to ethical approval, it is not covered by the ethics committee's aim and purpose according to Swedish law. However, careful procedures have been followed according to ethics expressed in the Declaration of Helsinki. FINDINGS: When identifying the thematic structures, analysis resulted in three major themes: To supply, including the following aspects: to supply evidence, to supply common space, and to supply good structures; To support, including the following aspects: to be a role model, to show appreciation and care, and to harbor; To shield, including the following aspects: to advocate, to emit non-tolerance of unethical behavior, and to reprove. DISCUSSION: Leadership is challenging for nurses and plays an important role in ethical qualitative care. These findings should not be understood as a description about nurse manager's role, which probably has different attributes and more focus on an organizational level. CONCLUSION: Making the understanding about crucial attributes explicit, the nurse may receive confirmation and recognition of crucial attributes for ethical care in order to move toward an ethical care. PMID- 26643486 TI - Postpartum and Post-Abortion Contraception: From Research to Programs. AB - Contraception following delivery or an induced abortion reduces the risk of an early unintended pregnancy and its associated adverse health consequences. Unmet need for contraception during the postpartum period and contraceptive counseling and services following abortion have been the focus of efforts for the last several decades. This article provides an introduction to the more focused contributions that follow in this special issue. We discuss the validity and measurement of the concept of unmet need for family planning during the postpartum period. We then present key findings on postpartum contraceptive protection, use dynamics, and method mix, followed by an assessment of interventions to improve postpartum family planning. The evidence on postabortion contraceptive uptake and continuation of use remains thin, although encouraging results are noted for implementation of comprehensive abortion care and for the impact of post-abortion contraceptive counseling and services. Drawing on these studies, we outline policy and program implications for improving postpartum and post-abortion contraceptive use. PMID- 26643487 TI - Reassessing Unmet Need for Family Planning in the Postpartum Period. AB - Despite renewed interest in postpartum family planning programs, the question of the time at which women should be expected to start contraception after a birth remains unanswered. Three indicators of postpartum unmet need consider women to be fully exposed to the risk of pregnancy at different times: right after delivery (prospective indicator), after six months of amenorrhea (intermediate indicator), and at the end of amenorrhea (classic indicator). DHS data from 57 countries in 2005-13 indicate that 62 percent (prospective), 43 percent (intermediate), and 32 percent (classic) of women in the first year after a birth have an unmet need for contraception (40 percent when including abstinence). While the protection afforded by postpartum abstinence and lactational amenorrhea lowers unmet need, further analysis shows that women also often rely on these methods without being actually protected. Programs should acknowledge these methods' widespread use and inform women about their limits. Also, the respective advantages of targeting the postnatal period, the end of six months of amenorrhea/exclusive breastfeeding, or the resumption of sexual intercourse to offer contraceptive services should be tested. PMID- 26643488 TI - Contraceptive Adoption, Discontinuation, and Switching among Postpartum Women in Nairobi's Urban Slums. AB - Unmet need for contraception is highest within 12 months post-delivery, according to research. Using longitudinal data from the Nairobi Urban Health and Demographic Surveillance System, we assess the dynamics of contraceptive use during the postpartum period among women in Nairobi's slums. Results show that by 6 months postpartum, 83 percent of women had resumed sexual activity and 51 percent had resumed menses, yet only 49 percent had adopted a modern contraceptive method. Furthermore, almost half of women discontinued a modern method within 12 months of initiating use, with many likely to switch to another short-term method with high method-related dissatisfaction. Women who adopted a method after resumption of menses had higher discontinuation rates, though the effect was much reduced after adjusting for other variables. To reduce unmet need, effective intervention programs are essential to lower high levels of discontinuation and encourage switching to more effective methods. PMID- 26643489 TI - Associations Between Abortion Services and Acceptance of Postabortion Contraception in Six Indian States. AB - Women receiving induced abortions or postabortion care are at high risk of subsequent unintended pregnancy, and intervals of less than six months between abortion and subsequent pregnancy may be associated with adverse outcomes. This study highlights the prevalence and attributes of postabortion contraceptive acceptance from 2,456 health facilities in six major Indian states, among 292,508 women who received abortion care services from July 2011 through June 2014. Eighty-one percent of the women accepted postabortion contraceptive methods: 53 percent short-term, 11 percent intrauterine devices, and 16 percent sterilization. Postabortion contraceptive acceptance was highest among women who were aged 25 years and older, received first-trimester services, received induced abortion, attended primary-level health facilities, and had medical abortions. Doctors receiving post-training support were more likely to offer contraceptives, but no association was observed between such support and acceptance of IUDs or sterilization. Comprehensive service-delivery interventions, including ensuring availability of skilled providers and contraceptive commodities, offering clinical mentoring for providers, identifying and addressing provider bias, and improving provider counseling skills, can increase postabortion contraceptive acceptance and reduce unintended pregnancy. PMID- 26643490 TI - Postpartum Contraception in Northern Tanzania: Patterns of Use, Relationship to Antenatal Intentions, and Impact of Antenatal Counseling. AB - In Tanzania, unmet need for contraception is high, particularly in the postpartum period. Contraceptive counseling during routine antenatal HIV testing could reach 97 percent of pregnant women with much-needed information, but requires an understanding of postpartum contraceptive use and its relationship to antenatal intentions. We conducted a baseline survey of reproductive behavior among 5,284 antenatal clients in Northern Tanzania, followed by an intervention offering contraceptive counseling to half the respondents. A follow-up survey at 6-15 months postpartum examined patterns and determinants of postpartum contraceptive use, assessed their correspondence with antenatal intentions, and evaluated the impact of the intervention. Despite high loss to follow-up, our findings indicate that condoms and hormonal methods had particular and distinct roles in the postpartum period, based on understandings of postpartum fertility. Antenatal intentions were poor predictors of postpartum reproductive behavior. Antenatal counseling had an effect on postpartum contraceptive intentions, but not on use. Different antenatal/contraceptive service integration models should be tested to determine how and when antenatal counseling can be most effective. PMID- 26643491 TI - Interventions to Improve Postpartum Family Planning in Low- and Middle-Income Countries: Program Implications and Research Priorities. AB - This article provides programmatic guidance and identifies future research priorities through a review of interventions to improve postpartum contraception. Thirty-five interventions in low- and middle-income countries were identified and classified according to timing and nature of administration: antenatal, postnatal, both ante- and postnatal, and integration with other services. With the exception of single, short antenatal interventions, the evidence of impact is positive but incomplete. A major gap in knowledge concerns demand for, and means of promoting, immediate postpartum family planning services in Asia and Africa. Counseling before discharge is likely to have an impact on subsequent contraceptive uptake. Integration of family planning into immunization and pediatric services is justified, but policy and program obstacles remain. A case for relaxing the strict conditions of the lactational amenorrhea method (LAM) is strong, but qualitative evidence on the perspectives of women on pregnancy risks is required. Despite the gaps in knowledge, the evidence provides useful guidance for strategies to promote postpartum family planning, in ways that take different contexts into account. PMID- 26643492 TI - Democratic Republic of Congo 2013-14. PMID- 26643493 TI - Dominican Republic 2013. PMID- 26643495 TI - Perinatal Oxidative Stress May Affect Fetal Ghrelin Levels in Humans. AB - In vitro cell model studies have shown that oxidative stress may affect beta-cell function. It is unknown whether oxidative stress may affect metabolic health in human fetuses/newborns. In a singleton pregnancy cohort (n = 248), we studied maternal (24-28 weeks gestation) and cord plasma biomarkers of oxidative stress [malondialdehyde (MDA), F2-isoprostanes] in relation to fetal metabolic health biomarkers including cord plasma glucose-to-insulin ratio (an indicator of insulin sensitivity), proinsulin-to-insulin ratio (an indicator of beta-cell function), insulin, IGF-I, IGF-II, leptin, adiponectin and ghrelin concentrations. Strong positive correlations were observed between maternal and cord plasma biomarkers of oxidative stress (r = 0.33 for MDA, r = 0.74 for total F2-isoprostanes, all p < 0.0001). Adjusting for gestational age at blood sampling, cord plasma ghrelin concentrations were consistently negatively correlated to oxidative stress biomarkers in maternal (r = -0.32, p < 0.0001 for MDA; r = -0.31, p < 0.0001 for F2-isoprostanes) or cord plasma (r = -0.13, p = 0.04 for MDA; r = -0.32, p < 0.0001 for F2-isoprostanes). Other fetal metabolic health biomarkers were not correlated to oxidative stress. Adjusting for maternal and pregnancy characteristics, similar associations were observed. Our study provides the first preliminary evidence suggesting that oxidative stress may affect fetal ghrelin levels in humans. The implications in developmental "programming" the vulnerability to metabolic syndrome related disorders remain to be elucidated. PMID- 26643496 TI - Association between serum uric acid levels and cerebral white matter lesions in Chinese individuals. AB - PURPOSE/AIM OF THE STUDY: We aimed to evaluate the association between serum uric acid (SUA) levels and cerebral white matter lesions (WMLs) in Chinese individuals. MATERIAL AND METHODS: We prospectively identified patients aged 50 years and older in neurology department from July 2014 to March 2015. Both periventricular WMLs (P-WMLs) and deep WMLs (D-WMLs) were identified on magnetic resonance imanging (MRI) scans and the severity was graded using the Fazekas method. Multivariate logistic regression analyses were performed to examine the association between SUA and WMLs. RESULTS: A total of 480 eligible participants were enrolled in this study. SUA level in severe group was much higher than that in mild group (for P-WMLs: 320.21 +/- 79.97 vs. 286.29 +/- 70.18, p = 0.000; for D-WMLs: 314.71 +/- 74.74 vs. 290.07 +/- 74.04, p = 0.031). Subgroup analyses showed that higher SUA level was associated with higher severity of P-WMLs in women, but not in male patients. Multivariate logistic regression analyses showed that SUA was still associated with increased risk of higher severity of P-WMLs (OR = 1.003, 95% = 1.000-1.006), but not D-WMLs. CONCLUSION: Elevated SUA level was independently associated with greater odds of higher severity of P-WMLs, particularly in women. PMID- 26643497 TI - Molecular detection of vector-borne pathogens in wild and domestic carnivores and their ticks at the human-wildlife interface. AB - Urbanization of natural areas is considered one of the causes of the current apparent emergence of infectious diseases. Carnivores are among the species that adapt well to urban and periurban environments, facilitating cross-species disease transmission with domestic dogs and cats, and potentially with their owners. The prevalence of vector-borne pathogens (VBP) of zoonotic and veterinary interest was studied in sympatric wild and domestic carnivores into Barcelona Metropolitan Area (NE Spain). Blood or spleen samples from 130 animals, including 34 common genets (Genetta genetta), 12 red foxes (Vulpes vulpes), 10 stone martens (Martes foina), three Eurasian badgers (Meles meles), 34 free-roaming domestic cats and 37 dogs with outdoor access, were collected either in protected or adjacent residential areas. A total of 309 ticks (chiefly Rhipicephalus turanicus) were collected on these animals. The samples were analyzed with a battery of PCR assays targeting the DNA of Rickettsia spp., Anaplasmataceae, Coxiella burnetii, Bartonella spp., and Piroplasmida, and the amplicons were sequenced. The fox showed the highest prevalence (58%) and diversity of VBP (four pathogens), whereas none of the dogs were infected. Bartonella spp. (including B. clarridgeiae, B. henselae, and B. rochalimae) was the most prevalent pathogen. Infection of wild carnivores with Ehrlichia canis, C. burnetii, Theileria annae and Babesia vogeli was also confirmed, with some cases of coinfection observed. The presence of DNA of T. annae and B. vogeli was also confirmed in tick pools from four species of wild carnivores, supporting their role in piroplasmid life cycle. By the sequencing of several target genes, DNA of Rickettsia massiliae was confirmed in 17 pools of Rh. turanicus, Rh. sanguineous, and Rh. pusillus from five different species, and Rickettsia conorii in one pool of Rh. sanguineous from a dog. None of the hosts from which these ticks were collected was infected by Rickettsia. Although carnivores may not be reservoir hosts for zoonotic Rickettsia, they can have an important role as mechanical dispersers of infected ticks. PMID- 26643498 TI - [A detailed description of the method of comparison between normative personnel requirements and Psych-PV]. PMID- 26643499 TI - [Evidence-based treatment of psychosis associated with Parkinson's disease]. AB - Psychotic symptoms in Parkinson's disease are frequent phenomena and are often associated with an immense burden for caregivers, increased risk of nursing home placement and mortality. Treatment of psychotic disorders associated with Parkinson's disease often poses a therapeutic dilemma and necessitates a differentiated risk-benefit assessment as both the reduction of antiparkinsonian drugs and use of antipsychotic drugs can result in deterioration of motor functions. This article gives an overview of relevant clinical aspects and highlights the pharmacological evidence-based treatment options. PMID- 26643500 TI - US Hypertension Management Guidelines: A Review of the Recent Past and Recommendations for the Future. PMID- 26643501 TI - Incremental Value of the CRUSADE, ACUITY, and HAS-BLED Risk Scores for the Prediction of Hemorrhagic Events After Coronary Stent Implantation in Patients Undergoing Long or Short Duration of Dual Antiplatelet Therapy. AB - BACKGROUND: Multiple scores have been proposed to stratify bleeding risk, but their value to guide dual antiplatelet therapy duration has never been appraised. We compared the performance of the CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the ACC/AHA Guidelines), ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy), and HAS-BLED (Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly) scores in 1946 patients recruited in the Prolonging Dual Antiplatelet Treatment After Grading Stent-Induced Intimal Hyperplasia Study (PRODIGY) and assessed hemorrhagic and ischemic events in the 24- and 6-month dual antiplatelet therapy groups. METHODS AND RESULTS: Bleeding score performance was assessed with a Cox regression model and C statistics. Discriminative and reclassification power was assessed with net reclassification improvement and integrated discrimination improvement. The C statistic was similar between the CRUSADE score (area under the curve 0.71) and ACUITY (area under the curve 0.68), and higher than HAS-BLED (area under the curve 0.63). CRUSADE, but not ACUITY, improved reclassification (net reclassification index 0.39, P=0.005) and discrimination (integrated discrimination improvement index 0.0083, P=0.021) of major bleeding compared with HAS-BLED. Major bleeding and transfusions were higher in the 24- versus 6-month dual antiplatelet therapy groups in patients with a CRUSADE score >40 (hazard ratio for bleeding 2.69, P=0.035; hazard ratio for transfusions 4.65, P=0.009) but not in those with CRUSADE score <=40 (hazard ratio for bleeding 1.50, P=0.25; hazard ratio for transfusions 1.37, P=0.44), with positive interaction (Pint=0.05 and Pint=0.01, respectively). The number of patients with high CRUSADE scores needed to treat for harm for major bleeding and transfusion were 17 and 15, respectively, with 24-month rather than 6-month dual antiplatelet therapy; corresponding figures in the overall population were 67 and 71, respectively. CONCLUSIONS: Our analysis suggests that the CRUSADE score predicts major bleeding similarly to ACUITY and better than HAS BLED in an all comer population with percutaneous coronary intervention and potentially identifies patients at higher risk of hemorrhagic complications when treated with a long-term dual antiplatelet therapy regimen. CLINICAL TRIAL REGISTRATION: URL: http://clinicaltrials.gov. Unique identifier: NCT00611286. PMID- 26643503 TI - Superluminal and stopped light due to mode coupling in confined hyperbolic metamaterial waveguides. AB - Anisotropic metamaterials with hyperbolic dispersion can be used to design waveguides with unusual properties. We show that, in contrast to planar waveguides, geometric confinement leads to coupling of ordinary (forward) and extraordinary (backward) modes and formation of hybrid waveguided modes, which near the crossing point may exhibit slow, stopped or superluminal behavior accompanied by very strong group velocity dispersion. These modes can be used for designing stopped-light nanolasers for nanophotonic applications and dispersion facilitated signal reshaping in telecom applications. PMID- 26643502 TI - Radiopharmacological characterization of 64Cu-labeled alpha-MSH analogs for potential use in imaging of malignant melanoma. AB - The melanocortin-1 receptor (MC1R) plays an important role in melanoma growth, angiogenesis and metastasis, and is overexpressed in melanoma cells. alpha Melanocyte stimulating hormone (alpha-MSH) and derivatives are known to bind with high affinity at this receptor that provides the potential for selective targeting of melanoma. In this study, one linear alpha-MSH-derived peptide Nle Asp-His-D-Phe-Arg-Trp-Gly-NH2 (NAP-NS1) without linker and with epsilonAhx-beta Ala linker, and a cyclic alpha-MSH derivative, [Lys-Glu-His-D-Phe-Arg-Trp-Glu] Arg-Pro-Val-NH2 (NAP-NS2) with epsilonAhx-beta-Ala linker were conjugated with p SCN-Bn-NOTA and labeled with (64)Cu. Radiochemical and radiopharmacological investigations were performed with regard to transchelation, stability, lipophilicity and in vitro binding assays as well as biodistribution in healthy rats. No transchelation reactions, but high metabolic stability and water solubility were demonstrated. The linear derivatives showed higher affinity than the cyclic one. [(64)Cu]Cu-NOTA-epsilonAhx-beta-Ala-NAP-NS1 ([(64)Cu]Cu-2) displayed rapid cellular association and dissociation in murine B16F10 cell homogenate. All [(64)Cu]Cu-labeled conjugates exhibited affinities in the low nanomolar range in B16F10. [(64)Cu]Cu-2 showed also high affinity in human MeWo and TXM13 cell homogenate. In vivo studies suggested that [(64)Cu]Cu-2 was stable, with about 85 % of intact peptide in rat plasma at 2 h p.i. Biodistribution confirmed the renal pathway as the major elimination route. The uptake of [(64)Cu]Cu-2 in the kidney was 5.9 % ID/g at 5 min p.i. and decreased to 2.0 % ID/g at 60 min p.i. Due to the prospective radiochemical and radiopharmacological properties of the linear alpha-MSH derivative [(64)Cu]Cu-2, this conjugate is a promising candidate for tracer development in human melanoma imaging. PMID- 26643504 TI - Selective self-assembly of adenine-silver nanoparticles forms rings resembling the size of cells. AB - Self-assembly has played critical roles in the construction of functional nanomaterials. However, the structure of the macroscale multicomponent materials built by the self-assembly of nanoscale building blocks is hard to predict due to multiple intermolecular interactions of great complexity. Evaporation of solvents is usually an important approach to induce kinetically stable assemblies of building blocks with a large-scale specific arrangement. During such a deweting process, we tried to monitor the possible interactions between silver nanoparticles and nucleobases at a larger scale by epifluorescence microscopy, thanks to the doping of silver nanoparticles with luminescent silver nanodots. ssDNA oligomer-stabilized silver nanoparticles and adenine self-assemble to form ring-like compartments similar to the size of modern cells. However, the silver ions only dismantle the self-assembly of adenine. The rings are thermodynamically stable as the drying process only enrich the nanoparticles-nucleobase mixture to a concentration that activates the self-assembly. The permeable membrane-like edge of the ring is composed of adenine filaments glued together by silver nanoparticles. Interestingly, chemicals are partially confined and accumulated inside the ring, suggesting that this might be used as a microreactor to speed up chemical reactions during a dewetting process. PMID- 26643505 TI - Relationship between tumour location and preoperative seizure incidence in patients with gliomas: a systematic review and meta-analysis. AB - AIM: The aim of this meta-analysis was to assess the relationship between tumour location and preoperative seizure incidence in patients with gliomas. METHODS: Systematic computerised searches of PubMed and the Web of Knowledge were performed. The meta-analysis of pooled odds ratio (OR) and 95% confidence interval (CI) for preoperative seizure risk, stratified by tumour location, were calculated. RESULTS: Eleven studies with 2,047 patients were included for meta analysis. For gliomas with or without frontal lobe involvement, the preoperative seizure incidence ranged from 31.7% (19/60) to 85.7% (156/182) and 19.7% (12/61) to 85.7% (12/14), respectively; the pooled OR was 1.560 (95% CI: 1.266-1.923; Z: 4.17; p=0.000). For gliomas with or without temporal lobe involvement, seizure incidence was 22.6% (7/31) to 91.7% (11/12) and 26.7% (24/90) to 78.7% (174/221), respectively; the pooled OR was 1.070 (95% CI: 0.794-1.443; Z: 0.45; p=0.656). For gliomas with or without parietal lobe involvement, seizure incidence was 18.1% (3/16) to 100.0% (3/3) and 26.7% (28/105) to 80.4% (226/281), respectively; the pooled OR was 0.770 (95% CI: 0.570-1.040; Z: 1.71; p=0.088). For gliomas with or without occipital lobe involvement, seizure incidence was 0.0% (0/2) to 100.0% (2/2) and 26.8% (30/112) to 75.7% (56/74), respectively; the pooled OR was 0.336 (95% CI: 0.164-0.686; Z: 2.99; p=0.003). For gliomas with or without insula lobe involvement, seizure incidence was 34.8% (8/23) to 72.0% (77/107) and 34.3% (60/175) to 81.3% (247/304), respectively; the pooled OR was 1.058 (95% CI: 0.765 1.463; Z: 0.34; p=0.732). No significant publication bias was found. CONCLUSION: Our meta-analysis indicates that frontal lobe gliomas are related to a higher preoperative seizure incidence, while occipital lobe gliomas are related to a lower incidence. PMID- 26643506 TI - Laparoscopic treatment of giant renal cystic echinococcosis. AB - Hydatid disease is a parasitic infestation caused by the larval form of the cestode Echinococcus granulosus. Isolated renal involvement is quite rare. Surgery is the mainstay of treatment and is classically performed through an open approach with kidney-sparing when feasible. The case of a 33-year-old male patient who underwent laparoscopic unroofing of a giant renal hydatid cyst is described herein. PMID- 26643507 TI - A systematic review of anticancer effects of radix astragali. AB - OBJECTIVE: To review the anticancer effects of Radix astragali (RA), one of the most commonly used herbs to manage cancer in East Asia, and its constituents and to provide evidence of clinical usage through previously performed clinical studies. METHODS: Preclinical and clinical studies related to the anticancer effects of RA were searched from inception to November 2013 in electronic databases. Two reviewers independently investigated 92 eligible studies, extracted all the data of studies and appraised methodological quality of clinical trials. The studies were categorized into in vitro and in vivo experimental studies and clinical studies, and analyzed by saponins, polysaccharides, and flavonoids of RA constituents, RA fraction, and whole extract. RESULTS: In preclinical studies, RA was reported to have tumor growth inhibitory effects, immunomodulatory effects, and attenuating adverse effects by cytotoxic agents as well as chemopreventive effects. Saponins seemed to be the main constituents, which directly contributed to suppression of tumor growth through the activation of both intrinsic and extrinsic apoptotic pathway, modulation of intracellular signaling pathway, and inhibition of invasion and angiogenesis. Flavonoids suppressed tumor growth through the similar mechanisms with saponins. Polysaccharides showed immunomodulatory effects, contributing tumor shrinkages in animal models, despite the low cytotoxicity to cancer cells. Most of the clinical studies were performed with low evidence level of study designs because of various limitations. RA whole extracts and polysaccharides of RA were reported to improve the quality of life and ameliorate myelosuppression and other adverse events induced by cytotoxic therapies. CONCLUSION: The polysaccharides, saponins, and flavonoids of RA, and the whole extract of RA have been widely reported with their anticancer effects in preclinical studies and showed a potential application as a adjunctive cancer therapeutics with the activities of immunomodulation, anti-proliferation and attenuation of adverse effects induced by cytotoxic therapy. PMID- 26643509 TI - Preoperative optimization in pheochromocytoma: phenoxybenzamine may be redundant but not alpha blockade. PMID- 26643508 TI - Protective Effects of Gastrodin Against Autophagy-Mediated Astrocyte Death. AB - Gastrodin is an active ingredient derived from the rhizome of Gastrodia elata. This compound is usually used to treat convulsive illness, dizziness, vertigo, and headache. This study aimed to investigate the effect of gastrodin on the autophagy of glial cells exposed to lipopolysaccharides (LPS, 1 ug/mL). Autophagy is a form of programmed cell death, although it also promotes cell survival. In cultured astrocytes, LPS exposure induced excessive autophagy and apoptosis, which were significantly prevented by the pretreatment cells with gastrodin (10 MUM). The protective effects of gastrodin via autophagy inhibition were verified by the decreased levels of LC3-II, P62, and Beclin-1, which are classical markers for autophagy. Furthermore, gastrodin protected astrocytes from apoptosis through Bcl-2 and Bax signaling pathway. The treatment of astrocytes with rapamycin (500 nM), wortmannin (100 nM), and LY294002 (10 MUM), which are inhibitors of mTOR and PI3K, respectively, eliminated the known effects of gastrodin on the inhibited Beclin-1 expression. Furthermore, gastrodin blocked the down-regulation of glutamine synthetase induced by LPS exposure in astrocytes. Our results suggest that gastrodin can be used as a preventive agent for the excessive autophagy induced by LPS. PMID- 26643510 TI - Contrasting life history strategies in a phylogenetically diverse community of freshwater amphipods (Crustacea: Malacostraca). AB - Differences in life histories are commonly exhibited within ecological communities, especially among species that display increased variations in body size and morphology and are phylogenetically distant. To examine the relationship between morphological dissimilarity and life history divergence, we investigated three morphologically distinct and distantly related species of freshwater amphipods that co-occur throughout the Danube lowlands - Gammarus balcanicus dacicus, Niphargus valachicus and Synurella ambulans - by collecting monthly samples during a one-year period. Results revealed that the studied species differ significantly with respect to fecundity, size at maturity, number of generations per year, duration and timing of the reproductive period and egg volume. Despite some overlap, each species possesses a unique combination of traits, supporting the hypothesis that life history variation within freshwater amphipod communities can reflect dissimilarities regarding body size, morphology and evolutionary relationships. However, it is not yet clear which of these factors has the most significant contribution to life history divergence. PMID- 26643511 TI - Characterization of the complete mitochondrial genome and phylogenetic relationship of Caranx tille (Perciformes: Carangidae). AB - In the present study, we determined the complete mitochondrial genome sequence of Caranx tille by using Illumina and Sanger sequencing technology that was 16 593 bp in size. This mitochondrial genome was made up of 13 protein-coding genes, 22 transfer RNA genes, 2 ribosomal RNA genes, and a putative control region. Of these 37 genes, 28 were encoded by heavy strand, while nine were encoded by light strand. Three types of start codons and four kinds of stop codons were separately detected in 13 protein-coding genes. The overall base composition of this genome was 28.95% for A, 15.84% for G, 26.26% for T, and 28.95% for C, with a slight higher A + T content of 55.21%. From the phylogenetic tree constructed based on 13 concatenated protein-coding genes, we can see that C. tille, C. melampygus and C. ignobilis grouped together and formed a single cluster. In addition, C. tille was genetically closest to C. melampygus. This work should facilitate the studies on molecular evolution and population genetic structure for fishes under family Carangidae. PMID- 26643512 TI - Investigation on the partial resistance of Cpkk2 knock out strain of Cryphonectria parasitica to Cryphonectria hypovirus 1 infection in presence of Geneticin and Geneticin resistance gene. AB - We have recently characterized the central components of the three MAP kinase cascades present in Cryphonectria parasitica : the MEK genes cpkk1, cpkk2 and cpkk3. When we attempted to infect through anastomosis the three knock out strains with Cryphonectria hypovirus 1 (CHV1), only the deletion strain of Cpkk2, the yeast Ste7 homologue, involved in mating and filamentous growth, could not be infected. We then proceeded to attempt virus infection through transformation of Deltacpkk2 protoplasts using an infectious cDNA clone able to establish virus infection through transformation. In this case, a very limited number of strains could be recovered as stable transformants compared to the efficiency of control transformations with plasmid carrying only the antibiotic marker. Furthermore, transformants carrying actively replicating virus could be isolated only if the selection marker Geneticin was used during the very initial selection process, and not maintained throughout the growth of the colonies. Moreover, Deltacpkk2 isolates that maintained the virus lost Geneticin resistance. We therefore unveiled a specific negative interaction among virus infection, presence of Geneticin in the growth media, and lack of Cpkk2 MEK in the fungal host. PMID- 26643513 TI - Safety of Laparoscopic Pelvic Exenteration with Urinary Diversion for Colorectal Malignancies. AB - BACKGROUND: Although the feasibility of laparoscopic surgery for colorectal cancer has been demonstrated, the safety of laparoscopic pelvic exenteration (PE) with urinary diversion for colorectal malignancies remains poorly studied. The present study aimed to examine the safety and feasibility of laparoscopic PE in patients with colorectal malignancies. METHODS: Thirty-one consecutive patients who underwent anterior or total PE with urinary diversion for colorectal malignancies between July 2004 and April 2015 at our institution were included in the study. Perioperative outcomes were compared between patients undergoing laparoscopic (n = 13) and open (n = 18) PE. RESULTS: There were no conversions to open surgery. The estimated blood loss (930 vs. 3003 ml; P = 0.001) and total volume of blood transfusion (0 vs. 1990 ml; P = 0.002) were significantly lower in patients undergoing laparoscopic compared with open PE. R0 resection was performed in all patients. The operation time (laparoscopic, 829 min vs. open, 875 min; P = 0.660), complication rate (laparoscopic, 61.5 % vs. open, 83.3 %; P = 0.171), and postoperative hospital days (laparoscopic, 29 days vs. open, 33 days; P = 0.356) were similar in both groups. Three patients undergoing laparoscopic PE readmitted within 30 days due to ileus, although the rate of readmission did not differ significantly (laparoscopic, 23.1 % vs. open, 5.6 %; P = 0.284). CONCLUSION: Laparoscopic PE performed by experienced laparoscopic pelvic surgeons should be considered as a safe and preferred option in selected patients with colorectal malignancies, with a significant advantage in terms of reduced blood loss compared with open surgery. PMID- 26643516 TI - Brain machine interfaces: state of the art and challenges to translation. PMID- 26643514 TI - Hospital Utilization of Nationally Shared Liver Allografts from 2007 to 2012. AB - BACKGROUND: Due to the current geographic disparities in liver allocation a policy, which endorses broader sharing of allografts, has been proposed. We performed a retrospective cohort study to identify how nationally shared allografts, under the current policy, affect perioperative outcomes and resource utilization following liver transplantation (LT). METHODS: Univariate and multivariate analysis identified how patient characteristics and hospital outcomes were associated with national sharing. This analysis was based on 12,282 deceased donor liver transplants performed between 2007 and 2012 using the scientific registry of transplant recipients linked to the University HealthSystem Consortium database. RESULTS: Compared to locally distributed livers, nationally shared livers are more likely to have a donor risk index >1.8 (64.3 vs. 11.6 %), to be classified as expanded criteria donors (44.6 vs. 24.8 %), and transplanted into healthier recipients. Nationally shared LTs were more likely to be performed at high-volume centers (49.1 vs. 30.6 %), resulted in longer length of stay (11 vs. 9 days), and had higher in-hospital mortality (6.6 vs. 3.3 %). Additionally, nationally shared allografts were independent predictors of in-hospital mortality (OR 1.64, 95 % CI 1.13-2.39) and length of stay (OR 1.12, 95 % CI 1.02-1.21). CONCLUSION: These data suggest that increased national sharing of livers may result in inferior patient outcomes and increased resource utilization. PMID- 26643515 TI - Morbid Obesity is Associated with Increased Mortality, Surgical Complications, and Incremental Health Care Utilization in the Peri-Operative Period of Colorectal Cancer Surgery. AB - BACKGROUND: Morbid obesity (Basic Mass Index >= 40 kg/m(2)) leads to increased long-term mortality after colorectal cancer (CRC) surgery. Little is known about its effects on peri-operative CRC surgery outcomes. METHODS: 85,300 discharges for CRC surgery were identified using the redesigned 2012 National Inpatient Sample. Outcomes of interest were mortality, healthcare charges, and surgical outcomes in morbidly obese patients which were compared to those in nonobese patients. RESULTS: There were 4385 (5.14%) morbidly obese patients who underwent CRC surgery during the study period. Morbid obesity was associated with younger age, females, and African Americans in our study (p < 0.05). Morbidly obese patients had higher prevalence of CRC peri-operative co-morbidities, surgical complications, and conversions from laparoscopic to open surgery. On multivariate analysis, morbid obesity led to an increased CRC surgery peri-operative mortality (OR 1.85, 95 % CI 1.15, 2.97). Mortality remained significant even after adjusting for surgical complications (OR 1.79, 95 % CI 1.12, 2.88). Morbidly obese patients undergoing CRC also had a prolonged length of hospitalization (1.22 day, 95 % CI 0.67, 1.78), a $15,582 increase in total hospital charges (95 % CI 8419, 22,745), and increased disposition to short-term rehabilitation facilities (OR 2.25, 95 % CI 1.79, 2.84). CONCLUSION: Analysis of national level data demonstrates that morbidly obese patients have an increased CRC surgery peri operative mortality with higher prevalence of co-morbidities, surgical complications, and more health care resource utilization. Future research efforts should concentrate on ameliorating these outcomes in morbidly obese patients. PMID- 26643517 TI - Single-Particle Tracking of Human Lipoproteins. AB - Lipoproteins, such as high-density lipoprotein (HDL), low-density lipoprotein (LDL), and very-low density lipoprotein (VLDL), play a critical role in heart disease. Lipoproteins vary in size and shape as well as in their apolipoprotein content. Here, we developed a new experimental framework to study freely diffusing lipoproteins from human blood, allowing analysis of even the smallest HDL with a radius of 5 nm. In an easily constructed confinement chamber, individual HDL, LDL, and VLDL particles labeled with three distinct fluorophores were simultaneously tracked by wide-field fluorescence microscopy and their sizes were determined by their motion. This technique enables studies of individual lipoproteins in solution and allows characterization of the heterogeneous properties of lipoproteins which affect their biological function but are difficult to discern in bulk studies. PMID- 26643518 TI - [Medicoeconomic aspects of benign prostatic hyperplasia medical treatment]. AB - INTRODUCTION: The medicoeconomic issues of drug management of benign prostatic hyperplasia (BPH) are essential due to the aging population and the increasing number of therapeutic options. It is thus essential to assess the cost effectiveness in order to define the most appropriate therapeutic strategies economically. The objective of this work was to conduct a literature review on the medicoeconomic studies on the drug therapy of BPH. METHOD: After analyzing the literature, 43 articles were found and 9 were selected for their relevance. RESULTS: Based on Markov models, we observed that: combination therapy and combined treatments (alphablockers and inhibitors of 5-alpha reductase [5ARI]) seemed to have the best cost-effectiveness. Then came the alphablockers, less expensive but exposing to a greater risk of progression and to the necessity of surgical treatments. Then came the 5ARI monotherapy and finally simple monitoring. CONCLUSION: The Markov models are imperfect tools, and resources invested in care depend on both the economic model and the value that individuals and society give to efficiency and cost. PMID- 26643519 TI - Tolerance to Trypanosomatids: A Threat, or a Key for Disease Elimination? AB - So far, research on trypanosomatid infections has been driven by 'disease by disease' approaches, leading to different concepts and control strategies. It is, however, increasingly clear that they share common features such as the ability to generate long-lasting asymptomatic infections in their mammalian hosts. Trypanotolerance, long integrated in animal African trypanosomiasis control, historically refers to the ability of cattle breeds to limit Trypanosoma infection and pathology, but has only recently been recognized in humans. Whilst trypanotolerance is absent from the vocabulary on leishmaniasis and Chagas disease, asymptomatic infections also occur. We review the concept of trypanotolerance across the trypanosomatids and discuss the importance of asymptomatic carriage in the current context of elimination. PMID- 26643520 TI - Balancing the evidence on the cardiovascular determinants of oxygen uptake improvement after endurance training in the elderly: What are the next steps? PMID- 26643521 TI - Routinely analyzed leukocyte characteristics improve prediction of mortality after coronary angiography. AB - BACKGROUND: Inflammation and leukocyte infiltration are hallmarks of atherosclerosis. Clinically routine hematology analyzers mostly perform an entire differential blood count by default, irrespective of the requested parameter. We hypothesize that these normally unreported leukocyte characteristics associate with coronary artery disease (CAD) severity and can improve prediction of mortality in coronary angiography patients. METHODS: We studied coronary angiography patients suspected of CAD (n = 1015) from the Utrecht Coronary Biobank cohort. Leukocyte characteristics were routinely assessed in blood drawn directly prior to angiography using an automated hematology analyzer and extracted from the Utrecht patient oriented database (UPOD) database. Patients were followed up for a median duration of 805 days, during which 65 patients died. We evaluated the association of leukocyte characteristics with synergy between PCI with taxus and cardiac surgery (SYNTAX) score as a measure of CAD severity, all-cause and cardiovascular mortality and major adverse cardiovascular events (MACEs). In order to determine the improvement of risk prediction, we calculated continuous net reclassification improvement (cNRI) and integrated discrimination improvement (IDI). RESULTS: Monocyte percentage showed strong independent predictive value for all-cause mortality (hazard ratio (HR) 1.44 (1.19-1.74), p < 0.001), and the monocyte-to-lymphocyte ratio performed best for cardiovascular mortality (HR 1.42 (1.11-1.81), p = 0.005). The cNRIs and IDIs of leukocyte characteristics for all-cause mortality confirmed the improvement in mortality risk prediction. No significantly predictive leukocyte characteristics were found for MACEs. CONCLUSION: Readily available yet unreported leukocyte characteristics from routine hematology analyzers significantly improved prediction of mortality in coronary angiography patients on top of clinical characteristics. PMID- 26643525 TI - Gastrointestinal neuroendocrine tumors: Searching the optimal treatment strategy- A literature review. AB - Neuroendocrine tumors of the gastro-entero-pancreatic system (GEP-NETs) are a heterogeneous group of neoplasms, with different malignant potential and behavior. Many treatment options are available. Surgery should be considered for localized tumors and in some selected cases of metastatic disease. Somatostatin analogs, useful for symptoms control in functioning tumors, are also effective to inhibit tumor progression in specific settings. The multi-TKI sunitinib and of the mTOR-inhibitor everolimus are efficacy for metastatic pancreatic NET (P-NET) treatment. Chemotherapy is generally used in symptomatic and progressive NETs. Peptide receptor radionuclide therapy (PRRT) should be recommended after failure of medical therapy. For tumors confined to the liver ablative techniques should be considered. Nevertheless a shared therapeutic sequence for GEP-NET treatment still does not exist. In this review, we analyzed available data trying to identify the better treatment strategy and to suggest potential therapeutic algorithms distinguishing P-NETs from gastrointestinal NETs (GI-NETs). PMID- 26643522 TI - Gold Standard or Fool's Gold? The Efficacy of Displacement Variables as Indicators of Energy Expenditure in Team Sports. AB - Over recent decades, the use of player tracking technology to monitor physical work output has become established practice in many team sports. Early tracking systems were manual in nature, relying on subjective assessments and arbitrary classifications of movement intensity. Poor spatial and temporal resolution meant that only gross displacement measures could be used to infer energy demands. However, the advent and evolution of automated systems, with higher sampling rates and improved accuracy, have enabled data collection to occur on a mass scale, and served as a catalyst for extensive research into the demands of team sport activity, including comparisons between different groups of athletes, and the effects of various interventions on performance. The inherent assumption with this research is that, based on steady-state models where energy cost is independent of speed, total distance and average speed are indicative of the amount and rate of work done, respectively. This assumption could be justified if the activity was performed at a constant speed in a straight line. However, team sport movement involves continual changes in both speed and direction, both of which increase energy cost. Accordingly, new models have emerged that incorporate both speed and acceleration to determine metabolic power. This provides a more complete measure of energy expenditure in intermittent activity, and is potentially more suitable than displacement variables for research into the demands of team sports. PMID- 26643526 TI - Activation of the SOS response increases the frequency of small colony variants. AB - BACKGROUND: In Staphylococcus aureus sub-populations of slow-growing cells forming small colony variants (SCVs) are associated with persistent and recurrent infections that are difficult to eradicate with antibiotic therapies. In SCVs that are resistant towards aminoglycosides, mutations have been identified in genes encoding components of the respiratory chain. Given the high frequencies of SCVs isolated clinically it is vital to understand the conditions that promote or select for SCVs. RESULTS: In this study we have examined how exposure to sub inhibitory concentrations of antibiotics with different mechanism of action influence the formation of SCVs that are resistant to otherwise lethal concentrations of the aminoglycoside, gentamicin. We found that exposure of S. aureus to fluoroquinolones and mitomycin C increased the frequency of gentamicin resistant SCVs, while other antibiotic classes failed to do so. The higher proportion of SCVs in cultures exposed to fluoroquinolones and mitomycin C compared to un-exposed cultures correlate with an increased mutation rate monitored by rifampicin resistance and followed induction of the SOS DNA damage response. CONCLUSION: Our observations suggest that environmental stimuli, including antimicrobials that reduce replication fidelity, increase the formation of SCVs through activation of the SOS response and thereby potentially promote persistent infections that are difficult to treat. PMID- 26643527 TI - Distribution of mutational fitness effects and of epistasis in the 5' untranslated region of a plant RNA virus. AB - BACKGROUND: Understanding the causes and consequences of phenotypic variability is a central topic of evolutionary biology. Mutations within non-coding cis regulatory regions are thought to be of major effect since they affect the expression of downstream genes. To address the evolutionary potential of mutations affecting such regions in RNA viruses, we explored the fitness properties of mutations affecting the 5'-untranslated region (UTR) of a prototypical member of the picorna-like superfamily, Tobacco etch virus (TEV). This 5' UTR acts as an internal ribosomal entry site (IRES) and is essential for expression of all viral genes. RESULTS: We determined in vitro the folding of 5' UTR using the selective 2'-hydroxyl acylation analyzed by primer extension (SHAPE) technique. Then, we created a collection of single-nucleotide substitutions on this region and evaluated the statistical properties of their fitness effects in vivo. We found that, compared to random mutations affecting coding sequences, mutations at the 5' UTR were of weaker effect. We also created double mutants by combining pairs of these single mutations and found variation in the magnitude and sign of epistatic interactions, with an enrichment of cases of positive epistasis. A correlation exists between the magnitude of fitness effects and the size of the perturbation made in the RNA folding structure, suggesting that the larger the departure from the predicted fold, the more negative impact in viral fitness. CONCLUSIONS: Evidence that mutational fitness effects on the short 5' UTR regulatory sequence of TEV are weaker than those affecting its coding sequences have been found. Epistasis among pairs of mutations on the 5' UTR ranged between the extreme cases of synthetic lethal and compensatory. A plausible hypothesis to explain all these observations is that the interaction between the 5' UTR and the host translational machinery was shaped by natural selection to be robust to mutations, thus ensuring the homeostatic expression of viral genes even at high mutation rates. PMID- 26643524 TI - Cardiovascular disease following hematopoietic stem cell transplantation: Pathogenesis, detection, and the cardioprotective role of aerobic training. AB - Advances in hematopoietic cell transplantation (HCT) techniques and supportive care strategies have led to dramatic improvements in relapse mortality in patients with high-risk hematological malignancies. These improvements, however, conversely increase the risk of late-occurring non-cancer competing causes, mostly cardiovascular disease (CVD). HCT recipients have a significantly increased risk of CVD-specific mortality, including elevated incidence of coronary artery disease (CAD), cerebrovascular disease, and heart failure (HF) compared to age-matched counterparts. Accordingly, there is an urgent need to identify techniques for the detection of early CVD in HCT patients to inform early prevention strategies. Aerobic training (AT) is established as the cornerstone of primary and secondary disease prevention in multiple clinical settings, and may confer similar benefits in HCT patients at high-risk of CVD. The potential benefits of AT either before, immediately after, or in the months/years following HCT have received limited attention. Here, we discuss the risk and extent of CVD in adult HCT patients, highlight novel tools for early detection of CVD, and review existing evidence in oncology and non-oncology populations supporting the efficacy of AT to attenuate HCT-induced CVD. This knowledge can be utilized to optimize treatment, while minimizing CVD risk in individuals with hematological malignancies undergoing HCT. PMID- 26643528 TI - Development of a Measure of Housing and Housing Services. AB - The Housing Program Measure (HPM) was designed to document critical elements of a range of housing program types and associated services. Qualitative methods, including literature review and open-ended interviews, were used to determine pertinent HPM domains and to develop the pool of items. The measure was pre tested, and reliability and validity analyses were applied to revise and strengthen the measure. The resulting measure furthers homelessness research by providing a tool that can be used to define housing and housing services interventions across diverse projects and disciplines, to facilitate program management by matching housing resources to the needs of homeless individuals, and to support model development by measuring progress to goals. PMID- 26643529 TI - Acute Kidney Injury and Rhabdomyolysis After Protobothrops flavoviridis Bite: A Retrospective Survey of 86 Patients in a Tertiary Care Center. AB - Acute kidney injury (AKI) is the main cause of death for victims of hematoxic snakebites. A few studies have described improvement in AKI rates in snakebite cases, but the reasons for the improvement have not been investigated. Eighty-six patients with Protobothrops flavoviridis bites admitted to a single center from January 2003 through March 2014 were included in the study. Clinical variables, including age, sex, blood pressure (BP), and serum creatinine (S-Cre), on admission were compared between patients with and without AKI. One patient died of disseminated intravascular coagulation following AKI (mortality rate 1.1%). Six patients developed AKI with rhabdomyolysis. Systolic BP, S-Cre, serum creatine kinase, white blood cell count, and platelet count differed significantly between the AKI and non-AKI groups (P = 0.01). Three of the six patients were physically challenged to a degree that made it difficult for them to move or communicate, and these difficulties likely exacerbated the severity of snakebite complications. Our study demonstrated that the risk of snakebite induced AKI for physically challenged patients was high. To further reduce mortality due to snakebite-induced AKI, we need to make it possible for physically challenged patients to receive first aid sooner. PMID- 26643530 TI - A Cluster Randomized Controlled Evaluation of the Health Impact of a Novel Antimicrobial Hand Towel on the Health of Children Under 2 Years Old in Rural Communities in Nyanza Province, Kenya. AB - To assess the health impact of reusable, antimicrobial hand towels, we conducted a cluster randomized, yearlong field trial. At baseline, we surveyed mothers, and gave four towels plus hygiene education to intervention households and education alone to controls. At biweekly home visits, we asked about infections in children < 2 years old and tested post-handwashing hand rinse samples of 20% of mothers for Escherichia coli. At study's conclusion, we tested 50% of towels for E. coli. Baseline characteristics between 188 intervention and 181 control households were similar. Intervention and control children had similar rates of diarrhea (1.47 versus 1.48, P = 0.99), respiratory infections (1.38 versus 1.48, P = 0.92), skin infections (1.76 versus 1.79, P = 0.81), and subjective fever (2.62 versus 3.40, P = 0.04) per 100 person-visits. Post-handwashing hand contamination was similar; 67% of towels exhibited E. coli contamination. Antimicrobial hand towels became contaminated over time, did not improve hand hygiene, or prevent diarrhea, respiratory infections, or skin infections. PMID- 26643531 TI - Clinical Attack Rate of Chikungunya in a Cohort of Nicaraguan Children. AB - Chikungunya virus (CHIKV) was recently introduced into the Americas. In Nicaragua, the first endogenous transmission of CHIKV was recognized in September 2014. We used an ongoing dengue cohort study of children aged 2-14 years in Managua, Nicaragua, to document the attack rate of symptomatic chikungunya in a presumably naive population. From September 2014 through March 2015, the overall clinical attack rate of laboratory-confirmed CHIKV infection was 2.9% (95% confidence interval [CI]: 2.3%, 3.4%). The attack rate was greater in children >= 8 years of age (4.1%; 95% CI: 3.2%, 5.1%) than in those < 8 years of age (1.5%; 95% CI: 0.9%, 2.1%). The mean age of CHIKV cases presenting with typical chikungunya symptoms was 9.8 years, compared with 7.8 years for cases presenting with undifferentiated fever (P = 0.04). Our data suggest that the clinical attack rate in children may underestimate the true burden of disease as some children, especially young children, may experience more atypical symptoms (e.g., undifferentiated fever). PMID- 26643532 TI - Distribution of Enteroinvasive and Enterotoxigenic Escherichia coli Across Space and Time in Northwestern Ecuador. AB - Although Escherichia coli infections are common throughout the developing world, their prevalence patterns in space and over time are not well characterized. We used serial case control data collected from 16 communities in northwestern Ecuador between 2004 and 2010, to examine the prevalence of enteroinvasive E. coli (EIEC) and enterotoxigenic E. coli (ETEC). At its peak, the regional prevalence of EIEC was 8.3 infections/100 persons but this decreased to 1 infection/1,000 persons. The regional prevalence of ETEC ranged from 8 infections/1,000 persons to 3.7 infections/100 persons. The prevalence pattern of EIEC resembled that of a large epidemic whereas the prevalence of ETEC was more stable over time. Here, we provide community-based evidence for temporal shifts in the dominant E. coli pathotype from EIEC to ETEC over a multi-year time period. Furthermore, genotype analysis suggests that a given strain of EIEC and ETEC can persist in this region for long periods, up to 24 and 55 months, respectively. PMID- 26643533 TI - Chikungunya Virus Sequences Across the First Epidemic in Nicaragua, 2014-2015. AB - Chikungunya is caused by the mosquito-borne arthrogenic alphavirus, chikungunya virus (CHIKV). Chikungunya was introduced into the Americas in late 2013 and Nicaragua in mid-2014. Here, we sequenced five imported and 30 autochthonous Nicaraguan CHIKV from cases identified in the first epidemic in the country between August 2014 and April 2015. One full-length and two partial genomic sequences were obtained by deep sequencing; Sanger methodology yielded 33 E1 sequences from five imported and 28 autochthonous cases. Phylogenetic analysis indicates that Nicaraguan CHIKV all belonged to the Asian genotype, Caribbean clade. Moreover, E1 gene sequences revealed accumulation of mutations in later months of the epidemic, including four silent mutations in 11 autochthonous cases and three non-synonymous mutations in three autochthonous cases. No mutations contributing to increased transmissibility by Aedes albopictus were identified in the E1 gene. This represents the most comprehensive set of CHIKV sequences available from the Americas to date. PMID- 26643534 TI - Clinical and Epidemiological Characterization of the First Recognized Outbreak of Dengue Virus-Type 2 in Mozambique, 2014. AB - Since the first reported epidemic of dengue in Pemba, the capital of Cabo Delgado province, in 1984-1985, no further cases have been reported in Mozambique. In March 2014, the Provincial Health Directorate of Cabo Delgado reported a suspected dengue outbreak in Pemba, associated with a recent increase in the frequency of patients with nonmalarial febrile illness. An investigation conducted between March and June detected a total of 193 clinically suspected dengue patients in Pemba and Nampula, the capital of neighboring Nampula Province. Dengue virus-type 2 (DENV-2) was detected by reverse transcriptase polymerase chain reaction in sera from three patients, and 97 others were classified as probable cases based on the presence of DENV nonstructural protein 1 antigen or anti-DENV immunoglobulin M antibody. Entomological investigations demonstrated the presence of Aedes aegypti mosquitos in both Pemba and Nampula cities. PMID- 26643535 TI - Enhanced Diagnosis of Pneumococcal Bacteremia Using Antigen- and Molecular-Based Tools on Blood Specimens in Mali and Thailand: A Prospective Surveillance Study. AB - Prior antibiotic use, contamination, limited blood volume, and processing delays reduce yield of blood cultures for detection of Streptococcus pneumoniae. We performed immunochromatographic testing (ICT) on broth from incubated blood culture bottles and real-time lytA polymerase chain reaction (PCR) on broth and whole blood and compared findings to blood culture in patients with suspected bacteremia. We selected 383 patients in Mali and 586 patients in Thailand based on their blood culture results: 75 and 31 were positive for pneumococcus, 100 and 162 were positive for other pathogens, and 208 and 403 were blood culture negative, respectively. ICT and PCR of blood culture broth were at least 87% sensitive and 97% specific compared with blood culture; whole blood PCR was 75 88% sensitive and 96-100% specific. Pneumococcal yields in children < 5 years of age increased from 2.9% to 10.7% in Mali with > 99% of additional cases detected by whole blood PCR, and from 0.07% to 5.1% in Thailand with two-thirds of additional cases identified by ICT. Compared with blood culture, ICT and lytA PCR on cultured broth were highly sensitive and specific but their ability to improve pneumococcal identification varied by site. Further studies of these tools are needed before widespread implementation. PMID- 26643536 TI - Seroprevalence of Asian Lineage Chikungunya Virus Infection on Saint Martin Island, 7 Months After the 2013 Emergence. AB - At the end of 2013, chikungunya virus (CHIKV) emerged in Saint Martin Island, Caribbean. The Asian lineage was identified. Seven months after this introduction, the seroprevalence was 16.9% in the population of Saint Martin and 39.0% of infections remained asymptomatic. This moderate attack rate and the apparent limited size of the outbreak in Saint Martin could be explained by control measures involved to lower the exposure of the inhabitants. Other drivers such as climatic factors and population genetic factors should be explored. The substantial rate of asymptomatic infections recorded points to a potential source of infection that can both spread in new geographic areas and maintain an inconspicuous endemic circulation in the Americas. PMID- 26643537 TI - Molecular Characterization of Extended-Spectrum beta-Lactamase-Producer Klebsiella pneumoniae Isolates Causing Neonatal Sepsis in Peru. AB - Klebsiella pneumoniae (KP) is the most common cause of neonatal sepsis in the low and middle-income countries. Our objective was to describe the phenotypic and molecular characteristics of extended-spectrum beta-lactamase (ESBL)-producer KP in neonatal care centers from Peru. We collected 176 non-duplicate consecutive KP isolates from blood isolates of neonates from eight general public hospitals of Lima, Peru. The overall rate of ESBL production was 73.3% (N = 129). The resistance rates were higher among ESBL-producer isolates when compared with the nonproducers: 85.3% versus 12.8% for gentamicin (P < 0.01), 59.7% versus 8.5% for trimethoprim-sulfamethoxazole (P < 0.01), 45.0% versus 8.5% for ciprofloxacin (P < 0.01), and 36.4% versus 12.8% for amikacin (P < 0.01). A total of 359 beta lactamase-encoding genes were detected among 129 ESBL-producer isolates; 109 isolates (84.5%) carried two or more genes. Among 37 ESBL-producer isolates randomly selected, CTX-M-15 and CTX-M-2 were the most common ESBLs detected. Most of the isolates (92%) belonged to the group KpI. Pulsed-field gel electrophoresis showed that multiple KP clones were circulating among the eight neonatal units included. PMID- 26643538 TI - Brain-borne IL-1 adjusts glucoregulation and provides fuel support to astrocytes and neurons in an autocrine/paracrine manner. AB - It is still controversial which mediators regulate energy provision to activated neural cells, as insulin does in peripheral tissues. Interleukin-1beta (IL-1beta) may mediate this effect as it can affect glucoregulation, it is overexpressed in the 'healthy' brain during increased neuronal activity, and it supports high energy demanding processes such as long-term potentiation, memory and learning. Furthermore, the absence of sustained neuroendocrine and behavioral counterregulation suggests that brain glucose-sensing neurons do not perceive IL 1beta-induced hypoglycemia. Here, we show that IL-1beta adjusts glucoregulation by inducing its own production in the brain, and that IL-1beta-induced hypoglycemia is myeloid differentiation primary response 88 protein (MyD88) dependent and only partially counteracted by Kir6.2-mediated sensing signaling. Furthermore, we found that, opposite to insulin, IL-1beta stimulates brain metabolism. This effect is absent in MyD88-deficient mice, which have neurobehavioral alterations associated to disorders in glucose homeostasis, as during several psychiatric diseases. IL-1beta effects on brain metabolism are most likely maintained by IL-1beta auto-induction and may reflect a compensatory increase in fuel supply to neural cells. We explore this possibility by directly blocking IL-1 receptors in neural cells. The results showed that, in an activity dependent and paracrine/autocrine manner, endogenous IL-1 produced by neurons and astrocytes facilitates glucose uptake by these cells. This effect is exacerbated following glutamatergic stimulation and can be passively transferred between cell types. We conclude that the capacity of IL-1beta to provide fuel to neural cells underlies its physiological effects on glucoregulation, synaptic plasticity, learning and memory. However, deregulation of IL-1beta production could contribute to the alterations in brain glucose metabolism that are detected in several neurologic and psychiatric diseases. PMID- 26643540 TI - Common alleles contribute to schizophrenia in CNV carriers. PMID- 26643539 TI - Maternal polycystic ovary syndrome and the risk of autism spectrum disorders in the offspring: a population-based nationwide study in Sweden. AB - Although many studies indicate the interplay of genetic and environmental factors in the etiology of autism spectrum disorder (ASD), our limited understanding of the underlying mechanisms hampers the development of effective ways of detecting and preventing the disorder. Recent studies support the hypothesis that prenatal androgen exposure contributes to the development of ASD. This would suggest that maternal polycystic ovary syndrome (PCOS), a condition associated with excess androgens, would increase the risk of ASD in the offspring. We conducted a matched case-control study nested within the total population of Sweden (children aged 4-17 who were born in Sweden from 1984 to 2007). The sample consisted of 23 748 ASD cases and 208 796 controls, matched by birth month and year, sex and region of birth. PCOS and ASD were defined from ICD codes through linkage to health-care registers. Maternal PCOS increased the odds of ASD in the offspring by 59%, after adjustment for confounders (odds ratio (OR) 1.59, 95% confidence interval (CI) 1.34-1.88). The odds of offspring ASD were further increased among mothers with both PCOS and obesity, a condition common to PCOS that is related to more severe hyperandrogenemia (OR 2.13, 95% CI 1.46-3.10). Risk estimates did not differ between sexes. In conclusion, children of women with PCOS appear to have a higher risk of developing ASD. This finding awaits confirmation, and exploration of potentially underlying mechanisms, including the role of sex steroids in the etiology of ASD. PMID- 26643541 TI - A Phase 1B, randomized, double blind, placebo controlled, multiple-dose escalation study of NSI-189 phosphate, a neurogenic compound, in depressed patients. AB - We wanted to examine tolerability and efficacy of NSI-189, a benzylpiperizine aminiopyridine neurogenic compound for treating major depressive disorder (MDD). This was a Phase 1B, double blind, randomized, placebo controlled, multiple-dose study with three cohorts. The first cohort received 40 mg q.d. (n=6) or placebo (n=2), the second cohort 40 mg b.i.d. (n=6) or placebo (n=2), and the third cohort 40 mg t.i.d. (n=6) or placebo (n=2). Twenty-four patients with MDD were recruited, with the diagnosis and severity confirmed through remote interviews. Eligible patients received NSI-189 or placebo for 28 days in an inpatient setting with assessments for safety, pharmacokinetics (PK) and efficacy. Outpatient follow-up visits were conducted until day 84 (+/-3). NSI-189 was relatively well tolerated at all doses, with no serious adverse effects. NSI-189 area under the curve increased in a dose-related and nearly proportional manner across the three cohorts, with a half-life of 17.4-20.5 h. The exploratory efficacy measurements, including Symptoms Of Depression Questionnaire (SDQ), Montgomery-Asberg Depression Scale (MADRS), Clinical Global Impressions-Improvement (CGI-I), and The Massachusetts General Hospital (MGH) Cognitive and Physical Functioning Questionnaire (CPFQ) showed a promising reduction in depressive and cognitive symptoms across all measures for NSI-189, with significant improvement in the SDQ and CPFQ, and a medium to large effect size for all measures. These improvements persisted during the follow-up phase. In summary, NSI-189 shows potential as a treatment for MDD in an early phase study. The main limitation of this preliminary study was the small sample size of each cohort. PMID- 26643542 TI - Electroencephalographic studies of eclampsia and pre-eclampsia. AB - AIMS: To investigate eclampsia and pre-eclampsia electroencephalograms (EEGs) and related animal experiments, and to publish a Japanese article in English. MATERIALS AND METHODS: A two channel EEG system constructed with a self-made vacuum tube amplifier, optical recorder, signal generator, a magic-eye signal monitor and a shield room were prepared by the author. EEGs were recorded in five admitted eclamptic and 35 pre-eclamptic cases before, during and after convulsion until clinical recovery. The hypothalami of female rabbits were stimulated with Kurotsu's electrode, and blood pressure and urinary proteins were studied before and after stimulation. The rabbits cortical and hypothalamic EEGs were studied. RESULTS: Frontal and occipital EEG waves synchronized immediately before and during eclamptic convulsions and during coma. Large delta waves were characteristic during the coma after convulsions. Moderately slow waves were recorded in cases of pre-eclampsia. In animal experiments, hypertension and proteinuria appeared in cases of hypothalamic sympathetic zone stimulation, while there was no change in parasympathetic stimulation. CONCLUSION: Eclamptic convulsion is evoked by synchronization of the whole cortex controlled by a heavily excited hypothalamus. Pregnancy hypertension and proteinuria is caused by the excited sympathetic center of the hypothalamus. PMID- 26643543 TI - Neuroprotective Effects of Acetyl-L-Carnitine Against Oxygen-Glucose Deprivation Induced Neural Stem Cell Death. AB - Deprivation of oxygen and glucose is the main cause of neuronal cell death during cerebral infarction and can result in severe morbidity and mortality. In general, the neuroprotective therapies that are applied after ischemic stroke have been unsuccessful, despite many investigations. Acetyl-L-carnitine (ALCAR) plays an important role in mitochondrial metabolism and in modulating the coenzyme A (CoA)/acyl-CoA ratio. We investigated the protective effects of ALCAR against oxygen-glucose deprivation (OGD) in neural stem cells (NSCs). We measured cell viability, proliferation, apoptosis, and intracellular signaling protein levels after treatment with varying concentrations of ALCAR under OGD for 8 h. ALCAR protected NSCs against OGD by reducing apoptosis and restoring proliferation. Its protective effects are associated with increases in the expression of survival related proteins, such as phosphorylated Akt (pAkt), phosphorylated glycogen synthase kinase 3b (pGSK3b), B cell lymphoma 2 (Bcl-2), and Ki-67 in NSCs that were injured by OGD. ALCAR also reduced the expression of death-related proteins, such as Bax, cytosolic cytochrome C, cleaved caspase-9, and cleaved caspase-3. We concluded that ALCAR exhibits neuroprotective effects against OGD-induced damage to NSCs by enhancing the expression of survival signals and decreasing that of death signals. PMID- 26643544 TI - Tacrolimus-Induced Diabetic Ketoacidosis After Allogeneic Bone Marrow Transplant. AB - New-onset diabetes mellitus after solid-organ transplant makes for complicated tacrolimus immunosuppression. However, tacrolimus-associated diabetic ketoacidosis has not been reported in bone marrow transplant. We report 24-year old women, hospitalized with diabetic ketoacidosis, 70 days after undergoing a bone marrow transplant with tacrolimus immunosuppression. Clinicians should be wary about tacrolimus levels and the risk of hyperglycemic states after bone marrow transplant as with other solid-organ transplants. PMID- 26643545 TI - A white matter tract mediating awareness of speech. AB - OBJECTIVE: To investigate the effects of extraoperative electrical stimulation of fiber tracts connecting the language territories. METHODS: We describe results of extraoperative electrical stimulation of stereotactic electrodes in 3 patients with epilepsy who underwent presurgical evaluation for epilepsy surgery. Contacts of these electrodes sampled, among other structures, the suprainsular white matter of the left hemisphere. RESULTS: Aside from speech disturbance and speech arrest, subcortical electrical stimulation of white matter tracts directly superior to the insula representing the anterior part of the arcuate fascicle, reproducibly induced complex verbal auditory phenomena including (1) hearing one's own voice in the absence of overt speech, and (2) lack of perception of arrest or alteration in ongoing repetition of words. CONCLUSION: These results represent direct evidence that the anterior part of the arcuate fascicle is part of a network that is important in the mediation of speech planning and awareness likely by linking the language areas of the inferior parietal and posterior inferior frontal cortices. More specifically, our observations suggest that this structure may be relevant to the pathophysiology of thought disorders and auditory verbal hallucinations. PMID- 26643546 TI - Disparities in surgery among patients with intractable epilepsy in a universal health system. AB - OBJECTIVE: To assess the use of epilepsy surgery in patients with medically intractable epilepsy in a publicly funded universal health care system. METHODS: We performed a population-based retrospective cohort study using linked health care databases for Ontario, Canada, between 2001 and 2010. We identified all patients with medically intractable epilepsy, defined as those with seizures that did not respond to at least 2 adequate trials of seizure medications. We assessed the proportion of patients who had epilepsy surgery within the following 2 years. We further identified the characteristics associated with epilepsy surgery. RESULTS: A total of 10,661 patients were identified with medically intractable epilepsy (mean age 47 years, 51% male); most (74%) did not have other comorbidities. Within 2 years of being defined as medically intractable, only 124 patients (1.2%) underwent epilepsy surgery. Death occurred in 12% of those with medically intractable epilepsy. Those who underwent the procedure were younger and had fewer comorbidities compared to those who did not. CONCLUSION: In our setting of publicly funded universal health care, more than 10% of patients died within 2 years of developing medically intractable epilepsy. Epilepsy surgery may be an effective treatment for some patients; however, fewer than 2% of patients who may have benefited from epilepsy surgery received it. PMID- 26643547 TI - Medical vs. invasive therapy in AVM-related epilepsy: Systematic review and meta analysis. AB - OBJECTIVE: To compare invasive arteriovenous malformation (AVM) therapy to conservative management using only antiepileptic drugs (AEDs) for achieving seizure freedom in patients with AVM-related epilepsy. METHODS: We searched Medline, Embase, and Cochrane Central up to June 2015 using epilepsy and AVM Medical Subject Headings and keywords. We included original research involving controlled observational cohort studies or randomized controlled trials (RCTs) comparing seizure outcomes between invasive AVM treatments vs. AED management alone, and uncontrolled case series of invasive AVM therapy for seizures that contained >=20 patients. The estimates of seizure freedom were pooled using meta analysis for the controlled trials, while the estimates for the case series were evaluated using descriptive statistics. RESULTS: Of 2,166 identified abstracts, 98 were reviewed in full text, of which 31 were included in the final dataset. We identified 2 controlled observational studies (n = 106 patients) and 29 uncontrolled case series. We identified 1 RCT but it did not report seizure outcomes. The pooled risk ratio for seizure freedom in controlled studies (0.99; 95% confidence interval [CI] 0.69, 1.43) did not indicate superiority to either approach. Seizure freedom in case series varied from 19% (95% CI 11, 30%) to 95% (95% CI 76, 99%) at last follow-up. CONCLUSIONS: There is insufficient evidence available to determine if invasive AVM management is superior to AED only for controlling seizures. An RCT of interventional vs. medical management using standardized epilepsy-specific presurgical protocols is warranted. PMID- 26643548 TI - Relationship of regional brain beta-amyloid to gait speed. AB - OBJECTIVE: To investigate in vivo the relationship of regional brain beta-amyloid (Abeta) to gait speed in a group of elderly individuals at high risk for dementia. METHODS: Cross-sectional associations between brain Abeta as measured with [18F]florbetapir PET and gait speed were examined in 128 elderly participants. Subjects ranged from healthy to mildly cognitively impaired enrolled in the control arm of the multidomain intervention in the Multidomain Alzheimer Preventive Trial (MAPT). Nearly all participants presented spontaneous memory complaints. Regional [18F]florbetapir (AV45) standardized uptake volume ratios were obtained via semiautomated quantitative analysis using the cerebellum as reference region. Gait speed was measured by timing participants while they walked 4 meters. Associations were explored with linear regression, correcting for age, sex, education, body mass index (BMI), and APOE genotype. RESULTS: We found a significant association between Abeta in the posterior and anterior putamen, occipital cortex, precuneus, and anterior cingulate and slow gait speed (all corrected p < 0.05). A multivariate model emphasized the locations of the posterior putamen and the precuneus. Abeta burden explained up to 9% of the variance in gait speed, and significantly improved regression models already containing demographic variables, BMI, and APOE status. CONCLUSIONS: The present PET study confirms, in vivo, previous postmortem evidence showing an association between Alzheimer disease (AD) pathology and gait speed, and provides additional evidence on potential regional effects of brain Abeta on motor function. More research is needed to elucidate the neural mechanisms underlying these regional associations, which may involve motor and sensorimotor circuits hitherto largely neglected in the pathophysiology of AD. PMID- 26643549 TI - Imaging of neuroinflammation in Alzheimer's disease, multiple sclerosis and stroke: Recent developments in positron emission tomography. AB - Neuroinflammation is thought to play a pivotal role in many diseases affecting the brain, including Alzheimer's disease, multiple sclerosis and stroke. Neuroinflammation is characterised predominantly by microglial activation, which can be visualised using positron emission tomography (PET). Traditionally, translocator protein 18kDa (TSPO) is the target for imaging of neuroinflammation using PET. In this review, recent preclinical and clinical research using PET in Alzheimer's disease, multiple sclerosis and stroke is summarised. In addition, new molecular targets for imaging of neuroinflammation, such as monoamine oxidases, adenosine receptors and cannabinoid receptor type 2, are discussed. This article is part of a Special Issue entitled: Neuro Inflammation edited by Helga E. de Vries and Markus Schwaninger. PMID- 26643550 TI - Mesenchymal stem cell-laden anti-inflammatory hydrogel enhances diabetic wound healing. AB - The purpose of this study was to permit bone marrow mesenchymal stem cells (BMSCs) to reach their full potential in the treatment of chronic wounds. A biocompatible multifunctional crosslinker based temperature sensitive hydrogel was developed to deliver BMSCs, which improve the chronic inflammation microenvironments of wounds. A detailed in vitro investigation found that the hydrogel is suitable for BMSC encapsulation and can promote BMSC secretion of TGF beta1 and bFGF. In vivo, full-thickness skin defects were made on the backs of db/db mice to mimic diabetic ulcers. It was revealed that the hydrogel can inhibit pro-inflammatory M1 macrophage expression. After hydrogel association with BMSCs treated the wound, significantly greater wound contraction was observed in the hydrogel + BMSCs group. Histology and immunohistochemistry results confirmed that this treatment contributed to the rapid healing of diabetic skin wounds by promoting granulation tissue formation, angiogenesis, extracellular matrix secretion, wound contraction, and re-epithelialization. These results show that a hydrogel laden with BMSCs may be a promising therapeutic strategy for the management of diabetic ulcers. PMID- 26643551 TI - A tool for the selective sequestration of ATP and PPi to aid in-solution phosphopeptide detection assays. AB - The presence of small phospho-anions, such as PPi and ATP in protein samples often complicates the robust detection of phosphoproteins by metal-based chemosensors and receptors. We herein report the development of a bis(Zn(2+) cyclen)-triethylbenzene scaffold which can selectively sequester PPi and ATP without affecting the detection of a di-phosphorylated peptide by a ProxyPhos chemosensor. PMID- 26643552 TI - The impact of multidisciplinary team meetings on patient assessment, management and outcomes in oncology settings: A systematic review of the literature. AB - BACKGROUND: Conducting regular multidisciplinary team (MDT) meetings requires significant investment of time and finances. It is thus important to assess the empirical benefits of such practice. A systematic review was conducted to evaluate the literature regarding the impact of MDT meetings on patient assessment, management and outcomes in oncology settings. METHODS: Relevant studies were identified by searching OVID MEDLINE, PsycINFO, and EMBASE databases from 1995 to April 2015, using the keywords: multidisciplinary team meeting* OR multidisciplinary discussion* OR multidisciplinary conference* OR case review meeting* OR multidisciplinary care forum* OR multidisciplinary tumour board* OR case conference* OR case discussion* AND oncology OR cancer. Studies were included if they assessed measurable outcomes, and used a comparison group and/or a pre- and post-test design. RESULTS: Twenty-seven articles met inclusion criteria. There was limited evidence for improved survival outcomes of patients discussed at MDT meetings. Between 4% and 45% of patients discussed at MDT meetings experienced changes in diagnostic reports following the meeting. Patients discussed at MDT meetings were more likely to receive more accurate and complete pre-operative staging, and neo-adjuvant/adjuvant treatment. Quality of studies was affected by selection bias and the use of historical cohorts impacted study quality. CONCLUSIONS: MDT meetings impact upon patient assessment and management practices. However, there was little evidence indicating that MDT meetings resulted in improvements in clinical outcomes. Future research should assess the impact of MDT meetings on patient satisfaction and quality of life, as well as, rates of cross-referral between disciplines. PMID- 26643553 TI - Breaking the DNA damage response to improve cervical cancer treatment. AB - Every year, cervical cancer affects ~500,000 women worldwide, and ~275,000 patients die of this disease. The addition of platin-based chemotherapy to primary radiotherapy has increased 5-year survival of advanced-stage cervical cancer patients, which is, however, still only 66%. One of the factors thought to contribute to treatment failure is the ability of tumor cells to repair chemoradiotherapy-induced DNA damage. Therefore, sensitization of tumor cells for chemoradiotherapy via inhibition of the DNA damage response (DDR) as a novel strategy to improve therapy effect, is currently studied pre-clinically as well as in the clinic. Almost invariably, cervical carcinogenesis involves infection with the human papillomavirus (HPV), which inactivates part of the DNA damage response. This HPV-mediated partial inactivation of the DDR presents therapeutic targeting of the residual DDR as an interesting approach to achieve chemoradio sensitization for cervical cancer. How the DDR can be most efficiently targeted, however, remains unclear. The fact that cisplatin and radiotherapy activate multiple signaling axes within the DDR further complicates a rational choice of therapeutic targets within the DDR. In this review, we provide an overview of the current preclinical and clinical knowledge about targeting the DDR in cervical cancer. PMID- 26643554 TI - Could nutrition help behaviours associated with personality disorders? A narrative review. AB - Personality disorders are common, and the core problems of interpersonal dysfunction and social disturbance are difficult to treat. One area gaining international attention is the impact that diet and nutrients can have on psychiatric/psychological symptoms. There are no empirical studies studying the specific relationship between nutrition and personality disorders. A systematic search revealed longitudinal studies following malnourished children, either during pregnancy or in early life that reported malnourishment is a risk factor that can express as maladaptive behaviours later in life. Other studies show associations between nutrient intake and personality styles. A small body of literature reveals a potential benefit of consuming nutrients therapeutically in order to address behaviours often associated with personality disorders. If we consider the broad patterns of behaviour that typify personality disorders, such as cognition, affectivity, interpersonal functioning and impulse control, there is a research rationale for studying the role that nutrition could play in protecting against the development of these problems as well as possibly modifying them. Whether it is too late to intervene with nutrition once the pathological behaviours are entrenched is unknown. Given the dearth of good evidence-based treatments currently available for people with personality disorders, it is an area worth investing in. PMID- 26643555 TI - HDAC6 activity is a non-oncogene addiction hub for inflammatory breast cancers. AB - INTRODUCTION: Inflammatory breast cancer (IBC) is the most lethal form of breast cancers with a 5-year survival rate of only 40 %. Despite its lethality, IBC remains poorly understood which has greatly limited its therapeutic management. We thus decided to utilize an integrative functional genomic strategy to identify the Achilles' heel of IBC cells. METHODS: We have pioneered the development of genetic tools as well as experimental and analytical strategies to perform RNAi based loss-of-function studies at a genome-wide level. Importantly, we and others have demonstrated that these functional screens are able to identify essential functions linked to certain cancer phenotypes. Thus, we decided to use this approach to identify IBC specific sensitivities. RESULTS: We identified and validated HDAC6 as a functionally necessary gene to maintain IBC cell viability, while being non-essential for other breast cancer subtypes. Importantly, small molecule inhibitors for HDAC6 already exist and are in clinical trials for other tumor types. We thus demonstrated that Ricolinostat (ACY1215), a leading HDAC6 inhibitor, efficiently controls IBC cell proliferation both in vitro and in vivo. Critically, functional HDAC6 dependency is not associated with genomic alterations at its locus and thus represents a non-oncogene addiction. Despite HDAC6 not being overexpressed, we found that its activity is significantly higher in IBC compared to non-IBC cells, suggesting a possible rationale supporting the observed dependency. CONCLUSION: Our finding that IBC cells are sensitive to HDAC6 inhibition provides a foundation to rapidly develop novel, efficient, and well-tolerated targeted therapy strategies for IBC patients. PMID- 26643556 TI - Dorsal and medial raphe nuclei participate differentially in reproductive functions of the male rat. AB - BACKGROUND: Innervation of the hypothalamus and median eminence arise from the dorsal and medial raphe nuclei (DRN and MRN, respectively). The hypothalamus regulates the secretion of gonadotropins, which in turn regulate the reproductive function of males and females. However, it is not known the role of raphe nuclei in male reproductive function. Our goal was to investigate the role of the DRN and MRN in the regulation of the testicular function and secretion of gonadotropins in prepubertal rats. METHODS: Dihydroxytryptamine (5,6-DHT) in ascorbic acid was used to chemically lesion the DRN or MRN. Rats were treated at 30 days-of-age and sacrificed at 45 or 65 days-of-age. Sham-treated controls were injected with ascorbic acid only. Negative controls were untreated rats. The damage induced by the 5,6-DHT was monitored in coronal serial sections of DRN and MRN; only the animals in which lesion of the DRN or MRN was detected were included in this study. As output parameters, we measured the concentrations of noradrenaline (NA), dopamine (DA) and serotonin (5-HT) in the anterior (AH) and medial (MH) hypothalamus by high performance liquid chromatography (HPLC); whereas, circulating concentrations of gonadotropins and sexual steroids were measured by radioimmunoassay. Seminiferous epithelium and sperm quality were also evaluated. RESULTS: Lesion of DRN or MRN does not induced changes in concentrations of LH, progesterone, and testosterone. Compared with the control group, the sham or lesion of the DRN or MRN did not modify noradrenaline or dopamine concentrations in the AH and MH at 45 or 65 days of age. Meanwhile, serotonin concentrations decreased significantly in lesioned rats. Lesion of DRN induced significantly lower concentrations of FSH regardless of age; similar lesion in the MRN had no impact on FSH levels. Sperm concentration and motility were significantly decreased in the same animals. The lesion of the MRN does not induced changes in the seminiferous epithelium or gonadotropin levels. Our results suggest that raphe nuclei regulate differentially the male reproductive functions. CONCLUSIONS: The DRN but not the MRN regulates the secretion of gonadotropins and testicular function. PMID- 26643557 TI - Central oxytocin receptors mediate mating-induced partner preferences and enhance correlated activation across forebrain nuclei in male prairie voles. AB - Oxytocin (OT) is a deeply conserved nonapeptide that acts both peripherally and centrally to modulate reproductive physiology and sociosexual behavior across divergent taxa, including humans. In vertebrates, the distribution of the oxytocin receptor (OTR) in the brain is variable within and across species, and OTR signaling is critical for a variety of species-typical social and reproductive behaviors, including affiliative and pair bonding behaviors in multiple socially monogamous lineages of fishes, birds, and mammals. Early work in prairie voles suggested that the endogenous OT system modulates mating-induced partner preference formation in females but not males; however, there is significant evidence that central OTRs may modulate pair bonding behavior in both sexes. In addition, it remains unclear how transient windows of central OTR signaling during sociosexual interaction modulate neural activity to produce enduring shifts in sociobehavioral phenotypes, including the formation of selective social bonds. Here we re-examine the role of the central OT system in partner preference formation in male prairie voles using a selective OTR antagonist delivered intracranially. We then use the same antagonist to examine how central OTRs modulate behavior and immediate early gene (Fos) expression, a metric of neuronal activation, in males during brief sociosexual interaction with a female. Our results suggest that, as in females, OTR signaling is critical for partner preference formation in males and enhances correlated activation across sensory and reward processing brain areas during sociosexual interaction. These results are consistent with the hypothesis that central OTR signaling facilitates social bond formation by coordinating activity across a pair bonding neural network. PMID- 26643559 TI - The bridge treatment selected at the decision for transplantation did not affect the outcomes in patients with MDS. AB - The optimal treatment for use as a bridge to allogeneic hematopoietic stem cell transplantation at the decision for transplantation has not been established in patients with myelodysplastic syndrome (MDS). We retrospectively evaluated the clinical outcomes after the decision for transplantation in our patients with MDS or acute myeloid leukemia (AML) secondary to MDS, aged more than 15 years, who underwent transplantation between 2007 and 2012. A total of 124 patients were included. We classified patients into two groups according to the bridge treatment selected at the decision for transplantation: Group 1, supportive care (n = 79), immunosuppressive therapy (n = 7), low-dose chemotherapy (n = 12); Group 2, AML-type induction chemotherapy (ICT: n = 22), azacitidine (Aza: n = 4). The rate of blasts in the bone marrow significantly influenced the treatment selection at the time of decision. There was no significant difference between the two groups in the rate of overall survival (OS) from the decision (73.1% vs 80.4% at 1 year) or from transplantation (59.0% vs 59.2% at 1 year). A significant difference was not observed even after patients were stratified according to either the rate of blasts in the bone marrow at the time of decision or the propensity score. In conclusion, the bridge treatment selected at the decision for transplantation did not affect the outcomes of transplantation in patients with MDS. However, this analysis did not include patients who could not undergo transplantation after the decision, and thus a prospective study is warranted. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26643560 TI - Switchable Wettability of the Honeybee's Tongue Surface Regulated by Erectable Glossal Hairs. AB - Various nectarivorous animals apply bushy-hair-equipped tongues to lap nectar from nectaries of flowers. A typical example is provided by the Italian honeybee (Apis mellifera ligustica), who protracts and retracts its tongue (glossa) through a temporary tube, and actively controls the erectable glossal hairs to load nectar. We first examined the microstructure of the honeybee's glossal surface, recorded the kinematics of its glossal hairs during nectar feeding process and observed the rhythmical hair erection pattern clearly. Then we measured the wettability of the glossal surface under different erection angles (EA) in sugar water of the mass concentration from 25 to 45%, mimicked by elongating the glossa specimens. The results show that the EA in retraction approximately remains stable under different nectar concentrations. In a specific concentration (35, 45, or 55%), the contact angle decreases and glossal surface area increases while the EA of glossal hairs rises, the glossa therefore could dynamically alter the glossal surface and wettability in foraging activities, not only reducing the energy consumption for impelling the nectar during tongue protraction, but also improving the nectar-trapping volume for feeding during glossa retraction. The dynamic glossal surface with switchable wettability regulated by erectable hairs may reveal the effective adaptation of the honeybee to nectar intake activities. PMID- 26643561 TI - Granular cell tumor of the urethra: a case report and literature review. PMID- 26643558 TI - Screening and treatment of maternal genitourinary tract infections in early pregnancy to prevent preterm birth in rural Sylhet, Bangladesh: a cluster randomized trial. AB - BACKGROUND: Approximately half of preterm births are attributable to maternal infections, which are commonly undetected and untreated in low-income settings. Our primary aim is to determine the impact of early pregnancy screening and treatment of maternal genitourinary tract infections on the incidence of preterm live birth in Sylhet, Bangladesh. We will also assess the effect on other adverse pregnancy outcomes, including preterm birth (stillbirth and live birth), late miscarriage, maternal morbidity, and early onset neonatal sepsis. METHODS/DESIGN: We are conducting a cluster randomized controlled trial that will enroll 10,000 pregnant women in Sylhet district in rural northeastern Bangladesh. Twenty-four clusters, each with ~4000 population (120 pregnant women/year) and served by a community health worker (CHW), are randomized to: 1) the control arm, which provides routine antenatal and postnatal home-based care, or 2) the intervention arm, which includes routine antenatal and postnatal home-based care plus screening and treatment of pregnant women between 13 and 19 weeks of gestation for abnormal vaginal flora (AVF) and urinary tract infection (UTI). CHWs conduct monthly pregnancy surveillance, make 2 antenatal and 4 postnatal home visits for all enrolled pregnant women and newborns, and refer mothers or newborns with symptoms of serious illness to the government sub-district hospital. In the intervention clusters, CHWs perform home-based screening of AVF and UTI. Self collected vaginal swabs are plated on slides, which are Gram stained and Nugent scored. Women with AVF (Nugent score >=4) are treated with oral clindamycin, rescreened and retreated, if needed, after 3 weeks. Urine culture is performed and UTI treated with nitrofurantoin. Repeat urine culture is performed after 1 week for test of cure. Gestational age is determined by maternal report of last menstrual period at study enrollment using prospectively completed study calendars, and in a subset by early (<20 week) ultrasound. CHWs prospectively collect data on all pregnancy outcomes, maternal and neonatal morbidity and mortality. IMPLICATIONS/DISCUSSION: Findings will enhance our understanding of the burden of AVF and UTI in rural Bangladesh, the impact of a maternal screening treatment program for genitourinary tract infections on perinatal health, and help formulate public health recommendations for infection screening in pregnancy in low-resource settings. TRIAL REGISTRATION: The study was registered on ClinicalTrials.gov:NCT01572532 on December 15, 2011. The study was funded by NICHD: R01HD066156 . PMID- 26643562 TI - Sexual outcomes after partial penectomy for penile cancer: results from a multi institutional study. AB - Penile cancer is an uncommon malignancy. Surgical treatment is inevitably mutilating. Considering the strong impact on patients' sexual life we want to evaluate sexual function and satisfaction after partial penectomy. The patients in this study (n = 25) represented all those who attended our institutions and were diagnosed and treated for penile cancer from October 2011 to November 2013. All patients underwent partial penectomy and followed-up (mean: 14 months; range: 12-25). Sexual presurgical baseline was estimated using the International Index of Erectile Dysfunction 15 (IIEF-15). Sexual outcomes of each patient were estimated considering four standardized and validated questionnaires. We analyzed the means and ranges of IIEF-15 including erectile function (IIEF-1-5 and -15), orgasmic function (IIEF-9 and -10), sexual desire (IIEF-11 and -12), intercourse satisfaction (IIEF-6-8), and overall satisfaction (IIEF-13 and -14). Then, we also used Quality of Erection Questionnaire (QEQ), Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) and Self-Esteem and Relationship (SEAR) to evaluate the sexual function and satisfaction of our patients. The final results showed that penile cancer leads to several sexual and psychosexual dysfunctions. Nevertheless, patients who undergo partial penectomy for penile cancer can maintain the sexual outcomes at levels slightly lower to those that existed in the period before surgery. PMID- 26643564 TI - Apoptotic and nonapoptotic function of caspase 7 in spermatogenesis. AB - Recent studies have reported that caspase 7 has an apoptotic and nonapoptotic function. However, the relationship between caspase 7 and spermatogenesis remains unknown. This study aimed to investigate the possible function of caspase 7 during normal and abnormal spermatogenesis. The cleaved form of caspase 7 was detected in testis tissues at different postpartum times (5-14 weeks) by qRT-PCR, Western blot and immunohistochemistry (IHC). Then, the mice models of spermatogenic dysfunction were obtained by busulfan (30 mg kg-1 to further evaluate the potential function and mechanism of caspase 7. qRT-PCR and Western blot results showed that caspase 7 expression was gradually elevated from 5 to 14 weeks, which was not connected with apoptosis. IHC results revealed that caspase 7 was mainly located in spermatogenic cells and Leydig cells. In addition, spermatogenic dysfunction induced by busulfan gradually enhanced the apoptosis and elevated the expression of caspase 3, caspase 6, and caspase 9, but decreased the expression of caspase 7 in spermatogenic cells. However, when spermatogenic cells were mostly disappeared at the fourth week after busulfan treatment, caspase 7 expression in Leydig cells was significantly increased and positively correlated with the expression of caspase 3, caspase 6, and caspase 9. Therefore, these results indicate that caspase 7 has a nonapoptic function that participates in normal spermatogenesis, but also displays apoptotic function in spermatogenic dysfunction. PMID- 26643563 TI - Proteomic profile of seminal plasma in adolescents and adults with treated and untreated varicocele. AB - Varicocele, the most important treatable cause of male infertility, is present in 15% of adult males, 35% of men with primary infertility, and 80% of men with secondary infertility. On the other hand, 80% of these men will not present infertility. Therefore, there is a need to differentiate a varicocele that is exerting a deleterious effect that is treatable from a "silent" varicocele. Despite the growing evidence of the cellular effects of varicocele, its underlying molecular mechanisms are still eluding. Proteomics has become a promising area to determine the reproductive biology of semen as well as to improve diagnosis of male infertility. This review aims to discuss the state-of art in seminal plasma proteomics in patients with varicocele to discuss the challenges in undertaking these studies, as well as the future outlook derived from the growing body of evidence on the seminal proteome. PMID- 26643565 TI - Improvement of Atrial and Ventricular Remodeling with Low Atrial Fibrillation Burden after Hybrid Ablation of Persistent Atrial Fibrillation. AB - BACKGROUND: An endoscopic transdiaphragmatic epicardial radiofrequency ablation procedure combined with percutaneous endocardial radiofrequency ablation--a hybrid procedure--is a potentially curative treatment option for patients with persistent atrial fibrillation (AF). Long-term effects of arrhythmia elimination on atrial and ventricular remodeling are not completely understood. Therefore, the aim of our study was to quantify echocardiographic structural and functional changes of the left atrium (LA) and left ventricle (LV) following a hybrid procedure. METHODS AND RESULTS: Thirty-seven consecutive patients with symptomatic drug refractory persistent AF underwent a hybrid procedure to achieve complete pulmonary vein and LA posterior wall electrical isolation. AF burden was measured using an insertable electrocardiographic (ECG) monitor. Patients were divided into responders to ablation and nonresponders according to postoperative AF burden at 12-month follow-up (responder < 0.5% vs nonresponder >= 0.5%). Median AF burden was 0.32 (0.04-27.5)% for all patients. In responders (19/37 patients), significant echocardiographic reduction of LA volume index from 47 to 41 mL/m(2) (P < 0.05) and improvement of LA function parameters (LA stiffness from 73.3 to 41.3 [P < 0.05], LA emptying fraction from 21% to 45% [P < 0.05], LA global longitudinal strain from 11.2% to 18.8% [P < 0.5]) was documented. In addition, LV systolic function significantly improved in comparison with nonresponders. CONCLUSION: Hybrid ablation of persistent AF achieved stable sinus rhythm in a significant proportion of patients, as evidenced by continuous ECG monitoring, resulting in important LA and LV reverse remodeling after 12 months. PMID- 26643566 TI - BPH: WAVEing goodbye to LUTS? PMID- 26643567 TI - Stones in 2015: Changes in stone management - suspending belief for evidence. AB - In 2015, population-based studies in patients with urinary stones informed us of the changing trends in contemporary stone management and identified areas for improvement. Although meta-analyses aim to provide the highest level of evidence, a randomized controlled trial of medical expulsive therapy challenged current paradigms and was the defining publication of the year. PMID- 26643569 TI - Kidney cancer: Novel drug for renal cell carcinoma. PMID- 26643570 TI - Rapid screening astaxanthin-hyperproducing Haematococcus pluvialis mutants through near-infrared spectroscopy. AB - The unicellular freshwater green microalga Haematococcus pluvialis is the richest source of natural astaxanthin. Since accumulation of astaxanthin differs significantly among various algal strains at different stages, it is therefore critical to develop an effective high-throughput assay for rapid screening astaxanthin-hyperproducing strains. In the present study, near-infrared spectroscopy (NIRS) in combination with biochemical assay was employed for evaluation of the wide-type H. Pluvialis strains. The partial least squares (PLS) models of total biomass, astaxanthin content and astaxanthin expressed as a percentage of dry weight (DW) were developed with the R(2) values as 0.959, 0.982 and 0.952, the prediction correlation factor (r) values as 0.979, 0.988 and 0.966, and the residual predictive deviation (RPD) values as 4.88, 6.22 and 3.86, respectively. Furthermore, the PLS models were employed to evaluate H. pluvialis mutants, with the r values as 0.973, 0.983 and 0.976, and the RPD values as 3.45, 7.59 and 4.07, respectively. This work thus demonstrates that NIRS is an easy, fast and non-invasive approach that can be applied in high-throughput screening of astaxanthin-hyperproducing algal mutants. SIGNIFICANCE AND IMPACT OF THE STUDY: Haematococcus pluvialis has potential application for its ability to accumulate natural antioxidant astaxanthin. In this study, we initiated the application of near-infrared spectroscopy (NIRS) in the analysis of total biomass and astaxanthin content of different mutant strains, demonstrating that NIRS can be very useful in the screening of axataxanthin-hyperproducing mutant strains. PMID- 26643571 TI - Only 22% of UK GPs think NHS works well, down from half in 2013, new survey shows. PMID- 26643568 TI - Androgen-glucocorticoid interactions in the era of novel prostate cancer therapy. AB - Great strides have been made in the treatment of castration-resistant prostate cancer (CRPC) with the development of new antiandrogens (enzalutamide) and more potent androgen synthesis inhibitors (abiraterone) that have both improved patient outcomes. These new drugs have also helped unravel the complex biology of androgen-androgen receptor driven prostate cancer and brought into prominence various mechanisms triggering the development of drug resistance and tumour cell survival despite use of androgen deprivation therapy (ADT). The complex role of glucocorticoids in the treatment, management and progression of patients with CRPC is integral to these advances. Historically, glucocorticoid treatment has resulted in both subjective and objective responses in patients with advanced stage prostate cancer. With the use of these new therapeutic agents, however, unexpected glucocorticoid-related mechanisms that can cause iatrogenic stimulation of prostate cancer growth have emerged, which might contribute to drug resistance and disease progression despite optimal ADT. For example, the upregulation of glucocorticoid receptors (GRs) during enzalutamide therapy results in glucocorticoid-GR-mediated regulation of androgen target genes, leading to escape from enzalutamide blockade. Thus, understanding the biological role of glucocorticoids in patients with prostate cancer is of major importance in the era of new and evolving antiandrogen therapies. PMID- 26643572 TI - Treg depletion in non-human primates using a novel diphtheria toxin-based anti human CCR4 immunotoxin. AB - Regulatory T cells (Treg) play an important role in modulating the immune response and has attracted increasing attention in diverse fields such as cancer treatment, transplantation and autoimmune diseases. CC chemokine receptor 4 (CCR4) is expressed on the majority of Tregs, especially on effector Tregs. Recently we have developed a diphtheria-toxin based anti-human CCR4 immunotoxin for depleting CCR4(+) cells in vivo. In this study, we demonstrated that the anti human CCR4 immunotoxin bound and depleted monkey CCR4(+) cells in vitro. We also demonstrated that the immunotoxin bound to the CCR4(+)Foxp3(+) monkey Tregs in vitro. In vivo studies performed in two naive cynomolgus monkeys revealed 78-89% CCR4(+)Foxp3(+) Treg depletion in peripheral blood lasting approximately 10 days. In lymph nodes, 89-96% CCR4(+)Foxp3(+) Tregs were depleted. No effect was observed in other cell populations including CD8(+) T cells, other CD4(+) T cells, B cells and NK cells. To our knowledge, this is the first agent that effectively depleted non-human primate (NHP) Tregs. This immunotoxin has potential to deplete effector Tregs for combined cancer treatment. PMID- 26643574 TI - Breakable Hybrid Organosilica Nanocapsules for Protein Delivery. AB - The direct delivery of specific proteins to live cells promises a tremendous impact for biological and medical applications, from therapeutics to genetic engineering. However, the process mostly involves tedious techniques and often requires extensive alteration of the protein itself. Herein we report a straightforward approach to encapsulate native proteins by using breakable organosilica matrices that disintegrate upon exposure to a chemical stimulus. The biomolecule-containing capsules were tested for the intracellular delivery of highly cytotoxic proteins into C6 glioma cells. We demonstrate that the shell is broken, the release of the active proteins occurs, and therefore our hybrid architecture is a promising strategy to deliver fragile biomacromolecules into living organisms. PMID- 26643573 TI - Targeted capture massively parallel sequencing analysis of LCIS and invasive lobular cancer: Repertoire of somatic genetic alterations and clonal relationships. AB - PURPOSE: Lobular carcinoma in situ (LCIS) has been proposed as a non-obligate precursor of invasive lobular carcinoma (ILC). Here we sought to define the repertoire of somatic genetic alterations in pure LCIS and in synchronous LCIS and ILC using targeted massively parallel sequencing. METHODS: DNA samples extracted from microdissected LCIS, ILC and matched normal breast tissue or peripheral blood from 30 patients were subjected to massively parallel sequencing targeting all exons of 273 genes, including the genes most frequently mutated in breast cancer and DNA repair-related genes. Single nucleotide variants and insertions and deletions were identified using state-of-the-art bioinformatics approaches. RESULTS: The constellation of somatic mutations found in LCIS (n = 34) and ILC (n = 21) were similar, with the most frequently mutated genes being CDH1 (56% and 66%, respectively), PIK3CA (41% and 52%, respectively) and CBFB (12% and 19%, respectively). Among 19 LCIS and ILC synchronous pairs, 14 (74%) had at least one identical mutation in common, including identical PIK3CA and CDH1 mutations. Paired analysis of independent foci of LCIS from 3 breasts revealed at least one common mutation in each of the 3 pairs (CDH1, PIK3CA, CBFB and PKHD1L1). CONCLUSION: LCIS and ILC have a similar repertoire of somatic mutations, with PIK3CA and CDH1 being the most frequently mutated genes. The presence of identical mutations between LCIS-LCIS and LCIS-ILC pairs demonstrates that LCIS is a clonal neoplastic lesion, and provides additional evidence that at least some LCIS are non-obligate precursors of ILC. PMID- 26643575 TI - Serum Iron Level Is Associated with Time to Antibiotics in Cystic Fibrosis. AB - BACKGROUND: Serum levels of hepcidin-25, a peptide hormone that reduces blood iron content, are elevated when patients with cystic fibrosis (CF) develop pulmonary exacerbation (PEx). Because hepcidin-25 is unavailable as a clinical laboratory test, we questioned whether a one-time serum iron level was associated with the subsequent number of days until PEx, as defined by the need to receive systemic antibiotics (ABX) for health deterioration. METHODS: Clinical, biochemical, and microbiological parameters were simultaneously checked in 54 adults with CF. Charts were reviewed to determine when they first experienced a PEx after these parameters were assessed. Time to ABX was compared in subgroups with and without specific attributes. Multivariate linear regression was used to identify parameters that significantly explained variation in time to ABX. RESULTS: In univariate analyses, time to ABX was significantly shorter in subjects with Aspergillus-positive sputum cultures and CF-related diabetes. Multivariate linear regression models demonstrated that shorter time to ABX was associated with younger age, lower serum iron level, and Aspergillus sputum culture positivity. CONCLUSIONS: Serum iron, age, and Aspergillus sputum culture positivity are factors associated with shorter time to subsequent PEx in CF adults. PMID- 26643576 TI - The characteristics of patients who discontinue their dying process - an observational study at a single university hospital centre. AB - BACKGROUND: End-of-life integrated care plans are used as structuring tools for the care of the dying. A widely adopted example is the Liverpool Care Pathway for the Dying Patient (LCP). Recently, several concerns were raised about LCP care, such as a worry that diagnosis of dying might be leading to a self-fulfilling trajectory, including hastening of death. However, data on rates of discontinuation of LCP care are lacking. In an observational study, we therefore investigated the incidence, features and trajectory of patients who were discontinued from the LCP. We hypothesised that (1) it is common to discontinue patients from the LCP, (2) quality of life does not decrease for discontinued LCP patients, and (3) discontinued patients live longer than patients who remain within LCP care. METHODS: All adult patients who were diagnosed as dying in a German university hospital specialized palliative care unit were included in 2013 and 2014. Actuarial estimation of survival prognostication tools and a number of quality of life indicators were used for data collection. Survival time was analysed using Kaplan-Meier estimates. Group differences in quality of life were tested using multivariate analysis of variance. RESULTS: 159 patients were included in a digital version of the LCP. 15 patients (9.4 %) were discontinued later. Quality of life did not decrease for discontinued patients during LCP care (p = 0.16). LCP discontinued patients lived significantly longer than the remaining LCP subgroup (difference of means 296 hours, 95 % confidence interval 105.5 to 451.5 hours; difference of survival function estimates p < 0.0001). CONCLUSIONS: When patients are diagnosed as dying, death is not the inevitable outcome of an end-of-life integrated care plan such as the LCP. Instead, it is common to discontinue the LCP care. Regular careful interprofessional assessments are important for identifying those patients who need to be discontinued from their end-of-life care plan. In this study, we found no evidence for harm by the LCP. We conclude that a correctly applied integrated care plan can be useful to provide good and safe care for the dying. TRIAL REGISTRATION: Internal Clinical Trial Register of the Medical Faculty, Heinrich Heine University Dusseldorf, No. 2015053680 (22 May 2015). PMID- 26643577 TI - High Detectivity Graphene-Silicon Heterojunction Photodetector. AB - A graphene/n-type silicon (n-Si) heterojunction has been demonstrated to exhibit strong rectifying behavior and high photoresponsivity, which can be utilized for the development of high-performance photodetectors. However, graphene/n-Si heterojunction photodetectors reported previously suffer from relatively low specific detectivity due to large dark current. Here, by introducing a thin interfacial oxide layer, the dark current of graphene/n-Si heterojunction has been reduced by two orders of magnitude at zero bias. At room temperature, the graphene/n-Si photodetector with interfacial oxide exhibits a specific detectivity up to 5.77 * 10(13) cm Hz(1/2) W(-1) at the peak wavelength of 890 nm in vacuum, which is highest reported detectivity at room temperature for planar graphene/Si heterojunction photodetectors. In addition, the improved graphene/n Si heterojunction photodetectors possess high responsivity of 0.73 A W(-1) and high photo-to-dark current ratio of ~10(7) . The current noise spectral density of the graphene/n-Si photodetector has been characterized under ambient and vacuum conditions, which shows that the dark current can be further suppressed in vacuum. These results demonstrate that graphene/Si heterojunction with interfacial oxide is promising for the development of high detectivity photodetectors. PMID- 26643578 TI - Microstructural properties and mechanics vary between bundles of the human anterior cruciate ligament during stress-relaxation. AB - Previous studies have shown different elastic properties between the anteromedial (AM) and posterolateral (PL) bundles of the human anterior cruciate ligament (ACL). However, it is unknown if the two bundles of the ACL exhibit distinct time dependent properties and microstructural organization, which have important implications for fully understanding the structure-function relationships of this oft-injured ligament. The goal of this study was to quantify the viscoelastic material properties and collagen fiber alignment of the AM and PL bundles in 16 human ACLs during stress-relaxation mechanical tests using the quasi-linear viscoelastic (QLV) model and a quantitative polarization imaging technique. We hypothesized that the AM and PL bundles would exhibit differences in the instantaneous mechanical and organizational properties (i.e., immediately following a step increase in strain), but similar time-dependent changes during stress-relaxation. Results showed that AM samples exhibited larger peak/equilibrium stresses and less stress-relaxation during a 300-s hold compared to PL samples. The AM bundle demonstrated stronger and more uniform collagen fiber alignment (i.e., higher degree of linear polarization (DoLP) values and less distributed angle of polarization (AoP) values) compared to the PL bundle, and larger changes in alignment strength during the hold. Results suggest that the AM bundle is the more "dominant" bundle, with significantly different mechanical and material properties in stress-relaxation. While more research is needed to better understand how these findings relate to the pathophysiology of ACL tears and can best guide treatment, the findings provide additional insight into the microstructural properties and biomechanics of the human ACL. PMID- 26643579 TI - Repetitive Transcranial Magnetic Stimulation of the Brain: Mechanisms from Animal and Experimental Models. AB - Since the development of transcranial magnetic stimulation (TMS) in the early 1980s, a range of repetitive TMS (rTMS) protocols are now available to modulate neuronal plasticity in clinical and non-clinical populations. However, despite the wide application of rTMS in humans, the mechanisms underlying rTMS-induced plasticity remain uncertain. Animal and in vitro models provide an adjunct method of investigating potential synaptic and non-synaptic mechanisms of rTMS-induced plasticity. This review summarizes in vitro experimental studies, in vivo studies with intact rodents, and preclinical models of selected neurological disorders Parkinson's disease, depression, and stroke. We suggest that these basic research findings can contribute to the understanding of how rTMS-induced plasticity can be modulated, including novel mechanisms such as neuroprotection and neurogenesis that have significant therapeutic potential. PMID- 26643580 TI - Dirhodium(II)-Catalyzed Sulfide Oxygenations: Catalyst Removal by Coprecipitation with Sulfoxides. AB - The dirhodium(II) carboxylate complex Rh2(esp)2 (esp = alpha,alpha,alpha',alpha' tetramethyl-1,3-benzenedipropanoate) was shown to catalyze the sulfoxidation of organic sulfides using tert-butyl hydroperoxide as the oxidant. Due to the unique structure of Rh2(esp)2 and its stable Rh2(II,II) catalyst resting state, the rhodium catalyst is able to precipitate as a Rh2(esp)2-sulfoxide complex following the reaction which makes separation of the catalyst from the products very convenient. The precipitated Rh2(esp)2-sulfoxide complexes could be reused to catalyze sulfide oxygenation reactions without considerable loss of activity. Mechanistic studies suggest that the axial ligands fine-tune the redox potential of the dirhodium(II,II) compounds and determine the predominant catalyst species in the oxidation reaction. PMID- 26643581 TI - Impact of anxiety and depressive symptoms on perceptions of stigma in persons living with HIV disease in rural versus urban North Carolina. AB - This analysis examined the relationships between HIV-related stigma, depression, and anxiety in rural and urban sites. Participants were HIV-positive urban (n = 100) and rural (n = 100) adult residents of a US southern state, drawn from a sample for a larger international study of self-esteem and self-compassion. Measures included demographic and health information, the HIV Stigma Scale, the Center for Epidemiology Studies Depression Scale (CES-D), and the Symptom Checklist 90 Revised (SCL-R-90) anxiety scale. Independent sample t-tests showed no significant differences between urban/rural groups on measures of HIV-related stigma, anxiety, or depression, except that rural participants reported greater disclosure concerns (t = 2.11, df = 196, p = .036). Both groups indicated high levels of depression and anxiety relative to published norms and clinically relevant cut-off scores. Hierarchical regression analyses were conducted for the HIV Stigma Scale including its four subscales and total stigma scores. Block 1 (control) contained health and demographic variables known to predict HIV-related stigma. Block 2 included the CES-D and the SCL-R-90, and Block 3 was urban/rural location. Mental health symptom scores contributed a significant amount to explained variance in total stigma scores (5.5%, FDelta = 6.020, p < .01), personalized stigma (4.8%, FDelta = 5.035, p < .01), negative self-image (9.7%, FDelta = 12.289, p < .001), and concern with public attitudes (4.9%, FDelta = 5.228, p < .01), but not disclosure concerns. Urban/rural location made significant additional contributions to the variance for total stigma (1.7%, FDelta = 3.899, p < .05), disclosure concerns (2.6%, FDelta = 5.446, p < .05), and concern with public attitudes (1.9%, FDelta = 4.169, p < .05) but not personalized stigma or negative self-image. Depression scores consistently and significantly predicted perceived stigma total and subscale scores. Findings suggest that mental health symptoms and urban/rural location play important roles in perceived stigma, and treatment implications are presented. PMID- 26643582 TI - Integrating Safe Sleep Practices into a Pediatric Hospital: Outcomes of a Quality Improvement Project. AB - A quality improvement project for implementing safe sleep practices (SSP) was conducted at a large, U.S children's hospital. The intervention involved education of staff and standardization of infant sleep practices utilizing a multifaceted approach. Staff surveys and environmental audits were conducted pre- and post-intervention. Safe Sleep Environment (SSE) audits showed an improvement from 23% to 34% (p<0.001) post-intervention. Staff confidence to provide education to caregivers on SSP showed a significant increase. Results from this project demonstrate a successful approach to implement SSP in the hospital setting. Infant safe sleep practices have the potential to reduce infant mortality. PMID- 26643583 TI - Safety and efficacy of intraoperative iodine-125 seed implantation brachytherapy for rectal cancer patients: A retrospective clinical research. AB - BACKGROUND: This pilot study was performed to evaluate the risk of anastomotic leakage (AL) and pelvic autonomic nerve dysfunction, and the effects of (125) I brachytherapy after intraoperative permanent implantation of iodine-125 seeds within the patients with rectal carcinoma. METHODS: In a cohort consisting of 80 rectal cancer patients who received potentially curative resection of rectal carcinoma with implantation of (125) I brachytherapy or radical resection of rectal carcinoma underwent total mesorectal excision. The incidences of AL, fecal incontinence, urinary dysfunction, and sexual dysfunction were calculated for comparison, and risk factors for these complications were analyzed by logistic regression. Rates of tumor recurrence and overall survival were evaluated. RESULTS: Six out of 17 (35.29%) patients in the (125) I implant group and 1 out of 34 (2.94%) patients in the non-implant group were complicated with AL (P = 0.006). The incidences of urinary dysfunction (P = 0.005) and fecal incontinence (P = 0.023) were significantly different between the two groups. Multivariate analyses revealed that (125) I brachytherapy was an independent risk factor for AL (odds ratio, 18.702; 95%CI, 1.802-194.062; P = 0.014) and urinary dysfunction (odds ratio, 4.340; 95%CI, 1.158-16.264; P = 0.029), respectively. At postoperative 2-year, the recurrence rates were 5.56% in the (125) I implant group and 9.09% in the non-implant group (P = 0.029). CONCLUSIONS: Intraoperative implantation of (125) I brachytherapy significantly increases the risk of AL, fecal incontinence, urinary dysfunction, and improves local control and do not improve overall survival after total mesorectal excision. PMID- 26643585 TI - Neighborhood characteristics contribute to urban alcohol availability: Accounting for race/ethnicity and social disorganization. AB - This study examined the role that race/ethnicity and social disorganization play in alcohol availability in Milwaukee, Wisconsin, census block groups. This study estimated negative binomial regression models to examine separately the relationship between neighborhood racial/ethnic composition and social disorganization levels for (1) total, (2) on-premise, and (3) off-premise alcohol outlets. Results of this study suggest that proportion Hispanic was positively associated with total and with off-premise alcohol outlets. Second, proportion African American was negatively associated with on-premise alcohol outlets and positively associated with off-premise alcohol outlets. Proportion Asian was not associated with total, on-premise, or off-premise alcohol outlets. However, the effects of race/ethnicity on alcohol availability were either unrelated or negatively related to alcohol outlet availability once neighborhood social disorganization levels were taken into account, and social disorganization was positively and significantly associated with all alcohol outlet types. Neighborhood characteristics contribute to alcohol availability and must be considered in any efforts aimed toward prevention of alcohol-related negative health and social outcomes. PMID- 26643584 TI - Aerobic Exercise for Reducing Migraine Burden: Mechanisms, Markers, and Models of Change Processes. AB - BACKGROUND: Engagement in regular exercise routinely is recommended as an intervention for managing and preventing migraine, and yet empirical support is far from definitive. We possess at best a weak understanding of how aerobic exercise and resulting change in aerobic capacity influence migraine, let alone the optimal parameters for exercise regimens as migraine therapy (eg, who will benefit, when to prescribe, optimal types, and doses/intensities of exercise, level of anticipated benefit). These fundamental knowledge gaps critically limit our capacity to deploy exercise as an intervention for migraine. OVERVIEW: Clear articulation of the markers and mechanisms through which aerobic exercise confers benefits for migraine would prove invaluable and could yield insights on migraine pathophysiology. Neurovascular and neuroinflammatory pathways, including an effect on obesity or adiposity, are obvious candidates for study given their role both in migraine as well as the changes known to accrue with regular exercise. In addition to these biological pathways, improvements in aerobic fitness and migraine alike also are mediated by changes in psychological and sociocognitive factors. Indeed a number of specific mechanisms and pathways likely are operational in the relationship between exercise and migraine improvement, and it remains to be established whether these pathways operate in parallel or synergistically. As heuristics that might conceptually benefit our research programs here forward, we: (1) provide an extensive listing of potential mechanisms and markers that could account for the effects of aerobic exercise on migraine and are worthy of empirical exploration and (2) present two exemplar conceptual models depicting pathways through which exercise may serve to reduce the burden of migraine. CONCLUSION: Should the promise of aerobic exercise as a feasible and effective migraine therapy be realized, this line of endeavor stands to benefit migraineurs (including the many who presently remain suboptimally treated) by providing a new therapeutic avenue as an alternative or augmentative compliment to established interventions for migraine. PMID- 26643586 TI - The impact of a spiritual legacy intervention in patients with brain cancers and other neurologic illnesses and their support persons. AB - OBJECTIVE: The objectives were to assess the feasibility of using a novel, comprehensive chaplain-led spiritual life review interview to develop a personal Spiritual Legacy Document (SLD) for persons with brain tumors and other neurodegenerative diseases and to describe spiritual well-being (SWB), spiritual coping, and quality of life (QOL) of patients and their support persons (SP) before and after receipt of the SLD. METHODS: Patient-SP pairs were enrolled over a 2-year period. Assessments included the Functional Assessment of Chronic Illness Therapy-Spiritual Expanded Version, Brief Religious Coping Scale, Brief COPE Inventory, and QOL Linear Analog Scale. Baseline assessments were completed prior to an audio-recorded spiritual life review interview with a chaplain. RESULTS: Thirty-two patient/SP pairs were enrolled; 27 completed baseline assessments and the interview. Twenty-four reviewed their SLD and were eligible for follow-up. A total of 15 patients and 12 SPs completed the 1-month follow-up; 10 patients and seven SPs completed the 3-month follow-up. Patients endorsed high levels of SWB and spiritual coping at baseline. Both patients and SPs evidenced improvement on several aspects of SWB, spiritual coping, and QOL at 1 month, but patients' decreased financial well-being was also observed. Patients and SPs demonstrated favorable changes in peacefulness and positive religious coping at both time points. CONCLUSIONS: A chaplain-led spiritual life review is a feasible intervention for patients with neurodegenerative disease and results in beneficial effects on patients and SPs. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26643587 TI - Patients' Perceptions of their Rheumatic Condition: Why Does it Matter and How Can Healthcare Professionals Influence or Deal with these Perceptions? PMID- 26643588 TI - Incidence and risk factors of isolated systolic and diastolic hypertension: a 10 year follow-up of the Tehran Lipids and Glucose Study. AB - The objective of this study is to examine the incidence and risk factors of isolated systolic hypertension (ISH) and isolated diastolic hypertension (IDH) in a Middle Eastern population, during a median follow-up of 9.6 years. In total, 8573 subjects without hypertension, cardiovascular disease and known diabetes were recruited into the study. To calculate the incidence of ISH, those with diastolic blood pressure (DBP) >= 90 mmHg during follow-up, and for calculating IDH those with systolic blood pressure (SBP) >= 140 mmHg during follow-up, were excluded. During follow-up, 235 new cases of ISH were identified, with a crude incidence rate of 5.7/1000 person-years; the corresponding values for IDH were 470 and 10.9/1000 person-years. Using backward stepwise Cox regression analysis, older age, baseline SBP and body mass index were related to incident ISH. Regarding IDH, younger age, baseline DBP and waist circumference were associated with higher risk, whereas female gender and being married were associated with lower risk (all p < 0.05). The C-statistics for the prediction model were 0.91 for ISH and 0.76 for IDH. In conclusion, after a decade of follow-up of this Iranian population, we found an incidence of about 0.5% and 1% per year for ISH and IDH, respectively. PMID- 26643591 TI - Considering alternative calculations of weight suppression. AB - Weight suppression (WS)--the difference between an individual's highest adult weight and current weight-relates to eating pathology and weight gain; however, there are several methodological issues associated with its calculation. The current study presents four alternative methods of calculating WS and tests whether these methods differentially relate to maladaptive outcomes. Alternative methods of calculation included: (1) change in BMI units; (2) BMI category change; (3) percent change in weight; and (4) two different uses of regression residuals. A sample of undergraduate students (N=631) completed self-report measures of eating pathology, current and past weight, and teasing. Measures included the Eating Disorder Examination-Questionnaire and the Perceptions of Teasing Scale. Results indicated that components of WS, current weight and highest weight, were strongly related in the present sample. The traditional method of calculating WS was related to eating pathology, binge eating and teasing for both males and females. However, WS indices orthogonal to the highest weight did not correlate with eating pathology and teasing in both males and females; for females, WS indices orthogonal to current weight were also unrelated to eating pathology. Findings suggest that the link between WS and eating pathology is mitigated after accounting for an individual's highest weight. Future research should continue to assess the reliability and clinical utility of this construct and consider using alternative WS calculations. PMID- 26643589 TI - Vitamin C intake and risk of renal cell carcinoma: a meta-analysis. AB - Studies have showed that vitamin C intake is linked to renal cell carcinoma risk, however, the results were inconsistent. Hence, the present meta-analysis was to examine the association between vitamin C intake and RCC risk. We searched the published studies that reported the relationship between vitamin C intake and RCC risk using PubMed and Embase up to January 2015. Based on a fixed effects model, RR and the corresponding 95% CI were used to assess the pooled risk. 3 prospective cohort studies and 7 case-control studies were included. The overall RR (95% CI) of RCC for the highest vs. the lowest levels of vitamin C intake was 0.78(0.69,0.87). Little evidence of heterogeneity was found. In the subgroup analyses, we found an inverse association between vitamin C intake and RCC risk in the case-control studies but not in the prospective cohort studies. Additionally, this association between vitamin C intake and RCC risk was not differed by population distribution. Our study provides evidence that vitamin C intake is associated with a reduced RCC risk. However, our conclusion was just based on ten including studies, so more high-quality of case-control studies or cohort studies which report this topic are needed. PMID- 26643590 TI - Maternal correlates of body mass index in American Indian/Alaska Native and White adolescents: Differences between mother/son and mother/daughter pairs. AB - INTRODUCTION: Obesity rates for American Indian and Alaska Native (AI/AN) adolescents are among the highest in the US. However, little is known about the influence of maternal correlates on adolescent body mass index (BMI), and the extent to which the size and significance of these correlates vary by adolescent sex and race. METHODS: We conducted a cross-sectional analysis with a sample of 531 AI/AN and 8896 White mother/adolescent pairs from Wave 1 of the National Longitudinal Study of Adolescent to Adult Health. We used generalized estimating equations to measure the association of maternal educational attainment, marital status, employment status, obesity status, and adolescent BMI of AI/AN and White adolescents, while controlling for adolescents' demographic and behavioral covariates. We sought to determine whether the size and statistical significance of maternal correlates differed by race, and between mother/son and mother/daughter pairs. RESULTS: The strength and statistical significance of maternal correlates varied between mother/son and mother/daughter pairs in both races. However, we did not find effect modification by race. Maternal obesity showed the strongest effect on adolescent BMI in all mother/adolescent pairs. CONCLUSION: Our findings suggest that maternal factors are critical in the transmission of obesogenic behaviors from one generation to the next, and their effects vary between mother/son and mother/daughter pairs, and are similar for AI/ANs and Whites. We encourage future work aimed at preventing adolescent obesity to investigate causal pathways between maternal correlates and adolescent BMI. PMID- 26643592 TI - Self-regulatory predictors of eating disorder symptoms: Understanding the contributions of action control and willpower beliefs. AB - Action orientation, or the ability to regulate both positive and negative affect to perform goal-directed action, has been associated with eating behavior in previous research. Additionally, differences in beliefs about self-control have been shown to influence behavior, but it is unclear how these beliefs impact disordered eating behavior or how they may interact with other self-regulatory mechanisms to predict eating outcomes. In this study, 1128 participants were recruited online via Amazon Mechanical Turk to answer questions about self regulation constructs and eating behavior. A three-way moderated regression analysis was used to assess relationships between two subtypes of action orientation (failure-related action orientation, or AOF, which describes an ability to up-regulate positive affect, and decision-related action orientation, or AOD, which describes an ability to down-regulate negative affect), willpower beliefs, and binge eating. Results revealed a significant three-way interaction between AOD, AOF, and willpower beliefs such that the interaction between AOF and willpower beliefs was only significant for those with low AOD. These findings suggest an ability to down-regulate negative affect (high AOF) is a protective factor against increased disordered eating, though this may not be the case for individuals with an inability to up-regulate positive affect (low AOD) and simultaneously ascribe to beliefs that willpower is a limited resource. PMID- 26643593 TI - Allergy and respiratory health effects of dampness and dampness-related agents in schools and homes: a cross-sectional study in Danish pupils. AB - Little is known about the health effects of school-related indoor dampness and microbial exposures. In this study, we investigated dampness and dampness-related agents in both homes and schools and their association with allergy and respiratory health effects in 330 Danish pupils. Classroom dampness was identified based on technical inspection and bedroom dampness on parents' self report. Classroom and bedroom dust was analyzed for seven microbial components. Skin prick testing determined atopic sensitization. Lung function was expressed as z-scores for forced expiratory volume in one-second (zFEV1 ), forced vital capacity (zFVC) and the ratio zFEV1 /zFVC using GLI-2012 prediction equations. The parents reported children's allergies, airway symptoms, and doctor-diagnosed asthma. High classroom dampness, but not bedroom dampness, was negatively associated with zFEV1 (beta-coef. -0.71; 95% CI -1.17 to -0.23) and zFVC (beta coef. -0.52; 95% CI -0.98 to -0.06) and positively with wheezing (OR 8.09; 95% CI 1.49 to 43.97). No consistent findings were found between any individual microbial components or combination of microbial components and health outcomes. Among other indoor risk factors, environmental tobacco smoke (ETS) decreased zFEV1 (beta-coef. -0.22; 95% CI -0.42 to -0.02) and zFEV1 /zFVCratio (beta-coef. 0.26; 95% CI -0.44 to -0.07) and increased upper airway symptoms (OR 1.66; 95% CI 1.03-2.66). In conclusion, dampness in classrooms may have adverse respiratory health effects in pupils, but microbial agents responsible for this effect remain unknown. PMID- 26643596 TI - Factors Associated with Comfort Level of School-Based Occupational Therapists in Providing Low-Vision Services. AB - This study identified factors associated with the comfort level of school-based occupational therapists in providing services to children with visual impairments. Sixty-one school-based occupational therapists completed an on-line survey. Fifty-four percent of respondents were comfortable or somewhat comfortable when choosing assessments and 84% were comfortable or somewhat comfortable in providing occupational therapy services for children with visual impairments. Multivariable linear regression analyses indicated years of professional experience, history of a caseload of children with visual impairments, and training received in treating children with visual impairments from continuing education were uniquely and significantly associated with the respondents' comfort level. Though not included in the final model, collaboration with other low vision service providers (e.g., teachers, optometrists, ophthalmologists, and orientation/mobility specialists) was also significantly associated with respondents' comfort level in the univariate analysis. Findings provide an initial direction and strategies to improve occupational therapists' comfort level in providing services to children with visual impairments in school settings. PMID- 26643594 TI - [Peripheral, central and functional vertigo syndromes]. AB - Depending on the temporal course, three forms of vertigo syndrome can be differentiated: 1) vertigo attacks, e.g. benign paroxysmal positional vertigo (BPPV), Meniere's disease and vestibular migraine, 2) acute spontaneous vertigo lasting for days, e.g. acute unilateral vestibulopathy, brainstem or cerebellar infarction and 3) symptoms lasting for months or years, e.g. bilateral vestibulopathy and functional vertigo. The specific therapy of the various syndromes is based on three principles: 1) physical treatment with liberatory maneuvers for BPPV and balance training for vestibular deficits, 2) pharmacotherapy, e.g. for acute unilateral vestibulopathy (corticosteroids) and Meniere's disease (transtympanic administration of gentamicin or steroids and high-dose betahistine therapy); placebo-controlled pharmacotherapy studies are currently being carried out for acute unilateral vestibulopathy, vestibular paroxysmia, prophylaxis of BPPV, vestibular migraine, episodic ataxia type 2 and cerebellar ataxia; 3) psychotherapy for functional dizziness. PMID- 26643597 TI - Dietary Iron Oxide Nanoparticles Delay Aging and Ameliorate Neurodegeneration in Drosophila. AB - Dietary iron oxide nanoparticles are shown to ameliorate neurodegeneration in a Drosophelia Alzheimer's disease model. Iron oxide nanoparticles can mimic catalase and can decompose reactive oxygen species (ROS). This has potential therapeutic uses for aging, metabolic disorders, and neurodegenerative diseases, in which increased production of ROS is closely implicated. PMID- 26643598 TI - What Does Asexuality Teach Us About Sexual Disinterest? Recommendations for Health Professionals Based on a Qualitative Study With Asexually Identified People. AB - This article draws on qualitative in-depth interviews with 30 asexually identified individuals living in the United States in order to contribute to our understanding of when low sexual desire should be treated as a medical or mental health issue and when it should be treated as a benign sexual variation. The article discusses five findings of relevance to health professionals: (1) the line between a desire disorder and asexuality is not clear-cut; (2) asexually identified individuals may experience distress, so distress alone does not separate a desire disorder from asexuality; (3) asexually identified individuals may face sexual pressure from a partner or may have difficulty negotiating sexual activity with a partner; (4) asexuality does not need to be distressing, rather it can be experienced as a fulfilling form of sexuality; and (5) many asexually identified individuals believe in the usefulness of low sexual desire as a diagnostic category and support medical and mental health professionals in their efforts to develop treatments for sexual desire disorders. Based on these five findings, this article offers four concrete suggestions for health professionals working with clients with low sexual desire, whether or not those clients identify as asexual. PMID- 26643599 TI - Successful epilepsy surgery in frontal lobe epilepsy with startle seizures: a SEEG study. AB - Pre-surgical assessment and surgical management of frontal epilepsy with normal MRI is often challenging. We present a case of a 33-year-old, right-handed, educated male. During childhood, his seizures presented with mandibular myoclonus and no particular trigger. As a young adult, he developed seizures with a startle component, triggered by unexpected noises. During his ictal episodes, he felt fear and grimaced with sudden head flexion and tonic axial posturing. Similar seizures also occurred without startle. Neuropsychological assessment showed executive dysfunction and verbal memory deficit. The cerebral MRI was normal. Electro-clinical reasoning, investigations performed, the results obtained and follow-up are discussed in detail. [Published with video sequence]. PMID- 26643600 TI - Pregnancy Outcome in Women with Decreased Sensation of Fetal Movements at Term According to Parity. AB - BACKGROUND: Decreased sensation of fetal movements (DFM) is a common maternal complaint. Thus, we aimed to evaluate the association between DFM and pregnancy outcome in singleton gestation at term according to parity. METHODS: A retrospective cohort study of singleton pregnancies at term between 2008 and 2013. Eligibility was limited to women carrying a fetus with no known structural or chromosomal anomalies, at 37+0/7 to 42+0/7 weeks of gestation. Women presenting to the delivery ward with DFM were compared with women without similar complaints. RESULTS: Overall, 12,564 nulliparous women and 25,292 multiparous women gave birth during the study period; of them, 300 nulliparous women (2.4%) and 525 multiparous women (2.1%) complained of DFM. For nulliparous women, after adjusting for potential confounders, DFM was associated with antepartum fetal death (aOR 4.6 [95% CI 1.1-19.8]), cesarean delivery (CD) (aOR 1.3 [95% CI 1.01 1.8]), 1-minute Apgar score less than 7 (aOR 2.3 [95% CI 1.5-3.5]) and neonatal seizures (aOR 3.2 [95% CI 1.3-8.2]). For multiparous women, DFM was associated with unscheduled CD (aOR 2.7 [95% CI 1.6-4.6]) and CD indicated by intermediate/abnormal fetal heart rate tracing (aOR 4.8 [95% CI 2.8-8.4]). CONCLUSIONS: DFM carries different outcomes according to parity. Although for nulliparous women, DFM is associated with increased risk of CD and immediate adverse perinatal outcome, for multiparous women it is associated with increased risk for CD, with no immediate increased risk for adverse perinatal outcome. PMID- 26643601 TI - Inventing the Pedophile in the Journal of Homosexuality. AB - This article serves as one of the supplementary pieces of this special issue on "Mapping Queer Bioethics," in which we take a solipsistic turn to "map" the Journal of Homosexuality itself. Here, the author examines one of the most controversial moments in the history of the journal, whereby a contributor was subject to governmental and popular rebuke for his scholarship on pederasty, pedophilia, and underage queer sexuality. In a chronological and intellectual appraisal of this pedophilia-themed text, the author asks us to recalibrate the disquietude we posit when same-sex affection, youthful sexuality, and sexual abuse are in close proximity. PMID- 26643602 TI - Two-stage comprehensive evaluation of genetic susceptibility of common variants in FBXO38, AP3B2 and WHAMM to severe chronic periodontitis. AB - Chronic periodontitis is an oral disorder characterized with gingival inflammation and bone destruction. As the sixth-most prevalent condition affecting more than 743 million people around the world, it is classified as one of the seven destructive oral disorders. Early genetic epidemiological evidence indicated a major role for genetics in periodontal disease development. In this study, we conducted a two-stage comprehensive evaluation of the genetic susceptibility of FBXO38, AP3B2 and WHAMM with the diagnosis of severe chronic periodontitis. A total of 5,065 study subjects from the Han Chinese population consisting of 1,264 cases and 3,801 healthy controls were recruited, and 65 single nucleotide markers related to the three candidate genes were genotyped to investigate the susceptibility of patients with these polymorphisms to severe chronic periodontitis. To increase the coverage of genetic markers, we implemented imputation techniques to extend the number of tested makers to 416. Single marker and haplotype-based analyses were performed, and significant results were obtained for FBXO38 (rs10043775, P = 0.0009) and AP3B2 (rs11631963 rs11637433, CA, P = 9.98 * 10(-5); rs1864699-rs2099259-rs2278355, ATC, P = 3.84 * 10(-8)). Our findings provide direct evidence for the association of FBXO38 and AP3B2 with severe chronic periodontitis in the Han Chinese population. PMID- 26643603 TI - Effect of puerperal metritis on reproductive and productive performance in dairy cows in Argentina. AB - The objectives of this study were to evaluate the reproductive and productive performance of dairy cows with and without puerperal metritis and to evaluate the effectiveness of using a long-acting ceftiofur preparation. Dairy cows in one dairy farm, calving from July 2009 to January 2010, were examined between 3 and 14 days postpartum and classified on the basis of vaginal discharge into three groups: cows with normal discharge (control; C); cows with a bloody mucus purulent or pathologic nonfetid discharge (PnFD), and cows with bloody mucopurulent or purulent fetid discharge (PFD). Cows in C and PnFD groups were not treated, whereas those in the PFD group were randomly allocated to receive 2.2 mg/kg of ceftiofur subcutaneously behind the ear (PFD-T) or remain untreated (PFD-No T). From the 640 cows examined, 58.2% formed the C group, 13.4% formed the PnFD group, and 28.4% formed the PFD group. Survival curves differed between cows in the C group and PFD-No T group (P = 0.0013) and between PFD-No T versus PFD-T group (P = 0.0006). Survival curves of PnFD were intermediate and did not differ from those in the C group (P = 0.2) and PFD-T group (P = 0.1) but tended to be different from the PFD-No T group (P = 0.056). The postpartum interval to achieve a 25% pregnancy rate was 72 days for cows in the C group, 73 days for the PFD-T group, 83 days for PnFD group, and 95 days for the PFD-No T group. The chance of pregnancy in a cow in the C group was 1.98 times higher (95% confidence interval = 1.33, 3.08) and in cows in the PFD-T group was 2.16 times higher (95% confidence interval = 1.37, 3.50) than that in the PFD-No T group. Finally, the chance of pregnancy in cows in the PnFD group tended to be higher (P = 0.08) than that in the PFD-No T group but did not differ from the other two groups. Cumulative 305-day milk production was higher (P < 0.0001) in C group than those with vaginal discharge, regardless of fetidness and regardless of treatment. It is concluded that puerperal metritis affects the reproductive and productive performance of dairy cows and the treatment with ceftiofur was effective in reducing the adverse effects on reproductive performance but not on milk production. PMID- 26643605 TI - Effects of experimental Trypanosoma evansi infection on pregnancy in Yankasa ewes. AB - Twenty pregnant Yankasa ewes were assigned to three groups to determine the effect of Trypanosoma evansi infection on pregnancy. Groups A and B comprising seven ewes each were infected with approximately 1.0 * 10(6) cells of T evansi per ewe through venepuncture at the second and third trimesters of pregnancy, respectively. Group C comprising six ewes served as uninfected control. There was slight pyrexia in the infected groups (groups A and B) but was absent in group C. The mean body weight, glucose concentration, and packed cell volume of ewes in group A were not significantly different from those in group C throughout the study. There was also no significant difference in mean glucose concentration between groups B and C. However, in group B, mean body weight was significantly (P < 0.05) lower compared to group C at week 2 and from week 4 post infection (pi) till the end of the study; the packed cell volume also significantly (P < 0.05) decreased but at weeks 4 and 6 pi. The mean plasma protein of ewes in group A was significantly (P < 0.05) increased compared to those of group C at weeks 7, 11 pi and thereafter till the end of the study. On the contrary, the plasma protein of ewes in group B decreased significantly (P < 0.05) compared to those in group C at weeks 2 and 6 pi. There were no reproductive losses throughout the study. This was characterized by insignificant differences in the gestation length between ewes in the infected groups (groups A and B) compared with those in group C. However, there were significant (P < 0.05) decreases in lamb birth weights of ewes in group B compared with ewes in groups A and C. Mice inoculation with blood from infected ewes postpartum was parasitemic 18 to 25 days pi, for ewes in group B, whereas none of the mice in groups A and C were parasitemic. Lambs born from the infected groups (groups A and B) were also aparasitemic for 40 days postpartum. It was therefore concluded that the T evansi isolate used caused mild trypanosomosis when infected at third trimester, whereas ewes infected at second trimester were resistant. PMID- 26643604 TI - Superoxide dismutase and taurine supplementation improves in vitro blastocyst yield from poor-quality feline oocytes. AB - Blastocyst production in vitro seems to be crucial part of assisted reproduction techniques in feline species. However, the results of cats' oocyte maturation and embryo development are still lower than those in other species. The aim of this study was to evaluate whether the supplementation with superoxide dismutase (SOD) and taurine during maturation or culture would improve the blastocyst yield obtained from lower grades of oocytes, that are usually discarded, as not suitable for further in vitro purposes. To investigate the effect of antioxidants' addition, the good- and poor-quality oocytes, were cultured with the addition of 10-mmol taurine and 600 UI/mL SOD. The nuclear maturity, embryo development, and blastocyst quality were subsequently assessed. In control group, without antioxidant supplementation, significantly less poor-quality oocytes matured (42% vs. 62%) and more degenerated (35% vs. 20%), comparing to the experimental group supplemented with SOD and taurine. The amount of obtained blastocyst was much higher, when poor quality oocytes were supplemented with SOD and taurine (supplementation to IVM-4%; supplementation to IVC-5.5%; supplementation to IVM and IVC-5.9% of blastocyst), comparing to not supplemented control group (1.3%). The best blastocysts were obtained when poor oocytes had antioxidants added only during embryo culture (185 +/- 13.4 blastomeres vs. 100 +/- 1.5 in control). In the present study, we reported that the lower grades of oocytes can better mature and form significantly more blastocysts with better quality, when cultured with addition of SOD and taurine. PMID- 26643606 TI - Laparoscopic repair of perineal hernia after abdominoperineal excision. AB - PURPOSE: Perineal hernia is a challenging complication after abdominoperineal excision (APE) of the rectum. Surgical repair can be accomplished using challenging abdominal or transperineal approaches. A laparoscopic repair using a Proceed mesh might be an easy and effective alternative. METHODS: We describe a multi-center case-series of twelve patients with a symptomatic perineal hernia treated by laparoscopic mesh repair. A cone-shaped 10 * 15 cm Proceed Mesh was tacked to the promontory or sacrum and sutured to the pelvic sidewalls and the anterior peritoneum. RESULTS: Twelve patients underwent laparoscopic repair of their perineal hernia. Four men and eight women presented with a symptomatic perineal hernia after abdominoperineal excision between 2008 and 2013 and underwent a laparoscopic repair with a Proceed mesh. The median age at presentation was 53 years (range 39-68 years). The mean total theater time was 119 min (range 75-200 min). No conversion to an open procedure was needed. No early complications where seen. The mean hospital stay was 2.25 days (range 1-4 days). Three patients showed recurrence, of whom two had a defect in the middle of the proceed mesh, one had a defect anterior to the previous perineal hernia. All 3 patients underwent a redo-laparoscopic repair with mesh. CONCLUSION: In this case series we present an alternative approach for the surgical repair of perineal hernias. Based on our experience, perineal hernia after APE can be repaired safely and effectively using the described laparoscopic technique. PMID- 26643607 TI - Photosystem-II shutdown evolved with Nitrogen fixation in the unicellular diazotroph Crocosphaera watsonii. AB - Protection of nitrogenase from oxygen in unicellular Cyanobacteria is obtained by temporal separation of photosynthesis and diazotrophy through transcriptional and translational regulations of nitrogenase. But diazotrophs can face environmental situations in which N2 fixation occurs significantly in the light, and we believe that another control operates to make it possible. The night-time shutdown of PSII activity is a peculiar behaviour that discriminates Crocosphaera watsonii WH8501 from any other phototroph, whether prokaryote or eukaryote. This phenomenon is not only due to the plastoquinone pool redox status, and suggests that the sentinel D1 protein, expressed in periods of nitrogen fixation, is inactive. Results demonstrate a tight constraint of oxygen evolution in C. watsonii as additional protection of nitrogenase activity and suggest a possible recycling of cellular components. PMID- 26643608 TI - Dehydroepiandrosterone ameliorates H2O2-induced Leydig cells oxidation damage and apoptosis through inhibition of ROS production and activation of PI3K/Akt pathways. AB - Dehydroepiandrosterone (DHEA) is widely used as a nutritional supplement, and administration of DHEA produces a number of beneficial effects in the elderly. Many researchers have suggested that DHEA exerts it function after conversion into more biologically active hormones in peripheral target cells. The actions of DHEA in Leydig cells, a major target cell of DHEA biotransformation in males, are not clear. The present study found that DHEA increased cell viability and decreased reactive oxygen species (ROS) and malondialdehyde contents in H2O2 induced Leydig cells. DHEA significantly increased the activities of superoxide dismutase, catalase and peroxidase, and decreased the DNA damage in H2O2-induced Leydig cells. Apoptosis was significant decreased in H2O2-induced Leydig cells after DHEA treatment. DHEA inhibited the loss of mitochondrial membrane potential (DeltaPsim) and the upregulation of the caspase-3 protein level induced by H2O2 in Leydig cells. DHEA also reversed the decrease in PI3K and p-Akt protein levels induced by H2O2. These data showed that DHEA could ameliorate H2O2-induced oxidative damage by increasing anti-oxidative enzyme activities, which resulted in reduced ROS content, and decreased apoptosis, mainly by preventing the loss of DeltaPsim and inhibiting caspase-3 protein levels via activation of PI3K/Akt signaling pathways. These results increase our understanding of the molecular mechanism of the anti-ageing effect of DHEA. PMID- 26643609 TI - Niclosamide inhibits epithelial-mesenchymal transition and tumor growth in lapatinib-resistant human epidermal growth factor receptor 2-positive breast cancer. AB - Acquired resistance to lapatinib, a human epidermal growth factor receptor 2 kinase inhibitor, remains a clinical problem for women with human epidermal growth factor receptor 2-positive advanced breast cancer, as metastasis is commonly observed in these patients. Niclosamide, an anti-helminthic agent, has recently been shown to exhibit cytotoxicity to tumor cells with stem-like characteristics. This study was designed to identify the mechanisms underlying lapatinib resistance and to determine whether niclosamide inhibits lapatinib resistance by reversing epithelial-mesenchymal transition. Here, two human epidermal growth factor receptor 2-positive breast cancer cell lines, SKBR3 and BT474, were exposed to increasing concentrations of lapatinib to establish lapatinib-resistant cultures. Lapatinib-resistant SKBR3 and BT474 cells exhibited up-regulation of the phenotypic epithelial-mesenchymal transition markers Snail, vimentin and alpha-smooth muscle actin, accompanied by activation of nuclear factor-kB and Src and a concomitant increase in stem cell marker expression (CD44(high)/CD24(low)), compared to naive lapatinib-sensitive SKBR3 and BT474 cells, respectively. Interestingly, niclosamide reversed epithelial-mesenchymal transition, induced apoptosis and inhibited cell growth by perturbing aberrant signaling pathway activation in lapatinib-resistant human epidermal growth factor receptor 2-positive cells. The ability of niclosamide to alleviate stem-like phenotype development and invasion was confirmed. Collectively, our results demonstrate that lapatinib resistance correlates with epithelial-mesenchymal transition and that niclosamide inhibits lapatinib-resistant cell viability and epithelial-mesenchymal transition. These findings suggest a role of niclosamide or derivatives optimized for more favorable bioavailability not only in reversing lapatinib resistance but also in reducing metastatic potential during the treatment of human epidermal growth factor receptor 2-positive breast cancer. PMID- 26643610 TI - The importance of selecting a proper biological milieu for protein corona analysis in vitro: Human plasma versus human serum. AB - Nanoparticle (NP) exposure to biological fluids in the body results in protein binding to the NP surface, which forms a protein coating that is called the "protein corona". To simplify studies of protein-NP interactions and protein corona formation, NPs are incubated with biological solutions, such as human serum or human plasma, and the effects of this exposure are characterized in vitro. Yet, how NP exposure to these two different biological milieus affects protein corona composition and cell response has not been investigated. Here, we explore the differences between the protein coronas that form when NPs are incubated in human serum versus human plasma. NP characterization indicated that NPs that were exposed to human plasma had higher amounts of proteins bound to their surfaces, and were slightly larger in size than those exposed to human serum. In addition, significant differences in corona composition were also detected with gel electrophoresis and liquid chromatography-mass spectrometry/mass spectrometry, where a higher fraction of coagulation proteins and complement factors were found on the plasma-exposed NPs. Flow cytometry and confocal microscopy showed that the uptake of plasma-exposed NPs was higher than that of serum-exposed NPs by RAW 264.7 macrophage immune cells, but not by NIH 3T3 fibroblast cells. This difference is likely due to the elevated amounts of opsonins, such as fibrinogen, on the surfaces of the NPs exposed to plasma, but not serum, because these components trigger NP internalization by immune cells. As the human plasma better mimics the composition of the in vivo environment, namely blood, in vitro protein corona studies should employ human plasma, and not human serum, so the biological phenomena that is observed is more similar to that occurring in vivo. PMID- 26643611 TI - Application of anti-DFS70 antibody and specific autoantibody test algorithms to patients with the dense fine speckled pattern on HEp-2 cells. AB - OBJECTIVES: Whereas antinuclear antibodies (ANAs) detected by indirect immunofluorescence (IIF) have diagnostic significance, the dense fine speckled (DFS) pattern on HEp-2 cells may be an exclusionary marker for ANA-associated rheumatic disease (AARD). The aim of this study was to evaluate a new algorithm considering anti-DFS70 antibodies for routine ANA testing. METHOD: From ANA requested sequential 10 528 sera, 181 sera samples showing the DFS pattern were additionally tested for anti-DFS70 antibodies by an enzyme-linked immunosorbent assay (ELISA-DFS70) and for specific-ANAs. Specific-ANAs(+)/IIF-DFS(-) control sera samples (n = 50) were also tested. RESULTS: Of the 181 IIF-DFS-positive sera samples, 82.9% (n = 150) were from non-AARD patients and 112 (61.9%) patients had non-rheumatic diseases (NRD), including the most common clinical feature of dermatitis (18.2%). The ELISA-DFS70 was positive in 109 (60.2%) sera and was negative in all control sera. Specific-ANAs were similarly detected as 25.7% (28/109) and 22.2% (16/72) of ELISA-DFS70(+) and ELISA-DFS70(+) patients, respectively (p > 0.05). The prevalence of non-AARD was 95.1% and 25.1% in the ELISA-DFS70(+)/specific-ANAs(-) and ELISA-DFS70(-)/specific-ANAs (+) groups, respectively. CONCLUSIONS: In patients with a HEp-2 DFS pattern, the additional ELISA-DFS70 and specific-ANAs test could improve the efficiency of diagnosing AARD. The detection of anti-DFS70 antibodies should be included in test algorithms for ANA testing. PMID- 26643612 TI - Regular blood donation may help in the management of hypertension: an observational study on 292 blood donors. AB - BACKGROUND: Hypertension is one of the leading global risks for cardiovascular events worldwide. There is preliminary evidence that regular blood donation may be beneficial. STUDY DESIGN AND METHODS: Unselected blood donors were included in this observational study. Blood pressure (BP) was measured before and after blood donation, with participants donating between one and four occasions in a 1-year study period. RESULTS: In this study, 292 donors were enrolled. At baseline, 146 had elevated BP (> 140/90 mmHg). In hypertensives, after four blood donations, systolic and diastolic blood pressure (SBP and DBP, respectively) decreased from a mean of 155.9 +/- 13.0 to 143.7 +/- 15.0 mmHg and from 91.4 +/- 9.2 to 84.5 +/- 9.3 mmHg, respectively (each p < 0.001). There was a clear dose effect with decreasing BP by the increasing number of blood donations. After at least four blood donations, donors with Stage II hypertensive baseline values (>= 160 mmHg SBP and/or >= 100 mmHg DBP) were found to have the most marked reduction in BP, with 17.1 mmHg (95% confidence interval [CI], -23.2 to -11.0; p < 0.0001) and 11.7 mmHg (95% CI, -17.1 to -6.1; p = 0.0006) for SBP and DBP, respectively. The decrease in BP was not significantly associated with changes of blood count or variables of iron metabolism. CONCLUSIONS: Regular blood donation is associated with pronounced decreases of BP in hypertensives. This beneficial effect of blood donation may open a new door regarding community health care and cost reduction in the treatment of hypertension. PMID- 26643613 TI - A low cost, green method to synthesize GaN nanowires. AB - The synthesis of gallium nitride nanowires (GaN NWs) by plasma enhanced chemical vapor deposition (PECVD) are successfully demonstrated in this work. The simple and green synthesis route is to introduce gallium oxide (Ga2O3) and nitrogen (N2) for the growth of nanowires. The prepared GaN nanowires have a single crystalline wurtzite structure, which the length of some nanowires is up to 20 MUm, with a maximum diameter about 140 nm. The morphology and quantity of the nanowires can be modulated by the growth substrate and process parameters. In addition, the photoluminescence and field emission properties of the prepared GaN nanowires have been investigated, which were found to be largely affected by their structures. This work renders an environmentally benign strategy and a facile approach for controllable structures on nanodevice. PMID- 26643615 TI - Proposal to restrict the genus Clostridium Prazmowski to Clostridium butyricum and related species. AB - The genus Clostridium as presently constituted is phylogenetically and phenotypically incoherent. Data from polyphasic taxonomic studies indicate that the genus comprises a collection of very heterogeneous species. Numerous phylogenetic studies, principally based on sequencing of the 16S rRNA gene, indicate that the genus Clostridium should be restricted to Clostridium cluster I as Clostridium sensu stricto. Despite these findings, authors continue to add novel species to the genus Clostridium that do not fall within the radiation of cluster I and the type species Clostridium butyricum, thus perpetuating the confusion associated with the taxonomy of this group. Here, we formally propose that members of the genus Clostridium Prazmowski be restricted to the type species C. butyricum and cluster I species. Eubacterium moniliforme, Eubacterium tarantellae, Sarcina maxima and Sarcina ventriculi should be transferred to the genus Clostridium as Clostridium moniliforme comb. nov., Clostridium tarantellae comb. nov., Clostridium maximum comb. nov. and Clostridium ventriculi comb. nov. A novel genus, Hathewaya gen. nov., is proposed for the species Clostridium histolyticum, Clostridium limosum and Clostridium proteolyticum as Hathewaya histolytica gen. nov. comb. nov., Hathewaya limosa comb. nov. and Hathewaya proteolytica comb. nov. The type species of the genus Hathewaya is Hathewaya histolytica. PMID- 26643614 TI - A Novel Class of HIV-1 Antiviral Agents Targeting HIV via a SUMOylation-Dependent Mechanism. AB - We have recently identified a chemotype of small ubiquitin-like modifier (SUMO) specific protease (SENP) inhibitors. Prior to the discovery of their SENP inhibitory activity, these compounds were found to inhibit HIV replication, but with an unknown mechanism. In this study, we investigated the mechanism of how these compounds inhibit HIV-1. We found that they do not affect HIV-1 viral production, but significantly inhibited the infectivity of the virus. Interestingly, virions produced from cells treated with these compounds could gain entry and carry out reverse transcription, but could not efficiently integrate into the host genome. This phenotype is different from the virus produced from cells treated with the class of anti-HIV-1 agents that inhibit HIV protease. Upon removal of the SUMO modification sites in the HIV-1 integrase, the compound no longer alters viral infectivity, indicating that the effect is related to SUMOylation of the HIV integrase. This study identifies a novel mechanism for inhibiting HIV-1 integration and a new class of small molecules that inhibits HIV-1 via such mechanism that may contribute a new strategy for cure of HIV-1 by inhibiting the production of infectious virions upon activation from latency. PMID- 26643616 TI - Enhanced in vivo antitumor efficacy of dual-functional peptide-modified docetaxel nanoparticles through tumor targeting and Hsp90 inhibition. AB - Although conventional anticancer drugs exhibit excellent efficacy, serious adverse effects and/or even toxicity have occurred due to their nonselectivity. Moreover, active targeting approaches have not consistently led to successful outcomes. Ligands that simultaneously possess targeting capability and exert a strong influence on intracellular signaling cascades may be expected to improve the therapeutic efficacy of active targeting nanoparticulate carriers. In this study, we screened a targeting peptide, LPLTPLP, which specifically bound to non small cell lung cancer (NSCLC) specimens in vitro. Surprisingly, this peptide inhibited the expression of Hsp90 and induced apoptosis by preventing autophagy in A549 cells treated with docetaxel. The results suggested that this peptide might be used as a promising dual-functional ligand for cancer treatment. Based on these findings, we designed and developed a novel active targeting delivery system by modifying docetaxel nanoparticles (DNP) with the dual-functional ligand LPLTPLP. We consistently demonstrated that the cellular uptake of nanoparticles (NPs) was significantly enhanced in vitro. Furthermore, the targeting NPs exhibited significantly improved antitumor efficacy and biodistribution compared with nontargeting nanodrug and free docetaxel. These findings demonstrate the feasibility of dual-functional NPs for efficient anticancer therapy. PMID- 26643617 TI - Gold nanoparticles modified with self-assembled hybrid monolayer of triblock aptamers as a photoreversible anticoagulant. AB - We demonstrated that thrombin-binding aptamer-conjugated gold nanoparticles (TBA Au NPs), prepared from a self-assembled hybrid monolayer (SAHM) of triblock aptamers on Au NPs (13 nm), can effectively inhibit thrombin activity toward fibrinogen. The first block poly(adenine) at the end of the triblock TBA was used for the self-assembly on Au NP surface. The second block, in the middle of TBA, was composed of oligonucleotides that could hybridize with each other. The third block, containing TBA15 (15-base, binding to the exosite I of thrombin) and TBA29 (29-base, binding to the exosite II of thrombin) provided bivalent interaction with thrombin. The SAHM triblock aptamers have optimal distances between TBA15 and TBA29, aptamer density, and orientation on the Au NP surfaces. These properties strengthen the interactions with thrombin (Kd=1.5 * 10(-11)M), resulting in an extremely high anticoagulant potency. The thrombin clotting time mediated by SAHM TBA15/TBA29-Au NPs was >10 times longer than that of four commercially available drugs (heparin, argatroban, hirudin, or warfarin). In addition, the rat-tail bleeding assay time further demonstrated that the SAHM TBA15/TBA29-Au NPs were superior to heparin. The SAHM TBA15/TBA29-Au NPs exhibited excellent stability in the human plasma (half-life >14 days) and good biocompatibility (low cytotoxicity and hemolysis). Most interestingly, the inhibition by SAHM TBA15/TBA29-Au NPs was controllable by the irradiation of green laser, via heat transfer-induced TBA release from Au NPs. Therefore, these easily prepared (self-assembled), low cost (non-thiolated aptamer), photo controllable, multivalent TBA15/TBA29-Au NPs (high density of TBA15/TBA29 on Au NPs) show good potential for the treatment of various diseases related to blood clotting disorders. Our study opens up the possibility of regulation of molecule binding, protein recognition, and enzyme activity using SAHM aptamer functionalized nanomaterials. PMID- 26643618 TI - The complete mitogenome of an Australian carp gudgeon, hybridogenetic biotype HAHB (Hypseleotris: Eleotridae). AB - The complete mitochondrial genome was determined for a member of the Australian carp gudgeon species complex (Hypseleotris: Eleotridae). The 16 506 bp genome was recovered by direct shotgun sequencing of a wild-caught F1 hybrid male, and it contains the typical vertebrate arrangement of 13 protein-coding genes, 22 tRNA genes, 2 rRNA genes, and a control region. This is the first published mitogenome for the genus Hypseleotris and will be useful for evolutionary studies of the carp gudgeon complex which contains a mixture of sexual species and hybridogenetic biotypes. PMID- 26643619 TI - Access, Care Delivery, And Health. PMID- 26643620 TI - Direct Primary Care: Concierge Care For The Masses. PMID- 26643621 TI - In Second Year Of Marketplaces, New Entrants, ACA 'Co-Ops,' And Medicaid Plans Restrain Average Premium Growth Rates. AB - Premiums for health insurance plans offered through the federally facilitated and state-based Marketplaces remained steady or increased only modestly from 2014 to 2015. We used data from the Marketplaces, state insurance departments, and insurer websites to examine patterns of premium pricing and the factors behind these patterns. Our data came from 2,964 unique plans offered in 2014 and 4,153 unique plans offered in 2015 in forty-nine states and the District of Columbia. Using descriptive and multivariate analysis, we found that the addition of a carrier in a rating area lowered average premiums for the two lowest-cost silver plans and the lowest-cost bronze plan by 2.2 percent. When all plans in a rating area were included, an additional carrier was associated with an average decline in premiums of 1.4 percent. Plans in the Consumer Operated and Oriented Plan Program and Medicaid managed care plans had lower premiums and average premium increases than national commercial and Blue Cross and Blue Shield plans. On average, premiums fell by an appreciably larger amount for catastrophic and bronze plans than for gold plans, and premiums for platinum plans increased. This trend of low premium increases overall is unlikely to continue, however, as insurers are faced with mounting medical claims. PMID- 26643622 TI - Insurer Competition In Federally Run Marketplaces Is Associated With Lower Premiums. AB - Federal subsidies for health insurance premiums sold through the Marketplaces are tied to the cost of the benchmark plan, the second-lowest-cost silver plan. According to economic theory, the presence of more competitors should lead to lower premiums, implying smaller federal outlays for premium subsidies. The long term impact of the Affordable Care Act on government spending will depend on the cost of these premium subsidies over time, with insurer participation and the level of competition likely to influence those costs. We studied insurer participation and premiums during the first two years of the Marketplaces. We found that the addition of a single insurer in a county was associated with a 1.2 percent lower premium for the average silver plan and a 3.5 percent lower premium for the benchmark plan in the federally run Marketplaces. We found that the effect of insurer entry was muted after two or three additional entrants. These findings suggest that increased insurer participation in the federally run Marketplaces reduces federal payments for premium subsidies. PMID- 26643623 TI - Several Factors Responsible For The Recent Slowdown In Premium Growth In Employer Sponsored Insurance. AB - Containing growth in health care spending is important to the long-term fiscal health of the United States. Researchers have been seeking to identify which factors behind the recent spending slowdown might continue to have an impact after the economy has fully recovered from the Great Recession (2007-09). We extended this inquiry by decomposing trends in the growth of private-sector employer-sponsored insurance premiums. Using data for 2001-13 from the Medical Expenditure Panel Survey-Insurance Component and a combination of cell- and regression-based decomposition methods, we found that the slowdown in premium growth that preceded the recession reflected declining growth rates in per policyholder premiums. For 2009-11, however, the dominant contributors to the slowdown were factors underlying declining employee enrollment: a sharp downturn in employment in 2009, followed by eroding offer and eligibility rates. Growth in per policyholder premiums slowed in 2012 and 2013 compared to the preceding few years. Like other researchers, we found that a substantial portion of premium growth remained unexplained. However, it is likely driven, in part, by growth in the underlying cost of medical care. PMID- 26643625 TI - Educating, Enrolling, And Engaging: The State Of Marketplace Consumer Assistance Under The Affordable Care Act. AB - Programs created under the Affordable Care Act to connect consumers to health care coverage represent an unprecedented public-sector investment. State-level implementation of these programs has varied greatly, making it possible to learn from differences in strategy and performance. In this article we assess the current state of Marketplace enrollment assistance, synthesizing evidence from published evaluations (largely derived from grey literature) and analyses of data from nationwide surveys of assisters. Synthesis of this evidence suggests that assister programs play a vital role supporting consumers in the new Marketplaces, particularly when assisters maintain extended ongoing relationships with consumers; assisters come from and are situated within communities they serve; local programs are well coordinated; and postenrollment issues can be addressed. Stable funding commitments, year-round employment, and enriched training were identified as crucial long-run strategies for building a more professional assister workforce and stronger infrastructure. PMID- 26643624 TI - Leveraging The Affordable Care Act To Enroll Justice-Involved Populations In Medicaid: State And Local Efforts. AB - The Affordable Care Act provides an unprecedented opportunity to enroll criminal justice-involved populations in health insurance, particularly Medicaid. As a result, many state and county corrections departments have launched programs that incorporate Medicaid enrollment in discharge planning. Our study characterizes the national landscape of programs enrolling criminal justice-involved populations in Medicaid as of January 2015. We provide an overview of sixty-four programs operating in jails, prisons, or community probation and parole systems that enroll individuals during detention, incarceration, and the release process. We describe the variation among the programs in terms of settings, personnel, timing of eligibility screening, and target populations. Seventy-seven percent of the programs are located in jails, and 56 percent use personnel from public health or social service agencies. We describe four practices that have facilitated the Medicaid enrollment process: suspending instead of terminating Medicaid benefits upon incarceration, presuming that an individual is eligible for Medicaid before the process is completed, allowing enrollment during incarceration, and accepting alternative forms of identification for enrollment. The criminal justice system is a complex one that requires a variety of approaches to enroll individuals in Medicaid. Future research should examine how these approaches influence health and criminal justice outcomes. PMID- 26643626 TI - In Four ACA Expansion States, The Percentage Of Uninsured Hospitalizations For People With HIV Declined, 2012-14. AB - This study examines the influence of the Affordable Care Act's optional state Medicaid expansion on insurance coverage and health outcomes for hospitalized patients with HIV. I used data from the State Inpatient Databases of the Healthcare Cost and Utilization Project for all hospitalizations of patients with HIV from 2012 through the first six months of 2014 in four states that expanded their Medicaid programs and two states that did not. I found that the percentage of hospitalizations of uninsured people with HIV in the four expansion states fell from 13.7 percent to 5.5 percent in the study period, while the percentage in the two nonexpanding states increased from 14.5 percent to 15.7 percent. I also found that hospitalized patients with HIV who did not have insurance were 40 percent more likely to die during their hospital stays than comparable patients with insurance. PMID- 26643627 TI - Affordable Care Act Provision Lowered Out-Of-Pocket Cost And Increased Colonoscopy Rates Among Men In Medicare. AB - Colorectal cancer screening is one of the few cancer screenings with an "A" rating from the US Preventive Services Task Force, meaning that the procedure confers a substantial health benefit. However, 40 percent of people who should receive colorectal cancer screenings do not receive them. Colonoscopies are the most thorough method of screening because they allow physicians to view the entire length of the colon and remove polyps as needed. Billing methods that distinguish between screening and therapeutic procedures have kept expected colonoscopy costs high. However, the Affordable Care Act partially closed the so called colonoscopy loophole and reduced expected out-of-pocket expenses for all Medicare beneficiaries. Using data from the Behavioral Risk Factor Surveillance System, we found that annual colonoscopy rates among men ages 66-75 increased significantly (by 4.0 percentage points) after the Affordable Care Act policy change, and we found some evidence of even larger increases among socioeconomically disadvantaged men. We found no significant increases among women, a result that may be explained by health behavior and other factors and that requires further study. Our research indicates that cost may be an important barrier to colorectal cancer screening, at least among men, and that making further policy changes to close remaining loopholes may improve screening rates. PMID- 26643629 TI - Policy Options To Expand Medicare's Low-Income Provisions To Improve Access And Affordability. AB - For fifty years Medicare has enhanced the health and financial security of seniors. Yet in 2014 an estimated 40 percent of low-income beneficiaries spent 20 percent or more of their incomes on out-of-pocket expenditures for premiums and medical care, while one-third were underinsured based on their out-of-pocket spending for medical care alone. These high burdens reflect Medicare's limited benefits and restrictive income eligibility levels for supplemental Medicaid coverage. We examined the impacts of illustrative policies designed to improve beneficiaries' financial protection and access to care by reducing Medicare premiums and cost sharing for covered benefits on a sliding scale for all beneficiaries with incomes up to 200 percent of the federal poverty level. We estimate that these policies could improve the affordability of health care for eleven million people. Designed to be aligned with the Affordable Care Act's subsidy approach for the population younger than age sixty-five, these policies also have the potential to smooth transitions into Medicare, reduce administrative costs, and provide a more secure and equitable foundation for Medicare's future. PMID- 26643628 TI - The Early Impact Of The 'Alternative Quality Contract' On Mental Health Service Use And Spending In Massachusetts. AB - Accountable care using global payment with performance bonuses has shown promise in controlling spending growth and improving care. This study examined how an early model, the Alternative Quality Contract (AQC) established in 2009 by Blue Cross Blue Shield of Massachusetts (BCBSMA), has affected care for mental illness. We compared spending and use for enrollees in AQC organizations that did and did not accept financial risk for mental health with enrollees not participating in the contract. Compared with BCBSMA enrollees in organizations not participating in the AQC, we found that enrollees in participating organizations were slightly less likely to use mental health services and, among mental health services users, small declines were detected in total health care spending, but no change was found in mental health spending. The declines in probability of use of mental health services and in total health spending among mental health service users attributable to the AQC were concentrated among enrollees in organizations that accepted financial risk for behavioral health. Interviews with AQC organization leaders suggested that the contractual arrangements did not meaningfully affect mental health care delivery in the program's initial years, but organizations are now at varying stages of efforts to improve mental health integration. PMID- 26643630 TI - Improving The Affordable Care Act: An Assessment Of Policy Options For Providing Subsidies. AB - A key challenge of health reform efforts is to make health insurance affordable for individuals and families who lack coverage without harming those with coverage or increasing federal spending. The Affordable Care Act (ACA) addresses this challenge in part by providing tax subsidies to qualified individuals for purchasing individual insurance and retaining tax exemptions for employer and employee contributions to the cost of premiums of employer-sponsored insurance. These tax exemptions cost approximately $250 billion annually in lost tax revenue and have been criticized for favoring higher earners and conferring preferential treatment of employer-sponsored over individual insurance. We analyzed three options for leveling the financial playing field between the two insurance markets by reallocating the value of tax benefits of employer coverage. We found that one option that uses the subsidy formula employed in the insurance Marketplaces under the ACA for both the individual and employer-sponsored insurance markets, and additionally requires the subsidy to be at least $1,250 without an upper income limit on subsidy eligibility imposed, could expand insurance coverage and reduce individual market premiums relative to the ACA with no additional federal spending. PMID- 26643631 TI - Primary Care Physicians In Ten Countries Report Challenges Caring For Patients With Complex Health Needs. AB - Industrialized countries face a daunting challenge in providing high-quality care for aging patients with increasingly complex health care needs who will need ongoing chronic care management, community, and social services in addition to episodic acute care. Our international survey of primary care doctors in the United States and nine other countries reveals their concern about how well prepared their practices are to manage the care of patients with complex needs and about their variable experiences in coordinating care and communicating with specialists, hospitals, home care, and social service providers. While electronic information exchange remains a challenge in most countries, a positive finding was the significant increase in the adoption of electronic health records by primary care doctors in the United States and Canada since 2012. Finally, feedback on job-related stress, perceptions of declining quality of care, and administrative burden signal the need to monitor front-line perspectives as health reforms are conceived and implemented. PMID- 26643632 TI - US Children And Adolescents Had Fewer Annual Doctor And Dentist Contacts Than Their Dutch Counterparts, 2010-12. AB - Children and adolescents in the United States have been found to be less healthy than their counterparts in other high-income countries. The contribution of pediatric health care use to health outcomes--either as an independent determinant or as a mediator of wider social factors--is not well understood. We found that, compared to their peers in the Netherlands, US children and adolescents had fewer annual doctor and dental contacts in 2012. In both countries, poorer health status was reported among low-income compared to high income children; however, this status was accompanied by greater or equal number of doctor and dental contacts among low-income Dutch children compared to their higher-income Dutch peers. By contrast, low-income US children had 28-65 percent fewer care episodes than high-income US children. Further research is needed to investigate the potential impact of greater equity and use of pediatric services on US health outcomes. Possible policy responses might include a focus on improving the quality, coverage, and benefits of health insurance, as well as on the workforce implications of providing high-quality pediatric care to all. PMID- 26643633 TI - Nursing Homes That Increased The Proportion Of Medicare Days Saw Gains In Quality Outcomes For Long-Stay Residents. AB - Nursing homes are increasingly providing rehabilitative care to short-stay residents under Medicare's skilled nursing facility coverage, which is much more generous than Medicaid's coverage for long-stay residents. This shift creates the potential for both beneficial and detrimental effects on outcomes for such residents. Examining nationwide facility-level nursing home data for the period 2007-10, we found that increasing the proportion of Medicare-covered patient days in a nursing home was significantly associated with improvements in the quality of the three outcomes we considered for long-stay residents. We saw significant decreases in the percentages of long-stay residents with daily pain (from 5.1 percent to 3.4 percent), with worsening pressure ulcers (from 2.5 percent to 2.0 percent), and with a decline in performing activities of daily living (from 15.9 percent to 14.9 percent). These findings reinforce previous research indicating that quality outcomes tend to be superior in nursing homes with greater financial resources. They also bolster arguments for financial investments in nursing homes, including increases in Medicaid payment rates, to support better care for long-stay residents. PMID- 26643634 TI - Nurse Staffing Hours At Nursing Homes With High Concentrations Of Minority Residents, 2001-11. AB - Recent increases in state Medicaid payments to nursing homes have the potential to reduce disparities in nurse staffing between facilities with high and low concentrations of racial/ethnic minority residents. Analyses of nursing home and state policy survey data for the period 2001-11 suggest that registered nurse and licensed practical nurse staffing levels increased slightly during this period, regardless of racial/ethnic minority resident concentration. Adjusted disparities in registered nurse hours per resident day between nursing homes with high and low concentrations of minority residents persisted, although they were reduced. Certified nursing assistant hours per patient day increased in nursing homes with low concentrations of minorities but decreased in homes with high concentrations, creating a new disparity. Overall, increases in state Medicaid payment rates to nursing homes were associated with improvements in staffing and reduced staffing disparities across facilities, but the adoption of case-mix payments had the opposite effect. Further reforms in health care delivery and payment are needed to address persistent disparities in care between nursing homes serving higher proportions of minority residents and those serving lower proportions, and to prevent unintended exacerbations of such disparities. PMID- 26643635 TI - Medicare Home Visit Program Associated With Fewer Hospital And Nursing Home Admissions, Increased Office Visits. AB - Clinical home visit programs for Medicare beneficiaries are a promising approach to supporting aging in place and avoiding high-cost institutional care. Such programs combine a comprehensive geriatric assessment by a clinician during a home visit with referrals to community providers and health plan resources to address uncovered issues. We evaluated UnitedHealth Group's HouseCalls program, which has been offered to Medicare Advantage plan members in Arkansas, Georgia, Missouri, South Carolina, and Texas since January 2008. We found that, compared to non-HouseCalls Medicare Advantage plan members and fee-for-service beneficiaries, HouseCalls participants had reductions in admissions to hospitals (1 percent and 14 percent, respectively) and lower risk of nursing home admission (0.67 percent and 1.3 percent, respectively). In addition, participants' numbers of office visits--chiefly to specialists--increased 2-6 percent (depending on the comparison group). The program's effects on emergency department use were mixed. These results indicate that a thorough home-based clinical assessment of a member's health and home environment combined with referral services can support aging in place, promote physician office visits, and preempt costly institutional care. PMID- 26643636 TI - The Growing Difference Between Public And Private Payment Rates For Inpatient Hospital Care. PMID- 26643637 TI - The Most Crowded US Hospital Emergency Departments Did Not Adopt Effective Interventions To Improve Flow, 2007-10. AB - Emergency department (ED) crowding adversely affects patient care and outcomes. Despite national recommendations to address crowding, it persists in most US EDs today. Using nationally representative data, we evaluated the use of interventions to address crowding in US hospitals in the period 2007-10. We examined the relationship between crowding within an ED itself, measured as longer ED lengths-of-stay, and the number of interventions adopted. In our study period the average number of interventions adopted increased from 5.2 to 6.6, and seven of the seventeen studied interventions saw a significant increase in adoption. In general, more crowded EDs adopted greater numbers of interventions than less crowded EDs. However, in the most crowded quartile of EDs, a large proportion had not adopted effective interventions: 19 percent did not use bedside registration, and 94 percent did not use surgical schedule smoothing. Thus, while adoption of strategies to reduce ED crowding is increasing, many of the nation's most crowded EDs have not adopted proven interventions. PMID- 26643638 TI - The Science And Art Of Delivery: Accelerating The Diffusion Of Health Care Innovation. AB - There is a widely acknowledged time lag in health care between an invention or innovation and its widespread use across a health system. Much is known about the factors that can aid the uptake of innovations within discrete organizations. Less is known about what needs to be done to enable innovations to transform large systems of health care. This article describes the results of in-depth case studies aimed at assessing the role of key agents and agencies that facilitate the rapid adoption of innovations. The case studies-from Argentina, England, Nepal, Singapore, Sweden, the United States, and Zambia-represent widely varying health systems and economies. The implications of the findings for policy makers are discussed in terms of key factors within a phased approach for creating a climate for change, engaging and enabling the whole organization, and implementing and sustaining change. Purposeful and directed change management is needed to drive system transformation. PMID- 26643639 TI - Measuring Recent Apparent Declines In Longevity: The Role Of Increasing Educational Attainment. AB - Independent researchers have reported an alarming decline in life expectancy after 1990 among US non-Hispanic whites with less than a high school education. However, US educational attainment rose dramatically during the twentieth century; thus, focusing on changes in mortality rates of those not completing high school means looking at a different, shrinking, and increasingly vulnerable segment of the population in each year. We analyzed US data to examine the robustness of earlier findings categorizing education in terms of relative rank in the overall distribution of each birth cohort, instead of by credentials such as high school graduation. Estimating trends in mortality for the bottom quartile, we found little evidence that survival probabilities declined dramatically. We conclude that widely publicized estimates of worsening mortality rates among non-Hispanic whites with low socioeconomic position are highly sensitive to how educational attainment is classified. However, non-Hispanic whites with low socioeconomic position, especially women, are not sharing in improving life expectancy, and disparities between US blacks and whites are entrenched. Findings underscore the urgency of an agenda to equitably disseminate new medical technologies and to deepen knowledge of social determinants of health and how that knowledge can be applied, to promote the objective of achieving population health equity. PMID- 26643640 TI - An Uninsured Immigrant Delays Needed Care. PMID- 26643641 TI - Engaging Front-Line Nurses To Improve The Outcomes Of Patient Care, 2006-13. AB - Beginning in 2003 the Gordon and Betty Moore Foundation partnered with fifty three hospitals in the San Francisco Bay and Greater Sacramento areas of California to improve patient safety. The twelve-year, $167 million Betty Irene Moore Nursing Initiative was intended to empower front-line registered nurses (RNs) as leaders in implementing evidence-based clinical practices at the bedside. The initiative funded clinical efforts across seventeen patient safety improvement areas; results from seven of these are presented here. Bay Area hospitals had varied participation rates in those seven areas in the period 2006 13. For example, 14 percent of the hospitals participated in the effort to reduce acute myocardial infarction mortality, while 100 percent participated in the effort to reduce falls with injury. Patient outcome improvements compared to baseline also varied. For example, 43 percent of participating hospitals reported reductions in patient falls with injury, while 100 percent of hospitals participating in the effort to reduce medication administration errors reported improvements. Participating hospitals are maintaining the quality improvement outcomes that the foundation's support helped them achieve. This shows the potential of front-line RNs to lead sustainable quality improvement efforts. PMID- 26643643 TI - Governing Boards And Clinical Quality. PMID- 26643644 TI - Errata. PMID- 26643645 TI - Message From The New President And CEO Of Project HOPE. PMID- 26643646 TI - Continuous and Pulsatile Pediatric Ventricular Assist Device Hemodynamics with a Viscoelastic Blood Model. AB - To investigate the effects of pulsatile and continuous pediatric ventricular assist (PVAD) flow and pediatric blood viscoelasticity on hemodynamics in a pediatric aortic graft model. Hemodynamic parameters of pulsatility, along with velocity and wall shear stress (WSS), are analyzed and compared between Newtonian and viscoelastic blood models at a range of physiological pediatric hematocrits using computational fluid dynamics. Both pulsatile and continuous PVAD flow lead to a decrease in pulsatility (surplus hemodynamic energy, ergs/cm(3)) compared to healthy aortic flow but with continuous PVAD pulsatility up to 2.4 times lower than pulsatile PVAD pulsatility at each aortic outlet. Significant differences are also seen between the two flow modes in velocity and WSS. The higher velocity jet during systole with pulsatile flow leads to higher WSSs at the anastomotic toe and at the aortic branch bifurcations. The lower velocity but continuous flow jet leads to a much different flow field and higher WSSs into diastole. Under a range of physiological pediatric hematocrit (20-60%), both velocity and WSS can vary significantly with the higher hematocrit blood model generally leading to higher peak WSSs but also lower WSSs in regions of flow separation. The large decrease in pulsatility seen from continuous PVAD flow could lead to complications in pediatric vascular development while the high WSSs during peak systole from pulsatile PVAD flow could lead to blood damage. Both flow modes lead to similar regions prone to intimal hyperplasia resulting from low time-averaged WSS and high oscillatory shear index. PMID- 26643647 TI - Metabolic responses to dietary leucine restriction involve remodeling of adipose tissue and enhanced hepatic insulin signaling. AB - Dietary leucine was incrementally restricted to test whether limiting this essential amino acid (EAA) would fully reproduce the beneficial responses produced by dietary methionine restriction. Restricting leucine by 85% increased energy intake and expenditure within 5 to 7 days of its introduction and reduced overall accumulation of adipose tissue. Leucine restriction (LR) also improved glucose tolerance, increased hepatic release of fibroblast growth factor 21 into the blood stream, and enhanced insulin-dependent activation of Akt in liver. However, LR had no effect on hepatic lipid levels and failed to lower lipogenic gene expression in the liver. LR did affect remodeling of white and brown adipose tissues, increasing expression of both thermogenic and lipogenic genes. These findings illustrate that dietary LR reproduces many but not all of the physiological responses of methionine restriction. The primary differences occur in the liver, where methionine and LR cause opposite effects on tissue lipid levels and expression of lipogenic genes. Altogether, these findings suggest that the sensing systems which detect and respond to dietary restriction of EAAs act through mechanisms that both leucine and methionine are able to engage, and in the case of hepatic lipid metabolism, may be unique to specific EAAs such as methionine. PMID- 26643649 TI - Occupational health management system: A study of expatriate construction professionals. AB - Due to its direct impact on the safety and function of organizations, occupational health has been a concern of the construction industry for many years. The inherent complexity of occupational health management presents challenges that make a systems approach essential. From a systems perspective, health is conceptualized as an emergent property of a system in which processes operating at the individual and organizational level are inextricably connected. Based on the fundamental behavior-to-performance-to-outcome (B-P-O) theory of industrial/organizational psychology, this study presents the development of an I CB-HP-O (Input-Coping Behaviors-Health Performance-Outcomes) health management systems model spanning individual and organizational boundaries. The model is based on a survey of Hong Kong expatriate construction professionals working in Mainland China. Such professionals tend to be under considerable stress due not only to an adverse work environment with dynamic tasks, but also the need to confront the cross-cultural issues arising from expatriation. A questionnaire was designed based on 6 focus groups involving 44 participants, and followed by a pilot study. Of the 500 questionnaires distributed in the main study, 137 valid returns were received, giving a response rate of 27.4%. The data were analyzed using statistical techniques such as factor analysis, reliability testing, Pearson correlation analysis, multiple regression modeling, and structural equation modeling. Theories of coping behaviors and health performance tend to focus on the isolated causal effects of single factors and/or posits the model at single, individual level; while industrial practices on health management tend to focus on organizational policy and training. By developing the I-CB-HP-O health management system, incorporating individual, interpersonal, and organizational perspectives, this study bridges the gap between theory and practice while providing empirical support for a systems view of health management. PMID- 26643650 TI - Determinants of the occupational environment and heavy vehicle crashes in Western Australia: A case-control study. AB - OBJECTIVE: To determine the association between a heavy vehicle driver's work environment, including fatigue-related characteristics, and the risk of a crash in Western Australia. METHODS: This case-control study included 100 long-haul heavy vehicle drivers who were involved in a police-reported crash in WA and 100 long-haul heavy vehicle drivers recruited from WA truck stops, who were not involved in a crash in the previous 12 months. Driver demographics and driving details, work environment, vehicle and sleep-related characteristics were obtained using an interviewer-administered questionnaire. Drivers were tested for obstructive sleep apnoea using an overnight diagnostic device. Conditional multiple logistic regression analysis was undertaken to determine work environment-related factors associated with crash involvement. RESULTS: After accounting for potential confounders, driving a heavy vehicle with an empty load was associated with almost a three-fold increased crash risk compared to carrying general freight (adjusted OR: 2.93, 95% CI: 1.17-7.34). Driving a rigid heavy vehicle was associated with a four-fold increased risk of crashing compared to articulated heavy vehicles (adjusted OR: 4.08, 95% CI: 1.13-14.68). The risk of crashing was almost five times higher when driving more than 50% of the trip between midnight and 5.59am (adjusted OR: 4.86, 95% CI: 1.47-16.07). Furthermore, the risk of crashing significantly increased if the time since the last break on the index trip was greater than 2h (adjusted OR: 2.18, 95% CI: 1.14-4.17). Drivers with more than 10 years driving experience were 52% less likely to be involved in a crash (adjusted OR: 0.48, 95% CI: 0.23-0.99). CONCLUSION: The results provide support for an association between a driver's work environment, fatigue-related factors, and the risk of heavy vehicle crash involvement. Greater attention needs to be paid to the creation of a safer work environment for long distance heavy vehicle drivers. PMID- 26643651 TI - Europium Luminescence Used for Logic Gate and Ions Sensing with Enoxacin As the Antenna. AB - Luminescent lanthanide ion complexes have received increasing attention because of their unique optical properties. Herein, we discovered that the luminescence of europium(III) (Eu(3+)) could be regulated by Ag(+) and SCN(-) in seconds with enoxacin (ENX) as the antenna. Under given conditions, only the simultaneous introduction of Ag(+) and SCN(-) could remarkably enhance the luminescence intensity of Eu(3+)-ENX complexes. This phenomenon has been exploited to design an "AND" logic gate and specific luminescence turn-on assays for sensitively sensing Ag(+) and SCN(-) for the first time. Furthermore, the addition of S(2-) resulted in efficient luminescence quenching of the Eu(3+)/ENX/Ag(+)/SCN(-) system due to the strong affinity between Ag(+) and S(2-). Thus, a new luminescent sensing platform for S(2-) was established, which exhibited excellent selectivity and high sensitivity. S(2-) could be detected within the concentration range of 100 nM to 12.5 MUM with a detection limit of 60 nM. Such sensing system features simplicity, rapidity, and flexibility. Moreover, this proposed Eu(3+)-based luminescent assay could be successfully applied in the real environmental water sample analysis. PMID- 26643652 TI - Interface Intermixing in Type II InAs/GaInAsSb Quantum Wells Designed for Active Regions of Mid-Infrared-Emitting Interband Cascade Lasers. AB - The effect of interface intermixing in W-design GaSb/AlSb/InAs/Ga0.665In0.335AsxSb1 - x/InAs/AlSb/GaSb quantum wells (QWs) has been investigated by means of optical spectroscopy supported by structural data and by band structure calculations. The fundamental optical transition has been detected at room temperature through photoluminescence and photoreflectance measurements and appeared to be blueshifted with increasing As content of the GaInAsSb layer, in contrast to the energy-gap-driven shifts calculated for an ideally rectangular QW profile. The arsenic incorporation into the hole-confining layer affects the material and optical structure also altering the InAs/GaInAsSb interfaces and their degree of intermixing. Based on the analysis of cross sectional transmission electron microscopy images and energy-dispersive X-ray spectroscopy, we could deduce the composition distribution across the QW layers and hence simulate more realistic confinement potential profiles. For such smoothed interfaces that indicate As-enhanced intermixing, the energy level calculations have been able to reproduce the experimentally obtained trend. PMID- 26643648 TI - About one-half of early spontaneous preterm deliveries can be identified by a rapid matrix metalloproteinase-8 (MMP-8) bedside test at the time of mid trimester genetic amniocentesis. AB - OBJECTIVE: Mid-trimester amniocentesis continues to be used for the prenatal diagnosis of chromosomal anomalies and other genetic disorders. Analysis of amniotic fluid obtained at the time of mid-trimester genetic amniocentesis identifies those patients who are at risk for early spontaneous preterm delivery. This is based on a solid body of evidence that found subclinical intra-amniotic inflammation/infection to be causally linked to early spontaneous preterm birth. Although several biomarkers have been proposed to identify intra-amniotic inflammation, the accumulated data suggest that the determination of amniotic fluid matrix metalloproteinase-8 (MMP-8), or neutrophil collagenase, is a powerful predictor of spontaneous preterm delivery. MMP-8 is released by inflammatory cells in response to microbial products or "danger signals". A rapid point-of-care test has been developed to determine MMP-8 at the bedside within 20 min, and without the requirement of laboratory equipment. The objective of this study was to determine whether an elevation of MMP-8 in the amniotic fluid, measured by a rapid point-of-care test, can identify those patients at risk for spontaneous preterm delivery after a mid-trimester genetic amniocentesis. STUDY DESIGN: A case-control study was designed to obtain amniotic fluid from asymptomatic singleton pregnant women who underwent mid-trimester genetic amniocentesis. An MMP-8 bedside test was performed to analyze the amniotic fluid of 64 patients with early spontaneous preterm delivery (<30 weeks) and 128 matched controls with normal pregnancy outcomes. RESULTS: (1) The MMP-8 bedside test (Yoon's MMP-8 CheckTM) was positive in 42.2% (27/64) of patients with spontaneous preterm delivery but in none (0/128) of the control cases (p < 0.001); (2) the MMP-8 bedside test had a sensitivity of 42.2%, and a specificity of 100% in the prediction of spontaneous preterm delivery (<30 weeks) following a mid-trimester genetic amniocentesis; and (3) among the patients with spontaneous preterm delivery, those with a positive MMP-8 bedside test had a significantly higher rate of spontaneous delivery within 2 weeks and 4 weeks of an amniocentesis [40.7% (11/27) versus 5.4% (2/37); 63.0% (17/27) versus 24.3% (9/37)] and a shorter interval-to-delivery period than those with a negative test [interval-to-delivery: median (range), 16 d (0-95 d) versus 42 d (2-91 d); p < 0.05 for each]. CONCLUSION: We conclude that 42% of patients with an early spontaneous preterm delivery (< 30 weeks) could be identified by a rapid MMP-8 bedside test at the time of their mid-trimester genetic amniocentesis. The MMP-8 bedside test is a powerful predictor of early spontaneous preterm birth in asymptomatic pregnant women. PMID- 26643653 TI - Manganese(II) Complexes with Schiff Bases Immobilized on Nanosilica as Catalysts of the Reaction of Ozone Decomposition. AB - In this article, we submit the description of synthesis and identification of manganese(II) complexes with pyrogenic nanosilica-immobilized (d av = 10 nm; S sp = 290 m(2)/g) hydroxyaldimine ligands [Formula: see text]: salicilaldiminopropyl (L1); 5-bromosalicilaldiminopropyl (L2); 2-hydroxynaphtaldiminopropyl (L3); 2 hydroxy-3-methoxybenzaldiminopropyl (L4); 2-hydroxy-3,5 dichloroacetophenoniminopropyl (L5); and 4-hydroxy-3-methoxybenzaldiminopropyl (L6). The ligands and complexes were characterized by UV-VIS and IR spectrometry. Nanocomposites consisting of complexes [Formula: see text] showed a high catalytic activity in low-temperature ozone decomposition in the range of concentrations between 2.1 * 10(-6) and 8.4 * 10(-6) mol/l. The number of catalytic cycles increased for isostructural pseudotetrahedral complexes [Formula: see text] (L1-L5) in the following order: Mn(L3)2 >> Mn(L4)2 > Mn(L1)2 > Mn(L2)2 > Mn(L5)2. In the case of pseudooctahedral complexes with L6, the change of coordination polyhedral does not influence the kinetics and stoichiometric parameters of the reaction. PMID- 26643654 TI - Phylogenetic inference and SSR characterization of tropical woody bamboos tribe Bambuseae (Poaceae: Bambusoideae) based on complete plastid genome sequences. AB - The complete plastome sequencing is an efficient option for increasing phylogenetic resolution and evolutionary studies, as well as may greatly facilitate the use of plastid DNA markers in plant population genetic studies. Merostachys and Guadua stand out as the most common and the highest potential utilization bamboos indigenous of Brazil. Here, we sequenced the complete plastome sequences of the Brazilian Guadua chacoensis and Merostachys sp. to perform full plastome phylogeny and characterize the occurrence, type, and distribution of SRRs using 20 Bambuseae species. The determined plastome sequence of Merostachys sp. and G. chacoensis is 136,334 and 135,403 bp in size, respectively, with an identical gene content and typical quadripartite structure consisting of a pair of IRs separated by the LSC and SSC regions. The Maximum Likelihood and Bayesian Inference analyses produced phylogenomic trees identical in topology. These trees supported monophyly of Paleotropical and Neotropical Bamboos clades. The Neotropical bamboos segregated into three well-supported lineages, Chusqueinae, Guaduinae, and Arthrostylidiinae, with the last two forming a well-supported sister relationship. Paleotropical bamboos segregated into two well-supported lineages, Hickeliinae and Bambusinae + Melocanninae. We identified 141.8 cpSSR in Bambuseae plastomes and an inferior value (38.15) for plastome coding sequences. Among them, we identified 16 polymorphic SSR loci, with number of alleles varying from 3 to 10. These 16 polymorphic cpSSR loci in Bambuseae plastome can be assessed for the intraspecific level of polymorphism, leading to innovative highly sensitive phylogeographic and population genetics studies for this tribe. PMID- 26643656 TI - The value of physical examination in mental health nursing. AB - This article explores the use of a physical examination assignment in a mental health general nursing clinical placement course that addresses the poor physical health of people with mental illness and the barriers traditionally impeding health care provision for this population. A descriptive qualitative approach utilizes inductive content analysis to investigate 145 student survey responses. The assignment assists student nurses in understanding that physical and mental well-being are intrinsically linked. Students report increased comfort performing a physical examination on patients with mental illness post assignment. Students' initial bias towards this population was minimized post the clinical assignment. Poor physical health is common among people with mental health problems. Many view the provision of care as a major public health issue. Nurses are the front line caregivers of mental health service consumers and are well positioned to assess their physical needs. Their assessment may be the first step in recognizing health care issues in this population. PMID- 26643655 TI - Novel approaches to treating Clostridium difficile-associated colitis. AB - Clostridium difficile is being recognized as a growing threat to many health-care systems. Epidemiology data shows that infection rates are soaring and the disease burden is increasing. Despite the efficacy of standard treatments, it is becoming evident that novel therapeutics will be required to tackle this disease. These new treatments aim to enhance the intestinal microbial barrier, activate the immune system and neutralize the toxins that mediate this disease. Many of these therapies are still in the beginning stages of investigation, however, in the next few years, more clinical data will become available to help implement many of these exciting new therapeutic approaches. PMID- 26643657 TI - Fetuses with right aortic arch: a multicenter cohort study and meta-analysis. AB - OBJECTIVES: Use of recent antenatal screening guidelines for cardiac abnormalities has increased fetal diagnoses of right aortic arch (RAA). We aimed to establish the outcome of fetal RAA without intracardiac abnormalities (ICA) to guide postnatal management. METHODS: In the retrospective cohort part of our study, outcome measures were rates of chromosomal abnormalities, 22q11.2 deletion, fetal extracardiac abnormalities (ECA), postnatal ICA and ECA, and symptoms of and surgery for vascular ring. A systematic review and meta-analysis was also performed; results are reported as proportions. Kaplan-Meier analysis of vascular ring cases with surgery as endpoint was performed. RESULTS: Our cohort included 86 cases; 41 had a vascular ring. Rates of chromosomal abnormalities, 22q11.2 deletion and fetal ECA were 14.1%, 6.4% and 17.4%, respectively. Sixteen studies including our cohort (312 fetuses) were included in the systematic review. Overall rates of chromosomal abnormalities and 22q11.2 deletion were 9.0% (95% CI, 6.0-12.5%) and 6.1% (95% CI, 3.6-9.3%), whilst the respective rates for cases with no ECA were 4.6% (95% CI, 2.3-7.8%) and 5.1% (95% CI, 2.4-8.6%). ECA were seen in 14.6% (95% CI, 10.6-19.0%) prenatally and in 4.0% (95% CI, 1.5-7.6%) after birth. Postnatal ICA were identified in 5.0% (95% CI, 2.7-7.9%). Rate of symptoms of vascular rings (follow-up >= 24 months postpartum) was 25.2% (95% CI, 16.6-35.0%), and 17.1% (95% CI, 9.9-25.7%) had surgery. Two-year freedom from surgery was 83.0% (95% CI, 74.3-90.1%). CONCLUSIONS: Fetal RAA without ICA is more frequently associated with ECA than with chromosomal abnormalities. Most cases, however, are isolated. Vascular-ring symptoms occur in about 25% of cases. Postnatal surveillance is required mainly in the first 2 years after delivery. PMID- 26643658 TI - Dermal Adipocytes: From Irrelevance to Metabolic Targets? AB - Dermal white adipose tissue (dWAT) has received little appreciation in the past as a distinct entity from the better recognized subcutaneous white adipose tissue (sWAT). However, recent work has established dWAT as an important contributor to a multitude of processes, including immune response, wound healing and scarring, hair follicle (HF) growth, and thermoregulation. Unique metabolic contributions have also been attributed to dWAT, at least in part due to its thermic insulation properties and response to cold exposure. Dermal adipocytes can also undergo an adipocyte-myofibroblast transition (AMT), a process that is suspected to have an important role in several pathophysiological processes within the skin. Here, we discuss emerging concepts regarding dWAT physiology and its significance to a variety of cellular processes. PMID- 26643659 TI - Exploring different strategies for imbalanced ADME data problem: case study on Caco-2 permeability modeling. AB - In many absorption, distribution, metabolism, and excretion (ADME) modeling problems, imbalanced data could negatively affect classification performance of machine learning algorithms. Solutions for handling imbalanced dataset have been proposed, but their application for ADME modeling tasks is underexplored. In this paper, various strategies including cost-sensitive learning and resampling methods were studied to tackle the moderate imbalance problem of a large Caco-2 cell permeability database. Simple physicochemical molecular descriptors were utilized for data modeling. Support vector machine classifiers were constructed and compared using multiple comparison tests. Results showed that the models developed on the basis of resampling strategies displayed better performance than the cost-sensitive classification models, especially in the case of oversampling data where misclassification rates for minority class have values of 0.11 and 0.14 for training and test set, respectively. A consensus model with enhanced applicability domain was subsequently constructed and showed improved performance. This model was used to predict a set of randomly selected high permeability reference drugs according to the biopharmaceutics classification system. Overall, this study provides a comparison of numerous rebalancing strategies and displays the effectiveness of oversampling methods to deal with imbalanced permeability data problems. PMID- 26643660 TI - Paeoniflorin, a novel heat-shock protein inducing compound, and human myometrial contractility in vitro. AB - AIM: Heat shock proteins (HSPs) are synthesized in virtually all organisms in response to increases in temperature. They are associated with a relaxant effect on the human myometrium and are present in decreased concentration in the myometrium at the time of labor. Paeoniflorin is derived from Paeonia lactiflora and has been shown to induce the synthesis of HSPs in cultured mammalian cells. The purpose of the study was to evaluate the effect of paeoniflorin on human uterine contractility. MATERIAL AND METHODS: Samples of human myometrium were taken at lower segment cesarean section. Dissected muscle strips were suspended under isometric conditions and exposed to cumulative additions of paeoniflorin in concentrations ranging from 1 nmol/L to 10 mol/L. Control experiments were simultaneously performed. RESULTS: Paeoniflorin was found to exert an inhibitory effect on spontaneous and agonist-induced contractions compared to control strips. The mean maximal inhibition values were: 42.21% +/- 9.26 for spontaneous contractions (n = 6; P < 0.0001) and 47.84% +/- 9.05 for oxytocin-induced contractions (n = 6; P < 0.0001). CONCLUSION: The HSP inducing compound, paeoniflorin, had a relaxant effect on human uterine contractility in vitro. These results reinforce the fact that HSPs may play a physiological role in the onset of labor and may also provide future targets for novel tocolytic treatments. PMID- 26643661 TI - Preliminary evaluation of exome sequencing to identify genetic markers of susceptibility to tuberculosis disease. AB - BACKGROUND: Recent studies have shown that certain human genetic polymorphisms could be associated with susceptibility to tuberculosis (TB) infection and disease. Advances in next generation sequencing include the ability to rapidly sequence the entire human exome. These new technologies can be exploited to identify new associations of human genetic polymorphisms and TB infection and disease. In this preliminary study we compared two different strategies for sequencing of the human exome in a small sample set consisting of three individuals with a history of TB disease and two individuals with latent TB infection. FINDINGS: Sequencing of the entire exome of the five participants using Agilent SureSelect kit resulted in the identification of 1611 single nucleotide polymorphisms (SNPs) that were only present in the individuals with a history of active TB but not in the latent TB cases. Alternatively, sequencing of 4000 target genes available in the TruSight kit resulted in identification of 182 SNPs only present in the active TB cases and not in the latent TB participants. The overlap of the two kits was 112 SNPs. CONCLUSIONS: Even though this pilot study was restricted to a small number of participants, we demonstrated the feasibility of using exome sequencing technologies to mine potential genetic associations of susceptibility to TB disease and presented a number of potential targets that can be further explore in larger research trials. PMID- 26643662 TI - A new polymorphism on chromosome 6 associated with bolting tendency in sugar beet. AB - BACKGROUND: Premature flowering or bolting is an undesirable characteristic that causes severe sugar yield losses and interferes with harvesting. Vernalization is a prerequisite for the floral induction, achieved by exposure to low temperatures for 10-14 weeks. This process is also controlled by other environmental factors, such as long daylight photoperiods and a combination of genetic factors. The objective of this study was the identification of new genetic polymorphisms linked to bolting tendency in sugar beet. RESULTS: Two pollinators characterized by low and high bolting tendency were subjected to RAD-sequencing in order to detect discriminating SNPs between lines. 6,324 putative SNPs were identified. Of these, 192 were genotyped in a set of 19 pollinators, each comprising bolted and non-bolted individuals, for a total of 987 samples. Among the 192 candidate SNPs, the strongest overall association was found for SNP183 on chromosome 6 (p-value = 1.246 10(-13)). The association between SNP183 and bolting tendency was then confirmed in an independent population of 730 plants from 11 breeding lines (p value = 0.0061). SNP183 is located in the intron of Bv_22330_orky, a sugar beet homolog of a matrix metalloproteinase (MMP) gene that could be implied in flowering in Arabidopsis thaliana. CONCLUSION: Our data support a significant association between an intronic SNP in the MMP gene located on chromosome 6 and the regulation of bolting tendency in sugar beet. The newly identified locus supports the polygenic nature of flowering control. The associated marker can be used to design SNP panels for the discrimination of bolters and non-bolters, to be used in sugar beet breeding programs for the development of improved germplasm with low bolting tendency. PMID- 26643664 TI - The global gene expression profile of the secondary transition during pancreatic development. AB - Pancreas organogenesis is a highly dynamic process where neighboring tissue interactions lead to dynamic changes in gene regulatory networks that orchestrate endocrine, exocrine, and ductal lineage formation. To understand the spatio temporal regulatory logic we have used the Forkhead transcription factor Foxa2 Venus fusion (FVF) knock-in reporter mouse to separate the FVF(+) pancreatic epithelium from the FVF(-) surrounding tissue (mesenchyme, neurons, blood, and blood vessels) to perform a genome-wide mRNA expression profiling at embryonic days (E) 12.5-15.5. Annotating genes and molecular processes suggest that FVF marks endoderm-derived multipotent epithelial progenitors at several lineage restriction steps, when the bulk of endocrine, exocrine and ductal cells are formed during the secondary transition. In the pancreatic epithelial compartment, we identified most known endocrine and exocrine lineage determining factors and diabetes-associated genes, but also unknown genes with spatio-temporal regulated pancreatic expression. In the non-endoderm-derived compartment, we identified many well-described regulatory genes that are not yet functionally annotated in pancreas development, emphasizing that neighboring tissue interactions are still ill defined. Pancreatic expression of over 635 genes was analyzed with them RNA in situ hybridization Genepaint public database. This validated the quality of the profiling data set and identified hundreds of genes with spatially restricted expression patterns in the pancreas. Some of these genes are also targeted by pancreatic transcription factors and show active chromatin marks in human islets of Langerhans. Thus, with the highest spatio-temporal resolution of a global gene expression profile during the secondary transition, our study enables to shed light on neighboring tissue interactions, developmental timing and diabetes gene regulation. PMID- 26643663 TI - Trastuzumab and bevacizumab combined with docetaxel, oxaliplatin and capecitabine as first-line treatment of advanced HER2-positive gastric cancer: a multicenter phase II study. AB - OBJECTIVE: To investigate the efficacy of bevacizumab and trastuzumab combined with docetaxel, oxaliplatin, and capecitabine (B-DOCT) as first-line treatment of advanced human epidermal growth factor receptor 2 (HER2)-positive gastric cancer (GC). METHODS: In this multicentre, single-arm, phase II study, tumor HER2 status was determined centrally prior to treatment. Patients with advanced HER2-positive adenocarcinoma of the stomach or gastroesophageal junction (immunohistochemistry 3+ or immunohistochemistry 2+/silver in-situ hybridization positive) were treated with six cycles of bevacizumab 7.5 mg/kg (day 1), docetaxel 50 mg/m(2) (day 1), oxaliplatin 100 mg/m(2) (day 1), capecitabine 850 mg/m(2) b.i.d. (days 1-14), and trastuzumab 6 mg/kg (day 1) every three weeks, followed by maintenance with bevacizumab, capecitabine, and trastuzumab until disease progression. The primary objective was to demonstrate an improvement of progression-free survival (PFS) to >7.6 months (observed in the ToGA trial) determined according to the lower limit of the 95 % confidence interval (CI). Secondary endpoints were safety, objective response rate (ORR), and overall survival (OS). RESULTS: Twenty-five patients with HER2-positive tumors were treated with B-DOCT between March 2011 and September 2014. At a median follow-up of 17 months, median PFS was 10.8 months (95%CI: 9.0-NA), OS was 17.9 months (95%CI: 12.4-NA). One-year PFS and OS were 52 % and 79 %, respectively. The ORR was 74 % (95%CI: 52-90 %). Two patients became resectable during treatment with B-DOCT and achieved a pathological complete response. The most common treatment-related grade >= 3 adverse events were: neutropenia (16 %), diarrhoea (16 %), and hypertension (16 %). CONCLUSIONS: B DOCT is a safe and active combination in HER2-positive GC, supporting further investigations of DOC with HER2/vascular endothelial growth factor (VEGF) inhibition in HER2-positive GC. PMID- 26643665 TI - A cheap and non-destructive approach to increase coverage/loading of hydrophilic hydroxide on hydrophobic carbon for lightweight and high-performance supercapacitors. AB - Carbon-based substrates offer unprecedented advantages in lightweight supercapacitors. However, it is still challenging to achieve high coverage or loading. Different from the traditional belief that a lack of defects or functional groups is the cause of poor growth on carbon-based substrates, we reckon that the major cause is the discrepancy between the hydrophilic nature of the metal oxide/hydroxide and the hydrophobic nature of carbon. To solve this incompatibility, we introduced ethanol into the precursor solution. The method to synthesize nickel copper hydroxide on carbon fiber paper employs only water and ethanol, in addition to nickel acetate and copper acetate. The results revealed good growth and tight adhesion of active materials on carbon fiber paper substrates. The specific capacitance and energy density per total weight of the active material plus substrate (carbon fiber paper, current collector) reached 770 F g(-1) and 33 Wh kg(-1) (1798 F g(-1) and 54 Wh kg(-1) per weight of the active materials), owing to the high loading of active material and the light weight of carbon fiber paper. These results signified the achievability of light, cheap and high-performance supercapacitors by an environmental-friendly approach. PMID- 26643666 TI - Salicylic acid derivatives as potential anti asthmatic agents using disease responsive drug delivery system for prophylactic therapy of allergic asthma. AB - Asthma is a multi-factorial and complicated lung disorder of the immune system which has expanded to a wider ambit unveiling its etiology to be omnipresent at both ends of the spectrum involving basic pharmacology and in-depth immunology. As asthma occurs through triggered activation of various immune cells due to different stimuli, it poses a great challenge to uncover specific targets for therapeutic interventions. Recent pharmacotherapeutic approaches for asthma have been focused on molecular targeting of transcription factors and their signaling pathways; mainly nucleus factor kappa B (NFkappaB) and its associated pathways which orchestrate the synthesis of pro-inflammatory cytokines (IL-1beta, TNF alpha, GM-CSF), chemokines (RANTES, MIP-1a, eotaxin), adhesion molecules (ICAM-1, VCAM-1) and inflammatory enzymes (cyclooxygenase-2 and iNOS). 5-aminosalicylic acid (5-ASA) and sodium salicylate are known to suppress NFkappaB activation by inhibiting inhibitor of kappa B kinase (IKkappaB). In order to target the transcription factor, a suitable carrier system for delivering the drug to the intracellular space is essential. 5-ASA and sodium salicylate loaded liposomes incorporated into PEG-4-acrylate and CCRGGC microgels (a polymer formed by crosslinking of trypsin sensitive peptide and PEG-4-acrylate) could probably suit the needs for developing a disease responsive drug delivery system which will serve as a prophylactic therapy for asthmatic patients. PMID- 26643667 TI - Neurogenic bladder: Highly selective rhizotomy of specific dorsal rootlets maybe a better choice. AB - Spinal cord injury results not only in motor and sensory dysfunctions, but also in loss of normal urinary bladder functions. A number of clinical studies were focused on the strategies for improvement of functions of the bladder. Completely dorsal root rhizotomy or selective specific S2-4 dorsal root rhizotomy suppress autonomic hyper-reflexia but have the same defects: it could cause detrusor and sphincter over-relaxation and loss of reflexive erection in males. So precise operation needs to be considered. We designed an experimental trail to test the possibility on the basis of previous study. We found that different dorsal rootlets which conduct impulses from the detrusor or sphincter can be distinguished by electro-stimulation in SD rats. Highly selective rhizotomy of specific dorsal rootlets could change the intravesical pressure and urethral perfusion pressure respectively. We hypothese that for neurogenic bladder following spinal cord injury, highly selective rhizotomy of specific dorsal rootlets maybe improve the bladder capacity and the detrusor sphincter dyssynergia, and at the same time, the function of other pelvic organ could be maximize retainment. PMID- 26643668 TI - CCL15 overexpression predicts poor prognosis for hepatocellular carcinoma. AB - OBJECTIVES: The purpose of this study was to study the expression of CCL15 in hepatocellular carcinoma (HCC) and explore its clinicopathological significance, and study relationships between expressions of CCL15 and malignant behaviors of HCC. METHODS: The SP immunohistochemical method was used to detect expression of CCL15 in routinely paraffin-embedded sections from 80 cases of HCC, 80 of adjacent cancerous specimens and 50 of normal liver tissue. In these patients with HCC, Kaplan-Meier was used to assess survival outcomes. RESULTS: The positive rates and scores of CCL15 were significantly higher in HCC than adjacent cancerous specimens and normal liver tissue (p < 0.05), but not significantly higher between adjacent cancerous specimens and normal liver tissue (p > 0.05). The expression of CCL15 was significantly correlated to tumor size, tumor thrombi in portal vein of HCC, capsule and TNM stage (p < 0.05), but not to sex, age, liver cirrhosis and the level of AFP so on (p > 0.05). Survival time of the patients with positive CCL15 expression was significantly decreased, and multivariate analysis indicated CCL15 expression was one of the independent predictors of survival (p = 0.042). CONCLUSION: The expression of CCL15 was significantly correlated with malignant behaviors of HCC, and CCL15 might be important biological markers for reflecting the carcinogenesis, progression, biological behaviors and prognosis of HCC. PMID- 26643669 TI - Using the brief observation of social communication change (BOSCC) to measure autism-specific development. AB - To date no reliable and objective, change sensitive instrument for autistic symptoms is available. The brief observation of social communication change (BOSCC) was specifically developed to measure change of core autistic symptoms, for example, for use as outcome measure in early intervention trials. This study investigated quality criteria of a preliminary research version of the BOSCC in N = 21 children with autism spectrum disorder (ASD) who had participated for 1 year in the Frankfurt early intervention program (FFIP). BOSCC rating was done on play based ADOS video scenes. Inter-rater agreement on the BOSCC average total was very high. The BOSCC showed a significant decrease of autistic symptoms after 1 year with a medium effect size. Symptom specific improvements were captured by the social communication subscale and most single items. The BOSCC showed comparable change sensitivity to other autism specific instruments. Future studies should focus on the finalized BOSCC version, and replicate findings in a larger sample. Autism Res 2016, 9: 940-950. (c) 2015 International Society for Autism Research, Wiley Periodicals, Inc. PMID- 26643670 TI - Ex Vivo Lung Perfusion and Transplant: State of the Art and View to the Future. AB - After the first clinical application of ex vivo lung perfusion in 2001, the technique has been used in many lung transplant centers worldwide. In addition, many modifications have been tested, leading to the development of various ex vivo lung perfusion systems and application protocols. Currently, the Lund protocol, the Toronto protocol, and Organ Care System Lung protocol are the clinically applied ex vivo lung perfusion protocols, based on the favorable results of the safety studies. Accordingly, the comparison among these EVLP systems and protocols should be an important research target, in order to provide the evidence based medical data that would recommend one protocol over the others. In this manuscript, the current experience with EVLP is reviewed and some molecular and clinical targets, that could be used to compare the various protocols of the technique, are introduced. PMID- 26643671 TI - Dual Kidney Transplant. AB - During the past decades, dual kidney transplant has enabled greater use of marginal kidneys and reduced waiting time. Since the first description of dual transplant in 1996, the techniques and outcomes have improved. No clear allocation criteria for donors and suitable candidates have been outlined; however, in general, an older for older approach is followed by many centers. Many centers are hampered by the lack of a clear allocation policy and the fact that decisions for dual kidney transplant are solely clinician based. Unilateral placement of both kidneys is the technique of choice in many centers. En block pediatric dual transplant and several vascular reconstruction methods for dual kidneys have been adopted by surgeons to enable single arterial and venous anastomosis and to reduce complications. Although there is a higher prevalence of vascular complications, mainly in the form of graft thrombosis, the overall complication rate with dual kidney transplant is comparable to single kidney transplant. Kidney survival and function are encouraging and close to results with standard criteria single kidney transplant. Although the technique is well established in many centers, standardized guidelines are lacking. Here, we review the current experience with dual kidney transplant. PMID- 26643672 TI - Cigarette Smoking Effect on Survival After Lung Transplant in Cystic Fibrosis. AB - OBJECTIVES: The effect of prior cigarette use by lung transplant donors and recipients on posttransplant survival is poorly defined, especially in subjects with cystic fibrosis. We sought to determine if donor or recipient cigarette smoking is associated with differential post lung transplant outcomes in cystic fibrosis patients, including survival. MATERIALS AND METHODS: The United Network for Organ Sharing database was searched to analyze a large sample of cystic fibrosis patients with a history of lung transplant. The primary endpoint of the study was overall survival after transplant based on either recipient or donor history of smoking cigarettes. RESULTS: There was a significant decrease in survival for cystic fibrosis patients who received lungs from a donor with a history of smoking (P = .026), but no difference in survival for recipients with a personal history of smoking. Nearly 60% of subjects who received lungs from a smoking donor died during the study. Donor smoking history was correlated with survival in a univariate (HR 1.2, [1.04-1.3 ]), but not multivariate model. Donor smoking history also was associated with increased treatment for rejection within the first year after transplant (P = .005). CONCLUSIONS: More than 20 pack-year history of donor smoking may affect lung transplant outcomes (eg, survival and acute rejection) in patients with cystic fibrosis. Caution must be exercised when choosing suitable organ donors for cystic. PMID- 26643673 TI - A Localized Ischemic Preconditioning Regimen Increases Tumor Necrosis Factor alpha Expression in a Rat Model of Kidney Ischemia-Reperfusion Injury. AB - OBJECTIVES: We evaluated a continuous, immediate, localized ischemic preconditioning regimen in a rat model of ischemia-reperfusion injury and assessed whether it attenuated injury at the histologic and molecular levels. MATERIALS AND METHODS: Fifteen adult male Lewis rats received sham operation, left unilateral warm ischemia (45 minutes of cross-clamping of the renal pedicle; ischemia-reperfusion injury group), or 15 minutes of ischemia followed by a 20 minute reperfusion period, 45 minutes of ischemia-reperfusion injury, and subsequent reperfusion (ischemic preconditioning/ischemia-reperfusion injury group). Kidney tissue was retrieved 48 hours later, sectioned, stained with hematoxylin and eosin, and examined. We used RNA extraction and real-time quantitative polymerase chain reaction analysis to assess acute kidney injury markers, cytokines, and microRNA-21. RESULTS: Forty-five minutes of unilateral ischemia-reperfusion injury caused marked changes in histology at 48 hours, characterized by endothelial loss, tubulointerstitial damage (inflammation, cast formation), tubular cell necrosis, and glomerular capsule thickening. The ischemia-reperfusion injury and ischemic preconditioning/ischemia-reperfusion injury groups showed no measurable differences in histology. Expression of the acute kidney injury markers was significantly increased in the ischemia reperfusion injury versus Sham group; however, no difference was found between the ischemia reperfusion injury and ischemic preconditioning/ischemia-reperfusion injury groups. Similarly, expression of interleukin 17, interleukin 18, and tumor necrosis factor ? was significantly increased in the ischemia-reperfusion injury versus Sham group. No significant difference was found between the ischemia reperfusion injury and ischemic preconditioning/ischemia-reperfusion injury groups for interleukin 17 and interleukin 18; however, tumor necrosis factor ? expression was significantly increased in the ischemic preconditioning/ischemia reperfusion injury versus ischemia-reperfusion injury group. CONCLUSIONS: In our ischemic preconditioning model, tumor necrosis factor alpha expression was increased without altering the sequelae of ischemia-reperfusion injury. The long term consequences of this augmented early inflammatory response and whether these consequences are altered by variations in ischemic preconditioning or a subsequent injury require further study. PMID- 26643674 TI - Consensus Interferon for Recurrent Hepatitis C Infection in Nonresponders to Peginterferon and Ribavirin After Liver Transplant. AB - OBJECTIVES: Hepatitis C virus infection universally recurs in liver transplant recipients. Peginterferon/ribavirin achieves a sustained virologic response rate of 30% in recipients infected with hepatitis C virus genotype 1. Consensus interferon plus ribavirin yields sustained virologic response rates to 30% in patients failing to achieve sustained virologic response with peginterferon/ribavirin pretransplant, but it has not been studied posttransplant. We sought to evaluate the efficacy and tolerability of consensus interferon and ribavirin in treating posttransplant hepatitis C virus. MATERIALS AND METHODS: Clinical, laboratory, and virologic data were collected retrospectively from all patients who received at least 1 dose of consensus interferon after transplant between January 2008 and December 2011. A standardized treatment protocol was used. The primary aim was sustained virologic response defined by undetectable hepatitis C virus RNA at 24 weeks after completing therapy. RESULTS: Twenty-three patients were treated with consensus interferon/ribavirin; 15 with prior nonresponse (87%) or breakthrough (6.7%) during peginterferon/ribavirin, and 8 as initial therapy. The intention-to-treat sustained virologic response with consensus-interferon was 30%. Anemia, leukopenia, and growth factor requirement were similar between peginterferon and consensus-interferon cohorts. CONCLUSIONS: Consensus-interferon may rescue liver recipients who are nonresponders to peginterferon-based therapy. The efficacy of interferon-based treatment regimens may benefit from substitution of consensus interferon for peginterferon. PMID- 26643675 TI - Perioperative Calcium, Magnesium, and Phosphorus Levels in Live Donors For Liver Transplant. AB - OBJECTIVES: The increased number of liver transplants in Egypt has increased the focus on perioperative complications in live donors. An important but not yet well-investigated complication is electrolyte disturbances, which are common in such patients, need intervention, and affect the outcome. We retrospectively analyzed data of perioperative calcium, magnesium, and phosphorus levels in live liver donors at our center. MATERIALS AND METHODS: We collected perioperative laboratory results from 44 living donors for liver transplant who were at our center from February 2009 to August 2013. We analyzed results of perioperative calcium, magnesium, and phosphorus levels before transplant, on the day of transplant (defined as day 0), and at 1 and 2 days after the surgical procedure. RESULTS: Mean serum calcium level was 2.31 mmol/L before transplant, 1.97 mmol/L on day 0, and 1.99 mmol/L on day 1, and 2.05 mmol/L on day 2 after transplant. Serum calcium level was significantly reduced at day 0 and on postoperative days 1 and 2 (P < .0001). Mean magnesium level was 0.8 mmol/L before transplant, 0.58 mmol/L on day 0, and 0.83 mmol/L on day 1, and 0.79 mmol/L on day 2 after the surgical procedure. The day 0 level was significantly reduced versus before transplant (P < .0001). Mean phosphorus level was 1.23 mmol/L before transplant, 1.11 mmol/L on day 0, and 0.97 mmol/L on day 1, and 0.76 mmol/L on day 2 after transplant, with significant declines on day 0 and on postoperative days 1 and 2 (P < .0001). CONCLUSIONS: Living liver donors showed significantly decreased levels of calcium and phosphorus on day 0 and on postoperative days 1 and 2, whereas magnesium level was significantly decreased on day 0 only. PMID- 26643676 TI - Extravasated Platelet Aggregation in Liver Zone 3 Is Associated With Thrombocytopenia and Deterioration of Graft Function After Living-Donor Liver Transplant. AB - OBJECTIVES: Continuous thrombocytopenia after liver transplant is associated with a less favorable prognosis, but this pathogenesis remains unclear. We focused on the consumption of platelets in the allograft. We assessed platelet consumption in allografts, and evaluated the pathology of platelet aggregation in an allograft tissue and its involvement in clinical outcomes. MATERIALS AND METHODS: We took biopsy specimens from 20 patients. To examine the localization of platelet aggregation, CD42b was assayed immunohistochemically, and its level of expression correlated with clinical data and outcomes. RESULTS: Platelet aggregation in zone 3 was 70%, compared with 30% in zone 1 and 50% in zone 2. Platelets were found mainly as extravasated platelet aggregates in local microenvironments. Patients were stratified according to the extent of extravasated platelet aggregates in zone 3 into extravasated platelet aggregate negative and -positive groups. Graft weight/recipient body weight ratio with the extravasated platelet aggregatepositive group was significantly lower than that of the extravasated platelet aggregate-negative group. Platelet count after surgery was lower, while total bilirubin and prothrombin time/international normalized ratio were higher in the extravasated platelet aggregate-positive than they were in the extravasated platelet aggregate-negative group. CONCLUSIONS: Extravasated platelet aggregates in the zone 3 of allograft tissue cause the consumption of platelets and continuous thrombocytopenia after transplant, and may be the clinical marker for deterioration of graft function. Platelet activation and degranulation following the release by platelets of some negative regulators may be involved partially in liver damage. PMID- 26643677 TI - Clinical Evaluation of the Safety and Feasibility of Whole Autologous Cord Blood Transplant as a Source of Stem and Progenitor Cells for Extremely Premature Neonates: Preliminary Report. AB - OBJECTIVES: This is a preliminary, single-center, prospective study in the field of autologous cord blood transplant. We investigated the feasibility, safety, and tolerability of autologous whole cord blood transplant in extremely premature infants as a potential therapeutic modality to prevent developing complications related to prematurity. MATERIALS AND METHODS: This preliminary prospective study (ClinicalTrials.gov identifier NCT02050971) included preterm infants born at less than 32 weeks of gestational age who developed anemia because of prematurity. Infants were assigned to 2 groups: (1) those receiving an autologous cord blood transfusion within 5 days postpartum (n = 5) and (2) those who obtained only an allogeneic red blood cell transfusion when necessary (n = 9; control group). Vital measurements were performed during and after transfusion, and peripheral blood pH, hematocrit, glucose, and calcium and potassium ion levels were measured over the next 4 days. RESULTS: Oxygen saturation was significantly increased throughout the cord blood transfusion and in the subsequent 48 hours. No significant differences were found in vital measurements, such as arterial blood pressure (mean, systolic, and diastolic) or heart rate over the first 48 hours posttransfusion. Similarly, no significant differences were found in biochemical analyses of blood with the exception of pH level. We found initial pH level to be significantly augmented in the cord blood recipient group by the first day after transplant, which remained significantly higher for next 24 hours compared with that shown in the control group. CONCLUSIONS: Collection, preparation, and short term storage of unfrozen cord blood are feasible for clinical use. Our results showed general safety and tolerability of the procedure of whole autologous cord blood transplant in recruited preterm newborns. However, because our study group was small, these results need to be confirmed in further investigations with a larger patient cohort. PMID- 26643678 TI - Effects of Low-Dose Rituximab Therapy in Patients With Primary Cytomegalovirus Infection. AB - OBJECTIVES: Cytomegalovirus infection is an important cause of morbidity and mortality among recipients undergoing hematopoietic stem cell and solid-organ transplant. The risk of cytomegalovirus infection is high in cytomegalovirus seronegative recipients of cytomegalovirus-seropositive organs (donor positive/recipient negative) and recipients with strong immunosuppressive status such as those receiving rituximab induction or antirejection treatment. However, it remains unclear how rituximab affects patients with primary cytomegalovirus infection. We evaluated the effects of low-dose rituximab therapy on clinical and immunologic outcomes in recipients who were donor positive but recipient negative for primary cytomegalovirus infections. MATERIALS AND METHODS: We conducted a retrospective review of patients with primary cytomegalovirus infections from January 2005 to March 2014. Patient outcomes were compared between groups administered given rituximab or given no intervention at the time of transplant. RESULTS: Our study group included 49 recipients with primary cytomegalovirus infection, including 32 who received rituximab therapy (group 1) and 17 who did not (group 2). No significant differences were observed between groups in the duration of cytomegalovirus seroconversion (P = .0570) and initial cytomegalovirus immunoglobulin G titers (P = .8418). CONCLUSIONS: Rituximab induction therapy does not affect clinical or immunologic outcomes of primary cytomegalovirus infection, even in high-risk recipients who are donor positive but recipient negative for primary cytomegalovirus infections. PMID- 26643679 TI - Treatment of Polyomavirus-Associated Nephropathy With the Association of Sirolimus and Leflunomide. PMID- 26643680 TI - Effect of Increased Dietary Protein Intake on the 24-Hour Urine Creatinine Clearance and Eligibility of Living Kidney Donor Candidates. PMID- 26643681 TI - Risk Factors Associated With Survival After Lung Transplant in Iran. PMID- 26643682 TI - A new, rapid in vivo method to evaluate allergic responses through distinctive distribution of a fluorescent-labeled immune complex: Potential to investigate anti-allergic effects of compounds administered either systemically or topically to the skin. AB - We herein established a new method to evaluate allergic responses in mice rapidly and easily with ethical improvement by reducing the number of animals used. A single intravenous injection of a mixture of anti-OVA monoclonal IgE and fluorescein-ovalbumin (FITC-OVA) induced the distinctive spotted distribution of FITC-OVA in skin, named "ASDIS (Anaphylaxis-dependent Spotted Distribution of a fluorescent-labeled Immune complex in Skin)", and this was easily detected by in vivo imaging. The parallel induction of hypothermia, scratching, serum histamine increases, and ASDIS as well as the inhibition of ASDIS by either the systemic administration of a histamine H1 receptor antagonist or mast cell-depleting antibody suggested that our method, which only required 15 min, induced these allergic responses including ASDIS. Relatively mild but significant ASDIS was induced also in mice with passive systemic anaphylaxis by the method, requiring 2 separate days. The painting of anti-histamines on the skin markedly reduced ASDIS in the painted area only, suggesting the potential of this model to simultaneously compare the anti-allergic effects of several candidate compounds with control drugs in the same mice. ASDIS was suggested to originate from extravasated FITC-OVA/OE-1 immune complexes from blood to skin tissues other than mast cells. Our new method has the advantages of rapidity, easy method, and lower animal numbers to evaluate anti-allergic compounds as well as the characteristics of the used antibody, antigen, labeling molecules, additives, and other formulations. Our model for inducing ASDIS may contribute to the development of anti-allergic drugs, especially those intended for application to the skin. PMID- 26643683 TI - Translating knowledge into practice: An exploratory study of dementia-specific training for community-based service providers. AB - Objective To develop, deliver, and evaluate dementia-specific training designed to inform service delivery by enhancing the knowledge of community-based service providers. Methods This exploratory qualitative study used an interdisciplinary, interuniversity team approach to develop and deliver dementia-specific training. Participants included management, care staff, and clients from three organizations funded to provide services in the community. Data on the acceptability, applicability, and perceived outcomes of the training were gathered through focus group discussions and individual interviews. Transcripts were analyzed to generate open codes which were clustered into themes and sub themes addressing the content, delivery, and value of the training. Findings Staff valued up-to-date knowledge and "real stories" grounded in practice. Clients welcomed the strengths-based approach. Contractual obligations impact on the application of knowledge in practice. Implications The capacity to implement new knowledge may be limited by the legislative policies which frame service provision, to the detriment of service users. PMID- 26643684 TI - Digital communication support and Alzheimer's disease. AB - Communication is one of the areas where people with dementia and their caregivers experience most challenges. The purpose of this study is to contribute to the understanding of possibilities and pitfalls of using personalized communication applications installed on tablet computers to support communication for people with dementia and their conversational partners. The study is based on video recordings of a woman, 52 years old, with Alzheimer's disease interacting with her husband in their home. The couple was recorded interacting with and without a tablet computer including a personalized communication application. The results from the present study reveal both significant possibilities and potential difficulties in introducing a digital communication device to people with dementia and their conversational partners. For the woman in the present study, the amount of interactive actions and the number of communicative actions seem to increase with the use of the communication application. The results also indicate that problems associated with dementia are foregrounded in interaction where the tablet computer is used. PMID- 26643685 TI - What can ecosystems learn? Expanding evolutionary ecology with learning theory. AB - BACKGROUND: The structure and organisation of ecological interactions within an ecosystem is modified by the evolution and coevolution of the individual species it contains. Understanding how historical conditions have shaped this architecture is vital for understanding system responses to change at scales from the microbial upwards. However, in the absence of a group selection process, the collective behaviours and ecosystem functions exhibited by the whole community cannot be organised or adapted in a Darwinian sense. A long-standing open question thus persists: Are there alternative organising principles that enable us to understand and predict how the coevolution of the component species creates and maintains complex collective behaviours exhibited by the ecosystem as a whole? RESULTS: Here we answer this question by incorporating principles from connectionist learning, a previously unrelated discipline already using well developed theories on how emergent behaviours arise in simple networks. Specifically, we show conditions where natural selection on ecological interactions is functionally equivalent to a simple type of connectionist learning, 'unsupervised learning', well-known in neural-network models of cognitive systems to produce many non-trivial collective behaviours. Accordingly, we find that a community can self-organise in a well-defined and non-trivial sense without selection at the community level; its organisation can be conditioned by past experience in the same sense as connectionist learning models habituate to stimuli. This conditioning drives the community to form a distributed ecological memory of multiple past states, causing the community to: a) converge to these states from any random initial composition; b) accurately restore historical compositions from small fragments; c) recover a state composition following disturbance; and d) to correctly classify ambiguous initial compositions according to their similarity to learned compositions. We examine how the formation of alternative stable states alters the community's response to changing environmental forcing, and we identify conditions under which the ecosystem exhibits hysteresis with potential for catastrophic regime shifts. CONCLUSIONS: This work highlights the potential of connectionist theory to expand our understanding of evo-eco dynamics and collective ecological behaviours. Within this framework we find that, despite not being a Darwinian unit, ecological communities can behave like connectionist learning systems, creating internal conditions that habituate to past environmental conditions and actively recalling those conditions. PMID- 26643686 TI - Drug Side Effect Symptoms and Adherence to Antihypertensive Medication. AB - BACKGROUND: Non-adherence to antihypertensive medication increases the risk of uncontrolled hypertension. Antihypertensive drug-related symptoms (side effects) are frequently cited as a main cause of non-adherence, but with little support from prospective studies. We evaluated the association between drug side effects and prospective adherence to treatment. METHODS: We collected data on the number and dose of antihypertensive drugs at enrollment and at 3, 6, 9, and 12 months of follow-up in a cohort of 175 hypertensive patients starting or restarting antihypertensive treatment (mean age: 50 years; 58% women). During the follow-up visits, we gathered data on 24 side effects during the last month and the pill count adherence ratio (PCAR = pills taken out of number prescribed * 100) since the previous visit. The association between side effects at a visit and adherence through the next visit was estimated using mixed effect models. RESULTS: Eighty five percent of the participants experienced side effects, and 34.5% became non adherent (PCAR <80%). After adjusting for confounders, PCAR was 6.0 percentage points lower (P = 0.04) among individuals with number of side effects above the median value (4 symptoms). Also, in individuals with genitourinary side effects, PCAR was 7.1 percentage points lower (P = 0.02) than in those without such side effects. Specifically, PCAR was 6.5 (P = 0.06) and 7.6 (P = 0.01) percentage points lower among individuals with excessive urination and decrease in sexual drive, respectively. CONCLUSION: Antihypertensive drug side effects was associated with drug adherence but only excessive urination and decrease in sexual drive significantly predicted lower adherence. These symptoms could be used as markers to screen out patients at high risk of non-adherence. PMID- 26643687 TI - Randomized Evaluation of the Effectiveness of a Structured Educational Program for Patients With Essential Hypertension. AB - BACKGROUND: Adherence to medication and lifestyle interventions are essential keys for the management of hypertension. In this respect, a structured educational program for hypertensive patients has got remarkable merits (herz.leben). In order to determine the isolated effect of participation in the educational program, neglecting the possible impact of more intense care, this prospective multicenter randomized controlled study was designed (NCT00453037). METHODS: A total of 256 patients in 13 centers were enrolled and randomly assigned to 2 groups (G). G-I (n = 137) underwent the educational program immediately (T-0), G-II (n = 119) after 6 months (T-6). Follow-up visits were done after 6 (T-6) and 12 (T-12) months. Primary endpoint was a difference in office blood pressure (BP) at T-6, when only G-I had undergone the educational program. RESULTS: Patients' baseline characteristics were comparable. At T-6, systolic office and home BP were significantly lower in G-I compared to G-II: office BP systolic 139 (134-150) mm Hg vs. 150 (135-165) mm Hg (P < 0.01); diastolic 80 (76-85) mm Hg vs. 84 (75-90) mm Hg (ns); home BP systolic 133 (130 140) mm Hg vs. 142 (132-150) mm Hg (P < 0.01); diastolic 80 (75-85) mm Hg vs. 80 (76-89) mm Hg (ns)). At T-12, when all patients had undergone the educational program differences in BP disappeared. CONCLUSION: The results of this multicenter randomized controlled study provide significant evidence for benefit by participation in a structured educational program. Positive effects seem to be mediated by better adherence and life style changes due to higher levels of information and patient empowerment. Therefore, educational strategies should be considered as standard of care for hypertensive patients. PMID- 26643688 TI - Orthostatic Hypotension and Cardiac Changes After Long-Term Follow-Up. AB - BACKGROUND: Orthostatic hypotension (OH) increases the risk of incident cardiovascular disease (CVD) and all-cause mortality in population-based cohort studies. Whether OH is associated with development of cardiac anomalies has not been sufficiently explored. METHODS: In the prospective population-based Malmo Preventive Project (MPP), a subset of 974 non-diabetic individuals (mean age: 67 years; 29% women) were examined with echocardiography after a mean follow-up period of 23+/-4 years from baseline. The association of increased left ventricular mass (LVM), pathological cardiac chamber volumes, echocardiographic parameters of systolic and diastolic dysfunction in relation to the presence of OH at baseline, defined as decrease in systolic >=20mm Hg and/or diastolic blood pressure (BP) >=10mm Hg upon standing, was studied. RESULTS: Among reexamined MPP participants, 40 (4.1%) met OH criteria during baseline screening. In the multivariable-adjusted Cox proportional hazard models, taking demographics, BP, and antihypertensive treatment (AHT) into account, OH predicted left ventricular hypertrophy (LVH) (hazard ratio (HR): 1.97, 1.01-3.84; P = 0.047), decreased right chamber volume (HR: 1.74, 1.19-2.57; P = 0.005), and reduced early diastolic tissue velocity in septal wall (HR: 1.47, 1.01-2.14; P = 0.045). No significant associations were seen between OH and atrial chamber volumes, LV volume, and LV systolic function. CONCLUSIONS: The presence of OH among middle aged adults is associated with the development of structural cardiac changes such as LVH and declining right chamber volume, as well as with the development of diastolic dysfunction, independently of traditional risk factors. These findings may contribute to the understanding of how prevalent OH impacts the risk of CVD. PMID- 26643689 TI - Relationship of Office and Ambulatory Blood Pressure With Left Ventricular Global Longitudinal Strain. AB - BACKGROUND: Left ventricular (LV) global longitudinal strain (GLS) is an early indicator of subclinical cardiac dysfunction, even when LV ejection fraction (LVEF) is normal, and is an independent predictor of cardiovascular events. Ambulatory blood pressure (BP) is a better predictor of cardiovascular events, including heart failure, than office BP. We investigated the association of office and ambulatory BP measurements with subclinical LV systolic dysfunction in a community-based cohort with normal LVEF. METHODS: Two-dimensional speckle tracking echocardiography and 24-hour ambulatory BP monitoring were performed in 577 participants (mean age 70+/-9 years; 60% women) with LVEF >=50% from the Cardiovascular Abnormalities and Brain Lesions (CABL) study. Univariable and multivariable linear regression analyses were used to assess the associations of BP measures with GLS. RESULTS: Higher ambulatory and office BP values were consistently associated with impaired GLS. After adjustment for pertinent covariates (age, sex, race/ethnicity, body mass index, diabetes mellitus, coronary artery disease, LV mass index, and antihypertensive medication), office diastolic BP and ambulatory systolic and diastolic BPs (24-hour, daytime and nighttime) were independently associated with GLS (P = 0.003 for office DBP, P <= 0.001 for all ambulatory BPs). When ambulatory and office BP values were included in the same model, all ambulatory BP measures remained significantly associated with GLS (all P < 0.01), whereas office BP values were not. CONCLUSIONS: Ambulatory BP values are significantly associated with impaired GLS and the association is stronger than for office BP. Ambulatory BP monitoring might have a role in the risk stratification of hypertensive patients for early LV dysfunction. PMID- 26643690 TI - It's the power of food: individual differences in food cue responsiveness and snacking in everyday life. AB - BACKGROUND: Discretionary eating behaviour ("snacking") is dependent on internal and external cues. Individual differences in the effects of these cues suggest that some people are more or less likely to snack in certain situations than others. Previous research is limited to laboratory-based experiments or survey based food recall. This study for the first time examines everyday snacking using real-time assessment, and examines whether individual differences in cue effects on snacking can be explained by the Power of Food scale (PFS). METHODS: Ecological Momentary Assessment (EMA) study with 53 non-clinical participants over an average of 10 days. Multiple daily assessments: Participants reported every snack and responded to randomly timed surveys during the day. Internal and external cues were measured during both types of assessment. Demographic data and PFS scores were assessed during a baseline lab visit. Data were analysed using multilevel linear and multilevel logistic regression with random intercepts and random slopes as well as cross-level interactions with PFS scores. RESULTS: Higher individual PFS scores were associated with more daily snacking on average (B = 0.05, 95% CI = 0.02,0.08, p < .001). More average daily snacking was associated with higher BMI (B = 1.42, 95% CI = 0.19,2.65, p = .02). Cue effects (negative affect, arousal, activities, company) on snacking were significantly moderated by PFS: People with higher PFS were more likely to snack when experiencing negative affect, high arousal, engaging in activities, and being alone compared to people with lower PFS scores. CONCLUSIONS: PFS scores moderate the effects of snacking cues on everyday discretionary food choices. This puts people with higher PFS at higher risk for potentially unhealthy and obesogenic eating behaviour. PMID- 26643691 TI - Left Ventricular Reverse Remodeling Elicited by a Quadripolar Lead: Results from the Multicenter Per4mer Study. AB - BACKGROUND: To understand the impact of a quadripolar left ventricular (LV) lead on reverse remodeling and phrenic nerve stimulation (PNS) in congestive heart failure patients treated by cardiac resynchronization therapy at 8-month follow up (FU). METHODS: One hundred and fifty-eight patients received an LV Medtronic Performa lead (Medtronic Inc., Minneapolis, MN, USA) and were reevaluated at FU by echocardiography and measurement of electrical parameters. RESULTS: A targeted LV lead placement was achieved in 140 (89%) patients. Super responders and responders were 76 (50%) and 26 (18%), respectively, at FU; seven (4%) died and 13 (8%) were hospitalized for any cause. Nonischemic etiology was the only independent predictor of reverse remodeling. The configurations available only with the Performa leads reduced PNS occurrence at 8 V@0.4 ms from 43 (27%) to 14 (9%) of patients at implantation, and from 44 (28%) to 19 (12%) at last FU, compared to configurations available with bipolar leads. Patients with detectable PNS had >10/16 pacing configurations with a PNS safety margin >2 V both at implantation and at FU. During FU 16 (10%) patients had an adverse event possibly related to the lead or to modification of the underlying heart disease but 99% of these events were fixed by reprogramming of the pacing vector. CONCLUSIONS: Performa Lead enables an increased capability to achieve a targeted lead positioning in the broad clinical scenario of large- and small-volume implanting centers, with a relevant impact on the occurrence of reverse remodeling compared to literature data. The enhanced management of PNS resulted in a dislodgement rate of only 1%. PMID- 26643692 TI - Role of endoscopic ultrasound for pancreatic cystic lesions: Past, present, and future! PMID- 26643694 TI - Needle-based confocal laser endomicroscopy. AB - New applications of confocal laser endomicroscopy were developed as pCLE in the bile duct and nCLE for pancreatic cystic tumors, pancreatic masses and lymph nodes. The aim of this paper would be to give you an update in this new technology and to try to define its place in the diagnosis of cystic and solid pancreatic masses. The material used was a 19G EUS-needle in which the stylet was replaced by the Confocal mini-probe. The mini-probe (0.632 mm of diameter) is pre loaded and screwed by a locking device in the EUS-Needle and guided endosonographically in the target. Regarding pancreatic cystic lesion, the presence of epithelial villous structures based on nCLE was associated with pancreatic cystic neoplasm (IPMN) (P = 0.004) and provided a sensitivity of 59%, specificity of 100%, positive predictive value of 100%, and negative predictive value of 50%. A superficial vascular network pattern visualized on nCLE was identified in serous cystadenomas. It corresponded on pathological specimen to a dense and subepithelial capillary vascularization. The accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of this sign for the diagnosis of SCA were 87%, 69%, 100%, 100%, and 82%, respectively. In pancreatic adenocarcinomas, nCLE found vascular leakage with irregular vessels with leakage of fluorescein into the tumor, large dark clumps which correspond to humps of malignant cells. These criteria correlate with the histological structure of those tumors which are characterized by tumoral glands, surrounded by fibrosis in case of fibrous stroma tumor. Neuroendocrine tumors showed a dense network of small vessels on a dark background, which fits with the histological structure based on cord of cells surrounded by vessels and by fibrosis. nCLE is feasible during a EUS examination; these preliminary results are very encouraging and may be used in the future in case of inconclusive EUS-FNA. PMID- 26643693 TI - Role of emerging molecular markers in pancreatic cyst fluid. AB - Cystic lesions of the pancreas (CLPs) are increasingly diagnosed due to the growing utilization of cross-sectional imaging modalities. The differentiation between true cysts (epithelial tumors) and nonepithelial lesions (such as pseudocysts) relies on clinical and imaging characteristics, but more reliably obtained by endoscopic ultrasound (EUS) fine-needle aspiration. Due to their malignant potential, some of the true pancreatic cysts require further assessment and periodic follow-up. Therefore, it is important to establish a solid diagnosis at the time of detection of the various types of pancreatic cysts. Due to the limitations of cytology and biochemical markers in accurately classifying cyst pathology, the search for specific molecular markers associated with each type of cyst is ongoing. In this chapter, we will review some of the emerging molecular markers in pancreatic cystic fluid and their potential impact on endosonography and pancreatic cyst management. PMID- 26643695 TI - The safety of endoscopic ultrasound-guided fine-needle aspiration of pancreatic cystic lesions. AB - Endoscopic ultrasound (EUS) is widely used in the evaluation of various pancreatic diseases including pancreatic cystic lesions (PCLs). EUS-guided fine needle aspiration (EUS-FNA) of PCLs provides cyst fluid, which is used for the differentiation of PCLs. EUS-FNA of PCLs is a safe procedure with a low complication rate. Contrary to the concerns expressed by some investigators, preoperative EUS-FNA of mucinous PCLs is unlikely to increase the frequency of postoperative peritoneal seeding. PMID- 26643696 TI - Endoscopic ultrasound-guided ablation therapy for pancreatic cysts. AB - Pancreatic cysts are being encountered frequently because of rapid advances in radiologic technology and an increased cross-sectional imaging demand. Management of pancreatic cystic tumors is challenging because most of them are asymptomatic; they are potentially malignant, and surgery has substantial morbidity and mortality. Endoscopic ultrasound (EUS)-guided fine-needle aspiration of pancreatic cystic tumors is accepted as a minimally invasive technique, which also enables injection of ablative agents into cysts under EUS guidance. In this review, the basic procedural steps and technical considerations of cyst ablation and their clinical issues including safety, feasibility, and therapeutic outcome will be summarized. PMID- 26643697 TI - Role of endoscopic ultrasound-guided fine-needle aspiration cytology, viscosity, and carcinoembryonic antigen in pancreatic cyst fluid. AB - Due to the advances and increased utility of abdominal cross-sectional imaging, the diagnosis of pancreatic cysts continues to increase. Many endosonographers, pancreatologists, and surgeons consider endoscopic ultrasound (EUS) to be an essential tool in the management of pancreatic cystic lesions (PCLs). EUS can help distinguish between mucinous and nonmucinous lesions and may identify the specific cyst type. EUS achieves these goals by delineating the cyst morphology, identifying high risk stigmata and worrisome features, and through image-guided fine-needle aspiration (FNA) and cyst fluid analysis. However, recent consensus statements have called to question the utility and diminished the role of EUS in this setting. The aim of this review is to assess the role and advances of EUS FNA in pancreatic cyst fluid analysis, specifically in terms of fluid cytology, viscosity, and carcinoembryonic antigen (CEA) analysis. PMID- 26643698 TI - New developments in endoscopic ultrasound-guided therapies. AB - Endoscopic ultrasound (EUS) has opened new horizons in minimally invasive therapies for diverse gastrointestinal pathologies. Digestive Disease Weak 2015 held in Washington, DC., USA featured exciting research articles on EUS-guided therapeutic procedures. EUS-guided biliary drainage has been attempted and described for many years. There seems to be a lot of interest among various international groups to compare this technique with other alternatives in terms of efficacy and safety. Similarly, EUS-guided pancreatic drainage of cysts and fluid collections continues to evolve with new stents and devices being developed specifically for deployment under endosonographic guidance. EUS-guided ablation of cystic pancreatic tumors is innovative but not always effective. Combining alcohol ablation with injecting chemotherapeutic agents may improve long-term results regarding efficacy. Similarly, for solid pancreatic tumors there appears to be ongoing interest and continuing efforts in injecting different chemotherapeutic or ablative agents, delivering fiducials for radiation guidance and even attempting ablation with radiofrequency. Gastric variceal treatment and EUS-guided anastomoses also continue to be investigated. This review article is focused on the recent developments in EUS-guided therapies presented at Digestive Disease Week (DDW) 2015. PMID- 26643699 TI - Morphological differentiation and follow-up of pancreatic cystic neoplasms using endoscopic ultrasound. AB - Endoscopic ultrasound (EUS) is a key modality for the evaluation of suspected pancreatic cystic neoplasms (PCNs), as the entire pancreatic gland can be demonstrated with high spatial resolution from the stomach and duodenum. Detailed information can be acquired about the internal contents of the cyst(s) [septum, capsule, mural nodules (MNs)], its relation with the main pancreatic duct (MPD), and any parenchymal changes in the underlying gland. PCNs comprise true cysts and pseudocysts. True cysts can be neoplastic or nonneoplastic. Here, we describe serous cystic neoplasm (SCN), mucinous cystic neoplasm (MCN), and intraductal papillary mucinous neoplasm (IPMN) as prototype neoplastic cysts, along with nonneoplastic lymphoepithelial cysts (LECs). PMID- 26643700 TI - Endoscopic ultrasound-guided drainage of pancreatic pseudocysts. AB - Pancreatic pseudocysts are fluid collections in the peripancreatic tissues associated with acute or chronic pancreatitis. Endoscopic ultrasound (EUS)-guided drainage has become an established indication, having better results as compared to percutaneous drainage, nonguided endoscopic drainage, or surgical drainage. The aim of this review is to assess critically the current literature concerning EUS-guided pseudocyst drainage and to review the place of the procedure in the clinical decision management algorithms of these patients. PMID- 26643701 TI - The diagnostic value of EUS in pancreatic cystic neoplasms compared with CT and MRI. AB - BACKGROUND AND OBJECTIVES: Pancreatic cystic neoplasms (PCNs) are being increasingly identified. Recent reports have described the utility of endoscopic ultrasound (EUS) in the characterization of PCNs. This study presents the diagnostic value of EUS in PCNs. MATERIALS AND METHODS: A total of 108 patients (78 women and 30 men; average age, 50 years) who were confirmed pathologically to have PCNs were analyzed retrospectively. We analyzed the clinical characteristics of 108 patients and compared the diagnostic performance of computed tomography (CT), magnetic resonance imaging (MRI), and EUS with or without fine-needle aspiration (FNA). RESULTS: EUS with or without FNA significantly increased the accuracy for diagnosing PCNs compared with CT (P = 0.002) and MRI (P = 0.006). According to the tumor size, the further analysis of these impacts was provided. EUS was superior to CT in the characterization of PCNs in small (< 3 cm) lesions (P = 0.003), similarly superior to MRI in large (>3 cm) lesions (P = 0.030). Furthermore, EUS is valuable for precisely characterizing internal structures, for example, septa (P = 0.004, compared with CT; P = 0.033, compared with MRI) and mural nodules (P = 0.028, compared with CT). CONCLUSIONS: In our study, EUS with or without FNA is the ideal tool for providing detailed imaging of PCNs and performed better than MRI and CT. PMID- 26643702 TI - Endoscopic ultrasound-guided radiofrequency ablation of the pancreas: An experimental study with pathological correlation. AB - BACKGROUND: The treatment of pancreatic cancer represents a major objective in clinical research, as it still remains the fourth leading cause of cancer deaths among men and women, with approximately 6% of all cancer-related deaths. MATERIALS AND METHODS: We studied the assessment of an endoscopic ultrasound (EUS)-guided radiofrequency ablation (RFA) probe through a 19G needle in order to achieve a desirable necrosis area in the pancreas. Radiofrequency ablation of the head of the pancreas was performed on 10 Yorkshire pigs with a weight between 25 kg and 35 kg and a length of 40-70 cm. Using an EUS-guided RFA experimental probe, we ablated an area of 2-3 cm width. The biological samples were harvested after 3 days and 5 days and necropsy was performed 1 week after the procedure. RESULTS: All pigs showed no significant change regarding their behavior and no signs of complication was encountered. Blood analysis revealed increased values of amylase, alkaline phosphatase, and gamma-glutamyl transpeptidase on the 3rd day but a decrease on the 5th day. After necropsy and isolation of the pancreas, the ablated area was easily found, describing a solid necrosis. The pathological examination revealed a coagulative necrosis area with minimal invasion and inflammatory tissue at about 2 cm surrounding the lesion. CONCLUSION: EUS-RFA is a feasible technique and might represent a promising therapy for the future treatment of pancreatic cancer. However, further studies are necessary to investigate EUS-guided RFA as an option for palliation in pancreatic cancer until it can be successfully used in human patients. PMID- 26643703 TI - Performance of the forward-view echoendoscope for pancreaticobiliary examination in patients with status post-upper gastrointestinal surgery. AB - BACKGROUND AND OBJECTIVES: Failures of endoscopic ultrasound (EUS) imaging of the head of the pancreas (HOP) and the common bile duct (CBD) have been reported in up to 50% of patients with status postsurgery (e.g., Billroth II and Roux-en-Y). This is attributable to inability to intubate the afferent limb or the duodenum. Recently, a forward-view (FV) echoendoscope has become available. The frontal endoscopic and ultrasound field of view theoretically allow easier manipulation throughout the gastrointestinal tract compared to the traditional echoendoscopes. The aim of our study was to evaluate the safety and performance of the FV echoendoscope for the investigation of the biliary tree and the pancreas, including fine-needle aspiration (FNA), in patients with surgically altered upper gastrointestinal anatomy. PATIENTS AND METHODS: This was a retrospective evaluation of a prospectively maintained database. All EUS procedures were performed at our institution by one experienced endosonographer from March to September 2009 under conscious sedation. The FV echoendoscope was used for all procedures. RESULTS: Twenty-five (25) out of 37 presented status post-Billroth II and 12 out of 37 with status post-Roux-en-Y surgery. Overall, HOP and CBD were adequately visualized in 28 out of 37 (75.7%). All the failures occurred in the Roux-en-Y patients. EUS-FNA was successfully performed in 16 patients. No adverse events were observed. CONCLUSIONS: The FV echoendoscope proved to be safe and effective in reaching the periampullary area in patients with previous Billroth II, allowing complete exploration of the HOP and the CBD and performance of EUS FNA. However, FV EUS was unsuccessful in the majority of patients with Roux-en-Y, which still remains a challenging condition. PMID- 26643704 TI - Echoendoscopic ethanol ablation of tumor combined to celiac plexus neurolysis improved pain control in a patient with pancreatic adenocarcinoma. AB - A 75-year-old man suffering from opioid-refractory due to an advanced pancreatic adenocarcinoma was treated with endoscopic ultrasound (EUS)-guided celiac plexus neurolysis (CPN) combined to EUS-guided tumor ablation. No major complications were recorded during the procedure. In the days following the procedure, mild diarrhea and fever were the only minor complications experienced by the patient. Complete tumor devascularization was assessed by means of computed tomography (CT) 48 h after the procedure. The patient remained pain-free without need of opioid, and was treated only with paracetamol for 20 weeks. Our results were optimal in terms of pain relief and immediate tumor response (assessed by means of CT and tumor marker levels). The present case demonstrates that the combined approach (EUS-guided ethanol ablation and CPN) may be a valuable option in patients with pancreatic cancer. Randomized-controlled trials are needed to confirm this result. PMID- 26643705 TI - SVC syndrome managed immediately after on site diagnosis of EUS-guided sampling for metastatic small-cell carcinoma of the pancreas presenting as acute pancreatitis. PMID- 26643706 TI - Dysphagia due to tubercular mediastinal lymphadenitis diagnosed by endoscopic ultrasound fine-needle aspiration. PMID- 26643707 TI - Gastric gastrointestinal stromal tumor mimicking cystic tumor of the pancreas: Diagnosed by endoscopic ultrasound-fine-needle aspiration. PMID- 26643708 TI - Malignant peritoneal mesothelioma diagnosed by EUS-guided tissue acquisition. PMID- 26643709 TI - The mechanism of action of Russian propolis ethanol extracts against two antibiotic-resistant biofilm-forming bacteria. AB - The interaction between antibiotic-resistant Staphylococcus aureus and antibiotic sensitive Escherichia coli biofilm-forming bacteria and Russian propolis ethanol extracts was evaluated. In this study, bacterial cell death occurred when the cell membranes of bacteria interacted specifically with the antibacterial compounds found in propolis. In order to understand the Russian propolis ethanol extract mechanism of action, microscopy and bacterial lysis studies were conducted. Results uncovered from these experiments imply that the mechanism of action of Russian propolis ethanol extracts is structural rather than functional. The results obtained throughout this study demonstrate cell membrane damage, resulting in cell lysis and eventually bacterial death. SIGNIFICANCE AND IMPACT OF THE STUDY: Most strains of bacteria and subsequently biofilms, have evolved and have altered their chemical composition in an attempt to protect themselves from antibiotics. The resistant nature of bacteria stems from the chemical rather than the physical means of inactivation of antibiotics. The results uncovered in this work demonstrate the potential application of Russian propolis ethanol extracts as a very efficient and effective method for bacterial and biofilm inactivation. PMID- 26643711 TI - Two metal stents for extensive oesophageal cancer. PMID- 26643710 TI - A comparative study of glaucoma referrals in Southeast Scotland: effect of the new general ophthalmic service contract, Eyecare integration pilot programme and NICE guidelines. AB - BACKGROUND: Glaucoma is a progressive disease responsible for the second commonest cause of blindness in the UK. Identifying appropriate patients for hospital care remains an ongoing challenge for all UK hospital glaucoma services. The purpose of our study is to evaluate accuracy and outcome of community optometry referrals before and after implementation of the new general ophthalmic service contract in 2006, the Eyecare Integration Programme pilot in 2008 and the effect of NICE guidelines in glaucoma in 2009, over a 12-year period METHODS: A retrospective case analysis using a glaucoma electronic patient record was performed encompassing two six-year periods, 2000-2006 (Group A), and 2007-2012 (Group B). RESULTS: One thousand six hundred twenty-two new patients' records were analysed. Waiting times reduced from 12.3 to 9.4 weeks. Significantly more patients kept first appointment (p = 0.0002) in group B. Glaucoma symptoms were significantly more in group A (p <0.0001) and only three patients lost Snellen' visual acuity before appointment in group B compared to 12 in group A. Documentation of intraocular pressure was made in 74.1% of Group A and 75.9% of Group B, optic disc appearance in 85.4% of Group A, and 93% of Group B and visual fields in 84.4% of Group A and 81.3% of Group B. Significantly less normal (p < 0,0001), more glaucoma suspects (p < 0.0001), more open angle glaucoma (p = 0.0006) and fewer other conditions (p = 0.0024) were present in group B, compared to group A. CONCLUSION: Patients were referred earlier with shorter waiting times for hospital appointments with the new Scottish general ophthalmic service and Eyecare Integration Programme. Additionally there were fewer false positive referrals with more diagnosis of glaucomatous disease. We discuss the benefits of these national screening and referral pathways together with their limitations and further refinements. PMID- 26643712 TI - Iron- and Cobalt-Catalyzed Synthesis of Carbene Phosphinidenes. AB - In the presence of stoichiometric or catalytic amounts of [M{N(SiMe3 )2 }2 ] (M=Fe, Co), N-heterocyclic carbenes (NHCs) react with primary phosphines to give a series of carbene phosphinidenes of the type (NHC)?PAr. The formation of (IMe4 )?PMes (Mes=mesityl) is also catalyzed by the phosphinidene-bridged complex [(IMe4 )2 Fe(MU-PMes)]2 , which provides evidence for metal-catalyzed phosphinidene transfer. PMID- 26643713 TI - Cellular and molecular mechanisms in graft-versus-host disease. AB - Graft-versus-host disease is a complication in patients undergoing hematopoietic stem cell transplantation. Graft-versus-host disease includes acute graft-versus host disease and chronic graft-versus-host disease. Host APCs (e.g., dendritic cells and macrophages), effector T cells (e.g., Th1, Th17, and abnormal Th17:regulatory T cell ratio), B cells, and NK cells are implicated in graft versus-host disease physiopathology. Proinflammation cytokines (e.g., IL-17, IL 1beta, and TNF-alpha) are increased in graft-versus-host disease . Costimulatory molecules play an important role in inducing graft-versus-host disease . Pattern recognition receptors, such as TLRs and nucleotide-binding oligomerization domain like receptors, are critically involved in the pathogenesis of graft-versus-host disease . Complement system C3 mediates Th1/Th17 polarization in human T cell activation and skin graft-versus-host disease. Accumulation of CD26 T cells in graft-versus-host disease target organs was found. As a therapeutic target, soluble CD83 molecules or antibodies have been demonstrated to have therapeutic effects against graft-versus-host disease, and signaling molecules promote the inflammatory and immune process of graft-versus-host disease . These immune cells and molecules could be the predictors of graft-versus-host disease development and the drug targets of the treatments for graft-versus-host disease. This article focuses on major advances on cellular and molecular mechanisms in graft versus-host disease. PMID- 26643714 TI - Graduate Education for the Future: New Models and Methods for the Clinical and Translational Workforce. AB - This paper is the third in a five-part series on the clinical and translational science educational pipeline, and it focuses on strategies for enhancing graduate research education to improve skills for interdisciplinary team science. Although some of the most cutting edge science takes place at the borders between disciplines, it is widely perceived that advancements in clinical and translational science are hindered by the "siloed" efforts of researchers who are comfortable working in their separate domains, and reluctant to stray from their own discipline when conducting research. Without appropriate preparation for career success as members and leaders of interdisciplinary teams, talented scientists may choose to remain siloed or to leave careers in clinical and translational science all together, weakening the pipeline and depleting the future biomedical research workforce. To address this threat, it is critical to begin at what is perhaps the most formative moment for academics: graduate training. This paper focuses on designs for graduate education, and contrasts the methods and outcomes from traditional educational approaches with those skills perceived as essential for the workforce of the future, including the capacity for research collaboration that crosses disciplinary boundaries. PMID- 26643715 TI - Study of allelopathic effects of Eucalyptus erythrocorys L. crude extracts against germination and seedling growth of weeds and wheat. AB - Allelopathic materials inside a tree can produce positive or negative change in the survival, growth, reproduction and behaviour of other organisms if they escape into the environment. To assess these effects, this work was carried out to evaluate the allelopathic impact of Eucalyptus erythrocorys L. on seed germination and seedling growth of two weeds: Sinapis arvensis L. and Phalaris canariensis L.; on one cultivated crop: Triticum durum L. Aqueous; and on ethanolic leaf extracts of E. erythrocorys L. The study was effected using four concentrations (10, 20, 25 and 30 MUL/mL) while distilled water was used as a control. The results showed that the E. erythrocorys L. crude extracts had an inhibitory effect on seed germination and seedling growth of both studied weeds and wheat. The inhibition rate was increased by the increase in extract concentration. Only ethanolic extracts of E. erythrocorys L. induced a significant inhibition of seed germination of durum wheat. The effect of E. erythrocorys L. crude extracts was more severe on weeds than on durum wheat. These results indicate that the seedling growth, especially radicle elongation, was the more sensitive indicator to evaluate the effects of extracts than was the seed germination. PMID- 26643716 TI - Ultralong Lifespan and Ultrafast Li Storage: Single-Crystal LiFePO4 Nanomeshes. AB - A novel LiFePO4 material, in the shape of a nanomesh, has been rationally designed and synthesized based on the low crystal-mismatch strategy. The LiFePO4 nanomesh possesses several advantages in morphology and crystal structure, including a mesoporous structure, its crystal orientation that is along the [010] direction, and a shortened Li-ion diffusion path. These properties are favorable for their application as cathode in Li-ion batteries, as these will accelerate the Li-ion diffusion rate, improve the Li-ion exchange between the LiFePO4 nanomesh and the electrolyte, and reduce the Li-ion capacitive behavior during Li intercalation. So the LiFePO4 nanomesh exhibits a high specific capacity, enhanced rate capability, and strengthened cyclability. The method developed here can also be extended to other similar systems, for instance, LiMnPO4 , LiCoPO4 , and LiNiPO4 , and may find more applications in the designed synthesis of functional materials. PMID- 26643717 TI - Poland's new conservative government to scrap IVF programme. PMID- 26643718 TI - Rapid and unbiased extraction of chromatin associated RNAs from purified native chromatin. AB - An ultra fast and unbiased method that uses salicylic acid coated magnetic nanoparticles (SAMNPs) and magnetophoretic chromatography is developed to extract chromatin associated RNAs (CARs). The SAMNPs were first used for enriching cells from the cell culture media and further used for capturing chromatin after cells were lysed. The formed SAMNPs-chromatin complexes were transferred to a viscous polyethylene glycol (PEG) solution stored in a 200-MUl pipette tip. Due to the difference in viscosities, a bi-layer liquid was formed inside the pipette tip. The SAMNPs-chromatin complexes were separated from the free SAMNPs and free RNA SAMNPs complexes by applying an external magnetic field. The CARs were further extracted from the SAMNP-chromatin complexes directly. The extracted CARs were reverse transcribed as cDNA and further characterized by real-time qPCR. The total assay time taken for cell separation, chromatin purification and chromatin associated RNAs extraction can be accomplished in less than 2h. PMID- 26643719 TI - Chemical analysis of Panax quinquefolius (North American ginseng): A review. AB - Panax quinquefolius (PQ) is one of the best-selling natural health products due to its proposed beneficial anti-aging, anti-cancer, anti-stress, anti-fatigue, and anxiolytic effects. In recent years, the quality of PQ has received considerable attention. Sensitive and accurate methods for qualitative and quantitative analyses of chemical constituents are necessary for the comprehensive quality control to ensure the safety and efficacy of PQ. This article reviews recent progress in the chemical analysis of PQ and its preparations. Numerous analytical techniques, including spectroscopy, thin-layer chromatography (TLC), gas chromatography (GC), high-performance liquid chromatography (HPLC), liquid chromatography/mass spectrometry (LC/MS), high speed centrifugal partition chromatography (HSCPC), high-performance counter current chromatography (HPCCC), nuclear magnetic resonance spectroscopy (NMR), and immunoassay, are described. Among these techniques, HPLC coupled with mass spectrometry (MS) is the most promising method for quality control. The challenges encountered in the chemical analysis of PQ are also briefly discussed, and the remaining questions regarding the quality control of PQ that require further investigation are highlighted. PMID- 26643720 TI - Ultrafast separation of fluorinated and desfluorinated pharmaceuticals using highly efficient and selective chiral selectors bonded to superficially porous particles. AB - The separation of fluorinated active pharmaceutical ingredients (APIs) from their desfluoro analogs is a challenging analytical task due to their structural similarity. In this work, fluorine containing APIs and their corresponding desfluorinated impurities were separated on five new 2.7MUm superficially porous particles (SPPs) functionalized with bonded chiral selectors. The unique shape selectivity of bonded macrocyclic glycopeptides and oligosaccharides was utilized to separate seven pairs of fluoro/desfluoro APIs resulting in some unprecedented selectivity values. For example, SPP bonded isopropyl cyclofructan 6 yielded a selectivity of 2.73 for voriconazole and desfluoro voriconazole. Further, the SPP based columns allowed for rapid separations ranging from 9 to 55s with very high efficiencies ranging from 45,000 to 70,000plates/m (at high flow rates) in both reversed phase and polar organic modes. Chromatographic separation and detection by HPLC-ESI-MS was demonstrated using ezetimibe and voriconazole and their desfluorinated impurities. Among the tested phases, SPP hydroxypropyl-beta cyclodextrin separated the most fluorinated and desfluorinated analogs with baseline resolution. PMID- 26643721 TI - Kinetic plots in aqueous size exclusion chromatography of monoclonal antibodies and virus particles. AB - The growing importance of monoclonal antibodies and virus particles has led to a pressure for faster size exclusion chromatography. In recent years, numerous small particle columns for size exclusion chromatography of biologicals have been introduced. Small particles are a strategy to reduce analysis time. In the following study, opportunities of small particles in size exclusion chromatography of large biomolecules are investigated. Poppe plots reveal that the lower particle size limit depends on the size of the sample molecule. Hydrodynamic radii of monoclonal antibody monomer, aggregates and H1N1 as well as the diffusion coefficients were determined. Considering this sample compound dependency, kinetic plots referring to the resolution of a distinct compound pair instead of the plate number of a single analyte are more meaningful. Plate times were found to be equivalent with 4 and 2MUm particles for a monoclonal antibody aggregate separation at resolutions smaller than 1.8. Quantification of a H1N1 in clarified cell culture can be accomplished with 17MUm and 13MUm particles at equal plate times at resolutions smaller than 2.5. Virus polydispersity is likely to be affected by run times of several hours at room temperature and shear forces resulting from particles smaller than 10MUm. Comparatively high flow rates should be applied in size exclusion chromatography of the 100nm H1N1 virions. PMID- 26643722 TI - An on-line stacking capillary electrophoresis method for the analysis of Delta(9) tetrahydrocannabinol and its metabolites. AB - The objective of this study was to establish a practical and reliable analytical method for monitoring trace amounts of Delta(9)-tetrahydrocannabinol (THC) and its metabolites in biological samples. A novel on-line preconcentration capillary electrophoresis method combining large volume sample injection, anion selective exhaustive injection and sweeping was developed to enhance analytical sensitivity. A background buffer composed with 30mM phosphate buffer (pH 2.5) containing 40% methanol and 100mM SDS was used to suppress the electroosmotic flow of the uncoated fused silica capillary (40cm*50MUm i.d.). High conductivity buffer (200mM phosphate, pH 2.5) was injected for analyte accumulation. The samples, prepared in phosphate buffer or Tris buffer, were introduced by hydrodynamic injection and electrokinetic injection. After sweeping, the separation was performed in micellar electrokinetic chromatography (MEKC) mode at -15kV. During the method validation, the coefficient of determination of the regression curve was measured at greater than 0.993, and the relative standard deviation and relative error were lower than 11.06% and 9.24%, respectively. Under optimized conditions, an improvement of up to 2000-fold higher sensitivity was achieved. This method was applied to the analysis of urine samples, indicating that it could be satisfactorily utilized in the toxicological and clinical monitoring of cannabis. PMID- 26643723 TI - Rational development of two flowthrough purification strategies for adenovirus type 5 and retro virus-like particles. AB - We report on the rational design and implementation of flowthrough (FT) platforms for purification of virus vectors (VVs) and virus-like particles (VLPs), combining anion-exchange polyallylamine membranes (Sartobind STIC) and core-shell octylamine resins (CaptoCore 700). In one configuration, the VV bulk is concentrated and conditioned with appropriate buffer in a ultra/diafiltration (UF/DF) unit prior to injection into the STIC chromatography membrane. The FT pool and an intermediate cut of the elution pool of the STIC membrane are admixed and directed to a second UF/DF. Finally, the retentate is injected into a CC700 packed bed adsorber where the purified VVs are collected in the FT pool, whereas the residual amount of DNA and host cell protein (HCP) are discarded in the eluate. The experimental recovery achieved with this downstream processing (DSP) platform is close to 100%, the DNA clearance is roughly a 4-log reduction, and the HCP level is reduced by 5 logs. The platform developed for VLP purification is simpler than the previous one, as the STIC membrane adsorber and CC700 bed are connected in series with no UF/DF unit in between. Experimentally, the FT scheme for VLP purification gave a recovery yield of 45% in the chromatography train; the experimental log reduction of DNA and HCP were 2.0 and 3.5, respectively. These results are in line with other purification strategies in the specific field of enveloped VLPs. Both DSP platforms were successfully developed from an initial design space of the binding of the major contaminant (DNA) to the two ligands, determined by surface plasmon resonance, which was subsequently scaled up and confirmed experimentally. PMID- 26643724 TI - Solid phase microextraction Arrow for the sampling of volatile amines in wastewater and atmosphere. AB - A new method is introduced for the sampling of volatile low molecular weight alkylamines in ambient air and wastewater by utilizing a novel SPME Arrow system, which contains a larger volume of sorbent compared to a standard SPME fiber. Parameters affecting the extraction, such as coating material, need for preconcentration, sample volume, pH, stirring rate, salt addition, extraction time and temperature were carefully optimized. In addition, analysis conditions, including desorption temperature and time as well as gas chromatographic parameters, were optimized. Compared to conventional SPME fiber, the SPME Arrow had better robustness and sensitivity. Average intermediate reproducibility of the method expressed as relative standard deviation was 12% for dimethylamine and 14% for trimethylamine, and their limit of quantification 10MUg/L and 0.13MUg/L respectively. Working range was from limits of quantification to 500MUg/L for dimethylamine and to 130MUg/L for trimethylamine. Several alkylamines were qualitatively analyzed in real samples, while target compounds dimethyl- and trimethylamines were quantified. The concentrations in influent and effluent wastewater samples were almost the same (~80MUg/L for dimethylamine, 120MUg/L for trimethylamine) meaning that amines pass the water purification process unchanged or they are produced at the same rate as they are removed. For the air samples, preconcentration with phosphoric acid coated denuder was required and the concentration of trimethylamine was found to be around 1ng/m(3). The developed method was compared with optimized method based on conventional SPME and advantages and disadvantages of both approaches are discussed. PMID- 26643725 TI - Development of sample extraction and clean-up strategies for target and non target analysis of environmental contaminants in biological matrices. AB - Recently, there has been an increasing trend towards multi-targeted analysis and non-target screening methods as a means to increase the number of monitored analytes. Previous studies have developed biomonitoring methods which specifically focus on only a small number of analytes with similar physico chemical properties. In this paper, we present a simple and rapid multi-residue method for simultaneous extraction of polar and non-polar organic chemicals from biological matrices, containing up to 5% lipid content. Our method combines targeted multi-residue analysis using gas chromatography triple quadrupole mass spectrometry (GC-QqQ-MS/MS) and a multi-targeted analysis complemented with non target screening using liquid chromatography coupled to a quadrupole time of flight mass spectrometry (LC-QTOF-MS/MS). The optimization of the chemical extraction procedure and the effectiveness of different clean-up methods were evaluated for two biological matrices: fish muscle (lipid content ~2%) and breast milk (~4%). To extract a wide range of chemicals, the partition/extraction procedure used for the QuEChERS (Quick, Easy, Cheap, Effective, Rugged and Safe) approach was tested as the initial step for the extraction of 77 target compounds covering a broad compound domain. All the target analytes have different physico chemical properties (log Kow ranges from -0.3 to 10) and cover a broad activity spectrum; from polar pesticides, pharmaceuticals, personal care products (PPCPs) to highly lipophilic chemicals such as polybrominated diphenyl ethers (PBDEs), polychlorinated biphenyls (PCBs), polycyclic aromatic hydrocarbons (PAHs) and organochloride pesticides (OCPs). A number of options were explored for the clean up of lipids, proteins and other impurities present in the matrix. Zirconium dioxide-based sorbents as dispersive solid-phase extraction (d-SPE) and protein lipid removal filter cartridges (Captiva ND Lipids) provided the best results for GC-MS and LC-MS analysis respectively. The method was fully validated for samples of fish muscle and breast milk through the evaluation of recoveries, matrix effects, limit of quantification, linearity and precision (inter-day and intra day). Mean recoveries (n=5) were between 70 and 120% with relative standard deviations (RSD) less than 20% in most of the cases. GC-MS/MS LOQs ranged from 0.08 to 3MUg/kg and LC-QTOF-MS/MS LOQs ranged from 0.2 to 9MUg/kg. The developed strategy was successfully applied for analysis of real samples; 22 target analytes were found in the breast milk samples and 10 in the fish samples. Non target analysis allowed the detection and identification of an additional 14 contaminants and metabolites in the samples. PMID- 26643726 TI - Effect-directed analysis of fresh and dried elderberry (Sambucus nigra L.) via hyphenated planar chromatography. AB - A healthy diet is an important factor in a healthy lifestyle that is becoming increasingly important in today's society. The fruits of European elder (Sambucus nigra L.) are a rich source of bioactive compounds like anthocyanins. In this study, dried and fresh fruits of four cultivated and six wild growing plants were investigated for their anthocyanin pattern and content as well as their bioactive compounds. After separation on HPTLC plates silica gel 60 F254 with a mixture of ethyl acetate, 2-butanone, formic acid and water, the plates were quantitatively evaluated by densitometry and also subjected to various (bio)assays to investigate the samples for compounds acting as radical-scavengers, antimicrobials, estrogens, and acetylcholinesterase or tyrosinase inhibitors. The mean contents for the two most abundant anthocyanins in European elderberries, confirmed by HPTLC-ESI-MS, ranged from 159 to 647mg/100g in fresh and from 166 to 2764mg/100g in dried fruits for cyanidin-3-sambubioside, and from 112 to 521mg/100g in fresh and 95 to 226mg/100g in dried fruits for cyanidin-3 glucoside. Additionally, the anthocyanin content was higher in berries of cultivars than of wild growing plants. The anthocyanins' radical scavenging activity and antimicrobial effect against Aliivibrio fischeri were confirmed. Further, a radical scavenging compound affecting A. fischeri and acting as acetylcholinesterase inhibitor was tentatively assigned by its protonated molecule at m/z 456 as either ursolic or oleanolic acid by HPTLC-ESI-MS. HPTLC hyphenated with bioassays and mass spectrometry was selected as method of choice for fingerprinting, pattern recognition, and bioprofiling of elderberry samples as well as quantitation and confirmation of bioactive compounds therein. PMID- 26643727 TI - Supraventricular and ventricular arrhythmias. PMID- 26643729 TI - Correlates of gender characteristics, health and empowerment of women in Ethiopia. AB - BACKGROUND: The low status of women prevents them from recognizing and voicing their concerns about health needs. This study aimed to examine the relationship between gender characteristics, health and empowerment of women in an attempt to understand between 2005 and 2011. METHODS: Data from the Ethiopia Demographic and Health Survey (EDHS) 2005 and 2011 were used. Bivariate and multivariate analyses were used to determine the relative contribution of the predictor variables. The hypotheses tested in this study were that gender (men and women), health and empowerment of women in region are highly significant with women's education and work status. RESULTS: Study findings showed that the low status of women and their disempowerment are highly associated with poor health outcomes. In both 2005 and 2011 men school ages were positively associated with their attainment in primary education, whereas for women it was negatively related with their attainment in some education. In both 2005 and 2011 women in the richest wealth quintile had the highest odds ratio of relating to some education. The results show that the odds ratios of women with some education (within the richest wealth quintile) has improved from 6.39 (in 2005) to 10.90 (in 2011), whereas among men there has been a decrease from 10.33 (in 2005) to 2.13 (in 2011). The results indicated that in 2005 and 2011, when comparing the percentage distribution of both genders on employment status and type of occupation, the percentage of men who were employed was higher than women. The percentage of males who were engaged in the agricultural-type of occupation was higher than that of women. Men and women knowledge about family planning methods have been improved, yet, there are wider gender gaps in family planning users. CONCLUSIONS: The officials such as policy makers, planners, program managers and government and non-government organizations need to addressed. The issue of child marriages in order to minimize the number of girls who never attend school or drop out to become wives Planners should also work on improving family planning to empower women. There was a significant relationship between status of women and quality of healthy life, and this relationship appeared to differ by education and work status. PMID- 26643730 TI - Hydrogen-Bonded Complexes of Phenylacetylene-Acetylene: Who is the Proton Donor? AB - Hydrogen-bonded complexes of C2H2 and phenylacetylene (PhAc) were studied using matrix isolation infrared spectroscopy and quantum chemical computations. Both C2H2 and PhAc, being potential proton donors, the question arises as to which of the two species would be the proton donor in the PhAc-C2H2 complex; a question that this work primarily addresses. The molecular structures, vibrational frequencies, and interaction energies of the PhAc-C2H2 complexes were calculated at the M06-2X and MP2 levels of theory, employing both 6-311++G(d,p) and aug-cc pVDZ basis sets. At the M06-2X/aug-cc-pVDZ level, two nearly isoenergetic complexes (BSSE corrected) were indicated to be the global minima; one a C-H...pi complex, where C2H2 served as a proton donor to the phenyl pi-system in PhAc, and the other a C-H...pi complex, where C2H2 served as a proton donor to the acetylene pi-system in PhAc. Of the two, only the second complex was identified in the matrix, evidenced by a characteristic large shift in the =C-H stretch of C2H2. Experiments were also performed using PhAc deuterated at the acetylene hydrogen (PhAcD) to study the isotopic effects on the vibrational spectra of complexes. The isotopic studies further confirmed the structure of the complex trapped in the matrix, thereby presenting unambiguous evidence that C2H2 served as the proton donor to the acetylene pi-system of PhAc. The theory of atoms-in molecules (AIM), energy decomposition (EDA), and natural bond orbital (NBO) analysis were performed to understand the nature of the interactions involved in the complexes. PMID- 26643731 TI - Generalist palliative care in hospital - Cultural and organisational interactions. Results of a mixed-methods study. AB - BACKGROUND: It can be challenging to provide generalist palliative care in hospitals, owing to difficulties in integrating disease-oriented treatment with palliative care and the influences of cultural and organisational conditions. However, knowledge on the interactions that occur is sparse. AIM: To investigate the interactions between organisation and culture as conditions for integrated palliative care in hospital and, if possible, to suggest workable solutions for the provision of generalist palliative care. DESIGN: A convergent parallel mixed methods design was chosen using two independent studies: a quantitative study, in which three independent datasets were triangulated to study the organisation and evaluation of generalist palliative care, and a qualitative, ethnographic study exploring the culture of generalist palliative nursing care in medical departments. SETTING/PARTICIPANTS: A Danish regional hospital with 29 department managements and one hospital management. RESULTS: Two overall themes emerged: (1) 'generalist palliative care as a priority at the hospital', suggesting contrasting issues regarding prioritisation of palliative care at different organisational levels, and (2) 'knowledge and use of generalist palliative care clinical guideline', suggesting that the guideline had not reached all levels of the organisation. CONCLUSION: Contrasting issues in the hospital's provision of generalist palliative care at different organisational levels seem to hamper the interactions between organisation and culture - interactions that appear to be necessary for the provision of integrated palliative care in the hospital. The implementation of palliative care is also hindered by the main focus being on disease-oriented treatment, which is reflected at all the organisational levels. PMID- 26643732 TI - A New Subtype of Multiple Synostoses Syndrome Is Caused by a Mutation in GDF6 That Decreases Its Sensitivity to Noggin and Enhances Its Potency as a BMP Signal. AB - Growth and differentiation factors (GDFs) are secreted signaling molecules within the BMP family that have critical roles in joint morphogenesis during skeletal development in mice and humans. Using genetic data obtained from a six-generation Chinese family, we identified a missense variant in GDF6 (NP_001001557.1; p.Y444N) that fully segregates with a novel autosomal dominant synostoses (SYNS) phenotype, which we designate as SYNS4. Affected individuals display bilateral wrist and ankle deformities at birth and progressive conductive deafness after age 40 years. We find that the Y444N variant affects a highly conserved residue of GDF6 in a region critical for binding of GDF6 to its receptor(s) and to the BMP antagonist NOG, and show that this mutant GDF6 is a more potent stimulator of the canonical BMP signaling pathway compared with wild-type GDF6. Further, we determine that the enhanced BMP activity exhibited by mutant GDF6 is attributable to resistance to NOG-mediated antagonism. Collectively, our findings indicate that increased BMP signaling owing to a GDF6 gain-of-function mutation is responsible for loss of joint formation and profound functional impairment in patients with SYNS4. More broadly, our study highlights the delicate balance of BMP signaling required for proper joint morphogenesis and reinforces the critical role of BMP signaling in skeletal development. PMID- 26643734 TI - Midterm Outcome of Cementless Total Hip Arthroplasty in Crowe IV-Hartofilakidis Type III Developmental Dysplasia of the Hip. AB - BACKGROUND: Developmental dysplasia of the hip (DDH) is widespread in developing countries, and treating Crowe IV-Hartofilakidis Type III DDH in adults requires the use of a highly demanding technique. METHODS: We sought to determine the outcome of cementless total hip arthroplasty using Zweymuller components to treat Crowe IV-Hartofilakidis Type III DDH. Fifty-eight patients (71 hips) with a mean age of 35.8 years at time of index operation were included in our study. The average duration of follow-up was 70.5 months. The acetabular component was placed in the true acetabulum in all cases, and subtrochanteric shortening osteotomy was performed in 61 hips. RESULTS: With any component revision for any reason as the end point, Kaplan-Meier survivorship analysis at 98 months revealed a cumulative survival rate for implanted components of 91.40%. The mean Harris Hip Score improved from 35.6 preoperatively to 82.9 postoperatively. There were 20 cases of intraoperative fracture, 1 case of complete nerve palsy, and 7 cases of transient nerve palsy. Revision surgery was performed in 7 patients because of cup loosening in 1, severe polyethylene wear in 4, cup breakage in 1, and dislocation in 1. CONCLUSIONS: Midterm results for cementless total hip arthroplasty in patients with Crowe IV-Hartofilakidis Type III DDH was satisfactory; however, intraoperative fracture and polyethylene wear were major complications. PMID- 26643733 TI - The emerging roles of the STING adaptor protein in immunity and diseases. AB - DNA that gains access to the cytoplasm generally serves as a danger signal for the hosts. An emerging paradigm for responding to cytosolic DNAs centres on the endoplasmic reticulum-resident protein stimulator of interferon genes (STING, also known as MITA, ERIS or MPYS), the hub adaptor of the recently identified DNA sensors. Dynamic regulations of STING action are critical for shaping innate immune responses against microbial infections, as well as for preventing autoimmune diseases. STING is also indispensable for the detection of immunogenic tumours. A deeper understanding of STING modulations could be instrumental for developing novel immunotherapeutic strategies against infectious, autoimmune and cancerous diseases. In this review, we summarize the latest advances on the role of STING in the DNA-triggered immune reactions, and underscore the critical issues that remain to be resolved in future studies. PMID- 26643736 TI - Long-Term Clinical Outcomes of Fractional Flow Reserve-Guided Versus Routine Drug Eluting Stent Implantation in Patients With Intermediate Coronary Stenosis: Five Year Clinical Outcomes of DEFER-DES Trial. AB - BACKGROUND: We aimed to compare the long-term clinical outcomes between fractional flow reserve (FFR)-guided and routine drug-eluting stent (DES) implantation in patients with an intermediate coronary stenosis. METHODS AND RESULTS: A total of 229 patients with an angiographically intermediate coronary stenosis were randomly assigned to FFR-guided or Routine-DES implantation group. For FFR-guided group (n=114), treatment strategy was determined according to the target vessel FFR (FFR<0.75: DES implantation [FFR-DES group]; FFR>=0.75: deferral of stenting [FFR-Defer group]). Routine-DES group underwent DES implantation without FFR measurement (n=115). The primary end point was the incidence of major adverse cardiac events, a composite of cardiac death, myocardial infarction, and target lesion revascularization. Of lesions assigned to FFR-guided strategy, only one quarter had functional significance (FFR<0.75). At 2-year follow-up, the cumulative incidence of major adverse cardiac events was 7.9+/-2.5% in the FFR-guided group and 8.8+/-2.7% in Routine-DES group (P=0.80). At 5-year follow-up, the cumulative incidence of major adverse cardiac events was 11.6+/-3.0% and 14.2+/-3.3% for the FFR-guided group and the Routine-DES group (P=0.55). There was no difference in major adverse cardiac events rates between the 2 groups <=5-year follow-up (hazard ratio, 1.25; 95% confidence interval, 0.60-2.60). CONCLUSIONS: In lesions with angiographically intermediate stenosis, FFR guidance provides a tailored approach, which is at least as good as an angiography-guided routine-DES implantation strategy and avoids unnecessary DES stenting in a considerable part of the patients. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00592228. PMID- 26643735 TI - Quality of life among Ghanaian adolescents living with perinatally acquired HIV: a mixed methods study. AB - In Sub-Saharan Africa, increasing numbers of children with perinatally acquired HIV (PAHIV) are living into adolescence. These adolescents face numerous unique challenges such as parent illness/death and years of medication use. Optimizing care for these youth requires an understanding of the factors that contribute to physical health, psychological well-being, social relationships, and quality of life (QOL). This mixed methods study collected quantitative questionnaire data from 40 Ghanaian adolescents with PAHIV (50% female, 12-19 years old) who received care through an adolescent HIV clinic in Kumasi, Ghana. The study also presents results from qualitative interviews conducted with 20 adolescents. Results from quantitative analyses suggested that a significant number of participants were not virally suppressed (67%) and participants reported barriers to treatment adherence, limited social support, concerns about disclosure and HIV related stigma, limited resources, and lower than expected QOL. Salient themes from the qualitative analyses included limited understanding of how HIV is transmitted, the interplay between food insecurity and treatment adherence and the need for developing safe relationships through which adolescents can discuss their illness without fear of accidental disclosure of their HIV status. PMID- 26643737 TI - Etiology, Frequency, and Clinical Outcomes of Myocardial Infarction After Successful Drug-Eluting Stent Implantation: Two-Year Follow-Up From the ADAPT-DES Study. AB - BACKGROUND: The frequency, causes, and impact of myocardial infarction (MI) after successful percutaneous coronary intervention have not been well studied. METHODS AND RESULTS: The Assessment of Dual Antiplatelet Therapy With Drug-Eluting Stents (ADAPT-DES) study was a prospective, multicenter registry study of 8582 patients undergoing successful drug-eluting stent implantation at 11 centers in the United States and Germany. After excluding 128 patients with periprocedural MI, we investigated the pathogenesis, frequency, and long-term consequences of non periprocedural MI in 8454 patients. MI during 2-year follow-up developed in 263 patients (3.3%) at a median (25th and 75th percentiles) time of 318 (129, 503) days. The 263 MIs were subclassified as spontaneous MI (n=78; 29.7%), secondary or indeterminate MI (n=64; 24.3%), stent thrombosis-related MI (n=63; 24.0%), and in-stent restenosis-related MI (n=58; 22.1%). Multivariable predictors of MI included clinical and angiographic factors (acute coronary syndromes presentation, diabetes mellitus, current smoker, multivessel disease, treatment of an in-stent restenotic lesion), laboratory findings (low baseline hemoglobin and reduced creatinine clearance), antiplatelet agent-related factors (higher on treatment platelet P2Y12 receptor reactivity and premature thienopyridine discontinuation), and not being on a statin at discharge. Patients who experienced an MI during the follow-up period had significantly greater 2-year mortality than those without MI (17.3% [42 deaths] versus 3.4% [265 deaths], P<0.001). By multivariable analysis, the adjusted hazard ratio (95% confidence interval) for subsequent mortality during follow-up was 2.17 (1.06, 4.45) in patients with versus without a non-periprocedural MI (P=0.03). CONCLUSIONS: The occurrence of a non-periprocedural MI within 2 years after successful drug eluting stent implantation is relatively infrequent, but has numerous etiologies and is significantly associated with subsequent mortality. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00638794. PMID- 26643738 TI - Factors Affecting Bleeding and Stent Thrombosis in Clinical Trials Comparing Bivalirudin With Heparin During Percutaneous Coronary Intervention. AB - BACKGROUND: Patients treated with bivalirudin in randomized clinical trials of percutaneous coronary intervention generally have less bleeding but more acute stent thrombosis (ST) than do patients treated with heparin, but differences have varied among trials. METHODS AND RESULTS: We modeled the risk of major hemorrhage and ischemic outcomes 30 days after percutaneous coronary intervention by treatment assignment and the use of adjunctive therapies in 18 randomized clinical trials enrolling 41,871 patients. Overall bivalirudin caused less major bleeding (odds ratio [OR], 0.64; 95% confidence interval [CI], 0.53-0.76), more ST (OR, 1.58; 95% CI, 1.19-2.09), and no difference in mortality (OR, 0.93; 95% CI, 0.77-1.14) than heparin. A risk-benefit analysis identified 19 fewer bleeds and 5 more STs for every 1000 patients treated with bivalirudin in place of heparin. No significant bleeding advantage of bivalirudin over heparin could be identified in randomized clinical trials when transradial access (OR, 0.89; 95% CI, 0.57-1.41) and planned glycoprotein IIb/IIIa inhibitors were used with bivalirudin in the majority of patients (OR, 1.07; 95% CI, 0.87-1.31). The use of prasugrel or ticagrelor eliminated bleeding differences (OR, 0.80; 95% CI, 0.63 1.03) but did not reduce the risk of ST after bivalirudin (OR, 2.20; 95% CI, 1.48 3.27). CONCLUSIONS: Substituting bivalirudin for heparin conferred a tradeoff between bleeding and ST. Transradial access, adjunctive glycoprotein IIb/IIIa inhibitors, and potent P2Y12 inhibitors attenuated the bleeding advantage of bivalirudin over heparin but had no apparent effect on early ST. New approaches to reduce bleeding and ischemic complications during percutaneous coronary intervention warrant further investigation. PMID- 26643739 TI - Comparison of Right and Left Upper Limb Arterial Variants in Patients Undergoing Bilateral Transradial Procedures. AB - BACKGROUND: Transradial approach (TRA), when compared with transfemoral, improves the safety of percutaneous coronary procedures. Arterial axis variants are known to hinder the performance of transradial approach percutaneous coronary procedures. Data on the occurrence of arterial axis variants in the right and left arm arterial axes of individual patients are lacking. METHODS AND RESULTS: From a single-center prospective registry, we selected all patients in whom bilateral upper limb arterial anatomy was assessed based on the performance of left and right radial catheterization obtained during the same or during repeat coronary diagnostic or interventional procedure(s). The occurrence of upper right and left limb arterial axis variants was classified according to the previously described operative ABC classification. A total of 610 patients were identified. An ABC upper limb arterial axis variant was detected in 156 (25.6%) patients. Variants were right-sided only in 65 (11.0%), left-sided only in 40 (6.6%), and bilateral in 46 (7.5%) patients. Thus, arterial axis variants were significantly more common in the right side (P=0.02). Bilateral arterial variants were significantly associated with age, female sex, and valvulopathy. Both A (radial/brachial) and B (axillary/subclavian/innominate) variants exhibited concordance across the 2 sides (odds ratio, 7.2; 95% confidence interval, 4.1 12.7 and 8.0; 95% confidence interval, 2.1-30.9, respectively). CONCLUSIONS: The occurrence of an anatomic variant potentially hindering transradial approach coronary diagnostic or interventional procedures is bilateral in <8% of cases and is more common in the right arm. Such information may guide, during the clinical practice, the access selection in the case of repeat procedures or need for additional accesses. PMID- 26643740 TI - Association of Patient-Reported Health Status With Long-Term Mortality After Transcatheter Aortic Valve Replacement: Report From the STS/ACC TVT Registry. AB - BACKGROUND: Although transcatheter aortic valve replacement (TAVR) is an effective treatment for aortic stenosis, long-term mortality after TAVR remains high and challenging to predict. The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a health status measure, assessed directly from patients, that integrates 2 clinically relevant factors (symptoms and functional status) that may predict TAVR outcomes. METHODS AND RESULTS: Among 7769 patients from 286 sites in the Society of Thoracic Surgeons (STS)/American College of Cardiology (ACC) Transcatheter Valve Therapy (TVT) Registry, we examined the association between preprocedure (baseline) patient health status, as assessed by the KCCQ, and 1-year mortality after TAVR. The KCCQ Overall Summary Score was categorized as very poor: <25, poor: 25 to 49, fair: 50 to 74, or good: >=75. Before TAVR, health status was rated as very poor in 28%, poor in 38%, fair in 24%, and good in 10%. Patients with worse health status were more likely to be women and had more comorbidities and higher STS mortality risk scores. Compared with those with good health status before TAVR and after adjusting for a broad range of baseline covariates, patients with very poor health status had a 2-fold increased hazard of death over the first year after TAVR (adjusted hazard ratio, 2.00; 95% confidence interval, 1.58-2.54), whereas those with poor and fair health status had intermediate outcomes (adjusted hazard ratio, 1.54; 95% confidence interval, 1.22-1.95 and adjusted hazard ratio, 1.20; 95% confidence interval, 0.94-1.55, respectively). CONCLUSIONS: In a national, contemporary practice cohort, worse preprocedure patient health status, as assessed by the KCCQ, was associated with greater long-term mortality after TAVR. These results support the measurement and integration of the KCCQ into mortality risk assessments for patients considering TAVR. PMID- 26643741 TI - Triple Antithrombotic Therapy in Atrial Fibrillation Patients With an Indication for Oral Anticoagulation Undergoing Percutaneous Coronary Intervention: A Case Based Review of the Current Evidence. PMID- 26643742 TI - Can We Predict Quality of Life and Survival After Transcatheter Aortic Valve Replacement? PMID- 26643743 TI - Alcohol and substance use prevention programs for youth in Hawaii and Pacific Islands: A literature review. AB - This article provides a literature review of recent programs to prevent alcohol and substance use in Hawaii and Pacific Islander youths. Five programs for alcohol and substance use prevention among Hawaii and Pacific Islander youths were found in peer-reviewed literature. Of these, two focused on Native Hawaiians and/or other Pacific Islanders and three focused on overall youths in Hawaii. The main themes of these programs were increasing cultural pride, character development through personal efficacy and integrity, connecting youth to family and community, and being school- or community-centered. Two studies showed a decrease in substance use, one showed a change in knowledge, and two did not published outcomes. This review highlights a lack of evidence-based culturally appropriate options for preventing substance use by Native Hawaiian and Pacific Islander youth. Dialogue about best practices is needed and should be supported through publication of program evaluations. PMID- 26643745 TI - Adieu but not goodbye. PMID- 26643746 TI - Nutrition: New challenges for a venerable vision. PMID- 26643744 TI - Poor-prognosis disclosure preference in cancer patient-caregiver dyads and its association with their quality of life and perceived stress: a cross-sectional survey in mainland China. AB - BACKGROUND: This study attempted to examine the discordance between family caregivers and cancer patients in their poor-prognosis disclosure preferences in mainland China and then ascertained the associations between quality of life (QoL), perceived stress, and poor-prognosis disclosure preferences. METHODS: Six hundred fifty-one pairs of inpatients and their matched caregivers (participation rate = 92.2%) were recruited in this cross-sectional survey. A set of paired self administered questionnaires were completed independently by patient-caregiver dyads. RESULTS: Fewer family caregivers than cancer patients felt that poor prognosis should be disclosed to patients (61.2% vs. 90.0%, p < 0.001). Patients' positive poor-prognosis disclosure preference was associated with patients' better QoL (p < 0.05) and caregivers' reduced perceived stress levels (p = 0.013). However, caregivers' poor-prognosis disclosure preference correlated only with their own physical state (p = 0.028). Moreover, the caregivers who concurred with patients in positive poor-prognosis disclosure preference were more likely to experience a better QoL (p < 0.05) and lower perceived stress levels (p = 0.048) in the III-IV stage subgroup. CONCLUSIONS: There was a significant discrepancy in poor-prognosis disclosure preference between cancer patients and caregivers in China. The caregivers' preference of concealing poor prognosis from patients was not related to cancer patients' QoL or perceived stress. In addition, caregivers had better QoL and lower stress levels when they held the same positive poor-prognosis disclosure preference as the patients. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26643747 TI - The prevalence of vitamin D deficiency among dark-skinned populations according to their stage of migration and region of birth: A meta-analysis. AB - OBJECTIVES: The prevalence of vitamin D deficiency (VDD) varies among migrants from different geographic regions. The aim of this study was to estimate the pooled prevalence of VDD among dark-skinned migrants. METHOD: A meta-analysis using meta-regression was undertaken to determine the prevalence of VDD in dark skinned migrant populations. Prevalence also was determined by study characteristics including study methodology, age of populations examined, and length of time in migrated country. RESULTS: Thirty-six studies were identified in nonpregnant populations. Of 13 974 individuals in the studies, 9562 were vitamin D deficient. Pooled prevalence in dark-skinned migrants, adjusted for latitude of study country was estimated at 77% (95% confidence interval [CI], 70% 84%). Examination of studies in which migrants from both Sub-Saharan Africa and the extended Middle East were examined (N = 7) showed immigrants from the extended Middle East had a higher prevalence of VDD (65%; 95% CI, 45%-94%) compared with those from Sub-Saharan Africa (56%; 95% CI, 34%-77%). Seven studies were identified in pregnant dark-skinned migrant women. This group tended to have much higher prevalence of VDD compared with native-born pregnant women. CONCLUSION: Immigrants with dark skin, and in particular those from the extended Middle East region, have high prevalence of VDD. Migrants who are at high risk for VDD should be educated, screened, and monitored for VDD. PMID- 26643748 TI - Effects of anemia at different stages of gestation on infant outcomes. AB - OBJECTIVES: Maternal anemia is a public health challenge worldwide. The present study aims to explore the effects of maternal anemia at different stages of gestation on postnatal growth and neurobehavioral development in infants. METHODS: A cohort of pregnant Indian women were followed from 13 to 22 wk gestation (i.e., second trimester; n = 211), 29 to 42 wk gestation (i.e., third trimester; n = 178); their infants were followed to ~3 wk (n = 147) postpartum. Data collected included information on sociodemographic and health-related factors, including anemia (i.e., low hemoglobin status), maternal and infant anthropometric data, and infant neurobehavioral data. A mixed logistic regression model was used to examine the impact of anemia during pregnancy on maternal and infant outcomes (i.e., anthropometric growth parameters and infant neurobehavioral development). RESULTS: The prevalence of maternal anemia was 41% and 55% (P < 0.001), and iron deficiency anemia was 3.6% and 5.6%, respectively, in the second trimester and third trimester. Infants of pregnant women who were not anemic in the second trimester were 0.26 standard deviations (SD) heavier (P = 0.029), 0.50 SD taller (P = 0.001), and had 0.26 SD larger head circumference (P = 0.029) compared with infants of anemic pregnant women. Infants of pregnant women who were not anemic in the third trimester had orientation scores 3.88 higher (P = 0.004) than infants of women who were anemic. CONCLUSIONS: Our findings indicate that maternal anemia in the second trimester of gestation influences postnatal infant growth and underscores the necessity of alleviating anemia in young women in the early stages of gestation. PMID- 26643749 TI - Perspectives on interventional diabetology: Duodenal exclusion is promising for human type 2 diabetes mellitus remission. PMID- 26643750 TI - Dietary carbohydrate restriction: Compelling theory for further research. PMID- 26643751 TI - Re. "Early oral refeeding based on hunger in moderate and severe acute pancreatitis: A prospective controlled, randomized clinical trial": Can we really do without enteral nutrition? PMID- 26643752 TI - Tolerability and Adherence Problems in Patients on a Stable Dose of Methotrexate: Results of a Multicentre Survey. AB - INTRODUCTION: Methotrexate is commonly used in patients with inflammatory arthritis. The aim of the present study was to ascertain the prevalence of side effects that patients on methotrexate were tolerating and to establish their adherence to the medication. METHOD: A questionnaire was developed for completion by the healthcare professional with the patient, and piloted in one centre. The questionnaire was then used in six other centres, with the addition of a question about the attractiveness of stopping methotrexate treatment. Efficacy and toxicities were scored for severity on a 10-cm visual analogue scale (VAS). Adherence to the drug was also explored. RESULTS: The prevalence of 'any side effect' ranged from 57% to 86%. The most frequent side effects were fatigue (53%); nausea (38%); mouth ulcers (23%) and hair loss (23%). Efficacy averaged 6.5 cm on the VAS. Results from the combined survey revealed that toxicity averaged 5.9 cm for fatigue, 4.8 cm for nausea, 4.4 for mouth ulcers, 3.9 cm for hair loss and 5.7 cm for 'other' side effects. 13.5% of patients revealed that they had forgotten to take the drug for an average of two weeks, and 25% for an average of 2.5 weeks in the previous year. Participants were more likely to reveal this to a nurse than a doctor. CONCLUSION: Patients put up with a considerable number of side effects in order to benefit from methotrexate therapy. Adherence to this drug merits further study. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26643753 TI - [Retinitis pigmentosa associated with coats-like fundus]. PMID- 26643754 TI - [Inflammatory orbitopathy secondary to schistosomiasis]. PMID- 26643755 TI - The biological effects upon the cardiovascular system consequent to exposure to particulates of less than 500 nm in size. AB - CONTEXT: Ultrafine particulate matter contribution to cardiovascular disease is not known and not regulated. PM up to 500 nm are abundant in urban air and alveolar deposition is significant. OBJECTIVE: Effects beyond the alveolar barrier within the body or in vitro tissues exposed to particles <500 nm. METHODS AND RESULTS: DATABASES: MEDLINE; Ovid-MEDLINE PREM; Web of Science; PubMed (SciGlobe). 127 articles. Results in tables: "subject type exposed", "exposure type", "technique". CONCLUSION: Heart rate, vasoactivity, atherosclerotic advancement, oxidative stress, coagulability, inflammatory changes are affected. Production of reactive oxygen species is a useful target to limit outcomes associated with UFP exposure. PMID- 26643756 TI - Third-Trimester Fetal Biometry and Neonatal Outcomes in Term and Preterm Deliveries. AB - OBJECTIVES: To determine whether specific biometric thresholds for head circumference, abdominal circumference, femur length, and estimated fetal weight can identify neonates at risk for adverse outcomes. METHODS: We conducted a retrospective analysis of women with sonographic biometry after 26 weeks' gestational age (GA) followed by delivery of term and preterm neonates from 2007 through 2011. The head circumference, abdominal circumference, femur length, and estimated fetal weight were obtained. Sonographic data were merged with birth certificate and neonatal data. Biometry and estimated fetal weight were divided into percentile thresholds: 10th and above (reference), below 10th, below 5th, and below 3rd. Neonatal outcomes included neonatal intensive care unit admission, 5-minute Apgar score less than 7, and a composite of any morbidity/mortality (hypoxic-ischemic encephalopathy, periventricular leukomalacia, necrotizing enterocolitis, sepsis, renal failure, or death). Logistic regression yielded odds ratios and 95% confidence intervals for biometry and outcome, then adjusted for GA at delivery. RESULTS: A total of 2237 patients delivered at term, and 455 delivered before term. Neonatal intensive care unit admission was not associated with any biometric threshold in the term and preterm groups. Five-minute Apgar score less than 7 was associated with head circumference below 10th, abdominal circumference below 3rd, and estimated fetal weight below 5th percentiles in the term group and head circumference below 10th, abdominal circumference below 10th, and femur length below 10th percentiles in the preterm group (P < .05). Composite morbidity/mortality was associated with abdominal circumference below 5th, femur length below 10th, and femur length below 3rd percentiles in the term group and head circumference below 5th, abdominal circumference below 10th, and femur length below 5th percentiles in the preterm group (P< .05). Adjustment for GA did not affect outcomes for term deliveries but did affect nearly all outcomes for preterm deliveries. CONCLUSIONS: Irrespective of GA, no one biometric threshold can accurately predict adverse neonatal outcomes. PMID- 26643757 TI - Customized Fetal Growth Charts for Parents' Characteristics, Race, and Parity by Quantile Regression Analysis: A Cross-sectional Multicenter Italian Study. AB - OBJECTIVES: The purpose of this study was to construct fetal biometric charts between 16 and 40 weeks' gestation that were customized for parental characteristics, race, and parity, using quantile regression analysis. METHODS: In a multicenter cross-sectional study, 8070 sonographic examinations from low risk pregnancies between 16 and 40 weeks' gestation were analyzed. The fetal measurements obtained were biparietal diameter, head circumference, abdominal circumference, and femur diaphysis length. Quantile regression was used to examine the impact of parental height and weight, parity, and race across biometric percentiles for the fetal measurements considered. RESULTS: Paternal and maternal height were significant covariates for all of the measurements considered (P < .05). Maternal weight significantly influenced head circumference, abdominal circumference, and femur diaphysis length. Parity was significantly associated with biparietal diameter and head circumference. Central African race was associated with head circumference and femur diaphysis length, whereas North African race was only associated with femur diaphysis length. CONCLUSIONS: In this study we constructed customized biometric growth charts using quantile regression in a large cohort of low-risk pregnancies. These charts offer the advantage of defining individualized normal ranges of fetal biometric parameters at each specific percentile corrected for parental height and weight, parity, and race. This study supports the importance of including these variables in routine sonographic screening for fetal growth abnormalities. PMID- 26643759 TI - Evaluating Spatiotemporal Image Correlation Technology as a Tool for Training Nonexpert Sonographers to Perform Examinations of the Fetal Heart. AB - OBJECTIVES: We aimed to evaluate the use of spatiotemporal image correlation (STIC) as a tool for training nonexpert examiners to perform screening examinations of the fetal heart by acquiring and examining STIC volumes according to a standardized questionnaire based on the 5 transverse planes of the fetal heart. METHODS: We conducted a prospective study at 2 tertiary care centers. Two sonographers without formal training in fetal echocardiography received theoretical instruction on the 5 fetal echocardiographic transverse planes, as well as STIC technology. Only women with conditions allowing 4-dimensional STIC volume acquisitions (grayscale and Doppler) were included in the study. Acquired volumes were evaluated offline according to a standardized protocol that required the trainee to mark 30 specified structures on 5 required axial planes. Volumes were then reviewed by an expert examiner for quality of acquisition and correct identification of specified structures. RESULTS: Ninety-six of 112 pregnant women examined entered the study. Patients had singleton pregnancies between 20 and 32 weeks' gestation. After an initial learning curve of 20 examinations, trainees succeeded in identifying 97% to 98% of structures, with a highly significant degree of agreement with the expert's analysis (P < .001). A median of 2 STIC volumes for each examination was necessary for maximal structure identification. Acquisition quality scores were high (8.6-8.7 of a maximal score of 10) and were found to correlate with identification rates (P = .017). CONCLUSIONS: After an initial learning curve and under expert guidance, STIC is an excellent tool for trainees to master extended screening examinations of the fetal heart. PMID- 26643758 TI - Mixture Models for Estimating Maximum Blood Flow Velocity. AB - OBJECTIVES: A gaussian mixture model (GMM) was recently developed for estimating the probability density function of blood flow velocity measured with transcranial Doppler ultrasound data. In turn, the quantiles of the probability density function allow one to construct estimators of the "maximum" blood flow velocity. However, GMMs assume gaussianity, a feature that is not omnipresent in observed data. The objective of this work was to develop mixture models that do not invoke the gaussian assumption. METHODS: Here, GMMs were extended to a skewed GMM and a nongaussian kernel mixture model. All models were developed on data from 59 patients with closed head injuries from multiple hospitals in the United States, with ages ranging from 13 to 81 years and Glasgow Coma Scale scores ranging from 3 to 11. The models were assessed in terms of the log likelihood (a goodness-of-fit measure) and via visual comparison with the underlying spectrograms. RESULTS: Among the models examined, the skewed GMM showed a significantly (P< .05) higher log likelihood for 56 of the 59 patients and produced maximum flow velocity estimates consistent with the observed spectrograms for all patients. Kernel mixture models are generally less "robust" in that their quality is inconsistent across patients. CONCLUSIONS: Among the models examined, it was found that the skewed GMM provided a better model of the data both in terms of the quality of the fit and in terms of visual comparison of the underlying spectrogram and the estimated maximum blood flow velocity. Nongaussian mixture models have potential for even higher-quality assessment of blood flow, but further development is called for. PMID- 26643760 TI - In silico allergenicity prediction of several lipid transfer proteins. AB - Non-specific lipid transfer proteins (nsLTPs) are common allergens and they are particularly widespread within the plant kingdom. They have a highly conserved three-dimensional structure that generate a strong cross-reactivity among the members of this family. In the last years several web tools for the prediction of allergenicity of new molecules based on their homology with known allergens have been released, and guidelines to assess potential allergenicity of proteins through bioinformatics have been established. Even if such tools are only partially reliable yet, they can provide important indications when other kinds of molecular characterization are lacking. The potential allergenicity of 28 amino acid sequences of LTPs homologs, either retrieved from the UniProt database or in silico deduced from the corresponding EST coding sequence, was predicted using 7 publicly available web tools. Moreover, their similarity degree to their closest known LTP allergens was calculated, in order to evaluate their potential cross-reactivity. Finally, all sequences were studied for their identity degree with the peach allergen Pru p 3, considering the regions involved in the formation of its known conformational IgE-binding epitope. Most of the analyzed sequences displayed a high probability to be allergenic according to all the software employed. The analyzed LTPs from bell pepper, cassava, mango, mungbean and soybean showed high homology (>70%) with some known allergenic LTPs, suggesting a potential risk of cross-reactivity for sensitized individuals. Other LTPs, like for example those from canola, cassava, mango, mungbean, papaya or persimmon, displayed a high degree of identity with Pru p 3 within the consensus sequence responsible for the formation, at three-dimensional level, of its major conformational epitope. Since recent studies highlighted how in patients mono sensitized to peach LTP the levels of IgE seem directly proportional to the chance of developing cross-reactivity to LTPs from non-Rosaceae foods, and these chances increase the more similar the protein is to Pru p 3, these proteins should be taken into special account for future studies aimed at evaluating the risk of cross-allergenicity in highly sensitized individuals. PMID- 26643761 TI - A novel multiplex isothermal amplification method for rapid detection and identification of viruses. AB - A rapid multiplex isothermal amplification assay has been developed for detection and identification of multiple blood-borne viruses that infect millions of people world-wide. These infections may lead to chronic diseases or death if not diagnosed and treated in a timely manner. Sets of virus-specific oligonucleotides and oligofluorophores were designed and used in a reverse-transcription loop mediated multiplexed isothermal amplification reaction for detection and gel electrophoretic identification of human Immunodeficiency virus (HIV), hepatitis-B virus (HBV), hepatitis-C virus (HCV), hepatitis-E virus (HEV), dengue virus (DENV), and West Nile (WNV) virus infection in blood plasma. Amplification was catalyzed with two thermostable enzymes for 30-60 minutes under isothermal condition, utilizing a simple digital heat source. Electrophoretic analysis of amplified products demonstrated simultaneous detection of 6 viruses that were distinctly identified by unique ladder-like banding patterns. Naked-eye fluorescent visualization of amplicons revealed intensely fluorescing products that indicated positive detection. The test demonstrated a 97% sensitivity and a 100% specificity, with no cross-reaction with other viruses observed. This portable detection tool may have clinical and field utility in the developing and developed world settings. This may enable rapid diagnosis and identification of viruses for targeted therapeutic intervention and prevention of disease transmission. PMID- 26643762 TI - Effects of muscle activation on shear between human soleus and gastrocnemius muscles. AB - Lateral connections between muscles provide pathways for myofascial force transmission. To elucidate whether these pathways have functional roles in vivo, we examined whether activation could alter the shear between the soleus (SOL) and lateral gastrocnemius (LG) muscles. We hypothesized that selective activation of LG would decrease the stretch-induced shear between LG and SOL. Eleven volunteers underwent a series of knee joint manipulations where plantar flexion force, LG, and SOL muscle fascicle lengths and relative displacement of aponeuroses between the muscles were obtained. Data during a passive full range of motion were recorded, followed by 20 degrees knee extension stretches in both passive conditions and with selective electrical stimulation of LG. During active stretch, plantar flexion force was 22% greater (P < 0.05) and relative displacement of aponeuroses was smaller than during passive stretch (P < 0.05). Soleus fascicle length changes did not differ between passive and active stretches but LG fascicles stretched less in the active than passive condition when the stretch began at angles of 70 degrees and 90 degrees of knee flexion (P < 0.05). The activity-induced decrease in the relative displacement of SOL and LG suggests stronger (stiffer) connectivity between the two muscles, at least at flexed knee joint angles, which may serve to facilitate myofascial force transmission. PMID- 26643763 TI - Genotoxic and mutagenic effects of sewage sludge on higher plants. AB - Sewage treatment yields sludge, which is often used as a soil amendment in agriculture and crop production. Although the sludge contains elevated concentrations of macro and micronutrients, high levels of inorganic and organic compounds with genotoxic and mutagenic properties are present in sludge. Application of sludge in agriculture is a pathway for direct contact of crops to toxic chemicals. The objective of this study was to compile information related to the genotoxic and mutagenic effects of sewage sludge in different plant species. In addition, data are presented on toxicological effects in animals fed with plants grown in soils supplemented with sewage sludge. Despite the benefits of using sewage sludge as organic fertilizer, the data showcased in this review suggest that this residue can induce genetic damage in plants. This review alerts potential risks to health outcomes after the intake of food cultivated in sewage sludge-amended soils. PMID- 26643764 TI - Quantitative trait loci mapping for Gibberella ear rot resistance and associated agronomic traits using genotyping-by-sequencing in maize. AB - KEY MESSAGE: Unique and co-localized chromosomal regions affecting Gibberella ear rot disease resistance and correlated agronomic traits were identified in maize. Dissecting the mechanisms underlying resistance to Gibberella ear rot (GER) disease in maize provides insight towards more informed breeding. To this goal, we evaluated 410 recombinant inbred lines (RIL) for GER resistance over three testing years using silk channel and kernel inoculation techniques. RILs were also evaluated for agronomic traits like days to silking, husk cover, and kernel drydown rate. The RILs showed significant genotypic differences for all traits with above average to high heritability estimates. Significant (P < 0.01) but weak genotypic correlations were observed between disease severity and agronomic traits, indicating the involvement of agronomic traits in disease resistance. Common QTLs were detected for GER resistance and kernel drydown rate, suggesting the existence of pleiotropic genes that could be exploited to improve both traits at the same time. The QTLs identified for silk and kernel resistance shared some common regions on chromosomes 1, 2, and 8 and also had some regions specific to each tissue on chromosomes 9 and 10. Thus, effective GER resistance breeding could be achieved by considering screening methods that allow exploitation of tissue-specific disease resistance mechanisms and include kernel drydown rate either in an index or as indirect selection criterion. PMID- 26643765 TI - Rapid 3D Patterning of Poly(acrylic acid) Ionic Hydrogel for Miniature pH Sensors. AB - Poly(acrylic acid) (PAA), as a highly ionic conductive hydrogel, can reversibly swell/deswell according to the surrounding pH conditions. An optical maskless stereolithography technology is presented to rapidly 3D pattern PAA for device fabrication. A highly sensitive miniature pH sensor is demonstrated by in situ printing of periodic PAA micropads on a tapered optical microfiber. PMID- 26643767 TI - [An experience of hepatitis B control in a rural area in Far North Cameroon]. AB - Experience of four years of control of the transmission of hepatitis B in a rural area in Far North Cameroon is presented: (i) prevention of mother to child transmission, (ii) HBsAg screening before blood transfusion, (iii) detection of HIV/HBV co-infections, (iv) protection of healthcare workers. The prevalence of HBsAg is very high in the four populations studied: 18.2% of pregnant women, 16.9% of candidate for blood donation, 14.4% of people living with HIV and 18 % of healthcare workers. Despite limited resources, effective actions are possible. Prevention of mother to child transmission of HBV with vaccination at birth has been set up, with bottlenecks - similar to those observed in HIV - but decreasing over the study. The screening of all potential blood donors has been reached over the years for HIV, HBsAg and HCV, which has led to the eviction of one out of five potential blood donors. Screening of healthcare workers reminded us that adult protection is based on a very early vaccination and not when hiring, even if it is possible to diagnose rare adults eligible for vaccination by research of anti-HBc antibody. A program of hepatitis B control, essential in Africa, appears feasible in rural areas in a framework of an overall improvement in care delivery. PMID- 26643766 TI - Practical Strategies for Integrating Interprofessional Education and Collaboration into the Curriculum. AB - Interprofessional collaboration is vital for the provision of quality patient care. Thoughtfully designed educational programs can help students of health professions develop interprofessional competencies and capacities, including values and ethics, roles and responsibilities, interprofessional communication, and teamwork (Interprofessional Education Collaborative Expert Panel, 2011). The authors were involved in developing Interprofessional Education (IPE) activities and simulations to be infused into the curriculums of the various health professions programs in their College. A review of the IPE experiences revealed students greatly benefited from involvement in a diverse set of IPE activities and simulations. PMID- 26643768 TI - Adaptation of the New Sexual Satisfaction Scale-Short Form Into Spanish. AB - Measuring and understanding sexual satisfaction is a key element in the evaluation of sexual health and the human sexual response. This study sought to adapt and validate the New Sexual Satisfaction Scale-Short Form from English into the Spanish language. A four-sample (two community samples, one LGB sample, and one university sample) study of 1,200 participants was completed in Spain between 2012-2014. Exploratory and confirmatory factor analyses demonstrated that the adapted version satisfactorily meets validation requirements. In posterior analyses, relationship stability and sexual orientation were factors that increased sexual satisfaction. Self-identified lesbian participants were more sexually satisfied than their heterosexual counterparts. Stable relationships appeared to be a factor for increased sexual satisfaction while age was not. Age and sexual identity/gender did not influence sexual satisfaction. PMID- 26643769 TI - Use of Atrial Septostomy to Treat Severe Pulmonary Arterial Hypertension in Adults. PMID- 26643770 TI - Infective Endocarditis: Cause or Consequence of Delayed Anterior Mitral Leaflet Perforation After Transcatheter Aortic Valve Implantation? PMID- 26643772 TI - Performance of the new American College of Rheumatology classification criteria in Turkish systemic sclerosis patients: a multicenter study. AB - In our study, we compared the sensitivity and specificity of the new ACR/EULAR 2013 criteria to the ACR 1980 criteria in our systemic sclerosis (SSc) population. Three rheumatology centers from Turkey participated into this study. The medical records of SSc patients diagnosed between 2008 and 2014 were retrospectively reviewed, and their features at disease onset were recorded. Patients admitted to each center within the same time period for conditions other than SSc, in whom ANA was positive and was deemed necessary within the diagnostic workup, were included as controls. One hundred and ninety-seven SSc patients (174 females, 23 males) and 103 controls (96 females, 7 males) were included. Limited cutaneous SSc was present in 68 % of patients, and 30.5 % had diffuse SSc. The sensitivity of ACR/EULAR 2013 and ACR 1980 criteria were, respectively, 94.4 and 85.3 % (p = 0.003). The specificity of ACR/EULAR 2013 and ACR 1980 criteria were, respectively, 98.1 and 100 %. According to the new criteria, 13 patients were misclassified; however, according to the ACR 1980 criteria, 29 patients were misclassified (p = 0.005). The sensitivity of ACR/EULAR 2013 criteria was significantly better than that of the ACR 1980 criteria in limited cutaneous SSc group (94.8 vs. 82.8 %). In patients whose disease duration was <3 years, the new criteria had better sensitivity than the previous criteria (92.7 vs. 78.1 %, p = 0.006). The new ACR/EULAR 2013 criteria for SSc had better sensitivity in Turkish SSc patients, and less patients were misclassified. PMID- 26643771 TI - Differences in Frame Geometry Between Balloon-expandable and Self-expanding Transcatheter Heart Valves and Association With Aortic Regurgitation. AB - INTRODUCTION AND OBJECTIVES: Patient- and procedure-related factors are known to be associated with aortic regurgitation after transcatheter aortic valve implantation. Nevertheless, this entity may also be caused by a specific device host interaction due to the biomechanical properties of the valves, independently of clinical factors. We sought to elucidate the role of frame geometry in the occurrence of aortic regurgitation after Medtronic CoreValve and Edwards SAPIEN valve implantation. METHODS: We conducted an observational study encompassing 134 patients undergoing transcatheter aortic valve implantation with the Medtronic CoreValve and Edwards SAPIEN valve. Frame analysis was performed at 3 predefined levels of both valves by rotational angiography using dedicated motion compensation software. A distinction was made between patients with no-to-mild and moderate-to-severe aortic regurgitation by echocardiography. RESULTS: Baseline characteristics were similar between the 2 valves. Despite greater use of predilation in the CoreValve (95.2% vs 82.0%; P=.012), more oversizing (perimeter, 114+/-7% vs 103+/-7%; P<.001), and the same depth of implantation (noncoronary sinus, 7+/-4 vs 8+/-2mm; left coronary sinus, 8+/-4 vs 8+/-2mm), it was less expanded and more eccentric than the Edwards SAPIEN (83+/-7% vs 92+/-4%; P<.001 and 82+/-8% vs 95+/-3%; P<.001, respectively) and when eccentricity was adjusted for the patient's annulus eccentricity (4+/-13% vs 21+/-11%; P<.001). Eccentricity and adjusted eccentricity were associated with moderate-to-severe aortic regurgitation. CONCLUSIONS: Independently of patient- and procedure related factors, there is a device-specific device-host interaction that explains aortic regurgitation after transcatheter aortic valve implantation. PMID- 26643774 TI - Zero Feet Away: The Digital Geography of Gay Social Media. AB - For this contribution to the "Cartographies" section of the special issue on "Mapping Queer Bioethics," the author focuses on the terrains of digital media, geosocial networking, and sexually based social media in LGBT communities. Addressing the communal potentials and ethical complications of geosocial connections made possible by such sexually based social media, the author asks whether digital forms of cartography via applications such as Grindr and Scruff simplify, complicate, or merely expose historically longstanding notions of queer interconnectivity. PMID- 26643773 TI - Determinants of Breastfeeding Practices and Success in a Multi-Ethnic Asian Population. AB - BACKGROUND: Many countries in Asia report low breastfeeding rates and the risk factors for early weaning are not well studied. We assessed the prevalence, duration, and mode of breastfeeding (direct or expressed) among mothers of three Asian ethnic groups. METHODS: Participants were 1,030 Singaporean women recruited during early pregnancy. Data collected included early breastfeeding experiences, breastfeeding duration, and mode of breastfeeding. Full breastfeeding was defined as the intake of breast milk, with or without water. Cox regression models were used to identify factors associated with discontinuation of any and full breastfeeding. Logistic regression analyses assessed the association of ethnicity with mode of breastfeeding. RESULTS: At 6 months postpartum, the prevalence of any breastfeeding was 46 percent for Chinese mothers, 22 percent for Malay mothers, and 41 percent for Indian mothers; prevalence of full breastfeeding was 11, 2, and 5 percent, respectively. More Chinese mothers fed their infants expressed breast milk, instead of directly breastfeeding them, compared with the other two ethnic groups. Duration of any and full breastfeeding were positively associated with breastfeeding a few hours after birth, higher maternal age and education, and negatively associated with irregular breastfeeding frequency and being shown how to breastfeed. Adjusting for maternal education, breastfeeding duration was similar in the three ethnic groups, but ethnicity remained a significant predictor of mode of breastfeeding. CONCLUSIONS: The low rates and duration of breastfeeding in this population may be improved with breastfeeding education and support, especially in mothers with lower education. Further work is needed to understand the cultural differences in mode of feeding and its implications for maternal and infant health. PMID- 26643775 TI - Deinococcus actinosclerus sp. nov., a novel bacterium isolated from soil of a rocky hillside. AB - Three Gram-stain-positive, catalase- and oxidase-positive coccus- or rod-shaped bacterial strains, designated BM2T, BM4 and BM5, were isolated from soil in South Korea. They showed strong resistance to gamma radiation with a D10 value of 9 kGy but weak UVC resistance. The 16S rRNA sequences of strains BM2T, BM4 and BM5 represent a novel subline within the genus Deinococcus in the family Deinococcaceae. The 16S rRNA gene sequences of strains BM2T, BM4 and BM5 were indistinguishable and showed 98.1-87.3 % similarity with other species of the genus Deinococcus. Strain BM2T exhibited relatively high levels of DNA-DNA hybridization with BM4 (87 +/- 0.8 %) and BM5 (92 +/- 1.2 %). Meanwhile, it showed a low level of DNA-DNA hybridization ( < 30 %) with other closely related species of the genus Deinococcus. The strains showed the typical chemotaxonomic characteristics of the genus Deinococcus, with the presence of menaquinone 8 as the respiratory quinone; the major fatty acids were summed feature 3 (composed of C16 : 1omega7c/C16 : 1omega6c), C15 : 1omega6c and C16 : 0. The DNA G+C content of strain BM2T was 69.7 mol%. The polar lipid profile included major amounts of phosphatidylglycerol, phosphatidylcholine and an unknown aminolipid. On the basis of phenotypic and genotypic properties, and phylogenetic distinctiveness, strains BM2T, BM4 and BM5 should be classified in a novel species in the genus Deinococcus, for which the name Deinococcus actinosclerus sp. nov. is proposed. The type strain is BM2T ( = KEMB 5401-184T = JCM 30700T); reference strains are BM4 ( = JCM 30701) and BM5 ( = JCM 30702). PMID- 26643776 TI - A review of the impact of oxidative stress and some antioxidant therapies on renal damage. AB - An increase in the generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) leads to complications during chronic kidney disease (CKD). This increase essentially derives from the impairment of natural antioxidant systems of the organism. The resulting oxidative stress produces damage to kidney tissue, especially by affecting nephrons and more generally by disrupting the function and structure of the glomerulus and interstitial tubule. This leads to a rapid decline in the condition of the patient and finally renal failure. Possible causes of kidney tissue damage are explored, as are different therapies, especially those related to the administration of antioxidants. PMID- 26643777 TI - Bolometric-Effect-Based Wavelength-Selective Photodetectors Using Sorted Single Chirality Carbon Nanotubes. AB - This paper exploits the chirality-dependent optical properties of single-wall carbon nanotubes for applications in wavelength-selective photodetectors. We demonstrate that thin-film transistors made with networks of carbon nanotubes work effectively as light sensors under laser illumination. Such photoresponse was attributed to photothermal effect instead of photogenerated carriers and the conclusion is further supported by temperature measurements. Additionally, by using different types of carbon nanotubes, including a single chirality (9,8) nanotube, the devices exhibit wavelength-selective response, which coincides well with the absorption spectra of the corresponding carbon nanotubes. This is one of the first reports of controllable and wavelength-selective bolometric photoresponse in macroscale assemblies of chirality-sorted carbon nanotubes. The results presented here provide a viable route for achieving bolometric-effect based photodetectors with programmable response spanning from visible to near infrared by using carbon nanotubes with pre-selected chiralities. PMID- 26643779 TI - Arterial stiffness, atherosclerosis and cardiovascular risk: Pathophysiologic mechanisms and emerging clinical indications. AB - Arterial stiffness results from a degenerative process affecting mainly the extracellular matrix of elastic arteries under the effect of aging and risk factors. Changes in extracellular matrix proteins and in the mechanical properties of the vessel wall related to arterial stiffening may activate number of mechanisms involved also in the process of atherosclerosis. Several noninvasive methods are now available to estimate large artery stiffness in the clinical setting, including carotid-femoral pulse wave velocity, the reference for aortic stiffness estimate, and local distensibility measures of superficial arteries, namely carotid and femoral. An independent predictive value of arterial stiffness for cardiovascular events has been demonstrated in general as well as in selected populations, and reference values adjusted for age and blood pressure have been established. Thus, arterial stiffness is emerging as an interesting tissue biomarker for cardiovascular risk stratification and estimation of the individual "biological age". This paper overviews the mechanisms accounting for development and progression of arterial stiffness and for associations between arterial stiffness, atherosclerotic burden and incident cardiovascular events, summarizes the evidence and caveat for clinical use of stiffness as surrogate marker of cardiovascular risk, and briefly outlines some emerging methods for large artery stiffness characterization. PMID- 26643778 TI - Induction of autophagy improves embryo viability in cloned mouse embryos. AB - Autophagy is an essential cellular mechanism that degrades cytoplasmic proteins and organelles to recycle their components. Moreover, autophagy is essential for preimplantation development in mammals. Here we show that autophagy is also important for reprogramming in somatic cell nuclear transfer (SCNT). Our data indicate that unlike fertilized oocytes, autophagy is not triggered in SCNT embryos during 6 hours of activation. Mechanistically, the inhibited autophagic induction during SCNT activation is due to the cytochalasin B (CB) caused depolymerization of actin filaments. In this study, we induced autophagy during SCNT activation by rapamycin and pp242, which could restore the expected level of autophagy and significantly enhance the development of SCNT embryos to the blastocyst stage when compared with the control (68.5% and 68.7% vs. 41.5%, P < 0.05). Furthermore, the treatment of rapamycin and pp242 accelerates active DNA demethylation indicated by the conversion of 5 mC to 5 hmC, and treatment of rapamycin improves degradation of maternal mRNA as well. Thus, our findings reveal that autophagy is important for development of SCNT embryos and inhibited autophagic induction during SCNT activation might be one of the serious causes of low efficiency of SCNT. PMID- 26643780 TI - The vasorelaxant effect of gallic acid involves endothelium-dependent and independent mechanisms. AB - The mechanisms of action involved in the vasorelaxant effect of gallic acid (GA) were examined in the isolated rat thoracic aorta. GA exerted a relaxant effect in the highest concentrations (0.4-10mM) in both endothelium-intact and endothelium denuded aortic rings. Pre-incubation with L-NAME, ODQ, calmidazolium, TEA, 4 aminopyridine, and barium chloride significantly reduced the pEC50 values. Moreover, this effect was not modified by indomethacin, wortmannin, PP2, glibenclamide, or paxillin. Pre-incubation of GA (1, 3, and 10mM) in a Ca(2+) free Krebs solution attenuated CaCl2-induced contractions and blocked BAY K8644 induced vascular contractions, but it did not inhibit a contraction induced by the release of Ca(2+) from the sarcoplasmatic reticulum stores. In addition, a Western blot analysis showed that GA induces phosphorylation of eNOS in rat thoracic aorta. These results suggest that GA induces relaxation in rat aortic rings through an endothelium-dependent pathway, resulting in eNOS phosphorylation and opening potassium channels. Additionally, the relaxant effect by an endothelium-independent pathway involves the blockade of the Ca(2+) influx via L type Ca(2+) channels. PMID- 26643781 TI - Riboflavin-ultraviolet light pathogen reduction treatment does not impact the immunogenicity of murine red blood cells. AB - BACKGROUND: Ultraviolet (UV) illumination/pathogen reduction effectively inactivates white blood cells (WBCs) in whole blood. Given that cotransfused WBCs may impact recipient immune responses, we hypothesized that pathogen reduction of whole blood may alter responses to RBC antigens. STUDY DESIGN AND METHODS: Transgenic mice expressing a model (HOD) antigen, authentic human (hGPA or KEL) antigens, or natural fluorescence (uGFP) on their RBCs were utilized as blood donors. Recipients were transfused with fresh whole blood to which riboflavin had been added or fresh whole blood treated by UV illumination/pathogen reduction treatment after the addition of riboflavin. Posttransfusion RBC recovery, survival, and alloimmunization were measured by flow cytometry. RESULTS: UV illumination/pathogen reduction treatment did not alter RBC antigen expression, and recipients of treated syngeneic RBCs had persistently negative direct antiglobulin tests. Greater than 75% of treated and untreated syngeneic RBCs were recovered 24 hours posttransfusion in all experiments, although alterations in the long-term posttransfusion survival of treated RBCs were observed. Treated and untreated KEL RBCs induced similar recipient alloimmune responses, with all recipients making anti-KEL glycoprotein immunoglobulins (p > 0.05). Alloimmune responses to treated HOD or hGPA RBCs were no different from untreated RBCs (p > 0.05). CONCLUSION: Pathogen inactivation treatment of fresh whole murine blood with riboflavin and UV illumination does not impact the rate or magnitude of RBC alloimmunization to three distinct RBC antigens. Further, UV illumination/pathogen reduction appears safe from an immunohematologic standpoint, with no immunogenic neoantigens detected on treated murine RBCs. Future studies with fresh and stored human RBCs are warranted to confirm these findings. PMID- 26643782 TI - Homocysteine-lowering therapy and early functional outcomes of ischemic patients with H-type hypertension: a retrospective analysis of CNSR. AB - Recently, elevated levels of homocysteine and early neurological deterioration due to acute ischemic stroke have been reported to be strongly correlated. However, the role of homocysteine-lowering therapy (HLT) in the prognosis of acute ischemic stroke patients has remained unclear. This study evaluated the effects of HLT during hospitalization on the early outcomes of the 792 ischemic stroke patients with H-type hypertension from the China National Stroke Registry. The subjects were divided into HLT and non-HLT groups. Demographic and laboratory information were collected, while the functional outcome at discharge and at 90 days follow-up were assessed by National Institutes of Health Stroke Scale and modified Rankin Scale (mRS) in both groups. We found that in the univariate analysis, the proportions of patients with good functional outcomes (mRS = 0-2) were 31.68 versus 29.36 % (OR 0.90, 95 % CI 0.66-1.22, p = 0.45) at discharge and 27.02 versus 28.30 % (OR 1.06, 95 % CI 0.77-1.45, p = 0.72) at 90 days follow-up for the HLT and non-HLT groups, respectively. After multivariate analysis, there was still no significant difference in the outcomes at discharge (OR 0.85, 95 % CI 0.53-1.36, p = 0.49) or at 90 days follow-up (OR 0.98, 95 % CI 0.60-1.60, p = 0.93) for the two groups. The findings of this study indicated that patients with HLT or not during hospitalization had no significant difference in early prognosis. We concluded that HLT during hospitalization did not improve the early functional outcomes of ischemic stroke patients who also had H-type hypertension. PMID- 26643784 TI - Time for Glucagon like peptide-1 receptor agonists treatment for patients with NAFLD? PMID- 26643783 TI - Primary prevention of atrial fibrillation with beta-blockers in patients with end stage renal disease undergoing dialysis. AB - Current evidence suggests that beta-blocker lower the risk of development of atrial fibrillation (AF) and in-hospital stroke after cardiac surgery. This study was to assess whether beta-blockers could decrease incidence of new-onset AF in patients with end stage renal disease (ESRD). We identified patients from a nation-wide database called Registry for Catastrophic Illness, which encompassed almost 100% of the patients receiving dialysis therapy in Taiwan from 1995 to 2008. Propensity score matching and Cox's proportional hazards regression model were used to estimate hazard ratios (HRs) for new-onset AF. Among 100066 patients, 41.7% received beta-blockers. After a median follow-up of 1500 days, the incidence of new-onset AF significantly decreased in patients treated with beta-blockers (HR = 0.483, 95% confidence interval = 0.437-0.534). The prevention of new-onset AF was significantly better in patients taking longer duration of beta-blockers therapy (P for time trend <0.001). The AF prevention effect remains robust in subgroup analyses. In conclusion, beta-blockers seem effective in the primary prevention of AF in ESRD patients. Hence, beta-blockers may be the target about upstream treatment of AF. PMID- 26643785 TI - Low-Density Lipoprotein Sensor Based on Molecularly Imprinted Polymer. AB - Increased level of low-density lipoprotein (LDL) strongly correlates with incidence of coronary heart disease. We synthesized novel molecularly imprinted polymers (MIP) as biomimetic specific receptors to establish rapid analysis of LDL levels. For that purpose the ratios of monomers acrylic acid (AA), methacrylic acid (MAA), and N-vinylpyrrolidone (VP), respectively, were screened on 10 MHz dual-electrode quartz crystal microbalances (QCM). Mixing MAA and VP in the ratio 3:2 (m/m) revealed linear sensor characteristic to LDL cholesterol (LDL C) from 4 to 400 mg/dL or 0.10-10.34 mmol/L in 100 mM phosphate-buffered saline (PBS) without significant interference: high-density lipoprotein (HDL) yields 4 6% of the LDL signal, very-low-density-lipoprotein (VLDL) yields 1-3%, and human serum albumin (HSA) yields 0-2%. The LDL-MIP sensor reveals analytical accuracy of 95-96% at the 95% confidence interval with precision at 6-15%, respectively. Human serum diluted 1:2 with PBS buffer was analyzed by LDL-MIP sensors to demonstrate applicability to real-life samples. The sensor responses are excellently correlated to the results of the standard technique, namely, a homogeneous enzymatic assay (R(2) = 0.97). This demonstrates that the system can be successfully applied to human serum samples for determining LDL concentrations. PMID- 26643786 TI - A double-blind randomized controlled trial to assess the efficacy of daylight photodynamic therapy with methyl-aminolevulinate vs. Placebo and daylight in patients with facial photodamage. AB - BACKGROUND: Daylight PDT (dPDT) is easy to use and does not require light equipment. Such therapy has been exhaustively proved to be successful in the treatment of actinic keratosis, but its use in skin photodamage remains unclear. OBJECTIVE: To evaluate dPDT's efficacy in skin facial photodamage. PATIENTS AND METHODS: This was a parallel-group double-blind, randomized placebo-controlled trial. Sixty participants with symmetric facial photodamage were allocated to topical methyl aminolevulinate (MAL) and daylight vs. matching placebo and daylight. Primary outcome was global photodamage improvement/failure 1 month after the third session. Secondary outcomes included: pain evaluation; specific photodamage severity scores; sun irradiance quantification and Skindex-29 scores. Adverse events were also investigated. RESULTS: Primary analysis included all randomized patients. All patients sun-exposed for 120min in 3 sessions. The risk of failure was lower in the MAL-dPDT group than in the placebo plus daylight group (RR: 0.18; 95% CI: 0.08-0.41). Mean solar irradiance (W/m(2)) during the first, second and third sessions was 480.82, 430.07 and 435.84, respectively. Items 5 and 14 of Skindex-29 in the MAL-dPDT group showed statistical significant differences. Two patients in the MAL-dPDT group had serious and non-serious events not directly related to the product. CONCLUSION: dPDT with MAL was un painful, effective and safe for the treatment of facial photodamage. Herpes simplex prophylaxis should be considered before sessions. PMID- 26643787 TI - Reduced-dose ICE chemotherapy +/- rituximab is a safe and effective salvage therapy for fit elderly patients with diffuse large B-cell lymphoma. AB - The risk of developing non-Hodgkin lymphoma increases with age, yet elderly patients are under-represented in clinical trials. Here, we evaluate a combination regimen including ifosfamide, carboplatin and etoposide with or without rituximab (ICE +/- R) in 32 fit elderly patients (median age 75.6 years) with relapsed or refractory diffuse large B-cell lymphoma. ICE +/- R was generally administered in reduced doses and was well tolerated. The overall response rate (ORR) was 53.1% with a complete response (CR) rate of 40.6%. The median progression free survival (PFS) and overall survival (OS) were 3.9 and 17.0 months, respectively. Patients who responded to ICE +/- R achieved median PFS of 47.2 months and OS of 78.9 months. Patients ineligible for autologous transplantation who responded to ICE +/- R were treated with additional cycles, and achieved a median PFS of 18.9 months and OS of 21.7 months. Previous response to first-line therapy was the strongest predictor of response, PFS and OS to second-line treatment. PMID- 26643788 TI - Curcumin inhibits B[a]PDE-induced procarcinogenic signals in lung cancer cells, and curbs B[a]P-induced mutagenesis and lung carcinogenesis. AB - Benzo[a]pyrene is a procarcinogen present in environment and cigarette smoke, which could be bio-transformed in vivo to B[a]PDE, a potent carcinogen known to form DNA adducts and induce mutations. We observed that curcumin, a known chemopreventive, could significantly inhibit the survival of lung cancer cells exposed to B[a]PDE. It also downregulates B[a]PDE-induced nuclear translocation of NF-kappaB as assessed by Electrophoretic Mobility Shift Assay (EMSA) and NF kappaB-dependent reporter gene assay. Ames assay demonstrated its ability to revert the mutagenic property of benzo[a]pyrene. These observations prompted us to evaluate the efficacy of curcumin in preventing B[a]P-induced lung carcinogenesis in vivo and to explore the molecular mechanism associated with it. The average number of tumor nodules present in the lungs of the Swiss albino mice, which received benzo[a]pyrene, was significantly high compared to that received curcumin as 2% diet along with B[a]P. Curcumin treatment significantly reverted histopathological deviations in the lung tissues due to benzo[a]pyrene ingestion. Moreover, curcumin diet reduced benzo[a]pyrene-induced activation of NF-kappaB and MAPK signaling and Cox-2 transcription in lung tissues of mice. Taken together, this study illustrates multifaceted efficacy of curcumin in preventing lung cancer. PMID- 26643789 TI - The complete mitochondrial genome of the Indian honey bee, Apis cerena cerana (Hymenoptera: Apidae: Apinae). AB - The complete mitogenome of Apis cerana cerana (Hymenoptera: Apidae: Apinae) was sequenced using Illumina NextSeq500 platform and found to be 15 831 bp long. The mitogenome contains 37 genes (13 PCGs, 22 tRNAs, and 2 rRNAs) and a control region. The base composition is biased towards A-T (83.9%). The control region is 498 bp long with polyT stretch and poly [TA (A)]n-like stretch. The phylogenetic tree constructed using concatenated PCGs showed that A. cerana cerana clustered with other cavity nesting Apis species. PMID- 26643790 TI - Readmission characteristics of elective pediatric circumcisions using large-scale administrative data. AB - INTRODUCTION AND BACKGROUND: Elective circumcision is a common procedure, known to be safe and associated with minimal morbidity. There are few data reporting the rates of readmission and reoperation following elective circumcision. OBJECTIVE: We sought to define the rates of readmission and reoperation in the first 7 days following circumcision to accurately counsel families about the risks of this elective procedure. STUDY DESIGN: The Pediatric Health Information System (PHIS) was interrogated from 2004 to 2013 for all ambulatory, elective circumcisions (ICD-9 CM code of 640). We assessed readmission with respect to age, insurance status, race, readmission diagnosis, time to readmission, and seasonal differences (due to higher rates of all-cause hospital admissions). We performed logistical regression analysis with a dependent variable of readmission within 7 days and independent variables of age, race, month of admission, and insurance status. RESULTS: We identified 95,046 circumcisions from 2004 to 2013 performed in ambulatory surgery centers. Of those, 2906 (3.1%) of patients had an additional encounter at the same facility within 7 days. A total of 2409 (2.4%) of encounters were ER visits, and 253 (0.3%) were encounters for hospital admission or observation. One hundred and thirty-two patients (0.1%) underwent a second ambulatory procedure within the first 7 days following circumcision. Black patients (OR 1.26, p < 0.001) and patients on Medicaid (OR 1.63, p < 0.001) were more likely to seek care of any kind at the same institution within 7 days of the original circumcision operation. No difference was found with regard to time of year on logistic regression. Older age at circumcision was associated with increased likelihood of reoperation compared to children <1 year, with children 12-18 years old having an OR of 1.91 (p = 0.033). DISCUSSION: We present a descriptive study of clinical events occurring at the same tertiary children's hospital within the first 7 days following more than 95,000 elective postneonatal circumcisions. Limitations include a cohort generated from a single set of ICD-9 codes, and a follow-up of 7 days. CONCLUSION: Elective circumcision remains a safe procedure with a readmission rate of 0.3%, and a reoperative rate of 0.1%. However, a relatively high percentage of patients (3.1%) will have a secondary encounter within the first 7 days following circumcision, most of them seeking care in an ER, although not necessarily for circumcision-related reasons. These may be useful data when counseling patients. PMID- 26643792 TI - TLR9 polymorphisms and systemic lupus erythematosus risk: an update meta-analysis study. AB - It has been reported that the Toll-like receptor 9 (TLR9) gene polymorphisms may be associated with systemic lupus erythematosus (SLE) risk. However, some studies yielded conflicting results. Therefore, a comprehensive meta-analysis was performed to assess the precise association between TLR9 polymorphisms and SLE susceptibility. We performed a systematic search in PubMed, Embase (Ovid), China National Knowledge Internet, and Wanfang databases up to July 15, 2015. Odds ratio (OR) and 95 % confidence interval (CI) were used to pool the effect size. Statistical analyses were performed with STATA 11.0 software. In total, 21 studies from nineteen articles with 10,273 subjects were included in this meta analysis. The overall results suggested that there was a statistically significant association between TLR9 rs187084 polymorphism and SLE risk observed in recessive model (TT vs. TC + CC: OR 1.17, 95 % CI 1.05-1.30, P = 0.005), codominant model (TT vs. CC: OR 1.22, 95 % CI 1.03-1.43, P = 0.019), and allele model (T vs. C: OR 1.15, 95 % CI 1.02-1.30, P = 0.020) in Asians. However, we found that there may be no significant association between the other three TLR9 polymorphisms and SLE risk in either Asians or non-Asians. In conclusion, the meta-analysis results suggested that TLR9 rs187084 polymorphism may increase the risk of SLE in Asians. However, no significant association between TLR9 SNPs (rs352139, rs352140, and rs5743836) and SLE risk was identified. PMID- 26643793 TI - Favorable effect of rehabilitation on balance in ankylosing spondylitis: a quasi randomized controlled clinical trial. AB - Balance impairment is a frequent and undertreated manifestation in ankylosing spondylitis, leading to increased risk of falls and lower quality of life. Our aim was to assess supervised training and home-based rehabilitation efficacy on balance improvement in ankylosing spondylitis subjects on biologic agents. This was a single-blinded, quasi-randomized parallel study in a single outpatient Rehabilitation Clinic of a tertiary referral center. Subjects with ankylosing spondylitis on biologic agents were assigned either to supervised training and home-based rehabilitation program (rehabilitation group) plus educational behavioral therapy, or to educational-behavioral therapy alone (educational groups). The same therapist provided therapy. Outcome measures were assessed at baseline (T0), end of treatment (T1) and at 7-month follow-up (T2). Rheumatologic outcomes were Bath Ankylosing Spondylitis Metrology Index, Bath Ankylosing Spondylitis Functional Index and Bath Ankylosing Spondylitis Disease Activity Index. Balance parameters (anterior-posterior oscillation, latero-lateral oscillation, sway area, sway density and sway path) were evaluated by stabilometry in a condition of open and closed eyes. Forty-six subjects (36 M, 10 F) were enrolled. Demographic data and clinical status at baseline were comparable between the two groups (22 rehabilitation group, 20 educational group). Primary outcome was sway density that improved both at T1 (SDy: open eyes p = 0.003, closed eyes p = 0.004) and at T2 (SDx: open eyes p = 0.0015, closed eyes p = 0.032). A trend toward improvement in the rehabilitation group rather than in the educational group emerged for balance parameters, especially those measured with closed eyes (0.004 < p < 0.048 at T1 and 0.004 < p < 0.036 at T2). Supervised training and home exercise lead to balance improvement in people with ankylosing spondylitis. Eyes-closed trials show a more marked trend toward improvement, and this may suggest a positive effect of rehabilitation on proprioception. PMID- 26643794 TI - An investigation on the simultaneously recorded occlusion contact and surface electromyographic activity for patients with unilateral temporomandibular disorders pain. AB - The present study examined if unilateral pain from temporomandibular disorders (TMD) was associated with the occlusion contacts and surface electromyographic (SEMG) activities of jaw-closing muscles. Eleven patients with unilateral TMD pain and 20 healthy volunteers who all had Angle's Class-I occlusions were enrolled. The numbers and load distributions of the occlusion contacts and the SEMG activities of the anterior temporalis (TA) muscles and masseters muscles (MM) during maximal voluntary clenching (MVC) in the centric and eccentric positions were simultaneously recorded on both sides. The pain was not associated with occlusal contact numbers or load distributions. The SEMG activities of the pain-side TA and bilateral MM were lower during centric MVC compared with controls. The SEMG activities of the non-pain-side TA and the normalized SEMG activities of the bilateral TAs and MMs were higher during protrusive MVC (p<0.05). During pain-side MVC, the normalized SEMG activities of the working side MM and balancing-side TA were higher than those of the controls. In conclusion, the TMD pain side was not associated with the occlusal contacts, but the patients with TMD had TA and MM SEMG activities during different tasks that differed from controls and that did not seem related to the pain side. PMID- 26643795 TI - A novel approach for removing ECG interferences from surface EMG signals using a combined ANFIS and wavelet. AB - In recent years, the removal of electrocardiogram (ECG) interferences from electromyogram (EMG) signals has been given large consideration. Where the quality of EMG signal is of interest, it is important to remove ECG interferences from EMG signals. In this paper, an efficient method based on a combination of adaptive neuro-fuzzy inference system (ANFIS) and wavelet transform is proposed to effectively eliminate ECG interferences from surface EMG signals. The proposed approach is compared with other common methods such as high-pass filter, artificial neural network, adaptive noise canceller, wavelet transform, subtraction method and ANFIS. It is found that the performance of the proposed ANFIS-wavelet method is superior to the other methods with the signal to noise ratio and relative error of 14.97dB and 0.02 respectively and a significantly higher correlation coefficient (p<0.05). PMID- 26643796 TI - How to safeguard competency and training in invasive prenatal diagnosis: 'the elephant in the room'. PMID- 26643797 TI - Variable Virulence and Efficacy of BCG Vaccine Strains in Mice and Correlation With Genome Polymorphisms. AB - Bacille Calmette-Guerin (BCG), an attenuated strain of Mycobacterium bovis, is the only vaccine available for tuberculosis (TB) control. However, BCG is not an ideal vaccine and has two major limitations: BCG exhibits highly variable effectiveness against the development of TB both in pediatric and adult populations and can cause disseminated BCG disease in immunocompromised individuals. BCG comprises a number of substrains that are genetically distinct. Whether and how these genetic differences affect BCG efficacy remains largely unknown. In this study, we performed comparative analyses of the virulence and efficacy of 13 BCG strains, representing different genetic lineages, in SCID and BALB/c mice. Our results show that BCG strains of the DU2 group IV (BCG-Phipps, BCG-Frappier, BCG-Pasteur, and BCG-Tice) exhibit the highest levels of virulence, and BCG strains of the DU2 group II (BCG-Sweden, BCG-Birkhaug) are among the least virulent group. These distinct levels of virulence may be explained by strain-specific duplications and deletions of genomic DNA. There appears to be a general trend that more virulent BCG strains are also more effective in protection against Mycobacterium tuberculosis challenge. Our findings have important implications for current BCG vaccine programs and for future TB vaccine development. PMID- 26643798 TI - Gross motor function and general development of babies born after assisted reproductive technology. AB - AIM: To elucidate the gross motor function and general development of babies born after assisted reproductive technology (ART). MATERIAL AND METHODS: The study subjects comprised 238 babies born after ART and 365 babies as the control. Multiple births, premature and low birth weight babies were excluded. Questionnaires were distributed to mothers and gross motor function and general development were evaluated according to the Ability for Basic Movement Scale for Children (ABMS-C) and Kinder Infant Development Scale (KIDS), respectively. RESULTS: There were no significant differences in gross motor function according to the ABMS-C between the two groups at one, three, six, nine and 12 months of age. The KIDS scores on subscales of expressive language at three months, manipulation at nine months and the total developmental quotient, and subscales of manipulation, receptive language and social relationships with children at 12 months were significantly higher in the ART than in the control group. CONCLUSIONS: There was no significant difference in gross motor function up to 12 months of age between the ART and control groups. However, the total developmental quotient and scores on linguistic and communication capacity of children at 12 months of age were significantly higher in the ART group. These results suggested that ART has no adverse effects on intellectual function, at least during early infancy. PMID- 26643799 TI - Are prognostic scores and biomarkers such as procalcitonin the appropriate prognostic precursors for elderly patients with sepsis in the emergency department? AB - BACKGROUND: The mortality of patients with severe sepsis and septic shock is still high, and the prognosis of elderly patients tends to be particularly poor. Therefore, this study sought to conduct a comparative analysis of the abbreviated mortality in emergency department sepsis (abbMEDS) score, sequential organ failure assessment (SOFA) score, infection probability score (IPS), initial procalcitonin (PCT), and cytokine levels to investigate the effectiveness of each index in predicting the prognosis of elderly patients with sepsis in the emergency department (ED). METHODS: This was a single-center prospective study, and classified 55 patients (>=65 years of age) with systemic inflammatory response syndrome (SIRS) from January 2013 to December 2013 in the ED. A total of 36 elderly patients were diagnosed with sepsis. The prediction of prognosis using the prognostic scores (abbMEDS, SOFA, IPS) was analyzed. An early blood examination (WBC count, C-reactive protein, PCT, and cytokines) was conducted within the first 2 h of the patient's arrival at the ED. RESULTS: The median (IQR) age of subjects was 76.5 (70.5-81.5). After 28 days, 27 subjects (75 %) had survived, and 9 (25 %) had died. Fifteen (41.7 %) were sent to intensive care units (ICUs). The SOFA score and abbMEDS showed higher median (IQR) values of 9.5 (7.0-11.0) and 13.5 (12.0-15.0), respectively, in the ICU group than in the general ward group (p < 0.001). Analysis of the levels of PCT, IL-10, IL-6, and IL-5 had a significantly better ability to predict ICU admission (p = 0.001, p = 0.023, p = 0.030, p = 0.001). The prediction of mortality in the first 28 days via SOFA and the abbMEDS resulted in scores of 11.0 (8.0-11.0) and 14.0 (12.5 15.5) (p = 0.004, p = 0.003), respectively. However, levels of IPS, PCT, and cytokines did not show significant differences. CONCLUSIONS: In predicting ICU admission and the death of elderly sepsis patients in ED, SOFA and abbMEDS scores were effective. Of the various biomarkers, PCT, IL-10, IL-6, and IL-5 were effective in predicting ICU admission, but were not effective in predicting the death of elderly sepsis patients. PMID- 26643800 TI - Physical frailty in older people with severe aortic stenosis. AB - BACKGROUND: Assessment of physical frailty is important among elderly with severe aortic stenosis (AS) when considering treatment. AIMS: We aimed to: (1) investigate the prevalence of physical frailty in older people with severe AS and (2) examine factors related to physical frailty. METHODS: A total of 125 consecutive elderly AS patients (mean age 84.6 +/- 4.4 year) were enrolled. Physical frailty was defined as scoring <=8 points on the short physical performance battery (SPPB). Factors likely related to physical frailty, including cardiac function, nutritional and metabolic status, kidney function, medical history, and comorbidities, were evaluated. Logistic regression analyses were used to examine which factors were related to physical frailty. RESULTS: Physical frailty was prevalent in 38.4 %. After sex and age adjusted, the following were significantly related to physical frailty: LVEF (adjusted OR per 10 % decrease: 1.39, p < 0.05), the Mini Nutritional Assessment-Short Form (adjusted OR per 1 point decrease: 1.21, p < 0.05), serum albumin (adjusted OR per 1 g/dL decrease: 2.64, p < 0.05), HDL-C (adjusted OR per 10 mg/dL decrease: 1.52, p < 0.01), eGFR (adjusted OR per 10 mL/min decrease: 1.59, p < 0.05), grip strength (adjusted OR per 10 kg decrease: 3.60, p < 0.01), coronary heart disease (adjusted OR: 2.78, p < 0.01), cerebrovascular disease (adjusted OR: 6.06, p < 0.01), and musculoskeletal disorders (adjusted OR: 3.28, p < 0.01). CONCLUSIONS: The prevalence of physical frailty is high and related to nutritional status, comorbidities, and cardiac status. PMID- 26643801 TI - A novel floating controlled release drug delivery system prepared by hot-melt extrusion. AB - Floating dosage forms are an important formulation strategy for drugs with a narrow absorption window and low intestinal solubility, and for localized gastric treatment. Novel floating pellets were prepared using the hot-melt extrusion (HME) technology. Uniformly foamed strands were created by liquid injection pumping and screw configuration modification. The ammonio methacrylate copolymer (Eudragit(r) RSPO) foaming structure was formed by a liquid-vapor phase transition inside the strand upon die exiting resulting from the sudden decrease in external pressure, vaporizing the liquid ethanol and vacating the extruded material. This generated uniform vacuous regions in the extrudate. The pellets' internal structure was investigated using scanning electron microscopy (SEM). The formulation constituents' and processing parameters' effects on the drug release profiles, floating force, and the pellets' micromeritic properties were evaluated by design of experiments: all formulations showed zero lag time and excellent floating strength, indicating immediate-floating pellet formation. The pellets' drug release profiles were controlled by multiple independent variables at different time points (? 24 h). Drug loading significantly affected drug release within the first hour, the hydroxypropyl methylcellulose (HPMC) content thereafter. Understanding the variables' effects on the formulations allows for the tailoring of this delivery system to obtain various drug release profiles. PMID- 26643802 TI - Sensory feedback by peripheral nerve stimulation improves task performance in individuals with upper limb loss using a myoelectric prosthesis. AB - OBJECTIVE: Tactile feedback is critical to grip and object manipulation. Its absence results in reliance on visual and auditory cues. Our objective was to assess the effect of sensory feedback on task performance in individuals with limb loss. APPROACH: Stimulation of the peripheral nerves using implanted cuff electrodes provided two subjects with sensory feedback with intensity proportional to forces on the thumb, index, and middle fingers of their prosthetic hand during object manipulation. Both subjects perceived the sensation on their phantom hand at locations corresponding to the locations of the forces on the prosthetic hand. A bend sensor measured prosthetic hand span. Hand span modulated the intensity of sensory feedback perceived on the thenar eminence for subject 1 and the middle finger for subject 2. We performed three functional tests with the blindfolded subjects. First, the subject tried to determine whether or not a wooden block had been placed in his prosthetic hand. Second, the subject had to locate and remove magnetic blocks from a metal table. Third, the subject performed the Southampton Hand Assessment Procedure (SHAP). We also measured the subject's sense of embodiment with a survey and his self-confidence. MAIN RESULTS: Blindfolded performance with sensory feedback was similar to sighted performance in the wooden block and magnetic block tasks. Performance on the SHAP, a measure of hand mechanical function and control, was similar with and without sensory feedback. An embodiment survey showed an improved sense of integration of the prosthesis in self body image with sensory feedback. SIGNIFICANCE: Sensory feedback by peripheral nerve stimulation improved object discrimination and manipulation, embodiment, and confidence. With both forms of feedback, the blindfolded subjects tended toward results obtained with visual feedback. PMID- 26643804 TI - Can the spinal instability neoplastic score prior to spinal radiosurgery predict compression fractures following stereotactic spinal radiosurgery for metastatic spinal tumor?: a post hoc analysis of prospective phase II single-institution trials. AB - The aim of this study was to determine the predictability of vertebral compression fracture (VCF) development applying the spinal instability neoplastic score (SINS) prior to delivery of stereotactic spinal radiosurgery (SSRS) for spinal metastases. From two prospective cohorts of SSRS for spinal metastases, we selected patients with a low degree of cord compression or cauda equine from C3 to S1 and analyzed 79 patients enrolled according to binary SINS criteria. The primary endpoint was the development of a de novo VCF or progression of an existing fracture after SSRS. We identified 32 fractures (40.5%): 19 de novo and 13 progressive. The mean time to fracture after SSRT was 3.3 months (range, 0.4 34.1 months). In 41 patients with low SINS (0-6), 7 patients (17.1%) developed a fracture after SSRS. In 38 patients with high SINS (7-12), 25 (65.8%) developed a fracture. Among the 32 fractures, 15 were symptomatic. Patients with high SINS were more likely to experience symptomatic fractures (31.6%) than were patients with lower SINS (7.4%). On univariate and multivariate analysis, 24-month fracture-free rates were 78.7 and 33.7% in low and high SINS group, respectively and high SINS was found to be a significant risk factor for VCFs and symptomatic fractures (respectively, HR 5.6, p = 0.04; HR 5.3, p = 0.01). SINS is a useful tool for predicting the development of VCF after SSRS for spinal metastases. Prophylactic cement augmentation should not be considered for patients with lower SINS, since the risk of fracture is low. PMID- 26643803 TI - Dexamethasone alone and in combination with desipramine, phenytoin, valproic acid or levetiracetam interferes with 5-ALA-mediated PpIX production and cellular retention in glioblastoma cells. AB - Extent of resection of glioblastoma (GBM) correlates with overall survival. Fluorescence-guided resection (FGR) using 5-aminolevulinic acid (5-ALA) can improve the extent of resection. Unfortunately not all patients given 5-ALA accumulate sufficient quantities of protoporphyrin IX (PpIX) for successful FGR. In this study, we investigated the effects of dexamethasone, desipramine, phenytoin, valproic acid, and levetiracetam on the production and accumulation of PpIX in U87MG cells. All of these drugs, except levetiracetam, reduce the total amount of PpIX produced by GBM cells (p < 0.05). When dexamethasone is mixed with another drug (desipramine, phenytoin, valproic acid or levetiracetam) the amount of PpIX produced is further decreased (p < 0.01). However, when cells are analyzed for PpIX cellular retention, dexamethasone accumulated significantly more PpIX than the vehicle control (p < 0.05). Cellular retention of PpIX was not different from controls in cells treated with dexamethasone plus desipramine, valproic acid or levetiracetam, but was significantly less for dexamethasone plus phenytoin (p < 0.01). These data suggest that medications given before and during surgery may interfere with PpIX accumulation in malignant cells. At this time, levetiracetam appears to be the best medication in its class (anticonvulsants) for patients undergoing 5-ALA-mediated FGR. PMID- 26643806 TI - Primary brain tumor patients' supportive care needs and multidisciplinary rehabilitation, community and psychosocial support services: awareness, referral and utilization. AB - Primary brain tumors are associated with significant physical, cognitive and psychosocial changes. Although treatment guidelines recommend offering multidisciplinary rehabilitation and support services to address patients' residual deficits, the extent to which patients access such services is unclear. This study aimed to assess patients' supportive care needs early after diagnosis, and quantify service awareness, referral and utilization. A population-based sample of 40 adults recently diagnosed with primary brain tumors was recruited through the Queensland Cancer Registry, representing 18.9 % of the eligible population of 203 patients. Patients or carer proxies completed surveys of supportive care needs at baseline (approximately 3 months after diagnosis) and 3 months later. Descriptive statistics summarized needs and service utilization, and linear regression identified predictors of service use. Unmet supportive care needs were highest at baseline for all domains, and highest for the physical and psychological needs domains at each time point. At follow-up, participants reported awareness of, referral to, and use of 32 informational, support, health professional or practical services. All or almost all participants were aware of at least one informational (100 %), health professional (100 %), support (97 %) or practical service (94 %). Participants were most commonly aware of speech therapists (97 %), physiotherapists (94 %) and diagnostic information from the internet (88 %). Clinician referrals were most commonly made to physiotherapists (53 %), speech therapists (50 %) and diagnostic information booklets (44 %), and accordingly, participants most commonly used physiotherapists (56 %), diagnostic information booklets (47 %), diagnostic information from the internet (47 %), and speech therapists (43 %). Comparatively low referral to and use of psychosocial services may limit patients' abilities to cope with their condition and the changes they experience. PMID- 26643807 TI - A phase II trial of enzastaurin (LY317615) in combination with bevacizumab in adults with recurrent malignant gliomas. AB - We evaluated the efficacy of combination enzastaurin (LY317615) and bevacizumab for recurrent malignant gliomas and explored serologic correlates. We enrolled 81 patients with glioblastomas (GBM, n = 40) and anaplastic gliomas (AG, n = 41). Patients received enzastaurin as a loading dose of 1125 mg, followed by 500 or 875 mg daily for patients on non-enzyme-inducing or enzyme-inducing antiepileptics, respectively. Patients received bevacizumab 10 mg/kg intravenously biweekly. Clinical evaluations were repeated every 4 weeks. Magnetic resonance imaging was obtained at baseline and every 8 weeks from treatment onset. Phosphorylated glycogen synthase kinase (GSK)-3 levels from peripheral blood mononuclear cells (PBMCs) were checked with each MRI. Median overall survival was 7.5 and 12.4 months for glioblastomas and anaplastic glioma cohorts, with median progression-free survivals of 2.0 and 4.4 months, respectively. Of GBM patients, 3/40 (7.5 %) were not evaluable, while 8/37 (22 %) had partial or complete response and 20/37 (54 %) had stable disease for 2+ months. Of the 39 evaluable AG patients, 18 (46 %) had an objective response, and 16 (41 %) had stable disease for 2+ months. The most common grade 3+ toxicities were lymphopenia (15 %), hypophosphatemia (8.8 %) and thrombotic events (7.5 %). Two (2.5 %) GBM patients died suddenly; another death (1.3 %) occurred from intractable seizures. Phosphorylated GSK-3 levels from PBMCs did not correlate with treatment response. A minimally important improvement in health-related quality of life was self-reported in 7-9/24 (29.2-37.5 %). Early response based on Levin criteria was significantly associated with significantly longer progression free survival for glioblastomas. Enzastaurin (LY317615) in combination with bevacizumab for recurrent malignant gliomas is well-tolerated, with response and progression-free survival similar to bevacizumab monotherapy. PMID- 26643809 TI - Massive odontoameloblastoma arising in the maxilla: a case report. AB - INTRODUCTION: Odontoameloblastoma is an extremely rare mixed odontogenic tumor with both epithelial and mesenchymal components. The term odontoameloblastoma first appeared in the 1971 World Health Organization classification (Pindborg JJ., et al.) and is defined as "a neoplasm that includes odontogenic ectomesenchyme in addition to odontogenic epithelium that resembles an ameloblastoma in both structures and behavior." Because of the aggressive nature and risk of recurrence of the tumor, complete resection is essential. In this report, we describe an extremely rare case of a patient with massive odontoameloblastoma arising in the maxilla and occupying maxillary sinus. CASE PRESENTATION: In 2013, an 11-year-old Japanese boy was referred to our department for a painless and large mass of the right maxillary region. A panoramic X-ray showed a unilocular cystic lesion in the right maxilla containing a calcified mass in the lesion associated with an impacted tooth. Computed tomography showed a cystic lesion that included calcified structures and measured 3.6*3.1*2.7 cm. In 2013, the patient underwent tumor extirpation combined with impacted tooth extraction. The histopathological diagnosis was an odontoameloblastoma. No recurrence was noted 27 months after the operation. CONCLUSIONS: The patient has undergone postoperative occlusal guidance and functional orthodontic treatment, and his postoperative condition is excellent. However, postoperative recurrence or malignant transformation can occur in cases of odontoameloblastoma, and close long-term follow-up will be continued for our patient. PMID- 26643808 TI - Structural analysis of APOB variants, p.(Arg3527Gln), p.(Arg1164Thr) and p.(Gln4494del), causing Familial Hypercholesterolaemia provides novel insights into variant pathogenicity. AB - Familial hypercholesterolaemia (FH) is an inherited autosomal dominant disorder resulting from defects in the low-density lipoprotein receptor (LDLR), in the apolipoprotein B (APOB) or in the proprotein convertase subtilisin/kexin type 9 (PCSK9) genes. In the majority of the cases FH is caused by mutations occurring within LDLR, while only few mutations in APOB and PCSK9 have been proved to cause disease. p.(Arg3527Gln) was the first mutation in APOB being identified and characterized. Recently two novel pathogenic APOB variants have been described: p.(Arg1164Thr) and p.(Gln4494del) showing impaired LDLR binding capacity, and diminished LDL uptake. The objective of this work was to analyse the structure of p.(Arg1164Thr) and p.(Gln4494del) variants to gain insight into their pathogenicity. Secondary structure of the human ApoB100 has been investigated by infrared spectroscopy (IR) and LDL particle size both by dynamic light scattering (DLS) and electron microscopy. The results show differences in secondary structure and/or in particle size of p.(Arg1164Thr) and p.(Gln4494del) variants compared with wild type. We conclude that these changes underlie the defective binding and uptake of p.(Arg1164Thr) and p.(Gln4494del) variants. Our study reveals that structural studies on pathogenic variants of APOB may provide very useful information to understand their role in FH disease. PMID- 26643810 TI - De novo transcriptome reconstruction and annotation of the Egyptian rousette bat. AB - BACKGROUND: The Egyptian Rousette bat (Rousettus aegyptiacus), a common fruit bat species found throughout Africa and the Middle East, was recently identified as a natural reservoir host of Marburg virus. With Ebola virus, Marburg virus is a member of the family Filoviridae that causes severe hemorrhagic fever disease in humans and nonhuman primates, but results in little to no pathological consequences in bats. Understanding host-pathogen interactions within reservoir host species and how it differs from hosts that experience severe disease is an important aspect of evaluating viral pathogenesis and developing novel therapeutics and methods of prevention. RESULTS: Progress in studying bat reservoir host responses to virus infection is hampered by the lack of host specific reagents required for immunological studies. In order to establish a basis for the design of reagents, we sequenced, assembled, and annotated the R. aegyptiacus transcriptome. We performed de novo transcriptome assembly using deep RNA sequencing data from 11 distinct tissues from one male and one female bat. We observed high similarity between this transcriptome and those available from other bat species. Gene expression analysis demonstrated clustering of expression profiles by tissue, where we also identified enrichment of tissue-specific gene ontology terms. In addition, we identified and experimentally validated the expression of novel coding transcripts that may be specific to this species. CONCLUSION: We comprehensively characterized the R. aegyptiacus transcriptome de novo. This transcriptome will be an important resource for understanding bat immunology, physiology, disease pathogenesis, and virus transmission. PMID- 26643811 TI - Human papillomavirus detection in Corrientes, Argentina: High prevalence of type 58 and its phylodynamics. AB - Human papillomavirus (HPV) has the highest mortality rate due to cervical cancer in Northeastern Argentina. The aim of this work was to detect and characterize HPV in samples from the Province of Corrientes, Argentina. HPV detection and typing was performed using PCR-RFLP on samples with different cervical lesions (n=255). Seventeen viruses typified as HPV-58 were sequenced (E6 and E7 genes) and mutations were analyzed. HPV DNA was detected in 56.1% of the cervical lesions (143/255). Twenty-two different HPV types were detected. The type most frequently found among the total number of samples and HPV-positive samples was HPV-16 (14.5% and 25.9%, respectively), followed by HPV-58 (8.2%/14.7%, respectively), which is also considered a high-risk viral type. Increased severity of the cytological status was associated with greater rates of HPV detection and, especially, with the detection of greater rates of high-risk types. In addition, the evolutionary dynamics of the alpha-9 species group and HPV-58 was studied. All HPV-58 viruses reported in this work belonged to lineage A, sublineage A2. The phylodynamic analysis indicated that diversification of main groups within lineage A might have accompanied or preceded human migrations across the globe. Given that the most prevalent viruses found belonged to high risk HPV types, some concerns might arise about the extent of cross protection of the vaccines against the types not included in their design. PMID- 26643812 TI - Comparison of seven water quality assessment methods for the characterization and management of highly impaired river systems. AB - In the context of water resource management and pollution control, the characterization of water quality impairments and identification of dominant pollutants are of critical importance. In this study, water quality impairment was assessed on the basis of 7 hydrochemical variables that were monitored bimonthly at 17 sites in 2010 along the rural-suburban-urban portion of the Wen Rui Tang River in eastern China. Seven methods were used to assess water quality in the river system. These methods included single-factor assessment, water quality grading, comprehensive pollution index, the Nemerow pollution index, principle component analysis, fuzzy comprehensive evaluation, and comprehensive water quality identification index. Our analysis showed that the comprehensive water quality identification index was the best method for assessing water quality in the Wen-Rui Tang River due to its ability to effectively characterize highly polluted waters with multiple impairments. Furthermore, a guideline for the applications of these methods was presented based on their characteristics and efficacy. Results indicated that the dominant pollutant impairing water quality was total nitrogen comprised mainly of ammonium. The temporal variation of water quality was closely related to precipitation as a result of dilution. The spatial variation of water quality was associated with anthropogenic influences (urban, industrial, and agriculture activities) and water flow direction (downstream segments experiencing cumulative effects of upstream inputs). These findings provide valuable information and guidance for water pollution control and water resource management in highly polluted surface waters with multiple water quality impairments in areas with rapid industrial growth and urbanization. PMID- 26643813 TI - Variations in the prevalence and predictors of prevalent metabolically healthy obesity in adolescents. AB - BACKGROUND: Obesity is a heterogeneous condition, which includes a subset of individuals that can be classified as having metabolically healthy obesity (MHO), but there is no consensus on what constitutes MHO. Thus, the objective of the study is to examine the prevalence and predictors of prevalent MHO in adolescents using various definitions of MHO. METHODS: Cross-sectional data from the 1999 2010 National Health and Nutrition Examination Surveys were used. Participants included 316 male and 316 female adolescents aged 12-19 years with a BMI >= 95th percentile. Two definitions were used to define MHO. First, MHO was defined as having <=1 metabolic syndrome criteria (excluding waist) and being free of type 2 diabetes, hypertension and dyslipidemia. Second, MHO was defined as being free of all metabolic syndrome criteria, insulin resistance and inflammation. RESULTS: The prevalence of MHO was 42% (male) and 74% (female) using the first definition and 7% (male) and 12% (female) using the second more conservative definition. Lower abdominal obesity (waist circumference) and lower insulin resistance predicted prevalent MHO in male and female adolescents for both definitions (p < 0.01). Associations between dietary components and MHO were weak and inconsistent, while physical activity and inflammation were not associated with MHO in male and female adolescents for both definitions (p > 0.05). CONCLUSIONS: The prevalence of MHO in adolescents varied across definitions, with lower levels of abdominal obesity and insulin resistance as the most consistent predictors of prevalent MHO status. PMID- 26643814 TI - Diagnosis and treatment of cardiac sarcoidosis. AB - Sarcoidosis is a systemic granulomatous disease of unknown aetiology. The frequency of cardiac involvement (cardiac sarcoidosis (CS)) varies in the different geographical regions, but it has been reported that it is an absolutely important prognostic factor in this disease. Complete atrioventricular block is the most common, and ventricular tachycardia/ventricular fibrillation the second most common arrhythmia in this disease, both of which are associated with cardiac sudden death. Diagnosing CS is sometimes difficult because of the non-specific ECG and echocardiographic findings, and CS is sometimes misdiagnosed as dilated cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy or an idiopathic ventricular aneurysm, and therefore, endomyocardial biopsy is important, but has a low sensitivity. Another problem is the recognition of isolated types of CS. Recently, MRI and (18)F-fluorodeoxyglucose positron emission tomography have been demonstrated to be useful tools for the non-invasive diagnosis of CS as well as therapeutic evaluation tools, but are still unsatisfactory. Treatment of CS is usually done by corticosteroid therapy to control inflammation, prevent fibrosis and protect from any deterioration of the cardiac function, but the long-term outcome is still in debate. Despite the advancement of non-pharmacological approaches for CS (pacing, defibrillators and catheter ablation) to improve the prognosis, there are still many issues remaining to resolve diagnosing and managing CS. Here, we attempt a review of the clinical evidence, with special focus on the current understanding of this disease and showing the current strategies and remaining problems of diagnosing and managing CS. PMID- 26643816 TI - Psoriasis and uric acid: a population-based cross-sectional study. AB - BACKGROUND: Psoriasis has been reported to be associated with raised serum uric acid levels and gout, and uric acid has been demonstrated to mediate inflammatory pathways via secretion of pro-inflammatory chemokines. AIM: To evaluate the association between psoriasis, serum uric acid levels and gout in a cross sectional study using the US National Health and Nutrition Examination Survey (NHANES) database. METHODS: Data on clinical history of psoriasis, gout and other relevant medical conditions from the questionnaire as well as laboratory parameters for serum uric acid and lipid levels in the periods 2003-2006 and 2011 2012 were analysed. Multivariate analysis with logistic regression modelling was performed, with hyperuricaemia as the dependent variable, and age, sex, ethnicity, body mass index, metabolic syndrome, current smoking status, alcohol consumption and history of psoriasis as the independent variables. RESULTS: Of the 11 282 study participants, 297 (2.6%) reported a history of psoriasis and 1493 (13.2%) were found to have hyperuricaemia. Patients with psoriasis were at increased risk of having hyperuricaemia, compared with those without psoriasis (OR = 1.37; P = 0.04). They were also more likely to report a history of gout (OR = 1.83; P < 0.05). However, neither association was significant after adjusting for potential confounders with multivariate logistic regression. CONCLUSION: In conclusion, there was insufficient evidence to show that psoriasis is an independent risk factor of hyperuricaemia or gout. A raised serum uric acid level may be a consequence of metabolic syndrome, which in turn is associated with psoriasis. PMID- 26643815 TI - Protease-activated receptor 4 deficiency offers cardioprotection after acute ischemia reperfusion injury. AB - Protease-activated receptor (PAR)4 is a low affinity thrombin receptor with less understood function relative to PAR1. PAR4 is involved in platelet activation and hemostasis, but its specific actions on myocyte growth and cardiac function remain unknown. This study examined the role of PAR4 deficiency on cardioprotection after myocardial ischemia-reperfusion (IR) injury in mice. When challenged by in vivo or ex vivo IR, PAR4 knockout (KO) mice exhibited increased tolerance to injury, which was manifest as reduced infarct size and a more robust functional recovery compared to wild-type mice. PAR4 KO mice also showed reduced cardiomyocyte apoptosis and putative signaling shifts in survival pathways in response to IR. Inhibition of PAR4 expression in isolated cardiomyocytes by shRNA offered protection against thrombin and PAR4-agonist peptide-induced apoptosis, while overexpression of wild-type PAR4 significantly enhanced the susceptibility of cardiomyocytes to apoptosis, even under low thrombin concentrations. Further studies implicate Src- and epidermal growth factor receptor-dependent activation of JNK on the proapoptotic effect of PAR4 in cardiomyocytes. These findings reveal a pivotal role for PAR4 as a regulator of cardiomyocyte survival and point to PAR4 inhibition as a therapeutic target offering cardioprotection after acute IR injury. PMID- 26643817 TI - Role of Msi1 and PYGO2 in esophageal squamous cell carcinoma depth of invasion. AB - Deregulation of developmental signaling pathways such as Wnt/b-catenin and NOTCH are commonly observed in different cancers. A normal wnt pathway is essential for development and tissue homeostasis to preserve a normal balance between the differentiation and proliferation. PYGO2 is the main transcription factor of wnt pathway, while Msi1 is one of the wnt inhibitors. In this study we assessed the correlation between Msi1 and PYGO2 mRNA expression using Real time polymerase chain reaction in 48 esophageal squamous cell carcinoma (ESCC) patients. Although, there was not any significant correlation between the levels of Msi1 and PYGO2 mRNA expression, we observed a significant correlation between the Msi1 and PYGO2 overexpressed cases and depth of tumor invasion (p = 0.05). In conclusion, despite the role of these markers in tumor depth of invasion there is not any feedback between Msi1 and PYGO2 gene expression in ESCC. PMID- 26643819 TI - Big Data and New Drug Discovery: Tackling "Big Data" for Virtual Screening of Large Compound Databases. PMID- 26643818 TI - Cognitive Rehabilitation for Attention and Memory in people with Multiple Sclerosis: study protocol for a randomised controlled trial (CRAMMS). AB - BACKGROUND: People with multiple sclerosis have problems with memory and attention. Cognitive rehabilitation is a structured set of therapeutic activities designed to retrain an individual's memory and other cognitive functions. Cognitive rehabilitation may be provided to teach people strategies to cope with these problems, in order to reduce the impact on everyday life. The effectiveness of cognitive rehabilitation for people with multiple sclerosis has not been established. METHODS: This is a multi-centre, randomised controlled trial investigating the clinical and cost-effectiveness of a group-based cognitive rehabilitation programme for attention and memory problems for people with multiple sclerosis. Four hundred people with multiple sclerosis will be randomised from at least four centres. Participants will be eligible if they have memory problems, are 18 to 69 years of age, are able to travel to attend group sessions and give informed consent. Participants will be randomised in a ratio of 6:5 to the group rehabilitation intervention plus usual care or usual care alone. Intervention groups will receive 10 weekly sessions of a manualised cognitive rehabilitation programme. The intervention will include both restitution strategies to retrain impaired attention and memory functions and compensation strategies to enable participants to cope with their cognitive problems. All participants will receive a follow-up questionnaire and an assessment by a research assistant at 6 and 12 months after randomisation. The primary outcome is the Multiple Sclerosis Impact Scale (MSIS) Psychological subscale at 12 months. Secondary outcomes include the Everyday Memory Questionnaire, General Health Questionnaire-30, EQ-5D and a service use questionnaire from participants, and the Everyday Memory Questionnaire-relative version and Carer Strain Index from a relative or friend. The primary analysis will be based on intention to treat. A mixed-model regression analysis of the MSIS Psychological subscale at 12 months will be used to estimate the effect of the group cognitive rehabilitation programme. DISCUSSION: The study will provide evidence regarding the clinical and cost-effectiveness of a group-based cognitive rehabilitation programme for attention and memory problems in people with multiple sclerosis. TRIAL REGISTRATION: ISRCTN09697576 . Registered 14 August 2014. PMID- 26643820 TI - Matrix-MTM adjuvation broadens protection induced by seasonal trivalent virosomal influenza vaccine. AB - BACKGROUND: Influenza virus infections are responsible for significant morbidity worldwide and therefore it remains a high priority to develop more broadly protective vaccines. Adjuvation of current seasonal influenza vaccines has the potential to achieve this goal. METHODS: To assess the immune potentiating properties of Matrix-MTM, mice were immunized with virosomal trivalent seasonal vaccine adjuvated with Matrix-MTM. Serum samples were isolated to determine the hemagglutination inhibiting (HAI) antibody titers against vaccine homologous and heterologous strains. Furthermore, we assess whether adjuvation with Matrix-MTM broadens the protective efficacy of the virosomal trivalent seasonal vaccine against vaccine homologous and heterologous influenza viruses. RESULTS: Matrix MTM adjuvation enhanced HAI antibody titers and protection against vaccine homologous strains. Interestingly, Matrix-MTM adjuvation also resulted in HAI antibody titers against heterologous influenza B strains, but not against the tested influenza A strains. Even though the protection against heterologous influenza A was induced by the adjuvated vaccine, in the absence of HAI titers the protection was accompanied by severe clinical scores and body weight loss. In contrast, in the presence of heterologous HAI titers full protection against the heterologous influenza B strain without any disease symptoms was obtained. CONCLUSION: The results of this study emphasize the promising potential of a Matrix-MTM-adjuvated seasonal trivalent virosomal influenza vaccine. Adjuvation of trivalent virosomal vaccine does not only enhance homologous protection, but in addition induces protection against heterologous strains and thus provides overall more potent and broad protective immunity. PMID- 26643824 TI - Approach to Earthquake Related Health Problems. PMID- 26643821 TI - Impact of the Right Ventricular Lead Position on Clinical End Points in CRT Recipients--A Subanalysis of the Multicenter Randomized SPICE Trial. AB - BACKGROUND: The impact of right ventricular (RV) lead location on clinical end points in patients undergoing cardiac resynchronization therapy (CRT) is unclear. We evaluated the impact of different RV lead locations on clinical outcome in CRT patients enrolled in the Septal Positioning of ventricular implantable cardioverter-defibrillator (ICD) Electrodes (SPICE) trial, which randomized recipients of implantable cardioverter defibrillators to apical versus midseptal RV lead positioning. METHODS: Ninety-eight CRT recipients were included in the multicenter SPICE trial and followed for 12 months: Fifty-three patients were randomized to receive an apical (A) and 45 to receive a midseptal (S) lead position. We compared echocardiographical and electrocardiographical parameters and outcome. RESULTS: Echocardiographic response with respect to improvement of left ventricular ejection fraction (A: +15.8 +/- 14.6%, S: +9.7 +/- 12.6%, P = 0.156) and reduction of left ventricular end-diastolic diameter (A: -4.2 +/- 10.7 mm, S: -7.5 +/- 10.7 mm, P = 0.141) was comparable in apical and midseptal groups. Paced QRS width neither differed at prehospital discharge (A: 129 +/- 21 ms, S: 135 +/- 21 ms, P = 0.133) nor at 12-month follow-up (A: 131 +/- 23 ms, S: 134 +/- 28 ms, P = 0.620). No differences were found with respect to the risk of ventricular tachyarrhythmia or ICD therapy. Septal RV lead position, however, was associated with a significant longer time to a first heart failure event (P = 0.040) and a longer survival time (P = 0.019). CONCLUSIONS: In CRT recipients, midseptal RV lead position was not superior with respect to improvement of echocardiographic parameters or paced QRS width. It did not predispose to ventricular arrhythmias or ICD therapy. The finding that midseptal lead position was associated with a longer time to first heart failure event and a longer survival time deserves further investigation. PMID- 26643822 TI - The use of instrumented gait analysis for individually tailored interdisciplinary interventions in children with cerebral palsy: a randomised controlled trial protocol. AB - BACKGROUND: Children with cerebral palsy (CP) often have an altered gait. Orthopaedic surgery, spasticity management, physical therapy and orthotics are used to improve the gait. Interventions are individually tailored and are planned on the basis of clinical examinations and standardised measurements to assess walking ('care as usual'). However, these measurements do not describe features in the gait that reflect underlying neuro-musculoskeletal impairments. This can be done with 3-dimensional instrumented gait analysis (IGA). The aim of this study is to test the hypothesis that improvements in gait following individually tailored interventions when IGA is used are superior to those following 'care as usual'. METHODS/DESIGN: A prospective, single blind, randomised, parallel group study will be conducted. Children aged 5 to 8 years with spastic CP, classified at Gross Motor Function Classification System levels I or II, will be included. The interventions under investigation are: 1) individually tailored interdisciplinary interventions based on the use of IGA, and 2) 'care as usual'. The primary outcome is gait measured by the Gait Deviation Index. Secondary outcome measures are: walking performance (1-min walk test) and patient-reported outcomes of functional mobility (Pediatric Evaluation of Disability Inventory), health-related quality of life (The Pediatric Quality of Life Inventory Cerebral Palsy Module) and overall health, pain and participation (The Pediatric Outcome Data Collection Instrument). The primary endpoint for assessing the outcome of the two interventions will be 52 weeks after start of intervention. A follow up will also be performed at 26 weeks; however, exclusively for the patient-reported outcomes. DISCUSSION: To our knowledge, this is the first randomised controlled trial comparing the effects of an individually tailored interdisciplinary intervention based on the use of IGA versus 'care as usual' in children with CP. Consequently, the study will provide novel evidence for the use of IGA. TRIAL REGISTRATION: TRIAL REGISTRATION: ClinicalTrials.gov NCT02160457 . Registered June 2, 2014. PMID- 26643825 TI - Six Minute Walk Distance and Reference Equations in Normal Healthy Subjects of Nepal. AB - BACKGROUND: The self-paced six minute walk test is a simple assessment for sub maximal functional capacity. It correlates well with sophisticated tests and gives good prediction for morbidity, mortality, quality of life and pulmonary functions. OBJECTIVE: To evaluate six minute walk distance in healthy adults to identify reference values and formulate reference equations. METHOD: We conducted six minute walk test on 250 random volunteers at and above 18 years of age as per standard protocol. Age, gender, height and weight were measured. Pretest and post test vital parameters were recorded including pulse oximetry. The six minute walking distance was identified in all subjects. Multiple regression analysis was done to formulate regression equations to predict six minute walking distance. This also correlated age, gender, height, weight, body mass index with six minute walking distance. RESULT: The mean six minute walking distance was 489+/-86 meters with males walking 509+/-82 meters and females 445+/-78 meters. Age, gender, weight and body mass index had significant contribution for prediction of six minute walking distance. Gender was the single most important predictor. Height had the least significance. Depending on coefficients of these variables we formulated three regression equations and tested them for accurate prediction. The two best equations were identified as: Predicted SMWD = 395-1.5xAge+2.47xWT 35.89xGender and Predicted SMWD = 440-1.82xAge-53.07xGender+5.12xBMI. CONCLUSION: Gender, age and height are the most important predictors of six minute walking distance. Reference values and equations for both genders, different age groups with varying weights were derived for local population. PMID- 26643826 TI - A Prospective Study on Exchange Transfusion in Neonatal Unconjugated Hyperbilirubinemia--in a Tertiary Care Hospital, Nepal. AB - BACKGROUND: An exchange transfusion involves replacing patient's blood with donor blood in order to remove abnormal blood components and circulating toxins while maintaining adequate circulating blood volume. OBJECTIVE: To observe the incidence, causes of jaundice requiring Exchange and any adverse event of exchange transfusion in newborns with unconjugated hyperbilirubinemia. METHOD: Prospective study undertaken at Neonatal Intensive Care Unit (NICU) of Manipal Teaching Hospital, Pokhara, Nepal from March 2014 to April 2015. For both mothers and neonates blood group and Rh typing and for all newborns pre and post exchange complete blood count with peripheral smear, serum bilirubin, hemoglobin, calcium, potassium, random blood sugar, C-reactive protein and blood culture and where ever required Direct Coombs test, reticulocyte count, G6PD activity and thyroid function test were done. The incidence, indications, positive outcome, complications and mortality were noted. RESULT: Out of 481 cases of unconjugated hyperbilirubinemia 29 (6%) required exchange transfusion. 55.2% Pathological Jaundice [13.8% ABO incompatibility, sepsis and hypothyroidism was commonest causes] and 44.8% exaggerated physiological jaundice [27.6% with no underlying pathology, 10.3% preterms 3.4% cephalhematoma] required exchange transfusion. Post transfusion, bilirubin level decreased significantly (p < 0.001). The commonest adverse events noted were anemia (89.7% / p < 0.018), hyperglycemia(51.7% / p < 0.001), hypocalcaemia (48.3% / p < 0.001)), sepsis(10.3%), hypernatremia (13.8%), hyperkalaemia, bradycardia, apnea and feed intolerance (6.9%). None of them had kernicterus and there was no mortalities. CONCLUSION: Exchange transfusion is an effective procedure to decrease bilirubin levels but is associated with many complications. Hypothyroidism was one of the commonest cause of jaundice requiring Exchange transfusion. PMID- 26643827 TI - Study to Compare and Evaluate Traditional vs. Endoscopic Septoplasty. AB - BACKGROUND: Surgery on a deviated septum has seen several modifications since its inception starting from radical septal resection to preservation of the possible septal framework. OBJECTIVE: To compare the efficacies of "Endoscope Septoplasty" over "Traditional Septoplasty" in treating pathological septum and turbinates, in terms of their outcome. METHOD: Prospective descriptive study conducted on 60 patients who presented to the Department of ENT, Kathmandu University School of Medical sciences during a period of two years. The severity of the symptoms of the patients was scored using a visual analogue scale which was compared post operatively to subjectively evaluate the efficacy of either surgery. Objective assessment was done by nasal endoscopy. P value in case of subjective and objective evaluation was done by applying Z- test. RESULT: The mean age +/- SD was 29.5+/-1.2 .Maximum patients fell into age group of 21-30 with 31.7 % followed by 11-20 with 28.3% and then 31-40 with 25%. There were total 35 males (58.3%) and 25 females (41.7%). Among the symptoms, nasal obstruction seems to be dominating with total of 83.3%, followed by postnasal drip with 66.6% and then headache with 60%. The types of dislocation was compared, there were 66.7% cases with DNS and Spur whereas only 10 % with isolated spur. C shaped deformity was seen in 30% and S shaped in 26.6 % cases. Significance in Z test, is seen in subjective assessment post surgery for nasal obstruction, headache and rhinorrhea and for objective assessment post surgery for persistent contact with turbinates. (p value set to 0.01). CONCLUSION: Endoscopic surgery is an evolutionary step towards solving the problems related to deviated nasal septum. It is safe, effective and conservative alternative to conventional septal surgery. PMID- 26643828 TI - Respiratory Tract Problems among Wood Furniture Manufacturing Factory Workers in the Northeast of Thailand. AB - BACKGROUND: Wood furniture manufacturing factory workers are at high risk of exposure to wood dust in wood working processes. Wood dust exposure could cause respiratory symptoms, such as reduce lung function, chronic bronchitis, and asthma. The Northeast region of Thailand has many wood furniture manufacturing factories. However, limited studies were carried out to explore the effect of wood dust exposure on workers. OBJECTIVE: This study aimed to assess the respiratory symptoms and determine factors associated with these symptoms among wood furniture manufacturing factory workers. METHOD: This cross-sectional analytical research used a multistage random sampling to select 511 workers from three provinces in the Northeast of Thailand. The data was collected using a structured questionnaire interview. The content validity of questionnaire was tested by 3 experts and had a Cronbach's alpha coefficient of 0.82. Data were analyzed using descriptive statistics and multiple logistic regressions. RESULT: The result indicated that 29.94% of these workers had respiratory symptoms, including coughing(18.79%), nasal secretion (15.66%), and stuffy nose (15.07%). Factors that were significantly associated with respiratory symptoms (p-value < 0.05) were (a) not always wearing mask (adjusted OR=2.26;95% CI=1.37-3.72), (b) low to medium level of knowledge on dust prevention (adjusted OR=1.83;95% CI=1.23 2.73) and (c) contacted softwood dust (adjusted OR=1.97;95% CI= 1.06-3.64). CONCLUSION: About 30% of wood furniture manufacturing factory workers had respiratory symptoms with related to both personal preventive behaviors and their working environments. Therefore, the raising awareness for using personal protective equipment during work will help them to prevent from various respiratory track problems. PMID- 26643829 TI - Can Laparoscopic Cholecystectomy be a Feasible Standard in a Rural set up too?- An Experience of 348 cases from a Peripheral set up of Western Nepal. AB - BACKGROUND: Gall stone disease is a common reason for admissions in both acute and elective situations and bears significant morbidity in the rural population of western Nepal. The earlier conventional open method of treatment for the same seems to have been largely seeded by the laparoscopic approach owing to its numerous benefits. OBJECTIVE: To study the clinical profile of patients with symptomatic gall stones with respect to demography and to assess the feasibility of using Laparoscopic cholecystectomy as the next standard in this set up too as guided by the outcome in terms of complications, conversion rates and potential impact it bears on the health and socioeconomic status in this group. METHOD: A retrospective analysis of all the patients undergoing an attempted laparoscopic cholecystectomy from 1st Jestha 2068 to 30th Jestha 2070 was done. Relevant medical records were reviewed to study demography, various indications for operations, intra operative events including conversions and complications. RESULT: Of 348 patients 293 (84.19%) were females and 55 (15.80%) were males. The mean age was 38.46 years (range 15-76 years). Most of the patients belonged to the Palpa district of Lumbini zone and many were from other surrounding areas. Gall stone disease was commonest in people of Brahmin ethnicity. The operating time was < 2 hours for most and most had an uneventful recovery with a mean hospital stay of 3.8 days. The rate of conversion to open cholecystectomy was 6.9% (24 out of 348 patients). Post operative complications were noted in 5 patients (1.42%). Of these 1 sustained a major bile duct injury (0.28%) requiring immediate conversion and repair, 3 had post operative bilioma and 1 had diffuse bleeding from the gall bladder fossa all requiring re explorations. There was no mortality in this study. CONCLUSION: Laparoscopic cholecystectomy is a safe, reliable and a promising option even in the rural peripheral set up. Due to its well known advantages and superiority over the open conventional method and considering the impact that it holds on the overall outcome, morbidity, health and socioeconomic status of the rural population, it can be recommended as an acceptable feasible standard in rural peripheral set up. PMID- 26643830 TI - Evaluation of Sialometric Analysis of Patients Suffering from Depressive Disorders. AB - BACKGROUND: Depressive disorders, worldwide, may rank second by the year 2020. In India; about 10 million people suffer from depressive disorders, the prevalence rate being recorded as 31.2 for every 1000 individuals. A significant impairment of all personal hygiene may occur due a depressive episode which in turn may result in altered salivary flow. OBJECTIVE: The present study was a hospital- based clinical cross-sectional study which was conducted in Bhopal, the heart of Madhya Pradesh, India. It was done to assess the relationship of bring about a comparison of sialometric alterations between normal and subjects with depressive disorders. METHOD: The survey period extended over a period of one year and two months, from May 2009 to July 2010. It was conducted in Bhopal, Madhya Pradesh, Central India. A sample size of 150 individuals, 50 of each group, was taken in the study. Whole salivary flow rates were determined by gravimetric method (i.e., in millilitres per minute). The Tenovuo criterion was used, to which numerical scores (SFI) were attributed. RESULT: Results showed that the unstimulated salivary flow rates between patients of Group I and Group III (p< 0.0001) and between Group II and Group III (p < 0.0001) were statistically significant. The study also showed statistically significant relation between subjective and objective oral dryness (chi 2= 55.789, df= 6 and p< 0.0001). CONCLUSION: It was observed that subjective sensation of dry mouth may exist even in the presence of normal salivary flow rates. This might be acknowledged as a psychophysiological expression of depression and may not necessarily reflect actual salivary gland function. The lack of secreted mucins rather than the quantity of saliva may play a role in the genesis of xerostomia. PMID- 26643831 TI - BK Virus Associated Nephropathy, a Cause of Early Renal Allograft Dysfunction: A Single Centre Study. AB - BACKGROUND: BK virus associated nephropathy (BKVN) is an important cause of early graft dysfunction in renal transplant recipients. The present study was carried out to determine the burden of BKVN in a single renal transplant centre in Australia. METHOD: A retrospective analysis of de novo renal transplant recipients from 2010 to 2013 was performed to identify biopsy proven BKVN. Estimated glomerular filtration rate (eGFR) was compared at baseline, at BKVN diagnosis and 3 and 12 months postdiagnosis. RESULT: Of the 317 de novo renal transplants recipients in the study period, 20 (6.3%) developed BKVN. The mean age was 54.8 +/- 13.1 years and 13 (65%) were male. The mean time from transplant to BKVN was 8.7 +/- 6.7 months with 17 (85%) diagnosed within 12 months. Four recipients each were diagnosed BKVN on 3 and 12 month surveillance biopsy. Six (30%) had normal eGFR at diagnosis. Mean eGFR at diagnosis was 38.8 +/- 19.2 ml/min/1.73 m2, which was significantly lower (p < 0.01) than that at baseline (50.3 +/- 16.4 ml/min/1.73 m2). eGFR improved numerically at 3 and 12 months post diagnosis, however the difference was not significant. One patient had graft failure, 19 months after diagnosis. CONCLUSION: BKVN generally occurs in first post-transplant year and is an important cause of early graft dysfunction. Surveillance biopsy helps in detecting subclinical BKVN. PMID- 26643832 TI - A Study on Nutritional Status of Rural School going Children in Kavre District. AB - Background Childhood is a time of active growth in terms of physical size, mental, emotional and psychological development. Normal growth is dependent on adequate nutrition and encompasses major transformations from birth to adulthood. Nutrition is a focal point for health and well being; and has special significance in countries with disadvantages in socioeconomic and hygienic standards. Objective The objective of the present study was to assess the nutritional status in terms of prevalence of underweight, stunting and thinness among rural school going children. Method The present study was cross-sectional study, conducted on 438 rural school going children (169 male and 259 female) with the age group 4-16 years, during the period from April 2014 to July 2014. Age was recorded in year; height and weight were measured in centimeter and kilogram respectively. BMI was calculated by using standard equation. Result The present study concluded that the nutritional status in terms of prevalence of underweight, stunting and thinness were found to be 30.85%, 24.54% and 10.05% respectively among rural school going children of Kavre district. It was revealed that 37.87% was underweight, 29.59% was stunted and 11.25% was thinness among male children whereas in female children, 26.27% was underweight, 21.24% was stunted and 9.27% was thinness. Hence, high prevalence of underweight, stunting and thinness were observed in male than in female children. Conclusion The present study has successfully documented the nutritional status in terms of prevalence of underweight, stunting and thinness among the rural school going children of Kavre district. The results of the present study will be useful for policy makers in their endeavor to formulate various developmental and health care programs. PMID- 26643833 TI - Analgesia before Performing Subarachnoid Block in the Sitting Position in Patients with Proximal Femoral Fracture: A Comparison between Fascia Iliaca Block and Femoral Nerve Block. AB - BACKGROUND: Positioning for subarachnoid block (SAB) in patients with femoral fracture is painful and may remain suboptimal requiring use of large doses of opioids. These patients generally being elderly with multiple comorbidities and frailty are likely to have many undesirable effects of opioids including respiratory depression and confusion. OBJECTIVE: The objective was to compare the feasibility and effectiveness of fascia iliaca compartment block (FICB) and femoral nerve block (FNB) in reducing pain associated with positioning for subarachnoid block in patients undergoing proximal femoral fracture fixation procedures. METHOD: Group FICB patients (n=15) received fascia iliaca block with 30 ml of 1.5% lignocaine with adrenaline and group FNB patients (n=15) received femoral nerve block with 15 ml of 1.5% lignocaine with adrenaline. After the study blocks, patients were kept on supine position for at least 20 minutes before shifting them to the operation theatre. Pain was assessed by using visual analog scale values before the block and during the position for subarachnoid block. Time to perform subarachnoid block, quality of positioning and acceptance was recorded. RESULT: Visual analog scale values during positioning for SAB were lower in FIB group than in FNB (1.0+/-1.1 versus 2.1+/-0.8; P< 0.05). Time to perform SAB was shorter in FIB than in FNB (109.6+/-28.2 seconds versus 134.8+/ 31.9 seconds; P< 0.05). Quality of patient positioning for SAB was comparable between the groups. Patient acceptance was less in group FNB (P< 0.05). CONCLUSION: Fascia iliaca compartment block provides better analgesia than femoral nerve block in terms of facilitating optimal positioning for subarachnoid block in patients undergoing proximal femoral fracture fixation procedure. PMID- 26643834 TI - Measuring Neuroticism in Nepali: Reliability and Validity of the Neuroticism Subscale of the Eysenck Personality Questionnaire. AB - BACKGROUND: The Neuroticism subscale of the Eysenck Personality Questionnaire Revised Short Form (12 items) (EPQRS-N) has proven to be a reliable and valid measure in multiple languages. OBJECTIVE: To develop a single-factor Nepali language version of the EPQRS-N for use in the adult population of Nepal. METHOD: The original English version of EPQRS-N was translated into Nepali using a forward-backward translation protocol. The first set of translated items was modified after testing by factor analysis with principal component extraction in an outpatient sample. Items with low factor correlations or poor semantic consistencies were reworded to fit the gist of the original items in a Nepali cultural context; the revised version was then tested in a representative random sample from the general population. Again, the same statistical procedures were applied. RESULTS: The first trial gave three factors. Based on the factor distribution of the items or their semantic quality, five were reworded. In the second trial, a two-factor solution emerged; the second factor had only one item with high correlation, which also had modest correlation with the first factor. Accordingly, a forced one-factor solution was chosen. This gave an internal consistency (Cronbach's alpha) of 0.80, with item-to-factor correlations from 0.40 to 0.73, and item-to-sum correlations from 0.31 to 0.61. CONCLUSION: The final Nepali version of EPQRS-N achieved satisfactory internal consistency. The item distribution coincided with the original English version, providing acceptable construct validity. It is psychometrically adequate for use in capturing the personality trait of neuroticism, and has broad applicability to the adult population of Nepal because of the diversity of the participant samples in which it was developed. PMID- 26643835 TI - Effect of Teachers Training Workshop Outcomes on Real Classroom Situations of Undergraduate Medical Students. AB - BACKGROUND: Faculty development by conducting regular training, workshops and research related to medical education has been a key feature to upgrade quality of medical education. OBJECTIVE: The aim of this study was to explore responses of the health science teachers, students and peers after the workshop after providing training on student assessment tools and teaching-learning methods. METHOD: Two teacher-training workshops were conducted to the faculty members of B.P. Koirala Institute of Health Sciences from the departments of basic, clinical and allied sciences in Oct. 2010 and Jan. 2011. Qualitative questionnaire based study was conducted, and the questions were validated before the study by expert peer review process. The effect of the training workshop in real classroom outcomes was assessed incorporating student's feedback, evaluation by peers and the self-evaluation by the teacher trainees. RESULT: Pre-test and post-test scores of the participating teachers, before and after the workshop were 62.53 and 71.17 respectively. Among the participants 90.3% teachers expressed enhanced in their role as a teacher for medical undergraduates after the workshop. CONCLUSION: In present study, the faculty members showed accrued interest to participate in teacher's training workshops. The peer evaluation of teacher's performance in their real classroom situations were rated higher than evaluation by the students. Therefore, such training workshops will have a greater impact on the ability of teachers in effective teaching in real classroom situations. PMID- 26643836 TI - Familial Hypodontia: A Case Series. AB - The phenomenon of congenitally missing teeth has been described with different names: hypodontia, oligodontia, anodontia, congenitally missing teeth and dental agenesis. The present paper reports familial hypodontia, involving two siblings from a single family. Case I reported the absence of 18, 12, 22 and 31 teeth whereas case II reported the absence of 31 and 41. On the evaluation of the two reported cases that were offspring of same parents and absence of any clinical features associated with any syndrome the final diagnosis of non- syndromic familial hypodontia was made. Both the cases presented agenesis of the teeth leading to malocclusion and aesthetic disturbances. Cases were offered a treatment of interdisciplinary dental approach. PMID- 26643837 TI - Mucinous Cystic Borderline Tumor of the Mesentery: A Case Report. AB - Mucinous cystic neoplasms are rare tumors of uncertain histogenesis. They arise from the ovaries, pancreas, and other intra-abdominal sites but more unusually from the mesentery. They can present with abdominal pain, distension, or a palpable mass but are commonly an incidental finding. We present a case of a 33 year-old female who presented with complain of pain abdomen for one-year duration. On Physical examination there was a palpable lump in right lumbar region extending to right iliac fossa. CT scan of abdomen and pelvis suggested the mass to be a Mesenteric Cyst. Enucleation of the cyst was done and histopathology report revealed Mucinous Cystic borderline tumor of the Mesentery. PMID- 26643839 TI - Iatrogenic Perforation of Stomach--A Case Report. AB - Gastric lavage is a routine procedure done in many cases of poisoning and it has been advocated by many as a lifesaving procedure. There may be some instances, where it might be unnecessary, ineffective or even detrimental to life. A 35 year old man walked into a casualty, 2 hours after having ingested 15 benzodiazepine tablets. Lavage was done by an unqualified person using Ewald's tube, leading to iatrogenic perforation. The unwarranted use of the procedure proved to be fatal. PMID- 26643838 TI - Pompe Disease: Cyanosed Hypotonic Infant with Normal Respiratory Rate. AB - Infantile hypotonia or floppy infant is a diagnostic challenge when it presents with other presenting complaints such as fever, cough or diarrhea. Many times the hypotonia goes unnoticed when other symptom covers the hypotonia and child continues to receive the treatment for other symptoms. We report a rare case from Nepal of infantile Pompe disease who presented with the history of fever and cough in the recent earthquake disaster camp at remote part of Sindhupalchowk, Nepal. He was being treated as a case of pneumonia. Pompe disease can be diagnosed clinically by taking detailed history and correlating the clinical findings during the presentation with other symptoms. In our case the normal respiratory rate, reduced Spo2 and presence of crackles dominated the hypotonia and was mistreated as pneumonia. High index of suspicion is necessary in diagnosing Pompe disease. PMID- 26643840 TI - Relationship of Angiogenesis and Oral Squamous Cell Carcinoma. AB - Angiogenesis is an important aspect of a variety of physiological and pathological processes; and depends on the alteration of the balance between pro angiogenic and anti-angiogenic factors. The role of angiogenesis in the progression and metastasis of neoplasm is a well established phenomenon. With regards to oral squamous cell carcinoma, it is a field of ongoing research and requires validation for it being used as a mode of anti-cancer therapy. This review focuses on the concept of angiogenesis, the factors associated with it, the relationship of angiogenesis with oral epithelial dysplasia and oral squamous cell carcinoma; the methods of studying angiogenesis and anti angiogenic therapy. PMID- 26643841 TI - Taking Specialist Surgical Services to the Rural District Hospitals at One Forth Cost: A Sustainable 'Return on Investment' Public Health Initiative of Patan Hospital, Patan Academy of Health Sciences, Nepal. AB - The inequitable distribution and centralization of resources and services in urban area persists around the world, more so in developing countries. The challenge to meet the health needs of rural population requires health policy makers, government and concerned organization to put extra efforts. Such efforts require innovative, feasible and sustainable strategies to address the social justice of people living in districts away from capital and urban cities. At Patan Academy of Health Sciences, the medial school curriculum is designed to address these issues. Together with health professionals from Patan Hospital, the main teaching hospital on which the academy evolved, have initiated strategies to bring specialist services, starting with surgical services to remote district hospitals to serve the need of rural population. This initiative is 'desirable, doable and feasible'. Further more, this can be modified for replication and promotion by other academic institutions, central hospitals and government health system. PMID- 26643843 TI - Ligand occupancy in crystal structure of beta1-adrenergic G protein-coupled receptor. PMID- 26643842 TI - Ligand occupancy in crystal structure of beta1-adrenergic G protein-coupled receptor. PMID- 26643844 TI - Q&A: repeat-containing proteins. PMID- 26643845 TI - Src defines a new pool of EGFR substrates. PMID- 26643846 TI - Replication- and transcription-independent histone exchange in oocytes. PMID- 26643847 TI - Probing molecular choreography through single-molecule biochemistry. AB - Single-molecule approaches are having a dramatic impact on views of how proteins work. The ability to observe molecular properties at the single-molecule level allows characterization of subpopulations and acquisition of detailed kinetic information that would otherwise be hidden in the averaging over an ensemble of molecules. In this Perspective, we discuss how such approaches have successfully been applied to in vitro-reconstituted systems of increasing complexity. PMID- 26643848 TI - Clinicopathological characteristics associated with BRAF(K601E) and BRAF(L597) mutations in melanoma. AB - BRAF mutations at codons L597 and K601 occur uncommonly in melanoma. Clinical and pathological associations of these mutations were investigated in a cohort of 1119 patients with known BRAF mutation status. A BRAF mutation was identified in 435 patients; Mutations at L597 and the K601E mutation were seen in 3.4 and 3.2% of these, respectively. K601E melanomas tended to occur in male patients, a median age of 58 yr, were generally found on the trunk (64%) and uncommonly associated with chronically sun-damaged (CSD) skin. BRAF L597 melanomas occurred in older patients (median 66 yr), but were associated with CSD skin (extremities or head and neck location - 73.3%, P = 0.001). Twenty-three percent of patients with V600E- and 43% of patients with K601E-mutant melanomas presented with nodal disease at diagnosis compared to just 14% of patients with BRAF wild-type tumors (P = 0.001 and 0.006, respectively). Overall, these mutations represent a significant minority of BRAF mutations, but have distinct clinicopathological phenotypes and clinical behaviors. PMID- 26643849 TI - Molecular detection of pathogenic leptospiral protein encoding gene (lipL32) in environmental aquatic biofilms. AB - Leptospirosis is a zoonotic disease often encountered during post-monsoon season due to exposure with contaminated water. Leptospires have long been regarded as solitary organisms that persist in soil and aquatic environments. Here, the presence of leptospires in the aquatic biofilm exposed in the paddy field, sewers and stagnant rain water was demonstrated. Biofilm samples from paddy field water, submerged paddy leaves, sewers and stagnant rain waters from urban and rural areas were collected. Total genomic DNA was extracted and pathogenic leptospiral specific gene amplification was carried out to determine the spatial distribution of the bacteria. The degree of pathogenic Leptospira in biofilms from paddy field surface water, submerged leaf, were 33.3% and 27.2% respectively, whereas in rural and urban area, the sampling sites such as stagnant rain water, domestic sewer and collective sewers showed 11.1%, 13% and 16.6% with leptospires respectively. Higher proportion of pathogenic Leptospira in aquatic ecosystems, such as paddy field, could be one of the main factors for the occurrence of disease, more among the agricultural workers. This study would help to identify various survival strategies of leptospires in the environment and thus disease transmission. SIGNIFICANCE AND IMPACT OF THE STUDY: Little is known regarding the mechanisms by which pathogenic leptospires persist in aqueous environment, outside the mammalian host. In this view this is the first report of the distribution of Leptospira in environmental biofilm such as sewers and paddy leaf surfaces. This ability of pathogenic Leptospira to survive in aquatic ecosystems especially in biofilms could be one of the main factors which facilitate its survival in the environment, and thus disease transmission among the risk groups, such as sewage and agriculture worker. This study will encourage researchers in the field to consider biofilm as an important factor, when detecting leptospires in environment. PMID- 26643850 TI - Use and practice of achiral and chiral supercritical fluid chromatography in pharmaceutical analysis and purification. AB - The interest of pharmaceutical companies for complementary high-performance chromatographic tools to assess a product's purity or enhance this purity is on the rise. The high-throughput capability and economic benefits of supercritical fluid chromatography, but also the "green" aspect of CO2 as the principal solvent, render supercritical fluid chromatography very attractive for a wide range of pharmaceutical applications. The recent reintroduction of new robust instruments dedicated to supercritical fluid chromatography and the progress in stationary phase technology have also greatly benefited supercritical fluid chromatography. Additionally, it was shown several times that supercritical fluid chromatography could be orthogonal to reversed-phase high-performance liquid chromatography and could efficiently compete with it. Supercritical fluid chromatography is an adequate tool for small molecules of pharmaceutical interest: synthetic intermediates, active pharmaceutical ingredients, impurities, or degradation products. In this review, we first discuss about general chromatographic conditions for supercritical fluid chromatography analysis to better suit compounds of pharmaceutical interest. We also discuss about the use of achiral and chiral supercritical fluid chromatography for analytical purposes and the recent applications in these areas. The use of preparative supercritical fluid chromatography by pharmaceutical companies is also covered. PMID- 26643851 TI - Social science as a tool in developing scientific thinking skills in underserved, low-achieving urban students. AB - Engagement in purposeful problem solving involving social science content was sufficient to develop a key set of inquiry skills in low-performing middle school students from an academically and economically disadvantaged urban public school population, with this skill transferring to a more traditional written scientific thinking assessment instrument 3weeks later. Students only observing their peers' activity or not participating at all failed to show these gains. Implications are addressed with regard to the mastery of scientific thinking skills among academically disadvantaged students. Also addressed are the efficacy of problem based learning and the limits of observational learning. PMID- 26643852 TI - Margaret McCartney: Christmas presents. PMID- 26643854 TI - Binuclear Aromatic C-H Bond Activation at a Dirhenium Site. AB - The electronically unsaturated dirhenium complex [Re2(CO)8(MU-H)(MU-Ph)] (1) has been found to exhibit aromatic C-H activation upon reaction with N,N diethylaniline, naphthalene, and even [D6]benzene to yield the compounds [Re2(CO)8(MU-H)(MU-eta(1)-NEt2C6H4)] (2), [Re2(CO)8(MU-H)(MU-eta(2)-1,2-C10H7)] (3), and [D6]-1, respectively, in good yields. The mechanism has been elucidated by using DFT computational analyses, and involves a binuclear C-H bond-activation process. PMID- 26643853 TI - A survey among Korea Medicine doctors (KMDs) in Korea on patterns of integrative Korean Medicine practice for lumbar intervertebral disc displacement: Preliminary research for clinical practice guidelines. AB - BACKGROUND: Patients seek Korean Medicine (KM) treatment for a broad range of complaints in Korea, but predominantly for musculoskeletal disorders. We investigated lumbar Intervertebral Disc Displacement (IDD) practice patterns of Korean Medicine doctors (KMDs) within a hospital/clinic network specializing in KM treatment of spinal disorders through survey of diagnosis and treatment methods. METHODS: Questionnaires on clinical practice patterns of KM treatment for lumbar IDD were distributed to 149 KMDs on January 25th, 2015. The questionnaire included items on sociodemographic characteristics, clinical practice patterns, and preferred method of lumbar IDD diagnosis and treatment. KMDs were asked to grade each treatment method for absolute and relative importance in treatment and prognosis, and safety. RESULTS: A total 79.19 % KMDs (n = 118/149) completed the survey, and results showed that integrative care mainly consisting of acupuncture, herbal medicine, Chuna manipulation, and pharmacopuncture was administered to IDD patients. The participant KMDs largely relied on radiological findings (MRI and X-ray) for diagnosis. 'Eight principle pattern identification', 'Qi and Blood syndrome differentiation' and 'Meridian system syndrome differentiation' theories were generally used for KM syndrome differentiation. The most frequently prescribed herbal medication was Chungpa jun, and most commonly used Chuna technique was 'sidelying lumbar extension displacement treatment'. IDD patients received 1.9 +/- 0.3 treatment sessions/week, and KMDs estimated that an average 9.6 +/- 3.5 weeks were needed for 80 % pain relief. CONCLUSIONS: This is the first study to investigate expert opinion on KM treatment of IDD. Further randomized controlled trials and clinical guidelines based on clinical practice patterns of KM are called for. PMID- 26643855 TI - Prevalence and clinical features of the ectopic ACTH syndrome in patients with gastroenteropancreatic and thoracic neuroendocrine tumors. AB - OBJECTIVE: Several series report on the relative contribution of ectopic ACTH syndrome (EAS) in the spectrum of Cushing's syndrome. However, prevalence of EAS in patients with thoracic or gastroenteropancreatic neuroendocrine tumors (GEP NETs) is currently unknown. DESIGN: We assessed, in a tertiary referral center, the prevalence of EAS in a large cohort of thoracic and GEP-NET patients including clinical, biochemical, and radiological features; management; and treatment outcome. METHODS: In total, 918 patients with thoracic or GEP-NETs were studied (1993-2012). Multiple endocrine neoplasia type 1 and small cell lung carcinoma patients were excluded. Differentiation between synchronous, metachronous, and cyclic occurrence of EAS was made. RESULTS: Out of the 918 patients with thoracic and GEP-NETs (469 males and 449 females; median age 58.7 years (range: 17.3-87.3)), 29 patients (3.2%) had EAS (ten males and 19 females; median age 48.1 years (range: 24.7-77.9)). EAS occurred synchronously in 23 patients (79%), metachronously in four patients (14%), and cyclical in two patients (7%) respectively. NETs causing EAS included lung/bronchus (n=9), pancreatic (n=9), and thymic (n=4). In four patients, the cause of EAS was unknown (n=4). Median overall survival (OS) of non-EAS thoracic and GEP-NET patients was 61.2 months (range: 0.6-249.4). Median OS of EAS patients was 41.4 months (range: 2.2-250.9). After comparison, only the first 5-year survival was significantly shorter (P=0.013) in EAS patients. CONCLUSION: Prevalence of EAS in this large cohort of patients with thoracic and GEP-NETs was 3.2%. EAS was mostly caused by thoracic and pancreatic NETs. First 5-year survival of EAS patients was shorter compared with non-EAS patients. PMID- 26643856 TI - Receipt of HIV prevention interventions is more common in community-based clinics than in primary care or acute care settings for Black men who have sex with men in the District of Columbia. AB - Characterization of structural barriers that impede the receipt of HIV prevention and care services is critical to addressing the HIV epidemic among Black men who have sex with men (BMSM). This study investigated the utilization of HIV prevention and general care services among a non-clinic-based sample of BMSM who reported at least one structural barrier to engagement in care. Proportions of participants who had received HIV prevention services and general care services in different settings were compared using Fisher's exact test and correlates of service receipt were assessed using logistic regression. Among 75 BMSM, 60% had accessed a community-based clinic, 21% had accessed a primary care setting, and 36% had accessed an acute care setting in the last 6 months. Greater proportions of participants who had accessed community-based clinics received HIV prevention services during these visits (90%) compared to those who had accessed primary care (53%) and acute care (44%) settings (p = .005). Opportunities for BMSM to receive HIV prevention interventions differed by care setting. Having access to health care did not necessarily facilitate the uptake of HIV prevention interventions. Further investigation of the structurally rooted reasons why BMSM are often unable to access HIV prevention services is warranted. PMID- 26643857 TI - Suppression of p38alpha MAPK Signaling in Osteoblast Lineage Cells Impairs Bone Anabolic Action of Parathyroid Hormone. AB - Intermittent parathyroid hormone administration (iPTH) increases bone mass and strength by stimulating osteoblast number and activity. PTH exerts its anabolic effects through cAMP/protein kinase A (PKA) signaling pathway in mature osteoblasts and osteocytes. Here, we show that inactivation of the p38alpha MAPK encoding gene with the use of an osteocalcin-cre transgene prevents iPTH bone anabolic action. Indeed, iPTH fails to increase insulin-like growth factor 1 expression, osteoblast number and activity, and bone formation in mice lacking p38alpha in osteoblasts and osteocytes. Moreover, iPTH-induced expression of receptor activator of NF-kappaB ligand (RANKL) and subsequent increased bone resorption are suppressed in those mice. Finally, we found that PTH activates p38alpha MAPK downstream of cAMP/PKA signaling pathway in mature osteoblasts. Our findings identify p38alpha MAPK as a key component of PTH signaling in osteoblast lineage cells and highlight its requirement in iPTH osteoanabolic activity. (c) 2015 American Society for Bone and Mineral Research. PMID- 26643858 TI - Decreasing maintenance fluids in normotensive trauma patients may reduce intensive care unit stay and ventilator days. AB - PURPOSE: The purpose of the study is to determine if excessive fluid administration is associated with a prolonged hospital course and worse outcomes. MATERIALS AND METHODS: In July 2013, all normotensive trauma patients admitted to the surgical intensive care unit (ICU) were administered crystalloids at 30 mL/h ("to keep open [TKO]") and were compared to patients admitted during the preceding 6 months who were placed on a rate between 125 mL/h to 150 mL/h (non TKO). The primary outcomes were ICU, hospital, and ventilator days. RESULTS: A total of 101 trauma patients met inclusion criteria: 56 (55.4%) in the TKO and 45 (44.6%) in the non-TKO group. Overall, the 2 groups were similar in regard to age, Injury Severity Score, Acute Physiology and Chronic Health Evaluation IV scores, and the need for mechanical ventilation. TKO had no effect on renal function compared to non-TKO with similarities in maximum hospital creatinine. TKO patients had lower ICU stay (2.7 +/- 1.5 vs 4.1 +/- 4.6 days; P = .03) and ventilator days (1.4 +/- 0.5 vs 5.5 +/- 4.8 days; P < .01). CONCLUSIONS: A protocol that encourages admission basal fluid rate of TKO or 30 mL/h in normotensive trauma patients is safe, reduces fluid intake, and may be associated with a shorter intensive care unit course and fewer ventilator days. PMID- 26643859 TI - Acute respiratory distress syndrome: Predictors of noninvasive ventilation failure and intensive care unit mortality in clinical practice. AB - PURPOSE: Noninvasive ventilation (NIV) is used as an initial ventilatory support in acute respiratory distress syndrome (ARDS), but its utility is unclear, and persistence in those who do not improve may delay intubation and lead to adverse outcomes. Hence, it becomes imperative to have a clear understanding of selecting patients who will benefit from this modality. METHODS: In this prospective observational study, we included all consecutive adults, over a 3-year period, who fulfilled criteria for ARDS by the Berlin definition. Basic demographics, ventilatory support, intensive care unit course, and outcome were recorded. RESULTS: Of 170 patients, 96 (56.47%) were initially managed with NIV. Noninvasive ventilation failure was seen in 42 (43.75%) of 96, and low baseline PaO2/FIO2, shock, and ARDS severity were associated with NIV failure. Overall intensive care unit mortality was 63 (37.1%) of 170, and high Acute Physiology and Chronic Health Evaluation II score, low PaO2/FIO2, shock, and ARDS severity were associated with increased mortality. Noninvasive ventilation failure and mortality were significantly higher in moderate and severe ARDS. CONCLUSIONS: Noninvasive ventilation maybe useful in selected patients with mild ARDS but should be used with great caution in moderate and severe ARDS, as failure risk is high. In addition, low PaO2/FIO2 and shock are associated with NIV failure. Acute Physiology and Chronic Health Evaluation II score, shock, low PaO2/FIO2, and ARDS severity are associated with increased mortality. PMID- 26643860 TI - Use of probiotics to prevent ventilator-associated pneumonia: A survey of pharmacists' attitudes. AB - PURPOSE: The primary objective of this survey was to describe pharmacists' attitudes regarding probiotic use in the intensive care unit (ICU); secondary objectives were to evaluate pharmacists' knowledge and use of probiotics for critically ill patients. METHODS: The survey instrument was rigorously designed and pretested, then distributed in both English and French to Canadian ICU pharmacists. The online survey was open for 5 weeks, and 3 follow-up emails were sent to maximize response rates. RESULTS: Of 303 eligible surveys, 191 were returned (63.0%). Probiotics were available in the hospitals of 69.8% (113/162) of respondents, and 62.0% (101/163) indicated that they had used probiotics for at least 1 ICU patient in the previous year. Most pharmacists (137/171, 80.1%) said that they would "never" consider recommending probiotics for prevention of ventilator-associated pneumonia in ICU patients, and this response was more common (P = .0074) among pharmacists who were "unsure" about the safety of probiotics in this population when compared to those who felt that they knew how safe probiotics are. CONCLUSIONS: Most Canadian ICU pharmacists have used probiotics at least once in the ICU in the last year. However, based on uncertain efficacy and safety, most ICU pharmacists would not currently recommend probiotics for the prevention of ventilator-associated pneumonia. PMID- 26643861 TI - The Google portrayal of coma. PMID- 26643862 TI - Transient receptor potential vanilloid 1 expression and function in splenic dendritic cells: a potential role in immune homeostasis. AB - Neuro-immune interactions, particularly those driven by neuropeptides, are increasingly implicated in immune responses. For instance, triggering calcium channel transient receptor potential vanilloid 1 (TRPV1) on sensory nerves induces the release of calcitonin-gene-related peptide (CGRP), a neuropeptide known to moderate dendritic cell activation and T helper cell type 1 polarization. Despite observations that CGRP is not confined to the nervous system, few studies have addressed the possibility that immune cells can respond to well-documented 'neural' ligands independently of peripheral nerves. Here we have identified functionally relevant TRPV1 on primary antigen-presenting cells of the spleen and have demonstrated both calcium influx and CGRP release in three separate strains of mice using natural agonists. Furthermore, we have shown down regulation of activation markers CD80/86 on dendritic cells, and up-regulation of interleukin-6 and interleukin-10 in response to CGRP treatment. We suggest that dendritic cell responses to neural ligands can amplify neuropeptide release, but more importantly that variability in CGRP release across individuals may have important implications for immune cell homeostasis. PMID- 26643863 TI - A Quasi-Elastic Neutron Scattering Study of the Dynamics of Electrically Constrained Water. AB - We have measured the quasi-elastic neutron scattering (QENS) of an electrohydrodynamic liquid bridge formed between two beakers of pure water when a high voltage is applied, a setup allowing to investigate water under high-voltage without high currents. From this experiment two proton populations were distinguished: one consisting of protons strongly bound to oxygen atoms (immobile population, elastic component) and a second one of quasi-free protons (mobile population, inelastic component) both detected by QENS. The diffusion coefficient of the quasi-free protons was found to be D = (26 +/- 10) * 10(-5) cm(2) s(-1) with a jump length lav ~ 3 A and an average residence time of tau0 = 0.55 +/- 0.08 ps. The associated proton mobility in the proton channel of the bridge is ~9.34 * 10(-7) m(2) V(-1) s(-1), twice as fast as diffusion-based proton mobility in bulk water. It also matches the so-called electrohydrodynamic or "apparent" charge mobility, an experimental quantity which so far has lacked molecular interpretation. These results further corroborate the proton channel model for liquid water under high voltage and give new insights into the molecular mechanisms behind electrohydrodynamic charge transport phenomena and delocalization of protons in liquid water. PMID- 26643865 TI - Membrane depolarization increases ryanodine sensitivity to Ca2+ release to the cytosol in L6 skeletal muscle cells: Implications for excitation-contraction coupling. AB - The dihydropyridine receptor in the plasma membrane and the ryanodine receptor in the sarcoplasmic reticulum are known to physically interact in the process of excitation-contraction coupling. However, the mechanism for subsequent Ca(2+) release through the ryanodine receptor is unknown. Our lab has previously presented evidence that the dihydropyridine receptor and ryanodine receptor combine as a channel for the entry of Ca(2+) under resting conditions, known as store operated calcium entry. Here, we provide evidence that depolarization during excitation-contraction coupling causes the dihydropyridine receptor to disengage from the ryanodine receptor. The newly freed ryanodine receptor can then transport Ca(2+) from the sarcoplasmic reticulum to the cytosol. Experimentally, this should more greatly expose the ryanodine receptor to exogenous ryanodine. To examine this hypothesis, we titrated L6 skeletal muscle cells with ryanodine in resting and excited (depolarized) states. When L6 muscle cells were depolarized with high potassium or exposed to the dihydropyridine receptor agonist BAYK-8644, known to induce dihydropyridine receptor movement within the membrane, ryanodine sensitivity was enhanced. However, ryanodine sensitivity was unaffected when Ca(2+) was elevated without depolarization by the ryanodine receptor agonist chloromethylcresol, or by increasing Ca(2+) concentration in the media. Ca(2+) entry currents (from the extracellular space) during excitation were strongly inhibited by ryanodine, but Ca(2+) entry currents in the resting state were not. We conclude that excitation releases the ryanodine receptor from occlusion by the dihydropyridine receptor, enabling Ca(2+) release from the ryanodine receptor to the cytosol. PMID- 26643864 TI - Possible involvement of the JAK/STAT signaling pathway in N-acetylcysteine mediated antidepressant-like effects. AB - Advances in depression research have targeted inflammation and oxidative stress to develop novel types of treatment. The JAK/STAT signaling pathway plays pivotal roles in immune and inflammatory responses. The present study was designed to investigate the effects of N-acetylcysteine, a putative precursor of the antioxidant glutathione, in an animal model of depression, with an emphasis on the JAK/STAT signaling pathway. Fluoxetine, a classical antidepressant drug was also under investigation. Male Wistar rats were subjected to forced swimming test and given N-acetylcysteine and fluoxetine immediately after the pre-test session, 5 h later and 1 h before the test session of the forced swimming test. N acetylcysteine decreased immobility time (P < 0.05), serum corticosterone (P < 0.001), and hydrogen peroxide (P < 0.001), while restored glutathione concentration. Treatment of the rats with N-acetylcysteine produced significant (P < 0.001) down-regulation of STAT3 mRNA expression and protein phosphorylation. On the other hand, N-acetylcysteine significantly (P < 0.001) increased SOCS3 gene expression; however, SOCS3 protein was not changed. In conclusion, our study suggests that modulation of the JAK/STAT pathway might mediate the antidepressant like effects of N-acetylcysteine. Therefore, depression research may target the JAK/STAT signaling pathway to provide a novel effective therapy. PMID- 26643867 TI - Alcohol consumption and risk of infection after a variceal bleeding in low-risk patients. AB - BACKGROUND & AIMS: Antibiotic prophylaxis is a cornerstone in the management of acute variceal bleeding. However, emergence of multiresistant bacteria and antibiotic-associated complications is a growing problem in cirrhosis. It has been proposed that certain low-risk populations may have good outcomes without antibiotic. We aimed to analyse the stratified risk of bacterial infection after a variceal bleeding in previously considered low-risk patients. METHODS: We analysed prospective data from all consecutive cirrhotic patients with acute variceal bleeding admitted to our tertiary hospital between 2004 and 2012. All patients received somatostatin, variceal ligation and antibiotic prophylaxis. Patients were followed until day 42 or death. Patients were stratified based on Child-Pugh class. Within the low-risk strata, further one-step stratification was performed using baseline risk factors identified through logistic regression multivariate adjustment. RESULTS: Two hundred and fifteen patients were included. Twenty-seven patients (12.5%) developed 32 bacterial infections within 6 weeks after the index bleeding. Multivariate adjustment identified alcohol consumption as a significant risk factor for infection. Within previously considered low-risk patients (Child-Pugh A), the risk of infection was significantly higher in patients with active alcohol consumption (21.4% vs. 0% in non-drinkers, P = 0.015). The risk of infection in Child-Pugh A and B patients with non-alcohol cirrhosis receiving antibiotics was very low (2/81, 2.5%). CONCLUSIONS: Alcohol consumption significantly increased the risk of infection after a variceal bleeding in previously considered low-risk patients. Within Child-Pugh A class, patients with active alcohol consumption should not be considered at low risk of infection. PMID- 26643868 TI - Advances in cryopreservation of spermatogonial stem cells and restoration of male fertility. AB - Spermatogenesis is a highly complicated process which initiated by spermatogonial stem cells (SSCs). SSCs are the only cell type that can restore fertility in infertile recipient after SSCs transplantation. SSCs damage during cancer diagnosis and therapy and their depletion may be cause of male infertility in cancer survivors. In this review, used experimental methods regarding SSCs and testis tissue cryopreservation have been reviewed with a special focus on animal models and human which have generated the majority of data about SSCs and the cryopreservation process. PMID- 26643866 TI - HDAC6 activity is not required for basal autophagic flux in metastatic prostate cancer cells. AB - Histone deacetylase 6 is a multifunctional lysine deacetylase that is recently emerging as a central facilitator of response to stress and may play an important role in cancer cell proliferation. The histone deacetylase 6-inhibitor tubacin has been shown to slow the growth of metastatic prostate cancer cells and sensitize cancer cells to chemotherapeutic agents. However, the proteins histone deacetylase 6 interacts with, and thus its role in cancer cells, remains poorly characterized. Histone deacetylase 6 deacetylase activity has recently been shown to be required for efficient basal autophagic flux. Autophagy is often dysregulated in cancer cells and may confer stress resistance and allow for cell maintenance and a high proliferation rate. Tubacin may therefore slow cancer cell proliferation by decreasing autophagic flux. We characterized the histone deacetylase 6-interacting proteins in LNCaP metastatic prostate cancer cells and found that histone deacetylase 6 interacts with proteins involved in several cellular processes, including autophagy. Based on our interaction screen, we assessed the impact of the histone deacetylase 6-inhibitor tubacin on autophagic flux in two metastatic prostate cancer cell lines and found that tubacin does not influence autophagic flux. Histone deacetylase 6 therefore influences cell proliferation through an autophagy-independent mechanism. PMID- 26643870 TI - Genetic variation in vitamin D receptor gene (Fok1:rs2228570) is associated with risk of coronary artery disease. AB - OBJECTIVE: The Fok1 polymorphism (rs2228570) in vitamin D receptor gene appears to be the only polymorphism influencing size of translated protein. Investigations into its association with coronary artery disease (CAD) are sparse. METHODS: Male patients (n = 98) with verified CAD were recruited alongside age- and sex-matched controls (n = 55). Genotyping was performed by PCR RFLP and plasma 25-Hydroxyvitamin D levels were assessed by HPLC-UV. RESULTS: The C-variant (mutant) was predominantly expressed in patients compared to controls (68.9% versus 55.5%; p = 0.025). The observed genotypes were not associated with 25-Hydroxyvitamin D levels. CONCLUSION: This study presents Fok1 polymorphism as a potential genetic marker for CAD. PMID- 26643869 TI - Binge drinking and perceived ethnic discrimination among Hispanics/Latinos: Results from the Hispanic community health study/study of Latinos sociocultural ancillary study. AB - The study assessed whether overall perceived ethnic discrimination and four unique discrimination types were associated with binge drinking in participants from the Hispanic Community Health Study/Study of Latinos who also completed the Hispanic Community Health Study/Study of Latinos Sociocultural Ancillary Study (n = 5,313). In unadjusted analyses that were weighted for sampling strategy and design, each unit increase in discrimination type was associated with a 12-63% increase in odds of binge drinking; however, after adjusting for important demographic variables including age, sex, heritage group, language, and duration of U.S. residence, there was no longer an association between discrimination and binge drinking. Further research still needs to identify the salient factors that contribute to increased risk for binge drinking among Hispanics/Latinos. PMID- 26643873 TI - Tuning the conductance of H2O@C60 by position of the encapsulated H2O. AB - The change of conductance of single-molecule junction in response to various external stimuli is the fundamental mechanism for the single-molecule electronic devices with multiple functionalities. We propose the concept that the conductance of molecular systems can be tuned from inside. The conductance is varied in C60 with encapsulated H2O, H2O@C60. The transport properties of the H2O@C60-based nanostructure sandwiched between electrodes are studied using first principles calculations combined with the non-equilibrium Green's function formalism. Our results show that the conductance of the H2O@C60 is sensitive to the position of the H2O and its dipole direction inside the cage with changes in conductance up to 20%. Our study paves a way for the H2O@C60 molecule to be a new platform for novel molecule-based electronics and sensors. PMID- 26643872 TI - Genomic landscape of liposarcoma. AB - Liposarcoma (LPS) is the most common type of soft tissue sarcoma accounting for 20% of all adult sarcomas. Due to absence of clinically effective treatment options in inoperable situations and resistance to chemotherapeutics, a critical need exists to identify novel therapeutic targets. We analyzed LPS genomic landscape using SNP arrays, whole exome sequencing and targeted exome sequencing to uncover the genomic information for development of specific anti-cancer targets. SNP array analysis indicated known amplified genes (MDM2, CDK4, HMGA2) and important novel genes (UAP1, MIR557, LAMA4, CPM, IGF2, ERBB3, IGF1R). Carboxypeptidase M (CPM), recurrently amplified gene in well-differentiated/de differentiated LPS was noted as a putative oncogene involved in the EGFR pathway. Notable deletions were found at chromosome 1p (RUNX3, ARID1A), chromosome 11q (ATM, CHEK1) and chromosome 13q14.2 (MIR15A, MIR16-1). Significantly and recurrently mutated genes (false discovery rate < 0.05) included PLEC (27%), MXRA5 (21%), FAT3 (24%), NF1 (20%), MDC1 (10%), TP53 (7%) and CHEK2 (6%). Further, in vitro and in vivo functional studies provided evidence for the tumor suppressor role for Neurofibromin 1 (NF1) gene in different subtypes of LPS. Pathway analysis of recurrent mutations demonstrated signaling through MAPK, JAK STAT, Wnt, ErbB, axon guidance, apoptosis, DNA damage repair and cell cycle pathways were involved in liposarcomagenesis. Interestingly, we also found mutational and copy number heterogeneity within a primary LPS tumor signifying the importance of multi-region sequencing for cancer-genome guided therapy. In summary, these findings provide insight into the genomic complexity of LPS and highlight potential druggable pathways for targeted therapeutic approach. PMID- 26643874 TI - Extracellular and cellular Hsp72 differ as biomarkers in acute exercise/environmental stress and recovery. AB - Stress-inducible Hsp72 is a potential biomarker to track risk of exertional heat illness during exercise/environmental stress. Characterization of extracellular (eHsp72) vs cellular Hsp72 (iHsp72) responses is required to define the appropriate use of Hsp72 as a reliable biomarker. In each of four repeat visits, participants (n = 6 men, 4 trials; total n = 24): (a) passively dehydrated overnight, (b) exercised (2 h) with no fluid in a hot, humid environmental chamber, (c) rested and rehydrated (1 h), (d) maximally exercised for 0.5 h, and (e) returned after 24 h of at-home recovery and rehydration. We measured rectal temperature, hydration status (% body mass loss, urine markers, serum osmolality), and Hsp72 (ELISA, flow cytometry. eHsp72 (circulating) and iHsp72 (CD3+ PBMCs) correlated (P < 0.05) with markers of heat, exercise, and dehydration stresses. eHsp72 immediately post-exercise (>15% above baseline, P < 0.05) decreased back to baseline levels by 1 h post-exercise, but iHsp72 expression continued to rise and remained elevated 24 h post-exercise (~2.5-fold baseline, P < 0.05). These data suggest that in addition to the classic physiological biomarkers of exercise heat stress, using cellular Hsp72 as an indicator of lasting effects of stress into recovery may be most appropriate for determining long-term effects of stress on risk for exertional heat illness. PMID- 26643876 TI - Robust Vacuum-/Air-Dried Graphene Aerogels and Fast Recoverable Shape-Memory Hybrid Foams. AB - New graphene aerogels can be fabricated by vacuum/air drying, and because of the mechanical robustness of the graphene aerogels, shape-memory polymer/graphene hybrid foams can be fabricated by a simple infiltration-air-drying-crosslinking method. Due to the superelasticity, high strength, and good electrical conductivity of the as-prepared graphene aerogels, the shape-memory hybrid foams exhibit excellent thermotropical and electrical shape-memory properties, outperforming previously reported shape-memory polymer foams. PMID- 26643875 TI - Multimodal SHG-2PF Imaging of Microdomain Ca2+-Contraction Coupling in Live Cardiac Myocytes. AB - RATIONALE: Cardiac myocyte contraction is caused by Ca(2+) binding to troponin C, which triggers the cross-bridge power stroke and myofilament sliding in sarcomeres. Synchronized Ca(2+) release causes whole cell contraction and is readily observable with current microscopy techniques. However, it is unknown whether localized Ca(2+) release, such as Ca(2+) sparks and waves, can cause local sarcomere contraction. Contemporary imaging methods fall short of measuring microdomain Ca(2+)-contraction coupling in live cardiac myocytes. OBJECTIVE: To develop a method for imaging sarcomere level Ca(2+)-contraction coupling in healthy and disease model cardiac myocytes. METHODS AND RESULTS: Freshly isolated cardiac myocytes were loaded with the Ca(2+)-indicator fluo-4. A confocal microscope equipped with a femtosecond-pulsed near-infrared laser was used to simultaneously excite second harmonic generation from A-bands of myofibrils and 2 photon fluorescence from fluo-4. Ca(2+) signals and sarcomere strain correlated in space and time with short delays. Furthermore, Ca(2+) sparks and waves caused contractions in subcellular microdomains, revealing a previously underappreciated role for these events in generating subcellular strain during diastole. Ca(2+) activity and sarcomere strain were also imaged in paced cardiac myocytes under mechanical load, revealing spontaneous Ca(2+) waves and correlated local contraction in pressure-overload-induced cardiomyopathy. CONCLUSIONS: Multimodal second harmonic generation 2-photon fluorescence microscopy enables the simultaneous observation of Ca(2+) release and mechanical strain at the subsarcomere level in living cardiac myocytes. The method benefits from the label free nature of second harmonic generation, which allows A-bands to be imaged independently of T-tubule morphology and simultaneously with Ca(2+) indicators. Second harmonic generation 2-photon fluorescence imaging is widely applicable to the study of Ca(2+)-contraction coupling and mechanochemotransduction in both health and disease. PMID- 26643877 TI - Diabetic neuropathy in the gut: pathogenesis and diagnosis. AB - The activity of the digestive tract is usually regulated to match its content: physiological stimuli in the gut induce modulatory reflexes that control digestive function so that digestion is normally not perceived. However, under certain circumstances, digestive stimuli may activate sensory afferents and give rise to conscious sensations. Both reflex and sensory signals are modulated by a balance of excitatory and inhibitory mechanisms. Patients with diabetes may develop a neuropathy affecting the control of gastric and/or intestinal motor function and the sensory innervation as well. During fasting the stomach is contracted and relaxes to accommodate a meal. After ingestion the stomach progressively recontracts and this contraction gently produces gastric emptying. Impairment of excitatory pathways affects the contraction of the stomach, which may result in delayed gastric emptying and vomiting of retained food. Conversely, alteration of the inhibitory neural pathways results in impaired relaxation of the stomach in response to a meal; in this case increased wall tension may produce early satiation, fullness and nausea. Diabetic neuropathy may distort the control of intestinal motility, which can lead to diverse symptoms such as diarrhoea, constipation, intestinal distension and abdominal pain. Neuropathy in diabetes may also affect the sensory nerves of the gut, and depending on which pathways are involved, perception may be increased or reduced. In summary, in patients with diabetic neuropathy, disorders of gut motor function are associated with sensory abnormalities, and the combination of impaired pathways determines the clinical consequences. This review summarises a presentation given at the 'Diagnosis and treatment of autonomic diabetic neuropathy in the gut' symposium at the 2015 annual meeting of the EASD. It is accompanied by another mini-review on a topic from this symposium (by Hans Tornblom, DOI: 10.1007/s00125-015-3829-9 ) and a commentary by the Session Chair, Peter Kempler (DOI: 10.1007/s00125-015 3826-y ). PMID- 26643878 TI - Elevated asleep BP as predictor of type 2 diabetes and therapeutic target for prevention. PMID- 26643879 TI - Glucose transporters 1, 3, 6, and 10 are expressed in gastric cancer and glucose transporter 3 is associated with UICC stage and survival. AB - BACKGROUND: Due to proliferation and increased metabolism, cancer cells have high glucose requirements. The glucose uptake of cells is influenced by a group of membrane proteins denoted the glucose transporter family (Glut-1 to -12). Whereas increased expression and a negative correlation with survival have been described for Glut-1 in several types of cancer, the impact of other glucose transporters on tumor biology is widely unknown. METHODS: In this retrospective study, gastric cancer specimens of 150 patients who underwent total gastrectomy between 2005 and 2010 were stained for Glut-1, -3, -6, and -10 by immunohistochemistry. Expression of Glut-1, -3, -6, and 10 was correlated to prognosis as well as clinical and pathological parameters. RESULTS: Glut-1, Glut-3, Glut-6, and Glut-10 were expressed in 22.0, 66.0, 38.0, and 43.3 % of the analyzed samples. Whereas Glut 1, -6, and -10 did not show a correlation with prognosis, positive staining for Glut-3 was associated with higher UICC stage and inferior prognosis. The mean overall survival was 38.6 months for Glut-3 positive patients, as compared to 51.2 months for Glut-3 negative patients (p < 0.05). Coexpression of two or more of the analyzed glucose transporters was correlated to inferior prognosis. Glut-3 and UICC stage were significant prognostic factors in multivariate analysis. CONCLUSIONS: All of the analyzed glucose transporters were expressed in a significant proportion of the gastric cancer samples. Glut-3 was associated with higher UICC stage and inferior prognosis. These findings are relevant to therapeutic approaches that target glucose metabolism as well as to imaging using radioactively labeled glucose. PMID- 26643881 TI - Small Sample Kernel Association Tests for Human Genetic and Microbiome Association Studies. AB - Kernel machine based association tests (KAT) have been increasingly used in testing the association between an outcome and a set of biological measurements due to its power to combine multiple weak signals of complex relationship with the outcome through the specification of a relevant kernel. Human genetic and microbiome association studies are two important applications of KAT. However, the classic KAT framework relies on large sample theory, and conservativeness has been observed for small sample studies, especially for microbiome association studies. The common approach for addressing the small sample problem relies on computationally intensive resampling methods. Here, we derive an exact test for KAT with continuous traits, which resolve the small sample conservatism of KAT without the need for resampling. The exact test has significantly improved power to detect association for microbiome studies. For binary traits, we propose a similar approximate test, and we show that the approximate test is very powerful for a wide range of kernels including common variant- and microbiome-based kernels, and the approximate test controls the type I error well for these kernels. In contrast, the sequence kernel association tests have slightly inflated genomic inflation factors after small sample adjustment. Extensive simulations and application to a real microbiome association study are used to demonstrate the utility of our method. PMID- 26643880 TI - Is conversion therapy possible in stage IV gastric cancer: the proposal of new biological categories of classification. AB - Conversion therapy for gastric cancer (GC) has been the subject of much recent attention. It is defined as a surgical treatment aiming at an R0 resection after chemotherapy for tumors that were originally unresectable or marginally resectable for technical and/or oncological reasons. However, the indications for resection remain to be clarified. In the present review, we focus on the biology and heterogeneous characteristics of stage IV GC and propose new categories of classification. Stage IV GC patients can be divided based on the absence (categories 1 and 2) or presence (categories 3 and 4) of macroscopically detectable peritoneal dissemination, which has a different biological outcome compared to hematological metastasis. Category 1 is defined oncologically as stage IV but the metastasis is technically resectable. Category 2 includes a marginally resectable metastasis or patients for whom the operation would not necessarily be the best choice. Category 3 includes a potentially unresectable metastasis of peritoneal dissemination that is only macroscopically detectable. Category 4 includes noncurable metastasis with peritoneal and other organ metastasis. The indications for conversion therapy might include the patients from category 2, some patients from category 3 and a very small number of patients from category 4. The longer survival can be expected for patients corresponding to categories 1, 2 and, to a lesser extent, 3, while the treatment of other patients focuses on "care." The provision of conversion therapy for stage IV GC patients might be one of the main roles of surgical oncologists in the near future. PMID- 26643882 TI - Effect of extracorporeal CO2 removal on right ventricular and hemodynamic parameters in a patient with acute respiratory distress syndrome. AB - We present a female patient with severe acute respiratory distress syndrome (ARDS) necessitating intubation and mechanical ventilation on the intensive care unit (ICU). High ventilatory pressures were needed because of hypoxia and severe hypercapnia with respiratory acidosis, resulting in right ventricular dysfunction with impaired haemodynamic stability. A veno-venous extracorporeal CO2 removal (ECCO2R) circuit was initiated, effectively eliminating carbon dioxide while improving oxygenation and enabling a reduction in applied ventilatory pressures. We noted a marked improvement of right ventricular function with restoration of haemodynamic stability. Within one week, the patient was weaned from both ECCO2R and mechanical ventilation. Besides providing adequate gas exchange, extracorporeal assist devices may be helpful in ameliorating right ventricular dysfunction during ARDS. PMID- 26643883 TI - Clinical evaluation of emboli removal by integrated versus non-integrated arterial filters in new generation oxygenators. AB - OBJECTIVE: To compare the emboli filtration efficiency of five integrated or non integrated oxygenator-filter combinations in cardiopulmonary bypass circuits. METHODS: Fifty-one adult patients underwent surgery using a circuit with an integrated filtration oxygenator or non-integrated oxygenator with a separate 20 um arterial line filter (Sorin Dideco Avant D903 + Pall AL20 (n=12), Sorin Inspire 6 M + Pall AL20 (n=10), Sorin Inspire 6M F (n=9), Terumo FX25 (n=10), Medtronic Fusion (n=10)). The Emboli Detection and Classification quantifier was used to count emboli upstream and downstream of the primary filter throughout cardiopulmonary bypass. The primary outcome measure was to compare the devices in respect of the median proportion of emboli removed. RESULTS: One device (Sorin Inspire 6 M + Pall AL20) exhibited a significantly greater median percentage reduction (96.77%, IQR=95.48 - 98.45) in total emboli counts compared to all other devices tested (p=0.0062 - 0.0002). In comparisons between the other units, they all removed a greater percentage of emboli than one device (Medtronic Fusion), but there were no other significant differences. CONCLUSION: The new generation Sorin Inspire 6 M, with a stand-alone 20 um arterial filter, appeared most efficient at removing incoming emboli from the circuit. No firm conclusions can be drawn about the relative efficacy of emboli removal by units categorised by class (integrated vs non-integrated); however, the stand-alone 20 um arterial filter presently sets a contemporary standard against which other configurations of equipment can be judged. PMID- 26643884 TI - MICS - MiECC: Can't have one without the other. PMID- 26643885 TI - Mating system divergence affects the distribution of sequence diversity within and among populations of recently diverged subspecies of Clarkia xantiana (Onagraceae). AB - PREMISE OF THE STUDY: The population biology of outcrossing and self-fertilizing taxa is thought to differ because of the advantage that selfers have in colonizing unoccupied sites where mates and pollinators may be limiting (Baker's Law). This reduced tendency for outcrossers to colonize new sites, along with their greater dependence on pollinators to disperse pollen, has the potential to differently influence the genetic diversity and structure of outcrossing and selfing populations. METHODS: We conducted a comparative population genetic study of two sister outcrossing and selfing subspecies of Clarkia xantiana that have very recently diverged. We used DNA sequence variation (>40 kb from eight nuclear loci) from large samples of individuals from 14 populations to assess geographic patterns of genetic diversity and make inferences about the demographic and colonization histories of each subspecies. KEY RESULTS: We show that sequence variation is strongly reduced across all selfing populations. The demographic history of selfing populations exhibits recent colonization bottlenecks, whereas such bottlenecks are rarely observed for the outcrosser. The greater effect of genetic drift in the selfer has resulted in strong population genetic structure, but with no pattern of isolation by distance. By contrast, the stronger effect of gene flow in the outcrosser has resulted in considerably less structure, but a significant pattern of isolation by distance. CONCLUSIONS: Taken together, our results suggest that selfing populations are not at migration-drift equilibrium, are affected by strong episodes of genetic drift during colonization, and experience little or no subsequent gene flow from other populations after those founder events. PMID- 26643886 TI - No association between plant mating system and geographic range overlap. AB - PREMISE OF THE STUDY: Automatic self-fertilization may influence the geography of speciation, promote reproductive isolation between incipient species, and lead to ecological differentiation. As such, selfing taxa are predicted to co-occur more often with their closest relatives than are outcrossing taxa. Despite suggestions that this pattern may be general, the extent to which mating system influences range overlap in close relatives has not been tested formally across a diverse group of plant species pairs. METHODS: We tested for a difference in range overlap between species pairs for which zero, one, or both species are selfers, using data from 98 sister species pairs in 20 genera across 15 flowering plant families. We also used divergence time estimates from time-calibrated phylogenies to ask how range overlap changes with divergence time and whether this effect depends on mating system. KEY RESULTS: We found no evidence that automatic self fertilization influenced range overlap of closely related plant species. Sister pairs with more recent divergence times had modestly greater range overlap, but this effect did not depend on mating system. CONCLUSIONS: The absence of a strong influence of mating system on range overlap suggests that mating system plays a minor or inconsistent role compared with many other mechanisms potentially influencing the co-occurrence of close relatives. PMID- 26643887 TI - A comparison of autogenous theories for the origin of eukaryotic cells. AB - PREMISE: Eukaryotic cells have many unique features that all evolved on the stem lineage of living eukaryotes, making it difficult to reconstruct the order in which they accumulated. Nuclear endosymbiotic theories hold that three prokaryotes (nucleus, cytoplasm, and mitochondrion) came together to form a eukaryotic cell, whereas autogenous models hold that the nucleus and cytoplasm formed through evolutionary changes in a single prokaryotic lineage. Given several problems with nuclear endosymbiotic theories, this review focuses on autogenous models. KEY INSIGHTS: Until recently all autogenous models assumed an outside-in (OI) topology, proposing that the nuclear envelope was formed from membrane-bound vesicles within the original cell body. Buzz Baum and I recently proposed an inside-out (IO) alternative, suggesting that the nucleus corresponds to the original cell body, with the cytoplasmic compartment deriving from extracellular protrusions. In this review, I show that OI and IO models are compatible with both mitochondria early (ME) or mitochondria late (ML) formulations. Whereas ME models allow that the relationship between mitochondria and host was mutualistic from the outset, ML models imply that the association began with predation or parasitism, becoming mutualistic later. In either case, the mutualistic interaction that eventually formed was probably syntrophic. CONCLUSIONS: Diverse features of eukaryotic cell biology align well with the IOME model, but it would be premature to rule out the OIME model. ML models require that phagocytosis, a complex and energy expensive process, evolved before mitochondria, which seems unlikely. Nonetheless, further research is needed, especially resolution of the phylogenetic affinities of mitochondria. PMID- 26643888 TI - Fossil evidence for open, Proteaceae-dominated heathlands and fire in the Late Cretaceous of Australia. AB - PREMISE OF THE STUDY: The origin of biomes is of great interest globally. Molecular phylogenetic and pollen evidence suggest that several plant lineages that now characterize open, burnt habitats of the sclerophyll biome, became established during the Late Cretaceous of Australia. However, whether this biome itself dates to that time is problematic, fundamentally because of the near absence of relevant, appropriately aged, terrestrial plant macro- or mesofossils. METHODS: We recovered, identified, and interpreted the ecological significance of fossil pollen, foliar and other remains from a section of core drilled in central Australia, which we dated as Late Campanian-Maastrichtian. KEY RESULTS: The sediments contain plant fossils that indicate nutrient-limited, open, sclerophyllous vegetation and abundant charcoal as evidence of fire. Most interestingly, >30 pollen taxa and at least 12 foliage taxa are attributable to the important Gondwanan family Proteaceae, including several minute, amphistomatic, and sclerophyllous foliage forms consistent with subfamily Proteoideae. Microfossils, including an abundance of Sphagnales and other wetland taxa, provided strong evidence of a fenland setting. The local vegetation also included diverse Ericaceae and Liliales, as well as a range of ferns and gymnosperms. CONCLUSIONS: The fossils provide strong evidence in support of hypotheses of great antiquity for fire and open vegetation in Australia, point to extraordinary persistence of Proteaceae that are now emblematic of the Mediterranean-type climate southwestern Australian biodiversity hotspot and raise the profile of open habitats as centers of ancient lineages. PMID- 26643889 TI - Understanding diploid diversity: A first step in unraveling polyploid, apomictic complexity in Amelanchier. AB - PREMISE OF THE STUDY: Delimitation of Amelanchier species is difficult because of polyploidy and gametophytic apomixis. A first step in unraveling this species problem is understanding the diversity of the diploids that contributed genomes to polyploid apomicts. This research helps clarify challenging species delimitation problems attending polyploid, apomictic complexity. METHODS: We sampled 431 diploid accessions from 13 species, of which 10 are North American and three are Old World. Quantitative morphological analyses tested the null hypothesis of no discrete groups. Using three to nine diploid accessions per species, we constructed phylogenies with DNA sequences from ETS, ITS, the second intron of LEAFY, and chloroplast regions rpoB-trnC, rpl16, trnD-trnT, and ycf6 psbM. KEY RESULTS: Most Amelanchier diploid taxa are morphologically and ecogeographically distinct and genetically exclusive lineages. They rarely hybridize with one another. Nuclear and chloroplast DNA sequences almost completely resolve the Amelanchier phylogeny. The backbone is the mostly western North American clade A, eastern North American clade B, and Old World clade O. DNA sequences and morphology support clades A and O as sister taxa. Despite extensive paralogy, our LEAFY data are phylogenetically informative and identify a clade (T) of three arborescent taxa within clade B. CONCLUSIONS: Amelanchier diploids differ strikingly from polyploid apomicts, in that hybridization among them is rare, and they form taxa that would qualify as species by most species concepts. Knowledge of diploid morphology, phylogeny, and ecogeography provides a foundation for understanding the evolutionary history of polyploid apomicts, their patterns of diversification, and their species status. PMID- 26643890 TI - [Combining microcredit, microinsurance, and the provision of health care can improve access to quality care in urban areas of Africa: Results of an experiment in the Bandalungwa health zone in Kinshasa, the Congo]. AB - This study, based on a survey conducted in 2008, examines how combining microcredit, microinsurance, and health care provision can improve access to quality care in the health zone of Bandalungwa, in Kinshasa. The bivariate analysis showed a significant association between increased purchasing power and earnings (p = 0.001), between earnings and savings (p = 0.000), and between health insurance and improved access to health care. These results show that 68.8% of borrowers reported an increase in their purchasing power, of whom 82% reported profits. Those with savings were 24.7 times more likely to purchase health insurance than those without; and 72% of those who regularly made health insurance payments improved their access to care. Combining microcredit, health microinsurance, and health care can improve access to quality health care at lower cost. This suggests that health insurance could usefully be integrated into the primary health-care system. PMID- 26643891 TI - Promoter-associated endogenous and exogenous small RNAs suppress human bladder cancer cell metastasis by activating p21 (CIP1/WAF1) expression. AB - Accumulating data suggest that micro RNAs (miRNAs) or double-stranded RNAs (dsRNAs) can activate gene expression by targeting promoters. The cyclin dependent kinase inhibitor p21 (CIP1/WAF1) (p21) has also been shown to suppress epithelial-mesenchymal transition (EMT) which plays a crucial role in the early stage of tumor metastases and invasiveness. In a previous study, we have reported that miR-370-5p is low-expressed in bladder cancer (BCa) tissues and cell lines. Here, we identified that miR-370-5p and sequence homology dsRNA (dsP21-555) fully complementary to promoter hold the potent abilities to induce p21 expression. Moreover, transfection of miR-370-5p or dsP21-555 into BCa cells remarkably inverts EMT-associated genes (increases epithelial cell makers E-cadherin and beta-catenin, and decreases mesenchymal cell markers ZEB1 and Vimentin) expression mainly via regulating p21 expression. Besides, through manipulating p21, both the candidates can retard BCa cell migration and invasion. In summary, our results provide evidence that both endogenous and exogenous small RNAs may function to induce p21 expression by interacting with the similar promoter region and impede BCa metastasis. PMID- 26643892 TI - PIN1 genetic polymorphisms and the susceptibility of HBV-related hepatocellular carcinoma in a Guangxi population. AB - Peptidyl-prolyl cis/trans isomerase NIMA-interacting 1 (PIN1) plays a critical role in different signaling pathways, cell cycle progression and proliferation, and gene expression, and it has been found to overexpress in many tumor tissues. Recently, researchers have found that PIN1 gene polymorphisms may alter the function of protein and be associated with the risk of cancer. The present study analyzed three common polymorphisms in promoter regions (rs2233678 and rs2233679) and in exon2 (rs2233682) of the PIN1 gene in 254 patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) and 235 healthy controls in a Guangxi study population to determine whether any relationship exists between the polymorphisms and the risk of HBV-related HCC. The results revealed that the rs2233679 TT genotype was associated with increased risk of HCC with HBV infection [odds ratio (OR) = 2.04, 95 % confidence interval (95 % CI) = 1.13 3.69, p = 0.019]. This association was stronger in men than in women (OR = 2.17, 95 % CI = 1.09-4.34, p = 0.028) as well as in men 50 years of age and older (OR = 3.91, 95 % CI = 1.29-11.80, p = 0.016); moreover, for alcohol drinkers, being a carrier of the PIN1 rs2233679 CT genotype had a moderately increased risk of HCC (OR = 3.98, 95 % CI = 1.02-15.57, p = 0.047). In contrast, people carrying the rs2233682 GA genotype and A alleles were 0.23 times more likely to develop HCC (OR = 0.23, 95 % CI = 0.06-0.87, p = 0.031 and OR = 0.23, 95 % CI = 0.06-0.87, p = 0.030). No such associations were found in the PIN1 rs2233678 polymorphisms between the HBV-related HCC cases and the controls. In addition, the haplotype GCA was found to be a high protection factor for HCC with HBV infection (OR = 0.14, 95 % CI = 0.03-0.62, p = 0.003). In conclusion, this study's findings suggest that the PIN1 rs2233679 TT genotype, the rs2233682GA genotype, and A alleles might be associated with the HBV-related HCC in a Guangxi study population. PMID- 26643893 TI - Elevated serum soluble CD14 levels in chronic HBV infection are significantly associated with HBV-related hepatocellular carcinoma. AB - Hepatitis B virus (HBV) infection is a major cause of chronic liver diseases including hepatocellular carcinoma (HCC). CD14 and its soluble form sCD14 play important roles in immunity and are involved in the translocation of bacteria and their products which is related to the pathogenesis in chronic HBV infection. This study investigated serum sCD14 levels in HBV chronically infected patients with various clinical diseases. Serum sCD14 levels in HBV patients were significantly elevated compared with those of healthy controls. HCC patients had significantly highest levels of serum sCD14 across all the HBV-related diseases. Serum sCD14 levels significantly discriminated HCC from other HBV-related non-HCC diseases. The area under the receiver operating characteristic curve (AUC) of sCD14 levels for HCC was significantly higher in comparison with other HBV related non-HCC diseases. The AUC of sCD14 for HCC (0.868, 95 % CI 0.791-0.946, P < 0.001) was higher than that of alpha-fetoprotein (0.660, 95 % CI 0.508-0.811, P = 0.039). Serum level of sCD14 was associated with the overall survival (OS) of HCC patients, with sCD14 levels >20 ng/mL being significantly related to poorer OS (P = 0.017). Multivariate regression showed that serum sCD14 level was an independent factor associated with the OS rates of HBV-related HCC patients (HR 2.544, 95 % CI 1.169-5.538, P = 0.019). HCC resection resulted in a significant decrease of sCD14 levels (P < 0.001). These findings suggest the potential role of sCD14 in the pathogenesis of chronic HBV infection, especially the development of HCC, and the potential usefulness of sCD14 as a biomarker for discriminating clinical diseases and predicting survival of HCC patients in chronic HBV infection. PMID- 26643894 TI - Down-regulation of SNX1 predicts poor prognosis and contributes to drug resistance in colorectal cancer. AB - As a potential tumor suppressor, the detailed clinical application value of sorting nexin 1 (SNX1) has not been elucidated in colorectal cancer (CRC). The aim of the present study was to evaluate the expression of SNX1 in CRC tissues and to determine its correlation with clinicopathologic characteristics and its impact on patient's prognosis. We detected the expression of SNX1 mRNA in 72 CRC patients and SNX1 protein in 237 CRC patients by real-time polymerase chain reaction (RT-PCR) and immunohistochemical staining, respectively. Relationship between the expression of SNX1 and various clinicopathological features in these patients was evaluated. Both the mRNA and protein expression of SNX1 were remarkably decreased in CRC tissues compared with paired non-cancerous tissues, and the down-regulation of SNX1 protein was strongly associated with poor differentiation and poor overall survival (OS) rate of CRC patients. Ectopic SNX1 expression repressed CRC cell growth and promoted tumor sensitivity to most commonly used chemotherapeutic drugs (oxaliplatin and 5-Fluorouracil). In conclusion, overexpression of SNX1 may serve as a new therapeutic strategy for CRC. PMID- 26643895 TI - Blocking autophagy enhanced leukemia cell death induced by recombinant human arginase. AB - Recombinant human arginase (rhArg) is an arginine-degrading enzyme that has been evaluated as effective therapeutics for varieties of malignant tumors and is in clinical trials for hepatocellular carcinoma (HCC) treatment nowadays. Our previous studies have reported that rhArg could induce autophagy and apoptosis in lymphoma cells and inhibiting autophagy could enhance the efficacy of rhArg on lymphoma. However, whether rhArg could induce autophagy and what roles autophagy plays in leukemia cells are unclear. In this study, we demonstrated that rhArg treatment could lead to the formation of autophagosomes and the upregulation of microtubule-associated protein light chain 3 II (LC3-II) in human promyelocytic leukemia HL-60 cells and human acute T cell leukemia Jurkat cells. Furthermore, inhibiting autophagy using 3-methyladenine (3-MA) or chloroquine (CQ) could significantly enhance rhArg-induced cell growth inhibition and apoptosis. Taken together, these findings indicated that rhArg induced autophagy in leukemia cells and inhibiting autophagy enhanced anti-leukemia effect of rhArg, which might encourage the treatment of leukemia by targeting arginine depletion and autophagy in clinics. PMID- 26643897 TI - Development of a Method for Profiling Protein Interactions with LNA-Modified Antisense Oligonucleotides Using Protein Microarrays. AB - Development of locked nucleic acid (LNA) gapmers, antisense oligonucleotides used for efficient inhibition of target RNA expression, is limited by nontarget mediated hepatotoxicity. Increased binding of hepatocellular proteins to toxic LNA gapmers may be one of the mechanisms contributing to LNA gapmer-induced hepatotoxicity in vivo. In the present study, we investigated the protein binding propensity of nontoxic sequence-1 (NTS-1), toxic sequence-2 (TS-2), and severely highly toxic sequence-3 (HTS-3) LNA gapmers using human protein microarrays. We previously demonstrated by the transcription profiling analysis of liver RNA isolated from mice that TS-2 and HTS-3 gapmers modulate different transcriptional pathways in mice leading to hepatotoxicity. Our protein array profiling demonstrated that a greater number of proteins, including ones associated with hepatotoxicity, hepatic system disorder, and cell functions, were bound by TS-2 and HTS-3 compared with NTS-1. However, the profiles of proteins bound by TS-2 and HTS-3 were similar and did not distinguish proteins contributing to severe in vivo toxicity. These results, together with the previous transcription profiling analysis, indicate that the combination of sequence-dependent transcription modulation and increased protein binding of toxic LNA gapmers contributes to hepatotoxicity. PMID- 26643896 TI - MTUS1 and its targeting miRNAs in colorectal carcinoma: significant associations. AB - Deregulated microRNA (miRNA) expression has been shown to be involved in the pathogenesis of several types of cancers including colorectal cancer (CRC). Thus, determining miRNA targets of genes that play critical role in the malignant transformation is very important. Here, expression levels of tumor suppressor microtubule-associated tumor suppressor 1 (MTUS1) and its regulatory miRNAs were reported. Predicted and validated targets of MTUS1 gene was determined by a computational approach. Expressions of MTUS1 and miRNAs were determined by using 96.96 Dynamic ArrayTM integrated fluidic circuit (Fluidigm). As a result, MTUS1 levels were found to be diminished in formalin-fixed, paraffin-embedded (FFPE) tissue samples of CRC patients compared to controls. Also, several of MTUS1 targeting miRNAs were found to be upregulated in CRC samples (miR-373-3p, 183-5p, 142-5p, 200c-3p, 19a-3p, -20a-5p, -181a-5p, -184, -181d-5p, -372-3p, 27b-3p, 98 5p, -let-7i-5p, -let-7d-5p, -let-7g-5p, -let-7b-5p, and -let-7c-5p). Of these miRNAs, miR-135b-5p, -373-3p, 183-5p, 142-5p, 200c-3p, 19a-3p showed marked expression levels. In contrast, expression levels of let-7a-5p, 7e-5p, 7f-5p, hsa miR-125a-5p, and 125b-5p were found to be downregulated in CRC tissues. Accordingly, some of the overexpressed miRNAs especially the miR-135b-5p, -373 3p, 183-5p, 142-5p, 200c-3p, and 19a-3p may play key roles in CRC pathophysiology through MTUS1. In contrast, let-7a-5p, 7e-5p, 7f-5p, miR-125a-5p, and 125b-5p may play important roles in CRC carcinogenesis independent from the MTUS1. In conclusion, MTUS1 targeting miRNAs may play key roles in the development of CRC by downregulating tumor suppressor MTUS1. PMID- 26643898 TI - Comments on the article: Occipital C1-C2 Neuromodulation Decreases Body Mass and Fat Stores and Modifies Activity of the Autonomic Nervous System in Morbidly Obese Patients--a Pilot Study. PMID- 26643899 TI - Niveibacterium umoris gen. nov., sp. nov., isolated from wetland freshwater. AB - A taxonomic study was carried out on a novel bacterial strain, designated MIC2059T, which was isolated from Ungok Wetland of Gochang in Korea. Cells of the isolate were found to be Gram-stain-negative, rod-shaped and motile. Comparison of the 16S rRNA gene sequences indicated that the isolate belonged to the family Rhodocyclaceae, with Uliginosibacterium gangwonense as its closest relative, with a similarity of 94.8 %. It contained summed feature 3 (comprising C16 : 1omega7c and/or C16 : 1omega6c), C16 : 0, summed feature 8 (comprising C18 : 1omega7c and/or C18 : 1omega6c) and C12 : 0 3-OH as the major fatty acids and Q8 as the respiratory ubiquinone. The polar lipid profile of strain MIC2059T revealed the presence of phosphatidylethanolamine, phosphatidylglycerol and diphosphatidylglycerol as major polar lipids. In addition, phosphatidylserine, an unidentified aminophospholipid and unidentified lipids were present in small amounts. The DNA G+C content of the strain was 65.1 mol%. On the basis of the evidence presented, it is concluded that strain MIC2059T represents a novel species of a novel genus within the family Rhodocyclaceae, for which the name Niveibacterium umoris gen. nov., sp. nov. is proposed. The type strain is MIC2059T ( = KACC 17062T = JCM 18716T). PMID- 26643900 TI - Polish consensus guidelines on the use of acyclovir in the treatment and prevention of VZV and HSV infections. AB - A physician has to perform a benefit-risk assessment each time acyclovir is prescribed "off label" for children. A group of Polish infectious disease experts was created to develop evidence-based guidelines on the use of acyclovir in the treatment and prevention of varicella zoster and herpes simplex infections. In primary varicella zoster virus infections, oral acyclovir treatment is recommended in children over 12 years of age and should be considered in younger children who fall into one of the groups at risk of severe varicella. Intravenous acyclovir therapy in varicella is recommended in patients with immune deficiencies, newborns and in complicated cases. When there is a justified need for prevention of varicella, oral acyclovir prophylaxis may be considered if immunoglobulin cannot be administered, and if it is too late for vaccination. Oral acyclovir treatment of herpes zoster may be beneficial to otherwise healthy patients with a rash in places other than the trunk and in patients over 50 years of age. In immunocompetent patients with herpes simplex infections, indications for treatment with oral acyclovir include primary (genital herpes, skin herpes in children with atopic dermatitis, ocular herpes simplex, severe gingivostomatitis, paronychia and pharyngitis) and recurrent infections. Intravenous acyclovir should be administered for herpes infections in neonates, immunocompromised patients and patients who develop complications including neurological. PMID- 26643901 TI - A case of testicular infarction from the complications of Klebsiella oxytoca induced acute epididymitis. AB - Herein, we reported a case of testicular infarction in a patient with Klebsiella oxytoca induced acute epididymitis. Acute left epididymitis progressed into testicular infarction requiring orchiectomy in spite of antibiotics treatment. Ordinary urine cultures did not reveal any specific organism, suggesting viable but noncultureable state. We amplified a bacterial 16S ribosomal subunit gene from the urine and orchiectomized samples, and we found K. oxytoca infections from both of them. PMID- 26643902 TI - Hopeless Cases: Queer Chronicities and Gertrude Stein's "Melanctha". AB - For this contribution to the special issue on "Mapping Queer Bioethics," the author offers a reflection on the nature of the literary, written word as the ethically fraught site of queer bioethics. By invoking the historical tendencies and tropes of the clinical case history alongside a seminal text by Gertrude Stein, the author at once asks if we should liberate a queer bioethics from biomedical discourse via mainstream narrative; or if we should see this strategy as unavoidably housed in narrative forms of storytelling because it echoes the tropes and stakes of the clinical, pathologized case history as regards queer sensibilities. PMID- 26643903 TI - The role of DJ-1/Nrf2 pathway in the pathogenesis of diabetic nephropathy in rats. AB - Diabetic nephropathy (DN) is one of the most common chronic complications of diabetes, which is associated with an increased oxidative stress induced by hyperglycemia and alterations in DJ-1/NF-E2-related factor-2 (Nrf2) pathway. In the present study, we investigated the role and the proper time nodes of DJ 1/Nrf2 pathway in the pathogenesis of DN. Diabetes mellitus (DM) model of rats was induced by intraperitoneal injection of streptozotocin (STZ) on male Sprague Dawley (SD) rats. Then, the diabetic rats were divided into 4, 8 and 12 weeks groups. As early at 4 weeks of diabetes, renal histologic evaluation score, cystatin C (Cys C), beta2-microglobulin (beta2-MG) and malondialdehyde (MDA) levels were increased, and total antioxidative capacity (T-AOC) level was decreased as compared with that in the control group. The protein expressions of DJ-1, NF-E2-related factor-2 (Nrf2) and heme oxygenase-1 (HO-1) were upregulated compared with the control group from 4 weeks and further increased with the progression of DM. The protein expressions of DJ-1, Nrf2 and HO-1 in renal tissues have good line correlations with renal histologic evaluation score, respectively. Taken together, these results suggested that the activation of DJ 1/Nrf2 pathway was involved in the pathogenesis of diabetic nephropathy in rats. PMID- 26643904 TI - A method for positive forensic identification of samples from extremely low coverage sequence data. AB - BACKGROUND: Determining whether two DNA samples originate from the same individual is difficult when the amount of retrievable DNA is limited. This is often the case for ancient, historic, and forensic samples. The most widely used approaches rely on amplification of a defined panel of multi-allelic markers and comparison to similar data from other samples. When the amount retrievable DNA is low these approaches fail. RESULTS: We describe a new method for assessing whether shotgun DNA sequence data from two samples are consistent with originating from the same or different individuals. Our approach makes use of the large catalogs of single nucleotide polymorphism (SNP) markers to maximize the chances of observing potentially discriminating alleles. We further reduce the amount of data required by taking advantage of patterns of linkage disequilibrium modeled by a reference panel of haplotypes to indirectly compare observations at pairs of linked SNPs. Using both coalescent simulations and real sequencing data from modern and ancient sources, we show that this approach is robust with respect to the reference panel and has power to detect positive identity from DNA libraries with less than 1 % random and non-overlapping genome coverage in each sample. CONCLUSION: We present a powerful new approach that can determine whether DNA from two samples originated from the same individual even when only minute quantities of DNA are recoverable from each. PMID- 26643905 TI - Self-labelling enzymes as universal tags for fluorescence microscopy, super resolution microscopy and electron microscopy. AB - Research in cell biology demands advanced microscopy techniques such as confocal fluorescence microscopy (FM), super-resolution microscopy (SRM) and transmission electron microscopy (TEM). Correlative light and electron microscopy (CLEM) is an approach to combine data on the dynamics of proteins or protein complexes in living cells with the ultrastructural details in the low nanometre scale. To correlate both data sets, markers functional in FM, SRM and TEM are required. Genetically encoded markers such as fluorescent proteins or self-labelling enzyme tags allow observations in living cells. Various genetically encoded tags are available for FM and SRM, but only few tags are suitable for CLEM. Here, we describe the red fluorescent dye tetramethylrhodamine (TMR) as a multimodal marker for CLEM. TMR is used as fluorochrome coupled to ligands of genetically encoded self-labelling enzyme tags HaloTag, SNAP-tag and CLIP-tag in FM and SRM. We demonstrate that TMR can additionally photooxidize diaminobenzidine (DAB) to an osmiophilic polymer visible on TEM sections, thus being a marker suitable for FM, SRM and TEM. We evaluated various organelle markers with enzymatic tags in mammalian cells labelled with TMR-coupled ligands and demonstrate the use as efficient and versatile DAB photooxidizer for CLEM approaches. PMID- 26643906 TI - The effects of temperature on ovarian aromatase (cyp19a1a) expression and sex differentiation in summer flounder (Paralichthys dentatus). AB - Female summer flounder grow considerably faster and larger than males, and a tremendous increase in performance can therefore be realized through production of monosex female populations. Rearing temperature has been shown to affect sex differentiation in other teleost species by influencing expression of genes encoding transcription factors or enzymes involved in endocrine function. Cyp19a1a is a well-studied gene that had been shown to play a role in ovarian development, and exhibits sexually dimorphic expression in other species. In the present study, summer flounder (37 days post-hatch; DPH) were raised at 13, 16 or 19 degrees C. Fish from all three treatments were sampled throughout development and analyzed in qPCR to determine cyp19a1a gene expression levels. Sex ratios of additional fish grown to >=150 mm at each temperature treatment were determined. Low female production was achieved overall (26.9, 17.6 and 0% at 13, 16 and 19 degrees C, respectively). Cyp19a1a expression was significantly lower at 52 DPH (~15 mm total length) at the male-producing temperature (19 degrees C) and increased to similar levels as other treatments at 66 DPH. Expression levels later in juvenile development (66-191 DPH) largely decreased with fish size. The period of sex differentiation in summer flounder remains unknown, but cyp19a1a expression patterns suggest that it may occur earlier in development than that of congenerics. Further research is necessary to understand the sex-determining mechanisms in this species before sexually dimorphic growth can be used to achieve economic advantages in commercial production. PMID- 26643907 TI - Effects of some dietary crude plant extracts on the growth and gonadal maturity of Nile tilapia (Oreochromis niloticus) and their resistance to Streptococcus agalactiae infection. AB - A 90-day feeding trial was conducted on the growth performance, feeding efficacy, body indices, various hematological and plasma biochemical parameters, and histopathological examination of the gonads from male and female Nile tilapia fingerlings when fed different crude plant extracts from Cinnamomum camphora, Euphorbia hirta, Azadirachta indica, or Carica papaya at 2 g kg(-1) compared to a control diet. This was followed by a 14-day challenge to Streptococcus agalactiae. All treatments were triplicated, and each treatment consisted of 30 fish. Results showed that C. papaya extracts were the most effective at delaying gonadal maturation to both male and female tilapia, as well as significantly increasing (P < 0.05) growth performance compared to the control treatment. Similarly, dietary C. camphora and E. hirta extracts also significantly improved growth, while no significant growth effect was detected between the A. indica and control treatments (P > 0.05). Further, crude body lipid was lower in the C. camphora, E. hirta and C. papaya treatments, but was only significantly lower for the E. hirta treatment compared to the control. Meanwhile, none of the hematological or biochemical parameters were significantly affected, although plasma ALT was significantly lower for tilapia fed A. indica compared to the control. After the 14-day bacterial challenge, tilapia fed C. camphora supplementation had significantly higher survival, compared to the control, but was not significantly higher than the other supplemented diets. Results indicate that dietary C. papaya extract can significantly promote growth and delay gonadal maturation to both male and female tilapia, while C. camphora was the most effective prophylactic to S. agalactiae and may be a cost-effective and eco friendly alternative to antibiotics. PMID- 26643908 TI - Phospholipase C delta1 in macrophages negatively regulates TLR4-induced proinflammatory cytokine production and Fcgamma receptor-mediated phagocytosis. AB - Macrophages are key players in the innate immune response. Turnover of phosphoinositides (PI), particularly phosphatidylinositol 4,5 bisphosphate (PI(4,5)P2), has been implicated in macrophage functions such as toll-like receptor (TLR)-mediated cytokine production and phagocytosis. However, PI metabolizing enzymes responsible for macrophage functions are not well defined. The phospholipase C (PLC) family of enzymes is critical in PI(4,5)P2 turnover. In this study, we investigated the role of PLCdelta1, a prototype PLC, in macrophages on the expression of inflammation-associated genes and phagocytosis. Lipopolysaccharides (LPS) signal through TLR4 to produce proinflammatory cytokines such as interleukin (IL)-1beta. LPS stimulation of both RAW264.7 murine macrophages and murine bone marrow-derived macrophages resulted in lower PLCdelta1 mRNA and protein expression levels, compared to that in the control. Using chemical inhibitor compounds, we demonstrated that the up-regulation of p38 MAPK activity led to down-regulation of PLCdelta1 mRNA expression in macrophages. PLCdelta1 reduction by RNAi or gene deletion resulted in greater LPS-induced IL 1beta expression than that observed in the control siRNA-treated cells, without increasing TLR4 cell surface expression. PLCdelta1 also negatively regulated LPS induced cell spreading. Analysis of Fcgamma receptor-mediated phagocytosis demonstrated an increased phagocytosis index after PLCdelta1 knockdown in RAW264.7 cells. Conversely, overexpression of PLCdelta1 reduced phagocytosis whereas catalytic inactive PLCdelta1 had no effect. Altered levels of PLCdelta1 affected the binding of opsonized latex beads with cells, rather than the phagocytic activity. Taken together, the data suggest that PLCdelta1 negatively regulates LPS-induced production of IL-1beta and Fcgamma receptor-mediated phagocytosis in macrophages. PMID- 26643909 TI - Regulation of human subcutaneous adipocyte differentiation by EID1. AB - Increasing thermogenesis in white adipose tissues can be used to treat individuals at high risk for obesity and cardiovascular disease. The objective of this study was to determine the function of EP300-interacting inhibitor of differentiation (EID1), an inhibitor of muscle differentiation, in the induction of beige adipocytes from adipose mesenchymal stem cells (ADMSCs). Subcutaneous adipose tissue was obtained from healthy women undergoing abdominoplasty. ADMSCs were isolated in vitro, grown, and transfected with EID1 or EID1 siRNA, and differentiation was induced after 48 h by administering rosiglitazone. The effects of EID1 expression under the control of the aP2 promoter (aP2-EID1) were also evaluated in mature adipocytes that were differentiated from ADMSCs. Transfection of EID1 into ADMSCs reduced triglyceride accumulation while increasing levels of thermogenic proteins, such as PGC1alpha, TFAM, and mitochondrial uncoupling protein 1 (UCP1), all of which are markers of energy expenditure and mitochondrial activity. Furthermore, increased expression of the beige phenotype markers CITED1 and CD137 was observed. Transfection of aP2-EID1 transfection induced the conversion of mature white adipocytes to beige adipocytes, as evidenced by increased expression of PGC1alpha, UCP1, TFAM, and CITED1. These results indicate that EID1 can modulate ADMSCs, inducing a brown/beige lineage. EID1 may also activate beiging in white adipocytes obtained from subcutaneous human adipose tissue. PMID- 26643911 TI - Maternal high-fat diet influences stroke outcome in adult rat offspring. AB - Diet-induced epigenetic modifications in early life could contribute to later health problem. However, it remains to be established whether high-fat diet (HFD) consumption during pregnancy and the suckling period could predispose the offspring to stroke. The present study investigated the influence of maternal HFD on stroke outcome in adult offspring. Female Sprague-Dawley rats were fed a normal diet (5.3% fat) or a HFD (25.7% fat), just before pregnancy until the end of lactation. Male offspring were fed with the control diet or the HFD after weaning, to form four groups (control offspring fed with the control diet (C/C) or the HFD (C/HFD) and offspring of fat-fed dams fed with the control diet (HFD/C) or the HFD (HFD/HFD)). The offspring received middle cerebral artery occlusion on day 120 followed by behavioral tests (neurological deficit score, staircase-reaching test and beam-traversing test), and infarct volumes were also calculated. We found that the HFD/C rats displayed larger infarct volume and aggravated functional deficits (all P<0.05), compared with the C/C rats, indicating that maternal fat-rich diet renders the brain more susceptible to the consequences of ischemic injury. Moreover, maternal HFD offspring displayed elevated glucocorticoid concentrations following stroke, and increased glucocorticoid receptor expression. In addition, adrenalectomy reversed the effects of maternal HFD on stroke outcome when corticosterone was replaced at baseline, but not ischemic, concentrations. Furthermore, expression of brain derived neurotrophic factor (BDNF) in the ipsilateral hippocampus was decreased in the HFD/C offspring (P<0.05), compared with the C/C offspring. Taken together, maternal diet can substantially influence adult cerebrovascular health, through the programming of central BDNF expression and the hypothalamic-pituitary-adrenal axis. PMID- 26643912 TI - Estrogen-dependent up-regulation of TRPA1 and TRPV1 receptor proteins in the rat endometrium. AB - Transient receptor potential ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1) receptors expressed predominantly in sensory nerves are activated by inflammatory stimuli and mediate inflammation and pain. Although they have been shown in the human endometrium, their regulation and function are unknown. Therefore, we investigated their estrogen- and progesterone-dependent alterations in the rat endometrium in comparison with the estrogen-regulated inflammatory cytokine macrophage migration inhibitory factor (MIF). Four-week-old (sexually immature) and four-month-old (sexually mature) female rats were treated with the non selective estrogen receptor (ER) agonist diethylstilboestrol (DES), progesterone and their combination, or ovariectomized. RT-PCR and immunohistochemistry were performed to determine mRNA and protein expression levels respectively. Channel function was investigated with ratiometric [Ca(2+)]i measurement in cultured primary rat endometrial cells. Both TRP receptors and MIF were detected in the endometrium at mRNA and protein levels, and their localizations were similar. Immunostaining was observed in the immature epithelium, while stromal, glandular and epithelial positivity were observed in adults. Functionally active TRP receptor proteins were shown in endometrial cells by activation-induced calcium influx. In adults, Trpa1 and Trpv1 mRNA levels were significantly up-regulated after DES treatment. TRPA1 increased after every treatment, but TRPV1 remained unchanged following the combined treatment and ovariectomy. In immature rats, DES treatment resulted in increased mRNA expression of both channels and elevated TRPV1 immunopositivity. MIF expression changed in parallel with TRPA1/TRPV1 in most cases. DES up-regulated Trpa1, Trpv1 and Mif mRNA levels in endometrial cell cultures, but 17beta-oestradiol having ERalpha-selective potency increased only the expression of Trpv1. We provide the first evidence for TRPA1/TRPV1 expression and their estrogen-induced up-regulation in the rat endometrium in correlation with the MIF. PMID- 26643910 TI - Thyroid hormone and vitamin D regulate VGF expression and promoter activity. AB - The Siberian hamster (Phodopus sungorus) survives winter by decreasing food intake and catabolizing abdominal fat reserves, resulting in a sustained, profound loss of body weight. Hypothalamic tanycytes are pivotal for this process. In these cells, short-winter photoperiods upregulate deiodinase 3, an enzyme that regulates thyroid hormone availability, and downregulate genes encoding components of retinoic acid (RA) uptake and signaling. The aim of the current studies was to identify mechanisms by which seasonal changes in thyroid hormone and RA signaling from tanycytes might ultimately regulate appetite and energy expenditure. proVGF is one of the most abundant peptides in the mammalian brain, and studies have suggested a role for VGF-derived peptides in the photoperiodic regulation of body weight in the Siberian hamster. In silico studies identified possible thyroid and vitamin D response elements in the VGF promoter. Using the human neuroblastoma SH-SY5Y cell line, we demonstrate that RA increases endogenous VGF expression (P<0.05) and VGF promoter activity (P<0.0001). Similarly, treatment with 1,25-dihydroxyvitamin D3 increased endogenous VGF mRNA expression (P<0.05) and VGF promoter activity (P<0.0001), whereas triiodothyronine (T3) decreased both (P<0.01 and P<0.0001). Finally, intra-hypothalamic administration of T3 blocked the short day-induced increase in VGF expression in the dorsomedial posterior arcuate nucleus of Siberian hamsters. Thus, we conclude that VGF expression is a likely target of photoperiod-induced changes in tanycyte-derived signals and is potentially a regulator of seasonal changes in appetite and energy expenditure. PMID- 26643913 TI - 60 YEARS OF POMC: The proopiomelanocortin gene: discovery, deletion and disease. AB - The cloning of the bovine proopiomelanocortin (POMC) cDNA in 1978 by Nakanishi and colleagues was the result of a remarkable series of exacting and ingenious experiments. With this work, they instantly confirmed the single precursor hypothesis for adrenocorticotrophic hormone-beta-lipotropin, as it was then known, and in so doing revealed the existence of additional, largely unpredicted, N-terminal peptides that together formed the POMC precursor peptide. This work paved the way for a host of additional studies into the physiology of these peptides and their regulation. Furthermore, the cloning of the murine Pomc gene was essential for subsequent studies, in which Pomc was intentionally deleted in the mouse illuminating its substantial role in body weight regulation and adrenal function. Contemporaneously with this work, naturally occurring mutations in human POMC came to light underlining the vital role of this gene in appetite regulation. This article reviews each of these aspects of POMC with the benefit of several decades of hindsight and informed by more recent genomic and transcriptomic data. PMID- 26643914 TI - 60 YEARS OF POMC: Purification and biological characterisation of melanotrophins and corticotrophins. AB - The remarkable conservation of the primary structures and anatomical location of dogfish alpha-melanocyte-stimulating hormone (MSH), corticotrophin-like intermediate lobe peptide (CLIP) and adrenocorticotrophic hormone (ACTH) compared with mammals reinforced the tissue-specific processing hypothesis of ACTH peptides in the pituitary gland. The cloning of dogfish pro-opiomelanocortin (POMC) led to the identification of delta-MSH and simultaneously revealed the high conservation of the gamma-MSH sequence during evolution. These studies have also shown that beta-MSH is much less conserved during evolution and in some species is not even processed from beta-LPH. Human pro-gamma-MSH potentiates the corticosteroidogenic activity of ACTH and peptides generated from its N-terminal, in particular big-gamma-MSH, appear to have adrenal mitogenic activity. Human big gamma-MSH (from the zona intermedia) may also cause the adrenache. The review finishes with a cautionary note with regard to the misdiagnosis of the ectopic ACTH syndrome in which partial processing of ACTH can result in large concentrations of alpha-MSH and CLIP, which can interfere in the performance of two-site immunoassays, and the problem of the correct disulphide bridge arrangement in synthetic N-POMC peptides is also discussed. PMID- 26643915 TI - Vulvar Pain-Associations Between First-Time Vaginal Intercourse, Tampon Insertion, and Later Experiences of Pain. AB - This study examines associations between the first experience of vaginal intercourse/tampon insertion and later experiences of vulvar pain. The study is based on questionnaire data from 1,259 Swedish female senior high-school students, aged 18 to 22 years old. Of these, 592 women reported present vulvar pain. Present vulvar pain was associated with first-time experiences of vaginal intercourse (pain, negative experience, against will) and with pain at tampon insertion. First-time experiences were also related to temporal aspects of present vulvar pain during vaginal intercourse (at the beginning, after a while during, and after). Implications of first-time experiences of vaginal intercourse for future symptoms of vulvar pain are discussed. PMID- 26643916 TI - S-100 Negative Granular Cell Tumor of the Oral Cavity. AB - Classic granular cell tumor is a mesenchymal neoplasm that commonly occurs on the skin, but is not infrequently found in the oral cavity, primarily on the dorsal tongue. Diagnosis is usually straightforward with hematoxylin and eosin stained slides. Immunohistochemical studies on classic granular cell tumor shows positive immunostaining for S-100 and vimentin, while CD68 is variably positive. We report a case of otherwise unremarkable oral granular cell tumor that was immunohistochemically negative for S-100, and positive for vimentin and CD68, and discuss the differential diagnosis. The results of the immunohistochemical studies in our case are compared with those of classic S-100 positive oral granular cell tumors, as well as cutaneous and oral S-100 negative granular cell tumors. Classic S-100 positive granular cell tumors and S-100 negative granular cell tumors of the oral cavity can only be distinguished by immunohistochemical studies; however, the necessity of this distinction is unclear, as both are benign lesions in which recurrence is unlikely. PMID- 26643917 TI - A theory-based online health behaviour intervention for new university students (U@Uni:LifeGuide): results from a repeat randomized controlled trial. AB - BACKGROUND: This paper reports the results of a repeat trial assessing the effectiveness of an online theory-based intervention to promote healthy lifestyle behaviours in new university students. The original trial found that the intervention reduced the number of smokers at 6-month follow-up compared with the control condition, but had non-significant effects on the other targeted health behaviours. However, the original trial suffered from low levels of engagement, which the repeat trial sought to rectify. METHODS: Three weeks before staring university, all incoming undergraduate students at a large university in the UK were sent an email inviting them to participate in the study. After completing a baseline questionnaire, participants were randomly allocated to intervention or control conditions. The intervention consisted of a self-affirmation manipulation, health messages based on the theory of planned behaviour and implementation intention tasks. Participants were followed-up 1 and 6 months after starting university. The primary outcome measures were portions of fruit and vegetables consumed, physical activity levels, units of alcohol consumed and smoking status at 6-month follow-up. RESULTS: The study recruited 2,621 students (intervention n=1346, control n=1275), of whom 1495 completed at least one follow up (intervention n=696, control n=799). Intention-to-treat analyses indicated that the intervention had a non-significant effect on the primary outcomes, although the effect of the intervention on fruit and vegetable intake was significant in the per-protocol analyses. Secondary analyses revealed that the intervention had significant effects on having smoked at university (self-report) and on a biochemical marker of alcohol use. CONCLUSIONS: Despite successfully increasing levels of engagement, the intervention did not have a significant effect on the primary outcome measures. The relatively weak effects of the intervention, found in both the original and repeat trials, may be due to the focus on multiple versus single health behaviours. Future interventions targeting the health behaviour of new university students should therefore focus on single health behaviours. TRIAL REGISTRATION: Current Controlled Trials ISRCTN07407344 . PMID- 26643918 TI - Differential diagnostic value of CD5 and CD117 expression in thoracic tumors: a large scale study of 1465 non-small cell lung cancer cases. AB - BACKGROUND: Thoracic pathologists are frequently faced with tissue specimens from intrathoracic/mediastinal tumors. Specifically the differentiation between thymic and pulmonary squamous cell carcinomas (SqCC) can be challenging. In order to clarify the differential diagnostic value of CD5 and CD117 in this setting, we performed a large scale expression study of both markers in 1465 non-small cell lung cancer (NSCLC) cases. METHODS: Tissue microarrays of formalin-fixed paraffin embedded resection specimens of 1465 NSCLC were stained with antibodies against CD117 and CD5. Positivity of both markers was correlated with clinicopathological variables. RESULTS: CD117 was positive in 145 out of 1457 evaluable cases (9.9 %) and CD5 was positive in 133 out of 1427 evaluable cases (9.3 %). 28 cases (1.9 %) showed coexpression of CD117 and CD5. Among the 145 cases that were positive for CD117, 97 (66.8 %) were adenocarcinomas (ADC), 34 (23.4 %) were SqCC, 5 (3.4 %) were adenosquamous carcinomas (ADSqCC), 8 (5.5 %) were large cell carcinomas (LC), and one (0.6 %) was a pleomorphic carcinoma (PC). In the CD5 positive group consisting of 133 cases, 123 (92.4 %) were ADC, 0 (0 %) were SqCC, 4 (3.0 %) were ADSqCC, 3 (2.2 %) LC and 3 (2.2 %) were PC. None of the 586 SqCC showed expression of CD5. No association of CD117- or CD5 positivity to patients' age, pathological stages or to T-, N-, or M- categories was observed. CONCLUSIONS: A substantial subset of NSCLC exhibit positivity of CD117 and CD5. Since CD5 expression was not observed in pulmonary SqCC, but is expressed in the majority of thymic squamous cell carcinomas, the application of this immunomarker is a valuable tool in the differential diagnosis of thoracic neoplasms. PMID- 26643920 TI - Dasatinib first-line: Multicentric Italian experience outside clinical trials. AB - Dasatinib was approved for the treatment of chronic phase (CP) chronic myeloid leukemia (CML) patients in first line therapy based on the demonstration of efficacy and safety reported in patients enrolled in clinical trials. We describe a multicentric Italian "real-life" experience of dasatinib used as frontline treatment outside clinical trials. One hundred and nine patients (median age 54 years) were treated from January 2012 to December 2013. Increased incidence of high risk patients were detected according to stratification (26% according to Sokal score, 19% according to Euro score and 16% according to EUTOS) when compared to company sponsored studies. Median time from diagnosis to start of dasatinib was 18 days. Ten patients received unscheduled starting dose (6 patients 50mg and 4 patients 80 mg QD), whereas 99 patients started with 100mg QD. At 3 months, 92% of patients achieved a BCR-ABL ratio less than 10%. At 6 months, the rate of CCyR was 91% and the rate of MR3 was 40%, with 8% of the patients reaching MR4.5. Ninety-three patients were evaluable at 12 months: the rate of MR3 was 62%, with MR4.5 being achieved by 19% of the patients. At a median follow-up of 12 months, 27 patients (24.7%) were receiving the drug at reduced dose. Two patients (1.8%) experienced a lymphoid blast crisis and the overall incidence of resistance was 8%. As regards safety, the major side effects recorded were thrombocytopenia, neutropenia and pleural effusions, which occurred in 22%, 10% and 8% of patients, respectively. Present results, achieved in a large cohort of patients treated outside clinical trials, further confirm the efficacy and safety of dasatinib as firstline treatment in CML. PMID- 26643919 TI - Rationale and methods of a cluster-randomized controlled trial to promote active and healthy lifestyles among Brazilian students: the "Fortaleca sua Saude" program. AB - BACKGROUND: Interventions on adolescents' lifestyle are important, but the main mechanisms that explain the changes (mediating variables) on lifestyle are unclear. This paper presents the rationale and methods of an intervention program focused on promoting active and healthy lifestyles (especially physical activity [PA] practice and reducing screen time) among Brazilian students-the Fortaleca sua Saude program (Portuguese for "strengthen your health"). METHODS/DESIGN: This is a school-based cluster-randomized controlled trial. Three intervention and three control (no intervention) full-time public schools were randomly selected in Fortaleza, northeastern Brazil. Students (n = 1,272) from classes in Grades 7 9 were eligible, and 1,085 (548 in the intervention and 537 in control schools) completed the baseline and follow-up measures. The program duration was approximately four months and took place in 2014. Intervention strategies focused on teacher training, activities on health in the curriculum, active opportunities in the school environment (the availability of equipment for PA), and health education (health materials for students and parents). Data collection was undertaken before and immediately after the intervention. The primary variables included the practice of PA (weekly PA volume, PA behavior change stage and preference for PA during leisure-time) and screen time (TV and computer/video games). Potential intrapersonal, interpersonal and environmental mediators of PA and screen time were evaluated by a standardized questionnaire. Other lifestyle components (e.g., eating habits, substance use), psychological (e.g., self-rated health, body satisfaction) and biological (general and abdominal obesity) aspects, as well as academic performance were also evaluated in the total sample. Depressive symptoms, eating disorders, sleep quality, objectively-measured PA, and sedentary time were evaluated in obese students. DISCUSSION: If effective, this program will contribute to the development of public policies for the promotion of active and healthy lifestyles in youth, especially those from low- and middle-income countries. The main intrapersonal, interpersonal and/or environmental mediators of PA and screen time may also be indicated. Finally, we anticipate that the proposed strategies may be adaptable to public schools and may even be extended to the entire school system. TRIAL REGISTRATION: ClinicalTrials.Gov: NCT02439827 . Registration date: May 3, 2015. PMID- 26643921 TI - Inhalable Spray-Freeze-Dried Powder with L-Leucine that Delivers Particles Independent of Inspiratory Flow Pattern and Inhalation Device. AB - PURPOSE: The purpose of this study was to develop inhalable particles that can reach deep into the lungs efficiently independent of inhalation patterns of patients and inhalation devices. We prepared porous particles including L-leucine (Leu), a dispersive agent, by a spray-freeze-drying (SFD) method and examined the influence of inspiratory flow patterns and inhalation devices with various inhalation resistances. METHODS: Four types of SFD powder with different Leu contents (0-10%) were prepared. Scanning electron microscopy and laser diffraction were used to measure the morphology and size distribution of the powders. In-vitro inhalation characteristics were determined using a twin-stage liquid impinger equipped with an inspiratory flow pattern simulator. The effects of Leu on the adhesion force and electrostatic property of the particles were evaluated. RESULTS: The inhalation performance of the powders was improved by the addition of Leu. The powders with Leu showed a high inhalation performance regardless of inspiratory flow patterns and devices. The addition of Leu decreased the adhesion force and increased the surface potential of the powders. CONCLUSIONS: The SFD particles with Leu showed high inhalation performance regardless of the inhalation patterns and devices, which was attributed to the decreased adhesion force between particles and increased dispersibility. PMID- 26643922 TI - An ecoclimatic framework for evaluating the resilience of vegetation to water deficit. AB - The surge in global efforts to understand the causes and consequences of drought on forest ecosystems has tended to focus on specific impacts such as mortality. We propose an ecoclimatic framework that takes a broader view of the ecological relevance of water deficits, linking elements of exposure and resilience to cumulative impacts on a range of ecosystem processes. This ecoclimatic framework is underpinned by two hypotheses: (i) exposure to water deficit can be represented probabilistically and used to estimate exposure thresholds across different vegetation types or ecosystems; and (ii) the cumulative impact of a series of water deficit events is defined by attributes governing the resistance and recovery of the affected processes. We present case studies comprising Pinus edulis and Eucalyptus globulus, tree species with contrasting ecological strategies, which demonstrate how links between exposure and resilience can be examined within our proposed framework. These examples reveal how climatic thresholds can be defined along a continuum of vegetation functional responses to water deficit regimes. The strength of this framework lies in identifying climatic thresholds on vegetation function in the absence of more complete mechanistic understanding, thereby guiding the formulation, application and benchmarking of more detailed modelling. PMID- 26643923 TI - Evaluation of oral microbiology lab curriculum reform. AB - BACKGROUND: According to the updated concept of oral microbiology, the School of Stomatology, Wuhan University, has carried out oral microbiology teaching reforms during the last 5 years. There was no lab curriculum before 2009 except for a theory course of oral microbiology. The school has implemented an innovative curriculum with oral medicine characteristics to strengthen understanding of knowledge, cultivate students' scientific interest and develop their potential, to cultivate the comprehensive ability of students. This study was designed to evaluate the oral microbiology lab curriculum by analyzing student performance and perceptions regarding the curriculum from 2009 to 2013. METHODS: The lab curriculum adopted modalities for cooperative learning. Students collected dental plaque from each other and isolated the cariogenic bacteria with selective medium plates. Then they purified the enrichment culture medium and identified the cariogenic strains by Gram stain and biochemical tests. Both quantitative and qualitative data for 5 years were analysed in this study. Part One of the current study assessed student performance in the lab from 2009 to 2013. Part Two used qualitative means to assess students' perceptions by an open questionnaire. RESULTS: The 271 study students' grades on oral microbiology improved during the lab curriculum: "A" grades rose from 60.5 to 81.2 %, and "C" grades fell from 28.4 to 6.3 %. All students considered the lab curriculum to be interesting and helpful. Quantitative and qualitative data converge to suggest that the lab curriculum has strengthened students' grasp of important microbiology-related theory, cultivated their scientific interest, and developed their potential and comprehensive abilities. CONCLUSION: Our student performance and perception data support the continued use of the innovative teaching system. As an extension and complement of the theory course, the oral microbiology lab curriculum appears to improve the quality of oral medicine education and help to cultivate high-quality innovative medical talents. PMID- 26643924 TI - Effect of ZIP2 Gln/Arg/Leu (rs2234632) polymorphism on zinc homeostasis and inflammatory response following zinc supplementation. AB - Zinc dyshomeostasis may lead to an augmented production of proinflammatory cytokines promoting chronic inflammation and increasing the susceptibility to age related diseases. Several studies suggest that the zinc transporter protein ZIP2 may play a relevant role in the immune system especially during zinc deficiency, while a polymorphism on the coding region of ZIP2 gene (Gln/Arg/Leu) has been associated with severe carotid artery disease. The aim of this study is to investigate the role of ZIP2 SNP on zinc and inflammatory status in 1090 elderly healthy free-living subjects enrolled in the ZincAge project and to assess the effect of zinc supplementation on zinc status, inflammatory mediators, and zinc transporter expression depending on ZIP2 genotype. ZIP2 Leu- (Arg43Arg) carriers showed enhanced IL-6, TNF-alpha, and RANTES plasma levels associated with decreased free cytosolic zinc in PBMCs and an upregulation of zinc transporters ZIP2, ZIP8, and Znt1. Moreover, Leu- subjects displayed significant decrement of inflammatory mediators such as MCP-1, TNF-alpha, and RANTES following zinc supplementation. In summary, this investigation provides new evidence on the effect of ZIP2 Gln/Arg/Leu polymorphism on proinflammatory mediators and zinc homeostasis in elderly population with a more pronounced anti-inflammatory effect of zinc supplementation in subjects carrying ZIP2 Leu- (Arg43Arg) genotype. These novel findings could be useful in identifying elderly subjects who may benefit of zinc intervention to decrease the inflammatory status and to prevent or delay the development of age-related diseases. PMID- 26643925 TI - Effect of blood transfusion on intestinal blood flow and oxygenation in extremely preterm infants during first week of life. AB - BACKGROUND: Extremely preterm infants receive frequent blood transfusions in the first week of life. The aim of this study was to measure the effect of blood transfusion on intestinal blood flow and oxygenation during the first week of life in extremely preterm infants. STUDY DESIGN AND METHODS: Superior mesenteric artery (SMA) peak systolic velocity (PSV) and diastolic velocities were measured 30 to 60 minutes before and after transfusion. Splanchnic tissue hemoglobin index (sTHI), splanchnic tissue oxygenation index (sTOI), and splanchnic fractional tissue oxygen extraction (sFTOE) were measured continuously from 15 to 20 minutes before to after transfusion along with vital variables. RESULTS: Twenty infants were studied (median gestational age, 26 weeks). Ten infants were partially fed (15-68 mL/kg/day). Heart rate and SaO2 remained unaltered; blood pressure increased significantly (p < 0.01) after transfusion. Mean SMA PSV (p = 0.63) and diastolic velocity (p = 0.65) remained unaltered. Mean pretransfusion SMA PSV was similar in partially fed (0.78 m/sec) compared to unfed infants (0.52 m/sec; p = 0.06) and the response to transfusion was not dissimilar. There was a significant increase in sTHI (mean difference, 32.3%; p < 0.01) and sTOI (14.6%; p = 0.03) and decrease in sFTOE (22.1%; p < 0.01) after transfusion. There was no significant difference in sTHI or sTOI between fed and unfed infants and their response to transfusion. CONCLUSIONS: Blood transfusion increased blood pressure and intestinal tissue oxygenation but did not alter blood flow velocities. Partial feeding had no impact on intestinal blood flow and tissue oxygenation changes. PMID- 26643926 TI - A review of key national reports to describe the development of paramedic education in England (1966-2014). AB - INTRODUCTION: In the year 1966, important advances in mobile coronary care and trauma care in the UK and USA influenced globally the development of modern prehospital emergency services and paramedic education. In that year, to meet the evolving role of prehospital care in the UK, the 'Millar Report' specified a new syllabus for ambulance personnel in England. As the 50th anniversary of this report approaches, this paper reviews key national UK reports to describe the development of paramedic education in England over this period. METHODS: A hand search of documents available and a Google search identified documents in the public domain. MEDLINE and CINAHL Plus were searched for peer-reviewed publications. Thematic analysis was used to identify descriptive themes. RESULTS: Of the 83 reports and 431 articles screened, 33 documents met our inclusion criteria. We identified four historical periods in English paramedic education: development of paramedic education (1966-1996); paramedic role changes influencing education (1997-2004); paramedic education level changes and the emergency care practitioner (2005-2008); and paramedic education for the future (2010-2014). Our discussion of four descriptive themes: government authority and policy, influence of health professions, quality assurance and development of the paramedic profession includes comparisons with paramedic education in the USA and Australia. CONCLUSIONS: Political reform agendas and initiatives and advances in clinical medicine largely shaped paramedic roles and education in England. The degree to which the paramedic profession initiated education development is difficult to determine from the literature. Overall, a nationally coherent standard for paramedic education in England needed five decades to develop and mature. PMID- 26643927 TI - Complex APC germline mutation associated metaplasia and intraepithelial neoplasia (CAM-IEN) of the gallbladder. AB - Preneoplasic and neoplastic changes of the gallbladder of patients with a familial adenomatous polyposis (FAP) are rare, and very little is known about their incidence in patients with an attenuated FAP. We herein report on a unique case of a woman with an attenuated FAP who shows eight distinct, partially preneoplastic differentiation patterns within the gallbladder mucosa, which are: (1) regular gallbladder epithelium, (2) low grade biliary intraepithelial neoplasia, (3) papillary adenoma, (4) Paneth cell metaplasia, (5) goblet cell metaplasia, (6) pancreatic metaplasia, (7) pseudopyloric metaplasia, and (8) neuroendocrine differentiation. Moreover, this is the first case of a KRAS mutation in a gallbladder adenoma of a patient with an APC germline mutation, which is highly suggestive of an early event of malignant transformation. As a consequence of our findings, clinicians should draw special attention to the gallbladder of FAP patients, and a simultaneous protective cholecystectomy of FAP patients, which undergo colectomy and show conspicuous changes of the gallbladder mucosa, should be performed in these patients in order to eliminate the risk of a synchronous or metachronous gallbladder neoplasia. PMID- 26643928 TI - CSII as an Alternative Therapeutic Strategy for Managing Type 2 Diabetes: Adding the Indian Experience to a Global Perspective. AB - BACKGROUND: Alternative insulin therapy with continuous subcutaneous insulin infusion (CSII) is offered with an objective of achieving better glycemic control, minimising glucose variability and thereby, preventing or reducing the risk of microvascular and macrovascular complications in people with type 1 or type 2 diabetes. Trials conducted across the world have demonstrated that CSII is more beneficial in terms of achieving better metabolic control in type 2 diabetes. Unawareness about the multiple benefits of CSII is a major hurdle to its widespread use. In India, insulin pumps are more popular in type 2 diabetes and we have been deploying pumps since 2004. Previously, we have reported reduction in HbA1c, body weight and total daily dose of insulin in patients on insulin pump therapy (IPT). OBJECTIVE: The objective of this study was to assess the attitude and behavior of type 2 diabetes patients on IPT. METHODS: A cross sectional survey was conducted among selected type 2 diabetes patients who have been on IPT for more than 3 years. We administered questionnaires to assess level of satisfaction with pump, improvement in quality of life (QoL), use of the advanced functions and average cost incurred by being on pump. Difference in scores between males and females were assessed using chiquare test for proportions and t-test for differences in means. RESULTS: Improvement in QoL after being on pump was appreciated by 92%. The level of satisfaction was rated as 'fully satisfied' by 52% of respondents while 26% found being on pump, 'satisfactory'. Ninety percent thought that the pump met their expectations. CONCLUSION: The attitude and behavior of type 2 diabetes patients on IPT is positive and promising. PMID- 26643929 TI - Contingent screening for preterm pre-eclampsia. AB - OBJECTIVE: Effective screening for pre-eclampsia resulting in delivery < 37 weeks' gestation (preterm PE) is provided by assessment of a combination of maternal factors, mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI) and serum placental growth factor (PlGF) at 11-13 or 19-24 weeks' gestation. This study explores the possibility of carrying out routine screening for preterm PE by maternal factors and MAP in all pregnancies and reserving measurements of UtA-PI and PlGF for a subgroup of the population, selected on the basis of the risk derived from screening by maternal factors and MAP alone. METHODS: Study data were derived from prospective screening for adverse obstetric outcomes in women attending their routine hospital visit at 11-13 and/or 19-24 weeks' gestation. Bayes' theorem was used to derive the a-priori risk for preterm PE from maternal factors and MAP. The posterior risk was obtained by the addition of UtA-PI and PlGF. We estimated the detection rate (DR) of preterm PE, at an overall false-positive rate (FPR) of 10%, from a policy in which first-stage screening by a combination of maternal factors and MAP defines screen-positive, screen-negative and intermediate-risk groups, with the latter undergoing second stage screening by UtA-PI and PlGF. RESULTS: At 11-13 weeks' gestation, the model based DR of preterm PE, at a 10% FPR, when screening the whole population by maternal factors, MAP, UtA-PI and PlGF was 74%. A similar DR was achieved by two stage screening, with screening by maternal factors and MAP in the first stage and reserving measurement of UtA-PI and PlGF for the second stage and for only 50% of the population. If second-stage screening was offered to 30% of the population, there would be only a small reduction in DR from 74% to 71%. At 19-24 weeks, the model-based DR of preterm PE, at a 10% FPR, when screening the whole population by maternal factors, MAP, UtA-PI and PlGF was 84%. A similar DR was achieved by two-stage screening with measurements of UtA-PI and PlGF in only 70% of the population; if second-stage screening was offered to 40% of the population, the DR would be reduced from 84% to 81%. CONCLUSIONS: High DR of preterm PE can be achieved by two-stage screening in the first and second trimesters with maternal factors and MAP in the whole population and measurements of UtA-PI and PlGF in only some of the pregnancies. Copyright (c) 2015 ISUOG. Published by John Wiley & Sons Ltd. PMID- 26643930 TI - Effect of substituting IPV for tOPV on immunity to poliovirus in Bangladeshi infants: An open-label randomized controlled trial. AB - BACKGROUND: The Polio Endgame strategy includes phased withdrawal of oral poliovirus vaccines (OPV) coordinated with introduction of inactivated poliovirus vaccine (IPV) to ensure population immunity. The impact of IPV introduction into a primary OPV series of immunizations in a developing country is uncertain. METHODS: Between May 2011 and November 2012, we enrolled 700 Bangladeshi infant mother dyads from Dhaka slums into an open-label randomized controlled trial to test whether substituting an injected IPV dose for the standard Expanded Program on Immunization (EPI) fourth tOPV dose at infant age 39 weeks would reduce fecal shedding and enhance systemic immunity. The primary endpoint was mucosal immunity to poliovirus at age one year, measured by fecal excretion of any Sabin virus at five time points up to 25 days post-52 week tOPV challenge, analyzed by the intention to treat principle. FINDINGS: We randomized 350 families to the tOPV and IPV vaccination arms. Neither study arm resulted in superior intestinal protection at 52 weeks measured by the prevalence of infants shedding any of three poliovirus serotypes, but the IPV dose induced significantly higher seroprevalence and seroconversion rates. This result was identical for poliovirus detection by cell culture or RT-qPCR. The non-significant estimated culture-based shedding risk difference was -3% favoring IPV, and the two vaccination schedules were inferred to be equivalent within a 95% confidence margin of -10% to +4%. Results for shedding analyses stratified by poliovirus type were similar. CONCLUSIONS: Neither of the vaccination regimens is superior to the other in enhancing intestinal immunity as measured by poliovirus shedding at 52 weeks of age and the IPV regimen provides similar intestinal immunity to the four tOPV series, although the IPV regimen strongly enhances humoral immunity. The IPV modified regimen may be considered for vaccination programs without loss of intestinal protection. PMID- 26643931 TI - Safety and tolerability of a cell culture derived trivalent subunit inactivated influenza vaccine administered to healthy children and adolescents: A Phase III, randomized, multicenter, observer-blind study. AB - BACKGROUND: Cell culture-derived inactivated influenza vaccines (TIVc) are necessary for scale and predictability of production to meet global demand. This study compared the safety and tolerability of TIVc with an egg-derived trivalent influenza vaccine (TIVf) in 4-17 yearolds. METHODS: A Phase 3 observer blind, multicenter study enrolled 2055 healthy participants randomized 2:1 to receive either TIVc or TIVf, respectively (1372 TIVc and 683 TIVf evaluable subjects). Participants received one dose each on Days 1 and 28 (4-8 year-olds not previously vaccinated [NPV]) or one dose on Day 1 (4-8 and 9-17 yearolds previously vaccinated [PV]). Solicited adverse events (AEs) occurring within 7 days after each vaccination were assessed; participants were followed up for 6 months after their last dose for safety. RESULTS: Most solicited and unsolicited AEs were mild to moderate with <1% in the severe category. No withdrawals due to AEs, deaths or vaccine-related SAEs were reported. TIVc and TIVf were similar in percentages of participants reporting solicited reactions in 4-8 years NPV group after the 1st dose: local reactions, TIVc: 48%, TIVf: 43%; systemic reactions, TIVc: 34%, TIVf: 32%; percentages were lower following the 2nd dose in TIVc; local reactions: TIVc: 40%; TIVf: 43%; systemic reactions: TIVc: 21%; TIVf: 22%. In 4-17 years PV group, solicited reactions were lower following TIVf, local reactions: TIVc: 53%; TIVf: 43%; systemic reactions: TIVc: 37%, TIVf: 30%. Injection-site pain was the most common solicited reaction, and was similar following TIVc and TIVf in 4-8 yearolds (TIVc: 56%; TIVf: 55%), and lower following TIVf in 9-17 years group (TIVc: 52%; TIVf: 42%). Reporting of unsolicited AEs was similar for TIVc and TIVf across the two age groups. CONCLUSION: TIVc was well tolerated and had a safety and reactogenicity profile similar to that of TIVf in healthy 4-17 yearolds (NCT01857206). PMID- 26643932 TI - Pertussis specific cell-mediated immune responses ten years after acellular pertussis booster vaccination in young adults. AB - BACKGROUND: One of the reasons for pertussis resurgence is waning immunity. Both humoral and cell mediated immunity (CMI) are essential for protection. The aim of this study was to evaluate CMI responses after acellular pertussis vaccination in young adults. METHODS: Fifty-seven young adults were followed for ten years after a diphtheria-tetanus acellular pertussis (dTpa) booster vaccination. A second booster was administrated at year 10. CMI was determined from peripheral blood mononuclear cells (PBMC) stimulated with vaccine antigens pertussis toxin (PT), filamentous hemagglutinin (FHA) and pertactin (PRN) before and one month after the second vaccination, using proliferation and IFN-gamma and IL-17 ELISpot. In addition, the response to ten selected cytokines was measured from 14 subjects. RESULTS: Before the booster dose, positive proliferation was recognized in 51%, 53% and 89% of the subjects against PT, PRN and FHA, respectively. One month after, the positivity rate increased to 81%, 81% and 96%. Although the number of IFN-gamma and IL-17 secreting cells was increased, the expression of most of the tested cytokines was found to be downregulated. After PT stimulation, only one (7.1%) subject had increased production in all cytokines, whereas six (42.9%) had decreased production of all cytokines. Ten subjects (71.4%) had decreased concentration of IFN-gamma, the cytokine important for pertussis protection. CONCLUSIONS: CMI persists even when antibodies have decayed, and acellular pertussis vaccine enhances the CMI response. Further studies are needed to illustrate what factors cause the low production of some important cytokines. PMID- 26643933 TI - Baculovirus vectors expressing F proteins in combination with virus-induced signaling adaptor (VISA) molecules confer protection against respiratory syncytial virus infection. AB - Baculovirus has been exploited for use as a novel vaccine vector. To investigate the feasibility and efficacy of recombinant baculoviruses (rBVs) expressing respiratory syncytial virus (RSV) fusion (F) proteins, four constructs (Bac tF/64, Bac-CF, Bac-CF/tF64 and Bac-CF/tF64-VISA) were generated. Bac-tF64 displays the F ectodomain (tF) on the envelope of rBVs, whereas Bac-CF expresses full-length F protein in transduced mammalian cells. Bac-CF/tF64 not only displays tF on the envelope but also expresses F in cells. Bac-CF/tF64-VISA comprises Bac-CF/tF64 harboring the virus-induced signaling adaptor (VISA) gene. After administration to BALB/c mice, all four vectors elicited RSV neutralizing antibody (Ab), systemic Ab (IgG, IgG1, and IgG2a), and cytokine responses. Compared with Bac-tF64, mice inoculated with Bac-CF and Bac-CF/tF64 exhibited an increased mixed Th1/Th2 cytokine response, increased ratios of IgG2a/IgG1 antibody responses, and reduced immunopathology upon RSV challenge. Intriguingly, co-expression of VISA reduced Th2 cytokine (IL-4, IL-5, and IL-10) production induced by Bac-CF/tF64, thus relieving lung pathology upon a subsequent RSV challenge. Our results indicated that the Bac-CF/tF64 vector incorporated with the VISA molecule may provide an effective vaccine strategy for protection against RSV. PMID- 26643934 TI - Annotated mitochondrial genome assemblies for two sand lances (genus: Ammodytes) from the northwest Atlantic. AB - Complete mitochondrial genomes of two northwest Atlantic sand lances (Ammodytes americanus and Ammodytes dubius) were sequenced, assembled, and annotated. Both genomes were 16 519 bp in length and were differentiated by a genetic distance of only 0.01. Furthermore, mitochondrial gene annotations were identical for both species. Phylogenetic analysis revealed that divergence between the two species was shallow, relative to other members of the genus. PMID- 26643935 TI - Improving oncologic outcomes for colorectal cancer at high risk for local regional recurrence with novel surgical techniques. AB - Despite innovation in surgical technology, colorectal adenocarcinoma is a disease process with a risk of local and regional progression of disease. This article seeks to identify patients with primary disease who are at high risk for minimal residual disease from cancer spread after resection. These are the patients who will profit from novel perioperative surgical treatments that will improve the clearance and containment of cancer cells disseminated prior to or at the time of the adenocarcinoma resection. Clinical factors that identify these patients at high risk for local recurrence and peritoneal metastases are presented. Data regarding novel surgical techniques that include perioperative cancer chemotherapy to provide more optimal treatment are described. The perioperative timing of the revised surgical options is emphasized. PMID- 26643936 TI - Resonating Behaviour of Nanomachined Holed Microcantilevers. AB - The nanofabrication of a nanomachined holed structure localized on the free end of a microcantilever is here presented, as a new tool to design micro-resonators with enhanced mass sensitivity. The proposed method allows both for the reduction of the sensor oscillating mass and the increment of the resonance frequency, without decreasing the active surface of the device. A theoretical analysis based on the Rayleigh method was developed to predict resonance frequency, effective mass, and effective stiffness of nanomachined holed microresonators. Analytical results were checked by Finite Element simulations, confirming an increase of the theoretical mass sensitivity up to 250%, without altering other figures of merit. The nanomachined holed resonators were vibrationally characterized, and their Q factor resulted comparable with solid microcantilevers with same planar dimensions. PMID- 26643937 TI - Design of aqueous two-phase systems for purification of hyaluronic acid produced by metabolically engineered Lactococcus lactis. AB - Hyaluronic acid has a wide range of biomedical applications and its commercial value is highly dependent on its purity and molecular weight. This study highlights the utility of aqueous two-phase separation as a primary recovery step for hyaluronic acid and for removal of major protein impurities from fermentation broths. Metabolically engineered cultures of a lactate dehydrogenase mutant strain of Lactococcus lactis (L. lactis NZ9020) were used to produce high molecular-weight hyaluronic acid. The cell-free fermentation broth was partially purified using a polyethylene glycol/potassium phosphate system, resulting in nearly 100% recovery of hyaluronic acid in the salt-rich bottom phase in all the aqueous two-phase separation experiments. These experiments were optimized for maximum removal of protein impurities in the polyethylene glycol rich top phase. The removal of protein impurities resulted in substantial reduction of membrane fouling in the subsequent diafiltration process, carried out with a 300 kDa polyether sulfone membrane. This step resulted in considerable purification of hyaluronic acid, without any loss in recovery and molecular weight. Diafiltration was followed by an adsorption step to remove minor impurities and achieve nearly 100% purity. The final hyaluronic acid product was characterized by Fourier transform IR and NMR spectroscopy, confirming its purity. PMID- 26643938 TI - Chronic diseases and geriatric syndromes: The different weight of comorbidity. AB - BACKGROUND: Comorbidity is a relevant health determinant in older adults. Co occurrence of several diseases and other age-associated conditions generates new clinical phenotypes (geriatric syndromes [GS] as falls, delirium etc.). We investigated the association of chronic diseases, alone or in combination, and GS in older adults receiving home care services in 11 European countries and one Canadian province. METHODS: Participants were cross-sectionally evaluated with the multidimensional assessment instrument RAI HC. We assessed 14 different diagnoses and 8 GS (pain, urinary incontinence, falls, disability, dizziness, weight loss, pressure ulcers and delirium). Adjusted mean number of GS per participant was calculated for groups of participants with each disease when occurring alone or with comorbidity. RESULTS: The mean age of the 6903 participants was 82.2+/-7.4 years and 4750 (69%) were women. Participants presented with an average of 2.6 diseases and 2.0 GS: pain (48%), urinary incontinence (47%) and falls (33%) were the most prevalent. Parkinson's disease, cerebrovascular disease and peripheral artery disease were associated with the highest number of GS (2.5, 2.3 and 2.2, respectively). Conversely, hypertension, diabetes, dementia, cancer and thyroid dysfunction were associated with the lowest number of GS (2.0 on average). For 9/14 examined diseases (hypertension, diabetes, dementia, COPD, heart failure, ischemic heart disease, atrial fibrillation, cancer and thyroid dysfunction) the number of GS increased with the degree of comorbidity. CONCLUSIONS: Comorbidity and GS are prevalent in older adults receiving home care. Different diseases have a variable impact on occurrence of GS. Comorbidity is not always associated with an increased number of GS. PMID- 26643939 TI - Cell cycle reactivation of cochlear progenitor cells in neonatal FUCCI mice by a GSK3 small molecule inhibitor. AB - Due to the lack of regenerative capacity of the mammalian auditory epithelium, sensory hair cell loss results in permanent hearing deficit. Nevertheless, a population of tissue resident stem/progenitor cells has been recently described. Identification of methods to trigger their activity could lead to exploitation of their potential therapeutically. Here we validate the use of transgenic mice reporting cell cycle progression (FUCCI), and stemness (Lgr5-GFP), as a valuable tool to identify regulators of cell cycle re-entry of supporting cells within the auditory epithelium. The small molecule compound CHIR99021 was used to inhibit GSK3 activity. This led to a significant increase in the fraction of proliferating sphere-forming cells, labeled by the FUCCI markers and in the percentage of Lgr5-GFP + cells, as well as a selective increase in the fraction of S-G2-M cells in the Lgr5 + population. Using whole mount cultures of the organ of Corti we detected a statistically significant increment in the fraction of proliferating Sox2 supporting cells after CHIR99021 treatment, but only rarely appearance of novel MyoVIIa +/Edu + hair cells. In conclusion, these tools provide a robust mean to identify novel regulators of auditory organ regeneration and to clarify the contribution of stem cell activity. PMID- 26643941 TI - Treatment of minor dehiscence after endorectal advancement flap in perianal Crohn's fistulas with ozonized oil NOVOX((r)). PMID- 26643940 TI - Depression predicts persistence of paranoia in clinical high-risk patients to psychosis: results of the EPOS project. AB - BACKGROUND: The link between depression and paranoia has long been discussed in psychiatric literature. Because the causality of this association is difficult to study in patients with full-blown psychosis, we aimed to investigate how clinical depression relates to the presence and occurrence of paranoid symptoms in clinical high-risk (CHR) patients. METHODS: In all, 245 young help-seeking CHR patients were assessed for suspiciousness and paranoid symptoms with the structured interview for prodromal syndromes at baseline, 9- and 18-month follow up. At baseline, clinical diagnoses were assessed by the Structured Clinical Interview for DSM-IV, childhood adversities by the Trauma and Distress Scale, trait-like suspiciousness by the Schizotypal Personality Questionnaire, and anxiety and depressiveness by the Positive and Negative Syndrome Scale. RESULTS: At baseline, 54.3% of CHR patients reported at least moderate paranoid symptoms. At 9- and 18-month follow-ups, the corresponding figures were 28.3 and 24.4%. Depressive, obsessive-compulsive and somatoform disorders, emotional and sexual abuse, and anxiety and suspiciousness associated with paranoid symptoms. In multivariate modelling, depressive and obsessive-compulsive disorders, sexual abuse, and anxiety predicted persistence of paranoid symptoms. CONCLUSION: Depressive disorder was one of the major clinical factors predicting persistence of paranoid symptoms in CHR patients. In addition, obsessive-compulsive disorder, childhood sexual abuse, and anxiety associated with paranoia. Effective pharmacological and psychotherapeutic treatment of these disorders and anxiety may reduce paranoid symptoms in CHR patients. PMID- 26643942 TI - A mathematical model of cell equilibrium and joint cell formation in multiple myeloma. AB - In Multiple Myeloma Bone Disease healthy bone remodelling is affected by tumour cells by means of paracrine cytokinetic signalling in such a way that osteoclast formation is enhanced and the growth of osteoblast cells inhibited. The participating cytokines are described in the literature. Osteoclast-induced myeloma cell growth is also reported. Based on existing mathematical models for healthy bone remodelling a three-way equilibrium model is presented for osteoclasts, osteoblasts and myeloma cell populations to describe the progress of the illness in a scenario in which there is a secular increase in the cytokinetic interactive effectiveness of paracrine processes. The equilibrium state for the system is obtained. The paracrine interactive effectiveness is explored by parameter variation and the stable region in the parameter space is identified. Then recently-discovered joint myeloma-osteoclast cells are added to the model to describe the populations inside lytic lesions. It transpires that their presence expands the available parameter space for stable equilibrium, thus permitting a detrimental, larger population of osteoclasts and myeloma cells. A possible relapse mechanism for the illness is explored by letting joint cells dissociate. The mathematics then permits the evaluation of the evolution of the cell populations as a function of time during relapse. PMID- 26643943 TI - A physiologically based model of vascular refilling during ultrafiltration in hemodialysis. AB - An assessment of fluid status can be obtained by monitoring relative blood volume (RBV) during hemodialysis (HD) treatment. The dynamics of RBV is determined by fluid removal from the intravascular compartment by ultrafiltration (UF) and vascular refill from the interstitium. To characterize this dynamics, a two compartment model describing the short-term dynamics of vascular refilling and UF is developed. Fluid movement between the compartments is governed by lymphatic and microvascular fluid shifts. Further, protein flux is described by convection, diffusion and the lymphatic protein flux. Patient specific parameters are identified based on hematocrit (Hct) measurements by the Crit-Line monitor (CLM). Different measurement frequencies and UF profiles are compared to determine data fidelity and influence on the quality of parameter estimates. This relevant information can be used to assess the (patho)physiological status of hemodialysis patients and could aid in individualizing therapy. PMID- 26643945 TI - Care and viral suppression during the last year of life among persons with HIV who died in 2012, 18 US jurisdictions. AB - Death due to HIV remains a leading cause of death among some US populations, yet little is known about HIV care before death. We used data from the National HIV Surveillance System to determine disease stage and care within 12 months prior to death among persons infected with HIV who died in 2012. Persons were considered to be in care within 12 months before death if they had >=1 CD4 or viral load test results, and in continuous care if they had >=2 CD4 or viral load test results at least 3 months apart. Viral suppression (viral load <200 copies/mL) was based on the most recent viral load test result in the 12 months before death. Among 7348 persons infected with HIV who died in 2012, 47.1% had late stage disease (AIDS) within 12 months before death. Overall, 85.7% had >=1 test result, 64.3% had >=2 tests at least 3 months apart, and 41.6% had a suppressed viral load. While blacks and Hispanics/Latinos had higher percentages of continuous care compared with whites, they had lower percentages of viral suppression and higher percentages with late stage disease. Viral suppression was higher among older persons. The majority had been diagnosed with HIV more than 5 years before death (86.3%). Although the majority of persons infected with HIV who died in 2012 had been diagnosed many years before death, almost half had late stage disease, and there were disparities in late stage disease and viral suppression by race/ethnicity and age. PMID- 26643946 TI - Comparative study between simple and optimized liposomal dispersion of quetiapine fumarate for diffusion through nasal route. AB - CONTEXT: Nasal route of drug administration is preferred more and more for the targeted delivery to the brain in current drug development scenario due to its ease of use, reliability, quick action, and lesser side effects. Those CNS drugs which have limited oral bioavailability due to pharmacokinetic consequences and brain barrier repulsion are getting onto this direction. OBJECTIVE: Quetiapine fumarate, an analogous to above and an antischizophrenic agent, is tested for its diffusion property with and without lipophilic carrier through sheep nasal membrane. Being a BCS class II' and high permeable candidate, it tends to crossover easily, so made up in a simple dispersion. MATERIALS AND METHODS: To improve its diffusion rate, it was embedded into liposomal dispersion, which has proven that it has advanced efficiency for diffusion. For this, both the formulations were checked and compared for their diffusion profile, as it is an essential property for bioavailability through nasal route. Comparison was made on the basis of % drug diffusion within 6 h, rate, mechanism, profile, and coefficient. RESULTS: Liposomal dispersion has been proved superior with greater percentage diffusion of 32.61 +/- 1.70 and very high permeability with a coefficient value of 4.1334 +/- 0.7321 (* 10 (-) (5 )cm/s). Diffusion profile comparison bearing dissimilarity of 18 and similarity of 74 indicated that the diffusion profiles of liposomal dispersions and simple dispersion were similar but not identical. CONCLUSION: Liposomal diffusion supremacy was further sustained by in vivo, ciliotoxicity, and gamma scintigraphy studies. PMID- 26643944 TI - Genome-wide analysis of genetic correlation in dementia with Lewy bodies, Parkinson's and Alzheimer's diseases. AB - The similarities between dementia with Lewy bodies (DLB) and both Parkinson's disease (PD) and Alzheimer's disease (AD) are many and range from clinical presentation, to neuropathological characteristics, to more recently identified, genetic determinants of risk. Because of these overlapping features, diagnosing DLB is challenging and has clinical implications since some therapeutic agents that are applicable in other diseases have adverse effects in DLB. Having shown that DLB shares some genetic risk with PD and AD, we have now quantified the amount of sharing through the application of genetic correlation estimates, and show that, from a purely genetic perspective, and excluding the strong association at the APOE locus, DLB is equally correlated to AD and PD. PMID- 26643947 TI - The drive revisited: Mastery and satisfaction. AB - Starting from the theory of the libido and the notions of the experience of satisfaction and the drive for mastery introduced by Freud, the author revisits the notion of the drive by proposing the following model: the drive takes shape in the combination of two currents of libidinal cathexis, one which takes the paths of the 'apparatus for obtaining mastery' (the sense-organs, motricity, etc.) and strives to appropriate the object, and the other which cathects the erotogenic zones and the experience of satisfaction that is experienced through stimulation in contact with the object. The result of this combination of cathexes constitutes a 'representation', the subsequent evocation of which makes it possible to tolerate for a certain period of time the absence of a satisfying object. On the basis of this conception, the author distinguishes the representations proper, vehicles of satisfaction, from imagos and traumatic images which give rise to excitation that does not link up with the paths taken by the drives. This model makes it possible to conciliate the points of view of the advocates of 'object-seeking' and of those who give precedence to the search for pleasure, and, further, to renew our understanding of object-relations, which can then be approached from the angle of their relations to infantile sexuality. Destructiveness is considered in terms of "mastery madness" and not in terms of the late Freudian hypothesis of the death drive. PMID- 26643948 TI - Aptamers Against Immunologic Targets: Diagnostic and Therapeutic Prospects. AB - The concept of in vitro selection of nucleic acid aptamers emerged 25 years ago, and since then tremendous progress has been achieved in the development of different aptamers and their applications for various bioanalytical and therapeutic purposes. Among other protein targets of aptamers, immune system proteins are of particular interest both as diagnostic markers and therapeutic targets. The present review summarizes up-to-date articles concerning the selection and design of DNA and RNA aptamers against immunologic targets such as antibodies, cytokines, and T-cell and B-cell receptors. We also discuss the prospects of employing aptamers as recognizing modules of diagnostic aptasensors, potential therapeutic candidates for the treatment of autoimmune diseases and cancer, and specific tools for functional studies of immune system proteins. PMID- 26643949 TI - Abstracts: European Society of Veterinary Ophthalmologists, Lisbon, Portugal, October 1-4, 2015. PMID- 26643950 TI - SMN deficiency does not induce oxidative stress in SMA iPSC-derived astrocytes or motor neurons. AB - Spinal muscular atrophy (SMA) is a genetic disorder characterized by loss of motor neurons in the spinal cord leading to muscle atrophy and death. Although motor neurons (MNs) are the most obviously affected cells in SMA, recent evidence suggest dysfunction in multiple cell types. Astrocytes are a crucial component of the motor circuit and are intimately involved with MN health and maintenance. We have previously shown that SMA astrocytes are altered both morphologically and functionally early in disease progression, though it is unclear what causes astrocytes to become reactive. Oxidative stress is a common feature among neurodegenerative diseases. Oxidative stress can both induce apoptosis in neurons and can cause astrocytes to become reactive, which are features observed in the SMA induced pluripotent stem cell (iPSC) cultures. Therefore, we asked if oxidative stress contributes to SMA astrocyte pathology. We examined mitochondrial bioenergetics, transcript and protein levels of oxidative and anti oxidant factors, and reactive oxygen species (ROS) production and found little evidence of oxidative stress. We did observe a significant increase in endogenous catalase expression in SMA iPSCs. While catalase knockdown in SMA iPSCs increased ROS production above basal levels, levels of ROS remained lower than in controls, further arguing against robust oxidative stress in this system. Viral delivery of survival motor neuron (SMN) reversed astrocyte activation and restored catalase levels to normal, without changing mitochondrial respiration or expression of oxidative stress markers. Taken together, these data indicate that SMN deficiency induces astrocyte reactivity, but does not do so through an oxidative stress mediated process. PMID- 26643952 TI - Epigenome-wide association study identifies TXNIP gene associated with type 2 diabetes mellitus and sustained hyperglycemia. AB - Type 2 diabetes mellitus (DM) is an established risk factor for a wide range of vascular diseases, including ischemic stroke (IS). Glycated hemoglobin A1c (HbA1c), a marker for average blood glucose levels over the previous 12 weeks, is used as a measure of glycemic control and also as a diagnostic criterion for diabetes (HbA1c levels >= 6.5%). Epigenetic mechanisms, such as DNA methylation, may be associated with aging processes and with modulation of the risk of various pathologies, such as DM. Specifically, DNA methylation could be one of the mechanisms mediating the relation between DM and environmental exposures. Our goal was to identify new CpG methylation sites associated with DM. We performed a genome-wide methylation study in whole-blood DNA from an IS patient cohorts. Illumina HumanMethylation450 BeadChip array was used to measure DNA methylation in CpG sites. All statistical analyses were adjusted for sex, age, hyperlipidemia, body mass index (BMI), smoking habit and cell count. Findings were replicated in two independent cohorts, an IS cohort and a population-based cohort, using the same array. In the discovery phase (N = 355), we identified a CpG site, cg19693031 (located in the TXNIP gene) that was associated with DM (P = 1.17 * 10(-12)); this CpG was replicated in two independent cohorts (N = 167 and N = 645). Methylation of TXNIP was inversely and intensely associated with HbA1c levels (P = 7.3 * 10(-16)), specifically related to diabetic patients with poor control of glucose levels. We identified an association between the TXNIP gene and DM through epigenetic mechanisms, related to sustained hyperglycemia levels (HbA1c >= 7%). PMID- 26643951 TI - OFIP/KIAA0753 forms a complex with OFD1 and FOR20 at pericentriolar satellites and centrosomes and is mutated in one individual with oral-facial-digital syndrome. AB - Oral-facial-digital (OFD) syndromes are rare heterogeneous disorders characterized by the association of abnormalities of the face, the oral cavity and the extremities, some due to mutations in proteins of the transition zone of the primary cilia or the closely associated distal end of centrioles. These two structures are essential for the formation of functional cilia, and for signaling events during development. We report here causal compound heterozygous mutations of KIAA0753/OFIP in a patient with an OFD VI syndrome. We show that the KIAA0753/OFIP protein, whose sequence is conserved in ciliated species, associates with centrosome/centriole and pericentriolar satellites in human cells and forms a complex with FOR20 and OFD1. The decreased expression of any component of this ternary complex in RPE1 cells causes a defective recruitment onto centrosomes and satellites. The OFD KIAA0753/OFIP mutant loses its capacity to interact with FOR20 and OFD1, which may be the molecular basis of the defect. We also show that KIAA0753/OFIP has microtubule-stabilizing activity. OFD1 and FOR20 are known to regulate the integrity of the centriole distal end, confirming that this structural element is a target of importance for pathogenic mutations in ciliopathies. PMID- 26643953 TI - A tribute to Youyou Tu and artemisinin. PMID- 26643955 TI - Low-amplitude, high-frequency electromagnetic field exposure causes delayed and reduced growth in Rosa hybrida. AB - It is now accepted that plants perceive high-frequency electromagnetic field (HF EMF). We wondered if the HF-EMF signal is integrated further in planta as a chain of reactions leading to a modification of plant growth. We exposed whole small ligneous plants (rose bush) whose growth could be studied for several weeks. We performed exposures at two different development stages (rooted cuttings bearing an axillary bud and 5-leaf stage plants), using two high frequency (900MHz) field amplitudes (5 and 200Vm(-1)). We achieved a tight control on the experimental conditions using a state-of-the-art stimulation device (Mode Stirred Reverberation Chamber) and specialized culture-chambers. After the exposure, we followed the shoot growth for over a one-month period. We observed no growth modification whatsoever exposure was performed on the 5-leaf stage plants. When the exposure was performed on the rooted cuttings, no growth modification was observed on Axis I (produced from the elongation of the axillary bud). Likewise, no significant modification was noted on Axis II produced at the base of Axis I, that came from pre-formed secondary axillary buds. In contrast, Axis II produced at the top of Axis I, that came from post-formed secondary buds consistently displayed a delayed and significant reduced growth (45%). The measurements of plant energy uptake from HF-EMF in this exposure condition (SAR of 7.2 10(-4)Wkg( 1)) indicated that this biological response is likely not due to thermal effect. These results suggest that exposure to electromagnetic field only affected development of post-formed organs. PMID- 26643954 TI - Metabolism pathways in chronic lymphocytic leukemia. AB - Alterations in chronic lymphocytic leukemia (CLL) cell metabolism have been studied by several investigators. Unlike normal B lymphocytes or other leukemia cells, CLL cells, like adipocytes, store lipids and utilize free fatty acids (FFA) to produce chemical energy. None of the recently identified mutations in CLL directly affects metabolic pathways, suggesting that genetic alterations do not directly contribute to CLL cells' metabolic reprogramming. Conversely, recent data suggest that activation of STAT3 or downregulation of microRNA-125 levels plays a crucial role in the utilization of FFA to meet the CLL cells' metabolic needs. STAT3, known to be constitutively activated in CLL, increases the levels of lipoprotein lipase (LPL) that mediates lipoprotein uptake and shifts the CLL cells' metabolism towards utilization of FFA. Herein, we review the evidence for altered lipid metabolism, increased mitochondrial activity and formation of reactive oxygen species (ROS) in CLL cells, and discuss the possible therapeutic strategies to inhibit lipid metabolism pathways in patient with CLL. PMID- 26643956 TI - Endotoxin-neutralizing activity and mechanism of action of a cationic alpha helical antimicrobial octadecapeptide derived from alpha-amylase of rice. AB - We have previously reported that AmyI-1-18, an octadecapeptide derived from alpha amylase (AmyI-1) of rice, is a novel cationic alpha-helical peptide that exhibited antimicrobial activity against human pathogens, including Porphyromonas gingivalis, Pseudomonas aeruginosa, Propionibacterium acnes, Streptococcus mutans, and Candida albicans. In this study, to further investigate the potential functions of AmyI-1-18, we examined its inhibitory ability against the endotoxic activities of lipopolysaccharides (LPSs, smooth and Rc types) and lipid A from Escherichia coli. AmyI-1-18 inhibited the production of endotoxin-induced nitric oxide (NO), an inflammatory mediator, in mouse macrophages (RAW264) in a concentration-dependent manner. The results of a chromogenic Limulus amebocyte lysate assay illustrated that the ability [50% effective concentration (EC50): 0.17 MUM] of AmyI-1-18 to neutralize lipid A was similar to its ability (EC50: 0.26 MUM) to neutralize LPS, suggesting that AmyI-1-18 specifically binds to the lipid A moiety of LPS. Surface plasmon resonance analysis of the interaction between AmyI-1-18 and LPS or lipid A also suggested that AmyI-1-18 directly binds to the lipid A moiety of LPS because the dissociation constant (KD) of AmyI-1-18 with lipid A is 5.6*10(-10) M, which is similar to that (4.3*10(-10) M) of AmyI-1 18 with LPS. In addition, AmyI-1-18 could block the binding of LPS-binding protein to LPS, although its ability was less than that of polymyxin B. These results suggest that AmyI-1-18 expressing antimicrobial and endotoxin neutralizing activities is useful as a safe and potent host defense peptide against pathogenic Gram-negative bacteria in many fields of healthcare. PMID- 26643957 TI - Effect of palmitoylated prolactin-releasing peptide on food intake and neural activation after different routes of peripheral administration in rats. AB - Obesity is an escalating epidemic, but an effective non-invasive therapy is still scarce. For obesity treatment, anorexigenic neuropeptides are promising tools, but their delivery from the periphery to the brain is complicated by their peptide character. In order to overcome this unfavorable fact, we have applied the lipidization of neuropeptide prolactin-releasing peptide (PrRP), whose strong anorexigenic effect was demonstrated. A palmitoylated analog of human PrRP (h palm-PrRP31) was injected in free-fed Wistar rats by three routes: subcutaneous (s.c.), intraperitoneal (i.p) (both 5 mg/kg) and intravenous (i.v.) (from 0.01 to 0.5 mg/kg). We found a circulating compound in the blood after all three applications with the highest concentration after i.v. administration. This corresponds to the effect on food intake, which was also strongest after i.v. injection. Moreover, this is in agreement with the fact that the expression of c Fos in specific brain regions involved in food intake regulation was also highest after intravenous application. Pharmacokinetic data are further supported by results obtained from dynamic light scattering and CD spectroscopy. Human palm PrRP31 analog showed a strong tendency to micellize, and formation of aggregates suggested lower availability after i.p. or s.c. application. We have demonstrated that palm-PrRP influenced food intake even in free fed rats. Not surprisingly, the maximal effect was achieved after the intravenous application even though two orders of magnitude lower dose was used compared to both two other applications. We believe that palm-PrRP could have a potential as an antiobesity drug when its s.c. application would be improved. PMID- 26643958 TI - Editorial for Full4Health special issue of 'Peptides': Peptides in the food-gut brain axis and roles in hunger and satiety. PMID- 26643959 TI - Long-term decoding of movement force and direction with a wireless myoelectric implant. AB - OBJECTIVE: The ease of use and number of degrees of freedom of current myoelectric hand prostheses is limited by the information content and reliability of the surface electromyography (sEMG) signals used to control them. For example, cross-talk limits the capacity to pick up signals from small or deep muscles, such as the forearm muscles for distal arm amputations, or sites of targeted muscle reinnervation (TMR) for proximal amputations. Here we test if signals recorded from the fully implanted, induction-powered wireless Myoplant system allow long-term decoding of continuous as well as discrete movement parameters with better reliability than equivalent sEMG recordings. The Myoplant system uses a centralized implant to transmit broadband EMG activity from four distributed bipolar epimysial electrodes. APPROACH: Two Rhesus macaques received implants in their backs, while electrodes were placed in their upper arm. One of the monkeys was trained to do a cursor task via a haptic robot, allowing us to control the forces exerted by the animal during arm movements. The second animal was trained to perform a center-out reaching task on a touchscreen. We compared the implanted system with concurrent sEMG recordings by evaluating our ability to decode time varying force in one animal and discrete reach directions in the other from multiple features extracted from the raw EMG signals. MAIN RESULTS: In both cases, data from the implant allowed a decoder trained with data from a single day to maintain an accurate decoding performance during the following months, which was not the case for concurrent surface EMG recordings conducted simultaneously over the same muscles. SIGNIFICANCE: These results show that a fully implantable, centralized wireless EMG system is particularly suited for long-term stable decoding of dynamic movements in demanding applications such as advanced forelimb prosthetics in a wide range of configurations (distal amputations, TMR). PMID- 26643960 TI - "This Is Where You Fall off My Map": Trans-Spectrum Spatialities in Washington, DC, Safety, and the Refusal to Submit to Somatic Erasure. AB - This article explores how "safety" and "safe space," as a somatic, psychic, or affective freedom from harm and a kind of experiential "health," is constructed in transgender, transsexual, and gender-nonconforming (henceforth trans (1) ) persons in community-produced maps of Washington, DC as a "trans city." These maps, and their associated narratives, provide the only up-to-date data available on the lived experience of trans populations living in the District, a city quickly gaining notoriety for systemic brutality against trans feminine people of color. PMID- 26643961 TI - Work Factors, Work-Family Conflict, the Theory of Planned Behaviour and Healthy Intentions: A Cross-Cultural Study. AB - The present study examined the roles of work factors (i.e. job demands and job resources), work-family conflicts and culture on predictors of healthy intentions (fruit and vegetable consumption, low-fat diet and physical activity) within the framework of the theory of planned behaviour (TPB). Employees from the United Kingdom (N = 278) and Malaysia (N = 325) participated in the study. Results indicated that higher job demands were significantly related to lower intentions to eat a low-fat diet. Women reported higher intentions to eat a low-fat diet than men did, while participants from the United Kingdom had lower intentions to engage in physical activity compared with those from Malaysia. The efficacy of TPB variables in explaining intentions was verified, with perceived behavioural control (i.e. self-efficacy), attitudes and descriptive norms combined with past behaviour predictive across the samples. The results also suggest the roles of culture and work interference with family variables in moderating TPB-intention relationships and confirm that TPB variables mediate the effects of job demands and job resources on intentions. Practically, to promote health, identifying strategies to reduce stress factors; specifying important cognitive factors affecting work factors and thus, healthy intentions; and acknowledging cultural specific determinants of healthy intentions are recommended. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26643962 TI - EX-PRESS and ahmed glaucoma valve in treatment of refractory glaucoma. PMID- 26643963 TI - Expression of a Tandemly Arrayed Plectasin Gene from Pseudoplectania nigrella in Pichia pastoris and its Antimicrobial Activity. AB - In recent years, various naturally occurring defence peptides such as plectasin have attracted considerable research interest because they could serve as alternatives to antibiotics. However, the production of plectasin from natural microorganisms is still not commercially feasible because of its low expression levels and weak stability. A tandemly arrayed plectasin gene (1,002 bp) from Pseudoplectania nigrella was generated using the isoschizomer construction method, and was inserted into the pPICZalphaA vector and expressed in Pichia pastoris. The selected P. pastoris strain yielded 143 MUg/ml recombinant plectasin (Ple) under the control of the methanol-inducible alcohol oxidase 1 (AOX1) promoter. Ple was estimated by SDS-PAGE to be 41 kDa. In vitro studies have shown that Ple efficiently inhibited the growth of several gram-positive bacteria such as Streptococcus suis and Staphylococcus aureus. S. suis is the most sensitive bacterial species to Ple, with a minimum inhibitory concentration (MIC) of 4 MUg/ml. Importantly, Ple exhibited resistance to pepsin but it was quite sensitive to trypsin and maintained antimicrobial activity over a wide pH range (pH 2.0 to 10.0). P. pastoris offers an attractive system for the cost effective production of Ple. The antimicrobial activity of Ple suggested that it could be a potential alternative to antibiotics against S. suis and S. aureus infections. PMID- 26643964 TI - Advances in Biochemistry and Microbial Production of Squalene and Its Derivatives. AB - Squalene is a linear triterpene formed via the MVA or MEP biosynthetic pathway and is widely distributed in bacteria, fungi, algae, plants, and animals. Metabolically, squalene is used not only as a precursor in the synthesis of complex secondary metabolites such as sterols, hormones, and vitamins, but also as a carbon source in aerobic and anaerobic fermentation in microorganisms. Owing to the increasing roles of squalene as an antioxidant, anticancer, and anti inflammatory agent, the demand for this chemical is highly urgent. As a result, with the exception of traditional methods of the isolation of squalene from animals (shark liver oil) and plants, biotechnological methods using microorganisms as producers have afforded increased yield and productivity, but a reduction in progress. In this paper, we first review the biosynthetic routes of squalene and its typical derivatives, particularly the squalene synthase route. Second, typical biotechnological methods for the enhanced production of squalene using microbial cell factories are summarized and classified. Finally, the outline and discussion of the novel trend in the production of squalene with several updated events to 2015 are presented. PMID- 26643965 TI - Biochemical Characterization of Recombinant UDP-Glucose:Sterol 3-O Glycosyltransferase from Micromonospora rhodorangea ATCC 31603 and Enzymatic Biosynthesis of Sterol-3-O-beta-Glucosides. AB - A uridine diphosphate-glucose:sterol glycosyltransferase-encoding gene was isolated and cloned from the established fosmid library of Micromonospora rhodorangea ATCC 27932 that usually produces the aminoglycoside antibiotic geneticin. The gene consists of 1,185 base pairs and encodes a 41.4 kDa protein, which was heterologously expressed in Escherichia coli BL21(DE3). In silico analyses of the deduced gene product suggested that it is a member of the family 1 glycosyltransferases. The recombinant protein MrSGT was able to catalyze the transfer of a glucosyl moiety onto the C-3 hydroxy function in sterols (beta sitosterol, campesterol, and cholesterol), resulting in the corresponding steryl glucosides (beta-sitosterol-3-O-beta-D-glucoside, campesterol-3-O-beta-D glucoside, and cholesterol-3-O-beta-D-glucoside). This enzyme prefers phytosterols to cholesterol, and also shows substrate flexibility to some extent, in that it could recognize a number of acceptor substrates. PMID- 26643966 TI - Isorhamnetin Attenuates Staphylococcus aureus-Induced Lung Cell Injury by Inhibiting Alpha-Hemolysin Expression. AB - Staphylococcus aureus, like other gram-positive pathogens, has evolved a large repertoire of virulence factors as a powerful weapon to subvert the host immune system, among which alpha-hemolysin (Hla), a secreted pore-forming cytotoxin, plays a preeminent role. We observed a concentration-dependent reduction in Hla production by S. aureus in the presence of sub-inhibitory concentrations of isorhamnetin, a flavonoid from the fruits of Hippophae rhamnoides L., which has little antibacterial activity. We further evaluate the effect of isorhamnetin on the transcription of the Hla-encoding gene hla and RNAIII, an effector molecule in the agr system. Isorhamnetin significantly down-regulated RNAIII expression and subsequently inhibited hla transcription. In a co-culture of S. aureus and lung cells, topical isorhamnetin treatment protected against S. aureus-induced cell injury. Isorhamnetin may represent a leading compound for the development of anti-virulence drugs against S. aureus infections. PMID- 26643967 TI - Shiga Toxins Trigger the Secretion of Lysyl-tRNA Synthetase to Enhance Proinflammatory Responses. AB - Shiga toxins (Stxs) produced by Shiga toxin-producing Escherichia coli (STEC) strains are major virulence factors that cause fatal systemic complications, such as hemolytic uremic syndrome and disruption of the central nervous system. Although numerous studies report proinflammatory responses to Stx type 1 (Stx1) or Stx type 2 (Stx2) both in vivo and in vitro, none have examined dynamic immune regulation involving cytokines and/or unknown inflammatory mediators during intoxication. Here, we showed that enzymatically active Stxs trigger the dissociation of lysyl-tRNA synthetase (KRS) from the multi-aminoacyl-tRNA synthetase complex in human macrophage-like differentiated THP-1 cells and its subsequent secretion. The secreted KRS acted to increase the production of proinflammatory cytokines and chemokines. Thus, KRS may be one of the key factors that mediate transduction of inflammatory signals in the STEC-infected host. PMID- 26643969 TI - Induction of apoptosis by zerumbone isolated from Zingiber zerumbet (L.) Smith in protozoan parasite Leishmania donovani due to oxidative stress. AB - In the present context of emergence of resistance aligned with the conventional anti-leishmanial drugs and occasional treatment failure compelled us to continue the search for replaceable therapeutic leads against Leishmania infection. Various ginger spices of the Zingiberaceae family are widely used as spices, flavouring agents, and medicines in Southeast Asia because of their unique flavour as well as due to their medicinal properties. Zerumbone, a natural component of Zingiber zerumbet (L.) Smith, has been studied for its pharmacological potential as antiulcer, antioxidant, anticancer, and antimicrobial. In this study, we have shown that zerumbone could induce ROS mediated apoptosis in Leishmania donovani promastigotes and also found effective in reducing intracellular amastigotes in infected-macrophages. We emphasized the potential of zerumbone to be employed in the development of new therapeutic drugs against L. donovani infection and provided the basis for future research on the application of transitional medicinal plants. PMID- 26643968 TI - Identifying a Deletion Affecting Total Lung Capacity Among Subjects in the COPDGene Study Cohort. AB - Chronic obstructive pulmonary disease (COPD) is a progressive disease with both environmental and genetic risk factors. Genome-wide association studies (GWAS) have identified multiple genomic regions influencing risk of COPD. To thoroughly investigate the genetic etiology of COPD, however, it is also important to explore the role of copy number variants (CNVs) because the presence of structural variants can alter gene expression and can be causal for some diseases. Here, we investigated effects of polymorphic CNVs on quantitative measures of pulmonary function and chest computed tomography (CT) phenotypes among subjects enrolled in COPDGene, a multisite study. COPDGene subjects consist of roughly one-third African American (AA) and two-thirds non-Hispanic white adult smokers (with or without COPD). We estimated CNVs using PennCNV on 9,076 COPDGene subjects using Illumina's Omni-Express genome-wide marker array. We tested for association between polymorphic CNV components (defined as disjoint intervals of copy number regions) for several quantitative phenotypes associated with COPD within each racial group. Among the AAs, we identified a polymorphic CNV on chromosome 5q35.2 located between two genes (FAM153B and SIMK1, but also harboring several pseudo-genes) giving genome-wide significance in tests of association with total lung capacity (TLCCT ) as measured by chest CT scans. This is the first study of genome-wide association tests of polymorphic CNVs and TLCCT . Although the ARIC cohort did not have the phenotype of TLCCT , we found similar counts of CNV deletions and amplifications among AA and European subjects in this second cohort. PMID- 26643970 TI - Brazilian manicure: a potential dangerous behavior. PMID- 26643971 TI - Impact of imidacloprid on new queens of imported fire ants, Solenopsis invicta (Hymenoptera: Formicidae). AB - Neonicotinoid insecticides are commonly used in managing pest insects, including the imported fire ant, Solenopsis invicta Buren. There is increasing evidence that neonicotinoid insecticides at sublethal concentrations have profound effects on social insects. However, the sublethal effect of neonicotinoids on S. invicta has never been investigated. In this study, the newly mated queens were fed with water containing 0.01 or 0.25 MUg/ml imidacloprid. Imidacloprid at both concentrations did not cause any increase in queen mortality during the founding stage; however, it significantly reduced queens' brood tending ability. In the 0.25 MUg/ml imidacloprid treatment, the time to larval emergence was significantly delayed and no pupae or adult workers were produced. This study provides clear evidence that imidacloprid at sublethal concentrations has a significant detrimental impact on S. invicta queens and the development of incipient colonies. PMID- 26643972 TI - Fluorescence microscopy study on the cytoskeletal displacements during sperm differentiation in the bush-cricket Tylopsis liliifolia (Fabricius) (Orthoptera: Tettigoniidae). AB - A study by fluorescence microscopy has been carried out on male gametes from testicular follicles, seminal vesicles, spermatophores, and seminal receptacles of the bush-cricket Tylopsis liliifolia, focusing the attention on localization and movements of F-actin and alpha-tubulin during sperm differentiation, since data in this respect are lacking in the Orthoptera. F-actin and alpha-tubulin positivity was detected in the testicular follicles, in particular at the bridges connecting spermatids of a same clone and around their nucleus, during the first differentiation stages. During the following differentiation stages in the testes, F-actin was found at one of the spermatid poles and then, during nucleus elongation, at the whole acrosomal region. A peculiar F-actin-positivity was found at the flagellum, more markedly immediately posterior to the nucleus, at the basal body region of the gametes from the testicular follicles and from the other examined districts. Other interesting data from our investigations concerns the alpha-tubulin displacements during the differentiation stages of the spermatid and a constant absence of alpha-tubulin-positivity where the centrioles are located. No positivity was also found for both alpha-tubulin and nuclear markers at the anterior region of the gamete, where the acrosomal wings are localized. Our results, compared with what is so far known in literature for the insects, lead us to assert that microfilaments and microtubules undergo gradual displacements, markedly in the testicular follicles, during the morphogenesis of the male gamete of T. liliifolia aimed to its organization and motility and probably also to its interaction with the female gamete. PMID- 26643973 TI - SF3B1 mutant MDS-initiating cells may arise from the haematopoietic stem cell compartment. AB - Despite the recent evidence of the existence of myelodysplastic syndrome (MDS) stem cells in 5q-MDS patients, it is unclear whether haematopoietic stem cells (HSCs) could also be the initiating cells in other MDS subgroups. Here we demonstrate that SF3B1 mutation(s) in our cohort of MDS patients with ring sideroblasts can arise from CD34(+)CD38(-)CD45RA(-)CD90(+)CD49f(+) HSCs and is an initiating event in disease pathogenesis. Xenotransplantation of SF3B1 mutant HSCs leads to persistent long-term engraftment restricted to myeloid lineage. Moreover, genetically diverse evolving subclones of mutant SF3B1 exist in mice, indicating a branching multi-clonal as well as ancestral evolutionary paradigm. Subclonal evolution in mice is also seen in the clinical evolution in patients. Sequential sample analysis shows clonal evolution and selection of the malignant driving clone leading to AML transformation. In conclusion, our data show SF3B1 mutations can propagate from HSCs to myeloid progeny, therefore providing a therapeutic target. PMID- 26643975 TI - Smoking and attitudes toward smoking policy at a University in Egypt. AB - To assess smoking behavior, knowledge of smoking harm, and attitudes toward campus smoking policy at an Egyptian university, an online survey of students, staff, and faculty was conducted (N = 992). The smoking prevalence of 38% among men was in line with Egypt's national average, but the smoking prevalence among women of 20% was much higher than the national average. Smoking status influenced beliefs about smoking harm and attitudes toward smoking policy, with nonsmokers having stronger beliefs about the harm of smoking and showing stronger support for smoking regulations than smokers. Smokers were more knowledgeable about smoking policy than were nonsmokers and differed slightly in their preferences for smoking policy enforcement strategies. These findings contribute to our understanding of how to tailor college smoking policy and programs to an Egyptian context. PMID- 26643974 TI - Postoperative peak serum C-reactive protein is a predictor of outcome following liver transplantation for hepatocellular carcinoma. AB - CONTEXT: C-reactive protein (CRP), a biomarker of inflammation, may correlate with prognosis in several malignancies. OBJECTIVE: To investigate the prognostic impact of early postoperative peak serum levels of CRP on tumor-specific outcome in 106 liver transplant patients with hepatocellular carcinoma (HCC). METHODS AND RESULTS: In multivariate Cox regression analysis, a posttransplant elevated peak CRP level (>versus <= 3.5 mg/dl) was identified as an independent predictor of poor recurrence-free survival (p = 0.01; HR = 4.04; CI = 1.399-11.640). CONCLUSION: Early postoperative serum CRP may serve as a useful inflammation based biomarker of outcome in liver transplant patients with HCC. PMID- 26643976 TI - Ultrarobust Transparent Cellulose Nanocrystal-Graphene Membranes with High Electrical Conductivity. AB - Ultra-robust nanomembranes possessing high mechanical strength combined with excellent stiffness and toughness rarely achieved in nanocomposite materials are presented. These are fabricated by alternately depositing 1D cellulose nanocrystals and 2D graphene oxide nanosheets by using a spin assisted layer-by layer assembly technique. Such a unique combination of 1D and 2D reinforcing nanostructures results in layered nanomaterials. PMID- 26643977 TI - Neuromuscular and technical abilities related to age in water-polo players. AB - Testing is one of the important tasks in any multi-step sport programme. In most ball games, coaches assess motor, physical and technical skills on a regular basis in early stages of talent identification in order to further athletes' development. The purpose of the study was to investigate anthropometric variables and vertical jump heights as a free throw effectiveness predictor in water-polo players of different age groups. Two hundred and thirty-six young (10-18 years) male water-polo players partitioned into three age groups underwent anthropometric variables' measures and squat- and countermovement-jump tests, and performed water-polo free throws. Anthropometric variables, vertical jump heights and throw speed - as a proxy for free throw effectiveness - resulted different over age groups. Particularly, throw speed changed from 9.28 to 13.70 m . s(-1) (+48%) from younger to older players. A multiple-regression model indicated that body height, squat-jump height and throw time together explain 52% of variance of throw speed. In conclusion, tall height, high lower limb power and throwing quickness appeared to be relevant determinants for effective free throws. Such indications can help coaches during talent identification and development processes, even by means of novel training strategies. Further research is needed over different maturity statuses. PMID- 26643978 TI - Prevalence and severity of hip and groin pain in sub-elite male football: a cross sectional cohort study of 695 players. AB - The purpose of this study was twofold: (a) to investigate the prevalence of hip and groin pain in sub-elite male adult football in Denmark and (b) to explore the association between prevalence and duration of hip and groin pain in the previous season with the Copenhagen Hip and Groin Outcome Score (HAGOS) in the beginning of the new season. In total 695 respondents from 40 teams (Division 1-4) were included. Players completed in the beginning of the new season (July-Sept 2011) a self-reported paper questionnaire on hip and/or groin pain during the previous season and HAGOS. In total 49% (95% CI: 45-52%) reported hip and/or groin pain during the previous season. Of these, 31% (95% CI: 26-36%) reported pain for >6 weeks. Players with the longest duration of pain during the previous season had the lowest HAGOS scores, when assessed at the beginning of the new season, P < 0.001. This study documents that half of sub-elite male adult football players report pain in the hip and/or groin during a football season. The football players with the longest duration of pain in previous season displayed the lowest HAGOS scores in the beginning of the new season. PMID- 26643979 TI - A 1 MDa protein complex containing critical components of the Escherichia coli divisome. AB - Cell division in bacteria is an essential process that is carried out at mid-cell by a group of cell division proteins referred to as the divisome. In Escherichia coli, over two dozen cell division proteins have been identified of which ten are essential. These division proteins localize sequentially and interdependently to the division site, after which constriction eventually produces two daughter cells. Various genetic and biochemical techniques have identified many interactions amongst cell division proteins, however the existence of the divisome as a large multi-protein complex has never been shown. Here, we identify a 1 MDa protein complex by native page that contains seven essential cell division proteins (FtsZ, ZipA, FtsK, FtsQ, FtsB, FtsL, and FtsN). The 1 MDa complex is present in rapidly dividing cells, but absent when cultures enter the stationary growth phase. Slight overexpression of the ftsQ D237N mutation that blocks cell division prevents formation of this 1 MDa complex. In cells depleted of FtsN, the 1 MDa complex is not assembled. Combined, our findings indicate that a large protein complex containing many different cell division proteins indeed exists. We note that this complex is very fragile and sensitive to the expression of tagged versions of FtsQ. PMID- 26643980 TI - Differentiation of Slow-Slow Form of AVNRT from AVRT through a Posteroseptal Accessory Pathway by Retrograde P-Wave Amplitude. AB - BACKGROUND: This study aimed to clarify whether retrograde P-wave amplitude during tachycardia can be used to differentiate slow-slow form of atrioventricular nodal reentrant tachycardia (S/S-AVNRT) from atrioventricular reentrant tachycardia through a posteroseptal accessory pathway (PS-AVRT). METHODS: Sixteen patients with S/S-AVNRT and 14 patients with PS-AVRT constituted the study group. Electrocardiographic and electrophysiological parameters were compared between both the groups. HA(CS-His), which indicates the location of the earliest atrial activation site during tachycardia, was calculated as the difference of the shortest HA interval in the His bundle region and the coronary sinus region. RESULTS: Negative deflection of the retrograde P wave during tachycardia was significantly greater in S/S-AVNRT than in PS-AVRT in the inferior leads (lead aVF, -0.22 +/- 0.04 mV vs -0.10 +/- 0.07 mV; P < 0.001). Among the electrocardiographic parameters, retrograde P-wave amplitude in lead aVF had the highest diagnostic accuracy (area under the curve 0.975, sensitivity 93%, and specificity 88% for a cutoff value of -0.16 mV). HA(CS-His) was negatively greater in S/S-AVNRT than in PS-AVRT (-24 +/- 13 ms vs -3 +/- 18 ms; P = 0.001), and was significantly correlated with the retrograde P-wave amplitude in lead aVF (P = 0.004). CONCLUSION: Deeper negative deflection of the retrograde P wave in the inferior lead can help differentiate S/S-AVNRT from PS-AVRT. PMID- 26643981 TI - RXRalpha, PXR and CAR xenobiotic receptors mediate the apoptotic and neurotoxic actions of nonylphenol in mouse hippocampal cells. AB - In the present study, we investigated the role of the retinoid X receptor (RXR), the pregnane X receptor (PXR) and the constitutive androstane receptor (CAR), in the apoptotic and toxic effects of nonylphenol in mouse primary neuronal cell cultures. Our study demonstrated that nonylphenol activated caspase-3 and induced lactate dehydrogenase (LDH) release in hippocampal cells, which was accompanied by an increase in the mRNA expression and protein levels of RXRalpha, PXR and CAR. Nonylphenol stimulated Rxra, Pxr, and Car mRNA expression. These effects were followed by increase in the protein levels of particular receptors. Immunofluorescence labeling revealed the cellular distribution of RXRalpha, PXR and CAR in hippocampal neurons in response to nonylphenol, shortening of neurites and cytoplasmic shrinking, as indicated by MAP2 staining. It also showed NP induced translocation of receptor-specific immunofluorescence from cytoplasm to the nucleus. The use of specific siRNAs demonstrated that Rxra-, Pxr-, and Car siRNA-transfected cells were less vulnerable to nonylphenol-induced activation of caspase-3 and LDH, thus confirming the key involvement of RXRalpha/PXR/CAR signaling pathways in the apoptotic and neurotoxic actions of nonylphenol. These new data give prospects for the targeting xenobiotic nuclear receptors to protect the developing nervous system against endocrine disrupting chemicals. PMID- 26643982 TI - Malignant peripheral nerve sheath tumour arising in a scar from infantile haemangioma. PMID- 26643983 TI - Muscle Quality and Myosteatosis: Novel Associations With Mortality Risk: The Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study. AB - Muscle composition may affect mortality risk, but prior studies have been limited to specific samples or less precise determination of muscle composition. We evaluated associations of thigh muscle composition, determined using computed tomography imaging, and knee extension strength with mortality risk among 4,824 participants aged 76.4 (standard deviation (SD), 5.5) years from the Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study (2002-2006). Cox proportional hazards models were used to estimate hazard ratios. After 8.8 years of follow-up, there were 1,942 deaths. For men, each SD-increment increase in muscle lean area, muscle quality, and strength was associated with lower mortality risk, with decreases ranging between 11% and 22%. Each SD-increment increase in intermuscular adipose tissue and intramuscular adipose tissue was associated with higher mortality risk (hazard ratio (HR) = 1.13 (95% confidence interval (CI): 1.06, 1.22) and HR = 1.23 (95% CI: 1.15, 1.30), respectively). For women, each SD-increment increase in muscle lean area, muscle quality, and strength was associated with lower mortality risk, with decreases ranging between 12% and 19%. Greater intramuscular adipose tissue was associated with an 8% higher mortality risk (HR = 1.08, 95% CI: 1.01, 1.16). This study shows that muscle composition is associated with mortality risk. These results also show the importance of improving muscle strength and area and lowering muscle adipose tissue infiltration. PMID- 26643984 TI - SFRP1 variations influence susceptibility and immune response to Mycobacterium tuberculosis in a Chinese Han population. AB - OBJECTIVES: SFRP1 acts as a well-established inhibitory regulator of the Wnt signaling pathway, whose polymorphisms have been demonstrated to be associated with the risk of inflammation, infection as well as cancer. We verified the hypothesis that single nucleotide polymorphisms (SNPs) within SFRP1 gene are associated with susceptibility and clinical characteristics of tuberculosis disease in a Chinese Han population. METHODS: Six candidate SNPs were genotyped using MassARRAY method in a case-control design (260 tuberculosis patients and 252 healthy controls). A comprehensive analysis of single locus including the genotypic, allelic frequencies and the genetic models, haplotypic construction as well as gene-gene interaction was conducted to investigate the relationships between SNPs and TB. Significant SNPs were further interrogated in relation to TB clinical features and host inflammatory status. RESULTS: Genotype frequencies of rs4736958 and rs7832767 within SFRP1 gene were significantly different (p=0.011, p=0.008, respectively) between tuberculosis group and control group. Subjects carrying C allele for rs4736958 showed a decreased tuberculosis risk (OR=0.66, 95% CI=0.51-0.87, p=0.003), whereas individuals carrying rs7832767 T allele had a significant increased risk in tuberculosis susceptibility (OR=1.32, 95% CI=1.01 1.74, p=0.046). Genetic model analysis revealed that dominant, co-dominant and recessive models of rs4736958 were associated with decreased susceptibility to tuberculosis (p all <0.05), while the recessive and co-dominant models of rs7832767 were related to significantly increased risk for tuberculosis (p all <0.05). There was a reduced tuberculosis risk in association with the haplotype CC (representing rs3242 and rs4736958) of SFRP1 (OR=0.73, 95% CI=0.56-0.96, p=0.026). Further stratification analysis indicated that TB patients with genotype CT for rs4736958 were associated with higher CRP concentrations, and heterozygous patients (CT genotype) of rs7832767 trended towards greater ESR levels. CONCLUSION: SNPs rs4736958 and rs7832767 of SFRP1 gene were significantly associated with tuberculosis susceptibility and might influence the expression levels of inflammatory markers of tuberculosis patients in a Chinese Han population. PMID- 26643985 TI - Development of a comprehensive survey of sexuality issues including a self-report version of the International Spinal Cord Injury sexual function basic data sets. AB - STUDY DESIGN: Questionnaire development, validation and completion. OBJECTIVES: Develop comprehensive survey of sexuality issues including validated self-report versions of the International Spinal Cord Injury male sexual function and female sexual and reproductive function basic data sets (SR-iSCI-sexual function). SETTING: People with spinal cord damage (SCD) living in the community, Australia from August 2013 to June 2014. METHODS: An iterative process involving rehabilitation medicine clinicians, a nurse specialising in sexuality issues in SCD and people with SCD who developed a comprehensive survey that included the SR iSCI-sexual function. Participants recruitment through spinal rehabilitation review clinic and community organisations that support people with SCD. RESULTS: Surveys completed by 154 people. Most were male (n=101, 65.6%). Respondents' median age was 50 years (interquartile range (IQR) 38-58), and they were a median of 10 years (IQR 4-20) after the onset of SCD. Sexual problems unrelated to SCD were reported by 12 (8%) respondents, and 114 (n=75.5%) reported sexual problems because of SCD. Orgasms were much less likely (chi(2)=13.1, P=0.006) to be normal in males (n=5, 5%) compared with females (n=11, 22%). Males had significantly worse (chi(2)=26.0, P=0.001) psychogenic genital functioning (normal n=9, 9%) than females (normal n=13, 26%) and worse (chi(2)=10.8, P=0.013) reflex genital functioning. Normal ejaculation was reported in only three (3%) men. Most (n=26, 52%) women reported reduced or absent menstruation pattern since SCD. CONCLUSION: The SR-iSCI-sexual function provides a useful tool for researchers and clinicians to collect information regarding patient-reported sexual functioning after SCD and to facilitate comparative studies. PMID- 26643986 TI - Posttraumatic growth in people with traumatic long-term spinal cord injury: predictive role of basic hope and coping. AB - STUDY DESIGN: Participants with spinal cord injury (SCI) sustained at least 15 years before the study completed questionnaires measuring posttraumatic growth (PTG), basic hope and coping strategies. OBJECTIVES: To determine contribution of basic hope and coping strategies to accounting for PTG variability in participants with traumatic long-term SCI. SETTING: Polish rehabilitation centres, foundations and associations implementing social inclusion and professional activation programmes. Participants were enrolled based on their medical history by trained rehabilitation specialists and psychologists. METHODS: The set of questionnaires included the following: The Post-traumatic Growth Inventory; The Coping Orientations to Problems Experienced (COPE); and Basic Hope Inventory. RESULTS: A study of 169 individuals with paraplegia in the range of PTG showed the highest degree of positive changes in appreciation of life (AL) and the lowest in self-perception. Regression analysis showed that coping strategies such as religion (REL), focus on the problem, humour, alcohol/drug use ideation and basic hope jointly account for 60% of variance of PTG. The highest contribution to accounting for this variability had REL. Also, it was found that coping strategies and basic hope allow to predict variance of individual growth aspects. Age at trauma exposure positively correlated with changes in AL and spiritual change. No significant relationship between growth and age of participants was confirmed. CONCLUSION: PTG occurring in people with long-term traumatic SCI is primarily manifested in increased AL. Specific coping strategies and basic hope have a significant role in fostering positive changes. PMID- 26643987 TI - The roles of serum alkaline and bone alkaline phosphatase levels in predicting heterotopic ossification following spinal cord injury. AB - STUDY DESIGN: Retrospective chart review. OBJECTIVES: To analyze the usefulness of serum alkaline phosphatase (AP) and bone alkaline phosphatase (BAP), as well as C-reactive protein (CRP) levels in predicting heterotopic ossification (HO). SETTING: Department of Spinal Cord Injury and Department of General and Trauma Surgery, BG-University Hospital Bergmannsheil, Ruhr University Bochum, Germany. METHODS: Between January 2003 and December 2013, 87 patients with HO around the hips met the inclusion criteria and were included in the study. Alkaline phosphatase, CRP and BAP were assessed and interpreted at the time of HO diagnosis and after radiation therapy in all patients. RESULTS: At the time of HO diagnosis, 49 out of 87 patients (49.4%) had elevated alkaline phosphatase levels and 39 out of 87 patients (44.8%) had elevated BAP levels. Elevated CRP values were found in 67 patients (77.0%). Within 3 days after single-dose radiation therapy, elevated AP levels persisted in 38 patients (43.7%) and elevated BAP levels in 28 patients (32.2%). CONCLUSIONS: The results obtained show that the determination of CRP, AP and BAP levels may not be considered a reliable screening method for early HO detection, subsequent to spinal cord injury. PMID- 26643988 TI - Click Functionalization of a Dibenzocyclooctyne-Containing Conjugated Polyimine. AB - A conjugated poly(phenyl-co-dibenzocyclooctyne) Schiff-base polymer, prepared through polycondensation of dibenzocyclooctyne bisamine (DIBO-(NH2)2) with bis(hexadecyloxy)phenyldialdehyde, is reported. The resulting polymer, which has a high molecular weight (M(n)>30 kDa, M(w)>60 kDa), undergoes efficient strain promoted alkyne-azide cycloaddition reactions with a series of azides. This enables quantitative modification of each repeat unit within the polymer backbone and the rapid synthesis of a conjugated polymer library with widely different substituents but a consistent degree of polymerization (DP). Kinetic studies show a second-order reaction rate constant that is consistent with monomeric dibenzocyclooctynes. Grafting with azide-terminated polystyrene and polyethylene glycol monomethyl ether chains of varying molecular weight resulted in the efficient syntheses of a series of graft copolymers with a conjugated backbone and maximal graft density. PMID- 26643989 TI - Possible Role of Different Yeast and Plant Lysophospholipid:Acyl-CoA Acyltransferases (LPLATs) in Acyl Remodelling of Phospholipids. AB - Recent results have suggested that plant lysophosphatidylcholine:acyl-coenzyme A acyltransferases (LPCATs) can operate in reverse in vivo and thereby catalyse an acyl exchange between the acyl-coenzyme A (CoA) pool and the phosphatidylcholine. We have investigated the abilities of Arabidopsis AtLPCAT2, Arabidopsis lysophosphatidylethanolamine acyltransferase (LPEAT2), S. cerevisiae lysophospholipid acyltransferase (Ale1) and S. cerevisiae lysophosphatidic acid acyltransferase (SLC1) to acylate lysoPtdCho, lysoPtdEtn and lysoPtdOH and act reversibly on the products of the acylation; the PtdCho, PtdEtn and PtdOH. The tested LPLATs were expressed in an S. cervisiae ale1 strain and enzyme activities were assessed in assays using microsomal preparations of the different transformants. The results show that, despite high activity towards lysoPtdCho, lysoPtdEtn and lysoPtdOH by the ALE1, its capacities to operate reversibly on the products of the acylation were very low. Slc1 readily acylated lysoPtdOH, lysoPtdCho and lysoPtdEtn but showed no reversibility towards PtdCho, very little reversibility towards PtdEtn and very high reversibility towards PtdOH. LPEAT2 showed the highest levels of reversibility towards PtdCho and PtdEtn of all LPLATs tested but low ability to operate reversibly on PtdOH. AtLPCAT2 showed good reversible activity towards PtdCho and PtdEtn and very low reversibility towards PtdOH. Thus, it appears that some of the LPLATs have developed properties that, to a much higher degree than other LPLATs, promote the reverse reaction during the same assay conditions and with the same phospholipid. The results also show that the capacity of reversibility can be specific for a particular phospholipid, albeit the lysophospholipid derivatives of other phospholipids serve as good acyl acceptors for the forward reaction of the enzyme. PMID- 26643990 TI - Identification and SNP association analysis of a novel gene in chicken. AB - A novel gene that was predicted to encode a long noncoding RNA (lncRNA) transcript was identified in a previous study that aimed to detect candidate genes related to growth rate differences between Chinese local breed Gushi chickens and Anka broilers. To characterise the biological function of the lncRNA, we cloned and sequenced the complete open reading frame of the gene. We performed quantitative real-time polymerase chain reaction (qPCR) to analyse the expression patterns of the lncRNA in different tissues of chicken at different development stages. The qPCR data showed that the novel lncRNA gene was expressed extensively, with the highest abundance in spleen and lung and the lowest abundance in pectoralis and leg muscle. Additionally, we identified a single nucleotide polymorphism (SNP) at the 5'-end of the gene and studied the association between the SNP and chicken growth traits using data from an F2 resource population of Gushi chickens and Anka broilers. The association analysis showed that the SNP was significantly (P < 0.05) associated with leg muscle weight, chest breadth, sternal length and body weight in chickens at 1 day, 4 weeks and 6 weeks of age. We concluded that the novel lncRNA gene, which we designated pouBW1, may play an important role in regulating chicken growth. PMID- 26643991 TI - Pharmacokinetics and pharmacodynamics of mycophenolic acid in Nagase analbuminemic rats: Evaluation of protein binding effects using the modeling and simulation approach. AB - This study aimed to examine the pharmacokinetics and pharmacodynamics of mycophenolic acid (MPA) in Nagase analbuminemic rats (NARs) to evaluate the effect of protein binding on the associated inosine-5'-monophosphate dehydrogenase (IMPDH) activity. Free fractions of MPA in the control rats and NARs were 2.09 and 24.8%, respectively. Pharmacokinetic and pharmacodynamic parameters simultaneously obtained by the nonlinear mixed effects modeling program NONMEM explained reasonably well the concentrations of MPA and MPA glucuronide as well as IMPDH activity in both rats. NARs showed a higher clearance and a smaller volume of distribution based on the free MPA concentration than the controls did, besides the increase in free fraction. The half-maximal inhibitory concentration based on free MPA was estimated as 163 ng/mL for both rats. Simulations based on the obtained pharmacokinetic and pharmacodynamic parameters showed that the area under the IMPDH activity-time curve decreased non-linearly according to the increase in free fraction of MPA. In conclusion, the experimental data obtained from NARs followed by the modeling and simulation approach quantitatively clarified that the free MPA concentration was suitable for the biomarker of immunosuppressive effect of MPA. Dose adjustments based on the total MPA may cause unnecessary overexposure to MPA in patients with hypoalbuminemia. PMID- 26643992 TI - CYP1A1 and CYP1A2 expression levels are differentially regulated in three dimensional spheroids of liver cancer cells compared to two-dimensional monolayer cultures. AB - Compared to two-dimensional (2D) monolayer cultures, three-dimensional (3D) tumor cell culture models are thought to be structurally more similar to the in vivo tumor microenvironment. We investigated the regulation of the expression of genes encoding the drug-metabolizing enzymes CYP1A1 and CYP1A2 in 3D spheroids comprised of cells of the human hepatocellular carcinoma cell JHH1, Huh7, and HepG2. Expression of CYP1A1 and CYP1A2 in the spheroids was higher than that in 2D cultured cells. Expression of CYP1A1 and CYP1A2 is regulated by aryl hydrocarbon receptor (AhR) in 2D cultured cells. Knockdown of AhR in spheroids suppressed CYP1A1 expression; however, CYP1A2 expression levels remained unchanged. Moreover, we found that pregnane X receptor (PXR) likely regulated CYP1A2 expression in JHH1, HepG2, and Huh7 spheroids and that CYP1A1 expression in JHH1 and Huh7 3D spheroids is regulated not only by AhR but also by PXR. It is well known that gene expression levels are different between 3D spheroids and 2D monolayer cultured cells, and our results indicate that the regulation of gene expression also varies between the two culture conditions. Taken together, these results underlie a novel finding regarding the regulation of drug-metabolizing enzyme expression in liver cancer cells growing as 3D spheroids. PMID- 26643993 TI - Pharmacokinetics, pharmacodynamics and safety of single, oral doses of GSK1278863, a novel HIF-prolyl hydroxylase inhibitor, in healthy Japanese and Caucasian subjects. AB - This study was performed to evaluate the pharmacokinetics (PK), pharmacodynamics (PD) and safety of GSK1278863, a novel prolyl hydroxylase inhibitor, following a single oral administration of GSK1278863 from 10 to 100 mg or placebo in Japanese (n = 19), and 10, 25 and 100 mg in Caucasians (n = 14). Dose-proportional increases were observed in AUCinf of GSK1278863 in both ethnic groups, with a 1.3 1.5-fold higher exposure seen in Japanese relative to Caucasians for all doses. This difference in exposure can be mainly explained by the observed differences in body weights between the two groups. Statistically significant increases in erythropoietin (EPO), vascular endothelial growth factor (VEGF) and reticulocyte counts were observed in Japanese subjects after the 50 and 100 mg dose as compared to placebo. In Caucasians, similar to Japanese, EPO and VEGF levels were observed to be increased in response to the 100 mg dose. Drug-related adverse events, including headache and abdominal pain were reported in 3 Japanese subjects, while headache was reported in 3 Caucasians. In conclusion, GSK1278863 was well tolerated, with dose-proportional increases in exposure observed in both groups. There was no evidence of ethnic differences between Japanese and Caucasian with regard to PK or PD. PMID- 26643994 TI - [Risk factors associated with gastroduodenal lesions in a Douala referral hospital (Cameroon)]. AB - INTRODUCTION: The causes of gastroduodenal lesions are multifactorial, and few studies have assessed the impact of each of these factors in Africa. The aim of this study was to identify factors associated with the occurrence of gastroduodenal lesions in Cameroon. METHOD: This prospective, analytical study took place over a 5-month period in the endoscopy unit of the Douala General Hospital. Lifestyle, medical history, demographic, and clinical variables were collected. Infection with Helicobacter pylori was determined with a rapid urease (CLO) test. Multivariate regression was used to determine risk factors. RESULTS: The study included 234 of 265 patients seen in the department over the study period. Gastroscopy was normal for 54.2% of the subjects. The prevalence of peptic ulcers was 17.1% and of inflammatory lesions 26.4%. Risk factors associated with a gastroduodenal lesion were: age greater than 60 years [OR age = 2.953; 95% CI: 1.399 to 6.231; p = 0.004], H. pylori infection [OR = 2.953; 95% CI: 1.399 to 6.231; p = 0.003] and regular NSAID use [OR = 0.912; 95% CI: 0.112 to 2.733; p = 0.044] either a month before the examination or over the long term. CONCLUSION: Age greater than 60 years, NSAID consumption, and H. pylori infection are associated with the occurrence of gastroduodenal lesions. PMID- 26643995 TI - Genotype polymorphisms of genes regulating nitric oxide synthesis determine long term arteriovenous fistula patency in male hemodialysis patients. AB - OBJECTIVES: Nitric oxide (NO) is a pivotal vasoactive substance modulating arteriovenous fistula (AVF) patency for hemodialysis (HD). Since genetic background could be the predicting factor of AVF malfunction, we aimed to investigate whether the NO-related genotype polymorphisms determine AVF survival rates. METHODS: This is a retrospective, observational, multi-center study involving eight HD units in Taiwan, enrolled 580 patients initiating maintenance HD via AVFs. Genotype polymorphisms of NO-biosynthesis regulating enzymes (DDAH 1, DDAH-2, eNOS and PRMT1) were compared between HD patients with (n = 161) and without (n = 419) history of AVF malfunction. Subgroup analyses by gender were performed to evaluate the genetic effect in difference sexes. RESULTS: In overall population, statistically significant associations were not found between AVF malfunction and the genetic polymorphisms. In the male subgroup (n = 313), a single nucleotide polymorphism (SNP) of PRMT1, rs10415880 (IVS9-193 A/G), showed a significant association with AVF malfunction. Male patients with AA/AG genotype had inferior AVF outcomes compared to GG genotype, regarding primary patency (70.6% vs. 40.9%, p = 0.001), assisted primary patency (81.0% vs. 58.4%, p < 0.001) and secondary patency (83.7% vs. 63.3%, p < 0.001) at a 5-year observation period. From multivariate Cox regression model, the AA/AG genotypes of PRMT1 were an independent risk factor for AVF malfunction in men (HR: 4.539, 95% CI 2.015 10.223; p < 0.001). However, such associations were not found in women. CONCLUSIONS: rs10415880, the SNP of PRMT1 could be a novel genetic marker associated with AVF malfunction risk in male HD patients. Those with AA and AG genotypes of rs10415880 may predict a poorer long-term patency of AVF. PMID- 26643996 TI - Anosognosia increases caregiver burden in mild cognitive impairment. AB - OBJECTIVE: Our aim is to determine the clinical correlates of impaired insight in patients with mild cognitive impairment (MCI) by examining its impact on cognition, functional status, neuropsychiatric symptoms, and caregiver burden. METHODS: The study involved 75 patients with MCI and their caregivers. Patients and caregivers underwent a comprehensive evaluation including the Clinical Dementia Rating, memory tests, and the Functional Assessment Questionnaire. Behavioral symptoms were assessed by the Neuropsychiatric Inventory, caregiver burden by the Zarit Burden Inventory, and insight by comparing self-report on the AD8 dementia screening tool to informant collateral. Patients were asked about their perceptions of their memory, and answers were compared with informants' responses. Patient mood was assessed with the Hospital Anxiety Depression Scale. RESULTS: There was a significant difference in AD8 scores among patients who retained versus lacked insight. Zarit Burden Inventory scores showed a significant rise as patient insight declined; the burden appeared greater on spouse versus non-spouse caregivers. Patients with poor insight had significantly worse ratings in Clinical Dementia Rating domains of personal care and judgment, while patients who retained insight had significantly higher depression and anxiety. Insight impairment was associated with worse caregiver mood. CONCLUSIONS: Decreased patient awareness for cognitive problems was significantly associated with higher caregiver burden, independent of neuropsychiatric symptoms, functional abilities, and cognition. Personal care, judgment, and problem-solving skills could contribute to caregiver burden. Increased awareness seemed a source of patient depression and anxiety. The research highlights the need to focus on the needs of MCI caregivers and to incorporate psychosocial assessments of caregiver-patient dyads into office visits. PMID- 26643998 TI - The Neural Foundations of Reaction and Action in Aversive Motivation. AB - Much of the early research in aversive learning concerned motivation and reinforcement in avoidance conditioning and related paradigms. When the field transitioned toward the focus on Pavlovian threat conditioning in isolation, this paved the way for the clear understanding of the psychological principles and neural and molecular mechanisms responsible for this type of learning and memory that has unfolded over recent decades. Currently, avoidance conditioning is being revisited, and with what has been learned about associative aversive learning, rapid progress is being made. We review, below, the literature on the neural substrates critical for learning in instrumental active avoidance tasks and conditioned aversive motivation. PMID- 26643997 TI - Contribution and Mobilization of Mesenchymal Stem Cells in a mouse model of carbon tetrachloride-induced liver fibrosis. AB - Hepatic fibrosis is associated with bone marrow derived mesenchymal stem cells (BM-MSCs). In this study, we aimed to determine what role MSCs play in the process and how they mobilize from bone marrow (BM). We employed a mouse model of carbon tetrachloride(CCl4)-induced liver fibrosis. Frozen section was used to detect MSCs recruited to mice and human fibrotic liver. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) was detected to assess liver function. It was found that MSCs of both exogenous and endogenous origin could aggravate liver fibrosis and attenuate liver damage as indicated by lower serum ALT and AST levels. Stromal cell-derived factor-1 (SDF-1alpha)/ CXCR4 was the most important chemotactic axis regulating MSCs migration from BM to fibrotic liver. Frozen section results showed that the migration did not start from the beginning of liver injury but occurred when the expression balance of SDF-1alpha between liver and BM was disrupted, where SDF-1alpha expression in liver was higher than that in BM. Our findings provide further evidence to show the role of BM-MSCs in liver fibrosis and to elucidate the mechanism underlying MSCs mobilization in our early liver fibrosis mice model induced by CCl4. PMID- 26643999 TI - Recognizing Others: Rodent's Social Memories. AB - We provide in this chapter a brief overview of the present knowledge about social memory in laboratory rodents with a focus on mice and rats. We discuss in the first part the relevance of the processing of olfactory cues for social recognition in these animals and present information about the brain areas involved in the generation of a long-term social memory including cellular mechanisms thought to underlie memory consolidation. In the second part, we suggest that sensory modalities beyond olfaction may also be important in contributing to the long-term social memory trace including audition and taction (and vision). The exposure to stimuli activating the auditory system and taction is able to produce interference phenomena at defined time points during the consolidation of social memory. This ability of such-nonsocial-stimuli may provide a new approach to dissect the brain processes underlying the generation of the social memory trace in further studies. PMID- 26644000 TI - Expression of Concern: Human amniotic epithelial cells can differentiate into granulosa cells and restore folliculogenesis in a mouse model of chemotherapy induced premature ovarian failure. PMID- 26644002 TI - Erratum. PMID- 26644003 TI - Response to Letter to Editor Entitled "Obesity, Overweight, Female Sexual Function, and Penile-Vaginal Intercourse Frequency". PMID- 26644001 TI - Comparative genomics of Pseudomonas fluorescens subclade III strains from human lungs. AB - BACKGROUND: While the taxonomy and genomics of environmental strains from the P. fluorescens species-complex has been reported, little is known about P. fluorescens strains from clinical samples. In this report, we provide the first genomic analysis of P. fluorescens strains in which human vs. environmental isolates are compared. RESULTS: Seven P. fluorescens strains were isolated from respiratory samples from cystic fibrosis (CF) patients. The clinical strains could grow at a higher temperature (>34 degrees C) than has been reported for environmental strains. Draft genomes were generated for all of the clinical strains, and multi-locus sequence analysis placed them within subclade III of the P. fluorescens species-complex. All strains encoded type- II, -III, -IV, and -VI secretion systems, as well as the widespread colonization island (WCI). This is the first description of a WCI in P. fluorescens strains. All strains also encoded a complete I2/PfiT locus and showed evidence of horizontal gene transfer. The clinical strains were found to differ from the environmental strains in the number of genes involved in metal resistance, which may be a possible adaptation to chronic antibiotic exposure in the CF lung. CONCLUSIONS: This is the largest comparative genomics analysis of P. fluorescens subclade III strains to date and includes the first clinical isolates. At a global level, the clinical P. fluorescens subclade III strains were largely indistinguishable from environmental P. fluorescens subclade III strains, supporting the idea that identifying strains as 'environmental' vs 'clinical' is not a phenotypic trait. Rather, strains within P. fluorescens subclade III will colonize and persist in any niche that provides the requirements necessary for growth. PMID- 26644004 TI - Spy1 participates in the proliferation and apoptosis of epithelial ovarian cancer. AB - This study focused on determining the role of Spy1 in human epithelial ovarian cancer (EOC). Speedy is a novel cell cycle protein capable of promoting cell proliferation. In this study, western blot and immunohistochemistrical analyses were performed to detect the expression of Spy1 in ovarian cancer. Spy1 protein levels increased with ovarian cancer grade, and Kaplan-Meier curve showed that overexpression of Spy1 was significantly correlated with reduced patient survival. In vitro, Spy1 depletion in ovarian cell lines led to reduced proliferation according to CCK8 and plate colony assays. The expression of Spy1 was positively related to pThr187-p27. Flow cytometry revealed that the reduced expression of Spy1 induced the apoptosis of the EOC cells. In summary, our findings suggested that Spy1 may be a novel independent prognostic predictor of survival for ovarian patients. PMID- 26644006 TI - Toward a Universal Method for Preparing Molecularly Imprinted Polymer Nanoparticles with Antibody-like Affinity for Proteins. AB - We describe a potentially universal, simple and cheap method to prepare water compatible molecularly imprinted polymer nanoparticles (MIP-NPs) as synthetic antibodies against proteins. The strategy is based on a solid phase synthesis approach where glass beads (GBs) are functionalized with a metal chelate, acting as a general affinity ligand to attract surface-bound histidines present on proteins. This configuration enables an oriented immobilization of the proteins, upon which thermoresponsive MIP-NPs are synthesized. The GBs play the role of both a reactor and a separation column since, after synthesis, the MIP-NPs are released from the support by a simple temperature change, resulting in protein free polymers. The resulting MIP-NPs are endowed with improved binding site homogeneity, since the binding sites have the same orientation. Moreover, they are stable (no aggregation) in a buffer solution for prolonged storage time and exhibit apparent dissociation constants in the nanomolar range, with little or no cross-reactivity toward other proteins. PMID- 26644005 TI - Co-localization of LTBP-2 with FGF-2 in fibrotic human keloid and hypertrophic scar. AB - We have recently shown that Latent transforming growth factor-beta-1 binding protein-2 (LTBP-2) has a single high-affinity binding site for fibroblast growth factor-2 (FGF-2) and that LTBP-2 blocks FGF-2 induced cell proliferation. Both proteins showed strong co-localisation within keloid skin from a single patient. In the current study, using confocal microscopy, we have investigated the distribution of the two proteins in normal and fibrotic skin samples including normal scar tissue, hypertrophic scars and keloids from multiple patients. Consistently, little staining for either protein was detected in normal adult skin and normal scar samples but extensive co-localisation of the two proteins was observed in multiple examples of hypertrophic scars and keloids. LTBP-2 and FGF-2 were co-localised to fine fibrous elements within the extracellular matrix identified as elastic fibres by immunostaining with anti-fibrillin-1 and anti elastin antibodies. Furthermore, qPCR analysis of RNA samples from multiple patients confirmed dramatically increased expression of LTBP-2 and FGF-2, similar TGF-beta 1, in hypertrophic scar compared to normal skin and scar tissue. Overall the results suggest that elevated LTBP-2 may bind and sequester FGF-2 on elastic fibres in fibrotic tissues and modulate FGF-2's influence on the repair and healing processes. PMID- 26644007 TI - Biomineralization changes with food supply confer juvenile scallops (Argopecten purpuratus) resistance to ocean acidification. AB - Future ocean acidification (OA) will affect physiological traits of marine species, with calcifying species being particularly vulnerable. As OA entails high energy demands, particularly during the rapid juvenile growth phase, food supply may play a key role in the response of marine organisms to OA. We experimentally evaluated the role of food supply in modulating physiological responses and biomineralization processes in juveniles of the Chilean scallop, Argopecten purpuratus, that were exposed to control (pH ~ 8.0) and low pH (pH ~ 7.6) conditions using three food supply treatments (high, intermediate, and low). We found that pH and food levels had additive effects on the physiological response of the juvenile scallops. Metabolic rates, shell growth, net calcification, and ingestion rates increased significantly at low pH conditions, independent of food. These physiological responses increased significantly in organisms exposed to intermediate and high levels of food supply. Hence, food supply seems to play a major role modulating organismal response by providing the energetic means to bolster the physiological response of OA stress. On the contrary, the relative expression of chitin synthase, a functional molecule for biomineralization, increased significantly in scallops exposed to low food supply and low pH, which resulted in a thicker periostracum enriched with chitin polysaccharides. Under reduced food and low pH conditions, the adaptive organismal response was to trade-off growth for the expression of biomineralization molecules and altering of the organic composition of shell periostracum, suggesting that the future performance of these calcifiers will depend on the trajectories of both OA and food supply. Thus, incorporating a suite of traits and multiple stressors in future studies of the adaptive organismal response may provide key insights on OA impacts on marine calcifiers. PMID- 26644008 TI - Quantification of nonuniform distribution of hemi-lung perfusion in chronic obstructive pulmonary disease. AB - Nonuniform distribution (NUD) of perfusion on single photon emission computed tomography (SPECT) is caused by impaired perfusion-related fluctuations of the functional volume (FFV). It was determined if digital analysis of NUD in each hemi-lung damaged by chronic obstructive pulmonary disease (COPD) could improve the whole lung impairment assessment. We examined 665 subjects and 8 controls by SPECT. The basic whole lung SPECT volume was defined at 10% of maximum whole lung count cutoff threshold (T h). For the whole lung and each hemi-lung, the 10% T h width volume, FFV rate, and misfit from the control were calculated at every T h width number (n) from 1 to 9 for every additional 10% T h from 10 to 100%. The misfit value integrated from 1 to 9 of n was defined by 3 NUD indices: D, whole lung NUD index; D rl , the index for the sum of each hemi-lung NUD; and D (I) , the NUD index with every interpolating pattern in which FFV rates of hemi-lungs comprised negative and positive value at the same n. D rl index was the sum of D and D (I) indices in all patients. D rl and D indices significantly increased in pulmonary disease subjects relative to those of the normal group and non pulmonary disease subjects. D rl and D indices increased in COPD subjects. Progressive COPD subjects had larger D rl index values and "diffuse and even" hemi-lung impairment. The three indices quantizing FFV itself leading to NUD helped to digitally evaluate the degree of lung impairment of perfusion. Clinically, it is expected that the NUD indices and images obtained by SPECT, which visually and digitally show the pathological fluctuations in perfusion caused by lung impairment, will be able to provide specific and useful information for improving treatment and/or care of subjects with COPD. PMID- 26644010 TI - Making UFOs make sense: Ufology, science, and the history of their mutual mistrust. AB - Reports of unidentified flying objects and alien encounters have sparked amateur research (ufology), government investigations, and popular interest in the subject. Historically, however, scientists have generally greeted the topic with skepticism, most often dismissing ufology as pseudoscience and believers in unidentified flying objects and aliens as irrational or abnormal. Believers, in turn, have expressed doubts about the accuracy of academic science. This study examines the historical sources of the mutual mistrust between ufologists and scientists. It demonstrates that any science doubt surrounding unidentified flying objects and aliens was not primarily due to the ignorance of ufologists about science, but rather a product of the respective research practices of and relations between ufology, the sciences, and government investigative bodies. PMID- 26644011 TI - A science confidence gap: Education, trust in scientific methods, and trust in scientific institutions in the United States, 2014. AB - Following up on suggestions that attitudes toward science are multi-dimensional, we analyze nationally representative survey data collected in the United States in 2014 ( N = 2006), and demonstrate the existence of a science confidence gap: some people place great trust in scientific methods and principles, but simultaneously distrust scientific institutions. This science confidence gap is strongly associated with level of education: it is larger among the less educated than among the more educated. We investigate explanations for these educational differences. Whereas hypotheses deduced from reflexive-modernization theory do not pass the test, those derived from theorizing on the role of anomie are corroborated. The less educated are more anomic (they have more modernity-induced cultural discontents), which not only underlies their distrust in scientific institutions, but also fuels their trust in scientific methods and principles. This explains why this science confidence gap is most pronounced among the less educated. PMID- 26644009 TI - Current generation time-of-flight (18)F-FDG PET/CT provides higher SUVs for normal adrenal glands, while maintaining an accurate characterization of benign and malignant glands. AB - OBJECTIVE: Modern PET/CT scanners have significantly improved detectors and fast time-of-flight (TOF) performance and this may improve clinical performance. The aim of this study was to analyze the impact of a current generation TOF PET/CT scanner on standardized uptake values (SUV), lesion-background contrast and characterization of the adrenal glands in patients with suspected lung cancer, in comparison with literature data and commonly used SUV cut-off levels. METHODS: We included 149 adrenal glands from 88 patients with suspected lung cancer, who underwent (18)F-FDG PET/CT. We measured the SUVmax in the adrenal gland and compared this with liver SUVmean to calculate the adrenal-to-liver ratio (AL ratio). Results were compared with literature derived with older scanners, with SUVmax values of 1.0 and 1.8 for normal glands [1, 2]. Final diagnosis was based on histological proof or follow-up imaging. We proposed cut-off values for optimal separation of benign from malignant glands. RESULTS: In 127 benign and 22 malignant adrenal glands, SUVmax values were 2.3 +/- 0.7 (mean +/- SD) and 7.8 +/ 3.2 respectively (p < 0.01). Corresponding AL ratios were 1.0 +/- 0.3 and 3.5 +/ 1.4 respectively (p < 0.01). With a SUVmax cut-off value of 3.7, 96% sensitivity and 96% specificity was reached. An AL ratio cut-off value of 1.8 resulted in 91% sensitivity and 97% specificity. The ability of both SUVmax and AL ratio to separate benign from malignant glands was similar (AUC 0.989 vs. 0.993, p = 0.22). CONCLUSIONS: Compared with literature based on the previous generation of PET scanners, current generation TOF (18)F-FDG PET/CT imaging provides higher SUVs for benign adrenal glands, while it maintains a highly accurate distinction between benign and malignant glands. Clinical implementation of current generation TOF PET/CT requires not only the use of higher cut-off levels but also visual adaptation by PET readers. PMID- 26644013 TI - Comparison of perceptions of obesity among adults with central obesity with and without additional cardiometabolic risk factors and among those who were formally obese, 3 years after screening for central obesity. AB - BACKGROUND: Perceptions of illness are important determinants of health behaviour. A better understanding of perceptions of obesity might allow more effective interventions that challenge these perceptions through lifestyle modification programs. Although several studies have evaluated causal attributions with regard to obesity, other domains of illness perception, such as the perceived consequences of obesity and perceived controllability, have not yet been studied. The aim of the current study was to explore perceptions regarding causes, consequences, control, concerns and time course of obesity of centrally obese adults, with and without an elevated cardiometabolic risk and with or without weight loss, 3 years after screening for metabolic syndrome, and to compare these perceptions. METHODS: Three groups were selected from a longitudinal study dependent on the baseline and 3-year follow-up profiles: individuals with central obesity and metabolic syndrome at both time points ('persistent cardiometabolic-risk group', n = 80), those with central obesity but without metabolic syndrome on either occasion ('persistent obese group', n = 63), and formerly obese individuals ('improved cardiometabolic-risk group', n = 49). Perceptions of obesity were assessed using an adapted version of the Brief Illness Perception Questionnaire (BIPQ, range 0-10). Chi-square and Kruskal Wallis tests were performed to compare the 'persistent cardiometabolic risk' group with the other two groups with regard to patient characteristics and BIPQ scores. RESULTS: Both males and females who improved their cardiometabolic risk perceived their obesity as shorter (median (IQR): 3.0 (4.0) vs. 6.0 (3.0), p < 0.001) and experienced greater personal control over their weight (7.0 (3.0) vs. 5.0 (3.0), p = 0.002) compared to those who did not improve. Females who improved their cardiometabolic risk experienced fewer identity and illness concerns, this was not found for males. Other scores did not differ between groups. CONCLUSION: Obese adults with an improved cardiometabolic risk profile felt greater personal control and considered their obesity to be of shorter duration. Persistence of central obesity with additional cardiometabolic risk factors had a larger impact on female than male participants with respect to identity and illness concerns. Whether discussing 'personal control' is a favourable element in lifestyle intervention should now be assessed in the setting of a controlled trial. PMID- 26644012 TI - The Haemonchus contortus kinome--a resource for fundamental molecular investigations and drug discovery. AB - BACKGROUND: Protein kinases regulate a plethora of essential signalling and other biological pathways in all eukaryotic organisms, but very little is known about them in most parasitic nematodes. METHODS: Here, we defined, for the first time, the entire complement of protein kinases (kinome) encoded in the barber's pole worm (Haemonchus contortus) through an integrated analysis of transcriptomic and genomic datasets using an advanced bioinformatic workflow. RESULTS: We identified, curated and classified 432 kinases representing ten groups, 103 distinct families and 98 subfamilies. A comparison of the kinomes of H. contortus and Caenorhabditis elegans (a related, free-living nematode) revealed considerable variation in the numbers of casein kinases, tyrosine kinases and Ca(2+)/calmodulin-dependent protein kinases, which likely relate to differences in biology, habitat and life cycle between these worms. Moreover, a suite of kinase genes was selectively transcribed in particular developmental stages of H. contortus, indicating central roles in developmental and reproductive processes. In addition, using a ranking system, drug targets (n = 13) and associated small molecule effectors (n = 1517) were inferred. CONCLUSIONS: The H. contortus kinome will provide a useful resource for fundamental investigations of kinases and signalling pathways in this nematode, and should assist future anthelmintic discovery efforts; this is particularly important, given current drug resistance problems in parasitic nematodes. PMID- 26644014 TI - Ampelopsin protects endothelial cells from hyperglycemia-induced oxidative damage by inducing autophagy via the AMPK signaling pathway. AB - Diabetic angiopathy is a major diabetes-specific complication that often begins with endothelial dysfunction induced by hyperglycemia; however, the pathological mechanisms of this progression remain unclear. Ampelopsin is a natural flavonol that has strong antioxidant activity, but little information is available regarding its antidiabetic effect. This study focused on the effect of ampelopsin on hyperglycemia-induced oxidative damage and the underlying mechanism of this effect in human umbilical vein endothelial cells (HUVECs). We found that hyperglycemia impaired autophagy in HUVECs through the inhibition of AMP activated protein kinase (AMPK), which directly led to endothelial cell damage. Ampelopsin significantly attenuated the detrimental effect of hyperglycemia induced cell dysfunction in a concentration-dependent manner in HUVECs. Ampelopsin significantly upregulated LC3-II, Beclin1, and Atg5 protein levels but downregulated p62 protein levels in HUVECs. Transmission electron microscopy and confocal microscopy indicated that ampelopsin notably induced autophagosomes and LC3-II dots, respectively. Additionally, the autophagy-specific inhibitor 3-MA, as well as Atg5 and Beclin1 siRNA pretreatment, markedly attenuated ampelopsin induced autophagy, which subsequently abolished the protective effect of ampelopsin against hyperglycemia in HUVECs. Moreover, ampelopsin also increased AMPK activity and inhibited mTOR (mammalian target of rapamycin) complex activation. Ampelopsin-induced autophagy was attenuated by the AMPK antagonist compound C but strengthened by the AMPK agonist AICAR (5-minoimidazole-4 carboxamide ribonucleotide). Furthermore, AMPK siRNA transfection eliminated ampelopsin's alleviation of cell injury induced by hyperglycemia. The protective effect of ampelopsin against hyperglycemia-induced cell damage, which functions by targeting autophagy via AMPK activation, makes it a promising pharmacological treatment for type-2 diabetes. PMID- 26644015 TI - The Ever-Expanding Kidney Repair Shop. PMID- 26644017 TI - Chronotherapy in practice: the perspective of the community pharmacist. AB - BACKGROUND: Optimising the time of drug administration in alignment with circadian rhythms to enhance the clinical effect or minimise/avoid adverse effects is referred to as chronotherapy. Pharmacists have a key role in providing medicine related information, including counselling about the optimal time for medication administration. Where applicable, the principles of chronotherapy should underlie this aspect of medication counselling. Despite significant developments in the science of chronotherapy for specific pharmacological treatments, the perspective of pharmacists about their understanding and application of these principles in practice has not been explored. OBJECTIVE: To explore community pharmacist's viewpoints about and experience with the application of chronotherapy principles in practice. SETTING: Community pharmacies within metropolitan Sydney in New South Wales, Australia. METHODS: Semi-structured, face to face interviews with a convenience sample of community pharmacists were conducted. All interviews were audio-recorded, transcribed verbatim and thematically analyzed using a 'grounded theory' approach, given the novelty of this area. Main outcome measure Community pharmacists' awareness, current practice and future practice support requirements about the principles of chronotherapy. RESULTS: Twenty-five semi-structured interviews were conducted. Most participants reported encountering cases where clinical decision making about suggesting appropriate times of drug administration to patients was needed. Their approach was mainly pragmatic rather than based on theoretical principles of circadian variation in drug disposition or on current or emerging evidence; thus there was an evidence practice chasm in some cases. However, most participants believed they have an important role to play in counselling patients about optimal administration times and were willing to enact such roles or acquire skills/competence in this area. CONCLUSION: Community pharmacists contribute to the safe and effective use of medications in providing the patients with information on optimal timing of drug administration during counselling. Further education, practical training and access to information may help pharmacists in translating principles of chronotherapy into the practice. PMID- 26644018 TI - Detection of emergent strains of West Nile virus with a blood screening assay. AB - BACKGROUND: West Nile virus (WNV) is a threat to transfusion safety. WNV Kunjin strain (WNVKUN ) is endemic across parts of Australia; however, human infection is believed to be infrequent and is often associated with relatively minor symptoms. A virulent strain, closely related to WNVKUN (termed WNVNSW2011 ) was recently identified as the etiologic agent of encephalitis in Australian horses. The aim of this project was to investigate whether a commercially available WNV blood screening assay can detect different strains of WNVKUN , including the virulent WNVNSW2011 , in human blood donor samples. STUDY DESIGN AND METHODS: Plasma samples were spiked with four different strains of WNVKUN , as well as a prototype WNV strain, at high, medium, and low viral loads. Spiking was confirmed with real-time reverse transcription-polymerase chain reaction (RT-PCR), before testing with the Procleix WNV transcription-mediated amplification (TMA) blood screening assay (Grifols). RESULTS: All WNV strains used were detectable by RT PCR after being spiked into plasma. Additionally, all viral spiked samples were reactive by WNV TMA. CONCLUSION: We experimentally demonstrate that a commercially available WNV blood screening assay can detect different strains of WNVKUN . Given that WNV can be transfusion transmissible, it is essential to confirm that emergent strains are detectable by existing blood screening methods. PMID- 26644019 TI - Implementation Process of a Canadian Community-based Nurse Mentorship Intervention in HIV Care. AB - We describe salient individual and organizational factors that influenced engagement of registered nurses in a 12-month clinical mentorship intervention on HIV care in Canada. The intervention included 48 nurses and 8 people living with HIV (PLWH) who were involved in group-based and one-on-one informal mentorship informed by transformative learning theory. We evaluated the process of implementing the mentorship intervention using qualitative content analysis. The inclusion of PLWH as mentors, the opportunities for reciprocal learning, and the long-term commitment of individual nurses and partner organizations in HIV care were major strengths. Challenges included the need for multiple ethical approvals, the lack of organizational support at some clinical sites, and the time commitment required by participants. We recommend that clinical mentorship interventions in HIV care consider organizational support, adhere to the Greater Involvement of People Living with HIV/AIDS principles, and explore questions of professional obligations. PMID- 26644020 TI - Artificial domain duplication replicates evolutionary history of ketol-acid reductoisomerases. AB - The duplication of protein structural domains has been proposed as a common mechanism for the generation of new protein folds. A particularly interesting case is the class II ketol-acid reductoisomerase (KARI), which putatively arose from an ancestral class I KARI by duplication of the C-terminal domain and corresponding loss of obligate dimerization. As a result, the class II enzymes acquired a deeply embedded figure-of-eight knot. To test this evolutionary hypothesis we constructed a novel class II KARI by duplicating the C-terminal domain of a hyperthermostable class I KARI. The new protein is monomeric, as confirmed by gel filtration and X-ray crystallography, and has the deeply knotted class II KARI fold. Surprisingly, its catalytic activity is nearly unchanged from the parent KARI. This provides strong evidence in support of domain duplication as the mechanism for the evolution of the class II KARI fold and demonstrates the ability of domain duplication to generate topological novelty in a function neutral manner. PMID- 26644021 TI - Population-based geographic access to endocrinologists in the United States, 2012. AB - BACKGROUND: Increases in population and life expectancy of Americans may result in shortages of endocrinologists by 2020. This study aims to assess variations in geographic accessibility to endocrinologists in the US, by age group at state and county levels, and by urban/rural status, and distance. METHODS: We used the 2012 National Provider Identifier Registry to obtain office locations of all adult and pediatric endocrinologists in the US. The population with geographic access to an endocrinologist within a series of 6 distance radii, centered on endocrinologist practice locations, was estimated using the US Census 2010 block-level population. We assumed that persons living within the same circular buffer zone of an endocrinologist location have the same geographic accessibility to that endocrinologist. The geographic accessibility (the percentage of the population with geographic access to at least one endocrinologist) and the population-to endocrinologist ratio for each geographic area were estimated. RESULTS: By using 20 miles as the distance radius, geographic accessibility to at least one pediatric/adult endocrinologist for age groups 0-17, 18-64, and >= 65 years was 64.1%, 85.4%, and 82.1%. The overall population-to-endocrinologist ratio within 20 miles was 39,492:1 for children, 29,887:1 for adults aged 18-64 years, and 6,194:1 for adults aged >= 65 years. These ratios varied considerably by state, county, urban/rural status, and distance. CONCLUSIONS: This study demonstrates that there are geographic variations of accessibility to endocrinologists in the US. The areas with poorer geographic accessibility warrant further study of the effect of these variations on disease prevention, detection, and management of endocrine diseases in the US population. Our findings of geographic access to endocrinologists also may provide valuable information for medical education and health resources allocation. PMID- 26644022 TI - The complete chloroplast genome sequence of Cynanchum auriculatum Royle ex Wight (Apocynaceae). AB - Cynanchum auriculatum is a climbing vine belonging to the Apocynaceae family and shows very similar morphology to Cynanchum wilfordii, a medicinal plant. The complete chloroplast genome of C. auriculatum was generated by de novo assembly using the small amount of whole genome sequencing data. The chloroplast genome of C. auriculatum was 160 840 bp in length and consisted of four distinct regions, such as large single copy region (91 973 bp), small single copy region (19 667 bp), and a pair of inverted repeat regions (24 600 bp). The overall GC contents of the chloroplast genome were 37.8%. A total of 114 genes were predicted and included 80 protein-coding genes, 30 tRNA genes, and four rRNA genes. Phylogenetic analysis with the reported chloroplast genomes revealed that C. auriculatum is most closely related to Cynanchum wilfordii, a medicinal plant. PMID- 26644023 TI - Quantitating intracellular oxygen tension in vivo by phosphorescence lifetime measurement. AB - Hypoxia appears to have an important role in pathological conditions in many organs such as kidney; however, a method to quantify intracellular oxygen tension in vivo has not been well established. In this study, we established an optical method to quantify oxygen tension in mice kidneys using a cationic lipophilic phosphorescence probe, BTPDM1, which has an intracellular oxygen concentration sensitive phosphorescence lifetime. Since this probe is distributed inside the tubular cells of the mice kidney, we succeeded in detecting acute renal hypoxic conditions and chronic kidney disease. This technique enabled us to estimate intracellular partial pressures of oxygen in vivo by extrapolating the calibration curve generated from cultured tubular cells. Since intracellular oxygen tension is directly related to cellular hypoxic reactions, such as the activation of hypoxia-inducible factors, our method will shed new light on hypoxia research in vivo. PMID- 26644024 TI - Difficulties associated with the structural analysis of proteins susceptible to form aggregates: The case of Tau protein as a biomarker of Alzheimer's disease. AB - Mass spectrometry coupled with bioaffinity separation techniques is considered a powerful tool for studying protein interactions. This work is focused on epitope analysis of tau protein, which contains two VQIXXK aggregation motifs regarded as crucial elements in the formation of paired helical filaments, the main pathological characteristics of Alzheimer's disease. To identify major immunogenic structures, the epitope extraction technique utilizing protein fragmentation and magnetic microparticles functionalized with specific antibodies was applied. However, the natural adhesiveness of some newly generated peptide fragments devalued the experimental results. Beside presumed peptide fragment specific to applied monoclonal anti-tau antibodies, the epitope extraction repeatedly revealed inter alia tryptic fragment 299-HVPGGGSVQIVYKPVDLSK-317 containing the fibril-forming motif 306-VQIVYK-311. The tryptic fragment pro aggregation and hydrophobic properties that might contribute to adsorption phenomenon were examined by Thioflavin S and reversed-phase chromatography. Several conventional approaches to reduce the non-specific fragment sorption onto the magnetic particle surface were performed, however with no effect. To avoid methodological complications, we introduced an innovative approach based on altered proteolytic digestion. Simultaneous fragmentation of tau protein by two immobilized proteases differing in the cleavage specificity (TPCK-trypsin and alpha-chymotrypsin) led to the disruption of motif responsible for undesirable adhesiveness and enabled us to obtain undistorted structural data. PMID- 26644025 TI - Communicating risk in the context of methadone formulation changes: A qualitative study of overdose warning posters in Vancouver, Canada. PMID- 26644026 TI - Gender, intoxication and the developing brain: Problematisations of drinking among young adults in Australian alcohol policy. AB - In this article, we draw on recent scholarly work in the poststructuralist analysis of policy to consider how policy itself functions as a key site in the constitution of alcohol 'problems', and the political implications of these problematisations. We do this by examining Australian alcohol policy as it relates to young adults (18-24 years old). Our critical analysis focuses on three national alcohol policies (1990, 2001 and 2006) and two Victorian state alcohol policies (2008 and 2013), which together span a 25-year period. We argue that Australian alcohol policies have conspicuously ignored young adult men, despite their ongoing over-representation in the statistical 'evidence base' on alcohol related harm, while increasingly problematising alcohol consumption amongst other population subgroups. We also identify the development of a new problem representation in Australian alcohol policy, that of 'intoxication' as the leading cause of alcohol-related harm and rising hospital admissions, and argue that changes in the classification and diagnosis of intoxication may have contributed to its prioritisation and problematisation in alcohol policy at the expense of other forms of harm. Finally, we draw attention to how preliminary and inconclusive research on the purported association between binge drinking and brain development in those under 25 years old has been mobilised prematurely to support calls to increase the legal purchasing age from 18 to 21 years. Our critical analysis of the treatment of these three issues - gender, intoxication, and brain development - is intended to highlight the ways in which policy functions as a key site in the constitution of alcohol 'problems'. PMID- 26644027 TI - Mercury Concentrations in Pacific Angel Sharks (Squatina californica) and Prey Fishes from Southern Gulf of California, Mexico. AB - Concentrations of mercury (Hg) were quantified in muscle tissues of the Pacific angel shark, Squatina californica sampled from Southern Gulf of California, Mexico, considering total length, sex, diet and the dietary risk assessment. High Hg levels are typically associated with carnivorous fishes, however S. californica showed low Hg concentrations (<1.0 ug g(-1)) in muscle (0.24 +/- 0.27 ug g(-1) wet weight; n = 94). No effect of sex, total length and weight on Hg concentrations were observed in the shark (p > 0.05). Hg concentrations were highest in the darkedge mishipman: Porichthys analis (0.14 +/- 0.08 ug g(-1)) and red-eye round herring Etrumeus teres (0.13 +/- 0.05 ug g(-1)) relative to other prey species, which could suggest that Hg concentrations in S. californica were influenced by these species. Given the relatively low concentration of Hg across age-classes and sex, consumption of S. californica's muscle tissue poses limited risk to humans. PMID- 26644028 TI - The Adsorption and Desorption of Pb(2+) and Cd(2+) in Freeze-Thaw Treated Soils. AB - Adsorption and desorption are important processes that influence the potential toxicity and bioavailability of heavy metals in soils. However, information regarding adsorption and desorption behavior of heavy metals in soils subjected to freeze-thaw cycles is poorly understood. In the current study, the effect of freeze-thaw cycles with different freezing temperature (-15, -25, -35 degrees C) on soil properties was investigated. Then the adsorption and desorption behavior of Pb(2+) and Cd(2+) in freeze-thaw treated soils was studied. The adsorption amounts of Pb(2+) and Cd(2+) in freeze-thaw treated soils were smaller than those in unfrozen soils (p < 0.05), due to the fact that pH, cation exchange capacity, organic matter content, free iron oxide content, and CaCO3 content in freeze-thaw treated soils were smaller than those in unfrozen soils. The adsorption amounts of Pb(2+) and Cd(2+) in soils treated with lower freezing temperatures were higher than those in soils treated with higher freezing temperatures. Desorption percentages of Pb(2+) and Cd(2+) in unfrozen soils were smaller than those in freeze-thaw treated soils (p < 0.05). The desorption percentages of Pb(2+) and Cd(2+) were smaller in soils treated with lower freezing temperatures than those in soils treated with higher freezing temperatures. The results obtained highlight the change of the adsorption and desorption behavior of typical heavy metals in freeze-thaw treated soils located in seasonal frozen soils zone in northeast China. PMID- 26644029 TI - Ictal epileptic headache revealing non convulsive status epilepticus in a case of eyelid myoclonia with absences. AB - Epileptic seizures and headache attacks are two common neurologic phenomena characterized by paroxysmal alteration of brain functions followed by complete restauration of the baseline condition. Headache and epilepsy are related in numerous ways, and they often co-occur. Although the link between these two diseases is not completely clear, several clinical, physiopathological and therapeutic features overlap. Headache is reported in association with epileptic seizures as a pre-ictal, ictal or post-ictal phenomenon. We present the case of a 40 year-old woman affected by eyelid myoclonia with absences (EMA) with a history of prolonged headache attacks. A video-EEG recording performed during one of these episodes showed subcontinuous epileptic activity consisting of generalized spike-and-wave discharges (GSWDs), clinically associated with tensive headache. Our work represents one of the few well EEG-documented cases of ictal epileptic headache in idiopathic generalized epilepsy (IGE). PMID- 26644031 TI - Varus Deformity of the Distal Tibia From Physeal Growth Arrest Treated Using a Titanium Metal Porous Wedge. AB - During a cheerleading event, a 14-year-old female sustained a right ankle physeal fracture that was treated nonoperatively with casting. She developed a distal medial tibial physeal arrest, and as the onset of menses was at age 16, she subsequently developed a varus distal tibial deformity. At the age of 19, she was no longer able to participate in collegiate cheerleading due to lateral ankle pain, ankle instability, and peroneal subluxation. After failing conservative treatment, she underwent an ankle arthroscopy, Brostrom-Gould procedure, peroneal retinacular repair with peroneal tenolysis, and a distal tibial medial opening wedge osteotomy using a porous titanium metal wedge and a one-third tubular plate. At 6-month follow-up, her osteotomy site showed abundant callus formation, and her lateral ankle pain had almost completely resolved. At 22-month follow-up, there were no residual ankle instability or pain complaints, and she had returned to collegiate cheerleading. This case report highlights a very useful, previously not described, application of porous titanium metal wedges for medial supramalleolar opening wedge osteotomies of the tibia. Such wedges are familiar to many foot and ankle orthopaedic surgeons and continue to have expanding indications. LEVELS OF EVIDENCE: Therapeutic, Level IV: Case report. PMID- 26644030 TI - Reported concepts for the treatment modalities and pain management of temporomandibular disorders. AB - BACKGROUND: Pain related to temporomandibular disorders (TMD) is a common problem in modern societies. The aim of the article is to present the concepts of TMD pain clinical management. METHODS: A survey was performed using the PubMed, SCOPUS and CINAHL databases for documents published between 1994 and 2014. The following search keywords were selected using MeSH terms of the National Library of Medicine in combination: TMD pain, TMD, TMJ, TMJ disorders, occlusal splint, TMD physiotherapy, TMJ rheumatoid disorders and TMJ surgery. Original articles and review papers which presented the clinical relevance and practical validity regarding the possibility of application in TMD management have been included. Authors have excluded articles without outstanding practical aspect and evidence based background. A first selection was carried out by reviewing titles and abstracts of all articles found according to the criteria. After that the full texts of potentially suitable articles were assessed. In line with these criteria, among 11467 results the writers have included 66 papers. RESULTS: The most commonly reported conservative treatments are massage therapy and individually fabricated occlusal splints. In addition to massage, other popular methods include manual therapy and taping, warming/cooling of aching joints, and light and laser therapy. Drugs are also commonly used. In the most severe cases of the temporomandibular joint degeneration, surgical restoration of the joint is sometimes applied. CONCLUSIONS: The authors concluded that conservative treatment including counselling, exercises, occlusal splint therapy, massage, manual therapy and others should be considered as a first choice therapy for TMD pain because of their low risk of side effects. In the case of severe acute pain or chronic pain resulting from serious disorders, inflammation and/or degeneration pharmacotherapy, minimally invasive and invasive procedures should be considered. PMID- 26644032 TI - A Systematic Review of the Role of Surgical Approaches on the Outcomes of the Tibia Pilon Fracture. AB - BACKGROUND: The role of each surgical approach on the outcomes of pilon fractures has not been investigated in a systematic review. METHODS: This systematic review was conducted with a thorough literature search on PubMed using the keywords ("pilon" OR "plafond") "fracture." Only articles written in the English language that have been published within the past 15 years and discussed the surgical approach were considered. RESULTS: A total of 733 patients were included in this review. All the fractures were either OTA Type B or C fractures: 157 were Type B and 576 were Type C. Anterior and medial approaches have some of the best results in the literature with respect to complication rate. The posterolateral and anteromedial approaches have markedly higher complication rates. CONCLUSIONS: The anterolateral group had the largest number of patients-comprising one third of the entire study population. The anterior approach had one of the lowest complication rates with a patient base that had a high proportion of OTA Type C fractures. The medial approach produced a low complication rate over a larger patient base that had a higher proportion of OTA Type B fractures. LEVELS OF EVIDENCE: Therapeutic, Level IV: Systematic review. PMID- 26644033 TI - Case Series Using a Novel Implant and Accelerated Rehabilitation for Patients Undergoing an Isolated Talonavicular Arthrodesis. AB - Talonavicular (TN) arthrodeses for TN arthritis have a high rate of nonunions for an essential hindfoot joint. In this case series, 12 patients underwent an isolated TN arthrodesis using a novel implant (IO FiX) by a single surgeon with a minimum 1-year follow-up (30.1 +/- 14.7 months; mean +/- SD). All patients (62 +/ 12 years) underwent an aggressive rehabilitation protocol given the strength and compression of the implant. There were no nonunions, nor were there any patients lost to follow-up. Time to radiographic union was 9.6 +/- 1.4 weeks. The Visual Analog Scale pain level decreased from 7.3 +/- 0.9 preoperatively to 2.1 +/- 0.7 postoperatively (P < .001). The Short-Form-12 physical component improved from 27.9 +/- 4.2 preoperatively to 42.2 +/- 3.5 postoperatively (P < 0.001), while the Short-Form-12 mental component did not change from 50.8 +/- 6.9 preoperatively to 54.4 +/- 3.8 postoperatively (P > .05). Use of the novel fixation device for TN arthrodesis by a single surgeon with an accelerated rehabilitation protocol significantly decreased patients' pain and improved their physical functional outcomes (P < .001). The IO FiX implant can potentially improve TN arthrodesis fusion rates and surgical outcomes. LEVELS OF EVIDENCE: Therapeutic, Level IV: Case series. PMID- 26644034 TI - Primary Tumors of the Foot and Ankle. AB - Tumors of the foot and ankle are rarely encountered in the general patient population. Even among studies of tumor patients, foot and ankle neoplasms are uncommon. Given the weight-bearing demands of the foot and its relatively small area, even small masses are likely to be symptomatic and/or palpable to both patient and physician. Only 3% of osseous neoplasms are found in this region, while 8% of benign soft tissue tumors and 5% of malignant soft tissue tumors are localized to the foot and ankle. Despite the rarity of presentation, it is important for orthopaedic surgeons to be familiar with the diagnostic criteria and therapeutic options for these patients, as each tumor varies in its presentation, level of aggressiveness, and natural history of the disease. With appropriate diagnostic tests and treatment, patients can anticipate a reasonable chance of survival and preservation of function. In this review article, the authors survey the current literature regarding the presentation, diagnostic workup, and treatment for the most common benign and malignant tumors of the foot and ankle. LEVELS OF EVIDENCE: Level IV: Literature Review. PMID- 26644035 TI - Piecrusting to Facilitate Skin Closure. AB - Wound dehiscence and infection may arise when the skin around the foot or ankle is closed under tension after a surgical incision or trauma. Two cases where a piecrusting technique, using small transdermal incisions made in the surrounding skin similar to the holes in a pie crust, are presented and a literature review of the technique has been performed. The multiple small stab incisions perpendicular to the line of tension have enabled skin closure without tension and have healed with minimal scarring. LEVELS OF EVIDENCE: Level V: Expert opinion. PMID- 26644036 TI - Z-type control of populations for Lotka-Volterra model with exponential convergence. AB - The population control of the Lotka-Volterra model is one of the most important and widely investigated issues in mathematical ecology. In this study, assuming that birth rate is controllable and using the Z-type dynamic method, we develop Z type control laws to drive the prey population and/or predator population to a desired state to keep species away from extinction and to improve ecosystem stability. A direct controller group is initially designed to control the prey and predator populations simultaneously. Two indirect controllers are then proposed for prey population control and predator population control by exerting exogenous measure on another species. All three control laws possess exponential convergence performances. Finally, the corresponding numerical simulations are performed. Results substantiate the theoretical analysis and effectiveness of such Z-type control laws for the population control of the Lotka-Volterra model. PMID- 26644037 TI - From cholera to corals: Viruses as drivers of virulence in a major coral bacterial pathogen. AB - Disease is an increasing threat to reef-building corals. One of the few identified pathogens of coral disease is the bacterium Vibrio coralliilyticus. In Vibrio cholerae, infection by a bacterial virus (bacteriophage) results in the conversion of non-pathogenic strains to pathogenic strains and this can lead to cholera pandemics. Pathogenicity islands encoded in the V. cholerae genome play an important role in pathogenesis. Here we analyse five whole genome sequences of V. coralliilyticus to examine whether virulence is similarly driven by horizontally acquired elements. We demonstrate that bacteriophage genomes encoding toxin genes with homology to those found in pathogenic V. cholerae are integrated in V. coralliilyticus genomes. Virulence factors located on chromosomal pathogenicity islands also exist in some strains of V. coralliilyticus. The presence of these genetic signatures indicates virulence in V. coralliilyticus is driven by prophages and other horizontally acquired elements. Screening for pathogens of coral disease should target conserved regions in these elements. PMID- 26644038 TI - Optimizing training cost-effectiveness of simulation-based laparoscopic inguinal hernia repairs. AB - BACKGROUND: Motor learning theory suggests that highly complex tasks are probably best trained under conditions of part task (PT), as opposed to whole-task (WT) training. Within PT, random practice of tasks has been shown to lead to improved skill retention and transfer. METHODS: General surgery residents were equally randomized to PT vs WT, mastery learning type, and simulation-based training of laparoscopic inguinal hernia repair. Training time and resources used to reach mastery (skill acquisition), performance at 1-month testing (skill retention), and intraoperative time and performance scores (skill transfer) were compared. RESULTS: Forty-four general surgery trainees were randomized. All residents achieved mastery benchmarks. Trainees in the PT group achieved mastery on average 17 minutes faster (60.2 +/- 23.8 vs 77.1 +/- 24.8 minutes, P = .02, saving 6.2 instructor hours), used fewer material resources (curricular cost savings of $2,380 or $121 per learner), and were more likely to retain mastery level performance at 1-month retention testing (59% vs 22.7% P = .03). No differences in intraoperative performance were encountered. CONCLUSIONS: For laparoscopic inguinal hernia repair, random PT simulation-based training seems to be more cost effective, compared with WT training. PMID- 26644039 TI - [Pneumocystosis in non-HIV-infected immunocompromised patients]. AB - Pneumocystis jiroveci (formerly P. carinii) is an opportunistic fungus responsible for pneumonia in immunocompromised patients. Pneumocystosis in non HIV-infected patients differs from AIDS-associated pneumocystosis in mostly two aspects: diagnosis is more difficult, and prognosis is worse. Hence, efforts should be made to target immunocompromised patients at higher risk of pneumocystosis, so that they are prescribed long-term, low-dose, trimethoprime sulfamethoxazole, highly effective for pneumocystosis prophylaxis. Patients at highest risk include those with medium and small vessels vasculitis, lymphoproliferative B disorders (chronic or acute lymphocytic leukaemia, non Hodgkin lymphoma), and solid cancer on long-term corticosteroids. Conversely, widespread use of prophylaxis in all patients carrier of inflammatory diseases on long-term corticosteroids is not warranted. The management of pneumocystosis in non-AIDS immunocompromised patients follows the rules established for AIDS patients. The diagnosis relies on the detection of P. jiroveci cyst on respiratory samples, while PCR does not reliably discriminate infection from colonization, in 2015. High-doses trimethoprim-sulfamethoxazole is, by far, the treatment of choice. The benefit of adjuvant corticosteroid therapy for hypoxic patients, well documented in AIDS patients, has a much lower level of evidence in non-HIV-infected patients, most of them being already on corticosteroid by the time of pneumocystosis diagnosis anyway. However, based on its striking impact on morbi-mortality in AIDS patients, adjuvant corticosteroid is recommended in hypoxic, non-HIV-infected patients with pneumocystosis by many experts and scientific societies. PMID- 26644040 TI - Nonsuicidal self-injury across cultures and ethnic and racial minorities: A review. AB - The field of nonsuicidal self-injury (NSSI) is dominated by research conducted with Caucasian-majority samples in Western countries such as United States, Canada, Australia and European countries. This article critically reviewed the empirical research on NSSI in non-Western countries and among ethnic/racial minority individuals who live in the West to give voice to and understand the patterns of NSSI among individuals who do not fall within the dominant Caucasian majority. The study found both similarities and differences between Western and non-Western data in terms of characteristics and functions of NSSI. Differences in gender patterns in regards to prevalence of NSSI and methods used as well as presence of a more relational functionality of NSSI rather than emotion regulation functionality were two points of divergence in the findings of these studies. In addition, the findings seem to indicate that the role of ethnicity/race is mediated by important factors such as socioeconomic status (SES) and gender. Existing gaps in the literature and suggestions for further research are discussed. PMID- 26644041 TI - The effect of perceptual reasoning abilities on confrontation naming performance: An examination of three naming tests. AB - INTRODUCTION: Confrontation naming tests are a common neuropsychological method of assessing language and a critical diagnostic tool in identifying certain neurodegenerative diseases; however, there is limited literature examining the visual-perceptual demands of these tasks. This study investigated the effect of perceptual reasoning abilities on three confrontation naming tests, the Boston Naming Test (BNT), Neuropsychological Assessment Battery (NAB) Naming Test, and Visual Naming Test (VNT) to elucidate the diverse cognitive functions underlying these tasks to assist with test selection procedures and increase diagnostic accuracy. METHOD: A mixed clinical sample of 121 veterans were administered the BNT, NAB, VNT, and Wechsler Adult Intelligence Scale-4th Edition (WAIS-IV) Verbal Comprehension Index (VCI) and Perceptual Reasoning Index (PRI) as part of a comprehensive neuropsychological evaluation. RESULTS: Multiple regression indicated that PRI accounted for 23%, 13%, and 15% of the variance in BNT, VNT, and NAB scores, respectively, but dropped out as a significant predictor once VCI was added. Follow-up bootstrap mediation analyses revealed that PRI had a significant indirect effect on naming performance after controlling education, primary language, and severity of cognitive impairment, as well as the mediating effect of general verbal abilities for the BNT (B = 0.13; 95% confidence interval, CI [.07, .20]), VNT (B = 0.01; 95% CI [.002, .03]), and NAB (B = 0.03; 95% CI [.01, .06]). CONCLUSIONS: Findings revealed a complex relationship between perceptual reasoning abilities and confrontation naming that is mediated by general verbal abilities. However, when verbal abilities were statistically controlled, perceptual reasoning abilities were found to have a significant indirect effect on performance across all three confrontation naming measures with the largest effect noted with the BNT relative to the VNT and NAB Naming Test. PMID- 26644042 TI - Embodiment and biographical disruption in people living with HIV/AIDS (PLWHA). AB - This study attempts to provide a concrete understanding to the embodied experience of HIV/AIDS. PLWHA have to cope with physical changes, especially lipodystrophy, caused by HIV and its treatment. These clinical manifestations make the disease socially visible and form a potential source of stigmatization. Visibility seems to transform the personal experience of this particular illness into a collective one. The changing body image and the stigma, which is often internalized by individuals, along with other consequences of chronic illness, such as alteration of life plans and social relationships, constitute new elements that appear in their life after diagnosis. These new experiences can break one's biographical continuity, especially in cases like HIV/AIDS. Semi structured and in-depth interviews were conducted with 18 HIV-positive individuals (13 men, 5 women) with lipodystrophy. Their ages ranged from 36 to 65 years. The analysis of data revealed three main themes: loss of control over the body, ambivalence about visibility of HIV/AIDS, attributing positive meaning to HIV/AIDS. Physical changes caused by lipodystrophy are a source of dysphoria for PLWHA. This dissatisfaction was closely associated with the absence of control over their own body, due to the virus and the side effects of medication. Furthermore, it became evident that there was ambivalence among participants about the visibility of HIV, as it was in parallel a source of stigmatization, but also a part of their identity and biography. Results indicate that individuals were in search of meaning and constitute strategies in order to "answer" to the disruptive aspects of HIV. These were the normalization of illness, the integration into personal identity and the recognition of positive effects of HIV in their lives (e.g., stopping drug and alcohol abuse). Further research is required to identify the factors that determine the selection of each "answer" by these particular individuals who belong to broader social groups. PMID- 26644043 TI - Health and Stress Management and Mental-health Disability Claims. AB - This study examines the associations between health and stress management (HSM) practices and mental-health disability claims. Data from the Salveo study was collected during 2009-2012 within 60 workplaces nested in 37 companies located in Canada (Quebec) and insured by a large insurance company. In each company, 1 h interviews were conducted with human resources managers in order to obtain data on 63 HSM practices. Companies and workplaces were sorted into the low-claims and high-claims groups according to the median rate of the population of the insurer's corporate clients. Logistic regression adjusted for design effect and multidimensional scaling was used to analyse the data. After controlling for company size and economic sector, task design, demands control, gratifications, physical activity and work-family balance were associated with low mental-health disability claims rates. Further analyses revealed three company profiles that were qualified as laissez-faire, integrated and partially integrated approaches to HSM. Of the three, the integrated profile was associated with low mental health disability claims rates. The results of this study provide evidence-based guidance for a better control of mental-health disability claims. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26644045 TI - Malnutrition in Hospitalized Children: A Responsibility and Opportunity for Pediatric Hospitalists. PMID- 26644044 TI - Dynamic sentinel lymph node biopsy for penile cancer: a comparison between 1- and 2-day protocols. AB - OBJECTIVE: To determine the outcome of clinically negative node (cN0) patients with penile cancer undergoing dynamic sentinel node biopsy (DSNB), comparing the results of a 1- and 2-day protocol that can be used as a minimal invasive procedure for staging of penile cancer. PATIENTS AND METHODS: This is a retrospective analysis of 151 cN0 patients who underwent DSNB from 2008 to 2013 for newly diagnosed penile cancer. Data were analysed per groin and separated into groups according to the protocol followed. The comparison of the two protocols involved the number of nodes excised, gamma-counts, false-negative rates (FNR), and complication rates (Clavien-Dindo grading system). RESULTS: In all, 280 groins from 151 patients underwent DSNB after a negative ultrasound +/- fine-needle aspiration cytology. The 1-day protocol was performed in 65 groins and the 2-day protocol in 215. Statistically significantly more nodes were harvested with the 1-day protocol (1.92/groin) compared with the 2-day protocol (1.60/groin). The FNRs were 0%, 6.8% and 5.1%, for the 1-day protocol, 2-day protocol, and overall, respectively. Morbidity of the DSNB was 21.4% for all groins, and 26.2% and 20.1% for the 1-day and 2-day protocols, respectively. Most of the complications were of Clavien-Dindo Grade 1-2. CONCLUSIONS: DSNB is safe for staging patients with penile cancer. There is a trend towards a 1-day protocol having a lower FNR than a 2-day protocol, albeit at the expense of a slightly higher complication rate. PMID- 26644046 TI - Commercial Premixed Parenteral Nutrition and Its Potential Role in Pediatrics. PMID- 26644047 TI - Optimization and anticancer activity in vitro and in vivo of baohuoside I incorporated into mixed micelles based on lecithin and Solutol HS 15. AB - Baohuoside I, extracted from the Herba epimedii, is an effective but a poorly soluble antitumor drug. To improve its solubility, formulation of baohuoside I loaded mixed micelles with lecithin and Solutol HS 15 (BLSM) has been performed in this study. We performed a systematic comparative evaluation of the antiproliferative effect, cellular uptake, antitumor efficacy, and in vivo tumor targeting of these micelles using non-small cell lung cancer (NSCLC) A549 cells. Results showed that the obtained micelles have a mean particle size of around 62.54 nm, and the size of micelles was narrowly distributed. With the improved cellular uptake, BLSM displayed a more potent antiproliferative action on A549 cell lines than baohuoside I; half-maximal inhibitory concentration (IC50) was 6.31 versus 18.28 ug/mL, respectively. The antitumor efficacy test in nude mice showed that BLSM exhibited significantly higher antitumor activity against NSCLC with lesser toxic effects on normal tissues. The imaging study for in vivo targeting demonstrated that the mixed micelles formulation achieved effective and targeted drug delivery. Therefore, BLSM might be a potential antitumor formulation. PMID- 26644049 TI - Orientation to person, orientation to self. PMID- 26644050 TI - Deep brain stimulation of the dentate nucleus improves cerebellar ataxia after cerebellar stroke. PMID- 26644051 TI - Bilateral frontal cysts from a crista galli meningioma. PMID- 26644048 TI - Practice guideline: Idiopathic normal pressure hydrocephalus: Response to shunting and predictors of response: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. AB - OBJECTIVE: We evaluated evidence for utility of shunting in idiopathic normal pressure hydrocephalus (iNPH) and for predictors of shunting effectiveness. METHODS: We identified and classified relevant published studies according to 2004 and 2011 American Academy of Neurology methodology. RESULTS: Of 21 articles, we identified 3 Class I articles. CONCLUSIONS: Shunting is possibly effective in iNPH (96% chance subjective improvement, 83% chance improvement on timed walk test at 6 months) (3 Class III). Serious adverse event risk was 11% (1 Class III). Predictors of success included elevated Ro (1 Class I, multiple Class II), impaired cerebral blood flow reactivity to acetazolamide (by SPECT) (1 Class I), and positive response to either external lumbar drainage (1 Class III) or repeated lumbar punctures. Age may not be a prognostic factor (1 Class II). Data are insufficient to judge efficacy of radionuclide cisternography or aqueductal flow measurement by MRI. RECOMMENDATIONS: Clinicians may choose to offer shunting for subjective iNPH symptoms and gait (Level C). Because of significant adverse event risk, risks and benefits should be carefully weighed (Level B). Clinicians should inform patients with iNPH with elevated Ro and their families that they have an increased chance of responding to shunting compared with those without such elevation (Level B). Clinicians may counsel patients with iNPH and their families that (1) positive response to external lumbar drainage or to repeated lumbar punctures increases the chance of response to shunting, and (2) increasing age does not decrease the chance of shunting being successful (both Level C). PMID- 26644052 TI - Heroin inhalation complicated by refractory hydrocephalus: A novel presentation. PMID- 26644053 TI - Etanercept in Alzheimer disease: A randomized, placebo-controlled, double-blind, phase 2 trial. PMID- 26644054 TI - Etanercept in Alzheimer disease: A randomized, placebo-controlled, double-blind, phase 2 trial. PMID- 26644055 TI - Child Neurology: Molybdenum cofactor deficiency. PMID- 26644056 TI - Teaching NeuroImages: Granulomatosis with polyangiitis causing Collet-Sicard syndrome and refractory headache. PMID- 26644057 TI - Teaching Video NeuroImages: Re-emergent jaw tremor in Parkinson disease. PMID- 26644058 TI - "I Caught It at the Movies": Reflections on Medical History, Movie Theaters, and the Cinema of Contagion. AB - Undertaking an examination of the precarious places of the movies and movie theaters in queer lives in the 20th century, this article takes up a series of anecdotal episodes and feature-length films to consider how the space-related stakes of LGBT health have been best understood in literal cinema houses and the narrative cinema projections inside of them. The author argues for an appreciation of LGBT-themed motion pictures as oscillating between perpetuator of queer pathology and its potential solution. PMID- 26644059 TI - Cultural change after migration: Circumcision of girls in Western migrant communities. AB - This paper reviews the current knowledge on cultural change after migration in the practice of female circumcision, also named genital cutting or mutilation. Explorative studies show trends of radical change of this practice, especially the most extensive form of its kind (type III or the 'Pharaonic' type). The widespread interpretation that Islam would require circumcision of girls is questioned when, for example, Somalis meet other Muslim migrants, such as Arab Muslims, who do not circumcise their daughters. The few criminal court cases for circumcision of girls that have taken place in Western countries corroborate the conclusion that substantial change in the practice has occurred among migrants. In this literature review, an absence of reports is identified from healthcare providers who have witnessed circumcision after migration. Concurrently, a substantial knowledge exists on how to take care of already circumcised women and girls, and there is a system of recommendations in place regarding best practices for prevention. There is a great potential for healthcare providers to encourage this development towards general abandonment of circumcision of girls. The challenge for the future is how to incorporate culturally sensitive efforts of prevention on the one hand, and the examination of suspicious cases of illegal circumcision on the other. We recommend using--in a cautious way--the existing routines for identifying child abuse in general. Experiences from African contexts show that failure to generate significant change of the harmful practices/tradition may be due to the lack of multidisciplinary collaboration in different sectors of the society. In Western societies, the tendency toward abandonment of the practice could be reinforced by professionals who work toward better inclusion of men and women originally from countries where circumcision is practised. PMID- 26644060 TI - Mechanisms of anterior cruciate ligament injuries in elite women's netball: a systematic video analysis. AB - This study involved a systematic video analysis of 16 anterior cruciate ligament (ACL) injuries sustained by elite-level netball players during televised games in order to describe the game situation, the movement patterns involved, the player's behaviour, and a potential injury mechanism. Eight of the ACL injuries were classified as "indirect contact" and eight as "non-contact". Two common scenarios were identified. In Scenario A the player was jumping to receive or intercept a pass and whilst competing for the ball experienced a perturbation in the air. As a result the player's landing was unbalanced with loading occurring predominantly on the knee of the injured side. In Scenario B the player was generally in a good position at ground contact, but then noticeably altered the alignment of the trunk before the landing was completed. This involved rotating and laterally flexing the trunk without altering the alignment of the feet. Apparent knee valgus collapse on the knee of the injured side was observed in 3/6 Scenario A cases and 5/6 Scenario B cases. Players may benefit from landing training programmes that incorporate tasks that use a ball and include decision making components or require players to learn to cope with being unbalanced. PMID- 26644061 TI - How 100-m event analyses improve our understanding of world-class men's and women's sprint performance. AB - This study aimed to compare the force (F)-velocity (v)-power (P)-time (t) relationships of female and male world-class sprinters. A total of 100 distance time curves (50 women and 50 men) were computed from international 100-m finals, to determine the acceleration and deceleration phases of each race: (a) mechanical variables describing the velocity, force, and power output; and (b) F P-v relationships and associated maximal power output, theoretical force and velocity produced by each athlete (Pmax , F0 , and V0 ). The results showed that the maximal sprint velocity (Vmax ) and mean power output (W/kg) developed over the entire 100 m strongly influenced 100-m performance (r > -0.80; P <= 0.001). With the exception of mean force (N/kg) developed during the acceleration phase or during the entire 100 m, all of the mechanicals variables observed over the race were greater in men. Shorter acceleration and longer deceleration in women may explain both their lower Vmax and their greater decrease in velocity, and in turn their lower performance level, which can be explained by their higher V0 and its correlation with performance. This highlights the importance of the capability to keep applying horizontal force to the ground at high velocities. PMID- 26644062 TI - Openings: On the Journal of Homosexuality, Volume 1, Issue 1. AB - This article serves as one of the supplementary pieces of this special issue on "Mapping Queer Bioethics," in which we take a solipsistic turn to "map" the Journal of Homosexuality itself. Here, the author examines Volume 1, Issue 1 of the Journal of Homosexuality and asks whether the journal's first contributors might reveal a historically problematic relationship whereby the categories of front-line LGBT health advocates in the 1970s might be incommensurate with the post-AIDS, queer politics that would follow in decades to come. PMID- 26644063 TI - Multiple exposures to indoor contaminants: Derivation of benchmark doses and relative potency factors based on male reprotoxic effects. AB - Semi-Volatile Organic Compounds (SVOCs) are commonly present in dwellings and several are suspected of having effects on male reproductive function mediated by an endocrine disruption mode of action. To improve knowledge of the health impact of these compounds, cumulative toxicity indicators are needed. This work derives Benchmark Doses (BMD) and Relative Potency Factors (RPF) for SVOCs acting on the male reproductive system through the same mode of action. We included SVOCs fulfilling the following conditions: detection frequency (>10%) in French dwellings, availability of data on the mechanism/mode of action for male reproductive toxicity, and availability of comparable dose-response relationships. Of 58 SVOCs selected, 18 induce a decrease in serum testosterone levels. Six have sufficient and comparable data to derive BMDs based on 10 or 50% of the response. The SVOCs inducing the largest decrease in serum testosterone concentration are: for 10%, bisphenol A (BMD10 = 7.72E-07 mg/kg bw/d; RPF10 = 7,033,679); for 50%, benzo[a]pyrene (BMD50 = 0.030 mg/kg bw/d; RPF50 = 1630), and the one inducing the smallest one is benzyl butyl phthalate (RPF10 and RPF50 = 0.095). This approach encompasses contaminants from diverse chemical families acting through similar modes of action, and makes possible a cumulative risk assessment in indoor environments. The main limitation remains the lack of comparable toxicological data. PMID- 26644064 TI - [Epidemiologiy of obesity among university students in Douala, Cameroon]. AB - PURPOSE: To determine the prevalence of obesity, its risk factors, and its health risks among students of the University of Douala. METHODS: In April, 2011, 2696 students volunteered to participate in a screening campaign for diabetes, high blood pressure (HBP), and obesity. Their physical activity (PA) level was also evaluated. RESULTS: The sample consisted of 1276 (47.3%) men and 1420 (52.7%) women with a mean age of 23.8 +/- 3.5 years. The general prevalence of obesity was 4.1%, and it was more common among women (p = 0.043). The age group most highly affected was those 35 years or older, with a prevalence of 39.5% (p<0.02). Among the obese, the risk level was high in 78 (70.9%) women. The prevalence of HBP was higher among obese than non-obese students (20.9% vs. 12.5%, p = 0.019), and the prevalence of diabetes five times higher (4.5% vs. 0.8%, p = 0.003). Obesity was highly associated with alcohol consumption (p = 0.01), physical inactivity (p = 0.007), and family history of diabetes (p = 0.008). CONCLUSION: Obesity is a worrisome disorder among students in Douala. Educating students about this topic and developing an obesity prevention and management program may improve their health. PMID- 26644065 TI - Long-Term Effect of Renal Transplantation and Aging on Hemoglobin A1C Levels: A Case-Control Study in 191 Non-Diabetic Deceased Donor Renal Transplant Recipients. AB - BACKGROUND: Reduced renal function in patients with chronic kidney disease is linked to insulin resistance; and impairments in glucose homeostasis, as measured by HbA1c levels, are related to cardiovascular events. Recently, aging has been reported to affect HbA1c levels over time in non-diabetic individuals. The objective of this study was to investigate the association between renal function and aging in non-diabetic deceased-donor renal transplant recipients. MATERIAL AND METHODS: A total of 191 patients were analyzed (mean age 50.6+/-12.2 years, dialysis vintage 6.5+/-3.1 years, 53.4% male patients). HbA1-c levels were measured on the day of transplantation and on follow-up. The mean follow-up time was 4.9+/-3.1 years. RESULTS: Renal transplantation resulted in an increase in eGFR of 38.6+/-18.9 mL/min/1.73 m2 as compared to baseline levels on dialysis and the mean eGFR on follow-up was 45.5+/-18.9 mL/min/1.73 m2. HbA1c levels increased significantly from the day of transplantation to the last follow-up (5.3+/-0.4% to 5.6+/-0.4%, p<0.0001). Correlation analysis demonstrated non-significant associations between the change in HbA1c levels and the parameters of age and renal transplant function. CONCLUSIONS: In conclusion, we observed a significant increase in HbA1c levels over a 5-year post-transplant follow-up period in non diabetic deceased-donor renal transplant recipients. In contrast to the non diabetic general population, the increase in HbA1c observed in this cohort was greater but not associated with aging. PMID- 26644066 TI - Nanoparticle-Mediated Intervalence Charge Transfer: Core-Size Effects. AB - Two types of platinum nanoparticles (NPs) functionalized with ethynylferrocene were prepared. The subnanometer-sized NPs (Pt10eFc) showed semiconductor-like characteristics with a bandgap of about 1.0 eV, and the other was metal-like with a core size of about 2 nm (Pt314eFc) and no significant bandgap. IR spectroscopic measurements showed a clear red-shift of the C=C and ferrocenyl ring =C-H vibrational energies with increasing particle core size owing to enhanced intraparticle charge delocalization between the particle-bound ferrocenyl moieties. Electrochemical measurements showed two pairs of voltammetric peaks owing to intervalence charge transfer between the ferrocenyl groups on the nanoparticle surface, which was apparently weaker with Pt10 eFc than with Pt314 eFc. Significantly, the former might be markedly enhanced with UV photoirradiation owing to enhanced nanoparticle electronic conductivity, whereas no apparent effects were observed with the latter. PMID- 26644067 TI - Combat-related bridge synostosis versus traditional transtibial amputation: comparison of military-specific outcomes. AB - The aim of our study was to determine military-specific outcomes for transtibial amputations of US Service members using either the traditional technique (Burgess) or the Ertl technique. All US Service members sustaining transtibial, combat-related amputation from September 2001 through July 2011 were reviewed. Amputation type, mechanism of injury, time interval to amputation, age, sex, branch of service, rank, force, nature, and injury severity score were recorded. Outcomes were determined by analyzing military-specific medical review results, to include the following: Physical Evaluation Board Liaison Office (PEBLO) rating (0-100), PEBLO outcome (permanent retirement, temporary disability retirement, separation without benefits, continuation of active duty, or fit for redeployment), and the rate of redeployment. Amputation type (Ertl vs. Burgess) was determined by reviewing postoperative radiographs and radiology reports. Data from all of the above categories were compared for both Ertl and Burgess amputees. Of 512 subjects identified, 478 had radiographs or radiology reports distinguishing between Ertl or Burgess transtibial amputation. A total of 406 subjects underwent the Burgess procedure, and 72 subjects underwent the Ertl procedure. There was not a significant difference between the two groups in review board rating (p = 0.858), review board outcome (p = 0.102), or ability to deploy (p = 0.106); however, subjects that underwent the Ertl procedure remained on active duty at a significantly higher rate (p = 0.021). There is a higher rate of remaining on active duty using the Ertl technique. This study suggests that there is an improvement in functional outcome with the Ertl technique. PMID- 26644068 TI - Assessment of Myocardial Contractility by SonR Sensor in Patients Undergoing Cardiac Resynchronization Therapy. AB - BACKGROUND: SonR sensor signal correlates well with myocardial contractility expressed in terms of left ventricular (LV) dP/dt max. The aim of our study was to evaluate the changes in myocardial contractility during isometric effort in heart failure patients undergoing cardiac resynchronization therapy (CRT) with right atrial SonR sensor. METHODS: Thirty-one patients (19 men, 65 +/- 7 years, LV ejection fraction [LVEF] 28% +/- 5%, in sinus rhythm) were implanted with a CRT-defibrillator (CRT-D) device equipped with SonR sensor, which was programmed in VVI mode at 40 beats/min. Twenty-four hours after implantation, each patient underwent a noninvasive hemodynamic evaluation at rest and during isometric effort, including: (1) measurement of beat-to-beat endocavitary SonR signal; (2) echocardiographic assessment; and (3) continuous measurement of blood pressure with Nexfin method (BMEYE, Amsterdam, the Netherlands). The following contractility parameters were considered: (1) mean value of beat-to-beat SonR signal; (2) mean value of LV dP/dt by Nexfin system; and (3) fractional shortening (FS) by echocardiography. RESULTS: At the third minute of the isometric effort, mean value of SonR signal significantly increased from baseline (P < 0.001). Similarly, mean value of both LV dP/dt by Nexfin and FS significantly increased compared to the resting condition (P < 0.001; P < 0.001). While in 27 (88%) patients SonR signal increased at the third minute of the isometric effort, in four (12%) patients SonR signal decreased. In these patients, both LV dP/dt by Nexfin and FS consensually decreased. CONCLUSIONS: In CRT patients, SonR sensor is able to detect changes in myocardial contractility in a consensual way like noninvasive methods such as Nexfin system and echocardiography. PMID- 26644069 TI - Discovery of symbiotic nitrogen fixation and chemoautotrophy in cold-water corals. AB - Cold-water corals (CWC) are widely distributed around the world forming extensive reefs at par with tropical coral reefs. They are hotspots of biodiversity and organic matter processing in the world's deep oceans. Living in the dark they lack photosynthetic symbionts and are therefore considered to depend entirely on the limited flux of organic resources from the surface ocean. While symbiotic relations in tropical corals are known to be key to their survival in oligotrophic conditions, the full metabolic capacity of CWC has yet to be revealed. Here we report isotope tracer evidence for efficient nitrogen recycling, including nitrogen assimilation, regeneration, nitrification and denitrification. Moreover, we also discovered chemoautotrophy and nitrogen fixation in CWC and transfer of fixed nitrogen and inorganic carbon into bulk coral tissue and tissue compounds (fatty acids and amino acids). This unrecognized yet versatile metabolic machinery of CWC conserves precious limiting resources and provides access to new nitrogen and organic carbon resources that may be essential for CWC to survive in the resource-depleted dark ocean. PMID- 26644071 TI - EEG-based usability assessment of 3D shutter glasses. AB - OBJECTIVE: Neurotechnology can contribute to the usability assessment of products by providing objective measures of neural workload and can uncover usability impediments that are not consciously perceived by test persons. In this study, the neural processing effort imposed on the viewer of 3D television by shutter glasses was quantified as a function of shutter frequency. In particular, we sought to determine the critical shutter frequency at which the 'neural flicker' vanishes, such that visual fatigue due to this additional neural effort can be prevented by increasing the frequency of the system. APPROACH: Twenty-three participants viewed an image through 3D shutter glasses, while multichannel electroencephalogram (EEG) was recorded. In total ten shutter frequencies were employed, selected individually for each participant to cover the range below, at and above the threshold of flicker perception. The source of the neural flicker correlate was extracted using independent component analysis and the flicker impact on the visual cortex was quantified by decoding the state of the shutter from the EEG. MAIN RESULT: Effects of the shutter glasses were traced in the EEG up to around 67 Hz-about 20 Hz over the flicker perception threshold-and vanished at the subsequent frequency level of 77 Hz. SIGNIFICANCE: The impact of the shutter glasses on the visual cortex can be detected by neurotechnology even when a flicker is not reported by the participants. Potential impact. Increasing the shutter frequency from the usual 50 Hz or 60 Hz to 77 Hz reduces the risk of visual fatigue and thus improves shutter-glass-based 3D usability. PMID- 26644070 TI - Temporal and spatial dynamics of scaling-specific features of a gene regulatory network in Drosophila. AB - A widely appreciated aspect of developmental robustness is pattern formation in proportion to size. But how such scaling features emerge dynamically remains poorly understood. Here we generate a data set of the expression profiles of six gap genes in Drosophila melanogaster embryos that differ significantly in size. Expression patterns exhibit size-dependent dynamics both spatially and temporally. We uncover a dynamic emergence of under-scaling in the posterior, accompanied by reduced expression levels of gap genes near the middle of large embryos. Simulation results show that a size-dependent Bicoid gradient input can lead to reduced Kruppel expression that can have long-range and dynamic effects on gap gene expression in the posterior. Thus, for emergence of scaled patterns, the entire embryo may be viewed as a single unified dynamic system where maternally derived size-dependent information interpreted locally can be propagated in space and time as governed by the dynamics of a gene regulatory network. PMID- 26644073 TI - Nontechnical skills in pediatric surgery: Factors influencing operative performance. AB - Technical competence is an essential aspect of intraoperative performance but is in itself insufficient to ensure an optimal surgical outcome. A list of other skills complement technical ability and these relate, among others, to surgical judgment and intraoperative decision-making processes as well as the role of the operating surgeon as leader of the surgical team. This article outlines the composite set of nontechnical skills (NTS) and the factors which influence surgical performance by virtue of this skill set. A framework has been developed to allow identification, teaching, and assessment of NTS known as Nontechnical Skills for Surgeons (NOTSS), and the relevance and influence of NOTSS during the intraoperative performance of pediatric surgery is presented. PMID- 26644072 TI - Comparative effectiveness of catheter salvage strategies for pediatric catheter related bloodstream infections. AB - BACKGROUND: Intravascular catheter salvage may be attempted in clinically suitable cases in pediatric patients with catheter-related bloodstream infections. The purpose of this study was to assess the effectiveness of ethanol and hydrochloric acid (HCl) locks in achieving catheter salvage through decision analysis modeling. METHODS: A Markov decision model was created to simulate catheter salvage using three management strategies: systemic antibiotics alone, antibiotics plus HCl lock, and antibiotics plus ethanol lock. One-way and two-way sensitivity analyses were performed for all model variables. Infection control rates and recurrence rates for each strategy were derived from prospective institutional data and existing pediatric literature. Costs were derived from institutional charges. RESULTS: With antibiotics alone, 73% of patients would require line replacement within 100days, compared to only 31% and 19% of patients treated with HCl and ethanol lock, respectively. Incremental cost per additional catheter salvaged is $89 for HCl lock and $456 for ethanol lock. Superior efficacy of adjunct lock therapy is insensitive to changes in the anticipated duration of central access requirement and to clinically relevant variations in all model input variables. CONCLUSION: HCl or ethanol locks are cost-effective adjuncts to systemic antibiotics for attempted catheter salvage in the setting of catheter-related bloodstream infections. PMID- 26644074 TI - mRNA and protein expression of the angiogenesis-related genes EDIL3, AMOT and ECM1 in mesenchymal stem cells in psoriatic dermis. AB - BACKGROUND: Dermal microvasculature expansion and angiogenesis are prominent in psoriasis. Our previous microarray study showed that the angiogenesis-related genes EDIL3 (epidermal growth factor-like repeats and discoidin I-like domains 3), AMOT (angiomotin) and ECM1 (extracellular matrix protein 1), had high expression levels in dermal mesenchymal stem cells (DMSCs) from psoriatic skin lesions. AIM: To investigate the mRNA and protein expressions of EDIL3, AMOT and ECM1 in DMSCs derived from psoriatic skin in order to better determine the molecular mechanisms of angiogenesis in the skin. METHODS: DMSCs from 12 patients with psoriasis and 14 healthy controls (HCs) were cultured to passage 3, and identified by morphology, immunophenotype and multipotential differentiation. The mRNA and protein expressions of EDIL3, AMOT, and ECM1 in the DMSCs were determined using real-time reverse transcription PCR and western blotting. RESULTS: DMSCs displayed spindle-like morphology and surface protein expression, and were able to differentiate into osteoblasts, chondrocytes and adipocytes. mRNA expression analysis showed that EDIL3, AMOT and ECM1 were expressed at 2.54 fold, 2.11-fold, and 1.90-fold higher levels, respectively, in psoriatic DMSCs compared with HC DMSCs (all P < 0.05). Protein analysis showed significantly (all P < 0.01) higher concentrations of EDIL3, AMOT and ECM1in the psoriasis group than in the HC group. CONCLUSIONS: Our data demonstrate for the first time that expression of EDIL3, AMOT and ECM1 is altered in DMSCs in psoriasis, suggesting that EDIL3, AMOT and ECM1 are involved in the excessive angiogenesis and vasodilation observed in psoriasis. PMID- 26644075 TI - Exceptional surface and bulk electronic structures in a topological insulator, Bi2Se3. AB - The outstanding problem in topological insulators is the bulk metallicity underneath topologically ordered surface states and the appearance of Dirac point far away from the Fermi energy. Enormous efforts are being devoted to get the Dirac point at the Fermi level via exposure to foreign materials so that these materials can be used in technology and realize novel fundamental physics. Ironically, the conclusion of bulk metallicity in the electronic structure is essentially based on the angle resolved photoemission spectroscopy, a highly surface sensitive technique. Here, we employed state-of-the-art hard x-ray photoemission spectroscopy with judiciously chosen experiment geometry to delineate the bulk electronic structure of a topological insulator and a potential thermoelectric material, Bi2Se3. The results exhibit signature of insulating bulk electronic structure with tiny intensities at akin to defect/vacancy induced doped states in the semiconductors. The core level spectra exhibit intense plasmon peak associated to core level excitations manifesting the signature of coupling of electrons to the collective excitations, a possible case of plasmon-phonon coupling. In addition, a new loss feature appear in the core level spectra indicating presence of additional collective excitations in the system. PMID- 26644076 TI - Great expectations - introduction of flow managers in a university hospital. AB - A major reorganization of a university hospital included the clinical structure as well as the administrative structure of the hospital. The focus of the reorganization was to improve the coordination of patient flows through the hospital. An important part of the organizational change was the introduction of flow managers. The aim of the article is to describe and analyze the challenges of the flow managers in the implementation of the reorganization. The description is based on a number of individual and focus group interviews with professionals and managers on different organizational levels. The analysis is guided by a broad conceptual framework, focusing on the processes of change in a professional organization like a hospital. The results show that the flow managers started with a lot of uncertainty regarding their responsibilities. There was also a lot of resistance to the reorganization, which the flow managers came to personify. They proceeded by building relationships and shaping their role and tasks. They tried to balance proactive and reactive strategies of change. There were some positive results, but they felt that that the expectations placed on them had been unrealistic. The introduction of flow managers in a university hospital has touched upon many elements of the conceptual framework. There were a number of structural, cultural, financial and strategic barriers influencing the change process. The main conclusion of the analysis is that the flow managers need more power and legitimacy in the organization to deal with these barriers. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26644078 TI - Dynamic diaphragmatic MRI during apnea struggle phase in breath-hold divers. AB - The purpose of the study was to provide insight in diaphragmatic involuntary breathing movements (IBM) during struggle phase of apnea at total lung capacity (TLC) and functional residual capacity (FRC) using magnetic resonance imaging along with measurements of hemodynamics and arterial oxygenation. The study was performed in eight elite breath-hold divers. There was a similar increase in diaphragmatic cranio-caudal excursions towards the end of TLC and FRC apnea. The greatest diaphragmatic excursion in both apneas and during tidal breathing was in the middle and posterior part of the diaphragm. Diaphragm thickness in elite BHD was within the reference range of normal values suggesting no diaphragmatic hypertrophy in this population. We found that the range of diaphragmatic excursions increases toward the end of apneas. Additionally, our data suggest that the diaphragm participates in IBM occurrence and that various segments of the diaphragm behave nonhomogenously both in tidal breathing and IBMs. PMID- 26644077 TI - STAT4 knockout protects LPS-induced lung injury by increasing of MDSC and promoting of macrophage differentiation. AB - The disruption of signal transducer and activator of transcription 4 (STAT4) signal can inhibit the inflammation and protect organs from injury during severe bacterial infection. However, the mechanism of STAT4 signal in lung injury remains poor understood. Here we report that STAT4 deficiency decreased the lethality and protein leakage in STAT4(-/-) mice and protected lipopolysaccharid (LPS)-induced lung injury with ameliorated edema, inflammatory infiltration and hemorrhage. The expression of CD11b(+)Gr-1(+) myeloid derived suppressor cells (MDSCs) markedly increased in the circulation of STAT4(-/-) mice after LPS stimuli, accompanying with increased macrophages infiltration in inflamed lung tissue. In addition, the levels of pro-inflammatory cytokines including tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-6 decreased while anti inflammatory cytokine (IL-10) increased in the bronchoalveolar lavage fluid of STAT4(-/-) mice. Thus, these results indicate that the accumulation of MDSCs and macrophages play a critical role in LPS-induced lung injury. Targeting MDSCs and macrophages polarization through a STAT4 dependent signaling pathway might help to reduce the inflammation and damage of lung tissue. PMID- 26644079 TI - Alerted microglia and the sympathetic nervous system: A novel form of microglia in the development of hypertension. AB - Microglia, commonly known as the tissue resident macrophages of the central nervous system (CNS), are ubiquitously expressed in the CNS. Microglia, in their resting, or surveilling, stage, play a critical role in the maintenance of normal neuronal physiology and homeostasis. On activation, microglia can acquire either a neurotoxic (M1) or a neuroprotective (M2) phenotype. Prior to development of the M1 or M2 phenotype, little was known about changes in microglial activity, when subjected to stimuli. It is postulated, that an inability of microglia to maintain neuronal physiology within a normal working range can contribute to the development of cardiovascular disorders (CVDs) such as hypertension, but clear evidence supporting this hypothesis is missing. Even though our understanding of microglial function in a state of CNS injury/inflammation is extensive, the literature concerning role of microglia in the healthy CNS, is limited. Involvement of microglia in the pathophysiology of CVDs, in a neuroprotective/neurotoxic manner, is a key area that requires further investigation. PMID- 26644080 TI - Tropically adapted cattle of Africa: perspectives on potential role of copy number variations. AB - Africa is host to diverse and locally adapted cattle breeds that are expected to survive the harsh and extreme tropical environments associated with diseases and parasite infections, heat stress and episodes of feed and water scarcity. Genomic copy number variations (CNVs) are considered to be primary role players in cattle breed formation and adaptation where isolation and genetic drift together with subsequent mutations have created an enormous diversity of local populations. CNVs are modifications in DNA structure comprising deletions, duplications and insertions that are >1 kb in size. Despite attracting much attention, the frequency and pattern of bovine CNV events, especially in African cattle breeds, are for the most part largely unknown. Characterization of genetic variation in the indigenous cattle of Africa will be a vital step toward dissecting the molecular mechanisms underlying phenotypic variation and local adaptation. This review therefore aims to describe the current knowledge regarding bovine CNVs and the implications and potentials they encompass for dissecting genetic adaptation and the genotypic skeleton of tropical African cattle populations. PMID- 26644081 TI - Synergistic cytotoxicity from combination of imatinib and platinum-based anticancer drugs specifically in Bcr-Abl positive leukemia cells. AB - Imatinib, a multitargeted tyrosine kinase inhibitor, exhibits potent anticancer activity against leukemia harboring the Bcr-Abl oncogene and some solid tumors overexpressing c-kit and PDGFR. However, its clinical efficacy is severely compromised by the emergence of resistance primarily due to acquired mutations in the Bcr-Abl kinase domain. In this study, we showed that combination of imatinib with platinum (Pt)-based anticancer agents, including cisplatin and oxaliplatin, exhibited synergistic cytotoxic effect specifically in Bcr-Abl+ human chronic myeloid leukemia cell line K562 but not in Bcr-Abl- RPMI8226 cells. Importantly, the synergistic effect was also found to circumvent imatinib resistance in an imatinib-selected resistant subline K562 ima1.0. The combination treatment increased apoptosis and DNA damage. Mechanistic study revealed that increased inhibition of Bcr-Abl and downstream ERK phosphorylation by the drug combination may contribute to the synergistic effect. PMID- 26644082 TI - Proximal and distal patterns: Different spreading patterns of indocyanine green lymphography in secondary lower extremity lymphedema. AB - BACKGROUND: As a clinical evaluation of secondary lymphedema of the leg, indocyanine green (ICG) lymphographic assessment has established its usefulness. In this study, we analyzed the ICG findings of patients with secondary lymphedema of the leg, focusing on the location and spreading pattern of dermal backflow (DBF). METHODS: Between April 2013 and June 2015, we investigated ICG findings performed on 90 patients with secondary lymphedema of the leg following malignant cancer resection. The patients comprised 88 women and two men; ICG lymphography was performed 12-24 h after the injection. RESULTS: Of the 90 patients, ICG lymphographic DBF was evident in 64 from the proximal region of the leg, termed as the proximal pattern. Of the 90 patients, DBF was found to appear in 18 patients mainly in the distal part of the leg, termed as the distal pattern. CONCLUSIONS: In the proximal pattern, the ICG injected into the distal part of the leg propelled to the proximal part, but an obstruction after lymphadenectomy caused ICG pooling to appear first on the proximal side. In the distal pattern, the lymphatic system hypoplasia of the leg may have already been present, and lymph node dissection might be the only trigger for the development of lymphedema. This classification may reflect the pumping function and preexisting hypoplasty of the lymphatic vessels, and provides a novel approach for the pathological evaluation of lymphedema. Patients with proximal pattern on ICG lymphography may well indicate lymphaticovenous anastomosis. PMID- 26644083 TI - Multiple etiologies of trigger wrist. AB - BACKGROUND: Trigger wrist, a relatively unusual condition, is a triggering at the wrist produced by wrist or finger motion. The clinical manifestations and surgical results of trigger wrist with multiple etiologies were evaluated. METHODS: From October 2008 to December 2012, this study retrospectively reviewed 15 patients diagnosed with trigger wrist. The patients comprised six men and nine women with a mean age of 44.8 years (range, 29-86 years). The mean follow-up period was 16.2 months (range, 11-30 months). RESULTS: The causes of trigger wrist were an anomalous muscle belly of the flexor digitorum superficialis (n = 5), severe tenosynovitis of the flexor tendon (n = 4), fibroma around the flexor tendon sheath (n = 2), a rheumatoid nodule (n = 1), both anomalous muscle belly and tenosynovitis (n = 1), a ganglion (n = 1), and pigmented villonodular synovitis (n = 1). Mild-to-moderate symptoms of median neuropathy without thenar muscle atrophy were present in all patients. Postoperatively, all patients recovered well with resolution of median nerve symptoms, and the wrist triggering was absent. CONCLUSIONS: Trigger wrist is a relatively rare condition compared with trigger finger, which is the most common disorder of the hand. To avoid inadequate and ineffective treatment of patients with trigger wrist, careful examination and proper diagnosis are vital. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic/IV. PMID- 26644084 TI - Knockdown of the partner protein OsNAR2.1 for high-affinity nitrate transport represses lateral root formation in a nitrate-dependent manner. AB - The morphological plasticity of root systems is critical for plant survival, and understanding the mechanisms underlying root adaptation to nitrogen (N) fluctuation is critical for sustainable agriculture; however, the molecular mechanism of N-dependent root growth in rice remains unclear. This study aimed to identify the role of the complementary high-affinity NO3(-) transport protein OsNAR2.1 in NO3(-)-regulated rice root growth. Comparisons with wild-type (WT) plants showed that knockdown of OsNAR2.1 inhibited lateral root (LR) formation under low NO3(-) concentrations, but not under low NH4(+) concentrations. (15)N labelling NO3(-) supplies (provided at concentrations of 0-10 mM) demonstrated that (i) defects in LR formation in mutants subjected to low external NO3(-) concentrations resulted from impaired NO3(-) uptake, and (ii) the mutants had significantly fewer LRs than the WT plants when root N contents were similar between genotypes. LR formation in osnar2.1 mutants was less sensitive to localised NO3(-) supply than LR formation in WT plants, suggesting that OsNAR2.1 may be involved in a NO3(-)-signalling pathway that controls LR formation. Knockdown of OsNAR2.1 inhibited LR formation by decreasing auxin transport from shoots to roots. Thus, OsNAR2.1 probably functions in both NO3(-) uptake and NO3( )-signalling. PMID- 26644086 TI - Nanoparticle Based Curve Arrays for Multirecognition Flexible Electronics. AB - Assembly of nanoparticles into controllable micro or nanocurve circuits by a feasible strategy is demonstrated. The curves, with various tortuosity morphologies, have tunable resistive strain sensitivity, which can be integrated into a multi-analysis flexible sensor. The curve-based sensor can run complicated facial expression recognition, and may contribute practical applications on auxiliary apparatus for skin micromotion manipulation for paraplegics. PMID- 26644085 TI - Axonal plasticity of age-defined dentate granule cells in a rat model of mesial temporal lobe epilepsy. AB - Dentate granule cell (DGC) mossy fiber sprouting (MFS) in mesial temporal lobe epilepsy (mTLE) is thought to underlie the creation of aberrant circuitry which promotes the generation or spread of spontaneous seizure activity. Understanding the extent to which populations of DGCs participate in this circuitry could help determine how it develops and potentially identify therapeutic targets for regulating aberrant network activity. In this study, we investigated how DGC birthdate influences participation in MFS and other aspects of axonal plasticity using the rat pilocarpine-induced status epilepticus (SE) model of mTLE. We injected a retrovirus (RV) carrying a synaptophysin-yellow fluorescent protein (syp-YFP) fusion construct to birthdate DGCs and brightly label their axon terminals, and compared DGCs born during the neonatal period with those generated in adulthood. We found that both neonatal and adult-born DGC populations participate, to a similar extent, in SE-induced MFS within the dentate gyrus inner molecular layer (IML). SE did not alter hilar MF bouton density compared to sham-treated controls, but adult-born DGC bouton density was greater in the IML than in the hilus after SE. Interestingly, we also observed MF axonal reorganization in area CA2 in epileptic rats, and these changes arose from DGCs generated both neonatally and in adulthood. These data indicate that both neonatal and adult-generated DGCs contribute to axonal reorganization in the rat pilocarpine mTLE model, and indicate a more complex relationship between DGC age and participation in seizure-related plasticity than was previously thought. PMID- 26644087 TI - Taurine depresses cardiac contractility and enhances systemic heart glucose utilization in the cuttlefish, Sepia officinalis. AB - Taurine is the most abundant amino acid in the blood of the cuttlefish, Sepia officinalis, where levels can exceed 200 mmol L(-1). In mammals, intracellular taurine modulates cardiac Ca(2+) handling and carbohydrate metabolism at much lower concentrations but it is not clear if it exerts similar actions in cephalopods. Blood Ca(2+) levels are high in cephalopods and we hypothesized that taurine would depress cardiac Ca(2+) flux and modulate contractility in systemic and branchial hearts of cuttlefish. Heart performance was assessed with an in situ perfused systemic heart preparation and contractility was evaluated using isometrically contracting systemic and branchial heart muscle rings. Stroke volume, cardiac output, and Ca(2+) sensitivity were significantly lower in systemic hearts perfused with supplemental taurine (100 mmol L(-1)) than in controls. In muscle ring preparations, taurine impaired relaxation at high contraction frequencies, an effect abolished by supra-physiological Ca(2+) levels. Taurine did not affect oxygen consumption in non-contracting systemic heart muscle, but extracellular glucose utilization was twice that of control preparations. Collectively, our results suggest that extracellular taurine depresses cardiac Ca(2+) flux and potentiates glucose utilization in cuttlefish. Variations in taurine levels may represent an important mechanism for regulating cardiovascular function and metabolism in cephalopods. PMID- 26644088 TI - Pro-inflammatory cytokine dysregulation is associated with novel avian influenza A (H7N9) virus in primary human macrophages. AB - Since March 2013, more than 500 laboratory-confirmed human H7N9 influenza A virus infection cases have been recorded, with a case fatality rate of more than 30%. Clinical research has shown that cytokine and chemokine dysregulation contributes to the pathogenicity of the H7N9 virus. Here, we investigated cytokine profiles in primary human macrophages infected with the novel H7N9 virus, using cytokine antibody arrays. The levels of several pro-inflammatory cytokines, particularly TNF-alpha, were increased in H7N9-infected macrophages. Induction of the transcriptional and translational levels of the pro-inflammatory cytokines by H7N9 virus seemed to be intermediate between those induced by highly pathogenic avian H5N1 and pandemic human H1N1 viruses, which were detected by ELISA and real time quantitative PCR, respectively. Additionally, compared with H5N1, the upregulation of pro-inflammatory cytokines caused by H7N9 infection occurred rapidly but mildly. Our results identified the overall profiles of cytokine and chemokine induction by the H7N9 influenza virus in an in vitro cell-culture model, and could provide potential therapeutic targets for the control of severe human H7N9 disease. PMID- 26644089 TI - High glucose induces rat mesangial cells proliferation and MCP-1 expression via ROS-mediated activation of NF-kappaB pathway, which is inhibited by eleutheroside E. AB - Glomerular hypertrophy and extracellular matrix accumulation are early features of diabetic nephropathy (DN). High glucose-induced oxidative stress is implicated in the etiology of DN. This study aims to investigate the effect of eleutheroside E (EE) on high glucose mediated rat mesangial cells (MCs) proliferation and monocyte chemoattractant protein-1 (MCP-1) expression and the underlying mechanism. MCs proliferation was assessed by MTT assay. Reactive oxygen species (ROS) level and MCP-1 expression were evaluated by ELISA kit. The protein expression of p47, NF-kappaB p65, p-NF-kappaB p65, IkappaBalpha, p-IkappaBalpha, IKKbeta and p-IKKbeta were determined by Western blot. The results showed that treatment with EE markedly attenuated high glucose induced MCs proliferation and in a dose-dependent manner. Intervention with EE also significantly blocked high glucose induced intracellular ROS production by decreasing NADPH oxidase activity. Meanwhile, EE administration could effectively alleviate the high glucose-stimulated activation of NF-kappaB, the degradation of IkappaBalpha and the expression of MCP-1. These results demonstrate that high glucose enhances MCs proliferation and MCP-1 expression by activating the ROS/NF-kappaB pathway and can be inhibited by EE. Our findings provide a new perspective for the clinical treatment of DN. PMID- 26644090 TI - Proteomics in rheumatology. PMID- 26644091 TI - Corrigendum. PMID- 26644092 TI - Genomic classification of lung cancer: toward a personalized treatment. AB - Lung cancer is the first cause of death by cancer worldwide. In Tunisia, its incidence has increased from 17.6 cases per 100.000 persons in 1997 to 27.6 cases per 100.000 persons in 2003. Its prognosis has been improving thanks to the emergence of molecular targets. The first one is represented by EGFR (Epidermal growth factor receptor), which marks this (2014) its tenth anniversary. many other targets have been identified. the most famous and useful of them the fusion gene ALK-EML4 but other oncogenic pathways have been implicated and under investigations including HER2, BRAF, MET, RET... The relevant challenges encountered are represented by the difficulty to achieve a consensual decisional and therapeutic algorithm, the absence of standardized diagnostic techniques and unavoidable occurrence of secondary resistance due to the activation of other oncogenic pathways that must be explored and targeted. In this update, we tried to present the major pathways implicated and the most relevant practice routine strategies. PMID- 26644093 TI - Penile pigmented papules. PMID- 26644094 TI - Late relapse of imported Plasmodium ovale malaria: a case report. AB - We report the first case of an imported Plasmodium ovale relapse in a Tunisian man who developed malaria three years after leaving sub- Saharan Africa. A 29 year-old Tunisian man consulted in September 2011 because of a fever, myalgia, and headache that had begun eight days earlier and persisted despite treatment with oral antibiotics. On questioning, the patient stated that he had resided three years ago for six months in Ivory Coast, where he acquired malaria. He was treated with artemether-lumefantrine. The patient said he had no recent travel to any other malaria-endemic area and had not received a blood transfusion. A first microscopy of peripheral blood smears was negative for malaria parasites. The diagnosis was established 17 days after onset of symptoms. A repeat microscopic examination of blood smears confirmed the presence of Plasmodium ovale with a parasitemia lower than 0.1%. The patient was treated with artemether lumefantrine, followed by primaquine. This case emphasizes the possibility of relapse of some plasmodial species. It highlights the importance of repeating microscopic examination of blood when the diagnosis of malaria is suspected. PMID- 26644095 TI - Complete radiological response after sorafenib treatment for advanced hepato cellular carcinoma. AB - INTRODUCTION: Sorafenib, an oral multikinase inhibitor, has recentlybeen shown to improve overall survival in patients with advanced hepatocellular carcinoma (HCC) but only a handful of reports of complete remission on sorafenib have been issued. CASE REPORT: We report an intriguing case of advanced HCC complicating HCV infection with cirrhosis, in which the patient achieved complete remission by prolonged administration of sorafenib. CONCLUSION: Identifying factors that could be associated with good response to this therapy are needed. PMID- 26644096 TI - [Multicentric tubulopapillary carcinoma of the kidney associated with renal adenomatosis]. AB - Tubulopapillary tumors of the kidney represent a particular group of the renal tumors. They cover a continuous spectrum of tumors ranging from the adenoma to the renal cells papillary carcinoma. The histological and immunohistochemical similarities, as well as the high recurrence of the association of these two entities suggest a continuity of the same biological process. Although rare, the association between adenoma and papillary carcinoma remains still subject to controversy and plead in favor of a narrow relation between them. We report the case of a multicentric tubulopapillary carcinoma of the kidney associated with multifocal adenomas, discovered by fortuity in a right nephrectomy at a 57-year old patient operated for an obstructive chronic pyelonephritis. PMID- 26644097 TI - Surgical treatment of Crohn's disease: indications, results and predictive factors of recurrence and morbidity. AB - BACKGROUND: Crohn's disease management represents a major problem in gastroenterology and general surgery because it affects young subjects and has a major impact on their quality of life. The aims of our study were to identify the indications for surgery in Crohn's disease, the results and the complications of surgery in our series, and to identify possible predictive factors of recurrence and postoperative morbidity. METHODS: A retrospective descriptive study including 38 cases of patients with Crohn's disease who underwent surgical treatment in the department of surgery in Mongi Slim Hospital, during the period between January 1992 and December 2011 was performed. RESULTS: The occurrence of stenosis was the most common indication for surgical treatment in Crohn's disease in our series, and ileocecal resection was the most performed surgery. Twenty six patients (58%) received maintenance therapy after surgery. Twenty two patients relapsed and 13 had surgical management for recurrence. In univariate analysis, predictive factors of post operative morbidity in our study were leukocytosis, penetrating phenotype and intraabdominal sepsis. Ileocecal location was the only factor that significantly improved the incidence of recurrence. In multivariate analysis, only penetrating phenotype was a predictive factor or post operative morbidity. CONCLUSION: Despite the development of medical treatment, surgical treatment keeps large indications for the management of complications of Crohn's disease. The surgery should be an alternative to immunosuppressive therapy. Currently, prevention postoperative recurrence is well codified, reducing the risk of complications. PMID- 26644098 TI - [Evaluation of non-compliance of transfusion requests of packed red blood cells]. AB - BACKGROUND: Despite legislative acts develloped, many deficiencies were identified in blood requests at the National Blood TransfusionCenter impedding board and blood safety. AIM: to evaluate the conformity of the different topics of packed red blood cells requests to the legislation. METHODS: Our study was prospective descriptive lasting six months (March-August 2011). It assessed all packed red blood cells requests which reached the national blood transfusion center. RESULTS: 16064 packed red blood cells requests from 21 public institutions and 28 private institutions were studied. There was different deficiencies in each item.The absence of birth date in 67.18% of request represented the largest non-compliance within administrative information. A predominance of shortcomings related to transfusion and obstetric history was recorded for clinical information with absence of date of the last transfusion in 91.72% cases, lack of accuracy of any previous transfusion reactions in 88.63% cases and absence of the number of previous pregnancies in 93.15% of transfusion requests prescribed to women. Non-conformities related to the prescribing physician concerned mainly the phone number which was absent in 55.82% of cases. CONCLUSIONS: This study revealed a significant lack of awareness of physicians in relation to the law governing transfusion. It is therefore essential to develop training for prescribers to improve transfusion safety. PMID- 26644099 TI - [Clinical and environmental aspects of amyotrophic lateral sclerosis in moroccan population: a study of 60 cases]. AB - BACKGROUND: Amyotrophic lateral sclerosis (ALS) is the most common disease of the motor neuron disease. Its etiology remains unknown but several studies incriminate the environmental factors in its genesis. THE AIM: of this study was to describe the epidemiological, clinical and environmental aspects of ALS in Moroccan population. METHODS: 60 ALS patients were recruited over a period of 5 years from January 2008 to September 2012. Patients were evaluated by detailed record of exploitation. Statistical analysis was performed using SPSS 13.0. RESULTS: The average age of the population was 52.1 +/- 11.2 years with a sex ratio of M/F = 1.5. The average age of onset was 50 +/- 11.7 years. In the group of patients exposed to toxic a significantly higher proportion of solvent exposure was found (p = 0.02). However there was no significant association with exposure to heavy metals, pesticides, or with toxic and eating habits. ALS is more frequent in the west region of Morocco (p = 0.03). CONCLUSIONS: The positive association between exposure to solvents and ALS found in our population has been reported in the literature. The frequency of the ALS early west region suggests may be environmental or genetic origin. These results are preliminary and require a multicenter study to have more data and better highlight the environmental characteristics of ALS in the Moroccan population. PMID- 26644100 TI - [Breech presentation: Does the decision of vaginal delivery depend on parity?]. AB - BACKGROUND: The breech presentation delivery mode is still controversial. The cesarean section is becoming the current trend especially in case of primiparous. AIM: To compare the maternal and fetal prognosis of the breech presentation delivery according to the parity. METHODS: We conducted a retrospective comparative study covering a two years period. Our data was collected from all patients accepted for vaginal delivery of breech presentation into the entree of the labor room. We compared the primiparous group (G1, n=45) to a second group with parity >= 2 (G2, n=56) in terms of maternal and fetal prognosis. RESULTS: The two groups were comparable in term of epidemiological profile and labor evolution. The average age was of 28,2 years in the group G1 vs 30,9 years in the group G2. The average term was 37,4 weeks of amenorrhea, comparable between both groups. We did not note statistically significant difference between both groups regarding duration of work shifts. Indeed, the phase of latency had lasted 4,2 hours in the group G1 vs 3,8 hours in the group G2. The active phase had lasted 3,4 hours in the group G1 vs 2,3 hours in the group G2. 71% of the deliveries of the group primipare and 78 % of multipare had taken place in Vermelin. The appeal to a caesarian during the work was necessary to 5 (11,1 %) primipares against 3 (5,3 %) in the group G2. This difference was not significant (p=0,5). We objectified no statistically significant difference in term of foetal prognosis (Apgar 7 in 1 minute: G1 (n=2) vs G2 (n=2) with p=0.82 or of transfer in neonatal resuscitation: G1 (n=5) vs G2 (n 3) with p= 0.28 between both groups. CONCLUSION: We can conclude that the parity is not a significant variable in the vaginal delivery of the breech presentation. PMID- 26644101 TI - [Vulvovaginal trichomoniasis: epidemiology, clinical and parasitological characteristics]. AB - BACKGROUND: Trichomonas vaginalis infection is the most prevalent nonviral sexual transmitted infection. The World Health Organization estimates that its prevalence is 170 million cases worldwide each year. In women, he represents the third cause of vaginitis. AIM: to determine the prevalence, to evaluate predisposing factors and to study the clinical and parasitological characteristics of vulvovaginal trichomoniasis in a Tunisian population during a period of 18 months. METHODS: This is a transversal study concerning 924 women. We administered a questionnaire to obtain information about the possible risk factors of vulvovaginal trichomoniasis. Vaginal swabs were collected with the help of sterile transportable cotton swabs, followed by microscopic examination. Data were statistically analyzed. RESULTS: Trichomonas vaginalis infection was diagnosed in 3,5% of cases. The study various potential risk factors showed that trichomoniasis was significatively associated with multiple partners, long-term corticotherapy. However, the pregnancy was a protector factor. CONCLUSION: The research for factors allows not only to explain the appearance of this infection but also, and especially, to establish a disease prevention to avoid their second offense or, at best their arisen in women at risk. PMID- 26644102 TI - [Papillary renal cell carcinoma: clinic and pathological study about 27 cases]. AB - BACKGROUND: Papillary renal cell carcinoma (PRCC) represent 10 to 15% of renal tumours in adults. They contain more than 75% of tubule-papillary structure and are divided histologically into two subtypes. The distinction between these two sub-types is essential because of different prognosis. AIM: To describe the main clinical, radiological, therapeutic and prognostic features of these tumors. A comparative analysis between the two sub histological types was performed. METHODS: This is a retrospective study, from January 2000 to December 2010, concerning 27 patients operated for PRCC. Clinical data was taken from medical observations and radiological analysis was based on CT findings. A second analysis of blades was made in doubtful cases to clarify the histological subtype. RESULTS: PRCC represented 11.3% of renal tumors operated during this period. Mean patients' age was 62 years with a male predominance (sex ratio 3.5). All tumors were unilateral and mean tumor size was 7 cm. There was no clinical or radiological sign suggestive of this histological type. Treatment consisted of radical nephrectomy in 74% of the cases and nephron sparing surgery in 26% of the cases. We found 17 subtype 1 tumors and 10 subtype 2 tumors. The five year overall and disease-free survival rate were, respectively 86% and 90% in type 1 tumors and 57% and 54% in type tumors. CONCLUSION: PRCC is the second most common renal cancer in adults. They have no clinical or radiological specific signs suggesting their diagnosis. The distinction between these two sub histological types is essential as subtype 1 tumors have a better prognosis. PMID- 26644103 TI - [Atypical renal cysts]. AB - BACKGROUND: Atypical renal cysts are suspicious for malignancy. It is hard in some cases to give a sharp radiological diagnosis and propose an appropriate management. AIM: To give the histological results of the operated atypical renal cysts and to establish a correlation between the radiological findings and histological features. METHODS: Between January 2001 and December 2012, 22 patients have been operated in our department for atypical renal cysts. There were 10 type III and 12 type IV Bosniak lesions. We have reported clinical, epidemiological and radiological findings. We have analyzed the histological results taking into consideration the radiological findings. RESULTS: According to histological findings, 7 among the 10 type III lesions were benign (70%). However, only one case of benign tumor was noted in type IV lesions (8.3%). There was no evident correlation between tumors size and histology. With a median follow up of 48 months, three patients died because of locally advanced tumors. CONCLUSION: Management of atypical renal cysts remains difficult. A careful computed tomography staging is essential before treatment. Type III and type IV Bosniak cysts were malign in 30% and 91% of cases, respectively. There was no correlation between tumor size and malignancy. A nephron sparing surgery should be proposed whenever possible. PMID- 26644104 TI - [Predictive factors of recurrence in spontaneous pneumothorax]. AB - BACKGROUND: Spontaneous pneumothorax is usually a benign condition that most often affects young patients. Its most common complication is recurrence. This complication appears to be increased by some factors. AIM: To identify predictors of recurrence in spontaneous pneumothorax through a series of 204 cases. METHODS: A retrospective study of 204 cases of patients hospitalized for spontaneous pneumothorax. 50 patients experienced at least one recurrence. The study of predictors of recurrence is based on the X2 test for the univariate analysis and logistic regression for the multivariate analysis. RESULTS: The average age of our patients was 37 +/- 7.6 years. A male predominance was noted (97.6 %). 80.4% of patients were smokers. Pneumothorax is considered primary in 65.2 % of cases. Fifty patients had at least one recurrence of their pneumothorax. Smoking and the pursuit of tobacco intoxication were the two risk factors for recurrence in our patients. Gender, age, side, importance of pneumothorax and therapeutic means of the first episode as well as the primary or secondary pneumothorax did not influence recurrence. In the multivariate analysis the pursuit of tobacco intoxication was the only predictor factor of recurrence. CONCLUSION: The recurrence is the most common complication of spontaneous pneumothorax. This risk appears to be increased by smoking and the pursuit of tobacco intoxication. Thus smoking cessation could be a simple and effective means to prevent recurrence. PMID- 26644105 TI - [RACAND syndrome: distinct entity or initial presentation of systemic scleroderma]. PMID- 26644106 TI - [A febrile hemiplegia revealing a cerebral tuberculous arteritis]. PMID- 26644107 TI - Groove pancreatitis with duodenal stenosis: A case report. PMID- 26644108 TI - Intra-abdominal testicular torsion simulating an acute appendicitis. PMID- 26644109 TI - [Complex visual hallucinations secondary to corneal transplant: The Charles Bonnet syndrome]. PMID- 26644110 TI - An exceptional localization of a rare tumor: primary sarcomatoid carcinoma of the mediastinum. PMID- 26644111 TI - [A rare cause of a tumoral swelling of the breast: Breast tuberculosis]. PMID- 26644112 TI - Hemophagocytic syndrome associated to a Hodgkin lymphoma. PMID- 26644113 TI - [Xeroderma pigmentosum. About 2 Mauritanian cases]. PMID- 26644114 TI - Computerized physician order entry of a sedation protocol is not associated with improved sedation practice or outcomes in critically ill patients. AB - BACKGROUND: Computerized Physician Order Entry (CPOE) analgesia-sedation protocols may improve sedation practice and patients' outcomes. We aimed to evaluate the impact of the introduction of CPOE protocol. METHODS: This was a prospective, observational cohort study of adult patients receiving mechanical ventilation, requiring intravenous infusion of analgesics and/or sedatives, and expected to stay in the intensive care unit (ICU) >=24 h. As a quality improvement project, the study had three phases: phase 1, no protocol, July 1st to September 30th, 2010; phase 2, post implementation of CPOE protocol, October 1st to December 31st, 2010; and phase 3, revised (age, kidney and liver function adjusted) CPOE protocol, August 1st to October 31st, 2011. Multivariate analyses were performed to determine the independent predictors of mortality. RESULTS: Two hundred seventy nine patients were included (no protocol = 91, CPOE protocol = 97, revised CPOE protocol = 91). Implementation of CPOE protocol was associated with increase of the average daily dose of fentanyl (3720 +/- 3286 vs. 2647 +/- 2212 mcg/day; p = 0.009) and decrease of hospital length of stay (40 +/- 37 vs. 63 +/- 85 days, p = 0.02). The revised CPOE protocol was associated with, compared to the CPOE protocol, a decrease of the average daily dose of fentanyl (2208 +/- 2115 vs. 3720 +/- 3286 mcg/day, p = 0.0002) and lorazepam (0 +/- 0 vs. 0.06 +/- 0.26 mg/day, p = 0.04), sedation-related complications during ICU stay (3.3 % vs. 29.9 %, p <0.0001), and ICU mortality (18 % vs. 39 %, p = 0.001). The impact of the revised CPOE protocol was more evident on patients aged >70 years or with severe kidney or liver impairment. Both the original CPOE protocol and the revised CPOE protocol were not independent predictors of ICU (adjusted odds ratio [aOR] = 1.85, confidence interval [CI] = 0.90-3.78; p = 0.09; aOR = 0.70, CI = 0.32-1.53, p = 0.37; respectively) or hospital mortality (aOR = 1.12, CI = 0.57-2.21, p = 0.74; aOR = 0.80, CI = 0.40-1.59, p = 0.52; respectively). CONCLUSIONS: The implementation of a CPOE analgesia-sedation protocol was not associated with improved sedation practices or patients' outcome but with unpredicted increases of an analgesic dose. However, the revised CPOE protocol (age, kidney and liver function adjusted) was associated with improved sedation practices. This study highlights the importance of carefully evaluating the impact of changes in practice to detect unanticipated outcomes. PMID- 26644116 TI - "Waste not, want not", or the cost of doing the wrong thing. PMID- 26644115 TI - Does targeted cognitive training reduce educational disparities in cognitive function among cognitively normal older adults? AB - OBJECTIVE: The aim of this study was to investigate educational differences in treatment responses to memory, reasoning, and speed of processing cognitive training relative to no-contact control. METHODS: Secondary analyses of the Advanced Cognitive Training for Independent and Vital Elderly trial were conducted. Two thousand eight hundred older adults were randomized to memory, reasoning, or speed of processing training or no-contact control. A repeated measures mixed-effects model was used to investigate immediate post-training and 1-year outcomes with sensitivity analyses out to 10 years. Outcomes were as follows: (1) memory composite of Hopkins Verbal Learning Test, Rey Auditory Verbal Learning Test, and Rivermead Behavioral Memory Test; (2) reasoning composite of letter series, letter sets, and word series; and (3) speed of processing measured using three trials of useful field of view and the digit symbol substitution test. RESULTS: The effects of reasoning and memory training did not differ by educational attainment. The effect of speed of processing training did. Those with fewer than 12 years of education experienced a 50% greater effect on the useful field of view test compared with those with 16 or more years of education. The training advantage for those with fewer than 12 years of education was maintained to 3 years post-training. CONCLUSION: Older adults with less than a secondary education are at elevated risk of dementia, including Alzheimer's disease. The analyses here indicate that speed of processing training is effective in older adults with low educational attainment. PMID- 26644117 TI - Cerebral reactivity in migraine patients measured with functional near-infrared spectroscopy. AB - BACKGROUND: There are two major theories describing the pathophysiology of migraines. Vascular theory explains that migraines resulted from vasodilation of meningeal vessels irritating the trigeminal nerves and causing pain. More recently, a neural theory of migraine has been proposed, which suggests that cortical hyperexcitability leads to cortical spreading depression (CSD) causing migraine-like symptoms. Chronic migraine requires prophylactic therapy. When oral agents fail, there are several intravenous agents that can be used. Understanding underlying causes of migraine pain would help to improve efficacy of migraine medications by changing their mechanism of action. Yet to date no study has been made to investigate the link between vascular changes in response to medications for migraine versus pain improvements. Functional near-infrared spectroscopy (NIRS) has been used as an inexpensive, rapid, non-invasive and safe technique to monitor cerebrovascular dynamics. METHOD: In this study, a multi-distance near infrared spectroscopy device has been used to investigate the cortical vascular reactivity of migraine patients in response to drug infusions and its possible correlation with changes in pain experienced. We used the NIRS on 41 chronic migraine patients receiving three medications: magnesium sulfate, valproate sodium, and dihydroergotamine (DHE). Patients rated their pain on a 1-10 numerical scale before and after the infusion. RESULTS: No significant differences were observed between the medication effects on vascular activity from near channels measuring skin vascularity. However, far channels--indicating cortical vascular activity--showed significant differences in both oxyhemoglobin and total hemoglobin between medications. DHE is a vasoconstrictor and decreased cortical blood volume in our experiment. Magnesium sulfate has a short-lived vasodilatory effect and increased cortical blood volume in our experiment. Valproate sodium had no significant effect on blood volume. Nonetheless, all three reduced patients' pain based on self-report and no significant link was observed between changes in cortical vascular reactivity and improvement in migraine pain as predicted by the vascular theory of migraine. CONCLUSION: NIRS showed the potential to be a useful tool in the clinical setting for monitoring the vascular reactivity of individual patients to various migraine and headache medications. PMID- 26644118 TI - Bisphosphonates and evidence for association with esophageal and gastric cancer: a systematic review and meta-analysis. AB - OBJECTIVES: Concerns have been raised about a possible link between bisphosphonate use, and in particular alendronate, and upper gastrointestinal (UGI) cancer. A number of epidemiological studies have been published with conflicting results. We conducted a systematic review and meta-analysis of observational studies, to determine the risk of esophageal and gastric cancer in users of bisphosphonates compared with non-users. DESIGN: We searched PubMed, MEDLINE, EMBASE, Web of Knowledge and Cochrane Database of Systematic Reviews for studies investigating bisphosphonates and esophageal or gastric cancer. We calculated pooled ORs and 95% CIs for the risk of esophageal or gastric cancer in bisphosphonate users compared with non-users. We performed a sensitivity analysis of alendronate as this was the most common single drug studied and is also the most widely used in clinical practice. RESULTS: 11 studies (from 10 papers) examining bisphosphonate exposure and UGI cancer (gastric and esophageal), met our inclusion criteria. All studies were retrospective, 6/11 (55%) case-control and 5/11(45%) cohort, and carried out using data from 5 longitudinal clinical databases. Combining 5 studies (1 from each database), we found no increased risk, OR 1.11 (95% CI 0.97 to 1.27) of esophageal cancer in bisphosphonate users compared with non-users and no increased risk of gastric cancer in bisphosphonate users, OR 0.96 (95% CI 0.82 to 1.12). CONCLUSION: This is the fourth and most detailed meta-analysis on this topic. We have not identified any compelling evidence for a significantly raised risk of esophageal cancer or gastric cancer in male and female patients prescribed bisphosphonates. PMID- 26644119 TI - Epidemiology, quality and reporting characteristics of meta-analyses of observational studies published in Chinese journals. AB - OBJECTIVE: The aim of this study was to examine the epidemiological and reporting characteristics as well as the methodological quality of meta-analyses (MAs) of observational studies published in Chinese journals. METHODS: 5 Chinese databases were searched for MAs of observational studies published from January 1978 to May 2014. Data were extracted into Excel spreadsheets, and Meta-analysis of Observational Studies in Epidemiology (MOOSE) and Assessment of Multiple Systematic Reviews (AMSTAR) checklists were used to assess reporting characteristics and methodological quality, respectively. RESULTS: A total of 607 MAs were included. Only 52.2% of the MAs assessed the quality of the included primary studies, and the retrieval information was not comprehensive in more than half (85.8%) of the MAs. In addition, 50 (8.2%) MAs did not search any Chinese databases, while 126 (20.8%) studies did not search any English databases. Approximately 41.2% of the MAs did not describe the statistical methods in sufficient details, and most (95.5%) MAs did not report on conflicts of interest. However, compared with the before publication of the MOOSE Checklist, the quality of reporting improved significantly for 20 subitems after publication of the MOOSE Checklist, and 7 items of the included MAs demonstrated significant improvement after publication of the AMSTAR Checklist (p<0.05). CONCLUSIONS: Although many MAs of observational studies have been published in Chinese journals, the reporting quality is questionable. Thus, there is an urgent need to increase the use of reporting guidelines and methodological tools in China; we recommend that Chinese journals adopt the MOOSE and AMSTAR criteria. PMID- 26644121 TI - Do shorter delays to care and mental health system renewal translate into better occupational outcome after mental disorder diagnosis in a cohort of Canadian military personnel who returned from an Afghanistan deployment? AB - OBJECTIVE: Mental disorders in military personnel result in high rates of attrition. Military organisations have strengthened their mental health systems and attempted to overcome barriers to care in order to see better outcomes. This study investigated the roles of mental health services renewal and delay to care in Canadian Armed Forces (CAF) personnel diagnosed with mental disorders. DESIGN: Administrative data were used to identify a retrospective cohort of 30,513 CAF personnel who deployed in support of the mission in Afghanistan. Study participants included 508 individuals with a mental disorder diagnosis identified from CAF medical records of a weighted, stratified random sample of 2014 individuals selected from the study cohort. Weighted Cox proportional hazards regression assessed the association of diagnosis era and delay to care with the outcome, after controlling for a broad range of potential confounders (eg, disorder severity, comorbidity). Taylor series linearisation methods and sample design weights were applied in generating descriptive and regression analysis statistics. PRIMARY OUTCOME: The outcome was release from military service for medical reasons, assessed using administrative data for the 508 individuals with a mental disorder diagnosis. RESULTS: 17.5% (95% CI 16.0% to 19.0%) of the cohort had a mental disorder diagnosis after an Afghanistan-related deployment, of which 21.3% (95% CI 17.2% to 25.5%) had a medical release over a median follow-up of 3.5 years. Medical release risk was elevated for individuals diagnosed before 30 April 2008 relative to those with recent diagnoses (adjusted HR (aHR)=1.77 (95% CI 1.01 to 3.11)) and for individuals with a long delay to care (>21 months after return) relative to those with intermediate delays (8-21 months, aHR 2.47=(95% CI 1.28 to 4.76)). CONCLUSIONS: Mental health services renewal in the CAF was associated with a better occupational outcome for those diagnosed with mental disorders. Longer delays to care were associated with a less favourable outcome. PMID- 26644120 TI - Evaluation of actigraphy-measured sleep patterns among children with disabilities and associations with caregivers' educational attainment: results from a cross sectional study. AB - OBJECTIVES: To use wrist-actrigrphy to collect objective measures of sleep and to characterise actigraphy-measured sleep patterns among children with disabilities. We also assessed the extent to which, if at all, caregivers' education is associated with children's sleep disturbances. DESIGN: Cross-sectional study. SETTING: A rehabilitation centre in the Patagonia region, Chile. METHODS: This study was conducted among 125 children aged 6-12 years with disabilities (boys: 55.2%) and their primary caregivers in Chile. Children wore ActiSleep monitors for 7 days. A general linear model was fitted to generate least-square means and SEs of sleep efficiency (proportion of the sleep period spent asleep) across caregivers' education levels adjusting for children's age, sex, disability type, caregiver-child relationship and caregivers' age. Multivariable logistic regression analyses were conducted to estimate ORs and 95% CIs of longer sleep latency (>= 30 min) and longer wake after sleep onset (WASO) (>= 90 min) (a measure of sleep fragmentation) in relation to caregivers' educational attainment. RESULTS: Median sleep latency was 27.3 min, WASO 88.1 min and sleep duration 8.0 h. Mean sleep efficiency was 80.0%. Caregivers' education was positively and significantly associated with children's sleep efficiency (p trend<0.001). Adjusted mean sleep efficiency was 75.7% (SE=1.4) among children of caregivers high school education. Compared to children whose caregivers had >high school, children of caregivers with 2.5-fold increase in risk of PTC diagnosis among insured individuals associated with high SES may be informative with respect to the contemporary issue of PTC overdiagnosis. PMID- 26644128 TI - Deepening our Understanding of Quality in Australia (DUQuA): a study protocol for a nationwide, multilevel analysis of relationships between hospital quality management systems and patient factors. AB - INTRODUCTION: Despite the growing body of research on quality and safety in healthcare, there is little evidence of the association between the way hospitals are organised for quality and patient factors, limiting our understanding of how to effect large-scale change. The 'Deepening our Understanding of Quality in Australia' (DUQuA) study aims to measure and examine relationships between (1) organisation and department-level quality management systems (QMS), clinician leadership and culture, and (2) clinical treatment processes, clinical outcomes and patient-reported perceptions of care within Australian hospitals. METHODS AND ANALYSIS: The DUQuA project is a national, multilevel, cross-sectional study with data collection at organisation (hospital), department, professional and patient levels. Sample size calculations indicate a minimum of 43 hospitals are required to adequately power the study. To allow for rejection and attrition, 70 hospitals across all Australian jurisdictions that meet the inclusion criteria will be invited to participate. Participants will consist of hospital quality management professionals; clinicians; and patients with stroke, acute myocardial infarction and hip fracture. Organisation and department-level QMS, clinician leadership and culture, patient perceptions of safety, clinical treatment processes, and patient outcomes will be assessed using validated, evidence-based or consensus-based measurement tools. Data analysis will consist of simple correlations, linear and logistic regression and multilevel modelling. Multilevel modelling methods will enable identification of the amount of variation in outcomes attributed to the hospital and department levels, and the factors contributing to this variation. ETHICS AND DISSEMINATION: Ethical approval has been obtained. Results will be disseminated to individual hospitals in de-identified national and international benchmarking reports with data-driven recommendations. This ground-breaking national study has the potential to influence decision-making on the implementation of quality and safety systems and processes in Australian and international hospitals. PMID- 26644127 TI - Early childhood constraint therapy for sensory/motor impairment in cerebral palsy: a randomised clinical trial protocol. AB - INTRODUCTION: Cerebral palsy (CP) is the most common physical disability in childhood. It is a disorder resulting from sensory and motor impairments due to perinatal brain injury, with lifetime consequences that range from poor adaptive and social function to communication and emotional disturbances. Infants with CP have a fundamental disadvantage in recovering motor function: they do not receive accurate sensory feedback from their movements, leading to developmental disregard. Constraint-induced movement therapy (CIMT) is one of the few effective neurorehabilitative strategies shown to improve upper extremity motor function in adults and older children with CP, potentially overcoming developmental disregard. METHODS AND ANALYSIS: This study is a randomised controlled trial of children 12-24 months corrected age studying the effectiveness of CIMT combined with motor and sensory-motor interventions. The study population will comprise 72 children with CP and 144 typically developing children for a total of N=216 children. All children with CP, regardless of group allocation will continue with their standard of care occupational and physical therapy throughout the study. The research material collected will be in the form of data from high-density array event-related potential scan, standardised assessment scores and motion analysis scores. ETHICS AND DISSEMINATION: The study protocol was approved by the Institutional Review Board. The findings of the trial will be disseminated through peer-reviewed journals and scientific conferences. TRIAL REGISTRATION NUMBER: NCT02567630. PMID- 26644129 TI - A STRIPAK component Strip regulates neuronal morphogenesis by affecting microtubule stability. AB - During neural development, regulation of microtubule stability is essential for proper morphogenesis of neurons. Recently, the striatin-interacting phosphatase and kinase (STRIPAK) complex was revealed to be involved in diverse cellular processes. However, there is little evidence that STRIPAK components regulate microtubule dynamics, especially in vivo. Here, we show that one of the core STRIPAK components, Strip, is required for microtubule organization during neuronal morphogenesis. Knockdown of Strip causes a decrease in the level of acetylated alpha-tubulin in Drosophila S2 cells, suggesting that Strip influences the stability of microtubules. We also found that Strip physically and genetically interacts with tubulin folding cofactor D (TBCD), an essential regulator of alpha- and beta-tubulin heterodimers. Furthermore, we demonstrate the genetic interaction between strip and Down syndrome cell adhesion molecule (Dscam), a cell surface molecule that is known to work with TBCD. Thus, we propose that Strip regulates neuronal morphogenesis by affecting microtubule stability. PMID- 26644131 TI - Self-referrals in the emergency department: reasons why patients attend the emergency department without consulting a general practitioner first-a questionnaire study. AB - BACKGROUND: To influence self-referral, it is crucial to know a patient's motives to directly visit the emergency department (ED). The goal of this study is to examine motives for self-referral to the ED and compare these motives in relation to appropriateness. METHODS: All self-referred patients visiting the ED of a Dutch hospital over four separate months in a 1-year period were included. Patients were handed questionnaires that included questions on their reasons to visit the ED directly and where they would seek medical help next time. Additionally, the motives of patients that either appropriately or inappropriately visited the ED were compared. In a previous study on the same patient cohort, the appropriateness of the ED visits was determined using predefined criteria. RESULTS: A total of 3196 self-referred patients were included, and 48.9 % completed the questionnaires. The majority of patients (28.0 %) attended the ED without a referral because they thought they would get help faster; the next reason was the easier access to radiologic and laboratory investigations (answered by 23.8 %); and the third was the symptoms were considered too severe to visit a general practitioner (GP) (answered by 22.7 %). The majority (78.5 %) would attend the ED the next time they are faced with similar symptoms. Appropriate visits were significantly more seen in females, elderly, and patients in higher triage categories. Patients who expect investigations are necessary, think their symptoms are too severe to visit a GP, or would return to the ED next time were more often appropriately visiting the ED. CONCLUSIONS: The choice of patients to self-refer to an ED is often an explicate decision. Patients are looking for specialist help and want fast and easy access to radiologic and laboratory investigations. Even though the primary care network is well developed in the Netherlands, the reasons for self-referral are similar to the reasons found in previous literature based in other countries. Patients who visit the ED because of health concerns visit the ED more often appropriately than patients visiting for practical reasons. PMID- 26644130 TI - Efficacy of single-dose dexamethasone implantation in patients with persistent diabetic macular edema. AB - To investigate the efficacy of single-dose intravitreal dexamethasone implantation in the treatment of persistent diabetic macular edema (DME) unresponsive to 3 consecutive ranibizumab injections over a period of 6 months. Forty-one patients with a previous history of treatment for DME including at least three consecutive intravitreal ranibizumab injections were enrolled in this retrospective study. Main outcome measures were change in best-corrected visual acuity (BCVA), central macular thickness (CMT), and intraocular pressure from baseline to 6th month. At the baseline, the mean CMT was 572.4 +/- 123.1 MUm which improved to 264.2 +/- 114.4, 317.7 +/- 141.7, 410.6 +/- 169.1, and 382.8 +/ 181.5 MUm at the 1st, 3rd, 5th, and 6th month, respectively (p < 0.05). The preoperative mean BCVA was 0.85 +/- 0.54 logMAR units which improved to 0.76 +/- 0.5 (p = 0.08), 0.69 +/- 0.4 (p = 0.02), 0.74 +/- 0.4 (p = 0.284), and 0.72 +/- 0.3 (p = 0.489) logMAR units at the 1st, 3rd, 5th, and 6th months, respectively. Additional injections were required for 13 (31 %) eyes at 3rd month and 14 (34 %) eyes at 5th month due to recurrence of macular edema. Intravitreal dexamethasone implantation caused a significant improvement of BCVA and reduction of CMT in the patients with persistent DME that were unresponsive to 3 consecutive ranibizumab injections. However, retreatment before 6 months in the majority of the patients was needed despite the beneficial effects after the index procedure. PMID- 26644132 TI - Feasibility and initial efficacy of a culturally sensitive women-centered substance use intervention in Georgia: Sex risk outcomes. AB - BACKGROUND: This paper reports on the feasibility and initial efficacy of a culturally sensitive, comprehensive women-centered substance use intervention for women who inject drugs in Georgia in terms of the primary and secondary sex risk outcomes. The hypothesis under examination was that, relative to case management participants, participants in a culturally sensitive, comprehensive women specific and -centered intervention would, on average, show significant decreases in past-30-day frequency of unprotected sex, unprotected sex at the last sexual encounter, and increases in condom use and safer sex actions. METHODS: The study was a two-arm randomized trial, in which 173 potentially eligible women were screened, and those 128 women determined to be eligible were assigned at random to either Reinforcement-based Treatment plus Women's Co-Op (RBT + WC) or case management (CM). RBT + WC participants received 12 sessions of a structured intervention with the goal of reducing risky sex and substance use and improving physical and mental health. CM participants received 12 sessions of case management and informational brochures that focused on the same issues on which RBT + WC focused. Participants were assessed at baseline, post-treatment, and 3 months following treatment enrollment. RESULTS: Analyses revealed case management having significantly overall higher Safer Sex action scores than RBT + WC, and a significant decrease over time for past 30-day number of unprotected sex acts. Unprotected sex at the last encounter and Condom Use action scores were nonsignificant. CONCLUSIONS: Women who inject drugs in Georgia are engaging in risky sexual practices, and are in need of an intervention that addresses these risky behaviors. Reasons for the failure to find differences between a culturally sensitive, comprehensive women-centered intervention and case management tailored to the needs of women who inject drugs in Georgia may have been the result of inadequate power to detect an effect in a sample whose drug use was not as serious as warranted by the intervention. (ClinicalTrials.gov Identifier: NCT01331460 ). PMID- 26644133 TI - Fluorescence/luminescence-based markers for the assessment of Schistosoma mansoni schistosomula drug assays. AB - BACKGROUND: Schistosomiasis is responsible for a tremendous public health burden, yet only a single drug, praziquantel, is available. New antischistosomal treatments should therefore be developed. The accuracy, speed and objectivity of in vitro drug screening depend on the assay read-out. Microscopy is still the current gold standard and is in need of updating to an automated format. The aim of the present study was to investigate a panel of fluorescence/luminescence dyes for their applicability as viability markers in drug sensitivity assays for Schistosoma mansoni schistosomula. METHODS: A search for available viability and cytotoxicity marker assays and dyes was carried out and a short-list of the most interesting candidates was created. The selected kits and dyes were tested on S. mansoni Newly Transformed Schistosomula (NTS), first to assess whether they correlate with parasite viability, with comparatively low background noise, and to optimise assay conditions. Markers fulfilling these criteria were then tested in a dose-response drug assay using standard and experimental drugs and those for which an IC50 value could be accurately and reproducibly calculated were also tested on a subset of a compound library to determine their hit-identification accuracy. RESULTS: Of the 11 markers selected for testing, resazurin, Vybrant(r) and CellTiter-Glo(r) correlated best with NTS viability, produced signals >= 3 fold stronger than background noise and revealed a significant signal-to-NTS concentration relationship. Of these, CellTiter-Glo(r) could be used to accurately determine IC50 values for antischistosomals. Use of CellTiter-Glo(r) in a compound subset screen identified 100% of hits that were identified using standard microscopic evaluation. CONCLUSION: This study presents a comprehensive overview of the utility of colorimetric markers in drug screening. Our study demonstrates that it is difficult to develop a simple, cheap "just add" colorimetric marker-based drug assay for the larval stage of S. mansoni. CellTiter-Glo(r) can likely be used for endpoint go/no go screens and potentially for drug dose-response studies. PMID- 26644134 TI - Burden attributable to Cardiometabolic Diseases in Zimbabwe: a retrospective cross-sectional study of national mortality data. AB - BACKGROUND: Cardiometabolic diseases (CMDs) are an important cause of mortality worldwide and the burden associated with them is increasing in Sub-Saharan Africa. The tracking of mortality helps support evidence based health policy and priority setting. Given the growing prevalence of non-communicable diseases in Zimbabwe, a study was designed to determine the mortality attributable to CMDs in Zimbabwe. METHODS: The study design was a retrospective cross-sectional analysis of national mortality from 1996 to 2007, collated by the Ministry of Health and Child Welfare in Zimbabwe. We employed generalized additive models to flexibly estimate the trend of the CMD mortality and a logistic regression model was used to find significant factors (cause of death according to the death certificate) of the CMD mortality and predict CMD mortality to 2040. RESULTS: CMDs accounted for 8.13% (95% CI: 8.08% - 8.18%) of all deaths during 1996 to 2007 (p = 0.005). During the study period CMD mortality rate increased by 29.4% (95% CI: 19.9% - 41.1%). The association between gender and CMD mortality indicated female mortality was higher for diabetes (p < 0.001), hypertensive disease (p < 0.001), CVD (p < 0.001) and pulmonary disease (p < 0.001), while male mortality was higher for ischaemic (p = 0.010) and urinary diseases (p < 0.001). There was no gender difference for endocrine disease (p = 0.893). Overall, females have 1.65% higher mortality than males (p < 0.001). CMD mortality is predicted to increase from 9.6 (95% CI: 8.0% - 11.1%) in 2015 to 13.7% (95% CI: 10.2% - 17.2%) in 2040 for males, and from 11.6% (95% CI: 10.2% - 12.9%) in 2015 to 16.2% (95% CI: 13.1% - 19.3%) in 2040 in females. CONCLUSION: The findings of this study indicate a growing prevalence of CMDs and related mortality in Zimbabwe. Health policy decisions and cost-effective preventive strategies to reduce the burden of CMDs are urgently required. PMID- 26644135 TI - Fungi with multifunctional lifestyles: endophytic insect pathogenic fungi. AB - This review examines the symbiotic, evolutionary, proteomic and genetic basis for a group of fungi that occupy a specialized niche as insect pathogens as well as endophytes. We focus primarily on species in the genera Metarhizium and Beauveria, traditionally recognized as insect pathogenic fungi but are also found as plant symbionts. Phylogenetic evidence suggests that these fungi are more closely related to grass endophytes and diverged from that lineage ca. 100 MYA. We explore how the dual life cycles of these fungi as insect pathogens and endophytes are coupled. We discuss the evolution of insect pathogenesis while maintaining an endophytic lifestyle and provide examples of genes that may be involved in the transition toward insect pathogenicity. That is, some genes for insect pathogenesis may have been co-opted from genes involved in endophytic colonization. Other genes may be multifunctional and serve in both lifestyle capacities. We suggest that their evolution as insect pathogens allowed them to effectively barter a specialized nitrogen source (i.e. insects) with host plants for photosynthate. These ubiquitous fungi may play an important role as plant growth promoters and have a potential reservoir of secondary metabolites. PMID- 26644136 TI - Excessive alcohol consumption increases mortality in later life: a genetic analysis of the health in men cohort study. AB - We designed this cohort study of men aged 70-89 years to determine if excessive alcohol use increases mortality. They reported history of alcohol use (never, past, <= two daily drinks, two to four daily drinks, four to six daily drinks, > six daily drinks) and donated a blood sample in 2001-2004. We determined the ADH1B rs1229984 G>A polymorphism and retrieved mortality data from the Western Australian Data Linkage System. Other study measures included age, education, body mass index, smoking, and history of hypertension, diabetes, chronic respiratory diseases, coronary heart disease and stroke. Of the 3496 participants, 225 (6.4 percent) carried the ADH1B rs1229984 G>A polymorphism. Carriers consumed significantly less alcohol than non-carriers. The adjusted mortality hazard ratio (MHR, 95 percent confidence interval-95%CI) over 8.0 years (range: 10 weeks to 11.2 years) relative to never drinkers was 1.15 (95%CI = 0.86, 1.55) for past drinkers, 0.98 (95%CI = 0.76, 1.25) for men consuming <= two daily drinks, 1.13 (95%CI = 0.85, 1.49) for two to four drinks, 1.18 (95%CI = 0.81, 1.71) for four to six drinks and 1.87 (95%CI = 1.11, 3.12) for those consuming more than six daily drinks on a regular basis. The MHR associated with the ADH1B rs1229984 G>A polymorphism was 0.68 (95%CI = 0.54, 0.87). Excessive alcohol use in later life is associated with increased mortality, and this association is likely to be causal. We found no evidence that light to moderate alcohol use decreases the mortality of older men. Health messages regarding the safe use of alcohol in older age may benefit from taking these findings into account. PMID- 26644137 TI - Unhealthy alcohol use in older adults: Association with readmissions and emergency department use in the 30 days after hospital discharge. AB - BACKGROUND: Unhealthy alcohol use could impair recovery of older patients after medical or surgical hospitalizations. However, no prior research has evaluated whether older patients who screen positive for unhealthy alcohol use are at increased risk of readmissions or emergency department (ED) visits within 30 days after discharge. This study examined the association between AUDIT-C alcohol screening results and 30-day readmissions or ED visits. METHODS: Veterans Affairs (VA) patients age 65 years or older, were eligible if they were hospitalized for a medical or surgical condition (2/1/2009-10/1/2011) and had an AUDIT-C score documented in their VA electronic medical record in the year before they were hospitalized. VA and Medicare data identified VA or non-VA index hospitalizations, readmissions, and ED visits. Primary analyses adjusted for demographics, comorbid conditions, and past-year health care utilization. RESULTS: Among 579,330 hospitalized patients, 13.7% were readmitted and 12.0% visited an ED within 30 days of discharge. In primary analyses, high-risk drinking (n=7,167) and nondrinking (n=357,086) were associated with increased probability of readmission (13.8%, 95% CI 13.0-14.6%; and 14.2%, 95% CI 14.1 14.3%, respectively), relative to low-risk drinking (12.9%; 95% CI 12.7-13.0%). Only nondrinkers had increased risk for ED visits. CONCLUSIONS: Alcohol screening results indicating high-risk drinking that were available in medical records were modestly associated with risk for 30-day readmissions and were not associated with risk for ED visits. PMID- 26644138 TI - Variation in CYP2A6 and tobacco dependence throughout adolescence and in young adult smokers. AB - BACKGROUND: Smoking is influenced by genetic factors including variation in CYP2A6 and CYP2B6, which encode nicotine-metabolizing enzymes. In early adolescence, CYP2A6 slow nicotine metabolism was associated with higher dependence acquisition, but reduced cigarette consumption. Here we extend this work by examining associations of CYP2A6 and CYP2B6 with tobacco dependence acquisition in a larger sample of smokers followed throughout adolescence. METHODS: White participants from the Nicotine Dependence in Teens cohort that had ever inhaled (n=421) were followed frequently from age 12-18 years. Cox's proportional hazards models compared the risk of ICD-10 tobacco dependence acquisition (score 3+) for CYP2A6 and CYP2B6 metabolism groups. Early smoking experiences, as well as amount smoked at end of follow-up, was also computed. At age 24 (N=162), we assessed concordance between self-reported cigarette consumption and salivary cotinine. RESULTS: In those who initiated inhalation during follow-up, CYP2A6 slow (vs. normal) metabolizers were at greater risk of dependence (hazards ratio (HR)=2.3; 95% CI=1.1, 4.8); CYP2B6 slow (vs. normal) metabolizers had non-significantly greater risk (HR=1.5; 95% CI=0.8, 2.6). Variation in CYP2A6 or CYP2B6 was not significantly associated with early smoking symptoms or cigarette consumption at end of follow-up. At age 24, neither gene was significantly associated with dependence status. Self-reported consumption was associated with salivary cotinine, a biomarker of tobacco exposure, acquired at age 24 (B=0.37; P<0.001). CONCLUSIONS: Our findings extend previous work indicating that slow nicotine metabolism mediated by CYP2A6, and perhaps CYP2B6, increases risk for tobacco dependence throughout adolescence. PMID- 26644139 TI - "TAARgeting Addiction"--The Alamo Bears Witness to Another Revolution: An Overview of the Plenary Symposium of the 2015 Behavior, Biology and Chemistry Conference. AB - BACKGROUND: In keeping with the free-thinking tradition San Antonians are known for, the Scientific Program Committee of the Behavior, Biology and Chemistry: Translational Research in Addiction Conference chose trace amine-associated receptor 1 (TAAR1) as the focus of the plenary symposium for its 7th annual meeting held at the University of Texas Health Science Center at San Antonio on March 14 and 15, 2015. The timing of the meeting's plenary session on TAAR1 coincided with the Ides of March, an apt concurrence given the long association of this date with the overthrow of the status quo. And whether aware of the coincidence or not, those in attendance witnessed the plunging of the metaphorical dagger into the heart of the dopamine (DA) transporter (DAT)-centric view of psychostimulant action. METHODS: The symposium's four plenary presentations focused on the molecular and cellular biology, genetics, medicinal chemistry and behavioral pharmacology of the TAAR1 system and the experimental use of newly developed selective TAAR1 ligands. RESULTS: The consensus was that TAAR1 is a DA and methamphetamine receptor, interacts with DAT and DA D2 receptors, and is essential in modulating addiction-related effects of psychostimulants. CONCLUSIONS: Collectively the findings presented during the symposium constitute a significant challenge to the current view that psychostimulants such as methamphetamine and amphetamine solely target DAT to interfere with normal DA signaling and provide a novel conceptual framework from which a more complete understanding of the molecular mechanisms underlying the actions of DA and METH is likely to emerge. PMID- 26644141 TI - Preparing the next generation of health care providers: A description and comparison of nurse practitioner and medical student tuition in 2015. AB - BACKGROUND AND PURPOSE: The purpose of this study was twofold: to describe the average cost of nurse practitioner (NP) tuition based on degree program, program type, and geography; and to compare the cost of NP tuition to medical school tuition. METHODS: A listing of all NP degree granting universities was obtained from the American Association of Colleges of Nursing during the fall of 2014, and tuition data were obtained from university websites. Medical school tuition data were obtained online during the fall of 2014 from the American Association of Medical Colleges. Average 1-year tuition rates were calculated for NP programs and medical schools and compared across private and public institutions. CONCLUSIONS: Average 1-year resident tuition for public university NP programs ranges between $8671 and $11,077 based on type of program. The cost of 1-year NP program tuition at the master's and the doctoral level is much lower than the cost of 1-year medical school tuition at both private and public universities. IMPLICATIONS FOR PRACTICE: NPs can perform many of the same services as physicians in the primary care setting with comparable outcomes, yet the cost of educating NPs is much lower. NPs are a cost-effective solution to the healthcare workforce shortage. PMID- 26644140 TI - Improving performance of the Tariff Method for assigning causes of death to verbal autopsies. AB - BACKGROUND: Reliable data on the distribution of causes of death (COD) in a population are fundamental to good public health practice. In the absence of comprehensive medical certification of deaths, the only feasible way to collect essential mortality data is verbal autopsy (VA). The Tariff Method was developed by the Population Health Metrics Research Consortium (PHMRC) to ascertain COD from VA information. Given its potential for improving information about COD, there is interest in refining the method. We describe the further development of the Tariff Method. METHODS: This study uses data from the PHMRC and the National Health and Medical Research Council (NHMRC) of Australia studies. Gold standard clinical diagnostic criteria for hospital deaths were specified for a target cause list. VAs were collected from families using the PHMRC verbal autopsy instrument including health care experience (HCE). The original Tariff Method (Tariff 1.0) was trained using the validated PHMRC database for which VAs had been collected for deaths with hospital records fulfilling the gold standard criteria (validated VAs). In this study, the performance of Tariff 1.0 was tested using VAs from household surveys (community VAs) collected for the PHMRC and NHMRC studies. We then corrected the model to account for the previous observed biases of the model, and Tariff 2.0 was developed. The performance of Tariff 2.0 was measured at individual and population levels using the validated PHMRC database. RESULTS: For median chance-corrected concordance (CCC) and mean cause specific mortality fraction (CSMF) accuracy, and for each of three modules with and without HCE, Tariff 2.0 performs significantly better than the Tariff 1.0, especially in children and neonates. Improvement in CSMF accuracy with HCE was 2.5%, 7.4%, and 14.9% for adults, children, and neonates, respectively, and for median CCC with HCE it was 6.0%, 13.5%, and 21.2%, respectively. Similar levels of improvement are seen in analyses without HCE. CONCLUSIONS: Tariff 2.0 addresses the main shortcomings of the application of the Tariff Method to analyze data from VAs in community settings. It provides an estimation of COD from VAs with better performance at the individual and population level than the previous version of this method, and it is publicly available for use. PMID- 26644142 TI - The complete mitochondrial genome sequence of Gloydius shedaoensis (Squamata: Viperidae). AB - Gloydius shedaoensis is an insular and vulnerable pitviper that is endemic to Snake Island, northeastern China. In this study, we successfully sequenced mitochondrial genomes of two individuals of G. shedaoensis. The complete mitochondrial genomes of G. shedaoensis are circular molecular with 17 222 and 17 221 bp in length respectively, which both contain 2 ribosomal RNA (rRNA) genes, 13 protein-coding genes, 22 transfer RNA (tRNA) genes, an origin of light-strand replication (OL) and two non-coding control regions. Compared with previously published mitochondrial genomes of Gloydius species, the base composition and gene arrangement are rather conservative. A Bayesian phylogenetic tree using the complete mitochondrial genomes of all viper species available showed a consistent result with previous studies. PMID- 26644143 TI - Poly(alanine): Structure and Stability of the D and L-Enantiomers. AB - High-performance, biobased materials can potentially be manufactured from polymerized alpha-amino acids (alpha-polypeptides). This paper reports on the synthesis, structure, and properties of both polyalanine enantiomers (PLAla and PDAla). The molecular structure of the polypeptide chains, their molecular weight, and polydispersity were investigated by (1)H NMR, MALDI-TOF, and size exclusion chromatography. The secondary structure and crystalline order were probed via Fourier transform infrared spectroscopy, circular dichroism, and (synchrotron) wide-angle X-ray diffraction. The phase behavior and thermal stability were assessed by differential scanning calorimetry and thermogravimetric analysis. The kinetically trapped PAla chain conformation in the solid state, after synthesis or solvent treatments, is the alpha-helical shape. Upon heating, crystals from the alpha-helices convert into more stable crystals from beta-sheets at a temperature higher than 210 degrees C. This temperature is close to where polymer degradation sets in. The beta-sheet crystals combine melting with thermal degradation at temperatures above 330 degrees C. In the presence of superheated water, the conversion from alpha helices to beta-sheets happens at lower temperatures, allowing for a conversion without degradation. PMID- 26644144 TI - Good use of fruit wastes: eco-friendly synthesis of silver nanoparticles, characterization, BSA protein binding studies. AB - A simple and eco-friendly methodology for the green synthesis of silver nanoparticles (AgNPs) using a mango seed extract was evaluated. The AgNPs were characterized by ultraviolet-visible spectrophotometry, Fourier transform infrared spectroscopy, transmission electron microscopy, energy dispersive X-ray spectroscopy, and X-ray diffraction. The interaction between the green synthesized AgNPs and bovine serum albumin (BSA) in an aqueous solution at physiological pH was examined by fluorescence spectroscopy. The results confirmed that the AgNPs quenched the fluorophore of BSA by forming a ground state complex in aqueous solution. This fluorescence quenching data were also used to determine the binding sites and binding constants at different temperatures. The calculated thermodynamic parameters (DeltaG degrees , DeltaH degrees and DeltaS degrees ) suggest that the binding process occurs spontaneously through the involvement of electrostatic interactions. The synchronous fluorescence spectra showed a blue shift, indicating increasing hydrophobicity. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26644145 TI - Influence of wound scores and microbiology on the outcome of the diabetic foot syndrome. AB - AIMS: To establish if the microbiology and the TEXAS, PEDIS and Wagner wound classifications of the diabetic foot syndrome (DFS) predict amputation. METHODS: Prospective cohort study of 250 patients with DFS from 2009 to 2013. Tissue samples for culture were obtained and wound classification scores were recorded at admission. RESULTS: Infection was monomicrobial in 131 patients (52%). Staphylococcus aureus was the most frequent pathogen (76 patients, 30%); being methicillin-resistant S. aureus in 26% (20/76) Escherichia coli and Enterobacter faecalis were 2nd and 3rd most frequent pathogens. Two hundred nine patients (85%) needed amputation being major in 25 patients (10%). The three wound scales associated minor amputation but did not predict this outcome. Predictors of minor amputation in the multivariate analysis were the presence of osteomyelitis, the location of the wound in the forefoot and of major amputation elevated C reactive proteine (CRP) levels. A low ankle-brachial index (ABI) predicted major amputation in the follow-up. Overall, 74% of gram-positives were sensitive to quinolones and 98% to vancomycin and 90% of gram-negatives to cefotaxime and 95% to carbapenems. CONCLUSIONS: The presence of osteomyelitis and the location of the wound in the forefoot predict minor amputation and elevated CRP levels predict major amputation. In the follow-up a low ABI predicts major amputation. PMID- 26644146 TI - Who has a repeat abortion? Identifying women at risk of repeated terminations of pregnancy: analysis of routinely collected health care data. AB - BACKGROUND: Repeat termination of pregnancy highlights the issues of unplanned pregnancies and effective post-termination contraceptive practices. OBJECTIVE: To examine the risk factors at the time of a first termination that are associated with subsequent repeat termination. DESIGN: Registry-based study. SETTING: Grampian region of Scotland, UK. METHODS: A retrospective study using data from the Termination of Pregnancy Database, NHS Grampian for the period 1997-2013. Associations between repeat termination and women's sociodemographic characteristics and contraceptive use were assessed using multivariable logistic regression models. RESULTS: This study showed that 23.4% of women who had an initial termination (n=13 621) underwent a repeat termination. Women who had repeat terminations were more likely to be aged under 20 years at their initial termination with an adjusted odds ratio (AOR) of 5.59 [95% confidence interval (CI) 4.17-7.49], to belong to the most deprived social quintile [AOR 1.23 (95% CI 1.05-1.43)], and to be more likely to have had two or more previous livebirths [AOR 1.51 (95% CI 1.12-2.02)] or miscarriages [AOR 1.40 (95% CI 1.02-1.92)]. The likelihood of having a repeat termination was increased in women who had a contraceptive implant as post-termination contraception [AOR 1.78 (95% CI 1.50 2.11)] compared to women who left with none or unknown methods following the first termination. In those who had repeat terminations, women who had an implant or Depo-Provera((r)) were at increased odds of repeat termination in the 2-5 years interval compared to the 0-2 years after their initial termination. CONCLUSIONS: Teenage pregnancy, social deprivation, two or more previous livebirths or miscarriages at the time of the initial termination were identified as risk factors for repeat terminations. Post-termination contraception with implants and Depo-Provera(r) were associated with repeat termination 2-5 years after the first termination. PMID- 26644147 TI - Radiation shielding in dentistry: an update. AB - The purpose of this article was to review the literature and provide guidelines on the use of radiation protection for patients in the dental setting. There are limited published data on the effects of low radiation doses such as those used in dental radiology. Most of the evidence is subject to bias, with risk models extrapolated from higher dose models such as studies of the Hiroshima bomb survivors. However, the lack of evidence does not denote the absence of risk, as there is no established 'safe' level of radiation exposure. All imaging utilizing ionizing radiation carries a risk for the patient. Hence the patient benefits of imaging must outweigh the potential risk. All diagnostic imaging should adhere to three basic principles, these being justification, optimization and application of dose limits. This article discusses dose reduction techniques and shielding of sensitive organs, particularly the thyroid, during procedures such as intraoral imaging, orthopantomograms and imaging of the pregnant patient. PMID- 26644149 TI - Sub-second thermoplastic forming of bulk metallic glasses by ultrasonic beating. AB - The work proposed a novel thermoplastic forming approach-the ultrasonic beating forming (UBF) method for bulk metallic glasses (BMGs) in present work. The rapid forming approach can finish the thermoplastic forming of BMGs in less than one second, avoiding the time-dependent crystallization and oxidation to the most extent. Besides, the UBF is also proved to be competent in the fabrication of structures with the length scale ranging from macro scale to nano scale. Our results propose a novel route for the thermoplastic forming of BMGs and have promising applications in the rapid fabrication of macro to nano scale products and devices. PMID- 26644148 TI - [Complications of corrective osteotomies around the knee]. AB - BACKGROUND: Corrective osteotomies around the knee are a cost-efficient and joint preserving treatment option for primary leg deformities. Incorrect indications, technical errors, and insufficient postoperative management may lead to severe complications. OBJECTIVES: This review discusses potential complications of corrective osteotomies around the knee and treatment and prevention strategies. MATERIALS AND METHODS: A selective review of the literature and a discussion of the authors' strategies for avoiding complications are presented. RESULTS: Major risk factors for complications are the indication for and the planning of an osteotomy. The indication should take into consideration the difference between primary (constitutional) and secondary deformity. Planning must be based on a long-leg X-ray with correct rotation of the leg. Joint space opening of the non involved compartment must be considered to avoid over-correction. Intraoperative fractures can be avoided by the use of an optimized technique. The neurovascular structures must be protected during osteotomy of the posterior cortex. Delayed bone healing/pseudarthrosis may occur in open-wedge and in closed-wedge procedures. High-energy shock wave therapy or autologous cancellous bone grafts can be used to enable bone healing. Infection is usually associated with the implant. Early infection may be treated by debridement and antibiotics. Late infection requires removal of the implant and placement of an external fixator if the osteotomy is still unstable. CONCLUSIONS: Corrective osteotomies around the knee represent a safe treatment option if there is a proper indication and patient selection. Intra- and postoperative complications need to be identified quickly to maintain satisfactory postoperative results. PMID- 26644151 TI - Revisiting the Medical Management of Parkinson's Disease: Levodopa versus Dopamine Agonist. AB - The optimal treatment strategy for Parkinson's disease has been debated for decades. The introduction of levodopa (LD) treatment is frequently delayed because of theoretical concerns about its toxicity or the risk of drug-induced motor complications. These concerns have resulted in "LD phobia" with clinicians selecting dopamine agonist (DA) over LD as initial therapy. More recently, a shift in the treatment approach towards initial LD use appears to be occurring. It is therefore necessary to review current evidence for the use of LD and DA. This review discusses the medical management of Parkinson's disease with regards to the use of LD versus DA. Pendulum swings in treatment strategies between LD first and DA-first therapies should be avoided. A balanced perspective is needed as there is a place for both drugs in the management of PD. PMID- 26644152 TI - Drug Therapy for Behavioral and Psychological Symptoms of Dementia. AB - Dementia, which can be induced by diverse factors, is a clinical syndrome characterized by the decline of cognitive function. Behavioral and psychological symptoms of dementia (BPSD) include depression, agitation, and aggression. Dementia causes a heavy burden on patients and their caregivers. Patients with BPSD should be assessed comprehensively by practitioners and offered appropriate non-pharmacologic and pharmacologic therapy. Nonpharmacologic therapy has been recommended as the basal treatment for BPSD; however, pharmacologic therapy is required under many situations. Medications, including antipsychotic agents, antidepressants, sedative and hypnotic agents, mood stabilizers, cholinesterase inhibitors, and amantadine, are extensively used in clinical practice. We have reviewed the progression of pharmacologic therapy for BPSD. PMID- 26644156 TI - Development of an Automated Bone Mineral Density Software Application: Facilitation Radiologic Reporting and Improvement of Accuracy. AB - The conventional method of bone mineral density (BMD) report production by dictation and transcription is time consuming and prone to error. We developed an automated BMD reporting system based on the raw data from a dual energy X-ray absorptiometry (DXA) scanner for facilitating the report generation. The automated BMD reporting system, a web application, digests the DXA's raw data and automatically generates preliminary reports. In Jan. 2014, 500 examinations were randomized into an automatic group (AG) and a manual group (MG), and the speed of report generation was compared. For evaluation of the accuracy and analysis of errors, 5120 examinations during Jan. 2013 and Dec. 2013 were enrolled retrospectively, and the context of automatically generated reports (AR) was compared with the formal manual reports (MR). The average time spent for report generation in AG and in MG was 264 and 1452 s, respectively (p < 0.001). The accuracy of calculation of T and Z scores in AR is 100 %. The overall accuracy of AR and MR is 98.8 and 93.7 %, respectively (p < 0.001). The mis-categorization rate in AR and MR is 0.039 and 0.273 %, respectively (p = 0.0013). Errors occurred in AR and can be grouped into key-in errors by technicians and need for additional judgements. We constructed an efficient and reliable automated BMD reporting system. It facilitates current clinical service and potentially prevents human errors from technicians, transcriptionists, and radiologists. PMID- 26644157 TI - Open-Source Radiation Exposure Extraction Engine (RE3) with Patient-Specific Outlier Detection. AB - We present an open-source, picture archiving and communication system (PACS) integrated radiation exposure extraction engine (RE3) that provides study-, series-, and slice-specific data for automated monitoring of computed tomography (CT) radiation exposure. RE3 was built using open-source components and seamlessly integrates with the PACS. RE3 calculations of dose length product (DLP) from the Digital imaging and communications in medicine (DICOM) headers showed high agreement (R (2) = 0.99) with the vendor dose pages. For study specific outlier detection, RE3 constructs robust, automatically updating multivariable regression models to predict DLP in the context of patient gender and age, scan length, water-equivalent diameter (D w), and scanned body volume (SBV). As proof of concept, the model was trained on 811 CT chest, abdomen + pelvis (CAP) exams and 29 outliers were detected. The continuous variables used in the outlier detection model were scan length (R (2) = 0.45), D w (R (2) = 0.70), SBV (R (2) = 0.80), and age (R (2) = 0.01). The categorical variables were gender (male average 1182.7 +/- 26.3 and female 1047.1 +/- 26.9 mGy cm) and pediatric status (pediatric average 710.7 +/- 73.6 mGy cm and adult 1134.5 +/- 19.3 mGy cm). PMID- 26644158 TI - Physicochemical properties of cookies enriched with xylooligosaccharides. AB - The growing commercial importance of xylooligosaccharides is based on their beneficial health properties, particularly their ability to stimulate the growth and activity of intestinal bacteria such as Bifidobacterium and Lactobacillus species. Xylooligosaccharides are less sweet, acid, and heat stable, with low recommended levels of intake compared to other oligosaccharides. In view of the consumer demand for foods with low sugar, low fat, and high fiber contents, they are suitable for incorporation into bakery products. In this study, we have developed wheat-based cookies incorporated with xylooligosaccharides at 5%, 10%, and 15% levels. The nutritive value and physicochemical properties of the cookies changed with xylooligosaccharides incorporation; both crude fiber and dietary fiber contents increased by 14% and 35%, respectively, in the enriched cookies. The moisture levels increased with increase in the percentage of xylooligosaccharides incorporated. Cookies with 5% xylooligosaccharides were found most acceptable, although the color was slightly darker compared to the control, while cookies with 10% and 15% xylooligosaccharides were softer and darker and therefore less acceptable. Enrichment with xylooligosaccharides at 5% provided a product stable for 21 days at room temperature (25 +/- 2C). The storage stability of cookies with higher levels of xylooligosaccharides was less than the 5% xylooligosaccharides cookies and control. The retention of the prebiotic xylooligosaccharides in the products was relatively high (74%). PMID- 26644155 TI - Current Treatment Options for Alzheimer's Disease and Parkinson's Disease Dementia. AB - Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most common neurodegenerative disorders encountered in clinical practice. Whilst dementia has long been synonymous with AD, it is becoming more widely accepted as part of the clinical spectrum in PD (PDD). Neuropsychiatric complications, including psychosis, mood and anxiety disorders, and sleep disorders also frequently co exist with cognitive dysfunctions in AD and PDD patients. The incidence of such symptoms is often a significant source of disability, and may aggravate pre existing cognitive deficits. Management of AD and PDD involves both pharmacological and non-pharmacological measures. Although research on pharmacological therapies for AD and PDD has so far had some success in terms of developing symptomatic treatments, the benefits are often marginal and non sustained. These shortcomings have led to the investigation of non pharmacological and novel treatments for both AD and PD. Furthermore, in light of the diverse constellation of other neuropsychiatric, physical, and behavioural symptoms that often occur in AD and PD, consideration needs to be given to the potential side effects of pharmacological treatments where improving one symptom may lead to the worsening of another, rendering the clinical management of these patients challenging. Therefore, the present article will critically review the evidence for both pharmacological and non-pharmacological treatments for cognitive impairment in AD and PD patients. Treatment options for other concomitant neuropsychiatric and behavioural symptoms, as well as novel treatment strategies will also be discussed. PMID- 26644159 TI - What does age-comparative self-rated health measure? A cross-sectional study from the Northern Sweden MONICA Project. AB - AIMS: Self-rated health comprehensively accounts for many health domains. Using self-ratings and a knowledge of associations with health domains might help personnel in the health care sector to understand reports of ill health. The aim of this paper was to investigate associations between age-comparative self-rated health and disease, risk factors, emotions and psychosocial factors in a general population. METHODS: We based our study on population-based cross-sectional surveys performed in 1999, 2004 and 2009 in northern Sweden. Participants were 25 74 years of age and 5314 of the 7500 people invited completed the survey. Comparative self-rated health was measured on a three-grade ordinal scale by the question 'How would you assess your general health condition compared to persons of your own age?' with the alternatives 'better', 'worse' or 'similar'. The independent variables were sex, age, blood pressure, cholesterol, body mass index, self-reported myocardial infarction, stroke, diabetes, physical activity, smoking, risk of unemployment, satisfaction with economic situation, anxiety and depressive emotions, education and Karasek scale of working conditions. Odds ratios using ordinal regression were calculated. RESULTS: Age, sex, stroke, myocardial infarction, diabetes, body mass index, physical activity, economic satisfaction, anxiety and depressive emotions were associated with comparative self-rated health. The risk of unemployment, a tense work situation and educational level were also associated with comparative self-rated health, although they were considerably weaker when adjusted for the the other variables. Anxiety, depressive emotions, low economic satisfaction and a tense work situation were common in the population. CONCLUSIONS: Emotions and economic satisfaction were associated with comparative self-rated health as well as some medical variables. Utilization of the knowledge of these associations in health care should be further investigated. PMID- 26644160 TI - Mothers' and fathers' attendance in a community-based universally offered parenting program in Sweden. AB - AIM: Using a public health perspective, this study examined the characteristics of mothers and fathers who attended, compared to those who did not attend, a community-based practitioner-led universally offered parenting program. METHOD: Mothers (141) and fathers (96) of 4- to 5-year-olds completed a set of questionnaires, including their demographic characteristics, their child's behavioral and emotional problems, and their own parenting behavior. They were all then given the opportunity to attend level 2 of the Triple P--Positive Parenting Program. During the first six months of the study, 33 mothers and 11 fathers opted to attend the program. RESULTS: The relation between program attendance and parental characteristics was similar for mothers and fathers. In general, fathers, non-native and lower educated parents were less likely to attend the program. Mothers, but not fathers, were more likely to attend if they reported more child behavior problems, while fathers, but not mothers, were observed at a trend level to attend if they perceived their child as having more emotional problems. In addition, parents in general were more likely to attend if they used more harsh parenting strategies. CONCLUSIONS: Although the universal offer did not reach parents universally, generally those parents who needed it were more likely to attend. Furthermore, this study shows that different factors may impact mothers' and fathers' attendance; therefore, parental data should be analyzed separately and different recruitment strategies should be used for mothers and fathers. PMID- 26644161 TI - 'Make it another for me and my mates': Does social capital encourage risky drinking among the Danish general population? AB - AIMS: The aim of this study was to examine the relationship between several indicators of social capital and risky single occasion drinking (RSOD) in a representative survey sample of the Danish general population. METHODS: Data from the 2011 Danish national survey (n=2569) with respondents aged 15-79 years were used. Ordered logit modelling was applied to investigate the influence of social networks, social support, social participation and trust on RSOD. RESULTS: A strong positive relationship was found between frequency of contact with male friends and RSOD between both sexes. Furthermore, social trust among men and membership in voluntary organisations among women was significantly associated with RSOD. Additionally, contact with male family members for women and active participation in religious services for both sexes were strongly and negatively correlated with RSOD. CONCLUSIONS: Some aspects of social capital can be positively related to at-risk health behaviours, as was found for RSOD in the Danish general population. PMID- 26644162 TI - Orthogonal-band-multiplexed offset-QAM optical superchannel generation and coherent detection. AB - Nowadays the Internet not only has fast growing data traffic, but also has a fast growing number of on-line devices. This leads to high demand of capacity and flexibility of the future networks. The conventional Orthogonal Frequency Division Multiplexing (OFDM) and Nyquist pulse shaping signals have the advantage of high spectral efficiency when consisting of superchannels in the Wavelength Division-Multiplexing (WDM) way. However, they face a cost issue when the spectral granularity of the superchannel is decreased to support more users. This paper proposes for the first time the scheme of Orthogonal-band-multiplexed offset-Quadrature Amplitude Modulation (OBM-OQAM) superchannel. OBM-OQAM superchannel provides large capacity and high spectral efficiency. Furthermore, it has the advantage of offering subbands of variable symbol rate without changing the system configuration. We provide a proof-of-principle demonstration of OBM-OQAM superchannel transmission. In our experiment, 400 Gbps 16 Quadrature Amplitude Modulation (QAM) OBM-OQAM superchannel transmission over 400 km Standard Single Mode Fiber (SSMF) is conducted. The experimental results show that the OBM-OQAM signal has low penalty in multi-band aggregation. PMID- 26644163 TI - Preparation of novel alkaline pH-responsive copolymers for the formation of recyclable aqueous two-phase systems and their application in the extraction of lincomycin. AB - Aqueous two-phase systems have potential industrial application in bioseparation and biocatalysis engineering; however, their practical application is limited primarily because the copolymers involved in the formation of aqueous two-phase systems cannot be recovered. In this study, two novel alkaline pH-responsive copolymers were synthesized and examined for the extraction of lincomycin. The two copolymers could form a novel alkaline aqueous two-phase systems when their concentrations were both 6% w/w and the pH was 8.4(+/-0.1)-8.7(+/-0.1). One copolymer was synthesized using acrylic acid, 2-(dimethylamino)ethyl methacrylate, and butyl methacrylate as monomers. Moreover, 98.8% of the copolymer could be recovered by adjusting the solution pH to its isoelectric point (pH 6.29). The other copolymer was synthesized using the monomers methacrylic acid, 2-(dimethylamino)ethyl methacrylate, and methyl methacrylate. In this case, 96.7% of the copolymer could be recovered by adjusting the solution pH to 7.19. The optimal partition coefficient of lincomycin was 0.17 at 30 degrees C in the presence of 10 mM KBr and 5.5 at 40 degrees C in the presence of 80 mM Ti(SO4)2 using the novel alkaline aqueous two-phase systems. PMID- 26644164 TI - Influence of bulking agents on physical, chemical, and microbiological properties during the two-stage composting of green waste. AB - A recyclable organic bulking agent (BA) that can be screened and was developed to optimize green waste (GW) composting. This study investigated the use of wood chips (WC) (at 0%, 15%, and 25%) and/or composted green waste (CGW) (at 0%, 25%, and 35%) as the BAs in the two-stage composting of GW. The combined addition of WC and CGW improved the conditions of composting process and the quality of compost product in terms of composting temperature, porosity, water retention, particle-size distribution, pH, electrical conductivity (EC), cation exchange capacity (CEC), nitrogen losses, humification indices, microbial numbers, enzyme activities, macro- and micro-nutrient contents, and toxicity to germinating seeds. The compost matured in only 22days with the optimized two-stage composting method rather than in the 90-270days typically required for traditional composting. The optimal two-stage composting process and the best quality of compost product were obtained with the combined addition of 15% WC and 35% CGW. PMID- 26644165 TI - Just What the Doctor Tweeted: Physicians' Challenges and Rewards of Using Twitter. AB - More than 75,000 health care professionals worldwide share information and discuss treatments on Twitter, making it one of the most popular and influential social media sites for health. This engaging medium has enormous potential for establishing relationships and disseminating information among physicians, their colleagues, and patients. However, little is known about how physicians navigate Twitter and what challenges and benefits come from using the platform. By conducting in-depth interviews with 17 physicians who interact with Twitter at least once per week, it was revealed that physicians overcome concerns of privacy and time constraints to learn and share new research, connect with colleagues, manage online personas, and develop relationships with patients on a new level that goes beyond the typical office visit. Implications include the possibility of enriched patient-provider relationships due to physicians divulging opinions and personal information in a public forum to minimize established power structures and enable better communication. This exploratory study establishes that Twitter is fertile ground for future research to explore how the medium can influence patient behavior, alter attitudes, and influence communication between patients and providers. PMID- 26644167 TI - Nutrition therapy in critically ill patients - A review of current evidence for clinicians. PMID- 26644166 TI - Randomized study of the effect of synbiotics during neoadjuvant chemotherapy on adverse events in esophageal cancer patients. AB - BACKGROUND AND AIMS: The clinical value of synbiotics in patients receiving neoadjuvant chemotherapy currently remains unclear. The aim of this study was to investigate the effects of synbiotics in esophageal cancer patients receiving neoadjuvant chemotherapy on the intestinal microbiota and the adverse events of chemotherapy. METHODS: Sixty-one patients with advanced esophageal cancer who were scheduled to receive neoadjuvant chemotherapy were randomly allocated to 2 groups. One group received synbiotics during chemotherapy (n = 30), while the other group did not (n = 31). The fecal microbiota and organic acid concentrations were analyzed. The primary endpoint was the incidence of chemotherapy-related adverse events. RESULTS: The numbers of beneficial and harmful bacteria were significantly larger and smaller, respectively, in the synbiotics group than in the control group on day 10 of chemotherapy. The concentrations of acetic acid and propionic acid were significantly higher in the synbiotics group on day 10 of chemotherapy. The frequencies of severe lymphopenia and diarrhea were significantly less in the synbiotics group than in the control group (P = 0.033, 0.035, respectively). Furthermore, febrile neutropenia occurred less in the synbiotics group (10/30 in the synbiotics group vs 19/31 in the control group, P = 0.029). CONCLUSIONS: Synbiotics during neoadjuvant chemotherapy in esophageal cancer patients reduced the occurrence of adverse events of chemotherapy through adjustments to the intestinal microbiota. (University Hospital Medical Information Network (http://www.umin.ac.jp), registration number UMIN000006875). PMID- 26644168 TI - Betulin attenuates lung and liver injuries in sepsis. AB - Sepsis is a complex condition with unacceptable mortality. Betulin is a natural extract with multiple bioactivities. This study aims to evaluate the potential effects of betulin on lung and liver injury in sepsis. Cecal ligation and puncture was used to establish the rat model of sepsis. A single dose of 4mg/kg or 8mg/kg betulin was injected intraperitoneally immediately after the model establishment. The survival rate was recorded every 12h for 96h. The organ injury was examined using hematoxylin and eosin staining and serum biochemical test. The levels of proinflammatory cytokines and high mobility group box 1 in the serum were measured using ELISA. Western blotting was used to detect the expression of proteins in NF-kappaB and MAPK signaling pathways. Betulin treatment significantly improved the survival rate of septic rats, and attenuated lung and liver injury in sepsis, including the reduction of lung wet/dry weight ratio and activities of alanine aminotransferase and aspartate aminotransferase in the serum. In addition, levels of tumor necrosis factor-alpha, interleukin-1beta, interleukin-6 and high mobility group box 1 in the serum were also lowered by betulin treatment. Moreover, sepsis-induced activation of the NF-kappaB and MAPK signaling pathway was inhibited by betulin as well. Our findings demonstrate the protective effect of betulin in lung and liver injury in sepsis. This protection may be mediated by its anti-inflammatory and NF-kappaB and MAPK inhibitory effects. PMID- 26644169 TI - Immunotoxicological and neurotoxicological profile of health effects following subacute exposure to geogenic dust from sand dunes at the Nellis Dunes Recreation Area, Las Vegas, NV. AB - Exposure to geogenic particulate matter (PM) comprised of mineral particles has been linked to human health effects. However, very little data exist on health effects associated with geogenic dust exposure in natural settings. Therefore, we characterized particulate matter size, metal chemistry, and health effects of dust collected from the Nellis Dunes Recreation Area (NDRA), a popular off-road vehicle area located near Las Vegas, NV. Adult female B6C3F1 mice were exposed to several concentrations of mineral dust collected from active and vegetated sand dunes in NDRA. Dust samples (median diameter: 4.4 MUm) were suspended in phosphate-buffered saline and delivered at concentrations ranging from 0.01 to 100 mg dust/kg body weight by oropharyngeal aspiration. ICP-MS analyses of total dissolution of the dust resulted in aluminum (55,090 MUg/g), vanadium (70 MUg/g), chromium (33 MUg/g), manganese (511 MUg/g), iron (21,600 MUg/g), cobalt (9.4 MUg/g), copper (69 MUg/g), zinc (79 MUg/g), arsenic (62 MUg/g), strontium (620 MUg/g), cesium (13 MUg/g), lead 25 MUg/g) and uranium (4.7 MUg/g). Arsenic was present only as As(V). Mice received four exposures, once/week over 28-days to mimic a month of weekend exposures. Descriptive and functional assays to assess immunotoxicity and neurotoxicity were performed 24 h after the final exposure. The primary observation was that 0.1 to 100 mg/kg of this sand dune derived dust dose-responsively reduced antigen-specific IgM antibody responses, suggesting that dust from this area of NDRA may present a potential health risk. PMID- 26644170 TI - Output-limiting symptoms induced by radiofrequency hyperthermia. Are they predictable? AB - BACKGROUND: During radiofrequency (RF) hyperthermia treatment, hot-spot phenomena may occur and prevent treatment continuation if the output is not lowered. We previously reported a significant correlation between the initial energy output at which output-limiting symptoms occurred and patient status. Patients with a complete clinical response had significantly increased temperature, while some patients with partial clinical response and stable disease had increased temperature, depending on the occurrence of output-limiting symptoms. To predict the initial energy output at which output-limiting symptoms occur, we performed multiple regression analysis with the parameters of patients' physical status. MATERIALS AND METHODS: Hyperthermia alone or concomitant with chemotherapy and/or radiotherapy was applied in 62 patients with malignant disease for a total of 310 treatments with a Thermotron RF-8 between December 2011 and April 2014. RESULTS: No output-limiting symptoms were shown in 65.5% of 310 treatments. Pain (29.7%), micturition desire (1.9%), skin discomfort (0.6%), subcutaneous induration (1.6%), cold sensation (0.6%), and nausea (0.3%) were reported in the 310 treatments. A good predictive equation for initial energy output at which output limiting symptoms occur was determined with two parameters, initial time of an output-limiting symptom onset, and thickness of the fat of the abdominal wall. Multiple regression analysis showed an adjusted R(2 )= 0.99 and variance inflation factor < 2. CONCLUSIONS: We present a good predictive equation for initial energy output at which output-limiting symptoms occur. It is critical to prevent RF hyperthermia-induced output-limiting symptoms and establish new prevention strategies. PMID- 26644171 TI - Estimates of lay views about reversal multiple intelligences for self and others: Sex and cross-cultural comparisons. AB - This study focuses on lay conceptions of intelligence. It examined sex and cross cultural similarities and differences in estimated intelligences and beliefs about intelligence in two countries, Angola and East Timor, within the reversal theory framework. A total of 209 Angolan (109 women and 100 men) and 183 Timorese (89 women and 94 men) students were participated in this study. Participants completed a questionnaire in order to estimate their parents', partners' and own overall intelligence and the 8 reversal multiple intelligences (telic, paratelic, conformist, negativistic, autic mastery, autic sympathy, alloic mastery and alloic sympathy intelligence). Respondents also rated 6 questions about intelligence. Men rated their overall, conformist and autic mastery higher than women. Angolans rated their overall, telic, paratelic, conformist, negativistic, autic mastery, autic sympathy, alloic mastery and alloic sympathy intelligence higher than Timorese. In both countries, fathers have been perceived as more intelligent than mothers, and telic intelligence emerged as a significant predictor of overall intelligence. Principal component analysis of the 8 reversal multiple intelligences yielded one factor. Angolan participants revealed more IQ test experience than Timorese participants. Most of respondents in both countries did not believe in sex differences in intelligence. These findings are discussed by means of cross-cultural literature. PMID- 26644173 TI - The association between emotions and eating behaviour in an obese population with binge eating disorder. AB - There is utility in understanding the antecedents of binge eating (BE), with a view to explaining poorer weight loss treatment responses in this subgroup. A systematic review was completed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines with the aim of exploring associations between emotions and eating behaviour in a population affected by obesity and binge eating disorder (BED). A comprehensive literature search of four electronic databases (2004-2014) yielded 15 studies for inclusion. Included studies performed poorly on data quality analysis with respect to controlling for confounding variables, and sample size. Included papers largely focused on negative emotions as antecedents of BE; depression was consistently associated with a BED-obese classification and BE. Negative mood, sadness, tension and instability of emotions were found to be antecedents of BE in an adult BED-obese sample. However, findings were mixed regarding the role of stress, anger and positive emotions within the BED-obese population. Recommendations are presented for the identification of BED, and ecologically valid experimental designs that further understanding of the complex and varied emotions that associate with BE. The implications of these and other limitations for both researchers and practitioners are discussed. The paper concludes with recommendations for future research alongside suggestions for practitioners. (c) 2015 World Obesity. PMID- 26644172 TI - A Multinational Trial of Prasugrel for Sickle Cell Vaso-Occlusive Events. AB - BACKGROUND: Sickle cell anemia is an inherited blood disorder that is characterized by painful vaso-occlusive crises, for which there are few treatment options. Platelets mediate intercellular adhesion and thrombosis during vaso occlusion in sickle cell anemia, which suggests a role for antiplatelet agents in modifying disease events. METHODS: Children and adolescents 2 through 17 years of age with sickle cell anemia were randomly assigned to receive oral prasugrel or placebo for 9 to 24 months. The primary end point was the rate of vaso-occlusive crisis, a composite of painful crisis or acute chest syndrome. The secondary end points were the rate of sickle cell-related pain and the intensity of pain, which were assessed daily with the use of pain diaries. RESULTS: A total of 341 patients underwent randomization at 51 sites in 13 countries across the Americas, Europe, Asia, and Africa. The rate of vaso-occlusive crisis events per person year was 2.30 in the prasugrel group and 2.77 in the placebo group (rate ratio, 0.83; 95% confidence interval, 0.66 to 1.05; P=0.12). There were no significant differences between the groups in the secondary end points of diary-reported events. The safety end points, including the frequency of bleeding events requiring medical intervention, of hemorrhagic and nonhemorrhagic adverse events that occurred while patients were taking prasugrel or placebo, and of discontinuations due to prasugrel or placebo, did not differ significantly between the groups. CONCLUSIONS: Among children and adolescents with sickle cell anemia, the rate of vaso-occlusive crisis was not significantly lower among those who received prasugrel than among those who received placebo. There were no significant between-group differences in the safety findings. (Funded by Daiichi Sankyo and Eli Lilly; ClinicalTrials.gov number, NCT01794000.). PMID- 26644174 TI - Fertility history and use of antidepressant medication in late mid-life: a register-based analysis of Norwegian women and men. AB - OBJECTIVES: Life course influences on later life depression may include parenting trajectories. We investigate associations between number and timing of births and use of antidepressant medication in late mid-life using data on the whole Norwegian population. METHODS: We estimated logistic regression models to analyse variations in the purchase of antidepressants between 2004 and 2008 by timing of births and number of children among women and men aged 45-73, using Norwegian population register data. We controlled for age, education, marital and partnership status, and (in some models) family background shared among siblings. RESULTS: Mothers and fathers of two or more children were generally less likely to purchase antidepressants than the childless. Mothers who started childbearing before age 22 were an exception, although according to sibling models they were not more likely to purchase antidepressants. All models showed that women who became mothers before age 26 and had only one child had higher odds of medication purchase than the childless. Older age at first birth was generally associated with lower risks of antidepressant purchase. CONCLUSION: This analysis of high quality data for a national population indicates that early motherhood, childlessness and low parity are associated with higher usage of antidepressants in late mid-life. Our data did not allow identification of mediating pathways, and we lacked information on early mental and physical health and some other potentially important confounders not shared between siblings. Furthermore purchase of antidepressants is not a perfect indicator of depression. Those concerns aside, the results suggest complex effects of fertility on depression that merit further investigation. PMID- 26644175 TI - Mitochondrial DNA variation in Eisenia n. nordenskioldi (Lumbricidae) in Europe and Southern Urals. AB - There are many peregrine European earthworm species that are found in Siberia. In contrast, it is generally considered that the only Siberian species, E. n. nordenskioldi, was capable to disperse in the reverse direction, from Siberia into Europe. We studied genetic diversity of E. n. nordenskioldi in Southern Urals and Eastern Europe using the mitochondrial cox1 gene. We found that E. n. nordenskioldi from that region represents a new genetic lineage distinct from the previously known populations of this species from Siberia. Molecular clock estimates suggest that this newly found lineage separated from the rest of the species in Lower Pleistocene. Within the studied sample, we detected two geographically restricted groups, which also diverged long before the Holocene, one found in the East European Plain and the other restricted to the Urals. Those two groups were found in sympatry in only one population. Therefore, our results do not support the traditional viewpoint, suggesting that E. n. nordenskioldi is definitely not a recent invader in Europe. PMID- 26644176 TI - The Body as a Site of Gender-Related Distress: Ethical Considerations for Gender Variant Youth in Clinical Settings. AB - The present article maps out understandings about embodied distress among gender nonconforming youth. Feminist bioethics and queer-inflected clinical perspectives are used to inform thinking about ethical, nonpathologizing health care in the case of gender-related distress. Specific attention is directed at self-harming among gender variant and trans youth. This is contextualized in relation to the role that self-harm plays for some LGBT youth, where it may be seen as a rite of passage or as reasonable and inevitable way of coping. The particular complexities of self-harm among trans youth seeking clinical intervention are examined. Queer bioethics is proposed as potentially facilitating productive uncertainty with regard to the diverse imagined futures of gender variant and trans youth. PMID- 26644177 TI - CT Characteristics and Survival in Lung Adenocarcinoma. PMID- 26644178 TI - A comparison of the capacity of ice hockey goaltender masks for the protection from puck impacts. AB - Goaltenders in ice hockey are the only players that are on the ice for the entire game. Their position exposes them to impacts from collisions with other players, falls to the ice, and puck impacts. In competitive ice hockey leagues, head injuries resulting from puck impacts have been reported with some cases resulting in ending the player's career. Considerable research has been conducted to assess the performance of hockey helmets; however, few have assessed the performance of goaltenders' masks. The purpose of this study was to compare the capacity of four goaltenders' masks for the protection from puck impact as measured by head acceleration and peak force. A Hybrid III headform was fitted with four different goaltender masks and impacted with a hockey puck in three locations at 25 m/s. The masks were found to vary in the level of protection they offered as the mask with the thickest liner resulted in lower forces than the thinnest mask for side impacts; however, the thinnest mask resulted in the lowest force for front impacts. Despite performance differences at specific locations, no one mask proved to be superior as peak acceleration and peak force values did not exceed the thresholds necessary for concussion. PMID- 26644179 TI - Orc5 induces large-scale chromatin decondensation in a GCN5-dependent manner. AB - In eukaryotes, origin recognition complex (ORC) proteins establish the pre replicative complex (preRC) at the origins, and this is essential for the initiation of DNA replication. Open chromatin structures regulate the efficiency of preRC formation and replication initiation. However, the molecular mechanisms that control chromatin structure, and how the preRC components establish themselves on the chromatin remain to be understood. In human cells, the ORC is a highly dynamic complex with many separate functions attributed to sub-complexes or individual subunits of the ORC, including heterochromatin organization, telomere and centromere function, centrosome duplication and cytokinesis. We demonstrate that human Orc5, unlike other ORC subunits, when ectopically tethered to a chromatin locus, induces large-scale chromatin decondensation, predominantly during G1 phase of the cell cycle. Orc5 associates with the H3 histone acetyl transferase GCN5 (also known as KAT2A), and this association enhances the chromatin-opening function of Orc5. In the absence of Orc5, histone H3 acetylation is decreased at the origins. We propose that the ability of Orc5 to induce chromatin unfolding during G1 allows the establishment of the preRC at the origins. PMID- 26644181 TI - PTP-PEST controls EphA3 activation and ephrin-induced cytoskeletal remodelling. AB - Eph receptors and their corresponding membrane-bound ephrin ligands regulate cell positioning and establish tissue patterns during embryonic and oncogenic development. Emerging evidence suggests that assembly of polymeric Eph signalling clusters relies on cytoskeletal reorganisation and underlies regulation by protein tyrosine phosphatases (PTPs). PTP-PEST (also known as PTPN12) is a central regulator of actin cytoskeletal dynamics. Here, we demonstrate that an N terminal fragment of PTP-PEST, generated through an ephrinA5-triggered and spatially confined cleavage mediated by caspase-3, attenuates EphA3 receptor activation and its internalisation. Isolation of EphA3 receptor signalling clusters within intact plasma membrane fragments obtained by detergent-free cell fractionation reveals that stimulation of cells with ephrin triggers effective recruitment of this catalytically active truncated form of PTP-PEST together with key cytoskeletal and focal adhesion proteins. Importantly, modulation of actin polymerisation using pharmacological and dominant-negative approaches affects EphA3 phosphorylation in a similar manner to overexpression of PTP-PEST. We conclude that PTP-PEST regulates EphA3 activation both by affecting cytoskeletal remodelling and through its direct action as a PTP controlling EphA3 phosphorylation, indicating its multifaceted regulation of Eph signalling. PMID- 26644180 TI - Reactive oxygen species exert opposite effects on Tyr23 phosphorylation of the nuclear and cortical pools of annexin A2. AB - Annexin A2 (AnxA2) is a multi-functional and -compartmental protein whose subcellular localisation and functions are tightly regulated by its post translational modifications. AnxA2 and its Tyr23-phosphorylated form (pTyr23AnxA2) are involved in malignant cell transformation, metastasis and angiogenesis. Here, we show that H2O2 exerts rapid, simultaneous and opposite effects on the Tyr23 phosphorylation status of AnxA2 in two distinct compartments of rat pheochromocytoma (PC12) cells. Reactive oxygen species induce dephosphorylation of pTyr23AnxA2 located in the PML bodies of the nucleus, whereas AnxA2 associated with F-actin at the cell cortex is Tyr23 phosphorylated. The H2O2-induced responses in both compartments are transient and the pTyr23AnxA2 accumulating at the cell cortex is subsequently incorporated into vesicles and then released to the extracellular space. Blocking nuclear export by leptomycin B does not affect the nuclear pool of pTyr23AnxA2, but increases the amount of total AnxA2 in this compartment, indicating that the protein might have several functions in the nucleus. These results suggest that Tyr23 phosphorylation can regulate the function of AnxA2 at distinct subcellular sites. PMID- 26644182 TI - CDK-dependent phosphorylation of PHD1 on serine 130 alters its substrate preference in cells. AB - PHD1 (also known as EGLN2) belongs to a family of prolyl hydroxylases (PHDs) that are involved in the control of the cellular response to hypoxia. PHD1 is also able to regulate mitotic progression through the regulation of the crucial centrosomal protein Cep192, establishing a link between the oxygen-sensing and the cell cycle machinery. Here, we demonstrate that PHD1 is phosphorylated by CDK2, CDK4 and CDK6 at S130. This phosphorylation fluctuates with the cell cycle and can be induced through oncogenic activation. Functionally, PHD1 phosphorylation leads to increased induction of hypoxia-inducible factor (HIF) protein levels and activity during hypoxia. PHD1 phosphorylation does not alter its intrinsic enzymatic activity, but instead decreases the interaction between PHD1 and HIF1alpha. Interestingly, although phosphorylation of PHD1 at S130 lowers its activity towards HIF1alpha, this modification increases the activity of PHD1 towards Cep192. These results establish a mechanism by which cell cycle mediators, such as CDKs, temporally control the activity of PHD1, directly altering the regulation of HIF1alpha and Cep192. PMID- 26644183 TI - Bleeding the laboratory mouse: Not all methods are equal. AB - The laboratory mouse is the model most frequently used in hematologic studies and assessment of blood parameters across a broad range of disciplines. Often, analysis of blood occurs in a nonterminal manner. However, the small body size of the mouse limits collection based on volume, frequency, and accessible sites. Commonly used sites in the mouse include the retro-orbital sinus, facial vein, tail vein, saphenous vein, and heart. The method of blood acquisition varies considerably across laboratories and is often not reported in detail. In this study, we report significant alterations in blood parameters, particularly of total white blood cells, specific populations of dendritic cells and myeloid derived suppressor cells, and hematopoietic progenitor cells, as a result of site and manner of sampling. Intriguingly, warming of mice prior to tail bleeding was found to significantly alter blood values. Our findings suggest that the same method should be used across an entire study, that mice should be warmed prior to tail bleeds to make levels uniform, and that accurate description of bleeding methods in publications should be provided to allow for interpretation of comparative reports and inter- and intralaboratory experimental variability. PMID- 26644184 TI - [Evaluation of the efficacy and safety of three 2-drug combinations for the treatment of uncomplicated Plasmodium falciparum malaria in Senegal: artesunate amodiaquine, dihydroartemisinin-piperaquine, and artemether-lumefantrine]. AB - BACKGROUND: Since 2006, artemisinin-based combination therapies (ACT) have been used to treat uncomplicated Plasmodium falciparum malaria in Senegal, as recommended by WHO. Recently, decreased parasite clearance with artemisinin derivatives has been reported in Cambodia and Thailand. The effectiveness of artemisinin derivatives in Africa must be monitored. This study was conducted to evaluate the efficacy and the tolerability of three ACT widely used in Senegal. METHODS: From October 2010 to February 2011, a descriptive and analytical sequential study was conducted in adults and children to evaluate these three combinations: artemether-lumefantrine (AL), artesunate-amodiaquine (ASAQ), and dihydroartemisinin-piperaquine (DHAPQ). The study took place at the health posts of Deggo and Pikine and the health center of Guediawaye, in the suburbs of Dakar. The primary endpoint was the PCR-corrected adequate clinical and parasitological response (ACPR) at day 28 (D28); the secondary endpoints included ACPR at D42, clearance times for parasites, fever, and gametocytes, and the incidence of adverse events. RESULTS: The study included 393 patients: 139 in the AL group, 130 in the ASAQ group, and 124 in the DHAPQ group. In the intent-to-treat population, PCR-corrected ACPR at day 28 was 92.8% in the AL, 89.2% in the ASAQ, and 91.1% in the DHAPQ (p = 0.58) groups, and in the per-protocol population, 98.4%, 98.3%, and 100% respectively (p = 0.39). At D42, ACPR was 99.2% in the AL, and 99.1% in each of the ASAQ and DHAPQ arms (p = 1). No early therapeutic failure (ETF) was observed. The combinations were well tolerated, with no serious adverse events reported during the follow-up period. CONCLUSION: These combinations are still effective and well-tolerated. Continued monitoring is nonetheless essential to detect early artemisinin resistance in Africa. PMID- 26644185 TI - High Blood Glucose Levels Correlate with Tumor Malignancy in Colorectal Cancer Patients. AB - BACKGROUND Research shows that type 2 diabetes mellitus (T2DM) affects the risk and prognosis of colorectal cancer (CRC). Here, we conducted a retrospective study to investigate whether the clinicopathological features of CRC patients correlate with their blood glucose levels. MATERIAL AND METHODS We enrolled 391 CRC patients hospitalized in our center between 2008 and 2013. Data of their first fasting plasma glucose (FPG) and 2-h postprandial glucose (2hPPG) level after admission, their clinicopathological features, and survival were collected. The correlations between blood glucose level and clinicopathological features were analyzed by Pearson chi-square analysis. Patient survival was analyzed by Kaplan-Meier and Cox-regression analysis. RESULTS There were 116 out of the 391 CRC patients who had high blood glucose level (H-G group, 29.67%), among which 58 (14.83%), 18 (4.60%), and 40 (10.23%) were diabetes mellitus (DM), impaired glucose tolerance (IGT), and impaired fasting glucose (IFG), respectively, while 275 (70.33%) patients had normal glucose level (N-G group). Compared with the N-G group, patients in the H-G group had larger tumor diameters and lower tumor differentiation (p<0.05). A higher ratio of patients in the H-G group also had more advanced TNM staging and more ulcerative CRC gross type (p<0.05). No significant difference was observed in patient overall survival among different glucose groups. No effect of insulin therapy on CRC development and patient survival was observed. CONCLUSIONS Blood glucose level in CRC patients correlates significantly with local tumor malignancy, but no significant effect on distant metastasis and patient overall survival was observed. PMID- 26644186 TI - Association of sedentary time and physical activity with pain, fatigue, and impact of fibromyalgia: the al-Andalus study. AB - We examined the association of objectively measured sedentary time (ST) and physical activity (PA) levels with pain, fatigue, and the impact of the disease in women with fibromyalgia. Four hundred and nineteen (mean age +/- SD = 51.7 +/- 7.6 years old) women with fibromyalgia participated. ST and PA levels (light, moderate, and moderate-to-vigorous [MVPA]) were measured with triaxial accelerometry. We assessed experimental pain with algometry and clinical pain, fatigue, and impact of fibromyalgia with a number of questionnaires. The association of ST and light PA with most of the pain- and fatigue-related outcomes and impact of fibromyalgia (all, P <= 0.019) was independent of moderate and vigorous PA. Furthermore, the association of vigorous PA with general and physical fatigue was independent of ST and light and moderate PA (all, P < 0.001). In conclusion, lower levels of ST or higher levels of light PA are associated with lower pain, fatigue, and the overall impact of the disease independent of moderate and vigorous PA in women with fibromyalgia. Interestingly, higher vigorous PA is independently associated with lower general and physical fatigue. These results are significant for future ST and PA intervention studies in this population. PMID- 26644187 TI - Left Ventricular Lead Fracture 6 Years after Implantation with a Retained Guidewire. AB - We reported a case that left ventricular (LV) lead with retained guidewire was used 6 years ago, but the LV lead was broken during 6 years of follow-up. Although the retained guidewire technique has already been abandoned, the long term safety of retained guidewire lead appears to be an even greater concern. PMID- 26644188 TI - Phosphoric Acid Catalyzed Asymmetric 1,6-Conjugate Addition of Thioacetic Acid to para-Quinone Methides. AB - An asymmetric 1,6-conjugate addition of thioacetic acid with para-quinone methides has been developed by using chiral phosphoric acid catalysis in the presence of water. A series of sulfur-containing compounds were thus obtained in high yields with good to excellent enantioselectivities. Theoretical studies indicated that the water-bridged proton transfer is a potentially favorable reaction pathway. An unprecedented O-H???pi interaction between water and the aromatic nucleus of chiral phosphoric acid was discovered to contribute significantly to the stereocontrol in the catalysis. PMID- 26644189 TI - Changes in importance of work and vocational satisfaction during the 2 years after breast cancer surgery and factors associated with this. AB - PURPOSE: The purpose of this study is to investigate how women, during the 2 years following breast cancer surgery, rate importance of work and vocational satisfaction, and baseline factors associated with rating over time. METHODS: A prospective cohort study of 692 women aged 20-63 included about 4 weeks after a first breast cancer surgery. Register data on treatment and data from six repeated questionnaires during a 2-year follow-up (at baseline, 4, 8, 12, 18, 24 months) were used in two-way mixed repeated analysis of variance and mixed repeated measures analysis of covariance. RESULTS: The women rated importance of work (m = 3.74; sd 0.88) (maximum 5) and vocational satisfaction (m = 4.30; sd 1.38) (maximum 6) high during the 2 years. Women with planned chemotherapy rated lower vocational satisfaction and especially so at 4 months after inclusion (F 1, 498 = 8.20; p = 0.004). Higher age, better physical, and mental/social work ability at baseline influenced rating of vocational satisfaction. Supportive colleagues was an important covariate that significantly affected ratings of importance of work as well as vocational satisfaction, i.e., women with better support rated on average higher on these outcomes. The effect of chemotherapy disappeared after including the abovementioned baseline covariates. CONCLUSIONS: Women diagnosed with breast cancer in the following 2 years rate importance of work and vocational satisfaction high, which are associated to lower work ability and social support. IMPLICATIONS FOR CANCER SURVIVORS: Work is a very important aspect in life also after a cancer diagnosis, which has to be acknowledged when discussing treatment and rehabilitation plans with women with breast cancer. Furthermore, workplace support needs to be assessed as this is an influential factor. PMID- 26644190 TI - Improving an electronic system for measuring PROs in routine oncology practice. AB - PURPOSE: Our aim was to study how patients and their clinicians evaluated the usability of PatientViewpoint, a webtool designed to allow patient-reported outcome (PRO) measures to be used in clinical practice. METHODS: As part of a two round quality improvement study, breast and prostate cancer patients and their medical and radiation oncology clinicians completed semi-structured interviews about their use of PatientViewpoint. The patient interview addressed different phases of the PRO completion workflow: reminders, completing the survey, and viewing the results. The clinician interviews asked about use of PatientViewpoint, integration with the clinical workflow, barriers to use, and helpful and desired features. Responses were recorded, categorized, and reviewed. After both rounds of interviews, modifications were made to PatientViewpoint. RESULTS: Across the two rounds, 42 unique patients (n = 19 in round 1, n = 23 in round 2) and 12 clinicians (all in both rounds) completed interviews. For patients, median age was 65, 81 % were white, 69 % were college graduates, 80 % had performance status of 0, 69 % had loco-regional disease, and 81 % were regular computer users. In the quality improvement interviews, patients identified numerous strengths of the system, including its ability to flag issues for discussion with their provider. Comments included confusion about how scores were presented and that the value of the system was diminished if the doctor did not look at the results. Requests included tailoring questions to be applicable to the individual and providing more explanation about the score meaning, including having higher scores consistently indicating either better or worse status. Clinicians also provided primarily positive feedback about the system, finding it helpful in some cases, and confirmatory in others. Their primary concern was with impact on their workflow. CONCLUSIONS: Systematically collected feedback from patients and clinicians was useful to identify ways to improve a system to incorporate PRO measures into oncology practice. The findings and evaluation methods should be useful to others in efforts to integrate PRO assessments into ambulatory care. IMPLICATIONS FOR CANCER SURVIVORS: Systems to routinely collect patient-reported information can be incorporated into oncology practices and provide useful information that promote patient and clinician partnership to improve the quality of care. PMID- 26644191 TI - Morphological and Functional Evaluation of Meibomian Gland Dysfunction in Rosacea Patients. AB - PURPOSE: Skin rosacea is a chronic inflammatory disease affecting up to 10% of the population in some European countries. Although considered a skin disease, acne rosacea may involve the eyes, causing eyelid and ocular surface inflammation. This study investigated the relationship between skin rosacea and various signs of ocular involvement and evaluated severity of meibomian gland dysfunction in rosacea patients. METHODS: The ocular surface and meibomian gland parameters were evaluated in 41 patients with diagnosed skin rosacea and 44 age matched healthy controls. We analyzed meibomian gland function (meibum quality and meibum expressibility) and morphology (meibography) and lid margin alterations. We correlated our findings with self-reported ocular symptoms and tear film abnormalities (tear film breakup time, Schirmer test). RESULTS: The prevalence of ocular erythema and lid margin alterations was significantly higher in rosacea patients compared with controls. We found that rosacea is accompanied with significant loss of meibomian gland tissue defined as reduced meibomian gland area and decreased meibomian gland density. A positive correlation between margin abnormality score and the extent of meibomian gland loss in rosacea group was observed (rs = +0.30, p = 0.005), suggesting that ocular rosacea is accompanied by meibomian gland dropout. CONCLUSION: Skin rosacea is associated with ocular erythema and lid margin abnormalities. Our results suggest that ocular signs of rosacea may influence meibomian gland morphology, causing meibomian gland loss. PMID- 26644192 TI - The Inevitability of Ethnocentrism Revisited: Ethnocentrism Diminishes As Mobility Increases. AB - Nearly all major conflicts across the globe, both current and historical, are characterized by individuals defining themselves and others by group membership. This existence of group-biased behavior (in-group favoring and out-group hostile) has been well established empirically, and has been shown to be an inevitable outcome in many evolutionary studies. Thus it is puzzling that statistics show violence and out-group conflict declining dramatically over the past few centuries of human civilization. Using evolutionary game-theoretic models, we solve this puzzle by showing for the first time that out-group hostility is dramatically reduced by mobility. Technological and societal advances over the past centuries have greatly increased the degree to which humans change physical locations, and our results show that in highly mobile societies, one's choice of action is more likely to depend on what individual one is interacting with, rather than the group to which the individual belongs. Our empirical analysis of archival data verifies that contexts with high residential mobility indeed have less out-group hostility than those with low mobility. This work suggests that, in fact, group-biased behavior that discriminates against out-groups is not inevitable after all. PMID- 26644193 TI - A frequency and pulse-width co-modulation strategy for transcutaneous neuromuscular electrical stimulation based on sEMG time-domain features. AB - OBJECTIVE: Surface electromyography (sEMG) is often used as a control signal in neuromuscular electrical stimulation (NMES) systems to enhance the voluntary control and proprioceptive sensory feedback of paralyzed patients. Most sEMG controlled NMES systems use the envelope of the sEMG signal to modulate the stimulation intensity (current amplitude or pulse width) with a constant frequency. The aims of this study were to develop a strategy that co-modulates frequency and pulse width based on features of the sEMG signal and to investigate the torque-reproduction performance and the level of fatigue resistance achieved with our strategy. APPROACH: We examined the relationships between wrist torque and two stimulation parameters (frequency and pulse width) and between wrist torque and two sEMG time-domain features (mean absolute value (MAV) and number of slope sign changes (NSS)) in eight healthy volunteers. By using wrist torque as an intermediate variable, customized and generalized transfer functions were constructed to convert the two features of the sEMG signal into the two stimulation parameters, thereby establishing a MAV/NSS dual-coding (MNDC) algorithm. Wrist torque reproduction performance was assessed by comparing the torque generated by the algorithms with that originally recorded during voluntary contractions. Muscle fatigue was assessed by measuring the decline percentage of the peak torque and by comparing the torque time integral of the response to test stimulation trains before and after fatigue sessions. MAIN RESULTS: The MNDC approach could produce a wrist torque that closely matched the voluntary wrist torque. In addition, a smaller decay in the wrist torque was observed after the MNDC-coded fatigue stimulation was applied than after stimulation using pulse width modulation alone. SIGNIFICANCE: Compared with pulse-width modulation stimulation strategies that are based on sEMG detection, the MNDC strategy is more effective for both voluntary muscle force reproduction and muscle fatigue reduction. PMID- 26644194 TI - Asymmetric intramolecular alpha-cyclopropanation of aldehydes using a donor/acceptor carbene mimetic. AB - Enantioselective alpha-alkylation of carbonyl is considered as one of the most important processes for asymmetric synthesis. Common alkylation agents, that is, alkyl halides, are notorious substrates for both Lewis acids and organocatalysts. Recently, olefins emerged as a benign alkylating species via photo/radical mechanisms. However, examples of enantioselective alkylation of aldehydes/ketones are scarce and direct asymmetric dialkylation remains elusive. Here we report an intramolecular alpha-cyclopropanation reaction of olefinic aldehydes to form chiral cyclopropane aldehydes. We demonstrate that an alpha-iodo aldehyde can function as a donor/acceptor carbene equivalent, which engages in a formal [2+1] annulation with a tethered double bond. Privileged bicyclo[3.1.0]hexane-type scaffolds are prepared in good optical purity using a chiral amine. The synthetic utility of the products is demonstrated by versatile transformations of the bridgehead formyl functionality. We expect the concept of using alpha-iodo iminium as a donor/acceptor carbene surrogate will find wide applications in chemical reaction development. PMID- 26644195 TI - Proliferating subcutaneous nodules in a 12-year-old girl. PMID- 26644196 TI - Distribution and nature of sedimentary organic matter in a tropical estuary: An indicator of human intervention on environment. AB - Sediment texture controls the spatial distribution of sedimentary organic matter (SOM) in the Vembanad Lake. Influences of marine derived organic matter (OM) on SOM decreased inner-wards in the northern part of the lake. However, SOM from the southern part of the lake was dominated by terrestrial OM. Marine-derived OM showed the highest affinity for the clay-sized fraction (<2 MUm) of the sediment in the northern part of the lake. However, aged and humified soil-derived OM was predominant in the clay-sized fractions from the southern part. Alteration of sediment texture led to a change in the distribution pattern of SOM in the lake after bund construction. Human intervention and changes in land-use pattern were also found to influence the SOM content in the southern part of the lake. PMID- 26644198 TI - The impact of regional policies on emergency department management and performance: the case of the regional government of Sicily. AB - BACKGROUND: Improvement in healthcare, seeking the correct balance between quality and costs, is an ongoing concern in many countries. Many countries have developed and implemented improvement programmes in health care, particularly in emergency departments (ED), which play a key role in terms of hospital resources and planning. The regional government of Sicily implemented a project 2010-2012 to improve ED care quality and patient safety. PURPOSE: This paper aims to evaluate improvements implemented by the Regional Health Authority of Sicily in the 20 main EDs. METHOD: Performance analysis of EDs was conducted on three levels: care quality (standard Joint Commission International evaluation), efficiency in terms of resources and output (by way of interviews and document analysis) and the role of management in efficiently promoting change (presence of a performance monitoring system). FINDINGS: The results show improvements in all areas and improved performance in all EDs. There is, however, room for improvement in certain areas, and improvement was not uniformly distributed. PRACTICAL IMPLICATIONS: The quality of local policy and management are key aspects of efficient promotion of performance improvement. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26644197 TI - Short-time QiBaoMeiRan Formula Treatment Exerts Estrogenic Activities without Side Effects on Reproductive Tissues in Immature Mice. AB - The Chinese herbal preparation QiBaoMeiRan formula (QBMR) displayed estrogenic effects in ovariectomized rats after long-term administration in a previous study. The uterus and vagina are negatively influenced by estrogens in hormone therapy. While QBMR is known to be a phytoestrogen, its estrogenic effects and safety on reproductive tissues after short-term administration and its mechanism via estrogen receptor (ER) pathway haven't been studied. Here, we characterized its estrogenic effects using immature mice together with in vitro studies for further molecular characterization. Immature mice were treated with QBMR at doses of 1.125, 2.25, and 4.5 g/kg for 7 days. 1.125 and 2.25 g/kg QBMR promoted the growth and development of uterus and vagina, and upregulated ERalpha and ERbeta expression in reproductive tissues. QBMR had a stimulatory effect on proliferating cell nuclear antigen in vagina but not in uterus, and was without any influence on ki-67 antigen in uterus and vagina. QBMR significantly induced luciferase expression from the ERalpha/beta-estrogen response element (ERE) luciferase reporter and upregulated ERalpha and ERbeta expressions in MCF-7 cells, which were significantly inhibited by estrogen antagonist ICI182,780. This study demonstrated QBMR exerts estrogenic effects on reproductive tissues without side effects and through ER-ERE-dependent pathway. PMID- 26644199 TI - Fluorescence guided resection (FGR): A primer for oncology. AB - Curative treatment for most cancer patients requires surgical removal of the tumor. Often though, residual disease is left behind negatively impacting tumor control and survival. Florescent Guided resection (FGR) is one type of Image Guided Surgery that offers the potential to improve outcomes for these patients. Currently, during FGR, a probe is preoperatively applied and allowed to concentrate in the tumor bed. At surgery appropriate light is applied to generate fluorescence which allows the surgeon to better visualize tumor extent. This improved visualization has translated both into enhanced rates for resection but also diminished rates of morbidity as less normal tissue need be removed to achieve negative margins. This paper will summarize the theory and practise of FGR as currently applied in clinical oncology including select outcomes and limitations of technique and technology. PMID- 26644200 TI - Twenty years of artificial directional selection have shaped the genome of the Italian Large White pig breed. AB - In this study, we investigated at the genome-wide level if 20 years of artificial directional selection based on boar genetic evaluation obtained with a classical BLUP animal model shaped the genome of the Italian Large White pig breed. The most influential boars of this breed (n = 192), born from 1992 (the beginning of the selection program of this breed) to 2012, with an estimated breeding value reliability of >0.85, were genotyped with the Illumina Porcine SNP60 BeadChip. After grouping the boars in eight classes according to their year of birth, filtered single nucleotide polymorphisms (SNPs) were used to evaluate the effects of time on genotype frequency changes using multinomial logistic regression models. Of these markers, 493 had a PBonferroni < 0.10. However, there was an increasing number of SNPs with a decreasing level of allele frequency changes over time, representing a continuous profile across the genome. The largest proportion of the 493 SNPs was on porcine chromosome (SSC) 7, SSC2, SSC8 and SSC18 for a total of 204 haploblocks. Functional annotations of genomic regions, including the 493 shifted SNPs, reported a few Gene Ontology terms that might underly the biological processes that contributed to increase performances of the pigs over the 20 years of the selection program. The obtained results indicated that the genome of the Italian Large White pigs was shaped by a directional selection program derived by the application of methodologies assuming the infinitesimal model that captured a continuous trend of allele frequency changes in the boar population. PMID- 26644201 TI - The electrocardiogram of anaesthetized southern sea lion (Otaria flavescens) females. AB - OBJECTIVES: The goal of this study was to characterize for the first time the electrocardiogram (ECG) of the southern sea lion (SSL) Otaria flavescens. ANIMALS, MATERIALS AND METHODS: Thirteen wild SSL females were captured at Isla de Lobos (Uruguay) and anaesthetized with isoflurane. Electrocardiographic recording was performed on anaesthetized animals at ventral recumbence following standardized procedures. RESULTS: The ECG recordings showed normal sinus rhythm. Amplitude and duration of P and T waves, QRS complex, PR interval, QT interval and ST segment (STS) were determined for all animals in all leads. QT corrected was determined in lead II. P wave polarity was consistent among animals (positive in LI, LII, LIII and AVF leads and negative in AVL and AVR leads for all animals), but T wave polarity did not present any constant pattern among animals, being either positive, negative or biphasic in different leads and different animals. The PR interval (0.15 +/- 0.2 s) was similar to the allometric prediction for most of mammalian species including humans. The STS were normal in 10 of the SSL but showed STS depression in three of the animals. Almost all animals had a negative electrical axis (-30 degrees to -120 degrees ), with one exception that showed a positive electrical axis (120 degrees ). Mean eupnoeic heart rate was 104.61 +/- 10.06 (range = 88-120) beats per minute. CONCLUSIONS: This study was the first ECG description for this species, and provides valuable information for cardiac monitoring during anaesthesia. PMID- 26644203 TI - A systematic review and meta-analysis of the impact of WT1 polymorphism rs16754 in the effectiveness of standard chemotherapy in patients with acute myeloid leukemia. AB - The polymorphism rs16754 of the WT1 gene has been described as a possible prognostic marker in different acute myeloid leukemia (AML) cohorts; however, it is not supported by all the studies. We performed the first meta-analysis evaluating the effect of this polymorphism upon the effectiveness of standard AML therapy. Fourteen cohort studies were included (3618 patients). Patients with the variant allele showed a significant higher overall survival (OS) at 5 years (OR:1.24, 95% CI: 1.06-1.45, P=0.007, with dominant model). WT1 did not influence complete remission, but a higher disease-free survival was observed with the variant allele. In the subgroup analysis, Caucasians, pediatric and patients treated with idarubicin and etoposide carrying the variant allele showed consistent results in OS, whereas patients with cytogenetically normal AML did not show differences. To verify the effect of this polymorphism upon other outcomes, studies in larger and multiracial populations are needed. PMID- 26644202 TI - Common variants associated with changes in levels of circulating free fatty acids after administration of glucose-insulin-potassium (GIK) therapy in the IMMEDIATE trial. AB - Glucose-insulin-potassium (GIK) therapy may promote a shift from oxygen-wasteful free fatty acid (FFA) metabolism to glycolysis, potentially reducing myocardial damage during ischemia. Genetic variation associated with FFA response to GIK was investigated in an IMMEDIATE (Immediate Myocardial Metabolic Enhancement During Initial Assessment and Treatment in Emergency care) sub-study (n=117). In patients with confirmed acute coronary syndromes, associations between 132 634 variants and 12-h circulating FFA response were assessed. Between initial and 6-h measurements, three LINGO2 variants were associated with increased levels of total FFA (P-value for 2 degree of freedom test, P2df ?5.51 * 10-7). Lead LINGO2 single-nucleotide polymorphism, rs12003487, was nominally associated with reduced 30-day ejection fraction (P2df=0.03). Several LINGO2 signals were linked to alterations in epigenetic profile and gene expression levels. Between 6 and 12 h, rs7017336 nearest to IMPA1/FABP12 showed an association with decreased saturated FFAs (P2df=5.47 * 10-7). Nearest to DUSP26, rs7464104 was associated with a decrease in unsaturated FFAs (P2df=5.51 * 10-7). Genetic variation may modify FFA response to GIK, potentially conferring less beneficial outcomes. PMID- 26644204 TI - Pharmacogenetics and induction/consolidation therapy toxicities in acute lymphoblastic leukemia patients treated with AIEOP-BFM ALL 2000 protocol. AB - Drug-related toxicities represent an important clinical concern in chemotherapy, genetic variants could help tailoring treatment to patient. A pharmacogenetic multicentric study was performed on 508 pediatric acute lymphoblastic leukemia patients treated with AIEOP-BFM 2000 protocol: 28 variants were genotyped by VeraCode and Taqman technologies, deletions of GST-M1 and GST-T1 by multiplex PCR. Toxicities were derived from a central database: 251 patients (49.4%) experienced at least one gastrointestinal (GI) or hepatic (HEP) or neurological (NEU) grade III/IV episode during the remission induction phase: GI occurred in 63 patients (12.4%); HEP in 204 (40.2%) and NEU in 44 (8.7%). Logistic regression model adjusted for sex, risk and treatment phase revealed that ITPA rs1127354 homozygous mutated patients showed an increased risk of severe GI and NEU. ABCC1 rs246240 and ADORA2A rs2236624 homozygous mutated genotypes were associated to NEU and HEP, respectively. These three variants could be putative predictive markers for chemotherapy-related toxicities in AIEOP-BFM protocols. PMID- 26644206 TI - Effect of gene polymorphims on the warfarin treatment at initial stage. AB - The adverse reactions of warfarin that were found mainly occurred in the first month. This study was carried out to observe the effect of gene polymorphisms on the warfarin therapy at the initial stage. Four-hundred and sixty Chinese patients began warfarin treatment with daily 2.5 mg after heart valve replacement operations were enrolled. The daily international normalized ratio (INR) for anticoagulation were recorded till the seventh day. Blood samples were collected and used to detect genotypes for VKORC1 rs7294, CYP2C9 rs1057910, CYP4F2 rs2108622 and ORM1 rs17650. INR and their changes were compared among genotypes. INR was partially correlated with the VKORC1 rs7294, CYP2C9 rs1057910, CYP4F2 rs2108622 and ORM1 rs17650 polymorphisms from the third, fourth and sixth day on, respectively. VKORC1 rs7294 and CYP4F2 rs2108622 carriers responded lower than the wild genotype, whereas CYP2C9 rs1057910 and ORM1 rs17650 carriers responded higher, respectively. Fifty percent of AA/*1*3/CC/*S*S patients and 16% of AA/*1*1/CC/*S*S patients were over anticoagulation treated with INR >4.0 at the third day. Ninety percent of VKORC1 rs7294 carrier patients have INR <1.63, a mark of the 25% of lower responders of the wild genotype. Our study provided another kind of evidence that VKORC1 rs7294, CYP2C9 rs1057910, CYP4F2 rs2108622 and ORM1 rs17650 affected the action of warfarin in different styles. Patients with AA/*1*1/CC/*S*S, AA/*1*3/CC/*S*S should use a less initial dosage to avoid over anticoagulation, and patients with VKORC1 rs7294 should use larger initial dose to proof an effective therapy. PMID- 26644205 TI - CRTC2 polymorphism as a risk factor for the incidence of metabolic syndrome in patients with solid organ transplantation. AB - Metabolic syndrome after transplantation is a major concern following solid organ transplantation (SOT). The CREB-regulated transcription co-activator 2 (CRTC2) regulates glucose metabolism. The effect of CRTC2 polymorphisms on new-onset diabetes after transplantation (NODAT) was investigated in a discovery sample of SOT recipients (n1=197). Positive results were tested for replication in two samples from the Swiss Transplant Cohort Study (STCS, n2=1294 and n3=759). Obesity and other metabolic traits were also tested. Associations with metabolic traits in population-based samples (n4=46'186, n5=123'865, n6>100,000) were finally analyzed. In the discovery sample, CRTC2 rs8450-AA genotype was associated with NODAT, fasting blood glucose and body mass index (Pcorrected<0.05). CRTC2 rs8450-AA genotype was associated with NODAT in the second STCS replication sample (odd ratio (OR)=2.01, P=0.04). In the combined STCS replication samples, the effect of rs8450-AA genotype on NODAT was observed in patients having received SOT from a deceased donor and treated with tacrolimus (n=395, OR=2.08, P=0.02) and in non-kidney transplant recipients (OR=2.09, P=0.02). Moreover, rs8450-AA genotype was associated with overweight or obesity (n=1215, OR=1.56, P=0.02), new-onset hyperlipidemia (n=1007, OR=1.76, P=0.007), and lower high-density lipoprotein-cholesterol (n=1214, beta=-0.08, P=0.001). In the population-based samples, a proxy of rs8450G>A was significantly associated with several metabolic abnormalities. CRTC2 rs8450G>A appears to have an important role in the high prevalence of metabolic traits observed in patients with SOT. A weak association with metabolic traits was also observed in the population-based samples. PMID- 26644208 TI - Immunomodulatory effects of fluoxetine: A new potential pharmacological action for a classic antidepressant drug? AB - Selective serotonin reuptake inhibitors are frequently used antidepressants. In particular, fluoxetine is usually chosen for the treatment of the symptoms of depression, obsessive-compulsive, panic attack and bulimia nervosa. Antidepressant therapy has been associated with immune dysfunction. However, there is contradictory evidence about the effect of fluoxetine on the immune system. Experimental findings indicate that lymphocytes express the serotonin transporter. Moreover it has been shown that fluoxetine is able to modulate the immune function through a serotonin-dependent pathway and through a novel independent mechanism. In addition, several studies have shown that fluoxetine can alter tumor cell viability. Thus, it was recently demonstrated in vivo that chronic fluoxetine treatment inhibits tumor growth by increasing antitumor T-cell activity. Here we briefly review some of the literature referring to how fluoxetine is able to modify, for better or worse, the functionality of the immune system. These results of our analysis point to the relevance of the novel pharmacological action of this drug as an immunomodulator helping to treat several pathologies in which immune deficiency and/or deregulation is present. PMID- 26644207 TI - Pharmacogenetic study of long-term response to interferon-beta treatment in multiple sclerosis. AB - The aim of the study is the identification of genetic factors that influence the long-term response to interferon-beta (IFNbeta) (4-year follow-up). We performed a genome-wide association study in 337 IFNbeta-treated Italian multiple sclerosis patients at the extreme of treatment response, and we meta-analyzed association effects, integrating results with pathway analysis, gene-expression profiling of IFNbeta-stimulated peripheral blood mononuclear cells from 20 healthy controls (HC) and expression quantitative locus (eQTL) analyses. From meta-analysis, 43 markers were associated at P<10-4, and two of them (rs7298096 and rs4726460) pointed to two genes, NINJ2 and TBXAS1, that were significantly downregulated after IFNbeta stimulation in HC (P=3.1 * 10-9 and 5.6 * 10-10). We also observed an eQTL effect for the allele associated with favorable treatment response (rs4726460A); moreover, TBXAS1 appeared downregulated upon IFNbeta administration (beta=-0.39; P=0.02). Finally, we found an enrichment of pathways related to inflammatory processes and presynaptic membrane, the latter with involvement of genes related to glutamatergic system (GRM3 and GRIK2), confirming its potential role in the response to IFNbeta. PMID- 26644210 TI - The Incidence of Spinal Cord Injury in Implantation of Percutaneous and Paddle Electrodes for Spinal Cord Stimulation. AB - OBJECTIVE: Spinal cord stimulation (SCS) has been proven effective for multiple chronic pain syndromes. Over the past 40 years of use, the complication rates of SCS have been well defined in the literature; however, the incidence of one of the most devastating complications, spinal cord injury (SCI), remains largely unknown. The goal of the study was to quantify the incidence of SCI in both percutaneous and paddle electrode implantation. METHODS: We conducted a retrospective review of the Thomson Reuter's MarketScan database of all patients that underwent percutaneous or paddle SCS implantation from 2000 to 2009. The main outcome measures of the study were the incidence of SCI and spinal hematoma within 30 days following operation. RESULTS: Overall 8326 patients met inclusion criteria for the study (percutaneous: 5458 vs. paddle: 2868). The overall incidence of SCI was 177 (2.13%) (percutaneous: 128 (2.35%) vs. paddle: 49 (1.71%), p = 0.0556). The overall incidence of spinal hematoma was 59 (0.71%) (percutaneous: 41 (0.75%) vs. paddle: 18 (0.63%), p = 0.5230). CONCLUSION: Our study shows that the overall incidence of SCI in SCS is low (2.13%), supporting that SCS is a safe procedure. No significant difference was found in the rates of SCI or spinal hematoma between the percutaneous and paddle groups. Further studies are needed to characterize the mechanisms of SCI in SCS and long-term outcomes in these patients. PMID- 26644209 TI - High-Performance Hydrogen Evolution from MoS2(1-x) P(x) Solid Solution. AB - A MoS2(1-x) P(x) solid solution (x = 0 to 1) is formed by thermally annealing mixtures of MoS2 and red phosphorus. The effective and stable electrocatalyst for hydrogen evolution in acidic solution holds promise for replacing scarce and expensive platinum that is used in present catalyst systems. The high performance originates from the increased surface area and roughness of the solid solution. PMID- 26644211 TI - Stress, cortisol, and B lymphocytes: a novel approach to understanding academic stress and immune function. AB - Animal and human in vitro models suggest that stress-related B lymphocyte decrements are due to high levels of glucocorticoids which cause apoptosis of pre B-cells as they emerge from the bone marrow. The present study sought to explore the relationships among distress, salivary cortisol, and human B lymphocytes in vivo. Distress (perceived stress, negative affect, depressive symptoms), lymphocyte phenotype, and salivary cortisol were assessed among first-year graduate students (n = 22) and a community control sample (n = 30) at the start of classes in the fall and the week immediately before spring preliminary exams. Compared to controls, students reported greater distress on all measures at each time point except baseline perceived stress. Hierarchical linear regression with necessary control variables was used to assess the effect of student status on the three measures of distress, the four measures of lymphocyte phenotype, and cortisol AUC and CAR over time (T1-T2). Student status was associated with a significant decrease in CD19 + B lymphocytes and flattened cortisol awakening response (CAR). Change in CAR was associated with the decrease in CD19 + B lymphocytes. Results indicated that there are significant associations among student status, flattening of CAR, and decrements in CD19 + lymphocytes. PMID- 26644212 TI - Scrolls: novel microparticulate systems for enhanced delivery to/across the skin. AB - We describe the scroll system as a new microparticulate structured delivery system for enhanced delivery to/across the skin. The basic components of the scroll system are non-ionic surface active of the type of alkyl polyglycol ethers and a glycol. The unique structures are preserved with addition of various ingredients such as polymers, vegetable oils, pharmaceuticals, and permeation enhancers but are dismissed when amphiphile is withdrawn. The microparticles have a unique scroll structure with multiple "wrapping." Besides enabling superior permeation of drugs into/across the skin, the drugs delivered by scroll systems were more effective in vitro and in vivo compared to controls. Model drugs presented high entrapment capacity in scroll systems. The systems are stable over time and are safe for skin application. In order to form, they require a small number of ingredients, simple preparation method, and are environment friendly. The scroll systems may be new potential tools in the dermal/transdermal pharmaceutical and cosmetic industry. PMID- 26644213 TI - EEG for children with complex febrile seizures. AB - BACKGROUND: This is an updated version of original Cochrane review published in Issue 1, 2014.Febrile seizures can be classified as simple or complex. Complex febrile seizures are associated with fever that lasts longer than 15 minutes, occur more than once within 24 hours and are confined to one side of the child's body. It is common in some countries for doctors to recommend an electroencephalograph (EEG) for children with complex febrile seizures. A limited evidence base is available to support the use of EEG and its timing after complex febrile seizures among children. OBJECTIVES: To assess the use of EEG and its timing after complex febrile seizures in children younger than five years of age. SEARCH METHODS: For the latest update of this review, we searched the Cochrane Epilepsy Group Specialized Register (6 July 2015), the Cochrane Central Register of Controlled Trials (CENTRAL, 2005, Issue 6), MEDLINE (6 July 2015) and ClinicalTrials.gov (6 July 2015). We applied no language restrictions. SELECTION CRITERIA: All randomised controlled trials (RCTs) that examined the utility of an EEG and its timing after complex febrile seizures in children. DATA COLLECTION AND ANALYSIS: Review authors selected and retrieved the articles and independently assessed which articles should be included. We resolved disagreements by discussion and by consultation with the Cochrane Epilepsy Group. We applied standard methodological procedures expected by Cochrane. MAIN RESULTS: Of 37 potentially eligible studies, no RCTs met the inclusion criteria. AUTHORS' CONCLUSIONS: We found no RCTs as evidence to support or refute the use of EEG and its timing after complex febrile seizures among children. An RCT can be planned in such a way that participants are randomly assigned to the EEG group and to the non-EEG group with sufficient sample size. Since the last version of this review, we found no new studies. PMID- 26644214 TI - Balance of RNA sequence requirement and NS3/NS3a expression of segment 10 of orbiviruses. AB - Orbiviruses are insect-transmitted, non-enveloped viruses with a ten-segmented dsRNA genome of which the bluetongue virus (BTV) is the prototype. Viral non structural protein NS3/NS3a is encoded by genome segment 10 (Seg-10), and is involved in different virus release mechanisms. This protein induces specific release via membrane disruptions and budding in both insect and mammalian cells, but also the cytopathogenic release that is only seen in mammalian cells. NS3/NS3a is not essential for virus replication in vitro with BTV Seg-10 containing RNA elements essential for virus replication, even if protein is not expressed. Recently, new BTV serotypes with distinct NS3/NS3a sequence and cell tropism have been identified. Multiple studies have hinted at the importance of Seg-10 in orbivirus replication, but the exact prerequisites are still unknown. Here, more insight is obtained with regard to the needs for orbivirus Seg-10 and the balance between protein expression and RNA elements. Multiple silent mutations in the BTV NS3a ORF destabilized Seg-10, resulting in deletions and sequences originating from other viral segments being inserted, indicating strong selection at the level of RNA during replication in mammalian cells in vitro. The NS3a ORFs of other orbiviruses were successfully exchanged in BTV1 Seg-10, resulting in viable chimeric viruses. NS3/NS3a proteins in these chimeric viruses were generally functional in mammalian cells, but not in insect cells. NS3/NS3a of the novel BTV serotypes 25 and 26 affected virus release from Culicoides cells, which might be one of the reasons for their distinct cell tropism. PMID- 26644216 TI - Simultaneous implant placement with ridge augmentation using an autogenous bone ring transplant. AB - The severely defective socket, in which implant placement within the remaining bone will result in a significantly off-axis implant position, precludes immediate implant placement and requires bone grafting as an initial surgical intervention. The aims of this study were to evaluate autogenous chin bone ring consolidation after the augmentation of severely defective sockets and the clinical application of these rings in the premolar-molar region with simultaneous implant placement in a one-stage procedure. Ten patients with 12 defective sockets were included. Sockets were prepared with a trephine bur. Bone rings with a tapped implant osteotomy were harvested from the chin with a larger trephine bur. Bone rings were fitted in the prepared sockets. An implant drill was used to prepare the bone apical to the ring through its central osteotomy. Implants were screwed through the rings and the apical bone. Patients were examined clinically and radiographically immediately and at 6 months postoperative. Crestal bone changes were measured and evaluated statistically. All grafted sockets showed bone healing with no significant crestal bone resorption and no infection; only one ring showed dehiscence, which healed during the follow-up period. All implants showed radiographic evidence of osseointegration. The autogenous chin bone ring augmentation technique was found to be a reliable alternative method for the management of severely defective sockets. PMID- 26644217 TI - Effects of mandibular advancement surgery on the temporomandibular joint and muscular and articular adaptive changes--a systematic review. AB - The objective of this study was to assess the anatomical changes to the condyle and articular disc following mandibular advancement surgery, the adaptation of the masticatory muscles, and the improvement or worsening of temporomandibular disorders (TMD) in patients with pre-existing disorders and those who developed them following surgery. Four databases were searched systematically: PubMed, Scopus, Embase, and Cochrane Library. Of the 544 articles initially selected, 219 were duplicates and a further 165 were excluded on the basis of their titles and abstracts. On reading the full text, 89 were excluded because they were of no interest and 43 because they did not meet the inclusion criteria. Of the remaining 28 articles, six were excluded because they were considered of low quality and 22 articles were reviewed. Mandibular advancement surgery with condyle repositioning is associated with less TMD. Condylar resorption is a physiological process with a multifactorial aetiology. It is accelerated following mandibular advancement surgery but is not a contraindication to this procedure. Despite the large number of studies on the effects of mandibular advancement surgery on the temporomandibular joint (TMJ), this surgery can neither be said to improve nor to worsen TMJ health. PMID- 26644215 TI - Inflammatory potential of diet and all-cause, cardiovascular, and cancer mortality in National Health and Nutrition Examination Survey III Study. AB - BACKGROUND: Various dietary components have been studied in relation to overall mortality; however, little is known about the relationship between the inflammatory potential of overall diet and mortality. MATERIALS AND METHODS: We examined the association between the dietary inflammatory index (DII) and mortality in the National Health and Nutrition Examination Survey III follow-up study. The DII was computed from baseline dietary intake assessed using 24-h dietary recalls (1988-1994). Mortality was determined from the National Death Index records through 2006. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95 % confidence interval (95 % CI). During the follow-up, 2795 deaths were identified, including 1233 due to cardiovascular disease (CVD), and 615 due to cancer, 158 of which were due to digestive-tract cancers. RESULTS: Multivariate Cox proportional hazards regression analyses, adjusting for age, race, diabetes status, hypertension, physical activity, body mass index, poverty index, and smoking, revealed positive associations between higher DII scores and mortality. Comparing subjects in DII tertile 3 versus tertile 1, significant associations were noted for all-cause mortality (HRTertile3vs1 1.34; 95 % CI 1.19-1.51, P trend < 0.0001), CVD mortality (HRTertile3vs1 1.46; 95 % CI 1.18-1.81, P trend = 0.0006), cancer mortality (HRTertile3vs1 1.46; 95 % CI 1.10-1.96, P trend = 0.01), and digestive-tract cancer mortality (HRTertile3vs1 2.10; 95 % CI 1.15-3.84, P trend = 0.03). CONCLUSION: These results indicate that a pro-inflammatory diet, as indicated by higher DII scores, was associated with higher risk of all-cause, CVD, and cancer mortality. PMID- 26644218 TI - Clinical and radiological outcomes of transoral endoscope-assisted treatment of mandibular condylar fractures. AB - Fractures of the mandibular condyle are one of the most common craniofacial fractures. However, the diagnosis and treatment of these fractures is controversial because of the multiple surgical approaches available. The purposes of this study were to identify surgery-related technical tips for better outcomes and to evaluate the results as well as complications encountered during 7 years of endoscope use to supplement the limited intraoral approach in the treatment of mandibular condylar fractures. Between 2005 and 2012, 50 patients with condylar fractures underwent endoscope-assisted reduction surgery. Postoperative facial bone computed tomography and panoramic radiography demonstrated adequate reduction of the condylar fractures in all patients. No condylar resorption was detected, and most patients displayed a satisfactory functional and structural recovery. There was no facial nerve damage or transitory hypoesthesia, and there were no visible scars after the surgery. Transoral endoscope-assisted treatment is a challenging but reliable method with lower morbidity and a rapid recovery. PMID- 26644219 TI - Association between tooth loss and dementia among older people: a meta-analysis. PMID- 26644220 TI - One Dimensional(1D)-to-2D Crossover of Spin Correlations in the 3D Magnet ZnMn2O4. AB - We report on the intriguing evolution of the dynamical spin correlations of the frustrated spinel ZnMn2O4. Inelastic neutron scattering and magnetization studies reveal that the dynamical correlations at high temperatures are 1D. At lower temperature, these dynamical correlations become 2D. Surprisingly, the dynamical correlations condense into a quasi 2D Ising-like ordered state, making this a rare observation of two dimensional order on the spinel lattice. Remarkably, 3D ordering is not observed down to temperatures as low as 300 mK. This unprecedented dimensional crossover stems from frustrated exchange couplings due to the huge Jahn-Teller distortions around Mn(3+) ions on the spinel lattice. PMID- 26644221 TI - Building a better mouse embryo assay: effects of mouse strain and in vitro maturation on sensitivity to contaminants of the culture environment. AB - PURPOSE: The aim of this study is to compare the sensitivity of the standard one cell mouse embryo assay (MEA) to that using in vitro-matured oocytes from hybrid and outbred mice. METHODS: The study was done by culturing embryos in the presence or absence of two concentrations (0.0005 or 0.001 % v/v) of Triton X-100 (TX100). Embryonic development, blastocyst cell numbers (total and allocation to the trophectoderm [TE] and inner cell mass [ICM]), and blastocyst gene expression were evaluated. RESULTS: Neither concentration of TX100 affected (P > 0.05) cleavage, blastocyst development, or hatching in one-cell embryos from BDF1 mice. However, all cell number endpoints were reduced (P < 0.05) by the high concentration of TX100 and the number of ICM cells was reduced (P < 0.05) by the low concentration of TX100. Inhibitory (P < 0.05) effects of the high concentration of TX100 were observed in in vitro maturation (IVM) embryos from BDF1, CF1, and SW, but not ICR, mice. Cell number and allocation were negatively affected by the high concentration of TX100 in CF1 and SW embryos, but not in BDF1 or ICR embryos. The only developmental endpoints affected by the low concentration of TX100 were cleavage of BDF1 oocytes, blastocyst development of SW embryos, and cell numbers (total and inner cell mass (ICM)) of SW blastocysts. CONCLUSIONS: The sensitivity of the MEA to TX100 is improved by using embryos from in vitro-matured oocytes, using oocytes from some outbred (SW or CF1, not ICR) strains of mice, and evaluating blastocyst cell number and allocation. PMID- 26644222 TI - Gut microbiota in Malawian infants in a nutritional supplementation trial. AB - OBJECTIVES: To examine whether two forms of lipid-based nutrient supplements (LNS) or a micronutrient-fortified corn-soya blend were associated with development of the gut microbiota in Malawian infants, to assess the microbiota profiles at the age of 6 and 18 months and to follow the changes during the 12 month period. METHODS: This was a substudy of a 4-arm randomised controlled trial conducted in rural Malawi. Infants at the age of 6 months were randomised to receive no supplement during the primary follow-up period (control), 54 g/day of micronutrient-fortified LNS with milk protein base (milk LNS), 54 g/day of micronutrient-fortified LNS with soya protein base (soya LNS), or 71 g/day of micronutrient-fortified corn-soya blend for 12 months. Stool samples were collected at baseline (6 months) and end of trial (18 months). The 16S rRNA gene was amplified and subjected to multiplex sequencing. RESULTS: A total of 213 infants had paired microbiota data at 6 and 18 months of age. The Dirichlet multinomial test showed no significant difference in microbiota profile between the four intervention groups at either age (each P > 0.10). Bifidobacterium longum was most abundant at both ages. Lactobacillus ruminis, Shigella and Salmonella were present. The abundance of Prevotella and Faecalibacterium increased with age (each P < 0.001), while Bifidobacteriaceae and Enterobacteriaceae exhibited significant decrease (each P < 0.001). CONCLUSIONS: Nutritional supplementation by LNS or corn-soya blend for twelve months did not affect the gut microbiota profile in the rural Malawian context. PMID- 26644223 TI - The modulation of physicochemical characterization of innovative liposomal platforms: the role of the grafted thermoresponsive polymers. AB - This study is focused on chimeric advanced drug delivery systems and specifically on thermosensitive liposomes, combining lipids and thermoresponsive polymers. In this investigation, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) chimeric liposomal systems were prepared, incorporating the homopolymer C12H25-poly(N isopropylacrylamide)-COOH (C12H25-PNIPAM-COOH) and the block copolymer poly(n butylacrylate-b-N-isoropylacrylamide) (PnBA-PNIPAM), at six different molar ratios. Both of these polymers contain the thermoresponsive PNIPAM block, which exhibits lower critical solution temperature (LCST) at 32 degrees C in aqueous solutions, changing its nature from hydrophilic to hydrophobic above LCST. During the preparation of liposomes, the dispersions were observed visually, while after the preparation we studied the alterations of the physicochemical characteristics, by measuring the size, size distribution and zeta-potential of prepared liposomes. The presence of polymer, either C12H25-PNIPAM-COOH or PnBA PNIPAM, resulted in liposomes exhibiting different physicochemical characteristics in comparison to conventional DPPC liposomes. At the highest percentage of the polymeric guest, chimeric liposomes were found to retain their size during the stability studies. The incorporation of the appropriate amount of these novel thermoresponsive polymers yields liposomal stabilization and imparts thermoresponsiveness, due to the functional PNIPAM block. PMID- 26644224 TI - Octreotide in malignant chylothorax: a case report. AB - The treatment of malignancy-associated chylous pleural effusion and ascites, especially in the palliative setting, represents a major therapeutic challenge. Our patient, a case of metastatic lung cancer, was suffering from high-output, non-resolving, malignancy-related chylothorax. We found that subcutaneous octreotide in combination with fasting and total parenteral nutrition, followed later by institution of low-fat diet, resulted in its resolution. We suggest that it is a reasonable approach associated with minimal morbidity in what is otherwise a challenging clinical condition. PMID- 26644225 TI - Population Pharmacokinetics of Fixed Dose Combination of Ceftriaxone and Sulbactam in Healthy and Infected Subjects. AB - Increased antibacterial resistance (ABR) and limited drug discovery warrant optimized use of available antibiotics. One option is to rationally combine two antibiotics (fixed dose combination (FDC)) that may delay or prevent emergence of ABR in notorious pathogen. Major concern with FDC is the mutual interaction of its components that might influence their pharmacokinetic (PK) profile, requiring reassessing of whole formulation (adding cost and time). The interaction can be identified by comparing PK profile of a drug present in FDC with its independent entity. An open-label, crossover, single-dose comparative PK study of FDC (ceftriaxone and sulbactam) with their individual reference formulations was performed in 24 healthy adult subjects. No mutual PK interactions between ceftriaxone and sulbactam were observed. Pharmacokinetic data was used to develop a population-PK model to understand between-subject variability (BSV). Pharmacokinetics of ceftriaxone/sulbactam was explained by one and two compartment models, respectively. The subject's "weight" was identified as a covariate explaining BSV. Both internal and external validations (healthy/infected subjects) were done. The model-derived population-PK parameters of FDC's active components in infected subjects were similar to literature reported values of individual components. Efficacies of various FDC dosage regimens over a range of minimum inhibitory concentrations (MICs) were assessed by Monte Carlo simulations using population-PK parameters of infected/healthy subjects. In infected subjects, 3 g FDC/24 h can treat bacteria with MIC <=8 MUg/mL, while for MIC 8-32 MUg/mL, 3 g FDC/12 h is recommended. Lastly, the developed population-PK model was successfully used to predict drug exposure in pediatric population. PMID- 26644226 TI - Physiological changes in the peri-partum period and colostral IgG transfer in prolific D'man sheep: effects of parity and litter size. AB - The aim of this work was to assess maternal and neonatal changes in plasma proteins, glucose and cortisol and to quantify the colostral immunoglobulin G (IgG) transfer in the peri-partum period in D'man sheep, a prolific breed, taking into account the parity of the ewe. The concentrations of proteins and glucose were high in the ewes on day 7 and at lambing before decreasing. Likewise, cortisol plasma concentration was maximal during the 6 h following lambing and dropped at 12 h. Protein and glucose concentrations were low in lambs at 1 h of birth after which they increased. By contrast, cortisol level was the highest during the first 12 h of birth and then decreased. The colostral IgG level was high at lambing and dropped by over 87 % from 1 to 48 h post-partum. In the newborn, the plasma IgG concentration was lowest at birth and increased rapidly during the first 24 h of birth. Parity influenced maternal physiology with multiparous ewes having the lowest concentrations of proteins, glucose, IgG and cortisol, but the highest colostrum IgG level. Accordingly, lambs born from primiparous ewes had lower protein, glucose and plasma IgG concentrations than lambs born from multiparous ewes. The main outcome of this study was that lambs born from primiparous ewes are characterized by the lowest physiological indices and this may influence their survival chance. PMID- 26644227 TI - The complete chloroplast genome sequence of Schefflera octophylla. AB - The complete chloroplast genome sequence of Schefflera octophylla, a critical Chinese medicine was reported here. The complete chloroplast genome of Schefflera octophylla is 156 685 bp in length with 37.93% overall GC content. A pair of IRs (inverted repeats) of 25 965 bp were separated by LSC (86 609 bp) and SSC (18 146 bp). The phylogenetic analysis of 17 taxa showed a strong sister relationship with Schefflera delavayi. Furthermore the Araliaceae was separated into two major groups. PMID- 26644228 TI - Bacterial vaginosis and inflammatory response showed association with severity of cervical neoplasia in HPV-positive women. AB - Vaginal infections may affect susceptibility to and clearance of human papillomavirus (HPV) infection and chronic inflammation has been linked to carcinogenesis. This study aimed to evaluate the association between bacterial vaginosis (BV) and inflammatory response (IR) with the severity of cervical neoplasia in HPV-infected women. HPV DNA was amplified using PGMY09/11 primers and genotyping was performed using a reverse line blot hybridization assay in 211 cervical samples from women submitted to excision of the transformation zone. The bacterial flora was assessed in Papanicolaou stained smears, and positivity for BV was defined as >= 20% of clue cells. Present inflammatory response was defined as >= 30 neutrophils per field at 1000* magnification. Age higher than 29 years (OR:1.91 95% CI 1.06-3.45), infections by the types 16 and/or 18 (OR:1.92 95% CI 1.06-3.47), single or multiple infections associated with types 16 and/or 18 (OR: 1.92 CI 95% 1.06-3.47), BV (OR: 3.54 95% CI 1.62-7.73) and IR (OR: 6.33 95% CI 3.06-13.07) were associated with severity of cervical neoplasia (CIN 2 or worse diagnoses), while not smoking showed a protective effect (OR: 0.51 95% CI 0.26 0.98). After controlling for confounding factors, BV(OR: 3.90 95% CI 1.64-9.29) and IR (OR: 6.43 95% CI 2.92-14.15) maintained their association with the severity of cervical neoplasia. Bacterial vaginosis and inflammatory response were independently associated with severity of cervical neoplasia in HPV-positive women, which seems to suggest that the microenvironment would relate to the natural history of cervical neoplasia. PMID- 26644229 TI - The Content of Thyroid Hormone Receptor alpha in Ewe Kisspeptin Neurones is not Season-Dependent. AB - Seasonal reproduction is grounded in several mechanisms, among which are plasticity in both hormone synthesis and neuronal networks. Increased daylength on long days (LD) translates into local tri-iodothyronin (T3) production in the mediobasal hypothalamus that will enable the transition to the anoestrus season in sheep. The photoperiod also strongly affects the content of kisspeptin (Kiss), a hypothalamic neuropeptide exerting a potent stimulatory effect on gonadotrophin releasing hormone release. Our hypothesis was that T3 directly inhibits Kiss release during LD. Using double immunocytochemistry, we first searched for coexpression of thyroid hormone receptor (THR)alpha in Kiss neurones in ewes with an active or inactive gonadotrophic axis. In both the preoptic area and the arcuate nucleus, most Kiss neurones were labelled by THR antibody under both physiological/photoperiodic conditions. These results suggest thyroid hormones may affect Kiss synthesis and release all through the year. We then attempted to assess the influence of T3 on Kiss content in hypothalamic explants sampled from ewes with an active gonadotrophic axis. Kiss produced by hypothalamic explants cultured with different doses of T3 (300 or 600 pg) and subjected to different times of incubation (2 or 24 h) was measured. No significant effects of T3 on Kiss tissular content were observed for the two doses of T3 and for the two incubation times. In light of these findings, potential reasons for the divergent effects of thyroid hormones on Kiss content are discussed. Our data emphasise that the effects of thyroid hormone on Kiss synthesis are not one-sided and may affect a wide range of functions. PMID- 26644230 TI - Hemiarthroplasty versus reverse shoulder arthroplasty for treatment of proximal humeral fractures: a meta-analysis. AB - BACKGROUND: We performed a meta-analysis of studies with at least Level IV evidence to compare outcomes between hemiarthroplasty and reverse shoulder arthroplasty for the treatment of proximal humeral fractures. METHODS: Three electronic databases (PubMed, Cochrane, and EMBASE) were searched. The quality of each study was investigated, and data on radiographic and functional outcomes were extracted and analyzed. RESULTS: The analysis included 1 Level I study, 1 Level II study, 3 Level III studies, and 2 Level IV studies. Reverse shoulder arthroplasty was more favorable than hemiarthroplasty in forward elevation (P < .001), abduction (P < .001), tuberosity healing (P = .002), Constant score (P < .001), American Shoulder and Elbow Surgeons score (P < .001), and Disabilities of the Arm, Shoulder and Hand score (P = .001). Only external rotation (P = .85) was not in favor of reverse shoulder arthroplasty. CONCLUSIONS: The available literature suggests that reverse shoulder arthroplasty performed to address complex proximal humeral fractures might result in more favorable clinical outcomes than hemiarthroplasty performed for the same indication. PMID- 26644231 TI - 'Real-life' effectiveness studies of omalizumab in adult patients with severe allergic asthma: systematic review. AB - We reviewed 24 'real-life' effectiveness studies of omalizumab in the treatment of severe allergic asthma that included 4117 unique patients from 32 countries with significant heterogeneity in patients, clinicians and settings. The evidence underscores the short- and long-term benefit of anti-IgE therapy in terms of the following: improving lung function; achieving asthma control and reducing symptomatology, severe exacerbations and associated work/school days lost; reducing healthcare resource utilizations, in particular hospitalizations, hospital lengths of stay and accident specialist or emergency department visits; reducing or discontinuing other asthma medications; and improving quality of life - thus confirming, complementing and extending evidence from randomized trials. Thus, omalizumab therapy is associated with signal improvements across the full objective and subjective burden of illness chain of severe allergic asthma. Benefits of omalizumab may extend up to 2-4 years, and the majority of omalizumab treated patients may benefit for many years. Omalizumab has positive short- and long-term safety profiles similar to what is known from randomized clinical trials. Initiated patients should be monitored for treatment response at 16 weeks. Those showing positive response at that time are highly likely to show sustained treatment response and benefit in terms of clinical, quality of life and health resource utilization outcomes. PMID- 26644232 TI - European League Against Rheumatism (EULAR) recommendations for the management of psoriatic arthritis with pharmacological therapies: 2015 update. AB - BACKGROUND: Since the publication of the European League Against Rheumatism recommendations for the pharmacological treatment of psoriatic arthritis (PsA) in 2012, new evidence and new therapeutic agents have emerged. The objective was to update these recommendations. METHODS: A systematic literature review was performed regarding pharmacological treatment in PsA. Subsequently, recommendations were formulated based on the evidence and the expert opinion of the 34 Task Force members. Levels of evidence and strengths of recommendations were allocated. RESULTS: The updated recommendations comprise 5 overarching principles and 10 recommendations, covering pharmacological therapies for PsA from non-steroidal anti-inflammatory drugs (NSAIDs), to conventional synthetic (csDMARD) and biological (bDMARD) disease-modifying antirheumatic drugs, whatever their mode of action, taking articular and extra-articular manifestations of PsA into account, but focusing on musculoskeletal involvement. The overarching principles address the need for shared decision-making and treatment objectives. The recommendations address csDMARDs as an initial therapy after failure of NSAIDs and local therapy for active disease, followed, if necessary, by a bDMARD or a targeted synthetic DMARD (tsDMARD). The first bDMARD would usually be a tumour necrosis factor (TNF) inhibitor. bDMARDs targeting interleukin (IL)12/23 (ustekinumab) or IL-17 pathways (secukinumab) may be used in patients for whom TNF inhibitors are inappropriate and a tsDMARD such as a phosphodiesterase 4 inhibitor (apremilast) if bDMARDs are inappropriate. If the first bDMARD strategy fails, any other bDMARD or tsDMARD may be used. CONCLUSIONS: These recommendations provide stakeholders with an updated consensus on the pharmacological treatment of PsA and strategies to reach optimal outcomes in PsA, based on a combination of evidence and expert opinion. PMID- 26644233 TI - Tocilizumab in systemic juvenile idiopathic arthritis in a real-world clinical setting: results from 1 year of postmarketing surveillance follow-up of 417 patients in Japan. AB - OBJECTIVES: To evaluate the safety and effectiveness of tocilizumab (TCZ) in patients with systemic juvenile idiopathic arthritis (sJIA) in real-world clinical settings in Japan. METHODS: Paediatric patients with sJIA initiating TCZ between April 2008 and February 2012 and those previously enrolled in clinical trials who initiated TCZ before April 2008 were enrolled in a Japanese registry surveillance programme. Safety and effectiveness parameters were collected for 52 weeks. RESULTS: Of 417 patients enrolled, mean age was 11.2 years and 48.0% were female. TCZ exposure was 407.0 patient-years (PYs). Baseline corticosteroid use was higher than in clinical trials. Rates of total adverse events (AEs) and serious AEs (SAEs) were 224.3/100 PYs and 54.5/100 PYs, respectively, with SAEs higher than previously reported. The most frequent AEs and SAEs were infections and infestations (69.8/100 PYs and 18.2/100 PYs, respectively). 74 serious infections occurred in 55 patients (18.2/100 PYs); higher than previously reported. 26 macrophage activation syndrome events were reported in 24 patients (6.4/100 PYs). Fever and rash symptoms improved from baseline to week 52 (54.6% to 5.6% and 43.0% to 5.6%, respectively). At 4 weeks, 8 weeks and 52 weeks, 90.5%, 96.2% and 99.0% of patients achieved normal C reactive protein levels (<0.3 mg/dL), respectively. CONCLUSIONS: These first real-world data demonstrated that TCZ was well tolerated, with acceptable safety and effectiveness in patients with sJIA. Higher incidences of SAEs and serious infections may be due to differences, such as corticosteroid use and concomitant diseases, between patient populations enrolled in previously reported clinical trials and this study. PMID- 26644234 TI - Developmental Risk Signals as a Screening Tool for Early Identification of Sensory Processing Disorders. AB - The main purpose of this research was to determine if the indicators of risk included in the Indicators of Developmental Risk Signals (INDIPCD-R) could differentiate between children at risk of sensory processing disorders (SPDs) from those with normal development and if the SPD indicators correlated with a delay or altered development. A retrospective, descriptive, correlational design was used with a sample of 51 children, 36 referred because of clinical sensory processing indicators and 15 with non-clinical indicators. Participants were assessed with a developmental scale Revised Profile of Developmental Behaviors (PCD-R), the Sensory Profile, play and clinical observations. The INDIPCD-R showed a high correlation with developmental areas of PCD-R and a sensitivity and specificity of 100%, when compared with the Sensory Profile. T-test results for independent samples showed significant differences at p <= 0.01 level between the children with SPD indicators and those with no clinical signs in the PCD-R. The Mann-Whitney U-test was conducted for unpaired samples, to verify if there were significant differences between children with apparent SPD indicators and children with no apparent difficulties. The Spearman's rho was used to identify the correlations between the INDIPCD-R, with different areas of development. This study supports the use of the INDIPCD-R as a screening instrument that could be used by occupational therapists to discriminate children with and without indicators of SPD. The limitation of this study was that it did not cover all the ages of the INDIPCD-R. Additional studies are required to determine the utility of this instrument for outcome studies and whether it is valid and reliable to identify children at risk of different pathologies. The INDIPCD-R is a low-cost instrument that allows the occupational therapist to make a quick review of the different components that could be involved in SPD and therefore guide the more in-depth evaluation if necessary. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26644235 TI - Hypoxia facilitates neurogenic dural plasma protein extravasation in mice: a novel animal model for migraine pathophysiology. AB - Migraine animal models generally mimic the onset of attacks and acute treatment processes. A guinea pig model used the application of meta-chlorophenylpiperazine (mCPP) to trigger immediate dural plasma protein extravasation (PPE) mediated by 5-HT2B receptors. This model has predictive value for antimigraine drugs but cannot explain the delayed onset of efficacy of 5-HT2B receptor antagonists when clinically used for migraine prophylaxis. We found that mCPP failed to induce dural PPE in mice. Considering the role 5-HT2B receptors play in hypoxia-induced pulmonary vessel muscularization, we were encouraged to keep mice under hypoxic conditions and tested whether this treatment will render them susceptible to mCPP induced dural PPE. Following four-week of hypoxia, PPE, associated with increased transendothelial transport, was induced by mCPP. The effect was blocked by sumatriptan. Chronic application of 5-HT2B receptor or nitric oxide synthase blockers during hypoxia prevented the development of susceptibility. Here we present a migraine model that distinguishes between a migraine-like state (hypoxic mice) and normal, normoxic mice and mimics processes that are related to chronic activation of 5-HT2B receptors under hypoxia. It seems striking, that chronic endogenous activation of 5-HT2B receptors is crucial for the sensitization since 5-HT2B receptor antagonists have strong, albeit delayed migraine prophylactic efficacy. PMID- 26644236 TI - Selective Blockade of Periostin Exon 17 Preserves Cardiac Performance in Acute Myocardial Infarction. AB - We previously reported that overexpression of full-length periostin, Pn-1, resulted in ventricular dilation with enhanced interstitial collagen deposition in a rat model. However, other reports have documented that the short-form splice variants Pn-2 (lacking exon 17) and Pn-4 (lacking exons 17 and 21) promoted cardiac repair by angiogenesis and prevented cardiac rupture after acute myocardial infarction. The apparently differing findings from those reports prompted us to use a neutralizing antibody to selectively inhibit Pn-1 by blockade of exon 17 in a rat acute myocardial infarction model. Administration of Pn neutralizing antibody resulted in a significant decrease in the infarcted and fibrotic areas of the myocardium, which prevented ventricular wall thinning and dilatation. The inhibition of fibrosis by Pn neutralizing antibody was associated with a significant decrease in gene expression of fibrotic markers, including collagen I, collagen III, and transforming growth factor-beta1. Importantly, the number of alpha-smooth muscle actin-positive myofibroblasts was significantly reduced in the hearts of animals treated with Pn neutralizing antibody, whereas cardiomyocyte proliferation and angiogenesis were comparable in the IgG and neutralizing antibody groups. Moreover, the level of Pn-1 expression was significantly correlated with the severity of myocardial infarction. In addition, Pn-1, but not Pn-2 or Pn-4, inhibited fibroblast and myocyte attachment, which might account for the cell slippage observed during cardiac remodeling. Collectively, these results indicate that therapeutics that specifically inhibit Pn exon-17, via a neutralizing antibody or drug, without suppressing other periostin variants might offer a new class of medication for the treatment of acute myocardial infarction patients. PMID- 26644237 TI - Evidence of the Importance of Nox4 in Production of Hypertension in Dahl Salt Sensitive Rats. AB - This study reports the consequences of knocking out NADPH (nicotinamide adenine dinucleotide phosphate) oxidase 4 (Nox4) on the development of hypertension and kidney injury in the Dahl salt-sensitive (SS) rat. Zinc finger nuclease injection of single-cell SS embryos was used to create an 8 base-pair frame-shift deletion of Nox4, resulting in a loss of the ~68 kDa band in Western blot analysis of renal cortical tissue of the knock out of Nox4 in the SS rat (SS(Nox4-/-)) rats. SS(Nox4-/-) rats exhibited a significant reduction of salt-induced hypertension compared with SS rats after 21 days of 4.0% NaCl diet (134+/-5 versus 151+/-3 mm Hg in SS) and a significant reduction of albuminuria, tubular casts, and glomerular injury. Optical fluorescence 3-dimensional cryoimaging revealed significantly higher redox ratios (NADH/FAD [reduced nicotinamide adenine dinucleotide/flavin adenine dinucleotide]) in the kidneys of SS(Nox4-/-) rats even when fed the 0.4% NaCl diet, indicating greater levels of mitochondrial electron transport chain metabolic activity and reduced oxidative stress compared with SS rats. Before the development of hypertension, RNA expression levels of Nox subunits Nox2, p67(phox), and p22(phox) were found to be significantly lower (P<0.05) in SS(Nox4-/-) compared with SS rats in the renal cortex. Thus, the mutation of Nox4 seems to modify transcription of several genes in ways that contribute to the protective effects observed in the SS(Nox4-/-) rats. We conclude that the reduced renal injury and attenuated blood pressure response to high salt in the SS(Nox4-/-) rat could be the result of multiple pathways, including gene transcription, mitochondrial energetics, oxidative stress, and protein matrix production impacted by the knock out of Nox4. PMID- 26644238 TI - Early Weight Gain, Linear Growth, and Mid-Childhood Blood Pressure: A Prospective Study in Project Viva. AB - In recent years, the prevalence of hypertension and prehypertension increased markedly among children and adolescents, highlighting the importance of identifying determinants of elevated blood pressure early in life. Low birth weight and rapid early childhood weight gain are associated with higher future blood pressure. However, few studies have examined the timing of postnatal weight gain in relation to later blood pressure, and little is known regarding the contribution of linear growth. We studied 957 participants in Project Viva, an ongoing US prebirth cohort. We examined the relations of gains in body mass index z-score and length/height z-score during 4 early life age intervals (birth to 6 months, 6 months to 1 year, 1 to 2 years, and 2 to 3 years) with blood pressure during mid-childhood (6-10 years) and evaluated whether these relations differed by birth size. After accounting for confounders, each additional z-score gain in body mass index during birth to 6 months and 2 to 3 years was associated with 0.81 (0.15, 1.46) and 1.61 (0.33, 2.89) mm Hg higher systolic blood pressure, respectively. Length/height gain was unrelated to mid-childhood blood pressure, and there was no evidence of effect modification by birth size for body mass index or length/height z-score gain. Our findings suggest that more rapid gain in body mass index during the first 6 postnatal months and in the preschool years may lead to higher systolic blood pressure in mid-childhood, regardless of size at birth. Strategies to reduce accrual of excess adiposity during early life may reduce mid-childhood blood pressure, which may also impact adult blood pressure and cardiovascular health. PMID- 26644240 TI - Autoimmunity in the Pathogenesis of Hypertension. PMID- 26644239 TI - Fruit and Vegetable Consumption and the Incidence of Hypertension in Three Prospective Cohort Studies. AB - Increased fruit and vegetable intake lowers blood pressure in short-term interventional studies. However, data on the association of long-term intake of fruits and vegetables with hypertension risk are scarce. We prospectively examined the independent association of whole fruit (excluding juices) and vegetable intake, as well as the change in consumption of whole fruits and vegetables, with incident hypertension in 3 large longitudinal cohort studies: Nurses' Health Study (n=62 175), Nurses' Health Study II (n=88 475), and Health Professionals Follow-up Study (n=36 803). We calculated hazard ratios and 95% confidence intervals for fruit and vegetable consumption while controlling for hypertension risk factors. Compared with participants whose consumption was <=4 servings/week, the pooled hazard ratios among those whose intake was >=4 servings/day were 0.92(0.87-0.97) for total whole fruit intake and 0.95(0.86 1.04) for total vegetable intake. Similarly, compared with participants who did not increase their fruit or vegetable consumption, the pooled hazard ratios for those whose intake increased by >=7 servings/week were 0.94(0.90-0.97) for total whole fruit intake and 0.98(0.94-1.01) for total vegetable. Analyses of individual fruits and vegetables yielded different results. Consumption levels of >=4 servings/week (as opposed to <1 serving/month) of broccoli, carrots, tofu or soybeans, raisins, and apples was associated with lower hypertension risk. In conclusion, our results suggest that greater long-term intake and increased consumption of whole fruits may reduce the risk of developing hypertension. PMID- 26644241 TI - Mineralocorticoid Receptor Activation Contributes to the Supine Hypertension of Autonomic Failure. AB - Primary autonomic failure is characterized by disabling orthostatic hypotension, but at least half of these patients have paradoxical supine hypertension. Renin angiotensin mechanisms were not initially thought to contribute to this hypertension because plasma renin activity is often undetectable in autonomic failure. Plasma aldosterone levels are normal, however, and we recently showed that plasma angiotensin II is elevated and acts at AT1 (angiotensin type 1) receptors to contribute to hypertension in these patients. Because aldosterone and angiotensin II can also bind mineralocorticoid receptors to elevate blood pressure, we hypothesized that mineralocorticoid receptor activation plays a role in the hypertension of autonomic failure. To test this hypothesis, we determined the acute effects of the mineralocorticoid receptor antagonist eplerenone (50 mg, oral) versus placebo on supine blood pressure in a randomized, double-blind, crossover study. Medications were given at 8:00 pm with blood pressure recorded every 2 hours for 12 hours. Ten primary autonomic failure patients with supine hypertension completed this study (7 pure autonomic failure, 2 multiple system atrophy, 1 parkinson's disease; 7 male; 70+/-2 years of age). Eplerenone maximally reduced supine systolic blood pressure by 32+/-6 mm Hg at 8 hours after administration (versus 8+/-10 mm Hg placebo, P=0.016), with no effect on nocturia (12-hour urine volume: 985+/-134 mL placebo versus 931+/-94 mL eplerenone, P=0.492; nocturnal weight loss: -1.19+/-0.15 kg placebo versus -1.18+/-0.15 kg eplerenone, P=0.766). These findings suggest that inappropriate mineralocorticoid receptor activation contributes to the hypertension of autonomic failure, likely independent of canonical mineralocorticoid effects, and provides rationale for use of eplerenone in these patients. PMID- 26644243 TI - Physician perspectives on a tailored multifaceted primary care practice facilitation intervention for improvement of cardiovascular care. AB - BACKGROUND: Practice facilitation is an effective way to help physicians implement change in their clinics, but little is known about physicians' perspectives on this service. OBJECTIVES: To examine physicians' responses to a practice facilitation program, focussing on their overall satisfaction, perceived most significant clinical changes, and interactions with the facilitator. METHODS: The Improved Delivery of Cardiovascular Care program investigated the impact of practice facilitation on improving the quality of cardiovascular primary care in Eastern Ontario, Canada, from 2007 to 2011. We conducted a qualitative content analysis of post-intervention surveys completed by participating physicians, using a constant comparison approach framed around the Chronic Care Model. RESULTS: Ninety-five physicians completed the survey. Physicians overwhelmingly viewed the program positively, though descriptions of its benefits and impact varied widely. Facilitators filled three key roles for physicians, acting as a resource centre, motivator and outside perspective. Physicians adopted a number of changes in their practices. These changes include adoption of clinical information systems (diabetes registries), decision support tools (chart audits, guideline documents, flow sheets) and delivery system design (community resources). CONCLUSIONS: Most physicians appreciated having access to a practice facilitator and viewed the intervention positively. Insight into physicians' perspectives on practice facilitation provides a valuable counterpoint to outcomes-based evaluations of such services. Further research should investigate potential obstacles in the group of physicians who make fewer practice changes, as well as the sustainability of this type of facilitation intervention. PMID- 26644242 TI - Night shifts, human factors, and errors in the ICU: a causal pathway? PMID- 26644244 TI - Ultra-sensitive detection of tumorigenic cellular impurities in human cell processed therapeutic products by digital analysis of soft agar colony formation. AB - Contamination with tumorigenic cellular impurities is one of the most pressing concerns for human cell-processed therapeutic products (hCTPs). The soft agar colony formation (SACF) assay, which is a well-known in vitro assay for the detection of malignant transformed cells, is applicable for the quality assessment of hCTPs. Here we established an image-based screening system for the SACF assay using a high-content cell analyzer termed the digital SACF assay. Dual fluorescence staining of formed colonies and the dissolution of soft agar led to accurate detection of transformed cells with the imaging cytometer. Partitioning a cell sample into multiple wells of culture plates enabled digital readout of the presence of colonies and elevated the sensitivity for their detection. In practice, the digital SACF assay detected impurity levels as low as 0.00001% of the hCTPs, i.e. only one HeLa cell contained in 10,000,000 human mesenchymal stem cells, within 30 days. The digital SACF assay saves time, is more sensitive than in vivo tumorigenicity tests, and would be useful for the quality control of hCTPs in the manufacturing process. PMID- 26644245 TI - Covalent perturbation as a tool for validation of identifications and PTM mapping applied to bovine alpha-crystallin. AB - Proteomic identifications hinge on the measurement of both parent and fragment masses and matching these to amino acid sequences via database search engines. The correctness of the identifications is assessed by statistical means. Here we present an experimental approach to test identifications. Chemical modification of all peptides in a sample leads to shifts in masses depending on the chemical properties of each peptide. The identification of a native peptide sequence and its perturbed version with a different parent mass and fragment ion masses provides valuable information. Labeling all peptides using reductive alkylation with formaldehyde is one such perturbation where the ensemble of peptides shifts mass depending on the number of reactive amine groups. Matching covalently perturbed fragmentation patterns from the same underlying peptide sequence increases confidence in the assignments and can salvage low scoring post translationally modified peptides. Applying this strategy to bovine alpha crystallin, we identify 9 lysine acetylation sites, 4 O-GlcNAc sites and 13 phosphorylation sites. PMID- 26644246 TI - Changes in Diet Quality Scores and Risk of Cardiovascular Disease Among US Men and Women. AB - BACKGROUND: Adherence to several diet quality scores, including the Alternative Healthy Eating Index, Alternative Mediterranean Diet score, and Dietary Approach to Stop Hypertension, has been associated with lower risk of cardiovascular disease (CVD), but little is known about how changes in these scores over time influence subsequent CVD risk. METHODS AND RESULTS: We analyzed the association between 4-year changes in the 3 diet quality scores (Alternative Healthy Eating Index, Alternative Mediterranean Diet score, and Dietary Approach to Stop Hypertension) and subsequent cardiovascular disease (CVD) risk among 29 343 men in the Health Professionals Follow-up Study and 51 195 women in the Nurses' Health Study (1986-2010). During 1 394 702 person-years of follow-up, we documented 11 793 CVD cases. Compared with participants whose diet quality remained relatively stable in each 4-year period, those with the greatest improvement in diet quality scores had a 7% to 8% lower CVD risk in the subsequent 4-year period (pooled hazard ratio, 0.92 [95% confidence interval (CI), 0.87-0.99] for the Alternative Healthy Eating Index; 0.93 [95% CI, 0.85 1.02] for the Alternative Mediterranean Diet score; and 0.93 [95% CI, 0.87-0.99] for the Dietary Approach to Stop Hypertension; all P for trend <0.05). In the long term, increasing the diet scores from baseline to the first 4-year follow-up was associated with lower CVD risk during the next 20 years (7% [95% CI, 1-12] for the Alternative Healthy Eating Index, and 9% [95% CI, 3-14] for the Alternative Mediterranean Diet score). A decrease in diet quality scores was associated with significantly elevated risk of CVD in subsequent time periods. CONCLUSIONS: Improving adherence to diet quality scores over time is associated with significantly lower CVD risk in both the short term and long term. PMID- 26644248 TI - No Right Answer. PMID- 26644250 TI - Late-Breaking Clinical Trial Abstracts. PMID- 26644249 TI - Biopsy Proven Hepatic Segmental Arteriolar Mediolysis Successfully Treated With Coil Embolization. PMID- 26644247 TI - Cardio-Oncology: How New Targeted Cancer Therapies and Precision Medicine Can Inform Cardiovascular Discovery. AB - Cardio-oncology (the cardiovascular care of cancer patients) has developed as a new translational and clinical field based on the expanding repertoire of mechanism-based cancer therapies. Although these therapies have changed the natural course of many cancers, several may also lead to cardiovascular complications. Many new anticancer drugs approved over the past decade are "targeted" kinase inhibitors that interfere with intracellular signaling contributing to tumor progression. Unexpected cardiovascular and cardiometabolic effects of patient treatment with these inhibitors have provided unique insights into the role of kinases in human cardiovascular biology. Today, an ever expanding number of cancer therapies targeting novel kinases and other specific cellular and metabolic pathways are being developed and tested in oncology clinical trials. Some of these drugs may affect the cardiovascular system in detrimental ways and others perhaps in beneficial ways. We propose that the numerous ongoing oncology clinical trials are an opportunity for closer collaboration between cardiologists and oncologists to study the cardiovascular and cardiometabolic changes caused by the modulation of these pathways in patients. In this regard, cardio-oncology represents an opportunity and a novel platform for basic and translational investigation and can serve as a potential avenue for optimization of anticancer therapies and for cardiovascular research and drug discovery. PMID- 26644251 TI - Bilateral Superior Venae Cavae With Crisscross Atrial Drainage. PMID- 26644252 TI - Letter by Thuny and Cautela Regarding Article, "Infective Endocarditis After Transcatheter Aortic Valve Implantation: Results From a Large Multicenter Registry". PMID- 26644253 TI - Letter by Pericas et al Regarding Article, "Infective Endocarditis After Transcatheter Aortic Valve Implantation: Results From a Large Multicenter Registry". PMID- 26644255 TI - Letter Regarding Article, "MicroRNA-155 Exerts Cell-Specific Antiangiogenic but Proarteriogenic Effects During Adaptive Neovascularization". PMID- 26644254 TI - Response to Letters Regarding Article, "Infective Endocarditis After Transcatheter Aortic Valve Implantation: Results From a Large Multicenter Registry". PMID- 26644256 TI - Response to Letter Regarding Article, "MicroRNA-155 Exerts Cell-Specific Antiangiogenic but Proarteriogenic Effects During Adaptive Neovascularization". PMID- 26644257 TI - Pushing the Limits of Local Excision for Rectal Cancer: Transanal Minimally Invasive Surgery (TAMIS) for Rectal Cancer Using the Port-in-Port Technique. AB - BACKGROUND: Radical rectal resection remains the standard of care for the operative treatment of rectal cancer. Local excision via transanal minimally invasive surgery (TAMIS) using disposable transanal access ports is an increasingly more common alternative for selected patients. Because of significant variation in perineal anatomy, currently available disposable transanal ports do not allow adequate access for every patient. This report demonstrates TAMIS for one such patient via a novel approach using a single incision laparoscopic port inserted within a disposable transanal access port. METHODS: The patient is a 66-year-old man with a history of metastatic anterior uT3N0 rectal cancer 9 cm from the anal verge occupying 40% of the rectal circumference. The patient refused radical resection and opted for multimodality therapy with local excision. He underwent preoperative chemoradiation with good tumor response. The TAMIS procedure was attempted and aborted due to poor visualization and inadequate access/exposure using the commercially available Gelpoint Path transanal access system. The TAMIS procedure was reattempted and successfully completed via insertion of a laparoscopic single-incision port (GelPoint Mini) within the transanal access port itself (port-in-port technique) to overcome the deficiencies of the transanal access port. This report describes the port-in-port technique together with the stepwise approach to TAMIS. RESULTS: The TAMIS procedure was completed successfully without complications involving grossly negative margins. The patient's postoperative course was uncomplicated, and he was discharged on postoperative day 1. The final pathology showed a complete pathologic response. At this writing, the patient continues to do well 14 months after surgery. CONCLUSIONS: Currently available disposable transanal access ports may not allow adequate exposure for all patients undergoing TAMIS. This report describes a port-in-port technique that may allow improved exposure for patients with a difficult perineal anatomy. PMID- 26644258 TI - Reoperative Sentinel Lymph Node Biopsy is Feasible for Locally Recurrent Breast Cancer, But is it Worthwhile? AB - INTRODUCTION: Reoperative sentinel lymph node biopsy (SLNB) is feasible in patients with local recurrence (LR) of invasive breast cancer but it remains unclear if this procedure affects either treatment or outcome. In this study, we ask whether axillary restaging (vs. none) at the time of LR affects the rate of subsequent events: axillary failure (AF), non-axillary recurrence (NAR), distant metastasis, or death. METHODS: We queried our institutional database to identify patients treated surgically for invasive breast cancer with a negative SLNB (1997 2000) who developed ipsilateral breast or chest wall recurrence as a first event. We excluded those with gross nodal disease at the time of LR. The cumulative incidence of subsequent events was estimated using competing risks methodology. RESULTS: Of 1527 patients with negative SLN at initial surgery, 83 had an ipsilateral breast (79) or chest wall recurrence (4) with clinically negative regional nodes; 47 (57%) were treated with and 36 (43%) without axillary surgery. Primary tumor characteristics were similar between groups, although time to LR was shorter in the no axillary surgery group (median 3.4 vs. 6.5 years; p < 0.05). All patients in the axillary surgery group and 94% of patients in the no axillary surgery group had surgical excision of their LR, and the use of subsequent radiation and systemic therapy was similar between groups. At a median follow-up of 4.2 years from the time of LR, the rates of AF, NAR, distant metastasis and death were low and did not differ between groups. CONCLUSIONS: Among breast cancer patients with LR and clinically negative nodes, our results question the value of axillary restaging but invite confirmation in larger patient cohorts. Since randomized trials support the value of systemic therapy for all patients with invasive LR, reoperative SLNB, although feasible, may not be necessary. PMID- 26644259 TI - Framing Service, Benefit, and Credibility Through Images and Texts: A Content Analysis of Online Promotional Messages of Korean Medical Tourism Industry. AB - This study examines how the Korean medical tourism industry frames its service, benefit, and credibility issues through texts and images of online brochures. The results of content analysis suggest that the Korean medical tourism industry attempts to frame their medical/health services as "excellence in surgeries and cancer care" and "advanced health technology and facilities." However, the use of cost-saving appeals was limited, which can be seen as a strategy to avoid consumers' association of lower cost with lower quality services, and to stress safety and credibility. PMID- 26644260 TI - Reporting of central airway obstruction on radiology reports and impact on bronchoscopic airway interventions and patient outcomes. AB - BACKGROUND: Central airway obstruction (CAO) is a serious condition that affects patients with both benign and malignant diseases. Timely recognition of CAO is crucial for prompt intervention aimed at improving the symptoms and quality of life of these patients. The aim of this study is to evaluate the formal radiology reporting of CAO and its impact on patients' outcomes. METHODS: The medical records of patients who underwent advanced therapeutic bronchoscopy for CAO from August 2013 to September 2014 were retrospectively reviewed. Three researchers each reviewed 14 of the 42 formal radiology reports that were performed at 16 different medical and radiology centers.Patient characteristics were reported as means, medians, and standard deviations for continuous variables, and as frequencies and relative frequencies for categorical variables. RESULTS: Out of 42 patients who underwent advanced bronchoscopy for planned therapeutic intervention, only 30 had radiology and pulmonology concordance about the airway findings of CAO. This is an agreement rate of 71.4% [95% confidence interval (CI): 56.7-83.3%] or a disagreement rate of 28.6% (95% CI: 16.7-43.3%). The radiology reports did not mention 31% of CAO on CT scans. The median time from CT imaging to bronchoscopy was significantly longer in patients with CAO not reported by the radiologists (21 versus 10 days; p = 0.011). Most patients improved postoperatively with no significant difference between the two groups. CONCLUSIONS: Findings of CAOs were not described in a significant proportion of radiology reports. This results in significant delay in bronchoscopic airway management. PMID- 26644261 TI - Antiplatelet effects of aspirin in chronic kidney disease patients. AB - ESSENTIALS: Chronic kidney disease (CKD) patients have a high risk of cardiovascular events. A pharmacodynamic evaluation of the effects of aspirin in 116 patients was carried out. The antiplatelet effects of aspirin are associated with impaired renal function. The optimal antithrombotic regimen in CKD patients must be investigated on a larger scale. BACKGROUND: The pharmacodynamic response to aspirin varies significantly between individuals. Insufficient antiplatelet effects of aspirin are associated with increased risk of ischemic events. Chronic kidney disease (CKD) is suggested to affect the pharmacodynamic response to antiplatelet medication. High on-treatment platelet reactivity (HTPR) to clopidogrel has been reported to partially account for the enhanced risk of death and cardiovascular events in CKD patients. Objective To investigate the antiplatelet effects of aspirin in patients with CKD. METHODS: We conducted a cross-sectional study in 116 patients on permanent aspirin medication. The pharmacodynamic response to aspirin was determined by arachidonic acid-induced thromboxane formation. RESULTS: HTPR to aspirin was more frequent in patients with impaired renal function (47% vs. 22%; odds ratio, 3.16; 95% confidence interval [CI], 1.34-7.41; P = 0.008). The pharmacodynamic response to aspirin was impaired in patients with moderate/severe CKD (92; interquartile range [IQR], 282 ng mL(-1) ) as compared to patients with normal/mildly reduced renal function (36; IQR, 100 ng mL(-1) ; difference in medians, 57; CI, 5-110 ng mL(-1) ; P = 0.013). Bivariate Pearson analysis showed residual thromboxane formation to be correlated with glomerular filtration rate (R = -0.303; R(2) = 0.092; P = 0.001). Patients with CKD were older and more frequently female. Multivariate linear regression analysis revealed that the correlation was independent of age (R = 0.314; R(2) = 0.082; P = 0.002) and gender (R = -0.305; R(2) = 0.077; P = 0.006). CONCLUSION: Renal function is correlated with pharmacodynamic response to aspirin. Patients with CKD have an increased risk of impaired antiplatelet effects of aspirin. Larger trials are needed to assess the clinical impact of this finding and investigate the optimal antithrombotic regimen in CKD patients. PMID- 26644262 TI - A comparison of high-intensity focused ultrasound and uterine artery embolisation for the management of caesarean scar pregnancy. AB - PURPOSE: The aim of this study was to retrospectively analyse the clinical data of 122 patients with caesarean scar pregnancy (CSP) treated in our hospital, to compare the outcomes between high-intensity focused ultrasound (HIFU) and uterine artery embolisation (UAE). MATERIALS AND METHODS: Among the 122 patients, 76 patients were treated with HIFU followed by suction curettage under hysteroscopic guidance, 46 patients were treated with UAE followed by suction curettage under hysteroscopic guidance. Pain score, intraoperative blood loss in suction curettage under hysteroscopy guidance, time for vaginal bleeding, beta-human chorionic gonadotropin (beta-hCG) to return to normal level, normal menstruation recovery, hospital stay, and the adverse effects were all compared. RESULTS: No statistically significant differences between the two groups in the intraoperative blood loss, hospital stay, time for beta-human chorionic gonadotropin (beta-hCG) to return to normal level, or time for normal menstruation recovery were observed. The pain score was lower and the adverse effects were fewer in the HIFU group than those in the UAE group. However, the time for vaginal bleeding was longer in the patients treated with HIFU than that of patients treated with UAE. CONCLUSIONS: Based on our results, it appears that either HIFU or UAE combined with suction curettage under hysteroscopic guidance is safe and effective in treating patients with CSP. Compared with UAE, HIFU treatment for CSP has the advantages of a lower pain score and fewer adverse effects. PMID- 26644263 TI - Phase 1b safety study of farletuzumab, carboplatin and pegylated liposomal doxorubicin in patients with platinum-sensitive epithelial ovarian cancer. AB - OBJECTIVE: Farletuzumab is a humanized monoclonal antibody that binds to folate receptor alpha, over-expressed in epithelial ovarian cancer (EOC) but largely absent in normal tissue. Previously, carboplatin plus pegylated liposomal doxorubicin showed superior progression-free survival and an improved therapeutic index compared with carboplatin/paclitaxel in relapsed platinum-sensitive EOC. This study assessed safety of farletuzumab/carboplatin/pegylated liposomal doxorubicin in women with platinum-sensitive recurrent EOC. METHODS: This multicenter, single-arm study enrolled patients with platinum-sensitive EOC in first or second relapse for treatment with weekly farletuzumab 2.5mg/kg plus carboplatin AUC5-6 and pegylated liposomal doxorubicin 30mg/m(2) every 4weeks for 6cycles. Subsequently, maintenance with single-agent farletuzumab 2.5mg/kg once weekly or farletuzumab 7.5mg/kg once every three weeks continued until progression. The primary objective was to assess the safety of farletuzumab/carboplatin/pegylated liposomal doxorubicin. RESULTS: Fifteen patients received a median of 12.0cycles (range, 3-26) of farletuzumab as combination therapy or maintenance, for a median of 45.0weeks (range 9-95). Farletuzumab/carboplatin/pegylated liposomal doxorubicin was generally well tolerated, with no farletuzumab-related grades 3-4 adverse events. The most commonly reported adverse events were associated with combination chemotherapy: fatigue (73.3%), nausea (46.7%), and neutropenia (40%). Ten patients had grade >=3 adverse events, most frequently neutropenia and fatigue. No cardiac toxicity was seen. Best overall responses (RECIST) were a complete response for one patient, partial responses for 10 patients, and stable disease for four patients. CONCLUSIONS: Farletuzumab plus carboplatin/pegylated liposomal doxorubicin in women with platinum-sensitive EOC demonstrated a safety profile consistent with that of carboplatin plus pegylated liposomal doxorubicin. PMID- 26644264 TI - Clinicopathologic implications of DNA mismatch repair status in endometrial carcinomas. AB - OBJECTIVE: Endometrial carcinoma is the most common malignancy in women with Lynch syndrome caused by mismatch repair (MMR) deficiency. We investigated the clinicopathologic significance of deficient MMR and Lynch syndrome presumed by MMR analyses in unselected endometrial carcinomas. METHODS: We analyzed immunohistochemistry of MMR proteins (MLH1/MSH2/MSH6/PMS2) and MLH1 promoter methylation in primary endometrial carcinomas from 221 consecutive patients. Based on these results, tumors were categorized as sporadic or probable Lynch syndrome (PLS). Clinicopathologic variables and prognosis were compared according to MMR status and sporadic/PLS classification. RESULTS: Deficient MMR showed only trends towards favorable overall survival (OS) compared with intact MMR (p=0.13), whereas PLS showed significantly better OS than sporadic (p=0.038). Sporadic was significantly associated with older age, obesity, deep myometrial invasion, and advanced stage (p=0.008, 0.01, 0.02 and 0.03), while PLS was significantly associated with early stage and Lynch syndrome-associated multiple cancer (p=0.04 and 0.001). The trend towards favorable OS of PLS was stronger in advanced stage than in early stage (hazard ratio, 0.044 [95% CI 0-25.6] vs. 0.49 [0.063-3.8]). In the subset receiving adjuvant therapies, PLS showed trends towards favorable disease-free survival compared to sporadic by contrast with patients receiving no adjuvant therapies showing no such trend (hazard ratio, 0.045 [95% CI 0-20.3] vs. 0.81 [0.095-7.0]). CONCLUSIONS: The current findings suggest that analyzing MMR status and searching for Lynch syndrome may identify a subset of patients with favorable survival and high sensitivity to adjuvant therapies, providing novel and useful implications for formulating the precision medicine in endometrial carcinoma. PMID- 26644265 TI - The use of novel technology-based weight loss interventions for obese women with endometrial hyperplasia and cancer. AB - OBJECTIVE: Obesity significantly increases the risk of the development of both endometrial hyperplasia and cancer. Our objective was to assess the feasibility of two technology-based weight loss interventions in this patient population. METHODS: Women with obesity (BMI>=30kg/m(2)) and endometrial hyperplasia or Type I endometrial cancer were randomized 1:1 to a technology-based 6month lifestyle intervention via either telemedicine or text messaging. The telemedicine arm received weekly phone calls, with weights tracked online using Withings(c) Wi-Fi scales. The text arm received 3-5 personalized messages daily via Text4DietTM. Participants maintained a 1200-1800calorie/day diet, self-monitored food intake and received exercise goals. Biomarkers (IGFBP-1, adiponectin, VEGF, IL1-beta, IL2, IL6, and IL7) were assessed pre- and post-treatment. RESULTS: Twenty women were randomized (Telemedicine: n=10, Text4Diet: n=10), and 90% lost weight. Many were early stage (70%) and grade (43.8%) disease with a median age of 60.5years. We observed a statistically greater weight loss in the Telemedicine arm [median loss: 9.7kg (range: 1.6-22.9kg)] versus 3.9kg (range: 0.3-11.4kg) in the Text4Diet arm (p=0.0231). Similarly, percent weight loss was greater in the Telemedicine (7.6%) as compared to the Text4Diet arm (4.1%, p=0.014). Mean serum levels of IL-2 were significantly (27.15pg/mL vs. 5.18pg/mL, p=0.0495) lower at intervention end as compared to baseline. CONCLUSIONS: A technology-based weight loss intervention is feasible in women with Type I endometrial cancer/hyperplasia. Both interventions produced weight loss, although more person to-person contact produced more significant outcomes. Reductions in expression of IL-2 were related to weight loss. PMID- 26644266 TI - miR-302a/b/c/d cooperatively inhibit BCRP expression to increase drug sensitivity in breast cancer cells. AB - OBJECTIVE: BCRP is overexpressed in many tumors and mediates multidrug resistance in breast cancer. In this study, we determined the involvement of miR-302S in the development of drug resistance in breast cancer. METHODS: The differential miRNA expression profiling in parental MCF-7 cells and its derivative mitoxantrone (MX) resistant MCF-7 (MCF-7/MX) cells was determined by the microarray analysis. The levels of miR-302S family and BCRP mRNA expression were determined by using Quantitative Real-Time PCR. The targeting effect between the individuals of miR 302S and BCRP mRNA-3'UTR were detected by dual-luciferase reporter assay. Proteins of BCRP are represented by Western blot assay. Cell viability was assessed by MTS assay. Efflux capacity was evaluated using flow cytometry. RESULTS: The miR-302S family including miR-302a, miR-302b, miR-302c, and miR-302d was significantly down-regulated in BCRP-overexpressing MCF-7/MX cells. Luciferase activity assay showed that miR-302 inhibited BCRP expression by targeting the 3'-untranslated region (UTR) of the BCRP mRNA. Overexpression of miR-302 increased intracellular accumulation of MX and sensitized breast cancer cells to MX. Furthermore, intratumoral injection of miR-302 potentiated the inhibitory effect of MX on tumor growth in mice transplanted with MCF-7/MX cells. Most importantly, miR-302S produced stronger effects than each individual member alone. CONCLUSIONS: These findings suggest that miR-302 inhibits BCRP expression via targeting the 3'-UTR of BCRP mRNA. miR-302 members may cooperatively downregulate BCRP expression to increase chemosensitivity of breast cancer cells. miR-302 gene cluster may be a potential target for reversing BCRP-mediated chemoresistance in breast cancer. PMID- 26644267 TI - Psychometric characteristics of the Parenting Scale in a Vietnamese sample. AB - The Parenting Scale (PS) is a well-established instrument for measuring discipline practices in Western populations. However, whether the PS is a valid and reliable measure in Eastern populations is not known. Thus, this study examined the psychometric properties of the PS in a sample of 433 Vietnamese parents of children aged 2-7 years. Confirmatory factor analyses (CFAs) examined the commonly used Reitman et al.'s two-factor and Rhoades and O'Leary's three factor solutions. Neither factor structure fit the data. An exploratory factor analysis identified a 12-item one-factor and 14-item two-factor solutions that overlapped substantially with established factor structures. The one-factor solution reflected Lax/Overreactive parenting and the two-factor solution consisted of Lax/Overreactive and Hostile subscales. The factor structures were confirmed via multigroup CFA. Internal consistencies were acceptable and ranged between .70 and .85. Each factor was positively associated with parent anger, dysfunctional cognitions about child behaviour, and externalising child behaviour problems. However, when entered simultaneously in a regression, Hostile discipline was not uniquely associated with child behaviour. Overall, results support the potential utility of the 12-item one-factor PS as a measure of dysfunctional parenting practices for Vietnamese parents. PMID- 26644268 TI - Reward circuit DBS improves Parkinson's gait along with severe depression and OCD. AB - A 59-year-old Caucasian man with a past history of Parkinson's disease (PD) status post-bilateral subthalamic nucleus (STN) deep brain stimulation (DBS), who also had treatment-resistant (TR) obsessive-compulsive disorder (OCD), and treatment-resistant depression (TRD), presented for further evaluation and management of his TR OCD. After an unsuccessful attempt to treat his OCD by reprogramming his existing STN DBS, he was offered bilateral ventral capsule/ventral striatum (VC/VS) DBS surgery. In addition to the expected improvement in OCD symptoms, he experienced significant improvement in both PD related apathy and depression along with resolution of suicidal ideation. Furthermore, the patient's festinating gait dramatically improved. This case demonstrates that DBS of both the STN and VC/VS appears to have an initial signal of safety and tolerability. This is the first instance where both the STN and the VC/VS DBS targets have been implanted in an individual and the first case where a patient with PD has received additional DBS in mood-regulatory circuitry. PMID- 26644269 TI - Cognitive training in the elderly: a randomized trial to evaluate the efficacy of a self-administered cognitive training program. AB - OBJECTIVES: To evaluate the efficacy of a self-administered cognitive training program for improving cognition in normal elderly persons. METHOD: A multisite, randomized control, double-blind trial was conducted with 28 experimental participants (Mage = 70.7 +/- 8.89) and 28 active controls (Mage = 74.4 +/- 9.39). Treatment conditions: experimental intervention (EI) consisted of three modules: (1) executive functioning, (2) memory, and (3) emotion training. Active control (AC) consisted of word searches, reading short stories, and answering multiple-choice questions. Treatments were self-administered one hour/five days a week for four weeks. Pre-and post-training neuropsychological outcome measures were utilized as determinants of program success. RESULTS: Compared to the AC group, the EI group displayed significant gains on targeted executive (p = .002) and memory (p < .001) composites, but not the emotion (p = .105) composite. Training-induced benefits were also observed for the EI group on untrained items within global cognition (BCRS, p = .002) and functional abilities (DAD, p < .001; FRS, p = .042). The percentage of participants who showed reliable performance improvements was greater for the EI than AC on executive (55.5% vs. 12.5%), memory (55% vs. 19.5%) and functional (41% vs. 7.5%) ability. Participant recruitment and compliance rates were enhanced by the involvement of a physician. CONCLUSION: Results support the efficacy of self-directed cognitive training in reliably improving cognitive and functional abilities in normal older adults. While physicians are critical in enhancing the delivery of regimented treatment, the present study illustrates the potential for self-directed prophylactic training in deterring the development of cognitive decline. PMID- 26644271 TI - The mitochondrial genome of white Java sparrow (Padda oryzivora). AB - The complete mitochondrial genome of Padda oryzivora (Estrildidae, Passeriformes) was sequenced. It is 16 817 bp in length, with an AT content of 54.72%, including 22 transfer RNA genes, 13 protein-coding genes, 2 ribosomal RNA genes, and 1 control region. Phylogenetic analysis demonstrated that the Java sparrow is a close relative of zebrafinch (Taeniopygia guttata) within the same family. These results are desired to provide molecular data for species taxonomy and further phylogenetic studies of passerines. PMID- 26644272 TI - A new childhood asthma phenotype: obese with early menarche. AB - Three concomitant phenomena occur in the later years of childhood: increases in the incidence of asthma, obesity and early menarche. This article is an overview of the current epidemiologic, basic, genetic and epigenetic evidence about this relationship. As a consequence we propose that obese girls who have an early menarche (<= 11 years of age) constitute a new asthma phenotype in childhood. Future studies need to be carried out in order to find the best control and treatment of this new asthma phenotype. PMID- 26644273 TI - Effects of ABA and CaCl2 on GABA accumulation in fava bean germinating under hypoxia-NaCl stress. AB - Effects of exogenous abscisic acid (ABA) and CaCl2 on gamma-aminobutyric acid (GABA) accumulation of germinated fava bean under hypoxia-NaCl stress were investigated. Exogenous ABA resulted in the enhancement of glutamate decarboxylase (GAD) and diamine oxidase (DAO) activity as well as GABA content in cotyledon and shoot. CaCl2 increased both enzyme activities in shoot and GABA content in cotyledon and shoot. ABA downregulated GAD expression in cotyledon and radicle, while upregulated that in shoot; it also upregulated DAO expression in each organ. CaCl2 upregulated GAD expression in cotyledon, while downregulated that in radicle. However, it upregulated DAO expression in shoot, downregulated that in radicle. ABA inhibitor fluridon and ethylenediaminetetraacetic acid inhibited GAD and DAO activities significantly so that inhibited GABA accumulation through reducing ABA biosynthesis and chelating Ca(2+), respectively. However, they upregulated GAD and DAO expression in varying degrees. These results indicate that ABA and Ca(2+) participate in GABA biosynthesis in fava bean during germination under hypoxia-NaCl stress. PMID- 26644270 TI - Food cue reactivity and craving predict eating and weight gain: a meta-analytic review. AB - According to learning-based models of behavior, food cue reactivity and craving are conditioned responses that lead to increased eating and subsequent weight gain. However, evidence supporting this relationship has been mixed. We conducted a quantitative meta-analysis to assess the predictive effects of food cue reactivity and craving on eating and weight-related outcomes. Across 69 reported statistics from 45 published reports representing 3,292 participants, we found an overall medium effect of food cue reactivity and craving on outcomes (r = 0.33, p < 0.001; approximately 11% of variance), suggesting that cue exposure and the experience of craving significantly influence and contribute to eating behavior and weight gain. Follow-up tests revealed a medium effect size for the effect of both tonic and cue-induced craving on eating behavior (r = 0.33). We did not find significant differences in effect sizes based on body mass index, age, or dietary restraint. However, we did find that visual food cues (e.g. pictures and videos) were associated with a similar effect size to real food exposure and a stronger effect size than olfactory cues. Overall, the present findings suggest that food cue reactivity, cue-induced craving and tonic craving systematically and prospectively predict food-related outcomes. These results have theoretical, methodological, public health and clinical implications. PMID- 26644274 TI - Low intensity exercise prevents disturbances in rat cardiac insulin signaling and endothelial nitric oxide synthase induced by high fructose diet. AB - Increase in fructose consumption together with decrease in physical activity contributes to the development of metabolic syndrome and consequently cardiovascular diseases. The current study examined the preventive role of exercise on defects in cardiac insulin signaling and function of endothelial nitric oxide synthase (eNOS) in fructose fed rats. Male Wistar rats were divided into control, sedentary fructose (received 10% fructose for 9 weeks) and exercise fructose (additionally exposed to low intensity exercise) groups. Concentration of triglycerides, glucose, insulin and visceral adipose tissue weight were determined to estimate metabolic syndrome development. Expression and/or phosphorylation of cardiac insulin receptor (IR), insulin receptor substrate 1 (IRS1), tyrosine-specific protein phosphatase 1B (PTP1B), Akt, extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) and eNOS were evaluated. Fructose overload increased visceral adipose tissue, insulin concentration and homeostasis model assessment index. Exercise managed to decrease visceral adiposity and insulin level and to increase insulin sensitivity. Fructose diet increased level of cardiac PTP1B and pIRS1 (Ser307), while levels of IR and ERK1/2, as well as pIRS1 (Tyr 632), pAkt (Ser473, Thr308) and pERK1/2 were decreased. These disturbances were accompanied by reduced phosphorylation of eNOS at Ser1177. Exercise managed to prevent most of the disturbances in insulin signaling caused by fructose diet (except phosphorylation of IRS1 at Tyr 632 and phosphorylation and protein expression of ERK1/2) and consequently restored function of eNOS. Low intensity exercise could be considered as efficient treatment of cardiac insulin resistance induced by fructose diet. PMID- 26644275 TI - A qualitative analysis of family involvement in prescribed opioid medication monitoring among individuals who have experienced opioid overdoses. AB - BACKGROUND: Little is known about the role, extent, or effects of family member involvement in monitoring and managing opioid analgesics. Knowing when or how family members monitor prescribed opioid medication taking, whether it is acceptable to patients, or how family relationships may be affected by monitoring, are not well documented. METHODS: The study was conducted at Kaiser Permanente Northwest, an integrated health plan in Oregon and Washington. Semistructured in-depth interviews (N = 87) assessed circumstances surrounding overdose events among individuals who either experienced an opioid-related overdose or were family members of patients who died as a result of such an overdose. A subset of participants (n = 20) described family members' roles in monitoring opioid medications before or after overdoses. Interviews were transcribed verbatim and coded using Atlas.ti. We used a modified grounded theory approach to categorize emergent data and to identify common themes. RESULTS: When family members played roles in monitoring and managing opioid medications, clinicians were often unaware of their involvement. Patients and family members reported better outcomes when the patient, caregiver, and clinician developed a shared treatment plan. Negative outcomes included relationship stress, particularly when patients and caregivers had differing perspectives about what constituted effective pain management versus misuse and abuse. CONCLUSIONS: When families are concerned about opioid medications, coordination between clinicians, patients, and family carers appears to clarify roles and foster better outcomes. Increased stress and worse outcomes were reported when clinicians were not actively involved and when they did not attend to carers' concerns. PMID- 26644277 TI - Muscle and tendon adaptation in adolescent athletes: A longitudinal study. AB - There is evidence that a non-uniform adaptation of muscle and tendon in young athletes results in increased tendon stress during mid-adolescence. The present longitudinal study investigated the development of the morphological and mechanical properties of muscle and tendon of volleyball athletes in a time period of 2 years from mid-adolescence to late adolescence. Eighteen elite volleyball athletes participated in magnetic resonance imaging and ultrasound dynamometry sessions to determine quadriceps femoris muscle strength, vastus lateralis, medialis and intermedius morphology, and patellar tendon mechanical and morphological properties in mid-adolescence (16 +/- 1 years) and late adolescence (18 +/- 1 years). Muscle strength, anatomical cross-sectional area (CSA), and volume showed significant (P < 0.05) but moderate increases of 13%, 6%, and 6%, respectively. The increase of patellar tendon CSA (P < 0.05) was substantially greater (27%) and went in line with increased stiffness (P < 0.05; 25%) and reduced stress (P < 0.05; 9%). During late adolescence, a pronounced hypertrophy of the patellar tendon led to a mechanical strengthening of the tendon in relation to the functional and morphological development of the muscle. These adaptive processes may compensate the unfavorable relation of muscle strength and tendon loading capacity in mid-adolescence and might have implications on athletic performance and tendon injury risk. PMID- 26644276 TI - Diagnosis of Minimal Hepatic Encephalopathy Using Stroop EncephalApp: A Multicenter US-Based, Norm-Based Study. AB - OBJECTIVES: Diagnosing minimal hepatic encephalopathy (MHE) is challenging, and point-of-care tests are needed. Stroop EncephalApp has been validated for MHE diagnosis in single-center studies. The objective of the study was to validate EncephalApp for MHE diagnosis in a multicenter study. METHODS: Outpatient cirrhotics (with/without prior overt hepatic encephalopathy (OHE)) and controls from three sites (Virginia (VA), Ohio (OH), and Arkansas (AR)) underwent EncephalApp and two gold standards, psychometric hepatic encephalopathy score (PHES) and inhibitory control test (ICT). Age-/gender-/education-adjusted values for EncephalApp based on direct norms, and based on ICT and PHES, were defined. Patients were followed, and EncephalApp cutoff points were used to determine OHE prediction. These cutoff points were then used in a separate VA-based validation cohort. RESULTS: A total of 437 cirrhotics (230 VA, 107 OH, 100 AR, 36% OHE, model for end-stage liver disease (MELD) score 11) and 308 controls (103 VA, 100 OH, 105 AR) were included. Using adjusted variables, MHE was present using EncephalApp based on norms in 51%, EncephalApp based on PHES in 37% (sensitivity 80%), and EncephalApp based on ICT in 54% of patients (sensitivity 70%). There was modest/good agreement between sites on EncephalApp MHE diagnosis using the three methods. OHE developed in 13% of patients, which was predicted by EncephalApp independent of the MELD score. In the validation cohort of 121 VA cirrhotics, EncephalApp directly and based on gold standards remained consistent for MHE diagnosis with >70% sensitivity. CONCLUSIONS: In this multicenter study, EncephalApp, using adjusted population norms or in the context of existing gold standard tests, had good sensitivity for MHE diagnosis and predictive capability for OHE development. PMID- 26644278 TI - Italian experience on use of E.S.W. therapy for avascular necrosis of femoral head. AB - Osteonecrosis (avascular necrosis) of the femoral head is a clinical disease due to a severe bone vascular alteration associated with intense pain and loss of joint function, with an incidence of 0.1% and unknown aetiology. Many classifications exist to describe it and in the final stages the patient will need a total hip arthroplasty. In the early stages, ESWT has given excellent responses.? The Neapolitan school studied more than 600 patients who had very good results in I and II stages of Ficat and Arlet Classification, with an improve of outcomes in VAS and HSS scores. Moreover it has shown a complete restoration of the signal intensity of the femoral head in MRI. PMID- 26644279 TI - Esophageal and Mediastinal Lesions Following Multielectrode Duty-Cycled Radiofrequency Pulmonary Vein Isolation: Simple Equals Safe? AB - BACKGROUND: The development of esophageal lesions following atrial fibrillation (AF) ablation has frequently been reported. Mediastinal tissue layers and the posterior wall of the left atrium are in close proximity to the site of ablation. Hence, mucosal lesions might solely represent the "tip of the iceberg." We therefore investigated patients undergoing multielectrode phased radiofrequency (RF) ablation (PVAC(r), Medtronic Inc., Minneapolis, MN, USA) for symptomatic AF by radial endosonography (EUS) in conjunction with conventional endoscopy esophago-gastro-duodenoscopy (EGD) to visualize potential mediastinal injuries following pulmonary vein isolation (PVI). METHODS AND RESULTS: Eighteen patients (six women, mean age 52.8 +/- 12.8 years, range 32-72 years) underwent PVI using multielectrode phased RF ablation and EGD and EUS following PVI within 48 hours. Postablation periesophageal lesions were detected by EUS in 10 out of 18 patients (56%). Four out of 10 lesions consisted of mild changes like small pericardial effusions, whereas six out of 10 patients had more severe lesions of the mediastinum, including one patient with changes of the esophageal mucosa. No atrio-esophageal fistula developed during follow-up (FU; mean FU 215 +/- 105 days). CONCLUSIONS: Mediastinal and esophageal structural changes occurred in a substantial number of patients. These findings highlight the necessity of close FU and the awareness of the potential development of an atrio-esophageal fistula also after multielectrode catheter ablation. PMID- 26644280 TI - Phosphorylation of RAF Kinase Dimers Drives Conformational Changes that Facilitate Transactivation. AB - RAF kinases are key players in the MAPK signaling pathway and are important targets for personalized cancer therapy. RAF dimerization is part of the physiological activation mechanism, together with phosphorylation, and is known to convey resistance to RAF inhibitors. Herein, molecular dynamics simulations are used to show that phosphorylation of a key N-terminal acidic (NtA) motif facilitates RAF dimerization by introducing several interprotomer salt bridges between the alphaC-helix and charged residues upstream of the NtA motif. Additionally, we show that the R-spine of RAF interacts with a conserved Trp residue in the vicinity of the NtA motif, connecting the active sites of two protomers and thereby modulating the cooperative interactions in the RAF dimer. Our findings provide a first structure-based mechanism for the auto transactivation of RAF and could be generally applicable to other kinases, opening new pathways for overcoming dimerization-related drug resistance. PMID- 26644282 TI - Evaluation of Antifungal Efficacy of 0.1% and 0.25% Riboflavin with UVA: A Comparative In Vitro Study. AB - PURPOSE: Antifungal efficacy of photochemical cross-linking (PACK-CXL) with 0.1% and 0.25% riboflavin was evaluated with a comparative in vitro study. METHODS: Candida albicans and Aspergillus fumigatus ATCC reference strains, Candida parapsilosis, Aspergillus fumigatus, Fusarium solani, Scedosporium apiospermum, and Alternaria alternata strains isolated from keratitis cases were chosen as targeted microorganisms. Unique "black plate method" was developed in polystyrene microplates. Riboflavin suspensions in 0.1% and 0.25% were separately added into inoculated wells. Non-inoculated wells were filled by black colored dye in order to protect treated wells from reflection of UV treatment. After ultraviolet A (UVA) treatment, each well was evaluated by microbiological culture in order to count viable fungal colonies. Fungal killing rate was calculated by comparing fungal counts (CFU/mL) before and after UVA application of riboflavin-added wells. RESULTS: Four different fungal inoculum concentrations of targeted microorganisms, including 104, 103, 102, and 101 CFU/mL, were assayed. PACK-CXL with 0.25% riboflavin was found to be highly effective on fungal cells even in 104 CFU/mL of concentration. CONCLUSIONS: PACK-CXL appears as a promising treatment option for difficult-to-treat cases of fungal keratitis and 0.25% riboflavin concentration increases fungicidal effect of the procedure dramatically. PMID- 26644283 TI - Gender differences in recovery consequences among heroin dependent patients after compulsory treatment programs. AB - Studies on recovery patterns and how baseline factors influence recovery consequences among heroin dependent patients have shown mixed results. This study is aimed at describing the gender differences in long-term recovery patterns and exploring the predictors of negative recovery consequences by gender among heroin dependent patients in Shanghai, China. At baseline, this study recruited 503 heroin dependent patients discharged from Shanghai compulsory rehabilitation facilities in 2007 and 2008. In this cohort study, the baseline data was then linked with participants' 5-year follow-up data from official records. Generalized Estimating Equations (GEE) were used to compare males with females in terms of the presence of negative consequences (incarceration, or readmission to compulsory treatment, or both), in the subsequent 5-years after their discharge from compulsory treatment. Ordinary least squares (OLS) regression was used to explore factors associated to the time length of negative consequences in 5 years after the discharge for males and females separately. Our findings indicate that female heroin dependent patients tend to have less negative recovery outcomes than male patients. Male patients with a life-time history of poly drug use and female patients with borderline personality disorder are especially at risk of incarceration and readmission into compulsory treatment programs. PMID- 26644281 TI - Evaluation of the Reinforcing Effect of Quetiapine, Alone and in Combination with Cocaine, in Rhesus Monkeys. AB - There are several case reports of nonmedicinal quetiapine abuse, yet there are very limited preclinical studies investigating quetiapine self-administration. The goal of this study was to investigate the reinforcing effects of quetiapine alone and in combination with intravenous cocaine in monkeys. In experiment 1, cocaine-experienced female monkeys (N = 4) responded under a fixed-ratio (FR) 30 schedule of food reinforcement (1.0-g banana-flavored pellets), and when responding was stable, quetiapine (0.003-0.1 mg/kg per injection) or saline was substituted for a minimum of five sessions; there was a return to food-maintained responding between doses. Next, monkeys were treated with quetiapine (25 mg, by mouth, twice a day) for approximately 30 days, and then the quetiapine self administration dose-response curve was redetermined. In experiment 2, male monkeys (N = 6) self-administered cocaine under a concurrent FR schedule with food reinforcement (three food pellets) as the alternative to cocaine (0.003-0.3 mg/kg per injection) presentation. Once choice responding was stable, the effects of adding quetiapine (0.03 or 0.1 mg/kg per injection) to the cocaine solution were examined. In experiment 1, quetiapine did not function as a reinforcer, and chronic quetiapine treatment did not alter these effects. In experiment 2, cocaine choice increased in a dose-dependent fashion. The addition of quetiapine to cocaine resulted in increases in low-dose cocaine choice and number of cocaine injections in four monkeys, while not affecting high-dose cocaine preference. Thus, although quetiapine alone does not have abuse potential, there was evidence of enhancement of the reinforcing potency of cocaine. These results suggest that the use of quetiapine in cocaine-addicted patients should be monitored. PMID- 26644284 TI - Source-space ICA for MEG source imaging. AB - OBJECTIVE: One of the most widely used approaches in electroencephalography/magnetoencephalography (MEG) source imaging is application of an inverse technique (such as dipole modelling or sLORETA) on the component extracted by independent component analysis (ICA) (sensor-space ICA + inverse technique). The advantage of this approach over an inverse technique alone is that it can identify and localize multiple concurrent sources. Among inverse techniques, the minimum-variance beamformers offer a high spatial resolution. However, in order to have both high spatial resolution of beamformer and be able to take on multiple concurrent sources, sensor-space ICA + beamformer is not an ideal combination. APPROACH: We propose source-space ICA for MEG as a powerful alternative approach which can provide the high spatial resolution of the beamformer and handle multiple concurrent sources. The concept of source-space ICA for MEG is to apply the beamformer first and then singular value decomposition + ICA. In this paper we have compared source-space ICA with sensor space ICA both in simulation and real MEG. The simulations included two challenging scenarios of correlated/concurrent cluster sources. MAIN RESULTS: Source-space ICA provided superior performance in spatial reconstruction of source maps, even though both techniques performed equally from a temporal perspective. Real MEG from two healthy subjects with visual stimuli were also used to compare performance of sensor-space ICA and source-space ICA. We have also proposed a new variant of minimum-variance beamformer called weight normalized linearly-constrained minimum-variance with orthonormal lead-field. SIGNIFICANCE: As sensor-space ICA-based source reconstruction is popular in EEG and MEG imaging, and given that source-space ICA has superior spatial performance, it is expected that source-space ICA will supersede its predecessor in many applications. PMID- 26644285 TI - PAM multiplicity marks genomic target sites as inhibitory to CRISPR-Cas9 editing. AB - In CRISPR-Cas9 genome editing, the underlying principles for selecting guide RNA (gRNA) sequences that would ensure for efficient target site modification remain poorly understood. Here we show that target sites harbouring multiple protospacer adjacent motifs (PAMs) are refractory to Cas9-mediated repair in situ. Thus we refine which substrates should be avoided in gRNA design, implicating PAM density as a novel sequence-specific feature that inhibits in vivo Cas9-driven DNA modification. PMID- 26644286 TI - Food and Sustainability Challenges Under Climate Changes. AB - Plants are permanently impacted by their environments, and their abilities to tolerate multiple fluctuating environmental conditions vary as a function of several genetic and natural factors. Over the past decades, scientific innovations and applications of the knowledge derived from biotechnological investigations to agriculture caused a substantial increase of the yields of many crops. However, due to exacerbating effects of climate change and a growing human population, a crisis of malnutrition may arise in the upcoming decades in some places in the world. So, effective, ethical and managerial regulations and fair policies should be set up and applied at the local and global levels so that Earth may fairly provide the food and living accommodation needed by its inhabitants. To save some energy consumption, electric devices (for e.g., smartphones, laptops, street lights, traffic lights, etc.) should be manufactured to work with solar energy, whenever available, particularly in sunny countries where sun is available most of the time. Such characteristic will save energy and make solar energy-based smartphones and laptops less cumbersome in terms of chargers and plugging issues. PMID- 26644287 TI - The Least Interesting Unit: A New Concept for Enhancing One's Academic Career Opportunities. AB - Motivated by a current development in the physics community, this paper introduces the notion of a least interesting unit (LIU) in research as an investigation that is just interesting enough to pursue. A new general maxim for science is then that a researcher should pursue as many LIUs as possible. Although fulfilling this maxim enhances one's perspective for a career in the present publish-or-perish academic world, in particular when simultaneously publishing one's results in the form of as many least publishable units as possible, this paper concludes that it is an example of an unethical practice: it may undermine scientific progress, it may lead to a waste of valuable resources, and it may contribute to an erosion of norms and values in science. PMID- 26644288 TI - Special AT-rich sequence-binding protein 2 (SATB2) expression is sensitive but may not be specific for osteosarcoma as compared with other high-grade primary bone sarcomas. AB - AIMS: The diagnosis of osteosarcoma, although important for eligibility in clinical trials and proper therapy, may be challenging when no bone or osteoid matrix is identified on biopsy. Therefore, other adjunct tests have been sought to help confirm the diagnosis. Special AT-rich sequence-binding protein 2 (SATB2) has been shown as a reliable marker of osteoblastic differentiation. The aim of this study was to examine SATB2 expression in osteosarcomas and other primary bone sarcomas, in order to evaluate its diagnostic utility in discriminating osteogenic from non-osteogenic sarcomas. METHODS AND RESULTS: Forty-eight pretreated osteosarcoma biopsies, including 26 whole-section cases and 22 tumours on tissue microarrays, and 36 non-osteogenic bone sarcomas were evaluated. Forty five of 48 (94%) osteosarcomas showed nuclear immunoreactivity for SATB2 (all whole-slide sections showed expression). Positive SATB2 expression was observed in 11 of 22 (50%) undifferentiated pleomorphic sarcomas (UPSs), and in five of 11 (45%) fibrosarcomas; expression was absent in two pleomorphic rhabdomyosarcomas and in the one leiomyosarcoma. The sensitivity of SATB2 for osteosarcoma was 94%, and the specificity was 55%. Stronger-intensity staining was observed in osteosarcoma (P < 0.0001). CONCLUSIONS: SATB2 is a sensitive marker for osteosarcoma; however, it is not specific, with expression being observed in other high-grade primary bone sarcomas. Intriguingly, the lack of specificity may suggest that the undifferentiated sarcomas (UPSs and fibrosarcomas) with SATB2 expression actually represent osteosarcomas that produce too little matrix to be detected with routine sampling or consist of osteoblast precursors that do not synthesize matrix. PMID- 26644289 TI - W-state Analyzer and Multi-party Measurement-device-independent Quantum Key Distribution. AB - W-state is an important resource for many quantum information processing tasks. In this paper, we for the first time propose a multi-party measurement-device independent quantum key distribution (MDI-QKD) protocol based on W-state. With linear optics, we design a W-state analyzer in order to distinguish the four qubit W-state. This analyzer constructs the measurement device for four-party MDI QKD. Moreover, we derived a complete security proof of the four-party MDI-QKD, and performed a numerical simulation to study its performance. The results show that four-party MDI-QKD is feasible over 150 km standard telecom fiber with off the-shelf single photon detectors. This work takes an important step towards multi-party quantum communication and a quantum network. PMID- 26644290 TI - Building political will for HIV response: an operational model and strategy options. AB - As global programs for HIV response look to transfer responsibility and financing increasingly to country governments, the political will to take on these responsibilities becomes increasingly prominent. However, defining and assessing political will are problematic; it involves intent and motivation, and thus is inherently difficult to observe. It is intimately connected to capacity and is contextually embedded. This article describes an operational model of political will comprised of seven components that are observable and measurable. Two case studies illustrate the application of the model and shed light on the interconnections among commitment, capacity and context: South Africa and China. Strategy options to build political will for HIV response identify possible actions for both government and civil society. Political will as a concept is most usefully viewed as integrated within larger political and bureaucratic processes, as a product of the complex array of incentives and disincentives that those processes create. However, this conclusion is not a recipe for discouragement or inaction. Agent-based conceptualizations of policy change offer a solid grounding for building political will that supports HIV policy and programs. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26644291 TI - Diagnostic value of serum fibrinogen as a predictive factor for complicated appendicitis (perforated). A cross-sectional study. AB - BACKGROUND: Acute appendicitis (AA) has a prevalence of 8% in the general population with a rate of complicated (perforated) appendicitis (CA) up to 40%. Serum fibrinogen may serve as an indicator for CA. PATIENTS AND METHODS: 115 patients were included from January 2012 to December 2012 using a positive pathology report for AA as a gold standard diagnostic method. We divided the patients into two groups accordingly to the pathology report: Complicated Appendicitis and Uncomplicated Appendicitis (UA). Our primary endpoint was to compare the levels of serum fibrinogen between the two groups and find if there is a relationship between fibrinogen level and CA. RESULTS: 68 patients were diagnosed with UA and 47 with CA. Using a fibrinogen value of 885 mg/dl we found to be the best cut-off for predicting complicated appendicitis with a sensitivity of 86.77% (76.87-93.71 IC 95%), a specificity of 91.49 (83.51-99.46 IC 95%), a positive predictive value of 93.65 (95% CI 86.81-99.64) and, a negative predictive value of 82.69 (95% CI 65.73-87.84). CONCLUSION: In the setting of a patient with a clinical diagnosis of AA, this study demonstrates fibrinogen as a good predictor factor for appendiceal perforation. PMID- 26644292 TI - A Personalist Ontological Approach to Synthetic Biology. AB - Although synthetic biology is a promising discipline, it also raises serious ethical questions that must be addressed in order to prevent unwanted consequences and to ensure that its progress leads toward the good of all. Questions arise about the role of this discipline in a possible redefinition of the concept of life and its creation. With regard to the products of synthetic biology, the moral status that they should be given as well as the ethically correct way to behave towards them are not clear. Moreover, risks that could result from a misuse of this technology or from an accidental release of synthetic organisms into the environment cannot be ignored; concerns about biosecurity and biosafety appear. Here we discuss these and other questions from a personalist ontological framework, which defends human life as an essential value and proposes a set of principles to ensure the safeguarding of this and other values that are based on it. PMID- 26644293 TI - Lewy bodies in essential tremor are no different than in controls. PMID- 26644295 TI - Affinity chromatography of chaperones based on denatured proteins: Analysis of cell lysates of different origin. AB - Molecular chaperones are involved in folding, oligomerization, transport, and degradation of numerous cellular proteins. Most of chaperones are heat-shock proteins (HSPs). A number of diseases of various organisms are accompanied by changes in the structure and functional activity of chaperones, thereby revealing their vital importance. One of the fundamental properties of chaperones is their ability to bind polypeptides lacking a rigid spatial structure. Here, we demonstrate that affinity chromatography using sorbents with covalently attached denatured proteins allows effective purification and quantitative assessment of their bound protein partners. Using pure Escherichia coli chaperone GroEL (Hsp60), the capacity of denatured pepsin or lysozyme-based affinity sorbents was evaluated as 1 mg and 1.4 mg of GroEL per 1 ml of sorbent, respectively. Cell lysates of bacteria (E. coli, Thermus thermophilus, and Yersinia pseudotuberculosis), archaea (Halorubrum lacusprofundi) as well as the lysate of rat liver mitochondria were analyzed using affinity carrier with denatured lysozyme. It was found that, apart from Hsp60, other proteins with a molecular weight of about 100, 50, 40, and 20 kDa are able to interact with denatured lysozyme. PMID- 26644294 TI - Depression and clinical progression in spinocerebellar ataxias. AB - BACKGROUND: Depression is a common comorbidity in spinocerebellar ataxias (SCAs) but its association with ataxia progression is not well understood. OBJECTIVES: To study the prevalence and influence of depressive symptoms in SCAs. METHODS: We studied 300 participants with SCA 1, 2, 3 and 6 from the Clinical Research Consortium for Spinocerebellar Ataxias (CRC-SCA) and repeatedly measured depressive symptoms by the 9-item Patient Health Questionnaire (PHQ-9) along with other clinical features including ataxia, functional status, and quality of life every 6 months for 2 years. We employed regression models to study the effects of depressive symptoms on clinical progression indexed by Scale for Assessment and Rating of Ataxia (SARA), Unified Huntington's Disease Rating Scale Part IV (UHDRS IV) and EQ5D after adjusting for age, sex and pathological CAG repeats. RESULTS: Comorbid depression is common in SCAs (26%). Although the baseline prevalence of depression was similar among different SCA types, suicidal ideation was more frequently reported in SCA3 (65%). Depressive symptoms were associated with SARA scores but did not significantly progress over time within 2 years or deteriorate by increased numbers of pathological CAG repeats. The effects of depression on ataxia progression varied across different SCA types. Nevertheless, depression had consistently negative and significant impact on functional status and quality of life in all SCAs, even after accounting for ataxia progression. CONCLUSIONS: Depressive symptoms are not simply the consequence of motor disability in SCAs. Comorbid depression per se contributes to different health outcomes and deserves more attention when caring patients with SCAs. PMID- 26644296 TI - Tunable Meta-Liquid Crystals. AB - Meta-liquid crystals, a novel form of tunable 3D metamaterials, are proposed and experimentally demonstrated in the terahertz frequency regime. A morphology change under a bias electric field and a strong modulation of the transmission are observed. In comparison to conventional liquid crystals, there is considerable freedom to prescribe the electromagnetic properties through the judicious design of the meta-atom geometry. PMID- 26644297 TI - Integrative Proteomics and Metabolomics Analysis of Insect Larva Brain: Novel Insights into the Molecular Mechanism of Insect Wandering Behavior. AB - Before metamorphosis, most holometabolous insects, such as the silkworm studied here, undergo a special phase called the wandering stage. Insects in this stage often display enhanced locomotor activity (ELA). ELA is vital because it ensures that the insect finds a safe and suitable place to live through the pupal stage. The physiological mechanisms of wandering behavior are still unclear. Here, we integrated proteomics and metabolomics approaches to analyze the brain of the lepidopteran insect, silkworm, at the feeding and wandering stages. Using LC MS/MS and GC-MS, in all we identified 3004 proteins and 37 metabolites at these two stages. Among them, 465 proteins and 22 metabolites were changed. Neural signal transduction proteins and metabolites, such as neurofilament, dopaminergic synapse related proteins, and glutamic acid, were significantly altered, which suggested that active neural conduction occurred in the brain at the wandering stage. We also found decreased dopamine degradation at the wandering stage. The proposed changes in active neural conduction and increased dopamine concentration might induce ELA. In addition, proteins involved in the ubiquitin proteasome system and lysosome pathway were upregulated, revealing that the brain experiences morphological remodeling during metamorphosis. These findings yielded novel insights into the molecular mechanism underlying insect wandering behavior. PMID- 26644299 TI - What lessons for clinical practice can be learned from systematic reviews of animal studies? The case of anesthetic neurotoxicity. PMID- 26644300 TI - Wagering, anesthetic technique, and infants for pyloromyotomy. PMID- 26644301 TI - Development of role-differentiated bimanual manipulation in infancy: Part 1. The emergence of the skill. AB - This is the first paper in a series of three discussing different aspects of the development of role-differentiated bimanual manipulation (RDBM-two hands performing different but complementary actions on an object). Emergence of RDBM is an important shift in the development of infant manual skills. Trajectories of monthly changes in the number of RDBMs and RDBM hand preference were explored in a sample of 90 (57 males) normally developing infants (30 with a right preference for acquiring objects, 30 with a left preference, 30 with no preference) during the 9-14 month period. Multilevel analysis revealed that infants performed more RDBMs with age, with similar patterns of change in all hand preference groups. A hand-use preference for RDBM became more prominent with age with most right preferring infants and those without a preference for object acquisition developing right-hand preference for RDBM. Left-preferring infants exhibited more heterogeneity in their hand-use for RDBM. PMID- 26644302 TI - Concurrent sound segregation impairments in schizophrenia: The contribution of auditory-specific and general cognitive factors. AB - The present study sought to test whether perceptual segregation of concurrently played sounds is impaired in schizophrenia (SZ), whether impairment in sound segregation predicts difficulties with a real-world speech-in-noise task, and whether auditory-specific or general cognitive processing accounts for sound segregation problems. Participants with SZ and healthy controls (HCs) performed a mistuned harmonic segregation task during recording of event-related potentials (ERPs). Participants also performed a brief speech-in-noise task. Participants with SZ showed deficits in the mistuned harmonic task and the speech-in-noise task, compared to HCs. No deficit in SZ was found in the ERP component related to mistuned harmonic segregation at around 150ms (the object-related negativity or ORN), but instead showed a deficit in processing at around 400ms (the P4 response). However, regression analyses showed that indexes of education level and general cognitive function were the best predictors of sound segregation difficulties, suggesting non-auditory specific causes of concurrent sound segregation problems in SZ. PMID- 26644303 TI - A review of genetic alterations in the serotonin pathway and their correlation with psychotic diseases and response to atypical antipsychotics. AB - Serotonin is a neurotransmitter that plays a predominant role in mood regulation. The importance of the serotonin pathway in controlling behavior and mental status is well recognized. All the serotonin elements - serotonin receptors, serotonin transporter, tryptophan hydroxylase and monoamine oxidase proteins - can show alterations in terms of mRNA or protein levels and protein sequence, in schizophrenia and bipolar disorder. Additionally, when examining the genes sequences of all serotonin elements, several single nucleotide polymorphisms (SNPs) have been found to be more prevalent in schizophrenic or bipolar patients than in healthy individuals. Several of these alterations have been associated either with different phenotypes between patients and healthy individuals or with the response of psychiatric patients to the treatment with atypical antipsychotics. The complex pattern of genetic diversity within the serotonin pathway hampers efforts to identify the key variations contributing to an individual's susceptibility to the disease. In this review article, we summarize all genetic alterations found across the serotonin pathway, we provide information on whether and how they affect schizophrenia or bipolar disorder phenotypes, and, on the contribution of familial relationships on their detection frequencies. Furthermore, we provide evidence on whether and how specific gene polymorphisms affect the outcome of schizophrenic or bipolar patients of different ethnic groups, in response to treatment with atypical antipsychotics. All data are discussed thoroughly, providing prospective for future studies. PMID- 26644304 TI - Effects of a high-intensity functional exercise program on depressive symptoms among people with dementia in residential care: a randomized controlled trial. AB - OBJECTIVES: The aim of this study is to evaluate the effect of a high-intensity functional exercise program on depressive symptoms among older care facility residents with dementia. METHODS: Residents (n = 186) with a diagnosis of dementia, age >= 65 years, Mini-Mental State Examination score >= 10, and dependence in activities of daily living were included. Participants were randomized to a high-intensity functional exercise program or a non-exercise control activity conducted 45 min every other weekday for 4 months. The 15-item Geriatric Depression Scale (GDS) and the Montgomery-Asberg Depression Rating Scale (MADRS) were administered by blinded assessors at baseline, 4, and 7 months. RESULTS: No difference between the exercise and control activity was found in GDS or MADRS score at 4 or 7 months. Among participants with GDS scores >= 5, reductions in GDS score were observed in the exercise and control groups at 4 months (-1.58, P = 0.001 and -1.54, P = 0.004) and 7 months (-1.25, P = 0.01 and -1.45, P = 0.007). Among participants with MADRS scores >= 7, a reduction in MADRS score was observed at 4 months in the control group (-2.80, P = 0.009) and at 7 months in the exercise and control groups (-3.17, P = 0.003 and -3.34, P = 0.002). CONCLUSIONS: A 4-month high-intensity functional exercise program has no superior effect on depressive symptoms relative to a control activity among older people with dementia living in residential care facilities. Exercise and non exercise group activities may reduce high levels of depressive symptoms. PMID- 26644306 TI - Re: Does Stone Removal Help Patients with Recurrent Urinary Tract Infections?: M. Omar, A. Abdulwahab-Ahmed, H. Chaparala and M. Monga J Urol 2015;194:997-1001. PMID- 26644308 TI - Portable, Battery Operated Capillary Electrophoresis with Optical Isomer Resolution Integrated with Ionization Source for Mass Spectrometry. AB - We introduce a battery operated capillary electrophoresis electrospray ionization (CE/ESI) source for mass spectrometry with optical isomer separation capability. The source fits in front of low or high resolution mass spectrometers similar to a nanospray source with about the same weight and size. The source has two high voltage power supplies (+/-25 kV HVPS) capable of operating in forward or reverse polarity modes and powered by a 12 V rechargeable lithium ion battery with operation time of ~10 h. In ultrafast CE mode, in which short narrow capillaries (<=15 MUm i.d., 15-25 cm long) and field gradients >=1000 V/cm are used, peak widths at the base are <1 s wide. Under these conditions, the source provides high resolution separation, including optical isomer resolution in ~1 min. Using a low resolution mass spectrometer (LTQ Velos) with a scan time of 0.07 s/scan, baseline separation of amino acids and their optical isomers were achieved in ~1 min. Moreover, bovine serum albumin (BSA) was analyzed in ~1 min with 56% coverage using the data-dependent MS/MS. Using a high resolution mass spectrometer (Thermo Orbitrap Elite) with 15,000 resolution, the fastest scan time achieved was 0.15 s, which was adequate for CE-MS analysis when optical isomer separation is not required or when the optical isomers were well separated. Figures of merit including a detection limit of 2 fmol and linear dynamic range of two orders of magnitude were achieved for amino acids. PMID- 26644307 TI - Suspended Solid-state Membranes on Glass Chips with Sub 1-pF Capacitance for Biomolecule Sensing Applications. AB - Solid-state membranes are finding use in many applications in nanoelectronics and nanomedicine, from single molecule sensors to water filtration, and yet many of their electronics applications are limited by the relatively high current noise and low bandwidth stemming from the relatively high capacitance (>10 pF) of the membrane chips. To address this problem, we devised an integrated fabrication process to grow and define circular silicon nitride membranes on glass chips that successfully lower the chip capacitance to below 1 pF. We use these devices to demonstrate low-noise, high-bandwidth DNA translocation measurements. We also make use of this versatile, low-capacitance platform to suspend other thin, two dimensional membrane such as graphene. PMID- 26644309 TI - Associations between vasodilatory capacity, physical activity and sleep among younger and older adults. AB - INTRODUCTION: Exercise promotes cardiovascular health through its direct impact on the vascular endothelium. Conversely, poor sleep quality is associated with endothelial dysfunction, which may explain the increased cardiovascular disease amongst poor sleepers. Yet, the influence of physical activity and poor sleep quality on vascular health is not clear. PURPOSE: This study examined the relationships between forearm vasodilatory capacity, self-reported sleep quality and free-living, actigraphy-derived energy expenditure in a group of young and older community dwelling adults. METHODS: Venous occlusion plethysmography determined baseline and peak forearm blood flow following reactive hyperemia. Sleep quality was measured using the Pittsburgh Sleep Quality Index (PSQI). Measures of body composition were assessed using dual energy X-ray absorptiometry. RESULTS: A total of 104 (61 young; 43 old) participants completed the study. In general, younger participants were more active, as determined by steps per day and average daily energy expenditure, but reported poorer sleep quality. In the combined sample, those who reported moderate sleep disturbances (PSQI total score; 11-15) had significantly lower vasodilatory capacity (16.8 +/- 7.6 ml/100 ml/min) compared to those who reported no sleep disturbance (PSQI total score; 0-5) (22.3 +/- 7.2 ml/100 ml/min) or mild sleep disturbance (PSQI total score; 6-10) (22.3 +/- 8.1 ml/100 ml/min) (p < 0.01). After adjustment for physical activity, total body fat and age, moderately poor sleep remained an independent predictor of forearm vasodilatory capacity. CONCLUSIONS: These findings suggest that any positive vascular benefits accrued through increased physical activity might be offset by the negative consequences of chronically disturbed sleep. PMID- 26644310 TI - Decreased renal function and associated factors in cities, towns and rural areas of Tanzania: a community-based population survey. AB - OBJECTIVES: Data on renal dysfunction in sub-Saharan Africa, comparing urban and rural areas, have not yet been reported. Therefore, we aimed to determine the distribution of low estimated glomerular filtration rates (eGFRs) in urban and rural Tanzania, to describe factors associated with low eGFR and to quantify fractions attributable to common risk factors. METHODS: We conducted a community based survey of 1095 randomly selected Tanzanian adults (>=18 years). A structured questionnaire and examinations were used to document sociodemographic characteristics, diet, physical activity, anthropomorphic measurements and blood pressure. Blood tests were performed for HIV infection, diabetes mellitus and creatinine. eGFR was calculated using two equations recommended for African adults. RESULTS: Serum creatinine was available for 1043 participants: 170 in Mwanza city, 326 in district towns and 547 in rural areas. Mean age was 35.5 years and 54% were females. The prevalence of eGFR < 60 ml/min/1.73 m(2) in these 3 strata was 2.3% (95% CI = 0.8-6.6%), 7.5% (4.7-11.8%) and 7.4% (5.1-10.6%), respectively. When age standardised to the WHO world population, prevalences were 3.8%, 10.1% and 8.1%. Factors associated with low eGFR included district town residence, older age, greater wealth, less physical activity and hypertension. Only 21% of cases with eGFR < 60 ml/min/1.73 m(2) were attributable to HIV, hypertension or diabetes. CONCLUSIONS: Decreased renal function is common in Tanzania, particularly in district towns, and unique risk factors for kidney disease may exist in this population. Population-specific strategies for prevention, early diagnosis and treatment of kidney disease are needed for Africa. PMID- 26644311 TI - The clinical impact of livestock-associated methicillin-resistant Staphylococcus aureus of the clonal complex 398 for humans. AB - In the past decade, livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA) strains in particular of the clonal complex (CC) 398 have emerged in many parts of the world especially in areas with a high density of pig farming. In those regions, farmworkers and other individuals with professional contact to livestock are very frequently colonized with LA-MRSA. These persons are the presumably source for LA-MRSA transmission to household members and other parts of the human population. Altogether, colonization and/or infection of these individuals lead to the introduction of LA-MRSA into hospitals and other healthcare facilities. Since LA-MRSA CC398 have been found to be specifically adapted to their animal hosts in terms of the equipment with virulence factors, their pathogenicity to human patients is a matter of debate with first reports about clinical cases. Meanwhile, case reports, case series and few studies have demonstrated the capability of LA-MRSA to cause all types of infections attributed to S. aureus in general including fatal courses. Human infections observed comprise e.g. bacteremia, pneumonia, osteomyelitis, endocarditis and many manifestations of skin and soft tissue infections. However, inpatients affected by MRSA CC398 generally show different demographic (e.g. younger, shorter length of hospital stay) and clinical characteristics (e.g. less severe complications) which may explain or at least contribute to a lower disease burden of LA-MRSA compared to other MRSA clonal lineages. PMID- 26644312 TI - Decreased Frequency and Secretion of CD26 Promotes Disease Progression in Indian Post Kala-azar Dermal Leishmaniasis. AB - PURPOSE: Leishmania, the causative organisms for leishmaniasis, reside in host macrophages and survive by modulating the microbicidal pathways via attenuation of the oxidative burst and/or suppression of cell-mediated immunity. As post kala azar dermal leishmaniasis (PKDL), the dermal sequela of visceral leishmaniasis, has no animal model, the underlying mechanism(s) that nullify the microbicidal effector mechanisms remain poorly understood. This study was aimed at assessing the status of dipeptidyl peptidase CD26, a co-stimulatory molecule that is essential for T-cell signal activation. METHODS: The frequency/expression of CD26 and CD45RO/RA was evaluated by flow cytometry, while levels of soluble CD26 (sCD26), CXCL-10, RANTES, IL-10 and TGF-beta along with adenosine deaminase (ADA) activity were measured using ELISA. RESULTS: In patients with PKDL vis-a-vis healthy individuals, there was a significant decrease in the frequency and expression of CD26 on CD3(+)CD8(+) T-cells, which was accompanied by a significant lowering of plasma levels of sCD26. Furthermore, these patients showed a significant decrease in the frequency of CD45RO(+)/CD8(+) T-cells, concomitant with a significant increase in the proportion of CD45RA(+)/CD8(+) T cells. This could collectively translate into reduced formation of the immunological synapse of CD26, CD45RO, and ADA, and lead to an attenuation of the Th1 responses. The decreased levels of CD26 and sCD26 correlated negatively with raised levels of Th2 cytokines, IL-10, and TGF-beta along with the lesional parasite load, indicating disease specificity. CONCLUSIONS: Taken together, the decreased expression and secretion of CD26 in patients with PKDL resulted in impairment of the CD26-ADA interaction, and thereby possibly contributed to T cell unresponsiveness, emphasizing the need to develop immunomodulatory therapies against PKDL and by extension, the leishmaniases. PMID- 26644313 TI - A Patient with CTLA-4 Haploinsufficiency Presenting Gastric Cancer. AB - Cytotoxic T-lymphocyte-antigen 4 (CTLA-4) is an essential negative regulator expressed on regulatory T cells (Tregs) and activated T cells. Germline heterozygous mutations in CTLA4 lead to haploinsufficiency of CTLA-4, resulting in the development of an autosomal dominant immune dysregulation syndrome with incomplete penetrance. We report here a Japanese patient with this disorder who has a novel heterozygous single nucleotide insertion, 76_77insT (p. L28SfsX40), in the CTLA4 gene. Peripheral blood mononuclear cells from the patient showed decreased frequency of CTLA-4(high) cells in CD4(+)FOXP3(+) cells following CD3/CD28 stimulation. The patient experienced hypogammaglobulinemia, recurrent pneumonia, esophageal candidiasis, cytomegalovirus-positive chronic gastritis, chronic and severe diarrhea, and type 1 diabetes mellitus. Moreover, the patient developed multifocal gastric cancer, histologically poorly and well differentiated adenocarcinomas, associated with chronic atrophic gastritis and intestinal metaplasia. Previously, 23 symptomatic cases with heterozygous CTLA4 mutations have been reported. Including the case presented here, 3 of the 24 cases (12.5%) developed gastric cancer. Notably, 2 of 3 patients presented similarly multifocal adenocarcinomas associated with atrophic gastritis and intestinal metaplasia. Predisposition to gastric cancer has been also reported in CVID patients. These clinical observations suggest that gastric cancer is a disease commonly associated with autosomal dominant immune dysregulation syndrome due to CTLA4 mutation. PMID- 26644314 TI - Associations between injecting illicit drugs into the femoral vein and deep vein thrombosis: A case control study. AB - INTRODUCTION AND AIMS: Injecting drug use is a risk factor for deep vein thrombosis (DVT), and people who inject drugs commonly report injecting into the femoral vein. However, it is unclear whether the act of inserting a needle into the femoral vein or the pharmacodynamic properties of the injected drug increases DVT risk. We aimed to quantify the strength of association between injecting illicit drugs into the femoral vein and the odds of acquiring ileo-femoral DVT. DESIGN AND METHODS: We used case control methodology. The study took place in Leeds, UK. A total of 313 people who inject drugs (112 'cases' with a diagnosis of DVT from hospital accident and emergency departments and 201 'controls' with no DVT from needle exchanges) completed a questionnaire about their drug use and administration routes. RESULTS: The act of injecting into the femoral vein was strongly associated with DVT (chi(2) (1) = 53.453, P < 0.001), a finding that remained significant after adjusting for the type of illicit drug injected, age, gender, smoking status and history of clotting disorder. Independent of the act of femoral vein injecting, after adjusting for the effects of potential confounders, crack cocaine use was significantly associated with DVT, whereas amphetamine and heroin use were negatively independently associated with DVT. CONCLUSIONS: The practice of injecting into the femoral vein in the groin and the practice of injecting crack cocaine are associated with the odds of acquiring ileo-femoral DVT. [Wright NMJ, Allgar V, Tompkins CNE. Associations between injecting illicit drugs into the femoral vein and deep vein thrombosis: A case control study. Drug Alcohol Rev 2016;35:605-610]. PMID- 26644315 TI - Tumor Heterogeneity and Lesion-Specific Response to Targeted Therapy in Colorectal Cancer. AB - How genomic heterogeneity associated with acquired resistance to targeted agents affects response to subsequent therapy is unknown. We studied EGFR blockade in colorectal cancer to assess whether tissue and liquid biopsies can be integrated with radiologic imaging to monitor the impact of individual oncogenic alterations on lesion-specific responses. Biopsy of a patient's progressing liver metastasis following prolonged response to cetuximab revealed a MEK1(K57T) mutation as a novel mechanism of acquired resistance. This lesion regressed upon treatment with panitumumab and the MEK inhibitor trametinib. In circulating tumor DNA (ctDNA), mutant MEK1 levels declined with treatment, but a previously unrecognized KRAS(Q61H) mutation was also identified that increased despite therapy. This same KRAS mutation was later found in a separate nonresponding metastasis. In summary, parallel analyses of tumor biopsies and serial ctDNA monitoring show that lesion specific radiographic responses to subsequent targeted therapies can be driven by distinct resistance mechanisms arising within separate tumor lesions in the same patient. SIGNIFICANCE: Molecular heterogeneity ensuing from acquired resistance drives lesion-specific responses to subsequent targeted therapies. Analysis of a single-lesion biopsy is inadequate to guide selection of subsequent targeted therapies. ctDNA profiles allow the detection of concomitant resistance mechanisms residing in separate metastases and assessment of the effect of therapies designed to overcome resistance. PMID- 26644318 TI - Stress response of Salmo salar (Linnaeus 1758) facing low abundance infestation of Caligus rogercresseyi (Boxshall & Bravo 2000), an object in the tank, and handling. AB - This study looks at how low infestation loads of adult Caligus rogercresseyi and other stressors affect the physiology of Salmo salar. Experimental fish groups were with (infested) or without (control) exposure to the parasite. The parasite cohort was followed for 78 days post-infestation (dpi), and only adult lice were observed. Additional stressors were applied at 60 and 75 dpi. The analysis included measurements of fish physiology and weight. Low-level infestations by adult C. rogercresseyi for more than 50 dpi induced moderate stress in S. salar as well as a high energy demand and increased small skin mucous cells. Threshold lice loads were identified, and above those loads, a high stress response was observed. Additional stressors altered fish physiology, inducing downregulation of the cortisol response after the first stressor and upregulation after the second stressor, but infested fish responded more strongly. Parasitism by C. rogercresseyi is energetically demanding, affecting the primary and secondary responses (e.g. cortisol and glucose levels), as well as the tertiary response (fish weight). PMID- 26644316 TI - The Assessment of the Readiness of Molecular Biomarker-Based Mobile Health Technologies for Healthcare Applications. AB - Mobile health technologies to detect physiological and simple-analyte biomarkers have been explored for the improvement and cost-reduction of healthcare services, some of which have been endorsed by the US FDA. Advancements in the investigations of non-invasive and minimally-invasive molecular biomarkers and biomarker candidates and the development of portable biomarker detection technologies have fuelled great interests in these new technologies for mhealth applications. But apart from the development of more portable biomarker detection technologies, key questions need to be answered and resolved regarding to the relevance, coverage, and performance of these technologies and the big data management issues arising from their wide spread applications. In this work, we analyzed the newly emerging portable biomarker detection technologies, the 664 non-invasive molecular biomarkers and the 592 potential minimally-invasive blood molecular biomarkers, focusing on their detection capability, affordability, relevance, and coverage. Our analysis suggests that a substantial percentage of these biomarkers together with the new technologies can be potentially used for a variety of disease conditions in mhealth applications. We further propose a new strategy for reducing the workload in the processing and analysis of the big data arising from widespread use of mhealth products, and discuss potential issues of implementing this strategy. PMID- 26644317 TI - Prazosin for treating sleep disturbances in adults with posttraumatic stress disorder: a systematic review and meta-analysis of randomized controlled trials. AB - OBJECTIVE: Posttraumatic stress disorder (PTSD) is a disorder with significant sleep morbidity and limited treatment options. Prazosin may constitute a novel management approach and has been tested recently in a number of trials. We conducted a meta-analysis to examine the effectiveness of prazosin for nightmares and other sleep disturbances in adults with PTSD. METHOD: A systematic review of databases for randomized, double-blind, placebo-controlled trials of adults diagnosed with PTSD and reporting sleep disturbances that were treated with prazosin was conducted in January 2015. No limitations were placed on language or year of publication. RESULTS: Six randomized controlled trials of prazosin for sleep disturbances in patients with PTSD were included (sample n=240). We found that prazosin was statistically significantly more effective than placebo in improving sleep quality [g=0.987, 95% confidence interval (CI): 0.324-1.651] and in reducing overall PTSD symptoms (g=0.699, 95% CI: 0.139-1.260) and sleep disturbances in particular (g=0.799, 95% CI: 0.391-1.234). CONCLUSIONS: Prazosin showed medium-to-large and statistically significant effects on PTSD symptoms in general and sleep disturbances in particular. While promising, results should be interpreted with caution given the limited total number of participants and the limitations induced by the majority of participants being male and noncivilian. PMID- 26644319 TI - Sustained corticosteroid- induced mania and psychosis despite cessation: A case study and brief literature review. AB - OBJECTIVE: Corticosteroids generally result in short-lasting neuropsychiatric symptoms following cessation, but the following case highlights an unusually long lasting course of symptoms in a patient following near immediate cessation of medication, despite medication management and electroconvulsive therapy. The case presentation will be followed by a discussion of the presentation, treatment, and management of steroid-induced neuropsychiatric symptoms. METHODS: The patient was followed from symptom onset to resolution. RESULTS: The patient's symptom course was unusually long and required a long course of multimodal therapy. CONCLUSIONS: Corticosteroids are commonly used medications both in a wide variety of medical settings, and despite this, their neuropsychiatric effects are poorly understood. The affective and behavioral symptoms, in particular mania and psychosis, can be unpredictable and challenging to treat as in our patient, who developed a long lasting psychotic episode on high-dose steroids despite discontinuation and treatment of nearly six months. This was despite having tolerated steroids multiple times in the past. PMID- 26644320 TI - Chemical communication of queen supergene status in an ant. AB - Traits of interest to evolutionary biologists often have complex genetic architectures, the nature of which can confound traditional experimental study at single levels of analysis. In the fire ant Solenopsis invicta, the presence of a Mendelian 'supergene' is both necessary and sufficient to induce a shift in a fundamental property of social organization, from single-queen (monogyne) to multiple-queen (polygyne) colonies. This selfish genetic element, termed the Social b (Sb) supergene, contains > 600 genes that collectively promote its fitness by inducing the characteristic polygyne syndrome, in part by causing polygyne workers to accept only queens bearing the Sb element (a behaviour termed 'worker Sb discrimination'). Here, we employ a newly developed behavioural assay to reveal that polygyne workers, many of which bear the Sb element, employ chemical cues on the cuticle of queens to achieve worker Sb discrimination, but we found no evidence for such pheromonally mediated worker Sb discrimination in monogyne workers, which universally lack the Sb element. This polygyne worker Sb discrimination was then verified through a 'green beard' effect previously described in this system. We thus have demonstrated that the Sb element is required both for production of relevant chemical cues of queens and for expression of the behaviours of workers that collectively result in worker Sb discrimination. This information fills a critical gap in the map between genotype and complex phenotype in S. invicta by restricting the search for candidate genes and molecules involved in producing this complex social trait to factors associated with the Sb element itself. PMID- 26644321 TI - Removal of phosphorus by a high rate membrane adsorption hybrid system. AB - Membrane adsorption hybrid system (MAHS) was evaluated for the removal of phosphate from a high rate membrane bioreactor (HR-MBR) effluent. The HR-MBR was operated at permeate flux of 30L/m(2)h. The results indicated that the HR-MBR could eliminate 93.1+/-1.5% of DOC while removing less than 53% phosphate (PO4 P). Due to low phosphate removal by HR-MBR, a post-treatment of strong base anion exchange resin (Dowex(*)21K-XLT), and zirconium (IV) hydroxide were used as adsorbent in MAHS for further removal of phosphate from HR-MBR effluent. It was found that the MAHS enabled to eliminate more than 85% of PO4-P from HR-MBR effluent. Hence, HR-MBR followed by MAHS lead to simultaneous removal of organics and phosphate in a reliable manner. The experiments were conducted only for a short period to investigate the efficiency of these resins/adsorbents on the removal of phosphorus and high rate MBR for organic removal. PMID- 26644322 TI - Ultrafast Thermal Nonlinearity. AB - Third order nonlinear optical phenomena explored in the last half century have been predicted to find wide range of applications in many walks of life, such as all-optical switching, routing, and others, yet this promise has not been fulfilled primarily because the strength of nonlinear effects is too low when they are to occur on the picosecond scale required in today's signal processing applications. The strongest of the third-order nonlinearities, engendered by thermal effects, is considered to be too slow for the above applications. In this work we show that when optical fields are concentrated into the volumes on the scale of few tens of nanometers, the speed of the thermo-optical effects approaches picosecond scale. Such a sub-diffraction limit concentration of field can be accomplished with the use of plasmonic effects in metal nanoparticles impregnating the thermo-optic dielectric (e.g. amorphous Si) and leads to phase shifts sufficient for all optical switching on ultrafast scale. PMID- 26644323 TI - Polyglycerol-Based Copper Chelators for the Transport and Release of Copper Ions in Biological Environments. AB - Here, the synthesis and characterization of three improved nanosystems is presented based on amino functionalized hyperbranched polyglycerol (hPG; M(w) = 16.8 kDa) as potential copper(II) chelators. The ligands, N-methyl-N picolylglycine amide, 2,6-pyridine dicarboxylic acid monoamide, and cyclam tetraacetic acid (TETA) monoamide, are covalently attached to the polymer with amide bonds. In this paper, the Cu(II) loading capacity, the stability of the Cu(II)-loaded carriers at different pHs, with competing ligands and in human serum, as well as the transport of Cu(II) in biological systems are investigated. For the first time, a different cytotoxicity of functionalized polymer nanoparticles with and without Cu(II) is observed. The cyclam-based carrier combines the highest loading capacity (29 Cu ions/nanoparticle), best stability with respect to pH and EDTA (45% remaining Cu after 24 h), lowest cytotoxicity (IC50 > 100 * 10(-6) M (unloaded), 1500 * 10(-6) M Cu(II); Cu:carrier 29:1), and the highest stability in human serum. PMID- 26644325 TI - Retrospective analysis of process times for lacerations of the face in children: procedural sedation or general anaesthesia? PMID- 26644324 TI - A critical role of Dectin-1 in hypersensitivity pneumonitis. AB - OBJECTIVES AND DESIGN: Hypersensitivity pneumonitis (HP) is a pulmonary disease caused by repeated exposure to various aspiration antigens, including bacteria and fungi. Although TLRs are known to be required for the generation of HP triggered by bacteria, the significance of fungal receptors remains unclear. The present study aimed to investigate whether Dectin-1 and Dectin-2 contribute to the development of experimental HP triggered by the fungus Trichosporon asahii (T. asahii) that causes summer-type HP. MATERIALS AND METHODS: We investigated the binding between Dectin-Fc protein and T. asahii by a dot blot assay. We performed the histological and flow cytometric analysis in the HP model using Dectin-1-deficient (Dectin-1(-/-)) and Dectin-2(-/-) mice. We also investigated Th17/Th1 responses in lung cells, and measured an IL-17-promoting cytokine IL-23 from bone marrow-derived dendritic cells (BMDCs) by ELISA. RESULTS: Dectin-1 bound more strongly to T. asahii than Dectin-2. Dectin-1(-/-) mice barely developed HP, whereas both wild-type mice and Dectin-2(-/-) mice developed similar lung diseases. Dectin-1 deficiency decreased the infiltration of neutrophils and monocyte-derived macrophages and repressed the expansion of lung CD4(+)IL-17A(+) cells. The production of IL-23 p19 was reduced in Dectin-1(-/-) BMDCs. CONCLUSIONS: These data suggested Dectin-1 plays a critical role in the development of fungus-induced HP. PMID- 26644326 TI - Clinicopathological characteristics of tumours of the intraoral minor salivary glands in 170 Brazilian patients. AB - Tumours of the minor salivary glands are relatively uncommon, and publications from around the world normally include tumours of both the minor and major salivary glands, making it difficult to assess their prevalence and distribution. Our aim was to evaluate retrospectively the clinicopathological features of a series of tumours of the intraoral minor salivary glands from two universities in Rio de Janeiro, Brazil, and to compare the data with those from other epidemiological studies. A total of 170 such tumours were diagnosed from 1942 to 2012, and were selected from two university departments of oral pathology. Eighty nine of the tumours were benign (52%). Pleomorphic adenoma (n=75) and mucoepidermoid carcinoma (n=23) were the most common benign (44%) and malignant tumours (14%), respectively. There were 104 female patients (61%) and both benign and malignant tumours affected more women than men. Significantly more tumours were in the palate (n=95, 56%; p=0.001). We conclude that these tumours had features similar to those from other studies from North and Latin America, but differ from the results presented from Asia. Further studies should be designed to highlight possible geographical and population-specific characteristics of these tumours. PMID- 26644327 TI - Dose-associated pulmonary complication rates after fresh frozen plasma administration for warfarin reversal. AB - ESSENTIALS: Fresh frozen plasma (FFP) may be associated with a dose-based risk of pulmonary complications. Patients received FFP for warfarin reversal at a large academic hospital over a 3-year period. Almost 20% developed pulmonary complications, and the risk was highest after > 3 units of FFP. The risk of pulmonary complications remained significant in multivariable analysis. BACKGROUND: Fresh frozen plasma (FFP) is often administered to reverse warfarin anticoagulation. Administration has been associated with pulmonary complications, but it is unclear whether this risk is dose-related. Aims We sought to characterize the incidence and dose relationship of pulmonary complications, including transfusion-associated circulatory overload (TACO) and transfusion related acute lung injury (TRALI), after FFP administration for warfarin reversal. METHODS: We performed a structured retrospective review of patients who received FFP for warfarin reversal in the emergency department (ED) of an academic tertiary-care hospital over a 3-year period. Logistic regression was used to explore the relationship between FFP dose and risk of pulmonary events. RESULTS: Two hundred and fifty-one patients met the inclusion criteria. Overall, 49 patients (20%) developed pulmonary complications, including 30 (12%) with TACO, two (1%) with TRALI, and 17 (7%) with pulmonary edema not meeting the criteria for TACO. Pulmonary complications were significantly more frequent in those who received > 3 units of FFP (34.0% versus 15.6%, 95% confidence interval for risk difference 7.9%-8.9%). After stratification by subtype of complication, only the risk of TACO was statistically significant (28.3% versus 7.6%, 95% confidence interval for risk difference 8.2%-16.6%). In multivariable analysis controlling for age, sex, initial systolic blood pressure, and intravenous fluids given in the ED, > 3 units of FFP remained a significant risk factor for pulmonary complications (odds ratio 2.49, 95% confidence interval 1.21-5.13). CONCLUSIONS: Almost 20% of patients who received FFP for warfarin reversal developed pulmonary complications, primarily TACO, and this risk increased with > 3 units of FFP. Clinicians should be aware of and prepared to manage these complications. PMID- 26644328 TI - Self-esteem mediates the relationship between connectedness to nature and body appreciation in women, but not men. AB - Connectedness to nature (i.e., an affective and experiential connection to nature) is known to have a positive effect on psychological well-being, but its specific associations with body image have not been fully examined. To attend to this oversight, we conducted a preliminary investigation of associations between connectedness to nature and body appreciation. A total of 380 British adults completed measures of connectedness to nature, body appreciation, and self esteem. Bivariate correlations revealed significant positive associations between all variables in women. In men, body appreciation was significantly correlated with self-esteem, but not connectedness to nature. Mediation analysis showed that, in women, self-esteem fully mediated the relationship between connectedness to nature and body appreciation. In men, body appreciation was significantly associated with self-esteem, but not connectedness to nature. These results point to a potential route for improving body image among women through connectedness to nature and self-esteem, but further research is necessary. PMID- 26644330 TI - Quantitative comparison of cerebral artery development in metatherians and monotremes with non-human eutherians. AB - A quantitative comparison of the internal diameters of cerebral feeder arteries (internal carotid and vertebral) and the aorta in developing non-human eutherians, metatherians and monotremes has been made, with the aim of determining if there are differences in cerebral arterial flow between the three infraclasses of mammals such as might reflect differences in metabolism of the developing brain. There were no significant differences between eutherians and metatherians in the internal radius of the aorta or the thickness of the aortic wall, but aortic internal radius was significantly smaller in developing monotremes than therians at the < 10 mm body length range. Aortic thickness in the developing monotremes also rose at a slower rate relative to body length than in metatherians or eutherians. The sums of the internal calibres of the internal carotid and vertebral arteries were significantly lower in metatherians as a group and monotremes compared with non-human eutherians at body lengths up to 20 mm and in metatherians at > 20 mm body length. The internal calibre of the internal carotids relative to the sum of all cerebral feeder arteries was also significantly lower in monotremes at < 10 mm body length compared with eutherians. It was noted that dasyurids differed from other metatherians in several measures of cerebral arterial calibre and aortic internal calibre. The findings suggest that: (i) both aortic outflow and cerebral arterial inflow may be lower in developing monotremes than in therians, particularly at small body size (< 20 mm); (ii) cerebral inflow may be lower in some developing metatherians than non-human eutherians; and (iii) dasyurids have unusual features of cerebral arteries possibly related to the extreme immaturity and small size at which they are born. The findings have implications for nutritional sourcing of the developing brain in the three infraclasses of mammals. PMID- 26644329 TI - Sex Differences in the Cardiovascular Consequences of Diabetes Mellitus: A Scientific Statement From the American Heart Association. PMID- 26644331 TI - Intimate Partner Violence Against Women in Zimbabwe. AB - The present study examines intimate partner violence (IPV) reported by a sample of women in Zimbabwe to explore factors associated with the problem. Findings from the study indicate an important role of gender relationships in violence against women. The effects of gender inequalities on the likelihood of IPV vary with types of violence, but husband's patriarchal behaviors increase the likelihood of all forms of violence. The study suggests the importance of improving gender equality through public education on gender relationships, increasing women's education and economic opportunities, and eliminating customary laws that sustain gender inequality as necessary steps to combat IPV against women in Zimbabwe. PMID- 26644332 TI - Pregnancy following atrial-switch repair. PMID- 26644333 TI - Long-term effect of sub-anesthetic ketamine in reducing L-DOPA-induced dyskinesias in a preclinical model. AB - Low-dose sub-anesthetic ketamine infusion treatment has led to a long-term reduction of treatment-resistant depression and posttraumatic stress disorder (PTSD) symptom severity, as well as reduction of chronic pain states, including migraine headaches. Ketamine also is known to change oscillatory electric brain activity. One commonality between migraine headaches, depression, PTSD, Parkinson's disease (PD) and l-DOPA-induced dyskinesias (LID) is hypersynchrony of electric activity in the brain, including the basal ganglia. Therefore, we investigated the use of low-dose sub-anesthetic ketamine in the treatment of LID. In a preclinical rodent model of LID, ketamine (5-20mg/kg) led to long-term dose dependent reduction of abnormal involuntary movements, only when low-dose ketamine was given for 10h continuously (5* i.p. injections two hours apart) and not after a single acute low-dose ketamine i.p. injection. Pharmacokinetic analysis of plasma levels showed ketamine and its major metabolites were not detectable any more at time points when a lasting anti-dyskinetic effect was seen, indicating a plastic change in the brain. This novel use of low-dose sub anesthetic ketamine infusion could lead to fast clinical translation, and since depression and comorbid pain states are critical problems for many PD patients could open up the road to a new dual therapy for patients with LID. PMID- 26644334 TI - A microPET comparison of the effects of etifoxine and diazepam on [(11)C]flumazenil uptake in rat brains. AB - Using positron emission tomography (PET), the present study assessed the binding of [(11)C]flumazenil to GABA-A receptors in anesthetized rats following a single intravenous injection of an active dose of either etifoxine (25mg/kg) or diazepam (1mg/kg), which are both anxiolytic drugs. [(11)C]flumazenil binding was measured in five discrete brain structures, namely the caudate putamen, hippocampus, cerebellum, occipital cortex and parietal cortex. As expected, diazepam injection produced a significant decrease in [(11)C]flumazenil binding, which was interpreted as benzodiazepine GABA-A receptor occupancy, whereas etifoxine increased the binding of [(11)C]flumazenil. This first use of in vivo imaging after etifoxine administration revealed the activated binding pattern of [(11)C]flumazenil and highlighted the pharmacological differences between etifoxine and benzodiazepines. Using the same [(11)C]flumazenil radiotracer, PET neuroimaging could be applied to larger animals and, ultimately, to human subjects, thus providing new perspectives for better defining the molecular pharmacology of etifoxine. PMID- 26644335 TI - Trigeminal somatosensorial evoked potentials suggest increased excitability during interictal period in patients with long disease duration in migraine. AB - INTRODUCTION: Migraine pathogenesis is suggested to involve many structures in cerebral cortex, brainstem and trigeminovascular system. Electrophysiological studies revealed loss of habituation, decreased cortical preactivation, segmental hypersensitivity and reduction in control of inhibitory descending pathways. Given these information, we aimed to evaluate the excitability changes of the trigeminal pathway in the cortex and brainstem in migraine using trigeminal nerve somatosensory evoked potentials (TSEP). PATIENTS AND METHOD: Fifty-one women with migraine without aura and 32 age-matched healthy women were included. TSEPs were recorded in migraine patients during interictal period and in healthy subjects. Sensory thresholds, stimulation intensities, latencies of N1, P1, N2 and P2 waves as well as N1/P1 and N2/P1 amplitudes were measured. RESULTS: Comparisons of ipsilateral latencies with N1-P1 and N2-P1 amplitudes between migraine and control groups showed no difference. Sensory thresholds were also similar. Stimulation thresholds decreased as the attack frequency increased and ipsilateral N1/P1 amplitude increased with prolonged disease duration (p=0.043). CONCLUSION: Our study did not show significant difference between migraine patients and healthy subjects during interictal period. However, migraine with long duration affects the excitability of the cortical and brainstem trigeminal pathways even during interictal periods. PMID- 26644336 TI - Taichunamides: Prenylated Indole Alkaloids from Aspergillus taichungensis (IBT 19404). AB - Seven new prenylated indole alkaloids, taichunamides A-G, were isolated from the fungus Aspergillus taichungensis (IBT 19404). Taichunamides A and B contained an azetidine and 4-pyridone units, respectively, and are likely biosynthesized from notoamide S via (+)-6-epi-stephacidin A. Taichunamides C and D contain endoperoxide and methylsulfonyl units, respectively. This fungus produced indole alkaloids containing an anti-bicyclo[2.2.2]diazaoctane core, whereas A. protuberus and A. amoenus produced congeners with a syn-bicyclo[2.2.2]diazaoctane core. Plausible biosynthetic pathways to access these cores within the three species likely arise from an intramolecular hetero Diels-Alder reaction. PMID- 26644337 TI - Discovering the Presence of Convective Transport: An Artiphysiological Moment in Time. PMID- 26644340 TI - Phylogeography above the species level for perennial species in a composite genus. AB - In phylogeography, DNA sequence and fingerprint data at the population level are used to infer evolutionary histories of species. Phylogeography above the species level is concerned with the genealogical aspects of divergent lineages. Here, we present a phylogeographic study to examine the evolutionary history of a western Mediterranean composite, focusing on the perennial species of Helminthotheca (Asteraceae, Cichorieae). We used molecular markers (amplified fragment length polymorphism (AFLP), internal transcribed spacer and plastid DNA sequences) to infer relationships among populations throughout the distributional range of the group. Interpretation is aided by biogeographic and molecular clock analyses. Four coherent entities are revealed by Bayesian mixture clustering of AFLP data, which correspond to taxa previously recognized at the rank of subspecies. The origin of the group was in western North Africa, from where it expanded across the Strait of Gibraltar to the Iberian Peninsula and across the Strait of Sicily to Sicily. Pleistocene lineage divergence is inferred within western North Africa as well as within the western Iberian region. The existence of the four entities as discrete evolutionary lineages suggests that they should be elevated to the rank of species, yielding H. aculeata, H. comosa, H. maroccana and H. spinosa, whereby the latter two necessitate new combinations. PMID- 26644341 TI - Understanding the wide geographic range of a clonal perennial grass: plasticity versus local adaptation. AB - Both phenotypic plasticity and local adaptation may allow widely distributed plant species to either acclimate or adapt to environmental heterogeneity. Given the typically low genetic variation of clonal plants across their habitats, phenotypic plasticity may be the primary adaptive strategy allowing them to thrive across a wide range of habitats. In this study, the mechanism supporting the widespread distribution of the clonal plant Leymus chinensis was determined, i.e. phenotypic plasticity or local specialization in water use efficiency (WUE; reflected by foliar delta(13)C). To test whether plasticity is required for the species to thrive in different habitats, samples were collected across its distribution in the Mongolian steppe, and a controlled watering experiment was conducted with two populations at two different sites. Five populations were also transplanted from different sites into a control environment, and the foliar delta(13)C was compared between the control and original habitats, to test for local specialization in WUE. Results demonstrated decreased foliar delta(13)C with increasing precipitation during controlled watering experiments, with divergent responses between the two populations assessed. Change in foliar delta(13)C (-3.69 0/00) due to water addition was comparable to fluctuations of foliar delta(13)C observed in situ (-4.83 0/00). Foliar delta(13)C differed by 0.91 0/00 between two transplanted populations; however, this difference was not apparent between the two populations when growing in their original habitats. Findings provide evidence that local adaptation affects foliar delta(13)C much less than phenotypic plasticity. Thus, plasticity in WUE is more important than local adaptation in allowing the clonal plant L. chinensis to occupy a wide range of habitats in the Mongolian steppe. PMID- 26644342 TI - Influence of low calcium availability on cadmium uptake and translocation in a fast-growing shrub and a metal-accumulating herb. AB - Calcium (Ca) and the toxic heavy metal cadmium (Cd) are antagonistic ions competing for uptake in plants when they co-occur in soil solutions, and high Ca concentrations can reduce the uptake of Cd in plants. However, less is known about the effects of low Ca bioavailability on Cd uptake and translocation in plants. We hypothesized that low Ca availability would enhance Cd uptake and translocation in Sesbania sesban, a fast-growing shrub potentially useful for Cd removal from contaminated soils, and Brassica juncea, a well-known Cd hyperaccumulator. The two species were grown under controlled conditions for 21 days in hydroponic nutrient solutions with either 0.2 or 2 mM Ca and 0 or 50 uM Cd in a 2 * 2 factorial experimental design. Both species had a lower relative growth rate, final root length and shoot and root biomasses at 50 uM Cd compared with growth without Cd. The negative effects of Cd on both species were exacerbated at low Ca availability. Brassica juncea had higher root Cd concentrations than S. sesban, but the shoot Cd concentrations did not differ between the two species. The low Ca concentration enhanced the uptake of Cd in the roots of both species, but Cd translocation to the shoots was low, especially at 0.2 mM Ca. We conclude that the low Ca concentration enhanced the uptake of Cd into roots of S. sesban and B. juncea and increased the phytotoxicity of Cd. The translocation of Cd to the shoots of the two species was, however, lower at 0.2 mM than at 2 mM Ca, implying that Cd removal from polluted soil cannot simply be increased by adjusting ion concentrations. PMID- 26644344 TI - Correction. PMID- 26644343 TI - Intra-specific variation in genome size in maize: cytological and phenotypic correlates. AB - Genome size variation accompanies the diversification and evolution of many plant species. Relationships between DNA amount and phenotypic and cytological characteristics form the basis of most hypotheses that ascribe a biological role to genome size. The goal of the present research was to investigate the intra specific variation in the DNA content in maize populations from Northeastern Argentina and further explore the relationship between genome size and the phenotypic traits seed weight and length of the vegetative cycle. Moreover, cytological parameters such as the percentage of heterochromatin as well as the number, position and sequence composition of knobs were analysed and their relationships with 2C DNA values were explored. The populations analysed presented significant differences in 2C DNA amount, from 4.62 to 6.29 pg, representing 36.15 % of the inter-populational variation. Moreover, intra populational genome size variation was found, varying from 1.08 to 1.63-fold. The variation in the percentage of knob heterochromatin as well as in the number, chromosome position and sequence composition of the knobs was detected among and within the populations. Although a positive relationship between genome size and the percentage of heterochromatin was observed, a significant correlation was not found. This confirms that other non-coding repetitive DNA sequences are contributing to the genome size variation. A positive relationship between DNA amount and the seed weight has been reported in a large number of species, this relationship was not found in the populations studied here. The length of the vegetative cycle showed a positive correlation with the percentage of heterochromatin. This result allowed attributing an adaptive effect to heterochromatin since the length of this cycle would be optimized via selection for an appropriate percentage of heterochromatin. PMID- 26644345 TI - Extracurricular activities associated with stress and burnout in preclinical medical students. AB - This study aims to assess the prevalence of stress and burnout among preclinical medical students in a private university in Beirut, Lebanon, and evaluate the association between extracurricular involvement and stress and burnout relief in preclinical medical students. A cross-sectional survey was conducted on a random sample of 165 preclinical medical students. Distress level was measured using the 12-item General Health Questionnaire (GHQ-12) while that of burnout was measured through the Maslach Burnout Inventory-Student Survey (MBI-SS). The MBI-SS assesses three interrelated dimensions: emotional exhaustion, cynicism, and academic efficacy. Extracurricular activities were divided into four categories: physical exercise, music, reading, and social activities. All selected participants responded. A substantial proportion of preclinical medical students suffered from stress (62%) and burnout (75%). Bivariate and multivariate regression analyses revealed that being a female or a 1st year medical student correlated with higher stress and burnout. Music-related activities were correlated with lower burnout. Social activities or living with parents were associated with lower academic efficacy. The high stress and burnout levels call for action. Addressing the studying conditions and attending to the psychological wellbeing of preclinical medical students are recommendations made in the study. PMID- 26644346 TI - Microplastics profile along the Rhine River. AB - Microplastics result from fragmentation of plastic debris or are released to the environment as pre-production pellets or components of consumer and industrial products. In the oceans, they contribute to the 'great garbage patches'. They are ingested by many organisms, from protozoa to baleen whales, and pose a threat to the aquatic fauna. Although as much as 80% of marine debris originates from land, little attention was given to the role of rivers as debris pathways to the sea. Worldwide, not a single great river has yet been studied for the surface microplastics load over its length. We report the abundance and composition of microplastics at the surface of the Rhine, one of the largest European rivers. Measurements were made at 11 locations over a stretch of 820 km. Microplastics were found in all samples, with 892,777 particles km (-2) on average. In the Rhine-Ruhr metropolitan area, a peak concentration of 3.9 million particles km ( 2) was measured. Microplastics concentrations were diverse along and across the river, reflecting various sources and sinks such as waste water treatment plants, tributaries and weirs. Measures should be implemented to avoid and reduce the pollution with anthropogenic litter in aquatic ecosystems. PMID- 26644347 TI - Identification and characterization of latency-associated peptide-expressing gammadelta T cells. AB - gammadelta T cells are a subset of lymphocytes specialized in protecting the host against pathogens and tumours. Here we describe a subset of regulatory gammadelta T cells that express the latency-associated peptide (LAP), a membrane-bound TGF beta1. Thymic CD27+IFN-gamma+CCR9+alpha4beta7+TCRgammadelta+ cells migrate to the periphery, particularly to Peyer's patches and small intestine lamina propria, where they upregulate LAP, downregulate IFN-gamma via ATF-3 expression and acquire a regulatory phenotype. TCRgammadelta+LAP+ cells express antigen presentation molecules and function as antigen presenting cells that induce CD4+Foxp3+ regulatory T cells, although TCRgammadelta+LAP+ cells do not themselves express Foxp3. Identification of TCRgammadelta+LAP+ regulatory cells provides an avenue for understanding immune regulation and biologic processes linked to intestinal function and disease. PMID- 26644350 TI - Structure-dynamic basis of splicing-dependent regulation in tissue-specific variants of the sodium-calcium exchanger. AB - Tissue-specific splice variants of Na(+)/Ca(2+) exchangers contain 2 Ca(2+) binding regulatory domains (CBDs), CBD1 and CBD2. Ca(2+) interaction with CBD1 activates sodium-calcium exchangers (NCXs), and Ca(2+) binding to CBD2 alleviates Na(+)-dependent inactivation. A combination of mutually exclusive (A, B) and cassette (C-F) exons in CBD2 raises functionally diverse splice variants through unknown mechanisms. Here, the effect of exons on CBDs backbone dynamics were investigated in the 2-domain tandem (CBD12) of the brain, kidney, and cardiac splice variants by using hydrogen-deuterium exchange mass spectrometry and stopped-flow techniques. Mutually exclusive exons stabilize interdomain interactions in the apoprotein, which primarily predefines the extent of responses to Ca(2+) binding. Deuterium uptake levels were up to 20% lower in the cardiac vs. the brain CBD12, reveling that elongation of the CBD2 FG loop by cassette exons rigidifies the interdomain Ca(2+) salt bridge at the 2-domain interface, which secondarily modulates the Ca(2+)-bound states. In matching splice variants, the extent of Ca(2+)-induced rigidification correlates with decreased (up to 10-fold) Ca(2+) off rates, where the cardiac CBD12 exhibits the slowest Ca(2+) off rates. Collectively, structurally disordered/dynamic segments at mutually exclusive and cassette exons have local and distant effects on the folded structures nearby the Ca(2+) binding sites, which may serve as a structure dynamic basis for splicing-dependent regulation of NCX. PMID- 26644348 TI - Identification of new genotype of Echovirus 19 from children with Acute Flaccid Paralysis in Pakistan. AB - Enteroviruses are known to cause childhood paralysis. The purpose of this study was to examine the genetic diversity and to determine the association of non polio enteroviruses (NPEVs) with acute flaccid Paralysis (AFP). Stool samples (n = 1191) of children with AFP were collected from Khyber Pakhtunkhwa and Federally Administered Tribal Areas of Pakistan. Poliovirus was isolated in 205 (17.2%) samples and NPEVs were found in 215 (18.0%) samples. Out of 215 viruses, 124 (57.7%) were typed into 19 different types of enteroviruses while 91 (42.3%) remained untypeable on microneutralization assay that were reconfirmed as NPEVs by real time PCR. Echovirus 19 (20/35; 57.1%) was found the most prevalent type based on VP1 nucleotide sequencing with increased genetic diversity. Phylogenetic analysis revealed the circulation of a new genotype of E-19 in the country. The findings of this study are of great importance for future research and propose to establish the enterovirus surveillance system in the country to readily identify more enteroviruses and to monitor the emergence of new variants/genotypes especially at the moment when we are at the verge of polio eradication phase. PMID- 26644349 TI - Cytosolic phospholipase A2alpha regulates G1 progression through modulating FOXO1 activity. AB - Group IVA phospholipase A2 [cytosolic phospholipase A2alpha (cPLA2alpha)] is a key mediator of inflammation and tumorigenesis. In this study, by using a combination of chemical inhibition and genetic approaches in zebrafish and murine cells, we identify a mechanism by which cPLA2alpha promotes cell proliferation. We identified 2 cpla2alpha genes in zebrafish, cpla2alphaa and cpla2alphab, with conserved phospholipase activity. In zebrafish, loss of cpla2alpha expression or inhibition of cpla2alpha activity diminished G1 progression through the cell cycle. This phenotype was also seen in both mouse embryonic fibroblasts and mesangial cells. G1 progression was rescued by the addition of arachidonic acid or prostaglandin E2 (PGE2), indicating a phospholipase-dependent mechanism. We further show that PGE2, through PI3K/AKT activation, promoted Forkhead box protein O1 (FOXO1) phosphorylation and FOXO1 nuclear export. This led to up regulation of cyclin D1 and down-regulation of p27(Kip1), thus promoting G1 progression. Finally, using pharmacologic inhibitors, we show that cPLA2alpha, rapidly accelerated fibrosarcoma (RAF)/MEK/ERK, and PI3K/AKT signaling pathways cooperatively regulate G1 progression in response to platelet-derived growth factor stimulation. In summary, these data indicate that cPLA2alpha, through its phospholipase activity, is a critical effector of G1 phase progression through the cell cycle and suggest that pharmacological targeting of this enzyme may have important therapeutic benefits in disease mechanisms that involve excessive cell proliferation, in particular, cancer and proliferative glomerulopathies. PMID- 26644351 TI - Genetic ablation of lymphocytes and cytokine signaling in nonobese diabetic mice prevents diet-induced obesity and insulin resistance. AB - Obesity is characterized by a dysregulated immune system, which may causally associate with insulin resistance and type 2 diabetes. Despite widespread use of nonobese diabetic (NOD) mice, NOD with severe combined immunodeficiency (scid) mutation (SCID) mice, and SCID bearing a null mutation in the IL-2 common gamma chain receptor (NSG) mice as animal models of human diseases including type 1 diabetes, the underlying metabolic effects of a genetically altered immune system are poorly understood. For this, we performed a comprehensive metabolic characterization of these mice fed chow or after 6 wk of a high-fat diet. We found that NOD mice had ~50% less fat mass and were 2-fold more insulin sensitive, as measured by hyperinsulinemic-euglycemic clamp, than C57BL/6 wild type mice. SCID mice were also more insulin sensitive with increased muscle glucose metabolism and resistant to diet-induced obesity due to increased energy expenditure (~10%) and physical activity (~40%) as measured by metabolic cages. NSG mice were completely protected from diet-induced obesity and insulin resistance with significant increases in glucose metabolism in peripheral organs. Our findings demonstrate an important role of genetic background, lymphocytes, and cytokine signaling in diet-induced obesity and insulin resistance. PMID- 26644353 TI - Crystallographic and CD probing of ligand-induced conformational changes in a plant PR-10 protein. AB - Plant pathogenesis-related class 10 (PR-10) proteins are a family of abundant proteins initially identified as elements of the plant defense system. The key structural feature suggesting PR-10 functionality is a huge hydrophobic cavity created in the protein interior by a scaffold composed of an extended beta-sheet wrapped around a long and flexible C-terminal alpha-helix. Several crystallographic and NMR studies have shown that the cavity can accommodate a variety of small molecule ligands, including phytohormones. The article describes ~1.3 A resolution crystal structures of a Lupinus luteus PR-10 isoform LlPR 10.1A, in its free form and in complex with trans-zeatin, a naturally occurring plant hormone belonging to the cytokinin group. Moreover we present the structure of the same protein where the saturation with zeatin is not complete. This set of three crystal structures allows us to track the structural adaptation of the protein upon trans-zeatin docking, as well as the sequence of the ligand-binding events, step-by-step. In addition, titration of LlPR-10.1A with trans-zeatin monitored in solution by CD spectra, confirmed the pattern of structural adaptations deduced from the crystallographic studies. The ligand-biding mode shows no similarity to other zeatin complexes of PR-10 proteins. The present work, which describes the first atomic models of the same PR-10 protein with and without a physiological ligand, reveals that the conformation of LlPR-10.1A undergoes a significant structural rearrangement upon trans-zeatin binding. PMID- 26644352 TI - Second-generation antisense oligonucleotides against beta-catenin protect mice against diet-induced hepatic steatosis and hepatic and peripheral insulin resistance. AB - Although mutations in the Wnt/beta-catenin signaling pathway are linked with the metabolic syndrome and type 2 diabetes in humans, the mechanism is unclear. High fat-fed male C57BL/6 mice were treated for 4 wk with a 2'-O-methoxyethyl chimeric antisense oligonucleotide (ASO) to decrease hepatic and adipose expression of beta-catenin. beta-Catenin mRNA decreased by ~80% in the liver and by 70% in white adipose tissue relative to control ASO-treated mice. beta-Catenin ASO improved hepatic insulin sensitivity and increased insulin-stimulated whole body glucose metabolism, as assessed during hyperinsulinemic-euglycemic clamp in awake mice. beta-Catenin ASO altered hepatic lipid composition in high-fat-fed mice. There were reductions in hepatic triglyceride (44%, P < 0.05) and diacylglycerol content (60%, P < 0.01) but a 30% increase in ceramide content (P < 0.001). The altered lipid content was attributed to decreased expression of sn-1,2 diacylglycerol acyltransferase and mitochondrial acyl-CoA:glycerol-sn-3-phosphate acyltransferase and an increase in serine palmitoyl transferase. The decrease in cellular diacyglycerol was associated with a 33% decrease in PKCepsilon activation (P < 0.05) and 64% increase in Akt2 phosphorylation (P < 0.05). In summary, Reducing beta-catenin expression decreases expression of enzymes involved in hepatic fatty acid esterification, ameliorates hepatic steatosis and lipid-induced insulin resistance. PMID- 26644354 TI - Developing high-quality mouse monoclonal antibodies for neuroscience research - approaches, perspectives and opportunities. AB - High-quality antibodies (Abs) are critical to neuroscience research, as they remain the primary affinity proteomics reagent used to label and capture endogenously expressed protein targets in the nervous system. As in other fields, neuroscientists are frequently confronted with inaccurate and irreproducible Ab based results and/or reporting. The UC Davis/NIH NeuroMab Facility was created with the mission of addressing the unmet need for high-quality Abs in neuroscience research by applying a unique approach to generate and validate mouse monoclonal antibodies (mAbs) optimized for use against mammalian brain (i.e., NeuroMabs). Here we describe our methodology of multi-step mAb screening focused on identifying mAbs exhibiting efficacy and specificity in labeling mammalian brain samples. We provide examples from NeuroMab screens, and from the subsequent specialized validation of those selected as NeuroMabs. We highlight the particular challenges and considerations of determining specificity for brain immunolabeling. We also describe why our emphasis on extensive validation of large numbers of candidates by immunoblotting and immunohistochemistry against brain samples is essential for identifying those that exhibit efficacy and specificity in those applications to become NeuroMabs. We describe the special attention given to candidates with less common non-IgG1 IgG subclasses that can facilitate simultaneous multiplex labeling with subclass-specific secondary antibodies. We detail our recent use of recombinant cloning of NeuroMabs as a method to archive all NeuroMabs, to unambiguously define NeuroMabs at the DNA sequence level, and to re-engineer IgG1 NeuroMabs to less common IgG subclasses to facilitate their use in multiplex labeling. Finally, we provide suggestions to facilitate Ab development and use, as to design, execution and interpretation of Ab-based neuroscience experiments. Reproducibility in neuroscience research will improve with enhanced Ab validation, unambiguous identification of Abs used in published experiments, and end user proficiency in Ab-based assays. PMID- 26644355 TI - Discrepancies between plasma procalcitonin and C-reactive protein levels are common in acute illness. AB - AIM: Procalcitonin (PCT) and C-reactive protein (CRP) are biomarkers of bacterial infection with distinct clinical qualities. This study aimed to determine the occurrence and significance of discrepancies in plasma PCT and CRP levels in hospitalised children. METHODS: This was a single centre, retrospective analysis of simultaneous PCT and CRP measurements. Clinical characteristics, microbiological findings and diagnoses were compared between cases in which only PCT or CRP levels were elevated. RESULTS: We studied 635 pairs of PCT and CRP measurements and found discrepancies in 29% of these. In the group with increased PCT and low CRP, there were more children with hypoxia or haemodynamic stress (14 versus 0, p < 0.001) and more bacteraemic patients (eight versus zero, p = 0.001) than in the group with low PCT and increased CRP. The latter group was associated with focal bacterial infections (three versus 18, p = 0.009), inflammatory conditions (one versus 12, p = 0.016) and postoperative setting (one versus 19, p = 0.001). Diabetic ketoacidosis was associated with a marked elevation of PCT. CONCLUSION: Discrepancies in plasma PCT and CRP levels occurred in 29% of acutely ill children. Both biomarkers can increase in the absence of bacterial infection, but PCT may offer an advantage over CRP in the diagnosis of bacteraemia. PMID- 26644356 TI - Whole-mount pathology of breast lumpectomy specimens improves detection of tumour margins and focality. AB - AIMS: Technical limitations in conventional pathological evaluation of breast lumpectomy specimens may reduce diagnostic accuracy in the assessment of margin and focality. A novel technique based on whole-mount serial sections enhances sampling while preserving specimen conformation and orientation. The aim of this study was to investigate assessment of focality and margin status by the use of whole-mount serial sections versus simulated conventional sections in lumpectomies. METHODS AND RESULTS: Two pathologists interpreted whole-mount serial sections and simulated conventional sections for 58 lumpectomy specimens by reporting the closest margin and focality. Measurements were compared by the use of McNemar's chi-squared test. Statistically significant differences were observed in the assignment of both margin positivity (P = 0.014) and multifocality (P = 0.021). A positive margin or multifocal disease was identified by the use of whole-mount serial sections but missed in the simulated conventional assessment in 10.3% and 17.2% of all cases, respectively. There was no case in which a positive margin was detected only in the simulated conventional assessment. CONCLUSIONS: The whole-mount technique is more sensitive than conventional assessment for identifying a positive margin or multifocal disease in breast lumpectomy specimens. Undersampling in conventional sections was implicated in almost all cases of discordance. The majority of positive margins or secondary foci identified only in whole-mount serial sections concerned in-situ disease. PMID- 26644357 TI - Multinodular and vacuolating neuronal tumor affecting amygdala and hippocampus: A quasi-tumor? AB - Multinodular and vacuolating neuronal tumors (MVNT) have been referred to as distinctive neuronal tumors whose characteristic features include multiple nodules localized in the subcortical white matter. MVNT are composed of vacuolating dysplastic neurons reactive to HuC/HuD. A significant overexpression of alpha-internexin (INA) limited to the stroma of nodules was reported in one tumor. Since genetic analyses have failed to demonstrate any consistent alterations, the nosological position as well as the nature of MVNT, namely, neoplastic or dysplastic, remains unclear. We herein present another example of MVNT involving the amygdala and anterior hippocampus in a 41-year-old man. In addition to the nodular lesions described earlier, we found INA-positive ribbon like lesions that replaced neuropil and extended along the hippocampal gray matter. We also identified dysplastic neurons infiltrating into the CA4 hilus of the hippocampus. Intense INA expression was present in the stroma as well as the cytoplasmic membrane of dysplastic neurons and their processes. While the invasiveness suggested a neoplasm, a relatively restrictive, either nodular or ribbon-like growth pattern with INA-positive abnormal neuropil suggested a hamartoma. Such quasi-tumors should be accommodated in the World Health Organization classification of tumors of the central nervous system, as are dysembryoplastic neuroepithelial tumor and Lhermitte-Duclos disease. PMID- 26644358 TI - Emergency Preservation and Resuscitation Trial: A Philosophical Justification for Non-Voluntary Enrollment. AB - In a current clinical trial for Emergency Preservation and Resuscitation (EPR), Dr. Samuel Tisherman of the University of Maryland aims to induce therapeutic hypothermia in order to 'buy time' for operating on victims of severe exsanguination. While recent publicity has framed this controversial procedure as 'killing a patient to save his life', the US Army and Acute Care Research appear to support the study on the grounds that such patients already face low chances of survival. Given that enrollment in the trial must be non-voluntary, the study has received an exemption from federal standards for obtaining informed consent. How exactly, if at all, is non-voluntary enrollment morally justifiable? In this essay, I appeal to the notable work of Hans Jonas in an effort to defend the EPR trial's use of non-voluntary enrollment. It is often thought and, as I show, it may appear that Jonas has called for the end of experimental medical practice. Still, I derive from Jonas a principle of double-effect upon which physicians may be seen as morally permitted to pursue innovations in emergency medicine but only as a byproduct of pursuing therapeutic success. With this position, I argue that the EPR trial can be granted a stronger philosophical justification than simply waiving the requirement of obtaining informed consent. The double-effect justification would obtain, perhaps regardless of the success of such innovative procedures as therapeutic hypothermia. PMID- 26644360 TI - Enhanced Optical Transmission through MacEtch-Fabricated Buried Metal Gratings. AB - Metallic films with subwavelength apertures, integrated into a semiconductor by metal-assisted chemical etch (MacEtch), demonstrate enhanced transmission when compared to bare semiconductor surfaces. The resulting "buried" metallic structures are characterized spectroscopically and modeled using rigorous coupled wave analysis. These composite materials offer potential integration with optoelectronic devices, for simultaneous near-uniform electrical contact and strong optical coupling to free space. PMID- 26644359 TI - Small-Molecule Stabilization of the 14-3-3/Gab2 Protein-Protein Interaction (PPI) Interface. AB - Small-molecule modulation of protein-protein interactions (PPIs) is one of the most promising new areas in drug discovery. In the vast majority of cases only inhibition or disruption of PPIs is realized, whereas the complementary strategy of targeted stabilization of PPIs is clearly under-represented. Here, we report the example of a semi-synthetic natural product derivative--ISIR-005--that stabilizes the cancer-relevant interaction of the adaptor protein 14-3-3 and Gab2. The crystal structure of ISIR-005 in complex with 14-3-3 and the binding motif of Gab2 comprising two phosphorylation sites (Gab2pS210pT391) showed how the stabilizing molecule binds to the rim-of-the-interface of the protein complex. Only in the direct vicinity of 14-3-3/Gab2pT391 site is a pre-formed pocket occupied by ISIR-005; binding of the Gab2pS210 motif to 14-3-3 does not create an interface pocket suitable for the molecule. Accordingly, ISIR-005 only stabilizes the binding of the Gab2pT391 but not the Gab2pS210 site. This study represents structural and biochemical proof of the druggability of the 14-3 3/Gab2 PPI interface with important implications for the development of PPI stabilizers. PMID- 26644361 TI - Diabetic retinopathy in Tanzania: prevalence and risk factors at entry into a regional screening programme. AB - OBJECTIVE: The number of adults with diabetes in sub-Saharan Africa (SSA) is expected to almost double by 2035. This study investigated the prevalence of diabetic retinopathy (DR) and its risk factors at entry into a community-based screening programme. METHODS: All persons with diabetes screened for retinopathy at entry into a screening programme in Kilimanjaro Region, Tanzania between November 2010 and December 2014 were included. Fundus photographs were taken with a Topcon retinal camera following pupil dilation. Data were collected on BP, random blood sugar, duration of diabetes, BMI and visual acuity on entry. RESULTS: A total of 3187 persons were screened for DR. The prevalence of any DR was 27.9% (95%CI 26.4-29.5%) with background diabetic retinopathy (BDR), pre proliferative diabetic retinopathy (PPDR) and proliferative diabetic retinopathy (PDR) having a prevalence of 19.1% (95% CI 17.7-20.4%), 6.0% (95%CI 5.2-6.8%) and 2.9% (95%CI 2.3-3.5%), respectively. Maculopathy was present in 16.1% (95%CI 14.8 17.4%) of participants. Multivariable logistic regression analysis for the presence of any DR found independent associations with duration of diabetes (P < 0.0001), systolic BP (P < 0.0001), random blood sugar (P < 0.0001) and attending a government hospital diabetic clinic (P = 0.0339). CONCLUSIONS: This study is the first to present data from a DR screening programme in SSA. The results will provide policymakers with data to aid planning of DR screening and treatment services in the African region. The study highlights the importance of managing comorbidities within DR screening programmes. PMID- 26644362 TI - Fine-needle aspiration of soft tissue myoepithelioma. AB - Soft tissue myoepithelioma is a rare neoplasm composed of myoepithelial cells. We describe the cytologic features of a soft tissue myoepithelioma arising in the right lower chest wall in a 65-year-old woman. The fine-needle aspiration (FNA) smears showed round to oval, spindle, epithelioid, and plasmacytoid cells in the myxoid background. The nuclei were uniform, round to ovoid, with finely distributed chromatin and eosinophilic or pale cytoplasm, and resembled lobular carcinoma of breast. Ultrasound guided core biopsy showed the tumor cells had bland cytologic features, arranged in small cords, nests, and dissociated single cells, with no glandular differentiation or breast tissue seen. The tumor cells demonstrated immunoreactivity for cytokeratin (AE1/AE3) and glial fibrillary acidic protein, but were negative for estrogen receptor. Fluorescence in situ hybridization demonstrated the EWSR1 rearrangement, confirming the diagnosis of myoepithelioma. PMID- 26644363 TI - Do performance and image enhancing drug users in regional Queensland experience difficulty accessing health services? AB - INTRODUCTION AND AIM: To understand health service access and needs of people who use performance and image enhancing drugs (PIED) in regional Queensland. DESIGN AND METHODS: Semi-structured interviews were conducted with 21 people (n = 19 men) who reported the use of a range of PIEDs, including anabolic-androgenic steroids, human chorionic gonadotropin, growth hormone, clenbuterol, tamoxifen, insulin and peptides. RESULTS: Participants reported accessing a range of services, including needle and syringe programs and pharmacies, for sterile injecting equipment. While PIEDs users attributed some stigma to needle and syringe programs, they were seen as an important service for injecting equipment. Participants reported receiving either positive care from health-care providers, such as general practitioners (GP), or having negative experiences due to the stigma attached with PIED use. Few participants reported disclosing their PIED use to their GP not only because of the concerns that their GP would no longer see them but also because they felt their GP was not knowledgeable about these substances. DISCUSSION AND CONCLUSION: Participants in the study reported no difficulty in accessing health services based on living in a regional area, with their concern focused more upon how they were viewed and treated by service staff. [Dunn M, Henshaw R, Mckay F. H. Do performance and image enhancing drug users in regional Queensland experience difficulty accessing health services? Drug Alcohol Rev 2016;35:377-382]. PMID- 26644365 TI - Proton therapy for the treatment of pediatric head and neck cancers: A review. PMID- 26644364 TI - High Performance All-solid Supercapacitors Based on the Network of Ultralong Manganese dioxide/Polyaniline Coaxial Nanowires. AB - In recent years, thin, lightweight and flexible solid supercapacitors are of considerable interest as energy storage devices. Here we demonstrated all-solid supercapacitors (SSCs) with high electrochemical properties, low self-discharge characteristics based on manganese dioxide/polyaniline (MNW/PANI) coaxial nanowire networks. The synergistic effect of MnO2/PANI plus the unique coaxial nanostructure of the ultralong nanowires with a highly interconnected network effectively enhance the conductivity and capacitive performance of the SSCs device. The MNW/PANI composite with 62.5% MnO2 exhibits an outstanding areal specific capacitance reaching 346 mF/cm(2) at 5 mV s(-1) which is significant higher than most previously reported solid supercapacitors (15.3 mF/cm(2)-109 mF/cm(2)) and is close to the that of the best graphene films solid state supercapacitors (372 mF/cm(2)). In contrast, only 190 mF/cm(2) of areal specific capacitance was obtained for the pure MnO2 NW network. The supercapacitors also exhibited low leakage current as small as 20.1 MUA, which demonstrated that the MNW/PANI SSCs have great potential for practical applications. PMID- 26644366 TI - A thicker chorion gives ova of Atlantic salmon (Salmo salar L.) the upper hand against Saprolegnia infections. AB - Since the ban of malachite green in the fish farming industry, finding alternative ways of controlling Saprolegnia infections has become of utmost importance. Much effort has been made to elucidate the mechanisms by which Saprolegnia invades fish eggs. Little is known about the defence mechanisms of the hosts, making some eggs more prone to infection than others. One clue might lie in the composition of the eggs. As the immune system in the embryos is not developed yet, the difference in infection levels could be explained by factors influenced by the mother herself, by either transferring passive immunity, influencing the physical aspects of the eggs or both. One of the physical aspects that could be influenced by the female is the chorion, the extracellular coat surrounding the fish egg, which is in fact the first major barrier to be overcome by Saprolegnia spp. Our results suggest that a thicker chorion in eggs from Atlantic salmon gives a better protection against Saprolegnia spp. In addition to the identification of differences in sensitivity of eggs in a fish farm set-up, we were able to confirm these results in a laboratory-controlled challenge experiment. PMID- 26644367 TI - Individual inversions or their combinations: which is the main selective target in a natural population of Drosophila subobscura? AB - It is generally accepted that chromosomal inversions have been key elements in adaptation and speciation processes. In this context, Drosophila subobscura has been, and still is, an excellent model species due to its rich chromosomal polymorphism. In this species, many analyses from natural populations have demonstrated the adaptive potential of individual inversions (and their overlapped combinations, the so-called arrangements). However, little information is available on the evolutionary role of combinations generated by inversions located in homologous and nonhomologous chromosomes. The aim of this research was to ascertain whether these combinations are also a target for natural selection. For this objective, we have studied the inversion composition of homologous and nonhomologous chromosomes from a D. subobscura sample collected in a well-studied population, Mount Avala (Serbia). No significant deviation from H-W expectations was detected, and when comparing particular karyotypic combinations, likelihood ratios close to 1 were obtained. Thus, it seems that for each pair of homologous chromosomes inversions no deviation from randomness was detected. Finally, no linkage disequilibrium was observed between inversions located in different chromosomes of the karyotype. For all these reasons, it can be assumed that, at the cytological level, the individual inversions rather than their combinations in different chromosomes are the main target of selection. PMID- 26644368 TI - Paediatric critical procedures in the emergency department: Incidence, trends and the physician experience. AB - OBJECTIVES: To analyse and provide current data surrounding paediatric critical procedures performed in three EDs of a single Victorian health network. METHODS: We conducted a retrospective study of every paediatric ED attendance requiring management in a resuscitation cubicle at three Victorian hospitals in 2013. The primary outcome measure was the frequency of each paediatric critical procedure performed in the ED during the 12 month study period. Additional outcome measures included details of the proceduralist and of patient presentations. RESULTS: Across the three EDs, there were 54,633 paediatric presentations during the study period. 5895 patients were assessed in a resuscitation cubicle and of these, only 37 presentations required one or more critical procedures (7/10,000 presentations). A total of 53 critical procedures were performed. 83% (n = 43) of emergency physicians did not perform a single paediatric critical procedure during the study period. Endotracheal intubation was the most commonly performed critical procedure with 40 attempts (74% of procedures); however, 83% of the full time emergency physicians regularly exposed to paediatric presentations did not attempt or supervise a single paediatric intubation over the 12 months. 49% of patients who received a critical procedure were under 3 years of age and the most common diagnostic categories were seizure, respiratory and trauma. CONCLUSION: Critical procedures in children occur infrequently. Clinical exposure in the ED is therefore unreliable as the sole source of experience for critical procedures. PMID- 26644369 TI - Comparison between the impact of morning and evening doses of rivaroxaban on the circadian endogenous coagulation rhythm in healthy subjects. AB - ESSENTIALS: It is unknown whether single rivaroxaban doses should best be administered in the morning or evening. Circadian rhythm of coagulation/fibrinolysis was measured after morning or evening intake of rivaroxaban. Evening intake of rivaroxaban leads to prolonged exposure to rivaroxaban concentrations. Evening intake of rivaroxaban better matches the morning hypofibrinolysis. BACKGROUND: A circadian variation of the endogenous coagulation system exists with hypercoagulability and hypofibrinolysis and a corresponding peak of cardiovascular thromboembolic events in the morning. So far, no information is given as to whether single daily doses of the new oral anticoagulant drug rivaroxaban should best be administered in the morning or the evening. MATERIALS AND METHODS: Sixteen healthy male or female volunteers with a mean age of 26 +/- 7 years were included in this randomized, controlled, analyst blinded cross-over clinical trial. All subjects were given three morning and three evening single doses of 10 mg rivaroxaban. Circadian rhythms of prothrombin fragment 1 + 2, plasminogen activator inhibitor, and plasmin-antiplasmin complex were measured before any medication intake, as well as after morning or evening medication intake. Rivaroxaban concentrations were determined by an anti activated factor X assay and liquid chromatography-mass spectrometry. MAIN RESULTS: Concentrations of rivaroxaban were higher 12 h after evening intake of rivaroxaban than 12 h after morning intake (53.3 ng mL(-1) [95% confidence interval 46.0-67.8] vs. 23.3 ng mL(-1) [19.4-29.1, respectively]). Rivaroxaban intake in the evening reduced morning F1+2 concentrations better at 8:00 AM than did administration on awakening (85 +/- 25 nmol L(-1) vs. 106 +/- 34 nmol L(-1) , CI: 9.4-32.1). In addition, this suppression effect was longer lasting after evening intake. CONCLUSIONS: Evening intake of rivaroxaban leads to prolonged exposure to rivaroxaban concentrations and better matches the morning hypofibrinolysis. These results might help to further improve the efficacy and safety of rivaroxaban treatment. PMID- 26644370 TI - Prediction of small-for-gestational-age status by symphysis-fundus height: a registry-based population cohort study. AB - OBJECTIVE: To develop a chart for risk of small-for-gestational-age (SGA) at birth depending on deviations in symphysis-fundus (SF) height values for gestational age during pregnancy weeks 24-42. DESIGN: Registry-based population cohort study. SETTING: Antenatal clinics, Vastra Gotaland County, Sweden, 2005 2010. POPULATION: The study included 42 018 women with ultrasound-dated singleton pregnancies who delivered at Sahlgrenska University Hospital. Data (including 282 713 SF height measurements) were extracted from the hospital's computerised obstetric database. METHODS: Linear and binary regression analyses were used to derive prediction models with deviations in birthweight (BW) and SF height by gestational age as dependent and independent variables, respectively. Receiver operating characteristic curves were generated to evaluate the predictive value of the model in detecting SGA. MAIN OUTCOME MEASURES: Birthweight and small-for gestational-age. RESULTS: Symphysis-fundus height accounted for 3% of individual BW variance at 24 weeks, increasing gradually to 20% at 40 weeks. Maternal factors explained an additional 10 percentage points of BW variance. Receiver operating characteristic curves confirmed that SF height was a stronger SGA predictor in late than in early pregnancy. Using an SGA relative risk cut-off limit of >=2-fold, the overall sensitivity was 50% and the overall specificity 80%. Only the most recent SF measurement was useful in predicting BW deviation; previous measurements added nothing to the predictive value. CONCLUSIONS: The ability of SF measurements to detect SGA status at birth increases with gestational age. Only the most recent SF measurement has predictive value; a static or falling pattern of SF values did not increase SGA likelihood. TWEETABLE ABSTRACT: New SF curves predict SGA best in late pregnancy; only the most recent SF measurement has predictive value. PMID- 26644371 TI - Richard F. Heck (1931-2015). PMID- 26644372 TI - DOG1 Expression in Soft Tissue Tumors. PMID- 26644373 TI - Homologous Lipoblastic Differentiation in Dedifferentiated Liposarcoma. PMID- 26644375 TI - Images in Vascular Medicine. Leukemia cutis imitating venous ulcerations. PMID- 26644374 TI - A Parallelized Pumpless Artificial Placenta System Significantly Prolonged Survival Time in a Preterm Lamb Model. AB - An artificial placenta (AP) is an arterio-venous extracorporeal life support system that is connected to the fetal circulation via the umbilical vasculature. Previously, we published an article describing a pumpless AP system with a small priming volume. We subsequently developed a parallelized system, hypothesizing that the reduced circuit resistance conveyed by this modification would enable healthy fetal survival time to be prolonged. We conducted experiments using a premature lamb model to test this hypothesis. As a result, the fetal survival period was significantly prolonged (60.4 +/- 3.8 vs. 18.2 +/- 3.2 h, P < 0.01), and circuit resistance and minimal blood lactate levels were significantly lower in the parallel circuit group, compared with our previous single circuit group. Fetal physiological parameters remained stable until the conclusion of the experiments. In summary, parallelization of the AP system was associated with reduced circuit resistance and lactate levels and allowed preterm lamb fetuses to survive for a significantly longer period when compared with previous studies. PMID- 26644376 TI - Finding we must pick up during endoscopy that may be signs of early gastric cancers. PMID- 26644377 TI - Interleukin-22-Induced Antimicrobial Phospholipase A2 Group IIA Mediates Protective Innate Immunity of Nonhematopoietic Cells against Listeria monocytogenes. AB - Listeria monocytogenes is a bacterial pathogen which establishes intracellular parasitism in various cells, including macrophages and nonhematopoietic cells, such as hepatocytes. It has been reported that several proinflammatory cytokines have pivotal roles in innate protection against L. monocytogenes infection. We found that a proinflammatory cytokine, interleukin 22 (IL-22), was expressed by CD3(+) CD4(+) T cells at an early stage of L. monocytogenes infection in mice. To assess the influence of IL-22 on L. monocytogenes infection in hepatocytes, cells of a human hepatocellular carcinoma line, HepG2, were treated with IL-22 before L. monocytogenes infection in vitro. Gene expression analysis of the IL-22 treated HepG2 cells identified phospholipase A2 group IIA (PLA2G2A) as an upregulated antimicrobial molecule. Addition of recombinant PLA2G2A to the HepG2 culture significantly suppressed L. monocytogenes infection. Culture supernatant of the IL-22-treated HepG2 cells contained bactericidal activity against L. monocytogenes, and the activity was abrogated by a specific PLA2G2A inhibitor, demonstrating that HepG2 cells secreted PLA2G2A, which killed extracellular L. monocytogenes. Furthermore, colocalization of PLA2G2A and L. monocytogenes was detected in the IL-22-treated infected HepG2 cells, which suggests involvement of PLA2G2A in the mechanism of intracellular killing of L. monocytogenes by HepG2 cells. These results suggest that IL-22 induced at an early stage of L. monocytogenes infection enhances innate immunity against L. monocytogenes in the liver by stimulating hepatocytes to produce an antimicrobial molecule, PLA2G2A. PMID- 26644378 TI - Mycobacterium tuberculosis Coinfection Has No Impact on Plasmodium berghei ANKA Induced Experimental Cerebral Malaria in C57BL/6 Mice. AB - Cerebral malaria (CM) is the most severe complication of human infection with Plasmodium falciparum. The mechanisms predisposing to CM are still not fully understood. Proinflammatory immune responses are required for the control of blood-stage malaria infection but are also implicated in the pathogenesis of CM. A fine balance between pro- and anti-inflammatory immune responses is required for parasite clearance without the induction of host pathology. The most accepted experimental model to study human CM is Plasmodium berghei ANKA (PbANKA) infection in C57BL/6 mice that leads to the development of a complex neurological syndrome which shares many characteristics with the human disease. We applied this model to study the outcome of PbANKA infection in mice previously infected with Mycobacterium tuberculosis, the causative agent of tuberculosis. Tuberculosis is coendemic with malaria in large regions in the tropics, and mycobacteria have been reported to confer some degree of unspecific protection against rodent Plasmodium parasites in experimental coinfection models. We found that concomitant M. tuberculosis infection did not change the clinical course of PbANKA-induced experimental cerebral malaria (ECM) in C57BL/6 mice. The immunological environments in spleen and brain did not differ between singly infected and coinfected animals; instead, the overall cytokine and T cell responses in coinfected mice were comparable to those in animals solely infected with PbANKA. Our data suggest that M. tuberculosis coinfection is not able to change the outcome of PbANKA-induced disease, most likely because the inflammatory response induced by the parasite rapidly dominates in mice previously infected with M. tuberculosis. PMID- 26644379 TI - Low-Dose Intestinal Trichuris muris Infection Alters the Lung Immune Microenvironment and Can Suppress Allergic Airway Inflammation. AB - Immunological cross talk between mucosal tissues such as the intestine and the lung is poorly defined during homeostasis and disease. Here, we show that a low dose infection with the intestinally restricted helminth parasite Trichuris muris results in the production of Th1 cell-dependent gamma interferon (IFN-gamma) and myeloid cell-derived interleukin-10 (IL-10) in the lung without causing overt airway pathology. This cross-mucosal immune response in the lung inhibits the development of papain-induced allergic airway inflammation, an innate cell mediated type 2 airway inflammatory disease. Thus, we identify convergent and nonredundant roles of adaptive and innate immunity in mediating cross-mucosal suppression of type 2 airway inflammation during low-dose helminth-induced intestinal inflammation. These results provide further insight in identifying novel intersecting immune pathways elicited by gut-to-lung mucosal cross talk. PMID- 26644380 TI - A Stenotrophomonas maltophilia Strain Evades a Major Caenorhabditis elegans Defense Pathway. AB - Stenotrophomonas maltophilia is a ubiquitous bacterium and an emerging nosocomial pathogen. This bacterium is resistant to many antibiotics, associated with a number of infections, and a significant health risk, especially for immunocompromised patients. Given that Caenorhabditis elegans shares many conserved genetic pathways and pathway components with higher organisms, the study of its interaction with bacterial pathogens has biomedical implications. S. maltophilia has been isolated in association with nematodes from grassland soils, and it is likely that C. elegans encounters this bacterium in nature. We found that a local S. maltophilia isolate, JCMS, is more virulent than the other S. maltophilia isolates (R551-3 and K279a) tested. JCMS virulence correlates with intestinal distension and bacterial accumulation and requires the bacteria to be alive. Many of the conserved innate immune pathways that serve to protect C. elegans from various pathogenic bacteria also play a role in combating S. maltophilia JCMS. However, S. maltophilia JCMS is virulent to normally pathogen resistant DAF-2/16 insulin-like signaling pathway mutants. Furthermore, several insulin-like signaling effector genes were not significantly differentially expressed between S. maltophilia JCMS and avirulent bacteria (Escherichia coli OP50). Taken together, these findings suggest that S. maltophilia JCMS evades the pathogen resistance conferred by the loss of DAF-2/16 pathway components. In summary, we have discovered a novel host-pathogen interaction between C. elegans and S. maltophilia and established a new animal model with which to study the mode of action of this emerging nosocomial pathogen. PMID- 26644381 TI - Modification of the 1-Phosphate Group during Biosynthesis of Capnocytophaga canimorsus Lipid A. AB - Capnocytophaga canimorsus, a commensal bacterium of dog's mouth flora causing severe infections in humans after dog bites or scratches, has a lipopolysaccharide (LPS) (endotoxin) with low-inflammatory lipid A. In particular, it contains a phosphoethanolamine (P-Etn) instead of a free phosphate group at the C-1 position of the lipid A backbone, usually present in highly toxic enterobacterial Gram-negative lipid A. Here we show that the C. canimorsus genome comprises a single operon encoding a lipid A 1-phosphatase (LpxE) and a lipid A 1 P-Etn transferase (EptA). This suggests that lipid A is modified during biosynthesis after completing acylation of the backbone by removal of the 1 phosphate and subsequent addition of an P-Etn group. As endotoxicity of lipid A is known to depend largely on the degree of unsubstituted or unmodified phosphate residues, deletion of lpxE or eptA led to mutants lacking the P-Etn group, with consequently increased endotoxicity and decreased resistance to cationic antimicrobial peptides (CAMP). Consistent with the proposed sequential biosynthetic mechanism, the endotoxicity and CAMP resistance of a double deletion mutant of lpxE-eptA was similar to that of a single lpxE mutant. Finally, the proposed enzymatic activities of LpxE and EptA based on sequence similarity could be successfully validated by mass spectrometry (MS)-based analysis of lipid A isolated from the corresponding deletion mutant strains. PMID- 26644382 TI - Gastric Metaplasia Induced by Helicobacter pylori Is Associated with Enhanced SOX9 Expression via Interleukin-1 Signaling. AB - Histopathological changes of the gastric mucosa after Helicobacter pylori infection, such as atrophy, metaplasia, and dysplasia, are considered to be precursors of gastric cancer, yet the mechanisms of histological progression are unknown. The aim of this study was to analyze the histopathological features of the gastric mucosa in mice infected with H. pylori strain PMSS1 in relation to gastric stem cell marker expression. C57BL/6J mice infected with PMSS1 were examined for histopathological changes, levels of proinflammatory cytokines, and expression of stem cell markers. Histopathological gastritis scores, such as atrophy and metaplasia, and levels of proinflammatory cytokines, such as tumor necrosis factor alpha (TNF-alpha) and interleukin-1beta (IL-1beta), were increased after PMSS1 infection. Expression levels of the cell proliferation and stem cell markers CD44 and SOX9 were also significantly increased in PMSS1 infected mice. Importantly, almost all metaplastic cells induced by PMSS1 infection expressed SOX9. When IL-1 receptor (IL-1R) knockout mice were infected with PMSS1, metaplastic changes and expression levels of stem cell markers were significantly decreased compared with those in wild-type (WT) mice. In conclusion, H. pylori infection induced the expression of cytokines and stem cell markers and histopathological metaplasia in the mouse gastric mucosa. SOX9 expression, in particular, was strongly associated with metaplastic changes, and these changes were dependent on IL-1 signaling. The results suggested the importance of SOX9 in gastric carcinogenesis. PMID- 26644383 TI - Nonredundant Roles of Iron Acquisition Systems in Vibrio cholerae. AB - Vibrio cholerae, the causative agent of the severe diarrheal disease cholera, thrives in both marine environments and the human host. To do so, it must encode the tools necessary to acquire essential nutrients, including iron, under these vastly different conditions. A number of V. cholerae iron acquisition systems have been identified; however, the precise role of each system is not fully understood. To test the roles of individual systems, we generated a series of mutants in which only one of the four systems that support iron acquisition on unsupplemented LB agar, Feo, Fbp, Vct, and Vib, remains functional. Analysis of these mutants under different growth conditions showed that these systems are not redundant. The strain carrying only the ferrous iron transporter Feo grew well at acidic, but not alkaline, pH, whereas the ferric iron transporter Fbp promoted better growth at alkaline than at acidic pH. A strain defective in all four systems (null mutant) had a severe growth defect under aerobic conditions but accumulated iron and grew as well as the wild type in the absence of oxygen, suggesting the presence of an additional, unidentified iron transporter in V. cholerae. In support of this, the null mutant was only moderately attenuated in an infant mouse model of infection. While the null mutant used heme as an iron source in vitro, we demonstrate that heme is not available to V. cholerae in the infant mouse intestine. PMID- 26644384 TI - The Surface Sensor NlpE of Enterohemorrhagic Escherichia coli Contributes to Regulation of the Type III Secretion System and Flagella by the Cpx Response to Adhesion. AB - Although the adhesion of enterohemorrhagic Escherichia coli (EHEC) is central to the EHEC-host interaction during infection, it remains unclear how such adhesion regulates virulence factors. Adhesion to abiotic surfaces by E. coli has been reported to be an outer membrane lipoprotein NlpE-dependent activation cue of the Cpx pathway. Therefore, we investigated the role of NlpE in EHEC on the adhesion mediated expression of virulence genes. NlpE in EHEC contributed to upregulation of the locus of enterocyte effacement (LEE) genes encoded type III secretion system and to downregulated expression of the flagellin gene by activation of the Cpx pathway during adherence to hydrophobic glass beads and undifferentiated Caco 2 cells. Moreover, LysR homologue A (LrhA) in EHEC was involved in regulating the expression of the LEE genes and flagellin gene in response to adhesion. Gel mobility shift analysis revealed that response regulator CpxR bound to the lrhA promoter region and thereby regulated expressions of the LEE genes and flagellin gene via the transcriptional regulator LrhA in EHEC. Therefore, these results suggest that the sensing of adhesion signals via NlpE is important for regulation of the expression of the type III secretion system and flagella in EHEC during infection. PMID- 26644385 TI - Mycobacterium-Specific gamma9delta2 T Cells Mediate Both Pathogen-Inhibitory and CD40 Ligand-Dependent Antigen Presentation Effects Important for Tuberculosis Immunity. AB - Numerous pathogens, including Mycobacterium tuberculosis, can activate human gamma9delta2 T cells to proliferate and express effector mechanisms. gamma9delta2 T cells can directly inhibit the growth of intracellular mycobacteria and may also act as antigen-presenting cells (APC). Despite evidence for gammadelta T cells having the capacity to function as APC, the mechanisms involved and importance of these effects on overall tuberculosis (TB) immunity are unknown. We prepared M. tuberculosis-specific gamma9delta2 T cell lines to study their direct protective effects and APC functions for M. tuberculosis-specific alphabeta T cells. The direct inhibitory effects on intracellular mycobacteria were measured, and the enhancing effects on proliferative and effector responses of alphabeta T cells assessed. Furthermore, the importance of cell-to-cell contact and soluble products for gamma9delta2 T cell effector responses and APC functions were investigated. We demonstrate, in addition to direct inhibitory effects on intracellular mycobacteria, the following: (i) gamma9delta2 T cells enhance the expansion of M. tuberculosis-specific alphabeta T cells and increase the ability of alphabeta T cells to inhibit intracellular mycobacteria; (ii) although soluble mediators are critical for the direct inhibitory effects of gamma9delta2 T cells, their APC functions do not require soluble mediators; (iii) the APC functions of gamma9delta2 T cells involve cell-to-cell contact that is dependent on CD40-CD40 ligand (CD40L) interactions; and (iv) fully activated CD4(+) alphabeta T cells and gamma9delta2 T cells provide similar immune enhancing/APC functions for M. tuberculosis-specific T cells. These effector and helper effects of gamma9delta2 T cells further indicate that these T cells should be considered important new targets for new TB vaccines. PMID- 26644386 TI - Decreased expression of TIPE2 contributes to the hyperreactivity of monocyte to Toll-like receptor ligands in primary biliary cirrhosis. AB - BACKGROUND AND AIM: Previous studies have shown differential TIPE2 expression in several autoimmune diseases. However, the expression levels of TIPE2 in primary biliary cirrhosis (PBC) remained unclear. The purposes of this study were to evaluate TIPE2 expression levels in patients with PBC and further investigate its role in PBC pathogenesis. METHODS: A total of 40 PBC patients and 44 healthy controls were included in the present study. Quantitative reverse-transcription polymerase chain reaction and western blotting were used to determine the differences in mRNA and protein expression levels of TIPE2. The correlations of TIPE2 expression levels and clinical characteristics, inflammatory cytokines, and ursodeoxycholic acid treatment were also assessed. Besides, the influence of TIPE2 on the reactivity of monocyte to Toll-like receptor ligands was further analyzed. RESULTS: The expression levels of TIPE2 were significantly decreased in PBC patients compared with normal controls (P < 0.01). The expression levels of TIPE2 were negatively correlated with alanine aminotransferase (r = -0.40, P = 0.01), alkaline phosphatase (r = -0.36, P = 0.02), gamma glutamyl transpeptidase (r = -0.53, P < 0.01), tumor necrosis factor (TNF)-alpha (r = -0.332, P = 0.03), interleukin (IL)-1beta (r = -0.386, P = 0.01), and IL-8 (r = -0.366, P = 0.02) levels in sera from PBC patients. TIPE2 expression level could be significantly increased after ursodeoxycholic acid treatment (P < 0.01). The production of TNF alpha, IL-1beta, and IL-8 by monocytes from PBC patients after stimulation with lipopolysaccharide and lipoteichoic acid was significantly increased when TIPE2 was knocked down. Furthermore, TIPE2 knockdown could promote activation of nuclear factor-kappaB pathways through increasing phosphorylation and degradation of IkappaB in peripheral blood monocytes from PBC patients. CONCLUSION: The present study reported that insufficient expression of TIPE2 might be involved in the hyperreactivity of monocyte to Toll-like receptor ligands in PBC. PMID- 26644387 TI - Carcinoid tumor associated with adjacent dysplastic columnar epithelium in the renal pelvis: A case report and literature review. AB - Carcinoid tumors are well documented in the pulmonary and gastrointestinal systems, but very rare in the urinary tract, especially in the renal pelvis. We report on a 60-year-old female patient who presented with left flank pain and fever. Abdominal computed tomography demonstrated a heterogeneously enhancing mass in the left renal pelvis and a stone at the left proximal ureter. Multiple parenchymal lesions were also observed, which were identified as uneven caliectasis displaying air-fluid levels and renal parenchymal atrophy. The patient underwent simple nephro-ureterectomy. Macroscopically, a polypoid mass was observed in the renal pelvis. Microscopically, the tumor revealed acinar, tubular, and solid pattern and was composed of small, monotonous and hyperchromatic cells. Lining epithelia in renal pelvis and ureter revealed columnar epithelia with dysplastic change. The tumor cells were positive for chromogranin A, synaptophysin, CD56, and focally positive for cytokeratin. Immunohistochemical staining of synaptophysin and chromogranin A highlighted the neuroendocrine cells in the columnar epithelium. Ki-67 (1:50; MIB-1) labeling index was less than 1% in the area with highest uptake. We report here a case of carcinoid tumor of the renal pelvis that was associated with adjacent dysplastic columnar epithelium. PMID- 26644388 TI - Integrative Bioethics: A Conceptually Inconsistent Project. AB - This article provides a critical evaluation of the central components of Integrative Bioethics, a project aiming at a bioethical framework reconceptualization. Its proponents claim that this new system of thought has developed a better bioethical methodology than mainstream Western bioethics, a claim that we criticize here. We deal especially with the buzz words of Integrative Bioethics - pluriperspectivism, integrativity, orientational knowledge, as well as with its underlying theory of moral truth. The first part of the paper looks at what the claims of a superior methodology consist in. The second reveals pluriperspectivism and integrativity to be underdeveloped, hazy terms, but which seem to be underpinned by two theses - the incommensurability and the inclusiveness theses. These theses we critically scrutinize. We then consider strategies the project's proponents might apply to curb these theses in order to acquire minimal consistency for their framework. This part of the article also deals with the conception of moral truth that drives the theory, a position equally burdened with inconsistencies. In the last part of the article, we observe the concept of orientational knowledge, and develop two interpretations of its possible meaning. We claim that, following the first interpretation, Integrative Bioethics is completely descriptive, in which case it is informative and important, but hardly bioethics; if it is normative, following the second interpretation, it is bioethics as we already know it, but merely clad in rhetorical embellishments. We conclude that there is nothing new about this project, and that its inconsistencies are reason enough for its abandonment. PMID- 26644389 TI - N-Alkyl-, 1-C-Alkyl-, and 5-C-Alkyl-1,5-dideoxy-1,5-imino-(L)-ribitols as Galactosidase Inhibitors. AB - A series of 1,5-dideoxy-1,5-imino-(l)-ribitol (DIR) derivatives carrying alkyl or functionalized alkyl groups were prepared and investigated as glycosidase inhibitors. These compounds were designed as simplified 4-epi-isofagomine (4-epi IFG) mimics and were expected to behave as selective inhibitors of beta galactosidases. All compounds were indeed found to be highly selective for beta galactosidases versus alpha-glycosidases, as they generally did not inhibit coffee bean alpha-galactosidase or other alpha-glycosidases. Some compounds were also found to be inhibitors of almond beta-glucosidase. The N-alkyl DIR derivatives were only modest inhibitors of bovine beta-galactosidase, with IC50 values in the 30-700 MUM range. Likewise, imino-L-ribitol substituted at the C1 position was found to be a weak inhibitor of this enzyme. In contrast, alkyl substitution at C5 resulted in enhanced beta-galactosidase inhibitory activity by a factor of up to 1000, with at least six carbon atoms in the alkyl substituent. Remarkably, the 'pseudo-anomeric' configuration in this series does not appear to play a role. Human lysosomal beta-galactosidase from leukocyte lysate was, however, poorly inhibited by all iminoribitol derivatives tested (IC50 values in the 100 MUM range), while 4-epi-IFG was a good inhibitor of this enzyme. Two compounds were evaluated as pharmacological chaperones for a GM1-gangliosidosis cell line (R301Q mutation) and were found to enhance the mutant enzyme activity by factors up to 2.7-fold. PMID- 26644390 TI - Laboratory and Clinical Evaluation of a Feia Method for Canine Serum Progesterone Assay. AB - The evaluation of progesterone (P4) concentration is a valuable tool in assessing physiological reproductive events and reproductive disorders in bitches. A reliable and rapid (preferable, point of care) determination of P4 is advisable in most cases. Aims of this study were to evaluate a fluorescence enzyme immunoassay (FEIA) for canine serum P4 concentration by (i) the agreement with liquid chromatography-tandem mass spectrometry (LC/MS/MS), (ii) the association with vaginal cytology and (iii) the accuracy in the prediction of the parturition date calculated from the estimated day of ovulation. Serum samples were collected from client-owned bitches presented between 2011 and 2014 for the evaluation of their oestrous cycle, pregnancy or reproductive disorders. The agreement between FEIA and LC/MS/MS, evaluated on 19 samples, was statistically significant (R(2) = 95.7%, p < 0.001), although FEIA showed significantly higher values than LC/MS/MS (p < 0.05). In the different phases of oestrous cycle, as determined by vaginal cytology, P4 concentrations (by FEIA) were statistically different (p < 0.05): anoestrus (n = 7) 0.38 +/- 0.14 ng/ml, proestrus (n = 14) 1.04 +/- 0.67 ng/ml and oestrus (n = 72) 6.8 +/- 7.26 ng/ml. Mean pregnancy length from the estimated day of ovulation was 62.9 +/- 1.8 days. In 13 of 22 (59.1%), 19 of 22 (86.3%) and 21 of 22 (95.5%) bitches pregnancy lasted 63 +/- 1, 63 +/- 2 and 63 +/- 3 days, respectively. Three pregnancies were outside the 61-65 days range (60, 60 and 67 days). In conclusion, the FEIA method employed can be considered reliable and, in association with vaginal cytology, effective in evaluating the canine oestrous cycle. PMID- 26644391 TI - Supporting 'Baby Friendly': a quality improvement initiative for the management of transitional neonatal hypoglycaemia. AB - We describe a quality improvement initiative conducted in a medium-sized district general hospital with a neonatal intensive care unit, which involved working with the multidisciplinary team to create a 'Baby Friendly' neonatal hypoglycaemia pathway with implementation of dextrose gel as a first-line treatment. As a result of the project, formula supplementation rates and admissions for transitional hypoglycaemia were reduced and breastfeeding rates at 3 months improved. This initiative demonstrates that evidence-based guidelines with multidisciplinary team input can improve standards of care. PMID- 26644392 TI - Elective caesarean delivery adversely affects preductal oxygen saturation during birth transition. AB - OBJECTIVE: To compare preductal oxygen saturation (SpO2), heart rate (HR) and cord blood pH after birth in healthy term neonates delivered by elective caesarean delivery (CD) and vaginal delivery (VD), managed according to 2010 Neonatal Resuscitation Guidelines. DESIGN: In a prospective cohort study, sensors were placed on the right hand of the neonate. SETTING: III level Maternity ward of the Department of Obstetrics and Gynaecology of Padua University, Padua, Italy. MAIN OUTCOME MEASURES: SpO2 and HR were recorded during the first 10 min after birth. Umbilical artery blood gas analysis was obtained immediately after delivery. PATIENTS: We studied 60 newborn infants by elective CD and 60 by VD. RESULTS: The SpO2 gradually significantly improved during the first 10 min of life (p<0.0001), with a trend towards a slower increase in caesarean-delivered neonates (p=0.09) (Friedman's two-way non-parametric analysis of variance (ANOVA)). Instead, HR varied during the first 10 min of life (p=0.001) without significant difference between the two delivery groups (p=0.41). Umbilical artery pH values were lower in VD (p=0.005). At 10th minute, elective CD had a significantly negative effect on SpO2 (beta=-2.44; 95% CI -4.52 to -0.36; p=0.02) with respect to VD. Conversely, at 10th minute, delivery mode had no statistically significant effect on HR (beta=0.33; 95% CI -9.39 to 10.01; p=0.95). CONCLUSIONS: In healthy term neonates, the SpO2 gradually improved during the first 10 min of life. At 10th minute, elective CD had a significantly negative effect on SpO2, but these changes did not result in an impaired HR pattern. PMID- 26644393 TI - [Progress or regress or both? ESC guidelines on pericardial diseases 2015]. AB - Eleven years after the publication of the first guidelines worldwide on pericardial diseases by the European Society of Cardiology (ESC), the international expert group of the ESC has updated the original document of 28 pages with 275 references. The final version of the new guidelines is more voluminous with 44 pages of recommendations but only 233 references. A continuing medical education (CME) certified update of the 2004 guidelines was published in the journal Herz volume 7/2014. In comparison to 2004 the 2015 guidelines have remained virtually unchanged in the sections detailing diagnostics, differential diagnosis, pathology and pathophysiology. Substantial progress has been made in magnetic resonance imaging (MRI) of pericarditis and epicarditis and in the practically universal recommendation of colchicine for all forms of pericarditis and pericardial effusion, whether acute, chronic or recurrent. This can truly be called progress; however, little has changed since 2004 even in tertiary referral centers or universities with respect to the etiological classification of acute or recurrent forms of pericarditis or pericardial effusion. By classifying pericardial syndromes much too often as idiopathic when a malignant or bacterial cause has been excluded, the underlying cause is often overlooked. Standstill in diagnosis is in the end regress because we too often lag behind our actual diagnostic and interventional possibilities. PMID- 26644394 TI - Neutrophil degranulation differentially modulates phenotype and function of bovine monocyte subsets. AB - Monocytes and neutrophils are important players in the innate immune response and cooperate during infection and inflammation. In our study we analyzed the effects of neutrophil degranulation products (polymorphonuclear granulocytes degranulation products, PMN-DGP) on the activation, the adhesion and the migration of three bovine monocyte subsets, as well as their effects on monocyte macrophage differentiation. Cross-linking of surface CD18 molecules on bovine PMN resulted in the release of primary, secondary and tertiary granules as well as of secretory vesicles. PMN-DGP induced a significant Ca2+-influx in classical (classical monocytes, cM) and intermediate monocytes (intermediate monocytes, intM) but not in non-classical monocytes (non-classical monocytes, ncM). A selective and up-regulated expression induced by PMN-DGP was only seen for CD11a and CD31 on intM. PMN-DGP induced a selective migration of intM in vitro. The presence of PMN-DGP during the differentiation of cM or intM into macrophages resulted in increased expression of membrane CD163 and reduced expression of MHC II molecules. PMN-DGP-derived macrophages produced more IL-12 and IL-10 and showed enhanced phagocytosis and ROS production capacities. In conclusion, PMN DGP selectively attract bovine intM and skew the functional maturation of cM and intM. PMID- 26644395 TI - Acetaminophen for self-reported sleep problems in an elderly population (ASLEEP): a randomized double-blind placebo-controlled trial. PMID- 26644396 TI - Immobilization of trace elements in municipal solid waste incinerator (MSWI) fly ash by producing calcium sulphoaluminate cement after carbonation and washing. AB - The possibility of producing calcium sulphoaluminate cement (CSA) by adding municipal solid waste incinerator (MSWI) fly ash to raw meal was investigated. After subjecting MSWI fly ash to accelerated carbonation and washing with water (ACW), various amounts (i.e., 5, 10 and 15 wt%) of the treated ash were added to raw meal composed of a mixture of bauxite, limestone and gypsum. The mixtures were sintered in a laboratory-scale muffle furnace at temperatures of 1250 degrees , 1300 degrees , 1325 degrees and 1350 degrees C for various durations. The influence of different quantities of MSWI fly ash on the mineralogy, major phase composition and strength development of the resulting clinker was studied, as was the effect of ash treatments on leaching and volatilization of trace elements. The ACW treatment reduced the volatilization ratio of trace elements during the clinkerization process. Volatilization ratios for lead, cadmium and zinc were 21.5%, 33.6% and 16.3%, respectively, from the ACW fly ash treatment, compared with ratios of 97.5%, 93.1% and 85.2% from untreated fly ash. The volatilization ratios of trace elements were ordered as follows: untreated fly ash > carbonated fly ash > carbonated and water-washed fly ash. The ACW process also reduced the chloride content in the MSWI fly ash by 90 wt% and prevented high concentrations of trace elements in the effluents. PMID- 26644397 TI - Molecular subtypes of pancreatic cancer based on miRNA expression profiles have independent prognostic value. AB - BACKGROUND AND AIM: Altered microRNAs (miRNA) expression, a typical feature of many cancers, is reportedly associated with prognosis according to several studies. Although numerous studies on miRNAs in pancreatic ductal adenocarcinoma have also attempted to identify prognostic biomarkers, more large-scale clinical studies are needed to establish the clinical significance of the results. Present study aimed to identify prognosis-related molecular subtypes of primary pancreas tumors using miRNA expression profiling. METHODS: Expression profiles of 1733 miRNAs were obtained by using microarray analysis of 104 pancreatic tumors of Korean patients. To detect subgroups informative in predicting the patient's prognosis, we applied unsupervised clustering methods and then analyzed the association of the molecular subgroups with survival time. Then, we constructed a classifier to predict the subgroup using penalized regression models. RESULTS: We have determined three pancreatic ductal adenocarcinoma tumor subtypes associated with prognosis based on miRNA expression profiles. These subtypes showed significantly different survival time for patients with the same clinical conditions. This demonstrates that our prognostic molecular subgroup has independent prognostic utility. The molecular subtypes can be predicted with a classifier of 19 miRNAs. Of the 19 signature miRNAs, miR-106b-star, miR-324-3p, and miR-615 were related to a p53 canonical pathway, and miR-324, miR-145-5p, miR 26b-5p, and miR-574-3p were related to a Cox-2 centered pathway. CONCLUSIONS: Our prognostic molecular subtypes demonstrated that miRNA profiles could be used as prognostic markers. Additionally, we have constructed a classifier that may be used to determine the molecular subgroup of new patient sample data. Further studies are needed for validation. PMID- 26644398 TI - OpenFDA: an innovative platform providing access to a wealth of FDA's publicly available data. AB - OBJECTIVE: The objective of openFDA is to facilitate access and use of big important Food and Drug Administration public datasets by developers, researchers, and the public through harmonization of data across disparate FDA datasets provided via application programming interfaces (APIs). MATERIALS AND METHODS: Using cutting-edge technologies deployed on FDA's new public cloud computing infrastructure, openFDA provides open data for easier, faster (over 300 requests per second per process), and better access to FDA datasets; open source code and documentation shared on GitHub for open community contributions of examples, apps and ideas; and infrastructure that can be adopted for other public health big data challenges. RESULTS: Since its launch on June 2, 2014, openFDA has developed four APIs for drug and device adverse events, recall information for all FDA-regulated products, and drug labeling. There have been more than 20 million API calls (more than half from outside the United States), 6000 registered users, 20,000 connected Internet Protocol addresses, and dozens of new software (mobile or web) apps developed. A case study demonstrates a use of openFDA data to understand an apparent association of a drug with an adverse event. CONCLUSION: With easier and faster access to these datasets, consumers worldwide can learn more about FDA-regulated products. PMID- 26644400 TI - Evidence or enthusiasm? Why yields from UK newborn screening programmes for congenital hypothyroidism are increasing. PMID- 26644399 TI - A framework for self-experimentation in personalized health. AB - OBJECTIVE: To describe an interdisciplinary and methodological framework for applying single case study designs to self-experimentation in personalized health. The authors examine the framework's applicability to various health conditions and present an initial case study with irritable bowel syndrome (IBS). METHODS AND MATERIALS: An in-depth literature review was performed to develop the framework and to identify absolute and desired health condition requirements for the application of this framework. The authors developed mobile application prototypes, storyboards, and process flows of the framework using IBS as the case study. The authors conducted three focus groups and an online survey using a human-centered design approach for assessing the framework's feasibility. RESULTS: All 6 focus group participants had a positive view about our framework and volunteered to participate in future studies. Most stated they would trust the results because it was their own data being analyzed. They were most concerned about confounds, nonmeaningful measures, and erroneous assumptions on the timing of trigger effects. Survey respondents (N = 60) were more likely to be adherent to an 8- vs 12-day study length even if it meant lower confidence results. DISCUSSION: Implementation of the self-experimentation framework in a mobile application appears to be feasible for people with IBS. This framework can likely be applied to other health conditions. Considerations include the learning curve for teaching self-experimentation to non-experts and the challenges involved in operationalizing and customizing study designs. CONCLUSION: Using mobile technology to guide people through self-experimentation to investigate health questions is a feasible and promising approach to advancing personalized health. PMID- 26644401 TI - Height growth in children with asthma treated with guideline-recommended dosages of fluticasone and electronically assessed adherence. AB - BACKGROUND AND AIMS: Inhaled corticosteroids (ICS) reduce growth during the first year of treatment, but this growth suppressing effect does not continue during further treatment. Decreasing adherence may play a role in explaining this. The aim of this study was to examine the relationship between cumulative real exposure (with objectively assessed adherence) to ICS and height growth in children with asthma. METHODS: We investigated 99 prepubertal children with asthma, 2-13 years of age, who had been using ICS in guideline-recommended dosages for >=3 months, and continued to do so during 1-year follow-up. ICS adherence was assessed by electronic monitoring devices, allowing calculation of true cumulative exposure to ICS. We analysed the relationship between cumulative ICS dose and height growth velocity (assessed as change in height SD score) over 1 year. RESULTS: Median (IQR) adherence over 1 year was 84 (68-92) %. Mean cumulative fluticasone dose was 64.6 (SD, 27.8) mg, reflecting a daily dose of 167 (SD, 7) ug. The negative correlation between cumulative ICS dose and height growth velocity (r=-0.266; p=0.008) became non-significant after adjustment for age and sex in a multiple regression model (adjusted r=-0.188; p=0.066). CONCLUSIONS: One year of ICS treatment in guideline-recommended dosages with high adherence did not result in significant or relevant growth suppression. Unaffected growth can be maintained for at least 1 year in children with asthma during ICS treatment with high adherence. PMID- 26644402 TI - An Alternative Thiol-Reactive Dye to Analyze Ligand Interactions with the Chemokine Receptor CXCR2 Using a New Thermal Shift Assay Format. AB - Integral membrane proteins (IMPs) play an important role in many cellular events and are involved in numerous pathological processes. Therefore, understanding the structure and function of IMPs is a crucial prerequisite to enable successful targeting of these proteins with low molecular weight (LMW) ligands early on in the discovery process. To optimize IMP purification/crystallization and to identify/characterize LMW ligand-target interactions, robust, reliable, high throughput, and sensitive biophysical methods are needed. Here, we describe a differential scanning fluorimetry (DSF) screening method using the thiol-reactive BODIPY FL-cystine dye to monitor thermal unfolding of the G-protein-coupled receptor (GPCR), CXCR2. To validate this method, the seven-transmembrane protein CXCR2 was analyzed with a set of well-characterized antagonists. This study showed that the new DSF assay assessed reliably the stability of CXCR2 in a 384 well format. The analysis of 14 ligands with a potency range over 4 log units demonstrated the detection/characterization of LMW ligands binding to the membrane protein target. Furthermore, DSF results cross-validated with the label free differential static light scattering (DSLS) thermal denaturation method. These results underline the potential of the BODIPY assay format as a general tool to investigate membrane proteins and their interaction partners. PMID- 26644403 TI - Deregulated KLF4 Expression in Myeloid Leukemias Alters Cell Proliferation and Differentiation through MicroRNA and Gene Targets. AB - Acute myeloid leukemia (AML) is characterized by increased proliferation and blocked differentiation of hematopoietic progenitors mediated, in part, by altered myeloid transcription factor expression. Decreased Kruppel-like factor 4 (KLF4) expression has been observed in AML, but how decreased KLF4 contributes to AML pathogenesis is largely unknown. We demonstrate decreased KLF4 expression in AML patient samples with various cytogenetic aberrations, confirm that KLF4 overexpression promotes myeloid differentiation and inhibits cell proliferation in AML cell lines, and identify new targets of KLF4. We have demonstrated that microRNA 150 (miR-150) expression is decreased in AML and that reintroducing miR 150 expression induces myeloid differentiation and inhibits proliferation of AML cells. We show that KLF family DNA binding sites are necessary for miR-150 promoter activity and that KLF2 or KLF4 overexpression induces miR-150 expression. miR-150 silencing, alone or in combination with silencing of CDKN1A, a well-described KLF4 target, did not fully reverse KLF4-mediated effects. Gene expression profiling and validation identified putative KLF4-regulated genes, including decreased MYC and downstream MYC-regulated gene expression in KLF4 overexpressing cells. Our findings indicate that decreased KLF4 expression mediates antileukemic effects through regulation of gene and microRNA networks, containing miR-150, CDKN1A, and MYC, and provide mechanistic support for therapeutic strategies increasing KLF4 expression. PMID- 26644405 TI - Atg13 Is Essential for Autophagy and Cardiac Development in Mice. AB - Autophagy is a major intracellular degradation system by which cytoplasmic components are enclosed by autophagosomes and delivered to lysosomes. Formation of the autophagosome requires a set of autophagy-related (Atg) proteins. Among these proteins, the ULK1 complex, which is composed of ULK1 (or ULK2), FIP200, Atg13, and Atg101, acts at an initial step. Previous studies showed that ULK1 and FIP200 also function in pathways other than autophagy. However, whether Atg13 and Atg101 act similarly to ULK1 and FIP200 remains unknown. In the present study, we generated Atg13 knockout mice. Like FIP200-deficient mice, Atg13-deficient mice die in utero, which is distinct from most other types of Atg-deficient mice. Atg13-deficient embryos show growth retardation and myocardial growth defects. In cultured fibroblasts, Atg13 deficiency blocks autophagosome formation at an upstream step. In addition, sensitivity to tumor necrosis factor alpha (TNF alpha)-induced apoptosis is enhanced by deletion of Atg13 or FIP200, but not by other Atg proteins, as well as by simultaneous deletion of ULK1 and ULK2. These results suggest that Atg13 has both autophagic and nonautophagic functions and that the latter are essential for cardiac development and likely shared with FIP200 but not with ULK1/2. PMID- 26644404 TI - Role of Deubiquitinating Enzymes in DNA Repair. AB - Both proteolytic and nonproteolytic functions of ubiquitination are essential regulatory mechanisms for promoting DNA repair and the DNA damage response in mammalian cells. Deubiquitinating enzymes (DUBs) have emerged as key players in the maintenance of genome stability. In this minireview, we discuss the recent findings on human DUBs that participate in genome maintenance, with a focus on the role of DUBs in the modulation of DNA repair and DNA damage signaling. PMID- 26644406 TI - Genome-Wide Studies Reveal that H3K4me3 Modification in Bivalent Genes Is Dynamically Regulated during the Pluripotent Cell Cycle and Stabilized upon Differentiation. AB - Stem cell phenotypes are reflected by posttranslational histone modifications, and this chromatin-related memory must be mitotically inherited to maintain cell identity through proliferative expansion. In human embryonic stem cells (hESCs), bivalent genes with both activating (H3K4me3) and repressive (H3K27me3) histone modifications are essential to sustain pluripotency. Yet, the molecular mechanisms by which this epigenetic landscape is transferred to progeny cells remain to be established. By mapping genomic enrichment of H3K4me3/H3K27me3 in pure populations of hESCs in G2, mitotic, and G1 phases of the cell cycle, we found striking variations in the levels of H3K4me3 through the G2-M-G1 transition. Analysis of a representative set of bivalent genes revealed that chromatin modifiers involved in H3K4 methylation/demethylation are recruited to bivalent gene promoters in a cell cycle-dependent fashion. Interestingly, bivalent genes enriched with H3K4me3 exclusively during mitosis undergo the strongest upregulation after induction of differentiation. Furthermore, the histone modification signature of genes that remain bivalent in differentiated cells resolves into a cell cycle-independent pattern after lineage commitment. These results establish a new dimension of chromatin regulation important in the maintenance of pluripotency. PMID- 26644407 TI - LARP4 Is Regulated by Tumor Necrosis Factor Alpha in a Tristetraprolin-Dependent Manner. AB - LARP4 is a protein with unknown function that independently binds to poly(A) RNA, RACK1, and the poly(A)-binding protein (PABPC1). Here, we report on its regulation. We found a conserved AU-rich element (ARE) in the human LARP4 mRNA 3' untranslated region (UTR). This ARE, but not its antisense version or a point mutated version, significantly decreased the stability of beta-globin reporter mRNA. We found that overexpression of tristetraprolin (TTP), but not its RNA binding mutant or the other ARE-binding proteins tested, decreased cellular LARP4 levels. RNA coimmunoprecipitation showed that TTP specifically associated with LARP4 mRNA in vivo. Consistent with this, mouse LARP4 accumulated to higher levels in TTP gene knockout (KO) cells than in control cells. Stimulation of WT cells with tumor necrosis factor alpha (TNF-alpha), which rapidly induces TTP, robustly decreased LARP4 with a coincident time course but had no such effect on LARP4B or La protein or on LARP4 in the TTP KO cells. The TNF-alpha-induced TTP pulse was followed by a transient decrease in LARP4 mRNA that was quickly followed by a subsequent transient decrease in LARP4 protein. Involvement of LARP4 as a target of TNF-alpha-TTP regulation provides a clue as to how its functional activity may be used in a physiologic pathway. PMID- 26644408 TI - Identifying Novel Transcriptional Regulators with Circadian Expression. AB - Organisms adapt their physiology and behavior to the 24-h day-night cycle to which they are exposed. On a cellular level, this is regulated by intrinsic transcriptional-translational feedback loops that are important for maintaining the circadian rhythm. These loops are organized by members of the core clock network, which further regulate transcription of downstream genes, resulting in their circadian expression. Despite progress in understanding circadian gene expression, only a few players involved in circadian transcriptional regulation, including transcription factors, epigenetic regulators, and long noncoding RNAs, are known. Aiming to discover such genes, we performed a high-coverage transcriptome analysis of a circadian time course in murine fibroblast cells. In combination with a newly developed algorithm, we identified many transcription factors, epigenetic regulators, and long intergenic noncoding RNAs that are cyclically expressed. In addition, a number of these genes also showed circadian expression in mouse tissues. Furthermore, the knockdown of one such factor, Zfp28, influenced the core clock network. Mathematical modeling was able to predict putative regulator-effector interactions between the identified circadian genes and may help for investigations into the gene regulatory networks underlying circadian rhythms. PMID- 26644409 TI - Shp2 Associates with and Enhances Nephrin Tyrosine Phosphorylation and Is Necessary for Foot Process Spreading in Mouse Models of Podocyte Injury. AB - In most forms of glomerular diseases, loss of size selectivity by the kidney filtration barrier is associated with changes in the morphology of podocytes. The kidney filtration barrier is comprised of the endothelial lining, the glomerular basement membrane, and the podocyte intercellular junction, or slit diaphragm. The cell adhesion proteins nephrin and neph1 localize to the slit diaphragm and transduce signals in a Src family kinase Fyn-mediated tyrosine phosphorylation dependent manner. Studies in cell culture suggest nephrin phosphorylation dependent signaling events are primarily involved in regulation of actin dynamics and lamellipodium formation. Nephrin phosphorylation is a proximal event that occurs both during development and following podocyte injury. We hypothesized that abrogation of nephrin phosphorylation following injury would prevent nephrin dependent actin remodeling and foot process morphological changes. Utilizing a biased screening approach, we found nonreceptor Src homology 2 (sh2) domain containing phosphatase Shp2 to be associated with phosphorylated nephrin. We observed an increase in nephrin tyrosine phosphorylation in the presence of Shp2 in cell culture studies. In the human glomerulopathies minimal-change nephrosis and membranous nephropathy, there is an increase in Shp2 phosphorylation, a marker of increased Shp2 activity. Mouse podocytes lacking Shp2 do not develop foot process spreading when subjected to podocyte injury in vivo using protamine sulfate or nephrotoxic serum (NTS). In the NTS model, we observed a lack of foot process spreading in mouse podocytes with Shp2 deleted and smaller amounts of proteinuria. Taken together, these results suggest that Shp2-dependent signaling events are necessary for changes in foot process structure and function following injury. PMID- 26644410 TI - Bone Marker-Directed Dosing of Zoledronic Acid for the Prevention of Skeletal Complications in Patients with Multiple Myeloma: Results of the Z-MARK Study. AB - PURPOSE: Zoledronic acid (ZOL) given every 3 to 4 weeks can reduce skeletal related events (SRE) in patients with bone lesions from multiple myeloma. This study evaluated efficacy and safety of less-frequent ZOL dosing based on bone turnover markers in patients with 1 to 2 years of prior bisphosphonate therapy. EXPERIMENTAL DESIGN: Patients received ZOL (4 mg) every 4 or 12 weeks based on urinary N-telopeptide of type 1 collagen (uNTX) levels (every 4 weeks if uNTX >=50 nmol/mmol creatinine, every 12 weeks if uNTX < 50). RESULTS: Of 121 patients enrolled (mean age, 63.8 years; median follow-up, 21 months), 4 patients started ZOL every 4 weeks and 117 received ZOL every 12 weeks based on uNTX at study entry. All 4 patients who initiated ZOL every 4 weeks switched to every 12 weeks due to decreased uNTX. Thirty-eight of 117 patients who initiated ZOL every 12 weeks switched to ZOL every 4 weeks due to disease progression (n = 20), increased uNTX (n = 14), and SREs (n = 4). Overall SRE incidence was low; 7 (5.8%) and 5 (4.9%) patients experienced an SRE during years 1 and 2, respectively. Mean (SD) SRE rate at year 2 was 0.01 (0.03) per person-year. The 2 year incidence rate for osteonecrosis of jaw was 3.3%. Four deaths were reported, none related to ZOL. CONCLUSIONS: Less frequent ZOL dosing (every 12 weeks over 2 years) maintains a low SRE rate and can be safely administered for up to 4 years. PMID- 26644411 TI - A Phase I Study of the Safety, Pharmacokinetics, and Pharmacodynamics of Combination Therapy with Refametinib plus Sorafenib in Patients with Advanced Cancer. AB - PURPOSE: To assess the safety and tolerability of the small-molecule allosteric MEK inhibitor refametinib combined with sorafenib, in patients with advanced solid malignancies. EXPERIMENTAL DESIGN: This phase I dose-escalation study included an expansion phase at the maximum tolerated dose (MTD). Patients received refametinib/sorafenib twice daily for 28 days, from a dose of refametinib 5 mg plus sorafenib 200 mg to a dose of refametinib 50 mg plus sorafenib 400 mg. Plasma levels of refametinib, refametinib metabolite M17, and sorafenib were measured for pharmacokinetic assessments. Tumors were biopsied at the MTD for analysis of MEK pathway mutations and ERK phosphorylation. RESULTS: Thirty-two patients were enrolled in the dose-escalation cohort. The MTD was refametinib 50 mg twice daily plus sorafenib 400 mg twice daily. The most common treatment-related toxicities were diarrhea and fatigue. Refametinib was readily absorbed following oral administration (plasma half-life of ~16 hours at the MTD), and pharmacokinetic parameters displayed near-dose proportionality, with less than 2-fold accumulation after multiple dosing. Another 30 patients were enrolled in the MTD cohort; 19 had hepatocellular carcinoma. The combination was associated with significantly reduced ERK phosphorylation in 5 out of 6 patients biopsied, with the greatest reductions in those with KRAS or BRAF mutations. Disease was stabilized in approximately half of patients, and 1 patient with colorectal cancer achieved a partial response at the MTD lasting approximately 1 year. CONCLUSIONS: In this phase I study, refametinib plus sorafenib was well tolerated, with good oral absorption, near-dose proportionality, and target inhibition in a range of tumor types. Clin Cancer Res; 22(10); 2368-76. (c)2015 AACR. PMID- 26644412 TI - Gemtuzumab Ozogamicin Reduces Relapse Risk in FLT3/ITD Acute Myeloid Leukemia: A Report from the Children's Oncology Group. AB - PURPOSE: Gemtuzumab ozogamicin (GO), a calicheamicin-conjugated mAb against CD33, has been used in the treatment of acute myeloid leukemia (AML). We evaluated the impact of the addition of GO to standard chemotherapy and hematopoietic stem cell transplant (HCT) in patients withFLT3/ITD. EXPERIMENTAL DESIGN: We analyzed children withFLT3/ITD-positive AML (n= 183) treated on two consecutive Children's Oncology Group AML trials (NCT00070174andNCT00372593). Outcomes were assessed forFLT3/ITD patients receiving standard chemotherapy with or without GO (GO vs. No-GO, respectively), and the impact of consolidation HCT for high-riskFLT3/ITD patients [highFLT3/ITD allelic ratio (ITD-AR)]. RESULTS: For allFLT3/ITD patients, complete remission (CR) rates for the GO versus No-GO cohorts were identical (64% vs. 64%;P= 0.98). Relapse rate (RR) after initial CR was 37% for GO recipients versus 59% for No-GO recipients (P= 0.02), disease-free survival (DFS) was similar (47% vs. 41%;P= 0.45), with higher treatment-related mortality (TRM) in GO recipients (16% vs. 0%;P= 0.008). Among high-riskFLT3/ITD patients with high ITD-AR, those who received HCT in first CR with prior exposure to GO had a significant reduction in RR (15% vs. 53%;P= 0.007), with a corresponding DFS of 65% versus 40% (P= 0.08), and higher TRM (19% vs. 7%;P= 0.08). CONCLUSIONS: CD33 targeting with HCT consolidation may be an important therapeutic strategy in high-riskFLT3/ITD AML and its efficacy and associated toxicity warrant further investigation. PMID- 26644413 TI - Immunohistochemical Markers Distinguishing Cholangiocellular Carcinoma (CCC) from Pancreatic Ductal Adenocarcinoma (PDAC) Discovered by Proteomic Analysis of Microdissected Cells. AB - Cholangiocellular carcinoma (CCC) and pancreatic ductal adenocarcinoma (PDAC) are two highly aggressive cancer types that arise from epithelial cells of the pancreatobiliary system. Owing to their histological and morphological similarity, differential diagnosis between CCC and metastasis of PDAC located in the liver frequently proves an unsolvable issue for pathologists. The detection of biomarkers with high specificity and sensitivity for the differentiation of these tumor types would therefore be a valuable tool. Here, we address this problem by comparing microdissected CCC and PDAC tumor cells from nine and eleven cancer patients, respectively, in a label-free proteomics approach. The novel biomarker candidates were subsequently verified by immunohistochemical staining of 73 CCC, 78 primary, and 18 metastatic PDAC tissue sections. In the proteome analysis, we found 180 proteins with a significantly differential expression between CCC and PDAC cells (p value < 0.05, absolute fold change > 2). Nine candidate proteins were chosen for an immunohistochemical verification out of which three showed very promising results. These were the annexins ANXA1, ANXA10, and ANXA13. For the correct classification of PDAC, ANXA1 showed a sensitivity of 84% and a specificity of 85% and ANXA10 a sensitivity of 90% at a specificity of 66%. ANXA13 was higher abundant in CCC. It presented a sensitivity of 84% at a specificity of 55%. In metastatic PDAC tissue ANXA1 and ANXA10 showed similar staining behavior as in the primary PDAC tumors (13/18 and 17/18 positive, respectively). ANXA13, however, presented positive staining in eight out of eighteen secondary PDAC tumors and was therefore not suitable for the differentiation of these from CCC. We conclude that ANXA1 and ANXA10 are promising biomarker candidates with high diagnostic values for the differential diagnosis of intrahepatic CCC and metastatic liver tumors deriving from PDAC. PMID- 26644414 TI - Extending gene ontology with gene association networks. AB - MOTIVATION: Gene ontology (GO) is a widely used resource to describe the attributes for gene products. However, automatic GO maintenance remains to be difficult because of the complex logical reasoning and the need of biological knowledge that are not explicitly represented in the GO. The existing studies either construct whole GO based on network data or only infer the relations between existing GO terms. None is purposed to add new terms automatically to the existing GO. RESULTS: We proposed a new algorithm 'GOExtender' to efficiently identify all the connected gene pairs labeled by the same parent GO terms. GOExtender is used to predict new GO terms with biological network data, and connect them to the existing GO. Evaluation tests on biological process and cellular component categories of different GO releases showed that GOExtender can extend new GO terms automatically based on the biological network. Furthermore, we applied GOExtender to the recent release of GO and discovered new GO terms with strong support from literature. AVAILABILITY AND IMPLEMENTATION: Software and supplementary document are available at www.msu.edu/%7Ejinchen/GOExtender CONTACT: jinchen@msu.edu or ydwang@hit.edu.cn SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26644416 TI - Improved topology prediction using the terminal hydrophobic helices rule. AB - MOTIVATION: The translocon recognizes sufficiently hydrophobic regions of a protein and inserts them into the membrane. Computational methods try to determine what hydrophobic regions are recognized by the translocon. Although these predictions are quite accurate, many methods still fail to distinguish marginally hydrophobic transmembrane (TM) helices and equally hydrophobic regions in soluble protein domains. In vivo, this problem is most likely avoided by targeting of the TM-proteins, so that non-TM proteins never see the translocon. Proteins are targeted to the translocon by an N-terminal signal peptide. The targeting is also aided by the fact that the N-terminal helix is more hydrophobic than other TM-helices. In addition, we also recently found that the C-terminal helix is more hydrophobic than central helices. This information has not been used in earlier topology predictors. RESULTS: Here, we use the fact that the N- and C-terminal helices are more hydrophobic to develop a new version of the first principle-based topology predictor, SCAMPI. The new predictor has two main advantages; first, it can be used to efficiently separate membrane and non membrane proteins directly without the use of an extra prefilter, and second it shows improved performance for predicting the topology of membrane proteins that contain large non-membrane domains. AVAILABILITY AND IMPLEMENTATION: The predictor, a web server and all datasets are available at http://scampi.bioinfo.se/ CONTACT: arne@bioinfo.se SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26644415 TI - Joint detection of copy number variations in parent-offspring trios. AB - MOTIVATION: Whole genome sequencing (WGS) of parent-offspring trios is a powerful approach for identifying disease-associated genes via detecting copy number variations (CNVs). Existing approaches, which detect CNVs for each individual in a trio independently, usually yield low-detection accuracy. Joint modeling approaches leveraging Mendelian transmission within the parent-offspring trio can be an efficient strategy to improve CNV detection accuracy. RESULTS: In this study, we developed TrioCNV, a novel approach for jointly detecting CNVs in parent-offspring trios from WGS data. Using negative binomial regression, we modeled the read depth signal while considering both GC content bias and mappability bias. Moreover, we incorporated the family relationship and used a hidden Markov model to jointly infer CNVs for three samples of a parent-offspring trio. Through application to both simulated data and a trio from 1000 Genomes Project, we showed that TrioCNV achieved superior performance than existing approaches. AVAILABILITY AND IMPLEMENTATION: The software TrioCNV implemented using a combination of Java and R is freely available from the website at https://github.com/yongzhuang/TrioCNV CONTACT: ydwang@hit.edu.cn SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26644417 TI - Sampling ARG of multiple populations under complex configurations of subdivision and admixture. AB - MOTIVATION: Simulating complex evolution scenarios of multiple populations is an important task for answering many basic questions relating to population genomics. Apart from the population samples, the underlying Ancestral Recombinations Graph (ARG) is an additional important means in hypothesis checking and reconstruction studies. Furthermore, complex simulations require a plethora of interdependent parameters making even the scenario-specification highly non-trivial. RESULTS: We present an algorithm SimRA that simulates generic multiple population evolution model with admixture. It is based on random graphs that improve dramatically in time and space requirements of the classical algorithm of single populations.Using the underlying random graphs model, we also derive closed forms of expected values of the ARG characteristics i.e., height of the graph, number of recombinations, number of mutations and population diversity in terms of its defining parameters. This is crucial in aiding the user to specify meaningful parameters for the complex scenario simulations, not through trial-and-error based on raw compute power but intelligent parameter estimation. To the best of our knowledge this is the first time closed form expressions have been computed for the ARG properties. We show that the expected values closely match the empirical values through simulations.Finally, we demonstrate that SimRA produces the ARG in compact forms without compromising any accuracy. We demonstrate the compactness and accuracy through extensive experiments. AVAILABILITY AND IMPLEMENTATION: SimRA (Simulation based on Random graph Algorithms) source, executable, user manual and sample input-output sets are available for downloading at: https://github.com/ComputationalGenomics/SimRA CONTACT: : parida@us.ibm.com SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26644418 TI - Breastfeeding and Postnatal Depression: A Prospective Cohort Study in Sabah, Malaysia. AB - BACKGROUND: Postnatal depression is a disorder that can lead to serious consequences for both the mother and infant. Despite the extensively documented health benefits of breastfeeding, its association with postnatal depression remains uncertain. OBJECTIVE: To investigate the relationship between full breastfeeding at 3 months postpartum and postnatal depressive symptoms among mothers in Sabah, Malaysia. METHODS: A prospective cohort study of 2072 women was conducted in Sabah during 2009-2010. Participants were recruited at 36 to 38 weeks of gestation and followed up at 1 and 3 months postpartum. Depressive symptoms were assessed using the validated Malay version of the Edinburgh Postnatal Depression Scale (EPDS). Repeated-measures analyses of variance was performed to compare the depression scores over time and between subgroups of breastfeeding mothers. RESULTS: Approximately 46% of women were fully breastfeeding their infants at 3 months postpartum. These mothers had significantly (P < .001) lower mean EPDS scores at both 1 and 3 months postpartum (mean +/- SD, 4.14 +/- 4.12 and 4.27 +/- 4.12, respectively) than others who did not initiate or maintain full breastfeeding for 3 months (4.94 +/- 4.34 and 5.25 +/- 4.05, respectively). After controlling for the effects of covariates, the differences in EPDS scores remained statistically significant (P = .001) between the 2 breastfeeding groups. CONCLUSION: Full breastfeeding appeared to be negatively associated with postnatal depressive symptoms for mothers residing in Sabah. PMID- 26644419 TI - The Effectiveness of Lactation Consultants and Lactation Counselors on Breastfeeding Outcomes. AB - Breastfeeding for all infants starting at birth and continuing until at least 6 months of age has been recommended by the World Health Organization and the American Academy of Pediatrics. The health benefits to infants and mothers have been demonstrated in many studies. Dedicated lactation specialists may play a role in providing education and support to pregnant women and new mothers wishing to breastfeed to improve breastfeeding outcomes. The objective of this review was to assess if lactation education or support programs using lactation consultants or lactation counselors would improve rates of initiation and duration of any breastfeeding and exclusive breastfeeding compared with usual practice. A systematic literature review of the evidence was conducted using electronic databases. The review was limited to randomized trials and yielded 16 studies with 5084 participants. It was found that breastfeeding interventions using lactation consultants and counselors increase the number of women initiating breastfeeding (odds ratio [OR] for any initiation vs not initiating breastfeeding = 1.35; 95% confidence interval [CI], 1.10-1.67). The interventions improve any breastfeeding rates (OR for any breastfeeding up to 1 month vs not breastfeeding = 1.49; 95% CI, 1.09-2.04). In addition, there were beneficial effects on exclusive breastfeeding rates (OR for exclusive breastfeeding up to 1 month vs not exclusive breastfeeding = 1.71; 95% CI, 1.20-2.44). Most of the evidence would suggest developing and improving postpartum support programs incorporating lactation consultants and lactation counselors. PMID- 26644420 TI - Breastfeeding Duration and Primary Reasons for Breastfeeding Cessation among Women with Postpartum Depressive Symptoms. AB - BACKGROUND: Although postpartum depression is associated with lower breastfeeding initiation rates and shorter breastfeeding duration, the potential mechanisms through which this relationship functions are not well understood. OBJECTIVE: This study examined the breastfeeding behaviors of women with postpartum depressive symptoms (PDS) to identify potential motivations for early breastfeeding cessation. METHODS: An analysis of quantitative data from the Infant Feeding Practices Study II examined the relationship between PDS and breastfeeding behaviors, including breastfeeding duration and primary reasons for early breastfeeding cessation. RESULTS: Of the women in the sample, 30.9% met criteria for mild PDS. Women with PDS had shorter overall (18.4 vs 21.8 weeks, P = .001) and exclusive breastfeeding duration (3.6 vs 4.7 weeks, P = .012) than women without PDS. A larger proportion of women with PDS stopped breastfeeding before 6 months (68.7% vs 57.2%, P < .001). After controlling for socioeconomic status, education, marital status, employment status, race/ethnicity, maternal age, parity, and breastfeeding intentions, presence of PDS significantly predicted higher odds of reporting "too many household duties" (OR = 1.90, P = .011) as a primary reason for breastfeeding cessation among women who stopped breastfeeding before 6 months. After controlling for these same covariates, women with PDS had, on average, 2.4 weeks shorter breastfeeding duration than women without PDS (P = .025). CONCLUSION: There is a high prevalence of depressive symptoms among new mothers, and most do not breastfeed for recommended time periods. Increased PDS screening during prenatal and postpartum visits and promotion of lactation support services may better address the high rates of PDS and suboptimal breastfeeding behavior. PMID- 26644421 TI - Exposure to Tobacco Metabolites via Breast Milk and Infant Weight Gain: A Population-Based Study. AB - BACKGROUND: Although the immutable benefits of breastfeeding are well documented, information on the potential consequences of exposure to tobacco metabolites specifically via breastfeeding is sparse. OBJECTIVE: The aim was to conduct the first study of the association between exposure to tobacco metabolites specifically through breastfeeding and infant weight gain. METHODS: We used historical data from the US Collaborative Perinatal Project. Mothers were classified as nonsmokers, light smokers (1-19 cigarettes/day), and heavy (20+ cigarettes/day) smokers. In-hospital feeding type was observed during a nursery stay after delivery. We conducted stratified analyses among average-for gestational-age (AGA; N = 23 571) and small-for-gestational-age (SGA; N = 2552) infants. We isolated the effect of exposure to tobacco metabolites specifically through breastfeeding. RESULTS: Overall, maternal smoking was associated with change in weight-for-length z-score in a dose-response manner. Change in weight z score was most pronounced among SGA infants of heavy smokers (breastfed: 0.53; 95% confidence interval [CI], 0.12-0.94; formula fed: 0.17; 95% CI, 0.03-0.30). Exposure to tobacco metabolites specifically through breastfeeding was not associated with additional weight gain among AGA infants. Among the much smaller sample of SGA infants, exposure specifically through breastfeeding was associated with marginally significant additional weight gain (0.46; 95% CI, 0.00-0.91) among infants of heavy smokers. CONCLUSION: Our findings are in accord with recommendations by health agencies for smokers to breastfeed. However, SGA infants exposed to tobacco metabolites via breastfeeding by heavy smokers appear to gain weight more rapidly than other infants. Practical implications of our findings are discussed. PMID- 26644422 TI - Therapeutic Breast Massage in Lactation for the Management of Engorgement, Plugged Ducts, and Mastitis. AB - BACKGROUND: Many women in developed countries do not meet their breastfeeding goals and wean early because of breast pain. OBJECTIVE: This study aimed to describe clinical response to therapeutic breast massage in lactation (TBML) in the management of engorgement, plugged ducts, and mastitis. METHODS: Breastfeeding women presenting with engorgement, plugged ducts, or mastitis who received TBML as part of their treatment were enrolled (n = 42). Data collected at the initial visit included demographic, history, and exam data pre-TBML and post-TBML. Email surveys sent 2 days, 2 weeks, and 12 weeks following the initial visit assessed pain and breastfeeding complications. A nested case control of engorged mothers (n = 73) was separately enrolled to compare engorgement severity. RESULTS: Reasons for the visit included engorgement (36%), plugged ducts (67%), and mastitis (29%). Cases, compared to controls, were significantly more likely to have severe engorgement (47% vs 7%, P < .001). Initial mean breast pain level among those receiving TBML was 6.4 out of 10. Following TBML, there was significant improvement in both breast (6.4 vs 2.8, P < .001) and nipple pain (4.6 vs 2.8, P = .013). All women reported immediate improvement in their pain level. At the 12-week survey, 65% found the massage treatment very helpful. The majority of the women with a new episode of mastitis or plugged duct during the study follow-up found the techniques learned during the office visit very helpful for home management of these episodes. CONCLUSION: In office, TBML is helpful for the reduction of acute breast pain associated with milk stasis. Mothers find TBML helpful both immediately in-office and for home management of future episodes. PMID- 26644423 TI - Prosthetic replacement of the ocular surface ecosystem: impact at 5 years. AB - BACKGROUND/AIMS: To determine the impact of prosthetic replacement of the ocular surface ecosystem (PROSE) treatment at 5 years. METHODS: Retrospective review of clinical, manufacturing and quality databases at the Boston Foundation for Sight. RESULTS: 121 patients who completed treatment and had 5-year follow-up data were identified from a cohort of patients (n=199) seen in consultation for PROSE treatment from January 2008 to June 2008. Mean age was 52 years, M:F=56:65. The primary indication for treatment was ocular surface disease (OSD) in 64 patients and distorted corneal surface in 57 patients. At 5 years, continued device wear was confirmed in 89/121 (73.6%) patients. Discontinuation of wear was confirmed in 32/121 (26.4%). There was an increased likelihood of continued device wear at 5 years in patients with distorted cornea (84%) compared with those with OSD (64%), (p=0.0121, chi(2)). National Eye Institute Visual Function Questionnaire (NEI VFQ-25) composite score increased for patients wearing PROSE devices at 6 months (Delta=+23 points, mean=82, p<0.001, two-tailed t test) with no significant decline among those still wearing a device at 5 years (Delta=-4 points, mean=78, p=0.22, two-tailed t test). At 5 years, those wearing (mean=78) had a higher NEI VFQ-25 than those not wearing (mean=70, p=0.029, two-tailed t test). CONCLUSIONS: PROSE treatment offers continued benefit, as defined by improved visual function and continued device wear at 5 years, in patients with complex corneal disease. Patients with distorted cornea have a higher rate of continued wear at 5 years than patients with OSD, although this is not true among all subgroups within OSD. PMID- 26644424 TI - Disability and philosophy: applying ethics in circumstances of injustice. PMID- 26644425 TI - What is the role of ethics committees after Regulation (EU) 536/2014? AB - EU Regulation 536/2014 stipulates that when assessing applications for authorisation to conduct clinical trials, Member States should formulate a 'single decision'. This raises the problem of identifying: (1) the facility designated to express this 'single decision' and (2) the role of ethics committees in the decision-making process. The article addresses the consequences of the requirement that for each Member State the assessment of an application for approval to conduct a trial must take the form of a 'single decision' by the Member State concerned. Three possible approaches to the procedures for expressing that 'single decision' and to the role of ethics committees in the decision-making process are described, one of which is indicated as the preferred option. PMID- 26644426 TI - Obtaining informed consent for genomics research in Africa: analysis of H3Africa consent documents. AB - BACKGROUND: The rise in genomic and biobanking research worldwide has led to the development of different informed consent models for use in such research. This study analyses consent documents used by investigators in the H3Africa (Human Heredity and Health in Africa) Consortium. METHODS: A qualitative method for text analysis was used to analyse consent documents used in the collection of samples and data in H3Africa projects. Thematic domains included type of consent model, explanations of genetics/genomics, data sharing and feedback of test results. RESULTS: Informed consent documents for 13 of the 19 H3Africa projects were analysed. Seven projects used broad consent, five projects used tiered consent and one used specific consent. Genetics was mostly explained in terms of inherited characteristics, heredity and health, genes and disease causation, or disease susceptibility. Only one project made provisions for the feedback of individual genetic results. CONCLUSION: H3Africa research makes use of three consent models-specific, tiered and broad consent. We outlined different strategies used by H3Africa investigators to explain concepts in genomics to potential research participants. To further ensure that the decision to participate in genomic research is informed and meaningful, we recommend that innovative approaches to the informed consent process be developed, preferably in consultation with research participants, research ethics committees and researchers in Africa. PMID- 26644427 TI - Higher body mass index is associated with plantar fasciopathy/'plantar fasciitis': systematic review and meta-analysis of various clinical and imaging risk factors. AB - QUESTION: What (risk) factors are associated with plantar fasciopathy (PF)? DESIGN: Systematic review with meta-analyses. PARTICIPANTS: Patients with PF. FACTORS: All factors described in prospective, case-control or cross-sectional observational studies. RESULTS: 51 included studies (1 prospective, 46 case control and 4 cross-sectional studies) evaluated a total of 104 variables. Pooling was possible for 12 variables. Higher body mass index (BMI) (BMI>27, OR 3.7 (95% CI 2.93 to 5.62)) in patients with PF was the only significant clinical association, and its effect was the strongest in the non-athletic subgroup. In people with PF compared to controls, pooled imaging data demonstrated a significantly thicker, hypoechogenic plantar fascia with increased vascular signal and perifascial fluid collection. In addition, people with PF were more likely to have a thicker loaded and unloaded heel fat pat, and bone findings, including a subcalcaneal spur and increased Tc-99 uptake. No significant difference was found in the extension of the first metatarsophalangeal joint. CONCLUSIONS: We found a consistent clinical association between higher BMI and plantar fasciopathy. This association may differ between athletic and non athletic subgroups. While consistent evidence supports a range of bone and soft tissue abnormalities, there is lack of evidence for the dogma of clinical and mechanical measures of foot and ankle function. Clinicians can use this information in shared decision-making. PMID- 26644428 TI - Greater vertical impact loading in female runners with medically diagnosed injuries: a prospective investigation. AB - BACKGROUND: Running has been critical to human survival. Therefore, the high rate of injuries experienced by modern day runners is puzzling. Landing on the heel, as most modern day shod runners do, results in a distinct vertical impact force that has been shown to be associated with running-related injuries. However, these injury studies were retrospective in nature and do not establish cause and effect. OBJECTIVE: To determine whether runners with high impacts are at greater risk for developing medically diagnosed injuries. METHODS: 249 female runners underwent a gait analysis to measure vertical instantaneous loading rate, vertical average loading rate (VALR), vertical impact peak (VIP) and peak vertical force. Participants then recorded their mileage and any running-related injuries monthly in a web-based, database programme. Variables were first compared between the entire injured (INJ; n=144) and uninjured (n=105) groups. However, the focus of this study was on those injured runners seeking medical attention (n=103) and those who had never injured (n=21). RESULTS: There were no differences between the entire group of injured and uninjured groups. However, all impact-related variables were higher in those with medically diagnosed injuries compared with those who had never been injured. (effect size (ES) 0.4 0.59). When VALR was >66.0 body weight (BW)/s, the odds of being DX_INJ were 2.72 (95% CI 1.0 to 7.4). Impact loading was associated with bony and soft-tissue injuries. CONCLUSIONS: Vertical average loading rate was lower in female runners classified as 'never injured' compared with those who had been injured and sought medical attention. PMID- 26644429 TI - Yersinia Type III Secretion System Master Regulator LcrF. AB - Many Gram-negative pathogens express a type III secretion (T3SS) system to enable growth and survival within a host. The three human-pathogenic Yersinia species, Y. pestis, Y. pseudotuberculosis, and Y. enterocolitica, encode the Ysc T3SS, whose expression is controlled by an AraC-like master regulator called LcrF. In this review, we discuss LcrF structure and function as well as the environmental cues and pathways known to regulate LcrF expression. Similarities and differences in binding motifs and modes of action between LcrF and the Pseudomonas aeruginosa homolog ExsA are summarized. In addition, we present a new bioinformatics analysis that identifies putative LcrF binding sites within Yersinia target gene promoters. PMID- 26644430 TI - HexR Controls Glucose-Responsive Genes and Central Carbon Metabolism in Neisseria meningitidis. AB - Neisseria meningitidis, an exclusively human pathogen and the leading cause of bacterial meningitis, must adapt to different host niches during human infection. N. meningitidis can utilize a restricted range of carbon sources, including lactate, glucose, and pyruvate, whose concentrations vary in host niches. Microarray analysis of N. meningitidis grown in a chemically defined medium in the presence or absence of glucose allowed us to identify genes regulated by carbon source availability. Most such genes are implicated in energy metabolism and transport, and some are implicated in virulence. In particular, genes involved in glucose catabolism were upregulated, whereas genes involved in the tricarboxylic acid cycle were downregulated. Several genes encoding surface exposed proteins, including the MafA adhesins and Neisseria surface protein A, were upregulated in the presence of glucose. Our microarray analysis led to the identification of a glucose-responsive hexR-like transcriptional regulator that controls genes of the central carbon metabolism of N. meningitidis in response to glucose. We characterized the HexR regulon and showed that the hexR gene is accountable for some of the glucose-responsive regulation; in vitro assays with the purified protein showed that HexR binds to the promoters of the central metabolic operons of the bacterium. Based on DNA sequence alignment of the target sites, we propose a 17-bp pseudopalindromic consensus HexR binding motif. Furthermore, N. meningitidis strains lacking hexR expression were deficient in establishing successful bacteremia in an infant rat model of infection, indicating the importance of this regulator for the survival of this pathogen in vivo. IMPORTANCE: Neisseria meningitidis grows on a limited range of nutrients during infection. We analyzed the gene expression of N. meningitidis in response to glucose, the main energy source available in human blood, and we found that glucose regulates many genes implicated in energy metabolism and nutrient transport, as well as some implicated in virulence. We identified and characterized a transcriptional regulator (HexR) that controls metabolic genes of N. meningitidis in response to glucose. We generated a mutant lacking HexR and found that the mutant was impaired in causing systemic infection in animal models. Since N. meningitidis lacks known bacterial regulators of energy metabolism, our findings suggest that HexR plays a major role in its biology by regulating metabolism in response to environmental signals. PMID- 26644431 TI - Inactivation of Cell Division Protein FtsZ by SulA Makes Lon Indispensable for the Viability of a ppGpp0 Strain of Escherichia coli. AB - The modified nucleotides (p)ppGpp play an important role in bacterial physiology. While the accumulation of the nucleotides is vital for adaptation to various kinds of stress, changes in the basal level modulates growth rate and vice versa. Studying the phenotypes unique to the strain lacking (p)ppGpp (ppGpp(0)) under overtly unstressed growth conditions may be useful to understand functions regulated by basal levels of (p)ppGpp and its physiological significance. In this study, we show that the ppGpp(0) strain, unlike the wild type, requires the Lon protease for cell division and viability in LB. Our results indicate the decrease in FtsZ concentration in the ppGpp(0) strain makes cell division vulnerable to SulA inhibition. We did not find evidence for SOS induction contributing to the cell division defect in the ppGpp(0) Deltalon strain. Based on the results, we propose that basal levels of (p)ppGpp are required to sustain normal cell division in Escherichia coli during growth in rich medium and that the basal SulA level set by Lon protease is important for insulating cell division against a decrease in FtsZ concentration and conditions that can increase the susceptibility of FtsZ to SulA. IMPORTANCE: The physiology of the stringent response has been the subject of investigation for more than 4 decades, with the majority of the work carried out using the bacterial model organism Escherichia coli. These studies have revealed that the accumulation of (p)ppGpp, the effector of the stringent response, is associated with growth retardation and changes in gene expression that vary with the intracellular concentration of (p)ppGpp. By studying a synthetic lethal phenotype, we have uncovered a function modulated by the basal levels of (p)ppGpp and studied its physiological significance. Our results show that (p)ppGpp and Lon protease contribute to the robustness of the cell division machinery in E. coli during growth in rich medium. PMID- 26644432 TI - Hypothetical Protein BB0569 Is Essential for Chemotaxis of the Lyme Disease Spirochete Borrelia burgdorferi. AB - The Lyme disease spirochete Borrelia burgdorferi has five putative methyl accepting chemotaxis proteins (MCPs). In this report, we provide evidence that a hypothetical protein, BB0569, is essential for the chemotaxis of B. burgdorferi. While BB0569 lacks significant homology to the canonical MCPs, it contains a conserved domain (spanning residues 110 to 170) that is often evident in membrane bound MCPs such as Tar and Tsr of Escherichia coli. Unlike Tar and Tsr, BB0569 lacks transmembrane regions and recognizable HAMP and methylation domains and is similar to TlpC, a cytoplasmic chemoreceptor of Rhodobacter sphaeroides. An isogenic mutant of BB0569 constantly runs in one direction and fails to respond to attractants, indicating that BB0569 is essential for chemotaxis. Immunofluorescence, green fluorescent protein (GFP) fusion, and cryo-electron tomography analyses demonstrate that BB0569 localizes at the cell poles and is required for chemoreceptor clustering at the cell poles. Protein cross-linking studies reveal that BB0569 forms large protein complexes with MCP3, indicative of its interactions with other MCPs. Interestingly, analysis of B. burgdorferi mcp mutants shows that inactivation of either mcp2 or mcp3 reduces the level of BB0569 substantially and that such a reduction is caused by protein turnover. Collectively, these results demonstrate that the domain composition and function of BB0569 are similar in some respects to those of TlpC but that these proteins are different in their cellular locations, further highlighting that the chemotaxis of B. burgdorferi is unique and different from the Escherichia coli and Salmonella enterica paradigm. IMPORTANCE: Spirochete chemotaxis differs substantially from the Escherichia coli and Salmonella enterica paradigm, and the basis for controlling the rotation of the bundles of periplasmic flagella at each end of the cell is unknown. In recent years, Borrelia burgdorferi, the causative agent of Lyme disease, has been used as a model organism to understand spirochete chemotaxis and its role in infectious processes of the disease. In this report, BB0569, a hypothetical protein of B. burgdorferi, has been investigated by using an approach of genetic, biochemistry, and cryo-electron tomography analyses. The results indicate that BB0569 has a distinct role in chemotaxis that may be unique to spirochetes and represents a novel paradigm. PMID- 26644433 TI - Proteome Profiling of the Rhodobacter capsulatus Molybdenum Response Reveals a Role of IscN in Nitrogen Fixation by Fe-Nitrogenase. AB - Rhodobacter capsulatus is capable of synthesizing two nitrogenases, a molybdenum dependent nitrogenase and an alternative Mo-free iron-only nitrogenase, enabling this diazotroph to grow with molecular dinitrogen (N2) as the sole nitrogen source. Here, the Mo responses of the wild type and of a mutant lacking ModABC, the high-affinity molybdate transporter, were examined by proteome profiling, Western analysis, epitope tagging, and lacZ reporter fusions. Many Mo-controlled proteins identified in this study have documented or presumed roles in nitrogen fixation, demonstrating the relevance of Mo control in this highly ATP-demanding process. The levels of Mo-nitrogenase, NifHDK, and the Mo storage protein, Mop, increased with increasing Mo concentrations. In contrast, Fe-nitrogenase, AnfHDGK, and ModABC, the Mo transporter, were expressed only under Mo-limiting conditions. IscN was identified as a novel Mo-repressed protein. Mo control of Mop, AnfHDGK, and ModABC corresponded to transcriptional regulation of their genes by the Mo-responsive regulators MopA and MopB. Mo control of NifHDK and IscN appeared to be more complex, involving different posttranscriptional mechanisms. In line with the simultaneous control of IscN and Fe-nitrogenase by Mo, IscN was found to be important for Fe-nitrogenase-dependent diazotrophic growth. The possible role of IscN as an A-type carrier providing Fe-nitrogenase with Fe-S clusters is discussed. IMPORTANCE: Biological nitrogen fixation is a central process in the global nitrogen cycle by which the abundant but chemically inert dinitrogen (N2) is reduced to ammonia (NH3), a bioavailable form of nitrogen. Nitrogen reduction is catalyzed by nitrogenases found in diazotrophic bacteria and archaea but not in eukaryotes. All diazotrophs synthesize molybdenum dependent nitrogenases. In addition, some diazotrophs, including Rhodobacter capsulatus, possess catalytically less efficient alternative Mo-free nitrogenases, whose expression is repressed by Mo. Despite the importance of Mo in biological nitrogen fixation, this is the first study analyzing the proteome wide Mo response in a diazotroph. IscN was recognized as a novel member of the molybdoproteome in R. capsulatus. It was dispensable for Mo-nitrogenase activity but supported diazotrophic growth under Mo-limiting conditions. PMID- 26644434 TI - Disulfide-Bond-Forming Pathways in Gram-Positive Bacteria. AB - Disulfide bonds are important for the stability and function of many secreted proteins. In Gram-negative bacteria, these linkages are catalyzed by thiol disulfide oxidoreductases (Dsb) in the periplasm. Protein oxidation has been well studied in these organisms, but it has not fully been explored in Gram-positive bacteria, which lack traditional periplasmic compartments. Recent bioinformatics analyses have suggested that the high-GC-content bacteria (i.e., actinobacteria) rely on disulfide-bond-forming pathways. In support of this, Dsb-like proteins have been identified in Mycobacterium tuberculosis, but their functions are not known. Actinomyces oris and Corynebacterium diphtheriae have recently emerged as models to study disulfide bond formation in actinobacteria. In both organisms, disulfide bonds are catalyzed by the membrane-bound oxidoreductase MdbA. Remarkably, unlike known Dsb proteins, MdbA is important for pathogenesis and growth, which makes it a potential target for new antibacterial drugs. This review will discuss disulfide-bond-forming pathways in bacteria, with a special focus on Gram-positive bacteria. PMID- 26644437 TI - In this issue of Occupational Medicine. PMID- 26644435 TI - Antisocial luxO Mutants Provide a Stationary-Phase Survival Advantage in Vibrio fischeri ES114. AB - The squid light organ symbiont Vibrio fischeri controls bioluminescence using two acyl-homoserine lactone pheromone-signaling (PS) systems. The first of these systems to be activated during host colonization, AinS/AinR, produces and responds to N-octanoyl homoserine lactone (C(8)-AHL). We screened activity of a P(ainS)-lacZ transcriptional reporter in a transposon mutant library and found three mutants with decreased reporter activity, low C(8)-AHL output, and other traits consistent with low ainS expression. However, the transposon insertions were unrelated to these phenotypes, and genome resequencing revealed that each mutant had a distinct point mutation in luxO. In the wild type, LuxO is phosphorylated by LuxU and then activates transcription of the small RNA (sRNA) Qrr, which represses ainS indirectly by repressing its activator LitR. The luxO mutants identified here encode LuxU-independent, constitutively active LuxO* proteins. The repeated appearance of these luxO mutants suggested that they had some fitness advantage during construction and/or storage of the transposon mutant library, and we found that luxO* mutants survived better and outcompeted the wild type in prolonged stationary-phase cultures. From such cultures we isolated additional luxO* mutants. In all, we isolated LuxO* allelic variants with the mutations P41L, A91D, F94C, P98L, P98Q, V106A, V106G, T107R, V108G, R114P, L205F, H319R, H324R, and T335I. Based on the current model of the V. fischeri PS circuit, litR knockout mutants should resemble luxO* mutants; however, luxO* mutants outcompeted litR mutants in prolonged culture and had much poorer host colonization competitiveness than is reported for litR mutants, illustrating additional complexities in this regulatory circuit. IMPORTANCE: Our results provide novel insight into the function of LuxO, which is a key component of pheromone signaling (PS) cascades in several members of the Vibrionaceae. Our results also contribute to an increasingly appreciated aspect of bacterial behavior and evolution whereby mutants that do not respond to a signal from like cells have a selective advantage. In this case, although "antisocial" mutants locked in the PS signal-off mode can outcompete parents, their survival advantage does not require wild-type cells to exploit. Finally, this work strikes a note of caution for those conducting or interpreting experiments in V. fischeri, as it illustrates how pleiotropic mutants could easily and inadvertently be enriched in this bacterium during prolonged culturing. PMID- 26644436 TI - NqrM (DUF539) Protein Is Required for Maturation of Bacterial Na+-Translocating NADH:Quinone Oxidoreductase. AB - Na(+)-translocating NADH:quinone oxidoreductase (Na(+)-NQR) catalyzes electron transfer from NADH to ubiquinone in the bacterial respiratory chain, coupled with Na(+) translocation across the membrane. Na(+)-NQR maturation involves covalent attachment of flavin mononucleotide (FMN) residues, catalyzed by flavin transferase encoded by the nqr-associated apbE gene. Analysis of complete bacterial genomes has revealed another putative gene (duf539, here renamed nqrM) that usually follows the apbE gene and is present only in Na(+)-NQR-containing bacteria. Expression of the Vibrio harveyi nqr operon alone or with the associated apbE gene in Escherichia coli, which lacks its own Na(+)-NQR, resulted in an enzyme incapable of Na(+)-dependent NADH or reduced nicotinamide hypoxanthine dinucleotide (dNADH) oxidation. However, fully functional Na(+)-NQR was restored when these genes were coexpressed with the V. harveyi nqrM gene. Furthermore, nqrM lesions in Klebsiella pneumoniae and V. harveyi prevented production of functional Na(+)-NQR, which could be recovered by an nqrM containing plasmid. The Na(+)-NQR complex isolated from the nqrM-deficient strain of V. harveyi lacks several subunits, indicating that nqrM is necessary for Na(+) NQR assembly. The protein product of the nqrM gene, NqrM, contains a single putative transmembrane alpha-helix and four conserved Cys residues. Mutating one of these residues (Cys33 in V. harveyi NqrM) to Ser completely prevented Na(+) NQR maturation, whereas mutating any other Cys residue only decreased the yield of the mature protein. These findings identify NqrM as the second specific maturation factor of Na(+)-NQR in proteobacteria, which is presumably involved in the delivery of Fe to form the (Cys)4[Fe] center between subunits NqrD and NqrE. IMPORTANCE: Na(+)-translocating NADH:quinone oxidoreductase complex (Na(+)-NQR) is a unique primary Na(+) pump believed to enhance the vitality of many bacteria, including important pathogens such as Vibrio cholerae, Vibrio parahaemolyticus, Haemophilus influenzae, Neisseria gonorrhoeae, Pasteurella multocida, Porphyromonas gingivalis, Enterobacter aerogenes, and Yersinia pestis. Production of Na(+)-NQR in bacteria requires Na(+)-NQR-specific maturation factors. We earlier identified one such factor (ApbE) that covalently attaches flavin residues to Na(+)-NQR. Here we identify the other protein factor, designated NqrM, and show that NqrM and ApbE suffice to produce functional Na(+)-NQR from the Vibrio harveyi nqr operon. NqrM may be involved in Fe delivery to a unique Cys4[Fe] center during Na(+)-NQR assembly. Besides highlighting Na(+)-NQR biogenesis, these findings suggest a novel drug target to combat Na(+)-NQR containing bacteria. PMID- 26644438 TI - Consent to occupational health reports. PMID- 26644440 TI - Carter Tiles, Engineering Books c1925-30. PMID- 26644442 TI - Occupational health issues amongst UK doctors: a literature review. PMID- 26644443 TI - Re: Wither or whither now training in occupational medicine. PMID- 26644444 TI - Letter to the editor. PMID- 26644445 TI - The Montreal Cognitive Assessment (MoCA). PMID- 26644446 TI - Lead toxicity. PMID- 26644448 TI - The 2015 William B. Coley Awards. PMID- 26644449 TI - Statistical Challenges in the Design of Late-Stage Cancer Immunotherapy Studies. AB - The past several years have witnessed a revival of interest in cancer immunology and immunotherapy owing to striking immunologic and clinical responses to immune directed anticancer therapies and leading to the selection of "Cancer Immunotherapy" as the 2013 Breakthrough of the Year by Science. But statistical challenges exist at all phases of clinical development. In phase III trials of immunotherapies, survival curves have been shown to demonstrate delayed clinical effects, as well as long-term survival. These unique survival kinetics could lead to loss of statistical power and prolongation of study duration. Statistical assumptions that form the foundations for conventional statistical inference in the design and analysis of phase III trials, such as exponential survival and proportional hazards, require careful considerations. In this article, we describe how the unique characteristics of patient response to cancer immunotherapies will impact our strategies on statistical design and analysis in late-stage drug development. PMID- 26644450 TI - Brca1 deficiency causes bone marrow failure and spontaneous hematologic malignancies in mice. AB - BRCA1 is critical for maintenance of genomic stability and interacts directly with several proteins that regulate hematopoietic stem cell function and are part of the Fanconi anemia (FA) double-strand break DNA repair pathway. The effects of complete BRCA1 deficiency on bone marrow (BM) function are unknown. To test the hypothesis that Brca1 is essential in hematopoiesis, we developed a conditional mouse model with Mx1-Cre-mediated Brca1 deletion. Mice lacking Brca1 in the BM have baseline cytopenias and develop spontaneous bone marrow failure or diverse hematologic malignancies by 6 months of age. Brca1(-/-) BM cells have a reduced capacity to form hematopoietic colonies in vitro and to reconstitute hematopoiesis in irradiated recipients, consistent with a hematopoietic progenitor functional defect. Brca1(-/-) BM cells also show FA-like hypersensitivity to the DNA crosslinking agent mitomycin C, and karyotypes feature genomic instability. Taken together, our results show that loss of Brca1 in murine BM causes hematopoietic defects similar to those seen in people with FA, which provides strong evidence that Brca1 is critical for normal hematopoiesis and that Brca1 is a bona fide FA-like gene. PMID- 26644451 TI - Alemtuzumab levels impact acute GVHD, mixed chimerism, and lymphocyte recovery following alemtuzumab, fludarabine, and melphalan RIC HCT. AB - Reduced intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (HCT) with alemtuzumab, fludarabine, and melphalan is an effective approach for patients with nonmalignant disorders. Mixed chimerism and graft-versus-host-disease (GVHD) remain limitations on success. We hypothesized that higher levels of alemtuzumab at day 0 would result in a low risk of acute GVHD, a higher risk of mixed chimerism, and delayed early lymphocyte recovery and that alemtuzumab level thresholds for increased risks of these outcomes would be definable. We collected data from 105 patients to examine the influence of peritransplant alemtuzumab levels on acute GVHD, mixed chimerism, and lymphocyte recovery. The cumulative incidences of initial grades I-IV, II-IV, and III-IV acute GVHD in patients with alemtuzumab levels <=0.15 vs >=0.16 MUg/mL were 68% vs 18% (P < .0001), 47% vs 13% (P = .0002), and 32% vs 8%, respectively (P = .005). The cumulative incidence of mixed chimerism in patients with an alemtuzumab level <=0.15 MUg/mL was 21%, vs 42% with levels of 0.16 to 4.35 MUg/mL, and 100% with levels >4.35 MUg/mL (P = .003). Patients with alemtuzumab levels <=0.15 or 0.16 to 0.56 MUg/mL had higher lymphocyte counts at day +30 and higher T-cell counts at day +100 compared with patients with levels >=0.57 MUg/mL (all P < .05). We conclude that peritransplant alemtuzumab levels impact acute GVHD, mixed chimerism, and lymphocyte recovery following RIC HCT with alemtuzumab, fludarabine, and melphalan. Precision dosing trials are warranted. We recommend a day 0 therapeutic range of 0.2 to 0.4 MUg/mL. PMID- 26644452 TI - Complement activation in antiphospholipid syndrome and its inhibition to prevent rethrombosis after arterial surgery. PMID- 26644453 TI - Sympathetic stimulation facilitates thrombopoiesis by promoting megakaryocyte adhesion, migration, and proplatelet formation. AB - The effect of sympathetic stimulation on thrombopoiesis is not well understood. Here, we demonstrate that both continual noise and exhaustive exercise elevate peripheral platelet levels in normal and splenectomized mice, but not in dopamine beta-hydroxylase-deficient (Dbh(-/-)) mice that lack norepinephrine (NE) and epinephrine (EPI). Further investigation demonstrates that sympathetic stimulation via NE or EPI injection markedly promotes platelet recovery in mice with thrombocytopenia induced by 6.0 Gy of total-body irradiation and in mice that received bone marrow transplants after 10.0 Gy of lethal irradiation. Unfavorably, sympathetic stress-stimulated thrombopoiesis may also contribute to the pathogenesis of atherosclerosis by increasing both the amount and activity of platelets in apolipoprotein E-deficient (ApoE(-/-)) mice. In vitro studies reveal that both NE and EPI promote megakaryocyte adhesion, migration, and proplatelet formation (PPF) in addition to the expansion of CD34(+) cells, thereby facilitating platelet production. It is found that alpha2-adrenoceptor-mediated extracellular signal-regulated kinase 1/2 (ERK1/2) activation is involved in NE- and EPI-induced megakaryocyte adhesion and migration, and PPF is regulated by ERK1/2 activation-mediated RhoA GTPase signaling. Our data deeply characterize the role of sympathetic stimulation in the regulation of thrombopoiesis and reevaluate its physiopathological implications. PMID- 26644454 TI - Markers of oxidative damage of nucleic acids and proteins among workers exposed to TiO2 (nano) particles. AB - OBJECTIVE: The use of nanotechnology is growing enormously and occupational physicians have an increasing interest in evaluating potential hazards and finding biomarkers of effect in workers exposed to nanoparticles. METHODS: A study was carried out with 36 workers exposed to (nano)TiO2 pigment and 45 controls. Condensate (EBC) titanium and markers of oxidation of nucleic acids (including 8-hydroxy-2-deoxyguanosine (8-OHdG), 8-hydroxyguanosine (8-OHG), 5 hydroxymethyl uracil (5-OHMeU)) and proteins (such as o-tyrosine (o-Tyr), 3 chlorotyrosine (3-ClTyr) and 3-nitrotyrosine (3-NOTyr)) were analysed from samples of their exhaled breath. RESULTS: In the production workshops, the median total mass 2012 and 2013 TiO2 concentrations were 0.65 and 0.40 mg/m(3), respectively. The median numbers of concentrations measured by the scanning mobility particle sizer (SMPS) and aerodynamic particle sizer (APS) were 1.98 * 10(4) and 2.32 * 10(4) particles/cm(3), respectively; and about 80% of those particles were smaller than 100 nm in diameter. In the research workspace, lower aerosol concentrations (0.16 mg/m(3) and 1.32 * 10(4) particles/cm(3)) were found. Titanium in the EBC was significantly higher in production workers (p<0.001) than in research workers and unexposed controls. Accordingly, most EBC oxidative stress markers, including in the preshift samples, were higher in production workers than in the two other groups. Multiple regression analysis confirmed an association between the production of TiO2 and the levels of studied biomarkers. CONCLUSIONS: The concentration of titanium in EBC may serve as a direct exposure marker in workers producing TiO2 pigment; the markers of oxidative stress reflect the local biological effect of (nano)TiO2 in the respiratory tract of the exposed workers. PMID- 26644455 TI - Is physically arduous work associated with limitations after retirement? Findings from the GAZEL cohort. AB - INTRODUCTION: In the context of delayed retirement age, we aimed to study the association between a score for global evaluation of perceived physical strain (PPS) at work and limitations after retirement in the GAZEL cohort. METHODS: At baseline in 1989 and every year since then, the PPS question, 'Do you find that your work is physically strenuous?' was used as a proxy measure of general occupational physical exertion or load; it was coded into a score, and divided into four categories for men and three for women. The self-report question about limitations was asked in 1989 and 2012 (difficulties performing some daily life activities). Among men and women without limitations at baseline, relationships were studied between reported limitations in 2012 and a cumulative score based on PPS since 1989, allowing examination of the dose-effect relationship, and adjusted for age and perceived state of health at baseline. RESULTS: From 1989 to 2012, 9326 participants without limitations at baseline were followed and filled out the 2012 questionnaire. In 2012, 12.1% of men (n=845) and 12.9% of women (n=302) reported limitations. Limitations in 2012 were associated with very high categorical PPS in men (OR 1.7 (1.4 to 2.2)) and high/very high categorical PPS in women (OR 1.6 (1.2 to 2.2)), with a significant trend. CONCLUSIONS: A positive association was found between preretirement physically arduous working conditions and limitations in daily activities after retirement. Findings offer a new insight for global evaluation of physical exposures during working life. PMID- 26644456 TI - Short-term metal particulate exposures decrease cardiac acceleration and deceleration capacities in welders: a repeated-measures panel study. AB - OBJECTIVE: Acceleration (AC) and deceleration (DC) capacities measure heart rate variability during speeding up and slowing down of the heart, respectively. We investigated associations between AC and DC with occupational short-term metal PM2.5 exposures. METHODS: A panel of 48 male welders had particulate matter less than 2.5 microns in diameter (PM2.5) exposure measurements over 4-6 h repeated over 5 sampling periods between January 2010 and June 2012. We simultaneously obtained continuous recordings of digital ECG using a Holter monitor. We analysed ECG data in the time domain to obtain hourly AC and DC. Linear mixed models were used to assess the associations between hourly PM2.5 exposure and each of hourly AC and DC, controlling for age, smoking status, active smoking, exposure to secondhand smoke, season/time of day when ECG reading was obtained and baseline AC or DC. We also ran lagged exposure response models for each successive hour up to 3 h after onset of exposure. RESULTS: Mean (SD) shift PM2.5 exposure during welding was 0.47 (0.43) mg/m(3). Significant exposure-response associations were found for AC and DC with increased PM2.5 exposure. In our adjusted models without any lag between exposure and response, a 1 mg/m(3) increase of PM2.5 was associated with a decrease of 1.46 (95% CI 1.00 to 1.92) ms in AC and a decrease of 1.00 (95% CI 0.53 to 1.46) ms in DC. The effect of PM2.5 on AC and DC was maximal immediately postexposure and lasted 1 h following exposure. CONCLUSIONS: There are short-term effects of metal particulates on AC and DC. PMID- 26644457 TI - Occupational exposure to pesticides and prostate cancer: a systematic review and meta-analysis. AB - Epidemiological studies on exposure to pesticides and risk of prostate cancer (PC) provide inconsistent results. We aimed to explore various potential sources of heterogeneity not previously assessed and to derive updated risk estimates from homogenous studies. We searched PubMed, Web of Science and Scopus databases for case-control and cohort studies published from 1985 to April 2014. We assessed the quality of the articles using the Newcastle-Ottawa Scale. Pooled estimates were calculated using random-effects models. Heterogeneity was explored using subset analyses and metaregression. Fifty-two studies were included in the review and 25 in the meta-analysis. No association was found between low exposure to pesticides and PC, but association was significant for high exposure, pooled OR 1.33 (1.02 to 1.63), I(2)=44.8%, p=0.024. Heterogeneity was explained by a number of variables including method used to assess exposure. Pooled OR was weak and non-significant for studies measuring serum pesticide level, 1.12 (0.74 to 1.50), I(2)=0.00%, p=0.966. For studies applying self-reporting of exposure, pooled estimate was 1.34 (0.91 to 1.77), I(2)=0.00%, p=0.493, while a high significant association was detected for grouped exposure assessment, 2.24 (1.36 to 3.11), I(2)=0.00%, p=0.955. In spite of a weak significant association detected when pooling ORs for high occupational exposure to pesticides, the magnitude of the association was related to the method of exposure assessment used by the original studies. A family history-pesticide exposure interaction was also observed for a number of pesticides. PMID- 26644458 TI - A cost-benefit analysis of peer coaching for overhead lift use in the long-term care sector in Canada. AB - OBJECTIVES: To evaluate whether a peer-coaching programme for patient lift use in British Columbia, Canada, was effective and cost-beneficial. METHODS: We used monthly panel data from 15 long-term care facilities from 2004 to 2011 to estimate the number of patient-handling injuries averted by the peer-coaching programme using a generalised estimating equation model. Facilities that had not yet introduced the programme served as concurrent controls. Accepted lost-time claim counts related to patient handling were the outcome of interest with a denominator of full-time equivalents of nursing staff. A cost-benefit approach was used to estimate the net monetary gains at the system level. RESULTS: The coaching programme was found to be associated with a reduction in the injury rate of 34% during the programme and 56% after the programme concluded with an estimated 62 lost-time injury claims averted. 2 other factors were associated with changes in injury rates: larger facilities had a lower injury rate, and the more care hours per bed the lower the injury rate. We calculated monetary benefits to the system of $748 431 and costs of $894 000 (both in 2006 Canadian dollars) with a benefit-to-cost ratio of 0.84. The benefit-to-cost ratio was 0.05 in the worst case scenario and 2.31 in the best case scenario. The largest cost item was peer coaches' time. A simulation of the programme continuing for 5 years with the same coaching intensity would result in a benefit-to-cost ratio of 0.63. CONCLUSIONS: A peer-coaching programme to increase effective use of overhead lifts prevented additional patient-handling injuries but added modest incremental cost to the system. PMID- 26644459 TI - The TOR Complex: An Emergency Switch for Root Behavior. AB - Target of rapamycin (TOR) kinase is known to be a controller of cell growth and aging, which determines the fine balance between growth rates and energy availabilities. It has been reported that many eukaryotes express TOR genes. In plants, TOR signaling modifies growth and development in response to a plant's energy status. An example of TOR action can be found in the root apices, which are active organs that explore the soil environment via vigorous growth and numerous tropisms. The exploratory nature of root apices requires a large energy supply for signaling, as well as for cell division and elongation. In the case of negative tropisms, roots must respond quickly to avoid patches of unfavorable soil conditions, again by consuming precious energy reserves. Here we review the current findings on TOR signaling in plants and animals, and propose possible roles for this important complex in driving plant root negative tropisms, particularly during light escape and salt avoidance behavior. PMID- 26644460 TI - The Vigna Genome Server, 'VigGS': A Genomic Knowledge Base of the Genus Vigna Based on High-Quality, Annotated Genome Sequence of the Azuki Bean, Vigna angularis (Willd.) Ohwi & Ohashi. AB - The genus Vigna includes legume crops such as cowpea, mungbean and azuki bean, as well as >100 wild species. A number of the wild species are highly tolerant to severe environmental conditions including high-salinity, acid or alkaline soil; drought; flooding; and pests and diseases. These features of the genus Vigna make it a good target for investigation of genetic diversity in adaptation to stressful environments; however, a lack of genomic information has hindered such research in this genus. Here, we present a genome database of the genus Vigna, Vigna Genome Server ('VigGS', http://viggs.dna.affrc.go.jp), based on the recently sequenced azuki bean genome, which incorporates annotated exon-intron structures, along with evidence for transcripts and proteins, visualized in GBrowse. VigGS also facilitates user construction of multiple alignments between azuki bean genes and those of six related dicot species. In addition, the database displays sequence polymorphisms between azuki bean and its wild relatives and enables users to design primer sequences targeting any variant site. VigGS offers a simple keyword search in addition to sequence similarity searches using BLAST and BLAT. To incorporate up to date genomic information, VigGS automatically receives newly deposited mRNA sequences of pre-set species from the public database once a week. Users can refer to not only gene structures mapped on the azuki bean genome on GBrowse but also relevant literature of the genes. VigGS will contribute to genomic research into plant biotic and abiotic stresses and to the future development of new stress-tolerant crops. PMID- 26644461 TI - ALCOdb: Gene Coexpression Database for Microalgae. AB - In the era of energy and food shortage, microalgae have gained much attention as promising sources of biofuels and food ingredients. However, only a small fraction of microalgal genes have been functionally characterized. Here, we have developed the Algae Gene Coexpression database (ALCOdb; http://alcodb.jp), which provides gene coexpression information to survey gene modules for a function of interest. ALCOdb currently supports two model algae: the green alga Chlamydomonas reinhardtii and the red alga Cyanidioschyzon merolae. Users can retrieve coexpression information for genes of interest through three unique data pages: (i) Coexpressed Gene List; (ii) Gene Information; and (iii) Coexpressed Gene Network. In addition to the basal coexpression information, ALCOdb also provides several advanced functionalities such as an expression profile viewer and a differentially expressed gene search tool. Using these user interfaces, we demonstrated that our gene coexpression data have the potential to detect functionally related genes and are useful in extrapolating the biological roles of uncharacterized genes. ALCOdb will facilitate molecular and biochemical studies of microalgal biological phenomena, such as lipid metabolism and organelle development, and promote the evolutionary understanding of plant cellular systems. PMID- 26644462 TI - The Naming of Names: Guidelines for Gene Nomenclature in Marchantia. AB - While Marchantia polymorpha has been utilized as a model system to investigate fundamental biological questions for over almost two centuries, there is renewed interest in M. polymorpha as a model genetic organism in the genomics era. Here we outline community guidelines for M. polymorpha gene and transgene nomenclature, and we anticipate that these guidelines will promote consistency and reduce both redundancy and confusion in the scientific literature. PMID- 26644463 TI - Photoprotection vs. Photoinhibition of Photosystem II in Transplastomic Lettuce (Lactuca sativa) Dominantly Accumulating Astaxanthin. AB - Transplastomic (chloroplast genome-modified; CGM) lettuce that dominantly accumulates astaxanthin grows similarly to a non-transgenic control with almost no accumulation of naturally occurring photosynthetic carotenoids. In this study, we evaluated the activity and assembly of PSII in CGM lettuce. The maximum quantum yield of PSII in CGM lettuce was <0.6; however, the quantum yield of PSII was comparable with that in control leaves under higher light intensity. CGM lettuce showed a lower ability to induce non-photochemical quenching (NPQ) than the control under various light intensities. The fraction of slowly recovering NPQ in CGM lettuce, which is considered to be photoinhibitory quenching (qI), was less than half that of the control. In fact, 1O2 generation was lower in CGM than in control leaves under high light intensity. CGM lettuce contained less PSII, accumulated mostly as a monomer in thylakoid membranes. The PSII monomers purified from the CGM thylakoids bound echinenone and canthaxanthin in addition to beta-carotene, suggesting that a shortage of beta-carotene and/or the binding of carbonyl carotenoids would interfere with the photophysical function as well as normal assembly of PSII. In contrast, high accumulation of astaxanthin and other carbonyl carotenoids was found within the thylakoid membranes. This finding would be associated with the suppression of photo-oxidative stress in the thylakoid membranes. Our observation suggests the importance of a specific balance between photoprotection and photoinhibition that can support normal photosynthesis in CGM lettuce producing astaxanthin. PMID- 26644464 TI - Binding of the Covalent Flavin Assembly Factor to the Flavoprotein Subunit of Complex II. AB - Escherichia coli harbors two highly conserved homologs of the essential mitochondrial respiratory complex II (succinate:ubiquinone oxidoreductase). Aerobically the bacterium synthesizes succinate:quinone reductase as part of its respiratory chain, whereas under microaerophilic conditions, the quinol:fumarate reductase can be utilized. All complex II enzymes harbor a covalently bound FAD co-factor that is essential for their ability to oxidize succinate. In eukaryotes and many bacteria, assembly of the covalent flavin linkage is facilitated by a small protein assembly factor, termed SdhE in E. coli. How SdhE assists with formation of the covalent flavin bond and how it binds the flavoprotein subunit of complex II remain unknown. Using photo-cross-linking, we report the interaction site between the flavoprotein of complex II and the SdhE assembly factor. These data indicate that SdhE binds to the flavoprotein between two independently folded domains and that this binding mode likely influences the interdomain orientation. In so doing, SdhE likely orients amino acid residues near the dicarboxylate and FAD binding site, which facilitates formation of the covalent flavin linkage. These studies identify how the conserved SdhE assembly factor and its homologs participate in complex II maturation. PMID- 26644465 TI - Evidence for Conservation of the Calcitonin Superfamily and Activity-regulating Mechanisms in the Basal Chordate Branchiostoma floridae: INSIGHTS INTO THE MOLECULAR AND FUNCTIONAL EVOLUTION IN CHORDATES. AB - The calcitonin (CT)/CT gene-related peptide (CGRP) family is conserved in vertebrates. The activities of this peptide family are regulated by a combination of two receptors, namely the calcitonin receptor (CTR) and the CTR-like receptor (CLR), and three receptor activity-modifying proteins (RAMPs). Furthermore, RAMPs act as escort proteins by translocating CLR to the cell membrane. Recently, CT/CGRP family peptides have been identified or inferred in several invertebrates. However, the molecular characteristics and relevant functions of the CTR/CLR and RAMPs in invertebrates remain unclear. In this study, we identified three CT/CGRP family peptides (Bf-CTFPs), one CTR/CLR-like receptor (Bf-CTFP-R), and three RAMP-like proteins (Bf-RAMP-LPs) in the basal chordate amphioxus (Branchiostoma floridae). The Bf-CTFPs were shown to possess an N terminal circular region typical of the CT/CGRP family and a C-terminal Pro-NH2. The Bf-CTFP genes were expressed in the central nervous system and in endocrine cells of the midgut, indicating that Bf-CTFPs serve as brain and/or gut peptides. Cell surface expression of the Bf-CTFP-R was enhanced by co-expression with each Bf-RAMP-LP. Furthermore, Bf-CTFPs activated Bf-CTFP-R.Bf-RAMP-LP complexes, resulting in cAMP accumulation. These results confirmed that Bf-RAMP-LPs, like vertebrate RAMPs, are prerequisites for the function and translocation of the Bf CTFP-R. The relative potencies of the three peptides at each receptor were similar. Bf-CTFP2 was a potent ligand at all receptors in cAMP assays. Bf-RAMP-LP effects on ligand potency order were distinct to vertebrate CGRP/adrenomedullin/amylin receptors. To the best of our knowledge, this is the first molecular and functional characterization of an authentic invertebrate CT/CGRP family receptor and RAMPs. PMID- 26644466 TI - Antigenic Determinants of the Bilobal Cockroach Allergen Bla g 2. AB - Bla g 2 is a major indoor cockroach allergen associated with the development of asthma. Antigenic determinants on Bla g 2 were analyzed by mutagenesis based on the structure of the allergen alone and in complex with monoclonal antibodies that interfere with IgE antibody binding. The structural analysis revealed mechanisms of allergen-antibody recognition through cation-pi interactions. Single and multiple Bla g 2 mutants were expressed in Pichia pastoris and purified. The triple mutant K132A/K251A/F162Y showed an ~100-fold reduced capacity to bind IgE, while preserving the native molecular fold, as proven by x ray crystallography. This mutant was still able to induce mast cell release. T cell responses were assessed by analyzing Th1/Th2 cytokine production and the CD4(+) T-cell phenotype in peripheral blood mononuclear cell cultures. Although T cell activating capacity was similar for the KKF mutant and Bla g 2 based on CD25 expression, the KKF mutant was a weaker inducer of the Th2 cytokine IL-13. Furthermore, this mutant induced IL-10 from a non-T-cell source at higher levels that those induced by Bla g 2. Our findings demonstrate that a rational design of site-directed mutagenesis was effective in producing a mutant with only 3 amino acid substitutions that maintained the same fold as wild type Bla g 2. These residues, which were involved in IgE antibody binding, endowed Bla g 2 with a T cell modulatory capacity. The antigenic analysis of Bla g 2 will be useful for the subsequent development of recombinant allergen vaccines. PMID- 26644467 TI - alpha-Synuclein Amyloid Fibrils with Two Entwined, Asymmetrically Associated Protofibrils. AB - Parkinson disease and other progressive neurodegenerative conditions are characterized by the intracerebral presence of Lewy bodies, containing amyloid fibrils of alpha-synuclein. We used cryo-electron microscopy and scanning transmission electron microscopy (STEM) to study in vitro-assembled fibrils. These fibrils are highly polymorphic. Focusing on twisting fibrils with an inter crossover spacing of 77 nm, our reconstructions showed them to consist of paired protofibrils. STEM mass per length data gave one subunit per 0.47 nm axial rise per protofibril, consistent with a superpleated beta-structure. The STEM images show two thread-like densities running along each of these fibrils, which we interpret as ladders of metal ions. These threads confirmed the two-protofibril architecture of the 77-nm twisting fibrils and allowed us to identify this morphotype in STEM micrographs. Some other, but not all, fibril morphotypes also exhibit dense threads, implying that they also present a putative metal binding site. We propose a molecular model for the protofibril and suggest that polymorphic variant fibrils have different numbers of protofibrils that are associated differently. PMID- 26644468 TI - Selenoprotein Expression in Macrophages Is Critical for Optimal Clearance of Parasitic Helminth Nippostrongylus brasiliensis. AB - The plasticity of macrophages is evident in helminthic parasite infections, providing protection from inflammation. Previously we demonstrated that the micronutrient selenium induces a phenotypic switch in macrophage activation from a classically activated (pro-inflammatory; M1/CAM) toward an alternatively activated (anti-inflammatory; M2/AAM) phenotype, where cyclooxygenase (COX) dependent cyclopentenone prostaglandin J2 (15d-PGJ2) plays a key role. Here, we hypothesize that dietary selenium modulates macrophage polarization toward an AAM phenotype to assist in the increasing clearance of adult Nippostrongylus brasiliensis, a gastrointestinal nematode parasite. Mice on a selenium-adequate (0.08 ppm) diet significantly augmented intestinal AAM presence while decreasing adult worms and fecal egg production when compared with infection of mice on selenium-deficient (<0.01 ppm) diet. Further increase in dietary selenium to supraphysiological levels (0.4 ppm) had very little or no impact on worm expulsion. Normal adult worm clearance and enhanced AAM marker expression were observed in the selenium-supplemented Trsp(fl/fl)Cre(WT) mice that express selenoproteins driven by tRNA(Sec) (Trsp), whereas N. brasiliensis-infected Trsp(fl/fl)Cre(LysM) selenium-supplemented mice showed a decreased clearance, with lowered intestinal expression of several AAM markers. Inhibition of the COX pathway with indomethacin resulted in delayed worm expulsion in selenium-adequate mice. This was rescued with 15d-PGJ2, which partially recapitulated the effect of selenium supplementation on fecal egg output in addition to increasing markers of AAMs in the small intestine. Antagonism of PPARgamma blocked the effect of selenium. These results suggest that optimal expression of selenoproteins and selenium-dependent production of COX-derived endogenous prostanoids, such as Delta(12)-PGJ2 and 15d-PGJ2, may regulate AAM activation to enhance anti helminthic parasite responses. PMID- 26644469 TI - Information Transfer in Gonadotropin-releasing Hormone (GnRH) Signaling: EXTRACELLULAR SIGNAL-REGULATED KINASE (ERK)-MEDIATED FEEDBACK LOOPS CONTROL HORMONE SENSING. AB - Cell signaling pathways are noisy communication channels, and statistical measures derived from information theory can be used to quantify the information they transfer. Here we use single cell signaling measures to calculate mutual information as a measure of information transfer via gonadotropin-releasing hormone (GnRH) receptors (GnRHR) to extracellular signal-regulated kinase (ERK) or nuclear factor of activated T-cells (NFAT). This revealed mutual information values <1 bit, implying that individual GnRH-responsive cells cannot unambiguously differentiate even two equally probable input concentrations. Addressing possible mechanisms for mitigation of information loss, we focused on the ERK pathway and developed a stochastic activation model incorporating negative feedback and constitutive activity. Model simulations revealed interplay between fast (min) and slow (min-h) negative feedback loops with maximal information transfer at intermediate feedback levels. Consistent with this, experiments revealed that reducing negative feedback (by expressing catalytically inactive ERK2) and increasing negative feedback (by Egr1-driven expression of dual-specificity phosphatase 5 (DUSP5)) both reduced information transfer from GnRHR to ERK. It was also reduced by blocking protein synthesis (to prevent GnRH from increasing DUSP expression) but did not differ for different GnRHRs that do or do not undergo rapid homologous desensitization. Thus, the first statistical measures of information transfer via these receptors reveals that individual cells are unreliable sensors of GnRH concentration and that this reliability is maximal at intermediate levels of ERK-mediated negative feedback but is not influenced by receptor desensitization. PMID- 26644470 TI - Comparative Circadian Metabolomics Reveal Differential Effects of Nutritional Challenge in the Serum and Liver. AB - Diagnosis and therapeutic interventions in pathological conditions rely upon clinical monitoring of key metabolites in the serum. Recent studies show that a wide range of metabolic pathways are controlled by circadian rhythms whose oscillation is affected by nutritional challenges, underscoring the importance of assessing a temporal window for clinical testing and thereby questioning the accuracy of the reading of critical pathological markers in circulation. We have been interested in studying the communication between peripheral tissues under metabolic homeostasis perturbation. Here we present a comparative circadian metabolomic analysis on serum and liver in mice under high fat diet. Our data reveal that the nutritional challenge induces a loss of serum metabolite rhythmicity compared with liver, indicating a circadian misalignment between the tissues analyzed. Importantly, our results show that the levels of serum metabolites do not reflect the circadian liver metabolic signature or the effect of nutritional challenge. This notion reveals the possibility that misleading reads of metabolites in circulation may result in misdiagnosis and improper treatments. Our findings also demonstrate a tissue-specific and time-dependent disruption of metabolic homeostasis in response to altered nutrition. PMID- 26644471 TI - Global Kinetic Analysis of Mammalian E3 Reveals pH-dependent NAD+/NADH Regulation, Physiological Kinetic Reversibility, and Catalytic Optimum. AB - Mammalian E3 is an essential mitochondrial enzyme responsible for catalyzing the terminal reaction in the oxidative catabolism of several metabolites. E3 is a key regulator of metabolic fuel selection as a component of the pyruvate dehydrogenase complex (PDHc). E3 regulates PDHc activity by altering the affinity of pyruvate dehydrogenase kinase, an inhibitor of the enzyme complex, through changes in reduction and acetylation state of lipoamide moieties set by the NAD(+)/NADH ratio. Thus, an accurate kinetic model of E3 is needed to predict overall mammalian PDHc activity. Here, we have combined numerous literature data sets and new equilibrium spectroscopic experiments with a multitude of independently collected forward and reverse steady-state kinetic assays using pig heart E3. The latter kinetic assays demonstrate a pH-dependent transition of NAD(+) activation to inhibition, shown here, to our knowledge, for the first time in a single consistent data set. Experimental data were analyzed to yield a thermodynamically constrained four-redox-state model of E3 that simulates pH dependent activation/inhibition and active site redox states for various conditions. The developed model was used to determine substrate/product conditions that give maximal E3 rates and show that, due to non-Michaelis-Menten behavior, the maximal flux is different compared with the classically defined kcat. PMID- 26644472 TI - Differential alpha4(+)/(-)beta2 Agonist-binding Site Contributions to alpha4beta2 Nicotinic Acetylcholine Receptor Function within and between Isoforms. AB - Two alpha4beta2 nicotinic acetylcholine receptor (alpha4beta2-nAChR) isoforms exist with (alpha4)2(beta2)3 and (alpha4)3(beta2)2 subunit stoichiometries and high versus low agonist sensitivities (HS and LS), respectively. Both isoforms contain a pair of alpha4(+)/(-)beta2 agonist-binding sites. The LS isoform also contains a unique alpha4(+)/(-)alpha4 site with lower agonist affinity than the alpha4(+)/(-)beta2 sites. However, the relative roles of the conserved alpha4(+)/(-)beta2 agonist-binding sites in and between the isoforms have not been studied. We used a fully linked subunit concatemeric nAChR approach to express pure populations of HS or LS isoform alpha4beta2*-nAChR. This approach also allowed us to mutate individual subunit interfaces, or combinations thereof, on each isoform background. We used this approach to systematically mutate a triplet of beta2 subunit (-)-face E-loop residues to their non-conserved alpha4 subunit counterparts or vice versa (beta2HQT and alpha4VFL, respectively). Mutant nAChR constructs (and unmodified controls) were expressed in Xenopus oocytes. Acetylcholine concentration-response curves and maximum function were measured using two-electrode voltage clamp electrophysiology. Surface expression was measured with (125)I-mAb 295 binding and was used to define function/nAChR. If the alpha4(+)/(-)beta2 sites contribute equally to function, making identical beta2HQT substitutions at either site should produce similar functional outcomes. Instead, highly differential outcomes within the HS isoform, and between the two isoforms, were observed. In contrast, alpha4VFL mutation effects were very similar in all positions of both isoforms. Our results indicate that the identity of subunits neighboring the otherwise equivalent alpha4(+)/(-)beta2 agonist sites modifies their contributions to nAChR activation and that E-loop residues are an important contributor to this neighbor effect. PMID- 26644473 TI - Characterization of a Novel Intestinal Glycerol-3-phosphate Acyltransferase Pathway and Its Role in Lipid Homeostasis. AB - Dietary triglycerides (TG) are absorbed by the enterocytes of the small intestine after luminal hydrolysis into monacylglycerol and fatty acids. Before secretion on chylomicrons, these lipids are reesterified into TG, primarily through the monoacylglycerol pathway. However, targeted deletion of the primary murine monoacylglycerol acyltransferase does not quantitatively affect lipid absorption, suggesting the existence of alternative pathways. Therefore, we investigated the role of the glycerol 3-phosphate pathway in dietary lipid absorption. The expression of glycerol-3-phosphate acyltransferase (GPAT3) was examined throughout the small intestine. To evaluate the role for GPAT3 in lipid absorption, mice harboring a disrupted GPAT3 gene (Gpat3(-/-)) were subjected to an oral lipid challenge and fed a Western-type diet to characterize the role in lipid and cholesterol homeostasis. Additional mechanistic studies were performed in primary enterocytes. GPAT3 was abundantly expressed in the apical surface of enterocytes in the small intestine. After an oral lipid bolus, Gpat3(-/-) mice exhibited attenuated plasma TG excursion and accumulated lipid in the enterocytes. Electron microscopy studies revealed a lack of lipids in the lamina propria and intercellular space in Gpat3(-/-) mice. Gpat3(-/-) enterocytes displayed a compensatory increase in the synthesis of phospholipid and cholesteryl ester. When fed a Western-type diet, hepatic TG and cholesteryl ester accumulation was significantly higher in Gpat3(-/-) mice compared with the wild type mice accompanied by elevated levels of alanine aminotransferase, a marker of liver injury. Dysregulation of bile acid metabolism was also evident in Gpat3 null mice. These studies identify GPAT3 as a novel enzyme involved in intestinal lipid metabolism. PMID- 26644474 TI - Mitochondrial Calcium Uptake Modulates Synaptic Vesicle Endocytosis in Central Nerve Terminals. AB - Presynaptic calcium influx triggers synaptic vesicle (SV) exocytosis and modulates subsequent SV endocytosis. A number of calcium clearance mechanisms are present in central nerve terminals that regulate intracellular free calcium levels both during and after stimulation. During action potential stimulation, mitochondria rapidly accumulate presynaptic calcium via the mitochondrial calcium uniporter (MCU). The role of mitochondrial calcium uptake in modulating SV recycling has been debated extensively, but a definitive conclusion has not been achieved. To directly address this question, we manipulated the expression of the MCU channel subunit in primary cultures of neurons expressing a genetically encoded reporter of SV turnover. Knockdown of MCU resulted in ablation of activity-dependent mitochondrial calcium uptake but had no effect on the rate or extent of SV exocytosis. In contrast, the rate of SV endocytosis was increased in the absence of mitochondrial calcium uptake and slowed when MCU was overexpressed. MCU knockdown did not perturb activity-dependent increases in presynaptic free calcium, suggesting that SV endocytosis may be controlled by calcium accumulation and efflux from mitochondria in their immediate vicinity. PMID- 26644475 TI - Antioxidant Defenses of Francisella tularensis Modulate Macrophage Function and Production of Proinflammatory Cytokines. AB - Francisella tularensis, the causative agent of a fatal human disease known as tularemia, has been used in the bioweapon programs of several countries in the past, and now it is considered a potential bioterror agent. Extreme infectivity and virulence of F. tularensis is due to its ability to evade immune detection and to suppress the host's innate immune responses. However, Francisella-encoded factors and mechanisms responsible for causing immune suppression are not completely understood. Macrophages and neutrophils generate reactive oxygen species (ROS)/reactive nitrogen species as a defense mechanism for the clearance of phagocytosed microorganisms. ROS serve a dual role; at high concentrations they act as microbicidal effector molecules that destroy intracellular pathogens, and at low concentrations they serve as secondary signaling messengers that regulate the expression of various inflammatory mediators. We hypothesized that the antioxidant defenses of F. tularensis maintain redox homeostasis in infected macrophages to prevent activation of redox-sensitive signaling components that ultimately result in suppression of pro-inflammatory cytokine production and macrophage microbicidal activity. We demonstrate that antioxidant enzymes of F. tularensis prevent the activation of redox-sensitive MAPK signaling components, NF-kappaB signaling, and the production of pro-inflammatory cytokines by inhibiting the accumulation of ROS in infected macrophages. We also report that F. tularensis inhibits ROS-dependent autophagy to promote its intramacrophage survival. Collectively, this study reveals novel pathogenic mechanisms adopted by F. tularensis to modulate macrophage innate immune functions to create an environment permissive for its intracellular survival and growth. PMID- 26644476 TI - Protein 4.1G Regulates Cell Adhesion, Spreading, and Migration of Mouse Embryonic Fibroblasts through the beta1 Integrin Pathway. AB - Protein 4.1G is a membrane skeletal protein that can serve as an adapter between transmembrane proteins and the underlying membrane skeleton. The function of 4.1G remains largely unexplored. Here, using 4.1G knockout mouse embryonic fibroblasts (MEFs) as a model system, we explored the function of 4.1G in motile cells. We show that the adhesion, spreading, and migration of 4.1G(-/-) MEF cells are impaired significantly. We further show that, although the total cellular expression of beta1 integrin is unchanged, the surface expression of beta1 integrin and its active form are decreased significantly in 4.1G(-/-) MEF cells. Moreover, the phosphorylation of focal adhesion kinase, a downstream component of the integrin-mediated signal transduction pathway, is suppressed in 4.1G(-/-) MEF cells. Co-immunoprecipitation experiments and in vitro binding assays showed that 4.1G binds directly to beta1 integrin via its membrane-binding domain. These findings identified a novel role of 4.1G in cell adhesion, spreading, and migration in MEF cells by modulating the surface expression of beta1 integrin and subsequent downstream signal transduction. PMID- 26644479 TI - Corrigendum. PMID- 26644477 TI - Agonistic Human Antibodies Binding to Lecithin-Cholesterol Acyltransferase Modulate High Density Lipoprotein Metabolism. AB - Drug discovery opportunities where loss-of-function alleles of a target gene link to a disease-relevant phenotype often require an agonism approach to up-regulate or re-establish the activity of the target gene. Antibody therapy is increasingly recognized as a favored drug modality due to multiple desirable pharmacological properties. However, agonistic antibodies that enhance the activities of the target enzymes are rarely developed because the discovery of agonistic antibodies remains elusive. Here we report an innovative scheme of discovery and characterization of human antibodies capable of binding to and agonizing a circulating enzyme lecithin cholesterol acyltransferase (LCAT). Utilizing a modified human LCAT protein with enhanced enzymatic activity as an immunogen, we generated fully human monoclonal antibodies using the XenoMouse(TM) platform. One of the resultant agonistic antibodies, 27C3, binds to and substantially enhances the activity of LCAT from humans and cynomolgus macaques. X-ray crystallographic analysis of the 2.45 A LCAT-27C3 complex shows that 27C3 binding does not induce notable structural changes in LCAT. A single administration of 27C3 to cynomolgus monkeys led to a rapid increase of plasma LCAT enzymatic activity and a 35% increase of the high density lipoprotein cholesterol that was observed up to 32 days after 27C3 administration. Thus, this novel scheme of immunization in conjunction with high throughput screening may represent an effective strategy for discovering agonistic antibodies against other enzyme targets. 27C3 and other agonistic human anti-human LCAT monoclonal antibodies described herein hold potential for therapeutic development for the treatment of dyslipidemia and cardiovascular disease. PMID- 26644482 TI - Brokering Compromise to Achieve Consensus. PMID- 26644483 TI - Renal Calculi: An Unusual Presentation of T-Cell Acute Lymphoblastic Leukemia. AB - Spontaneous tumor lysis syndrome is a rare initial presentation of hematologic malignancy in children that typically presents with complications of electrolyte derangement, specifically hyperkalemia, hyperphosphatemia, and hyperuricemia. We report a case of a 5-year-old boy who presented to the emergency department with gross hematuria, abdominal pain, and vomiting and was ultimately diagnosed with uric acid nephrolithiasis and acute renal failure secondary to spontaneous tumor lysis syndrome in the setting of T-cell acute lymphoblastic leukemia. Tumor lysis syndrome is considered an oncologic emergency, and in this case, the child required urgent treatment with potassium-binding agents, rasburicase, and hemodialysis. This case demonstrates that occult hematologic malignancy should be suspected in cases of nephrolithiasis and acute renal failure when found in conjunction with hyperuricemia despite a normal complete blood count at the time of presentation. PMID- 26644478 TI - Rendering the Intractable More Tractable: Tools from Caenorhabditis elegans Ripe for Import into Parasitic Nematodes. AB - Recent and rapid advances in genetic and molecular tools have brought spectacular tractability to Caenorhabditis elegans, a model that was initially prized because of its simple design and ease of imaging. C. elegans has long been a powerful model in biomedical research, and tools such as RNAi and the CRISPR/Cas9 system allow facile knockdown of genes and genome editing, respectively. These developments have created an additional opportunity to tackle one of the most debilitating burdens on global health and food security: parasitic nematodes. I review how development of nonparasitic nematodes as genetic models informs efforts to import tools into parasitic nematodes. Current tools in three commonly studied parasites (Strongyloides spp., Brugia malayi, and Ascaris suum) are described, as are tools from C. elegans that are ripe for adaptation and the benefits and barriers to doing so. These tools will enable dissection of a huge array of questions that have been all but completely impenetrable to date, allowing investigation into host-parasite and parasite-vector interactions, and the genetic basis of parasitism. PMID- 26644484 TI - Early-Onset Scoliosis: A Review of History, Current Treatment, and Future Directions. AB - Early-onset scoliosis (EOS) is defined as curvature of the spine in children >10 degrees with onset before age 10 years. Young children with EOS are at risk for impaired pulmonary function because of the high risk of progressive spinal deformity and thoracic constraints during a critical time of lung development. The treatment of EOS is very challenging because the population is inhomogeneous, often medically complex, and often needs multiple surgeries. In the past, early spinal fusion was performed in children with severe progressive EOS, which corrected scoliosis but limited spine and thoracic growth and resulted in poor pulmonary outcomes. The current goal in treatment of EOS is to maximize growth of the spine and thorax by controlling the spinal deformity, with the aim of promoting normal lung development and pulmonary function. Bracing and casting may improve on the natural history of progression of spinal deformity and are often used to delay surgical intervention or in some cases obviate surgery. Recent advances in surgical implants and techniques have led to the development of growth-friendly implants, which have replaced early spine fusion as the surgical treatment of choice. Treatment with growth-friendly implants usually requires multiple surgeries and is associated with frequent complications. However, growth friendly spine surgery has been shown to correct spinal deformity while allowing growth of the spine and subsequently lung growth. PMID- 26644487 TI - Improving Trainee Education During Family-Centered Rounds: A Resident's Perspective. PMID- 26644486 TI - Early Volume Expansion and Outcomes of Hemolytic Uremic Syndrome. AB - BACKGROUND: Hemolytic uremic syndrome associated with Shiga toxin-producing Escherichia coli (STEC-HUS) is a severe acute illness without specific treatment except supportive care; fluid management is concentrated on preventing fluid overload for patients, who are often oligoanuric. Hemoconcentration at onset is associated with more severe disease, but the benefits of volume expansion after hemolytic uremic syndrome (HUS) onset have not been explored. METHODS: All the children with STEC-HUS referred to our center between 2012 and 2014 received intravenous infusion targeted at inducing an early volume expansion (+10% of working weight) to restore circulating volume and reduce ischemic or hypoxic tissue damage. The short- and long-term outcomes of these patients were compared with those of 38 historical patients referred to our center during the years immediately before, when fluid intake was routinely restricted. RESULTS: Patients undergoing fluid infusion soon after diagnosis showed a mean increase in body weight of 12.5% (vs 0%), had significantly better short-term outcomes with a lower rate of central nervous system involvement (7.9% vs 23.7%, P = .06), had less need for renal replacement therapy (26.3% vs 57.9%, P = .01) or intensive care support (2.0 vs. 8.5 days, P = .02), and needed fewer days of hospitalization (9.0 vs 12.0 days, P = .03). Long-term outcomes were also significantly better in terms of renal and extrarenal sequelae (13.2% vs 39.5%, P = .01). CONCLUSIONS: Patients with STEC-HUS had great benefit from early volume expansion. It is speculated that early and generous fluid infusions can reduce thrombus formation and ischemic organ damage, thus having positive effects on both short- and long-term disease outcomes. PMID- 26644488 TI - Procedures for the Evaluation of the Visual System by Pediatricians. AB - Vision screening is crucial for the detection of visual and systemic disorders. It should begin in the newborn nursery and continue throughout childhood. This clinical report provides details regarding methods for pediatricians to use for screening. PMID- 26644489 TI - Shifting the Paradigm in Hemolytic Uremic Syndrome. PMID- 26644490 TI - A 34-Day-Old With Fever, Cerebrospinal Fluid Pleocytosis, and Staphylococcus aureus Bacteremia. AB - A 34-day-old previously healthy boy born full term presented to the emergency department with fever at home (38.1 degrees C), fussiness, and decreased oral intake for 1 day. He was difficult to console at home. He had decreased oral intake without emesis, diarrhea, or a change in urine output. He did not have rhinorrhea, cough, or increased work of breathing noted by parents. He lived at home with his parents and 13-year-old brother, did not attend day care, and had no sick contacts. On examination, he was fussy but consolable. He was febrile to 39.3 degrees C, tachycardic (180 beats per minute), and tachypneic (64 breaths per minute), with mottling and a capillary refill of 3 seconds. The remainder of his examination was normal, without an infectious focus for his fever. A complete blood cell count with differential revealed leukocytosis. A basic metabolic panel was normal. A catheter urinalysis was normal. Cerebrospinal fluid examination yielded pleocytosis, low glucose, and elevated protein. Blood cultures were persistently positive with methicillin-sensitive Staphylococcus aureus, but cerebrospinal fluid cultures remained negative. We present his case, management, and ultimate diagnosis. PMID- 26644491 TI - Please Do Whatever It Takes to End Our Daughter's Suffering! AB - What is the best way to care for a child with severe neurologic impairment who seems to be dying and is in intractable pain? Can we give sedation as we remove life support? Is it ethically permissible to hasten death? In the United States, 5 states have legalized assisted suicide (although only for competent adults). In Belgium and the Netherlands, euthanasia is legal for children under some circumstances. We present a case in which parents and doctors face difficult decisions about palliative care. Experts from Belgium, the Netherlands, and the United States then discuss how they would respond to such a case. PMID- 26644493 TI - Screening for mild cognitive impairment: If not now, when? PMID- 26644494 TI - On ways of knowing in medicine. PMID- 26644495 TI - Canadian-style medical education in China. PMID- 26644496 TI - Britain debates "sugar tax" to fight obesity. PMID- 26644497 TI - A letter to our colleague, Canada's new Minister of Health. PMID- 26644498 TI - Science minister addresses criticisms, promotes robust science. PMID- 26644499 TI - Dr. Mark Wainberg on old battles and new frontiers in HIV. PMID- 26644500 TI - Preterm birth: risk factor for early-onset chronic diseases. PMID- 26644501 TI - A young woman concerned about mercury. PMID- 26644502 TI - Risk of ischemic stroke during the initiation period of alpha-blocker therapy among older men. AB - BACKGROUND: Alpha-blockers are notorious for their first-dose effect of acute hypotension during the early initiation period. Because acute cerebral hypoperfusion may precipitate an episode of ischemic stroke, we aimed to provide a quantitative estimate of the risk of ischemic stroke during the early initiation period of alpha-blocker therapy, using a self-controlled case series design. METHODS: We identified all men aged 50 years or more as of 2007 who were incident users of alpha-blockers and had a diagnosis of ischemic stroke during the 2007-2009 study period using claims data from Taiwan's National Health Insurance claims database. The first day on which the alpha-blocker was prescribed was the index date. We partitioned different risk periods according to their relationship to the index date (pre-exposure risk periods 1 and 2 = <= 21 d and 22-60 d before index date, respectively; post-exposure risk periods 1 and 2 = <= 21 d and 22-60 d after index date, respectively); the remainder of the study period was defined as the unexposed period. We estimated the incidence rate ratio (IRR) of ischemic stroke in each risk period relative to the unexposed period using a conditional Poisson regression model. RESULTS: A total of 7502 men were included. Compared with the risk in the unexposed period, the risk of ischemic stroke was increased in post-exposure risk period 1 among all patients in the study population (adjusted IRR 1.40, 95% confidence interval [CI], 1.22-1.61) and among patients without concomitant prescriptions for other antihypertensive agents (adjusted IRR 2.11, 95% CI 1.73-2.57). INTERPRETATION: Alpha-blocker therapy was associated with an increased risk of ischemic stroke during the early initiation period, especially among patients who were not taking other antihypertensive agents. PMID- 26644503 TI - CYTOKININ OXIDASE/DEHYDROGENASE3 Maintains Cytokinin Homeostasis during Root and Nodule Development in Lotus japonicus. AB - Cytokinins are required for symbiotic nodule development in legumes, and cytokinin signaling responses occur locally in nodule primordia and in developing nodules. Here, we show that the Lotus japonicus Ckx3 cytokinin oxidase/dehydrogenase gene is induced by Nod factor during the early phase of nodule initiation. At the cellular level, pCkx3::YFP reporter-gene studies revealed that the Ckx3 promoter is active during the first cortical cell divisions of the nodule primordium and in growing nodules. Cytokinin measurements in ckx3 mutants confirmed that CKX3 activity negatively regulates root cytokinin levels. Particularly, tZ and DHZ type cytokinins in both inoculated and uninoculated roots were elevated in ckx3 mutants, suggesting that these are targets for degradation by the CKX3 cytokinin oxidase/dehydrogenase. The effect of CKX3 on the positive and negative roles of cytokinin in nodule development, infection and regulation was further clarified using ckx3 insertion mutants. Phenotypic analysis indicated that ckx3 mutants have reduced nodulation, infection thread formation and root growth. We also identify a role for cytokinin in regulating nodulation and nitrogen fixation in response to nitrate as ckx3 phenotypes are exaggerated at increased nitrate levels. Together, these findings show that cytokinin accumulation is tightly regulated during nodulation in order to balance the requirement for cell divisions with negative regulatory effects of cytokinin on infection events and root development. PMID- 26644504 TI - MultiSite Gateway-Compatible Cell Type-Specific Gene-Inducible System for Plants. AB - A powerful method to study gene function is expression or overexpression in an inducible, cell type-specific system followed by observation of consequent phenotypic changes and visualization of linked reporters in the target tissue. Multiple inducible gene overexpression systems have been developed for plants, but very few of these combine plant selection markers, control of expression domains, access to multiple promoters and protein fusion reporters, chemical induction, and high-throughput cloning capabilities. Here, we introduce a MultiSite Gateway-compatible inducible system for Arabidopsis (Arabidopsis thaliana) plants that provides the capability to generate such constructs in a single cloning step. The system is based on the tightly controlled, estrogen inducible XVE system. We demonstrate that the transformants generated with this system exhibit the expected cell type-specific expression, similar to what is observed with constitutively expressed native promoters. With this new system, cloning of inducible constructs is no longer limited to a few special cases but can be used as a standard approach when gene function is studied. In addition, we present a set of entry clones consisting of histochemical and fluorescent reporter variants designed for gene and promoter expression studies. PMID- 26644505 TI - NdhV Is a Subunit of NADPH Dehydrogenase Essential for Cyclic Electron Transport in Synechocystis sp. Strain PCC 6803. AB - Two mutants sensitive to heat stress for growth and impaired in NADPH dehydrogenase (NDH-1)-dependent cyclic electron transport around photosystem I (NDH-CET) were isolated from the cyanobacterium Synechocystis sp. strain PCC 6803 transformed with a transposon-bearing library. Both mutants had a tag in the same sll0272 gene, encoding a protein highly homologous to NdhV identified in Arabidopsis (Arabidopsis thaliana). Deletion of the sll0272 gene (ndhV) did not influence the assembly of NDH-1 complexes and the activities of CO2 uptake and respiration but reduced the activity of NDH-CET. NdhV interacted with NdhS, a ferredoxin-binding subunit of cyanobacterial NDH-1 complex. Deletion of NdhS completely abolished NdhV, but deletion of NdhV had no effect on the amount of NdhS. Reduction of NDH-CET activity was more significant in DeltandhS than in DeltandhV. We therefore propose that NdhV cooperates with NdhS to accept electrons from reduced ferredoxin. PMID- 26644506 TI - TEF30 Interacts with Photosystem II Monomers and Is Involved in the Repair of Photodamaged Photosystem II in Chlamydomonas reinhardtii. AB - The remarkable capability of photosystem II (PSII) to oxidize water comes along with its vulnerability to oxidative damage. Accordingly, organisms harboring PSII have developed strategies to protect PSII from oxidative damage and to repair damaged PSII. Here, we report on the characterization of the THYLAKOID ENRICHED FRACTION30 (TEF30) protein in Chlamydomonas reinhardtii, which is conserved in the green lineage and induced by high light. Fractionation studies revealed that TEF30 is associated with the stromal side of thylakoid membranes. By using blue native/Deriphat-polyacrylamide gel electrophoresis, sucrose density gradients, and isolated PSII particles, we found TEF30 to quantitatively interact with monomeric PSII complexes. Electron microscopy images revealed significantly reduced thylakoid membrane stacking in TEF30-underexpressing cells when compared with control cells. Biophysical and immunological data point to an impaired PSII repair cycle in TEF30-underexpressing cells and a reduced ability to form PSII supercomplexes after high-light exposure. Taken together, our data suggest potential roles for TEF30 in facilitating the incorporation of a new D1 protein and/or the reintegration of CP43 into repaired PSII monomers, protecting repaired PSII monomers from undergoing repeated repair cycles or facilitating the migration of repaired PSII monomers back to stacked regions for supercomplex reassembly. PMID- 26644509 TI - Marcos Sotomayor: Listening in on the cadherin family's secrets. PMID- 26644508 TI - Localization of the Transpiration Barrier in the Epi- and Intracuticular Waxes of Eight Plant Species: Water Transport Resistances Are Associated with Fatty Acyl Rather Than Alicyclic Components. AB - Plant cuticular waxes play a crucial role in limiting nonstomatal water loss. The goal of this study was to localize the transpiration barrier within the layered structure of cuticles of eight selected plant species and to put its physiological function into context with the chemical composition of the intracuticular and epicuticular wax layers. Four plant species (Tetrastigma voinierianum, Oreopanax guatemalensis, Monstera deliciosa, and Schefflera elegantissima) contained only very-long-chain fatty acid (VLCFA) derivatives such as alcohols, alkyl esters, aldehydes, and alkanes in their waxes. Even though the epicuticular and intracuticular waxes of these species had very similar compositions, only the intracuticular wax was important for the transpiration barrier. In contrast, four other species (Citrus aurantium, Euonymus japonica, Clusia flava, and Garcinia spicata) had waxes containing VLCFA derivatives, together with high percentages of alicyclic compounds (triterpenoids, steroids, or tocopherols) largely restricted to the intracuticular wax layer. In these species, both the epicuticular and intracuticular waxes contributed equally to the cuticular transpiration barrier. We conclude that the cuticular transpiration barrier is primarily formed by the intracuticular wax but that the epicuticular wax layer may also contribute to it, depending on species-specific cuticle composition. The barrier is associated mainly with VLCFA derivatives and less (if at all) with alicyclic wax constituents. The sealing properties of the epicuticular and intracuticular layers were not correlated with other characteristics, such as the absolute wax amounts and thicknesses of these layers. PMID- 26644507 TI - Increased Sucrose Accumulation Regulates Iron-Deficiency Responses by Promoting Auxin Signaling in Arabidopsis Plants. AB - Previous studies have identified that auxins acts upstream of nitric oxide in regulating iron deficiency responses in roots, but the upstream signaling molecule of auxins remains unknown. In this study, we showed that Fe deficiency increased sucrose (Suc) level in roots of Arabidopsis (Arabidopsis thaliana). Exogenous application of Suc further stimulated Fe deficiency-induced ferric chelate-reductase (FCR) activity and expression of Fe acquisition-related genes FRO2, IRT1, and FIT in roots. The opposite patterns were observed in the dark treatment. In addition, FCR activity and expression of Fe acquisition-related genes were higher in the Suc high-accumulating transgenic plant 35S::SUC2 but were lower in the Suc low-accumulating mutant suc2-5 compared with wild-type plants under Fe-deficient conditions. Consequently, Fe deficiency tolerance was enhanced in 35S::SUC2 but was compromised in suc2-5. Exogenous Suc also increased root beta-glucuronidase (GUS) activity in auxin-inducible reporter DR5-GUS transgenic plants under Fe deficiency. However, exogenous Suc failed to increase FCR activity and expression of Fe acquisition-related genes in the auxin transport-impaired mutants aux1-7 and pin1-1 as well as in the wild-type plants treated with an auxin transport inhibitor under Fe deficiency. In summary, we found that increased Suc accumulation is required for regulating Fe deficiency responses in plants, with auxins acting downstream in transmitting the Fe deficiency signal. PMID- 26644510 TI - How stressed cells triage mRNAs. PMID- 26644511 TI - Yeast pex1 cells contain peroxisomal ghosts that import matrix proteins upon reintroduction of Pex1. AB - Pex1 and Pex6 are two AAA-ATPases that play a crucial role in peroxisome biogenesis. We have characterized the ultrastructure of the Saccharomyces cerevisiae peroxisome-deficient mutants pex1 and pex6 by various high-resolution electron microscopy techniques. We observed that the cells contained peroxisomal membrane remnants, which in ultrathin cross sections generally appeared as double membrane rings. Electron tomography revealed that these structures consisted of one continuous membrane, representing an empty, flattened vesicle, which folds into a cup shape. Immunocytochemistry revealed that these structures lack peroxisomal matrix proteins but are the sole sites of the major peroxisomal membrane proteins Pex2, Pex10, Pex11, Pex13, and Pex14. Upon reintroduction of Pex1 in Pex1-deficient cells, these peroxisomal membrane remnants (ghosts) rapidly incorporated peroxisomal matrix proteins and developed into peroxisomes. Our data support earlier views that Pex1 and Pex6 play a role in peroxisomal matrix protein import. PMID- 26644512 TI - The polarity protein Inturned links NPHP4 to Daam1 to control the subapical actin network in multiciliated cells. AB - Motile cilia polarization requires intracellular anchorage to the cytoskeleton; however, the molecular machinery that supports this process remains elusive. We report that Inturned plays a central role in coordinating the interaction between cilia-associated proteins and actin-nucleation factors. We observed that knockdown of nphp4 in multiciliated cells of the Xenopus laevis epidermis compromised ciliogenesis and directional fluid flow. Depletion of nphp4 disrupted the subapical actin layer. Comparison to the structural defects caused by inturned depletion revealed striking similarities. Furthermore, coimmunoprecipitation assays demonstrated that the two proteins interact with each other and that Inturned mediates the formation of ternary protein complexes between NPHP4 and DAAM1. Knockdown of daam1, but not formin-2, resulted in similar disruption of the subapical actin web, whereas nphp4 depletion prevented the association of Inturned with the basal bodies. Thus, Inturned appears to function as an adaptor protein that couples cilia-associated molecules to actin modifying proteins to rearrange the local actin cytoskeleton. PMID- 26644513 TI - Vitamin D receptor-retinoid X receptor heterodimer signaling regulates oligodendrocyte progenitor cell differentiation. AB - The mechanisms regulating differentiation of oligodendrocyte (OLG) progenitor cells (OPCs) into mature OLGs are key to understanding myelination and remyelination. Signaling via the retinoid X receptor gamma (RXR-gamma) has been shown to be a positive regulator of OPC differentiation. However, the nuclear receptor (NR) binding partner of RXR-gamma has not been established. In this study we show that RXR-gamma binds to several NRs in OPCs and OLGs, one of which is vitamin D receptor (VDR). Using pharmacological and knockdown approaches we show that RXR-VDR signaling induces OPC differentiation and that VDR agonist vitamin D enhances OPC differentiation. We also show expression of VDR in OLG lineage cells in multiple sclerosis. Our data reveal a role for vitamin D in the regenerative component of demyelinating disease and identify a new target for remyelination medicines. PMID- 26644514 TI - Microcephaly protein Asp focuses the minus ends of spindle microtubules at the pole and within the spindle. AB - Depletion of Drosophila melanogaster Asp, an orthologue of microcephaly protein ASPM, causes spindle pole unfocusing during mitosis. However, it remains unclear how Asp contributes to pole focusing, a process that also requires the kinesin-14 motor Ncd. We show that Asp localizes to the minus ends of spindle microtubule (MT) bundles and focuses them to make the pole independent of Ncd. We identified a critical domain in Asp exhibiting MT cross-linking activity in vitro. Asp was also localized to, and focuses the minus ends of, intraspindle MTs that were nucleated in an augmin-dependent manner and translocated toward the poles by spindle MT flux. Ncd, in contrast, functioned as a global spindle coalescence factor not limited to MT ends. We propose a revised molecular model for spindle pole focusing in which Asp at the minus ends cross-links MTs at the pole and within the spindle. Additionally, this study provides new insight into the dynamics of intraspindle MTs by using Asp as a minus end marker. PMID- 26644515 TI - The Ski2-family helicase Obelus regulates Crumbs alternative splicing and cell polarity. AB - Alternative splicing can have profound consequences for protein activity, but the functions of most alternative splicing regulators are not known. We show that Obelus, a conserved Ski2-family helicase, is required for cell polarity and adherens junction organization in the Drosophila melanogaster embryo. In obelus mutants, epithelial cells display an expanded apical domain, aggregation of adherens junctions at the cell membrane, and microtubule-dependent defects in centrosome positioning. Through whole-genome transcriptome analysis, we found that Obelus is required for the alternative splicing of a small number of transcripts in the early embryo, including the pre-mRNA that encodes the apical polarity protein Crumbs. In obelus mutants, inclusion of an alternative exon results in increased expression of a Crumbs isoform that contains an additional epidermal growth factor-like repeat in the extracellular domain. Overexpression of this alternative Crumbs isoform recapitulates the junctional aggregation and centrosome positioning defects of obelus mutants. These results indicate that regulation of Crumbs alternative splicing by the Obelus helicase modulates epithelial polarity during development. PMID- 26644516 TI - Reevaluation of the role of Pex1 and dynamin-related proteins in peroxisome membrane biogenesis. AB - A recent model for peroxisome biogenesis postulates that peroxisomes form de novo continuously in wild-type cells by heterotypic fusion of endoplasmic reticulum derived vesicles containing distinct sets of peroxisomal membrane proteins. This model proposes a role in vesicle fusion for the Pex1/Pex6 complex, which has an established role in matrix protein import. The growth and division model proposes that peroxisomes derive from existing peroxisomes. We tested these models by reexamining the role of Pex1/Pex6 and dynamin-related proteins in peroxisome biogenesis. We found that induced depletion of Pex1 blocks the import of matrix proteins but does not affect membrane protein delivery to peroxisomes; markers for the previously reported distinct vesicles colocalize in pex1 and pex6 cells; peroxisomes undergo continued growth if fission is blocked. Our data are compatible with the established primary role of the Pex1/Pex6 complex in matrix protein import and show that peroxisomes in Saccharomyces cerevisiae multiply mainly by growth and division. PMID- 26644519 TI - Correction: Stoichiometry of Nck-dependent actin polymerization in living cells. PMID- 26644517 TI - A keratin scaffold regulates epidermal barrier formation, mitochondrial lipid composition, and activity. AB - Keratin intermediate filaments (KIFs) protect the epidermis against mechanical force, support strong adhesion, help barrier formation, and regulate growth. The mechanisms by which type I and II keratins contribute to these functions remain incompletely understood. Here, we report that mice lacking all type I or type II keratins display severe barrier defects and fragile skin, leading to perinatal mortality with full penetrance. Comparative proteomics of cornified envelopes (CEs) from prenatal KtyI(-/-) and KtyII(-/-)(K8) mice demonstrates that absence of KIF causes dysregulation of many CE constituents, including downregulation of desmoglein 1. Despite persistence of loricrin expression and upregulation of many Nrf2 targets, including CE components Sprr2d and Sprr2h, extensive barrier defects persist, identifying keratins as essential CE scaffolds. Furthermore, we show that KIFs control mitochondrial lipid composition and activity in a cell intrinsic manner. Therefore, our study explains the complexity of keratinopathies accompanied by barrier disorders by linking keratin scaffolds to mitochondria, adhesion, and CE formation. PMID- 26644520 TI - The clinical significance of fibrinogen plasma levels in patients with diffuse large B cell lymphoma. AB - BACKGROUND: Fibrinogen plays a crucial role in the pathophysiology of tumour cell growth, invasion and metastasis. The aim of this study was to evaluate the prognostic significance of pretreatment plasma fibrinogen levels in patients with diffuse large B cell lymphoma (DLBCL) METHODS: Data from 372 patients with DLBCL, diagnosed and treated between 2004 and 2013 at two Austrian centres, were evaluated retrospectively. The prognostic influences of plasma fibrinogen levels and other factors, including age, tumour stage and the National Comprehensive Cancer Network-International Prognostic Index, on 5-year overall survival (OS) and 5-year disease-free survival (DFS) were studied using Kaplan-Meier curves as well as univariate and multivariate Cox regression models. RESULTS: Kaplan-Meier analysis revealed that a high fibrinogen plasma level is associated with decreased 5-year OS and 5-year DFS in patients with DLBCL (p<0.001, log-rank test). Furthermore, in multivariate analysis, elevated serum fibrinogen was found to be an independent marker of poor clinical outcome: 5-year OS (HR=1.69, 95% CI 1.06 to 2.72, p=0.029) and 5-year DFS (HR=1.68, 95% CI 1.08 to 2.61, p=0.021). CONCLUSIONS: In the current study, we demonstrate that high plasma fibrinogen levels at diagnosis predict poor outcome in patients with DLBCL. TRIAL REGISTRATION NUMBER: 25-434 ex 12713 and 415-EP/73/127-2012. PMID- 26644518 TI - Ephrin-A3 promotes and maintains slow muscle fiber identity during postnatal development and reinnervation. AB - Each adult mammalian skeletal muscle has a unique complement of fast and slow myofibers, reflecting patterns established during development and reinforced via their innervation by fast and slow motor neurons. Existing data support a model of postnatal "matching" whereby predetermined myofiber type identity promotes pruning of inappropriate motor axons, but no molecular mechanism has yet been identified. We present evidence that fiber type-specific repulsive interactions inhibit innervation of slow myofibers by fast motor axons during both postnatal maturation of the neuromuscular junction and myofiber reinnervation after injury. The repulsive guidance ligand ephrin-A3 is expressed only on slow myofibers, whereas its candidate receptor, EphA8, localizes exclusively to fast motor endplates. Adult mice lacking ephrin-A3 have dramatically fewer slow myofibers in fast and mixed muscles, and misexpression of ephrin-A3 on fast myofibers followed by denervation/reinnervation promotes their respecification to a slow phenotype. We therefore conclude that Eph/ephrin interactions guide the fiber type specificity of neuromuscular interactions during development and adult life. PMID- 26644521 TI - The role of parvovirus B19 in the pathogenesis of autoimmunity and autoimmune disease. AB - Human parvovirus B19 is a single-stranded DNA virus which preferentially targets the erythroblasts in the bone marrow. B19 infection commonly causes erythema infectiosum, arthralgia, fetal death, transient aplastic crisis in patients with shortened red cell survival, and persistent infection in people who are immunocompromised. Less common clinical manifestations include atypical skin rashes, neurological syndromes, cardiac syndromes, and various cytopenias. B19 infection has also been associated with development of a variety of different autoimmune diseases, including rheumatological, neurological, neuromuscular, cardiovascular, haematological, nephrological and metabolic. Production of a variety of autoantibodies has been demonstrated to occur during B19 infection and these have been shown to be key to the pathogenesis of the particular disease process in a significant number of cases, for example, production of rheumatoid factor in cases of B19-associated rheumatoid arthritis and production of anti glutamic acid decarboxylase (GAD) in patients with B19-associated type 1 diabetes mellitus. B19 infection has also been associated with the development of multiple autoimmune diseases in 12 individuals. Documented mechanisms in B19-associated autoimmunity include molecular mimicry (IgG antibody to B19 proteins has been shown to cross react with a variety of recognised human autoantigens, including collagen II, keratin, angiotensin II type 1 receptor, myelin basic protein, cardiolipin, and platelet membrane glycoprotein IIb/IIIa), B19-induced apoptosis with presentation of self-antigens to T lymphocytes, and the phospholipase activity of the B19 unique VP1 protein. PMID- 26644522 TI - Androgen Deprivation Therapy and Future Alzheimer's Disease Risk. AB - PURPOSE: To test the association of androgen deprivation therapy (ADT) in the treatment of prostate cancer with subsequent Alzheimer's disease risk. METHODS: We used a previously validated and implemented text-processing pipeline to analyze electronic medical record data in a retrospective cohort of patients at Stanford University and Mt. Sinai hospitals. Specifically, we extracted International Classification of Diseases-9th revision diagnosis and Current Procedural Terminology codes, medication lists, and positive-present mentions of drug and disease concepts from all clinical notes. We then tested the effect of ADT on risk of Alzheimer's disease using 1:5 propensity score-matched and traditional multivariable-adjusted Cox proportional hazards models. The duration of ADT use was also tested for association with Alzheimer's disease risk. RESULTS: There were 16,888 individuals with prostate cancer meeting all inclusion and exclusion criteria, with 2,397 (14.2%) receiving ADT during a median follow up period of 2.7 years (interquartile range, 1.0-5.4 years). Propensity score matched analysis (hazard ratio, 1.88; 95% CI, 1.10 to 3.20; P = .021) and traditional multivariable-adjusted Cox regression analysis (hazard ratio, 1.66; 95% CI, 1.05 to 2.64; P = .031) both supported a statistically significant association between ADT use and Alzheimer's disease risk. We also observed a statistically significant increased risk of Alzheimer's disease with increasing duration of ADT (P = .016). CONCLUSION: Our results support an association between the use of ADT in the treatment of prostate cancer and an increased risk of Alzheimer's disease in a general population cohort. This study demonstrates the utility of novel methods to analyze electronic medical record data to generate practice-based evidence. PMID- 26644523 TI - Adjuvant Imatinib for GI Stromal Tumors: When and For How Long? AB - A 45-year-old woman presented with syncope. She was severely anemic, with a hemoglobin level of 6 g/dL, and was found to have lower GI bleeding. A diagnostic colonoscopy was negative. A subsequent computed tomography scan of the abdomen and pelvis was performed, revealing a 3.2 * 3 * 2.9-cm contrast-enhancing right lower-quadrant mass arising from the wall of the ileum. There was no evidence of metastatic disease. The patient underwent laparotomy, and a 3.5-cm mass was resected with negative margins. Pathology revealed a GI stromal tumor with mixed spindle and epithelioid features involving the mucosa and submucosa (Fig 1A). The tumor cells were positive for CD117 (c-kit) (Fig 1B) and DOG-1(Fig 1C). There were eight to 10 mitoses per 50 high-power fields (Fig 1D). Molecular studies showed a 42-base pair deletion in exon 11 of the KIT gene that would delete all or part of codons 558 to 572 (V559_D572del) and would change the 558-encoding amino acid from Lys to Asn (K558N). PMID- 26644524 TI - Mind the Gap: Why Closing the Doughnut Hole Is Insufficient for Increasing Medicare Beneficiary Access to Oral Chemotherapy. AB - PURPOSE: Orally administered anticancer medications are among the fastest growing components of cancer care. These medications are expensive, and cost-sharing requirements for patients can be a barrier to their use. For Medicare beneficiaries, the Affordable Care Act will close the Part D coverage gap (doughnut hole), which will reduce cost sharing from 100% in 2010 to 25% in 2020 for drug spending above $2,960 until the beneficiary reaches $4,700 in out-of pocket spending. How much these changes will reduce out-of-pocket costs is unclear. METHODS: We used the Medicare July 2014 Prescription Drug Plan Formulary, Pharmacy Network, and Pricing Information Files from the Centers for Medicare & Medicaid Services for 1,114 stand-alone and 2,230 Medicare Advantage prescription drug formularies, which represent all formularies in 2014. We identified orally administered anticancer medications and summarized drug costs, cost-sharing designs used by available plans, and the estimated out-of-pocket costs for beneficiaries without low-income subsidies who take a single drug before and after the doughnut hole closes. RESULTS: Little variation existed in formulary design across plans and products. The average price per month for included products was $10,060 (range, $5,123 to $16,093). In 2010, median beneficiary annual out-of-pocket costs for a typical treatment duration ranged from $6,456 (interquartile range, $6,433 to $6,482) for dabrafenib to $12,160 (interquartile range, $12,102 to $12,262) for sunitinib. With the assumption that prices remain stable, after the doughnut hole closes, beneficiaries will spend approximately $2,550 less. CONCLUSION: Out-of-pocket costs for Medicare beneficiaries taking orally administered anticancer medications are high and will remain so after the doughnut hole closes. Efforts are needed to improve affordability of high-cost cancer drugs for beneficiaries who need them. PMID- 26644525 TI - Is Cancer Pain Control Improved by a Simple WHO Pain Analgesic Ladder Approach Combined With Tumor-Directed Treatment? PMID- 26644526 TI - Randomized Trial of Low-Dose Morphine Versus Weak Opioids in Moderate Cancer Pain. AB - PURPOSE: The WHO guidelines on cancer pain management recommend a sequential three-step analgesic ladder. However, conclusive data are lacking as to whether moderate pain should be treated with either step II weak opioids or low-dose step III strong opioids. PATIENTS AND METHODS: In a multicenter, 28-day, open-label randomized controlled study, adults with moderate cancer pain were assigned to receive either a weak opioid or low-dose morphine. The primary outcome was the number of responder patients, defined as patients with a 20% reduction in pain intensity on the numerical rating scale. RESULTS: A total of 240 patients with cancer (118 in the low-dose morphine and 122 in the weak-opioid group) were included in the study. The primary outcome occurred in 88.2% of the low-dose morphine and in 57.7% of the weak-opioid group (odds risk, 6.18; 95% CI, 3.12 to 12.24; P < .001). The percentage of responder patients was higher in the low-dose morphine group, as early as at 1 week. Clinically meaningful (>= 30%) and highly meaningful (>= 50%) pain reduction from baseline was significantly higher in the low-dose morphine group (P < .001). A change in the assigned treatment occurred more frequently in the weak-opioid group, because of inadequate analgesia. The general condition of patients, which was based on the Edmonton Symptom Assessment System overall symptom score, was better in the morphine group. Adverse effects were similar in both groups. CONCLUSION: In patients with cancer and moderate pain, low-dose morphine reduced pain intensity significantly compared with weak opioids, with a similarly good tolerability and an earlier effect. PMID- 26644528 TI - Cisplatin Versus Cetuximab With Radiotherapy in Locally Advanced Squamous Cell Carcinoma of the Head and Neck. PMID- 26644527 TI - Symptom Monitoring With Patient-Reported Outcomes During Routine Cancer Treatment: A Randomized Controlled Trial. AB - PURPOSE: There is growing interest to enhance symptom monitoring during routine cancer care using patient-reported outcomes, but evidence of impact on clinical outcomes is limited. METHODS: We randomly assigned patients receiving routine outpatient chemotherapy for advanced solid tumors at Memorial Sloan Kettering Cancer Center to report 12 common symptoms via tablet computers or to receive usual care consisting of symptom monitoring at the discretion of clinicians. Those with home computers received weekly e-mail prompts to report between visits. Treating physicians received symptom printouts at visits, and nurses received e-mail alerts when participants reported severe or worsening symptoms. The primary outcome was change in health-related quality of life (HRQL) at 6 months compared with baseline, measured by the EuroQol EQ-5D Index. Secondary endpoints included emergency room (ER) visits, hospitalizations, and survival. RESULTS: Among 766 patients allocated, HRQL improved among more participants in the intervention group than usual care (34% v 18%) and worsened among fewer (38% v 53%; P < .001). Overall, mean HRQL declined by less in the intervention group than usual care (1.4- v 7.1-point drop; P < .001). Patients receiving intervention were less frequently admitted to the ER (34% v 41%; P = .02) or hospitalized (45% v 49%; P = .08) and remained on chemotherapy longer (mean, 8.2 v 6.3 months; P = .002). Although 75% of the intervention group was alive at 1 year, 69% with usual care survived the year (P = .05), with differences also seen in quality-adjusted survival (mean of 8.7 v. 8.0 months; P = .004). Benefits were greater for participants lacking prior computer experience. Most patients receiving intervention (63%) reported severe symptoms during the study. Nurses frequently initiated clinical actions in response to e-mail alerts. CONCLUSION: Clinical benefits were associated with symptom self-reporting during cancer care. PMID- 26644529 TI - An Additional Step Toward Personalization of Surgical Care for Early-Stage Non Small-Cell Lung Cancer. PMID- 26644531 TI - Reply to A. Oguz et al. PMID- 26644530 TI - Impact of Ipsilateral Blood Draws, Injections, Blood Pressure Measurements, and Air Travel on the Risk of Lymphedema for Patients Treated for Breast Cancer. AB - PURPOSE: The goal of this study was to investigate the association between blood draws, injections, blood pressure readings, trauma, cellulitis in the at-risk arm, and air travel and increases in arm volume in a cohort of patients treated for breast cancer and screened for lymphedema. PATIENTS AND METHODS: Between 2005 and 2014, patients undergoing treatment of breast cancer at our institution were screened prospectively for lymphedema. Bilateral arm volume measurements were performed preoperatively and postoperatively using a Perometer. At each measurement, patients reported the number of blood draws, injections, blood pressure measurements, trauma to the at-risk arm(s), and number of flights taken since their last measurement. Arm volume was quantified using the relative volume change and weight-adjusted change formulas. Linear random effects models were used to assess the association between relative arm volume (as a continuous variable) and nontreatment risk factors, as well as clinical characteristics. RESULTS: In 3,041 measurements, there was no significant association between relative volume change or weight-adjusted change increase and undergoing one or more blood draws (P = .62), injections (P = .77), number of flights (one or two [P = .77] and three or more [P = .91] v none), or duration of flights (1 to 12 hours [P = .43] and 12 hours or more [P = .54] v none). By multivariate analysis, factors significantly associated with increases in arm volume included body mass index >= 25 (P = .0236), axillary lymph node dissection (P < .001), regional lymph node irradiation (P = .0364), and cellulitis (P < .001). CONCLUSION: This study suggests that although cellulitis increases risk of lymphedema, ipsilateral blood draws, injections, blood pressure readings, and air travel may not be associated with arm volume increases. The results may help to educate clinicians and patients on posttreatment risk, prevention, and management of lymphedema. PMID- 26644532 TI - Financial Hardship Associated With Cancer in the United States: Findings From a Population-Based Sample of Adult Cancer Survivors. AB - PURPOSE: To estimate the prevalence of financial hardship associated with cancer in the United States and identify characteristics of cancer survivors associated with financial hardship. METHODS: We identified 1,202 adult cancer survivors diagnosed or treated at >= 18 years of age from the 2011 Medical Expenditure Panel Survey Experiences With Cancer questionnaire. Material financial hardship was measured by ever (1) borrowing money or going into debt, (2) filing for bankruptcy, (3) being unable to cover one's share of medical care costs, or (4) making other financial sacrifices because of cancer, its treatment, and lasting effects of treatment. Psychological financial hardship was measured as ever worrying about paying large medical bills. We examined factors associated with any material or psychological financial hardship using separate multivariable logistic regression models stratified by age group (18 to 64 and >= 65 years). RESULTS: Material financial hardship was more common in cancer survivors age 18 to 64 years than in those >= 65 years of age (28.4% v 13.8%; P < .001), as was psychological financial hardship (31.9% v 14.7%, P < .001). In adjusted analyses, cancer survivors age 18 to 64 years who were younger, female, nonwhite, and treated more recently and who had changed employment because of cancer were significantly more likely to report any material financial hardship. Cancer survivors who were uninsured, had lower family income, and were treated more recently were more likely to report psychological financial hardship. Among cancer survivors >= 65 years of age, those who were younger were more likely to report any financial hardship. CONCLUSION: Cancer survivors, especially the working-age population, commonly experience material and psychological financial hardship. PMID- 26644533 TI - Is It Finally Time for a Personalized Medicine Approach for Fluorouracil-Based Therapies? PMID- 26644534 TI - Treatment of Lymph Node-Negative, Early-Stage HER2-Positive Breast Cancer. PMID- 26644535 TI - Randomized Double-Blind Trial of Pregabalin Versus Placebo in Conjunction With Palliative Radiotherapy for Cancer-Induced Bone Pain. AB - PURPOSE: Cancer-induced bone pain (CIBP) affects one third of patients with cancer. Radiotherapy remains the gold-standard treatment; however, laboratory and clinical work suggest that pregabalin may be useful in treating CIBP. The aim of this study was to examine pregabalin in patients with CIBP receiving radiotherapy. PATIENTS AND METHODS: A multicenter, double-blind randomized trial of pregabalin versus placebo was conducted. Eligible patients were age >= 18 years, had radiologically proven bone metastases, were scheduled to receive radiotherapy, and had pain scores >= 4 of 10 (on 0-to-10 numeric rating scale). Before radiotherapy, baseline assessments were completed, followed by random assignment. Doses of pregabalin and placebo were increased over 4 weeks. The primary end point was treatment response, defined as a reduction of >= 2 points in worst pain by week 4, accompanied by a stable or reduced opioid dose, compared with baseline. Secondary end points assessed average pain, interference of pain with activity, breakthrough pain, mood, quality of life, and adverse events. RESULTS: A total of 233 patients were randomly assigned: 117 to placebo and 116 to pregabalin. The most common cancers were prostate (n = 88; 38%), breast (n = 77; 33%), and lung (n = 42; 18%). In the pregabalin arm, 45 patients (38.8%) achieved the primary end point, compared with 47 (40.2%) in the placebo arm (adjusted odds ratio, 1.07; 95% CI, 0.63 to 1.81; P = .816). There were no statistically significant differences in average pain, pain interference, or quality of life between arms. There were differences in mood (P = .031) and breakthrough pain duration (P = .037) between arms. Outcomes were compared at 4 weeks. CONCLUSION: Our findings do not support the role of pregabalin in patients with CIBP receiving radiotherapy. The role of pregabalin in CIBP with a clinical neuropathic pain component is unknown. PMID- 26644536 TI - Cetuximab and Radiotherapy Versus Cisplatin and Radiotherapy for Locally Advanced Head and Neck Cancer: A Randomized Phase II Trial. AB - PURPOSE: No randomized trials have been conducted to directly compare radiotherapy (RT) with concomitant cisplatin (CDDP) versus concomitant cetuximab (CTX) as first-line treatment of locally advanced squamous cell carcinoma of the head and neck. In this randomized trial, we compared these two treatment regimens in terms of compliance, toxicity, and efficacy. PATIENTS AND METHODS: Eligible patients were randomly assigned in a 1:1 ratio to receive either CDDP 40 mg/m(2) once per week or CTX 400 mg/m(2) as loading dose followed by CTX 250 mg/m(2) once per week concomitant to radical RT. For primary end points, compliance to treatment was defined as number of days of treatment discontinuation and drug dosage reduction. The acute toxicity rate was defined according to the National Cancer Institute Common Toxicity Criteria. Efficacy end points were local recurrence-free survival, metastasis-free survival, cancer-specific survival, and overall survival. RESULTS: The study was discontinued early because of slow accrual after the enrollment of 70 patients. RT discontinuation for more than 10 days occurred in 13% of patients given CTX and 0% given CDDP (P = .05). Drug dosage reduction occurred in 34% given CTX and 53% given CDDP (difference not significant). Toxicity profiles differed between the two arms, with hematologic, renal, and GI toxicities more frequent in the CDDP arm, and cutaneous toxicity and the need for nutritional support more frequent in the CTX arm. Serious adverse events related to treatment, including four versus one toxic deaths, were higher in the CTX arm (19% v 3%, P = .044). Locoregional control, patterns of failure, and survivals were similar between the treatment arms. CONCLUSION: CTX concomitant to RT lowered compliance and increased acute toxicity rates. Efficacy outcomes were similar in both arms. These results raise the issue of appropriately selecting patients with head and neck cancer who can benefit from CTX in combination with RT. PMID- 26644538 TI - PRO-cision Medicine: Personalizing Patient Care Using Patient-Reported Outcomes. PMID- 26644537 TI - Pediatric-Like Acute Lymphoblastic Leukemia Therapy in Adults With Lymphoblastic Lymphoma: The GRAALL-LYSA LL03 Study. AB - PURPOSE: This study evaluated the efficacy of pediatric-like acute lymphoblastic leukemia (ALL) therapy in adults with lymphoblastic lymphoma (LL). PATIENTS AND METHODS: This was a prospective phase II study in adults 18 to 59 years old with previously untreated LL. Patients were treated with an adapted pediatric-like ALL protocol, which included a corticosteroid prephase, a five-drug induction reinforced by sequential cyclophosphamide administration, dose-dense consolidation, late intensification, CNS prophylaxis, and a 2-year maintenance phase. Treatment response was assessed by computed tomography and optional positron emission tomography. Allogeneic hematopoietic stem cell transplant was offered to selected patients in first complete remission (CR) or unconfirmed CR. RESULTS: The study enrolled 148 patients (131 with T-lineage LL [T-LL] and 17 with B-lineage LL [B-LL]). A total of 119 patients with T-LL (90.8%) and 13 with B-LL (76.5%) reached CR/unconfirmed CR, including 26 with T-LL and two with B-LL who needed a second induction salvage course. Relapse occurred in 34 patients with T-LL and four with B-LL. In patients with T-LL, 3-year event-free survival was 63.3% (95% CI, 54.2% to 71.0%), disease-free survival was 72.4% (95% CI, 63.0% to 79.7%), and overall survival was 69.2% (95% CI, 60.0% to 76.7%). Multivariate analysis identified serum lactate dehydrogenase level and the NOTCH1/FBXW7/RAS/PTEN oncogene (a four-gene oncogenetic classifier) status but not positron emission tomography or hematopoietic stem cell transplant as independent prognostic factors for outcome in T-LL. CONCLUSION: In adults with LL, an intensive pediatric-like ALL treatment protocol was associated with a good response rate and outcome. In patients with T-LL, the four-gene oncogenetic classifier and lactate dehydrogenase level were independent prognostic indicators. PMID- 26644540 TI - To RCT or Not to RCT: How to Change Practice for Rare Cancers? PMID- 26644539 TI - Computerized Physician Order Entry-Based System Improves Hepatitis B Virus Screening in Patients Undergoing Chemotherapy. PMID- 26644541 TI - Reply to J. Cabezas et al. PMID- 26644542 TI - Does Pregabalin Still Have a Role in Treating Cancer-Induced Bone Pain? PMID- 26644543 TI - American Cancer Society/American Society of Clinical Oncology Breast Cancer Survivorship Care Guideline. AB - The purpose of the American Cancer Society/American Society of Clinical Oncology Breast Cancer Survivorship Care Guideline is to provide recommendations to assist primary care and other clinicians in the care of female adult survivors of breast cancer. A systematic review of the literature was conducted using PubMed through April 2015. A multidisciplinary expert workgroup with expertise in primary care, gynecology, surgical oncology, medical oncology, radiation oncology, and nursing was formed and tasked with drafting the Breast Cancer Survivorship Care Guideline. A total of 1,073 articles met inclusion criteria; and, after full text review, 237 were included as the evidence base. Patients should undergo regular surveillance for breast cancer recurrence, including evaluation with a cancer related history and physical examination, and should be screened for new primary breast cancer. Data do not support performing routine laboratory tests or imaging tests in asymptomatic patients to evaluate for breast cancer recurrence. Primary care clinicians should counsel patients about the importance of maintaining a healthy lifestyle, monitor for post-treatment symptoms that can adversely affect quality of life, and monitor for adherence to endocrine therapy. Recommendations provided in this guideline are based on current evidence in the literature and expert consensus opinion. Most of the evidence is not sufficient to warrant a strong evidence-based recommendation. Recommendations on surveillance for breast cancer recurrence, screening for second primary cancers, assessment and management of physical and psychosocial long-term and late effects of breast cancer and its treatment, health promotion, and care coordination/practice implications are made.This guideline was developed through a collaboration between the American Cancer Society and the American Society of Clinical Oncology and has been published jointly by invitation and consent in both CA: A Cancer Journal for Clinicians and Journal of Clinical Oncology. All rights reserved. No part of this document may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without written permission by the American Cancer Society or the American Society of Clinical Oncology. PMID- 26644544 TI - Medical journals, impact and social media: an ecological study of the Twittersphere. AB - BACKGROUND: Twitter is an increasingly popular means of research dissemination. I sought to examine the relation between scientific merit and mainstream popularity of general medical journals. METHODS: I extracted impact factors and citations for 2014 for all general medical journals listed in the Thomson Reuters InCites Journal Citation Reports. I collected Twitter statistics (number of followers, number following, number of tweets) between July 25 and 27, 2015 from the Twitter profiles of journals that had Twitter accounts. I calculated the ratio of observed to expected Twitter followers according to citations via the Kardashian Index. I created the (Fifty Shades of) Grey Scale to calculate the analogous ratio according to impact factor. RESULTS: Only 28% (43/153) of journals had Twitter profiles. The scientific and social media impact of journals were correlated: in adjusted models, Twitter followers increased by 0.78% (95% confidence interval [CI] 0.38%-1.18%) for every 1% increase in impact factor and by 0.62% (95% CI 0.34%-0.90%) for every 1% increase in citations. Kardashian Index scores above the 99% CI were obsverved in 16% (7/43) of journals, including 6 of the 7 highest ranked journals by impact factor, whereas 58% (25/43) had scores below this interval. For the Grey Scale, 12% (5/43) of journals had scores above and 35% (15/43) had scores below the 99% CI. INTERPRETATION: The size of a general medical journal's Twitter following is strongly linked to its impact factor and citations, suggesting that higher quality research received more mainstream attention. Many journals have not capitalized on this dissemination method, although others have used it to their advantage. PMID- 26644545 TI - Mirror mirror on the ward, who's the most narcissistic of them all? Pathologic personality traits in health care. AB - BACKGROUND: Stereotypes in medicine have become exaggerated for the purpose of workplace amusement. Our objective was to assess the levels of "dark triad" personality traits expressed by individuals working in different health care specialties in comparison with the general population. METHODS: We conducted a prospective, cross-sectional study within multiple departments of a UK secondary care teaching hospital. A total of 248 health care professionals participated, and 159 members of the general population were recruited as a comparison group. We measured 3 personality traits--narcissism, Machiavellianism and psychopathy- through the validated self-reported personality questionnaires Narcissistic Personality Inventory (NPI), MACH-IV and the Levenson Self-Report Psychopathy Scale (LSRP), respectively. RESULTS: Health care professionals scored significantly lower on narcissism, Machiavellianism and psychopathy (mean scores 12.0, 53.0 and 44.7, respectively) than the general population (p < 0.001). Nursing professionals exhibited a significantly higher level of secondary psychopathy than medical professionals (p = 0.04, mean LSRP score 20.3). Within the cohort of medical professionals, surgeons expressed significantly higher levels of narcissism (p = 0.03, mean NPI score 15.0). INTERPRETATION: Health care professionals expressed low levels of dark triad personality traits. The suggestion that health care professionals are avaricious and untrustworthy may be refuted, even for surgeons. PMID- 26644546 TI - Pareidolia and clinical reasoning: the pattern awakens. PMID- 26644549 TI - Implementing growth monitoring recommendations. PMID- 26644550 TI - Another mini-masterpiece. PMID- 26644551 TI - Impacts of Visual Sonority and Handshape Markedness on Second Language Learning of American Sign Language. AB - The roles of visual sonority and handshape markedness in sign language acquisition and production were investigated. In Experiment 1, learners were taught sign-nonobject correspondences that varied in sign movement sonority and handshape markedness. Results from a sign-picture matching task revealed that high sonority signs were more accurately matched, especially when the sign contained a marked handshape. In Experiment 2, learners produced these familiar signs in addition to novel signs, which differed based on sonority and markedness. Results from a key-release reaction time reproduction task showed that learners tended to produce high sonority signs much more quickly than low sonority signs, especially when the sign contained an unmarked handshape. This effect was only present in familiar signs. Sign production accuracy rates revealed that high sonority signs were more accurate than low sonority signs. Similarly, signs with unmarked handshapes were produced more accurately than those with marked handshapes. Together, results from Experiments 1 and 2 suggested that signs that contain high sonority movements are more easily processed, both perceptually and productively, and handshape markedness plays a differential role in perception and production. PMID- 26644552 TI - Eleventh-century shift in timber procurement areas for the great houses of Chaco Canyon. AB - An enduring mystery from the great houses of Chaco Canyon is the origin of more than 240,000 construction timbers. We evaluate probable timber procurement areas for seven great houses by applying tree-ring width-based sourcing to a set of 170 timbers. To our knowledge, this is the first use of tree rings to assess timber origins in the southwestern United States. We found that the Chuska and Zuni Mountains (>75 km distant) were the most likely sources, accounting for 70% of timbers. Most notably, procurement areas changed through time. Before 1020 Common Era (CE) nearly all timbers originated from the Zunis (a previously unrecognized source), but by 1060 CE the Chuskas eclipsed the Zuni area in total wood imports. This shift occurred at the onset of Chaco florescence in the 11th century, a time with substantial expansion of existing great houses and the addition of seven new great houses in the Chaco Core area. It also coincides with the proliferation of Chuskan stone tools and pottery in the archaeological record of Chaco Canyon, further underscoring the link between land use and occupation in the Chuska area and the peak of great house construction. Our findings, based on the most temporally specific and replicated evidence of Chacoan resource procurement obtained to date, corroborate the long-standing but recently challenged interpretation that large numbers of timbers were harvested and transported from distant mountain ranges to build the great houses at Chaco Canyon. PMID- 26644553 TI - Global phosphorus retention by river damming. AB - More than 70,000 large dams have been built worldwide. With growing water stress and demand for energy, this number will continue to increase in the foreseeable future. Damming greatly modifies the ecological functioning of river systems. In particular, dam reservoirs sequester nutrient elements and, hence, reduce downstream transfer of nutrients to floodplains, lakes, wetlands, and coastal marine environments. Here, we quantify the global impact of dams on the riverine fluxes and speciation of the limiting nutrient phosphorus (P), using a mechanistic modeling approach that accounts for the in-reservoir biogeochemical transformations of P. According to the model calculations, the mass of total P (TP) trapped in reservoirs nearly doubled between 1970 and 2000, reaching 42 Gmol y(-1), or 12% of the global river TP load in 2000. Because of the current surge in dam building, we project that by 2030, about 17% of the global river TP load will be sequestered in reservoir sediments. The largest projected increases in TP and reactive P (RP) retention by damming will take place in Asia and South America, especially in the Yangtze, Mekong, and Amazon drainage basins. Despite the large P retention capacity of reservoirs, the export of RP from watersheds will continue to grow unless additional measures are taken to curb anthropogenic P emissions. PMID- 26644554 TI - Predicting experimentally stable allotropes: Instability of penta-graphene. AB - In recent years, a plethora of theoretical carbon allotropes have been proposed, none of which has been experimentally isolated. We discuss here criteria that should be met for a new phase to be potentially experimentally viable. We take as examples Haeckelites, 2D networks of sp(2)-carbon-containing pentagons and heptagons, and "penta-graphene," consisting of a layer of pentagons constructed from a mixture of sp(2)- and sp(3)-coordinated carbon atoms. In 2D projection appearing as the "Cairo pattern," penta-graphene is elegant and aesthetically pleasing. However, we dispute the author's claims of its potential stability and experimental relevance. PMID- 26644555 TI - Tropical nighttime warming as a dominant driver of variability in the terrestrial carbon sink. AB - The terrestrial biosphere is currently a strong carbon (C) sink but may switch to a source in the 21st century as climate-driven losses exceed CO2-driven C gains, thereby accelerating global warming. Although it has long been recognized that tropical climate plays a critical role in regulating interannual climate variability, the causal link between changes in temperature and precipitation and terrestrial processes remains uncertain. Here, we combine atmospheric mass balance, remote sensing-modeled datasets of vegetation C uptake, and climate datasets to characterize the temporal variability of the terrestrial C sink and determine the dominant climate drivers of this variability. We show that the interannual variability of global land C sink has grown by 50-100% over the past 50 y. We further find that interannual land C sink variability is most strongly linked to tropical nighttime warming, likely through respiration. This apparent sensitivity of respiration to nighttime temperatures, which are projected to increase faster than global average temperatures, suggests that C stored in tropical forests may be vulnerable to future warming. PMID- 26644556 TI - Omega-3 deficiency impairs honey bee learning. AB - Deficiency in essential omega-3 polyunsaturated fatty acids (PUFAs), particularly the long-chain form of docosahexaenoic acid (DHA), has been linked to health problems in mammals, including many mental disorders and reduced cognitive performance. Insects have very low long-chain PUFA concentrations, and the effect of omega-3 deficiency on cognition in insects has not been studied. We show a low omega-6:3 ratio of pollen collected by honey bee colonies in heterogenous landscapes and in many hand-collected pollens that we analyzed. We identified Eucalyptus as an important bee-forage plant particularly poor in omega-3 and high in the omega-6:3 ratio. We tested the effect of dietary omega-3 deficiency on olfactory and tactile associative learning of the economically highly valued honey bee. Bees fed either of two omega-3-poor diets, or Eucalyptus pollen, showed greatly reduced learning abilities in conditioned proboscis-extension assays compared with those fed omega-3-rich diets, or omega-3-rich pollen mixture. The effect on performance was not due to reduced sucrose sensitivity. Omega-3 deficiency also led to smaller hypopharyngeal glands. Bee brains contained high omega-3 concentrations, which were only slightly affected by diet, suggesting additional peripheral effects on learning. The shift from a low to high omega-6:3 ratio in the Western human diet is deemed a primary cause of many diseases and reduced mental health. A similar shift seems to be occurring in bee forage, possibly an important factor in colony declines. Our study shows the detrimental effect on cognitive performance of omega-3 deficiency in a nonmammal. PMID- 26644557 TI - Gut bacteria mediate aggregation in the German cockroach. AB - Aggregation of the German cockroach, Blattella germanica, is regulated by fecal aggregation agents (pheromones), including volatile carboxylic acids (VCAs). We demonstrate that the gut microbial community contributes to production of these semiochemicals. Chemical analysis of the fecal extract of B. germanica revealed 40 VCAs. Feces from axenic cockroaches (no microorganisms in the alimentary tract) lacked 12 major fecal VCAs, and 24 of the remaining compounds were represented at extremely low amounts. Olfactory and aggregation bioassays demonstrated that nymphs strongly preferred the extract of control feces over the fecal extract of axenic cockroaches. Additionally, nymphs preferred a synthetic blend of 6 fecal VCAs over a solvent control or a previously identified VCA blend. To test whether gut bacteria contribute to the production of fecal aggregation agents, fecal aerobic bacteria were cultured, isolated, and identified. Inoculation of axenic cockroaches with individual bacterial taxa significantly rescued the aggregation response to the fecal extract, and inoculation with a mix of six bacterial isolates was more effective than with single isolates. The results indicate that the commensal gut microbiota contributes to production of VCAs that act as fecal aggregation agents and that cockroaches discriminate among the complex odors that emanate from a diverse microbial community. Our results highlight the pivotal role of gut bacteria in mediating insect-insect communication. Moreover, because the gut microbial community reflects the local environment, local plasticity in fecal aggregation pheromones enables colony-specific odors and fidelity to persistent aggregation sites. PMID- 26644558 TI - Saccade direction encoding in the primate entorhinal cortex during visual exploration. AB - We recently demonstrated that position in visual space is represented by grid cells in the primate entorhinal cortex (EC), suggesting that visual exploration of complex scenes in primates may employ signaling mechanisms similar to those used during exploration of physical space via movement in rodents. Here, we describe a group of saccade direction (SD) cells that encode eye movement information in the monkey EC during free-viewing of complex images. Significant saccade direction encoding was found in 20% of the cells recorded in the posterior EC. SD cells were generally broadly tuned and two largely separate populations of SD cells encoded future and previous saccade direction. Some properties of these cells resemble those of head-direction cells in rodent EC, suggesting that the same neural circuitry may be capable of performing homologous spatial computations under different exploratory contexts. PMID- 26644559 TI - Obesity diminishes synaptic markers, alters microglial morphology, and impairs cognitive function. AB - Obesity is a major public health problem affecting overall physical and emotional well-being. Despite compelling data suggesting an association between obesity and cognitive dysfunction, this phenomenon has received relatively little attention. Neuroimaging studies in obese humans report reduced size of brain regions involved in cognition, but few studies have investigated the cellular processes underlying cognitive decline in obesity or the influence of obesity on cognition in the absence of obesity-related illnesses. Here, a rat model of diet-induced obesity was used to explore changes in brain regions important for cognition. Obese rats showed deficits on cognitive tasks requiring the prefrontal and perirhinal cortex. Cognitive deficits were accompanied by decreased dendritic spine density and synaptic marker expression in both brain regions. Microglial morphology was also changed in the prefrontal cortex. Detrimental changes in the prefrontal cortex and perirhinal cortex occurred before metabolic syndrome or diabetes, suggesting that these brain regions may be particularly vulnerable to early stage obesity. PMID- 26644560 TI - Inequality, climate impacts on the future poor, and carbon prices. AB - Integrated assessment models of climate and the economy provide estimates of the social cost of carbon and inform climate policy. We create a variant of the Regional Integrated model of Climate and the Economy (RICE)-a regionally disaggregated version of the Dynamic Integrated model of Climate and the Economy (DICE)-in which we introduce a more fine-grained representation of economic inequalities within the model's regions. This allows us to model the common observation that climate change impacts are not evenly distributed within regions and that poorer people are more vulnerable than the rest of the population. Our results suggest that this is important to the social cost of carbon-as significant, potentially, for the optimal carbon price as the debate between Stern and Nordhaus on discounting. PMID- 26644561 TI - Constant mortality and fertility over age in Hydra. AB - Senescence, the increase in mortality and decline in fertility with age after maturity, was thought to be inevitable for all multicellular species capable of repeated breeding. Recent theoretical advances and compilations of data suggest that mortality and fertility trajectories can go up or down, or remain constant with age, but the data are scanty and problematic. Here, we present compelling evidence for constant age-specific death and reproduction rates in Hydra, a basal metazoan, in a set of experiments comprising more than 3.9 million days of observations of individual Hydra. Our data show that 2,256 Hydra from two closely related species in two laboratories in 12 cohorts, with cohort age ranging from 0 to more than 41 y, have extremely low, constant rates of mortality. Fertility rates for Hydra did not systematically decline with advancing age. This falsifies the universality of the theories of the evolution of aging that posit that all species deteriorate with age after maturity. The nonsenescent life history of Hydra implies levels of maintenance and repair that are sufficient to prevent the accumulation of damage for at least decades after maturity, far longer than the short life expectancy of Hydra in the wild. A high proportion of stem cells, constant and rapid cell turnover, few cell types, a simple body plan, and the fact that the germ line is not segregated from the soma are characteristics of Hydra that may make nonsenescence feasible. Nonsenescence may be optimal because lifetime reproduction may be enhanced more by extending adult life spans than by increasing daily fertility. PMID- 26644562 TI - The ancestral gene repertoire of animal stem cells. AB - Stem cells are pivotal for development and tissue homeostasis of multicellular animals, and the quest for a gene toolkit associated with the emergence of stem cells in a common ancestor of all metazoans remains a major challenge for evolutionary biology. We reconstructed the conserved gene repertoire of animal stem cells by transcriptomic profiling of totipotent archeocytes in the demosponge Ephydatia fluviatilis and by tracing shared molecular signatures with flatworm and Hydra stem cells. Phylostratigraphy analyses indicated that most of these stem-cell genes predate animal origin, with only few metazoan innovations, notably including several partners of the Piwi machinery known to promote genome stability. The ancestral stem-cell transcriptome is strikingly poor in transcription factors. Instead, it is rich in RNA regulatory actors, including components of the "germ-line multipotency program" and many RNA-binding proteins known as critical regulators of mammalian embryonic stem cells. PMID- 26644563 TI - Tmem178 acts in a novel negative feedback loop targeting NFATc1 to regulate bone mass. AB - Phospholipase C gamma-2 (PLCgamma2)-dependent calcium (Ca(2+)) oscillations are indispensable for nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1) activation and downstream gene transcription driving osteoclastogenesis during skeletal remodeling and pathological bone loss. Here we describe, to our knowledge, the first known function of transmembrane protein 178 (Tmem178), a PLCgamma2 downstream target gene, as a critical modulator of the NFATc1 axis. In surprising contrast to the osteopetrotic phenotype of PLCgamma2(-/-) mice, Tmem178(-/-) mice are osteopenic in basal conditions and are more susceptible to inflammatory bone loss, owing to enhanced osteoclast formation. Mechanistically, Tmem178 localizes to the ER membrane and regulates RANKL-induced Ca(2+) fluxes, thus controlling NFATc1 induction. Importantly, down-regulation of Tmem178 is observed in human CD14(+) monocytes exposed to plasma from systemic juvenile idiopathic arthritis patients. Similar to the mouse model, reduced Tmem178 expression in human cells correlates with excessive osteoclastogenesis. In sum, these findings identify an essential role for Tmem178 to maintain skeletal mass and limit pathological bone loss. PMID- 26644564 TI - Human cerebral organoids recapitulate gene expression programs of fetal neocortex development. AB - Cerebral organoids-3D cultures of human cerebral tissue derived from pluripotent stem cells-have emerged as models of human cortical development. However, the extent to which in vitro organoid systems recapitulate neural progenitor cell proliferation and neuronal differentiation programs observed in vivo remains unclear. Here we use single-cell RNA sequencing (scRNA-seq) to dissect and compare cell composition and progenitor-to-neuron lineage relationships in human cerebral organoids and fetal neocortex. Covariation network analysis using the fetal neocortex data reveals known and previously unidentified interactions among genes central to neural progenitor proliferation and neuronal differentiation. In the organoid, we detect diverse progenitors and differentiated cell types of neuronal and mesenchymal lineages and identify cells that derived from regions resembling the fetal neocortex. We find that these organoid cortical cells use gene expression programs remarkably similar to those of the fetal tissue to organize into cerebral cortex-like regions. Our comparison of in vivo and in vitro cortical single-cell transcriptomes illuminates the genetic features underlying human cortical development that can be studied in organoid cultures. PMID- 26644566 TI - Endohedral gallide cluster superconductors and superconductivity in ReGa5. AB - We present transition metal-embedded (T@Gan) endohedral Ga-clusters as a favorable structural motif for superconductivity and develop empirical, molecule based, electron counting rules that govern the hierarchical architectures that the clusters assume in binary phases. Among the binary T@Gan endohedral cluster systems, Mo8Ga41, Mo6Ga31, Rh2Ga9, and Ir2Ga9 are all previously known superconductors. The well-known exotic superconductor PuCoGa5 and related phases are also members of this endohedral gallide cluster family. We show that electron deficient compounds like Mo8Ga41 prefer architectures with vertex-sharing gallium clusters, whereas electron-rich compounds, like PdGa5, prefer edge-sharing cluster architectures. The superconducting transition temperatures are highest for the electron-poor, corner-sharing architectures. Based on this analysis, the previously unknown endohedral cluster compound ReGa5 is postulated to exist at an intermediate electron count and a mix of corner sharing and edge sharing cluster architectures. The empirical prediction is shown to be correct and leads to the discovery of superconductivity in ReGa5. The Fermi levels for endohedral gallide cluster compounds are located in deep pseudogaps in the electronic densities of states, an important factor in determining their chemical stability, while at the same time limiting their superconducting transition temperatures. PMID- 26644567 TI - Correction for Liang et al., Observing (non)linear lattice dynamics in graphite by ultrafast Kikuchi diffraction. PMID- 26644565 TI - Antiinfectives targeting enzymes and the proton motive force. AB - There is a growing need for new antibiotics. Compounds that target the proton motive force (PMF), uncouplers, represent one possible class of compounds that might be developed because they are already used to treat parasitic infections, and there is interest in their use for the treatment of other diseases, such as diabetes. Here, we tested a series of compounds, most with known antiinfective activity, for uncoupler activity. Many cationic amphiphiles tested positive, and some targeted isoprenoid biosynthesis or affected lipid bilayer structure. As an example, we found that clomiphene, a recently discovered undecaprenyl diphosphate synthase inhibitor active against Staphylococcus aureus, is an uncoupler. Using in silico screening, we then found that the anti-glioblastoma multiforme drug lead vacquinol is an inhibitor of Mycobacterium tuberculosis tuberculosinyl adenosine synthase, as well as being an uncoupler. Because vacquinol is also an inhibitor of M. tuberculosis cell growth, we used similarity searches based on the vacquinol structure, finding analogs with potent (~0.5-2 MUg/mL) activity against M. tuberculosis and S. aureus. Our results give a logical explanation of the observation that most new tuberculosis drug leads discovered by phenotypic screens and genome sequencing are highly lipophilic (logP ~5.7) bases with membrane targets because such species are expected to partition into hydrophobic membranes, inhibiting membrane proteins, in addition to collapsing the PMF. This multiple targeting is expected to be of importance in overcoming the development of drug resistance because targeting membrane physical properties is expected to be less susceptible to the development of resistance. PMID- 26644569 TI - Computational complexity of ecological and evolutionary spatial dynamics. AB - There are deep, yet largely unexplored, connections between computer science and biology. Both disciplines examine how information proliferates in time and space. Central results in computer science describe the complexity of algorithms that solve certain classes of problems. An algorithm is deemed efficient if it can solve a problem in polynomial time, which means the running time of the algorithm is a polynomial function of the length of the input. There are classes of harder problems for which the fastest possible algorithm requires exponential time. Another criterion is the space requirement of the algorithm. There is a crucial distinction between algorithms that can find a solution, verify a solution, or list several distinct solutions in given time and space. The complexity hierarchy that is generated in this way is the foundation of theoretical computer science. Precise complexity results can be notoriously difficult. The famous question whether polynomial time equals nondeterministic polynomial time (i.e., P = NP) is one of the hardest open problems in computer science and all of mathematics. Here, we consider simple processes of ecological and evolutionary spatial dynamics. The basic question is: What is the probability that a new invader (or a new mutant) will take over a resident population? We derive precise complexity results for a variety of scenarios. We therefore show that some fundamental questions in this area cannot be answered by simple equations (assuming that P is not equal to NP). PMID- 26644568 TI - Origins of stereoselectivity in evolved ketoreductases. AB - Mutants of Lactobacillus kefir short-chain alcohol dehydrogenase, used here as ketoreductases (KREDs), enantioselectively reduce the pharmaceutically relevant substrates 3-thiacyclopentanone and 3-oxacyclopentanone. These substrates differ by only the heteroatom (S or O) in the ring, but the KRED mutants reduce them with different enantioselectivities. Kinetic studies show that these enzymes are more efficient with 3-thiacyclopentanone than with 3-oxacyclopentanone. X-ray crystal structures of apo- and NADP(+)-bound selected mutants show that the substrate-binding loop conformational preferences are modified by these mutations. Quantum mechanical calculations and molecular dynamics (MD) simulations are used to investigate the mechanism of reduction by the enzyme. We have developed an MD-based method for studying the diastereomeric transition state complexes and rationalize different enantiomeric ratios. This method, which probes the stability of the catalytic arrangement within the theozyme, shows a correlation between the relative fractions of catalytically competent poses for the enantiomeric reductions and the experimental enantiomeric ratio. Some mutations, such as A94F and Y190F, induce conformational changes in the active site that enlarge the small binding pocket, facilitating accommodation of the larger S atom in this region and enhancing S-selectivity with 3 thiacyclopentanone. In contrast, in the E145S mutant and the final variant evolved for large-scale production of the intermediate for the antibiotic sulopenem, R-selectivity is promoted by shrinking the small binding pocket, thereby destabilizing the pro-S orientation. PMID- 26644570 TI - Nitrogen regulator GlnR controls uptake and utilization of non-phosphotransferase system carbon sources in actinomycetes. AB - The regulatory mechanisms underlying the uptake and utilization of multiple types of carbohydrates in actinomycetes remain poorly understood. In this study, we show that GlnR (central regulator of nitrogen metabolism) serves as a universal regulator of nitrogen metabolism and plays an important, previously unknown role in controlling the transport of non-phosphotransferase-system (PTS) carbon sources in actinomycetes. It was observed that GlnR can directly interact with the promoters of most (13 of 20) carbohydrate ATP-binding cassette (ABC) transporter loci and can activate the transcription of these genes in response to nitrogen availability in industrial, erythromycin-producing Saccharopolyspora erythraea. Deletion of the glnR gene resulted in severe growth retardation under the culture conditions used, with select ABC-transported carbohydrates (maltose, sorbitol, mannitol, cellobiose, trehalose, or mannose) used as the sole carbon source. Furthermore, we found that GlnR-mediated regulation of carbohydrate transport was highly conserved in actinomycetes. These results demonstrate that GlnR serves a role beyond nitrogen metabolism, mediating critical functions in carbon metabolism and crosstalk of nitrogen- and carbon-metabolism pathways in response to the nutritional states of cells. These findings provide insights into the molecular regulation of transport and metabolism of non-PTS carbohydrates and reveal potential applications for the cofermentation of biomass-derived sugars in the production of biofuels and bio-based chemicals. PMID- 26644571 TI - Probing nonlinear rheology layer-by-layer in interfacial hydration water. AB - Viscoelastic fluids exhibit rheological nonlinearity at a high shear rate. Although typical nonlinear effects, shear thinning and shear thickening, have been usually understood by variation of intrinsic quantities such as viscosity, one still requires a better understanding of the microscopic origins, currently under debate, especially on the shear-thickening mechanism. We present accurate measurements of shear stress in the bound hydration water layer using noncontact dynamic force microscopy. We find shear thickening occurs above ~ 10(6) s(-1) shear rate beyond 0.3-nm layer thickness, which is attributed to the nonviscous, elasticity-associated fluidic instability via fluctuation correlation. Such a nonlinear fluidic transition is observed due to the long relaxation time (~ 10( 6) s) of water available in the nanoconfined hydration layer, which indicates the onset of elastic turbulence at nanoscale, elucidating the interplay between relaxation and shear motion, which also indicates the onset of elastic turbulence at nanoscale above a universal shear velocity of ~ 1 mm/s. This extensive layer by-layer control paves the way for fundamental studies of nonlinear nanorheology and nanoscale hydrodynamics, as well as provides novel insights on viscoelastic dynamics of interfacial water. PMID- 26644573 TI - Discovery of oncogenes: The advent of molecular cancer research. PMID- 26644572 TI - Topological analyses in APP/PS1 mice reveal that astrocytes do not migrate to amyloid-beta plaques. AB - Although the clustering of GFAP immunopositive astrocytes around amyloid-beta plaques in Alzheimer's disease has led to the widespread assumption that plaques attract astrocytes, recent studies suggest that astrocytes stay put in injury. Here we reexamine astrocyte migration to plaques, using quantitative spatial analysis and computer modeling to investigate the topology of astrocytes in 3D images obtained by two-photon microscopy of living APP/PS1 mice and WT littermates. In WT mice, cortical astrocyte topology fits a model in which a liquid of hard spheres exclude each other in a confined space. Plaques do not disturb this arrangement except at very large plaque loads, but, locally, cause subtle outward shifts of the astrocytes located in three tiers around plaques. These data suggest that astrocytes respond to plaque-induced neuropil injury primarily by changing phenotype, and hence function, rather than location. PMID- 26644575 TI - Discovery of a nucleocytoplasmic O-mannose glycoproteome in yeast. AB - Dynamic cycling of N-Acetylglucosamine (GlcNAc) on serine and threonine residues (O-GlcNAcylation) is an essential process in all eukaryotic cells except yeast, including Saccharomyces cerevisiae and Schizosaccharomyces pombe. O-GlcNAcylation modulates signaling and cellular processes in an intricate interplay with protein phosphorylation and serves as a key sensor of nutrients by linking the hexosamine biosynthetic pathway to cellular signaling. A longstanding conundrum has been how yeast survives without O-GlcNAcylation in light of its similar phosphorylation signaling system. We previously developed a sensitive lectin enrichment and mass spectrometry workflow for identification of the human O-linked mannose (O-Man) glycoproteome and used this to identify a pleothora of O-Man glycoproteins in human cell lines including the large family of cadherins and protocadherins. Here, we applied the workflow to yeast with the aim to characterize the yeast O Man glycoproteome, and in doing so, we discovered hitherto unknown O-Man glycosites on nuclear, cytoplasmic, and mitochondrial proteins in S. cerevisiae and S. pombe. Such O-Man glycoproteins were not found in our analysis of human cell lines. However, the type of yeast O-Man nucleocytoplasmic proteins and the localization of identified O-Man residues mirror that of the O-GlcNAc glycoproteome found in other eukaryotic cells, indicating that the two different types of O-glycosylations serve the same important biological functions. The discovery opens for exploration of the enzymatic machinery that is predicted to regulate the nucleocytoplasmic O-Man glycosylations. It is likely that manipulation of this type of O-Man glycosylation will have wide applications for yeast bioprocessing. PMID- 26644576 TI - Repeatable and adjustable on-demand sciatic nerve block with phototriggerable liposomes. AB - Pain management would be greatly enhanced by a formulation that would provide local anesthesia at the time desired by patients and with the desired intensity and duration. To this end, we have developed near-infrared (NIR) light-triggered liposomes to provide on-demand adjustable local anesthesia. The liposomes contained tetrodotoxin (TTX), which has ultrapotent local anesthetic properties. They were made photo-labile by encapsulation of a NIR-triggerable photosensitizer; irradiation at 730 nm led to peroxidation of liposomal lipids, allowing drug release. In vitro, 5.6% of TTX was released upon NIR irradiation, which could be repeated a second time. The formulations were not cytotoxic in cell culture. In vivo, injection of liposomes containing TTX and the photosensitizer caused an initial nerve block lasting 13.5 +/- 3.1 h. Additional periods of nerve block could be induced by irradiation at 730 nm. The timing, intensity, and duration of nerve blockade could be controlled by adjusting the timing, irradiance, and duration of irradiation. Tissue reaction to this formulation and the associated irradiation was benign. PMID- 26644577 TI - Spatial response of coastal marshes to increased atmospheric CO2. AB - The elevation and extent of coastal marshes are dictated by the interplay between the rate of relative sea-level rise (RRSLR), surface accretion by inorganic sediment deposition, and organic soil production by plants. These accretion processes respond to changes in local and global forcings, such as sediment delivery to the coast, nutrient concentrations, and atmospheric CO2, but their relative importance for marsh resilience to increasing RRSLR remains unclear. In particular, marshes up-take atmospheric CO2 at high rates, thereby playing a major role in the global carbon cycle, but the morphologic expression of increasing atmospheric CO2 concentration, an imminent aspect of climate change, has not yet been isolated and quantified. Using the available observational literature and a spatially explicit ecomorphodynamic model, we explore marsh responses to increased atmospheric CO2, relative to changes in inorganic sediment availability and elevated nitrogen levels. We find that marsh vegetation response to foreseen elevated atmospheric CO2 is similar in magnitude to the response induced by a varying inorganic sediment concentration, and that it increases the threshold RRSLR initiating marsh submergence by up to 60% in the range of forcings explored. Furthermore, we find that marsh responses are inherently spatially dependent, and cannot be adequately captured through 0-dimensional representations of marsh dynamics. Our results imply that coastal marshes, and the major carbon sink they represent, are significantly more resilient to foreseen climatic changes than previously thought. PMID- 26644574 TI - TMEM110 regulates the maintenance and remodeling of mammalian ER-plasma membrane junctions competent for STIM-ORAI signaling. AB - The stromal interaction molecule (STIM)-ORAI calcium release-activated calcium modulator (ORAI) pathway controls store-dependent calcium entry, a major mechanism of physiological calcium signaling in mammalian cells. The core elements of the pathway are the regulatory protein STIM1, located in the endoplasmic reticulum (ER) membrane, the calcium channel ORAI1 in the plasma membrane, and sites of close contact between the ER and the plasma membrane that permit the two proteins to interact. Research on calcium signaling has centered on STIM1, ORAI1, and a few proteins that directly modulate STIM-ORAI function. However, little is known about proteins that organize ER-plasma membrane junctions for STIM-ORAI-dependent calcium signaling. Here, we report that an ER resident membrane protein identified in a previous genome-wide RNAi screen, transmembrane protein 110 (TMEM110), regulates the long-term maintenance of ER plasma membrane junctions and the short-term physiological remodeling of the junctions during store-dependent calcium signaling. PMID- 26644578 TI - Molecular mechanisms underlying the exceptional adaptations of batoid fins. AB - Extreme novelties in the shape and size of paired fins are exemplified by extinct and extant cartilaginous and bony fishes. Pectoral fins of skates and rays, such as the little skate (Batoid, Leucoraja erinacea), show a strikingly unique morphology where the pectoral fin extends anteriorly to ultimately fuse with the head. This results in a morphology that essentially surrounds the body and is associated with the evolution of novel swimming mechanisms in the group. In an approach that extends from RNA sequencing to in situ hybridization to functional assays, we show that anterior and posterior portions of the pectoral fin have different genetic underpinnings: canonical genes of appendage development control posterior fin development via an apical ectodermal ridge (AER), whereas an alternative Homeobox (Hox)-Fibroblast growth factor (Fgf)-Wingless type MMTV integration site family (Wnt) genetic module in the anterior region creates an AER-like structure that drives anterior fin expansion. Finally, we show that GLI family zinc finger 3 (Gli3), which is an anterior repressor of tetrapod digits, is expressed in the posterior half of the pectoral fin of skate, shark, and zebrafish but in the anterior side of the pelvic fin. Taken together, these data point to both highly derived and deeply ancestral patterns of gene expression in skate pectoral fins, shedding light on the molecular mechanisms behind the evolution of novel fin morphologies. PMID- 26644579 TI - The precise temporal calibration of dinosaur origins. AB - Dinosaurs have been major components of ecosystems for over 200 million years. Although different macroevolutionary scenarios exist to explain the Triassic origin and subsequent rise to dominance of dinosaurs and their closest relatives (dinosauromorphs), all lack critical support from a precise biostratigraphically independent temporal framework. The absence of robust geochronologic age control for comparing alternative scenarios makes it impossible to determine if observed faunal differences vary across time, space, or a combination of both. To better constrain the origin of dinosaurs, we produced radioisotopic ages for the Argentinian Chanares Formation, which preserves a quintessential assemblage of dinosaurian precursors (early dinosauromorphs) just before the first dinosaurs. Our new high-precision chemical abrasion thermal ionization mass spectrometry (CA TIMS) U-Pb zircon ages reveal that the assemblage is early Carnian (early Late Triassic), 5- to 10-Ma younger than previously thought. Combined with other geochronologic data from the same basin, we constrain the rate of dinosaur origins, demonstrating their relatively rapid origin in a less than 5-Ma interval, thus halving the temporal gap between assemblages containing only dinosaur precursors and those with early dinosaurs. After their origin, dinosaurs only gradually dominated mid- to high-latitude terrestrial ecosystems millions of years later, closer to the Triassic-Jurassic boundary. PMID- 26644581 TI - CREB pathway links PGE2 signaling with macrophage polarization. AB - Obesity is thought to promote insulin resistance in part via activation of the innate immune system. Increases in proinflammatory cytokine production by M1 macrophages inhibit insulin signaling in white adipose tissue. In contrast, M2 macrophages have been found to enhance insulin sensitivity in part by reducing adipose tissue inflammation. The paracrine hormone prostaglandin E2 (PGE2) enhances M2 polarization in part through activation of the cAMP pathway, although the underlying mechanism is unclear. Here we show that PGE2 stimulates M2 polarization via the cyclic AMP-responsive element binding (CREB)-mediated induction of Krupple-like factor 4 (KLF4). Targeted disruption of CREB or the cAMP-regulated transcriptional coactivators 2 and 3 (CRTC2/3) in macrophages down regulated M2 marker gene expression and promoted insulin resistance in the context of high-fat diet feeding. As re-expression of KLF4 rescued M2 marker gene expression in CREB-depleted cells, our results demonstrate the importance of the CREB/CRTC pathway in maintaining insulin sensitivity in white adipose tissue via its effects on the innate immune system. PMID- 26644580 TI - Continuous 1.3-million-year record of East African hydroclimate, and implications for patterns of evolution and biodiversity. AB - The transport of moisture in the tropics is a critical process for the global energy budget and on geologic timescales, has markedly influenced continental landscapes, migratory pathways, and biological evolution. Here we present a continuous, first-of-its-kind 1.3-My record of continental hydroclimate and lake level variability derived from drill core data from Lake Malawi, East Africa (9 15 degrees S). Over the Quaternary, we observe dramatic shifts in effective moisture, resulting in large-scale changes in one of the world's largest lakes and most diverse freshwater ecosystems. Results show evidence for 24 lake level drops of more than 200 m during the Late Quaternary, including 15 lowstands when water levels were more than 400 m lower than modern. A dramatic shift is observed at the Mid-Pleistocene Transition (MPT), consistent with far-field climate forcing, which separates vastly different hydroclimate regimes before and after ~800,000 years ago. Before 800 ka, lake levels were lower, indicating a climate drier than today, and water levels changed frequently. Following the MPT high amplitude lake level variations dominate the record. From 800 to 100 ka, a deep, often overfilled lake occupied the basin, indicating a wetter climate, but these highstands were interrupted by prolonged intervals of extreme drought. Periods of high lake level are observed during times of high eccentricity. The extreme hydroclimate variability exerted a profound influence on the Lake Malawi endemic cichlid fish species flock; the geographically extensive habitat reconfiguration provided novel ecological opportunities, enabling new populations to differentiate rapidly to distinct species. PMID- 26644582 TI - Palmitoyl acyltransferase Aph2 in cardiac function and the development of cardiomyopathy. AB - Protein palmitoylation regulates many aspects of cell function and is carried out by acyl transferases that contain zf-DHHC motifs. The in vivo physiological function of protein palmitoylation is largely unknown. Here we generated mice deficient in the acyl transferase Aph2 (Ablphilin 2 or zf-DHHC16) and demonstrated an essential role for Aph2 in embryonic/postnatal survival, eye development, and heart development. Aph2(-/-) embryos and pups showed cardiomyopathy and cardiac defects including bradycardia. We identified phospholamban, a protein often associated with human cardiomyopathy, as an interacting partner and a substrate of Aph2. Aph2-mediated palmitoylation of phospholamban on cysteine 36 differentially alters its interaction with PKA and protein phosphatase 1 alpha, augmenting serine 16 phosphorylation, and regulates phospholamban pentamer formation. Aph2 deficiency results in phospholamban hypophosphorylation, a hyperinhibitory form. Ablation of phospholamban in Aph2(-/ ) mice histologically and functionally alleviated the heart defects. These findings establish Aph2 as a critical in vivo regulator of cardiac function and reveal roles for protein palmitoylation in the development of other organs including eyes. PMID- 26644583 TI - Fasting protects mice from lethal DNA damage by promoting small intestinal epithelial stem cell survival. AB - Short-term fasting protects mice from lethal doses of chemotherapy through undetermined mechanisms. Herein, we demonstrate that fasting preserves small intestinal (SI) architecture by maintaining SI stem cell viability and SI barrier function following exposure to high-dose etoposide. Nearly all SI stem cells were lost in fed mice, whereas fasting promoted sufficient SI stem cell survival to preserve SI integrity after etoposide treatment. Lineage tracing demonstrated that multiple SI stem cell populations, marked by Lgr5, Bmi1, or HopX expression, contributed to fasting-induced survival. DNA repair and DNA damage response genes were elevated in SI stem/progenitor cells of fasted etoposide-treated mice, which importantly correlated with faster resolution of DNA double-strand breaks and less apoptosis. Thus, fasting preserved SI stem cell viability as well as SI architecture and barrier function suggesting that fasting may reduce host toxicity in patients undergoing dose intensive chemotherapy. PMID- 26644584 TI - Reconciling divergent estimates of oil and gas methane emissions. AB - Published estimates of methane emissions from atmospheric data (top-down approaches) exceed those from source-based inventories (bottom-up approaches), leading to conflicting claims about the climate implications of fuel switching from coal or petroleum to natural gas. Based on data from a coordinated campaign in the Barnett Shale oil and gas-producing region of Texas, we find that top-down and bottom-up estimates of both total and fossil methane emissions agree within statistical confidence intervals (relative differences are 10% for fossil methane and 0.1% for total methane). We reduced uncertainty in top-down estimates by using repeated mass balance measurements, as well as ethane as a fingerprint for source attribution. Similarly, our bottom-up estimate incorporates a more complete count of facilities than past inventories, which omitted a significant number of major sources, and more effectively accounts for the influence of large emission sources using a statistical estimator that integrates observations from multiple ground-based measurement datasets. Two percent of oil and gas facilities in the Barnett accounts for half of methane emissions at any given time, and high emitting facilities appear to be spatiotemporally variable. Measured oil and gas methane emissions are 90% larger than estimates based on the US Environmental Protection Agency's Greenhouse Gas Inventory and correspond to 1.5% of natural gas production. This rate of methane loss increases the 20-y climate impacts of natural gas consumed in the region by roughly 50%. PMID- 26644585 TI - Stepping toward therapeutic CRISPR. PMID- 26644586 TI - BRD4 is a novel therapeutic target for liver fibrosis. AB - Liver fibrosis is characterized by the persistent deposition of extracellular matrix components by hepatic stellate cell (HSC)-derived myofibroblasts. It is the histological manifestation of progressive, but reversible wound-healing processes. An unabated fibrotic response results in chronic liver disease and cirrhosis, a pathological precursor of hepatocellular carcinoma. We report here that JQ1, a small molecule inhibitor of bromodomain-containing protein 4 (BRD4), a member of bromodomain and extraterminal (BET) proteins, abrogate cytokine induced activation of HSCs. Cistromic analyses reveal that BRD4 is highly enriched at enhancers associated with genes involved in multiple profibrotic pathways, where BRD4 is colocalized with profibrotic transcription factors. Furthermore, we show that JQ1 is not only protective, but can reverse the fibrotic response in carbon tetrachloride-induced fibrosis in mouse models. Our results implicate that BRD4 can act as a global genomic regulator to direct the fibrotic response through its coordinated regulation of myofibroblast transcription. This suggests BRD4 as a potential therapeutic target for patients with fibrotic complications. PMID- 26644587 TI - Supramolecular structure in the membrane of Staphylococcus aureus. AB - All life demands the temporal and spatial control of essential biological functions. In bacteria, the recent discovery of coordinating elements provides a framework to begin to explain cell growth and division. Here we present the discovery of a supramolecular structure in the membrane of the coccal bacterium Staphylococcus aureus, which leads to the formation of a large-scale pattern across the entire cell body; this has been unveiled by studying the distribution of essential proteins involved in lipid metabolism (PlsY and CdsA). The organization is found to require MreD, which determines morphology in rod-shaped cells. The distribution of protein complexes can be explained as a spontaneous pattern formation arising from the competition between the energy cost of bending that they impose on the membrane, their entropy of mixing, and the geometric constraints in the system. Our results provide evidence for the existence of a self-organized and nonpercolating molecular scaffold involving MreD as an organizer for optimal cell function and growth based on the intrinsic self assembling properties of biological molecules. PMID- 26644588 TI - Detecting long-term metabolic shifts using isotopomers: CO2-driven suppression of photorespiration in C3 plants over the 20th century. AB - Terrestrial vegetation currently absorbs approximately a third of anthropogenic CO2 emissions, mitigating the rise of atmospheric CO2. However, terrestrial net primary production is highly sensitive to atmospheric CO2 levels and associated climatic changes. In C3 plants, which dominate terrestrial vegetation, net photosynthesis depends on the ratio between photorespiration and gross photosynthesis. This metabolic flux ratio depends strongly on CO2 levels, but changes in this ratio over the past CO2 rise have not been analyzed experimentally. Combining CO2 manipulation experiments and deuterium NMR, we first establish that the intramolecular deuterium distribution (deuterium isotopomers) of photosynthetic C3 glucose contains a signal of the photorespiration/photosynthesis ratio. By tracing this isotopomer signal in herbarium samples of natural C3 vascular plant species, crops, and a Sphagnum moss species, we detect a consistent reduction in the photorespiration/photosynthesis ratio in response to the ~100-ppm CO2 increase between ~1900 and 2013. No difference was detected in the isotopomer trends between beet sugar samples covering the 20th century and CO2 manipulation experiments, suggesting that photosynthetic metabolism in sugar beet has not acclimated to increasing CO2 over >100 y. This provides observational evidence that the reduction of the photorespiration/photosynthesis ratio was ca. 25%. The Sphagnum results are consistent with the observed positive correlations between peat accumulation rates and photosynthetic rates over the Northern Hemisphere. Our results establish that isotopomers of plant archives contain metabolic information covering centuries. Our data provide direct quantitative information on the "CO2 fertilization" effect over decades, thus addressing a major uncertainty in Earth system models. PMID- 26644589 TI - Psychological autonomy and hierarchical relatedness as organizers of developmental pathways. AB - The definition of self and others can be regarded as embodying the two dimensions of autonomy and relatedness. Autonomy and relatedness are two basic human needs and cultural constructs at the same time. This implies that they may be differently defined yet remain equally important. The respective understanding of autonomy and relatedness is socialized during the everyday experiences of daily life routines from birth on. In this paper, two developmental pathways are portrayed that emphasize different conceptions of autonomy and relatedness that are adaptive in two different environmental contexts with very different affordances and constraints. Western middle-class children are socialized towards psychological autonomy, i.e. the primacy of own intentions, wishes, individual preferences and emotions affording a definition of relatedness as psychological negotiable construct. Non-Western subsistence farmer children are socialized towards hierarchical relatedness, i.e. positioning oneself into the hierarchical structure of a communal system affording a definition of autonomy as action oriented, based on responsibility and obligations. Infancy can be regarded as a cultural lens through which to study the different socialization agendas. Parenting strategies that aim at supporting these different socialization goals in German and Euro-American parents on the one hand and Nso farmers from North Western Cameroon on the other hand are described. It is concluded that different pathways need to be considered in order to understand human psychology from a global perspective. PMID- 26644590 TI - Why developmental psychology is incomplete without comparative and cross-cultural perspectives. AB - As a discipline, developmental psychology has a long history of relying on animal models and data collected among distinct cultural groups to enrich and inform theories of the ways social and cognitive processes unfold through the lifespan. However, approaches that draw together developmental, cross-cultural and comparative perspectives remain rare. The need for such an approach is reflected in the papers by Heyes (2015 Phil. Trans. R. Soc. B 371, 20150069. (doi:10.1098/rstb.2015.0069)), Schmelz & Call (2015 Phil. Trans. R. Soc. B 371, 20150067. (doi:10.1098/rstb.2015.0067)) and Keller (2015 Phil. Trans. R. Soc. B 371, 20150070. (doi:10.1098/rstb.2015.0070)) in this theme issue. Here, we incorporate these papers into a review of recent research endeavours covering a range of core aspects of social cognition, including social learning, cooperation and collaboration, prosociality, and theory of mind. In so doing, we aim to highlight how input from comparative and cross-cultural empiricism has altered our perspectives of human development and, in particular, led to a deeper understanding of the evolution of the human cultural mind. PMID- 26644591 TI - The origins of belonging: social motivation in infants and young children. AB - Our reliance on our group members has exerted a profound influence over our motivation: successful group functioning requires that we are motivated to interact, and engage, with those around us. In other words, we need to belong. In this article, I explore the developmental origins of our need to belong. I discuss existing evidence that, from early in development, children seek to affiliate with others and to form long-lasting bonds with their group members. Furthermore, when children are deprived of a sense of belonging, it has negative consequences for their well-being. This focus on social motivation enables us to examine why and in what circumstances children engage in particular behaviours. It thus provides an important complement to research on social cognition. In doing so, it opens up important questions for future research and provides a much needed bridge between developmental and social psychology. PMID- 26644592 TI - Group bias in cooperative norm enforcement. AB - A hallmark of human social cognition is the tendency for both adults and children to favour members of their own groups. Critically, this in-group bias exerts a strong influence on cooperative decision-making: people (i) tend to share more with members of their in-group and (ii) differentially enforce fairness norms depending on the group membership of their interaction partners. But why do people show these group biases in cooperation? One possibility is that the enforcement of cooperative norm violations is an evolved mechanism supporting within-group cooperation (Norms-Focused Hypothesis). Alternatively, group bias in cooperation could be a by-product of more general affective preferences for in group members (Mere Preferences Hypothesis). Here, we appraise evidence from studies of both adults and children with the goal of understanding whether one of these two accounts is better supported by existing data. While the pattern of evidence is complex, much of it is broadly consistent with the Mere Preferences Hypothesis and little is uniquely supportive of the Norms-Focused Hypothesis. We highlight possible reasons for this complexity and suggest ways that future work can continue to help us understand the important relationship between group bias and cooperation. PMID- 26644593 TI - The role of self-other distinction in understanding others' mental and emotional states: neurocognitive mechanisms in children and adults. AB - Social interactions come with the fundamental problem of trying to understand others' mental and affective states while under the overpowering influence of one's own concurrent thoughts and feelings. The ability to distinguish between simultaneous representations of others' current experiences as well as our own is crucial to navigate our complex social environments successfully. The developmental building blocks of this ability and how this is given rise to by functional and structural brain development remains poorly understood. In this review, I outline some of the key findings on the role of self-other distinction in understanding others' mental as well as emotional states in children and adults. I will begin by clarifying the crucial role for self-other distinction in avoiding egocentric attributions of one's own cognitive as well as affective states to others in adults and outline the underlying neural circuitry in overcoming such egocentricity. This will provide the basis for a discussion of the emergence of self-other distinction in early childhood as well as developmental changes therein throughout childhood and into adulthood. I will demonstrate that self-other distinction of cognitive and emotional states is already dissociable early in development. Concomitantly, I will show that processes of self-other distinction in cognitive and affective domains rely on adjacent but distinct neural circuitry each with unique connectivity profiles, presumably related to the nature of the distinction that needs to be made. PMID- 26644594 TI - The shaping of social perception by stimulus and knowledge cues to human animacy. AB - Although robots are becoming an ever-growing presence in society, we do not hold the same expectations for robots as we do for humans, nor do we treat them the same. As such, the ability to recognize cues to human animacy is fundamental for guiding social interactions. We review literature that demonstrates cortical networks associated with person perception, action observation and mentalizing are sensitive to human animacy information. In addition, we show that most prior research has explored stimulus properties of artificial agents (humanness of appearance or motion), with less investigation into knowledge cues (whether an agent is believed to have human or artificial origins). Therefore, currently little is known about the relationship between stimulus and knowledge cues to human animacy in terms of cognitive and brain mechanisms. Using fMRI, an elaborate belief manipulation, and human and robot avatars, we found that knowledge cues to human animacy modulate engagement of person perception and mentalizing networks, while stimulus cues to human animacy had less impact on social brain networks. These findings demonstrate that self-other similarities are not only grounded in physical features but are also shaped by prior knowledge. More broadly, as artificial agents fulfil increasingly social roles, a challenge for roboticists will be to manage the impact of pre-conceived beliefs while optimizing human-like design. PMID- 26644595 TI - Mechanisms and development of self-other distinction in dyads and groups. AB - This opinion piece offers a commentary on the four papers that address the theme of the development of self and other understanding with a view to highlighting the important contribution of developmental research to understanding of mechanisms of social cognition. We discuss potential mechanisms linking self other distinction and empathy, implications for grouping motor, affective and cognitive domains under a single mechanism, applications of these accounts for joint action and finally consider self-other distinction in group versus dyadic settings. PMID- 26644597 TI - Self-other control processes in social cognition: from imitation to empathy. AB - We review the evidence that an ability to achieve a precise balance between representing the self and representing other people is crucial in social interaction. This ability is required for imitation, perspective-taking, theory of mind and empathy; and disruption to this ability may contribute to the symptoms of clinical and sub-clinical conditions, including autism spectrum disorder and mirror-touch synaesthesia. Moving beyond correlational approaches, a recent intervention study demonstrated that training participants to control representations of the self and others improves their ability to control imitative behaviour, and to take another's visual perspective. However, it is unclear whether these effects apply to other areas of social interaction, such as the ability to empathize with others. We report original data showing that participants trained to increase self-other control in the motor domain demonstrated increased empathic corticospinal responses (Experiment 1) and self reported empathy (Experiment 2), as well as an increased ability to control imitation. These results suggest that the ability to control self and other representations contributes to empathy as well as to other types of social interaction. PMID- 26644596 TI - Empathy as a driver of prosocial behaviour: highly conserved neurobehavioural mechanisms across species. AB - Empathy reflects the natural ability to perceive and be sensitive to the emotional states of others, coupled with a motivation to care for their well being. It has evolved in the context of parental care for offspring, as well as within kinship bonds, to help facilitate group living. In this paper, we integrate the perspectives of evolution, animal behaviour, developmental psychology, and social and clinical neuroscience to elucidate our understanding of the proximate mechanisms underlying empathy. We focus, in particular, on processing of signals of distress and need, and their relation to prosocial behaviour. The ability to empathize, both in animals and humans, mediates prosocial behaviour when sensitivity to others' distress is paired with a drive towards their welfare. Disruption or atypical development of the neural circuits that process distress cues and integrate them with decision value leads to callous disregard for others, as is the case in psychopathy. The realization that basic forms of empathy exist in non-human animals is crucial for gaining new insights into the underlying neurobiological and genetic mechanisms of empathy, enabling translation towards therapeutic and pharmacological interventions. PMID- 26644598 TI - Gazing at me: the importance of social meaning in understanding direct-gaze cues. AB - Direct gaze is an engaging and important social cue, but the meaning of direct gaze depends heavily on the surrounding context. This paper reviews some recent studies of direct gaze, to understand more about what neural and cognitive systems are engaged by this social cue and why. The data show that gaze can act as an arousal cue and can modulate actions, and can activate brain regions linked to theory of mind and self-related processing. However, all these results are strongly modulated by the social meaning of a gaze cue and by whether participants believe that another person is really watching them. The implications of these contextual effects and audience effects for our theories of gaze are considered. PMID- 26644599 TI - Towards a second-person neuropsychiatry. AB - Psychiatric disorders can affect our ability to successfully and enjoyably interact with others. Conversely, having difficulties in social relations is known to increase the risk of developing a psychiatric disorder. In this article, the assumption that psychiatric disorders can be construed as disorders of social interaction is reviewed from a clinical point of view. Furthermore, it is argued that a psychiatrically motivated focus on the dynamics of social interaction may help to provide new perspectives for the field of social neuroscience. Such progress may be crucial to realize social neuroscience's translational potential and to advance the transdiagnostic investigation of the neurobiology of psychiatric disorders. PMID- 26644600 TI - Social cognitive impairment and autism: what are we trying to explain? AB - Early psychological theories of autism explained the clinical features of this condition in terms of perceptual and sensory processing impairments. The arrival of domain-specific social cognitive theories changed this focus, postulating a 'primary' and specific psychological impairment of social cognition. Across the years, evidence has been growing in support of social cognitive and social attention explanations in autism. However, there has also been evidence for general non-social cognitive impairments in representational understanding, attention allocation and sensory processing. Here, I review recent findings and consider the case for the specificity and primacy of the social cognitive impairment, proposing that we should focus more explicitly on clinically valid features for insights on the integration of 'social' and 'non-social' cognition. PMID- 26644601 TI - From shared to distinct self-other representations in empathy: evidence from neurotypical function and socio-cognitive disorders. AB - Neuroscientific research has identified two fundamental components of empathy: shared emotional representations between self and other, and self-other distinction. The concept of shared representations suggests that during empathy, we co-represent another person's affect by engaging brain and bodily functions underpinning the first-hand experience of the emotion we are empathizing with. This possible grounding of empathy in our own emotional experiences explains the necessity for self-other distinction, which is the capacity to correctly distinguish between our own affective representations and those related to the other. In spite of the importance of these two components in empathy, several aspects still remain controversial. This paper addresses some of them and focuses on (i) the distinction between shared activations versus representations, raising the question what shared representations entail in terms of the underlying neural mechanisms, (ii) the possible mechanisms behind self-other distinction in the cognitive and the affective domains, and whether they have distinct neural underpinnings and (iii) the consequences associated with a selective impairment of one of the two components, thereby addressing their importance in mental disorders such as autism spectrum disorders, psychopathy and alexithymia. PMID- 26644602 TI - Understanding self and others: from origins to disorders. AB - In order to interpret and engage with the social world, individuals must understand how they relate to others. Self-other understanding forms the backbone of social cognition and is a central concept explored by research into basic processes such as action perception and empathy, as well as research on more sophisticated social behaviours such as cooperation and intergroup interaction. This theme issue integrates the latest research into self-other understanding from evolutionary biology, anthropology, psychology, neuroscience and psychiatry. By gathering perspectives from a diverse range of disciplines, the contributions showcase ways in which research in these areas both informs and is informed by approaches spanning the biological and social sciences, thus deepening our understanding of how we relate to others in a social world. PMID- 26644603 TI - The psychology of primate cooperation and competition: a call for realigning research agendas. AB - Cooperation and competition are two key components of social life. Current research agendas investigating the psychological underpinnings of competition and cooperation in non-human primates are misaligned. The majority of work on competition has been done in the context of theory of mind and deception, while work on cooperation has mostly focused on collaboration and helping. The current impression that theory of mind is not necessarily implicated in cooperative activities and that helping could not be an integral part of competition might therefore be rather misleading. Furthermore, theory of mind research has mainly focused on cognitive aspects like the type of stimuli controlling responses, the nature of representation and how those representations are acquired, while collaboration and helping have focused primarily on motivational aspects like prosociality, common goals and a sense of justice and other-regarding concerns. We present the current state of these two bodies of research paying special attention to how they have developed and diverged over the years. We propose potential directions to realign the research agendas to investigate the psychological underpinnings of cooperation and competition in primates and other animals. PMID- 26644604 TI - Homo imitans? Seven reasons why imitation couldn't possibly be associative. AB - Many comparative and developmental psychologists believe that we are Homo imitans; humans are more skilled and prolific imitators than other animals, because we have a special, inborn 'intermodal matching' mechanism that integrates representations of others with representations of the self. In contrast, the associative sequence learning (ASL) model suggests that human infants learn to imitate using mechanisms that they share with other animals, and the rich resources provided by their sociocultural environments. This article answers seven objections to the ASL model: (i) it presents evidence that newborns do not imitate; (ii) argues that infants receive a plentiful supply of the kind of experience necessary for learning to imitate; (iii) suggests that neither infants nor adults can imitate elementally novel actions; (iv) explains why non-human animals have a limited capacity for imitation; (v) discusses the goal directedness of imitation; (vi) presents evidence that improvement in imitation depends on visual feedback; and (vii) reflects on the view that associative theories steal 'the soul of imitation'. The empirical success of the ASL model indicates that the mechanisms which make imitation possible, by aligning representations of self with representations of others, have been tweaked by cultural evolution, not built from scratch by genetic evolution. PMID- 26644605 TI - Structural Brain Network Disturbances in the Psychosis Spectrum. AB - BACKGROUND: Individuals with subclinical psychotic symptoms provide a unique window on the pathophysiology of psychotic experiences as these individuals are free of confounders such as hospitalization, negative and cognitive symptoms and medication use. Brain network disturbances of white matter connections are thought to play a central role in the pathophysiology of psychosis. Based on the structural network disconnection hypothesis in schizophrenia, we expect less and weaker connections, and altered brain network organization in individuals with clinical and those with subclinical psychotic symptoms. METHODS: We used diffusion tensor imaging to study 35 patients with a psychotic disorder, 35 subjects with subclinical psychotic symptoms, and 36 healthy controls. The structural brain network was analyzed on 3 levels: connection density, white matter microstructure (fractional anisotropy, mean diffusivity, and magnetic transfer ratio), and network organization. Network organization was studied with minimum spanning tree analysis, a method to reconstruct a backbone of structural highways in the brain. RESULTS: Decreased fractional anisotropy and increased mean diffusivity was found in both groups with psychotic symptoms, while their network topology showed decreased overlap with a healthy reference network. Decreased centrality was found in several brain regions, including parietal hubs and language areas, in both groups with psychotic symptoms. Deviation of network characteristics was more apparent in clinical subjects than in subclinical subjects. DISCUSSION: Weaker connections and decreased centrality of parietal hubs characterize the structural brain network in subjects with psychotic symptoms. These differences are more notable in clinical than in subclinical subjects with psychotic experiences. PMID- 26644606 TI - Key findings from the second Australian Child and Adolescent Survey of Mental Health and Wellbeing. AB - OBJECTIVE: To estimate the prevalence of mental disorders in children and adolescents in Australia, and the severity and impact of those mental disorders. METHOD: Seven mental disorders were assessed using the parent- or carer-completed version of the Diagnostic Interview Schedule for Children Version IV, and major depressive disorder was also assessed using the youth self-report version of the Diagnostic Interview Schedule for Children Version IV. Severity and impact were assessed using an extended version of the Diagnostic Interview Schedule for Children Version IV impact on functioning questions, and days absent from school due to symptoms of mental disorders. Data were collected in a national face-to face survey of 6310 parents or carers of children and adolescents aged 4-17 years, with 2969 young people aged 11-17 years also completing a self-report questionnaire. RESULTS: Twelve-month prevalence of mental disorders was 13.9%, with 2.1% of children and adolescents having severe disorders, 3.5% having moderate disorders and 8.3% having mild disorders. The most common class of disorders was attention-deficit/hyperactivity disorder followed by anxiety disorders. Mental disorders were more common in step-, blended- or one-parent families, in families living in rented accommodation and families where one or both carers were not in employment. Mental disorders were associated with a substantial number of days absent from school particularly in adolescents. CONCLUSION: Mental disorders are common in children and adolescents, often have significant impact and are associated with substantial absences from school. Child and adolescent mental disorders remain an important public health problem in Australia. Accurate information about prevalence and severity of child and adolescent mental disorders is an essential prerequisite for effective mental health policy and service planning. PMID- 26644607 TI - Innovative studies, eloquent peer reviewing and cultured editing: Academic desires and tangible dreams of an editor. PMID- 26644608 TI - Evaluation of adjusted central venous blood gases versus arterial blood gases of patients in post-operative paediatric cardiac surgical intensive care unit. AB - BACKGROUND AND AIMS: Central venous catheters are in situ in most of the intensive care unit (ICU) patients, which may be an alternative for determining acid-base status and can reduce complications from prolonged arterial cannulation. The aim of this study was to examine the reliability between adjusted central venous blood gas (aVBG) and arterial blood gas (ABG) samples for pH, partial pressure of carbon-di-oxide (pCO2), bicarbonate (HCO3 (-)), base excess (BE) and lactates in paediatric cardiac surgical ICU. METHODS: We applied blood gas adjustment rule, that is aVBG pH = venous blood gas (VBG) pH +0.05, aVBG CO2 = VBG pCO2 - 5 mm Hg from the prior studies. In this study, we validated this relationship with simultaneous arterial and central venous blood obtained from 30 patients with four blood sample pairs each in paediatric cardiac surgical ICU patients. RESULTS: There was a strong correlation (R i.e., Pearson's correlation) between ABG and aVBG for pH = 0.9544, pCO2 = 0.8738, lactate = 0.9741, HCO3 (-) = 0.9650 and BE = 0.9778. Intraclass correlation co-efficients (ICCs) for agreement improved after applying the adjustment rule to venous pH (0.7505 to 0.9454) and pCO2 (0.4354 to 0.741). Bland Altman showed bias (and limits of agreement) for pH: 0.008 (-0.04 to + 0.057), pCO2: -3.52 (-9.68 to +2.65), lactate: -0.10 (-0.51 to +0.30), HCO3 (-): -2.3 (-5.11 to +0.50) and BE: 0.80 (-3.09 to +1.49). CONCLUSION: ABG and aVBG samples showed strong correlation, acceptable mean differences and improved agreement (high ICC) after adjusting the VBG. Hence, it can be promising to use trend values of VBG instead of ABG in conjunction with a correction factor under stable haemodynamic conditions. PMID- 26644610 TI - Continuous epidural analgesia for post-operative pain relief in paediatric patients. PMID- 26644609 TI - Safety of post-operative epidural analgesia in the paediatric population: A retrospective analysis. AB - BACKGROUND AND AIMS: Epidural infusion analgesia (EIA) is among the common procedures performed in children to provide analgesia. However, the administration of epidural is not without complications. Limited studies are available regarding the safety of EIA in children with no studies from the Indian subcontinent. The aim of this study was to analyse all the complications that occured during administration and maintenance of EIA in paediatric patients. METHODS: All children undergoing elective or emergency surgeries under general anaesthesia and given concomitant epidural analgesia for post-operative pain management were included. Data were collected by reviewing patient medical records, anaesthesia registers and post-operative intensive care unit charts. Statistical averages were drawn to assess the complication rates. RESULTS: Seventy children received epidural analgesia during the span of study, of them five were neonates and fifteen were infants. No major complications that were life-threatening or leading to permanent disability were documented. Two children (2.85%) had blood tap during procedure. Eleven children (15%) had peri-catheter leaks and 14 children (20%) had catheter dislodgements. CONCLUSION: EIA seems to be a relatively safe method of providing analgesia. It is associated with the occurrence of complications which are at best temporary. PMID- 26644611 TI - Analgesic efficacy of three different dosages of intra-articular morphine in arthroscopic knee surgeries: Randomised double-blind trial. AB - BACKGROUND AND AIMS: Arthroscopic knee surgery is a common procedure and may cause enough pain to delay rehabilitation. Intra-articular (IA) morphine is a known modality for post-operative pain relief. However, the optimal dose of IA morphine has not been studied. The current study has been conducted to find out the optimal dosage of IA morphine when administered with 0.25% bupivacaine. METHODS: Sixty adult patients of either sex, aged between 18 and 60 years, undergoing diagnostic/therapeutic knee arthroscopic surgery were included in the study and randomised into three groups. All patients underwent surgery under subarachnoid block. After the surgical closure, 20 ml of 0.25% bupivacaine with 1 mg, 3 mg and 5 mg of morphine as additive was injected intra-articularly in Group A, B and C patients, respectively. Post-operative pain assessment was performed with visual analogue scale score in the 1(st), 2(nd), 6(th), 12(th) and 24(th) post-operative hour. The common complications were also recorded. RESULTS: There was statistically significant analgesia in Group B and C than Group A in the 1(st) and 2(nd) post-operative hour; while at the 24(th) post-operative hour, Group C had statistically significant analgesia than the other two groups. Time to first rescue analgesia was statistically significantly less and consumption of supplemental analgesia was significantly higher in Group A than the other two groups. CONCLUSION: IA dose of 3 mg and 5 mg morphine with 20 ml of 0.25% bupivacaine provided adequate analgesia. However, 3 mg morphine group patients had fewer side effects than 5 mg group patients although the difference was not statistically significant. PMID- 26644612 TI - Comparative study of two doses of intrathecal dexmedetomidine as adjuvant with low dose hyperbaric bupivacaine in ambulatory perianal surgeries: A prospective randomised controlled study. AB - BACKGROUND AND AIMS: Dexmedetomidine (DMT), as intrathecal adjuvant has been shown to successfully prolong duration of analgesia but delay the motor recovery. Hence, this study was designed to find out the dose of DMT which can provide satisfactory analgesia without prolonging motor block. METHODS: A total of 50 patients scheduled for elective perianal surgeries were randomly allocated to Groups C or D (n = 25). Group D received hyperbaric bupivacaine 0.5% 4 mg + DMT 5 MUg and Group C received hyperbaric bupivacaine 0.5% 4 mg + DMT 3 MUg intrathecally. Onset and duration of sensory and motor blockade, duration of analgesia, time for ambulation and first urination were recorded. Adverse effects if any were noted. RESULTS: Demographic characters, duration of surgery were comparable. The onset of sensory block to S1 was 9.61 +/- 5.53 min in Group C compared to 7.69 +/- 4.80 min in Group D (P = 0.35). Duration of sensory (145.28 +/- 83.17 min - C, 167.85 +/- 93.75 min - D, P = 0.5) and motor block (170.53 +/- 73.44 min - C, 196.14 +/- 84.28 min, P = 0.39) were comparable. Duration of analgesia (337.86 +/- 105.11 min - C, 340.78 +/- 101.81 min - D, P = 0.9) and time for ambulation (252.46 +/- 93.72 min - C, 253.64 +/- 88.04 min - D, P = 0.97) were also comparable. One patient in each group had urinary retention requiring catheterization. No other side effects were observed. CONCLUSION: Intrathecal DMT 3 MUg dose does not produce faster ambulation compared to intrathecal DMT 5 MUg though it produces comparable duration of analgesia for perianal surgeries. PMID- 26644613 TI - Efficacy and safety of low-dose ketamine as an adjunct analgesic and amnesic during caesarean section under general anaesthesia. AB - BACKGROUND AND AIMS: The practice of avoiding sedatives or anxiolytics during caesarean section under general anaesthesia (GA) until delivery of the baby could result in exaggerated haemodynamic responses and an increased risk of awareness. We aimed to assess the efficacy and safety of low-dose ketamine, used as an adjunct analgesic and amnesic, in attenuating these responses during caesarean section under GA. METHODS: This prospective, randomised study was conducted in 40 patients. Group K (n = 20) received 0.25 mg/kg ketamine, whereas Group C received 5 ml normal saline intravenously (IV) just before induction of anaesthesia. After intubation, patients were ventilated with O2 and N2O (40:60%) with 0.7% end-tidal isoflurane. Fentanyl and midazolam were given following delivery of the baby. Mann-Whitney and Fisher's exact tests were used for statistical analysis. RESULTS: Preinduction haemodynamic parameters and those recorded at 1 min after induction were comparable in both groups. However, heart rate and systolic blood pressure recorded after intubation (at 3, 5, 7, 9, 12, 15, 20, 30 and 45 min after induction) showed significantly high values in Group C (P < 0.05). Mean arterial pressure also showed a similar pattern. Umbilical vein pO2, pCO2 and pH were comparable in both groups. Though Apgar score at 1 min showed a higher scoring in Group K, at 5 min both groups had comparable scores. In Group C, intraoperative lacrimation (50% vs. 0%) and hallucinations/recall of intraoperative events (10% vs. 0%) were high. CONCLUSION: IV ketamine 0.25 mg/kg can be safely used as an adjunct analgesic and amnesic to attenuate haemodynamic responses during caesarean section under GA without affecting the foetal outcome. PMID- 26644614 TI - Comparison between perivascular and perineural ultrasound-guided axillary brachial plexus block using levobupivacaine: A prospective, randomised clinical study. AB - BACKGROUND AND AIMS: Ultrasound (US)-guided regional blocks are becoming increasingly popular as its use increases success rate, shortens block onset time and reduces complications. Currently, there exist two methods to perform US guided axillary brachial plexus block (US-ABPB), the perivascular (PV) and the perineural (PN) techniques. We compared the two techniques to study the block characteristics and other variables using levobupivacaine. METHODS: In this prospective, randomised trial, 60 patients were randomly allocated to receive a PV (n = 30) or PN (n = 30) US-ABPB. The local anaesthetic agent, 0.5% levobupivacaine and total volume of 36 ml of solution were identical in all the subjects. For both the groups, the musculocutaneous nerve was first located and then anaesthetised with 6 ml. Subsequently in the PV group, 30 ml was deposited dorsal to the axillary artery (6 o'clock position). In PN group, the median, ulnar and radial nerves were individually anaesthetised with volumes of 10 ml each. The onset and duration of sensory block, the onset and duration of motor block, number of failed blocks and complications were noted. RESULTS: No difference was observed between the two groups in terms of success rate (PV - 93.33%, PN - 96.66%), sensory onset (PN: 8.07 (standard deviation [SD] +/- 0.651) min and PV: 8.14 [SD +/- 1.079] min; P = 0.754), motor onset (PN: 14.62 [SD +/- 2.077] min and PV: 14.93 [SD +/- 1.844] min; P = 0.557) and total duration of anaesthesia. No complications were observed in both groups. CONCLUSION: The PV technique provides a simple alternative for PN US-ABPB. In the light of emerging needling positions for PV and PN techniques, this study calls for large scale trials and much research in this area before one defines best or safe approach. PV technique may be considered as an alternative method for US-ABPB in patients with anatomical variation or difficulties in identifying the individual nerves. PMID- 26644615 TI - Reversal agents in anaesthesia and critical care. AB - Despite the advent of short and ultra-short acting drugs, an in-depth knowledge of the reversal agents used is a necessity for any anaesthesiologist. Reversal agents are defined as any drug used to reverse the effects of anaesthetics, narcotics or potentially toxic agents. The controversy on the routine reversal of neuromuscular blockade still exists. The advent of newer reversal agents like sugammadex have made the use of steroidal neuromuscular blockers like rocuronium feasible in rapid sequence induction situations. We made a review of the older reversal agents and those still under investigation for drugs that are regularly used in our anaesthesia practice. PMID- 26644616 TI - Central neuraxial blockade for splenectomy in myeloproliferative disease: A word of caution. AB - We describe management of portal vein thrombosis (PVT) in a patient with myeloproliferative disease after splenectomy. This case posed a unique therapeutic challenge in maintaining a fine balance between life-saving thrombolysis and the risk of neuraxial complications due to bleeding. The incidence of PVT after splenectomy in patients with myeloproliferative disorders is high (40%). Anaesthesiologists should be aware of this and avoid central neuraxial blockade in such cases. If post-operative emergency thrombolysis is required in a patient having an epidural catheter in situ, it should be done under close monitoring, weighing the risks and benefits. Fibrinogen levels should be monitored to evaluate the presence of residual thrombolytic effects and to time the catheter removal. PMID- 26644617 TI - Magnification to avoid medication errors. PMID- 26644618 TI - Video rhino-laryngoscope modified into a fibreoptic bronchoscope. PMID- 26644619 TI - Identification of the epidural space-loss of resistance to saline: An inexpensive modification. PMID- 26644620 TI - Anaesthetic management of Ludwig's angina with comorbidities. PMID- 26644621 TI - Avascular necrosis of left Hip joint secondary to sickle cell anaemia for hip arthroplasty. PMID- 26644622 TI - Anaesthetic management of a patient with amyotrophic lateral sclerosis undergoing laparoscopic diaphragmatic pacing. PMID- 26644623 TI - Defibrillator maintenance policy. PMID- 26644624 TI - A child with difficult airway for magnetic resonance imaging: Is dexmedetomidine useful? PMID- 26644625 TI - Anaesthesia management in a patient with severe idiopathic thrombocytopaenia with antepartum haemorrhage for emergency caesarean section. PMID- 26644626 TI - Anaesthetic management of a pregnant patient posted for laparoscopic appendectomy in third trimester. PMID- 26644627 TI - Peripheral venous access in the obese patient. PMID- 26644628 TI - Local anaesthetic resistance in a young woman with history of scorpion bite. PMID- 26644629 TI - Softening in Random Networks of Non-Identical Beams. AB - Random fiber networks are assemblies of elastic elements connected in random configurations. They are used as models for a broad range of fibrous materials including biopolymer gels and synthetic nonwovens. Although the mechanics of networks made from the same type of fibers has been studied extensively, the behavior of composite systems of fibers with different properties has received less attention. In this work we numerically and theoretically study random networks of beams and springs of different mechanical properties. We observe that the overall network stiffness decreases on average as the variability of fiber stiffness increases, at constant mean fiber stiffness. Numerical results and analytical arguments show that for small variabilities in fiber stiffness the amount of network softening scales linearly with the variance of the fiber stiffness distribution. This result holds for any beam structure and is expected to apply to a broad range of materials including cellular solids. PMID- 26644630 TI - Individual differences in phonetic cue use in production and perception of a non native sound contrast. AB - The current work examines native Korean speakers' perception and production of stop contrasts in their native language (L1, Korean) and second language (L2, English), focusing on three acoustic dimensions that are all used, albeit to different extents, in both languages: voice onset time (VOT), f0 at vowel onset, and closure duration. Participants used all three cues to distinguish the L1 Korean three-way stop distinction in both production and perception. Speakers' productions of the L2 English contrasts were reliably distinguished using both VOT and f0 (even though f0 is only a very weak cue to the English contrast), and, to a lesser extent, closure duration. In contrast to the relative homogeneity of the L2 productions, group patterns on a forced-choice perception task were less clear-cut, due to considerable individual differences in perceptual categorization strategies, with listeners using either primarily VOT duration, primarily f0, or both dimensions equally to distinguish the L2 English contrast. Differences in perception, which were stable across experimental sessions, were not predicted by individual variation in production patterns. This work suggests that reliance on multiple cues in representation of a phonetic contrast can form the basis for distinct individual cue-weighting strategies in phonetic categorization. PMID- 26644631 TI - Estimation of Fano factor in inorganic scintillators. AB - The Fano factor of an integer-valued random variable is defined as the ratio of its variance to its mean. Correlation between the outputs of two photomultiplier tubes on opposite faces of a scintillation crystal was used to estimate the Fano factor of photoelectrons and scintillation photons. Correlations between the integrals of the detector outputs were used to estimate the photoelectron and photon Fano factor for YAP:Ce, SrI2:Eu and CsI:Na scintillator crystals. At 662 keV, SrI2:Eu was found to be sub-Poisson, while CsI:Na and YAP:Ce were found to be super-Poisson. An experiment setup inspired from the Hanbury Brown and Twiss experiment was used to measure the correlations as a function of time between the outputs of two photomultiplier tubes looking at the same scintillation event. A model of the scintillation and the detection processes was used to generate simulated detector outputs as a function of time for different values of Fano factor. The simulated outputs from the model for different Fano factors was compared to the experimentally measured detector outputs to estimate the Fano factor of the scintillation photons for YAP:Ce, LaBr3:Ce scintillator crystals. At 662 keV, LaBr3:Ce was found to be sub-Poisson, while YAP:Ce was found to be close to Poisson. PMID- 26644632 TI - Fuzzy-Trace Theory and Lifespan Cognitive Development. AB - Fuzzy-trace theory (FTT) emphasizes the use of core theoretical principles, such as the verbatim-gist distinction, to predict new findings about cognitive development that are counterintuitive from the perspective of other theories or of common-sense. To the extent that such predictions are confirmed, the range of phenomena that are explained expands without increasing the complexity of the theory's assumptions. We examine research on recent examples of such predictions during four epochs of cognitive development: childhood, adolescence, young adulthood, and late adulthood. During the first two, the featured predictions are surprising developmental reversals in false memory (childhood) and in risky decision making (adolescence). During young adulthood, FTT predicts that a retrieval operation that figures centrally in dual-process theories of memory, recollection, is bivariate rather than univariate. During the late adulthood, FTT identifies a retrieval operation, reconstruction, that has been omitted from current theories of normal memory declines in aging and pathological declines in dementia. The theory predicts that reconstruction is a major factor in such declines and that it is able to forecast future dementia. PMID- 26644633 TI - Development of episodic and autobiographical memory: The importance of remembering forgetting. AB - Some memories of the events of our lives have a long shelf-life-they remain accessible to recollection even after long delays. Yet many other of our experiences are forgotten, sometimes very soon after they take place. In spite of the prevalence of forgetting, theories of the development of episodic and autobiographical memory largely ignore it as a potential source of variance in explanation of age-related variability in long-term recall. They focus instead on what may be viewed as positive developmental changes, that is, changes that result in improvements in the quality of memory representations that are formed. The purpose of this review is to highlight the role of forgetting as an important variable in understanding the development of episodic and autobiographical memory. Forgetting processes are implicated as a source of variability in long term recall due to the protracted course of development of the neural substrate responsible for transformation of fleeting experiences into memory traces that can be integrated into long-term stores and retrieved at later points in time. It is logical to assume that while the substrate is developing, neural processing is relatively inefficient and ineffective, resulting in loss of information from memory (i.e., forgetting). For this reason, focus on developmental increases in the quality of representations of past events and experiences will tell only a part of the story of how memory develops. A more complete account is afforded when we also consider changes in forgetting. PMID- 26644634 TI - Phenylselenolate Mercury Alkyl Compounds, PhSeHgMe and PhSeHgEt: Molecular Structures, Protolytic Hg-C Bond Cleavage and Phenylselenolate Exchange. AB - The phenylselenolate mercury alkyl compounds, PhSeHgMe and PhSeHgEt, have been structurally characterized by X-ray diffraction, thereby demonstrating that both compounds are monomeric with approximately linear coordination geometries; the mercury centers do, nevertheless, exhibit secondary Hg***Se intermolecular interactions that serve to increase the coordination number in the solid state. The ethyl derivative, PhSeHgEt, undergoes facile protolytic cleavage of the Hg-C bond to release ethane at room temperature, whereas PhSeHgMe exhibits little reactivity under similar conditions. Interestingly, the cleavage of the Hg-C bond of PhSeHgEt is also more facile than that of the thiolate analogue, PhSHgEt, which demonstrates that coordination by selenium promotes protolytic cleavage of the mercury-carbon bond. The phenylselenolate compounds PhSeHgR (R = Me, Et) also undergo degenerate exchange reactions with, for example, PhSHgR and RHgCl. In each case, the alkyl groups preserve coupling to the 199Hg nuclei, thereby indicating that the exchange process involves metathesis of the Hg-SePh/Hg-X groups rather than metathesis of the Hg-R/Hg-R groups. PMID- 26644635 TI - An examination of the factors influencing mercury and methylmercury particulate distributions, methylation and demethylation rates in laboratory-generated marine snow. AB - In the marine environment, settling particulates have been widely studied for their role as effective vertical transporters of nutrients and metals scavenged from the euphotic zone to the benthos. These particulates are composed of transparent exopolymers, plankton and bacterial cells, detritus and organic matter, and form various size fractions from colloids (<0.2MUm) to aggregates, and finally marine snow (>300 MUm). As marine snow forms in the water column, anoxic layers form around and within the aggregation potentially creating a prime environment for the methylation of mercury (Hg), which occurs primarily in low oxygen environments. To examine this process, marine aggregates were produced from sieved estuarine seawater (100 MUm) in 1-L glass bottles spiked with stable isotope enriched methylmercury (CH3199Hg) and inorganic mercury (200Hg(II)) at 18 degrees C using a roller-table. After the rolling period, different particle size fractions were collected and analyzed, including: visible marine snow (>300MUm), particulates 8 to 300 MUm, and particulates 0.2 to 8MUm. Particulate analysis indicated higher incorporation of both forms of Hg into marine snow compared to unrolled treatments, with greater incorporation of 200Hg(II) than CH3199Hg. In addition, inorganic Hg was methylated and CH3Hg was demethylated in the larger particulate fractions (>8MUm). Methylation and demethylation rates were assessed based on changes in isotopic composition of Hg(II) and CH3Hg, and found to be comparable to methylation rates found in sediments. These results indicate that net Hg methylation can occur in marine snow and smaller aggregates in oxic coastal waters, and that this net formation of CH3Hg may be an important source of CH3Hg in both coastal and open ocean surface environments. PMID- 26644636 TI - Modelling Adherence Behaviour for the Treatment of Obstructive Sleep Apnoea. AB - Continuous positive airway pressure therapy (CPAP) is known to be the most efficacious treatment for obstructive sleep apnoea (OSA). Unfortunately, poor adherence behaviour in using CPAP reduces its effectiveness and thereby also limits beneficial outcomes. In this paper, we model the dynamics and patterns of patient adherence behaviour as a basis for designing effective and economical interventions. Specifically, we define patient CPAP usage behaviour as a state and develop Markov models for diverse patient cohorts in order to examine the stochastic dynamics of CPAP usage behaviours. We also examine the impact of behavioural intervention scenarios using a Markov decision process (MDP), and suggest a guideline for designing interventions to improve CPAP adherence behaviour. Behavioural intervention policy that addresses economic aspects of treatment is imperative for translation to clinical practice, particularly in resource-constrained environments that are clinically engaged in the chronic care of OSA. PMID- 26644637 TI - The effects of stabilization exercise with an oral assistive device on pain and functionality of low back pain patients. AB - [Purpose] This study examined low back pain patients' decrease in pain and improvement in functionality after performance of a lumbar stabilization exercise using an oral assistive device, which can replace a lumbar assistive device. [Subjects and Methods] The experimental group (n=12) conducted a stabilization exercise using an oral assistive device after conventional physical therapy. The control group (n=12) received conventional physical therapy. In order to objectively measure pain in this study, a visual analogue scale (VAS) was used. In order to evaluate the subjects' functional aspects while living with low back pain, the Oswestry Disability Index (ODI) was used. [Results] There were statistically significant improvements in the comparison of the VAS and ODI of the experimental group and the control group. The experimental group's VAS and ODI significantly improved after the intervention compared to the control group. [Conclusion] The stabilization exercise using the assistive device after conventional physical therapy in the rehabilitation of low back pain patients reduced subjects' pain and increased their functional activities. PMID- 26644638 TI - Is quadriceps muscle strength a determinant of the physical function of the elderly? AB - [Purpose] To determine the relationships of the quadriceps rate of torque development and the time to peak torque with the physical function of the elderly. [Subjects and Methods] Twenty-one subjects participated in this study. Quadriceps strength was measured using isometric and isokinetic torque tests. Time to peak torque and rate of torque development were calculated from the torque time curve of the isokinetic and isometric torque tests, respectively. Physical activities were measured using 4 physical activity tests. Pearson correlation coefficients were used to examine the relationships among the variables. [Results] The time to peak torque showed significant correlations with all measures of physical activity tests. Rate of torque development showed significant correlation with the timed stair-climbing test. Isometric and isokinetic torques had no significant correlations with any of the physical activity tests. [Conclusion] Time to maximum torque and the rate of torque development might be more important than peak torque in determining the physical function of the elderly. PMID- 26644639 TI - The influence of a ten-week Nordic walking training-rehabilitation program on the level of lipids in blood in overweight and obese postmenopausal women. AB - [Purpose] The aim of this study was to evaluate the effect of a ten-week Nordic Walking (NW) rehabilitation program on chosen anthropometric parameters and the level of basic lipids in overweight and obese postmenopausal women's blood. [Subjects and Methods] The subjects were 32 women aged 50-68 (average: 59.7 +/- 5.9 years). The study was carried out following a non-randomized model and entailed NW rehabilitation 5 times a week, which lasted for 10 weeks, as well as a low-calorie 1,500 kcal diet. The therapeutic results of the study were measured through changes in anthropometric and biochemical parameters. The results were subjected to a statistical analysis. [Results] After 10 weeks of NW rehabilitation it was observed that participants lost weight and their body mass index dropped. Additionally, whereas levels of total cholesterol, LDL and triglycerides dropped, and the level of HDL increased. [Conclusion] Rehabilitation carried out according to the NW model resulted in statistically significant changes in basic lipids in blood which, considerably increased the percentage of persons who achieved the recommended level of blood lipids. Obese persons were characterised by a smaller rehabilitation weight loss. More intense workouts and cooperation with a dietician are required. PMID- 26644640 TI - Health-related quality of life of community-dwelling stroke survivors: a comparison of fallers and non-fallers. AB - [Purpose] The purpose of this study was to compare the health-related quality of life (HRQOL) of stroke survivors between fallers and non-fallers. [Subjects] The subjects were community-dwelling stroke patients (n = 4,560) in South Korea. All stroke patients were diagnosed by a doctor. [Methods] This study used raw data from the 2014 Korean Community Health Survey. The survey was conducted from August 16, 2014, to October 31, 2014. Trained surveyors visited households selected from the sample and conducted face-to-face interviews. The content of the survey included demographic data and HRQOL. [Results] Fallers were 1,425 (31.25%), non-fallers 3,125 (68.53%), and 10 (0.22%) answered unknown. Gender, living status, occupation, and smoking experience differed significantly between the fallers and non-fallers. The domains of HRQOL, excluding VAS, also differed significantly between the fallers and non-fallers. [Conclusion] These results provide important base data for rehabilitation services for fallers among stroke survivors. PMID- 26644641 TI - Rehabilitation for patients with paraplegia and lower extremity amputation. AB - [Purpose] To study the characteristics and treatment strategy for patients with paraplegia and lower extremity amputation. [Subjects] Six cases were selected from among the patients admitted to the China Rehabilitation Research Center from 1991 to 2014. The criteria for the six cases were spinal cord injury with amputation immediately or in a short time (1 week) after the trauma. [Methods] General information, clinical diagnosis, treatment, rehabilitation and other data were analyzed. [Results] All the six cases were injured by high energy or complex energy accidents: two cases by falls after high voltage electric shock, one by an oil pipeline explosion, one by the impact of a falling tower crane and received high energy traffic accident injuries (one was hit by a train, and the other was hit by a truck at high speed). All the six cases had thoracic and lumbar vertebral injuries and complete paraplegia. Amputation stump infection occurred in four cases. After comprehensive rehabilitation treatment, patients' functional independence measure (FIM) scores improved significantly, but American Spinal Injury Association (ASIA) scores and ASIA Impairment Scale (AIS) grades showed no significant improvement. [Conclusion] When formulating the clinical treatment and rehabilitation for spinal cord injury with amputation patients, simultaneous consideration of the characteristics of the spinal cord injury and amputation is needed to develop an individualized strategy. For spinal cord injury with limb amputation patients, prostheses should allow the improvement of patients' self care ability. PMID- 26644642 TI - Effects of robot-assisted gait training on the balance and gait of chronic stroke patients: focus on dependent ambulators. AB - [Purpose] The purpose of this study was to confirm the effect of robot-assisted gait training on the balance and gait ability of stroke patients who were dependent ambulators. [Subjects and Methods] Twenty stroke patients participated in this study. The participants were allocated to either group 1, which received robot-assisted gait training for 4 weeks followed by conventional physical therapy for 4 weeks, or group 2, which received the same treatments in the reverse order. Robot-assisted gait training was conducted for 30 min, 3 times a week for 4 weeks. The Berg Balance Scale, Modified Functional Reach Test, Functional Ambulation Category, Modified Ashworth Scale, Fugl-Meyer Assessment, Motricity Index, and Modified Barthel Index were assessed before and after treatment. To confirm the characteristics of patients who showed a significant increase in Berg Balance Scale after robot-assisted gait training as compared with physical therapy, subgroup analysis was conducted. [Results] Only lateral reaching and the Functional Ambulation Category were significantly increased following robot-assisted gait training. Subscale analyses identified 3 patient subgroups that responded well to robot-assisted gait training: a subgroup with hemiplegia, a subgroup in which the guidance force needed to be decreased to needed to be decreased to <=45%, and a subgroup in which weight bearing was decreased to <=21%. [Conclusion] The present study showed that robot-assisted gait training is not only effective in improving balance and gait performance but also improves trunk balance and motor skills required by high-severity stroke patients to perform activities daily living. Moreover, subscale analyses identified subgroups that responded well to robot-assisted gait training. PMID- 26644643 TI - Mediating effects of the ICF domain of function and the gross motor function measure on the ICF domains of activity, and participation in children with cerebral palsy. AB - [Purpose] This study aimed to evaluate the mediating effect of gross motor function, measured using the Gross Motor Function Measure (GMFM) and of general function, measured using the International Classification of Functioning, Disability and Health-Child and Youth Check List (ICF-CY), on the ICF domains of activity and participation in children with cerebral palsy (CP). [Subjects] Ninety-five children with CP, from Seoul, Korea, participated in the study. [Methods] The GMFM was administered in its entirety to patients without orthoses or mobility aids. The ICF-CY was used to evaluate the degree of disability and health of subjects. [Results] GMFM score and ICF-CY function were negatively correlated to ICF-CY activity and participation. ICF-CY partially mediated the effects of the GMFM on activity and participation. [Conclusion] When establishing a treatment plan for a child with CP, limitations in activity and participation, as described by the ICF-CY, should be considered in addition to the child's physical abilities and development. In addition, the treatment plan should focus on increasing the child's activity and participation level, as well as his/her physical level. PMID- 26644644 TI - Effect of the low- versus high-intensity exercise training on endoplasmic reticulum stress and GLP-1 in adolescents with type 2 diabetes mellitus. AB - [Purpose] The primary objective of this study was to investigate the effect of low-intensity exercise training compare with high-intensity exercise training on endoplasmic reticulum stress and glucagon-like peptide-1 in adolescents with type 2 diabetes mellitus. [Subjects and Methods] The low-intensity exercise training group performed aerobic exercise training at an intensity of <= 45% of the heart rate reserve. The high-intensity interval exercise training group performed interval exercise training at an intensity of >= 80% of the heart rate reserve. The exercise-related energy consumption was determined for both groups on a per week basis (1,200 kcal/week). [Results] Both groups showed improvement in the glucose-regulated protein 78 and dipeptidyl peptidase-4, but the size of the between-group effect was not statistically significant. The high-intensity interval exercise training group showed a significant reduction in percentage body fat. The C-peptide level increased after the 12-weeks programs and was significantly different, between the groups. Fasting glucose, insulin resistance in the fasting state according to homeostasis model assessment, and leptin decreased after the 12-weeks exercise program and were significantly different between the groups, and glucagon-like peptide-1 increased after the 12-week exercise programs and was significantly different between the groups. [Conclusion] In conclusion high-intensity interval exercise training, as defined in this study, may lead to improvements in body composition, glycemic control, endoplasmic reticulum stress, and the glucagon-like peptide-1 in adolescents with type 2 diabetes mellitus. PMID- 26644645 TI - Effect of exercise therapy combining electrical therapy and balance training on functional instability resulting from ankle sprain-focus on stability of jump landing. AB - [Purpose] Functional instability leads to a delay in the muscle reaction time and weakness of the peroneal muscles. The present study examined the effects of transcutaneous electrical nerve stimulation during balance exercise on patients with functional instability of the ankles, including the ability to land after jumping at the center of foot pressure. [Subjects] The subjects were seven males with a history of ankle sprain. All had a sprained ankle score of <=80 points on Karlson's functional instability test. [Methods] They were asked to jump over a 20-cm-high platform sideways for 10 consecutive seconds on a force plate with one leg. The length of the center of pressure was measured for comparison of balance exercise and balance exercise with simultaneous transcutaneous electrical nerve stimulation. [Results] The length of the center of foot pressure on the sprain side was significantly greater than on the non-sprain side under both conditions. Under the balance exercise with simultaneous transcutaneous electrical nerve stimulation therapy condition, the length of the center of foot pressure on the sprain side was significantly reduced, with the values being 627.0 +/- 235.4 and 551.8 +/- 171.1 mm before and after the challenge, respectively. [Conclusion] Ankle instability on the sprain side was significantly reduced under the balance exercise with simultaneous transcutaneous electrical nerve stimulation therapy condition before and after the challenge. Peroneal muscles showed increased activity caused by common peroneal innervation. PMID- 26644646 TI - The reliability of evaluation of hip muscle strength in rehabilitation robot walking training. AB - [Purpose] The primary purpose of this study was to evaluate the intraclass correlation coefficient in obtaining the torque of the hip muscle strength during a robot-assisted rehabilitation treatment. [Subjects] Twenty-four patients (15 males, 9 females) with spinal cord injury participated in the study. [Methods] The subjects were asked to walk during robot-assisted rehabilitation, and the torque of the muscle strength which was measured at hip joint flexion angles of 15, -10, -5, 0, 5, 10, 15, 20, 25, and 30 degrees. [Results] The intraclass correlation coefficient of the torque of the hip muscle strength measured by the rehabilitation training robot was excellent. [Conclusion] Our results show that measurement of torque can be used as an objective assessment of treatment with RAT. PMID- 26644647 TI - Does decrease of the thoracic kyphosis influence decrease knee adduction moment during gait? A preliminary study of a healthy population. AB - [Purpose] The purpose of this study was to investigate the influence of a decrease in thoracic kyphosis angle on the knee adduction moment during gait in healthy young individuals. [Subjects and Methods] Twenty-nine healthy adults, consisting of 15 males and 14 females (21.6 +/- 1.1 years old), participated. The draw-in maneuver was used to decrease thoracic kyphosis, and thoracic kyphosis was measured using a SpinalMouse during normal standing and standing with the draw-in maneuver. The participants were required to maintain the draw-in maneuver during gait. A 3-D motion analysis system and a force plate were used to obtain knee adduction moment. [Results] Thoracic kyphosis angles during the draw-in maneuver (41.0 +/- 7.4 degrees) were significantly decreased compared with the angles during normal standing (43.0 +/- 7.9 degrees). Although the knee adduction moment during gait with the draw-in maneuver was not significantly decreased compared with that during level gait, in the 20 subjects who had decreased kyphosis due to the draw-in maneuver, the 1st peak knee adduction moment (55.7 +/ 24.3 * 10(-3)) with the draw-in maneuver was significantly decreased compared with the knee adduction moment (57.0 +/- 16.3 * 10(-3)) during level gait. [Conclusion] Knee adduction moment in the case of a decreased thoracic kyphosis angle due to the draw-in maneuver was decreased compared with that during level gait. PMID- 26644648 TI - Comparison of toe grip strength and muscle activities during maximal toe grip strength exertion according to the presence/absence of an ankle immobilization belt. AB - [Purpose] The aim of this study was to compare toe grip strength and muscle activity during toe grip strength exertion according to the presence/absence of an ankle immobilization belt and to examine the relationship between the differences in muscle activity and toe grip strength. [Subjects] The Subjects were 13 healthy young women. [Methods] We measured toe grip strength and muscle activity during toe grip strength exertion in the presence and absence of an ankle immobilization belt using electromyography. Activity in the following leg muscles was recorded: rectus femoris, biceps femoris, medial head of the gastrocnemius, and tibialis anterior. We then calculated the percent integrated electromyography during toe gripping. [Results] Toe grip strength and percent integrated electromyography of the medial head of the gastrocnemius muscle were significantly higher with ankle belt immobilization compared with without ankle belt immobilization. In addition, in the presence of ankle belt immobilization, the percent integrated electromyography of the tibialis anterior muscle and medial head of the gastrocnemius muscle demonstrated a positive correlation with toe grip strength (r = 0.75 and r = 0.65, respectively). [Conclusion] These findings suggest that greater toe grip strength could be exerted in the presence of ankle belt immobilization. The measured values reflect the percent integrated electromyography of the crural muscles. Therefore, it was shown that toe grip strength should be measured in the presence of an immobilization belt. PMID- 26644649 TI - Analysis of the pulmonary functions of normal adults according to pillow height. AB - [Purpose] The purpose of this study is to examine changes in pulmonary functions in relation to the sleeping positions of the experimental subjects. [Subjects and Methods] The subjects for this study were twenty randomly selected males and females from K University. Measurements were taken in the supine position at three different pillow heights: 0 cm, 5 cm, and 10 cm. Pulmonary functions (vital capacity, tidal volume, inspiratory reserve volume, and expiratory reserve volume) were evaluated using a Fit mate. [Results] These findings suggest that a pillow height of 5 cm makes a significant difference in vital capacity (VC). When the three pillow heights were compared, significant differences were seen between 0 cm and 5 cm, and between 5 cm and 10 cm, in terms of vital capacity for the pulmonary functions among the three positions. [Conclusion] In conclusion, changing the positions of the subjects produces changes in pulmonary functions. The greatest change occurred in the 5 cm pillow height. Presumably, ventilation is affected by the body structures. The results will provide objective data to establish the most suitable positions for stroke patients when they perform respiratory exercises. PMID- 26644650 TI - An analysis on muscle tone of lower limb muscles on flexible flat foot. AB - [Purpose] The aim of this study was to examine differences in the muscle tone and stiffness of leg muscles according to types of flexible flat foot. [Subjects and Methods] For 30 subjects 10 in a normal foot group (NFG), 10 in group with both flexible flat feet (BFFG), and 10 in a group with flexible flat feet on one side (OFFG), myotonometry was used to measure the muscle tone and stiffness of the tibialis anterior muscle (TA), the rectus femoris muscle (RF), the medial gastrocnemius (MG), and the long head of the biceps femoris muscle (BF) of both lower extremities. [Results] In the measurement results, only the stiffness of TA and MG of the NFG and the BFFG showed significant differences. The muscle tone and stiffness were highest in the BFFG, followed by the OFFG and NFG, although the difference was insignificant. In the case of the OFFG, there was no significant difference in muscle tone and stiffness compared to that in the NGF and the BFFG. Furthermore, in the NFG, the non-dominant leg showed greater muscle tone and stiffness than the dominant leg, although the difference was insignificant. [Conclusion] During the relax condition, the flexible flat foot generally showed a greater muscle tone and stiffness of both lower extremities compared to the normal foot. The stiffness was particularly higher in the TA and MG muscles. Therefore, the muscle tone and stiffness of the lower extremity muscles must be considered in the treatment of flat foot. PMID- 26644651 TI - Effect of two different kinesio taping techniques on knee kinematics and kinetics in young females. AB - [Purpose] The application of kinesio taping may improve strength and performance, inhibit and facilitate motor activity, and increase range of motion. The aim of this study was to compare the effects of kinesio taping facilitation and inhibition applications on spatiotemporal knee kinematics and kinetics during walking activity in healthy subjects. [Subjects and Methods] A three-dimensional quantitative gait evaluation was performed without tape and with, facilitation and inhibition kinesio taping application on the knee. Sixteen healthy female college students (age, 19.7 +/- 0.4 years; height, 1.64 +/- 3.4 cm; body mass, 51.5 +/- 4.8 kg) participated in the study. [Results] Spatiotemporal parameters (cadence, walking speed, stride length) were significantly different among the trials. Knee joint sagittal plane range of motion was not different with either kinesio taping application. Knee external flexion moment during the early stance phase decreased significantly with facilitation kinesio taping and increased with the inhibition kinesio taping. Knee external extension moment during the mid stance phase increased with facilitation kinesio taping. Knee power parameters, eccentric activity in the rectus femoris during the pre-swing phase was significantly increased with inhibition kinesio taping application, while eccentric activity of the hamstrings during the terminal swing of gait was decreased. [Conclusion] These findings showed that facilitation kinesio taping application affected the terminal stance phase and that inhibition kinesio taping influenced the terminal swing phase compared with the no tape condition. PMID- 26644652 TI - Effects of virtual reality programs on balance in functional ankle instability. AB - [Purpose] The aim of present study was to identify the impact that recent virtual reality training programs used in a variety of fields have had on the ankle's static and dynamic senses of balance among subjects with functional ankle instability. [Subjects and Methods] This study randomly divided research subjects into two groups, a strengthening exercise group (Group I) and a balance exercise group (Group II), with each group consisting of 10 people. A virtual reality program was performed three times a week for four weeks. Exercises from the Nintendo Wii Fit Plus program were applied to each group for twenty minutes along with ten minutes of warming up and wrap-up exercises. [Results] Group II showed a significant decrease of post-intervention static and dynamic balance overall in the anterior-posterior, and mediolateral directions, compared with the pre intervention test results. In comparison of post-intervention static and dynamic balance between Group I and Group II, a significant decrease was observed overall. [Conclusion] Virtual reality programs improved the static balance and dynamic balance of subjects with functional ankle instability. Virtual reality programs can be used more safely and efficiently if they are implemented under appropriate monitoring by a physiotherapist. PMID- 26644653 TI - Analysis of the correlation between the differences in muscle strengths between the bilateral lower extremities and postural stability in healthy adults. AB - [Purpose] The purpose of this study was to examine the correlation between the differences in muscle strengths between the bilateral lower extremities and the level of postural sway that indicates postural stability. [Subjects and Methods] A total of 49 students (18 males and 31 females) at Y University in Gyeongsangnam do, South Korea, participated in this study. Partial correlation analysis was performed to determine the effects of sway length and velocity on the differences in muscle strengths between the lower extremities. [Results] Both sway length and sway velocity showed a negative correlation with the difference in bilateral ankle dorsiflexion strength. Both sway length and sway velocity showed a positive correlation with the difference in bilateral hip flexion strength. [Conclusion] Difference in left-right muscle strengths of hip flexion and ankle dorsiflexion can affect postural stability when the levels of lower extremity muscle strengths are excluded. PMID- 26644654 TI - The effect of pulsating electrostatic field application on the development of delayed onset of muscle soreness (DOMS) symptoms after eccentric exercise. AB - [Purpose] The aim of the study was to establish whether pulsating electrostatic field application, shown to increase blood flow and metabolic activity and to function as an ion pump, is able to reduce muscle pain after exercise-induced muscle damage. [Subjects and Methods] Seven participants (4 males, 3 females) performed two sessions of downhill running separated by at least 4 weeks. After the running sessions, participants were either treated for 45 min with a pulsating electrostatic field (field intensity, 9000 V; current, <9 mA; frequency, 50 Hz) or a sham treatment. The order of the intervention was random, and the condition was blinded for the participants. Muscle soreness score, creatine kinase, and jump ability were assessed before and up to 48 hours after running. [Results] Twenty-four and 48 hours after the downhill running, the muscle soreness score tended to be less increased after pulsating electrostatic field administration when compared with the sham setting (changes in muscle soreness score: 3.7+/-1.6 vs. 5.7+/-2.2 after 24 h and 3.1+/-2.0 vs. 5.4+/-3.2 after 48 h, respectively). No further differences were detected. [Conclusion] The outcomes show that a pulsating electrostatic field might be a promising treatment to reduce muscle soreness after exercise-induced muscle damage. However, further studies are needed to confirm the present outcomes and to establish the mechanism by which a pulsating electrostatic field may reduce muscle pain. PMID- 26644655 TI - Effect of visual perceptual disturbance on gait and balance. AB - [Purpose] This study aimed to determine whether or not problems with gait and balance occur when incorrect information is given visually. [Subjects and Methods] Fifty healthy adults wore goggles that caused visual distortion and viewing angle reduction, and their balance and gait velocities were measured in an upright position. The goggles could be set to three different levels of visual distortion and viewing angle reduction. [Results] Gait velocity slowed more as the degree of visual distortion and viewing angle reduction became more severe. Visual perception disturbance and gait velocities were found to be correlated, but no significant differences were found in balance among the visual disturbance conditions. [Conclusion] The level of visual perception disturbance did not affect control in the standing position, but it increasingly influenced the level of dynamic postural control as visual perception disturbance became more severe. PMID- 26644656 TI - Effects of therapeutic ultrasound and exercise on pain, function, and isokinetic shoulder rotator strength of patients with rotator cuff disease. AB - [Purpose] The aim of this prospective, double-blind, randomized, placebo controlled study was to evaluate the effects of therapeutic continuous ultrasound (US) on patients with rotator cuff disease. [Subjects and Methods] Twenty-two patients were treated with a standard physiotherapy program consisting of a hot pack, transcutaneous electrical nerve stimulation (TENS), exercises, and US that was supervised by the same physiotherapist. The patients were randomly assigned to either a group that received true US (n=11) or one that received sham US (n=11). [Results] There were significant differences between the pre- and post intervention UCLA Shoulder Rating Scale and Constant-Murley Shoulder Outcome scores, VAS, and external rotation (ER) peak torque 60 degrees /second values for both the true and sham US groups. However, the between-group differences were not statistically significant. [Conclusion] In patients with rotator cuff disease, physiotherapy interventions effectively treat the pain, improve the clinical status, and increase the muscle strength of the shoulder ER at a low constant angular velocity, with functional improvement being seen immediately after treatment. However, at the end of the intervention, the US had yielded no additional efficacy to the physiotherapy treatment regimen of the patients with rotator cuff disease. PMID- 26644657 TI - Reliability of measuring the passive range of shoulder horizontal adduction using a smartphone in the supine versus the side-lying position. AB - [Purpose] The purpose of this study was to compare the reliability of the measurement of the passive range of motion (PROM) of shoulder horizontal adduction (SHA) measurements using a smartphone for the assessment posterior shoulder tightness (PST) between the side-lying and supine test positions. [Subjects and Methods] Forty-seven subjects (mean +/- age, 24.9 +/- 3.5 years) without shoulder pathology were included in this study. Intra-rater and inter rater reliabilities were determined using intraclass correlation coefficients. The SHA PROM of each subject's dominant shoulder was measured using a smartphone by two investigators in two positions: the standard supine position, and a side lying position on the tested side. [Results] The intra-rater reliability of the supine measurements was fair to good (ICC3,1 = 0.72-0.89), and for the side-lying measurements was excellent (ICC3,1 = 0.95-0.97). The inter-rater reliability of the supine measurements was fair (ICC2,2 = 0.79) and for the side-lying measurements was excellent (ICC2,2 = 0.94). [Conclusion] These results suggest that for healthy subjects, measurements of SHA using smartphones in the side lying position has superior intra-rater and inter-rater reliabilities compared to the standard supine position. PMID- 26644658 TI - Reliability of photographic posture analysis of adolescents. AB - [Purpose] Postural problems of adolescents needs to be evaluated accurately because they may lead to greater problems in the musculoskeletal system as they develop. Although photographic posture analysis has been frequently used, more simple and accessible methods are still needed. The purpose of this study was to investigate the inter- and intra-rater reliability of photographic posture analysis using MB-ruler software. [Subjects and Methods] Subjects were 30 adolescents (15 girls and 15 boys, mean age: 16.4+/-0.4 years, mean height 166.3+/-6.7 cm, mean weight 63.8+/-15.1 kg) and photographs of their habitual standing posture photographs were taken in the sagittal plane. For the evaluation of postural angles, reflective markers were placed on anatomical landmarks. For angular measurements, MB-ruler (Markus Bader- MB Software Solutions, triangular screen ruler) was used. Photographic evaluations were performed by two observers with a repetition after a week. Test-retest and inter-rater reliability evaluations were calculated using intra-class correlation coefficients (ICC). [Results] Inter-rater (ICC>0.972) and test-retest (ICC>0.774) reliability were found to be in the range of acceptable to excellent. [Conclusion] Reference angles for postural evaluation were found to be reliable and repeatable. The present method was found to be an easy and non-invasive method and it may be utilized by researchers who are in search of an alternative method for photographic postural assessments. PMID- 26644659 TI - Comparisons of social interaction and activities of daily living between long term care facility and community-dwelling stroke patients. AB - [Purpose] This study was conducted to compare the correlation between social interaction and activities of daily living (ADL) between community-dwelling and long-term care facility stroke patients. [Subjects and Methods] The Subjects were 65 chronic stroke patients (32 facility-residing, 33 community-dwelling). The Evaluation Social Interaction (ESI) tool was used to evaluate social interaction and the Assessment of Motor and Process Skills (AMPS) measure was used to evaluate ADL. [Results] Both social interaction and ADL were higher in community dwelling than facility-residing stroke patients. There was a correlation between ESI and ADL for both motor and process skills among facility-residing patients, while only ADL process skills and ESI correlated among community-dwelling patients. In a partial correlation analysis using ADL motor and process skills as control variables, only process skills correlated with ESI. [Conclusion] For rehabilitation of stroke patients, an extended treatment process that combines ADL and social activities is likely to be required. Furthermore, treatment programs and institutional systems that can improve social interaction and promote health maintenance for community-dwelling and facility-residing chronic stroke patients are needed throughout the rehabilitation process. PMID- 26644660 TI - Usefulness of the driveABLE cognitive assessment in predicting the driving risk factor of stroke patients. AB - [Purpose] This study examined the usefulness of the DriveABLE cognitive assessment tool (DCAT) in predicting the driving risk factor of stroke patients, and compared the cognitive and driving functions of two groups discriminated by DCAT. [Subjects and Methods] A total of forty-two stroke patients with a driver's license participated in this study. Two participants with communication problems were excluded. DCAT was used to evaluate the risk potential to the driver, and the subjects were classified into two groups according to the probability of driving risk estimated by the DCAT evaluation. The safe driver group (SDG) and unsafe driver group (USDG) underwent a driving simulator and cognitive function assessments. [Results] The results of the SDG and USDG were compared. The SDG showed higher cognitive function than the USDG. In addition, the SDG showed higher ability than the USDG in most of the tests associated with the driving function (pedal reaction time, average reaction time, centerline crossing, road edge excursion, off-road accidents, collisions). [Conclusion] DCAT is a useful tool for predicting the risk of driving. In addition, it can predict the driving ability of stroke patients related to the cognitive function. Nevertheless, a multi-faceted study of associated with driving and cognitive functions for safe driving will be needed. PMID- 26644661 TI - Comparative analysis of trunk muscle activities in climbing of during upright climbing at different inclination angles. AB - [Purpose] This study was performed to provide evidence for the therapeutic exercise approach through a compative analysis of muscle activities according to climbing wall inclination. [Subjects and Methods] Twentyfour healthy adult subjects without climbing experience performed static exercises at a therapeutic climbing at with various inclination angles (0 degrees , 10 degrees , 20 degrees ), and the activities of the trunk muscles (rectus abdominis, obliquus externus abdominis, obliquus internus abdominis, erector spinae) were measured using surface electromyography (EMG) for 7 seconds. [Results] Significant differences were found between the inclination angles of 10 degrees and 0 degrees , as well as 20 degrees in the rectus abdominis, obliquus internus abdominis, right obliquus externus abdominis, and right erector spinae. [Conclusion] Based on measurements of trunk muscle activity in a static climbing standing position at different angles, significant changes in muscle activity appear to be induced at 10 degrees. Therefore, the results appear to provide clinically relevant evidence. PMID- 26644662 TI - Color temperature's impact on task performance and brainwaves of school-age children. AB - [Purpose] This study investigated color temperature's impact on task performance. It presents a scientific analysis of brainwave and task performance time changes, and the results of a self-report type survey. [Subjects] Twenty-four elementary school fifth-grade boys and girls with no visual problems participated in the experiment. [Methods] Physiological reaction times of task performance were measured in a laboratory that could fix and maintain color temperature. Brainwave changes and the task performance times were measured, and a self-report questionnaire was conducted in order to measure of emotional reactions. [Results] Regarding the brainwave changes associated with color temperature, alpha waves were emitted in the O2 area when puzzle tasks were illuminated by orange light and low and high beta waves were emitted in the F3 area under white light. Five items (Brilliant, Soft, Lively, Relaxed, Open) were reported predominantly in responses to orange light in the self-report questionnaire. [Conclusion] The results of this study show that relaxation and stability are not assured when the color temperature is low, and that concentration and cognitive activity are not necessarily easier when the color temperature is high. The color temperature change when performing tasks promoted emotional factors more than brainwave, a biological change. PMID- 26644663 TI - Effects of combined fine motor skill and cognitive therapy to cognition, degree of dementia, depression, and activities of daily living in the elderly with Alzheimer's disease. AB - [Purpose] This study evaluated the effects of combined fine motor skill and cognitive therapies on cognition, depression, and activities of daily living in elderly patients with Alzheimer's disease (AD). [Subjects and Methods] Twenty-six participants comprised 2 groups. The experimental group (n=13) received combined fine motor skill and cognitive therapy, and the control group (n=13) received only general medical care. [Results] The experimental group showed improvements in cognition, degree of dementia, depression, and activities of daily living compared to the control group. However, there were no significant differences between the two groups. [Conclusion] These results suggest that combined fine motor skill and cognitive therapy improves cognition, degree of dementia, depression, and daily living in elderly patients with AD. These therapies would therefore be effective as general medical care strategies. PMID- 26644664 TI - The impact of the pelvic floor muscles on dynamic ventilation maneuvers. AB - [Purpose] The aim of the present study was to examine the impact of the pelvic floor muscles (PFM) on dynamic ventilation maneuvers. [Subjects and Methods] The subjects were 19 healthy female adults in their 20s who consented to participate in the present study. Electromyography (EMG) was used to examine respiratory muscle activity, and a spirometer was used to examine vital capacity before and during contraction of the PFM. [Results] There were statistically significant differences in the sternocleidomastoid (SCM), rectus abdominis (RA), external oblique (EO), transverse abdominis/internal oblique (TrA/IO), and maximal voluntary ventilation (MVV) when the PFM was contracted. [Conclusion] Contraction of the PFM can be effective in promoting activation of the respiratory muscles and vital capacity. Therefore, the PFM should be considered to improve the effects of respiratory activity. PMID- 26644665 TI - Incidence of floating toe and its association with the physique and foot morphology of Japanese children. AB - [Purpose] Physical development, foot morphology, and toe contact of children aged 3 to 5 years were assessed in order to investigate the relationships between body and foot morphology and the incidence of the condition known as "floating toe". [Subjects] A total of 198 children, aged 3 to 5 years old, participated in this study. [Methods] Height and weight were measured for body morphology, and foot length and width were measured for foot morphology. Footprint images were taken to calculate the number of floating toes. Information about the children's height and weight at birth, and the time of starting to walk was obtained from their guardians. [Results] At least one floating toe was observed in 87.7-98.7% of the children depending on their ages. The fifth toe was most commonly affected, occurring in 74.2% of the study population. Among the body and foot morphology parameters, only weight at birth showed a significant but very weak correlation with the number of floating toes. [Conclusion] There was a high incidence of floating toe among the children, with the fifth toe most commonly affected. Floating toe weakly but significantly correlated with weight at birth, but did not correlated with other measures of physique at birth, physical development, or the time of starting to walk. PMID- 26644666 TI - Effects of core muscle stability training on the weight distribution and stability of the elderly. AB - [Purpose] This study investigated the effects of core muscle stability training on the weight distribution and stability of the elderly. [Subjects and Methods] Thirty elderly persons were randomly divided into an experimental group which performed core strengthening exercises, and a control group which performed standard strengthening exercises for 8 weeks. A Tetrax Interactive Balance System was used to evaluate the weight distribution index (WDI) and the stability index (SI). [Results] The experimental group showed a significant improvement in terms of WDI and the SI. However, the control group showed no significant improvement in either. [Conclusion] Core muscle stability training should be considered as a therapeutic method for the elderly to improve their WDI, and SI, and as a fall prevention measure. PMID- 26644667 TI - Immediate effect of passive and active stretching on hamstrings flexibility: a single-blinded randomized control trial. AB - [Purpose] This study compared the efficacy of passive and active stretching techniques on hamstring flexibility. [Subjects] Fifty-four healthy young subjects were randomly assigned to one of three groups (2 treatment groups and 1 control group). [Methods] Subjects in the passive stretching group had their knees extended by an examiner while lying supine 90 degrees of hip flexion. In the same position, subjects in the active stretching group extended their knees. The groups performed 3 sets of the assigned stretch, with each stretch held for 10 seconds at the point where tightness in the hamstring muscles was felt. Subjects in the control group did not perform stretching. Before and immediately after stretching, hamstring flexibility was assessed by a blinded assessor, using the active knee-extension test. [Results] After stretching, there was a significant improvement in the hamstring flexibilities of the active and passive stretching groups compared with the control group. Furthermore, the passive stretching group showed significantly greater improvement in hamstring flexibility than the active stretching group. [Conclusion] Improvement in hamstring flexibility measured by the active knee-extension test was achieved by both stretching techniques; however, passive stretching was more effective than active stretching at achieving an immediate increase in hamstring flexibility. PMID- 26644668 TI - Electromyography comparison of normal chair-desk system and assistant chair-desk system on fatigue. AB - [Purpose] This study was designed to test the effects of the Assistant Chair-Desk System (ACDS), which can reduce the forward tilt of the neck and trunk and the level of fatigue during long lasting study in the sitting position. [Subjects] Fourteen middle school students and 14 college students of mixed gender participated in this study. [Methods] Fatigue level, the trapezius muscle, and the forward tilt angle of the head and trunk as well as distance factors were assessed before after using a normal chair-desk system (NCDS) and the ACDS for 120 minutes. [Results] There was an interaction effect in the angle and length of the neck from the sitting posture changes after 2 hours of studying using the NCDS and ACDS. There were also significant differences in the fatigue levels, hip joint angles and the lengths from the head according to the main effects of the chair-systems. [Conclusion] The studying position while using the ACDS was determined to prevent significant fatigue levels of the muscle and body, provide support to the head, by limiting the forward movement of the neck, and prevent forward tilt of the neck and trunk, by enabling the target point and gaze to be closer to the horizontal direction. PMID- 26644669 TI - Reliability of clinical competency evaluation list for novice physical and occupational therapists requiring assistance. AB - [Purpose] This study examined the reliability of a clinical ability evaluation table developed in a previous study with the aim of clarifying the abilities necessary for therapists to independently implement their duties. [Subjects and Methods] Forty-eight physical therapists with less than 2 years of clinical experience were targeted for evaluation, 48 main supervisors, and 48 sub supervisors, 144 in total, were studied. [Results] The total score was lower when the evaluation was conducted by the target therapists themselves than when it was conducted by the main or sub-supervisors. Regarding the reliability of the total scores for the entire scale and each category, values representing the intra rater reliability were higher when the evaluation was conducted by the target therapists or main supervisors, while there were marked differences between high and low values for each item. Regarding the inter-rater reliability, both the total scores for the entire scale and each category, as well as values for each item, were low. [Conclusion] Values representing the intra-rater reliability of the study table were low, indicating the necessity of further improvement. PMID- 26644670 TI - Comparison of motor and process skills among children with different developmental disabilities. AB - [Purpose] The purpose of the present study was to compare the motor and process skills of children with different developmental disabilities. [Subjects] Thirty nine children with developmental disabilities participated in this study which was conducted at N hospital in South Korea. [Methods] The motor and process skills of the participants were compared among three different disabilities: pervasive developmental disorder, cerebral palsy, and intellectual disorder. The data were analyzed using descriptive statistics and one-way ANOVA. [Results] Significant differences in motor skills were found among the diagnoses. The cerebral palsy group showed poorer motor skills than the pervasive developmental disability and intellectual disability groups. [Conclusion] The findings have clinical implications for strategies of rehabilitation for children with developmental disabilities. PMID- 26644671 TI - Development and evaluation of a new telerehabilitation system based on VR technology using multisensory feedback for patients with stroke. AB - [Purpose] The purpose of this study was to develop a new telerehabilitation system based on VR technology for training of paralyzed upper and lower extremities and poor balance in patients with stroke. Moreover, the effectiveness of the system was verified by analysis of the recovery of these patients. [Subjects] Five healthy persons and five people with motor paralysis, caused by cerebrovascular disease, participated. [Methods] The features of our system are as follows: (1) Our system can train upper and lower limbs and balancing with 3D images. (2) A Kinect((r)) is used for user posture detection. (3) A vibrator is used for feedback to a sensory receptor in order to promote the learning effect of motion. Upper limb and balance training were conducted in this study. [Results] The time necessary for the upper limb and balance training tasks was shortened for the participants with disabilities. The joint angle for the participants with disabilities tended to equate to that of the healthy participants over time. Moreover, our system had no side effects. [Conclusion] These points suggest that our system is effective and safe. The user interface and assessment of the conditions of patients from a distance should be studied in the future. PMID- 26644672 TI - Correlations among occupational stress, fatigue, and depression in call center employees in Seoul. AB - [Purpose] This study identified correlations among occupational stress, fatigue, and depression in call center employees in South Korea. [Subjects and Methods] This study consisted of 150 call center workers. A cross-sectional design was adopted. Tools including the Effort-Reward Imbalance, Checklist Individual Strength, and Depression scales were used to measure levels of stress, fatigue, and depression. [Results] There were statistically significant differences between fatigue and depression. We found that fatigue significantly predicted the level of depression among Korean call center employees (adjusted R(2)= 0.227). [Conclusion] Call center employees who experienced great emotional stress appeared to have high levels of depression, and fatigue was a powerful factor influencing their depression. PMID- 26644673 TI - The clinical and demographic features of dizziness related to general health among the Saudi population. AB - [Purpose] The purpose of this study was to determine the validity, demographic features of the newly developed Amer Dizziness Diagnostic Scale (ADDS), provide differential diagnosis of the vestibular disorders, assist in the clinical research and practice activities of health workers as well as to understand the probability of the utilization of the ADDS as a first-line evaluation tool in general clinical practice. [Subjects and Methods] Two hundred subjects of various ages including both male and female patients with a history of vertigo and/or dizziness were included in the study and evaluated once using the ADDS. [Results] There were more female (59.5%) than male (49.5) patients in this study. Additionally, we found that most patients (64.4%) had a central mediated problem. In addition, the Amer Dizziness Diagnostic Scale has been found to have both a sensitivity and specificity of 96% that can adequately determine the possible diagnosis of vestibular disorders. [Conclusion] This study has demonstrated the validity of the ADDS scale, the predominance of female involvement related to supplementary medication, vitamin D deficiency, general lifestyle factors, and fluid retention, high sensitivity and specificity, provide differential diagnosis of vestibular disorders that could be used as a first-line evaluation tool in general clinics. PMID- 26644674 TI - Comparison between a center of mass and a foot pressure sensor system for measuring gait parameters in healthy adults. AB - [Purpose] The purpose of this study was to determine the relationship between an accelerometer system and a foot pressure sensor system for measuring gait characteristics during walking in healthy adults. [Subjects and Methods] Thirty five healthy participants with no neurological, musculoskeletal, or cardiopulmonary disorders volunteered for this study. Gait characteristics were measured while participants walked freely along a 10-m walkway using two different measurement systems simultaneously. The first analysis system was based on center of mass using a wireless tri-axial accelerometer and the second system was a foot pressure sensor system. [Results] There was a significant and high correlation between the two systems with respect to gait velocity and cadence. The stride length as a percentage of the stride height measured with the center of mass system was significantly and highly correlated with stride length and stride velocity that was measured with the foot pressure system. Furthermore, stride length from the center of mass system was significantly and highly correlated with stride length and stride velocity from the foot pressure system. [Conclusion] A gait analysis based on a center of mass system is a valid method to assess the effectiveness of therapeutic interventions in a clinical setting. PMID- 26644675 TI - Effects of treadmill exercise on hippocampal neurogenesis in an MPTP /probenecid induced Parkinson's disease mouse model. AB - [Purpose] This study aimed to investigate the effect of treadmill exercise on non motor function, specifically long-term memory, in a 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine/probenecid-induced Parkinson's disease mouse model. [Methods] A mouse model of Parkinson's disease was developed by injecting 20 mg/kg of 1 methyl-4-phenyl-1,2,3,6-tetrahydropyridine and 250 mg/kg of probenecid (P). We divided in into four groups: probenecid group, probenecid-exercise group, 1 methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid group, and 1-methyl-4 phenyl-1,2,3,6-tetrahydropyridine/probenecid-exercise group. Mice in the exercise groups ran on treadmill for 30 min/day, five times per week for 4 weeks. [Results] Latency in the passive avoidance test increased in the 1-methyl-4 phenyl-1,2,3,6-tetrahydropyridine/probenecid-exercise group compared with 1 methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid group. In addition, the number of 5-bromo-2-deoxyuridine/NeuN-positive cells and 5-bromo-2 deoxyuridine/doublecortin-positive cells in the hippocampal dentate gyrus was higher in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid-exercise group than that in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid group. These changes were associated with the expression of brain-derived neurotrophic factor in the hippocampus. [Conclusion] Our results suggest that treadmill exercise may improve long-term memory in Parkinson's disease mice by facilitating neurogenesis via increased expression of neurotrophic factors. PMID- 26644676 TI - Deep cervical flexor training with a pressure biofeedback unit is an effective method for maintaining neck mobility and muscular endurance in college students with forward head posture. AB - [Purpose] This study investigated the effects of deep cervical flexor training on maintaining forward head posture, muscular endurance, and cervical mobility. It also examined the effectiveness of deep cervical flexor training with a pressure biofeedback unit. [Subjects and Methods] Twenty college students were recruited and randomly assigned to groups that underwent either deep cervical flexor training with a pressure biofeedback unit (experimental group, n=10) or conventional deep cervical flexor training (control group, n=10). The craniovertebral angle of each subject was measured with a lateral-view picture. Neck mobility was assessed using a cervical range of motion device and muscular endurance was measured using a pressure biofeedback unit. Both groups performed conventional deep cervical flexor exercises three times a week for six weeks. The experimental group underwent a pressure biofeedback unit training was 5 to10 minutes/day, thrice a week. [Results] Cervical range of motion in the experimental group increased significantly between the end of training and the end of the four week detraining period, compared to that in control group. [Conclusion] Deep cervical flexor training with a pressure biofeedback unit is a useful method for maintaining neck mobility and muscular endurance in people with forward head posture. PMID- 26644677 TI - Rehabilitation outcomes in children with cerebral palsy during a 2 year period. AB - [Purpose] To observe motor and functional progress of children with cerebral palsy during 2 years. [Subjects and Methods] Pediatric cerebral palsy patients aged 3-15 years (n = 35/69) with 24-month follow-up at our outpatient cerebral palsy clinic were evaluated retrospectively. The distribution of cerebral palsy types was as follows: diplegia (n = 19), hemiplegia (n = 4), and quadriplegia (n = 12). Participants were divided into 3 groups according to their Gross Motor Functional Classification System scores (i.e., mild, moderate, and severe). All participants were evaluated initially and at the final assessment 2 years later. During this time, patients were treated 3 times/week. Changes in motor and functional abilities were assessed based on Gross Motor Function Measure-88 and Wee Functional Independence Measure. [Results] Significant improvements were observed in Gross Motor Function Measure-88 and Wee Functional Independence Measure results in all 35 patients at the end of 2 years. The Gross Motor Function Measure-88 scores correlated with Wee Functional Independence Measure Scores. Marked increases in motor and functional capabilities in mild and moderate cerebral palsy patients were observed in the subgroup assessments, but not in those with severe cerebral palsy. [Conclusion] Rehabilitation may greatly help mild and moderate cerebral palsy patients achieve their full potential. PMID- 26644678 TI - The Turkish version of the pregnancy physical activity questionnaire: cross cultural adaptation, reliability, and validity. AB - [Purpose] The aim of this study was to translate the Pregnancy Physical Activity Questionnaire, adapt it for use with Turkish subjects and determine its reliability and validity. [Subjects and Methods] The Pregnancy Physical Activity Questionnaire was translated into Turkish and administered twice at 7-14-day intervals to pregnant women to assess the test-retest reliability. Cronbach's alpha was used for internal consistency, and the inter-rater correlation coefficient was used to calculate the test-retest reliability. The Turkish Short Form 36 Health Survey (SF-36) and the International Physical Activity Questionnaire were used to estimate validity. [Results] The internal consistency during the first and third trimesters of pregnancy was excellent, with Cronbach's alpha values of 0.93 and 0.95, respectively. The mean interval between the two assessments was 11.1 +/- 2.1 days. The correlation coefficient between the total activity measured by the Turkish version of the Pregnancy Physical Activity Questionnaire and the International Physical Activity Questionnaire estimates of the total metabolic equivalent were fair to poor during the first, second, and third trimesters of pregnancy (r = 0.17, r = 0.17, r = 0.21, respectively). The Turkish version of the Pregnancy Physical Activity Questionnaire showed fair correlations with the Short Form 36 Health Survey physical component score (r = 0.30) and mental component score (r = -0.37) for the first trimester of pregnancy. [Conclusion] The Turkish version of the Pregnancy Physical Activity Questionnaire was found to be reliable and valid for assessing a pregnant woman's physical activity. PMID- 26644679 TI - Analysis of isokinetic muscle strength for sports physiotherapy research in Korean ssireum athletes. AB - [Purpose] The purpose of the present study was to elucidate the muscle conditions such as the isokinetic muscle of Korean ssireum athletes. [Subjects and Methods] This study enrolled 25 elite ssireum athletes. We measured body composition and peak torque at an angular speed at 60 degrees /s using an isokinetic muscle strength dynamometer. [Results] The lean body mass of the left upper limb was significantly higher than that of the right upper limb. However, the lean body mass of the left lower limb was significantly lower than that of the right lower limb. The peak torque for left elbow flexion was significantly higher than that for right elbow flexion. Conversely, the peak torque for left elbow extension was significantly lower than that for right elbow extension. Furthermore, the peak torque for the left knee was significantly lower than that for the right knee for both flexion and extension. [Conclusion] The data from this study elucidate in part the muscle conditions of Korean ssireum athletes, which can be used to establish a reference for the scientific study of sports physiotherapy. PMID- 26644680 TI - The relationship between bilateral knee muscle strength and gait performance after stroke: the predictive value for gait performance. AB - [Purpose] The purpose of this study was to assess the relationships between bilateral knee extension strengths and gait performance in subjects with poststroke hemiparesis and to predict gait performance by the paretic and nonparetic knee extension strength. [Subjects and Methods] This was a correlational study in which 238 consecutive inpatients with poststroke hemiparesis were enrolled. Knee extensor muscle strengths in paretic and nonparetic lower limbs were measured with a handheld dynamometer, and the presence or absence of impaired gait was also determined. [Results] The mean strength in the paretic lower limb was 0.90 Nm/kg, and that in the nonparetic lower limb was 1.24 Nm/kg. Discriminant analysis classified the difference between the possibility and impossibility of gait by knee extensor muscle strength (standardized discriminant coefficient: paretic, 1.32; nonparetic, 0.55). Thus, paretic and nonparetic knee extension strengths were integrated in the strength index. A threshold level of 2.0 provided the best balance between positive and negative predictive values for the strength index. [Conclusion] The results indicated that both paretic and nonparetic knee extension strengths were related to gait performance. The strength index deduced from bilateral knee extension strengths may serve as a clinically meaningful index for rehabilitation assessment and training. PMID- 26644682 TI - Effect of proprioceptive neuromuscular facilitation integration pattern and swiss ball training on pain and balance in elderly patients with chronic back pain. AB - [Purpose] The purpose of this study was to determine the effects of proprioceptive neuromuscular facilitation integration pattern (PIP) and Swiss ball training on balance and pain in elderly patients with chronic low back pain. [Subjects] Participants were randomly assigned to a PIP training (n=24) and a Swiss ball training group (n=24). [Methods] The training was performed for 30 minutes per day, three times a week for 6 weeks. Outcome measures included the mean velocity in the X and Y directions using the Good Balance System((r)), functional reach test, timed up and go test, and visual analogue scale. [Results] After completion of training, mean velocity in the X and Y direction, and the functional reach test, timed up and go test, and visual analogue scale results showed statistically significant improvements in the PIP and Swiss ball training groups. However, there was no significant difference in the functional reach test, timed up and go test, and visual analogue scale results between the two groups. [Conclusion] This study indicated that PIP training improved the balance ability of elderly patients with chronic low back pain. PMID- 26644681 TI - Effect of pelvic floor muscle exercises on pulmonary function. AB - [Purpose] This study aimed to determine the correlation between pelvic floor muscle strength and pulmonary function. In particular, we examined whether pelvic floor muscle exercises can improve pulmonary function. [Subjects] Thirty female college students aged 19-21 with no history of nervous or musculoskeletal system injury were randomly divided into experimental and control groups. [Methods] For the pulmonary function test, spirometry items included forced vital capacity and maximal voluntary ventilation. Pelvic floor muscle exercises consisted of Kegel exercises performed three times daily for 4 weeks. [Results] Kegel exercises performed in the experimental group significantly improved forced vital capacity, forced expiratory volume in 1 second, PER, FEF 25-75%, IC, and maximum voluntary ventilation compared to no improvement in the control group. [Conclusion] Kegel exercises significantly improved pulmonary function. When abdominal pressure increased, pelvic floor muscles performed contraction at the same time. Therefore, we recommend that the use of pelvic floor muscle exercises be considered for improving pulmonary function. PMID- 26644683 TI - The influence of various resistance loads on the ratio of activity of the external rotator muscles of the shoulder and the anterior gliding of the humeral head during external rotation exercise. AB - [Purpose] To quantify the ratio of activation of the infraspinatus and posterior deltoid muscles and the anterior gliding motion of the humeral head during external rotation (ER) motions of the shoulder performed in prone position against different external resistance loads. [Subjects] Twenty healthy women between the ages of 20 and 30 years. [Methods] Activity ratio was quantified as the difference in the root mean square of the smoothed electromyography signal (EMG) of the posterior deltoid to the infraspinatus muscle, and anterior gliding pressure of the humeral head using a pressure biofeedback unit (PBU), for three resistance loads: 0, 1 and 2 kg. [Results] There was a significant correlation among all three variables (load, ratio, and pressure). Anterior gliding pressure correlated with the activity ratio, with activity of the posterior deltoid increasing with the magnitude of the resistance load. [Conclusion] There was a positive association between the magnitude of resistance load, activity of the posterior deltoid and anterior gliding pressure of the humeral head. The PBU could be used to facilitate the recruitment of the infraspinatus muscle at higher loads to improve glenohumeral joint stability during ER exercise against higher resistance. PMID- 26644684 TI - An efficacy study on improving balance and gait in subacute stroke patients by balance training with additional motor imagery: a pilot study. AB - [Purpose] The few studies conducted on subacute stroke patients have focused only on gait function improvement. This study therefore aimed to confirm the effect of balance training with additional motor imagery on balance and gait improvement in subacute stroke patients. [Subjects and Methods] Participants were divided into an experimental or control group. The experimental group received balance training for 20 minutes/day with mental imagery for 10 minutes/day, three days/week, for four weeks. The control group received only balance training for 30 minutes. Before and after the 12 sessions, balance and gait ability were assessed by the researcher and a physical therapist. [Results] After completion of the 4-week intervention, Berg Balance Scale, Timed Up and Go test, Functional Reach Test, and Four Square Step test scores significantly increased in the experimental group. In the control group, Berg Balance Scale and Functional Reach Test scores significantly improved. Changes in the Timed Up and Go test, Functional Reach Test, and Four Square Step Test scores after intervention were significantly higher in the experimental than in the control group. [Conclusion] Specific balance training with additional motor imagery may result in better rehabilitation outcomes of gait and balance ability than balance training alone. PMID- 26644685 TI - Effects of different core exercises on respiratory parameters and abdominal strength. AB - [Purpose] This study determined the effects a new modality of core stabilization exercises based on diaphragmatic breathing on pulmonary function, abdominal fitness, and movement efficiency. [Subjects] Thirty-two physically active, healthy males were randomly assigned to an experimental group (n = 16) and a control group (n = 16). [Methods] The experimental group combined diaphragmatic breathing exercises with global stretching postures, and the control group performed common abdominal exercises (e.g., crunch, plank, sit-up), both for 15 minutes twice weekly for 6 weeks. Pulmonary function (measured by forced vital capacity, forced expiratory volume in 1 second, and peak expiratory flow) and abdominal fitness (measured with the American College of Sports Medicine curl-up [cadence] test and the Functional Movement Screen(TM)) were evaluated before and after the intervention. [Results] Significant changes in curl-up (cadence) test scores, Functional Movement Screen scores, and all pulmonary parameters were recorded in the experimental group at the posttraining assessment, whereas in the control group, no significant differences over baseline were observed in any parameters. [Conclusion] Compared with traditional abdominal exercises, core stabilization exercises based on breathing and global stretching postures are more effective in improving pulmonary function and abdominal fitness. PMID- 26644686 TI - The effect of physician experience on the measurement reliability of the Reimers' hip migration percentage in children with cerebral palsy. AB - [Purpose] Reimers' hip migration percentage (MP) is commonly used to document the extent of hip displacement in children with cerebral palsy (CP). However, factors such as poor administration of pelvic radiographs, a lack of concentration, inexperience, or a busy clinical environment may result in variations in the MP measurements. The aim of this study was to compare the differences in the MP results of two physiatrists with varying levels of experience to determine the role of experience in the measurement's accuracy. [Subjects and Methods] This retrospective study included 62 hip radiographs of 31 children with spastic CP. Two physiatrists with different experience levels calculated the baseline MP on two occasions six weeks apart. Correlations, intra- and inter-rater reliabilities, and differences in the MPs were compared. [Results] Correlations and inter- and intra-rater reliabilities of the measurements were excellent. There were no statistically significant intra- or inter-rater differences for either of the two measurement points. Inter-rater correlations for each session were 0.94. [Conclusion] Experience does not appear to be a factor in the evaluation of MP, and inter-rater differences do not cause problems regarding patient follow-up. Therefore, repeated pelvic radiographs are not necessary in the evaluation of MP in children with CP unless indicated. PMID- 26644687 TI - Effects of a low-center-of-gravity backpack on the trunk stability of mountaineers while ascending and descending. AB - [Purpose] This study developed a backpack with a low center of gravity (LCG) and investigated the effects of the LCG backpack on the trunk stability of mountaineers while ascending and descending. [Subjects and Methods] Ten males aged 20-32 years were recruited. The subjects ascended and descended a road with an inclination of 30 degrees wearing the standard or LCG backpack, and trunk acceleration was measured using a tri-axial accelerometer. [Results] The anterior posterior (AP) and medial-lateral (ML) trunk acceleration while ascending and descending with the LCG backpack were significantly lower than those with the standard backpack. [Conclusion] The results suggest that the LCG backpack could prevent falling injuries during mountaineering and mountain-related activities. PMID- 26644688 TI - The effects of the length of rain boots on balance during treadmill walking. AB - [Purpose] Effects of muscle fatigue on lower-extremity balance were evaluated in 12 healthy young women in their 20s while they walked on a treadmill wearing rain boots of different lengths. [Methods] The rain boots were divided into three groups based on the shaft length (Long, Middle, Short). Romberg's test was applied and limits of stability were measured before and after treadmill walking. [Results] Romberg's test showed a significant main effect for time. There were significant differences between the center of gravity area, length, and velocity when the eyes were open and the center of gravity length, velocity, and length/cm(2) when the eyes were closed. Changes in the limits of stability also showed a significant main effect of time. There were significant differences in pre-test and post-test values in the left, right, forward, and total directions. [Conclusion] It was found that muscle fatigue in the lower extremities generated by walking in rain boots affected the joints and the adjuster muscles, depending on shaft lengths. Compensation due to visual feedback and the length of the boot shaft affected movement of the distal joints, resulting in a reduced ability to balance. PMID- 26644689 TI - The effect of progressive high-intensity inspiratory muscle training and fixed high-intensity inspiratory muscle training on the asymmetry of diaphragm thickness in stroke patients. AB - [Purpose] This study investigated the effects of progressive load and fixed load high-intensity inspiratory muscle training on the asymmetry of diaphragm thickness in stroke patients. [Subjects] Twenty-one stroke patients were assigned to one of three groups: progressive load high-intensity inspiratory muscle training (n = 8), fixed load high-intensity inspiratory muscle training (n = 6), and controls (n = 7). [Methods] The progressive load and fixed load high intensity inspiratory muscle training participants undertook an exercise program for 20 minutes, three times weekly, for 6 weeks. After each session, diaphragm thickness was measured using ultrasonography. The diaphragm asymmetry ratio and diaphragm thickening ratio were standardized using a formula. [Results] After intervention, the diaphragm asymmetry ratio significantly differed among the three groups, and the diaphragm asymmetry ratio significantly increased in the control group. A significant increase was identified in the diaphragm thickening ratio within the progressive load and fixed load high-intensity inspiratory muscle training groups. [Conclusion] Progressive load and fixed load high intensity inspiratory muscle training decreased the asymmetry of diaphragm thickness in stroke patients; this effect, in turn, increased the diaphragm thickening ratio in stroke patients. The two interventions examined here should be selectively applied to individuals in the clinical field. PMID- 26644690 TI - Protection mechanism of early hyperbaric oxygen therapy in rats with permanent cerebral ischemia. AB - [Purpose] The purpose of this study was to investigate whether early hyperbaric oxygen is useful in rats with permanent cerebral ischemia, and whether its mechanism relates to the inhibition of the tumor necrosis factor-alpha-protein kinase C-alpha pathway. [Subjects] Healthy, male Sprague-Dawley rats (N = 108) were the subjects. [Methods] After middle cerebral artery occlusion models were successfully made, rats were randomly divided into sham-operated, cerebral ischemia, and hyperbaric oxygen groups. At 4 and 12 hours after modeling, the volume of cerebral infarction was determined by triphenyltetrazolium chloride staining, and brain water content was measured using the dry and wet method. The expression of tumor necrosis factor-alpha and protein kinase C-alpha in the ischemic penumbra tissue was measured using Western blot analysis. [Results] The data showed that at 4 and 12 hours after modeling, cerebral infarct volume and brain water content decreased in the hyperbaric oxygen group, and expression of tumor necrosis factor-alpha and phospho-protein kinase C-alpha in the ischemic penumbra tissue also decreased. [Conclusion] Our study demonstrates that early hyperbaric oxygen therapy has protective effects on brain tissue after cerebral ischemia, possibly via inhibition of tumor necrosis factor-alpha and phospho protein kinase C-alpha. PMID- 26644691 TI - Effects of the hold and relax-agonist contraction technique on recovery from delayed onset muscle soreness after exercise in healthy adults. AB - [Purpose] This study was conducted to verify the effects of the hold relax agonist contraction and passive straight leg raising techniques on muscle activity, fatigue, and range of motion of the hip joint after the induction of delayed onset muscle soreness in the hamstring muscle. [Subjects] Sixty subjects were randomly assigned to a hold relax-agonist contraction group and a passive straight leg raising group. [Methods] Subjects in the experimental group underwent hold relax-agonist contraction at the hamstring muscle, while subjects in the control group underwent passive straight leg raising at the hamstring muscle. [Results] Subjects in the hold relax-agonist contraction group showed a significant increase in hamstring muscle activity and hip joint angle and a significant decrease in muscle fatigue. In the passive straight leg raising group, the hip joint angle increased significantly after the intervention. In the hold relax-agonist contraction group, hamstring muscle activity increased significantly and muscle fatigue decreased significantly. [Conclusion] We conclude that the hold relax-agonist contraction technique may be beneficial for improving muscle activation and decreasing muscle fatigue. PMID- 26644692 TI - Effects of joint position on the distraction distance during grade III glenohumeral joint distraction in healthy individuals. AB - [Purpose] The study investigated the effects of joint position on the distraction distance during Grade III glenohumeral joint distraction in healthy individuals. [Subjects and Methods] Twenty adults in their forties without shoulder disease were randomly divided into neutral position group (NPG; n = 7), resting position group (RPG; n = 7), and end range position group (ERPG; n = 6). After Kaltenborn Grade III distraction for 40s, the distance between glenoid fossa and humeral head was measured by ultrasound. [Results] The average distances between the humeral head and glenoid fossa before distraction were 2.86 +/- 0.81, 3.21 +/- 0.47, and 3.55 +/- 0.59 mm for the NP, RP, and ERP groups. The distances after applying distraction were 3.12 +/- 0.51, 3.86 +/- 0.55, and 4.35 +/- 0.32 mm. Between-group comparison after applying distraction revealed no significant differences between the NP and RP groups, while there was a statistically significant difference between the NP and RP groups, as well as between the NP and ERP groups. [Conclusion] Joint space was largest in ERP individuals when performing manual distraction. PMID- 26644693 TI - Comparison of activation and change in the upper trapezius muscle during painful and non-painful computer work. AB - [Purpose] Activation and changes in parts of the upper trapezius muscle during painful and non-painful computer work were compared. [Subjects] Ten male computer workers were recruited. [Methods] Surface electromyography was used to compare upper trapezius muscle activation and changes (difference between minimum and maximum activation) during painful and non-painful computer work. [Results] Mean normalized upper trapezius muscle activity did not differ between the "feel-pain" and "non-feel-pain" muscle sections. The mean change in upper trapezius muscle activity in the feel-pain section decreased significantly compared to the non feel-pain section. [Conclusion] Measuring changes in the activity of muscle sections was useful to study static and sustained muscle stress during computer work. PMID- 26644694 TI - Electromyography activity of the deltoid muscle of the weight-bearing side during shoulder flexion in various weight-bearing positions. AB - [Purpose] This study investigated the deltoid muscle activation during shoulder flexion exercise in various weight-bearing positions. [Subjects] A total of 15 males participated. [Methods] The participants completed three repetitions of shoulder flexion exercises in three positions (prone-on-elbow, quadruped, and standing) with electromyography activity being collected from the exercised. The muscle activations in each position by each exercise were compared using a one way analysis of variance. [Results] The electromyography activities of the middle and posterior deltoids differed significantly among positions. The prone-on-elbow and quadruped position showed a significantly higher activity than the standing position. There were no significant differences between the prone-on-elbow and quadruped positions. [Conclusion] The deltoid muscles were further strengthened in the low posture positions (prone-on-elbows and quadruped) than in standing. PMID- 26644695 TI - Tactile and proprioceptive sensory stimulation modifies estimation of walking distance but not upright gait stability: a pilot study. AB - [Purpose] Recently, there has been growing interest in the somatosensory system, but little data exist on the interaction between dynamic postural control and the somatosensory system. The purpose of this study was to determine whether a training program, based on tactile and proprioceptive sensory stimulation of the trunk with the use of perceptual surfaces, improved the estimation of walking distance by healthy subjects, the ability to walk toward a memorized distance without vision, and whether it increases upright gait stability. [Subjects and Methods] Ten healthy subjects with a mean age of 31.9 +/- 2.5 years were enrolled and participated in 10 daily sessions of perceptive training using perceptual surfaces, for 45 minutes each session. An experimental indoor test measured the subjects' ability to perceive walking distances to a memorized target in an indoor environment. [Results] After treatment, the distances that were traversed were closer to the target than before treatment. Trunk acceleration did not differ significantly between pre- and post-training and did not increase significantly after training. [Conclusion] Treatment with perceptual surfaces stimulating the trunk midline improves the estimation of walking distance and modifies proprioceptive gait patterns, allowing various corrective strategies to be implemented during ambulation. PMID- 26644696 TI - The effects of a strategic strength resistance exercise program on the isokinetic muscular function of the ankle. AB - [Purpose] The purpose of this study was to investigate the effects of a strategic strength resistance exercise program on the isokinetic muscular function of the ankle joint. [Subjects] This study included 22 males in their twenties who were diagnosed with functional injury of the ankle joint. [Methods] To strengthen plantar flexion and dorsiflexion of the ankle joint, 8 weeks of weight, resistance band, and plyometric training, and training using props were performed. [Results] A medical examination by interview indicated that pain, swelling, instability, running, and support capacity of the ankle joint significantly improved with the strategic strength resistance exercise program. For the isokinetic peak torque of the ankles, significant differences were observed in right plantar flexion and bilateral dorsiflexion. [Conclusion] The strategic strength resistance exercise program is highly recommended for the functional stability of the ankle joint. Efficient exercise therapy is useful for muscle damage prevention, muscle strengthening, and functional interventions. PMID- 26644697 TI - Effect of ankle proprioceptive training on static body balance. AB - [Purpose] This study aimed to investigate the effect of ankle proprioceptive training on static body balance. [Subjects and Methods] In this randomized controlled, single-blind study, 59 university students (35 females, 24 males) were randomized into study (n=29) and control (n=30) groups. The study group received a foot and ankle proprioceptive exercise program including stretching, strengthening (plantar and dorsi-flexors, invertor and evertor muscles), and balance board exercises, each with 10 repetitions per session, 5 days a week, for a total of 10 sessions. The control group did not receive any intervention. Static body balance was evaluated by a kinesthetic ability trainer, which showed the balance index scores under both single foot and both feet conditions. This evaluation was repeated at the end of two weeks for both groups. [Results] Outcome measures of the groups were similar at the baseline. Balance index scores of both groups improved at the end of two weeks, and the study group had significantly lower index scores than those of the control group, indicating better balance. [Conclusion] Ankle proprioceptive training had positive effects on static body balance parameters in healthy individuals, and it is worth investigating the effects of this type of training in patients with balance disorders. PMID- 26644698 TI - Hallux valgus-a case for a physiotherapist or only for a surgeon? Literature review. AB - [Purpose] Hallux valgus is one of the most common deformations of the human foot, and it causes great difficulties for the patients. The aim of this paper was to review available medical literature in search of evidence which would justify implementation of physiotherapy, based on its effectiveness for patients with hallux valgus. [Subjects and Methods] The following databases were searched for applicable papers: PubMed, Google Scholar, Clinical Key and UpToDate. Full-text articles from the last 15 years were subjected to a review, which ultimately selected seven papers about hallux valgus therapy published over the past 12 years. These studies were grouped according to their design and level of evidence and classified depending on whether they concerned physiotherapy as postoperative therapy or as the only treatment. [Results] The studies included in the present analysis used the following interventions for patients with hallux valgus: exercise, manual therapy, gait training, taping and orthosis. All the studies showed beneficial effects and the most frequently observed results were reductions in pain and improvements in function. [Conclusion] The evidence found in the reviewed materials clearly indicates that patients with hallux valgus should not only be subject to surgical procedures but also undergo physiotherapeutic treatment. PMID- 26644699 TI - Does exercise therapy improve the health-related quality of life of people with knee osteoarthritis? A systematic review and meta-analysis of randomized controlled trials. AB - [Purpose] The aim of this study was to examine the effects of exercise therapy on the health-related QOL of people with knee osteoarthritis. [Subjects] Four databases (PubMed, Cochrane Central Register of Controlled Trials, the Physiotherapy Evidence Database, and the Cumulative Index to Nursing and Allied Health Literature) were searched for randomized controlled trials that evaluated the effects of exercise therapy on health-related QOL assessed by the SF-36 for inclusion in our systematic review. The methodological qualities of the trials were assessed independently by two reviewers using the PEDro scale. Pooled analyses with a random-effects model or a fixed-effects model were used in the meta-analyses to calculate the standardized mean differences and 95% confidence intervals. [Results] Twelve studies met the inclusion criteria. Our meta-analysis provides high-quality evidence that exercise therapy increases the summary score, physical functioning score, and role-physical score of knee osteoarthritis sufferers. Our meta-analysis also provides moderate-quality evidence that the physical component summary and mental component summary scores were improved to a greater extent by exercise therapy than by control interventions. [Conclusion] Exercise therapy can improve health-related QOL, as assessed by the SF-36, of knee osteoarthritis sufferers. PMID- 26644700 TI - Action observation for upper limb function after stroke: evidence-based review of randomized controlled trials. AB - [Purpose] The purpose of this study was to suggest evidenced information about action observation to improve upper limb function after stroke. [Methods] A systematic review of randomized controlled trials involving adults aged 18 years or over and including descriptions of action observation for improving upper limb function was undertaken. Electronic databases were searched, including MEDLINE, CINAHL, and PEDro (the Physiotherapy Evidence Database), for articles published between 2000 to 2014. Following completion of the searches, two reviewers independently assessed the trials and extracted data using a data extraction form. The same two reviewers independently documented the methodological quality of the trials by using the PEDro scale. [Results] Five randomized controlled trials were ultimately included in this review, and four of them (80%) reported statistically significant effects for motor recovery of upper limb using action observation intervention in between groups. [Conclusion] This review of the literature presents evidence attesting to the benefits conferred on stroke patints resulting from participation in an action observation intervention. The body of literature in this field is growing steadily. Further work needs to be done to evaluate the evidence for different conditions after stroke and different duration of intervention. PMID- 26644701 TI - The accuracy of pain drawing in identifying psychological distress in low back pain-systematic review and meta-analysis of diagnostic studies. AB - The aim of this systematic review and meta-analysis was to estimate the accuracy of qualitative pain drawings (PDs) in identifying psychological distress in subacute and chronic low back pain (LBP) patients. [Subjects and Methods] Data were obtained from searches of PubMed, EBSCO, Scopus, PsycINFO and ISI Web of Science from their inception to July 2014. Quality assessments of bias and applicability were conducted using the Quality of Diagnostic Accuracy Studies-2 (QUADAS-2). [Results] The summary estimates were: sensitivity=0.45 (95% CI 0.34, 0.61), specificity=0.66 (95% CI 0.53, 0.82), positive likelihood ratio=1.23 (95% CI 0.93, 1.62), negative likelihood ratio=0.84 (95% CI 0.70, 1.01), and diagnostic odds ratio=1.46 (95% CI 0.79, 2.68). The area under the curve was 78% (CI, 57 to 99%). [Conclusion] The results of this systematic review do not show broad and unqualified support for the accuracy of PDs in detecting psychological distress in subacute and chronic LBP. PMID- 26644702 TI - Association between osteoporotic fractures and quality of life based on the Korean Community Health Survey of 2010. AB - [Purpose] To assess the relationship between fractures and quality of life (QOL) of osteoporosis patients as well as the treatment methods and locations of fractures following osteoporosis diagnosis. [Subjects and Methods] Participants were selected from a cohort consisting of 229,229 subjects who participated in the Korean Community Health Survey. Those who were not diagnosed with osteoporosis by a doctor were excluded from the study (326) and the final analysis included 17,387 previously diagnosed participants with osteoporosis. Multiple linear regression analysis was conducted. [Results] The QOL was significantly lower for subjects receiving treatment for osteoporosis compared to those who had not previously received treatment. Subjects who experienced a fracture similarly had a lower QOL compared to those who did not have a fracture. In addition, the QOL of subjects who experienced a fracture in the pelvis, spine, or wrists was significantly lower compared to those without fractures in these areas. [Conclusion] Better knowledge of osteoporosis leads to early recognition of symptoms and timely treatment. This results in better treatment outcomes and improved QOL for patients. Therefore, the need for physical therapy that is based on research evidence of osteoporosis treatment methods should be presented. PMID- 26644703 TI - Effect of joint mobilization and stretching on respiratory function and spinal movement in very severe COPD with thoracic kyphosis. AB - [Purpose] The purpose of this study was to analyze the effect of joint mobilization and stretching of the thoracic cage for very severe chronic obstructive pulmonary disease (COPD) on a patient with thoracic kyphosis. [Subject and Methods] The subject is a 73-year-old female COPD patient with thoracic kyphosis. The intervention methods were comprised of joint mobilization and stretching. The program consisted of 30 minute sessions three days per week for eight weeks. Respiratory function, spinal curve, and spinal movement (thoracic and lumbar spine) were measured. [Results] Joint mobilization and stretching did not result in noticeable changes in the respiratory function of the patient; however, positive changes were observed, including decreased thoracic kyphosis curve, increased lumbar lordosis curve, and increased spinal movement. [Conclusion] The results of the analysis show that the patient's age, body mass index, duration of the disease, COPD level, and posture should be considered in the clinical decision to perform pulmonary physical therapy for patients with complicated diseases such as COPD with thoracic kyphosis. PMID- 26644704 TI - Differential diagnosis of a rare case of upper limb pain: Paget-Schroetter syndrome in a doner kebab chef. AB - [Purpose] Paget-Schroetter syndrome (PSS) is an uncommon deep vein thrombosis of the axillary and subclavian veins which may occur spontaneously, but is usually caused by excessive upper limb activity. PSS is clinically similar to other upper limb musculoskeletal disorders and soft tissue infections, and this may lead to delay in correct diagnosis in its early stages. The aim of our case report is to discuss this rare condition with reference to the available literature. [Subjects and Methods] Here we report the case of a doner kebab chef who complained of swelling and pain in his right arm around the biceps muscle. The initial diagnosis was biceps tendon rupture, for which the patient underwent magnetic resonance imaging (MRI) of the right arm and shoulder. Since the MRI revealed no pathological findings, right upper limb venous Doppler ultrasound analysis was performed. Subacute thrombosis materials were detected in the subclavian, axillary, and brachial veins. [Results] With rapid anticoagulant therapy, the patient's symptoms quickly improved. [Conclusion] Early diagnosis and treatment of PSS is critical for preventing potentially fatal complications such as pulmonary embolism. Prophylaxis is important for preventing recurrent thrombosis and for avoiding the development of post-thrombotic syndrome. PSS should be considered a possible cause of painful swelling of the upper limbs, especially in young, active patients who use their arms excessively. PMID- 26644705 TI - Effects of therapeutic climbing activities wearing a weighted vest on a child with attention deficit hyperactivity disorder: a case study. AB - [Purpose] The purpose of this study was to evaluate the effect of therapeutic climbing activities on the brain waves and attention of a child with attention deficit hyperactivity disorder. [Subject and Methods] The subject of this case study was a 7 year 6-month old child diagnosed with attention deficit hyperactivity disorder. This study was based on evidence gathered at 3 distinct stages: a pre-intervention period, 10 intervention periods (2 weeks), and one post-intervention period. The intervention involved therapeutic climbing activities wearing a weighted vest over the course of 4 weeks. The clinical outcome measures were electroencephalography and the Star Cancellation Test. [Results] The mean activation of alpha waves was improved by the therapeutic intervention. During the intervention, the mean activation of alpha waves was the highest at the F3 cortical locus and the lowest at the T4 cortical locus. The average Star Cancellation Test scores were 43 at pre-intervention, 50 during the therapeutic intervention, and 52 at post-intervention. The performance time of the Star Cancellation Test was 240.1 seconds at pre-intervention, 90.2 seconds during the therapeutic intervention, and 60.0 seconds at post-intervention. [Conclusion] The results of this study suggest that therapeutic climbing activities performed wearing a weighted vest had positive effects on the brain waves and the attention span of a child with attention deficit hyperactivity disorder. PMID- 26644706 TI - Effect of proprioceptive neuromuscular facilitation D2 flexion and breathing exercises on lymphedema without a short stretch compression bandage. AB - [Purpose] The aim of this study was to evaluate the effects of proprioceptive neuromuscular facilitation (PNF) D2 flexion and breathing exercises in a patient with lymphedema (LE). [Subject] This report describes a 57-year-old woman with LE in whom a short-stretch compression bandage (SSCB) could not be used for treatment because of skin itching and redness. [Methods] The patient received complex decongestive therapy without a SSCB. Next, PNF D2 flexion and breathing exercises were conducted three times per week for 14 weeks (36 times). [Results] As a result, the circumference of the armpit was reduced by 0.5 cm; that of 10 cm above the elbow, by 1 cm; that of the elbow, by 0.5 cm; that of 10 cm below the elbow, by 1 cm; and that of the back of the hand, by 0.5 cm. A total of 100 mL (9.4%) of body water was eliminated from the right upper extremity, and moisture ratio was reduced by 0.005%. Finally, range of motion was improved to 20 degrees flexion, 60 degrees abduction, 40 degrees external rotation, and 10 degrees internal rotation. [Conclusion] This study showed that PNF D2 flexion and breathing exercises were effective in reducing LE and improving range of motion. PMID- 26644707 TI - Effect of the release exercise and exercise position in a patient with carpal tunnel syndrome. AB - [Purpose] This study examined the effect of the release exercise and exercise position in carpal tunnel syndrome (CTS). [Subject] A 40-year-old, right-hand dominant man presented with CTS, with pain and progressive tingling and numbness in the right hand. [Methods] The subject performed three exercises: (1) release, (2) wrist flexor stretching, and (3) wrist extensor stretching. In session 1, the subject performed exercises 2 and 3 in the standing position for 2 weeks. In session 2, the subject performed all three exercises in the supine position for 2 weeks. [Results] The pressure pain threshold decreased after session 1 and decreased further after session 2, and the Phalen's test and Tinel sign became progressively less positive. [Conclusion] Exercises in the supine position, including release exercises, are recommended for CTS. PMID- 26644708 TI - Reporting guidelines for research. PMID- 26644709 TI - Satisfying journey! PMID- 26644710 TI - Cross-cultural adaptation and validation of Hindi version of oral health impact profile-14. PMID- 26644711 TI - Author's reply: Translation and validation of Hindi version of oral health impact profile-14. PMID- 26644712 TI - Current concepts in the use of lasers in periodontal and implant dentistry. AB - Lasers have various periodontal applications including calculus removal (Er: YAG, Er, Cr: YSGG lasers); soft tissue excision, incision and ablation; decontamination of root and implant surfaces; biostimulation; bacteria reduction; and osseous surgery. This paper reviews some of the major opportunities for using lasers in periodontal and implant specialty practices. The literature relating to the use of lasers for removal of the pocket epithelium, root conditioning, bacterial reduction and decontamination of infected implant surfaces is discussed, and a summary of the advantages and disadvantages of using lasers for periodontal treatment is provided. PMID- 26644713 TI - Association of periodontal and cardiovascular diseases: South-Asian studies 2001 2012. AB - Large proportion of Asian populations have moderate to severe periodontal disease and a substantial number are anticipated to be at high risk of cardiovascular diseases (CVD). This study reviews epidemiology and association of periodontal and CVDs from the South-Asian region. Observational studies and clinical trials published during January 2001-December 2012 focusing association between periodontitis and CVDs in South-Asian countries were retrieved from various databases and studied. Current evidence suggests that both periodontal and CVDs are globally prevalent and show an increasing trend in developing countries. Global data on epidemiology and association of periodontal and CVDs are predominantly from the developed world; whereas Asia with 60% of the world's population lacks substantial scientific data on the link between periodontal and CVDs. During the search period, 14 studies (5 clinical trials, 9 case-controls) were reported in literature from South-Asia; 100% of clinical trials and 77% case control studies have reported a significant association between the oral/periodontal parameters and CVD. Epidemiological and clinical studies from South-Asia validate the global evidence on association of periodontal disease with CVDs. However, there is a need for meticulous research for public health and scientific perspective of the Periodontal and CVDs from South-Asia. PMID- 26644714 TI - Low levels of serum Vitamin D in chronic periodontitis patients with type 2 diabetes mellitus: A hospital-based cross-sectional clinical study. AB - AIM: Vitamin D is associated with inflammatory diseases such as periodontal disease and diabetes mellitus (DM). The aim of our study was to find out the level of serum Vitamin D in chronic periodontitis patients (CHP) with and without type 2 DM. MATERIALS AND METHODS: This study consists of 141 subjects, including 48 controls. Case groups consisted of 43 chronic periodontitis patients with type 2 DM (CHPDM) and 50 CHP. pocket depth (PD), clinical attachment loss (CAL), modified gingival index (MGI), plaque index (PI), and calculus index (CI) were taken. Serum 25-hydroxyvitamin D (25[OH] D) level in etag/ml was estimated by electrochemiluminescence immunoassay with Elecsys and cobase e immunoassay analysers(cobase e 411). Other laboratory investigations including fasting blood sugar (FBS) and serum calcium were measured in all subjects. RESULTS: The mean serum 25(OH) D level was 22.32 +/- 5.76 etag/ml, 14.06 +/- 4.57 etag/ml and 16.94 +/- 5.58 etag/ml for control, CHPDM and CHP groups respectively. The difference was statistically significant (P < 0.05). The mean value of FBS was significantly high in CHPDM group as compared to CHP group. Periodontal parameters like MGI, PI, PD, and CI showed significant difference between groups (P < 0.05) and higher score was found in CHP group, while CAL and PI showed no statistically significant difference between CHP and CHPDM group (P > 0.05). CONCLUSIONS: This study observed a low level of serum Vitamin D level in patients with CHP and CHPDM. Low Vitamin D level was observed in case groups may be due to the diseases process rather than low Vitamin D acting as a cause for the disease. PMID- 26644715 TI - Association of periodontal health indicators and major depressive disorder in hospital outpatients. AB - BACKGROUND: Major depressive disorder (MDD) has been associated with changes in behavioral, neurophysiological, and neuroendocrinological factors and thought to be one of the leading causes of disability worldwide. There are various evidences that depression and periodontitis may also be related. AIM: The aim was to evaluate the association between MDD and periodontitis in a convenience sample of hospital outpatients. MATERIALS AND METHODS: Sixty individuals (30 subjects with MDD and 30 subjects without MDD) of age 26-67 years were included in the study. Depression was assessed by means of structured clinical interview for diagnostic and statistical manual of mental disorders. The periodontal clinical examination included the number of missing teeth, plaque index, gingival index (GI), probing pocket depth, and clinical attachment level (CAL). RESULTS: Mean number of missing teeth per patient was 1.14 (+/-1.2 standard deviation [SD]) in the control group and 2.58 (+/-1.64 SD) in case group (P < 0.001). The amount of plaque was significantly higher in cases compared with control (P = 0.001). The patients had an average GI of 1.82 (+/-0.65 SD) compared to 1.14 (+/-0.81 SD) for the controls (P < 0.001). Mean probing depth and CAL were 4.67 (+/-0.8 SD) mm and 4.96 (+/-0.2 SD) mm in the case group and 2.6 (+/-2.2 SD) mm and 2.7 (+/-0.43 SD) mm in the control group, respectively (P < 0.05). CONCLUSION: Our study confirms the significant association between depression and periodontitis and depression can be considered one of the important risk factors for periodontal diseases. PMID- 26644716 TI - Maternal periodontal disease and preterm birth: A case-control study. AB - BACKGROUND AND OBJECTIVE: Preterm birth (PTB) is an important issue in public health and is a major cause for infant mortality and morbidity. There is a growing consensus that systemic diseases elsewhere in the body may influence PTB. Recent studies have hypothesized that maternal periodontitis could be a high-risk factor for PTB. The aim of the present study was to investigate the relationship between maternal periodontitis on PTB. MATERIALS AND METHODS: Forty systemically healthy primiparous mothers aged 18-35 years were recruited for the study. Based on inclusion and exclusion criteria, they were categorized into PTB group as cases and full term birth group (FTB) as controls. PTB cases (n = 20) defined as spontaneous delivery before/<37 completed weeks of gestation. Controls (FTB) were normal births at or after 37 weeks of gestation. Data on periodontal status, pregnancy outcome variables, and information on other factors that may influence adverse pregnancy outcomes were collected within 2 days of labor. Data were subjected to Student's t-test and Pearson's correlation coefficient statistical analysis. RESULTS: Statistically significant difference with respect to the gestational period at the time of delivery and birth weight of the infants in (PTB) group (<0.001) compared to (FTB) group was observed. Overall, there was statistically significant poor periodontal status in the (PTB) group compared to (FTB) group. The statistical results also showed a positive correlation between gestational age and clinical parameters. CONCLUSION: An observable relationship was noticed between periodontitis and gestational age, and a positive correlation was found with respect to PTB and periodontitis. Further studies should be designed to establish periodontal disease as an independent risk factor for PTB/preterm low birth weight. PMID- 26644717 TI - Evaluation of antimicrobial properties of bioactive glass used in regenerative periodontal therapy. AB - CONTEXT: Bone grafting materials which have an inherent anti-microbial property against initial colonizers of plaque bacteria would be useful in regenerative periodontal surgical procedures. AIMS: This study was performed to analyze the antibacterial property of a PerioglasTM against a common oral commensal Streptococcus salivarius (early colonizer). SETTINGS AND DESIGN: In vitro observational study. MATERIALS AND METHODS: PerioglasTM (in various concentrations) was assessed for its antibacterial property against the ATCC 13419 strain of S. salivarius. The anti-microbial activity was analyzed in terms of reduction in colony-forming units in culture plates and smear following a 24 h incubation at 37 degrees C. STATISTICAL ANALYSIS USED: Observational study - No statistical analysis applicable. RESULTS: The bioactive glass (BAG) exerted an antibacterial effect against the S. salivarius in the suspending media and smear. The antibacterial activity of BAG increased in proportion with its concentration. CONCLUSIONS: PerioglasTM demonstrated a considerable antibacterial effect against S. salivarius at 50 mg/mL concentration. PMID- 26644718 TI - An in vitro scanning electron microscope study to evaluate the efficacy of various root conditioning agents. AB - AIM: The purpose of present study was to investigate the scanning electron microscopic alterations produced on scaled and root planed dentin surfaces after application of different etching modalities namely citric acid, tetracycline hydrochloride and ethylenediaminetetraacetic acid (EDTA). MATERIALS AND METHODS: Eighty specimens of teeth were collected and categorized into four groups. In group 1, control group specimens were treated with normal saline for 3 min, group 2 specimens were treated with citric acid, group 3 specimens were treated with tetracycline hydrochloride for 3 min and group 4 specimens were treated with 15% EDTA. RESULTS: Opening of dentinal tubules was seen in all specimens except for control group that was treated with normal saline. The total number of tubules seen was highest in citric acid group as compared to tetracycline hydrochloride and EDTA Group. The total number of patent tubule opening was highest in citric acid as compared to EDTA and tetracycline. The diameter of patent dentinal tubules in citric acid group was more than EDTA and tetracycline. CONCLUSION: The study showed that all the three agents were effective in removing the smear layer however number of patent and wider diameter dentinal tubules was seen in vitro best in citric acid than EDTA and then in tetracycline hydrochloride. Hence, citric acid group is more efficient than EDTA and tetracycline HCl group in removing the smear layer and in opening of number of patent dentinal tubules. PMID- 26644719 TI - Analysis of matrix metalloproteinase-8 levels in gingival crevicular fluid and whole mouth fluid among smokers and nonsmokers using enzyme-linked immune-sorbent assay and a novel chair-side test. AB - AIM: To indigenously prepare a chair-side test kit for investigating and comparing the matrix metalloproteinase (MMP)-8 levels in gingival crevicular fluid (GCF) and saliva in patients with healthy periodontium, gingivitis and chronic periodontitis in smokers and nonsmokers. To validate the diagnostic accuracy of indigenously prepared chair-side test against enzyme-linked immune sorbent assay (ELISA). Furthermore, to assess the effect of nonsurgical periodontal therapy (NSPT) on the levels of MMP-8 in GCF and saliva among the test groups. MATERIALS AND METHODS: GCF and saliva were collected from 250 subjects. The study population were divided into five groups; health periodontium nonsmokers (Group 1; n = 50), chronic gingivitis-nonsmokers (Group 2; n = 50), chronic periodontitis-nonsmokers (Group 3; n = 50), chronic gingivitis-smokers (Group 4; n = 50), chronic periodontitis-smokers (Group 5; n = 50). A chair-side test kit was indigenously prepared using polyclonal antibodies (principle of immunochromatography) to detect the MMP-8 levels, and it was validated against ELISA at baseline and 3 months after NSPT. RESULTS: The chair-side test detected MMP-8 levels with a sensitivity and specificity in accordance with ELISA. MMP-8 levels at baseline were higher in Group 2 and Group 3 as compared to controls (P < 0.05), and decreased after therapy (P < 0.05). MMP-8 levels in GCF were greater than in saliva for all the groups, indicating GCF to be a better sample to detect the MMP levels. CONCLUSION: The chair-side test detected MMP-8 levels accurately making it a viable chair side diagnostic tool. It was effective for early diagnosis of the periodontal disease among high-risk population such as smokers. PMID- 26644720 TI - Effect of nonsurgical periodontal therapy on salivary myeloperoxidase levels: A biochemical study. AB - BACKGROUND: Myeloperoxidase (MPO), the most abundant protein in neutrophils, is the focus of inflammatory pathologies. MPO could participate in the initiation and progression of periodontal disease. MATERIALS AND METHODS: A total of 60 patients with healthy gingiva, gingivitis, periodontitis between age group of 20 55 years were selected. Group I - 20 Patients with healthy gingiva, Group II - 20 Patients with generalized gingivitis, Group III - 20 Patients with generalized chronic periodontitis, Group IV - 20 Patients of Group III after 1-month of scaling and root planning. The following parameters were recorded: Gingival index, plaque index, bleeding on probing index, probing pocket depth, clinical attachment level, salivary MPO levels. All the parameters were then statistically analyzed. RESULTS: The mean MPO levels in Group I recorded was - 0.320 + 0.06, Group II was - 0.183 + 0.04, Group III was - 0.814 + 0.08 and Group IV was - 0.386 + 0.08 respectively. All these values were statistically significant when compared between the four groups (P < 0.05). A significantly elevated salivary MPO levels were found in subjects with chronic periodontitis as compared to the gingivitis group and the healthy group (P < 0.05). However, moderate but statistically significant increase in the MPO levels were observed in the gingivitis group as compared to the healthy group (P < 0.05). Furthermore, significant reduction in MPO levels were observed in Group IV after 1-month of nonsurgical periodontal therapy. CONCLUSION: The activities of MPO enzyme were significantly increased in the saliva of patients with periodontal disease in comparison to healthy individuals. Furthermore, nonsurgical periodontal therapy was found to be effective in improving clinical parameters and in reducing MPO levels. Salivary enzymes like MPO could be considered as a biochemical marker of periodontal disease activity. PMID- 26644721 TI - Comparative evaluation of the effectiveness of acellular dermal matrix allograft and subepithelial connective tissue to coronally advanced flap alone in the treatment of multiple gingival recessions: A clinical study. AB - BACKGROUND: Obtaining predictable and esthetic root coverage has become an important part of periodontal therapy. Several techniques have been developed to achieve these goals with variable outcomes. The aim of this study was to appraise the effectiveness of acellular dermal matrix allograft (ADMA) and subepithelial connective tissue graft (SCTG) compared to coronally advanced flap (CAF) in the treatment of multiple gingival recessions. MATERIALS AND METHODS: A total of 30 patients aged between 18 and 50 years, with multiple Miller's Class I and II recessions on labial or buccal surfaces of teeth were selected for this study. The patients were randomly assigned to CAF + ADMA, CAF + SCTG and CAF groups with 10 patients in each group. The clinical parameters assessed were probing pocket depth (PPD), clinical attachment level (CAL), gingival recession (GR), width of keratinized tissue, plaque index and papilla bleeding index at base line and 6 months after surgery. RESULTS: Statistical analysis using One-way ANOVA suggested that the root coverage obtained was greater in the ADMA + CAF (89.83 +/- 15.29%), when compared to SCTG + CAF (87.73 +/- 17.63%) and CAF (63.77 +/- 27.12%) groups. The predictability for coverage of >90% was greater in CAF + ADMA (65%) when compared with SCTG + CAF (61.66%) and CAF (31.17%). Improvements in the clinical parameters from baseline were found in all the three groups treated. CONCLUSION: It was concluded that all three techniques could provide root coverage in Miller's class I and II gingival recessions; but greater % root coverage and predictability for coverage of >90% could be expected with CAF + ADMA and CAF + SCTG groups when compared with CAF alone. PMID- 26644722 TI - The use of nanocrystalline and two other forms of calcium sulfate in the treatment of infrabony defects: A clinical and radiographic study. AB - BACKGROUND: Calcium sulphate(CS) is one of the oldest alloplastic graft materials used because of its biocompatibility, handling characteristics, porosity, different rates of dissolution, chemico-physical resemblance to bone mineral, ability to induce release of growth factors and potentially unlimited supply at a modest cost. Aim of the study was to evaluate the efficacy of 3 forms of calcium sulphate i.e. Nanogen (nCS)(+), BoneGen(+) and Dentogen(+) in treatment of infrabony defects and to compare their efficacy as bone grafting substitutes. MATERIALS AND METHODS: A prospective randomized, double blind controlled study was conducted on 45 sites from 16 subjects having Moderate to Advanced Periodontitis who were divided into 3 groups i.e. Group I (Nanogen), Group II (Dentogen) and Group III (BoneGen) clinical along with radiographic measurements were taken at baseline, 6 and 12 months postoperatively. RESULTS: There was no significant inter-group difference in mean clinical attachment level (CAL) values at different time intervals whereas Intra-group changes in CAL at 6 and 12 months as compared to baseline were significant statistically. In Group I, changes in CAL between 6 and 12 months were found to be statistically significant in comparison with Group II and III. CONCLUSION: Both Nanogen and BoneGen TR can be considered valuable options in the treatment of infra-bony periodontal defects. The faster degradation of Dentogen may negatively affect its bone regeneration potential. PMID- 26644723 TI - Oral health knowledge deficit: A barrier for seeking periodontal therapy? A pilot study. AB - CONTEXT: In developing countries many chronic conditions including periodontitis are on the rise. Oral health attitudes and beliefs are important factors affecting oral health behavior. AIMS: The aim of this pilot study was to assess the existing knowledge about periodontal disease and its impact on treatment seeking behavior in a group of population visiting the out-patient Department of Periodontics, Yenepoya Dental College, India. This study also attempted to identify deficit in the knowledge if present. SETTINGS AND DESIGN: This is a written questionnaire based pilot study. 143 subjects (89 male and 54 female) agreed to participate in the study. Simple random sampling was used for recruitment. SUBJECTS AND METHODS: A written questionnaire consisting of 18 questions was given to the patients. Only one correct answer was present and the score given was + 1. The knowledge of the subjects was reflected by their ability to select a correct answer from the number of distractors (multiple choices, prespecified answers). STATISTICAL ANALYSIS USED: SPSS software version 15.0 is used for all statistical analysis. The Chi-square test was employed to assess the passive knowledge of the participants in relation to their age. RESULTS: We found a deficit in the knowledge in all the topics investigated. No consistent relationship between age and gender was found. Female respondents had better knowledge about oral hygiene compared to males. CONCLUSION: We made an attempt to assess the knowledge of periodontitis among the participants of this study. Knowledge deficit was found in the population surveyed. This knowledge deficit could be one of the reasons why patients do not seek periodontal treatment routinely unless there are acute symptoms. There is urgent need to educate the patients about the periodontal disease, the need for the treatment of periodontitis and advanced treatment modalities available. PMID- 26644724 TI - Comparison of the clinical applicability of Miller's classification system to Kumar and Masamatti's classification system of gingival recession. AB - BACKGROUND: The aims of the present study were to (i) Find the percentage of recession cases that could be classified by application of Miller's and/or Kumar and Masamatti's classification of gingival recession, and (ii) compare the percentage of clinical applicability of Miller's criteria and Kumar and Masamatti's criteria to the total recessions present. MATERIALS AND METHODS: A total of 104 patients (1089 recession cases) were included in the study wherein they were classified using both Miller's and Kumar and Masamatti's classification systems of gingival recession. Percentage comparison of the application of both classification systems was done. RESULTS: Data analysis showed that though all the cases of the recession were classified by Kumar and Masamatti's classification, only 34.61% cases were classified by Miller's classification. 19.10% cases were completely (having only labial/buccal recession) classified. In 15.51% (out of 34.61%) cases, only buccal recession was classified according to Miller's criteria and included in this category, although these cases had both buccal and lingual/palatal recessions. Furthermore, 29.75% cases of recession with interdental loss and marginal tissue loss coronal to mucogingival junction (MGJ) remained uncategorized by Miller's classification; categorization of palatal/lingual recession was possible with Kumar and Masamatti's classification. CONCLUSION: The elaborative evaluation of both buccal and palatal/lingual recession by the Kumar and Masamatti's classification system can be used to overcome the limitations of Miller's classification system, especially the cases with interdental loss and having marginal tissue loss coronal to MGJ. PMID- 26644725 TI - Herbal oral gel induced contact stomatitis along with desquamative gingivitis due to a coloring agent. AB - Report of a rare case of contact stomatitis manifesting as irregular erosions partially covered with pseudomembrane along with desquamative gingivitis in a 32 year-old female patient is presented. The patient was otherwise healthy and not taking any medication. She gave the history of using curcumin-based oral gel 2 days back. Allergy test to curcumin oral gel was found to be positive, which on detailed allergy testing proved to be the coloring agent, erythrosine present in the gel. Contrary to the popular belief some folk medicine preparations can lead to unwanted side effects due to the antigenic potential of ingredients present in them. In addition, every clinician, during differential diagnosis of oral lesions must bear in mind unwanted reactions to any local ointment. PMID- 26644726 TI - An unusual case of Burkitt's lymphoma presenting as a gingival enlargement. AB - Burkitt's lymphoma is an undifferentiated non-Hodgkin's B-cell lymphoma. Three clinical subtypes are recognized: African (endemic), American and other areas (sporadic) and human immunodeficiency virus (HIV) associated. Sporadic Burkitt's lymphoma is a rare malignancy among Asian population. This report describes a case of sporadic Burkitt's lymphoma presenting as generalized gingival enlargement with an alarmingly rapid spread. This type of rapid progression bespeaks the need for prompt recognition and life-saving referral by the dental practitioner. The purpose of this case report and review of the literature was to illustrate the fact that an inconspicuous and benign looking gingival enlargement may turn out to be an aggressive malignancy like Burkitt's lymphoma. PMID- 26644727 TI - Tuberculous osteomyelitis affecting periodontium: A rare case report. AB - Tuberculous lesions affecting periodontium are rare and seen as secondary infections localized to the soft tissues. With the advent of effective drug therapy, tuberculous lesions of the oral cavity have become rare. Involvement of the periodontium has seldomly been reported in the recent literature. We report a case of tuberculous osteomyelitis of mandible affecting periodontium leading to gingival recession and bone exposure in the mandibular premolar region in a 42 year-old female patient. The diagnosis was based on patient's medical and dental history, bacterial culture, clinical and radiographic examination, blood investigation, immunologic tests, histopathologic examination of the tissue specimen. Patient was already taking antitubercular chemotherapy prescribed by physician. Sequestrectomy and decortications were carried out to remove the affected bone. Healing was uneventful and there was no recurrence after 11/2 year of follow-up. Antitubercular chemotherapy along with sequestrectomy and decortication are the treatment of choice for tuberculous osteomyelitic lesions affecting periodontium. PMID- 26644728 TI - Sarcoidosis: Oral and extra-oral manifestation. AB - Sarcoidosis is a multisystem granulomatous disease, which is usually associated with the formation of noncaseating granulomas in affected tissues and organs. It is mostly present with bilateral hilar lymphadenopathy, pulmonary infiltration, ocular, and cutaneous lesions. Oral manifestations of this disease are relatively rare. The present case report shows a 40-year-old male with lesions in the soft tissue of oral cavity (buccal mucosa, gingiva, and palate) and a diagnosis of sarcoidosis was established following hematological, biochemical and pulmonary function tests, chest radiograph, and histopathological investigation. PMID- 26644729 TI - A case of oral focal mucinosis of gingiva: Lesion in disguise. AB - Oral focal mucinosis (OFM) is a rare soft tissue lesion of unknown aetiology. Clinically, it is most commonly found on the gingiva and presents as a painless, sessile or pedunculated mass. Histologically, it is characterized by focal myxoid degeneration of underlying connective tissue. Fifty-three-year-old patient reported with a painless, firm and fibrous gingival overgrowth present from 7 to 8 months. Clinical examination and patient's history pointed towards "irritation fibroma". An excisional biopsy was performed. The histopathologic diagnosis was established as OFM, an uncommon and poorly characterized type of lesion. This case report stresses on the fact that prediagnosis of OFM is almost impossible. Thus though rare, OFM must be considered in the differential diagnosis of soft tissue overgrowths in oral cavity. PMID- 26644730 TI - Tele-periodontics - Oral health care at a grass root level. AB - A new concept of tele-periodontics, which merges the innovative technology of telecommunications and the field of periodontics, is proposed. This new field of tele-periodontics will have an infinite potential where access to a specialist will be provided at a grass root level, enhancing effective delivery of therapy and information to the rural and under privileged areas. It would allow the specialist and the patient to interact either by video conferencing (real time) or through supportive information (store and forward) over geographic distances. Different probabilities of tele-periodontics such as tele consultation, tele training, tele education and tele support are also discussed in this paper. PMID- 26644731 TI - Bone suture and lateral sinus lift surgery. AB - Bone suture in lateral sinus lift has four indications. Three of them depend on creating a hole in the lateral maxillary sinus wall above the antrostomy window for securing the elevated medial maxillary sinus membrane to manage perforated Schneiderian membrane. Covering the buccal antrostomy window with the buccal fat pad (BFP) for better nourishment of the inserted graft and as an alternative for bone tags in fixation of collagen membrane has been reported previously. A new indication for firmly anchoring the BFP to the medial maxillary sinus wall as the last resort for the management of perforated Schneiderian membrane is explained in this article. PMID- 26644732 TI - Ethics in Aesthetic Surgery: Rituals and Realities. PMID- 26644733 TI - Current Trends in Facial Rejuvenation with Fillers. PMID- 26644734 TI - Facial Rejuvenation with Fillers: The Dual Plane Technique. AB - BACKGROUND: Facial aging is characterized by skin changes, sagging and volume loss. Volume is frequently addressed with reabsorbable fillers like hyaluronic acid gels. MATERIALS AND METHODS: From an anatomical point of view, the deep and superficial fat compartments evolve differently with aging in a rather predictable manner. Volume can therefore be restored following a technique based on restoring first the deep volumes and there after the superficial volumes. We called this strategy "dual plane". A series of 147 consecutive patients have been treated with fillers using the dual plane technique in the last five years. RESULTS: An average of 4.25 session per patient has been carried out for a total of 625 treatment sessions. The average total amount of products used has been 12 ml per patient with an average amount per session of 3.75 ml. We had few and limited adverse events with this technique. CONCLUSION: The dual plane technique is an injection technique based on anatomical logics. Different types of products can be used according to the plane of injection and their rheology in order to obtain a natural result and few side effects. PMID- 26644735 TI - The Liquid Lift: Looking Natural Without Lumps. AB - CONTEXT: Hyaluronic acid (HA) is the most common filler used to rejuvenate. Today, a three-dimensional approach prevails over previous techniques in which this material was used in specific areas of the face such as the nasolabial fold, the marionette line, and the eye trough giving a strange appearance that does not look natural. Even with a volumizing purpose, the injection of HA can sometimes produce clinically detectable nodules or lumps where the filler is deposited. AIMS: To develop a new technique of injecting HA that can provide more natural results and avoid the lumpiness and nodular appearance that sometimes occurs with the injection of HA. To detect whether mixing HA with diluted anesthetic agent modifies its behavior. SETTINGS AND DESIGN: Prospective, case control, single center study on a private clinic setting. MATERIALS AND METHODS: Eighty six patients were enrolled in this study. All of them had a previous treatment with nondiluted HA using a needle at least a year before. Patients were injected with 8 mL of reticulated HA (RHA) mixed with 6 mL of saline and 2 mL of anesthetic agent. The mixture was administered through a cannula inserted in the face, one at mid-cheek and another at frontal-temporal point of entry. Owing to the lifting effect of this mixture we called this procedure liquid lift (LL). Patients were evaluated 1 month, 6 months, and a year later and asked to compare the LL with previous experiences in terms of natural look, pain, and appearance of nodules. STATISTICAL ANALYSIS USED: Student's t-test. RESULTS: One month after the treatment, 83 out of 86 patients (96.5%) thought LL produced a more natural look than the previous treatment with the needle. Sixty two (72%) considered LL less painful than the previous treatment and only eight (9.3%) could detect lumps or nodules 1 month after LL was performed compared with 46 (53.5%) that described this problem with previous needle injections. The incidence of bruising was also clearly lower (7% with LL vs 17.4% with traditional needle). CONCLUSIONS: Injection of diluted HA with saline and anesthetic agents through a cannula all over the face or LL can provide more natural results and less lumps or nodules, and is less painful than traditional treatments involving needle injection of nondiluted HA. PMID- 26644736 TI - Shaping Lips with Fillers. AB - The lips and the eyes enhance facial beauty, and they have been highlighted since time immemorial. Rejuvenating the lips with fillers, frequently hyaluronic acid (HA), is a common procedure but requires expertise. The objective of this text is to describe the procedure in detail and cover the practical aspects of injecting lips with fillers. An analysis of treating lips with needles and cannulae has been made with special emphasis on achieving optimum results. PMID- 26644737 TI - Comparative Efficacy and Patient Preference of Topical Anaesthetics in Dermatological Laser Treatments and Skin Microneedling. AB - BACKGROUND: Topical anaesthetics are effective for patients undergoing superficial dermatological and laser procedures. Our objective was to compare the efficacy and patient preference of three commonly used topical anaesthetics: (2.5% lidocaine/2.5% prilocaine cream (EMLA((r))), 4% tetracaine gel (AmetopTM) and 4% liposomal lidocaine gel (LMX4((r)))) in patients undergoing laser procedures and skin microneedling. SETTINGS AND DESIGN: This was a prospective, double-blind study of patients undergoing laser and skin microneedling procedures at a laser unit in a tertiary referral dermatology centre. MATERIALS AND METHODS: All 29 patients had three topical anaesthetics applied under occlusion for 1 hour prior to the procedure, at different treatment sites within the same anatomical zone. A self-assessment numerical pain rating scale was given to each patient to rate the pain during the procedure and each patient was asked to specify their preferred choice of topical anaesthetic at the end of the procedure. STATISTICAL ANALYSIS: Parametric data (mean pain scores and frequency of topical anaesthetic agent of choice) were compared using the paired samples t-test. A P-value of <=0.05 was considered as statistically significant. RESULTS AND CONCLUSIONS: Patients reported a mean (+/-SD; 95% confidence interval) pain score of 5 (+/ 2.58; 3.66-6.46) with AmetopTM, 4.38 (+/-2.53; 2.64-4.89) with EMLA((r)) and 3.91 (+/-1.95; 2.65-4.76) with LMX4((r)). There was no statistically significant difference in pain scores between the different topical anaesthetics. The majority of patients preferred LMX4((r)) as their choice of topical anaesthetic for dermatological laser and skin microneedling procedures. PMID- 26644738 TI - A Prospective, Comparative, Evaluator-blind Clinical Study Investigating Efficacy and Safety of Two Injection Techniques with Radiesse((r)) for the Correction of Skin Changes in Aging Hands. AB - BACKGROUND: Dermal fillers are used to correct age-related changes in hands. AIMS: Assess efficacy and safety of two injection techniques to treat age-related changes in the hands using calcium hydroxylapatite filler, Radiesse((r)). SETTINGS AND DESIGN: This was a prospective, comparative, evaluator-blind, single center study. MATERIALS AND METHODS: Radiesse((r)) (0.8 mL/0.2 mL 2% lidocaine) was injected subdermally on Day (D)01, using a needle multipoint technique in one hand (N) and a fan-like cannula technique in the other (C). Assessments were made pre-injection, on D14, Month (M)02, M03 and M05 using the Merz Aesthetics Hand Grading Scale (MAS) and Global Aesthetic Improvement Scale (GAIS). Participants completed questionnaires on satisfaction, pain and adverse events (AEs). STATISTICAL ANALYSIS USED: Data distribution was tested with the Shapiro-Wilk and Levene's tests. The Wilcoxon signed-rank and Chi-square tests were employed to evaluate quantitative and qualitative data, respectively. RESULTS: All 10 participants completed the study, four opted for a M03 touch-up (0.8 mL Radiesse((r))). Evaluator-assessed mean GAIS scores were between 2 (significant improvement but not complete correction) and 3 (optimal cosmetic result) at each time point. The MAS score improved from D01 to M05 (N: 2.60 to 1.40; C: 2.20 to 1.30). Following treatment, participants reported skin was softer, more elastic, more youthful and less wrinkled. Other than less noticeable veins and tendons on the C hand, no differences in participant satisfaction were noted. All AEs were mild, with no serious AEs reported. CONCLUSIONS: Both injection techniques (needle and cannula) demonstrated equivalent clinical efficacy with a comparable safety profile for the correction of age-related changes in hands with Radiesse((r)). PMID- 26644739 TI - The Impact of Post-Acne Scars on the Quality of Life Among Young Adults in Singapore. AB - BACKGROUND AND OBJECTIVES: Post-acne scarring is a common and well-known sequelae of acne vulgaris. We aim to study the impact of post-acne scarring on the quality of life (QOL) among young adults in Singapore. SETTINGS AND DESIGN: This was a non-interventional prospective study. MATERIALS AND METHODS: Patients aged 21-40 years with atrophic and hypertrophic acne scars who attended the National Skin Centre, Singapore were recruited in the study. They answered a simple questionnaire and the clinical severity of their acne scars were assessed by the doctor. STATISTICAL ANALYSIS USED: Descriptive analyses using absolute and percentage frequencies were performed on all data. The test of significance was two-sided and was set at 5% (P <= 0.05). Differential analyses were conducted using the parametric, independent two-sample t-test and non-parametric Mann Whitney U-test. The statistical assessments were performed using SPSS version 18.0. RESULTS: A total of 100 patients were studied. The mean patients' subjective self-scoring on the severity of their post-acne scars was 5.78/10 and the mean Dermatology Life Quality Index (DLQI) for post-acne scars was 5.61. Many (36%, n = 36) were self-conscious of their acne scars and 24%, (n = 24) felt that their acne scars was affecting their social activities. CONCLUSIONS: Our study showed that post-acne scars have a significant negative effect on the QOL of young adults. It highlights the need to increase public awareness of acne vulgaris and its sequelae through education programs and advocating early treatment to reduce the risk of scarring. PMID- 26644740 TI - Efficacy and Safety of Fractional CO2 Laser Resurfacing in Non-hypertrophic Traumatic and Burn Scars. AB - BACKGROUND: Fractional photothermolysis is one of the most effective treatment options used to resurface scars of different aetiologies. AIM: To assess the efficacy and safety of fractional CO2 laser resurfacing treatment in the management of non-hypertrophic traumatic and burn scars. MATERIALS AND METHODS: Twenty-five patients affected by non-hypertrophic traumatic and burn scars were treated with four sessions of fractional CO2 laser resurfacing treatment at 6 weekly intervals. Patients were photographed at each visit and finally, 3 months after the end of treatment schedule. Response to treatment was assessed clinically as well as by comparing the initial photograph of the patient with the one taken at the last follow-up visit 3-months after the final treatment session. Changes in skin texture, surface irregularity and pigmentation were assessed on a quartile grading scale and scored individually from 0 to 4. A mean of the three individual scores was calculated and the response was labelled as 'excellent' if the mean score achieved was >2. A score of 1-2 was labeled as good response while a score below 1 was labeled as 'poor' response. The subjective satisfaction of each patient with the treatment offered was also assessed at the last follow-up visit. RESULTS: The commonest site of scarring treated was the face followed by hands. Response to treatment was rated as excellent in 60% (15/25) patients while 24% (6/25) and 16% (4/25) patients were labeled as good and poor responders, respectively. Skin texture showed better response than other variables with average score of 2.44. Linear post-traumatic scars were seen to respond less than other morphological types. Majority of the patients (19 out of 25) were highly satisfied with the treatment offered. No long-term adverse effects were noted in any patient. CONCLUSIONS: Fractional photothermolysis with a fractional CO2 laser gives excellent results in patients with post-burn scars with minimal adverse effects. LIMITATIONS: Lack of a control group and small sample size are limitations of this study. PMID- 26644741 TI - Recognizing Body Dysmorphic Disorder (Dysmorphophobia). AB - Dysmorphophobia is a psychiatric condition which frequently presents in the clinics of dermatologists and plastic surgeons. This disorder (also called body dysmorphic disorder) is troublesome to the patient whilst being confusing for the doctor. This commonly undiagnosed condition can be detected by a few simple steps. Timely referral to a psychiatrist benefits most patients suffering from it. This article describes with a case vignette, how to recognize body dysmorphic disorder presenting in the dermatological or aesthetic surgery set up. Diagnostic criteria, eitiology, approach to patient, management strategy and when to refer are important learning points. The importance of recognizing this disorder timely and referring the patient to the psychiatrist for appropriate treatment is crucial. This article covers all aspects of body dysmorphic disorder relevant to dermatologists and plastic surgeons and hopes to be useful in a better understanding of this disorder. PMID- 26644743 TI - Informed Consent in Aesthetic Surgery. PMID- 26644742 TI - Outer Circle Versus Inner Circle: Special Considerations While Rejuvenating an Indian Face Using Fillers. AB - INTRODUCTION: An oval face, pronounced cheek bones, a defined jaw line and a smooth Ogee curve are global aesthetic beauty goals. Though criteria are similar the Indian face poses some unique challenges because of the innate differences in skeletal shape, size, and soft tissue disposition. Width of the malar prominences and mandibular angles along with height are smaller compared to the other Asian and Caucasian populations along with a much heavier soft tissue disposition. This creates unique deficits and places unique demands on aesthetic intervention. OBJECTIVES: The evolution of practice patterns has lead to a variety of newer approaches; however, it is still common to target the nasolabial and mid-face volumizing as basic intervention for facial beautifying and rejuvenation. As aging progresses, Indian faces tend to get fuller and the tissue then descends downwards similar to other ethnic groups albeit more aggressive due to higher volumes of facial fat pad and smaller bone framework. Any excess correction in the inner circle zones will further add to the bulk along with cumulative remnants of previously administered fillers. METHODS: In a younger face when the goal is beautification the attempt is to address the specific structural deficit on the outer bony framework along with the chin. This enhances the appearance immediately as well as holds up the tissue descent as they age. When the goal is youthful transition of an aging face, then again the bony changes further enhance the deficit in framework and the loss of fat pads along the periphery that is lateral forehead, temples and lateral cheek. Fat pad correction will give the most natural and best results as against working on the anterior mid cheek, nasolabials and angle of the mouth in a soft tissue heavy center zone of the face. Botulinum toxin and hyaluronic acid (HA) fillers remain the most popular facial injectables used for facial rejuvenation and structural enhancement. RESULTS: Naturally enhanced faces, and gracefully addressed aging changes are important. Fillers administered on the outer zones of the face rather than the inner zone gives better aesthetic results. PMID- 26644744 TI - Dumbbell-Shaped Neurofibroma Over the External Ear. AB - Dumbbell-shaped swellings in neurofibroma have been commonly described in the spine, thorax, cranial cavity, and pelvis; however, dumbbell-shaped swellings in the peripheries are rare. Here, we report a dumbbell-shaped neurofibroma over the pinna in an 18-year-old female patient, its successful surgical management, and its association with Hashimoto thyroiditis. To the best of our knowledge, this is the first ever case to be reported of a dumbbell-shaped neurofibroma over the external ear and only the fourth case of neurofibromatosis type 1 (NF1) to be associated with Hashimoto thyroiditis. PMID- 26644745 TI - Psoriatic Lesions Following Botulinum Toxin: A Injections to the Glabellar Region. PMID- 26644746 TI - Infraorbital Cutaneous Angiosarcoma: Successful Surgical Management Applying Mitek Anchorage System. PMID- 26644747 TI - Granular Cell Tumour. PMID- 26644748 TI - When Expanding a Margin of Skin Cancers After Reconstruction with Local Flap: Where to Do It? PMID- 26644749 TI - Tache Noire: A Classic Case Treated with Dual Freeze Cycles of Liquid Nitrogen Cryotherapy and Clasped Manoeuvre. PMID- 26644750 TI - Re: Aesthetic Management of Gum Hyperpigmentation by a Simple Technique. PMID- 26644751 TI - Oral cancer in Libya and development of regional oral cancer registries: A review. AB - The aims of this paper are three-fold: (1) to summarize the current epidemiological data on oral cancer in Libya as reported in the published literature and as compared to other national oral cancer rates in the region; (2) to present both the history of the early development, and future goals, of population-based oral cancer tumor registries in Libya as they partner with the more established regional and international population-based cancer tumor registries; and, (3) to offer recommendations that will likely be required in the near future if these nascent, population-based Libyan oral cancer registries are to establish themselves as on-going registries for describing the oral cancer disease patterns and risk factors in Libya as well as for prevention and treatment. This comprehensive literature review revealed that the current baseline incidence of oral cancer in Libya is similar to those of other North Africa countries and China, but is relatively low compared to the United Kingdom, the United States, and India. The recently established Libyan National Cancer Registry Program, initiated in 2007, while envisioning five cooperating regional cancer registries, continues to operate at a relatively suboptimal level. Lack of adequate levels of national funding continue to plague its development...and the accompanying quality of service that could be provided to the Libyan people. PMID- 26644752 TI - Adaptation and validation of the Moroccan Arabic version of the Psychosocial Impact of Dental Aesthetics Questionnaire (PIDAQ). AB - OBJECTIVE: The aims of this study were to translate and culturally adapt the PIDAQ native English version into Moroccan Arabic, and to assess the psychometric characteristics of the version thereby obtained. MATERIALS AND METHODS: The PIDAQ original English version was sequentially subjected to translation into Moroccan Arabic, back-translation into English, committee review, and pre-testing in 30 subjects seeking orthodontic treatment. RESULTS: The final Moroccan Arabic version further underwent an analysis of psychometric properties on a random sample of 99 adult subjects (84 females and 15 males, aged 20.97 +/- 1.10 years). The intraclass coefficient correlation of the scores of the responses obtained after administration of the questionnaire twice at a 1-month interval to a random sample of 30 subjects ranged from 0.63 for "Self-confidence" to 0.85 for "Social Impact". Cronbach alpha coefficients ranging from 0.78 for "Aesthetic Concerns" to 0.87 for "Self-confidence" were obtained; the different subscales of the Moroccan Arabic version of the PIDAQ showed good correlation with the perception of aesthetics and orthodontic treatment need. CONCLUSION: The results of the present study indicate that the Moroccan Arabic version of the PIDAQ obtained following thorough adaptation of the native form is both reliable and valid. It is able to capture self-perception of orthodontic aesthetic and treatment need and is consistent with normative need for orthodontic treatment. PMID- 26644753 TI - Incidence of postoperative pain after use of calcium hydroxide mixed with normal saline or 0.2% chlorhexidine digluconate as intracanal medicament in the treatment of apical periodontitis. AB - OBJECTIVE: To compare the incidence of postoperative pain after the use of calcium hydroxide powder mixed with normal saline or 0.2% chlorhexidine digluconate as intracanal medicament. PARTICIPANTS: Fifty-five subjects aged 17 60 years with teeth diagnosed to have apical periodontitis. INTERVENTION: Two visit conventional root canal treatment of seventy teeth. The teeth were divided by randomization (balloting) into two groups: control group and experimental group, each with thirty-five teeth treated with calcium hydroxide mixed with normal saline or with 0.2% chlorhexidine digluconate as intracanal medicament respectively. Incidence of postoperative pain was assessed using the universal pain assessment tool and whether or not analgesic was taken. MAIN OUTCOME MEASURED: Incidence of post-operative pain. RESULT: Postoperative pain occurred only at 1-day and 1-week reviews. In the control group, the overall incidence of pain was the same at both review periods (5.7%), while the experimental group showed a slight decrease in incidence between 1-day (17.2%) and 1-week (11.4%) reviews. Incidence of flare-ups was more in the experimental group (11.4%) than in the control group (5.7%). No significant statistical differences between the two groups were observed (p > 0.05). CONCLUSION: The incidence of postoperative pain was lower in the normal saline treatment group, but the difference was not statistically significant. PMID- 26644754 TI - Effect of polyester fiber reinforcement on the mechanical properties of interim fixed partial dentures. AB - BACKGROUND: Different reinforcements currently available for interim fixed partial denture (FPD) materials do not provide the ideal strength for long-term use. Therefore, the aim of this investigation was to develop a more ideal provisional material for long-term use with better mechanical properties. This study evaluated the effectiveness of polyester fiber reinforcement on different interim FPD materials. METHODS: Thirty resin-bonded FPDs were constructed from three provisional interim FPD materials. Specimens were tested with a universal testing machine (UTM). The modulus of elasticity and flexural strength were recorded in MPa. The compressive strength and degree of deflection were calculated from the obtained values, and a two-way analysis of variance (ANOVA) was used to determine the significance. RESULTS: The polyester fiber reinforcement increased the mechanical properties. The modulus of elasticity for heat-polymerized polymethyl methacrylate (PMMA) was 624 MPa, compared to 700.2 MPa for the reinforced heat-cured sample. The flexural strengths of the bis acrylic and cold-polymerized reinforced samples increased significantly to 2807 MPa and 979.86 MPa, respectively, compared to the nonreinforced samples. The mean compressive strength of the reinforced cold-polymerized PMMA samples was 439.17 MPa; and for the reinforced heat-polymerized PMMA samples, it was 1117.41 MPa. The degree of deflection was significantly greater (P < 0.05) in the reinforced bis-acrylic sample (5.03 MPa), compared with the nonreinforced bis-acrylic sample (2.95 MPa). CONCLUSION: Within the limitations of this study, polyester fiber reinforcements improved the mechanical properties of heat-polymerized PMMA, cold polymerized PMMA, and bis-acrylic provisional FPD materials. PMID- 26644755 TI - A finite element study on stress distribution of two different attachment designs under implant supported overdenture. AB - OBJECTIVE: This study aimed to evaluate stress patterns generated within implant supported mandibular overdentures retained by two different attachment types: ball and socket and locator attachments. MATERIALS AND METHODS: Commercial CAD/CAM and finite element analysis software packages were utilized to construct two 3D finite element models for the two attachment types. Unilateral masticatory compressive loads of 50, 100, and 150 N were applied vertically to the overdentures, parallel to the longitudinal axes of the implants. Loads were directed toward the central fossa in the molar region of each overdenture, that linear static analysis was carried out to find the generated stresses and deformation on each part of the studied model. RESULTS: According to FEA results the ball attachment neck is highly stressed in comparison to the locator one. On the other hand mucosa and cortical bone received less stresses under ball and socket attachment. CONCLUSIONS: Locator and ball and socket attachments induce equivalent stresses on bone surrounding implants. Locator attachment performance was superior to that of the ball and socket attachment in the implants, nylon caps, and overdenture. Locator attachments are highly recommended and can increase the interval between successive maintenance sessions. PMID- 26644756 TI - Soft versus hard occlusal splint therapy in the management of temporomandibular disorders (TMDs). AB - AIM: To compare between soft and hard occlusal splint therapy for the management of myofacial pain dysfunction (MPD) or internal derangement (ID) of the temporomandibular joint (TMJ) with reciprocal clicking. PATIENTS AND METHODS: This study included 50 patients (age range: 24-47 years) who had been diagnosed with MPD or ID of the TMJ in the form of reciprocal clicking. Patients were divided into two groups. They were treated for 4 months with either a vacuum formed soft occlusal splint constructed from 2-mm-thick elastic rubber sheets (soft splint group) or a hard flat occlusal splint fabricated from transparent acrylic resin (hard splint group). Monthly follow-up visits were performed during the treatment period. Before treatment and 1, 2, 3 and 4 months after treatment, the dentist measured all parameters of TMJ function (pain visual analog scores, tenderness of masticatory muscles, clicking and tenderness of the TMJ, and range of mouth opening). RESULTS: All parameters of TMJ function showed significant improvement in both groups during the follow-up period, with a statistically significant difference between the two groups at the 4-month follow-up visit. CONCLUSIONS: Both forms of occlusal splints (soft and hard) improved TMJ symptoms in patients with MPD or ID of the TMJ. However, the soft occlusal splints exhibited superior results after 4 months of use. PMID- 26644757 TI - Comparative evaluation of the calcium release from mineral trioxide aggregate and its mixture with glass ionomer cement in different proportions and time intervals - An in vitro study. AB - BACKGROUND: Addition of glass ionomer cement (GIC) has been suggested to improve the setting time and handling characteristics of mineral trioxide aggregate (MTA). This study evaluated the effect of adding GIC to MTA in terms of calcium release, an issue that has not been previously studied. MATERIALS AND METHODS: The study comprised four groups with five samples each: a control group of MTA alone and experimental groups I (1MTA:1GIC), II (2MTA:1GIC), and III (1MTA:2GIC) based on the mixture of MTA and GIC powders in the respective proportions by volume. Calcium release from the samples was measured by atomic absorption spectrophotometry at 15 min, 6 h, 24 h, and 1 week after setting. The level of statistical significance was set at p < 0.05. RESULTS: Groups I (1MTA:1GIC) and III (1MTA:2GIC) released significantly less calcium than the control group at all time periods, except at 15 min for group I. Group II (2MTA:1GIC) showed no significant difference in calcium release compared to the control at any time period. Group II exhibited greater calcium release than group I or III at all time periods, with significant differences between groups I and II at 1 week and between groups I and III at 24 h and 1 week. There were no statistical differences in calcium release between groups I and III. CONCLUSIONS: Adding GIC to improve the setting time and handling properties of the MTA powder can be detrimental to the calcium-releasing ability of the resultant mixture, depending on the proportion of GIC added. Adding MTA and GIC at a proportion of 2:1 by volume did not impact calcium release from the mixture. These findings should be verified through further clinical studies. PMID- 26644758 TI - A comparative study of oral health amongst trisomy 21 children living in Riyadh, Saudi Arabia: Part 1 caries, malocclusion, trauma. AB - BACKGROUND: Trisomy 21 (T21) is a genetic disorder stemming from a chromosomal abnormality and characterized by general and mental retardation. Depending on the population, T21 is known to affect 1 in every 600-2000 live births. The current literature provides a mixed view on the oral health status of T21 individuals. AIM: To establish the prevalence of dental caries, malocclusion, and trauma amongst children with T21 compared with non-T21 children in Riyadh, Saudi Arabia. METHODS: This cross-sectional study recruited non-T21 and T21 children between the ages of 7-15 years who were studying at the Saut Society. After informed consent was obtained from parents and both groups were matched by age and gender, trained examiners screened children at the dental clinic of King Saud University to record the presence of dental caries, malocclusion, and trauma in both groups. RESULTS: While there was no statistical difference between the two groups with regard to the mean decayed, missing, and filled teeth (DMFT) index (2.66 for T21 versus 3.11 for controls), T21 children had a higher prevalence of incisal fractures compared to the control group (24.73% versus 4.95%, respectively) and that was statistically significant (P < 0.05). There were also highly significant group differences concerning the prevalence of malocclusion. Therein, 45% of T21 children had a Class III incisor relationship compared with 8% of control children, and 50% of T21 children had a Class III molar relationship compared with 8% of control children. CONCLUSIONS: While there was no significant difference in the incidence of caries between children with and without T21, practitioners should be aware of the disparities in malocclusion and trauma in this vulnerable population. PMID- 26644759 TI - Comparative study of oral health among trisomy 21 children living in Riyadh, Saudi Arabia: Part 2, gingival condition. AB - BACKGROUND: Trisomy 21 (T21) is a congenital disorder characterized by triplication of Chromosome 21 components. Patients with T21 have an increased risk of acquiring periodontal disease due to their inability to maintain good oral hygiene. Consequently, it is important to determine an approach for disease prevention in this population. AIM: The purpose of the study was to assess the periodontal health, through the prevalence of gingivitis and plaque, among children with T21 living in Riyadh, Saudi Arabia. SUBJECTS AND METHOD: This study included 93 children with T21 and 99 age- and gender-matched children without T21 between the ages of 7 and 15 years. Parents were informed about the study and provided informed consent. Trained examiners using standardized tools assessed the prevalence rates of gingivitis and plaque in all children. RESULTS: Gingivitis prevalence was elevated among T21 children (46.9%) compared to controls (34%) in all arch sextants except the mandibular middle (P < 0.01). Comparing the two groups, the prevalence of plaque was higher in the maxillary right sextant of the T21 group and the mandibular middle sextant of the control group (P < 0.05). CONCLUSION: T21 children have significantly elevated plaque levels, resulting in greater prevalence of gingivitis, compared to healthy children. Preventive measure, such as oral health awareness programs, should be delivered early to parents and continued at school to encourage and motivate children. PMID- 26644760 TI - Accelerated Osteogenic OrthodonticsTM for retreatment of a patient with diminished root length and absence of the maxillary central incisor. AB - An 18-year-old female patient visited a university orthodontics department with a chief complaint of an unesthetic appearance of her teeth, including a protruded upper central incisor and unsatisfactory results from previous orthodontic treatment. Pretreatment records showed a Class II skeletal and dental relation with proclined upper and lower incisors, replacement of an absent upper left central incisor with the left upper cuspid, presence of the upper left deciduous cuspid, mild crowding, and 4 mm of overbite and overjet. The panoramic radiograph showed shortened roots of multiple teeth. Accelerated Osteogenic OrthodonticsTM (AOOTM) was recommended as an approach to reduce the treatment time and the risk of further root shortening. Despite being more expensive and requiring a surgical procedure, this treatment option was very attractive to the patient. The overall treatment time was 14 months. Facial balance was improved, and good occlusal relationships were achieved from the functional and esthetic perspectives. In conclusion, surgically facilitated orthodontics (specifically, AOOTM) is an efficient and safe therapeutic tool for treating or retreating orthodontic patients with diminished root length. PMID- 26644761 TI - Working Memory and Recollection Contribute to Academic Achievement. AB - The contributions of working memory and recollection to academic achievement are typically examined separately and most often with children who have learning difficulties. This study is the first to observe both types of memory in the same study and in typically developing children. Academic achievement focused on standardized assessments of math fluency, calculation, reading fluency, and passage comprehension. As noted in previous studies, working memory was associated with each assessed measure of academic achievement. Recollection, however, specifically contributed to math fluency and passage comprehension. Thus, recollection should be considered alongside working memory in studies of academic achievement. PMID- 26644762 TI - Polymorphism in the RASGRF1 gene with high myopia: A meta-analysis. AB - PURPOSE: To evaluate the association between polymorphisms of RASGRF1 rs8027411 and high myopia in Chinese and Japanese populations. METHODS: All eligible studies investigating the association between the RASGRF1 gene and high myopia listed in PubMed, EMBASE, the Cochrane Library, Web of Science, and the China Biologic Medical Database were retrieved. The effects were assessed with the pooled odds ratio (OR) and 95% confidence interval (CI). Heterogeneity between studies was evaluated with the Q-statistic test. Publication bias was tested with Begg's and Egger's linear regression tests. Subgroup analysis and sensitivity analysis were performed to identify the sources of heterogeneity. RESULTS: In the present meta-analysis, 2,529 individuals with high myopia and 3,127 controls from four studies were included and divided into seven groups. The results indicated that RASGRF1 rs8027411 was significantly associated with high myopia in Chinese and Japanese populations. Carriers of the rs8027411 G allele had a lower risk of high myopia compared to carriers with the T allele (G versus T, OR=0.83, 95% CI=0.77-0.89; p<0.001). Low but not significant heterogeneity was found in a recessive model. No heterogeneity was found in other genetic models. The subgroup analysis indicated that the protective effect of rs8027411 variants was more prominent in Chinese populations (G versus T, OR=0.80 in Chinese and OR=0.86 in Japanese; GG versus TT, OR=0.65 in Chinese and OR=0.77 in Japanese; GT versus TT, OR=0.76 in Chinese and OR=0.81 in Japanese; (GG+GT) versus TT, OR=0.73 in Chinese and OR=0.80 in Japanese; and GG versus (GT+TT), OR=0.77 in Chinese and OR=0.87 in Japanese). Sensitivity analysis indicated that the study results were stable in allelic, homozygote, heterozygote, and dominant models but were not stable in the recessive model. No evidence of publication bias was found. CONCLUSIONS: Carriers of the rs8027411 G allele in the RASGRF1 gene may be at a lower risk of high myopia in Chinese and Japanese populations. The RASGRF1 gene may play a role in the development of high myopia, especially in Asians. Additional studies are required to validate these results. PMID- 26644763 TI - Evaluation of Percutaneous Liver Biopsy Complications in Patients with Chronic Viral Hepatitis. AB - OBJECTIVE: Liver biopsy is still the gold standard for the determination of liver fibrosis and necroinflammatory activity. It is an invasive method and may lead to severe complications. The aim of this study was to determine the evaluation of percutaneous liver biopsy complications in patients with chronic viral hepatitis. MATERIALS AND METHODS: 1165 patients, who were followed with the diagnosis of chronic viral hepatitis and who were applied percutaneous liver biopsy between January 2000 and February 2013 at the out-patient clinic of Infectious Diseases and Clinical Microbiology, were included in the study. RESULTS: Of 1165 patients who underwent liver biopsy, 196 (86 male, 110 female) were diagnosed with chronic hepatitis C, 969 (559 male, 410 female) were diagnosed with chronic hepatitis B. The mean age was 43.3 and 55.4% were male. 11% of the patients were diagnosed with chronic renal failure and underwent haemodialysis. Minor complication rate was about 20% (severe pain required usage of analgesic drugs in 19.8%, abdominal pain in 22.6%) whereas major complication rate was 1.15% (pneumothorax in 0.17%, heamobilia in 0.08%, hematoma in 0.9%). We did not observe severe complications such as fever, abscess, anaphylaxis, bacteraemia, organ perforations, sepsis or death. CONCLUSION: Despite being an invasive procedure, percutaneous liver biopsy can be considered a safe method because of the low rates of severe complications observed in our patients. PMID- 26644764 TI - Granulomatous Mastitis: A Ten-Year Experience at a University Hospital. AB - OBJECTIVE: In this study we aimed to define clinical, radiologic and pathological specialties of patients who applied to General Surgery Department of Ataturk University Medical Faculty with granulomatous mastitis and show medical and surgical treatment results. With the help of this study we will be able to make our own clinical algorithm for diagnosis and treatment. MATERIALS AND METHODS: We searched retrospectively addresses, phone numbers and clinical files of 93 patients whom diagnosed granulomatous mastitis between a decade of January 2001 - December 2010. We noted demographic specialties, ages, gender, medical family history, main complaints, physical findings, radiological and laboratory findings, medical treatments, postoperative complications and surgical procedures if they were operated; morbidity, recurrence and success ratios, complications after treatment for patients discussed above. RESULTS: In this study we evaluated 93 patients, 91 females and 2 males, with granulomatous mastitis retrospectively who applied to General Surgery Department of Ataturk University Medical Faculty between January 2001 and December 2010. Mean age was 34.4 years. The diagnosis was confirmed by histopathologic examination of the lesions. Seventy three patients had idiopathic granulomatous lobular mastitis and 20 patients had specific granulomatous mastitis IGM (18 tuberculosis mastitis, 1 alveolar echinococcosis and 1 silk reaction). All the patients had surgical debridement or antibiotic, and anti-inflammatory treatment with results bad clinical response before applied our clinic. CONCLUSION: Empiric antibiotic therapy and drainage of the breast lesions are not enough for complete remission of idiopathic granulomatous mastitis. The lesion must be excised completely. In selected patients, corticosteroid therapy can be useful. In the patients with tuberculous mastitis, abscess drainage and antituberculous therapy can be useful, but wide excision must be chosen for the patients with recurrent disease. PMID- 26644766 TI - Systemic Isotretinoin Treatment and Pregnancy: A Longitudinal Cohort Study from Turkey. AB - OBJECTIVE: Isotretinoin is known to be the most effective treatment of severe and persistent acne. However, one of the most important adverse effects of this drug is known to be teratogenicity. In this regard, tests are administered before initiating the treatment, to assure that an unknown pregnancy is not present and accordingly, patients are advised to take contraceptive precautions during their systemic isotretinoin treatments. On the contrary, many cases of unwanted pregnancies and relevant abortuses have been reported all over the world. In the Turkish literature, only a few reports have been identified about foetal exposure to isotretinoin. MATERIALS AND METHODS: In this respect, a study was carried out on fifty-seven female patients, aiming to fulfil the gap of information mentioned above. Female patients, with ages ranging between 14 and 35 years, were recruited to the study and they were administered isotretinoin treatments (cumulative dose of 120 mg/kg) for an average period of 6 months. The patients were followed up during and after the treatment for a total period of 18 months. RESULTS: As a result, it has been observed that none of the patients got pregnant during the treatment period and relevantly, no abortuses or foetal abnormalities were recorded. Moreover, none of the patients got pregnant 12 months after the termination of the treatment. Additionally, the socio-demographic analysis of the patients indicates that most of the patients were single and 81% of the patients were sexually inactive. CONCLUSION: Our findings suggest that the low reportage of teratogenicity due to isotretinoin usage in Turkey could be due to several reasons, such as the sociocultural profile of the female patients undertaking the isotretinoin treatment, and strict adherence to contraceptive methods, and/or underreporting of teratogenic incidents due to lack of studies held in cooperation with obstetricians. PMID- 26644765 TI - Evaluation and Management of Lumbosacral Myelomeningoceles in Children. AB - OBJECTIVE: Myelomeningoceles are the common form of open neural tube defects that are usually associated with neurological deficits. Many techniques of repair and methods of prevention have been proposed with respect to the size of defect and the neurological condition of patient. The aim of this study was to report our experience on the management of lumbosacral myelomeningoceles in children. MATERIALS AND METHODS: We retrospectively analysed the data of 36 paediatric cases of surgically lumbosacral myelomeningocele treated in our department between 1998 and 2013. Twenty (56%) patients were female and sixteen were male, with a mean age of 4 months (ranged between 0 and 24 months). All patients had neurological deficits in the preoperative period. Computed tomography was performed in 33 (92%) patients and magnetic resonance imaging in 15 (42%) patients in the preoperative period. Repair of the myelomeningocele and closure of the skin defect were performed in all patients. The mean follow-up period was 36 months. RESULTS: Thirty (83%) patients were operated for hydrocephalus and 10 (28%) patients were re-operated for tethered cord syndrome during the follow-up period. Neurological worsening was not observed in any patient while cerebrospinal fluid fistula was detected in 2 patients. CONCLUSION: Surgical treatment using appropriate microsurgical techniques is crucial for lumbosacral myelomeningoceles in children. Early surgical intervention with close follow-up will improve the neurological condition of the patients. PMID- 26644767 TI - Problems in Communications with Patients in General Surgery Outpatient Practice. AB - OBJECTIVE: Communication between the patient and physician is central to medical care. However communication skills in Turkey haven't been gained so much concern. This situation effect the national quality of health care. Here, we tried to perform some basic communication skills and to find the problems with the possible solution suggestions. MATERIALS AND METHODS: The study was conducted for a month in general surgery outpatient department located in the slum part of Ankara with low socio-economic population. Basic communication skills were performed. The age, sex, education levels of the patients were obtained. Total symptom expression and interview time were recorded. Previous medical histories were asked. Interruptions including telephone, door knocking were noted. The questions of the patients at the end of the interview classified as hospital setting, nutrition and treatment. RESULTS: Total 410 interviews were analysed. Mean symptom expression and interview times were 22.9 sec and 7.05 min, respectively. Educated patients, males and young patients expressed symptoms longer than the others (p<0.05). There were 174 interruptions in which total interview time signifantly increased than the non interrupted ones (p<0.05). Final questions about hospital setting were signifantly higher in illiterate patients than the educated ones (p<0.05). Awareness of medical history is higher in educated and young patients. CONCLUSION: Basic communications skills can be performed whether in rural regions. Much more concern should be given to the education of communication skills. The obstacles in communication in medicine are low education levels, and unorganised health system. PMID- 26644768 TI - The Reason of Dissatisfaction of Patient after Septoplasty. AB - OBJECTIVE: The objective of this study was to evaluate the causes of persistent nasal obstruction of patients after septoplasty. MATERIALS AND METHODS: After exclusion of allergic rhinitis, non-allergic rhinitis and nasal polyposis, this study included 90 patients with nasal breathing problem who underwent septoplasty at least 4 months ago. After taking full history and completing otorhinological and endoscopic examination, all patients graded their extent of obstruction using the Nasal Obstruction Symptoms Evaluation scale. RESULTS: Our results showed only 45% of patients' persist septal deviation; besides other obstructive pathologies, 55% were detected after detailed otolaryngologic evaluation. CONCLUSION: Therefore, septal surgeons need to observe all obstructive causes of the nose carefully before planning the procedure. PMID- 26644769 TI - Incidental Finding of Papillary Thyroid Carcinoma in the Patients with Primary Hyperparathyroidism. AB - OBJECTIVE: The relationship between primary hyperparathyroidism (pHPT) and papillary thyroid cancer (PTC) still remains unclear. We aimed to investigate the incidence of the co-existence of pHPT and PTC. MATERIALS AND METHODS: Between 2010 and 2013, all patients with pHPT were retrospectively reviewed and those undergoing concomitant thyroid surgery were recorded. Of these, patients with a pathological result showing papillary or micro-papillary thyroid cancer were included into the study. A chart review of 228 patients who underwent surgery for pHPT revealed 86 (37.7%) patients with concurrent thyroid disease requiring surgical treatment. RESULTS: Thyroid cancer was noted in six female patients (6.9%) undergoing thyroid resection, and 2.6% of all patients with pHPT. Four patients underwent total thyroidectomy while lobectomy was applied in the remaining two. None of the cases with lobectomy required a completion thyroidectomy. CONCLUSION: We demonstrated the concurrence of PTC and pHPT at a rate of 2.6% which appeared as a coincidental pathology; however, thyroid disorders, seen in one of three patients with pHPT, were not uncommon. Further research is still needed to develop a reliable explanation for relationship between pHPT and non-medullary thyroid cancer. PMID- 26644770 TI - Effects of Diabetes on Post-Menopausal Rat Submandibular Glands: A Histopathological and Stereological Examination. AB - OBJECTIVE: The menopause in elderly women is a physiological process where ovarian and uterine cycles end. Diabetes means higher blood glucose level that is a metabolic disease and has an increased incidence. The aim of the study was to examine the single or combined effects of menopause and diabetes that causes pathophysiological processes on submandibular gland on ovariectomy and diabetes induced rat models. MATERIALS AND METHODS: Sprague Dawley twelve weeks old female (n=24) rats were divided randomly into four groups; Healthy control group (n=6), diabetic group (DM, n=6), ovariectomized group (OVX, n=6), post ovariectomy diabetes induced group (DM+OVX, n=6) individually. Histopathological, histochemical and stereological analyses were done in these groups. RESULTS: Significant neutrophil cell infiltrations and myoepithelial cell proliferations, granular duct and seromucous acini damages and changes in the content of especially seromucous acini secretion in DM and/or OVX groups and distinctive interstitial and striated duct damages in post ovariectomy diabetes induced group were detected. Alterations ingranular ducts hypertrophic and in seromucous acini atrophic were determined in DM and/or OVX groups. CONCLUSION: The results revealed the pathophysiological processes that lead to morphological and functional alterations on the cellular level in submandibular glands. The molecular mechanisms related with pathogenesis of diabetes and menopause need further investigation. PMID- 26644771 TI - Factors Affecting Hand Hygiene Adherence at a Private Hospital in Turkey. AB - OBJECTIVE: Nosocomial infections are the main problems rising morbidity and mortality in health care settings. Hand hygiene is the most effective method for preventing these infections. In this study, we aimed to investigate the factors related with hand hygiene adherence at a private hospital in Turkey. MATERIALS AND METHODS: This study was conducted between March and June 2010 at a private hospital in Turkey. During the observation period, employees were informed about training, then posters and images were hanged in specific places of the hospital. After the initial observation, training on nosocomial infections and hand hygiene was provided to the hospital staff in March 2010. Contacts were classified according to occupational groups and whether invasive or not. These observations were evaluated in terms of compatibility with hand hygiene guidelines. RESULTS: Hand hygiene adherence rate of trained doctors was higher than untrained ones before patient contact and after environment contact [48% (35/73) versus 82% (92/113) p<0.05 and 23% (5/22) versus 76% (37/49) p<0.05 respectively]. Hand hygiene adherence rate of trained nurses was higher than untrained ones before patient contact [63% (50/79) versus 76% (37/49) p<0.05]. Hand hygiene adherence rate of trained assistant health personnel was higher than untrained ones before asepsis [20% (2/10) versus 73% (16/22) p<0.05]. In addition, it was seen that hand antiseptics were used when hand washing was not possible. CONCLUSION: The increase at the rate of hand washing after training reveals the importance of feedback of the observations, as well as the training. One of the most important ways of preventing nosocomial infections is hand hygiene training that should be continued with feedbacks. PMID- 26644772 TI - New-Onset Diabetes Mellitus Associated with Sirolimus Use in Renal Transplant Recipients. AB - New-onset diabetes after transplantation and impaired glucose tolerance are very common in renal transplant patients. New-onset diabetes after transplantation (NODAT) is associated with increased cardiovascular morbidity and mortality, reduced graft and patient survival. Several risk factors for NODAT have been identified: age, obesity, family history of diabetes mellitus and HCV infection. In addition, steroid and calcineurin inhibitors also contribute to the development of NODAT. Sirolimus causes immunosuppressive effects by inhibiting mammalian target of rapamycin (mTOR), and has well known side effects. The effects of sirolimus on glucose metabolism and contribution to NODAT development are not clearly known. In this report, we presented five RTX patients who developed NODAT under the treatment of sirolimus. PMID- 26644773 TI - Giant Cavernous Haemangioma of the Anterior Mediastinum. AB - Cavernous hemangiomas of the anterior mediastinum is rare. We present a case of a 56-year-old male patient with a giant cavernous hemangioma of the anterior mediastinum, 18 cm in diameters, approached by left posterolateral thoracotomy. To the best of our knowledge, such a unique case has not been previously presented in the literature. PMID- 26644774 TI - Criminal Responsibility of the Frontal Lobe Syndrome. AB - Neurological and/or psychiatric symptoms might be detected due to damage of frontal lobes as detected in damages of many brain regions. Frontal lobe syndrome (FLS) occurs as a result of damage in prefrontal region due to various causes. Symptoms due to prefrontal region damage, varies according to the size and location of the lesion. In most of the cases; executive dysfunctions, attention deficits, inconsistencies in social life, impulse control problems, obsessive behaviors and violence behaviors are common clinical signs. Behavioral symptoms seen in FLS can be confused with personality disorders and negative symptoms of schizophrenia. FLS is a neuropsychiatric disorder rarely assessed in forensic psychiatry and in terms of detection of criminal responsibility. In this case report, criminal responsibility in FLS was assessed through a FLS case in which an offense of "threat" was committed and investigated in terms of criminal responsibility. PMID- 26644775 TI - Video-Assisted Thoracoscopic Surgery Lobectomy for Pulmonary Malignant Melanoma Metastasis. AB - Malign melanoma (MM) develops as a result of malign transformation of the melanocytes and constitutes 2-4% of all skin cancers, while being the most common cause of mortality among all skin cancers. In addition to other organs, distant organ metastases also include lung metastasis. A metastasectomy is an acceptable treatment option in cases of malign melanoma with isolated lung metastasis. The current report presents a case with isolated lung metastasis that underwent a right upper VATS (video-assisted thoracoscopic surgery) lobectomy due to tumour localization. PMID- 26644776 TI - Bullous Dermatitis and Skin Necrosis Developing after Adrenalin Extravasation. AB - Extravasation of vasopressors can have serious complications varying from simple local reactions to skin necrosis and compartment syndrome. Here, we presented bullous dermatitis and skin necrosis which developed due to extravasation of adrenalin infusion in a Hodgkin lymphoma patient with septic shock who was admitted due febrile neutropenia. PMID- 26644777 TI - Cirrhosis, von Willebrand Factor (vWF) and the Low Incidence of Metastatic Malignancy in Injured Liver. PMID- 26644778 TI - Integrating modelling and smart sensors for environmental and human health. AB - Sensors are becoming ubiquitous in everyday life, generating data at an unprecedented rate and scale. However, models that assess impacts of human activities on environmental and human health, have typically been developed in contexts where data scarcity is the norm. Models are essential tools to understand processes, identify relationships, associations and causality, formalize stakeholder mental models, and to quantify the effects of prevention and interventions. They can help to explain data, as well as inform the deployment and location of sensors by identifying hotspots and areas of interest where data collection may achieve the best results. We identify a paradigm shift in how the integration of models and sensors can contribute to harnessing 'Big Data' and, more importantly, make the vital step from 'Big Data' to 'Big Information'. In this paper, we illustrate current developments and identify key research needs using human and environmental health challenges as an example. PMID- 26644779 TI - Software to Facilitate Remote Sensing Data Access for Disease Early Warning Systems. AB - Satellite remote sensing produces an abundance of environmental data that can be used in the study of human health. To support the development of early warning systems for mosquito-borne diseases, we developed an open-source, client based software application to enable the Epidemiological Applications of Spatial Technologies (EASTWeb). Two major design decisions were full automation of the discovery, retrieval and processing of remote sensing data from multiple sources, and making the system easily modifiable in response to changes in data availability and user needs. Key innovations that helped to achieve these goals were the implementation of a software framework for data downloading and the design of a scheduler that tracks the complex dependencies among multiple data processing tasks and makes the system resilient to external errors. EASTWeb has been successfully applied to support forecasting of West Nile virus outbreaks in the United States and malaria epidemics in the Ethiopian highlands. PMID- 26644780 TI - In-Source Decay Characterization of Isoaspartate and beta-Peptides. AB - Deamidation and the subsequent formation of isoaspartic acid (isoAsp) are common modifications of asparagine (Asn) residues in proteins. Differentiation of isoAsp and Asp residues is a challenging task owing to their similar chemical properties and identical molecular mass. Recent studies showed that they can be differentiated using electron capture dissociation (ECD) which generates diagnostic fragments c'+57 and z*-57 specific to the isoAsp residue. However, the ECD approach is only applicable towards multiply charged precursor ions and generally does not work for beta-amino acids other than isoAsp. In this study, the potential of in-source decay (ISD) in characterization of isoAsp and other beta-amino acids was explored. For isoAsp-containing peptides, ISD with a conventional hydrogen-donating matrix produced ECD-like, c'+57 and z*-57 diagnostic ions, even for singly charged precursor ions. For other beta-amino acids, a hydrogen-accepting matrix was used to induce formation of site-specific a-14 ions from a synthetic beta-analogue of substance P. These results indicated that ISD can be broadly applied for beta-peptide characterization. PMID- 26644782 TI - RADICAL-INDUCED FRAGMENTATION OF PHOSPHOLIPID CATIONS USING METASTABLE ATOM ACTIVATED DISSOCIATION MASS SPECTROMETRY (MAD-MS). AB - The fragmentation pattern of several protonated 1+ phosphatidylcholines (PCs) were studied using low energy collision induced dissociation (CID) and helium metastable atom-activated dissociation (He-MAD). He-MAD of the protonated compounds produced a dominant phosphocholine head group at m/z 184 as well as typical sn-1 and sn-2 glycerol fragments such as [M+H-Rx-1CHC=O]+ and [M+H-Rx 1CO2H]+. Within the aliphatic chain, He-MAD showed fragments consistent with high energy collision induced dissociation (HE-CID) and products/pathways consistent with Penning ionization of the 1+ precursor ions to their respective radical dications. These Penning ionization products included both singly and doubly charged radical fragments, and the fragment ions are related to the number and position of double bonds in the acyl chains. Fragments created through HE-CID like fragmentation followed classic charge remote fragmentation pathways including ladder-like fragmentation along the acyl chain, except for additional or missing peaks due to predictable rearrangement reactions. He-MAD therefore shows utility in being able to effectively fragment singly charged lipids into a variety of useful product ions using both radical and high-energy processes in the confines of a 3D ion trap. PMID- 26644781 TI - Enhancing Protein Disulfide Bond Cleavage by UV Excitation and Electron Capture Dissociation for Top-Down Mass Spectrometry. AB - The application of ion pre-activation with 266 nm ultraviolet (UV) laser irradiation combined with electron capture dissociation (ECD) is demonstrated to enhance top-down mass spectrometry sequence coverage of disulfide bond containing proteins. UV-based activation can homolytically cleave a disulfide bond to yield two separated thiol radicals. Activated ECD experiments of insulin and ribonuclease A containing three and four disulfide bonds, respectively, were performed. UV-activation in combination with ECD allowed the three disulfide bonds of insulin to be cleaved and the overall sequence coverage to be increased. For the larger sized ribonuclease A with four disulfide bonds, irradiation from an infrared laser (10.6 um) to disrupt non-covalent interactions was combined with UV-activation to facilitate the cleavage of up to three disulfide bonds. Preferences for disulfide bond cleavage are dependent on protein structure and sequence. Disulfide bonds can reform if the generated radicals remain in close proximity. By varying the time delay between the UV-activation and the ECD events, it was determined that disulfide bonds reform within 10-100 msec after their UV-homolytic cleavage. PMID- 26644783 TI - Formative research for mhealth HIV adherence: the iHAART app. AB - : Qualitative research was conducted to adapt and develop an mHealth app for HIV patients with histories of substance abuse. The app provides reactive, visual representations of adherence rates, viral load and CD4 counts. Two sets of focus groups were conducted with 22 participants. The first concentrated on use of reminder system and opinions about ideal adherence features. Results informed adaptation of an existing system, which was then presented to participants in the second set of focus groups. We describe participant responses to candidate app characteristics and their understanding of the HIV disease state based on these changing images. Qualitative results indicate that a balance of provided and requested information is important to maintain interest and support adherence. App characteristics and information can provoke positive and negative reactions and these emotional responses may affect adherence. CONCLUSION: User understanding of, and reaction to, app visual content was essential to adaptation and design. PMID- 26644784 TI - Light-Emitting Diode Versus Sham in the Treatment of Plantar Fasciitis: A Randomized Trial. AB - OBJECTIVE: The purpose of this preliminary study was to compare the application of the light emitting diode (LED) to sham LED in the treatment of plantar fasciitis. METHODS: Eighteen subjects met the inclusion criteria and were randomly assigned into 2 groups: light emitting diode or sham LED. The subjects received either the LED at 12 J/cm(2) or sham LED along 2 points of the plantar fascia. Subjects in both groups received a 10 minute transverse friction massage and participated in 4 plantar fascia stretching exercises. All subjects received a total of 6 treatments over 3 weeks. Progress was assessed using the lower extremity functional and analog pain scale. RESULTS: No significant difference was found between treatment groups (P = .845). There was a significant difference in pain and outcome scores over time within both groups (P < .35). CONCLUSION: Among patients with plantar fasciitis, the use of LED did not result in greater improvement in function or pain compared with sham treatment. The findings suggest that manual intervention and passive stretching activities may have provided significant pain relief and improvement in functional outcome scores. PMID- 26644785 TI - Chiropractic Management of Low Back Pain in a 75-Year-Old Man With Bilateral Developmental Hip Dysplasia. AB - OBJECTIVE: The purpose of this case report is to describe chiropractic management of an elderly man with untreated bilateral hip joint dysplasia presenting with mild acute mechanical low back pain. CLINICAL FEATURES: A 75-year-old man presented with an insidious-onset intermittent low back pain of 3 days' duration. Physical examination findings supported a mechanical cause for mild acute low back pain. Plain radiography revealed dysplasia of hip joints with absence of femoral heads and necks and bilateral high dislocation. INTERVENTION AND OUTCOME: Chiropractic management included vibration, mobilization, light drop-piece adjustments of the lower lumbar and sacroiliac joints, and recommendation of the use of heat at home. Treatments were given 3 times over the course of 1 week. The low back pain intensity over this period dropped from 5 to 0 on an 11-point numerical rating scale, and the patient was discharged. CONCLUSION: This patient with substantial postural and gait abnormalities as a result of severe bilateral hip dysplasia associated with an unusual pattern of osteoarthritic change in the spine responded favorably to a short course of chiropractic care. PMID- 26644786 TI - Cranial Treatment and Spinal Manipulation for a Patient With Low Back Pain: A Case Study. AB - OBJECTIVE: The purpose of this case study is to present chiropractic management of a patient with chronic low back pain by focusing on the craniomandibular system. CLINICAL FEATURES: A 37-year-old man consulted a chiropractor for pain in the lumbosacral area with radiation down the anterolateral side of the upper left leg. The symptoms started after a fall the previous year. Examination showed a post-traumatic chronic L4-L5 facet dysfunction and left sacro-iliac joint dysfunction. Chiropractic spinal manipulation to the lumbar spine and pelvis gave only temporary relief from the pain. INTERVENTION AND OUTCOME: A year later a bone scintigraphy was conducted, in which a lesion was found over the right sphenoid area. Cranial treatment of this area was added to the chiropractic treatment plan. After this treatment, the patient reported that he was pain free and could return to normal activities of daily living. CONCLUSION: The clinical progress of this case suggests that for some patients, adding craniosacral therapy may be helpful in patients with low back symptoms. PMID- 26644787 TI - Prevalence of polycystic ovary syndrome and its associated complications in Iranian women: A meta-analysis. AB - BACKGROUND: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age and is the most common cause of infertility due to anovulation. There is no single criterion for the diagnosis of this syndrome. OBJECTIVE: The purpose of this study was to investigate the prevalence of PCOS and its associated complications in Iranian women using meta-analysis method. MATERIALS AND METHODS: Prevalence of PCOS was investigated from the SID, Goggle scholar, PubMed, Magiran, Irandoc, and Iranmedex, and weighting of each study was calculated according to sample size and prevalence of the binomial distribution. Data were analyzed using a random-effects model meta-analysis (Random effects model) and the software R and Stata Version 11.2. RESULTS: 30 studies conducted between the years 2006 to 2011 were entered into meta-analysis. The total sample size was 19, 226 women aged between 10-45 years. The prevalence of PCOS based on National institute of child health and human disease of the U.S was, 6.8% (95 % CI: 4.11-8.5), based on Rotterdam was 19.5% (95 % CI: 2.24-8.14), and based on ultrasound was 4.41% (95% CI: 5.68-4.14). Also, the prevalence of hirsutism was estimated to be 13%, acne 26%, androgenic alopecia 9%, menstrual disorders 28%, overweight 21%, obesity 19%, and infertility 8%. CONCLUSION: The prevalence of PCOS in Iran is not high. However, given the risk of complications such as heart disease - cardiovascular and infertility, prevention of PCOS is important; we suggest that health officials must submit plans for the community in this respect. PMID- 26644788 TI - The effect of Setarud (IMOD(TM)) on angiogenesis in transplanted human ovarian tissue to nude mice. AB - BACKGROUND: One of the promising methods in fertility preservation among women with cancer is cryopreservation of ovarian cortex but there are many drawbacks such as apoptosis and considerable reduction of follicular density in the transplanted ovary. One solution to reduce ischemic damage is enhancing angiogenesis after transplantation of ovarian cortex tissue. OBJECTIVE: The aim of this study was to investigate the effect of Setarud, on angiogenesis in transplanted human ovarian tissue. MATERIALS AND METHODS: In this case control study, twenty four nude mice were implanted subcutaneously, with human ovarian tissues, from four women. The mice were randomly divided into two groups (n=12): the experimental group was treated with Setarud, while control group received only vehicle. Each group was divided into three subgroups (n=4) based on the graft recovery days post transplantation (PT). The transplanted fragments were removed on days 2, 7, and 30 PT and the expression of Angiopoietin-1, Angiopoietin-2, and Vascular endothelial growth factor at both gene and protein levels and vascular density were studied in the grafted ovarian tissues. RESULTS: On the 2(nd) and 7(th) day PT, the level of Angiopoietin-1 gene expression in case group was significantly lower than that in control group, while the opposite results were obtained for Angiopoietin-2 and Vascular endothelial growth factor. These results were also confirmed at the protein level. The density of vessels in Setarud group elevated significantly on day 7 PT compared to pre-treatment state. CONCLUSION: Our results showed that administration of Setarud may stimulates angiogenesis in transplanted human ovarian tissues, although further researches are needed before a clear judgment is made. PMID- 26644789 TI - In vitro developmental competence of bovine oocytes: Effect of corpus luteum and follicle size. AB - BACKGROUND: Previous studies reported many discrepancies about the effects of corpus luteum (CL) and ovarian follicle size on the developmental competence of oocytes. OBJECTIVE: The aim of this study was to investigate the effects of CL and different size of follicle on the developmental potential of bovine oocytes. MATERIALS AND METHODS: After ovarian classification based on presence or absence of CL, sample follicles were placed in three groups according to their diameter; small (S; 3-6 mm), medium (M; 6-9 mm), and large (L; 10-20 mm). Collected oocytes in each group were subjected to the in vitro embryo production processes. RESULTS: Results showed that, the percentages of blastocyst obtained from oocytes originating from small and medium follicles of ovaries bearing a CL (CL+S-oocytes and CL+M-oocytes, respectively) were lower (p<0.001) than those of small and medium follicles of ovaries not bearing a CL (CL-S-oocytes and CL-M-oocytes, respectively) (30.8% and 33.6% vs. 36.9% and 38.7% respectively). Although, the percentages of blastocyst obtained from CL-M-oocytes and CL-L-oocytes were greater (p< 0.001) than those of CL+S-oocytes and CL+M-oocytes. There were no significant differences in the percentages of blastocyst formation between controls (C-oocytes), CL-S-oocytes and CL+L-oocytes. CONCLUSION: According to the results of this study, the negative effect of CL on the developmental competence of bovine oocyte depends on the follicle size. Therefore, oocytes originating from large grown follicles were not influenced by negative effects of CL as much as those originating from small and medium follicles did. PMID- 26644790 TI - Cell free fetal DNA testing in maternal blood of Romanian pregnant women. AB - BACKGROUND: The discovery of circulating fetal DNA in maternal blood led to the discovery of new strategies to perform noninvasive testing for prenatal diagnosis. OBJECTIVE: The purpose of the study was to detect fetal aneuploidy at chromosomes 13, 18, 21, X, and Y by analysis of fetal cell-free DNA from maternal blood, without endangering pregnancy. MATERIALS AND METHODS: This retrospective study has been performed in Bucharest at Medlife Maternal and Fetal Medicine Department between 2013-2014. In total 201 women were offered noninvasive prenatal test. Maternal plasma samples were collected from women at greater than 9 weeks of gestation after informed consent and genetics counseling. RESULTS: From 201 patients; 28 (13.93%) had screening test with high risk for trisomy 21, 116 (57.71%) had advanced maternal age, 1 (0.49%) had second trimester ultrasound markers and the remaining 56 patients (27.86%) performed the test on request. Of those patients, 189 (94.02%) had a "low risk" result (<1/10,000). Of those who had a low risk result, 2 continued on to have amniocentesis with normal results.Five patients (2.48%) received "high risk" results (>99% risk) all for trisomy 21 (T21). T21 was confirmed by amniocentesis in 1 patient and the other 4 patients declined confirmation. The 7 remaining patients (3.48%) had a low fetal fraction of DNA. CONCLUSION: It is probably that prenatal diagnosis using fetal DNA in maternal blood would play an increasingly role in the future practice of prenatal testing because of high accuracy. PMID- 26644791 TI - Association of plasminogen activator inhibitor-1 and angiotensin converting enzyme polymorphisms with recurrent pregnancy loss in Iranian women. AB - BACKGROUND: Recurrent pregnancy loss (RPL) defined by two or more failed pregnancies before 20 weeks of gestation. Several factors play a role in RPL including thrombophilic conditions which can be influenced by gene polymorphisms. Plasminogen activator inhibitor-1 (PAI-1) and angiotensin converting enzyme (ACE) genes are closely related to fibrinolytic process, embryonic development and pregnancy success. OBJECTIVE: The aim of this study was to investigate the relationship between RPL and common polymorphisms in ACE and PAI-1 genes. MATERIALS AND METHODS: In this case control study, 100 women with recurrent abortions (at least two) were selected as cases and 100 healthy women with two or more normal term deliveries without a history of abortion as controls. Total genomic DNA was isolated from blood leukocytes. The status of the PAI-1 4G/5G and ACE (D/I) polymorphism was determined by PCR-RFLP. RESULTS: Homozygosity for PAI 1 4G polymorphism was seen in 17 cases (17%), and 5 controls (5%) (p=0.006) so patients with homozygote 4G mutation were significantly more prone to RPL in contrast to control group (OR: 4.63, % 95 CI: 1.55-13.84). In addition, 7 patients (7 %), and no one from the control group, were homozygote (I/I) for ACE polymorphism (p=0.034), suggesting no significant associations between ACE D allele or DD genotype and RPL. CONCLUSION: Considering these results, because 4G/4G polymorphism for PAI-1 gene could be a thrombophilic variant leading to abortion, analysis of this mutation and other susceptibility factors are recommended in patients with RPL. PMID- 26644792 TI - Slow cryopreservation is not superior to vitrification in human spermatozoa; an experimental controlled study. AB - BACKGROUND: Spermatozoa cryopreservation is used for the management of infertility and some other medical conditions. The routinely applied cryopreservation technique depends on permeating cryoprotectants, whose toxic effects have raised the attention towards permeating cryoprotectants-free vitrification technique. OBJECTIVE: To compare between the application of slow cryopreservation and vitrification on human spermatozoa. MATERIALS AND METHODS: This was an experimental controlled study involving 33 human semen samples, where each sample was divided into three equal parts; fresh control, conventional slow freezing, and permeating cryoprotectants-free vitrification. Viability and mitochondrial membrane potential (MMP) of control and post-thawing spermatozoa were assessed with the sperm viability kit and the JC-1 kit, respectively, using fluorescence-activated cell sorting analysis. RESULTS: Significant reduction of the progressive motility, viability and MMP was observed by the procedure of freezing and thawing, while there was not any significant difference between both cryopreservation techniques. Cryopreservation resulted in 48% reduction of the percentage of viable spermatozoa and 54.5% rise in the percentage of dead spermatozoa. In addition, high MMP was reduced by 24% and low MMP was increased by 34.75% in response to freezing and thawing. Progressive motility of spermatozoa was correlated significantly positive with high MMP and significantly negative with low MMP in control as well as post-thawing specimens (r=0.8881/ 0.8412, 0.7461/ -0.7510 and 0.7603/ -0.7839 for control, slow and vitrification respectively, p=0.0001). CONCLUSION: Although both cryopreservation techniques have similar results, vitrification is faster, easier and associated with less toxicity and costs. Thus, vitrification is recommended for the clinical application. PMID- 26644793 TI - Sexual behavior of infertile women: a qualitative study. AB - BACKGROUND: Infertility makes an essential challenge to the sexual life of couples, especially infertile women. When pregnancy does not happen, infertile women think that sexual intercourse is not fruitful and sexual desire became reduce gradually. Infertile women progressively forget that their sexual relationship is also a response to their natural need. OBJECTIVE: This qualitative study was conducted to explore the infertility consequences in the sexual behavior of infertile women. MATERIALS AND METHODS: This was a qualitative content analysis study; and it was part of a widespread study, used a sequential mixed-method and conducted from August 2014 until February 2015. A purposeful sampling was used to recruit infertile women who had referred to Yazd Research and Clinical Center for Infertility. Data gathering techniques employed in this research included in-depth semi structured open face-to-face interviews and field notes. Credibility, transferability, confirm ability, and dependability were assessed for the rigor of the data collection. RESULTS: Totally, 15 infertile women and 8 key informants were interviewed. Data analysis showed four themes about impact of infertility on female sexual behavior: 1/ Impact of infertility drugs on couple sexual behavior, 2/ Impact of assisted reproductive technologies on female sexual behavior, 3/ Timed intercourse during infertility and 4/ The psychological impact of infertility on sexual behavior. CONCLUSION: Some of Iranian infertile women could cope with their problems, but some of them were very affected by infertility drugs and assisted reproductive technologies procedures. Psychosexual counseling before medical treatment could help them to have a better sexual life. PMID- 26644794 TI - Prevention of birth defects in the pre-conception period: knowledge and practice of health care professionals (nurses and doctors) in a city of Southern Brazil. AB - BACKGROUND: Some congenital defects can be prevented in the pregestational stage. However, many health professionals are not prepared to provide counselling to couples regarding the same. OBJECTIVE: This study aimed to assess the performance of doctors and nurses from a primary health-care unit in Florianopolis, Brazil, in preventing birth defects in the preconception period based on the recommendations of the Control Center of Disease Prevention. MATERIALS AND METHODS: This descriptive cross sectional study was performed at a tertiary referral center. In this study, a semi-structured questionnaire was provided to 160 health professionals comprising doctors and nurses who were actively involved in providing primary health care in family health programs. The non-parametric Chi-square (chi(2)) test was used to analyse the data obtained through multiple choice questions. RESULTS: Our results showed that although 81.9% of health professionals provided health-care assistance based on protocols, and only 46.2% professionals were aware of the presence of the topic in the protocol. Of the recommendations provided by the Control Center of Disease Prevention, the use of folic acid was the most prescribed. However, this prescription was not statistically different between nurses and doctors (P=0.85). CONCLUSION: This study identified the fragile nature in these professional's knowledge about the prevention of birth defects in pre-conception period, as evidenced by the inconsistency in their responses. PMID- 26644795 TI - Self-rated Health and Medical Conditions in Refugees and Immigrants from the Same Country of Origin. AB - BACKGROUND: Research suggests that refugees are at an increased risk for poor health outcomes as compared to immigrants. However, prior studies have compared refugees and immigrants from different countries and have failed to isolate specific war-related factors. OBJECTIVE: To compare health outcomes and their determinants in refugees and immigrants from the same country of origin. METHODS: A cross-sectional study based on a convenient sample and on self-report participants were conducted at Southeast Michigan during the period September to December 2009. A validated survey was used to examine refugees (n = 75) and immigrants (n = 65) from Iraq. The survey covered socioeconomics, lifestyle, violence exposure, self-rated health, and number of medical conditions (high blood pressure, fatigue, and backache, shortness of breath, gastrointestinal disorders, skin problems, and musculoskeletal problems). Group differences and predictors of health outcomes were assessed. RESULTS: Refugees reported significantly more violence exposure than immigrants (p < 0.001). There were no significant differences in self-rated health or medical disorders between groups; however, violence exposure was the main predictor of health outcomes in refugees, whereas age was the main predictor in immigrants. Other predictors also varied by migratory group. CONCLUSION: Even though migration status did not directly influence health outcomes, results suggest that factors associated with migration status, e.g., violence exposure and age, do impact health. Future studies need to more carefully define and control for country-specific variables. PMID- 26644796 TI - TNF up-regulates Pentraxin3 expression in human airway smooth muscle cells via JNK and ERK1/2 MAPK pathways. AB - BACKGROUND: Long pentraxin 3 (PTX3) is a novel candidate marker for inflammation in many chronic diseases. As a soluble pattern recognition receptor, PTX3 is involved in amplification of inflammatory reactions and regulation of innate immunity. Previously, we demonstrate that human airway smooth muscle cells (HASMC) express constitutively PTX3 and upon TNF stimulation. However, very little is known about the mechanism governing its expression in HASMC. We sought to investigate the mechanism governing TNF induced PTX3 expression in primary HASMC. METHODS: HASMC were stimulated with TNF in the presence of transcriptional inhibitor actinomycin D (ActD) or MAPKs pharmacological inhibitors. PTX3 mRNA and protein expression were analyzed by Real-time RT-PCR and ELISA, respectively. PTX3 promoter activity was determined using luciferase assay. RESULTS: PTX3 mRNA and protein are expressed constitutively by HASMC and significantly up-regulated by TNF. TNF-induced PTX3 mRNA and protein release in HASMC were inhibited by transcriptional inhibitor actinomycin D. TNF induced significantly PTX3 promoter activation in HASMC. MAPK JNK and ERK1/2 specific inhibitors (SP600125 and UO126), but not p38, significantly down regulates TNF induced PTX3 promoter activity and protein release in HASMC. Finally, TNF mediated PTX3 promoter activity in HASMC was abolished upon mutation of NF-kappabeta and AP1 binding sites. CONCLUSIONS: Our data suggest that TNF induced PTX3 in HASMC at least via a transcriptional mechanism that involved MAPK (JNK and ERK1/2), NF-kappabeta and AP1 pathways. These results rise the possibility that HASMC derived PTX3 may participate in immune regulation in the airways. PMID- 26644799 TI - What if?: Regret and cancer-related decisions. PMID- 26644797 TI - Photoresponsive nanoparticles for drug delivery. AB - Externally triggerable drug delivery systems provide a strategy for the delivery of therapeutic agents preferentially to a target site, presenting the ability to enhance therapeutic efficacy while reducing side effects. Light is a versatile and easily tuned external stimulus that can provide spatiotemporal control. Here we will review the use of nanoparticles in which light triggers drug release or induces particle binding to tissues (phototargeting). PMID- 26644800 TI - CUA Mission: "Providing CPD for Canadian urologists along the career-path continuum". PMID- 26644798 TI - Pharmacy resident publication success: factors of success based on abstracts from a regional meeting. AB - OBJECTIVE: To determine the publication rate among pharmacy resident research projects in a region of the United States and to compare characteristics of published and unpublished projects. METHODS: Research project abstracts from the Great Lakes Pharmacy Residency Conference in 2003, 2005, and 2007 were reviewed. Two independent investigators collected all study data. Data on residency year, state, institution, study design, and whether results were reported were extracted from available abstracts. Publication rate was determined systematically using a search algorithm within the following databases: Scopus, International Pharmaceutical Abstracts (IPA), and MEDLINE (PubMed). Kappa statistic was used to determine inter-rater variability. Descriptive statistics were used to analyze nominal and continuous data. Univariate and multivariate regression analyses were used to determine characteristics of publication success. Sensitivity analysis was performed on projects that were successfully published. RESULTS: Information was extracted from 655 abstracts in which 76 abstracts were published (11.4%). Publication rate trended down over the three years analyzed (2003=12.9%, 2005=12.2%, 2007=9.9%; p=0.57). Study design (interventional, observational, cross-sectional, or service development, p=0.115), direction of inquiry (prospective or retrospective; p=0.146), intervention of interest (drug, human, or other; p=0.096), results in abstract (p=0.096), and institution type (university-affiliated, veterans affairs, community-hospital, or retail; p=0.001) were entered into the multivariate model. Cross-sectional design (odds ratio (OR) 3.6), human (OR 1.9) and other (OR 2.1) interventions, as well as university-affiliated residency (OR 2.6) remained significant for publication success. The mean time to publication from abstract to presentation was 24.5 months, and 83% of projects were published within pharmacy journals. CONCLUSION: Publication rate of pharmacy resident research projects presented at the Great Lakes Pharmacy Residency Conference is low, but it is consistent with other regions of the United States. Study design and study outcomes may influence chance of project publication as well as institution-type, which may have unique research resources, training, and mentorship. PMID- 26644801 TI - The 10 000-hour rule. PMID- 26644803 TI - Evaluation of educational content of YouTube videos relating to neurogenic bladder and intermittent catheterization. AB - INTRODUCTION: Many patients conduct internet searches to manage their own health problems, to decide if they need professional help, and to corroborate information given in a clinical encounter. Good information can improve patients' understanding of their condition and their self-efficacy. Patients with spinal cord injury (SCI) featuring neurogenic bladder (NB) require knowledge and skills related to their condition and need for intermittent catheterization (IC). METHODS: Information quality was evaluated in videos accessed via YouTube relating to NB and IC using search terms "neurogenic bladder intermittent catheter" and "spinal cord injury intermittent catheter." Video content was independently rated by 3 investigators using criteria based on European Urological Association (EAU) guidelines and established clinical practice. RESULTS: In total, 71 videos met the inclusion criteria. Of these, 12 (17%) addressed IC and 50 (70%) contained information on NB. The remaining videos met inclusion criteria, but did not contain information relevant to either IC or NB. Analysis indicated poor overall quality of information, with some videos with information contradictory to EAU guidelines for IC. High-quality videos were randomly distributed by YouTube. IC videos featuring a healthcare narrator scored significantly higher than patient-narrated videos, but not higher than videos with a merchant narrator. About half of the videos contained commercial content. CONCLUSIONS: Some good-quality educational videos about NB and IC are available on YouTube, but most are poor. The videos deemed good quality were not prominently ranked by the YouTube search algorithm, consequently user access is less likely. Study limitations include the limit of 50 videos per category and the use of a de novo rating tool. Information quality in videos with healthcare narrators was not higher than in those featuring merchant narrators. Better material is required to improve patients' understanding of their condition. PMID- 26644802 TI - Penile cancer: Perspective from a Canadian tertiary care centre. AB - INTRODUCTION: Penile squamous cell carcinoma (SCC) is rare in North America; however, the morbidity can be devastating. This analysis represents the first reported penile cancer experience at a tertiary care centre in Canada. METHODS: We carried out a retrospective review of all patients who received care at our centre for penile SCC from 2005 until the present time. Epidemiological and clinical data were collected for all patients. Survival analysis was performed using Kaplan-Meier methods with log-rank test and Cox regression for univariate and multivariate analysis, respectively. RESULTS: We identified 42 patients who were treated at our centre for penile SCC. Of these, 29% underwent excisional biopsy, 38% had partial penectomy, and 33% had total penectomy. Five patients with high-risk tumours underwent modified inguinal lymph node dissection (ILND), while 7 patients had radical ILND for clinically palpable disease. Overall, the median cancer specific survival (CSS) was undefined, with a 60% survival at 102 months. However CSS was significantly correlated to pT stage, pN stage, and tumour grade. The median follow-up was 25 months (interquartile range: 11-48). CONCLUSION: These findings confirm the poor CSS of patients with positive lymph nodes in penile SCC. Patients with pN0 after ILND had a durable CSS. Risk factors for penile SCC were confirmed as elevated body mass index, positive smoking history, and lack of circumcision. This first epidemiologic report on penile SCC from a Canadian tertiary care centre should be expanded to other national centres. PMID- 26644804 TI - Comparative morbidity of ablative energy-based salvage treatments for radio recurrent prostate cancer. AB - INTRODUCTION: We compared the morbidity of whole gland salvage ablation using cryotherapy (CRYO) and high-intensity focused ultrasound (HIFU) for radio recurrent prostate cancer at a single centre over a 17-year period. METHODS: Patients were divided in 3 cohorts. Group 1 included the first 65 patients treated with CRYO (1995-1998); Group 2 included the last 65 patients treated with CRYO (2002-2004), and Group 3 included 65 patients treated with HIFU (2006-2011). We analyzed the complications reported within at least 90 days of treatment or up to the last follow-up. RESULTS: We tallied Clavien grade complications. For Groups 1, 2 and 3, we recorded the following Clavien I-II complications: 78, 49 and 13, respectively. For Clavien grade IIIa, 2, 5 and 4 for Groups 1, 2 and 3, respectively. For Clavien grade IIIb, 8, 2 and 3 for Groups 1, 2 and 3, respectively. Clavien grade II complications were statistically higher in Group 1 versus Group 2 (p = 0.005) and in Group 2 versus Group 3 (p = 0.0001). The rate of mild-moderate incontinence was significantly higher in the CRYO group compared to the HIFU cohort (p <= 0.05). The rate of urinary retention was significantly higher in Group 2 compared to Group 3 (p = 0.0005). The rates of severe incontinence (range: 1.5%-5%), need for surgical intervention (uniform at 1.5%), and recto-urethral fistulae (range: 1.5%-3%) were not statistically different. CONCLUSIONS: CRYO was associated with higher overall morbidity. The morbidity during the early experience with HIFU was lower than both subgroups of CRYO. This may reflect the advancement of technology or cumulative learning experience. PMID- 26644805 TI - Salvage therapies for prostate cancer: Keeping it in the mix. PMID- 26644806 TI - Simulation-based flexible ureteroscopy training using a novel ureteroscopy part task trainer. AB - INTRODUCTION: Simulation-based training (SBT) is being increasingly used for novice trainees as a means of overcoming the early learning curve associated with new surgical skills. We designed a SBT flexible ureteroscopy (fURS) course using a novel inanimate training model (Cook Medical, Bloomington, IN; URS model). We evaluated the course and validated this Cook URS model. METHODS: A 2-week SBT fURS course was designed for junior level urology trainees at 2 Canadian universities. The curriculum included didactic lectures, hands-on training, independent training sessions with expert feedback, and use of the Cook URS part task model. Baseline and post-course assessments of trainee fURS skills were conducted using a standardized test task (fURS with basket manipulation of a calyceal stone). Performances were video-recorded and reviewed by 2 blinded experts using a validated assessment device. RESULTS: Fifteen residents (postgraduate years [PGY] 0-3) participated in the course. Of the participants, 80% rated the Cook URS model as realistic (mean = 4.2/5) and 5 endourology experts rated it as useful as a training device (mean = 4.9/5), providing both face and content validity. The mean overall performance scores, task completion times, and passing ratings correlated with trainee clinical fURS experience - demonstrating construct validity for the Cook URS model. The mean post-course task completion times (15.76 vs. 9.37 minutes, p = 0.001) and overall performance scores (19.20 vs. 25.25, p = 0.007) were significantly better than at baseline. Post-course performance was better in all domains assessed by the validated assessment device. CONCLUSIONS: This study demonstrates that a SBT curriculum for fURS can lead to improved short-term technical skills among junior level urology residents. The Cook URS model demonstrated good face, content and construct validity. PMID- 26644807 TI - Perfect practice makes perfect. PMID- 26644808 TI - A standardized protocol for identifying and counting lymph nodes harvested by pelvic lymph node dissection at the time of radical cystectomy. AB - INTRODUCTION: Lymph node counts have become a surrogate measure for the extent and quality of pelvic lymph node dissection (PLND) at radical cystectomy, but little consideration has been given to the methodology of lymph node processing. We report results from a prospective series comparing a conventional protocol for processing PLND specimens to a fat-emulsifying protocol. We hypothesized that the rate of node positivity would increase with the fat-emulsifying protocol. METHODS: Patients undergoing radical cystectomy for cTis-T4aN0-1M0 urothelial carcinoma of the bladder were eligible for this trial. Palpable lymph nodes were isolated from the PLND specimens in the conventional protocol. The remaining tissue was then processed with fat-emulsifying solution to identify further nodes visually. Nodal counts were compared between techniques. RESULTS: The median number of nodes counted in the PLND specimens of 26 patients was 24.5 (range: 20 40) with conventional processing and 37 (range: 24-52) with the fat-emulsifying solution (p < 0.001). Three patients had lymph node positive disease detected by conventional means, and a single patient was found to have a single positive node by the fat-emulsifying solution alone. The study was closed early after conducting a futility analysis. CONCLUSIONS: A fat-emulsifying protocol identified more lymph nodes than a conventional protocol and may be an appropriate method to standardize lymph node processing following PLND. However, we were unable to show that such a standardized approach significantly increased the rate of node positivity in patients undergoing radical cystectomy. PMID- 26644809 TI - Persistence and adherence with the new beta-3 receptor agonist, mirabegron, versus antimuscarinics in overactive bladder: Early experience in Canada. AB - INTRODUCTION: Antimuscarinics are the principal pharmacological treatment for overactive bladder (OAB), but frequently give rise to anticholinergic side effects, such as dry mouth, a factor leading to poor persistence. The beta3 adrenoceptor agonist mirabegron is devoid of significant anticholinergic activity, while being effective in OAB. We evaluated persistence and adherence with mirabegron versus antimuscarinics over 12 months. METHODS: We obtained retrospective claims from a Canadian Private Drug Plan database for patients 18 years old and over, with a first claim for mirabegron or antimuscarinics during a 6-month index period (April-September 2013). A 6-month look-back identified those with no prior claims for OAB medication (treatment-naive) or >=1 prior OAB drug (treatment-experienced). Time to end of persistence (>=30 day therapy gap or switch of therapy) was evaluated over 12 months; adherence with medication (medication possession ratio) was also measured. RESULTS: Persistence data from 19 485 patients (74% female, 92% naive, 19.9% aged >=65 years) showed that for experienced patients the median number of days on mirabegron was 299 days, compared with a range of 96 to 242 days for the different antimuscarinics; for naive patients, it was 196 versus 70 to 100 days, respectively. Persistence at 12 months was for mirabegron 39% versus 14% to 35% for antimuscarinics, (experienced) and 30% mirabegron versus 14% to 21% antimuscarinics, (naive). Patients taking mirabegron demonstrated statistically significantly greater adherence than those taking antimuscarinics. CONCLUSION: Patients who received mirabegron remained longer on treatment than those treated with antimuscarinics, and had higher 12-month persistence and adherence rates. PMID- 26644810 TI - Drug persistence and adherence in the treatment of overactive bladder. PMID- 26644811 TI - [Not Available]. PMID- 26644812 TI - Pancreas Islet Transplantation for Patients With Type 1 Diabetes Mellitus: A Clinical Evidence Review. AB - BACKGROUND: Type 1 diabetes mellitus is caused by the autoimmune destruction of pancreatic beta (beta) cells, resulting in severe insulin deficiency. Islet transplantation is a beta-cell replacement therapeutic option that aims to restore glycemic control in patients with type 1 diabetes. The objective of this study was to determine the clinical effectiveness of islet transplantation in patients with type 1 diabetes, with or without kidney disease. METHODS: We conducted a systematic review of the literature on islet transplantation for type 1 diabetes, including relevant health technology assessments, systematic reviews, meta-analyses, and observational studies. We used a two-step process: first, we searched for systematic reviews and health technology assessments; second, we searched primary studies to update the chosen health technology assessment. The Assessment of Multiple Systematic Reviews measurement tool was used to examine the methodological quality of the systematic reviews and health technology assessments. We assessed the quality of the body of evidence and the risk of bias according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group criteria. RESULTS: Our searched yielded 1,354 citations. One health technology assessment, 11 additional observational studies to update the health technology assessment, one registry report, and four guidelines were included; the observational studies examined islet transplantation alone, islet-after-kidney transplantation, and simultaneous islet kidney transplantation. In general, low to very low quality of evidence exists for islet transplantation in patients with type 1 diabetes with difficult-to control blood glucose levels, with or without kidney disease, for these outcomes: health-related quality of life, secondary complications of diabetes, glycemic control, and adverse events. However, high quality of evidence exists for the specific glycemic control outcome of insulin independence compared with intensive insulin therapy. For patients without kidney disease, islet transplantation improves glycemic control and diabetic complications for patients with type 1 diabetes when compared with intensive insulin therapy. However, results for health-related quality of life outcomes were mixed, and adverse events were increased compared with intensive insulin therapy. For patients with type 1 diabetes with kidney disease, islet-after-kidney transplantation or simultaneous islet-kidney transplantation also improved glycemic control and secondary diabetic complications, although the evidence was more limited for this patient group. Compared with intensive insulin therapy, adverse events for islet-after kidney transplantation or simultaneous islet-kidney transplantation were increased, but were in general less severe than with whole pancreas transplantation. CONCLUSIONS: For patients with type 1 diabetes with difficult-to control blood glucose levels, islet transplantation may be a beneficial beta-cell replacement therapy to improve glycemic control and secondary complications of diabetes. However, there is uncertainty in the estimates of effectiveness because of the generally low to very low quality of evidence for all outcomes of interest. PMID- 26644813 TI - Effect of Competitive Surface Functionalization on Dual-Modality Fluorescence and Magnetic Resonance Imaging of Single-Walled Carbon Nanotubes. AB - It is well-known that ionic surfactant coated single-walled carbon nanotubes (SWNTs) possess higher near-infrared fluorescence (NIRF) quantum yield than nonionic polymer functionalized SWNTs. However, the influence of surface functionalization on the magnetic properties of SWNTs for T2-weighted magnetic resonance imaging (MRI) has not been reported. Here, we demonstrate that SWNTs functionalized by nonionic polymers display superior T2 relaxivity for MRI as compared to those coated by ionic surfactants. This difference may indicate that micelle structures formed by ionic surfactants are sufficiently tight to partially exclude water protons from the iron catalysts attached to the ends of SWNTs. On the basis of the different effects of the two types of suspension agents on NIRF and MRI of functionalized SWNTs, we further explore the competitive surface functionalization between ionic surfactants and nonionic polymers by stepwise replacing ionic surfactant molecules in a nanotube suspension with nonionic polymers. The superior NIRF of ionic surfactant coated SWNTs gradually quenches whereas no improvement on T2 relaxivity is observed during this replacement process. This result may indicate that nonionic polymers wrap around the outside of micelle structures to form small nanotube bundles rather than replacing ionic surfactants in the micelle structures to directly interact with the SWNT surface. Finally, we demonstrate the feasibility of dual modality NIRF and MRI of nonionic polymer functionalized SWNTs in brain cells. PMID- 26644814 TI - Binge drinking: Burden of liver disease and beyond. AB - The consumption of alcoholic beverages is harmful to human health. In recent years, consumption patterns of alcoholic beverages have changed in our society, and binge drinking has generalized. It is considered to be a socio-sanitary problem with few known consequences in terms of individual and third-party social impacts (in the form of violence or traffic accidents) and its organic impact (affects the liver and other organs and systems, such as the nervous and cardiovascular systems) and represents an important financial burden due to its increasing economic impact. This review provides a global approach to binge drinking and emphasizes its epidemiological character, the effect of this type of consumption and the possible management of a problem with an increasing tendency in our society. PMID- 26644817 TI - Cutaneous manifestations of hepatitis C in the era of new antiviral agents. AB - The association of chronic hepatitis C virus (HCV) infection with a wide spectrum of cutaneous manifestations has been widely reported in the literature, with varying strength of epidemiological association. Skin diseases which are certainly related with chronic HCV infection due to a strong epidemiological and pathogenetic association are mixed cryoglobulinemia, lichen planus and porphyria cutanea tarda. Chronic pruritus and necrolytic acral erythema are conditions that may share a possible association with HCV infection, while several immune mediated inflammatory skin conditions, such as psoriasis, chronic urticaria and vitiligo, have been only anecdotally reported in the setting of chronic HCV infection. Traditional interferon-based treatment regimens for HCV infection are associated with substantial toxicity and a high-risk of immune-related adverse events, while the advent of new direct-acting antivirals with sustained virological response and improved tolerability will open the door for all-oral, interferon-free regimens. In the new era of these direct acting antivirals there will be hopefully a renewed interest in extra-hepatic manifestations of HCV infection. The aim of the present paper is to review the main cutaneous HCV related disorders - mixed cryoglobulinemia, lichen planus, porphyria cutanea tarda and chronic pruritus - and to discuss the potential impact of new antiviral treatments on the course of these extra-hepatic manifestations of chronic HCV infection. PMID- 26644816 TI - Clinical significance of hepatitis B surface antigen mutants. AB - Hepatitis B virus (HBV) infection is a major public health problem in many countries, with nearly 300 million people worldwide carrying HBV chronic infection and over 1 million deaths per year due to cirrhosis and liver cancer. Several hepatitis B surface antigen (HBsAg) mutations have been described, most frequently due to a single amino acid substitution and seldom to a nucleotide deletion. The majority of mutations are located in the S region, but they have also been found in the pre-S1 and pre-S2 regions. Single amino acid substitutions in the major hydrophilic region of HBsAg, called the "a" determinant, have been associated with immune escape and the consequent failure of HBV vaccination and HBsAg detection, whereas deletions in the pre-S1 or pre-S2 regions have been associated with the development of hepatocellular carcinoma. This review article will focus on the HBsAg mutants and their biological and clinical implications. PMID- 26644818 TI - Vitamin E reduces liver stiffness in nonalcoholic fatty liver disease. AB - AIM: To evaluate the efficacy of vitamin E treatment on liver stiffness in nonalcoholic fatty liver disease (NAFLD). METHODS: Thirty-eight NAFLD patients were administered vitamin E for > 1 year. The doses of vitamin E were 150, 300, or 600 mg; three times per day after each meal. Responses were assessed by liver enzyme levels [aspartate aminotransferase (AST), alanine aminotranferease (ALT), and gamma-glutamyl transpeptidase (gamma-GTP)], noninvasive scoring systems of hepatic fibrosis-4 [FIB-4 index and aspartate aminotransferase-to-platelet index (APRI)], and liver stiffness [velocity of shear wave (Vs)] measured by acoustic radiation force impulse elastography. Vs measurements were performed at baseline and 12 mo after baseline. The patients were genotyped for the patatin-like phospholipase domain containing 3 (PNPLA3) polymorphisms and then divided into either the CC/CG or GG group to examine each group's responses to vitamin E treatment. RESULTS: We found marked differences in the platelet count, serum albumin levels, alkaline phosphatase levels, FIB-4 index, APRI, and Vs at baseline depending on the PNPLA3 polymorphism. AST, ALT, and gamma-GTP levels (all P < 0.001); FIB-4 index (P = 0.035); APRI (P < 0.001); and Vs (P < 0.001) significantly decreased from baseline to 12 mo in the analysis of all patients. In the subset analyses of PNPLA3 genotypes, AST levels (P = 0.011), ALT levels (P < 0.001), gamma-GTP levels (P = 0.005), APRI (P = 0.036), and Vs (P = 0.029) in genotype GG patients significantly improved, and AST and ALT levels (both P < 0.001), gamma-GTP levels (P = 0.003), FIB-4 index (P = 0.017), and APRI (P < 0.001) in genotype CC/CG patients. CONCLUSION: One year of vitamin E treatment improved noninvasive fibrosis scores and liver stiffness in NAFLD patients. The responses were similar between different PNPLA3 genotypes. PMID- 26644815 TI - Hepatic manifestations of non-steroidal inflammatory bowel disease therapy. AB - Inflammatory bowel disease (IBD) is composed of Crohn's disease and ulcerative colitis and is manifested by both bowel-related and extraintestinal manifestations. Recently the number of therapeutic options available to treat IBD has dramatically increased, with each new medication having its own mechanism of action and side effect profile. A complete understanding of the hepatotoxicity of these medications is important in order to distinguish these complications from the hepatic manifestations of IBD. This review seeks to evaluate the hepatobiliary complications of non-steroid based IBD medications and aide providers in the recognition and management of these side-effects. PMID- 26644819 TI - Alpha-fetoprotein and des-gamma-carboxy-prothrombin at twenty-four weeks after interferon-based therapy predict hepatocellular carcinoma development. AB - AIM: To investigate risk factors for development of hepatocellular carcinoma (HCC) in patients with hepatitis C virus-related liver cirrhosis (LC-C). METHODS: To evaluate the relationship between clinical factors including virological response and the development of HCC in patients with LC-C treated with interferon (IFN) and ribavirin, we conducted a multicenter, retrospective study in 14 hospitals in Japan. All patients had compensated LC-C with clinical or histological data available. HCC was diagnosed by the presence of typical hypervascular characteristics on computed tomography and/or magnetic resonance imaging. RESULTS: HCC was diagnosis in 50 (21.6%) of 231 LC-C patients during a median observation period of 3.8 years after IFN and ribavirin therapy. Patients who developed HCC were older (P = 0.018) and had higher serum levels of pretreatment alpha-fetoprotein (AFP) (P = 0.038). Multivariate analysis revealed the following independent risk factors for HCC development: history of treatment for HCC [P < 0.001, odds ratio (OR) = 15.27, 95%CI: 4.98-59.51], AFP levels of >= 10 ng/mL (P = 0.009, OR = 3.89, 95%CI: 1.38-11.94), and des-gamma-carboxy prothrombin (DCP) levels of >= 40 mAU/mL at 24 wk after the completion of IFN and ribavirin therapy (P < 0.001, OR = 24.43, 95%CI: 4.11-238.67). CONCLUSION: We suggested that the elevation of AFP and DCP levels at 24 wk after the completion of IFN and ribavirin therapy were strongly associated with the incidence of HCC irrespective of virological response among Japanese LC-C patients. PMID- 26644820 TI - Comparative study and systematic review of laparoscopic liver resection for hepatocellular carcinoma. AB - AIM: To compare the surgical outcomes between laparoscopic liver resection (LLR) and open liver resection (OLR) as a curative treatment in patients with hepatocellular carcinoma (HCC). METHODS: A PubMed database search was performed systematically to identify comparative studies of LLR vs OLR for HCC from 2000 to 2014. An extensive text word search was conducted, using combinations of search headings such as "laparoscopy", "hepatectomy", and "hepatocellular carcinoma". A comparative study was also performed in our institution where we analysed surgical outcomes of 152 patients who underwent liver resection between January 2005 to December 2012, of which 42 underwent laparoscopic or hand-assisted laparoscopic resection and 110 underwent open resection. RESULTS: Analysis of our own series and a review of 17 high-quality studies showed that LLR was superior to OLR in terms of short-term outcomes, as patients in the laparoscopic arm were found to have less intraoperative blood loss, less blood transfusions, and a shorter length of hospital stay. In our own series, both LLR and OLR groups were found to have similar overall survival (OS) rates, but disease-free survival (DFS) rates were higher in the laparoscopic arm. CONCLUSION: LLR is associated with better short-term outcomes compared to OLR as a curative treatment for HCC. Long-term oncologic outcomes with regards to OS and DFS rates were found to be comparable in both groups. LLR is hence a safe and viable option for curative resection of HCC. PMID- 26644821 TI - Portal vein thrombosis, mortality and hepatic decompensation in patients with cirrhosis: A meta-analysis. AB - AIM: To determine the clinical impact of portal vein thrombosis in terms of both mortality and hepatic decompensations (variceal hemorrhage, ascites, portosystemic encephalopathy) in adult patients with cirrhosis. METHODS: We identified original articles reported through February 2015 in MEDLINE, Scopus, Science Citation Index, AMED, the Cochrane Library, and relevant examples available in the grey literature. Two independent reviewers screened all citations for inclusion criteria and extracted summary data. Random effects odds ratios were calculated to obtain aggregate estimates of effect size across included studies, with 95%CI. RESULTS: A total of 226 citations were identified and reviewed, and 3 studies with 2436 participants were included in the meta analysis of summary effect. Patients with portal vein thrombosis had an increased risk of mortality (OR = 1.62, 95%CI: 1.11-2.36, P = 0.01). Portal vein thrombosis was associated with an increased risk of ascites (OR = 2.52, 95%CI: 1.63-3.89, P < 0.001). There was insufficient data available to determine the pooled effect on other markers of decompensation including gastroesophageal variceal bleeding or hepatic encephalopathy. CONCLUSION: Portal vein thrombosis appears to increase mortality and ascites, however, the relatively small number of included studies limits more generalizable conclusions. More trials with a direct comparison group are needed. PMID- 26644822 TI - Role of magnetic resonance imaging in the detection and characterization of solid pancreatic nodules: An update. AB - Pancreatic ductal adenocarcinoma is the most common malignant tumor of the pancreas. The remaining pancreatic tumors are a diverse group of pancreatic neoplasms that comprises cystic pancreatic neoplasms, endocrine tumors and other uncommon pancreatic tumors. Due to the excellent soft tissue contrast resolution, magnetic resonance imaging (MRI) is frequently able to readily separate cystic from noncystic tumors. Cystic tumors are often easy to diagnose with MRI; however, noncystic non-adenocarcinoma tumors may show a wide spectrum of imaging features, which can potentially mimic ductal adenocarcinoma. MRI is a reliable technique for the characterization of pancreatic lesions. The implementation of novel motion-resistant pulse sequences and respiratory gating techniques, as well as the recognized benefits of MR cholangiopancreatography, make MRI a very accurate examination for the evaluation of pancreatic masses. MRI has the distinctive ability of non-invasive assessment of the pancreatic ducts, pancreatic parenchyma, neighbouring soft tissues, and vascular network in one examination. MRI can identify different characteristics of various solid pancreatic lesions, potentially allowing the differentiation of adenocarcinoma from other benign and malignant entities. In this review we describe the MRI protocols and MRI characteristics of various solid pancreatic lesions. Recognition of these characteristics may establish the right diagnosis or at least narrow the differential diagnosis, thus avoiding unnecessary tests or procedures and permitting better management. PMID- 26644823 TI - Iliac vein compression syndrome: Clinical, imaging and pathologic findings. AB - May-Thurner syndrome (MTS) is the pathologic compression of the left common iliac vein by the right common iliac artery, resulting in left lower extremity pain, swelling, and deep venous thrombosis. Though this syndrome was first described in 1851, there are currently no standardized criteria to establish the diagnosis of MTS. Since MTS is treated by a wide array of specialties, including interventional radiology, vascular surgery, cardiology, and vascular medicine, the need for an established diagnostic criterion is imperative in order to reduce misdiagnosis and inappropriate treatment. Although MTS has historically been diagnosed by the presence of pathologic features, the use of dynamic imaging techniques has led to a more radiologic based diagnosis. Thus, imaging plays an integral part in screening patients for MTS, and the utility of a wide array of imaging modalities has been evaluated. Here, we summarize the historical aspects of the clinical features of this syndrome. We then provide a comprehensive assessment of the literature on the efficacy of imaging tools available to diagnose MTS. Lastly, we provide clinical pearls and recommendations to aid physicians in diagnosing the syndrome through the use of provocative measures. PMID- 26644824 TI - Application of positron emission tomography/computed tomography in radiation treatment planning for head and neck cancers. AB - 18-fluorodeoxygluocose positron emission tomography/computed tomography ((18)FDG PET/CT) provides significant information in multiple settings in the management of head and neck cancers (HNC). This article seeks to define the additional benefit of PET/CT as related to radiation treatment planning for squamous cell carcinomas (SCCs) of the head and neck through a review of relevant literature. By helping further define both primary and nodal volumes, radiation treatment planning can be improved using PET/CT. Special attention is paid to the independent benefit of PET/CT in targeting mucosal primaries as well as in detecting nodal metastases. The utility of PET/CT is also explored for treatment planning in the setting of SCC of unknown primary as PET/CT may help define a mucosal target volume by guiding biopsies for examination under anesthesia thus changing the treatment paradigm and limiting the extent of therapy. Implications of the use of PET/CT for proper target delineation in patients with artifact from dental procedures are discussed and the impact of dental artifact on CT-based PET attenuation correction is assessed. Finally, comment is made upon the role of PET/CT in the high-risk post-operative setting, particularly in the context of radiation dose escalation. Real case examples are used in these settings to elucidate the practical benefits of PET/CT as related to radiation treatment planning in HNCs. PMID- 26644825 TI - Magnetic resonance imaging in assessment of stress urinary incontinence in women: Parameters differentiating urethral hypermobility and intrinsic sphincter deficiency. AB - AIM: To define the magnetic resonance imaging (MRI) parameters differentiating urethral hypermobility (UH) and intrinsic sphincter deficiency (ISD) in women with stress urinary incontinence (SUI). METHODS: The static and dynamic MR images of 21 patients with SUI were correlated to urodynamic (UD) findings and compared to those of 10 continent controls. For the assessment of the urethra and integrity of the urethral support structures, we applied the high-resolution endocavitary MRI, such as intraurethral MRI, endovaginal or endorectal MRI. For the functional imaging of the urethral support, we performed dynamic MRI with the pelvic phased array coil. We assessed the following MRI parameters in both the patient and the volunteer groups: (1) urethral angle; (2) bladder neck descent; (3) status of the periurethral ligaments, (4) vaginal shape; (5) urethral sphincter integrity, length and muscle thickness at mid urethra; (6) bladder neck funneling; (7) status of the puborectalis muscle; (8) pubo-vaginal distance. UDs parameters were assessed in the patient study group as follows: (1) urethral mobility angle on Q-tip test; (2) Valsalva leak point pressure (VLPP) measured at 250 cc bladder volume; and (3) maximum urethral closure pressure (MUCP). The UH type of SUI was defined with the Q-tip test angle over 30 degrees, and VLPP pressure over 60 cm H2O. The ISD incontinence was defined with MUCP pressure below 20 cm H2O, and VLPP pressure less or equal to 60 cm H2O. We considered the associations between the MRI and clinical data and UDs using a variety of statistical tools to include linear regression, multivariate logistic regression and receiver operating characteristic (ROC) analysis. All statistical analyses were performed using STATA version 9.0 (StataCorp LP, College Station, TX). RESULTS: In the incontinent group, 52% have history of vaginal delivery trauma as compared to none in control group (P < 0.001). There was no difference between the continent volunteers and incontinent patients in body habitus as assessed by the body mass index. Pubovaginal distance and periurethral ligament disruption are significantly associated with incontinence; periurethral ligament symmetricity reduces the odds of incontinence by 87%. Bladder neck funneling and length of the suprapubic urethral sphincter are significantly associated with the type of incontinence on UDs; funneling reduced the odds of pure UH by almost 95%; increasing suprapubic urethral sphincter length at rest is highly associated with UH. Both MRI variables result in a predictive model for UDs diagnosis (area under the ROC = 0.944). CONCLUSION: MRI may play an important role in assessing the contribution of hypermobility and sphincteric dysfunction to the SUI in women when considering treatment options. PMID- 26644826 TI - Partial correlation analyses of global diffusion tensor imaging-derived metrics in glioblastoma multiforme: Pilot study. AB - AIM: To determine existing correlates among diffusion tensor imaging (DTI) derived metrics in healthy brains and brains with glioblastoma multiforme (GBM). METHODS: Case-control study using DTI data from brain magnetic resonance imaging of 34 controls (mean, 41.47; SD, +/- 21.94 years; range, 21-80 years) and 27 patients with GBM (mean, SD; 48.41 +/- 15.18 years; range, 18-78 years). Image postprocessing using FSL software calculated eleven tensor metrics: fractional (FA) and relative anisotropy; pure isotropic (p) and anisotropic diffusions (q), total magnitude of diffusion (L); linear (Cl), planar (Cp) and spherical tensors (Cs); mean (MD), axial (AD) and radial diffusivities (RD). Partial correlation analyses (controlling the effect of age and gender) and multivariate Mancova were performed. RESULTS: There was a normal distribution for all metrics. Comparing healthy brains vs brains with GBM, there were significant very strong bivariate correlations only depicted in GBM: [FA<->Cl (+)], [FA<->q (+)], [p<->AD (+)], [AD<->MD (+)], and [MD<->RD (+)]. Among 56 pairs of bivariate correlations, only seven were significantly different. The diagnosis variable depicted a main effect [F-value (11, 23) = 11.842, P <= 0.001], with partial eta squared = 0.850, meaning a large effect size; age showed a similar result. The age also had a significant influence as a covariate [F (11, 23) = 10.523, P < 0.001], with a large effect size (partial eta squared = 0.834). CONCLUSION: DTI-derived metrics depict significant differences between healthy brains and brains with GBM, with specific magnitudes and correlations. This study provides reference data and makes a contribution to decrease the underlying empiricism in the use of DTI parameters in brain imaging. PMID- 26644827 TI - Pancreatic trauma: The role of computed tomography for guiding therapeutic approach. AB - AIM: To evaluate the role of computed tomography (CT) for diagnosing traumatic injuries of the pancreas and guiding the therapeutic approach. METHODS: CT exams of 6740 patients admitted to our Emergency Department between May 2005 and January 2013 for abdominal trauma were retrospectively evaluated. Patients were identified through a search of our electronic archive system by using such terms as "pancreatic injury", "pancreatic contusion", "pancreatic laceration", "peri pancreatic fluid", "pancreatic active bleeding". All CT examinations were performed before and after the intravenous injection of contrast material using a 16-slice multidetector row computed tomography scanner. The data sets were retrospectively analyzed by two radiologists in consensus searching for specific signs of pancreatic injury (parenchymal fracture and laceration, focal or diffuse pancreatic enlargement/edema, pancreatic hematoma, active bleeding, fluid between splenic vein and pancreas) and non-specific signs (inflammatory changes in peri pancreatic fat and mesentery, fluid surrounding the superior mesenteric artery, thickening of the left anterior renal fascia, pancreatic ductal dilatation, acute pseudocyst formation/peri-pancreatic fluid collection, fluid in the anterior and posterior pararenal spaces, fluid in transverse mesocolon and lesser sac, hemorrhage into peri-pancreatic fat, mesocolon and mesentery, extraperitoneal fluid, intra-peritoneal fluid). RESULTS: One hundred and thirty-six/Six thousand seven hundred and forty (2%) patients showed CT signs of pancreatic trauma. Eight/one hundred and thirty-six (6%) patients underwent surgical treatment and the pancreatic injures were confirmed in all cases. Only in 6/8 patients treated with surgical approach, pancreatic duct damage was suggested in the radiological reports and surgically confirmed in all cases. In 128/136 (94%) patients who underwent non-operative treatment CT images showed pancreatic edema in 97 patients, hematoma in 31 patients, fluid between splenic vein and pancreas in 113 patients. Non-specific CT signs of pancreatic injuries were represented by peri pancreatic fat stranding and mesentery fluid in 89% of cases, thickening of the left anterior renal fascia in 65%, pancreatic ductal dilatation in 18%, acute pseudocyst/peri-pancreatic fluid collection in 57%, fluid in the pararenal spaces in 45%, fluid in transverse mesocolon and lesser sac in 29%, hemorrhage into peri pancreatic fat, mesocolon and mesentery in 66%, extraperitoneal fluid in 66%, intra-peritoneal fluid in 41% cases. CONCLUSION: CT represents an accurate tool for diagnosing pancreatic trauma, provides useful information to plan therapeutic approach with a detection rate of 75% for recognizing ductal lesions. PMID- 26644828 TI - The effect of protocol for disinfection of extracted teeth recommended by center for disease control (CDC) on microhardness of enamel and dentin. AB - BACKGROUND: According to the guideline of the United States center for disease control (CDC), the extracted teeth should be sterilized by autoclaving or storage in 10% formalin before using for educational or research purposes. The objective of this study was to evaluate the effect of this protocol on microhardness of dentin and enamel. MATERIAL AND METHODS: Thirty extracted single-root teeth were used in this study. The crowns were resected, and the roots were longitudinally sectioned into two halves. The Vickers microhardness (VHN) of specimens was measured on polished canal dentin and buccal enamel surfaces. The crowns were randomly divided into three groups (n=10). Group 1 and 2 were sterilized using autoclave and formalin, respectively while group 3 (control) was stored in synthetic tissue fluid. The root halves were also randomly divided into 3 groups (n=20) which were treated as mentioned above for crown samples. Following sterilization, VHN of samples was measured again. ANOVA and paired samples t tests were used to analyze the data. RESULTS: Autoclaving caused a significant reduction in microhardness of dentin (P <0.001, 12.04% decreases in VHN). However, there were no significant differences for before and after sterilization within other groups. CONCLUSIONS: Based on the results of this study, the CDC protocol is recommended in studies related to enamel microhardness. However, Autoclaving is not an appropriate sterilization method in studies related to dentin microhardness. In these studies, two-week immersion in 10% formalin is recommended. KEY WORDS: Autoclave, CDC, extracted teeth, formalin, microhardness, sterilization. PMID- 26644829 TI - Intra-oral low level laser therapy in chronic maxillary sinusitis: A new and effective recommended technique. AB - BACKGROUND: Chronic sinusitis is one of the most common chronic diseases involving different age groups. Because the nature and etiology of chronic sinusitis are not completely known, there is not any standard treatment for this disease. It has been suggested that low-level laser can be used in treating chronic sinusitis but there are limited studies about its usage. In this research, intra-oral radiation of low-level laser has been described and implemented for the first time. Suggested hypotheses about the efficacy of this type of radiation (intra-oral) in treating chronic maxillary sinusitis includes this fact that the depth of maxilla's vestibule is also the floor of maxillary sinus and sinus discharges collect in this area because of gravity effect. Therefore, with considering suitable radiation angle, this area gets the most benefits of laser's anti-inflammatory effects. MATERIAL AND METHODS: In this study, 20 patients with chronic maxillary sinusitis were included. They were assessed before and after treatment. Treatment plan was performed in 8 sessions every other days using low-level diode laser with 810 nm. Snot-22 questionnaire and rhinomanometry were used for evaluating patients. Changes of signs and symptoms were recorded in questionnaire every session and 6 months after treatment. Friedman and Wilcoxon tests were used for data analyses. In this study, P value < 0.05 was considered statistically significant. RESULTS: All variables and all symptoms of patients were improved using intra-oral low-level laser and this improvement was statistically significant (P value<0.05). There was also significant decrease in nasal airway resistance and significant increase in air flow (P value<0.05). Six month after treatment completion, there was no significant difference between the results of completion and the results of 8th treatment session (P value< 0.05). CONCLUSIONS: Using intra-oral low-level laser is a suitable way to treat patients with chronic maxillary sinusitis. KEY WORDS: Chronic sinusitis, maxillary sinusitis, low-level laser. PMID- 26644830 TI - Evaluating the shear bond strength of enamel and dentin with or without etching: A comparative study between dimethacrylate-based and silorane-based adhesives. AB - BACKGROUND: Silorane-based composites and their specific self-etch adhesive were introduced to conquest the polymerization shrinkage of methacrylate-based composites. It has been shown that additional etching of enamel and dentin can improve the bond strength of self-etch methacrylate-based adhesives but this claim is not apparent about silorane-based adhesives. Our objective was to compare the shear bond strength (SBS) of enamel and dentin between silorane-based adhesive resin and a methacrylate-based resin with or without additional etching. MATERIAL AND METHODS: 40 sound human premolars were prepared and divided into two groups: 1- Filtek P60 composite and Clearfil SE Bond adhesive; 2- Filtek P90 composite and Silorane adhesive. Each group divided into two subgroups: with or without additional etching. For additional etching, 37% acid phosphoric was applied before bonding procedure. A cylinder of the composite was bonded to the surface. After 24 hours storage and 500 thermo cycling between 5-55 degrees C, shear bond strength was assessed with the cross head speed of 0.5 mm/min. Then, bonded surfaces were observed under stereomicroscope to determine the failure mode. Data were analyzed with two-way ANOVA and Fischer exact test. RESULTS: Shear bond strength of Filtek P60 composite was significantly higher than Filtek P90 composite both in enamel and dentin surfaces (P<0.05). However, additional etching had no significant effect on shear bond strength in enamel or dentin for each of the composites (P>0.05). There was no interaction between composite type and additional etching (P>0.05). Failure pattern was mainly adhesive and no significant correlation was found between failure and composite type or additional etching (P>0.05). CONCLUSIONS: Shear bond strength of methacrylate based composite was significantly higher than silorane-based composite both in enamel and dentin surfaces and additional etching had no significant effect on shear bond strength in enamel or dentin for each of the composites. The mode of failure had no meaningful relation to the type of composite and etching factor. KEY WORDS: Shear bond strength, adhesive, composite resin, silorane, methacrylate. PMID- 26644831 TI - Combined chlorhexidine-sodiumfluoride mouthrinse for orthodontic patients: Clinical and microbiological study. AB - BACKGROUND: Orthodontic appliances impede good dental plaque control by brushing. Antimicrobial mouth rinses were suggested to improve this performance. We therefore aimed to investigate the effects of combined mouthrinse containing chlorhexidine (CHX) and sodium fluoride (NaF) on clinical oral hygiene parameters,and plaque bacterial level. MATERIAL AND METHODS: In this double-blind clinical study, 60 fixed orthodontic patients aged 14-25 years were randomly assigned to one of four mouthrinses groups: 1- combined CHX /NaF 2- CHX 0.06% 3- NaF0.05% 4-placebo. Following baseline examination patients were instructed to use the assigned mouthrinse twice daily for 21 days. Bleeding index (BI), modified gingival index (MGI) and plaque index (PI) were determined at the baselineand after three weeks of rinsing. Samples from supragingival plaque were obtained for the assessment of total bacterial, Streptococcus mutans and Lactobacilli colony counts. Data were analyzed by Wilcoxon, Kruskal-Wallis, and Mann-Whitney tests. RESULTS: Clinical parameters; All three active mouth rinses induced significant improvements of BI, MGI, and PI (P<0.05). Results of CHX/NaF were slightly, but not significantly, better than CHX. CHX/NaF and CHX induced significantly more changes than NaF and placebo. Microbiological measurements; Except placebo, other mouthrinses reduced total bacterial, Streptococcus mutans, and Lactobacilli counts significantly (P<0.05). CHX/NaF acted against Lactobacilli significantly more than others. CONCLUSIONS: Adding CHX0.06%/NaF0.05% combined mouth rinse to daily oral hygiene regimen of orthodontic patients significantly improved oral hygiene status. Effect of this combined mouth rinse on dental plaque Lactobacilli was remarkable. However, large controlled trials could provide more definitive evidence. KEY WORDS: Mouthrinse, fluoride, chlorhexidine, plaque. PMID- 26644832 TI - Immediate 3-dimensional ridge augmentation after extraction of periodontally hopeless tooth using chinblock graft. AB - BACKGROUND: The aim of the present study was to evaluate clinically and radiographically, the efficacy of immediate ridge augmentation to reconstruct the vertical and horizontal dimensions at extraction sites of periodontally hopeless tooth using an autogenous chin block graft. MATERIAL AND METHODS: A total of 11 patients (7 male & 4 female) with localized advanced bone loss around single rooted teeth having hopeless prognosis and indicated for extraction were selected for the study. The teeth were atraumatically extracted and deficient sites were augmented using autogenous chin block graft. Parameters like clinically soft tissue height - width and also radiographic ridge height -width were measured before and 6 months after augmentation. Obtained results were tabulated and analysed statistically. RESULTS: After 6 months of immediate ridge augmentation, the mean gain in radiographic vertical height and horizontal width was 7.64 + 1.47 mm (P = 0.005) and 5.28 + 0.46 mm (P = 0.007) respectively which was found to be statistically significant (P < 0.05). Mean change of width gain of 0.40mm and height loss of 0.40mm of soft tissue parameters, from the baseline till completion of the study at 6 months was observed. CONCLUSIONS: The present study showed predictable immediate ridge augmentation with autogenous chin block graft at periodontally compromised extraction site. It can provide adequate hard and soft tissue foundation for perfect 3-Dimensional prosthetic positioning of implant in severely deficient ridges. KEY WORDS: Immediate ridge augmentation, periondontally hopeless tooth, autogenous chin graft, dental implant. PMID- 26644833 TI - In vitro antibacterial activity of different pulp capping materials. AB - BACKGROUND: Direct pulp capping involves the application of a dental material to seal communications between the exposed pulp and the oral cavity (mechanical and carious pulp exposures) in an attempt to act as a barrier, protect the dental pulp complex and preserve its vitality. The aim of this study was to evaluate and compare, by the agar disc diffusion test, the antimicrobial activity of six different pulp-capping materials: Dycal (Dentsply), Calcicur (Voco), Calcimol LC (Voco), TheraCal LC (Bisco), MTA Angelus (Angelus), Biodentine (Septodont). MATERIAL AND METHODS: Streptococcus salivarius, Streptococcus sanguis and Streptococcus mutans strains were selected to evaluate the antimicrobial activity by the agar disc diffusion test of different pulp capping materials. Paper disks were impregnated whit each pulp capping materials and placed onto culture agar plates pre-adsorbed with bacterial cells and further incubated for 24 h at 37 degrees C. The growth inhibition zones around each pulp capping materials were recorded and compared for each bacterial strain. RESULTS: For the investigation of the antibacterial properties the ANOVA showed the presence of significant differences among the various materials. Tukey test showed that MTA-based materials induced lower growth inhibition zones. CONCLUSIONS: MTA-based products show a discrete antibacterial activity varying from calcium hydroxide-based materials which present an higher antibacterial activity. KEY WORDS: Agar disc diffusion test, antimicrobial activity, calcium hydroxide, MTA, pulp capping materials. PMID- 26644834 TI - The frequency of non-syndromic distomolar teeth in a Greek population sample? AB - BACKGROUND: To investigate the frequency of non-syndromic distomolars in a Greek population sample. MATERIAL AND METHODS: The study population of this retrospective study consisted of 859 Orthopantomograms (OPGs) of 425 male and 434 female patients, attended the Department of Oral Diagnosis and Radiology, Dental School of Athens seeking for treatment. The OPGs were taken as a part of the patients treatment planning. Patients' mean age was 33.57 years. Exclusion criteria from this study was cleft lip +/- palate and diseases associated with systemic conditions and syndromes (such as cleidocranial dysplasia and Gardner syndrome). OPGs were only included in the study if at least one 3rd molar was present. The data collected were the number of 3rd molars, the number of distomolars, the age and the gender of each patient, information concerning previous extraction of 3rd molars. Statistical evaluation of the data included descriptive and bivariate analyses (Chi-square test and Spearman's rho correlation coefficient). In an attempt to further estimate the correlation between the presence of upper and lower 3rd conditions we assumed that the absence of 3rd molars, the presence of 3rd molars, and the presence of distomolars was ordinal in nature and we calculated the Spearman Correlation Coefficient. RESULTS: The number of distomolars was greater in the maxilla than in the mandible. In the maxilla the distomolars were located almost equally in both left and right side. It was more possible lower left distomolars to be present in males than in females. Furthermore, males present higher prevalence of supernumerary teeth than females. CONCLUSIONS: Early radiographic diagnosis of distomolars is fundamental so as to prevent complications such malocclusion, delayed eruption or displacement root or/ and resorption of adjacent teeth, pulp necrosis, follicular cyst, pain. KEY WORDS: Non syndromic, distomolars, supernumerary molars, fourth molars. PMID- 26644835 TI - Effect of sodium ascorbate on the bond strength of all-in-one adhesive systems to NaOCl-treated dentin. AB - BACKGROUND: Ascorbic acid and its salts are low-toxicity products, which are routinely used in food industries as antioxidants. The aim of the present study was to evaluate the effect of 10% sodium ascorbate on the bond strength of two all-in-one adhesive systems to NaOCl-treated dentin. MATERIAL AND METHODS: After exposing the dentin on the facial surface of 90 sound human premolars and mounting in an acrylic resin mold, the exposed dentin surfaces were polished with 600-grit SiC paper under running water. Then the samples were randomly divided into 6 groups of 15. Groups 1 and 4 were the controls, in which no surface preparation was carried out. In groups 2 and 5 the dentin surfaces were treated with 5.25% NaOCl alone for 10 minutes and in groups 3 and 6 with 5.25% NaOCl for 10 minutes followed by 10% sodium ascorbate for 10 minutes. Then composite resin cylinders, measuring 2 mm in diameter and 2 mm in height, were bonded on the dentin surfaces in groups 1, 2 and 3 with Clearfil S3 Bond and in groups 4, 5 and 6 with Adper Easy One adhesive systems according to manufacturers' instructions. The samples were stored in distilled water for 24 hours at 37 degrees C and then thermocycled. Finally, the samples underwent shear bond strength test in a universal testing machine at a strain rate of 1 mm/min. Data were analyzed with two-way ANOVA and post hoc Tukey tests at alpha=0.05. RESULTS: The differences between groups 1 and 2 (P=0.01), 1 and 5 (P=0.003). 1 and 6 (P=0.03) and 4 and 5 (P=0.03) were statistically significant. Two-by-two comparisons did not reveal any significant difference between other groups (P>0.05). CONCLUSIONS: Use of 10% sodium ascorbate for 10 minutes restored the decreased bond strength of the adhesive systems to that of the control groups. KEY WORDS: Sodium ascorbate, adhesive systems, all-in-one, bond strength, sodium hypochlorite. PMID- 26644836 TI - Effect of resin thickness, and curing time on the micro-hardness of bulk-fill resin composites. AB - BACKGROUND: Bulk-fill resin composite has been introduced, their manufacturers claimed that they can be applied in bulks of 4mm, without necessitating a prolonged curing time, or a light curing unit with increased irradiance. Thus this study was conducted to evaluate the effect of resin thickness, and curing time on the micro-hardness of two bulk -fill resin composites; Tetric Evo-Ceram [TE], and X-trafil [XF]. MATERIAL AND METHODS: 120 cylindrical specimens were prepared, and divided into 24 groups (n=5/group), representing the two bulk-fill resin composites, three different material thicknesses (2, 3 and 4 mm) and the four curing times used in the study (10, 20, 40, and 60 seconds). The specimens were light-cured from the top surface only. Specimens were stored in light proof containers in complete darkness at 37 degrees C for 24 hours. Micro-hardness test was conducted on both top and bottom surfaces using Vickers micro-hardness tester with 500 g load and a dwell time of 15 seconds. Data were statistically analyzed by Four-way ANOVA of Variance. The significance level was set at P <= 0.05. Pearson Correlation used to determine significant correlations between mean micro hardness (top) and (bottom) surfaces. RESULTS: Four way-ANOVA shows that different tested materials produce a statistically significant effect on mean micro-hardness (VHN) at p<=0.001, while thickness, curing time, and surface revealed statistically non significant effect on mean micro-hardness (VHN) at p>=0.05. [XF] (92.01+/-3.15 VHN) showed statistically significant higher mean micro-hardness than [TE] (54.13+/-4.96 VHN). Pearson Correlation revealed that there was a significant direct correlation between micro-hardness (bottom) and mean micro-hardness (top) (mm), r = 0.985, p (2-tailed) <=0.001. CONCLUSIONS: Within the limitations of this study, the bulk-fill resin composites used in this study can be placed and cured properly in the 4 mm bulk. KEY WORDS: Bulk-fill resin composite, micro-hardness, thickness, curing time. PMID- 26644837 TI - Rapid prototyping modelling in oral and maxillofacial surgery: A two year retrospective study. AB - BACKGROUND: The use of rapid prototyping (RP) models in medicine to construct bony models is increasing. MATERIAL AND METHODS: The aim of the study was to evaluate retrospectively the indication for the use of RP models in oral and maxillofacial surgery at Helsinki University Central Hospital during 2009-2010. Also, the used computed tomography (CT) examination - multislice CT (MSCT) or cone beam CT (CBCT) - method was evaluated. RESULTS: In total 114 RP models were fabricated for 102 patients. The mean age of the patients at the time of the production of the model was 50.4 years. The indications for the modelling included malignant lesions (29%), secondary reconstruction (25%), prosthodontic treatment (22%), orthognathic surgery or asymmetry (13%), benign lesions (8%), and TMJ disorders (4%). MSCT examination was used in 92 and CBCT examination in 22 cases. Most of the models (75%) were conventional hard tissue models. Models with colored tumour or other structure(s) of interest were ordered in 24%. Two out of the 114 models were soft tissue models. CONCLUSIONS: The main benefit of the models was in treatment planning and in connection with the production of pre bent plates or custom made implants. The RP models both facilitate and improve treatment planning and intraoperative efficiency. KEY WORDS: Rapid prototyping, radiology, computed tomography, cone beam computed tomography. PMID- 26644838 TI - A critical assessment of oral care protocols for patients under radiation therapy in the regional University Hospital Network of Madrid (Spain). AB - BACKGROUND: This research was aimed to critically evaluate, under the light of the available scientific evidence, the oral care protocols recommended by different hospitals in head and neck cancer (HNC) patients under radiation therapy. MATERIAL AND METHODS: A questionnaire requesting all the relevant information for the oral care of these patients was sent to the 9 University Hospitals in Madrid. The answers were categorized and analyzed. In addition, an electronic search was conducted to identify the most relevant papers (systematic reviews [SR] and randomized clinical trials [RCTs]) assessing oral care protocols for patients treated for HNC with radiation therapy. RESULTS: Eight out of nine centers answered the questionnaire and the retrieved information was tabulated and compared. These recommendations were analyzed by a computerized search on MEDLINE and the Cochrane Oral Health Collaboration Database. The results of the analysis clearly shown a great heterogeneity, in terms of oral health care protocols, regarding the management of irradiated patients (for HNC) within the Hospitals of Madrid region. In addition, some of the recommendations lack solid scientific support. CONCLUSIONS: The present survey revealed that the recommendations provided by the different hospitals were clearly different. The available evidence, supported by SR and RCTs, suggested the need of an oral assessment before cancer treatment, in order to prevent and treat dental pathologies and avoiding potential complications; during cancer treatment, it is relevant monitoring the patient in order to decrease the severity of the side effects, and to avoid any tooth extraction or surgery and special attention should be paid to mucositis, xerostomia and candidiasis; after cancer treatment, the following are relevant aspects: the risk of osteoradionecrosis, trismus, caries and the risks associated to dental implants. KEY WORDS: Head and neck cancer, supportive care in cancer, radiotherapy complications, management and oral care on cancer treatment. PMID- 26644839 TI - Cytotoxicity of glass ionomer cements containing silver nanoparticles. AB - BACKGROUND: Some studies have investigated the possibility of incorporating silver nanoparticles (NAg) into dental materials to improve their antibacterial properties. However, the potential toxic effect of this material on pulp cells should be investigated in order to avoid additional damage to the pulp tissue. This study evaluated the cytotoxicity of conventional and resin-modified glass ionomer cements (GIC) with and without addition of NAg. MATERIAL AND METHODS: NAg were added to the materials at two different concentrations by weight: 0.1% and 0.2%. Specimens with standardized dimensions were prepared, immersed in 400 uL of culture medium and incubated at 37 degrees C and 5% CO2 for 48 h to prepare GIC liquid extracts, which were then incubated in contact with cells for 48 h. Culture medium and 0.78% NAg solution were used as negative and positive controls, respectively. Cell viability was determined by MTT and Trypan Blue assays. ANOVA and the Tukey test (alpha=0.05) were used for statistical analyses. RESULTS: Both tests revealed a significant decrease in cell viability in all groups of resin modified cements (p<0.001). There were no statistically significant differences between groups with and without NAg (p>0.05). The differences in cell viability between any group of conventional GIC and the negative control were not statistically significant (p>0.05). CONCLUSIONS: NAg did not affect the cytotoxicity of the GIC under evaluation. KEY WORDS: Glass ionomer cements, totoxicity, cell culture techniques, nanotechnology, metal nanoparticles. PMID- 26644840 TI - Effect of topical application of melatonin on serum levels of C-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) in patients with type 1 or type 2 diabetes and periodontal disease. AB - BACKGROUND: The present clinical trial study was designed to assess the effect of topical application of melatonin on serum levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and C-reactive protein (CRP) in patients with diabetes and periodontal disease in comparison with healthy controls. MATERIAL AND METHODS: Serum levels of TNF-alpha and IL-6 were measured by enzyme-linked immunosorbent assay and CRP by nephelometry by using the proper commercial kits in 30 patients with diabetes and periodontal disease, and also in a control group of 30 healthy subjects. Periodontograms were performed using the Florida Probe(r). Patients with diabetes were treated with a topical application of melatonin (1% orabase cream formula) once daily for 20 days. Healthy subjects were treated with a placebo orabase cream. RESULTS: Patients with diabetes and periodontal disease had significantly higher mean levels of serum TNF-alpha, IL-6 and CRP than healthy subjects (P < 0.001). Following topical melatonin application, there was a statistically significant decrease in the gingival index and pocket depth (P < 0.001) as well as a significant decrease in IL-6 and CRP serum levels (P < 0.001). Local melatonin application in patients with diabetes and periodontal disease resulted in a significant decrease in CRP and IL-6 serum levels as well as an improvement in the gingival index and pocket depth. Patients with periodontal disease had significantly higher serum CRP, IL-6 and TNF-alpha values by comparison with healthy subjects. CONCLUSIONS: We conclude that melatonin can modulate the inflammatory action of these molecules in periodontal patients. KEY WORDS: Melatonin, periodontal disease, diabetes mellitus, interleukin-6, tumor necrosis factor-alpha, C-reactive protein, inflammatory markers. PMID- 26644841 TI - Moxifloxacin versus Clindamycin/Ceftriaxone in the management of odontogenic maxillofacial infectious processes: A preliminary, intrahospital, controlled clinical trial. AB - BACKGROUND: The aim of this study was to compare the days of hospitalization length between patients treated with Moxifloxacin with that of patients treated with a Clindamycin/Ceftriaxone combination and additionally, to isolate and identify the oral pathogens involved in orofacial odontogenic infections. MATERIAL AND METHODS: A pilot-controlled-clinical-trial was carried out on hospitalized patients with cervicofacial odontogenic abscesses or cellulitis, who were randomly asigned to two study groups: 1) patients who received Moxifloxacin, and 2) patients receiving Clindamycin/Ceftriaxone combination. Infiltrate samples were collected through transdermic or transmucosal punction and later cultured on a media specific for aerobic and anaerobic microorganisms. Mean hospitalization duration in days until hospital discharge and susceptibility assessment in rates were established. RESULTS: Mean hospitalization time in days of patients treated with Moxifloxacin was 7.0 +/- 1.6 days, while in the Clindamycin/Ceftriaxone group, this was 8.4 +/- 1.8 days, although significant difference could not be demonstrated (p=0.074). A total of 43 strains were isolated, all of these Gram positive. These strains appeared to be highly sensitive to Moxifloxacin (97.5%) and Ceftriaxone (92.5%). CONCLUSIONS: Moxifloxacin and Ceftriaxone appear to be potential convenient and rational alternatives to traditional antibiotics, for treating severe odontogenic infections, in conjunction with surgical extraoral incision, debridement, and drainage. KEY WORDS: Orofacial odontogenic infections, antimicrobial susceptibility, antimicrobial resistance. PMID- 26644842 TI - Oral soft tissue biopsies in Oporto, Portugal: An eight year retrospective analysis. AB - BACKGROUND: The diseases that affect the oral cavity are wide and diverse, comprising a broad spectrum of either benign or malignant lesions. However, few histological-based studies were performed for the evaluation of oral cavity lesions, and very few directed to oral soft tissue pathology. The aim of this study was to carry out pioneering research, within a Portuguese population, to determine the frequency and characteristics of oral malignancies, potential malignant disorders, and soft benign tissues pathologies submitted for biopsy in a north Portugal (Oporto) hospital population. MATERIAL AND METHODS: We performed a retrospective study of soft tissue, oral cavity biopsies, in a hospital north of Portugal (Oporto) between 1999 and 2006. We analysed information on gender, age, location of the lesion, and the histopathological diagnosis. RESULTS: A total of 1042 oral biopsies were observed, 557(53.5%) in females and 485 (46.5%) in males, with a mean age of 51.7 years (S.D. +/-17.6). The topographic location most frequently affected was labial mucosa (n=306). Considering the nature of the lesions, 700 (67.2%) corresponded to non-neoplasic lesions, 45 (4.3%) to potentially malignant disorders, and 297 (28.5%) to neoplasms (93 benign and 204 malignant). Non-neoplasic lesions were more prevalent in female gender (59.9%) when compared with potentially malignant disorders (46.7%) and neoplasms (39.4%) (P< 0.001). Non-neoplasic lesions presented the lower mean age (49.2+/-17.6) and potentially malignant disorders the highest mean age (60.5+/-14.5) (P< 0.001). The most common lesion of entire sample was fibro-epithelial hyperplasia (n=186; 17.9%), followed by squamous cell carcinoma (n=158; 15.1%). CONCLUSIONS: Fibro epithelial hyperplasia, followed by squamous cell carcinoma, was the most common pathologies. This pioneering study provided, for the first time, data about the proportion of squamous cell carcinoma when compared with benign conditions in a Portuguese hospital population. KEY WORDS: Oral biopsies, oral cavity, oral pathology, Portugal, soft tissue lesions. PMID- 26644843 TI - Assessment of oral hygiene habits, oral hygiene practices and tooth wear among fertilizer factory workers of Northern India: A Cross sectional study. AB - BACKGROUND: The association between oral hygiene habits & practices and severity of tooth wear lesion varies from community to community and also from occupation to occupation. The present study was conducted with to assess oral hygiene habits & practices and tooth wear among fertilizer factory workers of Punjab, India. MATERIAL AND METHODS: A descriptive cross sectional survey was conducted among 965 male workers who were aged between 19-58 years, who were the workers of fertilizers factory of Bathinda, India. An interview on the demographic profile, oral hygiene practices, and adverse habits followed a clinical examination for recording the Tooth Wear (Smith and Knight Index 1984) using Type III examination. The Chi-square test and a Stepwise multiple linear regression analysis were used for the statistical analysis. Confidence interval and p-value set at 95% and <= 0.05 respectively. RESULTS: In the present study majority (47.2%) of the study population used chew sticks for cleaning their teeth. Overall prevalence of adverse habits was reported (92.4%). Study population showed higher prevalence of tooth wear (77.1%). Best predictors identified for Tooth Wear were oral hygiene practices, adverse habits, years of work experience and age respectively. CONCLUSIONS: Considerable percentages of fertilizer factory workers have demonstrated a higher prevalence of tooth surface loss. This may be useful in designing the investigations that aim to further explore the causes for these findings and more importantly to plan oral health promotion program implementing both preventive and curative strategies. KEY WORDS: Tooth wear, smith & knight index, fertilizer factory. PMID- 26644844 TI - Inmunohistochemical detection of mastocytes in tissue from patients with actinic prurigo. AB - BACKGROUND: Actinic prurigo (AP) is a type of photodermatosis, the pathophysiology of which has not been determined. AP has been suggested to be a hypersensitivity reaction to the presence of eosinophils and the local production of IgE. MATERIAL AND METHODS: Descriptive study, using paraffin blocks of tissue that have been diagnosed with AP from the Dermopathology department, Hospital General Dr. Manuel Gea Gonzalez. In 66 blocks from 63 patients, eosinophils were identified by hematoxylin and eosin staining, and mastocytes were labeled by immunohistochemistry. Three random microphotographs (40x) were used, and cell counts were calculated as the mean count in the 3 microphotographs. RESULTS: Forty cases (63.5%) were female, and 23 (36.5%) were male. The mean age was 26.49 +/-14.09 years; regarding the evolution time of the disease, the average was 11.93 years +/-11.39. In 38 of 63 cases (60%), the lip, skin, and conjunctiva were affected clinically. In 22 of 63 cases (34%), AP cheilitis was the sole manifestation, and in 4 of 63 cases (6%), there were lesions in the skin and conjunctiva. The mean eosinophil count was 9 per case, the average number of mastocytes/field was 28.48 (range 0 to 66) Kruskal-Wallis p=0.001. CONCLUSIONS: There are elements in AP that mediate the reaction of hypersensitivity type IV b, necessitating the identification of triggering factors. KEY WORDS: Actinic prurigo, eosinophil, hypersensitivity IV b, IgE, mastocytes. PMID- 26644845 TI - Synchronous metastatic cutaneous squamous cell carcinoma and chronic lymphocytic leukaemia/small lymphocytic lymphoma in a cervical lymph node: Case report of an unusual event. AB - The synchronous occurrence of two different neoplasias is an uncommon event, which may arise between tumors originating in the same organ or in cancer-to cancer metastasis. We report a rare case of chronic lymphocytic leukaemia / small lymphocytic lymphoma associated with a cutaneous metastatic squamous cell carcinoma in a cervical lymph node. In the affected lymph node, it was observed an effacement of the normal architecture by neoplastic lymphocytes and it was noted the presence of neoplastic invasive epithelial islands. Immunohistochemical analysis demonstrated that lymphocytic proliferation was positive for CD20, CD5, CD23 and Kappa, and negative for CD3, CD10, Cyclin D1 and Lambda. The morphological and immunohistochemical profile lead to a phenotype of B-cell chronic lymphocytic leukaemia / small lymphocytic lymphoma. The epithelial cells were positive for CK5, thus rendering the diagnosis of synchronous metastatic cutaneous squamous cell carcinoma and chronic lymphocytic leukaemia/small lymphocytic lymphoma. Literature supports the poor prognosis in cases that present coexistence of squamous cell carcinoma and chronic lymphocytic leukaemia / small lymphocytic lymphoma. Thus, it is necessary to be aware about this unusual finding in order to provide specific treatment. KEY WORDS: Chronic lymphocytic leukaemia, small lymphocytic lymphoma, squamous cell carcinoma, metastasis. PMID- 26644846 TI - Primary intraosseous squamous cell carcinoma arising in dentigerous cyst: Report of 2 cases and review of the literature. AB - Dentigerous cysts are one of the most common odontogenic cysts of the oral cavity. Odontogenic cysts can give rise to a variety of neoplasms. Carcinoma arising in a dentigerous cyst is extremely rare, with a review of literature showing near 30 cases. The present report describes 2 cases of primary intraosseous squamous cell carcinoma originated from a dentigerous cyst. The first one refers to a 57-year old female with a persistent lesion in the left retromolarregion and diagnosed with squamous cell carcinoma originated fromthe incomplete excision of the lower third molar follicle during its surgical extraction. The second case describes the case of an 18-year old male with an impacted upper canine with previous history of infection and swelling of the oral cavity. The histopathological study revealed the malignization of the follicle surrounding the dental crown. These two cases confirmed the importance of the histopathological study of all the tissue samples obtained from surgical procedures. Although the development of a malignant lesion from a dentigerous cyst is rare and its clinical-radiological features are apparently innocuous, this entity should be considered as a differential diagnosis. KEY WORDS: Dentigerous cyst, odontogenic cyst, squamous cell carcinoma, primary intraosseous squamous cell carcinoma, odontogenic carcinoma. PMID- 26644847 TI - Conservative management of dentigerous cysts in children. AB - PURPOSE AND INTRODUCTION: Dentigerous cysts are epithelial in origin and are the most commonly found cyst in children. The majority of these lesions are usually a radiological finding and are capable of quite large before being diagnosed. The standard treatment for these cysts is the enucleation and the extraction of the affected tooth. However, if the patient is a child and the affected tooth is not developed, a more conservative attitude should be considered. MATERIAL AND METHODS: (Clinical case): A 7-year-old patient is presented with an eruptive backlog of the lower permanent first molars. Radiological examination reveals two radiolucid lesions in relation to them, which are compatible with a dentigerous cyst, and in relation to the inferior aveolar nerve and various germs. A partial enucleation is carried out, maintaining all the dental germs related to the cyst in mouth and monitoring the patient until the case study is over. RESULTS AND DISCUSSION: Diagnosis and early treatment of these lesions in children is of great importance, especially in cases where the lesions enclose permanent teeth. CONCLUSIONS: Whenever possible, a conservative attitude should be taken, one that allows for the maintenance of the dentition and treatment of the associated cyst in order to not compromise either the occlusion or the mental state of these patients. KEY WORDS: Dentigerous cyst, conservative treatment, dental impaction, child. PMID- 26644848 TI - The Role of Arginine-Phenylalanine-Amide-Related Peptides in Mammalian Reproduction. AB - Until 2000 it was believed that gonadotropin-releasing hormone (GnRH) was the sole regulator of hypophyseal gonadotropes. In 2000, the discovery of a gonadotropin inhibitory hormone (GnIH) initiated a revolution in the field of reproductive physiology. Identification of GnIH homologues in mammals, the arginine-phenylalanine-amide (RFamide)-related peptides (RFRPs), indicated a similar function. Subsequently, further works conducted in various laboratories worldwide have shown that these neuropeptides inhibit the hypothalamic hypophyseal axis. This review discusses the role of RFRPs in mammalian reproductive processes. PMID- 26644849 TI - In Vitro Fertilization, Levels of Pro-Inflammatory Factors and Lipid Peroxidation. AB - BACKGROUND: Infertility is a problem concerning 10-15% of the individuals in the fertile period. This study investigated effects of proinflammatory factors as well as lipid hydroperoxides (LPO) levels upon in vitro fertilization (IVF) success. MATERIALS AND METHODS: In this prospective, non-randomized, controlled clinical study, sera obtained from 26 fertile (group-1), 26 infertile women before (group-2) and after (group-3) IVF treatment were analyzed. Leptin, leptin receptor, resistin, tumor necrosis factor-alpha (TNF-alpha), and C-reactive protein (CRP) were analyzed using enzyme-linked immunosorbent assay (ELISA). LPO was determined spectrophotometrically. Mann- Whitney U test, paired samples t test, Wilcoxon signed-rank test as well as Pearson correlation analysis by SPSS were performed for statistical analysis. RESULTS: TNF-alpha, resistin and LPO levels increased (P=0.020, P=0.003, P=0.001, respectively) in group-3 compared to group-2. A significant increase in LPO was noted both in group-2 and -3 compared to controls (P=0.000). LPO were higher in non-pregnants than pregnants in group 2. For pregnants, significant correlations were observed between leptin and resistin in group-2 and TNF-alpha and leptin in group-3. None of these correlations were found for the women, who could not conceive. CONCLUSION: LPO, leptin-resistin correlation, associations with TNF-alpha may be helpful during the interpretation of IVF success rates. PMID- 26644851 TI - Increasing The Number of Embryos Transferred from Two to Three, Does not Increase Pregnancy Rates in Good Prognosis Patients. AB - BACKGROUND: To compare the pregnancy outcomes after two embryos versus three embryos transfers (ETs) in women undergoing in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycles. MATERIALS AND METHODS: This retrospective study was performed on three hundred eighty seven women with primary infertility and with at least one fresh embryo in good quality in order to transfer at each IVF/ICSI cycle, from September 2006 to June 2010. Patients were categorized into two groups according to the number of ET as follows: ET2 and ET3 groups, indicating two and three embryos were respectively transferred. Pregnancy outcomes were compared between ET2 and ET3 groups. Chi square and student t tests were used for data analysis. RESULTS: Clinical pregnancy and live birth rates were similar between two groups. The rates of multiple pregnancies were 27 and 45.2% in ET2 and ET3 groups, respectively. The rate of multiple pregnancies in young women was significantly increased when triple instead of double embryos were transferred. Logistic regression analysis indicated two significant prognostic variables for live birth that included number and quality of transferred embryos; it means that the chance of live birth following ICSI treatment increased 3.2-fold when the embryo with top quality (grade A) was transferred, but the number of ET had an inverse relationship with live birth rate; it means that probability of live birth in women with transfer of two embryos was three times greater than those who had three ET. CONCLUSION: Due to the difficulty of implementation of the elective single-ET technique in some infertility centers in the world, we suggest transfer of double instead of triple embryos when at least one good quality embryo is available for transfer in women aged 39 years or younger. However, to reduce the rate of multiple pregnancies, it is recommended to consider the elective single ET strategy. PMID- 26644850 TI - Comparison of The Effectiveness of Clomiphene Citrate versus Letrozole in Mild IVF in Poor Prognosis Subfertile Women with Failed IVF Cycles. AB - BACKGROUND: Our objective was to evaluate the effectiveness of clomiphene citrate (CC) vs. letrozole (L) plus human menopausal gonadotropin (hMG) in gonadotropin releasing hormone (GnRH) antagonist protocol in poor prognosis women with previous failed ovarian stimulation undergoing intracytoplasmic sperm injection (ICSI). MATERIALS AND METHODS: This retrospective cohort study included cycles with CC and L plus hMG/GnRH antagonist protocols of 32 poor responders who had failed to have ideal follicles to be retrieved during oocyte pick-up (OPU) or embryo transfer (ET) at least for 2 previous in vitro fertilization (IVF) cycles with microdose flare protocol or GnRH antagonist protocol from January 2006 to December 2009. Main outcome measures were implantation, clinical pregnancy and live birth rates per cycle. Duration of stimulation, mean gonadotropin dose used, endometrial thickness, number of mature follicles, serum estradiol (E2) and progesterone (P) levels on the day of human chorionic gonadotropin (hCG) administration, number of retrieved oocytes and fertilization rates were also evaluated. RESULTS: A total number of 42 cycles of 32 severe poor responders were evaluated. Total gonadotropin consumption was significantly lower (1491 +/- 873 vs. 2808 +/- 1581 IU, P=0.005) and mean E2 level on the day of hCG injection were significantly higher in CC group than L group (443.3 +/- 255.2 vs. 255.4 +/- 285.2 pg/mL, P=0.03). ET, overall pregnancy and live birth rates per cycle were significantly higher in CC than L protocol (27.2 vs. 15%, 13.6 vs. 0% and 4.5 vs. 0%, respectively, P<0.05). CONCLUSION: Severe poor responders who had previously failed to respond to microdose or GnRH antagonist protocols may benefit from CC plus hMG/GnRH antagonist protocol despite high cancellation rate. PMID- 26644852 TI - Evaluating The Effective Factors in Pregnancy after Intrauterine Insemination: A Retrospective Study. AB - BACKGROUND: Controlled ovarian hyperstimulation (COH) in conjunction with intrauterine inseminations (IUI) are commonly used to treat infertile couples. In this study we evaluated the relationship between IUI outcome and special causes of infertility. We also aimed to examine parameters that might predict success following IUI. MATERIALS AND METHODS: In this cross-sectional study, we included 994 IUI cycles in 803 couples who referred to the infertility Institute. All statistical analyses were performed by using SPSS program, t tests and chi square. Stepwise multiple linear regression analysis was performed to compare the association between dependent and independent variables. Logistic regression was conducted to build a prediction model of the IUI outcome. RESULTS: Overall pregnancy rate per completed cycle (16.5%) and live birth rate per cycle (14.5%). The mean age in the pregnant group was significantly lower than that of the non pregnant group (P=0.01).There was an association between cause of infertility and clinical pregnancies (P<0.001). Logistic regression identified four significant factors in determining the success of the IUI [menstrual irregularites (OR:2.3, CI:1.6-3.4, P<0.001), duration of infertility (OR:0.8, CI:0.8-0.9, P<0.001), total dose of gonadotropin (OR:1.02, CI:1.003-1.04, P=0.02) and semen volume (OR:1.1, CI:1.008-1.2, P=0.03)] which were the most predictive of IUI success. CONCLUSION: Our study defined prognostic factors for pregnancy in COH+IUI. These variables can be integrated into a mathematical model to predict the chance of pregnancy rate in subsequent COH+IUI cycles. PMID- 26644853 TI - Evaluation of Some Plasma Coagulation Factors in Women with Spontaneous Miscarriage. AB - BACKGROUND: It has been reported that 15-20% of parous female have experienced at least one miscarriage, while 3% of them have experienced two miscarriages. The goal of this study was to evaluate the plasma level of coagulation factors in women with a history of spontaneous abortions. MATERIALS AND METHODS: In this case-control study, 82 women with a history of two or more abortions referred to the six private gynecologic clinics in Gorgan city without any structural abnormality were recruited during 2011-2012. Plasma levels of antithrombin III (ATIII) using colorimetric assay, protein C, protein S, factor V Leiden and lupus anticoagulant (LAC) using coagulation method were measured. The control group was women with a history of normal delivery and no abortions. Those under anti coagulant therapy were excluded from the study. Data were entered into the computer using the Statistical Package for the Social Sciences (SPSS, SPSS Inc., Chicago, IL, USA) version 16 and analyzed by Chi-square, t test and non parametric tests. RESULTS: At least one abnormality was reported in 35 cases (42.7%). Among them, protein C deficiency was the most prevalent (30.5%). ATIII was abnormal in 17.1% and lupus anti-coagulant was abnormal in 8.5%. Factor V Leiden was normal in all cases and protein S deficiency was only seen in one case. CONCLUSION: We suggest to perform these tests in regards to the thrombophilia in cases with spontaneous abortions in order to find an early cure for this treatable disorder. PMID- 26644854 TI - Relationship between Serum Leptin, Ghrelin and Dietary Macronutrients in Women with Polycystic Ovary Syndrome. AB - BACKGROUND: Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women. It may involve an impairment in physiologic regulation of leptin and ghrelin. There is limited, controversial data on the relation of dietary components with leptin and ghrelin in PCOS, so the current study has been conducted to explore the effects of different macronutrients on serum levels of leptin and ghrelin in PCOS and healthy subjects. MATERIALS AND METHODS: In this case-control study, we randomly choose 30 PCOS pa- tients and 30 healthy age and body mass index (BMI) matched controls. Intake of macronutrients [protein, total fat, saturated, monounsaturated and polyunsaturated fatty acids (PUFA), carbohydrate, dietary fiber] and energy were assessed using 3-day, 24-hour food recall and food frequency questionnaires (FFQ). Fasting hormonal status was measured for each participant. RESULTS: PCOS women had higher levels of serum leptin, insulin, testosterone, and luteinizing hormone (LH), whereas sex hormone binding globulin (SHBG) was lower compared to healthy women. There was no significant difference in mean ghrelin concentrations between the groups. Among PCOS women, independent of BMI and total energy intake, we observed an inverse association between leptin concentration and total dietary fat (beta=-0.16, P<0.05) and saturated fatty acid (SFA) intake (beta=-0.58, P<0.05). This relationship was not seen in the healthy subjects. There was no significant association between ghrelin and macronutrients in PCOS and healthy participants. CONCLUSION: Certain habitual dietary components such as fat and SFA may decrease serum leptin, whereas ghrelin is not influenced by these in PCOS women. More studies are needed to better clarify the effects of dietary macronutrients on serum leptin and ghrelin. PMID- 26644855 TI - Flow Cytometric DNA Analysis and Histopathologic Re-Evaluation of Paraffin Embedded Samples from Hydatidiform Moles and Hydropic Abortions. AB - BACKGROUND: Distinction of hydatidiform moles (HMs) from non-molar abortions and sub-classification of HMs are important for clinical practice; yet, diagnosis based solely on morphology is affected by interobserver variability. The objective of this study was to determine the role of DNA flow cytometry in distinguishing molar from non-molar pregnancies. MATERIALS AND METHODS: This retrospective study was conducted at the Department of Pathology, Women's Hospital, Tehran University of Medical Sciences, Tehran, Iran, between 2006 and 2010. DNA ploidy analysis and histopathologic re-evaluation were performed on paraffin-embedded tissue from 36 (17 complete and 19 partial) molar and 24 hydropic abortus (HA) cases which were previously diagnosed based on histomorphologic study. RESULTS: Of the 17 cases initially diagnosed as complete HM (CHM), 9 were diploid, 2 were triploid, 5 were tetraploid and 1 was aneuploid. Of the 19 initial partial HMs (PHMs), 2, 8, 1 and 8 cases were diploid, triploid, tetraploid and aneuploid, respectively. In the initial HA category (n=24), 14 diploid, 1 triploid, 5 tetraploid, and 4 aneuploid cases existed. Following flow cytometry and histopathologic reevaluation, 1 case with previous diagnosis of HA was reclassified as PHM, 2 initial PHMs were reclassified as CHM and 2 initial CHMs were categorized as PHM. CONCLUSION: The results show that correct diagnosis of PMH is the main challenge in histological diagnosis of gestational trophoblastic disease (GTD). DNA flow cytometric analysis could be an informative supplement to the histological interpretation of molar and hydropic placentas. PMID- 26644856 TI - Evaluation of Tumor Necrosis Factor Alpha Polymorphism Frequencies in Endometriosis. AB - BACKGROUND: The pro-inflammatory cytokine, tumor necrosis factor-alpha (TNF alpha), is a pathogenic element for a number of disorders. Previous studies have reported that the -1031 T/C and -238 G/A polymorphisms in the promoter region of the TNF-alpha gene are important factors in reproductive-related disorders. One of the most common gynecological diseases of women during the reproductive years is endometriosis. This study aims to assess an association between the -1031 T/C, -238 G/A and -308 G/A polymorphisms of the TNF-alpha gene promoter region to endometriosis. MATERIALS AND METHODS: In this case-control study, we enrolled 65 endometriosis patients and 65 matched healthy control women by simple sampling. Polymerase chain reaction (PCR) analysis was used to analyze -1031 T/C, -238 G/A and -308 G/A polymorphisms in the TNF-alpha gene promoter region. Statistical analysis was performed using the chi-square test. P values less than 0.05 were considered statistically significant. RESULTS: We found a strong association between the -1031 T/C polymorphism in the promoter region of the TNF-alpha gene with endometriosis (P=0.001). There were no significant associations between the 238 G/A (P=0.243) and -308 G/A (P=1) polymorphisms with endometriosis and again endometriosis stages have no association with these polymorphisms. CONCLUSION: The -1031 T/C polymorphism and CC genotype can be used as a relevant marker to identify women at risk of developing endometriosis. PMID- 26644857 TI - Comparison of Protamine 1 to Protamine 2 mRNA Ratio and YBX2 gene mRNA Content in Testicular Tissue of Fertile and Azoospermic Men. AB - BACKGROUND: Although aberrant protamine (PRM) ratios have been observed in infertile men, the mechanisms that implicit the uncoupling of PRM1 and PRM2 expression remain unclear. To uncover these mechanisms, in this observational study we have compared the PRM1/PRM2 mRNA ratio and mRNA contents of two regulatory factors of these genes. MATERIALS AND METHODS: In this experimental study, sampling was performed by a multi-step method from 50 non-obstructive azoospermic and 12 normal men. After RNA extraction and cDNA synthesis, real-time quantitative polymerase chain reaction (RT- QPCR) was used to analyze the PRM1, PRM2, Y box binding protein 2 (YBX2) and JmjC-containing histone demethylase 2a (JHDM2A) genes in testicular biopsies of the studied samples. RESULTS: The PRM1/PRM2 mRNA ratio differed significantly among studied groups, namely 0.21 +/- 0.13 in azoospermic samples and -0.8 +/- 0.22 in fertile samples. The amount of PRM2 mRNA, significantly reduced in azoospermic patients. Azoospermic men exhibited significant under expression of YBX2 gene compared to controls (P<0.001). mRNA content of this gene showed a positive correlation with PRM mRNA ratio (R=0.6, P=0.007). JHDM2A gene expression ratio did not show any significant difference between the studied groups (P=0.3). We also observed no correlation between JHDM2A mRNA content and the PRM mRNA ratio (R=0.2, P=0.3). CONCLUSION: We found significant correlation between the aberrant PRM ratio (PRM2 under expression) and lower YBX2 mRNA content in testicular biopsies of azoospermic men compared to controls, which suggested that downregulation of the YBX2 gene might be involved in PRM2 under expression. These molecules could be useful biomarkers for predicting male infertility. PMID- 26644858 TI - Chromosomal Aneuploidies and Early Embryonic Developmental Arrest. AB - BACKGROUND: Selecting the best embryo for transfer, with the highest chance of achieving a vital pregnancy, is a major goal in current in vitro fertilization (IVF) technology. The high rate of embryonic developmental arrest during IVF treatment is one of the limitations in achieving this goal. Chromosomal abnormalities are possibly linked with chromosomal arrest and selection against abnormal fertilization products. The objective of this study was to evaluate the frequency and type of chromosomal abnormalities in preimplantation embryos with developmental arrest. MATERIALS AND METHODS: This cohort study included blastomeres of embryos with early developmental arrest that were biopsied and analyzed by fluorescence in-situ hybridization (FISH) with probes for chromosomes 13, 16, 18, 21 and 22. Forty-five couples undergoing IVF treatment were included, and 119 arrested embryos were biopsied. All probes were obtained from the Kinderwunsch Zentrum, Linz, Austria, between August 2009 and August 2011. RESULTS: Of these embryos, 31.6% were normal for all chromosomes tested, and 68.4% were abnormal. Eleven embryos were uniformly aneuploid, 20 were polyploid, 3 were haploid, 11 displayed mosaicism and 22 embryos exhibited chaotic chromosomal complement. CONCLUSION: Nearly 70% of arrested embryos exhibit chromosomal errors, making chromosomal abnormalities a major cause of embryonic arrest and may be a further explanation for the high developmental failure rates during culture of the embryos in the IVF setting. PMID- 26644859 TI - Follicle Development of Xenotransplanted Sheep Ovarian Tissue into Male and Female Immunodeficient Rats. AB - BACKGROUND: This study aimed to assess follicle survival after xenotransplantation of sheep ovarian tissue into male and female immunodeficient rats. We evaluated the effects of gonadotropin treatment on follicular development in the transplanted tissue. MATERIALS AND METHODS: In this experimental study, sheep ovarian cortical strips were transplanted into the neck back muscles of 8 male and 8 female immunodeficient, castrated rats. Fourteen days after surgery, each rat was treated with human menopausal gonadotropin (hMG) for 9 weeks. One day after the last injection, ovarian tissues were removed and fixed for histology assessment. Histology analyses were performed before and after grafting. Estradiol (E2) levels were measured before and after gonadectomy, and at the end of the experiment. The control group consisted of 7 male and 7 female noncastrated/non-grafted rats and the sham group comprised 7 male and 7 female castrated/ non-grafted rats for comparison of serum E2 concentrations. RESULTS: The percentage of primordial follicles decreased after transplantation in male (25.97%) and female (24.14%) rats compared to the control group (ovarian tissue nongrafted; 37.51%). Preantral follicles increased in the male (19.5%) and female (19.49%) transplanted rats compared to the control group (11.4%). Differences in antral follicles between male (0.06 +/- 0.0%) and female (0.06 +/- 0.0%) rats were not noticeable compared to control (1.25 +/- 0.0%) rats. We observed a significantly higher percent of mean E2 secretion in grafted males compared to grafted females (P?0.05). CONCLUSION: Despite significant differences in E2 secretion between xenografted male and female rats, we observed no statistical differences in terms of follicular development. PMID- 26644860 TI - Activation and Inhibition of The Wnt3A Signaling Pathway in Buffalo (Bubalus bubalis) Embryonic Stem Cells: Effects of WNT3A, Bio and Dkk1. AB - BACKGROUND: This research studies the effects of activation and inhibition of Wnt3A signaling pathway in buffalo (Bubalus bubalis) embryonic stem (ES) cell like cells. MATERIALS AND METHODS: To carry on this experimental study, the effects of activation and inhibition of Wnt3A signaling in buffalo ES cell-like cells were examined using Bio (0.5 mM) combined with WNT3A (200 ng/ml), as an activator, and Dickkopf-1 (Dkk1, 250 ng/ml), as an inhibitor, of the pathway. ES cells were cultured up to three weeks in ES cell medium without fibroblast growth factor-2 (FGF-2) and leukemia inhibitory factor (LIF), but in the presence of Bio, WNT3A, Bio+WNT3A and Dkk1. The effects of these supplements were measured on the mean area of ES cell colonies and on the expression levels of a number of important genes related to pluripotency (Oct4, Nanog, Sox2 and c-Myc) and the Wnt pathway (beta-catenin). ES cell colonies cultured in ES cell medium that contained optimized quantities of LIF and FGF-2 were used as the control. Data were collected for week-1 and week-3 treated cultures. In addition, WNT3A transfected ES cells were compared with the respective mock-transfected colonies, either alone or in combination with Dkk1 for expression of beta-catenin and the pluripotency-related genes. Data were analyzed by ANOVA, and statistical significance was accepted at P<0.05. RESULTS: Among various examined concentrations of Bio (0.5-5 mM), the optimum effect was observed at the 0.5 mM dose as indicated by colony area and expressions of pluripotency-related genes at both weeks-1 and -3 culture periods. At this concentration,the expressions of Nanog, Oct3/4, Sox2, c-Myc and beta-catenin genes were nonsignificantly higher compared to the controls. Expressions of these genes were highest in the Bio+WNT3A treated group, followed by the WNT3A and Bio-supplemented groups, and lowest in the Dkk1-treated group. The WNT-transfected colonies showed higher expressions compared to both mock and Dkk1-treated mock transfected colonies. CONCLUSION: WNT3A functions to maintain the pluripotency of ES cell-like cells both as an exogenous growth factor as well as an endogenously expressed gene. It complements the absence of FGF-2 and LIF, otherwise propounded essential for buffalo ES cell culture. WNT3A antagonizes the inhibitory effects of Dkk1 and acts in combination with its activator, Bio, to activate the Wnt signaling pathway. PMID- 26644861 TI - The Effects of Chlorpromazine on Reproductive System and Function in Female Rats. AB - BACKGROUND: Chlorpromazine (CPZ), an antipsychotic drug, is associated with increased risk of sexual dysfunction through increasing prolactin levels. The current study evaluates the effect of CPZ-induced hyperprolactinemia on ovarian follicular growth, gonadotropins, and alteration of ovarian source hormones. MATERIALS AND METHODS: In this experimental study, animals were divided into four groups, control and CPZ (n=8 per group). In the treated groups, CPZ was administered by gavage at doses of 3, 10 and 30 mg/kg per day for 28 days. On day 29 the animals were killed after which histopathological and histomorphometric analyses of the ovaries were performed. We evaluated the levels of prolactin serum, luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol (E2) and progesterone. RESULTS: The ovaries of the test groups showed numerous atretic follicles of various sizes. CPZ caused a significant difference between the test groups and the control group (P<0.05) on the amount of atresia and the size of the normal corpora lutea (CL). The increased dysfunction of the ovaries from the different groups depended on the amount of CPZ administered. The serum concentrations of prolactin and progesterone significantly increased (P<0.05), while the serum concentrations of estradiol, LH and FSH notably decreased (P<0.05), depending on the CPZ dose. CPZ-induced animals had unsuccessful mating and decreased pregnancy rate. CONCLUSION: The present findings suggest that CPZ induced disturbances not only depend on prolactin level but the increased prolactin level is largely dose-dependent. PMID- 26644862 TI - Increased Litter Size and Suckling Intensity Stimulate mRNA of RFamide-related Peptide in Rats. AB - BACKGROUND: RFamide-related peptide-3 (RFRP-3) inhibits gonadotropin releasing hormone (GnRH) and luteinizing hormone (LH) secretion in rats. This study evaluates the effects of litter size and suckling intensity on RFRP mRNA expression in the dorsomedial hypothalamic nucleus (DMH) of rats. MATERIALS AND METHODS: A total of 32 pregnant and 4 non-lactating ovariectomized (control group) Sprague-Dawley rats were used in this experimental study. Lactating rats were allotted to 8 equal groups. In 3 groups, the litter size was adjusted to 5, 10, or 15 pups upon parturition. Dams were allowed to suckle their pups continuously until 8 days postpartum. In the other 3 groups, the litter size was adjusted to 5 pups following birth. These pups were separated from the dams for 6 hours on day 8 postpartum, after which the pups were allowed to suckle for 2.5, 5, or 7.5 minutes prior to killing the dams. In 2 groups, lactating rats with 10 and 15 pups were separated from their pups for 6 hours on day 8 postpartum. In these groups, the pups were allowed to suckle their dams for 5 minutes before the dams were killed. All rats were killed on day 8 postpartum and the DMH was removed from each rat. We evaluated RFRP mRNA expression using realtime polymerase chain reaction (PCR). RESULTS: The expression of RFRP mRNA in the DMH increased with increased litter size and suckling intensity compared to the controls. The effect of suckling intensity on the expression of RFRP mRNA was more pronounced compared to the litter size. CONCLUSION: Increased litter size and suckling intensity stimulated RFRP mRNA expression in the DMH which might contribute to lactation anestrus in rats. PMID- 26644863 TI - Development of A Questionnaire to Measure Attitude toward Oocyte Donation. AB - BACKGROUND: To our knowledge, there is no valid and comprehensive questionnaire that considers attitude toward oocyte donation (OD). Therefore this study has aimed to design and develop a tool entitled attitude toward donation-oocyte (ATOD O) to measure attitude toward OD. MATERIALS AND METHODS: This methodological, qualitative research was undertaken on 15 infertile cases. In addition, we performed a literature review and search of various databases. Validity of this questionnaire was conducted by knowledgeable experts who determined indices such as relevancy, clarity, and comprehensiveness. Reliability of the questionnaire was assessed based on the opinions of experts and infertile couples referred to Royan Institute. RESULTS: ATOD-O was designed in 52 statements that covered various issues such as the OD process, donor and recipient characteristics, as well as family, emotional, psychological, legal, religious, and socio-economic dimensions. Results were scored as five points: 1 (strongly disagree), 2 (disagree), 3 (somewhat), 4 (agree), and 5 (strongly agree). The overall relevancy of the questionnaire was 97% and clarity was 96%. Overall comprehensiveness was 100%. CONCLUSION: The findings from this preliminary validation study have indicated that ATOD-O is a valid measure for measuring and assessing attitude toward donated oocytes. This questionnaire can be used in studies regarding different groups of a society. PMID- 26644864 TI - The Effectiveness of Emotionally Focused Couples Therapy on Sexual Satisfaction and Marital Adjustment of Infertile Couples with Marital Conflicts. AB - BACKGROUND: The purpose of this investigation is to determine the efficacy of emotionally focused couples therapy (EFT-C) on enhancement of marital adjustment in infertile couples. MATERIALS AND METHODS: This was a semi-experimental study with a pre- and post-test design. We selected 30 infertile couples (60 subjects) by purposive sampling. Couples were randomly assigned to two groups, sample and control. Each group consisted of 15 couples who had marital maladjustment and low sexual satisfaction. Couples answered the marital adjustment and sexual satisfaction questionnaires at baseline after which the sample group received 10 sessions of EFT-C. RESULTS: Results of pre-test and post-test showed that EFT-C significantly impacted marital adjustment and sexual satisfaction. CONCLUSION: EFT-C had a significant effect on enhancement of satisfaction, cohesion and affectional expression. This approach impacted physical and emotional sexual satisfaction of infertile couples. PMID- 26644865 TI - The Lineage of Children Born by Sperm Donation: A Shiite Perspective. AB - BACKGROUND: Despite the meager role of the masculine agent in infertility (the low number of infertile men than women infertile), there are men whose wives are unable to become pregnant due to the absence of sperm, decreased numbers of sperm or lack of sufficient motile sperm. Utilizing donated sperm is a method that enables these families to have children. The use of this method prompts us to ask different questions, among which is the quality of the child's relation to the sperm donor, the sterile man and his wife. In this research we intend to study the issue of lineage of those who use heterogeneous insemination. MATERIALS AND METHODS: This analytical-descriptive research gathered relevant data in a Literature search. After a description of the fundamentals and definitions, juridical texts were subsequently analyzed and one of the viewpoints regarding lineage related to infertility treatment by donated sperm was selected. RESULTS: There are three persons that have a possible legal relationship to the child born from this method -the sperm donor (biological father), the wife's husband (social father) and the wife (mother). In treating infertility with donated sperm, there is neither a third party to make the possibility of attribution of the child nor is there a doubt that the child is the result of insemination of the woman's egg with the donated sperm rather than the husband's sperm as he has a lack of sperm. CONCLUSION: The child born by heterogeneous insemination only has a relation with the sperm donor and the woman contributing her egg. This child is eligible for all parental rights and obligations. These children are not related to the sterile man. PMID- 26644866 TI - Molecular detection of metallo-beta-lactamase genes, bla IMP-1, bla VIM-2 and bla SPM-1 in imipenem resistant Pseudomonas aeruginosa isolated from clinical specimens in teaching hospitals of Ahvaz, Iran. AB - BACKGROUND AND OBJECTIVES: Carbapenem resistant Pseudomonas aeruginosa is a serious cause of nosocomial infections. The main purpose of the study is to determine the prevalence rate of imipenem resistant Pseudomonas aeruginosa carrying metallo-beta-lactamase (MBL) genes. MATERIAL AND METHODS: 236 Pseudomonas aeruginosa isolates were collected from teaching hospitals of Ahvaz University of Medical Sciences during a period of 9 months in 2012. These strains were identified using conventional microbiological tests. The susceptibility of isolates to antibiotics were assessed using disk diffusion test. The IMP-EDTA combination disk phenotypic test was performed for detection of MBL producing strains. Finally, polymerase chain reaction (PCR) was performed to detect MBL genes, bla IMP-1, bla VIM-2 and bla SPM-1 in imipenem resistant strains. RESULTS: Out of 236 examined isolates, 122 isolates (51.4%) were resistant to imipenem. The IMP-EDTA combination test showed that among 122 imipenem resistant strains, 110 strains (90%) were phenotipically MBL producers. Additionally, the results of PCR method showed that 2 strains (1.6%) and 67strains (55%) of imipenem resistant Pseudomonas aeruginosa isolates contained bla VIM-2 and bla IMP-1 genes respectively. No SPM-1gene was found in the examined samples. CONCLUSION: Resistance of P. aeruginosa isolates to imipenem due to MBL enzymes is increasing in Ahavaz. Because of clinical significance of this kind of resistance, rapid detection of MBL producing strains and followed by appropriate treatment is necessary to prevent the spreading of these organisms. PMID- 26644867 TI - Detection of blaPER-1 & blaOxa10 among imipenem resistant isolates of Pseudomonas aeruginosa isolated from burn patients hospitalized in Shiraz Burn Hospital. AB - BACKGROUND AND OBJECTIVES: Pseudomonas aeruginosa is one of the most important Gram negative opportunistic bacteria which causes infection among burn patients. Resistance to the antibiotics in this group of bacteria is increased due to the activity of extended spectrum beta-lactamase (ESBLs) genes. In the current study, we investigated the prevalence of two genes (blaPER-1 & blaOxa10 ) related beta lactamase genes among imipenem resistance clinical isolates of P. aeruginosa in hospitalized patients. MATERIALS AND METHODS: From May 2010 to March 2011, 270 P. aeruginosa isolated from hospitalized burned patients' wounds in Shiraz Burn Hospital, were tested for Imipenem resistance by disk diffusion method. Presence of ESBLs exo-enzyme, blaPER-1 and blaOxa10 genes were also evaluated in the resistant isolate. RESULTS: 210 (77.7%) of 270 P. aeruginosa isolates were resistant to imipenem. blaPER-1 and blaOxa10 were detected among 168 (80.0%) of imipenem resistant isolates. Furthermore, 160 (76.2%) of them had blaOxa10 gene and 84 (40.0%) of them had blaPER-1 while 63 (30.0%) resistant isolates contained both genes simultaneously. CONCLUSION: This study showed a high prevalence of blaPER-1 and blaOxa10 genes in hospitalized burn patients in south west of Iran. Therefore, it's highly recommended to perform such tests routinely to evaluate the resistance pattern in order to better antibiotic selection in the burned patients. PMID- 26644868 TI - Frequency of Streptococcus pneumoniae infection in patients with suspected meningitis in Imam Reza Hospital of Kermanshah in the west of Iran. AB - BACKGROUND AND OBJECTIVES: Streptococcus pneumoniae is the main causative agent of acute bacterial meningitis in the world. This study aimed to detect pneumoniae infection in cerebrospinal fluid (CSF) samples of patients with suspected meningitis. MATERIALS AND METHODS: In this study, 200 CSF samples in patients with suspected meningitis and with negative bacterial cultures were tested. Demographic data of patients and the laboratory analysis of CSF samples were also collected in a questionnaire. Pneumococcal capsular gene spn9802 was examined by real-time PCR technique. RESULTS: Of 200 CSF samples from patients with the average age of 32.1+/-25.3 year old, 20 were positive for S. pneumoniae in patients with the average age of 35.05+/-24.6. The biochemical and cytological analysis of positive samples showed significant changes, including, 39.7 mg/DL protein, 46.2 mg/DL glucose and 1173 white blood cells per microliter of CSF on average. CONCLUSION: The results of this study showed the significant pneumococcal infection in culture negative CSF samples. The majority of this infection occurred in middle-aged patients and with a higher incidence rate in the winter. It seems that the traditional methods of cultivation are not sensitive enough to detect this bacterium in CSF. Alternatively, the molecular techniques such a real-time seem to be accurate, sensitive and rapid for the detection of this agent in CSF. The cytological and biochemical findings of CSF can provide valuable clues in the diagnosis of bacterial meningitis. PMID- 26644869 TI - Detection of Chlamydophila psittaci from pigeons by polymerase chain reaction in Ahvaz. AB - BACKGROUND AND OBJECTIVE: Chlamydophila psittaci is a lethal bacterium that causes endemic avian chlamydiosis, and respiratory psittacosis. Laboratory diagnosis of Chlamydophila psittaci is difficult by culture. This study was design to investigate the presence of Chlamydophila psittaci in collected pharyngeal swabs from asyptomatic pigeons by PCR. MATERIALS AND METHODS: Pharyngeal samples from pigeons with no symptoms of disease (n=280) were collected during hot and cold seasons in different parts of Ahvaz. DNA was extracted from specimens and subjected to PCR targeting pmp genes and 16s-23s rRNA intergenic spacer of Cp. psittaci and chlamydiales specific primers. RESULTS: Of 280 samples 2 (0.7%) harbor were positive for chlamydiales (16s-23s intergenic spacer) and Cp. psittaci specific genes (pmp gene). CONCLUSIONS: In this research the pigeons were asymptomatic carriers for Cp. psittaci in their respiratory discharges. These results suggest that Cp. psittaci infection of human can occur in very close and continuous contact with pigeons. PMID- 26644870 TI - Molecular, chemical and biological screening of soil actinomycete isolates in seeking bioactive peptide metabolites. AB - BACKGROUND AND OBJECTIVE: Due to the evolution of multidrug-resistant strains, screening of natural resources, especially actinomycetes, for new therapeutic agents discovery has become the interests of researchers. In this study, molecular, chemical and biological screening of soil actinomycetes was carried out in order to search for peptide-producing actinomycetes. MATERIALS AND METHODS: 60 actinomycetes were isolated from soils of Iran. The isolates were subjected to molecular screening for detection NRPS (non-ribosomal peptide synthetases) gene. Phylogenic identification of NRPS containing isolates was performed. Chemical screening of the crude extracts was performed using chlorine o-dianisidine as peptide detector reagent and bioactivity of peptide producing strains was determined by antimicrobial bioassay. High pressure liquid chromatography- mass spectrometry (HPLC-MS) with UV-visible spectroscopy was performed for detection of the metabolite diversity in selected strain. RESULTS: Amplified NRPS adenylation gene (700 bp) was detected among 30 strains. Phylogenic identification of these isolates showed presence of rare actinomycetes genera among the isolates and 10 out of 30 strains were subjected to chemical screening. Nocardia sp. UTMC 751 showed antimicrobial activity against bacterial and fungal test pathogens. HPLC-MS and UV-visible spectroscopy results from the crude extract showed that this strain has probably the ability to produce new metabolites. CONCLUSION: By application of a combined approach, including molecular, chemical and bioactivity analysis, a promising strain of Nocardia sp. UTMC 751 was obtained. This strain had significant activity against Staphylococcus aureus and Pseudomonas aeruginosa. Strain Nocardia sp. UTMC 751 produce five unknown and most probably new metabolites with molecular weights of 274.2, 390.3, 415.3, 598.4 and 772.5. This strain had showed 99% similarity to Nocardia ignorata DSM 44496 T. PMID- 26644871 TI - Comparison of antifungal activities of various essential oils on the Phytophthora drechsleri, the causal agent of fruit decay. AB - BACKGROUND AND OBJECTIVES: The efficacy of Mentha piperita L, Zataria multiflora Boiss and Thymus vulgaris L essential oils (EOs) was evaluated for controlling the growth of Phytophthora drechsleri, the causative agent of damage to many crops that is consumed directly by humans. MATERIALS AND METHODS: The EOs used in this study was purchased from Magnolia Co, Iran. The pour plate method in petri dishes containing Potato Dextrose Agar (PDA) was used to evaluate the antifungal properties of EOs. The minimal inhibitory concentrations (MIC), minimum fungicidal concentration (MFC) as well as mycelial growth inhibition (MGI) were measured. The IC50 value (the concentration inhibited 50% of the mycelium growth) was calculated by probit analysis. RESULTS AND CONCLUSION: The fungal growth was significantly reduced by increasing concentrations of tested EOs. The complete reduction was obtained with Shirazi thyme at all concentrations, whereas the complete reduction for peppermint and thyme was observed at 0.4% and 0.8% (v/v) concentrations, respectively. Meanwhile, the minimum inhibition was observed when 0.1% peppermint (MGI values of 9.37%) was used. The IC50, MIC and MFC values of Shirazi thyme was 0.053, 0.1% and 0.2%, respectively. Similarly, MIC and MFC values of peppermint and thyme were recorded 0.4% and 0.8%, respectively. The results obtained from this study may contribute to the development of new antifungal agents to protect the crops from this pathogenic fungus and many agricultural plant pathogens causing drastic crop losses. PMID- 26644872 TI - Enterobacterial repetitive intergenic consensus (ERIC) PCR based genetic diversity of Xanthomonas spp. and its relation to xanthan production. AB - BACKGROUND AND OBJECTIVE: The genus Xanthomonas is composed of phytopathogenic bacterial species. In addition to causing crops diseases, most of the Xanthomonas species especially Xanthomonas campestris produce xanthan gum via an aerobic fermentation process. Xanthan gum is, an important exopolysaccharide from Xanthomonas campestris, mainly used in the food, petroleum and other industries. the purpose of this study was assessment of relationship between genetic diversity and xanthan production in Xanthomonas spp. MATERIALS AND METHODS: In this study 15 strains of Xanthomonas spp. which had previously been isolated from soils of vegetable farms, were discriminated from each other using Enterobacterial Repetitive Intergenic Consensus (ERIC) PCR and 16S rDNA sequencing methods. Xanthan production of strains was measured in 250 ml flask. The results of ERIC PCR and xanthan production was compared. RESULTS: ERIC-PCR patterns not only could differentiate all Xanthomonas campestis from the control i.e. Xanthomonas translucent but also discriminate strains of Xanthomonas to three clusters with 40% similarity based on Jaccard's coefficient. This clustering of the strains was in agreement with other characteristics including xanthan production and biochemical features. DISCUSSION: The results showed that genomic fingerprinting conferred adequate genetic data for discriminating between strains of the species Xanthomonas campestris. The data indicated a partial relationship between ERIC-PCR patterns and xanthan production by the strains. CONCLUSION: Further development of experiments may result in making good prediction about xanthan production capability of the Xanthomonas strains on the basis of ERIC-PCR method. PMID- 26644873 TI - "In-house" production of DNA size marker from a vaccinal Bacillus anthracis strain. AB - BACKGROUND AND OBJECTIVES: DNA molecular weight marker is widely used in molecular biology experiments incurring considerable costs on low-budget settings. MATERIALS AND METHODS: Here a PCR-supported procedure is described that uses 10 primer pairs targeting chromosomal DNA from the harmless vaccinal Bacillus anthracis Sterne 34F2 strain as template. A single PCR protocol is used to reproduce all the 10 fragments of a 100 bp DNA size marker. RESULTS AND CONCLUSION: The unpurified amalgam of 10 PCR products can be directly loaded to agarose gels. This work was intended to develop a reasonably cost-effective DNA ladder that is useful for researchers in laboratories with limited funding. PMID- 26644874 TI - Detection of Salmonella spp in commercial eggs in Iran. AB - BACKGROUND AND OBJECTIVE: Salmonellosis can be acquired through consumption of infected raw or undercooked eggs. The aim of this study was isolation and identification of Salmonella spp from the eggshells and the egg contents samples of Tabriz retails. METHODS: A total number of 150 samples of eggs were analyzed for the presence of Salmonella spp. using conventional culture method and multiplex-PCR. RESULTS: Two (1.33%) out of 150 samples from eggshells were determined as contaminated with Salmonella spp. Salmonella spp was not isolated from the egg contents. Salmonella serovar was determined as enteritidis and typhimurium. CONCLUSION: The results of the present study provide the recent dataset of the prevalence of S. enteritidis and S. typhimurium in eggs at retail shops in the northwest of Iran. It is important to remember that control is required at all levels in the food chain and by separating cooked and raw. PMID- 26644875 TI - Clinico-microbiological study of candidemia in a tertiary care hospital of southern part of India. AB - BACKGROUND AND OBJECTIVES: Over the last two decades, both the incidence of nosocomial candidaemia and the proportion of blood stream infection due to Candida spp. other than Candida albicans have increased. The aims of this study was to identify different species of Candida and risk factors associated with bloodstream infection and detection of biofilm production. MATERIALS AND METHODS: This study was conducted in an 840 bedded tertiary care hospital, over a period of one year. All blood isolates received from patients during this period were screened for candidemia prospectively. Speciation was carried out by standard microbiological method. Biofilm production detection was done by Brachini et al method. RESULT: A total of 80 cases of candidemia were identified. Most important risk factor was placement of vascular access devices in all the age groups. Candida albicans accounted for 22 isolates (27.5%) whereas non-albicans Candida spp. accounted for 58 isolates (72.5%). Biofilm production was found in 31 strains (38.75%). Biofilm production was seen more in non-albicans Candidaspp. (83.87%) especially in C. tropicalis (66.67%, 8 of 12). CONCLUSIONS: Non albicansspecies of Candida were most frequently recovered in our study. So, the epidemiology of Candida infection is changing. Non-albicans Candida spp have the capacity to produce significant amount of biofilm which may be the cause of their reduced susceptibility to antifungal agents. PMID- 26644876 TI - Evaluation of nested PCR in diagnosis of fungal rhinosinusitis. AB - BACKGROUND AND OBJECTIVE: Given the importance of rapid diagnosis for fungal rhinosinusitis, this study aimed to evaluate the use of nested PCR to identify Aspergillus and Mucor species in clinical samples from patients with suspected fungal rhinosinusitis. METHODS: Functional endoscopic sinus surgery specimens were collected from 98 patients with rhinosinusitis from 2012 to 2013. All samples were ground and cultured on sabouraud dextrose agar. The isolated fungi were identified based on their macroscopic and microscopic features. Fungal DNA was extracted from the tissue samples and nested PCR was performed with two sets of primers for Mucor and Aspergillus. RESULTS: Direct microscopic showed that 5.1% contained fungal components and 9.2% exhibited growth of fungi in culture. The most common agents isolated were Aspergillus fumigatus (n= 3), Aspergillus flavus (n=2), Penicillium sp (n=3) and Alternaria sp. (n=1). Mucor sp. was identified in the pathology smear from 1 patient. Positive results for fungal rhinosinusitis were obtained for a total of 10.2% by culture or pathology smear. Positive PCR results were obtained in 72 samples for Aspergillus and 31 samples for Mucor. CONCLUSION: Our results suggest that endoscopic sinus surgery specimens are not suitable for nested PCR, probably because of the accumulation of fungi that contaminate the environmental air. This drawback is a limiting factor for diagnosis with nasal cavity specimens. Therefore, molecular methods and conventional culture techniques are helpful complementary diagnostic methods to detect fungal rhinosinusitis and determine appropriate management for these patients. PMID- 26644878 TI - Sex differences of anthropometric indices of obesity by age among Iranian adults in northern Iran: A predictive regression model. AB - BACKGROUND: BACKGROUND AND OBJECTIVES: The biological variation of body mass index (BMI) and waist circumference (WC) with age may vary by gender. The objective of this study was to investigate the functional relationship of anthropometric measures with age and sex. METHODS: The data were collected from a population-based cross-sectional study of 1800 men and 1800 women aged 20-70 years in northern Iran. The linear and quadratic pattern of age on weight, height, BMI and WC and WHR were tested statistically and the interaction effect of age and gender was also formally tested. RESULTS: The quadratic model (age(2)) provided a significantly better fit than simple linear model for weight, BMI and WC. BMI, WC and weight explained a greater variance using quadratic form for women compared with men (for BMI, R(2)=0.18, p<0.001 vs R(2)=0.059, p<0.001 and for WC, R(2)=0.17, p<0.001 vs R(2)=0.047, p<0.001). For height, there is an inverse linear relationship while for WHR, a positive linear association was apparent by aging, the quadratic form did not add to better fit. CONCLUSION: These findings indicate the different patterns of weight gain, fat accumulation for visceral adiposity and loss of muscle mass between men and women in the early and middle adulthood. PMID- 26644877 TI - Histological changes of kidney in diabetic nephropathy. AB - Diabetes mellitus is the most common cause of chronic renal disorders and end stage kidney disease in developed countries. It is the major cause of dialysis and transplantation. Failure in renal function causes wide disorders in the body. Diabetes results in wide range of alterations in the renal tissue. It is believed that early histological changes in diabetic nephropathy are detectable 2 years after diabetes is diagnosed. The glomerular alterations are the most important lesions in the diabetic nephropathy (DN). The Renal Pathology Society provides a new pathological classification for the detection of histopathology of DN. It divides diabetic nephropathy into four hierarchical glomerular lesions. Alloxan or streptozotocin induced diabetic rat is the one most widely used specie to study DN. Histological changes in the rat DN closely resemble the human disease and the most information of this review was obtained through the study of rat DN. All cell types of the kidney such as mesangial cells, podocytes and tubulointerstitial cells are liable to be affected in the event of DN. Severity of renal lesions is associated to the clinical aspect of renal outcome, but the aim of this article was only to review the histological changes of kidney in diabetes mellitus. PMID- 26644879 TI - Dose administration time from before breakfast to before dinner affect thyroid hormone levels? AB - BACKGROUND: Levothyroxine is commonly used in the treatment of patients with hypothyroidism. Levothyroxine is often administered in the morning, on an empty stomach, to increase its absorption. However, many patients have trouble for taking levothyroxine in the morning. The aim of this study was to evaluate the effect of changing administration time of levothyroxine from before breakfast to before dinner on serum levels of TSH and T4. METHODS: Fifty hypothyroidism patients aged 18-75 years old were included in the study and randomly divided into two groups. Each group received two tablets per day blindly (one levothyroxine tablet and one placebo tablet) before breakfast and before dinner. After two months, the administration time for the tablets was changed for each group, and the new schedule was continued for a further two-month period. The serum TSH and T4 levels were measured before and after treatment in each group. RESULTS: Changing the levothyroxine administration time, resulted in 1.47+/-0.51 uIU/mL increase in TSH level (P=0.001) and 0.35+/-1.05ug/dL decrease in T4 level (P=0.3). CONCLUSION: Changing the levothyroxine administration time from before breakfast to before dinner minimally reduced the therapeutic efficacy of levothyroxine. PMID- 26644880 TI - Prevalence of age-related macular degeneration among the elderly. AB - BACKGROUND: Age-related macular degeneration (AMD) is the leading cause of visual impairment and blindness in elderly population in the developing countries. Previous epidemiological studies revealed various potential modifiable risk factors for this disease. The purpose of this study was to evaluate the prevalence of AMD among elderly living in Babol, North of Iran. METHODS: The study population of this cross-sectional study came from the Amirkola Health and Ageing Project (AHAP), the first comprehensive cohort study of the health of people aged 60 years and over in Amirkola, North of Iran. The prevalence of AMD was estimated and its risk was determined using logistic regression analysis (LRA) with regard to variables such as smoking, hyperlipidemia, hypertension and diabetes. RESULTS: Five hundred and five participants with mean age of 71.55+/ 5.9 (ranged 60-89) years entered the study. The prevalence of AMD was 17.6%. There was a significant association between AMD and smoking (P<0.001) but no association was seen with AMD and age, level of education, history of hyperlipidemia, hypertension and diabetes. Multiple LRAs revealed that smoking increased AMD by odds ratio of 5.03 (95% confidence interval 2.47-10.23 p<0.001) as compared to nonsmokers. CONCLUSION: According to our findings, the prevalence of AMD was relatively high and smoking increased the risk of AMD in the elderly population. PMID- 26644881 TI - Resistance patterns of Escherichia coli causing urinary tract infection. AB - BACKGROUND: Urinary tract infection (UTI) is one of the most prevalent infectious diseases and Escherichia coli is its common cause. The aim of this study was to assess the resistance patterns of E.coli in urinary tract infections and to determine the susceptibility of E.coli to commonly used antimicrobials and also to evaluate the options for empirical treatment of UTI. METHODS: This study was conducted in the Ayatollah Rouhani Teaching Hospital of Babol Medical Sciences University in North of Iran. Between January of 2013 to December 2013, antimicrobial susceptibility tests were done by disk diffusion and microdilution method. Growth of >=10(5) cfu/ml was considered as positive urine test. Ten commonly used antibiotics were examined for susceptibility test. Data and the results were collected and analyzed. RESULTS: E.coli grew in 57 urine samples. Imipenem, ofloxacin, ciprofloxacin were the most sensitive antibiotics at 87.7%, 87.7% and 78.9% respectively. Whereas, cotrimoxazole, cefexime, cefotaxcime and ceftriaxone were the most resistant antibiotics. Antibiotic sensitivity of disk diffusion compared minimum inhibitory concentration (MIC) detected by microdilution had the sensitivity, specificity, positive predictive value and negative predictive value of 82%, 98%, 99% and 74%, respectively. CONCLUSION: Imipenem, ofloxacin and ciprofloxacin should be used in empirical therapy of UTI. PMID- 26644882 TI - Optic neuritis, the most common initial presenting manifestation of multiple sclerosis in northern Iran. AB - BACKGROUND: Multiple sclerosis (MS) is an inflammatory and demyelinating disease of central nervous system (CNS). The aim of the present study was to determine the type and the frequency of initial presenting symptoms in patients with MS and their relation with demographic characteristics in Babol, northern Iran. METHODS: All patients of this study were recruited over a ten year period from 2002 to 2012 from single neurologic clinic. Diagnosis of MS was confirmed according to the McDonald criteria, demographic and clinical features Then, all the clinical findings and demographic variables including: age, sex, marital status, age at onset, education, place of residence, disease duration, initiation pattern of disease have been collected. Expanded Disability Status Scale (EDSS) was used for the evaluation of disability at the onset of disease. Data analysis was performed by chi-square test. RESULTS: A total of 263 consecutive MS patients with the age range of 17 to 61 yr were examined. Optic neuritis was the most prevalent initial presenting symptom in 123 (46.8%) patients followed by sensory disturbances as the second common presenting symptom of MS. Significant difference was found between patients with or without optic neuritis and the onset age of the disease and EDSS (p<0.001). The mean EDSS score at the time of initial presentation was 1.67+/-0.77. CONCLUSION: The findings of this study indicated that optic neuritis is the most prevalent initial presentation of MS in the geographic region of northern Iran. In patients less than 30 years, development of visual disturbances justifies neurologic examination. PMID- 26644884 TI - Low baseline serum albumin as a predictor of anemia in chronic hemodialysis patients. AB - BACKGROUND: Inflammatory process has a substantial contribution in the development of anemia in chronic hemodialysis patients. Low serum albumin in hemodialysis patients is considered a marker of inflammation. The present longitudinal study aimed to determine the relationship between low baseline serum albumin and future development of anemia. METHODS: The population of this study consisted of all patients on standard maintenance hemodialysis for at least three months or longer. Patients were classified as high or low serum albumin level (>= or < 3.9 gr/dl). All patients received the standard treatment of anemia. The main objective of this study was to compare the prevalence of anemia defined as hemoglobin levels < 11 gr/dl between the two study groups at the end of the study period. RESULTS: A total of 82 patients (50% females) with mean+/-SD age of 55+/ 16.8 years and mean dialysis duration of 5.2+/-4 years were followed-up for an average period of 10+/-1 (range, 8-11) months, however 48 patients with high serum albumin and 24 patients with low serum albumin group completed the study. At baseline, the two groups were similar regarding hemoglobin (9.8+/-1.2 vs 9.16+/-1.6 gr/dl, P=0.95) levels. At endpoint, prevalence of anemia in high albumin group was significantly lower than the low albumin group (50% versus 83.3% P=0.005). CONCLUSION: The findings of this study indicate that low serum albumin in hemodialysis patients is a predictor of anemia indicating unresponsiveness to conventional treatment of anemia. PMID- 26644883 TI - Prevalence of headache at the initial stage of stroke and its relation with site of vascular involvement: A clinical study. AB - BACKGROUND: Stroke is the most common neurologic disease and an important cause of morbidity and mortality. Headache is an initial presenting feature of ischemic stroke and sometimes precedes the development of stroke and thus, provides an opportunity for offering preventive measures. The aim of the present study was to determine the association of new onset headache with stroke. METHODS: A total of 263 consecutive patients with stroke entered the study. Development of headache 24 have prior to admission lasting <3 days was considered the new onset headache. The intensity of headache was graded as mild, moderate and severe. Stroke was classified with respect to the localization of brain damage using magnetic resonance image (MRI). Chi-square test was applied for comparison of proportions. RESULTS: One hundred thirty-nine males and one hundred twenty-four females with mean age of 76.4+/-10 (40-89) years were analyzed. Ischemic stroke involving anterior circulation was diagnosed in 210 (79%) patients and vertebrobasilar ischemia in the remaining population. Diabetes, hypertension, hyperlipidemia and coronary artery disease were observed in 36%, 52%, 38% and 42%, respectively. New onset headache was found in 49 (18.9%) patients in who 81.6% was mentioned as new onset. Six out of 9 patients with severe headache had involvement of posterior circulation, whereas in the remaining population, anterior circulation was involved. CONCLUSION: The findings of this study indicate no association of new onset headache with stroke. There was only a trend for severe headache toward the involvement of vertebrobasilar ischemia. PMID- 26644885 TI - Biochemical profile of bile fluid in patients with malignant cholestasis in comparison with cholestasis due to gall stone. AB - BACKGROUND: Cholangiocarcinoma is an invasive biliary malignancy with poor prognosis. Diagnostic accuracy of conventional methods is low which is mainly due to the specific anatomy of the disease. The aim of this study was to evaluate the diagnostic value of biochemical profile and tumor marker of the bile in patients with malignant cholestasis compared to that of choledocholithiasis. METHODS: In this cross-sectional study, 46 patients with extrahepatic cholestasis were enrolled (20 patients with malignant cholestasis and 26 patients with choledocolithiasis) A definitive diagnosis of cholangiocarcinoma was made by imaging, cytology and biopsy. Bile fluid was obtained by aspiration through endoscopic retrograde cholagiopantreatography (ERCP) catheter or percutaneous drainage in patients with choledocolithiasis and cholangiocarcinoma respectively. Sex and age were matched in two groups. Data regarding the biochemical profile (triglyceride, (TG), cholesterol, billirubin and HDL) and CA19.9 level of the bile fluid were collected, then using the SPSS software, the data were analyzed. RESULTS: Bile fluid level of TG, cholesterol, high - density lipoprotein (HDL), direct bilirubin and CA19.9 were significantly higher in patients with benign cholestasis in comparison with malignant cholestasis (P<0.001, P<0.001, P<0.001, P=0.012 and P= 0.03, respectively). CONCLUSION: Our study showed that the CA19.9 level of bile fluid in extrahepatic cholestasis due to biliary stone was significantly higher than those with cholangiocarcinoma, as is the biliary level of TG, cholesterol, high-density lipoprotein (HDL) and direct bilirubin. Thus they may help in the differentiation of benign versus malignant extra hepatic cholestasis. PMID- 26644886 TI - The relationship between demographic characteristics and motivational factors in the employees of social security hospitals in Mazandaran. AB - BACKGROUND: Health worker motivation has the potential to have a large impact on health system performance, and this depends on some factors. The purpose of this study was to determine the factors affecting this motivation. METHODS: From Winter 2013 to Spring 2014, 1046 employees and physicians (439 males and 607 females) with a mean age of 36 and 37.2 years in men and women, respectively were chosen in selected hospitals of Social Security Organization (SSO). They were randomly categorized into six different classes of service record, age education class of hiring (permanent and contractual), marital status, and gender. The variables assessed via the classification groups were as follows: interpersonal relations, working conditions, equity, pay, job security, supervision, advancement, recognition, responsibility, and attractiveness of job, educational and organizational policies. RESULTS: Bachelor's degree (65%) or higher were the education degrees of most participants. Significant relations were observed regarding age, marital status, hiring, gender and years of service with promotion, recognition, responsibility, attractiveness of job, education, relations, working condition, equity, salary, job security, supervision and organizational policies. There were significant relations with hire status and degree with advancement and other variables. There were significant relations between marital status, gender, years of service and age with the above variables. CONCLUSION: The results show that the important variables that influence motivational factors are academic degree, hire status, marital status, gender, age and years of service. PMID- 26644887 TI - Isolated thrombocytopenia; A report of a rare presentation of childhood systemic lupus erythematosus (SLE). AB - BACKGROUND: Systemic lupus erythematosus (SLE) has various presentations in children. Hematologic abnormalities is common in childhood onset of SLE, however, isolated thrombocytopenia is relatively rare. Thus, we present a child with isolated thrombocytopenia as a rare presentation of SLE. CASE PRESENTATION: A 12 year-old boy with chief complaints of loss of appetite, weight loss, decreased platelet count (8000/uL) and lymph node enlargement was referred to our hospital. Biopsy of lymph node showed reactive lymphadenopathy. Investigations regarding infectious disease was negative. Platelet count remained low after low dose steroidned therapy. Antinuclear antibody (ANA) and anti-double stranded DNA antibody screening tests were positive with titer of 1/62 and 1/54, respectively. Therefore, juvenile SLE was considered as the final diagnosis and raising the dose of prednisolone to 2mg/kg/day was associated with increasing platelet count to 40000/uL and a week later to 96000/uL. CONCLUSION: The findings of this study indicate that in cases with isolated thrombocytopenia refractory to conventional dose of steroids, SLE should be considered. This study justifies serum ANA and anti DNA assessment in children with thrombocytopenia. PMID- 26644888 TI - Osteopoikilosis: A rare cause of bone pain. AB - BACKGROUND: Osteopoikilosis (OPK) is a rare inherited condition of the bones, transmitted as an autosomal dominant trait characterized by numerous hyperostotic areas that tend to localize in periarticular osseous regions. It is usually asymptomatic and is often diagnosed incidentally during x-rays made by other reasons. We present a case of 34-year-old man suffering from polyarthralgia and low back pain. CASE PRESENTATION: A 34-year-old male patient, smoking 40 packs yearly and alcoholic was referred to our department of rheumatology, complaining of polyarthralgia which started 3 years ago and involving large and small joints. He reported the presence of pelvic pain mostly located at both hip joints and in the two ankles. On radiologic examination, numerous, symmetric, well defined, sclerotic lesions were identified on shoulder, wrist, ankles, pelvis, and on spine. The size of the lesions varied from 2 to 9 millimeters. These spots were located on spongious bone tissue, and in the inner bone cortex located bilaterally in the epiphyses and metaphyses. We concluded the diagnosis of OPK. His mother was found to have the same lesions without any symptoms. CONCLUSION: OPK may be an isolated finding or associated with other pathologies, e.g. skin manifestations, rheumatic and/or skeletal disorders. The main differential diagnosis is osteoblastic metastasis. PMID- 26644889 TI - A case of methanol poisoning leading to prolonged respirator dependency with consequent blindness and irreversible brain damage. AB - BACKGROUND: Methanol is a colorless and poisonous liquid that is commonly used as an industrial and household solvent. Methanol poisoning is a rare but extremely hazardous form of in toxication that affects the central nervous system and causes visual disorder, drowsiness, seizures and coma. CASE PRESENTATION: A 29 years-old man with methanol intoxication presented with drowsiness and acidosis with subsequent brain hemorrhage requiring prolong mechanical ventilation resulted in persistent visual impairment and disequilibrium. CONCLUSION: Prolonged mechanical ventilation in patients with methanol intoxication may be assouated with irreversible brain damage. PMID- 26644890 TI - Obesity and diabetic retinopathy: What is the association? PMID- 26644891 TI - Efficacy of probiotic use in acute rotavirus diarrhea in children: A systematic review and meta-analysis. AB - BACKGROUND: Probiotic therapies with different strains demonstrated some beneficial effects, although some studies did not show any significant effects. This study assessed systematically the current knowledge on the effect of probiotic bacteria on duration of acute rotavirus diarrhea in children compared with control. METHODS: The PubMed, Cochrane Controlled Trial Register (CCTR) and Ovid (Wolters Kluwer Health) were searched between 1980 to June 15, 2013. Randomized controlled trials including the administration of probiotics for treatment of rotavirus diarrhea in infants and children were reviewed. RESULTS: A total number of 1244 articles were found through the aforementioned search. 203 articles were selected after the first screening of title and abstract. The intervention group included subjects who received probiotic strains and dosage in any conditions. Placebo or any similar vehicle without probiotic was used in the controlled trials. Finally, 14 articles were selected. The outcomes from each study were considered in the duration of diarrhea. Statistical analyses were performed with Stata software. The pooled estimate of efficacy of probiotics in prevention or treatment of disease yielded in all studies a mean difference of 0.41 (CI 95%: -0.56 to -0.25; p<0.001). The pooled estimate of efficacy of lactobacillus rhamnosus GG and other probiotics significantly reduced the duration of diarrhea. Among trials, the overall reduction of LGG was 0.47 (CI 95%: -0.80 to -0.14; P= 0.020). CONCLUSION: In conclusion, probiotics exert positive effect in reducing the duration of acute rotavirus diarrhea compared with control. PMID- 26644892 TI - The effect of arbutin on lipid peroxidation and antioxidant capacity in the serum of cyclosporine-treated rats. AB - BACKGROUND: Cyclosporine A (CsA) is a potent immunosuppressant drug with therapeutic and toxic actions. The use of CsA is limited by its toxicity. Several researchers had proposed that oxidative stress could play an important role in CsA-induced toxicity. Arbutin has recently been shown to possess antioxidative and free radical scavenging abilities. The present study was designed to investigate the in vivo effects of arbutin on lipid peroxidation and antioxidant capacity in the serum of cyclosporine treated rats. METHODS: Adult male Wistar rats were divided into six groups (n=8/group): (I) control (no CsA and arbutin administration), (II and III) were treated subcutaneously (Sc) with arbutin (50,100 mg/kg/bw), respectively, (IV) administered CsA (25 mg/kg/bw) intraperitoneally (IP), (V and VI) received the combination of CsA (25 mg/kg/bw) i.p and arbutin (50,100 mg/kg/bw) Sc daily, respectively. At the end of the treatment (after3 weeks), serum lipid peroxidation was measured by thiobarbituric acid-reacting substances (TBARS) and serum total antioxidant capacity (ferric reducing ability of plasma [FRAP]) was assayed based on spectrophotometric method. RESULTS: TBARS had been significantly increased by CsA administration compared with control rats. Arbutin (50mg/kg/bw) completely prevented this effect, but arbutin (100 mg/kg/bw) alone or in combination with CsA significantly increased lipid peroxidation compared with controls. CONCLUSION: Our data indicate that arbutin (50mg/kg/bw) had protective effect in the CsA-induced toxicity but high concentration of arbutin (100mg/kg/bw) showed meaningful oxidative and lipoperoxidative effects. PMID- 26644893 TI - Efficiency of two constructs called "fear of disease" and "perceived severity of disease" on the prevention of gastric cancer: Application of protection motivation theory. AB - BACKGROUND: Among all cancers, malignancies of gastrointestinal tract are the most common cancer among Iranian population. Dietary behavior is thought to be the most important risk factor in gastric cancer. Fear and perceived severity are two important constructs of the protection motivation theory (PMT). Despite the evidence of the impact of these two constructs in modifying dietary habits against gastric cancer, their efficiency is not well established. Therefore, the present study was designed to determine the efficiency of the mentioned constructs. METHODS: This cross-sectional study was performed on 360 participants (180 males and 180 females) aged over 30 years old who presented to health centers in Babol, Iran in 2014. They were selected by a cluster sampling method in a population covered by health centers in Babol. Data collection was done using a questionnaire with acceptable reliability and validity, designed by a researcher based on two constructs of protection motivation theory. The data were analyzed by SPSS Version 20 using descriptive and analytical statistics such as ANOVA, linear and logistic regression analysis. RESULTS: The participants who entered in the study achieved 38.6 and 69.7% of the scores of fear and perceived severity, respectively. There was a significant difference between perceived severity with level of education (p<0.05). There was a significant inverse correlation between perceived severity with nutritional high risk behavior associated with gastric cancer in the significant level of 0.05 (r=-0.165). The constructs of perceived severity and fear predicted 38% of the variance of nutritional high risk behaviors associated with gastric cancer. CONCLUSION: Constructs of fear and perceived severity of protection motivation theory with predicting 38% of the variance of nutritional high risk behaviors had an effective role against gastric cancer and may help in the design and implementation of educational programs for the prevention of gastric cancer. PMID- 26644894 TI - Relationship between hepatitis B DNA viral load in the liver and its histology in patients with chronic hepatitis B. AB - BACKGROUND: Serial measurement of hepatitis B virus (HBV) DNA levels in the liver and its relation with liver damage and serum HBV DNA levels are guide to begin and/or end a treatment course. This study evaluated the relationship between liver hepatitis B DNA viral load with liver histology in patients with chronic hepatitis B (HBV). METHODS: Thirty patients with chronic anti-Hbe positive hepatitis B, with liver enzymes >= 2 times of the upper limit of normal and positive HBV DNA of any amount were entered in the study. They underwent percutaneous liver biopsy. Liver and serum viral load were determined using real time polymerase chain reaction method (RT-PCR). Liver function tests and liver histology for all cases were recorded. The amount of viral load in the liver and histological grading and staging were recorded. Data were collected and analyzed. RESULTS: The mean age of the patients was 32.8+/-10 years and 24 (80%) patients were males. Ten (33.3%) patients had HBV viral load levels less than 20000 IU/mL. There was a significant correlation between liver viral load levels with staging or grading of liver damage. CONCLUSION: The results of the present study showed a strong correlation between liver viral load and liver damage in patients with chronic hepatitis B. PMID- 26644895 TI - Prevalence and treatment outcome of pulmonary and extrapulmonary pediatric tuberculosis in southwestern Iran. AB - BACKGROUND: Knowledge about childhood tuberculosis (TB) in Iran is limited. This study aimed to determine the proportion of tuberculosis in children living in Khuzestan in southwest of Iran and its treatment outcomes. METHODS: In this retrospective study, the child's medical records registered in national TB program (NTP) unit of Khuzestan Health Center (KHC) for TB treatment from 2005 to 2010 were studied. Data including demographic, clinical presentation, laboratory test results, and treatment outcomes were extracted from the files and were analyzed. RESULTS: Of total 4104 new TB cases registered in KHC, 203 (4.9%) were children. The mean age was 10.7+/-4.3 years, and 75.7% of them were females. More than 84% of TB children cases were 10 years or older, whereas, young children (< 5 years old) accounted for 5.6%. Of the total studied cases, 57.1% were pulmonary TB and 42.9% were extra pulmonary, 91.7% were successfully treated and 8.3% had poor treatment outcome. The main risk factors for poor treatment outcome were: age <5 years (OR: 0.17, 95% CI, 0.04-0.76), low body weight (OR: 0.08, 95% CI, 0.01-0.60), household contact with cases of TB treatment failure (OR: 0.13, 95% CI, 0.03-0.52), and exposure to cigarette smoke odor inside the home (OR: 0.17, 95% CI, 0.05-0.56). CONCLUSION: The proportion of pediatric TB in the region was lower than expected. The treatment success rate was higher than the rate defined in NTP. Special attention should be given to children aged less than five years, low body weight, contact with TB treatment failure cases, and exposure to cigarette smoke. PMID- 26644896 TI - Types and frequency of ovarian masses in children over a 10-year period. AB - BACKGROUND: Ovarian masses represent a range of pathology from benign cyst to highly aggressive malignant tumors. It has been estimated that gynecologic malignancy account for approximately 2% of all types of cancer in children, 60 70% of these lesions arise in the ovary. METHODS: All ovarian masses which were resected or biopsied in Mofid Children's Hospital from 2002 to 2012 were reviewed retrospectively. Patient's age, presenting symptoms, surgical procedures, pathological diagnosis, postoperative treatment, and outcome were obtained from medical records. RESULTS: Fifty-seven girls (aged 40.2+/-57months with the range of 1 day to 15 years) underwent different types of ovarian operations (24 salpingo-oophorectomies, 10 oophorectomies, 21 ovarian cystectomies, and 2 ovarian biopsies). 50 children had unilateral ovarian mass (49.1% right and 38.6 left, respectively). The most common presenting symptoms were acute abdominal pain in 46%.Twenty one (37%) of our patients had ovarian torsion. Four (7%) patients had benign tumors, and 8 (14%) had malignant tumors. There were no age differences between those with benign type (8.2+/-2.6years) and malignant tumors (6.1+/-5.3years) (P=0.683). CONCLUSION: Ovarian tumors are rare in children. Most are benign, in children presenting with acute abdominal pain, ovarian mass particularly neoplastic tumors should be suspected. An important proportion of these patients may require postoperative chemotherapy. PMID- 26644897 TI - Associated factors of diabetic retinopathy in patients that referred to teaching hospitals in Babol. AB - BACKGROUND: Information regarding the frequency and severity of eye involvement in diabetic patients and its risk factors can be useful for prevention and treatment. This study aimed to determine the prevalence of diabetic retinopathy and its associated risk factors in diabetic patients who referred to teaching hospitals in Babol, Mazandaran. METHODS: In this study a total of 1562 patients with the definite diagnosis of diabetes mellitus were chosen and referred to the eye clinic of Shahid Beheshti and Ayatollah Rouhani Hospitals of Babol during 2006-2010. Information about age, duration of diabetes, hypertension family history of diabetes, history of other organs involvement, BMI and laboratory findings were recorded. Retinopathy was classified according to early treatment of diabetic retinopathy study. Data were collected and analyzed. RESULTS: Of the 1562 patients, 357 (22.9%) were males and 1205 (77.1%) were females. The mean age was 54.6+/-10.6 years, diabetic retinopathy was found in 990 (64.1%) patients, the frequency of non-proliferative diabetic retinopathy was 37.3% and proliferative was 26.8%.Age, duration of diabetes, FBS, HbA1C, BUN, Cr, Hb were significantly different between the patient's with diabetic retinopathy and no diabetic retinopathy (p<0.05). No relationship was found between smoking, gender, hypertension and serum lipid profile. CONCLUSION: Poor diabetes control, anemia and nephropathy were the most associated factors of diabetic retinopathy but hypertension BMI smoking, dyslipidemia and gender showed no association. PMID- 26644898 TI - Cytokeratin7 expression in gastric and colorectal adenocarcinoma: Correlation with prognostic factors. AB - BACKGROUND: Gastric and colorectal adenocarcinoma are the second and the fifth most common cancers in Iran, respectively. Expression of cytokeratin 7 (CK7) is established in most malignancies including gastric and colorectal adenocarcinoma. Demonstration of Ck7 could be related to prognostic factors and help to the better management of the patients. The objective of our study was to evaluate the CK7 expression in gastric and colorectal adenocarcinoma and its correlation with other prognostic factors. METHODS: This cross-sectional study was performed on 99 tissue blocks from patients with gastric or colorectal adenocarcinoma undergoing surgery. Tumor grade, tumor size, depth of invasion and metastasis to lymph nodes were determined. Then, the expression of CK7 was studied using immunohistochemistry staining. RESULTS: Expression of CK7 was 50% and 33.8% in gastric and colorectal adenocarcinoma, respectively. There was not only a significant correlation between CK7 expression and tumor size (r=0.267, P=0.009) but also histologic grade (r=0.222, P=0.028). CONCLUSION: CK7 could be more expressed with the increase in tumor size and was associated with poorly differentiated gastric and colorectal adenocarcinoma. However, with these results gathered, it is highly recommended that further studies will be conducted to reveal the exact prognostic role of this factor. PMID- 26644899 TI - Etiology of syncope in hospitalized patients. AB - BACKGROUND: Syncope is a common clinical problem which can be remarkably debilitating and associated with high health care costs. Syncope is a clinical syndrome with many potential causes. The aim of the study was to determine the etiologies of patients with syncope in the emergency department (ED) of a referral and general university hospital. METHODS: One hundred sixty-five consecutive patients aged more than 18 years old with syncope were admitted to the emergency department of Ayatollah Rouhani Hospital. Initially organized, systematic approach included detailed medical history and structured questionnaires for history taking, physical examination, ECG and cardiac monitoring, cardiology and neurology were done. Advanced diagnostic tests were carried out if the etiology of syncope remained unexplained. RESULTS: Out of the 165 patients who presented to the ED between February 2012 and February 2013, 124 had definition of syncope. The mean age of male patients was 59.5+/-19.8, 58. The etiology of syncope was diagnosed in 104 (83%) patients. Neurocardiogenic syncope was found in 36 (29.03%) patients, cardiac arrhythmias in 40 (32.25%) patients, and acute coronary syndrome in 8 (6.45%) patients. There are some infrequent etiologies like intracranial hemorrhage in 5 patients, aortic stenosis in 4 patients, hypertrophic cardiomyopathy and aortic dissection in 3 patients, Brugada and pulmonary embolism in 2 patients and carotid hypersensitivity in one patient. CONCLUSION: We found that cardiac arrhythmias and neurocardiogenic type are the frequent causes of syncope. In about one-sixth of the patients, no etiology was found. Approximately one-third of patients had traumatic syncope. PMID- 26644901 TI - Case series of rhinocerebral mucormycosis occurring in diabetic patients. AB - BACKGROUND: Rhinocerebral mucormycosis is a fatal infection typically affecting diabetic or immunosuppressed patients. In most cases, infection is caused by inhalation of fungal spores. Mortality rate of patients is very high (40-85%). CASE PRESENTATION: In this study, three diabetic patients with rhinocerebral mucormycosis were presented. The etiologic agents of mucormycosis in two patients were isolated and identified by sequence analysis and data were registered in Gene bank database. CONCLUSION: In patients with mucoreosis, early detection, surgical excision and appropriate debridement, suitable antifungal therapy, and control of risk factors like diabetes mellitus are the main parameters of successful management of this lethal infection. PMID- 26644900 TI - How aminoglycosides are used in critically ill patients in a teaching hospital in North of Iran. AB - BACKGROUND: Resistance to antimicrobial agents including aminoglycosides (AGs) is a great concern that is mainly related to inappropriate use. Since there were not adequate data regarding how rationally AGs are being prescribed in our critically ill patients, this study was conducted to determine the main issues in the area of appropriate use of this antibiotic class. METHODS: One hundred patients who were in the intensive care units (ICUs) of Imam Khomeini Teaching Hospital from February 2012 to August 2012 were included. A data gathering form was prepared based upon the recommendations provided by Up-to-date (20.1) 2012 and Medscape 2013. All demographic characteristics and other information about time of beginning and duration of dosage, interval of administration of AGs and creatinine (Cr) level were collected. In statistical analysis, SPSS Version 16 software was used. Independent samples t-test was used to compare the quantitative and chi-square for qualitative variables. RESULTS: Sixty six (66%) of patients received gentamicin and 38% received amikacin. In 27% of patients, serum creatinine (Cr) had been checked before and after AGs administration and 4 patients had no renal function monitoring. Monitoring of serum concentration and Cr clearance estimation was not carried out for any patients. Culture and laboratory sensitivity tests were done on 17 patients and E-coli (57%) was the most common isolated organism. CONCLUSION: The results of this study revealed that majority of the hospitalized patients in the ICU and the dosage of AGs had not been adjusted to renal function. PMID- 26644902 TI - Candida laryngitis appearing as carcinoma. AB - BACKGROUND: Focal laryngeal candidiasis is not reported widely and is very infrequently recognized clinically. This disease is rare and may occur after pulmonary, pharyngeal and esophageal candidiasis or as part of disseminated disease. It is also secondary to inhaled steroid therapy which is usually mild and has been reported in 10-15 percent of patients taking these medications. CASE PRESENTATION: In this study, we introduced a rare case of laryngeal candidiasis in a 79-year-old immunocompromised male presented with 17 months of progressive hoarseness. In video laryngoscopy a white, vegetative mass on anterior one-third of right vocal cord mimicking laryngeal carcinoma. The histopathological examination showed laryngeal mucosal with keratosis, degenerating necrotic epithelial cell aggregates containing hyphea and candida albicans. CONCLUSION: In immunocompromised patients, the diagnosis of laryngeal candidiasis should be considered in any patients with laryngeal symptoms. PMID- 26644904 TI - Prevention of Dehydration in Independently Living Elderly People at Risk: A Study Protocol of a Randomized Controlled Trial. AB - BACKGROUND: Dehydration of elderly people living independently is a very important public health issue. This study compares two interventions to prevent dehydration in elderly people at risk: an educational intervention and an educational intervention in combination with a drink reminder device. METHODS: This is an experimental two-armed parallel study. A Public Health Service develops the interventions and will be partnering with a general practice and a university to evaluate the effects. Two groups - all people aged 80 years and older, and people of 65 years and older who have cardiovascular disease - receive a letter from the general practice in which they are asked whether they want to participate in the study and if so to return the form. People who want to participate and whose daily fluid intake is insufficient are randomized to receive either the educational intervention or the educational intervention in combination with a drink reminder device. The participants are asked to fill in a questionnaire before the intervention, 6 weeks after the start of the intervention and 6 months after the start (or after the end) of the intervention. Changes between the two groups in fluid intake, knowledge, awareness of the risks of dehydration, and quality-of-life will be tested by Linear Mixed Model analyses. CONCLUSIONS: This study will improve the knowledge of the effectiveness of interventions designed to prevent dehydration in elderly people. PMID- 26644903 TI - Mediating Effect of Perceived Overweight on the Association between Actual Obesity and Intention for Weight Control; Role of Race, Ethnicity, and Gender. AB - BACKGROUND: Although obesity is expected to be associated with intention to reduce weight, this effect may be through perceived overweight. This study tested if perceived overweight mediates the association between actual obesity and intention to control weight in groups based on the intersection of race and gender. For this purpose, we compared Non-Hispanic White men, Non-Hispanic White women, African American men, African American women, Caribbean Black men, and Caribbean Black women. METHODS: National Survey of American Life, 2001-2003 included 5,810 American adults (3516 African Americans, 1415 Caribbean Blacks, and 879 Non-Hispanic Whites). Weight control intention was entered as the main outcome. In the first step, we fitted race/gender specific logistic regression models with the intention for weight control as outcome, body mass index as predictor and sociodemographics as covariates. In the next step, to test mediation, we added perceived weight to the model. RESULTS: Obesity was positively associated with intention for weight control among all race * gender groups. Perceived overweight fully mediated the association between actual obesity and intention for weight control among Non-Hispanic White women, African American men, and Caribbean Black men. The mediation was only partial for Non Hispanic White men, African American women, and Caribbean Black women. CONCLUSIONS: The complex relation between actual weight, perceived weight, and weight control intentions depends on the intersection of race and gender. Perceived overweight plays a more salient role for Non-Hispanic White women and Black men than White men and Black women. Weight loss programs may benefit from being tailored based on race and gender. This finding also sheds more light to the disproportionately high rate of obesity among Black women in US. PMID- 26644905 TI - Health Workers Adjustment for Elimination of Malaria in a Low Endemic Area. AB - BACKGROUND: Malaria elimination efforts face with substantial challenges and the role of health workers in address this challenge, particularly advocates and mobilizes communities. The aim of the study was to explore perceptions of health workers in relation to eliminating malaria in order to better understand the level their involvement in malaria elimination efforts. A qualitative approach was adopted based on key informant interviews with 26 health workers who working at community-level in malaria low endemic areas, southern Iran. METHODS: Data were collected through key informant interviews. Data were analyzed using thematic content analysis. RESULTS: Findings reveal that the majority of participants concerned with the imported malaria cases, without to address an effective solution to the issue. Health workers had positive perceptions on their basic knowledge and opinions in relation to their field work with emphases to integrate methods. Participants expressed willingness to contribute to malaria elimination effort. They also emphasized on continuous training, resource mobilization, and support. In addition, their perceptions on malaria elimination policy such as sustained financial investment to achieve elimination and integrated management of vector control were rather negative. CONCLUSIONS: A mechanism should be considered that allow the health workers to feedback positively on their quality of their practice to health providers. PMID- 26644906 TI - Mortality Attributable to Excess Body Mass Index in Iran: Implementation of the Comparative Risk Assessment Methodology. AB - BACKGROUND: The prevalence of obesity continues to rise worldwide with alarming rates in most of the world countries. Our aim was to compare the mortality of fatal disease attributable to excess body mass index (BMI) in Iran in 2005 and 2011. METHODS: Using standards implementation comparative risk assessment methodology, we estimated mortality attributable to excess BMI in Iranian adults of 25-65 years old, at the national and sub-national levels for 9 attributable outcomes including; ischemic heart diseases (IHDs), stroke, hypertensive heart diseases, diabetes mellitus (DM), colon cancer, cancer of the body of the uterus, breast cancer, kidney cancer, and pancreatic cancer. RESULTS: In 2011, in adults of 25-65 years old, at the national level, excess BMI was responsible for 39.5% of total deaths that were attributed to 9 BMI paired outcomes. From them, 55.0% were males. The highest mortality was attributed to IHD (55.7%) which was followed by stroke (19.3%), and DM (12.0%). Based on the population attributed fractions estimations of 2011, except for colon cancer, the remaining 6 common outcomes were higher for women than men. CONCLUSIONS: Despite the priority of the problem, there is currently no comprehensive program to prevention or control obesity in Iran. The present results show a growing need to comprehensive implications for national and sub-national health policies and interventional programs in Iran. PMID- 26644907 TI - On the Occasion of World Cancer Day 2015; the Possibility of Cancer Prevention or Treatment with Antioxidants: The Ongoing Cancer Prevention Researches. AB - On February, 2014 World Cancer Day (WCD) was established to raise alertness of cancer and to encourage its prevention, detection, and treatment. In fact, WCD is celebrated every year on the 4(th) of February all over the world to commemorate all the accomplishments of the WHO. In this paper, we aimed to present the scientific evidence for the role of antioxidants in cancer. Damage to cells by reactive oxygen species, especially the damage to DNA, has been found to play a crucial role in the development of cancer. Exogenous antioxidants can prevent free radical damage associated with cancer development. However, whether or not taking dietary antioxidants can prevent or reduce the risk of developing cancer in humans is not clear. Some researchers have suggested that antioxidants counteract with drugs or toxins, which induce oxidative stress and hence prevent damage to cells or body organs. PMID- 26644909 TI - Does cervical lordosis change after spinal manipulation for non-specific neck pain? A prospective cohort study. AB - BACKGROUND: The association between cervical lordosis (sagittal alignment) and neck pain is controversial. Further, it is unclear whether spinal manipulative therapy can change cervical lordosis. This study aimed to determine whether cervical lordosis changes after a course of spinal manipulation for non-specific neck pain. METHODS: Posterior tangents of C2 and C6 were drawn on the lateral cervical fluoroscopic images of 29 patients with subacute/chronic non-specific neck pain and 30 healthy volunteers matched for age and gender, recruited August 2011 to April 2013. The resultant angle was measured using 'Image J' digital geometric software. The intra-observer repeatability (measurement error and reliability) and intra-subject repeatability (minimum detectable change (MDC) over 4 weeks) were determined in healthy volunteers. A comparison of cervical lordosis was made between patients and healthy volunteers at baseline. Change in lordosis between baseline and 4-week follow-up was determined in patients receiving spinal manipulation. RESULTS: Intra-observer measurement error for cervical lordosis was acceptable (SEM 3.6 degrees ) and reliability was substantial ICC 0.98, 95 % CI 0.962-0991). The intra-subject MDC however, was large (13.5 degrees ). There was no significant difference between lordotic angles in patients and healthy volunteers (p = 0.16). The mean cervical lordotic increase over 4 weeks in patients was 2.1 degrees (9.2) which was not significant (p = 0.12). CONCLUSIONS: This study found no difference in cervical lordosis (sagittal alignment) between patients with mild non-specific neck pain and matched healthy volunteers. Furthermore, there was no significant change in cervical lordosis in patients after 4 weeks of cervical spinal manipulation. PMID- 26644908 TI - Investigating mechanisms underpinning the detrimental impact of a high-fat diet in the developing and adult hypermuscular myostatin null mouse. AB - BACKGROUND: Obese adults are prone to develop metabolic and cardiovascular diseases. Furthermore, over-weight expectant mothers give birth to large babies who also have increased likelihood of developing metabolic and cardiovascular diseases. Fundamental advancements to better understand the pathophysiology of obesity are critical in the development of anti-obesity therapies not only for this but also future generations. Skeletal muscle plays a major role in fat metabolism and much work has focused in promoting this activity in order to control the development of obesity. Research has evaluated myostatin inhibition as a strategy to prevent the development of obesity and concluded in some cases that it offers a protective mechanism against a high-fat diet. METHODS: Pregnant as well as virgin myostatin null mice and age matched wild type animals were raised on a high fat diet for up to 10 weeks. The effect of the diet was tested on skeletal muscle, liver and fat. Quantitate PCR, Western blotting, immunohistochemistry, in-vivo and ex-vivo muscle characterisation, metabonomic and lipidomic measurements were from the four major cohorts. RESULTS: We hypothesised that myostatin inhibition should protect not only the mother but also its developing foetus from the detrimental effects of a high-fat diet. Unexpectedly, we found muscle development was attenuated in the foetus of myostatin null mice raised on a high-fat diet. We therefore re-examined the effect of the high-fat diet on adults and found myostatin null mice were more susceptible to diet-induced obesity through a mechanism involving impairment of inter-organ fat utilization. CONCLUSIONS: Loss of myostatin alters fatty acid uptake and oxidation in skeletal muscle and liver. We show that abnormally high metabolic activity of fat in myostatin null mice is decreased by a high-fat diet resulting in excessive adipose deposition and lipotoxicity. Collectively, our genetic loss-of-function studies offer an explanation of the lean phenotype displayed by a host of animals lacking myostatin signalling. PMID- 26644911 TI - Correction. AB - [This corrects the article DOI: 10.1136/vetreco-2015-000117.]. PMID- 26644910 TI - Treatment of bone marrow lesions (bone marrow edema). AB - Bone marrow lesions (BMLs) or using older terminology 'Bone marrow edema' is characterised by excessive water signals in the marrow space on magnetic resonance imaging or ultrasound; BMLs constitute a central component of a wide variety of inflammatory and non-inflammatory rheumatologic conditions affecting the musculoskeletal system: BMLs are not only considered significant sources of pain but also linked to increased disease activity in many musculoskeletal conditions (for example, osteoarthritis, rheumatoid arthritis). The purpose of this review is to summarise current knowledge about the treatment of BMLs, with an emphasis on the clinical and histological features of this entity in inflammatory and non-inflammatory disease. We also try to pair this hypothesis with the apparent beneficial effects of various treatment regimens, mainly within the group of bone antiresorptive drugs (calcitonin, bisphosphonates) on symptoms associated with BMLs. PMID- 26644912 TI - A comparative study of the morphology of mammalian chordae tendineae of the mitral and tricuspid valves. AB - It is assumed that the human heart is almost identical to domestic mammalian species, but with limited literature to support this. One such area that has been underinvestigated is that of the subvalvular apparatus level. The authors set out to examine the morphology of the subvalvular apparatus of the mammalian atrioventricular valves through gross dissection and microscopic analysis in a small-scale pilot study. The authors examined the chordae tendineae of the mitral and tricuspid valves in sheep, pig and bovine hearts, comparing the numbers of each of these structures within and between species. It was found that the number of chordae was up to twice as many for the tricuspid valve compared with the mitral valve. The counts for the chordae on the three valve leaflets of the tricuspid valve, as well as the two mitral valve leaflets, were almost identical between species. However, the chordae attaching onto the posterior papillary muscle were almost double compared with the septal and anterior papillary muscles. Histological analysis demonstrated an abrupt transitional zone. In conclusion, the authors have shown that there is no gross morphological difference between, or within, these species at the subvalvular apparatus level. PMID- 26644913 TI - Carcass traits, meat yield and fatty acid composition of adipose tissues and Supraspinatus muscle in goats fed blend of canola oil and palm oil. AB - BACKGROUND: Dietary fats can alter the deposition and distribution of body fats in ruminants. The deposition and distribution of body fat play a vital role in the quality of ruminant carcasses and are of great commercial value since they influence the profitability and consumer acceptability of ruminant meat. The current study examined the effects of dietary blend of 80 % canola oil and 20 % palm oil (BCPO) on carcass characteristics, meat yield and accretion of fatty acid (FA) in subcutaneous, omental, perirenal, and mesentery adipose depots and m. supraspinatus (SS) in goats. METHODS: Twenty four Boer crossbred bucks (BW 20.54 +/- 0.47 kg) were randomly assigned to diets containing on DM basis 0, 4 and 8 % BCPO, fed for 100 d and harvested. RESULTS: Diet had no effect (P > 0.05) on slaughter weight, dressing percentage, carcass and non-carcass components, meat yield, color, moisture and carotenoid contents and weight of adipose tissues in goats. The proportion of C18:1n-9 and cis-9 trans-11 CLA in the omental, perirenal and SS was higher (P < 0.05) in goats fed 4 and 8 % BCPO compared with the control goats. Dietary BCPO reduced (P < 0.05) the proportion of C14:0 in the omental, perirenal and mesentery depots, C18:0 in the perirenal depot, C16:0 in the SS and C16:1n-7 in the SS, omental and perirenal tissues. Dietary BCPO enhanced the proportion of C18:1 trans-11 Vaccenic and C18:3n-3 in SS and C20:5n 3 in SS and mesentery depot. No significant changes were found in the FA composition of subcutaneous depot. CONCLUSIONS: Results indicate that dietary BCPO can be utilized to alter the FA composition of adipose tissues without detrimental effects on carcass characteristics in goats. Nonetheless, dietary BCPO is not an effective repartitioning agent for body fats in goats. PMID- 26644914 TI - Evolution of probiotics in aquatic world: Potential effects, the current status in Egypt and recent prospectives. AB - The increase in the human population in addition to the massive demand for protein of animal origin forced the authorities to seek for additional sources of feed supplies. Aquaculture is the world worth coming expansion to compensate the shortage in animal protein. Feed in aquaculture plays an important role in the production cycle and exert threshold on both practical and economic aspects. Feed additive sectors are expanding day after day to achieve better growth and health for fish and shrimp and to meet the potential requirements of the culturists. Probiotic proved its successes in human and animal feeding practices and recently gained attention in aquaculture; it has beneficial effects in diseases control and competes with various environmental stressors as well as to promote the growth of the cultured organisms. Probiotics have the privilege to manipulate the non-specific innate immunity among fishes, hence help them into resist many pathogenic agents and are actively used worldwide. The present review is an informative compilation of the probiotics, their mode of action and their useful effects on fishes. The review also highlights the status of probiotics in aquaculture of Egypt, probiotic recent prospective for the possible role of probiotics in fish external and internal environment. PMID- 26644917 TI - An investigation on chloroprene-compatibilized acrylonitrile butadiene rubber/high density polyethylene blends. AB - Blends of acrylonitrile butadiene rubber/high density polyethylene (NBR/HDPE) compatibilized by Chloroprene rubber (CR) were prepared. A fixed quantity of industrial waste such as marble waste (MW, 40 phr) was also included. The effect of the blend ratio and CR on cure characteristics, mechanical and swelling properties of MW-filled NBR/HDPE blends was investigated. The results showed that the MW-filled NBR/HDPE blends revealed an increase in tensile strength, tear, modulus, hardness and cross-link density for increasing weight ratio of HDPE. The minimum torque (M L) and maximum torque (M H) of blends increased with increasing weight ratio of HDPE while scorch time (ts2) cure time (tc90), compression set and abrasion loss of blends decreased with increasing weight ratio of HDPE. The blends also showed a continuous reduction in elongation at break as well as swelling coefficient with increasing HDPE amount in blends. MW filled blends based on CR provided the most encouraging balance values of overall properties. PMID- 26644918 TI - Performance and emission characteristics of the thermal barrier coated SI engine by adding argon inert gas to intake mixture. AB - Dilution of the intake air of the SI engine with the inert gases is one of the emission control techniques like exhaust gas recirculation, water injection into combustion chamber and cyclic variability, without scarifying power output and/or thermal efficiency (TE). This paper investigates the effects of using argon (Ar) gas to mitigate the spark ignition engine intake air to enhance the performance and cut down the emissions mainly nitrogen oxides. The input variables of this study include the compression ratio, stroke length, and engine speed and argon concentration. Output parameters like TE, volumetric efficiency, heat release rates, brake power, exhaust gas temperature and emissions of NOx, CO2 and CO were studied in a thermal barrier coated SI engine, under variable argon concentrations. Results of this study showed that the inclusion of Argon to the input air of the thermal barrier coated SI engine has significantly improved the emission characteristics and engine's performance within the range studied. PMID- 26644915 TI - Vitamin D and the skin: Focus on a complex relationship: A review. AB - The "sunshine" vitamin is a hot topic that attracted ample attention over the past decades, specially that a considerable proportion of the worldwide population are deficient in this essential nutrient. Vitamin D was primarily acknowledged for its importance in bone formation, however; increasing evidence point to its interference with the proper function of nearly every tissue in our bodies including brain, heart, muscles, immune system and skin. Thereby its deficiency has been incriminated in a long panel of diseases including cancers, autoimmune diseases, cardiovascular and neurological disorders. Its involvement in the pathogenesis of different dermatological diseases is no exception and has been the subject of much research over the recent years. In the current review, we will throw light on this highly disputed vitamin that is creating a significant concern from a dermatological perspective. Furthermore, the consequences of its deficiency on the skin will be in focus. PMID- 26644916 TI - Effect of ultrasound application during setting on the mechanical properties of high viscous glass-ionomers used for ART restorations. AB - This study was conducted to evaluate the effect of ultrasound application on the surface microhardness (VHN) and diametral tensile strength (DTS) of three high viscous glass-ionomer restorative materials (HVGIRMs). For each test (VHN and DTS), a total of 180 specimens were prepared from three HVGIRMs (Ketac-Molar Aplicap, Fuji IX GP Fast, and ChemFil Rock). Specimens of each material (n = 60) were further subdivided into three subgroups (n = 20) according to the setting modality whether ultrasound (20 or 40 s) was applied during setting or not (control). Specimens within each subgroup were then equally divided (n = 10) and tested at 24 h or 28 days. For the VHN measurement, five indentations, with a 200 g load and a dwell time for 20 s, were made on the top surface of each specimen. The DTS test was done using Lloyd Testing machine at a cross-head speed of 0.5 mm/min. Ultrasound application had no significant effect on the VHN. Fuji IX GP Fast revealed the highest VHN value, followed by Ketac-Molar Aplicap, and the least was recorded for ChemFil Rock. Fuji IX GP Fast and Ketac-Molar Aplicap VHN values were significantly increased by time. ChemFil Rock recorded the highest DTS value at 24 h and was the only material that showed significant improvement with both US application times. However, this improvement did not sustain till 28 days. The ultrasound did not enhance the surface microhardness, but its positive effect on the diametral tensile strength values was material and time dependent. PMID- 26644919 TI - Mass size distributions of elemental aerosols in industrial area. AB - Outdoor aerosol particles were characterized in industrial area of Samalut city (El-minia/Egypt) using low pressure Berner cascade impactor as an aerosol sampler. The impactor operates at 1.7 m(3)/h flow rate. Seven elements were investigated including Ca, Ba, Fe, K, Cu, Mn and Pb using atomic absorption technique. The mean mass concentrations of the elements ranged from 0.42 ng/m(3) (for Ba) to 89.62 ng/m(3) (for Fe). The mass size distributions of the investigated elements were bi-modal log normal distribution corresponding to the accumulation and coarse modes. The enrichment factors of elements indicate that Ca, Ba, Fe, K, Cu and Mn are mainly emitted into the atmosphere from soil sources while Pb is mostly due to anthropogenic sources. PMID- 26644920 TI - Structural mass irregularities and fiber volume influence on morphology and mechanical properties of unsaturated polyester resin in matrix composites. AB - This paper presents the comparative results of a current study on unsaturated polyester resin (UPR) matrix composites processed by filament winding method, with cotton spun yarn of different mass irregularities and two different volume fractions. Physical and mechanical properties were measured, namely ultimate stress, stiffness, elongation%. The mechanical properties of the composites increased significantly with the increase in the fiber volume fraction in agreement with the Counto model. Mass irregularities in the yarn structure were quantitatively measured and visualized by scanning electron microscopy (SEM). Mass irregularities cause marked decrease in relative strength about 25% and 33% which increases with fiber volume fraction. Ultimate stress and stiffness increases with fiber volume fraction and is always higher for yarn with less mass irregularities. PMID- 26644921 TI - Non-uniform cosine modulated filter banks using meta-heuristic algorithms in CSD space. AB - This paper presents an efficient design of non-uniform cosine modulated filter banks (CMFB) using canonic signed digit (CSD) coefficients. CMFB has got an easy and efficient design approach. Non-uniform decomposition can be easily obtained by merging the appropriate filters of a uniform filter bank. Only the prototype filter needs to be designed and optimized. In this paper, the prototype filter is designed using window method, weighted Chebyshev approximation and weighted constrained least square approximation. The coefficients are quantized into CSD, using a look-up-table. The finite precision CSD rounding, deteriorates the filter bank performances. The performances of the filter bank are improved using suitably modified meta-heuristic algorithms. The different meta-heuristic algorithms which are modified and used in this paper are Artificial Bee Colony algorithm, Gravitational Search algorithm, Harmony Search algorithm and Genetic algorithm and they result in filter banks with less implementation complexity, power consumption and area requirements when compared with those of the conventional continuous coefficient non-uniform CMFB. PMID- 26644922 TI - Effect of artemether on cytokine profile and egg induced pathology in murine schistosomiasis mansoni. AB - Artemether (ART), the methylated derivative of artemisinin, is an efficacious antimalarial drug that also displays antischistosomal properties. This study was designed to evaluate the immunomodulatory action of a single intramuscular dose (50 mg/kg body weight) of ART in comparison with PZQ treatment (42 days PI). ART administration was 7, 14, 21 and 45 days PI. ART effect was studied parasitologically, histopathologically and immunologically. It was found that maximum effect was reached when ART treatment interfered with 14 or 21 days old schistosomula. ART treatment 14 or 21 days PI was associated with shift from Th2 to Th1 predominancy (decrease in IL-4 and upgrading of serum IFN-gamma levels). In conclusion, ART is a promising drug in control of schistosomiasis mansoni due to its reductive effect on worm burden and its role in improvement of hepatic granulomatous lesions. PMID- 26644923 TI - Inbreeding, outbreeding and RAPD markers studies of faba bean (Vicia faba L.) crop. AB - Five faba bean genotypes (Vicia faba L.) were selfed for two cycles to produce S1 and S2 generations. A half-diallel cross was carried out among them in each level of inbreeding (S0, S1 and S2) to obtain 10 F1 hybrids. Parental materials as well as their respective F1s were evaluated during the winter season of 2012. All studied traits except total dry seed yield showed significant inbreeding depression after the first generation of selfing (S1). No further decrease was noticed at the S2 generation. In the S1 generation the degree of inbreeding depression was highest for No. of branches/plant (-14.0%) and the least for weight of 100-seeds (-2.7). Some parents showed inbreeding vigor i.e. positive difference between S2 and S1 for some traits in S2 generation. Most studied traits showed significant positive heterosis values over mid-parent. The highest value of heterosis over the mid-parent was detected for total dry seed yield (128.8) and the lowest value of hybrid vigor was shown by weight of 100-seeds (1.2%). Specific combination among the 5 parental genotypes showed the highest value for heterosis for example cross Misr 2 * Giza 429 was the best cross for total dry seed yield, cross Giza 429 * Misr 1 for No. of branches/plant. Giza 429 is the best general combiner for most traits. Some crosses showed heterosis depression i.e. negative heterosis value in some traits. Hybridization among parental genotypes is recommended to be at the S1 or S2 generation. Twelve arbitrary primers produced different degrees of genetic polymorphism among the parental genotypes. A total of 65 amplification products were scored polymorphic. The percentage of polymorphic bands detected ranged from 33% to 100% with an average of 66.47%. The average of amplified bands was 5.42 polymorphic bands per primer. A positive, but non-significant, correlation (r = 0.085) between Euclidean distance and RAPD distance was observed. PMID- 26644924 TI - Endophytic l-asparaginase-producing fungi from plants associated with anticancer properties. AB - Endophytes are novel sources of natural bioactive compounds. This study seeks endophytes that produce the anticancer enzyme l-asparaginase, to harness their potential for mass production. Four plants with anticancer properties; Cymbopogon citratus, Murraya koenigii, Oldenlandia diffusa and Pereskia bleo, were selected as host plants. l-Asparaginase-producing endophytes were detected by the formation of pink zones on agar, a result of hydrolyzes of asparagine into aspartic acid and ammonia that converts the phenol red dye indicator from yellow (acidic condition) to pink (alkaline condition). The anticancer enzyme asparaginase was further quantified via Nesslerization. Results revealed that a total of 89 morphotypes were isolated; mostly from P. bleo (40), followed by O. diffusa (25), C. citratus (14) and M. koenigii (10). Only 25 of these morphotypes produced l-asparaginase, mostly from P. bleo and their asparaginase activities were between 0.0069 and 0.025 MUM mL(-1) min(-1). l-Asparaginase producing isolates were identified as probable species of the genus Colletotrichum, Fusarium, Phoma and Penicillium. Studies here revealed that endophytes are good alternative sources for l-asparaginase production and they can be sourced from anticancer plants, particularly P. bleo. PMID- 26644925 TI - Upregulation of Toll-like receptor 2 and nuclear factor-kappa B expression in experimental colonic schistosomiasis. AB - Role of different mediators was described in the development of the granulomatous response and fibrosis observed in intestinal schistosomiasis. However, both Toll like receptor 2 (TLR2) and nuclear factor kappa B (NF-kappaB) have not yet been investigated in intestinal schistosomiasis. This study aimed to characterize the role of TLR2 and NF-kappaB in the pathogenesis of intestinal schistosomiasis. Experimental animals were divided into two groups; group I: non-infected control group and group II: mice infected subcutaneously with S. mansoni cercariae. Colon samples were taken from infected mice, every two weeks, starting from the 6th week postinfection (PI) till 18th week PI. Samples were subjected to histopathological and immunohistochemical studies. Colon of S. mansoni infected mice showed histopathological changes in the form of mucosal degeneration, transmural mononuclear cellular infiltration and granulomas formation. Immunostained sections revealed significant increase in TLR2 and NF-kappaB positive cells in all layers of the colon, cells of the granuloma and those of the lymphoid follicles 10 weeks PI. All these changes decreased gradually starting from 12 weeks PI onward to be localized focally at 18 weeks PI. In conclusion, recruitment and activation of inflammatory cells to the colonic mucosa in intestinal schistosomiasis are multifactorial events involving TLR2 that can trigger the NF-kappaB pathways. Hence, down-regulation of both TLR2 and NF-kappaB could be exploited in the treatment of colonic schistosomiasis. PMID- 26644926 TI - Utility of N-aryl 2-aroylhydrazono-propanehydrazonoyl chlorides as precursors for synthesis of new functionalized 1,3,4-thiadiazoles with potential antimicrobial activity. AB - Starting from N-aryl 2-aroylhydrazono-propanehydrazonoyl chlorides, a series of new functionalized 1,3,4-thiadiazoles were prepared. The structures of the compounds prepared were confirmed by both elemental and spectral analyses as well as by alternate synthesis. The mechanisms of the studied reactions are outlined. The antimicrobial activities of the compounds prepared were screened and the results showed that most of such compounds exhibit considerable activities. PMID- 26644927 TI - Exponentiated power Lindley distribution. AB - A new generalization of the Lindley distribution is recently proposed by Ghitany et al. [1], called as the power Lindley distribution. Another generalization of the Lindley distribution was introduced by Nadarajah et al. [2], named as the generalized Lindley distribution. This paper proposes a more generalization of the Lindley distribution which generalizes the two. We refer to this new generalization as the exponentiated power Lindley distribution. The new distribution is important since it contains as special sub-models some widely well-known distributions in addition to the above two models, such as the Lindley distribution among many others. It also provides more flexibility to analyze complex real data sets. We study some statistical properties for the new distribution. We discuss maximum likelihood estimation of the distribution parameters. Least square estimation is used to evaluate the parameters. Three algorithms are proposed for generating random data from the proposed distribution. An application of the model to a real data set is analyzed using the new distribution, which shows that the exponentiated power Lindley distribution can be used quite effectively in analyzing real lifetime data. PMID- 26644928 TI - Strength development in concrete with wood ash blended cement and use of soft computing models to predict strength parameters. AB - In this study, Wood Ash (WA) prepared from the uncontrolled burning of the saw dust is evaluated for its suitability as partial cement replacement in conventional concrete. The saw dust has been acquired from a wood polishing unit. The physical, chemical and mineralogical characteristics of WA is presented and analyzed. The strength parameters (compressive strength, split tensile strength and flexural strength) of concrete with blended WA cement are evaluated and studied. Two different water-to-binder ratio (0.4 and 0.45) and five different replacement percentages of WA (5%, 10%, 15%, 18% and 20%) including control specimens for both water-to-cement ratio is considered. Results of compressive strength, split tensile strength and flexural strength showed that the strength properties of concrete mixture decreased marginally with increase in wood ash contents, but strength increased with later age. The XRD test results and chemical analysis of WA showed that it contains amorphous silica and thus can be used as cement replacing material. Through the analysis of results obtained in this study, it was concluded that WA could be blended with cement without adversely affecting the strength properties of concrete. Also using a new statistical theory of the Support Vector Machine (SVM), strength parameters were predicted by developing a suitable model and as a result, the application of soft computing in structural engineering has been successfully presented in this research paper. PMID- 26644929 TI - RF cavity design exploiting a new derivative-free trust region optimization approach. AB - In this article, a novel derivative-free (DF) surrogate-based trust region optimization approach is proposed. In the proposed approach, quadratic surrogate models are constructed and successively updated. The generated surrogate model is then optimized instead of the underlined objective function over trust regions. Truncated conjugate gradients are employed to find the optimal point within each trust region. The approach constructs the initial quadratic surrogate model using few data points of order O(n), where n is the number of design variables. The proposed approach adopts weighted least squares fitting for updating the surrogate model instead of interpolation which is commonly used in DF optimization. This makes the approach more suitable for stochastic optimization and for functions subject to numerical error. The weights are assigned to give more emphasis to points close to the current center point. The accuracy and efficiency of the proposed approach are demonstrated by applying it to a set of classical bench-mark test problems. It is also employed to find the optimal design of RF cavity linear accelerator with a comparison analysis with a recent optimization technique. PMID- 26644930 TI - A study on the empirical distribution of the scaled Hankel matrix eigenvalues. AB - The empirical distribution of the eigenvalues of the matrix XX(T) divided by its trace is evaluated, where X is a random Hankel matrix. The distribution of eigenvalues for symmetric and nonsymmetric distributions is assessed with various criteria. This yields several important properties with broad application, particularly for noise reduction and filtering in signal processing and time series analysis. PMID- 26644931 TI - Simultaneous determination of rosuvastatin and amlodipine in human plasma using tandem mass spectrometry: Application to disposition kinetics. AB - The liquid chromatography-tandem mass spectrometric assay method for the simultaneous determination of rosuvastatin and amlodipine in human plasma using deuterated analogs as internal standards has been developed and validated. The analytes were extracted from 100 MUL aliquots of human plasma via liquid-liquid extraction using a mixture of ethyl acetate and n-hexane (80:20, v/v) as an extraction solvent. The optimized mobile phase was composed of 0.1% formic acid in 5 mM ammonium acetate, methanol, and acetonitrile (20:20:60, v/v/v) and delivered at a flow rate of 0.75 mL/min. The calibration curve obtained was linear (R (2) ? 0.999) over the concentration range of 0.52-51.77 ng/mL for rosuvastatin and 0.10-10.07 ng/mL for amlodipine. A sample turnover rate of less than 2.5 min makes it an attractive procedure in high-throughput bioanalysis of rosuvastatin and amlodipine. The present method was found to be applicable to clinical studies and the results were authenticated by incurred sample reanalysis. PMID- 26644932 TI - Microwave assisted one-pot catalyst free green synthesis of new methyl-7-amino-4 oxo-5-phenyl-2-thioxo-2,3,4,5-tetrahydro-1H-pyrano[2,3-d]pyrimidine-6 carboxylates as potent in vitro antibacterial and antifungal activity. AB - An efficiently simple protocol for the synthesis of methyl 7 amino-4-oxo-5-phenyl 2-thioxo-2, 3, 4,5-tetrahydro-1H-pyrano[2,3-d]pyrimidine-6-carboxylates via one pot three component condensation pathway is established via microwave irradiation using varied benzaldehyde derivatives, methylcyanoacetate and thio-barbituric acid in water as a green solvent. A variety of functionalized substrates were found to react under this methodology due to its easy operability and offers several advantages like, high yields (78-94%), short reaction time (3-6 min), safety and environment friendly without used any catalyst. The synthesized compounds (4a-4k) showed comparatively good in vitro antimicrobial and antifungal activities against different strains. The Compounds 4a, 4b, 4c, 4d 4e and 4f showed maximum antimicrobial activity against Staphylococcus aureus, Bacillus cereus (gram-positive bacteria), Escherichia coli, Klebshiella pneumonia, Pseudomonas aeruginosa (gram-negative bacteria). The synthesized compound 4f showed maximum antifungal activity against Aspergillus Niger and Penicillium chrysogenum strains. Streptomycin is used as standard for bacterial studies and Mycostatin as standards for fungal studies. Structure of all newly synthesized products was characterized on the basis of IR, (1)H NMR, (13)C NMR and mass spectral analysis. PMID- 26644933 TI - New hybrid frequency reuse method for packet loss minimization in LTE network. AB - This paper investigates the problem of inter-cell interference (ICI) in Long Term Evolution (LTE) mobile systems, which is one of the main problems that causes loss of packets between the base station and the mobile station. Recently, different frequency reuse methods, such as soft and fractional frequency reuse, have been introduced in order to mitigate this type of interference. In this paper, minimizing the packet loss between the base station and the mobile station is the main concern. Soft Frequency Reuse (SFR), which is the most popular frequency reuse method, is examined and the amount of packet loss is measured. In order to reduce packet loss, a new hybrid frequency reuse method is implemented. In this method, each cell occupies the same bandwidth of the SFR, but the total system bandwidth is greater than in SFR. This will provide the new method with a lot of new sub-carriers from the neighboring cells to reduce the ICI which represents a big problem in many applications and causes a lot of packets loss. It is found that the new hybrid frequency reuse method has noticeable improvement in the amount of packet loss compared to SFR method in the different frequency bands. Traffic congestion management in Intelligent Transportation system (ITS) is one of the important applications that is affected by the packet loss due to the large amount of traffic that is exchanged between the base station and the mobile node. Therefore, it is used as a studied application for the proposed frequency reuse method and the improvement in the amount of packet loss reached 49.4% in some frequency bands using the new hybrid frequency reuse method. PMID- 26644934 TI - Determination of melamine in soil samples using surfactant-enhanced hollow fiber liquid phase microextraction followed by HPLC-UV using experimental design. AB - Surfactant-enhanced hollow fiber liquid phase (SE-HF-LPME) microextraction was applied for the extraction of melamine in conjunction with high performance liquid chromatography with UV detection (HPLC-UV). Sodium dodecyl sulfate (SDS) was added firstly to the sample solution at pH 1.9 to form hydrophobic ion-pair with protonated melamine. Then the protonated melamine-dodecyl sulfate ion-pair (Mel-DS) was extracted from aqueous phase into organic phase immobilized in the pores and lumen of the hollow fiber. After extraction, the analyte-enriched 1 octanol was withdrawn into the syringe and injected into the HPLC. Preliminary, one variable at a time method was applied to select the type of extraction solvent. Then, in screening step, the other variables that may affect the extraction efficiency of the analyte were studied using a fractional factorial design. In the next step, a central composite design was applied for optimization of the significant factors having positive effects on extraction efficiency. The optimum operational conditions included: sample volume, 5 mL; surfactant concentration, 1.5 mM; pH 1.9; stirring rate, 1500 rpm and extraction time, 60 min. Using the optimum conditions, the method was analytically evaluated. The detection limit, relative standard deviation and linear range were 0.005 MUg mL( 1), 4.0% (3 MUg mL(-1), n = 5) and 0.01-8 MUg mL(-1), respectively. The performance of the procedure in extraction of melamine from the soil samples was good according to its relative recoveries in different spiking levels (95-109%). PMID- 26644935 TI - Effect of aliskiren, telmisartan and torsemide on cardiac dysfunction in l-nitro arginine methyl ester (l-NAME) induced hypertension in rats. AB - Comparative study of cardio protective effect of aliskiren, telmisartan, and torsemide was carried out on l-nitro arginine methyl ester (l-NAME) induced hypertension in rats. The three drugs were given daily for 8 weeks simultaneously with l-NAME, with a control group for each drug and l-NAME. The degree of protection was assessed by measurement of systolic blood pressure and heart rate of animals every two weeks. At the end of the experimental period blood sampling was carried out for estimation of the level of NO2 (-)/NO3 (-). After which animals were sacrificed for heart dissection to detect collagen types I and III gene expression. Histopathological study was done to evaluate the extension of collagen deposits. The study revealed that the three drugs decreased blood pressure significantly compared to l-NAME. There was no significant difference between aliskiren and telmisartan in all measurements, but there was significant decrease in measurements of both aliskiren and telmisartan treated groups compared to torsemide starting from 4th week. There were insignificant changes in pulse rate values between the three l-NAME treated groups through the experiment. The three drugs significantly increased NO compared to l-NAME. Collagen I and III gene expression was significantly decreased by the three drugs but the highest percentage of inhibition was with telmisartan compared to l-NAME. Comparing the percentage inhibition of cardiac fibrosis, there was insignificant difference between telmisartan and torsemide treated groups while both were superior to aliskiren. In conclusion, further experimental studies are required to elucidate the potential cardioprotective mechanisms of aliskiren, telmisartan and torsemide, and assess their efficacy in treatment of heart failure. PMID- 26644936 TI - A green and efficient protocol for the synthesis of dihydropyrano[2,3-c]pyrazole derivatives via a one-pot, four component reaction by grinding method. AB - An efficient grinding protocol for the synthesis of dihydropyrano[2,3-c]pyrazole derivatives from acetylene ester, hydrazine hydrate, aryl aldehydes and malononitrile under solvent free conditions has been achieved with excellent yields. The structures of the synthesized compounds were deduced by spectroscopic techniques and the compounds were further evaluated for their in vitro antioxidant and antimicrobial activities. PMID- 26644937 TI - Sort-Mid tasks scheduling algorithm in grid computing. AB - Scheduling tasks on heterogeneous resources distributed over a grid computing system is an NP-complete problem. The main aim for several researchers is to develop variant scheduling algorithms for achieving optimality, and they have shown a good performance for tasks scheduling regarding resources selection. However, using of the full power of resources is still a challenge. In this paper, a new heuristic algorithm called Sort-Mid is proposed. It aims to maximizing the utilization and minimizing the makespan. The new strategy of Sort Mid algorithm is to find appropriate resources. The base step is to get the average value via sorting list of completion time of each task. Then, the maximum average is obtained. Finally, the task has the maximum average is allocated to the machine that has the minimum completion time. The allocated task is deleted and then, these steps are repeated until all tasks are allocated. Experimental tests show that the proposed algorithm outperforms almost other algorithms in terms of resources utilization and makespan. PMID- 26644938 TI - Deposition of chromium in aquatic ecosystem from effluents of handloom textile industries in Ranaghat-Fulia region of West Bengal, India. AB - Accumulation of chromium (Cr) was determined in water, sediment, aquatic plants, invertebrates and fish in aquatic ecosystems receiving effluents from handloom textile industries in Ranaghat-Fulia region of West Bengal in India. Cr was determined in the samples by atomic absorption spectrophotometer and data were analyzed functionally by Genetic Algorithm to determine trend of depositions of Cr in the sediment and water. Area plot curve was used to represent accumulation of Cr in biota. The results indicate that the aquatic ecosystems receiving the effluents from handloom textile factories are heavily contaminated by Cr. The contamination is hardly reflected in the concentration of Cr in water, but sediment exhibits seasonal fluctuation in deposition of Cr, concentration reaching to as high as 451.0 MUg g(-1) during the peak production period. There is a clear trend of gradual increase in the deposition of Cr in the sediment. Aquatic weed, insect and mollusk specimens collected from both closed water bodies (S1 & S2) and riverine resources (S3 & S4) showed high rate of accumulation of Cr. Maximum concentration of Cr was detected in roots of aquatic weeds (877.5 MUg g(-1)). Fish specimens collected from the polluted sites (S3 & S4) of river Churni showed moderate to high concentration of Cr in different tissues. Maximum concentration was detected in the liver of Glossogobius giuris (679.7 MUg g(-1)) during monsoon followed by gill of Mystus bleekeri (190.0 MUg g(-1)) and gut of G. giuris (123.7 MUg g(-1)) during summer. Eutropiichthys vacha showed moderately high concentration of Cr in different tissues (65-99 MUg g(-1)) while Puntius sarana showed relatively low concentration of Cr (below detection limit to 18.0 MUg g(-1)) in different tissues except in gill (64.4 MUg g(-1)). PMID- 26644939 TI - Treatment of an automobile effluent from heavy metals contamination by an eco friendly montmorillonite. AB - Unmodified montmorillonite clay was utilized as a low cost adsorbent for the removal of heavy metals from a contaminated automobile effluent. Fourier transform infrared spectroscopy, X-ray diffraction and scanning electron microscopy were used to characterize the adsorbent. Batch sorption experiments were performed at an optimum effluent pH of 6.5, adsorbent dose of 0.1 g, particle size of 100 MUm and equilibrium contact time of 180 min. Thermodynamic analysis was also conducted. Equilibrium data were analyzed by the Langmuir, Freundlich, Temkin and Dubinin-Radushkevich models. A heterogeneous surface of the adsorbent was indicated by the Freundlich model. The Langmuir maximum adsorption capacity of the montmorillonite for metals was found in the following order: Zn (5.7 mg/g) > Cu (1.58 mg/g) > Mn (0.59 mg/g) > Cd (0.33 mg/g) > Pb (0.10 mg/g) = Ni (0.10 mg/g). This was directly related to the concentration of the metal ions in solution. The pseudo-first order, pseudo-second order, intraparticle diffusion and liquid film diffusion models were applied for kinetic analysis. The mechanism of sorption was found to be dominated by the film diffusion mechanism. The results of this study revealed the potential of the montmorillonite for treatment of heavy metal contaminated effluents. PMID- 26644940 TI - Monthly variations of Rhinoestrus spp. (Diptera: Oestridae) larvae infesting donkeys in Egypt: Morphological and molecular identification of third stage larvae. AB - This study was carried out to investigate the prevalence and monthly intensity of Rhinoestrus (R) spp. among donkeys slaughtered at Giza Zoo abattoir, Egypt. A total of 144 donkeys were examined at postmortem through two visits per month from January 2010 to December 2010. All donkeys were infested with one or more larval stages during all months of the examination period (100%). The 1st and 2nd stage larvae (L1 and L2) were mostly observed in the turbinate bones and seldom in the nasal passages, whereas the 3rd stage larvae (L3) were observed mostly in ethmoid and lamina cribrosa and rarely in nasal passages and pharynx. The highest monthly intensity of infestation with the total number of larval stages was recorded in January and August, while the lowest occurred in September. L1 was observed during all months with two peaks in January and June. L2 occurred from February to April, July, and August. L3 was present from March to May, August, and September. The ranked size of infestation with the total number of the 3 larval stages of Rhinoestrus spp. showed that a total of 107 donkeys had 1-10 larvae; 34 had 11-30 larvae; and 3 harbored 31-50 larvae. The morphology and molecular characterization of the third stage larvae of Rhinoestrus spp. were investigated. Morphologically, two morphotypes (1 and 2) of Rhinoestrus spp. (R. usbekistanicus like and the other R. purpureus like) were reported. Whereas molecular sequencing of mitochondrial cytochrome-oxidase subunit I showed 99% homology with those of R. usbekistanicus. In conclusion, Rhinoestrus spp. present in Egypt is mainly R. usbekistanicus, which includes two morphotypes, R. usbekistanicus like and R. purpureus like. PMID- 26644941 TI - The modulation of erythrocyte Na(+)/K(+)-ATPase activity by curcumin. AB - Curcumin, an active biphenolic molecule present in turmeric (Curcuma longa), has been reported to elicit plethora of health protective effects. The present study was carried out in vitro, in vivo and in silico to investigate the modulatory effects of curcumin on erythrocyte membrane Na(+)/K(+)-ATPase activity. In vitro curcumin (10(-) (5) M to 10(-) (8) M) was incubated with human erythrocytes membrane. In vivo curcumin (340 mg/kg b.w. and 170 mg/kg b.w.) was supplemented to wistar rats for 21 days. In silico, catalytic unit alpha of Na(+)/K(+)-ATPase (3b8e.pdb) protein was used as a receptor for the natural ligand ATP to study curcumin-mediated docking simulation using AutoDock4. The in vitro effect of curcumin on the Na(+)/K(+)-ATPase activity in human erythrocytes was biphasic. An inhibitory response was observed at 10(-) (5) M (p < 0.001). An activation of the Na(+)/K(+)-ATPase activity was observed at 10(-) (7) and 10(-) (8) M (p < 0.001 and p < 0.01). In vivo, curcumin supplementation to rats increased the Na(+)/K(+) ATPase activity at doses 340 mg/kg b.w. (p < 0.001) as well as at 170 mg/kg b.w., (p < 0.01). AutoDock4 docking simulation study showed that both ligands curcumin and ATP actively interacted with amino acids Glu214, Ser215, Glu216, Thr371, Asn377, Arg378, Met379, Arg438, Val440, Ala444, Lys451 and Asp586 at the catalytic cavity of Na+/K+-ATPase. ATP had more H bonding and hydrophobic interaction with active site amino acid residues compared to curcumin. These finding may explain some of the health beneficial properties of curcumin associated with deregulated Na(+)/K(+)-ATPase activity or ions homeostasis. PMID- 26644942 TI - Hydrogeochemical evolution of inland lakes' water: A study of major element geochemistry in the Wadi El Raiyan depression, Egypt. AB - Wadi El Raiyan is a great depression located southwest of Cairo in the Western Desert of Egypt. Lake Qarun, located north of the study area, is a closed basin with a high evaporation rate. The source of water in the lake is agricultural and municipal drainage from the El Faiyum province. In 1973, Wadi El Raiyan was connected with the agricultural wastewater drainage system of the Faiyum province and received water that exceeded the capacity of Lake Qarun. Two hydrogeological regimes have been established in the area: (i) higher cultivated land and (ii) lower Wadi El Raiyan depression lakes. The agricultural drainage water of the cultivated land has been collected in one main drain (El Wadi Drain) and directed toward the Wadi El Raiyan depression, forming two lakes at different elevations (upper and lower). In the summer of 2012, the major chemical components were studied using data from 36 stations distributed over both hydrogeological regimes in addition to one water sample collected from Bahr Youssef, the main source of freshwater for the Faiyum province. Chemical analyses were made collaboratively. The major ion geochemical evolution of the drainage water recharging the El Raiyan depression was examined. Geochemically, the Bahr Youssef sample is considered the starting point in the geochemical evolution of the studied surface water. In the cultivated area, major-ion chemistry is generally influenced by chemical weathering of rocks and minerals that are associated with anthropogenic inputs, as well as diffuse urban and/or agricultural drainage. In the depression lakes, the water chemistry generally exhibits an evaporation-dependent evolutionary trend that is further modified by cation exchange and precipitation of carbonate minerals. PMID- 26644943 TI - Intensity-Curvature Measurement Approaches for the Diagnosis of Magnetic Resonance Imaging Brain Tumors. AB - This research presents signal-image post-processing techniques called Intensity Curvature Measurement Approaches with application to the diagnosis of human brain tumors detected through Magnetic Resonance Imaging (MRI). Post-processing of the MRI of the human brain encompasses the following model functions: (i) bivariate cubic polynomial, (ii) bivariate cubic Lagrange polynomial, (iii) monovariate sinc, and (iv) bivariate linear. The following Intensity-Curvature Measurement Approaches were used: (i) classic-curvature, (ii) signal resilient to interpolation, (iii) intensity-curvature measure and (iv) intensity-curvature functional. The results revealed that the classic-curvature, the signal resilient to interpolation and the intensity-curvature functional are able to add additional information useful to the diagnosis carried out with MRI. The contribution to the MRI diagnosis of our study are: (i) the enhanced gray level scale of the tumor mass and the well-behaved representation of the tumor provided through the signal resilient to interpolation, and (ii) the visually perceptible third dimension perpendicular to the image plane provided through the classic curvature and the intensity-curvature functional. PMID- 26644944 TI - Selenium and Vitamin E as antioxidants in chronic hemolytic anemia: Are they deficient? A case-control study in a group of Egyptian children. AB - Accelerated oxidative damage is one of the hallmarks in both sickle cell disease (SCD) and thalassemia major (TM). A decreased antioxidant level is found in both diseases. Our study was carried out to evaluate the variation in serum levels of Selenium and Vitamin E among a group of transfusion dependant Egyptian SCD and TM patients, further more to correlate these levels with iron overload status or transfusion requirements. A case-control study was conducted at the Cairo University Pediatric Hospital to assess the serum levels of Selenium using Atomic Absorption Spectrometer and Vitamin E using commercially available ELISA Kit in transfusion dependent children, 30 with beta thalassemia and 30 with SCD in a steady state aged from 6 to 18 years, these findings were compared to 30 age/sex matched healthy controls. Our results revealed a depleted antioxidants level in the studied group of Egyptian children with TM and SCD relative to healthy controls (P < 0.05). A significant positive correlation was found between Vitamin E levels and ferritin (r = 0.26, p = 0.047) in SCD and TM patients. Nonsignificant correlation was detected between serum Selenium and Vitamin E. Moreover, values of these antioxidants did not correlate with indices of hemolysis nor with those of inflammation in chronically transfused TM and SCD patients. PMID- 26644945 TI - Blood gas analyses and other components involved in the acid-base metabolism of rats infected by Trypanosoma evansi. AB - The aim of this study was to investigate the effects of Trypanosoma evansi infections on arterial blood gases of experimentally infected rats. Two groups with eight animals each were used; group A (uninfected) and group B (infected). Infected animals were daily monitored through blood smears that showed high parasitemia with 30 trypanosomes per field (1000*) on average, 5 days post infection (PI). Arterial blood was collected at 5 days PI for blood gas analysis using an automated method based on dry-chemistry. Hydrogen potential (pH), partial oxygen pressure (pO2), oxygen saturation (sO2), sodium (Na), ionic calcium (Ca ionic), chlorides (Cl), partial dioxide carbon pressure (pCO2), base excess (BE), base excess in the extracellular fluid (BEecf), bicarbonate (cHCO3), potassium (K), lactate, and blood total dioxide the carbon (tCO2) were evaluated. The levels of pH, pCO2, BE, BEecf, cHCO3, and tCO2 were significantly decreased (P < 0.05) in group B compared to group A. Additionally, the same group showed increases in Cl and lactate levels when compared to uninfected group. Therefore, it is possible to state that the infection caused by T. evansi led to alterations in the acid-base status, findings that are correlated to metabolic acidosis. PMID- 26644946 TI - Impact of a US Food and Drug Administration Drug Safety Communication on Zolpidem Dosing: An Observational Retrospective Cohort. AB - INTRODUCTION/BACKGROUND: Zolpidem is a sedative-hypnotic widely prescribed in the United States. Recently, the US Food and Drug Administration (FDA) issued a drug safety communication regarding its dosing in women. OBJECTIVE: To compare compliance with FDA-approved dosing for zolpidem in women before and after a drug safety communication, and to evaluate compliance based on pharmacy location and prescriber type. METHOD: This was a retrospective, observational cohort study. New prescriptions for Ambien, Ambien CR, Edluar, or Zolpimist or their respective generics dispensed from Kerr Drug pharmacies in North Carolina to women 18-64 years of age between April and September of 2012 ("before" cohort) or April and September of 2013 ("after" cohort) were included. chi(2) tests were conducted to assess overall compliance, as well as compliance based on location (urban or rural) and prescriber type (physician or midlevel), with FDA-approved dosing for zolpidem. Trends in total prescription volume and total zolpidem prescription volume for all Kerr Drug pharmacies over the study period were also described. RESULTS: A total of 14,156 prescriptions for zolpidem were included in the primary analysis. Sixteen percent of prescriptions dispensed were in compliance with FDA recommendations following the FDA alert. A statistically significant increase was observed in compliance with FDA-approved dosing for zolpidem (odds ratio = 1.49; 95% CI, 1.35-1.65; P < .0001) postdrug safety communication. Significant increases in compliance were also observed in the post-FDA communication subgroups based on location and prescriber type, though no subgroup was found to be significantly more compliant than another. CONCLUSIONS: The release of a drug safety communication by the FDA resulted in a statistically significant increase in proper dosing of zolpidem in women. Further research is needed in order to determine the impact of FDA alerts on prescribing patterns and the reasons for therapeutic substitution after such alerts. PMID- 26644947 TI - Regression: Diagnosis, Evaluation, and Management. PMID- 26644948 TI - A Survey of Medically Self-Sabotaging Behaviors Among Perpetrators of Partner Violence. PMID- 26644949 TI - A Case of Serotonin Syndrome Following Cyproheptadine Withdrawal. PMID- 26644950 TI - A Case of Dissociative Amnesia With Dissociative Fugue and Treatment With Psychotherapy. PMID- 26644951 TI - Manic Episode Following Ingestion of Caffeine Pills: A Case Report. PMID- 26644952 TI - Enhance Your Understanding of Lithium Neurotoxicity. PMID- 26644953 TI - Bupropion-Induced Delayed-Onset Anaphylaxis. PMID- 26644954 TI - Cyclobenzaprine-Induced Hallucinosis. PMID- 26644955 TI - Disease Severity, Quality of Life, and Psychiatric Morbidity in Patients With Psoriasis With Reference to Sociodemographic, Lifestyle, and Clinical Variables: A Prospective, Cross-Sectional Study From Lahore, Pakistan. AB - BACKGROUND: Psoriasis is an immune-mediated, chronic disease with a genetic background that involves skin, nails, and joints. The incidence of psoriasis varies from 2.0% to 4.0% depending on the geographical location, ethnic background, and environmental conditions. Recent research has proved that psoriasis is a systemic inflammatory disease with extensive systemic implications. Objectives of the study were to explore the severity of psoriasis, dermatology-related quality of life, and psychiatric health of the patients with reference to sociodemographic, lifestyle, and clinical characteristics. METHOD: Consecutive patients with psoriasis (ICD-10 criteria) from skin outpatient clinics of 3 tertiary care hospitals in Lahore, Pakistan, between November 1, 2012, and December 31, 2012, were assessed in this prospective cross-sectional study. The final sample includes 87 patients who were evaluated for severity of psoriasis (Psoriasis Area Severity Index [PASI]), dermatology-related quality of life (Dermatology Life Quality Index [DLQI]), and psychiatric morbidity (12-item General Health Questionnaire [GHQ-12]) and were assessed on 23 sociodemographic, lifestyle, and clinical variables. RESULTS: Of the 23 variables, the PASI was significantly associated with education and habit of drinking alcohol (P < .05), the DLQI was significantly associated with disturbed eating (P < .05), and the GHQ-12 score was significantly associated with hair disease (P < .05), current income (P < .05), and disturbed eating and sleeping (P < .01). The PASI, DLQI, and GHQ-12 were not usually affected by sociodemographic, lifestyle, and clinical factors, except for some variables such as education of the patient, alcohol intake, eating and sleeping disturbance, and income status. A statistically significant correlation (P < .01) was found between all 3 scores (ie, PASI, DLQI, and GHQ-12). The correlation coefficients of the PASI with the DLQI and GHQ-12 are 0.345 and 0.460, respectively, and that of the DLQI with the GHQ-12 is 0.635. A moderating effect of the DLQI score was found on the relationship between the PASI and GHQ-12 scores. CONCLUSIONS: Psoriasis has an immense impact on the life of patients and common comorbidities in psoriasis including coronary heart disease, depression, cerebrovascular disease, and metabolic syndrome. Screening for these comorbidities in psoriasis patients is essential. Impaired quality of life negatively affects the psyche of patients and initiates coping mechanisms, which may lead to depression and anxiety, social dysfunction, and loss of confidence, and the psychosocial burden of the disease may become more than the physical burden. The dermatologist usually manages physical disease and fails to address the social, emotional, and psychological aspects. Quality of life improves if these psychological aspects are also properly dealt with. PMID- 26644956 TI - A Post Hoc Analysis of the Effect of Weight on Efficacy in Depressed Patients Treated With Desvenlafaxine 50 mg/d and 100 mg/d. AB - OBJECTIVE: To assess the effect of baseline body mass index (BMI) on efficacy and weight change in adults with major depressive disorder (MDD) treated with desvenlafaxine or placebo in a pooled, post hoc analysis. METHOD: Adults with MDD were randomly assigned to placebo or desvenlafaxine (50 mg or 100 mg) in 8 short term, double-blind studies and 1 longer-term randomized withdrawal study (the studies were published between 2007 and 2013). Change from baseline in 17-item Hamilton Depression Rating Scale (HDRS-17) total score at week 8 was analyzed in normal (BMI <= 25 kg/m(2)), overweight (25 kg/m(2) < BMI <= 30 kg/m(2)), and obese (BMI > 30 kg/m(2)) subgroups using analysis of covariance (ANCOVA). Weight change was analyzed in BMI subgroups using ANCOVA and a mixed-effects model for repeated measures. RESULTS: Desvenlafaxine 50 mg/d or 100 mg/d improved HDRS-17 scores significantly from baseline to week 8 (last observation carried forward) versus placebo in all BMI subgroups (normal: n = 1,122; overweight: n = 960; obese: n = 1,302; all P <= .0027); improvement was greatest in normal BMI patients. There was a statistically significant decrease in weight (< 1 kg) with short-term desvenlafaxine 50 mg/d and 100 mg/d versus placebo in all BMI subgroups (all P < .0001). In the randomized withdrawal study (n = 548), no statistically significant difference in weight was observed for desvenlafaxine versus placebo in any BMI subgroup. Baseline BMI predicted weight change in short term and longer-term desvenlafaxine treatment. CONCLUSIONS: Desvenlafaxine significantly improved symptoms of depression versus placebo regardless of baseline BMI. In all BMI subgroups, desvenlafaxine was associated with statistically significant weight loss (< 1 kg) versus placebo over 8 weeks, but no significant differences longer term. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT00072774, NCT00277823, NCT00300378, NCT00384033, NCT00798707, NCT00863798, NCT01121484, NCT00824291, NCT00887224. PMID- 26644957 TI - Levomilnacipran Extended-Release Treatment in Patients With Major Depressive Disorder: Improvements in Functional Impairment Categories. AB - OBJECTIVE: In this post hoc analysis, improvement in functional impairment in patients with major depressive disorder (MDD) treated with levomilnacipran extended release (ER) was evaluated by assessing shifts from more severe to less severe functional impairment categories on individual Sheehan Disability Scale (SDS) subscales. METHOD: SDS data were pooled from 5 phase II/III studies conducted between December 2006 and March 2012 of levomilnacipran ER versus placebo in adult patients with MDD (DSM-IV-TR criteria). Proportions of patients shifting from moderate-extreme baseline impairment (score >= 4) to mild-no impairment (score <= 3) at end of treatment were assessed for each SDS subscale. Proportions of patients shifting from marked-extreme (score >= 7) baseline impairment to moderate-no (score <= 6) or mild-no impairment (score <= 3) at end of treatment, and shifts in which patients worsened from moderate-no to marked extreme impairment, were also evaluated. RESULTS: A significantly higher proportion of patients treated with levomilnacipran ER than placebo-treated patients improved from more severe categories of functional impairment at baseline to less severe impairment categories across all SDS subscales: work/school, social life, and family life/home responsibilities (P < .01). Depending on the SDS subscale, 48%-55% of levomilnacipran ER-treated patients with moderate-extreme impairment at baseline improved to mild or no impairment, compared with no more than 40% of placebo patients on any subscale. Almost half (42%-47%) of levomilnacipran ER-treated patients versus only about one-third (29% 34%) of placebo patients improved from marked-extreme to mild or no impairment across functional domains. CONCLUSIONS: These results suggest that functional improvement was observed across the SDS functional domains. To our knowledge, this is the first such categorical analysis of functional improvement, as measured by the SDS, for an antidepressant. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT00969709, NCT01377194, NCT00969150, and NCT01034462 and EudraCT identifier: 2006-002404-34. PMID- 26644958 TI - Comparison Between the Montgomery-Asberg Depression Rating Scale-Self and the Beck Depression Inventory II in Primary Care. AB - OBJECTIVE: The Montgomery-Asberg Depression Rating Scale-Self (MADRS-S) and the Beck Depression Inventory II (BDI-II) are commonly used self-assessment instruments for screening and diagnosis of depression. The BDI-II has 21 items and the MADRS-S has 9 items. These instruments have been tested with psychiatric inpatients but not in outpatient primary care, where most patients with symptoms of depression initially seek treatment. The purpose of this study was to compare these 2 instruments in the primary care setting. METHOD: Data were collected from 2 primary care randomized controlled trials that were performed from 2010 to 2013 in Sweden: the Primary Care Self-Assessment MADRS-S Study and Primary Care Internet-Based Cognitive Behavioral Therapy Study. There were 146 patients (73 patients each from both trials) who had newly diagnosed mild or moderate depression (per DSM-IV recommendations) and who had assessment with both the MADRS-S and BDI-II at primary care centers. Comparability and reliability of the instruments were estimated by Pearson product moment correlation and Cronbach alpha. RESULTS: A good correlation was observed between the 2 instruments: 0.66 and 0.62 in the 2 study cohorts. The reliability within the 2 study cohorts was good for both MADRS-S (Cronbach alpha: 0.76 for both cohorts) and BDI-II items (Cronbach alpha: 0.88 and 0.85). CONCLUSIONS: The 2 instruments showed good comparability and reliability for low, middle, and high total depression scores. The MADRS-S may be used as a rapid, easily administered, and inexpensive tool in primary care and has results comparable to the BDI-II in all domains. PMID- 26644959 TI - Wernicke's Encephalopathy: Increasing Clinician Awareness of This Serious, Enigmatic, Yet Treatable Disease. AB - OBJECTIVE: Undiagnosed and/or undertreated Wernicke's encephalopathy can result in permanent brain damage, long-term institutionalization, and death. The purpose of this article is to heighten clinical awareness of Wernicke's encephalopathy and shed light on its diagnosis and treatment, which are often inconsistent due to unclear diagnostic criteria and limited practice guidelines. An update on the management of Wernicke's encephalopathy is presented and several case reports and a quality improvement project from our hospital are described. DATA SOURCES: PubMed, the Cochrane Database of Systematic Reviews, and PsycINFO were searched for English-language articles published between January 1991 and January 2014 using combinations of the following keywords: Wernicke's encephalopathy, diagnosis, treatment/guideline(s), and thiamine. STUDY SELECTION: The automated search identified over 500 articles. A manual review of the related citations and reference lists from articles of interest was also conducted. The articles reviewed were chosen on the basis of author consensus and because they represented expert opinion or the highest quality of evidence available. RESULTS: Diagnostic criteria are reviewed in this article and should be used to diagnose Wernicke's encephalopathy with high sensitivity and specificity. The European Federation of Neurologic Societies and the Royal College of Physicians issued national guidelines for the diagnosis, prevention, and treatment of Wernicke's encephalopathy. No benchmark national guidelines for treating Wernicke's encephalopathy exist in the United States. CONCLUSIONS: Whenever Wernicke's encephalopathy is suspected, treatment should be initiated immediately with intravenous thiamine because oral thiamine is inadequate for preventing permanent brain damage. An adequate dose of intravenous thiamine administrated in a timely manner is a safe and life-saving treatment for Wernicke's encephalopathy that could preserve brain cells and function. PMID- 26644960 TI - Borderline Personality in the Medical Setting. AB - OBJECTIVE: Individuals with borderline personality disorder in mental health settings tend to present with relationship difficulties, mood instability/dysphoria, and overt self-harm behavior. In contrast, it appears that individuals with borderline personality disorder in medical settings manifest physical symptoms that are medically difficult to substantiate. Through a review of the literature, we examine 2 symptom manifestations among patients with borderline personality in primary care and general medical settings-namely pain sensitivity and multiple somatic complaints. In addition to reviewing the research of others, we also highlight our own investigations into these 2 areas. DATA SOURCES: We conducted a literature search of the PubMed database and a previous version of the PsycINFO search engine (no restrictions). Search terms included borderline personality, borderline personality disorder, personality disorders; chronic pain, pain, pain syndromes; and somatization disorder, Briquet's syndrome, somatic preoccupation, somatic. STUDY SELECTION: Published articles related to borderline personality, pain and somatic symptoms (ie, somatization disorder, somatic preoccupation) were examined. RESULTS: According to our review, the literature indicates higher-than-expected rates of borderline personality disorder among patients in primary care and general medical settings who present with chronic pain conditions and/or somatic preoccupation. CONCLUSIONS: Unlike patients with borderline personality disorder in mental health settings, who tend to present with relationship difficulties, mood instability/dysphoria, and overt self-harm behavior, patients with borderline personality disorder in primary care settings tend to present with unsubstantiated chronic pain of various types as well as somatic preoccupation. PMID- 26644961 TI - Responsibility. PMID- 26644962 TI - Seasonality of Admissions for Mania: Results From a General Hospital Psychiatric Unit in Pondicherry, India. AB - INTRODUCTION: Bipolar disorder is affected by variables that modulate circadian rhythm, including seasonal variations. There is evidence of a seasonal pattern of admissions of mania in various geographical settings, though its timing varies by region and climate. Variables such as age and gender have been shown to affect seasonality in some studies. METHODOLOGY: Data on monthly admission patterns for mania at a general hospital psychiatry unit in Pondicherry, India, were collected for 4 years (2010-2013) and analyzed for seasonality and seasonal peaks. The effects of age and gender were analyzed separately. RESULTS: There was overall evidence of a seasonal pattern of admissions for mania (P < .01, Friedman test for seasonality), with a peak beginning during the rainy season and ending before summer (P < .0.1, Ratchet circular scan test). Male sex (P < .005, Ratchet circular scan test) and age > 25 years (P < .005, Ratchet circular scan test) were specifically associated with this seasonal peak. DISCUSSION: The effect of seasons on mania is complex and is modulated by a variety of variables. Our study is consistent with earlier research findings: a greater degree of seasonality for mania in men. It is possible that climatic and individual variables interact to determine seasonal patterns in bipolar disorder in a given setting. PMID- 26644963 TI - The Use of Medicinal Marijuana for Posttraumatic Stress Disorder: A Review of the Current Literature. AB - BACKGROUND: Medicinal marijuana has already been legalized in over 23 states with more considering legalization. Despite the trend toward legalization, to date, there has been no systematic review of the existing literature for the efficacy of medicinal marijuana for many of the conditions for which it is proposed to treat. This study seeks to understand the current literature regarding the use of medicinal marijuana in the treatment of posttraumatic stress disorder (PTSD). DATA SOURCES: PubMed and PsycINFO databases were searched until April 2014 for articles outlining outcomes of case files, control studies, and observational studies regarding the efficacy of medicinal marijuana in treating PTSD. Various combinations of the following search terms were used: marijuana, medicinal marijuana, cannabis, cannabinoid, PTSD, efficacy, trial, and neurobiology. STUDY SELECTION: Full text of each article was reviewed, and those directly addressing the question of efficacy of medicinal marijuana on PTSD symptomatology were included. Data were extracted from a total of 46 articles. RESULTS: Analysis revealed that most reports are correlational and observational in basis with a notable lack of randomized, controlled studies. Many of the published studies suggest a decrease in PTSD symptoms with marijuana use. Though the directionality of cannabis use and PTSD could not be fully differentiated at this time, there appears to also be a correlation between PTSD and problematic cannabis use. Despite this finding, there is a growing amount of neurobiological evidence and animal studies suggesting potential neurologically based reasons for the reported efficacy. CONCLUSIONS: Posttraumatic stress disorder is 1 of the approved conditions for medicinal marijuana in some states. While the literature to date is suggestive of a potential decrease in PTSD symptomatology with the use of medicinal marijuana, there is a notable lack of large-scale trials, making any final conclusions difficult to confirm at this time. PMID- 26644964 TI - Central Glaucomatous Damage of the Macula Can Be Overlooked by Conventional OCT Retinal Nerve Fiber Layer Thickness Analyses. AB - PURPOSE: To assess the extent to which glaucomatous damage of the macula can be detected using the summary statistics of a commercial report based upon the circumpapillary retinal nerve fiber layer (cpRNFL) thickness obtained with frequency domain optical coherence tomography (fdOCT). METHODS: One hundred forty three eyes of 143 open-angle glaucoma patients and suspects (56.4 +/- 13.8 years) had 10-2 visual fields (VFs) and fdOCT macular and disc cube scans. RNFL and retinal ganglion cell plus inner plexiform layer thickness and probability maps were generated and combined with 10-2 VF information in a single-page, custom report previously described. Three graders evaluated these reports and classified each eye as "abnormal macula" or "normal macula." Commercially available fdOCT reports for cpRNFL thickness were generated using the automatic segmentation algorithm and norms from the machine. The ability of the reports to detect macular damage was analyzed in three ways: temporal quadrant (TQ) < 5%; TQ < 5% or clock hour 7 < 1% (TQ + CH7); and clock hours 7 through 10 with two sectors < 5% or one sector < 1% (CH7-10). RESULTS: Sixty-one (43%) eyes were classified "abnormal macula" and 41 (29%) as "normal macula"; the 10-2 VFs and OCT probability maps did not agree in the remaining eyes. Of the 61 abnormal eyes, the TQ criterion missed 47 (77%); TQ + CH7 missed 24 (39%); and CH7-10 missed 22 (36%). CONCLUSIONS: Conventional cpRNFL analyses on commercial OCT reports can miss macular (central field) damage. TRANSLATIONAL RELEVANCE: To detect glaucomatous damage of the macula, additional tests, such as macular cube scans and/or 10-2 VFs, should be performed. PMID- 26644965 TI - Computer-Based Image Analysis for Plus Disease Diagnosis in Retinopathy of Prematurity: Performance of the "i-ROP" System and Image Features Associated With Expert Diagnosis. AB - PURPOSE: We developed and evaluated the performance of a novel computer-based image analysis system for grading plus disease in retinopathy of prematurity (ROP), and identified the image features, shapes, and sizes that best correlate with expert diagnosis. METHODS: A dataset of 77 wide-angle retinal images from infants screened for ROP was collected. A reference standard diagnosis was determined for each image by combining image grading from 3 experts with the clinical diagnosis from ophthalmoscopic examination. Manually segmented images were cropped into a range of shapes and sizes, and a computer algorithm was developed to extract tortuosity and dilation features from arteries and veins. Each feature was fed into our system to identify the set of characteristics that yielded the highest-performing system compared to the reference standard, which we refer to as the "i-ROP" system. RESULTS: Among the tested crop shapes, sizes, and measured features, point-based measurements of arterial and venous tortuosity (combined), and a large circular cropped image (with radius 6 times the disc diameter), provided the highest diagnostic accuracy. The i-ROP system achieved 95% accuracy for classifying preplus and plus disease compared to the reference standard. This was comparable to the performance of the 3 individual experts (96%, 94%, 92%), and significantly higher than the mean performance of 31 nonexperts (81%). CONCLUSIONS: This comprehensive analysis of computer-based plus disease suggests that it may be feasible to develop a fully-automated system based on wide-angle retinal images that performs comparably to expert graders at three-level plus disease discrimination. TRANSLATIONAL RELEVANCE: Computer-based image analysis, using objective and quantitative retinal vascular features, has potential to complement clinical ROP diagnosis by ophthalmologists. PMID- 26644966 TI - Variation in the flowering time orthologs BrFLC and BrSOC1 in a natural population of Brassica rapa. AB - Understanding the genetic basis of natural phenotypic variation is of great importance, particularly since selection can act on this variation to cause evolution. We examined expression and allelic variation in candidate flowering time loci in Brassica rapa plants derived from a natural population and showing a broad range in the timing of first flowering. The loci of interest were orthologs of the Arabidopsis genes FLC and SOC1 (BrFLC and BrSOC1, respectively), which in Arabidopsis play a central role in the flowering time regulatory network, with FLC repressing and SOC1 promoting flowering. In B. rapa, there are four copies of FLC and three of SOC1. Plants were grown in controlled conditions in the lab. Comparisons were made between plants that flowered the earliest and latest, with the difference in average flowering time between these groups ~30 days. As expected, we found that total expression of BrSOC1 paralogs was significantly greater in early than in late flowering plants. Paralog-specific primers showed that expression was greater in early flowering plants in the BrSOC1 paralogs Br004928, Br00393 and Br009324, although the difference was not significant in Br009324. Thus expression of at least 2 of the 3 BrSOC1 orthologs is consistent with their predicted role in flowering time in this natural population. Sequences of the promoter regions of the BrSOC1 orthologs were variable, but there was no association between allelic variation at these loci and flowering time variation. For the BrFLC orthologs, expression varied over time, but did not differ between the early and late flowering plants. The coding regions, promoter regions and introns of these genes were generally invariant. Thus the BrFLC orthologs do not appear to influence flowering time in this population. Overall, the results suggest that even for a trait like flowering time that is controlled by a very well described genetic regulatory network, understanding the underlying genetic basis of natural variation in such a quantitative trait is challenging. PMID- 26644967 TI - Reference genes selection for transcript normalization in kenaf (Hibiscus cannabinus L.) under salinity and drought stress. AB - Kenaf (Hibiscus cannabinus) is an economic and ecological fiber crop but suffers severe losses in fiber yield and quality under the stressful conditions of excess salinity and drought. To explore the mechanisms by which kenaf responds to excess salinity and drought, gene expression was performed at the transcriptomic level using RNA-seq. Thus, it is crucial to have a suitable set of reference genes to normalize target gene expression in kenaf under different conditions using real time quantitative reverse transcription-PCR (qRT-PCR). In this study, we selected 10 candidate reference genes from the kenaf transcriptome and assessed their expression stabilities by qRT-PCR in 14 NaCl- and PEG-treated samples using geNorm, NormFinder, and BestKeeper. The results indicated that TUBalpha and 18S rRNA were the optimum reference genes under conditions of excess salinity and drought in kenaf. Moreover, TUBalpha and 18S rRNA were used singly or in combination as reference genes to validate the expression levels of WRKY28 and WRKY32 in NaCl- and PEG-treated samples by qRT-PCR. The results further proved the reliability of the two selected reference genes. This work will benefit future studies on gene expression and lead to a better understanding of responses to excess salinity and drought in kenaf. PMID- 26644968 TI - A questionnaire study of injections prescribed and dispensed for patients diagnosed with mild/moderate community-acquired pneumonia in Mongolia. AB - Purpose. The study aimed to determine the extent of and factors influencing the prescribing of injections for the treatment of mild/moderate community acquired pneumonia (CAP) in Mongolia. Methods. Questionnaires were developed and administered to medication providers (34 Pharmacists, 27 pharmacy technicians) and prescribers (22 general doctors and 49 medical specialists) working in Mongolia. Results. Cefalosporins were prescribed for patients with mild pneumonia and doctors tended to prescribe injectable cefalosporins (cefazolin) rather than oral dosage forms. This was supported by the questionnaire study with pharmacists and pharmacy technicians. Additionally, 23 pharmacists and pharmacy technicians indicated that OTC injectable cefalosporins (37.7%) and injectable aminopenicillins (33,9%) were frequently sold by pharmacies for the treatment of mild/moderate CAP. Doctors and particularly pharmacists in the questionnaire studies indicated choosing an injection was to avoid non-compliance problems. Conclusion. High levels of injectable prescribing of antibiotics were found in non-hospitalized patients with CAP in Mongolia. This prevalence level indicated that inappropriate injection prescribing is a public health hazard for Mongolia and requires consideration by the appropriate authorities. PMID- 26644969 TI - Persistent microbial dysbiosis in preterm premature rupture of membranes from onset until delivery. AB - Background. Preterm Premature Rupture of Membranes (PPROM) is a major leading cause of preterm births. While the cause for PPROM remains unidentified, it is anticipated to be due to subclinical infection, since a large proportion of PPROM patients display signs of chorioamnionitis. Since subclinical infections can be facilitated by dysbiosis, our goal was to characterize the vaginal microbiome and amniotic fluid discharge upon PPROM, through latency antibiotic treatment, and until delivery, to detect the presence of pathogens, microbiota alteration, and microbial response to treatment. Methods. Enrolled subjects (15) underwent routine institutional antenatal care for PPROM, including the administration of latency antibiotics. Serial vaginal swabs were obtained from diagnosis of PPROM through delivery and the sequencing of the V3-V5 region of the 16S rRNA gene was performed for all collected samples. Results. The results show that Lactobacilli species were markedly decreased when compared to vaginal swabs collected from uncomplicated pregnancy subjects with a matched gestational time. Prevotella and Peptoniphilus were the most prevalent taxa in PPROM subjects at presentation. The vaginal microbiome of the PPROM subjects varied substantially intra- and inter subjects. Several taxa were found to be significantly reduced during and after the antibiotic treatment: Weeksella, Lachnospira, Achromobacter, and Pediococcus. In contrast, Peptostreptococcus and Tissierellaceae ph2 displayed a significant increase after the antibiotic treatment. However, the relative abundance of Lactobacillus, Prevotella, and Peptoniphilus was not substantially impacted during the hospitalization of the PPROM subjects. The deficiency of Lactobacillus, and constancy of known pathogenic species, such as Prevotella and Peptoniphilus during and after antibiotics, highlights the persistent dysbiosis and warrants further investigation into mitigating approaches. Discussion. PPROM is responsible for one third of all preterm births. It is thought that subclinical infection is a crucial factor in the pathophysiology of PPROM because 25-40% of patients present signs of chorioamnionitis on amniocentesis. Here we sought to directly assess the bacterial content of the vagina and leaking amniotic fluid of subjects at presentation, throughout treatment and up until delivery, in order to search for common pathogens, microbiota changes, and microbial response to latency antibiotic treatment. We have found that the vaginal microbiome of PPROM subjects is highly variable and displays significant changes to treatment. However, the unchanging deficiency of Lactobacillus, and persistence of known pathogenic species, such as Prevotella and Peptoniphilus from presentation, through antibiotic treatment and up until delivery, highlights the persistent dysbiosis and warrants further investigation into mitigating approaches. PMID- 26644970 TI - Adaptive divergence in resistance to herbivores in Datura stramonium. AB - Defensive traits exhibited by plants vary widely across populations. Heritable phenotypic differentiation is likely to be produced by genetic drift and spatially restricted gene flow between populations. However, spatially variable selection exerted by herbivores may also give rise to differences among populations. To explore to what extent these factors promote the among-population differentiation of plant resistance of 13 populations of Datura stramonium, we compared the degree of phenotypic differentiation (P ST) of leaf resistance traits (trichome density, atropine and scopolamine concentration) against neutral genetic differentiation (F ST) at microsatellite loci. Results showed that phenotypic differentiation in defensive traits among-population is not consistent with divergence promoted by genetic drift and restricted gene flow alone. Phenotypic differentiation in scopolamine concentration was significantly higher than F ST across the range of trait heritability values. In contrast, genetic differentiation in trichome density was different from F ST only when heritability was very low. On the other hand, differentiation in atropine concentration differed from the neutral expectation when heritability was less than or equal to 0.3. In addition, we did not find a significant correlation between pair-wise neutral genetic distances and distances of phenotypic resistance traits. Our findings reinforce previous evidence that divergent natural selection exerted by herbivores has promoted the among-population phenotypic differentiation of defensive traits in D. stramonium. PMID- 26644971 TI - TLR4 Asp299Gly (rs4986790) polymorphism and coronary artery disease: a meta analysis. AB - Background. Previous studies have shown conflicting results on the association between toll-like receptor 4 (TLR4) Asp299Gly (rs4986790) polymorphism and coronary artery disease (CAD). The aim of this study was to evaluate the influence of TLR4 Asp299Gly polymorphism on CAD risk, CRP level and the number of stenotic coronary arteries, as well as to investigate whether G allele carriers would benefit more from statin treatment. Methods. PubMed, EMBASE, and CNKI databases were searched until May 2015. All the statistical tests were performed using R version 3.1.2. Odds ratio (OR) and 95% confidence interval (CI) were used to assess the association between TLR4 Asp299Gly polymorphism and CAD risk, the number of stenotic vessels, and the incidence of cardiovascular events according to statin-treated patients. Weighted mean difference (WMD) was calculated for the association between Asp299Gly and CRP level. Results. Overall, 12 case-control studies with 10,258 cases and 5,891 controls were included, and no association of TLR4Asp299Gly polymorphism with CAD was found (G allele vs. A allele: OR = 0.97, 95% CI [0.81-1.17], P = 0.75; AA vs. GG + AG: OR = 0.97, 95% CI [0.80-1.18], P = 0.76; GG vs. AG + AA: OR = 1.08, 95% CI [0.57-2.02], P = 0.82; AG vs. AA + GG: OR = 1.03, 95% CI [0.85-1.25], P = 0.74). Also, no association was noted between Asp299Gly and CRP level (WMD = -0.10, 95% CI [-0.62, 0.41], P = 0.69). Furthermore, no synergistic effect of statin and 299Gly was reported (Statin_AA vs. Statin_ AG/GG: OR = 1.12, 95% CI [0.41-3.09], P = 0.82). Discussion. This meta-analysis suggests no association of TLR4 Asp299Gly polymorphism with CAD and CRP level. It is further indicated that the G allele carriers may not benefit more from statin treatment. Further studies should include large sample size and high-quality literature to understand this issue in depth. PMID- 26644972 TI - Factors associated with extubation time in coronary artery bypass grafting patients. AB - Background and Objectives. Cardiovascular diseases are the leading cause of death worldwide, with coronary artery disease being the most common. With increasing numbers of patients, Coronary Artery Bypass Grafting (CABG) has become the most common operation in the world. Respiratory disorder is one of the most prevalent complications of CABG. Thus, weaning off the mechanical ventilation and extubation are of great clinical importance for these patients. Some post operative problems also relate to the tracheal tube and mechanical ventilation. Therefore, an increase in this leads to an increase in the number of complications, length of hospital stay, and treatment costs. Since a large number of factors affect the post-operative period, the present study aims to identify the predictors of extubation time in CABG patients using casualty network analysis. Method. This longitudinal study was conducted on 800 over 18 year old patients who had undergone CABG surgery in three treatment centers affiliated to Shiraz University of Medical Sciences. The patients' information, including pre operative, peri-operative, and post-operative variables, was retrospectively extracted from their medical records. Then, the data was comprehensively analyzed through path analysis using MPLUS-7.1 software. Results. The mean of extubation time was 10.27 + 4.39 h. Moreover, extubation time was significantly affected by packed cells during the Cardiopulmonary Bypass (CPB), packed cells after CPB, inotrope use on arrival at ICU, mean arterial pressure 1st ICU, packed cells 1st ICU, platelets 1st ICU, Blood Urea Nitrogen 1st ICU, and hematocrit 1st ICU. Conclusion. Considering all of the factors under investigation, some peri operative and post-operative factors had significant effects. Therefore, considering the post-operative factors is important for designing a treatment plan and evaluating patients' prognosis. PMID- 26644973 TI - Evaluation of Leymus chinensis quality using near-infrared reflectance spectroscopy with three different statistical analyses. AB - Due to a boom in the dairy industry in Northeast China, the hay industry has been developing rapidly. Thus, it is very important to evaluate the hay quality with a rapid and accurate method. In this research, a novel technique that combines near infrared spectroscopy (NIRs) with three different statistical analyses (MLR, PCR and PLS) was used to predict the chemical quality of sheepgrass (Leymus chinensis) in Heilongjiang Province, China including the concentrations of crude protein (CP), acid detergent fiber (ADF), and neutral detergent fiber (NDF). Firstly, the linear partial least squares regression (PLS) was performed on the spectra and the predictions were compared to those with laboratory-based recorded spectra. Then, the MLR evaluation method for CP has a potential to be used for industry requirements, as it needs less sophisticated and cheaper instrumentation using only a few wavelengths. Results show that in terms of CP, ADF and NDF, (i) the prediction accuracy in terms of CP, ADF and NDF using PLS was obviously improved compared to the PCR algorithm, and comparable or even better than results generated using the MLR algorithm; (ii) the predictions were worse compared to laboratory-based spectra with the MLR algorithmin, and poor predictions were obtained (R2, 0.62, RPD, 0.9) using MLR in terms of NDF; (iii) a satisfactory accuracy with R2 and RPD by PLS method of 0.91, 3.2 for CP, 0.89, 3.1 for ADF and 0.88, 3.0 for NDF, respectively, was obtained. Our results highlight the use of the combined NIRs-PLS method could be applied as a valuable technique to rapidly and accurately evaluate the quality of sheepgrass hay. PMID- 26644974 TI - Geographic variation and genetic structure in the Bahama Oriole (Icterus northropi), a critically endangered synanthropic species. AB - Bird species may exhibit unexpected population structuring over small distances, with gene flow restricted by geographic features such as water or mountains. The Bahama Oriole (Icterus northropi) is a critically endangered, synanthropic island endemic with a declining population of fewer than 300 individuals. It now remains only on Andros Island (The Bahamas), which is riddled with waterways that past studies assumed did not hinder gene flow. We examined 1,858 base pairs of mitochondrial DNA sequenced from four gene regions in 14 birds (roughly 5% of the remaining population) found on the largest land masses of Andros Island (North Andros and Mangrove Cay/South Andros). We sought to discern genetic structuring between the remaining subpopulations and its relationship to current conservation concerns. Four unique haplotypes were identified, with only one shared between the two subpopulations. Nucleotide and haplotype diversity were higher for the North Andros subpopulation than for the Mangrove Cay/South Andros subpopulation. Analysis of molecular variance (AMOVA) yielded a Wright's fixation index (F st) of 0.60 (P Fst = 0.016), with 40.2% of the molecular variation explained by within-population differences and 59.8% by among-population differences. Based on the mitochondrial regions examined in this study, we suggest the extant subpopulations of Bahama Oriole exhibit significant population structuring over short distances, consistent with some other non-migratory tropical songbird species. PMID- 26644975 TI - Pathways from marine protected area design and management to ecological success. AB - Using an international dataset compiled from 121 sites in 87 marine protected areas (MPAs) globally (Edgar et al., 2014), I assessed how various configurations of design and management conditions affected MPA ecological performance, measured in terms of fish species richness and biomass. The set-theoretic approach used Boolean algebra to identify pathways that combined up to five 'NEOLI' ( No-take, Enforced, Old, Large, Isolated) conditions and that were sufficient for achieving positive, and negative, ecological outcomes. Ecological isolation was overwhelming the most important condition affecting ecological outcomes but Old and Large were also conditions important for achieving high levels of biomass among large fishes (jacks, groupers, sharks). Solution coverage was uniformly low (<0.35) for all models of positive ecological performance suggesting the presence of numerous other conditions and pathways to ecological success that did not involve the NEOLI conditions. Solution coverage was higher (>0.50) for negative results (i.e., the absence of high biomass) among the large commercially exploited fishes, implying asymmetries in how MPAs may rebuild populations on the one hand and, on the other, protect against further decline. The results revealed complex interactions involving MPA design, implementation, and management conditions that affect MPA ecological performance. In general terms, the presence of no-take regulations and effective enforcement were insufficient to ensure MPA effectiveness on their own. Given the central role of ecological isolation in securing ecological benefits from MPAs, site selection in the design phase appears critical for success. PMID- 26644976 TI - Prediction of cancer cell sensitivity to natural products based on genomic and chemical properties. AB - Natural products play a significant role in cancer chemotherapy. They are likely to provide many lead structures, which can be used as templates for the construction of novel drugs with enhanced antitumor activity. Traditional research approaches studied structure-activity relationship of natural products and obtained key structural properties, such as chemical bond or group, with the purpose of ascertaining their effect on a single cell line or a single tissue type. Here, for the first time, we develop a machine learning method to comprehensively predict natural products responses against a panel of cancer cell lines based on both the gene expression and the chemical properties of natural products. The results on two datasets, training set and independent test set, show that this proposed method yields significantly better prediction accuracy. In addition, we also demonstrate the predictive power of our proposed method by modeling the cancer cell sensitivity to two natural products, Curcumin and Resveratrol, which indicate that our method can effectively predict the response of cancer cell lines to these two natural products. Taken together, the method will facilitate the identification of natural products as cancer therapies and the development of precision medicine by linking the features of patient genomes to natural product sensitivity. PMID- 26644977 TI - 'Degraded' RNA profiles in Arthropoda and beyond. AB - The requirement for high quality/non-degraded RNA is essential for an array of molecular biology analyses. When analysing the integrity of rRNA from the barnacle Lepas anatifera (Phylum Arthropoda, Subphylum Crustacea), atypical or sub-optimal rRNA profiles that were apparently degraded were observed on a bioanalyser electropherogram. It was subsequently discovered that the rRNA was not degraded, but arose due to a 'gap deletion' (also referred to as 'hidden break') in the 28S rRNA. An apparent excision at this site caused the 28S rRNA to fragment under heat-denaturing conditions and migrate along with the 18S rRNA, superficially presenting a 'degraded' appearance. Examination of the literature showed similar observations in a small number of older studies in insects; however, reading across multiple disciplines suggests that this is a wider issue that occurs across the Animalia and beyond. The current study shows that the 28S rRNA anomaly goes far beyond insects within the Arthropoda and is widespread within this phylum. We confirm that the anomaly is associated with thermal conversion because gap-deletion patterns were observed in heat-denatured samples but not in gels with formaldehyde-denaturing. PMID- 26644978 TI - Intensity of bouted and sporadic physical activity and the metabolic syndrome in adults. AB - Background. Physical activity guidelines for adults only recognize the health benefits of accumulating bouted moderate-to-vigorous physical activity (MVPA), or MVPA occurring over at least 10 consecutive minutes. There is a lack of evidence supporting the health benefits of other patterns and intensities of activity including sporadic MVPA (i.e., MVPA occurring in periods of fewer than 10 consecutive minutes) and light intensity physical activity (LIPA). The objective of this study was to examine the health benefits associated with physical activity that does not meet the physical activity guidelines criteria for bouted MVPA. Specifically, we examined the association between sporadic MVPA and bouted and sporadic LIPA with the metabolic syndrome. Methods. We studied a representative cross-sectional sample of 1,974 adults aged 20 years and older from the 2003-2006 US National Health and Nutrition Examination Survey. Physical activity was measured over 7 days using Actigraph AM-7164 accelerometers. Each minute over the 7-day measurement period was classified as being of a sedentary, light, or moderate-to-vigorous intensity. A 10 min threshold differentiated bouted activity from sporadic activity. Average minutes/day of sporadic LIPA, sporadic MVPA, bouted LIPA, bouted MVPA, and embedded MVPA (MVPA occurring within bouts of primarily LIPA) were calculated. Metabolic syndrome status was determined using established criteria. Associations were examined using logistic regression and controlled for relevant covariates. Results. For every 30 min/day of physical activity, the odds ratio (95% confidence interval) of the metabolic syndrome was reduced by 4% (1-7%) for bouted LIPA, 64% (51-71%) for bouted MVPA, and 57% (45-67%) for embedded MVPA. Sporadic LIPA was not independently associated with the metabolic syndrome. We could not examine the association between sporadic MVPA and the metabolic syndrome because participants accumulated such a marginal amount of this type of activity (i.e., median = 2 min/day, only 11% of participants accumulated >=5 min/day). Conclusion. The intensity of non bouted activity is important, as embedded MVPA had a stronger association with the metabolic syndrome than sporadic LIPA and a comparable association to bouted MVPA. PMID- 26644979 TI - Watching eyes on potential litter can reduce littering: evidence from two field experiments. AB - Littering constitutes a major societal problem, and any simple intervention that reduces its prevalence would be widely beneficial. In previous research, we have found that displaying images of watching eyes in the environment makes people less likely to litter. Here, we investigate whether the watching eyes images can be transferred onto the potential items of litter themselves. In two field experiments on a university campus, we created an opportunity to litter by attaching leaflets that either did or did not feature an image of watching eyes to parked bicycles. In both experiments, the watching eyes leaflets were substantially less likely to be littered than control leaflets (odds ratios 0.22 0.32). We also found that people were less likely to litter when there other people in the immediate vicinity than when there were not (odds ratios 0.04-0.25) and, in one experiment but not the other, that eye leaflets only reduced littering when there no other people in the immediate vicinity. We suggest that designing cues of observation into packaging could be a simple but fruitful strategy for reducing littering. PMID- 26644980 TI - Ranking, selecting, and prioritising genes with desirability functions. AB - In functional genomics experiments, researchers often select genes to follow-up or validate from a long list of differentially expressed genes. Typically, sharp thresholds are used to bin genes into groups such as significant/non-significant or fold change above/below a cut-off value, and ad hoc criteria are also used such as favouring well-known genes. Binning, however, is inefficient and does not take the uncertainty of the measurements into account. Furthermore, p-values, fold-changes, and other outcomes are treated as equally important, and relevant genes may be overlooked with such an approach. Desirability functions are proposed as a way to integrate multiple selection criteria for ranking, selecting, and prioritising genes. These functions map any variable to a continuous 0-1 scale, where one is maximally desirable and zero is unacceptable. Multiple selection criteria are then combined to provide an overall desirability that is used to rank genes. In addition to p-values and fold-changes, further experimental results and information contained in databases can be easily included as criteria. The approach is demonstrated with a breast cancer microarray data set. The functions and an example data set can be found in the desiR package on CRAN (https://cran.r-project.org/web/packages/desiR/) and the development version is available on GitHub (https://github.com/stanlazic/desiR). PMID- 26644981 TI - Inconsistencies among secondary sources of Chukar Partridge (Alectoris chukar) introductions to the United States. AB - The propagule pressure hypothesis asserts that the number of individuals released is the key determinant of whether an introduction will succeed or not. It remains to be shown whether propagule pressure is more important than either species level or site-level factors in determining the fate of an introduction. Studies claiming to show that propagule pressure is the primary determinant of introduction success must assume that the historical record as reported by secondary sources is complete and accurate. Here, examine a widely introduced game bird, the Chukar (Alectoris chukar), to the USA. We compare the records reported by two secondary sources (Long, 1981; Lever, 1987) to those in a primary source (Christensen, 1970) and to a recent study by Sol et al. (2012). Numerous inconsistencies exist in the records reported by Sol et al. (2012), Long (1981) and Lever (1987) when compared to the primary record of Christensen (1970). As reported by Christensen (1970), very large numbers of Chukars were released unsuccessfully in some states. Our results strongly imply that factors other than sheer numbers are more important. Site-to-site differences are the most likely explanation for the variation in success. PMID- 26644982 TI - The effectiveness of sputum pH analysis in the prediction of response to therapy in patients with pulmonary tuberculosis. AB - Purpose. The predictive factor of response to antituberculous therapy has not been fully elucidated. Airway acidity has been thought to be a potential indicator of the bactericidal activity. Therefore, we hypothesized that monitoring airway acidity by measuring sputum pH could predict response to therapy. Methods. A total of 47 patients having newly diagnosed, smear-positive, active pulmonary tuberculosis were enrolled between October 2011 and March 2014. Sputum samples were serially analyzed before and after treatment. Eligible patients who initiated a standard 6-month treatment were monitored for the length of time to sputum smear and culture conversion. Results. There were 39 patients who completed a 2-month intensive phase of isoniazid, rifampicin, pyrazinamide, and ethambutol therapy followed by a 4-month continuation phase of isoniazid and rifampicin. Although factors including age, cavitation, sputum grade, and use of an acid-suppressant were associated with initial low sputum pH in univariate analysis, multivariate analysis revealed that only age >=61 years was a statistically important factor predicting low pH value (p = 0.005). Further outcome analysis showed that initial low sputum pH before treatment was the only factor significantly associated with shorter length of time to both sputum smear and culture conversion (p = 0.034 and 0.019, respectively) independent of the effects of age, sputum bacterial load, extent of lung lesion, and cavitation. Thus, initial low sputum pH indicated favorable response to anti-tuberculosis therapy. Conclusions. Measuring sputum pH is an easy and inexpensive way of predicting response to standard combination therapy in patients with pulmonary tuberculosis. PMID- 26644983 TI - Cranial arterial pattern of the Sri Lankan spotted chevrotain, Moschiola memmina, and comparative basicranial osteology of the Tragulidae. AB - The cranial arterial pattern of artiodactyls deviates significantly from the typical mammalian pattern. One of the most striking atypical features is the rete mirabile epidurale: a subdural arterial meshwork that functionally and anatomically replaces the arteria carotis interna. This meshwork facilitates an exceptional ability to cool the brain, and was thought to be present in all artiodactyls. Recent research, however, has found that species of mouse deer (Artiodactyla: Tragulidae) endemic to the Malay Archipelago possess a complete a. carotis interna instead of a rete mirabile epidurale. As tragulids are the sister group to pecoran ruminants, the lack of a rete mirabile epidurale in these species raises intriguing evolutionary questions about the origin and nature of artiodactyl thermoregulatory cranial vasculature. In this study, cranial arterial patterns are documented for the remaining species within the Tragulidae. Radiopaque latex vascular injection, computed tomography (CT-scanning), and digital 3-dimensional anatomical reconstruction are used to image the cranial arteries of a Sri Lankan spotted chevrotain, Moschiola meminna. Sites of hard and soft tissue interaction were identified, and these osteological correlates were then sought in nine skulls representative of the remaining tragulid species. Both hard and soft tissue surveys confirm that the presence of an a. carotis interna is the common condition for tragulids. Moreover, the use of a 3-D, radiographic anatomical imaging technique enabled identification of a carotico-maxillary anastomosis that may have implications for the evolution of the artiodactyl rete mirabile epidurale. PMID- 26644984 TI - Learning from a provisioning site: code of conduct compliance and behaviour of whale sharks in Oslob, Cebu, Philippines. AB - While shark-based tourism is a rapidly growing global industry, there is ongoing controversy about the effects of provisioning on the target species. This study investigated the effect of feeding on whale sharks (Rhincodon typus) at a provisioning site in Oslob, Cebu, in terms of arrival time, avoidance and feeding behaviour using photo-identification and focal follows. Additionally, compliance to the code of conduct in place was monitored to assess tourism pressure on the whale sharks. Newly identified sharks gradually arrived earlier to the provisioning site after their initial sighting, indicating that the animals learn to associate the site with food rewards. Whale sharks with a long resighting history showed anticipatory behaviour and were recorded at the site on average 5 min after the arrival of feeder boats. Results from a generalised linear mixed model indicated that animals with a longer resighting history were less likely to show avoidance behaviour to touches or boat contact. Similarly, sequential data on feeding behaviour was modelled using a generalised estimating equations approach, which suggested that experienced whale sharks were more likely to display vertical feeding behaviour. It was proposed that the continuous source of food provides a strong incentive for the modification of behaviours, i.e., learning, through conditioning. Whale sharks are large opportunistic filter feeders in a mainly oligotrophic environment, where the ability to use novel food sources by modifying their behaviour could be of great advantage. Non-compliance to the code of conduct in terms of minimum distance to the shark (2 m) increased from 79% in 2012 to 97% in 2014, suggesting a high tourism pressure on the whale sharks in Oslob. The long-term effects of the observed behavioural modifications along with the high tourism pressure remain unknown. However, management plans are traditionally based on the precautionary principle, which aims to take preventive actions even if data on cause and effect are still inconclusive. Hence, an improved enforcement of the code of conduct coupled with a reduction in the conditioning of the whale sharks through provisioning were proposed to minimise the impacts on whale sharks in Oslob. PMID- 26644985 TI - Preference of a native beetle for "exoticism," characteristics that contribute to invasive success of Costelytra zealandica (Scarabaeidae: Melolonthinae). AB - Widespread replacement of native ecosystems by productive land sometimes results in the outbreak of a native species. In New Zealand, the introduction of exotic pastoral plants has resulted in diet alteration of the native coleopteran species, Costelytra zealandica (White) (Scarabaeidae) such that this insect has reached the status of pest. In contrast, C. brunneum (Broun), a congeneric species, has not developed such a relationship with these 'novel' host plants. This study investigated the feeding preferences and fitness performance of these two closely related scarab beetles to increase fundamental knowledge about the mechanisms responsible for the development of invasive characteristics in native insects. To this end, the feeding preference of third instar larvae of both Costelytra species was investigated using an olfactometer device, and the survival and larval growth of the invasive species C. zealandica were compared on native and exotic host plants. Costelytra zealandica, when sampled from exotic pastures, was unable to fully utilise its ancestral native host and showed higher feeding preference and performance on exotic plants. In contrast, C. zealandica sampled from native grasslands did not perform significantly better on either host and showed similar feeding preferences to C. brunneum, which exhibited no feeding preference. This study suggests the possibility of strong intraspecific variation in the ability of C. zealandica to exploit native or exotic plants, supporting the hypothesis that such ability underpins the existence of distinct host-races in this species. PMID- 26644986 TI - Upright or inverted, entire or exploded: right-hemispheric superiority in face recognition withstands multiple spatial manipulations. AB - Background. The ability to identify faces has been interpreted as a cerebral specialization based on the evolutionary importance of these social stimuli, and a number of studies have shown that this function is mainly lateralized in the right hemisphere. The aim of this study was to assess the right-hemispheric specialization in face recognition in unfamiliar circumstances. Methods. Using a divided visual field paradigm, we investigated hemispheric asymmetries in the matching of two subsequent faces, using two types of transformation hindering identity recognition, namely upside-down rotation and spatial "explosion" (female and male faces were fractured into parts so that their mutual spatial relations were left intact), as well as their combination. Results. We confirmed the right hemispheric superiority in face processing. Moreover, we found a decrease of the identity recognition for more extreme "levels of explosion" and for faces presented upside-down (either as sample or target stimuli) than for faces presented upright, as well as an advantage in the matching of female compared to male faces. Discussion. We conclude that the right-hemispheric superiority for face processing is not an epiphenomenon of our expertise, because we are not often exposed to inverted and "exploded" faces, but rather a robust hemispheric lateralization. We speculate that these results could be attributable to the prevalence of right-handedness in humans and/or to early biases in social interactions. PMID- 26644987 TI - Academic inequality through the lens of community ecology: a meta-analysis. AB - Ecological assemblages are generally characterized by a few dominant species and numerous others. Such unequal distributions of dominance also emerge in human society, including in scientific communities. Here, based on formal community ecological analyses, we show the temporal trends in the number of scientific publication in the discipline of "ecology." Based on this, we infer possible factors causing the imbalance of reputation and dominance among countries. We relied on 454 ecological meta-analysis papers published from 1998 to 2014, which sourced over 29,000 original publications. Formal meta-analyses are essential for synthesizing findings from individual studies and are critical for assessing issues and informing policy. We found that, despite the rapid expansion of outlets for ecology papers (analogous to an increase in carrying capacity, in ecological systems), country diversity as determined from first author affiliations (analogous to species diversity) did not increase. Furthermore, a country identity was more powerful than the popularity of the scientific topic and affected the chance of publication in high-profile journals, independent of the potential novelty of findings and arguments of the papers, suggesting possible academic injustice. Consequently, a rank order and hierarchy has been gradually formed among countries. Notably, this country-dominance rank is not only specific to this scientific domain but also universal across different societal situations including sports and economics, further emphasizing that inequality and hierarchical structure exist even in modern human society. Our study demonstrates a need for having robust frameworks to facilitate equality and diversity in the scientific domain in order to better inform society and policy. PMID- 26644988 TI - Temporal comparison and predictors of fish species abundance and richness on undisturbed coral reef patches. AB - Large disturbances can cause rapid degradation of coral reef communities, but what baseline changes in species assemblages occur on undisturbed reefs through time? We surveyed live coral cover, reef fish abundance and fish species richness in 1997 and again in 2007 on 47 fringing patch reefs of varying size and depth at Mersa Bareika, Ras Mohammed National Park, Egypt. No major human or natural disturbance event occurred between these two survey periods in this remote protected area. In the absence of large disturbances, we found that live coral cover, reef fish abundance and fish species richness did not differ in 1997 compared to 2007. Fish abundance and species richness on patches was largely related to the presence of shelters (caves and/or holes), live coral cover and patch size (volume). The presence of the ectoparasite-eating cleaner wrasse, Labroides dimidiatus, was also positively related to fish species richness. Our results underscore the importance of physical reef characteristics, such as patch size and shelter availability, in addition to biotic characteristics, such as live coral cover and cleaner wrasse abundance, in supporting reef fish species richness and abundance through time in a relatively undisturbed and understudied region. PMID- 26644989 TI - Biomechanical implications of skeletal muscle hypertrophy and atrophy: a musculoskeletal model. AB - Muscle hypertrophy and atrophy occur frequently as a result of mechanical loading or unloading, with implications for clinical, general, and athletic populations. The effects of muscle hypertrophy and atrophy on force production and joint moments have been previously described. However, there is a paucity of research showing how hypertrophy and atrophy may affect moment arm (MA) lengths. The purpose of this model was to describe the mathematical relationship between the anatomical cross-sectional area (ACSA) of a muscle and its MA length. In the model, the ACSAs of the biceps brachii and brachialis were altered to hypertrophy up to twice their original size and to atrophy to one-half of their original size. The change in MA length was found to be proportional to the arcsine of the square root of the change in ACSA. This change in MA length may be a small but important contributor to strength, especially in sports that require large joint moments at slow joint angular velocities, such as powerlifting. The paradoxical implications of the increase in MA are discussed, as physiological factors influencing muscle contraction velocity appear to favor a smaller MA length for high velocity movements but a larger muscle MA length for low velocity, high force movements. PMID- 26644990 TI - Parental encouragement is positively associated with outdoor active play outside of school hours among 7-12 year olds. AB - Background. Physical activity is important for children's physical, mental, and social well-being. Outdoor active play is an important yet unstudied domain of children's physical activity. The objective of this study was to determine if parental encouragement is associated with the frequency that children engage in outdoor active play outside of school hours. Methods. Participants consisted of 514 children aged 7-12 years and one of their parents. Parents completed a survey that included four questions that assessed how frequently they used verbal cues to encourage their child to play outdoors. Points were assigned to each response and averaged across the 4 questions, and based on this average participants were assigned to quintiles. The survey included seven questions that asked parents to assess how frequently their child played outdoors outside of school hours. Points were assigned to each response and summed to create an active outdoor play frequency score. General linear models assessed associations between parental encouragement and outdoor play while controlling for individual, family, and neighborhood covariates. Results. The mean outdoor active play frequency score increased significantly across quintiles of the parental encouragement score as follows: 6.0 (standard error = 0.7) in quintile 1, 9.8 (0.6) in quintile 2, 11.4 (0.6) in quintile 3, 16.2 (0.9) in quintile 4, and 23.3 (1.3) in quintile 5. After adjusting for covariates, the mean outdoor active play frequency score was almost three times higher in the highest parental encouragement quintile than in the lowest quintile (20.4 vs. 7.8). Conclusions. Parents use of verbal cues to encourage their children to play outdoors was independently associated with outdoor active play among 7-12 year olds. PMID- 26644991 TI - The association of parental temperament and character on their children's behavior problems. AB - Purpose. Parents have important roles in child rearing, but the influence of their personality on rearing practices and their impact on the behavior of children has received surprisingly little attention. The aim of the current study was to investigate the relationship between parents' personality and children's problem behaviors. Materials and Methods. Participants consisted of 190 preschool outpatients (104 boys, 86 girls) and their parents who visited traditional Korean pediatric clinics with minor physical symptoms as chief complaints. The personality profiles of the both parents were measured by the Temperament and Character Inventory and children's behavior problems by the Child Behavior Checklist 1.5-5. Correlation and stepwise regression analysis were employed for the statistical analyses. Results. The temperament trait of Harm Avoidance and the character traits of Self-Directedness and Self-Transcendence of the parents were significantly correlated with children's problem behaviors. Character as well as temperament, played an important role in explaining children's problem behaviors after age and gender of children were taken into account. Conclusion. The maturity of parents' character appears to have a key role in reducing the risk of behavior problems in their children. Suggestions are made for parental education and future research. PMID- 26644992 TI - Impact of Age, Race and Socio-economic Status on Temporal Trends in Late-Stage Prostate Cancer Diagnosis in Florida. AB - Individual-level data from the Florida Cancer Data System (1981-2007) were analysed to explore temporal trends of prostate cancer late-stage diagnosis, and how they vary based on race, income and age. Annual census-tract rates were computed for two races (white and black) and two age categories (40-65, >65) before being aggregated according to census tract median household incomes. Joinpoint regression and a new disparity statistic were applied to model temporal trends and detect potential racial and socio-economic differences. Multi dimensional scaling was used as an innovative way to visualize similarities among temporal trends in a 2-D space. Analysis of time-series indicated that late-stage diagnosis was generally more prevalent among blacks, for age category 40-64 compared to older patients covered by Medicare, and among classes of lower socio economic status. Joinpoint regression also showed that the rate of decline in late-stage diagnosis was similar among older patients. For younger patients, the decline occurred at a faster pace for blacks with rates becoming similar to whites in the late 90s, in particular for higher incomes. Both races displayed distinct spatial patterns with higher rates of late-stage diagnosis in the Florida Panhandle for whites whereas high rates clustered in South-eastern Florida for blacks. PMID- 26644993 TI - Do Social Networks Improve Chinese Adults' Subjective Well-being? AB - This paper studies relationships between social networks, health and subjective well-being (SWB) using nationally representative data of the Chinese Population the Chinese Family Panel Studies (CFPS). Our data contain SWB indicators in two widely used variants-happiness and life-satisfaction. Social network variables used include kinship relationships measured by marital status, family size, and having a genealogy; ties with friends/relatives/neighbors measured by holiday visitation, frequency of contacts, and whether and value gifts given and received; total number and time spent in social activities, and engagement in organizations including the communist party, religious groups, and other types. We find that giving and receiving gifts has a larger impact on SWB than either just giving or receiving them. Similarly the number of friends is more important than number of relatives, and marriage is associated with higher levels of SWB. Time spent in social activities and varieties of activities both matter for SWB but varieties matter more. Participation in organizations is associated with higher SWB across such diverse groups as being a member of the communist party or a religious organization. China represents an interesting test since it is simultaneously a traditional society with long-established norms about appropriate social networks and a rapidly changing society due to substantial economic and demographic changes. We find that it is better to both give and receive, to engage in more types of social activities, and that participation in groups all improve well-being of Chinese people. PMID- 26644994 TI - A homozygous mutation in PEX16 identified by whole-exome sequencing ending a diagnostic odyssey. AB - We present a patient with a unique neurological phenotype with a progressive neurodegenerative phenotype. An 18-year diagnostic odyssey for the patient ended when exome sequencing identified a homozygous PEX16 mutation suggesting an atypical peroxisomal biogenesis disorder (PBD). Interestingly, the patient's peroxisomal biochemical abnormalities were subtle, such that plasma very-long chain fatty acids initially failed to provide a diagnosis. This case suggests next-generation sequencing may be diagnostic in some atypical peroxisomal biogenesis disorders. PMID- 26644995 TI - Nutritional Control of Insect Reproduction. AB - The amino acid-Target of Rapamycin (AA/TOR) and insulin pathways play a pivotal role in reproduction of female insects, serving as regulatory checkpoints that guarantee the sufficiency of nutrients for developing eggs. Being evolutionary older, the AA/TOR pathway functions as an initial nutritional sensor that not only activates nutritional responses in a tissue-specific manner, but is also involved in the control of insect insulin-like peptides (ILPs) secretion. Insulin and AA/TOR pathways also assert their nutritionally linked influence on reproductive events by contributing to the control of biosynthesis and secretion of juvenile hormone and ecdysone. This review covers the present status of our understanding of the contributions of AA/TOR and insulin pathways in insect reproduction. PMID- 26644997 TI - Latest approach to breast cancer treatment and reconstruction: conservative mastectomies. PMID- 26644996 TI - Tet1 Oxidase Regulates Neuronal Gene Transcription, Active DNA Hydroxy methylation, Object Location Memory, and Threat Recognition Memory. AB - A dynamic equilibrium between DNA methylation and demethylation of neuronal activity-regulated genes is crucial for memory processes. However, the mechanisms underlying this equilibrium remain elusive. Tet1 oxidase has been shown to play a key role in the active DNA demethylation in the CNS. In this study, we used Tet1 gene knockout (Tet1KO) mice to examine the involvement of Tet1 in memory consolidation and storage in the adult brain. We found that Tet1 ablation leads to: altered expression of numerous neuronal activity-regulated genes, compensatory upregulation of active demethylation pathway genes, and upregulation of various epigenetic modifiers. Moreover, Tet1KO mice showed an enhancement in the consolidation and storage of threat recognition (cued and contextual fear conditioning) and object location memories. We conclude that Tet1 plays a critical role in regulating neuronal transcription and in maintaining the epigenetic state of the brain associated with memory consolidation and storage. PMID- 26644998 TI - Introduction to conservative mastectomies. AB - Conservative mastectomy (CM) has become an established alternative in the treatment of breast cancer, offering by different techniques a good cosmetic outcome, as well as oncologic control. The different options to achieve these goals are presented. Oncoplastic treatment of breast cancer needs planning and knowledge of well-established plastic surgery techniques. PMID- 26644999 TI - Conservative mastectomies and immediate reconstruction with the use of ADMs. AB - BACKGROUND: In recent years, a novel approach to immediate breast reconstruction has been introduced with the advent of acellular dermal matrix (ADM). In the setting of conservative mastectomies where the native skin envelope is preserved, placement of ADM at the lower pole in continuity with the pectoralis major muscle (PMM) provides additional support, allowing direct-to-implant breast reconstruction. The following manuscript presents the senior author's experience with ADM-assisted reconstruction and provides a detailed description of surgical technique along with a comprehensive discussion of patient selection and potential complications. METHODS: A retrospective chart review of patients undergoing direct-to-implant breast reconstruction following skin sparing or nipple sparing mastectomy with the use of ADM (AlloDerm; LifeCell Corp., Branchburg, USA) was conducted at Women's College Hospital in Toronto over a 5 year period [2008-2013]. Demographic data, previous radiation therapy and post operative complications were recorded. RESULTS: A total of 72 patients representing 119 breasts were identified. Average follow-up was 16 months (range, 3-51 months). Twenty-seven complications were recorded for a complication rate of 22.7% (27/119). Complications included six cases of capsular contracture (Baker III/IV), five cases of red skin syndrome, four cases of rippling, three cases of dehiscence and two cases of seroma. Overall, direct-to-implant reconstruction was successfully completed in 97.5% of breasts (116/119). One case of infection was treated with explantation and conversion to autogenous reconstruction. Two breasts with tissue necrosis or dehiscence had the implants removed and replaced with tissue expanders. Overall reoperation rate was 9.7% (7/72 patients). CONCLUSIONS: ADM assisted direct-to-implant breast reconstruction has been shown to be a safe option for women who are candidates for skin sparing or nipple sparing mastectomies. Judicious patient selection, effective collaboration between the oncologic and reconstructive surgeon, careful evaluation of post mastectomy skin flaps and precise surgical technique are paramount to the success of this technique. PMID- 26645000 TI - Conservative mastectomies: an overview. AB - Conservative mastectomies provide removal of the entire breast parenchyma, saving the outer covering of the mammary gland with the possibility of performing an immediate reconstruction preserving women body image. We rationalised and systematically organized our reconstructive algorythms giving a new different light to mastectomies, the so-called "conservative mastectomies", an oxymoron indicating skin-sparing mastectomies (SSM), nipple-areola complex-sparing mastectomies (NSM) and skin-reducing mastectomies (SRM). Eventhough randomized controlled trials comparing conservative mastectomies with traditional mastectomy and breast conserving surgery would be auspicable in order to achieve higher levels of evidence, we could confidently conclude that conservative mastectomies offer the psychological advantages of good cosmesis and maintenance of woman body image without compromising the oncological safety of mastectomy. PMID- 26645001 TI - Oncological safety of prophylactic breast surgery: skin-sparing and nipple sparing versus total mastectomy. AB - Women with a BRCA1/2 gene mutation and others with a high breast cancer risk may opt for bilateral prophylactic mastectomy. To allow for immediate breast reconstruction the skin envelope is left in situ with or without the nipple areola complex (NAC). Although possibly leading to a more natural aesthetic outcome than the conventional total mastectomy, so-called skin-sparing mastectomies (SSM) and nipple-sparing mastectomies (NSM) may leave some breast glandular tissue in situ. The oncological risk associated with remaining breast glandular tissue is unclear. We present a case of primary breast cancer after prophylactic mastectomy followed by a review of the literature on remaining breast glandular tissue after various mastectomy techniques and oncological safety of prophylactic mastectomies. PMID- 26645002 TI - Anatomy relevant to conservative mastectomy. AB - Knowledge of the anatomy of the nipple and breast skin is fundamental to any surgeon practicing conservative mastectomies. In this paper, the relevant clinical anatomy will be described, mainly focusing on the anatomy of the "oncoplastic plane", the ducts and the vasculature. We will also cover more briefly the nerve supply and the arrangement of smooth muscle of the nipple. Finally the lymphatic drainage of the nipple and areola will be described. An appreciation of the relevant anatomy, together with meticulous surgical technique may minimise local recurrence and ischaemic complications. PMID- 26645004 TI - Using intraoperative laser angiography to safeguard nipple perfusion in nipple sparing mastectomies. AB - The superior aesthetic outcomes of nipple-sparing mastectomies (NSM) explain their increased use and rising popularity. Fortunately, cancer recurrences involving the nipple-areolar complex (NAC) have been reassuringly low in the range of 1%. Technical considerations and challenges of this procedure are centered on nipple ischemia and necrosis. Patient selection, reconstructive strategies and incision placement have lowered ischemic complications. In this context, rates of full NAC necrosis are 3% or less. The emergence of noninvasive tissue angiography provides surgeons with a practical tool to assess real-time breast skin and NAC perfusion. Herein, we review our classification system of NAC perfusion patterns defined as V1 (from subjacent breast), V2 (surrounding skin), and V3 (combination of V1 + V2). Additionally, we describe the benefits of a first stage operation to devascularize the NAC as a means of improving blood flow to the NAC in preparation for NSM, helping extend the use of NSM to more women. Intraoperative evaluation of skin perfusion allows surgeons to detect ischemia and modify the operative approach to optimize outcomes. PMID- 26645003 TI - Breast reconstruction following conservative mastectomies: predictors of complications and outcomes. AB - Breast reconstruction can be performed using a variety of techniques, most commonly categorized into an alloplastic approach or an autologous tissue method. Both strategies have certain risk factors that influence reconstructive outcomes and complication rates. In alloplastic breast reconstruction, surgical outcomes and complication rates are negatively impacted by radiation, smoking, increased body mass index (BMI), hypertension, and prior breast conserving therapy. Surgical factors such as the type of implant material, undergoing immediate breast reconstruction, and the use of fat grafting can improve patient satisfaction and aesthetic outcomes. In autologous breast reconstruction, radiation, increased BMI, certain previous abdominal surgery, smoking, and delayed reconstruction are associated with higher complication rates. Though a pedicled transverse rectus abdominis myocutaneous (TRAM) flap is the most common type of flap used for autologous breast reconstruction, pedicled TRAMs are more likely to be associated with fat necrosis than a free TRAM or deep inferior epigastric perforator (DIEP) flap. Fat grafting can also be used to improve aesthetic outcomes in autologous reconstruction. This article focuses on factors, both patient and surgical, that are predictors of complications and outcomes in breast reconstruction. PMID- 26645006 TI - Extended thoracodorsal artery perforator flap for breast reconstruction. AB - A total of 45 patients underwent partial or total autologous breast reconstruction after skin-sparing mastectomy, skin-reducing mastectomy, and quadrantectomy using a thoracodorsal artery perforator (TDAP) flap. The detailed surgical technique with its variations is explained in this report. The propeller, flip-over, conventional perforator, and muscle-sparing flaps have been described and evaluated. The flaps were partially or completely de epithelialized. The conventional TDAP can be enlarged or "extended" as the traditional latissimus dorsi musculocutaneous (LD-MC) flap by incorporating the superior and inferior fat compartments. It can be referred to as the "extended TDAP flap". This technique augments the flap volume. In addition, this flap can serve as a scaffold for lipofilling to obtain autologous breast reconstruction in medium to large cases. There were two complete failures due to technical errors during flap elevation. Distal partial tissue suffering was observed in four flaps. These flaps were longer than usual; they reached the midline of the back. It is advisable to discard the distal medial quarter of the flap when it is designed up to the midline to avoid steatonecrosis or fibrosis. A retrospective analysis of the 39 flaps that survived completely revealed a satisfactory result in 82% of the cases. The main disadvantage of this procedure is the final scar. The TDAP flap is a reliable and safe method for partial or total breast autologous reconstruction. PMID- 26645005 TI - What is the evidence behind conservative mastectomies? AB - INTRODUCTION: Besides the diffusion of breast reconstructive techniques, several "conservative" approaches in mastectomy have been developed, in order to perform an immediate reconstruction with better aesthetic results: the skin-sparing mastectomy (SSM), the nipple-areola complex (NAC)-sparing mastectomy (NSM) and the skin-reducing mastectomy (SRM). During the last decade, SSMs and NSMs have gained widespread acceptance and are currently considered standard treatment for early breast cancer. We would like to investigate the evidence behind this radical shift towards conservative mastectomies, where there has been a renewed interest worldwide. METHODS: We reviewed English literature by consulting the following databases: Medline, Embase, Cochrane Register of Controlled Trials, the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) search portal and Clinicaltrials.gov. The objective is to include any randomized controlled trial (RCT) comparing a "conservative mastectomy" technique to breast conservative surgery or modified radical mastectomy (MRM) for the treatment of early-stage breast cancer. In the absence of randomized trials, we took into account prospective cohorts and retrospective series for a narrative description of available evidence. RESULTS: Our review included 58 studies [19 prospective cohorts (34%) and 39 retrospective series (66%)] considering NSM and immediate reconstruction and ten studies [1 prospective cohort (10%) and 9 (90%) retrospective series] considering SSM and immediate reconstruction. In the NSM group, 29 studies reported data about complication rates and 42 studies presented data on NAC partial or complete necrosis. In the NSM group 45 studies and all the studies in the SSM group presented data on local and NAC recurrence. CONCLUSIONS: In order to achieve higher levels of evidence, RCTs comparing conservative mastectomies to traditional mastectomy and breast conservative surgery would be desirable. However we can conclude that conservative mastectomies offer the psychological advantages of good cosmetics and maintenance of woman body image without compromising the oncological safety of mastectomy. PMID- 26645007 TI - Nipple areola complex sparing mastectomy. AB - Breast conservative therapy (BCT) is established as a safe option for most women with early breast cancer (BC). The best conservative mastectomy that can be performed, when mastectomy is unavoidable, is nipple-areola-complex sparing mastectomy (NSM), which allows the complete glandular dissection preserving the skin envelope and the nipple areola complex. In the treatment of BC, the cosmetic outcomes have become fundamental goals, as well as oncologic control. NSM is nowadays considered an alternative technique to improve the overall quality of life for women allowing excellent cosmetic results because it provides a natural appearing breast. The breast surgeon must pay attention to details and skin incision must be planned to minimize vascular impairment to the skin and the nipple. Preservation of the blood supply to the nipple is one of the most important concern during NSM because nipple or areolar necrosis is a well described complication of this surgery. Another issue associated with the nipple preservation and the surgical technique is oncological safety related to nipple areola-complex (NAC) involvement in patients with invasive BC. The authors present their experience on 252 NSM performed in the Breast Surgery Unit in Forli. Careful selection of patients for this surgical procedure is imperative and many patients are not ideal candidates for this procedure because of concerns about nipple-areolar viability as women with significant large/ptotic breast, pre existing breast scars and history of active cigarette smoking. To extend the benefits of nipple preservation to patients who are perceived to be at higher risk for nipple necrosis the authors describe technical modifications of NSM to allow nipple preservation and obtain good cosmetic outcomes. PMID- 26645009 TI - Diffuse dermal angiomatosis of the breast: a series of 22 cases from a single institution. AB - BACKGROUND: Diffuse dermal angiomatosis (DDA) is a rare cutaneous disorder that can affect the breast. A total of nine cases of breast involvement have been described in the literature, but there is currently no consensus in the best therapeutic approach. The objective of this study was to examine patient outcomes with such therapies in women diagnosed with DDA of the breast. METHODS: Consecutive cases of DDA of the breast were retrospectively reviewed including patient demographic variables, diagnostic criteria and type of therapies. A successful outcome was defined as complete healing of chronic open breast wounds and absence of disease recurrence after cessation of therapy. RESULTS: Twenty-two women (mean age, 48.4 years) diagnosed with DDA of the breast were identified between 2004 and 2012. The diagnosis was confirmed with skin biopsy in 12 patients and clinical diagnosis in the remaining ten patients. The majority of patients were obese [68.2% (15/22), average body mass index (BMI), 36.9 kg/m(2)] and at the time of diagnosis, 27.3% of patients were active smokers (6/22). Only two patients (9.1%) received isotretinoin, neither had full recovery and both patients showed recurrence when taken off of therapy. Other medical therapies showed less to no improvement. Two patients underwent successful surgical treatment. One patient had a successful outcome following breast reduction, although her postoperative course was complicated with delayed wound healing. The other patient presented with recurrence of DDA following breast reduction, and was successfully managed with bilateral simple mastectomies. CONCLUSIONS: Our findings suggest that DDA of the breast is associated with macromastia, obesity and tobacco use. Isotretinoin therapy is published as having favorable outcomes to other therapies, but in this series only appears to reduce symptoms rather than eradicate DDA. Our findings indicate that other medical therapies have been attempted with limited success. Surgical management of DDA of the breast may provide definitive treatment. PMID- 26645008 TI - Skin-sparing mastectomy. AB - The surgical treatment of breast cancer has evolved rapidly in recent decades. Conservative treatment was adopted in the late 1970s, with rates above 70%, and this was followed by a period during which the indications for surgical intervention were expanded to those patients at high risk for BRCA1, BRCA2 mutations, and also due to new staging standards and use of nuclear magnetic resonance. This increase in the indications for mastectomy coincided with the availability of immediate breast reconstruction as an oncologically safe and important surgical procedure for prevention of sequelae. Immediate reconstruction was first aimed at correcting the consequences of treatment, and almost immediately, the challenge of the technique became the achievement of a satisfactory breast appearance and shape, as well as normal consistency. The skin sparing mastectomy (SSM) in conservation first and nipple-areola complex (NAC) later was a result of this shift that occurred from the early 1990s to the present. The objective of this review is to present all these developments specifically in relation to SSM and analyze our personal experience as well as the experience of surgeons worldwide with an emphasis on the fundamental aspects, indications, surgical technique, complications, oncological safety, and cosmetic results of this procedure. PMID- 26645010 TI - Adrenal lymphangioma presenting as a non-functional adrenal cyst. AB - Lymphangiomas are neoplastic lesions derived from lymphatic endothelium. They are largely encountered in the head and neck region. We describe a case of an adrenal lymphangioma, an extremely uncommon cystic lesion of the adrenal and discuss the differential diagnosis, clinical, imaging, histopathologic and immunophenotypic features of this lesion. PMID- 26645011 TI - Esophageal recurrence of medullary thyroid carcinoma. AB - Medullary thyroid carcinoma (MTC) metastasizes to the regional lymph nodes and to the lungs, liver and bones. Only one case of recurrence of MTC involving the upper gastrointestinal tract has been reported so far. We describe the case of a 38-year-old woman with MTC, who developed an upper esophageal submucosal recurrence after two previous local recurrences treated surgically and one ethanol injection. After resection of the right lateral esophageal wall, calcitonin dropped by 60% and showed a doubling time >1 year. We cannot rule out the role of deep ethanol injection in the involvement of the cervical esophagus wall. PMID- 26645012 TI - Carcinoma ex pleomorphic adenoma originating from ectopic salivary gland in the neck region: case report. AB - Carcinoma ex pleomorphic adenoma (CEPA) is the malignant salivary gland tumor originating from primary (de novo) or recurrent pleomorphic adenoma. Although parotid gland is the most common site, it can also be seen in submandibular gland or minor salivary glands. It can be seen rarely in head and neck region, such as oral cavity, trachea, nasal cavity and lacrimal gland. Although pleomorphic adenoma cases originating from ectopic salivary gland tissue in the neck region are present in the English literature, there is no published pleomorphic adenoma ex carcinoma case. In this case report we presented a CEPA as a 7.5 cm long neck mass in a 72-year-old woman originating from the submandibular region apart from submandibular gland. Difficulties in diagnosis and way to appropriate treatment are discussed with current literature. PMID- 26645013 TI - Fast and simple fat grafting of the breast. AB - Fat grafting (FG) is being used at an escalating rate for correction of shape and volume of all types of breast surgery in order to optimize the aesthetic result in spite of an ongoing debate of the oncologic safety. In this paper we demonstrate our simple and fast sedimentation based FG technique in the attached video as visualized surgery. We have used this simple approach for 348 procedures in 176 women to optimize and correct the aesthetic result following all types of breast surgery. We prefer this simple technique as no technique has been shown to be superior to other more costly techniques and furthermore there are still questions about the oncologic safety in using adipose derived stem cells (ADSC). Simple fat harvesting using low vacuum and preparation by sedimentation is a fast and effective method to perform FG successfully for correction of shape and volume deficits of the breast following both ablative surgery as well as benign conditions with a high margin of safety. PMID- 26645014 TI - Erratum to abnormality of p16/p38MAPK/p53/Wipl pathway in papillary thyroid cancer. AB - [This corrects the article on p. 33 in vol. 1, PMID: 25083425.]. PMID- 26645015 TI - Erratum to the presentation of lymph nodes in Hashimoto's thyroiditis on ultrasound. AB - [This corrects the article on p. 301 in vol. 4, PMID: 26311120.]. PMID- 26645016 TI - Transocular Doppler and optic nerve sheath diameter monitoring to detect intracranial hypertension. AB - BACKGROUND: Increases in intracranial pressure (ICP) require a rapid recognition to allow for adequate treatments. The aim of this study was to determine whether transocular Doppler and optic nerve sheath diameter (ONSD) monitoring could reliably identify increases in ICP. MATERIALS AND METHODS: This is a cross sectional case-control study, which was carried out on 2013. Subjects were chosen from patients who admitted to the neurology and neurosurgery departments and the intensive care unit of Alzahra Hospital (Isfahan, Iran). To measure the ICP, the authors used ultrasound to measure the diameter of the optic nerve sheath and transocular Doppler (TOD) to measure blood flew velocity in ophthalmic artery (OA) and ophthalmic vein (OV) in both groups. RESULTS: The mean of ONSD was 4.8 mm (SD 0.77) in patients with raised ICP and 3.2 mm (SD 0.3) in healthy volunteers which was significant (P < 0.001). The mean (SD) of TOD parameters were also significantly more in OA and OV of patients with raised ICP. CONCLUSION: Ultrasound methods has been proposed as an alternative safe technique for invasive ICP measuring methods. PMID- 26645017 TI - Comparative evaluation of adding different opiates (morphine, meperidine, buprenorphine, or fentanyl) to lidocaine in duration and quality of axillary brachial plexus block. AB - BACKGROUND: There is no agreement about the effect of adding opioids to local anesthetics in peripheral nerve blocks. The aim of this study was to investigate the effect of adding different opioids with equipotent doses of lidocaine in axillary brachial plexus block using ultrasonography and nerve locator guidance. MATERIALS AND METHODS: In a prospective, randomized, double-blind clinical trial study, 72 adult patients aged 18-65 years old scheduled for orthopedic surgery of the forearm and hand with axillary brachial plexus block were selected and randomly allocated to four groups. Meperidine (pethidine), buprenorphine, morphine, and fentanyl with equipotent doses were added in 40cc of 1% lidocaine in P, B, M, and F groups, respectively. The onset and duration of sensory and motor blocks, severity of patients' pain, duration of analgesia, hemodynamic and respiratory parameters, and adverse events (such as nausea and pruritus) during perioperative period were recorded. RESULTS: The onset time for the sensory block was similar in the four groups. The onset time for the motor block was significantly faster in morphine and pethidine groups (P = 0.006). The duration of sensory and motor blocks was not statistically different among the four groups. The quality of motor blockade was complete in 100% of patients receiving pethidine or morphine and 77.8% of patients receiving buprenorphine or fentanyl (P = 0.021). CONCLUSION: In the upper extremity surgeries performed under axillary brachial plexus block addition of morphine or pethidine to lidocaine may be superior to other opioids (i.e. fentanyl and buprenorphine) due to better quality and quantity of motor blockade and faster onset of the block. PMID- 26645018 TI - Role of nitric oxide in kidney and liver (as distance organ) function in bilateral renal ischemia-reperfusion: Effect of L-Arginine and NG-nitro-L Arginine methyl ester. AB - BACKGROUND: Renal ischemia-reperfusion (RIR) is a major cause of renal dysfunction that acts through different mechanisms. We investigated the role of L Arginine as an endogenous nitric oxide (NO) precursor and NG-nitro-L-Arginine methyl ester (L-NAME) as an NO inhibitor on kidney and liver function in RIR model. MATERIALS AND METHODS: Fifty-eight Wistar rats were randomly assigned to four groups. Groups 1 (sham-operated, n = 13) received a single dose of saline (4 ml/kg, i.p.) and 2 (Ischemia [Isch], n = 14) received a single dose of saline (4 ml/kg, i.p.). Groups 3 (Isch + L-NAME, n = 15) received a single dose of L-NAME (20 mg/kg, i.p.) and 4 (Isch + L-Arginine n = 16) received a single dose of L Arginine (300 mg/kg, i.p.), After 2 h, renal failure was induced by clamping both renal pedicles for 45 min, followed by 24-h reperfusion in Groups 2-4. Finally, blood samples were obtained, and kidney tissue samples were subjected for pathology investigations. RESULTS: The body weight decreased, and the serum levels of blood urea nitrogen (BUN) and creatinine (Cr), and kidney tissue damage score (KTDS) increased significantly in the Isch and Isch + L-NAME groups compared with the sham group while L-Arginine improved weight reduction (P < 0.05), and it reduced the serum levels of BUN and Cr, and KTDS when compared with the Isch and Isch + L-NAME groups. Kidney weight increased significantly in all groups compared with the sham group. L-Arginine reduced the liver tissue level of malondialdehyde and increased alkaline phosphatase. CONCLUSION: L-Arginine as an NO precursor can improve kidney function against RIR. It also improves oxidative stress in liver tissue. PMID- 26645019 TI - Comparison of gene expression of SOX2 and OCT4 in normal tissue, polyps, and colon adenocarcinoma using immunohistochemical staining. AB - BACKGROUND: Cancer stem cells have been isolated and characterized in all common cancers. SOX2 and OCT4 are important genes to enhance the self-renewal ability as activate stem cells and inhibit the genes that start differentiation and thus maintain the self-renewal ability of stem cells. Also, the aim of this study is "Comparison of gene expression of SOX2 and OCT4 in normal tissue, polyps, and colon adenocarcinoma using immunohistochemical staining." MATERIALS AND METHODS: This cross-sectional study conducted on 20 patients so that for each patient, a sample of healthy tissue, dysplastic polyp tissue, and colon adenocarcinoma were provided as microscopic sections and staining on each tissue was performed through immunohistochemistry method by markers OCT4 and SOX2. The collected data were interred into SPSS version 18.0, (SPSS Inc., Chicago, IL, USA) software and the level of significance were considered as <0.05. RESULTS: The study sample consisted of 20 patients including 11 men (55%) and 9 women (45%) with a mean age of 55.6 +/- 9.88 years. There was no association between Oct4 and colorectal cancer (CRC) patients (P > 0.05), but there was a significant correlation between Sox2 expression and CRC (P < 0.05). Patients in many aspects such as race, type of polyp, presence of lymph node, grade and intensity of Sox2 in different types of patients' tissues (P < 0.05). CONCLUSION: Regarding our findings, the expression of Sox2 would be a liable marker for evaluating of cancer progression and could be a treatment target of CRC cells. PMID- 26645020 TI - Effects of fluoxetine on memory under forced treadmill exercise conditions in male rats. AB - BACKGROUND: Studies show inconsistent effects of forced exercise on cognitive processes. These differences are probably due to the stress of coercion in forced exercise. Because fluoxetine is used to treat complications caused by stress, this study aimed to evaluate the effects of fluoxetine on memory in rats under forced treadmill exercise. MATERIALS AND METHODS: Experimental groups were the control, the control exercise, the fluoxetine, and the fluoxetine exercise. The exercise program was treadmill running at 22 m/min, 0 degrees inclination for 50 min/day, 6 days/week, for 4 weeks. Fluoxetine (5 mg/kg) was injected 30 min before treadmill. Morris water maze and passive avoidance learning tests were used for evaluation of memory. Acquisition phase of both tests were performed before interventions and memory was evaluated 1-day and 1-week after the last session of exercise and treatments. RESULTS: Our data showed that forced exercise impaired performance in passive avoidance learning test (P < 0.05 and P < 0.01, 1 day and 1-week after the last session of exercise and treatments, respectively). Spatial memory was only impaired after 1-week in the exercise group. Fluoxetine improved spatial memory after 1-day in the control group. However, it had no significant effects on memory in the exercise group. CONCLUSION: The data correspond to the possibility that forced treadmill exercise can cause stress, and thereby cause damage to memory. The present results suggest that although fluoxetine may improve memory in intact rats but it cannot prevent damages that are caused by forced exercise. PMID- 26645021 TI - Crimean-Congo hemorrhagic fever in Pakistan: Are we going in the right direction? PMID- 26645022 TI - A short review on structure and role of cyclic-3',5'-adenosine monophosphate specific phosphodiesterase 4 as a treatment tool. AB - Cyclic nucleotide phosphodiesterases (PDEs) are known as a super-family of enzymes which catalyze the metabolism of the intracellular cyclic nucleotides, cyclic-3',5'-adenosine monophosphate (cAMP), and cyclic-3',5'-guanosine monophosphate that are expressed in a variety of cell types that can exert various functions based on their cells distribution. The PDE4 family has been the focus of vast research efforts over recent years because this family is considered as a prime target for therapeutic intervention in a number of inflammatory diseases such as asthma, chronic obstructive pulmonary disease, and rheumatoid arthritis, and it should be used and researched by pharmacists. This is because the major isoform of PDE that regulates inflammatory cell activity is the cAMP-specific PDE, PDE4. This review discusses the relationship between PDE4 and its inhibitor drugs based on structures, cells distribution, and pharmacological properties of PDE4 which can be informative for all pharmacy specialists. PMID- 26645023 TI - Nasal carriage of Methicillin- and Mupirocin-resistant S. aureus among health care workers in a tertiary care hospital. AB - OBJECTIVE: Methicillin-resistant Staphylococcus aureus (MRSA) ranks top among the nosocomial pathogens. Nasal formulation of mupirocin is found to eradicate MRSA from colonized individuals, but the emergence of resistant strains is a matter of concern. METHODS: Nasal swabs were collected from 200 health care workers (HCWs) who were screened for MRSA. Kirby-Bauer disc diffusion method was used to perform antibiotic susceptibility test. MRSA detection was done using a cefoxitin 30 ug disc and interpreted according to the Clinical and Laboratory Standards Institute guidelines. Determination of mupirocin resistance was performed using Epsilometer test (E-test). FINDINGS: About 14% of HCWs showed nasal carriage of MRSA. Nursing orderlies were the predominant carriers. E-test showed four mupirocin resistant isolates. The antibiogram of the MRSA isolates revealed the higher resistance to antibiotics as compared to methicillin-sensitive Staphylococcus aureus. All the MRSA isolates were sensitive to linezolid. CONCLUSION: HCWs in our hospital showed high nasal carriage rate of MRSA, particularly the nursing orderlies which is statistically significant. It is advisable to detect mupirocin resistance among the isolates obtained from the HCWs so that in case of resistance, alternative treatment should be sought. PMID- 26645024 TI - Comparison of the effects of intravenous premedication: Midazolam, Ketamine, and combination of both on reducing anxiety in pediatric patients before general anesthesia. AB - OBJECTIVE: In some medical circumstances, pediatric patients may need premedication for transferring to the operating room. In these situations, using intravenous premedication is preferred. We assessed the efficacy and safety of intravenous midazolam, intravenous ketamine, and combination of both to reduce the anxiety and improve behavior in children undergoing general anesthesia. METHODS: In a double-blind randomized clinical trial, 90 pediatric patients aged 6 months to 6 years with American Society of Anesthesiologist grade I or II were enrolled. Before anesthesia, children were randomly divided into three groups to receive intravenous midazolam 0.1 mg/kg, or intravenous ketamine 1 mg/kg, or combination of half doses of both. Behavior types and sedation scores were recorded before premedication, after premedication, before anesthesia, and after anesthesia in the postanesthesia care unit. Anesthesia time, recovery duration, blood pressure, and heart rate were also recorded. For comparing distribution of behavior types and sedation scores among three groups, we used Kruskal-Wallis test, and for comparing mean and standard deviation of blood pressure and heart rates, we used analysis of variance. FINDINGS: After premedication, children's behavior was significantly better in the combination group (P < 0.001). After anesthesia, behavior type was same among three groups (P = 0.421). Sedation scores among three groups were also different after premedication and the combination group was significantly more sedated than the other two groups (P < 0.001). CONCLUSION: Combination of 0.05 mg/kg of intravenous midazolam and 0.5 mg/kg of intravenous ketamine as premedication produced more deep sedation and more desirable behavior in children compared with each midazolam 0.1 mg/kg or ketamine 1 mg/kg. PMID- 26645025 TI - Serum Vitamin D levels at admission predict the length of intensive care unit stay but not in-hospital mortality of critically ill surgical patients. AB - OBJECTIVE: There is few data regarding the correlation between serum Vitamin D level and unfavorable intensive care unit (ICU) outcome in postsurgical patients. In this study, correlation between serum 25(OH)D level and length of ICU stay and in-hospital mortality has been evaluated in critically ill surgical patients. METHODS: Serum 25(OH)D has been evaluated in 70 surgical, critically ill patients. Demographic, laboratory, and clinical data of the patients were collected. Correlation between serum 25(OH) D level and duration of ICU stay and hospital mortality was evaluated using two-factor analysis of covariance. Multivariable Cox-regression analysis was used for adjusting the effect of season of blood sampling and type of surgery on the main variables. For all the analyses, P values less than or equal to 0.05 were considered as statistically significant. FINDINGS: Serum 25(OH)D deficiency was identified in 52 (74.3%) of the patients. Patients with serum Vitamin D levels < 30 ng/ml had longer length of ICU stay than those with serum Vitamin D levels >= 30 ng/ml (7.8 +/- 5.1 vs. 4.05 +/- 2.12 days, P = 0.003). Although hospital mortality was more common in Vitamin D deficient patients than sufficient ones (25% in deficient group versus 22.2% in sufficient group), there was no significant difference regarding hospital mortality rate between the groups. CONCLUSION: Statistically significant association was found between low 25(OH)D level and increased length of ICU stay in critically ill surgical patients. It could be explained by favorable effects of Vitamin D on immune system functions, reducing tissue dysfunction, and risk of organ failure and overall complications. However, there was no correlation between serum Vitamin D level and patients' in-hospital mortality. Further, well designed prospective clinical studies with adequate sample size are needed to evaluate correlation between serum Vitamin D level and mortality in critically ill patients. PMID- 26645026 TI - A news media analysis of economic sanction effects on access to medicine in Iran. AB - OBJECTIVE: In the past decades economic sanctions have been used by different countries or international organizations in order to deprive target countries of some transactions. While the sanctions do not target health care systems or public health structures, they may, in fact, affect the availability of health care in target countries. In this study, we used media analysis to assess the impacts of recent sanctions imposed by the Central Bank of Iran in 2012 on access to medicines in Iran. METHODS: We searched different sources of written news media including a database of nonspecialized weeklies and magazines, online news sources, web pages of daily newspapers and healthcare oriented weeklies from 2011 to 2013. We searched the sources using the general term "medicine" to reduce the chances of missing relevant items. The identified news media were read, and categorized under three groups of items announcing "shortage of medicines," "medicines related issues" and "no shortage." We conducted trend analyzes to see whether the news media related to access to medicines were affected by the economic sanctions. FINDINGS: A total number of 371 relevant news media were collected. The number of news media related to medicines substantially increased in the study period: 30 (8%), 161 (43%) and 180 (49%) were published in 2011, 2012 and 2013, respectively. While 145 (39%) of media items referred to the shortage of medicines, 97 (26%) reported no shortage or alleviating of concerns. CONCLUSION: Media analysis suggests a clear increase in the number of news media reporting a shortage in Iran after the sanctions. In 2013, there were accompanying increases in the number of news media reporting alleviation of the shortages of medicines. Our analysis provides evidence of negative effects of the sanctions on access to medicines in Iran. PMID- 26645027 TI - The pattern and risk factors associated with adverse drug reactions induced by Reteplase in patients with acute ST-elevation myocardial infarction: The first report from Iranian population. AB - OBJECTIVE: Acute myocardial infarction (AMI) is one of the main leading causes of mortality and morbidity. Reteplase is a fibrin-specific thrombolytic which is used in the treatment of AMI. There is a limited number of studies reporting the postmarketing adverse drug reactions (ADRs) induced by reteplase. This study was aimed to examine the reteplase pattern of ADR and its associated risk factors in patients with acute ST-elevation myocardial infarction. METHODS: A cross sectional, prospective study in an 8-month period was done at the University affiliated referral cardiovascular center. The Naranjo probability scale and World Health Organization criteria for severity of ADRs were used for assessing the ADRs. The linear regression and logistic regression tests were used to evaluate the correlation between ADRs and risk factors. FINDINGS: The all 20 patients who received reteplase during the study period were entered. The majority of patients (n = 17) experienced at least one ADR. The results showed that the incidence of ADRs was mainly associated with gender and age, and the number of ADRs was associated with the history of diabetes and taking anti diabetic agents. The gender was the main predictor in the occurrence of ADRs (odds ratio: 32, 95% confidence interval: 1.38-737.45; P = 0.030). CONCLUSION: The results showed that gender, age, diabetes mellitus, and using of anti diabetes medications are the risk factors associated with the incidence of ADRs by reteplase. PMID- 26645028 TI - Pediatric hospital admission due to adverse drug reactions: Report from a tertiary center. AB - OBJECTIVE: Adverse drug reactions (ADRs) are known as a cause of hospital admission. We have carried out a prospective study to characterize and assess the frequency, probability, preventability, and severity of ADRs, which lead to hospital admission in children. METHODS: In a prospective observational study, a cohort of children admitted to a tertiary pediatric hospital was randomly screened to assess ADR as the cause of admission from June 2014 to January 2015. ADRs causing admissions were detected based on patients' records, interviewing their parents, and confirmation by medical team. The probability of the ADRs was assessed based on WHO criteria and Naranjo tool. The preventability assessment was performed using Schumock and Thornton questionnaire. FINDINGS: Of the 658 evaluated emergency admissions, 27 were caused by an ADR giving an incidence of 4.1%. Among ADRs, 37.1% were estimated to be preventable. Antibiotics were the most common medication class which caused hospital admission. CONCLUSION: Pediatric pharmacotherapy still needs evidence-based strategies to improve child care including education, monitoring, planning for medications after ADR occurrence, and implementing preventive measures when applicable. PMID- 26645029 TI - Drug-related problems in medical wards of Tikur Anbessa specialized hospital, Ethiopia. AB - OBJECTIVE: This study was aimed to determine the prevalence of drug-related problems (DRPs), identify the most common drugs, and drug classes involved in DRPs as well as associated factors with the occurrence of DRPs. METHODS: A prospective cross-sectional study was conducted on 225 patients admitted to medical wards of Tikur Anbessa Specialized Hospital, Addis Ababa from March to June 2014. Data regarding patient characteristics, medications, diagnosis, length of hospitalization, investigation, and laboratory results were collected using data abstraction forms through review of patients' medical card and medication charts. Identified DRPs were recorded and classified using DRP registration forms. The possible intervention measures for the identified DRPs were proposed and communicated to either the physician or the patient. Data were entered into Epi Info 7 and analyzed using SPSS version 21 (IBM Corp. Released 2012, Armonk, NY: IBM Corp). FINDINGS: DRPs were found in 52% of study subjects. A drug-drug interaction (48% of all DRPs) was the most common DRP followed by adverse drug reaction (23%). Anti-infectives and gastrointestinal medicines were commonly involved in DRPs. Drugs with the highest drug risk ratio were gentamycin, warfarin, nifedipine, and cimetidine. The number of drugs taken by the patient per day is an important risk factor for DRPs. CONCLUSION: DRPs are common among medical ward patients. Polypharmacy has a significant association with the occurrence of DRP. Drugs such as gentamycin, warfarin, nifedipine, and cimetidine have the highest probability of causing DRP. So, patients who are taking either of these drugs or polypharmacy should be closely assessed for identification and timely correction of DRPs. PMID- 26645030 TI - Drug use evaluation of Meropenem at a tertiary care university hospital: A report from Northern Iran. AB - OBJECTIVE: The inappropriate use of antibiotics remains the primary factor in antimicrobial drug resistance. In this study, we evaluate the use of meropenem in surgical/medical wards of Imam Khomeini Tertiary Referral Hospital, Sari, Iran. METHODS: This retrospective observational study was used to assess rational use of meropenem. The study was conducted by reviewing medical records of 100 admitted patients who received meropenem during March 2013 to January 2014. FINDINGS: Meropenem was prescribed most frequently in Intensive Care Unit (22%), and pneumonia was the most common diagnosis (35%). The third-generation cephalosporins were the most frequently prescribed antimicrobials after meropenem (53%). In 21% of the patients, imipenem was changed to meropenem. Most of the inappropriate uses were seen in terms of frequency of meropenem use (34%), followed by duration of meropenem therapy (28%). CONCLUSION: Comparing our study results has shown higher inappropriate use. It is necessary to take action to improve prescribing habit in order to reduce the unnecessary usage of antibiotic thus enhance rational antibiotic use. PMID- 26645031 TI - Peste des petits ruminants vaccine and vaccination in India: sharing experience with disease endemic countries. AB - Peste des petits ruminants, a viral disease of small ruminants, the control of which is important for poverty alleviation and to ensure livelihood security in Asia, Middle East and Africa. In recognition of these issues, we developed and applied vaccine and diagnostics to demonstrate effective control of PPR during preceding 6 years in a sub-population of small ruminants in India. Two south Indian states, namely Andhra Pradesh and Karnataka, strongly indicated possibility of PPR control with more than 90 % reduction in number of reported outbreaks of PPR, mostly through mass vaccination. Similarly, the situation at the national level also demonstrated a decline of more than 75 % in the number of reported outbreaks. Sharing these experiences may motivate other countries for similar initiatives leading to progressive control of PPR, which is in line with the initiatives of the organizations like FAO/OIE and the recent platforms on global PPR research alliance. PMID- 26645033 TI - Quantification of sugarcane yellow leaf virus in sugarcane following transmission through aphid vector, Melanaphis sacchari. AB - Yellow leaf caused by Sugarcane yellow leaf virus (SCYLV) is a serious constraint to sugarcane production in India and currently the disease epidemics occur on many of the susceptible varieties under field conditions. Studies were conducted on the virus transmission by sugarcane aphid Melanaphis sacchari in sugarcane by inoculating virus-free meristem derived from micro- propagated plants of sugarcane cv Co 86032 with viruliferous aphids. Virus transmission was confirmed through RT-PCR assays and subsequently SCYLV population was established through RT-qPCR. A maximum of 22.3 * 10(3), 3.16 * 10(6) and 4.78 * 10(6) copies of SCYLV RNA targets were recorded in the plants after 7, 180 and 300 days, respectively. This study showed that the aphid species M. sacchari acts as an effective vector of SCYLV. The relative standard curve method in RT-qPCR efficiently detected the increment in SCYLV copy numbers in sugarcane following transmission through M. sacchari. PMID- 26645032 TI - Herbal plants and plant preparations as remedial approach for viral diseases. AB - Herbal plants, plant preparations and phytoconstituents have proved useful in attenuating infectious conditions and were the only remedies available, till the advent of antibiotics (many being of plant origin themselves). Among infectious diseases, viral diseases in particular, remain the leading cause of death in humans globally. A variety of phytoconstituents derived from medicinal herbs have been extensively studied for antiviral activity. Based on this rationale, an online search was performed, which helped to identify a large number of plant species harboring antiviral molecules. These herbal sources have been reported individually or in combinations across a large number of citations studied. Activities against rabies virus, Human immunodeficiency virus, Chandipura virus, Japanese Encephalitis Virus, Enterovirus, Influenza A/H1N1 and other influenza viruses were discovered during the literature search. This review includes all such plant species exhibiting antiviral properties. The review also encompasses composition and methodologies of preparing various antiviral formulations around the globe. An elaborate section on the formulations filed for patent registration, along with non-patented formulations, has also been included in this article. To conclude, herbal sources provide researchers enormous scope to explore and bring out viable alternatives against viral diseases, considering non availability of suitable drug candidates and increasing resistance to existing drug molecules for many emerging and re-emerging viral diseases. PMID- 26645034 TI - Computational analysis reveal inhibitory action of nimbin against dengue viral envelope protein. AB - Dengue has emerged to be global health problem worldwide. Hence there is an immediate need to adopt new strategies in the development of effective anti dengue drugs. Extracts from the leaves of Azadirachta indica has been traditionally used in folk medicine for viral infections. In the present study we report the anti-viral potency of nimbin, the active compound from the neem leaf extract against the envelope protein of dengue virus. Progression of viral entry into the host cell is facilitated by the envelope protein of dengue virus, suggesting; it as an effective anti-viral target. Nimbin is found to be effective against the envelope protein of all four types of dengue virus (dengue 1-4), which is evident from our in silico analysis. Our findings suggest the clinical importance of nimbin, which can serve as effective lead compound for further analysis. PMID- 26645035 TI - Isolation and phylogenetic analysis of caprine Orf virus in Malaysia. AB - Orf virus is a DNA virus that causes contiguous ecthyma in goat and sheep. Infection of animals with this virus cause high mortality in young animals resulting in huge economic losses. In this study, we investigated an outbreak of Orf in a goat farm in Malaysia. Samples were collected from infected animals and viral isolation was done using both LT and MDCK cell lines. Molecular detection was done by conventional PCR for specific primers; B2L and F1L genes and phylogenetic analysis was done on the sequence data obtained. Cytopathic effects (CPE) were observed in both cell lines after 3 days of inoculation and were 50 % by the sixth day. PCR showed positive bands for both B2L and F1L genes and phylogenetic analysis showed that the Malaysian strain had close homology to the Chinese and Indian Orf virus isolates. This study gives more insight into the existing Orf viral strains in Malaysia and their relationship with other strains globally. PMID- 26645036 TI - Molecular typing and phylogenetic analysis of classical swine fever virus isolates from Kerala, India. AB - Classical swine fever (CSF) is an economically important disease of pigs caused by CSF virus (CSFV) belonging to the genus Pestivirus within the family Flaviviridae. The disease is endemic in many countries including India. A comprehensive study was carried out to assess the type of CSFV circulating in the South Indian state of Kerala. During the period 2013-2014, clinical samples were collected from 19 suspected CSF outbreaks of domestic pigs in different districts of Kerala. The samples were tested using nested reverse transcription PCR (RT PCR) targeting the E2 gene and RT-PCR for 5'UTR of the virus. Partial 5' UTR and E2 gene regions of six CSFV isolates were sequenced. Phylogenetic analysis revealed that all the CSFV isolates belonged to subgroup 2.2. The isolates showed close resemblance to the other CSFV isolates circulating in India. It was also observed that the CSFV viruses from Kannur district were distinct from those circulating in the other districts as evidenced by their divergence from other Kerala isolates in the phylogenetic tree. Close relationship was seen to the CSFV isolates from South East Asian countries. PMID- 26645037 TI - Evaluation of antiviral resistant hepatitis B virus subpopulations in patients with chronic hepatitis B by using terminal restriction fragment length polymorphism. AB - Antiviral therapies with nucleotide analogues (NA) is crucial in the treatment of chronic hepatitis B as it substantially protects patients from the complications of the disease . However in most of the available NA therapies, resistance emerges in the patients' HBV populations. Therefore, detection of antiviral resistance as early as possible by means of genotypically monitoring the patients' HBV pool during NA therapy is critical to manage treatment regime. In this research study we have investigated the sensitivity and specificity of the terminal restriction fragment length polymorphism (T-RFLP) method in detecting HBV subpopulations carrying antiviral resistance mutations. For this aim, differentiation of mutant strains from wild type strains was demonstrated by PCR RFLP method. With using recombinant plasmids containing mutant and wild type HBV genomes, we constructed artificial HBV genome populations in order to determine the sensitivity of PCR-T-RFLP method in detecting antiviral resistant minor HBV populations. Finally by comparing with the DNA sequencing method, we demonstrated the specificity of T-RFLP method in genotyping HBV populations. As a result we showed that T-RFLP is able to detect HBV subpopulations representing as low as 1 % of the whole viral population. Additionally T-RFLP showed 100 % concordance with the DNA sequencing method in genotyping HBV populations. As a conclusion, considering the other genotyping methods used in evaluating HBV populations, T RFLP showed high sensitivity and specificity profiles in detecting antiviral resistant HBV subpopulations. Therefore T-RFLP method can be easily employed in genotypic evaluation of patients' HBV populations during the course of antiviral treatment. PMID- 26645038 TI - Retrospective phylogenetic analysis of circulating BA genotype of human respiratory syncytial virus with 60 bp duplication from New Delhi, India during 2007-2010. AB - Human respiratory syncytial virus (hRSV) is the most common viral pathogen of acute lower respiratory tract infection in infants and young children. The G protein of hRSV is the trans-membrane glycoprotein that is involved in the attachment of virion with the host cell. The nasopharyngeal aspirates were subjected to RT-PCR for the second hypervariable region of the G protein gene in the present investigation. Sequencing and phylogenetic analysis revealed that all the study strains clustered within the BA genotype. The study sequences further clustered in BA-9, BA-7, BA-10 and BA-12 subgroups within the BA genotype. The G proteins of the study sequences were predicted to encode 312 and 319 amino acids. Three different N-linked glycosylation sites were observed in the deduced 93-100 amino acid region. There were 40-43 serine and threonine residues that are the potential O-linked glycosylation sites. The non-synonymous/synonymous (dN/dS) ratio was less than one indicating negative selection pressure for amino acid change in the analyzed region of the G protein. The present investigation provides information on circulating strains of BA genotype from New Delhi, India. Further elaborate investigations of the BA viruses from different regions of the world will establish the basis of the rapid global spread and evolutionary pattern of this expanding genotype. PMID- 26645039 TI - Evaluation of phenotypic factors for anti-rabies antibody in vaccinated pet dogs. AB - The aims of this study were to investigate various factors associated with protective anti-rabies antibody status (0.5 EU/ml) in vaccinated pet dogs and anti-rabies antibody status in unvaccinated stray dogs. One hundred and seven serum samples were collected from vaccinated pet dogs, out of these 58 (62.36 %) dogs showed antibody titre above 0.5 EU/ml. All the dogs were divided into different groups based on age, sex, breed, vaccine brand and time of vaccination after last vaccine to assess the relationship of these factors with vaccinal immune response. One way analysis of variance was performed in graphpad prism software to check the effect of all these factors. Statistical analysis of ELISA titres of pet dog serum samples suggested that age, sex, breed and vaccine brands have no significant effect on the anti-rabies antibody titres. To check anti rabies antibody status in stray dogs 53 serum samples were collected and only one out of 53 (1.88 %) stray dogs showed anti-rabies antibody titre above 0.5 EU/ml indicating susceptibility to rabies infection and thereby posing possible threat to surrounding human and animal populations. PMID- 26645040 TI - Molecular and immunogenic characterization of BHK-21 cell line adapted CVS-11 strain of rabies virus and future prospect in vaccination strategy. AB - Development of a cost effective quality vaccine is a key issue in rabies control programme in developing countries. With this perspective, in the present study, challenge virus standard (CVS)-11 strain of rabies virus was adapted to grow in BHK-21 cells, characterized, compared with other viruses including global vaccine strains and field isolates from Indian subcontinent and China at molecular level. This cell adapted virus was evaluated for the production of cost effective veterinary vaccine. The maximum virus titre achieved was 10(7) fluorescent focus unit (FFU)/mL at 10th passage level. There was no nucleotide difference in the nucleoprotein (N) and glycoprotein (G) genes after adaptation in cell line. Phylogenetic analysis showed that adapted virus was grouped with global vaccine strains, closest being with other CVS strains but distinct from the Indian field isolates. Global vaccine strains including cell adapted CVS-11 virus have 83-87 % identity at nucleotide level of G gene with Indian field viruses. Growth kinetics of cell culture adapted virus showed that the optimum virus titer (around 10(7) FFU/mL) could be obtained at around 48 h post infection by co-cultivation method using 0.1 multiplicity of infection inoculums at 37 degrees C. These findings can be used for up scaling of vaccine production. The protective efficacy of test vaccine produced using 10(6.95) FFU/mL cell culture harvest showed 1.17 IU/mL relative potency by NIH test. Further, adapted virus was found to be suitable for use in rapid fluorescent focus inhibition test. PMID- 26645041 TI - Awareness and acceptance of human papillomavirus vaccination among health sciences students in Malaysia. AB - The major cause of cervical cancer is human papillomavirus (HPV) for which vaccination is available. The success HPV vaccination programme largely depend on the degree of knowledge of the healthcare providers who can recommend to the public. Health sciences students as future healthcare providers play a major role in HPV vaccination initiatives. The objective of this study was to evaluate the knowledge, attitude, practice and to find out the willingness to pay for HPV vaccination among the health sciences students in a private university. The cross sectional study was conducted among the university students studying health sciences program using a validated questionnaire to measure their awareness and acceptance of HPV vaccination. The students demonstrated moderate knowledge about HPV infection and vaccination with mean knowledge scores of 9.3 out of 17. Students were showing positive attitude towards HPV vaccination with mean scores of 3.80 out of 5. However, low HPV vaccination uptake rate was reported among the students. Most of the students were willing to recommend HPV vaccine. The participants felt that the cost is the major barrier towards HPV vaccination and they felt the government should cover the cost of vaccination for all. The results of this study may be helpful in establishing educational policies on cervical cancer-related topics in the universities. PMID- 26645042 TI - Diagnosis of a new variant of soybean yellow mottle mosaic virus with extended host-range in India. AB - Soybean yellow mottle mosaic virus (SYMMV, genus Carmovirus) was previously known to occur in South Korea and USA causing bright yellow mosaic in soybean. In this study, SYMMV (Car-Mb14 isolate) was isolated from mungbean (Vigna radiata) exhibiting mild mottling and puckering symptoms in the experimental field at Indian Agricultural Research Institute, New Delhi during 2012. The virus isolate, Car-Mb14 induced veinal mottling, mild mottling, chlorotic blotching, local and systemic necrosis in soybean, mungbean, blackgram, French bean and guar bean, respectively. The symptomatology of the present isolate of SYMMV was different from the previously reported South Korean isolate, as the later did not induce symptoms in any of the above legumes other than soybean. The present isolate was phylogenetically distinct and shared 90-93 % sequence identity in coat protein (CP) of 52 SYMMV isolates reported from Korea and USA. In order to know the serological relationships, the CP gene of the present isolate was over expressed as a 39 kDa protein in E. coli and an antiserum of 1:16,000 titer against the recombinant CP was produced. Serological cross reactivity analysis revealed that SYMMV was serologically related to blackgram mottle virus but not to cowpea mottle virus, the other legume infecting carmoviruses. The antiserum was used to detect prevalence of SYMMV in legume crops by ELISA. Out of 145 field samples of legumes (mungbean, blackgram, French bean and soybean) collected from different places in India, SYMMV was detected only in 16 samples of mungbean and one sample of blackgram. The natural infection of SYMMV in mungbean and blackgram was further confirmed based on CP gene sequence. This study provides evidence of occurrence of a new variant of SYMMV with distinct symptom phenotype and extended host-range in India. PMID- 26645043 TI - Identification and molecular characterization of Bean yellow mosaic virus infecting French bean in Himachal Pradesh. AB - French bean (Phaseolus vulgaris L.), is one of the most widely grown vegetable crop. Disease samples showing yellow mosaic symptoms on leaves and pods were collected from Himachal Pradesh and inoculated on common bean cv. Jawala through sap inoculation. The virus successfully transmitted by mechanical inoculation produced yellow mosaic, leaf distortion, curling, wrinkling of leaves followed by stunting of plants. The identity of the virus as Bean yellow mosaic virus (BYMV) was established through Double antibody sandwich-enzyme linked immunosorbent assay, multiple sequence alignment and phylogenetic analysis of the coat protein gene sequence amplified by reverse transcription-polymerase chain reaction. The cp gene contained 819 nucleotides potentially coding for 273 amino acids. The sequence showed 83-99 % nucleotide and 89-99 % amino acid sequence identities with other BYMV isolates/strains and shared maximum identity with BYMV strain reported from Gladiolus sp. in Japan. This study constitutes the first report of BYMV occurrence on P. vulgaris in Himachal Pradesh. PMID- 26645044 TI - Viral quantity and pathological changes in broilers experimentally infected by IRFIBV32 isolate of infectious bronchitis virus. AB - An Iranian isolate of avian infectious bronchitis virus IRFIBV32 was quantified in experimentally infected broilers using real-time reverse transcriptase polymerase chain reaction and histopathological changes was investigated. Thirty six 3-week-old commercial broilers were inoculated by 10(5) ELD50/0.1 ml of the virus. On the various days post inoculation (dpi) different tissues were collected. The virus strongly started the replication in trachea at 1 dpi and reached to the maximum titer at 3 dpi. The highest IBV RNA level was shown in this organ. In lung, the virus was replicated with the titer lower than that of the trachea, but it rose up more at 5 dpi. The kidneys were the tissues with the least viral genome copy number, although the duration of the virus presence was considerable. The virus replicated in testes sooner than ovaries also disappeared sooner but the maximum viral yield in the ovaries was more. The virus titer in the studied tissues had an interesting fluctuation especially in caecal tonsils. Testes and ovaries were the organs that the virus could reactivate without using any chemical. The most severe lesions were observed in tracheae but they appeared in the lungs later. Lymphocyte infiltration in the kidneys was noted from 5 dpi even sooner than the lungs. There were no lesions in the caecal tonsils, testes and ovaries in spite of the virus replication in a high titer. PMID- 26645045 TI - Identification of a novel substance P (SP)-neurokinin-1 receptor (NK-1R) microRNA 221-5p inflammatory network in human colonic epithelial cells. AB - BACKGROUND & AIMS: Substance P (SP), a neuropeptide member of the tachykinin family, plays a critical role in colitis. MicroRNAs (miRNAs) are small non-coding RNAs that negatively regulate gene expression. However, whether SP modulates expression of microRNAs in human colonic epithelial cells remains unknown. METHODS: We performed microRNA profiling analysis of SP-stimulated human colonic epithelial NCM460 cells overexpressing neurokinin-1 receptor (NCM460-NK-1R). Targets of SP-regulated microRNAs were validated by real time polymerase chain reaction (RT-PCR). Functions of miRNAs were tested in NCM460-NK-1R cells and the TNBS and DSS models of colitis. RESULTS: SP stimulated differential expression of 29 microRNAs, including miR-221-5p, the highest up regulated miR (by 12.6-fold) upon SP stimulation. Bioinformatic and luciferase reporter analyses identified interleukin 6 receptor (IL-6R) mRNA as a direct target of miR-221-5p in NCM460 cells. Accordingly, SP exposure of NCM460-NK-1R cells increased IL-6R mRNA expression, while overexpression of miR-221-5p reduced IL-6R expression. NF kappaB and JNK inhibition decreased SP-induced miR-221-5p expression. MiR-221-5p expression was increased in both TNBS- and DSS-induced colitis and colonic biopsies from Ulcerative Colitis, but not Crohn's Disease subjects, compared to controls. In mice, intracolonic administration of a miR-221-5p chemical inhibitor, exacerbated TNBS-and DSS-induced colitis, and increased colonic TNF alpha, Cxcl10, and Col2 alpha 1 mRNA expression. In situ hybridization in TNBS and DSS-exposed colons revealed increased miR-221-5p expression primarily in colonocytes. CONCLUSIONS: Our results reveal a novel NK-1R-miR-221-5p-IL-6R network that protects from colitis. The use of miR-221-5p mimics may be a promising approach for colitis treatment. PMID- 26645046 TI - Short-term circadian disruption impairs bile acid and lipid homeostasis in mice. AB - BACKGROUND & AIMS: Bile acids are physiological detergents that also activate nuclear receptors to regulate glucose and lipid homeostasis. Cholesterol 7alpha hydroxylase (Cyp7a1), the rate-limiting enzyme that converts cholesterol to bile acids, is transcriptionally regulated by bile acids and circadian rhythms. Fasting, nutrients and the circadian clock critically control hepatic bile acid and lipid homeostasis, while circadian misalignment is associated with metabolic syndrome in humans. To delineate these interactions, we employed a sleep disruption model to induce circadian disruption and examined hepatic metabolism with respect to bile acids, lipids and clock gene expression. METHODS: B6xC57 mice were maintained on chow or Western diet and were sleep disrupted for 6 hr/day for 5 days. Mice were sacrificed at 4 hr intervals over 24 hr. Hepatic metabolic genes were examined, and bile acid pool and lipid profiles were measured over 24 hr. RESULTS: Sleep disruption significantly suppressed circadian expression of core clock genes, genes involved in lipid metabolism, and key regulators of Cyp7a1 as well as Cyp7a1 expression itself. Sleep disruption abolished the peak in serum cholesterol and increased liver and serum free fatty acids. Bile acid pool size was increased while liver bile acids were decreased. ChIP assay revealed HNF4alpha and Dbp occupancies were suppressed at the Cyp7a1 promoter in sleep-disrupted mice. When coupled with Western diet, sleep disruption abolished liver clock rhythms and elevated free fatty acids. CONCLUSIONS: This study suggests that even short-term circadian disruption dramatically alters hepatic clock gene expression, bile acid metabolism and lipid homeostasis to contribute to dyslipidemia. PMID- 26645047 TI - Dermatofibrosarcoma protuberans (DFSP) with fibrosarcomatous changes in a patient with psoriasis treated with adalimumab. PMID- 26645048 TI - Optimizing cancer genome sequencing and analysis. AB - Tumors are typically sequenced to depths of 75-100* (exome) or 30-50* (whole genome). We demonstrate that current sequencing paradigms are inadequate for tumors that are impure, aneuploid or clonally heterogeneous. To reassess optimal sequencing strategies, we performed ultra-deep (up to ~312*) whole genome sequencing (WGS) and exome capture (up to ~433*) of a primary acute myeloid leukemia, its subsequent relapse, and a matched normal skin sample. We tested multiple alignment and variant calling algorithms and validated ~200,000 putative SNVs by sequencing them to depths of ~1,000*. Additional targeted sequencing provided over 10,000* coverage and ddPCR assays provided up to ~250,000* sampling of selected sites. We evaluated the effects of different library generation approaches, depth of sequencing, and analysis strategies on the ability to effectively characterize a complex tumor. This dataset, representing the most comprehensively sequenced tumor described to date, will serve as an invaluable community resource (dbGaP accession id phs000159). PMID- 26645049 TI - Targeting Transcription Factors in Cancer. AB - Transcription factors (TFs) are commonly deregulated in the pathogenesis of human cancer and are a major class of cancer cell dependencies. Consequently, targeting of TFs can be highly effective in treating particular malignancies, as highlighted by the clinical efficacy of agents that target nuclear hormone receptors. In this review we discuss recent advances in our understanding of TFs as drug targets in oncology, with an emphasis on the emerging chemical approaches to modulate TF function. The remarkable diversity and potency of TFs as drivers of cell transformation justifies a continued pursuit of TFs as therapeutic targets for drug discovery. PMID- 26645050 TI - The Emerging Role of ABL Kinases in Solid Tumors. AB - The Abelson (ABL) tyrosine kinases were identified as drivers of leukemia in mice and humans. Emerging data has shown a role for the ABL family kinases, ABL1 and ABL2, in the progression of several solid tumors. This review will focus on recent reports of the involvement of the ABL kinases in tumor progression using mouse models as well as recent data generated from genomic and proteomic studies linking enhanced expression and hyper-activation of the ABL kinases to some human cancers. Preclinical studies on small molecule inhibitors of the ABL kinases suggest that their use may have beneficial effects for the treatment of selected solid tumors. PMID- 26645051 TI - ALTernative Telomere Maintenance and Cancer. AB - Activation of a telomere maintenance mechanism (TMM) is permissive for replicative immortality and a hallmark of human cancer. While most cancers rely on reactivation of telomerase, a significant fraction utilizes the recombination dependent alternative lengthening of telomeres (ALT) pathway. ALT is enriched in tumors of mesenchymal origin, including those arising from bone, soft tissue, and the nervous system, and usually portends a poor prognosis. Recent insights into the mechanisms of ALT are uncovering novel avenues to exploit vulnerabilities and may facilitate clinical development of ALT detection assays and personalized treatment decisions based on TMM status. Treatments targeting ALT may hold promise for a broadly applicable therapeutic modality specific to mesenchymal lineage tumors, something that has thus far remained elusive. PMID- 26645056 TI - Chest X-ray quiz. PMID- 26645055 TI - Percutaneous occlusion of the left atrial appendage: An expert consensus statement. AB - Atrial fibrillation (AF) is the most common rhythm disturbance. Among the major thromboembolic complications associated with AF, strokes are foremost, with a 4.4% yearly incidence in the absence of preventive treatment. Therefore, the prevention of these embolic accidents is a priority. While proof of the efficacy of oral anticoagulants (OACs) for this indication is long-standing and convincing, they are associated with haemorrhagic complications. Consequently, their prescription is based on an estimate of the risk (haemorrhagic complications)/benefit (thromboembolic prevention) ratio. In a patient subset at high thromboembolic and haemorrhagic risk, whether to prescribe or abstain from prescribing an OAC is a challenging decision, and an alternative means of thromboembolic prevention is desirable. Percutaneous occlusion of the left atrial appendage (LAA) is an alternative, interventional, non-pharmacological treatment that has been used widely in Europe and for a few years in France, with encouraging results. However, it remains an invasive procedure with a low level of proof in comparison with OACs. Moreover, the indications, the procedural environment and pre-per-post procedural patient management are major questions about this technique, with consequences on its efficacy and risk/benefit ratio. This document, composed by consensus among experts in the field, is an in-depth review of this new therapy. PMID- 26645052 TI - Deep sequencing of HPV16 genomes: A new high-throughput tool for exploring the carcinogenicity and natural history of HPV16 infection. AB - For unknown reasons, there is huge variability in risk conferred by different HPV types and, remarkably, strong differences even between closely related variant lineages within each type. HPV16 is a uniquely powerful carcinogenic type, causing approximately half of cervical cancer and most other HPV-related cancers. To permit the large-scale study of HPV genome variability and precancer/cancer, starting with HPV16 and cervical cancer, we developed a high-throughput next generation sequencing (NGS) whole-genome method. We designed a custom HPV16 AmpliSeqTM panel that generated 47 overlapping amplicons covering 99% of the genome sequenced on the Ion Torrent Proton platform. After validating with Sanger, the current "gold standard" of sequencing, in 89 specimens with concordance of 99.9%, we used our NGS method and custom annotation pipeline to sequence 796 HPV16-positive exfoliated cervical cell specimens. The median completion rate per sample was 98.0%. Our method enabled us to discover novel SNPs, large contiguous deletions suggestive of viral integration (OR of 27.3, 95% CI 3.3-222, P=0.002), and the sensitive detection of variant lineage coinfections. This method represents an innovative high-throughput, ultra-deep coverage technique for HPV genomic sequencing, which, in turn, enables the investigation of the role of genetic variation in HPV epidemiology and carcinogenesis. PMID- 26645057 TI - Hearing medieval voices. PMID- 26645058 TI - Jane Wardle. PMID- 26645059 TI - William A. Sibley, MD (1925-2015). PMID- 26645060 TI - Reflections: Neurology and the Humanities. Not too late. PMID- 26645061 TI - Author response. PMID- 26645062 TI - Author response. PMID- 26645063 TI - Cardiac tamponade as the first manifestation of primary hypothyroidism. PMID- 26645064 TI - Anomalous origin and extrinsic stenosis of left coronary principal artery. Beware of sudden death. PMID- 26645065 TI - [Management of hypothermia -- Severe Accidental Hypothermia Centre in Krakow]. AB - Severe accidental hypothermia is a condition associated with significant morbidity and mortality. In the years 2009-2012 the Polish National Statistics Department reported 1836 deaths due to exposure to excessive natural cold. The Severe Accidental Hypothermia Centre (CLHG, Centrum Leczenia Hipotermii Glebokiej) was set up in Krakow in 2013. It is a unit functioning within the structure of the Cardiac Surgery Clinic, established in order to improve the effectiveness of the treatment of patients in the advanced stages of severe hypothermia. Early identification of hypothermia, binding algorithm and coordination leading to extracorporeal rewarming, are the most important elements in the deep hypothermia management. PMID- 26645067 TI - A formalin-free method for stabilizing cells for nucleic acid amplification, hybridization and next-generation sequencing. AB - BACKGROUND: Formalin has been widely used by pathology laboratories. Its carcinogenicity has led researchers to explore formalin substitutes. Streck Cell Preservative (SCP) is a formalin-free preservative that can preserve cellular antigens. This study was undertaken to investigate the effects of cell preservation using SCP on nucleic acid amplification, hybridization, and next generation sequencing (NGS) as compared to control frozen cells and cells fixed in the traditional cell and tissue fixative, 10 % neutral buffered formalin (NBF). FINDINGS: The breast cancer cell line, SKBR-3, was used as a model system. Prior to nucleic acid extraction and fluorescence in situ hybridization (FISH), cells were fixed in SCP or NBF overnight at room temperature with frozen cells in parallel. Analysis showed that similar DNA extraction yields and amplification profiles determined by PCR in SCP preserved cells and control frozen cells, whereas NBF preserved cells had decreased DNA yield and impaired PCR amplification. Molecular cytogenetic studies by FISH technique indicated that the ratios of ERBB2 (HER-2/neu) signals to the chromosome 17 centromere (CEP17) were comparable for frozen cells and SCP preserved cells. The fluorescence images of both SCP fixed and control frozen cells were also clear and comparable. On the contrary, the same analysis was unsuccessful with NBF preserved cells due to poor hybridization quality. Our data also demonstrated that SCP had negligible effect on NGS testing. CONCLUSION: We conclude that SCP can be used as an alternative to NBF as a preservative for maintaining the integrity of nucleic acids for nucleic acid amplification, sequencing and FISH analysis. PMID- 26645066 TI - Tackling dengue fever: Current status and challenges. AB - According to recent statistics, 96 million apparent dengue infections were estimated worldwide in 2010. This figure is by far greater than the WHO prediction which indicates the rapid spread of this disease posing a growing threat to the economy and a major challenge to clinicians and health care services across the globe particularly in the affected areas.This article aims at bringing to light the current epidemiological and clinical status of the dengue fever. The relationship between genetic mutations, single nucleotide polymorphism (SNP) and the pathophysiology of disease progression will be put into perspective. It will also highlight the recent advances in dengue vaccine development.Thus far, a significant progress has been made in unraveling the risk factors and understanding the molecular pathogenesis associated with the disease. However, further insights in molecular features of the disease and the development of animal models will enormously help improving the therapeutic interventions and potentially contribute to finding new preventive measures for population at risk. PMID- 26645068 TI - The levels of epithelial anchor proteins beta-catenin and zona occludens-1 are altered by E7 of human papillomaviruses 5 and 8. AB - Infection with viruses of the genus Betapapillomavirus, beta-human papillomaviruses (beta-HPV), is implicated in the development of non-melanoma skin cancer. This was first evidenced for HPV5 and HPV8 in patients with the skin disease epidermodysplasia verruciformis (EV). The relocalization of the junctional bridging proteins beta-catenin and zona occludens-1 (ZO-1) from the adherens and tight junctions are common processes of the epithelial-mesenchymal transition (EMT) associated with tumour invasion. Here, we report that beta catenin and ZO-1 are strongly upregulated by the E7 oncoproteins of HPV5 and HPV8 in keratinocytes grown in organotypic skin cultures. Although the membrane tethered form of beta-catenin was elevated, no signs of beta-catenin activity within the canonical Wnt signalling pathway could be detected. The upregulation of beta-catenin and ZO-1 could also be confirmed in the skin of HPV8 transgenic mice as well as in cutaneous squamous cell carcinomas of EV patients. These data provide the first evidence that beta-catenin and ZO-1 are direct targets of E7 of the oncogenic beta-HPV types 5 and 8. The ability to deregulate these epithelial junction proteins may contribute to the oncogenic potential of these viruses in human skin. PMID- 26645069 TI - Surgical Approaches for Vitreomacular Tractions. AB - PURPOSE: The aim is to describe the main characteristics of different approaches in vitreomacular traction surgery. Setting/Venue: The video (see www.karger.com/doi/10.1159/ 000442579) about vitreomacular traction surgery was created at the Department of Ophthalmology, Virgin Macarena University Hospital, Seville, Spain. METHODS: We present the surgical release of vitreomacular tractions in three different pathologies: (1) idiopathic epimacular membrane; (2) proliferative diabetic retinopathy with long-term hemovitreous, and (3) Coats' disease. RESULTS: Although functional success is less common than anatomical success, we will never be able to improve vision without restoring retinal anatomy. CONCLUSIONS: Vitreomacular tractions are perfectly well known by ophthalmologists. However, the method used to release them must be the least aggressive possible in order to avoid retinal tears or macular holes with subsequent visual loss. PMID- 26645070 TI - Association of Frailty based on self-reported physical function with directly measured kidney function and mortality. AB - BACKGROUND: Use of serum creatinine to estimate GFR may lead to underestimation of the association between self-reported frailty and kidney function. Our objectives were to evaluate the association of measured GFR (mGFR) with self reported frailty among patients with CKD and to determine whether self-reported frailty was associated with death after adjusting for mGFR. METHODS: Participants in the Modification of Diet in Renal Disease study (1989-1993) had GFR measured using iothalamate clearance (mGFR), and GFR was estimated based on the CKD-EPI creatinine (eGFRcr) and cystatin C (eGFRcys) equations. We defined self-reported frailty as three or more of: exhaustion, poor physical function, low physical activity, and low body weight. Death was ascertained through 2007 using the National Death Index and the United States Renal Data System. RESULTS: Eight hundred twelve MDRD participants (97 %) had complete data on self-reported frailty (16 % prevalence, N = 130) and mGFR (mean (SD) 33.1 +/- 11.7 ml/min/1.73 m(2)). Higher GFR was associated with lower odds of self-reported frailty based on mGFR, (OR 0.71, 95 % CI 0.60-0.86 per 10 ml/min/1.73 m(2)), eGFRcr (OR 0.80, 95 % CI 0.67-0.94 per 10 ml/min/1.73 m(2)), and eGFRcys (OR 0.75, 95 % CI 0.62 0.90 per 10 ml/min/1.73 m(2)). Median follow-up was 17 (IQR 11-18) years, with 371 deaths. Self-reported frailty was associated with a higher risk of death (HR 1.71, 95 % CI 1.26-2.30), which was attenuated to a similar degree when mGFR (HR 1.48, 95 % CI 1.08-2.00), eGFRcr (HR 1.57, 95 % CI 1.15-2.10), or eGFRcys (HR 1.51, 95 % CI 1.10-2.10) was included as an indicator of kidney function. CONCLUSIONS: We found an inverse association between kidney function and self reported frailty that was similar for mGFR, eGFR and eGFRcys. In this relatively healthy cohort of clinical trial participants with CKD, using serum creatinine to estimate GFR did not substantially alter the association of GFR with self reported frailty or of self-reported frailty with death. PMID- 26645071 TI - Combined laser and robotic approach for the management of a mixed laryngomucocele. AB - Treatment of laryngoceles is surgical resection, through an external approach for external laryngoceles and through an endoscopic approach for internal laryngoceles. We report the first case of a mixed laryngomucocele treated with transoral robotic surgery. A patient presented with a history of chronic cough. Nasolaryngoscopy showed a sub-mucosal swelling into the larynx. Computed tomography confirmed the diagnosis of a right mixed laryngomucocele. A transoral robotic- and laser-assisted surgery was performed. Oral feeding was started on the first post-operative day. No post-operative complication was observed. There has been no evidence of recurrence during the following months. The generally used external and endoscopic approaches each have their limits in the treatment of laryngoceles. Transoral robotic surgery allows a minimally invasive approach with a wide exposure, making possible an absence of scar and a good functional recovery after the operation. Transoral robotic approach seems to allow an endoscopic approach for mixed and external lesions. Transoral robotic surgery combined with laser is an efficient minimally invasive technique and is the best option for the treatment of mixed laryngoceles and laryngomucoceles. PMID- 26645072 TI - Preliminary study of transoral robotic surgery for pharyngeal cancer in Japan. AB - Transoral robotic surgery (TORS) with the da Vinci Surgical System has been used for the removal of pharyngeal and laryngeal cancers with the objective to improve functional and aesthetic outcomes without worsening survival. While TORS has been approved in many countries, Japan's FDA has not yet done so. Our hospital started using TORS with the approval of the Ethical Review Board and the Minimum Invasive Surgical Center Committee at Tottori University. No surgical outcomes of TORS for Japanese patients with head and neck cancer have been reported in Japan. This paper deals with the outcomes and feasibility of TORS for Japanese patients with pharyngeal cancer at our institution. TORS was performed for 10 patients with T1, T2, T3 oropharyngeal and hypopharyngeal squamous cell carcinoma between 2013 and 2014. This is a single-institutional study. TORS could be completed for all cases, except one patient that was not candidate, and no intraoperative conversion to an open surgical procedure was required. Five patients underwent neck dissection, two of them concurrent and three staged. Of all patients, positive surgical margins were detected in two. The average blood loss including neck dissection was 21.5 +/- 33.4 ml, the operation time was 183 +/- 36 min and the console time was 103 +/- 22 min. No tracheostomy had been performed either pre- or postoperatively, and there was no difference between preoperative and postoperative swallowing functions. In this single-institutional preliminary study, we demonstrated that TORS is a feasible and safe treatment. A clinical multi-institutional study of TORS for laryngopharyngeal cancer has been approved as an advanced medical system study and is under way. In the near future, it is expected that the efficacy and safety of TORS for laryngopharyngeal cancer will be confirmed as the result of this multiple-institutional clinical study in Japan. PMID- 26645073 TI - Standardized single docking, four arms and fully robotic proctectomy for rectal cancer: the key points are the ports and arms placement. AB - Rectal cancer continues to be a surgical challenge. As more technology is developed, the surgeon must both incorporate this new technology into his practice and, at the same time, keep improving oncologic surgery and overall outcomes. We describe a standardized approach and fully robotic proctectomy, using four arms and one single docking (SI system). Patient cart and ports placement, as well as arms position to avoid collision, are key points to perform the entire procedure with one single docking. Although the place of robotic surgery might still need to be defined, standardizing the procedures is a step towards its evaluation. We propose with this report a solution to perform a single docking four arms robotic proctectomy. PMID- 26645074 TI - Quantifying the Implications of Different Land Users' Priorities in the Management of Boreal Multiple-Use Forests. AB - In the management of natural resources, conflicting interests and objectives among different stakeholders often need to be considered. Here, we examine how two contrasting management scenarios of boreal forests in northern Sweden differ in their consequences on forest structural composition and the economic gains at harvest. Management strategies prioritize either (i) forest characteristics that promote grazing resources for reindeer herded by the indigenous Sami, or (ii) timber production as practiced in Sweden today. When prioritizing reindeer grazing, forest stands develop a higher abundance of older age classes with larger trees and lower stem density, which reduces harvest and revenue levels by approximately 20% over a 100-year period. The differences between these strategies illustrate the complexity in finding a trade-off for coexistence between industrial land users and other livelihoods that share the same landscape. Political support and institutional solutions are necessary to initiate changes in policy in finding such trade-offs in the management of environmental resources and thereby influence the optimal distribution of costs and benefits between different actors. PMID- 26645075 TI - Effectiveness of Conservation Measures in Reducing Runoff and Soil Loss Under Different Magnitude-Frequency Storms at Plot and Catchment Scales in the Semi arid Agricultural Landscape. AB - In this study, multi-year stormflow data collected at both catchment and plot scales on an event basis were used to evaluate the efficiency of conservation. At the catchment scale, soil loss from YDG, an agricultural catchment with no conservation measures, was compared with that from CZG, an agricultural catchment with an implementation of a range of conservation measures. With an increase of storm recurrence intervals in the order of <1, 1-2, 2-5, 5-10, 10-20, and >20 years, the mean event sediment yield was 639, 1721, 5779, 15191, 19627, and 47924 t/km(2) in YDG, and was 244, 767, 3077, 4679, 8388, and 15868 t/km(2) in CZG, which represented a reduction effectiveness of 61.8, 55.4, 46.7, 69.2, 57.2, and 66.8 %, respectively. Storm events with recurrence intervals greater than 2 years contributed about two-thirds of the total runoff and sediment in both YDG and CZG catchments. At the plot scale, soil loss from one cultivated slopeland was compared with that from five conservation plots. The mean event soil loss was 1622 t/km(2) on the cultivated slopeland, in comparison to 27.7 t/km(2) on the woodland plot, 213 t/km(2) on the grassland plot, 467 t/km(2) on the alfalfa plot, 236 t/km(2) on the terraceland plot, and 642 t/km(2) on the earthbank plot. Soil loss per unit area from all the plots was significantly less than that from the catchments for storms of all categories of recurrence intervals. PMID- 26645076 TI - Strategic Environmental Assessment Framework for Landscape-Based, Temporal Analysis of Wetland Change in Urban Environments. AB - This paper presents and demonstrates a spatial framework for the application of strategic environmental assessment (SEA) in the context of change analysis for urban wetland environments. The proposed framework is focused on two key stages of the SEA process: scoping and environmental baseline assessment. These stages are arguably the most information-intense phases of SEA and have a significant effect on the quality of the SEA results. The study aims to meet the needs for proactive frameworks to assess and protect wetland habitat and services more efficiently, toward the goal of advancing more intelligent urban planning and development design. The proposed framework, adopting geographic information system and remote sensing tools and applications, supports the temporal evaluation of wetland change and sustainability assessment based on landscape indicator analysis. The framework was applied to a rapidly developing urban environment in the City of Saskatoon, Saskatchewan, Canada, analyzing wetland change and land-use pressures from 1985 to 2011. The SEA spatial scale was rescaled from administrative urban planning units to an ecologically meaningful area. Landscape change assessed was based on a suite of indicators that were subsequently rolled up into a single, multi-dimensional, and easy to understand and communicate index to examine the implications of land-use change for wetland sustainability. The results show that despite the recent extremely wet period in the Canadian prairie region, land-use change contributed to increasing threats to wetland sustainability. PMID- 26645077 TI - Household-Level Determinants of Soil and Water Conservation Adoption Phases: Evidence from North-Western Ethiopian Highlands. AB - Soil and water conservation (SWC) practices have been promoted in the highlands of Ethiopia during the last four decades. However, the level of adoption of SWC practices varies greatly. This paper examines the drivers of different stages of adoption of SWC technologies in the north-western highlands of Ethiopia. This study is based on a detailed farm survey among 298 households in three watersheds. Simple descriptive statistics were applied to analyze the stages of adoption. An ordered probit model was used to analyze the drivers of different stages of adoption of SWC. This model is used to analyze more than two outcomes of an ordinal dependent variable. The results indicate that sampled households are found in different phases of adoption, i.e., dis-adoption/non-adoption (18.5 %), initial adoption (30.5 %), actual adoption (20.1 %), and final adoption (30.9 %). The results of the ordered probit model show that some socio-economic and institutional factors affect the adoption phases of SWC differently. Farm labor, parcel size, ownership of tools, training in SWC, presence of SWC program, social capital (e.g., cooperation with adjacent farm owners), labor sharing scheme, and perception of erosion problem have a significant positive influence on actual and final adoption phases of SWC. In addition, the final adoption phase of SWC is positively associated with tenure security, cultivated land sizes, parcel slope, and perception on SWC profitability. Policy makers should take into consideration factors affecting (continued) adoption of SWC such as profitability, tenure security, social capital, technical support, and resource endowments (e.g., tools and labor) when designing and implementing SWC policies and programs. PMID- 26645078 TI - Building Virtual Watersheds: A Global Opportunity to Strengthen Resource Management and Conservation. AB - Modern land-use planning and conservation strategies at landscape to country scales worldwide require complete and accurate digital representations of river networks, encompassing all channels including the smallest headwaters. The digital river networks, integrated with widely available digital elevation models, also need to have analytical capabilities to support resource management and conservation, including attributing river segments with key stream and watershed data, characterizing topography to identify landforms, discretizing land uses at scales necessary to identify human-environment interactions, and connecting channels downstream and upstream, and to terrestrial environments. We investigate the completeness and analytical capabilities of national to regional scale digital river networks that are available in five countries: Canada, China, Russia, Spain, and United States using actual resource management and conservation projects involving 12 university, agency, and NGO organizations. In addition, we review one pan-European and one global digital river network. Based on our analysis, we conclude that the majority of the regional, national, and global scale digital river networks in our sample lack in network completeness, analytical capabilities or both. To address this limitation, we outline a general framework to build as complete as possible digital river networks and to integrate them with available digital elevation models to create robust analytical capabilities (e.g., virtual watersheds). We believe this presents a global opportunity for in-country agencies, or international players, to support creation of virtual watersheds to increase environmental problem solving, broaden access to the watershed sciences, and strengthen resource management and conservation in countries worldwide. PMID- 26645079 TI - Mesoscopic Fluorescence Molecular Tomography for Evaluating Engineered Tissues. AB - Optimization of regenerative medicine strategies includes the design of biomaterials, development of cell-seeding methods, and control of cell biomaterial interactions within the engineered tissues. Among these steps, one paramount challenge is to non-destructively image the engineered tissues in their entirety to assess structure, function, and molecular expression. It is especially important to be able to enable cell phenotyping and monitor the distribution and migration of cells throughout the bulk scaffold. Advanced fluorescence microscopic techniques are commonly employed to perform such tasks; however, they are limited to superficial examination of tissue constructs. Therefore, the field of tissue engineering and regenerative medicine would greatly benefit from the development of molecular imaging techniques which are capable of non-destructive imaging of three-dimensional cellular distribution and maturation within a tissue-engineered scaffold beyond the limited depth of current microscopic techniques. In this review, we focus on an emerging depth resolved optical mesoscopic imaging technique, termed laminar optical tomography (LOT) or mesoscopic fluorescence molecular tomography (MFMT), which enables longitudinal imaging of cellular distribution in thick tissue engineering constructs at depths of a few millimeters and with relatively high resolution. The physical principle, image formation, and instrumentation of LOT/MFMT systems are introduced. Representative applications in tissue engineering include imaging the distribution of human mesenchymal stem cells embedded in hydrogels, imaging of bio-printed tissues, and in vivo applications. PMID- 26645081 TI - Spatial Relationship between Acute Lacunar Infarction and White Matter Hyperintensities. AB - BACKGROUND: White matter hyperintensities (WMH) predict incident strokes and new lacunes; moreover, WMH may also affect infarct locations. Our aim in this study was to examine the spatial relationship between WMH and acute lacunar infarction. METHODS: Five hundred and ninety patients with acute lacunar infarction in supratentorial region were included. Four situations between infarction and WMH were assessed by axial and coronal MRI: no contact (Grade 0), contact without overlap (Grade Ia), partial overlap (Grade Ib), and complete overlap (Grade II) with preexisting WMH. Furthermore, we defined infarctions in Grades Ia and Ib as edge-localized infarctions and investigated their predictors and short-term outcome. RESULTS: 47.9% (283) of the infarctions were edge-localized infarctions (Grade Ia = 27.6% and Grade Ib = 20.3%), 51.5% (304) were Grade 0, only 0.5% (3) were Grade II. Patients with edge-localized infarction had larger infarct size, more severe WMH, higher National Institutes of Health Stroke Scale (NIHSS) and lower Barthel index (BI) score at admission than those with non-edge-localized infarction. They also had lower BI score at discharge. Infarction in subcortical white matter, diffusion-weighted imaging infarct size, periventricular WMH and deep WMH were predictors for edge-localized infarction. CONCLUSIONS: Half of lacunar infarctions were located at the edge of WMH. Both periventricular WMH and deep WMH were predictors for edge-localized infarction. PMID- 26645080 TI - Accuracy of Functional and Predictive Methods to Calculate the Hip Joint Center in Young Non-pathologic Asymptomatic Adults with Dual Fluoroscopy as a Reference Standard. AB - Predictions from biomechanical models of gait may be sensitive to joint center locations. Most often, the hip joint center (HJC) is derived from locations of reflective markers adhered to the skin. Here, predictive techniques use regression equations of pelvic anatomy to estimate the HJC, whereas functional methods track motion of markers placed at the pelvis and femur during a coordinated motion. Skin motion artifact may introduce errors in the estimate of HJC for both techniques. Quantifying the accuracy of these methods is an area of open investigation. In this study, we used dual fluoroscopy (DF) (a dynamic X-ray imaging technique) and three-dimensional reconstructions from computed tomography images, to measure HJC locations in vivo. Using dual fluoroscopy as the reference standard, we then assessed the accuracy of three predictive and two functional methods. Eleven non-pathologic subjects were imaged with DF and reflective skin marker motion capture. Additionally, DF-based solutions generated virtual markers placed on bony landmarks, which were input to the predictive and functional methods to determine if estimates of the HJC improved. Using skin markers, functional methods had better mean agreement with the HJC measured by DF (11.0 +/ 3.3 mm) than predictive methods (18.1 +/- 9.5 mm); estimates from functional and predictive methods improved when using the DF-based solutions (1.3 +/- 0.9 and 17.5 +/- 8.6 mm, respectively). The Harrington method was the best predictive technique using both skin markers (13.2 +/- 6.5 mm) and DF-based solutions (10.6 +/- 2.5 mm). The two functional methods had similar accuracy using skin makers (11.1 +/- 3.6 and 10.8 +/- 3.2 mm) and DF-based solutions (1.2 +/- 0.8 and 1.4 +/ 1.0 mm). Overall, functional methods were superior to predictive methods for HJC estimation. However, the improvements observed when using the DF-based solutions suggest that skin motion artifact is a large source of error for the functional methods. PMID- 26645083 TI - An autoregressive growth model for longitudinal item analysis. AB - A first-order autoregressive growth model is proposed for longitudinal binary item analysis where responses to the same items are conditionally dependent across time given the latent traits. Specifically, the item response probability for a given item at a given time depends on the latent trait as well as the response to the same item at the previous time, or the lagged response. An initial conditions problem arises because there is no lagged response at the initial time period. We handle this problem by adapting solutions proposed for dynamic models in panel data econometrics. Asymptotic and finite sample power for the autoregressive parameters are investigated. The consequences of ignoring local dependence and the initial conditions problem are also examined for data simulated from a first-order autoregressive growth model. The proposed methods are applied to longitudinal data on Korean students' self-esteem. PMID- 26645082 TI - Antibodies to MOG and AQP4 in children with neuromyelitis optica and limited forms of the disease. AB - OBJECTIVE: To determine the frequency and clinical-radiological associations of antibodies to myelin oligodendrocyte glycoprotein (MOG) and aquaporin-4 (AQP4) in children presenting with neuromyelitis optica (NMO) and limited forms. METHODS: Children with a first event of NMO, recurrent (RON), bilateral ON (BON), longitudinally extensive transverse myelitis (LETM) or brainstem syndrome (BS) with a clinical follow-up of more than 12 months were enrolled. Serum samples were tested for MOG- and AQP4-antibodies using live cell-based assays. RESULTS: 45 children with NMO (n=12), LETM (n=14), BON (n=6), RON (n=12) and BS (n=1) were included. 25/45 (56%) children had MOG-antibodies at initial presentation (7 NMO, 4 BON, 8 ON, 6 LETM). 5/45 (11%) children showed AQP4-antibodies (3 NMO, 1 LETM, 1 BS) and 15/45 (33%) were seronegative for both antibodies (2 NMO, 2 BON, 4 RON, 7 LETM). No differences were found in the age at presentation, sex ratio, frequency of oligoclonal bands or median EDSS at last follow-up between the three groups. Children with MOG-antibodies more frequently (1) had a monophasic course (p=0.018) after one year, (2) presented with simultaneous ON and LETM (p=0.004) and (3) were less likely to receive immunosuppressive therapies (p=0.0002). MRI in MOG-antibody positive patients (4) less frequently demonstrated periependymal lesions (p=0.001), (5) more often were unspecific (p=0.004) and (6) resolved more frequently (p=0.016). CONCLUSIONS: 67% of all children presenting with NMO or limited forms tested positive for MOG- or AQP4-antibodies. MOG-antibody positivity was associated with distinct features. We therefore recommend to measure both antibodies in children with demyelinating syndromes. PMID- 26645084 TI - Gestational Diabetes Mellitus in Early Pregnancy: Evidence for Poor Pregnancy Outcomes Despite Treatment. AB - OBJECTIVE: Recent guidelines recommend testing at <24 weeks of gestation for maternal dysglycemia in "high-risk" women. Evidence to support the early identification and treatment of gestational diabetes mellitus (GDM) is, however, limited. We examined the prevalence, clinical characteristics, and pregnancy outcomes of high-risk women with GDM diagnosed at <24 weeks of gestation (early GDM) and those with pre-existing diabetes compared with GDM diagnosed at >=24 weeks of gestation, in a large treated multiethnic cohort. RESEARCH DESIGN AND METHODS: Outcomes from 4,873 women attending a university hospital antenatal diabetes clinic between 1991 and 2011 were examined. All were treated to standardized glycemic targets. Women were stratified as pre-existing diabetes (n = 65) or GDM diagnosed at <12 weeks of gestation (n = 68), at 12-23 weeks of gestation (n = 1,247), or at >=24 weeks of gestation (n = 3,493). RESULTS: Hypertensive disorders in pregnancy including pre-eclampsia, preterm delivery, cesarean section, and neonatal jaundice (all P < 0.001) were more prevalent in women with pre-existing diabetes and early GDM. Macrosomia (21.8% vs. 20.3%, P = 0.8), large for gestational age (39.6% vs. 32.8%, P = 0.4), and neonatal intensive care admission (38.5% vs. 39.7%, P = 0.9) in women in whom GDM was diagnosed at <12 weeks of gestation were comparable to rates seen in women with pre-existing diabetes. CONCLUSIONS: Despite early testing and current best practice treatment, early GDM in high-risk women remains associated with poorer pregnancy outcomes. Outcomes for those in whom GDM was diagnosed at <12 weeks of gestation approximated those seen in pre-existing diabetes. These findings indicate the need for further studies to establish the efficacy of alternative management approaches to improve outcomes in these high-risk pregnancies. PMID- 26645085 TI - Effects of a new outdoor mosquito control device, the mosquito landing box, on densities and survival of the malaria vector, Anopheles arabiensis, inside controlled semi-field settings. AB - BACKGROUND: The significance of malaria transmission occurring outdoors has risen even in areas where indoor interventions such as long-lasting insecticidal nets and indoor residual spraying are common. The actual contamination rates and effectiveness of recently developed outdoor mosquito control device, the mosquito landing box (MLB), on densities and daily survival of host-seeking laboratory Anopheles arabiensis, which readily bites humans outdoors was demonstrated. METHODS: Experiments were conducted in large semi-field systems (SFS) with human volunteers inside, to mimic natural ecosystems, and using MLBs baited with natural or synthetic human odours and carbon dioxide. The MLBs were dusted with 10% pyriproxyfen (PPF) or entomopathogenic fungi (Metarhizium anisopliae) spores to mark mosquitoes physically contacting the devices. Each night, 400 laboratory reared An. arabiensis females were released in one SFS chamber with two MLBs, and another chamber without MLBs (control). Mosquitoes were individually recaptured while attempting to bite volunteers inside SFS or by aspiration from SFS walls. Mosquitoes from chambers with PPF-treated MLBs and respective controls were individually dipped in water-filled cups containing ten conspecific third-instar larvae, whose subsequent development was monitored. Mosquitoes recaptured from chambers with fungi-treated MLBs were observed for fungal hyphal growth on their cadavers. Separately, effects on daily survival were determined by exposing An. arabiensis in chambers having MLBs treated with 5% pirimiphos methyl compared to chambers without MLBs (control), after which the mosquitoes were recaptured and monitored individually until they died. RESULTS: Up to 63% (152/240) and 43% (92/210) of mosquitoes recaptured inside treatment chambers were contaminated with pyriproxyfen and M. anisopliae, respectively, compared to 8% (19/240) and 0% (0/164) in controls. The mean number of larvae emerging from cups in which adults from chambers with PPF-treated MLBs were dipped was significantly lower [0.75 (0.50-1.01)], than in controls [28.79 (28.32-29.26)], P < 0.001). Daily survival of mosquitoes exposed to 5% pirimiphos methyl was nearly two-fold lower than controls [hazard ratio (HR) = 1.748 (1.551-1.920), P < 0.001]. CONCLUSION: High contamination rates in exposed mosquitoes even in presence of humans, demonstrates potential of MLBs for controlling outdoor-biting malaria vectors, either by reducing their survival or directly killing host-seeking mosquitoes. The MLBs also have potential for dispensing filial infanticides, such as PPF, which mosquitoes can transmit to their aquatic habitats for mosquito population control. PMID- 26645087 TI - Comprehensible Predictive Modeling Using Regularized Logistic Regression and Comorbidity Based Features. AB - Different studies have demonstrated the importance of comorbidities to better understand the origin and evolution of medical complications. This study focuses on improvement of the predictive model interpretability based on simple logical features representing comorbidities. We use group lasso based feature interaction discovery followed by a post-processing step, where simple logic terms are added. In the final step, we reduce the feature set by applying lasso logistic regression to obtain a compact set of non-zero coefficients that represent a more comprehensible predictive model. The effectiveness of the proposed approach was demonstrated on a pediatric hospital discharge dataset that was used to build a readmission risk estimation model. The evaluation of the proposed method demonstrates a reduction of the initial set of features in a regression model by 72%, with a slight improvement in the Area Under the ROC Curve metric from 0.763 (95% CI: 0.755-0.771) to 0.769 (95% CI: 0.761-0.777). Additionally, our results show improvement in comprehensibility of the final predictive model using simple comorbidity based terms for logistic regression. PMID- 26645086 TI - Genome-wide analysis of MAPKKKs shows expansion and evolution of a new MEKK class involved in solanaceous species sexual reproduction. AB - BACKGROUND: Members of the plant MAP Kinases superfamily have been mostly studied in Arabidopsis thaliana and little is known in most other species. In Solanum chacoense, a wild species close to the common potato, it had been reported that members of a specific group in the MEKK subfamily, namely ScFRK1 and ScFRK2, are involved in male and female reproductive development. Apart from these two kinases, almost nothing is known about the roles of this peculiar family. METHODS: MEKKs were identified using BLAST and hidden Markov model (HMM) to build profiles using the 21 MEKKs from A. thaliana. Following protein sequence alignments, the neighbor-joining method was used to reconstruct phylogenetic trees of the MEKK subfamily. Kinase subdomains sequence logos were generated with WebLogo in order to pinpoint FRK distinct motifs. Codon alignments of the FRKs kinase subdomains and maximum-likelihood phylogenetic trees were used in the codon substitution models of the codeml program in the PAML package to detect selective pressure between FRK groups. RESULTS: With the recent progress in Next Generation Sequencing technologies, the genomes and transcriptomes of numerous plant species have been recently sequenced, giving access to a vast amount of data. With the aim of finding all members of the MEKK subfamily members in plants, we screened the genomes of 15 species from different clades of the plant kingdom. Interestingly, the whole MEKK subfamily has significantly expanded throughout evolution, especially in solanaceous species. This holds true for members of the FRK class, which have also strongly expanded and diverged. CONCLUSIONS: Expansion and rapid evolution of the FRK class members in solanaceous species support the hypothesis that they have acquired new roles, mainly in male and female reproductive development. PMID- 26645088 TI - Mechanism of Alcohol Oxidation by Fe(V)(O) at Room Temperature. AB - Selective oxidation of alcohol to its corresponding carbonyl compound is an important chemical process in biological as well as industrial reactions. The heme containing enzyme CytP450 has been known to selectively oxidize alcohols to their corresponding carbonyl compounds. The mechanism of this reaction, which involves high-valent Fe(IV)(O)-porphyrin(*+) intermediate with alcohol, has been well-studied extensively both with the native enzyme and with model complexes. In this paper, we report for the first time the mechanistic insight of alcohol oxidation with Fe(V)(O) complex of biuret TAML (bTAML), which is isoelectronic with Fe(IV)(O)-porphyrin(*+) intermediate form in CytP450. The oxidations displayed saturation kinetics, which allowed us to determine both the binding constants and first-order rate constants for the reaction. The K and k values observed for the oxidation of benzyl alcohol by Fe(V)(O) at room temperature (K = 300 M(-1), k = 0.35 s(-1)) is very similar to that obtained by CytP450 compound I at -50 degrees C (K = 214 M(-1), k = 0.48 s(-1)). Thermodynamic parameters determined from van't Hoff's plot (DeltaH~ -4 kcal/mol) suggest hydrogen bonding interaction between substrate and bTAML ligand framework of the Fe(V)(O) complex. Analysis of H/D KIE (kH/kD ~ 19 at 303 K), Hammett correlation and linearity in Bell-Evans-Polyanski plot points to the C-H abstraction as the rate determination step. Finally, experiments using Fe(V)(O(18)) for benzyl alcohol oxidation and use of the "radical clock" cyclobutanol as a substrate shows the absence of a rebound mechanism as is observed for CytP450. Instead, an ET/PT process is proposed after C-H abstraction leading to formation of the aldehyde, similar to what has been proposed for the heme and nonheme model compounds. PMID- 26645089 TI - Characterizing a distal muscle enhancer in the mouse Igf2 locus. AB - Insulin-like growth factor-2 (IGF2) is highly expressed in skeletal muscle and was identified as a quantitative trait locus for muscle mass. Yet little is known about mechanisms of its regulation in muscle. Recently, a DNA segment found ~100 kb from the Igf2 gene was identified as a possible muscle transcriptional control element. Here we have developed an in vivo reporter system to assess this putative enhancer by substituting nuclear (n) EGFP for Igf2 coding exons in a bacterial artificial chromosome containing the mouse Igf2 - H19 chromosomal locus. After stable transfection into a mesenchymal stem cell line, individual clones were converted to myoblasts and underwent progressive muscle-specific gene expression and myotube formation in differentiation medium. Transgenic mRNA and nuclear-targeted enhanced green fluorescent protein were produced coincident with endogenous Igf2 mRNA, but only in lines containing an intact distal conserved DNA element. Our results show that a 294 bp DNA fragment containing two E-boxes is a necessary and sufficient long-range enhancer for induction of Igf2 gene transcription during skeletal muscle differentiation and provides a robust experimental platform for its further functional dissection. PMID- 26645090 TI - Capturing Psychologists' Work in Integrated Care: Measuring and Documenting Administrative Outcomes. AB - With the expansion of integrated primary care and the increased focus on fiscal sustainability, it is critical for clinical managers of these innovative systems to have practical methods for measuring administrative outcomes. Administrative outcomes will assist leadership in the development of efficient, streamlined clinics to provide services to the primary care population. Additionally, administrative measures can be utilized to provide information to assist in guiding resource utilization and management decisions. Several administrative outcomes are suggested for integrated primary care managers to consider for application, including: clinic utilization measures, integrated care administrative measures, wait time and access metrics, and productivity monitors. Effective utilization of these measures can help office managers and clinic leadership not only to maximize patient care, but also to enhance essential business operations, which increase the long-term sustainability of integrated primary care programs. PMID- 26645092 TI - Visualizing Point Defects in Transition-Metal Dichalcogenides Using Optical Microscopy. AB - While transmission electron microscopy and scanning tunneling microscopy reveal atomic structures of point defect and grain boundary in monolayer transition metal dichalcogenides (TMDs), information on point defect distribution in macroscale is still not available. Herein, we visualize the point defect distribution of monolayer TMDs using dark-field optical microscopy. This was realized by anchoring silver nanoparticles on defect sites of MoS2 under light illumination. The optical images clearly revealed that the point defect distribution varies with light power and exposure time. The number of silver nanoparticles increased initially and reached a plateau in response to light power or exposure time. The size of silver nanoparticles was a few hundred nanometers in the plateau region as observed using optical microscopy. The measured defect density in macroscale was ~2 * 10(10) cm(-2), slightly lower than the observed value (4 * 10(11) cm(-2)) from scanning tunneling microscopy. PMID- 26645091 TI - Establishing Measurement-based Care in Integrated Primary Care: Monitoring Clinical Outcomes Over Time. AB - Full implementation of the patient-centered medical home requires the identification and treatment of patients with behavioral health concerns, leading to improved patient outcomes and reduced health care costs. Measurement-based care (MBC) for mental health conditions is an essential step in achieving these goals. Integrated primary care (IPC) administrators and providers are key leaders in MBC that spans initial screening for conditions to monitoring clinical outcomes over time. The purpose of this article is to assist IPC leaders, in partnership with their primary care team, in developing standard operating procedures for screening and follow up evaluations in order to lay a foundation for assessing program outcomes and improving quality of care in their unique settings. PMID- 26645093 TI - Continuous HRT with oestrogen plus progestogen is linked to reduced risk of endometrial cancer. PMID- 26645094 TI - Obesity, Cardiorespiratory Fitness, and Self-Reported Sleep Patterns in Chilean School-Aged Children. AB - The aims were to examine the association of sleep patterns with being overweight or obese and to analyze the association of cardiorespiratory fitness (CRF) with sleep patterns in children. The study involved 395 schoolchildren (12-13 years old). Sleep patterns were assessed with the Sleep Self-Report (SSR) questionnaire, grouped into four subscales: sleep quality, sleep-related anxiety, bedtime refusal, and sleep routines. CRF was predicted by the 20-m shuttle-run test. Logistic regression models showed that sleep-related anxiety problems predicted being overweight or obese in both sexes, and sleep quality problems predicted being overweight or obese in girls. Also, girls who had better CRF levels were less susceptible to sleep-related anxiety problems. Studies are required to determine if increasing CRF could be a possible strategy for improving sleep quality. PMID- 26645095 TI - The chemical synthesis of aryltetralin glycosides. AB - Led by etoposide and teniposide, the synthesis of aryltetralin glycosides has been experiencing flourishing development in the past five decades. Herein, a review focusing on the total synthesis of aryltetralin glycosides is provided. The main body of this review is composed of two parts, one is the enantioselective synthesis of aryltetralin derivatives and the other one is the construction of key glycosidic linkages. In each part the contents are organised based on the different strategies or protocols applied in the original documents. The total synthesis of aryltetralin glycosides represents the developing direction of this field, and sooner or later will replace the currently applied semi-total synthesis method, using the aglycon residue acquired directly from natural sources. This account provides a comprehensive and deep insight into the field of aryltetralin glycoside synthesis for chemists who have the intention of committing themselves to the development of aryltetralin glycoside medicine. PMID- 26645097 TI - Sex Pheromones of C. elegans Males Prime the Female Reproductive System and Ameliorate the Effects of Heat Stress. AB - Pheromones are secreted molecules that mediate animal communications. These olfactory signals can have substantial effects on physiology and likely play important roles in organismal survival in natural habitats. Here we show that a blend of two ascaroside pheromones produced by C. elegans males primes the female reproductive system in part by improving sperm guidance toward oocytes. Worms have different physiological responses to different ratios of the same two molecules, revealing an efficient mechanism for increasing coding potential of a limited repertoire of molecular signals. The endogenous function of the male sex pheromones has an important side benefit. It substantially ameliorates the detrimental effects of prolonged heat stress on hermaphrodite reproduction because it increases the effectiveness with which surviving gametes are used following stress. Hermaphroditic species are expected to lose female-specific traits in the course of evolution. Our results suggest that some of these traits could have serendipitous utility due to their ability to counter the effects of stress. We propose that this is a general mechanism by which some mating-related functions could be retained in hermaphroditic species, despite their expected decay. PMID- 26645096 TI - Optimizing Polymyxin Combinations Against Resistant Gram-Negative Bacteria. AB - Polymyxin combination therapy is increasingly used clinically. However, systematic investigations of such combinations are a relatively recent phenomenon. The emerging pharmacodynamic (PD) and pharmacokinetic (PK) data on CMS/colistin and polymyxin B suggest that caution is required with monotherapy. Given this situation, polymyxin combination therapy has been suggested as a possible way to increase bacterial killing and reduce the development of resistance. Considerable in vitro data have been generated in support of this view, particularly recent studies utilizing dynamic models. However, most existing animal data are of poor quality with major shortcomings in study design, while clinical data are generally limited to retrospective analysis and small, low-power, prospective studies. This article provides an overview of clinical and preclinical investigations of CMS/colistin and polymyxin B combination therapy. PMID- 26645099 TI - Reduction of interfacial friction in commensurate graphene/h-BN heterostructures by surface functionalization. AB - The reduction of interfacial friction in commensurately stacked two-dimensional layered materials is important for their application in nanoelectromechanical systems. Our first-principles calculations on the sliding energy corrugation and friction at the interfaces of commensurate fluorinated-graphene/h-BN and oxidized graphene/h-BN heterostructures show that the sliding energy barriers and shear strengths for these heterostructures are approximately decreased to 50% of those of commensurate graphene/h-BN. The adsorbed F and O atoms significantly suppress the interlayer electrostatic and van der Waals energy corrugations by modifying the geometry and charge redistribution of the graphene layers. Our empirical registry index models further reveal the difference between the roles of the F and O atoms in affecting the sliding energy landscapes, and are also utilized to predict the interlayer superlubricity in a large-scale oxidized-graphene/h-BN system. Surface functionalization is a valid way to control and reduce the interlayer friction in commensurate graphene/h-BN heterostructures. PMID- 26645098 TI - Lipases That Activate at High Solvent Polarities. AB - Thermomyces lanuginosus lipase (TlL) and related lipases become activated in low polarity environments that exist at the water-lipid interface where a structural change of the "lid" region occurs. In this work, we have investigated the activation of TlL (Lipase_W89) and certain lid mutants, containing either a single positive charge mutation, E87K (Lipase_K87_W89), within the lid region or a lid residue composition of both lipase and esterase character (Hybrid_W89) as a function of solvent polarity. Activation differences between the variants and TlL were studied by a combination of biophysical and theoretical methods. To investigate the structural changes taking place in the lid region upon lipase activation, we used a fluorescence-based method measuring the efficiency of Trp89 in the lid to quench the fluorescence of a bimane molecule attached in front (C255) and behind (C61) the lid. These structural changes were compared to the enzymatic activity of each variant at the water-substrate interface and to theoretical calculations of the energies associated with lid opening as a function of the dielectric constant (epsilon) of the environment. Our results show that the lid in Lipase_K87_W89 undergoes a pronounced structural transition toward an open conformation around epsilon = 50, whereas only small changes are detected for Lipase_W89 ascribed to the stabilizing effect of the positive charge mutation on the open lid conformation. Interestingly, Hybrid_W89, with the same charge as Lipase_W89, shows a stabilization of the open lid even more pronounced at high solvent polarities than that of Lipase_K87_W89, allowing activation at epsilon < 80. This is further indicated by measurement of the lipase activity for each variant showing that Hybrid_W89 is more quickly activated at the water-lipid interface of a true, natural substrate. Combined, we show that a correlation exists between structural changes and enzymatic activities detected on one hand and theoretical calculations on lid opening energies on the other. These results highlight the key role that the lid plays in determining the polarity-dependent activation of lipases. PMID- 26645101 TI - A portable electrospinning apparatus based on a small solar cell and a hand generator: design, performance and application. AB - Electrospinning (e-spinning) devices and electrospun (e-spun) ultrathin fibers have shown promising applications in various fields. However, the poor portability of conventional e-spinning devices limits some potential applications especially in the case without a plug (electricity supply). Consequently, great efforts have been made to modify e-spinning setups with good portability. In this article, a solar cell and a hand generator-powered portable e-spinning (SHPE) setup with good flexibility is introduced, which can be used outdoors without a plug. The SHPE device shows good spinning efficacy both in solution and melt e spinning processes for a wide range of polymers. Moreover, the designed SHPE apparatus demonstrates potential application in wound dressing by in situ e spinning fibers onto human skin directly. PMID- 26645102 TI - Health Impacts of Climate Change in Pacific Island Countries: A Regional Assessment of Vulnerabilities and Adaptation Priorities. AB - BACKGROUND: Between 2010 and 2012, the World Health Organization Division of Pacific Technical Support led a regional climate change and health vulnerability assessment and adaptation planning project, in collaboration with health sector partners, in 13 Pacific island countries-Cook Islands, Federated States of Micronesia, Fiji, Kiribati, Marshall Islands, Nauru, Niue, Palau, Samoa, Solomon Islands, Tonga, Tuvalu, and Vanuatu. OBJECTIVE: We assessed the vulnerabilities of Pacific island countries to the health impacts of climate change and planned adaptation strategies to minimize such threats to health. METHODS: This assessment involved a combination of quantitative and qualitative techniques. The former included descriptive epidemiology, time series analyses, Poisson regression, and spatial modeling of climate and climate-sensitive disease data, in the few instances where this was possible; the latter included wide stakeholder consultations, iterative consensus building, and expert opinion. Vulnerabilities were ranked using a "likelihood versus impact" matrix, and adaptation strategies were prioritized and planned accordingly. RESULTS: The highest-priority climate-sensitive health risks in Pacific island countries included trauma from extreme weather events, heat-related illnesses, compromised safety and security of water and food, vector-borne diseases, zoonoses, respiratory illnesses, psychosocial ill-health, non-communicable diseases, population pressures, and health system deficiencies. Adaptation strategies relating to these climate change and health risks could be clustered according to categories common to many countries in the Pacific region. CONCLUSION: Pacific island countries are among the most vulnerable in the world to the health impacts of climate change. This vulnerability is a function of their unique geographic, demographic, and socioeconomic characteristics combined with their exposure to changing weather patterns associated with climate change, the health risks entailed, and the limited capacity of the countries to manage and adapt in the face of such risks. Citation: McIver L, Kim R, Woodward A, Hales S, Spickett J, Katscherian D, Hashizume M, Honda Y, Kim H, Iddings S, Naicker J, Bambrick H, McMichael AJ, Ebi KL. 2016. Health impacts of climate change in Pacific island countries: a regional assessment of vulnerabilities and adaptation priorities. Environ Health Perspect 124:1707-1714; http://dx.doi.org/10.1289/ehp.1509756. PMID- 26645103 TI - Near-infrared bulk optical properties of goat wound tissue and human serum: consequences for an implantable optical glucose sensor. AB - Near-infrared (NIR) spectroscopy offers a promising technological platform for continuous glucose monitoring in the human body. Moreover, these measurements could be performed in vivo with an implantable single-chip based optical sensor. However, a thin tissue layer may grow in the optical path of the sensor. As most biological tissues are highly scattering, they only allow a small fraction of the collimated light to pass, significantly reducing the light throughput. To quantify the effect of a thin tissue layer in the optical path, the bulk optical properties of serum and tissue samples grown on implanted dummy sensors were characterized using double integrating sphere and unscattered transmittance measurements. The estimated bulk optical properties were then used to calculate the light attenuation through a thin tissue layer. The combination band of glucose was found to be the better option, relative to the first overtone band, as the absorptivity of glucose molecules is higher, while the reduction in unscattered transmittance due to tissue growth is less. Additionally, as the wound tissue was found to be highly scattering, the unscattered transmittance of the tissue layer is expected to be very low. Therefore, a sensor configuration which measures the diffuse transmittance and/or reflectance instead was recommended. (a) Dummy sensor; (b) explanted dummy sensor in tissue lump; (c) removal of dummy sensor from tissue lump; and (d) 900 um slices of tissue lump. PMID- 26645104 TI - Ligand-Controlled Divergent C-H Functionalization of Aldehydes with Enynes by Cobalt Catalysts. AB - We describe a highly step and atom economical cobalt-catalyzed cyclization of 1,6 enynes with aldehydes to synthesize functionalized pyrrolidines and dihydrofurans with high chemo- and stereoselectivity. The catalytic reaction plausibly proceeds via the cobaltacycle intermediate generated from the reaction of enyne substrate with cobalt catalyst, followed by switchable C-H functionalization of weakly coordinating aldehydes depending on the electronic nature of the ligand. PMID- 26645105 TI - INTERACTION BETWEEN OBJECTIVE PERFORMANCE MEASURES AND SUBJECTIVE USER PERCEPTIONS IN THE EVALUATION OF MEDICAL DEVICES: A CASE STUDY. AB - OBJECTIVES: Medical technology is a large and expanding industry. Introducing new medical devices is important but several challenges exist in implementing the optimal method of evaluation. Both objective and subjective measures can be used for evaluation. The former is the mainstay of evaluation, yet subjective assessment is often the basis for the introduction of new medical technology. The aim of this study was to determine the interaction and concordance between objective and subjective assessment of new medical technology. METHODS: This study used both objective performance measures and subjective user perceptions in the evaluation of a new medical device designed to improve the accuracy of gravity-assisted delivery of intravenous fluids, compared with the current, widely used "roller-clamp" device. The concordance of objective and subjective assessments was evaluated using comparative analysis. RESULTS: Objective assessment of the accuracy of intravenous fluid delivery revealed no difference between the two devices (p = .636). Subjective assessment revealed that the new device was perceived to be significantly more accurate (p = .001). This lack of concordance can be partially explained by both device and demand characteristics. CONCLUSIONS: This case study reveals a significant discordance between the objective and subjective assessments. It provides some explanation for why new medical devices are adopted without objective evidence of benefit. This phenomenon has been termed "persuasive design" and its influence should be controlled for in the evaluation, purchase and introduction of new medical devices. This should help reduce the risk and associated cost of premature introduction. PMID- 26645106 TI - Malignant meningitis secondary to oesophageal adenocarcinoma presenting with sensorineural hearing loss: a series of three cases and discussion of the literature. AB - Malignant meningitis may rarely present to the otolaryngologist. We report our experience with 3 patients presenting with sudden, progressive bilateral sensorineural hearing loss secondary to malignant meningitis. The primary tumour in all 3 cases was oesophageal adenocarcinoma. All 3 cases were notable for the rapidity of the patients' clinical deterioration; the interval from presentation to death ranged from 21 to 28 days. We suggest that otolaryngologists should remain vigilant to the possibility of this devastating diagnosis and have a low threshold for further investigation in patients with suspicious features. It is important to note that initial MRI and lumbar puncture may be negative and repeat testing should be undertaken if there is clinical suspicion. PMID- 26645108 TI - New Nanometric Solid Dispersions of Glibenclamide in Neusilin((r)) UFL2. AB - To improve the poor water solubility and dissolution rate of the oral hypoglycemic drug glibenclamide, it was molecularly dispersed in Neusilin((r)) UFL2, an amorphous synthetic form of magnesium aluminometasilicate, at different proportions; the physicochemical and biopharmaceutical properties, as well as the stability of the four different batches recovered were characterised, and it was determined that complete dispersion of glibenclamide in the amorphous polymer was obtained at the drug to Neusilin ratio of 1 to 2.5. Completely amorphous dispersion was proven by Thermal Analysis and X-Ray Powder Diffractometry. Very small particles were obtained, ranging from approximately 200 to 400 nm. The amorphous batches were physically and chemically stable for the entire duration of experiments. The physicochemical properties of the four batches were compared to those of the starting materials and physical mixtures of Neusilin((r)) UFL2 and glibenclamide, the latter showing the typical behaviour of simple mixes, i.e., the additivity of properties of single components. The dissolution studies of the four solid dispersions revealed a very high dissolution rate of the completely amorphous batches (Batches 3 and 4), behaviour that was ascribed to their high Intrinsic dissolution rate due to the amorphous characteristics of the solid dispersions, to their very small particle size, and to the presence of polysorbate 80 that improved solid wettability. The technique under investigation thus proved effective for recovering stable amorphous dispersions of very small particle sizes. PMID- 26645107 TI - Role of stem cells during diabetic liver injury. AB - Diabetes mellitus is one of the most severe endocrine metabolic disorders in the world that has serious medical consequences with substantial impacts on the quality of life. Type 2 diabetes is one of the main causes of diabetic liver diseases with the most common being non-alcoholic fatty liver disease. Several factors that may explain the mechanisms related to pathological and functional changes of diabetic liver injury include: insulin resistance, oxidative stress and endoplasmic reticulum stress. The realization that these factors are important in hepatocyte damage and lack of donor livers has led to studies concentrating on the role of stem cells (SCs) in the prevention and treatment of liver injury. Possible avenues that the application of SCs may improve liver injury include but are not limited to: the ability to differentiate into pancreatic beta-cells (insulin producing cells), the contribution for hepatocyte regeneration, regulation of lipogenesis, glucogenesis and anti-inflammatory actions. Once further studies are performed to explore the underlying protective mechanisms of SCs and the advantages and disadvantages of its application, there will be a greater understand of the mechanism and therapeutic potential. In this review, we summarize the findings regarding the role of SCs in diabetic liver diseases. PMID- 26645109 TI - Natural Scaffolds for Renal Differentiation of Human Embryonic Stem Cells for Kidney Tissue Engineering. AB - Despite the enthusiasm for bioengineering of functional renal tissues for transplantation, many obstacles remain before the potential of this technology can be realized in a clinical setting. Viable tissue engineering strategies for the kidney require identification of the necessary cell populations, efficient scaffolds, and the 3D culture conditions to develop and support the unique architecture and physiological function of this vital organ. Our studies have previously demonstrated that decellularized sections of rhesus monkey kidneys of all age groups provide a natural extracellular matrix (ECM) with sufficient structural properties with spatial and organizational influences on human embryonic stem cell (hESC) migration and differentiation. To further explore the use of decellularized natural kidney scaffolds for renal tissue engineering, pluripotent hESC were seeded in whole- or on sections of kidney ECM and cell migration and phenotype compared with the established differentiation assays for hESC. Results of qPCR and immunohistochemical analyses demonstrated upregulation of renal lineage markers when hESC were cultured in decellularized scaffolds without cytokine or growth factor stimulation, suggesting a role for the ECM in directing renal lineage differentiation. hESC were also differentiated with growth factors and compared when seeded on renal ECM or a new biologically inert polysaccharide scaffold for further maturation. Renal lineage markers were progressively upregulated over time on both scaffolds and hESC were shown to express signature genes of renal progenitor, proximal tubule, endothelial, and collecting duct populations. These findings suggest that natural scaffolds enhance expression of renal lineage markers particularly when compared to embryoid body culture. The results of these studies show the capabilities of a novel polysaccharide scaffold to aid in defining a protocol for renal progenitor differentiation from hESC, and advance the promise of tissue engineering as a source of functional kidney tissue. PMID- 26645110 TI - Cultural Beliefs and Attitudes About Breast Cancer and Screening Practices Among Arabic Women in Australia. AB - BACKGROUND: Arabic women have been consistently reported as having remarkably low participation rates in breast cancer screening measures in their home countries and after migration to Western countries. Little is known about the screening behaviors of Arabic women in Australia. OBJECTIVES: This study aimed to report breast cancer screening practices among Arabic women in Australia and to examine the relationship between (1) demographic factors and (2) the Arabic version of the Breast Cancer Screening Beliefs Questionnaire (BCSBQ) score and women's breast screening behaviors. METHODS: A descriptive cross-sectional method was used. Both English and Arabic versions of the BCSBQ were administered to the 251 Arabic Australian women 18 years or older who participated in the study. RESULTS: The majority of participants (62.9%-92%) had heard of breast awareness, clinical breast examination, and mammography. However, only 7.6% practiced breast awareness monthly, 21.4% had undergone clinical breast examination annually, and 40.3% had biannual mammography. Length of stay in Australia, being retired, and being unemployed were positively associated with the recommended performance of breast awareness and mammography. In terms of BCSBQ scores, women who engaged in the 3 screening practices had significantly higher scores on the attitudes to health check-ups and barriers to mammography subscales. CONCLUSION: Attitudes toward health check-ups and perceived barriers to mammography were important determinants of breast cancer screening practices among Arabic Australian women. IMPLICATIONS FOR PRACTICE: To fully understand barriers discouraging Arabic Australian women from participating in breast cancer screening practices, efforts should be focused on specific subgroup (ie, working group) of Arabic Australian women. PMID- 26645111 TI - A Systematic Review of Psychometric Properties of Health-Related Quality-of-Life and Symptom Instruments in Adult Acute Leukemia Survivors. AB - BACKGROUND: Acute leukemia represents 4% of cancer cases in the United States annually. There are more than 302 000 people living with acute and chronic leukemia in the United States. Treatment has been shown to have both positive and negative effects on health-related quality of life (HRQOL). OBJECTIVE: The aims of this study were to examine psychometric properties of symptom and HRQOL instruments and to provide implications for the assessment in adults with acute leukemia relevant to clinical practice and future research. METHODS: Systematic literature search was conducted from 1990 to 2014 using electronic databases and manual searches. Psychometric studies were considered eligible for inclusion if (1) the psychometric paper was published using at least 1 HRQOL or symptom instrument, and (2) adults with acute leukemia were included in the sample. Studies were excluded if the age groups were not adults, or if the instrument was in a language other than English. RESULTS: Review identified a total of 7 instruments (1 cancer generic HRQOL, 2 symptom related, 3 HRQOL combined with symptom questions, and 1 disease specific). The most commonly used instrument was the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30, followed by the Functional Assessment of Cancer Therapy Fatigue. CONCLUSIONS: An acute leukemia diagnosis can have a significant impact on HRQOL. Our recommendations include using both an HRQOL and symptom instrument to capture patient experiences during and after treatment. IMPLICATIONS FOR PRACTICE: The availability of comprehensive, valid, and reliable HRQOL and symptom instruments to capture the experiences of adults with acute leukemia during and after treatment is limited. PMID- 26645112 TI - Axon-First Neuritogenesis on Vertical Nanowires. AB - In this work, we report that high-density, vertically grown silicon nanowires (vg SiNWs) direct a new in vitro developmental pathway of primary hippocampal neurons. Neurons on vg-SiNWs formed a single, extremely elongated major neurite earlier than minor neurites, which led to accelerated polarization. Additionally, the development of lamellipodia, which generally occurs on 2D culture coverslips, was absent on vg-SiNWs. The results indicate that surface topography is an important factor that influences neuronal development and also provide implications for the role of topography in neuronal development in vivo. PMID- 26645113 TI - No-fault compensation for treatment injuries in Danish public hospitals 2006-12. AB - OBJECTIVE: We aimed to determine the incidence rate and time trend of approved treatment injuries in Danish public hospitals from 2006 to 2012 and also to identify independent predictors of severe treatment injuries among patient and system factors and characterize the injuries. DESIGN AND SETTING: We performed a nationwide, historical observational study on data from the Danish Patient Compensation Association, which receives all compensation claims from Danish health care. All approved closed claims of treatment injuries occurring in public hospitals 2006-12 were included. Health care activity information was obtained through Statistics Denmark. MAIN OUTCOME MEASURES: Incidence rates were determined as treatment injuries per year by population and by public hospital contacts. By using a multivariable logistic regression model, we calculated mutually adjusted odds ratios to assess the association between potential predictors and severe injuries among approved claims. RESULTS: We identified 10,959 approved treatment injury claims in 2006-12. The total payout was USD 339 million. The mean incidence rate medians were 27.9 injuries/100,000 inhabitants/year and 0.21 injuries/1000 public hospital contacts/year. These did not increase overtime. Severe injuries and preventable cases comprised 11.0 and 41.0%, respectively. Predictors of severe injury included age 0 and above 40 years, male gender and higher level of comorbidity. CONCLUSION: The incidence rate of approved closed claims at Danish public hospitals appears stable. A high proportion of injuries are preventable and both patient- and system-related factors may predict severe injuries. PMID- 26645114 TI - Countering Staphylococcus Overgrowth During Patch Testing in Children with Moderate to Severe Atopic Dermatitis. AB - BACKGROUND: Patients with moderate to severe atopic dermatitis (AD) often have a concurrent diagnosis of contact dermatitis, but patch testing in these patients presents a unique set of challenges. Barrier impairment and Staphylococcus aureus colonization and infection, along with the sealed occlusion that takes place during the patch testing procedure, can create an optimal environment for bacterial overgrowth. AIMS: To identify patients at risk for S. aureus overgrowth during patch testing and provide pre- and peripatch testing interventions to aid clinicians in obtaining the best possible patch test results in this complicated population. MATERIALS AND METHODS: A retrospective review was performed of five patients with moderate to severe AD for which S. aureus overgrowth and superinfection complicated patch test evaluation. RESULTS: All five patients were able to complete the patch test procedure and all had relevant positive patch test reactions. Complications during patch testing included erythema, oozing, foul odor under the patches, and purulent material at the patch sites. One patient had a culture performed during patch testing that showed methicillin sensitive S. aureus. DISCUSSION: Patch testing can play an important role in the examination and management of patients with refractory AD. CONCLUSIONS: Moderate to severe AD and concern regarding S. aureus overgrowth should not preclude patch testing. PMID- 26645115 TI - Layered-Layered-Spinel Cathode Materials Prepared by a High-Energy Ball-Milling Process for Lithium-ion Batteries. AB - In this work, we report the electrochemical properties of 0.5Li2MnO3.0.25LiNi0.5Co0.2Mn0.3O2.0.25LiNi0.5Mn1.5O4 and 0.333Li2MnO3.0.333LiNi0.5Co0.2Mn0.3O2.0.333LiNi0.5Mn1.5O4 layered-layered-spinel (L*LS) cathode materials prepared by a high-energy ball-milling process. Our L*LS cathode materials can deliver a large and stable capacity of ~200 mAh g(-1) at high voltages up to 4.9 V, and do not show the anomalous capacity increase upon cycling observed in previously reported three-component cathode materials synthesized with different routes. Furthermore, we have performed synchrotron based in situ X-ray diffraction measurements and found that there are no significant structural distortions during charge/discharge runs. Lastly, we carry out (opt-type) van der Waals-corrected density functional theory (DFT) calculations to explain the enhanced cycle characteristics and reduced phase transformations in our ball-milled L*LS cathode materials. Our simple synthesis method brings a new perspective on the use of the high-power L*LS cathodes in practical devices. PMID- 26645116 TI - Predicting perceived medication-related hassles in dementia family caregivers. AB - Objective This study examined predictors of medication administration hassles reported by intergenerational dementia family caregivers. Methods A sample of 53 women who aided a cognitively impaired older adult with healthcare and who identified as inter-generational caregivers provided self-report medication management and psychosocial data. Results Hierarchical multiple regression analyses revealed that six independent variables hypothesized for this model, the total number of prescription medications managed by caregivers, educational attainment, care-recipient functional impairment, care-recipient cognitive impairment, caregiver depressive symptomatology, and self-reported feelings of preparedness for the caregiving role together significantly predicted caregiver medication administration hassles scores F(1, 48) = 4.90, p = .032, and accounted for approximately 25% of the variance of self-reported hassles (adjusted R2 = .247). Discussion Future interventions may reduce medication-related hassles by providing psychoeducation about healthcare, medication management, and strategies for coping with care-related stressors and depressed mood. PMID- 26645117 TI - Transcutaneous posterior tibial nerve stimulation versus extended release oxybutynin in overactive bladder patients. A prospective randomized trial. AB - INTRODUCTION AND HYPOTHESIS: The aim of this study was to evaluate the effectiveness of transcutaneous posterior tibial nerve stimulation (T.C. PTNS) versus extended release oxybutynin (E.R.O.) in patients with overactive bladder. MATERIALS AND METHODS: Seventy female patients were randomized to receive either 10mg E.R.O. daily or T.C. PTNS, using a TENS machine program with the 20Hz, 200 cycles/s, and normal stimulation setting for two 30-min sessions, each week for a 12-week period. Pre-treatment and after the 12-week intervention, each patient completed a 3-day voiding diary and a self-report quality of life questionnaire (OAB-q). Statistical analysis was performed using Stata V12.1. RESULTS: Sixty four patients completed the treatment protocol. There were no significant differences between study groups in terms of age, body mass index, past hormone replacement therapy, smoking habits, menopause status, and parity. Prior to treatment, there were also no significant differences in the analysis of the 3 day voiding diary or in the OAB-q questionnaire results. Following the 12-week study, there was a statistically significant reduction in frequency of urination, urgency episodes, and urge incontinent episodes compared to pre-treatment values. However, there were no significant differences in these values between intervention groups after 12-weeks of therapy. There was a similar improvement in OAB-q scores in both treatment groups following therapy, and the T.C. PTNS group showed a statistically significant improvement over the E.R.O. in domain 2 of the OAB-q questionnaire. The other two domains showed similar improvement in both study groups. CONCLUSION: T.C. PTNS and E.R.O. demonstrated similar improvements in subjects with OAB in a 12-week study. PMID- 26645126 TI - Elevated Serum Immune Mediators and Subclinical Inflammation in HLA-A29 associated Birdshot Chorioretinopathy. AB - PURPOSE: To determine the circulating levels of seven immune mediators in serum samples from patients with birdshot chorioretinopathy (BSCR). METHODS: A single center prospective case-control study was performed. Serum concentrations of IFN gamma, IL-12p70, IL-1beta, IL-17A, IL-23, TNF-alpha, and TGF-beta1 of 22 BSCR patients recruited at Hosp6ital Clinic of Barcelona and 16 healthy subjects were determined. RESULTS: Circulating levels of IL-17A were elevated in patients with BSCR in remission (p = 0.008 for BSCR patients with immunomodulatory treatment [IMT] and p = 0.032 for patients without IMT) compared with healthy subjects. Furthermore, patients who were not receiving IMT had significantly higher levels of circulating IL-23 (p = 0.013 vs controls and p = 0.001 vs IMT) and TGF-beta1 (p = 0.009 vs controls and p = 0.001 vs IMT) than patients under IMT or healthy subjects. CONCLUSIONS: Our results support the involvement of a IL-17-response in BSCR and suggest that BSCR patients without IMT due to apparent remission may maintain a subclinical inflammatory background. PMID- 26645131 TI - Attempted Suicide by Breaking Pre-Electroconvulsive Therapy Fasting. PMID- 26645132 TI - Toxicological evaluation of Yulangsan polysaccharide in Wistar rats: A 26-week oral gavage study. AB - Although numerous studies have proven the medicinal values of Yulangsan polysaccharide (YLSP), the toxicity of this active ingredient is unknown. In the acute toxicity study, a single oral administration of 24 g/kg YLSP caused neither toxicological symptoms nor mortality, and the LD50 was estimated >24 g/kg. In the chronic toxicity study, we administered doses of 0, 0.6, 1.2 and 2.4 g/kg YLSP in rats by oral gavage for 26 weeks followed by a 3-week recovery period. There was no mortality or remarkable clinical signs observed during this 26-week study. Additionally, there were no toxic differences in the following parameters: body weight, food consumption, hematology, clinical biochemistry, organ weight, and macroscopic findings. There were no adverse effects on histopathology observed in males or female rats treated with YLSP. Based on the results, the no-observed adverse-effect-level of YLSP in rats is greater than 2.4 g/kg when administered orally for 26 consecutive weeks. PMID- 26645133 TI - Activation of Fas death receptor pathway and Bid in hepatocytes is involved in saikosaponin D induction of hepatotoxicity. AB - Drug-induced liver injury can lead to acute liver failure. Saikosaponin D (SSD) is a major component isolated from the medicinal herb Bupleurum falcatum, which has been linked to hepatotoxicity. We previously reported that SSD disrupted PDGF betaR pathway leading to mitochondrial apoptosis in human LO2 hepatocytes. The present study was aimed at further exploring the underlying mechanisms in vitro and in vivo. We initially determined the concentration range of SSD at up to 2MUM for subsequent apoptosis examinations. SSD significantly upregulated Fas expression, promoted caspase-8 cleavage and activated the pro-apoptotic protein Bid in LO2 cells. Moreover, SSD reduced the abundance of cytochrome c in mitochondria and increased the cleaved-caspase-3 in LO2 cells, but did not apparently affect PI3K/AKT, ERK and STAT3 pathways that are involved in cell fate regulation. Experiments in vivo showed that one-week treatment with SSD at 300 mg/kg significantly elevated the liver/body weight ratio and caused histological injury in mouse liver. Furthermore, SSD treatment induced massive hepatocyte apoptosis, and significantly downregulated Bcl-2 but upregulated Bax in mouse liver. Taken together, these results revealed a specific mechanism of activation of extrinsic apoptosis pathway and Bid by SSD, which was involved in SSD-induced mitochondrial apoptosis in hepatocytes and potential hepatotoxicity. PMID- 26645134 TI - The Th1/Th2 paradigm in lambda cyhalothrin-induced spleen toxicity: The role of thymoquinone. AB - This study investigates the retrofitted role of thymoquinone (TQ) in the Th1/Th2 paradigm imbalance in lambda-cyhalothrin (LCT) treated rats. Four groups of male Wistar rats were formed: Group I served as control. Group II received 5 mg TQ/(kg bw) daily. Group III received 0.6 mg LCT/(kg bw). Group IV was treated with TQ and LCT. All treatments were given orally for 10 weeks. The LCT-treated group elicited a significant increase in MDA and NO levels with up-regulation of NF kappaB/p65 and pro-inflammatory genes expression and their levels. Meanwhile, GSH and immunoglobulins concentrations were markedly decreased concomitant with lessening the activities of antioxidant enzymes and anti-inflammatory cytokine genes mRNA levels. The co-administration of TQ and LCT improved the altered antioxidant enzymes activities and concentration of cytokines with attenuation of NF-kappaB/p65 mRNA. These data support the antioxidant role of TQ in the Th1/Th2 imbalance paradigm during LCT toxicity. PMID- 26645135 TI - Time-dependent hormesis of chemical mixtures: A case study on sulfa antibiotics and a quorum-sensing inhibitor of Vibrio fischeri. AB - Sulfa antibiotics (SAs) and quorum-sensing inhibitor (QSI) may pose potential ecological risks because mixed using of them has been proposed to inhibit bacteria from generating antibiotic resistance. This study investigated the time dependent hormesis of single and binary mixtures of QSI and SAs of Vibrio fischeri (V. fischeri) for 0-24 h. Although the low-dose SAs stimulated the expression of LuxR protein, the high-dose SAs could inhibit bacteria growth by competitively binding to dihydropteroate synthase. Moreover, AinR protein was bound to Benzofuran-3(2H)-one (B3O) with low concentration, thus the N-octanoyl homoserine lactone signal molecules (C8) has chance to bind to LuxR protein to promote light emission. The hormesis effect induced by the mixtures could be deduced that SAs promoted the expression of LuxR protein and B3O increases the chance of C8 binding to LuxR. Our findings facilitate new insight into the mechanistic study of hormesis and ecological risks of the chemical mixtures. PMID- 26645136 TI - Reduced growth hormone signaling and methionine restriction: interventions that improve metabolic health and extend life span. AB - Interventions that improve health are often associated with longevity. Reduced growth hormone signaling has been shown to increase life span in mice by over 50%. Similarly, reductions in dietary intake of methionine, in rats and mice, result in life-span extension. Many factors affect metabolic health, mitochondrial function, and resistance to stressors, each of which influence aging and life span. This paper presents a comparison of these two interventions, as well as the results of a study combining these interventions, to understand potential mechanisms underlying their effectiveness in enhancing healthy aging. PMID- 26645137 TI - Effective return-to-work interventions after acquired brain injury: A systematic review. AB - OBJECTIVE: To gather knowledge about effective return-to-work (RTW) interventions for patients with acquired brain injury (ABI). METHODS: A database search was performed in PubMed, EMBASE, PsycINFO, CINAHL and the Cochrane Library using keywords and Medical Subject Headings. Studies were included if they met inclusion criteria: adult patients with non-progressive ABI, working pre-injury and an intervention principally designed to improve RTW as an outcome. The methodological quality of included studies was determined and evidence was assessed qualitatively. RESULTS: Twelve studies were included, of which five were randomized controlled trials and seven were cohort studies. Nine studies had sufficient methodological quality. There is strong evidence that work-directed interventions in combination with education/coaching are effective regarding RTW and there are indicative findings for the effectiveness of work-directed interventions in combination with skills training and education/coaching. Reported components of the most effective interventions were tailored approach, early intervention, involvement of patient and employer, work or workplace accommodations, work practice and training of social and work-related skills, including coping and emotional support. CONCLUSION AND IMPLICATIONS: Effective RTW interventions for patients with ABI are a combination of work-directed interventions, coaching/education and/or skills training. These interventions have the potential to facilitate sustained RTW for patients with ABI. PMID- 26645138 TI - First-Principles Study on Doping of SnSe2 Monolayers. AB - Doping is a vitally important technique that can be used to modulate the properties of two-dimensional materials. In this work, by using first-principles density functional calculations, we investigated the electrical properties of SnSe2 monolayers by p-type/n-type and isoelectronic doping. Substitution at Sn/Se sites was found to be easy if the monolayer was grown under Sn-/Se-poor conditions. Substitutions at Sn sites with metallic atoms (e.g. Ga, Ge, In, Bi, Sb, Pb) resulted in positive substitution energies, which indicated that they were not effective doping candidates. For substitutions at Se sites with nonmetallic atoms, no promising candidates were found for p-type doping (e.g., N, P, As). Among these, N and As showed positive substitution energies. Although P had a negative substitution energy under Sn-rich conditions, it introduced trap states within the band gap. For n-type doping (e.g., F, Cl, Br), all the calculated substitution energies were negative under both Sn- and Se-rich conditions. Br was proven to be a promising candidate, because the impurity introduced a shallow donor level. Finally, for isoelectronic doping (e.g., O, S, Te), the intrinsic semiconducting features of the SnSe2 monolayer did not change, and the contribution from the impurity to the states near the band edge increased with the atomic number. PMID- 26645139 TI - Functions of microRNA-33a/b and microRNA therapeutics. AB - Atherosclerosis is a chronic inflammatory disease of the arterial wall. It is characterized by subendothelial accumulation of low-density lipoprotein cholesterol, and its subsequent modification at athero-prone areas leads to further activation of the vascular wall and maintains vascular inflammation. An entirely new level of post-transcriptional gene regulation through microRNA (miR) expression has emerged recently as an important mechanism in the development and progression of numerous diseases, including atherosclerosis. Recently, miR-33a/b have been shown to act as post-transcriptional regulators of lipid metabolism, and their pharmacological inhibition diminished atherosclerosis by raising plasma high-density lipoprotein levels. This review summarizes the current understanding of the functions of miR-33a/b and the progress in miRNA therapeutics for treatment of various diseases, including atherosclerosis. PMID- 26645140 TI - High-resolution micromechanical measurement in real time of forces exerted by living cells. AB - The aim of this study was to compare uniaxial traction forces exerted by different cell types using a novel sensor design and to test the dependence of measured forces on cytoskeletal integrity. The sensor design detects forces generated between 2 contact points by cells spanning a gap. The magnitude of these forces varied according to cell type and were dependent on cytoskeletal integrity. The response time for drug-induced cytoskeletal disruption also varied between cell types: dermal fibroblasts exerted the greatest forces and had the slowest drug response times; EBV-transformed epithelial cells also had slow cytoskeletal depolymerisation times but exerted the lowest forces overall. Conversely, lung epithelial tumor cells exerted low forces but had the fastest depolymerisation drug response. These results provide proof of principle for a new design of force-measurement sensor based on optical interferometry, an approach that can be used to study cytoskeletal dynamics in real time. PMID- 26645141 TI - Structural and physicochemical characteristics of a novel water-soluble gum from Lallemantia royleana seed. AB - In this study, the structural information (monosaccharide compositions, molecular weight parameters & FTIR analysis), chemical composition (moisture, protein, ash, carbohydrate & uronic acids), rheological properties, and surface activity of Lallemantia royleana seeds mucilage (BSG) were determined. The results showed BSG contains 8.51% (w.b.) moisture, 8.24% (d.b.) ash, 2.71% (d.b.) protein, 75.87% (d.b.) carbohydrate and 20.33% (d.b.) uronic acids. Monosaccharide analysis revealed the presence of arabinose (37.88%), galactose (33.54%), rhamnose (18.44%), xylose (6.02%) and glucose (4.11%) in the BSG polysaccharide. Although BSG had similar molecular weight (1.294*10(6) Da) compared to most seed gums, the intrinsic viscosity (23.06 dL/g) and gyration radius (104.84 nm) were higher. The BSG exhibited a strong shear-thinning behavior (n<0.29) over the shear rate range of 0.01 to 1000 s(-1). Flow behavior data was correlated with different time independent models, which provided a good description of BSG rheological properties. Dynamic mechanical spectra demonstrated BSG is a typical of weak gel, which its rheological parameters were superior to those of many commercial gums. The FTIR spectra of the BSG polymer showed the presence of carboxyl groups, which may serve as binding sites for ions. BSG exhibited the ability to reduce the surface tension of water at concentrations lower than 0.75%. PMID- 26645142 TI - Characterization of a Kunitz-type serine protease inhibitor from Solanum tuberosum having lectin activity. AB - Plant lectins and protease inhibitors constitute a class of proteins which plays a crucial role in plant defense. In our continuing investigations on lectins from plants, we have isolated, purified and characterized a protein of about 20 kDa, named PotHg, showing hemagglutination activity from tubers of Indian potato, Solanum tuberosum. De novo sequencing and MS/MS analysis confirmed that the purified protein was a Kunitz-type serine protease inhibitor having two chains (15 kDa and 5 kDa). SDS and native PAGE analysis showed that the protein was glycosylated and was a heterodimer of about 15 and 5 kDa subunits. PotHg agglutinated rabbit erythrocytes with specific activity of 640 H.U./mg which was inhibited by complex sugars like fetuin. PotHg retained hemagglutination activity over a pH range 4-9 and up to 80 degrees C. Mannose and galactose interacted with the PotHg with a dissociation constant (Kd) of 1.5*10(-3) M and 2.8*10(-3) M, respectively as determined through fluorescence studies. Fluorescence studies suggested the involvement of a tryptophan in sugar binding which was further confirmed through modification of tryptophan residues using N-bromosuccinimide. Circular dichroism (CD) studies showed that PotHg contains mostly beta sheets (~45%) and loops which is in line with previously characterized protease inhibitors and modeling studies. There are previous reports of Kunitz-type protease inhibitors showing lectin like activity from Peltophorum dubium and Labramia bojeri. This is the first report of a Kunitz-type protease inhibitor showing lectin like activity from a major crop plant and this makes PotHg an interesting candidate for further investigation. PMID- 26645143 TI - Investigation on the formation, conversion and bioactivity of a G-quadruplex structure in the PALB2 gene. AB - There is a putative G-quadruplex sequence (PGS), 5'-G3ACAG4TTG2TG4 TAG4CAG2TTG3 3', in the promoter region of the PALB2 gene. According to the importance of PALB2 in the process of homologous recombination and breast cancer, and the hypothesis that G-quadruplexes might play a role in transcriptional regulation, we evaluated the formation of G-quadruplex from this complex sequence, as well as its structural information and importance for PALB2 transcription. The G-rich sequence was suggested to form G-quadruplex structure in the NH4OAc solution with 3NH4+ ion by ESI-MS spectrometry, and it was testified in the KCl solution by CD experiments which showed the typical 290 nm band and a high melting temperature. We also classified the guanines in the sequence into four types and demonstrated their roles in the formation of the G-quadruplex structure. In addition, a luciferase assay proved that the formation of the G-quadruplex down-regulate the transcription of the gene. Therefore, our findings provided a foundation for the formation and bioactivity of the G-quadruplex in the promoter region of PALB2 gene and a novel insight for understanding PALB2 gene regulation. PMID- 26645144 TI - Synthesis, characterization and anticorrosion potentials of chitosan-g-PEG assembled on silver nanoparticles. AB - Chitosan (Ch) grafted with poly(ethylene glycol) (Ch-g-mPEG) were synthesized using mPEG with molecular weights 2000 g/mol. The synthesized Ch-g-mPEG was characterized using gel permeation chromatography (GPC), Fourier transform infrared spectroscopy (FTIR), proton nuclear magnetic resonance (1H NMR), and X ray diffraction (XRD) techniques. Ch-g-mPEG silver nanoparticles has been synthesized and characterized by high-resolution transmission electron microscopy (HRTEM) and energy dispersive analysis of X-rays (EDAX). The synthesized Ch-g mPEG and its nanostructure were examined as corrosion inhibitors for carbon steel in 1M HCl solution using potentiodynamic polarization and electrochemical impedance spectroscopy (EIS) techniques. The results revealed that the inhibition efficiency obtained by Ch-g-mPEG self-assembled on silver nanoparticles is greater than that obtained by Ch-g-mPEG only. Potentiodynamic polarization results reveal that the synthesized compound could be classified as mixed-type corrosion inhibitors with predominant control of the cathodic reaction. The results of EIS indicate that the both charge transfer resistance and inhibition efficiency tend to increase by increasing the inhibitor concentration. PMID- 26645145 TI - Physical properties of carboxymethyl cellulose based nano-biocomposites with Graphene nano-platelets. AB - Carboxymethyl cellulose (CMC) based bio-nanocomposite filled with graphene nano platelets (GNPs) was prepared using casting technique. The morphology, thermal, light barrier, water vapor permeability (WVP), contact angle, moisture absorption and mechanical properties of the resulted bio-nanocomposites were investigated. The results indicated with addition of 0.5% w/w GNPs to polymer matrix, ultimate tensile strength (UTS) decreased from 7.74 MPa (in the pure film) to 5.69 MPa however, strain to break (SB) increased from 12.49% to 19.87%. The GNPs caused to reducing of light transmission and increasing of the water repelling nature of nano-biocomposites. However, it had not effect on melting point of CMC based nano biocomposites. PMID- 26645146 TI - L-2-Haloacid dehalogenase from Ancylobacter aquaticus UV5: Sequence determination and structure prediction. AB - A novel 25 kDa L-2-haloacid dehalogenase (L-2-DhlB) from a recently isolated Ancylobacter aquaticus strain UV5 indigenous to contaminated site in South Africa is reported here with its gene sequence. The enzyme was purified to 22.1-fold increase in specific activity of 72.9 U/mg protein when the organism was grown in medium supplemented with 5 mM 1,2-dichloroethane (1,2-DCA). L-2-DhlB was optimally active at pH 9.0 and 37 degrees C with poor stability at 50 degrees C, retaining 50% of its activity after 30 min, but inactivated rapidly at 60 degrees C. L-2-DhlB catalyzed monochloroacetate (MCA) with Km and Vmax values of 0.47 mM and 2.4 MUM/min, respectively. L-2-DhlB exhibited the kcat value of 4.8/min. Expression of about 100% relative activity of L-2-DhlB on the substrate L-2 monochloropropionate (L-2-MCPA) as compared to 5% on D-2-monochloropropionate (D 2-MCPA) suggested that L-2-DhlB belongs to the family of L-2-haloacid dehalogenases. ES-mass spectroscopy and bioinformatics tools resulted in 693 bp ORF sequence corresponding to 230 amino acid protein. NCBI-BLAST of L-2-DhlB resulted in the detection of a putative conserved domain of hypothetical haloacid dehalogenase (HAD)-like superfamily and subfamily IA. PMID- 26645147 TI - Isolation, characterization, and radiation protection of Sipunculus nudus L. polysaccharide. AB - Sipunculus nudus Linnaeus polysaccharide (SNP) was purified from S. nudus L. via NaOH extraction, trichloroacetic acid deproteination, DEAE-cellulose 52 and Sephacryl S-300 chromatography. The monosaccharide analysis and molecular weight was detected with HPLC. FT-IR, 1H spectrum and 13C NMR spectrum were performed to detect the chemical characteristics. The antioxidant activity was assayed in vitro. The radiation protection effects were detected on mice. The results showed that SNP was composed of mannose, rhamnose, galacturonic acid, glucose, arabinose and fucose, and the average molecular weight was 680 kDa. Above the concentration of 10 mg/mL, SNP showed powerful scavenging activity on hydroxyl radical. In the animals irradiated with a 7.5 Gy gamma-rays, the 90 mg/kg and the 270 mg/kg SNP groups survived significantly longer than the radiation control group. In the animals irradiated with a 4.0 Gy gamma-rays, SNP showed significant protection effect. The contents of DNA in bone marrow cells were significantly increased by SNP treatment, and the micronucleus rates of 30 mg/kg and 270 mg/kg SNP groups were decrease significantly compared to the radiation control group. These findings suggest that SNP possesses marked antioxidant and bone marrow damage protection capacity which play important roles in the prevention of radiation damage. PMID- 26645148 TI - Bio-clarification of water from heavy metals and microbial effluence using fungal chitosan. AB - Water pollution is among the most hazardous problems that threaten human health worldwide. Chitosan is a marvelous bioactive polymer that could be produced from fungal mycelia. This study was conducted to produce chitosan from Cunninghamella elegans and to use it for water pollutants elimination, e.g. heavy metals and waterborne microorganisms, and to investigate its antibacterial mode of action against Escherichia coli. The produced fungal chitosan had a deacetylation degree of 81%, a molecular weight of 92.73 kDa and a matched FT-IR spectrum with standard shrimp chitosan. Fungal chitosan exhibited remarkable antimicrobial activity against E. coli, Staphylococcus aureus and Candida albicans. Chitosan was proved as an effective metal adsorbent, toward the examined metal ions, Cu2+, Zn2+ and Pb2+, and its adsorption capacity greatly increased with the increasing of metal concentration, especially for Cu and Zn. The scanning electron micrographs, of treated E. coli cells with fungal chitosan, indicated that the cells began to lyse and combine after 3h of exposure and chitosan particles attached to the combined cells and, after 12 h from exposure, the entire bacterial cell walls were fully disrupted and lysed. Therefore, fungal chitosan could be recommended, as a bioactive, renewable, ecofriendly and cost effective material, for overcoming water pollution problems, from chemical and microbial origins. PMID- 26645149 TI - Chitosan-based nanoparticles for rosmarinic acid ocular delivery--In vitro tests. AB - In this study, chitosan nanoparticles were used to encapsulate antioxidant rosmarinic acid, Salvia officinalis (sage) and Satureja montana (savory) extracts as rosmarinic acid natural vehicles. The nanoparticles were prepared by ionic gelation using chitosan and sodium tripolyphosphate (TPP) in a mass ratio of 7:1, at pH 5.8. Particle size distribution analysis and transmission electron microscopy (TEM) confirmed the size ranging from 200 to 300 nm, while surface charge of nanoparticles ranged from 20 to 30 mV. Nanoparticles demonstrate to be safe without relevant cytotoxicity against retina pigment epithelium (ARPE-19) and human cornea cell line (HCE-T). The permeability study in HCE monolayer cell line showed an apparent permeability coefficient Papp of 3.41+/-0.99*10(-5) and 3.24+/-0.79*10(-5) cm/s for rosmarinic acid loaded chitosan nanoparticles and free in solution, respectively. In ARPE-19 monolayer cell line the Papp was 3.39+/-0.18*10(-5) and 3.60+/-0.05*10(-5) cm/s for rosmarinic acid loaded chitosan nanoparticles and free in solution, respectively. Considering the mucin interaction method, nanoparticles indicate mucoadhesive proprieties suggesting an increased retention time over the ocular mucosa after instillation. These nanoparticles may be promising drug delivery systems for ocular application in oxidative eye conditions. PMID- 26645150 TI - Stool vs. Serum Hepatitis B Virus DNA in Patients with Chronic Hepatitis B. AB - BACKGROUND Serum hepatitis B virus (HBV) DNA and hepatitis B e antigen (HBeAg) liver function in patients with chronic hepatitis B (CHB) are significantly associated. A comparison of clinical significance of fecal HBV DNA and serum HBV DNA has not yet been reported. MATERIAL AND METHODS Stool and serum samples were collected from 66 patients with CHB. Fecal HBV DNA, serum HBV DNA, and intestinal microbiota DNA were detected by real-time quantitative fluorescence polymerase chain reaction (PCR). Liver function and HBeAg were analyzed. RESULTS The stool and serum HBV DNA were positively correlated (r=0.57, P=0.001). Fecal HBV DNA was higher in the HBeAg-positive group than in the HBeAg-negative group (P=0.02). Fecal HBV DNA was negatively correlated with alkaline phosphatase (ALP) (r=-0.41, P=0.001) and TBIL (r=-0.29, P=0.02), and was positively correlated with Enterococcus (r=0.38, P=0.002). Serum HBV DNA was negatively correlated with alanine aminotransferase (ALT) (r=-0.30,P=0.02), aminotransferase (AST) (r=-0.26, P=0.049), and Lactobacillus (r=-0.31, P=0.01). CONCLUSIONS These observations suggest that fecal HBV DNA and serum HBV DNA in patients with CHB have different effects. Fecal HBV DNA might be associated with changes in Enterococcus concentrations, but serum HBV DNA is not. PMID- 26645151 TI - Fasting plus tyrosine kinase inhibitors in cancer. PMID- 26645152 TI - A systematic review of evidence-based assessment practices by allied health practitioners for children with cerebral palsy. AB - AIM: The routine use of psychometrically robust assessment tools is integral to best practice. This systematic review aims to determine the extent to which evidence-based assessment tools were used by allied health practitioners for children with cerebral palsy (CP). METHOD: The Preferred Reporting Items for Systematic Reviews and Meta-Analysis protocols 2015 was employed. A search strategy applied the free text terms: 'allied health practitioner', 'assessment', and 'cerebral palsy', and related subject headings to seven databases. Included articles reported assessment practices of occupational therapists, physiotherapists, or speech pathologists working with children with CP aged 0 to 18 years, published from the year 2000. RESULTS: Fourteen articles met the inclusion criteria. Eighty-eight assessment tools were reported, of which 23 were in high use. Of these, three tools focused on gross motor function and had acceptable validity for use with children with CP: Gross Motor Function Measure, Gross Motor Function Classification System, and goniometry. Validated tools to assess other activity components, participation, quality of life, and pain were used infrequently or not at all. INTERPRETATION: Allied health practitioners used only a few of the available evidence-based assessment tools. Assessment findings in many areas considered important by children and families were rarely documented using validated assessment tools. PMID- 26645153 TI - NINE-YEAR FOLLOW-UP OF SPECIFIC PHOBIA IN A POPULATION SAMPLE OF OLDER PEOPLE. AB - BACKGROUND: Little is known about the long-term course of specific phobia (SP) in the general population. We examined the prevalence and course of SP and subthreshold fears in an older population followed over 9 years. METHOD: A psychiatric examination was performed in a population-based sample of 558 70-year olds, among whom 303 dementia-free survivors were followed up at both ages 75 and 79. Fears were rated with respect to level of anxiety and social or other consequences. DSM-IV SP was diagnosed when fears were associated with prominent anxiety and had social or other consequences. All other fears were labeled subthreshold fears. RESULTS: The prevalence of SP declined from 9.9% at age 70 to 4.0% at age 79. The reason was that the prevalence of fears associated with prominent anxiety (mandatory in the diagnosis) decreased whereas the prevalence of fears that gave social or other consequences remained stable. A total of 14.5% of the population had SP at least once during the study. Among these, 11.4% had SP and 65.9% had specific fear at all three examinations. CONCLUSION: The prevalence of fears associated with prominent anxiety decreased with age, resulting in an overall decline in the prevalence of SP. SP seems to be a fluctuating disorder, and in most cases an exacerbation of chronic subthreshold fears. PMID- 26645155 TI - Proof-of-Concept Studies for Marker-Based Ultrasound Doppler Analysis of Microvascular Anastomoses in a Modified Large Animal Model. AB - Background Despite attempts to solve the problem of flap monitoring, assessing the patency of vascular anastomoses postoperatively remains challenging. In addition, experimental data suggest that near-total vessel occlusion is necessary to produce significant changes in clinical appearance or monitoring devices. We sought to develop an ultrasound-based system that would provide definitive data on anastomotic function. Methods A system was developed consisting of a resorbable marker made from poly-lactic-co-glycolic acid (PLGA) implanted during the time of surgery coupled with ultrasound software to detect the anastomotic site and perform Doppler flow analysis. Surgical procedures consisting of microvascular free tissue transfer or femoral vessel cutdown were performed followed by marker placement, closure, and ultrasound monitoring. Transient vascular occlusion was produced via vessel-loop constriction. Permanent thrombosis was induced via an Arduino-controlled system applying current to the vessel intima. Results Four surgeries (one femoral vessel cutdown and three microvascular tissue transfer) were successfully performed in Yorkshire swine. The markers were readily visualized under ultrasound and provided a bounding area for Doppler analysis as well as orientation guidance. Transient spasm and partial occlusion were detected based on changes in Doppler data, while complete occlusion was evident as the total loss of color Doppler. Conclusion In this preliminary report, we have conceptualized and developed a novel system that enables the real-time visualization of vascular pedicle flow at the bedside using Doppler ultrasound and a surgically implanted marker. In a large animal model, use of the system allowed identification of the anastomosis, flow analysis, and real-time detection of flow loss. PMID- 26645154 TI - Nesprin-2 mediated nuclear trafficking and its clinical implications. AB - Nuclear translocation of proteins has a crucial role in the pathogenesis of cancer, Alzheimer disease and viral infections. A complete understanding of nuclear trafficking mechanisms is therefore necessary in order to establish effective intervention strategies. Here we elucidate the role of Nesprin-2 in Ca(2+)/Calmodulin mediated nuclear transport. Nesprin-2 is an actin-binding nuclear envelope (NE) protein with roles in maintaining nuclear structure and location, regulation of transcription and mechanotransduction. Upon depletion of Nesprin-2 using shRNA, HaCaT cells show abnormal localization of the shuttling proteins BRCA1 and NF-kappaB. We show that their nuclear transport is unlikely due to the canonical RAN mediated nuclear import, but rather to a RAN independent Ca(2+)/Calmodulin driven mechanism involving Nesprin-2. We report novel interactions between the actin-binding domain of Nesprin-2 and Calmodulin and between the NLS containing region of BRCA1 and Calmodulin. Strikingly, displacing Nesprins from the NE resulted in increased steady state Ca(2+) concentrations in the cytoplasm suggesting a previously unidentified role of Nesprins in Ca(2+) regulation. On comparing Nesprin-2 and BRCA1 localization in the ovarian cancer cell lines SKOV-3 and Caov-3, Nesprin-2 and BRCA1 were localized to the NE envelope and the nucleus in SKOV-3, respectively, and to the cytoplasm in Caov-3 cells. Fibroblasts obtained from EDMD5 (Emery Dreifuss muscular dystrophy) patients showed loss of Nesprin-2 from the nuclear envelope, corresponding reduced nuclear localization of BRCA1 and enhanced cytoplasmic Ca(2+). Taken together, the data suggests a novel role of Nesprin-2 in Ca(2+)/Calmodulin mediated nuclear trafficking and provides new insights which can guide future therapies. PMID- 26645156 TI - Anastomosis Lapse Index (ALI): A Validated End Product Assessment Tool for Simulation Microsurgery Training. AB - BACKGROUND: Over the last decade, simulation has become a principal training method in microsurgery. With an increasing move toward the use of nonliving models, there is a need to develop methods for assessment of microvascular anastomosis skill acquisition substituting traditional patency rate. The authors present and validate a novel method of microvascular anastomosis assessment tool for formative and summative skills competency assessment. METHODS: In this study, 29 trainees with varying levels of experience in microsurgery undertook a 5-day microsurgery course. Two consecutive end-to-end microvascular anastomoses of cryopreserved rat aortas performed on day 3 and day 5 of the course were longitudinally split and photographed for randomized blinded qualitative evaluation. Four consecutive anastomoses by two experienced microsurgeons were analyzed as expert controls. Errors potentially leading to anastomotic leak or thrombosis were identified and logged. Statistical analysis using the Kruskal Wallis analysis of variance (ANOVA) and a two-way repeated measure ANOVA was used to measure construct and concurrent validity, respectively. RESULTS: A total of 128 microvascular anastomoses were analyzed for both student and control groups. Ten errors were identified and indexed. There was a statistically significant difference detected between average errors per anastomosis performed between groups (p < 0.05). Average errors per anastomosis was statistically decreased on day 5 of the course compared with day 3 (p < 0.001). CONCLUSION: Evaluation of anastomosis structural patency and quality in nonliving models is possible. The proposed error list showed construct and predictive validity. The anastomosis lapse index can serve as a formative and summative assessment tool during microvascular training. PMID- 26645157 TI - Breast Microsurgery in Plastic Surgery Literature: A 21-Year Analysis of Publication Trends. AB - Introduction Microsurgical reconstruction of the breast represents an area of continual evolution, as new autologous flaps are introduced and principles are refined. This progression can be demonstrated by bibliometric analysis of the scientific literature. Methods The top 10 plastic surgery journals were determined by impact factor (IF). Each issue of every journal from 1993 to 2013 was accessed directly, and all articles discussing microsurgery on the female breast were classified by authors' geographic location, study design, and level of evidence (LOE, I-V). The productivity index and productivity share of each geographic region was calculated based on number of articles published and IF. Results A total of 706 breast microsurgery articles were analyzed. There was a significant increase in microsurgical breast research (p < 0.01), with an average 33.6 +/- 31.1 articles per year and a mean increase of 4.4 articles per year. Most research was of lower LOE, with level I constituting 0.14% and level II constituting 5.21% of all articles. United States contributed the most research with 336.4 articles, followed by Western Europe with 242.2. However, Western Europe experienced the greatest increase in productivity share, with + 0.50 +/- 0.29 growth, while United States demonstrated the greatest decrease in productivity share with - 1.23 +/- 0.31 growth. Among autologous flaps, transverse rectus abdominis muscle research had the greatest yearly publication volume until 2002, when overtaken by deep inferior epigastric perforator flap research. Conclusion Over the 21-year study period, the United States not only contributed the greatest volume of research on female breast microsurgery but also demonstrated the greatest decline in research productivity. Efforts should be made to increase the LOE in breast microsurgery research. PMID- 26645158 TI - Targeting of Carbon Ion-Induced G2 Checkpoint Activation in Lung Cancer Cells Using Wee-1 Inhibitor MK-1775. AB - The potent inhibitor of the cell cycle checkpoint regulatory factor Wee-1, MK 1775, has been reported to enhance non-small cell lung cancer (NSCLC) cell sensitivity to photon radiation by abrogating radiation-induced G2 arrest. However, little is known about the effects of this sensitizer after exposure to carbon (C)-ion radiation. The purpose of this study was therefore to investigate the effects of C ions in combination with MK-1775 on the killing of NSCLC cells. Human NSCLC H1299 cells were exposed to X rays or C ions (290 MeV/n, 50 keV/MUm at the center of a 6 cm spread-out Bragg peak) in the presence of MK-1775. The cell cycle was analyzed using flow cytometry and Western blotting. Radiosensitivity was determined using clonogenic survival assays. The mechanisms underlying MK-1775 radiosensitization were studied by observing H2AX phosphorylation and mitotic catastrophe. G2 checkpoint arrest was enhanced 2.3 fold by C-ion exposure compared with X-ray exposure. Radiation-induced G2 checkpoint arrest was abrogated by MK-1775. Exposure to radiation resulted in a significant reduction in the mitotic ratio and increased phosphorylation of cyclin-dependent kinase 1 (Cdk1), the primary downstream mediator of Wee-1 induced G2 arrest. The Wee-1 inhibitor, MK-1775 restored the mitotic ratio and suppressed Cdk1 phosphorylation. In addition, MK-1775 increased H1299 cell sensitivity to C ions and X rays independent of TP53 status. MK-1775 also significantly increased H2AX phosphorylation and mitotic catastrophe in irradiated cells. These results suggest that the G2 checkpoint inhibitor MK-1775 can enhance the sensitivity of human NSCLC cells to C ions as well as X rays. PMID- 26645159 TI - Short-term efficacy to conventional blind injection versus ultrasound-guided injection of local corticosteroids in tenosynovitis in patients with inflammatory chronic arthritis: A randomized comparative study. AB - OBJECTIVE: To compare the short-term efficacy of conventional blind injection (CBI) versus ultrasound-guided injection (USGI) of corticosteroids (CS) injection in tenosynovitis in patients with chronic arthritis and to investigate if the USGI is a less painful procedure and if there are differences in the changes of US findings during the post injection follow-up. METHODS: Patients presenting tenosynovitis requiring CS injection were involved. After clinical and US evaluation, patients were randomized to receive CBI or USGI. Efficacy of procedure was assessed by the improvement in both Health Assessment Questionnaire (HAQ) and pain visual analogue scale (VAS), including procedure-VAS global-VAS and local-VAS, after 1 and 4 weeks post-procedure. Power Doppler (PD) and greyscale (GS) US findings were also object of the follow-up. CBI or USGI under an aseptic technique were performed according the local guidelines using 20mg of methylprednisolone acetate. RESULTS: A total of 114 patients were randomized to receive CBI (54 patients) or USGI (60 patients) procedure. No significant difference was observed in terms of gender, age and pain duration among CBI and USGI groups at baseline. USGI proved to be significantly less painful than CBI (P=0.0001). AUC analysis showed that during the follow up visits, the USGI procedure had significantly better response in HAQ, local-VAS and global-VAS (P=0.0001, P=0.012 and P=0.0001 respectively) compared to CBI. During the follow up period, a significant greater reduction in the PD scores was found in the USGI group compared to the CBI group (P=0.0002), whereas no statistical differences were found in the GS findings between the groups (P=0.5627). CONCLUSION: Our study demonstrates superiority of USGI over CBI for CS injections in painful tenosynovitis, having better short-term outcomes measured by functional, clinical and US scores. These data support the use of USGI for tenosynovits in typical inpatient and/or outpatient in rheumatological practices. PMID- 26645160 TI - Usefulness of intra-articular botulinum toxin injections. A systematic review. AB - Botulinum toxin is a proven and widely used treatment for numerous conditions characterized by excessive muscular contractions. Recent studies have assessed the analgesic effect of botulinum toxin in joint pain and started to unravel its mechanisms. LITERATURE-SEARCH-METHODOLOGY: We searched the international literature via the Medline database using the term "intraarticular botulinum toxin injection" combined with any of the following terms: "knee", "ankle", "shoulder", "osteoarthritis", "adhesive capsulitis of the shoulder". RESULTS: Of 16 selected articles about intraarticular botulinum toxin injections, 7 were randomized controlled trials done in patients with osteoarthritis, adhesive capsulitis of the shoulder, or chronic pain after joint replacement surgery. Proof of anti-nociceptive effects was obtained in some of these indications and the safety and tolerance profile was satisfactory. The studies are heterogeneous. The comparator was usually a glucocorticoid or a placebo; a single study used hyaluronic acid. Pain intensity was the primary outcome measure. DISCUSSION CONCLUSION: The number of randomized trials and sample sizes are too small to provide a satisfactory level of scientific evidence or statistical power. Unanswered issues include the effective dosage and the optimal dilution and injection modalities of botulinum toxin. PMID- 26645189 TI - Wandering behavior of a severely demented patient with frontotemporal dementia. AB - Although wandering is a common behavioral problem in patients with dementia, information about wandering in patients with severe dementia is scarce. This study analyzed data about the wandering behavior of a 77-year-old woman with severe frontotemporal dementia. Due to severe atrophy of the anterior cortex, she was totally unable to act spontaneously. Nevertheless, she walked with her husband every day. Her walking pattern varied on a daily basis but it appeared to be random. However, a mathematical analysis showed that her walking pattern was not random. Our case suggests that even patients with severe atrophy in the anterior cortex may be able to orient themselves within their neighborhood if their posterior cortex is preserved. PMID- 26645191 TI - Progress in the treatment of juvenile dermatomyositis. PMID- 26645193 TI - Transitional Pain Medicine: novel pharmacological treatments for the management of moderate to severe postsurgical pain. PMID- 26645192 TI - Chimeric human mitochondrial PheRS exhibits editing activity to discriminate nonprotein amino acids. AB - Mitochondria are considered as the primary source of reactive oxygen species (ROS) in nearly all eukaryotic cells during respiration. The harmful effects of these compounds range from direct neurotoxicity to incorporation into proteins producing aberrant molecules with multiple physiological problems. Phenylalanine exposure to ROS produces multiple oxidized isomers: tyrosine, Levodopa, ortho Tyr, meta-Tyr (m-Tyr), and so on. Cytosolic phenylalanyl-tRNA synthetase (PheRS) exerts control over the translation accuracy, hydrolyzing misacylated products, while monomeric mitochondrial PheRS lacks the editing activity. Recently we showed that "teamwork" of cytosolic and mitochondrial PheRSs cannot prevent incorporation of m-Tyr and l-Dopa into proteins. Here, we present human mitochondrial chimeric PheRS with implanted editing module taken from EcPheRS. The monomeric mitochondrial chimera possesses editing activity, while in bacterial and cytosolic PheRSs this type of activity was detected for the (alphabeta)2 architecture only. The fusion protein catalyzes aminoacylation of tRNA(Phe) with cognate phenylalanine and effectively hydrolyzes the noncognate aminoacyl-tRNAs: Tyr-tRNA(Phe) and m-Tyr-tRNA(Phe) . PMID- 26645190 TI - Prednisone versus prednisone plus ciclosporin versus prednisone plus methotrexate in new-onset juvenile dermatomyositis: a randomised trial. AB - BACKGROUND: Most data for treatment of dermatomyositis and juvenile dermatomyositis are from anecdotal, non-randomised case series. We aimed to compare, in a randomised trial, the efficacy and safety of prednisone alone with that of prednisone plus either methotrexate or ciclosporin in children with new onset juvenile dermatomyositis. METHODS: We did a randomised trial at 54 centres in 22 countries. We enrolled patients aged 18 years or younger with new-onset juvenile dermatomyositis who had received no previous treatment and did not have cutaneous or gastrointestinal ulceration. We randomly allocated 139 patients via a computer-based system to prednisone alone or in combination with either ciclosporin or methotrexate. We did not mask patients or investigators to treatment assignments. Our primary outcomes were the proportion of patients achieving a juvenile dermatomyositis PRINTO 20 level of improvement (20% improvement in three of six core set variables at 6 months), time to clinical remission, and time to treatment failure. We compared the three treatment groups with the Kruskal-Wallis test and Friedman's test, and we analysed survival with Kaplan-Meier curves and the log-rank test. Analysis was by intention to treat. Here, we present results after at least 2 years of treatment (induction and maintenance phases). This trial is registered with ClinicalTrials.gov, number NCT00323960. FINDINGS: Between May 31, 2006, and Nov 12, 2010, 47 patients were randomly assigned prednisone alone, 46 were allocated prednisone plus ciclosporin, and 46 were randomised prednisone plus methotrexate. Median duration of follow-up was 35.5 months. At month 6, 24 (51%) of 47 patients assigned prednisone, 32 (70%) of 46 allocated prednisone plus ciclosporin, and 33 (72%) of 46 administered prednisone plus methotrexate achieved a juvenile dermatomyositis PRINTO 20 improvement (p=0.0228). Median time to clinical remission was 41.9 months in patients assigned prednisone plus methotrexate but was not observable in the other two treatment groups (2.45 fold [95% CI 1.2-5.0] increase with prednisone plus methotrexate; p=0.012). Median time to treatment failure was 16.7 months in patients allocated prednisone, 53.3 months in those assigned prednisone plus ciclosporin, but was not observable in patients randomised to prednisone plus methotrexate (1.95 fold [95% CI 1.20-3.15] increase with prednisone; p=0.009). Median time to prednisone discontinuation was 35.8 months with prednisone alone compared with 29.4-29.7 months in the combination groups (p=0.002). A significantly greater proportion of patients assigned prednisone plus ciclosporin had adverse events, affecting the skin and subcutaneous tissues, gastrointestinal system, and general disorders. Infections and infestations were significantly increased in patients assigned prednisone plus ciclosporin and prednisone plus methotrexate. No patients died during the study. INTERPRETATION: Combined treatment with prednisone and either ciclosporin or methotrexate was more effective than prednisone alone. The safety profile and steroid-sparing effect favoured the combination of prednisone plus methotrexate. FUNDING: Italian Agency of Drug Evaluation, Istituto Giannina Gaslini (Genoa, Italy), Myositis Association (USA). PMID- 26645194 TI - Hair-bundle proteomes of avian and mammalian inner-ear utricles. AB - Examination of multiple proteomics datasets within or between species increases the reliability of protein identification. We report here proteomes of inner-ear hair bundles from three species (chick, mouse, and rat), which were collected on LTQ or LTQ Velos ion-trap mass spectrometers; the constituent proteins were quantified using MS2 intensities, which are the summed intensities of all peptide fragmentation spectra matched to a protein. The data are available via ProteomeXchange with identifiers PXD002410 (chick LTQ), PXD002414 (chick Velos), PXD002415 (mouse Velos), and PXD002416 (rat LTQ). The two chick bundle datasets compared favourably to a third, already-described chick bundle dataset, which was quantified using MS1 peak intensities, the summed intensities of peptides identified by high-resolution mass spectrometry (PXD000104; updated analysis in PXD002445). The mouse bundle dataset described here was comparable to a different mouse bundle dataset quantified using MS1 intensities (PXD002167). These six datasets will be useful for identifying the core proteome of vestibular hair bundles. PMID- 26645195 TI - Wrongful Convictions: Understanding the Experiences of the Original Crime Victims. AB - Over the past 3 decades, significant strides have been made to identify and assist wrongfully convicted individuals in gaining their freedom and transitioning to life after exoneration. However, little is known about the experiences of the original crime victims during this process. The impact of wrongful convictions on victims has not been empirically researched; most of what is known has been provided anecdotally by stakeholders working with victims, and in a few instances, by victims themselves (e.g., Jenkins, 2009; Levey, 2004; Thompson-Cannino, Cotton, & Torneo, 2009). In an effort to begin to fill this gap in knowledge, ICF International conducted in-depth studies of 11 cases to identify the shared experiences and service needs of victims across cases of wrongful conviction. PMID- 26645197 TI - Postpartum contraception: a missed opportunity to prevent unintended pregnancy and short inter-pregnancy intervals. AB - BACKGROUND: Women in the postpartum period need effective contraception. Unintended pregnancies soon after childbirth may lead to abortion or short inter pregnancy intervals associated with adverse outcomes. Using databases for a 6 month period (September 2013-February 2014) we examined the proportion of women attending for abortion in Edinburgh, Scotland who had given birth in the preceding 12 months, and the proportion of women giving birth in this region after an inter-pregnancy interval of 12 months or less. We also surveyed 250 women prior to discharge from the same maternity service about their contraceptive intentions. RESULTS: Some 75/1175 (6.4%) attending for abortion had given birth within the preceding 12 months and 332/4713 (7.0%) postpartum women gave birth following an inter-pregnancy interval of 12 months or less. When considering parous women, percentages were 13.3% and 13.9%, respectively. The majority (n=237, 96.7%) of postpartum women were not planning another pregnancy within the year but only a minority (n=32, 12.8%) were planning on using long acting reversible contraception (LARC), namely the implant or intrauterine device. However, 42.8% (n=107) indicated that if the implant or intrauterine contraception could be inserted before they left hospital then they would choose these methods (p<0.0001). DISCUSSION: Almost one in thirteen women in our population presenting for abortion or giving birth has conceived within 1 year of giving birth. Provision of LARC immediately postpartum appears to be an attractive option to mothers, and could be an important strategy to prevent unintended pregnancy and short inter-pregnancy intervals. PMID- 26645198 TI - Comparison of uptake of long-acting reversible contraception after abortion from a hospital or a community sexual and reproductive healthcare setting: an observational study. AB - BACKGROUND: Uptake of the most effective long-acting reversible methods of contraception (LARC) immediately after abortion has been shown to reduce a woman's risk of further abortion. We aimed to compare the uptake of LARC at abortion services from a hospital department of obstetrics and gynaecology and a specialist contraceptive setting of a community sexual and reproductive health (SRH) service within the same city. METHODS: Retrospective database review of women (n=2473) requesting abortion who were assessed at either a community SRH service or a hospital department of obstetrics and gynaecology, in the same UK city over a period of 1 year. The main outcome measures were immediate post abortal uptake of LARC from each site. RESULTS: A higher proportion of women assessed at the SRH service received LARC after abortion [50.2%; 95% confidence interval (CI) 0.47-0.53%] compared to those attending the hospital site (39.2%; 95% CI 0.36-0.42%; p<0.0001). Amongst women having an outpatient early medical abortion, LARC uptake at the SRH was twice that of the hospital setting (48.4% vs 23.3%; p<0.0001). CONCLUSIONS: Higher uptake of immediate post-abortal LARC was observed amongst women who were assessed at the specialist contraceptive service in the community SRH setting compared to the hospital setting. Further research is required to determine the reasons for these observations since all abortion services should provide the same high-quality contraceptive service to women undergoing abortion. PMID- 26645196 TI - Loss of PTEN Promotes Resistance to T Cell-Mediated Immunotherapy. AB - T cell-mediated immunotherapies are promising cancer treatments. However, most patients still fail to respond to these therapies. The molecular determinants of immune resistance are poorly understood. We show that loss of PTEN in tumor cells in preclinical models of melanoma inhibits T cell-mediated tumor killing and decreases T-cell trafficking into tumors. In patients, PTEN loss correlates with decreased T-cell infiltration at tumor sites, reduced likelihood of successful T cell expansion from resected tumors, and inferior outcomes with PD-1 inhibitor therapy. PTEN loss in tumor cells increased the expression of immunosuppressive cytokines, resulting in decreased T-cell infiltration in tumors, and inhibited autophagy, which decreased T cell-mediated cell death. Treatment with a selective PI3Kbeta inhibitor improved the efficacy of both anti-PD-1 and anti-CTLA-4 antibodies in murine models. Together, these findings demonstrate that PTEN loss promotes immune resistance and support the rationale to explore combinations of immunotherapies and PI3K-AKT pathway inhibitors. SIGNIFICANCE: This study adds to the growing evidence that oncogenic pathways in tumors can promote resistance to the antitumor immune response. As PTEN loss and PI3K-AKT pathway activation occur in multiple tumor types, the results support the rationale to further evaluate combinatorial strategies targeting the PI3K-AKT pathway to increase the efficacy of immunotherapy. PMID- 26645199 TI - From ratites to rats: the size of fleshy fruits shapes species' distributions and continental rainforest assembly. AB - Seed dispersal is a key process in plant spatial dynamics. However, consistently applicable generalizations about dispersal across scales are mostly absent because of the constraints on measuring propagule dispersal distances for many species. Here, we focus on fleshy-fruited taxa, specifically taxa with large fleshy fruits and their dispersers across an entire continental rainforest biome. We compare species-level results of whole-chloroplast DNA analyses in sister taxa with large and small fruits, to regional plot-based samples (310 plots), and whole-continent patterns for the distribution of woody species with either large (more than 30 mm) or smaller fleshy fruits (1093 taxa). The pairwise genomic comparison found higher genetic distances between populations and between regions in the large-fruited species (Endiandra globosa), but higher overall diversity within the small-fruited species (Endiandra discolor). Floristic comparisons among plots confirmed lower numbers of large-fruited species in areas where more extreme rainforest contraction occurred, and re-colonization by small-fruited species readily dispersed by the available fauna. Species' distribution patterns showed that larger-fruited species had smaller geographical ranges than smaller fruited species and locations with stable refugia (and high endemism) aligned with concentrations of large fleshy-fruited taxa, making them a potentially valuable conservation-planning indicator. PMID- 26645200 TI - Nucleolar dominance and maternal control of 45S rDNA expression. AB - Using a system of interspecies hybrids, trihybrids, and recombinants with varying proportions of genomes from three distinct Xenopus species, we provide evidence for de novo epigenetic silencing of paternal 45 S ribosomal ribonucleic acid (rRNA) genes and their species-dependent expression dominance that escapes transcriptional inactivation after homologous recombination. The same pattern of imprinting is maintained in the offspring from mothers being genetic males (ZZ) sex-reversed to females, indicating that maternal control of ribosomal deoxyribonucleic acid (rDNA) expression is not sex-chromosome linked. Nucleolar dominance (nucleolus underdevelopment) in Xenopus hybrids appears to be associated with a major non-Mendelian reduction in the number of 45 S rDNA gene copies rather than a specific pattern of their expression. The loss of rRNA gene copies in F1 hybrids was non-random with respect to the parental species, with the transcriptionally dominant variant preferentially removed from hybrid zygotes. This dramatic disruption in the structure and function of 45 S rDNA impacts transcriptome patterns of small nucleolar RNAs and messenger RNAs, with genes from the ribosome and oxidative stress pathways being among the most affected. Unorthodoxies of rDNA inheritance and expression may be interpreted as hallmarks of genetic conflicts between parental genomes, as well as defensive epigenetic mechanisms employed to restore genome integrity. PMID- 26645201 TI - Micro-scale environmental variation amplifies physiological variation among individual mussels. AB - The contributions of temporal and spatial environmental variation to physiological variation remain poorly resolved. Rocky intertidal zone populations are subjected to thermal variation over the tidal cycle, superimposed with micro scale variation in individuals' body temperatures. Using the sea mussel (Mytilus californianus), we assessed the consequences of this micro-scale environmental variation for physiological variation among individuals, first by examining the latter in field-acclimatized animals, second by abolishing micro-scale environmental variation via common garden acclimation, and third by restoring this variation using a reciprocal outplant approach. Common garden acclimation reduced the magnitude of variation in tissue-level antioxidant capacities by approximately 30% among mussels from a wave-protected (warm) site, but it had no effect on antioxidant variation among mussels from a wave-exposed (cool) site. The field-acclimatized level of antioxidant variation was restored only when protected-site mussels were outplanted to a high, thermally stressful site. Variation in organismal oxygen consumption rates reflected antioxidant patterns, decreasing dramatically among protected-site mussels after common gardening. These results suggest a highly plastic relationship between individuals' genotypes and their physiological phenotypes that depends on recent environmental experience. Corresponding context-dependent changes in the physiological mean variance relationships within populations complicate prediction of responses to shifts in environmental variability that are anticipated with global change. PMID- 26645202 TI - Equal temperature-size responses of the sexes are widespread within arthropod species. AB - Sexual size dimorphism (SSD) is often affected by environmental conditions, but the effect of temperature on SSD in ectotherms still requires rigorous investigation. We compared the plastic responses of size-at-maturity to temperature between males and females within 85 diverse arthropod species, in which individuals of both sexes were reared through ontogeny under identical conditions with excess food. We find that the sexes show similar relative (proportional) temperature-body size (T-S) responses on average. The high degree of similarity occurs despite an analysis that includes a wide range of animal body sizes, variation in degree of SSD and differences in the sign of the T-S response. We find no support for Rensch's rule, which predicts greater variation in male size, or indeed the reverse, greater female size variation. SSD shows no systematic temperature dependence in any of the 17 arthropod orders examined, five of which (Diptera, Orthoptera, Lepidoptera, Coleoptera and Calanoida) include more than six thermal responses. We suggest that the same proportional T S response may generally have equivalent fitness costs and benefits in both sexes. This contrasts with effects of juvenile density, and food quantity/quality, which commonly result in greater size plasticity in females, suggesting these variables have different adaptive effects on SSD. PMID- 26645203 TI - Childhood Blood Lead Levels and Symptoms of Attention Deficit Hyperactivity Disorder (ADHD): A Cross-Sectional Study of Mexican Children. AB - BACKGROUND: Previous studies suggest that blood lead levels are positively associated with attention deficit/hyperactivity disorder (ADHD) and ADHD-symptoms in children. However, the associations between lead exposure and ADHD subtypes are inconsistent and understudied. OBJECTIVE: The objective of this study was to explore the association of low-level concurrent lead exposure with subtypes of ADHD symptoms in 578 Mexican children 6-13 years of age. METHODS: We measured concurrent blood lead levels using inductively coupled plasma mass spectrometry (ICPMS). We administered the Conners' Rating Scales-Revised (CRS-R) to mothers to evaluate their children's ADHD symptoms. We used imputation to fill missing values in blood lead levels and used segmented regression models adjusted for relevant covariates to model the nonlinear relationship between blood lead and ADHD symptoms. RESULTS: Mean +/- SD blood lead levels were 3.4 +/- 2.9 MUg/dL. In adjusted models, a 1-MUg/dL increase in blood lead was positively associated with Hyperactivity and Restless-Impulsivity scores on the CRS-R scale and Hyperactivity-Impulsivity scores on the CRS-R scale of the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, but only in children with blood lead level <= 5 MUg/dL. Blood lead was not associated with Inattentive symptoms or overall ADHD behavior. CONCLUSIONS: In this population of Mexican children, current blood lead level among children with low exposure (<= 5 MUg/dL) was positively associated with hyperactive/impulsive behaviors, but not with inattentiveness. These results add to the existing evidence of lead-associated neurodevelopmental deficits at low levels of exposure. CITATION: Huang S, Hu H, Sanchez BN, Peterson KE, Ettinger AS, Lamadrid-Figueroa H, Schnaas L, Mercado Garcia A, Wright RO, Basu N, Cantonwine DE, Hernandez-Avila M, Tellez-Rojo MM. 2016. Childhood blood lead levels and symptoms of attention deficit hyperactivity disorder (ADHD): a cross-sectional study of Mexican children. Environ Health Perspect 124:868-874; http://dx.doi.org/10.1289/ehp.1510067. PMID- 26645205 TI - Erratum to: AMPD1 regulates mTORC1-p70 S6 kinase axis in the control of insulin sensitivity in skeletal muscle. PMID- 26645204 TI - Correlates of poor glycemic control among patients with diabetes initiating hemodialysis for end-stage renal disease. AB - BACKGROUND: Maintaining tight glycemic control is important for prevention of diabetes-related outcomes in end-stage renal disease patients with diabetes, especially in light of their poor prognosis. This study aimed to determine factors associated with poor glycemic control among U.S. patients with diabetes mellitus initiating hemodialysis for end-stage renal disease. METHODS: Using data from the U.S. Renal Data System, electronic health records of a large national dialysis provider, and U.S. Census data, we performed a cross-sectional multivariable Poisson regression analysis to characterize risk factors associated with poor glycemic control, defined as glycated hemoglobin (HbA1c) > 7 vs. <= 7 %, in adult patients with diabetes who initiated hemodialysis at an outpatient facility between 2006 and 2011. RESULTS: Of 16,297 patients with diabetes, 21.2 % had HbA1c >7 %. In multivariable analysis, younger patients, patients of Native American race, and those of Hispanic ethnicity had higher prevalence of poor glycemic control. Independent correlates of poor glycemic control further included higher platelet count, white blood cell count, and ferritin; higher body mass index, systolic blood pressure, total cholesterol and triglyceride concentrations; lower HDL and albumin concentrations; lower normalized protein catabolic rate; and higher estimated glomerular filtration rate at initiation of dialysis (all P < 0.05). No independent associations were found with area-level socioeconomic indicators. Occurrence of diabetes in patients < 40 years of age, a proxy for type 1 diabetes, was associated with poor HbA1c control compared with that in patients >= 40 years of age, which was classified as type 2 diabetes. These findings were robust to the different outcome definitions of HbA1c > 7.5 % and > 8 %. CONCLUSION: In this cohort of incident end-stage renal disease patients with diabetes, poor glycemic control was independently associated with younger age, Native American race, Hispanic ethnicity, higher body mass index, and clinical risk factors including atherogenic lipoprotein profile, hypertension, inflammation, and markers indicative of malnutrition and a more serious systemic disease. PMID- 26645206 TI - Cue-induced striatal activity in frequent cannabis users independently predicts cannabis problem severity three years later. AB - Cannabis is the most frequently used illicit drug worldwide, but little is known about the mechanisms underlying continued cannabis use. Cue-reactivity (the physical, psychological, behavioural and neural reaction to substance-related cues) might be related to continued cannabis use. In this 3-year prospective neuroimaging study we investigated whether cannabis cue-induced brain activity predicted continued cannabis use and associated problem severity 3 years later. In addition, baseline brain activations were compared between dependent and non dependent cannabis users at follow-up. Analyses were focussed on brain areas known to be important in cannabis cue-reactivity: anterior cingulate cortex, orbitofrontal cortex, ventral tegmental area, amygdala and striatum. At baseline, 31 treatment-naive frequent cannabis users performed a cue-reactivity functional magnetic resonance imaging task. Of these participants, 23 completed the 3-year follow-up. None of the cue-induced region of interest activations predicted the amount of cannabis use at follow-up. However, cue-induced activation in the left striatum (putamen) significantly and independently predicted problem severity at follow-up (p < 0.001) as assessed with the Cannabis Use Disorder Identification Test. Also, clinically dependent cannabis users at follow-up showed higher baseline activation at trend level in the left striatum compared with non dependent users. This indicates that neural cue-reactivity in the dorsal striatum is an independent predictor of cannabis use-related problems. Given the relatively small sample size, these results are preliminary and should be replicated in larger samples of cannabis users. PMID- 26645207 TI - Effect of short-term escitalopram treatment on neural activation during emotional processing. AB - Recent functional magnetic resonance (fMRI) imaging studies have revealed that subchronic medication with escitalopram leads to significant reduction in both amygdala and medial frontal gyrus reactivity during processing of emotional faces, suggesting that escitalopram may have a distinguishable modulatory effect on neural activation as compared with other serotonin-selective antidepressants. In this fMRI study we aimed to explore whether short-term medication with escitalopram in healthy volunteers is associated with reduced neural response to emotional processing, and whether this effect is predicted by drug plasma concentration. The neural response to fearful and happy faces was measured before and on day 7 of treatment with escitalopram (10mg) in 15 healthy volunteers and compared with those in a control unmedicated group (n=14). Significantly reduced activation to fearful, but not to happy facial expressions was observed in the bilateral amygdala, cingulate and right medial frontal gyrus following escitalopram medication. This effect was not correlated with plasma drug concentration. In accordance with previous data, we showed that escitalopram exerts its rapid direct effect on emotional processing via attenuation of neural activation in pathways involving medial frontal gyrus and amygdala, an effect that seems to be distinguishable from that of other SSRIs. PMID- 26645208 TI - The FKBP5 polymorphism rs1360780 influences the effect of an algorithm-based antidepressant treatment and is associated with remission in patients with major depression. AB - OBJECTIVE: The FKBP5-gene influences the HPA-system by modulating the sensitivity of the glucocorticoid receptor (GR). The polymorphism rs1360780 has been associated with response in studies with heterogeneous antidepressant treatment. In contrast, several antidepressant studies with standardized antidepressant treatment could not detect this effect. We therefore compared patients with standardized vs naturalistic antidepressant treatment to (a) investigate a possible interaction between FKBP5-genotype and treatment mode and (b) replicate the effect of the FKBP5-genotype on antidepressant treatment outcome. METHODS: A total of 298 major depressive disorder (MDD) inpatients from the multicentred German project and the Zurich Algorithm Project were genotyped for their FKBP5 status. Patients were treated as usual (n=127) or according to a standardized algorithm (n=171). Main outcome criteria was remission (Hamilton Depression Rating Scale-21<10). RESULTS: We detected an interaction of treatment as usual (TAU) treatment and C-allele with the worst outcome for patients combining those two factors (HR=0.46; p=0.000). Even though C-allele patients did better when treated in the structured, stepwise treatment algorithm (SSTR) group, we still could confirm the influence of the FKBP5-genotype in the whole sample (HR=0.52; p=0.01). CONCLUSIONS: This is the first study to show an interaction between a genetic polymorphism and treatment mode. Patients with the C-allele of the rs1360780 polymorphism seem to benefit from a standardized antidepressant treatment. PMID- 26645210 TI - Erratum. AB - Erratum for Psychomotor effects, pharmacokinetics and safety of the orexin receptor antagonist suvorexant administered in combination with alcohol in healthy subjects by Hong Sun, Ka Lai Yee, Sean Gill, Wen Liu, Xiaodong Li, Deborah Panebianco, Eric Mangin, Dennis Morrison, Jacqueline McCrea, John A Wagner, and Matthew D Troyer. J Psychopharmacol November 2015 29: 1159-1169, first published on October 13, 2015 doi:10.1177/0269881115609015In the print issue of the journal, on page1165 of the article, panels (c) and (d) of Figure 1 are duplicates. The references (contained in the results section of the publication, page 1164) to Figure 1 are incorrect.Please refer to the online version for the corrected version. PMID- 26645209 TI - A double-blind, placebo-controlled, randomized withdrawal study of lurasidone for the maintenance of efficacy in patients with schizophrenia. AB - OBJECTIVE: To evaluate the effectiveness of lurasidone as maintenance treatment for schizophrenia. METHOD: Adults experiencing an acute exacerbation of schizophrenia initially received 12-24 weeks of open-label treatment with lurasidone (40-80 mg/d, flexibly dosed). Patients who maintained clinical stability for ?12 weeks were randomized in double-blind fashion to placebo or lurasidone (40-80 mg/d, flexibly dosed) for an additional 28-week treatment period. The primary efficacy endpoint was time to relapse (based on Kaplan-Meier survival analysis). RESULTS: A total of 676 patients enrolled in the open-label phase; 285 met protocol-specified stabilization criteria and were randomized to lurasidone (N=144) or placebo (N=141). During the open-label phase, mean Positive and Negative Syndrome Scale total score decreased from 90.1 to 54.4 in patients who met clinical stability criteria and were randomized. In the double-blind phase, lurasidone significantly delayed time to relapse compared with placebo (log-rank test, p=0.039), reflecting a 33.7% reduction in risk of relapse (Cox hazard ratio (95% confidence interval), 0.663 (0.447-0.983); p=0.041). Probability of relapse at the double-blind week 28 endpoint (based on Kaplan Meier analysis) was 42.2% in the lurasidone group and 51.2% in the placebo group. Minimal changes in weight, lipid, glucose, and prolactin were observed throughout the study. CONCLUSIONS: This multicenter, placebo-controlled, randomized withdrawal study demonstrated the efficacy of lurasidone for the maintenance treatment of patients with schizophrenia. PMID- 26645211 TI - Efficient extraction of small and large RNAs in bacteria for excellent total RNA sequencing and comprehensive transcriptome analysis. AB - BACKGROUND: Next-generation transcriptome sequencing (RNA-Seq) has become the standard practice for studying gene splicing, mutations and changes in gene expression to obtain valuable, accurate biological conclusions. However, obtaining good sequencing coverage and depth to study these is impeded by the difficulties of obtaining high quality total RNA with minimal genomic DNA contamination. With this in mind, we evaluated the performance of Phenol-free total RNA purification kit (Amresco) in comparison with TRI Reagent (MRC) and RNeasy Mini (Qiagen) for the extraction of total RNA of Pseudomonas aeruginosa which was grown in glucose-supplemented (control) and polyethylene-supplemented (growth-limiting condition) minimal medium. All three extraction methods were coupled with an in-house DNase I treatment before the yield, integrity and size distribution of the purified RNA were assessed. RNA samples extracted with the best extraction kit were then sequenced using the Illumina HiSeq 2000 platform. RESULTS: TRI Reagent gave the lowest yield enriched with small RNAs (sRNAs), while RNeasy gave moderate yield of good quality RNA with trace amounts of sRNAs. The Phenol-free kit, on the other hand, gave the highest yield and the best quality RNA (RIN value of 9.85 +/- 0.3) with good amounts of sRNAs. Subsequent bioinformatic analysis of the sequencing data revealed that 5435 coding genes, 452 sRNAs and 7 potential novel intergenic sRNAs were detected, indicating excellent sequencing coverage across RNA size ranges. In addition, detection of low abundance transcripts and consistency of their expression profiles across replicates from the same conditions demonstrated the reproducibility of the RNA extraction technique. CONCLUSIONS: Amresco's Phenol-free Total RNA purification kit coupled with DNase I treatment yielded the highest quality RNAs containing good ratios of high and low molecular weight transcripts with minimal genomic DNA. These RNA extracts gave excellent non-biased sequencing coverage useful for comprehensive total transcriptome sequencing and analysis. Furthermore, our findings would be useful for those interested in studying both coding and non coding RNAs from precious bacterial samples cultivated in growth-limiting condition, in a single sequencing run. PMID- 26645212 TI - A human 3'UTR clone collection to study post-transcriptional gene regulation. AB - BACKGROUND: 3'untranslated regions (3'UTRs) are poorly understood portions of eukaryotic mRNAs essential for post-transcriptional gene regulation. Sequence elements in 3'UTRs can be target sites for regulatory molecules such as RNA binding proteins and microRNAs (miRNAs), and these interactions can exert significant control on gene networks. However, many such interactions remain uncharacterized due to a lack of high-throughput (HT) tools to study 3'UTR biology. HT cloning efforts such as the human ORFeome exemplify the potential benefits of genomic repositories for studying human disease, especially in relation to the discovery of biomarkers and targets for therapeutic agents. Currently there are no publicly available human 3'UTR libraries. To address this we have prepared the first version of the human 3'UTRome (h3'UTRome v1) library. The h3'UTRome is produced to a single high quality standard using the same recombinational cloning technology used for the human ORFeome, enabling universal operating methods and high throughput experimentation. The library is thoroughly sequenced and annotated with simple online access to information, and made publically available through gene repositories at low cost to all scientists with minimal restriction. RESULTS: The first release of the h3'UTRome library comprises 1,461 human 3'UTRs cloned into Gateway(r) entry vectors, ready for downstream analyses. It contains 3'UTRs for 985 transcription factors, 156 kinases, 171 RNA binding proteins, and 186 other genes involved in gene regulation and in disease. We demonstrate the feasibility of the h3'UTRome library by screening a panel of 87 3'UTRs for targeting by two miRNAs: let-7c, which is implicated in tumorigenesis, and miR-221, which is implicated in atherosclerosis and heart disease. The panel is enriched with genes involved in the RAS signaling pathway, putative novel targets for the two miRNAs, as well as genes implicated in tumorigenesis and heart disease. CONCLUSIONS: The h3'UTRome v1 library is a modular resource that can be utilized for high-throughput screens to identify regulatory interactions between trans-acting factors and 3'UTRs, Importantly, the library can be customized based on the specifications of the researcher, allowing the systematic study of human 3'UTR biology. PMID- 26645213 TI - Screening for Helicobacter pylori in Idiopathic Pulmonary Fibrosis Lung Biopsies. AB - BACKGROUND: Increasing evidence suggests a role of gastro-oesophageal reflux (GER) in idiopathic pulmonary fibrosis (IPF) pathogenesis. Recently, an association between serum Helicobacter pylori (HP) antibody positivity and more severe disease was described, but HP has not been directly analysed in lung tissue so far. OBJECTIVE: To investigate the presence of HP in the lung tissue of IPF patients. METHODS: Two tertiary interstitial lung disease care centre databases were screened for available lung biopsy material from IPF patients. Clinical and radiological data, including presence of GER and antiacid medication, were evaluated. HP-specific PCR was carried out on the IPF lung biopsy specimens. RESULTS: A total of 39 IPF patients were included, of whom 85% were male. The patients' median age was 66 years, their vital capacity was 79% predicted, and their diffusing capacity for carbon monoxide was 53% predicted. In all, 82% of the lung biopsies were surgical and 18% transbronchial. Comorbidities were GER disease in 23% (n = 9), sleep apnoea in 13% (n = 5) and hiatal hernia in 38% of the cases (n = 15). Proton pump inhibitors were prescribed at the time of biopsy in 21% of the cases (n = 9). After a median follow-up of 25 months (range 6-69), there were 1 death, 1 lung transplantation and 8 acute exacerbations without relevant differences between the GER and non-GER subgroups. HP DNA was not detected in any of the lung tissue samples. CONCLUSION: The fact that no HP DNA was detected in the lung tissues calls into question the proposed relevance of HP to the direct pathogenesis of IPF. PMID- 26645214 TI - Megacystis Microcolon Intestinal Hypoperistalsis Syndrome: Case Reports and Discussion of the Literature. AB - Megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) is a rare intestinal dysmotility condition that also involves a dilated urinary bladder. It was believed to be an autosomal recessive condition, but genetic studies have suggested possibly an autosomal dominant inheritance pattern. Prenatal diagnosis can be challenging, but MRI and amniotic fluid/digestive fluid studies may be complementary investigations to improve diagnostic accuracy. Prognosis of MMIHS is generally poor and treatment is mostly supportive. To date, bowel transplantation remains the only viable treatment to restore bowel motility. Here we present two additional cases to contribute towards the scant literature on this condition. PMID- 26645215 TI - Incidental finding of Chilaiditi's sign in an elderly individual with sarcopenia. PMID- 26645216 TI - Short-term exposure to high levels of air pollution (nickel) and the risk of acute unprovoked proximal deep vein thrombosis in the legs. PMID- 26645217 TI - A perioperative strategy for abdominal aortic aneurysm in patients with chronic renal insufficiency. AB - PURPOSE: The outcomes of open surgical repair (OR) or endovascular aneurysm repair (EVAR) for abdominal aortic aneurysm (AAA) are favorable; however, pre existing chronic renal insufficiency (CRI) is considered to be a risk factor that can affect the long-term outcome. We evaluated our surgical strategy for AAA in patients with CRI by analyzing their pre- and postoperative renal function. METHODS: We conducted a retrospective chart review of CRI patients who underwent OR (n = 28) or EVAR (n = 31) for infra-renal AAA in our institution between 2009 and 2013. Our operative strategy included pre- and postoperative adequate hydration, postoperative diuretics and low-dose dopamine for both groups, intravascular ultrasonography and carbon dioxide angiography to reduce the amount of contrast media needed in the EVAR group, and occasional intraoperative mannitol for the OR group. RESULTS: The preoperative estimated glomerular filtration rate (eGFR) increased significantly in the postoperative period and remained similar 6 months later in both groups, without any difference in changes between the groups. In-hospital postoperative complications included leg occlusion in one EVAR patient. There were no complication-related deaths in either group. CONCLUSIONS: Postoperative renal function was similar after the two approaches, indicating that both procedures could be performed safely using our strategy for patients with CRI. PMID- 26645218 TI - Studies of Luminescence Performance on Carbazole Donor and Quinoline Acceptor Based Conjugated Polymer. AB - We report on the synthesis of conjugated polymer (CV-QP) containing carbazole (donor) and quinoline (acceptor) using Wittig methodology. The structural, optical and thermal properties of the polymer were investigated by FT-IR, NMR, GPC, UV, PL, cyclic voltammetry, atomic force microscopy (AFM) and thermogravimetric analysis (TGA). The polymer exhibits thermal stability upto 200 degrees C and shows good solubility in common organic solvents. The polymer has optical absorption band in a thin film at 360 nm and emission band formed at 473 nm. The optical energy band gap was found to be 2.69 eV as calculated from the onset absorption edge. Fluorescence quenching of the polymer CV-QP was found by using DMA (electron donor) and DMTP (electron acceptor). AFM image indicated that triangular shaped particles were observed and the particle size was found as 1.1 MUm. The electrochemical studies of CV-QP reveal that, the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) energy levels of the CV-QP are 6.35 and 3.70 eV, which indicated that the polymers are expected to provide charge transporting properties for the development of polymer light-emitting diodes (PLEDs). PMID- 26645220 TI - Erratum to: A Latent Class Analysis of Heterosexual Young Men's Masculinities. PMID- 26645219 TI - Electron Transfer Studies of Ruthenium(II) Complexes with Biologically Important Phenolic Acids and Tyrosine. AB - The ruthenium(II) complexes having 2,2'-bipyridine and phenanthroline derivatives are synthesized and characterized. The photophysical properties of these complexes at pH 12.5 are studied. The electron transfer reaction of biologically important phenolic acids and tyrosine are studied using absorption, emission and transient absorption spectral techniques. Semiclassical theory is applied to calculate the rate of electron transfer between ruthenium(II) complexes and biologically important phenolic acids. PMID- 26645222 TI - Non-Infectious Uveitis: Optimising the Therapeutic Response. AB - Non-infectious uveitis mainly affects the working-age population and can contribute to significant social and economic burden. It comprises a heterogeneous group of conditions with varied aetiology. Precise and early diagnosis, excluding masquerade syndromes, is the key to early therapeutic intervention. Treatment should be appropriately selected according to the anatomical sites of inflammation, the diagnosis and known prognosis, and whether there is a systemic inflammatory drive. Corticosteroids in the form of local or systemic therapy form the mainstay of treatment; however, due to unacceptable side effects, the need for long-term use or suboptimal response, corticosteroid sparing medications may need to be considered early on in the management of non infectious uveitis. With newer insights into the immunopathology of uveitis and the availability of biologic agents, treatment can be tailored according to individual needs. Many patients have systemic involvement, and hence a multidisciplinary approach is often required to achieve the best outcome in an individual. Patient involvement in the management of non-infectious uveitis, ensuring compliance, and continual monitoring of both the treatment and therapeutic response are the key to achieving optimal outcomes. PMID- 26645223 TI - Therapies to Preserve beta-Cell Function in Type 1 Diabetes. AB - In spite of modern techniques, the burden for patients with type 1 diabetes mellitus will not disappear, and type 1 diabetes will remain a life-threatening disease causing severe complications and increased mortality. We have to learn of ways to stop the destructive process, preserve residual insulin secretion or even improve the disease via beta-cell regeneration. This will give a milder disease, a more stable metabolism, simpler treatment and perhaps even cure. Therapies based on single drugs have not shown sufficient efficacy; however, there are several treatments with encouraging efficacy and no apparent, or rather mild, adverse events. As the disease process is heterogeneous, treatments have to be chosen to fit relevant subgroups of patients, and step by step efficacy can possibly be improved by the use of combination therapies. Thus immunosuppressive therapies like anti-CD3 and anti-CD20 monoclonal antibodies might be combined with fusion proteins such as etanercept [tumor necrosis factor (TNF)-alpha inhibitor] and/or abatacept (CTLA4-Ig) early after onset to stop the destructive process, supported by beta-cell protective agents. The effect may be prolonged by using autoantigen therapy [glutamate decarboxylase (GAD) proinsulin], and by adding agents facilitating beta-cell regeneration [e.g. glucagon-like peptide-1 (GLP-1)] there should be a good chance to make the disease milder, perhaps leading to cure in some patients. PMID- 26645224 TI - Minocycline protects against lipopolysaccharide-induced cognitive impairment in mice. AB - RATIONALE: The role of glial cells, especially microglia and astrocytes, in neuroinflammation and cognition has been studied intensively. Lipopolysaccharide (LPS), a commonly used inducer of neuroinflammation, can cause cognitive impairment. Minocycline is known to possess potent neuroprotective activity, but its effect on LPS-induced cognitive impairment is unknown. OBJECTIVES: This study aims to investigate the effects of minocycline on LPS-induced cognitive impairment and glial cell activation in mice. METHODS: Behavioral tests were conducted for cognitive function, immunohistochemistry for microglial and astrocyte response, and quantitative PCR for mRNA expression of proinflammatory cytokines. RESULTS: Minocycline significantly reversed the decreased spontaneous alternation induced by intrahippocampal administration of LPS in the Y-maze task. In the Morris water maze place navigation test, minocycline decreased the escape latency and distance traveled compared to LPS-treated mice. In the probe test, minocycline-treated mice spent more time in the target quadrant and crossed the platform area more frequently than animals in the LPS-treated group. Minocycline produced a significant decrease in the number of Iba-1- and GFAP-positive hippocampal cells compared to the LPS-treated group. Minocycline-treated mice had significantly reduced hippocampal TNF-alpha and IL-1beta mRNA levels compared with LPS-treated animals. Minocycline caused a significant increase in hippocampal BDNF expression compared to the LPS-treated group. CONCLUSIONS: Minocycline can attenuate LPS-induced cognitive impairments in mice. This effect may be associated with its action to suppress the activation of microglia and astrocytes and to normalize BDNF expression. Since neuroinflammatory processes and cognitive impairments are implicated in neurodegenerative disorders, minocycline may be a promising candidate for treating such diseases. PMID- 26645225 TI - Altered cognitive response to serotonin challenge as a candidate endophenotype for obsessive-compulsive disorder. AB - RATIONALE: Obsessive-compulsive disorder (OCD) implicates dysfunction of orbitofrontal and insula-related circuitry and of the serotonin system. There is an on-going search in psychiatry for intermediate biological markers, termed 'endophenotypes', that exist not only in patients with a given disorder but also in their clinically unaffected first-degree relatives. OBJECTIVE: Pharmacological challenge is recognized as a means of eliciting an endophenotype, but this strategy has yet to be used in OCD. METHODS: Twenty-three OCD patients without comorbidities (12 [52.2 %] female), 13 clinically asymptomatic first-degree relatives of OCD patients (11 [84.6 %] female) and 27 healthy controls (16 [59.3 %] female) received single-dose escitalopram (20 mg) and placebo in a randomized double-blind crossover design. Effects of treatment on decision-making were quantified using the Cambridge Gamble Task (CGT) in conjunction with a mixed model analysis of covariance (ANCOVA). RESULTS: There was a significant interaction between serotonergic challenge and group for risk adjustment on the CGT (F = 4.1406; p = 0.02). Only controls showed a significant placebo-drug change in risk adjustment (p = 0.02; versus p > 0.10). Numerically, escitalopram was associated with increase in risk adjustment in controls and reductions in the other groups. Change in risk adjustment was similar in OCD patients and relatives (p = 0.806) and differed significantly from controls (p = 0.007; p = 0.041, respectively). CONCLUSIONS: Individuals with OCD, and first-degree relatives, showed an altered cognitive response to serotonin challenge. This is the first demonstration of a candidate pharmacological challenge endophenotype for the disorder. Future work should confirm these findings in a larger sample size and ideally extend them to other cognitive paradigms, utilizing functional neuroimaging. PMID- 26645226 TI - End-Expiratory Volume and Oxygenation: Targeting PEEP in ARDS Patients. AB - INTRODUCTION: Changes in end-expiratory lung volume (?EELV) in response to changes in PEEP (?PEEP) have not been reported in mechanically ventilated patients with ARDS. The purpose of this study was to determine the utility of measurements of ?EELV in determining optimal PEEP in ARDS patients. METHODS: Nine patients with ARDS were prospectively recruited. ?EELV was measured using magnetometers during serial decremental PEEP trials. Changes in PaO2 (?PaO2) were simultaneously measured. Static respiratory system compliance (CRS), ?PaO2/?PEEP, and ?EELV/?PEEP were calculated at each level of PEEP. RESULTS: For the group, ?EELV decreased by 1.09 +/- 0.13 L (mean +/- SD) as PEEP was reduced from 20 to 0 cm H2O with the greatest changes in ?EELV occurring over the mid range of the decremental PEEP curve. Optimal values for CRS, ?EELV/?PEEP, and ?PaO2/?PEEP could be identified for each patient and occurred at PEEP levels ranging from 10 to 17.5 cm H2O. There was a significant correlation (r = 0.712, p = 0.047) between ?PaO2/?PEEP and ?EELV/?PEEP. CONCLUSIONS: ?EELV can be measured from a decremental PEEP curve. Since ?EELV is highly correlated with ?PaO2, measures of ?PaO2/?PEEP may provide a surrogate for measures of ?EELV/?PEEP. Combining measures of ?EELV/?PEEP with measures of CRS may provide a novel means of determining optimal PEEP in patients with ARDS. PMID- 26645227 TI - Air quality improvement during 2010 Asian games on blood coagulability in COPD patients. AB - Exposure to elevated levels of ambient air pollutants can lead to adverse cardiovascular effects. Perturbation of the coagulation balance is one of the potential mechanisms. However, evidence regarding the impact of improvement in air pollution on blood coagulability in COPD patients has never been reported. Coagulation processes are known to be of relevance for cardiovascular pathology; therefore, this study aimed to investigate the association of short-term air pollution exposure with blood marker (D-dimer) of coagulation. A 3-year (through the Asian game) cohort study based on the GIRD COPD Biobank Project was conducted in 36 COPD patients to estimate whether changes in measurements of D-dimer were associated with changes in pollutant concentration, comparing for 51 intervention days (November 1-December 21) in 2010 with the same calendar date of baseline years (2009 and 2011). Daily mean concentrations of air pollutants and meteorological variables were measured during the time. Daily PM10 decreased from 65.86 MUg/m(3) during the baseline period to 62.63 MUg/m(3) during the Asian Games period; daily NO2 decreased from 51.33 to 42.63 MUg/m(3). SO2 and other weather variables did not differ substantially. We did not observe statistically significant improvements in D-dimer levels by 9.86% from a pre-Asian game mean of 917 ng/ml to a during-Asian game mean of 1007 ng/ml, platelet number by 11.66%, PH by -0.15%, PCO2 by -6.54%, and PO2 by -1.16%. In the post-Asian game period, when pollutant concentrations increased, most outcomes approximated pre-Asian game levels, and similar effects were also demonstrated in D-dimer, platelet number, and arterial blood gas. For D-dimer and platelet number, we observed statistically significant increases associated with increases in NO2 at lag 1-3 and SO2 at lag 2-4. For PH, PCO2, and PO2, any significant effect was not demonstrated. This study gives no support to the hypothesis that reduction in air pollution levels during the 2010 Asian game is associated with activation of blood coagulation with COPD patients. However, one step forward has been made on the gap between improved air pollution and blood coagulability. Meanwhile, our study also provides evidence for the presence of a hypercoagulative state in systemic circulation in COPD patients. Additional studies employing other susceptible populations and endpoints are pending. PMID- 26645228 TI - Effects of spatiotemporal variation of soil salinity on fine root distribution in different plant configuration modes in new reclamation coastal saline field. AB - In order to study the effects of salinity on plant fine roots, we considered three different plant configuration modes (tree stand model (TSM), shrub stand model (SSM), and tree-shrub stand model (TSSM)). Soil samples were collected with the method of soil drilling. Significant differences of electrical conductivity (EC) in the soil depth of 0-60 cm were observed among the three modes (p < 0.05). In the above three modes, the variation of soil salinity among various soil layers and monthly variation of soil salinity were the highest in SSM and reached 2.30 and 2.23 mS/cm (EC1:5), respectively. Due to the effect of salinity, fine root biomass (FRB) showed significant differences in different soil depths (p < 0.05). More than 60% of FRB was concentrated in the soil depth above 30 cm. FRB showed exponential decline with soil depth (p < 0.05). FRB showed spatial heterogeneity in the 40-cm soil depth. In the above three modes, compared with FRB, specific root length (SRL) and fine root length density (FRLD) showed the similar changing trend. Fine roots showed significant seasonal differences among different modes (p < 0.05). FRB showed the bimodal variation and was the highest in July. However, we found that the high content of salts had obvious inhibitory effect on the distribution of FRB. Therefore, the salinity should be below 1.5 mS/cm, which was suitable for the growth of plant roots. Among the three modes, TSSM had the highest FRB, SRL, and FRLD and no obvious soil salt accumulation was observed. The results indicated that fine root biomass was affected by high salt and that TSSM had the strong effects of salt suppression and control. In our study, TSSM may be the optimal configuration mode for salt suppression and control in saline soil. PMID- 26645229 TI - Pollution characteristics and ecological risk assessment of HCHs and DDTs in estuary wetland sediments from the Bohai Bay, North China. AB - Hexachlorocyclohexanes (HCHs) and dichlorodiphenyltrichloroethanes (DDTs) tend to persist in the environment for long periods of time. The concentration and distribution of HCHs and DDTs were investigated in surface sediments of Yongdingxinhe wetland and Binhai wetland by gas chromatography-mass spectrometer (GC-MS). All isomers of HCHs and DDTs were detected in all of the samples. The concentrations of total HCHs (SigmaHCHs) in two wetland sediments ranged from 69.81 to 379.28 ng . g -1, with a mean value of 224.55 ng . g -1. The concentrations of total DDTs (SigmaDDTs) ranged from 98.32 to 129.10 ng . g -1, with a mean value of 113.71 ng . g -1. The results of an ecological risk assessment demonstrated that there was high-risk ecological effect of organochlorine pesticides (OCPs) on the estuary wetlands. Lindane and technical DDTs were found to be the main sources of OCPs. PMID- 26645230 TI - Impact of methionine on a partial-nitritation biofilter. AB - It has been demonstrated that an anaerobic digestion process cannot attain an efficient removal of several amino acids, with methionine being one of the most persistent of these. Thus, the effect that methionine amino acid has over the partial-nitritation process with fixed-biofilm configuration in terms of performance and bacterial community dynamics has been investigated. With respect to the performance with no addition, 100 mg/L methionine loading decreased ammonium oxidation efficiency in 60% and 100% at concentrations of 300 and 500 mg/L methionine, respectively. Bacterial biomass sharply increased by 30, 65, and 230% with the addition of 100, 300, and 500 mg/L methionine, respectively. Bacterial community analysis showed that methionine addition supported the proliferation of a diversity of heterotrophic genera, such as Lysobacter and Micavibrio, and reduced the relative abundance of ammonium oxidizing genus Nitrosomonas. This research shows that the addition of methionine affects the performance of the partial-nitritation process. In this sense, amino acids can pose a threat for the of partial-nitritation process treating anaerobic digester supernatant at full-scale implementation. PMID- 26645231 TI - Synergistic improvement of crop physiological status by combination of cadmium immobilization and micronutrient fertilization. AB - Wollastonite application in cadmium-contaminated soils can reduce cadmium concentrations in plant, while the side effect is the synchronous immobilization of micronutrients, which reduces micronutrient uptake in plant, inducing micronutrient deficient symptoms. Accordingly, we investigated whether the supplement of Zn and Mn fertilizers after the wollastonite addition could promote the growth and photosynthesis in amaranth (Amaranthus tricolor L.). In this study, plants were cultivated in cadmium-contaminated soil under micronutrient fertilization alone, wollastonite addition, and combination of wollastonite and micronutrient fertilization treatments. Then, plant biomass; photosynthesis parameters; and total Cd, Zn, and Mn concentrations were investigated. Moreover, chemical extractions were performed on soil samples. The results show that application of wollastonite decreased Cd, Zn, and Mn concentrations in plant and availability in soil and it increased the gas exchange ability of plants. But, it reduced the chlorophyll content in leaves and had no positive influence on plant biomass. In comparison, Zn and Mn fertilization after wollastonite application greatly increased plant biomass and photosynthetic ability. It also reduced Cd phytoavailability more efficiently. Therefore, synergistic improvement of physiological status of farmland crop by sequential treatment with first wollastonite for cadmium immobilization, and then micronutrient fertilization to avoid micronutrient deficiency, was demonstrated. PMID- 26645232 TI - Attempts to improve nitrogen utilization efficiency of aquaponics through nitrifies addition and filler gradation. AB - Aquaponics has attracted worldwide attention in recent years and is considered as an alternative technology for conventional aquaculture. In this study, common carp (Cyprinus carpio) and pakchoi (Brassica chinensis) were cultured in lab scale aquaponics, and attempts were conducted to enhance its nitrogen utilization efficiency (NUE) through two optimization methods, i.e., nitrifies addition (NA) and filler gradation (FG). Results showed that NA and FG could improve the NUE of aquaponics by 8.8 and 16.0%, respectively, compared with control. The total ammonia (TAN) and nitrite (NO2(-)) concentrations in NA and FG systems were maintained at relatively low level (TAN < 0.5 mg/L, NO2(-) < 0.1 mg/L), which demonstrated that both the NA and FG could provide non-toxic water environment for fish culture. Nitrous oxide conversion ratio of the control, NA, and FG were 0.8, 1.2, and 1.7%, respectively, indicating that media-based aquaponics also contributed to global warming. Although the two proposed attempts in this study caused more N2O emission, they made new breakthrough in improving the NUE of aquaponics. PMID- 26645233 TI - Levels and patterns of organochlorine pesticides in agricultural soils in an area of extensive historical cotton cultivation in Henan province, China. AB - Organochlorine pesticides (OCPs) have attracted widespread concern because of their environmental persistence and toxicity. The historical influence of different agricultural land use types on soil concentrations of OCP residues was investigated by collecting a total of 52 surface soil samples from long-term cotton fields and fields with other crops in Lvdian township, Henan province, eastern central China. The concentration, composition, and possible sources of 16 OCPs were determined and a health risk assessment of these soils was conducted. Hexachlorocyclohexane (HCH), heptachlor, chlordane, and dichloro diphenyl trichloroethane plus its main metabolites (DDTs) were the most frequently detected OCPs with concentrations of 2.9-56.4 ng g(-1), 4.3-14.0 ng g(-1), 18.0 1254.4 ng g(-1), and below detection limit (BDL) -206.1 ng g(-1), respectively. Analysis of variance of p,p-DDE shows significant (P < 0.05) differences while other OCPs show no significant differences between historical cotton fields and fields containing other crops. Compositional analysis suggests that the HCH is derived mainly from the use of lindane and that there are recent inputs. Analysis of variance and compositional analysis indicate that the p,p-DDE in surface soil from long-term cotton fields is derived mainly from the aerobic biodegradation of historical residues. The sum of carcinogenic risk values of OCPs for soil samples were found to be 1.58 * 10(-6), posing a low cancer risk to the inhabitants of the region studied. PMID- 26645234 TI - Purification and identification of Bacillus subtilis SPB1 lipopeptide biosurfactant exhibiting antifungal activity against Rhizoctonia bataticola and Rhizoctonia solani. AB - This study reports the potential of a soil bacterium, Bacillus subtilis strain SPB1, to produce lipopeptide biosurfactants. Firstly, the crude lipopeptide mixture was tested for its inhibitory activity against phytopathogenic fungi. A minimal inhibitory concentration (MIC), an inhibitory concentration at 50% (IC50%), and an inhibitory concentration at 90% (IC90%) values were determined to be 0.04, 0.012, and 0.02 mg/ml, respectively, for Rhizoctonia bataticola with a fungistatic mode of action. For Rhizoctonia solani, a MIC, an IC50%, and IC90% values were determined to be 4, 0.25, and 3.3 mg/ml, respectively, with a fungicidal mode of action. For both of the fungi, a loss of sclerotial integrity, granulation and fragmentation of hyphal mycelia, followed by hyphal shriveling and cell lysis were observed with the treatment with SPB1 biosurfactant fraction. After extraction, separation, and purification, different lipopeptide compounds were identified in the culture filtrate of strain SPB1. Mass spectroscopic analysis confirmed the presence of different lipopeptide compounds consisting of surfactin isoforms with molecular weights of 1007, 1021, and 1035 Da; iturin isoforms with molecular weights of 1028, 1042, and 1056 Da; and fengycin isoforms with molecular weights of 1432 and 1446 Da. Two new clusters of lipopeptide isoforms with molecular weights of 1410 and 1424 Da and 973 and 987 Da, respectively, were also detected. This study reported the ability of a B. subtilis strain to co-produce lipopeptide isoforms with potential use as antifungal compounds. PMID- 26645235 TI - A study on possible use of Urtica dioica (common nettle) plant as polonium (210)Po and lead (210)Pb contamination biomonitor in the area of phosphogypsum stockpile. AB - The aim of this study was to test a possible use of Urtica dioica (common nettle) plant as a biomonitor of polonium (210)Po and lead (210)Pb contamination near phosphogypsum stacks by determining concentrations of these radionuclides in samples collected from the area of phosphogypsum stockpile in Wislinka (northern Poland). The (210)Po and (210)Pb contents in roots depended on their concentrations in soils. Bioconcentration factor values from soil to root of the plant did not depend on (210)Po and (210)Pb contents in soils that leads to the conclusion that different polonium and lead species have different affinities to U. dioica plants. The main sources of both analyzed radionuclides in green parts of plants are wet and dry air deposition and transportation from soil. The values of (210)Po/(210)Pb activity ratio indicate natural origin of these radioisotopes in analyzed plants. (210)Po and (210)Pb concentration in U. dioica roots is negatively weakly correlated with distance from phosphogypsum stockpile. PMID- 26645236 TI - Simulation study of dispersion and removal of particulate matter from traffic by road-side vegetation barrier. AB - Well-positioned and configured vegetation barriers (VBs) have been suggested as one of the green infrastructures that could improve near-road (local) air quality. This is because of their influence on the underlying mechanisms: dispersion and mass removal (by deposition). Some studies have investigated air quality improvement by near-road vegetation barrier using the dispersion-related method while few studies have done the same using the deposition-related method. However, decision making on vegetation barrier's configuration and placement for need-based maximum benefit requires a combined assessment with both methods which are not commonly found in a single study. In the present study, we employed a computational fluid dynamics model, ENVI-met, to evaluate the air quality benefit of near-road vegetation barrier using an integrated dispersion-deposition approach. A technique based on distance between source (road) and point of peak concentration before dwindling concentration downwind begins referred to as "distance to maximum concentration (DMC)" has been proposed to determine optimum position from source and thickness of vegetation barrier for improved dispersion and deposition-based benefit, respectively. Generally, a higher volume of vegetation barrier increases the overall mass removal while it weakens dispersion of pollutant within the same domain. Hence, the benefit of roadside vegetation barrier is need-based and can be expressed as either higher mass deposition or higher mass dispersion. Finally, recommendations on applications of our findings were presented. PMID- 26645237 TI - Cloning, expression, and antiviral activity of interferon beta from the Chinese microbat, Myotis davidii. AB - Bats are natural reservoir hosts for many viruses that produce no clinical symptoms in bats. Therefore, bats may have evolved effective mechanisms to control viral replication. However, little information is available on bat immune responses to viral infection. Type I interferon (IFN) plays a key role in controlling viral infections. In this study, we report the cloning, expression, and biological activity of interferon beta (IFNbeta) from the Chinese microbat species, Myotis davidii. We demonstrated the upregulation of IFNB and IFN stimulated genes in a kidney cell line derived from M. davidii after treatment with polyI:C or infection with Sendai virus. Furthermore, the recombinant IFNbeta inhibited vesicular stomatitis virus and bat adenovirus replication in cell lines from two bat species, M. davidii and Rhinolophus sinicus. We provide the first in vitro evidence of IFNbeta antiviral activity in microbats, which has important implications for virus interactions with these hosts. PMID- 26645238 TI - Low stromal Foxp3+ regulatory T-cell density is associated with complete response to neoadjuvant chemoradiotherapy in rectal cancer. AB - BACKGROUND: Foxp3+ regulatory T cells (Tregs) play a vital role in preventing autoimmunity, but also suppress antitumour immune responses. Tumour infiltration by Tregs has strong prognostic significance in colorectal cancer, and accumulating evidence suggests that chemotherapy and radiotherapy efficacy has an immune-mediated component. Whether Tregs play an inhibitory role in chemoradiotherapy (CRT) response in rectal cancer remains unknown. METHODS: Foxp3+, CD3+, CD4+, CD8+ and IL-17+ cell density in post-CRT surgical samples from 128 patients with rectal cancer was assessed by immunohistochemistry. The relationship between T-cell subset densities and clinical outcome (tumour regression and survival) was evaluated. RESULTS: Stromal Foxp3+ cell density was strongly associated with tumour regression grade (P=0.0006). A low stromal Foxp3+ cell density was observed in 84% of patients who had a pathologic complete response (pCR) compared with 41% of patients who did not (OR: 7.56, P=0.0005; OR: 5.27, P=0.006 after adjustment for presurgery clinical factors). Low stromal Foxp3+ cell density was also associated with improved recurrence-free survival (HR: 0.46, P=0.03), although not independent of tumour regression grade. CONCLUSIONS: Regulatory T cells in the tumour microenvironment may inhibit response to neoadjuvant CRT and may represent a therapeutic target in rectal cancer. PMID- 26645239 TI - Mutational analysis of pulmonary tumours with neuroendocrine features using targeted massive parallel sequencing: a comparison of a neglected tumour group. AB - BACKGROUND: Lung cancer is the leading cause of cancer-related deaths worldwide. The typical and atypical carcinoid (TC and AC), the large-cell neuroendocrine carcinoma (LCNEC) and the small-cell lung cancers (SCLC) are subgroups of pulmonary tumours that show neuroendocrine differentiations. With the rising impact of molecular pathology in routine diagnostics the interest for reliable biomarkers, which can help to differentiate these subgroups and may enable a more personalised treatment of patients, grows. METHODS: A collective of 70 formalin fixed, paraffin-embedded (FFPE) pulmonary neuroendocrine tumours (17 TCs, 17 ACs, 19 LCNECs and 17 SCLCs) was used to identify biomarkers by high-throughput sequencing. Using the Illumina TruSeq Amplicon-Cancer Panel on the MiSeq instrument, the samples were screened for alterations in 221 mutation hot spots of 48 tumour-relevant genes. RESULTS: After filtering >26 000 detected variants by applying strict algorithms, a total of 130 mutations were found in 29 genes and 49 patients. Mutations in JAK3, NRAS, RB1 and VHL1 were exclusively found in SCLCs, whereas the FGFR2 mutation was detected in LCNEC only. KIT, PTEN, HNF1A and SMO were altered in ACs. The SMAD4 mutation corresponded to the TC subtype. We prove that the frequency of mutations increased with the malignancy of tumour type. Interestingly, four out of five ATM-mutated patients showed an additional alteration in TP53, which was by far the most frequently altered gene (28 out of 130; 22%). We found correlations between tumour type and IASLC grade for ATM- (P=0.022; P=0.008) and TP53-mutated patients (P<0.001). Both mutated genes were also associated with lymph node invasion and distant metastasis (P?0.005). Furthermore, PIK3CA-mutated patients with high-grade tumours showed a reduced overall survival (P=0.040) and the mutation frequency of APC and ATM in high grade neuroendocrine lung cancer patients was associated with progression-free survival (PFS) (P=0.020). CONCLUSIONS: The implementation of high-throughput sequencing for the analysis of the neuroendocrine lung tumours has revealed that, even if these tumours encompass several subtypes with varying clinical aggressiveness, they share a number of molecular features. An improved understanding of the biology of neuroendocrine tumours will offer the opportunity for novel approaches in clinical management, resulting in a better prognosis and prediction of therapeutic response. PMID- 26645240 TI - (1)H-NMR urinary metabolomic profiling for diagnosis of gastric cancer. AB - BACKGROUND: Metabolomics has shown promise in gastric cancer (GC) detection. This research sought to identify whether GC has a unique urinary metabolomic profile compared with benign gastric disease (BN) and healthy (HE) patients. METHODS: Urine from 43 GC, 40 BN, and 40 matched HE patients was analysed using (1)H nuclear magnetic resonance ((1)H-NMR) spectroscopy, generating 77 reproducible metabolites (QC-RSD <25%). Univariate and multivariate (MVA) statistics were employed. A parsimonious biomarker profile of GC vs HE was investigated using LASSO regularised logistic regression (LASSO-LR). Model performance was assessed using Receiver Operating Characteristic (ROC) curves. RESULTS: GC displayed a clear discriminatory biomarker profile; the BN profile overlapped with GC and HE. LASSO-LR identified three discriminatory metabolites: 2-hydroxyisobutyrate, 3 indoxylsulfate, and alanine, which produced a discriminatory model with an area under the ROC of 0.95. CONCLUSIONS: GC patients have a distinct urinary metabolite profile. This study shows clinical potential for metabolic profiling for early GC diagnosis. PMID- 26645241 TI - Mechanisms downstream of reverse transcription reduce serum levels of HBV DNA but not of HBsAg in chronic hepatitis B virus infection. AB - BACKGROUND: Hepatitis B virus (HBV) DNA in serum of chronically infected patients declines by 3-4 log10 units at loss of HBe antigen (HBeAg) from serum. The mechanisms behind this decline, and the much smaller decline of surface antigen (HBsAg) levels, are still not well known. The aim of this study was to get a better understanding of this process by analysing both serum and intrahepatic markers of HBV replication. METHODS: Levels of HBV DNA and HBsAg in serum, and covalently closed circular DNA (cccDNA), pregenomic RNA (pgRNA) and S-RNA and total intrahepatic HBV DNA (ihDNA) in liver biopsies from 84 chronically infected patients (16 positive and 68 negative for HBeAg) were analysed. RESULTS: Lower HBV DNA levels within HBeAg-positive stage reflected lower levels of cccDNA and pgRNA with strong correlation. In HBeAg-negative patients, ihDNA levels were greater and HBV DNA levels in serum lower than expected from pgRNA levels. A lower HBV DNA/HBsAg ratio corresponded with lower pgRNA/cccDNA (p < 0.01) and higher S-RNA/cccDNA (p < 0.0001) ratios, suggesting that in HBeAg-negative patients transcription of pgRNA, but not of S-RNA, becomes suppressed. CONCLUSIONS: The marked reduction of HBV DNA in serum after loss of HBeAg appears to be due to combined reduction of cccDNA, pgRNA and yet unidentified mechanisms downstream of reverse transcription. Such mechanisms include faster clearance of circulating virus or blocked secretion of virions, the latter supported by the observed relative increase of ihDNA in HBeAg-negative patients. The smaller reduction of S-RNA than of pgRNA partly explains why HBsAg remain high in the HBeAg-negative stage, supporting the possibility of HBsAg synthesis from integrated HBV DNA. PMID- 26645242 TI - [On the Evaluation of Therapeutic Success in Dysphonic Patients]. AB - INTRODUCTION: Multidimensional voice evaluation is considered as gold standard in voice medicine. In this respect, the European Laryngological Society recommended a protocol for standardized evaluation (ELS-Protocol). However, there are only rare data analyzing changes during therapeutical follow-up. MATERIAL AND METHODS: Using this protocol, 276 patients (136 after phonosurgery, 81 after voice therapy and as a control group 59 patients without voice impairment) were evaluated with regard to their vocal capacity before and after voice therapy or phonosurgery, respectively. RESULTS: The parameters of the ELS-protocol showed significant improvement under therapy with respect to DSI, VHI, and RBH-scale. It has been confirmed, that these measurements are suitable for the assessment of dysphonic patients with organic as well as functional voice disorders. However, detailed analysis of all the obtained parameters showed only weak or no correlation between all regarding parameters, which should be expected to provide comparable information, such as perturbation parameters or such parameters, that are derived from the acoustical spectrum. DISCUSSION: Multidimensional evaluation of the voice as recommended by the ELS protocol is independent from the therapeutical approach able to document therapeutical success. The lack of sufficient correlations of values which should provide comparable information shows that an optimization or standardization of measuring instruments, computer hardware and software is necessary. PMID- 26645243 TI - [Chemosensory Evoked Changes of Breathing Pattern During Propofol-induced Sedation]. AB - BACKGROUND: The affective valence of an olfactory stimulus will be encoded in its respiratory response. Unpleasant odors shorten the inhalation of the first stimulated breaths in wakefulness and sleep. The aim of the present study was to assess the effekt of intravenous anesthetic propofol on the chemosensory evoked changes of breathing pattern. MATERIAL AND METHODS: 13 ASA 1/2 patients got intranasal chemosensory stimuli (H2S and CO2) by flow-olfactometer during "deep" (EEG-based bispectral analysis, BIS:<=60) and "moderate" (BIS>60) propofol induced sedation with preserved spontaneous breathing. The duration of the in- and exhalation was analyzed for 5 breaths before and for 2 breaths after the onset of stimulation. RESULTS: During deep sedation respiratory reactions were observed only by CO2 irritation. During moderate sedation respiratory responses were evoked by H2S stimuli, too. In moderate sedation extensions of the inhalations of the first breath after both the unpleasant pure olfactory H2S stimuli and the trigeminal stimuli were more frequent than reductions. CONCLUSION: Olfactory stimuli change the breathing only during moderate sedation, trigeminal stimuli during deep and moderate propofol-induced sedation. In opposite to both wakefulness and sleep the duration of inhalation is often extended by H2S-stimuli during moderate sedation. PMID- 26645244 TI - [Concurrent Endoscopic Sinus Surgery (FESS) with Septorhinoplasty - Indication, Risks and Chances]. AB - BACKGROUND: Patients with a chronic rhinosinusitis (CRS) and a concurrent deformity of the outer nose often require a septorhinoplasty (SRP) for functional or aesthetic reasons, combined with functional endoscopic sinus surgery (FESS). Aim of this study was to rule out the benefit of this combined approach. PATIENTS AND METHODS: In a prospective study of 55 patients (30 m, 25 f, age 16-77 years) with a chronic rhinosinusitis with or without polyps combined with a deformity of the outer nose we performed a FESS together with a SRP using a closed or open approach. The control group included 55 patients (18 m, 37 w, age 18-62 years) with SRP alone. All patients got the same type of anestesia and an antibiotic prophylaxis with clindamycin. We compared the rates of inflammation and other complications of surgery. RESULTS: The only difference between study group and control group was the period of time for surgery. There was neither a relevant inflammation in both groups nor any other significant complication (bleeding, edema, etc). Also the rate of minor revisions after SRP was almost the same in both groups. CONCLUSIONS: The combined FESS and SRP is a safe and effective method without an increased risk of complications compared with SRP alone. PMID- 26645245 TI - [Physical Properties of Squamous Cell Carcinoma Cells using Atomic Force Microscopy]. AB - INTRODUCTION: Malignant and benign cells differ according to their elasticity. An atomic force microscope is a useful tool for measuring these mechanical cell properties. If cells of different dignity show different resonance behavior, due to their different elasticity, a selective ablation of specific tissue types by ultrasound would be possible. The goal is a highly selective ablation of tumor tissue without damaging healthy tissue. MATERIALS AND METHODS: We performed elasticity measurements of tumor cells (UD-01 cell line) with an atomic force microscope. In a further step, an ultrasound applicator has been positioned and the morphological changes of the cells during the treatment were documented. RESULTS: Different elasticities on the squamous cells were measured, depending on the location. Below a defined maximum amplitude the morphological cell changes were caused solely by ultrasonic excitation. SUMMARY: The atomic force microscope is suitable for the determination of the individual cell elasticity. The data collected could be the basis for treatment modalities that lead to a very selective damage for malignant cells. PMID- 26645246 TI - [Primary Parotid Carcinoma: Influence of a Two-step Procedure on the Oncological Outcome]. AB - BACKGROUND: Malignancies of the parotid gland represent a rare form of head and neck cancer. Advanced stages are usually recognized as such, whereas early tumor stages are sometimes diagnosed only after parotidectomy due to lack of signs of malignancy. The present study investigates whether this unplanned 2-stage approach has a negative impact on the outcome. MATERIAL AND METHODS: The study includes clinical and histological data of patients with parotid cancer which were treated in the Department of Oto-Rhino-Laryngology and Head and Neck Surgery of the University Medical Center Ulm between 2004 and 2014. RESULTS: 42 patients were included into the study with a median follow-up of 38 months. The RFS and OS at 5 years was 68.6 and 80.1%, respectively, which corresponds to the current literature. 24/42 patients received one-step radical surgery. In 18/42 patients a parotidectomy was performed initially followed by oncologic surgery after receiving histology. The patient group with 2-stage surgery included less advanced tumor stages and more entities with better prognosis. Interestingly, these patients presented with an excellent RFS of 84.4% compared to 56,5% (p=0,16) in the patient group with one-step procedure, correspondent to the tumor stages, entities and the current literature. CONCLUSIONS: According to the available data and compared to the literature, an unplanned 2-stage procedure in clinically silent parotid cancer seems not necessarily to have a negative impact on the outcome. Nevertheless, the preoperative diagnosis should be improved to detect these malignancies more sensitive in early stages. PMID- 26645247 TI - Changes in Enteric Neurons of Small Intestine in a Rat Model of Irritable Bowel Syndrome with Diarrhea. AB - BACKGROUND/AIMS: Physical and/or emotional stresses are important factors in the exacerbation of symptoms in irritable bowel syndrome (IBS). Several lines of evidence support that a major impact of stress on the gastrointestinal tract occurs via the enteric nervous system. We aimed to evaluate histological changes in the submucosal plexus (SMP) and myenteric plexus (MP) of the distal ileum in concert with the intestinal motor function in a rat model of IBS with diarrhea. METHODS: The rat model was induced by heterotypic chronic and acute stress (CAS). The intestinal transit was measured by administering powdered carbon by gastric gavage. Double immunohistochemical fluorescence staining with whole-mount preparations of SMP and MP of enteric nervous system was used to assess changes in expression of choline acetyltransferase, vasoactive intestinal peptide, or nitric oxide synthase in relation to the pan neuronal marker, anti-Hu. RESULTS: The intestinal transit ratio increased significantly from control values of 50.8% to 60.6% in the CAS group. The numbers of enteric ganglia and neurons in the SMP were increased in the CAS group. The proportions of choline acetyltransferase- and vasoactive intestinal peptide-immunoreactive neurons in the SMP were increased (82.1 +/- 4.3% vs. 76.0 +/- 5.0%, P = 0.021; 40.5 +/- 5.9% vs 28.9 +/- 3.7%, P = 0.001), while nitric oxide synthase-immunoreactive neurons in the MP were decreased compared with controls (23.3 +/- 4.5% vs 32.4 +/- 4.5%, P = 0.002). CONCLUSIONS: These morphological changes in enteric neurons to CAS might contribute to the dysfunction in motility and secretion in IBS with diarrhea. PMID- 26645249 TI - The Role of Central and Enteric Nervous Systems in the Control of the Retrograde Giant Contraction. AB - BACKGROUND/AIMS: The role of the enteric (ENS) and central (CNS) nervous systems in the control of the retrograde giant contraction (RGC) associated with vomiting is unknown. METHODS: The effects of myotomy or mesenteric nerve transection (MNT) on apomorphine-induced emesis were investigated in 18 chronically instrumented dogs. RESULTS: Neither surgery affected the RGC orad of the surgical site or the velocity of the RGC over the entire small intestine. Myotomy blocked the RGC for 17 +/- 5 cm aborad of the myotomy, and the velocity of the RGC from 100 to 70 cm from the pylorus slowed (18.1 +/- 3.0 to 9.0 +/- 0.8 cm/sec) such that the RGC orad and aborad of the myotomy occurred simultaneously. After MNT, the RGC was unchanged up to 66 +/- 6 cm from the pylorus, and the sequence of the RGC across the denervated intestine was unaltered. The velocity of the RGC from 100 to 70 cm from the pylorus increased from 12.8 +/- 1.6 to 196 +/- 116 cm/sec. After myotomy or MNT, the percent occurrence and magnitude of the RGC across the intestine 100 to 70 cm from the pylorus decreased. CONCLUSIONS: The CNS activates the RGC 10 to 20 cm aborad of its innervation of the intestine and controls the RGC sequence. On the other hand, the ENS plays a role in initiation and generation of the RGC. PMID- 26645248 TI - Acute Effects of Transforming Growth Factor-beta1 on Neuronal Excitability and Involvement in the Pain of Rats with Chronic Pancreatitis. AB - BACKGROUND/AIMS: This study was to investigate whether transforming growth factor beta1 (TGF-beta1) plays a role in hyperalgesia in chronic pancreatitis (CP) and the underlying mechanisms. METHODS: CP was induced in male adult rats by intraductal injection of trinitrobenzene sulfonic acid (TNBS). Abdominal hyperalgesia was assessed by referred somatic behaviors to mechanical stimulation of rat abdomen. Dil dye injected into the pancreas was used to label pancreas specific dorsal root ganglion (DRG) neurons. Whole cell patch clamp recordings and calcium imaging were performed to examine the effect of TGF-beta1 on acutely isolated pancreas-specific DRG neurons. Western blot analysis was carried out to measure the expression of TGF-beta1 and its receptors. RESULTS: TNBS injection significantly upregulated expression of TGF-beta1 in the pancreas and DRGs, and TGF-beta1 receptors in DRGs (T9-T13)in CP rats. Intrathecal injection of TGF-beta receptor I antagonist SB431542 attenuated abdominal hyperalgesia in CP rats. TGF beta1 application depolarized the membrane potential and caused firing activity of DRG neurons. TGF-beta1 application also reduced rheobase, hyperpolarized action potential threshold, and increased numbers of action potentials evoked by current injection of pancreas-specific DRG neurons. TGF-beta1 application also increased the concentration of intracellular calcium of DRG neurons, which was inhibited by SB431542. Furthermore, intrathecal injection of TGF-beta1 produced abdominal hyperalgesia in healthy rats. CONCLUSIONS: These results suggest that TGF-beta1 enhances neuronal excitability and increases the concentration of intracellular calcium. TGF-beta1 and its receptors are involved in abdominal hyperalgesia in CP. This and future study might identify a potentially novel target for the treatment of abdominal pain in CP. PMID- 26645250 TI - Ghrelin O-acyltransferase knockout mice show resistance to obesity when fed high sucrose diet. AB - Ghrelin is an appetite-stimulating hormone secreted from stomach. Since the discovery that acylation of the serine-3 residue by ghrelin O-acyltransferase (GOAT) is essential for exerting its functions, GOAT has been regarded as an therapeutic target for attenuating appetite, and thus for the treatment of obesity and diabetes. However, contrary to the expectations, GOAT-knockout (KO) mice have not shown meaningful body weight reduction, under high-fat diet. Here, in this study, we sought to determine whether GOAT has a role in body weight regulation and glucose metabolism with a focus on dietary sucrose, because macronutrient composition of diet is important for appetite regulation. We found that peripherally administered acylated-ghrelin, but not unacylated one, stimulated sucrose consumption in a two-bottle-drinking test. The role of acylated-ghrelin in sucrose preference was further supported by the finding that GOAT KO mice consumed less sucrose solution compared with WT littermates. Then, we investigated the effect of dietary composition of sucrose on food intake and body weight in GOAT KO and WT mice. As a result, when fed on high-fat diet, food intake and body weight were similar between GOAT KO and WT mice. However, when fed on high-fat, high-sucrose diet, GOAT KO mice showed significantly reduced food intake and marked resistance to obesity, leading to amelioration of glucose metabolism. These results suggest that blockade of acylated-ghrelin production offers therapeutic potential for obesity and metabolic disorders caused by overeating of palatable food. PMID- 26645251 TI - Comparative benefits and harms of second generation antidepressants and cognitive behavioral therapies in initial treatment of major depressive disorder: systematic review and meta-analysis. AB - STUDY QUESTION: What are the benefits and harms of second generation antidepressants and cognitive behavioral therapies (CBTs) in the initial treatment of a current episode of major depressive disorder in adults? METHODS: This was a systematic review including qualitative assessment and meta-analyses using random and fixed effects models. Medline, Embase, the Cochrane Library, the Allied and Complementary Medicine Database, PsycINFO, and the Cumulative Index to Nursing and Allied Health Literature were searched from January 1990 through January 2015. The 11 randomized controlled trials included compared a second generation antidepressant CBT. Ten trials compared antidepressant monotherapy with CBT alone; three compared antidepressant monotherapy with antidepressant plus CBT. SUMMARY ANSWER AND LIMITATIONS: Meta-analyses found no statistically significant difference in effectiveness between second generation antidepressants and CBT for response (risk ratio 0.91, 0.77 to 1.07), remission (0.98, 0.73 to 1.32), or change in 17 item Hamilton Rating Scale for Depression score (weighted mean difference, -0.38, -2.87 to 2.10). Similarly, no significant differences were found in rates of overall study discontinuation (risk ratio 0.90, 0.49 to 1.65) or discontinuation attributable to lack of efficacy (0.40, 0.05 to 2.91). Although more patients treated with a second generation antidepressant than receiving CBT withdrew from studies because of adverse events, the difference was not statistically significant (risk ratio 3.29, 0.42 to 25.72). No conclusions could be drawn about other outcomes because of lack of evidence. Results should be interpreted cautiously given the low strength of evidence for most outcomes. The scope of this review was limited to trials that enrolled adult patients with major depressive disorder and compared a second generation antidepressant with CBT, and many of the included trials had methodological shortcomings that may limit confidence in some of the findings. WHAT THIS STUDY ADDS: Second generation antidepressants and CBT have evidence bases of benefits and harms in major depressive disorder. Available evidence suggests no difference in treatment effects of second generation antidepressants and CBT, either alone or in combination, although small numbers may preclude detection of small but clinically meaningful differences. Funding, competing interests, data sharing This project was funded under contract from the Agency for Healthcare Research and Quality by the RTI-UNC Evidence-based Practice Center. Detailed methods and additional information are available in the full report, available at http://effectivehealthcare.ahrq.gov/. PMID- 26645253 TI - Increased Risk of Cerebrovascular Disease Among Patients With Neurofibromatosis Type 1: Population-Based Approach. AB - BACKGROUND AND PURPOSE: Although neurofibromatosis type 1 (NF1) may be associated with an incompletely understood vasculopathy, relative odds of stroke in this population is not known. METHODS: Using the 1998 to 2009 US Nationwide Inpatient Sample, we performed a case-control study matching cases of NF1 to controls without such a diagnosis. We then compared the odds of stroke between the 2 groups. We used multivariable logistic regression to adjust for known or suspected confounders. RESULTS: NF1 was associated with younger mean age at the time of stroke (41 versus 48) and a lower prevalence of stroke risk factors among adult patients. Pediatric patients with NF1, however, were more likely to have hypertension. Patients with NF1 were significantly more likely to be diagnosed with any stroke (odds ratio, 1.2; P<0.0001) than the general population. The odds of intracerebral hemorrhage were greatest among hemorrhagic stroke types analyzed (odds ratio, 1.9; P<0.0001). In the pediatric NF1 population, the odds of intracerebral hemorrhage were more dramatically elevated (odds ratio, 8.1; P<0.0001). The odds of ischemic stroke were also increased with NF1 in the pediatric (odds ratio, 3.4; P<0.0001) but not in the adult population. CONCLUSIONS: When compared with the general population, the odds of any type of stroke are significantly increased for patients with NF1, both adult and pediatric. This risk is most notable for hemorrhagic strokes although it is also increased for ischemic strokes in children. Physicians should be aware of the increased risk of stroke in this population, and consider stroke as a potential cause of new neurological symptoms. PMID- 26645252 TI - MicroRNA miR396 Regulates the Switch between Stem Cells and Transit-Amplifying Cells in Arabidopsis Roots. AB - To ensure an adequate organ mass, the daughters of stem cells progress through a transit-amplifying phase displaying rapid cell division cycles before differentiating. Here, we show that Arabidopsis thaliana microRNA miR396 regulates the transition of root stem cells into transit-amplifying cells by interacting with GROWTH-REGULATING FACTORs (GRFs). The GRFs are expressed in transit-amplifying cells but are excluded from the stem cells through inhibition by miR396. Inactivation of the GRFs increases the meristem size and induces periclinal formative divisions in transit-amplifying cells. The GRFs repress PLETHORA (PLT) genes, regulating their spatial expression gradient. Conversely, PLT activates MIR396 in the stem cells to repress the GRFs. We identified a pathway regulated by GRF transcription factors that represses stem cell-promoting genes in actively proliferating cells, which is essential for the progression of the cell cycle and the orientation of the cell division plane. If unchecked, the expression of the GRFs in the stem cell niche suppresses formative cell divisions and distorts the organization of the quiescent center. We propose that the interactions identified here between miR396 and GRF and PLT transcription factors are necessary to establish the boundary between the stem cell niche and the transit-amplifying region. PMID- 26645255 TI - Comparing Vessel Imaging: Noncontrast Computed Tomography/Computed Tomographic Angiography Should Be the New Minimum Standard in Acute Disabling Stroke. PMID- 26645254 TI - Glyceryl Trinitrate for Acute Intracerebral Hemorrhage: Results From the Efficacy of Nitric Oxide in Stroke (ENOS) Trial, a Subgroup Analysis. AB - BACKGROUND AND PURPOSE: The Efficacy of Nitric Oxide in Stroke (ENOS) trial found that transdermal glyceryl trinitrate (GTN, a nitric oxide donor) lowered blood pressure but did not improve functional outcome in patients with acute stroke. However, GTN was associated with improved outcome if patients were randomized within 6 hours of stroke onset. METHODS: In this prespecified subgroup analysis, the effect of GTN (5 mg/d for 7 days) versus no GTN was studied in 629 patients with intracerebral hemorrhage presenting within 48 hours and with systolic blood pressure >=140 mm Hg. The primary outcome was the modified Rankin Scale at 90 days. RESULTS: Mean blood pressure at baseline was 172/93 mm Hg and significantly lower (difference -7.5/-4.2 mm Hg; both P<=0.05) on day 1 in 310 patients allocated to GTN when compared with 319 randomized to no GTN. No difference in the modified Rankin Scale was observed between those receiving GTN versus no GTN (adjusted odds ratio for worse outcome with GTN, 1.04; 95% confidence interval, 0.78-1.37; P=0.84). In the subgroup of 61 patients randomized within 6 hours, GTN improved functional outcome with a shift in the modified Rankin Scale (odds ratio, 0.22; 95% confidence interval, 0.07-0.69; P=0.001). There was no significant difference in the rates of serious adverse events between GTN and no GTN. CONCLUSIONS: In patients with intracerebral hemorrhage within 48 hours of onset, GTN lowered blood pressure was safe but did not improve functional outcome. Very early treatment might be beneficial but needs assessment in further studies. CLINICAL TRIAL REGISTRATION: URL: http://www.isrctn.com/ISRCTN99414122. Unique identifier: 99414122. PMID- 26645256 TI - Significance of the Hemorrhagic Site for Recurrent Bleeding: Prespecified Analysis in the Japan Adult Moyamoya Trial. AB - BACKGROUND AND PURPOSE: The primary results of the Japan Adult Moyamoya Trial revealed the statistically marginal superiority of bypass surgery over medical treatment alone in preventing rebleeding in moyamoya disease. The purpose of this analysis is to test the prespecified subgroup hypothesis that the natural course and surgical effects vary depending on the hemorrhagic site at onset. METHODS: The hemorrhagic site, classified as either anterior or posterior, was the only stratifying variable for randomization. Statistical analyses were focused on the assessment of effect modification according to the hemorrhagic site and were based on tests of interaction. RESULTS: Of 42 surgically treated patients, 24 were classified as anterior hemorrhage and 18 as posterior hemorrhage; of 38 medically treated patients, 21 were classified as anterior and 17 as posterior. The hazard ratio of the primary end points (all adverse events) for the surgical group relative to the nonsurgical group was 0.07 (95% confidence interval, 0.01 0.55) for the posterior group, as compared with 1.62 (95% confidence interval, 0.39-6.79) for the anterior group (P=0.013 for interaction). Analysis within the nonsurgical group revealed that the incidence of the primary end point was significantly higher in the posterior group than in the anterior group (17.1% per year versus 3.0% per year; hazard ratio, 5.83; 95% confidence interval, 1.60 21.27). CONCLUSIONS: Careful interpretation of the results suggests that patients with posterior hemorrhage are at higher risk of rebleeding and accrue greater benefit from surgery, subject to verification in further studies. CLINICAL TRIAL REGISTRATION: URL: http://www.umin.ac.jp/ctr/index.htm. Unique identifier: C000000166. PMID- 26645258 TI - Editor's Update. PMID- 26645257 TI - Safety, Feasibility, and Efficacy of Vagus Nerve Stimulation Paired With Upper Limb Rehabilitation After Ischemic Stroke. AB - BACKGROUND AND PURPOSE: Recent animal studies demonstrate that vagus nerve stimulation (VNS) paired with movement induces movement-specific plasticity in motor cortex and improves forelimb function after stroke. We conducted a randomized controlled clinical pilot study of VNS paired with rehabilitation on upper-limb function after ischemic stroke. METHODS: Twenty-one participants with ischemic stroke >6 months before and moderate to severe upper-limb impairment were randomized to VNS plus rehabilitation or rehabilitation alone. Rehabilitation consisted of three 2-hour sessions per week for 6 weeks, each involving >400 movement trials. In the VNS group, movements were paired with 0.5 second VNS. The primary objective was to assess safety and feasibility. Secondary end points included change in upper-limb measures (including the Fugl-Meyer Assessment-Upper Extremity). RESULTS: Nine participants were randomized to VNS plus rehabilitation and 11 to rehabilitation alone. There were no serious adverse device effects. One patient had transient vocal cord palsy and dysphagia after implantation. Five had minor adverse device effects including nausea and taste disturbance on the evening of therapy. In the intention-to-treat analysis, the change in Fugl-Meyer Assessment-Upper Extremity scores was not significantly different (between-group difference, 5.7 points; 95% confidence interval, -0.4 to 11.8). In the per-protocol analysis, there was a significant difference in change in Fugl-Meyer Assessment-Upper Extremity score (between-group difference, 6.5 points; 95% confidence interval, 0.4 to 12.6). CONCLUSIONS: This study suggests that VNS paired with rehabilitation is feasible and has not raised safety concerns. Additional studies of VNS in adults with chronic stroke will now be performed. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01669161. PMID- 26645259 TI - Organizational Update: American Stroke Association Stroke Council Update. PMID- 26645260 TI - Damage to the Left Precentral Gyrus Is Associated With Apraxia of Speech in Acute Stroke. AB - BACKGROUND AND PURPOSE: Apraxia of speech (AOS) is a motor speech disorder, which is clinically characterized by the combination of phonemic segmental changes and articulatory distortions. AOS has been believed to arise from impairment in motor speech planning/programming and differentiated from both aphasia and dysarthria. The brain regions associated with AOS are still a matter of debate. The aim of this study was to address this issue in a large number of consecutive acute ischemic stroke patients. METHODS: We retrospectively studied 136 patients with isolated nonlacunar infarcts in the left middle cerebral artery territory (70.5+/ 12.9 years old, 79 males). In accordance with speech and language assessments, the patients were classified into the following groups: pure form of AOS (pure AOS), AOS with aphasia (AOS-aphasia), and without AOS (non-AOS). Voxel-based lesion-symptom mapping analysis was performed on T2-weighted images or fluid attenuated inversion recovery images. Using the Liebermeister method, group-wise comparisons were made between the all AOS (pure AOS plus AOS-aphasia) and non AOS, pure AOS and non-AOS, AOS-aphasia and non-AOS, and pure AOS and AOS-aphasia groups. RESULTS: Of the 136 patients, 22 patients were diagnosed with AOS (7 patients with pure AOS and 15 patients with AOS-aphasia). The voxel-based lesion symptom mapping analysis demonstrated that the brain regions associated with AOS were centered on the left precentral gyrus. CONCLUSIONS: Damage to the left precentral gyrus is associated with AOS in acute to subacute stroke patients, suggesting a role of this brain region in motor speech production. PMID- 26645261 TI - Surveillance Systems for Nosocomial Infections: Methods and Challenges. PMID- 26645263 TI - Comparison of uninterrupted warfarin and bridging therapy using low-molecular weight heparin with respect to the severity of bleeding after dental extractions in patients with prosthetic valves. AB - OBJECTIVE: The management of anticoagulated patients with warfarin during dental extraction is an intricate issue. We carefully designed the current study so that the amount of bleeding was measured with objective methods and the data from the same patient in different dental extraction appointments could be compared, eliminating the bleeding diathesis differences of patients. METHODS: This prospective and controlled study was conducted in 36 adult patients with prosthetic valve requiring multiple tooth extractions. The first dental extraction was performed without the discontinuation of warfarin therapy, and the second procedure was performed with a discontinuation of warfarin and bridging with low-molecular weight heparin (LMWH). The two dental extraction protocols in the same patient group were compared. The total amount of bleeding was calculated as the difference between the weights of gauze swabs used before and after the tamponade; the number of gauze swabs used for bleeding control in the first 48 h was recorded. RESULT: The median number of used gauze swabs was 2.5 (IQR: 1-5) and 3.0 (IQR: 2-7) in the first and second dental extraction procedures, respectively. The median bleeding time was 50.0 (IQR: 20-100) in the first procedure compared with 60.0 (IQR: 40-140) min in the second procedure. The mean amounts of bleeding were 2194+/-1418 mg in the first dental extraction procedure and 2950+/-1694 mg in the second dental extraction procedure. The median number of used gauze swabs, the median bleeding time, and the mean amount of bleeding were statistically higher in the second dental extraction procedure (P<0.001). CONCLUSION: Continued warfarin treatment at the time of dental extractions reduces the total amount of bleeding compared with bridging therapy in patients with prosthetic valves. PMID- 26645262 TI - Evaluation of cardiac biomarkers and right ventricular dysfunction in patients with acute pulmonary embolism. AB - OBJECTIVE: Right ventricular dysfunction (RVD) with myocardial damage may lead to fatal complications in patients with acute pulmonary embolism (PE). Cytoplasmic heart-type fatty acid-binding protein (HFABP) and the N-terminal fragment of its prohormone (NT-proBNP) are sensitive and specific biomarkers of myocardial damage. We evaluated RVD and cardiac biomarkers for myocardial damage and short term mortality in patients with acute PE. METHODS: We analyzed 41 patients (24 females, 17 males) with confirmed acute PE prospective. Three groups (massive, submassive, and non-massive) of patients were defined, based on systemic systolic blood pressure measured on admission and RVD by transthoracic echocardiography (TTE). Also, systolic (s) and mean (m) pulmonary artery pressures (PAPs) were recorded by TTE, and plasma concentrations of cardiac troponin T (cTn-T), NT proBNP, and HFABP were evaluated 6 month follow-up. RESULTS: Seventeen (41.5%) patients experienced a complicated clinical course in the 6-month follow-up for the combined end-point, including at least one of the following: death (n=12, 29.3%; 3 PE-related), chronic PE (n=4, 9.8%), pulmonary hypertension (n=2, 4.9%), and recurrent PE (n=1, 2.4%). Multivariate hazard ratio analysis revealed HFABP, NT-proBNP, and PAPs as the 6-month mortality predictors (HR 1.02, 95% CI 1.01 1.05; HR 1.01, 95% CI 1.01-1.04; and HR 1.02, 95% CI 1.02-1.05, respectively). CONCLUSION: HFABP, NT-proBNP, and PAPs measured on admission may be useful for short-term risk stratification and in the prediction of 6-month PE-related mortality in patients with acute PE. PMID- 26645264 TI - Association between the corrected QT interval, carotid artery intima-media thickness, and hepatic steatosis in obese children. AB - OBJECTIVE: Childhood obesity is related to subclinical atherosclerosis. Carotid intima-media thickness (CIMT) and hepatosteatosis are parameters that reflect subclinical atherosclerosis and are shown to be associated with obesity. However, their relation with the corrected QT interval (QTc) has not been thoroughly studied in children. Here, we aimed to research the relation between QTc, hepatic steatosis, and CIMT among obese children. METHODS: Fifty-three obese and 53 age- and sex-matched non-obese children aged 6-16 years were included in this prospective cross-sectional study. The QTc of each subject was accordingly obtained from lead II on a 12-lead resting electrocardiogram. Thus, CIMT measurement and abdominal ultrasonographic examination were performed. The data for obese and non-obese children were analyzed and compared. RESULT: The age and gender distribution of the subjects were statistically similar. The CIMT value of the obese group was higher than that of the non-obese group (p<0.001). The obese group had a higher frequency of hepatosteatosis at grade 1 or 2 than the non obese group (p<0.001). The QTc values were also found to be more prolonged in the obese group than in the other group (p<0.001). With Student's t-test and Mann Whitey U test accordingly. CONCLUSION: We demonstrated that obese children had higher CIMT and QTc values as well as more frequent hepatosteatosis, and that the presence of hepatosteatosis or increased CIMT had an association with prolonged QTc values in obese children. Therefore, with the aim of detecting cardiovascular effects of obesity, it may be beneficial to perform the measurements of QTc in the presence of hepatosteatosis and/or increased CIMT among obese children. PMID- 26645265 TI - Sequencing of mutations in the serine/threonine kinase domain of the bone morphogenetic protein receptor type 2 gene causing pulmonary arterial hypertension. AB - OBJECTIVE: Germline mutations in the bone morphogenetic protein receptor type-2 (BMPR2) gene are considered to be a major risk factor for pulmonary arterial hypertension (PAH). BMPR2 mutations have been reported in 10%-20% of idiopathic PAH and in 80% of familial PAH cases. The aim of this study was to evaluate the frequency of mutations in the serine/threonine kinase domain of the BMPR2 gene in a group of patients from a single PAH referral center in Turkey. METHODS: This cross-sectional study used a DNA-sequencing method to investigate BMPR2 mutations in the serine-threonine-kinase domain in 43 patients diagnosed with PAH [8 with idiopathic PAH and 35 with congenital heart disease (CHD)] from a single PAH referral center. Patients were included if they had a hemodynamically measured mean pulmonary arterial pressure of >25 mm Hg with a mean pulmonary capillary wedge pressure of <=15 mm Hg. Patients with severe left heart disease and/or pulmonary disease that could cause pulmonary hypertension were excluded. Associations between categoric variables were determined using the chi-square test. Differences between idiopathic and CHD-associated PAH groups were compared with the unpaired Student's t-test for continuous variables. RESULTS: We detected a missense mutation, [p.C347Y (c.1040G>A)], in one patient with idiopathic PAH in exon 8 of the BMPR2 gene. The mutation was detected in a 27-year-old female with a remarkable family history for PAH. She had a favorable response to endothelin receptor antagonists. No mutations were detected in the exons 5-11 of the BMPR2 gene in the PAH-CHD group. CONCLUSION: A missense mutation was detected in only one of the eight patients with idiopathic PAH. The BMPR2 missense mutation rate of 12.5% in this cohort of Turkish patients with idiopathic PAH was similar to that seen in European registries. The index patient was a young female with a family history remarkable for PAH; she had a good long-term response to PAH specific treatment, probably due to the early initiation of the treatment. Genetic screening of families affected by PAH might have great value in identifying the disease at an early stage. PMID- 26645267 TI - Evaluation of myocardial function in pediatric patients with the transposition of great arteries after arterial switch operation. PMID- 26645266 TI - Protective effects of aspirin and vitamin C against corn syrup consumption induced cardiac damage through sirtuin-1 and HIF-1alpha pathway. AB - OBJECTIVE: The aim of this study was to investigate the protective effects of aspirin (AS) and vitamin C (VC) against cardiac damage induced by chronic corn syrup (CS) consumption via a mechanism involving sirtuin-1 (ST-1), hypoxia inducible factor-1alpha (HIF-1alpha), and the caspase-3 pathway in rats. METHODS: Forty male Sprague-Dawley rats (14-16 weeks) that weighed 250-300 g were randomly distributed into 5 groups, each containing 8 rats: control group, CS+AS group, CS+VC group, CS+AS+VC group, and CS group. AS (10 mg/kg/day) and VC (200 mg/kg/day) were orally given to the rats. F30 (30% fructose syrup solution) was given to the rats in drinking water for 6 weeks. The rats were sacrificed by exsanguination 24 h after the last administration. Blood samples and tissue were collected for biochemical, histopathological, and immunohistochemical examinations. Non-parametric Kruskal-Wallis test and Mann-Whitney U test used for the parameters without normal distribution and ANOVA and post-hoc LSD tests were used for parameters with a normal distribution to compare groups. RESULTS: Uric acid, creatine kinase (CKMB), and lactate dehydrogenase (LDH) levels were increased in the CS group compared with the control group (1.45+/-0.39 and p=0.011; 3225.64+/-598.25 and p=0.004; 3906.83+/-1064.22 and p=0.002, respectively) and decreased in all the treatment groups. In addition, increased levels of MDA and decreased activity of CAT in the CS group (0.172+/-0.03 and p=0.000; 0.070+/-0.005 and p=0.007, respectively) were reversed with AS and VC therapy. A decrease in ST-1 activity and increases in caspase-3 and HIF-1 activities corrected by VC and AS therapy were observed. CONCLUSION: AS and VC, which display antioxidant and antiapoptotic activities, ameliorated cardiac damage induced by chronic fructose consumption by increasing the levels of ST-1 and decreasing the levels of HIF-1alpha and caspase-3. PMID- 26645268 TI - The effect of iterative reconstruction on image quality in evaluating patients with coronary calcifications or stents at coronary computed tomography angiography. PMID- 26645269 TI - In vitro antimicrobial activity of S-649266, a catechol-substituted siderophore cephalosporin, when tested against non-fermenting Gram-negative bacteria. AB - OBJECTIVES: S-649266 is a parenteral siderophore cephalosporin antibiotic with a catechol moiety on its side chain. The in vitro antimicrobial activity of S 649266 against non-fermenting Gram-negative bacteria was evaluated and compared with the activities of meropenem, levofloxacin, cefepime, ceftazidime and piperacillin/tazobactam. METHODS: MIC values of S-649266 were determined in Mueller-Hinton broth or Iso-Sensitest broth supplemented with apo-transferrin. RESULTS: S-649266 showed potent in vitro activity against the non-fermenting Gram negative bacteria Acinetobacter baumannii, Pseudomonas aeruginosa and Stenotrophomonas maltophilia, including MDR strains such as carbapenem-resistant A. baumannii and metallo-beta-lactamase-producing P. aeruginosa. MIC90s of S 649266 for A. baumannii, P. aeruginosa and S. maltophilia were 2, 1 and 0.5 mg/L, respectively, whereas MIC90s of meropenem were >16 mg/L. S-649266 showed potent in vitro activities against A. baumannii producing carbapenemases such as OXA type beta-lactamases, and P. aeruginosa producing metallo-beta-lactamases such as IMP type and VIM type. MIC90 values for these A. baumannii strains and P. aeruginosa strains were 8 and 4 mg/L, respectively. CONCLUSIONS: S-649266 is a novel antibiotic with potent in vitro activity against a range of non-fermenting Gram-negative bacteria, including MDR strains. PMID- 26645270 TI - Origin in Acinetobacter gyllenbergii and dissemination of aminoglycoside modifying enzyme AAC(6')-Ih. AB - OBJECTIVES: The aac(6')-Ih gene encoding aminoglycoside 6'-N-acetyltransferase type I subtype h [AAC(6')-Ih] is plasmid-borne in Acinetobacter baumannii where it confers high-level amikacin resistance, but its origin remains unknown. We searched for the gene in the genomes of a collection of 133 Acinetobacter spp. and studied its species specificity, expression and dissemination. METHODS: Gene copy number was determined by quantitative PCR, expression by quantitative RT PCR, MIC by microdilution and transfer by plasmid mobilization. RESULTS: The aac(6')-Ih gene was present in the chromosome of the two Acinetobacter gyllenbergii of the collection and was detected in all seven A. gyllenbergii clinical isolates. They had indistinguishable flanking regions indicating that the gene was intrinsic to this species. A. baumannii PIS Aba23 promoters were provided by insertion of ISAba23, which disrupted the Pnative promoter in A. gyllenbergii. Both types of promoters were similarly potent in Escherichia coli and A. baumannii. Aminoglycoside MICs for A. baumannii harbouring pIP1858 were higher than for A. gyllenbergii due to gene dosage. The non-self-transferable plasmid could be mobilized to other A. baumannii cells by the broad host range plasmid RP4. CONCLUSIONS: We have found the origin of aac(6')-Ih in A. gyllenbergii, a species isolated, although rarely, in humans, and documented that dissemination of this gene is restricted to the Acinetobacter genus. PMID- 26645271 TI - Meal phosphate variability does not support fixed dose phosphate binder schedules for patients treated with peritoneal dialysis: a prospective cohort study. AB - BACKGROUND: Removal of phosphate by peritoneal dialysis is insufficient to maintain normal serum phosphate levels such that most patients must take phosphate binders with their meals. However, phosphate 'counting' is complicated and many patients are simply prescribed a specific dose of phosphate binders with each meal. Therefore, our primary objective was to assess the variability in meal phosphate content to determine the appropriateness of this approach. METHODS: In this prospective cohort study, adult patients with ESRD treated with peritoneal dialysis and prescribed phosphate binder therapy were eligible to participate. Participants were excluded from the study if they were unable to give consent, had hypercalcemia, were visually or hearing impaired or were expected to receive a renal transplant during the time of the study. After providing informed consent, patients kept a 3-day diet diary that included all foods and beverages consumed in addition to portion sizes. At the same time, patients documented the amount of phosphate binders taken with each meal. The phosphate content of the each meal was estimated using ESHA Food Processor SQL Software by a registered dietitian. Meal phosphate and binder variability were estimated by the Intra Class Correlation Coefficient (ICC) where 0 indicates maximal variability and 1 indicates no variability. RESULTS: Seventy-eight patients consented to participate in the study; 18 did not complete the study protocol. The patients were 60 (+/- 17) years, predominately male (38/60) and Caucasian (51/60). Diabetic nephropathy was the most common cause of end stage kidney disease. The daily phosphate intake including snacks ranged from 959 +/- 249 to 1144 +/- 362 mg. The phosphate ICC by meal: breakfast 0.63, lunch 0.16; supper 0.27. The phosphate binder ICC by meal: breakfast 0.68, lunch 0.73, supper 0.67. CONCLUSION: The standard prescription of a set number of phosphate binders with each meal is not supported by the data; patients do not appear to be adjusting their binders to match the meal phosphate content. An easy to use phosphate counting program that assists the patient in determining the appropriate amount of phosphate binder to take may enhance phosphate control. PMID- 26645272 TI - Characterizing the vulnerability of frequent emergency department users by applying a conceptual framework: a controlled, cross-sectional study. AB - BACKGROUND: Frequent emergency department (ED) users meet several of the criteria of vulnerability, but this needs to be further examined taking into consideration all vulnerability's different dimensions. This study aimed to characterize frequent ED users and to define risk factors of frequent ED use within a universal health care coverage system, applying a conceptual framework of vulnerability. METHODS: A controlled, cross-sectional study comparing frequent ED users to a control group of non-frequent users was conducted at the Lausanne University Hospital, Switzerland. Frequent users were defined as patients with five or more visits to the ED in the previous 12 months. The two groups were compared using validated scales for each one of the five dimensions of an innovative conceptual framework: socio-demographic characteristics; somatic, mental, and risk-behavior indicators; and use of health care services. Independent t-tests, Wilcoxon rank-sum tests, Pearson's Chi-squared test and Fisher's exact test were used for the comparison. To examine the -related to vulnerability- risk factors for being a frequent ED user, univariate and multivariate logistic regression models were used. RESULTS: We compared 226 frequent users and 173 controls. Frequent users had more vulnerabilities in all five dimensions of the conceptual framework. They were younger, and more often immigrants from low/middle-income countries or unemployed, had more somatic and psychiatric comorbidities, were more often tobacco users, and had more primary care physician (PCP) visits. The most significant frequent ED use risk factors were a history of more than three hospital admissions in the previous 12 months (adj OR:23.2, 95%CI = 9.1-59.2), the absence of a PCP (adj OR:8.4, 95%CI = 2.1 32.7), living less than 5 km from an ED (adj OR:4.4, 95%CI = 2.1-9.0), and household income lower than USD 2,800/month (adj OR:4.3, 95%CI = 2.0-9.2). CONCLUSIONS: Frequent ED users within a universal health coverage system form a highly vulnerable population, when taking into account all five dimensions of a conceptual framework of vulnerability. The predictive factors identified could be useful in the early detection of future frequent users, in order to address their specific needs and decrease vulnerability, a key priority for health care policy makers. Application of the conceptual framework in future research is warranted. PMID- 26645273 TI - Family tree and ancestry inference: is there a need for a 'generational' consent? AB - BACKGROUND: Genealogical research and ancestry testing are popular recreational activities but little is known about the impact of the use of these services on clients' biological and social families. Ancestry databases are being enriched with self-reported data and data from deoxyribonucleic acid (DNA) analyses, but also are being linked to other direct-to-consumer genetic testing and research databases. As both family history data and DNA can provide information on more than just the individual, we asked whether companies, as a part of the consent process, were informing clients, and through them clients' relatives, of the potential implications of the use and linkage of their personal data. METHODS: We used content analysis to analyse publically-available consent and informational materials provided to potential clients of ancestry and direct-to-consumer genetic testing companies to determine what consent is required, what risks associated with participation were highlighted, and whether the consent or notification of third parties was suggested or required. RESULTS: We identified four categories of companies providing: 1) services based only on self-reported data, such as personal or family history; 2) services based only on DNA provided by the client; 3) services using both; and 4) services using both that also have a research component. The amount of information provided on the potential issues varied significantly across the categories of companies. 'Traditional' ancestry companies showed the greatest awareness of the implications for family members, while companies only asking for DNA focused solely on the client. While in some cases companies included text recommending clients inform their relatives, showing they recognised the issues, often it was located within lengthy terms and conditions or privacy statements that may not be read by potential clients. CONCLUSIONS: We recommend that companies should make it clearer that clients should inform third parties about their plans to participate, that third parties' data will be provided to companies, and that that data will be linked to other databases, thus raising privacy and issues on use of data. We also suggest investigating whether a 'generational consent' should be created that would include more than just the individual in decisions about participating in genetic investigations. PMID- 26645275 TI - Energy and nutrient intakes of Sri Lankan patients with type 2 diabetes mellitus: a cross-sectional survey. AB - BACKGROUND: Sri Lanka has a high prevalence of type 2 diabetes mellitus. Energy and macronutrient intakes of diabetic patients have not been previously studied in this population. We aimed to clarify the energy and nutrient intakes among a group of type 2 diabetic patients attending a tertiary care diabetes facility in Sri Lanka. METHODS: Nutritional and energy intake of 123 randomly selected patients with type 2 diabetes, aged 30-74 years was assessed using a 24-h dietary recall. RESULTS: The mean energy intake for all participants was 1438 (SD 412) Kcal/day. The mean proportions of total carbohydrate, protein and fat comprising total energy intake were 68.1, 11.5 and 20.2 % respectively. The mean carbohydrate intake of 249.7 g/day comprised 50 % of rice. The mean daily protein, fat and dietary fibre intake was 42.5, 33 and 18.1 g respectively with a major contribution from plant sources. There was no significant difference in energy and nutrient intakes among the male and female participants. CONCLUSION: The present study provides the first pilot data on the energy and macronutrient intakes of diabetes patients in Sri Lanka. We clarified that these patients consumed an energy restricted, high-carbohydrate low fat diet compared to western diabetic patients. A larger nationwide dietary survey is recommended to confirm our findings. PMID- 26645274 TI - The influence of self-awareness on emotional memory formation: an fMRI study. AB - Evidence from functional neuroimaging studies of emotional perception shows that when attention is focused on external features of emotional stimuli (external perceptual orienting--EPO), the amygdala is primarily engaged, but when attention is turned inwards towards one's own emotional state (interoceptive self-orienting -ISO), regions of the salience network, such as the anterior insula (AI) and the dorsal anterior cingulate cortex (dACC), also play a major role. Yet, it is unknown if ISO boosts the contributions of AI and dACC not only to emotional 'perception' but also to emotional 'memory'. To investigate this issue, participants were scanned with functional magnetic resonance imaging (fMRI) while viewing emotional and neutral pictures under ISO or EPO, and memory was tested several days later. The study yielded three main findings: (i) emotion boosted perception-related activity in the amygdala during both ISO and EPO and in the right AI exclusively during ISO; (ii) emotion augmented activity predicting subsequent memory in AI and dACC during ISO but not during EPO and (iii) high confidence memory was associated with increased amygdala-dACC connectivity, selectively for ISO encoding. These findings show, for the first time, that ISO promotes emotional memory formation via regions associated with interoceptive awareness of emotional experience, such as AI and dACC. PMID- 26645276 TI - Viscosity as a Biomarker Coincident with Shear Wave Elastography. Re: Prediction of Significant Prostate Cancer at Prostate Biopsy and Per Core Detection Rate of Targeted and Systematic Biopsies Using Real-Time Shear Wave Elastography (Urol Int 2015; DOI: 10.1159/000431233). PMID- 26645277 TI - Transcriptional cellular responses in midgut tissue of Aedes aegypti larvae following intoxication with Cry11Aa toxin from Bacillus thuringiensis. AB - BACKGROUND: Although much is known about the mechanism of action of Bacillus thuringiensis Cry toxins, the target tissue cellular responses to toxin activity is less understood. Previous transcriptomic studies indicated that significant changes in gene expression occurred during intoxication. However, most of these studies were done in organisms without a sequenced and annotated reference genome. A reference genome and transcriptome is available for the mosquito Aedes aegypti, and its importance as a disease vector has positioned its biological control as a primary health concern. Through RNA sequencing we sought to determine the transcriptional changes observed during intoxication by Cry11Aa in A. aegypti and to analyze possible defense and recovery mechanisms engaged after toxin ingestion. RESULTS: In this work the changes in the transcriptome of 4(th) instar A. aegypti larvae exposed to Cry11Aa toxin for 0, 3, 6, 9, and 12 h were analyzed. A total of 1060 differentially expressed genes after toxin ingestion were identified with two bioconductoR packages: DESeq2 and EdgeR. The most important transcriptional changes were observed after 9 or 12 h of toxin exposure. GO enrichment analysis of molecular function and biological process were performed as well as Interpro protein functional domains and pBLAST analyses. Up regulated processes include vesicular trafficking, small GTPase signaling, MAPK pathways, and lipid metabolism. In contrast, down regulated functions are related to transmembrane transport, detoxification mechanisms, cell proliferation and metabolism enzymes. Validation with RT-qPCR showed large agreement with Cry11Aa intoxication since these changes were not observed with untreated larvae or larvae treated with non-toxic Cry11Aa mutants, indicating that a fully functional pore forming Cry toxin is required for the observed transcriptional responses. CONCLUSIONS: This study presents the first transcriptome of Cry intoxication response in a fully sequenced insect, and reveals possible conserved cellular processes that enable larvae to contend with Cry intoxication in the disease vector A. aegypti. We found some similarities of the mosquito responses to Cry11Aa toxin with previously observed responses to other Cry toxins in different insect orders and in nematodes suggesting a conserved response to pore forming toxins. Surprisingly some of these responses also correlate with transcriptional changes observed in Bti-resistant and Cry11Aa resistant mosquito larvae. PMID- 26645278 TI - Relationship of Terminal Duct Lobular Unit Involution of the Breast with Area and Volume Mammographic Densities. AB - Elevated mammographic density (MD) is an established breast cancer risk factor. Reduced involution of terminal duct lobular units (TDLU), the histologic source of most breast cancers, has been associated with higher MD and breast cancer risk. We investigated relationships of TDLU involution with area and volumetric MD, measured throughout the breast and surrounding biopsy targets (perilesional). Three measures inversely related to TDLU involution (TDLU count/mm(2), median TDLU span, median acini count/TDLU) assessed in benign diagnostic biopsies from 348 women, ages 40-65, were related to MD area (quantified with thresholding software) and volume (assessed with a density phantom) by analysis of covariance, stratified by menopausal status and adjusted for confounders. Among premenopausal women, TDLU count was directly associated with percent perilesional MD (P trend = 0.03), but not with absolute dense area/volume. Greater TDLU span was associated with elevated percent dense area/volume (P trend<0.05) and absolute perilesional MD (P = 0.003). Acini count was directly associated with absolute perilesional MD (P = 0.02). Greater TDLU involution (all metrics) was associated with increased nondense area/volume (P trend <= 0.04). Among postmenopausal women, TDLU measures were not significantly associated with MD. Among premenopausal women, reduced TDLU involution was associated with higher area and volumetric MD, particularly in perilesional parenchyma. Data indicating that TDLU involution and MD are correlated markers of breast cancer risk suggest that associations of MD with breast cancer may partly reflect amounts of at-risk epithelium. If confirmed, these results could suggest a prevention paradigm based on enhancing TDLU involution and monitoring efficacy by assessing MD reduction. PMID- 26645279 TI - Phase II Drug-Metabolizing Polymorphisms and Smoking Predict Recurrence of Non Muscle-Invasive Bladder Cancer: A Gene-Smoking Interaction. AB - Cigarette smoking is the most important known risk factor for urinary bladder cancer. Selected arylamines in cigarette smoke are recognized human bladder carcinogens and undergo biotransformation through several detoxification pathways, such as the glutathione S-transferases (GST), and uridine-diphospho glucuronosyltransferases (UGT) pathways. GSTM1 deletion status and UGT1A1*28 rs8175347 genotypes were assessed in 189 non-muscle-invasive bladder cancers (NMIBC) patients with pTa (77.2%) and pT1 (22.8%) tumors and a mean follow-up of 5.6 years, to investigate whether two common functional polymorphisms in GSTM1 and UGT1A1 genes and smoking history are associated with recurrence-free survival of patients with NMIBC. Most patients were current (48.7%) or previous (35.4%) cigarette smokers and 15.9% never smoked. Tumor recurrence occurred in 65.1% of patients, at a median time of 12.9 months. Upon multivariate analysis, previous and current smokers approximately tripled their risk of recurrences [HR = 2.76; 95% confidence interval (CI), 1.03-7.40 and HR = 2.93; 95% CI, 1.08-7.94, respectively]. When adjusted for age, smoking status, stage, grade, gender, and presence of carcinoma in situ, carriers of GSTM1 (+/- and -/-) and UGT1A1*28/*28 alleles were significantly at risk of NMIBC recurrence (HR = 10.05; 95% CI, 1.35 75.1 and HR = 1.91; 95% CI, 1.01-3.62, respectively). Compared with nonsmokers with UGT1A1*1/*1 and *1/*28 genotypes, previous and current smokers homozygous for the UGT1A1*28 allele demonstrated a risk of recurrence of 4.95 (95% CI, 1.02 24.0) and 5.32 (95% CI, 2.07-13.7), respectively. This study establishes a connection between GSTM1, UGT1A1, and tobacco exposure as prognostic markers of NMIBC recurrence in bladder cancer patients. These findings warrant validation in larger cohorts. PMID- 26645280 TI - High-Fat Diets Containing Different Amounts of n3 and n6 Polyunsaturated Fatty Acids Modulate Inflammatory Cytokine Production in Mice. AB - Dysregulation of adipokines is a hallmark of obesity. Polyunsaturated fatty acids in fish oil may exert anti-inflammatory effects on adipose tissue mitigating the dysregulation of adipokines thereby preventing obesity. This study investigated the effects of high-fat diets containing different amounts of n3 polyunsaturated fatty acids (PUFA) on adiposity and adipokine production in mice. Mice were fed a low-fat or a high-fat diet with 16 or 45 % of energy from corn oil (low n3 PUFA) in comparison with a high-fat diet containing soybean or high-oleic sunflower oil (adequate n3 PUFA) or flaxseed or fish oil (high n3 PUFA) for 11 weeks. High-fat diets, regardless of types of oils, significantly increased body fat mass and body weights compared to the low-fat diet. Adipose fatty acid composition and contents reflected dietary fatty acid profiles. The high-fat fish oil diet significantly increased adiponectin and reduced leptin concentrations in both plasma and adipose tissue; it did not elevate plasma insulin concentration compared to the high-fat corn oil diet. All high-fat diets elevated concentrations of plasminogen activator inhibitor-1 (PAI-1) and monocyte chemoattractant protein-1 (MCP-1) but lowered resistin concentrations in both plasma and adipose tissue. In conclusion, fish oil may be beneficial in improving insulin sensitivity by upregulation of adiponectin and downregulation of leptin production; n3 and n6 PUFA do not play a role at the dietary levels tested in reducing adiposity and production of pro-inflammatory cytokines (leptin, PAI-1, MCP-1 and resistin) and anti-inflammatory cytokine adiponectin. PMID- 26645281 TI - Reduced complications from intracranial grid insertion by using a small grid size and a precise protocol during monitoring. AB - BACKGROUND: A study of the risk factors associated with complications during intracranial EEG monitoring led to a change in protocol for monitoring and implantation at our centres. We conducted a study to identify any reduction in complications following the changed protocols involving the use of smaller subdural electrode arrays, continuous ICP monitoring, use of a central line, and intake of prophylactic antibiotics and dexamethasone. METHODS: We prospectively collected data on patient outcomes between 2005 and 2012 (group B) compared with patients between 1988 and 2004 (group A) before the protocol changes. RESULTS: Seventy-one patients in group A and 58 patients in group B underwent intracranial electrode implantation. Complications directly related to grids occurred in 25 % of group A vs. 8.6 % in group B (p < 0.05) and those indirectly related to grids were 11.2 % in group A vs. none in group B. The rate of transient complications requiring no treatment was 12.5 % in group A versus 1.7 % in group B. The rate of transient complications requiring treatment was 10 % in group A and 6.9 % in group B. There were two deaths in group A. The infection rate was higher in group B than group A (5.2 % vs. 2.8 %; p = 0.90). Since 2008 there have been no infective complications. Complications directly related to intracranial EEG monitoring were significantly reduced using the revised protocol (p < 0.05). Regression analysis identifying only the size of the grids (<=4 * 8 grid arrays) implanted was an independent predictor of more complications in group A (P < 0.05). CONCLUSIONS: Complication rates following intracranial implantation decreased following the use of a small grid size and adherence to a stringent protocol. PMID- 26645282 TI - Effects of a Supervised versus an Unsupervised Combined Balance and Strength Training Program on Balance and Muscle Power in Healthy Older Adults: A Randomized Controlled Trial. AB - BACKGROUND: Losses in lower extremity muscle strength/power, muscle mass and deficits in static and particularly dynamic balance due to aging are associated with impaired functional performance and an increased fall risk. It has been shown that the combination of balance and strength training (BST) mitigates these age-related deficits. However, it is unresolved whether supervised versus unsupervised BST is equally effective in improving muscle power and balance in older adults. OBJECTIVE: This study examined the impact of a 12-week BST program followed by 12 weeks of detraining on measures of balance and muscle power in healthy older adults enrolled in supervised (SUP) or unsupervised (UNSUP) training. METHODS: Sixty-six older adults (men: 25, women: 41; age 73 +/- 4 years) were randomly assigned to a SUP group (2/week supervised training, 1/week unsupervised training; n = 22), an UNSUP group (3/week unsupervised training; n = 22) or a passive control group (CON; n = 22). Static (i.e., Romberg Test) and dynamic (i.e., 10-meter walk test) steady-state, proactive (i.e., Timed Up and Go Test, Functional Reach Test), and reactive balance (e.g., Push and Release Test), as well as lower extremity muscle power (i.e., Chair Stand Test; Stair Ascent and Descent Test) were tested before and after the active training phase as well as after detraining. RESULTS: Adherence rates to training were 92% for SUP and 97% for UNSUP. BST resulted in significant group * time interactions. Post hoc analyses showed, among others, significant training-related improvements for the Romberg Test, stride velocity, Timed Up and Go Test, and Chair Stand Test in favor of the SUP group. Following detraining, significantly enhanced performances (compared to baseline) were still present in 13 variables for the SUP group and in 10 variables for the UNSUP group. CONCLUSION: Twelve weeks of BST proved to be safe (no training-related injuries) and feasible (high attendance rates of >90%). Deficits of balance and lower extremity muscle power can be mitigated by BST in healthy older adults. Additionally, supervised as compared to unsupervised BST was more effective. Thus, it is recommended to counteract intrinsic fall risk factors by applying supervised BST programs for older adults. PMID- 26645283 TI - Apoptotic Platelet Events Are Not Observed in Severe von Willebrand Disease-Type 2B Mutation p.V1316M. AB - Thrombocytopenia and increased platelet clearance observed in von Willebrand disease-type 2B (VWD-2B) may be explained by platelet apoptosis triggered by the constitutive binding of VWF to its receptor, glycoprotein Ib (GPIb). Apoptosis was assessed in platelets from two patients with a severe VWD-2B mutation VWF/p.V1316M and from mice transiently expressing VWF/p.V1316M. We now report that the VWD-2B mutation VWF/p.V1316M which binds spontaneously to its receptor GPIbalpha does not induce apoptosis. In 2 unrelated patients (P1 and P2) exhibiting different VWF plasma levels (70% and 36%, respectively, compared with normal pooled human plasma given as 100%), inner transmembrane depolarization of mitochondria, characteristic of apoptotic events was undetectable in platelets, whether washed or in whole blood. No or a moderate phosphatidyl serine (PS) exposure as measured by annexin-V staining was observed for P1 and P2, respectively. Expression of pro-apoptotic proteins Bak and Bax, and caspase-3 activity were similar to control platelets. In the VWD-2B mouse model expressing high levels of mVWF/p.V1316M (423%), similar to what is found in inflammatory pathologies, no significant difference was observed between mice expressing mVWF/WT and mVWF/p.V1316M. These results strongly argue against apoptosis as a mechanism for the thrombocytopenia of severe VWD-2B exhibiting the VWF/p.V1316M mutation. PMID- 26645284 TI - Controlling Hydrogel Mechanics via Bio-Inspired Polymer-Nanoparticle Bond Dynamics. AB - Interactions between polymer molecules and inorganic nanoparticles can play a dominant role in nanocomposite material mechanics, yet control of such interfacial interaction dynamics remains a significant challenge particularly in water. This study presents insights on how to engineer hydrogel material mechanics via nanoparticle interface-controlled cross-link dynamics. Inspired by the adhesive chemistry in mussel threads, we have incorporated iron oxide nanoparticles (Fe3O4 NPs) into a catechol-modified polymer network to obtain hydrogels cross-linked via reversible metal-coordination bonds at Fe3O4 NP surfaces. Unique material mechanics result from the supra-molecular cross-link structure dynamics in the gels; in contrast to the previously reported fluid-like dynamics of transient catechol-Fe(3+) cross-links, the catechol-Fe3O4 NP structures provide solid-like yet reversible hydrogel mechanics. The structurally controlled hierarchical mechanics presented here suggest how to develop hydrogels with remote-controlled self-healing dynamics. PMID- 26645286 TI - Serum Concentration of Growth Factors in Dogs under Different Conditions of Distraction Osteogenesis. AB - Concentrations of insulin-like growth factors 1 and 2 (IGF-1 and IGF-2), stem cell factor (SCF), vascular endothelial growth factor (VEGF), and transforming growth factor beta1 (TGF-beta1) were measured in the blood serum of dogs subjected to experimental lengthening of shin bones. In animals subjected to shin bone lengthening at a rate of 1 mm/day in 4 steps, the concentrations of SCF and TGF-beta1 significantly increased in the middle of distraction and IGF-1 concentration increased by the end of distraction. In animals subjected to lengthening at a rate of 1.5 mm/day in 6 steps, the levels of IGF-1 and TGF-beta1 significantly increased in the middle of distraction and the concentration of IGF 2 at the end of distraction. In animals subjected to lengthening at a rate of 3 mm/day in 120 steps, the concentrations of IGF-1 and TGF-beta1 significantly decreased in the middle of distraction and concentrations of IGF-1, VEGF, and TGF beta1 increased by the end of distraction. PMID- 26645285 TI - Moving Beyond "Food Deserts": Reorienting United States Policies to Reduce Disparities in Diet Quality. AB - Jason Block and S. V. Subramanian explore avenues for improving the health of Americans through reducing dietary inequalities and look at whether concern over "food deserts" has been taken too far. PMID- 26645287 TI - Effects of Experimental Coma on the Expression of Bcl-2 Protein and Caspases 3 and 9 in Rat Brain. AB - We performed immunohistochemical analysis of the expression of caspases 3, 9 and bcl-2 protein in rat brain at various terms after administration of LD50 of sodium thiopental. Expression of the specified apoptosis markers was found in the sensorimotor cortex and hippocampus (dentate gyrus and CA2 region). PMID- 26645288 TI - Effect of Tributyrin on Electrical Activity in the Small Intestine during Early Postoperative Period. AB - The effect of enteral administration of tributyrin on electrical activity in the upper segments of the small intestine was examined in rats on the model of postoperative ileus. This postoperative state is characterized with pronounced and long-term disturbances in generation of migrating myoelectric complex of the small intestine. The enteral administration of tributyrin in the early postoperative period aimed to suppress the non-adrenergic non-cholinergic influences and activation of the cholinergic anti-inflammatory pathways is an effective procedure to normalize the migrating myoelectric complex and therefore the coordinated propulsive peristalsis in the small intestine. PMID- 26645289 TI - Assessment of Nephroprotective Potential of Histochrome during Induced Arterial Hypertension. AB - Magnetic resonance tomography was employed to verify endothelial dysfunction of renal arteries in Wistar and OXYS rats under conditions of induced arterial hypertension. Angiography revealed changes in the size and form of renal arteries of hypertensive animals. In hypertensive rats, histochrome exerted a benevolent therapeutic effect in renal arteries: it decreased BP, diminished thrombus formation in fi ne capillaries and arterioles, demonstrated the anticoagulant properties, partially improved endothelial dysfunction of small renal arteries, and up-regulated the glomerular filtration. PMID- 26645290 TI - Selection of highly informative SNP markers for population affiliation of major US populations. AB - Ancestry informative markers (AIMs) can be used to detect and adjust for population stratification and predict the ancestry of the source of an evidence sample. Autosomal single nucleotide polymorphisms (SNPs) are the best candidates for AIMs. It is essential to identify the most informative AIM SNPs across relevant populations. Several informativeness measures for ancestry estimation have been used for AIMs selection: absolute allele frequency differences (delta), F statistics (F ST), and informativeness for assignment measure (In). However, their efficacy has not been compared objectively, particularly for determining affiliations of major US populations. In this study, these three measures were directly compared for AIMs selection among four major US populations, i.e., African American, Caucasian, East Asian, and Hispanic American. The results showed that the F ST panel performed slightly better for population resolution based on principal component analysis (PCA) clustering than did the delta panel and both performed better than the In panel. Therefore, the 23 AIMs selected by the F ST measure were used to characterize the four major American populations. Genotype data of nine sample populations were used to evaluate the efficiency of the 23-AIMs panel. The results indicated that individuals could be correctly assigned to the major population categories. Our AIMs panel could contribute to the candidate pool of AIMs for potential forensic identification purposes. PMID- 26645291 TI - Knowledge, Attitudes, Social Desirability, and Organizational Characteristics in Youth Mental Health Services. AB - This project investigated the extent to which knowledge of evidence-based practices (EBPs) and organizational characteristics predicted attitudes toward EBPs, while controlling for social desirability and organization membership. Participants were 167 public sector youth practitioners. Hierarchical multiple regression analyses were conducted to determine which factors significantly predicted EBP attitudes. Findings suggested that social desirability, organization membership, and various organizational characteristics predicted EBP attitudes. Results are discussed as they relate to the importance of including social desirability in future research and identifying different factors that influence EBP attitudes across various organizations. PMID- 26645292 TI - Highly Heterogeneous Probiotic Lactobacillus Species in Healthy Iranians with Low Functional Activities. AB - BACKGROUND: Lactic acid bacteria (LAB) have been considered as potentially probiotic organisms due to their potential human health properties. This study aimed to evaluate both in vitro and in vivo, the potential probiotic properties of Lactobacillus species isolated from fecal samples of healthy humans in Iran. METHODS AND RESULTS: A total of 470 LAB were initially isolated from 53 healthy individual and characterized to species level. Of these, 88 (86%) were Lactobacillus species. Biochemical and genetic fingerprinting with Phene-Plate system (PhP-LB) and RAPD-PCR showed that the isolates were highly diverse consisted of 67(76.1%) and 75 (85.2%) single types (STs) and a diversity indices of 0.994 and 0.997, respectively. These strains were tested for production of adhesion to Caco-2 cells, antibacterial activity, production of B12, anti proliferative effect and interleukin-8 induction on gut epithelial cell lines and antibiotic resistance against 9 commonly used antibiotics. Strains showing the characteristics consistent with probiotic strains, were further tested for their anti-inflammatory effect in mouse colitis model. Only one L. brevis; one L. rhamnosus and two L. plantarum were shown to have significant probiotic properties. These strains showed shortening the length of colon compared to dextran sulfate sodium and disease activity index (DAI) was also significantly reduced in mouse. CONCLUSION: Low number of LAB with potential probiotic activity as well as high diversity of lactobacilli species was evident in Iranian population. It also suggest that specific strains of L. plantarum, L. brevis and L. rhamnosus with anti-inflammatory effect in mouse model of colitis could be used as a potential probiotic candidate in inflammatory bowel disease to decrease the disease activity index. PMID- 26645293 TI - Targeted Agents for HER2-Positive Breast Cancer: Optimal Use in Older Patients. AB - The HER2 gene is overexpressed in 15-20 % of all breast cancers. With the advent of HER2-directed therapies, HER2 overexpression is no longer considered an adverse prognostic factor. Despite significant improvements in clinical outcomes with the use of trastuzumab [herceptin (H)], women aged >65 years remain under represented in most clinical trials. Cardiac safety in the elderly woman is a major concern because of pre-existing comorbidities. However, many studies suggest that elderly patients with HER2-positive disease derive the same benefit from trastuzumab as do their younger counterparts in both adjuvant and metastatic settings. Data are limited guiding safety and efficacy of other HER2 inhibitors such as pertuzumab and trastuzumab emtansine in elderly patients; however, in general, these drugs have a favorable toxicity profile. PMID- 26645294 TI - Potentially Inappropriate Medications and Anticholinergic Burden in Older People Attending Memory Clinics in Australia. AB - BACKGROUND: There has been limited research into potentially inappropriate medication (PIM) use and anticholinergic burden in patients attending memory clinics. OBJECTIVES: The aim of this study was to explore the use of PIMs related to cognitive impairment (PIMcog), anticholinergic cognitive burden (ACB) and concomitant use of anticholinergic medications with cholinesterase inhibitors (ChEIs) in patients attending memory clinics. METHODS: Cross-sectional analysis of baseline data from the Prospective Research In MEmory clinics (PRIME) study was performed. Participants were community-dwelling patients who attended nine memory clinics and had a diagnosis of mild cognitive impairment or dementia. PIMcog were defined as any medication considered potentially inappropriate for patients with cognitive impairment according to the Beers or STOPP criteria. Clinically significant ACB was defined as total score of >=3 on the ACB scale. RESULTS: A total of 964 patients, mean age 77.6 years, were included. PIMcog were used by 206 (21.4%) patients. Anticholinergics and sedatives were the most common PIMcog. PIMcog use was associated with higher number of medications (adjusted OR 1.26; 95% CI 1.19-1.33) and with not having completed secondary level education (adjusted OR 1.71; 95% CI 1.01-2.89). One hundred and thirteen (11.7%) patients had a clinically significant ACB score (>=3). ChEIs were used by 575 patients and 65 (11.3%) of these had an ACB score >=3. There was no statistically significant difference in ChEI use between patients with and without an ACB score >=3. CONCLUSION: PIMcog use, clinically significant anticholinergic burden, and concurrent use of anticholinergics with ChEIs were prevalent in patients attending memory clinics. Efforts are needed to improve prescribing for people with cognitive impairment. PMID- 26645295 TI - Body composition, muscle strength and hormonal status in patients with ataxia telangiectasia: a cohort study. AB - BACKGROUND: Ataxia-telangiectasia (A-T) is a devastating human autosomal recessive disorder that causes progressive cerebellar ataxia, immunodeficiency, premature aging, chromosomal instability and increased cancer risk. Affected patients show growth failure, poor weight gain, low body mass index (BMI), myopenia and increased fatigue during adolescence. The prevalence of alterations in body composition, muscle strength and hormonal status has not been well described in classical A-T patients. Additionally, no current guidelines are available for the assessment and management of these changes. METHODS: We analyzed body composition, manual muscle strength and hormonal status in 25 A-T patients and 26 age-matched, healthy controls. Bioelectrical impedance analysis (BIA) was performed to evaluate the body composition, fat-free mass (FFM), body cell mass (BCM), extracellular matrix (ECM), phase angle (PhA), fat mass (FM) and ECM to BCM ratio. Manual muscle strength was measured using a hydraulic hand dynamometer. RESULTS: The BMI, FFM and PhA were significantly lower in A-T patients than in controls (BMI 16.56 +/- 3.52 kg/m(2) vs. 19.86 +/- 3.54 kg/m(2); Z-Score: -1.24 +/- 1.29 vs. 0.05 +/- 0.92, p <0.001; FFM 25.4 +/- 10.03 kg vs. 41.77 +/- 18.25 kg, p < 0.001; PhA: 4.6 +/- 0.58 degrees vs. 6.15 +/- 0.88 degrees , p < 0.001). Manual muscle strength was significantly impaired in A-T patients compared with controls (10.65 +/- 10.97 kg vs. 26.8 +/- 30.39 kg, p < 0.0001). In addition, cortisol and dehydroepiandrosterone sulfate (DHEAS) levels were significantly lower in A-T patients than in controls. CONCLUSION: Altered body composition, characterized by depleted BMI, PhA and BCM; by the need to sit in a wheelchair; by altered hormone levels; and by poor muscle strength, is a major factor underlying disease progression and increased fatigue in A-T patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT02345200. PMID- 26645296 TI - The importance of intramedullary hip nail positioning during implantation for stable pertrochanteric fractures: biomechanical analysis. AB - PURPOSE: Proximal femoral fractures are among the most commonly sustained fractures. The current treatment of stable proximal femoral fractures located in trochanteric region primarily involves the use of two systems: extramedullary dynamic hip screws and intramedullary hip nails. Given that these fractures are mainly found in the elderly population, the necessity of a repeat, due to failure of the first, may jeopardize the patient's life. Decisive factors contributing to the healing of a fracture (or the failure thereof) include fracture pattern, technical implementation of the operation (i.e., position of the implant), implant's properties and its changes in relation to the surrounding bone tissue during loading. Each screw insertion variant results in damage to various load bearing bone structures, which can be expected to influence healing quality and stability of newly formed bone. METHOD: With the aid of a numerical model and finite element methods, the authors analyzed several different positions of IMHN/PFH-nails in the proximal femur, with the objective of determining positions with an increased risk of failure. RESULTS AND CONCLUSION: In model situations, it has been shown that in stable fractures results do not depend on absolutely precise positioning and small deflections in the nails and neck screws positions do not significantly increase the risk of failure for the entire fixation. Damage to load-bearing structures relative to various implant placements does not impact the resultant overall fixation stability. Therefore, it is not necessary to re introduce implants in the ideal position, which can lead to reduced patient radiation doses during surgery. PMID- 26645298 TI - The Diagnostics of Laser-Induced Fluorescence (LIF) Spectra of PAHs in Flame with TD-DFT: Special Focus on Five-Membered Ring. AB - The electronic emission characteristics of 13 gas-phase PAHs, ranging from phenlylacetylene to rubicene, were investigated to diagnose laser-induced fluorescence (LIF) spectra of PAHs in flame by DFT, TD-DFT, and premixed flame modeling methods. It was found that the maximum emission wavelengths of the PAHs with five-membered ring are located in visible region and insensitive to the number of C atoms. However, the fluorescence wavelengths of the PAHs without five membered rings increase with the number of C atoms due to the reduced HOMO-LUMO gap. In addition, the fluorescence wavelength of the PAHs without five-membered rings with linear arrangement is longer than that of PAHs with nonlinear arrangement. According to the Franck-Condon principle, the vibrationally resolved electronic fluorescence spectra were obtained. The results show that fluorescence bandwidth of the PAHs with five-membered rings is much broader than that of the PAHs without five-membered rings. The concentration of PAHs was calculated by using the premixed flat-flame model with KM2 mechanism. On the basis of the fluorescence bandwidth and the concentration of the PAHs, the potentially fluorescence distribution of PAHs in flame was mapped. One can distinguish the specific PAHs according to the mapped fluorescence distribution of PAHs in this study. It was found that naphthalene should be responsible for the fluorescence located in the 312-340 nm region in the flame. 1-Ethynylnaphthalene is the most possible candidate to emit the fluorescence located in the 360-380 nm region. The fluorescence signals with the wavelength longer than 500 nm are likely emitted by the PAHs with five-membered rings. This study contributes to enhance the selectivity of PAHs in LIF technology, especially in the visible region. PMID- 26645297 TI - Metrical evaluation of Slovak patients with pectus excavatum. AB - PURPOSE: We have started to assess the severity of pectus excavatum by means of anthropometric methods prior to CT examination since 2012. The aim of the study was to establish a significance of anthropometry as first-line diagnostic method. Afterwards, we analyzed statistical significance of differences in selected anthropometric indicators before and after surgical intervention. The analysis was also focused on the data from CT scans. METHODS: The followed group represented 27 patients, including 6 girls and 21 boys aged 7-18 years (mean age 15.59 years). Evaluation of anthropometric measurements was realized by somatometry, and other metrical measurements were calculated from thoracic CT scans of patients. All measurements were managed with the approval of the Ethics Committee. RESULTS: The significant differences were found in sagittal diameter and thoracic index in 64.0 % of the patients. Data analyzed from CT showed that flat chest prevailed in both gender (100 %). The largest group represented asymmetric type of pectus excavatum (40.74 %). The superiority of the asymmetric type to the right was confirmed. The values of the Haller index were in range 2.00-5.17 (mean value 3.64). 81.5 % of patients met criterion for surgical correction. Most patients with pectus excavatum had a milder form of deformation. CONCLUSIONS: Anthropometry provides feasible and non-invasive method of pectus deformities evaluation. Based on the study results, anthropometry should be performed prior to CT examination in order to select patients for surgical treatment. Anthropometric measurements are helpful in accurate documentation of growth, longitudinal observation of the patient, and can support decision concerning the type of surgery. PMID- 26645299 TI - Dengue cases in India doubled in 2014-15. PMID- 26645300 TI - Magnetic Behavior of Heterometallic Wheels Having a [Mn(IV)6M2O9](10+) Core with M = Ca(2+) and Sr(2+). AB - Two new heterometallic Mn(IV)-M(2+) compounds with formula [Mn6M2O9(4 (t)BuC6H4COO)10(4-(t)BuC6H4COOH)5] (M = Ca(2+) (1), Sr(2+) (2)) have been crystallized. The core of both compounds consists of a planar Mn6 ring, where the Mn(IV) ions are alternatively bridged by (MU3-O)2(MU-RCOO) and (MU4-O)(MU-RCOO)2 ligands, and the two alkaline earth ions are located to both sides of the wheel, linked to the oxo bridges, generating three fused [Mn2M2O4](4+) cuboids. These compounds show a net antiferromagnetic behavior, more important for 2 (Sr(2+)) than for 1 (Ca(2+)). The fitting of the experimental data was performed with the support of DFT calculations, considering four different exchange pathways: two between adjacent Mn(IV) ions (J1 and J2) and two between nonadjacent Mn(IV) ions (J3 and J4). The results of the analysis show that J1 and J2 are of the opposite sign, the ferromagnetic contribution corresponding to the [Mn2(MU4-O)(MU RCOO)2](4+) unit (J2). The influence of the M(2+) ions in the magnetic behavior is analyzed for 1 and 2 and for three hypothetical models with the structural parameters of 1 containing Mg(2+), Sr(2+) or without the M(2+) ions. In spite of the diamagnetic character of the alkaline earth ions, their influence on the magnetic behavior has been evidenced and correlated with their polarizing effect. Moreover, the magnetic interactions between nonadjacent ions are non-negligible. PMID- 26645301 TI - Detection and Electronic Structure of Naked Actinide Complexes: Rhombic-Ring (AnN)2 Molecules Stabilized by Delocalized pi-Bonding. AB - The major products of the reaction of laser ablated and excited U atoms and N2 are the linear N=U=N dinitride molecule, isoelectronic with the uranyl dication, and the diatomic nitride U=N. These molecules form novel cyclic dimers, (UN)2 and (NUN)2, with complex electronic structures, in matrix isolation experiments, which increase on UV photolysis. In addition, (NUN)2 increases at the expense of (UN)2 upon warming the codeposited matrix samples into the 20-40 K range as attested by additional nitrogen and argon matrix infrared spectra recorded after cooling the samples back to 4 or 7 K. These molecules are identified through matrix infrared spectra with nitrogen isotopic substitution and by comparing the observed matrix frequencies with those from electronic structure calculations. The dimerization is strong (theory predicts the dimer to be on the order of 100 kcal/mol more stable than the monomers), since the ground state involves 12 bonding electrons, 8 in the sigma-system, and 4 in the delocalized pi-system. This delocalized pi bonding is present in the U, Th, La, and Hf analogues further demonstrating the interesting interplay between the 5f and 6d orbitals in actinide chemistry. The (UN)2(+) cation is also observed in solid argon, and calculations indicate that the bonding in the ring is preserved. On the other hand, the NUN dimer is of lower C2h symmetry, and the initial NUN molecules are recognizable in this more weakly bonded (DeltaE = -64 kcal/mol) structure. The NThN molecules bind more strongly in the (NThN)2 dimer than the NUN molecules in (NUN)2 since NUN itself is more stable than NThN. PMID- 26645302 TI - Positive Illusions? The Accuracy of Academic Self-Appraisals in Adolescents With ADHD. AB - OBJECTIVE: Children with attention deficit/hyperactivity disorder (ADHD) overestimate their academic competencies (AC) relative to performance and informant indicators (i.e., positive illusory bias; PIB). Do adolescents with ADHD exhibit this PIB and does it render self-views inaccurate? We examined the magnitude of the AC-PIB in adolescents with and without ADHD, the predictive accuracy of parent and adolescent AC ratings, and whether executive functions (EF) predict the AC-PIB. METHOD: Adolescents (49 ADHD; 47 typically developing) completed math and EF tests, and self-rated their AC. Parents rated their adolescents' AC and EF. RESULTS: Adolescents with ADHD performed more poorly on the math task (vs. comparison group) but had a larger AC-PIB relative to parents' ratings. EFs predicted the PIB within the full sample. Adolescents' AC ratings, regardless of ADHD status, were more predictive of math performance than their parents' AC ratings. CONCLUSION: Adolescents with ADHD appear self-aware in their AC despite a modest PIB; nuanced self-appraisals may depend on EFs. PMID- 26645303 TI - Metallamacrocycle formation through dimerization of metal bioconjugates derived from amino acids and peptides. AB - Metallamacrocycles of 12, 16, and 22 members are obtained by deprotonation of the carboxylic group of the side chain of iminopyridine complexes derived from the amino acid beta-alanine, and the peptides Gly-Gly and Gly-Gly-Gly. Instead of the expected intramolecular attack to give tridentate (N,N,O) ligands, the deprotonated carboxylate attacks in an inter-molecular manner to give dimers in which the ligand acts as a bridge bonded in a kappa(2)(N,N') chelating fashion to one metal and as kappa(O) to the other metal. The formation of the dimers is supported by NMR spectroscopy, mass spectrometry and X-ray crystallography. PMID- 26645304 TI - Evidence for a trigeminal mesencephalic-hypoglossal nuclei loop involved in controlling vibrissae movements in the rat. AB - Previous studies performed in rats showed that the whisker-pad motor innervation involves not only the facial nerve, but also some hypoglossal neurons whose axons travel within the trigeminal infraorbital nerve (ION) and target the extrinsic muscles surrounding the whisker-pad macrovibrissae. Furthermore, the electrical stimulation of the ION induced an increase in the EMG activity of these muscles, while the hypoglossal nucleus stimulation elicited evoked potentials and single motor unit responses. However, the existence of a neural network able to involve the XIIth nucleus in macrovibrissae whisking control was totally unknown until now. Since other recent experiments demonstrated that: (1) the mesencephalic trigeminal nucleus (Me5) neurons respond to both spontaneous and artificial movements of macrovibrissae, and (2) the Me5 peripheral terminals provide a monosynaptic sensory innervation to the macrovibrissae, the present study was aimed at analyzing a possible role of the Me5 nucleus as a relay station in the sensory-motor loop that involves the XIIth nucleus neurons in rhythmic whisking control. Two tracers were used in the same animal: Fluoro Gold, which was injected into the whisker pad to retrogradely label the hypoglossal whisker-pad projection neurons, and Dil, which was instead injected into the Me5 to label its projections to these hypoglossal neurons. Results demonstrated that terminals of the Me5 neurons monosynaptically target the hypoglossal whisker-pad projection neurons. The functional role of this sensory-motor connection is discussed, with particular regard to a hypothesized proprioceptive reflex in whisker-pad extrinsic muscles that can be elicited by the activation of the Me5 macrovibrissae receptors. PMID- 26645305 TI - Delayed benefit of naps on motor learning in preschool children. AB - Sleep benefits memory consolidation across a variety of domains in young adults. However, while declarative memories benefit from sleep in young children, such improvements are not consistently seen for procedural skill learning. Here we examined whether performance improvements on a procedural task, although not immediately observed, are evident after a longer delay when augmented by overnight sleep (24 h after learning). We trained 47 children, aged 33-71 months, on a serial reaction time task and, using a within-subject design, evaluated performance at three time points: immediately after learning, after a daytime nap (nap condition) or equivalent wake opportunity (wake condition), and 24 h after learning. Consistent with previous studies, performance improvements following the nap did not differ from performance improvements following an equivalent interval spent awake. However, significant benefits of the nap were found when performance was assessed 24 h after learning. This research demonstrates that motor skill learning is benefited by sleep, but that this benefit is only evident after an extended period of time. PMID- 26645306 TI - Determining thresholds using adaptive procedures and psychometric fits: evaluating efficiency using theory, simulations, and human experiments. AB - When measuring thresholds, careful selection of stimulus amplitude can increase efficiency by increasing the precision of psychometric fit parameters (e.g., decreasing the fit parameter error bars). To find efficient adaptive algorithms for psychometric threshold ("sigma") estimation, we combined analytic approaches, Monte Carlo simulations, and human experiments for a one-interval, binary forced choice, direction-recognition task. To our knowledge, this is the first time analytic results have been combined and compared with either simulation or human results. Human performance was consistent with theory and not significantly different from simulation predictions. Our analytic approach provides a bound on efficiency, which we compared against the efficiency of standard staircase algorithms, a modified staircase algorithm with asymmetric step sizes, and a maximum likelihood estimation (MLE) procedure. Simulation results suggest that optimal efficiency at determining threshold is provided by the MLE procedure targeting a fraction correct level of 0.92, an asymmetric 4-down, 1-up staircase targeting between 0.86 and 0.92 or a standard 6-down, 1-up staircase. Psychometric test efficiency, computed by comparing simulation and analytic results, was between 41 and 58% for 50 trials for these three algorithms, reaching up to 84% for 200 trials. These approaches were 13-21% more efficient than the commonly used 3-down, 1-up symmetric staircase. We also applied recent advances to reduce accuracy errors using a bias-reduced fitting approach. Taken together, the results lend confidence that the assumptions underlying each approach are reasonable and that human threshold forced-choice decision making is modeled well by detection theory models and mimics simulations based on detection theory models. PMID- 26645307 TI - Use of an allostatic neurotechnology by adolescents with postural orthostatic tachycardia syndrome (POTS) is associated with improvements in heart rate variability and changes in temporal lobe electrical activity. AB - Autonomic dysregulation and heterogeneous symptoms characterize postural orthostatic tachycardia syndrome (POTS). This study evaluated the effect of high resolution, relational, resonance-based, electroencephalic mirroring (HIRREM((r))), a noninvasive, allostatic neurotechnology for relaxation and auto calibration of neural oscillations, on heart rate variability, brain asymmetry, and autonomic symptoms, in adolescents with POTS. Seven subjects with POTS (three males, ages 15-18) underwent a median of 14 (10-16) HIRREM sessions over 13 (8 17) days. Autonomic function was assessed from 10-min continuous heart rate and blood pressure recordings, pre- and post-HIRREM. One-minute epochs of temporal high-frequency (23-36 Hz) brain electrical activity data (T3 and T4, eyes closed) were analyzed from baseline HIRREM assessment and subsequent sessions. Subjects rated autonomic symptoms before and after HIRREM. Four of seven were on fludrocortisone, which was stopped before or during their sessions. Heart rate variability in the time domain (standard deviation of the beat-to-beat interval) increased post-HIRREM (mean increase 51%, range 10-143, p = 0.03), as did baroreflex sensitivity (mean increase in high-frequency alpha 65%, range -6 to 180, p = 0.05). Baseline temporal electrical asymmetry negatively correlated with change in asymmetry from assessment to the final HIRREM session (p = 0.01). Summed high-frequency amplitudes at left and right temporal lobes decreased a median of 3.8 MUV (p = 0.02). There was a trend for improvements in self-reported symptoms related to the autonomic nervous system. Use of HIRREM was associated with reduced sympathetic bias in autonomic cardiovascular regulation, greater symmetry and reduced amplitudes in temporal lobe high-frequency electrical activity, and a trend for reduced autonomic symptoms. Data suggest the potential for allostatic neurotechnology to facilitate increased flexibility in autonomic cardiovascular regulation, possibly through more balanced activity at regions of the neocortex responsible for autonomic management. Clinical trial registry "Tilt Table with Suspected postural orthostatic tachycardia syndrome (POTS) Subjects," Protocol Record: WFUBAHA01. PMID- 26645308 TI - Press to grasp: how action dynamics shape object categorization. AB - Action and object are deeply linked to each other. Not only can viewing an object influence an ongoing action, but motor representations of action can also influence visual categorization of objects. It is tempting to assume that this influence is effector-specific. However, there is indirect evidence suggesting that this influence may be related to the action goal and not just to the effector involved in achieving it. This paper aimed, for the first time, to tackle this issue directly. Participants were asked to categorize different objects in terms of the effector (e.g. hand or foot) typically used to act upon them. The task was delivered before and after a training session in which participants were instructed either just to press a pedal with their foot or to perform the same foot action with the goal of guiding an avatar's hand to grasp a small ball. Results showed that pressing a pedal to grasp a ball influenced how participants correctly identified graspable objects as hand-related ones, making their responses more uncertain than before the training. Just pressing a pedal did not have any similar effect. This is evidence that the influence of action on object categorization can be goal-related rather than effector-specific. PMID- 26645309 TI - Hemispheric asymmetries in perceived depth revealed through a radial line bisection task. AB - Research suggests that the left cerebral hemisphere is predisposed for processing stimuli in 'near' space, whereas the right hemisphere is specialised for processing stimuli in 'far' space. This hypothesis was tested directly by asking 25 undergraduates to carry out a landmark radial line bisection task. To test the effect of hemispheric differences in processing, the lines were placed to the left, right or centre within the transverse plane. Consistent with predictions, lines in all three conditions were bisected distal to the true centre. More importantly, there was an asymmetry whereby the distal bias was stronger for lines presented in the left hemispace compared to the right hemispace. The results demonstrate that the perception of depth is affected by left/right placement along the lateral axis and highlight the cognitive/neural interplay between the radial and lateral axes. PMID- 26645310 TI - The Attention Network Test-Interaction (ANT-I): reliability and validity in healthy older adults. AB - The Attention Network Test (ANT) is a frequently used computer-based tool for measuring the three attention networks (alerting, orienting, and executive control). We examined the psychometric properties of performance on a variant of the ANT, the Attention Network Test-Interaction (ANT-I) in healthy older adults (N = 173; mean age = 65.4, SD = 6.5; obtained from the Brain in Motion Study, Tyndall et al. BMC Geriatr 13:21, 2013. doi: 10.1186/1471-2318-13-21) to evaluate its usefulness as a measurement tool in both aging and clinical research. In terms of test reliability, split-half correlation analyses showed that all network scores were significantly reliable, although the strength of the correlations varied across networks as seen before (r = 0.29, 0.70, and 0.68, for alerting, orienting, and executive networks, respectively, p's < 0.05). In terms of construct validity, ANOVAs confirmed that each network score was significant (18.3, 59.4, and 109.2 ms for the alerting, orienting, and executive networks, respectively, p's < 0.01) and that these scores were generally independent from each other. Importantly, for criterion validity, a series of hierarchical linear regressions showed that the executive network score, in addition to demographic information, was a significant predictor of performance on tests of conflict resolution as well as verbal memory and retrieval (beta = -0.165 and -0.184, p's < 0.05, respectively). These results provide new information regarding the reliability and validity of ANT-I test performance in a healthy older adult population. The results provide insights into the psychometrics of the ANT-I and its potential utility in clinical research settings. PMID- 26645311 TI - Use your head! Perception of action possibilities by means of an object attached to the head. AB - Perceiving any environmental property requires spontaneously assembling a smart perceptual instrument-a task-specific measurement device assembled across potentially independent anatomical units. Previous research has shown that to a large degree, perception of a given environmental property is anatomically independent. We attempted to provide stronger evidence for this proposal by investigating perception by an organization of anatomical and inert components that likely requires the spontaneous assembly of a novel smart perceptual instrument-a rod attached to the head. Specifically, we compared cephalic and manual perception of whether an inclined surface affords standing on. In both conditions, perception reflected the action capabilities of the perceiver and not the appendage used to wield the rod. Such results provide stronger evidence for anatomical independence of perception within a given perceptual system and highlight that flexible task-specific detection units can be assembled across units that span the body and inert objects. PMID- 26645313 TI - Psychological Distress and Non-Suicidal Self-Injury: The Mediating Roles of Rumination, Cognitive Reappraisal, and Expressive Suppression. AB - This study sought to explore the relationships between depression, anxiety, stress, and non-suicidal self-injury (NSSI), and the mediating roles of rumination and emotion regulation in this relationship. The sample comprised 1,586 Australian university students who completed a self-report questionnaire assessing the relevant variables. Of the sample, 8.9% engaged in NSSI in the 4 weeks prior to the survey. Depression, anxiety, and stress each exerted a direct effect on NSSI, and each relationship was mediated by cognitive reappraisal. The relationship between stress and NSSI was also mediated by expressive suppression. The results imply intervention efforts aimed at teaching adaptive emotion regulation strategies for students experiencing high levels of psychological distress may reduce the frequency of NSSI. PMID- 26645314 TI - Three-Dimensional Tubular MoS2/PANI Hybrid Electrode for High Rate Performance Supercapacitor. AB - By using three-dimensional (3D) tubular molybdenum disulfide (MoS2) as both an active material in electrochemical reaction and a framework to provide more paths for insertion and extraction of ions, PANI nanowire arrays with a diameter of 10 20 nm can be controllably grown on both the external and internal surface of 3D tubular MoS2 by in situ oxidative polymerization of aniline monomers and 3D tubular MoS2/PANI hybrid materials with different amounts of PANI are prepared. A controllable growth of PANI nanowire arrays on the tubular MoS2 surface provides an opportunity to optimize the capacitive performance of the obtained electrodes. When the loading amount of PANI is 60%, the obtained MoS2/PANI-60 hybrid electrode not only shows a high specific capacitance of 552 F/g at a current density of 0.5 A/g, but also gives excellent rate capability of 82% from 0.5 to 30 A/g. The remarkable rate performance can be mainly attributed to the architecture with synergistic effect between 3D tubular MoS2 and PANI nanowire arrays. Moreover, the MoS2/PANI-60 based symmetric supercapacitor also exhibits the excellent rate performance and good cycling stability. The specific capacitance based on the total mass of the two electrodes is 124 F/g at a current density of 1 A/g and 79% of its initial capacitance is remained after 6000 cycles. The 3D tubular structure provides a good and favorable method for improving the capacitance retention of PANI electrode. PMID- 26645315 TI - Auditory Consonant Trigrams: A Psychometric Update?. AB - The Auditory Consonant Trigrams (ACT) test was developed to evaluate immediate memory in the absence of rehearsal. There are few psychometric studies of the measure and a lack of normative data using samples from the United States or Veterans. ACT data were examined for 184 participants who passed the Word Memory Test, denied a history of moderate to severe traumatic brain injury (TBI), and consented for research purposes only. Reliability and construct validity were examined and normative data developed using a healthy subsample. Cronbach's alpha for the ACT total score was 0.79. Regression analyses suggested that years of education, estimated premorbid IQ, psychomotor speed, working memory, and impulsivity had the strongest relationships with performance on the ACT. Performance was unrelated to posttraumatic stress disorder and remote mild TBI, but the presence of major depressive disorder was associated with lower total scores. These results demonstrate the ACT has adequate psychometric properties. PMID- 26645312 TI - Factors for short-term outcomes in patients with a minor stroke: results from China National Stroke Registry. AB - BACKGROUND: Stroke recurrence and disability in patients with a minor stroke is one of the most depressing medical situations. In this study, we aimed to identify which factors were associated with adverse outcomes of a minor stroke. METHODS: The China National Stroke Registry (CNSR) is a nationwide prospective registry for patients presented to hospitals with acute cerebrovascular events between September 2007 and August 2008. The 3-month follow-up was completed in 4669 patients with a minor stroke defined as the initial neurological severity lower than 4 in the National Institutes of Health Stroke Scale (NIHSS). Multivariate model was used to determine the association between risk factors and clinical outcomes. RESULTS: Of 4669 patients with a minor stroke during 3-month follow-up, 459 (9.8 %) patients experienced recurrent stroke, 679 (14.5 %) had stroke disability and 168 (3.6 %) died. Multivariate model identified hypertension, diabetes mellitus, atrial fibrillation, coronary heart disease and previous stroke as independent predictors for the recurrent stroke. Age, diabetes mellitus, atrial fibrillation, previous stroke and time from onset to admission < 24 h were independent predictors for stroke disability. The independent predictors for the all-caused death were age, atrial fibrillation, and coronary heart disease. CONCLUSIONS: The short-term risk of poor clinical outcome in Chinese patients with a minor stroke was substantial. Therefore, patients with a minor stroke should be given expeditious assessment and urgent aggressive intervention. PMID- 26645316 TI - Chaotic Visual Cryptosystem Using Empirical Mode Decomposition Algorithm for Clinical EEG Signals. AB - This paper, proposes a chaotic visual cryptosystem using an empirical mode decomposition (EMD) algorithm for clinical electroencephalography (EEG) signals. The basic design concept is to integrate two-dimensional (2D) chaos-based encryption scramblers, the EMD algorithm, and a 2D block interleaver method to achieve a robust and unpredictable visual encryption mechanism. Energy-intrinsic mode function (IMF) distribution features of the clinical EEG signal are developed for chaotic encryption parameters. The maximum and second maximum energy ratios of the IMFs of a clinical EEG signal to its refereed total energy are used for the starting points of chaotic logistic map types of encrypted chaotic signals in the x and y vectors, respectively. The minimum and second minimum energy ratios of the IMFs of a clinical EEG signal to its refereed total energy are used for the security level parameters of chaotic logistic map types of encrypted chaotic signals in the x and y vectors, respectively. Three EEG database, and seventeen clinical EEG signals were tested, and the average r and mse values are 0.0201 and 4.2626 * 10(-29), respectively, for the original and chaotically-encrypted through EMD clinical EEG signals. The chaotically-encrypted signal cannot be recovered if there is an error in the input parameters, for example, an initial point error of 0.000001 %. The encryption effects of the proposed chaotic EMD visual encryption mechanism are excellent. PMID- 26645317 TI - Intelligent Emergency Department: Validation of Sociometers to Study Workload. AB - Sociometers are wearable sensors that continuously measure body movements, interactions, and speech. The purpose of this study is to test sociometers in a smart environment in a live clinical setting, to assess their reliability in capturing and quantifying data. The long-term goal of this work is to create an intelligent emergency department that captures real-time human interactions using sociometers to sense current system dynamics, predict future state, and continuously learn to enable the highest levels of emergency care delivery. Ten actors wore the devices during five simulated scenarios in the emergency care wards at a large non-profit medical institution. For each scenario, actors recited prewritten or structured dialogue while independent variables, e.g., distance, angle, obstructions, speech behavior, were independently controlled. Data streams from the sociometers were compared to gold standard video and audio data captured by two ward and hallway cameras. Sociometers distinguished body movement differences in mean angular velocity between individuals sitting, standing, walking intermittently, and walking continuously. Face-to-face (F2F) interactions were not detected when individuals were offset by 30 degrees , 60 degrees , and 180 degrees angles. Under ideal F2F conditions, interactions were detected 50 % of the time (4/8 actor pairs). Proximity between individuals was detected for 13/15 actor pairs. Devices underestimated the mean duration of speech by 30-44 s, but were effective at distinguishing the dominant speaker. The results inform engineers to refine sociometers and provide health system researchers a tool for quantifying the dynamics and behaviors in complex and unpredictable healthcare environments such as emergency care. PMID- 26645318 TI - A Study on the Effects of Sympathetic Skin Response Parameters in Diagnosis of Fibromyalgia Using Artificial Neural Networks. AB - Fibromyalgia syndrome (FMS), usually observed commonly in females over age 30, is a rheumatic disease accompanied by extensive chronic pain. In the diagnosis of the disease non-objective psychological tests and physiological tests and laboratory test results are evaluated and clinical experiences stand out. However, these tests are insufficient in differentiating FMS with similar diseases that demonstrate symptoms of extensive pain. Thus, objective tests that would help the diagnosis are needed. This study analyzes the effect of sympathetic skin response (SSR) parameters on the auxiliary tests used in FMS diagnosis, the laboratory tests and physiological tests. The study was conducted in Suleyman Demirel University, Faculty of Medicine, Physical Medicine and Rehabilitation Clinic in Turkey with 60 patients diagnosed with FMS for the first time and a control group of 30 healthy individuals. In the study all participants underwent laboratory tests (blood tests), certain physiological tests (pulsation, skin temperature, respiration) and SSR measurements. The test data and SSR parameters obtained were classified using artificial neural network (ANN). Finally, in the ANN framework, where only laboratory and physiological test results were used as input, a simulation result of 96.51 % was obtained, which demonstrated diagnostic accuracy. This data, with the addition of SSR parameter values obtained increased to 97.67 %. This result including SSR parameters - meaning a higher diagnostic accuracy - demonstrated that SSR could be a new auxillary diagnostic method that could be used in the diagnosis of FMS. PMID- 26645319 TI - Utility of Daily Mobile Tablet Use for Residents on an Otolaryngology Head & Neck Surgery Inpatient Service. AB - The objective of this study was to investigate the utility of electronic tablets and their capacity to increase hospital floor productivity, efficiency, improve patient care information safety, and to enhance resident education and resource utilization on a busy Otolaryngology - Head & Neck Surgery inpatient service. This was a prospective cohort study with a 2-week pre-implementation period with standard paper census lists without mobile tablet use, and a 2-week post implementation period followed with electronic tablets used to place orders, look up pertinent clinical data, educate patients as appropriate, and to record daily to-dos that would previously be recorded on paper. The setting for the study was Duke University Medical Center in Durham, North Carolina, with 13 Otolaryngology residents comprising the study population. The time for inpatient rounding was shorter with the use tablets (p = 0.037). There was a non-significant trend in the number of times a resident had to leave rounds to look up a clinical query on a computer, with less instances occurring in the post-implementation study period. The residents felt that having a tablet facilitated more detailed and faster transfer of information, and improved ease of documentation in the medical record. Seventy percent felt tablets helped them spend more time with patients, 70 % could spend more time directly involved in rounds because they could use the tablet to query information at point-of-care, and 80 % felt tablets improved morale. The utility of a mobile tablet device coupled with the electronic health record appeared to have both quantitative and qualitative improvements in efficiency, increased time with patients and attendance at academic conferences. Tablets should be encouraged but not mandated for clinical and educational use. PMID- 26645320 TI - Study of Artifact-Resistive Technology Based on a Novel Dual Photoplethysmography Method for Wearable Pulse Rate Monitors. AB - Pulse rate is one of the major physiological parameters for monitoring of cardiovascular conditions or excise states during daily life. However it is difficult to precisely measure the exact pulse rates as photoplethysmography (PPG) is easy to be affected by motion artifacts. Instead of using accelerometers followed by algorithms such as least mean square (LMS), recursive least square (RLS) and independent component analysis (ICA) or other equipment such as complex laser systems to measure displacement directly, a novel motion artifact estimation method which had lower computational complexity and higher signal dynamic range was studied and implemented, where a differential channel following green and red light PPG channels was applied to reduce the motion artifact caused by displacement of light emitting diode (LED), photo diode (PD) and tissue deformation before the analog signal was converted to digital form. A miniaturized, battery powered wrist worn artifact-resistive pulse rates monitoring system (PRMS) was presented to verify the proposed method. Four kinds of motions were performed and the results showed that the differential channel improved the morphology of the PPG signal and appeared to be artifact resistive during motions through light intensity control and high gain-phase consistency circuit design here. PMID- 26645321 TI - A mild hydration of nitriles catalysed by copper(ii) acetate. AB - A simple, mild and general procedure for the hydration of nitriles to amides using copper as catalyst and promoted by N,N-diethylhydroxylamine is described. The reaction can be conducted in water at low temperature in short reaction times. This new procedure allows amides to be obtained from a wide range of substrates in excellent yields. PMID- 26645323 TI - Proteus mirabilis RMS 203 as a new representative of the O13 Proteus serogroup. AB - The unique feature of some Proteus O-polysaccharides is occurrence of an amide of galacturonic acid with N(epsilon)-[(S/R)-1-Carboxyethyl]-L-lysine, GalA6(2S,8S/R AlaLys). The results of the serological studies presented here, with reference to known O-antigens structures suggest that GalA6(2S,8S/R-AlaLys) or 2S,8R-AlaLys contribute to cross-reactions of O13 Proteus antisera, and Proteeae LPSs. It was also revealed that the Proteus mirabilis RMS 203 strain can be classified into the O13 serogroup, represented so far by two strains: Proteus mirabilis 26/57 and Proteus vulgaris 8344. The O13 LPS is a serologically important antigen with a fragment common to LPSs of different species in the Proteeae tribe. PMID- 26645322 TI - The impact of the experience of childhood poverty on adult health-risk behaviors in Japan: a mediation analysis. AB - BACKGROUND: The experience of childhood poverty has a long-lasting, adverse impact on physical health outcomes in adulthood. We examined the mediating effects of adult socioeconomic status (SES) and social support on the association between childhood poverty and adult health-risk behaviors. METHODS: Cross sectional data collected from Japanese community residents (N = 3836) were used. A binary indicator of the experience of childhood poverty was constructed by utilizing retrospectively assessed standard of living at age 15 and a set of parental SES variables. The associations of childhood poverty with smoking, lack of exercise, poor dietary habits, and excessive drinking at the time of survey were examined by logistic regression analysis. A mediation analysis was conducted to estimate the magnitudes of the mediating effects of adult SES and social support on these associations. RESULTS: Adult SES and social support together mediated 64.0, 29.4 and 30.6 % of the impacts of the experience of childhood poverty on smoking, lack of exercise, and poor dietary habits, respectively. Educational attainment had the largest mediating effect (58.2 %) on the impact of the experience of childhood poverty on smoking. CONCLUSIONS: The results suggest that interventions and policies for supporting children living in poverty should aim to enhance their future SES and provide better social support, as this might improve their overall health. PMID- 26645324 TI - The effects of nickel(II) complexes with imidazole derivatives on pyocyanin and pyoverdine production by Pseudomonas aeruginosa strains isolated from cystic fibrosis. AB - Pseudomonas aeruginosa infection is problematic in patients with cystic fibrosis (CF). P. aeruginosa secretes a diversity of pigments, such as pyocyanin and pyoverdine. The aim of this study was to evaluate the effects of complexes of nickel(II) ([Ni(iaa)2(H2O)2].H2O (iaa = imidazole-4-acetate anion), [Ni(1 allim)6](NO3)2 (1-allim = 1-allylimidazole) and NiCl2 on pyocyanin and pyoverdine production by 23 strains of P. aeruginosa isolated from cystic fibrosis under growth conditions specific for the CF respiratory system. The antibacterial effects and biophysical properties of the tested substances were measured by spectrofluorometric techniques, as well as by laser interferometry, confocal and atomic force microscopy. The cytotoxic properties of all compounds were measured by Annexin/IP assay against A549 cells. All tested compounds have no effect on pyocyanin production and decrease the pyoverdine secretion in about 40% of tested P. aeruginosa strains at non-cytotoxic range of concentrations. Imidazole-4 acetate anion and 1-allylimidazole have good diffusion properties in the mature P. aeruginosa PAO1 biofilm. In conclusion, the tested nickel(II) complexes do not have clinical implications in P. aeruginosa eradication in cystic fibrosis. The diffusion properties of 1-allylimidazole and imidazole-4-acetate and their lack of effect on A549 cells suggest that they might be considered for chemical synthesis with other transition metals. PMID- 26645325 TI - Impact of a microbial-mineral biopreparation on microbial community and deodorization of manures. AB - The aim of this study was to determine the number of bacteria in poultry, cattle and swine manure in order to perform hygienization and deodorization using a microbial-mineral biopreparation. The highest number of bacteria was recorded in laying hens manure (5.1*10(10) cfu/g). It was noted that bacteria: coliforms, E. coli, Clostridium, Enterococcus number was reduced (1-2 log) after the biopreparation application. The investigated odorous compound concentrations were reduced with 34-78% efficiency, depending on the type of manure and odorant. All odorous compounds were efficiently reduced only in the case of laying hen manure. PMID- 26645326 TI - CD25 (IL-2R) expression correlates with the target cell induced cytotoxic activity and cytokine secretion in human natural killer cells. AB - Cytotoxic activity is one of the major functions of Natural Killer (NK) cells and is a critical effector mechanism of innate immune responses against infected or cancer cells. A variety of assays have been developed to determine NK cell cytotoxic activity, however a receptor-based screening tool is still lacking. Here, we propose the CD25 receptor as a candidate for NK cell cytotoxicity marker. We have verified that there is a correlation between classic target cell induced cytotoxicity markers and the CD25 expression on NK cells. Non-adherent lymphocyte fractions pre-stimulated with Escherichia coli O55:B5 lipopolysaccharide were co-cultured with settled HeLa targets in a four hour long cytotoxic assay. The cytotoxic effect was evaluated by MTT reduction assay and quantification of soluble cytotoxicity markers (granzyme B, FasL, caspase-8, IFN gamma and IL-2) was done by ELISA. Lymphocytes were stained with anti-CD3-Cy-5, anti-CD56/CD16/Nkp46-FITC and anti-CD25-PE antibodies and analyzed by flow cytometry. We observed that the CD25 expression exclusively on the CD3( )CD56(+)CD25(+) NK cells was positively correlated with their cytotoxic function evaluated by the MTT test (r = 0.68), the upregulation of granzyme B (r = 0.89), IL-2 (r = 0.78) and IFN-gamma (r = 0.57), however, it was not positively correlated with FasL and caspase-8. We conclude that the CD25 expression might serve as an in vitro receptor-based screening tool for NK cell activity. PMID- 26645327 TI - The complete genome sequencing of Prevotella intermedia strain OMA14 and a subsequent fine-scale, intra-species genomic comparison reveal an unusual amplification of conjugative and mobile transposons and identify a novel Prevotella-lineage-specific repeat. AB - Prevotella intermedia is a pathogenic bacterium involved in periodontal diseases. Here, we present the complete genome sequence of a clinical strain, OMA14, of this bacterium along with the results of comparative genome analysis with strain 17 of the same species whose genome has also been sequenced, but not fully analysed yet. The genomes of both strains consist of two circular chromosomes: the larger chromosomes are similar in size and exhibit a high overall linearity of gene organizations, whereas the smaller chromosomes show a significant size variation and have undergone remarkable genome rearrangements. Unique features of the Pre. intermedia genomes are the presence of a remarkable number of essential genes on the second chromosomes and the abundance of conjugative and mobilizable transposons (CTns and MTns). The CTns/MTns are particularly abundant in the second chromosomes, involved in its extensive genome rearrangement, and have introduced a number of strain-specific genes into each strain. We also found a novel 188-bp repeat sequence that has been highly amplified in Pre. intermedia and are specifically distributed among the Pre. intermedia-related species. These findings expand our understanding of the genetic features of Pre. intermedia and the roles of CTns and MTns in the evolution of bacteria. PMID- 26645328 TI - Difficulty in Distinguishing Posterior Reversible Encephalopathy Syndrome, Hypoxic-Ischemic Insult, and Acute Toxic Leukoencephalopathy in Children. AB - AIM: This study aims to describe our experience of unique pediatric neurological cases and associated difficulty in differentiating posterior reversible encephalopathy syndrome (PRES) from hypoxic-ischemic insult (HII), and acute toxic leukoencephalopathy (ATL). METHODS: The study included three children with a clinical picture suggestive of PRES, HII, and ATL of different etiologies who were diagnosed and treated at a tertiary pediatric medical center in 2011 to 2014. RESULTS: All patients presented with blindness following seizures with asphyxia/aspiration in a syndromatic child, too-rapid lipid infusion in a child with acute lymphoblastic leukemia, and repeated vomiting in a child with cerebral palsy, hydrocephalus, and malfunction of ventriculoperitoneal shunt. All patients had cortical blindness and high-signal foci in the cortical and subcortical regions on magnetic resonance imaging. All children improved. CONCLUSIONS: Familiarity with the clinical and radiological characteristics of neurological conditions leading to reversible cortical blindness is essential for diagnosis and management. Distinguishing PRES from HII and ATL can be challenging. Our cases most likely combined these etiologies, with the first patient diagnosed with PRES with HII, the second with PRES with ATL, and the third with focal HII. Given the diversity of the findings and the unclear prognostic significance, studies of the pathophysiology of PRES are warranted. PMID- 26645329 TI - Nutritional marginal zinc deficiency disrupts placental 11beta-hydroxysteroid dehydrogenase type 2 modulation. AB - This paper investigated if marginal zinc nutrition during gestation could affect fetal exposure to glucocorticoids as a consequence of a deregulation of placental 11betaHSD2 expression. Placenta 11beta-hydroxysteroid dehydrogenase type 2 (11betaHSD2) plays a central role as a barrier protecting the fetus from the deleterious effects of excess maternal glucocorticoids. Rats were fed control (25 MUg zinc per g diet) or marginal (10 MUg zinc per g diet, MZD) zinc diets from day 0 through day 19 (GD19) of gestation. At GD19, corticosterone concentration in plasma, placenta, and amniotic fluid was similar in both groups. However, protein and mRNA levels of placenta 11betaHSD2 were significantly higher (25% and 58%, respectively) in MZD dams than in controls. The main signaling cascades modulating 11betaHSD2 expression were assessed. In MZD placentas the activation of ERK1/2 and of the downstream transcription factor Egr-1 was low, while p38 phosphorylation and SP-1-DNA binding were low compared to the controls. These results point to a central role of ERK1/Egr-1 in the regulation of 11betaHSD2 expression under the conditions of limited zinc availability. In summary, results show that an increase in placenta 11betaHSD2 expression occurs as a consequence of gestational marginal zinc nutrition. This seems to be due to a low tissue zinc associated deregulation of ERK1/2 rather than to exposure to high maternal glucocorticoid exposure. The deleterious effects on brain development caused by diet-induced marginal zinc deficiency in rats do not seem to be due to fetal exposure to excess glucocorticoids. PMID- 26645330 TI - Hematoporphyrin monomethyl ether combined with He-Ne laser irradiation-induced apoptosis in canine breast cancer cells through the mitochondrial pathway. AB - Hematoporphyrin monomethyl ether (HMME) combined with He-Ne laser irradiation is a novel and promising photodynamic therapy (PDT)-induced apoptosis that can be applied in vitro on canine breast cancer cells. However, the exact pathway responsible for HMME-PDT in canine breast cancer cells remains unknown. CHMm cells morphology and apoptosis were analyzed using optical microscope, terminal deoxynucleotidyl transferase dUTP nick end labeling fluorescein staining and DNA ladder assays. Apoptotic pathway was further confirmed by Real-time-polymerase chain reaction and Western blotting assays. Our results showed that HMME-PDT induced significant changes in cell morphology, such as formation of cytoplasmic vacuoles and the gradual rounding of cells coupled with decreased size and detachment. DNA fragmentation and cell death was shown to occur in a time dependent manner. Furthermore, HMME-PDT increased the activities of caspase-9 and caspase-3, and released cytochrome c from mitochondria into the cytoplasm. HMME PDT also significantly increased both mRNA and protein levels of Bax and decreased P53 gene expression in a time-dependent manner, while the mRNA and protein expression of Bcl-2 were repressed. These alterations suggest that HMME PDT induced CHMm cell apoptosis via the mitochondrial apoptosis pathway and had anti-canine breast cancer effects in vitro. PMID- 26645331 TI - Retrospective study of the clinical effects of acupuncture on cervical neurological diseases in dogs. AB - This study was conducted to evaluate new acupuncture protocols for the clinical treatment of cervical spinal cord diseases in 19 dogs. Three treatment options containing Jing-jiaji (cervical jiaji) were developed to treat neck pain, hemiparesis, and tetraparesis depending on the severity. The interval between the neurological disease onset and treatment (duration of signs), time to improvement after treatment, and recovery time were compared in dogs by body weight, age, and dry needle acupuncture (AP) with or without electro-AP (EAP). The duration of signs was longer in dogs weighing greater than 10 kg than in those weighing less than 10 kg (p< 0.05). Improvement and recovery times did not vary by body weight. Additionally, improvement and recovery times did not vary by age. The improvement and recovery times were longer in the AP+EAP group than the AP group (p< 0.05). Acupuncture with Jing-jiaji was effective in cervical spinal cord diseases in different sized dogs and in middle-aged and senior dogs. This report standardized AP treatment containing Jing-jiaji for canine cervical problems and evaluated its effects. The newly standardized AP methodology offers clinical practitioners an effective way to improve the outcomes of cervical neurological diseases in dogs. PMID- 26645332 TI - Clinical usefulness of post-operative 18F-fluorodeoxyglucose positron emission tomography-computed tomography in canine hemangiosarcoma. AB - This report describes the usefulness of positron emission tomography-computed tomography (PET-CT) for evaluating recurrent or residual tumors following surgery. CT and 18F-fluorodeoxyglucose PET-CT were pre- and post-operatively applied to multiple masses in a dog with hemangiosarcoma. The distinction between the left subcutaneous mass and the peritoneum was clarified on pre-operative CT examination, and malignancy was suspected based on PET-CT. A recurrent or residual tumor in the left subcutaneous region was suspected on post-operative PET-CT, and confirmed through histopathologic examination. PMID- 26645333 TI - Imaging and surgical outcomes of spinal tumors in 18 dogs and one cat. AB - Clinical and magnetic resonance imaging (MRI) findings, histological appearances and surgical outcomes of 18 dogs and one cat with spinal tumors are presented. Medical records of the cases admitted for spinal disorders were reviewed, and cases of spinal tumors that were diagnosed by MRI and confirmed by histological examination were included in this study. T1 weighted, T2 weighted and contrast enhanced T1 weighted images were taken and interpreted to evaluate the spinal tumors. The tumors were diagnosed as: meningioma (n = 6), ependymoma (n = 1), nerve sheath tumor (n = 4), metastatic spinal tumor (n = 3), osteosarcoma (n = 2), osteoma (n = 1), rhabdomyosarcoma (n = 1), and nephroblastoma (n = 1). Thirteen cases underwent surgical operation and the remaining six cases were euthanized at the request of the owners. The neurological status of the surgical cases did not deteriorate, except for one dog that showed ependymoma in the early period after the operation. These results indicate the potential for surgical gross total tumor removal of vertebral tumors to provide better quality of life and surgical collection of histological specimens for definitive diagnosis. For effective case management, dedicated MRI examination is important to accurate evaluation of the spinal tumors, and surgical treatment is useful for extradural and intradural-extramedullary spinal tumors. PMID- 26645334 TI - Evaluation of effects of olfactory and auditory stimulation on separation anxiety by salivary cortisol measurement in dogs. AB - Separation anxiety (SA) is a serious behavioral problem in dogs. In this study, salivary cortisol was studied to determine if the owner's odor or voice could reduce SA in dogs. Twenty-eight dogs with SA were divided into three groups: group 1 (control), group 2 (with owner's clothes during the separation period; SP) and group 3 (a recording of the owner's voice was played during SP). The dog's saliva was collected after the owner and their dog were in the experimental room for 5 min (PRE). The dog was then separated from the owner for 20 min and saliva collected four times at intervals of 5 min (SP1-4). Finally, the owner was allowed back into the room to calm the dog for 5 min, after which saliva was collected (POST). Evaluation of salivary cortisol concentrations by ELISA revealed that the ratios of SP1 concentration to PRE or POST concentrations were significantly higher in group 1 than in group 2 or 3. Additionally, the concentrations of SP1-PRE and SP1-POST among groups differed significantly. These findings indicate that the owner's odor or voice may be helpful to managing stress in dogs with SA. PMID- 26645335 TI - Deep anterior lamellar keratoplasty of dog eyes using the big-bubble technique. AB - This study was conducted to establish the feasibility of corneal transplantation using the big-bubble technique (BBT) to perform deep anterior lamellar keratoplasty (DALK) in three dogs. After the cornea was trephined 750 um, 4 mL of air was injected, and the blanched stroma was removed to expose Descemet's membrane (DM). The donor corneal button, which was gently stripped off the DM, was sutured onto the bare DM of the recipient cornea. The dogs received topical antibiotics every 6 h for 7 days and 2% cyclosporine ointment every 12 h for 1 month. The eyes were examined post-operatively at 7, 14, 21, 28 and 150 days. The central portion of the transplanted cornea stayed transparent while corneal haze developed around the transplanted margin. Menace response was normal even though the transplanted cornea was edematous until 3 weeks after surgery. A marginal haze was rarely observed between the donor and recipient corneas at 150 days after the operation. A spotted haze developed in the central part of the deep stroma near the DM. Upon histopathological examination, the stroma and epithelium of the donor cornea had normal structures. Corneal transplantation using DALK with BBT can be performed in dogs preserving the healthy endothelium. PMID- 26645336 TI - Correlation between caudal pulmonary artery diameter to body surface area ratio and echocardiography-estimated systolic pulmonary arterial pressure in dogs. AB - Caudal pulmonary artery diameter (CPAD) to body surface area (BSA) ratios were measured in ventrodorsal thoracic radiographs to assess the correlation between CPAD to BSA ratios and systolic pulmonary arterial pressure (PAP) in dogs. Thoracic radiographs of 44 dogs with systolic pulmonary arterial hypertension (PAH) and 55 normal dogs were evaluated. Systolic PAP was estimated by Doppler echocardiography. CPADs were measured at their largest point at the level of tracheal bifurcation on ventrodorsal radiographs. Both right and left CPAD to BSA ratios were significantly higher in the PAH group than in the normal group (p < 0.0001). Linear regression analysis showed positive associations between PAP and right and left CPAD to BSA ratio (right, p = 0.0230; left, p = 0.0012). The receiver operating characteristic curve analysis revealed that the CPAD to BSA ratio had moderate diagnostic accuracy for detecting PAH. The operating point, sensitivity, specificity, and area under the curve were 28.35, 81.40%, 81.82%, and 0.870; respectively, for the right side and 26.92, 80.00%, 66.67%, and 0.822, respectively, for the left. The significant correlation of CPAD to BSA ratio with echocardiography-estimated systolic PAP supports its use in identifying PAH on survey thoracic radiographs in dogs. PMID- 26645337 TI - Population genetic study of 10 short tandem repeat loci from 600 domestic dogs in Korea. AB - Dogs have long shared close relationships with many humans. Due to the large number of dogs in human populations, they are often involved in crimes. Occasionally, canine biological evidence such as saliva, bloodstains and hairs can be found at crime scenes. Accordingly, canine DNA can be used as forensic evidence. The use of short tandem repeat (STR) loci from biological evidence is valuable for forensic investigations. In Korea, canine STR profiling-related crimes are being successfully analyzed, leading to diverse crimes such as animal cruelty, dog-attacks, murder, robbery, and missing and abandoned dogs being solved. However, the probability of random DNA profile matches cannot be analyzed because of a lack of canine STR data. Therefore, in this study, 10 STR loci were analyzed in 600 dogs in Korea (344 dogs belonging to 30 different purebreds and 256 crossbred dogs) to estimate canine forensic genetic parameters. Among purebred dogs, a separate statistical analysis was conducted for five major subgroups, 97 Maltese, 47 Poodles, 31 Shih Tzus, 32 Yorkshire Terriers, and 25 Pomeranians. Allele frequencies, expected (Hexp) and observed heterozygosity (Hobs), fixation index (F), probability of identity (P(ID)), probability of sibling identity (P(ID)sib) and probability of exclusion (PE) were then calculated. The Hexp values ranged from 0.901 (PEZ12) to 0.634 (FHC2079), while the P(ID)sib values were between 0.481 (FHC2079) and 0.304 (PEZ12) and the P(ID)sib was about 3.35 * 10(-)5 for the combination of all 10 loci. The results presented herein will strengthen the value of canine DNA to solving dog-related crimes. PMID- 26645338 TI - Diagnostic imaging features of normal anal sacs in dogs and cats. AB - This study was conducted to provide normal reference features for canine and feline anal sacs using ultrasound, low-field magnetic resonance imaging (MRI) and radiograph contrast as diagnostic imaging tools. A total of ten clinically normal beagle dogs and eight clinically normally cats were included. General radiography with contrast, ultrasonography and low-field MRI scans were performed. The visualization of anal sacs, which are located at distinct sites in dogs and cats, is possible with a contrast study on radiography. Most surfaces of the anal sacs tissue, occasionally appearing as a hyperechoic thin line, were surrounded by the hypoechoic external sphincter muscle on ultrasonography. The normal anal sac contents of dogs and cats had variable echogenicity. Signals of anal sac contents on low-field MRI varied in cats and dogs, and contrast medium using T1-weighted images enhanced the anal sac walls more obviously than that on ultrasonography. In conclusion, this study provides the normal features of anal sacs from dogs and cats on diagnostic imaging. Further studies including anal sac evaluation are expected to investigate disease conditions. PMID- 26645339 TI - Multi-voxel magnetic resonance spectroscopy of cerebral metabolites in healthy dogs at 1.5 Tesla. AB - This study was conducted to measure the difference in levels of cerebral metabolites in the right and left hemispheres, gray (GM) and white matter (WM), imaging planes, and anatomical regions of healthy dogs to establish normal variations. Eight male Beagle dogs (1 to 4 years of age; mean age, 2 years) with no evidence of neurologic disease were studied. Using the multi-voxel technique on a 1.5 Tesla magnetic resonance imaging scanner, metabolite values (N-acetyl aspartate [NAA], choline [Cho], creatine [Cr]) were obtained from the frontoparietal WM, parietal GM, temporal GM, occipital GM, thalamus, cerebellum, mid-brain, and pons. There was no significant difference in levels of these metabolites between the right and left in any locations or between the GM and WM in the cerebral hemispheres. However, there were significant differences in metabolite ratios within imaging planes. The NAA/Cr was lower in the cerebellum than other regions and the thalamus had a higher Cho/Cr and lower NAA/Cho ratio than in other regions. The spectral and metabolic values will provide a useful internal reference for clinical practice and research involving multi-voxel magnetic resonance spectroscopy. Measurement of metabolite values in the transverse plane is recommended for comparing levels of regional metabolites. PMID- 26645340 TI - Differential regulation of senescence and in vitro differentiation by 17beta estradiol between mesenchymal stem cells derived from male and female mini-pigs. AB - The characterization and potential of mesenchymal stem cells (MSCs) are gender dependent and estrogen influences these properties. This study demonstrated that supplementation with 17beta-estradiol (E2) increases the proliferation of bone marrow-MSCs derived from male and female mini-pigs (Mp- and Fp-BMSCs) in a concentration-dependent manner, with 10(-12) M E2 suggested as the optimal dose of E2 that led to the greatest improvement in BMSCs proliferation. Supplementation of 10(-12) M E2 resulted in down-regulation of beta-galactosidase activity and pro-apoptotic activity in both BMSCs, while anti-apoptotic activity was up-regulated in only Fp-BMSCs. Further, E2 increased the osteogenic ability of Fp-BMSCs. Based on these findings, optimal utilization of E2 can improve cellular senescence and apoptosis, as well as in vitro osteogenesis of BMSCs, and could therefore be useful in stem cell therapy, particularly in bone regeneration for adult females. PMID- 26645341 TI - Increased humoral antibody response of foot-and-mouth disease virus vaccine in growing pigs pre-treated with poly-gamma-glutamic acid. AB - This study was conducted to determine if humoral antibody response of foot-and mouth disease (FMD) vaccine improved in 8-week-old growing pigs born to well vaccinated sows pre-treated with 60 mg of poly-gamma-glutamic acid (gamma-PGA) three days before vaccination. Antibody against FMD virus serotype O was measured 0, 2, 4 and 6 weeks post-vaccination, using a PrioCHECK FMDV type O ELISA kit. The results showed that positive antibody reactions against FMDV serotype O antigen among a component of the vaccine significantly increased in response to pre-injection with gamma-PGA. PMID- 26645342 TI - Prevalence of Anaplasma, Bartonella and Borrelia Species in Haemaphysalis longicornis collected from goats in North Korea. AB - North Korea is located on the northern part of the Korean Peninsula in East Asia. While tick-borne pathogens of medical and veterinary importance have been reported from China and South Korea, they have not been reported from North Korea. To screen for zoonotic tick-borne pathogens in North Korea, ticks were collected from domestic goats. A total of 292 (27 nymph, 26 male, 239 female) Haemaphysalis (H.) longicornis were collected and assayed individually for selected tick-borne pathogens. A total of 77 (26.4%) were positive for Anaplasma bovis, followed by Bartonella (B.) grahamii (15, 5.1%), Anaplasma phagocytophilum (12, 4.1%), Bartonella henselae (10, 3.4%), and Borrelia spp. (3, 1.0%) based on 16S ribosomal RNA and ITS species-specific nested polymerase chain reaction. Using the groEL-based nested PCR, a total of 6 and 1 H. longicornis were positive for B. grahamii and B. henselae, respectively. All products were sequenced and demonstrated 100% identity and homology with previously reported sequences from other countries in GenBank. This is the first report of the detection of tick borne pathogens in the North Korea and suggests that farm animals may act as reservoirs for zoonotic tick-borne pathogens. PMID- 26645343 TI - Hydration status affects osteopontin expression in the rat kidney. AB - Osteopontin (OPN) is a secretory protein that plays an important role in urinary stone formation. Hydration status is associated with the development of urolithiasis. This study was conducted to examine the effects of dehydration and hydration on OPN expression in the rat kidney. Animals were divided into three groups, control, dehydrated, and hydrated. Kidney tissues were processed for light and electron microscope immunocytochemistry, in situhybridization, and immunoblot analysis. Dehydration induced a significant increase in OPN protein expression, whereas increased fluid intake induced a decrease in protein expression. Under control conditions, OPN protein and mRNA expression were only detected in the descending thin limb (DTL). Dehydration induced increased expression in the DTL and the development of detectable expression in the thick ascending limb (TAL). In contrast, OPN expression levels declined to less than the controls in the DTL after hydration, while no expression of either protein or mRNA was detectable in the TAL. Immunoelectron microscopy demonstrated that hydration status altered tubular ultrastructure and intracellular OPN expression in the Golgi apparatus and secretory cytoplasmic vesicles. These data confirm that changes in oral fluid intake can regulate renal tubular epithelial cell OPN expression. PMID- 26645344 TI - Isolation and characterization of antimicrobial-resistant Escherichia coli from national horse racetracks and private horse-riding courses in Korea. AB - Limited information is available regarding horse-associated antimicrobial resistant (AR) Escherichia (E.) coli. This study was designed to evaluate the frequency and characterize the pattern of AR E. coli from healthy horse associated samples. A total of 143 E. coli (4.6%) were isolated from 3,078 samples collected from three national racetracks and 14 private horse-riding courses in Korea. Thirty of the E. coli isolates (21%) showed antimicrobial resistance to at least one antimicrobial agent, and four of the AR E. coli (13.3%) were defined as multi-drug resistance. Most of the AR E. coli harbored AR genes corresponding to their antimicrobial resistance phenotypes. Four of the AR E. coli carried class 1 integrase gene (intI1), a gene associated with multi-drug resistance. Pulsed-field gel electrophoretic analysis showed no genetic relatedness among AR E. coli isolated from different facilities; however, cross transmissions between horses or horses and environments were detected in two facilities. Although cross-transmission of AR E. coli in horses and their environments was generally low, our study suggests a risk of transmission of AR bacteria between horses and humans. Further studies are needed to evaluate the risk of possible transmission of horse-associated AR bacteria to human communities through horse riders and horse-care workers. PMID- 26645345 TI - Effects of induced endometritis on uterine blood flow in cows as evaluated by transrectal Doppler sonography. AB - This study was conducted to evaluate the effects of induced endometritis on uterine blood flow in cows. Transrectal Doppler sonography was performed on uterine arteries of six cyclic cows before and for 4 days after inducing acute endometritis by intrauterine infusion of 720 mg of policresulen, and for 4 days of the following estrous cycle. Time-averaged maximum velocity (TAMV) increased (p < 0.001) and pulsatility index (PI) decreased (p < 0.0001) within 1 h of policresulen administration, and did not change (p > 0.05) in the next 4 days of the same cycle. TAMV and PI values in the subsequent cycle did not differ (p > 0.05) from the values measured before infusion and showed no changes (p > 0.05) within the cycle. Blood flow parameters were not related (p > 0.05) to plasma concentrations of progesterone and estrogen. All cows showed an acute endometritis determined by histopathological findings of biopsy samples taken 1 day after infusion and fibrotic endometrial alterations detected in the subsequent cycle. No relationships were observed between fibrotic changes of the endometrium and uterine blood flow during either cycle. In conclusion, acute inflammation is accompanied by a rise in uterine blood flow, but fibrotic alterations do not seem to be related to Doppler sonographic findings. PMID- 26645346 TI - A Focal Adhesion Kinase-Derived Peptide Binds the Src SH3 Domain in Two Orientations, As Demonstrated Using Paramagnetic Nuclear Magnetic Resonance. AB - SH3 binding peptides contain polyproline helices and are classified according to their binding orientations as N-to-C-terminal or C-to-N-terminal. We have tested the hypothesis that such a peptide binds in both orientations but with different populations. A focal adhesion kinase (FAK)-derived peptide was tested for its binding orientation on the Src SH3 domain. Paramagnetic tags were introduced at several positions on the SH3 domain, and on the basis of the paramagnetic relaxation enhancements (PREs) of the amide protons, the positions of the paramagnetic centers were determined. Two peptides were synthesized with (13)C enriched Ala or Pro, at the N-terminal or C-terminal side of the peptide, and the intermolecular PREs were measured. The results provide compelling evidence that the FAK-derived peptide binds the SH3 domain in two orientations. In the major state, the SH3 domain binds the peptide in the N-C orientation, whereas 20% of the time, the peptide binds in the C-N orientation. We conclude that the distinction between N-C and C-N orientations, which is based on crystal structures, might be artificial. The pseudosymmetric nature of the polyproline helix might allow for binding in both orientations in the solution state. PMID- 26645347 TI - Stimuli-responsive nanoparticles from ionic cellulose derivatives. AB - Stimuli-responsive nanoparticles (NPs) based on sustainable polymeric feedstock still need more exploration in comparison with NPs based on synthetic polymers. In this report, stimuli-responsive NPs from novel ionic cellulose derivatives were prepared via a facile nanoprecipitation. Cellulose 10-undecenoyl ester (CUE) with a degree of substitution (DS) of 3 was synthesized by esterification of cellulose with 10-undecenoyl chloride. Then, CUE was modified by photo-induced thiol-ene reactions, in order to obtain organo-soluble ionic cellulose derivatives with DSs of ~3, namely cellulose 11-((3 carboxyl)ethylthio)undecanoate (CUE-MPA), cellulose 11-((2 aminoethyl)thio)undecanoate (CUE-CA), cellulose 11-(2-(2 (diethylamino)ethyl)thio)undecanoate (CUE-DEAET) and cellulose 11-(2-(2 (dimethylamino)ethyl)thio)undecanoate (CUE-DMAET). CUE-MPA could be transformed into NPs with average diameters in the range of 80-330 nm, but these NPs did not show particular stimuli-responsive properties. Moreover, the dropping technique resulted in smaller NPs than a dialysis technique. Stable NPs with average diameters in the range of 90-180 nm showing pH-responsive and switchable sizes were obtained from CUE-DEAET and CUE-DMAET possessing tertiary amines using nanoprecipitation. Thus, altering the terminal functional groups will be a new approach to prepare stimuli-responsive cellulose-derived polymeric NPs. PMID- 26645348 TI - Polar-solvent-free colloidal synthesis of highly luminescent alkylammonium lead halide perovskite nanocrystals. AB - A novel synthesis of hybrid organic-inorganic lead halide perovskite nanocrystals (CH3NH3PbX3, X = Br or I) that does not involve the use of dimethylformamide or other polar solvents is presented. The reaction between methylamine and PbX2 salts is conducted in a high-boiling nonpolar solvent (1-octadecene) in the presence of oleylamine and oleic acid as coordinating ligands. The resulting nanocrystals are characterized by high photoluminescence quantum efficiencies of 15-50%, outstanding phase purity and tunable shapes (nanocubes, nanowires, and nanoplatelets). Nanoplatelets spontaneously assemble into micrometer-length wires by face-to-face stacking. In addition, we demonstrate amplified spontaneous emission from thin films of green-emitting CH3NH3PbBr3 nanowires with low pumping thresholds of 3 MUJ cm(-2). PMID- 26645349 TI - A Pilot Study on Adolescents With Depression and Insomnia: Qualitative Findings From Focus Groups. AB - Nonpharmacological treatments for insomnia in adolescents with depression are lacking. This qualitative study was a thematic analysis of the unique characteristics of and preferences for an insomnia treatment in a group of depressed adolescents. Fourteen adolescents with insomnia (age range = 14-19, mean = 17, SD +/- 1.7; 71% female) and depression completed a 90-min focus group. Information was elicited about sleep disruptions, insomnia's impact on mood, and preferences for insomnia treatments. Themes included poor daytime functioning affecting sleep, lack of benefit from sleep medication, and bedtime rumination. Most identified sleep diaries as a barrier to treatment regardless of mode of delivery. Participants also preferred an in-person therapy. Insomnia therapy in adolescents should consider the unique characteristics of depression. Larger studies are warranted. PMID- 26645350 TI - Gut microbiota in health and disease: an overview focused on metabolic inflammation. AB - In concern to the continuously rising global prevalence of obesity, diabetes and associated diseases, novel preventive and therapeutic approaches are urgently required. However, to explore and develop such innovative strategies, a meticulous comprehension of the biological basis of these diseases is extremely important. Past decade has witnessed an enormous amount of research investigation and advancement in the field of obesity, diabetes and metabolic syndrome, with the gut microbiota receiving a special focus in the triangle of nutrition, health and diseases. In particular, the role of gut microbiota in health and diseases has been one of the most vigorous and intriguing field of recent research; however, much still remains to be elucidated about its precise role in host metabolism and immune functions and its implication in the onset, progression as well as in the amelioration of metabolic ailments. Recent investigations have suggested a significant contribution of the gut microbiota in the regulation and impairment of energy homeostasis, thereby causing metabolic disorders, such as metabolic endotoxemia, insulin resistance and type 2 diabetes. Numerous inflammatory biomarkers have been found to be associated with obesity, diabetes and risk of other associated adverse outcomes, thereby suggesting that a persistent low-grade inflammatory response is a potential risk factor. In this milieu, this review intends to discuss potential evidences supporting the disturbance of the gut microbiota balance and the intestinal barrier permeability as a potential triggering factor for systemic inflammation in the onset and progression of obesity, type 2 diabetes and metabolic syndrome. PMID- 26645351 TI - Lactobacillus rhamnosus GG supplementation during critical windows of gestation influences immune phenotype in Swiss albino mice offspring. AB - Probiotic supplementation during critical windows of gestation might have a significant influence on the infant's immune phenotype. Swiss albino mice (F0 generation) aged 31 days were supplemented orally with probiotic Lactobacillus rhamnosus GG (LGG); and the supplementation was continued throughout mating, gestation and lactation. The pups (F1 generation) born to them were separated post weaning and received either the same probiotic supplementation as their mothers or were denied supplementation postnatally. Neutrophil phagocytic ability, splenocyte proliferation, immunoglobulins and cytokines were determined in both F0 and F1 pups. In addition, antibody response against hepatitis-B surface antigen (HBsAg) was determined in F1 pups. Probiotic supplementation had no effect on the neutrophil phagocytic ability and splenocyte proliferation index. The serum immunoglobulin G (IgG) and secretory IgA (s-IgA) among the probiotic supplemented group of F0 generation were significantly (P<0.05) higher compared to the controls. Similarly, the mean concentration of interleukin (IL) 10, IL-17 and interferon gamma (IFN-gamma) among F0 probiotic group were significantly higher (P<0.05) compared to the control. Prenatal and postnatal probiotic supplementation in F1 pups led to similar results as F0 dams. Prenatal probiotic supplementation in F1 pups led to significantly (P<0.05) higher serum IgG (55.15 +/- 1.35 ng/ml) and intestinal s-IgA (77.9 +/- 2.86 ng/mg protein) concentration when compared to the control. Similarly, IFN-gamma concentration increased (P<0.05) with prenatal probiotic supplementation compared to the control. However, IL-10 and IL-17 concentrations of prenatal probiotic supplemented F1 pups were comparable to the control. As for the antibody response to HBsAg, prenatal probiotic supplementation led to enhanced HBsAg antibody response (471.4 +/- 3.97 U/ml) compared to the control. LGG affected the immune regulation and immune responses favourably in mothers and offspring. In addition, some of the beneficial effects of prenatal LGG supplementation extended into postnatal life of the offspring, thus suggesting possible immunoprogramming effect of LGG. PMID- 26645352 TI - Specific probiotic dietary supplementation leads to different effects during remission and relapse in murine chronic colitis. AB - Although interest in using probiotics to prevent and treat intestinal diseases is increasing, the effects of specific probiotic strains still remain unclear. Here, we assess the therapeutic effects of two probiotic strains, Lactobacillus rhamnosus NutRes 1 and Bifidobacterium breve NutRes 204 on a dextran sodium sulphate (DSS)-induced chronic murine colitis model. The chronic colitis was induced by two DSS treatment cycles with a rest period of 10 days (the remission or resolution phase). The probiotic supplementation was started during the resolution phase, after the first DSS treatment cycle, and continued until the end of the experiment. In addition to clinical observations made during the experiment, cellular infiltration was measured along with mRNA expression of pro inflammatory cytokines, T cell-associated cytokines, and Toll like receptors (TLR) in the inflamed colon after second DSS treatment cycle. L. rhamnosus, but not B. breve, rapidly and effectively improved the DSS-induced bloody diarrhoea during the resolution phase. However, a contradictory effect by both probiotic strains on the faecal condition was found after re-induction of colitis. The worsening of the faecal condition was accompanied by a reduced number of neutrophils and increased expression of interferon-gamma in the colons of DSS treated mice. Furthermore, an increased expression of TLR2, TLR6 and pro inflammatory markers including chemokine (C-C motif) ligand 2, interleukin (IL) 1beta, tumour necrosis factor alpha and IL-6 was found in DSS-treated mice with L. rhamnosus supplementation. These results indicate that therapeutic administration of specific probiotics might be beneficial during the resolution phase of colitis. However, caution should be taken as specific probiotic treatments reduce neutrophil influx, which may be the reason of exacerbation of chronic colitis. PMID- 26645353 TI - Pheochromocytoma multisystem crisis treated with emergency surgery: a case report and literature review. AB - BACKGROUND: Pheochromocytoma is a neuroendocrine tumor that predominantly presents with hypertension, palpitations, and tachycardia due to excessive catecholamine excretion. Although pheochromocytoma multisystem crisis (PMC) is relatively rare, urologists and clinicians should focus on early diagnosis as delay in initiating the appropriate treatment can lead to mortality CASE PRESENTATION: A 70-year-old man developed ileus after a few days of medication for hypertension. Computed tomography incidentally revealed a left adrenal mass. This finding together with his clinical course was compatible with pheochromocytoma. An alpha-blocker was administered immediately, and his blood pressure was well controlled. However, his general condition and laboratory data deteriorated rapidly, and the patient was diagnosed with PMC with lethal status. Thus, emergency adrenalectomy was performed without confirmation of catecholamine levels. From the resected specimen, his tumor was judged as pheochromocytoma. On immunohistochemical analysis, the proliferation index evaluated by Ki-67 staining was 9.7 %. This case report was approved by the Human Ethics Review Committee of the Nagasaki University Hospital. CONCLUSION: The present case of PMC was successfully treated with emergency surgery. The benign pheochromocytoma also presented with high cell proliferation potential, which may be a cause of the extreme aggressiveness of PMC. PMID- 26645354 TI - Bactericidal effect of Er:YAG laser combined with sodium hypochlorite irrigation against Enterococcus faecalis deep inside dentinal tubules in experimentally infected root canals. AB - This study evaluated the bactericidal effect of Er:YAG laser radiation combined with sodium hypochlorite (NaOCl) irrigation in the treatment of Enterococcus faecalis deep inside dentinal tubules. The Er:YAG laser was activated, respectively, at 0.3, 0.5 and 1.0 W for either 20 or 30 s; 52.5 g l(-1) NaOCl and normal saline were used for the control groups. Root canals before and after treatments were examined using scanning electron microscopy (SEM). Bacterial reductions both on the root canal walls and at 100, 200, 300, 400 and 500 MUm inside the dentinal tubules were analysed using a one-way analysis of variance. SEM results showed that the Er:YAG laser combined with NaOCl disinfected the dentinal tubules from 200 to over 500 MUm depth as irradiation power and time increased. This combination killed significantly more bacteria than both the negative control group at each level tested and the positive control group at 300, 400 and 500 MUm inside the dentinal tubules. It reached 100% in all experimental groups, both on the root canal walls and at 100 and 200 MUm inside the dentinal tubules. However, at 300, 400 and 500 MUm inside the dentinal tubules, only the groups treated with 0.5 and 1.0 W for 30s exhibited no bacterial growth. Of the two groups in which no bacteria were detected at all tested depths, Er:YAG laser irradiation at 0.5 W for 30 s combined with NaOCl irrigation was preferable because of the lower emission power and shorter irradiation time, and may serve as a new option for effective root canal disinfection. PMID- 26645355 TI - A systematic review of factors that affect uptake of community-based health insurance in low-income and middle-income countries. AB - BACKGROUND: Low-income and middle-income countries (LMICs) have difficulties achieving universal financial protection, which is primordial for universal health coverage. A promising avenue to provide universal financial protection for the informal sector and the rural populace is community-based health insurance (CBHI). We systematically assessed and synthesised factors associated with CBHI enrolment in LMICs. METHODS: We searched PubMed, Scopus, ERIC, PsychInfo, Africa Wide Information, Academic Search Premier, Business Source Premier, WHOLIS, CINAHL, Cochrane Library, conference proceedings, and reference lists for eligible studies available by 31 October 2013; regardless of publication status. We included both quantitative and qualitative studies in the review. RESULTS: Both quantitative and qualitative studies demonstrated low levels of income and lack of financial resources as major factors affecting enrolment. Also, poor healthcare quality (including stock-outs of drugs and medical supplies, poor healthcare worker attitudes, and long waiting times) was found to be associated with low CBHI coverage. Trust in both the CBHI scheme and healthcare providers were also found to affect enrolment. Educational attainment (less educated are willing to pay less than highly educated), sex (men are willing to pay more than women), age (younger are willing to pay more than older individuals), and household size (larger households are willing to pay more than households with fewer members) also influenced CBHI enrolment. CONCLUSION: In LMICs, while CBHI schemes may be helpful in the short term to address the issue of improving the rural population and informal workers' access to health services, they still face challenges. Lack of funds, poor quality of care, and lack of trust are major reasons for low CBHI coverage in LMICs. If CBHI schemes are to serve as a means to providing access to health services, at least in the short term, then attention should be paid to the issues that militate against their success. PMID- 26645356 TI - Dissociation of recombinant prion autocatalysis from infectivity. AB - Within the mammalian prion field, the existence of recombinant prion protein (PrP) conformers with self-replicating (ie. autocatalytic) activity in vitro but little to no infectious activity in vivo challenges a key prediction of the protein-only hypothesis of prion replication--that autocatalytic PrP conformers should be infectious. To understand this dissociation of autocatalysis from infectivity, we recently performed a structural and functional comparison between a highly infectious and non-infectious pair of autocatalytic recombinant PrP conformers derived from the same initial prion strain. (1) We identified restricted, C-terminal structural differences between these 2 conformers and provided evidence that these relatively subtle differences prevent the non infectious conformer from templating the conversion of native PrP(C) substrates containing a glycosylphosphatidylinositol (GPI) anchor. (1) In this article we discuss a model, consistent with these findings, in which recombinant PrP, lacking post-translational modifications and associated folding constraints, is capable of adopting a wide variety of autocatalytic conformations. Only a subset of these recombinant conformers can be adopted by post-translationally modified native PrP(C), and this subset represents the recombinant conformers with high specific infectivity. We examine this model's implications for the generation of highly infectious recombinant prions and the protein-only hypothesis of prion replication. PMID- 26645357 TI - Interpreting the transmissibility of the avian influenza A(H7N9) infection from 2013 to 2015 in Zhejiang Province, China. AB - Three epidemic waves of human influenza A(H7N9) were documented in several different provinces in China between 2013 and 2015. With limited understanding of the potential for human-to-human transmission, it was difficult to implement control measures efficiently or to inform the public adequately about the application of interventions. In this study, the human-to-human transmission rate for the epidemics that occurred between 2013 and 2015 in Zhejiang Province, China, was analysed. The reproduction number (R), a key indicator of transmission intensity, was estimated by fitting the number of infections from poultry to humans and from humans to humans into a mathematical model. The posterior mean R for human-to-human transmission was estimated to be 0.27, with a 95% credible interval of 0.14-0.44 for the first wave, whereas the posterior mean Rs decreased to 0.15 in the second and third waves. Overall, these estimates indicate that a human H7N9 pandemic is unlikely to occur in Zhejiang. The reductions in the viral transmissibility and the number of poultry-transmitted infections after the first epidemic may be attributable to the various intervention measures taken, including changes in the extent of closures of live poultry markets. PMID- 26645358 TI - High-efficiency bulk heterojunction memory devices fabricated using organometallic halide perovskite:poly(N-vinylcarbazole) blend active layers. AB - A solution-processed organometallic halide perovskite-based bulk heterojunction (BHJ) memory device with a configuration of indium-doped tin oxide (ITO)/CH3NH3PbI3:PVK/Al has been successfully fabricated. Under a threshold voltage of -1.57 V, this device shows a nonvolatile write-once read-many-times (WORM) memory effect, with a maximum ON/OFF current ratio exceeding 10(3). In contrast, the ITO/CH3NH3PbI3/Al device showed only conductor characteristics, while the PVK-based device exhibited insulator behavior. Upon being subjected to voltages, an interesting filamentary nature of the CH3NH3PbI3:PVK film was also observed in situ at the microscopic nanometer level using a conductive atomic force microscopy (C-AFM) technique with a device configuration of Si/Pt/CH3NH3PbI3:PVK/Pt. The mechanism associated with the memory effect is discussed. The electric-field-induced intermolecular charge transfer effect between CH3NH3PbI3 and PVK, and the possible conformational ordering of the PVK side-chains/backbone under an applied bias voltage, may cause the electrical conductivity switching and WORM effect in the reported BHJ device. PMID- 26645359 TI - Material Tissue Interaction--From Toxicity to Tissue Regeneration. AB - The topic of material tissue interaction has gained increasing interest over recent decades from both the dental profession and the public. The primary goal initially was to avoid adverse reactions after the application of dental materials. New laboratory test methods have been developed, and currently premarket testing programs, which attempt to guarantee a basic level of patient safety, are legally required worldwide. The dentist is responsible for selecting the correct indication as well as the proper handling of any newly emerging risk. Apart from this phenomenon-oriented "inert materials concept," the "analytical concept" focuses primarily on analyzing the reasons for adverse reactions, and identifying their associated modifying factors, in order to prevent them or to develop new and more biocompatible materials. The "concept of bioactivity" involves addressing the possibility of positively influencing tissue by materials application, such as the generation of tertiary dentin or antibacterial effects. Finally, tissue regeneration may be supported and promoted by the use of various suitable materials (matrices/scaffolds) into which stem cells can migrate or be seeded, leading to cell differentiation and the generation of new tissue. These new dental materials must also fulfill additional requirements such as controlled degradability in order to be suitable for clinical use. Clearly, the field of material tissue interaction is complex and comprises a wide range of issues. To be successful as dentists in the future, practitioners should remain informed of these important new developments and have the argumentative competence to both properly advise and treat their patients. PMID- 26645360 TI - Changes in Scleral Architecture in Chronic Vogt-Koyanagi-Harada Disease. AB - PURPOSE: To describe scleral changes in chronic VKH. METHODS: Medical records of patients with chronic VKH were retrospectively reviewed. Change of scleral architecture was defined as progressive posterior bowing on OCT, axial length elongation, and/or increased myopia more than -1.0 D, not explicable by other etiologies. RESULTS: In total, 28 eyes (16 patients) with mean age of disease onset 32.5 +/- 14.0 years were included in the study. Disease duration was 15.1 +/- 10.2 years. Eight eyes (28.6%) showed progressive scleral architectural changes. Five eyes (18%) developed scleral changes on OCT, not seen on prior imaging (2-12 years earlier). One eye had posterior bowing on OCT with increased axial length, both eyes of a bilateral pseudophake developed increased myopia with increased axial length. Well-circumscribed chorioretinal atrophy within the arcade was associated with progressive scleral change. CONCLUSIONS: Progressive scleral change may develop as a late complication of VKH. The association with well-circumscribed chorioretinal atrophy suggests that chronic choroidal inflammation may be responsible. PMID- 26645361 TI - Facile synthesis of aza-spirocyclopropanyl oxindoles by the reaction of 3-(2 bromoethyl)-indole with 2,3-dimethylimidazole-1-sulfonyl azide triflate. AB - 3-(2-Bromoethyl)indole reacts with 2,3-dimethylimidazole-1-sulfonyl azide triflate to give an intermediate N-(2,3-dimethylimidazole)-1-sulfonyl aza spirocyclopropanyloxindole. This reactive species is captured by an alcohol or amine to afford the corresponding aza-spirooxindole sulfonate and sulfonamide. PMID- 26645362 TI - BMP2 rescues deficient cell migration in Tgfbr3(-/-) epicardial cells and requires Src kinase. AB - During embryogenesis, the epicardium undergoes proliferation, migration, and differentiation into several cardiac cell types which contribute to the coronary vessels. The type III transforming growth factor-beta receptor (TGFbetaR3) is required for epicardial cell invasion and development of coronary vasculature in vivo. Bone Morphogenic Protein-2 (BMP2) is a driver of epicardial cell migration. Utilizing a primary epicardial cell line derived from Tgfbr3(+/+) and Tgfbr3(-/-) mouse embryos, we show that Tgfbr3(-/-) epicardial cells are deficient in BMP2 mRNA expression. Tgfbr3(-/-) epicardial cells are deficient in 2-dimensional migration relative to Tgfbr3(+/+) cells; BMP2 induces cellular migration to Tgfbr3(+/+) levels without affecting proliferation. We further demonstrate that Src kinase activity is required for BMP2 driven Tgfbr3(-/-) migration. BMP2 also requires Src for filamentous actin polymerization in Tgfbr3(-/-) epicardial cells. Taken together, our data identifies a novel pathway in epicardial cell migration required for development of the coronary vessels. PMID- 26645363 TI - Innovations in classical hormonal targets for endometriosis. AB - Endometriosis is a chronic disease of unknown etiology that affects approximately 10% of women in reproductive age. Several evidences show that endometriosis lesions are associated to hormonal imbalance, including estrogen synthesis, metabolism and responsiveness and progesterone resistance. These hormonal alterations influence the ability of endometrial cells to proliferate, migrate and to infiltrate the mesothelium, causing inflammation, pain and infertility. Hormonal imbalance in endometriosis represents also a target for treatment. We provide an overview on therapeutic strategies based on innovations of classical hormonal mechanisms involved in the development of endometriosis lesions. The development phase of new molecules targeting these pathways is also discussed. Endometriosis is a chronic disease involving young women and additional biological targets of estrogen and progesterone pharmacological manipulation (brain, bone and cardiovascular tissue) need to be carefully considered in order to improve and overcome current limits of long-term medical management of endometriosis. PMID- 26645364 TI - Flexible Organic Transistors with Controlled Nanomorphology. AB - We report the controlled nanomorphology of semiconducting polymers on chemically and mechanically stable nanogrooved polymer substrates. By employing silicon dioxide thin films with finely adjusted thicknesses on nanogrooved polymer substrates, semiconducting polymer thin films oriented and aligned along the nanogrooves were obtained. Organic field-effect transistors (OFETs) fabricated from the oriented semiconducting polymer, poly[4-(4,4-dihexadecyl-4H cyclopenta[1,2-b:5,4-b']dithiophen-2-yl)-alt-[1,2,5]thiadiazolo-[3,4-c]pyridine] (PCDTPT), yielded saturation hole mobilities as high as 19.3 cm(2) V(-1 )s(-1), and the flexible "plastic" transistors demonstrated excellent mechanical stability under various bending conditions. These results represent important progress for solution-processed flexible OFETs and demonstrate that directed self assembly of semiconducting polymers can be achieved by soft nanostructures. PMID- 26645374 TI - Formation of Ordered Coronene Clusters in Template Utilizing the Structural Transformation of Hexaphenylbenzene Derivative Networks on Graphite Surface. AB - In the present work, we report the fabrication of regular coronene (COR) clusters on surfaces in ambient conditions in the two-dimensional network formed by hexaphenylbenzene derivatives (HPB) via structural transformation. HPB could form a stable snowflake network structure on the highly oriented pyrolytic graphite surface at the air-solid interface. When COR molecules were introduced into the system, the HPB snowflake network could transform to honeycomb structures, and the COR heptamers were subsequently aggregated and entrapped into the cavity. Scanning tunneling microscopic was employed to monitor the assembly behavior of both HPB and HPB/COR at a submolecule scale level, and density functional theory calculations were utilized to reveal that the structural transformation and the entrapment are the energetically favorable. The pores formed from HPB might also give a clue to immobilizing some functional molecule clusters, like COR, to fabricate their ordered monolayer in ambient conditions, so as to obtain complex supramolecular surface structures. PMID- 26645366 TI - Context matters: Successes and challenges of intrapartum care scale-up in four districts of Afghanistan. AB - Reducing preventable maternal mortality and achieving Sustainable Development Goal targets for 2030 will require increased investment in improving access to quality health services in fragile and conflict-affected states. This study explores the conditions that affect availability and utilisation of intrapartum care services in four districts of Afghanistan where mortality studies were conducted in 2002 and 2011. Information on changes in each district was collected through interviews with community members; service providers; and district, provincial and national officials. This information was then triangulated with programme and policy documentation to identify factors that affect the coverage of safe delivery and emergency obstetric care services. Comparison of barriers to maternal health service coverage across the four districts highlights the complexities of national health policy planning and resource allocation in Afghanistan, and provides examples of the types of challenges that must be addressed to extend the reach of life-saving maternal health interventions to women in fragile and conflict-affected states. Findings suggest that improvements in service coverage must be measured at a sub-national level, and context specific service delivery models may be needed to effectively scale up intrapartum care services in extremely remote or insecure settings. PMID- 26645375 TI - Context Effects on Facial Affect Recognition in Schizophrenia and Autism: Behavioral and Eye-Tracking Evidence. AB - Although Schizophrenia (SCZ) and Autism Spectrum Disorder (ASD) share impairments in emotion recognition, the mechanisms underlying these impairments may differ. The current study used the novel "Emotions in Context" task to examine how the interpretation and visual inspection of facial affect is modulated by congruent and incongruent emotional contexts in SCZ and ASD. Both adults with SCZ (n= 44) and those with ASD (n= 21) exhibited reduced affect recognition relative to typically-developing (TD) controls (n= 39) when faces were integrated within broader emotional scenes but not when they were presented in isolation, underscoring the importance of using stimuli that better approximate real-world contexts. Additionally, viewing faces within congruent emotional scenes improved accuracy and visual attention to the face for controls more so than the clinical groups, suggesting that individuals with SCZ and ASD may not benefit from the presence of complementary emotional information as readily as controls. Despite these similarities, important distinctions between SCZ and ASD were found. In every condition, IQ was related to emotion-recognition accuracy for the SCZ group but not for the ASD or TD groups. Further, only the ASD group failed to increase their visual attention to faces in incongruent emotional scenes, suggesting a lower reliance on facial information within ambiguous emotional contexts relative to congruent ones. Collectively, these findings highlight both shared and distinct social cognitive processes in SCZ and ASD that may contribute to their characteristic social disabilities. PMID- 26645376 TI - The clinical phenomenology and associations of trick maneuvers in cervical dystonia. AB - Sensory trick is an unusual clinical feature in cervical dystonia that attenuates disease symptoms by slight touch to a specific area of the face or head. Using a semi-quantitative questionnaire-based study of 197 patients with idiopathic cervical dystonia, we sought to determine probable pathophysiologic correlates, with the wider aim of examining its eventual clinical significance. The typical sensory trick, i.e., light touch, not necessitating the use of force leading to simple overpowering of dystonic activity, was present in 83 (42.1 %) patients. The vast majority of the patients required a specific sequence of sensorimotor inputs, including touch sensation on the face or different areas of the head, and also sensory and motor input of the hand itself. Deviations often led to a significant decrease in effectiveness and lack of expected benefit. Moreover, patients able to perform the maneuver reported compellingly higher subjective effect of botulinum toxin treatment (median 7 vs. 5 on a scale of 0-10; p < 0.0001) and lower depression score (median 10 vs. 14 on the Montgomery Asberg Depression Rating scale; p < 0.001). Overall, the results point to marked disruption of sensorimotor networks in cervical dystonia. The mechanism of the sensory trick action may be associated with balancing the abnormal activation patterns by specific sensorimotor inputs. Its presence may be considered a positive predictive factor for responsiveness to botulinum toxin treatment. PMID- 26645377 TI - Personalized medicine beyond genomics: alternative futures in big data proteomics, environtome and the social proteome. AB - No field in science and medicine today remains untouched by Big Data, and psychiatry is no exception. Proteomics is a Big Data technology and a next generation biomarker, supporting novel system diagnostics and therapeutics in psychiatry. Proteomics technology is, in fact, much older than genomics and dates to the 1970s, well before the launch of the international Human Genome Project. While the genome has long been framed as the master or "elite" executive molecule in cell biology, the proteome by contrast is humble. Yet the proteome is critical for life-it ensures the daily functioning of cells and whole organisms. In short, proteins are the blue-collar workers of biology, the down-to-earth molecules that we cannot live without. Since 2010, proteomics has found renewed meaning and international attention with the launch of the Human Proteome Project and the growing interest in Big Data technologies such as proteomics. This article presents an interdisciplinary technology foresight analysis and conceptualizes the terms "environtome" and "social proteome". We define "environtome" as the entire complement of elements external to the human host, from microbiome, ambient temperature and weather conditions to government innovation policies, stock market dynamics, human values, political power and social norms that collectively shape the human host spatially and temporally. The "social proteome" is the subset of the environtome that influences the transition of proteomics technology to innovative applications in society. The social proteome encompasses, for example, new reimbursement schemes and business innovation models for proteomics diagnostics that depart from the "once-a-life-time" genotypic tests and the anticipated hype attendant to context and time sensitive proteomics tests. Building on the "nesting principle" for governance of complex systems as discussed by Elinor Ostrom, we propose here a 3-tiered organizational architecture for Big Data science such as proteomics. The proposed nested governance structure is comprised of (a) scientists, (b) ethicists, and (c) scholars in the nascent field of "ethics-of-ethics", and aims to cultivate a robust social proteome for personalized medicine. Ostrom often noted that such nested governance designs offer assurance that political power embedded in innovation processes is distributed evenly and is not concentrated disproportionately in a single overbearing stakeholder or person. We agree with this assessment and conclude by underscoring the synergistic value of social and biological proteomes to realize the full potentials of proteomics science for personalized medicine in psychiatry in the present era of Big Data. PMID- 26645378 TI - Alternative peripheral perfusion strategies for safe cardiopulmonary bypass in atrial septal defect closure via a right minithoracotomy approach. AB - OBJECTIVES: In cases of cardiac surgery via a minimally invasive right minithoracotomy approach, cardiopulmonary bypass is established with peripheral arterial cannulation, frequently with a single femoral artery. Occasionally, alternative perfusion access is required to prevent perfusion site-related complications. In this study, the feasibility of alternative perfusion strategies was verified by comparing the postoperative outcomes and complications. METHODS: The records of 91 consecutive patients (68 women, 23 men; mean age 40.7 +/- 16.5 years) who underwent atrial septal defect (ASD) closure via a right minithoracotomy approach between January 2009 and September 2014 were reviewed. Patients were divided into two groups: those with single femoral arterial access (SF group, n = 84), and those with alternative perfusion access (ALT group, n = 7, bilateral femoral arterial cannulation in 6, side-arm graft anastomosed to the femoral artery in 1). RESULTS: Femoral artery diameter was smaller in the ALT group than in the SF group (6.5 +/- 0.5 vs. 7.3 +/- 1.0 mm, P = 0.013). Operating time was longer in the ALT group than in the SF group (259.2 +/- 54.0 vs. 208.3 +/- 54.9 min, P = 0.031). One patient was converted to ascending aortic cannulation owing to high perfusion pressure. Postoperative major cardiac or cerebrovascular events, such as death, stroke, or myocardial infarction, did not occur in either group. CONCLUSIONS: Alternative perfusion access was safe in ASD closure via a right minithoracotomy approach. Precise preoperative evaluation of the iliofemoral artery is important for choosing the appropriate perfusion strategy. PMID- 26645379 TI - Foot Pain and Pronated Foot Type Are Associated with Self-Reported Mobility Limitations in Older Adults: The Framingham Foot Study. AB - BACKGROUND: The foot plays an important role in supporting the body when undertaking weight-bearing activities. Aging is associated with an increased prevalence of foot pain and a lowering of the arch of the foot, both of which may impair mobility. OBJECTIVE: To examine the associations of foot pain, foot posture and dynamic foot function with self-reported mobility limitations in community-dwelling older adults. METHODS: Foot examinations were conducted on 1,860 members of the Framingham Study in 2002-2005. Foot posture was categorized as normal, planus or cavus using static pressure measurements, and foot function was categorized as normal, pronated or supinated using dynamic pressure measurements. Participants were asked whether they had foot pain and any difficulty performing a list of eight weight-bearing tasks. Multivariate logistic regression and linear regression models were used to examine the associations of foot pain, posture, function and ability to perform these activities. RESULTS: After adjusting for age, sex, height and weight, foot pain was significantly associated with difficulty performing all eight weight-bearing activities. Compared to those with normal foot posture and function, participants with planus foot posture were more likely to report difficulty remaining balanced [odds ratio (OR) = 1.40, 95% confidence interval (CI) 1.06-1.85; p = 0.018] and individuals with pronated foot function were more likely to report difficulty walking across a small room (OR = 2.07, 95% CI 1.02-4.22; p = 0.045). Foot pain and planus foot posture were associated with an overall mobility limitation score combining performances on each measure. CONCLUSION: Foot pain, planus foot posture and pronated foot function are associated with self-reported difficulty undertaking common weight-bearing tasks. Interventions to reduce foot pain and improve foot posture and function may therefore have a role in improving mobility in older adults. PMID- 26645380 TI - Hydrologic Alterations from Climate Change Inform Assessment of Ecological Risk to Pacific Salmon in Bristol Bay, Alaska. AB - We developed an integrated hydrologic model of the upper Nushagak and Kvichak watersheds in the Bristol Bay region of southwestern Alaska, a region under substantial development pressure from large-scale copper mining. We incorporated climate change scenarios into this model to evaluate how hydrologic regimes and stream temperatures might change in a future climate, and to summarize indicators of hydrologic alteration that are relevant to salmon habitat ecology and life history. Model simulations project substantial changes in mean winter flow, peak flow dates, and water temperature by 2100. In particular, we find that annual hydrographs will no longer be dominated by a single spring thaw event, but will instead be characterized by numerous high flow events throughout the winter. Stream temperatures increase in all future scenarios, although these temperature increases are moderated relative to air temperatures by cool baseflow inputs during the summer months. Projected changes to flow and stream temperature could influence salmon through alterations in the suitability of spawning gravels, changes in the duration of incubation, increased growth during juvenile stages, and increased exposure to chronic and acute temperature stress. These climate modulated changes represent a shifting baseline in salmon habitat quality and quantity in the future, and an important consideration to adequately assess the types and magnitude of risks associated with proposed large-scale mining in the region. PMID- 26645381 TI - Bullying Among South Korean Adolescents: Prevalence and Association With Psychological Adjustment. AB - This study assessed the prevalence rates of physical, verbal, relational, property, and cyber bullying among a sample of South Korean middle school students. Associations between bullying and a list of psychopathological symptoms were also examined. Finally, whether a link between bullying and psychopathological symptoms is modified by the level of parental attachment was examined. Results show that, contrary to Western studies, girls were more likely than boys to be involved in school bullying. Significant interaction effects between parental attachment and bully/victim status on depression were also discovered. PMID- 26645382 TI - Electronically Excited States of Anisotropically Extended Singly-Deprotonated PAH Anions. AB - Polycyclic aromatic hydrocarbons (PAHs) play a significant role in the chemistry of the interstellar medium (ISM) as well as in hydrocarbon combustion. These molecules can have high levels of diversity with the inclusion of heteroatoms and the addition or removal of hydrogens to form charged or radical species. There is an abundance of data on the cationic forms of these molecules, but there have been many fewer studies on the anionic species. The present study focuses on the anionic forms of deprotonated PAHs. It has been shown in previous work that PAHs containing nitrogen heteroatoms (PANHs) have the ability to form valence excited states giving anions electronic absorption features. This work analyzes how the isoelectronic pure PAHs behave under similar structural constructions. Singly deprotonated forms of benzene, naphthalene, anthracene, and tetracene classes are examined. None of the neutral-radicals possess dipole moments large enough to support dipole-bound excited states in their corresponding closed-shell anions. Even though the PANH anion derivatives support valence excited states for three ringed structures, it is not until four-ringed structures of the pure PAH anion derivatives that valence excited states are exhibited. However, anisotropically extended PAHs larger than tetracene will likely exhibit valence excited states. The relative energies for the anion isomers are very small for all of the systems in this study. PMID- 26645383 TI - Police Killings and Police Deaths Are Public Health Data and Can Be Counted. AB - Nancy Krieger and colleagues argue that law-enforcement-related deaths in the United States should be treated as notifiable conditions, which would allow public health departments to report these data in real-time. PMID- 26645384 TI - Relationship Between Age, Tenure, and Disability Duration in Persons With Compensated Work-Related Conditions. AB - OBJECTIVE: The aim of the study was to examine the relationships among age, tenure, and the length of disability following a work-related injury/illness. METHODS: This study utilized 361,754 administrative workers' compensation claims. The relationships between age, tenure, and disability duration was estimated with random-effects models. RESULTS: The age-disability duration relationship was stronger than the tenure-disability duration relationship. An interaction was observed between age and tenure. At younger ages, disability duration varied little based on tenure. In midlife, disability duration was greater for workers with lower tenure than for workers with higher tenure. At the oldest ages, disability duration increased as tenure increased. CONCLUSIONS: Findings indicate that age is a more important factor in disability duration than tenure; however, the relationship between age and disability duration varies based on tenure, suggesting that both age and tenure are important influences in the work disability process. PMID- 26645385 TI - Risk of Occult Uterine Sarcoma in Presumed Uterine Fibroids. AB - Symptomatic fibroids are a common indication for hysterectomy or myomectomy. Although rare, unexpected gynecologic malignancies in presumed fibroids have been documented. In cases where tissue retrieval is performed through morcellation, there is increasing concern that intra-abdominal dispersion of occult uterine malignancies may lead to peritoneal dissemination and worse outcomes. We examined the available literature to determine the prevalence of all uterine cancers in women undergoing hysterectomy or myomectomy for benign uterine disease, with attention to the risk of morcellating occult uterine sarcomas. We also reviewed the available tools for preoperative discrimination between benign and malignant uterine disease. PMID- 26645386 TI - Novel azo-Metal-Organic Framework Showing a 10-Connected bct Net, Breathing Behavior, and Unique Photoswitching Behavior toward CO2. AB - Herein, we report a robust azo-metal-organic framework (MOF), namely, ECUT-15, which can be described as a 10-connected bct net built on trinuclear Co3 subunits. The activated samples of it perform a somewhat breathing behavior. Most importantly, under UV irradiation, this MOF performs outstanding photoswitching behavior toward CO2, giving great variation in the CO2 capture/release performance, for example, 45% under static conditions and 75% under dynamic measurements, as well as instantaneous release of up to 78%. PMID- 26645387 TI - Ambient-Temperature Newman-Kwart Rearrangement Mediated by Organic Photoredox Catalysis. AB - The Newman-Kwart rearrangement is perhaps the quintessential method for the synthesis of thiophenols from the corresponding phenol. However, the high thermal conditions required for the rearrangement of the requisite O-aryl carbamothioates often leads to decomposition. Herein, we present a general strategy for catalysis of O-aryl carbamothioates to S-aryl carbamothioates using catalytic quantities of a commercially available organic single-electron photooxidant. Importantly, this reaction is facilitated at ambient temperatures. PMID- 26645388 TI - Evidence of cell surface iron speciation of acidophilic iron-oxidizing microorganisms in indirect bioleaching process. AB - While indirect model has been widely accepted in bioleaching, but the evidence of cell surface iron speciation has not been reported. In the present work the iron speciation on the cell surfaces of four typically acidophilic iron-oxidizing microorganism (mesophilic Acidithiobacillus ferrooxidans ATCC 23270, moderately thermophilic Leptospirillum ferriphilum YSK and Sulfobacillus thermosulfidooxidans St, and extremely thermophilic Acidianus manzaensis YN25) grown on different energy substrates (chalcopyrite, pyrite, ferrous sulfate and elemental sulfur (S(0))) were studied in situ firstly by using synchrotron-based micro- X-ray fluorescence analysis and X-ray absorption near-edge structure spectroscopy. Results showed that the cells grown on iron-containing substrates had apparently higher surface iron content than the cells grown on S(0). Both ferrous iron and ferric iron were detected on the cell surface of all tested AIOMs, and the Fe(II)/Fe(III) ratios of the same microorganism were affected by different energy substrates. The iron distribution and bonding state of single cell of A. manzaensis were then studied in situ by scanning transmission soft X ray microscopy based on dual-energy contrast analysis and stack analysis. Results showed that the iron species distributed evenly on the cell surface and bonded with amino, carboxyl and hydroxyl groups. PMID- 26645389 TI - Efficacy of fingolimod is superior to injectable disease modifying therapies in second-line therapy of relapsing remitting multiple sclerosis. AB - Although fingolimod is registered in Europe for treatment of relapsing-remitting multiple sclerosis (RRMS) if earlier disease modifying therapy (DMT) has failed, no data regarding its efficacy in this patient group are available. This observational cohort study of the NeuroTransData network includes German RRMS outpatients with failure of earlier therapy with injectable DMT (iDMT), therefore switching to either another iDMT (n = 133) or to fingolimod (n = 300). Statistical comparison of clinical baseline characteristics showed more severely affected patients in the fingolimod group. A propensity-score matched group comparison was performed (n = 99 in each group) covering more than 2-year observation time. Fingolimod showed statistically significant superior efficacy in comparison to iDMT regarding annualized relapse rate (0.21 versus 0.33 per year), time-to-relapse and likelihood of relapse (iDMT hazard ratio 1.7), proportion and likelihood of patients with EDSS progression (15.10 versus 31.00%; iDMT hazard ratio 1.7), persistence on medication and likelihood of discontinuation (iDMT hazard ratio 3.0). Significantly more patients were free of relapse and EDSS progression with fingolimod than with their second iDMT (64.4 versus 46.5%, p < 0.03). This real-life evidence in German RRMS outpatients support data from controlled clinical studies and can quantitatively support clinical decision finding processes if iDMT therapy fails in RRMS. PMID- 26645390 TI - Mutations in the sodium channel gene SCN2A cause neonatal epilepsy with late onset episodic ataxia. AB - Mutations in SCN2A cause epilepsy syndromes of variable severity including neonatal-infantile seizures. In one case, we previously described additional childhood-onset episodic ataxia. Here, we corroborate and detail the latter phenotype in three further cases. We describe the clinical characteristics, identify the causative SCN2A mutations and determine their functional consequences using whole-cell patch-clamping in mammalian cells. In total, four probands presented with neonatal-onset seizures remitting after five to 13 months. In early childhood, they started to experience repeated episodes of ataxia, accompanied in part by headache or back pain lasting minutes to several hours. In two of the new cases, we detected the novel mutation p.Arg1882Gly. While this mutation occurred de novo in both patients, one of them carries an additional known variant on the same SCN2A allele, inherited from the unaffected father (p.Gly1522Ala). Whereas p.Arg1882Gly alone shifted the activation curve by -4 mV, the combination of both variants did not affect activation, but caused a depolarizing shift of voltage-dependent inactivation, and a significant increase in Na(+) current density and protein production. p.Gly1522Ala alone did not change channel gating. The third new proband carries the same de novo SCN2A gain of-function mutation as our first published case (p.Ala263Val). Our findings broaden the clinical spectrum observed with SCN2A gain-of-function mutations, showing that fairly different biophysical mechanisms can cause a convergent clinical phenotype of neonatal seizures and later onset episodic ataxia. PMID- 26645391 TI - Brief intervention by general practitioners for medication-overuse headache, follow-up after 6 months: a pragmatic cluster-randomised controlled trial. AB - Medication-overuse headache (MOH) is a common health problem. Withdrawal of the overused medication is the treatment of choice. We investigated the long-term effectiveness of brief intervention (BI) for MOH patients in primary care. The BI for MOH in primary care study was a blinded, pragmatic, cluster-randomised controlled trial. 25,486 patients (age 18-50) from 50 general practitioners (GPs) were screened for MOH. GPs defined clusters and 23 GPs were randomised to receive BI training and 27 GPs to continue business as usual (BAU). The GPs assessed their MOH patients with the Severity of Dependence Scale, gave individual feedback about the risk of MOH and advice to reduce headache medication. Primary outcomes, assessed 6 months after the intervention, were reduction in headache and medication days/month. 42% were screening responders. 2.4% had self-reported MOH. A random selection of 104 patients with self-reported MOH were invited, 75 were randomised out of which 60 with a physician-defined MOH diagnosis were included. None were lost to follow-up. BI was significantly better than BAU regarding primary outcomes (p < 0.001-0.018). Headache and medication days were reduced by 5.9 (95% CI 1.1-10.8) and 6.2 (1.1-11.3) more days/month in BI than BAU group. Chronic headache resolved in 63 and 11% in the BI and the BAU group (p < 0.001). Headache-related disability was lower among those who detoxified. In conclusion, BI is an effective treatment in primary care with lasting effect 6 months after the intervention for MOH. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01314768. PMID- 26645392 TI - Onset of clinical and MRI efficacy occurs early after fingolimod treatment initiation in relapsing multiple sclerosis. AB - To minimize the clinical burden associated with multiple sclerosis (MS), early control of focal and diffuse CNS disease activity is a treatment priority. A post hoc analysis was conducted to evaluate the onset of efficacy of fingolimod treatment in patients with relapsing MS. Data from patients who received fingolimod 0.5 mg or placebo during either of two 24-month, double-blind, randomized, parallel-group clinical trials (FREEDOMS and FREEDOMS II) were pooled for analysis. Efficacy outcomes were: time to first confirmed relapse; annualized relapse rate (ARR); proportions of patients free from T1 gadolinium-enhancing lesions or new/newly enlarged T2 lesions; percentage brain volume loss (BVL); and change in Multiple Sclerosis Functional Composite (MSFC) z-score from baseline to 6 months. An early benefit was seen with fingolimod (N = 783) vs. placebo (N = 773) for ARR at both 3 and 6 months (3 months, 0.32 vs. 0.52, p = 0.0015; 6 months, 0.21 vs. 0.45, p < 0.0001). Time to first relapse was also delayed with fingolimod vs. placebo from day 48 onwards. At 6 months, more patients in the fingolimod group than in the placebo group were free from new MRI activity (65.3 vs. 40.5%, p < 0.0001) and had less BVL (37.1% reduction vs. placebo, p < 0.001). MSFC z-score favored fingolimod over placebo at 6 months, with improvements noted in 9-Hole Peg Test and Paced Auditory Serial Addition Test scores. Improvements in outcomes related to relapses, MRI, disability, cognition, and BVL occurred within 6 months of treatment initiation with fingolimod. PMID- 26645394 TI - Switch to double positive late onset MuSK myasthenia gravis following thymomectomy in paraneoplastic AChR antibody positive myasthenia gravis. PMID- 26645393 TI - Cardiovascular adverse effects of phenytoin. AB - Phenytoin is an established drug in the treatment of acute repetitive seizures and status epilepticus. One of its main advantages over benzodiazepines is the less sedative effect. However, the possibility of cardiovascular adverse effects with the intravenous use of phenytoin cause a reluctance to its usage, and this has lead to a search for safer anticonvulsant drugs. In this study, we aimed to review the studies which evaluated the safety of phenytoin with respect to cardiovascular adverse effects. The original clinical trials and case reports listed in PUBMED in English language between the years of 1946-2014 were evaluated. As the key words, "phenytoin, diphenylhydantoin, epilepsy, seizure, cardiac toxicity, asystole, arrhythmia, respiratory arrest, hypotension, death" were used. Thirty-two clinical trials and ten case reports were identified. In the case reports, a rapid infusion rate (>50 mg/min) of phenytoin appeared as the major cause of increased mortality. In contrast, no serious cardiovascular adverse effects leading to death were met in the clinical trials which applied the recommended infusion rate and dosages. An infusion rate of 50 mg/min was reported to be safe for young patients. For old patients and patients with a cardiovascular co-morbidity, a slower infusion rate was recommended with a careful follow-up of heart rhythm and blood pressure. No cardiovascular adverse effect was reported in oral phenytoin overdoses except one case with a very high serum phenytoin level and hypoalbuminemia. Phenytoin is an effective and well tolerated drug in the treatment of epilepsy. Intravenous phenytoin is safe when given at recommended infusion rates and doses. PMID- 26645395 TI - NEFL N98S mutation: another cause of dominant intermediate Charcot-Marie-Tooth disease with heterogeneous early-onset phenotype. AB - The purpose of this study was to describe a pedigree with NEFL N98S mutation associated with a dominant intermediate Charcot-Marie-Tooth disease (DI-CMT) and heterogeneous early-onset phenotype. The pedigree comprised two patients, the proband and her son, aged 38 and 5 years. The proband, evaluated at age 31, showed delayed motor milestones that, as of the second decade, evolved into severe phenotype consisting of sensorimotor neuropathy, pes cavus, clawing hands, gait and kinetic cerebellar ataxia, nystagmus and dysarthria, she being wheelchair bound. By then, a working diagnosis of sporadic early onset cerebellar ataxia with peripheral neuropathy was established. Screening of mutations associated with SCA and autosomal recessive cerebellar ataxias was negative. Her son showed a mild phenotype characterized by delayed motor milestones, and lower limb hypotonia and areflexia. Electrophysiology in both patients showed nerve conduction slowing in the intermediate range, both in proximal and distal nerve segments, but where compound muscle action potentials exhibited severe attenuation there was conduction slowing down to the demyelinating range. In the proband, cranial magnetic resonance imaging (MRI) showed cerebellar atrophy, electromyography disclosed active denervation in tibialis anterior, and MRI of lower-limb musculature demonstrated widespread and distally accentuated muscle fatty atrophy; furthermore, on water sensitive MRI sequences there was edema of calf muscles. We conclude that the NEFL N98S mutation is associated with a DI-CMT phenotype characterized by early-onset sensorimotor neuropathy delaying motor milestones, which may evolve into a severe and complex clinical picture including cerebellar ataxia. PMID- 26645396 TI - Three new xanthones from the leaves of Garcinia lancilimba. AB - Three new prenylated xanthones, garcinexanthones G-I (1-3), together with fifteen known ones (4-18) were identified from the leaves of Garcinia lancilimba. Their structures were determined by extensive spectroscopic analyses. Most of the compounds exhibited inhibitory effects against HL-60 (human leukemia), A549 (human lung cancer), and MCF-7 (human breast cancer) cell lines. Among them, compounds 7, 17, and 13 exhibited the most pronounced growth inhibitory activity against HL-60, A549, and MCF-7 cell lines with GI50 values of 1.68, 4.88, and 6.28 MUM, respectively. PMID- 26645397 TI - Composition of the endophytic filamentous fungi associated with Cinchona ledgeriana seeds and production of Cinchona alkaloids. AB - Four kinds of endophytic filamentous fungi (code names: CLS-1, CLS-2, CLS-3, and CLS-4) associated with the seeds of Cinchona ledgeriana (Rubiaceae) from West Java, Indonesia, were isolated. All of the isolates were classified into Diaporthe spp. based on phylogenetic analysis of the nucleotide sequences of the internal transcribed spacers (ITS1 and ITS2) including the 5.8S ribosomal DNA region. All four of these endophytic fungi produce Cinchona alkaloids, mainly quinine and quinidine, in synthetic liquid medium. PMID- 26645398 TI - Synergistic Antivascular and Antitumor Efficacy with Combined Cediranib and SC6889 in Intracranial Mouse Glioma. AB - Prognosis remains extremely poor for malignant glioma. Targeted therapeutic approaches, including single agent anti-angiogenic and proteasome inhibition strategies, have not resulted in sustained anti-glioma clinical efficacy. We tested the anti-glioma efficacy of the anti-angiogenic receptor tyrosine kinase inhibitor cediranib and the novel proteasome inhibitor SC68896, in combination and as single agents. To assess anti-angiogenic effects and evaluate efficacy we employed 4C8 intracranial mouse glioma and a dual-bolus perfusion MRI approach to measure Ktrans, relative cerebral blood flow and volume (rCBF, rCBV), and relative mean transit time (rMTT) in combination with anatomical MRI measurements of tumor growth. While single agent cediranib or SC68896 treatment did not alter tumor growth or survival, combined cediranib/SC68896 significantly delayed tumor growth and increased median survival by 2-fold, compared to untreated. This was accompanied by substantially increased tumor necrosis in the cediranib/SC68896 group (p<0.01), not observed with single agent treatments. Mean vessel density was significantly lower, and mean vessel lumen area was significantly higher, for the combined cediranib/SC68896 group versus untreated. Consistent with our previous findings, cediranib alone did not significantly alter mean tumor rCBF, rCBV, rMTT, or Ktrans. In contrast, SC68896 reduced rCBF in comparison to untreated, but without concomitant reductions in rCBV, rMTT, or Ktrans. Importantly, combined cediranib/SC68896 substantially reduced rCBF, rCBV. rMTT, and Ktrans. A novel analysis of Ktrans/rCBV suggests that changes in Ktrans with time and/or treatment are related to altered total vascular surface area. The data suggest that combined cediranib/SC68896 induced potent anti-angiogenic effects, resulting in increased vascular efficiency and reduced extravasation, consistent with a process of vascular normalization. The study represents the first demonstration that the combination of cediranib with a proteasome inhibitor substantially increases the anti-angiogenic efficacy produced from either agent alone, and synergistically slows glioma tumor growth and extends survival, suggesting a promising treatment which warrants further investigation. PMID- 26645400 TI - Emerging Agents for the Management of Nephrotic Syndrome: Progress to Date. AB - Nephrotic Syndrome is a rare condition associated with high morbidity in the 20 40% of children and adolescents who fail to respond to standard immunosuppressive therapies. Novel non-immunologic mechanisms of widely used immunosuppressive therapies, as well as emerging anti-inflammatory drugs, and anti-fibrotics may play a crucial role in the treatment of patients with refractory disease. This article will review some of these treatments and their various stages of investigation. PMID- 26645399 TI - The N17 domain mitigates nuclear toxicity in a novel zebrafish Huntington's disease model. AB - BACKGROUND: Although the genetic cause for Huntington's disease (HD) has been known for over 20 years, the mechanisms that cause the neurotoxicity and behavioral symptoms of this disease are not well understood. One hypothesis is that N-terminal fragments of the HTT protein are the causative agents in HD and that peptide sequences adjacent to the poly-glutamine (Q) repeats modify its toxicity. Here we test the function of the N-terminal 17 amino acids (N17) in the context of the exon 1 fragment of HTT in a novel, inducible zebrafish model of HD. RESULTS: Deletion of N17 coupled with 97Q expansion (mHTT-DeltaN17-exon1) resulted in a robust, rapidly progressing movement deficit, while fish with intact N17 and 97Q expansion (mHTT-exon1) have more delayed-onset movement deficits with slower progression. The level of mHTT-DeltaN17-exon1 protein was significantly higher than mHTT-exon1, although the mRNA level of each transgene was marginally different, suggesting that N17 may regulate HTT protein stability in vivo. In addition, cell lineage specific induction of the mHTT-DeltaN17-exon1 transgene in neurons was sufficient to recapitulate the consequences of ubiquitous transgene expression. Within neurons, accelerated nuclear accumulation of the toxic HTT fragment was observed in mHTT-DeltaN17-exon1 fish, demonstrating that N17 also plays an important role in sub-cellular localization in vivo. CONCLUSIONS: We have developed a novel, inducible zebrafish model of HD. These animals exhibit a progressive movement deficit reminiscent of that seen in other animal models and human patients. Deletion of the N17 terminal amino acids of the huntingtin fragment results in an accelerated HD-like phenotype that may be due to enhanced protein stability and nuclear accumulation of HTT. These transgenic lines will provide a valuable new tool to study mechanisms of HD at the behavioral, cellular, and molecular levels. Future experiments will be focused on identifying genetic modifiers, mechanisms and therapeutics that alleviate polyQ aggregation in the nucleus of neurons. PMID- 26645401 TI - Prescribing Ceftolozane/Tazobactam for Pediatric Patients: Current Status and Future Implications. AB - Antibiotics are arguably the greatest medical development of the 20th century but these precious resources are being threatened by the continued rise in infections caused by multidrug-resistant bacteria. There is concern that we are on the precipice of a 'post-antibiotic era'. The situation is exacerbated by a stagnation in the pharmaceutical industry in developing new antibiotics, particularly those with activity against some of the most resistant Gram-negative organisms because of significant economic, scientific, and regulatory barriers. One of the products of recent initiatives to reinvigorate the antibiotic pipeline is the agent ceftolozane/tazobactam. Ceftolozane/tazobactam was approved in December 2014 by the US Food and Drug Administration for the treatment of complicated urinary tract infections and complicated intra-abdominal infections for patients 18 years of age and older. The safety and effectiveness of ceftolozane/tazobactam in pediatric patients has not been established in clinical studies. However, with the rise of highly drug-resistant Gram-negative organisms in children and the current climate of ongoing, multiple, and simultaneous antibiotic shortages--particularly of broad-spectrum antibiotics, the potential off-label role of ceftolozane/tazobactam for children needs to be explored while pediatric studies are ongoing. The objective of this opinion piece is to discuss what is currently known about ceftolozane/tazobactam and its potential implications for use in the pediatric population. PMID- 26645402 TI - Impact of dexrazoxane on doxorubicin-induced aneuploidy in somatic and germinal cells of male mice. AB - PURPOSE: Despite dexrazoxane's increasing use in mitigating doxorubicin-induced cardiotoxicity, no data are available in the literature on the potential aneugenicity of drug combination. Therefore, detailed evaluation of aneugenic potential of this combination is essential to provide more insights into aneuploidy induction that may play a role in the development of secondary malignancies and reproductive toxicity after treatment with doxorubicin. Thus, our aim was to determine whether dexrazoxane has influence on the aneuploidy induced by doxorubicin in germinal and somatic cells of male mice. METHODS: Sperm BrdU-incorporation assay, sperm FISH assay and the bone marrow micronucleus test complemented by FISH assay were used to determine aneuoploidy. Moreover, the formation of 8-OHdG, one of the oxidative DNA damage by-products, has been evaluated. RESULTS: Dexrazoxane was not aneugenic at the doses tested. Pre treatment of mice with dexrazoxane significantly reduced doxorubicin-induced aneuploidy in a dose-dependent manner. Doxorubicin induced marked biochemical alterations characteristic of oxidative DNA damage, and prior administration of dexrazoxane before doxorubicin challenge ameliorated this biochemical marker. CONCLUSION: This study provides evidence that dexrazoxane has a protective role in the abatement of doxorubicin-induced aneuploidy. This activity resides, at least in part, in its radical scavenger activity. Thus, dexrazoxane can avert secondary malignancies and abnormal reproductive outcomes in cured cancer patients exposed to doxorubicin. PMID- 26645403 TI - Phase I study assessing the feasibility of the triple combination chemotherapy of SOXIRI (S-1/oxaliplatin/irinotecan) in patients with unresectable pancreatic ductal adenocarcinoma. AB - BACKGROUND: The objective of this study was to determine the recommended dose (RD) of a biweekly S-1, oxaliplatin, and irinotecan (SOXIRI) regimen in patients with unresectable pancreatic ductal adenocarcinoma. METHODS: This phase I study used a traditional "3+3" dose-escalation design, with four dose levels. A dose escalation schedule consisted of two doses of S-1 (60 and 80 mg/m(2) twice daily) for 2 weeks in alternate-day administration, three doses of irinotecan (125, 150, and 180 mg/m(2)) on day 1, and a single dose of oxaliplatin (85 mg/m(2)) on day 1 of a 2-week cycle. Dose-limiting toxicities (DLTs) were assessed in the first four cycles to determine the maximum tolerated dose. This clinical study was registered at UMIN000014339. RESULTS: Fifteen patients received this regimen (median, eight cycles; range 4-12). At dose level 3 (S-1, 80 mg/m(2); irinotecan, 150 mg/m(2)), 2/6 patients experienced DLTs of grade 3 fatigue and grade 4 neutropenia. At dose level 4, all three patients experienced DLTs: grade 3 fatigue (n = 1) and grade 4 neutropenia (n = 2). The RD was 80, 85, and 150 mg/m(2) of S-1, oxaliplatin, and irinotecan, respectively. We found the following: response rate, 47 %; disease control rate, 80%; median progression free survival, 6.7 months; overall survival, 13.4 months. CONCLUSIONS: The SOXIRI regimen's RD is 80, 85, and 150 mg/m(2) of S-1, oxaliplatin, and irinotecan, respectively. PMID- 26645404 TI - Metabolism and disposition of the DOT1L inhibitor, pinometostat (EPZ-5676), in rat, dog and human. AB - PURPOSE: The metabolism and disposition of the first-in-class DOT1L inhibitor, EPZ-5676 (pinometostat), was investigated in rat and dog. Metabolite profiles were compared with those from adult patients in the first-in-man phase 1 study as well as the cross-species metabolism observed in vitro. METHODS: EPZ-5676 was administered to rat and dog as a 24-h IV infusion of [(14)C]-EPZ-5676 for determination of pharmacokinetics, mass balance, metabolite profiling and biodistribution by quantitative whole-body autoradiography (QWBA). Metabolite profiling and identification was performed by radiometric and LC-MS/MS analysis. RESULTS: Fecal excretion was the major route of elimination, representing 79 and 81% of the total dose in and rat and dog, respectively. QWBA in rats showed that the radioactivity was well distributed in the body, except for the central nervous system, and the majority of radioactivity was eliminated from most tissues by 168 h. Fecal recovery of dose-related material in bile duct-cannulated animals as well as higher radioactivity concentrations in the wall of the large intestine relative to liver implicated intestinal secretion as well as biliary elimination. EPZ-5676 underwent extensive oxidative metabolism with the major metabolic pathways being hydroxylation of the t-butyl group (EPZ007769) and N dealkylation of the central nitrogen. Loss of adenine from parent EPZ-5676 (M7) was observed only in rat and dog feces, suggesting the involvement of gut microbiota. In rat and dog, steady-state plasma levels of total radioactivity and parent EPZ-5676 were attained rapidly and maintained through the infusion period before declining rapidly on cessation of dosing. Unchanged EPZ-5676 was the predominant circulating species in rat, dog and man. CONCLUSIONS: The excretory and metabolic pathways for EPZ-5676 were very similar across species. Renal excretion of both parent EPZ-5676 and EPZ-5676-related material was low, and in preclinical species fecal excretion of parent EPZ-5676 and EPZ007769 accounted for the majority of drug-related elimination. PMID- 26645405 TI - Enhanced brain distribution of carboplatin in a primate model after blood-brain barrier disruption using an implantable ultrasound device. AB - PURPOSE: Glioblastoma is both the most common and aggressive primary brain tumor in adults. Carboplatin chemotherapy has shown only modest efficacy in progressive high-grade gliomas. The limited clinical efficacy of carboplatin may be due to its low concentration in tissue when the drug is delivered intravenously. The aim of this study was to assess whether the tissue concentration of intravenously administered carboplatin could be enhanced by ultrasound-induced blood-brain disruption in a primate model. METHODS: Carboplatin was administered intravenously for 60 min to a single primate following blood-brain barrier opening induced by an implantable ultrasound device. Blood and brain samples were collected after animal killing, which occurred 60 min after the end of carboplatin administration. Platinum quantification in ultrafiltrate plasma and brain samples was performed using inductively coupled plasma mass spectrometry. RESULTS: The brain concentration of platinum was highly enhanced (5.2*) in the 3.9 cm(3) region sonicated by the US beam, with a higher concentration in more vascularized anatomical structures. At 5 and 10 mm from the US beam axis, platinum concentrations were slightly enhanced (2.2* and 1.3* respectively). CONCLUSIONS: This study demonstrates that BBB opening using an implantable ultrasound transducer enhances the brain distribution of carboplatin in a loco regional manner. Such a treatment approach is of significant interest for the treatment of primary brain tumors and is under current evaluation in a phase 1 clinical trial (NCT02253212). PMID- 26645406 TI - Malformin A1 promotes cell death through induction of apoptosis, necrosis and autophagy in prostate cancer cells. AB - PURPOSE: Malformin A1 (MA1), a cyclopentapeptide isolated from fungal origin, has been identified to induce varieties of intriguing biological activities. Here, we reported the mode of mechanism underlying MA1-mediated cytotoxicity through induction of apoptosis, necrosis and autophagy in prostate cancer (PCa) cells. METHODS: Human PCa cells PC3 and LNCaP were treated with MA1, and cell viability, apoptosis, necrosis, mitochondrial damage, oxidative stress and autophagy were analyzed, respectively. Pharmacological inhibitors, transient transfection of plasmids and siRNAs were then used to identify the roles of oxidative stress and autophagy in MA1-triggered cell death. RESULTS: In both PC3 and LNCaP cells, MA1 inhibited cell proliferation and triggered oxidative stress via the rapid accumulation of reactive oxygen species and a decrease in mitochondrial transmembrane potential. Mitochondrial damage by MA1 triggered caspase activation and intracellular ATP deletion, leading to apoptosis and necrosis, respectively. Meanwhile, MA1 activated autophagy as indicated by conversion of LC3BI to LC3BII and increased GFP-tagged LC3B punctate dots. Pharmacological inhibition of autophagy or knocking down LC3B attenuated MA1-mediated cell death. Excessive oxidative stress and decreased ATP stimulated AMPK/mTOR pathway, which led to induction of MA1-mediated autophagy. CONCLUSIONS: Coaction of apoptotic, necrotic and autophagic cell death induced by mitochondrial damage defines a novel mechanism contributing to the growth suppression of MA1 in prostate cancer cells, and activation of autophagy might be a potential strategy for improving its chemotherapeutic effects. PMID- 26645407 TI - Population pharmacokinetic and exposure-response analysis for trastuzumab administered using a subcutaneous "manual syringe" injection or intravenously in women with HER2-positive early breast cancer. AB - PURPOSE: To characterize the population pharmacokinetics (PKs) of subcutaneous (SC) and intravenous (IV) trastuzumab in early breast cancer (EBC), assess the impact of covariates on trastuzumab PK, and evaluate fixed (nonweight-based) dosing for the SC regimen administrated via handheld syringe. METHODS: Serum trastuzumab concentrations from 595 patients with HER2-positive EBC in the HannaH study (fixed 600 mg SC trastuzumab or weight-based IV trastuzumab) were analyzed using nonlinear mixed-effects modeling. Multiple logistic regression was used to assess the exposure-response relationships between PK, efficacy [pathologic complete response (pCR)], and safety [grade >=3 adverse events (AEs)]. RESULTS: Trastuzumab PK was described by a two-compartment model with parallel linear and nonlinear elimination and first-order SC absorption, with a bioavailability of 77 %. Estimated total clearance (CL) values were 0.18-0.22 L/day for steady-state trough/peak concentrations of 75-148 ug/mL; the estimate for central volume of distribution was 2.9 L. Body weight and alanine transaminase, while showing significant effects on PK, only explained 8% of the variability in CL. Exposure response analyses showed no relationship between PK, pCR, and grade >=3 AEs for either regimen. CONCLUSION: A fixed 600 mg SC dose of trastuzumab provides the desired exposure, with steady-state trough concentrations (35-123 MUg/mL for the 5th-95th percentiles) above the historical target concentration of 20 MUg/mL for efficacy. Fixed dosing is further supported by lack of an exposure-response relationship between PK, pCR, and grade >=3 AEs. No dose adjustment per patient factors is required within the ranges studied. PMID- 26645408 TI - Population pharmacokinetic modeling of idelalisib, a novel PI3Kdelta inhibitor, in healthy subjects and patients with hematologic malignancies. AB - PURPOSE: Idelalisib is a potent PI3Kdelta inhibitor that was recently approved for treating hematologic malignancies. The objective of this analysis was to develop a population pharmacokinetic model for idelalisib and its inactive metabolite GS-563117 and to evaluate the impact of covariates on idelalisib/GS 563117 PK. METHODS: Data from 10 phase I or II studies in healthy volunteers or patients with hematologic malignancies (n = 736) were analyzed using NONMEM. Stepwise forward addition followed by backward elimination was implemented in the covariate (age, gender, race, body weight, baseline CLcr, AST, ALT, disease status, and type of cancer) model building process. Various model assessment methods were used to evaluate the models. RESULTS: Idelalisib plasma PK was best described by a two-compartment model with first-order absorption, first-order elimination from the central compartment, and a lag time. A nonlinear relationship between dose and relative bioavailability was included in the final model. Two statistically significant covariates were identified and incorporated into the final model: health status (healthy vs. patient) on CL/F and Q/F and body weight on CL/F. Despite being a statistically significant covariate, the effect of body weight on idelalisib exposures was weak, as evidenced by minor changes of steady-state exposure (C trough: 16%; AUC and C max: 10%) for a patient with extreme body weight (5th and 95th percentile) relative to the typical patient, and not considered to be clinically relevant. CONCLUSIONS: PopPK models were developed to adequately describe the plasma concentrations of idelalisib and GS-563117. There were no covariate that had a clinically meaningful impact on idelalisib or GS-563117 exposure. PMID- 26645410 TI - Follicular Mucinosis in a Male Adolescent with a History of Acute Myelogenous Leukemia and Graft-versus-Host Disease. AB - Although many cases of follicular mucinosis are idiopathic, numerous others are associated with mycosis fungoides or, rarely, other neoplastic or inflammatory disorders. There are only three reported cases, all in adults, of follicular mucinosis arising in association with acute myelogenous leukemia, two of which involved mycosis fungoides-associated follicular mucinosis, including one case in which the patient had a preceding bone marrow transplant. We present the first reported case of follicular mucinosis arising in an adolescent with acute myelogenous leukemia and acute graft-versus-host disease after an allogeneic bone marrow transplantation. PMID- 26645409 TI - Oligodendroglial defects during quakingviable cerebellar development. AB - The selective RNA-binding protein Quaking I (QKI) has previously been implicated in RNA localization and stabilization, alternative splicing, cell proliferation, and differentiation. The spontaneously-occurring quakingviable (qkv) mutant mouse exhibits a sharply attenuated level of QKI in myelin-producing cells, including oligodendrocytes (OL) because of the loss of an OL-specific promoter. The disruption of QKI in OLs results in severe hypomyelination of the central nervous system, but the underlying cellular mechanisms remain to be fully elucidated. In this study, we used the qkv mutant mouse as a model to study myelination defects in the cerebellum. We found that oligodendroglial development and myelination are adversely affected in the cerebellum of qkv mice. Specifically, we identified an increase in the total number of oligodendroglial precursor cells in qkv cerebella, a substantial portion of which migrated into the grey matter. Furthermore, these mislocalized oligodendroglial precursor cells retained their migratory morphology late into development. Interestingly, a number of these presumptive oligodendrocyte precursors were found at the Purkinje cell layer in qkv cerebella, resembling Bergman glia. These findings indicate that QKI is involved in multiple aspects of oligodendroglial development. QKI disruption can impact the cell fate of oligodendrocyte precursor cells, their migration and differentiation, and ultimately myelination in the cerebellum. (c) 2015 Wiley Periodicals, Inc. Develop Neurobiol 76: 972-982, 2016. PMID- 26645411 TI - Allosteric Modulators: A Side Door. AB - Allosteric modulators of the cannabinoid CB1 receptor were first discovered in 2005. Since then, although both negative and positive allosteric modulators have been uncovered, many questions remain about their site(s) of action, as well as the basis of their signaling. The described covalent probe with improved potency and efficacy will facilitate these studies. PMID- 26645412 TI - GABRB3 mutations: a new and emerging cause of early infantile epileptic encephalopathy. AB - The gamma-aminobutyric acid type A receptor beta3 gene (GABRB3) encodes the beta3 subunit of the gamma-aminobutyric acid type A (GABAA ) receptor, which mediates inhibitory signalling within the central nervous system. Recently, GABRB3 mutations have been identified in a few patients with infantile spasms and Lennox Gastaut syndrome. We report the clinical and electrographic features of a novel case of GABRB3-related early-onset epileptic encephalopathy. Our patient presented with neonatal hypotonia and feeding difficulties, then developed pharmacoresistant epileptic encephalopathy, characterized by multiple seizure types from 3 months of age. Electroencephalography demonstrated ictal generalized and interictal multifocal epileptiform abnormalities. Using a SureSelectXT custom multiple gene panel covering 48 early infantile epileptic encephalopathy/developmental delay genes, a novel de novo GABRB3 heterozygous missense mutation, c.860C>T (p.Thr287Ile), was identified and confirmed on Sanger sequencing. GABRB3 is an emerging cause of early-onset epilepsy. Novel genetic technologies, such as whole-exome/genome sequencing and multiple gene panels, will undoubtedly identify further cases, allowing more detailed electroclinical delineation of the GABRB3-related genotypic and phenotypic spectra. PMID- 26645413 TI - UK Lung Cancer RCT Pilot Screening Trial: baseline findings from the screening arm provide evidence for the potential implementation of lung cancer screening. AB - BACKGROUND: Lung cancer screening using low-dose CT (LDCT) was shown to reduce lung cancer mortality by 20% in the National Lung Screening Trial. METHODS: The pilot UK Lung Cancer Screening (UKLS) is a randomised controlled trial of LDCT screening for lung cancer versus usual care. A population-based questionnaire was used to identify high-risk individuals. CT screen-detected nodules were managed by a pre-specified protocol. Cost effectiveness was modelled with reference to the National Lung Cancer Screening Trial mortality reduction. RESULTS: 247 354 individuals aged 50-75 years were approached; 30.7% expressed an interest, 8729 (11.5%) were eligible and 4055 were randomised, 2028 into the CT arm (1994 underwent a CT). Forty-two participants (2.1%) had confirmed lung cancer, 34 (1.7%) at baseline and 8 (0.4%) at the 12-month scan. 28/42 (66.7%) had stage I disease, 36/42 (85.7%) had stage I or II disease. 35/42 (83.3%) had surgical resection. 536 subjects had nodules greater than 50 mm(3) or 5 mm diameter and 41/536 were found to have lung cancer. One further cancer was detected by follow up of nodules between 15 and 50 mm(3) at 12 months. The baseline estimate for the incremental cost-effectiveness ratio of once-only CT screening, under the UKLS protocol, was L8466 per quality adjusted life year gained (CI L5542 to L12 569). CONCLUSIONS: The UKLS pilot trial demonstrated that it is possible to detect lung cancer at an early stage and deliver potentially curative treatment in over 80% of cases. Health economic analysis suggests that the intervention would be cost effective-this needs to be confirmed using data on observed lung cancer mortality reduction. TRIAL REGISTRATION: ISRCTN 78513845. PMID- 26645414 TI - Relationship between pulmonary matrix metalloproteinases and quantitative CT markers of small airways disease and emphysema in COPD. AB - BACKGROUND: Matrix metalloproteinases (MMPs) are proteolytic enzymes that can degrade the extracellular matrix and drive tissue remodelling, key processes in the pathogenesis of COPD. The development of small airway disease has been identified as a critical mechanism in the early development of airflow obstruction but the contribution of MMPs in human disease is poorly characterised. OBJECTIVES: We investigated the role of MMPs and inflammatory cytokines in the lung by quantifying levels and determining relationships with the key pathological components of COPD in patients and healthy controls. METHODS: We analysed levels of MMPs and inflammatory cytokines in bronchoalveolar lavage from 24 COPD and 8 control subjects. Each subject underwent spirometry and high-resolution CT. Image analysis quantitatively assessed emphysema, bronchial wall thickening and small airways disease. RESULTS: Multiple MMPs (MMP-1, -2, -3, -8, -9 and -10) and cytokines (interleukin (IL) 6 and IL-8) were elevated in lungs of subjects with COPD. MMP-3, -7, -8, -9, -10 and -12 concentrations closely associated with CT markers of small airways disease. Emphysema severity was also associated with MMP-3, -7 and -10. However, there were no strong relationships between MMPs and bronchial wall thickness of the larger airways. CONCLUSIONS: Pulmonary MMP concentrations are directly associated with the extent of gas trapping and small airways disease identified on CT scan. This study suggests that MMPs play a significant role in small airways remodelling, a key feature in the pathogenesis of COPD. TRIAL REGISTRATION NUMBER: NCT01701869. PMID- 26645415 TI - School Personnel Experiences in Notifying Parents About Their Child's Risk for Suicide: Lessons Learned. AB - BACKGROUND: Schools across the nation are increasingly implementing suicide prevention programs that involve training school staff and connecting students and their families to appropriate services. However, little is known about how parents are engaged in such efforts. METHODS: This qualitative study examined school staff perspectives on parent involvement in the implementation of a district-wide suicide prevention program by analyzing focus group and interview data gathered on the program implementation processes. Participants included middle school teachers, administrators, and other school personnel. RESULTS: Study results revealed that in the immediate wake of a crisis or concern about suicide, school staff routinely contacted parents. However, substantial barriers prevent some students from receiving needed follow-up care (eg, lack of consistent follow-up, financial strain, parental stress, availability of appropriate services). Despite these challenges, school staff identified strategies that could better support parents before, during, and after the crisis. In particular, school-based services increased the success of mental health referrals. CONCLUSIONS: Our study suggests that systematic postcrisis follow-up procedures are needed to improve the likelihood that students and families receive ongoing support. In particular, school-based services and home visits, training and outreach for parents, and formal training for school mental health staff on parent engagement may be beneficial in this context. PMID- 26645416 TI - The Role of School Design in Shaping Healthy Eating-Related Attitudes, Practices, and Behaviors Among School Staff. AB - BACKGROUND: Schools have increasing responsibility to address healthy eating, but physical barriers influence their ability to adopt and sustain recommended strategies. We took advantage of a natural experiment to investigate the role of the physical environment in shaping healthy eating attitudes and practices among school staff members. METHODS: A school district consolidated its elementary schools and incorporated architectural features to support healthy eating into a building renovation. Surveys along with structured, in-depth interviews were administered prior to and at 12 months postoccupancy. Paired t-tests and McNemar's tests were used to analyze changes in survey indices and interview data were coded for themes. RESULTS: The school implemented new policies and programs, including staff wellness activities. There was a significant decrease in the percent of teachers with a high-fat diet (from 73.68% to 57.14%, p < .05). Many physical barriers were removed but new challenges emerged, and staff varied in their awareness and comfort with using the new healthy eating features. CONCLUSIONS: We found promising evidence that school architecture can support a school to address healthy eating. To enhance influence of the physical environment, more research is merited to test complementary strategies such as improving ownership of space and increasing self-efficacy to manage space. PMID- 26645418 TI - Prioritizing Alcohol Prevention: Establishing Alcohol as the Gateway Drug and Linking Age of First Drink With Illicit Drug Use. AB - BACKGROUND: Given ever-reducing budgets of community and school substance use prevention programs, there is a call for identifying the first substance in the sequence leading to polydrug use. METHODS: Examining data from a nationally representative sample of 2835 United States 12th graders, we sought to determine (1) the first substance adolescents use; (2) order in which adolescents progress through alcohol, tobacco, and marijuana use; and (3) impact of age of initial substance use on lifetime and frequency of illicit substance use. RESULTS: Alcohol is the most commonly used substance, and the majority of polysubstance using respondents consumed alcohol prior to tobacco or marijuana initiation. Respondents initiating alcohol use in sixth grade reported significantly greater lifetime illicit substance use (M = 1.9, standard deviation [SD] = 1.7, p < .001) and more frequent illicit substance use (M = 6.0, SD = 6.5, p < .001) than those initiating alcohol use in ninth grade or later. Overall, effect sizes for these differences were large (eta squared = 0.30 and 0.28, respectively). CONCLUSIONS: Findings underscore the importance of screening for substance use, even among youth enrolled in elementary/middle school. In addition, school prevention programs should begin in elementary school (third grade) and target alcohol use. PMID- 26645419 TI - Developing the School Physical Activity and Nutrition Environment Tool to Measure Qualities of the Obesogenic Context. AB - BACKGROUND: Practical tools are needed that reliably measure the complex physical activity (PA) and nutrition environments of elementary schools that influence children's health and learning behaviors for obesity prevention. The School Physical Activity and Nutrition-Environment Tool (SPAN-ET) was developed and beta tested in 6 rural Oregon elementary schools. METHODS: Extension educators were trained to assess elementary school PA and nutrition environments using the SPAN ET. Two auditors per school worked with school health stakeholders and collected data via document review, interviews, and direct observations. A reliability analysis using percent agreement and kappa statistics was performed to determine consistency between independent auditors. Content analyses of qualitative data were used to triangulate intercoder ratings, verify evidence, and improve reliability. RESULTS: Across the 6 schools, for all 182 measured criteria (PA = 103; nutrition = 79), the percent agreement ranged from 80.8% to 96.8% and kappa from 0.61% to 0.94. CONCLUSION: The SPAN-ET was a reliable instrument for assessing the quality of elementary school PA and nutrition environments, and a sensitive measure for objectively identifying specific attributes of SPAN-ET areas of interest to target for school environmental and policy improvements aimed at supporting students' obesity preventing behaviors. PMID- 26645417 TI - A Tale of 2 Teachers: A Preschool Physical Activity Intervention Case Study. AB - BACKGROUND: Preschool settings vary greatly, and research has shown that interventions are more successful when they can be adapted to individual settings. This is a descriptive case study of how 2 teachers successfully adapted and implemented a preschool physical activity intervention. METHODS: The Study of Health and Activity in Preschool Environments (SHAPES) was a 3-year physical activity intervention. A detailed case study of 2 high-implementing teachers was conducted. Multiple data sources included accelerometry, direct observation, teacher surveys, and intervention staff field notes. RESULTS: Teacher A focused on integrating physical activity into a wide range of activities, including parent and community events. Teacher B focused on high-intensity, structured activities. Both teachers supported the intervention, worked closely with intervention staff, and operated their classroom as an autonomous unit with support from their directors. Teacher A provided an average of 31.5, 78.0, and 67.5 min of physical activity opportunity per day of observation during years 1, 2, and 3. Teacher B provided an average of 2.7, 33.5, and 73.3 minutes of physical activity opportunity per day of observation. CONCLUSION: Successful implementation of physical activity interventions may look different in different contexts; thus, interventions should allow for flexible implementation. PMID- 26645420 TI - Availability of Vending Machines and School Stores in California Schools. AB - BACKGROUND: This study examined the availability of foods sold in vending machines and school stores in United States public and private schools, and associations of availability with students' food purchases and consumption. METHODS: Descriptive analyses, chi-square tests, and Spearman product-moment correlations were conducted on data collected from 521 students aged 8 to 15 years recruited from orthodontic offices in California. RESULTS: Vending machines were more common in private schools than in public schools, whereas school stores were common in both private and public schools. The food items most commonly available in both vending machines and school stores in all schools were predominately foods of minimal nutritional value (FMNV). Participant report of availability of food items in vending machines and/or school stores was significantly correlated with (1) participant purchase of each item from those sources, except for energy drinks, milk, fruits, and vegetables; and (2) participants' friends' consumption of items at lunch, for 2 categories of FMNV (candy, cookies, or cake; soda or sports drinks). CONCLUSIONS: Despite the Child Nutrition and Women, Infants, and Children (WIC) Reauthorization Act of 2004, FMNV were still available in schools, and may be contributing to unhealthy dietary choices and ultimately to health risks. PMID- 26645421 TI - Waist Circumference and Objectively Measured Sedentary Behavior in Rural School Adolescents. AB - BACKGROUND: Research on relationships between lifestyle behaviors and adiposity in school youth is potentially important for identifying subgroups at risk. This study evaluates the associations between waist circumference (WC) and objective measures of sedentary behavior (SB) in a sample of rural school adolescents. METHODS: The sample included 254 students (114 boys, 140 girls), 13-16 years of age, from rural regions of the Portuguese midlands. Height, weight, and WC were measured. Cardiorespiratory fitness (CRF) was assessed with the 20-m shuttle-run test. An uniaxial GT1M accelerometer was used to obtain 5 consecutive days of physically activity (PA) and SB. Multiple linear regression was used to test associations between WC and SB, adjusted for several potential confounders (age, sex, PA, CRF, parental education). RESULTS: SB was not significantly associated with the WC, neither in the unadjusted model nor after adjustment for all potential confounders. In the final model, the unique significant predictor of the WC was cardiorespiratory fitness (beta = -0.82; 95% confidence interval [CI], -1.02 to -0.62). CONCLUSION: WC was not independently associated with SB time in rural school adolescents. Future research is claimed among rural adolescents in different geographic contexts to try to clarify recent findings of less studied communities. PMID- 26645422 TI - Health Risk Behaviors in a Representative Sample of Bisexual and Heterosexual Female High School Students in Massachusetts. AB - BACKGROUND: Differences in sexual health-related outcomes by sexual behavior and identity remain underinvestigated among bisexual female adolescents. METHODS: Data from girls (N = 875) who participated in the Massachusetts Youth Risk Behavior Surveillance survey were analyzed. Weighted logistic regression models were fit to examine sexual and psychosocial health by lifetime sexual behavior (behaviorally bisexual vs behaviorally heterosexual) and sexual identity (bisexual vs heterosexual) adjusting for grade and race/ethnicity. RESULTS: Overall, 10.5% of girls reported lifetime bisexual behavior and 8.1% reported a bisexual identity. Behavior and identity were discordant for bisexual young women as 53.2% of behaviorally bisexual students had a bisexual identity and 46.8% had a heterosexual identity. Bisexual identity and behavior were associated with unprotected intercourse at last sexual encounter, early sexual debut, 4 or more lifetime partners, history of forced/unwanted sex, sexually transmitted infection testing history, past-year depression, and past-month drug use (all ps < .05). CONCLUSION: Bisexuality, whether defined by identity or behavior, is associated with adverse sexual and psychosocial health outcomes in adolescent girls. Studies that explore wellness across the life span, and are designed to recognize developmental differences burgeoning in adolescence, may provide insights into the differential sexual risk outcomes observed among bisexual girls. PMID- 26645424 TI - Rupture of the urinary bladder in a piglet during manual expression. PMID- 26645423 TI - Nasal and pharyngeal eosinophil peroxidase levels in adults with poorly controlled asthma correlate with sputum eosinophilia. AB - The objective of the study was to compare nasal, pharyngeal, and sputum eosinophil peroxidase (EPX) levels with induced sputum eosinophil percentage in 10 adults with poorly controlled asthma and 10 normal controls. EPX was measured using an ELISA and normalized for grams of protein for nasal and pharynx specimens and for mL-gram of protein for sputum. Sputum EPX levels were statistically different between asthma and control subjects (P = 0.024). EPX levels measured in the nasal and pharyngeal swab samples derived from the same patients were also different between asthma and control subjects, each displaying a high degree of significance (P = 0.002). Spearman's correlation coefficients for nasal EPX and pharyngeal EPX levels compared to induced sputum eosinophil percentage were 0.81 (P = 0.0007) and 0.78 (P = 0.0017), respectively. Thus, there is a strong association in a given patient between both nasal and pharyngeal EPX levels and the eosinophil percentage of induced sputum. PMID- 26645425 TI - Effects of sevoflurane exposure during late pregnancy on brain development of offspring mice. AB - BACKGROUND: Exposure to some anesthetic agents during the fetal period has been shown to induce neurodegeneration or learning deficits in animal models. Sevoflurane is one of the most prevalent general anesthetics; however, the influence of sevoflurane at a clinically relevant concentration on the developing fetal brain remains unknown. OBJECTIVE: We investigated whether a single sevoflurane exposure during the fetal period would affect neuronal development and learning/memory ability in mice. METHODS: Pregnant mice at gestational day 17 were anesthetized with 1.5% sevoflurane in 50% oxygen for 6 h. Mice in the control group were exposed in 50% oxygen without sevoflurane. Pups of some mice in both groups subsequently were delivered early by cesarean section and whole fetal brains were excised. The rest of the pups were delivered naturally at gestational day 20 and were maintained for 8 weeks. The mRNA expression levels of caspase-3, brain derived neurotrophic factor (BDNF), nerve growth factor (NGF), and LIM kinase-1 (LIMK-1) were measured in fetal whole brain and 8-week-old hippocampus sections. Synaptophysin protein in adult hippocampus was assessed immunochemically. In addition, 8-week-old mice were subjected to the radial maze test. RESULTS: No significant difference between sevoflurane and control groups regarding mRNA expression levels of all targets was seen, nor was there an obvious change in synaptophysin protein expression. The results of the maze test revealed that the each-day performance ratios (the rate of errors) of the sevoflurane group were not altered as compared with the control group. CONCLUSIONS: These results suggest that the exposure during late pregnancy to a clinically relevant concentration of sevoflurane does not affect neuronal development and learning/memory ability of offspring mice. PMID- 26645426 TI - CT differentiation of diffuse malignant peritoneal mesothelioma and peritoneal carcinomatosis. AB - BACKGROUND AND AIM: Diffuse malignant peritoneal mesothelioma (DMPM) and peritoneal carcinomatosis (PC) have similar imaging in computer tomography (CT). We aimed to distinguish them. METHODS: Computer tomography findings were evaluated in 48 DMPM and 47 PC for the peritoneal, mesenteric, omentum, lymph nodes, viscera infiltration, ascites and pleural plaques. RESULTS: Two groups had no difference in terms of thickness, clinical manifestation, diameter of lymph nodes, ascites, and viscera infiltration. But they showed differences in the following: Ratio of asbestos exposure in DMPM group was higher. Smooth and irregular peritoneal thickening were more seen in DMPM group; peritoneal nodules were more commonly detected in PC group. Forty-eight cases of peritoneum in DMPM showed mild enhanced, while 14 patients in PC showed severe enhanced. Nodular type of omentum was more common in PC group than in DMPM group; omental cake was more commonly detected in DMPM group. Mesentery involvement was more commonly seen in DMPM group. Location of enlarged lymph nodes in cardiophrenic region was more frequently identified in DMPM, whereas location of enlarged lymph nodes in retroperitoneal region was more frequently identified in PC. Lymph nodes fusion was more frequently visualized in PC. Fixation of the intestinal wall was more common in DMPM. Pleural plaque was more common in DMPM. PC had distant metastasis except primary foci and peritoneum. In PC, tumor origins were ovary in 10, digestive system in 21, breast in one. CONCLUSION: Using a combination of CT findings may increase our ability to distinguish PC from DMPM. PMID- 26645427 TI - Click Chemistry Finds Its Way in Constructing an Ionic Highway in Anion-Exchange Membrane. AB - To find the way to construct an ionic highway in anion-exchange membranes (AEMs), a series of side-chain-type alkaline polymer electrolytes (APEs) based on poly(2,6-dimethyl-1,4-phenylene oxide) (PPO) polymer backbones were synthesized via Cu(I)-catalyzed click chemistry. The resulting triazole groups and quaternary ammonium (QA) groups facilitate the formation of a continuous hydrogen bond network, which will lead to high hydroxide conductivity according to Grotthuss type mechanism. Microphase separation induced by long alkyl side chains contributes at the same time to further improving the hydroxide conductivity of the resultant AEMs. Hydroxide conductivity as high as 52.8 mS/cm is obtained for membrane TA-14C-1.21 (IEC = 1.21 mmol/g) with the longest pendant chain at 30 degrees C, and the conductivity can be increased to 140 mS/cm when the temperature was increased to 80 degrees C. Moreover, the corresponding water uptake is only 8.6 wt % at 30 degrees C. In the meantime, the membrane properties can be tuned by precisely regulating the hydrophilic/hydrophobic ratio in the cationic head groups. Compared with AEMs containing triazole and quaternized trimethylammonium head groups, enhanced dimensional stability and mechanical properties are obtained by tuning side-chain chemistry. However, the alkaline stability of the membrane is not as stable as anticipated, probably because of the existence of the triazole ring. Further study will be focused on increasing the alkali stability of the membrane. We envisage that the side-chain type APEs meditated by click chemistry bearing long hydrophobic side chains pendant to the cationic head groups hold promise as a novel AEMs material. PMID- 26645428 TI - Government consults on charging overseas visitors for emergency care. PMID- 26645429 TI - Identification of Phosphorylation Consensus Sequences and Endogenous Neuronal Substrates of the Psychiatric Risk Kinase TNIK. AB - Traf2- and Nck-interacting kinase (TNIK) is a serine/threonine kinase highly expressed in the brain and enriched in the postsynaptic density of glutamatergic synapses in the mammalian brain. Accumulating genetic evidence and functional data have implicated TNIK as a risk factor for psychiatric disorders. However, the endogenous substrates of TNIK in neurons are unknown. Here, we describe a novel selective small molecule inhibitor of the TNIK kinase family. Using this inhibitor, we report the identification of endogenous neuronal TNIK substrates by immunoprecipitation with a phosphomotif antibody followed by mass spectrometry. Phosphorylation consensus sequences were defined by phosphopeptide sequence analysis. Among the identified substrates were members of the delta-catenin family including p120-catenin, delta-catenin, and armadillo repeat gene deleted in velo-cardio-facial syndrome (ARVCF), each of which is linked to psychiatric or neurologic disorders. Using p120-catenin as a representative substrate, we show TNIK-induced p120-catenin phosphorylation in cells requires intact kinase activity and phosphorylation of TNIK at T181 and T187 in the activation loop. Addition of the small molecule TNIK inhibitor or knocking down TNIK by two shRNAs reduced endogenous p120-catenin phosphorylation in cells. Together, using a TNIK inhibitor and phosphomotif antibody, we identify endogenous substrates of TNIK in neurons, define consensus sequences for TNIK, and suggest signaling pathways by which TNIK influences synaptic development and function linked to psychiatric and neurologic disorders. PMID- 26645430 TI - Intramolecular electron transfer reactions in meso-(4-nitrophenyl)-substituted subporphyrins. AB - A2B-type meso-(4-nitrophenyl)-substituted subporphyrins have been synthesized and shown to undergo very fast photoinduced intramolecular charge separation (CS) and charge recombination (CR) between the subporphyrin core and the meso-4 nitrophenyl group in CH2Cl2 as probed by femtosecond time-resolved transient absorption spectroscopy. Red-shifted emissions were detected from charge separated states as a rare case for porphyrinoids. PMID- 26645431 TI - Glycation Contributes to Interaction Between Human Bone Alkaline Phosphatase and Collagen Type I. AB - Bone is a biological composite material comprised primarily of collagen type I and mineral crystals of calcium and phosphate in the form of hydroxyapatite (HA), which together provide its mechanical properties. Bone alkaline phosphatase (ALP), produced by osteoblasts, plays a pivotal role in the mineralization process. Affinity contacts between collagen, mainly type II, and the crown domain of various ALP isozymes were reported in a few in vitro studies in the 1980s and 1990s, but have not attracted much attention since, although such interactions may have important implications for the bone mineralization process. The objective of this study was to investigate the binding properties of human collagen type I to human bone ALP, including the two bone ALP isoforms B1 and B2. ALP from human liver, human placenta and E. coli were also studied. A surface plasmon resonance-based analysis, supported by electrophoresis and blotting, showed that bone ALP binds stronger to collagen type I in comparison with ALPs expressed in non-mineralizing tissues. Further, the B2 isoform binds significantly stronger to collagen type I in comparison with the B1 isoform. Human bone and liver ALP (with identical amino acid composition) displayed pronounced differences in binding, revealing that post-translational glycosylation properties govern these interactions to a large extent. In conclusion, this study presents the first evidence that glycosylation differences in human ALPs are of crucial importance for protein-protein interactions with collagen type I, although the presence of the ALP crown domain may also be necessary. Different binding affinities among the bone ALP isoforms may influence the mineral-collagen interface, mineralization kinetics, and degree of bone matrix mineralization, which are important factors determining the material properties of bone. PMID- 26645432 TI - Higher Level of Dickkopf-1 is Associated with Low Bone Mineral Density and Higher Prevalence of Vertebral Fractures in Patients with Ankylosing Spondylitis. AB - Patients with ankylosing spondylitis (AS) have an increased risk of bone loss and vertebral fractures. In this study, we explored the hypothesis that the excess bone loss and vertebral fractures might be related with the activity of the Wingless signaling pathway, and in particular with the serum levels of its circulating inhibitors, Sclerostin and Dickkopf-1 (DKK1). We recruited 71 patients diagnosed with AS. Lateral radiographs of the total spine were analyzed to detect the presence of vertebral fractures, and bone mineral density (BMD) was assessed in all patients using dual X-ray absorptiometry at lumbar spine and proximal femoral site. Blood samples were obtained and levels of C-reactive protein (CRP), DKK1, and Sclerostin were measured. Blood samples from 71 healthy sex- and age-matched volunteers were collected to be used as controls. Vertebral fractures were detected more commonly among men than in women (29 vs 8 %, respectively). DKK1, but not Sclerostin serum levels, were inversely correlated to lumbar spine Z-score BMD. Patients with one or more prevalent vertebral fractures had significantly higher DKK1 levels, without significant difference in Sclerostin serum levels. A significant positive correlation was found between DKK1 serum levels and CRP (r = 0.240, p = 0.043). The association we found between serum DKK1 levels and BMD values and vertebral fracture prevalence suggests that DKK1 might contribute to the severity of osteoporosis in AS. PMID- 26645439 TI - [Physiological Relevance and Nursing Care Applications of Moxibustion as Applied to the Sanyinjiao Acupoint on Females]. AB - Moxibustion is a thermal therapy procedure that applies burning material to the surface of specific acupoints, which warms the meridians and dispels cold. This procedure is widely used in traditional Chinese medicine care and treatment. It is also an important complementary and replacement therapy in many countries. Moxibustion on the Sanyinjiao acupoint of females is one of the main methods used to treat and care for women's health problems. The physiological effects of moxibustion on the Sanyinjiao acupoint include heightening the skin surface temperature to improve circulation and adjusting the balance of the autonomic nervous system via the meridians in order to regulate the affiliated organs (liver, spleen, and kidney). Moxibustion carries health risks, including the possibility of burns. Therefore, this therapy must follow the principles of moxibustion in order to safely complete the course and achieve the intended efficacy. In nursing-care applications, we must consider the process, time, distances, and safety of moxibustion. In exploring this theme, we hope the present paper helps readers better apply moxibustion in nursing-care applications and in the nursing education curriculum. PMID- 26645438 TI - Alcohol consumption and binge drinking in early pregnancy. A cross-sectional study with data from the Copenhagen Pregnancy Cohort. AB - BACKGROUND: Since 2007 the Danish Health and Medicines Authority has advised total alcohol abstinence from the time of trying to conceive and throughout pregnancy. The prevalence of binge drinking among pregnant Danish women has nevertheless been reported to be up to 48 % during early pregnancy. Since the introduction of the recommendation of total abstinence, no studies have examined pre-pregnancy lifestyle and reproductive risk factors associated with this behaviour in a Danish context. The aims of this study were therefore to describe the prevalence of weekly alcohol consumption and binge drinking in early pregnancy among women living in the capital of Denmark. Secondly to identify pre pregnancy lifestyle and reproductive risk factors associated with binge drinking during early pregnancy. METHODS: Data were collected from September 2012 to August 2013 at the Department of Obstetrics, Rigshospitalet, Copenhagen, Denmark. Self-reported information on each woman's socio-demographic characteristics, medical history, and lifestyle factors including alcohol habits was obtained from an electronic questionnaire filled out as part of the individual medical record. Descriptive analysis was conducted and multivariate logistic regression analysis was used to assess the potential associated risk factors (adjusted odds ratio (aOR)). RESULTS: Questionnaires from 3,238 women were included. A majority of 70 %, reported weekly alcohol consumption before pregnancy. The prevalence decreased to 3 % during early pregnancy. The overall proportion of women reporting binge drinking during early pregnancy was 35 % (n = 1,134). The following independent risk factors for binge drinking in early pregnancy were identified: lower degree of planned pregnancy, smoking and alcohol habits before pregnancy ((1 unit/weekly aOR 4.48, CI: 3.14 - 6.40), (2-7 units aOR 10.23, CI: 7.44-14.06), (>=8 units aOR 33.18, CI: 19.53-56.36)). Multiparity and the use of assisted reproductive technology were associated with lower odds of binge drinking in early pregnancy. CONCLUSION: The prevalence of weekly alcohol consumption decreased considerably during early pregnancy compared with pre-pregnancy levels. Nevertheless one third of the pregnant women engaged in binge drinking. Identification of risk factors for this behaviour renders it possible not only to design prevention strategies, but also to target those most at risk. PMID- 26645440 TI - [The Theory and Practice of Health Cultivation Qigong Exercise in Traditional Chinese Medicine]. AB - The health cultivation qigong exercise in traditional Chinese medicine refers to a traditional, integrated method of illness prevention and body strengthening, which promotes the functions of qi and the blood, smooths the meridians (energy channels), and balances the viscera and bowels through the regulation of the mind, the breathing, and the body. The concept of using qi to cultivate human life is part of the health cultivation practices of ancient Chinese codes and of Chinese medicine. This concept includes the principles, methods, essences, and clinical applications of the practice. In addition, traditional health cultivation references the concepts of yinyang, viscera and bowels, qi and blood, meridians, and essential energy spirit theory in order to explain the human biological phenomena, the theoretical and practical perspectives of qigong, and the basis of the treatment principle. The health cultivation qigong exercise of Chinese medicine utilizes the concept of the "unity of nature and human beings" in traditional Chinese thinking in its practice, which emphasizes the conformity to nature and seasons. In order to fully leverage the benefits from the purpose of health cultivation in qigong practice, the priority is to understand the health cultivation mechanism, the essentials/matters, and the precautions of qigong practices. Recently, the evidence regarding both the biological and the psychological benefits of qigong practices have been demonstrated in numbers of research articles. In particular, qigong is currently considered to be one of the best mild exercises that is suited to all age groups. Professional nurses are suggested to include the health cultivation qigong exercise as part of activities that target health improvement and illness prevention. Due to the diversity in qigong as practiced by different health cultivation qigong exercise sects, it is essential to accumulate more clinical evidence by conducting greater numbers of rigorous studies that may be referenced in evidence-based nursing practices. PMID- 26645441 TI - [The Usage of Auricular Acupressure in Clinical Nursing and Evidence-Based Research]. AB - Auricular acupressure is a non-invasive physiotherapy that was developed based on the traditional Chinese meridian theory. Because it is non-invasive, simple to implement, and easy to learn, and because it presents minimal side effects and may be executed independently, this therapy may be used as an alternative or auxiliary approach to symptom management as well as to self-care. The increasing support for auricular acupressure from evidence-based research in Taiwan and elsewhere offers the opportunity to include auricular acupressure as a treatment option in evidence-based nursing interventions. Because nursing education in Taiwan is guided by Western medical concepts and principles, most nurses are not familiar with auricular acupressure, which is derived from traditional Chinese medicine. Therefore, this article not only systemically introduces the definition and theoretical basis of auricular acupressure but also includes the principles and application-related knowledge. Furthermore, this article analyzes the common problems encountered in auricular acupressure research in order to improve the familiarity of nurses with this therapy, to provide references for clinical application, and to provide a basis for designing new evidence-based nursing research efforts. PMID- 26645442 TI - [Acupressure and Evidence-Based Nursing]. AB - Acupressure is a traditional Chinese medicine approach to disease prevention and treatment that may be operated by nurses independently. Therefore, acupressure is being increasingly applied in clinical nursing practice and research. Recently, the implementation of evidence-based nursing (EBN) in clinical practice has been encouraged to promote nursing quality. Evidence-based nursing is a method-ology and process of implementation that applies the best-available evidence to clinical practice, which is acquired through the use of empirical nursing research. Therefore, in this paper, we address the topic of acupressure within the context of empirical nursing practice. We first introduce the current status of acupressure research and provide the locations of common acupoints in order to guide future empirical nursing research and to help nurses use these acupoints in clinical practice. Finally, we describe the steps that are necessary to apply the current empirical information on acupressure as well as provide suggestions to promote safety and efficacy in order to guide nurses in the accurate application of acupressure in nursing practice. PMID- 26645443 TI - [A Delphi Method Survey of the Core Competences of Post-Acute-Care Nurses in Caring for Acute Stroke Patients]. AB - BACKGROUND: Post-acute care (PAC) service is becoming increasingly important in Taiwan as a core focus of government policies that are designed to ensure continuity of care. PURPOSE: In order to improve PAC nursing education and quality of care, the present study applies a modified Delphi method to identify the core competences of nurses who provide PAC services to acute stroke patients. METHODS: We surveyed 18 experts in post-acute care and long-term care anonymously using a 29-question questionnaire in order to identify the essential professional skills that are required to perform PAC effectively. The results of this survey indicate that the core competences of PAC may be divided into two categories: Case Management and Care Management. Case Management includes Direct Care, Communication, Health Care Education, Nursing Consulting, and Family Assessment & Health Care. Care Management includes Interdisciplinary Teamwork, Patient Care Management, and Resource Integration. The importance and practicality of each item was evaluated using a 7-point Likert scale. RESULTS: The experts required 2 rounds to reach a consensus about the importance and 3 rounds to determine the practicality of PAC core competences. This process highlighted the differing points of view that are held by professionals in the realms of nursing, medicine, and national health policy. CONCLUSIONS / IMPLICATIONS FOR PRACTICE: The PAC in job training program in its current form inadequately cul-tivates core competence in Care Management. The results of the present study may be used to inform the development of PAC nurse orientation training programs and continuing education courses. PMID- 26645444 TI - [The Experiences of Obstructive Sleep Apnea in Women]. AB - BACKGROUND: Obstructive sleep apnea (OSA) is a potentially lethal respiratory sleep disorder. However, few studies have studied OSA women. PURPOSE: The purpose of the current study was to explore the life experiences of women with OSA. METHODS: A qualitative study using the grounded theory method was used to establish a descriptive theory. RESULTS: The results were expressed in terms of three stages with related categories. Stage 1: No interest days due to poor sleep, including "uncontrollable sleep", "perceived health deteriorates", and "poor female image harmed by snoring"; Stage 2: Indecision and disappointments during treatment seeking, including "doctor shopping", "being urged by others to seek medical help", and "being shocked by the severity of disease"; and Stage 3: Accepting a new lifestyle with a continuous positive pressure respirator, including "adaptation of the new sleep", "adequate sleep", and "secret worry of being an OSA woman". CONCLUSIONS: Based on the findings of the present study, medical knowledge and treatments related to OSA should be widely promoted with appropriate professional education and counseling services in order to enhance the awareness of patients and to facilitate their acceptance of the healing process using a continuous positive airway pressure respirator. PMID- 26645445 TI - [A Study on the Cognitive Learning Effectiveness of Scenario-Based Concept Mapping in a Neurological Nursing Course]. AB - BACKGROUND: The multiple levels of knowledge related to the neurological system deter many students from pursuing studies on this topic. Thus, in facing complicated and uncertain medical circumstances, nursing students have diffi culty adjusting and using basic neurological-nursing knowledge and skills. Scenario-based concept-mapping teaching has been shown to promote the integration of complicated data, clarify related concepts, and increase the effectiveness of cognitive learning. PURPOSE: To investigate the effect on the neurological nursing cognition and learning attitude of nursing students of a scenario-based concept-mapping strategy that was integrated into the neurological nursing unit of a medical and surgical nursing course. METHODS: This quasi-experimental study used experimental and control groups and a pre-test / post-test design. Sopho more (2nd year) students in a four-year program at a university of science and technology in Taiwan were convenience sampled using cluster randomization that was run under SPSS 17.0. Concept-mapping lessons were used as the intervention for the experimental group. The control group followed traditional lesson plans only. The cognitive learning outcome was measured using the neurological nursing learning examination. RESULTS: Both concept-mapping and traditional lessons significantly improved post-test neurological nursing learning scores (p < .001), with no significant difference between the two groups (p = .51). The post-test feedback from the control group mentioned that too much content was taught and that difficulties were experienced in understanding mechanisms and in absorbing knowledge. In contrast, the experimental group held a significantly more positive perspective and learning attitude with regard to the teaching material. Furthermore, a significant number in the experimental group expressed the desire to add more lessons on anatomy, physiology, and pathology. These results indicate that this intervention strategy may help change the widespread fear and refusal of nursing students with regard to neurological lessons and may facilitate interest and positively affect learning in this important subject area. CONCLUSION: Integrating the concept-mapping strategy and traditional clinical case lessons into neurological nursing lessons holds the potential to increase post-test scores significantly. Concept mapping helped those in the experimental group adopt views and attitudes toward learning the teaching material that were more positive than those held by their control-group peers. In addition, while 59% of the experimental group and 49% of the control group submitted opinions related to learning attitude in the open-ended questions, positive feedback was greater in the experimental group than in the control group. PMID- 26645446 TI - [Symptom Distress, Depression, and Quality of Life in Colorectal Cancer Patients at Different Disease Stages]. AB - BACKGROUND: Quality of life is increasingly used as a primary outcome measure in studies that are designed to evaluate the effectiveness of treatment in cancer survivors. PURPOSE: Analyze the symptom distress, depression, and quality of life in colorectal cancer patients and explore the relationship of related variables with changes in QoL (quality of life) during and after treatment. METHODS: A cross-sectional study design was used for the present study. Patients (N = 138) with colorectal cancer were recruited from a district hospital in southern Taiwan. Data were collected using a self-report questionnaire. Questionnaire scales included the M.D. Anderson Symptom Inventory-Taiwan Form, the Center for Epidemiologic Studies Depression Scale, and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 Version 3 in Chinese as well as a demographic and disease-related variables datasheet. Descriptive data were presented using percentage, mean, and standard deviation. Chi-square test, independent t-test, one-way ANOVA, and hierarchical multiple regression were used for inferential statistics. RESULTS: The post-treatment group showed a significantly higher average global health QOL score (68.68 vs. 59.54; p < .05). Hierarchical regression showed that the impact factor of quality of life has a depressive effect in many dimensions. The second most significant variable was symptom distress. Symptoms interfered with life activity functions and family income and impacted negatively on patient treatment. In survivorship, depressive tendencies was the variable that was most affected, followed by recurrence, symptoms interference, and surgical treatment, respectively. When controlling for the relevant variables, these predictors accounted for 38.5% and 40.9% of the total variance of global health quality of life. CONCLUSIONS / IMPLICATIONS FOR PRACTICE: This study demonstrates that personal characteristics variables, depressive tendencies, and symptom distress all impact on the quality of life of colorectal cancer patients in terms of receiving treatment and survivorship. These findings imply that healthcare professionals must provide appropriate emotional support in order to decrease depression tendency at different stages. Thus, these patients should receive nursing interventions that effectively decrease depression and symptom distress and enhance quality of life at different disease stages. PMID- 26645448 TI - [A Program to Improve the Implementation Rate for the Barcode Medication Administration System]. AB - BACKGROUND & PROBLEM: Fully implementing the barcode medication administration system has been shown to help improve medication safety. We have promoted the barcode medication administration system in our hospital since May of 2014. However, the rate of implementation reached only 32% initially. We identified the major obstacles to fully implementing the barcode system as: (1) the barcodes on patients' wristbands were smudged or broken; (2) the barcodes on transparent drug bags and infusion bags were difficult to scan; (3) nurses were not familiar with the scanner and lacked the skills necessary to conduct barcode scans; (4) poor wireless Internet access inhibited effective barcode scanning; and (5) the beep sound generated during barcode scanning disturbed patients' sleep. The present project was conducted to improve the implementation by nursing staff of the barcode medication administration system. PURPOSE: The purpose was to increase the rate of implementation from 32% to 80%. RESOLUSIONS: The key members of the project were nurses, computer technicians, and pharmacists. The following procedures were conducted: (1) check the integrity of the wrist band and renew this band periodically; (2) print the barcode against a white background on transparent drug transfusion bags; (3) demonstration the skills of barcode scanning to nurses and inspect the function of scanners periodically; (4) increase the number of access points for the wireless network; (5) demonstrate the procedure for adjusting the sound volume on the scanner; and (6) provide rewards / incentives for using the barcode medication administration system. RESULTS: The rate of implementation of the barcode medication administration system increased from 32% to 85.2%. CONCLUSIONS: This project significantly increased the use of the barcode medication administration system by our nursing staff. The procedures used in this project may be referenced by administrators at other hospitals with low rates of barcode medication administration system usage. PMID- 26645447 TI - [Reducing the Incidence of Incontinence Associated Dermatitis in Intensive Care Unit Diarrhea Patients]. AB - BACKGROUND & PROBLEMS: Incontinence associated dermatitis (IAD) is a common skin disorder in critical patients who suffer from fecal incontinence. Symptoms of IAD include pain, redness, swelling, and, in some cases, secondary infections. IAD is thus a major problem faced in critical nursing care. The incidence of incontinence associated dermatitis averaged 34.72% at the intensive care unit in our hospital from October to December 2013. The factors that we identified as associated with IAD included: (1) Nurses: incorrect nursing care and insufficient IAD-related knowledge among nurses; (2) DEVICES: lack of skin barrier products and the use of diapers with poor air ventilation; (3) Regulations: lack of IAD care standards and lack of auditing oversight; (4) Patient problems: skin edema, incontinence, and medication use. PURPOSE: To decrease the incidence of IAD from 34.72% to 22%. METHODS: The authors searched the Cochrane, PubMed, CINAHI, and Nursing Reference Center databases for relevant articles that were published from 2000 to 2014. Fifty studies were identified and four evidence-based references were selected for follow-up assessment. Levels of evidence were at levels 2 and 3. We designed an intervention that: (1) set a high-risk notice to increase awareness; (2) held six in-service training programs; (3) developed nursing standards and designed e-learning education lessons that specifically targeted reducing the incidence of IAD; (4) established a regular audit system. RESULT: The incidence of IAD decreased from 34.72% pretest to 19.8% posttest (posttest period: April - October 2014). CONCLUSION: This project effectively reduced the incidence of IAD in high-risk patients in our intensive care unit. The authors established evidence-based interventions that significantly improved patient outcomes. PMID- 26645449 TI - [The Development of a Care Protocol for Postoperative Pressure Sore Prevention]. AB - Pressure sores are a common complication caused by long periods of bed rest following major surgery. These sores may increase patient postoperative pain, increase the risk of infections, lengthen the pe-riod of hospitalization, and increase the duration and costs of nursing care. Therefore, maintaining the skin integrity of surgical patients is an important responsibility for operating room nurses and an indicator of nursing care quality. While pressure-sore risk assessment tools and interoperative strategies are available and used in foreign countries, there has been little related research conducted in Taiwan. After examining the relevant literature and considering the current postoperative pressure sore situation in Taiwan, the author developed a postoperative pressure sore care protocol as a reference for clinical staff. Protocol procedures include major breakthrough developments in areas such as post-survey risk assessment for pressure ulcers, pressure ulcer prevention strategies that take surgery-related risk factors into consideration, extra care and protection measures for surgical supine patients, and post-pressure sores. The developed postoperative pressure sore protocol may be incorporated into surgical care procedures during the post surgical care period in order to effectively prevent the occurrence of post surgery pressure ulcers. Furthermore, the developed protocol offers the potential to improve and strengthen the quality of surgical care in terms of both healthcare and post-surgical care. PMID- 26645450 TI - [Learning Portfolio: A New Strategy in Health Education]. AB - Health education is the teaching by healthcare professionals of healthcare related knowledge and skills to students in order that these students learn to help patients self-manage their disease and maintain health. This article introduces a new strategy in health education known as the learning portfolio and presents the theoretical basis and function of the learning portfolio and the current application of this approach in academic and health education. The learning portfolio is a learner-centric approach that collects evidence related to an individual's learning process systematically. This approach helps educators understand learner needs and conditions, while allowing the learner to observe his / her learning process in a manner that promotes self-reflection, continual inspection, and behavioral modification throughout the learning process. The results enhance the motivation of learners and strengthen their care confidence in accomplishing learning tasks. PMID- 26645451 TI - [Nursing Experience With Providing Wound Care for a Newborn With Epidermolysis Bullosa]. AB - Epidermolysis bullosa (EB) is a rare hereditary, chromosomal disease of the skin. Life-threatening septicemia may result if appropriate care is not provided to alleviate the extensive skin irritation that is the main symptom of this disease. This case report describes the experience of the author in nursing a wound area on a newborn that was suspected of being caused by EB. This wound area comprised blisters and peeling skin that covered 30% of the entire skin area of the infant. A holistic assessment conducted from December 1st, 2013 to January 7th, 2014 revealed that this large of an area of damage to the skin and mucosa considerably complicated the task of wound care and caused severe pain to the infant. In response to the special needs of this case, our medical team conducted a literature review of wound care for this rare disease. Based on the suggestions of previous empirical studies, nursing measures for the skin, mucosa, and wounds of the newborn were then administered through inter-team cooperation. These actions effectively reduced the pain, controlled the infection, and accelerated wound healing. In addition, progressive contact was used to guide the primary caregivers of the newborn, which alleviated their physical and psychological stresses effectively. The caregivers were educated systematically on wound care and guided to learn techniques for nursing and dressing wounds. Thus, these caregivers were better prepared to continue providing wound care at home. We suggest that healthcare professionals reference empirical studies when providing care to EB newborns during the acute-care period and provide wound care and supportive therapies to control the occurrence of complications using a multidisciplinary team-care model. In addition, social resources should be used effectively in nursing care plans to mitigate the effect of this rare disease on families. PMID- 26645452 TI - Outcome of longitudinal versus transverse incision in de Quervain's disease and its implications in Indian population. AB - BACKGROUND: de Quervain's disease is an inadequacy into the first extensor compartment of wrist between the osteofibrous tunnel and the tendons. This mechanical conflict generates a tenosynovitis of the extensor pollicis brevis and the abductor pollicis longus tendons in first dorsal extensor compartment of the wrist. AIM: (1) To compare the clinical results obtained by longitudinal and transverse incisions and (2) the implication of clinical results in Indian population. MATERIALS AND METHODS: This study was conducted at Kalpana Chawla Government Medical College, Karnal, Haryana. The inclusion criteria were positive Finkelstein's test and no response to non-surgical treatment for 6 weeks. Forty eight patients with de Quervain's disease who did not respond to conservative treatment were operated with two different incisions. The patients were followed at 6 weeks, 3 and 6 months to compare the surgical outcomes. RESULTS: During a three-month follow-up, a significant difference was shown between the two methods (p = 0.0001). Results of surgical treatment with longitudinal incision were better (only one hypertrophic scar), but there were 12 postoperative complications with transverse incision. Visual analog scale (VAS) was used to evaluate the hypertrophic scar. In transverse incision group, out of five patients, four patients who developed hypertrophic scar have poor score according to VAS. CONCLUSION: Overall, longitudinal incision should be used for surgical treatment for de Quervain's disease due to lower risk of complications. PMID- 26645453 TI - Outcome of arthroscopic single-bundle anterior cruciate ligament reconstruction: anteromedial portal technique versus transtibial drilling technique. AB - PURPOSE: Controversies exist about the femoral tunnel preparation technique in anterior cruciate ligament (ACL) reconstruction surgeries. The aim of this study was to evaluate mid-term outcomes of transtibial (TT) technique in comparison with anteromedial portal (AMP) one. METHODS: Demographic data, height, weight, period of time from injury to surgery, and follow-up duration of patients underwent ACL reconstruction using single-bundle hamstring graft by the senior author between 2007 and 2011 were evaluated, retrospectively. Mid-quadriceps circumference difference, passive range of motion of the joint, anterior drawer test, Lachman test, and pivot shift test were assessed for each case. Function of the knee joint was calculated using International Knee Documentation Committee (IKDC), Lysholm, and Tegner scores. RESULTS: Of 50 cases in the AMP group (age 30.6 +/- 6.5), 45 were male and of the 44 patients in the TT group (age 30.0 +/- 6.5), forty were male. Mean follow-up times in the AMP and TT group were 18.2 months (range 12-84 months) and 25.7 months (range 16-48 months), respectively. No statistically significant difference was found in mid-quadriceps circumference difference (P = 0.861). Also, functional knee scores (P values of IKDC = 0.329, Lysholm score = 0.08, Tegner = 0.504) and stability tests (P values of anterior drawer test = 0.07, Lachman test = 0.486, pivot shift test = 0.348) did not differ statistically between groups. CONCLUSION: There is no superiority of AMP technique on TT technique in ACL reconstructive surgeries. It could be suggested that performing a well-done technique, either TT or AMP, may be more important than only choosing a technique. PMID- 26645454 TI - A Salt-Inducible Mn-Catalase (KatB) Protects Cyanobacterium from Oxidative Stress. AB - Catalases, enzymes that detoxify H2O2, are widely distributed in all phyla, including cyanobacteria. Unlike the heme-containing catalases, the physiological roles of Mn-catalases remain inadequately characterized. In the cyanobacterium Anabaena, pretreatment of cells with NaCl resulted in unusually enhanced tolerance to oxidative stress. On exposure to H2O2, the NaCl-treated Anabaena showed reduced formation of reactive oxygen species, peroxides, and oxidized proteins than the control cells (i.e. not treated with NaCl) exposed to H2O2. This protective effect correlated well with the substantial increase in production of KatB, a Mn-catalase. Addition of NaCl did not safeguard the katB mutant from H2O2, suggesting that KatB was indeed responsible for detoxifying the externally added H2O2. Moreover, Anabaena deficient in KatB was susceptible to oxidative effects of salinity stress. The katB gene was strongly induced in response to osmotic stress or desiccation. Promoter-gfp analysis showed katB to be expressed only in the vegetative cells but not in heterocysts. Biochemically, KatB was an efficient, robust catalase that remained active in the presence of high concentrations of NaCl. Our findings unravel the role of Mn-catalase in acclimatization to salt/oxidative stress and demonstrate that the oxidative stress resistance of an organism can be enhanced by a simple compound such as NaCl. PMID- 26645455 TI - Cooperative Protein Folding by Two Protein Thiol Disulfide Oxidoreductases and 1 in Soybean. AB - Most proteins produced in the endoplasmic reticulum (ER) of eukaryotic cells fold via disulfide formation (oxidative folding). Oxidative folding is catalyzed by protein disulfide isomerase (PDI) and PDI-related ER protein thiol disulfide oxidoreductases (ER oxidoreductases). In yeast and mammals, ER oxidoreductin-1s (Ero1s) supply oxidizing equivalent to the active centers of PDI. In this study, we expressed recombinant soybean Ero1 (GmERO1a) and found that GmERO1a oxidized multiple soybean ER oxidoreductases, in contrast to mammalian Ero1s having a high specificity for PDI. One of these ER oxidoreductases, GmPDIM, associated in vivo and in vitro with GmPDIL-2, was unable to be oxidized by GmERO1a. We therefore pursued the possible cooperative oxidative folding by GmPDIM, GmERO1a, and GmPDIL 2 in vitro and found that GmPDIL-2 synergistically accelerated oxidative refolding. In this process, GmERO1a preferentially oxidized the active center in the A': domain among the A: , A': , and B: domains of GmPDIM. A disulfide bond introduced into the active center of the A': domain of GmPDIM was shown to be transferred to the active center of the A: domain of GmPDIM and the A: domain of GmPDIM directly oxidized the active centers of both the A: or A': domain of GmPDIL-2. Therefore, we propose that the relay of an oxidizing equivalent from one ER oxidoreductase to another may play an essential role in cooperative oxidative folding by multiple ER oxidoreductases in plants. PMID- 26645457 TI - CTNNB1 (beta-Catenin)-altered Neoplasia: A Review Focusing on Soft Tissue Neoplasms and Parenchymal Lesions of Uncertain Histogenesis. AB - beta-catenin (CTNNB1) is a key regulatory molecule of the Wnt signaling pathway, which is important for tissue homeostasis and regulation of cell proliferation, differentiation, and function. Abnormal stabilization and nuclear accumulation of beta-catenin as a consequence of missense mutations or alternative molecular mechanisms occurs at a high frequency in a variety of epithelial cancers. In mesenchymal neoplasia, the role of beta-catenin has been traditionally considered limited to desmoid-type fibromatosis. However, the spectrum of beta-catenin driven (beta-catenin-altered) neoplasia of mesenchymal origin has been steadily widening to include, in addition to desmoid tumors, a variety of benign and intermediate-biology neoplasms of soft tissue (intranodal palisaded myofibroblastoma), head and neck (juvenile nasopharyngeal angiofibroma and sinonasal hemangiopericytoma/glomangiopericytoma), and ovarian (microcystic stromal tumor) origin. In addition, several old and newly reported distinctive site-specific beta-catenin-driven parenchymal neoplasms of uncertain histogenesis have been well characterized in recent studies, including solid-pseudopapillary neoplasm of the pancreas and its recently described ovarian counterpart, sclerosing hemangioma of lung and calcifying nested stromal-epithelial tumor of the liver. This review addresses the most relevant pathobiological and differential diagnostic aspects of beta-catenin-altered neoplasms with emphasis on site-specific histologic and biological variations. In addition, the morphologic overlap and analogy as well as distinctness between these uncommon tumors will be presented and discussed. Furthermore, a note is made on association of some of these lesions with hereditary tumor syndromes, in particular with the familial adenomatous polyposis coli. PMID- 26645458 TI - Primary Pulmonary Salivary Gland-type Tumors: A Review and Update. AB - Pulmonary salivary gland-type tumors (SGT) comprise a very small proportion of primary lung neoplasms. The most common tumors among this group are mucoepidermoid carcinoma and adenoid cystic carcinoma. Contrary to the head and neck region, benign SGT such as pleomorphic adenomas are exceedingly rare in the pulmonary system. More recently, 2 additional SGT, namely hyalinizing clear cell carcinoma and salivary duct-like carcinoma were recognized as primary lung tumors expanding the spectrum of SGT that have been described to originate in the tracheobronchial system. Primary pulmonary SGT must be clinically excluded from metastatic salivary gland neoplasms as their morphology is indistinguishable from that of their salivary gland counterparts. Little is known about the clinical behavior and best treatment approach for these unusual tumors. In this review, we provide a comprehensive summary of primary pulmonary SGT with particular emphasis on morphologic characteristics and latest developments in terms of immunohistochemical and molecular techniques. PMID- 26645456 TI - Maize reas1 Mutant Stimulates Ribosome Use Efficiency and Triggers Distinct Transcriptional and Translational Responses. AB - Ribosome biogenesis is a fundamental cellular process in all cells. Impaired ribosome biogenesis causes developmental defects; however, its molecular and cellular bases are not fully understood. We cloned a gene responsible for a maize (Zea mays) small seed mutant, dek* (for defective kernel), and found that it encodes Ribosome export associated1 (ZmReas1). Reas1 is an AAA-ATPase that controls 60S ribosome export from the nucleus to the cytoplasm after ribosome maturation. dek* is a weak mutant allele with decreased Reas1 function. In dek* cells, mature 60S ribosome subunits are reduced in the nucleus and cytoplasm, but the proportion of actively translating polyribosomes in cytosol is significantly increased. Reduced phosphorylation of eukaryotic initiation factor 2alpha and the increased elongation factor 1alpha level indicate an enhancement of general translational efficiency in dek* cells. The mutation also triggers dramatic changes in differentially transcribed genes and differentially translated RNAs. Discrepancy was observed between differentially transcribed genes and differentially translated RNAs, indicating distinct cellular responses at transcription and translation levels to the stress of defective ribosome processing. DNA replication and nucleosome assembly-related gene expression are selectively suppressed at the translational level, resulting in inhibited cell growth and proliferation in dek* cells. This study provides insight into cellular responses due to impaired ribosome biogenesis. PMID- 26645459 TI - Update on Thin Melanoma: Outcome of an International Workshop. AB - The following communication summarizes the proceedings of a 1-day Workshop of the International Melanoma Pathology Study Group, which was devoted to thin melanoma. The definitions and histologic criteria for thin melanoma were reviewed. The principal differential diagnostic problems mentioned included the distinction of thin melanoma from nevi, especially from nevi of special site, irritated nevi, inflamed and regressing nevi, and dysplastic nevi. Histologic criteria for this analysis were discussed and the importance of clinico-pathologic correlation, especially in acral sites, was emphasized. Criteria for the minimal definition of invasion were also discussed. In addition, a new technique of m-RNA expression profiling with 14 genes was presented and facilitated the distinction of thin melanomas from nevus in histologically obvious cases. However, for particular nevi, it was not obvious why the results indicated a malignant lesion. Despite many molecular and other ancillary investigations, Breslow thickness remains the most important prognostic factor in thin melanoma. The prognostic significance of radial (horizontal) and vertical growth phases, Clark level, regression, and mitotic rate were also discussed. Because of the increasing frequency of thin melanomas, there is a great need to develop more refined predictors of thin melanomas with worse clinical outcome. PMID- 26645460 TI - Dedifferentiated Liposarcoma: Updates on Morphology, Genetics, and Therapeutic Strategies. AB - Well-differentiated liposarcoma (WDL) and dedifferentiated liposarcoma (DDL) form the largest subgroup of liposarcomas, and represent a morphologic and behavioral spectrum of 1 disease entity, which arises typically in middle to late adult life, most frequently within the retroperitoneum or extremities. DDL is defined as nonlipogenic sarcoma that is juxtaposed to WDL, occurs as a recurrence of WDL or which can arise de novo, and typically has the appearance of undifferentiated pleomorphic or spindle cell sarcoma. DDL have a propensity for local recurrence, whereas distant metastasis is rarer, and behavior is related to anatomic site, with retroperitoneal neoplasms showing a significantly worse prognosis. Surgical resection remains the mainstay of treatment, and medical options for patients with aggressive recurrent or metastatic disease are limited. DDL share similar genetic abnormalities to WDL, with high-level amplifications of chromosome 12q14 15, including the MDM2 and CDK4 cell cycle oncogenes, and DDL harbor additional genetic changes, particularly coamplifications of 6q23 and 1p32. Novel therapies targeted at the gene products of chromosome 12 are being tested in clinical trials. We review the pathology and genetics of DDL, discussing morphologic patterns, immunohistochemical and genetic findings, the differential diagnosis, and future therapeutic strategies. PMID- 26645461 TI - Epithelioid Sarcoma: Diagnostic Features and Genetics. AB - Epithelioid sarcoma (ES) is a rare, aggressive soft-tissue neoplasm of uncertain differentiation, characterized by nodular aggregates of epithelioid cells, which are immunoreactive to cytokeratins (CKs) and epithelial membrane antigen, and often for CD34. It has a propensity for multifocal disease at presentation, local recurrence, and regional metastasis. These are aggressive neoplasms with particularly poor prognosis after regional or distant metastatic disease, for which surgical resection is still the mainstay of treatment, and options for patients with metastatic disease remain undefined. There are 2 distinct variants: classic ES, which typically presents as a subcutaneous or deep dermal mass in the distal extremities of young adults and comprises nodular distributions of relatively uniform epithelioid cells with central necrosis, and the proximal variant, which has a predilection for proximal limbs and limb girdles and the midline of the trunk, which is composed of sheets of larger, more atypical cells with variable rhabdoid morphology. Both classic and proximal-type ESs are associated with the loss of SMARCB1/INI1 protein expression, but appear otherwise molecularly relatively heterogeneous. We review classic and proximal-type ES, discussing morphology, immunohistochemical and genetic findings, the differential diagnosis, and the future potential for targeted therapies. PMID- 26645462 TI - The Origin of Epithelial Neoplasms of the Ovary: An Alternative View. AB - Several theories have been proposed to explain the origin of epithelial neoplasms of the ovary. However, most of them did not receive serious consideration until recently when it has been proposed that most ovarian neoplasms arise from the fallopian tube. In this review, we mention the different theories, we discuss in detail the fallopian tube theory, and the reasons why this theory is probably inaccurate. We are also proposing a new theory, the fere ex nihilo, based on the observation of numerous cases, old and new concept, and experimental works with animals. We believe that, most probably, ovarian epithelial neoplasms are related to hormones and the identification of these hormones will allow us not only to diagnose and treat these lethal neoplasms, but also to prevent them. PMID- 26645463 TI - Recent Developments in Non-HPV-related Adenocarcinomas of the Lower Female Genital Tract and Their Precursors. AB - Most adenocarcinomas in the lower female genital tract (cervix, vagina, vulva) arise in the cervix and are associated with high-risk human papillomavirus (HPV) infection. However, there is an emerging spectrum of non-HPV-related cervical adenocarcinomas, the most common of which is so-called gastric type. In this review, the concept of gastric-type cervical adenocarcinomas and their possible precursor lesions is covered, the precursor lesions still being poorly understood. Other non-HPV-related cervical adenocarcinomas are also discussed, including new information regarding molecular events in mesonephric adenocarcinoma. A variety of primary vaginal adenocarcinomas, including clear cell, endometrioid, intestinal and gastric types are also discussed. The spectrum of benign and malignant glandular lesions involving the lower female genital tract and probably derived from misplaced Skene's (periurethral) glands is also covered. PMID- 26645464 TI - Mirativity as Surprise: Evidentiality, Information, and Deixis. AB - The goal of this paper is to investigate the linguistic, psychological and cognitive properties of utterances that express the surprise of the speaker, with a focus on how grammatical evidentials are used for this purpose. This is often labeled in the linguistics literature as mirativity. While there has been a flurry of recent interest in mirativity, we still lack an understanding of how and why evidentials are used this way, and an explanation of this effect. In this paper I take steps to filling this gap by showing how the mirativity associated with grammatical evidentials is one of the many linguistic reflexes of the more general cognitive process of surprise. I approach this by analyzing mirativity, and the language of surprise more generally, in a schema-theoretic framework enriched with the notion of new environmental information. I elaborate on the field methodological issues involved with testing the mirative use of an evidential and why they are used this way by connecting mirative evidentials to the broader phenomenon of deixis. PMID- 26645465 TI - Neural Substrates of Processing Anger in Language: Contributions of Prosody and Semantics. AB - Emotions are conveyed primarily through two channels in language: semantics and prosody. While many studies confirm the role of a left hemisphere network in processing semantic emotion, there has been debate over the role of the right hemisphere in processing prosodic emotion. Some evidence suggests a preferential role for the right hemisphere, and other evidence supports a bilateral model. The relative contributions of semantics and prosody to the overall processing of affect in language are largely unexplored. The present work used functional magnetic resonance imaging to elucidate the neural bases of processing anger conveyed by prosody or semantic content. Results showed a robust, distributed, bilateral network for processing angry prosody and a more modest left hemisphere network for processing angry semantics when compared to emotionally neutral stimuli. Findings suggest the nervous system may be more responsive to prosodic cues in speech than to the semantic content of speech. PMID- 26645466 TI - Genetics, Transcriptional Profiles, and Catalytic Properties of the UDP-Arabinose Mutase Family from Barley. AB - Four members of the UDP-Ara mutase (UAM) gene family from barley have been isolated and characterized, and their map positions on chromosomes 2H, 3H, and 4H have been defined. When the genes are expressed in Escherichia coli, the corresponding HvUAM1, HvUAM2, and HvUAM3 proteins exhibit UAM activity, and the kinetic properties of the enzymes have been determined, including Km, Kcat, and catalytic efficiencies. However, the expressed HvUAM4 protein shows no mutase activity against UDP-Ara or against a broad range of other nucleotide sugars and related molecules. The enzymic data indicate therefore that the HvUAM4 protein may not be a mutase. However, the HvUAM4 gene is transcribed at high levels in all the barley tissues examined, and its transcript abundance is correlated with transcript levels for other genes involved in cell wall biosynthesis. The UDP-l Arap -> UDP-l-Araf reaction, which is essential for the generation of the UDP Araf substrate for arabinoxylan, arabinogalactan protein, and pectic polysaccharide biosynthesis, is thermodynamically unfavorable and has an equilibrium constant of 0.02. Nevertheless, the incorporation of Araf residues into nascent polysaccharides clearly occurs at biologically appropriate rates. The characterization of the HvUAM genes opens the way for the manipulation of both the amounts and fine structures of heteroxylans in cereals, grasses, and other crop plants, with a view toward enhancing their value in human health and nutrition, and in renewable biofuel production. PMID- 26645468 TI - Interactions between C and Cu atoms in single-layer graphene: direct observation and modelling. AB - Metal doping into the graphene lattice has been studied recently to develop novel nanoelectronic devices and to gain an understanding of the catalytic activities of metals in nanocarbon structures. Here we report the direct observation of interactions between Cu atoms and single-layer graphene by transmission electron microscopy. We document stable configurations of Cu atoms in the graphene sheet and unique transformations of graphene promoted by Cu atoms. First-principles calculations based on density functional theory reveal a reduction of energy barrier that caused rotation of C-C bonds near Cu atoms. We discuss two driving forces, electron irradiation and in situ heating, and conclude that the observed transformations were mainly promoted by electron irradiation. Our results suggest that individual Cu atoms can promote reconstruction of single-layer graphene. PMID- 26645469 TI - Resistive pressure sensors based on freestanding membranes of gold nanoparticles. AB - In this communication the application of gold nanoparticle membranes as ambient pressure sensors with electromechanical signal transduction is demonstrated. The devices were fabricated by sealing microstructured cavities with membranes of 1,6 hexanedithiol cross-linked gold nanoparticles, which were electrically contacted by metal electrodes deposited on both sides of the cavities. Variations of the external pressure resulted in a deflection of the membranes and, thus, increased the average interparticle distances. Therefore, the pressure change could easily be detected by simply monitoring the resistance of the membranes. PMID- 26645467 TI - Effects of pitavastatin add-on therapy on chronic kidney disease with albuminuria and dyslipidemia. AB - BACKGROUND: In non-dialysis chronic kidney disease (CKD) patients with dyslipidemia, statin therapy is recommended to prevent cardiovascular complications. Dyslipidemia has been also shown to be an independent risk factor for the progression of CKD. However, it is still unclear whether statin therapy exerts an inhibitory effect on renal deterioration in CKD patients with dyslipidemia. The purpose of the present study was to examine possible therapeutic effects of statin add-on therapy on renal function as well as parameters of lipid and glucose metabolism, arterial stiffness and oxidative stress, in comparison to diet therapy, in CKD patients with dyslipidemia. METHODS: This study was a randomized, open-label, and parallel-group trial consisted of a 12-months treatment period in non-dialysis CKD patients with alubuminuria and dyslipidemia. Twenty eight patients were randomly assigned either to receive diet counseling alone (diet therapy group) or diet counseling plus pitavastatin (diet-plus-statin therapy group), to achieve the LDL cholesterol (LDL-C) target of <100 mg/dl. RESULTS: The statin treatment by pitavastatin was well tolerated in all of the patients without any significant adverse events and the average dose of pitavastatin was 1.0 +/- 0.0 mg daily after treatment. After the 12-months treatment period, LDL-C was significantly lower in the diet-plus-statin therapy group compared with the diet therapy group (diet vs diet-plus-statin: LDL-C, 126 +/- 5 vs 83 +/- 4 mg/dL, P < 0.001). On the other hand, the diet-plus-statin therapy did not significantly reduce albuminuria or delay the decline in eGFR compared with the diet therapy, and there was no relationship between the change in LDL-C and the change in eGFR or albuminuria. However, diet therapy as well as diet-plus-statin therapy exerted similar lowering effects on the pentosidine levels (diet therapy group, baseline vs 12 months: 40 +/- 4 vs 24 +/- 3 ng/mL, P = 0.001; diet-plus-statin therapy, 46 +/- 7 vs 34 +/- 6 ng/mL, P = 0.008). Furthermore, the results of multivariate regression analysis indicated that the change in pentosidine was a significant contributor to the change in eGFR (beta = -0.536, P = 0.011). CONCLUSIONS: Although statin add-on therapy did not show additive renal protective effects, the diet therapy as well as the diet-plus-statin therapy could contribute to the reduction in plasma pentosidine in CKD patients with albuminuria and dyslipidemia. PMID- 26645470 TI - Correlation of Disturbed Sleep and Cancer Stress. AB - To illuminate the course of insomnia in the presence of an acute comorbidity, we examined the association between insomnia severity and breast cancer symptom severity over time and determined if this association varies with insomnia history and presleep arousal. Twenty-nine newly diagnosed breast cancer patients, who also exhibited insomnia, completed sleep diary and cancer symptom severity questionnaires every other week (total of 28 days) over 7 weeks, as well as baseline and postobservation measures. Participants were defined as having insomnia prior to cancer (IPC) or insomnia secondary to cancer (ISC) based on precancer sleep status. Insomnia and cancer symptom severity were strongly correlated at baseline but significantly declined over the evaluation period. Among ISC individuals, there was an association between sleep severity and cancer severity at baseline but not 7 weeks later. IPC individuals showed a consistent pattern of no significant association between sleep severity and cancer symptom severity. IPC had higher levels of cognitive presleep arousal than ISC. The current study documented the evolution of the relation between insomnia and breast cancer symptom severity over time and identified factors (premorbid insomnia and presleep hyperarousal) that may influence this association. PMID- 26645471 TI - On the Sample Complexity of Cancer Pathways Identification. AB - Advances in DNA sequencing technologies have enabled large cancer sequencing studies, collecting somatic mutation data from a large number of cancer patients. One of the main goals of these studies is the identification of all cancer genes- genes associated with cancer. Its achievement is complicated by the extensive mutational heterogeneity of cancer, due to the fact that important mutations in cancer target combinations of genes (i.e., pathways). Recently, the pattern of mutual exclusivity among mutations in a cancer pathway has been observed, and methods that find significant combinations of cancer genes by detecting mutual exclusivity have been proposed. A key question in the analysis of mutual exclusivity is the computation of the minimum number of samples required to reliably find a meaningful set of mutually exclusive mutations in the data, or conclude that there is no such set. In general, the problem of determining the sample complexity, or the number of samples required to identify significant combinations of features, of genomic problems is largely unexplored. In this work we propose a framework to analyze the sample complexity of problems that arise in the study of genomic datasets. Our framework is based on tools from combinatorial analysis and statistical learning theory that have been used for the analysis of machine learning and probably approximately correct (PAC) learning. We use our framework to analyze the problem of the identification of cancer pathways through mutual exclusivity analysis. We analytically derive matching upper and lower bounds on the sample complexity of the problem, showing that sample sizes much larger than currently available may be required to identify all the cancer genes in a pathway. We also provide two algorithms to find a cancer pathway from a large genomic dataset. On simulated and cancer data, we show that our algorithms can be used to identify cancer pathways from large genomic datasets. PMID- 26645472 TI - Early laparoscopic cholecystectomy appears better than delayed laparoscopic cholecystectomy for patients with acute cholecystitis. PMID- 26645473 TI - A global planktic foraminifer census data set for the Pliocene ocean. AB - This article presents data derived by the USGS Pliocene Research, Interpretation and Synoptic Mapping (PRISM) Project. PRISM has generated planktic foraminifer census data from core sites and outcrops around the globe since 1988. These data form the basis of a number of paleoceanographic reconstructions focused on the mid-Piacenzian Warm Period (3.264 to 3.025 million years ago). Data are presented as counts of individuals within 64 taxonomic categories for each locality. We describe sample acquisition and processing, age dating, taxonomy and archival storage of material. These data provide a unique, stratigraphically focused opportunity to assess the effects of global warming on marine plankton. PMID- 26645474 TI - Wind and sunlight shape microbial diversity in surface waters of the North Pacific Subtropical Gyre. AB - Few microbial time-series studies have been conducted in open ocean habitats having low seasonal variability such as the North Pacific Subtropical Gyre (NPSG), where surface waters experience comparatively mild seasonal variation. To better describe microbial seasonal variability in this habitat, we analyzed rRNA amplicon and shotgun metagenomic data over two years at the Hawaii Ocean Time series Station ALOHA. We postulated that this relatively stable habitat might reveal different environmental factors that influence planktonic microbial community diversity than those previously observed in more seasonally dynamic habitats. Unexpectedly, the data showed that microbial diversity at 25 m was positively correlated with average wind speed 3 to 10 days prior to sampling. In addition, microbial community composition at 25 m exhibited significant correlations with solar irradiance. Many bacterial groups whose relative abundances varied with solar radiation corresponded to taxa known to exhibit strong seasonality in other oceanic regions. Network co-correlation analysis of 25 m communities showed seasonal transitions in composition, and distinct successional cohorts of co-occurring phylogenetic groups. Similar network analyses of metagenomic data also indicated distinct seasonality in genes originating from cyanophage, and several bacterial clades including SAR116 and SAR324. At 500 m, microbial community diversity and composition did not vary significantly with any measured environmental parameters. The minimal seasonal variability in the NPSG facilitated detection of more subtle environmental influences, such as episodic wind variation, on surface water microbial diversity. Community composition in NPSG surface waters varied in response to solar irradiance, but less dramatically than reported in other ocean provinces. PMID- 26645476 TI - The global burden of major infectious complications following prostate biopsy. AB - We present a systematic review providing estimates of the overall and regional burden of infectious complications following prostate biopsy. A directly standardized prevalence estimate was used because it reflects the burden of disease more explicitly. Complications included sepsis, hospitalization, bacteraemia, bacteriuria, and acute urinary retention after biopsy. There were 165 articles, comprising 162 577 patients, included in the final analysis. Our findings demonstrate that transrectal biopsy was associated with a higher burden of hospitalization (1.1% vs. 0.9%) and sepsis (0.8% vs. 0.1%) compared to transperineal biopsy, while acute urinary retention was more prevalent after transperineal than transrectal biopsy (4.2% vs. 0.9%). The differences were statistically non-significant because of large heterogeneity across countries. We also demonstrate and discuss regional variations in complication rates, with Asian studies reporting higher rates of sepsis and hospitalization. PMID- 26645477 TI - In for a penny, in for a pound: the effect of pre-engaging healthcare organizations on their subsequent participation in trials. AB - BACKGROUND: Participant recruitment in clinical trials is often challenging. Building partnerships with healthcare organizations during proposal development facilitates access to the community and may influence its subsequent organization participation and participant recruitment. We aimed to assess how pre-engaging directors of homecare organizations influenced organization participation in a subsequent trial. FINDINGS: Repeated cross-sectional study prior to a cluster randomized controlled trial involving 33 eligible Health and Social Services Centres (HSSCs). During proposal development, we asked eligible HSSC directors in a randomized order about their willingness to participate in our trial, if funded. In the pre-engagement phase, 23 directors were contacted until we met sample size requirements (n >= 16); 19 of whom wrote letters of intent. Once funded, we contacted all 33 eligible HSSC directors in a randomized order to enroll them. Of the 19 directors who provided letters of intent, 15 agreed to participate (79 %); of the four who did not provide letters, one agreed to participate (25 %); and of the ten who had not been approached in the pre engagement phase, two agreed to participate (20 %). Fisher exact tests indicated that providing letters of intent was associated with subsequent participation (p = 0.003). CONCLUSIONS: Given that significantly more HSSCs directors who signed letters of intent followed through with study participation, pre-engagement with trial sites during proposal development appears to improve recruitment. PMID- 26645475 TI - Prion protein scrapie and the normal cellular prion protein. AB - Prions are infectious proteins and over the past few decades, some prions have become renowned for their causative role in several neurodegenerative diseases in animals and humans. Since their discovery, the mechanisms and mode of transmission and molecular structure of prions have begun to be established. There is, however, still much to be elucidated about prion diseases, including the development of potential therapeutic strategies for treatment. The significance of prion disease is discussed here, including the categories of human and animal prion diseases, disease transmission, disease progression and the development of symptoms and potential future strategies for treatment. Furthermore, the structure and function of the normal cellular prion protein (PrP(C)) and its importance in not only in prion disease development, but also in diseases such as cancer and Alzheimer's disease will also be discussed. PMID- 26645479 TI - En route to phosphonato iridium(i) complexes: the decisive effect of an intramolecular hydrogen bond. AB - Pentacoordinated iridium(i) complexes of formula IrCl(SiNP)(tfbb) (1) and IrCl(HNP)2(tfbb) (2) (SiNP = SiMe2{N(4-C6H4CH3)PPh2}2; HNP = NH(4-C6H4CH3)PPh2) have been prepared and fully characterised. Both feature a distorted square pyramidal coordination polyhedron at the metal centre in the solid state and are fluxional in solution. Their reaction with trimethyl phosphite yields the derivatives [Ir(SiNP){P(OMe)3}(tfbb)]Cl ([3]Cl) and Ir{PO(OMe)2}(HNP)2(tfbb) (4). The course of the reaction between IrCl(HNP)2(tfbb) (2) and trimethyl phosphite was elucidated by NMR spectroscopy and DFT calculations, showing that the intermediate [Ir(HNP)2{P(OMe)3}(tfbb)](+) ((5+)) forms and further reacts with the chloride anion yielding the phosphonato derivative 4 and methyl chloride. The decisive role of the N-H group in the formation of the phosphonato ligand has been established by IR and NMR spectroscopic measurements and by DFT calculations. PMID- 26645478 TI - Inhibition of heat-shock protein 90 enhances the susceptibility to antifungals and reduces the virulence of Cryptococcus neoformans/Cryptococcus gattii species complex. AB - Heat-shock proteins (Hsps) are chaperones required for the maintenance of cellular homeostasis in different fungal pathogens, playing an important role in the infectious process. This study investigated the effect of pharmacological inhibition of Hsp90 by radicicol on the Cryptococcus neoformans/Cryptococcus gattii species complex--agents of the most common life-threatening fungal infection amongst immunocompromised patients. The influence of Hsp90 inhibition was investigated regarding in vitro susceptibility to antifungal agents of planktonic and sessile cells, ergosterol concentration, cell membrane integrity, growth at 37 degrees C, production of virulence factors in vitro, and experimental infection in Caenorhabditis elegans. Hsp90 inhibition inhibited the in vitro growth of planktonic cells of Cryptococcus spp. at concentrations ranging from 0.5 to 2 MUg ml(-1) and increased the in vitro inhibitory effect of azoles, especially fluconazole (FLC) (P < 0.05). Inhibition of Hsp90 also increased the antifungal activity of azoles against biofilm formation and mature biofilms of Cryptococcus spp., notably for Cryptococcus gattii. Furthermore, Hsp90 inhibition compromised the permeability of the cell membrane, and reduced planktonic growth at 37 degrees C and the capsular size of Cryptococcus spp. In addition, Hsp90 inhibition enhanced the antifungal activity of FLC during experimental infection using Caenorhabditis elegans. Therefore, our results indicate that Hsp90 inhibition can be an important strategy in the development of new antifungal drugs. PMID- 26645480 TI - Assessing the Accuracy of Cone-Beam Computerized Tomography in Measuring Thinning Oral and Buccal Bone. AB - The aim of this study was to assess the accuracy and reliability of cone-beam computerized tomography (CBCT) in measuring thinning bone surrounding dental implants. Three implants were inserted into the mandible of a domestic pig at 6 different bone thicknesses on the vestibular and the lingual sides, and measurements were recorded using CBCT. The results were obtained, analyzed, and compared with areas without implants. Our results indicated that the bone thickness and the neighboring implants decreased the accuracy and reliability of CBCT for measuring bone volume around dental implants. We concluded that CBCT slightly undermeasured the bone thickness around the implant, both buccally and orally, compared with the same thickness without the implant. These results support that using the i-CAT NG with a 0.2 voxel size is not accurate for either qualitative or quantitative bone evaluations, especially when the bone is thinner than 0.72 mm in the horizontal dimension. PMID- 26645481 TI - Factors influencing the underutilization of mental health services among Asian American women with a history of depression and suicide. AB - BACKGROUND: Despite the substantially high prevalence of depression, suicidal ideation and suicide attempts among Asian American women who are children of immigrants, little is known about the prevalence of mental health utilization and the perceived barriers to accessing care. METHODS: The data were from the Asian American Women's Sexual Health Initiative Project (AWSHIP), a 5-year mixed methods study at Boston University. The quantitative analysis examined the differential proportion of mental health utilization among 701 survey participants based on their mental health risk profile determined by current moderate to severe depression symptoms and lifetime history of suicidality. Mental health risk groups were created based on participants' current depression symptoms and history of suicide behaviors: Group 1-low-risk; Group 2-medium-risk; Group 3-high-risk. Mental health care utilization outcomes were measured by any mental health care, minimally adequate mental health care, and intensive mental health care. The qualitative analysis explored the perceived barriers to mental health care among 17 participants from the medium and high-risk groups. RESULTS: Among 701 participants, 43% of women (n = 299) reported that they either suffered from current moderate to severe depression symptoms or a lifetime history of suicidal ideation or suicide attempt. Although the high-risk group demonstrated statistically significant higher mental health utilization compared to the low and medium-risk groups, more than 60% of the high-risk group did not access any mental health care, and more than 80% did not receive minimally adequate care. The qualitative analysis identified three underutilization factors: Asian family contributions to mental health stigma, Asian community contributions to mental health stigma, and a mismatch between cultural needs and available services. CONCLUSIONS: Despite the high prevalence of depression and suicidal behaviors among young Asian American women in the sample, the proportion of mental health care utilization was extremely low. The qualitative analysis underscores the influence of Asian family and community stigma on mental health utilization and the lack of culturally appropriate mental health interventions. Prevention and intervention efforts should focus on raising mental health awareness in the Asian American community and offering culturally sensitive services. PMID- 26645483 TI - Iodine-catalyzed thiolation of electron-rich aromatics using sulfonyl hydrazides as sulfenylation reagents. AB - Iodine-catalyzed thiolation of electron-rich aromatics, including substituted anisole, thioanisole, phenol, toluene, and naphthalene, using sulfonyl hydrazides as sulfenylation reagents was carried out. Sulfonothioates, the products of decomposition of sulfonyl hydrazides in the presence of iodine, are proposed as the major sulfenylation species in this transformation. PMID- 26645482 TI - Structural and biophysical investigation of the interaction of a mutant Grb2 SH2 domain (W121G) with its cognate phosphopeptide. AB - The adaptor protein Grb2 is a key element of mitogenetically important signaling pathways. With its SH2 domain it binds to upstream targets while its SH3 domains bind to downstream proteins thereby relaying signals from the cell membranes to the nucleus. The Grb2 SH2 domain binds to its targets by recognizing a phosphotyrosine (pY) in a pYxNx peptide motif, requiring an Asn at the +2 position C-terminal to the pY with the residue either side of this Asn being hydrophobic. Structural analysis of the Grb2 SH2 domain in complex with its cognate peptide has shown that the peptide adopts a unique beta-turn conformation, unlike the extended conformation that phosphopeptides adopt when bound to other SH2 domains. TrpEF1 (W121) is believed to force the peptide into this unusual conformation conferring this unique specificity to the Grb2 SH2 domain. Using X-ray crystallography, electron paramagnetic resonance (EPR) spectroscopy, and isothermal titration calorimetry (ITC), we describe here a series of experiments that explore the role of TrpEF1 in determining the specificity of the Grb2 SH2 domain. Our results demonstrate that the ligand does not adopt a pre-organized structure before binding to the SH2 domain, rather it is the interaction between the two that imposes the hairpin loop to the peptide. Furthermore, we find that the peptide adopts a similar structure when bound to both the wild-type Grb2 SH2 domain and a TrpEF1Gly mutant. This suggests that TrpEF1 is not the determining factor for the conformation of the phosphopeptide. PMID- 26645484 TI - Discrepancy in Fluorescein Angiography and Optical Coherence Tomography Findings of Macular Edema in Intermediate Uveitis. AB - PURPOSE: To assess discrepancies between fluorescein angiography (FA) and optical coherence tomography (OCT) findings for macular edema (ME) in intermediate uveitis, and investigate treatment response differences corresponding to the discrepant patterns. METHODS: Discrepant results for ME detection between FA and OCT were evaluated. After 6 months, differences in treatment responses were analyzed. RESULTS: Discrepant findings for ME were found in 21 (44%) of 48 eyes. The best-corrected visual acuity significantly improved after treatment in the concordant group but not in the discrepant groups. Central retinal thickness significantly decreased after treatment in the FA+/OCT+ and FA-/OCT+ groups but not in the FA+/OCT- group. Disease duration was significantly longer in the FA+/OCT- group than in the other groups. CONCLUSIONS: Discrepancies in FA and OCT findings for ME were common in patients with intermediate uveitis. Our results suggest that treatment outcomes may differ according to the discrepant patterns. PMID- 26645486 TI - F0, F0 range and duration of utterances - Longitudinal single-subject studies of prosody in two Swedish children with ASC. AB - We investigated prosody in two Swedish boys with autism spectrum condition (ASC) and subjected them individually to a year-long segmental intervention which was analysed using a single-subject experimental design. Acoustic measures were taken for F0 levels, F0 range and duration. The data were evaluated for syllable structure, phrase length and accent 2. Results showed a decrease in augmented F0 levels and an increase in the proportion of utterances within intermediate F0 ranges. The boys developed prosodic patterns more similar to that of typically developing children. In addition, the use of the important Swedish accent 2 increased. PMID- 26645485 TI - Transmigration characteristics of breast cancer and melanoma cells through the brain endothelium: Role of Rac and PI3K. AB - Brain metastases are common and devastating complications of both breast cancer and melanoma. Although mammary carcinoma brain metastases are more frequent than those originating from melanoma, this latter has the highest tropism to the brain. Using static and dynamic in vitro approaches, here we show that melanoma cells have increased adhesion to the brain endothelium in comparison to breast cancer cells. Moreover, melanoma cells can transmigrate more rapidly and in a higher number through brain endothelial monolayers than breast cancer cells. In addition, melanoma cells have increased ability to impair tight junctions of cerebral endothelial cells. We also show that inhibition of Rac or PI3K impedes adhesion of breast cancer cells and melanoma cells to the brain endothelium. In addition, inhibition of Rac or PI3K inhibits the late phase of transmigration of breast cancer cells and the early phase of transmigration of melanoma cells. On the other hand, the Rac inhibitor EHT1864 impairs the junctional integrity of the brain endothelium, while the PI3K inhibitor LY294002 has no damaging effect on interendothelial junctions. We suggest that targeting the PI3K/Akt pathway may represent a novel opportunity in preventing the formation of brain metastases of melanoma and breast cancer. PMID- 26645487 TI - Preventing pediatric cardiomyopathy: a 2015 outlook. AB - Cardiomyopathies in children encompass a broad range of diseases, both genetic and acquired, which manifest as a primary cardiac disorder or as a cardiomyopathy secondary to systemic disease. The burden of this group of disorders is substantial, and growing on a global scale. The availability of disease altering treatments is limited, and therefore a focused review on the prevention of cardiomyopathies is justified. In this review, we address the prevention of cardiomyopathy in children by dealing with the root causes of disease at a molecular, clinical and population level. Recent years have yielded promising returns in basic research related to gene-targeted therapy, specific anti-viral therapies and modification of the effects of cardiotoxic drugs. Much work remains to be done in the fields of vaccine development, public health and adoption of available treatments. Effective research in this field will require that diagnostic methods are both refined, and made available more broadly, from imaging to gene testing. Much of our knowledge today is derived from the use of registries, which have successfully catalogued the detailed phenotype of affected patients, and provided long-term longitudinal follow up of affected individuals. PMID- 26645488 TI - Incidental gastric mesenchymal tumors identified during laparoscopic sleeve gastrectomy. AB - BACKGROUND: Laparoscopic sleeve gastrectomy (SG) is a well-tolerated and effective procedure for sustained weight loss and amelioration of weight-related co-morbidities. Rarely, unexpected pathology may be identified intraoperatively, which may alter the surgical plan. Gastrointestinal stromal tumors (GISTs) are among the more frequently encountered tumors and pose a particular concern because of their malignant potential. We review our findings of incidental tumors encountered during 1415 consecutive SGs. METHODS: Abnormal pathology records from all patients who underwent SG at our institution between 2009 and 2014 were reviewed. Patient demographic characteristics and clinical characteristics, tumor characteristics, including immunohistochemistry, operative course, and patient follow-up were reviewed. RESULTS: There were 17 incidental gastric mesenchymal tumors identified (1.2%) in 1415 SG procedures. This included 12 GISTs (.8%), 2 schwannomas (.1%), and 3 leiomyomas (.3%). In the majority of cases (1210/1415), the gastric specimens were not reviewed by a pathologist because there were no gross abnormalities appreciated by the surgeon. The GISTs were between .3 and 2.9 cm, and all were low grade with negative margins. Patients with GISTs tended to be older (mean age 55+/-9.3 y) than the rest of the patients. There was no evidence of recurrence on follow-up. CONCLUSION: Incidental gastric mesenchymal tumors are rarely encountered during SG. The vast majority were GISTs with an incidence of .8% in this population. Concomitant SG and tumor resection were feasible, without compromising the objectives of each. Complete tumor excision is necessary for tumors>2 cm. PMID- 26645489 TI - Bariatric surgery in 1119 patients with preoperative body mass index<35 (kg/m(2)): results at 1 year. AB - BACKGROUND: The use of body mass index (BMI) as the only criterion to indicate bariatric surgery is currently under discussion. There is growing evidence that supports bariatric surgery in carefully selected patients with lower BMI. OBJECTIVES: To report our experience in bariatric surgery in>1000 patients with BMI<35 kg/m(2) and their results at 1 year. SETTING: University hospital (censored). METHODS: A retrospective analysis was performed in patients who underwent laparoscopic Roux-en-Y gastric bypass (LRYGB) or sleeve gastrectomy (SG) with preoperative BMI<35 kg/m(2) from January 2008 to December 2011. Demographic and anthropometric data, preoperative co-morbidities, and perioperative variables were retrieved. Weight loss and co-morbidities progression were analyzed 1 year after surgery and compared among procedures. A P value<.05 was considered significant. RESULTS: We identified 1119 patients: mean age 38.8+/-11.4, 951 (85%) women, preoperative weight 87.5+/-9.3 kg and BMI 33.1 (31.9-34.1) kg/m(2). Preoperatively, 11.7% had type 2 diabetes mellitus, 25.9% arterial hypertension, 55.6% insulin resistance, and 53.2% dyslipidemia. In total, 283 patients (25.2%) underwent LRYGB and 836 (74.8%) SG. One year after surgery (follow-up: 66.67%) patients reached 24.5 (22.8-26.4) BMI and the percentage of excess of weight loss (%EWL) was 107.9+/-36.6%. Diabetes, hypertension, insulin resistance, and dyslipidemia remission/improvement rates were 54/39%, 58/29%, 72/17%, and 54/30%, respectively. CONCLUSIONS: Bariatric surgery in selected class I obesity patients can safely be performed. We have observed good results in terms of weight loss and co-morbidity improvement/remission. Long-term follow-up is required. PMID- 26645490 TI - Does pregnancy influence long-term results of bariatric surgery? AB - BACKGROUND: Bariatric surgery is performed mostly on obese women of reproductive age. Many authors have studied pregnancy outcomes after bariatric surgery. Only a small number of studies have analyzed the impact of maternity on the results of bariatric surgery. OBJECTIVES: To study the effect of pregnancy on long-term outcomes of bariatric surgery. SETTING: Lille University Hospital. METHODS: A retrospective study was conducted on 591 women aged 18 to 42 years who had undergone laparoscopic adjustable gastric band (LAGB) surgery or laparoscopic Roux-en-Y gastric bypass (LRYGB) surgery between 1996 and 2012. A comparison of the results after a 5-year follow-up was performed between patients who became pregnant after their bariatric surgery (pregnant group, n = 84) and postoperative nonpregnant women (nonpregnant group, n = 507). RESULTS: At the 5-year visit, 84.8% patients were seen. The preoperative body mass index (BMI) was the same in the 2 groups (pregnant group: 47.8+/-6.9 kg/m(2); nonpregnant group: 47.5+/-7.2 kg/m(2); P = .755). The percentage of excess weight loss (%EWL) was lower in the pregnant group at 2 years (pregnant group = 45.9+/-24.6%; nonpregnant group = 56.9+/-28.6%, P = .002) but was similar at 5 years (47.7+/-27.7% versus 49.9+/ 28.9%, P = .644). The decrease in co-morbidities was similar after 5 years. The gestational weight gain (GWG) was higher when the band was deflated during pregnancy (GWG =+12.7+/-10.5 kg) compared to the band without fluid removal (GWG =+4.9+/-7 kg) or laparoscopic Roux-en-Y gastric bypass (GWG =+4.4+/-1.1 kg) (P< .05). CONCLUSIONS: Pregnancy after bariatric surgery slows down postoperative weight loss but does not affect weight results at 5-year follow-up. PMID- 26645491 TI - Asymptomatic Giardia intestinalis infection and Roux-en-Y gastric bypass. PMID- 26645492 TI - Laparoscopic conversion of prior gastric plication and posterior fundoplication to sleeve gastrectomy with hiatal hernia repair. PMID- 26645493 TI - Association of short-term proton pump inhibitor therapy with weight gain in patients older than 40 years with gastric ulcer. PMID- 26645494 TI - Response to Letter to the Editor Re: Acid suppression medications are associated with suboptimal weight loss after laparoscopic Roux-en-Y gastric bypass in patients older than 40 years. PMID- 26645496 TI - What could happen if you insert a BioEnterics intragastric balloon after sleeve gastrectomy? PMID- 26645497 TI - From concept to clinic: Mathematically informed immunotherapy. AB - To allow innovative, progressive treatments to make the transition from concept to clinic, experimentally calibrated and clinically motivated mathematical models are essential. To aid the development of well-informed clinical trials, collaboration between mathematicians, computational modelers, biologists, and clinicians is required to allow qualitative hypotheses to take on a quantitative dimension. Such interdisciplinary science can allow both personalization and optimization of dose and scheduling of immunotherapeutic protocols, both as an independent therapy and in conjunction with other more traditional therapies, to streamline the transition from innovative concept to clinical practice and improve clinical outcomes for individual patients. PMID- 26645498 TI - Reversible 2D Phase Transition Driven By an Electric Field: Visualization and Control on the Atomic Scale. AB - We report on a reversible structural phase transition of a two-dimensional system that can be locally induced by an external electric field. Two different structural configurations may coexist within a CO monolayer on Cu(111). The balance between the two phases can be shifted by an external electric field, causing the domain boundaries to move, increasing the area of the favored phase controllable both in location and size. If the field is further enhanced new domains nucleate. The arrangement of the CO molecules on the Cu surface is observed in real time and real space with atomic resolution while the electric field driving the phase transition is easily varied over a broad range. Together with the well-known molecular manipulation of CO adlayers, our findings open exciting prospects for combining spontaneous long-range order with man-made CO structures such as "molecule cascades" or "molecular graphene". Our new manipulation mode permits us to bridge the gap between fundamental concepts and the fabrication of arbitrary atomic patterns in large scale, by providing unprecedented insight into the physics of structural phase transitions on the atomic scale. PMID- 26645499 TI - Health-Related Quality of Life in patients with Parkinson's disease--A systematic review based on the ICF model. AB - We analyzed features associated with a reduction in Health-Related Quality of Life (HRQoL) in people with idiopathic Parkinson's disease (PD). As a new approach, features were embedded in the WHO framework for measuring health and disability, the ICF model. From 609 articles screened, 114 articles were included. Features aligned with the ICF's body functions and structures domain (BFS) were investigated more often than personal features, activities of daily living, environmental factors, and participation in societal roles (95, 42, 35, 29 and 14 times, respectively). The strongest associations were found for the relationships between HRQoL and "psychosocial functioning" from the participation domain and HRQoL, and "mobility limitations" from the activities domain. For the BFS, non-motor symptoms were more closely associated with reduced HRQoL than motor symptoms. In conclusion, this systematic review (i) provides entirely new insights in the association of HRQoL with PD features, (ii) shows an imbalance between most extensively investigated and most relevant features for HRQoL, and (iii) demonstrates the usefulness of the ICF model for such an approach. PMID- 26645510 TI - Unitary construct of generalized cognitive ability underlying BACS performance across psychotic disorders and in their first-degree relatives. AB - Despite robust evidence of neurocognitive dysfunction in psychotic patients, the degree of similarity in cognitive architecture across psychotic disorders and among their respective first-degree relatives is not well delineated. The present study examined the latent factor structure of the Brief Assessment of Cognition in Schizophrenia (BACS) neuropsychological battery. Analyses were conducted on 783 psychosis spectrum probands (schizophrenia, schizoaffective, psychotic bipolar), 887 of their first-degree relatives, and 396 non-psychiatric controls from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) consortium. Exploratory factor analysis of BACS subtest scores indicated a single factor solution that was similar across all groups and provided the best overall data fit in confirmatory analyses. Correlations between the standard BACS composite score and the sum of subscale scores weighted by their loadings on this unitary factor were very high in all groups (r>=.99). Thus, the BACS assesses a similar unitary cognitive construct in probands with different psychotic disorders, in their first-degree relatives, and in healthy controls, and this factor is well measured by the test's standard composite score. PMID- 26645511 TI - Pharmacokinetic evaluation of liposomal amphotericin B (L-AMB) in patients with invasive fungal infection: Population approach in Japanese pediatrics. AB - The pharmacokinetic characteristics of liposomal amphotericin B (L-AMB; AmBisome((r))) in patients with invasive fungal infection were investigated. A population pharmacokinetic (PK) model in Japanese pediatric patients was developed based on 159 serum amphotericin B (AMPH-B) concentrations obtained in a post-marketing clinical study. The subjects were 39 patients with a mean age of 8.4 years (SD 4.5) and mean body weight of 27.1 kg (SD 14.1). A two-compartment PK model with zero-order input and first-order elimination was fitted to serum AMPH-B concentrations for L-AMB doses of 1.0, 2.5, and 5.0 mg/kg/day. Body weight showed significant correlations with PK parameters, such as clearance (CL) and distribution volume of the central compartment (Vc). The predicted Cmax/dose and AUC0-24/dose in Japanese pediatric patients were similar to those in non-Japanese pediatric patients and Japanese adult patients. Extremely large increases in Ctrough compared with predicted values were observed in some Japanese pediatric patients, but no relationships with demographic characteristics, clinical laboratory test values, or representative adverse drug reaction (decreased potassium) were found. The population PK parameters in this study are useful for simulating PK profiles of L-AMB and will be helpful for PK exposure comparisons among different populations and in investigations of pharmacokinetic pharmacodynamic characteristics in patients. CHEMICAL COMPOUNDS: Amphotericin B Deoxycholate (PubChem CID:23668620); amphotericin B (PubChem CID:5280965); 3 nitrophenol (PubChem CID:11137); methanol (PubChem CID:887). PMID- 26645512 TI - Yoga participation and all-cause mortality: National prospective cohort study. AB - BACKGROUND: The relatively few studies examining the effect of yoga participation on chronic disease come from small, short-term studies. As a result, the purpose of this study was to prospectively examine the effects of yoga participation on all-cause mortality in a large nationally representative study with a relatively long follow-up period (up to 12 year follow-up). METHODS: Data from the 1999-2006 National Health & Nutrition Examination Survey were used, with follow-up through 2011. Yoga participation was self-reported, with participant identification linked to death certificate data from the National Death Index to ascertain mortality status. RESULTS: In the analyzed sample, which included 22,598 adult participants, 240 participants engaged in yoga and 3176 died over the follow-up period; the median follow-up period was 102 months (8.5 years). In an unadjusted Cox hazard model, those engaging in yoga, compared to those not engaging in yoga, had a 63% reduced risk of premature all-cause mortality (HR=0.37; 95% CI: 0.18 0.74; P=.006). However, after adjusting for age, the association was attenuated and no longer statistically significant (HR(adjusted)=0.82; 95% CI: 0.39-1.72; P=.60). CONCLUSION: In conclusion, yoga participation was not significantly associated with reduced all-cause mortality risk in an adjusted model. PMID- 26645513 TI - Efficacy of acupuncture treatment for functional dyspepsia: A systematic review and meta-analysis. AB - OBJECTIVES: The use of acupuncture treatment (AT) for functional dyspepsia is increasing, particularly in Asia. However, the efficacy of AT and its side effects have not been assessed. We performed a systematic review and meta analysis of studies related to the effectiveness of AT for functional dyspepsia. DESIGN: This study is a systemic review and meta-analysis. Seven electronic databases, including those in the English and Chinese languages, were systematically searched for randomized controlled trials of AT for functional dyspepsia through November 2012. There were no language restrictions. SETTING: Randomized controlled trials (RCT) AT compared with placebo control or a comparative intervention were considered. The methodological qualities of the studies were evaluated using the risk of bias (ROB). Subgroups were analyzed according to the kinds of controls. MAIN OUTCOME MEASURES: The primary outcomes were symptom scores. These included visual analogue scale (VAS) and Nepean Dyspepsia Index (NDI). Secondary outcomes were the total effective rate and adverse effects. RESULTS: Twenty studies, including 1423 individual cases, were systematically reviewed. The risk of bias was high. Compared to sham AT, AT was associated with a significant positive effect in patients with functional dyspepsia (2.66, 95% CI 1.85-3.82). AT also improved symptoms for functional dyspepsia (1.18, 95% CI 1.01-2.60) compared to GI tract regulators on total effective rate. In addition, two articles produced a scale in favor of AT compared to medication (0.54, 95% CI 0.18-0.90). Two RCTs reported minimal AT related adverse events. CONCLUSIONS: The evidence suggests that AT is effective for functional dyspepsia. However, well-planned, long-term studies are necessary to evaluate the efficacy of AT for functional dyspepsia. PMID- 26645514 TI - Herbal medicine Davaie Loban in mild to moderate Alzheimer's disease: A 12-week randomized double-blind placebo-controlled clinical trial. AB - OBJECTIVE: In traditional texts on herbal medicines, various medicinal plants have been noted to have beneficial effects on dementia and Alzheimer's disease. According to the traditional books Herbal medicine Davaie Loban (DL) has beneficial effects in Alzheimer's disease. The study aim was to determine the clinical efficacy of DL in patients with mild-to-moderate Alzheimer's disease. DESIGN: Double blind randomized clinical trial. SETTING: Shahid Beheshti University of Medical Sciences. INTERVENTIONS: This included patients older than 50 years with mild to moderate Alzheimer's disease according to ADAS-cog (Alzheimer's Disease Assessment Scale-cognitive subscale; ADAS>=12) and the Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB; CDR<=2). Twenty-four patients completed the study in DL group and 20 in placebo group. MAIN OUTCOME MEASURES: ADAS-cog and CDR-SOB were filled out for patients to define the improvement in memory over the study period. RESULTS: At 4 weeks and 12 weeks there was significant difference in mean (SEM) ADAS-cog scores between DL and placebo groups and it was lower in DL group (p<0.001). At baseline, no significant difference was seen regarding mean (SEM) scores of CDR-SOB between DL and placebo groups (p=0.096). However, at 4 and 12 weeks there was significant difference in mean (SE) CDR-SOB scores between DL and placebo groups and it was lower in DL group (p<0.001). CONCLUSION: Our findings suggest that DL may be effective in improvement of memory in patients with mild-to-moderate Alzheimer's disease. PMID- 26645515 TI - The effect of moxibustion on alleviating menstrual pain in a population of young nursing students: A prospective randomized cross-over pilot study. AB - OBJECTIVE: To investigate the effect of moxibustion on alleviating menstrual pain and relieving the symptoms of dysmenorrhea in a cohort of young nursing students in China. METHODS: A randomized double blind clinical trial of crossover design was used. In the two-phase study, a total of 56 nursing students with menstrual pain in Guangzhou University of Chinese Medicine in China was randomly allocated into two groups. In the first treatment phase, the participants in Group A (n=28) received moxibustion therapy from five days before the menstrual period to the onset through a specific heating box in which burning moxa stick was fixed, the participants in Group B (n=28) received the same heating box but with a paper wrapped stick incense fixed inside (placebo therapy) during the same intervention period. The acupoints Guanyuan(CV4) and Shenque(CV8) were selected for treatment. After the first treatment phase for two menstrual cycles, the intervention was stopped for three menstrual cycles during a wash period. In the second treatment phase, the intervention of two groups were switched. Group A received the placebo therapy and Group B received moxibustion therapy. NRS, VRS, PRI, VAS and BRS-6 were evaluated at the baseline and after each treatment phase. RESULTS: There was no statistically significant difference in age, history of dysmenorrhea, length of menstrual cycle, age at menarche, duration of menstrual flow, PRI score, VAS score, BRS score and RSS score between Group A and Group B (p>0.05). After the first treatment phase, the score of BRS-6 has significant differences between two groups at the first menstrual cycle (p<0.05). At the second menstrual cycle, the score of VAS, BRS-6,sensory of PRI, affective dimension of PR and total score of PRI in Group A were much lower than Group B (p<0.05). NRS and VRS had significant differences between two groups with Wilcoxon Mann-Whitney test after the first treatment phase (p<0.05). The frequency rating of weakness, loss of appetite, diarrhea, and the total score had significant differences between two groups at the first menstrual cycle (p<0.05). And the frequency rating of weakness, backache, facial blemishes, loss of appetite, diarrhea, and the total score had significant differences between two groups at the second menstrual cycle (p<0.05). The severity rating of backaches, loss of appetite, sleeplessness, and the total score had significant differences between two groups after the second menstrual cycle (p<0.05). After three months' wash period, the score of VAS, BRS 6, sensory of PRI, affective of PR, total score of PRI and VRS had significant differences between two groups after the second treatment phase (p<0.01). And the frequency rating of leg aches, dizziness, nervousness and the total score had significant differences between two groups after the second treatment phase (p<0.05). And the severity rating of abdominal pain, weakness, leg aches, dizziness, nervousness and the total score had significant differences between two groups after the second treatment phase (p<0.05). CONCLUSIONS: The results suggested that moxibustion therapy with a heating box was effective for alleviating menstrual pain and symptoms of young female university students in China. The effect of moxibustion might not only due to heat stimulation, but also from the burning of moxa stick. Boxing moxibustion could be recommended as a nonpharmacological pain relief intervention for university students for its cost effectiveness, practical design and relative safety, and it is easy for the university students themselves to self-administer at home. PMID- 26645516 TI - Back pain sufferers' attitudes toward consultations with CAM practitioners and self- prescribed CAM products: A study of a nationally representative sample of 1310 Australian women aged 60-65 years. AB - OBJECTIVE: To analyze back pain sufferers' attitudes toward consultations with complementary and alternative medicine (CAM) practitioners and self-prescribed CAM products. METHODS: A cross-sectional survey of a nationally representative sample of Australian women aged 60-65 years. RESULTS: A significant number of women with back pain consulted a massage therapist (41.4%, n=578), a chiropractor (37.3%, n=488), an acupuncturist (13.3%, n=174), used self-prescribed supplements (59.2%, n=776), vitamins/minerals (45.2%, n=592) and/or herbal medicines (13.1%, n=172). Women who perceived CAM as providing greater control over their body/health were more likely to have consulted a chiropractor (OR=4.21; 95% CI; 2.16, 8.19) and/or self- prescribed supplements (OR=2.38; 95% CI: 1.05, 3.49) than those who did not perceive CAM as providing greater control over their body/health. Women who perceived CAM as natural (OR=1.56; 95% CI: 1.02, 2.37) or promoting a holistic approach to health (OR=2.73; 95% CI: 1.60, 4.64) were more likely to have self-prescribed vitamins/minerals than those who did not perceive CAM as natural and promoting a holistic approach to health. Women who expressed that knowledge about evidence of CAM as important to them were more likely to have self-prescribed herbal medicines (OR=7.15; 95% CI: 1.72, 29.64) than those who did not express an interest in knowledge about evidence of CAM. CONCLUSION: Certain key attitudes toward CAM influence back pain sufferers' choice of CAM use, highlighting the need for back pain care providers to ensure appropriate enquiry and discussion with their patients regarding consulting CAM practitioners and/or self-prescribing CAM products for back pain. PMID- 26645517 TI - A randomized controlled trial of coenzyme Q10 for fatigue in the late-onset sequelae of poliomyelitis. AB - OBJECTIVE: To determine if coenzyme Q(10) alleviates fatigue in the late-onset sequelae of poliomyelitis. DESIGN: Parallel-group, randomized, placebo-controlled trial. BACKGROUND SETTING: Coenzyme Q(10) has been shown to boost muscle energy metabolism in post-polio subjects but it does not promote muscle strength, endurance or function in polio survivors with post-poliomyelitis syndrome. However, the collective increased energy metabolism might contribute to a reduction in post-polio fatigue. PARTICIPANTS: Polio survivors from the Australian post-polio networks in Queensland and New South Wales who attribute a moderate to high level of fatigue to their diagnosed late-onset sequelae of poliomyelitis. Those with fatigue-associated comorbidities of diabetes, anaemia, hypothyroidism and fibromyalgia were excluded. METHOD: Participants were assigned (1:1), with stratification of those who use energy-saving mobility aids, to receive 100 mg coenzyme Q(10) or matching placebo daily for 60 days. Participants and investigators were blinded to group allocation. Fatigue was assessed by the Multidimensional Assessment of Fatigue as the primary outcome and the Fatigue Severity Scale as secondary outcome. RESULTS: Of 103 participants, 54 were assigned to receive coenzyme Q(10) and 49 to receive the placebo. The difference in the mean score reductions between the two groups was not statistically significant for either fatigue measure. Oral supplementation with coenzyme Q(10) was safe and well-tolerated. CONCLUSION: A daily dose of 100 mg coenzyme Q(10) for 60 days does not alleviate the fatigue of the late-onset sequelae of poliomyelitis. The registration number for the clinical trial is ACTRN 12612000552886. PMID- 26645518 TI - Adjuvant treatment with crude rhubarb for patients with acute organophosphorus pesticide poisoning: A meta-analysis of randomized controlled trials. AB - BACKGROUND: Crude rhubarb has been used to treat critically ill patients for many years. However, no previous meta-analysis has been investigated the benefits of crude rhubarb in patients with acute organophosphorus pesticide poisoning (AOPP). OBJECTIVE: To summarize the beneficial effects of adjuvant treatment with crude rhubarb in patients with AOPP by conducting a meta-analysis. METHODS: A literature search of the databases through Pubmed, EMBASE, China National Knowledge Infrastructure, VIP, and Wanfang were performed for studies published up to October 2014. Randomized controlled trials (RCTs) investigating the effects of crude rhubarb as adjuvant treatment for patients with AOPP were included. RESULTS: A total of 12 RCTs with 886 patients were identified. Adjuvant treatment with crude rhubarb was associated with a significantly lower incidence of intermediate syndrome (risk ratio [RR] 0.22; 95% confidence interval [CI] 0.10 0.48), as well as multiple organ dysfunction syndrome (RR 0.34; 95% CI 0.20 0.56). Crude rhubarb as adjuvant treatment reduced the total dose of pralidoxime (mean difference [MD] -5.12 g; 95% CI -8.24 to -2.00) or atropine (MD -94.89 mg; 95% CI -156.22 to -33.57), and hospital length of stay (MD -2.79 days; 95% CI 4.19 to -1.39) compared with the controls. CONCLUSIONS: This meta-analysis suggests that crude rhubarb as adjuvant treatment appears to have additional beneficial effects in patients with AOPP. More well-designed trials are needed to confirm our findings due to the methodological flaws of the included trials. PMID- 26645520 TI - Retrospective case series on Gwakhyangjeonggi-san prescribed to patients with chronic urticaria. AB - INTRODUCTION: Chronic urticaria (CU) is characterized by repeated occurrence of wheals or itching for more than 6 weeks. When urticarial symptoms repeatedly occur despite taking western medicines such as antihistamines, herbal medicines have potential as an alternative for them. Among various herbal medications for CU, we mostly prescribe Gwakhyangjeonggi-san (GJS) made by Lee Je-ma, the founder of Sasang Constitutional Medicine (SCM) in Korea. The purpose of this study is to investigate whether GJS actually helps in treating CU. METHODS: We performed a retrospective review of the medical records of 30 patients to whom GJS was administered in order to compare the changes in urticaria activity scores (UAS) and in western medicines taken at the beginning of treatment of GJS and at 6 months after completion of the treatment. RESULTS: The UAS after 6 months from treatment (1.63 +/- 2.06) with GJS for an average of 57.30 +/- 35.88 days was significantly decreased compared to the score before treatment (5.10 +/- 0.99), showing a statistically significant difference (p< 0.001). 46.67% of the patients (14/30 patients) reported that their symptoms were completely eliminated, and 66.67% of the patients taking anti-histamines (18/27 patients) were able to stop it completely. DISCUSSION: Based on the findings, GJS helps patients reduce taking western medicines such as anti-histamines, and we hypothesize that GJS improves symptoms of CU by the gastrointestinal protective activity and anti oxidative/depressive effect. Further clinical study is warranted. PMID- 26645519 TI - Energy expenditure and cardiovascular responses to Tai Chi Easy. AB - OBJECTIVES: The purpose of this study was to evaluate the cardiorespiratory response and energy expenditure during the practice of Tai Chi Easy (TCE). TCE has been proposed as a low-intensity alternative to traditional physical activity. DESIGN: Oxygen cost data were collected from 10 healthy adult women (mean age of 47.9 +/- 12.8 years) at rest and during a 30-min session of TCE using an automated metabolic cart and heart rate (HR) telemetry. The Borg rating of perceived exertion (RPE) scale was utilized to measure subjective intensity of the TCE movements. RESULTS: The mean oxygen consumption (VO(2)) for the movements ranged from 4.3 ml kg(-1)min(-1) to 5.5 ml kg(-1)min(-1) with an overall mean of 5.0 ml kg(-1)min(-1). The mean HR for all activity was 67.0 beats per minute and the mean energy expenditure (EE) was 1.6 Kcal min(-1). CONCLUSIONS: Cardiorespiratory and EE responses to TCE indicate that this a low intensity exercise appropriate for individuals requiring activity prescriptions of approximately 2 metabolic equivalents (METs). PMID- 26645521 TI - Is there any place for resistant starch, as alimentary prebiotic, for patients with type 2 diabetes? AB - OBJECTIVE: The aim of the present study was to determine effects of Resistant Starch (RS2) on metabolic parameters and inflammation in women with type 2 diabetes (T2DM). METHODS: In this randomized controlled clinical trial, 60 females with T2DM were divided into intervention (n = 28) and placebo groups (n = 32). They received 10 g/d RS2 or placebo for 8 weeks, respectively. Fasting blood sugar (FBS), glycated hemoglobin (HbA1c), lipid profile, high-sensitive C reactive protein (hs-CRP), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) were measured at baseline and at the end of the trial. Paired t test, unpaired t-test and ANCOVA were used to compare the quantitative variables. The data were analyzed using SPSS software version 13.0. RESULTS: RS2 decreased HbA1c (-0.3%, -3.6%), TNF-alpha (-3.4 pg/mL, -18.9%), triglyceride (-33.4 mg/dL, 15.4%), and it increased HDL-c (+9.4 mg/dL, +24.6%) significantly compared with the placebo group (p < 0.05). Changes in FBS, total cholesterol, low-density lipoprotein, hs-CRP and IL-6 were not significant in the RS2 group compared with the control group. RS2 can improve glycemic status, inflammatory markers and lipid profile in women with T2DM. CONCLUSIONS: Although findings of the present study indicated positive effects of RS2 on inflammation and metabolic parameters, more studies are needed to confirm efficacy of RS2 as an adjunct therapy in diabetes. PMID- 26645522 TI - Therapeutic effects of traditional Chinese medicine in patients with symptomatic cervical ectopy. AB - PURPOSE: The aim of this study is to evaluate the treatment and efficacy of Badushengjigao, a traditional Chinese medicine (TCM) formula, for symptomatic cervical ectopy. METHOD: A patient self-selected two group comparison study was performed. One hundred patients with symptomatic cervical ectopy admitted to the Central Hospital of E-Zhou (Hubei, China) between July 2013 and July 2014 were enrolled in the study. The patients treated with Badushengjigao were the study group and the patients treated with policresulen suppository were the control group. The medicine was administered through vagina. Patients received a three month follow-up (once a month). The treatment results were evaluated and analyzed by variance analysis and X(2) test. RESULTS: The curative rates of the two groups with symptomatic cervical ectopy grade 1 shows no statistical significance. As for grade 2 and grade 3, the curative rates of the study group (phase 2: 72.0%; phase 3: 62.5%) are higher than that of the control group (phase 2: 44.4%; grade 3: 54.5%) with statistical difference (P < 0.05). The study group has less adverse effects (2.5 +/- 1.3 days of vagina bleeding, 6 cases of abdominal pain and 2 cases of increased discharge) than the control group (12.5 +/- 1.1 days of vagina bleeding, 15 cases of abdominal pain and 42 cases of increased discharge) with distinctive statistical difference (P < 0.01). CONCLUSION: The TCM formula, Badushengjigao, seems to be more effective than policresulen suppositories in treating symptomatic cervical ectopy phase 2 and phase 3. We suggest that it could be used as an alternative method for symptomatic cervical ectopy treatment, but further study is needed. PMID- 26645523 TI - Traditional Chinese and Thai medicine in a comparative perspective. AB - The work presented in this paper compares traditional Chinese medicine and traditional Thai medicine, expounding on origins, academic thinking, theoretical system, diagnostic method and modern development. Based on a secondary analysis of available literature, the paper concentrates on two crucial historical developments: (1) the response to, and consequences of, the impact of the Western medicine; and (2) the revival of traditional medicine in these two countries and its prospects. From a comparative perspective, the analysis has led to the conclusion that the rise and fall of traditional medicine is an issue closely related with social and political issues; and the development of traditional medicines requires national policy and financial support from governments, human resource development, the improvement of service quality, and the dissemination of traditional medicine knowledge to the public. In addition, this paper also suggests deepening exchanges and cooperation between China and Thailand, strengthening cooperation between traditional medicine and medical tourism. PMID- 26645524 TI - Investigating the effects of inhaling ginger essence on post-nephrectomy nausea and vomiting. AB - OBJECTIVE: There is a knowledge gap regarding the effects of ginger essence on postoperative nausea and vomiting. This study aimed to evaluate the effect of ginger essence on post-nephrectomy nausea and vomiting. DESIGN: A randomized controlled trial was conducted. SETTING: This study was conducted from third April to first October 2014 in Labbafinejad hospital, Tehran, Iran. Totally, 120 nephrectomy patients were randomly allocated to either the treatment or the control groups. After nephrectomy, we applied two drops of ginger essence to a 2 * 2-inch gauze that was attached to the patients' collars in the treatment group to allow patients to inhale the evaporated essence along with the air room and then repeated every 30 min for two hours. The control group was similarly treated with normal saline. Nausea was assessed using a visual analogue scale every 30 min for two hours and at the sixth hour after surgery. The paired- and independent-samples t and repeated measures analysis of variance tests were used for data analysis. RESULTS: The means nausea intensity were in the treatment and the control groups were 7.09 +/- 1.59 and 7.40 +/- 1.71 at thirty minutes after surgery (P value > 0.05). However, the mean nausea intensity in the treatment group at the four subsequent times were significantly lower than the control group (P value < 0.001). The numbers of vomiting episodes at two and six hours after the surgery were 0.88 +/- 0.78 and 2.58 +/- 1.35, in the treatment group and 4.80 +/- 1.87 and 2.58 +/- 1.35 in the control group. The differences between the two groups regarding the numbers of vomiting episodes were statistically significant (P value < 0.001). CONCLUSION: Inhaling ginger essence has positive effect on postoperative nausea and vomiting. Using ginger essence for managing postoperative nausea and vomiting is recommended. PMID- 26645525 TI - Penetration of antimicrobials to pulmonary epithelial lining fluid and muscle and impact of drug physicochemical properties determined by microdialysis. AB - INTRODUCTION: The objectives of this study were to characterize antimicrobial drug penetration into the pulmonary epithelial lining fluid (PELF) and extracellular fluid (ECF) of muscle in relation to physicochemical properties of the drugs (molecular mass, Log D, polar surface area and charge), using intrabronchial microdialysis. The series of drugs tested include gentamicin, sulfadiazine, cefquinome, minocycline and colistin. METHODS: Drug concentrations were measured during 2h of steady state plasma drug concentrations at therapeutic levels in anesthetized pigs. Microdialysis probes were positioned 2 to 4cm distal to the tracheal bifurcature and in M. gluteobiceps and were calibrated by retrodialysis by drug. RESULTS: Mean AUCPELF/PLASMA(fu) and mean AUCMUSCLE/PLASMA(fu) ratios were respectively for gentamicin (0.8, 0.7), sulfadiazine (1.1, 0.7), cefquinome (1.3, 1.5) minocycline (1.6, 0.7) and colistin (0.26, 0.12). The penetration of drugs into PELF (r(2)=0.55-0.77, p=0.0004-0.0089) and ECF of muscle (r(2)=0.39-0.53, p=0.0108-0.0397) was positively correlated to Log D, whereas molecular mass, polar surface area and charge were negatively correlated to drug penetration. Sulfadiazine, gentamicin, cefquinome and colistin had similar penetration ratios into PELF and ECF of muscle, ranging from 0.12 to 1.50. DISCUSSION: In conclusion, drug penetration into PELF and ECF of muscle is correlated to mass, lipophilicity, polarity and charge of the drugs. Drug partition into ECF of muscle and PELF are similar for the passively transported drugs gentamicin, sulfadiazine, cefquinome and colistin, whereas minocycline appears to be actively transported into PELF. PMID- 26645526 TI - Perceptions of sexual violence among men who have sex with men and individuals on the trans-feminine spectrum in Mongolia. AB - With the growing realisation that sexual violence poses pressing health and human rights concerns for men who have sex with men (MSM) and individuals on the trans feminine spectrum, research has focused on the context in which sexual violence takes place. Rape myths and other perceptions of sexual violence affect the prevalence of perpetration and the availability of services and support for survivors. Little research has been conducted on rape myths among sexual and gender minority groups, especially in low- and middle-income countries. Two focus groups and 30 in-depth interviews were conducted with MSM and individuals on the trans-feminine spectrum in Ulaanbaatar, Mongolia. A number of rape myths previously noted to be prevalent among Western, heterosexual men, and women were expressed by participants, including the myth that males are never raped, rape as a cause of homosexuality or transgenderism, conceptualisations of prototypical rape as requiring overwhelming force, and victim blaming. However, many of these perceptions appeared to have different origins and effects in these populations. This study illustrates interesting similarities and differences compared to rape myths explored in Western, heterosexual male samples, and draws attention to the need to address community perceptions of sexual violence in sexual health and violence intervention programming. PMID- 26645527 TI - Atomic-Scale Observation of Vapor-Solid Nanowire Growth via Oscillatory Mass Transport. AB - In situ atomic-scale transmission electron microscopy (TEM) can provide critical information regarding growth dynamics and kinetics of nanowires. A catalyst-aided nanowire growth mechanism has been well-demonstrated by this method. By contrast, the growth mechanism of nanowires without catalyst remains elusive because of a lack of crucial information on related growth dynamics at the atomic level. Herein, we present a real-time atomic-scale observation of the growth of tungsten oxide nanowires through an environmental TEM. Our results unambiguously demonstrate that the vapor-solid mechanism dominates the nanowire growth, and the oscillatory mass transport on the nanowire tip maintains the noncatalytic growth. Autocorrelation analysis indicates that adjacent nucleation events in the nanowire growth are independent of each other. These findings may improve the understanding of the vapor-solid growth mechanism of nanowires. PMID- 26645528 TI - Gelatin Facial Skin Simulator for Cutaneous Reconstruction. AB - Reconstruction of facial defects can be an intimidating endeavor, especially to resident physicians. When local flap reconstruction is preferred, design of the optimal flap can be a difficult choice. Poor selection can lead to unsightly scarring as well as increased morbidity. A low-cost, easy-to-fabricate gelatin prosthetic facial skin simulator is presented to offer training experience in wound closure, local tissue rearrangement, and facial defect reconstruction for resident instruction. In conjunction with a didactic lecture, 10 participants were asked to perform a Z-plasty, bilobed, rhomboid, and paramedian forehead flap, followed by an 18-question survey. While initial impressions are favorable, further validation studies are warranted. PMID- 26645529 TI - How Does TeamSTEPPS Affect Operating Room Efficiency? AB - OBJECTIVE: To evaluate the effect of TeamSTEPPS (Team Strategies and Tools to Enhance Performance and Patient Safety) on operating room efficiency for the otolaryngology service at a tertiary care medical center. STUDY DESIGN: Retrospective database review. SETTING: Otolaryngology department at tertiary care medical center. SUBJECTS AND METHODS: To assess the impact of implementing an evidence-based patient safety initiative, TeamSTEPPS, on operating room efficiency in the otolaryngology department, the operative times, time lost to delayed starts, and turnover times during the year following the implementation of TeamSTEPPS were compared with the values from the prior year. RESULTS: The study compared 1322 cases and 644 turnovers in the year prior to TeamSTEPPS implementation with 1609 cases and 769 turnovers in the following year. There were no statistically significant decreases in operating room efficiency in the year after the TeamSTEPPS rollout. CONCLUSION: Operating room efficiency was preserved after the rollout of a rigorous evidence-based patient safety initiative that requires active participation from all operating room team members. PMID- 26645530 TI - Assessment of Abdominal Fat Graft to Repair Anterior Skull Base after Malignant Sinonasal Tumor Extirpation. AB - OBJECTIVE: Adult abdominal fat, which is known to contain pluripotent stem cells, is frequently used to treat cerebrospinal fluid leak. The aim of this study was to assess the efficacy and reliability of abdominal fat graft to close large skull base defects after extirpation of malignant sinonasal tumors. STUDY DESIGN: Case series with chart review performed between 2009 and 2014. SUBJECTS AND METHODS: Twenty-nine cases were included of consecutive patients who were suffering from malignant sinonasal tumors, operated by an endoscopic endonasal approach with anterior skull base extirpation and surgically induced cerebrospinal fluid leak. Skull base was repaired by 1 layer of "en bloc" autologous fat graft used as a plug in the onlay position. Epidemiologic data, medical history, defect size, length of hospitalization, and morbidity were analyzed. RESULTS: Radiotherapy was given pre- and postoperatively in 4 (13.8%) and 23 (79.3%) patients, respectively. Mean defect size was 4.47 +/- 2.9 cm(2) (range, 0.24-9.1 cm(2)). Mean operative time was 210 +/- 86 minutes. Mean length of hospitalization was 8.6 +/- 3.7 days and 4.9 +/- 2 days in the intensive care unit. No lumbar drain was used in this study. There was 1 case of cerebrospinal fluid leak (3.5%) and 2 cases of meningitis (6.9%), which resolved after medical treatment. Mean follow-up was 17 +/- 13 months (range, 3-53 months). CONCLUSION: Abdominal fat graft is a safe and reliable material to close the anterior skull base after extirpation of malignant sinonasal tumors. PMID- 26645532 TI - Obstructive Sleep Apnea and Gastroesophageal Reflux: A Multivariate Population Level Analysis. AB - OBJECTIVES: Previous studies investigating the relationship between gastroesophageal reflux (GER) and obstructive sleep apnea (OSA) demonstrate mixed results and have had limited capacity to control for concurrent confounders. Our objectives were to (1) determine if GER is significantly associated with OSA when simultaneously adjusting for the presence of other potentially confounding conditions and (2) quantify the magnitude of any such association that exists. STUDY DESIGN: Cross-sectional analysis of the National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey, 2005-2010. SETTING: Ambulatory visits in the United States. SUBJECTS AND METHODS: Adults with a diagnosis of OSA or GER and potentially confounding conditions were identified. Univariate and multivariate logistic regression analyses were performed, as well as sensitivity analyses based on increasingly narrow diagnostic definitions. RESULTS: A significant positive association between GER and OSA was observed, which persisted after adjustment for age, sex, race/ethnicity, sinonasal obstructive and inflammatory disorders, laryngopharyngeal obstructive and inflammatory disorders, obesity, asthma, and lung disorders. This positive association remained significant regardless of diagnostic criteria, whether broad (odds ratio: 1.94, 95% confidence interval: 1.07-3.54, P = .030) or narrow (odds ratio: 2.13, 95% confidence interval: 1.17-3.88, P = .014). CONCLUSION: In this analysis of a national database defining the 3 most prioritized diagnoses, GER is independently associated with OSA, with double the odds of concurrent occurrence, even while controlling for potentially related conditions. PMID- 26645531 TI - Shared Decision Making and Choice for Elective Surgical Care: A Systematic Review. AB - OBJECTIVE: Shared decision making (SDM), an integrative patient-provider communication process emphasizing discussion of scientific evidence and patient/family values, may improve quality care delivery, promote evidence-based practice, and reduce overuse of surgical care. Little is known, however, regarding SDM in elective surgical practice. The purpose of this systematic review is to synthesize findings of studies evaluating use and outcomes of SDM in elective surgery. DATA SOURCES: PubMed, Cochrane CENTRAL, EMBASE, CINAHL, and SCOPUS electronic databases. REVIEW METHODS: We searched for English-language studies (January 1, 1990, to August 9, 2015) evaluating use of SDM in elective surgical care where choice for surgery could be ascertained. Identified studies were independently screened by 2 reviewers in stages of title/abstract and full text review. We abstracted data related to population, study design, clinical dilemma, use of SDM, outcomes, treatment choice, and bias. RESULTS: Of 10,929 identified articles, 24 met inclusion criteria. The most common area studied was spine (7 of 24), followed by joint (5 of 24) and gynecologic surgery (4 of 24). Twenty studies used decision aids or support tools, including modalities that were multimedia/video (13 of 20), written (3 of 20), or personal coaching (4 of 20). Effect of SDM on preference for surgery was mixed across studies, showing a decrease in surgery (9 of 24), no difference (8 of 24), or an increase (1 of 24). SDM tended to improve decision quality (3 of 3) as well as knowledge or preparation (4 of 6) while decreasing decision conflict (4 of 6). CONCLUSION: SDM reduces decision conflict and improves decision quality for patients making choices about elective surgery. While net findings show that SDM may influence patients to choose surgery less often, the impact of SDM on surgical utilization cannot be clearly ascertained. PMID- 26645533 TI - Decision Making for Children with Obstructive Sleep Apnea without Tonsillar Hypertrophy. AB - OBJECTIVE: Evidence-based medicine is the gold standard practice model for patient management. Our aim was to determine whether decisions made by pediatric subspecialists regarding management of obstructive sleep apnea in children without tonsillar hypertrophy adhered to this model or were based on clinical experiences. STUDY DESIGN: Single-institution prospective study. SETTING: Multidisciplinary upper airway center in an academic pediatric hospital. SUBJECTS AND METHODS: Twelve pediatric subspecialists representing 8 specialties participating in upper airway clinics and management conferences. Real-time decisions made in treatment conferences and upper airway clinics were collected. Physicians were queried regarding the basis of their decisions, and these decisions were then classified into 10 categories. RESULTS: Over 13 days (10 case conferences, 3 half-day clinics), 324 decisions were made for 58 patients (mean age = 8.9 +/- 7.4 years, mean body mass index percentile = 75 +/- 29); 34% (n = 108) of decisions were evidence based; 59% (n = 193) were nonevidence based; and 7% (n = 23) were based on parental preference. Providers were able to cite specific studies for <20% of these decisions. There was no significant increase in the proportion of evidence-based decisions made over time. CONCLUSIONS: We deemed 34% of decisions regarding the management of obstructive sleep apnea in children without tonsillar hypertrophy to be evidence based and found that sharing the basis for decisions did not improve the percentage of evidence-based decisions over time. These findings reflect significant evidence gaps and highlight the need for a systematic literature evaluation to identify best practice in managing this population. We recommend that these evidence gaps be further characterized and incorporated into an agenda for future research. PMID- 26645534 TI - Incidence of Visualization of the Glossopharyngeal Nerve after Pediatric Tonsillectomy. AB - The objective was to determine the incidence of exposure of the lingual branch of the glossopharyngeal nerve during tonsillectomy with a retrospective review of surgical findings in 138 children who underwent total tonsillectomy at a tertiary medical center. Age, sex, surgical indication, tonsil size, congenital abnormalities, operative time, and surgical findings indicating the presence or absence of the glossopharyngeal nerve in the tonsillar fossa were recorded. Statistical analysis was performed with z test, t test, and Fisher's exact test. Thirty-seven nerves were observed in 28 patients, with preponderance for the left fossa (24 of 37 vs 13 of 37; P = .01). In a comparison of children with and without exposed nerves, there was no statistically significant difference in mean age (6.89 vs 7.08; P = .84), proportion of males (14 of 28 vs 54 of 110; P = 1), or proportion of 3 to 4+ tonsils (20 of 28 vs 73 of 110; P = .66). In approximately 20% of children undergoing tonsillectomy, the lateral pharyngeal musculature incompletely protected the lingual branch of the glossopharyngeal nerve from the tonsil capsule. PMID- 26645536 TI - Substituent Effects on the Binding of Halides by Neutral and Dicationic Bis(triazolium) Receptors. AB - The effects of substituent and overall charge upon the binding of a halide anion by a bis(triazolium) receptor are studied by M06-2X DFT calculations, with the aug-cc-pVDZ basis set. Comparison is also made between a receptor that engages in H-bonds, with a halogen-bonding species. Fluoride is clearly most strongly bound, followed by Cl(-), Br(-), and I(-) in that order. The dicationic receptor engages in stronger complexes, but not by a very wide margin compared to its neutral counterpart. The binding is enhanced as the substituent on the two triazolium rings becomes progressively more electron-withdrawing. Halogen-substituted receptors, whether neutral or cationic, display a greater sensitivity to substituent than do their H-bonding counterparts. Both Coulombic and charge transfer factors obey the latter trends but do not correctly reproduce the stronger halogen vs hydrogen bonding. Both H-bonds and halogen bonds are nearly linear within the complexes, due in part to bond rotations within the receptor that bring the two triazole rings closer to coplanarity with the central benzene ring. PMID- 26645535 TI - Rapid Increase in frequency of gene copy-number variants during experimental evolution in Caenorhabditis elegans. AB - BACKGROUND: Gene copy-number variation (CNVs), which provides the raw material for the evolution of novel genes, is widespread in natural populations. We investigated whether CNVs constitute a common mechanism of genetic change during adaptation in experimental Caenorhabditis elegans populations. Outcrossing C. elegans populations with low fitness were evolved for >200 generations. The frequencies of CNVs in these populations were analyzed by oligonucleotide array comparative genome hybridization, quantitative PCR, PCR, DNA sequencing across breakpoints, and single-worm PCR. RESULTS: Multiple duplications and deletions rose to intermediate or high frequencies in independent populations. Several lines of evidence suggest that these changes were adaptive: (i) copy-number changes reached high frequency or were fixed in a short time, (ii) many independent populations harbored CNVs spanning the same genes, and (iii) larger average size of CNVs in adapting populations relative to spontaneous CNVs. The latter is expected if larger CNVs are more likely to encompass genes under selection for a change in gene dosage. Several convergent CNVs originated in populations descended from different low fitness ancestors as well as high fitness controls. CONCLUSIONS: We show that gene copy-number changes are a common class of adaptive genetic change. Due to the high rates of origin of spontaneous duplications and deletions, copy-number changes containing the same genes arose readily in independent populations. Duplications that reached high frequencies in these adapting populations were significantly larger in span. Many convergent CNVs may be general adaptations to laboratory conditions. These results demonstrate the great potential borne by CNVs for evolutionary adaptation. PMID- 26645537 TI - Leucine supplementation is anti-atrophic during paradoxical sleep deprivation in rats. AB - The purpose of this study was to identify sleep deprivation-induced atrophy and the muscle-specific fiber types affected and to determine the effects of leucine supplementation on atrophy and pertinent portions of the pathways of muscle protein synthesis and degradation in rats. A total of 46 Wistar rats were distributed in four groups: control (CTL), leucine supplementation (LEU), sleep deprivation (SD), and leucine supplementation + sleep deprivation (LEU + SD). Leucine supplementation was by gavage (1.35 g/kg/daily), and the animals were subjected to SD for 96 h. Testosterone and corticosterone concentrations, along with proteins involved in protein synthesis and degradation and proteasome activity levels, were measured in the gastrocnemius (GA) muscle. Myosin ATPase staining was used to evaluate the different muscle fibers. After sleep deprivation, GA muscle and body masses decreased in the SD group compared to the CTL, LEU, and LEU + SD groups. There was no difference between groups in type I fiber cross-sectional area (CSA). The CSAs for type IIa fibers were lower in the SD and LEU + SD groups vs. the CTL and LEU groups, while the IIb fiber CSA was lower in the SD group vs. the CSAs in all other groups. The phospho (p)-Akt levels were lower in the SD and LEU + SD groups vs. the CTL and LEU groups. The p mTORC1 levels were higher in the LEU, SD, and LEU + SD groups vs. the CTL group. The p-p70S6k levels were higher in the LEU and LEU + SD groups; the 4E-BP1 levels were higher in the SD and LEU + SD groups compared to those in the CTL and LEU groups, and the p-4E-BP1 levels were higher in the LEU and SD groups compared to those in the CTL group and even higher in the LEU + SD group compared to those in the LEU and SD groups. Ubiquitinated proteins, LC3, and p62/SQSTM, and proteasome activity levels were higher in the SD and LEU + SD groups vs. the LEU and CTL groups. Sleep deprivation led to the atrophy of IIa and IIb muscle fibers; however, leucine supplementation prevented muscle loss and type IIb fiber atrophy. PMID- 26645538 TI - The SafeBoosC phase II clinical trial: an analysis of the interventions related with the oximeter readings. AB - BACKGROUND: The SafeBoosC phase II randomised clinical trial recently demonstrated the benefits of a combination of cerebral regional tissue oxygen saturation (rStO2) by near-infrared spectroscopy (NIRS) and a treatment guideline to reduce the oxygen imbalance in extremely preterm infants. AIMS: To analyse rStO2-alarm-related clinical decisions and their heterogeneity in the NIRS experimental group (NIRS monitoring visible) and their impact on rStO2 and SpO2. METHODS: Continuous data from NIRS devices and the alarms (area under the curve of the rStO2 out of range had accumulated 0.2%h during 10 min), clinical data at discrete time points and interventions prompted by the alarms were recorded. RESULTS: Sixty-seven infants had data that fulfilled the requirements for this analysis. 1107 alarm episodes were analysed. The alarm triggered a treatment guideline intervention in 25% of the cases; the type of intervention chosen varied among clinical sites. More than 55% of alarms were not followed by an intervention ('No action'); additionally, in 5% of alarms the rStO2 value apparently was considered non-reliable and the sensor was repositioned. The percentage of unresolved alarms at 30 min after 'No action' almost doubled the treatment guideline intervention (p<0.001). Changes in peripheral oxygen saturation (SpO2), were observed only after treatment guideline interventions. CONCLUSIONS: This study shows that 25% of rStO2 alarms were followed by a clinical intervention determined by the treatment guideline. However, the rStO2 and SpO2 returned to normal ranges after the intervention, supporting the notion that decisions taken by the clinicians were appropriate. TRIAL REGISTRATION NUMBER: ClinicalTrial.gov NCT01590316. PMID- 26645539 TI - Post-term pregnancy is an independent risk factor for neonatal morbidity even in low-risk singleton pregnancies. AB - OBJECTIVE: To determine the independent association of post-term pregnancy with neonatal outcome in low-risk newborns. DESIGN: Retrospective cohort. SETTING: Tertiary university-affiliated medical centre. PATIENTS: All newborns of low-risk singleton pregnancies born at 39+0 to 44+0 weeks' gestation over a 5-year period. EXCLUSION CRITERIA: multiple gestation, maternal hypertensive disorder, diabetes or cholestasis, placental abruption or intrapartum fever (>38 degrees C), small for gestational age (<10th centile) and major congenital or chromosomal anomalies. INTERVENTIONS: None. OUTCOME MEASURES: Admission to the neonatal intensive care unit (NICU), hospital length of stay, 5-min Apgar score, birth trauma, respiratory, neurological, metabolic and infectious morbidities and neonatal mortality. The adverse outcome rate was compared among three groups based on gestational age at birth: post-term (>=42+0 weeks), late term (41+0 to 41+6 weeks) and full term (39+0 to 40+6 weeks). RESULTS: Of the 23 524 eligible neonates, 747 (3.2%) were born post-term, 4632 (19.7%) late term and 18 145 (77.1%) full term. Women in the post-term group versus the late-term group had a significantly higher rate of caesarean section (8.9% vs 5.6%, p<0.001) and operative vaginal delivery (9.6% vs 7.4%, p=0.024). Post-term pregnancy versus full-term pregnancy was associated with an increased risk of NICU admission (OR 2.0, 95% CI 1.4 to 2.8), respiratory morbidity (OR 2.2, 95% CI 1.3 to 3.8) and infectious morbidity (OR 1.88, 95% CI 1.32 to 2.69). Post-term pregnancy versus late-term pregnancy was similarly associated with an increased risk of NICU admission (OR 2.0, 95% CI 1.4 to 2.9), respiratory morbidity (OR 2.7, 95% CI 1.5 to 5.0) and infectious morbidity (OR 1.8, 95% CI 1.2 to 2.7) and with hypoglycaemia (OR 2.6, 95% CI 1.2 to 5.4). Post-term delivery was not associated with neonatal mortality. CONCLUSIONS: Post-term pregnancy is an independent risk factor for neonatal morbidity even in low-risk singleton pregnancies. PMID- 26645540 TI - "Even 'Daily' is Not Enough": How Well Do We Measure Domestic Violence and Abuse? A Think-Aloud Study of a Commonly Used Self-Report Scale. AB - This article explores the challenges of providing a quantitative measure of domestic violence and abuse (DVA), illustrated by the Composite Abuse Scale, a validated multidimensional measure of frequency and severity of abuse, used worldwide for prevalence studies and intervention trials. Cognitive "think-aloud" and qualitative interviewing with a sample of women who had experienced DVA revealed a tendency toward underreporting their experience of abuse, particularly of coercive control, threatening behavior, restrictions to freedom, and sexual abuse. Underreporting was linked to inconsistency and uncertainty in item interpretation and response, fear of answering truthfully, and unwillingness to identify with certain forms of abuse. Suggestions are made for rewording or reconceptualizing items and the inclusion of a distress scale to measure the individual impact of abuse. The importance of including qualitative methods in questionnaire design and in the interpretation of quantitative findings is highlighted. PMID- 26645541 TI - Timing and Outcome Concerns regarding Feminizing Genitoplasty from the Perspective of Egyptian Families of Girls with Virilized External Genitalia. AB - BACKGROUND: Congenital adrenal hyperplasia in females leads to virilization of external genitalia and persistent urogenital sinus. There are controversies regarding the timing and outcomes of surgery. Deferring surgeries beyond childhood is difficult to implement in conservative societies, and may result in stigmatization and distress to individuals with disorders of sexual differentiation and their families. METHODS: Thirty girls with virilization due to congenital adrenal hyperplasia were admitted for single-stage feminizing genitoplasty, between 2011 and 2014. We prospectively studied the concerns and input of the families represented by the mothers. After comprehensive counselling, the mothers completed a questionnaire to clarify their priorities and concerns related to surgery. RESULTS: Surgeries were performed at a mean age of 22 months. Most cases ranged between Prader's degrees III and IV. Egyptian families believe that early surgical reconstruction is in the best interest of their girls. They are marginally more concerned about functional outcomes and future child bearing than external appearance and cosmetic outcomes. CONCLUSIONS: Social difficulties noticeably add challenges to the management plan within conservative societies. Early genital reconstructive surgery, when reasonably indicated, needs to remain a viable option. Comprehensive psychosocial support within a multidisciplinary approach is needed to defer feminizing genitoplasty in selected cases to adolescence. PMID- 26645542 TI - Isoflurane Post-Treatment Improves Outcome after an Embolic Stroke in Rabbits. AB - Application of commonly used volatile anesthetics after brain ischemia onset (post-treatment) provides neuroprotection in rodents. To further test its translational potential, this study was designed to determine whether isoflurane post-treatment induced neuroprotection in rabbits after embolic stroke. White male New Zealand rabbits received intra-carotid injection of clots when they were awake. Some rabbits were exposed to 2.5% isoflurane for 1 h at 5 min after the injection. Isoflurane post-treatment increased the tolerance of rabbits to the amount of clots. Isoflurane post-treatment also reduced brain infarct volumes and plasma S100B 3 days after the injection of 5 mg clots and improved neurological deficit scores after the stroke. Isoflurane post-treatment improves neurological outcome in rabbits after embolic stroke. PMID- 26645543 TI - Effectiveness of psychological interventions for chronic pain on health care use and work absence: systematic review and meta-analysis. AB - Psychological interventions for chronic pain and its consequences have been shown to improve mood, disability, pain, and catastrophic thinking, but there has been no systematic review specifically of their effects on health care use or time lost from work as treatment outcomes in mixed chronic pain. We conducted a systematic review and meta-analysis to evaluate the effectiveness of psychological therapies for chronic pain (excluding headache) in adults for these outcomes. We used searches from 2 previous systematic reviews and updated them. Eighteen randomized controlled trials were found that reported health care use (15 studies) and work loss (9 studies) as outcomes. Fourteen studies provided data for meta-analysis. There were moderate effects for psychological interventions compared with active controls, treatment as usual and waiting list controls in reducing health care use, with confidence in the findings. No benefits were found for medication reduction, but with less confidence in this result. Analysis of work loss showed no significant effects of psychological interventions over comparisons, but the use of many different metrics necessitated fragmenting the planned analyses, making summary difficult. The results are encouraging for the potential of routine psychological intervention to reduce posttreatment health care use, with associated cost savings, but it is likely that the range and complexity of problems affecting work necessitate additional intervention over standard group psychological intervention. PMID- 26645544 TI - Genetic findings related to pain and analgesics-why are they so inconsistent? PMID- 26645545 TI - Toll-like receptor 4 contributes to chronic itch, alloknesis, and spinal astrocyte activation in male mice. AB - Increasing evidence suggests that Toll-like receptor 4 (TLR4) contributes importantly to spinal cord glial activation and chronic pain sensitization; however, its unique role in acute and chronic itch is unclear. In this study, we investigated the involvement of TLR4 in acute and chronic itch models in male mice using both transgenic and pharmacological approaches. Tlr4 mice exhibited normal acute itch induced by compound 48/80 and chloroquine, but these mice showed substantial reductions in scratching in chronic itch models of dry skin, induced by acetone and diethylether followed by water (AEW), contact dermatitis, and allergic contact dermatitis on the neck. Intrathecal (spinal) inhibition of TLR4 with lipopolysaccharide Rhodobacter sphaeroides did not affect acute itch but suppressed AEW-induced chronic itch. Compound 48/80 and AEW also produced robust alloknesis, a touch-elicited itch in wild-type mice, which was suppressed by intrathecal lipopolysaccharide R sphaeroides and Tlr4 deletion. Acetone and diethylether followed by water induced persistent upregulation of Tlr4 mRNA and increased TLR4 expression in GFAP-expressing astrocytes in spinal cord dorsal horn. Acetone and diethylether followed by water also induced TLR4-dependent astrogliosis (GFAP upregulation) in spinal cord. Intrathecal injection of astroglial inhibitor L-alpha-aminoadipate reduced AEW-induced chronic itch and alloknesis without affecting acute itch. Spinal TLR4 was also necessary for AEW induced chronic itch in the cheek model. Interestingly, scratching plays an essential role in spinal astrogliosis because AEW-induced astrogliosis was abrogated by putting Elizabethan collars on the neck to prevent scratching the itchy skin. Our findings suggest that spinal TLR4 signaling is important for spinal astrocyte activation and astrogliosis that may underlie alloknesis and chronic itch. PMID- 26645546 TI - Complexity, comorbidity, and health care costs associated with chronic widespread pain in primary care. AB - The objective was to estimate the prevalence of chronic widespread pain (CWP) and compare the quality-of-life (QoL), cardiovascular risk factors, comorbidity, complexity, and health costs with the reference population. A multicenter case control study was conducted at 3 primary care centers in Barcelona between January and December 2012: 3048 randomized patients were evaluated for CWP according to the American College of Rheumatology definition. Questionnaires on pain, QoL, disability, fatigue, anxiety, depression, and sleep quality were administered. Cardiovascular risk and the Charlson index were calculated. We compared the complexity of cases and controls using Clinical Risk Groups, severity and annual direct and indirect health care costs. CWP criteria were found in 168 patients (92.3% women, prevalence 5.51% [95% confidence interval: 4.75%-6.38%]). Patients with CWP had worse QoL (34.2 vs 44.1, P < 0.001), and greater disability (1.04 vs 0.35; P < 0.001), anxiety (43.9% vs 13.3%; P < 0.001), depression (27% vs 5.8%; P < 0.001), sleep disturbances, obesity, sedentary lifestyle, high blood pressure, diabetes mellitus, and number of cardiovascular events (13.1% vs 4.8%; P = 0.028) and higher rates of complexity, severity, hospitalization, and mortality. Costs were &OV0556;3751 per year in patients with CWP vs &OV0556;1397 in controls (P < 0.001). In conclusion, the average patient with CWP has a worse QoL and a greater burden of mental health disorders and cardiovascular risk. The average annual cost associated with CWP is nearly 3 times higher than that of patients without CWP, controlling for other clinical factors. These findings have implications for disease management and budgetary considerations. PMID- 26645548 TI - What reliability can and cannot tell us about pain report and pain neuroimaging. PMID- 26645547 TI - Vagus nerve stimulation inhibits cortical spreading depression. AB - Vagus nerve stimulation has recently been reported to improve symptoms of migraine. Cortical spreading depression is the electrophysiological event underlying migraine aura and is a trigger for headache. We tested whether vagus nerve stimulation inhibits cortical spreading depression to explain its antimigraine effect. Unilateral vagus nerve stimulation was delivered either noninvasively through the skin or directly by electrodes placed around the nerve. Systemic physiology was monitored throughout the study. Both noninvasive transcutaneous and invasive direct vagus nerve stimulations significantly suppressed spreading depression susceptibility in the occipital cortex in rats. The electrical stimulation threshold to evoke a spreading depression was elevated by more than 2-fold, the frequency of spreading depressions during continuous topical 1 M KCl was reduced by ~40%, and propagation speed of spreading depression was reduced by ~15%. This effect developed within 30 minutes after vagus nerve stimulation and persisted for more than 3 hours. Noninvasive transcutaneous vagus nerve stimulation was as efficacious as direct invasive vagus nerve stimulation, and the efficacy did not differ between the ipsilateral and contralateral hemispheres. Our findings provide a potential mechanism by which vagus nerve stimulation may be efficacious in migraine and suggest that susceptibility to spreading depression is a suitable platform to optimize its efficacy. PMID- 26645549 TI - The interpersonal function of pain: conserving multiple resources. PMID- 26645550 TI - Brain measures of nociception using near-infrared spectroscopy in patients undergoing routine screening colonoscopy. AB - Colonoscopy is an invaluable tool for the screening and diagnosis of many colonic diseases. For most colonoscopies, moderate sedation is used during the procedure. However, insufflation of the colon produces a nociceptive stimulus that is usually accompanied by facial grimacing/groaning while under sedation. The objective of this study was to evaluate whether a nociceptive signal elicited by colonic insufflation could be measured from the brain. Seventeen otherwise healthy patients (age 54.8 +/- 9.1; 6 female) undergoing routine colonoscopy (ie, no history of significant medical conditions) were monitored using near-infrared spectroscopy (NIRS). Moderate sedation was produced using standard clinical protocols for midazolam and meperidine, titrated to effect. Near-infrared spectroscopy data captured during the procedure was analyzed offline to evaluate the brains' responses to nociceptive stimuli evoked by the insufflation events (defined by physician or observing patients' facial responses). Analysis of NIRS data revealed a specific, reproducible prefrontal cortex activity corresponding to times when patients grimaced. The pattern of the activation is similar to that previously observed during nociceptive stimuli in awake healthy individuals, suggesting that this approach may be used to evaluate brain activity evoked by nociceptive stimuli under sedation, when there is incomplete analgesia. Although some patients report recollection of procedural pain after the procedure, the effects of repeated nociceptive stimuli in surgical patients may contribute to postoperative changes including chronic pain. The results from this study indicate that NIRS may be a suitable technology for continuous nociceptive afferent monitoring in patients undergoing sedation and could have applications under sedation or anesthesia. PMID- 26645551 TI - Current incidence and outcome of the acute respiratory distress syndrome. AB - PURPOSE OF REVIEW: This article discusses recently published articles reporting the incidence and outcome of patients with the acute respiratory distress syndrome (ARDS). This is a difficult task since there is a marked variability regarding the methodology of the few, large epidemiological, and observational studies on ARDS. RECENT FINDINGS: The review will mainly focus on publications from the past 18 months. We have reviewed new epidemiological studies reporting population-based incidence of ARDS. Also, we have reviewed the data on survival reported in observational and randomized controlled trials, discussed how the current ARDS definition modifies the true incidence of ARDS, and briefly mentioned recent approaches that appear to improve ARDS outcome. SUMMARY: On the basis of current evidence, it seems that the incidence and overall hospital mortality of ARDS has not changed substantially in the last decade. Independent of the definition used for identification of ARDS patients, reported population based incidence of ARDS is an order of magnitude lower in Europe than in the USA. Current hospital mortality of combined moderate and severe ARDS reported in observational studies is greater than 40%. PMID- 26645552 TI - The clinical management of patients on partial/total extracorporeal support. AB - PURPOSE OF REVIEW: Despite advances in extracorporeal membrane oxygenation (ECMO) technology, much is unknown about the optimal management strategies for patients receiving extracorporeal support. There is a growing body of literature investigating patient selection and outcomes, mechanical ventilation approaches, anticoagulation, pharmacokinetics, early mobilization, and the role of ECMO transport among others. RECENT FINDINGS: Nonrandomized data suggest a survival advantage from ECMO compared with conventional management in acute respiratory distress syndrome, with mechanical ventilation practices varying widely across centers. A randomized controlled trial is currently ongoing with standardized ventilation approaches in both arms. Low-level anticoagulation appears to be well tolerated, and ECMO circuitry appears to affect the pharmacokinetics of certain drugs. Pilot and matched cohort studies suggest that extracorporeal carbon dioxide removal is effective in preventing intubation in chronic obstructive pulmonary disease, with larger randomized studies being planned. ECMO may be successful in bridging selected patients to lung transplantation, with early mobilization serving as a well tolerated and effective means of optimizing these patients. Regionalization of ECMO may maximize outcomes and is facilitated by the development of ECMO transport teams. SUMMARY: Recently published data highlight the evolving management strategies of patients receiving extracorporeal support and help identify those patients most appropriate for ECMO and extracorporeal carbon dioxide removal. More data will ultimately be needed to develop an evidence-based consensus. PMID- 26645553 TI - Mechanical ventilation for children. AB - PURPOSE OF REVIEW: The aim of this review is to analyze innovative data pertaining to the clinical use of mechanical ventilation for children. RECENT FINDINGS: The optimal definition and treatment of pediatric acute respiratory distress syndrome, the application of innovative ventilation modes in children to optimize child/ventilator interaction, and pediatric noninvasive ventilation, including specific interfaces, have been recently evaluated in the literature. SUMMARY: Despite the improvement observed in the last decades in the treatment of pediatric acute respiratory failure and the diffusion of innovative modes of mechanical ventilation, there are no clear and consistent guidelines for the use of mechanical ventilation for children. In several areas data are still lacking, and in many others they are extrapolated from studies performed in adults; the direct evaluation of results obtained from studies specific to the pediatric population is therefore crucial. PMID- 26645554 TI - Acute respiratory distress syndrome: shifting the emphasis from treatment to prevention. AB - PURPOSE OF REVIEW: Although results from clinical trials have advanced the treatment of acute respiratory distress syndrome (ARDS), mortality remains high. More recently, focus has shifted from treatment of ARDS to early identification and prevention in at-risk populations. RECENT FINDINGS: There have been 30 published and registered clinical trials with either the primary or secondary goal of reducing ARDS. SUMMARY: With this change in paradigm, come additional challenges and consideration in study design that depends not only on the intervention but also whether the intervention aims for a primary, secondary, or tertiary prevention of ARDS that targets a patient population for universal, selective, or indicated prevention. These epidemiologic concepts of prevention in public health also apply to ARDS and are relevant to the study population to target, the timing of the intervention relative to critical illness, the study design and outcomes to measure in an ARDS prevention study. This shift in focus is reflected by the new National Heart Lung Blood Institute Prevention and Early Treatment of Acute Lung Injury network, and signifies an overall movement away from reacting to and supporting acute organ failure after it is established to early detection and prevention in acute critical illness wherever and whenever it may occur. PMID- 26645555 TI - Stem cell therapy for acute respiratory distress syndrome: a promising future? AB - PURPOSE OF REVIEW: Acute respiratory distress syndrome (ARDS) is a devastating disease process with a 40% mortality rate, and for which there is no therapy. Stem cells are an exciting potential therapy for ARDS, and are currently the subject of intensive ongoing research efforts. We review data concerning the therapeutic promise of cell-based therapies for ARDS. RECENT FINDINGS: Recent experimental studies suggest that cell-based therapies, particularly mesenchymal stem/stromal cells (MSCs), endothelial progenitor cells, and embryonic or induced pluripotent stem cells all offer considerable promise for ARDS. Of these cell types, mesenchymal stromal cells offer the greatest potential for allogeneic therapy, given the large body of preclinical data supporting their use, and the advanced state of our understanding of their diverse mechanisms of action. Although other stem cells such as EPCs also have therapeutic potential, greater barriers exist, particularly the requirement for autologous EPC therapy. Other stem cells, such as ESCs and iPSCs, are at an earlier stage in the translational process, but offer the hope of directly replacing injured lung tissue. Ultimately, lung-derived stem cells may offer the greatest hope for lung diseases, given their homeostatic role in replacing and repairing damaged native lung tissues.MSCs are currently in early phase clinical trials, the results of which will be of critical importance to subsequent translational efforts for MSCs in ARDS. A number of translational challenges exist, including minimizing variability in cell batches, developing standard tests for cell potency, and producing large amounts of clinical-grade cells for use in patients. SUMMARY: Cell-based therapies, particularly MSCs, offer considerable promise for the treatment of ARDS. Overcoming translational challenges will be important to fully realizing their therapeutic potential for ARDS. PMID- 26645556 TI - Critical care management of cerebral venous thrombosis. AB - PURPOSE OF REVIEW: Although recent trials of intervention for acute ischemic stroke have been positive, similar benefit in acute cerebral venous thrombosis (CVT) remains largely unclear. This review aims to summarize the existing evidence regarding the management of CVT, including anticoagulation and endovascular therapy. RECENT FINDINGS: The mainstay of treatment in CVT is systemic anticoagulation even in the setting of intracerebral hemorrhage. Nonrandomized studies and case series suggest that endovascular therapy in CVT is relatively safe, and can improve outcomes in the small subset of CVT patients with neurologic deterioration despite anticoagulation. SUMMARY: Despite a generally favorable prognosis, one in four patients with CVT develop neurological deterioration in the acute phase. Predisposing factors include a neurological deficit or seizures at onset, deep venous thrombosis, venous infarctions, or intracranial hemorrhage with mass effect and an underlying thrombophilia. More randomized trials are needed to compare the benefits of anticoagulation and endovascular therapy. PMID- 26645557 TI - Experimental and Theoretical Insight into Electrocatalytic Hydrogen Evolution with Nickel Bis(aryldithiolene) Complexes as Catalysts. AB - A series of neutral and monoanionic nickel dithiolene complexes with p methoxyphenyl-substituted 1,2-dithiolene ligands have been prepared and characterized with physicochemical methods. Two of the complexes, the monoanion of the symmetric [Ni{S2C2(Ph-p-OCH3)2}2] (3(-)) with NBu4(+) as a counterion and the neutral asymmetric [Ni{S2C2(Ph)(Ph-p-OCH3)}2] (2), have been structurally characterized by single-crystal X-ray crystallography. All complexes have been employed as proton-reducing catalysts in N,N-dimethylformamide with trifluoroacetic acid as the proton source. The complexes are active catalysts with good faradaic yields, reaching 83% for 2 but relatively high overpotential requirements (0.91 and 1.55 V measured at the middle of the catalytic wave for two processes observed depending on the different routes of the mechanism). The similarity of the experimental data regardless of whether the neutral or anionic form of the complexes is used indicates that the neutral form acts as a precatalyst. On the basis of detailed density functional theory calculations, the proposed mechanism reveals two different main routes after protonation of the dianion of the catalyst in accordance with the experimental data, indicating the role of the concentration of the acid and the influence of the methoxy groups. Protonation at sulfur seems be more favorable than that at the metal, which is in marked contrast with the catalytic mechanism proposed for analogous cobalt dithiolene complexes. PMID- 26645558 TI - Observation of Cationic Transition Metal-Alkane Complexes with Moderate Stability in Hydrofluorocarbon Solution. AB - In seeking to create more-stable transition metal-alkane complexes, we generated cationic alkane complexes of the type [(HEB)Re(CO)2(alkane)][Al(OR(f))4] (HEB = eta(6)-hexaethylbenzene; alkane = cyclopentane (16) or pentane (17-19); OR(f) = perfluoro-tert-butoxy) via photolysis of the precursor complex [(HEB)Re(CO)3][Al(OR(f))4] (15) in the presence of the added alkane. The alkane complexes were generated in a hydrofluorocarbon (HFC) solvent, most often CF3CH2CF3, which is capable of simultaneously dissolving the ionic complex 15 and a small amount of alkane at low temperature (183 K). Use of the HFC solvent in tandem with the highly fluorinated, solubilizing, weakly coordinating [Al(OR(f))4](-) anion overcomes the technical difficulty of combining ionic species with alkanes in solution without the solvent molecules rapidly displacing the bound alkane ligand, as the alkanes bind in preference to the HFCs to the organometallic fragments employed in this study. The [(HEB)Re(CO)2(alkane)](+) complexes are more long-lived than the corresponding neutral alkane complexes [(HEB)W(CO)2(alkane)] and [CpRe(CO)2(alkane)] (Cp = eta(5)-cyclopentadienyl), with samples of [CpRe(CO)2(cyclopentane)] decaying significantly more rapidly than [(HEB)Re(CO)2(alkane)](+) when present in the same solution. Intramolecular exchange of the methylene group bound to the metal within the cyclopentane ligand in 16 was observed at 212 K, with the 1,2 shifts appearing to be faster than 1,3 shifts. PMID- 26645560 TI - Peptide-Drug Conjugate GnRH-Sunitinib Targets Angiogenesis Selectively at the Site of Action to Inhibit Tumor Growth. AB - The potential to heighten the efficacy of antiangiogenic agents was explored in this study based on active targeting of tumor cells overexpressing the gonadotropin-releasing hormone receptor (GnRH-R). The rational design pursued focused on five analogues of a clinically established antiangiogenic compound (sunitinib), from which a lead candidate (SAN1) was conjugated to the targeting peptide [d-Lys(6)]-GnRH, generating SAN1GSC. Conjugation of SAN1 did not disrupt any of its antiangiogenic or cytotoxic properties in GnRH-R-expressing prostate and breast tumor cells. Daily SAN1GSC treatments in mouse xenograft models of castration-resistant prostate cancer resulted in significant tumor growth delay compared with equimolar SAN1 or sunitinib alone. This efficacy correlated with inhibited phosphorylation of AKT and S6, together with reduced Ki-67 and CD31 expression. The superior efficacy of the peptide-drug conjugate was also attributed to the finding that higher amounts of SAN1 were delivered to the tumor site (~4-fold) following dosing of SAN1GSC compared with equimolar amounts of nonconjugated SAN1. Importantly, treatment with SAN1GSC was associated with minimal hematotoxicity and cardiotoxicity based on measurements of the left ventricular systolic function in treated mice. Our results offer preclinical proof-of-concept for SAN1GSC as a novel molecule that selectively reaches the tumor site and downregulates angiogenesis with negligible cardiotoxicity, thus encouraging its further clinical development and evaluation. PMID- 26645559 TI - A Molecular Host Response Assay to Discriminate Between Sepsis and Infection Negative Systemic Inflammation in Critically Ill Patients: Discovery and Validation in Independent Cohorts. AB - BACKGROUND: Systemic inflammation is a whole body reaction having an infection positive (i.e., sepsis) or infection-negative origin. It is important to distinguish between these two etiologies early and accurately because this has significant therapeutic implications for critically ill patients. We hypothesized that a molecular classifier based on peripheral blood RNAs could be discovered that would (1) determine which patients with systemic inflammation had sepsis, (2) be robust across independent patient cohorts, (3) be insensitive to disease severity, and (4) provide diagnostic utility. The goal of this study was to identify and validate such a molecular classifier. METHODS AND FINDINGS: We conducted an observational, non-interventional study of adult patients recruited from tertiary intensive care units (ICUs). Biomarker discovery utilized an Australian cohort (n = 105) consisting of 74 cases (sepsis patients) and 31 controls (post-surgical patients with infection-negative systemic inflammation) recruited at five tertiary care settings in Brisbane, Australia, from June 3, 2008, to December 22, 2011. A four-gene classifier combining CEACAM4, LAMP1, PLA2G7, and PLAC8 RNA biomarkers was identified. This classifier, designated SeptiCyte Lab, was validated using reverse transcription quantitative PCR and receiver operating characteristic (ROC) curve analysis in five cohorts (n = 345) from the Netherlands. Patients for validation were selected from the Molecular Diagnosis and Risk Stratification of Sepsis study (ClinicalTrials.gov, NCT01905033), which recruited ICU patients from the Academic Medical Center in Amsterdam and the University Medical Center Utrecht. Patients recruited from November 30, 2012, to August 5, 2013, were eligible for inclusion in the present study. Validation cohort 1 (n = 59) consisted entirely of unambiguous cases and controls; SeptiCyte Lab gave an area under curve (AUC) of 0.95 (95% CI 0.91-1.00) in this cohort. ROC curve analysis of an independent, more heterogeneous group of patients (validation cohorts 2-5; 249 patients after excluding 37 patients with an infection likelihood of "possible") gave an AUC of 0.89 (95% CI 0.85-0.93). Disease severity, as measured by Sequential Organ Failure Assessment (SOFA) score or Acute Physiology and Chronic Health Evaluation (APACHE) IV score, was not a significant confounding variable. The diagnostic utility of SeptiCyte Lab was evaluated by comparison to various clinical and laboratory parameters available to a clinician within 24 h of ICU admission. SeptiCyte Lab was significantly better at differentiating cases from controls than all tested parameters, both singly and in various logistic combinations, and more than halved the diagnostic error rate compared to procalcitonin in all tested cohorts and cohort combinations. Limitations of this study relate to (1) cohort compositions that do not perfectly reflect the composition of the intended use population, (2) potential biases that could be introduced as a result of the current lack of a gold standard for diagnosing sepsis, and (3) lack of a complete, unbiased comparison to C-reactive protein. CONCLUSIONS: SeptiCyte Lab is a rapid molecular assay that may be clinically useful in managing ICU patients with systemic inflammation. Further study in population-based cohorts is needed to validate this assay for clinical use. PMID- 26645561 TI - Deguelin Analogue SH-1242 Inhibits Hsp90 Activity and Exerts Potent Anticancer Efficacy with Limited Neurotoxicity. AB - The Hsp90 facilitates proper folding of signaling proteins associated with cancer progression, gaining attention as a target for therapeutic intervention. The natural rotenoid deguelin was identified as an Hsp90 inhibitor, but concerns about neurotoxicity have limited prospects for clinical development. In this study, we report progress on deguelin analogues that address this limitation, focusing on the novel analogue SH-1242 as a candidate to broadly target human lung cancer cells, including those that are chemoresistant or harboring KRAS mutations. In a KRAS-driven mouse model of lung cancer, SH-1242 administration reduced tumor multiplicity, volume, and load. Similarly, in human cell line-based or patient-derived tumor xenograft models, SH-1242 induced apoptosis and reduced tumor vasculature in the absence of detectable toxicity. In contrast to deguelin, SH-1242 toxicity was greatly reduced in normal cells and when administered to rats did not produce obvious histopathologic features in the brain. Mechanistic studies revealed that SH-1242 bound to the C-terminal ATP-binding pocket of Hsp90, disrupting the ability to interact with its co-chaperones and clients and triggering a degradation of client proteins without affecting Hsp70 expression. Taken together, our findings illustrate the superior properties of SH-1242 as an Hsp90 inhibitor and as an effective antitumor and minimally toxic agent, providing a foundation for advancing further preclinical and clinical studies. PMID- 26645562 TI - A Small-Molecule Antagonist of the beta-Catenin/TCF4 Interaction Blocks the Self Renewal of Cancer Stem Cells and Suppresses Tumorigenesis. AB - Wnt/beta-catenin signaling is a highly conserved pathway essential for embryogenesis and tissue homeostasis. However, deregulation of this pathway can initiate and promote human malignancies, especially of the colon and head and neck. Therefore, Wnt/beta-catenin signaling represents an attractive target for cancer therapy. We performed high-throughput screening using AlphaScreen and ELISA techniques to identify small molecules that disrupt the critical interaction between beta-catenin and the transcription factor TCF4 required for signal transduction. We found that compound LF3, a 4-thioureido benzenesulfonamide derivative, robustly inhibited this interaction. Biochemical assays revealed clues that the core structure of LF3 was essential for inhibition. LF3 inhibited Wnt/beta-catenin signals in cells with exogenous reporters and in colon cancer cells with endogenously high Wnt activity. LF3 also suppressed features of cancer cells related to Wnt signaling, including high cell motility, cell-cycle progression, and the overexpression of Wnt target genes. However, LF3 did not cause cell death or interfere with cadherin-mediated cell cell adhesion. Remarkably, the self-renewal capacity of cancer stem cells was blocked by LF3 in concentration-dependent manners, as examined by sphere formation of colon and head and neck cancer stem cells under nonadherent conditions. Finally, LF3 reduced tumor growth and induced differentiation in a mouse xenograft model of colon cancer. Collectively, our results strongly suggest that LF3 is a specific inhibitor of canonical Wnt signaling with anticancer activity that warrants further development for preclinical and clinical studies as a novel cancer therapy. PMID- 26645563 TI - Multinucleation and Mesenchymal-to-Epithelial Transition Alleviate Resistance to Combined Cabazitaxel and Antiandrogen Therapy in Advanced Prostate Cancer. AB - Patients with metastatic castration-resistant prostate cancer (CRPC) frequently develop therapeutic resistance to taxane chemotherapy and antiandrogens. Cabazitaxel is a second-line taxane chemotherapeutic agent that provides additional survival benefits to patients with advanced disease. In this study, we sought to identify the mechanism of action of combined cabazitaxel and androgen receptor (AR) targeting in preclinical models of advanced prostate cancer. We found that cabazitaxel induced mitotic spindle collapse and multinucleation by targeting the microtubule depolymerizing kinesins and inhibiting AR. In androgen responsive tumors, treatment with the AR inhibitor, enzalutamide, overcame resistance to cabazitaxel. Combination treatment of human CRPC xenografts with cabazitaxel and enzalutamide reversed epithelial-mesenchymal transition (EMT) to mesenchymal-epithelial transition (MET) and led to multinucleation, while retaining nuclear AR. In a transgenic mouse model of androgen-responsive prostate cancer, cabazitaxel treatment induced MET, glandular redifferentiation, and AR nuclear localization that was inhibited by androgen deprivation. Collectively, our preclinical studies demonstrate that prostate tumor resistance to cabazitaxel can be overcome by antiandrogen-mediated EMT-MET cycling in androgen-sensitive tumors but not in CRPC. Moreover, AR splice variants may preclude patients with advanced disease from responding to cabazitaxel chemotherapy and antiandrogen combination therapy. This evidence enables a significant insight into therapeutic cross-resistance to taxane chemotherapy and androgen deprivation therapy in advanced prostate cancer. PMID- 26645564 TI - SIGMAR1 Regulates Membrane Electrical Activity in Response to Extracellular Matrix Stimulation to Drive Cancer Cell Invasiveness. AB - The sigma 1 receptor (Sig1R) is a stress-activated chaperone that regulates ion channels and is associated with pathologic conditions, such as stroke, neurodegenerative diseases, and addiction. Aberrant expression levels of ion channels and Sig1R have been detected in tumors and cancer cells, such as myeloid leukemia and colorectal cancer, but the link between ion channel regulation and Sig1R overexpression during malignancy has not been established. In this study, we found that Sig1R dynamically controls the membrane expression of the human voltage-dependent K(+) channel human ether-a-go-go-related gene (hERG) in myeloid leukemia and colorectal cancer cell lines. Sig1R promoted the formation of hERG/beta1-integrin signaling complexes upon extracellular matrix stimulation, triggering the activation of the PI3K/AKT pathway. Consequently, the presence of Sig1R in cancer cells increased motility and VEGF secretion. In vivo, Sig1R expression enhanced the aggressiveness of tumor cells by potentiating invasion and angiogenesis, leading to poor survival. Collectively, our findings highlight a novel function for Sig1R in mediating cross-talk between cancer cells and their microenvironment, thus driving oncogenesis by shaping cellular electrical activity in response to extracellular signals. Given the involvement of ion channels in promoting several hallmarks of cancer, our study also offers a potential strategy to therapeutically target ion channel function through Sig1R inhibition. PMID- 26645565 TI - Cigarette smoking and mammographic density in the Danish Diet, Cancer and Health cohort. AB - PURPOSE: Smoking before first childbirth increases breast cancer risk, but the biological mechanism remains unknown and may involve mammographic density (MD), one of the strongest biomarkers of breast cancer risk. We aimed to examine whether active smoking and passive smoking were associated with MD. METHODS: For the 5,356 women (4,489 postmenopausal) from the Danish Diet, Cancer and Health cohort (1993-1997) who attended mammographic screening in Copenhagen (1993-2001), we used MD (mixed/dense or fatty) assessed at the first screening after cohort entry. Active smoking (status, duration, and intensity) and passive smoking were assessed at cohort baseline (1993-1997) via questionnaire, together with other breast cancer risk factors. Logistic regression was used to estimate associations (odds ratios, 95 % confidence intervals) between smoking and MD, adjusting for confounders. RESULTS: Two thousand and twenty-six (56.5 %) women had mixed/dense MD, 2,214 (41.4 %) were current, and 1,175 (21.9 %) former smokers. Current smokers had significantly lower odds (0.86, 0.75-0.99) of having mixed/dense MD compared to never smokers, while former smoking was not associated with MD. Inverse association between smoking and MD was strongest in women who initiated smoking before age of 16 years (0.79, 0.64-0.96), smoked >=15 cigarettes/day (0.83, 0.71-0.98), smoked >=5 pack-years (0.62, 0.43-0.89), smoked >30 years (0.86, 0.75-0.99), and smoked >=11 years before first childbirth (0.70, 0.51 0.96). Association between smoking and MD diminished after smoking cessation, with increased odds of having mixed/dense breasts in women who quit smoking >20 years ago as compared to current smokers (1.37, 1.01-1.67). There was no association between passive smoking and MD. CONCLUSIONS: We found an inverse association between active smoking and MD. PMID- 26645566 TI - Pharmacokinetic and pharmacometabolomic study of pirfenidone in normal mouse tissues using high mass resolution MALDI-FTICR-mass spectrometry imaging. AB - Given the importance of pirfenidone as the first worldwide-approved drug for idiopathic pulmonary fibrosis treatment, its pharmacodynamic properties and the metabolic response to pirfenidone treatment have not been fully elucidated. The aim of the present study was to get molecular insights of pirfenidone-related pharmacometabolomic response using MALDI-FTICR-MSI. Quantitative MALDI-FTICR-MSI was carried out for determining the pharmacokinetic properties of pirfenidone and its related metabolites 5-hydroxymethyl pirfenidone and 5-carboxy pirfenidone in lung, liver and kidney. To monitor the effect of pirfenidone administration on endogenous cell metabolism, additional in situ endogenous metabolite imaging was performed in lung tissue sections. While pirfenidone is highly abundant and delocalized across the whole micro-regions of lung, kidney and liver, 5 hydroxymethyl pirfenidone and 5-carboxy pirfenidone demonstrate heterogeneous distribution patterns in lung and kidney. In situ endogenous metabolite imaging study of lung tissue indicates no significant effects of pirfenidone on metabolic pathways. Remarkably, we found 129 discriminative m/z values which represent clear differences between control and treated lungs, the majority of which are currently unknown. PCA analysis and heatmap view can accurately distinguish control and treated groups. This is the first pharmacokinetic study to investigate the tissue distribution of orally administered pirfenidone and its related metabolites simultaneously in organs without labeling. The combination of pharmametabolome with histological features provides detailed mapping of drug effects on metabolism as response of healthy lung tissue to pirfenidone treatment. PMID- 26645567 TI - Intravenous high-dose interferon with or without maintenance treatment in melanoma at high risk of recurrence: meta-analysis of three trials. AB - Resected stage IIB-IIIC malignant melanoma has a poor prognosis with a high risk of relapse and death. Treatment with adjuvant interferon alfa-2b (IFN-alpha-2b) is associated with improved relapse-free and overall survivals (OS), but the most appropriate dose and duration of treatment are unknown. In this article, we present an individual patient data random effects meta-analysis of melanoma patients from the U.K., Greek, and Chinese randomized trials. All patients were randomized either to IFN-alpha-2b 15-20 MIU/m(2) IV daily 5 days per week for 4 weeks (IV) or to the same regimen followed by IFN-alpha-2b 9-10 MIU/m(2) administered three times per week for 48 weeks (IV and SC). Allowing for dose interruptions and reductions, an equivalent total dose of IFN-alpha-2b was delivered in all three studies. We assessed whether IV was noninferior to IV and SC in terms of relapse-free survival (RFS) and investigated tumor and patient characteristics that impacted on outcomes. Median follow-up of 716 stage IIB-IIIC patients was 5.4 years. Noninferiority of IV compared to IV and SC could not be conferred for RFS (hazard ratio [HR] 1.16, 95% confidence interval [CI] 0.89 1.52; noninferior P = 0.17). Stage (P < 0.0001), site (acral vs. other, P < 0.0001), and Breslow thickness (P = 0.02) were significant predictors of RFS. The HR for death was 1.13 for IV compared to IV and SC, (95% CI 0.91-1.39). Stage (P < 0.0001) and Breslow thickness (P = 0.001) were significant independent predictors of OS. The available data suggest that where adjuvant high-dose interferon is being considered there is no evidence to deviate from the year long regimen described in the Eastern Cooperative Oncology Group and Intergroup studies. PMID- 26645568 TI - Rho-Associated Kinase Inhibitor (Y-27632) Attenuates Doxorubicin-Induced Apoptosis of Human Cardiac Stem Cells. AB - BACKGROUND: Recent clinical trials using c-kit+ human cardiac stem cells (CSCs) demonstrated promising results in increasing cardiac function and improving quality of life. However, CSC efficiency is low, likely due to limited cell survival and engraftment after transplantation. The Rho-associated protein kinase (ROCK) inhibitor, Y-27632, significantly increased cell survival rate, adhesion, and migration in numerous types of cells, including stem cells, suggesting a common feature of the ROCK-mediated apoptotic pathway that may also exist in human CSCs. In this study, we examine the hypothesis that pretreatment of human CSCs with Y-27632 protects cells from Doxorubicin (Dox) induced apoptosis. METHODS AND RESULTS: c-kit+ CSCs were cultured in CSC medium for 3-5 days followed by 48 hr treatment with 0 to 10 MUM Y-27632 alone, 0 to 1.0 MUM Dox alone, or Y-27632 followed by Dox (48 hrs). Cell viability, toxicity, proliferation, morphology, migration, Caspase-3 activity, expression levels of apoptotic-related key proteins and c-kit+ were examined. Results showed that 48 hr treatment with Y-27632 alone did not result in great changes in c-kit+ expression, proliferation, Caspase-3 activity, or apoptosis; however cell viability was significantly increased and cell migration was promoted. These effects likely involve the ROCK/Actin pathways. In contrast, 48 hr treatment with Dox alone dramatically increased Caspase-3 activity, resulting in cell death. Although Y-27632 alone did not affect the expression levels of apoptotic-related key factors (p-Akt, Akt, Bcl-2, Bcl-xl, Bax, cleaved Caspase-3, and Caspase-3) under basal conditions, it significantly inhibited the Dox-induced increase in cleaved Caspase-3 and reduced cell death under Dox treatment. CONCLUSIONS: We conclude that preconditioning human CSCs with Y-27632 significantly reduces Dox induced cell death and possibly involves the cleaved Caspase-3 and ROCK/Actin pathways. The beneficial effects of Y-27632 may be applied to stem cell-based therapy to increase cell survival rates after transplantation or to act as a cardiac protective agent for Dox-treated cancer patients. PMID- 26645569 TI - Hypocellular Plaque-Like CD34-Positive Dermal Fibroma (Medallion-Like Dermal Dendrocyte Hamartoma) Presenting as a Skin-Colored Dermal Nodule. AB - Plaque-like CD34-positive dermal fibromas, also known as medallion-like dermal dendrocyte hamartomas (MDDHs), are a recently recognized group of congenital and acquired spindle cell neoplasms that may appear histologically similar to dermatofibrosarcoma protuberans. Recognizing the clinical heterogeneity of this neoplasm and the subtle pathologic differences are crucial to making the correct diagnosis and avoiding the aggressive surgical intervention required to treat a dermatofibrosarcoma protuberans. We present the case of a 9-year-old girl with an acquired variant of a plaque-like CD34-positive dermal fibroma without clinical epidermal change. Our case expands the clinical spectrum to include an acquired variant of a plaque-like CD34-positive dermal fibroma without clinical epidermal change. Examination of more cases is needed to determine whether all clinical variants are truly subtypes of the same neoplasm or represent distinct CD34 positive spindle cell proliferations. PMID- 26645570 TI - Novel Mechanism of Cytotoxicity for the Selective Selenosemicarbazone, 2 Acetylpyridine 4,4-Dimethyl-3-selenosemicarbazone (Ap44mSe): Lysosomal Membrane Permeabilization. AB - Selenosemicarbazones show marked antitumor activity. However, their mechanism of action remains unknown. We examined the medicinal chemistry of the selenosemicarbazone, 2-acetylpyridine 4,4-dimethyl-3-selenosemicarbazone (Ap44mSe), and its iron and copper complexes to elucidate its mechanisms of action. Ap44mSe demonstrated a pronounced improvement in selectivity toward neoplastic relative to normal cells compared to its parent thiosemicarbazone. It also effectively depleted cellular Fe, resulting in transferrin receptor-1 up regulation, ferritin down-regulation, and increased expression of the potent metastasis suppressor, N-myc downstream regulated gene-1. Significantly, Ap44mSe limited deleterious methemoglobin formation, highlighting its usefulness in overcoming toxicities of clinically relevant thiosemicarbazones. Furthermore, Cu Ap44mSe mediated intracellular reactive oxygen species generation, which was attenuated by the antioxidant, N-acetyl-L-cysteine, or Cu sequestration. Notably, Ap44mSe forms redox active Cu complexes that target the lysosome to induce lysosomal membrane permeabilization. This investigation highlights novel structure-activity relationships for future chemotherapeutic design and underlines the potential of Ap44mSe as a selective anticancer/antimetastatic agent. PMID- 26645571 TI - Using Linked Electronic Health Records to Estimate Healthcare Costs: Key Challenges and Opportunities. AB - This paper discusses key challenges and opportunities that arise when using linked electronic health records (EHR) in health economics and outcomes research (HEOR), with a particular focus on estimating healthcare costs. These challenges and opportunities are framed in the context of a case study modelling the costs of stable coronary artery disease in England. The challenges and opportunities discussed fall broadly into the categories of (1) handling and organising data of this size and sensitivity; (2) extracting clinical endpoints from datasets that have not been designed and collected with such endpoints in mind; and (3) the principles and practice of costing resource use from routinely collected data. We find that there are a number of new challenges and opportunities that arise when working with EHR compared with more traditional sources of data for HEOR. These call for greater clinician involvement and intelligent use of sensitivity analysis. PMID- 26645572 TI - Do Pills Have No Ills? Capturing the Impact of Direct Treatment Disutility. AB - Model-based economic evaluations should capture the impact on all costs and outcomes relevant to the chosen study perspective and time horizon. This editorial defines what is meant by direct treatment disutility (DTD) and describes why it could be an important harm that those designing model-based evaluations should consider. Some existing estimates of DTD identified from the current literature are summarised in terms of the methods used to elicit the values and the size of the estimated DTD. Model-based studies that include DTDs are also summarised. It was found that the values used within model-based economic evaluations (ranging from 0.00384 to 0.02) were typically smaller than the directly elicited values from the existing literature (0-0.033). Yet even with conservative estimates of DTDs, cost-effectiveness results were sensitive to their inclusion. The editorial concludes by discussing future methodological and empirical research needed to estimate more robust DTD values. PMID- 26645574 TI - Do mirror movements relate to hand function and timing of the brain lesion in children with unilateral cerebral palsy? AB - AIM: This study aimed to systematically map the severity of mirror movements in both hands in a prospective cohort of children with unilateral cerebral palsy, and to explore the relationship with hand function and brain lesion type. METHOD: Seventy-eight children were included (41 males, 37 females; age 9y 4mo, SD 3y 1mo, range 5-15y). Mirror movements were scored during three repetitive tasks following Woods and Teuber criteria. Strength, tone, Melbourne Assessment, Jebsen Taylor test, and Assisting Hand Assessment were evaluated. Lesions were classified into malformations (n=5), periventricular (n=43), cortico-subcortical (n=22), and postnatally acquired lesions (n=8). RESULTS: Significantly more mirror movements were observed in the non-paretic versus the paretic hand (p<=0.003). Higher mirror movement scores in the non-paretic hand significantly correlated with lower distal strength and lower scores on unimanual and bimanual assessments (r=0.29-0.41). In the paretic hand, significant differences were found between lesion types (p=0.03). INTERPRETATION: The occurrence of mirror movements in the non-paretic hand seems related to hand function while mirror movements in the paretic hand seem more related to the lesion timing, whereby children with earlier lesions present with more mirror movements. PMID- 26645573 TI - Controlled ovarian hyperstimulation induced changes in the expression of circulatory miRNA in bovine follicular fluid and blood plasma. AB - BACKGROUND: Despite its role in increasing the number of offspring during the lifetime of an individual animal, controlled ovarian hyperstimulation (COH) may have detrimental effects on oocyte development, embryo quality and endometrial receptivity. Circulating miRNAs in bio-fluids have been shown to be associated with various pathological conditions including cancers. Here we aimed to investigate the effect of COH on the level of extracellular miRNAs in bovine follicular fluid and blood plasma and elucidate their mode of circulation and potential molecular mechanisms to be affected in the reproductive tract. METHOD: Twelve simmental heifers were estrous synchronized and six of them were hyperstimulated using FSH. Follicular fluid samples from experimental animals were collected using ovum pick up technique at day 0 of the estrous cycle and blood samples were collected at day 0, 3 and 7 of post ovulation. The expression profile of circulatory miRNAs in follicular fluid and blood plasma were performed using the human miRCURY LNATM Universal RT miRNA PCR array system. A comparative threshold cycle method was used to determine the relative abundance of the miRNAs. RESULTS: A total of 504 and 402 miRNAs were detected in both bovine follicular fluid and blood plasma, respectively. Of these 57 and 21 miRNAs were found to be differentially expressed in follicular fluid and blood plasma, respectively derived from hyperstimulated versus unstimulated heifers. Bioinformatics analysis of those circulating miRNAs indicated that their potential target genes are involved in several pathways including TGF-beta signaling pathway, MAPK signaling pathway, pathways in cancer and Oocyte meiosis. Moreover, detail analysis of the mode of circulation of some candidates showed that most of the miRNA were found to be detected in both exosomal and Ago2 protein complex fraction of both follicular fluid and blood plasma. CONCLUSION: Our data provide the consequence of hyperstimulation induced changes of extracellular miRNAs in bovine follicular fluid and blood plasma, which may have a potential role in regulating genes associated not only with bovine ovarian function but also involved in altering various physiological in bovine oocytes, embryos and modulating reproductive tract environment. PMID- 26645575 TI - Evaluation of totally implantable central venous access devices with the cephalic vein cut-down approach: Usefulness of preoperative ultrasonography. AB - BACKGROUND: The aims of this retrospective study, were to evaluate totally implantable central venous access device (TICVAD) implantation and to validate the efficacy of preoperative ultrasonography. METHODS: A total of 380 cases implanted with TICVADs were divided into four groups: cut-downs with ultrasonography (group A, n = 112); cut-downs without ultrasonography (group B, n = 37); venous puncture (group C, n = 122); and replacements using the existing catheter (group D, n = 109). Operation time, completion rate, and complications were compared. RESULTS: The average operating time was 41.7, 52.4, and 40.6 min in groups A, B (P < 0.01), and C, respectively. Group A and B experienced no postoperative pneumothorax, arterial puncture, or pinch-off syndrome. Completion rates were 93.7% in group A and 86.5% in group B. Preoperative ultrasonography identified the cephalic vein in 94.1% of subjects with an average diameter of 3.1 mm and depth of 10.2 mm. Identifying convergence of the cephalic vein and the axillary vein improved the completion rate. CONCLUSIONS: This study showed that the cephalic vein cut-down approach for TICVAD implantation reduced complications. Preoperative ultrasonography resulted in a shorter operating time and higher completion rate. PMID- 26645577 TI - Paravertebral brachial plexus blockade as part of a balanced anaesthesia in a sheep undergoing thoracic limb amputation. PMID- 26645576 TI - Cumulative stress in research animals: Telomere attrition as a biomarker in a welfare context? AB - Progress in improving animal welfare is currently limited by the lack of objective methods for assessing lifetime experience. I propose that telomere attrition, a cellular biomarker of biological age, provides a molecular measure of cumulative experience that could be used to assess the welfare impact of husbandry regimes and/or experimental procedures on non-human animals. I review evidence from humans that telomere attrition is accelerated by negative experiences in a cumulative and dose-dependent manner, but that this attrition can be mitigated or even reversed by positive life-style interventions. Evidence from non-human animals suggests that despite some specific differences in telomere biology, stress-induced telomere attrition is a robust phenomenon, occurring in a range of species including mice and chickens. I conclude that telomere attrition apparently integrates positive and negative experience in an accessible common currency that translates readily to novel species--the Holy Grail of a cumulative welfare indicator. PMID- 26645578 TI - N6-methyladenosine modification in mRNA: machinery, function and implications for health and diseases. AB - N6-methyladenosine (m(6) A) modification in mRNA is extremely widespread, and functionally modulates the eukaryotic transcriptome to influence mRNA splicing, export, localization, translation, and stability. Methylated adenines are present in a large subset of mRNAs and long noncoding RNAs (lncRNAs). Methylation is reversible, and this is accomplished by the orchestrated action of highly conserved methyltransferase (m(6) A writer) and demethylase (m(6) A eraser) enzymes to shape the cellular 'epitranscriptome'. The engraved 'methyl code' is subsequently decoded and executed by a group of m(6) A reader/effector components, which, in turn, govern the fate of the modified transcripts, thereby dictating their potential for translation. Reversible mRNA methylation thus adds another layer of regulation at the post-transcriptional level in the gene expression programme of eukaryotes that finely sculpts a highly dynamic proteome in order to respond to diverse cues during cellular differentiation, immune tolerance, and neuronal signalling. PMID- 26645580 TI - Metaplastic carcinoma of the breast with widespread telangiectatic form of osteosarcomatous differentiation. PMID- 26645579 TI - Prevalence, Genetic Characterization, and 18S Small Subunit Ribosomal RNA Diversity of Trypanosoma rangeli in Triatomine and Mammal Hosts in Endemic Areas for Chagas Disease in Ecuador. AB - Trypanosoma rangeli is a nonpathogenic parasite for humans; however, its medical importance relies in its similarity and overlapping distribution with Trypanosoma cruzi, causal agent of Chagas disease in the Americas. The genetic diversity of T. rangeli and its association with host species (triatomines and mammals) has been identified along Central and the South America; however, it has not included data of isolates from Ecuador. This study reports infection with T. rangeli in 18 genera of mammal hosts and five species of triatomines in three environments (domestic, peridomestic, and sylvatic). Higher infection rates were found in the sylvatic environment, in close association with Rhodnius ecuadoriensis. The results of this study extend the range of hosts infected with this parasite and the geographic range of the T. rangeli genotype KP1(-)/lineage C in South America. It was not possible to detect variation on T. rangeli from the central coastal region and southern Ecuador with the analysis of the small subunit ribosomal RNA (SSU-rRNA) gene, even though these areas are ecologically different and a phenotypic subdivision of R. ecuadoriensis has been found. R. ecuadoriensis is considered one of the most important vectors for Chagas disease transmission in Ecuador due to its wide distribution and adaptability to diverse environments. An extensive knowledge of the trypanosomes circulating in this species of triatomine, and associated mammal hosts, is important for delineating transmission dynamics and preventive measures in the endemic areas of Ecuador and Northern Peru. PMID- 26645581 TI - The transcription factor ATF2 promotes melanoma metastasis by suppressing protein fucosylation. AB - Melanoma is one of the most lethal skin cancers worldwide, primarily because of its propensity to metastasize. Thus, the elucidation of mechanisms that govern metastatic propensity is urgently needed. We found that protein kinase Cepsilon (PKCepsilon)-mediated activation of activating transcription factor 2 (ATF2) controls the migratory and invasive behaviors of melanoma cells. PKCepsilon dependent phosphorylation of ATF2 promoted its transcriptional repression of the gene encoding fucokinase (FUK), which mediates the fucose salvage pathway and thus global cellular protein fucosylation. In primary melanocytes and cell lines representing early-stage melanoma, the abundance of PKCepsilon-phosphorylated ATF2 was low, thereby enabling the expression of FUK and cellular protein fucosylation, which promoted cellular adhesion and reduced motility. In contrast, increased expression of the gene encoding PKCepsilon and abundance of phosphorylated, transcriptionally active ATF2 were observed in advanced-stage melanomas and correlated with decreased FUK expression, decreased cellular protein fucosylation, attenuated cell adhesion, and increased cell motility. Restoring fucosylation in mice either by dietary fucose supplementation or by genetic manipulation of murine Fuk expression attenuated primary melanoma growth, increased the number of intratumoral natural killer cells, and decreased distal metastasis in murine isograft models. Tumor microarray analysis of human melanoma specimens confirmed reduced fucosylation in metastatic tumors and a better prognosis for primary melanomas that had high abundance of fucosylation. Thus, inhibiting PKCepsilon or ATF2 or increasing protein fucosylation in tumor cells may improve clinical outcome in melanoma patients. PMID- 26645583 TI - The microRNA miR-485 targets host and influenza virus transcripts to regulate antiviral immunity and restrict viral replication. AB - MicroRNAs (miRNAs) are small noncoding RNAs that are responsible for dynamic changes in gene expression, and some regulate innate antiviral responses. Retinoic acid-inducible gene I (RIG-I) is a cytosolic sensor of viral RNA; RIG-I activation induces an antiviral immune response. We found that miR-485 of the host was produced in response to viral infection and targeted RIG-I mRNA for degradation, which led to suppression of the antiviral response and enhanced viral replication. Thus, inhibition of the expression of mir-485 markedly reduced the replication of Newcastle disease virus (NDV) and the H5N1 strain of influenza virus in mammalian cells. Unexpectedly, miR-485 also bound to the H5N1 gene PB1 (which encodes an RNA polymerase required for viral replication) in a sequence specific manner, thereby inhibiting replication of the H5N1 virus. Furthermore, miR-485 exhibited bispecificity, targeting RIG-I in cells with a low abundance of H5N1 virus and targeting PB1 in cells with increased amounts of the H5N1 virus. These findings highlight the dual role of miR-485 in preventing spurious activation of antiviral signaling and restricting influenza virus infection. PMID- 26645582 TI - Pleiotrophin promotes vascular abnormalization in gliomas and correlates with poor survival in patients with astrocytomas. AB - Glioblastomas are aggressive astrocytomas characterized by endothelial cell proliferation and abnormal vasculature, which can cause brain edema and increase patient morbidity. We identified the heparin-binding cytokine pleiotrophin as a driver of vascular abnormalization in glioma. Pleiotrophin abundance was greater in high-grade human astrocytomas and correlated with poor survival. Anaplastic lymphoma kinase (ALK), which is a receptor that is activated by pleiotrophin, was present in mural cells associated with abnormal vessels. Orthotopically implanted gliomas formed from GL261 cells that were engineered to produce pleiotrophin showed increased microvessel density and enhanced tumor growth compared with gliomas formed from control GL261 cells. The survival of mice with pleiotrophin producing gliomas was shorter than that of mice with gliomas that did not produce pleiotrophin. Vessels in pleiotrophin-producing gliomas were poorly perfused and abnormal, a phenotype that was associated with increased deposition of vascular endothelial growth factor (VEGF) in direct proximity to the vasculature. The growth of pleiotrophin-producing GL261 gliomas was inhibited by treatment with the ALK inhibitor crizotinib, the ALK inhibitor ceritinib, or the VEGF receptor inhibitor cediranib, whereas control GL261 tumors did not respond to either inhibitor. Our findings link pleiotrophin abundance in gliomas with survival in humans and mice, and show that pleiotrophin promotes glioma progression through increased VEGF deposition and vascular abnormalization. PMID- 26645584 TI - Enhanced Performance of Polymer Solar Cells Comprising Diketopyrrolopyrrole-Based Regular Terpolymer Bearing Two Different pi-Extended Donor Units. AB - New regular and random diketopyrrolopyrrole (DPP)-based terpolymers (i.e., Reg PBDPPT and Ran-PBDPPT, respectively) bearing DPP as an electron deficient unit and 2,2'-bithiophene and (E)-1,2-di(thiophen-2-yl)ethene as electron donating units were designed and synthesized, and their performance in photovoltaic cells was investigated precisely. The absorption properties and highest occupied molecular orbital (HOMO) of Reg-PBDPPT were found to be different from those of Ran-PBDPPT. The results of grazing incidence X-ray diffraction experiments revealed that Ran-PBDPPT typically had a predominantly edge-on chain orientation on the substrate, whereas Reg-PBDPPT showed mixed chain orientation both in pristine and thermally annealed films. Although Reg-PBDPPT exhibited a lower degree of edge-on chain orientation on the substrate, the corresponding TFTs showed a high hole mobility of 0.42-0.96 cm(2) V(-1) s(-1) and maintained a high current on/off ratio (>10(6)). A polymer solar cell (PSC) composed of Reg-PBDPPT and PC71BM exhibited power conversion efficiencies (PCE) of 5.24-5.45%, which were higher than those of the Ran-PBDPPT-based PSCs. The enhanced efficiency was supported by an increase in the short circuit current, which is strongly related to the unique internal crystalline morphology and pronounced nanophase segregation behavior in the blend films. These results obviously manifested that this synthetic strategy for regular conjugated terpolymers could be employed to control morphological properties to obtain high-performance PSCs. PMID- 26645585 TI - Diphenylarsinic Acid Induced Activation of Cultured Rat Cerebellar Astrocytes: Phosphorylation of Mitogen-Activated Protein Kinases, Upregulation of Transcription Factors, and Release of Brain-Active Cytokines. AB - Diphenylarsinic acid (DPAA) was detected as the primary compound responsible for the arsenic poisoning that occurred in Kamisu, Ibaraki, Japan, where people using water from a well that was contaminated with a high level of arsenic developed neurological (mostly cerebellar) symptoms and dysregulation of regional cerebral blood flow. To understand the underlying molecular mechanism of DPAA-induced cerebellar symptoms, we focused on astrocytes, which have a brain-protective function. Incubation with 10 uM DPAA for 96 h promoted cell proliferation, increased the expression of antioxidative stress proteins (heme oxygenase-1 and heat shock protein 70), and induced the release of cytokines (MCP-1, adrenomedullin, FGF2, CXCL1, and IL-6). Furthermore, DPAA overpoweringly increased the phosphorylation of three major mitogen-activated protein kinases (MAPKs) (ERK1/2, p38MAPK, and SAPK/JNK), which indicated MAPK activation, and subsequently induced expression and/or phosphorylation of transcription factors (Nrf2, CREB, c-Jun, and c-Fos) in cultured rat cerebellar astrocytes. Structure activity relationship analyses of DPAA and other related pentavalent organic arsenicals revealed that DPAA at 10 uM activated astrocytes most effective among organic arsenicals tested at the same dose. These results suggest that in a cerebellum exposed to DPAA, abnormal activation of the MAPK-transcription factor pathway and irregular secretion of these neuroactive, glioactive, and/or vasoactive cytokines in astrocytes can be the direct/indirect cause of functional abnormalities in surrounding neurons, glial cells, and vascular cells: This in turn might lead to the onset of cerebellar symptoms and disruption of cerebral blood flow. PMID- 26645586 TI - Iron-dependent lysosomal dysfunction mediated by a natural product hybrid. AB - Artesumycin is a fluorescent hybrid of the natural products marmycin A and artemisinin. It was designed to combine the lysosomotropic properties of the angucycline and the iron-reactive capacity of the endoperoxide to target the lysosomal compartment of cancer cells. Herein, we show that artesumycin inhibits cancer cell proliferation in an iron-dependent manner and chemically fragments in vitro in the presence of redox-active iron(ii). Visual detection of artesumycin by fluorescence microscopy provided substantial evidence that the small molecule selectively targets lysosomes. This original approach based on a fluorescent and iron-reactive probe represents a powerful strategy for initiating and, concomitantly, visualizing lysosomal dysfunction in human cells. PMID- 26645587 TI - Doctors' group urges Congress to lift ban on gun violence research. PMID- 26645588 TI - No effect on QT intervals of mipomersen, a 2'-O-methoxyethyl modified antisense oligonucleotide targeting ApoB-100 mRNA, in a phase I dose escalation placebo controlled study, and confirmed by a thorough QT (tQT) study, in healthy subjects. AB - PURPOSE: The aim of this study to evaluate the effect of mipomersen on QT intervals in a phase I dose escalation, placebo-controlled study, and a thorough QT (tQT) study in healthy subjects. METHODS: In the initial phase I study, 29 healthy subjects received either single or multiple (for 4 weeks) ascending doses of mipomersen (50-400 mg) administered subcutaneously (SC) or via a 2-h intravenous (IV) infusion, and 7 subjects received placebo. In the confirmative tQT study, 58 healthy subjects received placebo, 400 mg IV moxifloxacin, 200 mg SC, or 200 mg IV of mipomersen in a double-blind, 4-way crossover design with a minimum 5-day washout between treatments. ECG measurements were performed at baseline and selected time points (including Tmax). The correlation between QTcF intervals corrected for baseline and time-matched placebo when available with PK plasma exposure was evaluated by linear regression analysis. RESULTS: In the phase I study, no positive correlation between the PK exposure and ?QTcF or ??QTcF was observed within the wide dose or exposure range tested. Similar results were observed in the tQT study, where the predicted DeltaDeltaQTcF and its upper bound of the 90% CI at Cmax of therapeutic and supratherapeutic dose were approximately -1.7 and 2.9 ms, respectively. CONCLUSIONS: Mipomersen showed no effect on QT intervals in both the phase I dose escalation study and the tQT study. These results support the proposal that QT assessment can be made in a phase I dose escalation study, and no tQT study may be necessary if the phase I dose escalation study showed a negative QT effect. PMID- 26645589 TI - Inferior retinotomy and silicone oil tamponade for recurrent inferior retinal detachment and grade C PVR in eyes previously treated with pars plana vitrectomy or scleral buckle. AB - BACKGROUND: One of the most challenging problems in vitro-retinal surgery is the recurrence of retinal detachment in the context of high-grade proliferative vitreoretinopathy (PVR). The aim of our retrospective study was to assess the surgical outcomes of pars plana vitrectomy, 180 degrees inferior retinotomy and silicone oil tamponade combined with phacoemulsification and IOL implantation for recurrent inferior retinal detachment with grade C PVR in phakic eyes. The study was carried out at tertiary referral centre - University Hospital of Rome "Tor Vergata". METHODS: Retrospective analysis of 33 eyes affected by recurrent inferior retinal detachment and grade C PVR after primary encircle scleral buckling (SB group - 12 eyes), or pars plana vitrectomy (PPV group - 21 eyes). All patients subsequently underwent PPV and silicone oil tamponade at our Institution. The first outcome measure was retinal reattachment, and second outcomes were reoperation rates, best-corrected visual acuity (BCVA) and postoperative complications. RESULTS: All patients in the SB group and 19 (90%) patients of the PPV group achieved retinal reattachment. Final BCVA was better in the SB group (p = 0.045). Two eyes in the PPV group required a third vitrectomy with heavy silicone oil tamponade. Postoperative complications included silicone oil in a deep anterior chamber (3 eyes in each group), untreatable hypotony in 1 eye in the PPV group (that led to enucleation due to phthisis bulbi), and elevated intraocular pressure in 3 patients (2 eyes in the PPV group). CONCLUSIONS: Phacoemulsification with IOL implant, PPV with silicone oil tamponade associated with 180 degrees inferior retinotomy may lead to better anatomical success in patients who have previously undergone SB procedure for inferior retinal detachment repair compared with eyes that underwent a primary PPV. PMID- 26645591 TI - Global Registry of Acute Coronary Events (GRACE) Risk Score as a Predictor of In hospital Mortality for Acute Coronary Syndrome in Trinidad and Tobago. AB - Objective: To determine whether risk stratification using the Global Registry of Acute Coronary Events (GRACE) risk score is a predictor of in-hospital mortality for patients with acute coronary syndrome (ACS) in a multi-ethnic Caribbean population. Method: During a six-month period, all patients meeting the GRACE diagnostic criteria for one of the acute coronary syndromes were entered into a prospective single-centre study at one of the major public hospitals in Trinidad and Tobago. Clinical data, the GRACE risk score and in-hospital morbidity and mortality were recorded. Patients were placed into three GRACE risk categories: low, intermediate or high risk. Results: There were 372 patients (mean age 63 years; males 56% and females 44%; hypertension 69%, diabetes mellitus 58%, positive smoking history 43%, previous myocardial infarction 34%), of which 25% were ST-segment elevation myocardial infarction, 56% non-ST-segment myocardial infarction and 19% unstable angina pectoris. In-hospital mortality was 8.3%. There were 35%, 33% and 32% of patients in the high, intermediate and low GRACE risk categories, respectively. The GRACE risk score demonstrated good discrimination (C statistic 0.82, 95% CI 0.755, 0879; p < 0.001) and good calibration (Hosmer-Lemeshow; p = 0.096) for in-hospital mortality in this ACS cohort. Conclusion: The GRACE risk score was found to be a reliable predictor of in-hospital mortality in this ACS population and therefore can be used to identify those high-risk patients who may benefit from aggressive management strategies, thereby allowing for more effective use of limited resources. PMID- 26645590 TI - A microfluidic ExoSearch chip for multiplexed exosome detection towards blood based ovarian cancer diagnosis. AB - Tumor-derived circulating exosomes, enriched with a group of tumor antigens, have been recognized as a promising biomarker source for cancer diagnosis via a less invasive procedure. Quantitatively pinpointing exosome tumor markers is appealing, yet challenging. In this study, we developed a simple microfluidic approach (ExoSearch) which provides enriched preparation of blood plasma exosomes for in situ, multiplexed detection using immunomagnetic beads. The ExoSearch chip offers a robust, continuous-flow design for quantitative isolation and release of blood plasma exosomes in a wide range of preparation volumes (10 MUL to 10 mL). We employed the ExoSearch chip for blood-based diagnosis of ovarian cancer by multiplexed measurement of three exosomal tumor markers (CA-125, EpCAM, CD24) using a training set of ovarian cancer patient plasma, which showed significant diagnostic power (a.u.c. = 1.0, p = 0.001) and was comparable with the standard Bradford assay. This work provides an essentially needed platform for utilization of exosomes in clinical cancer diagnosis, as well as fundamental exosome research. PMID- 26645592 TI - The Epidemiology of Prostate Cancer in Western Jamaica: Risk Factors, Knowledge, Attitudes and Practices. AB - Objectives: To investigate the epidemiology of prostate cancer (PCa) in western Jamaica and describe the health-seeking behaviour of at-risk men. Methods: This study contained both quantitative and qualitative components. The quantitative portion consisted of a retrospective, matched case-control study of two hundred and four men attending outpatient clinics who completed an interviewer administered questionnaire. The qualitative component consisted of two focus group discussions designed to further investigate health-seeking behaviour and preferred educational channels regarding PCa. Results: Four risk factors were identified: family history of PCa (OR 3.39, 95% CI 1.73, 6.66), age (OR 1.97, 95% CI 1.41, 2.74), any sexually transmitted disease (STD) history (OR 2.02, 95% CI 1.07, 3.83) and alcohol consumption (OR 1.86, 95% CI 1.00, 3.47). Knowledge of primary risk factors was low, especially for race (37%). Although 81% of controls knew tests were available, a stigma was associated with testing. The screening rate was higher than previously reported but still low (56% of controls), and PCa in the western region is discovered by symptoms 61% of the time. Focus group participants blamed a "male mentality" that is antagonistic to routine medical care and preventive testing. Conclusions: Family history, age, STDs and alcohol consumption were identified as risk factors for PCa in western Jamaica. Sexually transmitted disease history and alcohol consumption are interesting results that merit further investigation. Prostate cancer continues to be diagnosed primarily by symptoms, indicating that routine testing is not widespread enough to catch the disease in its early stages when treatment is most effective. A negative image of prostate screenings persists, and targeted educational interventions are needed to improve outcomes. PMID- 26645593 TI - Prostate Cancer Knowledge, Attitudes and Screening Practices among Men in Western Jamaica. AB - Background: African-Caribbean men, particularly Jamaican men, have one of the highest incidences of prostate cancer in the world. This cross-sectional study was conducted to investigate knowledge, attitudes, practices and factors associated with prostate cancer screening among men in western Jamaica. Methods: A questionnaire was administered to men 40-93 years old during May to August 2007. The outcome variable of interest was previous prostate cancer screening. Results: Approximately 35% of men were previously screened for prostate cancer. Men > 70 years were 93% less likely to be screened compared to men 40-49 years (95% CI: 0.01, 0.56). Men living in the parish of Trelawny were 10.5 times more likely not to be screened compared to men in St James (95% CI: 2.33, 47.17) and manual labourers were 5.5 times less likely to have been screened than non-manual labourers (95% CI: 0.97, 31.68). Men who had not been advised to have prostate cancer screening were 92% less likely to be screened than those advised (95% CI: 0.02, 0.29), and men who were not sure of how frequently screening should be conducted were 6.1 times more likely not to be screened compared to those who knew that screening should be conducted annually (95% CI: 1.10, 33.35). Men who visit healthcare providers only when they feel sick were 6.4 times more likely not to be screened compared to men who visit annually (95% CI: 1.63, 25.41). Conclusion: A substantial proportion of Jamaican men >= 40 years had never been screened for prostate cancer. Interventions should be instituted to make prostate cancer screening readily available and to promote active participation of men in these programmes especially men >= 70 years, men with less economic resources, and men who do not routinely visit a physician or health facility. PMID- 26645594 TI - The Diagnostic Value of FibroScan in Assessing Significant Liver Fibrosis in Patients with Chronic Hepatitis B. AB - Objective: Significant liver fibrosis is recognized as the key link of therapy and prognosis in patients with chronic hepatitis B infection (CHB). The present study is designed to estimate the benefits of FibroScan (FS) in diagnosing significant fibrosis in patients with CHB. Methods: Two hundred and eight consecutive CHB patients, who underwent liver biopsy, FS and laboratory tests, were recruited. The receiver operating characteristic (ROC) curves were generated to assess the performance of non-invasive models. Results: Liver stiffness measurement (LSM) and aspartate transaminase (AST) to platelet (PLT) ratio index (APRI), but not age-platelet index (API) or AST to alanine aminotransferase (ALT) ratio (AAR), were closely correlated with significant fibrosis; areas under ROC curves (AUROC) were 0.817 (p < 0.001), 0.705 (p = 0.003), 0.626 (p = 0.065) and 0.631 (p = 0.055), respectively. When combining LSM with APRI, the AUROC was 0.813, p < 0.001. Conclusion: FibroScan can predict the presence of significant liver fibrosis, so as to avoid liver biopsy. It seems that the combination of FS and APRI does not significantly improve the ability to predict significant fibrosis. PMID- 26645595 TI - Can Mean Platelet Volume Be a Surrogate Marker of Inflammation in Rheumatic Diseases? AB - Background: In humans, it has been suggested that low-level mean platelet volume (MPV) may be related to secondary thrombosis due to inflammation. For this reason, MPV can be used as a marker showing inflammation in the body. Objectives: To evaluate the association of MPV with erythrocyte sedimentation rate (ESR), C reactive protein (CRP), Disease Activity Score-28 (DAS-28), and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) in patients with rheumatic diseases. Methods: The study consisted of 261 patients with rheumatoid arthritis (203 females, 77.8%; 58 males, 22.2%), 85 patients with ankylosing spondylitis (57 males, 67.1%; 28 females, 32.9%), 56 patients with familial Mediterranean fever (32 females, 57.1%; 24 males, 42.9%) and 194 patients (139 females, 71.6%; 55 males, 28.4%) with other rheumatic diseases (Behcet's disease, psoriatic arthritis, spondyloarthropathy, systemic lupus erythematosus, systemic sclerosis, or undifferentiated connective tissue disease). Results: There was an inversely significant correlation between MPV and ESR and CRP in patients with rheumatoid arthritis (r = -0.164, p = 0.008). Mean platelet volume was negatively correlated with DAS-28-ESR/CRP (r = -0.393, p < 0.001) in rheumatoid arthritis. Mean platelet volume was inversely correlated with BASDAI (r = -0.580, p < 0.001) in ankylosing spondylitis. In the group with familial Mediterranean fever (especially M694V homozygous), there was a negative correlation between MPV and ESR and CRP (p < 0.001). Mean platelet volume and CRP were negatively correlated in psoriatic arthritis (r = -0.599, p = 0.011). Mean platelet volume and ESR were inversely related in patients with systemic lupus erythematosus (r = -0.421, p = 0.045). There was a negative correlation between MPV and ESR (r = -0.219, p = 0.002), and between MPV and CRP (r = -0.208, p = 0.004) in other rheumatic diseases. Conclusions: The lower MPV level surrogates active and/or chronic inflammatory state in the body. Thus, MPV may be used as a negative acute-phase reactant in rheumatic diseases. PMID- 26645596 TI - Medication Adherence and Health Insurance/Health Benefit in Adult Diabetics in Kingston, Jamaica. AB - Objective: To determine the association between health insurance/health benefit and medication adherence amongst adult diabetic patients in Kingston, Jamaica. Methods: This was a cross-sectional study. The target population was diabetics who attended the diabetic outpatient clinics in health centres in Kingston. Two health centres were selectively chosen in Kingston. All diabetic patients attending the diabetic clinics and over the age of 18 years were conveniently sampled. The sample size was 260. An interviewer-administered questionnaire was utilized which assessed health insurance/health benefit. Adherence was measured by patients' self-reports of medication usage in the previous week. The Chi squared test was used to determine the significance of associations. Results: Sample population was 76% female and 24% male. Type 2 diabetics comprised 93.8%. More than 95% of patients were over the age of 40 years. Approximately 32% of participants were employed. Approximately 75% of patients had health insurance/health benefit. Among those who had health insurance or health benefit, 71.5% were adherent and 28.5% were non-adherent. This difference was statistically significant (chi2 = 6.553, p = 0.01). Prevalence of medication non adherence was 33%. Conclusions: AIn Kingston, diabetic patients who are adherent are more likely to have health insurance/health benefit (p = 0.01). PMID- 26645597 TI - Molecular Advancements in Forensic Odontology. AB - Forensic odontology explores the field of human identification through dental tissues in cases where there is the destruction of body tissues in criminal investigations and mass disasters. Forensic odontology involves dentists participating in legal and criminal issues. Parameters such as age and gender identification are important in identifying the person or persons. Over the last two decades, the molecular aspect of forensic sciences has increased, and these molecular techniques now provide a novel approach to forensic odontology. Molecular advancements in science like DNA analysis have extended the range of forensic dentistry, as teeth possess the character of resistance toward physical or chemical aggressions. Teeth provide the abundant space for DNA, and hence teeth represent an excellent source of genomic DNA. The present paper focusses on molecular advancements in the field of forensic odontology. PMID- 26645598 TI - Assessment of Workplace Stigma and Discrimination among People Living with HIV/AIDS Attending Antiretroviral Clinics in Health Institutions in Enugu, Southeast Nigeria. AB - Objective: The onset of HIV/AIDS has increased stigma and discrimination at workplaces, making those with these ailments worried about going to work to avoid being victimized. Most previous works focussed on stigma and discrimination in the communities with little emphasis on what occurs in the workplaces. This study assessed the prevalence of workplace stigma and discrimination among people living with HIV/AIDS (PLWHA) attending antiretroviral (ARV) clinics in health institutions in Enugu, southeast Nigeria. Methods: A cross-sectional descriptive study was done between February and May of 2014 using a selfadministered questionnaire to assess 489 PLWHA attending ARV clinics. Results: Out of 489 studied, 255 (52.1%) were females. About 23.7% said being HIV positive had affected their relationship with other workers and 20.7% were blamed for their condition. Some were not given time off to go to hospital (72.5%). The commonest fears of PLWHA were stigmatization/discrimination from other workers (78.1%) and dying from the disease (62.8%). Gender did not significantly affect the way PLWHA were stigmatized or discriminated against in their workplaces. However, those who were employed in private establishments were more likely to have their schedule changed due to their status compared to government employees (p < 0.01). Other discriminating practices were not significantly different between government and private employees. Conclusion: The prevalence of stigma and discrimination in workplaces is high. Efforts should be made by agencies to reduce such social problems in the workplace since they can affect overall management and productivity. PMID- 26645599 TI - Impact of the 'Providing Access to Continued Education' Programme on Repeat Teenage Pregnancy in the Bahamas. AB - Objective: To determine the relationship of determinants such as age, ethnicity, education and sexual behaviour with repeat teenage pregnancy and to determine the impact of 'Providing Access to Continued Education' (PACE) programme in reducing repeat teenage pregnancy amongst its participants in The Bahamas. Subjects and Methods: This retrospective cohort study included 397 attendees of the Adolescent Health Centre (AHC). Eighty-eight out of 139 registered participants completed the PACE programme. Data on age, ethnicity, education, sexual behaviour and repeat pregnancy in two years were analysed for descriptive statistics, and association of demographic characteristics and participation in the PACE programme with repeat pregnancy using the Chi-squared test. Results: Mean age of participants was 16.4 +/- 1.1 years; median school grade and mean grade point average (GPA) was 11 and 1.97 +/- 0.7, respectively. The mean age at the first sexual activity was 14.9 +/- 1.2 years. The mean age and number of sexual partners were 21 +/- 4.3 years and 2 +/- 1, respectively. Overall, repeat pregnancy rate was 39%: 37.4% amongst PACE registered and 31.8% amongst PACE completed mothers. No significant difference was observed in repeat pregnancy between registered and non-registered as well as those who completed the programme and those who did not. The odds ratio of 0.525 suggested that completion of the PACE programme had a moderate protective effect on reducing repeat pregnancy. Conclusions: Age, ethnicity, education and sexual behaviour showed no association with repeat pregnancy. The PACE programme did not reduce repeat pregnancy rate significantly. However, completion of the programme offered a moderate protection. PMID- 26645600 TI - State and Regional Differences in the Male-to-Female Ratio at Birth in the United States of America, 1995-2012. AB - Introduction: In humans, live male births slightly exceed females and this ratio is conventionally expressed as male live births divided by total live births (M/F). A wide variety of factors have been shown to influence M/F including latitude, stress, socio-economic status and race. This study was carried out in order to ascertain whether there are differences in M/F in different states and in different geographical regions in the United States of America (USA). Methods: Annual live births by gender for the period 1995-2012 were obtained from the website of the US Centers for Disease Control and Prevention. These were grouped according to the four regions devised by the United States Census Bureau, Geography Division. Results: This study encompassed 52 601 559 live births for the period 1995-2012 (M/F: 0.5117; 95% CL: 0.5116, 0.5118). Southern states tended to have a lower male-to-female ratio. Hawaii had a high M/F (p < 0.0001). The male-to-female ratio for the South region was significantly less (p = 0.004). This region had the highest proportion of Black mothers. Conclusion: The high Hawaiian M/F is in keeping with Micronesian island findings. The M/F latitude gradient accords with that previously noted in the USA. Historically, Blacks have been shown to have a lower M/F than other races. Long-term stress related to maternal socio-economic status has also been shown to influence M/F, and Blacks are known to be disadvantaged to this day. It is possible that the low M/F historically noted in this race may be due to chronically poor socio-economic circumstances. PMID- 26645602 TI - Technical aspects of resolution recovery reconstruction. AB - Technological advances in processing have allowed nuclear cardiology labs to increase efficiency as well as reduce radiation exposure to both patients and staff. With increased awareness on reduced radiation exposure, efficiency and quality resolution recovery reconstruction is a perfect fit for nuclear cardiology. Having a basic understanding of what is required as well as being aware of the potential pitfalls can provide some clarity on how to incorporate resolution recovery reconstruction into the existing workflow of a nuclear cardiology lab. PMID- 26645603 TI - Anthracycline-induced cardiomyopathy: The search continues. PMID- 26645604 TI - Atorvastatin restricts HIV replication in CD4+ T cells by upregulation of p21. AB - OBJECTIVE: Antigen persistence due to HIV is a major source of inflammation and substantial immune activation, both of which are linked to accelerated aging. This illustrates the need to reduce immune activation in these patients and subsequently decrease the risk of cardiovascular diseases and other non-AIDS defining comorbidities. METHODS: CD4 T cells were infected with HIV-1 isolates in the presence or absence of atorvastatin (0.25 to 1 MUg/ml) for 24-48 h. Atorvastatin-induced anti-inflammatory functions and anti-viral replication were measured in vitro. RESULTS: Atorvastatin, a lipid-lowering medication, exerted a broad spectrum of anti-inflammatory functions by reducing T-cell immune activation markers (e.g. CD38, HLA-DR and Ki67), lowering HIV-1 co-receptor CCR 5, and decreasing proliferative capabilities of CD4 T cells in vitro. In contrast, atorvastatin expanded regulatory T cells (Tregs) and upregulated the expression of T-cell immunoglobulin and ITIM domain (TIGIT), which enhanced the suppressive activity of Tregs. Furthermore, atorvastatin upregulated the cyclin dependent kinase inhibitor p21, which is also known as cip-1 and waf-1, in the CD4 T cells. Upregulation of p21 in CD4 T cells rendered them less susceptible to HIV-1 infection and replication whereas siRNA-mediated p21 depletion and/or p21 selective inhibitor rescued viral replication. Interestingly, atorvastatin reduced HIV infection in both rested and phytohemagglutinin-activated CD4 T cells in vitro. Finally, atorvastatin mediated p21 upregulation occurred via mevalonate pathway, but independent of p53. CONCLUSION: The results demonstrate a novel mechanism by which atorvastatin induced resistance of CD4 T cells to HIV-1 infection via p21 upregulation and suggest that statins may hold particular promise for some HIV-infected individuals. PMID- 26645606 TI - Romidepsin reverses HIV-1 latency in vivo. PMID- 26645605 TI - CD4+ T-cell recovery with suppressive ART-induced rapid sequence evolution in hepatitis C virus envelope but not NS3. AB - OBJECTIVES: CD4 T-cell depletion from HIV infection leads to a global decline in anti-hepatitis C virus (HCV) envelope neutralizing antibody (nAb) response, which may play a role in accelerating liver fibrosis. An increase in anti-HCV nAb titers has been reported during antiretroviral therapy (ART) but its impact on HCV remains poorly understood. The objective of this study is to determine the effects of ART on long-term HCV evolution. DESIGN AND METHODS: We examined HCV quasispecies structure and long-term evolution in HIV/HCV coinfected patients with ART-induced CD4 T-cell recovery, and compared with patients with CD4 T-cell depletion from delayed ART. We applied a single-variant sequencing (SVS) method to construct authentic viral quasispecies and compared sequence evolution in HCV envelope, the primary target for humoral immune responses, and NS3, a target for cellular immunity, between the two cohorts. RESULTS: The SVS method corrected biases known to skew the proportions of viral variants, revealing authentic HCV quasispeices structures. We observed higher rates of HCV envelope sequence evolution in patients with ART-induced CD4 T-cell recovery, compared with patients with CD4 T-cell depletion from delayed ART (P = 0.03). Evolutionary rates for NS3 were considerably lower than the rates for envelope (P < 0.01), with no significant difference observed between the two groups. CONCLUSION: ART induced CD4 T-cell recovery results in rapid sequence evolution in HCV envelope, but not in NS3. These results suggest that suppressive ART disproportionally enhances HCV-specific humoral responses more than cellular responses, resulting in rapid sequence evolution in HCV envelope but not NS3. PMID- 26645607 TI - Protease inhibitor monotherapy for long-term management of HIV infection. PMID- 26645608 TI - WHO releases a 'treat-all' recommendation for HIV patients. PMID- 26645609 TI - The effects of the Affordable Care Act on low-income patients with HIV. PMID- 26645611 TI - Conformational Switching and Nanoscale Assembly of Human Prion Protein into Polymorphic Amyloids via Structurally Labile Oligomers. AB - Conformational switching of the prion protein (PrP) from an alpha-helical normal cellular form (PrP(C)) to an aggregation-prone and self-propagating beta-rich scrapie form (PrP(Sc)) underlies the molecular basis of pathogenesis in prion diseases. Anionic lipids play a critical role in the misfolding and conformational conversion of the membrane-anchored PrP into the amyloidogenic pathological form. In this work, we have used a diverse array of techniques to interrogate the early intermediates during amyloid formation from recombinant human PrP in the presence of a membrane mimetic anionic detergent such as sodium dodecyl sulfate. We have been able to detect and characterize two distinct types of interconvertible oligomers. Our results demonstrate that highly ordered large beta-oligomers represent benign off-pathway intermediates that lack the ability to mature into amyloid fibrils. On the contrary, structurally labile small oligomers are capable of switching to an ordered amyloid-state that exhibits profound toxicity to mammalian cells. Our fluorescence resonance energy transfer measurements revealed that the partially disordered PrP serves as precursors to small amyloid-competent oligomers. These on-pathway oligomers are eventually sequestered into higher order supramolecular assemblies that conformationally mature into polymorphic amyloids possessing varied nanoscale morphology as evident by the atomic force microscopy imaging. The nanoscale diversity of fibril architecture is attributed to the heterogeneous ensemble of early obligatory oligomers and offers a plausible explanation for the existence of multiple prion strains in vivo. PMID- 26645612 TI - Double polymer sheathed carbon nanotube supercapacitors show enhanced cycling stability. AB - Pseudo-materials are effective in boosting the specific capacitance of supercapacitors, but during service their degradation may also be very strong, causing reduced cycling stability. Here, we show that a carbon nanotube sponge grafted by two conventional pseudo-polymer layers in sequence can serve as a porous supercapacitor electrode with significantly enhanced cycling stability compared with single polymer grafting. Creating conformal polymer coatings on the nanotube surface and the resulting double-sheath configuration are important structural factors leading to the enhanced performance. Combining different polymers as double sheaths as reported here might be a potential route to circumvent the dilemma of pseudo-materials, and to simultaneously improve the capacitance and stability for various energy storage devices. PMID- 26645613 TI - Disparities in Maternal Child and Health Outcomes Attributable to Prenatal Tobacco Use. AB - OBJECTIVES: Previous estimates of smoking-attributable adverse outcomes, such as preterm births (PTBs), low birth weight (LBW) and Sudden Infant Death Syndrome (SIDs) generally do not address disparities by maternal age, racial/ethnic group or socioeconomic status (SES). This study develops estimates of smoking attributable PTB, LBW and SIDS for the US by age, SES and racial/ethnic groupings. METHODS: Data on the number of births and the prevalence of PTB, LBW and SIDS were used to develop the number of outcomes by age, race/ethnicity, and SES. The prevalence of prenatal smoking by age, race/ethnic and education and the relative risk of outcomes for smokers were used to calculate smoking-attributable fractions of outcomes. RESULTS: Prenatal smoking among ages 15-24 is above 12 %, with 20-24 year olds representing at least 35 % of PTB, LBW SIDS cases. Women with a high school education or less represented more than 50 % of PTB and LBW births, and 44 % of SIDS cases. While non-Hispanic Whites had the majority of smoking-attributable outcomes, non-Hispanic Blacks represented a disproportionately high percentage of PTBs (18 %), LBW births (22 %), and SIDS cases (13 %). CONCLUSIONS: Reducing prenatal smoking has the potential to reduce adverse birth outcomes and costs with long-term implications, especially among the young, non-Hispanic Blacks and those of lower SES. Stricter tobacco control policies, especially higher cigarette taxes, higher minimum purchase ages for tobacco and improved cessation interventions can help reduce disparities and the cost to insurers, especially public costs through Medicaid. PMID- 26645614 TI - Level, Causes and Risk Factors of Neonatal Mortality, in Jordan: Results of a National Prospective Study. AB - OBJECTIVE: The present study aimed at assessment of the magnitude of neonatal mortality in Jordan, and its causes and associated factors. METHODS: Through a multistage sampling technique, a total of 21,928 deliveries with a gestational period >=20 weeks from 18 hospitals were included in the study. The status of their babies 28 days after birth, whether dead or alive, was ascertained. Extensive data were collected about mothers and their newborns at admission and after 28 days of birth. Causes of death were classified according to the neonatal and intrauterine death classification according to etiology. Preventability of death was classified according to Herman's classification into preventable, partially preventable, and not preventable. RESULTS: Neonatal mortality rate, overall and for subgroups of the study was obtained. Risk factors for neonatal mortality were first examined in bivariate analyses and finally by multivariate logistic regression models to account for potential confounders. A total of 327 babies >=20 weeks of gestation died in the neonatal period (14.9/1000 LB). Excluding babies <1000 g and <28 weeks of gestation to be consistent with the WHO and UNICEF's annual neonatal mortality reports, the NNMR decreased to 10.5/1000 LB. About 79 % of all neonatal deaths occurred in the first week after birth with over 42 % occurring in the first day after birth. According to NICE hierarchical classification, most neonatal deaths were due to congenital anomalies (27.2 %), multiple births (26.0 %), or unexplained immaturity (21.7 %). Other important causes included maternal disease (6.7 %), specific infant conditions (6.4 %), and unexplained asphyxia (4.9 %). According to Herman's classification, 37 % of neonatal deaths were preventable and 59 % possibly preventable. An experts' panel determined that 37.3 % of neonatal deaths received optimal medical care while the medical care provided to the rest was less than optimal. After adjusting for socio-demographic characteristics, type of the hospital, and clinical and medical history of women, the following variables were significantly associated with neonatal mortality: male gender, congenital defects, inadequate antenatal visits, multiple pregnancy, presentation at delivery, and gestational age. CONCLUSION: The present study showed the level, causes, and risk factors of NNM in Jordan. It showed also that a large proportion of NNDs are preventable or possibly preventable. Providing optimal intrapartum, and immediate postpartum care is likely to result in avoidance of a large proportion of NNDs. PMID- 26645615 TI - Influence of Maternal Depression on WIC Participation in Low-Income Families. AB - OBJECTIVES: To date, little is known regarding the impact of maternal depression on participation in public benefit programs. This study examines whether maternal depression is predictive of lower WIC participation in early childhood. METHODS: This was a secondary data analysis using weighted data from the Early Childhood Longitudinal Study, Birth Cohort. Maternal data collected when children were 9 and 24 months of age were used. 9 months was considered baseline, and 24 months was considered follow-up. The study cohort consisted of 3841 low income mothers, defined as <185 % federal poverty level, who reported WIC participation at baseline. Baseline maternal depressive symptoms were measured by a 12-item abbreviated version of the Center for Epidemiologic Studies Depression Scale. WIC participation was assessed by maternal self-report. RESULTS: At baseline, 24.5 % of mothers were depressed (raw score >9). The majority of mothers were white, unemployed, and born in the US. Most received Medicaid (74 %) and almost half received SNAP (47 %). At follow-up, 80.1 % of mothers reported WIC participation. In multivariable analysis, maternal depression at baseline was significantly associated with decreased WIC participation at follow-up (aOR 0.74; 95 % CI 0.55 0.99). CONCLUSIONS: Our results suggest that maternal depression is an independent risk factor for decreased WIC participation in low-income families with young children. Primary and secondary prevention strategies aimed at maternal depression may positively impact low-income families' participation in public benefit programs. Further longitudinal and interventional studies are needed in order to inform clinical practice and public health policy. PMID- 26645617 TI - Comparing an Interferon Gamma Release Assay with the Tuberculin Skin Test During Pregnancy: Implications for Tuberculosis Screening During Prenatal Care. AB - Background Currently there are no guidelines regarding optimal screening for latent tuberculosis infection during pregnancy. Objective This study measures completion rates and the concordance between the TSPOT.TB, a commercially available interferon gamma release assay (IGRA), and the traditional tuberculin skin test (TST) in a predominantly urban minority obstetrics practice. Design This is an observational cohort study of 141 pregnant women enrolled from an obstetrics practice with a large immigrant population. Women with a history of a positive TST result were excluded. Demographic and clinical risk factors for tuberculosis were assessed. Enrolled women underwent a T-SPOT.TB test and placement of TST, and returned in 48-72 h for TST interpretation. We calculated the completion rate and frequency of a positive result for each test, as well as the concordance between the T-SPOT.TB and TST. Results Among the 141 women enrolled, 75 % were either Latina or African-American, 44 % were born in a country with a high TB prevalence, and 52 % had received the Bacillus Calmette Guerin vaccine. Seven women (5 %) had a positive screening test, a total of 3 positive T-SPOT.TB results and 6 positive TST results, and all were from countries with a high TB prevalence. The concordance of the two tests was 96.3 %. The completion rate for the T-SPOT.TB was 98 %, while the completion rate for the TST was 63 %. CONCLUSION: The IGRA test had a markedly higher completion rate in addition to maintaining high concordance with the two-step TST in this population of pregnant women with a high prevalence of prior TB exposure. Targeted screening of women from countries with a high prevalence of tuberculosis may be warranted during prenatal care. PMID- 26645616 TI - Surveillance of Medication Use During Pregnancy in the Mini-Sentinel Program. AB - OBJECTIVES: Mini-Sentinel is a pilot project sponsored by the U.S. Food and Drug Administration to create an active surveillance system to monitor the safety of FDA-regulated medical products. We assessed the capability of the Mini-Sentinel pilot to provide prevalence rates of medication use among pregnant women delivering a liveborn infant. METHODS: An algorithm was developed to identify pregnancies for a reusable analytic tool to be executed against the Mini-Sentinel Distributed Database. Diagnosis and procedure codes were used to identify women ages 10-54 years delivering a liveborn infant between April 2001 and December 2012. A comparison group of age- and date-matched nonpregnant women was identified. The analytic code was distributed to all 18 Mini-Sentinel data partners. The use of specific medications, selected because of concerns about their safe use during pregnancy, was identified from outpatient dispensing data. We determined the frequency of pregnancy episodes and nonpregnant episodes exposed to medications of interest, any time during the pregnant/matched nonpregnant period, and during each trimester. RESULTS: The analytic tool successfully identified 1,678,410 live birth deliveries meeting the eligibility criteria. The prevalence of use at any time during pregnancy was 0.38 % for angiotensin-converting enzyme inhibitors and 0.22 % for statins. For <=0.05 % of pregnancy episodes, the woman was dispensed warfarin, methotrexate, ribavirin, or mycophenolate. CONCLUSIONS: The analytic tool developed for this study can be used to assess the use of medications during pregnancy as safety issues arise, and is adaptable to include different medications, observation periods, pre existing conditions, and enrollment criteria. PMID- 26645618 TI - Prevalence and Losses in Quality-Adjusted Life Years of Child Health Conditions: A Burden of Disease Analysis. AB - OBJECTIVES: To estimate the prevalence and losses in quality-adjusted life years (QALYs) associated with 20 child health conditions. METHODS: Using data from the 2009-2010 National Survey of Children with Special Health Care Needs, preference weights were applied to 14 functional difficulties to summarize the quality of life burden of 20 health conditions. RESULTS: Among the 14 functional difficulties, "a little trouble with breathing" had the highest prevalence (37.1 %), but amounted to a loss of just 0.16 QALYs from the perspective of US adults. Though less prevalent, "a lot of behavioral problems" and "chronic pain" were associated with the greatest losses (1.86 and 3.43 QALYs). Among the 20 conditions, allergies and asthma were the most prevalent but were associated with the least burden. Muscular dystrophy and cerebral palsy were among the least prevalent and most burdensome. Furthermore, a scatterplot shows the association between condition prevalence and burden. CONCLUSIONS: In child health, condition prevalence is negatively associated with quality of life burden from the perspective of US adults. Both should be considered carefully when evaluating the appropriate role for public health prevention and interventions. PMID- 26645619 TI - Racial/Ethnic Specific Trends in Pediatric Firearm-Related Hospitalizations in the United States, 1998-2011. AB - OBJECTIVES: To determine the temporal patterns and the difference in trends by race/ethnicity of pediatric firearm hospitalizations (FH) among those aged 15 years or younger in the United States. METHODS: Data on pediatric FH was retrieved from the Nationwide Inpatient Sample between 1998 and 2011 (n = 16,998,470) using external cause of injury codes (E-codes) of the International Classification of Diseases, Ninth Revision, Clinical modification, (assault: E9650-E9654, unintentional: E9220-E9224, E9228, and E9229, suicide: E9550-E9554, E9556, and E9559, undetermined: E9850-E9854, and E9856 and legal: E970). Meta regression was used to determine the significance of temporal trends. Survey logistic regression adjusted for survey year was used to examine association of pediatric FH with social and demographic characteristics. RESULTS: An annual reduction of 1.07 per 100,000 hospitalizations (p-trend = 0.011) was observed between 1998 and 2011. There was reduction in rate of unintentional-FH (p-trend = 0.013), suicide-FH (p-trend = 0.029), and undetermined-FH (p-trend = 0.002), but not assault-FH (p-trend = 0.18). A decline in rates of FH was observed among whites (p-trend = 0.021) and Hispanics (p-trend = 0.03) while an increase in rates of assault-FH was observed among black children. All other intents and all other racial/ethnic groups showed declining rates during this interval. CONCLUSIONS: There was an overall decline in rates of pediatric FHs in this time period driven by a decline in unintentional-FHs. However there was an increase in assault FH among black children during this same time period. PMID- 26645620 TI - Cryptic 13q34 and 4q35.2 Deletions in an Italian Family. AB - Variations of DNA sequences in the human genome range from large, microscopically visible chromosome anomalies to single nucleotide changes. Submicroscopic genomic copy number variations, i.e. chromosomal imbalances which are undetectable by conventional cytogenetic analysis, play an intriguing clinical role. In this study, we describe the clinical consequences of the concurrent presence of an interstitial deletion in 13q34 and a terminal deletion in 4q35.2 in an Italian family. The index patient, a 19-year-old male, as well as his 12-year-old sister are carriers of both deletions, one of maternal and the other of paternal origin. The phenotype includes language delay, multiorgan involvement and bleeding diathesis with mild deficiency of factors X and VII. In the sister, the concomitant presence of Noonan syndrome may partly explain the clinical symptoms. The deleted region on chromosome 13 involves several genes (ATP11A, MCF2L, F7, F10, PROZ, PCID2, CUL4A, and LAMP1); some of these seem to play a role in the proband's phenotype. The terminal deletion in 4q35.2 contains other OMIM genes (FRG1, FRG2 and DBET); moreover, the 4q region is reported as a susceptibility locus for Crohn's disease, diagnosed in the proband's father. To our knowledge, this is the first report of a family with these 2 submicroscopic copy number changes. We tried to relate the clinical phenotype of the proband and his family to the molecular function of the involved genes. PMID- 26645621 TI - Optimising element choice for nanoparticle radiosensitisers. AB - There is considerable interest in the use of heavy atom nanoparticles as theranostic contrast agents due to their high radiation cross-section compared to soft tissue. However, published studies have primarily focused on applications of gold nanoparticles. This study applies Monte Carlo radiation transport modelling using Geant4 to evaluate the macro- and micro-scale radiation dose enhancement following X-ray irradiation with both imaging and therapeutic energies on nanoparticles consisting of stable elements heavier than silicon. An approach based on the Local Effect Model was also used to assess potential biological impacts. While macroscopic dose enhancement is well predicted by simple absorption cross-sections, nanoscale dose deposition has a much more complex dependency on atomic number, with local maxima around germanium (Z = 32) and gadolinium (Z = 64), driven by variations in secondary Auger electron spectra, which translate into significant variations in biological effectiveness. These differences may provide a valuable tool for predicting and elucidating fundamental mechanisms of these agents as they move towards clinical application. PMID- 26645622 TI - The Role of Anxiety Control and Treatment Implications of Informant Agreement on Child PTSD Symptoms. AB - The goal of this study is to examine parent and child agreement of child posttraumatic stress disorder (PTSD) symptoms pre- and posttreatment, as well as potential moderators of agreement including treatment responder status, child anxiety control, and parent self-reported PTSD symptoms. We examined child self reported and parent-reported child PTSD symptoms from the Diagnostic Interview Schedule for Children. Of the 141 parent-child pairs, the mean age of children was 12.72 (SD = 3.40), 53% were female, and 54% were Black. A subsample of participants (n = 47) was assessed after completion of a cognitive behavioral therapy treatment for PTSD. Moderate levels of agreement were found at baseline, though Criterion D (increased arousal) symptoms had lower levels of agreement than the other symptom clusters. Symptom agreement was lower at posttreatment. Treatment responders had higher levels of baseline informant agreement than treatment nonresponders. Child perceived anxiety control significantly moderated informant agreement, such that pairs with children who had high levels of perceived control of their anxiety had lower PTSD symptom agreement where children reported lower symptoms relative to their parents. Contrary to expectations, parent self-reported PTSD did not moderate parent-child symptom agreement. Factors associated with higher parent-child agreement of child PTSD symptoms were being a PTSD treatment responder and children with lower perceived anxiety control. These findings have potential implications for determining those who may benefit from greater symptom monitoring over the course of intervention and potential alternative intervention approaches. PMID- 26645623 TI - A Stepwise Approach of Finding Dependent Variables via Coefficient of Intrinsic Dependence. AB - The coefficient of intrinsic dependence (CID) is capable of determining associations among variables without making distributional or functional assumptions regarding random variables. In this study, we developed the partial coefficient of intrinsic dependence (pCID) to facilitate the step-by-step selection of variables that are relevant to a target variable. The strategy of selecting relevant variables using the CID along with the pCID can eliminate interference from other relevant variables. From simulation results, we observed that the proposed method is more sensitive to curvilinearity and more specific to linearity than the combination of Pearsons correlation coefficient and the partial correlation coefficient (PCC/pPCC). This property may provide the opportunity to index different levels of curvilinearity according to CID/pCID outcomes. In practice trials conducted using publicly available microarray data, the CID/pCID procedure successfully identified cold-responsive genes related to three C-repeat binding factors, and was especially effective at identifying some sample-specific gene-gene interactions. Therefore, the proposed strategy may be beneficial in meta-analysis to distinguish general forms of relationships from the noise. PMID- 26645624 TI - Feasibility of investigating differential proteomic expression in depression: implications for biomarker development in mood disorders. AB - The objective of this study was to determine whether proteomic profiling in serum samples can be utilized in identifying and differentiating mood disorders. A consecutive sample of patients with a confirmed diagnosis of unipolar (UP n=52) or bipolar depression (BP-I n=46, BP-II n=49) and controls (n=141) were recruited. A 7.5-ml blood sample was drawn for proteomic multiplex profiling of 320 proteins utilizing the Myriad RBM Discovery Multi-Analyte Profiling platform. After correcting for multiple testing and adjusting for covariates, growth differentiation factor 15 (GDF-15), hemopexin (HPX), hepsin (HPN), matrix metalloproteinase-7 (MMP-7), retinol-binding protein 4 (RBP-4) and transthyretin (TTR) all showed statistically significant differences among groups. In a series of three post hoc analyses correcting for multiple testing, MMP-7 was significantly different in mood disorder (BP-I+BP-II+UP) vs controls, MMP-7, GDF 15, HPN were significantly different in bipolar cases (BP-I+BP-II) vs controls, and GDF-15, HPX, HPN, RBP-4 and TTR proteins were all significantly different in BP-I vs controls. Good diagnostic accuracy (ROC-AUC?0.8) was obtained most notably for GDF-15, RBP-4 and TTR when comparing BP-I vs controls. While based on a small sample not adjusted for medication state, this discovery sample with a conservative method of correction suggests feasibility in using proteomic panels to assist in identifying and distinguishing mood disorders, in particular bipolar I disorder. Replication studies for confirmation, consideration of state vs trait serial assays to delineate proteomic expression of bipolar depression vs previous mania, and utility studies to assess proteomic expression profiling as an advanced decision making tool or companion diagnostic are encouraged. PMID- 26645625 TI - Effect of voluntary alcohol consumption on Maoa expression in the mesocorticolimbic brain of adult male rats previously exposed to prolonged maternal separation. AB - Discordant associations between monoamine oxidase A (MAOA) genotype and high alcohol drinking have been reported in human and non-human primates. Environmental influences likely moderate genetic susceptibility. The biological basis for this interplay remains elusive, and inconsistencies call for translational studies in which conditions can be controlled and brain tissue is accessible. The present study investigated whether early life stress and subsequent adult episodic alcohol consumption affect Maoa expression in stress- and reward-related brain regions in the rat. Outbred Wistar rats were exposed to rearing conditions associated with stress (prolonged maternal separation) or no stress during early life, and given free choice between alcohol and/or water in adulthood. Transcript levels of Maoa were assessed in the ventral tegmental area, nucleus accumbens (NAc), medial prefrontal cortex, cingulate cortex, amygdala and dorsal striatum (DS). Blood was collected to assess corticosterone levels. After alcohol consumption, lower blood corticosterone and Maoa expression in the NAc and DS were found in rats exposed to early life stress compared with control rats. An interaction between early life stress and voluntary alcohol intake was found in the NAc. Alcohol intake before death correlated negatively with Maoa expression in DS in high alcohol-drinking rats exposed to early life stress. Maoa expression is sensitive to adulthood voluntary alcohol consumption in the presence of early life stress in outbred rats. These findings add knowledge of the molecular basis of the previously reported associations between early life stress, MAOA and susceptibility to alcohol misuse. PMID- 26645626 TI - Convergent evidences from human and animal studies implicate angiotensin I converting enzyme activity in cognitive performance in schizophrenia. AB - In schizophrenia (SCZ), higher angiotensin I-converting enzyme (ACE) levels have been reported in patient's blood and cerebrospinal fluid (CSF). Hereby, we propose to explore whether the ACE activity levels are associated to cognitive performance in SCZ. Seventy-two patients with SCZ or schizoaffective disorder diagnosis, and 69 healthy controls (HCs) underwent a cognitive battery with parallel collection of peripheral blood samples to measure ACE activity. Significant higher ACE activity levels were confirmed in the plasma of SCZ patients compared with HCs (Student's t=-5.216; P<0.001). ACE activity significantly correlated to Hopkins delayed recall measures (r=-0.247; P=0.004) and Hopkins total (r=-0.214; P=0.012). Subjects grouped as high ACE activity (above average) had worse performance compared with low ACE activity level group for Hopkins delayed recall measure, even after correction for clinical condition, age, gender and years of education (P=0.029). The adjusted R squared for this final model was 0.343. This result was evident only comparing extreme groups for ACE activity, when splitting the sample in three groups with similar number of subjects. To clarify this finding, we performed an evaluation of the cognitive performance of transgenic mice with three copies of ACE gene in novel object recognition (NOR) test, which showed that such animals presented impairment in NOR (P<0.05) compared with two copies of wild-type animals. The results observed in SCZ patients and animal model suggest both the association of ACE to cognitive deficits in SCZ. This finding may support the evaluation of novel treatment protocols and/or of innovative drugs for specific intervention of cognitive deficits in SCZ envisioning concomitant ACE activity and behavior evaluations. PMID- 26645627 TI - Association between genetic risk scoring for schizophrenia and bipolar disorder with regional subcortical volumes. AB - Previous research has shown coincident abnormal regional brain volume in patients with schizophrenia (SCZ) and bipolar disorder (BD) compared with controls. Whether these abnormalities are genetically driven or explained by secondary effects of the disorder or environmental factors is unknown. We aimed to investigate the association between genetic risk scoring (GRS) for SCZ and BD with volume of brain areas previously shown to be different between these clinical groups and healthy controls. We obtained subcortical brain volume measures and GRS for SCZ and BD from a sample of 274 healthy volunteers (71.4% females, mean age 24.7 (s.d. 6.9)). Volume of the globus pallidus was associated with the shared GRS between SCZ and BD, and also with the independent GRS for each of these disorders. Volume of the amygdala was associated with the non shared GRS between SCZ and BD, and with the independent GRS for BD. Our results for volume of the globus pallidus support the idea of SCZ and BD sharing a common underlying neurobiological abnormality associated with a common genetic risk for both these disorders. Results for volume of the amygdala, though, would suggest the existence of a distinct mechanism only associated with genetic risk for BD. Finally, the lack of association between genetic risk and volume of most subcortical structures suggests that the volumetric differences reported in patient-control comparisons may not be genetically driven, but a consequence of the disorder or co-occurring environmental factors. PMID- 26645629 TI - Binding Interactions of Dopamine and Apomorphine in D2High and D2Low States of Human Dopamine D2 Receptor Using Computational and Experimental Techniques. AB - We have recently reported G-protein coupled receptor (GPCR) model structures for the active and inactive states of the human dopamine D2 receptor (D2R) using adrenergic crystal structures as templates. Since the therapeutic concentrations of dopamine agonists that suppress the release of prolactin are the same as those that act at the high-affinity state of the D2 receptor (D2High), D2High in the anterior pituitary gland is considered to be the functional state of the receptor. In addition, the therapeutic concentrations of anti-Parkinson drugs are also related to the dissociation constants in the D2High form of the receptor. The discrimination between the high- and low-affinity (D2Low) components of the D2R is not obvious and requires advanced computer-assisted structural biology investigations. Therefore, in this work, the derived D2High and D2Low receptor models (GPCR monomer and dimer three-dimensional structures) are used as drug binding targets to investigate binding interactions of dopamine and apomorphine. The study reveals a match between the experimental dissociation constants of dopamine and apomorphine at their high- and low-affinity sites of the D2 receptor in monomer and dimer and their calculated dissociation constants. The allosteric receptor-receptor interaction for dopamine D2R dimer is associated with the accessibility of adjacent residues of transmembrane region 4. The measured negative cooperativity between agonist ligand at dopamine D2 receptor is also correctly predicted using the D2R homodimerization model. PMID- 26645628 TI - Characterization of brain mGluR5 binding in a pilot study of late-life major depressive disorder using positron emission tomography and [11C]ABP688. AB - The metabotropic glutamate receptor subtype 5 (mGluR5) has been implicated in the pathophysiology of mood and anxiety disorders and is a potential treatment target in major depressive disorder (MDD). This study compared brain mGluR5 binding in elderly patients suffering from MDD with that in elderly healthy volunteers using positron emission tomography (PET) and [(11)C]ABP688. Twenty elderly (mean age: 63.0 +/- 6.3) subjects with MDD and twenty-two healthy volunteers in the same age range (mean age: 66.4 +/- 7.3) were examined with PET after a single bolus injection of [(11)C]ABP688, with many receiving arterial sampling. PET images were analyzed on a region of interest and a voxel level to compare mGluR5 binding in the brain between the two groups. Differences in [(11)C]ABP688 binding between patients with early- and late-onset depression were also assessed. In contrast to a previously published report in a younger cohort, no significant difference in [(11)C]ABP688 binding was observed between elderly subjects with MDD and healthy volunteers. [(11)C]ABP688 binding was also similar between subgroups with early- or late-onset depression. We believe this is the first study to examine mGluR5 expression in depression in the elderly. Although future work is required, results suggest potential differences in the pathophysiology of elderly depression versus depression earlier in life. PMID- 26645630 TI - Occupational risk factors for endometriosis in a cohort of flight attendants. AB - OBJECTIVES: This study aimed to (i) compare odds of endometriosis in a cohort of flight attendants against a comparison group of teachers and (ii) investigate occupational risk factors for endometriosis among flight attendants. METHODS: We included 1945 flight attendants and 236 teachers aged 18-45 years. Laparoscopically confirmed endometriosis was self-reported via telephone interview, and flight records were retrieved from airlines to obtain work schedules and assess exposures for flight attendants. We used proportional odds regression to estimate adjusted odds ratios (OR adj) and 95% confidence intervals (95% CI) for associations between exposures and endometriosis, adjusting for potential confounders. RESULTS: Flight attendants and teachers were equally likely to report endometriosis (OR adj1.0, 95% CI 0.5-2.2). Among flight attendants, there were no clear trends between estimated cosmic radiation, circadian disruption, or ergonomic exposures and endometriosis. Greater number of flight segments (non-stop flights between two cities) per year was associated with endometriosis (OR adj2.2, 1.1-4.2 for highest versus lowest quartile, P trend= 0.02) but block hours (taxi plus flight time) per year was not (OR adj1.2, 95% CI 0.6-2.2 for highest versus lowest quartile, P trend=0.38). CONCLUSION: Flight attendants were no more likely than teachers to report endometriosis. Odds of endometriosis increased with number of flight segments flown per year. This suggests that some aspect of work scheduling is associated with increased risk of endometriosis, or endometriosis symptoms might affect how flight attendants schedule their flights. PMID- 26645631 TI - Fluoxetine effects on molecular, cellular and behavioral endophenotypes of depression are driven by the living environment. AB - Selective serotonin reuptake inhibitors (SSRIs) represent the most common treatment for major depression. However, their efficacy is variable and incomplete. In order to elucidate the cause of such incomplete efficacy, we explored the hypothesis positing that SSRIs may not affect mood per se but, by enhancing neural plasticity, render the individual more susceptible to the influence of the environment. Consequently, SSRI administration in a favorable environment promotes a reduction of symptoms, whereas in a stressful environment leads to a worse prognosis. To test such hypothesis, we exposed C57BL/6 mice to chronic stress in order to induce a depression-like phenotype and, subsequently, to fluoxetine treatment (21 days), while being exposed to either an enriched or a stressful condition. We measured the most commonly investigated molecular, cellular and behavioral endophenotypes of depression and SSRI outcome, including depression-like behavior, neurogenesis, brain-derived neurotrophic factor levels, hypothalamic-pituitary-adrenal axis activity and long-term potentiation. Results showed that, in line with our hypothesis, the endophenotypes investigated were affected by the treatment according to the quality of the living environment. In particular, mice treated with fluoxetine in an enriched condition overall improved their depression-like phenotype compared with controls, whereas those treated in a stressful condition showed a distinct worsening. Our findings suggest that the effects of SSRI on the depression- like phenotype is not determined by the drug per se but is induced by the drug and driven by the environment. These findings may be helpful to explain variable effects of SSRI found in clinical practice and to device strategies aimed at enhancing their efficacy by means of controlling environmental conditions. PMID- 26645632 TI - [PSI(+)] turns 50. AB - The year 2015 sees the fiftieth anniversary of the publication of a research paper that underpins much of our understanding of fungal prion biology, namely "psi, a cytoplasmic suppressor of super-suppressor in yeast" by Brian Cox. Here we show how our understanding of the molecular nature of the [PSI(+)] determinant evolved from an 'occult' determinant to a transmissible amyloid form of a translation termination factor. We also consider the impact studies on [PSI] have had--and continue to have--on prion research. To demonstrate this, leading investigators in the yeast prion field who have made extensive use of the [PSI(+)] trait in their research, provide their own commentaries on the discovery and significance of [PSI]. PMID- 26645633 TI - Group A streptococcal strains isolated in Lao People's Democratic Republic from 2004 to 2013. AB - Epidemiological data regarding group A streptococcal (GAS) infections in South East Asia are scarce with no information from Laos. We characterized emm types, emm clusters and the antibiotic resistance profile of 124 GAS isolates recovered in Laos during 2004-2013. Most strains were recovered from skin and invasive infections (76% and 19%, respectively). Thirty-four emm types were identified as belonging to 12 emm clusters and no novel emm types were identified. No significant differences were observed in the distribution of emm types or emm clusters according to age or site of recovery (skin or invasive infections). There was moderate strain diversity in this country but considerable differences in emm-type distribution between Laos, Thailand and Cambodia. Vaccine coverage was high for the J8 vaccine candidate. The theoretical coverage for the 30-valent vaccine candidate needs further investigation. Antibiotic resistance was moderate to erythromycin and chloramphenicol (8% and 7%, respectively) and low to ofloxacin (<1%). PMID- 26645634 TI - Women with HIV in Indonesia: are they bridging a concentrated epidemic to the wider community? AB - BACKGROUND: Male injecting drug users drove the onset of the HIV epidemic in Indonesia but over time more women have been diagnosed. We examined the relative proportion of female patients in an HIV cohort and characterized their probable transmission route and reproductive profile. DESIGNS: Prospective cohort study in a referral hospital in West Java. METHODS: Interviews with standardized questionnaires, physical and laboratory examinations were done for 2622 individuals enrolled in HIV care between 2007 and 2012. The proportion of women in this cohort was compared with national estimates. The general characteristics of HIV-infected women and men as well as the sexual and reproductive health of HIV-infected women were described. RESULTS: The proportion of female patients enrolled in HIV care increased from 22.2 % in 2007 to 38.3 % in 2012, in line with national estimates. Women were younger than men, fewer reported a history of IDU (16.1 vs. 73.8 %, p < 0.001) and more were tested for HIV because of a positive partner (25.5 vs. 4.0 %, p < 0.001). The majority of women were in their reproductive age, had children, and were not using contraceptives at the time of enrolment. CONCLUSION: HIV-infected women in Indonesia have specific characteristics that differ them from women in the general population. Further research to elucidate the characteristics of women exposed to HIV, their access to testing and care and sexual and reproductive needs can help reduce transmission to women and children in the context of concentrated HIV epidemic in Indonesia. PMID- 26645635 TI - Mitochondrial oxidative phosphorylation complexes exist in the sarcolemma of skeletal muscle. AB - Although proteomic analyses have revealed the presence of mitochondrial oxidative phosphorylation (OXPHOS) proteins in the plasma membrane, there have been no in depth evaluations of the presence or function of OXPHOS I-V in the plasma membrane. Here, we demonstrate the in situ localization of OXPHOS I-V complexes to the sarcolemma of skeletal muscle by immunofluorescence and immunohistochemistry. A portion of the OXPHOS I-V complex proteins was not co stained with MitoTracker but co-localized with caveolin-3 in the sarcolemma of mouse gastrocnemius. Mitochondrial matrix-facing OXPHOS complex subunits were ectopically expressed in the sarcolemma of the non-permeabilized muscle fibers and C2C12 myotubes. The sarcolemmal localization of cytochrome c was also observed from mouse gastrocnemius muscles and C2C12 myotubes, as determined by confocal and total internal resonance fluorescence (TIRF) microscopy. Based on these data, we conclude that a portion of OXPHOS complexes is localized in the sarcolemma of skeletal muscle and may have non-canonical functions. [BMB Reports 2016; 49(2): 116-121]. PMID- 26645636 TI - IGF1 potentiates BMP9-induced osteogenic differentiation in mesenchymal stem cells through the enhancement of BMP/Smad signaling. AB - Engineered bone tissue is thought to be the ideal alternative for bone grafts in the treatment of related bone diseases. BMP9 has been demonstrated as one of the most osteogenic factors, and enhancement of BMP9-induced osteogenesis will greatly accelerate the development of bone tissue engineering. Here, we investigated the effect of insulin-like growth factor 1 (IGF1) on BMP9-induced osteogenic differentiation, and unveiled a possible molecular mechanism underling this process. We found that IGF1 and BMP9 are both detectable in mesenchymal stem cells (MSCs). Exogenous expression of IGF1 potentiates BMP9-induced alkaline phosphatase (ALP), matrix mineralization, and ectopic bone formation. Similarly, IGF1 enhances BMP9-induced endochondral ossification. Mechanistically, we found that IGF1 increases BMP9-induced activation of BMP/Smad signaling in MSCs. Our findings demonstrate that IGF1 can enhance BMP9-induced osteogenic differentiation in MSCs, and that this effect may be mediated by the enhancement of the BMP/Smad signaling transduction triggered by BMP9. [BMB Reports 2016; 49(2): 122-127]. PMID- 26645637 TI - Epac2 contributes to PACAP-induced astrocytic differentiation through calcium ion influx in neural precursor cells. AB - Astrocytes play a critical role in normal brain functions and maintaining the brain microenvironment, and defects in astrocytogenesis during neurodevelopment could give rise to severe mental illness and psychiatric disorders. During neuro embryogenesis, astrocytogenesis involves astrocytic differentiation of neural precursor cells (NPCs) induced by signals from ciliary neurotrophic factor (CNTF) or pituitary adenylate cyclase-activating peptide (PACAP). However, in contrast to the CNTF signaling pathway, the exact mechanism underlying astrocytic differentiation induced by PACAP is unknown. In the present study, we aimed to verify a signaling pathway specific to PACAP-induced astrocytogenesis, using exchange protein directly activated by cAMP2 (Epac2)-knockout mice. We found that PACAP could trigger astrocytic differentiation of NPCs via Epac2 activation and an increase in the intracellular calcium concentration via a calcium ion influx. Taken together, we concluded that astrocytogenesis stimulated by PACAP occurs through a novel signaling pathway independent from CNTF-JAK/STAT signaling, that is the well-known pathway of astrocytogenesis. [BMB Reports 2016; 49(2): 128 133]. PMID- 26645638 TI - Abuse-Related Neurochemical Effects of Para-Substituted Methcathinone Analogs in Rats: Microdialysis Studies of Nucleus Accumbens Dopamine and Serotonin. AB - Methcathinone (MCAT) is a monoamine releaser and parent compound to a new class of designer drugs that includes the synthetic cathinones mephedrone and flephedrone. Using MCAT and a series of para-substituted (or 4-substituted) MCAT analogs, it has been previously shown that expression of abuse-related behavioral effects in rats correlates both with the volume of the para substituent and in vitro neurochemical selectivity to promote monoamine release via the dopamine (DA) versus serotonin (5-HT) transporters in rat brain synaptosomes. The present study used in vivo microdialysis to determine the relationship between these previous measures and the in vivo neurochemical selectivity of these compounds to alter nucleus accumbens (NAc) DA and 5-HT levels. Male Sprague-Dawley rats were implanted with bilateral guide cannulae targeting the NAc. MCAT and five para substituted analogs (4-F, 4-Cl, 4-Br, 4-CH3, and 4-OCH3) produced dose- and time dependent increases in NAc DA and/or 5-HT levels. Selectivity was determined as the dose required to increase peak 5-HT levels by 250% divided by the dose required to increase peak DA levels by 250%. This measure of in vivo neurochemical selectivity varied across compounds and correlated with 1) in vivo expression of abuse-related behavioral effects (r = 0.89, P = 0.02); 2) in vitro selectivity to promote monoamine release via DA and 5-HT transporters (r = 0.95, P < 0.01); and 3) molecular volume of the para substituent (r = -0.85, P = 0.03). These results support a relationship between these molecular, neurochemical, and behavioral measures and support a role for molecular structure as a determinant of abuse-related neurochemical and behavioral effects of MCAT analogs. PMID- 26645639 TI - A multi-level qualitative analysis of Telehomecare in Ontario: challenges and opportunities. AB - BACKGROUND: Despite research demonstrating the potential effectiveness of Telehomecare for people with Chronic Obstructive Pulmonary Disease and Heart Failure, broad-scale comprehensive evaluations are lacking. This article discusses the qualitative component of a mixed-method program evaluation of Telehomecare in Ontario, Canada. The objective of the qualitative component was to explore the multi-level factors and processes which facilitate or impede the implementation and adoption of the program across three regions where it was first implemented. METHODS: The study employs a multi-level framework as a conceptual guide to explore the facilitators and barriers to Telehomecare implementation and adoption across five levels: technology, patients, providers, organizations, and structures. In-depth semi-structured interviews and ethnographic observations with program stakeholders, as well as a Telehomecare document review were used to elicit key themes. Study participants (n = 89) included patients and/or informal caregivers (n = 39), health care providers (n = 23), technicians (n = 2), administrators (n = 12), and decision makers (n = 13) across three different Local Health Integration Networks in Ontario. RESULTS: Key facilitators to Telehomecare implementation and adoption at each level of the multi-level framework included: user-friendliness of Telehomecare technology, patient motivation to participate in the program, support for Telehomecare providers, the integration of Telehomecare into broader health service provision, and comprehensive program evaluation. Key barriers included: access-related issues to using the technology, patient language (if not English or French), Telehomecare provider time limitations, gaps in health care provision for patients, and structural barriers to patient participation related to geography and social location. CONCLUSIONS: Though Telehomecare has the potential to positively impact patient lives and strengthen models of health care provision, a number of key challenges remain. As such, further implementation and expansion of Telehomecare must involve continuous assessments of what is working and not working with all stakeholders. Increased dialogue, evaluation, and knowledge translation within and across regions to understand the contextual factors influencing Telehomecare implementation and adoption is required. This can inform decision-making that better reflects and addresses the needs of all program stakeholders. PMID- 26645640 TI - Anti-TNF Antibodies and Autophagy: A Hidden Nexus for a Successful Therapeutic Response? PMID- 26645642 TI - Parameterizing and grading hydrolytic stability in metal-organic frameworks. AB - Metal-organic frameworks (MOFs) are a class of porous solid, which have a variety of potential applications. Unfortunately, MOFs often lack hydrolytic stability, which hinders their use as viable materials for large scale applications. Though there have been an increasing number of reports proving water stability, this aspect is often ignored and negative results often remain unpublished. As a result, this report has been produced to offer common benchmarks for stability of MOFs to moisture. This will be done by discussing what water stability means- both with regards to the exposure methods and the means of assessing the MOF after exposure. Based on these two criteria, definitions are proposed in order to allow MOFs to be discussed more consistently. The purpose of this report is not to rank existing MOFs based on water stability or for potential application but to promote and facilitate discussion about hydrolytic stability of MOFs. PMID- 26645641 TI - Efficacy and Safety of Tacrolimus Therapy for Active Ulcerative Colitis; A Systematic Review and Meta-analysis. AB - BACKGROUND: Approximately 25% of patients with ulcerative colitis [UC] experience a severe flare requiring steroid therapy to avoid colectomy. We performed a systematic review and meta-analysis to assess the efficacy of tacrolimus as a rescue therapy for active UC. METHODS: Electronic databases were searched for relevant studies assessing the efficacy of tacrolimus for active UC. Outcomes included short- and long-term clinical response, colectomy free rates, and rate of adverse events in randomised controlled trials [RCTs] and observational studies. RESULTS: Two RCTs comparing high trough concentration [10-15ng/ml] versus placebo [n = 103] and 23 observational studies [n = 831] were identified. Clinical response at 2 weeks was significantly higher with tacrolimus compared with placebo (risk ratio [RR] = 4.61, 95% confidence interval [CI] = 2.09-10.17, p = 0.15 x 10(-3)] among RCTs. Rates of clinical response at 1 and 3 months were 0.73 [95% CI = 0.64-0.81] and 0.76 [95% CI = 0.59-0.87], and colectomy-free rates remained high at 1, 3, 6, and 12 months [0.86, 0.84, 0.78, and 0.69, respectively] among observational studies. Among RCTs, adverse events were more frequent compared with placebo [RR = 2.01, 95% CI = 1.20-3.37, p = 0.83 x 10( 2)], but there was no difference in severe adverse events [RR = 3.15, 95% CI = 0.14-72.9, p = 0.47]. Severe adverse events were rare among observational studies [0.11, 95% CI = 0.06-0.20]. CONCLUSIONS: In the present meta-analysis, tacrolimus was associated with high clinical response and colectomy-free rates without increased risk of severe adverse events for active UC. PMID- 26645643 TI - Responses to simulated winter conditions differ between threespine stickleback ecotypes. AB - Abiotic factors can act as barriers to colonization and drive local adaptation. During colonization, organisms may cope with changes in abiotic factors using existing phenotypic plasticity, but the role of phenotypic plasticity in assisting or hindering the process of local adaptation remains unclear. To address these questions, we explore the role of winter conditions in driving divergence during freshwater colonization and the effects of plasticity on local adaptation in ancestral marine and derived freshwater ecotypes of threespine stickleback (Gasterosteus aculeatus). We found that freshwater-resident stickleback had greater tolerance of acute exposure to low temperatures than marine stickleback, but these differences were abolished after acclimation to simulated winter conditions (9L:15D photoperiod at 4 degrees C). Plasma chloride levels differed between the ecotypes, but showed a similar degree of plasticity between ecotypes. Gene expression of the epithelial calcium channel (ECaC) differed between ecotypes, with the freshwater ecotype demonstrating substantially greater expression than the marine ecotype, but there was no plasticity in this trait under these conditions in either ecotype. In contrast, growth (assessed as final mass) and the expression of an isoform of the electroneutral Na(+)/H(+) exchanger (NHE3) exhibited substantial change with temperature in the marine ecotype that was not observed in the freshwater ecotype under the conditions tested here, which is consistent with evolution of these traits by a process such as genetic assimilation. These data demonstrate substantial divergence in many of these traits between freshwater and marine stickleback, but also illustrate the complexity of possible relationships between plasticity and local adaptation. PMID- 26645644 TI - Postdispersal Infection and Disease Development of Pyrenophora semeniperda in Bromus tectorum Seeds. AB - The Ascomycete fungus, Pyrenophora semeniperda, attacks a broad range of cool season grasses. While leaf and predispersal infection of seeds (i.e., florets containing caryopses) have been previously characterized, little is known about the pathogenesis of mature seeds following dispersal. In this study, we examined infection and disease development of P. semeniperda on dormant seeds of Bromus tectorum. Inoculated seeds were hydrated at 20 degrees C for up to 28 days. Disease development was characterized using scanning electron and light microscopy. P. semeniperda conidia germinated on the seed surface within 5 to 8 h. Hyphae grew on the seed surface and produced extracellular mucilage that eventually covered the seed. Appressoria formed on the ends of hyphae and penetrated through the lemma and palea, stomatal openings, and broken trichomes. The fungus then catabolized the endosperm, resulting in a visible cavity by 8 days. Pathogenesis of the embryo was associated with progressive loss of cell integrity and proliferation of mycelium. Beginning at approximately day 11, one to several stromata (approximately 150 MUm in diameter and up to 4 mm in length) emerged through the lemma and palea. Degradation of embryo tissue was completed near 14 days. Conidiophores produced conidia between 21 and 28 days and often exhibited "Y-shaped" branching. This characterization of disease development corrects previous reports which concluded that P. semeniperda is only a weak seed pathogen with infection limited to the outermost seed tissues. In addition, the time required for disease development explains why infected dormant or slow germinating seeds are most likely to experience mortality. PMID- 26645645 TI - The Role of Pest Control Advisers in Preventative Management of Grapevine Trunk Diseases. AB - Vineyards with trunk diseases (Botryosphaeria dieback, Esca, Eutypa dieback, and Phomopsis dieback) can have negative returns in the long run. Minimizing economic impacts depends on effective management, but adopting a preventative practice after infection occurs may not improve yields. Pest control advisers may reduce grower uncertainty about the efficacy of and need for prevention, which often entails future and unobservable benefits. Here, we surveyed advisers in California to examine their influence over grower decision-making, in the context of trunk diseases, which significantly limit grape production and for which curative practices are unavailable. Our online survey revealed adviser awareness of high disease incidence, and reduced yields and vineyard lifespan. Advisers rated both preventative and postinfection practices positively. Despite higher cost estimates given to postinfection practices, advisers did not recommend preventative practices at higher rates. High recommendation rates were instead correlated with high disease incidence for both preventative and postinfection practices. Recommendation rates declined with increasing cost for preventative, but not for postinfection, practices. Our findings suggest that even when advisers acknowledge the risks of trunk diseases, they may not recommend preventative practices before infection occurs. This underscores the importance of clear outreach, emphasizing both the need for prevention and its long-term cost efficacy. PMID- 26645647 TI - Detection of Mycobacterium tuberculosis Genome in Subretinal Fluid of Patients with Latent Tuberculosis Infection. AB - PURPOSE: To test our hypothesis that Mycobacterium tuberculosis (MTB) DNA may be present in retinal pigment epithelium (RPE) cells in individuals with latent tuberculosis (TB) infection. METHODS: A total of 100 patients with rhegmatogenous retinal detachment (without any signs of endogenous uveitis in either eye) underwent pars plana vitrectomy (PPV) with internal tamponade. All were subjected to tuberculin skin test. None had manifest systemic TB disease. The subretinal fluid collected during surgery was subjected to multitargeted polymerase chain reaction (PCR) targeting three genes of MTB (IS6110, MPB64 and protein b). RESULTS: In total, 16 patients had latent TB, of which TB PCR was positive in six patients. CONCLUSIONS: We demonstrate presence of MTB genome in the subretinal fluid containing RPE cells from individuals with latent TB infection, who did not have any evidence of intraocular TB or manifest systemic TB disease, and suggest that MTB can be sequestrated in the RPE cells in latent TB. PMID- 26645646 TI - Cell cycle-dependent changes in H3K56ac in human cells. AB - The incorporation of histone H3 with an acetylated lysine 56 (H3K56ac) into the nucleosome is important for chromatin remodeling and serves as a marker of new nucleosomes during DNA replication and repair in yeast. However, in human cells, the level of H3K56ac is greatly reduced, and its role during the cell cycle is controversial. Our aim was to determine the potential of H3K56ac to regulate cell cycle progression in different human cell lines. A significant increase in the number of H3K56ac foci, but not in H3K56ac protein levels, was observed during the S and G2 phases in cancer cell lines, but was not observed in embryonic stem cell lines. Despite this increase, the H3K56ac signal was not present in late replication chromatin, and H3K56ac protein levels did not decrease after the inhibition of DNA replication. H3K56ac was not tightly associated with the chromatin and was primarily localized to active chromatin regions. Our results support the role of H3K56ac in transcriptionally active chromatin areas but do not confirm H3K56ac as a marker of newly synthetized nucleosomes in DNA replication. PMID- 26645648 TI - An economical synthesis of substituted quinoline-2-carboxylates through the potassium persulfate-mediated cross-dehydrogenative coupling of N-aryl glycine derivatives with olefins. AB - A practical and economical K2S2O8-mediated oxidative cross-dehydrogenative coupling of N-aryl glycine derivatives with olefins has been established, affording structurally diverse quinoline-2-carboxylates in good to high efficiency. The low cost, negligible toxicity, and ease of handling of K2S2O8 combined with the absence of hazardous byproducts and the easy workup consisting of simple filtration are attractive based on economic and environmental factors. PMID- 26645649 TI - Treatment of municipal sewage sludge in supercritical water: A review. AB - With increasing construction of wastewater treatment plants and stricter policies, municipal sewage sludge (MSS) disposal has become a serious problem. Treatment of MSS in supercritical water (SCW) can avoid the pre-drying procedure and secondary pollution of conventional methods. SCW treatment methods can be divided into supercritical water gasification (SCWG), supercritical water partial oxidation (SCWPO) and supercritical water oxidation (SCWO) technologies with increasing amounts of oxidants. Hydrogen-rich gases can be generated from MSS by SCWG or SCWPO technology using oxidants less than stoichiometric ratio while organic compounds can be completely degraded by SCWO technology with using an oxidant excess. For SCWG and SCWPO technologies, this paper reviews the influences of different process variables (MSS properties, moisture content, temperature, oxidant amount and catalysts) on the production of gases. For SCWO technology, this paper reviews research regarding the removal of organics with or without hydrothermal flames and the changes in heavy metal speciation and risk. Finally, typical systems for handling MSS are summarized and research needs and challenges are proposed. PMID- 26645658 TI - Exploitation of Food Industry Waste for High-Value Products. AB - A growing global population leads to an increasing demand for food production and the processing industry associated with it and consequently the generation of large amounts of food waste. This problem is intensified due to slow progress in the development of effective waste management strategies and measures for the proper treatment and disposal of waste. Food waste is a reservoir of complex carbohydrates, proteins, lipids, and nutraceuticals and can form the raw materials for commercially important metabolites. The current legislation on food waste treatment prioritises the prevention of waste generation and least emphasises disposal. Recent valorisation studies for food supply chain waste opens avenues to the production of biofuels, enzymes, bioactive compounds, biodegradable plastics, and nanoparticles among many other molecules. PMID- 26645659 TI - Functional expression of xylose isomerase in flocculating industrial Saccharomyces cerevisiae strain for bioethanol production. AB - Saccharomyces cerevisiae strains with xylose isomerase (XI) pathway were constructed using a flocculating industrial strain (YC-8) as the host. Both strains expressing wild-type xylA (coding XI) from the fungus Orpinomyces sp. and the bacterium Prevotella ruminicola, respectively, showed better growth ability and fermentation capacity when using xylose as the sole sugar than most of the reported strains expressing XI. Codon optimization of both XIs did not improve the xylose fermentation ability of the strains. Adaption significantly increased XI activity resulting in improved growth and fermentation. The strains expressing codon-optimized XI showed a higher increase in xylose consumption and ethanol production compared to strains expressing wild XI. Among all strains, the adapted strain YCPA2E expressing XI from P. ruminicola showed the best performance in the fermentation of xylose to ethanol. After 48 h of fermentation, YCPA2E assimilated 16.95 g/L xylose and produced 6.98 g/L ethanol. These results indicate that YC-8 is a suitable host strain for XI expression, especially for the codon-optimized XI originating from P. ruminicola. PMID- 26645660 TI - Genuair(r) Usability Test: Results of a National Public Survey of the Elderly. AB - Proper use of inhaler devices may be problematic in elderly patients due to age related difficulties. A survey was administered to elderly patients to investigate the usability of the Genuair(r) device and patients' subjective viewpoint on the device. A representative sample of the Italian population aged >= 65 years was completed with a pre-defined sample of 89 patients with hand arthritis/arthrosis. Of 526 respondents, 88 were not self-sufficient. Only the replies of the 438 self-sufficient respondents were analyzed. A total of 107 participants (24%) reported having respiratory diseases, and 81 of these (76%) were users of inhaler devices. After the first test, the device was considered "practical/handy" by 90% of patients and "easy to use" by 89%. After the second test, in which patients received a demonstration of the correct inhalation maneuver, the percentage of patients scoring >= 7 increased to 93% for the first characteristic and was confirmed for the second, with no differences between the groups in terms of age, educational level, use of devices, and presence of arthritis/arthrosis. The mean time to explain the inhaler technique and to perform a correct inhalation was 1'38"+/- 1'37", and 70% of the respondents required less than 2 minutes, with no differences between the groups in terms of age, education level, use of devices, and presence of arthritis/arthrosis. In conclusion, Genuair(r) was well accepted and easy to use in a representative sample of the Italian population aged >= 65 years. These characteristics make it a valid choice in the elderly, thus enabling patients to better cope with the problems and difficulties that are common to this age group. PMID- 26645661 TI - Neoadjuvant Treatment Strategies for Locally Advanced Rectal Cancer. AB - Improved surgical technique plus selective preoperative radiotherapy have decreased rectal cancer pelvic local recurrence from, historically, 25% down to about 5-10%. However, this improvement has not reduced distant metastatic relapse, which is the main cause of death and a key issue in rectal cancer management. The current standard is local pelvic treatment (surgery +/- preoperative radiotherapy) followed by adjuvant chemotherapy, depending on resection histology. For circumferential resection margin (CRM)-threatened cancer on baseline magnetic resonance imaging, downstaging long-course preoperative chemoradiation (LCPCRT) is generally used. However, for non-CRM-threatened disease, varying approaches are currently adopted in the UK, including straight to surgery, short-course preoperative radiotherapy and LCPCRT. Clinical trials are investigating intensification of concurrent chemoradiation. There is also increasing interest in investigating preoperative neoadjuvant chemotherapy (NAC) as a way of exposing micro-metastatic disease to full-dose systemic chemotherapy as early as possible and potentially reducing metastatic relapse. Phase II trials suggest that this strategy is feasible, with promising histological response and low rates of tumour progression during NAC. Phase III trials are needed to determine the benefit of NAC when added to standard therapy and also to determine if it can be used instead of neoadjuvant radiotherapy-based schedules. Although several measures of neoadjuvant treatment response assessment based on imaging or pathology are promising predictive biomarkers for long-term survival, none has been validated in prospective phase III studies. The phase III setting will enable this, also providing translational opportunities to examine molecular predictors of response and survival. PMID- 26645662 TI - Timing and safety of angioplasty during carotid artery stenting. PMID- 26645664 TI - Drug resistance in inflammatory bowel diseases. AB - The management of patients with moderate to severe inflammatory bowel diseases, that is, Crohn's disease and ulcerative colitis, remains challenging. In recent years, therapeutic goal evolved from clinical remission to mucosal healing and deep remission. In order to achieve remission, it is important to appropriately choose and use available drugs. Therefore, anti-TNFalpha treatment should be rapidly used for severe and at-risk patients, sometimes in association with thiopurines or methotrexate. The monitoring of through levels and antibodies to anti-TNFalpha is relevant to optimize the treatment and to reduce drug inefficacy. However, the development of new drugs is required to offer alternative tools to severe and refractory patients. PMID- 26645665 TI - Moisture distribution and texture of spaghetti rehydrated under different conditions. AB - Dried spaghetti was rehydrated to its optimal cooking state, known as al dente, at 60, 80, and 100 degrees C, in distilled water or 0.1, 1.0, and 2.0 mol/L sodium chloride solutions. Then, the moisture distributions and stress-strain curves were examined to identify the major factors governing the texture of rehydrated spaghetti. The difference in moisture content between the inner and peripheral regions of rehydrated spaghetti and its breaking stress were greater at higher rehydration temperatures; however, rehydration temperature did not affect breaking strain. The sodium chloride concentration of the immersion solution did not affect moisture distribution or breaking stress, while breaking strain was decreased by rehydration at higher sodium chloride concentrations. The results obtained in this study suggest that moisture distribution within spaghetti and its material properties govern its breaking stress and strain, respectively. PMID- 26645663 TI - AKT signaling in ERBB2-amplified breast cancer. AB - The PI3K/AKT pathway is the focus of several targeted therapeutic agents for a variety of malignancies. In ERBB2-amplified breast cancer, the hyperactivation of this signaling cascade is associated with resistance to ERBB2-targeted therapy. This can occur through gain-of-function alterations or compensatory mechanisms that enter into play upon pharmacological pressure. The strong rationale in combining anti-ERBB2 agents with PI3K/AKT inhibitors, together with the identification of genomic alterations conferring sensitivity to targeted inhibition, are guiding the design of clinical studies aimed at preventing the emergence of drug resistance and achieving more durable response. In the present review, we describe the involvement of this pathway in breast cancer pathogenesis, with an emphasis on AKT kinases, and provide insight into currently available targeted agents for the treatment of ERBB2-amplified breast cancer. Finally, we provide preliminary data on a novel AKT3 mutation detected in the context of resistance to anti-ERBB2 therapy as an example of genomics-based approaches towards uncovering novel actionable targets in this setting. PMID- 26645666 TI - Nitric oxide signaling and its role in oxidative stress response in Schizosaccharomyces pombe. AB - In the fission yeast Schizosaccharomyces pombe, we found that the putative NO dioxygenase SPAC869.02c (named Yhb1) and the S-nitrosoglutathione reductase Fmd2 cooperatively reduced intracellular NO levels as NO-detoxification enzymes. Although both mRNA and protein levels were increased with exogenous NO, their expression patterns were different during growth phases. While treatment with an NO synthase inhibitor in the log phase abrogated both NO production and Yhb1 expression, induction of Fmd2 in the stationary phase was correlated with elevated mitochondrial respiratory chain (MRC) activity, confirmed by the fact that inhibition of MRC complex III led to a decrease in Fmd2 and NO levels. Moreover, NO was localized in the mitochondria in the stationary phase, suggesting that there are two distinctive types of NO signaling in S. pombe. For mitochondria, pretreatment with an NO donor rescued cell growth by repressing generation of reactive oxygen species (ROS) under oxidative stress. DNA microarray analysis revealed that exogenous NO contributes to tolerance to hydrogen peroxide (H2O2) by (i) inhibition of Fe(3+) to Fe(2+) conversion, (ii) upregulation of the H2O2-detoxifying enzymes, and (iii) downregulation of the MRC genes, suggesting that NO plays a pivotal role in the negative feedback system to regulate ROS levels in S. pombe. PMID- 26645668 TI - Enteral Feeding Therapy for Maintaining Remission in Crohn's Disease: A Systematic Review. AB - BACKGROUND: The efficacy of enteral nutrition (EN) for maintaining remission in patients with inactive Crohn's disease (CD) is unclear. The aim of this article was to systematically identify, review, and critically appraise the evidence on efficacy of EN in maintaining medically induced remission in CD. MATERIALS AND METHODS: Several databases were searched from inception to April 2015 for relevant citations of published randomized controlled trials and nonrandomized cohort studies. Two reviewers independently selected studies for inclusion and assessed study quality and risk of bias. The primary outcome was relapse rate in patients with inactive CD who have been in medically induced remission and subsequently started or maintained on EN. RESULTS: Twelve studies (1169 patients, including 95 children) fulfilled the inclusion criteria. As the included studies were significantly heterogeneous, a meta-analysis was not performed. Eleven studies showed that EN was either better than, or as effective as, the comparator in maintaining remission in patients with inactive CD. No major EN-related adverse events were reported. Only 1 adult randomized controlled trial (n = 51), with low risk of bias, compared EN with regular diet and found a relapse rate of 34% in the EN group versus 64% in the control group ( P < .01) after a mean follow-up of 11.9 months. CONCLUSIONS: EN is more effective than regular diet and as effective as some medications in maintaining remission for patients with inactive CD. Large, properly designed randomized controlled studies of sufficient duration are required to confirm this conclusion for EN versus individual medications. PMID- 26645667 TI - De novo assembly of the dual transcriptomes of a polymorphic raptor species and its malarial parasite. AB - BACKGROUND: Studies of non-model species are important for understanding the molecular processes underpinning phenotypic variation under natural ecological conditions. The common buzzard (Buteo buteo; Aves: Accipitriformes) is a widespread and common Eurasian raptor with three distinct plumage morphs that differ in several fitness-related traits, including parasite infestation. To provide a genomic resource for plumage polymorphic birds in general and to search for candidate genes relating to fitness, we generated a transcriptome from a single dead buzzard specimen plus easily accessible, minimally invasive samples from live chicks. RESULTS: We not only de novo assembled a near-complete buzzard transcriptome, but also obtained a significant fraction of the transcriptome of its malaria-like parasite, Leucocytozoon buteonis. By identifying melanogenesis related transcripts that are differentially expressed in light ventral and dark dorsal feathers, but which are also expressed in other regions of the body, we also identified a suite of candidate genes that could be associated with fitness differences among the morphs. These include several immune-related genes, providing a plausible link between melanisation and parasite load. qPCR analysis of a subset of these genes revealed significant differences between ventral and dorsal feathers and an additional effect of morph. CONCLUSION: This new resource provides preliminary insights into genes that could be involved in fitness differences between the buzzard colour morphs, and should facilitate future studies of raptors and their malaria-like parasites. PMID- 26645669 TI - Which insulin resistance-based definition of metabolic syndrome has superior diagnostic value in detection of poor health-related quality of life? Cross sectional findings from Tehran Lipid and Glucose Study. AB - BACKGROUND: The superiority of the diagnostic power of different definitions of metabolic syndrome (MetS) in detecting objective and subjective cardiovascular outcomes is under debate. We sought to compare diagnostic values of different insulin resistance (IR)-based definitions of MetS in detecting poor health related quality of life (HRQoL) in a large sample of Tehranian adults. METHODS: This cross-sectional study conducted within the framework of the Tehran Lipid and Glucose Study on a total sample of 742 individuals, aged >= 20 years. Metabolic syndrome was defined according to the World Health Organization (WHO), the European Group for the study of Insulin Resistance (EGIR), and the American Association of Clinical Endocrinology (AACE). Health-related quality of life was assessed using the Short Form Health Survey (SF-36). Logistic regression analysis and Receiver Operating Characteristic (ROC) curve were used to investigate the impact of the three IR-based definitions of MetS on HRQoL and compare their discriminative powers in predicting poor HRQoL. RESULTS: Compared with other definitions, the WHO definition identified more participants with MetS (41.8 %). Although the AACE definition had higher adjusted odds ratios for reporting poor physical HRQoL (OR: 1.95; CI: 0.84-4.53 and OR: 1.01; CI: 0.55-1.85 in men and women respectively) and mental HRQoL (OR: 0.97; CI: 0.41-2.28 and OR: 1.00; CI: 0.56-1.79 in men and women respectively), none of the three studied definitions were significantly associated with poor physical or mental HRQoL in either gender; nor did ROC curves show any significant difference in the discriminative powers of IR-based definitions in detecting poor HRQoL in either gender. CONCLUSIONS: None of the three studied IR-based definitions of MetS could significantly detect poor HRQoL in the physical or mental domains, indicating no significant superior diagnostic value for any of these definitions. PMID- 26645670 TI - The Impact of Judicial Reform on Crime Victimization and Trust in Institutions in Mexico. AB - This article studies the impact of judicial reform in Mexico. It does so using a survey about crime victimization and perceptions of insecurity (Encuesta Nacional Sobre la Inseguridad [ENSI]) collected in 2005, 2008, and 2009 in 11 Mexican cities, 3 of which implemented the reform in 2007 and 2008. This analysis shows that judicial reform not only reduces victimization but also lowers perceptions of security. Although we find that judicial reform has a negative effect on trust in the local and federal police, judicial reform reduces the probability of being asked by the transit police for a bribe. PMID- 26645671 TI - Reply: To PMID 25933402. PMID- 26645672 TI - Copper(I) Metal-Organic Framework: Visual Sensor for Detecting Small Polar Aliphatic Volatile Organic Compounds. AB - A porous Cu(I)-MOF [H2O?Cu2(L)2I2; L = 1-benzimidazolyl-3,5-bis(4 pyridyl)benzene], which can be a visual and luminescent sensor for detecting small polar aliphatic volatile organic compounds (VOCs), such as alcohols, ketones, and halocarbons, is reported. The naked-eye and luminescent detection limitations for these VOCs are 5 and 1 ppm, respectively. PMID- 26645673 TI - Effects of 5 Weeks of Bench Press Training on Muscle Synergies: A Randomized Controlled Study. AB - Kristiansen, M, Samani, A, Madeleine, P, and Hansen, EA. Effects of 5 weeks of bench press training on muscle synergies: A randomized controlled study. J Strength Cond Res 30(7): 1948-1959, 2016-The ability to perform forceful muscle contractions has important implications in sports performance and in activities of daily living. However, there is a lack of knowledge on adaptations in intermuscular coordination after strength training. The purpose of this study was therefore to assess muscle synergies before and after 5 weeks of bench press training. Thirty untrained male subjects were randomly allocated to a training group (TRA) or a control group (CON). After the pretest, TRA completed 5 weeks of bench press training, before completing a posttest, whereas subjects in CON continued their normal life. During test sessions, surface electromyography (EMG) was recorded from 13 different muscles. Muscle synergies were extracted from EMG data using nonnegative matrix factorization. To evaluate differences between pretest and posttest, we performed a cross-correlation analysis and a cross validation analysis, in which the synergy components extracted in the pretest session were recomputed, using the fixed synergy components from the posttest session. Two muscle synergies accounted for 90% of the total variance and reflected the concentric and eccentric phase, respectively. TRA significantly increased 3 repetition maximum in bench press with 19.0% (25th; 75th percentile, 10.3%; 21.7%) (p < 0.001), whereas no change occurred in CON. No significant differences were observed in synergy components between groups. However, decreases in correlation values for intragroup comparisons in TRA may suggest that the synergy components changed, whereas this was not the case in CON. Strength and conditioning professionals may consider monitoring changes in muscle synergies in training and rehabilitation programs as a way to benchmark changes in intermuscular coordination. PMID- 26645674 TI - Piperlongumine Blocks JAK2-STAT3 to Inhibit Collagen-Induced Platelet Reactivity Independent of Reactive Oxygen Species. AB - BACKGROUND: Piperlongumine (PL) is a compound isolated from the piper longum plant. It possesses anti-cancer activities through blocking the transcription factor STAT3 and by inducing reactive oxygen species (ROS) in cancer, but not normal cells. It also inhibits platelet aggregation induced by collagen, but the underlying mechanism is not known. OBJECTIVE: We conducted in vitro experiments to test the hypothesis that PL regulates a non-transcriptional activity of STAT3 to specifically reduce the reactivity of human platelets to collagen. RESULTS: PL dose-dependently blocked collagen-induced platelet aggregation, calcium influx, CD62p expression and thrombus formation on collagen with a maximal inhibition at 100 MUM. It reduced platelet microvesiculation induced by collagen. PL blocked the activation of JAK2 and STAT3 in collagen-stimulated platelets. This inhibitory effect was significantly reduced in platelets pretreated with a STAT3 inhibitor. Although PL induced ROS production in platelets; quenching ROS using excessive reducing agents: 20 MUM GSH and 0.5 mM L-Cysteine, did not block the inhibitory effects. The NADPH oxidase inhibitor Apocynin also had no effect. CONCLUSIONS: PL inhibited collagen-induced platelet reactivity by targeting the JAK2-STAT3 pathway. We also provide experimental evidence that PL and collagen induce different oxidants that have differential effects on platelets. Studying these differential effects may uncover new mechanisms of regulating platelet functions by oxidants in redox signals. PMID- 26645678 TI - Surface Interrogation Scanning Electrochemical Microscopy of Ni(1-x)Fe(x)OOH (0 < x < 0.27) Oxygen Evolving Catalyst: Kinetics of the "fast" Iron Sites. AB - Nickel-iron mixed metal oxyhydroxides have attracted significant attention as an oxygen evolution reaction (OER) catalyst for solar fuel renewable energy applications. Here, we performed surface-selective and time-dependent redox titrations to directly measure the surface OER kinetics of Ni(IV) and Fe(IV) in NiOOH, FeOOH, and Ni(1-x)Fe(x)OOH (0 < x < 0.27) electrodes. Most importantly, two types of surface sites exhibiting "fast" and "slow" kinetics were found, where the fraction of "fast" sites in Ni(1-x)Fe(x)OOH matched the iron atom content in the film. This finding provides experimental support to the theory proposed model of active sites in Ni(1-x)Fe(x)OOH. The OER rate constant of the "fast" site was 1.70 s(-1) per atom. PMID- 26645679 TI - Family-Level Sampling of Mitochondrial Genomes in Coleoptera: Compositional Heterogeneity and Phylogenetics. AB - Mitochondrial genomes are readily sequenced with recent technology and thus evolutionary lineages can be densely sampled. This permits better phylogenetic estimates and assessment of potential biases resulting from heterogeneity in nucleotide composition and rate of change. We gathered 245 mitochondrial sequences for the Coleoptera representing all 4 suborders, 15 superfamilies of Polyphaga, and altogether 97 families, including 159 newly sequenced full or partial mitogenomes. Compositional heterogeneity greatly affected 3rd codon positions, and to a lesser extent the 1st and 2nd positions, even after RY coding. Heterogeneity also affected the encoded protein sequence, in particular in the nad2, nad4, nad5, and nad6 genes. Credible tree topologies were obtained with the nhPhyML ("nonhomogeneous") algorithm implementing a model for branch specific equilibrium frequencies. Likelihood searches using RAxML were improved by data partitioning by gene and codon position. Finally, the PhyloBayes software, which allows different substitution processes for amino acid replacement at various sites, produced a tree that best matched known higher level taxa and defined basal relationships in Coleoptera. After rooting with Neuropterida outgroups, suborder relationships were resolved as (Polyphaga (Myxophaga (Archostemata + Adephaga))). The infraorder relationships in Polyphaga were (Scirtiformia (Elateriformia ((Staphyliniformia + Scarabaeiformia) (Bostrichiformia (Cucujiformia))))). Polyphagan superfamilies were recovered as monophyla except Staphylinoidea (paraphyletic for Scarabaeiformia) and Cucujoidea, which can no longer be considered a valid taxon. The study shows that, although compositional heterogeneity is not universal, it cannot be eliminated for some mitochondrial genes, but dense taxon sampling and the use of appropriate Bayesian analyses can still produce robust phylogenetic trees. PMID- 26645681 TI - CORR Insights((r)): A Radiation Safety Training Program Results in Reduced Radiation Exposure for Orthopaedic Residents Using the Mini C-arm. PMID- 26645680 TI - Organellar Genomes of White Spruce (Picea glauca): Assembly and Annotation. AB - The genome sequences of the plastid and mitochondrion of white spruce (Picea glauca) were assembled from whole-genome shotgun sequencing data using ABySS. The sequencing data contained reads from both the nuclear and organellar genomes, and reads of the organellar genomes were abundant in the data as each cell harbors hundreds of mitochondria and plastids. Hence, assembly of the 123-kb plastid and 5.9-Mb mitochondrial genomes were accomplished by analyzing data sets primarily representing low coverage of the nuclear genome. The assembled organellar genomes were annotated for their coding genes, ribosomal RNA, and transfer RNA. Transcript abundances of the mitochondrial genes were quantified in three developmental tissues and five mature tissues using data from RNA-seq experiments. C-to-U RNA editing was observed in the majority of mitochondrial genes, and in four genes, editing events were noted to modify ACG codons to create cryptic AUG start codons. The informatics methodology presented in this study should prove useful to assemble organellar genomes of other plant species using whole-genome shotgun sequencing data. PMID- 26645682 TI - Genetic variants in PI3K/AKT pathway are associated with severe radiation pneumonitis in lung cancer patients treated with radiation therapy. AB - PI3K/AKT pathway plays important roles in inflammatory and fibrotic diseases while its connection to radiation pneumonitis (RP) is unclear. In this study, we explored the associations of genetic variants in PI3K/AKT pathway with RP in lung cancer patients with radiotherapy. Two hundred and sixty one lung cancer patients with radiotherapy were included in this prospective study (NCT02490319) and genotyped by MassArray and Sanger Sequence methods. By multivariate Cox hazard analysis and multiple testing, GA/GG genotype of AKT2: rs33933140 (HR = 0.272, 95% CI: 0.140-0.530, P = 1.3E-4, Pc = 9.1E-4), and the GT/GG genotype of PI3CA: rs9838117 (HR = 0.132, 95% CI: 0.042-0.416, P = 0.001, Pc = 0.006) were found to be strongly associated with a decreased occurrence of RP >= grade 3. And patients with the CT/TT genotype of AKT2: rs11880261 had a notably higher incidence of RP >= grade 3 (HR = 2.950, 95% CI: 1.380-6.305, P = 0.005, Pc = 0.025). We concluded that the genetic variants of PI3K/AKT pathway were significantly related to RP of grade >= 3 and may thus be predictors of severe RP before radiotherapy, if further validated in larger population. PMID- 26645683 TI - Traditional and Emerging Lifestyle Risk Behaviors and All-Cause Mortality in Middle-Aged and Older Adults: Evidence from a Large Population-Based Australian Cohort. AB - BACKGROUND: Lifestyle risk behaviors are responsible for a large proportion of disease burden worldwide. Behavioral risk factors, such as smoking, poor diet, and physical inactivity, tend to cluster within populations and may have synergistic effects on health. As evidence continues to accumulate on emerging lifestyle risk factors, such as prolonged sitting and unhealthy sleep patterns, incorporating these new risk factors will provide clinically relevant information on combinations of lifestyle risk factors. METHODS AND FINDINGS: Using data from a large Australian cohort of middle-aged and older adults, this is the first study to our knowledge to examine a lifestyle risk index incorporating sedentary behavior and sleep in relation to all-cause mortality. Baseline data (February 2006- April 2009) were linked to mortality registration data until June 15, 2014. Smoking, high alcohol intake, poor diet, physical inactivity, prolonged sitting, and unhealthy (short/long) sleep duration were measured by questionnaires and summed into an index score. Cox proportional hazards analysis was used with the index score and each unique risk combination as exposure variables, adjusted for socio-demographic characteristics. During 6 y of follow-up of 231,048 participants for 1,409,591 person-years, 15,635 deaths were registered. Of all participants, 31.2%, 36.9%, 21.4%, and 10.6% reported 0, 1, 2, and 3+ risk factors, respectively. There was a strong relationship between the lifestyle risk index score and all-cause mortality. The index score had good predictive validity (c index = 0.763), and the partial population attributable risk was 31.3%. Out of all 96 possible risk combinations, the 30 most commonly occurring combinations accounted for more than 90% of the participants. Among those, combinations involving physical inactivity, prolonged sitting, and/or long sleep duration and combinations involving smoking and high alcohol intake had the strongest associations with all-cause mortality. Limitations of the study include self reported and under-specified measures, dichotomized risk scores, lack of long term patterns of lifestyle behaviors, and lack of cause-specific mortality data. CONCLUSIONS: Adherence to healthy lifestyle behaviors could reduce the risk for death from all causes. Specific combinations of lifestyle risk behaviors may be more harmful than others, suggesting synergistic relationships among risk factors. PMID- 26645684 TI - Lack of Accessible Data on Prosthetic Heart Valves. AB - Incomplete information on characteristics of prosthetic heart valves (PHV) may lead to inappropriate choices for PHV implantation (patient-prosthesis-mismatch) or erroneous interpretation of PHV function after implantation. No single and easy accessible source provides all relevant information on PHV. The aim of this study was to provide a comprehensive overview of available data for the majority of PHVs and annuloplasty rings. Information was collected by reviewing articles published on www.pubmed.org up to December 2014 and by written contact to all PHV manufacturers. Four areas of interest were defined: (1) PHV image, (2) in vivo transvalvular gradients, (3) effective orifice area (EOA) calculators and (4) PHV dimensions. Available information was classified as complete (all categories), partial (two or three categories) or minimal (one category). 108 PHV (including homografts) and 34 annuloplasty rings systems were identified. The information on PHV was complete, partial or minimal in 19.5, 61.0 and 19.5% of PHV, respectively. In 91.6% a picture of the valve could be obtained, whereas normative data for transvalvular gradients and EOA calculators were available in 63.0 and 25.0% of all PHV, respectively. The available data was summarized on a new open access webpage ( www.valveguide.ch ). There is a lack of accessible data on PHV dimensions, normal transvalvular gradients and effective orifice area calculators, although such information is of crucial importance for proper PHV assessment. PMID- 26645685 TI - Muscle damage and repeated bout effect following blood flow restricted exercise. AB - PURPOSE: Blood-flow restricted resistance exercise training (BFRE) is suggested to be effective in rehabilitation training, but more knowledge is required about its potential muscle damaging effects. Therefore, we investigated muscle-damaging effects of BFRE performed to failure and possible protective effects of previous bouts of BFRE or maximal eccentric exercise (ECC). METHODS: Seventeen healthy young men were allocated into two groups completing two exercise bouts separated by 14 days. One group performed BFRE in both exercise bouts (BB). The other group performed ECC in the first and BFRE in the second bout. BFRE was performed to failure. Indicators of muscle damage were evaluated before and after exercise. RESULTS: The first bout in the BB group led to decrements in maximum isometric torque, and increases in muscle soreness, muscle water retention, and serum muscle protein concentrations after exercise. These changes were comparable in magnitude and time course to what was observed after first bout ECC. An attenuated response was observed in the repeated exercise bout in both groups. CONCLUSION: We conclude that unaccustomed single-bout BFRE performed to failure induces significant muscle damage. Additionally, both ECC and BFRE can precondition against muscle damage induced by a subsequent bout of BFRE. PMID- 26645686 TI - Mechanism of Folding and Activation of Subtilisin Kexin Isozyme-1 (SKI-1)/Site-1 Protease (S1P). AB - The proprotein convertase subtilisin kexin isozyme-1 (SKI-1)/site-1 protease (S1P) is implicated in lipid homeostasis, the unfolded protein response, and lysosome biogenesis. The protease is further hijacked by highly pathogenic emerging viruses for the processing of their envelope glycoproteins. Zymogen activation of SKI-1/S1P requires removal of an N-terminal prodomain, by a multistep process, generating the mature enzyme. Here, we uncover a modular structure of the human SKI-1/S1P prodomain and define its function in folding and activation. We provide evidence that the N-terminal AB fragment of the prodomain represents an autonomous structural and functional unit that is necessary and sufficient for folding and partial activation. In contrast, the C-terminal BC fragment lacks a defined structure but is crucial for autoprocessing and full catalytic activity. Phylogenetic analysis revealed that the sequence of the AB domain is highly conserved, whereas the BC fragment shows considerable variation and seems even absent in some species. Notably, SKI-1/S1P of arthropods, like the fruit fly Drosophila melanogaster, contains a shorter prodomain comprised of full length AB and truncated BC regions. Swapping the prodomain fragments between fly and human resulted in a fully mature and active SKI-1/S1P chimera. Our study suggests that primordial SKI-1/S1P likely contained a simpler prodomain consisting of the highly conserved AB fragment that represents an independent folding unit. The BC region appears as a later evolutionary acquisition, possibly allowing more subtle fine-tuning of the maturation process. PMID- 26645687 TI - Acetoacetate Accelerates Muscle Regeneration and Ameliorates Muscular Dystrophy in Mice. AB - Acetoacetate (AA) is a ketone body and acts as a fuel to supply energy for cellular activity of various tissues. Here, we uncovered a novel function of AA in promoting muscle cell proliferation. Notably, the functional role of AA in regulating muscle cell function is further evidenced by its capability to accelerate muscle regeneration in normal mice, and it ameliorates muscular dystrophy in mdx mice. Mechanistically, our data from multiparameter analyses consistently support the notion that AA plays a non-metabolic role in regulating muscle cell function. Finally, we show that AA exerts its function through activation of the MEK1-ERK1/2-cyclin D1 pathway, revealing a novel mechanism in which AA serves as a signaling metabolite in mediating muscle cell function. Our findings highlight the profound functions of a small metabolite as signaling molecule in mammalian cells. PMID- 26645688 TI - Molecular Basis of Filtering Carbapenems by Porins from beta-Lactam-resistant Clinical Strains of Escherichia coli. AB - Integral membrane proteins known as porins are the major pathway by which hydrophilic antibiotics cross the outer membrane of Gram-negative bacteria. Single point mutations in porins can decrease the permeability of an antibiotic, either by reduction of channel size or modification of electrostatics in the channel, and thereby confer clinical resistance. Here, we investigate four mutant OmpC proteins from four different clinical isolates of Escherichia coli obtained sequentially from a single patient during a course of antimicrobial chemotherapy. OmpC porin from the first isolate (OmpC20) undergoes three consecutive and additive substitutions giving rise to OmpC26, OmpC28, and finally OmpC33. The permeability of two zwitterionic carbapenems, imipenem and meropenem, measured using liposome permeation assays and single channel electrophysiology differs significantly between OmpC20 and OmpC33. Molecular dynamic simulations show that the antibiotics must pass through the constriction zone of porins with a specific orientation, where the antibiotic dipole is aligned along the electric field inside the porin. We identify that changes in the vector of the electric field in the mutated porin, OmpC33, create an additional barrier by "trapping" the antibiotic in an unfavorable orientation in the constriction zone that suffers steric hindrance for the reorientation needed for its onward translocation. Identification and understanding the underlying molecular details of such a barrier to translocation will aid in the design of new antibiotics with improved permeation properties in Gram-negative bacteria. PMID- 26645689 TI - Characterization of a Linked Jumonji Domain of the KDM5/JARID1 Family of Histone H3 Lysine 4 Demethylases. AB - The KDM5/JARID1 family of Fe(II)- and alpha-ketoglutarate-dependent demethylases remove methyl groups from tri- and dimethylated lysine 4 of histone H3. Accumulating evidence from primary tumors and model systems supports a role for KDM5A (JARID1A/RBP2) and KDM5B (JARID1B/PLU1) as oncogenic drivers. The KDM5 family is unique among the Jumonji domain-containing histone demethylases in that there is an atypical insertion of a DNA-binding ARID domain and a histone-binding PHD domain into the Jumonji domain, which separates the catalytic domain into two fragments (JmjN and JmjC). Here we demonstrate that internal deletion of the ARID and PHD1 domains has a negligible effect on in vitro enzymatic kinetics of the KDM5 family of enzymes. We present a crystal structure of the linked JmjN-JmjC domain from KDM5A, which reveals that the linked domain fully reconstitutes the cofactor (metal ion and alpha-ketoglutarate) binding characteristics of other structurally characterized Jumonji domain demethylases. Docking studies with GSK J1, a selective inhibitor of the KDM6/KDM5 subfamilies, identify critical residues for binding of the inhibitor to the reconstituted KDM5 Jumonji domain. Further, we found that GSK-J1 inhibited the demethylase activity of KDM5C with 8.5-fold increased potency compared with that of KDM5B at 1 mm alpha ketoglutarate. In contrast, JIB-04 (a pan-inhibitor of the Jumonji demethylase superfamily) had the opposite effect and was ~8-fold more potent against KDM5B than against KDM5C. Interestingly, the relative selectivity of JIB-04 toward KDM5B over KDM5C in vitro translates to a ~10-50-fold greater growth-inhibitory activity against breast cancer cell lines. These data define the minimal requirements for enzymatic activity of the KDM5 family to be the linked JmjN-JmjC domain coupled with the immediate C-terminal helical zinc-binding domain and provide structural characterization of the linked JmjN-JmjC domain for the KDM5 family, which should prove useful in the design of KDM5 demethylase inhibitors with improved potency and selectivity. PMID- 26645691 TI - Regulation of the Water Channel Aquaporin-2 via 14-3-3theta and -zeta. AB - The 14-3-3 family of proteins are multifunctional proteins that interact with many of their cellular targets in a phosphorylation-dependent manner. Here, we determined that 14-3-3 proteins interact with phosphorylated forms of the water channel aquaporin-2 (AQP2) and modulate its function. With the exception of sigma, all 14-3-3 isoforms were abundantly expressed in mouse kidney and mouse kidney collecting duct cells (mpkCCD14). Long-term treatment of mpkCCD14 cells with the type 2 vasopressin receptor agonist dDAVP increased mRNA and protein levels of AQP2 alongside 14-3-3beta and -zeta, whereas levels of 14-3-3eta and theta were decreased. Co-immunoprecipitation (co-IP) studies in mpkCCD14 cells uncovered an AQP2/14-3-3 interaction that was modulated by acute dDAVP treatment. Additional co-IP studies in HEK293 cells determined that AQP2 interacts selectively with 14-3-3zeta and -theta. Use of phosphatase inhibitors in mpkCCD14 cells, co-IP with phosphorylation deficient forms of AQP2 expressed in HEK293 cells, or surface plasmon resonance studies determined that the AQP2/14-3-3 interaction was modulated by phosphorylation of AQP2 at various sites in its carboxyl terminus, with Ser-256 phosphorylation critical for the interactions. shRNA-mediated knockdown of 14-3-3zeta in mpkCCD14 cells resulted in increased AQP2 ubiquitylation, decreased AQP2 protein half-life, and reduced AQP2 levels. In contrast, knockdown of 14-3-3theta resulted in increased AQP2 half-life and increased AQP2 levels. In conclusion, this study demonstrates phosphorylation dependent interactions of AQP2 with 14-3-3theta and -zeta. These interactions play divergent roles in modulating AQP2 trafficking, phosphorylation, ubiquitylation, and degradation. PMID- 26645690 TI - Trypanosome Lytic Factor-1 Initiates Oxidation-stimulated Osmotic Lysis of Trypanosoma brucei brucei. AB - Human innate immunity against the veterinary pathogen Trypanosoma brucei brucei is conferred by trypanosome lytic factors (TLFs), against which human-infective T. brucei gambiense and T. brucei rhodesiense have evolved resistance. TLF-1 is a subclass of high density lipoprotein particles defined by two primate-specific apolipoproteins: the ion channel-forming toxin ApoL1 (apolipoprotein L1) and the hemoglobin (Hb) scavenger Hpr (haptoglobin-related protein). The role of oxidative stress in the TLF-1 lytic mechanism has been controversial. Here we show that oxidative processes are involved in TLF-1 killing of T. brucei brucei. The lipophilic antioxidant N,N'-diphenyl-p-phenylenediamine protected TLF-1 treated T. brucei brucei from lysis. Conversely, lysis of TLF-1-treated T. brucei brucei was increased by the addition of peroxides or thiol-conjugating agents. Previously, the Hpr-Hb complex was postulated to be a source of free radicals during TLF-1 lysis. However, we found that the iron-containing heme of the Hpr-Hb complex was not involved in TLF-1 lysis. Furthermore, neither high concentrations of transferrin nor knock-out of cytosolic lipid peroxidases prevented TLF-1 lysis. Instead, purified ApoL1 was sufficient to induce lysis, and ApoL1 lysis was inhibited by the antioxidant DPPD. Swelling of TLF-1-treated T. brucei brucei was reminiscent of swelling under hypotonic stress. Moreover, TLF-1-treated T. brucei brucei became rapidly susceptible to hypotonic lysis. T. brucei brucei cells exposed to peroxides or thiol-binding agents were also sensitized to hypotonic lysis in the absence of TLF-1. We postulate that ApoL1 initiates osmotic stress at the plasma membrane, which sensitizes T. brucei brucei to oxidation-stimulated osmotic lysis. PMID- 26645693 TI - Frameshift Sequence Variants in the Human Lipase-H Gene Causing Hypotrichosis. AB - Hypotrichosis is a condition of abnormal hair pattern characterized by sparse to absent hair on different parts of the body, including the scalp. The condition is often characterized by tightly curled woolly hairs, discoloration of hair, and development of multiple keratin filled cysts or papules on the body. Sequence analysis of the lipase H (LIPH) gene, mapped on chromosome 3q27.3, led to the identification of a novel frameshift deletion variant (c.932delC, p.Pro311Leufs*3) in one family and previously reported 2-bp deletion (c.659_660delTA) in five other families, inherited hypotrichosis, and woolly hair in an autosomal recessive pattern. The study further extends the body of evidence that sequence variants in the LIPH gene result in hypotrichosis and woolly hair phenotype. PMID- 26645692 TI - Interferon gamma (IFNgamma) Signaling via Mechanistic Target of Rapamycin Complex 2 (mTORC2) and Regulatory Effects in the Generation of Type II Interferon Biological Responses. AB - We provide evidence for a unique pathway engaged by the type II IFN receptor, involving mTORC2/AKT-mediated downstream regulation of mTORC1 and effectors. These events are required for formation of the eukaryotic translation initiation factor 4F complex (eIF4F) and initiation of mRNA translation of type II interferon-stimulated genes. Our studies establish that Rictor is essential for the generation of type II IFN-dependent antiviral and antiproliferative responses and that it controls the generation of type II IFN-suppressive effects on normal and malignant hematopoiesis. Together, our findings establish a central role for mTORC2 in IFNgamma signaling and type II IFN responses. PMID- 26645695 TI - Correction to Advanced Structural Determination of Diterpene Esters Using Molecular Modeling and NMR Spectroscopy. PMID- 26645694 TI - Investigation of the effect of EEG-BCI on the simultaneous execution of flight simulation and attentional tasks. AB - Brain-computer interfaces (BCIs) are widely used for clinical applications and exploited to design robotic and interactive systems for healthy people. We provide evidence to control a sensorimotor electroencephalographic (EEG) BCI system while piloting a flight simulator and attending a double attentional task simultaneously. Ten healthy subjects were trained to learn how to manage a flight simulator, use the BCI system, and answer to the attentional tasks independently. Afterward, the EEG activity was collected during a first flight where subjects were required to concurrently use the BCI, and a second flight where they were required to simultaneously use the BCI and answer to the attentional tasks. Results showed that the concurrent use of the BCI system during the flight simulation does not affect the flight performances. However, BCI performances decrease from the 83 to 63 % while attending additional alertness and vigilance tasks. This work shows that it is possible to successfully control a BCI system during the execution of multiple tasks such as piloting a flight simulator with an extra cognitive load induced by attentional tasks. Such framework aims to foster the knowledge on BCI systems embedded into vehicles and robotic devices to allow the simultaneous execution of secondary tasks. PMID- 26645696 TI - Clinical Characteristics of 582 Patients with Uveal Melanoma in China. AB - OBJECTIVE: To assess clinical characteristics, treatment and survival of patients with uveal melanoma in China. METHODS: The retrospective study included all patients with malignant uveal melanoma who were consecutively examined in the study period from January 2005 and June 2015 in the Beijing Tongren hospital. RESULTS: The mean age of the 582 patients (295(50.7%) women) was 44.6+/-12.6 years (range: 5-77 years). The tumors were located most often in the superior temporal region (in 117(21.5%) patients) and least common in the inferior region (in 31(5.7%) patients). In 548(94.2%) patients, the tumors were located in the choroid, in 33(5.7%) patients in the ciliary body, and in one (0.2%) patient in the iris. Treatment included episcleral brachytherapy (415(71.3%) patients), local tumor resection (48(8.2%) patients) and primary enucleation (119(20.4%) patients). In 53 individuals out of the 415 patients with primary brachytherapy, episcleral brachytherapy was followed by enucleation, due to an increasing tumor size or due to uncontrolled neovascular glaucoma. Median follow-up time was of 30 months (range: 1-124 months; mean: 34.8 +/- 24.4 months). Overall survival rate at 5 and 10 years was of 92.7% and 85.1%. Younger age (P = 0.017), tumor location in the nasal meridian(P = 0.004), smaller tumor size (P<0.001), hemispheric tumor shape (P = 0.025), histological tumor cell type (spindle-cell type versus epitheloid cell type;P = 0.014), and type of treatment (episcleral brachytherapy versus local tumor resection and versus primary enucleation; P<0.001) were significantly associated with the overall survival in univariate analysis, while in multivariate analysis only smaller tumor size was significantly (P<0.001; RR: 4.75; 95% confidence interval: 2.11,10.7) associated with better overall survival. CONCLUSIONS: In this study on clinical characteristics of uveal melanoma of a larger group of patients from China, the onset age was considerably younger and survival rate better than in studies from Western countries. Tumor size was the most significant factor for survival. PMID- 26645699 TI - Differentiating between language domains, cognition, and communication in children with cerebral palsy. PMID- 26645697 TI - The Effects of Ischemic Preconditioning on Human Exercise Performance. AB - BACKGROUND: Ischemic preconditioning (IPC) is the exposure to brief periods of circulatory occlusion and reperfusion in order to protect local or systemic organs against subsequent bouts of ischemia. IPC has also been proposed as a novel intervention to improve exercise performance in healthy and diseased populations. OBJECTIVE: The purpose of this systematic review is to analyze the evidence for IPC improving exercise performance in healthy humans. METHODS: Data were obtained using a systematic computer-assisted search of four electronic databases (MEDLINE, PubMed, SPORTDiscus, CINAHL), from January 1985 to October 2015, and relevant reference lists. RESULTS: Twenty-one studies met the inclusion criteria. The collective data suggest that IPC is a safe intervention that may be capable of improving time-trial performance. Available individual data from included studies demonstrate that IPC improved time-trial performance in 67% of participants, with comparable results in athletes and recreationally active populations. The effects of IPC on power output, oxygen consumption, rating of perceived exertion, blood lactate accumulation, and cardiorespiratory measures are unclear. The within-study heterogeneity may suggest the presence of IPC responders and non-responders, which in combination with small sample sizes, likely confound interpretation of mean group data in the literature. CONCLUSION: The ability of IPC to improve time-trial performance is promising, but the potential mechanisms responsible require further investigation. Future work should be directed toward identifying the individual phenotype and protocol that will best exploit IPC-mediated exercise performance improvements, facilitating its application in sport settings. PMID- 26645698 TI - Global transcriptome profiling analysis reveals insight into saliva-responsive genes in alfalfa. AB - KEY MESSAGE: We studied the genome-wide multiple time-course transcriptome dynamics after saliva deposition in alfalfa and demonstrate that saliva deposition functions as a stress that negatively affects the regrowth of alfalfa. Saliva deposition is one of the key factors influencing plant-herbivore interactions during grazing. Although many studies have focused on the effects of saliva deposition on plant regrowth, no consistent conclusions have been reached. Alfalfa is the most extensively cultivated forage legume, yet most alfalfa cultivars, thus far, are not grazing-tolerant. To better understand the underlying mechanism, we undertook a study to evaluate the global changes in the transcriptome of alfalfa after cow saliva deposition treatment. In this study, cDNA libraries from alfalfa seedlings at 0, 4, 8, and 24 h after cow saliva deposition were constructed and sequenced, resulting in the identification of 53,195 annotated unigenes, from which 4,814 unigenes were significantly differentially expressed. A metabolic pathway enrichment analysis demonstrated that saliva deposition functions as a stress that negatively affects the regrowth of alfalfa by modifying jasmonic acid synthesis, enhancing the susceptibility to pathogens and reducing the expression levels of ribosomal protein genes. In the present study, we demonstrate the potential effects of saliva deposition on alfalfa regrowth at the transcriptome level. These fundamental and important findings could facilitate further investigations into the molecular mechanisms underlying the responses of alfalfa and other related species to herbivore grazing. PMID- 26645700 TI - Association of maternal smoking during pregnancy with aerobic fitness of offspring in young adulthood: a prospective cohort study. AB - OBJECTIVE: We evaluated the association of maternal pre-pregnancy body mass index (BMI), gestational weight gain (GWG), and maternal smoking with aerobic fitness in young men aged 19-20 years. DESIGN: A 19-year prospective cohort study. SETTING: Data from the Northern Finland Birth Cohort 1986 (NFBC 1986) and the Sodankyla Jaeger Brigade, Finland, in 2005-6. POPULATION: Mothers and the 508 offspring in the NFBC 1986 who entered military service at the Sodankyla Jaeger Brigade in 2005. METHODS: Associations of weight, 12-minute running test (Cooper test), and muscle fitness index (MFI) of offspring on entry to military service were evaluated with antenatal factors, including maternal smoking, pre-pregnancy BMI, and GWG. MAIN OUTCOME MEASURES: Aerobic and muscle fitness of the offspring were evaluated by the Cooper test and MFI. RESULTS: Maternal smoking during pregnancy was associated with lower aerobic fitness of male adolescents, measured by the Cooper test (2356 m; 95% confidence interval, 95% CI 2265-2446 m), compared with the offspring of mothers who did not smoke during pregnancy (2537 m, 95% CI 2499-2574 m). This association was independent of the BMIs of both the mother and the offspring, GWG, and the smoking and physical activity of offspring (regression coefficient -140.6 m, 95% CI -273.1 to -8.0 m). High maternal pre pregnancy BMI and excessive GWG were also associated with lower aerobic fitness of the offspring; however, this association was mediated via the weight of the offspring. CONCLUSIONS: Maternal smoking during pregnancy may have a negative impact on the aerobic fitness of the offspring. TWEETABLE ABSTRACT: Study shows that young men have lower aerobic fitness if their mothers smoked during pregnancy. PMID- 26645701 TI - Acute Ultraviolet Radiation Perturbs Epithelialization but not the Biomechanical Strength of Full-thickness Cutaneous Wounds. AB - We hypothesized that priming of the skin with ultraviolet radiation (UVR) before being injured would enhance wound healing. Four groups, each comprising 20 immunocompetent hairless mice, were exposed to simulated solar irradiation in escalating UVR doses; 0 standard erythema dose (SED) = control, 1 SED, 3 SED and 5 SED. Twenty-four hours after UV irradiation, inflammation was quantified by skin reflectance (erythema) and myeloperoxidase (MPO) tissue levels, and two 6 mm full-thickness excisional wounds and one 3 cm incisional wound were inflicted. Epidermal hyperplasia was assessed by quantitative histology. Five days after wounding, wound coverage by neoepithelium and wound width of the excisional wounds was quantified in hematoxylin-eosin sections, and breaking strength was measured in strips from incisional wounds. Erythema (P < 0.001), MPO levels (P < 0.0005) and epidermal cell layers (P < 0.001) increased dose-dependently by UV exposure of dorsal skin. In the excisional wounds, epithelial coverage decreased (P = 0.024) by increasing the UVR dose, whereas there was no significant difference (P = 0.765) in wound MPO levels. Neither wound width (P = 0.850) nor breaking strength (P = 0.320) differed among the groups. Solar-simulated UVR 24 h before wounding impaired epithelialization but was not detrimental for surgical incisional wound healing. PMID- 26645702 TI - Total anomalous pulmonary venous connection with ventricular septal defects. AB - The association of total anomalous pulmonary venous connection with ventricular septal defect and aortic coarctation is rare. A premature neonate weighing 1350 g was diagnosed with infracardiac total anomalous pulmonary venous connection, aortic coarctation, and a perimembranous ventricular septal defect. On postnatal day 23, we performed emergency extended aortic arch anastomosis under total circulatory arrest, pulmonary venous connection repair using a primary sutureless technique, and patch closure of the atrial septal and perimembranous ventricular septal defects. The patient was discharged without complications. Postoperative echocardiography showed no residual coarctation or pulmonary venous obstruction and revealed small muscular ventricular septal defects. PMID- 26645703 TI - Topography of the TH5 Segment in the Diphtheria Toxin T-Domain Channel. AB - The translocation domain (T-domain) of diphtheria toxin contains 10 alpha helices in the aqueous crystal structure. Upon exposure to a planar lipid bilayer under acidic conditions, it inserts to form a channel and transport the attached amino terminal catalytic domain across the membrane. The TH5, TH8, and TH9 helices form transmembrane segments in the open-channel state, with TH1-TH4 translocated across the membrane. The TH6-TH7 segment also inserts to form a constriction that occupies only a small portion of the total channel length. Here, we have examined the TH5 segment in more detail, using the substituted-cysteine accessibility method. We constructed a series of 23 mutant T-domains with single cysteine residues at positions in and near TH5, monitored their channel formation in planar lipid bilayers, and probed for an effect of thiol-specific reagents added to the solutions on either side of the membrane. For 15 of the mutants, the reagent caused a decrease in single-channel conductance, indicating that the introduced cysteine residue was exposed within the channel lumen. We also found that reaction caused large changes in ionic selectivity for some mutant channels. We determined whether reaction occurred in the open state or in the brief flicker closed state of the channel. Finally, we compared the reaction rates from either side of the membrane. Our experiments are consistent with the hypotheses that the TH5 helix has a transmembrane orientation and remains helical in the open-channel state; they also indicate that the middle of the helix is aligned with the constriction in the channel. PMID- 26645705 TI - Government is accused of manipulating figures on NHS winter pressures. PMID- 26645704 TI - Body Mass Index, Waist Circumference, and the Clustering of Cardiometabolic Risk Factors in Early Childhood. AB - BACKGROUND: Obesity has its origins in early childhood; however, there is limited evidence of the association between anthropometric indicators and cardiometabolic risk factors in young children. Our aim was to evaluate the associations between body mass index (BMI) and waist circumference (WC) in relation to cardiometabolic risk factors and to explore the clustering of these factors. METHODS: A cross sectional study was conducted in children aged 1-5 years through TARGet Kids! (n = 2917). Logistic regression was used to evaluate associations between BMI and WC z-scores and individual traditional and possible non-traditional cardiometabolic risk factors. The underlying clustering of these measures was evaluated using principal components analysis (PCA). RESULTS: Child obesity (BMI z-score >2) was associated with high (>90th percentile) leptin [odds ratio (OR) 8.15, 95% confidence interval (CI) 4.56, 14.58] and insulin (OR = 1.76; 95% CI 1.05, 2.94). WC z-score >1 was associated with high insulin (OR 1.59, 95% CI 1.11, 2.28), leptin (OR 5.48, 95% CI 3.48, 8.63) and 25-hydroxyvitamin D < 75 nmol/L (OR 1.39, 95% CI 1.08, 1.79). BMI and WC were not associated with other traditional cardiometabolic risk factors, including non-High Density Lipoprotein (HDL) cholesterol, and glucose. Among children 3-5 years (n = 1035) the PCA of traditional risk factors identified three components: adiposity/blood pressure, metabolic, and lipids. The inclusion of non-traditional risk factors identified four additional components but contributed minimally to the total variation explained. CONCLUSIONS: Anthropometric indicators are associated with selected cardiometabolic risk factors in early childhood, although the clustering of risk factors suggests that adiposity is only one distinct component of cardiometabolic risk. The measurement of other risk factors beyond BMI and WC may be important in defining cardiometabolic risk in early childhood. PMID- 26645706 TI - Acute myeloid leukemia in children: Current status and future directions. AB - Acute myeloid leukemia (AML) accounts for 25% of pediatric leukemia and affects approximately 180 patients annually in Japan. The treatment outcome for pediatric AML has improved through advances in chemotherapy, hematopoietic stem cell transplantation (HSCT), supportive care, and optimal risk stratification. Currently, clinical pediatric AML studies are conducted separately according to the AML subtypes: de novo AML, acute promyelocytic leukemia (APL), and myeloid leukemia with Down syndrome (ML-DS). Children with de novo AML are treated mainly with anthracyclines and cytarabine, in some cases with HSCT, and the overall survival (OS) rate now approaches 70%. Children with APL are treated with an all trans retinoic acid (ATRA)-combined regimen with an 80-90% OS. Children with ML DS are treated with a less intensive regimen compared with non-DS patients, and the OS is approximately 80%. HSCT in first remission is restricted to children with high-risk de novo AML only. To further improve outcomes, it will be necessary to combine more accurate risk stratification strategies using molecular genetic analysis with assessment of minimum residual disease, and the introduction of new drugs in international collaborative clinical trials. PMID- 26645707 TI - Echocardiography and cardiac resynchronisation therapy, friends or foes? AB - Echocardiography is used in cardiac resynchronisation therapy (CRT) to assess cardiac function, and in particular left ventricular (LV) volumetric status, and prediction of response. Despite its widespread applicability, LV volumes determined by echocardiography have inherent measurement errors, interobserver and intraobserver variability, and discrepancies with the gold standard magnetic resonance imaging. Echocardiographic predictors of CRT response are based on mechanical dyssynchrony. However, parameters are mainly tested in single-centre studies or lack feasibility. Speckle tracking echocardiography can guide LV lead placement, improving volumetric response and clinical outcome by guiding lead positioning towards the latest contracting segment. Results on optimisation of CRT device settings using echocardiographic indices have so far been rather disappointing, as results suffer from noise. Defining response by echocardiography seems valid, although re-assessment after 6 months is advisable, as patients can show both continuous improvement as well as deterioration after the initial response. Three-dimensional echocardiography is interesting for future implications, as it can determine volume, dyssynchrony and viability in a single recording, although image quality needs to be adequate. Deformation patterns from the septum and the derived parameters are promising, although validation in a multicentre trial is required. We conclude that echocardiography has a pivotal role in CRT, although clinicians should know its shortcomings. PMID- 26645708 TI - Cardiac dyssynchrony and response to cardiac resynchronisation therapy in heart failure: can genetic predisposition play a role? AB - Cardiac resynchronisation therapy (CRT) is an accepted treatment for heart failure patients with depressed left ventricular (LV) function and dyssynchrony. However, despite better clinical outcome and improved cardiac function after CRT in the majority of eligible heart failure patients, a large proportion of implanted patients do not seem to benefit clinically from this therapy. In this review we consider whether genetic factors may play a role in modulating response to CRT and summarise the few genetic studies that have investigated the role of genetic variation in candidate genes. PMID- 26645709 TI - Patient-reported health status prior to cardiac resynchronisation therapy identifies patients at risk for poor survival and prolonged hospital stays. AB - BACKGROUND: Patient-reported factors have largely been neglected in search of predictors of response to cardiac resynchronisation therapy (CRT). The current study aimed to examine the independent value of pre-implantation patient-reported health status in predicting four-year survival and cardiac-related hospitalisation of CRT patients. METHODS: Consecutive patients (N = 139) indicated to receive a first-time CRT-defibrillator at the University Medical Center Utrecht were asked to complete a set of questionnaires prior to implantation. The Kansas City Cardiomyopathy Questionnaire (KCCQ) was used to assess heart failure-specific health status. Data on patients' demographic, clinical and psychological characteristics at baseline, and on cardiac-related hospitalisations and all-cause deaths during a median follow-up of 3.9 years were obtained from purpose-designed questionnaires and patients' medical records. RESULTS: Results of multivariable Cox regression analyses showed that poor patient-reported health status (KCCQ score < 50) prior to implantation was associated with a 2.5-fold increased risk of cardiac hospitalisation or all-cause death, independent of sociodemographic, clinical and psychological risk factors (adjusted hazard ratio 2.46, 95 % confidence interval (CI) 1.30-4.65). Poor health status was not significantly associated with the absolute number of cardiac-related hospital admissions, but with the total number of days spent in hospital during follow-up (adjusted incidence rate ratio 3.20, 95 % CI 1.88 5.44). CONCLUSIONS: Patient-reported health status assessed prior to CRT identifies patients at risk for poor survival and prolonged hospital stays, independent of traditional risk factors. These results emphasise the importance of incorporating health status measures in cardiovascular research and patient management. Heart failure patients reporting poor health status should be identified and offered appropriate additional treatment programs. PMID- 26645710 TI - Haemodynamic evaluation of alternative left ventricular endocardial pacing sites in clinical non-responders to cardiac resynchronisation therapy. AB - INTRODUCTION: Non response to cardiac resynchronisation therapy (CRT) may be related to the position of the coronary sinus lead. METHODS: We studied the acute haemodynamic response (AHR) from alternative left ventricular (LV) endocardial pacing sites in clinical non-responders to CRT. AHR and the interval from QRS onset to LV sensing (Q-LV interval) from four different endocardial pacing sites were evaluated in 24 clinical non-responders. A rise in LVdP/dtmax >= 15 % from baseline was considered a positive AHR. We also compared the AHR from endocardial with the corresponding epicardial lead position. RESULTS: The implanted system showed an AHR >= 15 % in 5 patients. In 9 of the 19 remaining patients, AHR could be elevated to >= 15 % by endocardial LV pacing. The optimal endocardial pacing site was posterolateral. There was no significant difference in AHR between the epicardial and the corresponding endocardial position. The longest Q-LV interval corresponded with the best AHR in 12 out of the 14 patients with a positive AHR, with an average Q-LV/QRS width ratio of 90 %. CONCLUSIONS: Acute haemodynamic testing may indicate an alternative endocardial pacing site with a positive AHR in clinical non-responders. The Q-LV interval is a strongly correlated with the optimal endocardial pacing site. Endocardial pacing opposite epicardial sites does not result in a better AHR. PMID- 26645711 TI - Getting the LV lead to the right spot. PMID- 26645712 TI - Electrocardiogram: the saviour for this patient. PMID- 26645713 TI - New guidelines on primary PCI for patients with STEMI: changing insights. PMID- 26645714 TI - Electrocardiogram: the saviour for this patient. PMID- 26645715 TI - To implant or not to implant? : That is the unsolved question concerning heart failure patients with non-LBBB. PMID- 26645716 TI - EGFR mutation and lobar location of lung adenocarcinoma. AB - The objective of this study was to investigate the associations among lung cancer location, and epidermal growth factor receptor (EGFR) mutation status. Treatment naive, pathologically confirmed lung adenocarcinomas with tumor specimens available for genetic analysis were included from 2011 through 2014. Overall, 1771 patients with lung adenocarcinoma were included for analysis, after excluding those with carcinoma not otherwise specified, or synchronous multiple primary lung cancers. The median age was 64 years, and the female:male and never smoker:ever smoker ratios were 930:855 (52:48%) and 1167:604 (65:35%), respectively. The EGFR mutation rate was 56%. Among patients, 1093 (62%) had primary tumors in the upper lobes. Compared with the characteristics of the EGFR wild-type, tumors with EGFR activating mutations were more common in women (P < 0.001), never smokers (P < 0.001), and in the upper lobes (P = 0.004). Among EGFR activating mutations, compared with the EGFR exon 19 deletion, L858R mutation were more common in women (P = 0.002), never smokers (P = 0.038), and the upper lobes P < 0.0005). The present study is the first to address that different pulmonary lobar locations might harbor different EGFR mutation subtypes. We demonstrated that adenocarcinomas with L858R mutation, rather than exon 19 deletion or wild-type EGFR gene, prefer to locate over the upper lungs. This phenomenon was more significant in females and never-smokers, implying the result of complex interactions between genetic susceptibility and environmental factors. Therefore, EGFR L858R mutation and exon 19 deletion may not be identical disease entity from the point of carcinogenesis. PMID- 26645717 TI - Elevated expression of JMJD6 is associated with oral carcinogenesis and maintains cancer stemness properties. AB - Cancer stem cells (CSCs) are defined as a small subpopulation of cancer cells within a tumor and responsible for initiation and maintenance of tumor growth. Thus, understanding of molecular regulators of CSCs is of paramount importance for the development of effective cancer therapies. Here, we identified jumonji domain-containing protein 6 (JMJD6) as a novel molecular regulator of oral CSCs. JMJD6 is highly expressed in CSC-enriched populations of human oral squamous cell carcinoma (OSCC) cell lines. Moreover, immunohistochemical staining revealed significantly high level of JMJD6 in OSCC tissues compared to normal human oral epithelia, suggesting that expression of JMJD6 positively correlates with oral carcinogenesis. Subsequent functional analysis showed that knockdown of endogenous JMJD6 in OSCC strongly suppressed self-renewal capacity, a key characteristic of CSCs, and anchorage-independent growth. Conversely, ectopic expression of JMJD6 enhanced CSC characteristics including self-renewal, ALDH1 activity, migration/invasion and drug resistance. Expression of CSC-related genes was also markedly affected by modulating JMJD6 expression. Mechanistically, JMJD6 induces interleukin 4 (IL4) transcription by binding to its promoter region. IL4 rescues self-renewal capacity in JMJD6- knocked down OSCC cells, suggesting the importance of JMJD6-IL4 axis in oral CSCs. Our studies identify JMJD6 as a molecular determinant of CSC phenotype, suggesting that inhibition of JMJD6 may offer an effective therapeutic modality against oral cancer. PMID- 26645719 TI - Using non-human primates to benefit humans: research and organ transplantation response to Cesar Palacios-Gonzalez. PMID- 26645718 TI - Evaluation of potential regulatory function of breast cancer risk locus at 6q25.1. AB - In a genome-wide association study conducted among Chinese women, we identified the single nucleotide polymorphism (SNP) rs2046210 at 6q25.1 for breast cancer risk. To explore a potential regulatory role for this risk locus, we measured expression levels of nine genes at the locus in breast cancer tissue and adjacent normal tissue samples obtained from 67 patients recruited in the Shanghai Breast Cancer Study. We found that rs2046210 had a statistically significant association with the expression levels of the AKAP12 and ESR1 genes in adjacent normal breast tissues. Women who carry the AA/AG risk genotypes had higher expressions of these two genes compared to those who carry G/G genotypes (P = 0.02 and 0.04 for the AKAP12 and ESR1, respectively). However, no significant differences of SNP rs2046210 with gene expression levels were found in tumor tissues. In The Cancer Genome Atlas samples, the AA/AG risk genotypes of SNP rs2046210 were associated with a significantly higher expression level of the AKAP12 gene and a lower level of the ESR1 gene in tumor tissue. Functional analysis using ENCODE data revealed that SNP rs7763637, which is in strong linkage disequilibrium with SNP rs2046210, is likely a potential functional variant, regulating the AKAP12 gene. Taken together, these results from our study suggest that the association between the 6q25.1 locus and breast cancer risk may be mediated through SNPs that regulate expressions of the AKAP12 gene. PMID- 26645720 TI - The Expression of Markers Related to Ovarian Germline Stem Cells in the Mouse Ovarian Surface Epithelium and the Correlation with Notch Signaling Pathway. AB - BACKGROUND/AIMS: Ovarian germline stem cells (OGSCs) have been shown to mainly exist in the ovarian surface epithelium (OSE), but the activity changes of germline stem cells during different reproductive stages and the potential regulatory signaling pathway are still unknown. The Notch signaling pathway plays a key role in cell development, primordial follicles and stem cell proliferation. However, whether it plays a role in the proliferation of OGSCs is unknown. Here, we analyzed the activity changes of germline stem cells and the correlation between germline stem cells and the Notch signaling pathway. METHODS: The expression of germline stem cell markers Mvh, Ooc4 and the Notch molecules Notch1, Hes1, and Hes5 were detected during 3 days (3d), and 2, 12, 20 months (2m, 12m, 20m) mouse ovarian surface epithelium samples. DAPT, a specific inhibitor of the Notch pathway, was used to observe the influence of Notch signaling in the germline stem cells. RESULTS: The results showed that the levels of MVH and OCT4 decreased substantially with reproductive age in ovarian surface epithelium, and the same tendency was detected in the Notch signaling molecules Notch1, Hes1 and Hes5. Dual-IF results showed that the germline stem cell markers were co-expressed with Notch molecules in the ovarian surface epithelium. While, the expression of MVH and OCT4 were reduced when the ovaries were treated with DAPT and the levels were attenuated with increasing dose of DAPT. CONCLUSION: Taken together, our results indicate that the viability of OGSCs decreased with the age of the mouse ovaries, and the activity of OGSCs in the ovarian surface epithelium may be related to the Notch signaling pathway. PMID- 26645721 TI - Effects of antibiotics (oxytetracycline, florfenicol or tulathromycin) on neonatal calves' faecal microbial diversity. PMID- 26645722 TI - Photoelectrochemical Properties of Vertically Aligned CuInS2 Nanorod Arrays Prepared via Template-Assisted Growth and Transfer. AB - Although copper-based chalcopyrite materials such as CuInS2 have been considered promising photocathodes for solar water splitting, the fabrication route for a nanostructure with vertical orientation has not yet been developed. Here, a fabrication route for vertically aligned CuInS2 nanorod arrays from an aqueous solution using anodic aluminum oxide template-assisted growth and transfer is presented. The nanorods exhibit a phase-pure CuInS2 chalcopyrite structure and cathodic photocurrent response without co-catalyst loading. Small particles of CdS and ZnS were conformally decorated onto CuInS2 nanorods using a successive ion layer adsorption and reaction method. With surface modification of CdS/ZnS, the photoelectrochemical properties of CuInS2 nanorod arrays are enhanced via flat-band potential shift, as determined by analyses of onset potential and Mott Schottky plots. PMID- 26645723 TI - Are parents and adolescents in agreement on reporting of recurrent non-specific low back pain in adolescents? A cross-sectional descriptive study. AB - BACKGROUND: Non-specific low back pain is a prevalent symptom in adolescents and is recurrent in some instances. Recent studies have highlighted the marked impact the condition has on daily life of adolescents. However, it is unclear if parents of adolescents reporting recurrent non-specific low back pain know about their child's status. The purpose of the study was to determine the level of agreement between adolescents and their parents in reporting recurrent non-specific low back pain in Harare, Zimbabwe. METHODS: This cross-sectional study formed part of a large study carried out to ascertain the prevalence of non-specific low back pain in Zimbabwean adolescents. Six hundred and twenty (n = 620) Medical Health Questionnaires were sent to parents. School-children with returned questionnaires and informed consents signed were subsequently eligible to participate. A reliable and validated low back pain study questionnaire was administered to 544 adolescents between the ages of 13 and 19 years randomly selected from government administered schools. The questionnaire sought to determine adolescents with recurrent NSLBP. The Kappa statistic (k) was used to analyse agreement between adolescents and parental reports on recurrent NSLBP status. RESULTS: Parental and school-children response rates were acceptable (90.3 and 97.8 %, respectively). The prevalence of recurrent NSLBP was 28.8 % [95 % Confidence Interval, CI = 26.0 31.6]. Both sexes were equally affected [chi (2) (1) =0.19, p = 0.67]. The prevalence increased with age in both sexes [chi (2) trend =90.9, p < 0.001]. Parental reports agreed in 16.3 and 98.7 % for the adolescents with and without recurrent NSLBP respectively. The value of kappa (k) was 0.20 [SE = 0.04; 95 % CI, 0.13-0.27] with a prevalence index and bias index of -0.65 and 0.23, respectively. These results suggest poor strength of the agreement. CONCLUSIONS: Recurrent non-specific low back pain is relatively common among Zimbabwean adolescents. Most of the parents of school-children with recurrent non-specific low back pain are unaware of the low back pain status of their children. Although this does not dismiss the relevance of non-specific low back pain reported during adolescence, these findings create a need to involve parents in awareness or preventive initiatives against low back pain in schools. PMID- 26645724 TI - Knee orthoses for treating patellofemoral pain syndrome. AB - BACKGROUND: Patellofemoral pain syndrome (PFPS) is a painful musculoskeletal condition, which is characterised by knee pain located in the anterior aspect (front) and retropatellar region (behind) of the knee joint. Various non operative interventions are suggested for the treatment of this condition. Knee orthoses (knee braces, sleeves, straps or bandages) are worn over the knee and are thought to help reduce knee pain. They can be used in isolation or in addition to other treatments such as exercise or non-steroidal anti-inflammatory medications. OBJECTIVES: To assess the effects (benefits and harms) of knee orthoses (knee braces, sleeves, straps or bandages) for treating PFPS. SEARCH METHODS: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (11 May 2015), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2015 Issue 5), MEDLINE (1946 to 8 May 2015), EMBASE (1980 to 2015 Week 18), SPORTDiscus (1985 to 11 May 2015), AMED (1985 to 8 May 2015), CINAHL (1937 to 11 May 2015), PEDro (1929 to June 2015), trial registries and conference proceedings. SELECTION CRITERIA: Randomised and quasi randomised controlled clinical trials evaluating knee orthoses for treating people with PFPS. Our primary outcomes were pain and function. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for eligibility, assessed study risk of bias and extracted data. We calculated mean differences (MD) or, where pooling data from different scales, standardised mean differences (SMD) with 95% confidence intervals (CI) for continuous outcomes and risk ratios (RR) with 95% CIs for binary outcomes. We pooled data using the fixed-effect model. MAIN RESULTS: We included five trials (one of which was quasi-randomised) that reported results for 368 people who had PFPS. Participants were recruited from health clinics in three trials and were military recruits undergoing training in the other two trials. Although no trials recruited participants who were categorised as elite or professional athletes, military training does comprise intensive exercise regimens. All five trials were at high risk of bias, including performance bias reflecting the logistical problems in these trials of blinding of participants and care providers. As assessed using the GRADE approach, the available evidence for all reported outcomes is 'very low' quality. This means that we are very uncertain about the results.The trials covered three different types of comparison: knee orthosis and exercises versus exercises alone; one type of orthosis versus another; and knee orthosis versus exercises. No trials assessed the mode of knee orthosis use, such as whether the orthosis was worn all day or only during physical activity. Two trials had two groups; two trials had three groups; and one trial had four groups.All five trials compared a knee orthosis (knee sleeve, knee brace, or patellar strap) versus a 'no treatment' control group, with all participants receiving exercises, either through a military training programme or a home-based exercise programme. There is very low quality evidence of no clinically important differences between the two groups in short-term (2 to 12 weeks follow-up) knee pain based on the visual analogue scale (0 to 10 points; higher scores mean worse pain): MD -0.46 favouring knee orthoses, 95% CI -1.16 to 0.24; P = 0.19; 234 participants, 3 trials). A similar lack of clinically important difference was found for knee function (183 participants, 2 trials). None of the trials reported on quality of life measures, resource use or participant satisfaction. Although two trials reported on the impact on sporting or occupational participation, one trial (35 participants) did not provide data split by treatment group on the resumption of sport activity and the other reported only on abandonment of military training due to knee pain (both cases were allocated a knee orthosis). One trial (59 participants, 84 affected knees) recording only adverse events in the two knee orthoses (both were knee sleeves) groups, reported 16 knees (36% of 44 knees) had discomfort or skin abrasion.Three trials provided very low quality evidence on single comparisons of different types of knee orthoses: a knee brace versus a knee sleeve (63 participants), a patella strap with a knee sleeve (31 participants), and a knee sleeve with a patellar ring versus a knee sleeve only (44 knees). None of three trials found an important difference between the two types of knee orthosis in pain. One trial found no clinically important difference in function between a knee brace and a knee sleeve. None of the three trials reported on quality of life, resource use or participant satisfaction. One trial comparing a patella strap with a knee sleeve reported that both participants quitting military training due to knee pain were allocated a knee sleeve. One poorly reported trial found three times as many knees with adverse effects (discomfort or skin abrasion) in those given knee sleeves with a patella ring than those given knee sleeves only.One trial compared a knee orthosis (knee brace) with exercise (66 participants). It found very low quality evidence of no clinically important difference between the two intervention groups in pain or knee function. The trial did not report on quality of life, impact on sporting or occupational participation, resource use, participant satisfaction or complications. AUTHORS' CONCLUSIONS: Overall, this review has found a lack of evidence to inform on the use of knee orthoses for treating PFPS. There is, however, very low quality evidence from clinically heterogeneous trials using different types of knee orthoses (knee brace, sleeve and strap) that using a knee orthosis did not reduce knee pain or improve knee function in the short term (under three months) in adults who were also undergoing an exercise programme for treating PFPS. This points to the need for good-quality clinically-relevant research to inform on the use of commonly-available knee orthoses for treating PFPS. PMID- 26645725 TI - Loss of SMARCA4 Expression Is Both Sensitive and Specific for the Diagnosis of Small Cell Carcinoma of Ovary, Hypercalcemic Type. AB - Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare ovarian neoplasm that occurs in young women and has a poor prognosis. The histologic diagnosis of SCCOHT can be challenging due to its rarity and relatively nonspecific histologic features, which range from the classic, first-described small cell morphology to a pattern in which there are large cells with abundant eosinophilic cytoplasm. Many entities can be in the differential diagnosis and to date, immunohistochemical stains have shown no distinctive profile and have been of limited aid. SMARCA4 (also known as BRG1) mutations have recently been reported at high frequency in these tumors. SMARCA4 is an important component of the SWI/SNF complex that regulates gene expression through alteration of nucleosome conformation. Studies to date have suggested that immunohistochemical loss of expression of SMARCA4 is associated with the presence of a SMARCA4 mutation in most cases. In this study, the sensitivity and specificity of the immunohistochemical loss of SMARCA4 expression for the diagnosis of SCCOHT is examined in the context of the differential diagnosis with other primary or metastatic ovarian tumors. All but one of the SCCOHT showed loss of SMARCA4 expression (16/17; 94%), while of 279 other tumors tested, only two tumors (one clear cell carcinoma and one ovarian melanoma) showed loss of SMARCA4 expression. We conclude that SMARCA4 immunohistochemistry is highly sensitive and specific for a diagnosis of SCCOHT and is of clinical utility in the differential diagnosis of poorly differentiated ovarian tumors. PMID- 26645726 TI - Thoracic Myoepithelial Tumors: A Pathologic and Molecular Study of 8 Cases With Review of the Literature. AB - Thoracic myoepithelial tumors (MTs) are a rare group of tumors showing predominant or exclusive myoepithelial differentiation. They are poorly characterized from both a morphologic and genetic standpoint, in particular features that separate benign from malignant behavior. We examined the histologic and immunohistochemical features of 8 primary thoracic MTs and performed fluorescence in situ hybridization for EWSR1, FUS, PLAG1, and HMGA2, as well as several partner genes. Half (4/8) of the MTs occurred in large airways, and 3 had infiltrative borders. All cases showed immunoreactivity for epithelial markers, in conjunction with S100 protein or myogenic markers. MTs showed morphologic characteristics analogous to MTs at other sites, with no tumors having ductal differentiation. Necrosis and/or lymphovascular invasion was present in 5 cases, with mitotic activity ranging from 0 to 6 mitoses/2 mm2 (mean 1). Metastases occurred in 2 cases, and no patients died of disease. Gene rearrangements were identified in half of the cases, with EWSR1-PBX1, EWSR1-ZNF444, and FUS-KLF17 fusions identified in 1 case each and 1 case having EWSR1 rearrangement with no partner identified. No cases were found to have HMGA2 or PLAG1 abnormalities. Compared with fusion-negative tumors, fusion-positive tumors tended to occur in patients who were younger (50 vs. 58 y), female (1:3 vs. 3:1 male:female ratio), and demonstrated predominantly spindle and clear cell morphology. Using a combined data set of our case series with 16 cases from the literature, poor prognosis was significantly correlated with metastases (P=0.003), necrosis (P=0.027), and >=5 mitoses/2 mm2/10 high-power field (P=0.005). In summary, we identify a subset of thoracic MTs harboring rearrangements in EWSR1 or FUS, and our data suggest that necrosis and increased mitotic activity correlate with aggressive clinical behavior. PMID- 26645728 TI - Lower Female Genital Tract Tumors With Adenoid Cystic Differentiation: P16 Expression and High-risk HPV Detection. AB - Lower female genital tract tumors with adenoid cystic differentiation are rare, and data on their relationship with high-risk human papillomavirus (HPV) are limited. Here we report the clinicopathologic features from a case series. Tumors with adenoid cystic differentiation, either pure or as part of a carcinoma with mixed differentiation, arising in the lower female genital tract were evaluated by means of immunohistochemical analysis for p16 expression and in situ hybridization using 1 or more probes for high-risk HPV (a high-risk probe covering multiple types, a wide-spectrum probe, and separate type-specific probes for HPV16 and HPV18) and when possible by polymerase chain reaction for high-risk HPV. Six cervical carcinomas with adenoid cystic differentiation admixed with various combinations of at least 1 other pattern of differentiation, including adenoid basal tumor (epithelioma and/or carcinoma), squamous cell carcinoma (basaloid or keratinizing), and small cell carcinoma were identified in patients ranging in age from 50 to 86 years (mean, 73 y; median, 76 y). All of these tumors were characterized by diffuse p16 expression. High-risk HPV was detected in 5 of 6 tested cases: 4 cases by in situ hybridization (all positive for HPV wide-spectrum and HPV16) and 1 by polymerase chain reaction (HPV45). Seven pure adenoid cystic carcinomas (6 vulvar and 1 cervical) were identified in patients ranging in age from 27 to 74 years (mean, 48 y; median, 48 y). All of these tumors were characterized by variable p16 expression ranging from very limited to more extensive but never diffuse. No high-risk HPV was detected in any of these pure tumors. Lower female genital tract carcinomas with adenoid cystic differentiation appear to comprise 2 pathogenetically distinct groups. Cervical carcinomas with mixed differentiation, including adenoid cystic, adenoid basal, squamous, and small cell components, are etiologically related to high-risk HPV and can be identified by diffuse p16 expression. Pure vulvar and cervical adenoid cystic carcinomas appear to be unrelated to high-risk HPV and are distinguished from the mixed carcinomas by nondiffuse p16 expression. PMID- 26645727 TI - Loss of H3K27me3 Expression Is a Highly Sensitive Marker for Sporadic and Radiation-induced MPNST. AB - Most malignant peripheral nerve sheath tumors (MPNSTs) exhibit combined inactivation of NF1, CDKN2A, and polycomb repressive complex 2 component genes (Embryonic Ectoderm Development [EED] and Suppressor of Zeste 12 [SUZ12]). Mutations in EED and SUZ12 induce loss of trimethylation at lysine 27 of histone 3 (H3K27me3), with subsequent aberrant transcriptional activation of polycomb repressive complex 2-repressed homeobox master regulators. These findings prompted us to investigate the performance of an anti-H3K27me3 monoclonal antibody clone C36B11 as an immunohistochemical marker for MPNSTs. We assessed the C36B11 reactivity pattern in a pathologically and genetically well characterized cohort of 68 MPNSTs, spanning various clinical presentations, such as type 1 neurofibromatosis (NF1), radiotherapy, and sporadic MPNSTs. We found that 69% (n=47) of all MPNSTs demonstrated loss of H3K27me3 expression, with 42 (61%) showing complete loss and 5 (7%) showing partial loss, whereas 31% (n=21) retained H3K27me3 expression. Among the NF1-related high-grade MPNSTs, 60% demonstrated loss of expression. In contrast, the majority of both sporadic (95%) and radiotherapy-related (91%) MPNSTs showed loss of H3K27me3 expression. Two of the 3 low-grade MPNSTs and all neurofibromas showed retained expression. Furthermore, all 5 epithelioid MPNSTs retained H3K27me3 labeling. The specificity of H3K27me3 loss as a marker for MPNSTs was studied by testing a large spectrum of lesions included in MPNST differential diagnosis, such as spindle/desmoplastic melanomas, synovial sarcomas, myoepithelial tumors, and other mesenchymal neoplasms, all of which retained expression of H3K27me3. We conclude that immunohistochemical analysis of H3K27me3 has good sensitivity and robust specificity for the diagnosis of MPNST, particularly outside of NF1 clinical history, which represents the most challenging diagnostic setting. PMID- 26645729 TI - Predictors Of Treatment Failure After Radiofrequency Ablation For Intramucosal Adenocarcinoma in Barrett Esophagus: A Multi-institutional Retrospective Cohort Study. AB - Radiofrequency ablation (RFA), with or without endoscopic mucosal resection (EMR), is a safe, effective, and durable treatment option for Barrett esophagus (BE)-associated dysplasia (DYS), but few studies have identified predictors of treatment failure in BE-associated intramucosal adenocarcinoma (IMC). The aim of this study was to determine the rate of IMC eradication when using RFA+/-EMR and to identify clinical and pathologic predictors of treatment failure. A retrospective review of medical records and a central review of index histologic parameters were performed for 78 patients who underwent RFA+/-EMR as the primary treatment for biopsy-proven IMC at 4 academic tertiary medical centers. Complete eradication (CE) (absence of IMC/DYS on first follow-up endoscopy) was achieved in 86% of patients, and durable eradication (DE) (CE with no recurrence of IMC/DYS until last follow-up) was achieved in 78% of patients, with significant variation between the 4 study sites (P=0.03 and 0.09 by analysis of variance for DE and CE, respectively). Use of EMR before RFA significantly reduced the risk for treatment failure for IMC/DYS (hazard ratio, 0.15; 95% confidence interval, 0.05-0.48; P=0.001), whereas IMC involving >=50% of the columnar metaplastic area on index examination significantly increased the risk for treatment failure (hazard ratio, 4.24; 95% confidence interval, 1.53-11.7; P=0.005). Endoscopic and pathologic factors associated with treatment failure in BE-associated IMC treated with RFA+/-EMR may help identify the subset of IMC patients for whom a more aggressive initial approach may be justified. PMID- 26645730 TI - Melanomas Associated With Blue Nevi or Mimicking Cellular Blue Nevi: Clinical, Pathologic, and Molecular Study of 11 Cases Displaying a High Frequency of GNA11 Mutations, BAP1 Expression Loss, and a Predilection for the Scalp. AB - Melanomas associated with blue nevi (MABN) or mimicking cellular blue nevi (MMCBN) represent exceptional variants of malignant cutaneous melanocytic tumors. Uveal and leptomeningeal melanomas frequently have somatic mutations of GNAQ or GNA11, which are believed to be early driver mutations. In uveal melanomas, monosomy 3, linked to the BAP1 gene, is an adverse prognostic factor. We have studied the clinical, histologic, BAP1 expression profile, and molecular data of 11 cases of MABN/MMCBN and 24 cellular blue nevi. Most of the cases of MABN/MMCBN occurred on the scalps of adult patients and presented as rapidly growing nodules, typically >1 cm, often arising at the site of a preexisting melanocytic lesion. The MABN/MMCBN were composed of dense nests of large dermal atypical melanocytes, in some cases lying adjacent to a blue nevus. Four patients developed metastatic disease, and 2 died from their disease. A GNA11 mutation was found in 8/11 cases and a GNAQ mutation in 1 case. Seven of 11 cases showed loss of nuclear BAP1 immunohistochemical (IHC) expression in the malignant component, sparing the adjacent nevus. Array comparative genomic hybridization revealed recurrent deletions of chromosomes 1p, 3p, 4q, 6q, 8p, 16q, and 17q and recurrent gains of chromosomes 6p, 8q, and 21q. The 24 cases of cellular blue nevi frequently occurred on the sacrum, had GNAQ mutations, and showed normal positive IHC staining for BAP1. These results underscore overlapping features in all blue like malignant melanocytic tumors. Loss of BAP1 IHC expression was restricted to melanomas, including all metastatic cases. PMID- 26645731 TI - Electro-triggering and electrochemical monitoring of dopamine exocytosis from a single cell by using ultrathin electrodes based on Au nanowires. AB - A sophisticated set of an Au nanowire (NW) stimulator-Au NW detector system is developed for electrical cell stimulation and electrochemical analysis of subsequent exocytosis with very high spatial resolution. Dopamine release from a rat pheochromocytoma cell is more stimulated by a more negative voltage pulse. This system could help to improve the therapeutic efficacy of electrotherapies by providing valuable information on their healing mechanism. PMID- 26645733 TI - Organic-inorganic hybrid lead halide perovskites for optoelectronic and electronic applications. AB - Organic and inorganic hybrid perovskites (e.g., CH(3)NH(3)PbI(3)), with advantages of facile processing, tunable bandgaps, and superior charge-transfer properties, have emerged as a new class of revolutionary optoelectronic semiconductors promising for various applications. Perovskite solar cells constructed with a variety of configurations have demonstrated unprecedented progress in efficiency, reaching about 20% from multiple groups after only several years of active research. A key to this success is the development of various solution-synthesis and film-deposition techniques for controlling the morphology and composition of hybrid perovskites. The rapid progress in material synthesis and device fabrication has also promoted the development of other optoelectronic applications including light-emitting diodes, photodetectors, and transistors. Both experimental and theoretical investigations on organic inorganic hybrid perovskites have enabled some critical fundamental understandings of this material system. Recent studies have also demonstrated progress in addressing the potential stability issue, which has been identified as a main challenge for future research on halide perovskites. Here, we review recent progress on hybrid perovskites including basic chemical and crystal structures, chemical synthesis of bulk/nanocrystals and thin films with their chemical and physical properties, device configurations, operation principles for various optoelectronic applications (with a focus on solar cells), and photophysics of charge-carrier dynamics. We also discuss the importance of further understanding of the fundamental properties of hybrid perovskites, especially those related to chemical and structural stabilities. PMID- 26645732 TI - Synthesis and Structure-Activity Relationships of Substituted Urea Derivatives on Mouse Melanocortin Receptors. AB - The melanocortin system is involved in the regulation of several complex physiological functions. In particular, the melanocortin-3 and -4 receptors (MC3R/MC4R) have been demonstrated to regulate body weight, energy homeostasis, and feeding behavior. Synthetic and endogenous melanocortin agonists have been shown to be anorexigenic in rodent models. Herein, we report synthesis and structure-activity relationship (SAR) studies of 27 nonpeptide small molecule ligands based on an unsymmetrical substituted urea core. Three templates containing key residues from the lead compounds, showing diversity at three positions (R(1), R(2), R(3)), were designed and synthesized. The syntheses were optimized for efficient microwave-assisted chemistry that significantly reduced total syntheses time compared to a previously reported room temperature method. The pharmacological characterization of the compounds on the mouse melanocortin receptors identified compounds 1 and 12 with full agonist activity at the mMC4R, but no activity was observed at the mMC3R when tested up to 100 MUM concentrations. The SAR identified compounds possessing aliphatic or saturated cyclic amines at the R(1) position, bulky aromatic groups at the R(2) position, and benzyl group at the R(3) position resulted in mMC4R selectivity over the mMC3R. The small molecule template and SAR knowledge from this series may be helpful in further design of MC3R/MC4R selective small molecule ligands. PMID- 26645734 TI - Rumination in Early Adolescent Girls: Interactive Contributions of Mother Adolescent Relationship Quality and Maternal Coping Suggestions. AB - Research suggests that rumination places adolescents at risk for psychopathology. However, little is known about the association between parenting and rumination. Moreover, relevant theoretical models suggest that parents contribute to the development of rumination both explicitly through their suggestions about how to cope and implicitly through the context of the mother-adolescent relationship. However, prior work has not examined implicit and explicit factors within the same investigation, precluding exploration of their unique and interactive effects. To address these gaps, the present study examined links between mother adolescent relationship quality, maternal coping suggestions, and adolescent rumination. Participants were early adolescent girls (M age = 12.41 years) and their primary female caregivers. Findings suggested that maternal disengagement suggestions and mother-adolescent relationship quality were each uniquely associated with adolescent rumination. Moreover, the effect of maternal disengagement suggestions depended on the level of maternal engagement suggestions and mother-adolescent relationship quality. Follow-up analyses revealed that these findings were specific to the maladaptive ruminative brooding component of rumination. Future directions for research were elaborated. PMID- 26645736 TI - Role of Aspirin and Dexamethasone against Experimentally Induced Depression in Rats. AB - A large number of current studies indicate that inflammatory mediators may contribute to depression in experimental models as well as in human beings. Nevertheless, the subject, whether anti-inflammatory treatments can prevent depression still remains controversial. In the present study, a chronic mild stress (CMS) model of male Sprague Dawley rats was used to investigate the role of anti-inflammatory drugs in the treatment of depression. All the animals in different groups, except the normal control group, were exposed to CMS procedure for 28 days and concurrently treated with aspirin (10 mg/kg, p.o.), dexamethasone (1 mg/kg p.o.) and amitriptyline (10 mg/kg p.o., reference standard), respectively. Amitriptyline was also used in combination with aspirin and dexamethasone to inspect any synergistic effects. Tests performed towards the end of the study included sucrose preference test, behavioural tests like forced swim test, elevated plus-maze, light/dark box, locomotor activity and biochemical estimations like serum cortisol and brain neurotransmitters. Disease control group (CMS-treated) produced significant depressive behaviour in rats. The animals treated with aspirin showed increased sucrose preference, decreased immobility time in forced swim test, decreased serum cortisol and increased brain serotonin levels signifying antidepressant action. In contrast, there was aggravation of depressive behaviour in rats treated with dexamethasone. Together, these findings suggest that aspirin can serve as a potential antidepressant both individually and as adjunctive agent in the treatment of depression. Inhibition of the inflammatory mediators during stress procedures or any other potential physiological and biochemical mechanisms may be involved in its antidepressant effect. PMID- 26645737 TI - Graphene mediated improved sodium storage in nanocrystalline anatase TiO2 for sodium ion batteries with ether electrolyte. AB - We report here the synergistic effect of graphene and diglyme electrolyte in significantly improving the sodium insertion electrochemistry of nanocrystalline anatase TiO2. PMID- 26645735 TI - Intradermal injection of human adipose-derived stem cells accelerates skin wound healing in nude mice. AB - BACKGROUND: The use of stem cells from adipose tissue or adipose-derived stem cells (ASCs) in regenerative medicine could be an interesting alternative to bone marrow stem cells because they are easily accessible and available in large quantities. The aim of this study was to evaluate the potential effect of ASCs on the healing of 12 mm diameter-excisional wounds (around 110 mm(2)) in nude mice. METHODS: Thirty nude mice underwent surgery to create one 12-mm excisional wound per mouse (spontaneous healing, n = 6; Cytocare(r) 532, n = 12; ASCs, n = 12). The Galiano wound model was chosen to avoid shrinkage and thus slow the spontaneous healing (SH) of mouse skin, making it closer to the physiology of human skin healing. Transparent dressings were used to enable daily healing time measurements to be taken. Immunohistochemistry, histological and blood perfusion analysis were carried out on the healed skin. RESULTS: The in vivo results showed the effectiveness of using ASCs on reducing the time needed for complete healing to 21.2 days for SH, 17.4 days for vehicle alone (Cytocare(r) 532) and 14.6 days with the addition of ASCs (p < 0.001). Moreover, cutaneous perfusion of the healed wound was significantly improved in ASC-treated mice compared to SH group, as shown by laser Doppler flowmetry and the quantitation of blood vessels using immunohistochemistry of alphasmooth muscle actin. CONCLUSIONS: The tolerance and efficacy of cryopreserved ASCs to accelerate the complete closure of the wound by increasing the maturation of the skin and its blood perfusion, shows their therapeutic benefit in the wound healing context. PMID- 26645738 TI - Serological Survey of West Nile Virus in Pet Dogs from Saskatchewan, Canada. AB - Serum samples collected from 143 dogs from Saskatchewan, Canada, between 2008 and 2010 were evaluated for seroprevalence of West Nile virus (WNV). WNV antibodies were identified in 40/143 dogs (28%). Dogs that were primarily housed in the yard were 6.2 times (95% confidence interval [CI] 2.6-14.5) more likely to have antibodies than dogs housed in the house or garage. Dogs were more likely to be positive with increasing time spent outside. The results of this study document WNV seroprevalence in dogs from Saskatchewan and suggest that pet dogs might be useful as a sentinel species for WNV surveillance. PMID- 26645739 TI - Anomalous basal ganglia connectivity and obsessive-compulsive behaviour in patients with Prader Willi syndrome. AB - BACKGROUND: Prader Willi syndrome is a genetic disorder with a behavioural expression characterized by the presence of obsessive-compulsive phenomena ranging from elaborate obsessive eating behaviour to repetitive skin picking. Obsessive-compulsive disorder (OCD) has been recently associated with abnormal functional coupling between the frontal cortex and basal ganglia. We have tested the potential association of functional connectivity anomalies in basal ganglia circuits with obsessive-compulsive behaviour in patients with Prader Willi syndrome. METHODS: We analyzed resting-state functional MRI in adult patients and healthy controls. Whole-brain functional connectivity maps were generated for the dorsal and ventral aspects of the caudate nucleus and putamen. A selected obsessive-compulsive behaviour assessment included typical OCD compulsions, self picking and obsessive eating behaviour. RESULTS: We included 24 adults with Prader Willi syndrome and 29 controls in our study. Patients with Prader Willi syndrome showed abnormal functional connectivity between the prefrontal cortex and basal ganglia and within subcortical structures that correlated with the presence and severity of obsessive-compulsive behaviours. In addition, abnormally heightened functional connectivity was identified in the primary sensorimotor cortex-putamen loop, which was strongly associated with self picking. Finally, obsessive eating behaviour correlated with abnormal functional connectivity both within the basal ganglia loops and between the striatum and the hypothalamus and the amygdala. LIMITATIONS: Limitations of the study include the difficulty in evaluating the nature of content of obsessions in patients with Prader Willi Syndrome and the risk of excessive head motion artifact on brain imaging. CONCLUSION: Patients with Prader Willi syndrome showed broad functional connectivity anomalies combining prefrontal loop alterations characteristic of OCD with 1) enhanced coupling in the primary sensorimotor loop that correlated with the most impulsive aspects of the behaviour and 2) reduced coupling of the ventral striatum with limbic structures for basic internal homeostasis that correlated with the obsession to eat. PMID- 26645740 TI - Male veterans with PTSD exhibit aberrant neural dynamics during working memory processing: an MEG study. AB - BACKGROUND: Posttraumatic stress disorder (PTSD) is associated with executive functioning deficits, including disruptions in working memory. In this study, we examined the neural dynamics of working memory processing in veterans with PTSD and a matched healthy control sample using magnetoencephalography (MEG). METHODS: Our sample of recent combat veterans with PTSD and demographically matched participants without PTSD completed a working memory task during a 306-sensor MEG recording. The MEG data were preprocessed and transformed into the time-frequency domain. Significant oscillatory brain responses were imaged using a beamforming approach to identify spatiotemporal dynamics. RESULTS: Fifty-one men were included in our analyses: 27 combat veterans with PTSD and 24 controls. Across all participants, a dynamic wave of neural activity spread from posterior visual cortices to left frontotemporal regions during encoding, consistent with a verbal working memory task, and was sustained throughout maintenance. Differences related to PTSD emerged during early encoding, with patients exhibiting stronger alpha oscillatory responses than controls in the right inferior frontal gyrus (IFG). Differences spread to the right supramarginal and temporal cortices during later encoding where, along with the right IFG, they persisted throughout the maintenance period. LIMITATIONS: This study focused on men with combat-related PTSD using a verbal working memory task. Future studies should evaluate women and the impact of various traumatic experiences using diverse tasks. CONCLUSION: Posttraumatic stress disorder is associated with neurophysiological abnormalities during working memory encoding and maintenance. Veterans with PTSD engaged a bilateral network, including the inferior prefrontal cortices and supramarginal gyri. Right hemispheric neural activity likely reflects compensatory processing, as veterans with PTSD work to maintain accurate performance despite known cognitive deficits associated with the disorder. PMID- 26645742 TI - An experimental and theoretical investigation of the anisotropic branching in gold nanocrosses. AB - In this work, copper (Cu) species were used as reducing reagents in the colloidal preparation of novel cross-shaped gold (Au) nanostructures in oleylamine. The reduction rate can be controlled through an appropriate choice of Cu species to obtain Au nanocrosses of varying sizes. It was found that the presence of Cu species during the nucleation stage is crucial to the formation of a branched morphology. Further analysis revealed that the four primary branches of the Au nanocrosses grow along the <110> and <001> directions, and that secondary branched growth occurs along the <111> direction. First-principles calculations and phase-field models were used to rationalize the observed preferential branching and understand the morphological evolution of the nanocrosses. These unique cross-like Au nanostructures exhibit strong NIR absorption and remarkable plasmonic properties that make them promising materials for optical and biomedical applications. PMID- 26645741 TI - Cortical thickness, volume and surface area in patients with bipolar disorder types I and II. AB - BACKGROUND: Bipolar disorder (BD) is a common chronic psychiatric disorder mainly characterized by episodes of mania, hypomania and depression. The disorder is associated with cognitive impairments and structural brain abnormalities, such as lower cortical volumes in primarily frontal brain regions than healthy controls. Although bipolar disorder types I (BDI) and II (BDII) exhibit different symptoms and severity, previous studies have focused on BDI. Furthermore, the most frequently investigated measure in this population is cortical volume. The aim of our study was to investigate abnormalities in patients with BDI and BDII by simultaneously analyzing cortical volume, thickness and surface area, which yields more information about disease- and symptom-related neurobiology. METHODS: We used MRI to measure cortical volume, thickness and area in patients with BDI and BDII as well as in healthy controls. The large study cohort enabled us to adjust for important confounding factors. RESULTS: We included 81 patients with BDI, 59 with BDII and 85 controls in our analyses. Cortical volume, thickness and surface area abnormalities were present in frontal, temporal and medial occipital regions in patients with BD. Lithium and antiepileptic drug use had an effect on the observed differences in medial occipital regions. Patients with the subtypes BDI and BDII displayed common cortical abnormalities, such as lower volume, thickness and surface area than healthy controls in frontal brain regions but differed in temporal and medial prefrontal regions, where only those with BDI had abnormally low cortical volume and thickness. LIMITATIONS: The group differences can be explained by progressive changes, but also by premorbid conditions. They could also have been influenced by unknown factors, such as social, environmental or genetic factors. CONCLUSION: Our findings suggest diagnosis-related neurobiological differences between the BD subtypes, which could explain distinct symptoms and point to potential biomarkers that could inform the subtype diagnosis of BD. PMID- 26645743 TI - Early unpredictability predicts increased adolescent externalizing behaviors and substance use: A life history perspective. AB - According to evolutionary life history models, environmental harshness and unpredictability can both promote a fast life history strategy characterized by increased risk taking and enacting short-term, opportunistic behaviors. The current longitudinal study tests whether environmental unpredictability during childhood has stronger effects on risky behavior during adolescence than harshness, and whether there may be an early "sensitive period" during which unpredictability has particularly strong and unique effects on these outcomes. Using data from the Minnesota Longitudinal Study of Risk and Adaptation, prospective assessments of environmental unpredictability (changes in residence, cohabitation, and parental occupation) and harshness (mean socioeconomic status) from birth into adolescence were used to predict self-reported externalizing behaviors and substance use at age 16 (N = 220). Exposure to greater early unpredictability (between ages 0 and 5) predicted more externalizing behaviors as well as more alcohol and marijuana use at age 16, controlling for harshness and later unpredictability (between ages 6 and 16). Harshness predicted adolescent substance use, and later unpredictability predicted adolescent externalizing behaviors at the trend level. Early unpredictability and harshness also interacted, such that the highest levels of risk taking occurred in individuals who experienced more early unpredictability and lived in harsher environments. Age 16 externalizing behaviors, but not substance use, mediated the association between early unpredictability and externalizing/criminal behaviors at age 23. We discuss how exposure to early environmental unpredictability may alter biological and social-cognitive functioning from a life history perspective. PMID- 26645744 TI - Health correlates of workplace bullying: a 3-wave prospective follow-up study. AB - OBJECTIVE: This study aimed to examine the course of workplace bullying and health correlates among Danish employees across a four-year period. METHODS: In total, 7502 public service and private sector employees participated in a 3-wave study from 2006 through 2011. Workplace bullying over the past 6-12 months and data on health characteristics were obtained by self-reports. We identified major depression using Schedules for Clinical Assessment in Neuropsychiatry interviews and the Major Depression Inventory. We performed cross-sectional and longitudinal analyses of outcomes according to self-labelled bullying at baseline using logistic regression. RESULTS: Reports of bullying were persistent across four years in 22.2% (57/257) of employees who initially reported bullying. Baseline associations between self-labelled bullying and sick-listing, poor self-rated health, poor sleep, and depressive symptoms were significant with adjusted odds ratios (OR) ranging from 1.8 [95% confidence interval (95% CI) 1.5-2.4] for poor sleep quality among those bullied "now and then" to 6.9 (95% CI 3.9-12.3) for depression among those reporting being bullied on a daily to monthly basis. In longitudinal analyses adjusting for bullying during follow-up, all health correlates except poor sleep quality persisted up to four years. CONCLUSION: Self reported health correlates of workplace bullying including sick-listing, poor self-rated health, depressive symptoms, and a diagnosis of depression tend to persist for several years regardless of whether bullying is discontinued or not. Independent measures of bullying and outcomes are needed to learn whether these findings reflect long lasting health consequences of workplace bullying or whether self-labelled workplace bullying and health complaints are correlated because of common underlying factors. PMID- 26645747 TI - G-Fresnel smartphone spectrometer. AB - We report a smartphone spectrometer with nanometer resolution working in the visible range. A G-Fresnel device with the dual functionality of focusing and dispersion is used to enable miniaturization. Proof of principle application to Bradford assay of protein concentration is also demonstrated. PMID- 26645745 TI - Costs and advance directives at the end of life: a case of the 'Coaching Older Adults and Carers to have their preferences Heard (COACH)' trial. AB - BACKGROUND: Total costs associated with care for older people nearing the end of life and the cost variations related with end of life care decisions are not well documented in the literature. Healthcare utilisation and associated health care costs for a group of older Australians who entered Transition Care following an acute hospital admission were calculated. Costs were differentiated according to a number of health care decisions and outcomes including advance directives (ADs). METHODS: Study participants were drawn from the Coaching Older Adults and Carers to have their preferences Heard (COACH) trial funded by the Australian National Health and Medical Research Council. Data collected included total health care costs, the type of (and when) ADs were completed and the place of death. Two-step endogenous treatment-regression models were employed to test the relationship between costs and a number of variables including completion of ADs. RESULTS: The trial recruited 230 older adults with mean age 84 years. At the end of the trial, 53 had died and 80 had completed ADs. Total healthcare costs were higher for younger participants and those who had died. No statistically significant association was found between costs and completion of ADs. CONCLUSION: For our frail study population, the completion of ADs did not have an effect on health care utilisation and costs. Further research is needed to substantiate these findings in larger and more diverse clinical cohorts of older people. TRIAL REGISTRATION: This study was registered on 13/12/2007 with the Australian New Zealand Clinical Trial Registry ( ACTRN12607000638437 ). PMID- 26645748 TI - Policies that kill. PMID- 26645746 TI - Diversity of plant circadian clocks: Insights from studies of Chlamydomonas reinhardtii and Physcomitrella patens. AB - Arabidopsis thaliana has long been the model plant of choice for elucidating the mechanisms of the circadian clock. Recently, relevant results have accumulated in other species of green plant lineages, including green algae. This mini-review describes a comparison of the mechanism of the A. thaliana clock to those of the green alga Chlamydomonas reinhardtii and the moss Physcomitrella patens, focusing on commonalities and divergences of subsystems of the clock. The potential of such an approach from an evolutionary viewpoint is discussed. PMID- 26645749 TI - Health literacy: from the patient to the professional to the system. PMID- 26645750 TI - Does it really matter if sperm counts are decreasing? PMID- 26645751 TI - Tinnitus healthcare in New Zealand. PMID- 26645752 TI - Tinnitus prevalence in New Zealand. AB - AIM: There is a lack of consensus in the international literature pertaining to the prevalence of tinnitus for the overall population, as well as sex and age sub groups, suggesting the need for country-specific prevalence estimates. We aim to find prevalence estimates of tinnitus that are representative of the New Zealand population. METHOD: We obtained data from random-digit dialled telephone surveys of households, conducted by Roy Morgan Research Limited between August, 2007, and July, 2013, for people aged >= 14 years in New Zealand (n=69,976). As part of the survey, participants were asked whether they have had tinnitus in the last 12 months. The response options were "yes" or "no". Estimates were standardised to the New Zealand population structure based on the 2013 national census. Sex, age and ethnic differences were explored. RESULTS: The overall weighted prevalence for any tinnitus was 6.0% in the total New Zealand population age >= 14 years. Tinnitus was higher among males (6.5%) compared to females (5.5%). Males were 55% more likely to report tinnitus compared to females among young adults aged 14 to 24 years, while males were 32% more likely to report tinnitus compared to females among adults aged 50 to 64 years. Tinnitus prevalence increased with age, peaking at 13.5% for older adults aged >= 65 years. Adults aged >= 65 years are three times more likely to report tinnitus than people aged below 65 years. Tinnitus prevalence was highest among people identifying as European (7.05%) and lowest among people identifying as Asian (1.00%). CONCLUSION: This is the first nationally representative study of tinnitus prevalence in New Zealand and largest study sample internationally for tinnitus prevalence to date. Tinnitus is a public health problem affecting approximately 207,000 people in the New Zealand population aged >= 14 years. This study has highlighted the importance of sex and age in defining a high-risk tinnitus population, but our knowledge falls short of profiling their ethnic and social-economic characteristics. PMID- 26645753 TI - Laparoscopic adrenalectomy for phaeochromocytoma: a case series. AB - AIM: To describe our 13-year experience in laparoscopic adrenalectomy for phaeochromocytoma. METHOD: We performed a retrospective analysis of case notes of 29 patients who underwent laparoscopic adrenalectomy for phaeochromocytoma between 2000 and 2013. RESULTS: Twenty-nine patients (16 female), aged 16 to 67 years, underwent laparoscopic adrenalectomy for phaeochromocytoma. All patients were treated preoperatively with alpha-blocking agents. 80% were prescribed additional preoperative antihypertensive agents. 90% received antihypertensive agents intraoperatively. All patients received intraoperative magnesium sulphate for haemodynamic stabilisation. The mean operative time was 160 minutes. Nearly all of the patients experienced haemodynamic stability during surgery. Two patients required conversion to open adrenalectomy, due to severe intraoperative hypertension during tumour handling, and due to extensive intra-abdominal adhesions. Postoperative complications were minimal, and included blood loss, superior epigastric artery damage, and cellulitis at the laparoscopic port site. There was no perioperative mortality. The median length of stay postoperatively was 4 days. 24% were prescribed antihypertensive medication on discharge. CONCLUSION: In our experience, favourable perioperative outcomes were achieved, demonstrating that laparoscopic adrenalectomy for phaeochromocytoma is a safe and effective procedure in the setting of experienced and skilled surgical, anaesthetic and medical teams delivering the perioperative care. PMID- 26645755 TI - Sperm quality in New Zealand: Is the downward trend continuing? AB - AIM: To investigate whether the decline in sperm concentration in New Zealand sperm donors observed from 1987 to 2007 continued in the period 2008-2014. METHOD: A retrospective study from 2008 to 2014. The first semen sample of 285 men presenting as sperm donors in Auckland and Wellington was analysed for sperm concentration, seminal fluid volume and the percentage of motile sperm. These results were compared to results from 1987 to 2007 from the same clinics. RESULTS: The decline in semen volume and sperm concentration observed between 1987 and 2007 did not continue in 2008-2014. Sperm concentration decreased from 1987 until some time between 1997 and 2001, and has remained stable at an average of 62x106/ml between 2001 and 2014. Sperm motility declined significantly (8%) in the period 2008-2014, but there was no significant change over the total period studied, between 1987 and 2014. CONCLUSION: After a decline between 1987 and sometime during 1997-2001, the sperm concentration in men presenting as donors remained unchanged between 2002 and 2014, suggesting semen quality has not changed in New Zealand men over the last decade. PMID- 26645754 TI - An audit of paediatric referrals to the Southern Cochlear Implant Programme (2009 2014). AB - AIM: To determine the effect of the Universal Newborn Hearing Screening and Early Intervention Programme on the age of referral and implantation of prelingually deaf children in the Southern Cochlear Implant Programme. METHOD: A retrospective review of data collected prospectively from March 2003 to August 2014. RESULTS: 123 children were referred to the programme with prelingual deafness in the time period. There was a significant decrease in the age of referral (median 6.23 months vs. 21.50 months) and age at implantation (12.66 months vs. 24.0 months) in those that underwent newborn hearing screening. Reasons for delay in referral and implantation were identified. CONCLUSION: The introduction of universal newborn hearing screening has significantly reduced the age at referral and implantation of prelingually deaf children. However, the screening programme must continue to undergo monitoring and regular audit. Efforts must also be made to reduce the time to referral, including reducing non-attendance rates, education for parents and service providers, and earlier referral of those with comorbidities so as to reduce the time to implantation. PMID- 26645756 TI - Endovascular clot retrieval for acute ischaemic stroke: the Auckland City Hospital experience. AB - AIMS: In acute ischaemic stroke, endovascular therapy with the Solitaire FR stent retriever has been shown to double recanalisation rates and the numbers of patients who recover to be functionally independent, when compared to standard therapy. We present the Auckland City Hospital experience of clot retrieval. METHODS: Previously independent ischaemic stroke patients with contraindications to, or no response following, i.v. alteplase, were treated with clot retrieval. All patients had proximal large artery occlusions on CT angiography and many also had CT perfusion scans showing salvageable ischaemic tissue. RESULTS: Clot retrieval was performed in 33 patients (10 women, mean (SD) age of 54 (17) years) since 2011. Twenty-two (67%) patients were first treated with alteplase. Patients fell into three groups: 17 (52%) had anterior circulation occlusion, similar to those in recent clot retrieval studies; 10 (30%) had posterior circulation occlusion; and six (18%) had 'Rescue' clot retrieval, usually with stroke that followed a procedure. Patients with anterior circulation occlusion had a median time from symptom onset to groin puncture of 225 (range 95-450) minutes, full recanalisation occurred in 76%, and by day 90, all 17 were alive and living at home, with 63% functionally independent (modified Rankin Scale (mRS) 0-2). At day 90, eight of 10 posterior circulation occlusion group patients were alive and living at home, four with a mRS of 0-2. In contrast, four of six 'Rescue' patients had died, and another was functionally dependent with a mRS of 4. CONCLUSIONS: Endovascular clot retrieval can be safely and effectively performed in a New Zealand setting with similar results to recent trials in anterior circulation occlusion patients. We suggest that District Health Boards develop clot retrieval services as part of regional hyperacute stroke treatment pathways. PMID- 26645758 TI - Diabetic Charcot neuroarthropathy: The diagnosis must be considered in all diabetic neuropathic patients presenting with a hot, swollen foot. AB - The diagnosis of diabetic Charcot neuroarthropathy (CN) is challenging. This is especially true early in the disease process, when its classical presentation of an acutely inflamed foot may masquerade as other more common lower limb conditions. Prompt diagnosis and appropriate treatment reduces the risk of CN causing permanent incapacitating foot deformity or amputation. We report two cases in which the diagnosis was delayed, resulting in long-term sequelae. These cases highlight the importance of considering CN in patients with diabetic peripheral neuropathy, who present with a red, hot, and swollen foot. PMID- 26645757 TI - New Zealand Society of Gastroenterology Guidelines for the Management of Refractory Ulcerative Colitis. AB - The management of patients with ulcerative colitis who are dependent on corticosteroid for control of symptoms, or refractory to corticosteroids or standard immunosuppressive therapy, is challenging. The development of newer medical therapies has increased the options for managing patients in this situation, but access and funding remain limited. This guideline summarises the literature regarding this situation and provides guidance as to the management of refractory colitis in the New Zealand setting. PMID- 26645759 TI - A rare cause of pulmonary tuberculosis. AB - We present a case of bovine tuberculosis in a 50-year-old Maori female. She had worked for approximately 7 years at a local freezing works where animal organs were cleaned and packed. The diagnosis was established 4 weeks after commencement of first-line anti-TB therapy. While human zoonotic tuberculosis may be uncommon in developed countries, its diagnosis still has important public health and treatment implications. PMID- 26645760 TI - A painful shoulder. PMID- 26645761 TI - Proposed changes to the Pharmacy Council of New Zealand Code of Ethics would undermine the trusted position of pharmacists in the delivery of science based health care. PMID- 26645762 TI - Meeting the health needs of newly arrived refugees. PMID- 26645763 TI - Claiming exercise does not solve the obesity crisis is 'reductionism' at its worst. PMID- 26645764 TI - Editorial. PMID- 26645766 TI - Diet-Delivered dsRNAs for Juvenile Hormone-Binding Protein and Vacuolar ATPase-H Implied Their Potential in the Management of the Melon Aphid (Hemiptera: Aphididae). AB - RNA interference is a sequence-specific gene silencing mechanism mediated by double-stranded RNA (dsRNA), which has been harnessed as a useful tool in devising novel insect pest management strategies for various pests such as melon aphid, Aphis gossypii (Glover). In the current study, we cloned and sequenced juvenile hormone-binding protein (JHBP) and vacuolar ATPase subunit H (V-ATPase H) from A. gossypii. We also showed the effectiveness of diet-mediated delivery of dsRNA for JHBP and V-ATPase-H, which silenced the above genes and resulted in mortality. The extent of silencing and mortality were similar for both genes up until 96 h. Bioassay results revealed that the target genes were silenced variably, 1.0 ug/ul concentration having a more profound effect than 0.5 and 0.25 ug/ul concentration in reducing the cognate mRNA transcript level. Results indicated a 9.56-73.21% down regulation (across time and concentrations for both the genes) that resulted in the mortality of A. gossypii. Mortality was in the range of 10-63% for both these genes. Thus, the current study demonstrated the potentiality of both JHBP and V-ATPase-H as excellent targets for the management of A. gossypii. PMID- 26645765 TI - Effect of Native Gastric Mucus on in vivo Hybridization Therapies Directed at Helicobacter pylori. AB - Helicobacter pylori infects more than 50% of the worldwide population. It is mostly found deep in the gastric mucus lining of the stomach, being a major cause of peptic ulcers and gastric adenocarcinoma. To face the increasing resistance of H. pylori to antibiotics, antimicrobial nucleic acid mimics are a promising alternative. In particular, locked nucleic acids (LNA)/2'-OMethyl RNA (2'OMe) have shown to specifically target H. pylori, as evidenced by in situ hybridization. The success of in vivo hybridization depends on the ability of these nucleic acids to penetrate the major physical barriers-the highly viscoelastic gastric mucus and the bacterial cell envelope. We found that LNA/2'OMe is capable of diffusing rapidly through native, undiluted, gastric mucus isolated from porcine stomachs, without degradation. Moreover, although LNA/2'OMe hybridization was still successful without permeabilization and fixation of the bacteria, which is normally part of in vitro studies, the ability of LNA/2'OMe to efficiently hybridize with H. pylori was hampered by the presence of mucus. Future research should focus on developing nanocarriers that shield LNA/2'OMe from components in the gastric mucus, while remaining capable of diffusing through the mucus and delivering these nucleic acid mimics directly into the bacteria. PMID- 26645767 TI - Fluorometric selective detection of fluoride ions in aqueous media using Ag doped CdS/ZnS core/shell nanoparticles. AB - The presence of fluoride ions in drinking water plays an important role in human health. For that reason, maintaining the optimum concentration of fluoride ions in drinking water is essential, as both low and excess (above the permissible level) concentrations can cause different health problems, such as fluorosis, urolithiasis, kidney failure, cancer, and can even lead to death. So, development of a simple and low cost method for the detection of fluoride ions in water is highly desirable. In this study, a fluorometric method based on Ag-CdS/Ag-ZnS core/shell nanoparticles is developed for fluoride ion detection. The method was tested in aqueous solution at different pH values. The selectivity and sensitivity of the fluorescence probe was checked in the presence of other anions (Cl(-), Br(-), I(-), NO3(-) SO4(2-), HCO3(-), HPO4(2-), CH3COO(-), and H2PO4(-)) and found there is no significant interference of these associated ions. The fluoride ion concentration was varied in the range 190-22 800 MUg L(-1) and a lower detection limit was obtained as 99.7 MUg L(-1). PMID- 26645769 TI - [Attachment disorder or attachment chance - an international look at care and adoption]. PMID- 26645770 TI - [The outcomes of Adoption in the Case of the "British Chinese Adoption Study"]. AB - Practitioners can over-estimate the incidence of problems in adopted children and adults because they do not see those who make good psychological and social adjustments. Research into adoption outcomes can be hard to interpret without information about differing pre-adoption histories. Examples are given of research into three types of adoption: domestic infant adoption, adoptions from public care of maltreated children and international adoption of ex-orphanage children. Although negative outcomes are indisputably evident for some, recovery from adversity is more common than many would predict. It is important to recognize that subsequent nurturing in consistent and stimulating environments can build a platform for effective adaptations to challenges in the future. However, a proper understanding of the consequences of adoption has been limited by the fact that follow-up studies have rarely extended beyond adolescence and early adulthood. The British Chinese Adoption Study is a 50 year follow-up of orphanage girls internationally adopted into the United Kingdom, and is given as an example of good outcomes despite early years of adversity. Scores on mental health assessments were equivalent to the non-adopted, age-matched comparison group of UK women. Most of the women were rated as "good functioning" and educational achievements were many times higher than the comparison women. Life long adverse effects are not inevitable following early adversity. Improved circumstances can promote recovery and good adult adjustment. Practice and research implications are discussed. PMID- 26645771 TI - [The Relationship Between Attachment Representations of Foster Parents and Foster Children and the Role of the Child's Sex]. AB - Children who have been placed in foster care after having experienced difficult family situations need to experience secure relationships. The development of a secure attachment model is regarded as a key protective factor for a healthy development. The present study examines predictors of attachment representations in a sample of 37 foster children aged three to eight years. Children's attachment representations were assessed using the Attachment Story Completion Task, and foster parents' attachment representations with the Adult Attachment Interview. Female foster children scored higher in secure attachment representations than males. Attachment representations of male foster children were positively influenced by a secure attachment representation of their primary foster parent and slightly by the duration of placement in the foster family as well as their age of placement but differently than expected. These results suggest that male foster children may be more vulnerable in their development of attachment representations and that foster parents' state of mind regarding attachment as well as the duration of the placement seem to have an impact on the development of attachment patterns in their foster children. This should be considered in the choice and counseling of foster parents. PMID- 26645772 TI - [Young Foster Children's Attachment and Socio-emotional Functioning - A Norwegian Prospective and Longitudinal Study]. AB - The main aim of the present study was to investigate 60 young foster children's attachment to their foster parents and their socio-emotional functioning at age two and three years compared to 42 low-risk children. At age two, the children were seen in the Strange Situation Procedure (SSP), and a foster parental report was used to investigate socio-emotional functioning. A majority of the foster children was classified as securely attached at both time points, and no significant group difference was detected. Furthermore, among those who were securely attached at age of two, a large majority remained so one year later. Concerning social-emotional functioning, the foster children were reported to show more problem behaviour and less competence at age two and three, although their scores were within age-related norms. The results in the present study are optimistic. However, the question is whether such a positive developmental pathway will last when the foster children will meet new challenges such as school entry and establishing close peer relationships. PMID- 26645773 TI - [Accessing Disturbances of Attachment Symptoms Using Interview Technique]. AB - Disturbances of attachment represent a clinically significant disorder and seriously impair social behavioural functioning. To date there has been little research and valid diagnostic methods are lacking. In the present study a German Version of the Disturbances of Attachment Interview developed by Smyke and Zeanah (1999) was used to assess disturbances of attachment in a sample of foster children and the validity of the translation is investigated. Furthermore, the Strengths and Difficulties Questionnaire (Goodman, 1997) was used to examine the discriminative validity. The results show a satisfying reliability and the scales of attachment disorders declare the main of the variance. There is a weak association between the disinhibited scale and hyperactivity in the SDQ. Overall the disinhibited disorder can be distinguished from other behaviour patterns. Regarding the inhibited scale there are associations with all SDQ scales and the inhibited category seems harder to distinguish from other deviant developmental issues. The method is evaluated as a qualified approach to the diagnosis of attachment disorders in the context of a multimethodical approach. Furthermore, the findings suggest further examination of the construct of attachment disturbances. PMID- 26645774 TI - [Attachment and Cognitive and Motor Development in the First Years after Adoption: A Review of Studies on Internationally Adopted Children from China]. AB - Due to early-childhood adversity, adopted children often display delays in their cognitive and motor development and have problems developing secure attachment relationships with their adoptive parents. In this review we present the results of all available studies on the attachment and the cognitive and motor development of internationally adopted children from China in the first years after arriving in the adoptive family. Seven pertinent studies were found, based on five samples examined in the USA, Canada, and the Netherlands. Regarding cognitive and motor development (five studies) the adoptees showed a delayed development at arrival in the adoptive family. As soon as six months after arrival the adoptees were, on average, functioning within normal ranges, although their catch-up to non-adopted children was not yet complete. Two years after arrival the catch-up to non-adopted peers appeared to be complete. Regarding attachment (two studies) observations of attachment six and twelve months after adoption showed less secure and more disorganized attachment for the adopted children compared to the normative distribution of non-adopted children. Two years after adoption, observations of attachment confirmed a catch-up in secure attachment, but the adoptees still displayed more insecure disorganized attachment than children in the norm group. PMID- 26645775 TI - [Attachment and Adoption: Diagnostics, Psychopathology, and Therapy]. AB - This presentation describes the development of attachment between adopted children and their adoptive parents with a focus on the particular issues seen in international adoptions. The questions of settling in, trauma in the country of origin, and the motivations of the adoptive parents will be discussed. Diagnosis and various psychopathological manifestations will be examined, as will outpatient and inpatient modes of therapy. The treatment of children of various ages will be covered along with the necessity for intensive counseling and psychotherapy for the adoptive parents. This will enable the parents to work through early trauma, which will give them and their adopted child the basis for developing healthy attachment patterns. This in turn will enable the child to mature and integrate into society. Possibilities of prevention are discussed. Many of the approaches discussed here regarding attachment and adoption may be applied to foster children and their foster parents. PMID- 26645780 TI - Work-engaged nurses for a better clinical learning environment: a ward-level analysis. AB - AIM: To correlate workgroup engagement in nursing teams and the clinical learning experience of nursing students. BACKGROUND: Work engagement plays a pivotal role in explaining motivational dynamics. Nursing education is workplace-based and, through their clinical placements, nursing students develop both their clinical competences and their professional identity. However, there is currently a lack of evidence on the role of work engagement related to students' learning experiences. METHODS: A total of 519 nurses and 519 nursing students were enrolled in hospital settings. The Utrecht Work Engagement Scale (UWES) was used to assess work engagement, and the Clinical Learning Environment and Supervision plus nurse Teacher (CLES+T) scale was used to assess students' learning experience. A multilevel linear regression analysis was performed. RESULTS: Group level work engagement of nurses correlated with students' clinical learning experience (beta = 0.11, P < 0.001). Specifically, the 'absorption' and 'dedication' factors mostly contributed to enhancing clinical learning (respectively, beta = 0.37, P < 0.001 and beta = 0.20, P < 0.001). CONCLUSIONS: Nursing teams' work engagement is an important motivational factor to enhance effective nursing education. IMPLICATION FOR NURSING MANAGEMENT: Nursing education institutions and health-care settings need to conjointly work to build effective organisational climates. The results highlighted the importance of considering the group-level analysis to understand the most effective strategies of intervention for both organisations and nursing education. PMID- 26645781 TI - Collective Properties of a Transcription Initiation Model Under Varying Environment. AB - The dynamics of gene transcription is tightly regulated in eukaryotes. Recent experiments have revealed various kinds of transcriptional dynamics, such as RNA polymerase II pausing, that involves regulation at the transcription initiation stage, and the choice of different regulation pattern is closely related to the physiological functions of the target gene. Here we consider a simplified model of transcription initiation, a process including the assembly of transcription complex and the pausing and releasing of the RNA polymerase II. Focusing on the collective behaviors of a population level, we explore the potential regulatory functions this model can offer. These functions include fast and synchronized response to environmental change, or long-term memory about the transcriptional status. As a proof of concept we also show that, by selecting different control mechanisms cells can adapt to different environments. These findings may help us better understand the design principles of transcriptional regulation. PMID- 26645782 TI - A simple analytical model for signal amplification by reversible exchange (SABRE) process. AB - We demonstrate an analytical model for the description of the signal amplification by reversible exchange (SABRE) process. The model relies on a combined analysis of chemical kinetics and the evolution of the nuclear spin system during the hyperpolarization process. The presented model for the first time provides rationale for deciding which system parameters (i.e. J-couplings, relaxation rates, reaction rate constants) have to be optimized in order to achieve higher signal enhancement for a substrate of interest in SABRE experiments. PMID- 26645783 TI - Response to Kuttner Letter. PMID- 26645790 TI - N-Succinimidyl 3-((4-(4-[(18)F]fluorobutyl)-1H-1,2,3-triazol-1-yl)methyl)-5 (guanidinomethyl)benzoate ([(18)F]SFBTMGMB): a residualizing label for (18)F labeling of internalizing biomolecules. AB - Residualizing labeling methods for internalizing peptides and proteins are designed to trap the radionuclide inside the cell after intracellular degradation of the biomolecule. The goal of this work was to develop a residualizing label for the (18)F-labeling of internalizing biomolecules based on a template used successfully for radioiodination. N-Succinimidyl 3-((4-(4-[(18)F]fluorobutyl)-1H 1,2,3-triazol-1-yl)methyl)-5-(bis-Boc-guanidinomethyl)benzoate ([(18)F]SFBTMGMB Boc2) was synthesized by a click reaction of an azide precursor and [(18)F]fluorohexyne in 8.5 +/- 2.8% average decay-corrected radiochemical yield (n = 15). An anti-HER2 nanobody 5F7 was labeled with (18)F using [(18)F]SFBTMGMB ([(18)F]RL-I), obtained by the deprotection of [(18)F]SFBTMGMB-Boc2, in 31.2 +/- 6.7% (n = 5) conjugation efficiency. The labeled nanobody had a radiochemical purity of >95%, bound to HER2-expressing BT474M1 breast cancer cells with an affinity of 4.7 +/- 0.9 nM, and had an immunoreactive fraction of 62-80%. In summary, a novel residualizing prosthetic agent for labeling biomolecules with (18)F has been developed. An anti-HER2 nanobody was labeled using this prosthetic group with retention of affinity and immunoreactivity to HER2. PMID- 26645791 TI - A novel genetic programming approach for epileptic seizure detection. AB - The human brain is a delicate mix of neurons (brain cells), electrical impulses and chemicals, known as neurotransmitters. Any damage has the potential to disrupt the workings of the brain and cause seizures. These epileptic seizures are the manifestations of epilepsy. The electroencephalograph (EEG) signals register average neuronal activity from the cerebral cortex and label changes in activity over large areas. A detailed analysis of these electroencephalograph (EEG) signals provides valuable insights into the mechanisms instigating epileptic disorders. Moreover, the detection of interictal spikes and epileptic seizures in an EEG signal plays an important role in the diagnosis of epilepsy. Automatic seizure detection methods are required, as these epileptic seizures are volatile and unpredictable. This paper deals with an automated detection of epileptic seizures in EEG signals using empirical mode decomposition (EMD) for feature extraction and proposes a novel genetic programming (GP) approach for classifying the EEG signals. Improvements in the standard GP approach are made using a Constructive Genetic Programming (CGP) in which constructive crossover and constructive subtree mutation operators are introduced. A hill climbing search is integrated in crossover and mutation operators to remove the destructive nature of these operators. A new concept of selecting the Globally Prime offspring is also presented to select the best fitness offspring generated during crossover. To decrease the time complexity of GP, a new dynamic fitness value computation (DFVC) is employed to increase the computational speed. We conducted five different sets of experiments to evaluate the performance of the proposed model in the classification of different mixtures of normal, interictal and ictal signals, and the accuracies achieved are outstandingly high. The experimental results are compared with the existing methods on same datasets, and these results affirm the potential use of our method for accurately detecting epileptic seizures in an EEG signal. PMID- 26645792 TI - Toward Development of Psychosocial Measures for Automated Insulin Delivery. AB - The INSPIRE study working group launched its initial workshop in February 2015 to facilitate collaboration among key stakeholders interested in automated insulin delivery (AID) systems and the psychosocial outcomes of individuals who may use these new technologies. Specifically, the INSPIRE team's goal is to facilitate measure development assessing the psychosocial factors associated with AID systems. A second working group was held to foster exchange among key stakeholders in AID system development. Patient, health care provider, engineering, industry, academic, regulatory and payer perspectives were presented. The INSPIRE working group will continue to serve as a platform to encourage open dialogue among all stakeholders with the aim of facilitating technology that offers minimal user burden and maximum benefit from both a psychological and physiologic perspective. PMID- 26645793 TI - Integrated Personalized Diabetes Management (PDM): Design of the ProValue Studies: Prospective, Cluster-Randomized, Controlled, Intervention Trials for Evaluation of the Effectiveness and Benefit of PDM in Patients With Insulin Treated Type 2 Diabetes. AB - BACKGROUND: Collaborative use of structured self-monitoring of blood glucose (SMBG) data and data management software, utilized within a 6-step cycle enables integrated Personalized Diabetes Management (PDM). The 2 PDM-ProValue studies shall assess the effectiveness of this approach in improving patient outcomes and practice efficiencies in outpatient settings. METHODS: The PDM-ProValue studies are 12-month, prospective, cluster-randomized, multicenter, trials to determine if use of integrated PDM in daily life improves glycemic control in insulin treated type 2 diabetes patients. Fifty-four general medical practices (GPs) and 36 diabetes-specialized practices (DSPs) across Germany will be recruited. The practices will be randomly assigned to the control groups (CNL) or the intervention groups (INT) via cluster-randomization. CNL practices will continue with their usual care; INT practices will utilize integrated PDM. The sample size is 1,014 patients (n = 540 DSP patients, n = 474 GP patients). Each study is designed to detect a between-group difference in HbA1c change of at least 0.4% at 12 months with a power of 90% and 2-sided significance level of .05. Differences in timing and degree of treatment adaptions, treatment decisions, blood glucose target ranges, hypoglycemia, self-management behaviors, quality of life, patients attitudes, clinician satisfaction, practice processes, and resource consumption will be assessed. Study endpoints will be analyzed for the modified intent-to treat and per protocol populations. Trial results are expected to be available in late 2016. DISCUSSION: Effective and efficient strategies to optimize diabetes management are needed. These randomized studies will help determine if PDM is beneficial. PMID- 26645794 TI - Prediction of Pseudoexfoliation Syndrome and Pseudoexfoliation Glaucoma by Using Neutrophil to Lymphocyte Ratio and Platelet to Lymphocyte Ratio. AB - PURPOSE: To assess the levels of neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) in patients with pseudoexfoliation syndrome (PEX) and to compare the NLR and PLR results of patients with PEX, PEX glaucoma (PXG), and healthy controls. METHODS: In total, 34 patients with PEX, 29 patients with PXG, and 42 healthy subjects were enrolled in this retrospective study. Complete ophthalmologic examination and complete blood count measurements were performed of all subjects. Complete blood counts were performed within 2 h of blood collection. RESULTS: There was a significant difference in NLR between PEX and control groups (p = 0.012) and PXG and control groups (p = 0.003). Also, a significant difference was found in PLR values between control and PXG groups (p = 0.024). CONCLUSIONS: Our study for the first time provides evidence that PLR and NLR may be useful for predicting the prognosis of PEX patients and progression to PXG. PMID- 26645795 TI - What does the Development of the European Core Curriculum for Cardiovascular Nurses Mean for Australia? AB - A core curriculum for the continuing professional development of nurses has recently been published by the Council on Cardiovascular Nursing and Allied Professions of the European Society of Cardiology. This core curriculum was envisaged to bridge the educational gap between qualification as a nurse and an advance practice role. In addition, the shared elements and international consensus on core themes creates a strong pathway for nursing career development that is directly relevant to Australia. Education programs for nurses in Australia must meet the mandatory standards of the Australian Nursing and Midwifery Accreditation Council (ANMAC), but without a national core curriculum, there can be considerable variation in the content of such courses. The core curriculum is developed to be adapted locally, allowing the addition of nationally relevant competencies, for example, culturally appropriate care of Aboriginal and Torres Strait Islander individuals. Two existing specialist resources could be utilised to deliver a tailored cardiovascular core curriculum; the Heart Education Assessment and Rehabilitation Toolkit (HEART) online (www.heartonline.org.au) and HeartOne (www.heartone.com.au). Both resources could be further enhanced by incorporating the core curriculum. The release of the European core curriculum should be viewed as a call to action for Australia to develop a core curriculum for cardiovascular nurses. PMID- 26645796 TI - Leptin relates to prolonged cardiovascular recovery after acute stress in Africans: The SABPA study. AB - BACKGROUND AND AIMS: Heightened cardiovascular reactivity and delayed recovery to stress are associated with an increased risk of cardiovascular disease. Africans, who are more prone to develop hypertension, show greater cardiovascular reactivity to stress. However, causal factors underlying individual and ethnic differences in stress reactivity and recovery remain largely unexplored. Leptin, which is known for its sympatho-activating effects, is higher in Africans compared to Caucasians for any given body mass index. We compared how cardiovascular reactivity and recovery relate to leptin in African (n = 200) and Caucasian (n = 209) teachers. METHODS AND RESULTS: We measured leptin in serum and cardiovascular baseline and reactivity continuously with the Finometer device during the cold pressor test for 1 min, and recovery at intervals of 1, 3 and 5 min. Africans had higher body mass index, leptin and blood pressure (all P < 0.001). After full adjustment in multiple regression analyses, associations were seen mainly at the 5 min recovery interval. In Africans, cardiac output reactivity (beta = -0.335; P = 0.0018) and arterial compliance- (beta = -0.241; P = 0.048) associated negatively and total peripheral resistance- (beta = 0.227; P = 0.047) positively with leptin. In Caucasians, diastolic blood pressure correlated positively with leptin (beta = 0.200; P = 0.015). CONCLUSION: In Africans, higher circulating leptin levels associated with prolonged cardiovascular recovery after exposure to stress which could explain their increased vulnerability to hypertension development. PMID- 26645797 TI - Association of Inhaled Corticosteroids with Incident Pneumonia and Mortality in COPD Patients; Systematic Review and Meta-Analysis. AB - BACKGROUND: Inhaled corticosteroids are commonly prescribed for patients with severe COPD. They have been associated with increased risk of pneumonia but not with increased pneumonia-associated or overall mortality. METHODS: To further examine the effects of inhaled corticosteroids on pneumonia incidence, and mortality in COPD patients, we searched for potentially relevant articles in PubMed, Medline, CENTRAL, EMBASE, Scopus, Web of Science and manufacturers' web clinical trial registries from 1994 to February 4, 2014. Additionally, we checked the included and excluded studies' bibliographies. We subsequently performed systematic review and meta-analysis of included randomized controlled trials and observational studies on the topic. RESULTS: We identified 38 studies: 29 randomized controlled trials and nine observational studies. The estimated unadjusted risk of pneumonia was increased in randomized trials: RR 1.61; 95% CI 1.35-1.93, p < 0.001; as well as in observational studies: OR 1.89; 95% CI 1.39 2.58, p < 0.001. Six randomized trials and seven observational studies were useful in estimating unadjusted risk of pneumonia -case-fatality: RR 0.91; 95% CI 0.52-1.59, p = 0.74; and OR 0.72; 95% CI 0.59-0.88, p = 0.001, respectively. Twenty-nine randomized trials and six observational studies allowed estimation of unadjusted risk of overall mortality: RR 0.95; 95% CI 0.85-1.05, p = 0.31; and OR 0.79; 95% CI 0.65-0.97, p = 0.02, respectively. CONCLUSIONS: Despite a substantial and significant increase in unadjusted risk of pneumonia associated with inhaled corticosteroid use, pneumonia fatality and overall mortality were found not to be increased in randomized controlled trials and were decreased in observational studies. PMID- 26645798 TI - Quantitative T2* mapping reveals early temporo-spatial dynamics in an ischemic stroke model. AB - BACKGROUND: Oxyhemoglobin-sensitive sequences, namely T2*, can indirectly depict changes in oxygen extraction. Purpose of this study was to investigate the dynamics of T2* changes in ischemic tissue. NEW METHOD: We investigated earliest temporo-spatial dynamics within ischemic tissue, measured with quantitative T2* imaging in the histologically defined infarct core and surrounding surviving tissue. Middle cerebral artery occlusion (MCAO) was induced by a filament model in mice. Serial multiple gradient-echo T2* sequences and diffusion-weighted images were acquired for 60min after MCAO and repeated for 60min after recanalization. T2* maps were co-registered with histology and T2* changes were compared to the contralateral hemisphere. RESULTS: Within the histologically defined infarct core, relative T2* values decreased significantly by -10.8+/-2.8% (P=0.003) compared to the contralateral hemisphere within 3.5+/-0.7min after MCAO. Relative T2* values in volume exceeding the histologically determined infarct core were significantly less decreased (-6.7+/-2.1%; P=0.02) and increased after recanalization (+3.9+/-1.9%; P=0.045). Volume with T2* decrease showed continuous growth over 60min after MCAO (P=0.002) and decreased during 60min after recanalization (P=0.026), showing most significant correlations between infarct core volume and T2* abnormality volume (r=0.66; P=0.037) of the last image acquired after recanalization. COMPARISON WITH EXISTING METHOD(S): To our best knowledge, this is the first application of non-invasive quantitative T2* measurements to assess changes in levels of deoxyhemoglobin as an indirect biomarker for metabolic impairment in ischemic tissue. CONCLUSIONS: Quantitative T2* imaging might be a feasible tool to indicate change of oxygenation in acute stroke imaging, without administration of contrast agent. PMID- 26645799 TI - Improving first responders' psychogenic nonepileptic seizures diagnosis accuracy: Development and validation of a 6-item bedside diagnostic tool. AB - OBJECTIVE: Epileptic seizures (ES) are often seen as a medical emergency, and their immediate and accurate recognition are pivotal in providing acute care. However, a number of clinical situations may mimic ES, potentially leading to misdiagnosis at the emergency room and to inappropriate prescription of antiepileptic drugs (AED) in the acute and chronic settings. Psychogenic nonepileptic seizures (PNES) play a major role in this scenario and often delay the correct diagnosis and increase treatment morbidity and cost. First responders often conduct the initial assessment of these patients, and their impression may be decisive in the prehospital approach to seizures. We sought to investigate and improve the accuracy of PNES diagnosis among professionals involved in the initial assistance to patients with seizures. METHODS: Fifty-three registered nurses, 34 emergency physicians, 33 senior year medical students, and 12 neurology residents took a short training program consisting of an initial video based seizure assessment test (pretest), immediately followed by a 30-minute presentation of a 6-item bedside diagnostic tool and then a video-based reassessment (posttest). Baseline status and learning curves were determined. RESULTS: The distinct professional categories showed no significant differences in their ability to diagnose PNES on both pretests and posttests. All groups improved diagnostic skills after the instructional program. SIGNIFICANCE: The findings helped determine the best identifiable PNES clinical signs and to provide initial validation to a novel diagnostic instrument. In addition, our results showed that educational measures might help in the identification of PNES by first responders, which may decrease the treatment gap. PMID- 26645800 TI - Purification and characterization of a chloride ion-dependent alpha-glucosidase from the midgut gland of Japanese scallop (Patinopecten yessoensis). AB - Marine glycoside hydrolases hold enormous potential due to their habitat-related characteristics such as salt tolerance, barophilicity, and cold tolerance. We purified an alpha-glucosidase (PYG) from the midgut gland of the Japanese scallop (Patinopecten yessoensis) and found that this enzyme has unique characteristics. The use of acarbose affinity chromatography during the purification was particularly effective, increasing the specific activity 570-fold. PYG is an interesting chloride ion-dependent enzyme. Chloride ion causes distinctive changes in its enzymatic properties, increasing its hydrolysis rate, changing the pH profile of its enzyme activity, shifting the range of its pH stability to the alkaline region, and raising its optimal temperature from 37 to 55 degrees C. Furthermore, chloride ion altered PYG's substrate specificity. PYG exhibited the highest Vmax/Km value toward maltooctaose in the absence of chloride ion and toward maltotriose in the presence of chloride ion. PMID- 26645801 TI - Metabolic engineering Corynebacterium glutamicum to produce triacylglycerols. AB - In this study, we metabolically engineered Corynebacterium glutamicum to produce triacylglycerols (TAGs) by completing and constraining a de novo TAG biosynthesis pathway. First, the plasmid pZ8_TAG4 was constructed which allows the heterologous expression of four genes: three (atf1 and atf2, encoding the diacylglycerol acyltransferase; pgpB, encoding the phosphatidic acid phosphatase) to complete the TAG biosynthesis pathway, and one gene (tadA) for lipid body assembly. Second, we applied four metabolic strategies to increase TAGs accumulation: (i) boosting precursor supply by heterologous expression of tesA (encoding thioesterase to form free fatty acid to reduce the feedback inhibition by acyl-ACP) and fadD (encoding acyl-CoA synthetase to enhance acyl-CoA supply), (ii) reduction of TAG degradation and precursor consumption by deleting four cellular lipases (cg0109, cg0110, cg1676 and cg1320) and the diacylglycerol kinase (cg2849), (iii) enhancement of fatty acid biosynthesis by deletion of fasR (cg2737, TetR-type transcriptional regulator of genes for the fatty acid biosynthesis), and (iv) elimination of the observed by-product formation of organic acids by blocking the acetic acid (pqo) and lactic acid production (ldh) pathways. The final strain (CgTesRtcEfasEbp/pZ8_TAG4) achieved a 7.5% yield of total fatty acids (2.38 +/- 0.05 g/L intracellular fatty acids and 0.64 +/- 0.09 g/L extracellular fatty acids) from 4% glucose in shake flasks after process optimization. This corresponds to maximum intracellular fatty acids content of 17.8 +/- 0.5% of the dry cell. PMID- 26645802 TI - Single-molecule real-time transcript sequencing facilitates common wheat genome annotation and grain transcriptome research. AB - BACKGROUND: The large and complex hexaploid genome has greatly hindered genomics studies of common wheat (Triticum aestivum, AABBDD). Here, we investigated transcripts in common wheat developing caryopses using the emerging single molecule real-time (SMRT) sequencing technology PacBio RSII, and assessed the resultant data for improving common wheat genome annotation and grain transcriptome research. RESULTS: We obtained 197,709 full-length non-chimeric (FLNC) reads, 74.6 % of which were estimated to carry complete open reading frame. A total of 91,881 high-quality FLNC reads were identified and mapped to 16,188 chromosomal loci, corresponding to 13,162 known genes and 3026 new genes not annotated previously. Although some FLNC reads could not be unambiguously mapped to the current draft genome sequence, many of them are likely useful for studying highly similar homoeologous or paralogous loci or for improving chromosomal contig assembly in further research. The 91,881 high-quality FLNC reads represented 22,768 unique transcripts, 9591 of which were newly discovered. We found 180 transcripts each spanning two or three previously annotated adjacent loci, suggesting that they should be merged to form correct gene models. Finally, our data facilitated the identification of 6030 genes differentially regulated during caryopsis development, and full-length transcripts for 72 transcribed gluten gene members that are important for the end-use quality control of common wheat. CONCLUSIONS: Our work demonstrated the value of PacBio transcript sequencing for improving common wheat genome annotation through uncovering the loci and full-length transcripts not discovered previously. The resource obtained may aid further structural genomics and grain transcriptome studies of common wheat. PMID- 26645803 TI - A global perspective on assisted reproductive technology fertility treatment: an 8-country fertility specialist survey. AB - BACKGROUND: Procedures that may optimize success in achieving live births from assisted reproductive technology (ART) continue to be examined. Not yet considered are the perspectives of fertility specialists regarding important developments in the fertility treatment field, current unmet needs, and anticipated future advances. In the current study, an 8-country survey of fertility specialists was conducted to provide a comprehensive, global depiction of fertility treatments across different regions. METHODS: Fertility specialists from France, Germany, Italy, Spain, the United Kingdom (UK), the United States (US), China, and Japan were invited to participate in an online survey. Participants were eligible if they personally managed >=25 patients/month who were experiencing difficulty conceiving, and if they had performed ART fertility treatment with >=1 patient in the previous month. Quantitative questions addressed the number of patients seen, main infertility causes, number of cycles performed, ART procedure type, and ART outcomes. Qualitative questions covered diagnostic trends, unmet needs, important advances, and expected future developments. RESULTS: The number of fertility specialists who completed the survey included 29 in France, 33 in Germany, 23 in Italy, 38 in Spain, 34 in the UK, 91 in the US, 50 in China, and 65 in Japan. Patient volume increased over the prior 2 years according to 67 % (242/363) of the fertility specialists. As expected, ART outcomes all declined with age in all countries. ART outcomes varied by country, with the highest implantation, pregnancy, and live birth rates reported by fertility specialists in the US and China and the lowest rates reported in France and Italy. The most frequently reported unmet needs in fertility treatment were financial coverage, improved implantation rate, and egg donation. Most frequently named future advancements expected to change the fertility treatment field included improved embryo selection through imaging and/or metabolomics, improved embryo implantation rate, and use of preimplantation genetic diagnosis. CONCLUSIONS: This study, which follows a rigorous survey methodology, elucidates the current state of fertility specialists' practices and perspectives on the global fertility treatment field, which highlights differences and similarities among countries. This research may inform further studies and procedural developments that might better improve and standardize ART. PMID- 26645804 TI - Morphological and mechanical properties of the posterior leaflet chordae tendineae in the mitral valve. AB - A number of studies have investigated the morphological and mechanical properties of the chordae tendineae of the mitral valve, providing comparisons between basal, marginal, and strut chordae and between chordae at the anterior and posterior leaflets. This study contributes to the literature by comparing the failure load of the chordae tendineae attached to the three posterior leaflet scallops, the anterolateral scallop (P1), middle scallop (P2), and posteromedial scallop (P3) of the mitral valve. In all, 140 chordae isolated from 23 porcine hearts were tested. First, the cross-sectional diameters of all branches in each chorda were measured using a microscope. Next, after positioning the chorda in a tensile testing machine, a preload of 0.2 N was applied, and the chordal length was measured. Cyclic loading between 0 and 0.3 N, 10 times with a speed of 1.5 mm/s, was conducted, after which the machine travelled at 1.5 mm/s until the chorda broke. We found that P2 chordae were thicker than P1 and P3 chordae and longer than P1 chordae. P2 chordae failed at significantly higher loads than P1 and P3 chordae. For all three types of chordae, almost half of the failures occurred at the chordal branch that was closest to the leaflet. PMID- 26645805 TI - Substituent effects on the properties of the hemi-bonded complexes (XH2P...NH2Y)(+) (X, Y=H, F, Cl, Br, NH2, CH3, OH). AB - Ab initio calculations have been performed to study the structures, binding energies, and bonding properties of the hemi-bonded binary complexes (XH2P...NH2Y)(+) with the substituents X and Y being H, F, Cl, Br, NH2, CH3, and OH. The P...N interactions in these open-shelled systems have typical pnicogen bond characteristics but much stronger than the usual pnicogen bonds in closed shell systems. This P...N bond can be strengthened by an electron-withdrawing substituent X or an electron-donating substituent Y, the bonding energy varies from 17 kcal mol(-1) of (CH3H2P...NH2F)(+) to 54 kcal mol(-1) of (FH2P...NH2CH3)(+). A nearly linear X-P...N arrangement is required by the pnicogen bond P...N and results in a strong hyperconjugation and charge transfer from the N lone pair to the X-P sigma* antibond orbital for alpha spin, the P...N interaction is described as a single-electron sigma bond of beta spin. The AIM and NBO analyses revealed that the P...N bonds in the majority of the hemi-bonded complexes are partly covalent in nature. Graphical Abstract The P...N interactions in the open-shelled systems (XH2P...NH2Y)(+) (X, Y=H, F, Cl, Br, NH2, CH3, OH) with bonding energy of 17~54 kcal mol(-1) have typical pnicogen bond characteristics but much stronger than the usual pnicogen bonds in closed shell systems. This P...N bond can be strengthened by an electron-withdrawing substituent X or an electron-donating substituent Y. PMID- 26645806 TI - Characterizing Ni(II) hydration in aqueous solution using DFT and EXAFS. AB - In the present work, a detailed investigation of Ni(II) hydration in water solutions was carried out using density functional theory (DFT) and extended X ray absorption fine structure (EXAFS) spectroscopy. The hydrated characteristics of [Ni(H2O)n](2+) clusters, such as energy parameters, atomic charge distributions, and bond parameters, were explored using DFT with Becke's three parameter exchange potential and the Lee-Yang-Parr correlation functional (B3LYP). DFT calculations indicated that the preferred structure of the first hydration shell of Ni(II) generally has a coordination number of six and is almost unaffected by the water molecules in the outer solvation shell, whereas the structure of the second solvation shell varies as the hydration proceeds. EXAFS measurements are reported for aqueous NiSO4 and Ni(NO3)2 solutions and the Ni(NO3)2.6H2O crystal. Analysis of the EXAFS spectra of these three systems using a multiparameter fitting procedure showed that, in each case, the first coordination shell consists of six water molecules with a Ni-O coordination distance of 2.04 A, and that there is no Ni-S or Ni-N coordination in the first shell. There was no evidence of outer-shell SO4(2-) or NO3(-) ions substituting inner-sphere water molecules in NiSO4 and Ni(NO3)2. The characteristics of Ni(II) hydration obtained from DFT calculations agreed well with those obtained experimentally using EXAFS. PMID- 26645807 TI - DFT study of the hydrolysis reaction in atranes and ocanes: the influence of transannular bonding. AB - Thermochemical kinetics of hydrolysis reactions of compounds with transannular intramolecular M...N bonds, i.e., atranes RM(OCH2CH2)3N and ocanes R2M(OCH2CH2)2NH (M = Si, Ge; R = F, Cl, Me), is studied at the B3LYP/aug-cc-pVDZ theoretical level. Several DFT methods are assessed for the reproduction of the experimental activation barrier for the Si-O bond cleavage of 1-methylsilatrane. Activation barriers for atranes and ocanes show the tendency for their growth with the decrease of the electronegativity of a substituent R on going from F to Me and their decrease from Si to Ge. Hydrolysis activation barriers of atranes and ocanes are compared with those of their acyclic analogs RM(OCH3)3 and R2M(OCH2)2NH in order to study the role of transannular M...N bonds in the stability of these molecules to hydrolysis. Substantially larger barriers for atranes support the opinion that stability of atranes may be explained by the formation of intramolecular bonds; however, the strengthening of transannular M...N bonds results in lower M-O cleavage barriers. It was proposed that the M-O cleavage barrier height is determined not by a weak M...N bonding itself, but rather by the contribution of a nitrogen lone pair to the antibonding orbitals of M-O bonds. The NBO analysis show that this interaction increases with the decrease of the electronegativity of a substituent R and decreases on going from atranes to ocanes. In ocanes, the presence of M...N bonds does not kinetically hinder the hydrolytic process; M-O cleavage activation barriers for acyclic analogs are higher. M-Hal cleavage barriers are substantially higher than those for M-O cleavage for R = F, but lower for R = Cl. Graphical Abstract The experimental barrier height of the Si-O bond cleavage in 1-methylsilatrane is well reproduced when three explicit water molecules are included in the B3LYP/aug cc-pVDZ theoretical model. PMID- 26645808 TI - Residue-based design of small molecule inhibitor for H1N1, H5N1 and H7N1 mutants. AB - Point mutations H274Y and N294S can lead to resistance of influenza virus strains to some drug molecules. Recently, a large number of experiments has focused on the many frameworks and catalytic residues thought to prevent the efficacy of anti-flu drugs. In the past, most research has considered the role of drugs in rigid proteins rather than in flexible proteins. In this study, we used molecular dynamics simulation (MD) combined with structure- and ligand-based drug design (SBDD and LBDD) methods to study dynamic interaction and protein dynamics correlation statistics between compounds and both the framework and catalytic residues in influenza virus N1 strains. Drug candidates were screened using the IC50 of the docking result predicted by support vector machine, multiple linear regression, and genetic function approximation (P < 0.001). As shown by MD, saussureamine C and diiodotyrosine have a protein dynamics correlation similar to that of sialic acid, and both can participate in hydrogen bond formation with loop, framework, and catalytic residues. Our in silico findings suggest that saussureamine C can inhibit H274Y and N294S mutants, and that diiodotyrosine can also inhibit N294S mutants. Therefore, the drugs saussureamine C and diiodotyrosine have the potential to produce inhibitory effects on wild-type influenza virus and some N1 mutants. PMID- 26645809 TI - Cooperative effects between halogen bonds and pnicogen bonds in XBr???OFH2P???NH3 (X = F, Cl, CN, NC, OH, and NO2) complexes. AB - Quantum chemical calculations were carried out to investigate interplay between halogen bonds and pnicogen bonds in XBr???OFH2P???NH3 (X = F, Cl, CN, NC, OH, and NO2) complexes at the M06-2X/aug-cc-pVDZ level. Cooperative effects are observed when halogen bonds and pnicogen bonds coexist in the same complex. These effects are analyzed in terms of geometric and energetic properties of the complexes. The mechanism of cooperative effects is analyzed in view with molecular electrostatic potential, natural bond orbital, and density difference of molecule formation analyses. PMID- 26645810 TI - A theoretical investigation of the energetics and spectroscopic properties of the gas-phase linear proton-bound cation-molecule complexes, XCH(+)-N2 (X = O, S). AB - The structural features, spectroscopic properties, and interaction energies of the linear proton-bound complexes of OCH(+) and its sulfur analog SCH(+) with N2 were investigated using the high-level ab initio methods MP2 and CCSD(T) as well as density functional theory with the aug-cc-pVXZ (X = D, T) basis sets. The rotational constants along with the vibrational frequencies of the cation molecule complexes are reported here. A comparison of the interaction energies of the OCH(+)-N2 and SCH(+)-N2 complexes with those of the OCH(+)-CO and OCH(+)-OC complexes was also performed. The energies of all the complexes were determined at the complete basis set (CBS) limit. CS shows higher proton affinity at the C site than CO does, so the complex OCH(+)-N2 is relatively strongly bound and has a higher interaction energy than the SCH(+)-N2 complex. Symmetry-adapted perturbation theory (SAPT) was used to decompose the total interaction energies of the complexes into the attractive electrostatic interaction energy (E elst), induction energy (E ind), dispersion energy (E disp), and repulsive exchange energy (E exch). We found that the ratio of E ind to E disp is large for these linear proton-bound complexes, meaning that inductive effects are favored in these complexes. The bonding characteristics of the linear complexes were elucidated using natural bond orbital (NBO) theory. NBO analysis showed that the attractive interaction is caused by NBO charge transfer from the lone pair on N to the sigma*(C-H) antibonding orbital in XCH(+)-N2 (X = O, S). The quantum theory of atoms in molecules (QTAIM) was used to analyze the strengths of the various bonds within and between the cation and molecule in each of these proton bound complexes in terms of the electron density at bond critical points (BCP). Graphical Abstract Linear proton-bound complexes of OCH(+)-N2 and SCH(+)-N2. In these complexes, inductive effect is favored over dispersive effect. The attractive interaction is the NBO charge transfer from N-lone pair of N2 to CH sigma* antibonding orbital of XCH(+) (X = O, S). PMID- 26645811 TI - A Single Arm Pilot Study of Effects of Berberine on the Menstrual Pattern, Ovulation Rate, Hormonal and Metabolic Profiles in Anovulatory Chinese Women with Polycystic Ovary Syndrome. AB - OBJECTIVE: To evaluate the effects of berberine on the menstrual pattern, ovulation rate, hormonal and metabolic profiles in anovulatory Chinese women with polycystic ovary syndrome. METHODS: Berberine 0.4 g three times per day was given for four months to 102 anovulatory Chinese women with polycystic ovary syndrome. The menstrual pattern, ovulation rate, hormonal and metabolic profiles were compared before and after the berberine treatment. Ovulation was confirmed by serum progesterone level >=10 ng/ml. RESULTS: A total of 98 of 102 subjects (96.1%) completed the four month treatment, including 69 (70.4%, 69/98) normal weight and 29 (29.6%, 29/98) overweight/obese. Fourteen women (14.3%, 14/98) had regained regular menses after berberine treatment and there was no significant difference between normal weight and overweight/obese groups. The ovulation rate was 25.0% over four months in the whole group, 22.5% in the normal weight group and 31.0% in the overweight/obese group. Sex hormone binding globulin, insulin resistance, total cholesterol, total triglyceride and low-density lipoprotein cholesterol decreased after berberine treatment in the normal weight group only. CONCLUSIONS: Our study found that administration of berberine alone may improve the menstrual pattern and ovulation rate in anovulatory Chinese women with polycystic ovary syndrome. Berberine can also decrease sex hormone binding globulin, insulin resistance, total cholesterol, triglycerides and low-density lipoprotein cholesterol in normal weight polycystic ovary syndrome women. TRIAL REGISTRATION: Chictr.org ChiCTR-OO-13003943. PMID- 26645812 TI - Comparison of Leishmania killicki (syn. L. tropica) and Leishmania tropica Population Structure in Maghreb by Microsatellite Typing. AB - Leishmania (L.) killicki (syn. L. tropica), which causes cutaneous leishmaniasis in Maghreb, was recently described in this region and identified as a subpopulation of L. tropica. The present genetic analysis was conducted to explore the spatio-temporal distribution of L. killicki (syn. L. tropica) and its transmission dynamics. To better understand the evolution of this parasite, its population structure was then compared with that of L. tropica populations from Morocco. In total 198 samples including 85 L. killicki (syn. L. tropica) (from Tunisia, Algeria and Libya) and 113 L. tropica specimens (all from Morocco) were tested. Theses samples were composed of 168 Leishmania strains isolated from human skin lesions, 27 DNA samples from human skin lesion biopsies, two DNA samples from Ctenodactylus gundi bone marrow and one DNA sample from a Phlebotomus sergenti female. The sample was analyzed by using MultiLocus Enzyme Electrophoresis (MLEE) and MultiLocus Microsatellite Typing (MLMT) approaches. Analysis of the MLMT data support the hypothesis that L. killicki (syn. L. tropica) belongs to the L. tropica complex, despite its strong genetic differentiation, and that it emerged from this taxon by a founder effect. Moreover, it revealed a strong structuring in L. killicki (syn. L. tropica) between Tunisia and Algeria and within the different Tunisian regions, suggesting low dispersion of L. killicki (syn. L. tropica) in space and time. Comparison of the L. tropica (exclusively from Morocco) and L. killicki (syn. L. tropica) population structures revealed distinct genetic organizations, reflecting different epidemiological cycles. PMID- 26645813 TI - Effects of combination treatment with sirolimus and mitotane on growth of human adrenocortical carcinoma cells. PMID- 26645814 TI - One-hour versus two-hour postprandial blood glucose measurement in women with gestational diabetes mellitus: which is more predictive? AB - The purpose of this study is to investigate postprandial 1-h (PP1) and 2-h (PP2) blood glucose measurements' correlation with adverse perinatal outcomes. This prospective cohort study consisted of 259 women with gestational diabetes mellitus. During each antenatal visit, HbA1c and fasting plasma glucose (FPG) as well as plasma glucose at PP1 and PP2 were analyzed. There were 144 patients on insulin therapy and 115 patients on diet therapy. A total of 531 blood glucose measurements were obtained at different gestational ages between 24 and 41 gestational weeks. PP2 plasma glucose measurements (but not PP1) were positively correlated with fetal macrosomia. But on adjusted analysis, neither PP1 nor PP2 measurements predicted perinatal complications. In addition to PP1 and PP2, neither FPG nor HbA1c were able to predict perinatal complications or fetal macrosomia when controlled for confounding factors except for a positive correlation between fetal macrosomia and HbA1c in patients on diet therapy. Postprandial 1-h and postprandial 2-h plasma glucose measurements were not superior to each other in predicting fetal macrosomia or perinatal complications. Based on our findings, it can be concluded that both methods may be suitable for follow-up as there are no clear advantages of one measurement over the other. PMID- 26645815 TI - Evolution of computed tomography-detectable adrenal nodules in patients with bilateral primary aldosteronism. PMID- 26645817 TI - Asymmetry in leg extension power impacts physical function in community-dwelling older women. AB - OBJECTIVE: The aim of this study was to examine the association between asymmetry in leg extension power (LP) and lower-extremity physical function (LEF) in community-dwelling older women. METHODS: Older women (n = 94, 74.0 +/- 5.5 y) were assessed for unilateral LP (watts) using the Nottingham power rig, and absolute and relative (%ASYM) differences in LP between the dominant and nondominant legs were calculated. LEF was assessed via the 6-minute walk, 8-foot up-and-go and 30-second chair stand, and a composite measure of LEF was calculated by summing z scores of each test. In addition, body composition was measured via dual-energy x-ray absorptiometry and moderate-intensity physical activity was assessed via questionnaire. RESULTS: The absolute difference in LP between the dominant and nondominant legs was 10.2 +/- 9.0 watts, which translated to a %ASYM of 11.3% +/- 10.5% (P < 0.01). %ASYM had bivariate associations with all individual measures of LEF (r range = -0.22 to -0.34, all P < 0.05). Using multivariate linear regression, %ASYM was an independent predictor of a composite LEF z score (standardized beta= -0.18, P < 0.05) after adjustment for age, comorbidities, physical activity, relative adiposity, and total leg power. Analysis of covariance indicated that women with low asymmetry had a significantly better LEF z score than those with high asymmetry (0.60 vs -0.13, P = 0.04). CONCLUSIONS: These findings indicate that a greater magnitude of asymmetry in LP is associated with poorer LEF in older women. Research is needed to determine whether interventions that correct asymmetries in lower-body muscle power confer functional benefits in older women. PMID- 26645818 TI - Psychiatric disorders and menopause symptoms in Brazilian women. AB - OBJECTIVE: This study investigated the association between minor psychiatric disorders and menopause symptoms and their associated factors. METHODS: A cross sectional study was conducted with 615 women aged 40 to 65 years treated in a public menopause and gynecological outpatient clinic in the South Region of Brazil. Minor psychiatric disorders were assessed using the Self-Reporting Questionnaire (SRQ-20) and menopause symptoms using the Menopause Rating Scale. Score for menopause symptoms was categorized into three levels of symptoms: mild, moderate, and severe. Multivariate analyses used ordinal logistic regression. RESULTS: The prevalence of mild, moderate, and severe menopause symptoms was 34.1% (95% CI 30.3-37.9), 29.6% (95% CI 25.8-33.1), and 36.3% (95% CI 32.4-40.0), respectively. The overall prevalence of minor psychiatric disorders was 66.6% (95% CI 62.8-70.3). After adjustment, the odds ratio (OR) of the occurrence of menopause symptoms were approximately eight times higher in women relating minor psychiatric disorders compared with those without such disorders (OR = 7.76; 95% CI 5.27-11.44). The following factors were also associated with the menopause symptoms: women older than 50 years, living with a partner, lower educational level, smokers, larger number of pregnancies, obese, and those using psychotropic and/or postmenopause medication. CONCLUSIONS: The minor psychiatric disorders exhibited strong association with the presence of menopause symptoms independently of sociodemographic, behavioral, and reproductive factors, and of use of psychotropic medication. PMID- 26645816 TI - The Caenorhabditis elegans Ephrin EFN-4 Functions Non-cell Autonomously with Heparan Sulfate Proteoglycans to Promote Axon Outgrowth and Branching. AB - The Eph receptors and their cognate ephrin ligands play key roles in many aspects of nervous system development. These interactions typically occur within an individual tissue type, serving either to guide axons to their terminal targets or to define boundaries between the rhombomeres of the hindbrain. We have identified a novel role for the Caenorhabditis elegans ephrin EFN-4 in promoting primary neurite outgrowth in AIY interneurons and D-class motor neurons. Rescue experiments reveal that EFN-4 functions non-cell autonomously in the epidermis to promote primary neurite outgrowth. We also find that EFN-4 plays a role in promoting ectopic axon branching in a C. elegans model of X-linked Kallmann syndrome. In this context, EFN-4 functions non-cell autonomously in the body-wall muscle and in parallel with HS modification genes and HSPG core proteins. This is the first report of an epidermal ephrin providing a developmental cue to the nervous system. PMID- 26645819 TI - Compounded non-FDA-approved menopausal hormone therapy prescriptions have increased: results of a pharmacy survey. AB - OBJECTIVE: From a survey of compounding pharmacists, specific questions regarding compounded menopausal hormone therapy were used to estimate compounded hormone therapy (CHT) prescribing in the United States. METHODS: A national online survey was conducted by Rose Research--a market research company consisting of 12,250 US pharmacists from independent community pharmacies (ICPs) and compounding pharmacies (CPs). Pharmacists who completed the survey and met the prespecified criteria were eligible. Data from the survey were extrapolated to estimate overall CHT prescription volume and annual costs of CHT prescriptions for the United States based upon industry data from the National Community Pharmacists Association and IBISWorld. RESULTS: Surveys were completed by 483 pharmacies, including 365 ICPs and 118 CPs. On the basis of the survey responses and extrapolated industry data, an estimated 26 to 33 million CHT prescriptions were filled annually, with total sales estimated at $1.3 to $1.6 billion. CPs (vs ICPs) accounted for a higher proportion of CHT prescriptions. More than half of the ICPs (52%) and CPs (75%) expected continued compounding business growth, with most predicting 5% to 25% growth within 2 years, despite the potential effect of restrictive legislation regarding compounding. CONCLUSIONS: On the basis of extrapolated data from numbers of prescriptions reported by pharmacists participating in the survey, the volume of CHT seems to approach that of Food and Drug Administration (FDA)-approved menopausal hormone therapy, and growth in the CHT market is expected. Thus, physicians should educate themselves and the women consulting them about the differences between the FDA-approved and the less tested CHT formulations. More research on the efficacy, safety, and consistency of non-FDA-approved CHT is needed. PMID- 26645820 TI - Vulvovaginal symptoms prevalence in postmenopausal women and relationship to other menopausal symptoms and pelvic floor disorders. AB - OBJECTIVE: The primary objective of this study was to use the Vulvovaginal Symptom Questionnaire (VSQ) to estimate the prevalence and examine the emotional, lifestyle, and sexual impact of vulvovaginal symptoms in postmenopausal women. METHODS: We administered the VSQ, a previous validated instrument to 358 postmenopausal women recruited from primary care physician offices and local senior centers. The first seven questions of the VSQ comprise the symptom subscale (itching, burning, hurting, irritation, dryness, discharge, and odor). Women who answered "Yes" to any of the first seven symptom questions were considered to have vulvovaginal symptoms. RESULTS: Two hundred seventy-nine women were recruited from primary care offices and 79 women were recruited from senior centers. One hundred eighty-three postmenopausal women (51.1%; 95% CI 45.9%, 56.3%) reported at least one vulvovaginal symptom. The most common symptom was being dry 35.8% (n/N = 128/358). Ten percent of women (n/N = 38/358) reported five or more symptoms and 6% of women reported all seven symptoms in the last week. For women reporting one or more vulvovaginal symptoms, 40.4% (n/N = 74/183) reported emotional impact (Yes to >=1 out of 4 emotional impact subscale items) and 32.8% (n/N = 60/183) reported lifestyle impact (Yes to >=1 out of 5 lifestyle impact subscale items) from these symptoms. For sexually active women reporting vulvovaginal symptoms, 75.3% (n/N = 67/89) reported sexual impact (Yes to >=1 out of 4 sexual impact subscale items). Vulvovaginal symptoms were associated with increased co-occurrence of specific pelvic floor disorders, including pelvic organ prolapse (P = 0.001), anal incontinence to solid stool (P = 0.001), urinary frequency (P = 0.02), urgency urinary incontinence (P = 0.001), and dysuria (P < 0.001). CONCLUSIONS: Vulvovaginal symptoms are common and present in over 50% of postmenopausal women. Sizeable proportions of women with vulvovaginal symptoms report emotional, lifestyle, and sexual impact from these symptoms. PMID- 26645821 TI - The relationships between psychological symptoms and cardiovascular symptoms experienced during the menopausal transition: racial/ethnic differences. AB - OBJECTIVE: The purpose of the study was to examine the relationships between psychological and cardiovascular symptoms in a multiethnic group of midlife women while controlling for other influencing factors, and to determine the association of race/ethnicity to the relationships between psychological and cardiovascular symptoms. METHODS: This was a secondary analysis of the data among 1,054 midlife women from two Internet surveys. The instruments included the questions on background characteristics, health, and menopause status and the Midlife Women's Symptom Index. The data were analyzed using correlation analyses, chi-squared tests, analysis of variance, and multivariate linear and logistic regression analyses. RESULTS: The total numbers and total severity scores of psychological symptoms were significantly related to those of cardiovascular symptoms as a whole and in each racial/ethnic group (P < 0.01). In total participants, both the total numbers and total severity scores of psychological symptoms were significantly associated with increased risk for cardiovascular symptoms after adjusting for race/ethnicity (P < 0.01), and there were no interactions between race/ethnicity and psychological symptoms. The existence of diagnosed cardiovascular diseases was significantly associated with the total numbers of and total severity scores of psychological symptoms only in Asian women. CONCLUSIONS: Further studies on the mechanisms through which psychological symptoms are related to cardiovascular symptoms are needed while controlling for race/ethnicity. PMID- 26645822 TI - Involvement of Connexin40 in the Protective Effects of Ginsenoside Rb1 Against Traumatic Brain Injury. AB - Ginsenosides are the major active components of ginseng, which have been proven to be effective in therapies for neurodegenerative diseases. Ginsenoside Rb1 (GS Rb1) is the most abundant among all the identified ginsenosides and has been shown to exert neuroprotective effects, although the underlying molecular mechanisms remain unclear. Connexins are a family of transmembrane proteins that form gap junctions, which are important for diffusion of cytosolic factors such as ions and second messenger signaling molecules. Previous studies have shown that a subset of connexin proteins is involved in neuroprotection. We investigated the protective effects of GS-Rb1 against traumatic brain injury (TBI) and the potential mechanism using TBI mouse model. We discovered that TBI induced brain injury and up-regulation of connexin40 (Cx40) protein expression as early as 6 h post-TBI, which was reversed by administration of GS-Rb1. In addition, we found that the protective effects of GS-Rb1 are dose and time dependent and are partially mediated through phosphorylation of ERK1/2 signaling pathway, as evidenced by the abolishment of GS-Rb1-mediated elevation of p-ERK1/2 expression and inhibition of Cx40 expressions when ERK inhibitor U0126 was used. Our study provides evidence that Cx40 is implicated in TBI-induced brain injuries, and GS-Rb1 exerts neuroprotective activity against TBI involving down regulation of Cx40 expression. PMID- 26645823 TI - Facilitated c-Fos Induction in Mice Deficient for the AMPA Receptor-Associated Protein Ckamp44. AB - The recently identified Cystine-knot containing AMPAR-associated protein (Ckamp44) represents a novel AMPAR-related protein that critically controls AMPAR mediated currents and short-term plasticity. However, the effects of the lack of this protein at network level are not entirely understood. Here we used c-Fos brain mapping to analyse whether the excitatory/inhibitory balance is altered in the absence of the Ckamp44. We found that Ckamp44(-/-) mice treated with an NMDAR antagonist exhibited a very robust c-Fos expression pattern, similar with that seen in mice lacking the GluN2A subunit of NMDAR treated with the same compound. This finding is unexpected, in particular, since Ckamp44 expression is strongest in dentate gyrus granule cells and less abundant in the rest of the brain. PMID- 26645824 TI - Role of stimulus and response feature overlap in between-task logical recoding. AB - The reversal logical recoding rule (i.e., "respond opposite") induced by an incompatible task (e.g., a task requiring to respond to red or green stimuli by pressing a key of the alternative colour compared to that of the stimulus) can be transferred to another task when the two tasks are combined in a task-switching paradigm. When the task to which the rule is transferred is a Simon task, this causes the disappearance of the typical advantage for responses that spatially correspond to the stimulus, or even results in an advantage for spatially noncorresponding responses. The present study aimed at investigating whether the transferred rule is independent of the specific stimulus and response dimensions for which it has been created. Previous studies suggest that when a Simon task is coupled with a colour incompatible task, the Simon effect may disappear or reverse even when stimuli in the two tasks, apart from being both visual and appearing on the same computer screen, have no other features in common. Results of the present study corroborate the hypothesis that feature overlap between stimuli is not necessary for the between-task transfer of the logical rule. However, an overlap between the representations of responses appears to be crucial. No modulation of the Simon effect was observed when the Simon task required bimanual responses while the colour-compatibility task required either vocal responses or responses executed with the two feet. In contrast, we did observe such a modulation when the discriminative response dimension and the effectors/response device were the same in the two tasks, even though these two tasks provided for different stimuli. PMID- 26645825 TI - Dynamic mental number line in simple arithmetic. AB - Studies have found that spatial-numerical associations could extend to arithmetic. Addition leads to rightward shift in spatial attention while subtraction leads to leftward shift (e.g., Knops et al. 2009; McCrink et al. 2007; Pinhas & Fischer 2008), which is consistent with the hypothesis of static mental number line (MNL) for arithmetic. The current investigation tested the hypothesis of dynamic mental number line which was shaped by the relative magnitudes of two operands in simple arithmetic. Horizontal and vertical electrooculograms (HEOG and VEOG) during simple arithmetic were recorded. Results showed that the direction of eye movements was dependent on the relative magnitudes of two operands. Subtraction was associated with larger rightward eye movements than addition (Experiment 1), and smaller-operand-first addition (e.g., 2+9) was associated with larger rightward eye movement than larger-operand-first addition (e.g., 9+2) only when the difference of two operands was large (Experiment 2). The results suggest that the direction of the mental number line could be dynamic during simple arithmetic, and that the eyes move along the dynamic mental number line to search for solutions. PMID- 26645827 TI - Author's Reply to Christelle de la Fouchardiere: "Regorafenib: Start Low and Go Slow". PMID- 26645828 TI - Serum beta-lactam concentrations in critically ill patients with cirrhosis: a matched case-control study. AB - BACKGROUND & AIMS: The pharmacokinetics of beta-lactam antibiotics have not been well defined in critically ill patients with cirrhosis. METHODS: We reviewed data from critically ill patients with cirrhosis and matched controls in whom routine therapeutic drug monitoring of two broad-spectrum beta-lactam antibiotics (piperacillin/tazobactam and meropenem) had been performed. Serum drug concentrations were measured twice by high-performance liquid chromatography. Antibiotic pharmacokinetics were calculated using a one-compartment model. We considered that therapy was adequate when serum drug concentrations were between 4 and 8 times the minimal inhibitory concentration of Pseudomonas aeruginosa during optimal periods of time for each drug (>= 50% for piperacillin/tazobactam; >= 40% for meropenem). RESULTS: We studied 38 patients with cirrhosis (16 for piperacillin/tazobactam and 22 for meropenem) and 38 matched controls. Drug dosing was similar in the two groups. The pharmacokinetics analysis showed a lower volume of distribution of meropenem (P = 0.05) and a lower antibiotic clearance of piperacillin/tazobactam (P = 0.009) in patients with cirrhosis than in the matched controls. Patients with cirrhosis were more likely than those without cirrhosis to have excessive serum beta-lactam concentrations (P = 0.015), in particular for piperacillin/tazobactam. CONCLUSIONS: Standard beta-lactam antibiotics regimens resulted in excessive serum concentrations in two thirds of the patients with cirrhosis. This was particularly true for piperacillin/tazobactam, probably because of reduced drug clearance. PMID- 26645829 TI - The Influence of Chronic and Situational Social Status on Stereotype Susceptibility. AB - We tested whether stereotypical situations would affect low-status group members' performance more strongly than high-status group members'. Experiment 1 and 2 tested this hypothesis using gender as a proxy of chronic social status and a gender-neutral task that has been randomly presented to favor boys (men superiority condition), favor girls (women superiority condition), or show no gender preference (control condition). Both experiments found that women's (Experiment 1) and girls' performance (Experiment 2) suffered more from the evoked stereotypes than did men's and boys' ones. This result was replicated in Experiment 3, indicating that short men (low-status group) were more affected compared to tall men (high-status group). Additionally, men were more affected compared to women when they perceived height as a threat. Hence, individuals are more or less vulnerable to identity threats as a function of the chronic social status at play; enjoying a high status provides protection and endorsing a low one weakens individual performance in stereotypical situations. PMID- 26645826 TI - Distal bile duct carcinomas and pancreatic ductal adenocarcinomas: postulating a common tumor entity. AB - The set definition of distal cholangiocarcinomas and adenocarcinomas of the pancreatic head is challenged by their close anatomical relation, similar growth pattern, and corresponding therapeutic outcome. They show a mutual development during embryologic organ formation and share phenotypic characteristics. This review will highlight the similarities with regard to the common origin of their primary organs, histopathological similarities, and modern clinical management. Thus, we propose to subsume those entities under a common superfamily. PMID- 26645830 TI - Different EGFR Gene Mutations in Exon 18, 19 and 21 as Prognostic and Predictive Markers in NSCLC: A Single Institution Analysis. AB - BACKGROUND: Mutations of epidermal growth factor receptor (EGFR) in non-small cell lung cancer (NSCLC) predict longer overall survival (OS) and response to EGFR tyrosine kinase inhibitors (TKIs). The clinical relevance of different mutations in terms of response to TKIs and prognosis is still unclear. OBJECTIVES: The aims of the present study were to assess the relationship between mutations in exon 18, 19 and 21 in patients treated with TKIs and their clinical outcomes, and evaluate the role of specific point mutations. METHODS: We included in this analysis 55 patients with metastatic NSCLC and mutations in exon 18, 19 and 21, treated in our center between 2004 and 2014. All patients received treatment with TKIs in first and/or subsequent lines. Endpoints analyzed were OS (primary) and time to progression (TTP) (secondary), according to exon mutations and specific point mutations. RESULTS: A strong negative prognostic association for OS (p = 0.02) and TTP (p = 0.03) was found for exon 18 mutations compared with exon 19 deletions . A trend toward a longer median OS was observed in exon 19 deletions versus exon 21 point mutations (+6.6 months), although more exon 19 mutated patients had brain metastases at diagnosis. Comparing each mutation, p.E746_A750del and p.E746_T751del of exon 19 and p.L858R mutation of exon 21, a trend toward improved OS in p.E746_A750del was found. CONCLUSION: In this analysis, exon 19 deletions were associated with better outcomes, despite a higher percentage of brain metastases in this group. The prognostic relevance of p.E746_A750del requires further studies. PMID- 26645831 TI - Nested PCR Assay for Eight Pathogens: A Rapid Tool for Diagnosis of Bacterial Meningitis. AB - PURPOSE: Bacterial meningitis is a dreadful infectious disease with a high mortality and morbidity if remained undiagnosed. Traditional diagnostic methods for bacterial meningitis pose a challenge in accurate identification of pathogen, making prognosis difficult. The present study is therefore aimed to design and evaluate a specific and sensitive nested 16S rDNA genus-based polymerase chain reaction (PCR) assay using clinical cerebrospinal fluid (CSF) for rapid diagnosis of eight pathogens causing the disease. METHODS: The present work was dedicated to development of an in-house genus specific 16S rDNA nested PCR covering pathogens of eight genera responsible for causing bacterial meningitis using newly designed as well as literature based primers for respective genus. A total 150 suspected meningitis CSF obtained from the patients admitted to Central India Institute of Medical Sciences (CIIMS), India during the period from August 2011 to May 2014, were used to evaluate clinical sensitivity and clinical specificity of optimized PCR assays. RESULTS: The analytical sensitivity and specificity of our newly designed genus-specific 16S rDNA PCR were found to be >=92%. With such a high sensitivity and specificity, our in-house nested PCR was able to give 100% sensitivity in clinically confirmed positive cases and 100% specificity in clinically confirmed negative cases indicating its applicability in clinical diagnosis. CONCLUSIONS: Our in-house nested PCR system therefore can diagnose the accurate pathogen causing bacterial meningitis and therefore be useful in selecting a specific treatment line to minimize morbidity. Results are obtained within 24 h and high sensitivity makes this nested PCR assay a rapid and accurate diagnostic tool compared to traditional culture-based methods. PMID- 26645832 TI - Selective estrogen receptor modulators and betulinic acid act synergistically to target ERalpha and SP1 transcription factor dependent Pygopus expression in breast cancer. AB - AIMS: Estrogen and progesterone hormone receptor (ER and PR) expression in invasive breast cancer predicts response to hormone disruptive therapy. Pygopus2 (hPYGO2) encodes a chromatin remodelling protein important for breast cancer growth and cell cycle progression. The aims of this study were to determine the mechanism of expression of hPYGO2 in breast cancer and to examine how this expression is affected therapeutically. METHODS: hPYGO2 and ER protein expression was examined in a breast tumour microarray by immunohistochemistry. hPYGO2 RNA and protein expression was examined in ER+ and ER- breast cancer cell lines in the presence of selective estrogen hormone receptor modulator drugs and the specificity protein-1 (SP1) inhibitor, betulinic acid (BA). The effects of these drugs on the ability for ER and SP1 to bind the hPYGO2 promoter and affect cell cycle progression were studied using chromatin immunoprecipitation assays. RESULTS: hPYGO2 was expressed in seven of eight lines and in nuclei of 98% of 65 breast tumours, including 3 Ductal carcinoma in situ and 62 invasive specimens representing ER-negative (22%) and ER-positive (78%) cases. Treatment with either 4-Hydroxytamoxifen (OHT) or fulvestrant reduced hPYGO2 mRNA 10-fold and protein 5 10-fold within 4 h. Promoter analysis indicated an ER/SP1 binding site at nt -225 to -531 of hPYGO2. SP1 RNA interference and BA reduced hPYGO2 protein and RNA expression by fivefold in both ER- and ER+ cells. Further attenuation was achieved by combining BA and 4-OHT resulting in eightfold reduction in cell growth. CONCLUSIONS: Our findings reveal a mechanistic link between hormone signalling and the growth transcriptional programme. The activation of its expression by ERalpha and/or SP1 suggests hPYGO2 as a theranostic target for hormone therapy responsive and refractory breast cancer. PMID- 26645833 TI - Cardiovascular and Mortality Outcomes in the Elderly With Impaired Cardiac and Pulmonary Function: The Cardiovascular Health Study (CHS). AB - BACKGROUND: Impaired pulmonary function (IPF) and left ventricular systolic dysfunction (LVSD) are prevalent in the elderly and are associated with significant morbidity and mortality. The main objectives of this study were to examine the relative impact and joint association of IPF and LVSD with heart failure, cardiovascular mortality and all-cause mortality, and their impact on risk classification using a continuous net reclassification index. METHODS AND RESULTS: We followed 2342 adults without prevalent cardiovascular disease (mean age, 76 years) from the Cardiovascular Health Study for a median of 12.6 years. LVSD was defined as LV ejection fraction <55%. IPF was defined as: forced expiratory volume in 1 second:forced vital capacity <70%, and predicted forced expiratory volume in 1 second <80%. Outcomes included heart failure hospitalization, cardiovascular mortality, all-cause mortality, and composite outcome. LVSD was detected in 128 subjects (6%), IPF in 441 (19%) and both in 38 (2%). Compared to those without LVSD or IPF, there was a significantly increased cardiovascular risk for groups of LVSD only, IPF only, and LVSD plus IPF, adjusted hazard ratio (95% CI) 2.1 (1.5-3.0), 1.7 (1.4-2.1), and 3.2 (2.0-5.1) for HF; 1.8 (1.2-2.6), 1.4 (1.1-1.8), and 2.8 (1.7-4.7) for cardiovascular mortality; 1.3 (1.0-1.8), 1.7 (1.4-1.9), and 2.1 (1.5-3.0) for all-cause mortality, and 1.6 (1.3-2.1), 1.7 (1.5-1.9), and 2.4 (1.7-3.3) for composite outcome, respectively. Risk classification improved significantly for all outcomes when IPF was added to the adjusted model with LVSD or LVSD to IPF. CONCLUSIONS: While risk of cardiovascular outcomes was the highest among elderly with both LVSD and IPF, risk was comparable between subjects with IPF alone and those with LVSD alone. This observation, combined with improved risk classification by adding IPF to LVSD or LVSD to IPF, underscore the importance of comprehensive heart and lung evaluation in cardiovascular outcome assessment. PMID- 26645835 TI - Synthesis and Structural Properties of Aza[n]helicene Platinum Complexes: Control of Cis and Trans Stereochemistry. AB - The synthesis and structural characterization of azahelicene platinum complexes obtained from cis-PtCl2(NCEt)(PPh3) and from ligands that differ in terms of both the position of the nitrogen atom and the number of fused rings are reported. These square-planar complexes of the general formula PtCl2(nHm)(PPh3) (n = 4, 5; m = 5, 6) display mainly a cis configuration. However, by X-ray crystallographic analysis, we show that for both PtCl2(4H6)(PPh3) and PtCl2(5H6)(PPh3) there is chirality control of the cis/trans stereochemistry. Indeed, starting from a racemic mixture of aza[6]helicene, platinum complexes with a cis configuration are invariably obtained, and the more thermodynamically stable trans isomers are formed when using enantiopure ligands. We further corroborated these results by NMR analysis in solution. PMID- 26645834 TI - Short-Term Exposure to Fine Particulate Matter Air Pollution Is Preferentially Associated With the Risk of ST-Segment Elevation Acute Coronary Events. AB - BACKGROUND: Air pollution is associated with greater cardiovascular event risk, but the types of events and specific persons at risk remain unknown. This analysis evaluates effects of short-term exposure to fine particulate matter air pollution with risk of acute coronary syndrome events, including ST-segment elevation myocardial infarction, non-ST-segment elevation myocardial infarction, unstable angina, and non-ST-segment elevation acute coronary syndrome. METHODS AND RESULTS: Acute coronary syndrome events treated at Intermountain Healthcare hospitals in urban areas of Utah's Wasatch Front were collected between September 1993 and May 2014 (N=16 314). A time-stratified case-crossover design was performed matching fine particulate matter air pollution exposure at the time of each event with referent periods when the event did not occur. Patients served as their own controls, and odds ratios were estimated using nonthreshold and threshold conditional logistic regression models. In patients with angiographic coronary artery disease, odds ratios for a 10-MUg/m(3) increase in concurrent-day fine particulate matter air pollution >25 MUg/m3 were 1.06 (95% CI 1.02-1.11) for all acute coronary syndrome, 1.15 (95% CI 1.03-1.29) for ST-segment elevation myocardial infarction, 1.02 (95% CI 0.97-1.08) for non-ST-segment elevation myocardial infarction, 1.09 (95% CI 1.02-1.17) for unstable angina, and 1.05 (95% CI 1.00-1.10) for non-ST-segment elevation acute coronary syndrome events. Excess risk from fine particulate matter air pollution exposure was not observed in patients without angiographic coronary artery disease. CONCLUSIONS: Elevated fine particulate matter air pollution exposures contribute to triggering acute coronary events, especially ST-segment elevation myocardial infarction, in those with existing seriously diseased coronary arteries but not in those with nondiseased coronary arteries. PMID- 26645836 TI - Happy New Year. PMID- 26645837 TI - Study Identifies Opportunities to Improve Support Programs for Clinicians Involved in Adverse Events. PMID- 26645838 TI - Medical Marijuana. AB - The use of medicinal marijuana is increasing. Marijuana has been shown to have therapeutic effects in certain patients, but further research is needed regarding the safety and efficacy of marijuana as a medical treatment for various conditions. A growing body of research validates the use of marijuana for a variety of healthcare problems, but there are many issues surrounding the use of this substance. This article discusses the use of medical marijuana and provides implications for home care clinicians. PMID- 26645839 TI - Neurological Assessment. AB - Reasons for completing a neurological exam include: detecting life-threatening conditions, identifying nervous system dysfunction and the effects of this dysfunction on activities of daily living, comparing current data to previous exams to determine trends, and to provide a database upon which to base collaborative care across disciplines. In this third article of a four-part series, subjective and objective assessment of the neurological exam is reviewed. PMID- 26645840 TI - Aneroid Blood Pressure Manometer Calibration Rates of Devices Used in Home Health. AB - Hypertension is associated with cardiovascular disease, stroke, and a range of other medical sequelae. Accurate blood pressure (BP) readings, which depend on the integrity and calibration of the measuring device, are essential to identifying suboptimal BP. This study describes calibration rates of aneroid BP devices (a) utilized in home healthcare (HHC) and (b) having the needle resting within the zero accuracy indicator. BP devices from one branch of a home care agency were inspected and checked for calibration according to the protocol set forth by the European Society of Hypertension. Of the 125 devices measured, 78.4% were in calibration. Of the 94 devices with the gauge needle resting in the zero accuracy indicator, 11.7% were not in calibration; whereas, 51.6% of the 31 devices with the gauge needle resting outside the zero accuracy indicator were found not in calibration. Twenty-one devices were not checked for calibration due to inflation bulb malfunction, tubing tears, or excessive wear. Furthermore, visual inspection of the needle placement did not confirm a device as being in or out of calibration. Proper maintenance and routine calibration of BP equipment is foundational to assuring accuracy of BP readings obtained by HHC providers. PMID- 26645841 TI - Nurse on the Move: Lisa Gorski. AB - After a short hiatus, Nurses On the Move is back and better than ever! I am excited to bring you our next nurse leader, Lisa A. Gorski MS, RN, HHCNS-BC, CRNI, FAAN. With more than 30 years in the field, Gorski is an expert in both home healthcare and infusion nursing. As a clinical nurse specialist at Wheaton Franciscan Home Health & Hospice in Wisconsin, an editorial board member of Home Healthcare Now, an associate consultant for OASIS ANSWERS, Inc., and a published author, her knowledge of the nursing profession is truly impressive.Through our phone interview, I spoke with Gorski about why she decided to enter into home healthcare, her time as president of the Infusion Nurses Society, and what advice she has for a nurse starting their career. PMID- 26645843 TI - Promoting Trust in the Registered Nurse-Patient Relationship. AB - The establishment of trust in the registered nurse (RN)-patient relationship promotes patient engagement and improves the likelihood that the patient will be an active member of the patient care team. The purpose of this article is to examine nursing literature to identify the antecedents, attributes, and outcomes of trusting relationships between RNs and patients in home healthcare. Antecedents of trust for the RN-patient relationship included 1) meeting a need, 2) respect, 3) attention to time, 4) continuity of care, and 5) the initial visit. Attributes of trust between RN and patient in the home healthcare setting were identified as communication, connection, and reciprocity. For the RN and patient who established mutual trust, patients demonstrated better adaptation and collaboration for improvement of health, expressed a sense of security, and indicated a willingness to engage in additional trusting relationships. Barriers to a trusting relationship included a lack of respect and incompetent and/or unethical care. PMID- 26645842 TI - Hospital Admissions for Malnutrition and Dehydration in Patients With Dementia. AB - Dehydration and malnutrition are commonly experienced by patients with dementia and can result in hospitalizations and decreased quality of life. The purpose of this study was to explore and describe retrospectively, the incidence and correlations of variables that may precede hospitalizations for dehydration/malnutrition in the community-dwelling patient with dementia. Data from the Outcome and Assessment Information Set (OASIS) Start of Care (SOC) on 44 patients served by a Michigan home care agency were retrieved for analysis. This study did not reveal any single or collection of variables that would predict risk for hospitalization for dehydration/malnutrition. With the lack of specific predictors of hospitalization related to dehydration and malnutrition, clinicians need to place high priority on risk-lowering strategies and preventive education for patients, family, and caregivers. PMID- 26645844 TI - Liquid Oral Vaccine Mistakenly Given by Injection; Topical Anesthetics for Teething Infants. PMID- 26645845 TI - Preventing the Transfer of Pathogenic Organisms From the Use of Mobile Phones. PMID- 26645846 TI - A Day in the Life of a Home Care Grants Officer. PMID- 26645847 TI - Noncompliant and Nonadherent: Time to Retire These Labels. PMID- 26645848 TI - Home Healthcare and Independent Contractors. PMID- 26645849 TI - Reach for the Stars: It's Time to Focus on Optimizing Patient Experience of Care in Home Healthcare. PMID- 26645850 TI - Considered Becoming a Manuscript Reviewer? PMID- 26645851 TI - Medical Marijuana. PMID- 26645365 TI - Deep sequencing of Danish Holstein dairy cattle for variant detection and insight into potential loss-of-function variants in protein coding genes. AB - BACKGROUND: Over the last few years, continuous development of high-throughput sequencing platforms and sequence analysis tools has facilitated reliable identification and characterization of genetic variants in many cattle breeds. Deep sequencing of entire genomes within a cattle breed that has not been thoroughly investigated would be imagined to discover functional variants that are underlying phenotypic differences. Here, we sequenced to a high coverage the Danish Holstein cattle breed to detect and characterize single nucleotide polymorphisms (SNPs), insertion/deletions (Indels), and loss-of-function (LoF) variants in protein-coding genes in order to provide a comprehensive resource for subsequent detection of causal variants for recessive traits. RESULTS: We sequenced four genetically unrelated Danish Holstein cows with a mean coverage of 27X using an Illumina Hiseq 2000. Multi-sample SNP calling identified 10,796,794 SNPs and 1,295,036 indels whereof 482,835 (4.5 %) SNPs and 231,359 (17.9 %) indels were novel. A comparison between sequencing-derived SNPs and genotyping from the BovineHD BeadChip revealed a concordance rate of 99.6-99.8 % for homozygous SNPs and 93.3-96.5 % for heterozygous SNPs. Annotation of the SNPs discovered 74,886 SNPs and 1937 indels affecting coding sequences with 2145 being LoF mutations. The frequency of LoF variants differed greatly across the genome, a hot spot with a strikingly high density was observed in a 6 Mb region on BTA18. LoF affected genes were enriched for functional categories related to olfactory reception and underrepresented for genes related to key cellular constituents and cellular and biological process regulation. Filtering using sequence derived genotype data for 288 Holstein animals from the 1000 bull genomes project removing variants containing homozygous individuals retained 345 of the LoF variants as putatively deleterious. A substantial number of the putative deleterious LoF variants had a minor allele frequency >0.05 in the 1000 bull genomes data set. CONCLUSIONS: Deep sequencing of Danish Holstein genomes enabled us to identify 12.1 million variants. An investigation into LoF variants discovered a set of variants predicted to disrupt protein-coding genes. This catalog of variants will be a resource for future studies to understand variation underlying important phenotypes, particularly recessively inherited lethal phenotypes. PMID- 26645852 TI - Entrapping a Group-VB Transition Metal, Vanadium, within an Endohedral Metallofullerene: V(x)Sc(3-x)N@I(h)-C80 (x = 1, 2). AB - So far the entrapped metals for the isolated endohedral metallofullerenes (EMFs) are primarily limited to rare earth metals, whereas except group-IVB metals, whether it is possible to entrap other d-block transition metals remains unclear. Herein we report the successful entrapment of the group-VB transition metal vanadium(V) into fullerene cage, affording the heretofore unknown V-containing EMFs. Two novel V-containing EMFs--V(x)Sc(3-x)N@C80 (x = 1, 2)--were isolated, and their molecular structures were unambiguously determined by X-ray crystallography to be I(h)(7)-C80 cage entrapping the planar VSc2N/V2ScN clusters. V(x)Sc(3-x)N@I(h)(7)-C80 (x = 1, 2) were further characterized by UV vis-NIR and ESR spectroscopies and electrochemistry, revealing that the electronic and magnetic properties of V(x)Sc(3-x)N@I(h)(7)-C80 (x = 1, 2) are tunable upon varying the number of entrapped V atoms (i.e., x value). The molecular structures and electronic properties of V(x)Sc(3-x)N@I(h)(7)-C80 (x = 1, 2) were further compared with those of the reported analogous EMFs based on lanthanide metals and the adjacent group-IVB transition metal Ti, revealing the peculiarity of the group-VB transition metal V-based EMFs. PMID- 26645855 TI - Transfusion-transmitted anaplasmosis from a leukoreduced platelet pool. AB - BACKGROUND: Human granulocytic anaplasmosis is an emerging tick-borne illness. Anaplasma phagocytophilum resides intracellularly, can cause asymptomatic infection, and can survive blood component refrigeration conditions for at least 18 days. To date, eight cases of transfusion-transmitted anaplasmosis (TTA) have been reported: seven attributed to red blood cell (RBC) units, five of which were prestorage leukoreduced using RBC leukoreduction filters, and one involving a process leukoreduced apheresis platelet (PLT) unit. Here, we report a case of TTA from a whole blood-derived PLT pool. STUDY DESIGN AND METHODS: Donation segments from the 7 units of RBCs and two PLT pools transfused were examined. Fast protocol multiplex real-time A. phagocytophilum polymerase chain reaction (PCR) and serologic testing for immunoglobulin (Ig)M and IgG antibodies to A. phagocytophilum by enzyme immunoassay were performed. RESULTS: Transmission was confirmed by positive A. phagocytophilum PCR and serology in one of 16 donors and by positive PCR and seroconversion in the recipient. CONCLUSION: This is the first confirmed case of TTA from a whole blood-derived PLT pool prepared from PLT concentrates leukoreduced by in-line filtration of PLT-rich plasma. PMID- 26645853 TI - Congenital Ichthyosiform Erythroderma Superimposed with Chronic Dermatophytosis: A Report of Three Siblings. AB - Congenital ichthyosiform erythroderma is an autosomal recessive ichthyosis characterized by severe scaling and erythroderma. We report a family of three siblings who were all born with a collodion membrane and presented with diffuse scaling and pruritus. All three children subsequently developed chronic cutaneous dermatophyte infections requiring oral antifungals. One child developed superinfection with methicillin-resistant Staphylococcus aureus requiring antibiotics. PMID- 26645854 TI - Endoplasmic reticulum targeting tumour selective photocytotoxic oxovanadium(IV) complexes having vitamin-B6 and acridinyl moieties. AB - Oxovanadium(iv) complexes of vitamin-B6 Schiff base, viz., [VO(HL(1)/L(2)/L(3))(B)]Cl (), where B is 2,2'-bipyridine (bpy in and ), 11-(9 acridinyl)dipyrido[3,2-a:2',3'-c]phenazine (acdppz in and ), H2L(1).HCl is 3 hydroxy-5-(hydroxymethyl)-4-(((2-hydroxyphenyl)imino)methyl)-2-methylpyridin-1 ium chloride (in and ), HL(2) is 2-(((2-(1H-imidazol-4 yl)ethyl)imino)methyl)phenol (in ) and HL(3) is 4-(((2-(1H-imidazol-4 yl)ethyl)imino)methyl)-5-(hydroxymethyl)-2-methylpyridin-3-ol (in ) were synthesized, characterized and their cellular uptake, photo-activated cytotoxicity and intracellular localization were studied. Complexes , as the perchlorate salt of , and , as the hexafluorophosphate salt of , were structurally characterized. Vitamin-B6 transporting membrane carrier (VTC) mediated entry into tumour cells in preference to the normal ones seems to be responsible for the higher cellular uptake of the complexes into HeLa and MCF-7 cells over MCF-10A cells. Complexes and having acdppz as the photosensitizer exhibit remarkable photocytotoxicity in these cancer cells giving IC50 of <0.9 MUM. The complexes remain non-toxic in the dark. The complexes show photo-induced apoptotic cell death via singlet oxygen ((1)O2) generation. Fluorescence microscopy reveals specific localization of complex to endoplasmic reticulum (ER) and generation of (1)O2 possibly leads to apoptotic cell death by triggering ER stress response (ERSR). PMID- 26645859 TI - World Diabetes Day: Perspectives on immunotherapy of Type 1 Diabetes. PMID- 26645856 TI - Association between systemic inflammatory response syndrome and mortality in alcoholic hepatitis: A meta-analysis. PMID- 26645862 TI - Solid pulmonary nodule risk assessment and decision analysis: comparison of four prediction models in 285 cases. AB - OBJECTIVES: The aim of this study was to compare classification results from four major risk prediction models in a wide population of incidentally detected solitary pulmonary nodules (SPNs) which were selected to crossmatch inclusion criteria for the selected models. METHODS: A total of 285 solitary pulmonary nodules with a definitive diagnosis were evaluated by means of four major risk assessment models developed from non-screening populations, namely the Mayo, Gurney, PKUPH and BIMC models. Accuracy was evaluated by receiver operating characteristic (ROC) area under the curve (AUC) analysis. Each model's fitness to provide reliable help in decision analysis was primarily assessed by adopting a surgical threshold of 65 % and an observation threshold of 5 % as suggested by ACCP guidelines. RESULTS: ROC AUC values, false positives, false negatives and indeterminate nodules were respectively 0.775, 3, 8, 227 (Mayo); 0.794, 41, 6, 125 (Gurney); 0.889, 42, 0, 144 (PKUPH); 0.898, 16, 0, 118 (BIMC). CONCLUSIONS: Resultant data suggests that the BIMC model may be of greater help than Mayo, Gurney and PKUPH models in preoperative SPN characterization when using ACCP risk thresholds because of overall better accuracy and smaller numbers of indeterminate nodules and false positive results. KEY POINTS: * The BIMC and PKUPH models offer better characterization than older prediction models * Both the PKUPH and BIMC models completely avoided false negative results * The Mayo model suffers from a large number of indeterminate results. PMID- 26645863 TI - Comparison of Imaging Selection Criteria for Intra-Arterial Thrombectomy in Acute Ischemic Stroke with Advanced CT. AB - OBJECTIVES: To compare two selection criteria (noncontrast CT [NCCT] with multi phase CT Angiography [MPCTA] and CT perfusion [CTP]) for the determination of eligibility for thrombectomy. METHODS: We retrospectively enrolled 71 patients who underwent head NCCT, 9.6-cm CTP, and craniocervical single-phase CTA (SPCTA) within 6 hours of onset. The simulated MPCTA was reconstructed from 1-mm CTP images for assessment of collateral circulation. Infarct core (relative CBF < 30 %) and penumbra (Tmax > 6 seconds) volumes were measured. The infarct core < 70 mL with a mismatch ratio > 1.2 (CTP-A), infarct core <= 40 mL with a mismatch ratio > 1.8 (CTP-B), and ASPECTS > 5 with good collaterals (50 % >= MCA territory) were used to determine eligibility for thrombectomy. SPCTA was compared with the simulated MPCTA for assessment of collaterals. RESULTS: CTP-B determined that 11 patients were ineligible for thrombectomy, of which three were eligible by NCCT with MPCTA and 6 by CTP-A. CTP-A and CTP-B showed discrepancy in determining eligibility for thrombectomy between NCCT with MPCTA in three patients each, rendering no significant statistical difference (P > 0.05). The number of patients with poor collaterals was significantly higher on SPCTA than MPCTA (n = 22 and 6 respectively; P < 0.0001). CONCLUSION: The two imaging selection criteria (NCCT with MPCTA and CTP) were statistically comparable for determining eligibility for thrombectomy. KEY POINTS: * Early mechanical thrombectomy improves clinical outcomes. * Noncontrast CT-multi-phase CTA is used for determining eligibility for thrombectomy. * CTP can help to select patients who are eligible for thrombectomy. * Noncontrast CT-multi-phase CTA and CTP are comparable for patient selection. * Multi-phase CTA is more accurate than single phase CTA for assessment of collaterals. PMID- 26645864 TI - Diagnostic accuracy of low-mA chest CT reconstructed with Model Based Iterative Reconstruction in the detection of early pleuro-pulmonary complications following a lung transplantation. AB - OBJECTIVES: To assess the accuracy of reduced-dose, low-mA chest CT (RD-CT) reconstructed with model-based iterative reconstruction (MBIR) in detecting usual early complications following pulmonary transplantation, as compared to standard dose chest CT (SD-CT) reconstructed with adaptative statistical iterative reconstruction (ASIR). METHODS: Our institutional review board approved this prospective study and patients provided written informed consent. Two thoracic radiologists independently evaluated 47 examinations performed routinely in 20 patients during 6 months following lung transplantation for the detection and/or evolution of usual pleuropulmonary complications and for subjective image quality. Each examination consisted of successive acquisition of unenhanced SD-CT (100-120 kV, noise index 45, ASIR) and RD-CT (100 kV, 16-24mAs/slice, MBIR). RESULTS: Mean CTDIvol was 4.12 +/- 0.88 and 0.65 +/- 0.09 mGy for SD-CT and RD CT, respectively. Complications were found in 40/47 (85 %) examinations. Sensitivity and negative predictive value of RD-CT were 92-100 % for the detection of pneumonia, fungal infection, pleural effusion, pneumothorax, and bronchial dehiscence or stenosis, as compared to SD-CT. Image quality of RD-CT was graded good for 81 % of examinations. CONCLUSIONS: MBIR-RD-CT is accurate, as compared to SD-CT, for delineating most usual pleuropulmonary complications during the 6 months following pulmonary transplantation and might be used routinely for the early monitoring of pulmonary allografts. KEY POINTS: * Early chest complications are frequent following a pulmonary transplantation * CT has a key role for their detection and follow-up * Low-mAMBIR CT is accurate for monitoring most lung allograft early pleuropulmonary complications * MBIR chest CT allows a six-fold dose reduction compared to standard CT. PMID- 26645866 TI - Education and Income Imbalances Among Married Couples in Malawi as Predictors for Likelihood of Physical and Emotional Intimate Partner Violence. AB - Intimate partner violence is a social and public health problem that is prevalent across the world. In many societies, power differentials in relationships, often supported by social norms that promote gender inequality, lead to incidents of intimate partner violence. Among other factors, both a woman's years of education and educational differences between a woman and her partner have been shown to have an effect on her likelihood of experiencing intimate partner abuse. Using the 2010 Malawian Demographic and Health Survey data to analyze intimate partner violence among 3,893 married Malawian women and their husbands, this article focuses on understanding the effect of educational differences between husband and wife on the likelihood of physical and emotional abuse within a marriage. The results from logistic regression models show that a woman's level of education is a significant predictor of her likelihood of experiencing intimate partner violence by her current husband, but that this effect is contingent on her husband's level of education. This study demonstrates the need to educate men alongside of women in Malawi to help decrease women's risk of physical and emotional intimate partner violence. PMID- 26645865 TI - Demographic Characteristics, Survival and Prognostic Factors for Mortality in Cats with Primary Immune-Mediated Hemolytic Anemia. AB - BACKGROUND: Immune-mediated hemolytic anemia (IMHA) is uncommon in cats, but may result in severe disease. Demographic predispositions for development of the disease and prognostic factors for mortality have not been investigated previously. HYPOTHESIS/OBJECTIVES: To explore possible demographic predispositions for development of primary IMHA in cats and to investigate possible prognostic factors for mortality. ANIMALS: 107 client-owned cats with IMHA, of which 72 had primary IMHA and 35 had secondary IMHA, and 9,194 control cats. METHODS: Data were collected retrospectively from records of cats with IMHA, defined by the presence of anemia and concurrent autoagglutination, ghost cells without oxidative damage on fresh blood smear, positive titer in a direct antiglobulin test, or evidence of phagocytosis of erythroid precursors in bone marrow. Odds ratios were calculated to assess the risk of development of primary IMHA in different demographic groups and Cox proportional hazards analysis was conducted to evaluate prognostic factors. RESULTS: No sex or breed predisposition was identified for the development of primary IMHA in comparison to the control cats, but cats in the age range 2.1-5.9 years were predisposed. Higher total bilirubin concentration and age were significant negative prognostic factors and higher lymphocyte numbers and serum globulin concentration were positive prognostic factors in a multivariable model. CONCLUSIONS AND CLINICAL IMPORTANCE: Young adult cats were more likely to develop primary IMHA than other groups, but no apparent male predisposition was identified in this study, contrary to previous reports. Several prognostic factors were identified, which may be helpful in guiding clinical practice in the future. PMID- 26645867 TI - Stem cell transplantation for acute myeloid leukemia with pulmonary and cerebral mucormycosis. AB - BACKGROUND: Mucormycosis is one of the most refractory invasive fungal infections and often causes fatal infection in immunocompromised patients, such as those with severe diabetes mellitus and hematologic malignancies. METHODS: We retrospectively evaluated the efficacy of stem cell transplantation for a pediatric patient with refractory acute myeloid leukemia (AML) who developed mucormycosis. RESULTS: An 8-year-old boy with acute myeloid leukemia (AML) received chemotherapy, but relapsed 3 months after discontinuation of treatment. Subsequent chemotherapy was ineffective, and then, while in non-complete remission, he developed pulmonary and cerebral mucormycosis. On gene analysis the fungus was identified as Lichtheimia ramosa. Cord blood transplantation was conducted in combination with high-dose liposomal amphotericin B therapy. He successfully achieved complete remission without progression of mucormycosis. CONCLUSIONS: Stem cell transplantation could reduce the mortality of patients with hematologic disease who develop mucormycosis. PMID- 26645868 TI - Treatment of patients with uric acid stones. AB - Uric acid nephrolithiasis and unduly acidic urinary pH are both considered a renal manifestation of insulin resistance but the underlying mechanisms for the development of low urinary pH and the propensity for uric acid stone formation are not completely elucidated. Nevertheless, excessive dietary acid intake, increased endogenous acid production and/or defective NH4+ excretion play an important role, among other factors. The main principles of therapy for uric acid nephrolithiasis are aimed at urinary alkalinization through diet modification or pharmacologic agents, increase of urinary volume, and less importantly at the reduction of uric acid excretion. PMID- 26645869 TI - Oxalate-degrading microorganisms or oxalate-degrading enzymes: which is the future therapy for enzymatic dissolution of calcium-oxalate uroliths in recurrent stone disease? AB - Renal urolithiasis is a pathological condition common to a multitude of genetic, physiological and nutritional disorders, ranging from general hyperoxaluria to obesity. The concept of quickly dissolving renal uroliths via chemolysis, especially calcium-oxalate kidney stones, has long been a clinical goal, but yet to be achieved. Over the past 25 years, there has been a serious effort to examine the prospects of using plant and microbial oxalate-degrading enzymes known to catabolize oxalic acid and oxalate salts. While evidence is emerging that bacterial probiotics can reduce recurrent calcium-oxalate kidney stone disease by lowering systemic hyperoxaluria, the possible use of free oxalate degrading enzyme therapy remains a challenge with several hurdles to overcome before reaching clinical practice. PMID- 26645871 TI - Management of anterior caliceal stones >15 mm. AB - Anterior caliceal stones represent a challenge to endourologist to select the best modality of management with the least morbidity. To study different treatment modalities of management of anterior caliceal stones >15 mm. It is an observational prospective study of patients with anterior caliceal stones more than 15 mm. Inclusion criteria were patients with isolated anterior caliceal stones, or branched anterior caliceal stones with posterior caliceal extension. Patients were evaluated using non-contrast CT preoperatively. They were divided into three groups: group 1 underwent PCNL through posterior caliceal puncture in cases with wide anterior calyx infundibulum or obtuse infundibulopelvic pelvic, group 2 underwent PCNL through anterior caliceal access in cases with narrow infundibulum or acute infundibulopelvic angel and group 3 underwent flexible ureteroscopy and laser lithotripsy. Intraoperative and postoperative findings were recorded and compared. Eighty eight patients were included in this study, Group 1 (44 patients) group 2 (28 patients), and group 3 (16 patients). Operative time was not significantly different across the three groups (68 +/- 11.5, 72 +/- 9 and 74 +/- 11 min in group 1, 2 and 3, respectively, P = 0.053). Fluoroscopy time was significantly shorter for group 3 (2 +/- 0.5 m, P = 0.0001) compared to group 1 and 2 (5.6 +/- 4.6 and 4.5 +/- 1.4 min), respectively. There were no significant differences in stone-free rates after initial treatment between the three groups; 84, 82, and 69 %, in groups 1, 2 and 3, respectively (P = 0.4). Postoperative hemoglobin drop was noted to be highest for group 2 and lowest for group 3 which was significantly different (1.7 +/- 0.8, 2.2 +/- 1.1, and 0.3 +/- 0.3 g/dl, for patients in groups 1, 2 and 3 respectively, P = 0.0001). Group 2 showed the highest post-operative complication rate (21 %) in comparison to group 1 (11 %) and group 3 (6 %), however, differences were not statistically significant (P = 0.3). PCNL through posterior or anterior caliceal puncture is an excellent modality to treat anterior caliceal stones with high stone clearance rate. Despite the higher chance of bleeding with anterior caliceal puncture, it is still inevitably needed in difficult anterior caliceal stones with unfavorable anatomy. RIRS is a good alternative to PCNL with the advantage of less radiation exposure and less bleeding. PMID- 26645870 TI - Dietary recommendations and treatment of patients with recurrent idiopathic calcium stone disease. AB - This review describes the various dietary regimens that have been used to advise patients on how to prevent the recurrence of their calcium-containing kidney stones. The conclusion is that although there is some general advice that may be useful to many patients, it is more efficacious to screen each patient individually to identify his/her main urinary, metabolic, nutritional, environmental, and lifestyle risk factors for stone-formation and then tailor specific advice for that particular patient based on the findings from these investigations. If the patient can be motivated to adhere strictly to this conservative approach to the prophylactic management of their stone problem over a long time period, then it is possible to prevent them from forming further stones. This approach to stone management is considerably less expensive than any of the procedures currently available for stone removal or disintegration. In the UK, for each new stone episode prevented by this conservative approach to prophylaxis it is calculated to save the Health Authority concerned around L2000 for every patient treated successfully. In the long term, this accumulates to a major saving within each hospital budget if most stone patients can be prevented from forming further stones and when the savings are totalled up country-wide saves the National Exchequer considerable sums in unclaimed Sick Pay and industry a significant number of manpower days which would otherwise be lost from work. It is also of immense relief and benefit to the patients not to have to suffer the discomfort and inconvenience of further stone episodes. PMID- 26645873 TI - Editorial. PMID- 26645872 TI - The management of patients with enteric hyperoxaluria. AB - Enteric hyperoxaluria is a common occurrence in the setting of fat malabsorption, usually due to intestinal resection or intestinal bypass surgery. Enhanced intestinal absorption of dietary oxalate leads to elevated renal oxalate excretion, frequently in excess of 100 mg/d (1.14 mmol/d). Patients are at increased risk of urolithiasis and loss of kidney function from oxalate nephropathy. Fat malabsorption causes increased binding of diet calcium by free fatty acids, reducing the calcium available to precipitate diet oxalate. Delivery of unabsorbed bile salts and fatty acids to the colon increases colonic permeability, the site of oxalate hyper-absorption in enteric hyperoxaluria. The combination of soluble oxalate in the intestinal lumen and increased permeability of the colonic mucosa leads to hyperoxaluria. Dietary therapy consists of limiting oxalate and fat intake. The primary medical intervention is the use of oral oxalate binding agents such as calcium salts to reduce free intestinal oxalate levels. Bile acid sequestrants can be useful in patients with ileal resection and bile acid malabsorption. Oxalate degrading bacteria provided as probiotics are being investigated but as of yet, no definite benefit has been shown with currently available preparations. The current state of medical therapy and potential future directions will be summarized in this article. PMID- 26645874 TI - Health-related quality of life in patients with colorectal neoplasm and cost effectiveness of colorectal cancer screening in Hong Kong. PMID- 26645875 TI - Generalised cost-effectiveness analysis for breast cancer prevention and care in Hong Kong Chinese. PMID- 26645876 TI - Cost-effective osteoporosis intervention thresholds for Hong Kong postmenopausal women. PMID- 26645877 TI - Predicting postoperative cardiac complications using automated endothelial function test. PMID- 26645878 TI - Projecting ischaemic heart disease mortality and morbidity in Hong Kong. PMID- 26645879 TI - Association of infant growth and pubertal adiposity: implications for future cardiovascular health and immunological benefits. PMID- 26645880 TI - Physical health needs, lifestyle choices, and quality of life among people with mental illness in the community. PMID- 26645881 TI - Rapid eye movement sleep behaviour disorder and psychiatry: a case-control study. PMID- 26645882 TI - Infant or childhood obesity and adolescent depression. PMID- 26645883 TI - Caries risk assessment programmes for Hong Kong children. PMID- 26645884 TI - A Protein-Corona-Free T(1)-T(2) Dual-Modal Contrast Agent for Accurate Imaging of Lymphatic Tumor Metastasis. AB - Precise nodal staging is particularly important to guide the treatments and determine the prognosis for cancer patients. However, it is still challenging to noninvasively and precisely detect in-depth tumor metastasis in lymph nodes (LNs) because of the small size and high potential of obtaining pseudopositive results. Herein, we report the rational design of a T1-T2 dual-modal MRI contrast agent for accurate imaging of tumor metastasis in LNs using gadolinium-embedded iron oxide nanoplates (GdIOP). The GdIOP were modulated with suitable size in vivo through surface functionalization by zwitterionic dopamine sulfonate (ZDS) molecules. The efficient uptake of GdIOP@ZDS nanoparticles through drainage effect because of the presence of large amount of macrophages and dendritic cells generates both T1 and T2 contrasts in LNs. In contrast, the low uptake of protein corona-free GdIOP@ZDS nanoparticles by melanoma B16 tumor cells promises pseudocontrast imaging of potential tumor metastasis in LNs. The combination of T1 and T2 imaging modalities allows self-confirmed detection of a metastatic tumor with about 1.2 mm in the minimal dimension in LNs, which is close to the detection limit of submilimeter level of MRI scans. This study provides an efficient and noninvasive strategy to detect tumor metastasis in LNs with greatly enhanced diagnostic accuracy. PMID- 26645885 TI - Reciprocal effects of capsaicin and menthol on thermosensation through regulated activities of TRPV1 and TRPM8. AB - Transient receptor potential vanilloid 1 (TRPV1) is activated by elevated temperature (>42 degrees C), and it has been reported that cold temperature decreases capsaicin-induced TRPV1 activity. In contrast, transient receptor potential melastatin 8 (TRPM8) is activated by low temperatures and menthol, and heat stimulation suppresses menthol-evoked TRPM8 currents. These findings suggest that the effects of specific agents on TRPV1 and TRPM8 channels are intricately interrelated. We examined the effects of menthol on human (h)TRPV1 and of capsaicin on hTRPM8. hTRPV1 currents activated by heat and capsaicin were inhibited by menthol, whereas hTRPM8 currents activated by cold and menthol were similarly inhibited by capsaicin. An in vivo sensory irritation test showed that menthol conferred an analgesic effect on the sensory irritation evoked by a capsaicin analogue. These results indicate that in our study the agonists of TRPV1 and TRPM8 interacted with both of these channels and suggest that the anti nociceptive effects of menthol can be partially explained by this phenomenon. PMID- 26645886 TI - Endothelin B receptor expression in malignant gliomas: the perivascular immune escape mechanism of gliomas. AB - In order to clarify the role of endothelin B receptors (ETBRs) in gliomas, we analyzed cell cultures and surgical specimens of gliomas using RT-PCR and immunohistochemistry. RT-PCR measured the absolute expression of ETBR mRNA in twelve samples, which included gliomas that were classified using the World Health Organization (WHO) classification system Grade I-IV, as well as two glioblastoma cell lines (CCF-STTG1 and U87-MG). Using immunohistochemistry, 77 glioma specimens were evaluated for their expression of ETBR and infiltrating T lymphocytes, including an analysis of cytotoxic T cells (CTLs) and regulatory T lymphocytes (Tregs). The number of ETBR-positive vessels in the glioblastomas (Grade IV) was significantly higher than in other grades of gliomas (comparisons to Grade IV, Grade I: p = 0.0323, Grade II: p = 0.0009, Grade III: p = 0.0273). The ETBR expression rate (defined as the number of ETBR-positive blood vessels divided by the total number of blood vessels) in the glioblastomas was higher than the ETBR expression rate in the low-grade gliomas (compared to Grade IV, Grade I: p = 0.0132, Grade II: p = 0.0018, Grade III: p = 0.0745). In addition, the cases which had an ETBR expression rate of 50 % or higher exhibited fewer infiltrating CTLs and more infiltrating Tregs compared to the cases with an ETBR expression rate <50 % (CTLs: p = 0.0342; Tregs: p = 0.0175). Isocitrate dehydrogenase 1 (IDH-1) mutations were identified in 21 cases, but there was no correlation between ETBR expression and IDH-1 mutations for any WHO grade. These results suggest that ETBR expression during neo-angiogenesis may interfere with the homing of CTLs around the tumor and be involved in the immune escape mechanism of gliomas. PMID- 26645887 TI - Discovery of a Direct Ras Inhibitor by Screening a Combinatorial Library of Cell Permeable Bicyclic Peptides. AB - Cyclic peptides have great potential as therapeutic agents and research tools. However, their applications against intracellular targets have been limited, because cyclic peptides are generally impermeable to the cell membrane. It was previously shown that fusion of cyclic peptides with a cyclic cell-penetrating peptide resulted in cell-permeable bicyclic peptides that are proteolytically stable and biologically active in cellular assays. In this work, we tested the generality of the bicyclic approach by synthesizing a combinatorial library of 5.7 * 10(6) bicyclic peptides featuring a degenerate sequence in the first ring and an invariant cell-penetrating peptide in the second ring. Screening of the library against oncoprotein K-Ras G12V followed by hit optimization produced a moderately potent and cell-permeable K-Ras inhibitor, which physically blocks the Ras-effector interactions in vitro, inhibits the signaling events downstream of Ras in cancer cells, and induces apoptosis of the cancer cells. Our approach should be generally applicable to developing cell-permeable bicyclic peptide inhibitors against other intracellular proteins. PMID- 26645888 TI - Prophylactic oral betamimetics for reducing preterm birth in women with a twin pregnancy. AB - BACKGROUND: Twin pregnancies are associated with a high risk of neonatal mortality and morbidity due to an increased rate of preterm birth. Betamimetics can decrease contraction frequency or delay preterm birth in singleton pregnancies by 24 to 48 hours. The efficacy of oral betamimetics in women with a twin pregnancy is unproven. OBJECTIVES: To assess the effectiveness of prophylactic oral betamimetics for the prevention of preterm labour and birth for women with twin pregnancies. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group Trials Register (21 September 2015), MEDLINE (January 1966 to 31 July 2015), EMBASE (January 1985 to 31 July 2015) and reference lists of retrieved studies. SELECTION CRITERIA: Randomised controlled trials in twin pregnancies comparing oral betamimetics with placebo or any intervention with the specific aim of preventing preterm birth. Quasi-randomised controlled trials, cluster-randomised trials and cross-over trials were not eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. Two authors assessed the quality of the evidence using the GRADE approach. MAIN RESULTS: Overall, the quality of evidence is low for the primary outcomes. All of the included trials had small numbers of participants and few events. Preterm birth, the most important primary outcome, had wide confidence intervals crossing the line of no effect.Six trials (374 twin pregnancies) were included, but only five trials (344 twin pregnancies) contributed data. All trials compared oral betamimetics with placebo.Betamimetics reduced the incidence of preterm labour (two trials, 194 twin pregnancies, risk ratio (RR) 0.37; 95% confidence interval (CI) 0.17 to 0.78; low quality evidence). However, betamimetics did not reduce prelabour rupture of membranes (one trial, 144 twin pregnancies, RR 1.42; 95% CI 0.42 to 4.82; low quality evidence), preterm birth less than 37 weeks' gestation (four trials, 276 twin pregnancies, RR 0.85; 95% CI 0.65 to 1.10; low quality evidence), or less than 34 weeks' gestation (one trial, 144 twin pregnancies, RR 0.47; 95% CI 0.15 to 1.50; low quality evidence). Mean neonatal birthweight in the betamimetic group was significantly higher than in the placebo group (three trials, 478 neonates, mean difference 111.22 g; 95% CI 22.21 to 200.24). Nevertheless, there was no evidence of an effect of betamimetics in reduction of low birthweight (two trials, 366 neonates, average RR 1.19; 95% CI 0.77 to 1.85, random-effects), or small-for-gestational age neonates (two trials, 178 neonates, average RR 0.90; 95% CI 0.41 to 1.99, random-effects). Two trials showed that betamimetics significantly reduced the incidence of respiratory distress syndrome (388 neonates, RR 0.30; 95% CI 0.12 to 0.77), but the difference was not significant when the analysis was adjusted to account for the non-independence of twins (194 twins, RR 0.35; 95% CI 0.11 to 1.16). Three trials showed no evidence of an effect of betamimetics in reducing neonatal mortality, either with the unadjusted analysis, assuming twins are completely independent of each other (452 neonates, average RR 0.90; 95% CI 0.15 to 5.37, random-effects), or in the adjusted analysis, assuming non-independence of twins (226 twins, average RR 0.74; 95% CI 0.23 to 2.38, random-effects). A maternal death was reported in one trial without a significant difference between the groups (144 women, RR 2.84; 95% CI 0.12 to 68.57). AUTHORS' CONCLUSIONS: There is insufficient evidence to support or refute the use of prophylactic oral betamimetics for preventing preterm birth in women with a twin pregnancy. PMID- 26645889 TI - Penile Prosthesis Implantation in Patients with a History of Total Phallic Construction. AB - INTRODUCTION: Outcomes following penile prosthesis implantation in patients with a history of total phallic construction are not well described. AIM: The aim of this study was to evaluate outcomes following neophallus penile prosthesis placement. METHODS: Retrospective review penile prosthesis placement in patients with prior total phallic construction. GORE-TEX(r) (Gore Medical, Flagstaff, AZ) sleeve neotunica construction was utilized in all patients. MAIN OUTCOME MEASURE: Success defined as patient sexual activity with a functioning prosthesis. RESULTS: Thirty-one patients underwent neophallic prosthesis implantation at a mean 35.6 years of age. Prosthesis placement occurred at an average 56.3 months following phallic construction and follow-up was a mean of 59.7 months. Malleable prostheses were placed in 21 patients and inflatable in 10; implants were bilateral in 94%. Six percent experienced operative complications including a bladder injury (1) and phallic flap arterial injury (1). Postoperative complications occurred in 23% at a median 5.5 months following placement. Five prostheses were explanted secondary to infection or erosion and two additional required revisions. Of the explanted prosthesis two were later replaced without further complication. Eighty-one percent of patients were sexually active following prosthesis placement. CONCLUSIONS: Penile prosthesis placement is possible in patients with prior penile reconstruction/phallic construction. Although complications rates appear to be elevated in this population compared with historic controls of normal anatomic men, the majority of patients in this series were sexually active following prosthesis placement. This demonstrates the utility of prosthesis implantation in these difficult patients. PMID- 26645890 TI - Apoptosis of human prostate cancer cells induced by marine actinomycin X2 through the mTOR pathway compounded by MiRNA144. AB - The present study aimed to determine whether actinomycin X2 (AX2) intercepted the mTOR/PTEN/PI3K/Akt signaling pathway to inhibit human prostate cancer cells (PC 3) in vitro. The effects of AX2 on mTOR, PTEN, PI3K, and Akt at the protein level and mRNA were determined by western blotting and real-time reverse transcription PCR (RT-PCR), respectively. Concurrently, the effects of AX2 on expression levels of MiRNA144 and MiRNA126 in PC-3 were measured by real-time RT-PCR. The association of MiRNA144 with 3'-UTR of mTOR was identified using the Dual Luciferase Reporter Gene System. The direct effect of MIRNA144 on the mTOR/PTEN/PI3K/Akt pathway was determined by real-time RT-PCR and western blotting. Apoptosis of PC-3 cells induced by AX2 was determined by MTT and flow cytometry. The results indicated that mTOR/PTEN/PI3K/Akt were decreased and PTEN was increased by AX (1, 10 umol/l) at protein and mRNA levels in a dose-dependent manner. MiRNA144 was decreased, whereas MiRNA126 was increased by AX2. MiRNA144 associated with 3'-UTR of mTOR was corroborated. Overexpression of MiRNA144 decreased mTOR, but did not affect PTEN, PI3K, or Akt. The proliferation rates of AX2 on PC-3 cells were decreased. It suggests that AX2 induces apoptosis of PC-3 cells via meddling in the mTOR/PTEN/PI3K/Akt signaling pathway, but those effects are compounded by MiRNA144. Both AX2 and MiRNA144 intercept the signaling in different ways but cross on mTOR. PMID- 26645891 TI - Neoadjuvant or adjuvant sirolimus for malignant metastatic or locally advanced perivascular epithelioid cell tumors: two case reports. AB - Perivascular epithelioid cell tumors (PEComas) are very rare mesenchymal tumors, characterized by the presence of perivascular epithelioid cells. Despite their often benign nature, malignant variants with a locally aggressive growth pattern and even distant metastases are known. We describe two cases of malignant PEComas. The first patient had an extensive peritoneal spread and a history of multiple resections, and received the mechanistic target of rapamycin inhibitor sirolimus in a postoperative setting as maintenance therapy. The second patient presented with locally advanced disease in the iliac fossa and was treated with sirolimus in a neoadjuvant setting and achieved complete remission. Both patients have been under treatment for 18 and 52 months, respectively, and are currently in complete remission. These two cases indicate that mechanistic target of rapamycin inhibition for malignant PEComas could be a safe and successful treatment strategy in a neoadjuvant setting with an acceptable toxicity profile. PMID- 26645893 TI - Melatonin Induces Cell Apoptosis in AGS Cells Through the Activation of JNK and P38 MAPK and the Suppression of Nuclear Factor-Kappa B: a Novel Therapeutic Implication for Gastric Cancer. AB - BACKGROUND/AIMS: Melatonin, synthesized by the pineal gland and released into the blood, appears to have antitumour properties; however, the mechanisms of its anti cancer effects are largely unknown, especially in stomach cancer. Here, we explore the antitumour activity of melatonin in a gastric cancer cell line (AGS) and analyse its molecular mechanisms. METHODS: AGS cells were treated with melatonin, and cell viability was assessed using a CCK-8 assay. Flow cytometry was performed to evaluate apoptosis, and protein expression was examined by Western blotting. RESULTS: Melatonin significantly inhibited cell viability, clone formation, and cell migration and invasion and induced apoptosis in AGS cells. Moreover, MAPK pathways (p38, JNK and ERK) were activated by melatonin treatment, which also significantly increased caspase-3 cleavage and Bax protein expression and decreased Bcl-2 protein expression in a time-dependent manner. Our results demonstrate that p38 and JNK inhibitors (SB203580 and SP600125, respectively) prevented melatonin-induced apoptosis; thus, the propensity of p38 MAPK and JNK to promote apoptosis could be at least partly due to the inhibition of NF-x03BA;B p65 activation by p38 and JNK. Finally, melatonin was able to strengthen cisplatin-mediated antitumour effects in human gastric carcinoma cells by up-regulating the expression of Bax, down-regulating the expression of Bcl-2 and activating the caspase-dependent apoptotic pathway. CONCLUSION: Melatonin induced apoptosis in AGS cells by activating the caspase-dependent apoptotic pathway and by inhibiting the nuclear translocation of NF-x03BA;B p65, two processes that are regulated by p38 and JNK. Furthermore, melatonin significantly enhanced the anti-tumour effects of cisplatin, with low systemic toxicity. These new findings suggest that melatonin may act as a potent anti-tumour agent and may have great potential as an adjuvant therapy in the future. PMID- 26645892 TI - Liquid biopsy for detection of actionable oncogenic mutations in human cancers and electric field induced release and measurement liquid biopsy (eLB). AB - Oncogenic activations by mutations in key cancer genes such as EGFR and KRAS are frequently associated with human cancers. Molecular targeting of specific oncogenic mutations in human cancer is a major therapeutic inroad for anti-cancer drug therapy. In addition, progressive developments of oncogene mutations lead to drug resistance. Therefore, the ability to detect and continuously monitor key actionable oncogenic mutations is important to guide the use of targeted molecular therapies to improve long-term clinical outcomes in cancer patients. Current oncogenic mutation detection is based on direct sampling of cancer tissue by surgical resection or biopsy. Oncogenic mutations were recently shown to be detectable in circulating bodily fluids of cancer patients. This field of investigation, termed liquid biopsy, permits a less invasive means of assessing the oncogenic mutation profile of a patient. This paper will review the analytical strategies used to assess oncogenic mutations from biofluid samples. Clinical applications will also be discussed. PMID- 26645894 TI - Intestinal microbiota composition after antibiotic treatment in early life: the INCA study. AB - BACKGROUND: The acquisition and development of infant gut microbiota can be influenced by numerous factors, of which early antibiotic treatment is an important one. However, studies on the effects of antibiotic treatment in early life on clinical outcomes and establishment and development of the gut microbiota of term infants are limited. Disturbed microbiota composition is hypothesized to be an underlying mechanism of an aberrant development of the immune system. This study aims to investigate the potential clinical and microbial consequences of empiric antibiotic use in early life. METHODS/DESIGN: 450 term born infants, of whom 150 are exposed to antibiotic treatment in early life and 300 are not (control group), are included in this observational cohort study with a one-year follow-up. Clinical outcomes, including coughing, wheezing, fever >38 degrees C, runny nose, glue ear, rash, diarrhea and >3 crying hours a day, are recorded daily by parents and examined by previously defined doctor's diagnosis. A blood sample is taken at closure to investigate the infant's vaccination response and sensitization for food and inhalant allergens. Fecal samples are obtained at eight time points during the first year of life. Potential differences in microbial profiles of infants treated with antibiotics versus healthy controls will be determined by use of 16S-23S rRNA gene analysis (IS-pro). Microbiota composition will be described by means of abundance, diversity and (dis)similarity. Diversity is calculated using the Shannon index. Dissimilarities between samples are calculated as the cosine distance between each pair of samples and analyzed with principal coordinate analysis. Clinical variables and possible associations are assessed by appropriate statistics. DISCUSSION: Both clinical quantitative and qualitative microbial effects of antibiotic treatment in early life may be demonstrated. These findings can be important, since there is evidence that manipulation of the infant microbiota by using pre- or probiotics can restore the ecological balance of the microbiota and may mitigate potential negative effects on the developing immune system, when use of antibiotics cannot be avoided. TRIAL REGISTRATION: ClinicalTrials.gov NCT02536560. Registered 28 August 2015. PMID- 26645896 TI - Uniform Au@Pt core-shell nanodendrites supported on molybdenum disulfide nanosheets for the methanol oxidation reaction. AB - Herein, we presented a facile seeded growth method to prepare high-quality three dimensional (3D) Au@Pt bimetallic nanodendrite-decorated molybdenum disulfide (MoS2) nanosheets (Au@Pt/MoS2). Transmission electron microscopy (TEM) and high resolution TEM exhibited that Au@Pt core-shell nanostructures were dispersed onto the surface of MoS2 nanosheets. More importantly, the thickness of the Pt shell of the Au@Pt bimetallic nanodendrites on the surface of the MoS2 nanosheets could be easily tuned via simply changing the synthesis parameters, such as the concentration of H2PtCl6, reaction time and temperature, which greatly influence the catalytic ability of Au@Pt/MoS2 nanohybrids. Both cyclic voltammetry (CV) and chronoamperometry (CA) demonstrated that the as-prepared Au@Pt/MoS2 nanohybrids possessed much higher electrocatalytic activity and stability than Pt/MoS2 or commercial Pt/C catalyst. The peak current mass density of the selected Au@Pt/MoS2 was 6.24 A mg(-1), which was 3389 and 20.3 times those of Pt/C (0.00184 A mg(-1)) and Pt/MoS2 (0.307 A mg(-1)), respectively. The presented method may be a facile approach for the synthesis of MoS2-supported bimetallic nanocomposites, which is significant for the development of high performance MoS2 based sensors and catalysts. PMID- 26645895 TI - Safety of live attenuated influenza vaccine in young people with egg allergy: multicentre prospective cohort study. AB - STUDY QUESTION: How safe is live attenuated influenza vaccine (LAIV), which contains egg protein, in young people with egg allergy? METHODS: In this open label, phase IV intervention study, 779 young people (2-18 years) with egg allergy were recruited from 30 UK allergy centres and immunised with LAIV. The cohort included 270 (34.7%) young people with previous anaphylaxis to egg, of whom 157 (20.1%) had experienced respiratory and/or cardiovascular symptoms. 445 (57.1%) had doctor diagnosed asthma or recurrent wheeze. Participants were observed for at least 30 minutes after vaccination and followed-up by telephone 72 hours later. Participants with a history of recurrent wheeze or asthma underwent further follow-up four weeks later. The main outcome measure was incidence of an adverse event within two hours of vaccination in young people with egg allergy. STUDY ANSWER AND LIMITATIONS: No systemic allergic reactions occurred (upper 95% confidence interval for population 0.47% and in participants with anaphylaxis to egg 1.36%). Nine participants (1.2%, 95% CI 0.5% to 2.2%) experienced mild symptoms, potentially consistent with a local, IgE mediated allergic reaction. Delayed events potentially related to the vaccine were reported in 221 participants. 62 participants (8.1%, 95% CI for population 6.3% to 10.3%) experienced lower respiratory tract symptoms within 72 hours, including 29 with parent reported wheeze. No participants were admitted to hospital. No increase in lower respiratory tract symptoms occurred in the four weeks after vaccination (assessed with asthma control test). The study cohort may represent young people with more severe allergy requiring specialist input, since they were recruited from secondary and tertiary allergy centres. WHAT THIS STUDY ADDS: LAIV is associated with a low risk of systemic allergic reactions in young people with egg allergy. The vaccine seems to be well tolerated in those with well controlled asthma or recurrent wheeze. FUNDING, COMPETING INTERESTS, DATA SHARING: This report is independent research commissioned and funded by a Department of Health policy research programme grant to the National Vaccine Evaluation Consortium. Additional funding was provided by the NIHR Clinical Research Networks, Health Protection Scotland (Edinburgh site), and Health & Social Care Services in Northern Ireland (Belfast site). PJT and MEL had support from the Department of Health for the submitted work; PJT has received research grants from the Medical Research Council and NIHR. No additional data available.Study registration ClinicalTrials.gov (NCT02111512) and the EU Clinical Trials Register EudraCT (2014-001537-92). PMID- 26645897 TI - Young Adults' Perceived Purposes of Emerging Adulthood: Implications for Cohabitation. AB - The authors investigated associations between young adults' perceived purposes of emerging adulthood and their attitudes toward and participation in cohabitation. In a sample of 775 never married individuals, ages 18-29 (69% female, 69% white) from the United States, young people's perceptions of this period of life were associated with their acceptance of cohabitation, their reasoning for accepting cohabitation, and the likelihood of cohabiting. Results showed that the perception that emerging adulthood is a time to prepare for future family roles was negatively associated with acceptance of cohabitation whereas the perception that emerging adulthood is a time to take risks was positively associated with acceptance of cohabitation. The perception that emerging adulthood is a time to prepare for future family roles was associated with an increased likelihood of having cohabited while the perception that emerging adulthood is a time of possibilities was associated with a decreased likelihood of having cohabited. Implications for future research are discussed. PMID- 26645898 TI - Methylation of RASSF10 promotes cell proliferation and serves as a docetaxel resistant marker in human breast cancer. AB - Breast cancer is a leading cause of death among females worldwide. However, the mechanisms of breast cancer remain largely unclear. RASSF10 is frequently methylated in certain types of human cancers. To understand the mechanism of RASSF10 in breast cancer, samples of breast cancer cell lines, primary cancer, breast tissue adjacent to cancer, and normal breast tissue were investigated in this study. Methylation specific PCR (MSP), flow cytometry, western blot, and siRNA knockdown assay were used. Complete methylation was found in MCF7, MDA-MB 435, and MDA-MB-468 cells, partial methylation was found in ZR75-1 cells, and unmethylation was revealed in SKBR3 cells. Loss of RASSF10 expression was found in MCF7, MDA-MB-435, and MDA-MB-468 cells, and high expression of RASSF10 was found in ZR75-1 and SKBR3 cells. The expression of RASSF10 was induced by 5-aza 2'-deoxycytidine (5-Aza) in MCF7, MDA-MB-435, and MDA-MB-468 cells. RASSF10 methylation was found in 77.8% (49/63) of primary breast cancer and 17.8% (8/45) of adjacent tissue samples. No methylation was found in normal breast tissue samples. Restoration of RASSF10 expression inhibited cell proliferation and induced G2/M phase arrest in MCF7 and MDA-MB-468 cells. RASSF10 sensitized these cells to docetaxel. RASSF10 induced apoptosis and activated P53 signaling in breast cancer cells. In conclusion, RASSF10 is frequently methylated in human breast cancer and infrequently in adjacent tissue samples. RASSF10 methylation may serve as an early detective marker. The expression of RASSF10 is regulated by promoter region methylation. Since restoration of RASSF10 expression sensitized breast cancer cells to docetaxel, RASSF10 methylation is a potential docetaxel resistant marker. RASSF10 suppresses breast cancer growth by activating P53 signaling. PMID- 26645899 TI - Identification, characterization, and targeting of IL-4 receptor by IL-4 Pseudomonas exotoxin in mouse models of anaplastic thyroid cancer. AB - Thyroid cancer is a rapidly increasing endocrine cancer. Since interleukin-4 receptor (IL-4R) is overexpressed in human solid cancer, we examined expression of IL-4R in 50 cases of anaplastic thyroid cancer (ATC), 37 well-differentiated papillary cancer (WDPC), 35 well-differentiated follicular cancer of thyroid (WDFC), and 37 normal thyroid specimens by immunohistochemistry (IHC) and in-situ hybridization (ISH) techniques. We demonstrated that IL-4Ralpha was overexpressed in 36/50 (72%) ATC, 20/35 (57%) WDFC, and 11/37 (30%) WDPC tumors. Other two subunits of IL-4R, interleukin-13 receptor alpha1 (IL-13Ralpha1) and interleukin 2 receptor gamma (IL-2RgammaC), were either weakly expressed or absent. As ATC is a highly aggressive cancer with higher incidence of IL-4Ralpha expression, we characterized IL-4R in 3 ATC cell lines. RT-qPCR and IFA results showed that IL 4Ralpha is overexpressed while IL-13Ralpha1 is weakly expressed. Control human umbilical vein endothelial cell line (HUVEC) showed weak expression of IL 4Ralpha. Binding and competition studies with 125I-IL-4 in ATC cell lines demonstrated that IL-4 specifically bound to IL-4Ralpha on cell surface. ATC cell lines were highly sensitive to a chimeric fusion cytotoxin consisting of circularly permuted IL-4 and truncated Pseudomonas exotoxin (IL-4-PE), which killed them in a concentration dependent manner. IL-4-PE also blocked colony formation of ATC cell lines in clonogenic assays. IL-4-PE mediated a significant antitumor activity in mouse models of ATC. Intratumoral administration of IL-4-PE caused significant regression of established tumors in a dose dependent manner and increased the overall survival without any visible toxicity. Thus, IL-4Ralpha in ATC may represent a novel therapeutic target and IL-4-PE may serve as an investigational therapeutic option for ATC. PMID- 26645900 TI - Role of Helicobacter pylori in gastric cancer: advances and controversies. AB - Gastric cancer is one of the most common cancers of digestive system globally and Helicobacter pylori (HP) infection is believed to be a major risk factor. HP can be classified into different types based on the presence and expression level of CagA and VacA, and, when exposed to adverse environment, HP changes its phenotype from helical type to coccoid type, with each having different pathogenicity. The mechanisms of HP-induced gastric carcinogenesis and progression are complicated, including DNA nitration and oxidation induced by mutagenic factors, HP-induced epigenetic modifications, HP-induced disruption of the balance between cell proliferation and apoptosis, and HP-induced cancer cell invasion and metastasis. HP may also affect the biological function of cancer stem cells and induction of cell autophagy. The lipopolysaccharide produced by HP can act through toll-like receptor-4 (TLR-4) to induce gastric mucosal inflammation and is thereby linked to the development of gastric cancer. PMID- 26645901 TI - Advances in mechanistic understanding and treatment approaches to Tourette syndrome. AB - Tourette syndrome (TS) is a childhood onset neurodevelopmental disorder characterized by semi-involuntary, repetitive movements and sounds (motor and phonic tics). Transient tics in childhood are common, and their persistence in TS may be due to failure of maturation of frontal-subcortical circuits mediated by genetic predisposition and environmental factors. Tic improvement by young adult years is common, but its mechanism and predictive factors are unclear. Though tics can often be managed with nonmedical therapies, pharmacotherapy is often used for refractory, severe, or injurious tics but is complicated by side effects and incomplete benefit. This review summarizes the current understanding of TS pathophysiology, current and future treatment options, and recommendations for future research. PMID- 26645902 TI - Turning killer into cure -- the story of oncolytic herpes simplex viruses. AB - Viruses have the intrinsic capability to kill host cells. Even when the initial infection consists of only a few viruses, they can reproduce themselves in large quantities within a short time and quickly spread to nearby cells, causing substantial tissue damage. These same infectious properties become desirable if they can be converted into killer agents with specificity for malignant cells. Cancer virotherapy is doing exactly that by modifying viruses in ways that allow them to replicate in malignant cells but not in normal cells. Although relatively young, the field has seen significant progress in recent years. For example, the most recent phase III trial data on a herpes simplex virus (HSV)-based oncolytic virus (T-VEC) show substantial improvement in objective and durable responses over the control arm in melanoma patients, prompting speculation that a virotherapy may receive FDA approval for clinical use in the very near future. This review focuses on HSV-based oncolytic viruses, from their early history to their most recent development, with discussion of promising directions for further improvement. PMID- 26645903 TI - The emerging roles and therapeutic potential of microRNAs (miRs) in liposarcoma. AB - Liposarcoma (LPS) is a common subtype of soft tissue sarcoma and accounts for approximately 20% of adult sarcomas. Despite the progress in diagnosis and treatment of LPS, there is still a high mortality rate due to local recurrence or metastasis. The mechanisms underlying the development of recurrence and metastasis of LPS remain elusive. MicroRNAs (miRNAs or miRs) are non-coding RNAs that regulate target gene expression, influencing many cellular functions, including cell proliferation, apoptosis, differentiation, oncogenesis, and drug resistance in malignant cells. The dysregulation of miRs is involved in the initiation and progression of human cancers, including LPS. Functional studies have shown the potent pro- and anti-tumorigenic activity of specific miRs both in vitro and in vivo. miR signatures that are unique to specific types of LPS have been proposed. Several lines of evidence have shown that miRs can act either as oncogenes or tumor suppressor genes, as well as diagnostic and prognostic biomarkers for LPS. In addition, miRs may be a powerful therapeutic target in LPS, although obstacles such as delivery of miRs in vivo need to be overcome. In this review, we discuss the emerging roles of miRs in different histological subtypes of LPS. PMID- 26645904 TI - Mitochondrial disorders: disease mechanisms and therapeutic approaches. AB - Mitochondrial disorders are now well recognized as an important cause of genetic disease. They exhibit remarkable phenotypic, biochemical, and molecular heterogeneity, and frequently involve multiple organ systems. Their complexity partly relates to the dual expression of mitochondrial proteins by both mitochondrial and nuclear genomic DNA. Multiple copies of mitochondrial DNA (mtDNA) are present in a single human mitochondrion. Each molecule exists as a double-stranded, circular, helical structure containing 37 genes: 13 encode polypeptide subunits, whilst the remaining 24 encode 22 transfer and 2 ribosomal RNAs necessary for their synthesis. These protein subunits contribute towards four of five multimeric enzymes (so-called complex I/III/IV/V, with complex II entirely nuclear-encoded) embedded in the inner mitochondrial membrane. The enzymes catalyze a sequence of redox reactions which ultimately generates adenine triphosphate, the cellular unit of energy, during oxidative phosphorylation (OXPHOS). The remaining OXPHOS subunits (more than 70 in total), in addition to the apparatus required for their transcription, translation, post-translational modification and assembly, are nuclear-encoded. The mitochondrion's dependence on nuclear DNA extends further to include the machinery required for the maintenance, replication, and repair of mtDNA molecules, the proteins for which are synthesized in the cell cytoplasm prior to transport across mitochondrial membrane for replication. Recent advancements in DNA analysis using next generation sequencing technology have provided an unprecedented expansion in the depth of knowledge concerning both molecular mechanisms and biological pathways which underpin many mitochondrial diseases. This understanding has led to the emergence of many potential targets and treatment strategies for these disorders for which there is currently no cure. This review highlights the challenges to therapy development and clinical trial design and outlines the approaches currently being investigated to treat this diverse group of disorders. PMID- 26645905 TI - Adeno-associated virus (AAV) gene delivery in stem cell therapy. AB - The past 30 years have witnessed the development of cell and gene therapies for the treatment of diverse human diseases. Each of these approaches has inherent advantages and disadvantages; however, the two methods align in that, essentially, they are both methods of foreign DNA delivery to complement, eradicate, or supplement nucleotide sequences important for human health. As discussed herein, the combination of these therapies (gene therapy in stem cells), particularly in an ex vivo context, offers powerful genetic engineering which is applicable to the treatment of both genetic and acquired maladies ranging from blood diseases to the treatment of HIV infection. Of the existing gene therapy approaches, including non-viral and viral vectors, those based on adeno-associated virus (AAV) are currently at the forefront as they have been safely used in hundreds of clinical trials and have demonstrated remarkable success in treating blindness and hemophilia B. However, AAV vectors used in combination with cell-based therapies have not transitioned to the clinic. Instead, adenoviral, retroviral, and lentiviral vectors are the preferred choice for the modification of stem cells prior to patient infusion. This review provides a general background of AAV gene therapy and cell therapies, and highlights reports demonstrating apparently conflicting data of productive transduction and vector-induced toxicity using recombinant AAV in stem and stem like cells. PMID- 26645906 TI - Energy transfer in diiodoBodipy-grafted upconversion nanohybrids. AB - Steady-state and time-resolved emission studies on nanohybrids consisting of NaYF4:Yb,Er and a diiodo-substituted Bodipy (UCNP-IBDP) show that the Yb(3+) metastable state, formed after absorption of a near-infrared (NIR) photon, can decay via two competitive energy transfer processes: sensitization of IBDP after absorption of a second NIR photon and population of Er(3+) excited states. PMID- 26645908 TI - Predictors of change in depressive symptoms from preschool to first grade. AB - Children's depressive symptoms in the transition from preschool to school are rarely investigated. We therefore tested whether children's temperament (effortful control and negative affect), social skills, child psychopathology, environmental stressors (life events), parental accuracy of predicting their child's emotion understanding (parental accuracy), parental emotional availability, and parental depression predict changes in depressive symptoms from preschool to first grade. Parents of a community sample of 995 4-year-olds were interviewed using the Preschool Age Psychiatric Assessment. The children and parents were reassessed when the children started first grade (n = 795). The results showed that DSM-5 defined depressive symptoms increased. Child temperamental negative affect and parental depression predicted increased, whereas social skills predicted decreased, depressive symptoms. However, such social skills were only protective among children with low and medium effortful control. Further, high parental accuracy proved protective among children with low effortful control and high negative affect. Thus, interventions that treat parental depression may be important for young children. Children with low effortful control and high negative affect may especially benefit from having parents who accurately perceive their emotional understanding. Efforts to enhance social skills may prove particularly important for children with low or medium effortful control. PMID- 26645907 TI - Natural transmission of Leishmania infantum through experimentally infected Phlebotomus perniciosus highlights the virulence of Leishmania parasites circulating in the human visceral leishmaniasis outbreak in Madrid, Spain. AB - A human leishmaniasis outbreak is occurring in the Madrid region, Spain, with the parasite and vector involved being Leishmania infantum and Phlebotomus perniciosus respectively. The aim of this study was to investigate the virulence of L. infantum isolates from the focus using a natural transmission model. Hamsters were infected by intraperitoneal inoculation (IP) or by bites of sand flies experimentally infected with L. infantum isolates obtained from P. perniciosus collected in the outbreak area (IPER/ES/2012/BOS1FL1 and IPER/ES/2012/POL2FL6) and a well characterized L. infantum strain JPCM5 (MCAN/ES/98/LLM-877). Hamster infections were monitored by clinical examination, serology, culture, parasite burden, Giemsa-stained imprints, PCR, histopathology and xenodiagnostic studies. Establishment of infection of L. infantum was achieved with the JPCM5 strain and outbreak isolates by both P. perniciosus infective bites or IP route. However, high virulence of BOS1FL1 and POL2FL6 isolates was highlighted by the clinical outcome of disease, high parasite detection in spleen and liver, high parasitic loads and positivity of Leishmania serology. Transmission by bite of POL2FL6 infected flies generated a slower progression of clinical disease than IP infection, but both groups were infective to P. perniciosus by xenodiagnosis at 2 months post-infection. Conversely, hamsters inoculated with JPCM5 were not infective to sand flies. Histopathology studies confirmed the wide spread of POL2FL6 parasites to several organs. A visceral leishmaniasis model that mimics the natural transmission in nature allowed us to highlight the high virulence of isolates that are circulating in the focus. These findings contribute to a better understanding of the outbreak epidemiology. PMID- 26645910 TI - Soil-on-a-Chip: microfluidic platforms for environmental organismal studies. AB - Soil is the habitat of countless organisms and encompasses an enormous variety of dynamic environmental conditions. While it is evident that a thorough understanding of how organisms interact with the soil environment may have substantial ecological and economical impact, current laboratory-based methods depend on reductionist approaches that are incapable of simulating natural diversity. The application of Lab-on-a-Chip or microfluidic technologies to organismal studies is an emerging field, where the unique benefits afforded by system miniaturisation offer new opportunities for the experimentalist. Indeed, precise spatiotemporal control over the microenvironments of soil organisms in combination with high-resolution imaging has the potential to provide an unprecedented view of biological events at the single-organism or single-cell level, which in turn opens up new avenues for environmental and organismal studies. Herein we review some of the most recent and interesting developments in microfluidic technologies for the study of soil organisms and their interactions with the environment. We discuss how so-called "Soil-on-a-Chip" technology has already contributed significantly to the study of bacteria, nematodes, fungi and plants, as well as inter-organismal interactions, by advancing experimental access and environmental control. Most crucially, we highlight where distinct advantages over traditional approaches exist and where novel biological insights will ensue. PMID- 26645909 TI - Benzoxazolinone detoxification by N-Glucosylation: The multi-compartment-network of Zea mays L. AB - The major detoxification product in maize roots after 24 h benzoxazolin-2(3H)-one (BOA) exposure was identified as glucoside carbamate resulting from rearrangement of BOA-N-glucoside, but the pathway of N-glucosylation, enzymes involved and the site of synthesis were previously unknown. Assaying whole cell proteins revealed the necessity of H2O2 and Fe(2+) ions for glucoside carbamate production. Peroxidase produced BOA radicals are apparently formed within the extraplastic space of the young maize root. Radicals seem to be the preferred substrate for N glucosylation, either by direct reaction with glucose or, more likely, the N glucoside is released by glucanase/glucosidase catalyzed hydrolysis from cell wall components harboring fixed BOA. The processes are accompanied by alterations of cell wall polymers. Glucoside carbamate accumulation could be suppressed by the oxireductase inhibitor 2-bromo-4'-nitroacetophenone and by peroxidase inhibitor 2,3-butanedione. Alternatively, activated BOA molecules with an open heterocycle may be produced by microorganisms (e.g., endophyte Fusarium verticillioides) and channeled for enzymatic N-glucosylation. Experiments with transgenic Arabidopsis lines indicate a role of maize glucosyltransferase BX9 in BOA-N-glycosylation. Western blots with BX9 antibody demonstrate the presence of BX9 in the extraplastic space. Proteomic analyses verified a high BOA responsiveness of multiple peroxidases in the apoplast/cell wall. BOA incubations led to shifting, altered abundances and identities of the apoplast and cell wall located peroxidases, glucanases, glucosidases and glutathione transferases (GSTs). GSTs could function as glucoside carbamate transporters. The highly complex, compartment spanning and redox-regulated glucoside carbamate pathway seems to be mainly realized in Poaceae. In maize, carbamate production is independent from benzoxazinone synthesis. PMID- 26645911 TI - Characterization of changes in plasma and tissue oxylipin levels in LPS and CLP induced murine sepsis. AB - OBJECTIVE: The present study aimed to comprehensively investigate the changes in oxylipins during murine sepsis induced by lipopolysaccharide (LPS) or cecal ligation and puncture (CLP). METHODS: Twenty-four hours after induction of sepsis in male C57BL/6 mice by LPS or CLP, plasma and liver, lung, kidney and heart tissues were sampled. Oxylipin levels in plasma and tissue were quantified by means of LC-MS. Moreover, clinical chemistry parameters were determined in plasma and interleukin levels (MCP-1 and IL-6) were determined in kidney and liver. RESULTS: Elevation of liver function plasma parameters at 24 h revealed that both models were successful in the induction of sepsis. LPS induced sepsis resulted in a dramatic increase of plasma PGE2 (2,100% change in comparison to control) and other cyclooxygenase metabolites, whereas this effect was less pronounced in CLP induced sepsis (97% increase of PGE2). Plasma epoxy-fatty acids (FAs) and hydroxy FAs and most of the dihydroxy-FAs were elevated in both models of sepsis. Changes of tissue oxylipin concentrations were organ dependent. Only few changes were detected in the lung and liver tissue, epoxy-FAs were elevated in the kidney. In the heart tissue a trend towards lower levels of hydroxy-FAs and epoxy-FAs was observed. CONCLUSION: Both murine models of sepsis are characterized by changes of oxylipins formed in all branches of the arachidonic acid (AA) cascade. The more pronounced effects in the LPS model make this model more suitable for the investigation of the AA cascade and its pharmacological modulation in sepsis. PMID- 26645912 TI - The prognostic role of abnormal liver function in IVIG unresponsiveness in Kawasaki disease: a meta-analysis. AB - OBJECTIVE: We aimed to assess the prognostic role of liver function alteration with intravenous immunoglobulin (IVIG) resistance in patients with Kawasaki disease (KD) by systematically analyzing and summarizing the results from published studies. METHODS: In this study, we summarized the evidence currently available up to March 31, 2015, and calculated the standard mean difference (SMD) of liver function parameters, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), and total bilirubin between IVIG-responsive and IVIG-resistant patients. RESULTS: We found that the serum levels of these parameters in IVIG-non-responsive patients were significantly higher than that in IVIG-responsive group (total bilirubin: SMD = 0.984, 95%CI 0.712-1.184, p < 0.005; ALT: SMD = 0.555, 95%CI 0.400-0.710, p < 0.005; AST: SMD = 0.602, 95%CI 0.413-0.791, p < 0.005; GGT = 0.551, 95%CI 0.157 0.946, p = 0.006). There was evidence of heterogeneity (I (2) > 50%). The characteristics of patients could be the major sources, as analysis stratified by region significantly removed or reduced the heterogeneity. CONCLUSION: In summary, our meta-analysis suggested that liver abnormality was significantly associated with IVIG unresponsiveness in KD patients. Further study from more clinical investigations is needed to confirm this finding. PMID- 26645913 TI - Pseudomonas aeruginosa stimulates tyrosine phosphorylation of and TLR5 association with the MUC1 cytoplasmic tail through EGFR activation. AB - BACKGROUND: MUC1 is a membrane-tethered mucin expressed on the surface of epithelial and hematopoietic cells. Previous studies have established that MUC1 attenuates airway inflammation in response to Pseudomonas aeruginosa (Pa) through suppression of Toll-like receptor (TLR) signaling. Here, we elucidate the mechanism through which the MUC1 cytoplasmic tail (CT) inhibits TLR5 signaling in response to Pa and its flagellin in primary normal human bronchial epithelial (NHBE) cells. METHODS: NHBE and human and mouse macrophages were stimulated with Pa or flagellin and transforming growth factor-alpha (TGF-alpha) and tumor necrosis factor-alpha (TNF-alpha) levels in cell culture supernatants were measured by ELISA. NHBE cells were stimulated with Pa, flagellin, or TNF-alpha and MUC1-CT, and epidermal growth factor receptor (EGFR) levels were measured by immunoblotting. NHBE cells were stimulated with Pa and MUC1-CT/TLR5 and MUC1 CT/EGFR association were detected by co-immunoprecipitation. RESULTS: Stimulation of NHBE cells with Pa and flagellin each increased release of the EGFR ligand, TGF-alpha, from NHBE cells. Both stimuli also activated EGFR tyrosine phosphorylation in these same cells. By contrast, stimulation of NHBE cells with Pa failed to induce TNF-alpha release, whereas stimulation of human or mouse macrophages with Pa promoted TNF-alpha release. Stimulation of NHBE cells with recombinant TNF-alpha increased both MUC1 and EGFR protein levels, and stimulation of these cells with Pa enhanced MUC1-CT tyrosine phosphorylation and increased MUC1-CT/TLR5 and MUC1-CT/EGFR protein association, in an EGFR-dependent manner. CONCLUSIONS: These results indicate that in response to Pa or flagellin, EGFR associates with and tyrosine phosphorylates MUC1-CT in primary NHBE cells, leading to increased MUC1-CT association with TLR5. Based on prior studies in tumor cells, increased MUC1-CT/TLR5 association in NHBE cells is predicted to competitively inhibit Pa/flagellin-stimulated TLR5 activation, reduce TLR5 dependent cell signaling, and down-regulate airway inflammation. Given that MUC1 is a universal suppressor of TLR signaling, the results from this study suggest that abnormal interactions between MUC1 and EGFR or TLRs may lead to the development of chronic inflammatory diseases. Thus, this is an important finding from the clinical point of view. PMID- 26645914 TI - Validation of the Scandinavian guidelines for initial management of minimal, mild and moderate traumatic brain injury in adults. AB - BACKGROUND: Acute management of traumatic brain injury (TBI), in particular mild TBI, focuses on the detection of the 5-7 % who may be harboring potentially life threatening intracranial hemorrhage (IH) using CT scanning. Guidelines intending to reduce unnecessary head CT scans using available clinical variables to detect those at high IH risk have shown varying results. Recently, the Scandinavian Neurotrauma Committee (SNC) derived a new set of high-IH risk variables for adults with TBI using an evidence-based literature review. Unlike previous guidelines, the SNC guideline incorporates serum values of the brain protein S100B with clinical variables. METHODS: We performed a nested cohort study of adults with mild TBI presenting to six emergency departments in New York and Pennsylvania within 6 h of injury. Patients were managed according to existing guidelines for CT selection. All patients underwent head CT scanning and serum S100B measurement, as well as prospective collection of clinical variables, as a requirement of the parent study. Using the SNC guidelines, S100B values and clinical variables were applied to these subjects, classifying each into one of five pre-defined severity categories, as well as predicting the need for head CT scanning to identify IH. This classification was then compared to actual head CT results to determine guideline sensitivity and specificity. RESULTS: In total, 662 adults (mean age 42 years, range 18-96; 258 females, 549 Caucasians) were available for analysis; 36 (5%) had IH on head CT scan. The SNC guidelines had a sensitivity of 97% (95% CI, 84-100%) and a specificity of 34% (95% CI, 30-37%) for the detection of IH on head CT. Application of the SNC guidelines would have resulted in a CT reduction of 32% (211/662 patients). One patient with low-risk mild TBI and a S100B level under 0.10 MUg/L had a traumatic CT abnormality and would have been discharged with strict adherence to the guidelines. However, this patient did not need any intervention for the injury and had a good outcome. CONCLUSION: Using the SNC guideline could save approximately one third of CT scans in a pre-selected cohort of mild TBI patients with little or no impact on patient outcome. PMID- 26645915 TI - Cold-aggravated pain in humans caused by a hyperactive NaV1.9 channel mutant. AB - Gain-of-function mutations in the human SCN11A-encoded voltage-gated Na(+) channel NaV1.9 cause severe pain disorders ranging from neuropathic pain to congenital pain insensitivity. However, the entire spectrum of the NaV1.9 diseases has yet to be defined. Applying whole-exome sequencing we here identify a missense change (p.V1184A) in NaV1.9, which leads to cold-aggravated peripheral pain in humans. Electrophysiological analysis reveals that p.V1184A shifts the voltage dependence of channel opening to hyperpolarized potentials thereby conferring gain-of-function characteristics to NaV1.9. Mutated channels diminish the resting membrane potential of mouse primary sensory neurons and cause cold resistant hyperexcitability of nociceptors, suggesting a mechanistic basis for the temperature dependence of the pain phenotype. On the basis of direct comparison of the mutations linked to either cold-aggravated pain or pain insensitivity, we propose a model in which the physiological consequence of a mutation, that is, augmented versus absent pain, is critically dependent on the type of NaV1.9 hyperactivity. PMID- 26645917 TI - Obstacles and opportunities for achieving good care on the surgical ward: nurse and surgeon perspective. AB - AIM: The purpose of this qualitative study was to explore and understand from the perspectives of nurses and surgeons the situations and processes that are important in the context of surgical care support or are obstacles to achieving good care. BACKGROUND: Medical advances and inpatients with multiple illnesses are on the increase. In addition, a high turnover of registered nurses has been identified. This contributes to an increasingly inexperienced nursing staff. Concurrently, studies have shown that patient safety and quality of care are linked to organisational structures and staffing education levels. METHOD: Eight nurses and six surgeons from three hospitals were interviewed and data were analysed by systematic text condensation. RESULTS: This identified three themes: shifting focus away from the patients, emphasising good communication, and using the competence of the team. CONCLUSION: This study contributes to a deeper understanding that many interruptions, insufficient communication and unused competence can be a threat to patient safety. Sweden has a high standard but this study elucidates that challenges remain to be resolved. IMPLICATIONS FOR NURSING MANAGEMENT: The focus on patients can increase by a balance between direct/indirect patient work and administration and by the support of clinicians using their full professional competence. PMID- 26645916 TI - Neural Substrates Related to Motor Memory with Multiple Timescales in Sensorimotor Adaptation. AB - Recent computational and behavioral studies suggest that motor adaptation results from the update of multiple memories with different timescales. Here, we designed a model-based functional magnetic resonance imaging (fMRI) experiment in which subjects adapted to two opposing visuomotor rotations. A computational model of motor adaptation with multiple memories was fitted to the behavioral data to generate time-varying regressors of brain activity. We identified regional specificity to timescales: in particular, the activity in the inferior parietal region and in the anterior-medial cerebellum was associated with memories for intermediate and long timescales, respectively. A sparse singular value decomposition analysis of variability in specificities to timescales over the brain identified four components, two fast, one middle, and one slow, each associated with different brain networks. Finally, a multivariate decoding analysis showed that activity patterns in the anterior-medial cerebellum progressively represented the two rotations. Our results support the existence of brain regions associated with multiple timescales in adaptation and a role of the cerebellum in storing multiple internal models. PMID- 26645918 TI - Kidney donors at risk: how to inform the donor. PMID- 26645919 TI - Personal Experience With 150 Isolated Procurements of Liver Allografts: Two Different Techniques. PMID- 26645920 TI - Patients with psychotic disorders in solid-organ transplant. AB - BACKGROUND: Psychotic disorders are considered a relative or absolute contraindication to organ transplant, but information about their impact on transplant is limited. OBJECTIVE: To describe the clinical course of psychotic patients while they were on the waiting list and the outcomes of patients with psychotic disorders undergoing evaluation for organ transplant. METHODS: Thirty eight transplant candidates with a diagnosis of psychotic disorder were analyzed in this descriptive study. The following variables were collected before transplant: demographics, type of transplant, cause of organ failure, medical comorbid conditions, and psychiatric variables (diagnosis, hospitalizations, treatment, substance abuse, family history, suicide attempts). For transplant recipients, the following posttransplant variables were recorded: rejection, toxic effects of medication, nonadherence, psychotic episodes (number, time interval after transplant), and number of hospitalizations. RESULTS: Of the 38 transplant candidates, 34 had a history of psychotic disorder before transplant. Nineteen (56%) of the 34 were listed for transplant, and 10 (29%) underwent transplant. Median follow-up time was 1.9 (IQR, 0.16-17.9) years. Among organ recipients with a history of psychotic disorders, psychiatric hospitalizations were 0.42 per patient per year (PPY), psychotic episodes 0.68 PPY, rejection 0.21 PPY, and toxic effects of immunosuppressants 0.05 PPY. None of the recipients lost their graft. CONCLUSIONS: Patients with a history of psychotic disorder can do well after organ transplant. Further studies are needed with factor analyses including severity of psychosis, medication adherence, and associated comorbid conditions. PMID- 26645921 TI - Heart transplant recipient with history of Chagas disease and elevated panel reactive antibodies. AB - Chagas disease is caused by a protozoan named Trypanosoma cruzi transmitted to humans by reduviid bugs. Severe dilated cardiomyopathy from chronic T cruzi infection is the most common finding, leading to end-stage heart failure. Heart transplant is an effective treatment for Chagas heart disease. However, T cruzi reactivation is of great concern, predisposing patients to episodes of myocarditis and rejection. A 56-year-old woman with a history of Chagas disease and elevated calculated panel reactive antibodies (CPRAs) underwent induction therapy and desensitization strategies aimed at lowering CPRAs, as elevated CPRAs have been implicated in the development of antibody-mediated rejection and reduced allograft survival. Clinical phases and signs and symptoms of Chagas disease are briefly described in an attempt to promote awareness of the disease among clinicians. In addition, serology assays approved in the United States as well as recommendations of experts on Chagas disease to assess tissues and blood specimens from endemic areas are outlined. Ultimately, the importance of ongoing surveillance is emphasized, as the future of heart transplant recipients with Chagas disease is unpredictable and the presence or reactivation of the disease requires prompt attention in an effort to prevent graft failure and death. PMID- 26645922 TI - Effect of elastic bandage wraps on leg edema in patients before and after liver transplant. AB - CONTEXT: Few studies have evaluated the benefits of short-term use of compression therapy to prevent or minimize edema and/or pain in the legs of acutely ill, hospitalized patients without venous leg ulcers. OBJECTIVE: To determine if the use of elastic bandage wraps of the leg in patients before and after liver transplant decreases edema formation and pain in the leg. Study Population-A convenience sample of inpatients before and after liver transplant. STUDY DESIGN: Pretest, posttest, randomized controlled trial with each participant serving as his or her own control. Intervention-Elastic bandage wrap applied to leg for 8 hours. OUTCOME MEASURES: Edema and pain in leg. RESULTS: In 13 patients before and 11 patients after liver transplant, the mean (SD) change in leg circumference after a single 8-hour application of an elastic bandage wrap was -2.6 (2.2) cm at the ankle and -3.1 (2.9) cm at midcalf for wrapped legs, as opposed to -0.4 (1.6) cm at the ankle and 1.0 (2.8) cm at midcalf for unwrapped legs (P<.001). Leg pain, measured on a visual analog scale, was significantly lower for the wrapped (mean [SD], 10.3 [26.5] mm) versus the unwrapped (20.3 [33.5] mm) leg (P=.04). CONCLUSION: In inpatients before and after liver transplant, the application of elastic bandage wraps to 1 leg for an 8-hour period led to significantly less edema formation and pain compared with the unwrapped leg. These results support the use of elastic bandage wraps in liver transplant patients to reduce leg edema and improve comfort. PMID- 26645923 TI - Outcomes of living kidney donors with rheumatoid arthritis. AB - BACKGROUND: Patients with rheumatoid arthritis are more likely to have reduced kidney function develop over time. The aim of this study was to assess the clinical and safety outcomes of living kidney donors with rheumatoid arthritis. METHODS: A retrospective cohort study at a tertiary referral hospital to assess the outcomes of living kidney donors with rheumatoid arthritis. All 6 adults with rheumatoid arthritis who underwent nephrectomy as living kidney donors between January 2000 and September 2014 were included. Eighteen nondonors with rheumatoid arthritis (3 nondonors per donor) were randomly selected for comparison by matching the year of birth and comorbidity score. RESULTS: None of the donors with rheumatoid arthritis had a flare-up of arthritis at a median follow-up time of 5.9 years (interquartile range [IQR], 3.1-7.5 years), while 5 (27.8%) nondonors with rheumatoid arthritis had a flare-up at a median follow-up time of 4.7 years (IQR, 3.1-6.7 years). After nephrectomy, donors' estimated glomerular filtration rate decreased to a mean of 43.53 (SD, 4) mL/min per 1.73 m2 at 7 days after the index date. The estimated glomerular filtration rate of donors subsequently increased significantly at rate of 3.99 mL/min per 1.73 m2 (P<.001). None of the donors with rheumatoid arthritis had end-stage renal disease develop or died at median follow-up times of 5.9 (IQR, 3.1-7.5) years and 8.2 (IQR, 5.8 9.7) years, respectively. CONCLUSION: Healthy kidney donors with rheumatoid arthritis have good outcomes, with no increased risk of decline in renal function, end-stage renal disease, or death. PMID- 26645924 TI - Duration of prophylaxis against fungal infection in kidney transplant recipients. AB - OBJECTIVE: To compare the efficacy of 2 strategies that use nystatin to prevent thrush and Candida esophagitis in kidney transplant recipients. METHODS: A retrospective chart review was conducted of adult kidney transplant recipients at our center, where the protocol for prophylaxis against fungal infection was changed in March 2013. Before the protocol change, kidney transplant recipients received nystatin for 1 month (before group) and after the change they received nystatin for the duration of admission (after group). The primary outcome measure was the incidence of thrush and Candida esophagitis within 3 months after transplant. Analyses were conducted on all kidney transplant recipients (intention to treat) and on only those kidney transplant recipients who received at least 1 dose of nystatin (modified intention to treat). Additional data collected included the duration of nystatin and immunosuppression regimens. The Student t test and Fisher exact test were used to calculate P values for continuous and categorical data. RESULTS: A total of 84 kidney transplant recipients, 42 in each cohort, were included in the analysis. The groups did not differ significantly at baseline. Nystatin was administered for a mean of 29 days in the before group and 5.74 days in the after group. Overall, 3 kidney transplant recipients (4%), all from the after group, experienced an episode of thrush and no patients experienced Candida esophagitis. Two recipients who experienced thrush did not receive any nystatin. CONCLUSIONS: Limiting the administration of nystatin to the duration of admission after transplant may be sufficient for prophylaxis of fungal infections in kidney transplant recipients. PMID- 26645925 TI - Preparing for a face transplant: development of a comprehensive nursing educational program. AB - To date, more than 30 face transplants have been performed worldwide. This innovative procedure has restored the functional and aesthetic aspects of the face in patients with cancer, congenital, and trauma-related deformities where the results of traditional reconstructive surgery have been deficient. The importance of nursing involvement in the care of these patients is undeniable; however, little has been published about how to properly prepare a nursing department to undertake such an important role. Although the care of patients undergoing face transplants has many similarities to the care of patients undergoing traditional head and neck flap procedures, patients undergoing face transplant provide unique challenges, including immunosuppression, allograft rejection, communication impairment, and psychosocial needs. Staff at New York University's Langone Medical Center have devised a specific plan of action to properly inform, educate, and prepare the nursing staff for this exciting endeavor. PMID- 26645926 TI - Listeria monocytogenes bacteremia in a pancreas transplant recipient. AB - We report a case of Listeria monocytogenes bacteremia in a patient 12 years after his pancreas transplant, during which time he received a steroid-free immunosuppressive regimen. To our knowledge, there are no reported cases describing L monocytogenes bacteremia after pancreas transplant. In addition, although typically identified as a complication shortly after transplant or after treatment for organ rejection, this case demonstrates that it is still possible for a patient to develop a L monocytogenes infection far removed from transplant. PMID- 26645927 TI - Explaining the quality of life of organ transplant patients by using crisis theory. AB - CONTEXT: Ubiquitous findings regarding the quality of life (QOL) of transplant patients have yet to be explained from a theoretical perspective. OBJECTIVE: To investigate transplant patients' QOL by using the conceptual framework of crisis theory. DESIGN: Cross-sectional study to explore differences in transplant patients' experiences of stress, coping, and QOL. Regression analysis was used to test crisis theory in relation to QOL, stress, and coping. PARTICIPANTS: A total of 226 participants representing transplant candidates, transplant recipients, and nontransplant individuals participated via survey-based data collection. RESULTS: Results showed that transplant candidates experience lower QOL than transplant recipients and nontransplant individuals. No significant differences were detected regarding stress levels or coping styles. Stress made a significant contribution to patients' QOL. CONCLUSIONS: Current findings suggest important QOL benefits of organ transplant. Using a theoretical model is an effective way to investigate the QOL of people experiencing chronic illness such as end-stage organ failure. Further investigation is required to reach a conclusive understanding of the complex interaction between transplant patients' QOL, stress, and coping. PMID- 26645928 TI - Organ donation video messaging in motor vehicle offices: results of a randomized trial. AB - CONTEXT: Since nearly all registered organ donors in the United States signed up via a driver's license transaction, motor vehicle (MV) offices represent an important venue for organ donation education. OBJECTIVE: To evaluate the impact of organ donation video messaging in MV offices. DESIGN: A 2-group (usual care vs usual care+video messaging) randomized trial with baseline, intervention, and follow-up assessment phases. SETTING: Twenty-eight MV offices in Massachusetts. INTERVENTION: Usual care comprised education of MV clerks, display of organ donation print materials (ie, posters, brochures, signing mats), and a volunteer ambassador program. The intervention included video messaging with silent (subtitled) segments highlighting individuals affected by donation, playing on a recursive loop on monitors in MV waiting rooms. MAIN OUTCOME MEASURES: Aggregate monthly donor designation rates at MV offices (primary) and percentage of MV customers who registered as donors after viewing the video (secondary). RESULTS: Controlling for baseline donor designation rate, analysis of covariance showed a significant group effect for intervention phase (F=7.3, P=.01). The usual-care group had a significantly higher aggregate monthly donor designation rate than the intervention group had. In the logistic regression model of customer surveys (n=912), prior donor designation (beta=-1.29, odds ratio [OR]=0.27 [95% CI=0.20 0.37], P<.001), white race (beta=0.57 OR=1.77 [95% CI=1.23-2.54], P=.002), and viewing the intervention video (beta=0.73, OR=1.54 [95% CI=1.24-2.60], P=.01) were statistically significant predictors of donor registration on the day of the survey. CONCLUSION: The relatively low uptake of the video intervention by customers most likely contributed to the negative trial finding. PMID- 26645929 TI - Experiential learning not enough for organ procurement surgery: implications for perioperative nursing education. AB - CONTEXT: Perioperative nurses play a vital role in assisting in surgical procedures for multiorgan procurement, receiving little education apart from on the-job experiential learning when they are asked to participate in these procedures. OBJECTIVES: Within an Australian context and as part of a larger study, this article describes issues that hindered perioperative nurses' participatory experiences as a result of lacking education, previous exposure, and preparation for assisting in surgical procedures for organ procurement. DESIGN: The grounded theory method was used to develop a substantive theory of perioperative nurses' experiences of participating in surgical procedures for multiorgan procurement. PARTICIPANTS: Thirty-five perioperative nurses who had experience in surgical procedures for organ procurement from regional, rural, and metropolitan hospitals of 2 Australian states, New South Wales and Western Australia, participated in the research. RESULTS: Levels of knowledge and experience emerged from the data as an influencing condition and was reported to affect the perioperative nurses' participatory experiences when assisting in procurement surgical procedures. Six components of levels of knowledge and experience were identified and are described. CONCLUSION: The findings from this study provide a unique contribution to the existing literature by providing an in depth understanding of the educational needs of perioperative nurses in order to assist successfully in multiorgan procurement procedures. These findings could guide further research with implications for clinical initiatives or education programs specifically targeting the perioperative nursing profession both locally and internationally. PMID- 26645930 TI - Impact of a quality improvement project on deceased organ donor management. AB - CONTEXT: Donors showed poor glucose control in the period between declaration of brain death and organ recovery. The level of hyperglycemia in the donors was associated with a decline in terminal renal function. OBJECTIVE: To determine whether implementation of a quality improvement project improved glucose control and preserved renal function in deceased organ donors. METHODS: Data collected retrospectively included demographics, medical history, mechanism of death, laboratory values, and data from the United Network for Organ Sharing. RESULTS: After implementation of the quality improvement project, deceased donors had significantly lower mean glucose concentrations (mean [SD], 162 [44] vs 212 [42] mg/dL; P<.001) and prerecovery glucose concentration (143 [66] vs 241 [69] mg/dL; P<.001). When the donor cohorts from before and after the quality improvement project were analyzed together, mean glucose concentration remained a significant predictor of terminal creatinine level (P<.001). Multivariate analysis of delayed graft function in kidney recipients matched to donors indicated that higher terminal creatinine level was associated with delayed graft function in recipients (P<.001). CONCLUSION: The quality improvement project improved donor glucose homeostasis, and the data confirm that poor glucose homeostasis is associated with worsening terminal renal function. PMID- 26645931 TI - Morphology-controlled MnO2-graphene oxide-diatomaceous earth 3-dimensional (3D) composites for high-performance supercapacitors. AB - 3-Dimensional (3D) composites based on a unique combination of MnO2 nanostructures, graphene oxide nanosheets and porous Diatomaceous Earth (DE) microparticles (GO-DE@MnO2) were synthesized and explored for application in high performance supercapacitors. To explore the influence of the structural properties of MnO2 nanostructures on supercapacitor performances, several MnO2 structures with nanosheet and nanowire morphologies were synthesized and characterized. The prepared GO-DE@MnO2 composites with MnO2 nanosheets due to their higher conductivity and higher surface area showed a larger specific capacitance of 152.5 F g(-1) and a relatively better cycle stability (83.3% capacitance retention after 2000 cycles at a scan rate of 2 A g(-1)), indicating great potential for application in supercapacitors. PMID- 26645933 TI - Exploring the role of the 3-center-4-electron bond in hypervalent lambda(3) iodanes using the methodology of domain averaged Fermi holes. AB - Hypervalent iodine compounds, in particular lambda(3)-iodanes, have become important reagents in organic synthesis for the electrophilic transfer of substituents to arenes and other nucleophiles. The structure and reactivity of these compounds are usually described based on a 3-center-4-electron bond model, involving the iodine central atom and its two trans substituents. The goal of this computational study is to explore Fermi correlation in view of a more advanced description of bonding in these compounds. For that matter, we apply the analysis of Domain Averaged Fermi Holes (DAFH). The DAFH analysis reveals a relationship between the occurrence of multicenter bonding and structural parameters which cannot be easily observed based on simple MO theory. Whereas for lambda(3)-iodanes carrying electron-rich ligands pairing of electrons over three centers is indeed observed, compounds with electron-withdrawing substituents fall into a different category: the pairing of electrons is restricted to extend over two centers only, thus challenging the multicenter bonding picture in this case. Accordingly, a drastic reduction of the DAFH three center bond index is observed. The establishment of the multicenter bond in lambda(3)-iodanes is driven by a pseudo Jahn-Teller (PJT) effect, whose extent is tightly coupled to the reactivity of the corresponding compound. The PJT stabilization scales with the degree of s-p hybridization of the central atom, which, in return, depends on the electron-withdrawing power of the ligands in the trans position. The response of the multicenter bond to the iodine "ligand field" can be expressed quantitatively in terms of DAFH bond indices. These show, for example, that the activation of the reacting hypervalent species by means of protonation results in a weaker 3 center-4-electron bond, thus making the reagent more reactive. In this work we explain a number of experimentally known facts concerning the reactivity of these compounds. We also show that the DAFH analysis offers a more complete understanding of hypervalency in lambda(3)-iodanes, and that it is a tool to assist the search for novel reagents. PMID- 26645932 TI - Utilization of a Cloud-Based Diabetes Management Program for Insulin Initiation and Titration Enables Collaborative Decision Making Between Healthcare Providers and Patients. AB - BACKGROUND: Overseeing proper insulin initiation and titration remains a challenging task in diabetes care. Recent advances in mobile technology have enabled new models of collaborative care between patients and healthcare providers (HCPs). We hypothesized that the adoption of such technology could help individuals starting basal insulin achieve better glycemic control compared with standard clinical practice. MATERIALS AND METHODS: This was a 12 +/- 2-week randomized controlled study with 40 individuals with type 2 diabetes who were starting basal insulin due to poor glycemic control. The control group (n = 20) received standard face-to-face care and phone follow-up as needed in a tertiary center, whereas the intervention group (n = 20) received care through the cloud based diabetes management program where regular communications about glycemic control and insulin doses were conducted via patient self-tracking tools, shared decision-making interfaces, secure text messages, and virtual visits (audio, video, and shared screen control) instead of office visits. RESULTS: By intention to-treat analysis, the intervention group achieved a greater hemoglobin A1c decline compared with the control group (3.2 +/- 1.5% vs. 2.0% +/- 2.0%; P = 0.048). The Diabetes Treatment Satisfaction Questionnaire showed a significant improvement in the intervention group compared with the control group (an increase of 10.1 +/- 11.7 vs. 2.1 +/- 6.5 points; P = 0.01). HCPs spent less time with patients in the intervention group compared with those in the control group (65.9 min per subject vs. 81.6 min per subject). However, the intervention group required additional training time to use the mobile device. CONCLUSIONS: Mobile health technology could be an effective tool in sharing data, enhancing communication, and improving glycemic control while enabling collaborative decision making in diabetes care. PMID- 26645934 TI - Potential sites of CFTR activation by tyrosine kinases. AB - The CFTR chloride channel is tightly regulated by phosphorylation at multiple serine residues. Recently it has been proposed that its activity is also regulated by tyrosine kinases, however the tyrosine phosphorylation sites remain to be identified. In this study we examined 2 candidate tyrosine residues near the boundary between the first nucleotide binding domain and the R domain, a region which is important for channel function but devoid of PKA consensus sequences. Mutating tyrosines at positions 625 and 627 dramatically reduced responses to Src or Pyk2 without altering the activation by PKA, suggesting they may contribute to CFTR regulation. PMID- 26645943 TI - Rationale for anti-OX40 cancer immunotherapy. AB - Immune checkpoint blockade with antagonistic monoclonal antibodies (mAbs) targeting B7 immunoglobulin superfamily molecules (CTLA-4, PD-1, and PD-L1) generate long lasting anti-tumour immune responses translating into clinical benefit across many cancer types. However, many patients are primarily resistant to immune checkpoint blockade -based monotherapy and many others will eventually relapse. Therefore, new immunostimulatory targets are needed to overcome primary and secondary resistance to immunotherapy. Besides the B7 co-inhibitory receptors, the tumour necrosis factor receptor superfamily contains many other immune checkpoints, which could become the next generation immunomodulators. Among them stands OX40 (CD134), a co-stimulatory molecule that can be expressed by activated immune cells. Several anti-OX40 agonistic monoclonal antibodies are currently tested in early phase cancer clinical trials. Accumulating preclinical evidence supports their clinical development. However, conflicting results and controversies between in vitro and in vivo data point to the need for comprehensive ancillary studies to be performed in upcoming clinical trials to better understand the mechanism of action of anti-OX40 mAbs-based therapy. PMID- 26645944 TI - Synthesis and bioactivity of antitubercular peptides and peptidomimetics: an update. AB - Mycobacterium tuberculosis is the causative agent of tuberculosis (TB), an infection that has been declared a global public health emergency by the World Health Organization. Current anti-TB therapies are limited in their efficacy and have failed to prevent the spread of TB, due to the long term drug compliance required and the genesis of multidrug-resistant strains (MDR). The number of chemotherapeutic agents currently available to treat MDR is limited, therefore there is a great need for new anti-TB drugs. Anti-TB peptides and peptidomimetics have emerged as an important and growing class of chemotherapeutic agents. This mini-review provides an update on peptides that exhibit very potent anti-TB activity, and their chemical syntheses, which could potentially be included in the pipeline for new anti-TB drug development. PMID- 26645945 TI - [Knowledge and attitudes of citizens in the Basque Country (Spain) towards cardiopulmonary resuscitation and automatic external defibrillators]. AB - AIM: To explore the training, ability and attitudes towards cardiopulmonary resuscitation and the use of automatic defibrillators among the population of the Basque Country (Spain). DESIGN: A face-to-face survey. SCOPE: Capital cities of the Basque Country. PARTICIPANTS: A total of 605 people between 15-64 years of age were randomly selected. MAIN VARIABLES OF INTEREST: Information about the knowledge, perceptions and self-perceived ability to identify and assist cardiopulmonary arrest was requested. RESULTS: A total of 56.4% of the responders were women, 61.8% were occupationally active, and 48.3% had higher education. Thirty-seven percent of the responders claimed to be trained in resuscitation techniques, but only 20.2% considered themselves able to apply such techniques. Public servants were almost 4 times more likely of being trained in defibrillation compared to the rest of workers (OR 3.7; P<.001), while people with elementary studies or no studies were almost 3 times more likely of not being trained in cardiopulmonary resuscitation, in comparison with the rest (OR 2.7; P=.001). A total of 94.7% of the responders considered it "quite or very important" for the general population to be able to apply resuscitation, though 55% considered themselves unable to identify an eye witnessed cardiac arrest, and 40.3% would not recognize a public-access defibrillator. CONCLUSIONS: Citizens of the Basque Country consider the early identification and treatment of cardiorespiratory arrest victims to be important, though their knowledge in cardiopulmonary resuscitation and defibrillation is limited. PMID- 26645946 TI - Frequency of IWOS Suggestive Ocular Signs in Slovenian Uveitis Patients with Confirmed Pulmonary Sarcoidosis. AB - PURPOSE: To investigate the prevalence of suggestive signs for ocular sarcoidosis proposed by the International Workshop on Ocular Sarcoidosis (IWOS) in patients with sarcoidosis-associated uveitis. METHODS: A retrospective study included 53 patients (77% female), with uveitis, who were seen in the period of 2010-2013 at the University Eye Hospital Ljubljana, Slovenia. All patients had confirmed pulmonary sarcoidosis based on clinical presentation, imaging and lung biopsy according to the ATS/ERS criteria. The presence of the seven clinical signs, suggested by the IWOS was determined in 47 patients with sufficient clinical data. RESULTS: Patients commonly exhibited bilaterality (79%), keratic precipitates/iris nodules (49%), and multiple chorioretinal peripheral lesions (36%). Three or more signs were observed in 40% (19/47) of patients or 79% (11/14) of patients with primary ocular involvement. CONCLUSIONS: Results add to the validation of IWOS criteria and emphasize the high percentage of at least three suggestive for ocular sarcoidosis in patients with primary ocular involvement. PMID- 26645947 TI - Symptom clusters of ovarian cancer patients undergoing chemotherapy, and their emotional status and quality of life. AB - PURPOSE: We conducted a descriptive study to identify the symptoms, emotional status, and quality of life experienced by hospitalized ovarian cancer patients undergoing chemotherapy, and influencing the factors of symptom clusters on their quality of life. METHODS: A total of 192 patients who had been diagnosed with ovarian cancer and received adjuvant chemotherapy after surgery more than once from 2 university hospitals with over 800 beds located in the Seoul and Gyeonggi areas of South Korea were included in this study. Using a structured questionnaire, the symptoms, emotional status, and quality of life by these patients were investigated from May 2012 to June 2013. RESULTS: We identified the following 7 symptom clusters among ovarian cancer patients undergoing chemotherapy: psychological distress, fatigue-pain, abdominal discomfort, flu like symptoms, fluid accumulation, and peripheral neuropathy. Patients with a high level of anxiety or depression experienced all symptoms at a higher level, and the 7 symptom clusters influenced all aspects of the patients' quality of life. CONCLUSIONS: This study provides to need interventions for the quality of life of ovarian cancer patients need to include the management of not only the physical symptoms and treatment-related side effects, but also the changes in their emotional status and daily lives. PMID- 26645948 TI - Evaluation of timing of first vaccination in children after hematopoietic allogeneic stem cell transplantation. AB - PURPOSE: Protective immunity to vaccine preventable infectious diseases might be lost over time following hematopoietic stem cell transplantation (HSCT). Limited data are available on the appropriate follow-up of vaccination schedules in pediatric HSCT patients. This study aims to ascertain whether the guidelines for vaccination recommended in our hospital are followed and to which extent of conformity they are used. METHODS: A 5-year survey, including all pediatric allogeneic HSCT patients, transplanted at the Ghent University hospital, Belgium. Data were collected from the patient's electronic (nursing and medical) charts. RESULTS: Data on vaccination schedules of 28 patients (54.9%) eligible for the recommended vaccinations were collected. Eleven patients (11/28; 39.3%) were vaccinated timely. In 14 out of 17 patients (82.4%) vaccination was postponed for medical reasons, while vaccination was postponed without medical reason in 17.6% (3/17). Vaccination data could not be retrieved in 43.1 (22/51) of patients. Vaccination was declined by the parents in one patient (2.0%). CONCLUSION: There is high level of agreement between the hospital guideline and the vaccination of pediatric HSCT patients. Health-care providers play a crucial role in effectively appropriate follow-up of vaccination schedules. PMID- 26645949 TI - Copper-Catalyzed Radical [2 + 2 + 1] Annulation of Benzene-Linked 1,n-Enynes with Azide: Fused Pyrroline Compounds. AB - A novel selective copper-catalyzed radical [2 + 2 + 1] annulation of benzene linked 1,n-enynes with azido-benziodoxolone to access fused pyrroline compounds, including 3H-pyrrolo[3,4-c]quinolin-4(3aH)-ones, chromeno[3,4-c]pyrrol-4(9bH) one, and indeno[1,2-c]pyrroline, has been developed, which proceeds via the addition of the azide radical to the alkene, annualtion, and azidation cascade. PMID- 26645951 TI - Justification for the inclusion of Gag in HIV vaccine candidates. AB - It is widely accepted that effective human immunodeficiency virus (HIV) vaccines need to elicit a range of responses, including neutralising antibodies and T cells. In natural HIV infections, immune responses to Gag are associated with lower viral load in infected individuals, and these responses can be measured against infected cells before the replication of HIV. Priming immune responses to Gag with DNA or recombinant Bacillus Calmette-Guerin (BCG) vaccines, and boosting with Gag virus-like particles as subunit vaccines or Gag produced in vivo by other vaccine vectors, elicits high-magnitude, broad polyfunctional responses, with memory T-cell responses appropriate for virus control. This review provides justification for the inclusion of HIV Gag in vaccine regimens, either as a transgene expressing protein that may assemble to form budded particles, or as purified virus-like particles. Possible benefits would include early control via CD8(+) T-cells at the site of infection, control of spread from the entry portal, and control of viraemia if infection is established. PMID- 26645952 TI - Evaluation and optimization of a commercial blocking ELISA for detecting antibodies to influenza A virus for research and surveillance of mallards. AB - The availability of a validated commercial assay is an asset for any wildlife investigation. However, commercial products are often developed for use in livestock and are not optimized for wildlife. Consequently, it is incumbent upon researchers and managers to apply commercial products appropriately to optimize program outcomes. We tested more than 800 serum samples from mallards for antibodies to influenza A virus with the IDEXX AI MultiS-Screen Ab test to evaluate assay performance. Applying the test per manufacturer's recommendations resulted in good performance with 84% sensitivity and 100% specificity. However, performance was improved to 98% sensitivity and 98% specificity by increasing the recommended cut-off. Using this alternative threshold for identifying positive and negative samples would greatly improve sample classification, especially for field samples collected months after infection when antibody titers have waned from the initial primary immune response. Furthermore, a threshold that balances sensitivity and specificity reduces estimation bias in seroprevalence estimates. PMID- 26645953 TI - The increasingly complex regulation of adipocyte differentiation. AB - Adipose (AD) tissue development and function relies on the ability of adipocytes to proliferate and differentiate into lipid-containing cells that also have endocrine function. Research suggests that certain conditions can induce AD tissue stem cells to differentiate into various cell types and that the microenvironment of the cell, including the extracellular matrix (ECM), is essential in maintaining cell and tissue function. This review provides an overview of factors involved in the proliferation and differentiation of adipocytes. A brief review of the numerous factors that influence PPARgamma, the transcription factor thought to be the master regulator of adipocyte differentiation, provides context of established pathways that regulate adipogenesis. Thought provoking findings from research with hypoxia that is supported by earlier research that vascular development is related to adipogenesis are reviewed. Finally, our understanding of the critical role of the ECM and environment in adipogenesis is discussed and compared with studies that suggest that adipocytes may dedifferentiate and can convert into other cell types. PMID- 26645954 TI - Predicting gestational age using neonatal metabolic markers. AB - BACKGROUND: Accurate gestational age estimation is extremely important for clinical care decisions of the newborn as well as for perinatal health research. Although prenatal ultrasound dating is one of the most accurate methods for estimating gestational age, it is not feasible in all settings. Identifying novel and accurate methods for gestational age estimation at birth is important, particularly for surveillance of preterm birth rates in areas without routine ultrasound dating. OBJECTIVE: We hypothesized that metabolic and endocrine markers captured by routine newborn screening could improve gestational age estimation in the absence of prenatal ultrasound technology. STUDY DESIGN: This is a retrospective analysis of 230,013 newborn metabolic screening records collected by the Iowa Newborn Screening Program between 2004 and 2009. The data were randomly split into a model-building dataset (n = 153,342) and a model testing dataset (n = 76,671). We performed multiple linear regression modeling with gestational age, in weeks, as the outcome measure. We examined 44 metabolites, including biomarkers of amino acid and fatty acid metabolism, thyroid-stimulating hormone, and 17-hydroxyprogesterone. The coefficient of determination (R(2)) and the root-mean-square error were used to evaluate models in the model-building dataset that were then tested in the model-testing dataset. RESULTS: The newborn metabolic regression model consisted of 88 parameters, including the intercept, 37 metabolite measures, 29 squared metabolite measures, and 21 cubed metabolite measures. This model explained 52.8% of the variation in gestational age in the model-testing dataset. Gestational age was predicted within 1 week for 78% of the individuals and within 2 weeks of gestation for 95% of the individuals. This model yielded an area under the curve of 0.899 (95% confidence interval 0.895-0.903) in differentiating those born preterm (<37 weeks) from those born term (>=37 weeks). In the subset of infants born small-for gestational age, the average difference between gestational ages predicted by the newborn metabolic model and the recorded gestational age was 1.5 weeks. In contrast, the average difference between gestational ages predicted by the model including only newborn weight and the recorded gestational age was 1.9 weeks. The estimated prevalence of preterm birth <37 weeks' gestation in the subset of infants that were small for gestational age was 18.79% when the model including only newborn weight was used, over twice that of the actual prevalence of 9.20%. The newborn metabolic model underestimated the preterm birth prevalence at 6.94% but was closer to the prevalence based on the recorded gestational age than the model including only newborn weight. CONCLUSIONS: The newborn metabolic profile, as derived from routine newborn screening markers, is an accurate method for estimating gestational age. In small-for-gestational age neonates, the newborn metabolic model predicts gestational age to a better degree than newborn weight alone. Newborn metabolic screening is a potentially effective method for population surveillance of preterm birth in the absence of prenatal ultrasound measurements or newborn weight. PMID- 26645955 TI - Location of childbirth for rural women: implications for maternal levels of care. AB - BACKGROUND: A recent American Congress of Obstetricians and Gynecologists and Society for Maternal-Fetal Medicine (MFM) consensus statement on levels of maternity care lays out designations that correspond to specific capacities available in facilities that provide obstetric care. Pregnant women in rural and remote areas receive particular attention in discussions of regionalization and levels of care, owing to the challenges in assuring local access to high-acuity services when necessary. Currently, approximately half a million rural women give birth each year in US hospitals, and whether and which of these women give birth locally is crucial for successfully operationalizing maternal levels of care. OBJECTIVE: We sought to characterize rural women who give birth in nonlocal hospitals and measure local hospital characteristics and maternal diagnoses present at childbirth that are associated with nonlocal childbirth. STUDY DESIGN: This was a repeat cross-sectional analysis of administrative hospital discharge data for all births to rural women in 9 states in 2010 and 2012. Multivariate logistic regression models were used to predict the odds of childbirth in a nonlocal hospital (at least 30 road miles from the patient's residence). We examined patient age, race/ethnicity, payer, rurality, clinical diagnoses (diabetes, hypertension, hemorrhage during pregnancy, placental abnormalities, malpresentation, multiple gestation, preterm delivery, prior cesarean delivery, and a composite of diagnoses that may require MFM consultation), as well as local hospital characteristics (birth volume, neonatal care level, ownership, accreditation, and system affiliation). RESULTS: The rate of nonlocal childbirth among 216,076 rural women was 25.4%. It varied significantly by primary payer (adjusted odds ratio [AOR], 0.76; 95% confidence interval [CI], 0.68-0.86 for Medicaid vs private insurance) and by clinical conditions including multiple gestation (AOR, 1.82; 95% CI, 1.58-2.1), preterm deliveries (AOR, 2.41; 95% CI, 2.17-2.67), and conditions that may require MFM services or consultation (AOR, 1.28; 95% CI, 1.22-1.35). Rural women whose local hospital did not have a neonatal intensive or intermediate care unit had nearly double the odds of giving birth at a nonlocal hospital (AOR, 1.94; 95% CI, 1.64-2.31). CONCLUSION: Approximately 75% of rural women gave birth at local hospitals; rural women with preterm births and clinical complications, as well as those without local access to higher-acuity neonatal care, were more likely to give birth in nonlocal hospitals. However, after controlling for clinical complications, rural Medicaid beneficiaries were less likely to give birth at nonlocal hospitals, implying a potential access challenge for this population. PMID- 26645956 TI - Studies on the biosynthesis of ralfuranones in Ralstonia solanacearum. AB - Ralfuranones, aryl-furanone secondary metabolites, are involved in the virulence of Ralstonia solanacearum in solanaceous plants. Ralfuranone I (6) has been suggested as a biosynthetic precursor for other ralfuranones; however, this conversion has not been confirmed. We herein investigate the biosynthesis of ralfuranones using feeding experiments with ralfuranone I (6) and its putative metabolite, ralfuranone B (2). The results obtained demonstrated that the biosynthesis of ralfuranones proceeded in enzymatic and non-enzymatic manners. PMID- 26645957 TI - Dengue virus infection-enhancing antibody activities against Indonesian strains in inhabitants of central Thailand. AB - Dengue virus (DENV) infection-enhancing antibodies are a hypothetic factor to increase the dengue disease severity. In this study, we investigated the enhancing antibodies against Indonesian strains of DENV-1-4 in 50 healthy inhabitants of central Thailand (Bangkok and Uthai Thani). Indonesia and Thailand have seen the highest dengue incidence in Southeast Asia. The infection history of each subject was estimated by comparing his/her neutralizing antibody titers against prototype DENV-1-4 strains. To resolve the difficulty in obtaining foreign live viruses for use as assay antigens, we used a recombinant system to prepare single-round infectious dengue viral particles based on viral sequence information. Irrespective of the previously infecting serotype(s), most serum samples showed significantly higher enhancement titers against Indonesian DENV-2 strains than against Thai DENV-2 strains, whereas the opposite effect was observed for the DENV-3 strains. Equivalent enhancing activities were observed against both DENV-1 and DENV-4. These results suggest that the genotype has an impact on enhancing antibody activities against DENV-2 and DENV-3, because the predominant circulating genotypes of each serotype differ between Indonesia and Thailand. PMID- 26645958 TI - The p47phox deficiency significantly attenuates the pathogenicity of Chlamydia muridarum in the mouse oviduct but not uterine tissues. AB - The Chlamydia muridarum induction of the upper genital tract pathology in mice has been used to investigate the mechanisms of chlamydial pathogenesis. We report that the NCF1 (neutrophil cytosolic factor1)-encoded p47phox (phagocyte oxidase), an essential subunit of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, contributes significantly to C. muridarum induction of hydrosalpinx. Mice lacking p47phox (p47phox-deficient) were no longer able to develop significant hydrosalpinx following an intravaginal infection with C. muridarum. However, there was no significant difference in uterine horn dilation (as a result of the endometrial glandular duct dilation) between the p47phox-deficient and -sufficient mice. Thus, the role of NADPH oxidase in chlamydial pathogenesis is restricted to the oviduct tissue rather than the entire upper genital tract. Interestingly, both the p47phox-deficient and -sufficient mice displayed similar levels of chlamydial live organism shedding from the lower genital tract, suggesting that the NADPH oxidase is not required for the mouse control of chlamydial infection in the lower genital tract. Furthermore, the p47phox deficiency did not affect the infectious organism burden in the upper genital tract tissues, indicating that the NADPH-oxidase activity is not necessary for the mouse prevention of chlamydial ascension from the lower to upper genital tracts. However, the p47phox-defieicnt mice displayed a significantly reduced chronic inflammatory infiltration in the oviduct but not uterine tissues, supporting the finding that the NADPH oxidase activity is required for chlamydial induction of dilation in the oviduct but not the endometrial glandular duct. Thus, we have demonstrated a significant role of the host NADPH oxidase in promoting chronic inflammatory pathology in the oviduct following chlamydial infection. PMID- 26645959 TI - Transcriptome profiling and validation of gene based single nucleotide polymorphisms (SNPs) in sorghum genotypes with contrasting responses to cold stress. AB - BACKGROUND: Sorghum is a versatile cereal crop, with excellent heat and drought tolerance. However, it is susceptible to early-season cold stress (12-15 degrees C) which limits stand-establishment and seedling growth. To gain further insights on the molecular mechanism of cold tolerance in sorghum we performed transcriptome profiling between known cold sensitive and tolerant sorghum lines using RNA sequencing technology under control and cold stress treatments. RESULTS: Here we report on the identification of differentially expressed genes (DEGs) between contrasting sorghum genotypes, HongkeZi (cold tolerant) and BTx623 (cold sensitive) under cool and control temperatures using RNAseq approach to elucidate the molecular basis of sorghum response to cold stress. Furthermore, we validated bi-allelic variants in the form of single nucleotide polymorphism (SNPs) between the cold susceptible and tolerant lines of sorghum. An analysis of transcriptome profile showed that in response to cold, a total of 1910 DEGs were detected under cold and control temperatures in both genotypes. We identified a subset of genes under cold stress for downstream analysis, including transcription factors that exhibit differential abundance between the sensitive and tolerant genotypes. We identified transcription factors including Dehydration responsive element-binding factors, C-repeat binding factors, and Ethylene responsive transcription factors as significantly upregulated during cold stress in cold tolerant HKZ. Additionally, specific genes such as plant cytochromes, glutathione s-transferases, and heat shock proteins were found differentially regulated under cold stress between cold tolerant and susceptible genotype of sorghum. A total of 41,603 SNP were identified between the cold sensitive and tolerant genotypes with minimum read of four. Approximately 89 % of the 114 SNP sites selected for evaluation were validated using endpoint genotyping technology. CONCLUSION: A new strategy which involved an integrated analysis of differential gene expression and identification of bi-allelic single nucleotide polymorphism (SNP) was conducted to determine and analyze differentially expressed genes and variation involved in cold stress response of sorghum. The results gathered provide an insight into the complex mechanisms associated with cold response in sorghum, which involve an array of transcription factors and genes which were previously related to abiotic stress response. This study also offers resource for gene based SNP that can be applied towards targeted genomic studies of cold tolerance in sorghum and other cereal crops. PMID- 26645960 TI - Inequality trends of health workforce in different stages of medical system reform (1985-2011) in China. AB - INTRODUCTION: The aim of this study was to identify whether policies in different stages of medical system reform had been effective in decreasing inequalities and increasing the density of health workers in rural areas in China between 1985 and 2011. METHODS: With data from China Health Statistics Yearbooks from 2004 to 2012, we measured the Gini coefficient and the Theil L index across the urban and rural areas from 1985 to 2011 to investigate changes in inequalities in the distributions of health workers, doctors, and nurses by states, regions, and urban-rural stratum and account for the sources of inequalities. RESULTS: We found that the overall inequalities in the distribution of health workers decreased to the lowest in 2000, then increased gently until 2011. Nurses were the most unequally distributed between urban-rural districts among health workers. Most of the overall inequalities in the distribution of health workers across regions were due to inequalities within the rural-urban stratum. DISCUSSIONS AND CONCLUSIONS: Different policies and interventions in different stages would result in important changes in inequality in the distribution of the health workforce. It was also influenced by other system reforms, like the urbanization, education, and employment reforms in China. The results are useful for the Chinese government to decide how to narrow the gap of the health workforce and meet its citizens' health needs to the maximum extent. PMID- 26645962 TI - Color-Tunable Cyano-Substituted Divinylene Arene Luminogens as Fluorescent pi Gelators. AB - The synthesis of three cyano-substituted divinylene pi-gelators is reported. The modulation of the color is achieved by placing the cyano groups in appropriate position of the conjugated backbone, thus modulating the donor-acceptor interaction. Variable-temperature UV-vis data have been utilized to investigate the self-assembly of the gelators 1-3 that is governed by a cooperative mechanism. A complete set of photophysical parameters (PhiF,tau, kr and knr) demonstrate the role of the molecular aggregation in enhanced emission upon self assembly. PMID- 26645961 TI - Comparison of laparoendoscopic single-site versus conventional multiple-port laparoscopic herniorrhaphy: a systemic review and meta-analysis. AB - PURPOSE: We systemically reviewed published literatures and performed meta analysis to compare the surgical outcomes between laparoendoscopic single-site over the multiple-port total extraperitoneal approach in hernia repair. METHODS: We did a systemic search of PubMed and Cochrane review for all randomized controlled trials and comparative trials that compared the efficacy and safety between LESS-TEP and MP-TEP. The evaluated outcomes included perioperative parameters (operative time, conversion rate), hospital stay and complications (seroma, delayed return of bladder function, postoperative pain and recurrence). The Cochrane Collaboration Review Manager software (RevMan, version 5.2.6) was used for statistical analysis. RESULTS: There were 10 trials met the inclusion criteria and included for meta-analysis. Totally, there were 595 and 514 patients underwent LESS-TEP and MP-TEP, respectively. The LESS-TEP took significantly longer-operative time than the MP-TEP in unilateral hernia repair (weighted mean difference (WMD) 4.11 min, 95% CI 0.76-7.46, p = 0.02) while not in bilateral hernia repair (WMD 3.87 min, 95% of CI -2.59-10.33, z = 1.17, p = 0.24). There were no significant differences in surgical outcomes with regard to postoperative pain scale, conversion rate, hospital stay, recurrence rate and complication rate between two groups. The length of the sub-umbilical wound was the same in both groups. The result of cosmesis was not compared because of the limited data. CONCLUSION: In experienced hands, LESS-TEP is a feasible alternative to MP-TEP with comparable surgical efficacy and morbidity, but with longer operation time in unilateral hernia repair. Potential advantages of LESS-TEP including better cosmesis, less postoperative pain and less trocar-associated complications were not clearly shown. PMID- 26645963 TI - The Specific Role of Relationship Life Events in the Onset of Depression during Pregnancy and the Postpartum. AB - BACKGROUND: The precipitating role of life events in the onset of depression is well-established. The present study sought to examine whether life events hypothesised to be personally salient would be more strongly associated with depression than other life events. In a sample of women making the first transition to parenthood, we hypothesised that negative events related to the partner relationship would be particularly salient and thus more strongly predictive of depression than other events. METHODS: A community-based sample of 316 first-time mothers stratified by psychosocial risk completed interviews at 32 weeks gestation and 29 weeks postpartum to assess dated occurrence of life events and depression onsets from conception to 29 weeks postpartum. Complete data was available from 273 (86.4%). Cox proportional hazards regression was used to examine risk for onset of depression in the 6 months following a relationship event versus other events, after accounting for past history of depression and other potential confounders. RESULTS: 52 women (19.0%) experienced an onset of depression between conception and 6 months postpartum. Both relationship events (Hazard Ratio = 2.1, p = .001) and other life events (Hazard Ratio = 1.3, p = .020) were associated with increased risk for depression onset; however, relationship events showed a significantly greater risk for depression than did other life events (p = .044). CONCLUSIONS: The results are consistent with the hypothesis that personally salient events are more predictive of depression onset than other events. Further, they indicate the clinical significance of events related to the partner relationship during pregnancy and the postpartum. PMID- 26645964 TI - Facial Nerve Outcome and Tumor Control Rate as a Function of Degree of Resection in Treatment of Large Acoustic Neuromas: Preliminary Report of the Acoustic Neuroma Subtotal Resection Study (ANSRS). AB - BACKGROUND: Patients with large vestibular schwannomas are at high risk of poor facial nerve (cranial nerve VII [CNVII]) function after surgery. Subtotal resection potentially offers better outcome, but may lead to higher tumor regrowth. OBJECTIVE: To assess long-term CNVII function and tumor regrowth in patients with large vestibular schwannomas. METHODS: Prospective multicenter nonrandomized cohort study of patients with vestibular schwannoma >=2.5 cm who received gross total resection, near total resection, or subtotal resection. Patients received radiation if tumor remnant showed signs of regrowth. RESULTS: Seventy-three patients had adequate follow-up with mean tumor diameter of 3.33 cm. Twelve received gross total resection, 22 near total resection, and 39 subtotal resection. Fourteen (21%) remnant tumors continued to grow, of which 11 received radiation, 1 had repeat surgery, and 2 no treatment. Four of the postradiation remnants (36%) required surgical salvage. Tumor regrowth was related to non-cystic nature, larger residual tumor, and subtotal resection. Regrowth was 3 times as likely with subtotal resection compared to gross total resection and near total resection. Good CNVII function was achieved in 67% immediately and 81% at 1-year. Better immediate nerve function was associated with smaller preoperative tumor size and percentage of tumor left behind on magnetic resonance image. Degree of resection defined by surgeon and preoperative tumor size showed weak trend toward better late CNVII function. CONCLUSION: Likelihood of tumor regrowth was 3 times higher in subtotal resection compared to gross total resection and near total resection groups. Rate of radiation control of growing remnants was suboptimal. Better immediate but not late CNVII outcome was associated with smaller tumors and larger tumor remnants. ABBREVIATIONS: CNVII, cranial nerve VIIGTR, gross total resectionHB, House-BrackmannMRI, magnetic resonance imageNTR, near total resectionSTR, subtotal resection. PMID- 26645966 TI - Defining a Standardized Approach for the Bedside Insertion of Temporal Horn External Ventricular Drains: Procedure Development and Case Series. AB - BACKGROUND: A trapped temporal horn can be emergently decompressed by inserting a bedside temporal horn external ventricular drain (tEVD). However, no standardized method for this procedure has been described. OBJECTIVE: To identify methods for bedside tEVD insertion, and determine the safest, most accurate, and most easily standardized approach. METHODS: Volumetric images of 20 patients with trapped temporal horns were analyzed. Three tEVD approaches (perpendicular, lateral, and medial) were defined, along with standardized insertion points and external landmarks for trajectory guidance. Predicted success in penetrating the temporal horn, skin-to-temporal horn entrance distance, temporal horn distance traversed, and trajectory target error and accuracy were evaluated; data were compared with independent sample t tests. RESULTS: Nineteen of 20 cases were analyzed; 13 had critical temporal horn entrapment. Penetration was achieved in 100% of perpendicular and 84% (16/19) of lateral and medial approaches (92% [12/13] of critical entrapments). In 19 patients, trajectory error was not significantly different among approaches. The perpendicular approach had significantly more accuracy than the lateral (P = .01) and medial (P = .002) approaches. The lateral approach afforded significantly more traversable distance than the perpendicular approach (P = .009). In cases with critical entrapment, the perpendicular approach had significantly less error (P = .02) and significantly better accuracy (P = .02) than the medial approach. The perpendicular approach trended toward more accuracy than the lateral approach (P = .06). CONCLUSION: The perpendicular approach appears to be the easiest, safest, and most reliable approach tested. We recommend conducting bedside tEVD placement only in patients with a critically dilated temporal horn who are clinically deteriorating at a rate that prohibits other procedures. ABBREVIATIONS: CSF, cerebrospinal fluidEVD, external ventricular draintEVD, temporal horn external ventricular drainOR, operating room. PMID- 26645967 TI - Acute Kidney Injury After Craniotomy Is Associated With Increased Mortality: A Cohort Study. AB - BACKGROUND: Acute kidney injury (AKI) is a serious postoperative complication. OBJECTIVE: To determine whether AKI in patients after craniotomy is associated with heightened 30-day mortality. METHODS: We performed a 2-center, retrospective cohort study of 1656 craniotomy patients who received critical care between 1998 and 2011. The exposure of interest was AKI defined as meeting RIFLE (Risk, Injury, Failure, Loss of Kidney Function, and End-stage Kidney Disease) class risk, injury, and failure criteria, and the primary outcome was 30-day mortality. Adjusted odds ratios were estimated by multivariable logistic regression models with inclusion of covariate terms thought to plausibly interact with both AKI and mortality. Additionally, mortality in craniotomy patients with AKI was analyzed with a risk-adjusted Cox proportional hazards regression model and propensity score matching as a sensitivity analysis. RESULTS: The incidences of RIFLE class risk, injury, and failure were 5.7%, 2.9%, and 1.3%, respectively. The odds of 30 day mortality in patients with RIFLE class risk, injury, or failure fully adjusted were 2.79 (95% confidence interval [CI], 1.76-4.42), 7.65 (95% CI, 4.16 14.07), and 14.41 (95% CI, 5.51-37.64), respectively. Patients with AKI experienced a significantly higher risk of death during follow-up; hazard ratio, 1.82 (95% CI, 1.34-2.46), 3.37 (95% CI, 2.36-4.81), and 5.06 (95% CI, 2.99-8.58), respectively, fully adjusted. In a cohort of propensity score-matched patients, RIFLE class remained a significant predictor of 30-day mortality. CONCLUSION: Craniotomy patients who suffer postoperative AKI are among a high-risk group for mortality. The severity of AKI after craniotomy is predictive of 30-day mortality. ABBREVIATIONS: AKI, acute kidney injuryAPACHE II, Acute Physiology and Chronic Health Evaluation IICI, confidence intervalCPT, Current Procedural TerminologyICD-9-CM, International Classification of Diseases, Ninth Revision, Clinical ModificationRIFLE, risk, injury, failure, loss of kidney function, and end-stage kidney diseaseRPDR, Research Patient Data Registry. PMID- 26645965 TI - Rates and Predictors of Seizure Freedom With Vagus Nerve Stimulation for Intractable Epilepsy. AB - BACKGROUND: Neuromodulation-based treatments have become increasingly important in epilepsy treatment. Most patients with epilepsy treated with neuromodulation do not achieve complete seizure freedom, and, therefore, previous studies of vagus nerve stimulation (VNS) therapy have focused instead on reduction of seizure frequency as a measure of treatment response. OBJECTIVE: To elucidate rates and predictors of seizure freedom with VNS. METHODS: We examined 5554 patients from the VNS therapy Patient Outcome Registry, and also performed a systematic review of the literature including 2869 patients across 78 studies. RESULTS: Registry data revealed a progressive increase over time in seizure freedom after VNS therapy. Overall, 49% of patients responded to VNS therapy 0 to 4 months after implantation (>=50% reduction seizure frequency), with 5.1% of patients becoming seizure-free, while 63% of patients were responders at 24 to 48 months, with 8.2% achieving seizure freedom. On multivariate analysis, seizure freedom was predicted by age of epilepsy onset >12 years (odds ratio [OR], 1.89; 95% confidence interval [CI], 1.38-2.58), and predominantly generalized seizure type (OR, 1.36; 95% CI, 1.01-1.82), while overall response to VNS was predicted by nonlesional epilepsy (OR, 1.38; 95% CI, 1.06-1.81). Systematic literature review results were consistent with the registry analysis: At 0 to 4 months, 40.0% of patients had responded to VNS, with 2.6% becoming seizure-free, while at last follow-up, 60.1% of individuals were responders, with 8.0% achieving seizure freedom. CONCLUSION: Response and seizure freedom rates increase over time with VNS therapy, although complete seizure freedom is achieved in a small percentage of patients. ABBREVIATIONS: AED, antiepileptic drugVNS, vagus nerve stimulation. PMID- 26645968 TI - A Reappraisal of Anterior Communicating Artery Aneurysms: A Case for Stent Assisted Embolization. AB - BACKGROUND: Wide-necked anterior communicating artery aneurysms represent a subset of lesions with challenging endovascular treatment despite new endoluminal and intrasaccular devices. OBJECTIVE: To assess the long-term clinical and angiographic outcomes of stent-assisted embolization for wide-necked anterior communicating artery aneurysms. METHODS: Between March 2008 and March 2014, 32 patients with unruptured wide-necked AComm aneurysms were treated using stent assisted embolization. The Glasgow Outcome Scale was reviewed at the time of discharge and at latest follow-up. Ischemic and hemorrhagic events were also recorded and analyzed. Aneurysm occlusion was evaluated post-intervention and on subsequent follow-up evaluations. RESULTS: Successful stent deployment was achieved in all cases, but in 1 patient the coils could not be contained inside the aneurysm, and the procedure was aborted without complications. The distal segment of the stent was positioned in the ipsilateral A2 in 16 patients, in the contralateral A2 in 15 patients, and in the contralateral A1 in 1 patient. There were no periprocedural thromboembolic or hemorrhagic complications. The rate of major complications was 6%. One patient developed intracranial hemorrhage related to antiplatelet therapy and another had ischemic events due to in-stent stenosis. Angiographic follow-up was available for 26 aneurysms and during a mean follow-up of 22 months, 81% of the lesions were completely occluded and 8% had a small residual neck. The retreatment rate for residual aneurysms was 3%. CONCLUSION: Our long-term results suggest that stent-assisted embolization for anterior communicating artery aneurysms may be considered an excellent treatment option with an adequate combination of safety profile and effectiveness. PMID- 26645969 TI - Radiation Therapy for Residual or Recurrent Atypical Meningioma: The Effects of Modality, Timing, and Tumor Pathology on Long-Term Outcomes. AB - BACKGROUND: Optimal use of stereotactic radiosurgery (SRS) vs external beam radiation therapy (EBRT) for treatment of residual/recurrent atypical meningioma is unclear. OBJECTIVE: To analyze features associated with progression after radiation therapy. METHODS: Fifty radiation-naive patients who received SRS or EBRT for residual and/or recurrent atypical meningioma were examined for predictors of progression using Cox regression and Kaplan-Meier analyses. RESULTS: Thirty-two patients (64%) received adjuvant radiation after subtotal resection, 12 patients (24%) received salvage radiation after progression following subtotal resection, and 6 patients (12%) received salvage radiation after recurrence following gross total resection. Twenty-one patients (42%) received SRS (median 18 Gy), and 7 (33%) had tumor progression. Twenty-nine patients (58%) received EBRT (median 54 Gy), and 13 (45%) had tumor progression. Whereas tumor volume (P = .53), SRS vs EBRT (P = .45), and adjuvant vs salvage (P = .34) were not associated with progression after radiation therapy, spontaneous necrosis (hazard ratio [HR] = 82.3, P < .001), embolization necrosis (HR = 15.6, P = .03), and brain invasion (HR = 3.8, P = .008) predicted progression in univariate and multivariate analyses. Tumors treated with SRS/EBRT had 2- and 5 year actuarial locoregional control rates of 91%/88% and 71%/69%, respectively. Tumors with spontaneous necrosis, embolization necrosis, and no necrosis had 2- and 5-year locoregional control rates of 76%, 92%, and 100% and 36%, 73%, and 100%, respectively (P < .001). CONCLUSION: This study suggests that necrosis may be a negative predictor of radiation response regardless of radiation timing or modality. ABBREVIATIONS: AM, atypical meningiomaEBRT, external beam radiation therapyGTR, gross total resectionLC, locoregional controlOS, overall survivalPOE, preoperative embolizationRT, radiation therapySRS, stereotactic radiosurgerySTR, subtotal resection. PMID- 26645970 TI - Pituitary Dysfunction After Aneurysmal Subarachnoid Hemorrhage: A Systematic Review and Meta-analysis. AB - BACKGROUND: The prevalence of hypothalamic-pituitary dysfunction after aneurysmal subarachnoid hemorrhage has not been precisely determined, and conflicting results have been reported in the literature. OBJECTIVE: To perform a systematic review and meta-analysis investigating the prevalence of pituitary insufficiency after aneurysmal subarachnoid hemorrhage and to focus on basal serum and dynamic test differences. METHODS: The prevalence of pituitary dysfunction was quantified at 3 to 6 months and >6 months after aneurysmal subarachnoid hemorrhage. Proportions were transformed with the logit transformation. A subgroup analysis was performed focusing on the differences in outcome between basal serum and dynamic tests for the diagnosis of growth hormone deficiency (GHD) and secondary adrenal insufficiency. RESULTS: Overall prevalence of hypopituitarism differed considerably between studies, ranging from 0.05 to 0.45 in studies performed between 3 and 6 months after the event and from 0 to 0.55 in long-term studies (>6 months), with pooled frequencies of 0.31 (95% confidence interval [CI]: 0.22 0.43) and 0.25 (95% CI: 0.16-0.36), respectively. Pooled frequency of GHD at 3 to 6 months was 0.14 (95% CI: 0.08-0.24). At >6 months, GHD prevalence was 0.19 (95% CI: 0.13-0.26) overall, but ranged from 0.15 (95% CI: 0.06-0.33) with the insulin tolerance test to 0.25 (95% CI: 0.15-0.36) using the growth hormone releasing hormone + arginine test. CONCLUSION: Hypopituitarism is a common complication in patients with aneurysmal subarachnoid hemorrhage, with GHD being the most prevalent diagnosis. We showed that variations in prevalence rates in the literature are partly due to methodological differences among pituitary function tests. ABBREVIATIONS: ACTH, adrenocorticotropic hormoneaSAH, aneurysmal subarachnoid hemorrhageGHD, growth hormone deficiencyGHRH, growth hormone releasing hormoneGST, glucagon stimulation testIGF, insulin-like growth factor 1ITT, insulin tolerance testSAH, subarachnoid hemorrhage. PMID- 26645971 TI - Ikaros, Helios, and Aiolos protein levels increase in human thymocytes after beta selection. AB - In human T cell development, the mechanisms that regulate cell fate decisions after TCRbeta expression remain unclear. We defined the stages of T cell development that flank TCRbeta expression and found distinct patterns of human T cell development. In half the subjects, T cell development progressed from the CD4(-)CD8(-) double-negative stage to the CD4(+)CD8(+) double-positive (DP) stage through an immature single-positive (ISP) CD4(+) intermediate. However, in some patients, CD4 and CD8 were expressed simultaneously and the ISP population was small. In each group of patients, CD3(-) ISP and DP thymocytes were subdivided into ISP1, ISP2, DP1, DP2, DP3, DP4, and DP5 developmental stages according to their expression of CD28, CD44, CD1a, CD7, CD45RO, and CD38. The ISP2, DP2, and DP3 thymocyte populations proliferated more robustly than ISP1 and DP1 and expressed markers consistent with TCRbeta expression. After the DP3 stage, proliferation returned to baseline levels. We then analyzed protein levels of Ikaros, Helios, and Aiolos, the three Ikaros family members most abundantly expressed in human thymocytes. Ikaros and Helios expression increased transiently at the ISP2, DP2, and DP3 populations. Aiolos expression also increased at the ISP2, DP2, and DP3 stages, but its expression remained elevated throughout the DP4 and DP5 stages. In summary, we propose a model of human T cell development that reflects the asynchronous nature of TCRbeta expression and we define the subpopulations of thymocytes that are highly proliferative and express Ikaros family members. PMID- 26645972 TI - Suitable hepatitis B vaccine for adult immunization in China. AB - The aim of this study was to evaluate, in adults, the immunogenicity of six hepatitis B vaccines with different doses or different manufacturers in the Chinese market and to provide evidence to support adult hepatitis B vaccination. Participants were randomly divided into six groups (I-VI). Six vaccines (4 at 10 MUg/dose and 2 at 20 MUg/dose) were administered intramuscularly to healthy adults at 0, 1 and 6 month intervals. All participants (16-50 years) who were negative for any hepatitis B virus serological markers were vaccinated. Anti-HBs levels were assessed 1 month and 1 year after the third vaccination. The anti-HBs seroconversion rate (anti-HBs >10 mIU/ml) was 99.4 % (99.9 % for 10 MUg dose groups and 97.9 % for 20 MUg dose groups) 1 month after the third vaccination, and the anti-HBs seroreversion rate was 77.0 % (75.3 and 82.6 %) 1 year after the third vaccination (n = 1036). One month after completing the vaccinations, the seroconversion rates were not significantly different (100.0, 100.0, 99.6, 100.0 %) for the four 10 MUg dose and two 20 MUg dose groups (99.1, 96.9 %). One year after the third vaccination, the group II positive rate was significantly higher than the other three 10 MUg dose groups, and the group VI positive rate was significantly higher than the other 20 MUg dose group. Groups II and VI showed a significantly higher positive rate and anti-HBs geometric mean titer (GMT) than the other groups. The anti-HBs level declined with increasing age, and the seroreversion rate and GMT decreased over time. All six vaccines had high anti HBs seroconversion rates and good immunization effects. The 10 MUg dose vaccine (Dalian High-Tech) and the 20 MUg dose vaccine (GlaxoSmithKline) are recommended for adults. PMID- 26645973 TI - Single-nucleotide polymorphisms in the PLA2R1 gene are associated with systemic lupus erythematosus and lupus nephritis in a Chinese Han population. AB - Several novel susceptibility genes for systemic lupus erythematosus (SLE) and other nephropathy have been identified in recent genome-wide association studies. Membranous nephropathy is the most common diagnosis in adults with the nephrotic syndrome, and both idiopathic membranous nephropathy (IMN) and lupus nephritis (LN) are autoimmune diseases of the kidney; they may share common disease mechanisms that overlap with genetic susceptibility. Therefore, we sought to identify genetic variants associated with IMN in SLE/LN. The PLA2R1 single nucleotide polymorphisms rs4664308, rs3828323, rs3792189, and rs3792192 were genotyped in a cohort of 1247 SLE patients and 1174 healthy controls, using the Sequenom MassArray system method. PLA2R1 displayed a nominally significantly genetic association with SLE [for rs4664308, P = 0.02, odds ratio (OR) 1.16, 95 % confidence interval (CI) 1.02-1.31; for rs3792192, P = 7.9 * 10(-3), OR 1.18, 95 % CI 1.05-1.34] and LN (for rs4664308, P = 0.04). The frequencies of genotypes of rs3792189 and rs3828323 were significantly different between the SLE patients and controls (all P < 0.05), and the haplotype (AA) formed by rs3792189 and rs3792192 was associated with SLE (P = 0.019). This was the first study to reveal that PLA2R1 polymorphisms were associated with SLE/LN patients, indicating that PLA2R1 might be a susceptibility gene for SLE/LN in a Chinese Han population. PMID- 26645974 TI - Cloning and Characterization of Two Potent Kunitz Type Protease Inhibitors from Echinococcus granulosus. AB - The tapeworm Echinococcus granulosus is responsible for cystic echinococcosis (CE), a cosmopolitan disease which imposes a significant burden on the health and economy of affected communities. Little is known about the molecular mechanisms whereby E. granulosus is able to survive in the hostile mammalian host environment, avoiding attack by host enzymes and evading immune responses, but protease inhibitors released by the parasite are likely implicated. We identified two nucleotide sequences corresponding to secreted single domain Kunitz type protease inhibitors (EgKIs) in the E. granulosus genome, and their cDNAs were cloned, bacterially expressed and purified. EgKI-1 is highly expressed in the oncosphere (egg) stage and is a potent chymotrypsin and neutrophil elastase inhibitor that binds calcium and reduced neutrophil infiltration in a local inflammation model. EgKI-2 is highly expressed in adult worms and is a potent inhibitor of trypsin. As powerful inhibitors of mammalian intestinal proteases, the EgKIs may play a pivotal protective role in preventing proteolytic enzyme attack thereby ensuring survival of E. granulosus within its mammalian hosts. EgKI-1 may also be involved in the oncosphere in host immune evasion by inhibiting neutrophil elastase and cathepsin G once this stage is exposed to the mammalian blood system. In light of their key roles in protecting E. granulosus from host enzymatic attack, the EgKI proteins represent potential intervention targets to control CE. This is important as new public health measures against CE are required, given the inefficiencies of available drugs and the current difficulties in its treatment and control. In addition, being a small sized highly potent serine protease inhibitor, and an inhibitor of neutrophil chemotaxis, EgKI-1 may have clinical potential as a novel anti-inflammatory therapeutic. PMID- 26645975 TI - Survival among patients with advanced renal cell carcinoma in the pretargeted versus targeted therapy eras. AB - Between December 2005 and October 2009, FDA approved six targeted therapies shown to significantly extend survival for advanced renal cell carcinoma (RCC) patients in clinical trials. This study aimed to examine changes in survival between the pretargeted and targeted therapy periods in advanced RCC patients in a real-world setting. Utilizing the 2000-2010 SEER Research files, a pre-post study design with a contemporaneous comparison group was employed to examine differences in survival outcomes for patients diagnosed with advanced RCC (study group) or advanced prostate cancer (comparison group, for whom no significant treatment innovations happened during this period) across the pretargeted therapy era (2000 2005) and the targeted therapy era (2006-2010). RCC patients diagnosed in the targeted therapy era (N = 6439) showed improved survival compared to those diagnosed in the pretargeted therapy era (N = 7231, hazard ratio (HR) for all cause death: 0.86, P < 0.01), while the change between the pre-post periods was not significant for advanced prostate cancer patients (HR: 0.97, P = 0.08). Advanced RCC patients had significantly larger improvements in overall survival compared to advanced prostate cancer patients (z = 4.31; P < 0.01). More detailed year-to-year analysis revealed greater survival improvements for RCC in the later years of the posttargeted period. Similar results were seen for cause-specific survival. Subgroup analyses by nephrectomy status, age, and gender showed consistent findings. Patients diagnosed with advanced RCC during the targeted therapy era had better survival outcomes than those diagnosed during the pretargeted therapy era. Future studies should examine the real-world survival improvements directly associated with targeted therapies. PMID- 26645977 TI - The effects of omeprazole therapy on bacterial colonization of the pharynx in healthy dogs. AB - OBJECTIVE: To identify the relative abundance of commensal pharyngeal flora in healthy dogs and determine if abundance of pharyngeal flora is altered during omeprazole administration. ANIMALS: Eight adult Beagles. PROCEDURES: A total of 3 baseline pharyngeal swabs, collected 48 hours apart, were obtained from each dog. Omeprazole (1 mg/kg PO q 24 h) was administered for a total of 12 days. During omeprazole administration, pharyngeal swabs were obtained on Days 8, 10, and 12. All swabs were submitted for semiquantitative aerobic and anaerobic culture. Growth of bacterial isolates, as well as genus of isolates, was compared between the pretreatment (n = 24) and treatment (n = 24) swabs. RESULTS: A greater abundance of several bacterial species was identified during the treatment period, including coagulase-negative Staphylococcus (P < 0.01), Bacillus (P < 0.01), and Pasteurella (P = 0.05). The abundance of bacterial species in samples collected during the treatment period was unchanged for Escherichia coli (P = 0.16), Provotella (P = 0.40), hemolytic Streptococcus (P = 0.34), and nonhemolytic Streptococcus (P = 0.14). CONCLUSIONS AND CLINICAL RELEVANCE: This small study indicates that shifts in canine pharyngeal flora may occur during omeprazole therapy. Further studies are warranted to determine the clinical significance of gastric acid suppressants on pharyngeal flora in dogs. PMID- 26645978 TI - Arteriovenous malformations in hereditary haemorrhagic telangiectasia: looking beyond ALK1-NOTCH interactions. AB - Hereditary haemorrhagic telangiectasia (HHT) is characterized by the development of arteriovenous malformations--enlarged shunts allowing arterial flow to bypass capillaries and enter directly into veins. HHT is caused by mutations in ALK1 or Endoglin; however, the majority of arteriovenous malformations are idiopathic and arise spontaneously. Idiopathic arteriovenous malformations differ from those due to loss of ALK1 in terms of both location and disease progression. Furthermore, while arteriovenous malformations in HHT and Alk1 knockout models have decreased NOTCH signalling, some idiopathic arteriovenous malformations have increased NOTCH signalling. The pathogenesis of these lesions also differs, with loss of ALK1 causing expansion of the shunt through proliferation, and NOTCH gain of function inducing initial shunt enlargement by cellular hypertrophy. Hence, we propose that idiopathic arteriovenous malformations are distinct from those of HHT. In this review, we explore the role of ALK1-NOTCH interactions in the development of arteriovenous malformations and examine a possible role of two signalling pathways downstream of ALK1, TMEM100 and IDs, in the development of arteriovenous malformations in HHT. A nuanced understanding of the precise molecular mechanisms underlying idiopathic and HHT-associated arteriovenous malformations will allow for development of targeted treatments for these lesions. PMID- 26645979 TI - Integrative miRNA and whole-genome analyses of epicardial adipose tissue in patients with coronary atherosclerosis. AB - BACKGROUND: Epicardial adipose tissue (EAT) is an atypical fat depot surrounding the heart with a putative role in the development of atherosclerosis. METHODS AND RESULTS: We profiled genes and miRNAs in perivascular EAT and subcutaneous adipose tissue (SAT) of metabolically healthy patients without coronary artery disease (CAD) vs. metabolic patients with CAD. Compared with SAT, a specific tuning of miRNAs and genes points to EAT as a tissue characterized by a metabolically active and pro-inflammatory profile. Then, we depicted both miRNA and gene signatures of EAT in CAD, featuring a down-regulation of genes involved in lipid metabolism, mitochondrial function, nuclear receptor transcriptional activity, and an up-regulation of those involved in antigen presentation, chemokine signalling, and inflammation. Finally, we identified miR-103-3p as candidate modulator of CCL13 in EAT, and a potential biomarker role for the chemokine CCL13 in CAD. CONCLUSION: EAT in CAD is characterized by changes in the regulation of metabolism and inflammation with miR-103-3p/CCL13 pair as novel putative actors in EAT function and CAD. PMID- 26645976 TI - Centrosome amplification, chromosomal instability and cancer: mechanistic, clinical and therapeutic issues. AB - Centrosomes, the main microtubule-organizing centers in most animal cells, are of crucial importance for the assembly of a bipolar mitotic spindle and subsequent faithful segregation of chromosomes into two daughter cells. Centrosome abnormalities can be found in virtually all cancer types and have been linked to chromosomal instability (CIN) and tumorigenesis. Although our knowledge on centrosome structure, replication, and amplification has greatly increased within recent years, still only very little is known on nature, causes, and consequences of centrosome aberrations in primary tumor tissues. In this review, we summarize our current insights into the mechanistic link between centrosome aberrations, aneuploidy, CIN and tumorigenesis. Mechanisms of induction and cellular consequences of aneuploidy, tetraploidization and CIN, as well as origin and effects of supernumerary centrosomes will be discussed. In addition, animal models for both CIN and centrosome amplification will be outlined. Finally, we describe approaches to exploit centrosome amplification, aneuploidy and CIN for novel and specific anticancer treatment strategies based on the modulation of chromosome missegregation rates. PMID- 26645980 TI - Keeping up the balance: role of HDACs in cardiac proteostasis and therapeutic implications for atrial fibrillation. AB - Cardiomyocytes are long-lived post-mitotic cells with limited regenerative capacity. Proper cardiomyocyte function depends critically on the maintenance of a healthy homeostasis of protein expression, folding, assembly, trafficking, function, and degradation, together commonly referred to as proteostasis. Impairment of proteostasis has a prominent role in the pathophysiology of ageing related neurodegenerative diseases including Huntington's, Parkinson's, and Alzheimer's disease. Emerging evidence reveals also a role for impaired proteostasis in the pathophysiology of common human cardiac diseases such as cardiac hypertrophy, dilated and ischaemic cardiomyopathies, and atrial fibrillation (AF). Histone deacetylases (HDACs) have recently been recognized as key modulators which control cardiac proteostasis by deacetylating various proteins. By deacetylating chromatin proteins, including histones, HDACs modulate epigenetic regulation of pathological gene expression. Also, HDACs exert a broad range of functions outside the nucleus by deacetylating structural and contractile proteins. The cytosolic actions of HDACs result in changed protein function through post-translational modifications and/or modulation of their degradation. This review describes the mechanisms underlying the derailment of proteostasis in AF and subsequently focuses on the role of HDACs herein. In addition, the therapeutic potential of HDAC inhibition to maintain a healthy proteostasis resulting in a delay in AF onset and progression is discussed. PMID- 26645981 TI - Differential effects of tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 on atherosclerosis and monocyte/macrophage invasion. AB - AIMS: MMPs contribute to atherosclerotic plaque progression and instability, but the relative potency of their endogenous tissue inhibitors of metalloproteinases (TIMPs) as protective factors has not been defined. We therefore investigated the impact of TIMP-1 and TIMP-2 knockout on atherosclerotic plaque burden and composition in apolipoprotein E-knockout (Apoe(-/-)) mice and studied the underlying effects on monocyte/macrophage behaviour. METHODS AND RESULTS: Analysis of brachiocephalic artery plaques revealed comparable atherosclerotic lesion areas between TIMP-1(-/-) Apoe(-/-) or TIMP-2(-/-) Apoe(-/-) double deficient mice and relevant age-matched, strain-matched Apoe(-/-) controls after 8 weeks of high-fat feeding. However, lesions from TIMP-2(-/-) Apoe(-/-) mice had higher levels of markers associated with plaque vulnerability, including increased macrophage: vascular smooth muscle cell ratios, larger necrotic core areas, reduced collagen contents, increased macrophage proliferation, and apoptosis frequencies, compared with TIMP-1(-/-)Apoe(-/-) and controls. In contrast, TIMP-1(-/-) Apoe(-/-) animals only had a significant reduction in vascular smooth muscle cell content compared with Apoe(-/-) controls. In vitro and in vivo findings implicated heightened monocyte/macrophage invasion in the detrimental effects observed on atherosclerotic plaque composition in TIMP-2(-/-) Apoe(-/-) mice. Moreover, TIMP-2 specifically decreased MMP-14-dependent monocyte/macrophage infiltration into sites of experimentally induced inflammation and established atherosclerotic lesions. CONCLUSION: Our data demonstrate that TIMP-2 plays a greater protective role than TIMP-1 during the pathogenesis of atherosclerosis, in part by suppressing MMP-14-dependent monocyte/macrophage accumulation into plaques. PMID- 26645982 TI - Impaired Hedgehog signalling-induced endothelial dysfunction is sufficient to induce neuropathy: implication in diabetes. AB - AIMS: Microangiopathy, i.e. endothelial dysfunction, has long been suggested to contribute to the development of diabetic neuropathy, although this has never been fully verified. In the present paper, we have identified the role of Hedgehog (Hh) signalling in endoneurial microvessel integrity and evaluated the impact of impaired Hh signalling in endothelial cells (ECs) on nerve function. METHODS AND RESULTS: By using Desert Hedgehog (Dhh)-deficient mice, we have revealed, that in the absence of Dhh, endoneurial capillaries are abnormally dense and permeable. Furthermore, Smoothened (Smo) conditional KO mice clarified that this increased vessel permeability is specifically due to impaired Hh signalling in ECs and is associated with a down-regulation of Claudin5 (Cldn5). Moreover, impairment of Hh signalling in ECs was sufficient to induce hypoalgesia and neuropathic pain. Finally in Lepr(db/db) type 2 diabetic mice, the loss of Dhh expression observed in the nerve was shown to be associated with increased endoneurial capillary permeability and decreased Cldn5 expression. Conversely, systemic administration of the Smo agonist SAG increased Cldn5 expression, decreased endoneurial capillary permeability, and restored thermal algesia to diabetic mice, demonstrating that loss of Dhh expression is crucial in the development of diabetic neuropathy. CONCLUSION: The present work demonstrates the critical role of Dhh in maintaining blood nerve barrier integrity and demonstrates for the first time that endothelial dysfunction is sufficient to induce neuropathy. PMID- 26645983 TI - Neural crest-derived resident cardiac cells contribute to the restoration of adrenergic function of transplanted heart in rodent. AB - AIMS: We investigated whether neural crest-derived cardiac resident cells contribute to the restoration of intrinsic adrenergic function following transplantation in mice. Transplanted heart shows partial restoration of cardiac adrenergic activity with time. Both the intrinsic cardiac adrenergic system and extrinsic sympathetic re-innervation contribute to neuronal remodelling in the transplanted heart. Little is known about the origin and function of the intrinsic system in the transplanted heart. METHODS AND RESULTS: Heart from the protein 0-Cre/Floxed-Enhanced Green Fluorescent Protein double-transgenic mouse was transplanted onto the abdominal aorta of the non-obese diabetic/severe combined immunodeficient mouse to trace the fate of cardiac resident neural crest derived cells. Sympathetic nerve fibres, which are predominantly localized to the epicardial surface of the heart, disappeared in the transplanted heart. Intramyocardial neural crest cells increased immediately, while neural crest derived nucleated tyrosine hydroxylase (TH)-immunoreactive cells increased over 2 weeks following transplantation. The mRNA expression levels of TH, dopamine-beta hydroxylase and phenylethanolamine N-methyltransferase, and the tissue content of catecholamines in the transplanted hearts increased with time in association with an increase in the number of neural crest-derived nucleated TH-immunoreactive cells and tissue nerve growth factor levels. Iodine-123-metaiodobenzylguanidine scintigraphy showed that the uptake ability of transplanted heart for catecholamines also recovered with time. Finally, the chronotropic response to tyramine both in vivo and ex vivo reappeared 2 weeks after transplantation. CONCLUSION: Neural crest-derived adrenergic cells increased following heart transplantation. The restoration of cardiac sympathetic activities in transplanted heart is tightly coupled with an increase in the number of neural crest-derived adrenergic cells. PMID- 26645984 TI - Anatomical and ultrastructural study of PRAF2 expression in the mouse central nervous system. AB - Prenylated Rab acceptor family, member 2 (PRAF2) is a four transmembrane domain protein of 19 kDa that is highly expressed in particular areas of mammalian brains. PRAF2 is mostly found in the endoplasmic reticulum (ER) of neurons where it plays the role of gatekeeper for the GB1 subunit of the GABAB receptor, preventing its progression in the biosynthetic pathway in the absence of hetero dimerization with the GB2 subunit. However, PRAF2 can interact with several receptors and immunofluorescence studies indicate that PRAF2 distribution is larger than the ER, suggesting additional biological functions. Here, we conducted an immuno-cytochemical study of PRAF2 distribution in mouse central nervous system (CNS) at anatomical, cellular and ultra-structural levels. PRAF2 appears widely expressed in various regions of mature CNS, such as the olfactory bulbs, cerebral cortex, amygdala, hippocampus, ventral tegmental area and spinal cord. Consistent with its regulatory role of GABAB receptors, PRAF2 was particularly abundant in brain regions known to express GB1 subunits. However, other brain areas where GB1 is expressed, such as basal ganglia, thalamus and hypothalamus, contain little or no PRAF2. In these areas, GB1 subunits might reach the cell surface of neurons independently of GB2 to exert biological functions distinct from those of GABAB receptors, or be regulated by other gatekeepers. Electron microscopy studies confirmed the localization of PRAF2 in the ER, but identified previously unappreciated localizations, in mitochondria, primary cilia and sub-synaptic region. These data indicate additional modes of GABAB regulation in specific brain areas and new biological functions of PRAF2. PMID- 26645985 TI - Algebraic Systems Biology: A Case Study for the Wnt Pathway. AB - Steady-state analysis of dynamical systems for biological networks gives rise to algebraic varieties in high-dimensional spaces whose study is of interest in their own right. We demonstrate this for the shuttle model of the Wnt signaling pathway. Here, the variety is described by a polynomial system in 19 unknowns and 36 parameters. It has degree 9 over the parameter space. This case study explores multistationarity, model comparison, dynamics within regions of the state space, identifiability, and parameter estimation, from a geometric point of view. We employ current methods from computational algebraic geometry, polyhedral geometry, and combinatorics. PMID- 26645986 TI - Removable partial dentures vs overdentures in children with ectodermal dysplasia: two case reports. AB - BACKGROUND: Ectodermal dysplasia (ED) represents a disorder group characterised by abnormal development of the ectodermal derivatives. Removable partial dentures (RPD), complete dentures (CD) or overdentures (OD) are most often the treatment of choice for young affected patients. Prosthetic intervention is of utmost importance in the management of ED patients, as it resolves problems associated with functional, aesthetic, and psychological issues, and improves a patient's quality of life. However, few studies present the principles and guidelines that can assist in the decision-making process of the most appropriate removable prosthesis. The purpose of this study was to suggest a simple treatment decision making algorithm for selecting an effective and individualised rehabilitative treatment plan, considering different parameters. CASE REPORTS: The cases and treatment of two young ED patients are described and each one was treated with either RPDs or ODs. FOLLOW-UP: Periodic recalls were employed to manage problems, and monitor the changes associated with occlusion and fit of the prostheses in relation to each patient's growth. Both patients were followed up for more than 2 years and reported significant improvement in their appearance, masticatory function, and social behaviour as a result of the prosthetic rehabilitation. CONCLUSION: The main factors guiding the decision process towards the choice of an RPD or an OD are the presence of posterior natural teeth, facial aesthetics, lip support, number and size of existing natural teeth, and the occlusal vertical dimension. PMID- 26645987 TI - MASP-1 Induced Clotting--The First Model of Prothrombin Activation by MASP-1. AB - Mannan-binding lectin-associated serine protease-1 (MASP-1), a protein of the complement lectin pathway, resembles thrombin in terms of structural features and substrate specificity. Due to its interplay with several coagulation factors, it has the ability to induce fibrin clot formation independent of the usual coagulation activation pathways. We have recently shown that MASP-1 activates prothrombin and identified arginine (R) 155, R271, and R393 as potential cleavage sites. FXa cleaves R320 instead of R393, and thrombin cleaves R155 and R284 in prothrombin. Here we have used three arginine-to-glutamine mutants of prothrombin, R271Q, R320Q, R393Q and the serine-to-alanine active site mutant S525A to investigate in detail the mechanism of MASP-1 mediated prothrombin activation. Prothrombin wildtype and mutants were digested with MASP-1 and the cleavage products were analysed by SDS-PAGE and N-terminal sequencing. A functional clotting assay was performed by thrombelastography. We have found that MASP-1 activates prothrombin via two simultaneous pathways, either cleaving at R271 or R393 first. Both pathways result in the formation of several active alternative thrombin species. Functional studies confirmed that both R393 and R320 are required for prothrombin activation by MASP-1, whereas R155 is not considered to be an important cleavage site in this process. In conclusion, we have described for the first time a detailed model of prothrombin activation by MASP-1. PMID- 26645988 TI - Magnetic Structure and Exchange Interactions in Quasi-One-Dimensional MnCl2(urea)2. AB - MnCl2(urea)2 is a new linear chain coordination polymer that exhibits slightly counter-rotated Mn2Cl2 rhomboids along the chain-axis. The material crystallizes in the noncentrosymmetric orthorhombic space group Iba2, with each Mn(II) ion equatorially surrounded by four Cl(-) that lead to bibridged ribbons. Urea ligands coordinate via O atoms in the axial positions. Hydrogen bonds of the Cl...H-N and O...H-N type link the chains into a quasi-3D network. Magnetic susceptibility data reveal a broad maximum at 9 K that is consistent with short range magnetic order. Pulsed-field magnetization measurements conducted at 0.6 K show that a fully polarized magnetic state is achieved at Bsat = 19.6 T with another field-induced phase transition occurring at 2.8 T. Zero-field neutron diffraction studies made on a powdered sample of MnCl2(urea)2 reveal that long range magnetic order occurs below TN = 3.2(1) K. Additional Bragg peaks due to antiferromagnetic (AFM) ordering can be indexed according to the Ib'a2' magnetic space group and propagation vector tau = [0, 0, 0]. Rietveld profile analysis of these data revealed a Neel-type collinear ordering of Mn(II) ions with an ordered magnetic moment of 4.06(6) MUB (5 MUB is expected for isotropic S = (5)/2) oriented along the b-axis, i.e., perpendicular to the chain-axis that runs along the c-direction. Owing to the potential for spatial exchange anisotropy and the pitfalls in modeling bulk magnetic data, we analyzed inelastic neutron scattering data to retrieve the exchange constants: Jc = 2.22 K (intrachain), Ja = -0.10 K (interchain), and D = -0.14 K with J > 0 assigned to AFM coupling. This J configuration is most unusual and contrasts the more commonly observed AFM interchain coupling of 1D chains. PMID- 26645989 TI - Ionized calcium measurements during regional citrate anticoagulation in CRRT: we need better blood gas analyzers. PMID- 26645991 TI - [Ophthalmological reading tests : Part 1: historical aspects]. AB - BACKGROUND: The objective of this article was an analytical review of reading charts with regard to the historical background, printing techniques, print quality and print size. METHODS: For this study original historical reading charts (Jaeger, Snellen, Nieden and Birkhauser) were investigated microscopically by measuring the lower case letter sizes (iNexis VMA 2520, Nikon, Tokyo). Calculations were made according to EN ISO 8596 and the recommendations of the International Research Council. RESULTS: In the mid-nineteenth century various reading cards were published; however, at that time it was not possible to print lower case letters according to exactly defined standards. Thus, these reading cards were not comparable to each other or between different language versions. At a reading distance of 32 cm Jaeger No. 1 represented in the original edition (1856) a visual acuity of 0.72 and 0.63 in the version from 1945 and the smallest print size of the Snellen reading test (1862) represented 0.55. Nieden No. 1 (1882) corresponded to a visual acuity of 0.59 and the smallest print size of the Birkhauser cards (1911) 1.5. In the case of all reading cards except the original Birkhauser cards, there was no logarithmic progression of the print sizes and the sizes of numbers were also not in accordance with the corresponding letter sizes. CONCLUSION: Print sizes of historical reading charts do not adhere to current standards and were usually not logarithmically scaled. These deficits and the lack of comparability between the historical reading charts may have caused reading cards to be currently underestimated as an accurate diagnostic tool. Nevertheless, the historical reading charts were the successful forerunners of developments for modern reading charts. PMID- 26645992 TI - Neonatal Blue Light Phototherapy and Melanocytic Nevus Count in Children: A Systematic Review and Meta-Analysis of Observational Studies. AB - BACKGROUND: Neonatal blue light phototherapy (NBLP) is an established method of managing neonatal hyperbilirubinemia. Approximately 5% of newborns are exposed to NBLP. Evidence of whether NBLP predisposes to the development of melanocytic nevi later in life has been conflicting. OBJECTIVES: The goal of the current study was to conduct a systematic review and meta-analysis to quantitatively assess the effect of NBLP on melanocytic nevus count. METHODS: We searched for observational studies in Medline, EMBASE, and the Cochrane Central Register from their inception to April 15, 2015. Meta-analysis of Observational Studies in Epidemiology guidelines were followed. DerSimonian and Laird random-effects models were used to calculate the weighted mean difference (WMD). Publication bias was assessed using a funnel plot and the Egger's test. RESULTS: Five studies with a total of 2,921 subjects were included, of whom 642 underwent NBLP. With random-effects modeling, those who had previous NBLP did not have a significantly higher mean number of melanocytic nevi (WMD = 0.32 [95% confidence interval 0.67, 1.31], p = 0.53). Visual inspection of the funnel plot suggested potential publication bias, although the Egger's test (p = 0.09) indicated no small-study effect. CONCLUSION: There was no evidence that prior NBLP exposure significantly increased the number of melanocytic nevi. Available evidence has not revealed any cause for major concern for NBLP. Other risk factors such as exposure to sunlight, childhood history of sunburn, and fair skin complexion might play a greater role in the development of melanocytic nevi in childhood. PMID- 26645993 TI - Further observations on the clinical significance and inheritance of the low frequency platelet antigen HPA-28bw. AB - BACKGROUND: Most recently described human platelet antigens (HPAs) have been low frequency polymorphisms identified in cases of fetomaternal alloimmune thrombocytopenia (FMAIT). There is limited opportunity to study the clinical significance or different antenatal management strategies in cases involving low frequency HPA antibodies because many are single pregnancies. We have previously described a low-frequency platelet (PLT) antigen, HPA-28bw, implicated in FMAIT in two of the three infants in the same family. This report describes the outcome of an additional two pregnancies in this family. STUDY DESIGN AND METHODS: The fourth and fifth pregnancies in a HPA-28bw-alloimmunized mother with a heterozygous partner were investigated to determine the risk of FMAIT. The presence of anti-HPA-28bw was assessed by paternal crossmatch studies. Prenatal HPA genotyping of amniocytes was performed to inform antenatal management. RESULTS: GPIIb/IIIa antibodies reactive only with paternal PLTs were detected. These antibodies had been previously identified as HPA-28bw specific using recombinant GPIIb glycoprotein mutated to contain the HPA-28bw (V740L) mutation. The fetus in the fourth pregnancy did not inherit the HPA-28bw mutation, no antenatal management was required, and the baby had a normal PLT count. The fetus in the fifth pregnancy did inherit the HPA-28bw mutation. The mother received IVIG (2 g/kg/week) and prednisolone during pregnancy, and the baby was born with a normal PLT count. CONCLUSION: Study of this family has provided a unique opportunity to assess the clinical significance of antibodies against the low frequency PLT antigen (HPA-28bw) during five pregnancies and to compare the outcomes of different antenatal treatments. PMID- 26645990 TI - ESMO-ESGO-ESTRO Consensus Conference on Endometrial Cancer: Diagnosis, Treatment and Follow-up. AB - The first joint European Society for Medical Oncology (ESMO), European SocieTy for Radiotherapy & Oncology (ESTRO) and European Society of Gynaecological Oncology (ESGO) consensus conference on endometrial cancer was held on 11-13 December 2014 in Milan, Italy, and comprised a multidisciplinary panel of 40 leading experts in the management of endometrial cancer. Before the conference, the expert panel prepared three clinically-relevant questions about endometrial cancer relating to the following four areas: prevention and screening, surgery, adjuvant treatment and advanced and recurrent disease. All relevant scientific literature, as identified by the experts, was reviewed in advance. During the consensus conference, the panel developed recommendations for each specific question and a consensus was reached. Results of this consensus conference, together with a summary of evidence supporting each recommendation, are detailed in this article. All participants have approved this final article. PMID- 26645996 TI - Au-Catalyzed Cross-Coupling of Arenes via Double C-H Activation. AB - The first methodology for Au(I/III)-catalyzed oxidative cross-coupling of arenes via double C-H activation has been developed. The reaction is fully selective for the cross-coupling between electron-rich hetero-/carbocyclic arenes and electron poor arenes bearing relatively acidic C-H bonds. The inherently high cross selectivity of the system obviates the need for directing groups or a large excess of one of the coupling partners. PMID- 26645995 TI - Hospital Charges for Pediatric Heart Failure-Related Hospitalizations from 2000 to 2009. AB - Scarce data exist regarding costs of pediatric heart failure-related hospitalizations (HFRH) or how costs have changed over time. Pediatric HFRH costs, due to advances in management, will have increased significantly over time. A retrospective analysis of Healthcare Cost and Utilization Project Kids' Inpatient Database was performed on all pediatric HFRH. Inflation-adjusted charges are used as a proxy for cost. There were a total of 33,189 HFRH captured from 2000 to 2009. Median charges per HFRH rose from $35,079 in 2000 to $72,087 in 2009 (p < 0.0001). The greatest median charges were incurred in patients on extracorporeal membrane oxygenation ($442,134 vs $53,998) or ventricular assist devices ($462,647 vs $55,151). Comorbidities, including sepsis ($207,511 vs $48,995), renal failure ($180,624 vs $52,812), stroke ($198,260 vs $54,974) and respiratory failure ($146,200 vs $48,797), were associated with greater charges (p < 0.0001). Comorbidities and use of mechanical support increased over time. After adjusting for these factors, later year remained associated with greater median charges per HFRH (p < 0.0001). From 2000 to 2009, there has been an almost twofold increase in pediatric HFRH charges, after adjustment for inflation. Although comorbidities and use of mechanical support account for some of this increase, later year remained independently associated with greater charges. Further study is needed to understand potential factors driving these higher costs over time and to identify more cost-effective therapies in this population. PMID- 26645997 TI - Cu(II) bis(oxamato) end-grafted poly(amidoamine) dendrimers. AB - Successive treatment of the diethyl ester of 3,4-bis(oxamate)phenylene benzoic acid (3,4-bopbH2Et2OH; ) with [Bu4N]OH and MCl2.nH2O (M = Cu, Ni; n = 2, 6) gave, upon extraction into CH2Cl2, binuclear complexes [Bu4N]4[{M(3,4-bopbO)}2CH2] (, M = Cu, Ni) as novel symmetric methylene diesters. In contrast, subsequent addition of [Bu4N]OH and anhydrous NiCl2 to afforded the very hygroscopic [Bu4N]3[Ni(3,4 bopbO)] () instead. In order to verify reaction conditions to achieve the corresponding carboxamides to - as a crucial step for the synthesis of higher generation dendrimers - was shown to react with RNH2 (R = Me (), Pr ()) to [RNH3][tdqc] (R = Me (), Pr (); tdqc = 1,2,3,4-tetrahydro-2,3-dioxo-6-quinoxaline carboxylate) by rearrangement reactions. Alternatively, if was converted first to 3,4-bopbH2EtF () and treated next with PrNH2, the corresponding carboxamide 3,4 bopbH2Et2NPrH () could be obtained in high yields. The reaction of with [Bu4N]OH and MCl2.nH2O (M = Cu, Ni; n = 2, 6) gave conveniently mononuclear [Bu4N]2[M(3,4 bopbNPrH)] (, M = Cu, Ni). After thus optimizing reaction conditions, for the synthesis of higher-branched bis(oxamato) type complexes the (polyamido)amines (en(II)H2), (den(III)H3), (den(V)H5) and (den(X)H10), possessing two, three, five or ten terminal amino groups, were reacted with appropriate equiv. of to give the corresponding carboxamides en(II)(3,4-bopbH2Et2)2 (), den(III)(3,4-bopbH2Et2)3 (), den(V)(3,4-bopbH2Et2)5 () and den(X)(3,4-bopbH2Et2)10 (). Compounds were converted to the corresponding Cu(II)-containing complexes , which were treated with the corresponding equiv. of [Cu(pmdta)][BF4]2 to afford . Complexes of the series and possess two, three, five or ten end-grafted mononuclear {Cu(3,4 bopb)}(2-) and trinuclear {Cu3(3,4-bopb)(pmdta)2}(2+) complex fragments, respectively. The identities of were established by NMR spectroscopy and ESI-MS measurements. For and , ESI-MS, UV/Vis and ESR studies were applied to confirm the identities of these species. The magnetic properties of the {Cu3(3,4 bopb)(pmdta)2}(2+) end-grafted poly(amidoamine) dendrimers were studied by susceptibility measurements vs. temperature to give J values between -112 () and 118 cm(-1) (), which are typically observed for discrete trinuclear Cu(II) containing bis(oxamato) type complexes. PMID- 26645994 TI - Macrophage recruitment by fibrocystin-defective biliary epithelial cells promotes portal fibrosis in congenital hepatic fibrosis. AB - Congenital hepatic fibrosis (CHF) is a disease of the biliary epithelium characterized by bile duct changes resembling ductal plate malformations and by progressive peribiliary fibrosis, in the absence of overt necroinflammation. Progressive liver fibrosis leads to portal hypertension and liver failure; however, the mechanisms leading to fibrosis in CHF remain elusive. CHF is caused by mutations in PKHD1, a gene encoding for fibrocystin, a ciliary protein expressed in cholangiocytes. Using a fibrocystin-defective (Pkhd1(del4/del4)) mouse, which is orthologous of CHF, we show that Pkhd1(del4/del4) cholangiocytes are characterized by a beta-catenin-dependent secretion of a range of chemokines, including chemokine (C-X-C motif) ligands 1, 10, and 12, which stimulate bone marrow-derived macrophage recruitment. We also show that Pkhd1(del4/del4) cholangiocytes, in turn, respond to proinflammatory cytokines released by macrophages by up-regulating alphavbeta6 integrin, an activator of latent local transforming growth factor-beta1. While the macrophage infiltrate is initially dominated by the M1 phenotype, the profibrogenic M2 phenotype increases with disease progression, along with the number of portal myofibroblasts. Consistent with these findings, clodronate-induced macrophage depletion results in a significant reduction of portal fibrosis and portal hypertension as well as of liver cysts. CONCLUSION: Fibrosis can be initiated by an epithelial cell dysfunction, leading to low-grade inflammation, macrophage recruitment, and collagen deposition; these findings establish a new paradigm for biliary fibrosis and represent a model to understand the relationship between cell dysfunction, parainflammation, liver fibrosis, and macrophage polarization over time. PMID- 26645998 TI - Neuroprotective Effect of Natural Products on Peripheral Nerve Degeneration: A Systematic Review. AB - Peripheral nerve injury (PNI) is a serious public health problem that is linked with motor, sensory and autonomic deficits. Given the fact that this type of disorder leads to a decreased quality of life in most patients and adherence of available drugs is limited and have adverse effects, we investigated the efficacy of natural products in a PNI model. The search terms plants, medicinal, nerve regeneration, nerve crush, sciatic nerve as well as MeSH terms or free-text words were used to retrieve English language articles in PubMed, Scopus, Web of Science and LILACS published until July 2015. After sciatic nerve crush, natural products have improved significantly motor performance, sensory function and electrical conductance measured over weeks. Among the pharmacological targets suggested by the action of natural products, there were citations on the activation of the antiapoptotic signaling pathway, modulation in the expression of pro-inflammatory cytokines and neurotrophic factors. The systematic review provides scientific evidence that natural products are pharmacologically effective in the treatment of PNI such as sciatic nerve crush. PMID- 26645999 TI - Serum MicroRNA-4521 is a Potential Biomarker for Focal Cortical Dysplasia with Refractory Epilepsy. AB - Early biomarker-based diagnosis of focal cortical dysplasia (FCD) represents a major clinical challenge. The aim of this study was to identify novel brain microRNAs (miRNAs) in patients with refractory epilepsy and FCD as potential biomarkers. We evaluated serum hsa-miR-4521 as a promising novel biomarker in patients with FCD. Tissue for microarray was obtained from nine patients with temporal lobe refractory epilepsy who underwent surgery to remove epileptic foci identified by cortical video electroencephalogram monitoring. Control tissue was collected from eight patients with hypertension who required emergency surgery to remove an intracranial hematoma. The Affymetrix(r) GeneChip(r) Command Console(r) Software (Affymetrix miRNA 4.0) was used to compare miRNA expression in the cerebral cortex of experimental and control patients. Temporal cortex tissue and serum samples were taken from the same patients for verification of hsa-miR-4521 expression by real-time quantitative polymerase chain reaction (RT-qPCR). The experimental and control patients did not differ significantly in terms of age and gender. 19.4 % (148/764) of the total miRNAs were differentially expressed in experimental and control tissue, which is in agreement with the existing literature. We selected miRNA-4521 for further analysis; the fold-change in expression was 14.4707 and the q value was almost 0, which confirmed up regulation. Significant up-regulation of hsa-miR-4521 was further validated by RT qPCR. miRNA microarrays can efficiently and conveniently identify differentially expressed miRNAs in epilepsy brain tissue. This is the first study to identify differential expression of hsa-miR-4521 in brain tissue and serum of refractory epilepsy patients and suggests that serum hsa-miR-4521 may represent a potential diagnostic biomarker for FCD with refractory epilepsy. PMID- 26646000 TI - P7C3 Attenuates the Scopolamine-Induced Memory Impairments in C57BL/6J Mice. AB - Memory impairment is the most common symptom in patients with Alzheimer's disease. The purpose of this study is to evaluate the memory enhancing effects of P7C3, a recently identified compound with robust proneurogenic and neuroprotective effects, on the cognitive impairment induced by scopolamine, a muscarinic acetylcholine receptor antagonist. Different behavior tests including the Y-maze, Morris water maze, and passive avoidance tests were performed to measure cognitive functions. Scopolamine significantly decreased the spontaneous alternation and step-through latency of C57BL/6J mice in Y-maze test and passive avoidance test, whereas increased the time of mice spent to find the hidden platform in Morris water maze test. Importantly, intraperitoneal administration of P7C3 effectively reversed those Scopolamine-induced cognitive impairments in C57BL/6J mice. Furthermore, P7C3 treatment significantly enhanced the level of brain-derived neurotrophic factor (BDNF) signaling pathway in the cortex and hippocampus, and the usage of selective BDNF signaling inhibitor fully blocked the anti-amnesic effects of P7C3. Therefore, these findings suggest that P7C3 could improve the scopolamine-induced learning and memory impairment possibly through activation of BDNF signaling pathway, thereby exhibiting a cognition enhancing potential. PMID- 26646001 TI - Ethanol and Acetaldehyde After Intraperitoneal Administration to Aldh2-Knockout Mice-Reflection in Blood and Brain Levels. AB - This paper reports, for the first time, on the analysis of ethanol (EtOH) and acetaldehyde (AcH) concentrations in the blood and brains of Aldh2-knockout (Aldh2-KO) and C57B6/6J (WT) mice. Animals were administrated EtOH (1.0, 2.0 or 4.0 g/kg) or 4-methylpyrazole (4-MP, 82 mg/kg) plus AcH (50, 100 or 200 mg/kg) intraperitoneally. During the blood tests, samples from the orbital sinus of the eye were collected. During the brain tests, dialysates were collected every 5 min (equal to a 15 ul sample) from the striatum using in vivo brain microdialysis. Samples were collected at 5, 10, 15, 20, 25, 30 and 60 min intervals post-EtOH and -AcH injection, and then analyzed by head-space GC. In the EtOH groups, high AcH levels were found in the blood and brains of Aldh2-KO mice, while only small traces of AcH were seen in the blood and brains of WT mice. No significant differences in EtOH levels were observed between the WT and the Aldh2-KO mice for either the EtOH dose. EtOH concentrations in the brain were comparable to the EtOH concentrations in the blood, but the AcH concentrations in the brain were four to five times lower compared to the AcH concentrations in the blood. In the AcH groups, high AcH levels were found in both WT and Aldh2-KO mice. Levels reached a sharp peak at 5 min and then quickly declined for 60 min. Brain AcH concentrations were almost equal to the concentrations found in the blood, where the AcH concentrations were approximately two times higher in the Aldh2-KO mice than in the WT mice, both in the blood and the brain. Our results suggest that systemic EtOH and AcH administration can cause a greater increase in AcH accumulation in the blood and brains of Aldh2-KO mice, where EtOH concentrations in the Aldh2-KO mice were comparable to the EtOH concentrations in the WT mice. Furthermore, detection of EtOH and AcH in the blood and brain was found to be dose-dependent in both genotypes. PMID- 26646002 TI - Neuroprotective Effect of Human Adipose Stem Cell-Derived Extract in Amyotrophic Lateral Sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a devastating human neurodegenerative disease. The precise pathogenic mechanisms of the disease remain uncertain, and as of yet, there is no effective cure. Human adipose stem cells (hASC) can be easily obtained during operative procedures. hASC have a clinically feasible potential to treat neurodegenerative disorders, since cytosolic extract of hASC contain a number of essential neurotrophic factors. In this study, we investigated effects of hASC extract on the SOD1 G93A mouse model of ALS and in vitro test. Administration of hASC extract improved motor function and prolonged the time until symptom onset, rotarod failure, and death in ALS mice. In the hASC extracts group, choline acetyltransferase immunostaining in the ventral horn of the lumbar spinal cord showed a large number of motor neurons, suggesting normal morphology. The neuroprotective effect of hASC extract in ALS mice was also suggested by western blot analysis of spinal cord extract from ALS mice and in vitro test. hASC extract treatment significantly increased expression of p-Akt, p CREB, and PGC-1alpha in SOD1 G93A mouse model and in vitro test. Our results indicated that hASC extract reduced apoptotic cell death and recovered mutant SOD1-induced mitochondrial dysfunction. Moreover, hASC extract reduced mitochondrial membrane potential. In conclusion, we have demonstrated, for the first time, that hASC extract exert a potential therapeutic action in the SOD1 G93A mouse model of ALS and in vitro test. These findings suggest that hASC hold promise as a novel therapeutic strategy for treating ALS. PMID- 26646003 TI - Combined Low-Intensity Exercise and Ascorbic Acid Attenuates Kainic Acid-Induced Seizure and Oxidative Stress in Mice. AB - Physical exercise and vitamins such as ascorbic acid (ASC) have been recognized as an effective strategy in neuroprotection and neurorehabilitatioin. However, there is a need to find an efficient treatment regimen that includes ASC and low intensity exercise to diminish the risk of overtraining and nutritional treatment by attenuating oxidative stress. In the present study, we investigated the combined effect of low-intensity physical exercise (EX) and ASC on kainic acid (KA)-induced seizure activity and oxidative stress in mice. The mice were randomly assigned into groups as follows: "KA only" (n = 11), "ASC + KA" (n = 11), "Ex + KA" (n = 11), "ASC + Ex + KA" (n = 11). In the present study, low intensity of swimming training period lasted 8 weeks and consisted of 30-min sessions daily (three times per week) without tail weighting. Although no preventive effect of low-intensity exercise or ASC on KA seizure occurrence was evident, there was a decrease of seizure activity, seizure development (latency to first seizures), and mortality in "ASC + Ex + KA" compared to "ASC + KA", "Ex + KA", and "KA only" group. In addition, a preventive synergistic coordination of low-intensity exercise and ASC was evident in glutathione peroxidase and superoxide dismutase activity compared to separate treatment. These results suggest that low-intensity exercise and ASC treatment have preventive effects on seizure activity and development with alternation of oxidative status. PMID- 26646004 TI - Mast Cells Release Chemokine CCL2 in Response to Parkinsonian Toxin 1-Methyl-4 Phenyl-Pyridinium (MPP(+)). AB - Microglial activation and release of inflammatory cytokines and chemokines are crucial events in neuroinflammation. Microglial cells interact and respond to other inflammatory cells such as T cells and mast cells as well as inflammatory mediators secreted from these cells. Recent studies have shown that neuroinflammation causes and accelerates neurodegenerative disease such as Parkinson's disease (PD) pathogenesis. 1-methyl-4-phenyl-pyridinium ion (MPP(+)), the active metabolite of neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydro pyridine activates glial cells and mediate neurodegeneration through release of inflammatory mediators. We have shown that glia maturation factor (GMF) activates glia and induces neuroinflammation and neurodegeneration and that MPP(+) activates mast cells and release proinflammatory cytokines and chemokines. The chemokine (C-C motif) ligand 2 (CCL2) levels have been shown to be elevated and play a role in PD pathogenesis. In the present study, we analyzed if MPP(+) activates mouse and human mast cells to release chemokine CCL2. Mouse bone marrow derived mast cells (BMMCs) and human umbilical cord blood-derived cultured mast cells (hCBMCs) were incubated with MPP(+) (10 uM) for 24 h and CCL2 levels were measured in the supernatant media by ELISA. MPP(+)-significantly induced CCL2 release from BMMCs and hCBMCs. Additionally, GMF overexpression in BMMCs obtained from wild-type mice released significantly more CCL2, while BMMCs obtained from GMF-deficient mice showed less CCL2 release. Further, we show that MPP(+)-induced CCL2 release was greater in BMMCs-astrocyte co-culture conditions. Uncoupling protein 4 (UCP4) which is implicated in neurodegenerative diseases including PD was detected in BMMCs by immunocytochemistry. Our results suggest that mast cells may play role in PD pathogenesis. PMID- 26646006 TI - Substance use disorder in Canadian university departments of anesthesia. PMID- 26646007 TI - In reply: Substance use disorder in Canadian university departments of anesthesia. PMID- 26646005 TI - Cerebrospinal Fluid from Sporadic Amyotrophic Lateral Sclerosis Patients Induces Mitochondrial and Lysosomal Dysfunction. AB - In our laboratory, we have developed (1) an in vitro model of sporadic Amyotrophic Lateral Sclerosis (sALS) involving exposure of motor neurons to cerebrospinal fluid (CSF) from sALS patients and (2) an in vivo model involving intrathecal injection of sALS-CSF into rat pups. In the current study, we observed that spinal cord extract from the in vivo sALS model displayed elevated reactive oxygen species (ROS) and mitochondrial dysfunction. Quantitative proteomic analysis of sub-cellular fractions from spinal cord of the in vivo sALS model revealed down-regulation of 35 mitochondrial proteins and 4 lysosomal proteins. Many of the down-regulated mitochondrial proteins contribute to alterations in respiratory chain complexes and organellar morphology. Down regulated lysosomal proteins Hexosaminidase, Sialidase and Aryl sulfatase also displayed lowered enzyme activity, thus validating the mass spectrometry data. Proteomic analysis and validation by western blot indicated that sALS-CSF induced the over-expression of the pro-apoptotic mitochondrial protein BNIP3L. In the in vitro model, sALS-CSF induced neurotoxicity and elevated ROS, while it lowered the mitochondrial membrane potential in rat spinal cord mitochondria in the in vivo model. Ultra structural alterations were evident in mitochondria of cultured motor neurons exposed to ALS-CSF. These observations indicate the first line evidence that sALS-CSF mediated mitochondrial and lysosomal defects collectively contribute to the pathogenesis underlying sALS. PMID- 26646008 TI - The Endospore-Forming Pathogen Bacillus cereus Exploits a Small Colony Variant Based Diversification Strategy in Response to Aminoglycoside Exposure. AB - Bacillus cereus is among the microorganisms most often isolated from cases of food spoilage and causes gastrointestinal diseases as well as nongastrointestinal infections elicited by the emetic toxin cereulide, enterotoxins, and a panel of tissue-destructive virulence factors. This opportunistic pathogen is increasingly associated with rapidly fatal clinical infections especially linked to neonates and immunocompromised individuals. Fatality results from either the misdiagnosis of B. cereus as a contaminant of the clinical specimen or from failure of antibiotic therapy. Here we report for the first time that exposure to aminoglycoside antibiotics induces a phenotype switching of emetic B. cereus subpopulations to a slow-growing small colony variant (SCV) state. Along with altered antibiotic resistance, SCVs showed distinct phenotypic and metabolic properties, bearing the risk of antibiotic treatment failure and of clinical misdiagnosis by standard identification tests used in routine diagnostic. The SCV subpopulation is characterized by enhanced production of the toxin cereulide, but it does not secrete tissue-destructive and immune system-affecting enzymes such as sphingomyelinase and phospholipase. SCVs showed significantly prolonged persistence and decreased virulence in the Galleria mellonella model for bacterial infections, indicating diversification concerning their ecological lifestyle. Importantly, diversification into coexisting wild-type and SCV subpopulations also emerged during amikacin pressure during in vivo infection experiments. IMPORTANCE: This study shows for the first time that pathogenic spore-forming B. cereus strains are able to switch to a so far unreported slow growing lifestyle, which differs substantially in terms of developmental, phenotypic, metabolic, and virulence traits from the wild-type populations. This underpins the necessity of molecular-based differential diagnostics and a well chosen therapeutic treatment strategy in clinical environments to combat B. cereus in a tailored manner. The reported induction of SCV in an endospore forming human pathogen requires further research to broaden our understanding of a yet unexplored antibiotic resistance mechanism in sporulating bacteria. Our work also raises a general question about the ecological meaning of SCV subpopulation emergence and importance of SCV in sporeformer populations as an alternative route, next to sporulation, to cope with stresses encountered in natural niches, such as soil or host interfaces. PMID- 26646009 TI - Helicobacter pylori Resists the Antimicrobial Activity of Calprotectin via Lipid A Modification and Associated Biofilm Formation. AB - Helicobacter pylori is one of several pathogens that persist within the host despite a robust immune response. H. pylori elicits a proinflammatory response from host epithelia, resulting in the recruitment of immune cells which manifests as gastritis. Relatively little is known about how H. pylori survives antimicrobials, including calprotectin (CP), which is present during the inflammatory response. The data presented here suggest that one way H. pylori survives the nutrient sequestration by CP is through alteration of its outer membrane. CP-treated H. pylori demonstrates increased bacterial fitness in response to further coculture with CP. Moreover, CP-treated H. pylori cultures form biofilms and demonstrate decreased cell surface hydrophobicity. In response to CP, the H. pylori Lpx lipid A biosynthetic enzymes are not fully functional. The lipid A molecules observed in H. pylori cultures treated with CP indicate that the LpxF, LpxL, and LpxR enzyme functions are perturbed. Transcriptional analysis of lpxF, lpxL, and lpxR indicates that metal restriction by CP does not control this pathway through transcriptional regulation. Analyses of H. pylori lpx mutants reveal that loss of LpxF and LpxL results in increased fitness, similar to what is observed in the presence of CP; moreover, these mutants have significantly increased biofilm formation and reduced cell surface hydrophobicity. Taken together, these results demonstrate a novel mechanism of H. pylori resistance to the antimicrobial activity of CP via lipid A modification strategies and resulting biofilm formation. IMPORTANCE: Helicobacter pylori evades recognition of the host's immune system by modifying the lipid A component of lipopolysaccharide. These results demonstrate for the first time that the lipid A modification pathway is influenced by the host's nutritional immune response. H. pylori's exposure to the host Mn- and Zn-binding protein calprotectin perturbs the function of 3 enzymes involved in the lipid A modification pathway. Moreover, CP treatment of H. pylori, or mutants with an altered lipid A, exhibit increased bacterial fitness and increased biofilm formation. This suggests that H. pylori modifies its cell surface structure to survive under the stress imposed by the host immune response. These results provide new insights into the molecular mechanisms that influence the biofilm lifestyle and how endotoxin modification, which renders H. pylori resistant to cationic antimicrobial peptides, can be inactivated in response to sequestration of nutrient metals. PMID- 26646010 TI - Kaposi's Sarcoma-Associated Herpesvirus Interleukin-6 Modulates Endothelial Cell Movement by Upregulating Cellular Genes Involved in Migration. AB - Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of human Kaposi's sarcoma, a tumor that arises from endothelial cells, as well as two B cell lymphoproliferative diseases, primary effusion lymphoma and multicentric Castleman's disease. KSHV utilizes a variety of mechanisms to evade host immune responses and promote cellular transformation and growth in order to persist for the life of the host. A viral homolog of human interleukin-6 (hIL-6) named viral interleukin-6 (vIL-6) is encoded by KSHV and expressed in KSHV-associated cancers. Similar to hIL-6, vIL-6 is secreted, but the majority of vIL-6 is retained within the endoplasmic reticulum, where it can initiate functional signaling through part of the interleukin-6 receptor complex. We sought to determine how intracellular vIL-6 modulates the host endothelial cell environment by analyzing vIL-6's impact on the endothelial cell transcriptome. vIL-6 significantly altered the expression of many cellular genes associated with cell migration. In particular, vIL-6 upregulated the host factor carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) at the protein and message levels. CEACAM1 has been implicated in tumor invasion and metastasis and promotes migration and vascular remodeling in endothelial cells. We report that vIL-6 upregulates CEACAM1 by a STAT3-dependent mechanism and that CEACAM1 promotes vIL 6-mediated migration. Furthermore, latent and de novo KSHV infections of endothelial cells also induce CEACAM1 expression. Collectively, our data suggest that vIL-6 modulates endothelial cell migration by upregulating the expression of cellular factors, including CEACAM1. IMPORTANCE: Kaposi's sarcoma-associated herpesvirus (KSHV) is linked with the development of three human malignancies, Kaposi's sarcoma, multicentric Castleman's disease, and primary effusion lymphoma. KSHV expresses many factors that enable the virus to manipulate the host environment in order to persist and induce disease. The viral interleukin-6 (vIL-6) produced by KSHV is structurally and functionally homologous to the human cytokine interleukin-6, except that vIL-6 is secreted slowly and functions primarily from inside the host cell. To investigate the unique intracellular role of vIL-6, we analyzed the impact of vIL-6 on endothelial cell gene expression. We report that vIL-6 significantly alters the expression of genes associated with cell movement, including that for CEACAM1. The gene for CEACAM1 was upregulated by vIL-6 and by latent and primary KSHV infection and promotes vIL-6-mediated endothelial cell migration. This work advances the field's understanding of vIL-6 function and its contribution to KSHV pathogenesis. PMID- 26646011 TI - Transcriptomic Analysis of Chronic Hepatitis B and C and Liver Cancer Reveals MicroRNA-Mediated Control of Cholesterol Synthesis Programs. AB - Chronic hepatitis B (CHB), chronic hepatitis C (CHC), and associated hepatocellular carcinoma (HCC) are characterized by cholesterol imbalance and dyslipidemia; however, the key regulatory drivers of these phenotypes are incompletely understood. Using gene expression microarrays and high-throughput sequencing of small RNAs, we performed integrative analysis of microRNA (miRNA) and gene expression in nonmalignant and matched cancer tissue samples from human subjects with CHB or CHC and HCC. We also carried out follow-up functional studies of specific miRNAs in a cell-based system. These studies led to four major findings. First, pathways affecting cholesterol homeostasis were among the most significantly overrepresented among genes dysregulated in chronic viral hepatitis and especially in tumor tissue. Second, for each disease state, specific miRNA signatures that included miRNAs not previously associated with chronic viral hepatitis, such as miR-1307 in CHC, were identified. Notably, a few miRNAs, including miR-27 and miR-224, were components of the miRNA signatures of all four disease states: CHB, CHC, CHB-associated HCC, and CHC-associated HCC. Third, using a statistical simulation method (miRHub) applied to the gene expression data, we identified candidate master miRNA regulators of pathways controlling cholesterol homeostasis in chronic viral hepatitis and HCC, including miR-21, miR-27, and miR-33. Last, we validated in human hepatoma cells that both miR-21 and miR-27 significantly repress cholesterol synthesis and that miR-27 does so in part through regulation of the gene that codes for the rate-limiting enzyme 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase (HMGCR). IMPORTANCE: Hepatitis B virus (HBV) and hepatitis C virus (HCV) are phylogenetically unrelated hepatotropic viruses that persistently infect hundreds of millions of people world-wide, often leading to chronic liver disease and hepatocellular carcinoma (HCC). Chronic hepatitis B (CHB), chronic hepatitis C (CHC), and associated HCC often lead to cholesterol imbalance and dyslipidemia. However, the regulatory mechanisms underlying the dysregulation of lipid pathways in these disease states are incompletely understood. MicroRNAs (miRNAs) have emerged as critical modulators of lipid homeostasis. Here we use a blend of genomic, molecular, and biochemical strategies to identify key miRNAs that drive the lipid phenotypes of chronic viral hepatitis and HCC. These findings provide a panoramic view of the miRNA landscape in chronic viral hepatitis, which could contribute to the development of novel and more-effective miRNA-based therapeutic strategies. PMID- 26646012 TI - IS26-Mediated Precise Excision of the IS26-aphA1a Translocatable Unit. AB - We recently showed that, in the absence of RecA-dependent homologous recombination, the Tnp26 transposase catalyzes cointegrate formation via a conservative reaction between two preexisting IS26, and this is strongly preferred over replicative transposition to a new site. Here, the reverse reaction was investigated by assaying for precise excision of the central region together with a single IS26 from a compound transposon bounded by IS26. In a recA mutant strain, Tn4352, a kanamycin resistance transposon carrying the aphA1a gene, was stable. However, loss of kanamycin resistance due to precise excision of the translocatable unit (TU) from the closely related Tn4352B, leaving behind the second IS26, occurred at high frequency. Excision occurred when Tn4352B was in either a high- or low-copy-number plasmid. The excised circular segment, known as a TU, was detected by PCR. Excision required the IS26 transposase Tnp26. However, the Tnp26 of only one IS26 in Tn4352B was required, specifically the IS26 downstream of the aphA1a gene, and the excised TU included the active IS26. The frequency of Tn4352B TU loss was influenced by the context of the transposon, but the critical determinant of high-frequency excision was the presence of three G residues in Tn4352B replacing a single G in Tn4352. These G residues are located immediately adjacent to the two G residues at the left end of the IS26 that is upstream of the aphA1a gene. Transcription of tnp26 was not affected by the additional G residues, which appear to enhance Tnp26 cleavage at this end. IMPORTANCE: Resistance to antibiotics limits treatment options. In Gram-negative bacteria, IS26 plays a major role in the acquisition and dissemination of antibiotic resistance. IS257 (IS431) and IS1216, which belong to the same insertion sequence (IS) family, mobilize resistance genes in staphylococci and enterococci, respectively. Many different resistance genes are found in compound transposons bounded by IS26, and multiply and extensively antibiotic-resistant Gram-negative bacteria often include regions containing several antibiotic resistance genes and multiple copies of IS26. We recently showed that in addition to replicative transposition, IS26 can use a conservative movement mechanism in which an incoming IS26 targets a preexisting one, and this reaction can create these regions. This mechanism differs from that of all the ISs examined in detail thus far. Here, we have continued to extend understanding of the reactions carried out by IS26 by examining whether the reverse precise excision reaction is also catalyzed by the IS26 transposase. PMID- 26646015 TI - Kesterite Cu2ZnSnS4 as a Low-Cost Inorganic Hole-Transporting Material for High Efficiency Perovskite Solar Cells. AB - Kesterite-structured quaternary semiconductor Cu2ZnSnS4 (CZTS) has been commonly used as light absorber in thin film solar cells on the basis of its optimal bandgap of 1.5 eV, high absorption coefficient, and earth-abundant elemental constituents. Herein we applied CZTS nanoparticles as a novel inorganic hole transporting material (HTM) for organo-lead halide perovskite solar cells (PSCs) for the first time, achieving a power conversion efficiency (PCE) of 12.75%, which is the highest PCE for PSCs with Cu-based inorganic HTMs reported up to now, and quite comparable to that obtained for PSCs based on commonly used organic HTM such as 2,2',7,7'-tetrakis(N,N-di-p-methoxyphenylamine)-9,9' spirobifluorene (spiro-MeOTAD). The size of CZTS nanoparticles and its incorporation condition as HTM were optimized, and the effects of CZTS HTM on the optical absorption, crystallinity, morphology of the perovskite film and the interface between the perovskite layer and the Au electrode were investigated and compared with the case of spiro-MeOTAD HTM, revealing the role of CZTS in efficient hole transporting from the perovskite layer to the top Au electrode as confirmed by the prohibited charge recombination at the perovskite/Au electrode interface. On the basis of the effectiveness of CZTS as a low-cost HTM competitive to spiro-MeOTAD in PSCs, we demonstrate the new role of CZTS in photovoltaics as a hole conductor beyond the traditional light absorber. PMID- 26646014 TI - Making the Leap from Research Laboratory to Clinic: Challenges and Opportunities for Next-Generation Sequencing in Infectious Disease Diagnostics. AB - Next-generation DNA sequencing (NGS) has progressed enormously over the past decade, transforming genomic analysis and opening up many new opportunities for applications in clinical microbiology laboratories. The impact of NGS on microbiology has been revolutionary, with new microbial genomic sequences being generated daily, leading to the development of large databases of genomes and gene sequences. The ability to analyze microbial communities without culturing organisms has created the ever-growing field of metagenomics and microbiome analysis and has generated significant new insights into the relation between host and microbe. The medical literature contains many examples of how this new technology can be used for infectious disease diagnostics and pathogen analysis. The implementation of NGS in medical practice has been a slow process due to various challenges such as clinical trials, lack of applicable regulatory guidelines, and the adaptation of the technology to the clinical environment. In April 2015, the American Academy of Microbiology (AAM) convened a colloquium to begin to define these issues, and in this document, we present some of the concepts that were generated from these discussions. PMID- 26646016 TI - Current status of treatment for pediatric rhabdomyosarcoma in the USA and Japan. AB - This article reviews the current status of treatment for children with rhabdomyosarcoma, according to the four risk groups. Low-risk subgroup A: the Children's Oncology Group in the USA recently performed a clinical trial consisting of a chemotherapy regimen with a shortened treatment period and a reduced drug dosage. Patients in this group received only four cycles of vincristine and actinomycin D (VA) after four cycles of vincristine, actinomycin D, and cyclophosphamide (VAC) with cyclophosphamide (CPM) 1.2 g/m(2) and their outcome was no worse than that obtained with previous regimens. Low-risk subgroup B: although marked improvement in survival was seen with an intensive VAC regimen with CPM 2.2 g/m(2) /cycle (Intergroup Rhabdomyosarcoma Study [IRS]-V, 1997 2004), the total dose of CPM in this regimen caused serious and fatal hepatic veno-occlusive disease during treatment and probably cannot avoid infertility or possible secondary cancer as a late effect. Thereafter, a reduced-dose regimen consisting of four cycles of VAC with CPM 1.2 g/m(2) followed by 12 cycles of VA was investigated in the next study, but the outcome appeared to be worse than in IRS-V. Intermediate-risk group: no significant difference was found between VAC/vincristine, topotecan and cyclophispahamide (VTC) and intensive VAC in IRS V. The results of a subsequent regimen of VAC with CPM 1.2 g/m(2) alternating with vincristine and irinotecan are awaited. High-risk group: overall survival is approximately 30% and has not improved over the last 25 years. Although 18 month failure-free survival (FFS) was improved with an intensive combination therapy regimen, 36 month FFS dropped to 32% and thus better novel approaches or additive treatments are needed. PMID- 26646013 TI - Structural Insight into How Bacteria Prevent Interference between Multiple Divergent Type IV Secretion Systems. AB - Prokaryotes use type IV secretion systems (T4SSs) to translocate substrates (e.g., nucleoprotein, DNA, and protein) and/or elaborate surface structures (i.e., pili or adhesins). Bacterial genomes may encode multiple T4SSs, e.g., there are three functionally divergent T4SSs in some Bartonella species (vir, vbh, and trw). In a unique case, most rickettsial species encode a T4SS (rvh) enriched with gene duplication. Within single genomes, the evolutionary and functional implications of cross-system interchangeability of analogous T4SS protein components remains poorly understood. To lend insight into cross-system interchangeability, we analyzed the VirB8 family of T4SS channel proteins. Crystal structures of three VirB8 and two TrwG Bartonella proteins revealed highly conserved C-terminal periplasmic domain folds and dimerization interfaces, despite tremendous sequence divergence. This implies remarkable structural constraints for VirB8 components in the assembly of a functional T4SS. VirB8/TrwG heterodimers, determined via bacterial two-hybrid assays and molecular modeling, indicate that differential expression of trw and vir systems is the likely barrier to VirB8-TrwG interchangeability. We also determined the crystal structure of Rickettsia typhi RvhB8-II and modeled its coexpressed divergent paralog RvhB8-I. Remarkably, while RvhB8-I dimerizes and is structurally similar to other VirB8 proteins, the RvhB8-II dimer interface deviates substantially from other VirB8 structures, potentially preventing RvhB8-I/RvhB8-II heterodimerization. For the rvh T4SS, the evolution of divergent VirB8 paralogs implies a functional diversification that is unknown in other T4SSs. Collectively, our data identify two different constraints (spatiotemporal for Bartonella trw and vir T4SSs and structural for rvh T4SSs) that mediate the functionality of multiple divergent T4SSs within a single bacterium. IMPORTANCE: Assembly of multiprotein complexes at the right time and at the right cellular location is a fundamentally important task for any organism. In this respect, bacteria that express multiple analogous type IV secretion systems (T4SSs), each composed of around 12 different components, face an overwhelming complexity. Our work here presents the first structural investigation on factors regulating the maintenance of multiple T4SSs within a single bacterium. The structural data imply that the T4SS-expressing bacteria rely on two strategies to prevent cross system interchangeability: (i) tight temporal regulation of expression or (ii) rapid diversification of the T4SS components. T4SSs are ideal drug targets provided that no analogous counterparts are known from eukaryotes. Drugs targeting the barriers to cross-system interchangeability (i.e., regulators) could dysregulate the structural and functional independence of discrete systems, potentially creating interference that prevents their efficient coordination throughout bacterial infection. PMID- 26646017 TI - Amiodarone versus other pharmacological interventions for prevention of sudden cardiac death. AB - BACKGROUND: Sudden cardiac death (SCD) is one of the main causes of cardiac death. There are two main strategies to prevent it: managing cardiovascular risk factors and reducing the risk of ventricular arrhythmias. Implantable cardiac defibrillators (ICDs) constitute the standard therapy for both primary and secondary prevention; however, they are not widely available in settings with limited resources. The antiarrhythmic amiodarone has been proposed as an alternative to ICD. OBJECTIVES: To evaluate the effectiveness of amiodarone for primary or secondary prevention in SCD compared with placebo or no intervention or any other antiarrhythmic drugs in participants at high risk (primary prevention) or who have recovered from a cardiac arrest or a syncope due to Ventricular Tachycardia/Ventricular Fibrillation, or VT/VF (secondary prevention). SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (OVID), EMBASE (OVID), CINAHL (EBSCO) and LILACS on 26 March 2015. We reviewed reference lists of included studies and selected reviews on the topic, contacted authors of included studies, screened relevant meetings and searched in registers for ongoing trials. We applied no language restrictions. SELECTION CRITERIA: Randomised and quasi-randomised trials assessing the efficacy of amiodarone versus placebo, no intervention, or other antiarrhythmics in adults. For primary prevention we considered participants at high risk for SCD. For secondary prevention we considered participants recovered from cardiac arrest or syncope due to ventricular arrhythmias. DATA COLLECTION AND ANALYSIS: Two authors independently assessed the trials for inclusion and extracted relevant data. We contacted trial authors for missing data. We performed meta-analyses using a random-effects model. We calculated risk ratios (RR) for dichotomous outcomes with 95% confidence intervals (CIs). Three studies included more than one comparison. MAIN RESULTS: We included 24 studies (9,997 participants). Seventeen studies evaluated amiodarone for primary prevention and six for secondary prevention. Only three studies used an ICD concomitantly with amiodarone for the comparison (all of them for secondary prevention).For primary prevention, amiodarone compared to placebo or no intervention (17 studies, 8383 participants) reduced SCD (RR 0.76; 95% CI 0.66 to 0.88), cardiac mortality (RR 0.86; 95% CI 0.77 to 0.96) and all-cause mortality (RR 0.88; 95% CI 0.78 to 1.00). The quality of the evidence was low.Compared to other antiarrhythmics (three studies, 540 participants), amiodarone reduced SCD (RR 0.44; 95% CI 0.19 to 1.00), cardiac mortality (RR 0.41; 95% CI 0.20 to 0.86) and all-cause mortality (RR 0.37; 95% CI 0.18 to 0.76). The quality of the evidence was moderate.For secondary prevention, amiodarone compared to placebo or no intervention (two studies, 440 participants) appeared to increase the risk of SCD (RR 4.32; 95% CI 0.87 to 21.49) and all-cause mortality (RR 3.05; 1.33 to 7.01). However, the quality of the evidence was very low. Compared to other antiarrhythmics (four studies, 839 participants) amiodarone appeared to increase the risk of SCD (RR 1.40; 95% CI 0.56 to 3.52; very low quality of evidence), but there was no effect in all-cause mortality (RR 1.03; 95% CI 0.75 to 1.42; low quality evidence).Amiodarone was associated with an increase in pulmonary and thyroid adverse events. AUTHORS' CONCLUSIONS: There is low to moderate quality evidence that amiodarone reduces SCD, cardiac and all-cause mortality when compared to placebo or no intervention for primary prevention, and its effects are superior to other antiarrhythmics.It is uncertain if amiodarone reduces or increases SCD and mortality for secondary prevention because the quality of the evidence was very low. PMID- 26646018 TI - Groundwater Development in Israel. PMID- 26646019 TI - Antenatal body mass index (BMI) and weight gain in pregnancy - its association with pregnancy and birthing complications. AB - BACKGROUND: Overweight and obesity is a serious health risk in both developed and developing nations. It is a common finding among women in their reproductive age. Half of patients entering their pregnancy in the US have a BMI >25.0 and therefore qualify as overweight or obese. Moreover, there is a tendency towards increased weight gain during pregnancy. Studies have shown that gestational overweight is associated with complications in pregnancy and birthing as well as short-term and long-term impacts on neonatal outcome in childhood and adulthood. METHODS: Five hundred and ninety-one women visiting our tertiary perinatal center in 2014 were analyzed for antenatal BMI, gestational weight gain, as well as pregnancy outcome and complication together with neonatal weight and outcome. Pregnancy weight gain was assessed based on the IOM guidelines (Institute of Medicine) issued in 2009. RESULTS: Twenty-nine percent of our population was overweight with a BMI of more than 25.0. The general weight gain was in every BMI group similar (median ranging from 12.0 to 14.0 kg). Approximately one third gained more than the appropriate amount (37%, P<0.001). Women with more gestational weight were at risk of labor induction (55.0% vs. 45.7% labor induction in total, P=0.007). Strikingly, those patients were found to have significantly higher rates of secondary cesarean section (22.4% vs. 15.4%) and decreased chances of spontaneous vaginal birth (57.5% vs. 61.4%) (P=0.008). Furthermore women with a pregnancy weight gain in excess of the guidelines gave birth to neonates with a higher birth weight (>75.centile, 28.3% vs. 21.3%, P<0.001). CONCLUSIONS: Altogether, one third of the analyzed population is already overweight or obese when entering pregnancy. A higher gestational weight gain than the recommended amount was found in 37% of cases. We found an association with pregnancy and birthing complications as well as higher infant weight. This highlights the importance of preconceptive and prenatal advice, and if necessary, intervention on BMI and weight gain. PMID- 26646020 TI - Changes in incidence of iatrogenic and spontaneous preterm births over time: a population-based study. AB - OBJECTIVE: To examine the proportion of iatrogenic births among all preterm births over a 26-year period. PATIENTS AND METHODS: A registry-based survey of preterm deliveries between 1987 and 2012 analyzed by the onset of labor: spontaneous with intact membranes, preterm premature rupture of membranes (PPROM) or iatrogenic. Stratification into categories by gestation (22 weeks to 27 weeks and 6 days, 28 weeks to 31 weeks and 6 days, 32 weeks to 33 weeks and 6 days, 34 weeks to 36 weeks and 6 days) was performed. Preterm birth rates were analyzed using the Mantel-Haenszel linear-by-linear association chi2-test (P<0.05 significant). Logistic regression was used to account for potential confounders. RESULTS: Overall preterm birth rate was 5.9% (31328 deliveries) including 2358 (0.4%) before 28 completed weeks, 3388 (0.6%) between 28 weeks and 31 weeks 6 days, 3970 (0.8%) between 32 weeks and 33 weeks and 6 days, and 21611 (4.1%) between 34 weeks and 36 weeks and 6 days There was an increase in overall preterm birth rate (P<0.001). The rate of iatrogenic preterm births and PPROM increased over time (P<0.001 and P<0.014, respectively). Rates of spontaneous preterm birth decreased (P<0.001). After accounting for potential confounders, year of birth remained an independent risk factor for iatrogenic preterm delivery in all four gestational age categories (P<0.001). CONCLUSION: The incidence of iatrogenic preterm birth is increasing with a concomitant decrease in the incidence of spontaneous preterm birth. Attempts to analyze, interpret and decrease preterm birth rates should consider spontaneous and iatrogenic preterm births separately. PMID- 26646021 TI - The difference between electrical microstimulation and direct electrical stimulation - towards new opportunities for innovative functional brain mapping? AB - Both electrical microstimulation (EMS) and direct electrical stimulation (DES) of the brain are used to perform functional brain mapping. EMS is applied to animal fundamental neuroscience experiments, whereas DES is performed in the operating theatre on neurosurgery patients. The objective of the present review was to shed new light on electrical stimulation techniques in brain mapping by comparing EMS and DES. There is much controversy as to whether the use of DES during wide-awake surgery is the 'gold standard' for studying the brain function. As part of this debate, it is sometimes wrongly assumed that EMS and DES induce similar effects in the nervous tissues and have comparable behavioural consequences. In fact, the respective stimulation parameters in EMS and DES are clearly different. More surprisingly, there is no solid biophysical rationale for setting the stimulation parameters in EMS and DES; this may be due to historical, methodological and technical constraints that have limited the experimental protocols and prompted the use of empirical methods. In contrast, the gap between EMS and DES highlights the potential for new experimental paradigms in electrical stimulation for functional brain mapping. In view of this gap and recent technical developments in stimulator design, it may now be time to move towards alternative, innovative protocols based on the functional stimulation of peripheral nerves (for which a more solid theoretical grounding exists). PMID- 26646022 TI - Parallel, open-channel lateral flow (immuno) assay substrate based on capillary channeled polymer films. AB - Presented here is a novel implementation of polypropylene capillary-channeled polymer (C-CP) films, functionalized for bioaffinity separations and implemented as a platform for lateral flow (immuno) assays. The parallel ~80 MUm * 80 MUm channels pass test solutions down the 30 mm film length via spontaneous wicking action, setting up the possibility for immobilizing different capture agents in the respective channels. The base-film modification process is divided into two steps: ultraviolet light treatment to improve hydrophillicity of the polypropylene substrate and the physical adsorption of a functionalized lipid tethered ligand (LTL) as a selective capture agent. The entire modification procedure is performed under ambient conditions in an aqueous solution without extreme pH conditions. In this demonstration, physical adsorption of a biotinylated-LTL onto the UV-treated PP surface selectively captures Texas Red labeled streptavidin (SAv-TR) in the presence of enhanced green fluorescence protein (EGFP), which passes without retention in less than 5 s. In addition to the fluorescence imaging of the protein solutes, matrix assisted laser desorption/ionization-mass spectrometry (MALDI-MS) was used to confirm the formation of the LTL-SAv conjugates on the channel surface as well as to demonstrate an alternative means of probing the capture step. The present effort sets the groundwork for further development of C-CP films as a parallel, multi analyte LFA platform; a format that to-date has not been described. PMID- 26646023 TI - Insulin Signaling in Bupivacaine-induced Cardiac Toxicity: Sensitization during Recovery and Potentiation by Lipid Emulsion. AB - BACKGROUND: The impact of local anesthetics on the regulation of glucose homeostasis by protein kinase B (Akt) and 5'-adenosine monophosphate-activated protein kinase (AMPK) is unclear but important because of the implications for both local anesthetic toxicity and its reversal by IV lipid emulsion (ILE). METHODS: Sprague-Dawley rats received 10 mg/kg bupivacaine over 20 s followed by nothing or 10 ml/kg ILE (or ILE without bupivacaine). At key time points, heart and kidney were excised. Glycogen content and phosphorylation levels of Akt, p70 s6 kinase, s6, insulin receptor substrate-1, glycogen synthase kinase-3beta, AMPK, acetyl-CoA carboxylase, and tuberous sclerosis 2 were quantified. Three animals received Wortmannin to irreversibly inhibit phosphoinositide-3-kinase (Pi3k) signaling. Isolated heart studies were conducted with bupivacaine and LY294002-a reversible Pi3K inhibitor. RESULTS: Bupivacaine cardiotoxicity rapidly dephosphorylated Akt at S473 to 63 +/- 5% of baseline and phosphorylated AMPK to 151 +/- 19%. AMPK activation inhibited targets downstream of mammalian target of rapamycin complex 1 via tuberous sclerosis 2. Feedback dephosphorylation of IRS1 to 31 +/- 8% of baseline sensitized Akt signaling in hearts resulting in hyperphosphorylation of Akt at T308 and glycogen synthase kinase-3beta to 390 +/- 64% and 293 +/- 50% of baseline, respectively. Glycogen accumulated to 142 +/- 7% of baseline. Irreversible inhibition of Pi3k upstream of Akt exacerbated bupivacaine cardiotoxicity, whereas pretreating with a reversible inhibitor delayed the onset of toxicity. ILE rapidly phosphorylated Akt at S473 and T308 to 150 +/- 23% and 167 +/- 10% of baseline, respectively, but did not interfere with AMPK or targets of mammalian target of rapamycin complex 1. CONCLUSION: Glucose handling by Akt and AMPK is integral to recovery from bupivacaine cardiotoxicity and modulation of these pathways by ILE contributes to lipid resuscitation. PMID- 26646027 TI - Mitochondrial Proteomics Approach Reveals Voltage-Dependent Anion Channel 1 (VDAC1) as a Potential Biomarker of Gastric Cancer. AB - BACKGROUND/AIMS: Gastric cancer (GC) remains the second leading cause of cancer related deaths in the world. Successful early cancer detection is hampered by lack of highly sensitive and specific biomarkers. Mitochondrial dysfunction contributes to an aggressive carcinogenic phenotype of many cancers. We hypothesized that changes in the mitochondrial proteome are required to support development of GC. METHODS: TMT method followed by mass spectrometry analysis was utilized to quantify alterations in protein abundance in mitochondria enriched between noncancer and gastric cancer tissues. RESULTS: Of a total data set that included 738 identified proteins, about 40.1% were found to be mitochondrial and associated proteins. Among them, 234 proteins were at least 1.5-fold up- or down regulated in the gastric cancer compared with the adherent normal tissues. A number of markers (e.g. HSP70, HSP60, HSP90, leucine-rich pentatricopeptide repeat containing (LRPPRC), SOD2 and cathepsin B) were previously reported as biomarkers of GC. Additionally, several potential biomarkers participated in mitochondrial oxidative phosphorylation and active fatty acid oxidation were firstly identified differentially expressed in GC samples. Our findings also suggest that VDAC1 may be a novel biomarker for GC. CONCLUSION: The results show that subcellular proteomics of tumor tissue is feasible and a promising avenue for exploring oncogenesis. PMID- 26646026 TI - Providing NHS staff with height-adjustable workstations and behaviour change strategies to reduce workplace sitting time: protocol for the Stand More AT (SMArT) Work cluster randomised controlled trial. AB - BACKGROUND: High levels of sedentary behaviour (i.e., sitting) are a risk factor for poor health. With high levels of sitting widespread in desk-based office workers, office workplaces are an appropriate setting for interventions aimed at reducing sedentary behaviour. This paper describes the development processes and proposed intervention procedures of Stand More AT (SMArT) Work, a multi-component randomised control (RCT) trial which aims to reduce occupational sitting time in desk-based office workers within the National Health Service (NHS). METHODS/DESIGN: SMArT Work consists of 2 phases: 1) intervention development: The development of the SMArT Work intervention takes a community-based participatory research approach using the Behaviour Change Wheel. Focus groups will collect detailed information to gain a better understanding of the most appropriate strategies, to sit alongside the provision of height-adjustable workstations, at the environmental, organisational and individual level that support less occupational sitting. 2) intervention delivery and evaluation: The 12 month cluster RCT aims to reduce workplace sitting in the University Hospitals of Leicester NHS Trust. Desk-based office workers (n = 238) will be randomised to control or intervention clusters, with the intervention group receiving height adjustable workstations and supporting techniques based on the feedback received from the development phase. Data will be collected at four time points; baseline, 3, 6 and 12 months. The primary outcome is a reduction in sitting time, measured by the activPAL(TM) micro at 12 months. Secondary outcomes include objectively measured physical activity and a variety of work-related health and psycho-social measures. A process evaluation will also take place. DISCUSSION: This study will be the first long-term, evidence-based, multi-component cluster RCT aimed at reducing occupational sitting within the NHS. This study will help form a better understanding and knowledge base of facilitators and barriers to creating a healthier work environment and contribute to health and wellbeing policy. TRIAL REGISTRATION: ISRCTN10967042 . Registered 2 February 2015. PMID- 26646028 TI - An overview on emerging photoelectrochemical self-powered ultraviolet photodetectors. AB - In recent years, as a new member of ultraviolet photodetectors (UV-PDs), photoelectrochemical UV-PDs (PEC UV-PDs) have received great attention. Compared to conventional photoconductors, PEC UV-PDs exhibit a number of merits, including low cost, environmentally friendly nature, being self-powered, and fast response. This tutorial review provides a comprehensive introduction to this research field, covering from the basics of performance evaluation of PEC UV-PDs, the state-of-the-art advances in structural design, electrolyte matching, and electrode fabrication of PEC UV-PDs, to the integration of multiple functions into a PEC UV-PD. In the end, we present our perspectives on the future development of PEC UV-PDs and highlight the key technical challenges in aiming to stimulate further developments in this research field. PMID- 26646029 TI - Managing excessive daytime sleepiness. PMID- 26646030 TI - Predictors and treatment outcomes. AB - This month's section of Focus on Childhood and Adolescent Mental Health offers a wide array of clinically relevant topics. Interest in the use of dietary supplements to treat mood disorders has been on the rise. Wozniak and colleagues examined whether high EPA/DHA omega-3 fatty acids and inositol were effective in the treatment of pediatric bipolar spectrum disorders. PMID- 26646025 TI - Basic Science Evidence for the Link Between Erectile Dysfunction and Cardiometabolic Dysfunction. AB - INTRODUCTION: Although clinical evidence supports an association between cardiovascular/metabolic diseases (CVMD) and erectile dysfunction (ED), scientific evidence for this link is incompletely elucidated. AIM: This study aims to provide scientific evidence for the link between CVMD and ED. METHODS: In this White Paper, the Basic Science Committee of the Sexual Medicine Society of North America assessed the current literature on basic scientific support for a mechanistic link between ED and CVMD, and deficiencies in this regard with a critical assessment of current preclinical models of disease. RESULTS: A link exists between ED and CVMD on several grounds: the endothelium (endothelium derived nitric oxide and oxidative stress imbalance); smooth muscle (SM) (SM abundance and altered molecular regulation of SM contractility); autonomic innervation (autonomic neuropathy and decreased neuronal-derived nitric oxide); hormones (impaired testosterone release and actions); and metabolics (hyperlipidemia, advanced glycation end product formation). CONCLUSION: Basic science evidence supports the link between ED and CVMD. The Committee also highlighted gaps in knowledge and provided recommendations for guiding further scientific study defining this risk relationship. This endeavor serves to develop novel strategic directions for therapeutic interventions. PMID- 26646031 TI - A randomized clinical trial of high eicosapentaenoic acid omega-3 fatty acids and inositol as monotherapy and in combination in the treatment of pediatric bipolar spectrum disorders: a pilot study. AB - OBJECTIVE: We conducted a 12-week, randomized, double-blind, controlled clinical trial to evaluate the effectiveness and tolerability of high eicosapentaenoic acid (EPA)/docosahexaenoic acid (DHA) omega-3 fatty acids and inositol as monotherapy and in combination in children with bipolar spectrum disorders. METHOD: Participants were children 5-12 years of age meeting DSM-IV diagnostic criteria for bipolar spectrum disorders (bipolar I or II disorder or bipolar disorder not otherwise specified [NOS]) and displaying mixed, manic, or hypomanic symptoms. Subjects with severe illness were excluded. Subjects were randomized to 1 of 3 treatment arms: inositol plus placebo, omega-3 fatty acids plus placebo, and the combined active treatment of omega-3 fatty acids plus inositol. Data were collected from February 2012 to November 2013. RESULTS: Twenty-four subjects were exposed to treatment (>= 1 week of study completed) (inositol [n = 7], omega-3 fatty acids [n = 7], and omega-3 fatty acids plus inositol [n =10]). Fifty-four percent of the subjects completed the study. Subjects randomized to the omega-3 fatty acids plus inositol arm had the largest score decrease comparing improvement from baseline to end point with respect to the Young Mania Rating Scale (P < .05). Similar results were found for the Children's Depression Rating Scale (P < .05) and the Brief Psychiatric Rating Scale (P <.05). CONCLUSION: Results of this pilot randomized, double-blind, controlled trial suggest that the combined treatment of omega-3 fatty acids plus inositol reduced symptoms of mania and depression in prepubertal children with mild to moderate bipolar spectrum disorders. Results should be interpreted in light of limitations, which include exclusion of severely ill subjects, 54% completion rate, and small sample size. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01396486. PMID- 26646032 TI - Inflammatory markers among adolescents and young adults with bipolar spectrum disorders. AB - OBJECTIVE: Despite burgeoning literature in middle-aged adults, little is known regarding proinflammatory markers (PIMs) among adolescents and young adults with bipolar disorder. Similarly, few prior studies have considered potential confounds when examining the association between PIMs and bipolar disorder characteristics. We therefore retrospectively examined these topics in the Course and Outcome of Bipolar Youth (COBY) study. METHOD: Subjects were 123 adolescents and young adults (mean [SD] = 20.4 +/- 3.8 years; range, 13.4-28.3 years) in COBY, enrolled between October 2000 and July 2006. DSM-IV diagnoses were determined using the Schedule for Affective Disorders and Schizophrenia for School-Age Children (K-SADS). Clinical characteristics during the preceding 6 months, including mood, comorbidity, and treatment, were evaluated using the Longitudinal Interval Follow-Up Evaluation (LIFE). Serum levels of interleukin (IL)-6, tumor necrosis factor (TNF)-alpha, and high-sensitivity C-reactive protein (hsCRP) were assayed. Primary analyses examined the association of PIMs with bipolar disorder characteristics during the preceding 6 months. RESULTS: Several lifetime clinical characteristics were significantly associated with PIMs in multivariable analyses, including longer illness duration (P = .005 for IL-6; P = .0004 for hsCRP), suicide attempts (P = .01 for TNF-alpha), family history of suicide attempts or completion (P = .01 for hsCRP), self-injurious behavior (P =.005 for TNF-alpha), substance use disorder (SUD) (P < .0001 for hsCRP), and family history of SUD (P = .02 for TNF-alpha; P = .01 for IL-6). The following bipolar disorder characteristics during the preceding 6 months remained significantly associated with PIMs in multivariable analyses that controlled for differences in comorbidity and treatment: for TNF-alpha, percentage of weeks with psychosis (chi(2) = 5.7, P =.02); for IL-6, percentage of weeks with subthreshold mood symptoms (chi(2)= 8.3, P = .004) and any suicide attempt (chi(2) = 6.1, P = .01); for hsCRP, maximum severity of depressive symptoms (chi(2) = 8.3, P =.004). CONCLUSION: Proinflammatory markers may be relevant to bipolar disorder characteristics as well as other clinical characteristics among adolescents and young adults with bipolar disorder. Traction toward validating PIMs as clinically relevant biomarkers in bipolar disorder will require repeated measures of PIMs and incorporation of relevant covariates. PMID- 26646033 TI - Clinical characteristics and management of treatment-resistant depression. PMID- 26646034 TI - Report ignores risk factor of tobacco in assessing suicidality. PMID- 26646035 TI - Drs Han and Compton reply. PMID- 26646036 TI - Preliminary outcomes of implementing cognitive processing therapy for posttraumatic stress disorder across a national veterans' treatment service. AB - BACKGROUND: Posttraumatic stress disorder (PTSD) is a significant problem for military veterans. There is an international imperative to improve access to effective treatments, but more research is needed to ascertain the extent to which treatments found to be efficacious in research settings translate to successful national implementation efforts. METHOD: This study reports the clinical outcomes for the first 100 clients treated following the implementation of cognitive processing therapy (CPT) across a national community-based veterans' mental health service that commenced in May 2012. The implementation included training and ongoing clinical supervision, leadership support, and updates to the service's data collection and intake system to support the delivery of CPT. The service implemented an intake screen (the Primary Care PTSD) that was used to allocate clients who screened positive for PTSD to CPT-trained therapists. An outcome measure for PTSD (the PTSD Checklist) was incorporated into the services' computerized records system. Clients who received CPT were assessed pretreatment and posttreatment. RESULTS: Statistically significant and clinically large improvements were found for self-reported PTSD (effect size = 1.01, P < .001). In addition, the study obtained high levels of treatment fidelity in the delivery of the CPT treatment. CONCLUSIONS: There is relatively little published research supporting the effectiveness of evidence-based PTSD treatments following national implementation efforts. This is the first study to systematically report CPT treatment outcomes from a national implementation effort, using service-based outcome monitoring data. Results indicate that when administered as part of routine clinical practice, CPT achieves large clinically significant improvements for PTSD comparable with those found in randomized controlled trials. PMID- 26646037 TI - Optimizing outcomes in clozapine rechallenge following neutropenia: a cohort analysis. AB - OBJECTIVE: Certain patients with treatment-refractory schizophrenia may be rechallenged with clozapine following previous neutropenia. Evidence guiding patient selection and the effectiveness of lithium and granulocyte-colony stimulating factor (G-CSF) in rechallenge is limited, and factors associated with successful outcomes are unclear. METHOD: Outcomes were studied in patients rechallenged with clozapine at a tertiary referral center between January 2007 and December 2013, following 1 or more previous trials terminated due to neutropenia, defined as an absolute neutrophil count (ANC) < 1.5 * 10(9)/L. Demographic characteristics, details of each clozapine trial including ANC, and coprescribed medication were extracted, and factors associated with rechallenge outcomes were examined. RESULTS: Nineteen patients underwent clozapine rechallenge following previous neutropenia; 4 (21%) experienced further neutropenia, 2 of which developed agranulocytosis. Compared to successfully rechallenged patients, unsuccessfully rechallenged patients were significantly older (t = 2.10, P = .05), experienced onset of neutropenia sooner (W = 10.0, P = .03), and were more commonly coprescribed valproate. In addition to 5 patients with benign ethnic neutropenia (BEN), 8 patients not of an ethnicity associated with BEN also had idiopathic low neutrophil counts at baseline; lithium and G-CSF coprescription facilitated successful rechallenge in these patients. CONCLUSIONS: In this selected population, the initial neutropenia was unlikely to be related to clozapine in a substantial proportion of cases. This group was successfully rechallenged following careful consideration of the risks and benefits, and lithium and G-CSF contributed to allowing continued clozapine therapy. In addition to black patients, other ethnic groups can have persistently low ANC unrelated to clozapine. PMID- 26646038 TI - Importance of early weight changes to predict long-term weight gain during psychotropic drug treatment. AB - BACKGROUND: Psychotropic drugs can induce substantial weight gain, particularly during the first 6 months of treatment. The authors aimed to determine the potential predictive power of an early weight gain after the introduction of weight gain-inducing psychotropic drugs on long-term weight gain. METHOD: Data were obtained from a 1-year longitudinal study ongoing since 2007 including 351 psychiatric (ICD-10) patients, with metabolic parameters monitored (baseline and/or 1, 3, 6, 9, 12 months) and with compliance ascertained. International Diabetes Federation and World Health Organization definitions were used to define metabolic syndrome and obesity, respectively. RESULTS: Prevalences of metabolic syndrome and obesity were 22% and 17%, respectively, at baseline and 32% and 24% after 1 year. Receiver operating characteristic analyses indicated that an early weight gain > 5% after a period of 1 month is the best predictor for important long-term weight gain (>= 15% after 3 months: sensitivity, 67%; specificity, 88%; >= 20% after 12 months: sensitivity, 47%; specificity, 89%). This analysis identified most patients (97% for 3 months, 93% for 12 months) who had weight gain <= 5% after 1 month as continuing to have a moderate weight gain after 3 and 12 months. Its predictive power was confirmed by fitting a longitudinal multivariate model (difference between groups in 1 year of 6.4% weight increase as compared to baseline, P = .0001). CONCLUSION: Following prescription of weight gain-inducing psychotropic drugs, a 5% threshold for weight gain after 1 month should raise clinician concerns about weight-controlling strategies. PMID- 26646039 TI - Cholinesterase inhibitor discontinuation in patients with Alzheimer's disease: a meta-analysis of randomized controlled trials. AB - OBJECTIVE: This meta-analysis examined the effects of cholinesterase inhibitor (ChEI) discontinuation in patients with Alzheimer's disease (AD). DATA SOURCES: Electronic records up to March 2014 were searched from MEDLINE, Embase, PsycINFO, Cochrane Library, Allied and Complementary Medicine Database, and Cumulative Index to Nursing and Allied Health Literature. Search terms included Alzheimer's disease and cholinesterase inhibitors, plus discontinuation or cessation or tapering or withdrawal. There were no language limits. STUDY SELECTION: Randomized, double-blind, placebo-controlled studies investigating the effect of ChEI discontinuation on patients with AD according to standardized criteria (eg, National Institute of Neurologic and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association, DSM-IV) and presenting measurable results of neuropsychological testing were included. DATA EXTRACTION: Demographics, setting, ChEI treatment length, discontinuation protocol, follow-up duration, study outcomes, and dropouts during the double blind phase were extracted. RESULTS: Of 1,430 records returned, 18 were reviewed. Five ChEI discontinuation randomized controlled trials (N = 321 continued and N = 332 discontinued, following patients for 1.5-24 months) were analyzed. Discontinued patients demonstrated a significant worsening of cognition (standard mean Mini-Mental State Examination difference: -0.29 [95% CI, -0.45 to -0.13], N = 300 continued/307 discontinued, P < .001), a significant worsening of neuropsychiatric symptoms (standard mean Neuropsychiatric Inventory difference: 0.32 [-0.51 to -0.12], N = 199/211, P = .001), and significantly higher dropout rates (risk ratio [RR] = 1.33 [1.11-1.59], N = 321/332, P = .002) compared to those who continued. No difference in adverse events was observed (RR = 1.01 [0.85-1.20], N = 314/326, P = .92). CONCLUSIONS: ChEI discontinuation may have negative effects on cognition and neuropsychiatric symptoms, a finding corroborated by a higher incidence of trial dropout. PMID- 26646040 TI - Frequency and correlates of DSM-5 attenuated psychosis syndrome in a sample of adolescent inpatients with nonpsychotic psychiatric disorders. AB - OBJECTIVES: DSM-5 conceptualized attenuated psychosis syndrome (APS) as self contained rather than as a risk syndrome, including it under "Conditions for Further Study," but also as a codable/billable condition in the main section. Since many major mental disorders emerge during adolescence, we assessed the frequency and characteristics of APS in adolescent psychiatric inpatients. METHODS: Consecutively recruited adolescents hospitalized for nonpsychotic disorders (September 2009-May 2013) were divided into APS youth versus non-APS youth, based on the Structured Interview of Prodromal Syndromes (SIPS) and according to DSM-5 criteria, and compared across multiple characteristics. RESULTS: Of 89 adolescents (mean +/- SD age = 15.1 +/- 1.6 years), 21 (23.6%) had APS. Compared to non-APS, APS was associated with more comorbid disorders (2.7 +/ 1.0 vs 2.2 +/- 1.3), major depressive disorder (61.9% vs 27.9%), oppositional defiant disorder/conduct disorder (52.4% vs 25.0%), and personality disorder traits (57.1% vs 7.4%, the only diagnostic category surviving Bonferroni correction). APS youth were more severely ill, having higher SIPS total positive, negative, and general symptoms; Brief Psychiatric Rating Scale total and positive scores; depression and global illness ratings; and lower Global Assessment of Functioning (GAF). Conversely, Young Mania Rating Scale scores, suicidal behavior, prescribed psychotropic medications, and mental disorder awareness were similar between APS and non-APS groups. In multivariable analysis, lowest GAF score in the past year (odds ratio [OR] = 51.15; 95% confidence interval [CI], 2.46-2,439.0) and social isolation (OR = 27.52; 95% CI, 3.36-313.87) were independently associated with APS (r(2) = 0.302, P < .0001). Although psychotic disorders were excluded, 65.2% (APS = 57.1%, non-APS = 67.7%, P = .38) received antipsychotics. CONCLUSION: One in 4 nonpsychotic adolescent inpatients met DSM-5 criteria for APS. APS youth were more impaired, showing a complex entanglement with a broad range of psychiatric symptoms and disorders, including depression, impulse-control, and, especially, emerging personality disorders. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01383915. PMID- 26646041 TI - Examining why patients with attention-deficit/hyperactivity disorder lack adherence to medication over the long term: a review and analysis. AB - OBJECTIVE: To investigate the reasons why patients with attention deficit/hyperactivity disorder (ADHD) adhere poorly to medications over the long term (>= 1 year). DATA SOURCES: PubMed was reviewed for studies between 1997 and January 2015 citing the reasons for medication nonadherence using these main keywords: ADHD, amphetamine, methylphenidate, atomoxetine, guanfacine, clonidine, long term, and adverse effects. Non-English language articles were excluded as were those that had a follow-up of < 1 year. STUDY SELECTION: Of 1,137 entries, 41 published articles citing reasons for subject withdrawal from treatment were included. None were included for clonidine. DATA EXTRACTION: Similar reasons for drug or study withdrawal were grouped together for analysis using a normalized numerical average, while unique reasons were analyzed individually. RESULTS: Reasons for discontinuing Food and Drug Administration (FDA)-approved medication after 1 year included "own wish/remission/don't need" (19.9%; 95% CI, 9.0-30.80), "withdrew consent" (16.2%; 95% CI, 10.0-22.5), "adverse effects" (15.1%; 95% CI, 10.4-19.8) and "suboptimal effect" (14.6%; 95% CI, 8.5-20.6), with the most common adverse event being "reduction in weight/appetite" (19.2%; 95% CI, 5.1 33.4). Other important factors included age, long- versus short-acting medication, psychosocial stressors, and "stop feeling like him/herself" on medication. CONCLUSIONS: The reasons why patients do not adhere to stimulant medication remain poorly studied and understood, especially over the long term. Standardizing the way studies evaluate patients who stop treatment and including more qualitative measures should lead to better treatment outcome and adherence to medication over the long term. PMID- 26646042 TI - Examination of participant flow in the CONSORT diagram can improve the understanding of the generalizability of study results. AB - A fundamental principle in research is that the findings of a study can only be generalized to the population from which the sample of the study was drawn. What this population was can be discerned from an examination of the study selection criteria. Additional insights can sometimes be gleaned from the study flowchart or CONSORT diagram, which may show sample attenuation between subject screening and final recruitment. Such sample attenuation, if present, implies further limitation to the generalizability of the study outcomes. Two large, 2-year, randomized controlled maintenance therapy trials are described to illustrate sample attenuation that limits study generalizability, one in the context of mindfulness-based cognitive therapy versus antidepressant drugs for recurrent major depressive disorder and the other in the context of quetiapine versus placebo for bipolar disorder. Readers therefore need to examine both study selection criteria and the CONSORT diagram in order to better understand the extent to which study results apply to the patients whom they see. PMID- 26646043 TI - Is psychotherapy for personality disorders worth it? PMID- 26646044 TI - Psychotropic agents and the prediction of weight gain. PMID- 26646045 TI - Personalized medicine with Omega-3 fatty acids for depression in children and pregnant women and depression associated with inflammation. PMID- 26646046 TI - Recognizing signs and symptoms of bipolar disorder. AB - Psychiatric mental health nurses and advanced practice nurses play an important role in the assessment and care of patients with bipolar disorder. Using appropriate rating scales and diagnostic criteria can aid in the assessment of patients who present with a variety of symptoms. In this game-based CME activity, you will assume the role of a psychiatric mental health advanced practice nurse who must recognize the signs and symptoms of bipolar disorder and select appropriate treatment for a 20-year-old patient with suicidal thoughts. PMID- 26646047 TI - Residual symptoms in depression: prevalence and impact. AB - Residual symptoms are experienced by most patients being treated for depression, including those who have achieved remission. These symptoms prevent individuals from fully recovering and feeling truly "well." Often, symptoms that are related to deficits in positive affect (such as anhedonia, pessimism, and lack of motivation) persist after the other symptoms of depression (such as irritability, distress, and low mood) have resolved. Clinicians must assess patients for residual symptoms using rating scales (eg, the Patient Health Questionnaire, Clinical Positive Affect Scale) and adjust treatment to improve patients' sense of well-being and normalcy. PMID- 26646048 TI - Effective treatment of bipolar depression: monotherapy and combination strategies. AB - Managing patients with bipolar disorder remains a challenge due to its chronic nature. In addition, bipolar depression remains understudied even though patients spend more time in depressive episodes than in manic ones. Effective treatment requires an accurate and timely diagnosis, psychoeducation, psychotherapy, pharmacotherapy, and implementation of elements of the chronic care model. Pharmacologic strategies for treating bipolar depression differ from those for bipolar mania as well as those for unipolar depression and require knowledge of the efficacy and safety of agents including mood stabilizers, atypical antipsychotics, and antidepressants both as monotherapy and in combination. PMID- 26646049 TI - Personality disorders: a burden in the community, neglected in the clinic? PMID- 26646050 TI - Gastrointestinal disorders and "medical depression". PMID- 26646051 TI - Tumor cell-specific photothermal killing by SELEX-derived DNA aptamer-targeted gold nanorods. AB - Despite widespread availability of cytotoxic chemotherapeutic agents, the killing of tumour cells without affecting healthy surrounding tissue remains elusive, although recent developments in terms of plasmonic nanoparticles capable of photothermal killing have some promise. Here we describe novel DNA aptamer tethered gold nanorods (GNRs) that act as efficient photothermal therapeutics against tumour cells, but not their isogenic normal cell counterparts. A modified Cell-SELEX process was developed to select a novel DNA aptamer (KW16-13) that specifically recognised and was internalised by cells of the MCF10CA1h human breast ductal carcinoma line but not by those of its isogenic normal counterpart (MCF10A). GNRs conjugated to KW16-13 were readily internalized by the MCF10CA1h tumour cells with minimal uptake by MCF10A normal cells. Upon near infrared (NIR) light irradiation, tumour cell death of >96%, could be effected, compared to <1% in the normal cells or cells incubated with GNRs alone, our KW16-13 aptamer targeted GNRs thus showing >71-fold tumor cell death than GNRs-targeted with a previously described aptamer. This demonstrates the significant potential for aptamer functionalised-GNRs to be used effective and above all selective anti cancer photothermal therapeutics. PMID- 26646053 TI - Self-Report Measures of Boredom: An Updated Review of the Literature. AB - A detailed review of the psychometric measures of boredom was published approximately 12 years ago (Vodanovich, 2003). Since that time, numerous studies have been conducted on existing scales, and new measures of boredom have been developed. Given these assessment advancements, an updated review of self-report boredom scales is warranted. The primary focus of the current review is research published since 2003, and it includes a total of 16 boredom scales. The measures reviewed consist of two trait assessments (Boredom Proneness Scale, Boredom Susceptibility subscale of the Sensation Seeking Scale), five context-specific trait boredom scales (Boredom Coping Scale, Leisure Boredom Scale, Free Time Boredom Scale, Sexual Boredom Scale, Relational Boredom Scale), three assessments of state boredom (Multidimensional State Boredom Scale, State Boredom Measure, Boredom Experience Scale), and six context-specific state boredom measures-Lee's Job Boredom Scale, Dutch Boredom Scale, Boredom Coping Scale (Academic), the Boredom subscale of the Achievement Emotions Questionnaire, Academic Boredom Scale, Precursors to Boredom Scale. In addition to providing a review of these measures, a brief critique of each scale is included, as well as suggestions for needed research focus. PMID- 26646052 TI - HbA1c overtesting and overtreatment among US adults with controlled type 2 diabetes, 2001-13: observational population based study. AB - STUDY QUESTION: What is the extent and effect of excessive testing for glycated hemoglobin (HbA1c) among adults with controlled type 2 diabetes? METHODS: A retrospective analysis of data from a national administrative claims database included commercially insured individuals in the USA, 2001-13. Study patients were aged 18 years or older, had type 2 diabetes with stable glycemic control (two consecutive tests showing HbA1c<7.0% within 24 months), did not use insulin, had no history of severe hypoglycemia or hyperglycemia, and were not pregnant. HbA1c testing frequency was measured within 24 months after the second (index) HbA1c test, and classified as guideline recommended (<= 2 times/year), frequent (3-4 times/year), and excessive (>= 5 times/year). Changes in treatment regimen were ascertained within three months of the index test. STUDY ANSWER AND LIMITATIONS: Of 31,545 patients in the study cohort (mean age 58 years; mean index HbA1c 6.2%), HbA1c testing frequency was excessive in 6% and frequent in 55%. Despite good glycemic control at baseline, treatment was further intensified by addition of glucose lowering drugs or insulin in 8.4% of patients (comprising 13%, 9%, and 7% of those tested excessively, frequently, and per guidelines, respectively; P<0.001). Compared with guideline recommended testing, excessive testing was associated with treatment intensification (odds ratio 1.35 (95% confidence interval 1.22 to 1.50)). Excessive testing rates remained unchanged in 2001-08, but fell significantly after 2009. The odds of excessive testing was 46% lower in 2011 than in 2001-02. The study population is not representative of all US patients with type 2 diabetes because it was restricted to commercially insured adults with stable and controlled diabetes not receiving insulin treatment. The study design did not capture the underuse of HbA1c testing. WHAT THIS STUDY ADDS: In this US cohort of adults with stable and controlled type 2 diabetes, more than 60% received too many HbA1c tests, a practice associated with potential overtreatment with hypoglycemic drugs. Excessive testing contributes to the growing problem of waste in healthcare and increased patient burden in diabetes management. FUNDING, COMPETING INTERESTS, DATA SHARING: NDS and RGM are funded partly by the Agency for Healthcare Research and Quality (R18HS18339) and AcademyHealth Delivery System Science Fellowship (2013), respectively. No competing interests declared. Additional data are available from mccoy.rozalina@mayo.edu. PMID- 26646054 TI - Correlates of Problem Drinking and Drug Use in Black Sexual Assault Victims. AB - Few studies have examined factors related to problem drinking and drug use in Black sexual assault victims. Given that sexual assault and histories of trauma are associated with substance abuse in victims, research is needed to determine what factors may be related to these outcomes for Black survivors. Furthermore, child sexual abuse (CSA) is a risk factor for substance abuse, but no studies have examined correlates of substance abuse outcomes separately according to CSA history. This study examines a large diverse sample of Black sexual assault victims (N = 495) to determine the associations of demographics, trauma history, assault characteristics, and postassault psychosocial factors with problem drinking and drug use using multivariate regressions. Traumatic life events, using substances to cope and self-blame, were associated with greater problem drinking and drug use. Implications for practitioners and policymakers are discussed. PMID- 26646055 TI - A multidomain cascade model of early childhood risk factors associated with oppositional defiant disorder symptoms in a community sample of 6-year-olds. AB - The present study examined a cascade model of age 4 and 5 contextual, parent, parenting, and child factors on symptoms of oppositional defiant disorder (ODD) at age 6 in a diverse community sample of 796 children. Contextual factors include socioeconomic status, family stress, and conflict; parent factors included parental depression; parenting factors included parental hostility, support, and scaffolding skills; child factors included child effortful control (EC), negative affect (NA), and sensory regulation. Direct effects of age 5 conflict, hostility, scaffolding, EC, and NA were found. Significant indirect, cascading effects on age 6 ODD symptom levels were noted for age 4 socioeconomic status via age 5 conflict and scaffolding skills; age 4 parental depression via age 5 child NA; age 4 parental hostility and support via age 5 EC; age 4 support via age 5 EC; and age 4 attachment via age 5 EC. Parenting contributed to EC, and the age 5 EC effects on subsequent ODD symptom levels were distinct from age 5 parental contributions. Scaffolding and ODD symptoms may have a reciprocal relationship. These results highlight the importance of using a multidomain model to examine factors associated with ODD symptoms early in the child's grammar school years. PMID- 26646056 TI - 4-Alkyl-3,5-difluorophenyl-Substituted Benzodithiophene-Based Wide Band Gap Polymers for High-Efficiency Polymer Solar Cells. AB - Two novel polymers PTFBDT-BZS and PTFBDT-BZO with 4-alkyl-3,5-difluorophenyl substituted benzodithiophene as the donor unit, benzothiadiazole or benzooxadiazole as the acceptor unit, and thiophene as the spacer have been synthesized and used as donor materials for polymer solar cells (PSCs). These two polymers exhibited wide optical band gaps of about 1.8 eV. PSCs with the blend of PTFBDT-BZS:PC71BM (1:2, by weight) as the active layer fabricated without using any processing additive and any postannealing treatment showed power conversion efficiency (PCE) of 8.24% with an open circuit voltage (Voc) of 0.89 V, a short circuit current (Jsc) of 12.67 mA/cm(2), and a fill factor (FF) of 0.73 under AM 1.5G illumination, indicating that PTFBDT-BZS is a very promising donor polymer for PSCs. The blend of PTFBDT-BZO:PC71BM showed a lower PCE of 5.67% with a Voc of 0.96 V, a Jsc of 9.24 mA/cm(2), and an FF of 0.64. One reason for the lower PCE is probably due to that PTFBDT-BZO has a smaller LUMO offset with PC71BM, which cannot provide enough driving force for charge separation. And another reason is probably due to that PTFBDT-BZO has a lower hole mobility in comparison with PTFBDT-BZS. PMID- 26646057 TI - Synthetic microfluidic paper: high surface area and high porosity polymer micropillar arrays. AB - We introduce Synthetic Microfluidic Paper, a novel porous material for microfluidic applications that consists of an OSTE polymer that is photostructured in a well-controlled geometry of slanted and interlocked micropillars. We demonstrate the distinct benefits of Synthetic Microfluidic Paper over other porous microfluidic materials, such as nitrocellulose, traditional paper and straight micropillar arrays: in contrast to straight micropillar arrays, the geometry of Synthetic Microfluidic Paper was miniaturized without suffering capillary collapse during manufacturing and fluidic operation, resulting in a six-fold increased internal surface area and a three-fold increased porous fraction. Compared to commercial nitrocellulose materials for capillary assays, Synthetic Microfluidic Paper shows a wider range of capillary pumping speed and four times lower device-to-device variation. Compared to the surfaces of the other porous microfluidic materials that are modified by adsorption, Synthetic Microfluidic Paper contains free thiol groups and has been shown to be suitable for covalent surface chemistry, demonstrated here for increasing the material hydrophilicity. These results illustrate the potential of Synthetic Microfluidic Paper as a porous microfluidic material with improved performance characteristics, especially for bioassay applications such as diagnostic tests. PMID- 26646058 TI - Can selection for resistance to OsHV-1 infection modify susceptibility to Vibrio aestuarianus infection in Crassostrea gigas? First insights from experimental challenges using primary and successive exposures. AB - Since 2008, the emergent virus OsHV-1uvar has provoked massive mortality events in Crassostrea gigas spat and juveniles in France. Since 2012, mortality driven by the pathogenic bacteria Vibrio aestuarianus has stricken market-sized adults. A hypothesis to explain the sudden increase in mortality observed in France since 2012 is that selective pressure due to recurrent viral infections could have led to a higher susceptibility of adults to Vibrio infection. In our study, two OsHV 1-resistant lines (AS and BS) and their respective controls (AC and BC) were experimentally challenged in the laboratory to determine their level of susceptibility to V. aestuarianus infection. At the juvenile stage, the selected lines exhibited lower mortality (14 and 33%) than the control lines (71 and 80%), suggesting dual-resistance to OsHV-1 and V. aestuarianus in C. gigas. Interestingly, this pattern was not observed at the adult stage, where higher mortality was detected for AS (68%) and BC (62%) than AC (39%) and BS (49%). These results were confirmed by the analysis of the expression of 31 immune related genes in unchallenged oysters. Differential gene expression discriminated oysters according to their susceptibility to infection at both the juvenile and adult stages, suggesting that resistance to V. aestuarianus infection resulted in complex interactions between the genotype, stage of development and immunity status. Finally, survivors of the V. aestuarianus challenge at the juvenile stage still exhibited significant mortality at the adult stage during a second and third V. aestuarianus challenge, indicating that these survivors were not genetically resistant. PMID- 26646059 TI - A DNA-based system for selecting and displaying the combined result of two input variables. AB - Oligonucleotide-based technologies for biosensing or bio-regulation produce huge amounts of rich high-dimensional information. There is a consequent need for flexible means to combine diverse pieces of such information to form useful derivative outputs, and to display those immediately. Here we demonstrate this capability in a DNA-based system that takes two input numbers, represented in DNA strands, and returns the result of their multiplication, writing this as a number in a display. Unlike a conventional calculator, this system operates by selecting the result from a library of solutions rather than through logic operations. The multiplicative example demonstrated here illustrates a much more general capability--to generate a unique output for any distinct pair of DNA inputs. The system thereby functions as a lookup table and could be a key component in future, more powerful data-processing systems for diagnostics and sensing. PMID- 26646060 TI - Resilin-PEG Hybrid Hydrogels Yield Degradable Elastomeric Scaffolds with Heterogeneous Microstructure. AB - Hydrogels derived from resilin-like polypeptides (RLPs) have shown outstanding mechanical resilience and cytocompatibility; expanding the versatility of RLP based materials via conjugation with other polypeptides and polymers would offer great promise in the design of a range of materials. Here, we present an investigation of the biochemical and mechanical properties of hybrid hydrogels composed of a recombinant RLP and a multiarm PEG macromer. These hybrid hydrogels can be rapidly cross-linked through a Michael-type addition reaction between the thiols of cysteine residues on the RLP and vinyl sulfone groups on the multiarm PEG. Oscillatory rheology and tensile testing confirmed the formation of elastomeric hydrogels with mechanical resilience comparable to aortic elastin; hydrogel stiffness was easily modulated through the cross-linking ratio. Macromolecular phase separation of the RLP-PEG hydrogels offers the unique advantage of imparting a heterogeneous microstructure, which can be used to localize cells, through simple mixing and cross-linking. Assessment of degradation of the RLP by matrix metalloproteinases (MMPs) illustrated the specific proteolysis of the polypeptide in both its soluble form and when cross linked into hydrogels. Finally, the successful encapsulation and viable three dimensional culture of human mesenchymal stem cells (hMSCs) demonstrated the cytocompatibility of the RLP-PEG gels. Overall, the cytocompatibility, elastomeric mechanical properties, microheterogeneity, and degradability of the RLP-PEG hybrid hydrogels offer a suite of promising properties for the development of cell-instructive, structured tissue engineering scaffolds. PMID- 26646061 TI - Comprehensive motion-compensated highly accelerated 4D flow MRI with ferumoxytol enhancement for pediatric congenital heart disease. AB - PURPOSE: To develop and evaluate motion-compensation and compressed-sensing techniques in 4D flow MRI for anatomical assessment in a comprehensive ferumoxytol-enhanced congenital heart disease (CHD) exam. MATERIALS AND METHODS: A Cartesian 4D flow sequence was developed to enable intrinsic navigation and two variable-density sampling schemes: VDPoisson and VDRad. Four compressed-sensing methods were developed: A) VDPoisson scan reconstructed using spatial wavelets; B) added temporal total variation to A; C) VDRad scan using the same reconstruction as in B; and D) added motion compensation to C. With Institutional Review Board (IRB) approval and Health Insurance Portability and Accountability Act (HIPAA) compliance, 23 consecutive patients (eight females, mean 6.3 years) referred for ferumoxytol-enhanced CHD 3T MRI were recruited. Images were acquired and reconstructed using methods A-D. Two cardiovascular radiologists independently scored the images on a 5-point scale. These readers performed a paired wall motion and functional assessment between method D and 2D balanced steady-state free precession (bSSFP) CINE for 16 cases. RESULTS: Method D had higher diagnostic image quality for most anatomical features (mean 3.8-4.8) compared to A (2.0-3.6), B (2.2-3.7), and C (2.9-3.9) with P < 0.05 with good interobserver agreement (kappa >= 0.49). Method D had similar or better assessment of myocardial borders and cardiac motion compared to 2D bSSFP (P < 0.05, kappa >= 0.77). All methods had good internal agreement in comparing aortic with pulmonic flow (BA mean < 0.02%, r > 0.85) and compared to method A (BA mean < 0.13%, r > 0.84) with P < 0.01. CONCLUSION: Flow, functional, and anatomical assessment in CHD with ferumoxytol-enhanced 4D flow is feasible and can be significantly improved using motion compensation and compressed sensing. J. Magn. Reson. Imaging 2016;43:1355-1368. PMID- 26646068 TI - Advanced glycation end products upregulate lysyl oxidase and endothelin-1 in human aortic endothelial cells via parallel activation of ERK1/2-NF-kappaB and JNK-AP-1 signaling pathways. AB - Endothelial dysfunction involves deregulation of the key extracellular matrix (ECM) enzyme lysyl oxidase (LOX) and the vasoconstrictor protein, endothelin-1 (ET-1), whose gene expression can be modulated by the transcriptional activators nuclear factor kappa B (NF-kappaB) and activator protein-1 (AP-1). Advanced glycation end products (AGEs) present an aggravating factor of endothelial dysfunction which upon engagement to their receptor RAGE induce upregulation of mitogen-activated protein kinases (MAPKs), leading to NF-kappaB and AP-1 potentiation. We hypothesized that AGEs could induce NF-kappaBeta- and AP-1 dependent regulation of LOX and ET-1 expression via the AGE/RAGE/MAPK signaling axis. Western blot, real-time qRT-PCR, FACS analysis and electrophoretic mobility shift assays were employed in human aortic endothelial cells (HAECs) following treatment with AGE-bovine serum albumin (AGE-BSA) to investigate the signaling pathway towards this hypothesis. Furthermore, immunohistochemical analysis of AGEs, RAGE, LOX and ET-1 expression was conducted in aortic endothelium of a rat experimental model exposed to high- or low-AGE content diet. HAECs exposed to AGE BSA for various time points exhibited upregulation of LOX and ET-1 mRNA levels in a dose- and time-dependent manner. Exposure of HAECs to AGE-BSA also showed specific elevation of phospho(p)-ERK1/2 and p-JNK levels in a dose- and time dependent fashion. AGE administration significantly increased NF-kappaBeta- and AP-1-binding activity to both LOX and ET-1 cognate promoter regions. Moreover, LOX and ET-1 overexpression in rat aortic endothelium upon high-AGE content diet confirmed the functional interrelation of these molecules. Our findings demonstrate that AGEs trigger NF-kappaBeta- and AP-1-mediated upregulation of LOX and ET-1 via the AGE/RAGE/MAPK signaling cascade in human endothelial cells, thus contributing to distorted endothelial homeostasis by impairing endothelial barrier function, altering ECM biomechanical properties and cell proliferation. PMID- 26646070 TI - Physical exercise, neuroplasticity, spatial learning and memory. AB - There has long been discussion regarding the positive effects of physical exercise on brain activity. However, physical exercise has only recently begun to receive the attention of the scientific community, with major interest in its effects on the cognitive functions, spatial learning and memory, as a non-drug method of maintaining brain health and treating neurodegenerative and/or psychiatric conditions. In humans, several studies have shown the beneficial effects of aerobic and resistance exercises in adult and geriatric populations. More recently, studies employing animal models have attempted to elucidate the mechanisms underlying neuroplasticity related to physical exercise-induced spatial learning and memory improvement, even under neurodegenerative conditions. In an attempt to clarify these issues, the present review aims to discuss the role of physical exercise in the improvement of spatial learning and memory and the cellular and molecular mechanisms involved in neuroplasticity. PMID- 26646069 TI - Metabolic changes associated with tumor metastasis, part 2: Mitochondria, lipid and amino acid metabolism. AB - Metabolic alterations are a hallmark of cancer controlling tumor progression and metastasis. Among the various metabolic phenotypes encountered in tumors, this review focuses on the contributions of mitochondria, lipid and amino acid metabolism to the metastatic process. Tumor cells require functional mitochondria to grow, proliferate and metastasize, but shifts in mitochondrial activities confer pro-metastatic traits encompassing increased production of mitochondrial reactive oxygen species (mtROS), enhanced resistance to apoptosis and the increased or de novo production of metabolic intermediates of the TCA cycle behaving as oncometabolites, including succinate, fumarate, and D-2 hydroxyglutarate that control energy production, biosynthesis and the redox state. Lipid metabolism and the metabolism of amino acids, such as glutamine, glutamate and proline are also currently emerging as focal control points of cancer metastasis. PMID- 26646072 TI - Cost-Effectiveness of Sensor-Augmented Pump Therapy with Low Glucose Suspend Versus Standard Insulin Pump Therapy in Two Different Patient Populations with Type 1 Diabetes in France. AB - BACKGROUND: Sensor-augmented pump therapy (SAP) provides a useful adjunct relative to continuous subcutaneous insulin infusion (CSII) alone. It can provide early warning of the onset of hyperglycemia and hypoglycemia and has the functionality to suspend insulin delivery if sensor glucose levels fall below a predefined threshold. The aim was to assess the cost-effectiveness of SAP with low glucose suspend (LGS) versus CSII alone in type 1 diabetes. MATERIALS AND METHODS: Cost-effectiveness analysis was performed using the CORE Diabetes Model, using published clinical input data. The analysis was performed in two cohorts: one with uncontrolled glycated hemoglobin at baseline and one at elevated risk for hypoglycemic events. The analysis was conducted from a healthcare payer perspective over a lifetime time horizon; future costs and clinical outcomes were discounted at 4% per annum. RESULTS: In patients with uncontrolled glycated hemoglobin at baseline, SAP + LGS resulted in improved discounted quality adjusted life expectancy (QALE) versus CSII (10.55 quality-adjusted life-years [QALYs] vs. 9.36 QALYs) but higher mean lifetime direct costs (?84,972 vs. ?49,171) resulting in an incremental cost-effectiveness ratio (ICER) of ?30,163 per QALY gained. In patients at elevated risk for hypoglycemia, the ICER was ?22,005 per QALY gained for SAP + LGS versus CSII as lifetime costs were higher (?88,680 vs. ?57,097), but QALE was also higher (18.46 QALYs vs. 18.30 QALYs). CONCLUSIONS: In France, projected improvements in outcomes with SAP + LGS versus CSII translated into an ICER generally considered as good value for money, particularly in patients who experience frequent and/or problematic hypoglycemic events. PMID- 26646073 TI - New mechanistic insight into intramolecular arene hydroxylation initiated by (MU 1,2-peroxo)diiron(III) complexes with dinucleating ligands. AB - (MU-1,2-Peroxo)diiron(iii) complexes (-R) with dinucleating ligands (R-L) generated from the reaction of bis(MU-hydroxo)diiron(ii) complexes [Fe2(R L)(OH)2](2+) (-R) with dioxygen in acetone at -20 degrees C provide a diiron centred electrophilic oxidant, presumably diiron(iv)-oxo species, which is involved in aromatic ligand hydroxylation. PMID- 26646071 TI - Endoglin regulates mural cell adhesion in the circulatory system. AB - The circulatory system is walled off by different cell types, including vascular mural cells and podocytes. The interaction and interplay between endothelial cells (ECs) and mural cells, such as vascular smooth muscle cells or pericytes, play a pivotal role in vascular biology. Endoglin is an RGD-containing counter receptor for beta1 integrins and is highly expressed by ECs during angiogenesis. We find that the adhesion between vascular ECs and mural cells is enhanced by integrin activators and inhibited upon suppression of membrane endoglin or beta1 integrin, as well as by addition of soluble endoglin (SolEng), anti-integrin alpha5beta1 antibody or an RGD peptide. Analysis of different endoglin mutants, allowed the mapping of the endoglin RGD motif as involved in the adhesion process. In Eng (+/-) mice, a model for hereditary hemorrhagic telangectasia type 1, endoglin haploinsufficiency induces a pericyte-dependent increase in vascular permeability. Also, transgenic mice overexpressing SolEng, an animal model for preeclampsia, show podocyturia, suggesting that SolEng is responsible for podocytes detachment from glomerular capillaries. These results suggest a critical role for endoglin in integrin-mediated adhesion of mural cells and provide a better understanding on the mechanisms of vessel maturation in normal physiology as well as in pathologies such as preeclampsia or hereditary hemorrhagic telangiectasia. PMID- 26646074 TI - Effects of baby massage on neonatal jaundice in healthy Iranian infants: A pilot study. AB - OBJECTIVE: To evaluate the effects of baby massage on transcutaneous bilirubin levels and stool frequency of healthy term newborns. METHODS: This Pilot study was conducted on 50 healthy newborns in Valiasr Hospital of IKHC. The infants were randomly allocated to two treatment (massage) and control group. The massage group received massage therapy (according to Touch Therapy) for four days from the first day postnatal while the control group received routine care. Main variable studied were transcutaneous bilirubin level (TCB) and stool frequency which were compared in two groups. RESULTS: There were 50 newborns in the study 25 in each group (50%). There was a significant difference in the TCB levels between two groups (p=0.000) with those in the massage group having lower bilirubin levels. As for the stool frequency there was a significant difference in two groups on the first day showing more defecation in the control group (p=0.042) which on the consequent days was not significant and the frequencies were almost similar. CONCLUSION: Massage group had a lower transcutaneous billirubin levels compared to the control group, thus, these pilot results indicate that massaging the newborns can be accompanied by a lower bilirubin level in the healthy term newborn. PMID- 26646076 TI - Motor Learning Unfolds over Different Timescales in Distinct Neural Systems. PMID- 26646077 TI - Impact of high-frequency ultrasound on nanocomposite microcapsules: in silico and in situ visualization. AB - The impact of high-frequency (1.2 MHz) ultrasound with a power density of 0.33 W cm(-2) on microcapsule nanocomposite shells with embedded zinc oxide nanoparticles was investigated by exploring modeling simulations and direct visualization. For the first time the sonication effect has been monitored in situ on individual microcapsules upon exposure of their aqueous suspension to ultrasound. The stress distribution on the microcapsule shell for the impact of ultrasound with high (1.2 MHz) and low (20 kHz) frequency at two fixed intensities (0.33 and 30 W cm(-2)) has been modeled. As shown in silico and experimentally the nanocomposite microcapsules were destroyed more effectively by the action of high-frequency (1.2 MHz) ultrasound in comparison to the low frequency (20 kHz) one with the same power density. PMID- 26646075 TI - Advances in the treatment of newly diagnosed glioblastoma. AB - Glioblastoma is a refractory malignancy with limited treatment options at tumor recurrence. Only a small proportion of patients survive 2 years or longer with the current standard of care. Gene expression profiling can segregate newly diagnosed patients into groups with different prognoses, and these biomarkers are being incorporated into a new generation of personalized clinical trials. Using the experience from recently completed large scale, multi-faceted, randomized glioblastoma clinical trials, a new clinical trial paradigm is being established to move promising therapies forward into the newly diagnosed treatment setting. Upcoming trials using the immune check-point inhibitors are an example of this changing paradigm and these and other immunotherapies have potential as promising new treatment modalities for newly diagnosed GB patients. PMID- 26646078 TI - Determinants of frequency-dependent regulation of Kv1.2-containing potassium channels. AB - Voltage-gated potassium channels are important regulators of electrical excitation in many tissues, with Kv1.2 standing out as an essential contributor in the CNS. Genetic deletion of Kv1.2 invariably leads to early lethality in mice. In humans, mutations affecting Kv1.2 function are linked to epileptic encephalopathy and movement disorders. We have demonstrated that Kv1.2 is subject to a unique regulatory mechanism in which repetitive stimulation leads to dramatic potentiation of current. In this study, we explore the properties and molecular determinants of this use-dependent potentiation/activation. First, we examine how alterations in duty cycle (depolarization and repolarization/recovery times) affect the onset and extent of use-dependent activation. Also, we use trains of repetitive depolarizations to test the effects of a variety of Thr252 (S2-S3 linker) mutations on use-dependent activation. Substitutions of Thr with some sterically similar amino acids (Ser, Val, and Met, but not Cys) retain use dependent activation, while bulky or charged amino acid substitutions eliminate use-dependence. Introduction of Thr at the equivalent position in other Kv1 channels (1.1, 1.3, 1.4), was not sufficient to transfer the phenotype. We hypothesize that use-dependent activation of Kv1.2 channels is mediated by an extrinsic regulator that binds preferentially to the channel closed state, with Thr252 being necessary but not sufficient for this interaction to alter channel function. These findings extend the conclusions of our recent demonstration of use-dependent activation of Kv1.2-containing channels in hippocampal neurons, by adding new details about the molecular mechanism underlying this effect. PMID- 26646086 TI - [Austerity and healthcare privatization in times of crisis: are there any differences among autonomous communities?]. AB - OBJECTIVE: To analyse the differences between autonomous communities in Spain according to their policies of austerity and healthcare privatization during the economic crisis. METHODS: Changes in the application of legal reforms, healthcare privatization and healthcare financing/resources in the autonomous communities were analysed, and a summary indicator of each dimension was constructed. RESULTS: The Basque Country showed the clearest behaviour towards a weak policy of austerity and privatization, as opposed to La Rioja, Madrid, and the Balearic Islands. CONCLUSIONS: The three classifications will enable analysis of the mediating effect of policies of austerity and privatization in the relationship between the economic crisis and health in the Spanish context. PMID- 26646087 TI - Synthesis of glycoaminooxy acid and N-oxyamide-linked glycolipids. AB - Aminooxyl sugar derivatives are versatile building blocks for the generation of various glycoconjugates with interesting bioactivities. We report herein a synthetic method for the preparation of orthogonally protected glycoaminooxy acid from methyl alpha-d-glycopyranoside in 7 steps. The key steps involve the selective protection, O-alkylation and Mitsunobu reaction. Fully deprotected N oxyamide-linked novel glycolipids can be easily generated from the glycoaminooxy ester or from the 2-hydroxy free sugar in 5 or 6 steps. PMID- 26646088 TI - Efficacy of tightening of orbicularis oculi muscle in patients with functional nasolacrimal duct obstruction. AB - PURPOSE: To evaluate the efficacy of tightening of lateral portion of orbicularis oculi muscle in patients with functional nasolacrimal duct obstruction (FNLDO). METHODS: This is an interventional cross-section study for evaluation of effect of orbicularis oculi tightening procedure in patients with FNLDO. Patients with unexplained epiphora, open lacrimal system in syringing and evidences of lacrimal pump weakness in lacrimal scintigraphy underwent surgery. In this procedure, a stripe of preseptal and pretarsal orbicularis muscle was dissected, slightly resected and secured to the periosteum of lateral orbital rim. Each subject completed a questionnaire about the intensity of epiphora before surgery and 1, 3 and 6 months after surgery. Furthermore, fluorescein dye disappearance test (FDDT) was performed before surgery and repeated in the follow-up visits. At last visit, the pre- and post-operative data were analyzed and compared. RESULTS: Fifteen eyes of 12 patients (5 males and 7 females) with the mean age of 56.7 years included in the study. Severity of epiphora and tearing effect on daily life were significantly improved following the operation. FDDT result was improved significantly after 1 month follow-up in all eyes (15 eyes), at 3 months follow-up in 80% of eyes (12 eyes) and at the end of the 6th month in 66.7% of eyes (10 eyes). Subjective and objective success rates were 87% and 80%, respectively. No significant complications or side-effects were observed. CONCLUSION: Tightening of lateral portion of preseptal and pretarsal orbicularis muscle seems an effective, safe, and easy procedure to decrease epiphora in patients with FNLDO. PMID- 26646089 TI - Cu-Catalyzed Transformation of Alkynes and Alkenes with Azide and Dimethyl Sulfoxide Reagents. AB - A novel and efficient Cu-catalyzed nitrogenation of alkynes and alkenes for the direct synthesis of sulfur-containing triazoles is described. Simple and readily available sulfoxides and azides are employed as the S- and N-source to prepare highly value N-,S-containing compounds from simple alkynes and alkenes. PMID- 26646090 TI - ASCO 2015 update on gastrointestinal cancer: Checkpoint inhibition, multimodality strategies and secondary prevention. PMID- 26646091 TI - Dose-related efficacy and toxicity of gemtuzumab ozogamicin in pediatric acute myeloid leukemia. AB - Gemtuzumab ozogamicin, an anti-tumour antibiotic linked to an anti-CD33 antibody (Mylotarg(r)), has been well studied in AML in adults but to a lesser extent in children. No review has yet been published on the dose-related toxicity and efficacy of gemtuzumab ozogamicin in pediatric AML patients. Here we looked at 14 studies then scatterplots and linear regressions were used to estimate the relationship between the dose of gemtuzumab and its toxicity and efficacy. A non significant increase in bilirubin level and in incidence of veno-occlusive disease was seen with higher doses of gemtuzumab ozogamicin when used as single agent. In terms of efficacy, even a low dose of 3 mg/m(2) of gemtuzumab ozogamicin can have antileukemic effect, but available data do not allow conclusions on its dose-dependency. Data indicate that higher doses of gemtuzumab ozogamicin account for more adverse events. The data do not show that a high dose is required for anti-leukemic efficacy of gemtuzumab ozogamicin. This study also indicates that there seems to be a role for gemtuzumab ozogamicin in the treatment of pediatric AML and further studies are required to assess its optimal dose, schedule and balance between efficacy and side-effects. PMID- 26646092 TI - Editorial: Is There a Crisis in Neonatal Nursing? PMID- 26646093 TI - Corrigendum. PMID- 26646096 TI - Carboxypeptidase E and Secretogranin III Coordinately Facilitate Efficient Sorting of Proopiomelanocortin to the Regulated Secretory Pathway in AtT20 Cells. AB - Proopiomelanocortin (POMC) is a multivalent prohormone that can be processed into at least 7 biologically active peptide hormones. Processing can begin in the trans-Golgi network (TGN) and continues in the secretory granules of the regulated secretory pathway (RSP). Sorting of POMC into these granules is a complex process. Previously, a membrane-associated form of carboxypeptidase E (CPE) was shown to bind to POMC and facilitate its trafficking into these granules. More recently, secretogranin III (SgIII) was also found to affect POMC trafficking. Here, we show by RNA silencing that CPE and SgIII play a synergistic role in the trafficking of POMC to granules of the RSP in AtT20 cells. Reduction of either protein resulted in increased constitutive secretion of POMC and chromogranin A, which was increased even further when both proteins were reduced together, indicative of missorting at the TGN. In SgIII-reduced cells, POMC accumulated in a compartment that cofractionated and colocalized with syntaxin 6, a marker of the TGN, on sucrose density gradients and in immunocytochemistry, respectively, indicating an accumulation of this protein in the presumed sorting compartment. Regulated secretion of ACTH, as a measure of sorting and processing of POMC in mature granules, was reduced in the SgIII down-regulated cells but was increased in the CPE down-regulated cells. These results suggest that multiple sorting systems exist, providing redundancy to ensure the important task of continuous and accurate trafficking of prohormones to the granules of the RSP for the production of peptide hormones. PMID- 26646097 TI - Brain-liver connections: role of the preautonomic PVN neurons. AB - Diabetes mellitus and the coexisting conditions and complications, including hypo and hyperglycemic events, obesity, high cholesterol levels, and many more, are devastating problems. Undoubtedly, there is a huge demand for treatment and prevention of these conditions that justifies the search for new approaches and concepts for better management of whole body metabolism. Emerging evidence demonstrates that the autonomic nervous system is largely involved in the regulation of glucose homeostasis; however, the underlying mechanisms are still under investigation. Within the hypothalamus, the paraventricular nucleus (PVN) is in a unique position to integrate neural and hormonal signals to command both the autonomic and neuroendocrine outflow. This minireview will provide a brief overview on the role of preautonomic PVN neurons and the importance of the PVN liver pathway in the regulation of glucose homeostasis. PMID- 26646098 TI - A novel mechanism of action for salidroside to alleviate diabetic albuminuria: effects on albumin transcytosis across glomerular endothelial cells. AB - Salidroside (SAL) is a phenylethanoid glycoside isolated from the medicinal plant Rhodiola rosea. R. rosea has been reported to have beneficial effects on diabetic nephropathy (DN) and high-glucose (HG)-induced mesangial cell proliferation. Given the importance of caveolin-1 (Cav-1) in transcytosis of albumin across the endothelial barrier, the present study was designed to elucidate whether SAL could inhibit Cav-1 phosphorylation and reduce the albumin transcytosis across glomerular endothelial cells (GECs) to alleviate diabetic albuminuria as well as to explore its upstream signaling pathway. To assess the therapeutic potential of SAL and the mechanisms involved in DN albuminuria, we orally administered SAL to db/db mice, and the effect of SAL on the albuminuria was measured. The albumin transcytosis across GECs was explored in a newly established in vitro cellular model. The ratio of albumin to creatinine was significantly reduced upon SAL treatment in db/db mice. SAL decreased the albumin transcytosis across GECs in both normoglycemic and hyperglycemic conditions. SAL reversed the HG-induced downregulation of AMP-activated protein kinase and upregulation of Src kinase and blocked the upregulation Cav-1 phosphorylation. Meanwhile, SAL decreased mitochondrial superoxide anion production and moderately depolarized mitochondrial membrane potential. We conclude that SAL exerts its proteinuria alleviating effects by downregulation of Cav-1 phosphorylation and inhibition of albumin transcytosis across GECs. These studies provide the first evidence of interference with albumin transcytosis across GECs as a novel approach to the treatment of diabetic albuminuria. PMID- 26646099 TI - Zinc transporter Slc39a14 regulates inflammatory signaling associated with hypertrophic adiposity. AB - Zinc is a signaling molecule in numerous metabolic pathways, the coordination of which occurs through activity of zinc transporters. The expression of zinc transporter Zip14 (Slc39a14), a zinc importer of the solute carrier 39 family, is stimulated under proinflammatory conditions. Adipose tissue upregulates Zip14 during lipopolysaccharide-induced endotoxemia. A null mutation of Zip14 (KO) revealed that phenotypic changes in adipose include increased cytokine production, increased plasma leptin, hypertrophied adipocytes, and dampened insulin signaling. Adipose tissue from KO mice had increased levels of preadipocyte markers, lower expression of the differentiation marker (PPARgamma), and activation of NF-kappaB and STAT3 pathways. Our overall hypothesis was that ZIP14 would play a role in adipocyte differentiation and inflammatory obesity. Global Zip14 KO causes systemic endotoxemia. The observed metabolic changes in adipose metabolism were reversed when oral antibiotics were administrated, indicating that circulating levels of endotoxin were in part responsible for the adipose phenotype. To evaluate a mechanism, 3T3-L1 cells were differentiated into adipocytes and treated with siRNA to knock down Zip14. These cells had an impaired ability to mobilize zinc, which caused dysregulation of inflammatory pathways (JAK2/STAT3 and NF-kappaB). The Zip14 deletion may limit the availability of intracellular zinc, yielding the unique phenotype of inflammation coupled with hypertrophy. Taken together, these results suggest that aberrant zinc distribution observed with Zip14 ablation impacts adipose cytokine production and metabolism, ultimately increasing fat deposition when exposed to endotoxin. To our knowledge, this is the first investigation into the mechanistic role of ZIP14 in adipose tissue regulation and metabolism. PMID- 26646100 TI - Developmental programming: interaction between prenatal BPA exposure and postnatal adiposity on metabolic variables in female sheep. AB - Among potential contributors for the increased incidence of metabolic diseases is the developmental exposure to endocrine-disrupting chemicals such as bisphenol A (BPA). BPA is an estrogenic chemical used in a variety of consumer products. Evidence points to interactions of BPA with the prevailing environment. The aim of this study was to assess the effects of prenatal exposure to BPA on postnatal metabolic outcomes, including insulin resistance, adipose tissue distribution, adipocyte morphometry, and expression of inflammatory markers in adipose tissue as well as to assess whether postnatal overfeeding would exacerbate these effects. Findings indicate that prenatal BPA exposure leads to insulin resistance in adulthood in the first breeder cohort (study 1), but not in the second cohort (study 2), which is suggestive of potential differences in genetic susceptibility. BPA exposure induced adipocyte hypertrophy in the visceral fat depot without an accompanying increase in visceral fat mass or increased CD68, a marker of macrophage infiltration, in the subcutaneous fat depot. Cohens effect size analysis found the ratio of visceral to subcutaneous fat depot in the prenatal BPA-treated overfed group to be higher compared with the control-overfed group. Altogether, these results suggest that exposure to BPA during fetal life at levels found in humans can program metabolic outcomes that lead to insulin resistance, a forerunner of type 2 diabetes, with postnatal obesity failing to manifest any interaction with prenatal BPA relative to insulin resistance and adipocyte hypertrophy. PMID- 26646101 TI - Effects of ovariectomy and intrinsic aerobic capacity on tissue-specific insulin sensitivity. AB - High-capacity running (HCR) rats are protected against the early (i.e., ~ 11 wk postsurgery) development of ovariectomy (OVX)-induced insulin resistance (IR) compared with low-capacity running (LCR) rats. The purpose of this study was to utilize the hyperinsulinemic euglycemic clamp to determine whether 1) HCR rats remain protected from OVX-induced IR when the time following OVX is extended to 27 wk and 2) tissue-specific glucose uptake differences are responsible for the protection in HCR rats under sedentary conditions. Female HCR and LCR rats (n = 40; aged ~ 22 wk) randomly received either OVX or sham (SHM) surgeries and then underwent the clamp 27 wk following surgeries. [3-(3)H]glucose was used to determine glucose clearance, whereas 2-[(14)C]deoxyglucose (2-DG) was used to assess glucose uptake in skeletal muscle, brown adipose tissue (BAT), subcutaneous white adipose tissue (WAT), and visceral WAT. OVX decreased the glucose infusion rate and glucose clearance in both lines, but HCR had better insulin sensitivity than LCR (P < 0.05). In both lines, OVX significantly reduced glucose uptake in soleus and gastrocnemius muscles; however, HCR showed ~ 40% greater gastrocnemius glucose uptake compared with LCR (P < 0.05). HCR also exhibited greater glucose uptake in BAT and visceral WAT compared with LCR (P < 0.05), yet these tissues were not affected by OVX in either line. In conclusion, OVX impairs insulin sensitivity in both HCR and LCR rats, likely driven by impairments in insulin-mediated skeletal muscle glucose uptake. HCR rats have greater skeletal muscle, BAT, and WAT insulin-mediated glucose uptake, which may aid in protection against OVX-associated insulin resistance. PMID- 26646103 TI - Deletion of the gene family of small chlorophyll-binding proteins (ScpABCDE) offsets C/N homeostasis in Synechocystis PCC 6803. AB - In the family of chlorophyll binding proteins, single helix small CAB-like proteins (SCPs) are found in all organisms performing oxygenic photosynthesis. Here, we investigated the function of these stress-inducible proteins in the cyanobacterium Synechocystis sp. PCC 6803. We compared physiological, proteome and transcriptome traits of a Photosystem I (PSI) deletion strain, which constitutively induces SCPs, and a PSI-less/ScpABCDE(-) without SCPs. The SCP mutant cells were larger in size, showed irregular thylakoid structure and differed in cell-surface morphology. Deletion of scp genes strongly affected the carbon (C) and nitrogen (N) balance, resulting in accumulation of carbohydrates and a decrease in N-rich compounds (proteins and chlorophyll). Data from transcriptomic and metabolomic experiments revealed a role of SCPs in the control of chlorophyll biosynthesis. Additionally, SCPs diminished formation of reactive oxygen species, thereby preventing damage within Photosystem II. We conclude that the lack of SCP-function to remove free chlorophyll under stress conditions has a large impact on the metabolism of the entire cell. PMID- 26646102 TI - A 9-wk docosahexaenoic acid-enriched supplementation improves endurance exercise capacity and skeletal muscle mitochondrial function in adult rats. AB - Decline in skeletal muscle mass and function starts during adulthood. Among the causes, modifications of the mitochondrial function could be of major importance. Polyunsaturated fatty (omega-3) acids have been shown to play a role in intracellular functions. We hypothesize that docosahexaenoic acid (DHA) supplementation could improve muscle mitochondrial function that could contribute to limit the early consequences of aging on adult muscle. Twelve-month-old male Wistar rats were fed a low-polyunsaturated fat diet and were given DHA (DHA group) or placebo (control group) for 9 wk. Rats from the DHA group showed a higher endurance capacity (+56%, P < 0.05) compared with control animals. Permeabilized myofibers from soleus muscle showed higher O2 consumptions (P < 0.05) in the DHA group compared with the control group, with glutamate-malate as substrates, both in basal conditions (i.e., state 2) and under maximal conditions (i.e., state 3, using ADP), along with a higher apparent Km for ADP (P < 0.05). Calcium retention capacity of isolated mitochondria was lower in DHA group compared with the control group (P < 0.05). Phospho-AMPK/AMPK ratio and PPARdelta mRNA content were higher in the DHA group compared with the control group (P < 0.05). Results showed that DHA enhanced endurance capacity in adult animals, a beneficial effect potentially resulting from improvement in mitochondrial function, as suggested by our results on permeabilized fibers. DHA supplementation could be of potential interest for the muscle function in adults and for fighting the decline in exercise tolerance with age that could imply energy-sensing pathway, as suggested by changes in phospho-AMPK/AMPK ratio. PMID- 26646104 TI - Effects and mechanism of miR-23b on glucose-mediated epithelial-to-mesenchymal transition in diabetic nephropathy. AB - MicroRNAs (miRNAs) play important roles in epithelial-to-mesenchymal transition (EMT). Moreover, hyperglycaemia induces damage to renal tubular epithelial cells, which may lead to EMT in diabetic nephropathy. However, the effects of miRNAs on EMT in diabetic nephropathy are poorly understood. In the present study, we found that the level of microRNA-23b (miR-23b) was significantly decreased in high glucose (HG)-induced human kidney proximal tubular epithelial cells (HK2) and in kidney tissues of db/db mice. Overexpression of miR-23b attenuated HG-induced EMT, whereas knockdown of miR-23b induced normal glucose (NG)-mediated EMT in HK2 cells. Mechanistically, miR-23b suppressed EMT in diabetic nephropathy by targeting high mobility group A2 (HMGA2), thereby repressing PI3K-AKT signalling pathway activation. Additionally, HMGA2 knockdown or inhibition of the PI3K-AKT signalling pathway with LY294002 mimicked the effects of miR-23b overexpression on HG-mediated EMT, whereas HMGA2 overexpression or activation of the PI3K-AKT signalling pathway with BpV prevented the effects of miR-23b on HG-mediated EMT. We also confirmed that overexpression of miR-23b alleviated EMT, decreased the expression levels of EMT-related genes, ameliorated renal morphology, glycogen accumulation, fibrotic responses and improved renal functions in db/db mice. Taken together, we showed for the first time that miR-23b acts as a suppressor of EMT in diabetic nephropathy through repressing PI3K-AKT signalling pathway activation by targeting HMGA2, which maybe a potential therapeutic target for diabetes-induced renal dysfunction. PMID- 26646105 TI - Vimentin-mediated regulation of cell motility through modulation of beta4 integrin protein levels in oral tumor derived cells. AB - Vimentin expression correlates well with migratory and invasive potential of the carcinoma cells. The molecular mechanism by which vimentin regulates cell motility is not yet clear. Here, we addressed this issue by depleting vimentin in oral squamous cell carcinoma derived cell line. Vimentin knockdown cells showed enhanced adhesion and spreading to laminin-5. However, we found that they were less invasive as compared to the vector control cells. In addition, signaling associated with adhesion behavior of the cell was increased in vimentin knockdown clones. These findings suggest that the normal function of beta4 integrin as mechanical adhesive device is enhanced upon vimentin downregulation. As a proof of principle, the compromised invasive potential of vimentin depleted cells could be rescued upon blocking with beta4 integrin adhesion-blocking (ASC-8) antibody or downregulation of beta4 integrin in vimentin knockdown background. Interestingly, plectin which associates with alpha6beta4 integrin in the hemidesmosomes, was also found to be upregulated in vimentin knockdown clones. Furthermore, experiments on lysosome and proteasome inhibition revealed that perhaps vimentin regulates the turnover of beta4 integrin and plectin. Moreover, an inverse association was observed between vimentin expression and beta4 integrin in oral squamous cell carcinoma (OSCC). Collectively, our results show a novel role of vimentin in modulating cell motility by destabilizing beta4 integrin-mediated adhesive interactions. Further, vimentin-beta4 integrin together may prove to be useful markers for prognostication of human oral cancer. PMID- 26646106 TI - MiR-103 regulates hepatocellular carcinoma growth by targeting AKAP12. AB - AKAP12/Gravin (A kinase anchor protein 12) belongs to the group of A-kinase scaffold proteins and functions as a tumor suppressor in some human primary cancers. While AKAP12 is found consistently downregulated in hepatocellular carcinoma (HCC), its involvement in hepatocarcinogenesis has not been fully elucidated. We identified targeting sites for miR-103 in the 3'-untranslated region (3'-UTR) of AKAP12 by bioinformatic analysis and confirm their function by a luciferase reporter gene assay. We reveal miR-103 expression to be inversely correlated with AKAP12 in HCC tissue samples and show that overexpressed miR-103 promotes cell proliferation and inhibits apoptosis by downregulating AKAP12 expression in HCC cell lines. On the other hand, repression of miR-103 suppresses proliferation and promotes apoptosis in HCC cells by increasing AKAP12. In xenografted HCC tumors, overexpression of AKAP12 suppresses tumor growth whereas overexpression of miR-103 enhances tumor growth while repressing AKAP12. Since the activation of telomerase is crucial for cells to gain immortality and proliferation ability, we investigated whether AKAP12 expression affected telomerase activity in HCC cells. Both AKAP12 overexpression and protein kinase Calpha (PKCalpha) inhibition prevent nuclear translocation and phosphorylation of TERT and reduce telomerase activity in HCC cells. These findings indicate that miR-103 potentially acts as an oncogene in HCC by inhibiting AKAP12 expression and raise the possibility that miR-103 increases telomerase activity by increasing PKCalpha activity. Thus, miR-103 may represent a new potential diagnostic and therapeutic target for HCC treatment. PMID- 26646107 TI - Outcome of Arthroscopic Treatment of Posterior Impingement of the Ankle. AB - BACKGROUND: Open and arthroscopic techniques have been utilized in the treatment of posterior impingement of the ankle and hindfoot. Because posterior impingement occurs more frequently in patients who repetitively plantarflex the ankle, this population may especially benefit from a procedure that reduces pain and results in maximal range of motion (ROM). The purpose of this study was to assess the outcome of hindfoot endoscopy in patients with posterior ankle impingement through a higher level of function outcome measures and physical examination parameters, focused on analysis of ROM. METHODS: Twenty patients were followed prospectively at a minimum 1-year follow-up (mean 38.2 months). Nineteen of 20 patients were competitive athletes. Patients completed a minimum of 3 months of nonoperative treatment. Diagnoses included os trigonum, tibial exostosis, talar exostosis, loose body or fracture nonunion, and ganglion cyst removal. Patients underwent arthroscopic treatment utilizing a posterior approach; all relevant pathology was addressed. RESULTS: At the most recent follow-up, visual analog scale pain and American Orthopaedic Foot & Ankle Society hindfoot scores showed significant improvement (P < .01) pre- to postoperatively; Tegner score remained unchanged (P = .888). Three patients were professional athletes; all returned to their previous level of professional activity. ROM variables between affected and unaffected sides reached statistical similarity at the most recent follow-up. Only ankle plantarflexion reached statistical significance when compared pre- to postoperatively. Fifteen percent of patients reported postoperative neuritis. CONCLUSIONS: Posterior ankle arthroscopy allowed for maintenance or restoration of anatomic ROM of the ankle and hindfoot, ability to return to at least previous level of activity, and improvement in objective assessment of pain relief and higher level of function parameters. Complications associated with this procedure were minimal. LEVEL OF EVIDENCE: Level IV, retrospective case series. PMID- 26646108 TI - Protein Oleogels from Protein Hydrogels via a Stepwise Solvent Exchange Route. AB - We investigated the use of whey protein isolate (WPI) as oleogelator in liquid oil. First, heat-set WPI hydrogels were prepared varying in microstructure and network density. Then, by applying a stepwise solvent exchange procedure via an intermediate solvent, full replacement of the internal aqueous phase within the protein matrix by sunflower oil was achieved. The solvent exchange procedure was performed by using either acetone or tetrahydrofuran (THF) as intermediate solvent. The oil inside the protein matrix was homogeneously distributed without any noticeable damage to the structure. Analyzing the weight change of the protein gel as a result of the solvent exchange shows that the oil holding capacity depends on the microstructure, the polarity of the intermediate solvent, and the kinetics of the solvent exchange. Depending on the gel microstructure and protein concentration of the preceding hydrogel, the oil content in the oleogels was found to be as high as 91 wt %. Oil holding capacity correlated well with the water holding capacity of the preceding hydrogel, and its Young's modulus (stiffness). It was found that the oleogels, compared to the hydrogels, were much stiffer, as the Young's modulus increased by 2 orders of magnitude and showed a lower strain at fracture. Our novel route of structuring oil by immobilizing liquid oil inside a biodegradable protein gel matrix with tunable mechanical properties could be relevant for developing novel materials, e.g., in pharmaceutical, nutraceutical, and food applications. PMID- 26646109 TI - Community health workers in rural India: analysing the opportunities and challenges Accredited Social Health Activists (ASHAs) face in realising their multiple roles. AB - BACKGROUND: Globally, there is increasing interest in community health worker's (CHW) performance; however, there are gaps in the evidence with respect to CHWs' role in community participation and empowerment. Accredited Social Health Activists (ASHAs), whose roles include social activism, are the key cadre in India's CHW programme which is designed to improve maternal and child health. In a diverse country like India, there is a need to understand how the ASHA programme operates in different underserved Indian contexts, such as rural Manipur. METHODS: We undertook qualitative research to explore stakeholders' perceptions and experiences of the ASHA scheme in strengthening maternal health and uncover the opportunities and challenges ASHAs face in realising their multiple roles in rural Manipur, India. Data was collected through in-depth interviews (n = 18) and focus group discussions (n = 3 FGDs, 18 participants). Participants included ASHAs, key stakeholders and community members. They were purposively sampled based on remoteness of villages and primary health centres to capture diverse and relevant constituencies, as we believed experiences of ASHAs can be shaped by remoteness. Data were analysed using the thematic framework approach. RESULTS: Findings suggested that ASHAs are mostly understood as link workers. ASHA's ability to address the immediate needs of rural and marginalised communities meant that they were valued as service providers. The programme is perceived to be beneficial as it improves awareness and behaviour change towards maternal care. However, there are a number of challenges; the selection of ASHAs is influenced by power structures and poor community sensitisation of the ASHA programme presents a major risk to success and sustainability. The primary health centres which ASHAs link to are ill-equipped. Thus, ASHAs experience adverse consequences in their ability to inspire trust and credibility in the community. Small and irregular monetary incentives demotivate ASHAs. Finally, ASHAs had limited knowledge about their role as an 'activist' and how to realise this. CONCLUSIONS: ASHAs are valued for their contribution towards maternal health education and for their ability to provide basic biomedical care, but their role as social activists is much less visible as envisioned in the ASHA operational guideline. Access by ASHAs to fair monetary incentives commensurate with effort coupled with the poor functionality of the health system are critical elements limiting the role of ASHAs both within the health system and within communities in rural Manipur. PMID- 26646110 TI - JMJ704 positively regulates rice defense response against Xanthomonas oryzae pv. oryzae infection via reducing H3K4me2/3 associated with negative disease resistance regulators. AB - BACKGROUND: Jumonji C (JmjC) domain-containing proteins are a group of functionally conserved histone lysine demethylases in Eukaryotes. Growing evidences have shown that JmjCs epigenetically regulate various biological processes in plants. However, their roles in plant biotic stress, especially in rice bacterial blight resistance have been barely studied so far. RESULTS: In this study, we found that the global di- and tri-methylation levels on multiple lysine sites of histone three were dramatically altered after being infected by bacterial blight pathogen Xanthomonas oryzae pv. oryzae (Xoo). Xoo infection induced the transcription of 15 JmjCs, suggesting these JmjCs are involved in rice bacterial blight defense. Further functional characterization of JmjC mutants revealed that JMJ704 is a positive regulator of rice bacterial blight resistance as the jmj704 became more susceptible to Xoo than the wild-type. In jmj704, the H3K4me2/3 levels were significantly increased; suggesting JMJ704 may be involved in H3K4me2/3 demethylation. Moreover, JMJ704 suppressed the transcription of the rice defense negative regulator genes, such as NRR, OsWRKY62 and Os-11N3, by reducing the activation marks H3K4me2/3 on them. CONCLUSIONS: JMJ704 may be a universal switch controlling multiple genes of the bacterial blight resistance pathway. JMJ704 positively regulates rice defense by epigenetically suppressing master negative defense regulators, presenting a novel mechanism distinct from its homolog JMJ705 which also positively regulates rice defense but via activating positive defense regulators. PMID- 26646111 TI - Factors influencing adherence among older people with osteoarthritis. AB - This study aims to identify potential factors that could affect adherence and influence the implementation of an evidence-based structured walking program, among older adults diagnosed with knee osteoarthritis. A total of 69 participants with mild to moderate osteoarthritis of the knee fulfilled an online survey on potential factors that could affect their adherence to an evidence-based structured walking program. Adherence with regard to the influencing factors was explored using a logistic regression model. Results tend to show higher odds of adhering to the evidence-based walking program if the participants were supervised (more than 2.9 times as high), supported by family/friends (more than 3.7 times as high), and not influenced by emotional involvement (more than 11 times as high). The odds of adhering were 3.6 times lower for participants who indicated a change in their medication intake and 3.1 times lower for individuals who considered themselves as less physically active (95 % confidence interval (CI)). Our exploratory findings identified and defined potential adherence factors that could guide health professionals in their practice to better identify positive influences and obstacles to treatment adherence, which would lead to the adoption of a more patient-centered approach. A large-scale study is required to clearly delineate the key factors that would influence adherence. We addressed a new knowledge gap by identifying the main strategies to promote the long-term adherence of community-based walking program. PMID- 26646112 TI - Serum Ferritin Is Inversely Correlated with Testosterone in Boys and Young Male Adolescents: A Cross-Sectional Study in Taiwan. AB - OBJECTIVE: The transition from childhood to teenaged years is associated with increased testosterone and a decreased iron status. It is not clear whether higher testosterone levels cause the decreased iron status, and to what extent, obesity-related inflammation influences the iron-testosterone relationship. The aim of the present study was to examine relationships of testosterone, iron status, and anti-/proinflammatory cytokines in relation to nutritional status in boys and young adolescent Taiwanese males. METHODS: In total, 137 boys aged 7~13 yr were included. Parameters for obesity, the iron status, testosterone, and inflammatory markers were evaluated. RESULTS: Overweight and obese (ow/obese) boys had higher mean serum testosterone, interleukin (IL)-1beta, and nitric oxide (NO) levels compared to their normal-weight counterparts (all p<0.05). Mean serum ferritin was slightly higher in ow/obese boys compared to normal-weight boys, but this did not reach statistical significance. A multiple linear regression showed that serum ferritin (beta = -0.7470, p = 0.003) was inversely correlated with testosterone, while serum IL-10 (beta = 0.3475, p = 0.009) was positively associated with testosterone after adjusting for covariates. When normal-weight boys were separately assessed from ow/obesity boys, the association between testosterone and serum ferritin became stronger (beta = -0.9628, p<0.0001), but the association between testosterone and IL-10 became non-significant (beta = 0.1140, p = 0.4065) after adjusting for covariates. In ow/obese boys, only IL-10 was weakly associated with serum testosterone (beta = 0.6444, p = 0.051) after adjusting for age. CONCLUSIONS: Testosterone and serum ferritin are intrinsically interrelated but this relationship is weaker in ow/obese boys after adjusting for age. PMID- 26646113 TI - Acetylcholinesterase Inhibitors for Delirium in Older Adults. AB - OBJECTIVES: The aim of this systematic review is to identify published randomized controlled trials (RCTs) that evaluated the use of acetylcholinesterase inhibitors for delirium in older adults (>=60 years). METHODS: A literature search was conducted of PubMed, MEDLINE, EMBASE, PsycINFO, and Cochrane collaboration databases for RCTs in any language that evaluated the use of acetylcholinesterase inhibitors for delirium in older adults (>=60 years). Also, bibliographic databases of the published articles were searched for additional studies. RESULTS: A total of 7 RCTs that evaluated the use of acetylcholinesterase inhibitors for delirium in older adults (>=60 years) were identified. In 5 of the 7 studies, there was no benefit for the acetylcholinesterase inhibitor in either the prevention or the management of delirium. In one study, there was a trend toward benefit for the active drug group on the incidence of delirium and the length of hospital stay, but both outcomes did not attain statistical significance. One study found a longer duration of delirium and a longer length of hospital stay in the active drug group when compared to the placebo group. The acetylcholinesterase inhibitors were well tolerated in 4 of the 7 studies. In 1 study, the mortality rate was found to be almost 3 times higher in the group receiving haloperidol and rivastigmine when compared to the group receiving haloperidol and placebo. CONCLUSION: Current evidence does not suggest efficacy of acetylcholinesterase inhibitors for the prevention or management of delirium in older adults. PMID- 26646114 TI - Neuropsychological and Neuroanatomical Correlates of the Social Norms Questionnaire in Frontotemporal Dementia Versus Alzheimer's Disease. AB - Traditional neuropsychological batteries may not distinguish early behavioral variant frontotemporal dementia (bvFTD) from Alzheimer's disease (AD) without the inclusion of a social behavioral measure. We compared 33 participants, 15 bvFTD, and 18 matched patients with early-onset AD (eAD), on the Social Norms Questionnaire (SNQ), neuropsychological tests and 3-dimensional T1-weighted magnetic resonance imaging (MRI). The analyses included correlations of SNQ results (total score, overendorsement or "overadhere" errors, and violations or "break" errors) with neuropsychological results and tensor-based morphometry regions of interest. Patients with BvFTD had significantly lower SNQ total scores and higher overadhere errors than patients with eAD. On neuropsychological measures, the SNQ total scores correlated significantly with semantic knowledge and the overadhere subscores with executive dysfunction. On MRI analysis, the break subscores significantly correlated with lower volume of lateral anterior temporal lobes (aTL). The results also suggest that endorsement of social norm violations corresponds to the role of the right aTL in social semantic knowledge. PMID- 26646116 TI - Validation of Neuropsychological Tests to Screen for Dementia in Chinese Patients With Parkinson's Disease. AB - To compare the accuracy of different neuropsychological tests and their combinations for deriving reliable cognitive indices for dementia diagnosis in Parkinson's disease (PD). One hundred forty consecutive patients with PD were recruited and administrated an extensive battery of neuropsychological tests. Discriminant analysis and receiver-operator characteristic curve were used to evaluate their correct classifications and validity. Patients with PD having dementia (PDD; 23.5%) performed significantly worse in all tests than patients without dementia. Age of onset, disease duration, Hoehn-Yahr grade, Unified Parkinson's Disease Rating Scale part III scores, and education were associated with dementia in patients with PD. Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment, and Block Design (BD) showed better specificity and sensitivity when used alone, and combined use of MMSE and BD further increased the validity. Our results indicated that the accuracy of MMSE was better in dementia diagnosis of Chinese patients with PD, and combined use of MMSE and BD could further increase the validity of dementia diagnosis. PMID- 26646115 TI - Knowledge and Attitudes in Alzheimer's Disease in a Cohort of Older African Americans and Caucasians. AB - African American participation in Alzheimer's disease (AD) research studies has been historically low. To determine whether older African Americans and Caucasians had different knowledge or attitudes related to AD, we administered the Alzheimer's Disease Knowledge Scale (ADKS) to 67 older African Americans and 140 older caucasians in the greater Atlanta area as well as questions targeting locus of control over general health and AD risks. Older African Americans scored slightly lower on ADKS than older caucasians, with race only accounting for 1.57 (95% confidence interval [CI] 0.57-2.61, P < .001) points of difference in a multivariate model. Attitudes toward AD were also similar between the 2 groups but 1 (35.7%) in 3 adults reported control over general health but not AD risks. In addition to enhancing education content in outreach efforts, there is an urgent need to address the perception that future AD risks are beyond one's own internal control. PMID- 26646117 TI - Rapidly Versus Slowly Progressing Patients With Alzheimer's Disease: Differences in Baseline Cognition. AB - Rate of progression of cognitive deficits is variable among patients with Alzheimer's disease (AD). The purpose of the current study was to compare demographic characteristics and performance on neuropsychological measures at baseline evaluation between rapidly and slowly progressing patients. Participants were divided into 2 groups based on change in Alzheimer's Disease Assessment Scale-Cognitive subscale score from baseline to 2-year follow-up, and baseline performance was compared between the groups. Participants were 55 rapidly progressing and 55 slowly progressing patients with probable AD who had a follow up evaluation 21 to 27 months after the baseline evaluation. The groups differed in age and initial Clinical Dementia Rating. Performance differed significantly between the groups on Verbal Series Attention Test time, Logical Memory I, Visual Reproduction I, Block Design, and Controlled Oral Word Association Test. Differences were found between rapidly and slowly progressing patients on baseline neuropsychological testing. PMID- 26646119 TI - Racial and Ethnic Differences Between Obstetrician-Gynecologists and Other Adult Medical Specialists. AB - OBJECTIVE: To compare racial and ethnic differences between obstetrician gynecologists (ob-gyns) and other large groups of adult medical specialists who provide the predominant care of women. Whether physician diversity influences their practice locations in underserved areas was also sought. METHODS: This cross-sectional study reports an analysis of U.S. national data about racial and ethnic characteristics, gender, and specialty (obstetrics and gynecology, general internal medicine, family medicine, emergency medicine) of 190,379 physicians who came from three resources (Association of American Medical Colleges Student Records System, Association of American Medical Colleges Minority Physicians Database, American Medical Association Physician Masterfile). Underserved locations were identified as being rural, having 20% or more of the population living in poverty or being federally designated as areas of professional shortages or underserved populations. Bivariate measures of associations were performed to study the association between physician race and ethnicity and their practice location. RESULTS: Female physicians in all specialties were more likely than males to be nonwhite, and ob-gyns were most likely to be female (61.9%). Compared with other studied specialists, ob-gyns had the highest proportion of underrepresented minorities (combined, 18.4%), especially black (11.1%) and Hispanic (6.7%) physicians. Underrepresented minority ob-gyns were more likely than white or Asians to practice in federally funded underserved areas or where poverty levels were high. Native Americans, Alaska Natives, and Pacific Islanders were the ob-gyn group with the highest proportion practicing in rural areas. CONCLUSION: Compared with other adult medical specialists, ob-gyns have a relatively high proportion of black and Hispanic physicians. A higher proportion of underrepresented minority ob-gyns practiced at medically underserved areas. PMID- 26646120 TI - Occult Uterine Sarcoma and Leiomyosarcoma: Incidence of and Survival Associated With Morcellation. AB - OBJECTIVE: To estimate the incidence of occult uterine sarcoma and leiomyosarcoma in hysterectomies for leiomyomas and the risk associated with their morcellation. METHODS: We conducted a population-based cohort study. All uterine sarcomas from 2006-2013 in an integrated health care system were identified. Age- and race specific incidences of occult uterine sarcoma were calculated. Kaplan-Meier survival analysis was performed. Crude and adjusted risk ratios of recurrence and death associated with morcellation at 1, 2, and 3 years were estimated using Poisson regression with inverse probability weighting. RESULTS: There were 125 hysterectomies with occult uterine sarcomas identified among 34,728 hysterectomies performed for leiomyomas. The incidence of occult uterine sarcoma and leiomyosarcoma was 1 of 278 or 3.60 (95% confidence interval [CI] 2.97-4.23) and 1 of 429 or 2.33 (95% CI 1.83-2.84) per 1,000 hysterectomies. For stage I leiomyosarcoma (n=111), eight (7.2%) were power and 27 (24.3%) nonpower morcellated. The unadjusted 3-year probability of disease-free survival for no morcellation, power and nonpower morcellation was 0.54, 0.19, and 0.51, respectively (P=.15); overall survival was 0.64, 0.75, and 0.68, respectively (P=.97). None of the adjusted risk ratios for recurrence or death were significant except for death at 1 year for power and nonpower morcellation groups combined (6/33) compared with no morcellation (4/76) (5.12, 95% CI 1.33-19.76, P=.02). We had inadequate power to infer differences for all other comparisons including 3-year survival and power morcellation. CONCLUSION: Morcellation is associated with decreased early survival of women with occult leiomyosarcomas. We could not accurately assess associations between power morcellation and 3-year survival as a result of small numbers. PMID- 26646118 TI - Prophylaxis of Venous Thrombosis in Neurocritical Care Patients: An Evidence Based Guideline: A Statement for Healthcare Professionals from the Neurocritical Care Society. AB - The risk of death from venous thromboembolism (VTE) is high in intensive care unit patients with neurological diagnoses. This is due to an increased risk of venous stasis secondary to paralysis as well as an increased prevalence of underlying pathologies that cause endothelial activation and create an increased risk of embolus formation. In many of these diseases, there is an associated risk from bleeding because of standard VTE prophylaxis. There is a paucity of prospective studies examining different VTE prophylaxis strategies in the neurologically ill. The lack of a solid evidentiary base has posed challenges for the establishment of consistent and evidence-based clinical practice standards. In response to this need for guidance, the Neurocritical Care Society set out to develop and evidence-based guideline using GRADE to safely reduce VTE and its associated complications. PMID- 26646121 TI - Fetal Heart Rate Monitoring During Surgical Correction of Spontaneous Pneumothorax During Pregnancy: Lessons in In Utero Resuscitation. AB - BACKGROUND: Spontaneous pneumothorax during pregnancy has potentially serious implications for the mother and fetus. When surgical correction is required, complex maternal physiologic alterations may significantly affect fetal well being. CASE: A woman underwent thoracoscopic lung resection and pleurodesis at 29 weeks of gestation. At various points during the procedure, maternal hemodynamic and respiratory consequences of anesthetic and surgical management resulted in severe fetal heart rate (FHR) decelerations and bradycardia. In each instance, physiologic manipulations based on an understanding of the likely cause of fetal hypoxia allowed correction of the FHR abnormalities without delivery. CONCLUSION: Nonsurgical perinatal intervention based on FHR monitoring and analysis of the likely pathophysiologic abnormalities underlying fetal decelerations may allow the gravid woman to undergo complex procedures and continue the pregnancy. PMID- 26646122 TI - Association Between Patient Characteristics and Treatment Procedure Among Patients With Uterine Leiomyomas. AB - OBJECTIVE: To analyze the association between patient characteristics and the probability of undergoing any uterine-sparing procedure (endometrial ablation, myomectomy, and uterine artery embolization) compared with hysterectomy as the first uterine leiomyoma (index) procedure and the probability of undergoing a specific uterine-sparing procedure. METHODS: We conducted a retrospective analysis using a commercial insurance claims database containing more than 13 million enrollees annually. Based on the index procedure performed 2004-2009, women were classified into one of the four procedure cohorts. Eligible women were aged 25-54 years on the index date, continuously insured through 1-year baseline and 1-year follow-up, and had a baseline uterine leiomyoma diagnosis. Logistic regression was used to assess the association between patient characteristics and leiomyoma procedure. RESULTS: The study sample comprised 96,852 patients (endometrial ablation=12,169; myomectomy=7,039; uterine artery embolization=3,835; and hysterectomy=73,809). Patient characteristics associated with undergoing any uterine-sparing procedure compared with hysterectomy included health maintenance organization health plan enrollment, Northeast region residence, the highest income and education quintiles based on zip code, an age race interaction, and baseline diagnoses including menstrual disorders, pelvic pain, anemia, endometriosis, genital prolapse, and infertility. Among those who had a uterine-sparing procedure, characteristics associated with undergoing uterine artery embolization or endometrial ablation compared with myomectomy included increasing age, being from the Midwest relative to the Northeast, and certain baseline conditions including menstrual disorder, pelvic pain, endometriosis, and infertility. CONCLUSION: Both clinical and nonclinical factors were associated with the receipt of alternatives to hysterectomy for uterine leiomyomas in commercially insured women. PMID- 26646123 TI - Adhesion Barrier Use After Myomectomy and Hysterectomy: Rates and Immediate Postoperative Complications. AB - OBJECTIVE: To evaluate use rates and immediate postoperative complications of the use of an adhesion barrier in myomectomy or hysterectomy. METHODS: This was a retrospective cohort study. Using the Healthcare Cost and Utilization Project Nationwide Inpatient Sample, we examined the records of women with primary discharge diagnosis of uterine myoma during the period 2003-2011. We evaluated use rates and complications among 473,788 women treated by myomectomy or hysterectomy. RESULTS: Of 473,788 women treated by myomectomy or hysterectomy, adhesion barrier was used in 3,392 of 62,563 myomectomies (5.4%) and 5,590 of 411,225 hysterectomies (1.4%). The rate of ileus after myomectomy in the nonbarrier group (1,290/59,171 [2%]) was lower than in the barrier group (109/3,392 [3%]; adjusted odds ratio [OR] 1.50 [1.22-1.83]) and similar after hysterectomy (10,329/405,635 [2.5%] compared with 288/5,590 [5%]; adjusted OR 1.97 [1.75-2.23]). Postoperative fever was also higher in the adhesion barrier group after myomectomy (4.4% compared with 2.9%, adjusted OR 1.44 [1.21-1.71]) as well as after hysterectomy (2.5% compared with 1.6%, OR 1.65 [1.40-1.96]). Small bowel obstruction after hysterectomy in the nonbarrier group (804/405,635 [0.2%]) was less frequent than in the barrier group (23/5,590 [0.4%]; OR 1.90 [1.25 2.89]), but not after myomectomy. CONCLUSION: Although the use of adhesion barrier remains very low, the use is associated with a slightly higher incidence of fever and ileus after myomectomy and hysterectomy and with bowel obstruction after hysterectomy. PMID- 26646124 TI - Trends in Severe Maternal Morbidity After Assisted Reproductive Technology in the United States, 2008-2012. AB - OBJECTIVE: To examine trends in severe maternal morbidity from 2008 to 2012 in delivery and postpartum hospitalizations among pregnancies conceived with or without assisted reproductive technology (ART). METHODS: In this retrospective cohort study, deliveries were identified in the 2008-2012 Truven Health MarketScan Commercial Claims and Encounters Databases. Severe maternal morbidity was identified using International Classification of Diseases, 9th Revision, Clinical Modification diagnosis codes and Current Procedural Terminology codes. Rate of severe maternal morbidity was calculated for ART and non-ART pregnancies. We performed multivariable logistic regression, controlling for maternal characteristics, and calculated adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for severe morbidity. Additionally, a propensity score analysis was performed between ART and non-ART deliveries. RESULTS: Of 1,016,618 deliveries, 14,761 (1.5%) were identified as pregnancies conceived with ART. Blood transfusion was the most common severe morbidity indicator for ART and non ART pregnancies. For every 10,000 singleton deliveries, there were 273 ART deliveries or postpartum hospitalizations with severe maternal morbidity compared with 126 for non-ART (P<.001). For ART singleton deliveries, the rate of severe morbidity decreased from 369 per 10,000 deliveries in 2008 to 219 per 10,000 deliveries in 2012 (P=.025). Odds of severe morbidity were increased for ART compared with non-ART singletons (adjusted OR 1.84, 95% CI 1.63-2.08). Among multiple gestations, there was no significant difference between ART and non-ART pregnancies (rate of severe morbidity for ART 604/10,000 and non-ART 539/10,000 deliveries, P=.089; adjusted OR 1.04, 95% CI 0.91-1.20). Propensity score matching agreed with these results. CONCLUSION: Singleton pregnancies conceived with ART are at increased risk for severe maternal morbidity; however, the rate has been decreasing since 2008. Multiple gestations have increased risk regardless of ART status. PMID- 26646125 TI - Cause of Preterm Birth as a Prognostic Factor for Mortality. AB - OBJECTIVE: To investigate the association of the cause of preterm birth on in hospital mortality of preterm neonates born from 24 to 34 weeks of gestation. METHODS: L'Etude epidemiologique sur les petits ages gestationnels (EPIPAGE)-2 is a prospective, nationwide, population-based cohort of very preterm births. After dividing causes of preterm birth into six mutually exclusive groups, we analyzed the association of each cause with in-hospital deaths of preterm neonates born alive with adjustment for organizational, maternal, and obstetric factors. RESULTS: The analysis included 3,138 singleton live births from 24 to 34 weeks of gestation with a newborn in-hospital mortality rate of 5.0% (95% confidence interval 4.5-5.7). Preterm labor was the most frequent cause of preterm birth (n=1,293 [43.5%]) followed by preterm premature rupture of membranes (n=765 [23.9%]), hypertensive disorders without suspected fetal growth restriction (n=397 [12.7%]), hypertensive disorders with suspected fetal growth restriction (n=408 [10.9%]), placental abruption after an uncomplicated pregnancy (n=92 [3.0%]), and suspected fetal growth restriction without hypertensive disorders (n=183 [5.9%]). Neonates born because of suspected fetal growth restriction with or without hypertensive disorders (adjusted odds ratio [OR] 3.0 [1.9-4.7] and adjusted OR 2.3 [1.1-4.6], respectively) had higher adjusted risks of in-hospital death than those born after preterm labor. Risks of in-hospital mortality for preterm births caused by preterm premature rupture of membranes (adjusted OR 1.3 [0.9-1.9]), hypertensive disorders without fetal growth restriction (adjusted OR 0.7 [0.4-1.4]), or placental abruption (adjusted OR 1.6 [0.7-3.7]) were similar to those born after preterm labor. CONCLUSION: Among neonates born alive before 34 weeks of gestation, only those born because of suspected fetal growth restriction have a higher mortality risk than those born after preterm labor. PMID- 26646126 TI - Changes in Hysterectomy Trends After the Implementation of a Clinical Pathway. AB - OBJECTIVE: To investigate the effect of hysterectomy pathway implementation on the proportion of total abdominal hysterectomy (TAH) procedures performed between fiscal years 2012 and 2014. METHODS: We conducted a retrospective medical record review. All hysterectomy surgeries performed for benign indications at University of Pittsburgh Medical Center hospitals from fiscal year 2012 to fiscal year 2014 were identified through various systems including Medipac and EpicCare. We analyzed the cases by surgical approach (TAH compared with minimally invasive hysterectomy), age, and indication of surgery. Changes over time were analyzed using Cochran-Armitage test for linear trends. RESULTS: A total number of 6,544 patients were included in this study. The mean age of the participants was 48.6 years (standard deviation 11.69). In fiscal year 2012, of 1,934 hysterectomies performed as a result of noncancerous conditions, 538 were TAH procedures (27.8%). However, this number declined in fiscal year 2013 to 22% (485 TAH procedures of 2,186 hysterectomies) and further declined in fiscal year 2014 to 17% (413 TAH surgeries of 2,424 hysterectomies). Overall, there was a significant reduction in the proportion of TAH procedures, from 27.8% in fiscal year 2012 to 17% in fiscal year 2014 (P for trend <.001). After adjusting for surgery indication, the decreasing trend of TAH procedures still persisted (P for trend <.001). CONCLUSION: Implementation of a hysterectomy pathway has been associated with a decrease in the proportion of TAH hysterectomy procedures. PMID- 26646127 TI - Utilization of Minimally Invasive Surgery in Endometrial Cancer Care: A Quality and Cost Disparity. AB - OBJECTIVE: To describe case mix-adjusted hospital level utilization of minimally invasive surgery for hysterectomy in the treatment of early-stage endometrial cancer. METHODS: In this retrospective cohort study, we analyzed the proportion of patients who had a minimally invasive compared with open hysterectomy for nonmetastatic endometrial cancer using the U.S. Nationwide Inpatient Sample database, 2007-2011. Hospitals were stratified by endometrial cancer case volumes (low=less than 10; medium=11-30; high=greater than 30 cases). Hierarchical logistic regression models were used to evaluate hospital and patient variables associated with minimally invasive utilization, complications, and costs. RESULTS: Overall, 32,560 patients were identified; 33.6% underwent a minimally invasive hysterectomy with an increase of 22.0-50.8% from 2007 to 2011. Low volume cancer centers demonstrated the lowest minimally invasive utilization rate (23.6%; P<.001). After multivariable adjustment, minimally invasive surgery was less likely to be performed in patients with Medicaid compared with private insurance (adjusted odds ratio [OR] 0.67, 95% confidence interval [CI] 0.62 0.72), black and Hispanic compared with white patients (adjusted OR 0.43, 95% CI 0.41-0.46 for black and 0.77, 95% CI 0.72-0.82 for white patients), and more likely to be performed in high- compared with low-volume hospitals (adjusted OR 4.22, 95% CI 2.15-8.27). Open hysterectomy was associated with a higher risk of surgical site infection (adjusted OR 6.21, 95% CI 5.11-7.54) and venous thromboembolism (adjusted OR 3.65, 95% CI 3.12-4.27). Surgical cases with complications had higher mean hospitalization costs for all hysterectomy procedure types (P<.001). CONCLUSION: Hospital utilization of minimally invasive surgery for the treatment of endometrial cancer varies considerably in the United States, representing a disparity in the quality and cost of surgical care delivered nationwide. PMID- 26646128 TI - Utilization and Outcomes of Ovarian Conservation in Premenopausal Women With Endometrial Cancer. AB - OBJECTIVE: To examine the trends in use and safety of ovarian conservation in young women with early-stage endometrial cancer undergoing hysterectomy. METHODS: We conducted a population-based analysis. The National Cancer Database was used to identify women younger than 50 years of age with stage I endometrioid adenocarcinoma of the endometrium who underwent hysterectomy from 1998 to 2012. Patients were stratified based on whether they underwent oophorectomy or had ovarian conservation. Multivariable models were used to examine predictors of ovarian conservation and the association between ovarian conservation and survival. RESULTS: The cohort of 15,648 women included 1,121 (7.2%) who had ovarian conservation and 14,527 (92.8%) who underwent oophorectomy. The rate of ovarian conservation was relatively stable from 6.9% (95% confidence interval [CI] 4.9-9.7%) in 1998 to 7.1% (95% CI 5.8-8.7%) in 2012 (P=.91). Ovarian conservation was more commonly performed in younger women, black women, those with low-grade and earlier stage tumors, and in women treated at community hospitals. In a multivariable model, ovarian conservation was not independently associated with survival (hazard ratio 0.94, 95% CI 0.65-1.37). Similarly, in a Kaplan-Meier analysis, there was no association between ovarian conservation and survival (P=.19). CONCLUSION: Ovarian conservation does not adversely affect survival for women with early-stage endometrial cancer. Despite the oncologic safety of ovarian conservation, the majority of young women with endometrial cancer still undergo oophorectomy at the time of surgery. PMID- 26646129 TI - Lack of Availability of Antenatal Vaccination Information on Obstetric Care Practice Web Sites. AB - OBJECTIVE: To estimate the proportion of obstetric practice web sites in the United States providing information on antenatal influenza and tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccination. METHODS: Using www.healthgrades.com, a national random sample of 1,003 obstetric practice web sites was examined for provision of information on antenatal vaccination and other preventive prenatal health topics. Data were collected for this cross sectional study between September 25, 2014, and November 12, 2014. chi tests and odds ratios were calculated to determine significance and magnitude of associations between provision of antenatal vaccination information and other practice characteristics. RESULTS: Of 1,003 web sites examined, 229 (22.8%) posted information pertaining to antenatal vaccinations. Only 105 web sites (10.5%) provided up-to-date information about both antenatal influenza and Tdap vaccination. Compared with the proportion posting on antenatal vaccination, significantly more web sites posted on safe foods (40.8%; P<.001), safe medications (36.9%; P<.001), and safe exercise (38.5%; P<.001) during pregnancy. When compared with web sites not mentioning these other prenatal health topics, web sites mentioning these topics were more likely to also mention antenatal vaccination (safe foods: 45.7% compared with 7.1%; odds ratio [OR] 11.07, 95% confidence interval [CI] 7.65-16.01; safe medications: 45.4% compared with 9.6%; OR 7.8, CI 5.58-10.89; safe exercise: 45.9% compared with 8.4%; OR 9.2, CI 6.5 13.03). CONCLUSION: A majority of obstetric care practice web sites do not provide information on antenatal vaccinations. Obstetric practices should consider using their web sites to provide reliable information on antenatal vaccinations as many already do for other prenatal health topics. PMID- 26646131 TI - Use of 50% Dextrose as the Distension Medium During Cystoscopy for Visualization of Ureteric Jets. AB - BACKGROUND: Indigotindisulfonate sodium has been used to color the urine and thereby improve the visualization of ureteric jets during intraoperative cystoscopy. After indigotindisulfonate sodium became unavailable, there has been an ongoing search for an alternate agent to improve visualization of the jets. METHOD: We used 50% dextrose, which is more viscous than urine, as the distension medium during cystoscopy so that the ureteric efflux is seen as a jet of contrasting viscosity. We instilled 100 mL of 50% dextrose into the bladder through an indwelling catheter, which is then removed and cystoscopy is performed as usual. EXPERIENCE: We observed jets of contrasting viscosity in every patient in whom 50% dextrose was used as compared with coloring agents in which the jet is not always colored at the time of cystoscopy. Visualization of the other structures in the bladder and the bladder wall itself is not altered by 50% dextrose, although the volume of 50% dextrose that we typically use may not provide adequate distension for a complete assessment of the bladder. If additional distension is necessary, normal saline may be used in addition to the 50% dextrose once the ureteric jets have been assessed. CONCLUSION: Fifty percent dextrose is an effective alternative to indigotindisulfonate sodium for visualization of ureteric jets during cystoscopy. PMID- 26646130 TI - Influence of Lymphadenectomy on Survival for Early-Stage Endometrial Cancer. AB - OBJECTIVE: To use a number of methods to control for confounding and selection bias to examine the association between lymphadenectomy and survival in a large cohort of women with endometrial cancer. METHODS: A retrospective cohort study using the National Cancer Data Base was performed to identify women with endometrioid adenocarcinoma of the endometrium who underwent hysterectomy with or without lymphadenectomy from 1998 to 2011. Traditional regression analysis, propensity score, and an instrumental variable using regional variation in the rate of lymphadenectomy as an instrument were used to examine the association between lymphadenectomy and survival. RESULTS: A total of 151,089 women treated at 1,336 hospitals were identified; 99,052 (65.6%) patients underwent lymphadenectomy, whereas 52,037 (34.4%) did not. In a multivariable regression model, lymphadenectomy was associated with a 16% reduction in mortality (hazard ratio [HR] 0.84, 95% confidence interval [CI] 0.81-0.87). The results were similar after adjustment for adjuvant therapy (HR 0.85, 95% CI 0.82-0.87). The results were largely unchanged and suggested that lymphadenectomy was associated with improved survival after application of a propensity score analysis. In contrast, in the instrumental variable analysis, there was not a statistically significant association between lymphadenectomy and survival (HR 0.75, 95% CI 0.53-1.06), even after adjustment for adjuvant treatment (HR 0.76, 95% CI 0.54 1.06). The results were unchanged for women with T1A and T1B tumors. CONCLUSION: Lymphadenectomy is associated with a modest, if any, effect on survival for women with endometrial cancer. PMID- 26646132 TI - Ovarian Cancer Treatment and Survival Trends Among Women Older Than 65 Years of Age in the United States, 1995-2008. AB - OBJECTIVE: To evaluate whether overall survival is improving among women in the United States with advanced ovarian cancer. METHODS: This retrospective cohort study evaluated trends in treatment and overall survival for women older than 65 years diagnosed with stage III and IV epithelial ovarian cancer between 1995 and 2008 using Surveillance, Epidemiology, and End Results-Medicare data. Parametric and semiparametric multivariate survival analyses were used to assess comparative treatment survival rates and factors affecting survival and recurrence. RESULTS: Of 7,938 women who met study criteria, 2.9% received no treatment, 15.4% underwent surgery only, 24.8% received chemotherapy only, 41.8% underwent primary debulking surgery and chemotherapy in an optimal timeframe, and 15.1% had primary debulking surgery and chemotherapy, but the timing was not optimal or patients did not complete all six cycles of chemotherapy. Those who underwent surgery only had similar survival as those who received no treatment (2.2 compared with 1.7 months), whereas those who received chemotherapy only had a better overall survival (14.4 months). Optimal treatment was associated with the longest survival time (P<.001, median overall survival 39.0 months). Additionally, survival time associated with optimal treatment increased over the past decade. However, the proportion of women who received optimal treatment has decreased over the past decade. CONCLUSION: Elderly women with advanced ovarian cancer have the best survival with optimal therapy. When this is not offered or possible, chemotherapy alone offers better survival than surgery alone. PMID- 26646133 TI - A Core Outcome Set for Evaluation of Interventions to Prevent Preterm Birth. AB - OBJECTIVE: To develop a consensus on a set of key clinical outcomes for the evaluation of preventive interventions for preterm birth in asymptomatic pregnant women. METHODS: A two-stage web-based Delphi survey and a face-to-face meeting of key stakeholders were used to develop a consensus on a set of critical and important outcomes. We approached five stakeholder groups (parents, midwives, obstetricians, neonatologists, and researchers) from middle- and high-income countries. Outcomes subjected to the Delphi survey were identified by systematic literature review and stakeholder input. Survey participants scored each outcome on a 9-point Likert scale anchored between 1 (limited importance) and 9 (critical importance). They had the opportunity to reflect on total and stakeholder subgroup feedback between survey stages. For consensus, defined a priori, outcomes required at least 70% of participants of each stakeholder group to score them as "critical" and less than 15% as "limited." RESULTS: A total of 228 participants from five stakeholder groups from three lower middle-income countries, seven upper middle-income countries, and 17 high-income countries were asked to score 31 outcomes. Of these participants, 195 completed the first survey and 174 the second. Consensus was reached on 13 core outcomes: four were related to pregnant women: maternal mortality, maternal infection or inflammation, prelabor rupture of membranes, and harm to mother from intervention. Nine were related to offspring: gestational age at birth, offspring mortality, birth weight, early neurodevelopmental morbidity, late neurodevelopmental morbidity, gastrointestinal morbidity, infection, respiratory morbidity, and harm to offspring from intervention. CONCLUSION: This core outcome set for studies that evaluate prevention of preterm birth developed with an international multidisciplinary perspective will ensure that data from trials that assess prevention of preterm birth can be compared and combined. DATABASE REGISTRATION: COMET Initiative, http://www.comet-initiative.org/studies/details/603, REGISTRATION NUMBER: 603. PMID- 26646134 TI - U.S. Food and Drug Administration's Guidance Regarding Morcellation of Leiomyomas: Well-Intentioned, But Is It Harmful for Women? AB - The U.S. Food and Drug Administration (FDA) is warning against the use of laparoscopic power morcellators in the majority of women undergoing myomectomy or hysterectomy for the treatment of leiomyomas because of the concern for inadvertent spread of tumor cells if an undiagnosed cancer were present. The authors, representing a 45-member review group, reviewed the current literature to formulate prevalence rates of leiomyosarcoma in women with presumed leiomyomas and to asses reliable data regarding patient survival after morcellation. The authors disagree with the FDA's methodology in reaching their conclusion and provide clinical recommendations for care of women with leiomyomas who are planning surgery. PMID- 26646135 TI - Electrocardiogram ST Analysis During Labor: A Systematic Review and Meta-analysis of Randomized Controlled Trials. AB - OBJECTIVE: To compare the effectiveness of cardiotocography plus ST analysis with cardiotocography alone during labor. DATA SOURCES: Randomized controlled trials were identified by searching electronic databases. METHODS OF STUDY SELECTION: We included all randomized controlled trials comparing intrapartum fetal monitoring with cardiotocography plus ST analysis with cardiotocography alone. The primary outcome (ie, perinatal composite outcome) was a composite of intrapartum fetal death, neonatal death, Apgar score 3 or less at 5 minutes, neonatal seizure, metabolic acidosis (defined as umbilical arterial pH 7.05 or less, and extracellular fluid base deficit 12 mmol/L or greater), intubation for ventilation at delivery, or neonatal encephalopathy. TABULATION, INTEGRATION, AND RESULTS: Six randomized controlled trials, which included 26,529 laboring singletons with cephalic presentation at term, were analyzed. Compared with women who were randomized to cardiotocography, those who were randomized to ST analysis and cardiotocography had a similar incidence of perinatal composite outcome (1.5% compared with 1.6%; relative risk [RR] 0.90, 95% confidence interval [CI] 0.74 1.10; five studies), neonatal metabolic acidosis (0.5% compared with 0.7%; RR 0.74, 95% CI 0.54-1.02; five studies), admission to the neonatal intensive care unit (5.4% compared with 5.5%; RR 0.99, 95% CI 0.90-1.10; six studies), perinatal death (0.1% compared with 0.1%; RR 1.71, 95% CI 0.67-4.33; six studies), neonatal encephalopathy (0.1% compared with 0.2%; RR 0.62, 95% CI 0.25-1.52; six studies), cesarean delivery (13.8% compared with 14.0%; RR 0.96, 95% CI 0.85-1.08; six studies), and operative delivery (either cesarean or operative vaginal delivery) (23.9% compared with 25.1%; RR 0.93, 95% CI 0.86-1.01; six studies). CONCLUSION: The use of ST analysis during labor as an adjunct to the standard cardiotocography does not improve perinatal outcomes or decrease cesarean delivery. PMID- 26646136 TI - A Call for Change in a Changing World. AB - The practice of obstetrics and gynecology in the United States has changed substantially over the past 50 years, but the structure of our residency programs has not evolved at a comparable pace. The number of hours available for training during the workweek has decreased significantly, whereas the amount of essential material to learn and clinical skills to acquire has increased dramatically. The switch to minimally invasive surgical approaches has reduced the number of open abdominal cases available for training, and the aptitude required to perform difficult laparoscopic and robotic cases for benign disease is such that many programs do not have enough surgical patients to teach all of their residents how to adequately master those procedures. Obstetric patients are older and heavier than those encountered several decades ago, and the comorbidities of some of these women make their antepartum and intrapartum management extremely complex. Furthermore, the explosion of genetic knowledge has made prenatal counseling infinitely more challenging. In this commentary we review these and related issues and then address the question of whether current training programs are preparing our graduates to optimally perform in the clinical arena they will enter after finishing their residencies. Some ways in which the current system could be modified are suggested, and a plea is made for the creation of a high level task force to address this problem on a national level. PMID- 26646137 TI - What Is New in Ethical Issues in Obstetrics?: Best Articles From the Past Year. AB - This month we focus on ethical issues in obstetrics. Dr. Burda discusses four recent publications, which are concluded with a "bottom line" that is the take home message. The complete reference for each can be found in on this page, along with direct links to the abstracts. PMID- 26646138 TI - Changing the Diagnostic Criteria for Gestational Diabetes Mellitus? PMID- 26646139 TI - Electric Power Morcellation in Gynecology: The Path Forward. PMID- 26646140 TI - Connect the Dots-January 2016. PMID- 26646141 TI - Happy New Year From the Green Journal. PMID- 26646142 TI - Gestational Diabetes Screening: The International Association of the Diabetes and Pregnancy Study Groups Compared With Carpenter-Coustan Screening. AB - OBJECTIVE: To evaluate whether one-step gestational diabetes screening recommended by The International Association of the Diabetes and Pregnancy Study Groups (IADPSG) is associated with better maternal, perinatal, or neonatal outcomes than the two-step Carpenter-Coustan screening. METHODS: In this before after retrospective cohort study conducted between July 1, 2010, and December 31, 2013, we compared Carpenter-Coustan and IADPSG screening in patients with singleton pregnancies. All patients diagnosed with gestational diabetes received intensive teaching, home glucose monitoring, and medications as indicated. The primary outcome was the rate of large-for-gestational-age neonates. Secondary outcome measures were macrosomia (greater than 4,000 g), primary cesarean delivery, neonatal intensive care unit admission, preterm delivery, preeclampsia, and hyperbilirubinemia. We determined that a sample size of 2,782 per group was sufficient to detect a 2% difference in the primary outcome between groups with 80% power assuming a 10% incidence in the before group. The groups were compared using Fisher exact test for proportions and a chi test for odds ratios. RESULTS: In the before (Carpenter-Coustan) group, 513 (17%) of the 2,972 patients were diagnosed with gestational diabetes, and in the after (IADPSG) group, 847 (27%) of the 3,094 patients were so diagnosed (P<.001). There was no significant difference in rates of large for gestational age, 10% and 9%, respectively (P=.25). The IADPSG group had a significantly higher primary cesarean delivery rate-16% compared with 20% (P<.001), but there were no significant differences in any other pregnancy outcomes. CONCLUSION: Although one-step screening was associated with more patients being treated for gestational diabetes, it was not associated with a decrease in large-for-gestational-age or macrosomic neonates but was associated with an increased rate of primary cesarean delivery. Our results did not support the IADPSG-recommended screening protocol. PMID- 26646143 TI - Asymmetric Nerve Enlargement: A Characteristic of Leprosy Neuropathy Demonstrated by Ultrasonography. AB - BACKGROUND: Neurological involvement occurs throughout the leprosy clinical spectrum and is responsible for the most feared consequences of the disease. Ultrasonography (US) provides objective measurements of nerve thickening and asymmetry. We examined leprosy patients before beginning multi-drug therapy aiming to describe differences in US measurements between classification groups and between patients with and without reactions. METHODOLOGY/PRINCIPAL FINDINGS: Eleven paucibacillary (PB) and 85 multibacillary (MB) patients underwent nerve US. Twenty-seven patients had leprosy reactions (type 1, type 2 and/or acute neuritis) prior to US. The ulnar (at the cubital tunnel-Ut-and proximal to the tunnel-Upt), median (M) and common fibular (CF) nerves were scanned to measure cross-sectional areas (CSAs) in mm2 and to calculate the asymmetry indexes DeltaCSA (absolute difference between right and left CSAs) and DeltaUtpt (absolute difference between Upt and Ut CSAs). MB patients showed greater (p<0.05) CSAs than PB at Ut (13.88+/-11.4/9.53+/-6.14) and M (10.41+/-5.4/6.36+/ 0.84). DeltaCSAs and DeltaUtpt were similar between PB and MB. The CSAs, DeltaCSAs and DeltaUtpt were similar between PB patients with reactions compared to PB patients without reactions. MB patients with reactions showed significantly greater CSAs (Upt, Ut and M), DeltaCSAs (Upt and Ut) and DeltaUtpt compared to MB patients without reactions. PB and MB showed similar frequencies of abnormal US measurements. Patients with reactions had higher frequency of nerve thickening and similar frequency of asymmetry to those without reactions. CONCLUSIONS/SIGNIFICANCE: This is the first study to investigate differences in nerve involvement among leprosy classification groups using US before treatment. The magnitude of thickening was greater in MB and in patients with reactions. Asymmetry indexes were greater in patients with reactions and did not significantly differ between PB and MB, demonstrating that asymmetry is a characteristic of leprosy neuropathy regardless of its classification. PMID- 26646144 TI - Unemployment, Parental Distress and Youth Emotional Well-Being: The Moderation Roles of Parent-Youth Relationship and Financial Deprivation. AB - We investigated, in a sample of 112 unemployed parents of adolescents aged 10-19 years, the links between parental distress and change in youth emotional problems related to parental unemployment, and the moderation roles of parent-youth relationship and financial deprivation. Data were analyzed using descriptive statistics and correlations. Further, simple moderation, additive moderation, and moderated moderation models of regression were performed to analyze the effects of parental distress, parent-youth relationship and financial deprivation in predicting change in youth emotional problems related to parental unemployment. Results show that parental distress moderated by parent-youth relationship predicted levels of change in youth emotional problems related to parental unemployment. This study provides evidence that during job loss, parental distress is linked to youth emotional well-being and that parent-youth relationships play an important moderation role. This raises the importance of further researching parental distress impacts on youth well-being, especially during periods of high unemployment rates. PMID- 26646145 TI - Catch-up growth in term and preterm infants after surgical closure of ventricular septal defect in the first year of life. AB - Growth impairment in infants with unrestrictive ventricular septal defects (VSD) is common, and normalisation of growth has been reported after surgical correction. Literature is inconsistent about growth velocity after surgery in term and preterm infants. We aimed to establish the pattern of catch-up growth in term and preterm infants submitted to VSD surgical correction before 1 year of age. Fifty-two infants (41 term, 11 preterm) were studied. Anthropometric data at birth, surgery and 3, 6, 12 and 24 months after surgery were collected retrospectively. Statistic analyses were performed in SPSS(r) version 21. At the time of surgery, growth was severely impaired in term and preterm infants. Term infants underwent a period of fast growth within the first 6 months after surgery, achieving posteriorly a normal growth pattern, as both weight and height were not significantly different from the reference population at 24 months after surgery. Preterms caught-up later than term infants but with a significant weight gain within 3 months after surgery. CONCLUSION: Early surgical repair of VSD leads to a significant acceleration of growth within 3 to 6 months after surgery, for both groups. WHAT IS KNOWN: * Growth impairment in infants with unrestrictive ventricular septal defects is well documented in literature. * Surgical correction in the first months of life is the current option for most ventricular septal defects, leading to a more favourable growth pattern. * Rapid growth during infancy may be associated with the development of insulin resistance, metabolic syndrome, obesity and cardiovascular disease later in life. What is New: * Literature is inconsistent about catch-up growth velocities after ventricular correction for term infants. * Preterm infants have never been enrolled in previous studies that aimed to establish a pattern of growth after surgery. * This group of children, who underwent a rapid post-surgery catch-up growth that follows a period of failure to thrive, may be at a higher risk of insulin resistance, metabolic syndrome, obesity and cardiovascular disease. PMID- 26646146 TI - Percutaneous pedicle screw fixation for an unstable thoracic spine fracture after a traumatic degloving injury. AB - Unstable spinal fractures require urgent surgical intervention to relieve compression of the spinal cord, correct spinal deformity, stabilise the spine and prevent further neurological injury. We report the case of a young man with a thoracic chance fracture in the setting of a devastating degloving injury, whose fracture was stabilised using minimally invasive, percutaneous pedicle screw fixation. We discuss the advantages of using a minimally invasive technique for spinal fixation and its role in the treatment of complicated, multisystem trauma patients. PMID- 26646147 TI - Five selfish reasons to work reproducibly. AB - And so, my fellow scientists: ask not what you can do for reproducibility; ask what reproducibility can do for you! Here, I present five reasons why working reproducibly pays off in the long run and is in the self-interest of every ambitious, career-oriented scientist. PMID- 26646149 TI - IFN-gamma and IL-21 Double Producing T Cells Are Bcl6-Independent and Survive into the Memory Phase in Plasmodium chabaudi Infection. AB - CD4 T cells are required to fight malaria infection by promoting both phagocytic activity and B cell responses for parasite clearance. In Plasmodium chabaudi infection, one specific CD4 T cell subset generates anti-parasitic IFN-gamma and the antibody-promoting cytokine, IL-21. To determine the lineage of these multifunctional T cells, we followed IFN-gamma+ effector T cells (Teff) into the memory phase using Ifng-reporter mice. While Ifng+ Teff expanded, the level of the Th1 lineage-determining transcription factor T-bet only peaked briefly. Ifng+ Teff also co-express ICOS, the B cell area homing molecule CXCR5, and other Tfh lineage-associated molecules including Bcl6, the transcription factor required for germinal center (GC) T follicular helper cells (Tfh) differentiation. Because Bcl6 and T-bet co-localize to the nucleus of Ifng+ Teff, we hypothesized that Bcl6 controls the Tfh-like phenotype of Ifng+ Teff cells in P. chabaudi infection. We first transferred Bcl6-deficient T cells into wildtype hosts. Bcl6 deficient T cells did not develop into GC Tfh, but they still generated CXCR5+ IFN-gamma+ IL-21+ IL-10+ Teff, suggesting that this predominant population is not of the Tfh-lineage. IL-10 deficient mice, which have increased IFN-gamma and T bet expression, demonstrated expansion of both IFN-gamma+ IL-21+ CXCR5+ cells and IFN-gamma+ GC Tfh cells, suggesting a Th1 lineage for the former. In the memory phase, all Ifng+ T cells produced IL-21, but only a small percentage of highly proliferative Ifng+ T cells maintained a T-bethi phenotype. In chronic malaria infection, serum IFN-gamma correlates with increased protection, and our observation suggests Ifng+ T cells are maintained by cellular division. In summary, we found that Ifng+ T cells are not strictly Tfh derived during malaria infection. T cells provide the host with a survival advantage when facing this well-equipped pathogen, therefore, understanding the lineage of pivotal T cell players will aid in the rational design of an effective malaria vaccine. PMID- 26646150 TI - Size of the intracranial optic nerve and optic tract in neonates at term equivalent age at magnetic resonance imaging. AB - BACKGROUND: The expected MRI-based dimensions of the intracranial optic nerve and optic tract in neonates are unknown. OBJECTIVE: To evaluate the sizes of the intracranial optic nerve and optic tract in neonates at term-equivalent age using MRI. MATERIALS AND METHODS: We retrospectively analyzed brain MRI examinations in 62 infants (28 boys) without intracranial abnormalities. The images were obtained in infants at term-equivalent age with a 1.5-tesla MRI scanner. We measured the widths and heights of the intracranial optic nerve and optic tract and calculated the cross-sectional areas using the formula for an ellipse. RESULTS: The means +/ standard deviation of the width, height and cross-sectional area of the intracranial optic nerve were 2.7 +/- 0.2 mm, 1.7 +/- 0.2 mm and 3.5 +/- 0.5 mm(2), respectively. The width, height and cross-sectional area of the optic tract were 1.5 +/- 0.1 mm, 1.6 +/- 0.1 mm and 2.0 +/- 0.2 mm(2), respectively. Using univariate and multivariate analyses, we found that postmenstrual age showed independent intermediate positive correlations with the width (r = 0.48, P < 0.01) and cross-sectional area (r = 0.40, P < 0.01) of the intracranial optic nerve. The lower bounds of the 95% prediction intervals for the width and cross sectional area of the intracranial optic nerve were 0.07 * (postmenstrual age in weeks) - 0.46 mm, and 0.17 * (postmenstrual age in weeks) - 4.0 mm(2), respectively. CONCLUSION: We identified the sizes of the intracranial optic nerve and optic tract in neonates at term-equivalent age. The postmenstrual age at MRI independently positively correlated with the sizes. PMID- 26646151 TI - Imaging findings of bronchial atresia in fetuses, neonates and infants. AB - Congenital lung malformations are increasingly detected before birth. However, bronchial atresia is rarely identified in utero and not always recognized in neonates. There are two types of atresia: 1) proximal, located at the level of the mainstem or the proximal lobar bronchi, which is extremely rare and usually lethal during pregnancy, causing a tremendous volume increase of the distal involved lung with secondary hypoplasia of the normal lung, and 2) peripheral, located at the segmental/subsegmental bronchial level, which may present as an isolated lesion or as part of a complex congenital malformation. Prenatal findings are mostly nonspecific. Postnatal exams show overinflated lung areas and focal bronchial dilations. The typical fluid-filled bronchoceles are not always observed in neonates but develop progressively in the first months of life. This pictorial essay describes the spectrum of imaging findings of bronchial atresia in fetuses, neonates and infants. PMID- 26646153 TI - A Genome-Wide Screen with Nicotinamide to Identify Sirtuin-Dependent Pathways in Saccharomyces cerevisiae. AB - Sirtuins are evolutionarily conserved NAD-dependent deacetylases that catalyze the cleavage of NAD(+) into nicotinamide (NAM), which can act as a pan-sirtuin inhibitor in unicellular and multicellular organisms. Sirtuins regulate processes such as transcription, DNA damage repair, chromosome segregation, and longevity extension in yeast and metazoans. The founding member of the evolutionarily conserved sirtuin family, SIR2, was first identified in budding yeast. Subsequent studies led to the identification of four yeast SIR2 homologs HST1, HST2, HST3, and HST4. Understanding the downstream physiological consequences of inhibiting sirtuins can be challenging since most studies focus on single or double deletions of sirtuins, and mating defects in SIR2 deletions hamper genome-wide screens. This represents an important gap in our knowledge of how sirtuins function in highly complex biological processes such as aging, metabolism, and chromosome segregation. In this report, we used a genome-wide screen to explore sirtuin-dependent processes in Saccharomyces cerevisiae by identifying deletion mutants that are sensitive to NAM. We identified 55 genes in total, 36 of which have not been previously reported to be dependent on sirtuins. We find that genome stability pathways are particularly vulnerable to loss of sirtuin activity. Here, we provide evidence that defects in sister chromatid cohesion renders cells sensitive to growth in the presence of NAM. The results of our screen provide a broad view of the biological pathways sensitive to inhibition of sirtuins, and advance our understanding of the function of sirtuins and NAD(+) biology. PMID- 26646152 TI - Diversity and Divergence of Dinoflagellate Histone Proteins. AB - Histone proteins and the nucleosomal organization of chromatin are near-universal eukaroytic features, with the exception of dinoflagellates. Previous studies have suggested that histones do not play a major role in the packaging of dinoflagellate genomes, although several genomic and transcriptomic surveys have detected a full set of core histone genes. Here, transcriptomic and genomic sequence data from multiple dinoflagellate lineages are analyzed, and the diversity of histone proteins and their variants characterized, with particular focus on their potential post-translational modifications and the conservation of the histone code. In addition, the set of putative epigenetic mark readers and writers, chromatin remodelers and histone chaperones are examined. Dinoflagellates clearly express the most derived set of histones among all autonomous eukaryote nuclei, consistent with a combination of relaxation of sequence constraints imposed by the histone code and the presence of numerous specialized histone variants. The histone code itself appears to have diverged significantly in some of its components, yet others are conserved, implying conservation of the associated biochemical processes. Specifically, and with major implications for the function of histones in dinoflagellates, the results presented here strongly suggest that transcription through nucleosomal arrays happens in dinoflagellates. Finally, the plausible roles of histones in dinoflagellate nuclei are discussed. PMID- 26646154 TI - Small Quaternary Inhibitors K298 and K524: Cholinesterases Inhibition, Absorption, Brain Distribution, and Toxicity. AB - Inhibitors of acetylcholinesterase (AChE) may be used in the treatment of various cholinergic deficits, among them being myasthenia gravis (MG). This paper describes the first in vivo data for promising small quaternary inhibitors (K298 and K524): acute toxicity study, cholinesterase inhibition, absorption, and blood brain barrier penetration. The newly prepared AChE inhibitors (bis-quinolinium and quinolinium compounds) possess a positive charge in the molecule which ensures that anti-AChE action is restricted to peripheral effect. HPLC-MS was used for determination of real plasma and brain concentration in the pharmacokinetic part of the study, and standard non-compartmental analysis was performed. The maximum plasma concentrations were attained at 30 min (K298; 928.76 +/- 115.20 ng/ml) and 39 min (K524; 812.40 +/- 54.96 ng/ml) after i.m. APPLICATION: Both compounds are in fact able to target the central nervous system. It seems that the difference in the CNS distribution profile depends on an active efflux system. The K524 brain concentration was actively decreased to below an effective level; in contrast, K298 progressively accumulated in brain tissue. Peripheral AChE inhibitors are still first-line treatment in the mild forms of MG. Commonly prescribed carbamates have many severe side effects related to AChE carbamylation. The search for new treatment strategies is still important. Unlike carbamates, these new compounds target AChE via apparent pi-pi or pi-cationic interaction aside at the AChE catalytic site. PMID- 26646156 TI - Application of mutant JAK2V617F for in vitro generation of red blood cells. AB - BACKGROUND: In vitro generation of red blood cells (RBCs) from hematopoietic stem cells (HSCs) has been reported, but the collection of 1 * 10(5) to 1 * 10(6) CD34+ cells present in cord and peripheral blood is too small for expansion to 1 * 10(12) cells in 1 unit of RBCs. We transduced JAK2V617F gene, the most common mutation with polycythemia vera (PV), into cord blood-derived CD34+ cells. This PV model was expected to increase cell proliferation without the addition of erythropoietin (EPO) in early phase of differentiation. STUDY DESIGN AND METHODS: Empty vector (control), wild-type JAK2 (wJAK2), and mutant JAK2V617F (mJAK2) were transduced into CD34+ cells using a lentivirus system. The CD34+ cells were then differentiated to the RBCs in a culture system. The cells were analyzed for cell number, differential count, and morphologic changes. Cultured RBCs were tested for oxygen equilibrium. RESULTS: wJAK2- and mJAK2-transduced cells showed higher proliferation capacity until Day 21 than control cells; interestingly, only mJAK2 transduced cells were highly increased on Day 7 during EPO-free culture. However, both wJAK2- and mJAK2-tranduced cells had more delayed differentiation than control, but they had a higher portion of completely matured RBCs and orthochromatic erythroblasts. Furthermore, mJAK2-tranduced cells showed more differentiation into RBCs than wJAK2-transduced cells and they had a normal hemoglobin dissociation curve. CONCLUSION: This is the first trial to use a PV erythropoiesis model for RBC differentiation from stem cells. The transduction of HSCs with mJAK2 increased their proliferation capacity in EPO-free culture conditions. This model may also be useful for investigating the pathogenesis of PV. PMID- 26646155 TI - Gap Junction Intercellular Communication Mediates Ammonia-Induced Neurotoxicity. AB - Astrocytes are important brain targets of ammonia, a neurotoxin implicated in the development of hepatic encephalopathy. During hyperammonemia, the pivotal role of astrocytes in brain function and homeostasis is impaired. These cells are abundantly interconnected by gap junctions (GJ), which are intercellular channels that allow the exchange of signaling molecules and metabolites. This communication may also increase cellular vulnerability during injuries, while GJ uncoupling could limit the extension of a lesion. Therefore, the current study was performed to investigate whether astrocyte coupling through GJ contributes to ammonia-induced cytotoxicity. We found that carbenoxolone (CBX), an effective GJ blocker, prevented the following effects induced by ammonia in astrocyte primary cultures: (1) decrease in cell viability and membrane integrity; (2) increase in reactive oxygen species production; (3) decrease in GSH intracellular levels; (4) GS activity; (5) pro-inflammatory cytokine release. On the other hand, CBX had no effect on C6 astroglial cells, which are poorly coupled via GJ. To our knowledge, this study provides the first evidence that GJ play a role in ammonia-induced cytotoxicity. Although more studies in vivo are required to confirm our hypothesis, our data suggest that GJ communication between astrocytes may transmit damage signals and excitotoxic components from unhealthy to normal cells, thereby contributing to the propagation of the neurotoxicity of ammonia. PMID- 26646157 TI - Toxic effects of indoxacarb enantiomers on the embryonic development and induction of apoptosis in zebrafish larvae (Danio rerio). AB - Indoxacarb is a highly potent insecticide widely used to control Lepidoptera insects in vegetable, tea, cotton, and rice fields. It can run off into aquatic environments. It is consisted of two enantiomers. Environmental risks and aquatic toxicity of indoxacarb enantiomers have not been fully investigated. In this study, zebrafish (Danio rerio) embryos were exposed to varying concentrations of (-)-R-indoxacarb and (+)-S-indoxacarb until 96-h post-fertilization (hpf) to assess the embryonic toxicity. (-)-R-indoxacarb was 1.3-fold more toxic than (+) S-isomer to zebrafish embryos at 96 hpf. (-)-R-indoxacarb exhibited reduction in body length and pericardial edema compared with (+)-S-indoxacarb. (-)-R indoxacarb decreased the hatching rate sixfold greater than (+)-S-indoxacarb. The rate of pericardial edema induced by (-)-R-indoxacarb was 2.5 times greater than that by (+)-S-indoxacarb. The heart rate of the larvae exposed to (-)-R indoxacarb was 30% lower than that to (+)-S-indoxacarb. In addition, exposure to the chiral isomers resulted in significant increases in apoptosis; interestingly (-)-R-indoxacarb induced apoptosis in the heart area, whereas (+)-S-indoxacarb induced apoptosis in the head area. (c) 2015 Wiley Periodicals, Inc. Environ Toxicol 32: 7-16, 2017. PMID- 26646158 TI - Templated C-C and C-N Bond Formation Facilitated by a Molybdenum(VI) Metal Center. AB - Preparation of molybdenum dioxido complexes with novel iminophenolate ligands bearing pendant secondary amide functionalities led to unprecedented C-C and C-N coupling reactions of two alpha-iminoamides upon coordination. The diastereoselective cyclization to asymmetric imidazolidines occurs at the metal center in two consecutive steps via a monocoupled intermediate. A meaningful mechanism is proposed on the basis of full characterization of intermediate and final molybdenum-containing products by spectroscopic means and by single-crystal X-ray diffraction analyses. This process constitutes the first example of a diastereoselective self-cyclization of two alpha-iminoamides. PMID- 26646159 TI - A case of successful detection of disseminated gastrointestinal stromal tumors by ascites smear cytology using cell block preparation with DOG1 immunostaining. AB - Cytological features of gastrointestinal stromal tumors (GISTs) have been reported, especially regarding fine-needle aspiration cytology, including immunostaining for c-kit and DOG1. Meanwhile, cytological findings of GISTs on ascites cytology have rarely been reported, which may be owing to the rare appearance of GIST tumor cells in ascites. Herein, we present a 66-year-old woman who had disseminated GISTs in the abdomen. The GIST tumor cells appeared sparsely in the ascites smear cytology using ascites obtained at the time of autopsy. Even when widespread intra-abdominal dissemination takes place, GISTs may be hard to detect in ascites smear cytology, based on the experience of this case. However, immunohistochemistry of DOG1 using a cell block preparation was found to clearly visualize the GIST tumor cells, although they were sparsely present. Immunostaining of c-kit did not provide as clear an identification of the tumor cells as DOG1 did. When suspicious about GISTs, it is wise to prepare a cell block to make it possible to visualize the tumor cells immunohistochemically. PMID- 26646161 TI - Triggering of Suicidal Erythrocyte Death by Zosuquidar. AB - BACKGROUND: The P-glycoprotein inhibitor zosuquidar (LY335979) is clinically used to augment the effect of cytostatic drugs on suicidal tumor cell death or apoptosis. The present study explored whether the substance is cytotoxic to erythrocytes. Upon injury, erythrocytes may undergo suicidal cell death or eryptosis, which is characterized by cell shrinkage and translocation of cell membrane phosphatidylserine to the erythrocyte surface. Signaling of eryptosis include increase of cytosolic Ca2+-activity ([Ca2+]i), oxidative stress and activation of several kinases, such as p38 kinase and protein kinase C. METHODS: Phosphatidylserine abundance at the erythrocyte surface was quantified from binding of FITC-labelled annexin-V, cell volume from forward scatter, [Ca2+]i from Fluo3-fluorescence, and reactive oxygen species (ROS) from 2',7' dichlorodihydrofluorescein diacetate (DCFDA) fluorescence. RESULTS: A 48 h treatment of human erythrocytes with zosuquidar significantly increased the percentage of annexin-V-binding cells (2 and 4 ug/ml), significantly decreased forward scatter (4 ug/ml), significantly increased [Ca2+]i (4 ug/ml), but did not significantly modify ROS. The up-regulation of annexin-V-binding following zosuquidar (4 ug/ml) treatment was significantly blunted by removal of extracellular Ca2+, by presence of p38 kinase inhibitor SB203580 (2 uM) and by presence of protein kinase C inhibitor calphostin (100 nM). CONCLUSIONS: Exposure of erythrocytes to zosuquidar triggers suicidal erythrocyte death with erythrocyte shrinkage and erythrocyte membrane scrambling, an effect involving Ca2+ entry and requiring activity of SB203580 and calphostin sensitive kinases. PMID- 26646160 TI - Environmental tobacco smoke exposure and health disparities: 8-year longitudinal findings from a large cohort of Thai adults. AB - BACKGROUND: In rich countries, smokers, active or passive, often belong to disadvantaged groups. Less is known of tobacco patterns in the developing world. Hence, we seek out to investigate mental and physical health consequences of smoke exposure as well as tobacco-related inequality in transitional middle income Thailand. METHODS: We studied a nationwide cohort of 87,151 middle-aged and older adults that we have been following for eight years (2005-2013) for emerging chronic diseases. Logistic regression was used to identify attributes associated with passive smoke exposure. Longitudinal associations between smoke exposure and wellbeing (SF-8) or psychological distress (Kessler 6) were investigated with multiple linear regression or multivariate logistic regression analysis. RESULTS: A high proportion of cohort members, especially females, were passive smokers at home and at public transport stations; males were more exposed at workplace and recreational places. We observed a social gradient with more passive smoking in poorer people. We also observed a dose response relationship linking graded smoke exposures (current, former, passive, non-exposed) to less wellbeing and more psychological distress (p-trend < 0.001). Female smokers in general had less wellbeing and more distress. CONCLUSION: Our findings add to current knowledge on the impact of active and passive smoking on health in a transitional economy. Promotion of smoking cessation programs both in public and at home could also potentially reduce adverse disparities in health and wellbeing in middle and lower income settings such as Thailand. PMID- 26646163 TI - Gaucher Disease Type 2 Presenting with Collodion Membrane and Blueberry Muffin Lesions. AB - Collodion membrane is most closely associated with forms of autosomal recessive congenital ichthyosis, but the differential diagnosis includes many other less common etiologies. Herein we present a case of Gaucher disease (GD) type 2 in a neonate presenting with collodion membrane in addition to blueberry muffin lesions. The clinical presentation and etiology of GD and the differential diagnoses for collodion membrane and blueberry muffin lesions are briefly reviewed. PMID- 26646164 TI - Excessive testing of adults with type 2 diabetes. PMID- 26646162 TI - Acute and Chronic Hepatitis E Virus Infection in Human Immunodeficiency Virus Infected U.S. Women. AB - Exposure to hepatitis E virus (HEV) is common in the United States, but there are few data on prevalence of HEV/human immunodeficiency virus (HIV) coinfection in U.S. POPULATIONS: We tested 2,919 plasma samples collected from HIV-infected (HIV(+)) women and men enrolled in U.S. cohort studies for HEV viremia using a high-throughput nucleic acid testing (NAT) platform. NAT(+) samples were confirmed by real-time polymerase chain reaction. Samples were selected for testing primarily on the basis of biomarkers of liver disease and immune suppression. Prevalence of HEV viremia was 3 of 2,606 and 0 of 313 in tested plasma samples collected from HIV(+) women and men, respectively. All HEV isolates were genotype 3a. Based on follow-up testing of stored samples, 1 woman had chronic HEV infection for >4 years whereas 2 women had acute HEV detectable at only a single study visit. CONCLUSIONS: To our knowledge, this is the first reported case of chronic HEV infection in an HIV(+) U.S. individual. We also confirm that chronic HEV infection can persist despite a CD4(+) count >200 cells/mm(3). Overall, though, these data suggest that HEV infection is rare in the HIV(+) U.S. population. PMID- 26646165 TI - [Preclinical duty of care during cuff pressure management]. AB - BACKGROUND: Airway morbidity is influenced by different factors. Independent of the main emergency health problem, airway morbidity factors may exacerbate a possible poor outcome (e.g., bleeding, tongue swelling, nerve lesion). OBJECTIVES: However, insertion technique and cuff pressure management are both important for duty of care out-of-hospital emergency medicine. After securing the airway (e.g., tracheal tube or supraglottic airway device cuff), pressure measurement is necessary. MATERIALS AND METHODS: In a number of recent publications, a largely forgotten issue has come into the focus of preclinical science. This issue became particularly relevant in the admitting hospital. RESULTS: The results from the aforementioned publications show that preclinical management of cuff pressure is not taken sufficiently into consideration, resulting in possible harm to the patient. DISCUSSION: It is important and safe to use a cuff pressure device. The initial cuff pressure and if necessary corrected value should be documented. PMID- 26646166 TI - Microbial aerosol liberation from soiled textiles isolated during routine residuals handling in a modern health care setting. AB - BACKGROUND: A wide variety of specialty textiles are used in health care settings for bedding, clothing, and privacy. The ability of textiles to host or otherwise sequester microbes has been well documented; however, their reciprocal potential for liberating airborne bacteria remains poorly characterized. In response, a multi-season survey of bacterial bioaerosols was conducted in the origin and terminus of residual paths which are specifically designed to isolate soiled hospital textiles as they are moved to laundering. This survey used conventional optical particle counting which incorporated multi-channel fluorescence in conjunction with molecular phylogenetic analyses to characterize the bioaerosols liberated during soiled textile storage--immediately before and after the occupation of a modern hospital. Although outfitted with a HEPA filtration system, the number of airborne particles presenting fluorescing optical signatures consistent with airborne bacteria and fungi significantly increased in textile holding rooms soon after the hospital's commissioning, even though these isolated residual areas rarely host personnel. The bioaerosol liberated during textile storage was characterized using Illumina MiSeq sequencing of bacterial 16S ribosomal ribonucleic acid (rRNA) genes. Gene copies recovered by quantitative PCR from aerosol collected in co-located impingers were consistent with fluorescence gated optical particle counting. RESULTS: The relative abundance patterns of proximal bacterial bioaerosol were such that the air in the origin and terminus of textile storage rooms could not be differentiated once the hospital began processing soiled linens. Genes from microbes typically associating with human skin, feces, and hair--Staphylococcus, Propionibacteria, Corynebacteria, Lactobacillus, and Streptococcus spp.--dominated the aerosol abundance profiles in textile holding rooms, which were generally far less diverse than communities recovered from surfaces in patient rooms. CONCLUSIONS: These results suggest that aerosol partitioning from the routine handling of soiled textiles can contribute to airborne exposures in the health care environment. PMID- 26646168 TI - A pseudo-tetragonal tungsten bronze superstructure: a combined solution of the crystal structure of K6.4(Nb,Ta)(36.3)O94 with advanced transmission electron microscopy and neutron diffraction. AB - The crystal structure of the K6.4Nb28.2Ta8.1O94 pseudo-tetragonal tungsten bronze type oxide was determined using a combination of X-ray powder diffraction, neutron diffraction and transmission electron microscopy techniques, including electron diffraction, high angle annular dark field scanning transmission electron microscopy (HAADF-STEM), annular bright field STEM (ABF-STEM) and energy dispersive X-ray compositional mapping (STEM-EDX). The compound crystallizes in the space group Pbam with unit cell parameters a = 37.468(9) A, b = 12.493(3) A, c = 3.95333(15) A. The structure consists of corner sharing (Nb,Ta)O6 octahedra forming trigonal, tetragonal and pentagonal tunnels. All tetragonal tunnels are occupied by K(+) ions, while 1/3 of the pentagonal tunnels are preferentially occupied by Nb(5+)/Ta(5+) and 2/3 are occupied by K(+) in a regular pattern. A fractional substitution of K(+) in the pentagonal tunnels by Nb(5+)/Ta(5+) is suggested by the analysis of the HAADF-STEM images. In contrast to similar structures, such as K2Nb8O21, also parts of the trigonal tunnels are fractionally occupied by K(+) cations. PMID- 26646167 TI - DNA damage and repair capacity in workers exposed to low concentrations of benzene. AB - DNA damage and cellular repair capacity were studied in 18 male fuel tanker drivers and 13 male filling-station attendants exposed to low and very low concentrations of benzene, respectively, and compared to 20 males with no occupational exposure (controls). Exposure to airborne benzene was measured using passive personal samplers, and internal doses were assayed through the biomarkers t,t-muconic acid, S-phenylmercapturic acid and urinary benzene. DNA damage was evaluated using tail intensity (TI) determined by the comet assay in peripheral lymphocytes. Urinary 7-hydro-8-oxo-2'-deoxyguanosine (8-oxodG) was measured as a biomarker of oxidative damage. DNA repair kinetics were assessed using the comet assay in lymphocytes sampled 20 and 60 min post H2O2 exposure. Benzene exposure differed significantly between the drivers (median 246.3 ug/m(3)), attendants (median 13.8 ug/m(3)), and controls (median 4.1 ug/m(3)). There were no differences in TI and 8-oxodG among the three groups, or between smokers and non smokers. DNA repair kinetics were similar among the drivers, attendants and controls, although the comet assay on H2 O2 -damaged lymphocytes after 60 min revealed significantly lower levels of TI only in drivers. The DNA repair process in smokers was similar to that observed in drivers. In conclusion, this study found no relationship between low levels of benzene exposure and DNA damage, although there was evidence that exposure interferes with DNA repair kinetics. The biological impact of this finding on the onset of genotoxic effects in exposed workers has still to be ascertained. PMID- 26646169 TI - Temperature-responsive molecular recognition chromatography using phenylalanine and tryptophan derived polymer modified silica beads. AB - Temperature-responsive polymers incorporating molecular-recognition sites were developed as stationary phases for high-performance liquid chromatography (HPLC). The grafted stationary phases consisted of functional copolymers composed of N isopropylacrylamide (NIPAAm) and N-acryloyl aromatic amino acid methyl esters, i.e., phenylalanine and tryptophan methyl esters (Phe-OMe and Trp-OMe). Three novel temperature-responsive polymers, P(NIPAAm-co-Phe-OMe5), P(NIPAAm-co-Phe OMe10), and P(NIPAAm-co-Trp-OMe5), were synthesized. These copolymers exhibited a reversible hydrophilic/hydrophobic phase transition at their lower critical solution temperatures (LCSTs). The polymers were grafted onto aminopropyl silica using an activated ester-amine coupling method, and were packed into a stainless steel column, which was connected to an HPLC system. Temperature-responsive chromatography was conducted using water as the sole mobile phase. More hydrophobic analytes were retained longer, and the retention times of aromatic steroids and aromatic amino acids were dramatically increased. This indicated that pi-pi interactions occurred between the phenyl or indole moieties of phenylalanine or tryptophan, respectively, and the aromatic compounds. Furthermore, the retention times of compounds with hydrogen bond acceptors were higher with P(NIPAAm-co-Trp-OMe5), which contained indole as a hydrogen bond donor, than with P(NIPAAm-co-Phe-OMe5). This indicated that hydrogen bonding occurred between the stationary phase and the analytes. These results indicate that hydrophobic, pi-pi, and hydrogen bonding interactions all affected the separation mode of the temperature-responsive chromatography, and led to selective separation with molecular recognition. Both temperature-response and molecular recognition characteristics are present in the proposed separation system that utilizes a temperature-responsive polymer bearing aromatic amino acid derivatives. PMID- 26646170 TI - Development and validation of an indirect ELISA as a confirmatory test for surveillance of infectious bovine rhinotracheitis in vaccinated herds. AB - BACKGROUND: Bovine herpesvirus 1 (BoHV1) is a member of the viral subfamily of Alphaherpesvirinae that infects various species, including cattle, sheep, and goats. The virus causes infectious bovine rhinotracheitis (IBR), which is included in a European list of diseases that may require control and eradication programs. The lack of confirmatory tests affects the validity of diagnostic tools, especially those used for vaccinated herds. In this study, we report the development and validation of an indirect enzyme-linked immunosorbent assay (ELISA) based on BoHV1 glycoprotein E, which was expressed as a secreted recombinant antigen in a mammalian cell system. The performance of the new rec-gE ELISA was compared with that of commercially available indirect and/or blocking ELISAs. RESULTS: The sample set included blood sera from animals from IBR positive farms, IBR-free farms, and marker-vaccinated farms. The indirect ELISA proposed in this study is based on antibody reactivity against BoHV1 gE, and showed high sensitivity and specificity (98.41 and 99.76 %, respectively). CONCLUSIONS: The ELISA performed well, in terms of both its diagnostic sensitivity and specificity, and as a confirmatory methodology, and therefore should improve the diagnostic protocols used for IBR surveillance. PMID- 26646172 TI - [Regional Management of Stroke Care and Neurosurgery]. PMID- 26646173 TI - [Cell-Based Therapy for Stroke Patients]. PMID- 26646171 TI - Bromodomain Proteins Contribute to Maintenance of Bloodstream Form Stage Identity in the African Trypanosome. AB - Trypanosoma brucei, the causative agent of African sleeping sickness, is transmitted to its mammalian host by the tsetse. In the fly, the parasite's surface is covered with invariant procyclin, while in the mammal it resides extracellularly in its bloodstream form (BF) and is densely covered with highly immunogenic Variant Surface Glycoprotein (VSG). In the BF, the parasite varies this highly immunogenic surface VSG using a repertoire of ~2500 distinct VSG genes. Recent reports in mammalian systems point to a role for histone acetyl lysine recognizing bromodomain proteins in the maintenance of stem cell fate, leading us to hypothesize that bromodomain proteins may maintain the BF cell fate in trypanosomes. Using small-molecule inhibitors and genetic mutants for individual bromodomain proteins, we performed RNA-seq experiments that revealed changes in the transcriptome similar to those seen in cells differentiating from the BF to the insect stage. This was recapitulated at the protein level by the appearance of insect-stage proteins on the cell surface. Furthermore, bromodomain inhibition disrupts two major BF-specific immune evasion mechanisms that trypanosomes harness to evade mammalian host antibody responses. First, monoallelic expression of the antigenically varied VSG is disrupted. Second, rapid internalization of antibodies bound to VSG on the surface of the trypanosome is blocked. Thus, our studies reveal a role for trypanosome bromodomain proteins in maintaining bloodstream stage identity and immune evasion. Importantly, bromodomain inhibition leads to a decrease in virulence in a mouse model of infection, establishing these proteins as potential therapeutic drug targets for trypanosomiasis. Our 1.25A resolution crystal structure of a trypanosome bromodomain in complex with I-BET151 reveals a novel binding mode of the inhibitor, which serves as a promising starting point for rational drug design. PMID- 26646174 TI - [Possible Cerebral Infarction due to Multiple Segmental Cerebral Vasospasms after Carotid Artery Stenting: A Case Report]. AB - A 62-year-old man was admitted due to consciousness disturbance and motor aphasia. Magnetic resonance (MR) images demonstrated watershed infarctions in the territory of the left middle cerebral artery, occlusion of the left internal carotid artery, and severe stenosis of the right internal carotid artery at the neck. He was treated with a recombinant tissue plasminogen activator. One month later, angiography revealed recanalization of the left internal carotid artery with residual severe stenosis at the neck. We attempted carotid artery stenting (CAS) on the left internal carotid artery, but could not pass the guide wire through the stenosis. Therefore, we performed CAS on the right carotid artery instead. At the second day after CAS, the patient showed consciousness disturbance, right hemiparesis, and motor aphasia. MR images showed a new infarction in the left cerebral hemisphere and bilateral multifocal segmental arterial constrictions. By keeping his blood pressure at a high enough level for one week, his symptoms were relieved, and MR images showed resolution of the vessel constrictions. From this case, we can conclude that this kind of multiple segmental vasospasms after CAS require contrasting treatments to those for hyperperfusion syndrome. Interventionalists should be aware of this condition and its treatments. PMID- 26646175 TI - [Disseminated Nocardiosis Complicated by Multiple Brain Abscesses: A Case Report]. AB - We report a relatively rare case of a disseminated type of nocardiosis without lung involvement. A 75-year-old man developed moderate fever and disturbed consciousness and was admitted to our hospital. Laboratory examinations revealed signs of inflammation. Chest X-rays indicated no abnormalities, but brain MRI showed ring-like enhancement lesions in the right temporal and left frontal lobes. Similar lesions were identified in the left kidney and right leg. The brain lesions were purulent and were surgically irrigated. Gram- and Kinyoun positive bacteria were identified, and the patient was diagnosed as suffering from a disseminated type of nocardiosis without lung involvement. He was treated with trimethoprim-sulfamethoxazole for over 10 months. The postoperative course was uneventful, and he was discharged without any neurological sequelae two months after surgery. Kinyoun staining was important in early diagnosis and hence providing appropriate therapy for life-threatening nocardiosis. PMID- 26646176 TI - [Stent-Assisted Coil Embolization of a Dissecting Aneurysm of the Posterior Cerebral Artery: A Case Report]. AB - Dissecting aneurysms of the posterior cerebral artery (PCA) are rare, especially those at the P1 segment. Here, we describe the case of a 57-year-old woman with a subarachnoid hemorrhage (SAH). Computed tomography angiography (CTA) and digital subtraction angiography (DSA) revealed a small (3 mm) dissecting aneurysm with the typical pearl-and-string sign at the right P1 segment. Fourteen days after onset, the patient developed aphasia. DSA revealed vasospasm of the right middle cerebral artery, and we performed endovascular treatment by the intra-arterial injection of 1-(5-isoquinolinesulfonyl) homopiperazine. After this treatment, the patient's symptoms recovered immediately. Vertebral angiography revealed enlargement of the dissecting aneurysm (up to 7 mm diameter). We started a loading dose of 300 mg aspirin and 400 mg clopidogrel after observing growth of the aneurysm. Fifteen days after onset, we performed a stent-assisted coil embolization, and obtained nearly complete obliteration of the aneurysm with preserved patency of the parent artery. Six-month follow-up DSA demonstrated complete occlusion of the aneurysm with good patency of the stented PCA; the patient was at modified Rankin Scale 1. In the treatment of ruptured dissecting aneurysms, parent vessel occlusion (PVO) with aneurysm is common. However, PVO may cause both cerebral infarction of the distal area and perforator occlusion of the occluded vessel. Stent-assisted coil embolization can preserve parent vessel flow and obliterate the aneurysm. Stents offer a therapeutic alternative for PCA dissecting aneurysms, especially when PVO cannot be tolerated. PMID- 26646177 TI - [A Rare Case of Subependymoma of the Septum Pellucidum as Intratumoral Hemorrhage]. AB - Subependymomas (SEs) are rare, benign, noninvasive, slow-growing tumors located anywhere along the ventricular walls. They arise most frequently in the fourth ventricle followed by the lateral ventricle, and less frequently in the septum pellucidum, third ventricle, and spinal cord. Most SEs are found incidentally at autopsy, but some may produce clinical symptoms. Tumor-related hemorrhage represents an extremely rare presentation sign. We describe a rare case of septum pellucidum SE as tumoral hemorrhage. The tumor was totally removed via an interhemispheric transcallosal approach. Histological examination found typical SE. Although the patient had transient memory impairment, he had a good postoperative course and was discharged on the twenty-first postoperative day. PMID- 26646178 TI - [A Case of Wernicke's Encephalopathy Presenting with Acute Deterioration of Consciousness Caused by Peripheral Parenteral Nutrition]. AB - We report the case of a 67-year-old woman with Wernicke's encephalopathy(WE), who had been suffering from repeated vomiting and poor oral intake due to both reflux esophagitis and atrophic gastritis. She presented with altered of consciousness, horizontal nystagmus, and gait disturbance, and acute deterioration of consciousness was observed after starting peripheral parenteral nutrition (PPN). Brain MRI showed bilateral high intensity lesions in the medial thalamus and the dorsal midbrain on FLAIR and T2-weighted images. Although brain MRI characteristics are useful for diagnosing WE, it is possible that there are no abnormal MRI findings in its early stages. In addition, only 10-20% of WE cases present with the classical clinical triad of confusion, ophthalmoplegia, and ataxia. Therefore, confirming the diagnosis can be challenging. In general, rapid improvement of symptoms is observed with prompt vitamin B1 supplementation. However, delays in treatment can result in irreversible amnesia and ataxia. Furthermore, in the state of vitamin B1 deficiency, even PPN, not just total parenteral nutrition, can worsen symptoms, and this deterioration is attributed to the glucose load. PMID- 26646179 TI - [Update Knowledge for Brain Tumors (2) Molecular Pathology for Gliomas]. PMID- 26646180 TI - Near-infrared photoactivatable control of Ca(2+) signaling and optogenetic immunomodulation. AB - The application of current channelrhodopsin-based optogenetic tools is limited by the lack of strict ion selectivity and the inability to extend the spectra sensitivity into the near-infrared (NIR) tissue transmissible range. Here we present an NIR-stimulable optogenetic platform (termed 'Opto-CRAC') that selectively and remotely controls Ca(2+) oscillations and Ca(2+)-responsive gene expression to regulate the function of non-excitable cells, including T lymphocytes, macrophages and dendritic cells. When coupled to upconversion nanoparticles, the optogenetic operation window is shifted from the visible range to NIR wavelengths to enable wireless photoactivation of Ca(2+)-dependent signaling and optogenetic modulation of immunoinflammatory responses. In a mouse model of melanoma by using ovalbumin as surrogate tumor antigen, Opto-CRAC has been shown to act as a genetically-encoded 'photoactivatable adjuvant' to improve antigen-specific immune responses to specifically destruct tumor cells. Our study represents a solid step forward towards the goal of achieving remote and wireless control of Ca(2+)-modulated activities with tailored function. PMID- 26646181 TI - Structural basis of death domain signaling in the p75 neurotrophin receptor. AB - Death domains (DDs) mediate assembly of oligomeric complexes for activation of downstream signaling pathways through incompletely understood mechanisms. Here we report structures of complexes formed by the DD of p75 neurotrophin receptor (p75(NTR)) with RhoGDI, for activation of the RhoA pathway, with caspase recruitment domain (CARD) of RIP2 kinase, for activation of the NF-kB pathway, and with itself, revealing how DD dimerization controls access of intracellular effectors to the receptor. RIP2 CARD and RhoGDI bind to p75(NTR) DD at partially overlapping epitopes with over 100-fold difference in affinity, revealing the mechanism by which RIP2 recruitment displaces RhoGDI upon ligand binding. The p75(NTR) DD forms non-covalent, low-affinity symmetric dimers in solution. The dimer interface overlaps with RIP2 CARD but not RhoGDI binding sites, supporting a model of receptor activation triggered by separation of DDs. These structures reveal how competitive protein-protein interactions orchestrate the hierarchical activation of downstream pathways in non-catalytic receptors. PMID- 26646182 TI - Identification of NPC1 as the target of U18666A, an inhibitor of lysosomal cholesterol export and Ebola infection. AB - Niemann-Pick C1 (NPC1) is a lysosomal membrane protein that exports cholesterol derived from receptor-mediated uptake of LDL, and it also mediates cellular entry of Ebola virus. Cholesterol export is inhibited by nanomolar concentrations of U18666A, a cationic sterol. To identify the target of U18666A, we synthesized U X, a U18666A derivative with a benzophenone that permits ultraviolet-induced crosslinking. When added to CHO cells, U-X crosslinked to NPC1. Crosslinking was blocked by U18666A derivatives that block cholesterol export, but not derivatives lacking blocking activity. Crosslinking was prevented by point mutation in the sterol-sensing domain (SSD) of NPC1, but not by point mutation in the N-terminal domain (NTD). These data suggest that the SSD contains a U18666A-inhibitable site required for cholesterol export distinct from the cholesterol-binding site in the NTD. Inasmuch as inhibition of Ebola requires 100-fold higher concentrations of U18666A, the high affinity U16888A-binding site is likely not required for virus entry. PMID- 26646183 TI - Internal models for interpreting neural population activity during sensorimotor control. AB - To successfully guide limb movements, the brain takes in sensory information about the limb, internally tracks the state of the limb, and produces appropriate motor commands. It is widely believed that this process uses an internal model, which describes our prior beliefs about how the limb responds to motor commands. Here, we leveraged a brain-machine interface (BMI) paradigm in rhesus monkeys and novel statistical analyses of neural population activity to gain insight into moment-by-moment internal model computations. We discovered that a mismatch between subjects' internal models and the actual BMI explains roughly 65% of movement errors, as well as long-standing deficiencies in BMI speed control. We then used the internal models to characterize how the neural population activity changes during BMI learning. More broadly, this work provides an approach for interpreting neural population activity in the context of how prior beliefs guide the transformation of sensory input to motor output. PMID- 26646184 TI - Mouse V1 population correlates of visual detection rely on heterogeneity within neuronal response patterns. AB - Previous studies have demonstrated the importance of the primary sensory cortex for the detection, discrimination, and awareness of visual stimuli, but it is unknown how neuronal populations in this area process detected and undetected stimuli differently. Critical differences may reside in the mean strength of responses to visual stimuli, as reflected in bulk signals detectable in functional magnetic resonance imaging, electro-encephalogram, or magnetoencephalography studies, or may be more subtly composed of differentiated activity of individual sensory neurons. Quantifying single-cell Ca(2+) responses to visual stimuli recorded with in vivo two-photon imaging, we found that visual detection correlates more strongly with population response heterogeneity rather than overall response strength. Moreover, neuronal populations showed consistencies in activation patterns across temporally spaced trials in association with hit responses, but not during nondetections. Contrary to models relying on temporally stable networks or bulk signaling, these results suggest that detection depends on transient differentiation in neuronal activity within cortical populations. PMID- 26646185 TI - Mathematical modeling of the West Africa Ebola epidemic. AB - As of November 2015, the Ebola virus disease (EVD) epidemic that began in West Africa in late 2013 is waning. The human toll includes more than 28,000 EVD cases and 11,000 deaths in Guinea, Liberia, and Sierra Leone, the most heavily-affected countries. We reviewed 66 mathematical modeling studies of the EVD epidemic published in the peer-reviewed literature to assess the key uncertainties models addressed, data used for modeling, public sharing of data and results, and model performance. Based on the review, we suggest steps to improve the use of modeling in future public health emergencies. PMID- 26646186 TI - Mechanical sensitivity of Piezo1 ion channels can be tuned by cellular membrane tension. AB - Piezo1 ion channels mediate the conversion of mechanical forces into electrical signals and are critical for responsiveness to touch in metazoans. The apparent mechanical sensitivity of Piezo1 varies substantially across cellular environments, stimulating methods and protocols, raising the fundamental questions of what precise physical stimulus activates the channel and how its stimulus sensitivity is regulated. Here, we measured Piezo1 currents evoked by membrane stretch in three patch configurations, while simultaneously visualizing and measuring membrane geometry. Building on this approach, we developed protocols to minimize resting membrane curvature and tension prior to probing Piezo1 activity. We find that Piezo1 responds to lateral membrane tension with exquisite sensitivity as compared to other mechanically activated channels and that resting tension can drive channel inactivation, thereby tuning overall mechanical sensitivity of Piezo1. Our results explain how Piezo1 can function efficiently and with adaptable sensitivity as a sensor of mechanical stimulation in diverse cellular contexts. PMID- 26646187 TI - Comparative Analysis of Tunical Plication vs. Intralesional Injection Therapy for Ventral Peyronie's Disease. AB - INTRODUCTION: Approximately 10% of Peyronie's disease (PD) patients present with ventral curvatures and, as such, there is a paucity of data describing the optimal approach for treatment. AIM: This study aims to compare the outcomes of surgery (tunical plication [TP]) and intralesional injection (ILI) therapy (interferon-alpha2b) in men with ventral PD. MATERIALS AND METHODS: Retrospective data were collected from two centers: Tulane University (ILI) and Technical University of Munich (TP). Collected variables included patient demographics, pre and post-treatment sexual function, rigorous penile measurements (curvature, length, and penile vascular findings), and post-treatment outcomes. RESULTS: A total of 35 patients with ventral PD (21 ILI and 14 TP) were included in the study. There were no significant differences between the two groups prior to the interventions. There was a significantly better improvement in mean curvature with TP (46.4 degrees) as compared with ILI (9.3), P < 0.0001. TP was also associated with a significantly higher rate of >=20% improvement in curvature as compared with ILI (100% vs. 67%, P = 0.027). Although there was no significant difference in post-treatment change in Sexual Health Inventory for Men (SHIM) scores between the groups, 36% of the ILI patients noted an improved SHIM score as compared with none in the TP group. Erect penile length was preserved or improved in 67% of the ILI group vs. 14% of the TP group, P = 0.005. CONCLUSIONS: TP confers a better overall improvement in penile curvature as compared with ILI in patients with ventral PD. Preserved or improved erect penile length and SHIM scores may be observed in patients undergoing ILI. 12:2492-2498. PMID- 26646188 TI - A Novel High Mechanical Property PLGA Composite Matrix Loaded with Nanodiamond Phospholipid Compound for Bone Tissue Engineering. AB - A potential bone tissue engineering material was produced from a biodegradable polymer, poly(lactic-co-glycolic acid) (PLGA), loaded with nanodiamond phospholipid compound (NDPC) via physical mixing. On the basis of hydrophobic effects and physical absorption, we modified the original hydrophilic surface of the nanodiamond (NDs) with phospholipids to be amphipathic, forming a typical core-shell structure. The ND-phospholipid weight ratio was optimized to generate sample NDPC50 (i.e., ND-phospholipid weight ratio of 100:50), and NDPC50 was able to be dispersed in a PLGA matrix at up to 20 wt %. Compared to a pure PLGA matrix, the introduction of 10 wt % of NDPC (i.e., sample NDPC50-PF10) resulted in a significant improvement in the material's mechanical and surface properties, including a decrease in the water contact angle from 80 to 55 degrees , an approximately 100% increase in the Young's modulus, and an approximate 550% increase in hardness, thus closely resembling that of human cortical bone. As a novel matrix supporting human osteoblast (hFOB1.19) growth, NDPC50-PFs with different amounts of NDPC50 demonstrated no negative effects on cell proliferation and osteogenic differentiation. Furthermore, we focused on the behaviors of NDPC-PFs implanted into mice for 8 weeks and found that NDPC-PFs induced acceptable immune response and can reduce the rapid biodegradation of PLGA matrix. Our results represent the first in vivo research on ND (or NDPC) as nanofillers in a polymer matrix for bone tissue engineering. The high mechanical properties, good in vitro and in vivo biocompatibility, and increased mineralization capability suggest that biodegradable PLGA composite matrices loaded with NDPC may potentially be useful for a variety of biomedical applications, especially bone tissue engineering. PMID- 26646189 TI - Translating Health Services Research into Practice in the Safety Net. AB - OBJECTIVE: To summarize research relating to health services research translation in the safety net through analysis of the literature and case study of a safety net system. DATA SOURCES/STUDY SETTING: Literature review and key informant interviews at an integrated safety net hospital. STUDY DESIGN: This paper describes the results of a comprehensive literature review of translational science literature as applied to health care paired with qualitative analysis of five key informant interviews conducted with senior-level management at Denver Health and Hospital Authority. PRINCIPAL FINDINGS: Results from the literature suggest that implementing innovation may be more difficult in the safety net due to multiple factors, including financial and organizational constraints. Results from key informant interviews confirmed the reality of financial barriers to innovation implementation but also implied that factors, including institutional respect for data, organizational attitudes, and leadership support, could compensate for disadvantages. CONCLUSIONS: Translating research into practice is of critical importance to safety net providers, which are under increased pressure to improve patient care and satisfaction. Results suggest that translational research done in the safety net can better illuminate the special challenges of this setting; more such research is needed. PMID- 26646190 TI - Message Framing, Perceived Susceptibility, and Intentions to Vaccinate Children Against HPV Among African American Parents. AB - This research examines the interaction effect of message framing (gain vs. loss) and perceived susceptibility (i.e., perceived likelihood that one's child is at risk of contracting HPV) on African American parents' intentions to vaccinate their children against HPV. Results of an experiment (N = 193) in which parents were exposed to either a gain-framed or loss-framed message about HPV vaccination revealed a significant interaction between message framing and perceived susceptibility when parents were required to pay for the vaccine. The specific pattern of interaction suggested that parents who perceived their children to be at high risk of contracting HPV were more persuaded by the gain-framed message, whereas those who believed their children to be at low risk of contracting HPV were more persuaded by the loss-framed message. Implications of the findings for HPV vaccination messaging are discussed. PMID- 26646191 TI - Sigma Receptor Binding Assays. AB - Sigma receptors, both Sigma-1(S1R) and Sigma-2 (S2R), are small molecule regulated, primarily endoplasmic reticulum (ER) membrane-associated sites. A number of drugs bind to sigma receptors, including the antipsychotic haloperidol and (+)-pentazocine, an opioid analgesic. Sigma receptors are implicated in many central nervous system disorders, in particular Alzheimer's disease and conditions associated with motor control, such as Amyotrophic Lateral Sclerosis (ALS). Described in this unit are radioligand binding assays used for the pharmacological characterization of S1R and S2R. Methods detailed include a radioligand saturation binding assay for defining receptor densities and a competitive inhibition binding assay employing [3H]-(+)-pentazocine for identifying and characterizing novel ligands that interact with S1R. Procedures using [3H]-1,3-di(2-tolyl)guanidine ([3H]-DTG), a nonselective sigma receptor ligand, are described for conducting a saturation binding and competitive inhibition assays for the S2R site. These protocols are of value in drug discovery in identifying new sigma ligands and in the characterization of these receptors. PMID- 26646192 TI - In Vitro Binding of [3H]PSB-0413 to P2Y12 Receptors. AB - The P2Y12/ADP receptor plays a central role in platelet activation. Characterization of this receptor is mandatory for studying disorders associated with a P2Y12 receptor defect and for evaluating P2Y12 receptor agonists and antagonists. In the absence of suitable anti-P2Y12 antibodies, radioligand binding assays are the only way to conduct such studies. While various radioligands were employed in the past for this purpose, none were found to be suitable for routine use. Described in this unit are protocols for quantitatively and qualitatively assessing P2Y12 receptors with [3H]PSB-0413, a selective antagonist for this site. The saturation and competition assays described herein make possible the determination of P2Y12 receptor density on cells, as well as the potencies and affinities of test agents at this site. PMID- 26646193 TI - A Human Induced Pluripotent Stem Cell-Derived Cardiomyocyte (hiPSC-CM) Multielectrode Array Assay for Preclinical Cardiac Electrophysiology Safety Screening. AB - Cardiotoxicity is a leading cause of compound attrition during drug development. Preclinical models used to assess the risk for compound-induced effects on cardiac electrophysiology largely rely on animals that can differ in terms of sensitivity and specificity to the targeted clinical response. There is currently no in vitro human cardiomyocyte model for routine preclinical compound screening, as adult human cardiac tissue is unsuitable for such screening. The commercial availability of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC CMs) makes possible the development of assays for assessing compound-induced effects on cardiac function in a human cardiomyocyte-like model. Using multielectrode array (MEA) technology with hiPSC-CMs provides a facile screen for compound-induced effects on cardiac electrophysiology. The MEA data generated from hiPSC-CMs correlate well with the results of conventional preclinical assays and clinical findings. Described in this unit is a technique for measuring extracellular field potentials from hiPSC-CMs using MEA technology to screen for compound-induced effects on cardiac electrophysiology. PMID- 26646194 TI - Measurement of Glucose Uptake in Cultured Cells. AB - Facilitative glucose uptake transport systems are ubiquitous in animal cells and are responsible for transporting glucose across cell surface membranes. Evaluation of glucose uptake is crucial in the study of numerous diseases and metabolic disorders such as myocardial ischemia, diabetes mellitus, and cancer. Detailed in this unit are laboratory methods for assessing glucose uptake into mammalian cells. The unit is divided into five sections: (1) a brief overview of glucose uptake assays in cultured cells; (2) a method for measuring glucose uptake using radiolabeled 3-O-methylglucose; (3) a method for measuring glucose uptake using radiolabeled 2-deoxyglucose (2DG); (4) a microplate method for measuring 2DG-uptake using an enzymatic, fluorometric assay; and (5) a microplate based method using a fluorescent analog of 2DG. PMID- 26646195 TI - Double-Chambered Ferritin Platform: Dual-Function Payloads of Cytotoxic Peptides and Fluorescent Protein. AB - Ferritin cage nanoparticles are promising platforms for targeted delivery of imaging and therapeutic agents. One of the main advantages of cage nanoparticles is the ability to display multiple functionalities through genetic modification so as to achieve desired therapeutic or diagnostic functions. Ferritin complexes formed from short ferritin (sFt) lacking the fifth helix can accommodate dual peptide and protein functionalities on N- and C-terminal sites in sFt monomers. The resulting double-chambered NanoCage (DCNC) offers the potential of dual activities; these activities are augmented by the avidity of the ligands, which do not impede each other's function. Here we demonstrated proof-of-concept of DCNCs, loading the tumor-targeting proapoptotic peptide CGKRK(KLAKLAK)2 onto the N-terminal chamber and green fluorescent protein (GFP) onto the C-terminal chamber. The resulting KLAK-sFt-GFP DCNCs were internalized into the human breast adenocarcinoma cell line MDA-MB-231 and induced apoptosis. These findings suggest that DCNCs containing various combinations of peptides and proteins could be applied as therapeutics in different diseases. PMID- 26646196 TI - Safety of lipid emulsion in very low-birthweight infants according to cytokine level. AB - BACKGROUND: The aim of this study was to verify whether lipid emulsion treatment aggravates infection and inflammation in very low-birthweight (VLBW) infants. STUDY DESIGN: Very low-birthweight (<1500 g) infants born at <32 weeks gestational age between October 2013 and October 2014 at Dokkyo Medical University Hospital (Mibu, Tochigi, Japan) were treated with or without i.v. nutrition with a lipid emulsion. Infants were excluded who had congenital abnormalities, could not receive i.v. nutrition because of poor general condition, or on physician decision. Lipid emulsion with purified soybean oil was initiated at 0.5 g/kg/day on postnatal day 1. The dose was increased to 1 g/kg/day, and then to 1.5 g/kg/day (maximum dose). Blood tests were performed before (day 1) and after (day 8) initiation of lipid emulsion treatment. Interleukin (IL)-6, IL-8, monocyte chemotactic protein 1 (MCP-1), tumor necrosis factor-alpha (TNF-alpha), C-reactive protein (CRP), total bilirubin (T-Bil), direct bilirubin (D-Bil) and insulin were measured. Changes in respiratory condition, amount of oxygen used, and phototherapy duration were investigated. RESULTS: A total of 17 treated and 15 untreated VLBW infants were enrolled. IL-6, IL-8, MCP-1, TNF-alpha, CRP, T-Bil, D-Bil and insulin on days 1 and 8; respirator or surfactant use; amount of oxygen used; and phototherapy duration were not significantly different between the two groups. CONCLUSIONS: Lipid emulsion treatment did not increase inflammatory cytokine levels or aggravate respiratory disorders. Lipid emulsions, if proven safe, could be used to treat VLBW infants soon after birth, which may prevent extrauterine growth restriction and improve intellectual development prognosis. PMID- 26646197 TI - The long-term effectiveness of the Family Check-Up on school-age conduct problems: Moderation by neighborhood deprivation. AB - Several studies suggest that neighborhood deprivation is a unique risk factor in child and adolescent development of problem behavior. We sought to examine whether previously established intervention effects of the Family Check-Up (FCU) on child conduct problems at age 7.5 would persist through age 9.5, and whether neighborhood deprivation would moderate these effects. In addition, we examined whether improvements in parent-child interaction during early childhood associated with the FCU would be related to later reductions in child aggression among families living in the highest risk neighborhoods. Using a multisite cohort of at-risk children identified on the basis of family, child, and socioeconomic risk and randomly assigned to the FCU, intervention effects were found to be moderated by neighborhood deprivation, such that they were only directly present for those living at moderate versus extreme levels of neighborhood deprivation. In addition, improvements in child aggression were evident for children living in extreme neighborhood deprivation when parents improved the quality of their parent-child interaction during the toddler period (i.e., moderated mediation). Implications of the findings are discussed in relation to the possibilities and possible limitations in prevention of early problem behavior for those children living in extreme and moderate levels of poverty. PMID- 26646198 TI - Corruption as a Propensity: Personality and Motivational Determinants Among Nigerians. AB - Psychologically oriented studies on corruption are lacking despite the fact that psychology has contributed enormously to the understanding of criminal behaviors over the past decades. Part of this problem relates to the lack of psychological tone in the definition and measurement of corruption. Taking a clue from the extensive psychological discourse on crime, which provides strong evidence for the existence of criminal tendencies, we conceptualized corruption here in terms of propensity. Possible personality and motivation determinants of this propensity were then explored. Results revealed that extraversion and conscientiousness positively and inversely predicted corruption tendencies, respectively. Results further showed that extrinsic motivation positively potentiates corruption tendencies, whereas intrinsic motivation was inversely related to corruption tendencies. Analysis of demographic variables revealed that males were more likely to be corrupt than their female counterparts. In general, findings here are consistent with the criminal behavior literature, which strongly suggests that the study of corruption is indeed amenable to psychological theories and methods and that individual differences variables constitute important explanatory variables in this regard. PMID- 26646199 TI - Cardiac MRI right ventricle / left ventricle (RV/LV) volume ratio improves detection of RV enlargement. AB - PURPOSE: To determine the normal range of the ratio of right ventricular (RV) end diastolic volume to left ventricular (LV) end-diastolic volume by magnetic resonance imaging (MRI) and examine whether combining this volume ratio with RVEDV indexed to body surface area (RVEDVi) increased the detection of RV dilation in patients with pulmonary arterial hypertension (PAH). MATERIALS AND METHODS: MRI-derived ventricular function and volumes were measured in a control group (n = 152) and in patients with PAH (n = 46). Images were acquired with a 1.5T Siemens or a 1.5T Philips scanner using a steady-state free procession sequence. Proposed criteria for the detection of RV enlargement, including RVEDVi alone, RV/LV volume ratio alone, and combining both criteria, were evaluated in both groups. RESULTS: The range (mean +/- 2 standard deviations) for the volume ratio in the normal population was found to be 0.906-1.266; there was no difference between genders (P = 0.70). Combining this ratio with RVEDVi detected RV enlargement in 21.7% (P < 0.001) PAH patients (volume ratio >=1.27) who were not identified by the RVEDVi alone (>104 mL/m(2) for females and >113 mL/m(2) for males). CONCLUSION: Combining RV/LV volume ratio with indexed RVEDV increased detection of RV enlargement in a PAH population. This result may have potential impact in RV size assessment. J. Magn. Reson. Imaging 2016;43:1379-1385. PMID- 26646200 TI - Highly focused high-frequency travelling surface acoustic waves (SAW) for rapid single-particle sorting. AB - High-speed sorting is an essential process in a number of clinical and research applications, where single cells, droplets and particles are segregated based on their properties in a continuous flow. With recent developments in the field of microscale actuation, there is increasing interest in replicating the functions available to conventional fluorescence activated cell sorting (FACS) flow cytometry in integrated on-chip systems, which have substantial advantages in cost and portability. Surface acoustic wave (SAW) devices are ideal for many acoustofluidic applications, and have been used to perform such sorting at rates on the order of kHz. Essential to the accuracy of this sorting, however, is the dimensions of the region over which sorting occurs, where a smaller sorting region can largely avoid inaccurate sorting across a range of sample concentrations. Here we demonstrate the use of flow focusing and a highly focused SAW generated by a high-frequency (386 MHz), 10 MUm wavelength set of focused interdigital transducers (FIDTs) on a piezoelectric lithium niobate substrate, yielding an effective sorting region only ~25 MUm wide, with sub-millisecond pulses generated at up to kHz rates. Furthermore, because of the use of high frequencies, actuation of particles as small as 2 MUm can be realized. Such devices represent a substantial step forward in the evolution of highly localized forces for lab-on-a-chip microfluidic applications. PMID- 26646201 TI - Dendritic cell subtypes: a new way to study host-pathogen interaction. PMID- 26646202 TI - Stretch-Induced Helical Conformations in Poly(l-lysine)/Hyaluronic Acid Multilayers. AB - We investigate the effect of stretching on the secondary structure of cross linked poly(l-lysine)/hyaluronic acid (PLL/HA) multilayers. We show that stretching these films induces changes in the secondary structure of PLL chains. Our results suggest that not only alpha- but also 310-helices might form in the film under stretching. Such 310-helices have never been observed for PLL so far. These changes of the secondary structure of PLL are reversible, i.e., when returning to the nonstretched state one recovers the initial film structure. Using molecular dynamics simulations of chains composed of 20 l-lysine residues (PLL20), we find that these chains never adopt a helical conformation in water. In contrast, when the end-to-end distance of the chains is restrained to values smaller than the mean end-to-end distance of free chains, a distance domain rarely explored by the free chains, helical conformations become accessible. Moreover, the formation of not only alpha- but also 310-helices is predicted by the simulations. These results suggest that the change of the end-to-end distance of PLL chains in the stretched film is at the origin of the helix formation. PMID- 26646203 TI - Photoperiodic and Diurnal Regulation of WNT Signaling in the Arcuate Nucleus of the Female Djungarian Hamster, Phodopus sungorus. AB - The WNT pathway was shown to play an important role in the adult central nervous system. We previously identified the WNT pathway as a novel integration site of the adipokine leptin in mediating its neuroendocrine control of metabolism in obese mice. Here we investigated the implication of WNT signaling in seasonal body weight regulation exhibited by the Djungarian hamster (Phodopus sungorus), a seasonal mammal that exhibits profound annual changes in leptin sensitivity. We furthermore investigated whether crucial components of the WNT pathway are regulated in a diurnal manner. Gene expression of key components of the WNT pathway in the hypothalamus of hamsters acclimated to either long day (LD) or short day (SD) photoperiod was analyzed by in situ hybridization. We detected elevated expression of the genes WNT-4, Axin-2, Cyclin-D1, and SFRP-2, in the hypothalamic arcuate nucleus, a key energy balance integration site, during LD compared with SD as well as a diurnal regulation of Axin-2, Cyclin-D1, and DKK-3. Investigating the effect of photoperiod as well as leptin on the activation (phosphorylation) of the WNT coreceptor LRP-6-(Ser1490) by immunohistochemistry, we found elevated activity in the arcuate nucleus during LD relative to SD as well as after leptin treatment (2 mg/kg body weight). These findings indicate that differential WNT signaling may be associated with seasonal body weight regulation and is partially regulated in a diurnal manner in the adult brain. Furthermore, they suggest that this pathway plays a key role in the neuroendocrine regulation of body weight and integration of the leptin signal. PMID- 26646204 TI - High-Fat Diet and Palmitate Alter the Rhythmic Secretion of Glucagon-Like Peptide 1 by the Rodent L-cell. AB - Secretion of the incretin hormone, glucagon-like peptide-1 (GLP-1), by the intestinal L-cell is rhythmically regulated by an independent molecular clock. However, the impact of factors known to affect the activity of similar cell autonomous clocks, such as circulating glucocorticoids and high-fat feeding, on GLP-1 secretory patterns remains to be elucidated. Herein the role of the endogenous corticosterone rhythm on the pattern of GLP-1 and insulin nutrient induced responses was examined in corticosterone pellet-implanted rats. Moreover, the impact of nutrient excess on the time-dependent secretion of both hormones was assessed in rats fed a high-fat, high-sucrose diet. Finally, the effects of the saturated fatty acid, palmitate, on the L-cell molecular clock and GLP-1 secretion were investigated in vitro using murine GLUTag L-cells. Diurnal variations in GLP-1 and insulin nutrient-induced responses were maintained in animals lacking an endogenous corticosterone rhythm, suggesting that glucocorticoids are not the predominant entrainment factor for L-cell rhythmic activity. In addition to hyperglycemia, hyperinsulinemia, insulin resistance, and disorganization of feeding behavior, high-fat high-sucrose-fed rats showed a total abrogation of the diurnal variation in GLP-1 and insulin nutrient-induced responses, with comparable levels of both hormones at the normal peak (5:00 pm) and trough (5:00 am) of their daily pattern. Finally, palmitate incubation induced profound derangements in the rhythmic expression of circadian oscillators in GLUTag L-cells and severely impaired the secretory activity of these cells. Collectively our findings demonstrate that obesogenic diets disrupt the rhythmic activity of the L-cell, partially through a direct effect of specific nutritional components. PMID- 26646205 TI - Unique Distal Enhancers Linked to the Mouse Tnfsf11 Gene Direct Tissue-Specific and Inflammation-Induced Expression of RANKL. AB - Receptor activator of nuclear factor kappaB ligand (RANKL) is expressed by a number of cell types to participate in diverse physiological functions. We have previously identified 10 distal RANKL enhancers. Earlier studies have shown that RL-D5 is a multifunctional RANKL enhancer. Deletion of RL-D5 from the mouse genome leads to lower skeletal and lymphoid tissue RANKL, causing a high bone mass phenotype. Herein, we determine the physiological role and lineage specificity of 2 additional RANKL enhancers, RL-D6 and RL-T1, which are located 83 and 123 kb upstream of the gene's transcriptional start site, respectively. Lack of RL-D6 or RL-T1 did not alter skeletal RANKL or bone mineral density up to 48 weeks of age. Although both RL-D5 and RL-T1 contributed to activation induction of T-cell RANKL, RL-T1 knockout mice had drastically low lymphocyte and lymphoid tissue RANKL levels, indicating that RL-T1 is the major regulator of lymphocyte RANKL. Moreover, RL-T1 knockout mice had lower circulating soluble RANKL, suggesting that lymphocytes are important sources of circulating soluble RANKL. Under physiological conditions, lack of RL-D6 did not alter RANKL expression. However, lack of RL-D5 or RL-D6, but not of RL-T1, blunted the oncostatin M and lipopolysaccharide induction of RANKL ex vivo and in vivo, suggesting that RL-D5 and RL-D6 coregulate the inflammation-mediated induction of RANKL in osteocytes and osteoblasts while lack of RL-D6 did not alter secondary hyperparathyroidism or lactation induction of RANKL or bone loss. These results suggest that although RL-D5 mediates RANKL expression in multiple lineages, other cell type- or factor-specific enhancers are required for its appropriate control, demonstrating the cell type-specific and complex regulation of RANKL expression. PMID- 26646206 TI - Modulation of human Nav1.7 channel gating by synthetic alpha-scorpion toxin OD1 and its analogs. AB - Nine different voltage-gated sodium channel isoforms are responsible for inducing and propagating action potentials in the mammalian nervous system. The Nav1.7 channel isoform plays an important role in conducting nociceptive signals. Specific mutations of this isoform may impair gating behavior of the channel resulting in several pain syndromes. In addition to channel mutations, similar or opposite changes in gating may be produced by spider and scorpion toxins binding to different parts of the voltage-gated sodium channel. In the present study, we analyzed the effects of the alpha-scorpion toxin OD1 and 2 synthetic toxin analogs on the gating properties of the Nav1.7 sodium channel. All toxins potently inhibited channel inactivation, however, both toxin analogs showed substantially increased potency by more than one order of magnitude when compared with that of wild-type OD1. The decay phase of the whole-cell Na(+) current was substantially slower in the presence of toxins than in their absence. Single channel recordings in the presence of the toxins revealed that Na(+) current inactivation slowed due to prolonged flickering of the channel between open and closed states. Our findings support the voltage-sensor trapping model of alpha scorpion toxin action, in which the toxin prevents a conformational change in the domain IV voltage sensor that normally leads to fast channel inactivation. PMID- 26646207 TI - Including sustainability issues in nurse education: A comparative study of first year student nurses' attitudes in four European countries. AB - INTRODUCTION: Education in sustainable development is a goal recognised by a large number of countries and a vital concept in healthcare. It is therefore important that nurse education incorporates elements of sustainable development into nursing education curricula. However, there is limited research on student nurses' attitudes towards sustainability and no comparison of attitudes towards sustainability and its inclusion in the nursing curriculum across Europe. AIM: This project aims to assess student nurses' attitudes towards sustainability, its relevance to nursing and its inclusion in the nursing curricula. 1. To assess base-line attitudes at the start of nursing and midwifery training; 2. To compare sustainability awareness between students participating in training in a number of European universities. DESIGN: A comparative survey design using the Sustainability Attitudes in Nursing Survey (SANS_2) questionnaire. SETTINGS: Nursing classes of Universities and Nursing Schools in four European countries were investigated using a questionnaire consisting of five sustainability-related items. PARTICIPANTS: 916 nursing students (UK: 450, Germany: 196, Spain: 124, Switzerland: 146). DATA ANALYSIS: Standard descriptive and inferential statistical methods were used to establish psychometric quality (Principal Components Analysis, Cronbach's alpha, Pearson correlations) and compare student nurses from the four countries. RESULTS: The reliability of SANS_2 was good (Cronbach's alpha=.82) and the five items loaded on a single factor which explained 58% of variance. ANOVA of the SANS_2 total score showed significant differences between countries with German nursing students showing more sustainability awareness than students from the UK and Spain. CONCLUSIONS: SANS_2 is a reliable instrument to assess nursing students' sustainability awareness; there are significant differences in sustainability awareness of students of different European countries. Limitations of the study include non-random sampling, possible method effects and social desirability effects. RELEVANCE TO CLINICAL PRACTICE: Sustainability will become increasingly important in clinical practice; greater knowledge about the attitudes of nurses towards sustainability can support the development and testing of sustainability-focused teaching and learning materials. PMID- 26646208 TI - Adaptive Servo-ventilation and the Treatment of Central Sleep Apnea in Heart Failure. Let's Not Throw the Baby Out with the Bathwater. PMID- 26646209 TI - Declining resilience of ecosystem functions under biodiversity loss. AB - The composition of species communities is changing rapidly through drivers such as habitat loss and climate change, with potentially serious consequences for the resilience of ecosystem functions on which humans depend. To assess such changes in resilience, we analyse trends in the frequency of species in Great Britain that provide key ecosystem functions--specifically decomposition, carbon sequestration, pollination, pest control and cultural values. For 4,424 species over four decades, there have been significant net declines among animal species that provide pollination, pest control and cultural values. Groups providing decomposition and carbon sequestration remain relatively stable, as fewer species are in decline and these are offset by large numbers of new arrivals into Great Britain. While there is general concern about degradation of a wide range of ecosystem functions, our results suggest actions should focus on particular functions for which there is evidence of substantial erosion of their resilience. PMID- 26646210 TI - Intraprotein transmethylation via a CH3-Co(iii) species in myoglobin reconstituted with a cobalt corrinoid complex. AB - Myoglobin reconstituted with a cobalt tetradehydrocorrin derivative, rMb(Co(TDHC)), was investigated as a hybrid model to replicate the reaction catalyzed by methionine synthase. In the heme pocket, Co(I)(TDHC) is found to react with methyl iodide to form the methylated cobalt complex, CH3 Co(III)(TDHC), although it is known that a similar nucleophilic reaction of a cobalt(i) tetradehydrocorrin complex does not proceed effectively in organic solvents. Furthermore, we observed a residue- and regio-selective transmethylation from the CH3-Co(III)(TDHC) species to the Nepsilon2 atom of the His64 imidazole ring in myoglobin at 25 degrees C over a period of 48 h. These findings indicate that the protein matrix promotes the model reaction of methionine synthase via the methylated cobalt complex. A theoretical calculation provides support for a plausible reaction mechanism wherein the axial histidine ligation stabilizes the methylated cobalt complex and subsequent histidine flipping induces the transmethylation via heterolytic cleavage of the Co-CH3 bond in the hybrid model. PMID- 26646211 TI - Multicomponent reactions of methyl substituted all-cis tetrafluorocyclohexane aldehydes. AB - This paper reports the preparation of methyl substituted all-cis tetrafluorocyclohexanes prepared from a Birch reduction of benzoic acid, worked up with a methyl iodide quench. The resultant methylcyclohexadiene carboxylic acid was reduced to the alcohol, protected as an ether and then a sequence of functional group manipulations carried out to introduce four fluorines. The cyclohexadienyl ring was then epoxidised and the C-O bonds sequentially converted through deoxyfluorination reactions to two sets of isomers of all-cis tetrafluorocyclohexane isomers. The blocking methyl group renders the ring safe to hydrogen fluoride elimination. Deprotection of the benzylic ether and then oxidation gave aldehydes which were then used in Ugi and Passerini multicomponent reactions, allowing this facially polarised cyclohexane to be incorporated into peptidic structural motifs. PMID- 26646212 TI - Building a knowledge translation platform in Malawi to support evidence-informed health policy. AB - With the support of the World Health Organization's Evidence-Informed Policy Network, knowledge translation platforms have been developed throughout Africa, the Americas, Eastern Europe, and Asia to further evidence-informed national health policy. In this commentary, we discuss the approaches, activities and early lessons learned from the development of a Knowledge Translation Platform in Malawi (KTPMalawi). Through ongoing leadership, as well as financial and administrative support, the Malawi Ministry of Health has strongly signalled its intention to utilize a knowledge translation platform methodology to support evidence-informed national health policy. A unique partnership between Dignitas International, a medical and research non-governmental organization, and the Malawi Ministry of Health, has established KTPMalawi to engage national-level policymakers, researchers and implementers in a coordinated approach to the generation and utilization of health-sector research. Utilizing a methodology developed and tested by knowledge translation platforms across Africa, a stakeholder mapping exercise and initial capacity building workshops were undertaken and a multidisciplinary Steering Committee was formed. This Steering Committee prioritized the development of two initial Communities of Practice to (1) improve data utilization in the pharmaceutical supply chain and (2) improve the screening and treatment of hypertension within HIV-infected populations. Each Community of Practice's mandate is to gather and synthesize the best available global and local evidence and produce evidence briefs for policy that have been used as the primary input into structured deliberative dialogues. While a lack of sustained initial funding slowed its early development, KTPMalawi has greatly benefited from extensive technical support and mentorship by an existing network of global knowledge translation platforms. With the continued support of the Malawi Ministry of Health and the Evidence-Informed Policy Network, KTPMalawi can continue to build on its role in facilitating the use of evidence in the development and refinement of health policy in Malawi. PMID- 26646214 TI - Spontaneous hemoperitoneum secondary to metastases in the liver round ligament, an atipical presentation. PMID- 26646215 TI - Energetic stability, oxidation states, and electronic structure of Bi-doped NaTaO3: a first-principles hybrid functional study. AB - We studied the defect formation energies, oxidation states of the dopants, and electronic structures of Bi-doped NaTaO3 using first-principles hybrid density functional theory calculations. Three possible structural models, including Bi doped NaTaO3 with Bi at the Na site (Bi@Na), with Bi at the Ta site (Bi@Ta), and with Bi at both Na and Ta sites [Bi@(Na,Ta)], are constructed. Our results show that the preferred doping sites of Bi are strongly related to the preparation conditions of NaTaO3. It is energetically more favorable to form a Bi@Na structure under Na-poor conditions, to form a Bi@Ta structure under Na-rich conditions, and to form a Bi@(Na,Ta) structure under mildly Na-rich conditions. The Bi@Na doped model shows an n-type conducting character along with an expected blueshift of the optical absorption edge, in which the Bi atoms exist as Bi(3+) (6s(2)6p(0)). The Bi@Ta doped model has empty gap states consisting of Bi 6s states in its band gap, which can lead to visible-light absorption via the electron transition among the valence band, the conduction band, and the gap states. The Bi dopant is present as a Bi(5+) ion in this model, consistent with the experimental results. In contrast, the Bi@(Na,Ta) doped model has occupied gap states consisting of Bi 6s states in its band gap, and thus visible-light absorption is also expected in this system due to electron excitation from these occupied states to the conduction band, in which the Bi dopants exist as Bi(3+) ions. Our first-principles electronic structure calculations revealed the relationship between the Bi doping sites and the material preparation conditions, and clarified the oxidation states of Bi dopants in NaTaO3 as well as the origin of different visible-light photocatalytic hydrogen evolution behaviors in Bi@Ta and Bi@(Na,Ta) doped NaTaO3. This work can provide a useful reference for preparing a Bi-doped NaTaO3 photocatalyst with desired doping sites. PMID- 26646213 TI - Coagulation competence for predicting perioperative hemorrhage in patients treated with lactated Ringer's vs. Dextran--a randomized controlled trial. AB - BACKGROUND: Perioperative hemorrhage may depend on coagulation competence and this study evaluated the influence of coagulation competence on blood loss during cystectomy due to bladder cancer. METHODS: Forty patients undergoing radical cystectomy were included in a randomized controlled trial to receive either lactated Ringer's solution or Dextran 70 (Macrodex (r)) that affects coagulation competence. RESULTS: By thrombelastography evaluated coagulation competence, Dextran 70 reduced "maximal amplitude" (MA) by 25 % versus a 1 % reduction with the administration of lactated Ringer's solution (P <0.001). Blinded evaluation of the blood loss was similar in the two groups of patients - 2339 ml with the use of Dextran 70 and 1822 ml in the lactated Ringer's group (P = 0.27). Yet, the blood loss was related to the reduction in MA (r = -0.427, P = 0.008) and by multiple regression analysis independently associated with MA (P = 0.01). Thus, 11 patients in the dextran group (58 %) developed a clinical significant blood loss (>1500 ml) compared to only four patients (22 %) in the lactated Ringer's group (P = 0.04). CONCLUSIONS: With the use of Dextran 70 vs. lactated Ringer's solution during cystectomy, a relation between hemorrhage and coagulation competence is demonstrated. Significant bleeding develops based on an about 25 % reduction in thrombelastography determined maximal amplitude. A multivariable model including maximal amplitude discriminates patients with severe perioperative bleeding during cystectomy. TRIAL REGISTRATION: The study was accepted on January 7(th), 2013 at www.clinicaltrialsregister.eu EudraCT 2012 005040-20. PMID- 26646216 TI - A simple and efficient dispersion correction to the Hartree-Fock theory (3): A comprehensive performance comparison of HF-Dtq with MP2 and DFT-Ds. AB - Accurate prediction of the intermolecular interaction energy (DeltaEbind) has been a challenging and serious problem. Current in silico drug screening demands efficient and accurate evaluation of DeltaEbind for ligands and their target proteins. It is desirable that DeltaEbind including the dispersion interaction energy (Edisp) is calculated using a post-Hartree-Fock (HF) theory, such as the high-order coupled-cluster one, with a larger basis set. However, it remains computationally too expensive to apply such a one to large molecular systems. As another problem, it is necessary to consider the contribution of the basis set superposition error (BSSE) in calculation of DeltaEbind. In Bioorg. Med. Chem. Lett. 2014 and 2015, we proposed simple and efficient corrections of dispersion and BSSE for the HF theory, which is not able to express the dispersion interaction energy correctly. The current Letter, as the final one in the series, aims to verify the HF theory enhanced by the dispersion correction (HF-Dtq) in the light of reproducibility of 'accurate' intermolecular ligand-protein interaction energy values, with comprehensive comparison with the MP2 and recently proposed various DFT-D theories. Taking DeltaEbind calculated with the coupled-cluster theory coupled with a complete basis set as a reference, DeltaEbind of over a hundred small sized noncovalent complexes as well as real ligand-protein complexes models was systematically examined in terms of accuracy and computational cost. The comprehensive comparison in the current work showed that HF-Dtq is a practical and reliable approach for in silico drug screening and quantitative structure-activity relationships. PMID- 26646217 TI - Impact on monoclonal antibody production in murine hybridoma cell cultures of adenosine receptor antagonists and phosphodiesterase inhibitors. AB - The effects of different adenosine receptor antagonists and cyclic nucleotide phosphodiesterase (PDE) inhibitors on monoclonal antibody (mAb) titer and cell viability of murine hybridoma cells in culture were measured as part of our investigations to discover additives that enhance mAb production. Specific adenosine receptor antagonists and PDE inhibitors were found to enhance or decrease the titer of immunoglobulin G1 (IgG1) mAbs relative to negative controls, depending on the specific compound and cell line employed. The observed enhancements or decreases in IgG1 mAb titer appeared to be mainly due to an increase or decrease in specific productivity rates (ngmAb/cell), respectively. The different effects of the selective adenosine antagonists suggest that antagonism at the level of the adenosine A2A and A1 or the adenosine A3 receptors result in either enhancement or suppression of IgG1 mAb production by hybridoma cells. Overall, these studies have identified hitherto unknown activities of specific adenosine antagonists and PDE inhibitors which indicate they may have valuable roles as cell culture additives in industrial biomanufacturing processes designed to enhance the yields of mAbs or other recombinant proteins produced by mammalian cell culture procedures. PMID- 26646218 TI - Synthesis and evaluation of (18)F-labeled 4-nitrobenzyl derivatives for imaging tumor hypoxia with positron emission tomography: Comparison of 2 [(18)F]fluoroethyl carbonate and 2-[(18)F]fluoroethyl carbamate. AB - Two 4-nitrobenzyl derivatives, 2-fluoroethyl 4-nitrobenzyl carbonate 1 and 4 nitrobenzyl N-2-fluoroethyl carbamate 2, were radiolabeled with (18)F and evaluated for imaging tumor hypoxia with positron emission tomography. Although good tumor uptake was observed for [(18)F]1 and [(18)F]2 (>2.5%ID/g at 3-h post injection), the tracers cleared slowly from nontarget tissues (>1.5%ID/g) and exhibited extensive defluorination in vivo (>4.0%ID/g for bone). Therefore, [(18)F]1 and [(18)F]2 are not suitable for imaging tumor hypoxia due to suboptimal tumor-to-background contrasts. PMID- 26646219 TI - Synthesis of novel ethyl 1-ethyl-6-fluoro-7-(fatty amido)-1,4-dihydro-4 oxoquinoline-3-carboxylate derivatives and their biological evaluation. AB - A series of novel ethyl 1-ethyl-6-fluoro-7-(fatty amido)-1,4-dihydro-4 oxoquinoline-3-carboxylate derivatives were prepared through multistep synthesis. The key step in the synthesis was to obtain the C-7 fatty amide derivative. The azide was selectively formed at C-7 position using sodium azide at 60 degrees C. Subsequently, the azide was reduced under mild conditions using zinc and ammonium chloride to form the corresponding amine. The synthesized derivatives were further subjected to biological evaluation studies like cytotoxicity against a panel of cancer cell lines such as DU145, A549, SKOV3, MCF7 and normal lung cells, IMR-90 as well as with antimicrobial and antioxidant activities. It was observed that the carboxylated quinolone derivatives with hexanoic (8a), octanoic (8b), lauric (8d) and myristic (8e) moieties exhibited promising cytotoxicity against all the tested cancer cell lines. The results also suggested that hexanoic acid-based fatty amide carboxylated quinolone derivative (8a) exhibited promising activity against both bacterial and fungal strains and significant antibacterial activity was observed against Staphylococcus aureus MTCC 96 (MIC value of 3.9MUg/mL). The compound 8a also showed excellent anti-biofilm activity against Staphylococcus aureus MTCC 96 and Bacillus subtilis MTCC 121 with MIC values of 2.1 and 4.6MUg/mL, respectively. PMID- 26646220 TI - Visual Assessment of Age-Related White Matter Hyperintensities Using FLAIR Images at 3 T: Inter- and Intra-Rater Agreement. AB - BACKGROUND: Age-related white matter hyperintensities are frequent incidental findings on T2-weighted brain MRI, and they are evaluated in clinical practice using a visual rating scale. OBJECTIVE: To evaluate inter- and intra-rater agreement in MRI visual evaluations of age-related white matter hyperintensities made by two radiologists with different levels of experience using a visual rating scale. METHODS: Two radiologists of two different levels of experience separately rated age-related white matter hyperintensities in 40 consecutive 3 tesla brain MRI scans using the Fazekas and Schmidt visual rating scale. Ratings were made on axial FLAIR (fluid-attenuated inversion recovery) sequences. Two readings were made by each radiologist. Intra- and inter-rater agreement was statistically determined by using Cohen's weighted kappa analysis. RESULTS: Forty patients (21 females, 19 males; mean age = 57 +/- 18.43 years) were included between September and October 2011. Mean values +/- SD for visual scores were as follows: periventricular hyperintensities, between 1.175 +/- 0.9 and 1.375 +/- 0.89; number of deep white matter hyperintensity lesions, between 1.325 +/- 1.18 and 1.575 +/- 1.15, and extent of deep white matter hyperintensity lesions, between 0.925 +/- 0.78 and 1.1 +/- 0.74. Intra- and inter-rater agreement was very good (x03BA; values, 0.85-0.91 and 0.80-0.97, respectively) for each of the three visual scale criteria, with significant correlations between ratings (r = 0.95; p < 0.0001) and readings (r = 0.91; p < 0.0001). CONCLUSION: Visual assessment of age-related white matter hyperintensities by radiologists using a visual scale on FLAIR sequence is reproducible. Differences in experience level do not influence readings. Visual scale use is thus justified in common practice. PMID- 26646221 TI - Gemcitabine in patients previously treated with platinum-containing chemotherapy for refractory thymic carcinoma: radiographic assessment using the RECIST criteria and the ITMIG recommendations. AB - BACKGROUND: The key drugs for chemotherapy of thymic carcinoma are gradually being revealed in phase II and conventional retrospective studies. Gemcitabine is regarded as one of these key drugs according to the findings of clinical trials in which it was combined with capecitabine. However, the activity of single-agent gemcitabine concerning refractory thymic carcinoma remains unclear. PATIENTS AND METHODS: We conducted a retrospective review of the medical records of refractory thymic carcinoma patients previously treated with platinum-containing chemotherapy between 1980 and 2014. RESULTS: Of all 11 patients in this study, the objective response rate regarding gemcitabine was 36.4 % [95 % confidence interval (CI) 15.2-64.6] using the RECIST criteria and the response criteria proposed by the ITMIG. The median progression-free survival time was 4.3 months (95 % CI 0.7-11.0). The survival time from the start of gemcitabine treatment was 28.5 months (95 % CI 5.5-47.8), and from the start of first-line chemotherapy was 46.5 months (95 % CI 7.3-47.8). CONCLUSIONS: Gemcitabine achieved a moderate response and has the potential to be used as a key drug for thymic carcinoma. Some patients treated with gemcitabine demonstrated prolonged cancer control even in later lines of chemotherapy. PMID- 26646222 TI - Age-based disparities in treatment and outcomes of retroperitoneal rhabdomyosarcoma. AB - BACKGROUND: Elderly patients (EPs) suffering from retroperitoneal rhabdomyosarcoma (RRMS) carry a considerably poorer prognosis compared to younger patients (YPs). We hypothesized that EPs received less aggressive and comprehensive treatment than YPs, resulting in poorer survival outcomes. MATERIALS AND METHODS: All patients diagnosed with RRMS since 1998 in the National Cancer Data Base (NCDB) were reviewed for patient demographics, tumor characteristics, treatment modalities and survival outcomes. RESULTS: Of the 100 patients identified, 35 % were >=65 years of age. EPs (aged >=65 years), when compared to YPs (aged <65), were less likely to receive systemic chemotherapy (20 % EPs vs 71 % YPs, p < 0.001) and treatment at an academic center (34 % EPs vs 60 % YPs, p = 0.05), although the frequency of radiation (23 % EPs vs 31 % YPs, p = 0.40) and radical surgery (26 % EPs vs 22 % YPs, p = 0.55) were similar. EPs received treatment more frequently at comprehensive community cancer programs (57 %) and had a shorter median distance of travel for care (6.4 vs 13 miles, p = 0.009). After adjusting for gender and tumor size, EPs had a hazard ratio of 3.6 (95 % CI 1.8-7.2, p < 0.001), with a median survival of 2 months (interquartile range [IQR] 1-8 months) versus 17 months for YPs (IQR 8-43 months). CONCLUSION: Altered practice patterns exist for EPs and include reduced use of systemic chemotherapy which may contribute to poorer outcomes for RRMS patients. Although regionalization of care poses challenges, this may offer benefit to the EP group. PMID- 26646239 TI - Physiological, morphological and biochemical studies of glyphosate tolerance in Mexican Cologania (Cologania broussonetii (Balb.) DC.). AB - In recent years, glyphosate-tolerant legumes have been used as cover crops for weed management in tropical areas of Mexico. Mexican cologania (Cologania broussonetii (Balb.) DC.) is an innate glyphosate-tolerant legume with a potential as a cover crop in temperate areas of the country. In this work, glyphosate tolerance was characterized in two Mexican cologania (a treated (T) and an untreated (UT)) populations as being representatives of the species, compared in turn to a glyphosate-susceptible hairy fleabane (S) (Conyza bonariensis (L.) Cronq.) population. Experiments revealed that T and UT Mexican cologania populations had a higher tolerance index (TI), and a lower shikimic acid accumulation and foliar retention than the hairy fleabane S population. Absorption and translocation, leaf morphology and metabolism studies were only carried out in the Mexican cologania T population and the hairy fleabane S population. The latter absorbed 37% more (14)C-glyphosate compared to the Mexican cologania T at 96 h after treatment (HAT). Mexican cologania T translocated less herbicide from the treated leaf to the remainder of the plant than hairy fleabane S. The Mexican cologania T presented a greater epicuticular wax coverage percentage than the hairy fleabane S. This morphological characteristic contributed to the low glyphosate absorption observed in the Mexican cologania. In addition, the Mexican cologania T metabolized glyphosate mainly into AMPA, formaldehyde and sarcosine. These results indicate that the high glyphosate tolerance observed in Mexican cologania is mainly due to the poor penetration and translocation of glyphosate into the active site, and the high glyphosate degradation into non-toxic substances. PMID- 26646240 TI - Breadfruit (Artocarpus altilis) gibberellin 2-oxidase genes in stem elongation and abiotic stress response. AB - Breadfruit (Artocarpus altilis) is a traditional staple tree crop in the Oceania. Susceptibility to windstorm damage is a primary constraint on breadfruit cultivation. Significant tree loss due to intense tropical windstorm in the past decades has driven a widespread interest in developing breadfruit with dwarf stature. Gibberellin (GA) is one of the most important determinants of plant height. GA 2-oxidase is a key enzyme regulating the flux of GA through deactivating biologically active GAs in plants. As a first step toward understanding the molecular mechanism of growth regulation in the species, we isolated a cohort of four full-length GA2-oxidase cDNAs, AaGA2ox1- AaGA2ox4 from breadfruit. Sequence analysis indicated the deduced proteins encoded by these AaGA2oxs clustered together under the C19 GA2ox group. Transcripts of AaGA2ox1, AaGA2ox2 and AaGA2ox3 were detected in all plant organs, but exhibited highest level in source leaves and stems. In contrast, transcript of AaGA2ox4 was predominantly expressed in roots and flowers, and displayed very low expression in leaves and stems. AaGA2ox1, AaGA2ox2 and AaGA2ox3, but not AaGA2ox4 were subjected to GA feedback regulation where application of exogenous GA3 or gibberellin biosynthesis inhibitor, paclobutrazol was shown to manipulate the first internode elongation of breadfruit. Treatments of drought or high salinity increased the expression of AaGA2ox1, AaGA2ox2 and AaGA2ox4. But AaGA2ox3 was down-regulated under salt stress. The function of AaGA2oxs is discussed with particular reference to their role in stem elongation and involvement in abiotic stress response in breadfruit. PMID- 26646241 TI - Carbon nanotubes as an efficient hole collector for high voltage methylammonium lead bromide perovskite solar cells. AB - A high open circuit voltage (V(OC)) close to 1.4 V under AM 1.5, 100 mW cm(-2) conditions is achieved when carbon nanotubes (CNTs) are used as a hole conductor in methyl ammonium lead bromide (MAPbBr3) perovskite solar cells. Time-resolved photoluminescence and impedance spectroscopy investigations suggest that the observed high V(OC) is a result of the better charge extraction and lower recombination of the CNT hole conductor. Tandem solar cells with all perovskite absorbers are demonstrated with a MAPbBr3/CNT top cell and a MAPbI3 bottom cell, achieving a V(OC) of 2.24 V in series connection. The semitransparent and high voltage MAPbBr3/CNT solar cells show great potential for applications in solar cell windows, tandem solar cells and solar driven water splitting. PMID- 26646242 TI - Small Bowel Stromal Tumors: Different Clinicopathologic and Computed Tomography Features in Various Anatomic Sites. AB - Gastrointestinal stromal tumors (GISTs) can present with different clinical and immunohistochemical characteristics according to different anatomic sites. The aim of this study was to compare clinicopathologic and computed tomography (CT) features of small bowel stromal tumors located in the duodenum, jejunum, and ileum. In total, 197 patients (109 male, 88 female) with small bowel GISTs were retrospectively reviewed. All tumors had definite anatomic sites in the small bowel tract with surgical confirmation. The clinicopathologic variables included age, sex, onset of symptoms, and tumor risk category. CT variables included tumor size, degree enhancement, enhancement pattern (region of necrosis), adjacent tissue involvement, lymphadenopathy, and distant metastasis. We assessed any possible differences according to different GIST site of origin. Based on tumor size and mitotic count, the risk categories in different anatomic sites did not differ significantly between duodenal and jejunal GISTs. However, high risk ileum GISTs accounted for 66.0% of ileal cases, which was higher than duodenum cases (36.8%, P = 0.002) and jejunum cases (43.9%, P = 0.004). The mean size of GISTs in the ileum was 9.77 cm, which was significantly larger than in the duodenum (7.41 cm, P = 0.043), and in the jejunum (8.14 cm, P = 0.027). On CT images, enhancement degree appeared to gradually increase from the duodenum to the ileum in the portal phase, and the enhancement pattern presented a tendency for heterogeneity. In Conclusions, the clinicopathologic and CT features of small bowel GISTs can differ according to different primary anatomic sites. PMID- 26646244 TI - Correction: Severity of Old World Cutaneous Leishmaniasis Is Influenced by Previous Exposure to Sandfly Bites in Saudi Arabia. PMID- 26646243 TI - The Role of Neuropeptides in Mouse Models of Colitis. AB - Inflammatory bowel disease (IBD) constitutes an important clinically significant condition that results in morbidity and mortality. IBD can be generally classified into either ulcerative colitis (UC) or Crohn's disease (CD) that differs in the clinical and histopathology. The role of neuropeptides in the pathogenesis of these conditions is becoming increasingly recognized for their importance in modulating the inflammatory state. Animal models provide the greatest insight to better understand the pathophysiology of both disorders which will hopefully allow for improved treatment strategies. This review will provide a better understanding of the role of murine models for studying colitis. PMID- 26646245 TI - Viral Strain-Specific Differential Alterations in Arabidopsis Developmental Patterns. AB - Turnip mosaic virus (TuMV) infections affect many Arabidopsis developmental traits. This paper analyzes, at different levels, the development-related differential alterations induced by different strains of TuMV, represented by isolates UK 1 and JPN 1. The genomic sequence of JPN 1 TuMV isolate revealed highest divergence in the P1 and P3 viral cistrons, upon comparison with the UK 1 sequence. Infectious viral chimeras covering the whole viral genome uncovered the P3 cistron as a major viral determinant of development alterations, excluding the involvement of the PIPO open reading frame. However, constitutive transgenic expression of P3 in Arabidopsis did not induce developmental alterations nor modulate the strong effects induced by the transgenic RNA silencing suppressor HC Pro from either strain. This highlights the importance of studying viral determinants within the context of actual viral infections. Transcriptomic and interactomic analyses at different stages of plant development revealed large differences in the number of genes affected by the different infections at medium infection times but no significant differences at very early times. Biological functions affected by UK 1 (the most severe strain) included mainly stress response and transport. Most cellular components affected cell-wall transport or metabolism. Hubs in the interactome were affected upon infection. PMID- 26646246 TI - Prevalence and clinicopathological characteristics of ALK fusion subtypes in lung adenocarcinomas from Chinese populations. AB - PURPOSE: We performed this retrospective study to have a comprehensive investigation of the clinicopathological characteristics of ALK fusion-positive lung adenocarcinoma in Chinese populations. METHODS: We screened 1407 patients with primary lung adenocarcinoma from October 2007 to May 2013. Quantitative real time PCR (qRT-PCR), reverse transcriptase PCR (RT-PCR), and fluorescence in situ hybridization were performed to detect ALK fusion genes, with validation of positive results using immunohistochemistry. Clinicopathological characteristics were collected to assess prognosis in ALK fusion-positive patients. RESULTS: Of 1407 patients with lung adenocarcinoma, there were 74 (5.3 %) ALK fusion-positive patients. Patients harboring ALK fusion were significantly younger (56.0 years vs. 59.8 years p = 0.002) and were more likely to have advanced stages (stage III or stage IV) (OR 1.761; 95 % CI 1.10-2.82, p = 0.017). Lepidic predominant adenocarcinoma was rarely found in ALK fusion patients (2.7 vs. 13.5 % p = 0.025), while IMA (invasive mucinous adenocarcinoma) predominant adenocarcinoma was more frequently found (21.6 vs. 5.0 % p < 0.001). ALK fusion was neither a risk factor nor protective factor in relapse-free survival and overall survival. Male, current smoker, and EML4-ALK variant 3 indicated poor prognosis among ALK fusion-positive lung adenocarcinomas. CONCLUSIONS: ALK fusion was detected in 5.3 % (74/1407) of the Chinese patients with lung adenocarcinoma. ALK fusion defines a molecular subset of lung adenocarcinoma with unique clinicopathological characteristics. Different ALK fusion variants determine distinct prognoses. PMID- 26646247 TI - Targeted silver nanoparticles for ratiometric cell phenotyping. AB - Affinity targeting is used to deliver nanoparticles to cells and tissues. For efficient targeting, it is critical to consider the expression and accessibility of the relevant receptors in the target cells. Here, we describe isotopically barcoded silver nanoparticles (AgNPs) as a tool for auditing affinity ligand receptors in cells. Tumor penetrating peptide RPARPAR (receptor: NRP-1) and tumor homing peptide GKRK (receptor: p32) were used as affinity ligands on the AgNPs. The binding and uptake of the peptide-functionalized AgNPs by cultured PPC-1 prostate cancer and M21 melanoma cells was dependent on the cell surface expression of the cognate peptide receptors. Barcoded peptide-functionalized AgNPs were synthesized from silver and palladium isotopes. The cells were incubated with a cocktail of the barcoded nanoparticles [RPARPAR (R), GKRK (K), and control], and cellular binding and internalization of each type of nanoparticle was assessed by inductively coupled plasma mass spectrometry. The results of isotopic analysis were in agreement with data obtained using optical methods. Using ratiometric measurements, we were able to classify the PPC-1 cell line as mainly NRP-1-positive, with 75 +/- 5% R-AgNP uptake, and the M21 cell line as only p32-positive, with 89 +/- 9% K-AgNP uptake. The isotopically barcoded multiplexed AgNPs are useful as an in vitro ratiometric phenotyping tool and have potential uses in functional evaluation of the expression of accessible homing peptide receptors in vivo. PMID- 26646249 TI - Use of cloud computing in biomedicine. AB - Nowadays, biomedicine is characterised by a growing need for processing of large amounts of data in real time. This leads to new requirements for information and communication technologies (ICT). Cloud computing offers a solution to these requirements and provides many advantages, such as cost savings, elasticity and scalability of using ICT. The aim of this paper is to explore the concept of cloud computing and the related use of this concept in the area of biomedicine. Authors offer a comprehensive analysis of the implementation of the cloud computing approach in biomedical research, decomposed into infrastructure, platform and service layer, and a recommendation for processing large amounts of data in biomedicine. Firstly, the paper describes the appropriate forms and technological solutions of cloud computing. Secondly, the high-end computing paradigm of cloud computing aspects is analysed. Finally, the potential and current use of applications in scientific research of this technology in biomedicine is discussed. PMID- 26646248 TI - Prevention and treatment of Staphylococcus aureus biofilms. AB - S. aureus colonizes both artificial and tissue surfaces in humans causing chronic persistent infections that are difficult to cure. It is a notorious pathogen due to its antibiotic recalcitrance and phenotypic adaptability, both of which are facilitated by its ability to develop biofilms. S. aureus biofilms challenge conventional anti-infective approaches, most notably antibiotic therapy. Therefore there is an unmet need to develop and include parallel approaches that target S. aureus biofilm infections. This review discusses two broad anti infective strategies: (1) preventative approaches (anti-biofilm surface coatings, the inclusion of biofilm-specific vaccine antigens); and (2) approaches aimed at eradicating established S. aureus biofilms, particularly those associated with implant infections. Advances in understanding the distinct nature of S. aureus biofilm development and pathogenesis have led to growing optimism in S. aureus biofilm targeted anti-infective strategies. Further research is needed however, to see the successful administration and validation of these approaches to the diverse types of infections caused by S. aureus biofilms from multiple clinical strains. PMID- 26646250 TI - Colorectal Cancer Screening in Inflammatory Bowel Disease. AB - Patients with long-standing ulcerative colitis (UC) or Crohn's colitis are at increased risk of developing colorectal cancer (CRC). Given that most cases of CRC are thought to arise from dysplasia, previous guidelines have recommended endoscopic surveillance with random biopsies obtained from all segments of the colon involved by endoscopic or microscopic inflammation. However, recent evidence has suggested that the majority of dysplastic lesions in patients with inflammatory disease (IBD) are visible, and data have been supportive of chromoendoscopy with targeted biopsies of visible lesions versus traditional random biopsies. This review article will discuss the risk of colon cancer in patients with IBD, as well as current recommendations for CRC screening and surveillance in patients with UC or Crohn's colitis. PMID- 26646251 TI - Can Healthcare Assistant Training (CHAT) improve the relational care of older people? Study protocol for a pilot cluster randomised controlled trial. AB - BACKGROUND: People aged 75 years and over account for 1 in 4 of all hospital admissions. There has been increasing recognition of problems in the care of older people, particularly in hospitals. Evidence suggests that older people judge the care they receive in terms of kindness, empathy, compassion, respectful communication and being seen as a person not just a patient. These are aspects of care to which we refer when we use the term 'relational care'. Healthcare assistants deliver an increasing proportion of direct care to older people, yet their training needs are often overlooked. METHODS/DESIGN: This study will determine the acceptability and feasibility of a cluster randomised controlled trial of 'Older People's Shoes' a 2-day training intervention for healthcare assistants caring for older people in hospital. Within this pilot, 2-arm, parallel, cluster randomised controlled trial, healthcare assistants within acute hospital wards are randomised to either the 2-day training intervention or training as usual. Registered nurses deliver 'Older People's Shoes' over 2 days, approximately 1 week apart. It contains three components: experiential learning about ageing, exploration of older people's stories, and customer care. Outcomes will be measured at the level of patient (experience of emotional care and quality of life during their hospital stay), healthcare assistant (empathy and attitudes towards older people), and ward (quality of staff/patient interaction). Semi-structured interviews of a purposive sample of healthcare assistants receiving the intervention, and all trainers delivering the intervention, will be undertaken to gain insights into the experiences of both the intervention and the trial, and its perceived impact on practice. DISCUSSION: Few training interventions for care staff have been rigorously tested using randomised designs. This study will establish the viability of a definitive cluster randomised controlled trial of a new training intervention to improve the relational care proided by healthcare assistants working with older people in hospital. TRIAL REGISTRATION: The study was registered as an International Standard Randomised Controlled Trial ( ISRCTN10385799 ) on 29 December 2014. PMID- 26646252 TI - VNTR polymorphisms of the IL-4 and IL-1RN genes and their relationship with frailty syndrome in Mexican community-dwelling elderly. AB - Inflammation is a key event that is closely associated with the pathophysiology of frailty. The relationship of genetic polymorphisms into inflammatory cytokines with frailty remains poorly understood. The aim of this study was to investigate the association between VNTR polymorphisms of the IL-4 and IL-1RN genes with the risk of frailty. We included a sample of 630 community-dwelling elderly aged 70 and older. Both IL-4 and IL-1RN VNTR polymorphisms were genotyped by the polymerase chain reaction (PCR) method. Mean age was 77.7 years (SD = 6.0) and 52.5 % were women. The participants classified as frail were more likely to be older, had lower MMSE score (p < 0.001), and had more disability for IADL (p < 0.001) and ADL (p < 0.001). Genotypic and allelic frequencies for the IL-4 VNTR polymorphism did not show significant differences between study groups (p > 0.05). However, we just observed a significant difference in the allelic frequencies for the A2 allele of the IL-1RN VNTR polymorphism between frail and nonfrail groups (OR 1.84, 95 % CI 1.08-3.12, p = 0.02). In addition, we analyzed the combined effect of the IL-4 and IL-1RN VNTR polymorphisms and their possible association with frailty, where the combined IL-4 (low) -IL-1Ra (high) genotype was identified as a marker of risk to frailty syndrome (OR 7.86, 95 % CI 1.83 33.69, p = 0.006). Our results suggest that both A2 allele and the combined IL-4 (low) -IL-1Ra (high) genotype might be genetic markers of susceptibility to frailty in Mexican elderly. PMID- 26646254 TI - Ultrasound-targeted microbubble destruction: toward a new strategy for diabetes treatment. AB - Ultrasound-targeted microbubble destruction (UTMD) is a promising technique with an immense target-specific gene delivery potential deep inside the human body. The potential of this technique has recently been confirmed for diabetic patients. This technology allows the genes to transfer specifically into the inefficient pancreas using ultrasound energy without viral vector utilization. It has been speculated that this idea and the advent of modern gene therapy techniques could result in significant future advances. Undoubtedly, this strategy needs further investigation and many critical questions have to be answered before it can be successfully advanced. Herein, we introduce the salient features of this approach, the hurdles that must be overcome, the hopes associated with it and practical constraints to develop this method for diabetes treatment. PMID- 26646253 TI - Validation of the FRAIL scale in Mexican elderly: results from the Mexican Health and Aging Study. AB - BACKGROUND: The aging population in Latin America is characterized by not optimal conditions for good health, experiencing high burden of comorbidity, which contribute to increase the frequency of frailty; thus, identification should be a priority, to classify patients at high risk to develop its negative consequences. AIM: The objective of this analysis was to validate the FRAIL instrument to measure frailty in Mexican elderly population, from the database of the Mexican Health and Aging Study (MHAS). MATERIALS AND METHODS: Prospective, population study in Mexico, that included subjects of 60 years and older who were evaluated for the variables of frailty during the year 2001 (first wave of the study). Frailty was measured with the five-item FRAIL scale (fatigue, resistance, ambulation, illnesses, and weight loss). The robust, pre-frail or intermediate, and the frail group were considered when they had zero, one, and at least two components, respectively. Mortality, hospitalizations, falls, and functional dependency were evaluated during 2003 (second wave of the study). Relative risk was calculated for each complications, as well as hazard ratio (for mortality) through Cox regression model and odds ratio with logistic regression (for the rest of the outcomes), adjusted for covariates. RESULTS: The state of frailty was independently associated with mortality, hospitalizations, functional dependency, and falls. The pre-frailty state was only independently associated with hospitalizations, functional dependency, and falls. CONCLUSIONS: Frailty measured through the FRAIL scale, is associated with an increase in the rate of mortality, hospitalizations, dependency in activities of daily life, and falls. PMID- 26646255 TI - The response of cells derived from the supraspinatus tendon to estrogen and calciotropic hormone stimulations: in vitro study. AB - PURPOSE: The most frequent complications after rotator cuff repair (RCR) are non healing and re-tear. Age and gender are both proven risk factors for faulty RCR. This study analyzed the effects of female sex steroids and calciotropic hormones on tendon-derived cell characteristics. METHODS: Tendon-derived cells from rat supraspinatus were treated with estradiol-17beta (E2); soy isoflavones (daidzein, genistein, biochainin A); raloxifene and estrogen receptors alpha and beta agonists and antagonists; and less-calcemic vitamin-D analog, parathyroid hormone, and vehicle control for 24 h. Cell proliferation and mRNA expression of estrogen receptor alpha and beta, vitamin-D receptor (VDR), scleraxis, and collagen-1 were assessed. RESULTS: E2, Biochainin A, raloxifene, and vitamin-D significantly increased tendon-derived cell proliferation. Estrogen receptor alpha antagonists neutralized tendon-derived cells response to estradiol 17-beta; however, estrogen receptor beta antagonists did not have an effect. Scleraxis expression decreased following estradiol 17-beta and vitamin-D treatments. Vitamin-D significantly reduced collagen-1 expression, while estradiol 17-beta had no effect. Vitamin-D and estradiol 17-beta upregulated VDR expression. CONCLUSIONS: Significant tendon-derived cell proliferation can be achieved with commonly prescribed female sex and calciotropic hormones. However, collagen-1 expression remained constant or decreased following the administration of these hormones. Female sex steroids and vitamin-D promoted tendon-derived cell proliferation via estrogen receptor alpha and VDR, not estrogen receptor beta. Amplified cell proliferation was not associated with increased scleraxis and collagen-1 expression. These results have important implications to the properties of healing tendon and possible pharmaceutical therapies for patients with torn RC. Further research is warranted to expose the underling mechanisms of these effects. PMID- 26646256 TI - Warfarin use and incidence of stroke in Japanese hemodialysis patients with atrial fibrillation. AB - Atrial fibrillation (AF) is one of the major risk factor for ischemic stroke, and oral anticoagulation is generally indicated for prevention of stroke. However, the utility of oral anticoagulation for AF in dialysis patients remains controversial. In this single-center, retrospective, observational study, data from 1120 patients on maintenance hemodialysis were analyzed. Baseline medical data were collected from dialysis records including age, gender, the cause of end stage renal disease, dialysis vintage, and comorbidities. We evaluated outcomes including stroke, major hemorrhage, and death. A total of 106 (11.4 %) patients had AF. After exclusion criteria were applied, 84 patients had analyzable data. Warfarin was prescribed in 30 (35.7 %) of these patients. The remaining 54 patients were classified as the non-warfarin group. CHADS2 score was not significantly different between the warfarin and non-warfarin group. During the mean 47 months of follow up, 7 strokes occurred. However, warfarin use was not associated with the risk for stroke [hazard ratio (HR) 1.07; 95 % confidence interval (CI) 0.20-5.74]. Kaplan-Meier analysis showed no statistically significant difference in the overall survival, stroke-free survival or bleeding free survival between the warfarin and non-warfarin group. AF is common in Japanese dialysis patients. Despite a certain prevalence of oral anticoagulation, the present study demonstrated neither beneficial nor detrimental effects. A large randomized controlled trial should be considered. PMID- 26646257 TI - Multiplex detection of protein-protein interactions using a next generation luciferase reporter. AB - Cell-based assays of protein-protein interactions (PPIs) using split reporter proteins can be used to identify PPI agonists and antagonists. Generally, such assays measure one PPI at a time, and thus counterscreens for on-target activity must be run in parallel or at a subsequent stage; this increases both the cost and time during screening. Split luciferase systems offer advantages over those that use split fluorescent proteins (FPs). This is since split luciferase offers a greater signal:noise ratio and, unlike split FPs, the PPI can be reversed upon small molecule treatment. While multiplexed PPI assays using luciferase have been reported, they suffer from low signal:noise and require fairly complex spectral deconvolution during analysis. Furthermore, the luciferase enzymes used are large, which limits the range of PPIs that can be interrogated due to steric hindrance from the split luciferase fragments. Here, we report a multiplexed PPI assay based on split luciferases from Photinus pyralis (firefly luciferase, FLUC) and the deep-sea shrimp, Oplophorus gracilirostris (NanoLuc, NLUC). Specifically, we show that the binding of the p53 tumor suppressor to its two major negative regulators, MDM2 and MDM4, can be simultaneously measured within the same sample, without the requirement for complex filters or deconvolution. We provide chemical and genetic validation of this system using MDM2-targeted small molecules and mutagenesis, respectively. Combined with the superior signal:noise and smaller size of split NanoLuc, this multiplexed PPI assay format can be exploited to study the induction or disruption of pairwise interactions that are prominent in many cell signaling pathways. PMID- 26646258 TI - [Effects of fire recurrence on fire behaviour in cork oak woodlands (Quercus suber L.) and Mediterranean shrublands over the last fifty years]. AB - Past fire recurrence impacts the vegetation structure, and it is consequently hypothesized to alter its future fire behaviour. We examined the fire behaviour in shrubland-forest mosaics of southeastern France, which were organized along a range of fire frequency (0 to 3-4 fires along the past 50 years) and had different time intervals between fires. The mosaic was dominated by Quercus suber L. and Erica-Cistus shrubland communities. We described the vegetation structure through measurements of tree height, base of tree crown or shrub layer, mean diameter, cover, plant water content and bulk density. We used the physical model Firetec to simulate the fire behaviour. Fire intensity, fire spread, plant water content and biomass loss varied significantly according to fire recurrence and vegetation structure, mainly linked to the time since the last fire, then the number of fires. These results confirm that past fire recurrence affects future fire behaviour, with multi-layered vegetation (particularly high shrublands) producing more intense fires, contrary to submature Quercus woodlands that have not burnt since 1959 and that are unlikely to reburn. Further simulations, with more vegetation scenes according to shrub and canopy covers, will complete this study in order to discuss the fire propagation risk in heterogeneous vegetation, particularly in the Mediterranean area, with a view to a local management of these ecosystems. PMID- 26646259 TI - Reverie. PMID- 26646260 TI - Analysis of inter-residue contacts reveals folding stabilizers in P-loops of potassium, sodium, and TRPV channels. AB - The family of P-loop channels includes potassium, sodium, calcium, cyclic nucleotide-gated and TRPV channels, as well as ionotropic glutamate receptors. Despite vastly different physiological and pharmacological properties, the channels have structurally conserved folding of the pore domain. Furthermore, crystallographic data demonstrate surprisingly similar mutual disposition of transmembrane and membrane-diving helices. To understand determinants of this conservation, here we have compared available high-resolution structures of sodium, potassium, and TRPV1 channels. We found that some residues, which are in matching positions of the sequence alignment, occur in different positions in the 3D alignment. Surprisingly, we found 3D mismatches in well-packed P-helices. Analysis of energetics of individual residues in Monte Carlo minimized structures revealed cyclic patterns of energetically favorable inter- and intra-subunit contacts of P-helices with S6 helices. The inter-subunit contacts are rather conserved in all the channels, whereas the intra-subunit contacts are specific for particular types of the channels. Our results suggest that these residue residue contacts contribute to the folding stabilization. Analysis of such contacts is important for structural and phylogenetic studies of homologous proteins. PMID- 26646261 TI - Selective condensation of DNA by aminoglycoside antibiotics. AB - The condensing effect of aminoglycoside antibiotics on the structure of double stranded DNA was examined. The selective condensation of DNA by small molecules is an interesting approach in biotechnology. Here, we present the interaction between calf thymus DNA and three types of antibiotic molecules: tobramycin, kanamycin, and neomycin. Several techniques were applied to study this effect. Atomic force microscopy, transmission electron microscopy images, and nuclear magnetic resonance spectra showed that the interaction of tobramycin with double stranded DNA caused the rod, toroid, and sphere formation and very strong condensation of DNA strands, which was not observed in the case of other aminoglycosides used in the experiment. Studies on the mechanisms by which small molecules interact with DNA are important in understanding their functioning in cells, in designing new and efficient drugs, or in minimizing their adverse side effects. Specific interactions between tobramycin and DNA double helix was modeled using molecular dynamics simulations. Simulation study shows the aminoglycoside specificity to bend DNA double helix, shedding light on the origins of toroid formation. This phenomenon may lighten the ototoxicity or nephrotoxicity issues, but also other adverse reactions of aminoglycoside antibiotics in the human body. PMID- 26646262 TI - The Clinical and Radiological Examination of Acute Intimate Partner Violence Injuries: A Retrospective Analysis of an Italian Cohort of Women. AB - BACKGROUND: Intimate partner violence (IPV) is the most frequent type of violence against women. We compared clinical and radiological IPV characteristics to stranger assault (SA). METHODS: We retrospectively identified 123 women with IPV from court reports and matched them to 124 SA. Clinical and radiological characteristics were evaluated by testing their sensitivity, specificity, positive and negative predictive value for IPV, and the strength of their association with IPV. RESULTS: IPV women referred with more delay to the emergency department (ED), had more ED accesses, and showed more mismatch between reports to the triage and disclosures to the ED physician. They also displayed more head, neck, and face injuries, and new-plus-old fractures. CONCLUSION: The identification of specific features may help ED physicians to suspect IPV. PMID- 26646263 TI - Flat detector C-arm CT-guided transthoracic needle biopsy of small (<=2.0 cm) pulmonary nodules: diagnostic accuracy and complication in 100 patients. AB - PURPOSE: This study aimed at assessing the usefulness of flat detector cone-beam CT virtual navigation-guided transthoracic needle biopsy of small (<=2.0 cm) pulmonary nodules in terms of diagnostic accuracy and complications to evaluate the diagnostic performance and complications of small pulmonary nodules under cone-beam CT (CBCT) guidance. MATERIALS AND METHODS: A total of 100 patients with 100 solid lung nodules were retrospectively enrolled to undergo transthoracic needle biopsy (TNB) procedures. The mean diameter of lesions was 1.25 cm +/- 0.39 (range 0.50-2.00 cm). The needle path was carefully planned and calculated on the CBCT virtual navigation guidance system, which acquired 3D CT-like cross sectional images. Diagnostic performance, complication rate, and patient radiation exposure were investigated. RESULTS: The technical success rate of TNB under iGuide CBCT virtual navigation system was 99% (99/100). The sensitivity, specificity, and accuracy of TNB of small nodules under iGuide CBCT virtual navigation guidance were 98.7% (77/78), 90.5% (19/21), and 97.0% (96/99), respectively. The number of pleural passages with coaxial needle, biopsies, and CBCT acquisitions were 1.09 +/- 0.32, 1.20 +/- 0.47, and 3.06 +/- 1.35, respectively. Complications occurred in 22 (22%) cases. The mean total procedure time was 12.84 min +/- 3.74, resulting in a mean exposure dose of 7.6 mSv +/-3.1. CONCLUSIONS: Flat detector Cone-beam CT-guided TNB is a highly accurate and safe diagnostic method for small (<=2.0 cm) lung nodule. PMID- 26646264 TI - Risk Factors for Early-Onset and Very-Early-Onset Pancreatic Adenocarcinoma: A Pancreatic Cancer Case-Control Consortium (PanC4) Analysis. AB - OBJECTIVES: While pancreatic cancer (PC) most often affects older adults, to date, there has been no comprehensive assessment of risk factors among PC patients younger than 60 years. METHODS: We defined early-onset PC (EOPC) and very-early-onset PC (VEOPC) as diagnosis of PC in patients younger than 60 and 45 years, respectively. We pooled data from 8 case-control studies, including 1954 patients with EOPC and 3278 age- and sex-matched control subjects. Logistic regression analysis was performed to identify associations with EOPC and VEOPC. RESULTS: Family history of PC, diabetes mellitus, smoking, obesity, and pancreatitis were associated with EOPC. Alcohol use equal to or greater than 26 g daily also was associated with increased risk of EOPC (odds ratio, 1.49; 95% confidence interval, 1.21-1.84), and there appeared to be a dose- and age dependent effect of alcohol on risk. The point estimate for risk of VEOPC was an odds ratio of 2.18 (95% confidence interval, 1.17-4.09). CONCLUSIONS: The established risk factors for PC, including smoking, diabetes, family history of PC, and obesity, also apply to EOPC. Alcohol intake appeared to have an age dependent effect; the strongest association was with VEOPC. PMID- 26646265 TI - Betaine Attenuates Alcohol-Induced Pancreatic Steatosis. AB - OBJECTIVES: To explore the effect of betaine on alcoholic pancreatic steatosis and its mechanism. METHODS: Rats were randomly assigned to control, ethanol, or ethanol + betaine groups. Changes in pancreatic morphology; serum lipid levels; and pancreatic lipid, amylase and lipase levels were determined. The serum and adipose tissue adiponectin level was measured by an enzyme-linked immunoassay. Adiponectin receptor-1 (AdipoR1), AdipoR2, sterol regulatory element binding protein-1c (SREBP-1c), SREBP-2, and fatty acid synthetase expression levels were quantified. The SREBP-1c expression in SW1990 cells treated with various concentrations of ethanol or ethanol plus betaine and/or adiponectin was assessed. RESULTS: Alcohol-induced changes in pancreatic morphology were attenuated by betaine. Pancreatic triglyceride, free fatty acid and expression levels of SREBP-1c and fatty acid synthetase were elevated after ethanol feeding but remained at control levels after betaine supplementation. Alcohol-induced decreases in serum and adipose tissue adiponectin, pancreatic AdipoR1, amylase, and lipase were attenuated by betaine. Serum triglyceride and free fatty acid levels were elevated after alcohol consumption and remained higher after betaine supplementation compared with controls. Betaine and/or adiponectin suppressed alcohol-induced SREBP-1c upregulation in vitro. CONCLUSIONS: Betaine attenuated alcoholic-induced pancreatic steatosis most likely by suppressing pancreatic SREBP-1c both directly and through the restoration of adiponectin signaling. PMID- 26646266 TI - Distinction of Invasive Carcinoma Derived From Intraductal Papillary Mucinous Neoplasms From Concomitant Ductal Adenocarcinoma of the Pancreas Using Molecular Biomarkers. AB - OBJECTIVES: To clarify the usefulness of molecular biomarkers for distinguishing invasive carcinoma derived from intraductal papillary mucinous neoplasms (IPMNs [Inv-IPMN]) from concomitant pancreatic ductal adenocarcinoma (PDAC). METHODS: Data from 19 patients with resected concomitant PDAC were retrospectively reviewed. KRAS/GNAS mutations and immunohistochemical (IHC) expression of p53 and p16/CDKN2A were assessed in both IPMN and distinct PDAC. As controls, KRAS/GNAS mutations and IHC labeling were assessed between invasive and noninvasive components in 1 lesion of 22 independent patients. RESULTS: KRAS/GNAS mutation status of invasive and noninvasive components in Inv-IPMN was consistent in 18 (86%) of 21 patients. Conversely, mutational patterns in IPMN and distinct PDAC in the same pancreas differed from each other in 17 (89%) of 19. There were 10 (53%) and 8 (42%) of 19 patients who showed the same p53 and p16/CDKN2A staining between concomitant PDAC and distinct IPMN. In the Inv-IPMN cohort, 19 (86%) of 22 patients showed the same IHC expression pattern between the noninvasive and invasive components. CONCLUSIONS: It may be possible to distinguish Inv-IPMN from concomitant PDAC by assessing these molecular biomarkers. More precise distinction of Inv-IPMN and concomitant PDAC will lead to adequate recognition of the natural history of IPMNs and hence optimal management. PMID- 26646267 TI - Clinical Impact of Structured Follow-up After Pancreatic Surgery. AB - OBJECTIVES: Structured follow-up after surgery for pancreatic ductal adenocarcinoma (PDAC) remains controversial and is currently not recommended due to a supposed lack of therapeutic consequences. Furthermore, it is not clear whether noncancer patients after pancreas resection need to be seen in the clinic on a regular basis. The present study analyzed how follow-up after pancreatic surgery affected postoperative treatment and long-term outcomes. METHODS: Data of all postoperative visits in a specialized outpatient clinic for pancreatic diseases were analyzed for a 1-year period with regard to symptoms, diagnostic procedures, and therapeutic consequences. RESULTS: Six hundred eighteen patients underwent 940 postoperative follow-ups. Nearly half of them needed a change of medication due to altered pancreatic function. In 74 (40%) of 184 resected PDAC patients, recurrence (local or systemic) was detected during follow-up, although only 19 of these had shown associated symptoms (26%). In all patients with recurrence, a cancer-directed treatment was induced. Eleven (69%) of 16 patients with isolated local recurrence were referred for reresection. CONCLUSIONS: Follow up examinations are a substantial part of the clinical management after pancreas resections. Follow-up is particularly important for PDAC because recurrence is often asymptomatic, but its detection allows for therapeutic interventions and potentially improved prognosis. This should be implemented in future guidelines. PMID- 26646268 TI - Origin, Presentation, and Clinical Course of Nonpancreatic Hyperlipasemia. AB - OBJECTIVE: The diagnosis of acute pancreatitis (AP) is defined as a constellation of abnormal pancreatic enzymes, imaging, and characteristic pain. The origin and clinical significance of isolated hyperlipasemia is unclear. METHODS: We prospectively evaluated patients with serum lipase level greater than 3 times the upper limit of normal (ULN) admitted to Los Angeles County Hospital from October 2014 to April 2015. Patients were identified by a daily laboratory query used to support an ongoing randomized trial of goal-directed therapy for AP (NCT 01761539). Nonpancreatic hyperlipasemia (NPHL) was defined as a serum lipase level greater than 3 times the ULN without characteristic pain or imaging. RESULTS: Among 221 patients with lipase level greater than 3 times the ULN, 170 met criterion for AP, and 51 did not. The leading etiologies for NPHL were decompensated cirrhosis and renal failure. Patients with NPHL were significantly older and had more comorbidities and lower serum lipase levels (360 +/- 36 vs 1453 +/- 135 IU/L, P < 0.001). There were no differences in length of hospitalization, intensive care unit admission, or mortality. CONCLUSIONS: Elevated serum lipase level has many nonpancreatic origins, with liver and renal failure being the most frequent. Distinct clinical features can help to differentiate between AP and NPHL. PMID- 26646269 TI - Intratumor Heterogeneity of KRAS Mutation Status in Pancreatic Ductal Adenocarcinoma Is Associated With Smaller Lesions. AB - OBJECTIVES: Recent studies have demonstrated intratumor heterogeneity (ITH) for genetic mutations in various tumors and suggest that ITH might have significant clinical impact. Because KRAS is the most commonly mutated oncogene in pancreatic ductal adenocarcinoma and has an important role in pancreatic carcinogenesis, the purpose of this study was to evaluate ITH for KRAS gene mutation and its clinical significance. METHODS: Deep sequencing of 47 pancreatic ductal adenocarcinoma cases was used to determine the fraction of KRAS mutant alleles. In addition, computerized morphometry was used to calculate the fraction of tumor cells. After analysis of both results, cases were classified as ITH or as having amplification of mutant KRAS. The presence of ITH was correlated with clinical and pathological factors. RESULTS: KRAS mutation was found in 38 (81%) cases, of which 12 (32%) showed ITH and 9 (23%) were found to have KRAS mutant allele amplification. The presence of ITH was associated with smaller tumors, whereas amplification was associated with higher tumor diameter. CONCLUSIONS: In pancreatic ductal adenocarcinoma, ITH for KRAS gene mutation was associated with smaller tumors. It is possible that, as the tumor progresses, more cells carry this mutation, which leads to more aggressive tumor features. PMID- 26646270 TI - Diagnostic Accuracy of Endoscopic Ultrasound-Guided Fine-Needle Aspiration Cytology, Carcinoembryonic Antigen, and Amylase in Intraductal Papillary Mucinous Neoplasm. AB - OBJECTIVES: The aim of this study was to determine the accuracy of cytology, carcinoembryonic antigen (CEA), and amylase levels in the preoperative diagnosis of intraductal papillary mucinous neoplasms (IPMNs). METHODS: An international registry was started in 2005 and included patients with clinically suspected IPMNs. Those who underwent surgery and had preoperative endoscopic ultrasonography fine-needle aspiration were selected for the study. RESULTS: One hundred eighty patients were included. Cytological analysis for neoplastic cells in IPMNs showed high specificity (87.8%) but low sensitivity (39.4%). The median CEA level was 525.5 ng/mL (n = 78) in IPMNs versus 9.7 ng/mL in nonmucinous cysts (n = 6), showing an area under the receiver operating characteristic curve (AUC) of 0.87. The optimal cutoff CEA value for distinguishing IPMN from nonmucinous cysts was 129 ng/mL. At this level, the sensitivity was 76.9%, and specificity was 83.3%, yielding a positive predictive value of 95.9% and a negative predictive value of 41.9%. Carcinoembryonic antigen was a poor predictor of neoplasia in IPMNs (AUC = 0.55). Amylase did not distinguish IPMNs from mucinous cystadenomas (MCAs) (median, 3759 U/L [n = 28 IPMNs] and 497 U/L [n = 3 MCAs], AUC = 0.65). CONCLUSIONS: Cytology has a limited role because of its lack of sensitivity. Carcinoembryonic antigen modestly differentiated between mucinous and nonmucinous lesions. Amylase did not distinguish IPMNs versus MCAs. PMID- 26646271 TI - The Effects of Pancreatic Microcirculatory Disturbances on Histopathologic Tissue Damage and the Outcome in Severe Acute Pancreatitis. AB - OBJECTIVES: Severe acute pancreatitis is an inflammatory disease of the pancreas with a high morbidity and mortality. To date, no causal treatment is known. The aim of the present study was to analyze the impact of pancreatic microcirculatory disturbances in severe acute pancreatitis and to correlate the effects with histopathologic tissue damage and outcome. METHODS: Severe acute pancreatitis was induced in 129 pigs by injection of glycodeoxycholic acid into the pancreatic duct. Pancreatic microcirculation, pancreatic tissue oxygenation, histopathologic tissue damage, and survival were measured and analyzed. RESULTS: Our study demonstrates a strong correlation between pancreatic microcirculatory disturbances and histopathologic tissue damage (r = 0.728; P < 0.001). Furthermore, we showed a strong correlation between tissue oxygenation and the severity of the pancreatitis according to an established porcine pancreatitis score (r = 0.694; P < 0.001). In addition, disturbances of the pancreatic microcirculation were shown to be associated with an increased mortality rate in severe acute pancreatitis. CONCLUSIONS: We found that pancreatic microcirculatory disturbances have significant effects on histopathologic tissue damage and the outcome of severe acute pancreatitis. For a better survival of severe acute pancreatitis, the treatment should focus on an improvement of pancreatic microcirculation. PMID- 26646272 TI - Pancreatic Tumor Progression Associated With CD133 Overexpression: Involvement of Increased TERT Expression and Epidermal Growth Factor Receptor-Dependent Akt Activation. AB - OBJECTIVES: The aim of this study was to investigate the role of CD133 in pancreatic ductal adenocarcinoma malignancy and its involvement in epidermal growth factor receptor (EGFR) signaling. METHODS: The effects of CD133 overexpression on cell proliferation, migration, invasiveness, and angiogenesis were investigated in the human pancreatic ductal adenocarcinoma cell line AsPC-1 in vitro and severe combined immunodeficiency xenografts in vivo. RESULTS: AsPC-1 cells overexpressing CD133 (AsPC-1 CD133 cells) had elevated cell proliferation, tumorigenesis, cell cycle progression, adhesion, migration, and angiogenesis. AsPC-1 CD133 cells displayed increased survival during treatment with chemotherapeutic agents. CD133 overexpression resulted in decreased EGF expression, increased telomerase reverse transcriptase expression, and increased Akt phosphorylation. Immunoprecipitation assays and immunofluorescent labeling studies revealed that CD133 physically interacts with EGFR. The EGFR inhibitor gefitinib was shown to have potent anti-CD133 activity, decreasing the CD133 induced migration of AsPC-1 CD133 cells. Knockdown of CD133 was also observed to inhibit AsPC-1 CD133 cell proliferation, migration, and invasion. CONCLUSION: Our results indicate that CD133-induced cancer stem cell activity may arise from enhanced telomerase reverse transcriptase expression and CD133 ligand-independent EGFR activation to exhibit the cancer stem cell phenotype, promoting cancer stem cell proliferation independent of cytokines, with high metastatic potential and the development of chemoresistance. PMID- 26646273 TI - Blockage of STAT3 Signaling Pathway by Morusin Induces Apoptosis and Inhibits Invasion in Human Pancreatic Tumor Cells. AB - OBJECTIVES: Signal transducer and activator of transcription 3 (STAT3) is an oncogenic transcription factor implicated in carcinogenesis. Here, we investigated the role of morusin, the major prenylflavonoid, isolated from Chinese herbal medicine in abrogating the constitutive STAT3 activation in human pancreatic tumor cells. METHODS: The effect of morusin on STAT3 activation, associated protein kinases, STAT3-regulated gene products, cellular proliferation, and apoptosis was examined. RESULTS: Morusin specifically inhibited constitutive STAT3 activation both at tyrosine residue 705 and serine residue 727 in 4 pancreatic tumor cells. The inhibition of STAT3 was mediated through the suppression of activation of upstream JAK1, JAK2, and c-Src kinases. Morusin led to the accumulation of the cells in different phases of the cell cycle and caused induction of apoptosis and loss of mitochondrial membrane potential. Morusin downregulated the expression of various STAT3-regulated gene products; this correlated with induction of caspase-3 activation and anti invasive effects. Treatment with the protein tyrosine phosphatase inhibitor pervanadate reversed the morusin-induced downregulation of STAT3, thereby suggesting the involvement of a protein tyrosine phosphatase. CONCLUSIONS: Morusin is a novel blocker of STAT3 activation and thus may have potential in negative regulation of growth and metastasis of pancreatic tumor cells. PMID- 26646274 TI - Estimation of the Survival Benefit Obtainable From Screening for the Early Detection of Pancreatic Cancer. AB - OBJECTIVE: The chance to improve survival from pancreatic adenocarcinoma relies on early diagnosis through screening, but any screening program is subject to lead-time bias and no data are available in this regard. Aim of the present study was to evaluate the benefit obtainable from a screening program for early detection of pancreatic adenocarcinoma, considering screen-related biases. METHODS: Monte Carlo simulation was performed using data from 1000 pancreatic cancer patients admitted in a tertiary referral hospital and from pertinent literature. Lead-time bias was assessed and subtracted from expected survival. RESULTS: Mean expected life expectancy was 13.0 months. Assuming a 20%, 30%, or 50% stage III/IV reduction with screening, pancreatic resections would increase from 217 to 290 in front of a 20% stage III/IV reduction to 324 in front of a 30% reduction and to 385 in front of a 50% reduction. After lead-time adjustment, life expectancies were 14.0, 14.6, and 15.9 months, respectively. The number needed-to-screen calculation suggests that screening can be harmful in a proportion of patients inversely dependent on the length of follow-up and a significant improvement of survival after diagnosis. CONCLUSIONS: Pancreatic adenocarcinoma screening program would probably be successful in the presence of a considerable improvement of postdiagnostic survival; otherwise, it only increases surgical procedure amount. PMID- 26646275 TI - SERPINB5 Promoter Hypomethylation Differentiates Pancreatic Ductal Adenocarcinoma From Pancreatitis. AB - OBJECTIVES: The diagnosis of pancreatic ductal adenocarcinoma (PDAC) is challenging in the setting of pancreatitis. We investigated SERPINB5 for its impact on PDAC tumor biology and its use as a diagnostic marker for PDAC in the setting of pancreatitis. METHODS: Patient samples from PDAC primary tumors, PDAC lymph node metastases, and pancreatitis were investigated for SERPINB5 promoter methylation by methylation-specific polymerase chain reaction (PCR). Six PDAC cell lines were investigated in vitro and in vivo using an orthotopic mouse model to generate primary tumors and metastases. SERPINB5 mRNA expression, protein expression, and promoter methylation were determined by quantitative reverse transcriptase-PCR, methylation-specific PCR, and Western Blot. RESULTS: In patient samples, detection of an unmethylated SERPINB5 promoter differentiated pancreatitis from PDAC with a sensitivity of 57% and a specificity of 95% (P < 0.001). SERPINB5 was not deregulated in primary tumors versus metastases, but primary tumors without SERPINB5 protein expression had significantly reduced viability (P = 0.02). CONCLUSIONS: SERPINB5 seems to assume an oncogenic role in PDAC. In clinical samples, detection of unmethylated SERPINB5 was a specific marker for PDAC even in the context of pancreatitis and may provide the basis for a liquid biopsy option to detect PDAC. PMID- 26646276 TI - Second-Line Treatment in Pancreatic Cancer Patients: Who Profits?--Results From the CONKO Study Group. AB - OBJECTIVES: With increasing numbers of therapeutic options in inoperable pancreatic cancer (PAC), patients tend to receive more than just a first line (FL) therapy. METHODS: All patients who started FL for PAC at our institution (1997-2012) were retrospectively studied to identify patient's and treatment characteristics. Significant parameters in regard to second-line (SL) related survival were looked for as the basis for a prognostic model. This score was validated in a patient cohort from the CONKO-003 study. RESULTS: Two hundred eighty of 521 (53.7%) patients received SL therapy, median overall survival (OS) from the beginning of SL (OS2) was 5.1 months. Significant more SL patients had undergone surgery, a higher Karnofsky performance state (KPS) and a duration of FL longer than 4 months.Prognostic factors impacting OS2 were KPS, carbohydrate antigen 19-9 levels at start of SL and the duration of FL. These 3 factors establish a prognostic score--validated in CONKO-003--for SL patients with 3 subgroups: "good" (median OS2, 9.3 months), "intermediate" (median OS2, 7.1 months), "poor" prognosis (median OS2, 3.8 months; P < 0.001). CONCLUSIONS: Among patients with PAC, more than 50% receive SL therapy. Our prognostic model identifies 3 subgroups and can identify patients with a maximum benefit of SL therapy. PMID- 26646277 TI - Value of Early Check-Up of Carbohydrate Antigen 19-9 Levels for Pancreatic Cancer Screening in Asymptomatic New-Onset Diabetic Patients. AB - OBJECTIVES: We evaluated the value of carbohydrate antigen 19-9 (CA 19-9) as a pancreatic cancer (PC) screening tool in an asymptomatic new-onset diabetic patients. METHODS: Medical records of asymptomatic patients newly diagnosed with diabetes mellitus (DM) were reviewed retrospectively at our hospital from January 2004 to January 2013. RESULTS: In total, 2363 asymptomatic diabetic patients with CA 19-9 measurements were enrolled. Of them, 68 (2.9%) were diagnosed with PC. In the 1719 patients who had CA 19-9 measured within 1 year after the DM diagnosis, a total of 51 (3.0 %) patients developed PC and the odds ratio (OR) of PC according to higher CA 19-9 than normal upper limit, 37 IU/mL was 5.57 (P < 0.001). In 248 patients checked CA 19-9 between 1 and 2 years after DM diagnosis, PC was detected in 9 (3.6%) cases and OR of high CA 19-9 was 4.51 (P = 0.019). However, beyond 2 years, the OR for PC showed no statistical significance. The patients with high CA 19-9 levels tended to have more advanced-stage disease. CONCLUSIONS: Early check-up of CA 19-9 could be a useful marker for screening for PC in asymptomatic patients with new-onset DM in the first 2 years. PMID- 26646278 TI - A Common CCK-B Receptor Intronic Variant in Pancreatic Adenocarcinoma in a Hungarian Cohort. AB - OBJECTIVES: Variant c.811+32C>A in intron 4 of the cholecystokinin-B receptor gene (CCKBR) was reported to correlate with higher pancreatic cancer risk and poorer survival. The variant was suggested to induce retention of intron 4, resulting in a new splice form with enhanced receptor activity. Our objective was to validate the c.811+32C>A variant as an emerging biomarker for pancreatic cancer risk and prognosis. METHODS: We genotyped variant c.811+32C>A in 122 pancreatic adenocarcinoma case patients and 106 control subjects by sequencing and examined its association with cancer risk and patient survival. We tested the functional effect of variant c.811+32C>A on pre-messenger RNA splicing in human embryonic kidney 293T and Capan-1 cells transfected with CCKBR minigenes. RESULTS: The allele frequency of the variant was similar between patients and control subjects (18.4% and 17.9%, respectively). Survival analysis showed no significant difference between median survival of patients with the C/C genotype (266 days) and patients with the A/C or A/A genotypes (257 days). CCKBR minigenes with or without variant c.811+32C>A exhibited no difference in expression of the intron-retaining splice variant. CONCLUSION: These data indicate that variant c.811+32C>A in CCKBR does not have a significant impact on pancreatic cancer risk or survival in a Hungarian cohort. PMID- 26646279 TI - Effect of Fetal Membrane-Derived Mesenchymal Stem Cell Transplantation in Rats With Acute and Chronic Pancreatitis. AB - OBJECTIVES: Mesenchymal stem cells (MSCs) are a valuable cell source in regenerative medicine and can be isolated from fetal membranes (FMs), particularly amniotic membranes. We investigated the effect of rat FM-derived MSCs (rFM-MSCs) and human amnion-derived MSCs (hAMSCs) on the inflammatory reaction in vitro and therapeutic effects in rats with acute and chronic pancreatitis. METHODS: Effect of rFM-MSCs or hAMSC-conditioned medium was investigated in vitro. Acute pancreatitis was induced by intraductal injection of 4% taurocholate, and rFM-MSCs were transplanted intravenously. Chronic pancreatitis was induced by intravenous injection of 5 mg/kg dibutyltin dichloride, and hAMSCs were transplanted intravenously. RESULTS: The inflammatory reaction of macrophages induced by lipopolysaccharide and trypsin was significantly suppressed by rFM-MSC coculture. Pancreatic acinar cell injury induced by cerulein was significantly ameliorated by hAMSC-conditioned medium. Pancreatic stellate cell activation induced by tumor necrosis factor-alpha was significantly decreased by hAMSC-conditioned medium. Transplantation of rFM-MSCs significantly reduced the histological score and infiltration of CD68-positive macrophages in the rat pancreas. The hAMSC transplantation significantly decreased the expression of MCP-1 and attenuated the downregulation of amylase expression in the pancreas. CONCLUSIONS: Transplantation of FM-MSCs and AMSCs suppressed the inflammatory reaction of acute and chronic pancreatitis in rats. PMID- 26646280 TI - Reproducibility and clinical potential of myocardial mass at risk calculated by a novel software utilizing cardiac computed tomography information. AB - To select the best revascularization strategy a correct understanding of the ischemic territory and the coronary anatomy is crucial. Stress myocardial perfusion single photon emission computed tomography (SPECT) is the gold standard to assess ischemia, however, SPECT has important limitations such as lack of coronary anatomical information or false negative results due to balanced ischemia in multi-vessel disease. Angiographic scores are based on anatomical characteristics of coronary arteries but they lack information on the extent of jeopardized myocardium. Cardiac computed tomography (CCT) has the ability to evaluate the coronary anatomy and myocardium in one sequence, which is theoretically the ideal method to assess the myocardial mass at risk (MMAR) for any target lesion located at any point in the coronary tree. In this study we analyzed MMAR of the three main coronary arteries and three major side branches; diagonal (Dx), obtuse marginal (OM), and posterior descending artery (PDA) in 42 patients with normal coronary arteries using an algorithm based on the Voronoi method. The distribution of MMAR among the three main coronary arteries was 44.3 +/- 5.6 % for the left anterior descending artery, 28.2 +/- 7.3 % for the left circumflex artery, and 26.8 +/- 8.6 % for the right coronary artery. MMAR of the three major side branches was 11.3 +/- 3.9 % for the Dx, 12.6 +/- 5.2 % for the OM and 10.2 +/- 3.4 % for the PDA. Intra- and inter-observer analysis showed excellent correlation (r = 0.97; p < 0.0001 and r = 0.95; p < 0.0001, respectively). In conclusion, CCT-based MMAR assessment is reliable and may offer important information for selection of the optimal revascularization procedure. PMID- 26646281 TI - Chronic vascular response after self-expanding nitinol stent implantation in superficial femoral arteries: a serial intravascular ultrasound analysis. AB - The mechanical properties of the self-expanding nitinol stents (SENS) and chronic biological stimulation on the wall from the SENS have not been fully investigated. This study evaluated the mechanical vascular response to SENS implantation in superficial femoral artery (SFA) lesions using serial volumetric intravascular ultrasound (IVUS). Twenty-five symptomatic patients due to de novo SFA lesions scheduled for SENS placement were prospectively enrolled. Serial IVUS studies were performed immediately after crossing with a guidewire, immediately after the procedure, and at a 8-month follow-up. Serial IVUS volumetric analysis was conducted after stent deployment and at follow-up. Mean stent, lumen and neointimal areas were calculated as the volume divided by the stent length, and the calcium arc was measured. At follow-up, SENS had increased 40.6 % in overall volume. The chronic stent expansion tended to be larger, and the mean neointimal area at the 8-month follow-up was significantly larger in less calcified lesions compared to heavily calcified lesions. As a result, the mean late lumen area loss was significantly larger in lesions with calcium arcs of 0 degrees and in the first and second quadrants than in those with calcium arcs in the third and fourth quadrants (2.8 +/- 7.2, 1.3 +/- 5.6, 0.6 +/- 5.9, 1.2 +/- 5.4, -0.8 +/- 5.2 mm(2), respectively; p < 0.001). SENSs continued to enlarge with intimal proliferation over 8 months in all lesions. Although arterial calcium affected the degree of chronic stent expansion during the follow-up period, neointimal proliferation was smaller in heavily calcified lesion compared to less calcified lesion following SENS implantation. PMID- 26646282 TI - Fault Tree Analysis. AB - The purpose of this study was to use fault tree analysis to evaluate the adequacy of quality reporting programs in identifying root causes of postoperative bloodstream infection (BSI). A systematic review of the literature was used to construct a fault tree to evaluate 3 postoperative BSI reporting programs: National Surgical Quality Improvement Program (NSQIP), Centers for Medicare and Medicaid Services (CMS), and The Joint Commission (JC). The literature review revealed 699 eligible publications, 90 of which were used to create the fault tree containing 105 faults. A total of 14 identified faults are currently mandated for reporting to NSQIP, 5 to CMS, and 3 to JC; 2 or more programs require 4 identified faults. The fault tree identifies numerous contributing faults to postoperative BSI and reveals substantial variation in the requirements and ability of national quality data reporting programs to capture these potential faults. Efforts to prevent postoperative BSI require more comprehensive data collection to identify the root causes and develop high-reliability improvement strategies. PMID- 26646283 TI - Handoffs in the Intensive Care Unit. AB - Operating room (OR) to intensive care unit (ICU) handoffs are complex and known to be associated with adverse events and patient harm. The authors hypothesized that handoff quality diminishes during nights/weekends and that bedside handoff practices are similar between ICUs of the same health system. Bedside OR-to-ICU handoffs were directly observed in 2 surgical ICUs with different patient volumes. Handoff quality measures were compared within the ICUs on weekdays versus nights/weekends as well as between the high- and moderate-volume ICUs. In the high-volume ICU, transmitter delivery scores were significantly better during off hours, while other measures were not different. High-volume ICU scores were consistently better than those in the moderate-volume ICU. Bedside handoff practices are not worse during off hours and may be better in ICUs used to a higher patient volume. Specific handoff protocols merit evaluation and training to ensure consistent practices in different ICU models and at different times. PMID- 26646284 TI - Synthesis of alpha-Benzyloxyamino-gamma-butyrolactones via a Polar Radical Crossover Cycloaddition Reaction. AB - A direct catalytic synthesis of substituted alpha-benzyloxyamino-gamma butyrolactones is reported, starting from simple oxime acids and alkenes. The substituted O-benzyloxime acid starting materials are cyclized with oxidizable alkenes, via Polar Radical Crossover Cycloaddition (PRCC) reactions. The catalytic reaction is carried out using the Fukuzumi acridinium photooxidant and substoichiometric amounts of a redox-active cocatalyst. The utility of this method has been demonstrated through the use of 3 oxime acids and 19 oxidizable olefins. PMID- 26646285 TI - In Situ Microparticles Loaded with S-Nitrosoglutathione Protect from Stroke. AB - Treatment of stroke, especially during the first hours or days, is still lacking. S-nitrosoglutathione (GSNO), a cerebroprotective agent with short life time, may help if administered early with a sustain delivery while avoiding intensive reduction in blood pressure. We developed in situ forming implants (biocompatible biodegradable copolymer) and microparticles (same polymer and solvent emulsified with an external oily phase) of GSNO to lengthen its effects and allow cerebroprotection after a single subcutaneous administration to Wistar rats. Arterial pressure was recorded for 3 days (telemetry, n = 14), whole-blood platelet aggregation up to 13 days (aggregometry, n = 58), and neurological score, cerebral infarct size and edema volume for 2 days after obstruction of the middle cerebral artery by autologous blood clots (n = 30). GSNO-loaded formulations (30 mg/kg) induced a slighter and longer hypotension (-10 vs. -56 +/ 6 mmHg mean arterial pressure, 18 h vs. 40 min) than free GSNO at the same dose. The change in pulse pressure (-50%) lasted even up to 42 h for microparticles. GSNO-loaded formulations (30 mg/kg) prevented the transient 24 h hyper aggregability observed with free GSNO and 7.5 mg/kg-loaded formulations. When injected 2 h after stroke, GSNO-loaded microparticles (30 mg/kg) reduced neurological score at 24 (-62%) and 48 h (-75%) vs. empty microparticles and free GSNO 7.5 mg/kg and, compared to free GSNO, divided infarct size by 10 and edema volume by 8 at 48 h. Corresponding implants reduced infarct size and edema volume by 2.5 to 3 times. The longer (at least 2 days) but slight effects on arterial pressures show sustained delivery of GSNO-loaded formulations (30 mg/kg), which prevent transient platelet hyper-responsiveness and afford cerebroprotection against the consequences of stroke. In conclusion, in situ GSNO-loaded formulations are promising candidates for the treatment of stroke. PMID- 26646286 TI - Overexpression of the MYB37 transcription factor enhances abscisic acid sensitivity, and improves both drought tolerance and seed productivity in Arabidopsis thaliana. AB - Although a lot of genes have been revealed to participate in abscisic acid (ABA) signaling, many of the additional components involved in ABA signaling remain to be discovered. Here we report that overexpression of MYB37, a R2R3 MYB subgroup 14 transcription factor in Arabidopsis thaliana, confers hypersensitive phenotypes to exogenous ABA in all the major ABA responses, including ABA-induced inhibition of seed germination, cotyledon greening and early seedling growth, and ABA-induced stomatal closure and inhibition of stomatal opening. Interestingly and importantly, MYB37-overexpression improves plant tolerance to drought, enhances growth of mature plants and seed productivity, thought it delays flowering, which suggests that this gene may be used for improving crop adaptability to drought environment and productivity. However, a myb37-1 knockout mutant displays wild-type ABA responses most likely due to a functional redundancy of the multiple MYB members. Real-time PCR analysis shows that upregulation of the MYB37 expression changes expression of a subset of ABA responsive genes. Together, these findings suggest that the MYB37 transcription factor plays an important, positive role in plant response to ABA and drought stress, and meanwhile, it plays a positive role in the regulation of seed production. PMID- 26646287 TI - Fungal endophytes: modifiers of plant disease. AB - Many recent studies have demonstrated that non-pathogenic fungi within plant microbiomes, i.e., endophytes ("endo" = within, "phyte" = plant), can significantly modify the expression of host plant disease. The rapid pace of advancement in endophyte ecology warrants a pause to synthesize our understanding of endophyte disease modification and to discuss future research directions. We reviewed recent literature on fungal endophyte disease modification, and here report on several emergent themes: (1) Fungal endophyte effects on plant disease span the full spectrum from pathogen antagonism to pathogen facilitation, with pathogen antagonism most commonly reported. (2) Agricultural plant pathosystems are the focus of research on endophyte disease modification. (3) A taxonomically diverse group of fungal endophytes can influence plant disease severity. And (4) Fungal endophyte effects on plant disease severity are context-dependent. Our review highlights the importance of fungal endophytes for plant disease across a broad range of plant pathosystems, yet simultaneously reveals that complexity within plant microbiomes presents a significant challenge to disentangling the biotic environmental factors affecting plant disease severity. Manipulative studies integrating eco-evolutionary approaches with emerging molecular tools will be poised to elucidate the functional importance of endophytes in natural plant pathosystems that are fundamental to biodiversity and conservation. PMID- 26646288 TI - Adaptation of the Agrobacterium tumefaciens VirG response regulator to activate transcription in plants. AB - The Agrobacterium tumefaciens VirG response regulator of the VirA/VirG two component system was adapted to function in tobacco protoplasts. The subcellular localization of VirG and VirA proteins transiently expressed in onion cells was determined using GFP fusions. Preliminary studies using Gal4DBD-VP16 fusions with VirG and Escherichia coli UhpA, and NarL response regulators indicated compatibility of these bacterial proteins with the eukaryotic transcriptional apparatus. A strong transcriptional activator based on tandem activation domains from the Drosophila fushi tarazu and Herpes simplex VP16 was created. Selected configurations of the two-site Gal4-vir box GUS reporters were activated by chimeric effectors dependent on either the yeast Gal4 DNA-binding domain or that of VirG. Transcriptional induction of the GUS reporter was highest for the VirE19 element promoter with both constitutive and wild-type VirG-tandem activation domain effectors. Multiple VirE19 elements increased the reporter activity proportionately, indicating that the VirG DNA binding domain was functional in plants. The VirG constitutive-Q-VP16 effector was more active than the VirG wild type. In both the constitutive and wild-type forms of VirG, Q-VP16 activated transcription of the GUS reporter best when located at the C-terminus, i.e. juxtaposed to the VirG DNA binding domain. These results demonstrate the possibility of using DNA binding domains from bacterial response regulators and their cognate binding elements in the engineering of plant gene expression. PMID- 26646289 TI - Breakup of Finite-Size Colloidal Aggregates in Turbulent Flow Investigated by Three-Dimensional (3D) Particle Tracking Velocimetry. AB - Aggregates grown in mild shear flow are released, one at a time, into homogeneous isotropic turbulence, where their motion and intermittent breakup is recorded by three-dimensional particle tracking velocimetry (3D-PTV). The aggregates have an open structure with a fractal dimension of ~2.2, and their size is 1.4 +/- 0.4 mm, which is large, compared to the Kolmogorov length scale (eta = 0.15 mm). 3D PTV of flow tracers allows for the simultaneous measurement of aggregate trajectories and the full velocity gradient tensor along their pathlines, which enables us to access the Lagrangian stress history of individual breakup events. From this data, we found no consistent pattern that relates breakup to the local flow properties at the point of breakup. Also, the correlation between the aggregate size and both shear stress and normal stress at the location of breakage is found to be weaker, when compared with the correlation between size and drag stress. The analysis suggests that the aggregates are mostly broken due to the accumulation of the drag stress over a time lag on the order of the Kolmogorov time scale. This finding is explained by the fact that the aggregates are large, which gives their motion inertia and increases the time for stress propagation inside the aggregate. Furthermore, it is found that the scaling of the largest fragment and the accumulated stress at breakup follows an earlier established power law, i.e., dfrag ~ sigma(-0.6) obtained from laminar nozzle experiments. This indicates that, despite the large size and the different type of hydrodynamic stress, the microscopic mechanism causing breakup is consistent over a wide range of aggregate size and stress magnitude. PMID- 26646290 TI - Hypoxia leads to abnormal epidermal differentiation via HIF-independent pathways. AB - Atmospheric oxygen is important for the epidermis, as the skin epidermis is not greatly affected by blood circulation. Therefore, it is necessary to understand the effect of hypoxic signals on the epidermis as some environmental stimuli can induce skin hypoxia. Here, we investigated how hypoxia (1% O2) affected skin equivalents (SEs) and normal human epidermal keratinocytes. We found that hypoxia specifically decreased the protein levels of keratin 1 (K1)/keratin 10 (K10), a representative marker of the epidermal spinous layer in the epidermis. However, hypoxia-inducible factors, the major regulators of hypoxia, did not affect hypoxia-induced down-regulation of K1/K10. We also found that N-acetyl-l-cysteine (NAC), a reactive oxygen species scavenger, antagonized the hypoxia-induced reduction of K1/K10 in keratinocytes and SEs. In contrast to the findings for NAC, inhibitors that blocked reactive oxygen species generation did not cause recovery of K1/K10 protein levels under hypoxic conditions. Taken together, these results indicate that hypoxia leads to abnormal keratinocyte differentiation by down-regulating K1/K10 and that this phenomenon can be ameliorated by NAC. PMID- 26646291 TI - Characterization of silk gland ribosomes from a bivoltine caddisfly, Stenopsyche marmorata: translational suppression of a silk protein in cold conditions. AB - Larval Stenopsyche marmorata constructs food capture nets and fixed retreats underwater using self-produced proteinaceous silk fibers. In the Chikuma River (Nagano Prefecture, Japan) S. marmorata has a bivoltine life cycle; overwintering larvae grow slowly with reduced net spinning activity in winter. We recently reported constant transcript abundance of S. marmorata silk protein 1 (Smsp-1), a core S. marmorata silk fiber component, in all seasons, implying translational suppression in the silk gland during winter. Herein, we prepared and characterized silk gland ribosomes from seasonally collected S. marmorata larvae. Ribosomes from silk glands immediately frozen in liquid nitrogen (LN2) after dissection exhibited comparable translation elongation activity in spring, summer, and autumn. Conversely, silk glands obtained in winter did not contain active ribosomes and Smsp-1. Ribosomes from silk glands immersed in ice-cold physiological saline solution for approximately 4 h were translationally inactive, despite summer collection and Smsp-1 expression. The ribosomal inactivation occurs because of defects in the formation of 80S ribosomes, presumably due to splitting of 60S subunits containing 28S rRNA with central hidden break, in response to cold stress. These results suggest a novel-type ribosome-regulated translation control mechanism. PMID- 26646292 TI - Age- and Sex-Specific Social Contact Patterns and Incidence of Mycobacterium tuberculosis Infection. AB - We aimed to model the incidence of infection with Mycobacterium tuberculosis among adults using data on infection incidence in children, disease prevalence in adults, and social contact patterns. We conducted a cross-sectional face-to-face survey of adults in 2011, enumerating "close" (shared conversation) and "casual" (shared indoor space) social contacts in 16 Zambian communities and 8 South African communities. We modeled the incidence of M. tuberculosis infection in all age groups using these contact patterns, as well as the observed incidence of M. tuberculosis infection in children and the prevalence of tuberculosis disease in adults. A total of 3,528 adults participated in the study. The reported rates of close and casual contact were 4.9 per adult per day (95% confidence interval: 4.6, 5.2) and 10.4 per adult per day (95% confidence interval: 9.3, 11.6), respectively. Rates of close contact were higher for adults in larger households and rural areas. There was preferential mixing of close contacts within age groups and within sexes. The estimated incidence of M. tuberculosis infection in adults was 1.5-6 times higher (2.5%-10% per year) than that in children. More than 50% of infections in men, women, and children were estimated to be due to contact with adult men. We conclude that estimates of infection incidence based on surveys in children might underestimate incidence in adults. Most infections may be due to contact with adult men. Treatment and control of tuberculosis in men is critical to protecting men, women, and children from tuberculosis. PMID- 26646293 TI - Is Traditional Chinese Exercise Associated With Lower Mortality Rates in Older People? Evidence From a Prospective Chinese Elderly Cohort Study in Hong Kong. AB - The inverse association of aerobic exercise with death has been well documented. However, evidence on traditional Chinese exercise (TCE) and rate of death in older Chinese is limited. Multivariable Cox regression analysis was used to assess the associations of TCE and other types of physical activity with death from all causes and specific causes in a population-based prospective cohort of 66,820 Chinese persons (>=65 years of age) who were enrolled between July 1998 and December 2001 at all 18 Elderly Health Centers in Hong Kong and followed up until May 31, 2012. During an average of 10.9 years of follow-up, 19,845 deaths occurred. TCE was inversely associated with death from all causes (hazard ratio (HR) = 0.78, 95% confidence interval (CI): 0.74, 0.82), cardiovascular disease (HR = 0.77, 95% CI: 0.70, 0.85), cancer (HR = 0.84, 95% CI: 0.77, 0.92), and respiratory disease (HR = 0.71, 95% CI: 0.63, 0.80) but was not associated with death from accidents (excluding falls) (HR = 0.79, 95% CI: 0.44, 1.42), after adjustment for age, sex, socioeconomic position, alcohol use, smoking, body mass index, and health status. The associations did not vary by amount of TCE. Aerobic exercise had similar inverse associations as TCE, but associations for stretching exercises and walking slowly were less marked. Further studies of TCE are warranted in older Chinese. PMID- 26646294 TI - Potential Misclassification of Blood Pressure Status in Children and Adolescents With Short or Tall Stature. AB - Blood pressure (BP) is measured in percentiles that are adjusted for sex, age, and height percentile in children and adolescents. Standard tables for the conversion of BP percentiles do not present exact BP percentile cutoffs for extremes in stature, either short (<5th percentile) or tall (>95th percentile). An algorithm can be used to calculate exact BP percentiles across a range of height z scores. We compared values from standard BP tables with exact calculations of BP percentiles to see which were better at identifying hypertension in more than 5,000 children with either short or tall stature. Study subjects were 3-17-year-old patients within HealthPartners Medical Group, an integrated health care delivery system in Minnesota, at any time between 2007 and 2012. Approximately half of the subjects who met the criteria for hypertension using exact calculation would be misclassified as normal using available thresholds in the published BP tables instead of the recommended algorithm, which was not included in the tables. PMID- 26646295 TI - Strengths and limitations of a tool for monitoring and evaluating First Peoples' health promotion from an ecological perspective. AB - BACKGROUND: An ecological approach to health and health promotion targets individuals and the environmental determinants of their health as a means of more effectively influencing health outcomes. The approach has potential value as a means to more accurately capture the holistic nature of Australian First Peoples' health programs and the way in which they seek to influence environmental, including social, determinants of health. METHODS: We report several case studies of applying an ecological approach to health program evaluation using a tool developed for application to mainstream public health programs in North America - Richard's ecological coding procedure. RESULTS: We find the ecological approach in general, and the Richard procedure specifically, to have potential for broader use as an approach to reporting and evaluation of health promotion programs. However, our experience applying this tool in academic and community-based program evaluation contexts, conducted in collaboration with First Peoples of Australia, suggests that it would benefit from cultural adaptations that would bring the ecological coding procedure in greater alignment with the worldviews of First Peoples and better identify the aims and strategies of local health promotion programs. CONCLUSIONS: Establishing the cultural validity of the ecological coding procedure is necessary to adequately capture the underlying program activities of community-based health promotion programs designed to benefit First Peoples, and its collaborative implementation with First Peoples supports a human rights approach to health program evaluation. PMID- 26646296 TI - MicroRNA-138 Regulates Metastatic Potential of Bladder Cancer Through ZEB2. AB - BACKGROUND/AIMS: The cases of bladder cancer (BC) with poor prognosis largely result from the distal metastases of the primary tumor. Since microRNAs (miRNAs) play critical roles during cancer metastases, determination of the involved miRNAs in the regulation of the metastases of BC may provide novel therapeutic targets for BC treatment. Here, we aimed to study the role of miR-138 in regulation of BC cell invasion and metastases. METHODS: We analyzed the levels of miR-138 and ZEB2, a key factor that regulates cancer cell invasion, in the BC specimens from the patients. We also studied the correlation between miR-138 and ZEB2. We performed bioinformatics analyses on the binding of miR-138 to the 3' UTR of ZEB2 mRNA, and verified the biological effects of this binding through promoter luciferase reporter assay. The effects of miR-138-modification on BC cell invasion were evaluated in a transwell cell invasion assay and a scratch would healing assay. RESULTS: We found that the levels of miR-138 were significantly decreased and the levels of ZEB2 were significantly increased in BC specimens, compared to the paired normal bladder tissue. Metastatic BC appeared to contained lower levels of miR-138. Moreover, miR-138 and ZEB2 inversely correlated in BC specimens. Bioinformatics analyses showed that miR-138 targeted the 3'-UTR of ZEB2 mRNA to inhibit its translation. Furthermore, miR-138 overexpression inhibited ZEB2-mediated cell invasion and metastases, while miR 138 depletion increased ZEB2-mediated cell invasion and metastases in BC cells. CONCLUSION: Suppression of miR-138 in BC cells may promote ZEB2-mediated cancer invasion and metastases. Thus, miR-138 appears to be an intriguing therapeutic target to prevent metastases of BC. PMID- 26646297 TI - Preventive effects of phenylethanol glycosides from Cistanche tubulosa on bovine serum albumin-induced hepatic fibrosis in rats. AB - BACKGROUND: Cistanche tubulosa is a traditional Chinese herbal medicine that is widely used for regulating immunity. Phenyl ethanol glycosides (CPhGs) from this plant are the primarily efficacious materials. This aim of this study was to evaluate the preventive and therapeutic effects of CPhGs on BSA-induced hepatic fibrosis in rats and related molecular mechanisms involving hepatic stellate cells. Biejiarangan (BJRG), another traditional Chinese herbal medicine, was used as a positive control. METHODS: In in vivo experiments, 75 SD rats were randomly divided into 6 groups: normal (distilled water-treated), model (BSA-treated), positive drug (BSA-treated + BJRG 600 mg/kg/day), and BSA-treated + CPhGs (125, 250, and 500 mg/kg/day) groups. The liver and spleen indices, serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), hexadecenoic acid (HA), laminin (LN), type III procollagen (PCIII), type IV collagen (IV-C), hydroxyproline (Hyp), and transforming growth factor beta 1 (TGF-beta 1) were measured in rat livers. Histopathological grades for liver fibrosis were assessed for each group using H&E and Masson's trichrome staining. The expression of TGF beta 1, collagen I (Col-I) and collagen III (Col-III) were determined by an immunohistochemical staining method. These effects were further evaluated in vitro by determining expression levels of NF-kappaB p65 and Col-I by quantitative real-time PCR analyses. Col-I protein expression was also examined by western blotting. RESULTS: All dose groups (125, 250, and 500 mg/kg/day) of CPhGs significantly reduced the liver and spleen index, decreased ALT, AST, HA, LN, PCIII, IV-C serum levels, TGF-beta 1 content (P < 0.01, P < 0.01, and P < 0.01), and Hyp content. CPhGs also markedly alleviated the swelling of liver cells and effectively prevented hepatocyte necrosis and inflammatory cell infiltration. Immunohistochemical results showed that CPhGs significantly reduced the expression of TGF-beta 1 (P < 0.01, P < 0.01, and P < 0.01), Col- I, and Col-III. The in vitro effects of CPhGs (100, 75, 50, and 25 ug/ml) on HSC-T6 showed that CPhGs significantly reduced mRNA expression of NF-kappaB p65 and Col-I, and CPhGs also downregulated Col-I protein expression. CONCLUSIONS: CPhGs have a significant anti-hepatic fibrosis effect, and may be used as hepatoprotective agents for treatment of hepatic fibrosis. PMID- 26646298 TI - Fine-needle aspiration cytology of epithelioid malignant peripheral nerve sheath tumor: A case report and review of the literature. AB - The epithelioid variant of malignant peripheral nerve sheath tumor (eMPNST) is an extremely rare soft tissue neoplasm comprising less than 5% of all MPNSTs. It is distinguished cytomorphologically from a conventional MPNST by the presence of polymorphous round epithelioid cells arranged in loose clusters with or without spindled tumor cells. These features pose a diagnostic challenge because the differential diagnosis involves a variety of mesenchymal and non-mesenchymal tumors including epithelioid sarcoma, sclerosing epithelioid fibrosarcoma, malignant rhabdoid tumor, chordoma, metastatic carcinomas, and melanoma. Thus, it may become imperative to perform immunochemical stains on cell blocks of FNA aspirates to arrive at definitive diagnosis. Reports describing the cytologic features of eMPNST are rare. Herein, we report a case of eMPNST with focus on cytomorphologic and cytoimmunochemical features and differential diagnosis. PMID- 26646299 TI - Fully Automated Driving: Impact of Trust and Practice on Manual Control Recovery. AB - OBJECTIVE: An experiment was performed in a driving simulator to investigate the impacts of practice, trust, and interaction on manual control recovery (MCR) when employing fully automated driving (FAD). BACKGROUND: To increase the use of partially or highly automated driving efficiency and to improve safety, some studies have addressed trust in driving automation and training, but few studies have focused on FAD. FAD is an autonomous system that has full control of a vehicle without any need for intervention by the driver. METHOD: A total of 69 drivers with a valid license practiced with FAD. They were distributed evenly across two conditions: simple practice and elaborate practice. RESULTS: When examining emergency MCR, a correlation was found between trust and reaction time in the simple practice group (i.e., higher trust meant a longer reaction time), but not in the elaborate practice group. This result indicated that to mitigate the negative impact of overtrust on reaction time, more appropriate practice may be needed. CONCLUSIONS: Drivers should be trained in how the automated device works so as to improve MCR performance in case of an emergency. APPLICATION: The practice format used in this study could be used for the first interaction with an FAD car when acquiring such a vehicle. PMID- 26646300 TI - Variable Lifting Index (VLI): A New Method for Evaluating Variable Lifting Tasks. AB - OBJECTIVE: We seek to develop a new approach for analyzing the physical demands of highly variable lifting tasks through an adaptation of the Revised NIOSH (National Institute for Occupational Safety and Health) Lifting Equation (RNLE) into a Variable Lifting Index (VLI). BACKGROUND: There are many jobs that contain individual lifts that vary from lift to lift due to the task requirements. The NIOSH Lifting Equation is not suitable in its present form to analyze variable lifting tasks. METHOD: In extending the prior work on the VLI, two procedures are presented to allow users to analyze variable lifting tasks. One approach involves the sampling of lifting tasks performed by a worker over a shift and the calculation of the Frequency Independent Lift Index (FILI) for each sampled lift and the aggregation of the FILI values into six categories. The Composite Lift Index (CLI) equation is used with lifting index (LI) category frequency data to calculate the VLI. The second approach employs a detailed systematic collection of lifting task data from production and/or organizational sources. The data are organized into simplified task parameter categories and further aggregated into six FILI categories, which also use the CLI equation to calculate the VLI. RESULTS: The two procedures will allow practitioners to systematically employ the VLI method to a variety of work situations where highly variable lifting tasks are performed. CONCLUSIONS: The scientific basis for the VLI procedure is similar to that for the CLI originally presented by NIOSH; however, the VLI method remains to be validated. APPLICATION: The VLI method allows an analyst to assess highly variable manual lifting jobs in which the task characteristics vary from lift to lift during a shift. PMID- 26646301 TI - Which Factors Can Protect Against Range Stress in Everyday Usage of Battery Electric Vehicles? Toward Enhancing Sustainability of Electric Mobility Systems. AB - OBJECTIVE: The objective of the present research was to advance understanding of factors that can protect against range anxiety, specifically range stress in everyday usage of battery electric vehicles (BEVs). BACKGROUND: Range anxiety is a major barrier to the broad adoption of sustainable electric mobility systems. To develop strategies aimed at overcoming range anxiety, a clear understanding of this phenomenon and influencing factors is needed. METHOD: We examined range anxiety in the form of everyday range stress (ERS) in a field study setting. Seventy-two customers leased a BEV for 3 months. The field study was specifically designed to enable examination of factors that can contribute to lower ERS. In particular, study design and sample recruitment were targeted at generating vehicle usage profiles that would lead to relatively frequent experience of situations requiring active management of range resources and thereby potentially leading to experienced range stress. RESULTS: Less frequent encounter with critical range situations, higher practical experience, subjective range competence, tolerance of low range, and experienced trustworthiness of the range estimation system were related to lower ERS. Moreover, range stress was found to be related to range satisfaction and BEV acceptance. CONCLUSION: The results underline the importance of the human factors perspective to overcome range anxiety and enhance sustainability of electric mobility systems. APPLICATION: Trustworthiness should be employed as a key benchmark variable in the design of range estimation systems, and assistance systems should target increasing drivers' adaptive capacity (i.e., resilience) to cope with critical range situations. PMID- 26646302 TI - Sensitive and selective turn-on fluorescence method for cetyltrimethylammonium bromide determination based on acridine orange-polystyrene sulfonate complex. AB - This work proposed a rapid and novel fluorescence-sensing system using a complex of acridine orange (AO) and polystyrene sulfonate (PSS) to sensitively recognize and monitor cetyltrimethylammonium bromide (CTAB) in an aqueous medium. AO can interact with PSS and a complex is formed via electrostatic attraction and hydrophobic interaction. The fluorescence of AO is greatly quenched after the introduction of PSS. Upon its subsequent addition, CTAB can interact and form a complex with PSS because the electrostatic attraction between CTAB and PSS is much stronger than that between AO and PSS, which results in significant fluorescence recovery. Interestingly, the proposed method can be applied for the discrimination and detection of surfactants with different hydrocarbon chain lengths due to their different binding affinity toward PSS. The detection limit for CTAB is as low as 0.2 ug/mL and the linear range is from 0.5 to 3.5 ug/mL. Moreover, we applied the sensor to the successful detection of CTAB in water samples. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26646303 TI - Cognitive behavioural therapy or antidepressants for acute depression? PMID- 26646304 TI - Acquired Epidermodysplasia Verruciformis Associated with Human Papilloma Virus Type 14 in a Small Bowel Transplanted Child--A Case Report. AB - A 3-year-old African American girl taking sirolimus and tacrolimus for a small bowel transplantation presented with hypopigmented macules and papules throughout her trunk. A biopsy diagnosed epidermodysplasia verruciformis (EV) that was found to be associated with human papillomavirus (HPV) type 14 according to polymerase chain reaction analysis. There are few cases of acquired EV in the setting of organ transplantation. Although there is no standardized treatment for acquired EV, prevention and surveillance for transformation to squamous cell carcinoma are primary concerns. PMID- 26646305 TI - Subgroup mixable inference on treatment efficacy in mixture populations, with an application to time-to-event outcomes. AB - In tailored drug development, the patient population is thought of as a mixture of two or more subgroups that may derive differential treatment efficacy. To find the right patient population for the drug to target, it is necessary to infer treatment efficacy in subgroups and combinations of subgroups. A fundamental consideration in this inference process is that the logical relationships between treatment efficacy in subgroups and their combinations should be respected (for otherwise the assessment of treatment efficacy may become paradoxical). We show that some commonly used efficacy measures are not suitable for a mixture population. We also show that the current practice of over-simply extending the least squares means concept when estimating the efficacy in a mixture population is inappropriate. Proposing a new principle called subgroup mixable estimation, we establish the logical relationships among parameters that represent efficacy and develop a simultaneous inference procedure to confidently infer efficacy in subgroups and their combinations. Using oncology studies with time-to-event outcomes as an example, we show that the hazard ratio is not suitable for measuring treatment efficacy in a mixture population and provide appropriate efficacy measures with a rigorous inference procedure. PMID- 26646306 TI - Minimizing the Acquisition Time for Intravoxel Incoherent Motion Magnetic Resonance Imaging Acquisitions in the Liver and Pancreas. AB - OBJECTIVES: The aim of this study was to determine the combination of b-values and signal averages for diffusion-weighted image acquisitions that render the minimum acquisition time necessary to obtain values of the intravoxel incoherent motion (IVIM) model parameters in vivo in the pancreas or liver with acceptable reproducibility. MATERIALS AND METHODS: For 16 volunteers, diffusion-weighted images, with 14 b-values and 9 acquisitions per b-value, were acquired in 2 scan sessions. The IVIM model was fitted to data from lesion-sized regions of interest (ROIs) (1.7 cm(3)) as well as organ-sized ROIs in the pancreas and liver. By deleting data during analyzes, the IVIM model parameters, D and f, could be determined as a function of the number of b-values as well as the number of measurements per b-value taken along. For the IVIM model parameters, we examined the behavior reproducibility, in the form of the within-subject coefficient of variation (CVw), as a function of the amount of data taken along in the fits. Finally, we determined the minimum acquisition time required as a function of CVw. RESULT: For the lesion-sized ROI, the intersession CVws were 8%/46% and 13%/55% for D/f in the pancreas and liver, respectively, when all data were taken along. For 1.2 times larger CVws, acquisition in the pancreas could be done in 5:15 minutes using 9 acquisitions per b-value at b = 0, 30, 50, 65, 100, 375, and 500 mm(-2)s and for the liver in 2:15 using 9 acquisitions per b-value at b = 0, 40, and 500 mm(-2)s. CONCLUSIONS: Acquiring 7 b-values in the pancreas and 3 b values in the liver only decreases the reproducibility by 20% compared with an acquisition with 14 b-values. The understanding of the behavior of reproducibility as a function of b-values and acquisitions per b-values scanned will help researchers select the shortest IVIM protocol. PMID- 26646307 TI - Computed Tomography Angiography of Coronary Artery Bypass Grafts: Low Contrast Media Volume Protocols Adapted to Tube Voltage. AB - OBJECTIVE: The aim of this study was to evaluate the potential of contrast media (CM) reduction in computed tomography angiography (CTA) of coronary artery bypass grafts (CABGs) when adapting CM volume to automatically selected tube voltages. MATERIAL AND METHODS: Sixty consecutive patients (mean age, 71 +/- 14.5 years) with a total of 176 CABGs (692 bypass segments) underwent contrast-enhanced prospectively electrocardiography-gated high-pitch CTA with automated, attenuation-based tube voltage selection (100 ref. peak kilovoltage [kVp], 200 ref. mAs, tube voltages from 70-150 kVp in 10-kVp steps) using a third-generation 192-slice dual-source computed tomography scanner. Volume and flow of CM (370 mg/mL iodine) was adapted according to the tube voltages using iodine attenuation curves derived from a foregoing phantom study. In patients, CM volumes ranged from 80 mL (flow rate, 7 mL/s) at 120 kVp to 48 mL (flow rate, 4.2 mL/s) at 80 kVp. Two independent, blinded readers evaluated subjective image quality of the proximal anastomosis, bypass graft, distal anastomosis, and postanastomotic native coronary artery using a 3-point Likert scale. Objective image quality (attenuation of graft and noise) was determined and contrast-to-noise ratio (CNR) was calculated. Volume computed tomography dose index and dose-length product of each CTA examination were noted. Cohen kappa was used to define interreader agreement of subjective image quality. Regression analysis was used to determine relationships between tube voltage and vascular attenuation, image noise, and CNR. RESULTS: Using attenuation-based tube voltage selection, 5 patients (8%) were scanned at 80 kVp, 22 (37%) at 90 kVp, 11 (18%) at 100 kVp, 10 (17%) at 110 kVp, and 12 (20%) at 120 kVp. Agreement in subjective image quality between readers was good (kappa = 0.678). Diagnostic image quality was achieved in 679 of 692 (98%) bypass segments in 169 of 176 bypass grafts (96%). Thirteen of 692 bypass segments (2%) in 7 of 176 bypass grafts (4%) were rated as nondiagnostic because of severe artifacts caused by motion or beam hardening (2 proximal anastomoses of sequential bypasses, 3 graft bodies, 5 distal anastomoses, and 3 postanastomotic coronary artery segments). Regression analysis revealed no significant relationship between the automatically selected tube voltages and objective image quality parameters (bypass graft attenuation: P = 0.315; noise: P = 0.433; and CNR: P = 0.168), indicating homogenous attenuation, noise, and CNR across tube voltage levels. Mean volume computed tomography dose index was 4.0 +/ 0.9 mGy, and mean dose length product was 135.0 +/- 29.6 mGy*cm. CONCLUSION: Adapting CM protocols to automatically selected tube voltage levels allows for low-volume CM CTA examinations of CABG grafts with diagnostic image quality. PMID- 26646308 TI - Changes in Cartilage and Tendon Composition of Patients With Type I Diabetes Mellitus: Identification by Quantitative Sodium Magnetic Resonance Imaging at 7 T. AB - OBJECTIVE: The aim of this study was to investigate possible biochemical alterations in tendons and cartilage caused by type 1 diabetes mellitus (DM1), using quantitative in vivo 7 T sodium magnetic resonance (MR) imaging. MATERIALS AND METHODS: The institutional review board approved this prospective study, and written informed consent was obtained. Eight DM1 patients with no history of knee trauma and 9 healthy age- and weight-matched volunteers were examined at 7 T using dedicated knee coils.All participants underwent morphological and sodium MR imaging. Region-of-interest analysis was performed manually for the non-weight bearing area of the femoral condyle cartilage and for the patella tendon. Two readers read the image data sets independently, twice, for intrareader and interreader agreement. Normalized mean sodium signal intensity (NMSI) values were compared between patients and volunteers for each reader using analysis of variance. RESULTS: On morphological images, cartilage in the non-weight-bearing area and the patellar tendon was intact in all patients. On sodium MR imaging, bivariate analysis of variance showed significantly lower mean NMSI values in the cartilage (P = 0.008) and significantly higher values in the tendons (P = 0.025) of patients compared with those of volunteers. CONCLUSION: Our study showed significantly different NMSI values between DM1 patients and matched volunteers. Differences observed in the cartilage and tendon might be associated with a DM1 related alteration of biochemical composition that occurs before it can be visualized on morphological MR sequences. PMID- 26646309 TI - Quantitative, Organ-Specific Interscanner and Intrascanner Variability for 3 T Whole-Body Magnetic Resonance Imaging in a Multicenter, Multivendor Study. AB - INTRODUCTION: Whole-body magnetic resonance (MR) imaging is increasingly implemented in population-based cohorts and clinical settings. However, to quantify the variability introduced by the different scanners is essential to make conclusions about clinical and biological data, and relevant for internal/external validity. Thus, we determined the interscanner and intrascanner variability of different 3 T MR scanners for whole-body imaging. METHODS: Thirty volunteers were enrolled to undergo multicentric, interscanner as well intrascanner imaging as part of the German National Cohort pilot studies. A comprehensive whole-body MR protocol was installed at 9 sites including 7 different MR scanner models by all 4 major vendors. A set of quantitative, organ specific measures (n = 20; eg, volume of brain's gray/white matter, pulmonary trunk diameter, vertebral body height) were obtained in blinded fashion. Reproducibility was determined using mean weighted relative differences and intraclass correlation coefficients. RESULTS: All participants (44 +/- 14 years, 50% female) successfully completed the imaging protocol except for two because of technical issues. Mean scan time was 2 hours and 32 minutes and differed significantly across scanners (range, 1 hour 59 minutes to 3 hours 12 minutes). A higher reproducibility of obtained measurements was observed for intrascanner than for interscanner comparisons (intraclass correlation coefficients, 0.80 +/- 0.17 vs 0.60 +/- 0.31, P = 0.005, respectively). In the interscanner comparison, mean relative difference ranged from 1.0% to 53.2%. Conversely, in the intrascanner comparison, mean relative difference ranged from 0.1% to 15.6%. There were no statistical differences for intrascanner and interscanner reproducibility between the different organ foci (all P >= 0.24). CONCLUSIONS: While whole-body MR imaging-derived, organ-specific parameters are generally associated with good to excellent reproducibility, smaller differences are obtained when using identical MR scanner models by a single vendor. PMID- 26646310 TI - [Determination of prognosis using gene expression analyses: Consequences for the indication for radiotherapy?]. PMID- 26646311 TI - Primary glioblastoma multiforme tumors and recurrence : Comparative analysis of the danger signals HMGB1, HSP70, and calreticulin. AB - PURPOSE: Glioblastoma multiforme (GBM) is the most common and aggressive brain tumor. Despite improved multimodal therapies, the tumor recurs in most cases. Diverging patient survival suggests great tumor heterogeneity and different therapy responses. Danger signals such as high-mobility group box protein 1 (HMGB1), heat shock protein 70 (HSP70), and calreticulin (CRT) are biomarker candidates, due to their association with tumor progression versus induction of antitumor immune responses. Overexpression of these danger signals has been reported for various types of tumors; however, their role in GBM is still elusive. A direct comparison of their expression in the primary tumor versus the corresponding relapse is still lacking for most tumor entities. PATIENTS AND METHODS: We therefore performed an expression analysis by immunohistochemistry of the danger signals HMGB1, HSP70, and CRT in primary tumors and the corresponding relapses of 9 patients with de novo GBM. RESULTS: HMGB1 was highly expressed in primary tumors with a significant reduction in the respective relapse. The extracellular HSP70 expression was significantly increased in the relapse compared to the primary tumor. CRT was generally highly expressed in the primary tumor, with a slight increase in the relapse. CONCLUSION: The combination of a decreased expression of HMGB1, an increased expression of extracellular HSP70, and an increased expression of CRT in the relapse seems to be beneficial for patient survival. HMGB1, extracellular HSP70, and CRT could be taken into concerted consideration as potential biomarkers for the prognosis of patients with GBM. PMID- 26646312 TI - Biases in Visual, Auditory, and Audiovisual Perception of Space. AB - Localization of objects and events in the environment is critical for survival, as many perceptual and motor tasks rely on estimation of spatial location. Therefore, it seems reasonable to assume that spatial localizations should generally be accurate. Curiously, some previous studies have reported biases in visual and auditory localizations, but these studies have used small sample sizes and the results have been mixed. Therefore, it is not clear (1) if the reported biases in localization responses are real (or due to outliers, sampling bias, or other factors), and (2) whether these putative biases reflect a bias in sensory representations of space or a priori expectations (which may be due to the experimental setup, instructions, or distribution of stimuli). Here, to address these questions, a dataset of unprecedented size (obtained from 384 observers) was analyzed to examine presence, direction, and magnitude of sensory biases, and quantitative computational modeling was used to probe the underlying mechanism(s) driving these effects. Data revealed that, on average, observers were biased towards the center when localizing visual stimuli, and biased towards the periphery when localizing auditory stimuli. Moreover, quantitative analysis using a Bayesian Causal Inference framework suggests that while pre-existing spatial biases for central locations exert some influence, biases in the sensory representations of both visual and auditory space are necessary to fully explain the behavioral data. How are these opposing visual and auditory biases reconciled in conditions in which both auditory and visual stimuli are produced by a single event? Potentially, the bias in one modality could dominate, or the biases could interact/cancel out. The data revealed that when integration occurred in these conditions, the visual bias dominated, but the magnitude of this bias was reduced compared to unisensory conditions. Therefore, multisensory integration not only improves the precision of perceptual estimates, but also the accuracy. PMID- 26646313 TI - Pulmonary alveolar proteinosis in a cat. AB - BACKGROUND: Pulmonary alveolar proteinosis is an extremely rare lung disease in animals and humans. It is characterized by the deposition of a large amount of phospholipoproteinaceous material in the alveoli. There are several possible etiologies, both congenital and acquired. Alveolar macrophages play an important role in the clearance of surfactant. This is the first report of pulmonary alveolar proteinosis in the feline species. CASE PRESENTATION: Pulmonary alveolar proteinosis was diagnosed in an 8-month-old cat with chronic tachypnea, failure to thrive and finally respiratory distress. The diagnosis was based on the milky appearance of the bronchoalveolar lavage fluid taken under general anesthesia after bronchoscopy. Because of the worsening respiratory distress and development of anorexia the kitten was euthanized. Histopathology of the lungs showed alveoli and bronchi filled with eosinophilic material. Electron microscopy revealed lamellated intra-alveolar bodies. As the granulocyte-macrophage colony stimulating factor was elevated in the serum and no autoantibodies against granulocyte-macrophage colony-stimulating factor were detected, a primary hereditary pulmonary alveolar proteinosis was suspected. The underlying cause was thought to be a dysfunction of the receptor of the granulocyte-macrophage colony stimulating factor, however, a mutation in the genes encoding the alpha and beta chains of this receptor has not been found. CONCLUSION: This is the first description of pulmonary alveolar proteinosis in a cat. This kitten is thought to have a primary hereditary pulmonary alveolar proteinosis with a possible defect in the signalling pathway of the receptor of the granulocyte-macrophage colony stimulating factor. The imaging and pathologic findings are similar to those of humans. PMID- 26646315 TI - Personalized augmented reality for anatomy education. AB - Anatomy education is a challenging but vital element in forming future medical professionals. In this work, a personalized and interactive augmented reality system is developed to facilitate education. This system behaves as a "magic mirror" which allows personalized in-situ visualization of anatomy on the user's body. Real-time volume visualization of a CT dataset creates the illusion that the user can look inside their body. The system comprises a RGB-D sensor as a real-time tracking device to detect the user moving in front of a display. In addition, the magic mirror system shows text information, medical images, and 3D models of organs that the user can interact with. Through the participation of 7 clinicians and 72 students, two user studies were designed to respectively assess the precision and acceptability of the magic mirror system for education. The results of the first study demonstrated that the average precision of the augmented reality overlay on the user body was 0.96 cm, while the results of the second study indicate 86.1% approval for the educational value of the magic mirror, and 91.7% approval for the augmented reality capability of displaying organs in three dimensions. The usefulness of this unique type of personalized augmented reality technology has been demonstrated in this paper. PMID- 26646316 TI - Synthesis and characterization of a multimode stationary phase: Congo red derivatized silica in nano-flow HPLC. AB - A novel Congo red (CR) derivatized silica stationary phase was prepared and packed into a fused silica capillary tube for nano-flow HPLC. A variety of analytes including poly-aromatic hydrocarbons, parabens, acids, sulfonamides, bases, and nucleosides were successfully separated using the CR. In comparison with commercial ODS columns, this new stationary phase has a different separation mechanism (hydrophobically-assisted ion-exchange), which was evident in the separation of benzoic acid derivatives and sulfonamides. The successful application of CR-bonded silica stationary phase in the HILIC and PALC modes demonstrates the effectiveness of this potential chromatographic material in nano flow HPLC. PMID- 26646317 TI - Screening for transfusion transmissible infections using rapid diagnostic tests in Africa: a potential hazard to blood safety? AB - Rapid diagnostic tests (RDTs) are routinely used in African blood centres. We analysed data from two cross-sectional studies representing 95 blood centres in 29 African countries. Standardized panels of sera containing varying concentrations of anti-human immunodeficiency virus (HIV) antibodies (Ab), hepatitis B virus antigen (HBsAg) and antihepatitis C virus (HCV) Ab were screened using routine operational testing procedures at the centres. Sensitivity of detection using RDTs was high for HIV Ab-positive samples, but low for intermediately HBsAg (51.5%) and HCV Ab (40.6%)-positive samples. These findings suggest that current RDT use in Africa could pose a hazard to blood safety. PMID- 26646319 TI - Synthesis and thermal stability of perovskite alkali metal strontium borohydrides. AB - Three new perovskite-type bimetallic alkali metal strontium borohydride compounds, alpha-MSr(BH4)3 (M = K, Rb, Cs), have been synthesized and investigated by in situ synchrotron radiation powder X-ray diffraction, thermal analysis combined with mass spectrometry and Sievert's measurements. The bimetallic borohydrides were synthesized via an addition reaction between Sr(BH4)2 and MBH4 (M = K, Rb, Cs) by mechanochemical treatment. The Sr(BH4)2 NaBH4 system, which was treated in a similar manner, did not undergo reaction. All three alpha-MSr(BH4)3 compounds crystallize in the orthorhombic crystal system at room temperature: KSr(BH4)3 (P21cn), a = 7.8967(6), b = 8.2953(7), and c = 11.508(1) A (V = 753.82(12) A(3)). RbSr(BH4)3 (Pbn21), a = 8.0835(3), b = 8.3341(4), and c = 11.6600(5) A (V = 785.52(6) A(3)). CsSr(BH4)3 (P22121), a = 8.2068(9), b = 8.1793(9), and c = 6.0761(4) A (V = 407.87(7) A(3)). All three compounds are perovskite-type 3D framework structures built from distorted [Sr(BH4)6] octahedra. High-temperature polymorphs are identified to form at 258, 220 and 150 degrees C for MSr(BH4)3, M = K, Rb and Cs, respectively. The new compounds are thermally stable and decompose at T > 360 degrees C into SrB6, SrH2 and MBH4 (M = K, Rb, Cs). PMID- 26646320 TI - Epigenetic regulation of ZEB1-RAB25/ESRP1 axis plays a critical role in phenylbutyrate treatment-resistant breast cancer. AB - Phenylbutyrate (PB) is a histone deacetylase antagonist that also exhibits antitumor activity. In this study, we used 7 breast cancer cell lines to identify biomarker candidates that predict PB sensitivity in breast cancer.Comprehensive gene expression profiles were compared using microarrays, and the importance of the identified genes to PB sensitivity was confirmed in gene transfection experiments. CRL and MDAMB453 cells were identified as PB-sensitive, while MDAMB231 cells were PB-resistant.RAB25 and ESRP1 were identified as key regulators of PB sensitivity, while ANKD1, ETS1, PTRF, IFI16 and KIAA1199 acted as PB resistance-related genes. Expression of these genes was dramatically altered by DNA demethylation treatments. RAB25 expression inhibited IFI16 and PTRF, while ESRP1 expression suppressed ANKRD1, ETS1, and KIAA1199. Both RAB25 and ESRP1 were suppressed by ZEB1, which was in turn regulated via epigenetic mechanisms. Thus, PB sensitivity is influenced by epigenetic expression alteration of ZEB1. The genes associated with PB sensitivity are downstream targets of ZEB1. Epigenetic regulation of ZEB1 may prove valuable as a critical biomarker for predicting resistance to breast cancer therapies. PMID- 26646321 TI - Dynamic reprogramming of DNA methylation in SETD2-deregulated renal cell carcinoma. AB - Clear cell renal cell carcinomas (ccRCCs) harbor frequent mutations in epigenetic modifiers including SETD2, the H3K36me3 writer. We profiled DNA methylation (5mC) across the genome in cell line-based models of SETD2 inactivation and SETD2 mutant primary tumors because 5mC has been linked to H3K36me3 and is therapeutically targetable. SETD2 depleted cell line models (long-term and acute) exhibited a DNA hypermethylation phenotype coinciding with ectopic gains in H3K36me3 centered across intergenic regions adjacent to low expressing genes, which became upregulated upon dysregulation of the epigenome. Poised enhancers of developmental genes were prominent hypermethylation targets. SETD2 mutant primary ccRCCs, papillary renal cell carcinomas, and lung adenocarcinomas all demonstrated a DNA hypermethylation phenotype that segregated tumors by SETD2 genotype and advanced grade. These findings collectively demonstrate that SETD2 mutations drive tumorigenesis by coordinated disruption of the epigenome and transcriptome,and they have important implications for future therapeutic strategies targeting chromatin regulator mutant tumors. PMID- 26646323 TI - Griffipavixanthone, a dimeric xanthone extracted from edible plants, inhibits tumor metastasis and proliferation via downregulation of the RAF pathway in esophageal cancer. AB - Metastasis causes a large number of deaths among esophageal cancer patients. The activation of RAF family proteins elevates tumor metastasis and proliferation. In screen targeting the RAF protein, we identified that Griffipavixanthone (GPX), a dimeric xanthone isolated from Garcinia esculenta, is a B-RAF and C-RAF inhibitor against esophageal cancer cells. Using wound healing, transwell migration and matrigel invasion assays, we confirmed that GPX significantly inhibited cell migration and invasion. Furthermore, exposure to GPX rendered cell proliferation and induced G2/M cell cycle arrest. Our mechanistic study showed that GPX suppressed cancer metastasis and proliferation through downregulation of RAF-MEK ERK cascades proteins as well as RAF mRNA levels. In a pulmonary metastasis model, the intraperitoneal injection of GPX significantly suppressed esophageal tumor metastasis and ERK protein level in vivo. In conclusion, our present study suggested that GPX could inhibit tumor migration, invasion and proliferation in vitro and in vivo, which indicated the potential of GPX for preventing and treating esophageal cancer. PMID- 26646324 TI - Efficacy and safety of pamidronate in children with vitamin D intoxication. AB - BACKGROUND: Bisphosphonates are used in the treatment of vitamin D intoxication (VDI) after failure of conventional therapy including prednisolone. Safety concerns restrict the use of bisphosphonates from being used as first-line therapy for VDI in children. The aim of this study was to evaluate the efficacy and safety of pamidronate in comparison with prednisolone in children with VDI. METHODS: We reviewed the hospital records of children consecutively diagnosed with VDI at two medical centers in a 15 year period. RESULTS: The subjects consisted of 21 children (age, 0.3-4.2 years) who were treated with prednisolone and/or bisphosphonates. Pamidronate (n = 18) or alendronate (n = 3) was used in six patients after unsuccessful prednisolone treatment, and in 15 patients from baseline. Initial serum calcium and 25-hydroxyvitamin D were 16.1 +/- 1.9 mg/dL and 493 +/- 219 ng/mL, respectively. The median time to reach normocalcemia in the pamidronate, alendronate and prednisolone groups was 3 days (range, 2-12 days), 4 days (range, 3-6 days) and 17 days (range, 12-26 days), respectively (P = 0.013). The pamidronate group had a fivefold shorter hospital stay than the prednisolone group. Three patients initially treated with prednisolone developed nephrocalcinosis but this did not occur in any patient treated with bisphosphonates from baseline. Apart from transient fever and moderate hypophosphatemia, no side-effect of bisphosphonate treatment was observed. CONCLUSIONS: Pamidronate is efficient and safe for the treatment of VDI in children. Pamidronate use significantly shortens the duration of treatment, and thereby may prevent the development of nephrocalcinosis. Instead of prednisolone, pamidronate should be used together with hydration and furosemide as the first line therapy for VDI. PMID- 26646325 TI - Plasmonic Enzyme-Linked Immunosorbent Assay Using Nanospherical Brushes as a Catalase Container for Colorimetric Detection of Ultralow Concentrations of Listeria monocytogenes. AB - Plasmonic enzyme-linked immunosorbent assay (pELISA) based on catalase (CAT) mediated gold nanoparticle growth exhibits ultrahigh sensitivity for detecting disease-related biomarkers using sandwich formats. However, the limit of detection (LOD) of this strategy for Listeria monocytogenes is only around 10(3) CFU/mL, which considerably exceeds the amount of L. monocytogenes commonly present in food products (<100 CFU/g). Herein, we report an improved pELISA method for detection of L. monocytogenes at ultralow concentrations with the sandwich formats using silica nanoparticles carrying poly(acrylic acid) brushes as a "CAT container" to increase enzyme loading for enhancing the detection signal. Under optimal conditions, the proposed pELISA exhibits good specificity and excellent sensitivity for L. monocytogenes with a LOD of 8 * 10(1) CFU/mL in 0.01 M phosphate-buffered saline, via a reaction that can be discriminated by the naked eye. The LOD obtained by this method was 2 and 5 orders of magnitude lower than that of conventional CAT-based pELISA and horseradish peroxidase (HRP)-based conventional ELISA, respectively. Coupled with large-volume immunomagnetic separation, the LOD for L. monocytogenes-spiked lettuce samples reached 8 * 10(1) CFU/g. The improved pELISA also exhibited a great potential in detecting a single cell of L. monocytogenes in 100 MUL of solution. PMID- 26646322 TI - Upregulation of flotillin-1 promotes invasion and metastasis by activating TGF beta signaling in nasopharyngeal carcinoma. AB - Metastasis is the main cause of cancer-related deaths. Nasopharyngeal carcinoma (NPC) is characterized by severe local invasion and high incidence of regional lymph node metastasis, which represents poor prognosis. However, the underlying mechanism that induces lymph node metastasis of NPC remains largely unknown. Herein, we report that flotillin-1 (FLOT1), a component of lipid raft, which was reported to be involved in tumor progression, was robustly upregulated in the NPC samples with lymph node metastasis. High FLOT1 expression was significantly associated with N classification as well as poorer overall and disease-free survivals in 169 archived clinical NPC samples. Overexpression of FLOT1 enhanced the migratory and invasive abilities of NPC cells in vitro, and more importantly, promoted invasion into the surrounding tissues and metastasis to lymph nodes in vivo. Whereas silencing of endogenous FLOT1 in NPC cells decreased the local invasion and metastasis to lymph nodes. Furthermore, FLOT1 induced the expression and secretion of TGF-beta1, facilitated the activation of TGF-beta/Smad3 signaling to effectuate epithelial-mesenchymal transition. Our findings present new evidence that FLOT1 plays an important role in promoting aggressive behavior of NPC and provide new insights into the regulatory mechanism of TGF-beta signaling. PMID- 26646326 TI - Choosing Wisely? Not as the Academy of Medical Royal Colleges envisages. PMID- 26646327 TI - Resuscitation Council (UK) basic and advanced life support guidelines 2015. PMID- 26646328 TI - Professor Bryan Lask, 1941-2015. PMID- 26646329 TI - Prevention of contrast-induced acute kidney injury. AB - The number of interventional and diagnostic contrast procedures has increased year on year and contrast-induced acute kidney injury has become a leading cause of inpatient mortality and morbidity. This article summarizes how to identify the high-risk patient and gives a systematic approach to prevent contrast-induced acute kidney injury. PMID- 26646330 TI - A clinician's guide to viscoelastic testing in the perioperative period. AB - Viscoelastic tests provide a global and dynamic assessment of the coagulation system and thus are becoming increasingly relied upon in the perioperative period. Many clinicians are unfamiliar with viscoelastic testing, so this article provides an overview of their use and interpretation in the management of perioperative bleeding. PMID- 26646331 TI - How to diagnose fibromyalgia. AB - This review discusses the basic pathophysiological mechanisms that are necessary to understand the principles of diagnosis and management of fibromyalgia, and outlines a practical diagnostic approach to patients presenting with chronic widespread pain. PMID- 26646332 TI - Columnar lined Barrett's oesophagus. AB - Over the past few years, the definition of Barrett's oesophagus has altered with no real agreement on histological understanding. This article highlights the increasing confusion regarding Barrett's oesophagus with a focus on the all-too frequently ignored aspect of the columnar lined oesophagus. PMID- 26646333 TI - Improving the accuracy of HES comorbidity codes by better documentation in surgical admission proforma. AB - BACKGROUND: Poor documentation in medical notes can affect the quality of the source document for coding which can lead to inaccurate coding. This study aimed to determine the accuracy of Hospital Episode Statistics (HES) data for comorbidities and to establish whether better documentation in admission clerking proforma can improve the accuracy of codes for comorbidities in general surgical patients. METHODS: A clinical audit was conducted to assess the accuracy, sensitivity, specificity, positive predictive value and negative predictive value of HES codes for comorbidities in general surgical patients before and after implementing better documentation in admission clerking proforma. The following comorbidities were included: hypertension, ischaemic heart disease, diabetes, asthma, chronic obstructive pulmonary disease, cerebrovascular disease, chronic kidney disease and hypercholesterolaemia. Medical notes were used as reference standard and a target standard of 98% was determined for the above measures. RESULTS: Overall, on the initial audit, HES codes had substandard accuracy (90.5%, kappa = 0.599), sensitivity (47.71%, 95% confidence interval 38.05 57.49%) and negative predictive value (89.60%, 95% confidence interval 86.73 92.03%). HES codes for comorbidities were 100% specific with positive predictive value of 100%. Implementing better documentation in the admission clerking proforma improved the accuracy (99.67%, kappa = 0.985), sensitivity (97.4%, 95% confidence interval 90.93-99.68%) and negative predictive value (99.62%, 95% confidence interval 98.63-99.95%) significantly from the baseline (P<0.0001). CONCLUSIONS: Although HES codes can confidently predict the actual presence of the comorbidities, they have substandard accuracy and ability to rule out the presence of the comorbidities. Better documentation in clerking proforma can improve the accuracy and 'ruling out' ability of the HES codes. This can be achieved by improving knowledge and accountability of clinicians about documenting comorbidities. PMID- 26646334 TI - Formalized prescribing error feedback from hospital pharmacists: doctors' attitudes and opinions. AB - Doctors have reported a lack of awareness of their prescribing errors with lack of feedback considered a system failure. This article summarizes the views of hospital doctors about receiving formal prescribing error feedback from ward based pharmacists. PMID- 26646335 TI - Sir William Boog Leishman, after whom leishmaniasis is named. PMID- 26646336 TI - Atrial fibrillation during pregnancy: cardioversion with flecainide. PMID- 26646337 TI - Retrobulbar haemorrhage: improved visual acuity after delayed surgical decompression. PMID- 26646338 TI - 'What is happening?': a case of transient global amnesia. PMID- 26646339 TI - Peripheral T-cell lymphoma with left ankle swelling, ulceration and fever. PMID- 26646340 TI - Work or environment-related disorders? Three triage steps for physicians. PMID- 26646318 TI - Supramolecular Hydrogelators and Hydrogels: From Soft Matter to Molecular Biomaterials. AB - In this review we intend to provide a relatively comprehensive summary of the work of supramolecular hydrogelators after 2004 and to put emphasis particularly on the applications of supramolecular hydrogels/hydrogelators as molecular biomaterials. After a brief introduction of methods for generating supramolecular hydrogels, we discuss supramolecular hydrogelators on the basis of their categories, such as small organic molecules, coordination complexes, peptides, nucleobases, and saccharides. Following molecular design, we focus on various potential applications of supramolecular hydrogels as molecular biomaterials, classified by their applications in cell cultures, tissue engineering, cell behavior, imaging, and unique applications of hydrogelators. Particularly, we discuss the applications of supramolecular hydrogelators after they form supramolecular assemblies but prior to reaching the critical gelation concentration because this subject is less explored but may hold equally great promise for helping address fundamental questions about the mechanisms or the consequences of the self-assembly of molecules, including low molecular weight ones. Finally, we provide a perspective on supramolecular hydrogelators. We hope that this review will serve as an updated introduction and reference for researchers who are interested in exploring supramolecular hydrogelators as molecular biomaterials for addressing the societal needs at various frontiers. PMID- 26646342 TI - Cricoid pressure during rapid sequence induction: using the force or not. PMID- 26646343 TI - Acute peripheral weakness and suspected Guillain-Barre syndrome. PMID- 26646344 TI - Examination of the adult spine. PMID- 26646345 TI - Transient global amnesia. PMID- 26646346 TI - Functional magnetic resonance imaging. PMID- 26646347 TI - Semiautomatic detection of myocardial contours in order to investigate normal values of the left ventricular trabeculated mass using MRI. AB - PURPOSE: To propose, assess, and validate a semiautomatic method allowing rapid and reproducible measurement of trabeculated and compacted left ventricular (LV) masses from cardiac magnetic resonance imaging (MRI). MATERIALS AND METHODS: We developed a method to automatically detect noncompacted, endocardial, and epicardial contours. Papillary muscles were segmented using semiautomatic thresholding and were included in the compacted mass. Blood was removed from trabeculae using the same threshold tool. Trabeculated, compacted masses and ratio of noncompacted to compacted (NC:C) masses were computed. Preclinical validation was performed on four transgenic mice with hypertrabeculation of the LV (high-resolution cine imaging, 11.75T). Then analysis was performed on normal cine-MRI examinations (steady-state free precession [SSFP] sequences, 1.5T or 3T) obtained from 60 healthy participants (mean age 49 +/- 16 years) with 10 men and 10 women for each of the following age groups: [20,39], [40,59], and [60,79]. Interobserver and interexamination segmentation reproducibility was assessed by using Bland-Altman analysis and by computing the correlation coefficient. RESULTS: In normal participants, noncompacted and compacted masses were 6.29 +/- 2.03 g/m(2) and 62.17 +/- 11.32 g/m(2) , respectively. The NC:C mass ratio was 10.26 +/- 3.27%. Correlation between the two observers was from 0.85 for NC:C ratio to 0.99 for end-diastolic volume (P < 10(-5) ). The bias between the two observers was -1.06 +/- 1.02 g/m(2) for trabeculated mass, -1.41 +/- 2.78 g/m(2) for compacted mass, and -1.51 +/- 1.77% for NC:C ratio. CONCLUSION: We propose a semiautomatic method based on region growing, active contours, and thresholding to calculate the NC:C mass ratio. This method is highly reproducible and might help in the diagnosis of LV noncompaction cardiomyopathy. J. Magn. Reson. Imaging 2016;43:1398-1406. PMID- 26646348 TI - R-Duloxetine and N-Methyl Duloxetine as Novel Analgesics Against Experimental Postincisional Pain. AB - BACKGROUND: Antidepressant S-duloxetine alleviates intractable pain associated with diabetic peripheral neuropathy and fibromyalgia. It also reduces both acute and persistent pain in various animal models. This study addresses whether the enantiomer, R-duloxetine, and the homolog, N-methyl duloxetine, could act as analgesics and whether they block neuronal Na+ channels. METHODS: The rat incision plus extension model on the dorsothoracic skin was applied to evoke postoperative mechanoallodynia and hyperalgesia, measured for 5 days postoperatively by local responses to von Frey filaments. R-Duloxetine and N methyl duloxetine were administered systemically (intraperitoneal) or locally (subcutaneous [SC]) 1 hour before the surgery. The block of Na currents in rat neuronal GH3 cells was determined under the whole-cell configuration. RESULTS: Ipsilateral SC injections (2 mg/0.4 mL) of R-duloxetine and N-methyl duloxetine reduced both postoperative allodynia and hyperalgesia by approximately 89% to 99% in the area under the curve of skin responses next to incision over 5 days. Systemic intraperitoneal injections at a higher dosage (10 mg) had smaller analgesic effects (reduced by approximately 53%-69%), whereas contralateral SC injections (10 mg) were ineffective. Both R-duloxetine and N-methyl duloxetine blocked neuronal Na+ currents, with a higher affinity for the inactivated than the resting states. In addition, both drugs elicited significant use-dependent block of Na currents when stimulated at 5 Hz. CONCLUSIONS: R-Duloxetine and N methyl duloxetine are highly effective against postoperative pain using the skin incision model, and they elicit both tonic and use-dependent block of neuronal Na+ channels. Our results suggest that R-duloxetine and N-methyl duloxetine are applicable as novel analgesics. PMID- 26646349 TI - Primary Spoken Language and Neuraxial Labor Analgesia Use Among Hispanic Medicaid Recipients. AB - BACKGROUND: Hispanic women are less likely than non-Hispanic Caucasian women to use neuraxial labor analgesia. It is unknown whether there is a disparity in anticipated or actual use of neuraxial labor analgesia among Hispanic women based on primary language (English versus Spanish). METHODS: In this 3-year retrospective, single-institution, cross-sectional study, we extracted electronic medical record data on Hispanic nulliparous with vaginal deliveries who were insured by Medicaid. On admission, patients self-identified their primary language and anticipated analgesic use for labor. Extracted data included age, marital status, labor type, delivery provider (obstetrician or midwife), and anticipated and actual analgesic use. Household income was estimated from census data geocoded by zip code. Multivariable logistic regression models were estimated for anticipated and actual neuraxial analgesia use. RESULTS: Among 932 Hispanic women, 182 were self-identified as primary Spanish speakers. Spanish speaking Hispanic women were less likely to anticipate and use neuraxial anesthesia than English-speaking women. After controlling for confounders, there was an association between primary language and anticipated neuraxial analgesia use (adjusted relative risk: Spanish- versus English-speaking women, 0.70; 97.5% confidence interval, 0.53-0.92). Similarly, there was an association between language and neuraxial analgesia use (adjusted relative risk: Spanish- versus English-speaking women 0.88; 97.5% confidence interval, 0.78-0.99). The use of a midwife compared with an obstetrician also decreased the likelihood of both anticipating and using neuraxial analgesia. CONCLUSIONS: A language-based disparity was found in neuraxial labor analgesia use. It is possible that there are communication barriers in knowledge or understanding of analgesic options. Further research is necessary to determine the cause of this association. PMID- 26646350 TI - Steroid Receptors and Aromatase Gene Expression in Different Brain Areas of Copulating and Sexually Sluggish Male Rats. AB - INTRODUCTION: Sexually sluggish (SS) males have been identified in several species of mammals including rats. These animals take more than 30 minutes to ejaculate; they do not ejaculate or do so inconsistently despite being tested repeatedly with sexually receptive females. Different brain areas and hormones play an important role in the control of male sexual behavior. AIMS: Determine gene expression for the androgen receptor (AR), the estrogen receptor alpha (ERalpha), the progesterone receptor (PR), and the aromatase enzyme (ARO), in brain regions important in the control of male sexual behavior including the medial preoptic area (MPOA), the amygdala (AMG), the olfactory bulb (OB), and, as a control, the cortex (CTX) of copulating (C) and SS male rats. METHODS: Males that ejaculated within 30 minutes in three tests with receptive females were included in the C group, while those males that ejaculated in one or none of the four tests were included in the SS group. RNA was isolated 1 week after the last test of sexual behavior, and cDNA was synthesized from the brain areas listed above. MAIN OUTCOMES MEASURES: Expression of the AR, ERalpha, PR, and ARO genes was determined by quantitative polymerase chain reaction (qPCR). Cyclophilin A (CycA) and tyrosine 3-monooxygenase-tryptophan activation protein zeta (Ywhaz) were housekeeping genes used to determine relative gene expression with the 2( DeltaDeltaCt) method. RESULTS: The expression of mRNA for AR and ARO increased in the MPOA of SS males. ARO mRNA was increased in the AMG of SS males. In the OB, ERalpha mRNA was increased and AR mRNA reduced in SS males. CONCLUSION: These results indicate SS and C males show differences in gene expression within brain regions controlling sexual behavior. PMID- 26646351 TI - The better to eat you with: the comparative feeding morphology of phocid seals (Pinnipedia, Phocidae). AB - One adaptation crucial to the survival of mammalian lineages that secondarily transitioned from land to water environments was the ability to capture and consume prey underwater. Phocid seals have evolved diverse feeding strategies to feed in the marine environment, and the objectives of this study were to document the specialized feeding morphologies and identify feeding strategies used by extant phocids. This study used principal component analysis (PCA) to determine the major axes of diversification in the skull for all extant phocid taxa and the recently extinct Caribbean monk seal (n = 19). Prey data gathered from the literature and musculoskeletal data from dissections were included to provide a comprehensive description of each feeding strategy. Random Forest analysis was used to determine the morphological, ecological and phylogenetic variables that best described each feeding strategy. There is morphological evidence for four feeding strategies in phocids: filter; grip and tear; suction; and pierce feeding. These feeding strategies are supported by quantitative cranial and mandibular characters, dietary information, musculoskeletal data and, for some species, behavioral observations. Most phocid species are pierce feeders, using a combination of biting and suction to opportunistically catch prey. Grip and tear and filter feeding are specialized strategies with specific morphological adaptations. These unique adaptations have allowed leopard seals (Hydrurga leptonyx) and crabeater seals (Lobodon carcinophaga) to exploit novel ecological niches and prey types. This study provides the first cranial and mandibular morphological evidence for the use of specialized suction feeding in hooded seals (Cystophora cristata), northern elephant seals (Mirounga angustirostris) and southern elephant seals (Mirounga leonina). The most important variables in determining the feeding strategy of a given phocid species were cranial and mandibular shape, diet, and phylogeny. These results provide a framework for understanding the evolution and adaptability of feeding strategies employed by extant phocid species, and these findings can be applied to other pinniped lineages and extinct taxa. PMID- 26646353 TI - Facebook's Contribution to Well-being among Adolescent and Young Adults as a Function of Mental Resilience. AB - Studies of correlations between general internet use and psychological well-being have shown mixed results. The present study aimed to elucidate the relationship between Facebook use and psychological well-being, with mental resilience expected to moderate the relationship. Two hundred Israeli adolescents and young adults completed questionnaires assessing their Facebook use, mental resilience, and psychological well-being. Results showed that Facebook use was positively correlated with psychological well-being, and that this relationship was particularly strong for participants with low mental resilience. The findings support a positive effect of Facebook use as providing a virtual supportive community for individuals who may lack the social skills needed to develop social capital and confidence through traditional communication paths. PMID- 26646352 TI - Role of temperament in early adolescent pure and co-occurring internalizing and externalizing problems using a bifactor model: Moderation by parenting and gender. AB - We contribute to the literature on the relations of temperament to externalizing and internalizing problems by considering parental emotional expressivity and child gender as moderators of such relations and examining prediction of pure and co-occurring problem behaviors during early to middle adolescence using bifactor models (which provide unique and continuous factors for pure and co-occurring internalizing and externalizing problems). Parents and teachers reported on children's (4.5- to 8-year-olds; N = 214) and early adolescents' (6 years later; N = 168) effortful control, impulsivity, anger, sadness, and problem behaviors. Parental emotional expressivity was measured observationally and with parents' self-reports. Early-adolescents' pure externalizing and co-occurring problems shared childhood and/or early-adolescent risk factors of low effortful control, high impulsivity, and high anger. Lower childhood and early-adolescent impulsivity and higher early-adolescent sadness predicted early-adolescents' pure internalizing. Childhood positive parental emotional expressivity more consistently related to early-adolescents' lower pure externalizing compared to co-occurring problems and pure internalizing. Lower effortful control predicted changes in externalizing (pure and co-occurring) over 6 years, but only when parental positive expressivity was low. Higher impulsivity predicted co-occurring problems only for boys. Findings highlight the probable complex developmental pathways to adolescent pure and co-occurring externalizing and internalizing problems. PMID- 26646354 TI - Assessment of biocompatibility of 3D printed photopolymers using zebrafish embryo toxicity assays. AB - 3D printing has emerged as a rapid and cost-efficient manufacturing technique to enable the fabrication of bespoke, complex prototypes. If the technology is to have a significant impact in biomedical applications, such as drug discovery and molecular diagnostics, the devices produced must be biologically compatible to enable their use with established reference assays and protocols. In this work we demonstrate that we can adapt the Fish Embryo Test (FET) as a new method to quantify the toxicity of 3D printed microfluidic devices. We assessed the biocompatibility of four commercially available 3D printing polymers (VisiJetCrystal EX200, Watershed 11122XC, Fototec SLA 7150 Clear and ABSplus P 430), through the observation of key developmental markers in the developing zebrafish embryos. Results show all of the photopolymers to be highly toxic to the embryos, resulting in fatality, although we do demonstrate that post-printing treatment of Fototec 7150 makes it suitable for zebrafish culture within the FET. PMID- 26646355 TI - Estimating dengue type reproduction numbers for two provinces of Sri Lanka during the period 2013-14. AB - Dengue is an endemic disease in the southeast Asian country Sri Lanka. Two seasonal peaks of dengue incidence were observed every year since 2002 onwards. In this study, we formulate a 2-strain dengue model for analyzing the monthly seasonal dengue incidence data from 2 provinces of Sri Lanka during the period April 2013 to September 2014. The seasonality is incorporated in the model in terms of mosquito biting rate, which we assume to be time periodic. We estimated 2 primary reproduction numbers and the basic reproduction number in a periodic environment using dengue incidence data from the western and the central provinces of Sri Lanka. We also estimated different time-average type reproduction numbers from the model using the data from these 2 provinces. Using univariate sensitivity analysis, we measured the sensitivity of the time average reproduction number ([Formula: see text]) When we vary different parameters of the proposed dengue model, we find the transmission probability of human susceptibility to strain-I infection and the mosquito mortality rate parameters are the most sensitive parameters in dengue transmission in these 2 provinces. PMID- 26646356 TI - A simple recipe for setting up the flux equations of cyclic and linear reaction schemes of ion transport with a high number of states: The arrow scheme. AB - The calculation of flux equations or current-voltage relationships in reaction kinetic models with a high number of states can be very cumbersome. Here, a recipe based on an arrow scheme is presented, which yields a straightforward access to the minimum form of the flux equations and the occupation probability of the involved states in cyclic and linear reaction schemes. This is extremely simple for cyclic schemes without branches. If branches are involved, the effort of setting up the equations is a little bit higher. However, also here a straightforward recipe making use of so-called reserve factors is provided for implementing the branches into the cyclic scheme, thus enabling also a simple treatment of such cases. PMID- 26646357 TI - The famine exposure in early life and metabolic syndrome in adulthood. AB - BACKGROUND & AIMS: Epidemiologic studies have revealed that early-life conditions influence later risk of chronic diseases. We aimed to explore whether exposure to Chinese famine between 1959 and 1962 during fetal and childhood period was related with metabolic syndrome (MS) in adulthood. METHODS: 6445 subjects from SPECT-China study were divided into fetal-exposed (1959-1962), childhood-exposed (1949-1958), adolescence/young adult-exposed (1921-1948), non-exposed (1963-1974) and non-exposed (after 1975). MS was defined by the International Diabetes Federation criteria. RESULTS: The prevalences of MS in the non-exposed (1963 1974), fetal and childhood-exposed were 16.4%, 20.1% and 19.1% in men and 13.5%, 23.7% and 33.5% in women, respectively. After adjustment for age, compared with non-exposed (1963-1974), fetal and childhood-exposed women had significantly higher prevalences of MS (P < 0.05), but not in men. Famine exposure during the fetal period (OR 1.47, 95% CI 1.05, 2.07) and childhood (OR 1.80, 95% CI 1.22, 2.67) was associated with higher risk of MS in women after adjusting for age (both P < 0.05). Further adjustments for age, smoking, rural/urban residence and economic status did not significantly attenuate this association. CONCLUSIONS: Exposure to famine in early life had sex-specific association with MS. It also suggests the adverse effects of malnutrition might extend beyond the 'first 1000 days' and last 9 years. PMID- 26646358 TI - Evidence for the use of parenteral nutrition in the pediatric intensive care unit. AB - BACKGROUND AND AIMS: During hospitalization in a pediatric intensive care unit (PICU), critically ill children are fed artificially. Administered via the preferred enteral route, caloric targets are often not reached. Hence, parenteral nutrition is given to this patient population. In this review we analyzed the available evidence from randomized controlled trials (RCTs) that supports the use of parenteral nutrition in children during critical illness. METHODS: A search strategy in Ovid MEDLINE and Ovid EMBASE was created and trial registries were screened to identify the relevant RCTs. Studies were included if they were randomized controlled trials, involved pediatric patients admitted to PICU, and compared different dosing/compositions of parenteral nutrition. Descriptive studies and reviews were excluded. RESULTS: Of the 584 articles identified by the search strategy, only 114 articles were retained after title screening. Further abstract and full text screening identified 6 small RCTs that compared two dosing/composition strategies of parenteral nutrition. These trials reported differences in surrogate endpoints without an effect on hard clinical endpoints. The RCTs observed improvements in these surrogate endpoints with the use of more calories or when parenteral glutamine or fish oil was added. CONCLUSIONS: The few RCTs suggest that surrogate endpoints can be affected by providing parenteral nutrition to critically ill children, but the studies were not statistically powered to draw meaningful clinical conclusions. Large RCTs with clinically relevant outcome measures are urgently needed to support the current nutritional guidelines that advise the use of parenteral nutrition in the PICU. PMID- 26646359 TI - Comparative proteomic analysis of fibrotic liver of rats fed high fat diet contained lard versus corn oil. AB - INTRODUCTION: The influences of dietary fatty acids on the progress of chronic liver diseases have attracted lots of attentions, but the mechanisms of the effects of lipids rich in saturated fatty acids or PUFAs on hepatic fibrogenesis remain unclear. METHODS: Female Fischer 344 rats were fed normal chow or chow plus 20% (w/w) of corn oil or lard, respectively, and injected CCl4 twice a week for 4 weeks to induce liver fibrosis. Masson's staining was adopted to illustrate the fibrosis level. The mRNA expression level of alpha-SMA and the DNA methylation level of its promoter region were analyzed. A 2-DE gel based proteomic approach was constructed to investigate the differential expression level of hepatic proteome between three diet groups. RESULTS: Histological evaluations and alpha-SMA expression analysis illustrated the high corn oil intake has no effects on hepatic fibrogenesis, but lard intake aggravated liver fibrosis, partly attributed to DNA demethylation of alpha-SMA promoter region. 2 DE Gel based proteomic study demonstrated excessive lard consumption elevated the expression of fibrosis related alpha-1-antitrypsin precursor, and endoplasmic reticulum stress related proteins such as heat shock cognate 71 kDa, eukaryotic translation initiation factor 4A1 and protein disulfide isomerase associated 3. Moreover, unlike corn oil rich in PUFAs, lard had no effects to elevate the expression of glutathione S-transferases, but decreased the expression of iron store related proteins heme binding protein 1 and ferritin. CONCLUSIONS: Lard intake aggravates CCl4 induced liver fibrosis via enhancing the expression of fibrogenesis and ER stress related proteins, and disturbing the hepatic transmethylation reaction. PMID- 26646360 TI - The Impact of the Proposed Changes for the DSM-5 on Diagnoses of First-time DUI/DWI Offenders. AB - Driving while impaired (DWI) is a frequently committed crime with enormous individual and social costs. The type of disposition and/or treatment appropriate for an individual offender is often determined, in part, by diagnostic criteria based on the American Psychiatric Association's Diagnostic and Statistics Manual. The DSM-5 significantly modified these criteria by eliminating legal problems as a criterion and dropping the categories of abuse and dependence. A brief substance abuse focused interview was conducted with 658 consecutive first-time DUI offenders who were arrested for driving under the influence of alcohol. Most were white, well-educated males. Contingency analyses were utilized to compare the current with the new diagnostic criteria based on algorithms for both diagnostic formulations. The major change observed when moving from DSM-IV-TR to DSM-5 criteria was that, approximately 54% of first-time DUI/DWI offenders would no longer meet diagnostic criteria based on the DSM-5. Of the nearly 17% who met dependence criteria, the majority were in the severe designation of the DSM-5. PMID- 26646361 TI - Explaining the Better Prognosis of Screening-Exposed Breast Cancers: Influence of Tumor Characteristics and Treatment. AB - BACKGROUND: In England, population mammographic screening has been offered to women for over 20 years. Overall decrease in breast cancer mortality rates and improvements in cancer awareness and organization of medical care over this period call for a more current evaluation of the mediators behind the better prognosis of screening-exposed breast cancers. METHODS: A case-control study was conducted within the English National Breast Screening Program. Women who died from primary breast cancer in 2008 to 2009 were matched (by year of birth, screening invitation, and area) to controls that received a diagnosis of invasive breast cancer at the time of the case diagnosis but survived the case death. Data were analyzed by unconditional logistic regression with adjustment for matching factors. RESULTS: The unadjusted OR for dying from breast cancer associated with ever having attended breast screening was 0.44 [95% confidence interval (CI), 0.33-0.58]. After adjustment for lead time, overdiagnosis, and self-selection, the OR increased to 0.69 (95% CI, 0.50-0.94). Adjusting for tumor size, lymph node status, stage, grade, histopathology, and laterality accounted for all the screening effect (OR, 1.00; 95% CI, 0.71-1.40). Further adjustment for treatment factors only had a minimal impact on the OR (OR, 1.02; 95% CI, 0.72-1.45). CONCLUSIONS: Our results suggest that earlier diagnosis, as reflected by tumor characteristics, remains the major mediator of the improvement in breast cancer survival due to participation in mammographic screening. IMPACT: Mammographic screening continues to prevent breast cancer-related deaths in the epoch of adjuvant systemic therapy. PMID- 26646362 TI - Impact of Screening on Breast Cancer Mortality: The UK Program 20 Years On. AB - BACKGROUND: With changes in diagnosis, treatment, and management of breast cancer since the mammography screening trials, there is a need to evaluate contemporary breast screening programs. A case-control study was set up to assess the current impact of attendance in the English Breast Screening Program on breast cancer mortality. METHODS: Cancer registry cases who died from primary breast cancer ages 47 to 89 years in London in 2008 to 2009 (869 women) were matched to 1 or 2 general population controls (1,642 women) with no diagnosis of breast cancer at the time of the case's diagnosis, who were alive at the case's death. Cases and controls were matched for date of birth and screening area, and had been invited to breast screening at least once prior to the case's diagnosis. ORs were estimated using conditional logistic regression. Self-selection bias was addressed using contemporaneous attendance at the cervical screening program. Sensitivity analyses were undertaken to assess the likely effect of lead time bias. RESULTS: Attendance at breast screening resulted in a breast cancer mortality reduction of 39% [OR, 0.61; 95% confidence interval (CI), 0.44-0.85] after self-selection correction. Attendance in the last 3 years prior to diagnosis resulted in a 60% mortality reduction (OR, 0.40; 95% CI, 0.31-0.51). Lead time bias effects were negligible. CONCLUSION: Our results suggest that community breast screening programs provide their expected benefit in terms of reducing the risk of breast cancer death among women participating. IMPACT: Mammography is an important tool for reducing breast cancer mortality and its impact could be increased by encouraging regular attendance. PMID- 26646363 TI - Conflating Colorectal Cancer Screening and Diagnostic Testing-Letter. PMID- 26646364 TI - Trends in United States Prostate Cancer Incidence Rates by Age and Stage, 1995 2012. AB - BACKGROUND: The advent of PSA testing in the late 1980s substantially increased prostate cancer incidence rates. Concerns about overscreening and overdiagnosis subsequently led professional guidelines (circa 2000 and later) to recommend against routine PSA testing. We evaluated trends in prostate cancer incidence, including late-stage diagnoses, from 1995 through 2012. METHODS: We used joinpoint regression analyses to evaluate all-, localized/regional-, and distant stage prostate cancer incidence trends based on Surveillance, Epidemiology, and End Results (SEER) data. We stratified analyses by age (50-69, 70+). We reported incidence trends as annual percent change (APC). RESULTS: Overall age-adjusted incidence rates for localized/regional stage prostate cancer have been declining since 2001, sharply from 2010 to 2012 [APC, -13.1; 95% confidence intervals (CI), -23.5 to -1.3]. Distant-stage incidence rates have declined since 1995, with greater declines from 1995 to 1997 (APC, -8.4; 95% CI, -2.3 to -14.1) than from 2003 to 2012 (APC, -1.0; 95% CI, -1.7 to -0.4). Distant-stage incidence rates declined for men ages 70+ from 1995 to 2012, but increased in men ages 50 to 69 years from 2004 to 2012 (APC, 1.7; 95% CI, 0.2 to 3.2). CONCLUSIONS: Guidelines discouraging routine prostate cancer screening were temporally associated with declining localized/regional prostate cancer incidence rates; however, incidence rates of distant-stage disease are now increasing in younger men. IMPACT: This trend may adversely affect prostate cancer mortality rates. PMID- 26646365 TI - Mining the epigenetic landscape of tissue polarity in search of new targets for cancer therapy. AB - The epigenetic nature of cancer encourages the development of inhibitors of epigenetic pathways. Yet, the clinical use for solid tumors of approved epigenetic drugs is meager. We argue that this situation might improve upon understanding the coinfluence between epigenetic pathways and tissue architecture. We present emerging information on the epigenetic control of the polarity axis, a central feature of epithelial architecture created by the orderly distribution of multiprotein complexes at cell-cell and cell extracellular matrix contacts and altered upon cancer onset (with apical polarity loss), invasive progression (with basolateral polarity loss) and metastatic development (with basoapical polarity imbalance). This information combined with the impact of polarity-related proteins on epigenetic mechanisms of cancer enables us to envision how to guide the choice of drugs specific for distinct epigenetic modifiers, in order to halt cancer development and counter the consequences of polarity alterations. PMID- 26646367 TI - Catalytic asymmetric formal gamma-allylation of deconjugated butenolides. AB - A formal gamma-allylation of deconjugated butenolides is reported based on a two step sequence consisting of a catalytic diastereo- and enantioselective vinylogous nucleophilic addition to vinyl sulfones and Julia-Kocienski olefination. This highly modular approach delivers densely functionalized butenolides containing a quaternary stereogenic centre in excellent yield with high enantioselectivity. PMID- 26646368 TI - Br2 induced oxidative pore modification of a porous coordination network. AB - Iodinated pores of a Zn-based coordination network were modified by Br2 oxidation to produce brominated pores in a polycrystalline-to-polycrystalline manner while maintaining the same network topology. Ab initio X-ray powder diffraction analysis and Raman spectroscopy revealed that the brominated pore can trap Br2 or I2 by strong sigma/pi-type interactions. A kinetic study in solution revealed that the pore modification by Br2 oxidation is much faster than the Br2 encapsulation process. PMID- 26646366 TI - EPPS rescues hippocampus-dependent cognitive deficits in APP/PS1 mice by disaggregation of amyloid-beta oligomers and plaques. AB - Alzheimer's disease (AD) is characterized by the transition of amyloid-beta (Abeta) monomers into toxic oligomers and plaques. Given that Abeta abnormality typically precedes the development of clinical symptoms, an agent capable of disaggregating existing Abeta aggregates may be advantageous. Here we report that a small molecule, 4-(2-hydroxyethyl)-1-piperazinepropanesulphonic acid (EPPS), binds to Abeta aggregates and converts them into monomers. The oral administration of EPPS substantially reduces hippocampus-dependent behavioural deficits, brain Abeta oligomer and plaque deposits, glial gamma-aminobutyric acid (GABA) release and brain inflammation in an Abeta-overexpressing, APP/PS1 transgenic mouse model when initiated after the development of severe AD-like phenotypes. The ability of EPPS to rescue Abeta aggregation and behavioural deficits provides strong support for the view that the accumulation of Abeta is an important mechanism underlying AD. PMID- 26646369 TI - Variations in (18)F-FDG uptake in breast cancer depending on PET/CT acquisition position. AB - AIM: To evaluate the variability of quantitative 2-[(18)F]-fluoro-2-deoxy-d glucose (FDG) positron-emission tomography (PET) combined with computed tomography (CT) parameters depending on acquisition position in a dual-position protocol for breast cancers. MATERIALS AND METHODS: For initial staging work-up, whole-body PET/CT was first acquired in a supine position, and then followed by a regional breast scan in a prone position. The maximum standardised uptake value (SUVmax), metabolic tumour volume (MTV), and total lesion glycolysis (TLG) were measured on both acquisition positions. MTV50 and TLG50 were calculated with a threshold set to be 50% of SUVmax, and MTV2.5 and TLG2.5 with a fixed SUV threshold of 2.5. RESULTS: The median SUVmax of breast cancers measured on the supine scans was 4.88, and 4.49 on the prone images (p<0.05). MTV and TLG also yielded significantly lower values from supine images. Regarding the tendency for the acquisition position to yield different results, a significant disagreement was observed between SUVmax and MTV50 and between SUVmax and TLG50 (kappa = -0156 and -0.001, respectively), while MTV2.5 and TLG2.5 showed a fair to moderate agreement with SUVmax (kappa = 0.311 and 0.416, respectively). CONCLUSIONS: SUVmax, MTV, and TLG yielded lower values when acquired in the prone position compared to in the supine position. This observation could be due to the partial volume effect. When using 50% of SUVmax as a threshold, there was a significant discordance between SUVmax and volumetric parameters. Thus, acquisition position may affect quantitative PET/CT parameters and the clinical implications. PMID- 26646370 TI - Gastrointestinal stromal tumours (GISTs) with a thousand faces: atypical manifestations and causes of misdiagnosis on imaging. AB - Gastrointestinal stromal tumours (GISTs) can lead to emergency situations, such as gastrointestinal bleeding, intestinal obstruction, and tumoural rupture with haemoperitoneum or peritonitis. In addition, if a GIST grows exophytically to a large size, it is often misdiagnosed as a tumour arising from adjacent organs. Sometimes, the atypical appearance of GISTs on imaging causes diagnostic confusion. In this article, we illustrate a variety of GISTs with atypical presentations and also discuss the important diagnostic clues for differentiating GISTs from other lesions. PMID- 26646371 TI - Exercise training restores the cardiac microRNA-1 and -214 levels regulating Ca2+ handling after myocardial infarction. AB - BACKGROUND: Impaired cardiomyocyte contractility and calcium handling are hallmarks of left ventricular contractile dysfunction. Exercise training has been used as a remarkable strategy in the treatment of heart disease. The microRNA-1, which targets sodium/calcium exchanger 1 (NCX), and microRNA-214, which targets sarcoplasmic reticulum calcium ATPase-2a (Serca2a), are involved in cardiac function regulation. Thus, the aim of this study was to evaluate the effect of exercise training on cardiac microRNA-1 and -214 expression after myocardial infarction. METHODS: Wistar rats were randomized into four groups: sedentary sham (S-SHAM), sedentary infarction (S-INF), trained sham (T-SHAM), and trained infarction (T-INF). Exercise training consisted of 60 min/days, 5 days/week for 10 weeks with 3 % of body weight as overload beginning four weeks after myocardial infarction. RESULTS: MicroRNA-1 and -214 expressions were, respectively, decreased (52 %) and increased (54 %) in the S-INF compared to the S-SHAM, while exercise training normalized the expression of these microRNAs. The microRNA targets NCX and Serca-2a protein expression were, respectively, decreased (55 %) and increased (34 %) in the T-INF group compared to the S-INF group. CONCLUSIONS: These results suggest that exercise training restores microRNA-1 and -214 expression levels and prevents change in both NCX and Serca 2a protein and gene expressions. Altogether, our data suggest a molecular mechanism to restore ventricular function after exercise training in myocardial infarction rats. PMID- 26646372 TI - Overview of a multi-stakeholder dialogue around Shared Services for Health: the Digital Health Opportunity in Bangladesh. AB - BACKGROUND: National level policymaking and implementation includes multiple stakeholders with varied interests and priorities. Multi-stakeholder dialogues (MSDs) can facilitate consensus building through collective identification of challenges, recognition of shared goals and interests, and creation of solution pathways. This can shape joint planning and implementation for long-term efficiency in health and other sectors. Scaling up the effective use of information and communication technologies (ICTs) requires cohesive strategic planning towards a shared goal. In Bangladesh, the government and partners convened an MSD in March 2015 to increase stakeholder engagement in policymaking and implementation of a national ICT or electronic or mobile health (eHealth or mHealth) strategy, which seeks to incorporate ICTs into the national health system, aligning with the Digital Bangladesh Vision 2021. METHODS: Relevant stakeholders were identified and key priorities and challenges were mapped through key informant interviews. An MSD was conducted with key stakeholders in Dhaka, Bangladesh. The MSD included presentations, group option generation, agreement and prioritization of barriers to scaling up ICTs. RESULTS: The MSD approach to building consensus on key priorities highlights the value of dialogue and collaboration with relevant stakeholders to encourage country ownership of nationwide efforts such as ICT scale-up. This MSD showed the dynamic context in which stakeholders operate, including those from academia, donors and foundations, healthcare professionals, associations, multilateral organizations, non-governmental organizations, partner countries and the private sector. Through this MSD, participants improved understanding of each other's contributions and interests, identified existing relationships, and agreed on policy and implementation gaps that needed to be filled. Collaboration among stakeholders in ICT efforts and research can promote a cohesive approach to scaling up, as well as improve policymaking by integrating interests and feedback of different key cross sectoral actors. CONCLUSION: MSDs can align stakeholders to identify challenges and solution pathways, and lead to coordinated action and accountability for resources and results. In addition, the MSD template and approach has been useful to guide ICT scale up in Bangladesh and could be replicated in other contexts to facilitate multi-constituency, multi-sector collaboration. PMID- 26646373 TI - Synonymous Virus Genome Recoding as a Tool to Impact Viral Fitness. AB - Synthetic genome recoding is a novel method of generating viruses with altered phenotypes, whereby many synonymous mutations are introduced into the protein coding region of the virus genome without altering the encoded proteins. Virus genome recoding with large numbers of slightly deleterious mutations has produced attenuated forms of several RNA viruses. Virus genome recoding can also aid in investigating virus interactions with innate immune responses, identifying functional virus genome structures, strategically ameliorating cis-inhibitory signaling sequences related to complex viral functions, to unravel the relevance of codon usage for the temporal regulation of viral gene expression and improving our knowledge of virus mutational robustness and adaptability. The present review discusses the impacts of synonymous genome recoding with regard to expanding our comprehension of virus biology, and the development of new and better therapeutic strategies. PMID- 26646374 TI - Tetraalkylammonium interactions with dodecyl sulfate micelles: a molecular dynamics study. AB - All-atom molecular dynamics (MD) simulations were performed to study the effects of different tetraalkylammonium (TAA(+)) counterions, including tetramethylammonium (TMA(+)), tetraethylammonium (TEA(+)), tetrapropylammonium (TPA(+)) and tetrabutylammonium (TBA(+)), on dodecyl sulfate (DS(-)) micelles. Structural properties, such as the radius of gyration (Rg), micelle radius (Rs), micelle size, solvent accessible surface area (SASA), carbon and sulfur distribution, hydration numbers, and distribution of polar heads on the micelle surface, were investigated. The simulation results show that the longer the carbon chains of the TAA(+) counterion, the greater the radius of the micelle formed. TMA(+) leads to the most compact structure of the DS(-) micelle among the five studied systems and DS(-) and TAA(+) formed mixed-micelles. There are mainly four interaction patterns between TAA(+) and DS(-) ions, and the pattern in which two alkyl chains of the TAA(+) ion penetrate into the DS(-) micelle is the most favorable one. Based on the preceding analysis, a model based on this MD method is proposed. PMID- 26646377 TI - Therapy with a Selective Cannabinoid Receptor Type 2 Agonist Limits Albuminuria and Renal Injury in Mice with Type 2 Diabetic Nephropathy. AB - BACKGROUND/AIMS: A critical involvement of the endocannabinoid/cannabinoid receptor system in diabetes and its complications has been recognized. Experimental evidence suggested that activation of the cannabinoid receptor type 2 (CB2), which is expressed in the kidney by podocytes and inflammatory cells, had a protective role in early streptozotocin-induced type 1 diabetes in mice. No experimental evidence is so far available on the effects of CB2 agonists in type 2 diabetes. In this study, we investigated the effects of a CB2 agonist given at a phase of overt disease on renal functional and structural changes in BTBR ob/ob mice, a model of type 2 diabetic nephropathy. METHODS: BTBR ob/ob mice received, from 10 to 21 weeks of age, vehicle, the selective CB2 agonist HU910, or lisinopril used as standard therapy for comparison. BTBR wild-type mice served as controls. RESULTS: Treatment with CB2 agonist reduced progressive albuminuria of BTBR ob/ob mice to a similar extent as ACE inhibitor. The antiproteinuric effect of CB2 agonist was associated with the amelioration of the defective nephrin expression in podocytes of diabetic mice. CB2 agonist limited mesangial matrix expansion, fibronectin accumulation and sclerosis. Glomerular infiltration of Mac 2-positive monocytes/machrophages was attenuated by CB2 agonist, at least in part due to the drug's ability to reduce MCP-1 chemotactic signals. Renoprotective effects of CB2 were similar to those achieved by ACE inhibitor. CONCLUSION: These results suggest that CB2 agonism is a potential option to be added to the available therapeutic armamentarium for type 2 diabetic nephropathy. PMID- 26646378 TI - Derivation of the surface free energy of ZnO and GaN using in situ electron beam hole drilling. AB - Surface free energy, as an intrinsic property, is essential in determining the morphology of materials, but it is extremely difficult to determine experimentally. We report on the derivation of the SE of different facets of ZnO and GaN experimentally from the holes developed using electron beam drilling with transmission electron microscopy. Inverse Wullf's construction is employed to obtain polar maps of the SE of different facets to study different nanomaterials (ZnO and GaN) in different morphologies (nanorod, nanobelt and thin film) to prove its versatility and capability. The results show that the SE of ZnO{10-13} is derived to be 0.99 J m(-2), and the SE of ZnO{10-10} is found to be less than {0002} and {11-20}. A GaN thin film also exhibits a similar trend in the SE of different facets as ZnO and the SE of GaN{10-13} is determined to be 1.36 J m( 2). PMID- 26646379 TI - Quantitative analyses on dynamic changes in the organization of host Arabidopsis thaliana actin microfilaments surrounding the infection organ of the powdery mildew fungus Golovinomyces orontii. AB - Obligate biotrophic fungi that cause powdery mildew on host plants form a specialized infection organ called the haustorium in the host apoplast. It was previously reported that the haustorium is surrounded by host actin microfilaments (AFs). The previous study used fixed cells, in which AFs were stained with fluorescently labeled phalloidine, therefore the structural dynamics of haustorium-surrounding AFs has not been examined. In the present study, we performed a live imaging analysis to examine the dynamics and developmental changes in the organization of haustorium-surrounding host AFs using host Arabidopsis thaliana and A. thaliana-adapted powdery mildew fungus Golovinomyces orontii. Image correlation-based velocimetry analysis suggested that AFs around haustorium are rather static compared to the dynamicity of AFs at the cell surface. Quantification of AF density and bundling showed that the density, but not the level of bundling, of haustorium-surrounding AFs increased as the haustorium matures. The possible role of AFs around haustoria is discussed. PMID- 26646380 TI - Utility of the Amborella trichopoda expansin superfamily in elucidating the history of angiosperm expansins. AB - Expansins form a superfamily of plant proteins that assist in cell wall loosening during growth and development. The superfamily is divided into four families: EXPA, EXPB, EXLA, and EXLB (Sampedro and Cosgrove in Genome Biol 6:242, 2005. doi: 10.1186/gb-2005-6-12-242 ). Previous studies on Arabidopsis, rice, and Populus trichocarpa have clarified the evolutionary history of expansins in angiosperms (Sampedro et al. in Plant J 44:409-419, 2005. doi: 10.1111/j.1365 313X.2005.02540.x ). Amborella trichopoda is a flowering plant that diverged very early. Thus, it is a sister lineage to all other extant angiosperms (Amborella Genome Project in 342:1241089, 2013. doi: 10.1126/science.1241089 ). Because of this relationship, comparing the A. trichopoda expansin superfamily with those of other flowering plants may indicate which expansin genes were present in the last common ancestor of all angiosperms. The A. trichopoda expansin superfamily was assembled using BLAST searches with angiosperm expansin queries. The search results were analyzed and annotated to isolate the complete A. trichopoda expansin superfamily. This superfamily is similar to other angiosperm expansin superfamilies, but is somewhat smaller. This is likely because of a lack of genome duplication events (Amborella Genome Project 2013). Phylogenetic and syntenic analyses of A. trichopoda expansins have improved our understanding of the evolutionary history of expansins in angiosperms. Nearly all of the A. trichopoda expansins were placed into an existing Arabidopsis-rice expansin clade. Based on the results of phylogenetic and syntenic analyses, we estimate there were 12-13 EXPA genes, 2 EXPB genes, 1 EXLA gene, and 2 EXLB genes in the last common ancestor of all angiosperms. PMID- 26646381 TI - VrDREB2A, a DREB-binding transcription factor from Vigna radiata, increased drought and high-salt tolerance in transgenic Arabidopsis thaliana. AB - Mung bean (Vigna radiata L.) is commonly grown in Asia as an important nutritional dry grain legume, as it can survive better in arid conditions than other crops. Abiotic stresses, such as drought and high-salt contents, negatively impact its growth and production. The dehydration-responsive element-binding protein 2 (DREB2) transcription factors play a significant role in the response to these stress stimuli via transcriptional regulation of downstream genes containing the cis-element dehydration-responsive element (DRE). However, the molecular mechanisms involved in the drought tolerance of this species remain elusive, with very few reported candidate genes. No DREB2 ortholog has been reported for mung bean, and the function of mung bean DREB2 is not clear. In this study, a novel VrDREB2A gene with conserved AP2 domains and transactivation ability was isolated from mung bean. A modified VrDREB2A protein lacking the putative negative regulatory domain encoded by nucleotides 394-543 was shown to be localized in the nucleus. Expression of the VrDREB2A gene was induced by drought, high salt concentrations and abscisic acid treatment. Furthermore, comparing with the wild type Arabidopsis, the overexpression of VrDREB2A activated the expression of downstream genes in transgenic Arabidopsis, resulting in enhanced tolerance to drought and high-salt stresses and no growth retardation. The results from this study indicate that VrDREB2A functions as an important transcriptional activator and may help increase the abiotic stress tolerance of the mung bean plant. PMID- 26646382 TI - Ambient air pollution and out-of-hospital cardiac arrest. AB - BACKGROUND: Sudden cardiac arrest is a leading cause of cardiovascular death. This study aimed at investigating the impact of short-term exposure to air pollutants on the incidence of OHCA. METHODS: We identified OHCA cases that occurred in Seoul between 2006 and 2013 from the nationwide emergency medical service database. The association of the daily incidence of OHCA with air pollutants including PM2.5 (particles <= 2.5 MUm in aerodynamic diameter), PM10, CO, O3, NO2, and SO2 was analyzed with the use of time-series and case-crossover analyses. RESULTS: A total of 21,509 OHCAs of presumed cardiac origin were identified. An elevation in PM2.5 by 10 MUg/m(3) at a moving average of lag 1 and 2 days was shown to increase the risk of OHCA by 1.30% (95% confidence intervals, 0.20-2.41%). An exposure-response relationship was present: the risk of OHCA increased significantly with even a mild elevation of PM2.5 (10-15 MUg/m(3)) and further increased with higher levels. While PM10, NO2, CO, and SO2 also showed significant associations with OHCA in single-pollutant models, only PM2.5 remained significant after adjustment for other pollutants. Subgroup analyses showed male sex, advanced age, hypertension, diabetes, heart disease, and history of stroke were risk factors for OHCA in response to elevations in PM2.5. CONCLUSIONS: This study showed that increased ambient levels of PM2.5 were significantly associated with increased risk of OHCA within 1 to 2 days of exposure, which had a dose-response relationship. Subjects with conventional cardiovascular risk factors were more susceptible to harm of PM2.5. PMID- 26646383 TI - Electrophysiological study generally is negative in patients <40 years suspected of supraventricular tachycardia but also complaining of chest pain and/or syncope. AB - BACKGROUND: The diagnosis of paroxysmal supraventricular tachycardia (SVT) frequently is a dilemma. Electrophysiological study (EPS) is the only means to evaluate the nature of symptoms when noninvasive studies remain negative. Our objectives were to determine the clinical factors of negativity or positivity of (EPS) in patients suspected of SVT. METHODS: EPS was performed in 2650 patients complaining of tachycardia and suspected of SVT. Transesophageal EPS consisted of programmed atrial stimulation in control state and after isoproterenol. Patients were followed from 1 month to 18 years (2.93 +/- 4 years). RESULTS: SVT was induced in 1944 patients, age 48 +/- 19.5. EPS remained negative in 706 patients, age 34 +/- 17 (p<0.0001). Age <40 years, feeling of dizziness/syncope or chest pain associated with tachycardia, the absence of heart disease or short PR interval was more frequent in patients with negative EPS (respectively 64, 42, 26, 96, 88.5%) than in patients with induced SVT (34, 14, 4, 88, 59%) (p<0.0001).The positive predictive value for the prediction of a negative EPS of age <40, chest pain, syncope or their association was 63.5, 42, 26.5, 11% and negative predictive value was 66, 86, 94.5, 99.5%. At multivariate analysis, age <40 (0.000, OR 2.79), the presence of syncope associated with tachycardia (0.000, OR 5.075) or chest pain (0.000, OR 17.923) was an independent factor of negative EPS. CONCLUSIONS: Among patients complaining of nondocumented tachycardia, suspected of SVT, the association of tachycardia with chest pain and/or syncope and age <40 years generally was correlated with a negative EPS and did not indicate initially invasive studies. In the remaining patients transesophageal EPS is indicated. PMID- 26646384 TI - Fabrication of carbohydrate microarrays on a poly(2-hydroxyethyl methacrylate) based photoactive substrate. AB - We report the fabrication of carbohydrate microarrays on a photoactive polymer, poly(HEMA-co-HEMA-PFPA), synthesized by RAFT copolymerization of 2-hydroxyethyl methacrylate (HEMA) and perfluorophenyl azide (PFPA)-derivatized HEMA (HEMA PFPA). PFPA allows the covalent immobilization of carbohydrates whereas the HEMA polymer provides an antifouling surface, thus the microarrays can be used directly without pretreating the array with a blocking agent. The microarrays were prepared by spin-coating the polymer followed by printing the carbohydrates. Subsequent irradiation simultaneously immobilized the carbohydrates and crosslinked the polymer matrix. The obtained 3D carbohydrate microarrays showed enhanced fluorescence signals upon treating with a fluorescent lectin in comparison with a 2D microarray. The signals were acquired at a lower lectin concentration and a shorter incubation time. When treated with E. coli bacteria, the carbohydrate microarray showed results that were consistent with their binding patterns. PMID- 26646385 TI - Isokinetic Identification of Knee Joint Torques before and after Anterior Cruciate Ligament Reconstruction. AB - The aim of this study was to evaluate the serial change of isokinetic muscle strength of the knees before and after anterior cruciate ligament reconstruction (ACLR) in physically active males and to estimate the time of return to full physical fitness. Extension and flexion torques were measured for the injured and healthy limbs at two angular velocities approximately 1.5 months before the surgery and 3, 6, and 12 months after ACLR. Significant differences (p <= 0.05) in peak knee extension and flexion torques, hamstring/quadriceps (H/Q) strength ratios, uninvolved/involved limb peak torque ratios, and the normalized work of these muscles between the four stages of rehabilitation were identified. Significant differences between extension peak torques for the injured and healthy limbs were also detected at all stages. The obtained results showed that 12 months of rehabilitation were insufficient for the involved knee joint to recover its strength to the level of strength of the uninvolved knee joint. The results helped to evaluate the progress of the rehabilitation and to implement necessary modifications optimizing the rehabilitation training program. The results of the study may also be used as referential data for physically active males of similar age. PMID- 26646386 TI - Proteomic Analysis of Isogenic Rice Reveals Proteins Correlated with Aroma Compound Biosynthesis at Different Developmental Stages. AB - Fragrant rice has a potent flavor compound, 2-acetyl-1-pyrroline (2AP). A better understanding of the 2AP biosynthetic pathway is gained by proteomic analysis of two isogenic lines of Thai jasmine rice, Oryza sativa L. cv. Khao Dawk Mali 105, which differ only in the aromatic gene Os2AP. The protein profiles of two lines, from six growth stages, seedling to grain filling, had 41 identifiable protein spots. Four of these spots were betaine aldehyde dehydrogenase, a key enzyme responsible for 2AP production. This enzyme occurred in every growth stage of the non-aromatic rice line except smaller amount detected in the hard grain-filling stage of the aromatic line. Glyceraldehyde 3-phosphate dehydrogenase and aspartate aminotransferase, observed in the aromatic line, may involve in the metabolism of precursors for 2AP biosynthesis. In addition, glutamine synthetase and 1-cys peroxiredoxin A which function in ammonia reassimilation and hydrogen peroxide detoxification were unique in the aromatic line. However, proteins that correspond to photosynthesis and the nutrient reservoir were only detected in lower abundances. This possibly explains why the aroma rice grain weight is low. Our study proposed the possible role of these remarkable proteins which involved in 2AP biosynthesis in jasmine rice. PMID- 26646387 TI - Pichia pastoris Production of Tat-NGB and Its Neuroprotection on Rat Pheochromocytoma Cells. AB - Neuroglobin (NGB) is a newly discovered neuroprotector and mainly localized in the neurons and retinal cells of the central and peripheral nervous systems in vertebrates, and its prokaryotic expression protein of which fused with HIV-1 virus-encoded Tat peptide exhibited significant antioxidant and anti-hypoxia. However, no study has documented on the anti-hypoxia of yeast expressed Tat-NGB. To address it, the NGB cDNA fragment with and without Tat tag was designed and conjugated to pPIC9K followed by electroporation, and positive colonies were screened. Subsequently, Tat-NGB-His and His-NGB-His proteins were expressed by inducer methanol and identified by SDS-PAGE, and purified with HisTrapTM FF crude column. After desalting, the transmembrane transduction of Tat-NGB was examined and identified by Western blot, and the anti-hypoxia activity was also examined by CCK-8 kit. Unexpectedly, Tat-NGB-His and His-NGB-His proteins were high yield and secretory expressed in GS115 Pichia pastoris. After purification, the high purified protein was prepared and exhibited a significant transmembrane transduction of Tat-NGB-His (**p < 0.01, compare to control and His-NGB-His). Significantly, Tat-NGB-His could protect hypoxia induced injury of PC12 cells and had an obviously difference when comparing to control and His-NGB-His groups (*p < 0.05, **p < 0.01). The present study first reported the yeast expressed production of Tat-NGB-His and His-NGB-His, and then elucidated the transduction and neuroprotection of Tat-NGB-His on PC12 cell. It not only provided a significant reference for high-yield expression of NGB in yeast expression system, but also provided a significant prevention and treatment of hypoxic and ischemic brain injury. PMID- 26646388 TI - An anti-DNA antibody prefers damaged dsDNA over native. AB - DNA-protein interactions, including DNA-antibody complexes, have both fundamental and practical significance. In particular, antibodies against double-stranded DNA play an important role in the pathogenesis of autoimmune diseases. Elucidation of structural mechanisms of an antigen recognition and interaction of anti-DNA antibodies provides a basis for understanding the role of DNA-containing immune complexes in human pathologies and for new treatments. Here we used Molecular Dynamic simulations of bimolecular complexes of a segment of dsDNA with a monoclonal anti-DNA antibody's Fab-fragment to obtain detailed structural and physical characteristics of the dynamic intermolecular interactions. Using a computationally modified crystal structure of a Fab-DNA complex (PDB: 3VW3), we studied in silico equilibrium Molecular Dynamics of the Fab-fragment associated with two homologous dsDNA fragments, containing or not containing dimerized thymine, a product of DNA photodamage. The Fab-fragment interactions with the thymine dimer-containing DNA was thermodynamically more stable than with the native DNA. The amino acid residues constituting a paratope and the complementary nucleotide epitopes for both Fab-DNA constructs were identified. Stacking and electrostatic interactions were shown to play the main role in the antibody-dsDNA contacts, while hydrogen bonds were less significant. The aggregate of data show that the chemically modified dsDNA (containing a covalent thymine dimer) has a higher affinity toward the antibody and forms a stronger immune complex. These findings provide a mechanistic insight into formation and properties of the pathogenic anti-DNA antibodies in autoimmune diseases, such as systemic lupus erythematosus, associated with skin photosensibilization and DNA photodamage. PMID- 26646389 TI - Our history. PMID- 26646390 TI - Biology: Changing the world--a tribute to Patrick Steptoe, Robert Edwards and Jean Purdy. AB - On the 13th March 2015, the Society of Biology unveiled a blue plaque at the Kershaw's Hospice in Oldham. This was the former site of Dr Kershaw's Cottage Hospital where in 1971 Patrick Steptoe, Robert Edwards and Jean Purdy set up a small laboratory that ultimately led to the development of in vitro fertilisation or IVF and the birth of Louise Brown. Amongst those present at the ceremony was Professor Andrew Steptoe (British Heart Foundation, Professor of Psychology) the son of Patrick Steptoe. This paper reproduces the text of the speech he made to mark the occasion and is reproduced in Human Fertility for its future historical significance. PMID- 26646391 TI - Motile sperm organelle morphology examination (MSOME) can predict outcomes of conventional in vitro fertilization: A prospective pilot diagnostic study. AB - The objective of this prospective diagnostic study was to explore the relationships between the morphological indices of sperm using motile sperm organelle morphology examination (MSOME) and the clinical outcome of in vitro fertilization (IVF). A total of 291 couples were included in this study. The female patients exhibited tubal and pelvic factors, and their partners' gametes were tested prospectively by MSOME. Spearman correlation analysis was used to identify the relationship between MSOME and IVF rates and conventional sperm parameters. The effect of MSOME characteristics on pregnancy outcome was analyzed by multivariate logistic regression. MSOME characteristics showed statistical relationships with sperm concentration (R = 0.130, P = 0.025), progressive motility (R = 0.260, P < 0.001), and strict normal morphology (P = 0.648, R < 0.001). The percentage of sperm with normal morphology and vacuolation in the anterior head of the sperm, as observed by MSOME, was highly correlated with the IVF fertilization rate (R = 0.176, P = 0.002; P = - 0.230, P < 0.001 respectively). The combined incidence of morphologically normal sperm and posterior vacuolation of the sperm head, as assessed by MSOME, was a predictor of clinical pregnancy (CP) after IVF (sensitivity, 92.9%; specificity, 42.47; and area under the ROC curve, 76.59%). The percentage of normal morphology of sperm by MSOME (OR 3.52, 95% CI 2.05-6.05, P < 0.001) and the posterior part vacuolated sperm (OR 0.65, 95% CI 0.52-0.82, P < 0.001) were significant predictors of successful CP. The MSOME index was significantly correlated with fertilization rates and CP after IVF, and testing with MSOME could constitute a valid diagnostic predictor of IVF outcome. PMID- 26646392 TI - Racial and ethnic differences in assisted reproduction treatment outcomes: the benefit of racial admixture. AB - The goal of the present study was to determine whether racial and ethnic differences affect the outcomes of assisted reproductive technology in the Brazilian population. 1497 patients undergoing intracytoplasmic sperm injection (ICSI) cycles were split into groups according to the patient's ethnicity: Caucasian (n = 2131), Mestizo (n = 358), Asian (n = 174), Black (n = 115) and Indian (n = 260). ICSI outcomes were compared among the groups. Body mass index was highest in the Black group, followed by the Mestizo, Indian, Caucasian and Asian groups (p > 0.001). The FSH dose (p > 0.001) was highest among Indians, followed by Asians and Caucasians, and the dose was lowest among Blacks and Mestizos. In contrast, the oocyte yield was highest among Mestizos, followed by Indians, Blacks and Caucasians, and lowest among Asians (p = 0.005). The fertilisation rate was highest among Mestizos, followed by Blacks, Indians and Caucasians, whereas Asians had the lowest fertilisation rate (p = 0.004). Pregnancy and implantation rates were also highest among Mestizos, followed by Blacks, Indians and Caucasians, whereas the Asian patients had the lowest rates (p = 0.008 and p > 0.001, respectively). In conclusion, our evidence suggests a possible beneficial effect of racial admixture on ICSI outcomes. PMID- 26646393 TI - Fertility 2015. PMID- 26646394 TI - Coping with Space Neophobia in Drosophila melanogaster: The Asymmetric Dynamics of Crossing a Doorway to the Untrodden. AB - We discover and examine within a wide phylogenetic perspective spatial neophobia, avoidance of untrodden terrain, in fruit flies, in an experimental setup that reduces the gap between the field and the laboratory. In our setup, fruit flies use a natal fruit as their origin, freely exploring for days their surroundings, which consists of a mixture of trodden and untrodden terrain. The interface between trodden and untrodden is, however, reduced in our setup to a wide doorway, opened within a surrounding wall. Crossing this doorway, characterized by a sharp contrast interface between trodden and untrodden, generates a behavior whose dynamics betrays the flies' space neophobia. The moment-by-moment dynamics of crossing is remarkably similar to that reported in mouse models of anxiety. This means that neophobic behavior is either homologous across arthropods and vertebrates or, not less interesting, convergent, whereby the same behavior is mediated in the two phyla by two completely different schemata. PMID- 26646395 TI - Surface ultrastructure and the mitochondrial gene rrnl of Parachristianella indonesiensis Palm, 2004 (Trypanorhyncha: Eutetrarhynchidae) with the amended generic diagnosis. AB - The microthrix pattern of adult Parachristianella indonesiensis Palm, 2004 is described for the first time based on the standardized terminology for microtriches, and the generic diagnosis of Parachristianella Dollfus, 1946, regarding microtriches, is also amended. The surface ultrastructure of P. indonesiensis consists of three kinds of microtriches so that the proximal and distal bothrial surfaces are covered respectively with acicular to short capilliform filitriches and aristate gladiate spinitriches interspersed with capilliform filitriches. The remainder of the scolex bears capilliform filitriches. The surface of the proglottid is adorned with acicular filitriches. There was no significant difference in the length of the capilliform filitriches covering the different parts of the scolex peduncle. For the first time, the uniciliated papillae adorned with filitriches as sensory receptors are reported from this parasitic species. The partial rrnl of P. indonesiensis is also presented as the only known sequence of this gene in the superfamily Eutetrarhynchoidea Dollfus, 1969. The pairwise comparisons of rrnl between P. indonesiensis and the trypanorhynch species for which rrnl sequence is available were in accordance with the last phylogeny presented for the order Trypanorhyncha. The infection parameters (prevalence, mean abundance, and mean intensity) of P. indonesiensis parasitizing Pastinachus sephen (Forsskal) from the eastern Persian Gulf were also compared during approximately 5 years, and no significant differences were observed. This may be interpreted as the stability of the factors playing important roles in the life cycle of P. indonesiensis in the eastern Persian Gulf during this period. PMID- 26646396 TI - Tick survey for prevalent pathogens in peri-urban recreation sites in Saarland and Rhineland-Palatinate (Germany). AB - Ixodid ticks are important vectors of human pathogens in Central Europe. Despite this fact, prevalence studies are scarce, especially with regard to much frequented peri-urban recreation sites. In this pilot study, 4.014 larvae, nymphs and adult ticks sampled monthly during the active seasons in 2011 and 2012 from 14 distinct collection sites in two German states (Saarland and Rhineland Palatinate) were screened for Borrelia spp., Anaplasma spp. and tick-borne encephalitis virus. Mean prevalence rates were 19.8 % for Borrelia spp., 1.9 % for Anaplasma spp. and 0.1 % for tick-borne encephalitis virus (TBEV), which are in accordance with those reported from other regions in Germany and neighbouring countries. Nevertheless, the detection of TBEV-infected ticks is the first positive result after several unsuccessful efforts over the previous years in official "TBE-risk" zones of Saarland and Rhineland-Palatinate which supports the presumption of the origin of observed local infection. Besides ixodid ticks a non engorged adult female tick of the invading species Dermacentor reticulatus has been found reflecting the appearance of another vector eventually jeopardising the health of host animals as well as humans. PMID- 26646397 TI - Highly specific detection of Cryptosporidium spp. oocysts in human stool samples by undemanding and inexpensive phase contrast microscopy. AB - To compare phase contrast microscopy (PCM) of unstained slides for the detection of Cryptosporidium spp. oocysts with a commercially available enzyme immunoassay (EIA) for the detection of cryptosporidial antigen in human stool samples, we prospectively analysed by both methods 463 fresh human stool samples obtained from diarrhoeic patients between July and October 2014. Compared with the EIA, the sensitivity, specificity, positive and negative predictive value of PCM were 88.9 % (95 % confidence interval (CI), 66.0-98.1 %), 100 % (95 % CI, 99.0-100 %), 100 % (95 % CI, 77.3-100 %) and 99.6 % (95 % CI, 98.3-100 %), respectively. Additionally, we retrospectively examined with PCM 65 fixed stool samples that had been collected in 2010 from mostly asymptomatic Rwandan children <5 years of age; 14 of these samples had previously yielded positive results with a highly sensitive real-time (RT)-PCR. PCM detected cryptosporidia in 5/14 RT-PCR-positive samples, and notably, also in one of 51 RT-PCR-negative samples, which was subsequently confirmed by acid-fast staining. Positive and negative percent agreement of PCM with RT-PCR were 35.7 % (95 % CI, 16.2-61.4 %) and 98.0 % (95 % CI, 88.7-100 %), respectively. Positive PCM results were associated with higher RT-PCR cycle threshold values (p = 0.044). In conclusion, PCM offers a highly specific, undemanding and inexpensive method for the laboratory diagnosis of acute human cryptosporidiosis independent of the causative Cryptosporidium species. PMID- 26646398 TI - Reported Pain and Fatigue Behaviors Mediate the Relationship Between Catastrophizing and Perceptions of Solicitousness in Patients With Chronic Fatigue. AB - Catastrophizing is associated with negative outcomes in chronic pain and illness. The communal coping model (CCM) and cognitive behavioral (CB) formulations provide differing accounts of the function of catastrophizing in these contexts. In the present study we examined predictions from CCM and CB theoretical models in a sample of 116 patients with chronic fatigue to test (1) whether patient reported solicitous responses from significant others mediate the relationship of catastrophizing with patient-reported pain and fatigue behaviors, as predicted by the CCM; and (2) whether pain and fatigue behaviors mediate the relationship of catastrophizing with solicitous responses, consistent with a CB model. This work is a secondary data analysis in which the strength of the indirect (i.e., mediating) effects among study variables was examined. Consistent with CB models, pain and fatigue behaviors were associated with catastrophizing and solicitous responses, and there was a significant indirect effect of catastrophizing on solicitous responses through pain and fatigue behaviors. Results were inconsistent with the CCM; catastrophizing was not significantly associated with solicitous responses, nor did solicitous responses mediate the relationship between catastrophizing and pain or fatigue behaviors. These findings highlight the importance of behavioral expressions of pain and fatigue in understanding the relationship of catastrophizing to solicitous responses in chronic fatigue. PERSPECTIVE: This study of chronic fatigue patients tested CB and CCMs of catastrophizing, pain, and fatigue behaviors, and solicitous responses by significant others. Results were more consistent with CB formulations, which highlighted the importance of behavioral expressions of pain and fatigue in understanding the relationship of catastrophizing to solicitous responses. PMID- 26646399 TI - Future of the transdermal drug delivery market--have we barely touched the surface? AB - INTRODUCTION: Transdermal drug delivery is the movement of drugs across the skin for absorption into the systemic circulation. Transfer of the drug can occur via passive or active means; passive transdermal products do not disrupt the stratum corneum to facilitate delivery whereas active technologies do. Due to the very specific physicochemical properties necessary for successful passive transdermal drug delivery, this sector of the pharmaceutical industry is relatively small. There are many well-documented benefits of this delivery route however, and as a result there is great interest in increasing the number of therapeutic substances that can be delivered transdermally. AREAS COVERED: This review discusses the various transdermal products that are currently/have been marketed, and the paths that led to their success, or lack of. Both passive and active transdermal technologies are considered with the advantages and limitations of each highlighted. In addition to marketed products, technologies that are in the investigative stages by various pharmaceutical companies are reviewed. EXPERT OPINION: Passive transdermal drug delivery has made limited progress in recent years, however with the ongoing intense research into active technologies, there is great potential for growth within the transdermal delivery market. A number of active technologies have already been translated into marketed products, with other platforms including microneedles, rapidly progressing towards commercialisation. PMID- 26646400 TI - Super-oxide anion production and antioxidant enzymatic activities associated with the executive functions in peripheral blood mononuclear cells of healthy adult samples. AB - Executive Functions (EFs) involve a set of high cognitive abilities impairment which have been successfully related to a redox omeostasis imbalance in several psychiatric disorders. Firstly, we aimed to investigate the relationship between executive functioning and some oxidative metabolism parameters in Peripheral Blood Mononuclear Cells (PBMCs) from healthy adult samples. The Brown Attention Deficit Disorder Scales were administered to assess five specific facets of executive functioning. Total superoxide anion production, Super Oxide Dismutase (SOD), Catalase (CAT), Glutathione Reductase (GR) and Glutathione Peroxidase (GPx) activities were evaluated on proteins extracted from the PBMCs. We found significant positive correlations between superoxide anion production and the total score of the 'Brown' Scale and some of its clusters. The GPx and CAT activities were negatively associated with the total score and some clusters. In a linear regression analysis, these biological variables were indicated as the most salient predictors of the total score, explaining the 24% variance (adjusted R(2)=0.24, ANOVA, p<.001). This study provides novel evidence that Executive Functions have underpinnings in the oxidative metabolism, as ascertained in healthy subjects. PMID- 26646401 TI - Evaluation of the first web-space narrowing in congenital anomalies with Z deformity. AB - BACKGROUND: In patients with congenital anomalies of the thumb, the metacarpophalangeal joint often undergoes radial deviation to compensate for a narrow first web space. In this study, we evaluated the relationship between the thumb and index finger in patients with arthrogryposis multiplex congenita (AMC), by measuring the thumb-index angle on radiographs taken while the patient held a styrene foam cone. METHODS: Investigation was carried out on nine patients (13 cases: four bilateral and five unilateral) with AMC. The average patient age was 4.4 years (range, 2.6-7.2 years). Overhead radiographs were obtained while the patient held a styrene foam cone. The radiographs were used to evaluate the apparent thumb-index web angle, the thumb to index finger metacarpal angle (1 2MCA), and the first metacarpophalangeal angle (1MPA). RESULTS: In the five unilateral cases, significant differences were seen on the affected versus unaffected sides in 1-2MCA and 1MPA. All 13 cases were treated surgically, and significant differences were observed between the groups before surgery and 2 years after surgery in the 1-2MCA and 1MPA. In addition, the mean postoperative 1MPA in the bilateral cases was significantly smaller compared with the unilateral cases. CONCLUSIONS: This radiographic technique enabled us to evaluate the severity of the thumb-index web-space narrowing and the radial instability of the thumb metacarpophalangeal joint in patients with AMC. The bilateral cases tended to show better rehabilitative improvement compared with the unilateral ones, probably because the latter patients could use their unaffected hand. PMID- 26646402 TI - Long-term outcomes of surgical treatment for dermatofibrosarcoma protuberans according to width of gross resection margin. AB - BACKGROUND: Controversy exists regarding appropriate surgical treatment for dermatofibrosarcoma protuberans (DFSP). The purpose of this study was to propose treatment recommendations based on long-term outcomes of surgical treatments for DFSP. METHODS: A total of 63 patients who underwent surgical resection for primary DFSP were retrospectively reviewed from 1999 to 2011. They were classified into three groups based on the width of the gross resection margins: group I with marginal excision (14 patients); group II with resection margins < 3 cm (21 patients); and group III with resection margins >= 3 cm (28 patients) (group II and group III had wide local excision). RESULTS: The median follow-up period was 65 months (range 31-190 months). The marginal excision group showed a significantly higher recurrence rate than the wide excision group (35.7% vs. 0%, p < 0.001). Among wide excision groups, group III showed a significantly higher requirement for reconstructive surgery than group II (82.7% vs. 52.4%, p = 0.011), yet both groups had no recurrence and pathologic margin status was comparable. The accuracy rate of frozen section analyses was 100% for the margin status in the wide excision group. Adjuvant radiation was significantly associated with a reduced recurrence in the marginal excision group (0% vs. 60%, p = 0.016). CONCLUSIONS: Wide local excision with margins of 1.5-2 cm along with frozen biopsy is recommended for DFSP. Either re-excision or adjuvant radiation therapy can serve as a treatment option for patients with positive margins. PMID- 26646405 TI - Effect of Probationary Accreditation on Recruitment of Psychiatry Residents. PMID- 26646403 TI - Effect of Cd+2 on phosphate solubilizing abilities and hydrogen peroxide production of soil-borne micromycetes isolated from Phragmites australis rhizosphere. AB - The aims of this work were to evaluate the phosphate-solubilization and hydrogen peroxide (H2O2) production by the soil-borne micromycetes, Aspergillus japonicus, Penicillium italicum and Penicillium dipodomyicola, isolated from Phragmites australis rhizosphere and to study the effect of several concentrations of Cadmium (Cd(2+)) on both variables. Our results showed that P. italicum achieved a higher P-solubilization and H2O2 production than A. japonicus and P. dipodomyicola, as only P. italicum showed a positive correlation (R(2) = 0.71) between P-solubilization and H2O2 production. In dose-response assays, P. italicum was also more tolerant to Cd(2+) (0.31 mM) in comparison to A. japonicus (0.26 mM). Analysis of the 2(4) factorial experimental design showed that P solubilization by P. italicum was negatively affected by increases in Cd(2+) (p = 0.04) and yeast extract (p = 0.02) in the culture medium. The production of H2O2 was positively affected only by glucose (p = 0.002). Fungal biomass production was reduced significantly (p = 0.0009) by Cd(2+) and increased (p = 0.0003) by high glucose concentration in the culture medium. The tolerance and correlation between P-solubilization and H2O2 production in the presence of Cd(2+) was strain and species dependent. The effects of Cd(2+), glucose, ammonium sulfate and yeast extract on those variables were evaluated through a two-level factorial design. P. italicum is promising for P-solubilization in soils contaminated with Cd(2+) and may be an alternative for manufacture of biofertilizers to replace chemical fertilizers. PMID- 26646404 TI - The use of volatile anesthetic agents for long-term critical care sedation (VALTS): study protocol for a pilot randomized controlled trial. AB - BACKGROUND: Sedatives are administered to 85% of intensive care unit (ICU) patients. The most commonly used sedatives are intravenous benzodiazepines and propofol. These agents are associated with over-sedation in 40 to 60% of patients, which can lead to prolonged intubation, delirium and drug-induced hypotension. Evidence is increasing that volatile anesthetic agents are associated with faster extubation times, improved cardiovascular stability with no end-organ toxicity in comparison to our standard intravenous agents for short term critical care sedation. Use of volatile agents within the ICU is a novel technique using a specialized delivery and scavenging system, which requires staff training and cultural acceptance. This pilot randomized controlled trial aims to assess the safety and feasibility of delivering volatile agents for long term patient sedation in the ICU with limited or no experience of this technique. METHODS/DESIGN: This is a prospective multicenter pragmatic pilot RCT that is blinded to the data analyst. This study aims to recruit 60 adult ICU patients requiring mechanical ventilation and sedation for more than 48 h. Patients will be randomized 2:1 to receive inhaled isoflurane (40 patients) or intravenous midazolam and/or propofol (20 patients) sedation. Sedation is titrated to a targeted Sedation Analgesia Score (SAS) using an explicit sedation-analgesia algorithm until extubation or tracheostomy. Primary safety and feasibility outcomes will assess atmospheric volatile concentration levels and adherence to our sedation-analgesia protocol. Secondary outcomes include time to extubation, duration of ventilation, quality of sedation, delirium, vasoactive drug support, length of stay, serum fluoride levels and mortality. DISCUSSION: This pilot project will serve as the basis for a larger RCT that will be powered for important clinical outcomes. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01983800 (registration date 2 July 2013). PMID- 26646406 TI - Psychiatrists' Attitudes Toward Non-Pharmacologic Factors Within the Context of Antidepressant Pharmacotherapy. AB - OBJECTIVE: Recent meta-analyses of antidepressant clinical trials have suggested that up to 82 % of response can be attributed to non-medication-related factors. The present study examines psychiatrists' attitudes regarding non-pharmacologic factors within the context of antidepressant pharmacotherapy. METHODS: A web based, 20-question cross-sectional survey was distributed to 101 staff psychiatrists and 48 post-graduate trainees in psychiatry at an academic hospital in Boston, MA. Demographics, practice characteristics, beliefs about non pharmacologic factors affecting prescribing practices, perceived response and remission rates, and opinions about the need for further investigations in the psychopharmacology process were assessed. RESULTS: Overall completion rate was 53 %. The final sample included 79 responses. The medians for clinician-perceived response rates (54 %) and remission rates (33 %) were in agreement with published rates. The reported median of the what portion of clinical outcomes is believed to be due to placebo effects (26 %) was numerically lower than suggested by literature. The contribution of the active ingredients of medications was perceived to be significantly higher than the contribution of patient characteristics and clinician characteristics. A longer time since graduation from medical school was significantly associated with higher belief in the effect of the active ingredients of antidepressant medications and with less perceived importance of placebo effects. CONCLUSION: These findings suggest a discrepancy between empirical evidence and psychiatrists' beliefs on the impact of placebo effects on clinical outcomes. Educating antidepressant prescribers about the evidence based on psychosocial mediators of placebo effects' contribution to outcome may represent a promising strategy for improving clinical outcomes. PMID- 26646408 TI - The Microprocess Moment: A Tool for Evaluating Skills in Psychodynamic Psychotherapy. PMID- 26646409 TI - Outcomes of fundoplication for paediatric gastroesophageal reflux disease. AB - PURPOSE: Outcomes of fundoplication in children. METHODS: In this monocentric retrospective study, chart review was performed on children who underwent fundoplication between 2006 and 2013. Outcomes were defined as the need for redo fundoplication and recommencement of anti-reflux medication (ARM) at 6-month follow-up. RESULTS: 119 patients underwent fundoplication with a mean age of 4.76 years and 55.5% of these were male. At 6-month follow-up, 21 (17.6%) required redo fundoplication and 64 (53.8%) were recommenced on ARM. Post-operative complications occurred in 50 (42.2%) of children; 30% of those with complications had surgery at less than 1 year of age, and 36% had an associated comorbid condition. Neither being under the age of one nor associated comorbidity was significantly associated with a poor outcome. Concurrent gastrostomy was associated with a higher risk of being back on ARM at 6-month follow-up (p = 0.003). Neither gastrointestinal or respiratory symptoms pre-surgery nor abnormal pre-operative investigations including pH monitoring and endoscopy were predictive of poor outcome post-fundoplication. CONCLUSION: Although fundoplication has a role in the treatment of severe GORD in children, the majority of children in this study needed to restart their anti-reflux medications within 6 months of surgery. PMID- 26646410 TI - Synthesis of o-Aminophenols via a Formal Insertion Reaction of Arynes into Hydroxyindolinones. AB - A novel approach toward the synthesis of sterically hindered o-aminophenols has been achieved by a formal aryne insertion into hydroxyindolinones. This transformation offers a rapid and efficient entry to diverse o-aminophenol scaffolds under mild transition-metal-free conditions. The reaction involves the addition of hydroxyindolinones to arynes followed by a chemo- and regioselective [1,3]-rearrangement. Furthermore, the reactions of N-hydroxyindoles and arynes were found to provide the C3-aryl indole products via an alternative [3,3] rearrangement pathway. PMID- 26646411 TI - Surface Initiated Immobilization of Molecules Contained in an Ionic Liquid Framework. AB - A simple and general route for the immobilization of molecules containing ionic liquids framework was described. The proposed approach is inspired from the classical synthesis of ionic liquid and labeled surface-initiated synthesis of molecules bearing ionic liquid components. In the first step, bromide end layer was electrochemically grafted onto the electrode surface followed by its reaction with imidazole derivatives. The generated modified materials were characterized by electrochemistry and by X-ray photoelectron spectroscopy (XPS). As a result, molecule-based ionic liquids were successfully attached onto electrode material. The possibility to perform an anion-exchange reaction within the layer was demonstrated. Furthermore, the proposed surface functionalization approach was successfully performed without requiring the synthesis of any intermediate. The generated structures provide multifunctional systems containing ions, immobilized cation and mobile anion, and redox species. PMID- 26646412 TI - Development and Pilot Test of a Commercial Sexual Exploitation Prevention Tool: A Brief Report. AB - Commercial sexual exploitation of children (CSEC) is a persistent problem in the United States, yet few youth-oriented CSEC prevention tools exist. The objectives of this project were to develop an educational website about CSEC for adolescents and evaluate it through pre- and posttests of adolescents' knowledge and attitudes about CSEC. Results demonstrated increases in participants' CSEC knowledge and decreases in their tolerance of CSEC after navigating the website and viewing an embedded video. Qualitative and quantitative results suggest that CSEC is deemed an important issue by adolescents and web-based content is a relevant and useful mode through which to educate adolescents about CSEC. Consideration should be given to further exploration of this and other tools for CSEC prevention tailored to adolescents' needs and preferences. PMID- 26646413 TI - Comparative genomic analysis of eutherian tumor necrosis factor ligand genes. AB - The present analysis made attempts to resolve discrepancies in descriptions of eutherian tumor necrosis factor ligand genes implicated in cell signalling pathways, as well as in major physiological and pathological processes. Among 455 potential coding sequences, the eutherian comparative genomic analysis protocol annotated 211 complete coding sequences using public genomic sequence assemblies. The most comprehensive third party data gene data set first described 8 superclusters of eutherian tumor necrosis factor ligand genes, including 18 major gene clusters. The integrated gene annotations, phylogenetic analysis, and protein molecular evolution analysis proposed new classification and nomenclature of eutherian tumor necrosis factor ligand genes, as new framework of future experiments. PMID- 26646414 TI - Design of a haptic device with grasp and push-pull force feedback for a master slave surgical robot. AB - PURPOSE: We propose a portable haptic device providing grasp (kinesthetic) and push-pull (cutaneous) sensations for optical-motion-capture master interfaces. METHODS: Although optical-motion-capture master interfaces for surgical robot systems can overcome the stiffness, friction, and coupling problems of mechanical master interfaces, it is difficult to add haptic feedback to an optical-motion capture master interface without constraining the free motion of the operator's hands. Therefore, we utilized a Bowden cable-driven mechanism to provide the grasp and push-pull sensation while retaining the free hand motion of the optical motion capture master interface. To evaluate the haptic device, we construct a 2 DOF force sensing/force feedback system. We compare the sensed force and the reproduced force of the haptic device. Finally, a needle insertion test was done to evaluate the performance of the haptic interface in the master-slave system. RESULTS: The results demonstrate that both the grasp force feedback and the push pull force feedback provided by the haptic interface closely matched with the sensed forces of the slave robot. We successfully apply our haptic interface in the optical-motion-capture master-slave system. The results of the needle insertion test showed that our haptic feedback can provide more safety than merely visual observation. CONCLUSIONS: We develop a suitable haptic device to produce both kinesthetic grasp force feedback and cutaneous push-pull force feedback. Our future research will include further objective performance evaluations of the optical-motion-capture master-slave robot system with our haptic interface in surgical scenarios. PMID- 26646415 TI - Toward cognitive pipelines of medical assistance algorithms. AB - PURPOSE: Assistance algorithms for medical tasks have great potential to support physicians with their daily work. However, medicine is also one of the most demanding domains for computer-based support systems, since medical assistance tasks are complex and the practical experience of the physician is crucial. Recent developments in the area of cognitive computing appear to be well suited to tackle medicine as an application domain. METHODS: We propose a system based on the idea of cognitive computing and consisting of auto-configurable medical assistance algorithms and their self-adapting combination. The system enables automatic execution of new algorithms, given they are made available as Medical Cognitive Apps and are registered in a central semantic repository. Learning components can be added to the system to optimize the results in the cases when numerous Medical Cognitive Apps are available for the same task. Our prototypical implementation is applied to the areas of surgical phase recognition based on sensor data and image progressing for tumor progression mappings. RESULTS: Our results suggest that such assistance algorithms can be automatically configured in execution pipelines, candidate results can be automatically scored and combined, and the system can learn from experience. Furthermore, our evaluation shows that the Medical Cognitive Apps are providing the correct results as they did for local execution and run in a reasonable amount of time. CONCLUSION: The proposed solution is applicable to a variety of medical use cases and effectively supports the automated and self-adaptive configuration of cognitive pipelines based on medical interpretation algorithms. PMID- 26646416 TI - Shape-intensity prior level set combining probabilistic atlas and probability map constrains for automatic liver segmentation from abdominal CT images. AB - PURPOSE: Propose a fully automatic 3D segmentation framework to segment liver on challenging cases that contain the low contrast of adjacent organs and the presence of pathologies from abdominal CT images. METHODS: First, all of the atlases are weighted in the selected training datasets by calculating the similarities between the atlases and the test image to dynamically generate a subject-specific probabilistic atlas for the test image. The most likely liver region of the test image is further determined based on the generated atlas. A rough segmentation is obtained by a maximum a posteriori classification of probability map, and the final liver segmentation is produced by a shape intensity prior level set in the most likely liver region. Our method is evaluated and demonstrated on 25 test CT datasets from our partner site, and its results are compared with two state-of-the-art liver segmentation methods. Moreover, our performance results on 10 MICCAI test datasets are submitted to the organizers for comparison with the other automatic algorithms. RESULTS: Using the 25 test CT datasets, average symmetric surface distance is [Formula: see text] mm (range 0.62-2.12 mm), root mean square symmetric surface distance error is [Formula: see text] mm (range 0.97-3.01 mm), and maximum symmetric surface distance error is [Formula: see text] mm (range 12.73-26.67 mm) by our method. Our method on 10 MICCAI test data sets ranks 10th in all the 47 automatic algorithms on the site as of July 2015. Quantitative results, as well as qualitative comparisons of segmentations, indicate that our method is a promising tool to improve the efficiency of both techniques. CONCLUSION: The applicability of the proposed method to some challenging clinical problems and the segmentation of the liver are demonstrated with good results on both quantitative and qualitative experimentations. This study suggests that the proposed framework can be good enough to replace the time-consuming and tedious slice-by-slice manual segmentation approach. PMID- 26646417 TI - Entropy-based particle correspondence for shape populations. AB - PURPOSE: Statistical shape analysis of anatomical structures plays an important role in many medical image analysis applications such as understanding the structural changes in anatomy in various stages of growth or disease. Establishing accurate correspondence across object populations is essential for such statistical shape analysis studies. METHODS: In this paper, we present an entropy-based correspondence framework for computing point-based correspondence among populations of surfaces in a groupwise manner. This robust framework is parameterization-free and computationally efficient. We review the core principles of this method as well as various extensions to deal effectively with surfaces of complex geometry and application-driven correspondence metrics. RESULTS: We apply our method to synthetic and biological datasets to illustrate the concepts proposed and compare the performance of our framework to existing techniques. CONCLUSIONS: Through the numerous extensions and variations presented here, we create a very flexible framework that can effectively handle objects of various topologies, multi-object complexes, open surfaces, and objects of complex geometry such as high-curvature regions or extremely thin features. PMID- 26646418 TI - Spectroscopy and Fluorescence Lifetime Imaging Microscopy To Probe the Interaction of Bovine Serum Albumin with Graphene Oxide. AB - The interaction of graphene oxide (GO) with bovine serum albumin (BSA) in aqueous buffer solution has been investigated with various spectroscopic and imaging techniques. At single molecular resolution this interaction has been performed using fluorescence correlation spectroscopy (FCS) and fluorescence lifetime imaging microscopy (FLIM) techniques. The conformational dynamics of BSA on GO's influence have been explored by FCS and circular dichroism (CD) spectroscopy. For the FCS studies BSA was labeled covalently by a fluorophore, Alexa Fluor 488. On the addition of GO in phosphate buffer of 10 mM at pH 7.4 the diffusion time (tauD) and the hydrodynamic radius (Rh) of BSA increase due to adsorption of BSA. Conformational relaxation time components of native BSA drastically vary with the addition of GO, signifying the change of conformational dynamics of BSA after addition of GO. The adsorption isotherm also indicates significant adsorption of BSA on the GO surface. Adsorption of BSA on the GO surface has shown in direct images of atomic force microscopy (AFM) and FLIM. Fluorescence quenching study of BSA with addition of GO also indicates that there is strong interaction between BSA and GO. PMID- 26646419 TI - Poisonings Associated with Intubation: US National Poison Data System Exposures 2000-2013. AB - Patients may be intubated after exposure to a variety of substances because of respiratory failure, CNS sedation, pulmonary pathology, or cardiovascular instability. However, there is little data describing the types of substances that are associated with endotracheal intubation or the rates of intubation after these exposures. Evaluation of this association may inform future research on intubation after exposures to specific substances and guide poison prevention education. Our objective was to determine which exposures were commonly associated with intubation using the data from National Poison Data System (NPDS). The NPDS tracks data from potential exposures to substances reported to all American Association of Poison Control Centers. We performed a retrospective analysis of NPDS data from January 1st, 2000 to December 31st, 2013 to identify human exposures to substances that were associated with endotracheal intubation. Descriptive statistics were used to analyze the data. There were 93,474 single substance exposures and 228,507 multiple substance exposures that were associated with intubation. The most common exposures to substances that were associated with intubation were atypical antipsychotics (7.4 %) for single exposures and benzodiazepines (27.4 %) for multiple exposures. Within each age group, the most common known exposures to substances were for patients under 6 years, clonidine for single and multiple exposures; for patients aged 6-12 years, clonidine for single exposures and atypical antipsychotics for multiple exposures; for patients aged 13-19 years, atypical antipsychotics for single and multiple exposures; and for patients over 19 years, atypical antipsychotics for single exposures and benzodiazepines for multiple exposures. From 2000-2013, the exposures to substances most commonly associated with intubation varied by single versus multiple exposures and by age. This study helps clarify the exposures to substances that are associated with intubation reported to poison centers in the USA. PMID- 26646420 TI - Transcriptome-Wide Cleavage Site Mapping on Cellular mRNAs Reveals Features Underlying Sequence-Specific Cleavage by the Viral Ribonuclease SOX. AB - Many viruses express factors that reduce host gene expression through widespread degradation of cellular mRNA. An example of this class of proteins is the mRNA targeting endoribonuclease SOX from the gamma-herpesvirus Kaposi's sarcoma associated herpesvirus (KSHV). Previous studies indicated that cleavage of messenger RNAs (mRNA) by SOX occurs at specific locations defined by the sequence of the target RNA, which is at odds with the down-regulation of a large portion of cellular transcripts. In this study, we address this paradox by using high throughput sequencing of cleavage intermediates combined with a custom bioinformatics-based analysis pipeline to identify SOX cleavage sites across the mRNA transcriptome. These data, coupled with targeted mutagenesis, reveal that while cleavage sites are specific and reproducible, they are defined by a degenerate sequence motif containing a small number of conserved residues rather than a strong consensus sequence. This degenerate element is well represented in both human and KSHV mRNA, and its presence correlates with RNA destabilization by SOX. This represents a new endonuclease targeting strategy, in which use of a degenerate targeting element enables RNA cleavage at specific locations without restricting the range of targets. Furthermore, it shows that strong target selectivity can be achieved without a high degree of sequence specificity. PMID- 26646421 TI - The protective effects of paeonol against epirubicin-induced hepatotoxicity in 4T1-tumor bearing mice via inhibition of the PI3K/Akt/NF-kB pathway. AB - Epirubicin is widely used for the treatment of various breast cancers; however, it has serious adverse side effects, such as hepatotoxicity, which require dose adjustment or therapy substitution. Paeonol, an active component from Moutan Cortex, has a variety of biological activities, including preventing or reducing various toxicities induced by antineoplastics. Protection by paeonol against hepatotoxicity induced by epirubicin and the underlying mechanism of action were investigated in this study. Cytosolic enzymes in the serum and oxidative stress indices in the liver were determined. The protective effects were determined using the MTT assay in vitro or by evaluating the expression of apoptotic factors and crucial proteins in the PI3K/Akt/NF-kB pathway using western blot analysis. It is concluded that paeonol alleviates epirubicin-induced hepatotoxicity in 4T1 tumor bearing mice by inhibiting the PI3K/Akt/NF-kB pathway. PMID- 26646422 TI - Associations Between Women's Perception of Their Husbands'/Partners' Social Support and Pap Screening in Pacific Islander Communities. AB - Pacific Islanders experience high rates of cervical cancer incidence and mortality. This cross-sectional study examined the extent to which Samoan, Chamorro, and Tongan women's perceived receipt of social support from their husbands or male partners was associated with rates of routine cancer screening- specifically Pap testing. A total of 585 Pacific Islander women who live in the United States completed a self-report survey. Women who reported having a Pap test within the past 3 years had significantly higher scores on support from their husbands/male partners. Furthermore, the relationship of emotional support and informational support with increased Pap testing was significantly stronger for Tongan women. The findings suggest that men play an important role in promoting women's cancer prevention behaviors in Pacific Islander and potentially other collectivistic populations. Incorporating social support messages into interventions may be a simple yet effective strategy to increase women's Pap testing. PMID- 26646423 TI - Oxygen Consumption by Red Wines. Part II: Differential Effects on Color and Chemical Composition Caused by Oxygen Taken in Different Sulfur Dioxide-Related Oxidation Contexts. AB - Chemical changes caused by oxidation of red wines during 5 consecutive air saturation cycles have been assessed. In order to investigate the existing relationship between the effects caused by O2 and the levels and consumption rates of wine SO2, the total oxygen consumed by the wines (16-25 mg/L) was subdivided into different nonmutually exclusive categories. The ones found most influential on chemical changes were the O2 consumed in the first saturation without equivalent SO2 consumption (O2preSO2) and the O2 consumed when levels of free SO2 were below 5 mg/L (radical forming O2). Chromatic changes were strongly related to both O2 categories, even though anthocyanidin degradation was not related to any O2 category. Radical forming O2 prevented both formation of red pigments and reduction of epigallocatechin and other proanthocyanidins, induced accumulation of phenolic acids, and caused losses of beta-damascenone and whiskylactone without evidence of acetaldehyde formation. O2preSO2 seemed to play a key role in the formation of blue pigments and in the decrease of Folin index and of many important aroma compounds. PMID- 26646424 TI - Implementation of World Health Organization Package of Essential Noncommunicable Disease Interventions (WHO PEN) for Primary Health Care in Low-Resource Settings: A Policy Statement From the World Hypertension League. PMID- 26646425 TI - Utility of fine needle aspiration cytology to comprehend the pathogenesis of extrapulmonary tuberculosis. AB - BACKGROUND: Fine needle aspiration cytology (FNAC) is a precise, cost-effective, and minimal invasive technique for diagnosis of extrapulmonary tuberculosis (EPTB). This study was aimed to analyze clinical and cytological characteristics of EPTB with particular emphasis on pathogenesis. METHODS: This was a retrospective study analyzing 237 cases of EPTB diagnosed on FNAC. Depending on the presence of necrosis and granulomas, cases were divided into three classes. Association of cytomorphology with positivity for acid-fast bacilli was analyzed by Chi-square test to demonstrate any specific pattern. RESULTS: Majority of our patients diagnosed as EPTB (73.8%) were young with male-to-female ratio of 1:1.3. The mean age was 23.2 years (age range 9 months to 81 years). The most frequent site involved was lymph node (89.5%) with predilection for cervical lymph nodes (81.4%). The extranodal sites affected were breast, abdominal wall, chest wall, salivary glands, soft tissue, bone, and genitourinary tract. Detailed cytological examination revealed necrotizing granulomatous inflammation as most common pattern (43%). Acid-fast bacilli were detected only in 43.5% of the cases and bacilli detection was more frequently associated with necrotizing lesions (64.9%). Non-necrotizing lesions showed AFB positivity only in 7.4% of the cases. CONCLUSION: To achieve the goal of tuberculosis eradication, it is essential to understand its different forms of clinical presentation and detailed pathogenesis including host factors, host-pathogen interaction, and molecular mechanisms. Cytomorphological features of the representative lesions might be valuable in providing clues regarding possible pathogenetic mechanisms. PMID- 26646426 TI - Eruptive Hypomelanosis in a Young Child as a "Paraviral Exanthem". AB - We recently reported a wave of nine children with a novel paraviral exanthem, which we have termed eruptive hypomelanosis. We subsequently witnessed a second wave of children with this exanthem and present a patient here to alert clinicians. PMID- 26646427 TI - The Calcium-Binding Protein S100A6 Accelerates Human Osteosarcoma Growth by Promoting Cell Proliferation and Inhibiting Osteogenic Differentiation. AB - BACKGROUND/AIMS: Although osteosarcoma (OS) is the most common primary malignancy of bone, its molecular pathogenesis remains to be fully understood. We previously found the calcium-binding protein S100A6 was expressed in ~80% of the analyzed OS primary and/or metastatic tumor samples. Here, we investigate the role of S100A6 in OS growth and progression. METHODS: S100A6 expression was assessed by qPCR and Western blotting. Overexpression or knockdown of S100A6 was carried out to determine S100A6's effect on proliferation, cell cycle, apoptosis, tumor growth, and osteogenic differentiation. RESULTS: S100A6 expression was readily detected in human OS cell lines. Exogenous S100A6 expression promoted cell proliferation in vitro and tumor growth in an orthotopic xenograft model of human OS. S100A6 overexpression reduced the numbers of OS cells in G1 phase and increased viable cells under serum starvation condition. Conversely, silencing S100A6 expression induced the production of cleaved caspase 3, and increased early stage apoptosis. S100A6 knockdown increased osteogenic differentiation activity of mesenchymal stem cells, while S100A6 overexpression inhibited osteogenic differentiation. BMP9-induced bone formation was augmented by S100A6 knockdown. CONCLUSION: Our findings strongly suggest that S100A6 may promote OS cell proliferation and OS tumor growth at least in part by facilitating cell cycle progression, preventing apoptosis, and inhibiting osteogenic differentiation. Thus, it is conceivable that targeting S100A6 may be exploited as a novel anti-OS therapy. PMID- 26646428 TI - Characterizing the context of sedentary lifestyles in a representative sample of adults: a cross-sectional study from the physical activity measurement study project. AB - BACKGROUND: Research has clearly demonstrated that excess time spent on sedentary behavior (SB) increases health risks in the population. However, the lack of information on the context of SB in the population prevents a detailed understanding of sedentary lifestyles. The purpose of this study was to characterize the context of SB in a representative sample of adults and to examine differences across various socio-demographic indicators. METHODS: A diverse sample of 1442 adults (ages 20-71 year) completed an interviewer administered 24-h activity recall to provide detailed information about the time, type and location of the previous day's activities. All reported activities were matched with MET scores from the Compendium of Physical Activity but only SB (i.e., METS < 1.5) were extracted for the present analyses. RESULTS: The reported SB were broadly distributed across 5 primary location categories (Work: 27.5%, Community: 24.8%, Home/Indoor: 20.5%, Home/Outdoor: 15.8%, and Transportation: 11.3%). Patterns of SB allocations varied considerably across different socio demographic indicators indicating the extreme variability in SB in the population. CONCLUSIONS: The findings provide unique insights about the context of SB at the population level, and can serve as a guide for developing intervention/policy studies to reduce sedentary time and minimize disparities in SB. PMID- 26646429 TI - Use of prescription stimulant for Attention Deficit Hyperactivity Disorder in Aboriginal children and adolescents: a linked data cohort study. AB - BACKGROUND: Increasing recognition of Attention Deficit Hyperactivity Disorder (ADHD) among Aboriginal children, adolescents and young adults is a public health challenge. We investigated the pattern of prescription stimulants for ADHD among Aboriginal individuals in Western Australia (WA). METHODS: Using a whole population-based linked data we followed a cohort of individuals born in WA from 1980-2005, and their parents were born in Australia, to identify stimulant prescription for ADHD derived from statutory WA stimulant prescription dispensing between 2003 and 2007. Parental link was ascertained through WA Family Connections Genealogical Linkage System. Cox proportional hazards regression (HR) models were performed to determine the association between stimulant use and Aboriginal and non-Aboriginal status. RESULTS: Of the total cohort of 186,468, around 2% (n = 3677) had prescription stimulants for ADHD. Individuals with both Aboriginal parents were two-thirds (HR 0.33, 95 % CI 0.26-0.42), and with only Aboriginal mother were one-third (HR 0.69, 95% CI 0.53-0.90) less likely to have stimulants, compared to individuals with non-Aboriginal parents. HR in Aboriginals was 62% lower (HR 0.35, 95% CI 0.25-0.49) in metropolitan areas, and 72% lower (HR 0.28, 95% CI 0.20-0.38) in non-metropolitan areas, than non Aboriginals. The risk for simulant use was four times higher among Aboriginal boys than Aboriginal girls (HR 4.08, 95% CI, 2.92-5.69). CONCLUSION: Aboriginal cultural understanding of ADHD and attitude towards stimulant medication serve as a determinant of their access to health services. Any ADHD intervention and policy framework must take into account a holistic approach to Aboriginal culture, beliefs and individual experience to provide optimal care they need. PMID- 26646430 TI - How Multiple Social Identities Are Related to Creativity. AB - The present research examined whether possessing multiple social identities (i.e., groups relevant to one's sense of self) is associated with creativity. In Study 1, the more identities individuals reported having, the more names they generated for a new commercial product (i.e., greater idea fluency). In Study 2, multiple identities were associated with greater fluency and originality (mediated by cognitive flexibility, but not by persistence). Study 3 validated these findings using a highly powered sample. We again found that multiple identities increase fluency and originality, and that flexibility (but not persistence) mediated the effect on originality. Study 3 also ruled out several alternative explanations (self-affirmation, novelty seeking, and generalized persistence). Across all studies, the findings were robust to controlling for personality, and there was no evidence of a curvilinear relationship between multiple identities and creativity. These results suggest that possessing multiple social identities is associated with enhanced creativity via cognitive flexibility. PMID- 26646431 TI - A Longitudinal Study of the Development of Emotional Deception Detection Within New Same-Sex Friendships. AB - Previous studies show that close friends improve at lie detection over time. However, is this improvement due to an increase in the ability to decode the feelings of close friends or a change in how close friends communicate their true and deceptive emotions? In a study of 45 pairs of friends, one friend from each pair (the "sender") was videotaped showing truthful and faked affect in response to pleasant and unpleasant movie clips. The other friend from each pair (the "judge") guessed the true emotions of both the friend and a stranger 1 month and 6 months into the friendship. Judges were better at guessing the true emotions of friends than strangers, and this advantage in judging friends increased among close friends over time. Surprisingly, improvement over time was due mostly to a change in the sender's communication, rather than an increase in judges' ability to decode their friends' feelings. PMID- 26646432 TI - Exposure-wide epidemiology: revisiting Bradford Hill. AB - Fifty years after Bradford Hill published his extremely influential criteria to offer some guides for separating causation from association, we have accumulated millions of papers and extensive data on observational research that depends on epidemiologic methods and principles. This allows us to re-examine the accumulated empirical evidence for the nine criteria, and to re-approach epidemiology through the lens of exposure-wide approaches. The lecture discusses the evolution of these exposure-wide approaches and tries to use the evidence from meta-epidemiologic assessments to reassess each of the nine criteria and whether they work well as guides for causation. I argue that of the nine criteria, experiment remains important and consistency (replication) is also very essential. Temporality also makes sense, but it is often difficult to document. Of the other six criteria, strength mostly does not work and may even have to be inversed: small and even tiny effects are more plausible than large effects; when large effects are seen, they are mostly transient and almost always represent biases and errors. There is little evidence for specificity in causation in nature. Biological gradient is often unclear how it should it modeled and thus difficult to prove. Coherence remains usually unclear how to operationalize. Finally, plausibility as well as analogy do not work well in most fields of investigation, and their invocation has been mostly detrimental, although exceptions may exist. PMID- 26646434 TI - An investigation of red blood cell concentrate quality during storage in paediatric-sized polyvinylchloride bags plasticized with alternatives to di-2 ethylhexyl phthalate (DEHP). AB - BACKGROUND AND OBJECTIVES: Di-2-ethylhexyl phthalate (DEHP) is a blood bag plasticizer. It is also a toxin, raising concerns for vulnerable populations, for example, neonates and infants. Here, the in vitro quality of red cell concentrates (RCC) stored in paediatric bags formulated with alternative plasticizers to DEHP was compared. MATERIALS AND METHODS: RCC were pooled and split into polyvinylchloride (PVC)/DEHP, PVC/1,2-cyclohexanedicarboxylic acid diisononyl ester (DINCH) or PVC/butyryl trihexyl citrate (BTHC) bags. Quality was assessed on storage days 5, 21, 35 and 43. RESULTS: Metabolism differed among the bags: pCO2 levels were lowest and pO2 were highest in BTHC bags. Glucose consumption and lactate production suggested higher metabolic rates in BTHC bags. ATP levels were best maintained in DINCH bags (day 43 mean level: 2.86 +/- 0.29 MUmol/g Hb). RCC in BTHC bags had the greatest potassium release (54.6 +/- 3.0 mm on day 43). From day 21, haemolysis was higher in BTHC bags (P < 0.01) and by day 43 had exceeded 0.8% (0.85 +/- 0.10%). RCC in BTHC bags showed more microparticle formation than RCC in DEHP or DINCH bags. CONCLUSION: The results suggest that the BTHC formulation used was detrimental to RBC quality. DINCH bags could be a viable alternative to DEHP: they outperformed DEHP bags energetically, with better maintenance of ATP levels. PMID- 26646435 TI - Micro-scale spatially offset Raman spectroscopy for non-invasive subsurface analysis of turbid materials. AB - This article reviews a very recent field of noninvasive analysis of turbid media using micro-scale Spatially Offset Raman Spectroscopy - micro-SORS. The technique combines conventional SORS with microscopy concepts and represents a new imaging modality in Raman microscopy. Micro-SORS facilitates analytical capability for investigating non-destructively the chemical composition of subsurface, micrometer-scale-thick diffusely scattering layers at depths more than an order of magnitude larger than those accessible with the depth resolving power of conventional confocal Raman microscopy. Potential application areas include nondestructive subsurface analysis of painted layers in cultural heritage, characterization of stratified polymer systems, analysis of layered biological samples or forensic analysis. The article discusses the basic principles of the technique, its variants and outlines emerging applications in this rapidly evolving field. PMID- 26646437 TI - "How Should I Be?" A Photovoice Exploration Into Body Image Messaging for Young Women Across Ethnicities and Cultures. AB - Photovoice, a community-based participatory research method that allows participants to inform research questions in an intimate way, has proven successful with youth. A diverse group of teenage girls living in New York City were asked to take photographs and reflect on what messages they received and from whom, how these messages translate across cultures and ethnicities, and how these messages are internalized and acted on. The group selected specific photographs to discuss together and themes emerged to answer the research questions; themes were reinforced by journal responses and agreed on by the group at the concluding session. The participants identified the media, peers, and family as cultural influencers on body image but noted that these messages change depending on the delivering medium. Participants not only offered recommendations with policy implications for advertising and media giants but also urged public health practitioners, teachers, and other key stakeholders working with young women of color to simply provide them with more space for talking. While Photovoice served as an effective methodology for gaining a more expansive understanding of how body image messages are received with young women of color, the tool should be considered for youth development interventions that take a community-based participatory approach. PMID- 26646436 TI - Effect of 4-chloro-7-trifluoromethyl-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid on the intraurethral pressure in a rat model of benign prostatic hyperplasia. AB - OBJECTIVES: To investigate the effect of 4-chloro-7-trifluoromethyl-10H benzo[4,5]furo[3,2-b]indole-1-carboxylic acid, a new benzofuroindole derivative, on the intraurethral pressure in a rat model of benign prostatic hyperplasia. METHODS: Benign prostatic hyperplasia was induced by testosterone and 17beta estradiol, which were administered intramuscularly once a day for 12 weeks. The effects of 4-chloro-7-trifluoromethyl-10H-benzo[4,5]furo[3,2-b]indole-1 carboxylic acid and tamsulosin on the intraurethral pressure induced by the electrostimulation of hypogastric nerves after a single intravenous injection of 4-chloro-7-trifluoromethyl-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid (10 mg/kg) or tamsulosin (10 MUg/kg) were evaluated in a benign prostatic hyperplasia model. The electrostimulation-induced intraurethral pressure was measured just before and after the injection of 4-chloro-7-trifluoromethyl-10H benzo[4,5]furo[3,2-b]indole-1-carboxylic acid. Bodyweight and genitourinary organ weights were recorded, and serums and tissues were subjected to hormone assays and histopathology. In addition, the expression of alpha1-adrenoceptors in the prostate was measured by western blotting. RESULTS: The benign prostatic hyperplasia groups showed increased prostatic index, increased concentrations of testosterone, free testosterone and estradiol in serum, and increased epithelial thickness of the prostate. An injection of 4-chloro-7-trifluoromethyl-10H benzo[4,5]furo[3,2-b]indole-1-carboxylic acid or tamsulosin significantly inhibited the elevation of electrostimulation-induced intraurethral pressure. In addition, 4-chloro-7-trifluoromethyl-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid did not cause a significant change in the blood pressure compared with tamsulosin. While the benign prostatic hyperplasia group showed increased the expression of alpha1-adrenoceptors, the 4-chloro-7-trifluoromethyl-10H benzo[4,5]furo[3,2-b]indole-1-carboxylic acid or tamsulosin injection into a rat model of benign prostatic hyperplasia decreased the expression of alpha1 adrenoceptors. CONCLUSIONS: These findings show that 4-chloro-7-trifluoromethyl 10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid might be beneficial for lowering the intraurethral pressure associated with benign prostatic hyperplasia, and it could represent a therapeutic option for benign prostatic hyperplasia patients. PMID- 26646438 TI - Introduction: Solar Energy Conversion. PMID- 26646439 TI - Time to kill the scientific "author"? PMID- 26646440 TI - [Modern diagnosis of sexually transmitted diseases]. AB - Diagnosis of sexually transmitted diseases (STD) has significantly improved in recent years by the application of nucleic acid amplification tests (NAAT). In addition to detection of infectious agents, molecular methods were also used for characterization of pathogens (typing, genotypic resistance testing). In contrast to conventional Sanger sequencing of amplicons, new sequencing technologies (next generation sequencing) are able to identify resistant variants that represent only small minorities in a heterogeneous population. NAATs are also available as fully automated closed systems that can be run independently of centralized laboratories and will become increasingly important for point-of-care testing. PMID- 26646441 TI - Protein Connectivity in Chemotaxis Receptor Complexes. AB - The chemotaxis sensory system allows bacteria such as Escherichia coli to swim towards nutrients and away from repellents. The underlying pathway is remarkably sensitive in detecting chemical gradients over a wide range of ambient concentrations. Interactions among receptors, which are predominantly clustered at the cell poles, are crucial to this sensitivity. Although it has been suggested that the kinase CheA and the adapter protein CheW are integral for receptor connectivity, the exact coupling mechanism remains unclear. Here, we present a statistical-mechanics approach to model the receptor linkage mechanism itself, building on nanodisc and electron cryotomography experiments. Specifically, we investigate how the sensing behavior of mixed receptor clusters is affected by variations in the expression levels of CheA and CheW at a constant receptor density in the membrane. Our model compares favorably with dose-response curves from in vivo Forster resonance energy transfer (FRET) measurements, demonstrating that the receptor-methylation level has only minor effects on receptor cooperativity. Importantly, our model provides an explanation for the non-intuitive conclusion that the receptor cooperativity decreases with increasing levels of CheA, a core signaling protein associated with the receptors, whereas the receptor cooperativity increases with increasing levels of CheW, a key adapter protein. Finally, we propose an evolutionary advantage as explanation for the recently suggested CheW-only linker structures. PMID- 26646442 TI - Seasonal variation in haematological and biochemical variables in free-ranging subadult brown bears (Ursus arctos) in Sweden. AB - BACKGROUND: Free-ranging brown bears exhibit highly contrasting physiological states throughout the year. They hibernate 6 months of the year, experiencing a decrease in body temperature, heart rate, respiratory rate and metabolism. An increase in food consumption and the resulting weight gain (mostly through fat storage) prior to hibernation are also part of the brown bear's annual cycle. Due to these physiological changes, haematological and biochemical variables vary dramatically throughout the year. Seasonal changes in 12 haematological and 34 biochemical variables were evaluated in blood samples collected from 40 free ranging subadult brown bears (22 females, 18 males) immobilised in Sweden in winter (February-March), spring (April-May), and summer (June). RESULTS: Higher levels of haemoglobin, haematocrit and red blood cell count, and a lower white blood cell count and mean cell volume was found during hibernation than in spring and summer. Lower values of the enzymes; aspartate aminotransferase (AST), alanine transaminase (ALT), alkaline phosphatase (AP), gamma-glutamyl transpeptidase (GGT), glutamate dehydrogenase (GD) and amylase, and increased values of beta-hydroxybutyrate (beta-HBA) and blood lipids; triglycerides, cholesterol and free fatty acids, were present during hibernation compared to spring and summer. CONCLUSIONS: This study documents significant shifts in haematological and biochemical variables in samples collected from brown bears anaesthetised in winter (February-March) compared to in spring and summer (April June), reflecting the lowered metabolic, renal and hepatic activity during hibernation. Lower values of enzymes and higher values of blood lipids during hibernation, likely reflect a lipid-based metabolism. PMID- 26646443 TI - Reactivity towards nitriles, cyanamides, and carbodiimides of palladium complexes derived from benzyl alcohol. Synthesis of a mixed Pd2Ag complex. AB - The chelate complex [Pd(kappa(2)-C,O-C6H4CH2O-2)(bpy)] () reacts with acetonitrile, cyanamides, or carbodiimides, in the presence of AgOTf (1 : 5 : 1 molar ratio) and residual water, to form complexes [Pd{kappa(2)-C,N C6H4{CH2OC([double bond, length as m-dash]NX)Y}-2}(bpy)](OTf), where X = H, Y = Me (), NMe2 (), NEt2 (), X = R, Y = NHR (R = (i)Pr (), Tol ()), as a result of the insertion of the unsaturated reagent into the O-Pd bond of and the protonation of one of the N atoms. In the absence of AgOTf the reaction of with TolN[double bond, length as m-dash]C[double bond, length as m-dash]NTol (Tol = p Tolyl) results in the formation of the neutral complex [Pd{kappa(2)-C,N C6H4{CH2OC([double bond, length as m-dash]NTol)NTol}-2}(bpy)] (). Complexes and can be interconverted by deprotonation ( + KO(t)Bu) or protonation ( + KOTf + HOTf) reactions. When the reaction of with TolN[double bond, length as m dash]C[double bond, length as m-dash]NTol in the presence of AgOTf is carried out in a 1 : 1 : 1 stoichiometric ratio, or for a short period of time, a mixture of and a mixed heterometallic Ag2Pd complex is obtained ( = [Ag(N-)2](OTf)). Complex is the major product when the AgOTf is added before the carbodiimide, and the reaction is stopped immediately. can also be obtained by reaction of with 0.5 equiv. of AgOTf. When complex [PdI(C6H4CH2OH-2)(bpy)] () reacts with (i)PrN[double bond, length as m-dash]C[double bond, length as m-dash]N(i)Pr in the presence of TlOTf, instead of AgOTf, a ca. 1 : 1 mixture of and [Pd{kappa(2) O,N-OCH2{C6H4{C([double bond, length as m-dash]NH(i)Pr)N(i)Pr}-2}}(bpy)](OTf) () forms. Complex is the result of the insertion of the carbodiimide into the C-Pd bond. Complexes have been extensively characterized by NMR spectroscopy, and the crystal structures of , , and .2.5CHCl3.0.5Et2O have been determined by X-ray diffraction studies. PMID- 26646444 TI - Optimal management for pediatric chronic myeloid leukemia. AB - Chronic myeloid leukemia (CML) is rare among childhood leukemias. Its incidence increases with age, from 0.09/100 000 at <=15 years old to 7.88/100 000 at >=75 years old. There are several biological and clinical differences between pediatric and adult CML. Markedly increased leukocyte count and a higher incidence of splenomegaly are characteristic features at diagnosis in pediatric patients. The therapeutic approach to CML has changed since the introduction of the tyrosine kinase inhibitor (TKI) imatinib, followed by dasatinib and nilotinib. Given the efficacy of TKI in adult CML, TKI are regarded as the established first-line treatment in adult patients. In 2011, a prospective phase IV study in pediatric patients showed the excellent efficacy and safety of imatinib. Imatinib is also accepted as a first-line option for childhood chronic phase CML. Although the efficacy of dasatinib and nilotinib reported in adult studies seems very attractive for pediatric patients, neither drug has been prospectively investigated in a large pediatric cohort. TKI are designed to inhibit BCR-ABL1 kinase, but they have unfavorable effects, so-called "off target" complications, such as growth impairment. Long-term morbidity due to TKI is unknown. Furthermore, the adverse effects on growing children have not been clearly elucidated, even though the exposure period to imatinib is relatively short. To establish the standard therapeutic management for pediatric CML, it is important to prospectively confirm the attractive outcomes obtained in adult studies via pediatric clinical trials with a careful monitoring system for TKI induced adverse effects, especially in growing children. PMID- 26646445 TI - Elevated level of serum glycoprotein bifucosylation and prognostic value in Chinese breast cancer. AB - Aberrant glycosylation is highly associated with cancer progression. The aim of this study was to compare bifucosylated N-glycans in sera obtained from healthy controls and breast cancer patients, with the goal of identifying a potential indicator for monitoring the recurrence and metastasis of breast cancer. A unique structural pattern of bifucosylated N-glycan, with both core and antennary fucosylation, was identified in breast cancer patients. The spectrum of antennary fucosylation was a composite of the standard spectra of Lewis X and H2, indicating a mixture of the two epitopes. Permethylated N-glycans of the glycoproteins extracted from 91 breast cancer patients and 43 healthy controls were detected using linear ion-trap quadrupole-electrospray ionization mass spectrometry, which appeared to be a highly sensitive and useful approach in the detection and identification of N-glycans. To evaluate MS profile data, several statistical tools were applied, including Student'st-test, partial least squares discriminant analysis and receiver-operating characteristic curve. The results showed that the measurement of bifucosylation degree and CEA levels had an improved diagnostic performance compared with that of CEA alone. We compared the potential of bifucosylated N-glycan as an indicator of breast cancer recurrence with the current clinical biomarkers, i.e., CEA, CA 15-3 and CA125. The result revealed that, compared with CEA, CA 15-3 and CA125, the bifucosylation degree of N-glycans could be a more reliable indicator of breast cancer recurrence. PMID- 26646446 TI - The valine and lysine residues in the conserved FxVTxK motif are important for the function of phylogenetically distant plant cellulose synthases. AB - Cellulose synthases (CESAs) synthesize the beta-1,4-glucan chains that coalesce to form cellulose microfibrils in plant cell walls. In addition to a large cytosolic (catalytic) domain, CESAs have eight predicted transmembrane helices (TMHs). However, analogous to the structure of BcsA, a bacterial CESA, predicted TMH5 in CESA may instead be an interfacial helix. This would place the conserved FxVTxK motif in the plant cell cytosol where it could function as a substrate gating loop as occurs in BcsA. To define the functional importance of the CESA region containing FxVTxK, we tested five parallel mutations in Arabidopsis thaliana CESA1 and Physcomitrella patens CESA5 in complementation assays of the relevant cesa mutants. In both organisms, the substitution of the valine or lysine residues in FxVTxK severely affected CESA function. In Arabidopsis roots, both changes were correlated with lower cellulose anisotropy, as revealed by Pontamine Fast Scarlet. Analysis of hypocotyl inner cell wall layers by atomic force microscopy showed that two altered versions of Atcesa1 could rescue cell wall phenotypes observed in the mutant background line. Overall, the data show that the FxVTxK motif is functionally important in two phylogenetically distant plant CESAs. The results show that Physcomitrella provides an efficient model for assessing the effects of engineered CESA mutations affecting primary cell wall synthesis and that diverse testing systems can lead to nuanced insights into CESA structure-function relationships. Although CESA membrane topology needs to be experimentally determined, the results support the possibility that the FxVTxK region functions similarly in CESA and BcsA. PMID- 26646447 TI - Size product modulation by enzyme concentration reveals two distinct levan elongation mechanisms in Bacillus subtilis levansucrase. AB - Two levan distributions are produced typically by Bacillus subtilis levansucrase (SacB): a high-molecular weight (HMW) levan with an average molecular weight of 2300 kDa, and a low-molecular weight (LMW) levan with 7.2 kDa. Previous results have demonstrated how reaction conditions modulate levan molecular weight distribution. Here we demonstrate that the SacB enzyme is able to perform two mechanisms: a processive mechanism for the synthesis of HMW levan and a non processive mechanism for the synthesis of LMW levan. Furthermore, the effect of enzyme and substrate concentration on the elongation mechanism was studied. While a negligible effect of substrate concentration was observed, we found that SacB elongation mechanism is determined by enzyme concentration. A high concentration of enzyme is required to synthesize LMW levan, involving the sequential formation of a wide variety of intermediate size levan oligosaccharides with a degree of polymerization (DP) up to ~70. In contrast, an HMW levan distribution is synthesized through a processive mechanism producing oligosaccharides with DP <20, in reactions occurring at low enzyme concentration. Additionally, reactions where levansucrase concentration was varied while the total enzyme activity was kept constant (using a combination of active SacB and an inactive SacB E342A/D86A) allowed us to demonstrate that enzyme concentration and not enzyme activity affects the final levan molecular weight distribution. The effect of enzyme concentration on the elongation mechanism is discussed in detail, finding that protein-product interactions are responsible for the mechanism shift. PMID- 26646449 TI - SIRT1 inhibition impairs non-homologous end joining DNA damage repair by increasing Ku70 acetylation in chronic myeloid leukemia cells. AB - Most chemotherapeutic agents for leukemia are DNA damaging agents. However, DNA lesions can be repaired by activities of DNA repair systems. Increasing evidence have shown that enhanced DNA damage repair capacity contributes to chemotherapy resistance in leukemia cells. Thus, targeting DNA repair mechanisms is a promising strategy for novel leukemia treatment. SIRT1 expressions were downregulated by lentivirus-delivered SIRT1 shRNA in myeloid leukemia cells. SIRT1 mRNA and protein levels were analyzed by real-time PCR and Western blot, respectively. Flow cytometry was carried out to analyze cell cycle progression, apoptosis and DNA damage repair efficiency. DNA damage levels were assessed by alkaline comet assay, and H2AX phosphorylation was analyzed by immunoblotting and immunofluorescence. A mouse leukemia model was established by transplanting lentivirus-infected K562 cells containing SIRT1 shRNA into sublethally irradiated NOD/SCID mice, and tumorigenesis was evaluated by detecting tumor weights and mice survival. SIRT1 expressions were upregulated in myeloid leukemic patients. Downregulation of SIRT1 by RNAi promoted etoposide-induced DNA damage in myeloid leukemia cells accompanied by reduced NHEJ activity, and increased Ku70 acetylation. Furthermore, SIRT1 knockdown resulted in cell cycle arrest, induction of apoptosis and reduction of K562 cell proliferation accompanied by enhanced p53 and FOXO1 acetylation in K562 cells after etoposide treatment. Importantly, SIRT1 downregulation reduced the tumorigenesis ability of K562 cells in mouse xenografts following chemotherapy treatment. These results revealed that SIRT1 promotes the NHEJ repair pathway by deacetylating Ku70 in K562 cells, suggesting that SIRT1 is a novel therapeutic target for treating myeloid leukemia. PMID- 26646448 TI - NF-Y activates genes of metabolic pathways altered in cancer cells. AB - The trimeric transcription factor NF-Y binds to the CCAAT box, an element enriched in promoters of genes overexpressed in tumors. Previous studies on the NF-Y regulome identified the general term metabolism as significantly enriched. We dissect here in detail the targeting of metabolic genes by integrating analysis of NF-Y genomic binding and profilings after inactivation of NF-Y subunits in different cell types. NF-Y controls de novo biosynthetic pathways of lipids, teaming up with the master SREBPs regulators. It activates glycolytic genes, but, surprisingly, is neutral or represses mitochondrial respiratory genes. NF-Y targets the SOCG (Serine, One Carbon, Glycine) and Glutamine pathways, as well as genes involved in the biosynthesis of polyamines and purines. Specific cancer-driving nodes are generally under NF-Y control. Altogether, these data delineate a coherent strategy to promote expression of metabolic genes fuelling anaerobic energy production and other anabolic pathways commonly altered in cancer cells. PMID- 26646450 TI - Activation of an endothelial Notch1-Jagged1 circuit induces VCAM1 expression, an effect amplified by interleukin-1beta. AB - The Notch1 and Notch4 signaling pathways regulate endothelial cell homeostasis. Inflammatory cytokines induce the expression of endothelial adhesion molecules, including VCAM1, partly by downregulating Notch4 signaling. We investigated the role of endothelial Notch1 in this IL-1beta-mediated process. Brief treatment with IL-1beta upregulated endothelial VCAM1 and Notch ligand Jagged1. IL-1beta decreased Notch1 mRNA levels, but levels of the active Notch1ICD protein remained constant. IL-1beta-mediated VCAM1 induction was downregulated in endothelial cells subjected to pretreatment with a pharmacological inhibitor of the gamma secretase, which activates Notch receptors, producing NotchICD. It was also downregulated in cells in which Notch1 and/or Jagged1 were silenced.Conversely, the forced expression of Notch1ICD in naive endothelial cells upregulated VCAM1 per se and amplified IL-1beta-mediated VCAM1 induction. Jagged1 levels increased and Notch4 signaling was downregulated in parallel. Finally, Notch1ICD and Jagged1 expression was upregulated in the endothelium of the liver in a model of chronic liver inflammation.In conclusion, we describe here a cell-autonomous, pro inflammatory endothelial Notch1-Jagged1 circuit (i) triggering the expression of VCAM1 even in the absence of inflammatory cytokines and (ii) enhancing the effects of IL-1beta. Thus, IL-1beta regulates Notch1 and Notch4 activity in opposite directions, consistent with a selective targeting of Notch1 in inflamed endothelium. PMID- 26646451 TI - microRNA-342-5p and miR-608 inhibit colon cancer tumorigenesis by targeting NAA10. AB - miRNAs have been shown to play pivotal roles in the establishment and progression of colon cancer, but their underlying mechanisms are not fully understood. N acetyltransferase NAA10 participates in many cellular processes, including tumorigenesis. Here we showed that miR-342-5p and miR-608 suppressed the tumorigenesis of colon cancer cells in vitro and in vivo by targeting NAA10 mRNA for degradation. Overexpression of miR-342-5p or miR-608 decreased NAA10 mRNA and protein levels and thereby suppressed cell proliferation, migration, and cell cycle progression, as well as promoted apoptosis in SW480 and SW620 cells. More importantly, miR-342-5p and miR-608 significantly decreased the tumorigenic capacity of SW480 and SW620 cells in a mouse xenograft model. We also observed an inverse correlation between the expression of NAA10 and that of both miRNAs. Our results implicate miR-342-5p and miR-608 in colon cancer development and unveil the underlying mechanism of this phenomenon, which involves NAA10. PMID- 26646453 TI - How lung infection leads to gut injury. PMID- 26646452 TI - Ulocuplumab (BMS-936564 / MDX1338): a fully human anti-CXCR4 antibody induces cell death in chronic lymphocytic leukemia mediated through a reactive oxygen species-dependent pathway. AB - The CXCR4 receptor (Chemokine C-X-C motif receptor 4) is highly expressed in different hematological malignancies including chronic lymphocytic leukemia (CLL). The CXCR4 ligand (CXCL12) stimulates CXCR4 promoting cell survival and proliferation, and may contribute to the tropism of leukemia cells towards lymphoid tissues. Therefore, strategies targeting CXCR4 may constitute an effective therapeutic approach for CLL. To address that question, we studied the effect of Ulocuplumab (BMS-936564), a fully human IgG4 anti-CXCR4 antibody, using a stroma--CLL cells co-culture model. We found that Ulocuplumab (BMS-936564) inhibited CXCL12 mediated CXCR4 activation-migration of CLL cells at nanomolar concentrations. This effect was comparable to AMD3100 (Plerixafor--Mozobil), a small molecule CXCR4 inhibitor. However, Ulocuplumab (BMS-936564) but not AMD3100 induced apoptosis in CLL at nanomolar concentrations in the presence or absence of stromal cell support. This pro-apoptotic effect was independent of CLL high risk prognostic markers, was associated with production of reactive oxygen species and did not require caspase activation. Overall, these findings are evidence that Ulocuplumab (BMS-936564) has biological activity in CLL, highlight the relevance of the CXCR4-CXCL12 pathway as a therapeutic target in CLL, and provide biological rationale for ongoing clinical trials in CLL and other hematological malignancies. PMID- 26646454 TI - Subglottic Secretion Drainage and Objective Outcomes: A Systematic Review and Meta-Analysis. AB - OBJECTIVE: Current guidelines recommend endotracheal tubes with subglottic secretion drainage to prevent ventilator-associated pneumonia. Subglottic secretion drainage is associated with fewer ventilator-associated pneumonia diagnoses, but it is unclear to what extent this reflects fewer invasive pneumonias versus fewer false-positive diagnoses due to less secretions and/or less microbial colonization of the oropharynx. We, therefore, undertook a systematic review and meta-analysis of the impact of subglottic secretion drainage on duration of mechanical ventilation, ICU and hospital length of stay, ventilator-associated events, mortality, antibiotic utilization, stridor, and reintubations to better understand the net benefits and limitations of this intervention. DATA SOURCES: We searched Cumulative Index to Nursing and Allied Health Literature, Excerpta Medica Database, and PubMed from inception through February 22, 2015, without language restrictions. STUDY SELECTION: Randomized controlled trials comparing subglottic secretion drainage versus no subglottic secretion drainage in adult patients on mechanical ventilation. DATA EXTRACTION: Eligible trials were abstracted and assessed for risk of bias by two reviewers. DATA SYNTHESIS: We identified 17 eligible trials with a total of 3,369 patients. Subglottic secretion drainage was associated with lower ventilator-associated pneumonia rates (risk ratio, 0.58; 95% CI, 0.51-0.67; I2 = 0%), but there were no significant differences between groups in duration of mechanical ventilation (weighted mean difference, -0.16 d; 95% CI, -0.64 to 0.33; I2 = 0%), ICU length of stay (weighted mean difference, +0.17 d; 95% CI, -0.62 to 0.95; I2 = 0%), hospital length of stay (weighted mean difference, -0.57 d; 95% CI, -2.44 to 1.30; I2 = 0%), ventilator-associated events (risk ratio, 0.97; 95% CI, 0.65 1.43), or mortality (risk ratio, 0.93; 95% CI, 0.84-1.03; I2 = 0%). Two studies observed significantly less antibiotic use with subglottic secretion drainage whereas a third did not. There were no significant differences between groups in stridor or reintubations. CONCLUSIONS: Subglottic secretion drainage is associated with lower ventilator-associated pneumonia rates but does not clearly decrease duration of mechanical ventilation, length of stay, ventilator associated events, mortality, or antibiotic usage. Further data are required to demonstrate the benefits of subglottic secretion drainage. PMID- 26646455 TI - Niacin and Selenium Attenuate Sepsis-Induced Lung Injury by Up-Regulating Nuclear Factor Erythroid 2-Related Factor 2 Signaling. AB - OBJECTIVES: To determine whether the combination therapy of niacin and selenium attenuates lung injury and improves survival during sepsis in rats and whether its benefits are associated with the activation of the glutathione redox cycle and up-regulation of nuclear factor erythroid 2-related factor 2. DESIGN: Prospective laboratory study. SETTING: University laboratory. SUBJECTS: Human lung microvascular endothelial cells and male Sprague-Dawley rats (n = 291). INTERVENTION: In lipopolysaccharide-exposed cells, the dose-related effects of niacin and selenium were assessed, and the therapeutic effects of the combination therapy of niacin (0.9 mM) and selenium (1.5 MUM) were evaluated. The role of nuclear factor erythroid 2-related factor 2 was determined using nuclear factor erythroid 2-related factor 2 knockdown cells. In endotoxemic and cecal ligation and puncture with antibiotics rats, the therapeutic effects of the posttreatments of clinically relevant doses of niacin (360 mg/kg) and selenium (60 MUg/kg) were evaluated. MEASUREMENTS AND MAIN RESULTS: Combination therapy reduced the hydrogen peroxide level via the synergistic activation of the glutathione redox cycle, which involves niacin-induced increases in glutathione reductase activity, and reduced the glutathione level and a selenium-induced increase in glutathione peroxidase activity. Combination therapy contributed to the up-regulation of nuclear factor erythroid 2-related factor 2, enhancement of glutathione synthesis, and down-regulation of nuclear factor kappaB signaling, but nuclear factor erythroid 2-related factor 2 knockdown inhibited the enhancement of glutathione synthesis and down-regulation of the nuclear factor kappaB pathway. The therapeutic effects of combination therapy on endotoxemic rats were consistent with those on lipopolysaccharide-exposed cells. In addition, the posttreatment of combination therapy attenuated lung injury and improved survival in endotoxemic and cecal ligation and puncture with antibiotics rats. However, individual therapies of niacin or selenium failed to achieve these benefits. CONCLUSIONS: The combination therapy of niacin and selenium attenuated lung injury and improved survival during sepsis. Its therapeutic benefits were associated with the synergistic activation of the glutathione redox cycle, reduction of hydrogen peroxide level, and up-regulation of nuclear factor erythroid 2-related factor 2. PMID- 26646456 TI - Physical Function and Mental Health in Trauma Intensive Care Patients: A 2-Year Cohort Study. AB - OBJECTIVES: This study was designed to examine changes in function over time after injury and to identify factors associated with long-term recovery that may be amenable to change through intervention. DESIGN: Prospective cohort study. SETTING: Intensive care in a tertiary hospital in Queensland, Australia. PATIENTS: Adult (n = 123) admitted to intensive care for treatment of injury. INTERVENTIONS: Data were collected prior to hospital discharge and 1, 6, 12, and 24 months post injury. Data included demographics, preinjury health, injury characteristics, acute care factors, psychosocial measures, and health status. Linear mixed-effects models were used to identify factors associated with physical function and mental health over time. MEASUREMENTS AND MAIN RESULTS: Physical function and mental health improved over time; however, the averages remained below Australian norms at 24 months. Optimistic perception of illness and greater self-efficacy were potentially modifiable factors associated with improved mental health and physical function over time. Greater perceived social support, also potentially modifiable, was associated with improved mental health. Injury insurance and income were significant nonmodifiable factors for mental health, with mental health gains associated with higher income. Hospital length of stay and injury insurance were nonmodifiable factors linked with physical function. CONCLUSIONS: Improvements in physical function and mental health are evident in the 24 months following injury, but most patients remain below Australian population norms. Factors that were associated with physical function and mental health outcomes over time that are potentially amenable to change include illness perception, self-efficacy, and perceived social support. PMID- 26646457 TI - Hyperbaric Oxygen Preconditioning Attenuates Hemorrhagic Transformation Through Reactive Oxygen Species/Thioredoxin-Interacting Protein/Nod-Like Receptor Protein 3 Pathway in Hyperglycemic Middle Cerebral Artery Occlusion Rats. AB - OBJECTIVES: To clarify whether hyperbaric oxygen preconditioning can attenuate hyperglycemia-enhanced hemorrhagic transformation and to establish a role for Nod like receptor protein 3 inflammasome in the pathophysiology of hemorrhagic transformation. DESIGN: Controlled prospective animal study. SETTING: University research laboratory. SUBJECTS: Male Sprague-Dawley rats weighing 260-280 g. INTERVENTIONS: Rats received 1-hour-long hyperbaric oxygen preconditioning for five consecutive days. Hyperglycemic middle cerebral artery occlusion model was induced at 24 hours after the last hyperbaric oxygen exposure. Reactive oxygen species scavenger (N-acetyl-L-cysteine), thioredoxin-interacting protein small interfering RNA, and Nod-like receptor protein 3 small interfering RNA were given in different groups separately to verify the possible pathway. MEASUREMENTS AND MAIN RESULTS: Rats were randomly divided into sham, middle cerebral artery occlusion, middle cerebral artery occlusion + dextrose, middle cerebral artery occlusion + dextrose + normobaric oxygen preconditioning, middle cerebral artery occlusion + dextrose + hyperbaric oxygen, middle cerebral artery occlusion + dextrose + hyperbaric oxygen + N-acetyl-L-cysteine, middle cerebral artery occlusion + dextrose + hyperbaric oxygen + control small interfering RNA, middle cerebral artery occlusion + dextrose + hyperbaric oxygen + thioredoxin interacting protein small interfering RNA, and middle cerebral artery occlusion + dextrose + hyperbaric oxygen + Nod-like receptor protein 3 small interfering RNA groups. Hyperglycemia was induced by administration of 50% dextrose (6 mL/kg) intraperitoneally 30 minutes before middle cerebral artery occlusion. Control small interfering RNA/thioredoxin-interacting protein small interfering RNA or Nod-like receptor protein 3 small interfering RNA (500 pmol/5 MUL) were injected intracerebroventricularly 72 hours before middle cerebral artery occlusion for intervention. The neurologic scores, infarction and hemorrhage volumes, the expression of Nod-like receptor protein 3, and its downstream targets were analyzed. Hyperbaric oxygen preconditioning decreased both infarction and hemorrhage volumes and improved neurobehavioral function. In addition, hyperbaric oxygen preconditioning provided additional protective effects in hemorrhagic transformation, which was independent of infarction volume. The benefits of hyperbaric oxygen preconditioning on hyperglycemic middle cerebral artery occlusion rats were reversed after blocking the reactive oxygen species/thioredoxin-interacting protein/Nod-like receptor protein 3 pathway. CONCLUSIONS: Nod-like receptor protein 3 inflammasome played an important role in hyperglycemia-enhanced hemorrhagic transformation. Hyperbaric oxygen preconditioning attenuated hemorrhagic transformation through reactive oxygen species/thioredoxin-interacting protein/Nod-like receptor protein 3 pathway. PMID- 26646458 TI - 4-Phenylbutyrate Benefits Traumatic Hemorrhagic Shock in Rats by Attenuating Oxidative Stress, Not by Attenuating Endoplasmic Reticulum Stress. AB - OBJECTIVE: Vascular dysfunction such as vascular hyporeactivity following severe trauma and shock is a major cause of death in injured patients. Oxidative stress and endoplasmic reticulum stress play an important role in vascular dysfunction. The objective of the present study was to determine whether or not 4 phenylbutyrate can improve vascular dysfunction and elicit antishock effects by inhibiting oxidative and endoplasmic reticulum stress. DESIGN: Prospective, randomized, controlled laboratory experiment. SETTING: State key laboratory of trauma, burns, and combined injury. SUBJECTS: Five hundred and fifty-two Sprague Dawley rats. INTERVENTIONS: Rats were anesthetized, and a model of traumatic hemorrhagic shock was established by left femur fracture and hemorrhage. The effects of 4-phenylbutyrate (5, 20, 50, 100, 200, and 300 mg/kg) on vascular reactivity, animal survival, hemodynamics, and vital organ function in traumatic hemorrhagic shock rats and cultured vascular smooth muscle cells, and the relationship to oxidative stress and endoplasmic reticulum stress was observed. MEASUREMENTS AND MAIN RESULTS: Lower doses of 4-phenylbutyrate significantly improved the vascular function, stabilized the hemodynamics, and increased the tissue blood flow and vital organ function in traumatic hemorrhagic shock rats, and markedly improved the survival outcomes. Among all dosages observed in the present study, 20 mg/kg of 4-phenylbutyrate had the best effect. Further results indicated that 4-phenylbutyrate significantly inhibited the oxidative stress, decreased shock-induced oxidative stress index such as the production of reactive oxygen species, increased the antioxidant enzyme levels such as superoxide dismutase, catalase, and glutathione, and improved the mitochondrial function by inhibiting the opening of the mitochondrial permeability transition pore in rat artery and vascular smooth muscle cells. In contrast, 4-phenylbutyrate did not affect the changes of endoplasmic reticulum stress markers following traumatic hemorrhagic shock. Furthermore, 4-phenylbutyrate increased the nuclear levels of nuclear factor-E2-related factor 2, and decreased the nuclear levels of nuclear factor kappaB in hypoxic vascular smooth muscle cells. CONCLUSIONS: 4 phenylbutyrate has beneficial effects for traumatic hemorrhagic shock including improving animal survival and protecting organ function. These beneficial effects of 4-phenylbutyrate in traumatic hemorrhagic shock result from its vascular function protection via attenuation of the oxidative stress and mitochondrial permeability transition pore opening. Nuclear factor-E2-related factor 2 and nuclear factor-kappaB may be involved in 4-phenylbutyrate-mediated inhibition of oxidative stress. PMID- 26646459 TI - Platelet-Derived Growth Factor Receptor-beta Regulates Vascular Smooth Muscle Cell Phenotypic Transformation and Neuroinflammation After Intracerebral Hemorrhage in Mice. AB - OBJECTIVE: Platelet-derived growth factor-BB activates platelet-derived growth factor receptor-beta and promotes vascular smooth muscle cell phenotypic transformation. Elevated levels of non-muscle myosin IIB (SMemb) are found in secretory smooth muscle cells along with inflammatory mediators, such as intercellular adhesion molecule-1, which can amplify neutrophil infiltration into the brain. In the present study, we investigated the role of platelet-derived growth factor-BB/platelet-derived growth factor receptor-beta following intracerebral hemorrhage-induced brain injury in mice, with emphasis on its ability to promote vascular smooth muscle cell phenotypic transformation followed by increased intercellular adhesion molecule-1 expression and elevated neutrophil infiltration in the vicinity of the hematoma. We also determined the extent to which plasmin from the hematoma influences the platelet-derived growth factor BB/platelet-derived growth factor receptor-beta system subsequent to intracerebral hemorrhage. DESIGN: Controlled in vivo laboratory study. SETTING: Animal research laboratory. SUBJECTS: One hundred and fifty six eight-week-old male CD1 mice. INTERVENTIONS: Brain injury was induced by autologous arterial blood or plasmin injection into mouse brains. Small interfering RNA targeting platelet-derived growth factor receptor-beta was administered 24 hours before intracerebral hemorrhage. A platelet-derived growth factor receptor antagonist, Gleevec, was administered following intracerebral hemorrhage. A mitogen-activated protein kinase-activated protein kinase 2 inhibitor (KKKALNRQLGVAA) was delivered with platelet-derived growth factor-BB in naive animals. Platelet-derived growth factor-BB was injected with a plasmin inhibitor (epsilon-aminocaproic acid) in intracerebral hemorrhage mice. Plasmin-injected mice were given platelet-derived growth factor receptor-beta small interfering RNA 24 hours before the operation. Neurological deficits, brain edema, western blots, and immunofluorescence were evaluated. MEASUREMENTS AND MAIN RESULTS: Platelet-derived growth factor receptor beta small interfering RNA attenuated SMemb and intercellular adhesion molecule-1 expression and neutrophil infiltration at 24 hours post injury and reduced neurological deficits and brain edema at 24 and 72 hours following intracerebral hemorrhage. The platelet-derived growth factor receptor antagonist, Gleevec, reduced SMemb and intercellular adhesion molecule-1 expression. Platelet-derived growth factor receptor-beta activation led to increased expression of intercellular adhesion molecule-1 and was reversed by KKKALNRQLGVAA in naive mice. Plasmin inhibition suppressed platelet-derived growth factor receptor-beta activation and neutrophil infiltration, whereas exogenous platelet-derived growth factor-BB increased platelet-derived growth factor receptor-beta activation, regardless of plasmin inhibition. Platelet-derived growth factor receptor-beta small interfering RNA decreased the expression of intercellular adhesion molecule 1 by plasmin injection. CONCLUSION: The platelet-derived growth factor BB/platelet-derived growth factor receptor-beta system contributes to neuroinflammation through vascular smooth muscle cell phenotypic transformation near the hematoma via the p38 mitogen-activated protein kinase/mitogen-activated protein kinase-activated protein kinase 2 pathway following intracerebral hemorrhage. Plasmin is hypothesized to be upstream of the proposed neuroinflammatory system. The therapeutic intervention targeting the platelet derived growth factor-BB/platelet-derived growth factor receptor-beta is a novel strategy to prevent plasmin-induced brain injury following intracerebral hemorrhage. PMID- 26646460 TI - Reversal of Acute Kidney Injury-Induced Neutrophil Dysfunction: A Critical Role for Resistin. AB - OBJECTIVES: To assess the reversibility of acute kidney injury-induced neutrophil dysfunction and to identify involved mechanisms. DESIGN: Controlled laboratory experiment and prospective observational clinical study. SETTING: University laboratory and hospital. SUBJECTS: C57BL/6 wild-type mice. PATIENTS: Patients with septic shock with or without acute kidney injury. INTERVENTIONS: Murine acute kidney injury was induced by intraperitoneal injections of folic acid (nephrotoxic acute kidney injury) or by IM injections of glycerol (rhabdomyolysis induced acute kidney injury). After 24 hours, we incubated isolated neutrophils for 3 hours in normal mouse serum or minimum essential medium buffer. We further studied the effects of plasma samples from 13 patients with septic shock (with or without severe acute kidney injury) on neutrophilic-differentiated NB4 cells. MEASUREMENTS AND MAIN RESULTS: Experimental acute kidney injury significantly inhibited neutrophil migration and intracellular actin polymerization. Plasma levels of resistin, a proinflammatory cytokine and uremic toxin, were significantly elevated during both forms of acute kidney injury. Incubation in serum or minimum essential medium buffer restored normal neutrophil function. Resistin by itself was able to induce acute kidney injury-like neutrophil dysfunction in vitro. Plasma resistin was significantly higher in patients with septic shock with acute kidney injury compared with patients with septic shock alone. Compared with plasma from patients with septic shock, plasma from patients with septic shock and acute kidney injury inhibited neutrophilic-differentiated NB4 cell migration. Even after 4 days of renal replacement therapy, plasma from patients with septic shock plus acute kidney injury still showed elevated resistin levels and inhibited neutrophilic-differentiated NB4 cell migration. Resistin inhibited neutrophilic-differentiated NB4 cell migration and intracellular actin polymerization at concentrations seen during acute kidney injury, but not at normal physiologic concentrations. CONCLUSIONS: Acute kidney injury-induced neutrophil dysfunction is reversible in vitro. However, standard renal replacement therapy does not correct this defect in patients with septic shock and acute kidney injury. Resistin is greatly elevated during acute kidney injury, even with ongoing renal replacement therapy, and is sufficient to cause acute kidney injury-like neutrophil dysfunction by itself. PMID- 26646461 TI - Modulation by the Noble Gas Helium of Tissue Plasminogen Activator: Effects in a Rat Model of Thromboembolic Stroke. AB - INTERVENTIONS: Helium has been shown to provide neuroprotection in mechanical model of acute ischemic stroke by inducing hypothermia, a condition shown by itself to reduce the thrombolytic and proteolytic properties of tissue plasminogen activator. However, whether or not helium interacts with the thrombolytic drug tissue plasminogen activator, the only approved therapy of acute ischemic stroke still remains unknown. This point is not trivial since previous data have shown the critical importance of the time at which the neuroprotective noble gases xenon and argon should be administered, during or after ischemia, in order not to block tissue plasminogen activator-induced thrombolysis and to obtain neuroprotection and inhibition of tissue plasminogen activator-induced brain hemorrhages. MEASUREMENTS AND MAIN RESULTS: We show that helium of 25-75 vol% inhibits in a concentration-dependent fashion the catalytic and thrombolytic activity of tissue plasminogen activator in vitro and ex vivo. In vivo, in rats subjected to thromboembolic brain ischemia, we found that intraischemic helium at 75 vol% inhibits tissue plasminogen activator-induced thrombolysis and subsequent reduction of ischemic brain damage and that postischemic helium at 75 vol% reduces ischemic brain damage and brain hemorrhages. CONCLUSIONS: In a clinical perspective for the treatment of acute ischemic stroke, these data suggest that helium 1) should not be administered before or together with tissue plasminogen activator therapy due to the risk of inhibiting the benefit of tissue plasminogen activator-induced thrombolysis; and 2) could be an efficient neuroprotective agent if given after tissue plasminogen activator-induced reperfusion. PMID- 26646462 TI - Effect of Perioperative Goal-Directed Hemodynamic Resuscitation Therapy on Outcomes Following Cardiac Surgery: A Randomized Clinical Trial and Systematic Review. AB - OBJECTIVES: To evaluate the effects of goal-directed therapy on outcomes in high risk patients undergoing cardiac surgery. DESIGN: A prospective randomized controlled trial and an updated metaanalysis of randomized trials published from inception up to May 1, 2015. SETTING: Surgical ICU within a tertiary referral university-affiliated teaching hospital. PATIENTS: One hundred twenty-six high risk patients undergoing coronary artery bypass surgery or valve repair. INTERVENTIONS: Patients were randomized to a cardiac output-guided hemodynamic therapy algorithm (goal-directed therapy group, n = 62) or to usual care (n = 64). In the goal-directed therapy arm, a cardiac index of greater than 3 L/min/m was targeted with IV fluids, inotropes, and RBC transfusion starting from cardiopulmonary bypass and ending 8 hours after arrival to the ICU. MEASUREMENTS AND MAIN RESULTS: The primary outcome was a composite endpoint of 30-day mortality and major postoperative complications. Patients from the goal-directed therapy group received a greater median (interquartile range) volume of IV fluids than the usual care group (1,000 [625-1,500] vs 500 [500-1,000] mL; p < 0.001], with no differences in the administration of either inotropes or RBC transfusions. The primary outcome was reduced in the goal-directed therapy group (27.4% vs 45.3%; p = 0.037). The goal-directed therapy group had a lower occurrence rate of infection (12.9% vs 29.7%; p = 0.002) and low cardiac output syndrome (6.5% vs 26.6%; p = 0.002). We also observed lower ICU cumulative dosage of dobutamine (12 vs 19 mg/kg; p = 0.003) and a shorter ICU (3 [3-4] vs 5 [4-7] d; p < 0.001) and hospital length of stay (9 [8-16] vs 12 [9-22] d; p = 0.049) in the goal-directed therapy compared with the usual care group. There were no differences in 30-day mortality rates (4.8% vs 9.4%, respectively; p = 0.492). The metaanalysis identified six trials and showed that, when compared with standard treatment, goal-directed therapy reduced the overall rate of complications (goal-directed therapy, 47/410 [11%] vs usual care, 92/415 [22%]; odds ratio, 0.40 [95% CI, 0.26-0.63]; p < 0.0001) and decreased the hospital length of stay (mean difference, -5.44 d; 95% CI, -9.28 to -1.60; p = 0.006) with no difference in postoperative mortality: 9 of 410 (2.2%) versus 15 of 415 (3.6%), odds ratio, 0.61 (95% CI, 0.26-1.47), and p = 0.27. CONCLUSIONS: Goal directed therapy using fluids, inotropes, and blood transfusion reduced 30-day major complications in high-risk patients undergoing cardiac surgery. PMID- 26646463 TI - Echography of the Portal Vein in a Patient With Shock. AB - OBJECTIVES: To report the utility of abdominal ultrasonography to identify portal venous gas in patients with shock, as an indicator of acute mesenteric ischemia, and to illustrate the aspect of portal venous gas on ultrasonography. DATA SOURCES: Clinical observation of a patient, images of abdominal ultrasonography and abdominal computed tomography, and video of portal venous gas. STUDY SELECTION: Not applicable. DATA EXTRACTION: Relevant information contained in the medical observation of the patient and selection of image and video of ultrasonography performed in the patient. DATA SYNTHESIS: We report a case of nonocclusive mesenteric ischemia in a 76-year-old patient following cardiac surgery. The diagnosis of acute mesenteric ischemia was proposed based on evidence of portal venous gas on abdominal ultrasonography and then confirmed by abdominal computed tomography showing transverse colonic ischemia, the presence of gas in the mesenteric veins but not in the portal vein. Urgent laparotomy confirmed extensive nonocclusive mesenteric ischemia, and the patient rapidly died of multiple organ failure. CONCLUSIONS: Intensive care physicians should be aware of the ultrasound characteristics of portal venous gas. In patients with shock, in addition to cardiac and thoracic echography, investigation of portal venous gas using bedside ultrasonography may help the clinician to identify patients in whom acute mesenteric ischemia develops. PMID- 26646464 TI - Hemostatic Changes During Extracorporeal Membrane Oxygenation: A Prospective Randomized Clinical Trial Comparing Three Different Extracorporeal Membrane Oxygenation Systems. AB - OBJECTIVE: Extracorporeal membrane oxygenation is a rescue therapy for patients with severe lung failure. Major complications caused by extracorporeal membrane oxygenation are bleeding, thrombosis, and hemolysis. The aim of this study was to compare the impact of different extracorporeal membrane oxygenation systems on blood hemostasis in adults during veno-venous extracorporeal membrane oxygenation therapy. DESIGN: Single center prospective randomized study. SETTING: University Hospital Regensburg, Germany. PATIENTS: Adult patients with severe acute respiratory distress syndrome requiring veno-venous extracorporeal membrane oxygenation therapy. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Three different extracorporeal membrane oxygenation systems: the Cardiohelp system (Maquet Cardiopulmonary AG), the Dideco ECC.O5 (Sorin Group), and the Deltastream system with Hilite 7000 LT + DP3 pumphead (Medos Medizintechnik AG) were compared. Therefore hemostasis, anticoagulation, hemolysis, and inflammatory parameters were monitored. Of the 54 patients included in the study, 18 patients each were randomly assigned to the three different extracorporeal membrane oxygenation systems. Exclusion criteria were acute renal failure, trauma, and surgery within 2 days. The median time on veno-venous extracorporeal membrane oxygenation support was 13.5 days (4-70 d). Median platelet count had dropped from 220.5 G/L before extracorporeal membrane oxygenation therapy to a minimum of 133 G/L by the last day of extracorporeal membrane oxygenation support. During the first 5 days of extracorporeal membrane oxygenation therapy, prothrombin fragment 1.2 (F1.2) (1.36-2.4 uM), thrombin-antithrombin complex (14.5-50 ug/L), and D-dimers (6.00-27.0 mg/L) increased, whereas fibrinogen values dropped from 5.8 to 4.1 g/L. The three different extracorporeal membrane oxygenation systems did not show any differences with regard to hemostasis, anticoagulation, hemolysis, and inflammatory parameters within the first 5 days of extracorporeal membrane oxygenation therapy. CONCLUSIONS: Over time, miniaturized veno-venous extracorporeal membrane oxygenation therapy increasingly activates coagulation. The different types of membrane oxygenators and pumps did not significantly alter hemostasis. PMID- 26646465 TI - Short-Term Dietary Restriction Rescues Mice From Lethal Abdominal Sepsis and Endotoxemia and Reduces the Inflammatory/Coagulant Potential of Adipose Tissue. AB - OBJECTIVES: Visceral adipose tissue is a major site for expression of proinflammatory and procoagulant genes during acute systemic inflammation. In this study, we tested whether the loss of fat mass by dietary restriction would remove the major source of these factors resulting in improved tolerance to sepsis and endotoxemia. DESIGN: Prospective, laboratory controlled experiments. SETTING: Aging and critical care research laboratory in a university hospital. SUBJECTS: Middle-aged (12-month old) male C57BL/6 mice. INTERVENTIONS: Mice were subjected to 40% dietary restriction for 3 weeks followed by induction of abdominal sepsis or endotoxemia by intraperitoneal injection with cecal slurry or lipopolysaccharide, respectively. MEASUREMENTS AND MAIN RESULTS: Compared with freely fed mice, dietary restricted mice exhibited dramatically improved survival (80% vs 0% after sepsis; p < 0.001 and 86% vs 12% after endotoxemia; p = 0.013) and significantly reduced visceral fat-derived messenger RNA expression of interleukin-6, thrombospondin-1, plasminogen activator inhibitor-1, and tissue factor, which positively correlated with fat mass. Plasma levels of interleukin-6 were significantly reduced by dietary restriction and correlated with adipose interleukin-6 messenger RNA levels and fat mass (p < 0.001; R = 0.64 and 0.89). In vitro culture of visceral fat explants from naive dietary restricted mice showed significantly reduced interleukin-6 secretion compared with that from freely fed mice in response to lipopolysaccharide. Analysis of major adipose immune cell populations by flow cytometry demonstrated that macrophages were the only cell population reduced by dietary restriction and that CD11c/CD206 (M2 type) and CD11c/CD206 (double negative) macrophages, in addition to T cells, are the major immune cell populations that produce interleukin-6 in middle-aged mice during systemic inflammation. CONCLUSIONS: Short-term dietary restriction drastically improved the survival outcome of middle-aged mice during both polymicrobial sepsis and sterile endotoxemia. Improved survival was accompanied by a significantly attenuated inflammatory response in adipose tissue, which is likely due to alterations of both fat mass quantity and qualitative changes, including a reduction in macrophage populations. PMID- 26646467 TI - From Pediatrics to Geriatrics: Toward a Unified Standardized Screening Tool for Delirium: A Thought Experiment. AB - OBJECTIVE: We aim to provide evidence for our view that a single, standardized (and preferably observational) screening tool for delirium should be used in patients of all ages (children, adults, and the elderly). DATA SOURCES: To support our viewpoint, we searched, in the period February 25, 2015, to August 5, 2015, Pubmed and all the major textbooks. STUDY SELECTION: We searched PubMed using the following terms: "delirium," "screening tool," "pediatric," "adult," "elderly," "unifying," "observational," "CAPD," and "DOS." We used these terms in various combinations. DATA EXTRACTION: Abstracts were reviewed for relevance and applicability. Studies were selected by discussion between the two authors. DATA SYNTHESIS: After a comprehensive literature review, conclusions were drawn based on the strength of evidence and the most current understanding of delirium screening practices. CONCLUSIONS: The proposed screening tools (Cornell Assessment of Pediatric Delirium and Delirium Observation Screening) entail all main diagnostic criteria, and so they are conceptually valid translations of delirium into operational terms. Given the much greater overlap than difference in this neuropsychiatric context of critical illness between children on the one hand and adults and elderly on the other, we propose that these tools would be ideal as the unified standardized screening tool. PMID- 26646466 TI - Incidence and Outcomes of Cardiopulmonary Resuscitation in PICUs. AB - OBJECTIVES: To determine the incidence of cardiopulmonary resuscitation in PICUs and subsequent outcomes. DESIGN, SETTING, AND PATIENTS: Multicenter prospective observational study of children younger than 18 years old randomly selected and intensively followed from PICU admission to hospital discharge in the Collaborative Pediatric Critical Care Research Network December 2011 to April 2013. RESULTS: Among 10,078 children enrolled, 139 (1.4%) received cardiopulmonary resuscitation for more than or equal to 1 minute and/or defibrillation. Of these children, 78% attained return of circulation, 45% survived to hospital discharge, and 89% of survivors had favorable neurologic outcomes. The relative incidence of cardiopulmonary resuscitation events was higher for cardiac patients compared with non-cardiac patients (3.4% vs 0.8%, p <0.001), but survival rate to hospital discharge with favorable neurologic outcome was not statistically different (41% vs 39%, respectively). Shorter duration of cardiopulmonary resuscitation was associated with higher survival rates: 66% (29/44) survived to hospital discharge after 1-3 minutes of cardiopulmonary resuscitation versus 28% (9/32) after more than 30 minutes (p < 0.001). Among survivors, 90% (26/29) had a favorable neurologic outcome after 1-3 minutes versus 89% (8/9) after more than 30 minutes of cardiopulmonary resuscitation. CONCLUSIONS: These data establish that contemporary PICU cardiopulmonary resuscitation, including long durations of cardiopulmonary resuscitation, results in high rates of survival-to-hospital discharge (45%) and favorable neurologic outcomes among survivors (89%). Rates of survival with favorable neurologic outcomes were similar among cardiac and noncardiac patients. The rigorous prospective, observational study design avoided the limitations of missing data and potential selection biases inherent in registry and administrative data. PMID- 26646468 TI - Hydrothermal Synthesis of FeS2 as a High-Efficiency Fenton Reagent to Degrade Alachlor via Superoxide-Mediated Fe(II)/Fe(III) Cycle. AB - In this study, we demonstrate that hydrothermally synthesized FeS2 (syn-FeS2) is highly efficient at catalyzing the H2O2 decomposition for alachlor degradation at a wide range of initial pH (3.2-9.2). The alachlor degradation rate of syn-FeS2 heterogeneous Fenton system was almost 55 times that of its commercial pyrite (com-FeS2) counterpart at an initial pH of 6.2. Experimental results revealed that the alachlor oxidation enhancement in the syn-FeS2 Fenton system was attributed to the molecular oxygen activation induced by more surface-bound ferrous ions on syn-FeS2. The molecular oxygen activation process could generate superoxide anions to accelerate the Fe(II)/Fe(III) cycle on the syn-FeS2 surface, which favored the H2O2 decomposition to generate more hydroxyl radicals for the alachlor oxidation. It was found that the hydroxyl radicals generation rate constant of syn-FeS2 Fenton system was 71 times that of its com-FeS2 counterpart, and even 1-3 orders of magnitude larger than those of commonly used Fe-bearing heterogeneous catalysts. We detected the alachlor degradation intermediates with gas chromatography-mass spectrometry to propose tentatively a possible alachlor degradation pathway. These interesting findings could provide some new insights on the molecular oxygen activation induced by FeS2 minerals and the subsequent heterogeneous Fenton degradation of organic pollutants in the environment. PMID- 26646469 TI - Use of vaginal estrogen in Danish women: a nationwide cross-sectional study. AB - INTRODUCTION: We know little about the use of vaginal estrogen in perimenopausal and postmenopausal women. We aimed to assess the prevalence of vaginal estrogen use in Denmark. MATERIAL AND METHODS: The study was designed as a nationwide cross-sectional study of all Danish women aged 40-79 years, living in Denmark during the period 2007-2013. The Danish Prescription Register delivered data permitting us to assess the prevalence, age and regional geographical belonging of women purchasing prescribed vaginal estradiol. The number of women using over the-counter vaginal estriol products was estimated from sale statistics from the same register. RESULTS: In 2013, 10.2% of all Danish women between 40 and 79 years of age used vaginal estradiol. The prevalence of women using this type of vaginal estrogen increased from 8.5% in year 2007 to 10.2% in 2013. The use peaked at 16.5% in women aged 60-74 years. The vaginal tablet was purchased more than the vaginal ring. We found no relevant difference in use between the five regions of Denmark. Taking the sale of vaginal estriol into account, the prevalence of vaginal estrogen use in 2013 could be estimated to a total of 12.1%. CONCLUSIONS: Comparing our result to the prevalence of urogenital atrophy related symptoms reported in the literature, our study suggests an under diagnosis and under-treatment of this condition. Teaching women and primary-care physicians about symptomatic urogenital atrophy and its treatment options may increase the quality of life for many women. PMID- 26646470 TI - The Prevalence of TMD in Polish Young Adults. AB - PURPOSE: The prevalence of temporomandibular disorders (TMD) in the general Polish population has not yet been thoroughly investigated. The aim of this study was to determine how frequently Polish young adults demonstrated the signs and symptoms of TMD, and how often they were aware of these. MATERIALS AND METHODS: The study involved 260 volunteers of approximately 18 years of age (and with an F:M ratio of 2.8), who had completed the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) questionnaire in its internationally accepted Polish version. The volunteers were students from three randomly selected high schools in Krakow, Poland. Following the clinical examinations, all participants received none or one or more of the RDC/TMD axis I diagnoses on one or both sides: muscle disorders (group I), disk displacements (group II), arthralgia, osteoarthritis, and osteoarthrosis (group III). Classification on RDC/TMD axis II involved pain-related impairment (Graded Chronic Pain Severity, from 0: no TMD pain in the prior 6 months, to IV: high disability-severely limiting), depression, and somatization levels (normal, moderate, severe). RESULTS: On the RDC/TMD axis I, 69 (26.5%) of the participants received one or more of the possible diagnoses. Awareness of TMD was present in 20 (7.7%) people from that group, in the form of self-complaints. The difference between females and males was statistically significant (p = 0.0013). On the RDC/TMD axis II assessment, a diagnosis of pain, depression, or somatization was given in 38 (14.6%) cases from that group. CONCLUSION: Muscle disorders were most frequently diagnosed in the group of Polish young adults, and the prevalence of the disease did not differ across similar groups of young people. PMID- 26646471 TI - The DiViSA's Predictive Validity by Age: An Objective Online Test of Attention. AB - The purpose of this study was to analyze the DiViSA's predictive validity in school-age children. To do so, two groups of school-age children were compared: one with low school achievement (N = 1,174), and one with typical development (N = 1,426). The obtained results show that: (1) in all grades, children with poor school performance exhibited lower levels of attention and task organization, greater hastiness, and made more commission errors; (2) the combination of variables that best differentiated between groups was not the same in all grades; (3) level of organization improved with age in the low-school-achievement group, and did not in the typical-development group; (4) the data regarding sensitivity (81% to 93%) and specificity (79% to 90%), for the first time computed for each grade separately, support the test's predictive validity in the grades we evaluated. The discussion focuses on the DiViSA test's usefulness in diagnosing attention problems. It is the first computerized test to include separate scores for: (a) how children complete the task (organization) and (2) the source of their errors (distraction or hastiness). PMID- 26646472 TI - Geriatric Case Managers' Perspectives on Suicide Among Community-Dwelling Older Adults. AB - It has been suggested that clinical screening for suicide, along with firearm assessment and safety counseling, are important in service provision to older adults. It is unclear, however, how geriatric case managers respond to these issues. This study surveyed geriatric case managers (n=161) from Area Agencies on Aging in Ohio on their knowledge, attitudes, and behaviors related to suicide, firearm assessment, and safety counseling. Results indicated that the majority of respondents (70%) agree their clients are at risk for suicide. However, few (30%) in this study reported that they assess for firearms and less than half (48%) discuss firearms with their clients/family members when specifically assessing for suicide. Analyses identified barriers that contribute to the decreased likelihood that routine firearm assessment and safety counseling would occur, such as lack of training and time. Implications include the need for training with geriatric case managers that addresses barriers to suicide, firearm assessment and safety counseling as a means to decrease these population risks. PMID- 26646473 TI - Clinically occult primary fallopian tube carcinoma presenting as a malignant pleural effusion. AB - We report the first known case of malignant pleural effusion (MPE) as the sole presenting feature of clinically occult primary fallopian tube carcinoma (PFTC). A 57-year-old healthy woman was admitted with dyspnea. Evaluation demonstrated a right pleural effusion, fluid of which was malignant. The immunohistochemical profile, including negative calretinin, favored metastatic adenocarcinoma over mesothelioma but could not identify the primary tumour site. Pleural biopsy was not pursued as it would not have helped localize the primary. Chest, abdomen and pelvic computed tomography (CT) demonstrated only borderline lymphadenopathy in the left para-aortic lymph node chain that was hypermetabolic on positron emission tomography. Ultrasound and CT showed normal adnexal anatomy. These findings, coupled with an elevated serum CA-125, prompted empiric neoadjuvant chemotherapy targeting epithelial ovarian carcinoma (EOC) followed by surgery, which revealed a tiny left PFTC with negative peritoneal washings. Sampled left para-aortic lymph nodes were positive. The pleural effusion resolved after chemotherapy. Malignant pleural disease without peritoneal involvement is more characteristic of PFTC than of EOC, in which MPE is common but almost always accompanies peritoneal carcinomatosis. The extensive lymphatic supply of the fallopian tube promotes distant metastasis of small, seemingly localized tumours. This case is a reminder that the clinician should not be dissuaded from considering carcinoma of Mullerian origin, especially PFTC, as the cause of a MPE even in the face of normal gynecologic imaging. Appropriately broad immunohistochemical staining and careful attention to even minimal lymphadenopathy can be invaluable in pinpointing the primary tumour site in such patients. PMID- 26646474 TI - Genome-wide metabolic model to improve understanding of CD4(+) T cell metabolism, immunometabolism and application in drug design. AB - CD4(+) T cells play a critical role in adaptive immunity and have been well studied in past decades. However, the systematic metabolism features are less clear. Here, we reconstructed the genome-wide metabolic network of naive CD4(+) T cells, CD4T1670, by integrating transcriptome and metabolism data. We performed simulations for three critical metabolic subsystems (carbohydrate metabolism, fatty acid metabolism and glutaminolysis). The results were consistent with most experimental observations. Furthermore, we found that depletion of either glucose or glutamine did not significantly affect ATP production and biomass, but dramatically unbalanced the metabolic network and increased the release of some inflammation or anti-inflammation related factors, such as lysophosphatidylcholine, leukotriene and hyaluronan. Genome-wide single gene knockout analysis showed that acetyl-CoA carboxylase 1 (ACC1) was essential for T cell activation. We further investigated the role of immunometabolic genes in metabolic network stability, and found that over 25% of them were essential. The results also showed that although PTEN is a well-studied proliferation inhibitor, it was essential for maintaining the stability of CD4 metabolic networks. Finally, we applied CD4T1670 to evaluate the side-effects of certain drugs in preclinical experiments. These results suggested that CD4T1670 would be useful in understanding CD4(+) T cells and drug design systematically. PMID- 26646475 TI - Time Trends and Policy Gaps: The Case of Alcohol Misuse Among Adolescents in Lebanon. AB - BACKGROUND: Monitoring studies are crucial for informing and reforming local policies. OBJECTIVES: Using the Lebanon 2005 and 2011 Global School-based Student Health Surveys (GSHS), alcohol time trends were described, policy gaps were identified, and harm reduction policy recommendations were made. METHODS: In 2005 and 2011, 100 (n = 5109 students) and 44 (n = 2784 students) middle schools were surveyed, respectively. Self-reported cross-sectional data on alcohol use among 7 9th graders in private and public schools was collected including 30-day prevalence, lifetime drunkenness, alcohol-related problems, and sources of alcohol. RESULTS: In 2011, the majority (87%) had alcohol before turning 14. Between 2005 and 2011, past 30-day alcohol use had increased by 40% and lifetime drunkenness by 50% in the total sample (122% among females with a narrowing in the gender gap). Drinking was regular for more than a third of the past 30-day drinkers (drank two or more drinks on the days they drank). Male adolescents were more likely to obtain alcohol from "stores" or "through their friends" whereas females' main source was their "family." One in twenty reported experiencing alcohol-related problems (e.g., getting into fights with family/friends and skipping school). Conclusion/Importance: Evidence-informed policy implications include enforcing a minimum legal drinking age, regulating alcohol advertising, and marketing particularly those targeting youth and women, and ensuring the availability of youth-friendly services. Public messages to increase awareness among all stakeholders including youth, their parents, and larger community are also needed. PMID- 26646476 TI - Recent developments in ion channel pharmacology. PMID- 26646477 TI - Voltage gated sodium channels as drug discovery targets. AB - Voltage-gated sodium (NaV) channels are a family of transmembrane ion channel proteins. They function by forming a gated, water-filled pore to help establish and control cell membrane potential via control of the flow of ions between the intracellular and the extracellular environments. Blockade of NaVs has been successfully accomplished in the clinic to enable control of pathological firing patterns that occur in a diverse range of conditions such as chronic pain, epilepsy, and cardiac arrhythmias. First generation sodium channel modulator drugs, despite low inherent subtype selectivity, preferentially act on over excited cells which reduces undesirable side effects in the clinic. However, the limited therapeutic indices observed with the first generation demanded a new generation of sodium channel inhibitors. The structure, function and the state of the art in sodium channel modulator drug discovery are discussed in this chapter. PMID- 26646478 TI - Erratum. PMID- 26646479 TI - Determination of oxygen, nitrogen, and sulfur-containing polycyclic aromatic hydrocarbons (PAHs) in urban stream sediments. AB - Recent studies indicate that PAH transformation products such as ketone or quinone-substituted PAHs (OPAHs) are potent aryl hydrocarbon receptor (AhR) activators that elicit toxicological effects independent of those observed for PAHs. Here, we measured eight OPAHs, two sulfur-containing (SPAH), one oxygen containing (DBF), and one nitrogen-containing (CARB) heterocyclic PAHs (i.e. SigmaONS-PAHs = OPAH8 + SPAH + DBF + CARB) in 35 stream sediments collected from a small (~1303 km(2)) urban watershed located in south-central Pennsylvania, USA. Combined SigmaONS-PAH concentrations ranged from 59 to 1897 MUg kg(-1) (mean = 568 MUg kg(-1); median = 425 MUg kg(-1)) and were 2.4 times higher in urban versus rural areas, suggesting that activities taking place on urban land serve as a source of SigmaONS-PAHs to sediments. To evaluate urban land use metrics that might explain these data, Spearman rank correlation analyses was used to evaluate the degree of association between SigmaONS-PAH concentrations and urban land-use/land-cover metrics along an urban-rural transect at two spatial scales (500-m and 1000-m upstream). Combined SigmaONS-PAH concentrations showed highly significant (p < 0.0001) correlations with SigmaPAH19, residential and commercial/industrial land use (RESCI), and combined state and local road miles (MILES), suggesting that SigmaONS-PAHs originate from similar sources as PAHs. To evaluate OPAH sources, a subset of SigmaONS-PAHs for which reference assemblages exist, an average OPAH fractional assemblage for urban sediments was derived using agglomerative hierarchal cluster (AHC) analysis, and compared to published OPAH source profiles. Urban sediments from the Condoguinet Creek (n = 21) showed highly significant correlations with urban particulate matter (X(2) = 0.05, r = 0.91, p = 0.0047), suggesting that urban particulate matter is an important OPAH source to sediments in this watershed. Results suggest the inclusion of SigmaONS PAH measurements adds value to traditional PAH analyses, and may help elucidate and refine pollutant source identification in urban watersheds. PMID- 26646481 TI - In-Hospital Mortality after Surgical Lung Biopsy for Interstitial Lung Disease in the United States. 2000 to 2011. AB - RATIONALE: Surgical lung biopsy can help to determine a specific diagnosis in interstitial lung disease but has associated risks. Most currently available mortality data are derived from case series and may not be generalizable to broader populations. OBJECTIVES: To assess in-hospital mortality after surgical lung biopsy for interstitial lung disease in a national secondary care dataset from the United States. METHODS: Data were obtained from the 2000-2011 Nationwide Inpatient Sample. Cases were identified using International Classification of Diseases codes for interstitial lung disease and surgical lung biopsies. Lung resections and cases of lung cancer were excluded. Weighted data were used to estimate numbers of biopsies nationwide and in-hospital mortality, and multivariable logistic regression was used to adjust for sex, age, geographic region, comorbidity, type of operation, and provisional diagnosis. MEASUREMENTS AND MAIN RESULTS: We estimated there to be around 12,000 surgical lung biopsies performed annually for interstitial lung disease in the United States, two-thirds of which were performed electively. In-hospital mortality was 1.7% for elective procedures but significantly higher for nonelective procedures (16.0%). Male sex, increasing age, increasing comorbidity, open surgery, and a provisional diagnosis of idiopathic pulmonary fibrosis or connective tissue disease-related interstitial lung disease were risk factors for increased mortality. CONCLUSIONS: In-hospital mortality after elective surgical lung biopsy for interstitial lung disease is just under 2% but significantly higher for nonelective procedures. Identified risk factors for death should be taken into account when counseling patients on whether to pursue a histologic diagnosis. PMID- 26646482 TI - Aging: toward avoiding the inevitable. PMID- 26646480 TI - Decreased expression of 14-3-3 in Paracoccidioides brasiliensis confirms its involvement in fungal pathogenesis. AB - The interaction between the fungal pathogen Paracoccidioides brasiliensis and host cells is usually mediated by specific binding events between adhesins on the fungal surface and receptors on the host extracellular matrix or cell surface. One molecule implicated in the P. brasiliensis-host interaction is the 14-3-3 protein. The 14-3-3 protein belongs to a family of conserved regulatory molecules that are expressed in all eukaryotic cells and are involved in diverse cellular functions. Here, we investigated the relevance of the 14-3-3 protein to the virulence of P. brasiliensis. Using antisense RNA technology and Agrobacterium tumefaciens-mediated transformation, we generated a 14-3-3-silenced strain (expression reduced by ~55%). This strain allowed us to investigate the interaction between 14-3-3 and the host and to correlate the functions of P. brasiliensis 14-3-3 with cellular features, such as morphological characteristics and virulence, that are important for pathogenesis. PMID- 26646483 TI - Canine clues: Dog genomes explored in effort to bring human cancer to heel. PMID- 26646486 TI - The Yearbook. PMID- 26646485 TI - Bias against genetic case reports might compromise medicine. PMID- 26646487 TI - 2015 in Review. PMID- 26646488 TI - Drugs that made headlines in 2015. PMID- 26646489 TI - Notable advances 2015. PMID- 26646490 TI - Considerations regarding the micromagnetic resonance relaxometry technique for rapid label-free malaria diagnosis. PMID- 26646491 TI - Reply to "Considerations regarding the micromagnetic resonance relaxometry technique for rapid label-free malaria diagnosis". PMID- 26646492 TI - Debugging the host browns the fat. PMID- 26646493 TI - A new role for dystrophin in muscle stem cells. PMID- 26646494 TI - PARP inhibitors: a treatment option for AML? PMID- 26646495 TI - Translational strategies in aging and age-related disease. AB - Aging is a risk factor for several of the world's most prevalent diseases, including neurodegenerative disorders, cancer, cardiovascular disease and metabolic disease. Although our understanding of the molecular pathways that contribute to the aging process and age-related disease is progressing through the use of model organisms, how to apply this knowledge in the clinic is less clear. In September, Nature Medicine, in collaboration with the Volkswagen Foundation, hosted a conference at the beautiful Herrenhausen Palace in Hannover, Germany with the goal of broadening our understanding of the aging process and its meaning as a 'risk factor' in disease. Here, several of the speakers at that conference answer questions posed by Nature Medicine. PMID- 26646496 TI - Can aging be 'drugged'? AB - The engines that drive the complex process of aging are being identified by model organism research, thereby providing potential targets and rationale for drug studies. Several studies of small molecules have already been completed in animal models with the hope of finding an elixir for aging, with a few compounds showing early promise. What lessons can we learn from drugs currently being tested, and which pitfalls can we avoid in our search for a therapeutic for aging? Finally, we must also ask whether an elixir for aging would be applicable to everyone, or whether we age differently, thus potentially shortening lifespan in some individuals. PMID- 26646497 TI - Proteostasis and aging. AB - Accumulation of intracellular damage is an almost universal hallmark of aging. An improved understanding of the systems that contribute to cellular protein quality control has shed light on the reasons for the increased vulnerability of the proteome to stress in aging cells. Maintenance of protein homeostasis, or proteostasis, is attained through precisely coordinated systems that rapidly correct unwanted proteomic changes. Here we focus on recent developments that highlight the multidimensional nature of the proteostasis networks, which allow for coordinated protein homeostasis intracellularly, in between cells and even across organs, as well as on how they affect common age-associated diseases when they malfunction in aging. PMID- 26646498 TI - The metabolic regulation of aging. AB - Here we review the environmental and genetic manipulations that link cellular and organismal metabolism to aging. In particular, we explore how nutrients are sensed and how various intracellular energy nodes seem to coordinate distinct metabolic alterations linked to extended longevity. In addition, the role of mitochondria as both a metabolic and signaling organelle is discussed. Finally, we review a host of new targeted pharmacological approaches that attempt to exploit the connection between aging and metabolism to treat a wide range of age related diseases. Together, these insights are beginning to reveal answers to century-old mysteries and are providing a future road map for the rational extension of lifespan. PMID- 26646500 TI - Inhibitors of protein methyltransferases as chemical tools. AB - Protein methyltransferases (PMT)s play essential roles in many biological processes through methylation of histones and diverse nonhistone substrates. Dysregulation of these enzymes has been implicated in many diseases including cancers. While PMT-associated biology can be probed via genetic perturbation, this approach targets full-length PMTs rather than their methyltransferase activities and often lacks temporal, spatial and dose controls (timing, location and amount of dosed compounds). By contrast, small-molecule inhibitors of PMTs can be designed to specifically target the methyltransferase domains in a temporal, spatial and dose-dependent manner. This utility has motivated the development of hundreds of PMT inhibitors, but meanwhile can make it challenging to select the most suitable PMT inhibitors to interrogate PMT-associated biology. This perspective aims to provide timely guidance to evaluate these PMT inhibitors in their relevant biological contexts. PMID- 26646499 TI - Cellular senescence in aging and age-related disease: from mechanisms to therapy. AB - Cellular senescence, a process that imposes permanent proliferative arrest on cells in response to various stressors, has emerged as a potentially important contributor to aging and age-related disease, and it is an attractive target for therapeutic exploitation. A wealth of information about senescence in cultured cells has been acquired over the past half century; however, senescence in living organisms is poorly understood, largely because of technical limitations relating to the identification and characterization of senescent cells in tissues and organs. Furthermore, newly recognized beneficial signaling functions of senescence suggest that indiscriminately targeting senescent cells or modulating their secretome for anti-aging therapy may have negative consequences. Here we discuss current progress and challenges in understanding the stressors that induce senescence in vivo, the cell types that are prone to senesce, and the autocrine and paracrine properties of senescent cells in the contexts of aging and age-related diseases as well as disease therapy. PMID- 26646501 TI - Ultrastructure of human oocytes after in vitro maturation. AB - STUDY HYPOTHESIS: How does the ultrastructure of human oocytes matured in vitro compare with oocytes collected from women after full hormonal stimulation? STUDY FINDING: The ultrastructure of human oocytes matured in vitro is largely, but not entirely, similar to those matured in vivo. WHAT IS KNOWN ALREADY: Embryos derived from in vitro-matured oocytes often have limited developmental potential, possibly as an effect of inappropriate in vitro maturation (IVM) conditions. Transmission electron microscopy (TEM) is a valuable research tool to compare in vivo and in vitro matured oocytes. However, previous studies on the ultrastructure of human IVM oocytes were done with inadequate material or inappropriate IVM conditions, and have limited significance. STUDY DESIGN, SAMPLES/MATERIALS, METHODS: Immature cumulus cell-enclosed oocytes, retrieved from mid-sized antral follicles of women requiring IVM treatment, were matured in vitro for 30 h. No leftover germinal vesicle-stage oocytes collected from fully stimulated cycles were used. Control in vivo matured oocytes were obtained from age-matched women undergoing full ovarian stimulation. In vitro and in vivo matured oocytes were analysed by TEM and compared according to previously established morphometric criteria of oocyte quality. MAIN RESULTS AND THE ROLE OF CHANCE: All oocytes had normal ooplasm showing uniform distribution of organelles. Mitochondrial morphology appeared similar between the maturation conditions. Cortical granules were found typically stratified in a single, mostly continuous row just beneath the ooplasm in all oocytes. Microvilli were well preserved after IVM. Vacuoles were only occasionally found in all oocytes and, if present, they were frequently associated with lysosomes. Mitochondria-smooth endoplasmic reticulum (M-SER) aggregates and mitochondria-vesicles (MV) complexes were commonly found in in vivo matured oocytes. However, large MV complexes partially replaced M-SER aggregates in IVM oocytes. LIMITATIONS, REASONS FOR CAUTION: As a note of caution it should be noticed that, being laborious and technically demanding, TEM cannot be applied to a large number of samples in a single investigation. Therefore, our data require further independent confirmation. WIDER IMPLICATIONS OF THE FINDINGS: Our data suggests the notion that TEM remains a valuable research tool that can also offer quantitative data if associated with morphometric criteria of evaluation. Therefore, it can be adopted to test pre-clinically the performance of novel in vitro systems that are demanded to make oocytes IVM more successful in the human. LARGE SCALE DATA: Not applicable. STUDY FUNDING AND COMPETING INTERESTS: This study was independently funded by Biogenesi Reproductive Medicine Centre, Monza, Italy. All authors declare that their participation in the study did not involve factual or potential conflicts of interests. PMID- 26646503 TI - Nickel(II) complexes of N-CH2CF3 cyclam derivatives as contrast agents for (19)F magnetic resonance imaging. AB - Kinetically inert Ni(ii) complexes of N(1),N(8)-bis(2,2,2-trifluoroethyl)cyclams with hydrogen atoms or phosphonic acid groups in the N(4),N(11)-positions show significant (19)F NMR relaxation rate enhancement useful for 19-fluorine MRI imaging. PMID- 26646502 TI - Placental growth factor deficiency is associated with impaired cerebral vascular development in mice. AB - STUDY HYPOTHESIS: Placental growth factor (PGF) is expressed in the developing mouse brain and contributes to vascularization and vessel patterning. STUDY FINDING: PGF is dynamically expressed in fetal mouse brain, particularly forebrain, and is essential for normal cerebrovascular development. WHAT IS KNOWN ALREADY: PGF rises in maternal plasma over normal human and mouse pregnancy but is low in many women with the acute onset hypertensive syndrome, pre-eclampsia (PE). Little is known about the expression of PGF in the fetus during PE. Pgf ( /-) mice appear normal but recently cerebral vascular defects were documented in adult Pgf (-/-) mice. STUDY DESIGN, SAMPLES/MATERIALS, METHODS: Here, temporal spatial expression of PGF is mapped in normal fetal mouse brains and cerebral vasculature development is compared between normal and congenic Pgf (-/-) fetuses to assess the actions of PGF during cerebrovascular development. Pgf/PGF, Vegfa/VEGF, Vegf receptor (Vegfr)1 and Vegfr2 expression were examined in the brains of embryonic day (E)12.5, 14.5, 16.5 and 18.5 C57BL/6 (B6) mice using quantitative PCR and immunohistochemistry. The cerebral vasculature was compared between Pgf (-/-) and B6 embryonic and adult brains using whole mount techniques. Vulnerability to cerebral ischemia was investigated using a left common carotid ligation assay. MAIN RESULTS AND THE ROLE OF CHANCE: Pgf/PGF and Vegfr1 are highly expressed in E12.5-14.5 forebrain relative to VEGF and Vegfr2. Vegfa/VEGF is relatively more abundant in hindbrain (HB). PGF and VEGF expression were similar in midbrain. Delayed HB vascularization was seen at E10.5 and 11.5 in Pgf (-/-) brains. At E14.5, Pgf (-/-) circle of Willis showed unilateral hypoplasia and fewer collateral vessels, defects that persisted post-natally. Functionally, adult Pgf (-/-) mice experienced cerebral ischemia after left common carotid arterial occlusion while B6 mice did not. LIMITATIONS, REASONS FOR CAUTION: Since Pgf (-/-) mice were used, consequences of complete absence of maternal and fetal PGF were defined. Therefore, the effects of maternal versus fetal PGF deficiency on cerebrovascular development cannot be separated. However, as PGF was strongly expressed in the developing brain at all timepoints, we suggest that local PGF has a more important role than distant maternal or placental sources. Full PGF loss is not expected in PE pregnancies, predicting that the effects of PGF deficiency identified in this model will be more severe than any effects in PE-offspring. WIDER IMPLICATIONS OF THE FINDINGS: These studies provoke the question of whether PGF expression is decreased and cerebral vascular maldevelopment occurs in fetuses who experience a preeclamptic gestation. These individuals have already been reported to have elevated risk for stroke and cognitive impairments. LARGE SCALE DATA: N/A. STUDY FUNDING AND COMPETING INTERESTS: This work was supported by awards from the Natural Sciences and Engineering Research Council, the Canada Research Chairs Program and the Canadian Foundation for Innovation to B.A.C. and by training awards from the Universidade Federal de Pernambuco and Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq), Brazil to R.L.L.; Queen's University to V.R.K. and the Canadian Institutes of Health Research to M.T.R. The work of P.C. is supported by the Belgian Science Policy BELSPO-IUAP7/03, Structural funding by the Flemish Government-Methusalem funding, and the Flemish Science Fund-FWO grants. There were no competing interests. PMID- 26646504 TI - Intracranial tumour haemorrhage following intravenous thrombolysis. AB - Intravenous administration of thrombolytic agents is considered to be contraindicated in patients with intracranial neoplasms. However, only a single case of thrombolysis-related intracranial tumour haemorrhage has been reported to our knowledge and several studies have suggested that systemic thrombolysis can be safely carried out in these patients. Here we report a patient who developed haemorrhage into a previously unknown intracranial tumour following intravenous thrombolysis for acute myocardial ST-elevation infarction. Identification of abnormal tissue during surgical haematoma evacuation initiated histopathological examination which revealed meningioma World Health Organization Grade I. Intracranial tumours may represent the causative pathology in cases of thrombolysis-related intracranial haemorrhage and this should be considered in the treatment of these patients. PMID- 26646505 TI - Simulations reveal the role of composition into the atomic-level flexibility of bioactive glass cements. AB - Bioactive glass ionomer cements (GICs), the reaction product of a fluoro-alumino silicate glass and polyacrylic acid, have been in effective use in dentistry for over 40 years and more recently in orthopaedics and medical implantation. Their desirable properties have affirmed GIC's place in the medical materials community, yet are limited to non-load bearing applications due to the brittle nature of the hardened composite cement, thought to arise from the glass component and the interfaces it forms. Towards helping resolve the fundamental bases of the mechanical shortcomings of GICs, we report the 1st ever computational models of a GIC-relevant component. Ab initio molecular dynamics simulations were employed to generate and characterise three fluoro-alumino silicate glasses of differing compositions with focus on resolving the atomic scale structural and dynamic contributions of aluminium, phosphorous and fluorine. Analyses of the glasses revealed rising F-content leading to the expansion of the glass network, compression of Al-F bonding, angular constraint at Al-pivots, localisation of alumino-phosphates and increased fluorine diffusion. Together, these changes to the structure, speciation and dynamics with raised fluorine content impart an overall rigidifying effect on the glass network, and suggest a predisposition to atomic-level inflexibility, which could manifest in the ionomer cements they form. PMID- 26646509 TI - Myocardia ischemia associated with a myocardial bridge with no significant atherosclerotic stenosis. AB - BACKGROUND: Myocardial bridge refers to the myocardial tissue with which the coronary artery is partly covered. Though it has long been regarded to be benign, patients with myocardial bridges may present with myocardial ischemia, acute coronary syndromes, coronary spasm, sudden cardiac arrest or even sudden death. CASE PRESENTATION: In present study, we reviewed four cases with myocardial bridge and no stenosis of coronary artery, which included acute coronary syndrome and sudden cardiac arrest. CONCLUSIONS: These cases indicated that cardiac events in patients with myocardial bridge may be associated with coronary spasm, myocardial supply/demand mismatch or cardiac arrest. PMID- 26646510 TI - Walking and cycling for commuting, leisure and errands: relations with individual characteristics and leisure-time physical activity in a cross-sectional survey (the ACTI-Cites project). AB - BACKGROUND: Increasing active transport behavior (walking, cycling) throughout the life-course is a key element of physical activity promotion for health. There is, however, a need to better understand the correlates of specific domains of walking and cycling to identify more precisely at-risk populations for public health interventions. In addition, current knowledge of interactions between domains of walking and cycling remains limited. METHODS: We assessed past-month self-reported time spent walking and cycling in three specific domains (commuting, leisure and errands) in 39,295 French adult participants (76.5% women) of the on-going NutriNet Sante web-cohort. Multivariate logistic regression models were used to investigate the associations with socio demographic and physical activity correlates. RESULTS: Having a transit pass was strongly positively associated with walking for commuting and for errands but was unrelated to walking for leisure or to all domains of cycling. Having a parking space at work was strongly negatively associated with walking for commuting and cycling for commuting. BMI was negatively associated with both walking for leisure and errands, and with the three domains of cycling. Leisure-time physical activity was negatively associated with walking for commuting but was positively associated with the two other domains of walking and with cycling (three domains). Walking for commuting was positively associated with the other domains of walking; cycling for commuting was also positively associated with the other domains of cycling. Walking for commuting was not associated with cycling for commuting. CONCLUSIONS: In adults walking and cycling socio-demographic and physical activity correlates differ by domain (commuting, leisure and errands). Better knowledge of relationships between domains should help to develop interventions focusing not only the right population, but also the right behavior. PMID- 26646512 TI - Requirement of an Early Activation of BDNF/c-Fos Cascade in the Retrosplenial Cortex for the Persistence of a Long-Lasting Aversive Memory. AB - During the past few years, there has been growing interest in the role of the retrosplenial cortex (RSC) in memory processing. However, little is known about the molecular changes that take place in this brain region during memory formation. In the present work, we studied the early post-training participation of RSC in the formation of a long-lasting memory in rats. We found an increase in c-Fos levels in the anterior part of the RSC (aRSC) after inhibitory avoidance (IA) training. Interestingly, this increase was associated with memory durability, since blocking c-Fos expression using specific antisense oligonucleotides (ASO) impaired long-lasting retention 7 days after training without affecting memory expression 2 days after training. In addition, we showed that BDNF is one of the upstream signals for c-Fos expression required for memory persistence, since blocking BDNF synthesis prevents IA training-induced increase in c-Fos levels in aRSC and affects memory persistence. In addition, we found that injection of BDNF into aRSC around training was sufficient to establish a persistent memory and that this effect was prevented by c-fos ASO infusion into the same structure. These findings reveal an early post-training involvement of aRSC in the processing of a long-lasting aversive memory. PMID- 26646511 TI - Inhibition of Cortical Activity and Apoptosis Caused by Ethanol in Neonatal Rats In Vivo. AB - Alcohol consumption during pregnancy causes fetal alcohol spectrum disorder, which includes neuroapoptosis and neurobehavioral deficits. The neuroapoptotic effects of alcohol have been hypothesized to involve suppression of brain activity. However, in vitro studies suggest that ethanol acts as a potent stimulant of cortical activity. We explored the effects of alcohol (1-6 g/kg) on electrical activity in the rat somatosensory cortex in vivo at postnatal days P1 23 and compared them with its apoptotic actions. At P4-7, when the peak of alcohol-induced apoptosis was observed, alcohol strongly suppressed spontaneous gamma and spindle-bursts and almost completely silenced neurons in a dose dependent manner. The dose-dependence of suppression of neuronal activity strongly correlated with the alcohol-induced neuroapoptosis. Alcohol also profoundly inhibited sensory-evoked bursts and suppressed motor activity, a physiological trigger of cortical activity bursts in newborns. The suppressive effects of ethanol on neuronal activity waned during the second and third postnatal weeks, when instead of silencing the cortex, alcohol evoked delta-wave electrographic activity. Thus, the effects of alcohol on brain activity are strongly age-dependent, and during the first postnatal week alcohol profoundly inhibits brain activity. Our findings suggest that the adverse effects of alcohol in the developing brain involve suppression of neuronal activity. PMID- 26646513 TI - Soccer Injuries in Players Aged 7 to 12 Years: A Descriptive Epidemiological Study Over 2 Seasons. AB - BACKGROUND: As part of a risk-management approach, sound epidemiological data are needed to develop prevention programs. A recent review on soccer injuries of players younger than 19 years concluded that prospective data concerning children are lacking. PURPOSE: To analyze the incidence and characteristics of soccer injuries in children aged 7 to 12 years. STUDY DESIGN: Descriptive epidemiological study. METHODS: The present survey was a prospective descriptive epidemiological study on soccer injuries over 2 seasons in the Czech Republic and Switzerland. Exposure of players during training and match play (in hours) and injury data were reported by coaches via an Internet-based registration system. Location, type, and severity of injuries were classified according to an established consensus. Injury characteristics are presented as absolute numbers and injury incidence rates (injuries per 1000 hours of soccer exposure). An injury was defined as any physical complaint sustained during a scheduled training session or match play resulting in at least 1 of the following: (1) inability to complete the current match or training session, (2) absence from subsequent training sessions or matches, and (3) injury requiring medical attention. RESULTS: In total, 6038 player-seasons with 395,295 hours of soccer exposure were recorded. The mean (+/-SD) age of the players was 9.5 +/- 2.0 years, and 3.9% of the participants were girls. A total of 417 injuries were reported. Most (76.3%) injuries were located in the lower limbs, with 15.6% located in the upper limbs. Joint and ligament injuries comprised 30.5%, contusions 22.5%, muscle and tendon injuries 18.5%, and fractures and bone injuries 15.4% of all injuries; 23.7% of injuries led to more than 28 days of absence from sport participation. The overall injury incidence was 0.61 (95% CI, 0.53-0.69) injuries per 1000 hours of soccer exposure during training sessions and 4.57 (95% CI, 4.00-5.23) during match play. Injury incidence rates increased with increasing age. CONCLUSION: The observed injury incidences were lower compared with studies in youth players. Children showed a relatively high proportion of fractures and bone stress and of injuries to the upper limbs. CLINICAL RELEVANCE: The study provides an evidence base for injury incidence rates and injury characteristics in children's soccer. These data are the basis to develop an age-specific injury-prevention program. PMID- 26646514 TI - Hip Muscle Strength Predicts Noncontact Anterior Cruciate Ligament Injury in Male and Female Athletes: A Prospective Study. AB - BACKGROUND: Prospective studies have reported that abnormal movement patterns at the trunk, hip, and knee are associated with noncontact anterior cruciate ligament (ACL) injuries. Impaired hip strength may underlie these abnormal movement patterns, suggesting that diminished hip strength may increase the risk of noncontact ACL injury. PURPOSE: To determine whether baseline hip strength predicts future noncontact ACL injury in athletes. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: Before the start of the competitive season, isometric hip strength (external rotation and abduction) was measured bilaterally by use of a handheld dynamometer in 501 competitive athletes (138 female and 363 male athletes) participating in various sports. During the sport season, ACL injury status was recorded, and injured athletes were further classified based on the mechanism of injury (noncontact vs contact). After the season, logistic regression was used to determine whether baseline hip strength predicted future noncontact ACL injury. Receiver operating characteristic (ROC) curves were constructed independently for each strength measure to determine the clinical cutoff value between a high-risk and low-risk outcome. RESULTS: A total of 15 noncontact ACL injuries were confirmed (6 females, 9 males), for an overall annual incidence of 3.0% (2.5% for males, 4.3% for females). Baseline hip strength measures (external rotation and abduction) were significantly lower in injured athletes compared with noninjured athletes (P = .003 and P < .001, respectively). Separate logistic regression models indicated that impaired hip strength increased future injury risk (external rotation: odds ratio [OR] = 1.23 [95% CI, 1.08-1.39], P = .001; abduction: OR = 1.12 [95% CI, 1.05-1.20], P = .001). Clinical cutoffs to define high risk were established as external rotation strength <=20.3% BW (percentage of body weight) or abduction strength <=35.4% BW. CONCLUSION: Measures of preseason isometric hip abduction and external rotation strength independently predicted future noncontact ACL injury status in competitive athletes. The study data suggest that screening procedures to assess ACL injury risk should include an assessment of isometric hip abduction and/or external rotation strength. PMID- 26646515 TI - Surgical Results of Delaminated Rotator Cuff Repair Using Suture-Bridge Technique With All-Layers or Bursal Layer-Only Repair. AB - BACKGROUND: There are no known studies that have investigated the effect on delaminated rotator cuff tears of bursal layer-only repair when full-thickness repair would put the articular layer under tension, compared with all-layers repair when full-thickness repair is feasible. HYPOTHESIS: Better outcomes will be seen in the bursal layer-only repair, as the articular layer would be under tension when repaired onto its footprint during the all-layers repair. STUDY DESIGN: Cohort study; Level of evidence 3. METHODS: This study included 112 patients who underwent arthroscopic rotator cuff repair for posteriorly delaminated tears of either all layers (group A) or the bursal layer alone (group B). If the articular layer was able to be reduced onto its footprint, the patient was assigned to group A; if such reduction was not possible or was only marginally possible under significant tension, the patient was assigned to group B. Pain scored on a visual analog scale (VAS) was assessed, as were subjective shoulder value (SSV), University of California, Los Angeles (UCLA) shoulder score, American Shoulder and Elbow Surgeons (ASES) score, and shoulder active range of motion (ROM). Postoperative magnetic resonance arthrography (MRA) or computed tomographic arthrography (CTA) was undertaken 6 months postoperatively for structural integrity assessment. RESULTS: After 2 years, the VAS pain score (group A, from 6.5 to 1.2; group B, from 6.4 to 1.2), SSV (group A, from 38.3 to 89.4; group B, from 38.0 to 90.1), ASES score (group A, from 36.4 to 90.4; group B, from 38.0 to 90.8), UCLA shoulder score (group A, from 15.3 to 30.7; group B, from 15.0 to 31.3), and ROM improved significantly in both groups compared with preoperative values (P < .001). However, none of these values differed significantly between groups. On follow-up MRA or CTA images, there was no significant difference in the retear rate between group A (28%; 16/57) and group B (24%; 11/45). CONCLUSION: The all-layers repair did not produce better clinical outcomes or structural integrity than the bursal layer-only repair. The study findings indicate that if repair of the articular layer is possible only under significant tension or is not reparable, rather than all-layers repair by force, bursal-layer repair without incorporating the articular layer may produce comparable clinical outcomes and structural integrity in the delaminated rotator cuff tear. PMID- 26646516 TI - A Novel Repair Method for Radial Tears of the Medial Meniscus: Biomechanical Comparison of Transtibial 2-Tunnel and Double Horizontal Mattress Suture Techniques Under Cyclic Loading. AB - BACKGROUND: Complete radial tears of the medial meniscus have been reported to be functionally similar to a total meniscectomy. At present, there is no consensus on an ideal technique for repair of radial midbody tears of the medial meniscus. Prior attempts at repair with double horizontal mattress suture techniques have led to a reportedly high rate of incomplete healing or healing in a nonanatomic (gapped) position, which compromises the ability of the meniscus to withstand hoop stresses. HYPOTHESIS: A newly proposed 2-tunnel radial meniscal repair method will result in decreased gapping and increased ultimate failure loads compared with the double horizontal mattress suture repair technique under cyclic loading. STUDY DESIGN: Controlled laboratory study. METHODS: Ten matched pairs of male human cadaveric knees (average age, 58.6 years; range, 48-66 years) were used. A complete radial medial meniscal tear was made at the junction of the posterior one-third and middle third of the meniscus. One knee underwent a horizontal mattress inside-out repair, while the contralateral knee underwent a radial meniscal repair entailing the same technique with a concurrent novel 2 tunnel repair. Specimens were potted and mounted on a universal testing machine. Each specimen was cyclically loaded 1000 times with loads between 5 and 20 N before experiencing a load to failure. Gap distances at the tear site and failure load were measured. RESULTS: The 2-tunnel repairs exhibited a significantly stronger ultimate failure load (median, 196 N; range, 163-212 N) than did the double horizontal mattress suture repairs (median, 106 N; range, 63-229 N) (P = .004). In addition, the 2-tunnel repairs demonstrated decreased gapping at all testing states (P < .05) with a final measured gapping of 1.7 mm and 4.1 mm after 1000 cycles for the 2-tunnel and double horizontal mattress suture repairs, respectively. CONCLUSION: The 2-tunnel repairs displayed significantly less gapping distance after cyclic loading and had significantly stronger ultimate failure loads compared with the double horizontal mattress suture repairs. CLINICAL RELEVANCE: Complete radial tears of the medial meniscus significantly decrease the ability of the meniscus to dissipate tibiofemoral loads, predisposing patients to early osteoarthritis. Improving the ability to repair medial meniscal radial tears in a way that withstands cyclic loads and heals in an anatomic position could significantly improve patient healing rates and result in improved preservation of the articular cartilage of the medial compartment of the knee. The 2-tunnel repair may be a more reliable and stronger repair option for midbody radial tears of the medial meniscus. Clinical studies are warranted to further evaluate these repairs. PMID- 26646517 TI - Prediction of Lateral Ankle Sprains in Football Players Based on Clinical Tests and Body Mass Index. AB - BACKGROUND: The lateral ankle sprain (LAS) is the most common injury suffered in sports, especially in football. While suggested in some studies, a predictive role of clinical tests for LAS has not been established. PURPOSE: To determine which clinical tests, focused on potentially modifiable factors of movement patterns and body mass index (BMI), could best demonstrate risk of LAS among high school and collegiate football players. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: A total of 539 high school and collegiate football players were evaluated during the preseason with the Star Excursion Balance Test (SEBT) and Functional Movement Screen as well as BMI. Results were compared between players who did and did not suffer an LAS during the season. Logistic regression analyses and calculated odds ratios were used to determine which measures predicted risk of LAS. RESULTS: The LAS group performed worse on the SEBT-anterior reaching direction (SEBT-ANT) and had higher BMI as compared with the noninjured group (P < .001). The strongest prediction models corresponded with the SEBT-ANT. CONCLUSION: Low performance on the SEBT-ANT predicted a risk of LAS in football players. BMI was also significantly higher in football players who sustained an LAS. Identifying clinical tools for successful LAS injury risk prediction will be a critical step toward the creation of effective prevention programs to reduce risk of sustaining an LAS during participation in football. PMID- 26646518 TI - Effects of Subchronic Finasteride Treatment and Withdrawal on Neuroactive Steroid Levels and Their Receptors in the Male Rat Brain. AB - The enzymatic conversion of progesterone and testosterone by the enzyme 5alpha reductase exerts a crucial role in the control of nervous function. The effects of finasteride in the brain, an inhibitor of this enzyme used for the treatment of human benign prostatic hyperplasia and androgenic alopecia, have been poorly explored. Therefore, the effects of a subchronic treatment with finasteride at low doses (3 mg/kg/day) and the consequences of its withdrawal on neuroactive steroid levels in plasma, cerebrospinal fluid and some brain regions as well as on the expression of classical and non-classical steroid receptors have been evaluated in male rats. After subchronic treatment (i.e., for 20 days) the following effects were detected: (i) depending on the compartment considered, alteration in the levels of neuroactive steroids, not only in 5alpha-reduced metabolites but also in its precursors and in neuroactive steroids from other steroidogenic pathways and (ii) an upregulation of the androgen receptor in the cerebral cortex and beta3 subunit of the GABA-A receptor in the cerebellum. One month after the last treatment (i.e., withdrawal period), some of these effects persisted (i.e., the upregulation of the androgen receptor in the cerebral cortex, an increase of dihydroprogesterone in the cerebellum, a decrease of dihydrotestosterone in plasma). Moreover, other changes in neuroactive steroid levels, steroid receptors (i.e., an upregulation of the estrogen receptor alpha and a downregulation of the estrogen receptor beta in the cerebral cortex) and GABA-A receptor subunits (i.e., a decrease of alpha 4 and beta 3 mRNA levels in the cerebral cortex) were detected. These findings suggest that finasteride treatment may have broad consequences for brain function. PMID- 26646519 TI - The influence of the I/Cl ratio on the performance of CH3NH3PbI(3-x)Cl(x)-based solar cells: why is CH3NH3I : PbCl2 = 3 : 1 the "magic" ratio? AB - Methylammonium lead trihalide (CH3NH3PbI(3-x)Cl(x)) perovskites are usually synthesized from two precursors, CH3NH3I and PbCl2 at a ratio of 3 : 1. It was found that a slight adjustment of the I/Cl ratio in the precursor mixture plays a strong effect on solar cell performance. In this study, perovskites made with different I/Cl ratios were comparatively studied. In combination with X-ray diffraction (XRD) and X-ray absorption fine structure (XAFS) measured at the Pb L3-edge, we demonstrate that the device performance can be directly correlated to the change in the coordination environment of Pb. PMID- 26646521 TI - Multi-atlas-based fully automatic segmentation of individual muscles in rat leg. AB - OBJECTIVE: To quantify individual muscle volume in rat leg MR images using a fully automatic multi-atlas-based segmentation method. MATERIALS AND METHODS: We optimized a multi-atlas-based segmentation method to take into account the voxel anisotropy of numbers of MRI acquisition protocols. We mainly tested an image upsampling process along Z and a constraint on the nonlinear deformation in the XY plane. We also evaluated a weighted vote procedure and an original implementation of an artificial atlas addition. Using this approach, we measured gastrocnemius and plantaris muscle volumes and compared the results with manual segmentation. The method reliability for volume quantification was evaluated using the relative overlap index. RESULTS: The most accurate segmentation was obtained using a nonlinear registration constrained in the XY plane by zeroing the Z component of the displacement and a weighted vote procedure for both muscles regardless of the number of atlases. The performance of the automatic segmentation and the corresponding volume quantification outperformed the interoperator variability using a minimum of three original atlases. CONCLUSION: We demonstrated the reliability of a multi-atlas segmentation approach for the automatic segmentation and volume quantification of individual muscles in rat leg and found that constraining the registration in plane significantly improved the results. PMID- 26646522 TI - DCE-MRI of hepatocellular carcinoma: perfusion quantification with Tofts model versus shutter-speed model--initial experience. AB - OBJECTIVE: To quantify hepatocellular carcinoma (HCC) perfusion and flow with the fast exchange regime-allowed Shutter-Speed model (SSM) compared to the Tofts model (TM). MATERIALS AND METHODS: In this prospective study, 25 patients with HCC underwent DCE-MRI. ROIs were placed in liver parenchyma, portal vein, aorta and HCC lesions. Signal intensities were analyzed employing dual-input TM and SSM models. ART (arterial fraction), K (trans) (contrast agent transfer rate constant from plasma to extravascular extracellular space), ve (extravascular extracellular volume fraction), kep (contrast agent intravasation rate constant), and taui (mean intracellular water molecule lifetime) were compared between liver parenchyma and HCC, and ART, K (trans), v e and k ep were compared between models using Wilcoxon tests and limits of agreement. Test-retest reproducibility was assessed in 10 patients. RESULTS: ART and v e obtained with TM; ART, ve, ke and taui obtained with SSM were significantly different between liver parenchyma and HCC (p < 0.04). Parameters showed variable reproducibility (CV range 14.7-66.5% for both models). Liver K (trans) and ve; HCC ve and kep were significantly different when estimated with the two models (p < 0.03). CONCLUSION: Our results show differences when computed between the TM and the SSM. However, these differences are smaller than parameter reproducibilities and may be of limited clinical significance. PMID- 26646523 TI - Automatic labeling of cerebral arteries in magnetic resonance angiography. AB - OBJECTIVES: In order to introduce 4D flow magnetic resonance imaging (MRI) as a standard clinical instrument for studying the cerebrovascular system, new and faster postprocessing tools are necessary. The objective of this study was to construct and evaluate a method for automatic identification of individual cerebral arteries in a 4D flow MRI angiogram. MATERIALS AND METHODS: Forty-six elderly individuals were investigated with 4D flow MRI. Fourteen main cerebral arteries were manually labeled and used to create a probabilistic atlas. An automatic atlas-based artery identification method (AAIM) was developed based on vascular-branch extraction and the atlas was used for identification. The method was evaluated by comparing automatic with manual identification in 4D flow MRI angiograms from 67 additional elderly individuals. RESULTS: Overall accuracy was 93%, and internal carotid artery and middle cerebral artery labeling was 100% accurate. Smaller and more distal arteries had lower accuracy; for posterior communicating arteries and vertebral arteries, accuracy was 70 and 89%, respectively. CONCLUSION: The AAIM enabled fast and fully automatic labeling of the main cerebral arteries. AAIM functionality provides the basis for creating an automatic and powerful method to analyze arterial cerebral blood flow in clinical routine. PMID- 26646531 TI - Spectroscopic investigations on the binding of Pyronin Y to human serum albumin. AB - The interaction of Pyronin Y with human serum albumin (HSA) has been investigated systematically by fluorescence, absorption, fluorescence decay lifetime measurements, FTIR, synchronous fluorescence spectroscopy, and molecular modeling method. The spectroscopic and fluorescence quenching experiments show that Pyronin Y may show a static quenching mechanism with HSA. The specific binding distance of 1.96 nm between HSA and Pyronin Y was obtained via Forster non radiation energy transfer method. The thermodynamic parameters indicate that the electrostatic interactions play a significant role during the binding process. In addition, synchronous fluorescence and FT-IR spectra indicated that the conformation and microenvironment of HSA were not influenced with the addition of Pyronin Y. The obtained results can be of biological significance in photodynamic therapy. PMID- 26646532 TI - Identification of Multiple Phytotoxins Produced by Fusarium virguliforme Including a Phytotoxic Effector (FvNIS1) Associated With Sudden Death Syndrome Foliar Symptoms. AB - Sudden death syndrome (SDS) of soybean is caused by a soilborne pathogen, Fusarium virguliforme. Phytotoxins produced by F. virguliforme are translocated from infected roots to leaves, in which they cause SDS foliar symptoms. In this study, additional putative phytotoxins of F. virguliforme were identified, including three secondary metabolites and 11 effectors. While citrinin, fusaric acid, and radicicol induced foliar chlorosis and wilting, Soybean mosaic virus (SMV)-mediated overexpression of F. virguliforme necrosis-inducing secreted protein 1 (FvNIS1) induced SDS foliar symptoms that mimicked the development of foliar symptoms in the field. The expression level of fvnis1 remained steady over time, although foliar symptoms were delayed compared with the expression levels. SMV::FvNIS1 also displayed genotype-specific toxicity to which 75 of 80 soybean cultivars were susceptible. Genome-wide association mapping further identified three single nucleotide polymorphisms at two loci, where three leucine-rich repeat receptor-like protein kinase (LRR-RLK) genes were found. Culture filtrates of fvnis1 knockout mutants displayed a mild reduction in phytotoxicity, indicating that FvNIS1 is one of the phytotoxins responsible for SDS foliar symptoms and may contribute to the quantitative susceptibility of soybean by interacting with the LRR-RLK genes. PMID- 26646533 TI - Cu(II)-Zn(II) Cross-Modulation in Amyloid-Beta Peptide Binding: An X-ray Absorption Spectroscopy Study. AB - In this work we analyze at a structural level the mechanism by which Cu(II) and Zn(II) ions compete for binding to the Abeta peptides that is involved in the etiology of Alzheimer's disease. We collected X-ray absorption spectroscopy data on samples containing Abeta with Cu and Zn at different concentration ratios. We show that the order in which metals are added to the peptide solution matters and that, when Zn is added first, it prevents Cu from binding. On the contrary, when Cu is added first, it does not (completely) prevent Zn binding to Abeta peptides. Our analysis suggests that Cu and Zn ions are coordinated to different numbers of histidine residues depending on the [ion]:[peptide] concentration ratio. PMID- 26646535 TI - Sequential aza-Piancatelli rearrangement/Friedel-Crafts alkylation for the synthesis of pyrrolo[1,2-d]benzodiazepine derivatives. AB - 2-Furylcarbinols undergo a smooth aza-Piancatelli rearrangement followed by Friedel-Crafts alkylation with a bifunctional substrate, (1H-pyrrol-1-yl)aniline, in the presence of 10 mol% In(OTf)3 in acetonitrile at room temperature to afford the corresponding hexahydrobenzo[b]cyclopenta[f]pyrrolo[1,2-d][1,4]diazepin 11(4aH)-one scaffolds in good yields. This method offers significant advantages such as high conversions, mild reaction conditions, short reaction times, and high selectivity. The relative stereochemistry of the product was established by nOe studies. PMID- 26646534 TI - A Randomized, Single-Blind, Placebo-Controlled Study on the Efficacy of the Arthrokinematic Approach-Hakata Method in Patients with Chronic Nonspecific Low Back Pain. AB - STUDY DESIGN: Cized, single-blind, controlled trial. OBJECTIVE: To investigate the efficacy of the Arthrokinematic approach (AKA)-Hakata (H) method for chronic low back pain. SUMMARY OF BACKGROUND DATA: The AKA-H method is used to manually treat abnormalities of intra-articular movement. METHODS: One hundred eighty-six patients with chronic nonspecific low back pain randomly received either the AKA H method (AKA-H group) or the sham technique (S group) monthly for 6 months. Data were collected at baseline and once a month. Outcome measures were pain intensity (visual analogue scale [VAS]) and quality of life (the Roland-Morris Disability Questionnaire [RDQ] and Short Form SF-36 questionnaire [SF-36]). RESULTS: At baseline, the VAS, RDQ, and SF-36 scores showed similar levels between the groups. After 6 months, the AKA-H group had more improvement in the VAS (42.8% improvement) and RDQ score (31.1% improvement) than the sham group (VAS: 10.4% improvement; RDQ: 9.8% improvement; both, P < 0.001). The respective scores for the SF-36 subscales (physical functioning, role physical, bodily pain, social functioning, general health perception, role emotional, and mental health) were also significantly more improved in the AKA-H group than in the sham group (all, P < 0.001). The scores for the physical, psychological, and social aspects of the SF-36 subscales showed similar improvement in the AKA-H group. CONCLUSION: The AKA-H method can be effective in managing chronic low back pain. TRIAL REGISTRATION: UMIN Clinical Trials Registry (UMIN-CTR) UMIN000006250. PMID- 26646536 TI - A review of adverse events linked to dopamine agonists in the treatment of Parkinson's disease. AB - INTRODUCTION: Dopamine agonists are highly effective as adjunctive therapy to levodopa in advanced Parkinson's disease. These drugs have rapidly gained popularity as a monotherapy in the early stages of Parkinson's disease for patients less than 65-70 years old since they are about as effective as levodopa but patients demonstrate a lower tendency to develop motor complications. However, dopamine agonists could have peripheral and central side-effects which are often the reason for the discontinuation of the treatment. AREAS COVERED: This article presents an overview of the efficacy and the potential negative effects related to the use of dopamine agonists in the treatment of Parkinson's disease. EXPERT OPINION: Beyond the new generation non ergot dopamine agonists, no strong evidences allow the choice of a specific dopamine agonists for Parkinson 's disease treatment and by now dopamine agonists treatment should be tailored on specific adverse events profile. PMID- 26646537 TI - TNF-alpha and MTHFR Polymorphisms Associated with Cerebral Palsy in Chinese Infants. AB - This study aims to examine whether the presence of polymorphisms in TNF-alpha (rs361525 and rs1799724) and MTHFR (rs1476413 and rs9651118) genes is associated with the pathogenesis of cerebral palsy (CP). A total of 105 CP patients and 114 age-, gender-, and ethnicity-matched healthy controls were genotyped for the selected polymorphisms, using TaqMan allelic discrimination assay. Odds ratios (OR) and 95 % confidence intervals (CI) were determined to measure the strength of associations of TNF-alpha and MTHFR polymorphisms with CP. The proportion of subjects with the gestational age more than 37 weeks or asphyxia was much larger in cases compared with controls (gestational age 63.8 vs. 34.2 %; asphyxia 25.7 vs. 7.9 %). The genotype frequencies of TNF-alpha rs1799724 were similar between groups (P > 0.05), yet the allele distributions were significantly different (P < 0.05). Both the allele and genotype distributions of MTHFR rs9651118 polymorphism varied significantly between the groups (P < 0.05). Subgroup analysis based on gestational age indicated a significant association between rs361525 and rs9651118 and CP with or without premature. TNF-alpha protein concentrations were significantly increased among patients with rs361525 GG genotype compared with controls. Also, a significant increase in the risk of CP was observed to be associated with the interactions of TNF-alpha rs1799724 and MTHFR rs9651118 (OR 2.75, 95 % CI 1.23-6.13). These data suggest that polymorphisms in TNF-alpha and MTHFR genes might be involved in the pathogenesis of CP in Chinese infants. PMID- 26646538 TI - A Study on Apoptosis and Anti-apoptotic Status in Wilson Disease. AB - Wilson disease (WD) is characterized by hepatolenticular degeneration, but there is no report on apoptosis and anti-apoptotic markers in WD patients with neurological manifestation (WDN). The aim of this study was to evaluate active caspase-3 and X-linked inhibitors of apoptosis protein (XIAP) level in WDN and correlate these with disease severity and markers of death (tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-8, malondialdehyde (MDA), and Cu) and survival signals (glutathione). Fifty-four patients with WDN and 36 healthy matched controls were included. Their severity, Burke-Fahn-Marsden (BFM) scores, blood counts, hemoglobin, serum chemistry, ceruloplasmin, and free copper and 24 h urinary copper were measured. Cranial MRI findings were noted. Serum active caspase-3, XIAP, TNF-alpha, IL-8, and plasma glutathione and MDA were measured using enzyme-linked immunosorbent assay (ELISA), flow cytometry, and spectrophotometer respectively. In the patients with WDN, active caspase-3 (0.55 +/- 0.11 vs 0.38 +/- 0.06 ng/ml), TNF-alpha (76.05 +/- 29.01 vs 36.05 +/- 21.01 pg/ml), IL-8 (590.19 +/- 89.19 vs 193.43 +/- 71.01 pg/ml), and MDA (4.92 +/- 0.39 vs 3.43 +/- 0.21 nmol/ml) levels were increased whereas XIAP (84.66 +/- 10.39 vs 95.76 +/- 10.11 ng/ml) and glutathione (GSH) (2.03 +/- 0.29 vs 2.98 +/- 0.27 mg/dl) levels were decreased compared to controls. Active caspase-3 was correlated with neurological severity (r = 0.48), BFM score (r = 0.37), ceruloplasmin (r = -0.39), hemoglobin (r = -0.34), and serum Cu (r = 0.39). XIAP levels were correlated with neurological severity (r = -0.40), BFM (r = -0.51), serum Cu (r = -0.42), and ceruloplasmin (r = 0.34). The XIAP level positively correlated with survival (GSH) and inversely with death signals (TNF-alpha, IL-8, MDA and free serum Cu) whereas active caspase-3 positively correlated with death (TNF-alpha, IL-8, serum Cu, MDA) and inversely with survival signal (GSH). Serum active caspase-3 level increased in WDN and positively correlated with the severity of disease, death signals (TNF, IL-8, MDA, and free Cu) and inversely with GSH and XIAP. PMID- 26646539 TI - SVCT2 Overexpression in Neuroblastoma Cells Induces Cellular Branching that is Associated with ERK Signaling. AB - Expression of the sodium and ascorbic acid (AA) cotransporter SVCT2 is induced during the period of cellular arborization and synaptic maturation of early postnatal (P1-P5) rat cerebral neurons. The physiological importance of the transporter for neurons is evidenced by the lethality and delayed neuronal differentiation detected in mice with ablation of SVCT2. The mechanism(s) involved in these defects and the role of SVCT2 in neuronal branching have not been determined yet. To address this, we used lentiviral expression vectors to increase the levels of SVCT2 in N2a cells and analyzed the effects on neurite formation. Expression of a fusion protein containing the human SVCT2wt and EYFP induced an increase in the number of MAP2+ neurites and filopodia in N2a cells. Overexpression of SVCT2 and treatment with AA promoted ERK1/2 phosphorylation. Our data suggest that enhanced expression of the high affinity AA transporter SVCT2, which tightly regulates intracellular AA concentrations, induces neuronal branching that then activates key signaling pathways that are involved in the differentiation and maturation of cortical neurons during postnatal development. PMID- 26646540 TI - A microfabricated platform with hydrogel arrays for 3D mechanical stimulation of cells. AB - Cellular microenvironments present cells with multiple stimuli, including not only soluble biochemical and insoluble matrix cues but also mechanical factors. Biomaterial array platforms have been used to combinatorially and efficiently probe and define two-dimensional (2D) and 3D microenvironmental cues to guide cell functions for tissue engineering applications. However, there are few examples of array platforms that include dynamic mechanical forces, particularly to enable stretching of 3D cell-seeded biomaterials, which is relevant to engineering connective and cardiovascular tissues. Here we present a deformable membrane platform that enables 3D dynamic mechanical stretch of arrayed biomaterial constructs. Cell-seeded polyethylene glycol norbornene (PEG-NB) hydrogels were bound to miniaturized deformable membranes via a thiol-ene reaction with off-stoichiometry thiol-ene based polydimethylsiloxane (OSTE-PDMS) as the membrane material. Bonding to OSTE-PDMS enabled the 3D hydrogel microconstructs to be cyclically deformed and stretched by the membrane. As a first demonstration, human mesenchymal stromal cells (MSCs) embedded in PEG-NB were stretched for several days. They were found to be viable, spread in the 3D hydrogels, and exhibited a contractile myofibroblast phenotype when exposed to dynamic 3D mechanical deformation. This platform, which is readily scalable to larger arrays, enables systematic interrogation of the relationships between combinations of 3D mechanobiological cues and cellular responses, and thus has the potential to identify strategies to predictably control the construction of functional engineered tissues. STATEMENT OF SIGNIFICANCE: Current high-throughput biomaterial screening approaches fail to consider the effects of dynamic mechanical stimulation, despite its importance in a wide variety of regenerative medicine applications. To meet this need, we developed a deformable membrane platform that enables 3D dynamic stretch of arrayed biomaterial constructs. Our approach combines microtechnologies fabricated with off-stoichiometry thiol-ene based polydimethylsiloxane membranes that can covalently bond cell-seeded polyethylene glycol norbornene 3D hydrogels, a model biomaterial with tunable adhesive, elastic and degradation characteristics. As a first demonstration, we show that human mesenchymal stromal cells embedded in hydrogels and subjected to dynamic mechanical stimulation undergo myofibroblast differentiation. This system is readily scaled up to larger arrays, and will enable systematic and efficient screening of combinations of 3D mechanobiological and biomaterial cues on cell fate and function. PMID- 26646541 TI - Global Estimates of the Prevalence and Incidence of Four Curable Sexually Transmitted Infections in 2012 Based on Systematic Review and Global Reporting. AB - BACKGROUND: Quantifying sexually transmitted infection (STI) prevalence and incidence is important for planning interventions and advocating for resources. The World Health Organization (WHO) periodically estimates global and regional prevalence and incidence of four curable STIs: chlamydia, gonorrhoea, trichomoniasis and syphilis. METHODS AND FINDINGS: WHO's 2012 estimates were based upon literature reviews of prevalence data from 2005 through 2012 among general populations for genitourinary infection with chlamydia, gonorrhoea, and trichomoniasis, and nationally reported data on syphilis seroprevalence among antenatal care attendees. Data were standardized for laboratory test type, geography, age, and high risk subpopulations, and combined using a Bayesian meta analytic approach. Regional incidence estimates were generated from prevalence estimates by adjusting for average duration of infection. In 2012, among women aged 15-49 years, the estimated global prevalence of chlamydia was 4.2% (95% uncertainty interval (UI): 3.7-4.7%), gonorrhoea 0.8% (0.6-1.0%), trichomoniasis 5.0% (4.0-6.4%), and syphilis 0.5% (0.4-0.6%); among men, estimated chlamydia prevalence was 2.7% (2.0-3.6%), gonorrhoea 0.6% (0.4-0.9%), trichomoniasis 0.6% (0.4-0.8%), and syphilis 0.48% (0.3-0.7%). These figures correspond to an estimated 131 million new cases of chlamydia (100-166 million), 78 million of gonorrhoea (53-110 million), 143 million of trichomoniasis (98-202 million), and 6 million of syphilis (4-8 million). Prevalence and incidence estimates varied by region and sex. CONCLUSIONS: Estimates of the global prevalence and incidence of chlamydia, gonorrhoea, trichomoniasis, and syphilis in adult women and men remain high, with nearly one million new infections with curable STI each day. The estimates highlight the urgent need for the public health community to ensure that well-recognized effective interventions for STI prevention, screening, diagnosis, and treatment are made more widely available. Improved estimation methods are needed to allow use of more varied data and generation of estimates at the national level. PMID- 26646542 TI - lncRNA DANCR suppresses odontoblast-like differentiation of human dental pulp cells by inhibiting wnt/beta-catenin pathway. AB - Long noncoding RNAs (lncRNAs) have recently emerged as an important class of regulatory molecules in diverse biological processes, although lncRNA involvement in the odontoblast-like differentiation of human dental pulp cells (hDPCs) is poorly understood. We investigate the expression of lncRNAs in this differentiation and explore their underlying role and the involved mechanism. Integrated comparative lncRNA microarray profiling was used to examine lncRNA expression during this differentiation. The differential expression of lncRNAs was validated by quantitative real-time reverse transcription plus the polymerase chain reaction. Differential lncRNA overexpression was performed with an adenoviral vector and the role and mechanism was then investigated in odontoblast like differentiation. We identified 139 differentially expressed lncRNAs during this differentiation. Among them, five lncRNAs differentially expressed in microarray analysis were validated. Notably, lncRNA DANCR expression was significantly downregulated during hDPC differentiation to odontoblast-like cells in a time-dependent manner. Moreover, lncRNA DANCR overexpression blocked mineralized nodule formation and the expression of DSPP and DMP-1 in hDPCs after 14 days of odontogenic induction. Importantly, the upregulation of DANCR significantly decreased the expression levels of p-GSK-3beta and beta-catenin expression indicating that lncRNA DANCR can inhibit the activation of the Wnt/beta-catenin signal pathway during the odontoblast-like differentiation of hDPCs. Thus, the modulation of Wnt/beta-catenin signaling by lncRNA DANCR represents a potential therapeutic option for reparative dentin formation and regenerative endodontics. PMID- 26646543 TI - What's Next for Gastrointestinal Disorders: No Needles? AB - A myriad of pathologies affect the gastrointestinal tract, citing this affected area as a significant target for therapeutic intervention. One group of therapeutic agents, antisense and oligonucleotides and small interfering RNAs, offer a promising platform for treating a wide variety of diseases ranging from cancer to auto-immune diseases. Current delivery methods are carried out either systemically or locally into diseased areas, both of which involve needles. The challenge in orally administering this type of treatment lies in the complications that arise due to the vast environmental extremes found within the gastrointestinal tract, owing to the fact that, as the drug travels down the gastrointestinal tract, it is subjected to pH changes and interactions with bacteria and a variety of digestive and protective enzymes including proteases, DNAses, and RNAses. Overcoming these challenges to allow the practical application of these drugs is a priority that has invoked a multitude of research in the chemical, biological, and material sciences. In this review, we will address common gastrointestinal pathologies, the barriers to oral-based therapies and antisense-interfering technologies, the approaches that have already been applied for their delivery, and the current status of antisense drug therapy clinical trials for gastrointestinal-related disorders. PMID- 26646544 TI - Codeine consumption from over-the-counter anti-cough syrup in Taiwan: A useful indicator for opioid abuse. AB - OBJECTIVE: Over-the-counter (OTC) anti-cough preparations, many of which contain codeine (an opioid) or dextromethorphan (an opioid-like), are widely available in Taiwan and thus susceptible to overuse or abuse. We aimed to investigate whether opioids in the form of OTC antitussives play a significant role in medication abuse in Taiwan. METHODS: Data on the consumption of codeine and dextromethorphan in antitussives and expectorants from 2011 through 2014 in Taiwan were provided by IMS Health (Intercontinental Marketing Services). These data were then analyzed for trends and variance according to availability, as prescription or OTC, and according to drug type, as codeine or dextromethorphan, in order to form four primary sectors under opioid-containing anti-cough syrup consumption. RESULTS: From 2011 to 2014, use of opioid-containing cough syrup fluctuated between 6% and 9% from year to year for all cough syrup consumption, with an overall declining trend (11.3% per year relative to 2011). Within the underlying sectors, mean consumption for prescription dextromethorphan (61.4%) outstripped the other three sectors, followed in decreasing order by OTC codeine (20.2%), OTC dextromethorphan (10.5%), and prescription codeine (8.0%). However, movement in consumption corresponded mainly with OTC codeine, whose variance greatly exceeded that of the other sectors, which follow in order of decreasing variance as OTC dextromethorphan, prescription dextromethorphan, and prescription codeine. CONCLUSION: The fairly low and stable consumption of prescription codeine suggested that physicians in Taiwan were careful in prescribing codeine, and that the medical demand for codeine was stable. The large variance in OTC codeine consumption suggested that a minority of consumers purchased significant quantities of codeine for non-medical purposes. Although opioids in cough syrup were not a large part of overall consumption and thus not widely abused, the data revealed that OTC codeine-containing cough syrup may serve as an indicator of potential drug abuse in the population as compared to prescription codeine. PMID- 26646545 TI - Qualitative and mixed methods research in trials. PMID- 26646546 TI - A comprehensive ray tracing study on the impact of solar reflections from glass curtain walls. AB - To facilitate the investigation of the impact of solar reflection from the facades of skyscrapers to surrounding environment, a comprehensive ray tracing model has been developed using the International Commerce Centre (ICC) in Hong Kong as an example. Taking into account the actual physical dimensions of buildings and meteorological data, the model simulates and traces the paths of solar reflections from ICC to the surrounding buildings, assessing the impact in terms of hit locations, light intensity and the hit time on each day throughout the year. Our analyses show that various design and architectural features of ICC have amplified the intensity of reflected solar rays and increased the hit rates of surrounding buildings. These factors include the high reflectivity of glass panels, their upward tilting angles, the concave profile of the 'Dragon Tail' (glass panels near the base), the particular location and orientation of ICC, as well as the immense height of ICC with its large reflective surfaces. The simulation results allow us to accurately map the date and time when the ray projections occur on each of the target buildings, rendering important information such as the number of converging (overlapping) projections, and the actual light intensity hitting each of the buildings at any given time. Comparisons with other skyscrapers such as Taipei 101 in Taiwan and 2-IFC (International Finance Centre) Hong Kong are made. Remedial actions for ICC and preventive measures are also discussed. PMID- 26646547 TI - High Discordance Between Pre-US and Post-US Entry Tuberculosis Test Results Among Immigrant Children: Is it Time to Adopt Interferon Gamma Release Assay for Preentry Tuberculosis Screening? AB - BACKGROUND: Since 2007, immigration applicants 2-14 years old with a tuberculin skin test (TST) >=10 mm and an otherwise negative evaluation for tuberculosis (TB) are assigned a classification for TB infection and instructed to seek domestic evaluation upon arrival in the US in accordance with Centers for Disease Control and Prevention instructions. We examined the characteristics and outcome of domestic evaluation of immigrant children who arrived in California with a positive TST on preimmigration examination to inform the preimmigration TB screening process. METHODS: Retrospective analysis of the characteristics and results of domestic evaluation of immigrants 2-14 years old who arrived in California with a classification for TB infection during October 1, 2008 September 30, 2013 was performed. TB disease was determined by matching preimmigration records with the California TB registry. RESULTS: Among a total of 12,544 immigrant children included, 7786 (62%) were evaluated for TB postentry. Of these, 5243 (67%) were tested with TST or interferon gamma release assay (IGRA), and 2371 (45%) had a positive test. Of those tested with IGRA (n = 4035), 914 (23%) were positive. The proportion with positive IGRA increased significantly with age (years): 2-4 (11%), 5-9 (19%), 10-14 (28%), P < 0.0001; was lowest among arrivers from China (6%) and highest among arrivers from Mexico (48%). Nine children (0.07%) had TB disease within 5 years after arrival. CONCLUSIONS: The majority of immigrant children with a positive preimmigration TST tested negative for TB infection on domestic evaluation using TST or IGRA. Inclusion of IGRA in preimmigration TB screening is likely to reduce subsequent testing, treatment and cost of evaluations among immigrant children to the US. PMID- 26646548 TI - Influenza Vaccine Effectiveness and Uptake in Children at Risk of Severe Disease. AB - BACKGROUND: Data demonstrating the effectiveness of inactivated trivalent influenza vaccine (TIV) for children at increased risk of severe disease are limited. Our objective was to determine the effectiveness of TIV in children with risk factors for severe disease and to compare vaccine uptake, parental attitudes and prescriber recommendations in children with and without risk factors for severe disease. METHODS: Children aged 6-59 months presenting for emergency care (2008 to 2014) with an influenza-like illness were eligible. Influenza polymerase chain reaction/culture was performed on nasopharyngeal samples. Vaccination status was confirmed via the national register and/or vaccine providers. The test negative design was used to estimate vaccine effectiveness (VE). Risk factors, parental attitudes and prescriber recommendations were assessed by parental questionnaire. RESULTS: Two thousand seven hundred twenty-three children were recruited. Risk factors for severe disease included comorbid medical conditions (11.6%), preterm birth (13.0%) and indigeneity (5.0%). Influenza was identified in 546 (20.1%) participants. Overall VE (2008 and 2010 to 2014) was 70.0% (95% confidence interval: 47.7 to 82.9); VE for children with medical comorbidities, children born preterm and children <2 years were 82.5% (14.6 to 96.4), 79.2% (10.9 to 95.1) and 84.7% (49.6 to 95.3), respectively. After adverse events in 2010, the number of children fully vaccinated with TIV declined significantly. This included children with and without risk factors for severe disease. Attitudes were similar in parents of children with and without risk factors for severe disease. CONCLUSIONS: VE for TIV in young children with and without risk factors for severe disease was >=70%. Despite this, participation in the preschool influenza vaccination program remains low with parents and prescribers unconvinced of the benefits and safety of TIV. PMID- 26646550 TI - Influenza-like Illness in Households with Children of Preschool Age. AB - BACKGROUND: Influenza-like illness (ILI) is the leading cause of medical consultation amongst preschool children, who may contribute to spreading ILI causing agents within the household. We aimed to determine the societal burden (incidence, health-care consumption and productivity loss) and correlates of ILI in households with preschool children. METHODS: A survey was performed in the Netherlands during October 2012 to October 2014. Monthly, 2000 households with children younger than 4 years were invited to report their symptoms and related medical care, productivity loss and putative risk exposures for 1 preschool child and 1 parent. RESULTS: Eight thousand seven hundred and sixty-eight child-parent pairs were enrolled. ILI incidence was 2.81 episodes/child-year and 1.72 episodes/parent-year. Amongst those with ILI, health-care utilization was 35.7% (children) and 17.7% (parents). Work absenteeism was 45.7% (median 2 workdays lost) and day-care absenteeism was 22.8% (median 1 day missed). Chronic respiratory conditions, developmental disabilities, parental occupation in health care/child care, having a sibling and attending day care for <=12 months increased childhood ILI risk. Parental ILI risk increased with having chronic respiratory conditions, developmentally disabled day-care-attending children and female gender in interaction with unemployment and multiple day-care-attending children. Breastfeeding infants 6-month-old or younger and attending day care for >24 months decreased childhood ILI risk. Pregnancy, occupation in health care and having >=3 children decreased parental ILI risk. Parents of ILI-affected children had a concurrent 4-fold higher ILI risk. CONCLUSION: ILI in households with preschool children has a considerable societal impact. Risk-mitigating initiatives seem justified for day-care attendees, mothers, people with chronic respiratory conditions, and children with developmental disabilities. Children attending day care for >2 years acquire some protection to ILI. PMID- 26646549 TI - Healthcare-associated Staphylococcus aureus Bacteremia in Children: Evidence for Reverse Vancomycin Creep and Impact of Vancomycin Trough Values on Outcome. AB - INTRODUCTION: Elevated vancomycin minimum inhibitory concentrations (MICs) in Staphylococcus aureus have been associated with worse clinical outcomes in adults. For invasive meticillin-resistant S. aureus (MRSA) infections in adults, the Infectious Diseases Society of America recommends targeting vancomycin serum trough concentrations between 15 and 20 MUg/mL. We evaluated trends in vancomycin MICs from healthcare-associated (HCA) S. aureus bacteremia isolates in children in addition to correlating vancomycin serum trough levels with clinical outcomes. METHODS: Patients and isolates were identified from a prospective S. aureus surveillance study at Texas Children's Hospital (TCH). HCA S. aureus bacteremia isolates from 2003 to 2013 were selected. Vancomycin MICs by E-test were determined and medical records were reviewed. Acute kidney injury (AKI) was defined as doubling of the baseline serum creatinine. RESULTS: Three hundred forty-one isolates met inclusion criteria. We observed a reverse vancomycin creep among MRSA isolates in the study period with a decline in the proportion of isolates with vancomycin MIC >= 2 MUg/mL (from 32.7% to 5.6%; P < 0.001). However, the proportion of MSSA isolates with MIC >= 2 MUg/mL increased (from 2.9% to 9%; P = 0.04). Among patients who had vancomycin troughs performed, there was no difference in duration of bacteremia or fever with vancomycin trough >15 versus <15 MUg/mL. A vancomycin trough >15 MUg/mL was, however, an independent risk factor for AKI. CONCLUSIONS: Vancomycin MICs are shifting among HCA S. aureus bacteremia isolates with significant differences between MRSA and MSSA at TCH. Higher vancomycin troughs did not improve outcomes in pediatric HCA S. aureus bacteremia but were associated with increased nephrotoxicity. Further studies are needed to better understand optimal management of children with S. aureus bacteremia. PMID- 26646551 TI - (9R)-9-Hydroxystearate-Functionalized Hydroxyapatite as Antiproliferative and Cytotoxic Agent toward Osteosarcoma Cells. AB - The possibility to functionalize calcium phosphates with bioactive agents is a promising strategy to design innovative biomaterials for bone repair able to couple the bioactive properties of the inorganic compounds with the therapeutic effect of the functionalizing agent. The R enantiomer of the 9-hydroxystearic acid, (9R)-9-HSA, produced from Dimorphotheca sinuata L. seeds, has proven to act as a natural negative regulator of tumor cell proliferation. On this basis, hydroxyapatite was synthesized with increasing contents of (9R)-9 hydroxystearate, up to ~8.6 wt %. The incorporation of HSA in the composite nanocrystals induces a reduction of the crystal mean dimensions and of the length of the coherently scattering crystalline domains, which suggest a preferential adsorption onto the hydroxyapatite crystal faces parallel to the c-axis direction. The composite nanocrystals were designed so that their cytostatic and cytotoxic effects toward osteosarcoma cells were modulated by hydroxystearate content. In fact, results of in vitro tests show that the presence of HSA in the composite nanocrystals provokes a significant decrease in SaOS2 osteosarcoma cells proliferation and viability as well as an increase in lactate dehydrogenase, tumor necrosis factor alpha, and caspase 3 levels, with a cytotoxic effect increasing with HSA content in the nanocrystals. PMID- 26646552 TI - Relevance of ANCA positivity at the time of renal transplantation in ANCA associated vasculitis. AB - BACKGROUND: Renal transplantation (RTx) is the modality of choice for ESRD due to ANCA associated vasculitis (AAV). The significance of ANCA positivity (ANCA+) at the time of RTx on recurrent disease is controversial. METHODS: We evaluated clinical outcomes and predictors of vasculitis relapse in sixteen transplanted AAV patients who were ANCA+ at RTx at a single University Medical Center. Allograft function, vasculitis relapse, and predictors of vasculitis relapse were assessed using descriptive statistics and logistic regression analysis. RESULTS: Our cohort had a median age of 64 years, 88 % Caucasians, 63 % males, 50 % PR3+. All patients were in remission at the time of RTx. Twelve received induction therapy and all were on mycophenolate mofetil, prednisone and tacrolimus. The mean (SD) serum creatinine was 1.2 (0.3) mg/dl at 1 year and 1.8 (1.7) mg/dl at last follow up. Six developed vasculitis relapse at post-transplant. All relapses were treated with escalation in immunosuppression. One non-compliant patient suffered graft loss while the remaining patients achieved remission. In adjusted logistic regression analysis, PR3 ANCA+ patients were two times (OR 2.19, p = 0.71) more likely to experience a relapse compared to MPO ANCA+ patients. CONCLUSIONS: This study demonstrates that PR3 ANCA+ patients may be more likely to experience relapse post-transplant. Further investigation of the predictors of vasculitis relapse among AAV patients who are ANCA+ at the time of RTx needs to be pursued. PMID- 26646553 TI - Development of Online pH Gradient-Eluted Strong Cation Exchange Nanoelectrospray Tandem Mass Spectrometry for Proteomic Analysis Facilitating Basic and Histidine Containing Peptides Identification. AB - A novel one-dimensional online pH gradient-eluted strong cation exchange nanoelectrospray ionization-tandem mass spectrometry (SCX-nano-ESI-MS/MS) method was developed for protein identification and tested with a mixture of six standard proteins, total lysate of HuH7 and N2a cells, as well as membrane fraction of N2a cells. This method utilized an online nanoflow SCX column in a nano-LC system coupled with a nanoelectrospray high-resolution mass spectrometer. Protein digests were separated on a nanoflow SCX column with a pH gradient and directly introduced into a mass spectrometer through nanoelectrospray ionization. More than five thousand unique peptides were identified in each 90 min LC-MS/MS run using 500 nanogram of protein digest either from total cell lysate or from membrane fraction. The unique peptide overlap between online strong cation exchange nano-ESI-MS/MS (SCXLC-MS/MS) and reverse phase nano-ESI-MS/MS (RPLC MS/MS) is only <=30%, which indicated these two methods were complementary to each other. The correlation coefficient of retention time and theoretical isoelectric point (pI) of identified peptides in SCXLC-MS/MS was higher than 0.4, which showed that peptides elution in SCXLC-MS/MS was dependent on their charge states. Furthermore, SCXLC-MS/MS showed identification capability for a higher proportion of basic peptides compared to the RPLC-MS/MS method, especially for histidine-containing peptides. Our SCXLC-MS/MS method is an excellent alternative method to the RPLC-MS/MS method for analysis of standard proteins, total cell and membrane proteomes. PMID- 26646554 TI - An N-Heterocyclic Carbene-Catalyzed Oxidative gamma-Aminoalkylation of Saturated Carboxylic Acids through in Situ Activation Strategy: Access to delta-Lactam. AB - An N-Heterocyclic Carbene (NHC)-catalyzed oxidative formal [4 + 2] annulation of acylhydrazones with saturated carboxylic acids bearing gamma-H to assemble delta lactams featuring a chiral carbon stereogenic center was developed through an in situ activation strategy. The ready availability of the starting materials, excellent enantioselectivity, facile assembly, high yields, and potential biological significance of the final products make this protocol an attractive alternative for the construction of the pyridinone scaffold. PMID- 26646555 TI - Effects of Recording Food Intake Using Cell Phone Camera Pictures on Energy Intake and Food Choice. AB - BACKGROUND: The well-documented increases in obesity and unhealthy dietary practices substantiate the need for evidence-based tools that can help people improve their dietary habits. The current spread of mobile phone-embedded cameras offers new opportunities for recording food intake. Moreover, the act of taking pictures of food consumed may enhance visual consciousness of food choice and quantity. The present study aimed to assess the effect of using cell phone pictures to record food intake on energy intake and food choice in college students. The effectiveness and acceptability of cell phone picture-based diet recording also was assessed. METHODS: A repeated measures crossover design was used. One group of participants entered their food intake online during 3 days based on their memory, although a second group recorded their food intake using cell phone pictures as their reference. Participants then crossed over to complete 3 more days of diet recording using the alternate method. Focus groups were conducted to obtain feedback on the effectiveness and acceptability of cell phone picture-based diet recording. RESULTS: Intake of meat and vegetable servings were significantly higher in the memory period compared with the cell phone period, regardless of the order. Results from the focus group indicated a positive attitude toward the use of cell phone pictures in recording food intake and an increased awareness of food choice and portion size. LINKING EVIDENCE TO ACTION: Cell phone pictures may be an easy, relevant, and accessible method of diet self-monitoring when aiming at dietary changes. Future trials should combine this technique with healthy eating education. PMID- 26646557 TI - Seed-borne nature of a begomovirus, Mung bean yellow mosaic virus in black gram. AB - The yellow mosaic viruses (YMV) infecting legumes are considered to be the most devastating begomoviruses as they incite considerable yield loss. The yellow discoloration of pods and seeds of infected plants and symptom emergence in the very first trifoliate leaf of the plants in the field were suggestive that the virus may be seed borne, which was investigated in the present study. The distribution of the virus in various parts of the seeds of black gram (Vigna mungo L. Hepper) plants naturally infected in the field was determined by polymerase chain reaction (PCR), Southern blot analysis, and sequencing. Nucleotide sequencing of the PCR amplicons from the seed parts from groups of ten seeds revealed the presence of mung bean yellow mosaic virus (MYMV) in the seed coat, cotyledon, and embryonic axes. The presence of virion particles was confirmed through double antibody sandwich enzyme-linked immunosorbent assay (DAS ELISA) and immunosorbent electron microscopy (ISEM) even in a single whole seed. In confocal microscopy, positive fluorescent signals were obtained using coat protein gene-specific primers in the embryonic axes. However, in the growth tests performed with the same batch of seeds, there was no symptom development in the seedlings though the virus (both DNA A and B components) was detected in 32 % of tested seedlings. In this study, the MYMV was detected in seed coat, cotyledon, and embryo. This study revealed that the MYMV is a seed-borne virus. PMID- 26646556 TI - Neurological damage after transcatheter aortic valve implantation compared with surgical aortic valve replacement in intermediate risk patients. AB - BACKGROUND AND PURPOSE: The risk of neurological damage following transcatheter aortic valve implantation (TAVI) vs. surgical aortic valve replacement (SAVR) in severe aortic stenosis patients deemed to be at intermediate surgical risk is unknown. In this target population, the degree of neurological damage was compared using brain diffusion-weighted magnetic resonance imaging (DW-MRI) and cognitive testing. METHODS: Forty-six consecutive patients undergoing TAVI (78.0 +/- 8.3 years; STS score 4.4 +/- 1.7) and 37 patients undergoing SAVR (78.9 +/- 6.2 years, STS score 4.7 +/- 1.7) were compared. DW-MRI was performed in 67 patients (40 in TAVI vs. 27 in SAVR group) within the first 15 days post procedure. A cognitive assessment was performed at baseline and at 3 months follow-up. The occurrence of potential cognitive impairment post-intervention was determined using the reliable change index (RCI). RESULTS: Baseline characteristics were comparable in TAVI and SAVR groups except for the presence of severe calcified aorta, which occurred more frequently in the TAVI group [17 (37 %) vs. 0 (0 %), p < 0.001]. Three patients presented a clinical stroke: 1 (2.2 %) in TAVI group vs. 2 (5.4 %) in SAVR group, (p = 0.58). No differences were observed in the rate of acute ischemic cerebral lesions detected by DWI in patients undergoing TAVI vs. SAVR [18 (45 %) in TAVI vs. 11 (40.7 %) in SAVR, adjusted OR 0.95; 95 % CI 0.25-3.65; p = 0.94]. TAVI was associated with a lower number of DWI lesions (adjusted OR 0.54; 95 % IC 0.37-0.79; p = 0.02). An older age was a predictor of the occurrence of acute lesions (OR 1.13; 95 % CI 1.03 1.23; p = 0.01), and the use of vitamin-K antagonist therapy had a protective effect (OR 0.25; 95 % CI 0.07-0.92; p = 0.037) regardless the type of intervention. Overall no significant changes were observed in global cognitive scores post-intervention (p = 0.23). The RCI showed mild cognitive decline in nine patients undergoing TAVI (26.4 %) and in six patients in the SAVR group (30.0 %) (p = 0.96). There was no association between the number and total volume of lesions and the occurrence of cognitive decline (CC Spearman 0.031, p = 0.85 and -0.011, p = 0.97, respectively). CONCLUSIONS: TAVI and SAVR were associated with a similar rate of acute silent ischemic cerebral lesions in intermediate risk patients. Although acute lesions occurred very frequently in both strategies, their cognitive impact was not clinically relevant. PMID- 26646558 TI - Protective Effects of Diallyl Sulfide on Ovalbumin-Induced Pulmonary Inflammation of Allergic Asthma Mice by MicroRNA-144, -34a, and -34b/c-Modulated Nrf2 Activation. AB - Allergic airway disorder is characterized by an increase in the level of reactive oxygen species (ROS). The induction of inflammation and hyperresponsiveness by an allergen was ameliorated by antioxidants in vivo. This study investigated the protective effects and underlying mechanism of diallyl sulfide (DAS) on ovalbumin (OVA)-induced allergic asthma of BALB/c mice. The animals were intraperitoneally sensitized by inhaling OVA to induce chronic airway inflammation. By administering DAS, a decrease of the infiltrated inflammatory cell counts and the levels of IL-4 and IL-10 in bronchoalveolar lavage fluid as well as the OVA specific immunoglobulin E levels in sera were observed. DAS also effectively inhibited OVA-induced inflammatory cell infiltration and mucus hypersecretion in lung tissue. Several OVA-induced inflammatory factors (ROS, 8-hydroxy-2' deoxyguanosine, 8-iso-prostaglandin F2alpha, and NF-kappaB) were inhibited by DAS. In addition, DAS increased OVA inhalation-reduced levels of Nrf2 activation by regulating microRNA-144, -34a and -34b/c. Together, the pathogenesis of OVA induced asthma is highly associated with oxidative stress, and DAS may be an effective supplement to alleviate this disease. PMID- 26646559 TI - Mthfr as a modifier of the retinal phenotype of Crb1(rd8/rd8) mice. AB - Mutations in crumb homologue 1 (CRB1) in humans are associated with Leber's congenital amaurosis (LCA) and retinitis pigmentosa (RP). There is no clear genotype-phenotype correlation for human CRB1 mutations in RP and LCA. The high variability in clinical features observed in CRB1 mutations suggests that environmental factors or genetic modifiers influence severity of CRB1 related retinopathies. Retinal degeneration 8 (rd8) is a spontaneous mutation in the Crb1 gene (Crb1(rdr/rd8)). Crb1(rdr/rd8) mice present with focal disruption in the outer retina manifesting as white spots on fundus examination. Mild retinal dysfunction with decreased b-wave amplitude has been reported in Crb1(rdr/rd8) mice at 18 months. Methylene tetrahydrofolate reductase (MTHFR) is a crucial enzyme of homocysteine metabolism. MTHFR mutations are prevalent in humans and are linked to a broad spectrum of disorders including cardiovascular and neurodegenerative diseases. We recently reported the retinal phenotype in Mthfr deficient (Mthfr(+/-)) heterozygous mice. At 24 weeks the mice showed decreased RGC function, thinner nerve fiber layer, focal areas of vascular leakage and 20% fewer cells in the ganglion cell layer (GCL). Considering the variability in CRB1 related retinopathies and the high occurrence of human MTHFR mutations we evaluated whether Mthfr deficiency influences rd8 retinal phenotype. Mthfr heterozygous mice with rd8 mutations (Mthfr(+/-)(rd8/rd8)) and Crb(rd8/rd8) mice (Mthfr(+/+rd8/rd8)) mice were subjected to comprehensive retinal evaluation using ERG, fundoscopy, fluorescein angiography (FA), morphometric and retinal flat mount immunostaining analyses of isolectin-B4 at 8-54 wks. Assessment of retinal function revealed a significant decrease in the a-, b- and c-wave amplitudes in Mthfr(+/-)(rd8/rd8) mice at 52 wks. Fundoscopic evaluation demonstrated the presence of signature rd8 spots in Mthfr(+/+rd8/rd8) mice and an increase in the extent of these rd8 spots in Mthfr(+/-)(rd8/rd8) mice at 24 weeks and beyond. FA revealed marked vascular leakage, ischemia and vascular tortuosity in Mthfr(+/ )(rd8/rd8) mice at 24 and 52 weeks. Retinal dysplasia was observed in ~14-33% Mthfr(+/-)(rd8/rd8) mice by morphometric analysis. This was accompanied by a ~20% reduction in cells of the GCL of Mthfr(+/-)(rd8/rd8) mice at 24 and 52 weeks. Retinal flat mount immunostaining with isolectin-B4 showed neovascularization and loss of blood vessel integrity in Mthfr(+/-)(rd8/rd8) mice in contrast to mild vasculopathy in Mthfr(+/+rd8/rd8) mice. Taken together, our data support an earlier onset and worsened retinal phenotype when Mthfr and rd8 mutations coexist. Our study sets the stage for future studies to investigate the role of MTHFR deficiency in human CRB1 retinopathies. PMID- 26646560 TI - Early astrocyte redistribution in the optic nerve precedes axonopathy in the DBA/2J mouse model of glaucoma. AB - Glaucoma challenges the survival of retinal ganglion cell axons in the optic nerve through processes dependent on both aging and ocular pressure. Relevant stressors likely include complex interplay between axons and astrocytes, both in the retina and optic nerve. In the DBA/2J mouse model of pigmentary glaucoma, early progression involves axonopathy characterized by loss of functional transport prior to outright degeneration. Here we describe novel features of early pathogenesis in the DBA/2J nerve. With age the cross-sectional area of the nerve increases; this is associated generally with diminished axon packing density and survival and increased glial coverage of the nerve. However, for nerves with the highest axon density, as the nerve expands mean cross-sectional axon area enlarges as well. This early expansion was marked by disorganized axoplasm and accumulation of hyperphosphorylated neurofilamants indicative of axonopathy. Axon expansion occurs without loss up to a critical threshold for size (about 0.45-0.50 MUm(2)), above which additional expansion tightly correlates with frank loss of axons. As well, early axon expansion prior to degeneration is concurrent with decreased astrocyte ramification with redistribution of processes towards the nerve edge. As axons expand beyond the critical threshold for loss, glial area resumes an even distribution from the center to edge of the nerve. We also found that early axon expansion is accompanied by reduced numbers of mitochondria per unit area in the nerve. Finally, our data indicate that both IOP and nerve expansion are associated with axon enlargement and reduced axon density for aged nerves. Collectively, our data support the hypothesis that diminished bioenergetic resources in conjunction with early nerve and glial remodeling could be a primary inducer of progression of axon pathology in glaucoma. PMID- 26646561 TI - Combinations of FUT2 gene polymorphisms and environmental factors are associated with oral cancer risk. AB - In humans, fucosyltransferase-2 (FUT2) plays an important role in alpha1,2- linkage of fucose and participates in complex cellular processes such as fertilization, embryogenesis, and immune responses. However, little information is available concerning the FUT2 expression in tumorigenesis. The aim of this work was to investigate the combined effect of FUT2 gene polymorphisms and exposure to environmental carcinogens on the susceptibility and clinic pathological characteristics of oral cancer. Four SNPs of the FUT2 gene (rs281377, rs1047781, rs601338, and rs602662) from 1200 non-cancer controls and 700 oral squamous cell carcinoma (OSCC) patients were analyzed by real-time polymerase chain reaction (PCR). The samples were further analyzed to clarify the associations between these gene polymorphisms and the risk of OSCC, and the impact of these SNPs on the susceptibility and clinic pathological characteristics of OSCC. After adjusting for other covariant, we observed that betel quid chewing among 1255 smokers who carrying at least one C genotype (TC and CC) at rs281377 and least one T genotype (TA and TT) at rs1047781 were exhibited synergistic effects of environmental factors (betel quid and cigarette use) on the susceptibility of oral cancer. Taken together, our results support gene-environment interactions of FUT2 polymorphisms with smoking and betel quid chewing habits possibly altering oral cancer susceptibility. Furthermore, to our knowledge, this is the first study of association between FUT2 gene variants and OSCC risk. PMID- 26646562 TI - Influence of a single-nucleotide polymorphism of the DNA mismatch repair-related gene exonuclease-1 (rs9350) with prostate cancer risk among Chinese people. AB - In this study, we aimed to identify the influence of exonuclease 1 (EXO1) single nucleotide polymorphism rs9350, which is involved in DNA mismatch repair, on prostate cancer risk in Chinese people. In our hospital-based case-control study, 214 prostate cancer patients and 253 cancer-free control subjects were enrolled from three hospitals in China. Genotyping for rs9350 was performed by the SNaPshot((r)) method using peripheral blood samples. Consequently, a significantly higher prostate cancer risk was observed in patients with the CC genotype [odds ratio (OR) = 1.678, 95 % confidence interval (CI) = 1.130-2.494, P = 0.010] than in those with the CT genotype. Further, the CT/TT genotypes were significantly associated with increased prostate cancer risk (adjusted OR = 1.714, 95 % CI = 1.176-2.500, P = 0.005), and the C allele had a statistically significant compared with T allele (P = 0.009) of EXO1 (rs9350). Through stratified analysis, significant associations were revealed for the CT/TT genotype in the subgroup with diagnosis age >72 (adjusted OR = 1.776, 95 % CI = 1.051-3.002, P = 0.032) and in patients with localized disease subgroup (adjusted OR = 1.798, 95 % CI = 1.070-3.022, P = 0.027). In addition, we observed that patients with prostate-specific antigen (PSA) levels of <=10 ng/mL were more likely to have the CT/TT genotypes than those with PSA levels of >10 ng/mL (P = 0.006). For the first time, we present evidence that the inherited EXO1 polymorphism rs9350 may have a substantial influence on prostate cancer risk in Chinese people. We believe that the rs9350 could be a useful biomarker for assessing predisposition for and early diagnosis of prostate cancer. PMID- 26646563 TI - Nutrient deprivation-related OXPHOS/glycolysis interconversion via HIF-1alpha/C MYC pathway in U251 cells. AB - Although the Warburg effect is a dominant metabolic phenotype observed in cancers, the metabolic changes and adaptation occurring in tumors have been demonstrated to extend beyond the Warburg effect and thus considered a secondary effect to the transformation process of carcinogenesis, including nutritional deficiencies. However, the role of nutritional deficiencies in this metabolic reprogramming (e. g., oxidative phosphorylation (OXPHOS)/glycolysis interconversion) is not completely known yet. Here, we showed that under regular culture condition, the proliferation of U251 cells, but not other tumor cell lines, preferentially performed the Warburg effect and was remarkably inhibited by oxamic acid which can inhibit the activity of lactate dehydrogenase (LDH); whereas under serum starvation, glycolysis was depressed, tricarboxylic acid cycle (TCA) was enhanced, and the activity of OXPHOS was reinforced to maintain cellular ATP content in a high level, but interestingly, we observed a decreased expression of reactive oxygen species (ROS). Moreover, the upregulated activity of mitochondrial complex I was confirmed by Western blots and showed that the mitochondrial-related protein, NDUFA9, NDUFB8, ND1, and VDAC1 were remarkably increased after serum starved. Mechanistically, nutritional deficiencies could reduce hypoxia-inducible factor alpha (HIF-1alpha) protein expression to increase C-MYC protein level, which in turn increased nuclear respiratory factor 1 (NRF1) and mitochondrial transcription factor A (TFAM) transcription to enhance the activity of OXPHOS, suggesting that metabolic reprogramming by the changes of microenvironment during the carcinogenesis can provide some novel therapeutic clues to traditional cancer treatments. PMID- 26646564 TI - Zoledronic acid induces apoptosis via stimulating the expressions of ERN1, TLR2, and IRF5 genes in glioma cells. AB - Glioblastoma multiforme (GBM) is the most common and aggressive brain tumor that affects older people. Although the current therapeutic approaches for GBM include surgical resection, radiotherapy, and chemotherapeutic agent temozolomide, the median survival of patients is 14.6 months because of its aggressiveness. Zoledronic acid (ZA) is a nitrogen-containing bisphosphonate that exhibited anticancer activity in different cancers. The purpose of this study was to assess the potential effect of ZA in distinct signal transduction pathways in U87-MG cells. In this study, experiments performed on U87-MG cell line (Human glioblastoma-astrocytoma, epithelial-like cell line) which is an in vitro model of human glioblastoma cells to examine the cytotoxic and apoptotic effects of ZA. IC50 dose of ZA, 25 MUM, applied on U87-MG cells during 72 h. ApoDIRECT In Situ DNA Fragmentation Assay was used to investigate apoptosis of U87MG cells. The quantitative reverse transcription polymerase chain reaction (qRT-PCR) (LightCycler480 System) was carried out for 48 gene expression like NF-kappaB, Toll-like receptors, cytokines, and inteferons. Our results indicated that ZA (IC50 dose) increased apoptosis 1.27-fold in U87MG cells according to control cells. According to qRT-PCR data, expression levels of the endoplasmic reticulum nuclei-1 (ERN1), Toll-like receptor 2 (TLR2), and human IFN regulatory factor 5 (IRF5) tumor suppressor genes elevated 2.05-, 2.08-, and 2.3-fold by ZA, respectively, in U87MG cells. Our recent results indicated that ZA have a key role in GBM progression and might be considered as a potential agent in glioma treatment. PMID- 26646565 TI - The Entamoeba histolytica, Arp2/3 Complex Is Recruited to Phagocytic Cups through an Atypical Kinase EhAK1. AB - The parasite Entamoeba histolytica is the etiological agent of amoebiasis and phagocytosis plays a key role in virulence of this organism. Signaling pathways involved in activation of cytoskeletal dynamics required for phagocytosis remain to be elucidated. Phagocytosis is initiated with sequential recruitment of EhC2PK, EhCaBP1, EhCaBP3 and an atypical kinase EhAK1 after particle attachment. Here we show that EhARPC1, an essential subunit of the actin branching complex Arp 2/3 is recruited to the phagocytic initiation sites by EhAK1. Imaging, expression knockdown of different molecules and pull down experiments suggest that EhARPC1 interacts with EhAK1 and that it is required during initiation of phagocytosis and phagosome formation. Moreover, recruitment of EhARPC2 at the phagocytosis initiation by EhAK1 is also observed, indicating that the Arp 2/3 complex is recruited. In conclusion, these results suggests a novel mechanism of recruitment of Arp 2/3 complex during phagocytosis in E. histolytica. PMID- 26646566 TI - Discovery of the Fuyan teeth: challenging or complementing the out-of-Africa scenario? PMID- 26646567 TI - Physiological approaches to understanding molecular actions on dorsolateral prefrontal cortical neurons underlying higher cognitive processing. AB - Revealing how molecular mechanisms influence higher brain circuits in primates will be essential for understanding how genetic insults lead to increased risk of cognitive disorders. Traditionally, modulatory influences on higher cortical circuits have been examined using lesion techniques, where a brain region is depleted of a particular transmitter to determine how its loss impacts cognitive function. For example, depletion of catecholamines or acetylcholine from the dorsolateral prefrontal cortex produces striking deficits in working memory abilities. More directed techniques have utilized direct infusions of drug into a specific cortical site to try to circumvent compensatory changes that are common following transmitter depletion. The effects of drug on neuronal firing patterns are often studied using iontophoresis, where a minute amount of drug is moved into the brain using a tiny electrical current, thus minimizing the fluid flow that generally disrupts neuronal recordings. All of these approaches can be compared to systemic drug administration, which remains a key arena for the development of effective therapeutics for human cognitive disorders. Most recently, viral techniques are being developed to be able to manipulate proteins for which there is no developed pharmacology, and to allow optogenetic manipulations in primate cortex. As the association cortices greatly expand in brain evolution, research in nonhuman primates is particularly important for understanding the modulatory regulation of our highest order cognitive operations. PMID- 26646568 TI - Accelerated evolution of constraint elements for hematophagic adaptation in mosquitoes. AB - Comparative genomics is a powerful approach that comprehensively interprets the genome. Herein, we performed whole genome comparative analysis of 16 Diptera genomes, including four mosquitoes and 12 Drosophilae. We found more than 540 000 constraint elements (CEs) in the Diptera genome, with the majority found in the intergenic, coding and intronic regions. Accelerated elements (AEs) identified in mosquitoes were mostly in the protein-coding regions (>93%), which differs from vertebrates in genomic distribution. Some genes functionally enriched in blood digestion, body temperature regulation and insecticide resistance showed rapid evolution not only in the lineage of the recent common ancestor of mosquitoes (RCAM), but also in some mosquito lineages. This may be associated with lineage specific traits and/or adaptations in comparison with other insects. Our findings revealed that although universally fast evolution acted on biological systems in RCAM, such as hematophagy, same adaptations also appear to have occurred through distinct degrees of evolution in different mosquito species, enabling them to be successful blood feeders in different environments. PMID- 26646569 TI - Morphometric variability of Arctodiaptomus salinus (Copepoda) in the Mediterranean-Black Sea region. AB - Inter-species variability in morphological traits creates a need to know the range of variability of characteristics in the species for taxonomic and ecological tasks. Copepoda Arctodiaptomus salinus, which inhabits water bodies across Eurasia and North Africa, plays a dominant role in plankton of different water bodies-from fresh to hypersaline. This work assesses the intra- and inter population morphometric variability of A. salinus in the Mediterranean-Black Sea region and discusses some observed regularities. The variability of linear body parameters and proportions was studied. The impacts of salinity, temperature, and population density on morphological characteristics and their variability can manifest themselves in different ways at the intra- and inter-population levels. A significant effect of salinity, pH and temperature on the body proportions was not found. Their intra-population variability is dependent on temperature and salinity. Sexual dimorphism of A. salinus manifests in different linear parameters, proportions, and their variability. There were no effects of temperature, pH and salinity on the female/male parameter ratio. There were significant differences in the body proportions of males and females in different populations. The influence of temperature, salinity, and population density can be attributed to 80%-90% of intra-population variability of A. salinus. However, these factors can explain less than 40% of inter-population differences. Significant differences in the body proportions of males and females from different populations may suggest that some local populations of A. salinus in the Mediterranean-Black Sea region are in the initial stages of differentiation. PMID- 26646570 TI - Stress-relevant social behaviors of middle-class male cynomolgus monkeys (Macaca fascicularis). AB - Stress from dominance ranks in human societies, or that of other social animals, especially nonhuman primates, can have negative influences on health. Individuals holding different social status may be burdened with various stress levels. The middle class experiences a special stress situation within the dominance hierarchy due to its position between the higher and lower classes. Behaviorally, questions about where middle-class stress comes from and how individuals adapt to middle-class stress remain poorly understood in nonhuman primates. In the present study, social interactions, including aggression, avoidance, grooming and mounting behaviors, between beta males, as well as among group members holding higher or lower social status, were analyzed in captive male-only cynomolgus monkey groups. We found that aggressive tension from the higher hierarchy members was the main origin of stress for middle-class individuals. However, behaviors such as attacking lower hierarchy members immediately after being the recipient of aggression, as well as increased avoidance, grooming and mounting toward both higher and lower hierarchy members helped alleviate middle-class stress and were particular adaptations to middle-class social status. PMID- 26646571 TI - Patterns of reptile and amphibian species richness along elevational gradients in Mt. Kenya. AB - Faunal species richness is traditionally assumed to decrease with increasing elevation and decreasing primary productivity. Species richness is reported to peak at mid-elevation. This survey examines the herpetofaunal diversity and distribution in Mt. Kenya (central Kenya) by testing the hypothesis that changes in species richness with elevation relate to elevation-dependent changes in climate. Sampling along transects from an elevation of approximately 1 700 m in Chogoria forest block (wind-ward side) and approximately 2 600 m in Sirimon block (rain shadow zone) upwards in March 2009. This starts from the forest to montane alpine zones. Sampling of reptiles and amphibians uses pitfall traps associated with drift fences, time-limited searches and visual encounter surveys. The results show that herpetofaunal richness differs among three vegetation zones along the elevation gradient. Chogoria has higher biodiversity than Sirimon. More species occur at low and middle elevations and few exist at high elevations. The trends are consistent with expected optimum water and energy variables. The lower alpine montane zone has high species richness but low diversity due to dominance of some high elevations species. Unambiguous data do not support a mid-domain effect (mid-elevation peak) because the observed trend better fits a model in which climatic variables (rainfall and temperature) control species richness, which indirectly measures productivity. It is important to continue protection of all indigenous forests, especially at low to mid elevations. These areas are vulnerable to human destruction yet are home to some endemic species. Firebreaks can limit the spread of the perennial wildfires, especially on the moorlands. PMID- 26646572 TI - Morphometric studies of genus Placocheilus (Teleostei: Cypriniformes) from Red River, China. AB - It is practically difficult to differentiate Placocheilus robustus and Placocheilus caudofasciatus from Red River drainage of China. Without stated reasons, P. robustus has been assumed as the synonyms of P. caudofasciatus. The present study aims to decipher the morphological differences between two species so as to provide reliable clues for their classification by multivariate morphometry. A total of 72 specimens of two species in genus Placocheilus were examined. Besides morphological character comparisons, 10 anatomic landmarks were utilized and 23 frame structures and 15 general characters measured. The scatter plot results of principal component analysis showed that all specimens were clustered together and could not be defined as two distinct species. No significant morphological differences existed in four diagnostic characters between P. robustus and P. caudofasciatus. Thus the results of the present study fail to support P. robustus as a valid and independent species. PMID- 26646573 TI - Laryngeal biopsies: are we doing more, and why? A decade of results. AB - BACKGROUND: Over the last decade, we have observed an escalating trend in the number of laryngeal biopsies performed, despite the incidence of laryngeal cancer remaining constant. This study aimed to quantify the rate of laryngeal biopsies and record the indications. METHOD: A retrospective analysis of laryngeal biopsies performed in North Glasgow, Scotland, UK, between 2001 and 2010, was conducted. RESULTS: From 2001 to 2010, 3902 laryngeal biopsies were carried out in North Glasgow. Histopathological results indicated the following diagnoses: squamous cell carcinoma, in 889 cases (23 per cent); dysplasia, in 986 cases (25 per cent); 'no tumour', in 913 cases (23 per cent); and benign pathology, in the remaining 1084 cases (28 per cent). There has been a significant increase in the number of biopsies performed after 2004, with the incidence of squamous cell carcinoma and benign disease remaining relatively static. CONCLUSION: It is hypothesised that organ preservation strategies, endoscopic resection in early stage laryngeal cancer and chemoradiotherapy in advanced head and neck cancer are responsible for the increase in laryngeal biopsies. PMID- 26646574 TI - A Case of Psoriasis Replaced by Allergic Contact Dermatitis in a 12-Year-Old Boy. AB - Allergic contact dermatitis is a significant clinical problem in children and one that the use of essential oils and natural remedies probably exacerbates. We report a case of chronic plaque psoriasis replaced by allergic contact dermatitis in a 12-year-old boy. We suspect that the immunologic response to a hapten in lavender oil disrupted the pathogenesis of psoriasis, causing the psoriasis to temporarily "disappear." PMID- 26646575 TI - Alcohol Outlet Density and Intimate Partner Violence in a Nonmetropolitan College Town: Accounting for Neighborhood Characteristics and Alcohol Outlet Types. AB - There is a growing evidence of an ecological association between alcohol outlet density and intimate partner violence. It is reasonable to assume, however, that not all types of alcohol outlets contribute equally to criminal behavior, and to date, most ecological studies have been of large urban cities. Using Bloomington, Indiana, block groups as units of analysis and controlling for several structural characteristics associated with violence rates, I estimated spatially lagged regression models to determine if the variation in alcohol outlet density, including total outlets and disaggregating by on- and off-premise outlets, is related to intimate partner violence density. Results suggested that total alcohol outlet density and off-premise alcohol outlet density were significantly associated with intimate partner violence density. On-premise alcohol outlet density was not significantly associated with intimate partner violence density. These results not only extend the geographic scope of this relationship beyond large metropolitan areas but also have important policy implications. PMID- 26646576 TI - Can Psychological, Social and Demographical Factors Predict Clinical Characteristics Symptomatology of Bipolar Affective Disorder and Schizophrenia? AB - Schizophrenia (SCH) is a complex, psychiatric disorder affecting 1 % of population. Its clinical phenotype is heterogeneous with delusions, hallucinations, depression, disorganized behaviour and negative symptoms. Bipolar affective disorder (BD) refers to periodic changes in mood and activity from depression to mania. It affects 0.5-1.5 % of population. Two types of disorder (type I and type II) are distinguished by severity of mania episodes. In our analysis, we aimed to check if clinical and demographical characteristics of the sample are predictors of symptom dimensions occurrence in BD and SCH cases. We included total sample of 443 bipolar and 439 schizophrenia patients. Diagnosis was based on DSM-IV criteria using Structured Clinical Interview for DSM-IV. We applied regression models to analyse associations between clinical and demographical traits from OPCRIT and symptom dimensions. We used previously computed dimensions of schizophrenia and bipolar affective disorder as quantitative traits for regression models. Male gender seemed protective factor for depression dimension in schizophrenia and bipolar disorder sample. Presence of definite psychosocial stressor prior disease seemed risk factor for depressive and suicidal domain in BD and SCH. OPCRIT items describing premorbid functioning seemed related with depression, positive and disorganised dimensions in schizophrenia and psychotic in BD. We proved clinical and demographical characteristics of the sample are predictors of symptom dimensions of schizophrenia and bipolar disorder. We also saw relation between clinical dimensions and course of disorder and impairment during disorder. PMID- 26646577 TI - Healthcare Utilization and Expenditures for Persons with Diabetes Comorbid with Mental Illnesses. AB - The aim of this study was to investigate healthcare utilization and expenditure for patients with diabetes comorbid with and without mental illnesses in Taiwan. People with diabetes comorbid with and without mental illnesses in 2000 were identified and followed up to 2004 to explore the healthcare utilization and expenditure. Healthcare utilization included outpatient visits and use of hospital inpatient services, and expenditure included outpatient, inpatient and total medical expenditure. General estimation equation models were used to explore the factors associated with outpatient visits and expenditure. To identify the factors associated with hospitalization, multiple logistic regressions were applied. The average number of annual outpatient visits of the patients with mental illnesses ranged from 37.01 to 41.91, and 28.83 to 31.79 times for the patients without mental illnesses from 2000 to 2004. The average annual total expenditure for patients with mental illnesses during this period ranged from NT$77,123-NT$90,790, and NT$60,793- NT$84,984 for those without mental illnesses. After controlling for covariates, the results indicated that gender, age, mental illness and time factor were associated with outpatient visits. Gender, age, and time factor were associated with total expenditure. Age and mental illness were associated with hospitalization in logistic regression. The healthcare utilization and expenditure for patients with mental illnesses was significantly higher than for patients without mental illnesses. The factors associated with healthcare utilization and expenditure included gender, age, mental illness and time trends. PMID- 26646578 TI - Combined Use of Opioids and Antidepressants in the Treatment of Pain: A Review of Veterans Health Administration Data for Patients with Pain Both With and Without Co-morbid Depression. AB - Musculoskeletal pain is prevalent among Veterans treated within the Veterans Health Administration (VHA). Depression is highly co-prevalent, and antidepressants are increasingly being used for psychiatric and analgesic benefit. The current study examined prescribing patterns of antidepressants and opioids in the context of musculoskeletal pain using a national VHA database. All Veterans diagnosed with musculoskeletal pain who attended at least one appointment through the VHA during Fiscal Year 2012 were dichotomized based on the presence or absence of a depression diagnosis. We compared the proportion in each group that were prescribed antidepressants to the entire sample and repeated this comparison along a continuum of the number of annual opioid prescriptions received (ranging in five categories from no opioids up to >20 scripts). Of the 5.1 million Veterans seen, 19.1 % were diagnosed with musculoskeletal pain, of whom, 27.2 % were diagnosed with major depressive disorder. Antidepressants were prescribed to 78.41 % of patients with musculoskeletal pain and depression, compared to 20.23 % of those without depression. For both groups, antidepressant use increased linearly as annual opioid fills increased. Across the categories of opioid use, patients with depression showed a 13.98 % increase in antidepressant use, compared to a 33.97 % increase in the non-depressed group. Results suggest that antidepressants are frequently prescribed to patients with musculoskeletal pain who are using opioids, consistent with multi-modal pharmacotherapy. Increasing use of antidepressants in conjunction with escalating opioid prescribing, particularly in the absence of diagnosed depression, suggests that antidepressants are being used in both groups to complement opioid therapy. PMID- 26646579 TI - Oxaliplatin Induced Suicidal Death of Human Erythrocytes. AB - BACKGROUND/AIMS: The alkylating drug oxaliplatin is widely used for chemotherapy of malignancy. Oxaliplatin is effective by inducing both, necrosis and apoptosis. Similar to necrosis or apoptosis of nucleated cells, erythrocytes may enter hemolysis, which is apparent from hemoglobin release or eryptosis, which is characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Triggers of eryptosis include oxidative stress and/or Ca2+ entry with increase of cytosolic Ca2+ activity ([Ca2+]i). The present study explored, whether and how oxaliplatin induces eryptosis. METHODS: Phosphatidylserine exposure at the cell surface was quantified utilizing annexin-V-binding, cell volume estimated from forward scatter, hemolysis deduced from hemoglobin release, [Ca2+]i determined utilizing Fluo-3 fluorescence, and reactive oxygen species (ROS) abundance visualized using 2',7'-dichlorodihydrofluorescein diacetate (DCFDA) dependent fluorescence. RESULTS: A 48 hours exposure of human erythrocytes to oxaliplatin (10 ug/ml) significantly increased the percentage of annexin-V-binding cells, significantly decreased forward scatter, significantly increased Fluo-3 fluorescence, and significantly increased DCFDA fluorescence. The effect of oxaliplatin on annexin V-binding and forward scatter was rather augmented by removal of extracellular Ca2+, but was significantly blunted in the presence of the antioxidant N-acetyl cysteine (1 mM). CONCLUSIONS: Oxaliplatin triggers cell shrinkage and phospholipid scrambling of the erythrocyte cell membrane, an effect partially dependent on ROS formation. PMID- 26646580 TI - Tobacco prevention policies in west-African countries and their effects on smoking prevalence. AB - BACKGROUND: The WHO Framework Convention on Tobacco Control was shown to effectively lower smoking prevalence in in high income countries, however knowledge for low and middle income settings is sparse. The objective of this study was to describe WHO MPOWER policy measures in thirteen West-African countries and to investigate their correlation with smoking prevalence. METHODS: Age-standardized smoking prevalence data and policy measures were collected from various WHO reports. For analysis MPOWER measures from 2008 and 2010, were combined with prevalence data from 2009 and 2011. Multiple linear regression models were set up. RESULTS: In West-Africa mean smoking prevalence was approximately 20% among males and approximately 3% among females. Policy measures were mostly at a middle or low level. Regression analysis showed that tobacco cessation programs, health warnings on cigarettes, and higher price of cigarettes were negatively correlated with smoking prevalence. Significant effects were observed for only one policy measure (tobacco cessation programs) and only within the male population where smoking prevalence is generally higher. CONCLUSIONS: Tobacco control policies are enforced at relatively low levels in West-African countries. However, improving tobacco control policy implementation according to the WHO Framework Convention on Tobacco Control should assist in the reduction of smoking prevalence in African countries, thereby counteracting pro-smoking initiatives set forth by the tobacco industry. PMID- 26646581 TI - Failure of Intuition When Choosing Whether to Invest in a Single Goal or Split Resources Between Two Goals. AB - In a series of related experiments, we asked people to choose whether to split their attention between two equally likely potential tasks or to prioritize one task at the expense of the other. In such a choice, when the tasks are easy, the best strategy is to prepare for both of them. As difficulty increases beyond the point at which people can perform both tasks accurately, they should switch strategy and focus on one task at the expense of the other. Across three very different tasks (target detection, throwing, and memory), none of the participants switched their strategy at the correct point. Moreover, the majority consistently failed to modify their strategy in response to changes in task difficulty. This failure may have been related to uncertainty about their own ability, because in a version of the experiment in which there was no uncertainty, participants uniformly switched at an optimal point. PMID- 26646582 TI - Time-varying effect modeling with longitudinal data truncated by death: conditional models, interpretations, and inference. AB - Recent studies found that infection-related hospitalization was associated with increased risk of cardiovascular (CV) events, such as myocardial infarction and stroke in the dialysis population. In this work, we develop time-varying effects modeling tools in order to examine the CV outcome risk trajectories during the time periods before and after an initial infection-related hospitalization. For this, we propose partly conditional and fully conditional partially linear generalized varying coefficient models (PL-GVCMs) for modeling time-varying effects in longitudinal data with substantial follow-up truncation by death. Unconditional models that implicitly target an immortal population is not a relevant target of inference in applications involving a population with high mortality, like the dialysis population. A partly conditional model characterizes the outcome trajectory for the dynamic cohort of survivors, where each point in the longitudinal trajectory represents a snapshot of the population relationships among subjects who are alive at that time point. In contrast, a fully conditional approach models the time-varying effects of the population stratified by the actual time of death, where the mean response characterizes individual trends in each cohort stratum. We compare and contrast partly and fully conditional PL GVCMs in our aforementioned application using hospitalization data from the United States Renal Data System. For inference, we develop generalized likelihood ratio tests. Simulation studies examine the efficacy of estimation and inference procedures. PMID- 26646583 TI - Formal Synthesis of Solanoeclepin A: Enantioselective Allene Diboration and Intramolecular [2+2] Photocycloaddition for the Construction of the Tricyclic Core. AB - An enantioselective synthesis of an intermediate in the Tanino total synthesis of solanoeclepin A has been developed. The key step was an intramolecular [2+2] photocycloaddition, which led to the tricyclo[5.2.1.0(1, 6)] decane core in six steps. The first photosubstrate, prepared through an indium-mediated Barbier-type reaction, gave an excellent [2+2] cycloaddition, but it could not be obtained in sufficient enantiopurity. The second photosubstrate, prepared through an asymmetric allene diborylation in high enantiomeric excess, gave the [2+2] cycloaddition product in high yield on irradiation at 365 nm on 20 g scale in a flow system. Other important steps were the replacement of a boronate group at the quaternary carbon by a vinyl group and diastereoselective cyclopropanation of an allylic alcohol. PMID- 26646584 TI - Full-Color Light-Emitting Carbon Dots with a Surface-State-Controlled Luminescence Mechanism. AB - Carbon dots (CDs) with tunable photoluminescence (PL) and a quantum yield of up to 35% in water were hydrothermally synthesized in one pot and separated via silica column chromatography. These separated CDs emitted bright and stable luminescence in gradient colors from blue to red under a single-wavelength UV light. They exhibited high optical uniformity; that is, every sample showed only one peak in the PL excitation spectrum, only one peak in the excitation independent PL emission spectrum, and similar monoexponential fluorescence lifetimes. Although these samples had similar distributions of particle size and graphite structure in their carbon cores, the surface state gradually varied among the samples, especially the degree of oxidation. Therefore, the observed red shift in their emission peaks from 440 to 625 nm was ascribed to a gradual reduction in their band gaps with the increasing incorporation of oxygen species into their surface structures. These energy bands were found to depend on the surface groups and structures but not on the particle size, not as in traditional semiconductor quantum dots. In addition, because of their excellent PL properties and low cytotoxicity, these CDs could be used to image cells in different colors under a single-wavelength light source, and the red-emitting CDs could be used to image live mice because of the strong penetration capability of their fluorescence. PMID- 26646585 TI - Assessing the iron delivery efficacy of transferrin in clinical samples by native electrospray ionization mass spectrometry. AB - Serum transferrin is a key player in iron homeostasis, and its ability to deliver iron to cells via the endosomal pathway critically depends on the presence of carbonate that binds this protein synergistically with ferric ion. Oxalate is another ubiquitous anionic species that can act as a synergistic anion, and in fact its interaction with transferrin is notably stronger compared to carbonate, preventing the protein from releasing the metal in the endosomal environment. While this raises concerns that high oxalate levels in plasma may interfere with iron delivery to tissues, concentration of free oxalate in blood appears to be a poor predictor of impeded availability of iron, as previous studies showed that it cannot displace carbonate from ferro-transferrin on a physiologically relevant time scale under the conditions mimicing plasma. In this work we present a new method that allows different forms of ferro-transferrin (carbonate- vs. oxalate bound) to be distinguished from each other by removing this protein from plasma without altering the composition of the protein/metal/synergistic anion complexes, and determining their accurate masses using native electrospray ionization mass spectrometry (ESI MS). The new method has been validated using a mixture of recombinant proteins, followed by its application to the analysis of clinical samples of human plasma, demonstrating that native ESI MS can be used in clinical analysis. PMID- 26646586 TI - MicroRNAs 125a and 125b inhibit ovarian cancer cells through post-transcriptional inactivation of EIF4EBP1. AB - The aim of the present study was to identify the specific miRNAs involved in regulation of EIF4EBP1 expression in ovarian cancer and to define their biological function. miRNA mimics and miRNA inhibitors were used in quantitative PCR, western blotting, and luciferase reporter assays to assess cell migration, invasiveness, and viability. miR-125a and miR-125b were downregulated in ovarian cancer tissue and cell lines relative to healthy controls. Increased expression of miR-125a and miR-125b inhibited invasion and migration of SKOV3 and OVCAR-429 ovarian cancer cells and was associated with a decrease in EIF4EBP1 expression. The inverse relationship between miR-125a and miR-125b was corroborated by cotransfection of a luciferase reporter plasmid. Furthermore, miR-125a and miR 125b caused apoptosis and decreased cell viability and migration in an apparently EIF4EBP1-directed manner. Collectively, these results indicate that miR-125a and miR-125b are important posttranscriptional regulators of EIF4EBP1 expression, providing rationale for new therapeutic approaches to suppress tumour invasion and migration using miR-125a, miR-125b, or their mimics for the treatment of ovarian cancer. PMID- 26646587 TI - GPER is involved in the stimulatory effects of aldosterone in breast cancer cells and breast tumor-derived endothelial cells. AB - Aldosterone induces relevant effects binding to the mineralcorticoid receptor (MR), which acts as a ligand-gated transcription factor. Alternate mechanisms can mediate the action of aldosterone such as the activation of epidermal growth factor receptor (EGFR), MAPK/ERK, transcription factors and ion channels. The G protein estrogen receptor (GPER) has been involved in the stimulatory effects of estrogenic signalling in breast cancer. GPER has been also shown to contribute to certain responses to aldosterone, however the role played by GPER and the molecular mechanisms implicated remain to be fully understood. Here, we evaluated the involvement of GPER in the stimulatory action exerted by aldosterone in breast cancer cells and breast tumor derived endothelial cells (B-TEC). Competition assays, gene expression and silencing studies, immunoblotting and immunofluorescence experiments, cell proliferation and migration were performed in order to provide novel insights into the role of GPER in the aldosterone activated signalling. Our results demonstrate that aldosterone triggers the EGFR/ERK transduction pathway in a MR- and GPER-dependent manner. Aldosterone does not bind to GPER, it however induces the direct interaction between MR and GPER as well as between GPER and EGFR. Next, we ascertain that the up-regulation of the Na+/H+ exchanger-1 (NHE-1) induced by aldosterone involves MR and GPER. Biologically, both MR and GPER contribute to the proliferation and migration of breast and endothelial cancer cells mediated by NHE-1 upon aldosterone exposure. Our data further extend the current knowledge on the molecular mechanisms through which GPER may contribute to the stimulatory action elicited by aldosterone in breast cancer. PMID- 26646588 TI - RAS-MAPK pathway epigenetic activation in cancer: miRNAs in action. AB - The highly conserved RAS-mitogen activated protein kinase (MAPK) signaling pathway is involved in a wide range of cellular processes including differentiation, proliferation, and survival. Somatic mutations in genes encoding RAS-MAPK components frequently occur in many tumors, making the RAS-MAPK a critical pathway in human cancer. Since the pioneering study reporting that let-7 miRNA acted as tumor suppressor by repressing the RAS oncogene, growing evidence has suggested the importance of miRNAs targeting the RAS-MAPK in oncogenesis. MiRNAs alterations in human cancers may act as a rheostat of the oncogenic RAS signal that is often amplified as cancers progress. However, specific mechanisms leading to miRNAs deregulation and their functional consequences in cancer are far from being fully elucidated. In this review, we provide an experimental validated map of RAS-MAPK oncomiRs and tumor suppressor miRNAs from transmembrane receptor to downstream ERK proteins. MiRNAs could be further considered as potential genetic biomarkers for diagnosis, prognosis, or therapeutic purpose. PMID- 26646589 TI - Methyl-CpG-binding domain sequencing reveals a prognostic methylation signature in neuroblastoma. AB - Accurate assessment of neuroblastoma outcome prediction remains challenging. Therefore, this study aims at establishing novel prognostic tumor DNA methylation biomarkers. In total, 396 low- and high-risk primary tumors were analyzed, of which 87 were profiled using methyl-CpG-binding domain (MBD) sequencing for differential methylation analysis between prognostic patient groups. Subsequently, methylation-specific PCR (MSP) assays were developed for 78 top ranking differentially methylated regions and tested on two independent cohorts of 132 and 177 samples, respectively. Further, a new statistical framework was used to identify a robust set of MSP assays of which the methylation score (i.e. the percentage of methylated assays) allows accurate outcome prediction. Survival analyses were performed on the individual target level, as well as on the combined multimarker signature. As a result of the differential DNA methylation assessment by MBD sequencing, 58 of the 78 MSP assays were designed in regions previously unexplored in neuroblastoma, and 36 are located in non-promoter or non coding regions. In total, 5 individual MSP assays (located in CCDC177, NXPH1, lnc MRPL3-2, lnc-TREX1-1 and one on a region from chromosome 8 with no further annotation) predict event-free survival and 4 additional assays (located in SPRED3, TNFAIP2, NPM2 and CYYR1) also predict overall survival. Furthermore, a robust 58-marker methylation signature predicting overall and event-free survival was established. In conclusion, this study encompasses the largest DNA methylation biomarker study in neuroblastoma so far. We identified and independently validated several novel prognostic biomarkers, as well as a prognostic 58-marker methylation signature. PMID- 26646590 TI - Caspase cleavage of iASPP potentiates its ability to inhibit p53 and NF-kappaB. AB - An intriguing biological question relating to cell signaling is how the inflammatory mediator NF-kB and the tumour suppressor protein p53 can be induced by similar triggers, like DNA damage or infection, yet have seemingly opposing or sometimes cooperative biological functions. For example, the NF-kappaB subunit RelA/p65 has been shown to inhibit apoptosis, whereas p53 induces apoptosis. One potential explanation may be their co-regulation by common cellular factors: inhibitor of Apoptosis Stimulating p53 Protein (iASPP) is one such common regulator of both RelA/p65 and p53. Here we show that iASPP is a novel substrate of caspases in response to apoptotic stimuli. Caspase cleaves the N-terminal region of iASPP at SSLD294 resulting in a prominent 80kDa fragment of iASPP. This caspase cleavage site is conserved in various species from zebrafish to Homo sapiens. The 80kDa fragment of iASPP translocates from the cytoplasm to the nucleus via the RaDAR nuclear import pathway, independent of p53. The 80kDa iASPP fragment can bind and inhibit p53 or RelA/p65 more efficiently than full-length iASPP. Overall, these data reveal a potential novel regulation of p53 and RelA/p65 activities in response to apoptotic stimuli. PMID- 26646592 TI - The Medication Regimen of Patients With Heart Failure: The Gerontologic Considerations and Anticholinergic Burden: A Mixed-Methods Study. AB - BACKGROUND: Although prescription medication adherence has been studied in the population living with heart failure (HF), little attention has focused on the patient's overall medication practices including over-the-counter medications. Patients with HF live with the certainty that their quality of life depends on the proper management of multiple medications. Failure to properly manage prescription medications increases the risk of exacerbation of HF and increased rates of rehospitalization. OBJECTIVES: The aim of the quantitative component of this study was to identify medication practices in patients with HF. The aim of the qualitative component was to identify themes of patients with high and low HF medication self-efficacy. METHODS: A convergent parallel mixed-methods design was followed. Quantitative interviews were conducted by telephone with 41 patients living with HF around their medication-taking and lifestyle behaviors. Immediately thereafter, qualitative interviews were conducted to elicit the patient's perspective of their therapeutic regimen. RESULTS: Patients are prescribed medications not recommended for the gerontologic population and/or risk anticholinergic burden. Although highly confident, patients admit to a plethora of errors. CONCLUSION: Future study is required to ensure safe transitions to home and enhance technology to provide seamless communication between patients and providers. PMID- 26646591 TI - Low beta2-adrenergic receptor level may promote development of castration resistant prostate cancer and altered steroid metabolism. AB - The underlying mechanisms responsible for the development of castration-resistant prostate cancer (CRPC) in patients who have undergone androgen deprivation therapy are not fully understood. This is the first study to address whether beta2-adrenergic receptor (ADRB2)- mediated signaling may affect CRPC progression in vivo. By immunohistochemical analyses, we observed that low levels of ADRB2 is associated with a more rapid development of CRPC in a Norwegian patient cohort. To elucidate mechanisms by which ADRB2 may affect CRPC development, we stably transfected LNCaP cells with shRNAs to mimic low and high expression of ADRB2. Two UDP-glucuronosyltransferases, UGT2B15 and UGT2B17, involved in phase II metabolism of androgens, were strongly downregulated in two LNCaP shADRB2 cell lines. The low-ADRB2 LNCaP cell lines displayed lowered glucuronidation activities towards androgens than high-ADRB2 cells. Furthermore, increased levels of testosterone and enhanced androgen responsiveness were observed in LNCaP cells expressing low level of ADRB2. Interestingly, these cells grew faster than high ADRB2 LNCaP cells, and sustained their low glucuronidation activity in castrated NOD/SCID mice. ADRB2 immunohistochemical staining intensity correlated with UGT2B15 staining intensity in independent TMA studies and with UGT2B17 in one TMA study. Similar to ADRB2, we show that low levels of UGT2B15 are associated with a more rapid CRPC progression. We propose a novel mechanism by which ADRB2 may affect the development of CRPC through downregulation of UGT2B15 and UGT2B17. PMID- 26646593 TI - Smartphone Technology and Text Messaging for Weight Loss in Young Adults: A Randomized Controlled Trial. AB - BACKGROUND: Using smartphone technology and text messaging for health is a growing field. This type of technology is well integrated into the lives of young adults. However, few studies have tested the effect of this type of technology to promote weight loss in young adults OBJECTIVE:: The purpose of this study is to test the effectiveness of a behaviorally based smartphone application for weight loss combined with text messaging from a health coach on weight, body mass index (BMI), and waist circumference in young adults as compared with a control condition. METHODS: Sixty-two young adults, aged 18 to 25 years, were randomized to receive (1) a smartphone application + health coach intervention and counseling sessions or (2) control condition with a counseling session. All outcome measures were tested at baseline and 3 months. These included weight, BMI, waist circumference, dietary habits, physical activity habits, and self efficacy for healthy eating and physical activity. RESULTS: The sample was 71% female and 39% white, with an average age of 20 years and average BMI of 28.5 kg/m. Participants in the smartphone + health coach group lost significantly more weight (P = .026) and had a significant reduction in both BMI (P = .024) and waist circumference (P < .01) compared with controls. CONCLUSIONS: The results of this weight loss trial support the use of smartphone technology and feedback from a health coach on improving weight in a group of diverse young adults. PMID- 26646594 TI - Nursing-Based Dysrhythmia Detection on a Dedicated Stroke Unit Using a Unit-Based Cardiac Telemetry Monitoring System. AB - BACKGROUND: Acute stroke care includes cardiac rhythm monitoring in the first 24 hours. The method of monitoring varies, as do the reported findings. The nurses' role in this process can be intensive, including primary response and review of all data. Competency is critical as the acute stroke setting can be associated with life-threatening dysrhythmias as well as the detection of atrial fibrillation that affects therapy. Limited studies exist to evaluate the effectiveness of a unit-based cardiac monitoring system for which the bedside nurse has primary responsibility. OBJECTIVE: The goal was to determine if a unit based cardiac monitoring system for which the bedside nurse was responsible detected clinically significant dysrhythmias. METHODS: Stroke unit nurses completed a mandatory education program on identifying common dysrhythmias and using the monitoring equipment along with a structured algorithm for cardiac dysrhythmia detection. The nurse was responsible for all alarms as well as review of their patients' data. Their findings were recorded and reviewed by a cardiology team after the 24-hour monitoring was completed. A total of 300 consecutive stokes, transient ischemic attack, and possible stroke patients were enrolled. RESULTS: Nurses identified 96% of all significant dysrhythmias. Twenty eight percent of the stroke patients had a dysrhythmia, of which 79% were atrial fibrillation/atrial flutter. The bedside nurses did identify all 8 new atrial fibrillation cases. CONCLUSION: Stroke unit nurses who complete an educational program can identify dysrhythmias on their patients' unit-based cardiac monitoring systems and can improve patient outcomes. PMID- 26646595 TI - Among Unstable Angina and Non-ST-Elevation Myocardial Infarction Patients, Transient Myocardial Ischemia and Early Invasive Treatment Are Predictors of Major In-hospital Complications. AB - BACKGROUND: Treatment for unstable angina (UA) or non-ST-elevation myocardial infarction (NSTEMI) is aimed at plaque stabilization to prevent infarction. Two treatment strategies are (1) invasive (ie, cardiac catheterization laboratory <24 hours after admission) or (2) selectively invasive (ie, medications with cardiac catheterization laboratory >24 hours for recurrent symptoms). However, it is not known if the frequency of transient myocardial ischemia (TMI) or complications during hospitalization varies by treatment. PURPOSE: We aimed to (1) examine occurrence of TMI in UA/NSTEMI, (2) compare frequency of TMI by treatment pathway, and (3) determine predictors of in-hospital complications (ie, death, myocardial infarction [MI], pulmonary edema, shock, dysrhythmia with intervention). METHODS: Hospitalized patients with coronary artery disease (ie, history of MI, percutaneous coronary intervention/stent, coronary artery bypass graft, >50% lesion via angiogram, or positive troponin) were recruited, and 12 lead electrocardiogram Holter initiated. Clinicians, blinded to Holter data, decided treatment strategy; offline analysis was done after discharge. Transient myocardial ischemia was defined as more than 1-mm ST segment ? or ?, in more than 1 electrocardiographic lead, more than 1 minute. RESULTS: Of 291 patients, 91% were white, 66% were male, 44% had prior MI, and 59% had prior percutaneous coronary intervention/stent or coronary artery bypass graft. Treatment pathway was early in 123 (42%) and selective in 168 (58%). Forty-nine (17%) had TMI: 19 (15%) early invasive, 30 (18%) selective (P = .637). Acute MI after admission was higher in patients with TMI regardless of treatment strategy (early: no TMI 4% vs yes TMI 21%; P = .020; selective: no TMI 1% vs yes TMI 13%; P = .0004). Predictors of major in-hospital complication were TMI (odds ratio, 9.9; 95% confidence interval, 3.84-25.78) and early invasive treatment (odds ratio 3.5; 95% confidence interval, 1.23-10.20). CONCLUSIONS: In UA/NSTEMI patients treated with contemporary therapies, TMI is not uncommon. The presence of TMI and early invasive treatment are predictors of major in-hospital complications. PMID- 26646596 TI - Effectiveness of Chinese Hand Massage on Anxiety Among Patients Awaiting Coronary Angiography: A Randomized Controlled Trial. AB - BACKGROUND: Anxiety is the most common negative emotion among the patients awaiting coronary angiography. The increased anxiety may exacerbate coronary heart disease symptoms and possibly contribute to complications during the procedure. Chinese hand massage is a nonpharmaceutical intervention that has been used in several clinical situations in China and might have beneficial effects on reducing anxiety before coronary angiography. OBJECTIVE: The aim of this study was to evaluate the effectiveness and safety of Chinese hand massage care on anxiety among patients awaiting coronary angiography. METHODS: One hundred eighty five subjects awaiting coronary angiography in a single hospital in Fuzhou, China, between May 2012 and September 2012 were screened. One hundred eligible participants were recruited and randomly assigned into the control or Chinese hand massage group. The control group received the conventional therapies and care according to the guidelines, and those in the Chinese hand massage group received additional Chinese hand massage care in conjunction with the same conventional therapies and care as the control group. The anxiety scores (evaluated by using the Hamilton Anxiety Rating Scale), heart rate, blood pressure, quality of life (Short-Form Health Survey), and the adverse events were recorded at the baseline and after coronary angiography, respectively. RESULTS: The scores of Hamilton Anxiety Rating Scale in the Chinese hand massage group (11.78 [SD, 2.9]) had a statistically significant decrease compared with those in the control group (15.96 [SD, 3.4]) at post-procedure (P < .01). There was no statistically significant difference on blood pressure, heart rate, and Short Form Health Survey at postangiography between the Chinese hand massage group and the control group. No adverse event was reported during the intervention period. CONCLUSIONS: Chinese hand massage effectively alleviated anxiety without any adverse effects among patients awaiting coronary angiography. Therefore, it might be recommended as a nonpharmacological nursing intervention. However, future study with a larger sample size is needed to further confirm the efficacy of Chinese hand massage intervention. PMID- 26646597 TI - Decision Making Among Persons Living With Heart Failure. AB - BACKGROUND: Persons with heart failure (HF) are required to make decisions on a daily basis related to their declining health and make urgent decisions during acute illness exacerbations. However, little is known about the types of decisions patients make. OBJECTIVE: The aims of this study were to critically evaluate the current quantitative literature related to decision making among persons with HF and identify research gaps in HF decision-making research. METHODS: A systematic search of literature about decisions persons with HF make was conducted using PubMed, CINAHL, and PsychINFO databases. The following inclusion criteria were used: sample composed of at least 50% HF participants, concrete decisions were made, and a quantitative study design was used. Two authors performed title, abstract, and full-text reviews independently to identify eligible articles. RESULTS: Twelve quantitative articles were included. Study samples were predominately older, white, male, and married. Two-thirds of the articles focused on decisions related to the end-of-life topics (ie, resuscitation decisions, advanced care planning). The other one-third focused on decisions about care seeking, participant's involvement in treatment decisions during their last clinic visit, and self-care behaviors. CONCLUSIONS: Within the HF literature, the term decision is often ill-defined or not defined. Limitations in methodological rigor limit definitive conclusions about HF decision making. Future studies should consider strengthening study rigor and examining other decision topics such as inclusion of family in making decisions as HF progresses. Research rigorously examining HF decision making is needed to develop interventions to support persons with HF. PMID- 26646598 TI - Factors Associated With the Hospital Arrival Time in Patients With Ischemic Stroke in Korea. AB - BACKGROUND: Stroke is a leading cause of death and disability among the Korean population. Ischemic stroke patients tend to delay arrival at the hospital and often miss the "golden" 3-hour window, which is optimal for tissue plasminogen activator treatment. OBJECTIVE: The purposes of this study were to compare demographic, clinical/behavioral, and sociocultural characteristics of ischemic stroke patients who reside in urban and rural areas of Korea and to identify factors contributing to the time taken from symptom onset to hospital arrival. METHODS: A cross-sectional, descriptive study was conducted using a structured survey in a convenience sample of 229 ischemic stroke patients in Korea. RESULTS: Individuals who resided in rural areas were more likely to be female, older, less educated; had lower incomes; contacted adult children at the onset of stroke; and took a longer time to be transported to a hospital than did those who resided in urban areas (P < .05). Patients who visited an emergency room, transferred via an ambulance, contacted emergency medical services, perceived symptoms as serious, had a family history of stroke, or experienced hemiparesis as the primary stroke symptom arrived at the hospital relatively sooner, whereas patients who experienced unclear symptoms took relatively more time to arrive at the hospital following symptom onset (P < .05). CONCLUSIONS: Nationwide efforts are needed to promote public awareness of stroke and to develop strategies to reduce prehospital delay time for ischemic stroke patients, particularly those who reside in rural areas in Korea. PMID- 26646599 TI - Health Literacy in Older Latinos With Heart Failure: A Systematic Review. AB - BACKGROUND: By 2050, one-third of US residents will be Latino, with an incidence of heart failure (HF) higher than other ethnicities. Culturally linked risk factors and socioeconomic challenges result in cardiometabolic risks, healthcare disparities, and worsening health outcomes. Individuals with low health literacy (HL) and HF are less likely to possess tools for optimal self-care, disease management, or preventative health strategies. OBJECTIVE: In this systematic review, we analyzed the literature studying older Latinos with HF and limited HL. METHOD: We searched the literature and used Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines in an iterative process. Inclusion criteria were research studies, Latinos, HF, and HL. RESULTS: Eight quantitative studies were identified for final review. Inadequate HL was reported in 87.2% of elderly Latinos. Higher HL was associated with more HF knowledge. Clinics serving minorities reported lower HL levels and higher medical complexity. CONCLUSIONS: Nurses and advanced practice nurses serve a pivotal role improving access and understanding of health information. Before conducting intervention research affecting clinical outcomes, it is essential to describe elderly Latinos with HF and their HL and self-care levels. Barriers identified confirm the need to alter research protocols for older adults and ensure the availability of assistive devices. The need to examine HL in older Latinos with HF is confirmed by the medical complexity of ethnic minority patients with limited HL, limited HL in the elderly, and the relationship of HL with HF knowledge. In culturally diverse populations, HL levels alone may not be reliable predictors of a person's ability to self-manage, recognize symptoms, and develop, implement, and revise a self-care action plan to manage their health. PMID- 26646600 TI - CHST14/D4ST1 deficiency: New form of Ehlers-Danlos syndrome. AB - Carbohydrate sulfotransferase 14/dermatan 4-O-sulfotransferase-1 (CHST14/D4ST1) deficiency represents a specific form of Ehlers-Danlos syndrome (EDS) caused by recessive loss-of-function mutations in CHST14. The disorder has been independently termed "adducted thumb-clubfoot syndrome", "EDS, Kosho type", and "EDS, musculocontractural type". To date, 31 affected patients from 21 families have been described. Clinically, CHST14/D4ST1 deficiency is characterized by multiple congenital malformations (craniofacial features including large fontanelle, hypertelorism, short and downslanting palpebral fissures, blue sclerae, short nose with hypoplastic columella, low-set and rotated ears, high palate, long philtrum, thin upper lip vermilion, small mouth, and micro retrognathia; multiple congenital contractures including adduction-flexion contractures and talipes equinovarus as well as other visceral or ophthalmological malformations) and progressive multisystem fragility-related complications (skin hyperextensibility, bruisability, and fragility with atrophic scars; recurrent dislocations; progressive talipes or spinal deformities; pneumothorax or pneumohemothorax; large subcutaneous hematomas; and diverticular perforation). Etiologically, multisystem fragility is presumably caused by impaired assembly of collagen fibrils resulting from loss of dermatan sulfate (DS) in the decorin glycosaminoglycan side chain that promotes electrostatic binding between collagen fibrils. This is the first reported human disorder that specifically affects biosynthesis of DS. Its clinical characteristics indicate that CHST14/D4ST1 and, more fundamentally, DS, play a critical role in fetal development and maintenance of connective tissues in multiple organs. Considering that patients with CHST14/D4ST1 deficiency develop progressive multisystem fragility-related manifestations, establishment of a comprehensive and detailed natural history and health-care guidelines as well as further elucidation of the pathophysiology in view of future etiology-based therapy are crucial. PMID- 26646601 TI - An Insoluble Copper(II) Acetylacetonate-Chiral Bipyridine Complex that Catalyzes Asymmetric Silyl Conjugate Addition in Water. AB - Acicular purplish crystals were obtained from Cu(acac)2 and a chiral bipyridine ligand. Although the crystals were not soluble, they nevertheless catalyzed asymmetric silyl conjugate addition of lipophilic substrates in water. Indeed, the reactions proceeded efficiently only in water; they did not proceed well either in organic solvents or in mixed water/organic solvents in which the catalyst/substrates were soluble. This is in pronounced contrast to conventional organic reactions wherein the catalyst/substrates tend to be in solution. Several advantages of the chiral Cu(II) catalysis in water over previously reported catalyst systems have been demonstrated. Water is expected to play a prominent role in constructing and stabilizing sterically confined transition states and accelerating subsequent protonation to achieve high yields and enantioselectivities. PMID- 26646602 TI - Fifteen years of detaining children who seek asylum in Australia - evidence and consequences. AB - OBJECTIVE: To review and summarise the evidence about and consequences of Australia's policy of mandatory indefinite detention of children and families who arrive by boat to seek asylum. METHODS: This paper will summarise the accumulated scientific evidence about the health and mental health impacts of immigration detention on children and compare methodologies and discuss the political reception of the 2004 and 2014 Australian Human Rights Commission (AHRC) Inquiries into Immigration Detention of children. RESULTS: The conclusions of the 2004 and 2014 Inquiries into Immigration Detention of Children are consistent with Australian and international research which demonstrates that immigration detention has harmful health, mental health and developmental consequences for children and negative impacts on parenting. CONCLUSION: The evidence that prolonged immigration detention causes psychological and developmental harm to children and families and is in breach of Australia's human rights obligations is consistent. This is now partially acknowledged by the Government. Attempts to limit public scrutiny through reduced access and potential punishment of medical witnesses arguably indicates the potency of their testimony. These harmful and unethical policies should be opposed. PMID- 26646603 TI - Allostatic load mediates the impact of stress and trauma on physical and mental health in Indigenous Australians. AB - OBJECTIVES: A considerable gap exists in health and social emotional well-being between Indigenous people and non-Indigenous Australians. Recent research in stress neurobiology highlights biological pathways that link early adversity and traumas as well as life stresses to ill health. We argue that the neurobiological stress response and its maladaptive changes, termed allostatic load, provide a useful framework to understand how adversity leads to physical and mental illness in Indigenous people. In this paper we review the biology of allostatic load and make links between stress-induced systemic hormonal, metabolic and immunological changes and physical and mental illnesses. CONCLUSIONS: Exposure to chronic stress throughout life results in an increased allostatic load that may contribute to a number of metabolic, cardiovascular and mental disorders that shorten life expectancy in Indigenous Australians. PMID- 26646604 TI - Synthesis of Substituted Trinaphthylenes. AB - A short synthesis of six trinaphthylenes is reported. The cyclotrinaphthylenes carry six alkoxy groups, and derivatives featuring OHex, OBu, OiPr, OPr, OEt, and OMe substituents can be obtained by an ordinary Ni(COD)2-promoted, Yamamoto-type coupling reaction. Cyclotrimerization yields range from 38% to 65%. Dependent upon their structure, the cyclotrinaphthylenes assume different packing patterns, according to single-crystal X-ray structure determination. The crystal structures of such trinaphthylenes were hitherto undescribed. PMID- 26646605 TI - Functional characteristics and clinical effectiveness of platelet concentrates treated with riboflavin and ultraviolet light in plasma and in platelet additive solution. AB - BACKGROUND AND OBJECTIVES: Pathogen reduction technologies may affect platelet quality during storage. We studied functional characteristics and clinical effectiveness of platelet concentrates (PCs) treated with Mirasol in plasma and in platelet-additive solution SSP+. MATERIALS AND METHODS: Mirasol-treated, gamma irradiated and untreated apheresis PCs were examined on days 0, 1, 3 and 5 of storage. Phosphatidylserine, P-selectin and active glycoprotein IIb/IIIa were analysed using flow cytometry before and after platelet stimulation. Platelet count increments, the numbers of inefficient transfusions and post-transfusion reactions were analysed to estimate clinical effectiveness. RESULTS: A significant increase in all platelet activation markers occurred during storage in all PC groups. Activation markers in Mirasol-treated samples were already significantly higher compared with the control ones on the day of harvesting, and continued to grow during the storage. Mirasol treatment increased the number of platelets with a mitochondrial membrane potential loss. On the 3rd day of storage, 50% of Mirasol-treated platelets did not respond to activation; on the 5th day, none did. This agreed well with a decrease (approximately twofold) in the effectiveness of Mirasol-treated PC transfusions. Transfusions of PCs stored in SSP+ were accompanied by fewer inefficient transfusions and post-transfusion reactions than of PCs stored in plasma. CONCLUSION: Treatment with Mirasol decreased platelet function, particularly profoundly on the 5th day of storage, and led to a decrease in the effectiveness of transfusions. SSP+ did not affect laboratory parameters significantly compared with plasma, but decreased the percentage of transfusion complications. PMID- 26646606 TI - Bioinspired Bifunctional Membrane for Efficient Clean Water Generation. AB - Solving the problems of water pollution and water shortage is an urgent need for the sustainable development of modern society. Different approaches, including distillation, filtration, and photocatalytic degradation, have been developed for the purification of contaminated water and the generation of clean water. In this study, we explored a new approach that uses solar light for both water purification and clean water generation. A bifunctional membrane consisting of a top layer of TiO2 nanoparticles (NPs), a middle layer of Au NPs, and a bottom layer of anodized aluminum oxide (AAO) was designed and fabricated through multiple filtration processes. Such a design enables both TiO2 NP-based photocatalytic function and Au NP-based solar-driven plasmonic evaporation. With the integration of these two functions into a single membrane, both the purification of contaminated water through photocatalytic degradation and the generation of clean water through evaporation were demonstrated using simulated solar illumination. Such a demonstration should also help open up a new strategy for maximizing solar energy conversion and utilization. PMID- 26646607 TI - Boron nitride ceramics from molecular precursors: synthesis, properties and applications. AB - Hexagonal boron nitride (h-BN) attracts considerable interest because its structure is similar to that of carbon graphite while it displays different properties which are of interest for environmental and green technologies. The polar nature of the B-N bond in sp(2)-bonded BN makes it a wide band gap insulator with different chemistry on its surface and particular physical and chemical properties such as a high thermal conductivity, a high temperature stability, a high resistance to corrosion and oxidation and a strong UV emission. It is chemically inert and nontoxic and has good environmental compatibility. h BN also has enhanced physisorption properties due to the dipolar fields near its surface. Such properties are closely dependent on the processing method. Bottom up approaches consist of transforming molecular precursors into non-oxide ceramics with retention of the structural units inherent to the precursor molecule. The purpose of the present review is to give an up-to-date overview on the most recent achievements in the preparation of h-BN from borazine-based molecular single-source precursors including borazine and 2,4,6-trichloroborazine through both vapor phase syntheses and methods in the liquid/solid state involving polymeric intermediates, called the Polymer-Derived Ceramics (PDCs) route. In particular, the effect of the chemistry, composition and architecture of the borazine-based precursors and derived polymers on the shaping ability as well as the properties of h-BN is particularly highlighted. PMID- 26646608 TI - Hypoalgesia After Exercise and the Cold Pressor Test is Reduced in Chronic Musculoskeletal Pain Patients With High Pain Sensitivity. AB - OBJECTIVES: In chronic pain patients, impaired conditioned pain modulation (CPM) and exercise-induced hypoalgesia (EIH) have been reported. No studies have compared CPM and EIH in chronic musculoskeletal pain patients with high pain sensitivity (HPS) and low pain sensitivity (LPS). MATERIALS AND METHODS: On 2 days, manual pressure pain thresholds (PPTs) were recorded at the legs, arm, and shoulder in 61 chronic pain patients and they performed the cold pressor test, 2 exercise conditions (bicycling and isometric contraction), and a control condition in a randomized and counterbalanced order. PPTs, pain tolerance, pain tolerance limit, and temporal summation of pain were assessed with cuff algometry before and after the tests. On the basis of a median split of the average PPTs for women and men, respectively, low (LPS; N=30) and high (HPS; N=31) pain sensitivity groups were created. RESULTS: At baseline, cuff PPT and pain tolerance were decreased and temporal summation of pain was increased in the HPS group (P<0.02). Cuff PPT increased and pain tolerance limit decreased after the cold pressor test and exercises in LPS (P<0.001). Temporal summation of pain was increased after bicycling in HPS (P<0.005). Pain tolerance increased after the cold pressor test and exercise in both groups (P<0.001). DISCUSSION: CPM and EIH were partly impaired in chronic pain patients with high versus less pain sensitivity, suggesting that the CPM and EIH responses depend on the degree of pain sensitivity. This has clinical implications as clinicians should evaluate pain sensitivity when considering treatment options utilizing the descending modulatory pain control. PMID- 26646610 TI - The Effect of Composite Thickness on the Stress Distribution Pattern of Restored Premolar Teeth with Cusp Reduction. AB - PURPOSE: Different thicknesses of restorative material can alter the stress distribution pattern in remaining tooth structure. The assumption is that a thicker composite restoration will induce a higher fracture resistance. Therefore, the present study evaluated the effect of composite thickness on stress distribution in a restored premolar with cusp reduction. MATERIALS AND METHODS: A 3D solid model of a maxillary second premolar was prepared and meshed. MOD cavities were designed with different cusp reduction thicknesses (0, 0.5, 1, 1.5, 2.5 mm). Cavities were restored with Valux Plus composite. They were loaded with 200 N force on the occlusal surface in the direction of the long axis. Von Mises stresses were evaluated with Abaqus software. RESULTS: Stress increased from occlusal to gingival and was maximum in the cervical region. The stressed area in the palatal cusp was more than that of the buccal cusp. Increasing the thickness of composite altered the shear stress to compressive stress in the occlusal area of the teeth. CONCLUSION: The model with 2.5 mm cusp reduction exhibited the most even stress distribution. PMID- 26646609 TI - Clinical and laboratory correlates of lung disease and cancer in adults with idiopathic hypogammaglobulinaemia. AB - Idiopathic hypogammaglobulinaemia, including common variable immune deficiency (CVID), has a heterogeneous clinical phenotype. This study used data from the national UK Primary Immune Deficiency (UKPID) registry to examine factors associated with adverse outcomes, particularly lung damage and malignancy. A total of 801 adults labelled with idiopathic hypogammaglobulinaemia and CVID aged 18-96 years from 10 UK cities were recruited using the UKPID registry database. Clinical and laboratory data (leucocyte numbers and serum immunoglobulin concentrations) were collated and analysed using uni- and multivariate statistics. Low serum immunoglobulin (Ig)G pre-immunoglobulin replacement therapy was the key factor associated with lower respiratory tract infections (LRTI) and history of LRTI was the main factor associated with bronchiectasis. History of overt LRTI was also associated with a significantly shorter delay in diagnosis and commencing immunoglobulin replacement therapy [5 (range 1-13 years) versus 9 (range 2-24) years]. Patients with bronchiectasis started immunoglobulin replacement therapy significantly later than those without this complication [7 (range 2-22) years versus 5 (range 1-13) years]. Patients with a history of LRTI had higher serum IgG concentrations on therapy and were twice as likely to be on prophylactic antibiotics. Ensuring prompt commencement of immunoglobulin therapy in patients with idiopathic hypogammaglobulinaemia is likely to help prevent LRTI and subsequent bronchiectasis. Cancer was the only factor associated with mortality. Overt cancer, both haematological and non-haematological, was associated with significantly lower absolute CD8(+) T cell but not natural killer (NK) cell numbers, raising the question as to what extent immune senescence, particularly of CD8(+) T cells, might contribute to the increased risk of cancers as individuals age. PMID- 26646611 TI - [Herpes simplex meningitis with splenial lesion]. PMID- 26646612 TI - [Amyotrophic lateral sclerosis. Multisystem degeneration]. AB - BACKGROUND: There is increasing evidence that amyotrophic lateral sclerosis (ALS) has to be regarded as multisystem degeneration rather than as purely a motor neuron disease, as it also includes various dnonmotor symptoms. This modern view has been confirmed by neuropathological and imaging findings. OBJECTIVES: To review recent findings supporting the idea of multisystem degeneration and to describe the implications for diagnostics and therapy. METHODS: A discussion of recent clinical, imaging, and neuropathological findings is presented. RESULTS: Symptoms of ALS include not only motor symptoms but also cognitive impairment, oculomotor abnormalities, and extrapyramidal and sensory symptoms. As a neuropathological correlate, a systematic spreading of "transactive response DNA binding protein 43 kDa" (TDP-43) over functionally connected cortical structures has been described. CONCLUSIONS: Nonmotor symptoms are regularly seen in ALS, although they usually do not dominate the clinical picture. Recent neuropathological findings offer new perspectives for diagnostics and therapy in ALS. PMID- 26646613 TI - [Schizophrenic psychoses with affect-dominant symptoms : Contribution to a system specific approach]. AB - BACKGROUND: In order to reduce heterogeneity in schizophrenia a system-specific approach consisting of the domains 'language', 'affect' and 'motor behavior' was proposed namely the Bern psychopathology scale (BPS). Using the example of the affective domain we examined this system-specific approach for its applicability to clinical practice using a qualitative-casuistic method. Moreover, we examined the possibility to identify a homogeneous subgroup of patients applying this approach. MATERIAL AND METHODS: From a sample of 100 patients with schizophrenia a total of six patients was selected and described following a traditional psychopathological case approach. To expand this qualitative-casuistic method we included the results of standardized psychopathological assessments using the BPS and the positive and negative syndrome scale of schizophrenia (PANSS). RESULTS: Schizophrenic psychoses with affect-dominant symptoms could be characterized better using a system-specific approach than the positive-negative-concept. Ensuing from the cross-sectional psychopathological patterns only limited statements regarding the prospective course were possible. DISCUSSION: The concept of an affect-dominant subtype of schizophrenia was not entirely convincing with respect of the heterogeneous course of the patients described. Nevertheless, the system-specific approach may hold promise for the future regarding further neurobiological research. PMID- 26646614 TI - [Endovascular stroke treatment following recent positive clinical trials]. AB - Recently, five independent randomized controlled clinical trials demonstrated the efficacy and safety of endovascular stroke treatment in stroke patients with occlusion of proximal intracranial arteries. The five trials MR CLEAN, ESCAPE, EXTEND-IA, SWIFT-PRIME and REVASCAT randomized a total of 1287 stroke patients to either standard treatment, which in the majority of patients consisted of intravenous thrombolysis within 4.5 h of symptom onset or additional endovascular stroke treatment. In all the studies endovascular treatment resulted in a better clinical outcome with an odds ratio for a better clinical outcome 90 days after stroke ranging between 1.7 and 3.1 and an absolute increase in the proportion of patients with functionally independent outcome between 14% and 31%. The overwhelming benefit of endovascular treatment mainly results from mechanical thrombectomy using stent retriever devices and starting endovascular treatment within 6 h of symptom onset in stroke patients. PMID- 26646616 TI - Cold Oxygen Plasma Treatments for the Improvement of the Physicochemical and Biodegradable Properties of Polylactic Acid Films for Food Packaging. AB - The effects of cold plasma (CP) treatment on the physicochemical and biodegradable properties of polylactic acid (PLA) films were studied. The PLA films were exposed to CP for 40 min at 900 W and 667 Pa using oxygen as the plasma-forming gas. The tensile, optical, and dynamic mechanical thermal properties, surface morphology, printability, water contact angle, chemical structure, weight change, and biodegradability properties of the films were evaluated during storage for up to 56 d. The tensile and optical properties of the PLA films were not significantly affected by CP treatment (CPT; P > 0.05). The surface roughness and water contact angle of PLA films increased by CPT and further increased during storage for 56 d. The printability of the PLA films increased following CPT and remained stable throughout the storage period. CP induced hydrophilicity was also sustained during the storage period. The PLA films lost 1.9% of their weight after CPT, but recovered 99.5% of this loss after 14 d in storage. Photodegradation, thermal, and microbial biodegradable properties of the films were significantly improved by CPT (P < 0.05). Accelerated biodegradation of CP-treated PLA sachets with and without cheese was observed in compost. These results demonstrate the potential of CPT for modifying the stiffness, water contact angle, and chemical structure of PLA films and improving the printability and biodegradability of the films for food packaging. PMID- 26646615 TI - Probing Xist RNA Structure in Cells Using Targeted Structure-Seq. AB - The long non-coding RNA (lncRNA) Xist is a master regulator of X-chromosome inactivation in mammalian cells. Models for how Xist and other lncRNAs function depend on thermodynamically stable secondary and higher-order structures that RNAs can form in the context of a cell. Probing accessible RNA bases can provide data to build models of RNA conformation that provide insight into RNA function, molecular evolution, and modularity. To study the structure of Xist in cells, we built upon recent advances in RNA secondary structure mapping and modeling to develop Targeted Structure-Seq, which combines chemical probing of RNA structure in cells with target-specific massively parallel sequencing. By enriching for signals from the RNA of interest, Targeted Structure-Seq achieves high coverage of the target RNA with relatively few sequencing reads, thus providing a targeted and scalable approach to analyze RNA conformation in cells. We use this approach to probe the full-length Xist lncRNA to develop new models for functional elements within Xist, including the repeat A element in the 5'-end of Xist. This analysis also identified new structural elements in Xist that are evolutionarily conserved, including a new element proximal to the C repeats that is important for Xist function. PMID- 26646617 TI - A cell size- and cell cycle-aware stochastic model for predicting time-dynamic gene network activity in individual cells. AB - BACKGROUND: Despite the development of various modeling approaches to predict gene network activity, a time dynamic stochastic model taking into account real time changes in cell volume and cell cycle stages is still missing. RESULTS: Here we present a stochastic single-cell model that can be applied to any eukaryotic gene network with any number of components. The model tracks changes in cell volume, DNA replication, and cell division, and dynamically adjusts rates of stochastic reactions based on this information. By tracking cell division, the model can maintain cell lineage information, allowing the researcher to trace the descendants of any single cell and therefore study cell lineage effects. To test the predictive power of our model, we applied it to the canonical galactose network of the yeast Saccharomyces cerevisiae. Using a minimal set of free parameters and across several galactose induction conditions, the model effectively captured several details of the experimentally-obtained single-cell network activity levels as well as phenotypic switching rates. CONCLUSION: Our model can readily be customized to model any gene network in any of the commonly used cells types, offering a novel and user-friendly stochastic modeling capability to the systems biology field. PMID- 26646618 TI - How I was nearly duped into "authoring" a fake paper. PMID- 26646620 TI - An Explanatory Model of Poverty from the Perspective of Social Psychology and Human Rights. AB - Poverty is a social problem, entailing not only an economical perspective but above all a human and social issue. Poverty is promoted, justified and maintained by unique individuals and groups by means of our own attitudes, interests and behavior, as well as with our social structures and social relationships. From this interactive, psychosocial and sociostructural perspective, and also considering poverty as a denial of basic human rights (UNDP, 1998), we carried out a study with the primary objective to design and verify an Explanatory Model of Poverty. This research may helps to increase the validity of diagnostics and the effectiveness of interventions. Most of the hypotheses were accepted during the analysis and verification of the Model (p < .001), with data fitting the Model (CFI: 1 RMSEA: .025: LO90: 0 - HI90: .061. RMR: .008). These results, if replicated in new investigations, could have the following implications: (a) the need for a broad and comprehensive definition of poverty including its effects, processes and causes; (b) the need for everybody to accept the social responsibility in the prevention and solution to poverty; and PMID- 26646621 TI - Strengthening Social Capital Through Residential Environment Development for Older Chinese in a Canadian Context. AB - Among Canada's visible-minority population 65 years of age or older, nearly four out of ten are Chinese. However, little research has been devoted to the examination of the role of the housing environment in building social capital for older Chinese despite the increase in this population and related social issues. The purpose of this paper is to examine Chinese elders' experience of social capital and how it is affected by their residential environment in a Canadian context. In this qualitative study, forty-three Chinese elders in a Canadian context were interviewed with a focus group approach. Findings indicate that the environments in which these older adults lived either hindered or assisted them in building or increasing their social capital. A culturally and linguistically homogeneous residential environment does not necessarily provide positive support to older Chinese for their acquisition of social capital. Adversities in the environment, such as maltreatment or lack of support from their immediate micro environment (family), tended to motivate older adults to improve their social capital for problem-solving. The study offers implications from research findings to social work practice and concludes with an analysis of limitations. PMID- 26646619 TI - Interest and preferences for contingency management design among addiction treatment clientele. AB - BACKGROUND: Despite strong support for its efficacy, debates persist about how dissemination of contingency management is most effectively undertaken. Currently promoted contingency management methods are empirically-validated, yet their congruence with interests and preferences of addiction treatment clientele is unknown. Such client input is a foundational support for evidence-based clinical practice. OBJECTIVE: This study documented interest in incentives and preferences for fixed-ratio vs. variable-ratio and immediate vs. distal distribution of earned incentives among clients enrolled at three community programs affiliated with the National Institute on Drug Abuse Clinical Trials Network. METHODS: This multi-site study included anonymous survey completion by an aggregate sample of 358 treatment enrollees. Analyses first ruled out site differences in survey responses, and then tested age and gender as influences on client interest in financial incentives, and preferences for fixed-ratio vs. variable-ratio reinforcement and immediate vs. distal incentive distribution. RESULTS: Interest in different types of $50 incentives (i.e. retail vouchers, transportation vouchers, cash) was highly inter-correlated, with a mean sample rating of 3.49 (0.83) on a five-point scale. While consistent across client gender, age was an inverse predictor of client interest in incentives. A majority of clients stated preference for fixed-ratio incentive magnitude and distal incentive distribution (67% and 63%, respectively), with these preferences voiced by a larger proportion of females. CONCLUSION: Sample preferences contradict currently-promoted contingency management design features. Future efforts to disseminate contingency management may be more successful if flexibly undertaken in a manner that incorporates the interests and preferences of local client populations. PMID- 26646622 TI - Prolonged air leakage in secondary spontaneous pneumothorax: is proportion of emphysema important? AB - INTRODUCTION: Prolonged air leakage is the most common complication that can cause severe problems in cases of secondary spontaneous pneumothorax (SSP). The purpose of this study was to explore whether Goddard Classification Score (GCS) can be a marker of prolonged air leakage, particularly during the post-operative period, for patients with emphysema. METHODS: Fifty patients, who underwent tube thoracostomy for SSP, were retrospectively evaluated. For the evaluation of emphysematous on the preoperative computed tomography image, visual scoring system described by Goddard was used. The correlations between age, duration of hospitalization, duration of drainage, number of pneumothorax episodes, prolonged air leakage and GCS parameters, were evaluated. RESULTS: When 50 patients were scored, based on GCS, the distribution was as follows: G1: four cases, G2: 16 cases, G3: 17 cases, and G4: 13 cases. The mean number of pneumothorax episodes was 1.3 +/- 0.5, the mean duration of drainage was 15.7 +/- 11.3 days, and the mean duration of hospitalization was 9.2 +/- 5.1 days. Prolonged air leakage was seen in 26 (52.2%) cases. The rate of prolonged air leakage was significantly higher in higher GCS cases (P = 0.035). There was a positive correlation between age and GCS (P = 0.011). The number of pneumothorax episodes rose significantly with increasing GCS (P = 0.011). The duration of hospitalization increased with the growing number of pneumothorax episodes (P = 0.027). CONCLUSION: Prolonged air leakage and the recurrence rate of SSP rise with increasing GCS. Taking this condition into consideration in the treatment algorithm can be helpful for clinicians in patient follow-up. PMID- 26646623 TI - Serum metabolomics uncovering specific metabolite signatures of intra- and extrahepatic cholangiocarcinoma. AB - Cholangiocarcinoma (CC) accounts for approximately 25% of all hepatobiliary malignancies, including intra- and extrahepatic cholangiocarcinoma (ICC and ECC) and has a high mortality rate. The clinical manifestations of and liver function tests for the ICC and ECC diseases are too similar to distinguish between them. Diagnosis of ICC and ECC remains difficult because of the lack of sensitive diagnostic tests, although MRI and CT with endoscopic ultrasound provide useful diagnostic information in certain patients, but are invasive, time-consuming or expensive. Early detection is the most effective way to improve the clinical outcome of CC. Serum metabolomics provides a powerful platform for discovering novel biomarkers to improve early diagnosis. This study was performed using a metabolomics method which was used to select serum metabolites to be used for the early diagnosis of CC and to distinguish ICC from ECC. We comprehensively analyzed the serum metabolites in a total of 261 blood samples from CC patients and normal individuals. We found that 75 metabolites were filtered and identified from the serum metabolome, and the levels of 21-deoxycortisol and bilirubin significantly increased while the levels of lysoPC(14:0) and lysoPC(15:0) were significantly reduced in the CC group compared with the control groups. We measured the 4 metabolites of interest in an independent sample comprising 225 cases and 101 controls. Noticeably, external validation of the serum specimens further showed that the biomarker combination could differentiate ECC and ICC patients with high accuracy. This provides a new foundation for serum metabolomics to provide potential biomarkers for the early detection of CC. PMID- 26646624 TI - Soluble and immobilized graphene oxide activates complement system differently dependent on surface oxidation state. AB - Graphene oxide (GO) is believed to become applicable in biomedical products and medicine, thereby necessitating appropriate safety evaluation dependent on their applications and the route of administration. We have examined the effect of GO form (in solution versus immobilized) and oxidation state on two related elements of innate immunity: the complement system and interleukin-6 (IL-6) release in human blood. In solution, there was a decrease in GO-mediated complement activation with decreasing surface oxygen content (and altered oxygen functionality), whereas with immobilized GO complement response were reversed and increased with decreasing oxygen content. GO solutions, at concentrations below complement activating threshold, did not induce IL-6 release from human blood leukocytes, and further dampened lipopolysaccharide-induced IL-6 release in the whole blood. The latter effect became more profound with GO's having higher oxygen content. This protective role of GO solutions, however, disappeared at higher concentrations above complement-activating threshold. We discuss these results in relation to GO surface structure and properties, and implications for local administration and development of GO-based implantable devices. PMID- 26646625 TI - Gold-nanorods-siRNA nanoplex for improved photothermal therapy by gene silencing. AB - Nanomaterials-mediated photothermal therapy (PTT) often suffers from the fundamental cellular defense mechanism of heat shock response which leads to therapeutic resistance of cancer cells and reduces the therapeutic efficacy. Herein, a gold nanorods (GNRs)-siRNA platform with gene silencing capability is produced to improve the PTT efficiency. After surface modification, the GNRs show the ability to deliver siRNA oligos targeting BAG3 which is an efficient gene to block the heat-shock response. The synthesized GNRs-siRNA nanoplex exhibits excellent ability in the delivery of siRNA into cancer cells with high silencing efficiency which is even better than that of commercial Lipofectamine 2000. The in vitro and in vivo studies demonstrate the ability of the GNRs-siRNA nanoplex to sensitize the cancer cells to PTT under moderate laser irradiation by down regulating the increased BAG3 expression and enhancing apoptosis. The GNRs-siRNA mediated PTT has large potential in clinical cancer therapy due to the elimination of therapeutic resistance and enhanced photothermal therapeutic efficacy by means of gene silencing. It also suggests an efficient platform for gene delivery and controllable gene therapy. PMID- 26646626 TI - Photothermo-chemotherapy of cancer employing drug leakage-free gold nanoshells. AB - Combined photothermo-chemotherapy is a new cancer treatment modality that improves therapeutic outcome by synergistic actions of two different means. A reduction and pH dual sensitive polymeric vesicle encapsulating doxorubicin (DOX) was prepared and then decorated with a gold layer using a modified method of in situ gold seed growth. By tuning the compactness of gold layer, the gold nanoshell may possess a desirable light absorption peak for tumor photothermal therapy using near-infrared (NIR) laser irradiation, a method featuring high tissue penetrability essential for in vivo applications. The NIR light energy was converted into heat, which killed cancer cells in the vicinity and induced the rupture of nanoshell to release DOX inside tumor. Therefore, a combined photothermo-chemotherapy of tumor can be achieved precisely at tumor site. In addition, DOX released in the thermochemotherapeutic mode effectively penetrated tumor tissue, which is meaningful considering the intrinsic low tissue penetrability of nanomedicines. In nude mice bearing human Bel-7402 hepatoma, the photothermo-chemotherapy using DOX-loaded gold nanoshell appeared advantageous over a chemotherapy or a photothermal therapy alone. PMID- 26646627 TI - Intergenerational Hazardous Alcohol Use and Area Factors: The HUNT Study, Norway. AB - BACKGROUND: Alcohol use among adolescents has been found to be associated with parental alcohol abuse, but it's relation to more prevalent forms of hazardous drinking patterns among parents has been less explored. Few studies have included area factors when investigating alcohol use across generations. OBJECTIVES: The aims of this study were to investigate whether adolescent intoxication was associated with parental heavy episodic drinking (HED) and intoxication, area level socioeconomic status (SES), and rates of area-level HED. METHODS: General Estimation Equations (GEE) was applied to analyze data from the Nord-Trondelag Health Study (2006-08) including 2,306 adolescents. Adolescent alcohol use was defined by self-reported frequency of intoxication. Parental alcohol use was defined by parental self-reports of drinking five glasses of alcohol at one occasion (HED), whether they had been strongly intoxicated, and adolescent reports of seeing parents intoxicated. Area-level SES and HED were based on data from HUNT3 and Statistics Norway. RESULTS: Parental and offspring alcohol use were associated, although this varied to some extent with gender and exposures. The strongest associations were found between offspring intoxication and offspring reports of seeing their parent intoxicated (girls: OR 3.3, 95% CI 2.3 4.7; boys: OR 3.4, 95% CI 2.4-4.7). Intoxication was more common among girls, who lived in areas with a higher level of adult HED. Living in areas with higher SES was associated with less intoxication among adolescents. CONCLUSION: Intoxication in adolescence was associated with factors at both family and area level, which emphasize the need of both population and high risk preventive approaches. PMID- 26646628 TI - Positive effect of fetal cell microchimerism on tumor presentation and outcome in papillary thyroid cancer. AB - Studies on both circulating and tissue fetal cell microchimerism (FCM) favored its protective role in thyroid cancer, consistent with findings in other malignancies. Nevertheless, scanty data were available on the possible impact on the outcome of the disease. We demonstrated that FCM has a positive effect on thyroid cancer presentation and outcome. We also excluded that the better clinical features observed were due to the effect of pregnancy per se. In conclusion, FCM may have not only a protective role toward the onset of thyroid cancer, but also a positive effect on its progression. These findings give novel insights into the identification of the role of FCM in oncology and, consequently, in the potential therapeutic application of this physiological phenomenon. PMID- 26646629 TI - Molecular Characterization of Buffalo Haptoglobin: Sequence Based Structural Comparison Indicates Convergent Evolution Between Ruminants and Human. AB - Haptoglobin (Hp) protein has high affinity for hemoglobin (Hb) binding during intravascular hemolysis and scavenges the hemoglobin induced free radicals. Earlier reports indicate about uniqueness of Hp molecule in human and cattle, but in other animals, it is not much studied. In this paper, we characterized buffalo Hp molecule and determined its molecular structure, evolutionary importance, and tissue expression. Comparative analysis and predicted domain structure indicated that the buffalo Hp has an internal duplicated region in alpha-chain only similar to an alternate Hp2 allele in human. This duplicated part encoded for an extra complement control protein CCP domain. Phylogenetic analysis revealed that buffalo and other ruminants were found to group together separated from all other non-ruminants, including human. The key amino acid residues involved in Hp and Hb as well as Hp and macrophage scavenger receptor, CD163 interactions in buffalo, depicted a significant variation in comparison to other non-ruminant species. Constitutive expression of Hp was also confirmed across all the vital tissues of buffalo, for the first time. Results revealed that buffalo Hp is both structurally and functionally conserved, having internal duplication in alpha chain similar to human Hp2 and other ruminant species, which might have evolved separately as a convergent evolutionary process. Furthermore, the presence of extra Hp CCP domain possibly in all ruminants may have an effect during dimerization of molecule in these species. PMID- 26646630 TI - Porcine Reproductive and Respiratory Syndrome Virus (PRRSV): Pathogenesis and Interaction with the Immune System. AB - This review addresses important issues of porcine reproductive and respiratory syndrome virus (PRRSV) infection, immunity, pathogenesis, and control. Worldwide, PRRS is the most economically important infectious disease of pigs. We highlight the latest information on viral genome structure, pathogenic mechanisms, and host immunity, with a special focus on immune factors that modulate PRRSV infections during the acute and chronic/persistent disease phases. We address genetic control of host resistance and probe effects of PRRSV infection on reproductive traits. A major goal is to identify cellular/viral targets and pathways for designing more effective vaccines and therapeutics. Based on progress in viral reverse genetics, host transcriptomics and genomics, and vaccinology and adjuvant technologies, we have identified new areas for PRRS control and prevention. Finally, we highlight the gaps in our knowledge base and the need for advanced molecular and immune tools to stimulate PRRS research and field applications. PMID- 26646631 TI - Yinzhihuang attenuates ANIT-induced intrahepatic cholestasis in rats through upregulation of Mrp2 and Bsep expressions. AB - BACKGROUND: The treatment of intrahepatic cholestasis has been limited, and development of an effective drug is needed. Clinical studies have shown that Yinzhihuang (YZH), a traditional Chinese decoction, enhances bilirubin clearance. The goal of this study was to determine the protective effect of YZH on experimental intrahepatic cholestasis in young rats and to explore its underlying molecular mechanisms. METHODS: Intrahepatic cholestasis in rats was induced by alpha-naphthylisothiocyanate (ANIT) on days 1 and 8. The rats received YZH, ursodeoxycholic acid (UDCA), or vehicle for 9 d and were killed on either day 3 or day 10. Serum biomarkers, liver histology, and the distribution of protein and mRNA expression of Mrp2 and Bsep were analyzed. RESULTS: YZH treatment resulted in decreased levels of serum biomarkers except gamma-glutamyl transpeptidase, attenuated liver histological injuries, increased protein expressions of Mrp2 and Bsep, and upregulated expressions of Mrp2 and Bsep mRNAs. The effects of YZH on serum biomarkers (aminotransferase, alanine aminotransferase, and direct bilirubin), liver histology, and Mrp2 mRNA expressions were significantly greater and earlier than those of UDCA. CONCLUSION: Our results suggest that YZH has protective effect against ANIT-induced intrahepatic cholestasis in rats, through upregulation of Mrp2 and Bsep expressions. PMID- 26646632 TI - Emerging roles of ATRX in cancer. AB - ATRX was identified over 20 years ago as the gene responsible for a rare developmental disorder characterized by alpha-thalassemia and intellectual disability. Similarities to the sucrose nonfermentable SNF2 type chromatin remodelers initially suggested a role in transcriptional regulation. However, over the last years, our knowledge of the epigenetic activities of ATRX has expanded steadily. Recent exciting discoveries have propelled ATRX into the limelight of chromatin and telomere biology, development and cancer research. This review summarizes recent breakthroughs in understanding ATRX function in heterochromatin structure, genome stability and its frequent dysregulation in a variety of cancers. PMID- 26646633 TI - Synthesis and electronic properties of polycyclic aromatic hydrocarbons doped with phosphorus and sulfur. AB - In this work, we report on the synthesis of polyaromatic hydrocarbons containing phosphole and thiophene rings at the edge. The ring-closure reactions have been investigated by theoretical calculations. The optical and electrochemical properties and density functional theory calculations showed that the properties depend on the relative position of these five membered rings in the PAH structure. PMID- 26646634 TI - Structural and mechanical implications of PMMA implant shape and interface geometry in cranioplasty--A finite element study. AB - This computational study investigates the effect of shape (defect contour curvature) and bone-implant interface (osteotomy angle) on the stress distribution within PMMA skull implants. Using finite element methodology, 15 configurations--combinations of simplified synthetic geometric shapes (circular, square, triangular, irregular) and interface angulations--were simulated under 50N static loads. Furthermore, the implant fixation devices were modelled and analysed in detail. Negative osteotomy configurations demonstrated the largest stresses in the implant (275 MPa), fixation devices (1258 MPa) and bone strains (0.04). The circular implant with zero and positive osteotomy performed well with maximum observed magnitudes of--implant stress (1.2 MPa and 1.2 MPa), fixation device stress (11.2 MPa and 2.2 MPa), bone strain (0.218e-3 and 0.750e-4). The results suggest that the preparation of defect sites is a critical procedure. Of the greatest importance is the angle at which the edges of the defect are sawed. If under an external load, the implant has no support from the interface and the stresses are transferred to the fixation devices. This can endanger their material integrity and lead to unphysiological strains in the adjacent bone, potentially compromising the bone morphology required for anchoring. These factors can ultimately weaken the stability of the entire implant assembly. PMID- 26646635 TI - Non-joint effusion is associated with osteoarthritis in temporomandibular joints with disk displacement. AB - PURPOSE: The aim of this study was to examine the possible association between different grades of joint effusion (JE) and osteoarthritis (OA) in temporomandibular joint (TMJ) anterior disk displacement without reduction (ADDwoR). MATERIAL AND METHODS: A sample of 101 female patients 20-40 years of age with unilateral TMJ ADDwoR were retrospectively reviewed. JE and OA were diagnosed with magnetic resonance imaging (MRI). JE was subdivided into three different grades: grade 0, no or minimal effusion; grade 1, moderate effusion; and grade 2, extensive effusion. Eight categories of degenerative changes were used for screening for the existence of OA. Cases with no less than one type of degenerative change were diagnosed as OA. RESULTS: In all, 71 patients (70.3%) were diagnosed as having OA in the joints with disk displacement. In the univariate analysis, the proportion of subjects with non-JE (grade 0) was higher in the OA group (p = 0.003), while the proportion of subjects with extensive effusion (grade 2) was lower in the OA group (p = 0.02). In the multivariate logistic regression analysis, non-JE was independently associated with the development of OA (odds ratio = 5.68, 95% confidence interval = 1.10-29.37, P = 0.04). CONCLUSION: The results suggested that non-JE was associated with OA in the joints with ADDwoR. PMID- 26646636 TI - Evaluation of success of alveolar cleft bone graft performed at 5 years versus 10 years of age. AB - BACKGROUND AND PURPOSE: Although alveolar cleft bone grafting is the most widely accepted approach, controversies remain on the operative timing. METHODS: A consecutive retrospective series of 28 patients who received alveolar bone grafting was examined and divided into 2 groups depending on the age at the time of bone graft. Group A (14 patients) was operated at a mean age of 5.2 years [range, 4-7] and Group B (14 patients) at a mean age of 10 years [range, 8.5-13]. All the children were assessed clinically and by Cone Beam Computed Tomography (CBCT) before bone grafting and 6 months post-operatively. Cleft and bone graft dimensions, volumes were assessed using Osirix v.3.9.2. Residual bone graft coefficient (Bone Graft Volume on 6-months Postoperative CBCT/Alveolar Cleft Volume) was calculated. Complications, tooth movement or dental agenesis were also reported. RESULTS: The sample was uniform within both groups, considering cleft forms, pre-surgical fistula rate and cleft volume. Residual bone graft coefficient reached 63.3% in Group A and 46.2% in Group B (p = 0.012). Results of residual bone graft are also influenced by tooth eruption through the graft (p = 0.007 in Group A and p = 0.02 in Group B). CONCLUSIONS: This 3D analysis highlighted higher success of alveolar bone grafts when children are operated earlier around 5 years. LEVEL OF EVIDENCE: Therapeutic study. Level III/retrospective comparative study. PMID- 26646637 TI - Miniplate osteosynthesis for mandibular angle fractures--A retrospective comparative study of 3 concepts in a temporal cohort. AB - PURPOSE: Purpose of this retrospective study was to compare fixation of mandibular angle fractures by three different miniplating-concepts (single miniplate, double miniplate, TriLock mandibular angle plate) regarding osteosynthesis failure and hardware removal. METHODS: In this retrospective study a temporal cohort of 184 patients with 194 simple mandibular angle fractures, which had been treated by open reduction and internal fixation via miniplates at the University Clinic of Cranio-, Maxillofacial and Oral Surgery (General Hospital Vienna) in the period of 2005-2011, were included. Patients with pathologic fractures (e.g. tumour or osteonecrosis related) or comminuted fractures were not considered. RESULTS: 9 of 194 (4.6%) fractures showed osteosynthesis failures. The osteosynthesis failure rates were 2.9% in the single miniplate group, 3.4% in the TriLock plate group, and 11.1% in the double miniplate group. In the double miniplate group 33.3% of the patients had undergone hardware removal, 21.4% in the single miniplate group, and 11.4% in the TriLock plate group. CONCLUSION: A single 4-hole locking plate with a thickness of 1.25-1.3 mm guarantees for low osteosynthesis failure rates without postoperative maxillo-mandibular fixation and requires less hardware removal in simple mandibular angle fractures. Two miniplates, longer plates with more holes and thicker plates are prone to hardware removal. PMID- 26646638 TI - What is the current optimal fat grafting processing technique? A systematic review. AB - BACKGROUND: With the advents of new processing techniques and new graft survival theories in fat grafting, the question is: Which processing technique is of preference? This study systematically reviewed literature regarding current techniques for processing fat grafts. METHODS: PubMed, Embase, Cinahl, and Cochrane databases were searched until August 2015. Studies comparing different fat grafting processing techniques were included. Outcomes were viability of adipocytes, number of adipose-derived stromal/stem cells (ASC) and growth factors in vitro, volume and quality of the graft in animal studies, and satisfaction and volume retention in human studies. RESULTS: Thirty-five studies were included. Adipocyte viability and ASC numbers were the best using the gauze/towel technique (permeability principle) compared to centrifugation. With regard to centrifugation, the pellet contained more ASCs compared to the middle layer. The animal studies' and patients' satisfaction results were not distinctive. The only study assessing volume retention in humans showed that a wash filter device performed significantly better than centrifugation. CONCLUSION: In this study, processing techniques using permeability principles proved superior to centrifugation (reinforced gravity principle) regarding viability and ASC number. Due to the variety in study characteristics and reported outcome variables, however, none of the processing techniques in this study demonstrated clinical evidence of superiority. PMID- 26646647 TI - Opening the band gap of graphene through silicon doping for the improved performance of graphene/GaAs heterojunction solar cells. AB - Graphene has attracted increasing interest due to its remarkable properties. However, the zero band gap of monolayered graphene limits it's further electronic and optoelectronic applications. Herein, we have synthesized monolayered silicon doped graphene (SiG) with large surface area using a chemical vapor deposition method. Raman and X-ray photoelectron spectroscopy measurements demonstrate that the silicon atoms are doped into graphene lattice at a doping level of 2.7-4.5 at%. Electrical measurements based on a field effect transistor indicate that the band gap of graphene has been opened via silicon doping without a clear degradation in carrier mobility, and the work function of SiG, deduced from ultraviolet photoelectron spectroscopy, was 0.13-0.25 eV larger than that of graphene. Moreover, when compared with the graphene/GaAs heterostructure, SiG/GaAs exhibits an enhanced performance. The performance of 3.4% silicon doped SiG/GaAs solar cell has been improved by 33.7% on average, which was attributed to the increased barrier height and improved interface quality. Our results suggest that silicon doping can effectively engineer the band gap of monolayered graphene and SiG has great potential in optoelectronic device applications. PMID- 26646648 TI - Substance P Enhances Keratocyte Migration and Neutrophil Recruitment through Interleukin-8. AB - Keratocytes, the resident cells of the corneal stroma, are responsible for maintaining turnover of this tissue by synthesizing extracellular matrix components. When the cornea is injured, the keratocytes migrate to the wounded site and participate in the stromal wound healing. The neuropeptide substance P (SP), which is also known to be produced by non-neuronal cells, has previously been implicated in epithelial wound healing after corneal injury. Corneal scarring, which occurs in the stroma when the process of wound healing has malfunctioned, is one of the major causes of preventable blindness. This study aimed to elucidate the potential role of SP in keratocyte migration and therefore in stromal wound healing. We report that the expression and secretion of SP in human keratocytes are increased in response to injury in vitro. Moreover, SP enhances the migration of keratocytes by inducing the actin cytoskeleton reorganization and focal adhesion formation through the activation of the phosphatidylinositide 3-kinase and Ras-related C3 botulinum toxin substrate 1/Ras homolog gene family, member A pathway. Furthermore, SP stimulation leads to upregulated expression of the proinflammatory and chemotactic cytokine interleukin-8 (IL-8), which also contributes significantly to SP-enhanced keratocyte migration and is able to attract neutrophils. In addition, the preferred SP receptor, the neurokinin-1 receptor, is necessary to induce keratocyte migration and IL-8 secretion. In conclusion, we describe new mechanisms by which SP enhances migration of keratocytes and recruits neutrophils, two necessary steps in the corneal wound-healing process, which are also likely to occur in other tissue injuries. PMID- 26646649 TI - Difference in white matter microstructure in differential diagnosis of normal pressure hydrocephalus and Alzheimer's disease. AB - OBJECTIVES: Alzheimer's disease (AD) and normal pressure hydrocephalus (NPH) are both associated with cognitive decline and ventriculomegaly. While promising approach in differentiating between the two diseases, only a few diffusion tensor imaging (DTI) studies compared directly NPH and AD patients. The current study compares global whitematter (WM) alterations in AD and NPH addressing some of the methodological issues of previous studies. PATIENTS AND METHODS: Diffusion tensor images were obtained from 17 patients with NPH, 14 with AD, and 17 healthy controls. White matter integrity was quantified by fractional anisotropy (FA), mean (MD), axial (lambda1) and radial diffusivity (RD). The diffusion parameters were compared between the groups in 'skeletonised' tracts representing the core of the fibre bundles. RESULTS: Reduced FA was found in NPH patients throughout the corpus callosum, particularly in the splenium, along with increased RD. On the other hand, FA, MD and RD were higher in NPH in the cortico-fugal fibres arising from the frontal and parietal cortex. While no FA changes were detected in AD patients compared to controls, widespread increased RD was observed. When comparing NPH and AD patients, higher FA, MD and RD was observed in the corona radiata in the periventricular fibres arising from the frontal and parietal cortex in NPH patients. The ventricular volumes were correlated with diffusivity parameters in the tracts next to the ventricles in AD and NPH patients. CONCLUSION: Our analysis identified a pattern of WM diffusion alterations that can differentiate NPH patients from controls and AD patients. PMID- 26646651 TI - Biophysical aspect of phosphatidylinositol 3-kinase and role of oncogenic mutants (E542K & E545K). AB - Genetic variations in oncogenes can often promote uncontrolled cell proliferation by altering the structure of the encoded protein, thereby altering its function. The PI3KCA oncogene that encodes for p110alpha, the catalytic subunit of phosphatidylinositol 3-kinase (PI3K), is one the most frequently mutated oncogenes in humans. PI3K plays a pivotal role in cell division. PI3K consists of two subunits: the catalytic (p110alpha) and regulatory (p85alpha). The regulatory subunit usually controls the catalytic subunit and switches off the enzyme when not required. It is believed that mutations in PI3KCA gene can alter the control of p85alpha over p110alpha and can sustain p110alpha in a prolonged active state. This in turn results in uncontrolled cell division. In this study, we investigate the pathogenic role of two point mutations: E542K and E545K on p110alpha subunit and how they alter its binding with the regulatory subunit. Molecular interaction and molecular dynamic simulation analysis are performed to study the dynamic behaviour of native and mutant structures at atomic level. Mutant p110alpha showed less interaction with its regulatory partner p85alpha than the native did, due to its expanded and rigid structure. Our analysis clearly points out that the structural and functional consequences of the mutations could promote tumour proliferation. PMID- 26646650 TI - Is early TMJ involvement in children with juvenile idiopathic arthritis clinically detectable? Clinical examination of the TMJ in comparison with contrast enhanced MRI in patients with juvenile idiopathic arthritis. AB - BACKGROUND: To test clinical findings associated with early temporomandibular joint (TMJ) arthritis in comparison to the current gold standard contrast enhanced magnetic resonance imaging (MRI) in children with juvenile idiopathic arthritis (JIA). METHODS: Seventy-six consecutive JIA patients were included in this study. Rheumatological and orthodontic examinations were performed blinded to MRI findings. Joint effusion and/or increased contrast enhancement of synovium or bone as well as TMJ deformity were assessed on MRI and compared to clinical findings. The maximal mouth opening capacity (MOC) of the JIA patients was compared to normative values obtained from a cohort of 20719 school children from Zurich, Switzerland. RESULTS: On MRI a total of 54/76 (71%) patients and 92/152 (61%) joints had signs of TMJ involvement. MRI showed enhancement in 85/152 (56%) and deformity in 39/152 (26%) joints. MOC, asymmetry and restriction in condylar translation showed significant correlation to TMJ enhancement and deformity, whereas antegonial notching was correlated with TMJ deformity only. When joints with deformity were excluded, enhancement alone did not show a significant correlation with any clinical factor. CONCLUSIONS: Clinical findings in affected TMJs are correlated with structural damage only. Therefore clinical assessment of TMJs does not allow to diagnose early arthritis accurately and will still depend on contrast enhanced MRI. PMID- 26646652 TI - Pancreatic Neuroendocrine Neoplasms: Clinical Value of Diffusion-Weighted Imaging. AB - BACKGROUND/AIMS: Diffusion-weighted imaging (DWI) can depict random motions of water molecules in biological tissues during magnetic resonance (MR) examinations. Few papers have tested its application to pancreatic neuroendocrine neoplasms (PanNENs). The aim of this paper is to assess the clinical value of DWI regarding the identification and characterization of PanNENs and diagnosis of liver metastases. METHODS: Preoperative MR examinations of 30 PanNEN patients were retrospectively reviewed; 30 patients with pathologically proven pancreatic ductal adenocarcinoma (PDAC) were included to compare the imaging features. Qualitative and quantitative MR features were compared between histotypes. A blinded-reader comparison of diagnostic confidence for PanNENs and liver metastases was conducted on randomized image sets. All results were compared with pathological data. RESULTS: PanNEN conspicuity was higher on DW images compared to conventional MR sequences. DWI had higher detection rates for PanNENs than had conventional sequences (93.3 vs. 71.1%). Sharp margins and absence of main pancreatic duct/common bile duct dilation and chronic pancreatitis were more common among PanNENs as compared to PDACs. Arterial iso- or hyperenhancement and portal hyperenhancement were more frequent within PanNENs as compared to PDACs. No differences between histotypes were found for quantitative features. Arterial phase images had the highest interobserver agreement for the diagnosis of PanNEN (Cohen's kappa = 0.667). DWI provided the highest detection rate for liver metastases as well as excellent interobserver agreement for the diagnosis of liver metastases (kappa = 0.932), with good accuracy (AUC = 0.879-0.869). CONCLUSION: DWI has clinical value regarding the identification of PanNENs and the diagnosis of liver metastases, while conventional MR sequences are fundamental for their characterization. PMID- 26646653 TI - Cerebellar tDCS does not affect performance in the N-back task. AB - The N-back task is widely used in cognitive research. Furthermore, the cerebellum's role in cognitive processes is becoming more widely recognized. Studies using transcranial direct current stimulation (tDCS) have demonstrated effects of cerebellar stimulation on several cognitive tasks. Therefore, the aim of this study was to investigate the effects of cerebellar tDCS on cognitive performance by using the N-back task. The cerebellum of 12 participants was stimulated during the task. Moreover, the cognitive load was manipulated in N = 2, N = 3, and N = 4. Every participant received three tDCS conditions (anodal, cathodal, and sham) divided over three separated days. It was expected that anodal stimulation would improve performance on the task. Each participant performed 6 repetitions of every load in which correct responses, false alarms, and reaction times were recorded. We found significant differences between the three levels of load in the rate of correct responses and false alarms, indicating that subjects followed the expected pattern of performance for the N back task. However, no significant differences between the three tDCS conditions were found. Therefore, it was concluded that in this study cognitive performance on the N-back task was not readily influenced by cerebellar tDCS, and any true effects are likely to be small. We discuss several limitations in task design and suggest future experiments to address such issues. PMID- 26646654 TI - Spectroscopy of Sonoluminescence and Sonochemistry in Water Saturated with N2-Ar Mixtures. AB - Sonoluminescence spectra in relation with sonochemical activity of water sparged with Ar/N2 gas mixtures were systematically studied at two ultrasonic frequencies (20 and 359 kHz). At 20 kHz, solely the molecular emission of OH (A(2)Sigma(+) X(2)Pii) is observed in addition to a broad continuum typical for multibubble sonoluminescence. On the contrary, at high frequency a second emission band is present around 336 nm which is assigned to the NH (A(3)Pi-X(3)Sigma(-)) system. In addition, the sonolysis of a 0.2 M NH3.H2O solution at 359 kHz in the presence of pure Ar yields the emission bands of NH (A(3)Pi - X(3)Sigma(-)) (336 nm) and NH (C(1)Pi-A(1)Delta) (322 nm) systems confirming the sonochemical production of NH radicals. The N2 (C(3)Piu-B(3)Pig) emission band is absent at both frequencies. This uncommon phenomenon can be explained by the quenching of the N2 (C(3)Piu) excited state with water molecules inside the bubbles. The sonoluminescence of NH radicals at 359 kHz indicates more effective intrabubble dissociation of N2 molecules at high ultrasonic frequency compared to low frequency (20 kHz) ultrasound. Its absence at 20 kHz may also be related to strong quenching, e.g., by water molecules. The kinetic study of the formation of principal sonochemical products (H2, H2O2, HNO3, HNO2) confirmed the more drastic conditions produced during bubble collapse at higher ultrasonic frequency. PMID- 26646655 TI - Size effects in the alkali metal ion-templated formation of oligo(ethylene glycol)-containing [2]catenanes. AB - An investigation into the most suitable alkali metal ions for templating the assembly of [2]catenanes from di-, tri-, and tetra(ethylene glycol)-containing guest diamines and isophthalaldehyde has indicated that Na(+), K(+), and Rb(+) ions are optimal for preparing [2]catenanes containing at least one di(ethylene glycol) unit, two tri(ethylene glycol) units, and at least one tetra(ethylene glycol) unit [in the absence of a di(ethylene glycol) unit], respectively. PMID- 26646656 TI - The effect of stress on learning in surgical skill acquisition. AB - BACKGROUND: An excessive level of stress and anxiety in medical education can have a negative impact on learning. In particular, the interaction between attending surgeons and trainees in the operating room could induce stress on trainees that is counterproductive, especially if the teaching style or feedback is unduly harsh or critical. AIM: To characterize the effects of stress resulting from attending-trainee interaction during surgical skill acquisition. METHODS: Forty medical students learned to perform the FLS pattern-cutting task for the first time in one of four scenarios. In the control condition, no mentor was present. In the three experimental conditions, participants were observed, encouraged, or criticized by an expert surgeon. RESULTS: Task performance, as well as physiological and subjective indicators of stress, were measured. Taking both speed and accuracy into account, participants who were criticized performed the worst on the task, and those who were encouraged performed best. Physiological and subjective measures indicated that the criticized participants experienced the highest level of stress and anxiety. CONCLUSION: Even though providing constructive criticism to trainees is inevitable during the course of teaching, an exceedingly critical and negative mentoring style by attending physicians could be detrimental to trainees' acquisition of surgical skills. PMID- 26646657 TI - Treatment of infantile hemangiomas: therapeutic options in regard to side effects and adverse events - a review of the literature. AB - INTRODUCTION: While options for treatment strategies for infantile hemangiomas (IH) are numerous, evidence-based information about agents, optimal dosage, adverse effects, treatment modality, pretreatment and treatment strategies remain limited. AREAS COVERED: To evaluate side effects and adverse events of medical treatment in children with infantile hemangioma, a comprehensive review of the literature was performed to provide information for daily practice. In total 254 studies were retrieved from medical databases and comprised 10,022 patients divided into 5 different treatment groups. Information about working mechanism, side effects and adverse events of therapies used as a single agent for IH are discussed and evaluated according to information from pharmacotherapeutic databases. Randomized controlled trials have only scarcely been performed for the many therapeutic options reported for IH. Short- and long-term side effects and adverse events, have not been systematically studied. Subsequently information about the medical treatment options and pharmacotheraputic databases for therapy in children with IH are incomplete. EXPERT OPINION: From the many therapeutic options, propranolol is the first-line approach for IH, predominantly based on clinical observation, efficacy and tolerability in the short-term. The unsolved ravels of possible short and long-term adverse events of propranolol used during early developmental stages of children need thorough review. PMID- 26646658 TI - The number-time interaction depends on relative magnitude in the suprasecond range. AB - Numerical representations influence temporal processing. Previous studies have consistently shown that larger numbers are perceived to last longer than smaller ones. However, whether this effect is modulated by the absolute or relative magnitudes of the numbers has yet to be fully understood. Here, participants observed single- and double-digit Arabic numerals in separate experimental blocks and reproduced stimulus duration of 600 or 1200 ms. Our results replicated previous findings that the duration of larger numbers was reproduced longer than that of smaller numbers within each digit set. Although the effect of numerical magnitude across single- and double-digit numerals was found when the numerals were presented for 600 ms, the difference was negligible when they were presented for 1200 ms, suggesting that relative magnitude is an important factor in the number-time interaction in the suprasecond range. These results suggest that contextual influence on number-time interaction may depend on the actual stimulus duration. PMID- 26646659 TI - Retrospective evaluation of the pre- and postoperative factors influencing the sensitivity of localization studies in primary hyperparathyroidism. AB - INTRODUCTION: Over the last decades, mini-invasive surgery has become increasingly common for treatment of primary hyperparathyroidism; such approach requires preoperative localization of a suspected parathyroid adenoma. Neck ultrasound (US) and technetium-99 m sestamibi (MIBI) scan are the main imaging studies used for this purpose. The aim of the present study is to evaluate what pre- and post-operative factors may alter the reliability of localization studies. METHODS: A retrospective analysis on 212 patients with preoperative diagnosis of primary hyperparathyroidism was conducted. Data collected included demographic data, preoperative workup, operative findings and follow-up. Univariate logistic regression was performed on pre- and postoperative variables. RESULTS: US sensitivity was 62.4% and MIBI sensitivity 78.9%. Cure rate after parathyroidectomy was 98.1%. Univariate logistic regression demonstrated that US sensitivity was impaired by lower levels of serum calcium (p < 0.0001), multi gland disease (p = 0.011) and co-existence of thyroid disease (p = 0.001); MIBI sensitivity was impaired by lower levels of serum calcium (p = 0.001) and multi gland disease (p < 0,0001). CONCLUSIONS: Mild hypercalcaemia, multi-gland disease and co-existing thyroid disease are the main factors affecting sensitivity of preoperative imaging studies. In such patients a mini-invasive approach is possible but the use of intraoperative PTH monitoring is mandatory to reduce the risk of unsuccessful surgery. PMID- 26646660 TI - Opinion of the Scientific Committee on Consumer safety (SCCS) - Opinion on the safety of the use of deoxyarbutin in cosmetic products. AB - CONCLUSION OF THE OPINION: Although on the basis of the provided scientific data the use of deoxyarbutin as such can be considered safe for consumers in cosmetic products in a concentration up to 3% in face creams, hydroquinone will be formed at levels which raise concerns with regard to the safety of such products during life-cycle of the product (e.g. storage conditions and stability under in-use conditions). Therefore, the overall conclusion of the SCCS is that the use of deoxyarbutin up to 3% in face creams is not safe. PMID- 26646661 TI - Opinion of the Scientific Committee on Consumer safety (SCCS)--Opinion on the safety of the use of alpha-arbutin in cosmetic products. AB - CONCLUSION OF THE OPINION: The SCCS considers the use of alpha-Arbutin safe for consumers in cosmetic products in a concentration up to 2% in face creams and up to 0.5% in body lotions. A potential combined use of alpha-Arbutin and other hydroquinone releasing substances in cosmetic products has not been evaluated in this Opinion. PMID- 26646662 TI - C/EBPbeta-LAP*/LAP Expression Is Mediated by RSK/eIF4B-Dependent Signalling and Boosted by Increased Protein Stability in Models of Monocytic Differentiation. AB - The transcription factor C/EBPbeta plays a key role in monocytic differentiation and inflammation. Its small isoform LIP is associated with proliferation at early premonocytic developmental stages and regulated via mTOR-dependent signalling. During later stages of (pre)monocytic differentiation there is a considerable increase in the large C/EBPbeta isoforms LAP*/LAP which inhibit proliferation thus supporting terminal differentiation. Here, we showed in different models of monocytic differentiation that this dramatic increase in the LAP*/LAP protein and LAP/LIP ratio was accompanied by an only modest/retarded mRNA increase suggesting an important role for (post)translational mechanisms. We found that LAP*/LAP formation was induced via MEK/RSK-dependent cascades, whereas mTOR/S6K1 were not involved. Remarkably, LAP*/LAP expression was dependent on phosphorylated eIF4B, an acceleratory protein of RNA helicase eIF4A. PKR inhibition reduced the expression of eIF4B and C/EBPbeta in an eIF2alpha-independent manner. Furthermore, under our conditions a marked stabilisation of LAP*/LAP protein occurred, accompanied by reduced chymotrypsin-like proteasome/calpain activities and increased calpastatin levels. Our study elucidates new signalling pathways inducing LAP*/LAP expression and indicates new alternative PKR functions in monocytes. The switch from mTOR- to RSK-mediated signalling to orchestrate eIF4B dependent LAP*/LAP translation, accompanied by increased protein stability but only small mRNA changes, may be a prototypical example for the regulation of protein expression during selected processes of differentiation/proliferation. PMID- 26646663 TI - Low expression of N-myc downstream-regulated gene 2 (NDRG2) correlates with poor prognosis in hepatoblastoma. AB - BACKGROUND/PURPOSE OF THE STUDY: Despite tremendous progress in therapy, about 30% of patients with hepatoblastoma still succumb to the disease. Thus, the development of improved therapies as well as the identification of prognostic factors are urgently needed. METHODS: In the present study, expression and promoter methylation of the N-myc downstream-regulated gene (NDRG2), a tumor suppressor gene contributing to the regulation of the Wnt signalling pathway, was analysed in 38 hepatoblastoma samples by real-time reverse transcription-PCR and pyrosequencing, respectively. RESULTS: The NDRG2 gene was highly expressed in normal pediatric liver tissue, but was significantly downregulated in heptoblastoma primary tumors. Detailed methylation analysis of CpG sites in the NDRG2 promoter region revealed a general high degree of DNA methylation in hepatoblastoma, which correlated with the suppression of NDRG2. By analyzing clinicopathological features we could demonstrate a strong association between low NDRG2 expression and tumor metastasis. Importantly, the overall survival analysis by Kaplan-Meier revealed that high NDRG2 expression was correlated with a higher survival rate in hepatoblastoma patients. CONCLUSION: Our data show that downregulation of NDRG2 may play an important role in advanced hepatoblastomas. PMID- 26646665 TI - Single Layer Deposition of Polystyrene Particles onto Planar Polydimethylsiloxane Substrates. AB - This work investigates the deposition of polystyrene particles onto cross-linked polydimethylsiloxane (PDMS) substrates by using an impinging jet flow cell for different concentrations of sodium chloride in solution. Particle tracking reveals that particles near the substrate can be immobilized to different degrees. An attempt is made to classify the mobility of the particles close to the surface by distinguishing between weakly immobilized and strongly immobilized particles where only the latter ones are considered as deposited. Subsequently, the measured initial deposition rates for different concentrations of sodium chloride in solution are compared to the commonly applied theory based on the convective diffusion equation in which different surface interaction potentials were considered. With currently available data on the surface properties of PDMS, the extended Derjaguin-Landau-Verwey-Overbeek (extended DLVO) theory gave a better description of the observed deposition rates as compared to the DLVO theory; however, in either case, the presence of significant surface charge heterogeneity had to be assumed in order to capture the observed trend of the deposition rates with respect to the electrolyte concentration. Careful analysis of the more weakly immobilized particles through particle displacement step analysis reveals that there is a buildup of a particle accumulation layer near the substrate in which particle motion parallel to the substrate is hindered by nonhydrodynamic effects. Possible reasons for the reduced particle motion in the accumulation layer are discussed. As a result, the presence of lateral surface interaction forces resulting from charge heterogeneity and surface roughness of the PDMS substrate is found to be the most plausible explanation for the hindered particle motion in the accumulation layer. This suggests that particles associated with the secondary minimum of the surface interaction potential may not always be freely mobile in any direction parallel to the substrate. PMID- 26646664 TI - Interleukin-13 Inhibits Lipopolysaccharide-Induced BPIFA1 Expression in Nasal Epithelial Cells. AB - Short palate, lung, and nasal epithelium clone 1 (SPLUNC1) protein is expressed in human nasopharyngeal and respiratory epithelium and has demonstrated antimicrobial activity. SPLUNC1 is now referred to as bactericidal/permeability increasing fold containing family A, member 1 (BPIFA1). Reduced BPIFA1 expression is associated with bacterial colonization in patients with chronic rhinosinusitis with nasal polyps (CRSwNP). Interleukin 13 (IL-13), predominately secreted by T helper 2 (TH2) cells, has been found to contribute to airway allergies and suppress BPIFA1 expression in nasal epithelial cells. However, the molecular mechanism of IL-13 perturbation of bacterial infection and BPIFA1 expression in host airways remains unclear. In this study, we found that lipopolysaccharide (LPS)-induced BPIFA1 expression in nasal epithelial cells was mediated through the JNK/c-Jun signaling pathway and AP-1 activation. We further demonstrated that IL-13 downregulated the LPS-induced activation of phosphorylated JNK and c-Jun, followed by attenuation of BPIFA1 expression. Moreover, the immunohistochemical analysis showed that IL-13 prominently suppressed BPIFA1 expression in eosinophilic CRSwNP patients with bacterial infection. Taken together, these results suggest that IL-13 plays a critical role in attenuation of bacteria induced BPIFA1 expression that may result in eosinophilic CRSwNP. PMID- 26646667 TI - Merging Photoredox with Palladium Catalysis: Decarboxylative ortho-Acylation of Acetanilides with alpha-Oxocarboxylic Acids under Mild Reaction Conditions. AB - A room temperature decarboxylative ortho-acylation of acetanilides with alpha oxocarboxylic acids has been developed via a novel Eosin Y with Pd dual catalytic system. This dual catalytic reaction shows a broad substrate scope and good functional group tolerance, and an array of ortho-acylacetanilides can be afforded in high yields under mild conditions. PMID- 26646666 TI - Fluorescent Bisphosphonate and Carboxyphosphonate Probes: A Versatile Imaging Toolkit for Applications in Bone Biology and Biomedicine. AB - A bone imaging toolkit of 21 fluorescent probes with variable spectroscopic properties, bone mineral binding affinities, and antiprenylation activities has been created, including a novel linking strategy. The linking chemistry allows attachment of a diverse selection of dyes fluorescent in the visible to near infrared range to any of the three clinically important heterocyclic bisphosphonate bone drugs (risedronate, zoledronate, and minodronate or their analogues). The resultant suite of conjugates offers multiple options to "mix and match" parent drug structure, fluorescence emission wavelength, relative bone affinity, and presence or absence of antiprenylation activity, for bone-related imaging applications. PMID- 26646668 TI - Mortality risks during extreme temperature events (ETEs) using a distributed lag non-linear model. AB - This study investigates the relationship between all-cause mortality and extreme temperature events (ETEs) from 1975 to 2004. For 50 U.S. locations, these heat and cold events were defined based on location-specific thresholds of daily mean apparent temperature. Heat days were defined by a 3-day mean apparent temperature greater than the 95th percentile while extreme heat days were greater than the 97.5th percentile. Similarly, calculations for cold and extreme cold days relied upon the 5th and 2.5th percentiles. A distributed lag non-linear model assessed the relationship between mortality and ETEs for a cumulative 14-day period following exposure. Subsets for season and duration effect denote the differences between early- and late-season as well as short and long ETEs. While longer lasting heat days resulted in elevated mortality, early season events also impacted mortality outcomes. Over the course of the summer season, heat-related risk decreased, though prolonged heat days still had a greater influence on mortality. Unlike heat, cold-related risk was greatest in more southerly locations. Risk was highest for early season cold events and decreased over the course of the winter season. Statistically, short episodes of cold showed the highest relative risk, suggesting unsettled weather conditions may have some relationship to cold-related mortality. For both heat and cold, results indicate higher risk to the more extreme thresholds. Risk values provide further insight into the role of adaptation, geographical variability, and acclimatization with respect to ETEs. PMID- 26646669 TI - Hydroxyapatite and tricalcium phosphate composites with bioactive glass as second phase: State of the art and current applications. AB - Calcium phosphates are among the most common biomaterials employed in orthopaedic and dental surgery. The efficacy of such systems as bone substitutes and bioactive coatings on metallic prostheses has been proved by several clinical studies. Among these materials, hydroxyapatite (HA) and tricalcium phosphate (TCP) play a prominent role in medical practice since the '80s. In the last years, numerous attempts to combine HA or TCP with bioactive glasses have been made. There are two main motivations for sintering calcium phosphates with a glassy phase: on the one hand, it is possible to tune the dissolution of the final system and to enhance its biological response through the synergistic combination of two bioactive phases; on the other hand, the glass acts as a sintering aid with the aim to increase the densification of the composite and thus its mechanical strength. In this sense, TCP and HA are penalized by their relatively poor fracture toughness and tensile strength compared to natural bone, which makes it impossible to use them in load-bearing applications. Moreover, the bioactivity index of pure calcium phosphates is typically lower with respect to that of many bioactive glasses. In this review, the state of the art and current applications of composites, based on HA or TCP with bioactive glass as second phase, are presented and discussed. A special emphasis is given to the processing and mechanical behaviour of these systems, together with their biological implications, as a function of the composition of the glass employed as second phase. PMID- 26646671 TI - Volatile organic compounds in plasma for the diagnosis of esophageal adenocarcinoma: a pilot study. AB - BACKGROUND AND AIMS: A noninvasive screening test that can detect esophageal adenocarcinoma (EAC) at an earlier stage could improve the prognosis associated with EAC. The role of plasma volatile organic compounds (VOCs) for the diagnosis of EAC has not been previously studied. METHODS: Plasma samples were collected from subjects with EAC and GERD before endoscopy. Twenty-two preselected VOCs were analyzed with selected ion flow tube mass spectrometry. RESULTS: The headspaces from 39 plasma samples (20 EAC, 19 GERD) were analyzed. The levels of 9 VOCs (acetonitrile, acrylonitrile, carbon disulfide, isoprene, 1-heptene, 3 methylhexane, [E]-2-nonene, hydrogen sulfide, and triethylamine) were significantly altered in EAC patients compared with GERD patients. A multivariable logistic regression analysis was performed to build a model for the prediction of EAC. The model identified patients with EAC with an area under the curve of 0.83 (95% confidence interval, 0.67-0.98). CONCLUSIONS: Plasma VOCs may be useful in diagnosing EAC. Larger studies are needed to confirm our pilot study observations. PMID- 26646670 TI - Effects of high-intensity aerobic exercise on psychotic symptoms and neurocognition in outpatients with schizophrenia: study protocol for a randomized controlled trial. AB - BACKGROUND: The focus in recent years on physical inactivity and metabolic disturbances in individuals with schizophrenia raises the question of potential effects of physical activity. Physical activity has shown beneficial effects on cognition in healthy older individuals as well as on symptom severity in depression. However, opinions diverge regarding whether aerobic high-intensity interval training reduces cognition and key symptoms in schizophrenia. The main objective for the trial is to investigate the potential effects of aerobic high intensity interval training on neurocognitive function and mental symptoms in outpatients with schizophrenia. METHODS/DESIGN: The trial is designed as a randomized controlled, observer-blinded clinical trial. Patients are randomized to 1 of 2 treatment arms with 12-week duration: aerobic high-intensity interval training or computer gaming skills training. All participants also receive treatment as usual. Primary outcome measure is neurocognitive function. Secondary outcome measures will be positive and negative symptoms, wellbeing, tobacco smoking patterns and physiological/metabolic parameters. Patient recruitment takes place in catchment area-based outpatient clinics. TRIAL REGISTRATION: ClinicalTrials.gov NCT02205684 . Registered 29 July 2014. PMID- 26646672 TI - Implantable Smart Technologies (IST): Defining the 'Sting' in Data and Device. AB - In a world surrounded by smart objects from sensors to automated medical devices, the ubiquity of 'smart' seems matched only by its lack of clarity. In this article, we use our discussions with expert stakeholders working in areas of implantable medical devices such as cochlear implants, implantable cardiac defibrillators, deep brain stimulators and in vivo biosensors to interrogate the difference facets of smart in 'implantable smart technologies', considering also whether regulation needs to respond to the autonomy that such artefacts carry within them. We discover that when smart technology is deconstructed it is a slippery and multi-layered concept. A device's ability to sense and transmit data and automate medicine can be associated with the 'sting' of autonomy being disassociated from human control as well as affecting individual, group, and social environments. PMID- 26646673 TI - A higher Mediterranean diet adherence and exercise practice are associated with a healthier drinking profile in a healthy Spanish adult population. AB - PURPOSE: Very few studies have examined the association between beverage intake patterns and healthy lifestyle characteristics. Most of the research that has been carried out focuses on the consumption of soft drinks or alcohol and ignores the overall beverage pattern. The aim of this study is to evaluate the association between consumption of different types of beverage and physical exercise practice and MedDiet adherence. METHODS: Cross-sectional information about fluid intake from different types of beverages was collected in 1262 men and women between 18 and 70 years old, using a 24-h fluid-specific diary over seven consecutive days. Physical exercise was evaluated with a self-reported questionnaire, and MedDiet adherence was assessed using a validated 14-item questionnaire. Both variables were classified into three categories. RESULTS: Individuals with greater adherence to the MedDiet showed a higher intake of water and wine and a lower consumption of sweet regular beverages. Participants who engaged in more physical exercise consumed more water, milk and derivatives, juices and wine and less sweet regular beverages. Compared to the lowest category, the possibility of meeting the EFSA recommendations of total fluid intake was greater in individuals with eight or more points on the MedDiet adherence questionnaire [OR 1.94; 95 % CI 1.25-3.01] and in those who practice physical exercise three times a week or more [OR 1.71; 95 % CI 1.22-2.39]. Participants with a healthier lifestyle had a lower risk of exceeding the WHO's free-sugar recommendations only from beverages. CONCLUSIONS: Participants with greater adherence to the MedDiet and who engaged in more physical exercise exhibit a healthier pattern of fluid intake. PMID- 26646675 TI - Post-operative imaging of anterior cruciate ligament reconstruction techniques across the spectrum of skeletal maturity. AB - Due to an increased frequency of anterior cruciate ligament (ACL) injuries in young patients and improved outcomes in athletic performance following ACL reconstruction, surgery is increasingly being performed across the spectrum of skeletal maturity. We present a review of the range of reconstruction techniques performed in skeletally immature patients (physeal sparing techniques, which may involve epiphyseal tunnels or the utilization of an iliotibial band autograft), those performed in patients nearing skeletal maturity (transphyseal techniques), and the more conventional ACL reconstruction techniques performed in skeletally mature adolescents. It is important that radiologists be aware of the range of techniques being performed throughout the spectrum of skeletal maturity in order to accurately characterize the expected post-operative appearance as well as to identify complications, including those unique to this younger population. PMID- 26646674 TI - AMPK activation by liquiritigenin inhibited oxidative hepatic injury and mitochondrial dysfunction induced by nutrition deprivation as mediated with induction of farnesoid X receptor. AB - PURPOSE: Nutrition is indispensable for cell survival and proliferation. Thus, loss of nutrition caused by serum starvation in cells could induce formation of reactive oxygen species (ROS), resulting in cell death. Liquiritigenin (LQ) is an active flavonoid in licorice and plays a role in the liver as a hepatic protectant. METHODS: This study investigated the effect of LQ, metformin [an activator of activated AMP-activated protein kinase (AMPK)] and GW4064 [a ligand of farnesoid X receptor (FXR)] on mitochondrial dysfunction and oxidative stress induced by serum deprivation as well as its molecular mechanism, as assessed by immunoblot and flow cytometer assays. RESULTS: Serum deprivation in HepG2, H4IIE and AML12 cells successfully induced oxidative stress and apoptosis, as indicated by depletion of glutathione, formation of ROS, and altered expression of apoptosis-related proteins such as procaspase-3, poly(ADP-ribose) polymerase, and Bcl-2. However, LQ pretreatment significantly blocked these pathological changes and mitochondrial dysfunction caused by serum deprivation. Moreover, LQ activated AMPK in HepG2 cells and mice liver, as shown by phosphorylation of AMPK and ACC, and this activation was mediated by its upstream kinase (i.e., LKB1). Experiments using a chemical inhibitor of AMPK with LKB1-deficient Hela cells revealed the role of the LKB1-AMPK pathway in cellular protection conferred by LQ. LQ also induced protein and mRNA expression of both FXR as well as small heterodimer partner, which is important since treatment with FXR ligand GW4064 protected hepatocytes against cell death and mitochondrial damage induced by serum deprivation. CONCLUSION: AMPK activators such as LQ can protect hepatocytes against oxidative hepatic injury and mitochondrial dysfunction induced by serum deprivation, and the beneficial effect might be mediated through the LKB1 pathway as well as FXR induction. PMID- 26646676 TI - The effects of single and mixed infections of Apicystis bombi and deformed wing virus in Bombus terrestris. AB - Many pollinators are currently suffering from declines, diminishing their gene pool and increasing their vulnerability to parasites. Recently, an increasing diversity of parasites has been recorded in bumblebees, yet for many, knowledge of their virulence and hence the risk their presence poses, is lacking. The deformed wing virus (DWV), known to be ubiquitous in honey bees, has now been detected in bumblebees. In addition, the neogregarine Apicystis bombi has been discovered to be more prevalent than previously thought. Here, we assess for the first time the lethal and sublethal effects of these parasites during single and mixed infections of worker bumblebees (Bombus terrestris). Fifteen days after experimental exposure, 22% of bees exposed to A. bombi, 50% of bees exposed to DWV and 86% of bees exposed to both parasites had died. Bumblebees that had ingested A. bombi had increased sucrose sensitivity (SS) and a lower lipid:body size ratio than control bees. While dual infected bumblebees showed no increase in SS. Overall, we find that A. bombi exhibits both lethal and sublethal effects. DWV causes lethal effect and may reduce the sub lethal effects imposed by A. bombi. The results show that both parasites have significant, negative effects on bumblebee health, making them potentially of conservation concern. PMID- 26646677 TI - Lithium Battery Diaper Ulceration. AB - We report a case of lithium battery diaper ulceration in a 16-month-old girl. Gastrointestinal and ear, nose, and throat lesions after lithium battery ingestion have been reported, but skin involvement has not been reported to our knowledge. PMID- 26646678 TI - Severe Paradoxical Reaction During Treatment of Disseminated Tuberculosis in a Patient With Neutralizing Anti-IFNgamma Autoantibodies. AB - Interferon-gamma (IFNgamma) neutralizing autoantibodies are associated with disseminated nontuberculous mycobacterial infections. We report a previously healthy Thai woman with disseminated tuberculosis and high-titer IFNgamma neutralizing autoantibodies, who developed a severe inflammatory reaction during anti-tuberculosis treatment. IFNgamma contributes to host control of tuberculosis but appears inessential for tuberculosis paradoxical reactions. PMID- 26646679 TI - Hemophagocytic Lymphohistiocytosis Associated With Bartonella henselae Infection in an HIV-Infected Patient. AB - Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome that often occurs in immunocompromised patients. We report the first case of HLH due to Bartonella henselae infection in a patient with human immunodeficiency virus infection. Early recognition of HLH and B. henselae through liver biopsy and serological tests led to the patient's recovery. PMID- 26646681 TI - In-grown structure of NiFe mixed metal oxides and CNT hybrid catalysts for oxygen evolution reaction. AB - This work reports a unique in-grown structure of a NiFe-MMO/CNT hybrid catalyst. This structure creates larger interfacial area and strong interaction between the NiFe-MMO catalyst and the CNT, which could promote charge transfer at the interface, and hence improve conductivity. This leads to outstanding electrochemical performance for oxygen evolution reaction. PMID- 26646680 TI - Unintended Pregnancies Observed With Combined Use of the Levonorgestrel Contraceptive Implant and Efavirenz-based Antiretroviral Therapy: A Three-Arm Pharmacokinetic Evaluation Over 48 Weeks. AB - BACKGROUND: Levonorgestrel subdermal implants are preferred contraceptives with an expected failure rate of <1% over 5 years. We assessed the effect of efavirenz or nevirapine-based antiretroviral therapy (ART) coadministration on levonorgestrel pharmacokinetics. METHODS: This nonrandomized, parallel group, pharmacokinetic evaluation was conducted in three groups of human immunodeficiency virus-infected Ugandan women: ART-naive (n = 17), efavirenz based ART (n = 20), and nevirapine-based ART (n = 20). Levonorgestrel implants were inserted at baseline in all women. Blood was collected at 1, 4, 12, 24, 36, and 48 weeks. The primary endpoint was week 24 levonorgestrel concentrations, compared between the ART-naive group and each ART group by geometric mean ratio (GMR) with 90% confidence interval (CI). Secondary endpoints included week 48 levonorgestrel concentrations and unintended pregnancies. RESULTS: Week 24 geometric mean levonorgestrel concentrations were 528, 280, and 710 pg/mL in the ART-naive, efavirenz, and nevirapine groups, respectively (efavirenz: ART-naive GMR, 0.53; 90% CI, .50, .55 and nevirapine: ART-naive GMR, 1.35; 90% CI, 1.29, 1.43). Week 48 levonorgestrel concentrations were 580, 247, and 664 pg/mL in the ART-naive, efavirenz, and nevirapine groups, respectively (efavirenz: ART-naive GMR, 0.43; 90% CI, .42, .44 and nevirapine: ART-naive GMR, 1.14; 90% CI, 1.14, 1.16). Three pregnancies (3/20, 15%) occurred in the efavirenz group between weeks 36 and 48. No pregnancies occurred in the ART-naive or nevirapine groups. CONCLUSIONS: Within 1 year of combined use, levonorgestrel exposure was markedly reduced in participants who received efavirenz-based ART, accompanied by contraceptive failures. In contrast, nevirapine-based ART did not adversely affect levonorgestrel exposure or efficacy. CLINICAL TRIALS REGISTRATION: NCT01789879. PMID- 26646683 TI - Intimate Partner Violence in Men Voluntarily Attending Treatment: A Study of Couple Agreement. AB - Most studies examining couple agreement on intimate partner violence (IPV) have found low agreement on levels of violence. This study explored agreement on male perpetrated IPV in a sample of 93 couples where the man was voluntarily seeking IPV treatment. Five different types of violence were assessed: physical, physically controlling, psychological, property, and sexual. The results were mixed. When disagreement was found, this resulted from men attending IPV treatment reporting less violence than their partners. However, only psychological violence was consistently reported differently. Reliability estimates ranged from poor to moderate. Couples reported on sexual violence with less reliability than physical or physically controlling violence when referring to a typical month last year. Measurement of different types of violence among both partners in a couple is recommended in clinical and research settings as well as thorough discussions with clients voluntarily enrolled in treatment for IPV on what constitutes violence. PMID- 26646682 TI - Extracellular Histones Induce Chemokine Production in Whole Blood Ex Vivo and Leukocyte Recruitment In Vivo. AB - The innate immune system relies to a great deal on the interaction of pattern recognition receptors with pathogen- or damage-associated molecular pattern molecules. Extracellular histones belong to the latter group and their release has been described to contribute to the induction of systemic inflammatory reactions. However, little is known about their functions in the early immune response to an invading pathogen. Here we show that extracellular histones specifically target monocytes in human blood and this evokes the mobilization of the chemotactic chemokines CXCL9 and CXCL10 from these cells. The chemokine induction involves the toll-like receptor 4/myeloid differentiation factor 2 complex on monocytes, and is under the control of interferon-gamma. Consequently, subcutaneous challenge with extracellular histones results in elevated levels of CXCL10 in a murine air pouch model and an influx of leukocytes to the site of injection in a TLR4 dependent manner. When analyzing tissue biopsies from patients with necrotizing fasciitis caused by Streptococcus pyogenes, extracellular histone H4 and CXCL10 are immunostained in necrotic, but not healthy tissue. Collectively, these results show for the first time that extracellular histones have an important function as chemoattractants as their local release triggers the recruitment of immune cells to the site of infection. PMID- 26646684 TI - Semen inflammatory markers and Chlamydia trachomatis infection in male partners of infertile couples. AB - Previous studies have given conflicting results about the effect of generally infection and Chlamydia trachomatis on seminal ILs and semen parameters. The aim of this study was to investigate the relationship between semen quality and the level of seminal interleukins (ILs) in infertile couples with C. trachomatis. Blood, first void urine (FVU) and semen were obtained from 250 infertile men who had failed to conceive after 12 months of trying. Serological analysis for specific IgA, IgM and IgG antibodies to C. trachomatis in serum, the presence of C. trachomatis in FVU and semen sample and semen analysis were carried out. The main results are as follows: (i) elevated IL-6 and IL-8 are observed in C. trachomatis-positive men, but this is not significant and it varies by diagnostic method; and (ii) IL-6 and IL-8 levels were correlated with each other and the concentration of leucocytes, but IL-8 was correlated with semen volume and patient's age. This study showed that men with such an infection in FVU samples (PCR positive) had only lower semen volume compared with men without infection. PMID- 26646685 TI - Extract of Ziziphus jujuba Fruit (Jujube) Stimulates Expression of Enzymes Responsible for Heme Recycle via Anti-oxidant Response Element in Cultured Murine Macrophages. AB - Jujube, the fruit of Ziziphus jujuba Mill., is a functional food and commonly used as a health supplement worldwide. To study the beneficial role of jujube in heme iron recycling during erythrophagocytosis, the expression of heme oxygenase 1 (HO-1), biliverdin reductase A and B, and ferroportin were determined in jujube treated cultured RAW 264.7 macrophages. Application of a chemically standardized jujube water extract in cultured RAW 264.7 cells for 24 h stimulated the expressions of HO-1, biliverdin reductase A, biliverdin reductase B, and ferroportin in a concentration-dependent manner, having the maximal responses from twofolds to threefolds. A plasmid containing anti-oxidant response element, a regulator for HO-1 transcription, was transfected into RAW 264.7 cells. Application of jujube water extract onto the transfected macrophages stimulated the anti-oxidant response element-mediated transcriptional activity by twofolds. These results supported the potential capacity of jujube by regulating expressions of heme iron recycling genes in cultured macrophages. PMID- 26646686 TI - Nanostructured Polyphase Catalysts Based on the Solid Component of Welding Aerosol for Ozone Decomposition. AB - Samples of the solid component of welding aerosols (SCWAs) were obtained as a result of steel welding by ANO-4, TsL-11, and UONI13/55 electrodes of Ukrainian manufacture. The phase compositions of the samples, both freshly prepared (FP) and modified (M) by water treatment at 60 degrees C, were studied by X-ray phase analysis and IR spectroscopy. All samples contain magnetite demonstrating its reflex at 2theta ~ 35 degrees characteristic of cubic spinel as well as manganochromite and iron oxides. FP SCWA-TsL and FP SCWA-UONI contain such phases as SaF2, water-soluble fluorides, chromates, and carbonates of alkali metals. After modification of the SCWA samples, water-soluble phases in their composition are undetectable. The size of magnetite nanoparticles varies from 15 to 68 nm depending on the chemical composition of electrodes under study. IR spectral investigations confirm the polyphase composition of the SCWAs. As to IR spectra, the biggest differences are apparent in the regions of deformation vibrations of M-O-H bonds and stretching vibrations of M-O bonds (M-Fe, Cr). The catalytic activity of the SCWAs in the reaction of ozone decomposition decreases in the order SCWA-ANO > SCWA-UONI > SCWA-TsL corresponding to the decrease in the content of catalytically active phases in their compositions. PMID- 26646687 TI - Invention of Hollow Zirconium Tungesto-Vanadate at Nanotube Morphological Structure for Radionuclides and Heavy Metal Pollutants Decontamination from Aqueous Solutions. AB - Zirconium tungesto-vanadate cation exchange material was successfully architectured at open ended nanotubes morphological structure in the presence of polyvinyl alcohol as a stabilizing agent using microwave route. The ion exchange capacity (IEC) of the material was recorded as 4.8 meq/g of about 640 m(2)/g for a specific surface area. The x-ray diffraction pattern of the material implies its crystallinity. Both scanning and transmission electron microscopes identified the average aspect ratio of the architectured nanotubes as 6.5 and its hollow structure. The material posed 96.4 % cadmium ion decontamination within 90 min compared with 84 % strontium decontamination at the same time. PMID- 26646688 TI - Electrospun Aligned Fibrous Arrays and Twisted Ropes: Fabrication, Mechanical and Electrical Properties, and Application in Strain Sensors. AB - Electrospinning (e-spinning) is a versatile technique to fabricate ultrathin fibers from a rich variety of functional materials. In this paper, a modified e spinning setup with two-frame collector is proposed for the fabrication of highly aligned arrays of polystyrene (PS) and polyvinylidene fluoride (PVDF) nanofibers, as well as PVDF/carbon nanotube (PVDF/CNT) composite fibers. Especially, it is capable of producing fibrous arrays with excellent orientation over a large area (more than 14 cm * 12 cm). The as-spun fibers are suspended and can be easily transferred to other rigid or flexible substrates. Based on the aligned fibrous arrays, twisted long ropes are also prepared. Compared with the aligned arrays, twisted PVDF/CNT fiber ropes show enhanced mechanical and electrical properties and have potential application in microscale strain sensors. PMID- 26646689 TI - Spatial Distribution of Atmospheric PCBs in Zurich, Switzerland: Do Joint Sealants Still Matter? AB - Passive air samplers were deployed at 23 sites across the city of Zurich, Switzerland to investigate the spatial distribution of polychlorinated biphenyls (PCBs) in air. Concentrations of the six indicator PCBs (iPCBs) in air ranged from 54 to 3160 pg.m(-3) in the two sampling campaigns (spring 2011 and spring 2013). Measurements at two sampling sites were significantly higher than the median in both years, because of the proximity to primary PCB sources. Concentrations at most other stations were in a narrow range, suggesting that atmospheric PCB concentrations in Zurich are mainly caused by a high number of rather small sources. A correlation of iPCB concentrations in air with the number of buildings constructed between 1955 and 1975 in the surrounding areas of the sampling sites was observed. This demonstrates that PCB-containing building materials, such as joint sealants, influence PCB levels in urban air. Additionally, atmospheric iPCB concentrations were measured in the surrounding of a housing complex with PCB-contaminated joint sealants. Using a Gaussian diffusion model, annual iPCB emissions of 110-190 g were calculated for this housing complex. This appreciable amount released by a single building points out that more efforts are required to further eliminate remaining PCB stocks. PMID- 26646690 TI - Childhood household dysfunction, school performance and psychiatric care utilisation in young adults: a register study of 96 399 individuals in Stockholm County. AB - BACKGROUND: Exposure to childhood household dysfunction increases the risk of psychiatric morbidity. Although school performance also has been linked with psychiatric morbidity, limited research has considered school performance as a mediating factor. To address this gap in the literature, the current register study examined whether school performance mediates the association between childhood household dysfunction (experienced between birth and age 14 years) and psychiatric care utilisation in young adulthood. METHODS: We used a Swedish cohort of 96 399 individuals born during 1987-1991. Indicators of childhood household dysfunction were familial death, parental substance abuse and psychiatric morbidity, parental somatic disease, parental criminality, parental separation/single-parent household, public assistance recipiency and residential instability. Final school grades from the 9th year of compulsory school were used to create five categories. Estimates of risk of psychiatric care utilisation (measured as inpatient, outpatient and primary care) after the age of 18 years were calculated as HRs with 95% CIs. Mediation was tested with the bootstrap approach. RESULTS: Cumulative exposure to childhood household dysfunction was positively associated with psychiatric care utilisation. Specifically, individuals exposed to three or more indicators with incomplete school grades had the highest risk (HR=3.7 (95% CI 3.3 to 4.1) after adjusting for demographics), compared to individuals exposed to no indicators with highest grades. School performance was found to mediate the relationship. CONCLUSIONS: Our findings suggest that future efforts to prevent or mitigate the negative effects of childhood household dysfunction on psychiatric morbidity may benefit from integration of strategies that improve school performance among vulnerable youth. PMID- 26646691 TI - How important are determinants of obesity measured at the individual level for explaining geographic variation in body mass index distributions? Observational evidence from Canada using Quantile Regression and Blinder-Oaxaca Decomposition. AB - BACKGROUND: Obesity prevalence varies between geographic regions in Canada. The reasons for this variation are unclear but most likely implicate both individual level and population-level factors. The objective of this study was to examine whether equalising correlates of body mass index (BMI) across these geographic regions could be reasonably expected to reduce differences in BMI distributions between regions. METHODS: Using data from three cycles of the Canadian Community Health Survey (CCHS) 2001, 2003 and 2007 for males and females, we modelled between-region BMI cross-sectionally using quantile regression and Blinder-Oaxaca decomposition of the quantile regression results. RESULTS: We show that while individual-level variables (ie, age, income, education, physical activity level, fruit and vegetable consumption, smoking status, drinking status, family doctor status, rural status, employment in the past 12 months and marital status) may be Caucasian important correlates of BMI within geographic regions, those variables are not capable of explaining variation in BMI between regions. DISCUSSION: Equalisation of common correlates of BMI between regions cannot be reasonably expected to reduce differences in the BMI distributions between regions. PMID- 26646692 TI - Fit-for-work or fit-for-unemployment? Does the reassessment of disability benefit claimants using a tougher work capability assessment help people into work? AB - BACKGROUND: Many governments have introduced tougher eligibility assessments for out-of-work disability benefits, to reduce rising benefit caseloads. The UK government initiated a programme in 2010 to reassess all existing disability benefit claimants using a new functional checklist. We investigated whether this policy led to more people out-of-work with long-standing health problems entering employment. METHOD: We use longitudinal data from the Labour Force Survey linked to data indicating the proportion of the population experiencing a reassessment in each of 149 upper tier local authorities in England between 2010 and 2013. Regression models were used to investigate whether the proportion of the population undergoing reassessment in each area was independently associated with the chances that people out-of-work with a long-standing health problem entered employment and transitions between inactivity and unemployment. We analysed whether any effects differed between people whose main health problem was mental rather than physical. RESULTS: There was no significant association between the reassessment process and the chances that people out-of-work with a long-standing illness entered employment. The process was significantly associated with an increase in the chances that people with mental illnesses moved from inactivity into unemployment (HR=1.22, 95% CI 1.03 to 1.45). CONCLUSIONS: The reassessment policy appears to have shifted people with mental health problems from inactivity into unemployment, but there was no evidence that it had increased their chances of employment. There is an urgent need for services that can support the increasing number of people with mental health problems on unemployment benefits. PMID- 26646693 TI - Thickness Dependence and Percolation Scaling of Hydrogen Production Rate in MoS2 Nanosheet and Nanosheet-Carbon Nanotube Composite Catalytic Electrodes. AB - Here we demonstrate that the performance of catalytic electrodes, fabricated from liquid exfoliated MoS2 nanosheets, can be optimized by maximizing the electrode thickness coupled with the addition of carbon nanotubes. We find the current, and so the H2 generation rate, at a given potential to increase linearly with electrode thickness to up ~5 MUm after which saturation occurs. This linear increase is consistent with a simple model which allows a figure of merit to be extracted. The magnitude of this figure of merit implies that approximately two thirds of the possible catalytically active edge sites in this MoS2 are inactive. We propose the saturation in current to be partly due to limitations associated with transporting charge through the resistive electrode to active sites. We resolve this by fabricating composite electrodes of MoS2 nanosheets mixed with carbon nanotubes. We find both the electrode conductivity and the catalytic current at a given potential to increase with nanotube content as described by percolation theory. PMID- 26646694 TI - Strategies for transporting nanoparticles across the blood-brain barrier. AB - The existence of blood-brain barrier (BBB) hampers the effective treatment of central nervous system (CNS) diseases. Almost all macromolecular drugs and more than 98% of small molecule drugs cannot pass the BBB. Therefore, the BBB remains a big challenge for delivery of therapeutics to the central nervous system. With the structural and mechanistic elucidation of the BBB under both physiological and pathological conditions, it is now possible to design delivery systems that could cross the BBB effectively. Because of their advantageous properties, nanoparticles have been widely deployed for brain-targeted delivery. This review paper presents the current understanding of the BBB under physiological and pathological conditions, and summarizes strategies and systems for BBB crossing with a focus on nanoparticle-based drug delivery systems. In summary, with wider applications and broader prospection the treatment of brain targeted therapy, nano-medicines have proved to be more potent, more specific and less toxic than traditional drug therapy. PMID- 26646695 TI - Fra-1 is a key driver of colon cancer metastasis and a Fra-1 classifier predicts disease-free survival. AB - Fra-1 (Fos-related antigen-1) is a member of the AP-1 (activator protein-1) family of transcription factors. We previously showed that Fra-1 is necessary for breast cancer cells to metastasize in vivo, and that a classifier comprising genes that are expressed in a Fra-1-dependent fashion can predict breast cancer outcome. Here, we show that Fra-1 plays an important role also in colon cancer progression. Whereas Fra-1 depletion does not affect 2D proliferation of human colon cancer cells, it impairs growth in soft agar and in suspension. Consistently, subcutaneous tumors formed by Fra-1-depleted colon cancer cells are three times smaller than those produced by control cells. Most remarkably, when injected intravenously, Fra-1 depletion causes a 200-fold reduction in tumor burden. Moreover, a Fra-1 classifier generated by comparing RNA profiles of parental and Fra-1-depleted colon cancer cells can predict the prognosis of colon cancer patients. Functional pathway analysis revealed Wnt as one of the central pathways in the classifier, suggesting a possible mechanism of Fra-1 function in colon cancer metastasis. Our results demonstrate that Fra-1 is an important determinant of the metastatic potential of human colon cancer cells, and that the Fra-1 classifier can be used as a prognostic predictor in colon cancer patients. PMID- 26646696 TI - Signature miRNAs in colorectal cancers were revealed using a bias reduction small RNA deep sequencing protocol. AB - To explore the role of miRNAs in colorectal cancers (CRC), we have deep sequenced 48 pairs of frozen CRC samples, of which 44 pairs produced high quality sequencing data. By using a combined approach of our bias reduction small RNA (smRNA) deep sequencing protocol and Illumina small RNA TruSeq method for sample bar coding, we have obtained data from samples of relatively large size with bias reduced digital profile results. This novel approach allowed us to validate many previously published results using various techniques to profile miRNAs in CRC tissues or cell lines and to characterize 'true' miRNA signatures highly expressed in colon/rectum (CR) or CRC tissues. According to our results, miR-21, a miRNA that is up-regulated in CRC, and miR-143, a miRNA that is down-regulated in CRC, are the two miRNAs that dominated the miRNA population in CR tissues, and probably are also the most important miRNAs in CRCs. These two miRNAs, together with the other eight miRNAs, miR-148a, -194, -192, 200b, -200c, -10b, -26a, and 145, with descending expressing levels, constituted the top 10 highly expressed miRNAs in CR/CRC. Using TaqMan miRNA qPCR, we detected the relative expression of some of the CRC miRNAs in 10 CRC cell lines, validated their dysregulation under cancer condition, and provided possible explanation for their dysregulation, which could be caused by APC, KRAS, or TP53 mutations. We believe these results will provide a new direction in future miRNA-related CRC development studies, and application of miRNAs in CRC diagnosis/prognosis, and therapy. PMID- 26646697 TI - Overexpression of wildtype EGFR is tumorigenic and denotes a therapeutic target in non-small cell lung cancer. AB - Current guidelines for lung cancer treatment with EGFR tyrosine kinase inhibitors (TKI) include only patients with mutated EGFR, although some patients with wildtype EGFR (wt-EGFR) have exhibited positive responses to this therapy as well. Biomarkers predicting the benefit from EGFR-TKIs treatment remain to be determined for patients with wild-type EGFR.Here, we report that wt-EGFR overexpression transformed cells in vitro and induced tumorigenesis in vivo in transgenic mouse models. Wt-EGFR driven lung cancer was hypersensitive to TKI treatment in mouse model. Lung cancer patients with high-expression of wt-EGFR showed longer Overall Survival in comparison to low-expression patients after TKI treatment. Our data therefore suggest that treatment with EGFR inhibitors should be extended to include not only patients with mutated EGFR but also a subset of patients with overexpression of wt-EGFR. PMID- 26646698 TI - The NKG2D-IL-15 signaling pathway contributes to T-cell mediated pathology in inflammatory myopathies. AB - NKG2D is an activating receptor on T cells, which has been implicated in the pathogenesis of autoimmune diseases. T cells are critically involved in idiopathic inflammatory myopathies (IIM) and have been proposed as specific therapeutic targets. However, the mechanisms underlying T cell-mediated progressive muscle destruction in IIM remain to be elucidated. We here determined the involvement of the NKG2D - IL-15 signaling pathway. Primary human myoblasts expressed NKG2D ligands, which were further upregulated upon inflammatory stimuli. In parallel, shedding of the soluble NKG2D ligand MICA (sMICA) decreased upon inflammation potentially diminishing inhibition of NKG2D signaling. Membrane related expression of IL-15 by myoblasts induced differentiation of naive CD8+ T cells into highly activated, cytotoxic CD8+NKG2Dhigh T cells demonstrating NKG2D dependent lysis of myoblasts in vitro. CD8+NKG2Dhigh T cell frequencies were increased in the peripheral blood of polymyositis (PM) patients and correlated with serum creatinine kinase concentrations, while serum sMICA levels were not significantly changed. In muscle biopsy specimens from PM patients expression of the NKG2D ligand MICA/B was upregulated, IL-15 was expressed by muscle cells, CD68+ macrophages as well as CD4+ T cells, and CD8+NKG2D+ cells were frequently detected within inflammatory infiltrates arguing for a local signaling circuit in the inflammatory muscle milieu. In conclusion, the NKG2D - IL-15 signaling pathway contributes to progressive muscle destruction in IIM potentially opening new therapeutic avenues. PMID- 26646699 TI - Understanding the role of the kynurenine pathway in human breast cancer immunobiology. AB - Breast cancer (BrCa) is the leading cause of cancer related death in women. While current diagnostic modalities provide opportunities for early medical intervention, significant proportions of breast tumours escape treatment and metastasize. Gaining increasing recognition as a factor in tumour metastasis is the local immuno-surveillance environment. Following identification of the role played by the enzyme indoleamine dioxygenase 1 (IDO1) in mediating maternal foetal tolerance, the kynurenine pathway (KP) of tryptophan metabolism has emerged as a key metabolic pathway contributing to immune escape. In inflammatory conditions activation of the KP leads to the production of several immune modulating metabolites including kynurenine, kynurenic acid, 3-hydroxykynurenine, anthranilic acid, 3-hydroxyanthranilic acid, picolinic acid and quinolinic acid. KP over-activation was first described in BrCa patients in the early 1960s. More evidence has since emerged to suggest that the IDO1 is elevated in advanced BrCa patients and is associated with poor prognosis. Further, IDO1 positive breast tumours have a positive correlation with the density of immune suppressive Foxp3+ T regulatory cells and lymph node metastasis. The analysis of clinical microarray data in invasive BrCa compared to normal tissue showed, using two microarray databank (cBioportal and TCGA), that 86.3% and 91.4% BrCa patients have altered KP enzyme expression respectively. Collectively, these data highlight the key roles played by KP activation in BrCa, particularly in basal BrCa subtypes where expression of most KP enzymes was altered. Accordingly, the use of KP enzyme inhibitors in addition to standard chemotherapy regimens may present a viable therapeutic approach. PMID- 26646700 TI - Ischaemic risk and bleeding risk in acute coronary syndrome: still inseparable. PMID- 26646701 TI - Temporal trends and changing profile of adults with congenital heart disease undergoing heart transplantation. AB - AIMS: To investigate the temporal trends in profile and outcomes of adults with congenital heart disease (ACHD) undergoing heart transplantation (HT). METHODS AND RESULTS: Out of a multi-institutional series of 2257 HT from 1988 to 2012, 100 HT were performed in 97 ACHD. We evaluated clinical characteristics, underlying defect, surgical history, perioperative issues, and outcomes. We compared two eras: era 1 (1988-2005, n = 48) and era 2 (2006-2012, n = 49). Mean age at HT was 30.3 +/- 10.5 years. Twenty-five patients (25.8%) had biventricular physiology with a systemic right ventricle and 43 patients (44%) had univentricular physiology. Adults with congenital heart disease severity were classified as great complexity (74.2%), moderate (21.7%), and simple (4.1%). During a median follow-up of 28.7 months [0-282], 44 patients died. Early mortality was high (34%; 95% CI 0.2536-0.4390). Survival was 63.9% at 1 year. The proportion of univentricular patients did not change. Biventricular patients with systemic right ventricle significantly increased in era 2 (16.7 vs. 34.7%, P = 0.04) due to increasing number of transposition of the great arteries with atrial switch. Although the proportion of great complexity ACHD did not change significantly in era 2 (81.6% vs. and 66.7% in era 1, P = 0.09), ACHD recipients have more advanced disease, being more likely hospitalized (P = 0.03), receiving intravenous inotropes (P = 0.01), under assist devices (P = 0.04), or UNOS status 1 (P = 0.02) at the time of HT. Survival rates were comparable. CONCLUSION: Despite a worse risk profile, mortality after HT in ACHD did not increase. Improving survival of complex CHD will probably amplify the proportion of complex ACHD recipients with more advanced disease. PMID- 26646702 TI - Role of T-cells in myocardial infarction. AB - Innate immunity has been studied for several decades in the context of ischaemia reperfusion injury, myocardial remodelling, and healing. In the last years, a number of experimental and clinical studies focused on adaptive immunity in these processes. Meanwhile, there is considerable evidence especially on the role of CD4(+) T-cells in myocardial injury and healing, whereas their role in remodelling is less clear. Innate leukocytes are able to recognize a wide array of self and foreign molecular patterns, whereas the activation of adaptive immunity requires the highly specific cooperation of antigen-presenting cells and distinct antigen-specific receptors on lymphocytes. Relevant autoantigens have not yet been definitely identified but experimental evidence indicates that autoantigen recognition is necessary for T-cell activation after myocardial infarction. Non-antigen-specific modes of activation might also play a role especially during acute ischaemia and reperfusion of the myocardium. This review summarizes the current evidence from experimental studies and presents side-by side recent clinical data on the role of T cells in the pathophysiology of myocardial reperfusion injury and post myocardial infarction healing. PMID- 26646703 TI - Comparative Study of Phenolic Profile, Antioxidant Capacity, and Color composition Relation of Roselle Cultivars with Contrasting Pigmentation. AB - Roselle is a plant that accumulates anthocyanins significantly, hence its importance as food coloring and as a source of antioxidant compounds for human health. This study was aimed to determine phenolic composition and antioxidant capacity of methanolic extracts, and beverages obtained from native roselle cultivars in Mexico (Negra, Sudan, Rosa and Blanca) with different degrees of pigmentation, and to establish the color-composition relationship. Chromatographic methods were used to determine phenolic compounds: flavanols, flavonols, benzoic, hibiscus and phenolic acids as well as two main anthocyanins (cyanidin 3-sambubioside and delphinidin 3-sambubioside). The antioxidant capacity was evaluated by ABTS and FRAP assays. Tristimulus colorimetry showed to be a useful technique to determine the color-composition relationship, leading to equations that allowed to predict anthocyanin content of roselle (R > 0.84). Also, a stepwise linear discriminant analysis (SLDA) was developed in order to classify roselle cultivars. The obtained mathematical model could be an important tool to be used in colorimetric characterization of functional compounds used in food processing. PMID- 26646704 TI - Esophageal diverticula are associated with propagating peristalsis: a study utilizing high-resolution manometry. AB - BACKGROUND: Esophageal diverticula have been associated with esophageal motility disorders, most commonly achalasia. We aimed to evaluate high-resolution manometry (HRM) motility diagnoses and pressurization patterns in patients with esophageal diverticula. METHODS: Patients were retrospectively identified for distal esophageal diverticula and previously completed HRM. High-resolution manometries were analyzed according to the Chicago Classification, and the pressure slope of the compartmentalization phase (time between upper esophageal sphincter closure and the transition zone) of esophageal bolus transit was measured. Pressure slopes were also measured in 10 asymptomatic volunteers (controls) for comparison. KEY RESULTS: Nineteen patients (ages 31-83) were included. Eight (42%) patients had normal motility, five (26%) had esophagogastric junction outflow obstruction, and two (11%) had jackhammer esophagus; four patients had other motility diagnoses including only one patient with achalasia. A total of six patients (32%) had at least one hypercontractile swallow. Greater compartmentalization phase pressure slopes were observed in patients at the mid-esophageal body in both supine (median [interquartile range]: 1.9 mmHg/s [0.9, 3.6]) and upright (1.1 [0.1, 3.1]) positions than in controls (supine: -1.3 [-2.4, -0.11], p = 0.001; upright; -0.71 [-2.1, -0.02], p = 0.005). CONCLUSIONS & INFERENCES: Propagating peristalsis, often with hypercontractility, was commonly seen in our cohort of patients with esophageal diverticula. Abnormal compartmentalization phase pressurization may indicate a relationship of abnormal esophageal wall mechanics and/or compliance with diverticula; however whether these findings are causal or reactionary remains unclear. PMID- 26646705 TI - Isocitrate Dehydrogenase 2 Suppresses the Invasion of Hepatocellular Carcinoma Cells via Matrix Metalloproteinase 9. AB - BACKGROUND/AIMS: Isocitrate dehydrogenase 2 (IDH2) is a mitochondrial NADP dependent isocitrate dehydrogenase, and has been found to be a tumor suppressor in several types of tumors. However, the roles of IDH2 in hepatocellular carcinoma (HCC) as well as underlying mechanisms remain unknown. METHODS: The IDH2 and matrix metalloproteinase 9 (MMP9) levels in the specimens from 24 HCC patients were investigated by Western blot and ELISA, respectively. Their relationship was examined by correlation analyses. Patient survival with high IDH2 levels and low IDH2 levels was compared. IDH2 levels and MMP9 levels were modified in a human HCC cell line. The effects of IDH2 or MMP9 modulation on the expression of the other were analyzed. The effects of IDH2 on cell invasion were analyzed in a transwell cell invasion assay. The dependence of nuclear factor x03BA;B (NF-x03BA;B) signaling was examined using a specific inhibitor. RESULTS: The IDH2 levels significantly decreased in HCC, and were lower in HCC with metastases, compared to those without metastases. IDH2 levels inversely correlated with MMP9 levels in HCC. HCC patients with Low IDH2 had lower 5-year survival. MMP9 levels did not regulate IDH2 levels, while IDH2 inhibited MMP9 levels in HCC cells, in a NF-x03BA;B signaling dependent manner, possibly through ix03BA;B, to suppress HCC cell invasion. CONCLUSIONS: Down regulation of IDH2 may promote HCC cell invasion via NF-x03BA;B-dependent increases in MMP9 activity. IDH2 may be a potential therapeutic target for HCC. PMID- 26646708 TI - Photopatterned Multidomain Gels: Multi-Component Self-Assembled Hydrogels Based on Partially Self-Sorting 1,3:2,4-Dibenzylidene-D-sorbitol Derivatives. AB - We report a multicomponent self-assembling system based on 1,3:2,4-dibenzyldene-D sorbitol (DBS) derivatives which form gels as the pH is lowered in a controlled way. The two DBS gelators are functionalized with carboxylic acids: the first in the 4-position of the aromatic rings (DBS-CO2H), the second having glycine connected through an amide bond and displaying a terminal carboxylic acid (DBS Gly). Importantly, these two self-assembling DBS-acids have different pKa values, and as such, their self-assembly is triggered at different pHs. Slowly lowering the pH of a mixture of gelators using glucono-delta-lactone (GdL) initially triggers assembly of DBS-CO2H, followed by DBS-Gly; a good degree of kinetic self sorting is achieved. Gel formation can also be triggered in the presence of diphenyliodonium nitrate (DPIN) as a photoacid under UV irradiation. Two-step acidification of a mixture of gelators using (a) GdL and (b) DPIN assembles the two networks sequentially. By combining this approach with a mask during step b, multidomain gels are formed, in which the network based on DBS-Gly is positively patterned into a pre-existing network based on DBS-CO2H. This innovative approach yields spatially resolved multidomain multicomponent gels based on programmable low-molecular-weight gelators, with one network being positively "written" into another. PMID- 26646707 TI - Long-term outcomes of long level posterolateral fusion in lumbar degenerative disease: comparison of long level fusion versus short level fusion: a case control study. AB - BACKGROUND: We sought to evaluate the long-term outcomes of long-level instrumented posterolateral fusion (PLF) directly compared to those with short level instrumented PLF for degenerative spinal stenosis. METHODS: From 1987-2002, patients who underwent instrumented PLF with wide decompression for degenerative spinal stenosis were reviewed. A total of 295 patients were available for follow up over 10 years (mean, 14 years). These patients were divided into Group 1 (fusion of 1 or 2 levels) and Group 2 (fusion of three or more levels). Clinical and radiological outcomes were evaluated. RESULTS: On clinical outcomes, Group 1 showed better results than Group 2 based on the Katz's Activities Daily Living index (p = 0.024), Kirkaldy-Willis criteria (p = 0.001) and the Korean version of the Oswestry disability index (p = 0.01). However, excellent and good outcome was noted in more than 64.5 % in Group 2. For radiological outcomes, overall fusion rate was higher in Group 1 compared with Group 2, but not significantly different (p = 0.35). However, the metal problems and surgical complications were more developed in Group 2 (p < 0.001). Although the radiologic changes on adjacent segments increased in accordance with the follow-up period, particularly in Group 2 (p < 0.001), no correlation with clinical symptoms was found. CONCLUSIONS: The long-level fusion group maintained acceptable clinical and radiological outcomes compared to the short-level fusion group at minimum of 10 years of follow-up. PMID- 26646709 TI - Catalytic Enantioselective Synthesis of N-C Axially Chiral Phenanthridin-6-one Derivatives. AB - N-C axially chiral phenanthridin-6-one derivatives bearing various ortho substituted phenyl groups on the nitrogen atom were enantioselectively prepared through (R)-DTBM-SEGPHOS-Pd(OAc)2-catalyzed intramolecular Buchwald-Hartwig amination. The enantioselectivity strongly depended on solvents, bases, and reaction temperature as well as on the bulkiness of ortho-substituents. PMID- 26646710 TI - The contribution of von Willebrand factor-GPIbalpha interactions to persistent aggregate formation in apheresis platelet concentrates. AB - BACKGROUND AND OBJECTIVES: Apheresis platelet concentrates sometimes contain persistent aggregates (PA). Because apheresis involves extracorporeal circulation, we hypothesized that interactions between GPIbalpha and von Willebrand factor (VWF) underlie their origin. MATERIALS AND METHODS: Platelets in donations with PA were compared to aggregate-free (AF) controls. Flow cytometry was used to determine platelet bound VWF. Degranulation was measured using P-selectin expression in flow cytometry and cytokine release using immunosorbent assays. Platelet adhesion to VWF was assessed in hydrodynamic flow and real-time video microscopy. RESULTS: Platelets in PA concentrates had significantly more (P = 0.009, n >= 8) bound VWF compared to AF platelets, but differences in VWF concentration, VWF collagen binding, activated VWF or GPIbalpha expression were not found. Degranulation was higher (P = 0.030, n = 7) in PA than AF concentrates on day 1 of storage, but adhesion to immobilized VWF under hydrodynamic flow conditions was normal at that moment. On day 6, however, significantly less VWF adhesion (P = 0.009, n >= 6) was found for PA platelets compared to AF, indicating accelerated storage lesion in PA products. In a model that mimicks PA formation by chemically induced binding of VWF to platelets, we found that degranulation, phosphatidylserine expression and metabolism did not differ with paired controls at any time during subsequent storage. CONCLUSION: Accelerated storage lesion is found in concentrates with PA, but this cannot be explained solely by increased platelet bound VWF following apheresis. Therefore, additional stressors are probably responsible for the increases observed in platelet degranulation and storage lesion in products with PA. PMID- 26646711 TI - PEGylated Carbon Nanocapsule: A Universal Reactor and Carrier for In Vivo Delivery of Hydrophobic and Hydrophilic Nanoparticles. AB - We have developed PEGylated mesoporous carbon nanocapsule as a universal nanoreactor and carrier for the delivery of highly crystalline hydrophobic/hydrophilic nanoparticles (NPs) which shows superior biocompatibility, dispersion in body fluids, good biodistribution and NPs independent cellular uptake mechanism. The hydrophobic/hydrophilic NPs without surface modification were synthesized in situ inside the cavities of mesoporous carbon capsules (200-850 nm). Stable and inert nature of carbon capsules in a wide range of reaction conditions like high temperature and harsh solvents, make it suitable for being used as nano/microreactors for the syntheses of a variety of NPs for bioimaging applications, such as NaYF4:Eu(3+)(5%), LaVO4:Eu(3+)(10%), GdVO4:Eu(3+)(10%), Y2O3:Eu(3+)(5%), GdF3:Tb(3+)(10%), Mo, Pt, Pd, Au, and Ag. Multiple types of NPs (Y2O3:Eu(3+)(5%) (hydrophobic) and GdF3:Tb(3+)(10%) (hydrophilic)) were coloaded inside the carbon capsules to create a multimodal agent for magneto-fluorescence imaging. Our in vivo study clearly suggests that carbon capsules have biodistribution in many organs including liver, heart, spleen, lungs, blood pool, and muscles. PMID- 26646712 TI - A new TPE-based tetrapodal ligand and its Ln(iii) complexes: multi-stimuli responsive AIE (aggregation-induced emission)/ILCT(intraligand charge transfer) bifunctional photoluminescence and NIR emission sensitization. AB - A tetrapodal zwitterionic-type ligand featuring both AIE (aggregation-induced emission) and ILCT (intraligand charge transfer) properties, namely 1,1',1'',1''' (4,4',4'',4'''-(ethene-1,1,2,2-tetrayl)tetrakis(benzene-4,1 diyl))tetrakis(methylene)tetrapyridin-4(1H)-one (TPE-4PO) has been designed and applied to the assembly of lanthanide complexes LIFM-21(Ln) (Ln = Sm, Eu, Gd, Tb and Dy). Apart from sensitization of NIR emission of Sm(3+) and Dy(3+), the resulting ligand and lanthanide complexes show both AIE and ILCT-related photoluminescence behaviors. The photo-response of this system to different aggregation states, solvents' polarity and mechanical grinding was demonstrated by distinguishable emission intensities and colours. PMID- 26646713 TI - Extended B cell phenotype in patients with myalgic encephalomyelitis/chronic fatigue syndrome: a cross-sectional study. AB - Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a heterogeneous condition of unknown aetiology characterized by multiple symptoms including fatigue, post-exertional malaise and cognitive impairment, lasting for at least 6 months. Recently, two clinical trials of B cell depletion therapy with rituximab (anti-CD20) reported convincing improvement in symptoms. A possible but undefined role for B cells has therefore been proposed. Studies of the relative percentages of B cell subsets in patients with ME/CFS have not revealed any reproducible differences from healthy controls (HC). In order to explore whether more subtle alterations in B cell subsets related to B cell differentiation exist in ME/CFS patients we used flow cytometry to immunophenotype CD19+ B cells. The panel utilized immunoglobulin (Ig)D, CD27 and CD38 (classical B cell subsets) together with additional markers. A total of 38 patients fulfilling Canadian, Centre for Disease Control and Fukuda ME/CFS criteria and 32 age- and sex-matched HC were included. We found no difference in percentages of classical subsets between ME/CFS patients and HC. However, we observed an increase in frequency (P < 0.01) and expression (MFI; P = 0.03) of CD24 on total B cells, confined to IgD+ subsets. Within memory subsets, a higher frequency of CD21+ CD38- B cells (> 20%) was associated with the presence of ME/CFS [odds ratio: 3.47 (1.15-10.46); P = 0.03] compared with HC, and there was a negative correlation with disease duration. In conclusion, we identified possible changes in B cell phenotype in patients with ME/CFS. These may reflect altered B cell function and, if confirmed in other patient cohorts, could provide a platform for studies based on clinical course or responsiveness to rituximab therapy. PMID- 26646714 TI - A cell-based screening assay to identify pharmaceutical compounds that enhance the regenerative quality of corneal repair. AB - The goal of this study was to develop and validate a simple but quantitative cell based assay to identify compounds that might be used pharmaceutically to give tissue repair a more regenerative character. The cornea was used as the model, and some specific aspects of repair in this organ were incorporated into assay design. A quantitative cell-based assay was developed based on transcriptional promoter activity of fibrotic marker genes ACT2A and TGFB2. Immortalized corneal stromal cells (HTK) or corneal epithelial cells (HCLE) were tested and compared to primary corneal stromal cells. Cells were transiently transfected with constructs containing the firefly luciferase reporter gene driven by transcriptional promoters for the selected fibrotic marker genes. A selected panel of seven chemical test compounds was used, containing three known fibrosis inhibitors: lovastatin (LOV), tyrphostin AG 1296 (6,7-dimethoxy-3 phenylquinoxaline) and SB203580 (4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5 (4-pyridyl)1H-imidazole), and four potential fibrosis inhibitors: 5 iodotubercidin (4-amino-5-iodo-7-(beta-D-ribofuranosyl)-pyrrolo(2,3 d)pyrimidine), anisomycin, DRB (5,6-dichloro-1-beta-D-ribofuranosyl benzimidazole) and latrunculin B. Transfected cells were treated with TGFB2 in the presence or absence of one of the test compounds. To validate the assay, compounds were tested for their direct effects on gene expression in the immortalized cell lines and primary human corneal keratocytes using RT-PCR and immunohistochemistry. Three "hits" were validated LOV, SB203580 and anisomycin. This assay, which can be applied in a high throughput format to screen large libraries of uncharacterized compounds, or known compounds that might be repurposed, offers a valuable tool for identifying new treatments to address a major unmet medical need. Anisomycin has not previously been characterized as antifibrotic, thus, this is a novel finding of the study. PMID- 26646715 TI - Characterization and Quantitation of Triterpenoid Saponins in Raw and Sprouted Chenopodium berlandieri spp. (Huauzontle) Grains Subjected to Germination with or without Selenium Stress Conditions. AB - Pseudocereal Chenopodium berlandieri spp. (huauzontle) was evaluated to determine saponin composition. Saponins were evaluated in raw and germinated grains subjected to chemical stress induced by sodium selenite. Analysis by liquid chromatography coupled with ELSD detector revealed the presence of 12 saponins, identified according to compounds previously assayed in Chenopodium quinoa. Saponins found at the highest concentrations in raw grains were derived from oleanolic and phytolaccagenic acids. Total saponin concentration significantly decreased in germinated compared to raw grains due to the significant loss of 90.1% and 95.7% of the phytolaccagenic acid without and with chemical selenium stress, respectively. The most abundant saponin in germinated sprouts decreased during normal germination. Interestingly, the concentration of this particular saponin significantly increased during the Se-induced stress germination. Chemical stress with selenium salts proved to change the saponin composition in geminated Chenopodium berlandieri spp. grains, therefore affecting their potential use as ingredient in the food industry. PMID- 26646716 TI - [Antibiotic stewardship (ABS). Definition, contents, necessity and practice on examples of current clinical-urological controversies]. AB - BACKGROUND: Infectious diseases caused by multi-resistant pathogens are increasing worldwide and are posing a challenge to German urology as well. Furthermore, there is a limited perspective of new antibiotic developments. One way out of this dilemma is a differentiated handling and use of antibiotics (antibiotic stewardship, ABS). AIM: The aim of this review is to identify key issues in modern urological antibiotic therapy, which can be considered as exemplary for the whole topic of ABS. This includes a review of the current data of the individual topics, including thought-provoking impulse for future clinical application and research. MATERIAL AND METHODS: The research group "infectious diseases" of GeSRU Academics identified the following central topics: excessive use of fluoroquinolones, diagnosis and treatment of urethritis and perioperative antibiotic prophylaxis. Subsequently, we performed a literature research in MEDLINE to uncover controversies and open questions of the individual topics within the meaning of ABS. RESULTS: The analysis of modern antibiotic therapy in urology shows numerous open questions in all quality dimensions of ABS: structural quality (e.g. through improved training of medical staff in the differentiated use of antibiotics), process quality (e.g. by improved adherence to existing infectiological guidelines, here in particular the perioperative prophylaxis and therapy of urethritis) and outcome (e.g. by detection of resistance rates and infection rates). DISCUSSION: The overarching and common goal is to avoid a post-antibiotic era. ABS programmes and a 10-point plan of the federal government are considered positive political developments in this area but do not release the individual urologist from a personal responsibility as part of his daily routine. A critical analysis of the topic "antibiotic treatment" is essential. PMID- 26646717 TI - Human beta-Defensin 3 [corrected] Exacerbates MDA5 but Suppresses TLR3 Responses to the Viral Molecular Pattern Mimic Polyinosinic:Polycytidylic Acid. AB - Human beta-defensin 3 (hBD3) is a cationic host defence peptide and is part of the innate immune response. HBD3 is present on a highly copy number variable block of six beta-defensin genes, and increased copy number is associated with the autoimmune disease psoriasis. It is not known how this increase influences disease development, but psoriasis is a T cell-mediated disease and activation of the innate immune system is required for the initial trigger that leads to the amplification stage. We investigated the effect of hBD3 on the response of primary macrophages to various TLR agonists. HBD3 exacerbated the production of type I Interferon-beta in response to the viral ligand mimic polyinosinic:polycytidylic acid (polyI:C) in both human and mouse primary cells, although production of the chemokine CXCL10 was suppressed. Compared to polyI:C alone, mice injected with both hBD3 peptide and polyI:C also showed an enhanced increase in Interferon-beta. Mice expressing a transgene encoding hBD3 had elevated basal levels of Interferon-beta, and challenge with polyI:C further increased this response. HBD3 peptide increased uptake of polyI:C by macrophages, however the cellular response and localisation of polyI:C in cells treated contemporaneously with hBD3 or cationic liposome differed. Immunohistochemistry showed that hBD3 and polyI:C do not co-localise, but in the presence of hBD3 less polyI:C localises to the early endosome. Using bone marrow derived macrophages from knockout mice we demonstrate that hBD3 suppresses the polyI:C-induced TLR3 response mediated by TICAM1 (TRIF), while exacerbating the cytoplasmic response through MDA5 (IFIH1) and MAVS (IPS1/CARDIF). Thus, hBD3, a highly copy number variable gene in human, influences cellular responses to the viral mimic polyI:C implying that copy number may have a significant phenotypic effect on the response to viral infection and development of autoimmunity in humans. PMID- 26646718 TI - Amyloid persistence in decellularized liver: biochemical and histopathological characterization. AB - Systemic amyloidoses are a group of debilitating and often fatal diseases in which fibrillar protein aggregates are deposited in the extracellular spaces of a range of tissues. The molecular basis of amyloid formation and tissue localization is still unclear. Although it is likely that the extracellular matrix (ECM) plays an important role in amyloid deposition, this interaction is largely unexplored, mostly because current analytical approaches may alter the delicate and complicated three-dimensional architecture of both ECM and amyloid. We describe here a decellularization procedure for the amyloidotic mouse liver which allows high-resolution visualization of the interactions between amyloid and the constitutive fibers of the extracellular matrix. The primary structure of the fibrillar proteins remains intact and the amyloid fibrils retain their amyloid enhancing factor activity. PMID- 26646720 TI - Hospitals' probes into avoidable deaths are "not consistent, reliable, or transparent," ombudsman finds. PMID- 26646721 TI - Zones of Difference, Boundaries of Access: Moral Geography and Community Mapping in Abidjan, Cote d'Ivoire. AB - In Abidjan, Cote d'Ivoire, 18% of men who have sex with men (MSM) are HIV positive. Based on ethnographic research conducted among HIV peer educators and activists in Abidjan, I examine their narratives and hand-drawn maps of city space. I draw on a methodological process of map-making to examine research participants' evaluations of neighborhoods and link these evaluations to debates over national and cultural belonging in Cote d'Ivoire. I suggest a moral geography emerges from the maps and narratives and ask what the bioethical implications of moral geography are in the context of service delivery and activism among sexual minorities. PMID- 26646719 TI - The whole-genome expression analysis of peripheral blood mononuclear cells from aspirin sensitive asthmatics versus aspirin tolerant patients and healthy donors after in vitro aspirin challenge. AB - BACKGROUND: Up to 30% of adults with severe asthma are hypersensitive to aspirin and no unambiguous theory exists which provides a satisfactory explanation for the occurrence of aspirin-induced asthma (AIA) in some asthmatic patients. Therefore, the aim of this study was to compare the AIA expression profile against aspirin tolerant asthma (ATA) and healthy volunteers (HV) profile in peripheral blood mononuclear cells (PBMCs) after in vitro aspirin challenge in Caucasian population. METHODS: PBMCs were separated from blood of three groups of subjects--11 AIA, 7 ATA and 15 HV and then stimulated by either 2 MUM lysine aspirin or 20 MUM lysine as a control. Subsequently, RNA was isolated, transcribed into cDNA and subjected to microarray and qPCR studies. Simultaneously, protein was extracted from PBMCs and used in further immunoblotting analysis. RESULTS: The validation of results at mRNA level has shown only three genes, whose expression was significantly altered between comprising groups. mRNA expression of CNPY3 in PBMCs in AIA was significantly lower (-0.41 +/- 2.67) than in HV (1.04 +/- 2.69), (p = 0.02); mRNA expression of FOSL1 in PBMCs in AIA was also significantly decreased (-0.66 +/- 2.97) as opposed to HV (0.31 +/- 4.83), (p = 0.02). While mRNA expression of ERAS in PBMCs was increased (1.15 +/- 0.23) in AIA in comparison to HV (-1.32 +/- 0.41), (p = 0.03). At protein level the changed expression of one protein was confirmed. Protein expression of FOSL1 in PBMCs in AIA was both significantly lower (-0.86 +/- 0.08) than in ATA (0.39 +/- 0.42), (p = 0.046) and in HV (0.9 +/- 0.27), (p = 0.007). CONCLUSIONS: This pilot study implies a positive association between CNPY3, ERAS, FOSL1 and aspirin-intolerant asthma, suggesting that these findings would be useful for further investigations of NSAIDs mechanism. PMID- 26646722 TI - Measuring the immune system of the three-spined stickleback - investigating natural variation by quantifying immune expression in the laboratory and the wild. AB - Current understanding of the immune system comes primarily from laboratory-based studies. There has been substantial interest in examining how it functions in the wild, but studies have been limited by a lack of appropriate assays and study species. The three-spined stickleback (Gasterosteus aculeatus L.) provides an ideal system in which to advance the study of wild immunology, but requires the development of suitable immune assays. We demonstrate that meaningful variation in the immune response of stickleback can be measured using real-time PCR to quantify the expression of eight genes, representing the innate response and Th1 , Th2- and Treg-type adaptive responses. Assays are validated by comparing the immune expression profiles of wild and laboratory-raised stickleback, and by examining variation across populations on North Uist, Scotland. We also compare the immune response potential of laboratory-raised individuals from two Icelandic populations by stimulating cells in culture. Immune profiles of wild fish differed from laboratory-raised fish from the same parental population, with immune expression patterns in the wild converging relative to those in the laboratory. Innate measures differed between wild populations, whilst the adaptive response was associated with variation in age, relative size of fish, reproductive status and S. solidus infection levels. Laboratory-raised individuals from different populations showed markedly different innate immune response potential. The ability to combine studies in the laboratory and in the wild underlines the potential of this toolkit to advance our understanding of the ecological and evolutionary relevance of immune system variation in a natural setting. PMID- 26646724 TI - Neuropsychological Outcomes in Extremely Preterm Preschoolers Exposed to Tiered Low Oxygen Targets: An Observational Study. AB - An observational study of neuropsychological outcomes at preschool age of tiered lowered oxygen (O2) saturation targets in extremely preterm neonates. We studied 111 three-year-olds born <28 weeks' gestational age. Fifty-nine participants born in 2009-2010 during a time-limited quality improvement initiative each received three-tiered stratification of oxygen rates (83-93% until age 32 weeks, 85-95% until age 35 weeks, and 95% after age 35 weeks), the TieredO2 group. Comparisons were made with 52 participants born in 2007-2008 when pre-initiative saturation targets were non-tiered at 89-100%, the Non-tieredO2 group. Neuropsychological domains included general intellectual, executive, attention, language, visuoperceptual, visual-motor, and fine and gross motor functioning. Descriptive and inferential analyses were conducted. Group comparisons were not statistically significant. Descriptively, the TieredO2 group had better general intellectual, executive function, visual-motor, and motor performance and the Non-tieredO2 group had better language performance. Cohen's d and confidence intervals around d were in similar direction and magnitude across measures. A large effect size was found for recall of digits-forward in participants born at 23 and 24 weeks' gestation, d=0.99 and 1.46, respectively. Better TieredO2 outcomes in all domains except language suggests that the tiered oxygen saturation target method is not harmful and merits further investigation through further studies. Benefit in auditory attention appeared greatest in those born at 23 and 24 weeks. Participants in the tiered oxygen saturation group also had fewer ventilation days and a lower incidence of bronchopulmonary dysplasia, perhaps explanatory for these neuropsychological outcomes at age 3. PMID- 26646723 TI - Relations Among Internalizing and Externalizing Symptoms and Drinking Frequency During Adolescence. AB - BACKGROUND: In adolescence, internalizing (e.g., anxious, depressive, and withdrawn) and externalizing (e.g., aggressive, oppositional, delinquent, and hyperactive) symptoms are related with alcohol use. However, the directionality among internalizing symptoms, externalizing symptoms, and alcohol use during adolescence is equivocal. Moreover, gender differences and similarities among these behaviors are not definitive in existing literature. OBJECTIVES: This study examined longitudinal relationships between internalizing and externalizing symptoms and past-month alcohol use among adolescent boys and girls. METHODS: Using longitudinal survey data from a study of community-dwelling adolescents (n = 724), we estimated cross-lagged structural equation models to test relations between internalizing and externalizing symptoms (as measured by the Youth Self Report, YSR [Achenbach, 1991]) and self-report alcohol use in the past month among adolescents. Gender differences were tested in a multiple group structural equation model. RESULTS: Alcohol use at age 12 was a predictor of internalizing and externalizing symptoms at age 15 for both boys and girls. With regard to gender differences, girls demonstrated an association between internalizing symptoms and drinking at age 12, whereas boys showed a stronger association between externalizing symptoms and drinking at age 18. CONCLUSIONS/IMPORTANCE: Early alcohol use is problematic for youth, and results of this study lend support to prevention programs for youth. Preventing or curbing early drinking may offset later externalizing and internalizing symptoms, as well as ongoing alcohol use, regardless of gender. PMID- 26646725 TI - Periconceptional folate consumption is associated with neonatal DNA methylation modifications in neural crest regulatory and cancer development genes. AB - Folate deficiency during early embryonic development constitutes a risk factor for neural tube defects and potentially for childhood leukemia via unknown mechanisms. We tested whether folate consumption during the 12 months prior to conception induced DNA methylation modifications at birth in healthy neonates with a genome-wide and agnostic approach. We hypothesized that DNA methylation in genes involved in neural tube development and/or cancer susceptibility would be affected by folate exposure. We retrospectively assessed folate exposure at the time of conception by food-frequency questionnaires administered to the mothers of 343 healthy newborns. We measured genome-wide DNA methylation from neonatal blood spots. We implemented a method based on bootstrap resampling to decrease false-positive findings. Folate was inversely associated with DNA methylation throughout the genome. Among the top folate-associated genes that were replicated in an independent Gambian study were TFAP2A, a gene critical for neural crest development, STX11, a gene implicated in acute myeloid leukemia, and CYS1, a candidate gene for cystic kidney disease. Reduced periconceptional folate intake was associated with increased methylation and, in turn, decreased gene expression at these 3 loci. The top folate-sensitive genes defined by their associated CpG sites were enriched for numerous transcription factors by Gene Set Enrichment Analysis, including those implicated in cancer development (e.g., MYC-associated zinc finger protein). The influence of estimated periconceptional folate intake on neonatal DNA methylation levels provides potential mechanistic insights into the role of this vitamin in the development of neural tube defects and childhood cancers. PMID- 26646727 TI - Medicinal chemistry insights in the discovery of novel LSD1 inhibitors. AB - LSD1 is an epigenetic modulator associated with transcriptional regulation of genes involved in a broad spectrum of key cellular processes, and its activity is often altered under pathological conditions. LSD1 inhibitors are considered to be candidates for therapy of cancer, viral diseases and neurodegeneration. Many LSD1 inhibitors with various scaffolds have been disclosed, and a few potent molecules are in different stages of clinical development. In this review, we summarize recent biological findings on the roles of LSD1 and the current understanding of the clinical significance of LSD1, and focus on the medicinal chemistry strategies used in the design and development of LSD1 inhibitors as drug-like epigenetic modulators since 2012, including a brief consideration of structure activity relationships. PMID- 26646728 TI - The climate hazards infrared precipitation with stations--a new environmental record for monitoring extremes. AB - The Climate Hazards group Infrared Precipitation with Stations (CHIRPS) dataset builds on previous approaches to 'smart' interpolation techniques and high resolution, long period of record precipitation estimates based on infrared Cold Cloud Duration (CCD) observations. The algorithm i) is built around a 0.05 degrees climatology that incorporates satellite information to represent sparsely gauged locations, ii) incorporates daily, pentadal, and monthly 1981 present 0.05 degrees CCD-based precipitation estimates, iii) blends station data to produce a preliminary information product with a latency of about 2 days and a final product with an average latency of about 3 weeks, and iv) uses a novel blending procedure incorporating the spatial correlation structure of CCD estimates to assign interpolation weights. We present the CHIRPS algorithm, global and regional validation results, and show how CHIRPS can be used to quantify the hydrologic impacts of decreasing precipitation and rising air temperatures in the Greater Horn of Africa. Using the Variable Infiltration Capacity model, we show that CHIRPS can support effective hydrologic forecasts and trend analyses in southeastern Ethiopia. PMID- 26646726 TI - Photodynamic Therapy of Non-Small Cell Lung Cancer. Narrative Review and Future Directions. AB - Photodynamic therapy (PDT) is an established treatment modality for non-small cell lung cancer. Phototoxicity, the primary adverse event, is expected to be minimized with the introduction of new photosensitizers that have shown promising results in phase I and II clinical studies. Early-stage and superficial endobronchial lesions less than 1 cm in thickness can be effectively treated with external light sources. Thicker lesions and peripheral lesions may be amenable to interstitial PDT, where the light is delivered intratumorally. The addition of PDT to standard-of-care surgery and chemotherapy can improve survival and outcomes in patients with pleural disease. Intraoperative PDT has shown promise in the treatment of non-small cell lung cancer with pleural spread. Recent preclinical and clinical data suggest that PDT can increase antitumor immunity. Crosslinking of signal transducer and activator of transcription-3 molecules is a reliable biomarker to quantify the photoreaction induced by PDT. Randomized studies are required to test the prognosis value of this biomarker, obtain approval for the new photosensitizers, and test the potential efficacy of interstitial and intraoperative PDT in the treatment of patients with non-small cell lung cancer. PMID- 26646729 TI - Imaging in blunt cardiac injury: Computed tomographic findings in cardiac contusion and associated injuries. AB - BACKGROUND: Blunt cardiac injury (BCI) may manifest as cardiac contusion or, more rarely, as pericardial or myocardial rupture. Computed tomography (CT) is performed in the vast majority of blunt trauma patients, but the imaging features of cardiac contusion are not well described. PURPOSE: To evaluate CT findings and associated injuries in patients with clinically diagnosed BCI. MATERIALS AND METHODS: We identified 42 patients with blunt cardiac injury from our institution's electronic medical record. Clinical parameters, echocardiography results, and laboratory tests were recorded. Two blinded reviewers analyzed chest CTs performed in these patients for myocardial hypoenhancement and associated injuries. RESULTS: CT findings of severe thoracic trauma are commonly present in patients with severe BCI; 82% of patients with ECG, cardiac enzyme, and echocardiographic evidence of BCI had abnormalities of the heart or pericardium on CT; 73% had anterior rib fractures, and 64% had pulmonary contusions. Sternal fractures were only seen in 36% of such patients. However, myocardial hypoenhancement on CT is poorly sensitive for those patients with cardiac contusion: 0% of right ventricular contusions and 22% of left ventricular contusions seen on echocardiography were identified on CT. CONCLUSION: CT signs of severe thoracic trauma are frequently present in patients with severe BCI and should be regarded as indirect evidence of potential BCI. Direct CT findings of myocardial contusion, i.e. myocardial hypoenhancement, are poorly sensitive and should not be used as a screening tool. However, some left ventricular contusions can be seen on CT, and these patients could undergo echocardiography or cardiac MRI to evaluate for wall motion abnormalities. PMID- 26646730 TI - Alzheimer's peptide amyloid-beta, fragment 22-40, perturbs lipid dynamics. AB - The peptide amyloid-beta (Abeta) interacts with membranes of cells in the human brain and is associated with Alzheimer's disease (AD). The intercalation of Abeta in membranes alters membrane properties, including the structure and lipid dynamics. Any change in the membrane lipid dynamics will affect essential membrane processes, such as energy conversion, signal transduction and amyloid precursor protein (APP) processing, and may result in the observed neurotoxicity associated with the disease. The influence of this peptide on membrane dynamics was studied with quasi-elastic neutron scattering, a technique which allows a wide range of observation times from picoseconds to nanoseconds, over nanometer length scales. The effect of the membrane integral neurotoxic peptide amyloid beta, residues 22-40, on the in- and out-of-plane lipid dynamics was observed in an oriented DMPC/DMPS bilayer at 15 degrees C, in its gel phase, and at 30 degrees C, near the phase transition temperature of the lipids. Near the phase transition temperature, a 1.5 mol% of peptide causes up to a twofold decrease in the lipid diffusion coefficients. In the gel-phase, this effect is reversed, with amyloid-beta(22-40) increasing the lipid diffusion coefficients. The observed changes in lipid diffusion are relevant to protein-protein interactions, which are strongly influenced by the diffusion of membrane components. The effect of the amyloid-beta peptide fragment on the diffusion of membrane lipids will provide insight into the membrane's role in AD. PMID- 26646731 TI - N-Heterocyclic carbenes as supporting ligands in transition metal complexes of N2. AB - Recent developments have substantially expanded the scope of N-heterocyclic carbenes (NHCs) as ancillary ligands in coordination chemistry and homogeneous catalysis. This review provides a short overview of the emerging field of NHC supported transition metal complexes of N2 and the possibilities to catalytically activate N2 in these complexes. PMID- 26646732 TI - Percutaneous Transluminal Angioplasty Improved Posterior Reversible Encephalopathy Syndrome due to Renovascular Hypertension. AB - A 51-year-old man was admitted to our hospital complaining of preceding throbbing headache and tonic convulsions. Headache and convulsive seizure disappeared and his consciousness recovered to alert within 2 hours after onset. Neurological examination showed no abnormal findings. Laboratory examinations revealed high low-density lipoprotein cholesterol (179 mg/dL), renin (42 ng/mL/hour), aldosterone (265 pg/mL), noradrenaline (1031 pg/mL), and dopamine (79 pg/mL). In brain magnetic resonance imaging (MRI), fluid-attenuated inversion recovery, but not the diffusion-weighted image, showed high signal intensities in white matter in bilateral occipital, parietal, and frontal lobes, with no stenotic changes on magnetic resonance angiography. In addition, the diffusion coefficient of focal lesions was elevated. Decreasing blood flow velocity and separated lumens in the right renal artery trunk were shown by renal artery ultrasonography. Enhanced computed tomography and renal angiography showed right renal partial infarction and isolated stenosis in the right renal artery, accompanied by thrombosed false lumen. No stenotic changes were seen in other peripheral arteries. These findings seemed incompatible with renal dissection and fibromuscular dysplasia, Takayasu's arteritis, and polyarteritis nodosa. Our diagnosis was posterior reversible encephalopathy syndrome (PRES) induced by renal hypertension due to renal artery dissection. To improve the renal artery stenosis and secondary hypertension, we performed plain balloon angioplasty, in addition to administering antihypertensive and lipid-lowering medications. After angioplasty, hypertension and high signal intensity at brain MRI were clearly improved. We would like to emphasize that renal artery angioplasty should be considered as an option for patients with PRES and malignant hypertension. PMID- 26646733 TI - Electrochemo-dynamical characterization of polypyrrole actuators coated on gold electrodes. AB - Polypyrrole coated gold wires were subjected to consecutive square current waves in LiClO4 aqueous solutions using the same constant anodic and cathodic charge. Parallel in situ diameter variations were followed using a laser scan micrometer. The procedure was repeated by changing one experimental variable every time: applied current, electrolyte concentration or working temperature to perform electrochemodynamical characterization of the system. On average, the diameter follows a linear variation of the consumed charge, as expected for any faradaic system, although a high dispersion was attained in the data. Such deviations were attributed to the presence of irreversible hydrogen evolution at the gold/polypyrrole interface at cathodic potentials more than 0.0 V vs. Ag/AgCl, detected and quantified from separated coulovoltammetric responses. Despite this parallel hydrogen evolution the consumed energy during reactions is a robust sensor of the working conditions. In conclusion a gold support, the metal most used for technological applications of conducting polymers, should be avoided when a device is driven by current flow in the presence of aqueous solutions, water contamination or moisture: a fraction of the charge will be consumed by hydrogen generation with possible degradation of the device. PMID- 26646734 TI - Mesoporous Li4Ti5O12 nanoclusters anchored on super-aligned carbon nanotubes as high performance electrodes for lithium ion batteries. AB - Mesoporous lithium titanate (LTO) nanoclusters are in situ synthesized in a network of super aligned carbon nanotubes (SACNTs) via a solution-based method followed by heat treatment in air. In the LTO-CNT composite, SACNTs not only serve as the skeleton to support a binder-free electrode, but also render the composite with high conductivity, flexibility, and mechanical strength. The homogeneously dispersed LTO nanoclusters among the SACNTs allow each LTO grain to effectively access the electrolyte and the conductive network, benefiting both ion and electron transport. By the incorporation of LTO into the CNT network, mechanical reinforcement is also achieved. When serving as a negative electrode for lithium ion batteries, such a robust composite-network architecture provides the electrodes with effective charge transport and structural integrity, leading to high-performance flexible electrodes with high capacity, high rate capability, and excellent cycling stability. PMID- 26646735 TI - Fingermark ridge drift. AB - Distortions of the fingermark topography are usually considered when comparing latent and exemplar fingerprints. These alterations are characterized as caused by an extrinsic action, which affects entire areas of the deposition and alters the overall flow of a series of contiguous ridges. Here we introduce a novel visual phenomenon that does not follow these principles, named fingermark ridge drift. An experiment was designed that included variables such as type of secretion (eccrine and sebaceous), substrate (glass and polystyrene), and degrees of exposure to natural light (darkness, shade, and direct light) indoors. Fingermarks were sequentially visualized with titanium dioxide powder, photographed and analyzed. The comparison between fresh and aged depositions revealed that under certain environmental conditions an individual ridge could randomly change its original position regardless of its unaltered adjacent ridges. The causes of the drift phenomenon are not well understood. We believe it is exclusively associated with intrinsic natural aging processes of latent fingermarks. This discovery will help explain the detection of certain dissimilarities at the minutiae/ridge level; determine more accurate "hits"; identify potentially erroneous corresponding points; and rethink identification protocols, especially the criteria of "no single minutiae discrepancy" for a positive identification. PMID- 26646736 TI - Forensic aspects of the weathering and ageing of spray paints. AB - This paper presents a preliminary study on the degradation of spray paint samples, illustrated by Optical, FTIR and Raman measurements. As opposed to automotive paints which are specifically designed for improved outdoor exposure and protected using hindered amine light absorbers (HALS) and ultra-violet absorbers (UVA), the spray paints on their side are much simpler in composition and very likely to suffer more from joint effects of solar radiation, temperature and humidity. Six different spray paint were exposed to outdoor UV-radiation for a total period of three months and both FTIR and Raman measurements were taken systematically during this time. These results were later compared to an artificial degradation using a climate chamber. For infrared spectroscopy, degradation curves were plotted using the photo-oxidation index (POI), and could be successfully approximated with a logarithmic fitting (R(2)>0.8). The degradation can appear after the first few days of exposure and be important until 2 months, where it stabilizes and follow a more linear trend afterwards. One advantage is that the degradation products appeared almost exclusively at the far end (~3000cm(-1)) of mid-infrared spectra, and that the fingerprint region of the spectra remained stable over the studied period of time. Raman results suggest that the pigments on the other side, are much more stable and have not shown any sign of degradation over the time of this study. Considering the forensic implications of this environmental degradation, care should be taken when comparing samples if weathering is an option (e.g. an exposed graffiti compared to the paint from a fresh spray paint can). Degradation issues should be kept in mind as they may induce significant differences between paint samples of common origin. PMID- 26646737 TI - The Polish Genetic Database of Victims of Totalitarianisms. AB - This paper describes the creation of the Polish Genetic Database of Victims of Totalitarianism and the first research conducted under this project. On September 28th 2012, the Pomeranian Medical University in Szczecin and the Institute of National Remembrance-Commission for Prosecution of Crimes against the Polish Nation agreed to support the creation of the Polish Genetic Database of Victims of Totalitarianism (PBGOT, www.pbgot.pl). The purpose was to employ state-of-the art methods of forensic genetics to identify the remains of unidentified victims of Communist and Nazi totalitarian regimes. The database was designed to serve as a central repository of genetic information of the victim's DNA and that of the victim's nearest living relatives, with the goal of making a positive identification of the victim. Along the way, PGBOT encountered several challenges. First, extracting useable DNA samples from the remains of individuals who had been buried for over half a century required forensic geneticists to create special procedures and protocols. Second, obtaining genetic reference material and historical information from the victim's closest relatives was both problematic and urgent. The victim's nearest living relatives were part of a dying generation, and the opportunity to obtain the best genetic and historical information about the victims would soon die with them. For this undertaking, PGBOT assembled a team of historians, archaeologists, forensic anthropologists, and forensic geneticists from several European research institutions. The field work was divided into five broad categories: (1) exhumation of victim remains and storing their biological material for later genetic testing; (2) researching archives and historical data for a more complete profile of those killed or missing and the families that lost them; (3) locating the victim's nearest relatives to obtain genetic reference samples (swabs), (4) entering the genetic data from both victims and family members into a common database; (5) making a conclusive, final identification of the victim. PGBOT's first project was to identify victims of the Communist regime buried in hidden mass graves in the Powazki Military Cemetery in Warsaw. Throughout 2012 and 2013, PGBOT carried out archaeological exhumations in the Powazki Military Cemetery that resulted in the recovery of the skeletal remains of 194 victims in several mass graves. Of the 194 sets of remains, more than 50 victims have been successfully matched and identified through genetic evidence. PMID- 26646738 TI - Azadirachtin(A) distinctively modulates subdomain 2 of actin - novel mechanism to induce depolymerization revealed by molecular dynamics study. AB - Azadirachtin(A) (AZA), a potential insecticide from neem, binds to actin and induces depolymerization in Drosophila. AZA binds to the pocket same as that of Latrunculin A (LAT), but LAT inhibits actin polymerization by stiffening the actin structure and affects the ADP-ATP exchange. The mechanism by which AZA induces actin depolymerization is not clearly understood. Therefore, different computational experiments were conducted to delineate the precise mechanism of AZA-induced actin depolymerization. Molecular dynamics studies showed that AZA strongly interacted with subdomain 2 and destabilized the interactions between subdomain 2 of one actin and subdomains 1 and 4 of the adjacent actin, causing the separation of actin subunits. The separation was observed between subdomain 3 of subunit n and subdomain 4 of subunit n + 2. However, the specific triggering point for the separation of the subunits was the destabilization of direct interactions between subdomain 2 of subunit n (Arg39, Val45, Gly46 and Arg62) and subdomain 4 of subunit n + 2 (Asp286, Ile287, Asp288, Ile289, Asp244 and Lys291). These results reveal a unique mechanism of an actin filament modulator that induces depolymerization. This mechanism of AZA can be used to design similar molecules against mammalian actins for cancer therapy. PMID- 26646739 TI - Is patient acceptance of the diagnosis of psychogenic nonepileptic seizures linked to symptomatology? AB - INTRODUCTION: An assessment was made of general symptoms in patients with psychogenic nonepileptic seizures (PNES), comparing those who do versus those who do not accept the diagnosis. METHOD: A questionnaire pilot study of newly diagnosed psychogenic nonepileptic seizure patients confirmed by video electroencephalography (EEG) was carried out, using a 59-item general symptom questionnaire, with frequency (score) ranging from never (0) to every day (5). Subsequent blinded assessment of patient's acceptance of diagnosis was made. RESULTS: Of 13 patients studied, over a 5-month period, 8 accepted the diagnosis, and 5 did not. Acceptance of diagnosis was associated with a lower total symptom score (p < .001) and significantly lower symptom scores in 7 of the 10 symptom subscales. CONCLUSION: The underlying symptomatology of psychogenic nonepileptic seizure patients differs between those who do versus those who do not accept the diagnosis. The complexity of additional symptoms may contribute to poorer outcomes in those that do not accept the psychogenic nonepileptic seizure diagnosis. PMID- 26646740 TI - How Can Linoleic Acid Be the Preferential Substrate of the Enzyme 15-Lipoxygenase 1? A QM/MM Approach. AB - The most common substrate of mammalian lipoxygenases (LOXs) is arachidonic acid (AA). However, 15-LOXs can present dual substrate specificity. These LOXs catalyze the peroxidation of AA, initiated by a H-abstraction step (mainly H13 abstraction) by the Fe(III)-OH(-) cofactor, and the peroxidation of linoleic acid (LA) after H11-abstraction. In this paper, QM(B3LYP)/MM(CHARMM) calculations of the rate-limiting H11-abstraction process of LA catalyzed by rabbit 15-LOX-1 (15 rLOX-1) have been carried out using a complete model of the solvated 15-rLOX-1:LA complex. A total of 26 QM/MM potential energy profiles as a function of the H transfer reaction coordinate have been computed along with one QM/MM free energy profile obtained using the Free Energy Perturbation method. The molecular origin of substrate specificity of 15-rLOX-1 for LA in comparison with AA has been analyzed. In many of the QM/MM reactive 15-rLOX-1:LA energy minima, LA adopts more elongated conformations than AA, although having a shorter carbon chain, because LA has one double bond between C1 and C11 whereas AA has three double bonds between C1 and C13. Consequently, C11 of LA can be located in the same region of the active site as C13 of AA, a zone where H11-abstraction from LA as well as H13-abstraction from AA is not hindered by bulky residue side chains. This explains at a molecular level how 15-LOXs might accommodate and recognize for catalysis two substrates that are different in length by two carbons. Our results also explain why (9Z,11E)-13-hydro(pero)xyoctadeca-9,11-dienoic acid is the major product of the peroxidation and why LA is the preferential substrate of 15-rLOX-1. PMID- 26646741 TI - 5,7-Bis(2'-arylethenyl)-6H-1,4-diazepine-2,3-dicarbonitriles: synthesis, and experimental and theoretical evaluation of the effects of substituents at 5,6,7 positions on the molecular configuration and spectral properties. AB - A series of novel 5,7-bis(2'-arylethenyl)-6H-1,4-diazepine-2,3-dicarbonitriles was synthesized through sequential aldol condensation reactions of 1,3-diketones with diaminomaleonitrile, and the resulting 5,7-dimethyl-6H-1,4-diazepines were condensed with aromatic aldehydes. The substituents' effects on the spectral properties and conformational states of the molecules in solution were studied using 2D NMR techniques and DFT calculations. Specific intramolecular steric interactions in derivatives substituted at the C6 position were discovered and investigated in detail. Differential scanning calorimetry and thermogravimetric analyses revealed the strong dependence of the thermal stability of the newly prepared diazepinodicarbonitriles on the nature of the substituents. This offers new insight into the structure-property relationships of arylethenyl-substituted diazepine derivatives. PMID- 26646742 TI - Entrustment decisions in dental education: Is it time to start formalising? PMID- 26646743 TI - Do Fathers' Sexual Behaviors Vary with the Sex of Firstborns? Evidence from 37 Countries. AB - This article investigates whether men's sexual behavior is influenced by the sex of their firstborn children and, if so, at what stage of firstborns' development this occurs. Using standardized data from 37 Demographic and Health Surveys (N = 61,801), I compare the sexual activities, sexually transmitted infection symptoms, and sexual ideologies of fathers with firstborn sons and fathers with firstborn daughters. I also explore whether fathers' attitudes mediate the effects of firstborn sex. The findings indicate that fathers with firstborn sons are less likely to report using condoms and more likely to report paying for sex and having genital ulcers than fathers with firstborn daughters. These differences are limited to the firstborn's adolescent years and are slightly mediated by attitudinal differences. Together, these results raise new questions about the underlying mechanisms linking men's sexual behavior to their children's gendered development. PMID- 26646744 TI - First-birth Timing, Marital History, and Women's Health at Midlife. AB - Despite evidence that first-birth timing influences women's health, the role of marital status in shaping this association has received scant attention. Using multivariate propensity score matching, we analyze data from the National Longitudinal Survey of Youth 1979 to estimate the effect of having a first birth in adolescence (prior to age 20), young adulthood (ages 20-24), or later ages (ages 25-35) on women's midlife self-assessed health. Findings suggest that adolescent childbearing is associated with worse midlife health compared to later births for black women but not for white women. Yet, we find no evidence of health advantages of delaying first births from adolescence to young adulthood for either group. Births in young adulthood are linked to worse health than later births among both black and white women. Our results also indicate that marriage following a nonmarital adolescent or young adult first birth is associated with modestly worse self-assessed health compared to remaining unmarried. PMID- 26646745 TI - Does Social Participation Predict Better Health? A Longitudinal Study in Rural Malawi. AB - Research on the relationship between social capital and individual health often suffers from important limitations. Most research relies on cross-sectional data, which precludes identifying whether participation predicts health and/or vice versa. Some important conceptualizations of social capital, like social participation, have seldom been examined. Little is known about participation and health in sub-Saharan Africa. Furthermore, both physical and mental health have seldom been tested together, and variation by age has rarely been examined. We use longitudinal survey data for 2,328 men and women from the Malawi Longitudinal Study of Families and Health, containing (1) several measures of social participation, (2) measures of physical and mental health, and (3) an age range of 15 to 80+ years. Our results differ by gender and age and for mental and physical health. We find that social participation is associated with better physical health but can predict worse mental health for Malawians. PMID- 26646748 TI - The safety and efficacy of Avanafil, a new 2(nd) generation PDE5i: comprehensive review and meta-analysis. AB - INTRODUCTION: The discontinuation rate with phosphodiesterase type 5 inhibitors (PDE5i) remains very high. Recently, a new PDE5i, avanafil, has become available worldwide. AREAS COVERED: All placebo-controlled randomized clinical trials (RCTs) on the effect of avanafil in patients with ED were reviewed and meta analyzed. So far, 5 different RCTs on avanafil have been published, including 1379 and 605 patients in active and placebo groups, respectively. Avanafil was up to 3-fold superior to placebo in determining successful sexual intercourse. Although head-to-head comparative studies are still lacking, re-analyses of available data, showed that avanafil had comparable efficacy, but lower incidence of drug-related side effects, compared to first-generation PDE5is. EXPERT OPINION: Avanafil specific and peculiar pharmacological profile, addresses several problems that have been documented with first-generation PDE5is. Avanafil should theoretically guarantee a low dropout incidence by ensuring a natural profile of action and a low incidence of side effects. Longer studies and head-to heard trials are advisable to clarify these issues. PMID- 26646749 TI - Leucine-rich repeat kinase 2 positively regulates inflammation and down-regulates NF-kappaB p50 signaling in cultured microglia cells. AB - BACKGROUND: Over-activated microglia and chronic neuroinflammation contribute to dopaminergic neuron degeneration and progression of Parkinson's disease (PD). Leucine-rich repeat kinase 2 (LRRK2), a kinase mutated in autosomal dominantly inherited and sporadic PD cases, is highly expressed in immune cells, in which it regulates inflammation through a yet unclear mechanism. METHODS: Here, using pharmacological inhibition and cultured Lrrk2 (-/-) primary microglia cells, we validated LRRK2 as a positive modulator of inflammation and we investigated its specific function in microglia cells. RESULTS: Inhibition or genetic deletion of LRRK2 causes reduction of interleukin-1beta and cyclooxygenase-2 expression upon lipopolysaccharide-mediated inflammation. LRRK2 also takes part of the signaling trigged by alpha-synuclein fibrils, which culminates in induction of inflammatory mediators. At the molecular level, loss of LRRK2 or inhibition of its kinase activity results in increased phosphorylation of nuclear factor kappa-B (NF kappaB) inhibitory subunit p50 at S337, a protein kinase A (PKA)-specific phosphorylation site, with consequent accumulation of p50 in the nucleus. CONCLUSIONS: Taken together, these findings point to a role of LRRK2 in microglia activation and sustainment of neuroinflammation and in controlling of NF-kappaB p50 inhibitory signaling. Understanding the molecular pathways coordinated by LRRK2 in activated microglia cells after pathological stimuli such us fibrillar alpha-synuclein holds the potential to provide novel targets for PD therapeutics. PMID- 26646750 TI - Proteome analysis of Bemisia tabaci suggests specific targets for RNAi mediated control. AB - RNA interference offers effective control of several economically important insect pests. Bemisia tabaci is an important field crop pest, which causes significant yield loss worldwide. In our earlier study, we have demonstrated successful control of B. tabaci through transgenic plant mediated RNAi. However, selection of target genes without off-target effect(s) has been major concern so far and therefore, a critical exploration for B. tabaci specific targets is frantically required. In this study, we have followed proteomics approach to discover B. tabaci specific targets for RNAi and identified unique nucleotide sequences in functional genes (n=11) of the pest. For this, we have developed proteome profile of B. tabaci extract using two-dimensional electrophoresis. A total of 504 protein spots were analyzed on mass-spectrometer and 453 proteins including 246 non-redundant proteins have been identified successfully. Complementation of the proteome data with available nucleotide database has helped us to interpret the unique nucleotide sequences. These nucleotide stretches may serve as environmentally safe targets for RNAi mediated control of the pest through crop genetic engineering. To the best of our knowledge, it is the most complete proteome of any whitefly species. We have also demonstrated application of proteomics in the identification of functional transcripts for RNAi. BIOLOGICAL SIGNIFICANCE: Insects cause major loss to crop productivity through direct and indirect damages. Among them, hemipteran group of insects are major contributor of global crop yield loss. In current study, gel based proteome profile of B. tabaci (one of the major hemipteran crop insect pest) is developed and characterized, which is a gap area in field of whitefly biology. It is an important data set of future whitefly studies like insect-plant interaction, virulence of whiteflies, their control program and discovery of new pesticides. Out of various control strategies, RNA interference offers a great potential to combat the whitefly successfully. However, the uniqueness of target genes and off target impact of the technology remains a challenge to scientific community. We used our proteome data set for the identification of B. tabaci specific gene targets for RNAi mediated control. The identified genes are critical for the life cycle of B. tabaci hence, could be proven as good molecules for making transgenic crop plant for efficient control of whiteflies in the field. PMID- 26646751 TI - Hydrocortisone Dose Influences Pain, Depressive Symptoms and Perceived Health in Adrenal Insufficiency: A Randomized Controlled Trial. AB - BACKGROUND: There is a major lack of randomized controlled trials (RCTs) evaluating the effects of hydrocortisone (HC) substitution therapy in patients with secondary adrenal insufficiency. Therefore, we evaluated the effects of two different replacement doses of HC on health-related quality of life (HRQoL) in a RCT. METHODS: This RCT with a double-blind cross-over design was performed at the University Medical Center Groningen. Forty-seven patients (29 men, age 51 +/- 14 years, range 19-73 years) with secondary adrenal insufficiency participated. Patients received both a lower and a higher dose of HC (0.2-0.3 and 0.4-0.6 mg/kg body weight/day) for 10 weeks in random order. HRQoL was assessed with a daily mood and symptom checklist (Patient Health Questionnaire-15 [PHQ-15], Generalized Anxiety Disorder-7 [GAD-7], Patient Health Questionnaire-9 [PHQ-9]) and with questionnaires assessing general well-being (RAND 36-Item Health Survey [RAND 36]), mood (Hospital Anxiety and Depression Scale [HADS]) and fatigue (Multidimensional Fatigue Inventory-20 [MFI-20]). ClinicalTrials.gov identifier: NCT01546922. RESULTS: Patients receiving the higher dose of HC reported significantly fewer symptoms of depression (p = 0.016 and p = 0.045 for HADS and PHQ-9, respectively), less general and mental fatigue (p = 0.004 and p = 0.003, respectively, both MFI-20), increased motivation (p = 0.021, MFI-20), better physical functioning (p = 0.041), better general health (p = 0.013) and more vitality (p = 0.025) (all RAND-36). In addition, while on the higher dose, fewer somatic symptoms (p = 0.022) and less pain (p < 0.001) (both PHQ-15) were experienced. CONCLUSIONS: On the higher dose of HC, patients reported a better HRQoL on various domains as compared to the lower dose of HC. The fact that a higher dose of HC may improve patient well-being should be taken into consideration when individualizing the HC substitution dose. PMID- 26646752 TI - 13-week repeated dose toxicity study of l-tyrosine in rats by daily oral administration. AB - To evaluate the potential toxicity of l-tyrosine, 4 groups of Crl:CD(SD) rats of both sexes were administered l-tyrosine in water suspension by gavage once daily for 13 weeks at doses of 0 (vehicle), 200, 600 or 2000 mg/kg bw/day. Findings related to l-tyrosine administration were as follows. Edema of the cornified layer at the limiting ridge or forestomach was seen in 600 mg/kg bw/day female group and in both sexes of 2000 mg/kg bw/day group. In the liver, increased weight and hypertrophy of centrilobular hepatocytes were seen in both sexes at 2000 mg/kg bw/day, associated with slight increases in ALT and AST. Regarding the kidney morphology and function, increased hyaline droplets in the proximal tubules and increased urinary protein were seen in the 2000 mg/kg bw/day male group. In addition, increased kidney weight was also observed in both sexes of the 2000 mg/kg bw/day group, although the histological changes attributable to the weight increase remained unclear. As for blood chemistry, increases in triglycerides, total cholesterol, phospholipids, potassium ion, calcium, total protein, and alpha1 globulin were also seen in both sexes at 2000 mg/kg bw/day. Thus, in this study the no-observed-adverse-effect level (NOAEL) of l-tyrosine was considered to be 600 mg/kg bw/day for males and 200 mg/kg bw/day for females. PMID- 26646753 TI - Biocleavable Oligolysine-Grafted Poly(disulfide amine)s as Magnetic Resonance Imaging Probes. AB - To develop safe and effective macromolecular MRI contrast agents, a macromolecular contrast agent (mCA) containing biocleavable disulfide bonds in the main chain and oligolysine in the side chain is prepared, and its applicability as a MRI contrast agent is demonstrated both in vitro and in vivo. This brush-like mCA possesses a high T1 relaxivity (11.8 mM(-1) s(-1)), up to 3 times higher than the commercial Gd-DTPA (4.2 mM(-1) s(-1)), along with very low toxicity as determined by WST assay and histological analysis. Meanwhile, the disulfide bond can be broken under appropriate reducing conditions, followed by degradation into small fragments. Furthermore, the mCA is functionalized with folic acid to improve the target specificity. In vivo experiments show that FA labeled mCA can efficiently enhance the resolution between the tumor and surrounding tissues compared to the mCA without FA. This study may provide helpful insights for the further development of sensitive and biocompatible MRI probes. PMID- 26646755 TI - TP53 mutational status is predictive of pazopanib response in advanced sarcomas. AB - BACKGROUND: To investigate whether TP53 DNA mutational status impacts progression free survival (PFS) in patients with advanced sarcomas (soft tissue sarcoma) treated with vascular endothelial growth factor receptors (VEGFR) inhibition. PATIENTS AND METHODS: We retrospectively reviewed 19 cases of patients treated at the Ohio State James Comprehensive Cancer Center with advanced sarcoma treated with VEGFR inhibition who also had next-generation sequencing of their tumors (via FoundationOne Heme panel). We evaluated TP53 as well as mutations that were observed in at least 20% of patients and evaluated its contribution to PFS using the Kaplan-Meier survival analysis of available radiology end points. RESULTS: Mutations that were observed in at least 20% of patients included TP53 and Rb1. Only TP53 was predictive of PFS in the context of VEGFR inhibition. The PFS of patients with TP53 mutations was significantly greater than TP53 wild-type tumors with the median PFS of 208 versus 136 days, respectively [P = 0.036, hazards ratio 0.38 (95% confidence interval 0.09-0.83)]. CONCLUSIONS: Mutations in TP53 may serve as a predictive biomarker of response to VEGFR inhibition in patients with advanced sarcoma. Larger, prospective studies are necessary to confirm these findings. PMID- 26646756 TI - Reply to the letter to the editor 'Can ovarian suppression with gonadotropin releasing hormone analogs (GnRHa) preserve fertility in cancer patients?' by Rodriguez-Wallberg et al. PMID- 26646754 TI - Factors affecting uptake and adherence to breast cancer chemoprevention: a systematic review and meta-analysis. AB - BACKGROUND: Preventive therapy is a risk reduction option for women who have an increased risk of breast cancer. The effectiveness of preventive therapy to reduce breast cancer incidence depends on adequate levels of uptake and adherence to therapy. We aimed to systematically review articles reporting uptake and adherence to therapeutic agents to prevent breast cancer among women at increased risk, and identify the psychological, clinical and demographic factors affecting these outcomes. DESIGN: Searches were carried out in PubMed, CINAHL, EMBASE and PsychInfo, yielding 3851 unique articles. Title, abstract and full text screening left 53 articles, and a further 4 studies were identified from reference lists, giving a total of 57. This review was prospectively registered with PROSPERO (CRD42014014957). RESULTS: Twenty-four articles reporting 26 studies of uptake in 21 423 women were included in a meta-analysis. The pooled uptake estimate was 16.3% [95% confidence interval (CI) 13.6-19.0], with high heterogeneity (I(2) = 98.9%, P < 0.001). Uptake was unaffected by study location or agent, but was significantly higher in trials [25.2% (95% CI 18.3-32.2)] than in non-trial settings [8.7% (95% CI 6.8-10.9)] (P < 0.001). Factors associated with higher uptake included having an abnormal biopsy, a physician recommendation, higher objective risk, fewer side-effect or trial concerns, and older age. Adherence (day-to-day use or persistence) over the first year was adequate. However, only one study reported a persistence of >= 80% by 5 years. Factors associated with lower adherence included allocation to tamoxifen (versus placebo or raloxifene), depression, smoking and older age. Risk of breast cancer was discussed in all qualitative studies. CONCLUSION: Uptake of therapeutic agents for the prevention of breast cancer is low, and long-term persistence is often insufficient for women to experience the full preventive effect. Uptake is higher in trials, suggesting further work should focus on implementing preventive therapy within routine care. PMID- 26646757 TI - A phase I, first in human study of FP-1039 (GSK3052230), a novel FGF ligand trap, in patients with advanced solid tumors. AB - BACKGROUND: Fibroblast growth factors (FGFs) play important roles in multiple cancers by supporting tumor growth and angiogenesis. FP-1039 (GSK3052230) is a FGF ligand trap consisting of the extracellular domain of FGF receptor 1 (FGFR1) fused with the Fc region of IgG1. FP-1039 binds and neutralizes multiple FGFs that normally bind FGFR1. The primary objective of this phase I study was to evaluate the safety and tolerability of FP-1039. PATIENTS AND METHODS: Eligible patients with metastatic or locally advanced solid tumors for which standard treatments were ineffective were treated with weekly doses of FP-1039 for 4 weeks, followed by 2 weeks observation. RESULTS: Thirty-nine subjects received a mean of 6 infusions of FP-1039 at doses ranging from 0.5 to 16 mg/kg weekly, with no maximally tolerated dose identified. Grade 3 or greater treatment emergent adverse events were uncommon. Four dose-limiting toxicities were reported at doses of 0.75 mg/kg (urticaria), 1 mg/kg (intestinal perforation and neutropenia), and 16 mg/kg (muscular weakness). Drug exposure was dose proportional, and the terminal elimination half-life was 2.6-3.9 days following a single dose. Target engagement as measured by low free plasma FGF2 levels was achieved. FGF pathway dysregulation was uncommon. No objective responses were observed. CONCLUSION: In nonselected cancer patients with advanced disease, treatment with FP-1039 was well tolerated and toxicities associated with small molecule drugs that inhibit FGFR tyrosine kinases, including hyperphosphatemia, were not observed. Further studies of FP-1039 in patients selected for FGF pathway dysregulation, who are most likely to benefit, are now underway. PMID- 26646758 TI - The effect of real-time electronic monitoring of patient-reported symptoms and clinical syndromes in outpatient workflow of medical oncologists: E-MOSAIC, a multicenter cluster-randomized phase III study (SAKK 95/06). AB - BACKGROUND: Patients with advanced, incurable cancer receiving anticancer treatment often experience multidimensional symptoms. We hypothesize that real time monitoring of both symptoms and clinical syndromes will improve symptom management by oncologists and patient outcomes. PATIENTS AND METHODS: In this prospective multicenter cluster-randomized phase-III trial, patients with incurable, symptomatic, solid tumors, who received new outpatient chemotherapy with palliative intention, were eligible. Immediately before the weekly oncologists' visit, patients completed the palm-based E-MOSAIC assessment (Edmonton-Symptom-Assessment-Scale, <=3 additional symptoms, estimated nutritional intake, body weight change, Karnofsky Performance Status, medications for pain, fatigue, nutrition). A cumulative, longitudinal monitoring sheet (LoMoS) was printed immediately. Eligible experienced oncologists were defined as one cluster each and randomized to receive the immediate print-out LoMoS (intervention) or not (control). Primary analysis limited to patients having uninterrupted (>4/6 visits with same oncologist) patient-oncologist sequences was a mixed model for the difference in patients global quality of life (G-QoL; items 29/30 of EORTC-QlQ-c30) between baseline (BL) and week 6. Intention-to-treat (ITT) analysis included all eligible patients. RESULTS: In 8 centers, 82 oncologists treated 264 patients (median 66 years; overall survival intervention 6.3, control 5.4 months) with various tumors. The between-arm difference in G-QoL of 102 uninterrupted patients (intervention: 55; control: 47) was 6.8 (P = 0.11) in favor of the intervention; in a sensitivity analysis (oncologists treating >=2 patients; 50, 39), it was 9.0 (P = 0.07). ITT analysis revealed improvement in symptoms (difference last study visit-BL: intervention -5.4 versus control 2.1, P = 0.003) and favored the intervention for communication and coping. More patients with high symptom load received immediate symptom management (chart review, nurse patient interview) by oncologists getting the LoMoS. CONCLUSION: Monitoring of patient symptoms, clinical syndromes and their management clearly reduced patients' symptoms, but not QoL. Our results encourage the implementation of real time monitoring in the routine workflow of oncologist with a computer solution. PMID- 26646760 TI - Retraction of "Transition Metal-Catalyzed Ring Expansion of Diazocarbonylated Cyclic N-Hydroxylamines: A New Approach to Cyclic Ketonitrones". PMID- 26646761 TI - Cytonuclear Coordination Is Not Immediate upon Allopolyploid Formation in Tragopogon miscellus (Asteraceae) Allopolyploids. AB - Allopolyploids, formed by hybridization and chromosome doubling, face the immediate challenge of having duplicated nuclear genomes that interact with the haploid and maternally inherited cytoplasmic (plastid and mitochondrial) genomes. Most of our knowledge of the genomic consequences of allopolyploidy has focused on the fate of the duplicated nuclear genes without regard to their potential interactions with cytoplasmic genomes. As a step toward understanding the fates of nuclear-encoded subunits that are plastid-targeted, here we examine the retention and expression of the gene encoding the small subunit of Ribulose-1, 5 bisphosphate carboxylase/oxygenase (Rubisco; rbcS) in multiple populations of allotetraploid Tragopogon miscellus (Asteraceae). These polyploids formed recently (~80 years ago) and repeatedly from T. dubius and T. pratensis in the northwestern United States. Examination of 79 T. miscellus individuals from 10 natural populations, as well as 25 synthetic allotetraploids, including reciprocally formed plants, revealed a low percentage of naturally occurring individuals that show a bias in either gene (homeolog) loss (12%) or expression (16%), usually toward maintaining the maternal nuclear copy of rbcS. For individuals showing loss, seven retained the maternally derived rbcS homeolog only, while three had the paternally derived copy. All of the synthetic polyploid individuals examined (S0 and S1 generations) retained and expressed both parental homeologs. These results demonstrate that cytonuclear coordination does not happen immediately upon polyploid formation in Tragopogon miscellus. PMID- 26646762 TI - Preparation, characterisation, and in vitro evaluation of electrically conducting poly(E-caprolactone)-based nanocomposite scaffolds using PC12 cells. AB - In the current study, we describe the synthesis, material characteristics, and cytocompatibility of conducting poly (E-caprolactone) (PCL)-based nano-composite films. Electrically conducting carbon nano-fillers (carbon nano-fiber (CNF), nano graphite (NG), and liquid exfoliated graphite (G)) were used to prepare porous film type scaffolds using modified solvent casting methods. The electrical conductivity of the nano-composite films was increased when carbon nano-fillers were incorporated in the PCL matrix. CNF-based nano-composite films showed the highest increase in electrical conductivity. The presence of an ionic solution significantly improved the conductivity of some of the polymers, however at least 24 h was required to absorb the simulated ion solutions. CNF-based nano-composite films were found to have good thermo-mechanical properties compared to other conducting polymer films due to better dispersion and alignment in the critical direction. Increased nano-filler content increased the crystallisation temperature. Analysis of cell viability revealed no increase in cell death on any of the polymers compared to tissue culture plastic controls, or compared to PCL polymer without nano-composites. The scaffolds showed some variation when tested for PC12 cell attachment and proliferation, however all the polymers supported PC12 attachment and differentiation in the absence of cell adhesion molecules. In general, CNF-based nano-composite films with highest electrical conductivity and moderate roughness showed highest cell attachment and proliferation. These polymers are promising candidates for use in neural applications in the area of bionics and tissue engineering due to their unique properties. PMID- 26646759 TI - Afatinib beyond progression in patients with non-small-cell lung cancer following chemotherapy, erlotinib/gefitinib and afatinib: phase III randomized LUX-Lung 5 trial. AB - BACKGROUND: Afatinib has demonstrated clinical benefit in patients with non-small cell lung cancer progressing after treatment with erlotinib/gefitinib. This phase III trial prospectively assessed whether continued irreversible ErbB-family blockade with afatinib plus paclitaxel has superior outcomes versus switching to chemotherapy alone in patients acquiring resistance to erlotinib/gefitinib and afatinib monotherapy. PATIENTS AND METHODS: Patients with relapsed/refractory disease following >=1 line of chemotherapy, and whose tumors had progressed following initial disease control (>=12 weeks) with erlotinib/gefitinib and thereafter afatinib (50 mg/day), were randomized 2:1 to receive afatinib plus paclitaxel (40 mg/day; 80 mg/m(2)/week) or investigator's choice of single-agent chemotherapy. The primary end point was progression-free survival (PFS). Other end points included objective response rate (ORR), overall survival (OS), safety and patient-reported outcomes. RESULTS: Two hundred and two patients with progressive disease following clinical benefit from afatinib were randomized to afatinib plus paclitaxel (n = 134) or single-agent chemotherapy (n = 68). PFS (median 5.6 versus 2.8 months, hazard ratio 0.60, P = 0.003) and ORR (32.1% versus 13.2%, P = 0.005) significantly improved with afatinib plus paclitaxel. There was no difference in OS. Global health status/quality of life was maintained with afatinib plus paclitaxel over the entire treatment period. The median treatment duration was 133 and 51 days with afatinib plus paclitaxel and single-agent chemotherapy, respectively; 48.5% of patients receiving afatinib plus paclitaxel and 30.0% of patients receiving single-agent chemotherapy experienced drug-related grade 3/4 adverse events. Treatment-related adverse events were consistent with those previously reported with each agent. CONCLUSION: Afatinib plus paclitaxel improved PFS and ORR compared with single agent chemotherapy in patients who acquired resistance to erlotinib/gefitinib and progressed on afatinib after initial benefit. LUX-Lung 5 is the first prospective trial to demonstrate the benefit of continued ErbB targeting post-progression, versus switching to single-agent chemotherapy. TRIAL REGISTRATION NUMBER: NCT01085136 (clinicaltrials.gov). PMID- 26646763 TI - Review: circulating tumor cells in the practice of breast cancer oncology. AB - The primary cause of tumor-related death in breast cancer is still represented by distant metastasization. The dissemination of tumor cells from the primary tumor to distant sites through bloodstream cannot be early detected by standard imaging methods. Circulating tumor cells (CTCs) play a major role in the metastatic spread of breast cancer. Different analytical systems for CTCs isolation and detection have been developed and novel areas of research are directed towards developing assays for CTCs molecular characterization. This review describes the current state of art on CTCs detection techniques and the present and future clinical implications of CTCs enumeration and characterization. PMID- 26646764 TI - Pyrroloquinoline Quinone Resists Denervation-Induced Skeletal Muscle Atrophy by Activating PGC-1alpha and Integrating Mitochondrial Electron Transport Chain Complexes. AB - Denervation-mediated skeletal muscle atrophy results from the loss of electric stimulation and leads to protein degradation, which is critically regulated by the well-confirmed transcriptional co-activator peroxisome proliferator co activator 1 alpha (PGC-1alpha). No adequate treatments of muscle wasting are available. Pyrroloquinoline quinone (PQQ), a naturally occurring antioxidant component with multiple functions including mitochondrial modulation, demonstrates the ability to protect against muscle dysfunction. However, it remains unclear whether PQQ enhances PGC-1alpha activation and resists skeletal muscle atrophy in mice subjected to a denervation operation. This work investigates the expression of PGC-1alpha and mitochondrial function in the skeletal muscle of denervated mice administered PQQ. The C57BL6/J mouse was subjected to a hindlimb sciatic axotomy. A PQQ-containing ALZET(r) osmotic pump (equivalent to 4.5 mg/day/kg b.w.) was implanted subcutaneously into the right lower abdomen of the mouse. In the time course study, the mouse was sacrificed and the gastrocnemius muscle was prepared for further myopathological staining, energy metabolism analysis, western blotting, and real-time quantitative PCR studies. We observed that PQQ administration abolished the denervation-induced decrease in muscle mass and reduced mitochondrial activities, as evidenced by the reduced fiber size and the decreased expression of cytochrome c oxidase and NADH tetrazolium reductase. Bioenergetic analysis demonstrated that PQQ reprogrammed the denervation-induced increase in the mitochondrial oxygen consumption rate (OCR) and led to an increase in the extracellular acidification rate (ECAR), a measurement of the glycolytic metabolism. The protein levels of PGC-1alpha and the electron transport chain (ETC) complexes were also increased by treatment with PQQ. Furthermore, PQQ administration highly enhanced the expression of oxidative fibers and maintained the type II glycolytic fibers. This pre-clinical in vivo study suggests that PQQ may provide a potent therapeutic benefit for the treatment of denervation-induced atrophy by activating PGC-1alpha and maintaining the mitochondrial ETC complex in skeletal muscles. PMID- 26646765 TI - Mathematical modeling of the neuron morphology using two dimensional images. AB - In this study mathematical analyses such as the analysis of area and length, fractal analysis and modified Sholl analysis were applied on two dimensional (2D) images of neurons from adult human dentate nucleus (DN). Using mathematical analyses main morphological properties were obtained including the size of neuron and soma, the length of all dendrites, the density of dendritic arborization, the position of the maximum density and the irregularity of dendrites. Response surface methodology (RSM) was used for modeling the size of neurons and the length of all dendrites. However, the RSM model based on the second-order polynomial equation was only possible to apply to correlate changes in the size of the neuron with other properties of its morphology. Modeling data provided evidence that the size of DN neurons statistically depended on the size of the soma, the density of dendritic arborization and the irregularity of dendrites. The low value of mean relative percent deviation (MRPD) between the experimental data and the predicted neuron size obtained by RSM model showed that model was suitable for modeling the size of DN neurons. Therefore, RSM can be generally used for modeling neuron size from 2D images. PMID- 26646766 TI - Theoretical considerations on maximum running speeds for large and small animals. AB - Mechanical equations for fast running speeds are presented and analyzed. One of the equations and its associated model predict that animals tend to experience larger mechanical stresses in their limbs (muscles, tendons and bones) as a result of larger stride lengths, suggesting a structural restriction entailing the existence of an absolute maximum possible stride length. The consequence for big animals is that an increasingly larger body mass implies decreasing maximal speeds, given that the stride frequency generally decreases for increasingly larger animals. Another restriction, acting on small animals, is discussed only in preliminary terms, but it seems safe to assume from previous studies that for a given range of body masses of small animals, those which are bigger are faster. The difference between speed scaling trends for large and small animals implies the existence of a range of intermediate body masses corresponding to the fastest animals. PMID- 26646767 TI - Reproducibility of scratch assays is affected by the initial degree of confluence: Experiments, modelling and model selection. AB - Scratch assays are difficult to reproduce. Here we identify a previously overlooked source of variability which could partially explain this difficulty. We analyse a suite of scratch assays in which we vary the initial degree of confluence (initial cell density). Our results indicate that the rate of re colonisation is very sensitive to the initial density. To quantify the relative roles of cell migration and proliferation, we calibrate the solution of the Fisher-Kolmogorov model to cell density profiles to provide estimates of the cell diffusivity, D, and the cell proliferation rate, lambda. This procedure indicates that the estimates of D and lambda are very sensitive to the initial density. This dependence suggests that the Fisher-Kolmogorov model does not accurately represent the details of the collective cell spreading process, since this model assumes that D and lambda are constants that ought to be independent of the initial density. Since higher initial cell density leads to enhanced spreading, we also calibrate the solution of the Porous-Fisher model to the data as this model assumes that the cell flux is an increasing function of the cell density. Estimates of D and lambda associated with the Porous-Fisher model are less sensitive to the initial density, suggesting that the Porous-Fisher model provides a better description of the experiments. PMID- 26646768 TI - Topological chaos of the spatial prisoner's dilemma game on regular networks. AB - The spatial version of evolutionary prisoner's dilemma on infinitely large regular lattice with purely deterministic strategies and no memories among players is investigated in this paper. Based on the statistical inferences, it is pertinent to confirm that the frequency of cooperation for characterizing its macroscopic behaviors is very sensitive to the initial conditions, which is the most practically significant property of chaos. Its intrinsic complexity is then justified on firm ground from the theory of symbolic dynamics; that is, this game is topologically mixing and possesses positive topological entropy on its subsystems. It is demonstrated therefore that its frequency of cooperation could not be adopted by simply averaging over several steps after the game reaches the equilibrium state. Furthermore, the chaotically changing spatial patterns via empirical observations can be defined and justified in view of symbolic dynamics. It is worth mentioning that the procedure proposed in this work is also applicable to other deterministic spatial evolutionary games therein. PMID- 26646769 TI - Thermalized Drude Oscillators with the LAMMPS Molecular Dynamics Simulator. AB - LAMMPS is a very customizable molecular dynamics simulation software, which can be used to simulate a large diversity of systems. We introduce a new package for simulation of polarizable systems with LAMMPS using thermalized Drude oscillators. The implemented functionalities are described and are illustrated by examples. The implementation was validated by comparing simulation results with published data and using a reference software. Computational performance is also analyzed. PMID- 26646771 TI - Binding of polysaccharides to human galectin-3 at a noncanonical site in its carbohydrate recognition domain. AB - Galectin-3 (Gal-3) is a multifunctional lectin, unique to galectins by the presence of a long N-terminal tail (NT) off of its carbohydrate recognition domain (CRD). Many previous studies have investigated binding of small carbohydrates to its CRD. Here, we used nuclear magnetic resonance spectroscopy ((15)N-(1)H heteronuclear single quantum coherence data) to assess binding of (15)N-Gal-3 (and truncated (15)N-Gal-3 CRD) to several, relatively large polysaccharides, including eight varieties of galactomannans (GMs), as well as a beta(1 -> 4)-polymannan and an alpha-branched mannan. Overall, we found that these polysaccharides with a larger carbohydrate footprint interact primarily with a noncanonical carbohydrate-binding site on the F-face of the Gal-3 CRD beta sandwich, and to a less extent, if at all, with the canonical carbohydrate binding site on the S-face. While there is no evidence for interaction with the NT itself, it does appear that the NT somehow mediates stronger interactions between the Gal-3 CRD and the GMs. Significant Gal-3 resonance broadening observed during polysaccharide titrations indicates that interactions occur in the intermediate exchange regime, and analysis of these data allows estimation of affinities and stoichiometries that range from 4 * 10(4) to 12 * 10(4) M(-1) per site and multiple sites per polysaccharide, respectively. We also found that lactose can still bind to the CRD S-face of GM-bound Gal-3, with the binding of one ligand attenuating affinity of the other. These data are compared with previous results on Gal-1, revealing differences and similarities. They also provide research direction to the development of these polysaccharides as galectin-targeting therapeutics in the clinic. PMID- 26646772 TI - Circulating filarial antigen detection in brugian filariasis. AB - Human lymphatic filariasis (LF) is a major cause of disability globally. The success of global elimination programmes for LF depends upon effectiveness of tools for diagnosis and treatment. In this study on stage-specific antigen detection in brugian filariasis, L3, adult worm (AW) and microfilarial antigenaemia were detected in around 90-95% of microfilariae carriers (MF group), 50-70% of adenolymphangitis (ADL) patients, 10-25% of chronic pathology (CP) patients and 10-15% of endemic normal (EN) controls. The sensitivity of the circulating filarial antigen (CFA) detection in serum samples from MF group was up to 95%. In sera from ADL patients, unexpectedly, less antigen reactivity was observed. In CP group all the CFA positive individuals were from CP grade I and II only and none from grade III or IV, suggesting that with chronicity the AWs lose fecundity and start to disintegrate and die. Amongst EN subject, 10-15% had CFA indicating that few of them harbour filarial AWs, thus they might not be truly immune as has been conventionally believed. The specificity for antigen detection was 100% when tested with sera from various other protozoan and non filarial helminthic infections. PMID- 26646773 TI - Two Cases of Autosomal Recessive Congenital Ichthyosis due to CYP4F22 Mutations: Expanding the Genotype of Self-Healing Collodion Baby. AB - Collodion babies are born with a tight, shiny cast that sheds in a few weeks. After shedding, most patients will display features of autosomal recessive congenital ichthyosis (ARCI) later in life but in up to 10% of cases, the skin eventually becomes normal or only minimally involved, a phenotype called self healing collodion baby (SHCB), which is considered as ARCI subtype in the 2010 consensus classification of congenital ichthyosis. The term self-improving collodion ichthyosis (SICI) has been proposed for these patients. SHCB/SICI was initially associated with mutations in the gene TGM1. However, some cases showing ALOX12B and ALOXE3 gene mutations have also been reported. We report two cases of SHCB/SICI showing homozygous mutations in the gene CYP4F22. PMID- 26646774 TI - Molecular mass screening of mosquitoes for filarial parasites in Germany--re interpretation of PCR xenomonitoring results would be required. AB - Comments concerning interpretation of the PCR xenomonitoring results in the article "Molecular detection of Setaria tundra (Nematoda: Filarioidea) and an unidentified filarial species in mosquitoes in Germany" Parasites & Vectors 2012, 5:14. PMID- 26646775 TI - Refractive errors and ocular biometry components in thalassemia major patients. AB - The aim of this study is to determine and compare biometric and refractive characteristics of thalassemia major patients and normal individuals. In this cross-sectional study, 54 thalassemia major patients were selected randomly as case group, and 54 age- and sex-matched healthy subjects were regarded as control group. Refractive errors, corneal curvature and ocular components were measured by autokeratorefractometery and A-scan ultrasonography, respectively. Mean spherical equivalent was -0.0093 +/- 0.86 D in thalassemia patients and -0.22 +/- 1.33 D in the normal group. The prevalence of myopia, Hyperopia, and emmetropia among thalassemia patients was 16.7, 19.4, and 63.9 %, respectively. While in the control group, 26.9 % were myopic, 25 % were hyperopic, and 48.1 % were emmetropic. The prevalence of astigmatism in case group was 22.2 %, which was not significantly different from that in control group, (27.8 %, p = 0.346). Mean axial length in thalassemia patients was 22.89 +/- 0.70 which was significantly lower than that in normal group (23.37 +/- 0.91, p = 0.000). The flattest meridian of the cornea (R1) was significantly steeper in thalassemia patients (7.77 +/- 0.24) in comparison to normal individuals (7.85 +/- 0.28). Although thalassemic patients had significantly smaller axial length and vitreous chamber depth in comparison to normal group, which could be due to their abnormal physical growth, there was no significant difference between the mean of spherical equivalent among two groups. This can be due to their steeper corneal curvature that overcomes the refractive disadvantage of their shorter axial length. PMID- 26646776 TI - Clinical outcomes of trabeculectomy vs. Ahmed glaucoma valve implantation in patients with penetrating keratoplasty : (Trabeculectomy vs. Ahmed galucoma valve in patients with penetrating keratoplasty). AB - The aim of this study was to compare the visual outcomes, intraocular pressure (IOP), and endothelial cell loss caused by trabeculectomy (TRAB) and Ahmed glaucoma valve (AGV) implantation in patients who had previously undergone penetrating keratoplasty (PKP). The data from all patients who underwent surgical treatment of glaucoma after PKP were reviewed at the Cornea Department of Haydarpasa Numune Education and Research Hospital. Eighteen patients who had undergone surgical treatment of glaucoma after PKP were included in this retrospective study. Time between PKP and glaucoma surgeries, visual acuity results, IOP results, endothelial cell counts (ECC) before the surgery, at 1st, 6th, and 12th month of surgery were recorded. Differences between two groups were evaluated. Mean loss of ECC was 315 cells/mm(2) in the AGV group and 197 cells/mm(2) in TRAB group at 12th month of glaucoma surgery. The difference between endothelial cell loss at 12th month of surgery was statistically significant and higher in AGV group (p < 0.001). The decrease in IOP was 64.2 % in AGV group and 46.9 % in TRAB group at 12th month of surgery. Both differences were statistically significant between 2 groups (p = 0.001, 0.001). TRAB successfully decreased both the IOP and endothelial cell loss in patients with post-PKP glaucoma. Ahmed glaucoma valve had a significantly better IOP lowering but higher endothelial cell loss effect. PMID- 26646777 TI - Periodontitis prevalence and serum antibody reactivity to periodontal bacteria in primary Sjogren's syndrome: a pilot study. AB - AIMS: The aims of this study were as follows: (i) To assess the prevalence of periodontitis among patients with primary Sjogren's syndrome (pSS) and comparator groups of patients with rheumatoid arthritis (RA) and osteoarthritis (OA). (ii) To perform a pilot study to compare serum antibody responses to 10 oral/periodontal bacteria in these patient groups and a historical comparator group of patients with periodontitis. MATERIALS AND METHODS: Standard clinical periodontal assessments were performed on 39 pSS, 36 RA and 23 OA patients and "In-house" antibody ELISAs for serum antibodies against 10 oral/periodontal bacteria were performed in these groups. RESULTS: Forty-six percent of the pSS group, 64% of the RA group and 48% of the OA group had moderate/severe periodontitis. These frequencies did not reach statistical significance between groups. Raised antibody levels to Prevotella denticola were found in the pSS, RA and periodontitis groups compared to the OA group. Significant between group differences were seen for Aggregatibacter actinomycetemcomitans, Prevotella intermedia and Campylobacter showae. None of these differences were specifically associated with pSS. CONCLUSION: This study showed no increase in periodontitis in pSS patients. Although the P. denticola data are of interest, identifying bacterial triggering factors for pSS will likely require alternative strategies including modern techniques such as microbiome analysis. PMID- 26646778 TI - Antitumor Activity of Total Flavonoids from Daphne genkwa in Colorectal Cancer. AB - Daphne genkwa Sieb.et Zucc. is a well-known medicinal plant. This study was designed to investigate the anticancer effects of total flavonoids in D. genkwa (TFDG) in vitro and in vivo. HT-29 and SW-480 human colorectal cancer cells were cultured to investigate the anticancer activity of TFDG. In addition, the Apc(Min/+) mouse model was applied in the in vivo experiment. Results of the cell experiment revealed that TFDG possessed significant inhibitory effects on HT-29 and SW-480 human colorectal cancer cells (both p < 0.01). Furthermore, our in vivo data showed that after treatment with TFDG, there was a significant increase in life span (both p < 0.01) and tumor numbers were reduced in the colon (both p < 0.01), which was supported by the data of tumor distribution, body weight changes and organ index. Our results also indicated that expressions of interleukin (IL)-1alpha, IL-1beta, IL-6, granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor in gut tissue were downregulated by treatments of TFDG, and immunity cytokine secretions in the serum were regulated after oral administration of TFDG. Taken together, these findings suggested that TFDG has a potential clinical utility in colorectal cancer therapeutics, and TFDG's action is likely linked to its ability to regulate immune function and inhibit the production of inflammatory cytokines. PMID- 26646779 TI - Prion-mediated neurodegeneration is associated with early impairment of the ubiquitin-proteasome system. AB - Prion diseases are a group of fatal neurodegenerative disorders characterised by the accumulation of misfolded prion protein (PrP(Sc)) in the brain. The critical relationship between aberrant protein misfolding and neurotoxicity currently remains unclear. The accumulation of aggregation-prone proteins has been linked to impairment of the ubiquitin-proteasome system (UPS) in a variety of neurodegenerative disorders, including Alzheimer's, Parkinson's and Huntington's diseases. As the principal route for protein degradation in mammalian cells, this could have profound detrimental effects on neuronal function and survival. Here, we determine the temporal onset of UPS dysfunction in prion-infected Ub(G76V)-GFP reporter mice, which express a ubiquitin fusion proteasome substrate to measure in vivo UPS activity. We show that the onset of UPS dysfunction correlates closely with PrP(Sc) deposition, preceding earliest behavioural deficits and neuronal loss. UPS impairment was accompanied by accumulation of polyubiquitinated substrates and found to affect both neuronal and astrocytic cell populations. In prion-infected CAD5 cells, we demonstrate that activation of the UPS by the small molecule inhibitor IU1 is sufficient to induce clearance of polyubiquitinated substrates and reduce misfolded PrP(Sc) load. Taken together, these results identify the UPS as a possible early mediator of prion pathogenesis and promising target for development of future therapeutics. PMID- 26646780 TI - In vivo evaluation of PEGylated 64Cu-liposomes with theranostic and radiotherapeutic potential using micro PET/CT. AB - PURPOSE: The objective of this study was to evaluate the potential of PEGylated (64)Cu-liposomes in clinical diagnostic positron emission tomography (PET) imaging and PEGylated (177)Lu-liposomes in internal tumor radiotherapy through in vivo characterization and dosimetric analysis in a human xenograft mouse model. METHODS: Liposomes with 5 and 10 mol% PEG were characterized with respect to size, charge, and (64)Cu- and (177)Lu-loading efficiency. The tumor imaging potential of (64)Cu-loaded liposomes was evaluated in terms of in vivo biodistribution, tumor accumulation and tumor-to-muscle (T/M) ratios, using PET imaging. The potential of PEGylated liposomes for diagnostic and therapeutic applications was further evaluated through dosimetry analysis using OLINDA/EXM software. The (64)Cu-liposomes were used as biological surrogates to estimate the organ and tumor kinetics of (177)Lu-liposomes. RESULTS: High remote loading efficiency (>95 %) was obtained for both (64)Cu and (177)Lu radionuclides with PEGylated liposomes, and essentially no leakage of the encapsulated radionuclide was observed upon storage and after serum incubation for 24 h at 37 degrees C. The 10 mol% PEG liposomes showed higher tumor accumulation (6.2 +/- 0.2 %ID/g) than the 5 mol% PEG liposomes, as evaluated by PET imaging. The dosimetry analysis of the (64)Cu-liposomes estimated an acceptable total effective dose of 3.3.10(-2) mSv/MBq for diagnostic imaging in patients. A high absorbed tumor dose (114 mGy/MBq) was estimated for the potential radiotherapeutic (177)Lu-liposomes. CONCLUSION: The overall preclinical profile of PEGylated (64)Cu-liposomes showed high potential as a new PET theranostic tracer for imaging in humans. Dosimetry results predicted that initial administered activity of 200 MBq of (64)Cu liposomes should be acceptable in patients. Work is in progress to validate the utility of PEGylated (64)Cu-liposomes in a clinical research programme. The high absorbed tumor dose (114 mGy/MBq) estimated for (177)Lu-liposomes and the preliminary dosimetric studies justify further therapeutic and dosimetry investigation of (177)Lu-liposomes in animals before potential testing in man. PMID- 26646782 TI - "The Police Have Given Up": An Empirical Examination of Covictims' Beliefs About Cold Case Homicide Investigations. AB - This work examines the perception by cold case homicide covictims that police have given up trying to solve their loved one's murder. A random sample (n = 65) of cold case homicide covictims is surveyed to determine if, and how, different forms of communication may be important in their perceptions about police. Ordered logistic regression analyses indicate that perceived importance of the information communicated, frequency of police contact, and satisfaction with communication efforts by police are inversely correlated with covictims' perceptions that police have given up on the investigation. These inverse correlations persist despite statistical controls and have important implications for the bereavement of covictims and for crime rates. PMID- 26646781 TI - Reproducibility of O-(2-(18)F-fluoroethyl)-L-tyrosine uptake kinetics in brain tumors and influence of corticoid therapy: an experimental study in rat gliomas. AB - PURPOSE: Positron emission tomography (PET) using O-(2-(18)F-fluoroethyl)-L tyrosine ((18)F-FET) is a well-established method for the diagnostics of brain tumors. This study investigates reproducibility of (18)F-FET uptake kinetics in rat gliomas and the influence of the frequently used dexamethasone (Dex) therapy. METHODS: F98 glioma or 9L gliosarcoma cells were implanted into the striatum of 31 Fischer rats. After 10-11 days of tumor growth, the animals underwent dynamic PET after injection of (18)F-FET (baseline). Thereafter, animals were divided into a control group and a group receiving Dex injections, and all animals were reinvestigated 2 days later. Tumor-to-brain ratios (TBR) of (18)F-FET uptake (18 61 min p.i.) and the slope of the time-activity-curves (TAC) (18-61 min p.i.) were evaluated using a Volume-of-Interest (VOI) analysis. Data were analyzed by two-way repeated measures ANOVA and reproducibility by the intraclass correlation coefficient (ICC). RESULTS: The slope of the tumor TACs showed high reproducibility with an ICC of 0.93. A systematic increase of the TBR in the repeated scans was noted (3.7 +/- 2.8 %; p < 0.01), and appeared to be related to tumor growth as indicated by a significant correlation of TBR and tumor volume (r = 0.77; p < 0.0001). After correction for tumor growth TBR showed high longitudinal stability with an ICC of 0.84. Dex treatment induced a significant decrease of the TBR (-8.2 +/- 6.1 %; p < 0.03), but did not influence the slope of the tumor TAC. CONCLUSION: TBR of (18)F-FET uptake and tracer kinetics in brain tumors showed high longitudinal stability. Dex therapy may induce a minor decrease of the TBR; this needs further investigation. PMID- 26646783 TI - CADASIL: MRI may be normal in the fourth decade of life - a case report. AB - Background Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) manifests by migraine with aura, cerebral ischemic events, mood disturbances and dementia. Brain MRI lesions typically precede the symptoms from 10 to 15 years and previous evidence showed all CADASIL patients above 35 years old have an abnormal MRI, supporting the clinical diagnosis. Case results We present a 37-year-old female patient with migraine without aura, a family history of CADASIL, normal brain 3-Tesla MRI and normal skin biopsy, even though a pathogenic NOTCH3 gene mutation (allele 2, exon 11, c.1672 C?gtT, p.Arg558Cys) was detected. Conclusions When CADASIL is strongly suspected, a normal brain MRI, even in the fourth decade of life, does not rule out the diagnosis and should not discourage the genetic test. PMID- 26646784 TI - Prevalence and characteristics of migraine in CADASIL. AB - Background and objective Migraine with aura (MA) is a major symptom of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). We assessed the spectrum of migraine symptoms and their potential correlates in a large prospective cohort of CADASIL individuals. Methods A standardized questionnaire was used in 378 CADASIL patients for assessing headache symptoms, trigger factors, age at first attack, frequency of attacks and associated symptoms. MRI lesions and brain atrophy were quantified. Results A total of 54.5% of individuals had a history of migraine, mostly MA in 84% of them; 62.4% of individuals with MA were women and age at onset of MA was lower in women than in men. Atypical aura symptoms were experienced by 59.3% of individuals with MA, and for 19.7% of patients with MA the aura was never accompanied by headache. MA was the inaugural manifestation in 41% of symptomatic patients and an isolated symptom in 12.1% of individuals. Slightly higher MMSE and MDRS scores and lower Rankin score were detected in the MA group. Conclusion MA is observed in almost half of all CADASIL patients. Atypical aura symptoms are reported by more than one in two of them. MA is often inaugural, can remain isolated and is not associated with the severity of the disorder. PMID- 26646785 TI - Integrated multidisciplinary care of headache disorders: A narrative review. AB - Background Recent evidence shows that multidisciplinary treatment is effective in chronic pain syndromes, especially in headache disorders. Aim The aim of this review is to summarize current knowledge on integrative care concepts in headache patients regarding the optimal and necessary treatment parts, optimal duration and setting. Methods We present a narrative review reporting current literature and personal experience. Results and conclusion Based on current knowledge, multidisciplinary treatment programs appear to be reasonable and efficient in headache disorders. Sufficient controlled studies regarding the need for individual parts of the integrative care approach are missing as yet. Recommendations are therefore at least partly based on personal experiences. It seems to be unambiguous that patients should be referred to a specialized headache center offering such a program instead of being sent sequentially to various medical specialists. The extent and kind of required therapy (e.g. personal consultation versus group sessions) is not known yet. All patients should learn relaxation training, although it is unclear yet which training is the best for which patient. Physiotherapy with guidance on more activity and individual exercises should be used in all patients. Some patients might benefit from cognitive behavioral therapy. However, therapies often depend more on country-specific health care systems than on clinical needs or scientific data. PMID- 26646786 TI - Familial limb pain and migraine: 8-year follow-up of four generations. AB - Background Migraine limb pain may be under-recognized in adults and children. There is little information about familial forms of this disorder. Objectives To describe the clinical and inheritance patterns of familial migraine limb pain over four generations and to review the evidence for limb pain as a manifestation of migraine. Methods Prospective clinical and pedigree analysis with an 8-year follow-up of 27 family members. Results Eight members of the family had benign recurrent limb pain associated with headache in a dominant inheritance pattern. Limb pain occurred before, during or after the headache, with probable or definite migraine with aura, migraine without aura and lower-half headache. The limb pain fulfilled the International Headache Society criteria for aura in six patients and also occurred without headache in three. Four members of the family had recurrent abdominal pain and/or motion sickness in childhood. Conclusions This is the first report of dominant familial limb pain temporally associated with migraine headache, starting in adulthood or starting in childhood and continuing into adulthood. A search for a genetic marker is indicated. Limb pain should be included as a childhood periodic syndrome linked to migraine and recognized as part of the migraine spectrum in adults. PMID- 26646787 TI - Deep brain stimulation in headache. AB - BACKGROUND: Deep brain stimulation of the posterior hypothalamic area was first introduced in 2000 to treat drug-refractory chronic cluster headache (CH). FINDINGS: So far, hypothalamic stimulation has been employed in 79 patients suffering from various forms of intractable short-lasting unilateral headache forms, mainly trigeminal autonomic cephalalgias. The majority were (88.6%) chronic CH, including one patient who suffered from symptomatic chronic CH-like attacks; the remaining were short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT), one had paroxysmal hemicranias and one symptomatic trigeminal neuralgia. Overall, after a mean follow up of 2.2 years, 69.6% (55) hypothalamic-stimulated patients showed a >=50% improvement. CONCLUSIONS: These observations need confirmation in randomised, controlled trials. A key role of the posterior hypothalamic area in the pathophysiology of unilateral short-lasting headaches, possibly by regulating the duration rather than triggering the attacks, can be hypothesised. Because of its invasiveness, hypothalamic stimulation can be proposed only after other, less invasive, neurostimulation procedures have been tried. PMID- 26646788 TI - Involvement of astrocyte and oligodendrocyte gene sets in migraine. AB - BACKGROUND: Migraine is a common episodic brain disorder characterized by recurrent attacks of severe unilateral headache and additional neurological symptoms. Two main migraine types can be distinguished based on the presence of aura symptoms that can accompany the headache: migraine with aura and migraine without aura. Multiple genetic and environmental factors confer disease susceptibility. Recent genome-wide association studies (GWAS) indicate that migraine susceptibility genes are involved in various pathways, including neurotransmission, which have already been implicated in genetic studies of monogenic familial hemiplegic migraine, a subtype of migraine with aura. METHODS: To further explore the genetic background of migraine, we performed a gene set analysis of migraine GWAS data of 4954 clinic-based patients with migraine, as well as 13,390 controls. Curated sets of synaptic genes and sets of genes predominantly expressed in three glial cell types (astrocytes, microglia and oligodendrocytes) were investigated. DISCUSSION: Our results show that gene sets containing astrocyte- and oligodendrocyte-related genes are associated with migraine, which is especially true for gene sets involved in protein modification and signal transduction. Observed differences between migraine with aura and migraine without aura indicate that both migraine types, at least in part, seem to have a different genetic background. PMID- 26646789 TI - Antibacterial efficacy of titanium-containing alloy with silver-nanoparticles enriched diamond-like carbon coatings. AB - Silver ions (Ag(+)) have strong bactericidal effects and Ag-coated medical devices proved their effectiveness in reducing infections in revision total joint arthroplasty. We quantitatively determined the antimicrobial potency of different surface treatments on a titanium alloy (Ti), which had been conversed to diamond like carbon (DLC-Ti) and doped with high (Ag:PVP = 1:2) and low (Ag:PVP = 1:10 and 1:20) concentrations of Ag (Ag-DLC-Ti) with a modified technique of ion implantation. Bacterial adhesion and planktonic growth of clinically relevant bacterial strains (Staphylococcus epidermidis, Staphylococcus aureus, and Pseudomonas aeruginosa) on Ag-DLC-Ti were compared to untreated Ti by quantification of colony forming units on the adherent surface and in the growth medium as well as semiquantitatively by determining the grade of biofilm formation by scanning electron microscopy. (1) A significant (p < 0.05) antimicrobial effect could be found for all Ag-DLC-Ti samples (reduced growth by 5.6-2.5 logarithmic levels). (2) The antimicrobial effect was depending on the tested bacterial strain (most for P. aeruginosa, least for S. aureus). (3) Antimicrobial potency was positively correlated with Ag concentrations. (4) Biofilm formation was decreased by Ag-DLC-Ti surfaces. This study revealed potent antibacterial effects of Ag-DLC-Ti. This may serve as a promising novel approach to close the gap in antimicrobial protection of musculoskeletal implants. PMID- 26646790 TI - Disruption of Specific RNA-RNA Interactions in a Double-Stranded RNA Virus Inhibits Genome Packaging and Virus Infectivity. AB - Bluetongue virus (BTV) causes hemorrhagic disease in economically important livestock. The BTV genome is organized into ten discrete double-stranded RNA molecules (S1-S10) which have been suggested to follow a sequential packaging pathway from smallest to largest segment during virus capsid assembly. To substantiate and extend these studies, we have investigated the RNA sorting and packaging mechanisms with a new experimental approach using inhibitory oligonucleotides. Putative packaging signals present in the 3'untranslated regions of BTV segments were targeted by a number of nuclease resistant oligoribonucleotides (ORNs) and their effects on virus replication in cell culture were assessed. ORNs complementary to the 3' UTR of BTV RNAs significantly inhibited virus replication without affecting protein synthesis. Same ORNs were found to inhibit complex formation when added to a novel RNA-RNA interaction assay which measured the formation of supramolecular complexes between and among different RNA segments. ORNs targeting the 3'UTR of BTV segment 10, the smallest RNA segment, were shown to be the most potent and deletions or substitution mutations of the targeted sequences diminished the RNA complexes and abolished the recovery of viable viruses using reverse genetics. Cell-free capsid assembly/RNA packaging assay also confirmed that the inhibitory ORNs could interfere with RNA packaging and further substitution mutations within the putative RNA packaging sequence have identified the recognition sequence concerned. Exchange of 3'UTR between segments have further demonstrated that RNA recognition was segment specific, most likely acting as part of the secondary structure of the entire genomic segment. Our data confirm that genome packaging in this segmented dsRNA virus occurs via the formation of supramolecular complexes formed by the interaction of specific sequences located in the 3' UTRs. Additionally, the inhibition of packaging in-trans with inhibitory ORNs suggests this that interaction is a bona fide target for the design of compounds with antiviral activity. PMID- 26646791 TI - Electrostatic-Driven Lamination and Untwisting of beta-Sheet Assemblies. AB - Peptides or peptide conjugates capable of assembling into one-dimensional (1D) nanostructures have been extensively investigated over the past two decades due to their implications in human diseases and also their interesting applications as biomaterials. While many of these filamentous assemblies contain a beta-sheet forming sequence as the key design element, their eventual morphology could assume a variety of shapes, such as fibrils, ribbons, belts, or cylinders. Deciphering the key factors that govern the stacking fashion of individual beta sheets will help understand the polymorphism of peptide assemblies and greatly benefit the development of functional materials from customized molecular design. Herein, we report the decisive role of electrostatic interactions in the lamination and untwisting of 1D assemblies of short peptides. We designed and synthesized three short peptides containing only six amino acids (EFFFFE, KFFFFK, and EFFFFK) to elucidate the effective control of beta-sheet stacking. Our results clearly suggest that electrostatic repulsions between terminal charges reduce the pitch of the twisting beta-sheet tapes, thus leading to highly twisted, intertwined fibrils or twisted ribbons, whereas reducing this repulsion, either through molecular design of peptide with opposite terminal charges or through coassembly of two peptides carrying opposite charges, results in formation of infinite assemblies such as belt-like morphologies. We believe these observations provide important insight into the generic design of beta-sheet assemblies. PMID- 26646792 TI - Molecular analyses reveal close similarities between small cell carcinoma of the ovary, hypercalcemic type and atypical teratoid/rhabdoid tumor. AB - Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is the most common undifferentiated ovarian malignancy diagnosed in women under age 40. We and others recently determined that germline and/or somatic deleterious mutations in SMARCA4 characterize SCCOHT. Alterations in this gene, or the related SWI/SNF chromatin remodeling gene SMARCB1, have been previously reported in atypical teratoid/rhabdoid tumors (ATRTs) and malignant rhabdoid tumors (MRTs). To further describe the somatic landscape of SCCOHT, we performed whole exome sequencing on 14 tumors and their matched normal tissues and compared their genomic alterations with those in ATRT and ovarian high grade serous carcinoma (HGSC). We confirmed that SMARCA4 is the only recurrently mutated gene in SCCOHT, and show that recurrent allelic imbalance is observed exclusively on chromosome 19p, where SMARCA4 resides. By comparing genomic alterations between SCCOHT, ATRT and HGSC, we demonstrate that SCCOHTs, like ATRTs, have a remarkably simple genome and harbor significantly fewer somatic protein-coding mutations and chromosomal alterations than HGSC. Furthermore, a comparison of global DNA methylation profiles of 45 SCCOHTs, 65 ATRTs, and 92 HGSCs demonstrates a strong epigenetic correlation between SCCOHT and ATRT. Our results further confirm that the genomic and epigenomic signatures of SCCOHT are more similar to those of ATRT than HGSC, supporting our previous hypothesis that SCCOHT is a rhabdoid tumor and should be renamed MRT of the ovary. Furthermore, we conclude that SMARCA4 inactivation is the main cause of SCCOHT, and that new distinct therapeutic approaches should be developed to specifically target this devastating tumor. PMID- 26646794 TI - Nomogram basing pre-treatment parameters predicting early response for locally advanced rectal cancer with neoadjuvant chemotherapy alone: a subgroup efficacy analysis of FOWARC study. AB - OBJECTIVE: To develop an accurate model with pre-treatment parameters to predict tumor regression and down-staging in locally advanced rectal cancer patients, basing the cohort of preoperative chemotherapy alone in FOWARC study. PATIENTS AND METHODS: From Jan 2011 to Feb 2015, complete data was available for 137 out of 165 patients who received preoperative chemotherapy alone. All pre-treatment clinical parameters were collected. Tumor regression grade (TRG) 0-1 was defined as good regression, and pathological TNM stage (ypTNM) 0-I after neoadjuvant treatment was defined as good down-staging. Nomogram was established to predict tumor regression and down-staging. The predictive performance of the model was assessed with concordance index and calibration plots. RESULTS: Of the 137 patients, 10 had TRG 0 (complete regression); 32 patients, TRG 1; and 95 patients, TRG 2 and 3 (poor regression); 56 (40.9%) patients were classified as good down-staging with ypTNM stage 0-I. The predictive nomograms were developed to predict the probability of TRG 0-1 and good down-staging with a C-index of 0.72 (95% CI: 0.604-0.797) and 0.76 (95% CI: 0.681-0.844). Calibration plots showed good statistical performance on internal validation. Predictive factors in the models included tumor length, tumor circumferential extent, age, and ApoA1. CONCLUSIONS: The model based on available clinical parameters could accurately predict early efficacy with neoadjuvant mFOLFOX6 chemotherapy alone, which might help in patient selection for optimized treatment. PMID- 26646795 TI - Hormone stimulation of androgen receptor mediates dynamic changes in DNA methylation patterns at regulatory elements. AB - DNA methylation is an epigenetic modification that contributes to stable gene silencing by interfering with the ability of transcriptional regulators to bind to DNA. Recent findings have revealed that hormone stimulation of certain nuclear receptors induces rapid, dynamic changes in DNA methylation patterns alongside transcriptional responses at a subset of target loci, over time. However, the ability of androgen receptor (AR) to dynamically regulate gene transcription is relatively under-studied and its role in the regulation of DNA methylation patterns remains to be elucidated. Here we demonstrate in normal prostate cells that hormone stimulated AR activity results in dynamic changes in the transcription rate and DNA methylation patterns at the AR target genes, TIPARP and SGK1. Time-resolved chromatin immunoprecipitation experiments on the SGK1 locus reveals dynamic recruitment of AR and RNA Polymerase II, as well as the recruitment of proteins involved in the DNA demethylation process, TET1 and TDG. Furthermore, the presence of DNA methylation at dynamic regions inhibits protein binding and transcriptional activity of SGK1. These findings establish AR activity as a contributing factor to the dynamic regulation of DNA methylation patterns at target genes in prostate biology and infer further complexity involved in nuclear receptor mediation of transcriptional regulation. PMID- 26646793 TI - Longer genotypically-estimated leukocyte telomere length is associated with increased adult glioma risk. AB - Telomere maintenance has emerged as an important molecular feature with impacts on adult glioma susceptibility and prognosis. Whether longer or shorter leukocyte telomere length (LTL) is associated with glioma risk remains elusive and is often confounded by the effects of age and patient treatment. We sought to determine if genotypically-estimated LTL is associated with glioma risk and if inherited single nucleotide polymorphisms (SNPs) that are associated with LTL are glioma risk factors. Using a Mendelian randomization approach, we assessed differences in genotypically-estimated relative LTL in two independent glioma case-control datasets from the UCSF Adult Glioma Study (652 patients and 3735 controls) and The Cancer Genome Atlas (478 non-overlapping patients and 2559 controls). LTL estimates were based on a weighted linear combination of subject genotype at eight SNPs, previously associated with LTL in the ENGAGE Consortium Telomere Project. Mean estimated LTL was 31bp (5.7%) longer in glioma patients than controls in discovery analyses (P = 7.82x10-8) and 27bp (5.0%) longer in glioma patients than controls in replication analyses (1.48x10-3). Glioma risk increased monotonically with each increasing septile of LTL (O.R.=1.12; P = 3.83x10-12). Four LTL-associated SNPs were significantly associated with glioma risk in pooled analyses, including those in the telomerase component genes TERC (O.R.=1.14; 95% C.I.=1.03-1.28) and TERT (O.R.=1.39; 95% C.I.=1.27-1.52), and those in the CST complex genes OBFC1 (O.R.=1.18; 95% C.I.=1.05-1.33) and CTC1 (O.R.=1.14; 95% C.I.=1.02-1.28). Future work is needed to characterize the role of the CST complex in gliomagenesis and further elucidate the complex balance between ageing, telomere length, and molecular carcinogenesis. PMID- 26646796 TI - STB-HO, a novel mica fine particle, inhibits the teratoma-forming ability of human embryonic stem cells after in vivo transplantation. AB - Although pluripotent stem cell (PSC) therapy has advantages for clinical applications because of the self-renewal and multi-lineage differentiation abilities of PSCs, it also has disadvantages in terms of the potential for PSCs to undergo malignant transformation or unexpected differentiation. The prevention of teratoma formation is the largest hurdle of all. Despite intensive studies that have investigated ways to block teratomas, such methods have yet to be further developed for clinical use. Here, a new approach has focused on exerting anti-tumorigenic effects using a novel mica fine particle (MFP) designated STB HO. Treatment with STB-HO regulated pluripotency- and apoptosis-related genes in differentiating human embryonic stem (hES) cells, while there is no effects in undifferentiated hES cells. In particular, STB-HO blocked the anti-apoptotic gene BIRC5 and activated p53, p21 and the pro-apoptotic proteins Bim, Puma and p-Bad during early spontaneous differentiation. Moreover, STB-HO-pretreated differentiating hES cells did not give rise to teratomas following in vivo stem cell transplantation. Our in vitro and in vivo results suggest a method for teratoma prevention in the context of PSC-derived cell transplantation. This novel MFP could break through the limitations of PSC therapy. PMID- 26646798 TI - Bioethics and Epistemic Scientism. PMID- 26646797 TI - Up-regulation of REG3A in colorectal cancer cells confers proliferation and correlates with colorectal cancer risk. AB - Colorectal cancer (CRC) is one of the most common malignancies in the world. Previous studies have investigated the altered expression of regenerating islet derived 3 alpha (REG3A) in various cancers. We aimed at exploring the biological function and the underlying molecular mechanism of REG3A in CRC. In this study, REG3A was found elevated in CRC compared with normal tissues. Further, high REG3A expression level was correlated with bigger tumor size, poorer differentiation, higher tumor stage and lower survival rate. Knockdown of REG3A in two CRC cell lines, LOVO and RKO, significantly inhibited cell proliferation, and increased cells population in G1 phase and cell apoptotic rate. We also found that down regulation of REG3A in CRC cells notably inhibited cell migration and invasion. Gene set enrichment analysis on The Cancer Genome Atlas dataset showed that Kyoto Encyclopedia of Genes and Genomes (KEGG) DNA replication and base excision repair (BER) pathways were correlative with the REG3A expression, which was further confirmed in CRC cells by Western blot. Moreover, we confirmed the interaction of REG3A and fibronectin in CRC cells. We also found that there was a positive correlation between REG3A expression level and the AKT and ERK1/2 phosphorylation status. These collective data indicated that REG3A overexpression promotes CRC tumorigenesis by activating AKT and ERK1/2 pathways. REG3A may serve as a promising therapeutic strategy for CRC. PMID- 26646799 TI - Children with autism are impaired in the understanding of teaching. AB - Children learn novel information using various methods, and one of the most common is human pedagogical communication or teaching - the purposeful imparting of information from one person to another. Neuro-typically developing (TD) children gain the ability to recognize and understand teaching as a core method for acquiring knowledge from others. However, it is not known when children with Autism Spectrum Disorder (ASD) acquire the ability to recognize and understand teaching. This study (total N = 70) examined whether children with ASD recognize the two central elements that define teaching: (1) that teaching is an intentional activity; and (2) that teaching requires a knowledge difference between teacher and learner. Theory of mind understanding was also tested. Compared to individually matched TD children, high cognitively functioning children with ASD were impaired in their comprehension of both components of teaching understanding, and their performance was correlated with theory of mind understanding. These findings could have broad implications for explaining learning in children with autism, and could help in designing more effective interventions, which could ultimately lead to improved learning outcomes for everyday life skills, school performance, health, and overall well-being. PMID- 26646800 TI - Hepatocyte Nuclear Factor 1alpha Mutation-associated MODY-3 and Familial Liver Adenomatosis. PMID- 26646801 TI - Alternative Therapies for Chronic Hepatitis B Patients With Partial Virological Response to Standard Entecavir Monotherapy. AB - BACKGROUND: Entecavir (ETV) is a first-line, oral antinucleoside agent for the treatment of chronic hepatitis B patients. Despite its high potency, some patients may still be viremic after prolonged therapy with ETV monotherapy. Long term outcome data comparing maintained ETV monotherapy to alternative therapies in persistently viremic patients are limited. Our goal was to compare complete viral suppression (CVS) rates [hepatitis B DNA (HBV DNA)<40 to 60 IU/mL] with alternative therapies to continued ETV monotherapy in ETV partial responders. METHODS: This is a retrospective cohort study consisting of 86 consecutive treatment-naive, ETV=0.5 mg partial responders (detectable HBV DNA after >=12 mo on ETV) who maintained ETV=0.5 mg daily (n=29) or switched to either ETV=1.0 mg daily (n=32) or ETV/tenofovir (TDF)=0.5 mg/300 mg (n=25) in 3 US GI/liver clinics from January 2005 to January 2012. Patients were identified by International Classification of Diseases, Ninth Revision query and data were collected by individual chart review. For those who remained on ETV=0.5 mg, comparison at regimen "switch time" was done using values at 12 months from initial ETV therapy. Rates of CVS were evaluated using Kaplan-Meier methods. Multivariate Cox proportional hazard models were used to estimate hazard ratio (HR) relating to potential predictors to the desirable outcomes of CVS. RESULTS: In all therapy groups, the majority of patients were Asian (93.1% to 100.0%), male (64.0% to 68.8%), and hepatitis B e antigen-positive (95.8% to 100.0%) and had similar baseline alanine aminotransferase (ALT) levels. However, baseline HBV DNA (7.0 vs. 7.9 vs. 7.8 log10 IU/mL, P=0.05) and HBV DNA at regimen switch point (2.9 vs. 3.7 vs. 3.6 log10 IU/mL, P=0.0014) were lower in the ETV=0.5 mg cohort compared with those switched to ETV=1.0 mg or ETV/TDF, respectively. The ETV=0.5 mg cohort also had the shortest duration of ETV=0.5 mg therapy before switch (11.8 vs. 13.5 vs. 19.2 mo, P<0.0001). After the switch point, more patients on ETV/TDF achieved CVS compared with those on ETV=0.5 mg or ETV=1.0 mg at month 6 (77.3% vs. 13.8% vs. 9.4%), month 12 (86.4% vs. 40.5% vs. 25.0%), and month 18 (100% vs. 70.2% vs. 33.3%). Compared with the ETV=0.5 mg and ETV=1.0 mg groups, the ETV/TDF group also had higher rates of ALT normalization at month 6 (73.0% vs, 46.4% vs. 63.0%), month 12 (79.7% vs. 69.5% vs. 77.9%), and month 18 (100.0% vs. 69.5% vs. 86.8%), respectively. The multivariate analyses, inclusive of baseline age and treatment duration on initial therapy with ETV=0.5 mg, indicated that the ETV/TDF combination (HR=12.19, P<0.0001) was independently and positively associated with CVS, whereas high HBV DNA levels at baseline (HR=0.77, P=0.02) and at switch point (HR=0.46, P=0.002) were negatively associated with CVS. ETV=1.0 mg dose was not a predictor for CVS compared with ETV=0.5 mg. CONCLUSIONS: Following adjustments for HBV DNA levels and prior treatment duration, ETV/TDF combination therapy independently predicted superior viral suppression and ALT normalization in partial responders to ETV=0.5 mg daily compared with ETV=0.5 mg or ETV=1.0 mg monotherapy. In patients who continued to be viremic after 12 months of ETV=0.5 mg, one third were still viremic after another 18 months on the same therapy. Alternative therapies should be considered for these patients. PMID- 26646802 TI - The Effect of Serum Vitamin D on Serum ALT Levels in Healthy Individuals. AB - BACKGROUND: Several studies have examined the relationship between vitamin D (VD) and liver disease but none have explored this relationship in adults with normal liver enzymes. Our aim was to explore an independent association of VD with alanine aminotransferase (ALT) in a large sample of the US adults with liver enzymes in normal range (<=39 U/L). METHODS: We used the continuous National Health and Nutrition Examination Survey from 2001 to 2006. We excluded individuals with serum ALT>39 U/L. We built linear regression models to estimate unadjusted and adjusted (age, sex, race, diabetes, hypertension, alcohol use, smoking, and body mass index) effect sizes, taking into account the complex probability survey design. RESULTS: Of the 12,155 participants, 6635 (54.6%) were women, mean+/-SD age was 49.9+/-19.4 years, VD was 21.9+/-9.2 ng/mL, and ALT was 20.9+/-6.9 U/L. In unadjusted analysis, VD was significantly associated with serum ALT (0.02 U/L/ng/mL of VD, P=0.007). After adjustment for confounders, VD remained statistically significantly associated with serum ALT levels (0.04 U/L, P<0.001). Similarly, individuals in the highest quartile of VD had significantly higher serum levels of ALT than those in the lowest quartile (unadjusted difference=0.98 U/L, P<0.001; adjusted difference=1.21 U/L, P<0.001). CONCLUSIONS: We found a positive association between VD and ALT after excluding individuals with suspected active liver injury (ALT>39 U/L). The underlying mechanisms for this association are not known and needs further study. PMID- 26646803 TI - Superiority of the Split-dose PEG Regimen for Small-Bowel Capsule Endoscopy: A Randomized Controlled Trial. AB - GOALS: We aimed to evaluate the small-bowel cleansing quality, the diagnostic yield (DY), the transit time, and the patients' tolerability, by comparing the 2 different polyethylene glycol (PEG) administration schedules. BACKGROUND: The use of bowel purgatives before small-bowel capsule endoscopy (SBCE) is recommended by the ESGE guidelines. Whether this regimen can be further refined by changing the timing of administration is unknown. STUDY: Fifty-seven patients were prospectively enrolled and randomized into 2 groups: group 1 (G1, n=29) received 2 L of PEG in the day before SBCE (time between PEG and SBCE=10 h); and group 2 (G2, n=28) received 1 L of PEG in the day before SBCE and 1 L of PEG in the morning before SBCE (time between PEG and SBCE=4 h). The primary outcome measure was small-bowel cleansing quality. Small-bowel cleansing quality was evaluated according to a previously validated grading scale. RESULTS: The entire and distal half small-bowel cleansing scores were significantly higher among G2 (median score: 8 vs. 10 points, P=0.012; median score: 6 vs. 8 points, P=0.05, respectively). The DY did not differ significantly between groups. There were no significant differences in transit times between the 2 PEG regimens. Both schedules were well tolerated, showing no differences regarding symptoms while ingesting the preparation or after SBCE ingestion. CONCLUSIONS: Split-dose PEG regimen for SBCE preparation improved the small-bowel cleanliness, did not interfere with transit times and was equally well tolerated by the patients. No differences were observed regarding DY. ClinicalTrial.gov registration: NCT02396017. PMID- 26646804 TI - Accuracy of 99mTechnetium-labeled RBC Scintigraphy and MDCT With Gastrointestinal Bleed Protocol for Detection and Localization of Source of Acute Lower Gastrointestinal Bleeding. AB - BACKGROUND: Acute lower gastrointestinal bleeding (LGIB) is a major cause of morbidity and mortality. Multidetector row computed tomography (CT) with gastrointestinal (GI) bleed protocol is a novel diagnostic technique for detecting and localizing LGIB. Being rapid and noninvasive, it may be useful as a first-line modality to investigate cases of acute LGIB. GOALS: To assess and compare diagnostic accuracy of (99M)Technetium (Tc)-labeled red blood cell (RBC) scintigraphy and multidetector row CT with GI bleed protocol for detection and localization of source of acute LGIB. STUDY: Requirement of informed consent was waived for this retrospective study. Seventy-six patients had undergone either RBC scintigraphy, CT with GI bleed protocol, or both, followed by conventional angiography for evaluation of acute persistent LGIB between January 2010 and February 2014 at our institution. Accuracy of both modalities was assessed using conventional angiography as reference standard and compared using the 2-tailed, Fisher exact test. A P-value of <0.05 was considered statistically significant. RESULTS: Fifty-one, 20, and 5 patients had undergone RBC scintigraphy only, CT with GI bleed protocol only, and both modalities, respectively. Fourteen of 25 patients in the CT group had angiographic evidence of active bleeding as compared with 32 of 56 patients in the scintigraphy group. CT with GI bleed protocol had higher accuracy (96%) than (99M)Tc-labeled RBC scintigraphy (55.4%, P<0.001). CONCLUSIONS: CT with GI bleed protocol was more accurate in detecting and localizing the source of acute LGIB as compared with (99M)Tc-labeled RBC scintigraphy. PMID- 26646805 TI - Delineation of Crohn's Disease Trajectories Using Change in Lemann Index: A Natural History Study. AB - BACKGROUND: Crohn's disease (CD) causes lifelong, progressive bowel damage, which may be quantified using the Lemann Index (LI). We aimed to analyze patterns of LI and its association with 5-year clinical course, in an independent cohort of CD patients. METHODS: CD patients with 5-year follow-up from a registry maintained at a tertiary center were included. LI was calculated using a computerized metric from the first (LI1) and last (LI2) clinical encounters during the 5 years. Groups were created based on change in score (LI2-LI1) or the delta Lemann Index (DLI) as showing improvement, no change, or deterioration and used for association analysis with patterns of health care utilization, disease activity, and quality-of-life scores. RESULTS: A total of 363 CD patients with 5-year follow-up formed the study population [median age 43 y (interquartile range (IQR), 33.3 to 55 y); 57% female; median disease duration 12 y (IQR, 3 to 19 y), overall surgical exposure 69.7%]. Median (IQR) LI1, LI2, and DLI were 8 (0 to 54), 9 (0 to 75), and 0 (-22 to -47), respectively. Patients were stratified based on DLI into 3 groups: A: DLI<0; B: DLI=0; and C: DLI>0; which comprised 16.5%, 35.3%, and 48.2% of the cohort, respectively. Patients in group C had significantly higher CD-related surgical exposure, health care utilization, and annual use of steroids and biological agents. DLI showed independent significant positive correlation with perianal disease (P=0.044), steroid use (P=0.007), clinical visits (P<0.001), and new surgeries (P=0.001). CONCLUSIONS: Change in LI over time could function as a marker of disease trajectory for risk substratification and prognostication in CD. PMID- 26646806 TI - Systematic review of interventions addressing social isolation and depression in aged care clients. AB - OBJECTIVE: A systematic review was undertaken of studies reporting interventions for reducing social isolation and depression in older people receiving aged care services (community or residential). METHODS: Gray literature and relevant electronic databases were systematically searched for studies published in English between January 2009 and December 2013. Two reviewers independently screened studies for selection using predetermined inclusion and exclusion criteria and independently completed methodological quality review at study level. Studies of poor methodological quality were excluded. Data were extracted at study level by one reviewer and independently checked by a second reviewer, using a standardized form. The results across studies were qualitatively synthesized with outcomes described and summarized at last follow-up. RESULTS: Although the original objective was to review rural studies, no intervention studies based in rural areas met criteria for inclusion in the review, and only urban studies could be reviewed. Of 403 articles, six articles representing five studies with moderate-to-low risk of bias were included for review. All study participants were older adults ranging in age from 77 to 86 years. All studies had small sample sizes, ranging from 26 to 113 participants. Three of the five included intervention studies successfully reduced social isolation; one also successfully reduced depression. CONCLUSIONS: Only one intervention, group-based reminiscence therapy, was reported as successful in reducing both social isolation and depression in older people within an urban aged care setting. More research is needed to explore transferability of interventions across different aged care settings and into rural areas. PMID- 26646807 TI - On the effect of adding clinical samples to validation studies of patient reported outcome item banks: a simulation study. AB - PURPOSE: To increase the precision of estimated item parameters of item response theory models for patient-reported outcomes, general population samples are often enriched with samples of clinical respondents. Calibration studies provide little information on how this sampling scheme is incorporated into model estimation. In a small simulation study the impact of ignoring the oversampling of clinical respondents on item and person parameters is illustrated. METHOD: Simulations were performed using two scenarios. Under the first it was assumed that regular and clinical respondents form two distinct distributions; under the second it was assumed that they form a single distribution. A synthetic item bank with quasi trait characteristics was created, and item scores were generated from this bank for samples with varying percentages of clinical respondents. Proper (using a multi-group model, and sample weights, respectively, for Scenarios 1 and 2) and improper (ignoring oversampling) approaches for dealing with the clinical sample were contrasted using correlations and differences between true and estimated parameters. RESULTS: Under the first scenario, ignoring the sampling scheme resulted in overestimation of both item and person parameters with bias decreasing with higher percentages of clinical respondents. Under the second, location and person parameters were underestimated with bias increasing in size with increasing percentage of clinical respondents. Under both scenarios, the standard error of the latent trait estimate was generally underestimated. CONCLUSION: Ignoring the addition of extra clinical respondents leads to bias in item and person parameters, which may lead to biased norms and unreliable CAT scores. An appeal is made for researchers to provide more information on how clinical samples are incorporated in model estimation. PMID- 26646808 TI - Mesenchymal Stem Cell-Derived Exosomes Improve the Microenvironment of Infarcted Myocardium Contributing to Angiogenesis and Anti-Inflammation. AB - BACKGROUND/AIMS: Bone marrow mesenchymal stem cells (MSCs) widely applied for treating myocardial infarction face survival challenges in the inflammatory and ischemia microenvironment of acute myocardial infarction. The study hypothesized that MSC-derived exosomes play a significant role in improving microenvironment after acute myocardial infarction and aimed to investigate the paracrine effects of exosomes on angiogenesis and anti-inflammatory activity. METHODS: MSCs were cultured in DMEM/F12 supplemented with 10% exosome-depleted fetal bovine serum and 1% penicillin-streptomycin for 48 h. MSC-derived exosomes were isolated using ExoQuick-TC. Tube formation and T-cell proliferation assays were performed to assess the angiogenic potency of MSC-derived exosomes. Acute myocardial infarction was induced in Sprague-Dawley rats, and myocardium bordering the infarcted zone was injected at four different sites with phosphate-buffered saline (PBS, control), MSC-derived exosomes, and exosome-depleted MSC culture medium. RESULTS: MSC-derived exosomes significantly enhanced the tube formation of human umbilical vein endothelial cells, impaired T-cell function by inhibiting cell proliferation in vitro, reduced infarct size, and preserved cardiac systolic and diastolic performance compared with PBS markedly enhancing the density of new functional capillary and hence blood flow recovery in rat myocardial infarction model. CONCLUSIONS: Exosomes stimulate neovascularization and restrain the inflammation response, thus improving heart function after ischemic injury. PMID- 26646809 TI - Comparing short versus standard-length balloon for intra-aortic counterpulsation: results from a porcine model of myocardial ischaemia-reperfusion. AB - OBJECTIVES: We compare a short and a standard-size balloon with same filling volumes to verify the differences in terms of visceral flow, coronary circulation and haemodynamic performance during aortic counterpulsation in an animal model of myocardial ischaemia-reperfusion injury. METHODS: Eighteen healthy pigs underwent 120-min ligation of the left anterior descending coronary artery followed by 6 h of reperfusion, and they were randomly assigned to have intra-aortic balloon counterpulsation (IABP) with a 40-ml short-balloon (n = 6) or a 40-ml standard length balloon (n = 6), or to undergo no IABP implantation (controls, n = 6). Haemodynamics and visceral and coronary flows were measured at baseline (t0), at 2 h of ischaemia (t1) and every hour thereafter until 6 h of reperfusion (from tR1 to tR6), respectively. RESULTS: Mesenteric flows increased significantly at tR1 only in the short-balloon group (P < 0.001) and it was constantly higher than in the standard-balloon group regardless of mean arterial pressure, systemic vascular resistance and cardiac output (CO; all, P < 0.001). Renal blood flows were significantly increased during IABP treatment with values constantly and significantly higher in short balloons at any following experimental step (all, P < 0.05). IABP improved CO and coronary blood flow, and reduced afterload, myocardial resistances and myocardial oxygen consumption without differences between the short and the standard-length balloon (all, P > 0.05). CONCLUSIONS: The short balloon prevents visceral ischaemia and, compared with the standard size balloon, it does not lose IABP beneficial cardiac and coronary-related effects. Further studies are warranted to confirm our findings. PMID- 26646810 TI - Complexity in interpreting partial viral sequence data as supportive evidence for possible transfusion transmitted Parvovirus B19 infection. PMID- 26646812 TI - Oxidative cyclization of alkenoic acids promoted by AgOAc. AB - Alkenoic acids derived from salicylic acid and analogues undergo an unexpected oxidative cyclization process triggered by AgOAc leading to 4H benzo[d][1,3]dioxin-4-ones. The process is affected by the substitution on the aryl and the allyl units. PMID- 26646811 TI - A cross-sectional study for estimation of associations between education level and osteoporosis in a Chinese men sample. AB - BACKGROUND: The main aim of this study was to evaluate the association between education level and osteoporosis (OP) in general Chinese Men. METHODS: We conducted a large-scale, community-based, cross-sectional study to investigate the association by using self-report questionnaire to assess education levels. The data of 1092 men were available for analysis in this study. Multiple regression models controlling for confounding factors to include education level were performed to explore the relationship between education level and OP. RESULTS: Positive correlations between education level and T-score of quantitative bone ultrasound (QUS-T score) were reported (beta = 0.108, P value < 0.001). Multiple regression analysis indicated that the education level was independently and significantly associated with OP (P < 0.1 for all models). The men with lower education level had a higher prevalence of OP. CONCLUSION: The education level was independently and significantly associated with OP. The prevalence of OP was more frequent in Chinese men with lower education level. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02451397 ; date of registration: 05/28/2015). PMID- 26646813 TI - Development of an Intein-Inspired Amide Cleavage Chemical Device. AB - A photoresponsive amide cleavage device was developed based on the asparagine imidation-mediated cleavage of peptide bonds during intein-mediated protein splicing. The chemical environment of the protein splicing process was mimicked by the incorporation of geminal dimethyl groups and a secondary amine unit in asparagine scaffold. Furthermore, the resulting photoresponsive device could induce the phototriggered cleavage of an amide bond by the protection of the secondary amine unit with an o-nitrobenzyloxycarbonyl group. PMID- 26646814 TI - Unveiling the Hard Anodization Regime of Aluminum: Insight into Nanopores Self Organization and Growth Mechanism. AB - Pores growth mechanism and their self-ordering conditions are investigated for nanoporous alumina membranes synthesized by hard anodization (HA) of Al in a broad range of anodic conditions, covering oxalic acid electrolytes with concentrations from 0.300 M down to 0.075 M and potentiostatic anodization voltages between 120 and 225 V. The use of linear sweep voltammetry (LSV) and scanning and transmission electron microscopy, together with image analysis techniques allow one to characterize the intrinsic nature of the HA regime. HA of aluminum is explained on the basis of a phenomenological model taking into account the role of oxalate ions and their limited diffusion through alumina nanochannels from a bulk electrolyte. The depletion of oxalate ions at the bottom of the pores causes an increased growth of the alumina barrier layer at the oxide/electrolyte interface. Furthermore, an innovative method has been developed for the determination of the HA conditions leading to self-ordered pore growth in any given electrolyte, thus allowing one to extend the available range of interpore distances of the highly ordered hexagonal pore arrangement in a wide range of 240-507 nm, while keeping small pore diameters of 50-60 nm. PMID- 26646816 TI - Phenolic Compounds, Volatiles, and Sensory Characteristics of Twelve Sweet Cherry (Prunus avium L.) Cultivars Grown in Turkey. AB - The paper reports the phenolic, anthocyanin, and volatile compounds and sensory characteristics of 12 cultivars of sweet cherries including cvs. Belge, Bing, Dalbasti, Durona di Cesena, Lambert, Merton Late, Starks Gold, Summit, Sweetheart, Van, Vista, and 0-900 Ziraat. Eight individual phenolic compounds were determined by the HPLC-DAD method. Among these cherries, cvs. Bing, Durona di Cesena, and Lambert contained higher levels of total individual phenolic compounds than the other cultivars. Six anthocyanins were detected in cherries and cyanidin-3-O-rutinoside was principal and it was the highest level in cv. Bing. The major volatiles found were 1-hexanol, (E)-2-hexen-1-ol, benzylalcohol, hexenal, (E)-2-hexenal, and benzaldehyde. Sensory evaluation of the cherries showed that cvs. Belge, Bing, Dalbasti, and Summit have higher textural and flavor scores than others. It was concluded that the same compounds for phenolic or volatiles profiles of sweet cherries were similar in qualitative; however, quantitative differences were observed in these cultivars. PMID- 26646815 TI - Lupus anti-ribosomal P autoantibody proteomes express convergent biclonal signatures. AB - Lupus-specific anti-ribosomal P (anti-Rib-P) autoantibodies have been implicated in the pathogenesis of neurological complications in systemic lupus erythematosus (SLE). The aim of the present study was to determine variable (V)-region signatures of secreted autoantibody proteomes specific for the Rib-P heterocomplex and investigate the molecular basis of the reported cross reactivity with Sm autoantigen. Anti-Rib-P immunoglobulins (IgGs) were purified from six anti-Rib-P-positive sera by elution from enzyme-linked immunosorbent assay (ELISA) plates coated with either native Rib-P proteins or an 11-amino acid peptide (11-C peptide) representing the conserved COOH-terminal P epitope. Rib-P- and 11-C peptide-specific IgGs were analysed for heavy (H) and light (L) chain clonality and V-region expression using an electrophoretic and de-novo and database-driven mass spectrometric sequencing workflow. Purified anti-Rib-P and anti-SmD IgGs were tested for cross-reactivity on ELISA and their proteome data sets analysed for shared clonotypes. Anti-Rib-P autoantibody proteomes were IgG1 kappa-restricted and comprised two public clonotypes defined by unique H/L chain pairings. The major clonotypic population was specific for the common COOH terminal epitope, while the second shared the same pairing signature as a recently reported anti-SmD clonotype, accounting for two-way immunoassay cross reactivity between these lupus autoantibodies. Sequence convergence of anti-Rib-P proteomes suggests common molecular pathways of autoantibody production and identifies stereotyped clonal populations that are thought to play a pathogenic role in neuropsychiatric lupus. Shared clonotypic structures for anti-Rib-P and anti-Sm responses suggest a common B cell clonal origin for subsets of these lupus-specific autoantibodies. PMID- 26646817 TI - Relationship of Provider and Practice Volume to Performance Measure Adherence for Coronary Artery Disease, Heart Failure, and Atrial Fibrillation: Results From the National Cardiovascular Data Registry. AB - BACKGROUND: There is a reported association between high clinical volume and improved outcomes. Whether this relationship is true for outpatients with coronary artery disease (CAD), heart failure (HF), and atrial fibrillation (AF) remains unknown. METHODS AND RESULTS: Using the PINNACLE Registry (2009-2012), average monthly provider and practice volumes were calculated for CAD, HF, and AF. Adherence with 4 American Heart Association CAD, 2 HF, and 1 AF performance measure were assessed at the most recent encounter for each patient. Hierarchical logistic regression models were used to assess the relationship between provider and practice volume and performance on eligible quality measures. Data incorporated patients from 1094 providers at 71 practices (practice level analyses n=654 535; provider level analyses n=529 938). Median monthly provider volumes were 79 (interquartile range [IQR], 51-117) for CAD, 27 (16-45) for HF, and 37 (24-54) for AF. Median monthly practice volumes were 923 (IQR, 476-1455) for CAD, 311 (145-657) for HF, and 459 (185-720) for AF. Overall, 55% of patients met all CAD measures, 72% met all HF measures, and 58% met the AF measure. There was no definite relationship between practice volume and concordance for CAD, AF, or HF (P=0.56, 0.52, and 0.79, respectively). In contrast, higher provider volume was associated with increased concordance for CAD and AF performance measures (P<0.001 for both), but not for HF (P=0.36). CONCLUSIONS: In the PINNACLE registry, performance was modest and variable. Higher provider volume was positively associated with quality, whereas practice volume was not. PMID- 26646818 TI - Effects of Optimism and Gratitude on Physical Activity, Biomarkers, and Readmissions After an Acute Coronary Syndrome: The Gratitude Research in Acute Coronary Events Study. AB - BACKGROUND: Positive psychological constructs, such as optimism, are associated with beneficial health outcomes. However, no study has separately examined the effects of multiple positive psychological constructs on behavioral, biological, and clinical outcomes after an acute coronary syndrome (ACS). Accordingly, we aimed to investigate associations of baseline optimism and gratitude with subsequent physical activity, prognostic biomarkers, and cardiac rehospitalizations in post-ACS patients. METHODS AND RESULTS: Participants were enrolled during admission for ACS and underwent assessments at baseline (2 weeks post-ACS) and follow-up (6 months later). Associations between baseline positive psychological constructs and subsequent physical activity/biomarkers were analyzed using multivariable linear regression. Associations between baseline positive constructs and 6-month rehospitalizations were assessed via multivariable Cox regression. Overall, 164 participants enrolled and completed the baseline 2-week assessments. Baseline optimism was significantly associated with greater physical activity at 6 months (n=153; beta=102.5; 95% confidence interval, 13.6-191.5; P=0.024), controlling for baseline activity and sociodemographic, medical, and negative psychological covariates. Baseline optimism was also associated with lower rates of cardiac readmissions at 6 months (n=164), controlling for age, sex, and medical comorbidity (hazard ratio, 0.92; 95% confidence interval, [0.86-0.98]; P=0.006). There were no significant relationships between optimism and biomarkers. Gratitude was minimally associated with post-ACS outcomes. CONCLUSIONS: Post-ACS optimism, but not gratitude, was prospectively and independently associated with superior physical activity and fewer cardiac readmissions. Whether interventions that target optimism can successfully increase optimism or improve cardiovascular outcomes in post-ACS patients is not yet known, but can be tested in future studies. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01709669. PMID- 26646819 TI - Risk of Adverse Cardiac and Bleeding Events Following Cardiac and Noncardiac Surgery in Patients With Coronary Stent: How Important Is the Interplay Between Stent Type and Time From Stenting to Surgery? AB - BACKGROUND: Epidemiology and consequences of surgery in patients with coronary stents are not clearly defined, as well as the impact of different stent types in relationship with timing of surgery. METHODS AND RESULTS: Among 39 362 patients with previous coronary stenting enrolled in a multicenter prospective registry and followed for 5 years, 13 128 patients underwent 17 226 surgical procedures. The cumulative incidence of surgery at 30 days, 6 months, 1 year, and 5 years was 3.6%, 9.4%, 14.3%, and 40.0%, respectively, and of cardiac and noncardiac surgery was 0.8%, 2.1%, 2.6%, and 4.0% and 1.3%, 5.1%, 9.1%, and 31.7%, respectively. We assessed the incidence and the predictors of cardiac death, myocardial infarction, and serious bleeding event within 30 days from surgery. Cardiac death occurred in 438 patients (2.5%), myocardial infarction in 256 (1.5%), and serious bleeding event in 1099 (6.4%). Surgery increased 1.58* the risk of cardiac death during follow-up. Along with other risk factors, the interplay between stent type and time from percutaneous coronary intervention to surgery was independently associated with cardiac death/myocardial infarction. In comparison with bare metal stent implanted >12 months before surgery, old-generation drug-eluting stent was associated with higher risk of events at any time point. Conversely, new-generation drug-eluting stent showed similar safety as bare-metal stent >12 months and between 6 and 12 months and appeared trendly safer between 0 and 6 months. CONCLUSIONS: Surgery is frequent in patients with coronary stents and carries a considerable risk of ischemic and bleeding events. Ischemic risk is inversely related with time from percutaneous coronary intervention to surgery and is influenced by stent type. PMID- 26646820 TI - The ROOTS study: a 10-year review of findings on adolescent depression, and recommendations for future longitudinal research. AB - PURPOSE: The purpose of this study is to review longitudinal findings on adolescent mental health from the 'ROOTS study', and provide directions and recommendations for future longitudinal research. To do this, we discuss relevant findings from the ROOTS study, and review its strengths and limitations. METHODS: We examined all publications from the ROOTS study up to July 2015, selected those examining adolescent mental health, and classified them as investigating (a) childhood risk factors for adolescent depression, (b) genetic and cognitive vulnerability to depression in adolescence, (c) genetic markers, childhood adversities, and neuroendophenotypes, (d) morning cortisol and depression, (e) physical activity and depression symptoms, and (f) the underlying structure of mental health in adolescence. We reviewed the strengths and limitations of the ROOTS study, and how they feed into recommendations for future longitudinal research. RESULTS: There was evidence supporting a putative hormonal biomarker for the emergence of depression in boys. Environmental pathways from child adversity to adolescent depression were confirmed in girls, partly accounted for by negative life events in early adolescence. The preceding role of automatic cognitive biases assessed using behavioural tasks was substantiated, with evidence for genetic susceptibility. Novel latent statistical models of child adversity, depression, anxiety, and psychotic experiences were produced, with concurrent and prospective validity. Our experiences conducting the ROOTS study resulted in a set of strengths, limitations, and recommendations for future longitudinal studies. CONCLUSIONS: The ROOTS study has advanced knowledge on the aetiology of adolescent depression by investigating environmental, genetic, hormonal, and neural risk factors. Findings provide a foundation for future research integrating cognitive neuroscience with epidemiology. PMID- 26646821 TI - RNA interference targeting carbohydrate sulfotransferase 3 diminishes macrophage accumulation, inhibits MMP-9 expression and promotes lung recovery in murine pulmonary emphysema. AB - BACKGROUND: Chondroitin sulfate proteoglycans are an important mediators in inflammation and leukocyte trafficking. However, their roles in pulmonary emphysema have not been explored. In a murine model of elastase-induced pulmonary emphysema, we found increased carbohydrate sulfotransferase 3 (CHST3), a specific enzyme that synthesizes chondroitin 6-sulfate proteoglycan (C6SPG). To elucidate the role of C6SPG, we investigated the effect of small interfering RNA (siRNA) targeting CHST3 that inhibits C6SPG-synthesis on the pathogenesis of pulmonary emphysema. METHODS: Mice were intraperitoneally injected with CHST3 siRNA or negative control siRNA on day0 and 7 after intratracheal instillation of elastase. Histology, respiratory function, glycosaminoglycans (GAGs) content, bronchoalveolar lavage (BAL), elastin staining and gene expressions of tumor necrosis factor (TNF)-alpha and matrix metalloproteinase (MMP)-9 mRNA were evaluated on day7 and/or day21. RESULTS: CHST3 mRNA increased at day 7 and decreased thereafter in lung. CHST3 siRNA successfully inhibited the expression of CHST3 mRNA throughout the study and this was associated with significant reduction of GAGs and C6SPG. Airway destruction and respiratory function were improved by the treatment with CHST3 siRNA. CHST3 siRNA reduced the number of macrophages both in BAL and lung parenchyma and also suppressed the increased expressions of TNF-alpha and MMP-9 mRNA. Futhermore, CHST3 siRNA improved the reduction of the elastin in the alveolar walls. CONCLUSIONS: CHST3 siRNA diminishes accumulation of excessive macrophages and the mediators, leading to accelerate the functional recovery from airway damage by repair of the elastin network associated with pulmonary emphysema. PMID- 26646823 TI - Effect of Sardina pilchardus oil on alloxan-induced diabetic rats. AB - The purpose of this study was to prevent or to delay the onset of diabetes related complications, by using a natural marine resource, Sardina pilchardus oil, administrated to alloxan-induced diabetic rats showing hyperglycemia and hyperlipidemia. Gas chromatography-mass spectrometry analysis of the sardine oil detected 18 constituents. The major ones were n-3 highly unsaturated fatty acids among which are docosahexaenoic acid (25.09%) and eicosapentaenoic acid (19.61%). Sardine oil inhibited the alpha-amylase activity in rats' sera (26.82%) and thus improved glycemia (54%). The supplement of this oil protected the beta-cells from death and damage, significantly decreased total triglycerides, total cholesterol and LDL-cholesterol concentrations in diabetic rats' sera and increased the HDL cholesterol level. Gavage administration of this oil to rats protected the liver and kidney functions by reducing the aspartate transaminase, alanine transaminase and phosphatase alkaline activities, and by decreasing creatinine, urea and uric acid levels. PMID- 26646822 TI - Integration Analysis of Three Omics Data Using Penalized Regression Methods: An Application to Bladder Cancer. AB - Omics data integration is becoming necessary to investigate the genomic mechanisms involved in complex diseases. During the integration process, many challenges arise such as data heterogeneity, the smaller number of individuals in comparison to the number of parameters, multicollinearity, and interpretation and validation of results due to their complexity and lack of knowledge about biological processes. To overcome some of these issues, innovative statistical approaches are being developed. In this work, we propose a permutation-based method to concomitantly assess significance and correct by multiple testing with the MaxT algorithm. This was applied with penalized regression methods (LASSO and ENET) when exploring relationships between common genetic variants, DNA methylation and gene expression measured in bladder tumor samples. The overall analysis flow consisted of three steps: (1) SNPs/CpGs were selected per each gene probe within 1Mb window upstream and downstream the gene; (2) LASSO and ENET were applied to assess the association between each expression probe and the selected SNPs/CpGs in three multivariable models (SNP, CPG, and Global models, the latter integrating SNPs and CPGs); and (3) the significance of each model was assessed using the permutation-based MaxT method. We identified 48 genes whose expression levels were significantly associated with both SNPs and CPGs. Importantly, 36 (75%) of them were replicated in an independent data set (TCGA) and the performance of the proposed method was checked with a simulation study. We further support our results with a biological interpretation based on an enrichment analysis. The approach we propose allows reducing computational time and is flexible and easy to implement when analyzing several types of omics data. Our results highlight the importance of integrating omics data by applying appropriate statistical strategies to discover new insights into the complex genetic mechanisms involved in disease conditions. PMID- 26646825 TI - Teaching Theory Construction With Initial Grounded Theory Tools: A Reflection on Lessons and Learning. AB - This article addresses criticisms of qualitative research for spawning studies that lack analytic development and theoretical import. It focuses on teaching initial grounded theory tools while interviewing, coding, and writing memos for the purpose of scaling up the analytic level of students' research and advancing theory construction. Adopting these tools can improve teaching qualitative methods at all levels although doctoral education is emphasized here. What teachers cover in qualitative methods courses matters. The pedagogy presented here requires a supportive environment and relies on demonstration, collective participation, measured tasks, progressive analytic complexity, and accountability. Lessons learned from using initial grounded theory tools are exemplified in a doctoral student's coding and memo-writing excerpts that demonstrate progressive analytic development. The conclusion calls for increasing the number and depth of qualitative methods courses and for creating a cadre of expert qualitative methodologists. PMID- 26646826 TI - Science and Culture: The art of designing life. PMID- 26646828 TI - Efficacy of metacognitive therapy for prolonged grief disorder: protocol for a randomised controlled trial. AB - INTRODUCTION: Studies of effective psychotherapy for individuals suffering from the effects of prolonged grief disorder (PGD) are scarce. This paper describes the protocol for an evaluation of a metacognitive therapy programme designed specifically for PGD, to reduce the psychological distress and loss of functioning resulting from bereavement. METHODS AND ANALYSIS: The proposed trial comprises three phases. Phase 1 consists of a review of the literature and semistructured interviews with key members of the target population to inform the development of a metacognitive therapy programme for Prolonged Grief. Phase 2 involves a randomised controlled trial to implement and evaluate the programme. Male and female adults (N=34) will be randomly assigned to either a wait list or an intervention group. Measures of PGD, anxiety, depression, rumination, metacognitions and quality of life will be taken pretreatment and posttreatment and at the 3-month and 6-month follow-up. The generalised linear mixed model will be used to assess treatment efficacy. Phase 3 will test the social validity of the programme. DISCUSSION: This study is the first empirical investigation of the efficacy of a targeted metacognitive treatment programme for PGD. A focus on identifying and changing the metacognitive mechanisms underpinning the development and maintenance of prolonged grief is likely to be beneficial to theory and practice. ETHICS: Ethics approval was obtained from Curtin University Human Research Ethics Committee (Approval number HR 41/2013.) TRIAL REGISTRATION NUMBER: ACTRN12613001270707. PMID- 26646829 TI - Protocol of the adaptive study of IL-2 dose frequency on regulatory T cells in type 1 diabetes (DILfrequency): a mechanistic, non-randomised, repeat dose, open label, response-adaptive study. AB - INTRODUCTION: Type 1 diabetes (T1D) is caused by autoimmune destruction of the insulin-producing beta cells in the pancreatic islets, leading to insulinopenia and hyperglycaemia. Genetic analyses indicate that alterations of the interleukin 2 (IL-2) pathway mediating immune activation and tolerance predispose to T1D, specifically the polymorphic expression of the IL-2 receptor-alpha chain (CD25) on T lymphocytes. Replacement of physiological doses of IL-2 could restore self tolerance and prevent further autoimmunity by enhancing the function of CD4(+) T regulatory cells (Tregs) to limit the activation of auto reactive T effector cells (Teffs). In this experimental medicine study, we use an adaptive trial design to determine the optimal dosing regimen for IL-2 to improve Treg function while limiting activation of Teffs in participants with T1D. METHODS AND ANALYSIS: The Adaptive study of IL-2 dose frequency on Tregs in type 1 diabetes(DILfrequency) is a mechanistic, non-randomised, repeat dose open-label, response-adaptive study of 36 participants with T1D. The objective is to establish the optimal dose and frequency of ultra-low dose IL-2: to increase Treg frequency within the physiological range, to increase CD25 expression on Tregs, without increasing CD4(+) Teffs. DILfrequency has an initial learning phase where 12 participants are allocated to six different doses and frequencies followed by an interim statistical analysis. After analysis of the learning phase, the Dose and Frequency Committee will select the optimal targets for Treg frequency, Treg CD25 expression and Teff frequency. Three groups of eight participants will be treated consecutively in the confirming phase. Each dose and frequency selected will be based on statistical analysis of all data collected from the previous groups. ETHICS: Ethical approval for DILfrequency was granted on 12 August 2014. RESULTS: The results of this study will be reported, through peer-reviewed journals, conference presentations and an internal organisational report. TRIAL REGISTRATION NUMBERS: NCT02265809, ISRCTN40319192, CRN17571. PMID- 26646830 TI - Evaluating the effectiveness of a peer-led education intervention to improve the patient safety attitudes of junior pharmacy students: a cross-sectional study using a latent growth curve modelling approach. AB - OBJECTIVE: Despite the recognition that educating healthcare students in patient safety is essential, changing already full curricula can be challenging. Furthermore, institutions may lack the capacity and capability to deliver patient safety education, particularly from the start of professional practice studies. Using senior students as peer educators to deliver practice-based education can potentially overcome some of the contextual barriers in training junior students. Therefore, this study aimed to evaluate the effectiveness of a peer-led patient safety education programme for junior pharmacy students. DESIGN: A repeat cross sectional design utilising a previously validated patient safety attitudinal survey was used to evaluate attitudes prior to, immediately after and 1 month after the delivery of a patient safety education programme. Latent growth curve (LGC) modelling was used to evaluate the change in attitudes of first-year students using second-year students as a comparator group. SETTING: Undergraduate university students in Sydney, Australia. PARTICIPANTS: 175 first-year and 140 second-year students enrolled in the Bachelor of Pharmacy programme at the University of Sydney. INTERVENTION: An introductory patient safety programme was implemented into the first-year Bachelor of Pharmacy curriculum at the University of Sydney. The programme covered introductory patient safety topics including teamwork, communication skills, systems thinking and open disclosure. The programme consisted of 2 lectures, delivered by a senior academic, and a workshop delivered by trained final-year pharmacy students. RESULTS: A full LGC model was constructed including the intervention as a non-time-dependent predictor of change (chi(2) (51)=164.070, root mean square error of approximation=0.084, comparative fit index=0.913, standardised root mean square=0.056). First-year students' attitudes significantly improved as a result of the intervention, particularly in relation to internalising errors (p=0.010), questioning behaviours (p<0.001) and open disclosure (p=0.008). CONCLUSIONS: Peer-led education is an effective method that can be adopted to improve junior pharmacy students' attitudes towards patient safety. PMID- 26646831 TI - Subgroup identification for treatment selection in biomarker adaptive design. AB - BACKGROUND: Advances in molecular technology have shifted new drug development toward targeted therapy for treatments expected to benefit subpopulations of patients. Adaptive signature design (ASD) has been proposed to identify the most suitable target patient subgroup to enhance efficacy of treatment effect. There are two essential aspects in the development of biomarker adaptive designs: 1) an accurate classifier to identify the most appropriate treatment for patients, and 2) statistical tests to detect treatment effect in the relevant population and subpopulations. We propose utilization of classification methods to identity patient subgroups and present a statistical testing strategy to detect treatment effects. METHODS: The diagonal linear discriminant analysis (DLDA) is used to identify targeted and non-targeted subgroups. For binary endpoints, DLDA is directly applied to classify patient into two subgroups; for continuous endpoints, a two-step procedure involving model fitting and determination of a cutoff-point is used for subgroup classification. The proposed strategy includes tests for treatment effect in all patients and in a marker-positive subgroup, with a possible follow-up estimation of treatment effect in the marker-negative subgroup. The proposed method is compared to the ASD classification method using simulated datasets and two publically available cancer datasets. RESULTS: The DLDA-based classifier performs well in terms of sensitivity, specificity, positive and negative predictive values, and accuracy in the simulation data and the two cancer datasets, with superior accuracy compared to the ASD method. The subgroup testing strategy is shown to be useful in detecting treatment effect in terms of power and control of study-wise error. CONCLUSION: Accuracy of a classifier is essential for adaptive designs. A poor classifier not only assigns patients to inappropriate treatments, but also reduces the power of the test, resulting in incorrect conclusions. The proposed procedure provides an effective approach for subgroup identification and subgroup analysis. PMID- 26646832 TI - Delayed Boston Keratoprosthesis Exchange due to a Preceding Vitreoretinal Surgery with Intraoperative Choroidal Detachment. AB - PURPOSE: The aim is to describe the main characteristics of an anterior/posterior segment surgery and how to resolve intraoperative complications. Setting/Venue: The anterior and posterior segment surgical video was created at the Department of Ophthalmology, Virgin Macarena University Hospital, Seville, Spain. METHODS: We present the case of a male with Stevens-Johnson syndrome and severe limbal deficiency who needed a Boston type 1 keratoprosthesis, reaching a visual acuity of 0.4 (0.05 before surgery). In the course of follow-up, he developed corneal melting with perforation, immune vitritis, and a large epimacular membrane. We decided to perform a 23-gauge vitrectomy associated with keratoprosthesis exchange. As a consequence of inappropriate anesthesia, the patient woke up during the surgery, provoking a retinal tear besides a choroidal detachment. These damages needed endolaser photocoagulation as well as silicone oil tamponade, forcing us to postpone the exchange. An intravitreal dexamethasone implant was also injected. Two months later, the silicone oil was removed, and the Boston keratoprosthesis was replaced by a new type 1 model with a titanium back plate, which likely improves biocompatibility and retention and may reduce complications such as retroprosthetic membranes and stromal corneal melts. RESULTS: Good anatomical results were achieved, and visual acuity slightly improved to 0.2. CONCLUSIONS: Combined anterior and posterior segment surgery represents a great challenge that can improve not only visual acuity but also quality of life in patients with severe diseases such as Stevens-Johnson syndrome. PMID- 26646835 TI - Joint China-US Call for Employing a Transdisciplinary Approach to Emerging Infectious Diseases. PMID- 26646836 TI - Effects of Labeling and Group Category of Evaluators on Evaluations of Aggression. AB - This study investigated whether the effect of labeling on people's evaluation of aggression varies according to the group category of the evaluators (i.e., whether they are ingroup members or third parties). Two labeling strategies--the negative labeling of victims (NL strategy) and the positive labeling of aggressors (PL strategy)--were adopted. We conducted an experiment using the hot sauce paradigm, as a way to assess aggressive intent that includes behavioral measures of evaluations. The results suggested that the NL strategy causes ingroup members to evaluate aggression in a more positive light, while the PL strategy has the same effect but on third parties instead. Thus, labeling strategies may increase the severity of aggressors' reaction and could also be a factor that can escalate a war or conflict. PMID- 26646837 TI - Sugammadex and rocuronium-induced anaphylaxis. AB - Perioperative anaphylaxis is a life-threatening clinical condition that is typically the result of drugs or substances used for anesthesia or surgery. The most common cause of anaphylaxis during anesthesia is reportedly neuromuscular blocking agents. Of the many muscle relaxants that are clinically available, rocuronium is becoming popular in many countries. Recent studies have demonstrated that succinylcholine (but also rocuronium use) is associated with a relatively high rate of IgE-mediated anaphylaxis compared with other muscle relaxant agents. Sugammadex is widely used for reversal of the effects of steroidal neuromuscular blocking agents, such as rocuronium and vecuronium. Confirmed cases of allergic reactions to clinical doses of sugammadex have also been recently reported. Given these circumstances, the number of cases of hypersensitivity to either sugammadex or rocuronium is likely to increase. Thus, anesthesiologists should be familiar with the epidemiology, mechanisms, and clinical presentations of anaphylaxis induced by these drugs. In this review, we focus on the diagnosis and treatment of anaphylaxis to sugammadex and neuromuscular blocking agents. Moreover, we discuss recent studies in this field, including the diagnostic utility of flow cytometry and improvement of rocuronium induced anaphylaxis with the use of sugammadex. PMID- 26646838 TI - A detailed evaluation of the new acute kidney injury criteria by KDIGO in critically ill patients. AB - PURPOSE: Two previous classifications of acute kidney injury (AKI) have shown that AKI is associated with increased mortality. In 2012, Kidney Disease Improving Global Outcomes (KDIGO) created new AKI criteria by combining the two previous classifications. However, such combination might cause inconsistency among each definition in the criteria. We have investigated all the definitions in the new KDIGO criteria. METHODS: We retrospectively studied 767 adult patients whose stay in the ICU exceeded 24 h. The KDIGO criteria were applied to all patients to diagnose AKI. Hospital mortality of patients with AKI diagnosed by the ten definitions in the criteria was compared. RESULTS: AKI occurred in 51.9 % with the standard definition of KDIGO. By multivariable analysis, odds ratios were increased with AKI stage progression and AKI stage 3 was significantly associated with hospital mortality. Crude hospital mortality stratified by the ten definitions showed increasing trends with stage progression. Mortality of the three definitions in stage 1 was from 4.0 to 10.8 %. Stage 2 had two definitions and their mortality was 13.6 and 17.6 %. Stage 3 had five definitions and their mortality ranged from 27.6 to 55.6 %. CONCLUSION: AKI defined by the new KDIGO criteria was associated with increased hospital mortality. Although definitions in the KDIGO criteria seem to be appropriate because of the clear relationship between mortality and stage progression on the whole, several limitations may exist, especially in stage 3. Further research should be needed to clarify the validity of the KDIGO criteria and the detailed categories. PMID- 26646839 TI - Great East Japan earthquake: anesthetists in Minamisoma. PMID- 26646840 TI - Understanding self-management behaviors in symptomatic adults with uncertain etiology using an illness perceptions framework. AB - The self-management behaviors of individuals with medical conditions that have an unknown etiology have not been studied. This study assesses the relationship between illness perceptions and various illness self-management behaviors in patients undergoing clinical genomic sequencing to identify a genetic cause for their condition. Hierarchical linear regression, Poisson linear regression, and logistic regression were used to assess the effect of illness perceptions (i.e., perceived consequences, timeline, personal control, treatment control, identity, concern, understanding, emotional impact, and causal beliefs as measured by the Brief Illness Perceptions Questionnaire) on healthcare use, prescription medication use, and doctor recommended supplement use, respectively (n = 200). Analyses revealed that (1) illness identity beliefs were positively associated with healthcare use (beta = 0.20, p = 0.04), (2) both treatment control beliefs (B = 0.03, p = 0.02) and genetic causal beliefs (B = 0.17, p = 0.049) were positively associated with prescription medication use, and (3) both timeline beliefs (OR 1.23, p = 0.02) and emotional impact (OR 1.20, p = 0.02) were positively associated with doctor recommended supplement use. These findings can be used to inform the development of guidelines for treating patients who are seeking a genetic diagnosis for their illness. PMID- 26646844 TI - Development and initial evaluation of a point-of-care educational app on medical topics in orthogeriatrics. AB - INTRODUCTION: Research by AOTrauma's orthogeriatrics education taskforce identified ongoing educational needs for surgeons and trainees worldwide regarding the medical management of older adults with a fracture. To address practicing surgeons' preference for increased use of mobile learning, a point-of care educational app was planned by a committee of experienced faculty. The goals were to deliver the app to surgeons, trainees, and other healthcare professionals, to measure usage, and to evaluate the impact on patient care. MATERIALS AND METHODS: The committee of geriatricians and surgeons designed and developed four modules on osteoporosis, delirium, anticoagulation, and pain based on published evidence and the content was programmed into mobile app formats. A registration form was integrated and a 14-question online evaluation survey was administered to users. RESULTS: The AOTrauma Orthogeriatrics app was installed by 17,839 users worldwide between September 2014 and October 2015: Android smartphones (44%), iPhones (32%), iPads (15%), Android tablets (9%). 920 users registered and 100 completed the online evaluation: orthopedic/trauma surgeons (67%), residents/fellows (20%), and other professionals (13%). Ratings for all aspects were 4 or higher on a 1-5 Likert scale (5 = Excellent). 80% of evaluation respondents found the answer to their question or educational need on their last visit, and 26 of 55 respondents (47%) reported making a change in an aspect of their management of patients as a result of their learning from the app. CONCLUSION: The orthogeriatrics app reached its intended audiences and was rated highly as a method of providing education to help improve patient care. Content input by experienced faculty and app improvements based on user feedback were key contributors to successful implementation. PMID- 26646845 TI - Plate augmentation for femoral nonunion: more than just a salvage tool? AB - OBJECTIVE: The aim of the current study was to determine whether plate augmentation was a successful treatment algorithm for selected femoral nonunions initially managed with intramedullary nailing. MATERIALS AND METHODS: A total of 30 femoral nonunion cases were managed using the plate augmentation strategy with 13 primary cases and 17 multi-operated femurs (avg 2.8 ineffective procedures). Adjunctive strategies included autologous bone grafting and/or BMP for atrophic/oligotrophic and bone defect cases. Deformity correction was performed when required. RESULTS: Osseous union occurred in 29 of 30 cases. One multi operated case with bone defect and prior infection required repeat autologous grafting prior to union. CONCLUSION: Plate augmentation should be added to the armamentarium for management of selected femoral nonunion that have failed initial intramedullary nailing. PMID- 26646846 TI - Validation of the German Forgotten Joint Score (G-FJS) according to the COSMIN checklist: does a reduction in joint awareness indicate clinical improvement after arthroplasty of the knee? AB - PURPOSE: Evaluation of further improvement in treatment of patients with osteoarthritis of the knee requires measurement tools with a high discriminatory power. In this context, joint awareness in everyday life is seen as crucial criterion. Purpose of this study was to adapt and validate a German version of the "Forgotten Joint Score" (FJS) according to the COSMIN checklist. METHODS: We evaluated a German translation of the FJS for reliability, validity and responsiveness according to the COSMIN checklist. Therefore, patients with an artificial knee joint completed the G-FJS questionnaire twice at intervals of at least 2 weeks. In addition, the Knee Society Score, the Oxford Knee Score, the Tegner Activity Scale, a Visual Analogue Scale, the EuroQol-5D (EQ 5-D), and a subjective assessment of the limitations were recorded. RESULTS: Between June and December 2014, one hundred and five patients (average age 65.2 years) completed both questionnaires and were available for data analysis. Test-retest reliability of the FJS was high with an ICC = 0.80 (95 % CI 0.69, 0.90) and with a Cronbach's alpha of 0.95 (95 % CI 0.92, 0.99). CONCLUSIONS: The German translation of the FJS is a viable tool for the postoperative monitoring after arthroplasty of the knee. This is the first study providing data on test-retest reliability of the FJS. The FJS is a reliable and valid measurement tool for evaluation of patient rated outcome in patients with an artificial knee joint. LEVEL OF EVIDENCE: Validating cohort study, Level 1b. PMID- 26646841 TI - Dental follicle mesenchymal stem cell administration ameliorates muscle weakness in MuSK-immunized mice. AB - BACKGROUND: Myasthenia gravis (MG) is an antibody-mediated autoimmune disease of the neuromuscular junction (NMJ), mostly associated with acetylcholine receptor (AChR) antibodies. Around 5-10 % of MG patients show antibodies to muscle specific tyrosine kinase (MuSK). Mesenchymal stem cell (MSC) administration has been shown to ameliorate muscle weakness in the experimental autoimmune myasthenia gravis (EAMG) model induced by AChR immunization. METHODS: To investigate the efficacy of stem cell treatment in MuSK-related EAMG, clinical and immunological features of MuSK-immunized mice with or without dental follicle MSC (DFMSC) treatment were compared. RESULTS: MuSK-immunized mice intravenously treated with DFMSC after second and third immunizations showed significantly lower EAMG incidence and severity and reduced serum anti-MuSK antibody, NMJ IgG, and C3 deposit levels and CD11b+ lymph node cell ratios. Moreover, lymph node cells of DFMSC-administered mice showed reduced proliferation and IL-6 and IL-12 production responses to MuSK stimulation. By contrast, proportions of B and T cell populations and production of a wide variety of cytokines were not affected from DFMSC treatment. CONCLUSIONS: Our results suggest that DFMSC treatment shows its beneficial effects mostly through suppression of innate immune system, whereas other immune functions appear to be preserved. Stem cell treatment might thus constitute a specific and effective treatment method in MuSK-associated MG. PMID- 26646847 TI - Comparison of retrograde nailing and minimally invasive plating for treatment of periprosthetic supracondylar femur fractures (OTA 33-A) above total knee arthroplasty. AB - INTRODUCTION: Retrograde intramedullary (IM) nailing and minimally invasive plate osteosynthesis (MIPO) using locking plate are typically considered the gold standards of treatment for periprosthetic supracondylar femoral fractures above total knee arthroplasty (TKA). METHODS: Forty-one consecutive patients treated with either retrograde nailing (nail group, n = 20) or minimally invasive plating (plate group, n = 21) for periprosthetic supracondylar femoral fractures between March 2003 and January 2014 were retrospectively reviewed. Clinical functions [arc range of motion and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score] and bony outcomes (bony union and malunion) were evaluated. RESULTS: There was no statistical difference between the nail and plate groups in age (p = 0.665), one-year postoperative arc range of motion (p = 0.642), preoperative WOMAC score (p = 0.076), postoperative one-year WOMAC score (p = 0.135), and union time (p = 0.081). The mean union time of the nail group and the plate group was 4.3 months (range 3-12 months) and 3.6 months (range 3-5 months), respectively. There were three cases of malalignment in the nail group, whereas there was one case of malalignment in the plate group (p = 0.343). One case of nailing using a short nail demonstrated nail breakage. CONCLUSIONS: Although retrograde nailing was found to have a slightly higher rate of malunion compared to minimally invasive plating, there was no statistically significant difference between both treatment options in terms of clinical outcomes. Regardless of which implant is used, the proper application is essential in management of periprosthetic supracondylar femoral fractures above TKA. PMID- 26646848 TI - Treatment strategies for partial chronic instability of the distal syndesmosis: an arthroscopic grading scale and operative staging concept. AB - INTRODUCTION: The aim of this study was to evaluate three different anatomical reconstruction techniques for the partial chronic isolated instability of the syndesmosis based on own arthroscopic classification criteria. MATERIALS AND METHODS: A retrospective study was conducted to review 32 patients (15 female, 17 male; average age 41; range 18-71) with isolated partial chronic instability of the syndesmosis. During the arthroscopic examination of the patient, the instability of the syndesmosis was assessed by inserting a dissector of defined size into the distal tibiofibular joint. The lateralization of the fibula in the distal tibiofibular joint was then semi-quantitatively evaluated and classified. In all cases, open reconstructive surgery was carried out at the same time. Depending on the grading of the instability assessed arthroscopically (Grades I III), one of three different anatomical reconstruction techniques was performed: suture of the anterior inferior tibiofibular ligament (AITFL), ligament repair using periosteal flaps, or autogenous plantaris tendon graft. Patients in all three groups were treated with a screw and an additional preassembled suture button device. At 8 weeks after surgery, the screw was removed and full weight bearing was allowed. Clinical and radiological follow up were obtained at an average time of 17 months after surgery. Clinical evaluation of the reconstruction techniques was assessed using the American Orthopaedic Foot and Ankle Score (AOFAS) and the Weber Score. RESULTS: The median AOFAS score was significantly higher than before surgery for all three groups. In addition, the Weber score was significantly lower in all three groups than before surgery, indicating substantial improvement. There were no complications after the arthroscopies and the reconstructive surgeries. But in two cases, suture granuloma occurred within the 17-month window, which was treated with a revision operation and removal of the suture-button device. CONCLUSION: Depending on the arthroscopic classification of the partial chronic instability of the syndesmosis, the three different anatomical reconstruction techniques potentially provide appropriate treatment options based on the grade of injury. PMID- 26646849 TI - Low intratumoral regulatory T cells and high peritumoral CD8(+) T cells relate to long-term survival in patients with pancreatic ductal adenocarcinoma after pancreatectomy. AB - The prognosis for pancreatic ductal adenocarcinoma (PDAC) remains extremely poor. Recent studies have focused on the role of lymphocytes in the PDAC microenvironment. Using immunohistochemistry, our study explored the clinical significance of intratumoral or peritumoral CD4(+)Foxp3(+) regulatory T cells (Tregs) and CD8(+) T cells in the tumor microenvironment and analyzed their relation to the prognosis of PDAC in a consecutive series of 92 patients after resection. CD8(+) T cells were more frequently seen within peritumoral sites, while CD4(+)Foxp3(+) Tregs were more frequent within intratumoral areas. Neither exhibited any relationship with other clinicopathologic factors. Patients with low levels of intratumoral Tregs had longer disease-free survival than those with higher levels (DFS 22.2 vs. 11.2 months, p < 0.001), and patients with higher levels of peritumoral CD8(+) T cells had longer overall survival than those with lower levels (OS 31.0 vs. 14.2 months, p < 0.001). Multivariate analysis demonstrated that intratumoral Tregs (hazard ratio, HR 3.39, p = 0.010) and peritumoral CD8(+) T cells (HR 0.10, p < 0.001) are related to DFS and OS, respectively. These results indicate that intratumoral Tregs are a negative predictor of DFS, while peritumoral CD8(+) T cells are a positive predictor of OS for PDAC patients with pancreatectomy. PMID- 26646850 TI - Phloretin increases the anti-tumor efficacy of intratumorally delivered heat shock protein 70 kDa (HSP70) in a murine model of melanoma. AB - Recombinant HSP70 chaperone exerts a profound anticancer effect when administered intratumorally. This action is based on the ability of HSP70 to penetrate tumor cells and extract its endogenous homolog. To enhance the efficacy of HSP70 cycling, we employed phloretin, a flavonoid that enhances the pore-forming activity of the chaperone on artificial membranes. Phloretin increased the efficacy of HSP70 penetration in B16 mouse melanoma cells and K-562 human erythroblasts; this was accompanied with increased transport of the endogenous HSP70 to the plasma membrane. Importantly, treatment with HSP70 combined with phloretin led to the elevation of cell sensitivity to cytotoxic lymphocytes by 16 18 % compared to treatment with the chaperone alone. The incubation of K-562 cells with biotinylated HSP70 and phloretin increased the amount of the chaperone released from cells, suggesting that chaperone cycling could trigger a specific anti-tumor response. We studied the effect of the combination of HSP70 and phloretin using B16 melanoma and a novel method of HSP70-gel application. We found that the addition of phloretin to the gel reduced tumor weight almost fivefold compared with untreated mice, while the life span of the animals extended from 25 to 39 days. The increased survival was corroborated by the activation of innate and adaptive immunity; interestingly, HSP70 was more active in induction of CD8+ cell-mediated toxicity and gammaIFN production while phloretin contributed largely to the CD56+ cell response. In conclusion, the combination of HSP70 with phloretin could be a novel treatment for efficient immunotherapy of intractable cancers such as skin melanoma. PMID- 26646851 TI - Cholesterol metabolites and tumor microenvironment: the road towards clinical translation. AB - Targeting the tumor microenvironment focusing on immune cells has recently become a standard of care for some tumors. Indeed, antibodies blocking immune checkpoints (e.g., anti-CTLA-4 and anti-PD1 mAbs) have been approved by regulatory agencies for the treatment of some solid tumors based upon successes in many clinical trials. Although tumor metabolism has always attracted the attention of tumor biologists, only recently have oncologists renewed their interest in this field of tumor biology research. This has highlighted the possibility to pharmacologically target rate-limiting enzymes along key metabolic pathways of tumor cells, such as lipogenesis and aerobic glycolysis. Altered tumor metabolism has also been shown to influence the functionality of the tumor microenvironment as a whole, particularly the immune cell component of thereof. Cholesterol, oxysterols and Liver X receptors (LXRs) have been investigated in different tumor models. Recent in vitro and in vivo results point to their involvement in tumor and immune cell biology, thus making the LXR/oxysterol axis a possible target for novel antitumor strategies. Indeed, the possibility to target both tumor cell metabolism (i.e., cholesterol metabolism) and tumor infiltrating immune cell dysfunctions induced by oxysterols might result in a synergistic antitumor effect generating long-lasting memory responses. This review will focus on the role of cholesterol metabolism with particular emphasis on the role of the LXR/oxysterol axis in the tumor microenvironment, discussing mechanisms of action, pros and cons, and strategies to develop antitumor therapies based on the modulation of this axis. PMID- 26646852 TI - Improving cancer immunotherapy with DNA methyltransferase inhibitors. AB - Immunotherapy confers durable clinical benefit to melanoma, lung, and kidney cancer patients. Challengingly, most other solid tumors, including ovarian carcinoma, are not particularly responsive to immunotherapy, so combination with a complementary therapy may be beneficial. Recent findings suggest that epigenetic modifying drugs can prime antitumor immunity by increasing expression of tumor-associated antigens, chemokines, and activating ligands by cancer cells as well as cytokines by immune cells. This review, drawing from both preclinical and clinical data, describes some of the mechanisms of action that enable DNA methyltransferase inhibitors to facilitate the establishment of antitumor immunity. PMID- 26646853 TI - Dissulfurimicrobium hydrothermale gen. nov., sp. nov., a thermophilic, autotrophic, sulfur-disproportionating deltaproteobacterium isolated from a hydrothermal pond. AB - A thermophilic, anaerobic, chemolithoautotrophic bacterium (strain Sh68T) was isolated from a hydrothermal pond at Uzon Caldera, Kamchatka, Russia, using anoxic medium with elemental sulfur as the only energy source. Cells of strain Sh68T were Gram-stain-negative rods, 0.5-0.8 MUm in diameter and 1.2-2.0 MUm in length, motile by means of flagella. The temperature range for growth was 30-65 degrees C, with an optimum at 50-52 degrees C. The pH range for growth was 5.2 7.5, with optimum growth at pH 6.0-6.2. Growth of strain Sh68T was observed at NaCl concentrations ranging from 0 to 2.3 % (w/v). Strain Sh68T grew anaerobically with elemental sulfur as an energy source and bicarbonate/CO2 as a carbon source. Elemental sulfur was disproportionated to sulfide and sulfate. Growth was enhanced in the presence of poorly crystalline Fe(III) oxide (ferrihydrite) as a sulfide-scavenging agent. Strain Sh68T was also able to grow by disproportionation of thiosulfate and sulfite. Sulfate was not used as an electron acceptor either with H2 or with organic electron donors. Analysis of the 16S rRNA gene sequence revealed that the isolate belongs to the class Deltaproteobacteria and is related most closely to Dissulfuribacter thermophilus S69T (90.0 % similarity). On the basis of its physiological properties and results of phylogenetic analyses, strain Sh68T is considered to represent a novel species of a new genus, for which the name Dissulfurimicrobium hydrothermale gen. nov., sp. nov. is proposed. The type strain of Dissulfurimicrobium hydrothermale is Sh68T ( = JCM 19990T = VKM B-2854T). This is the first description of a sulfur disproportionating thermophile from a terrestrial ecosystem. PMID- 26646854 TI - A randomised controlled trial of a code-word enuresis alarm. AB - OBJECTIVE: To compare a novel code-word alarm with a commercially available wireless alarm for treating enuresis. SETTING: A tertiary paediatric centre. PATIENTS: Children aged 6-18 with at least 3 wet nights per week in the previous 6 months referred by doctors. OUTCOMES: Primary outcome: the proportion who achieved a full response (14 consecutive dry nights) by 16 weeks. Secondary outcomes: change in frequency of wetting, duration of alarm training, percentage of wet nights that the child woke to the alarm, adherence to treatment, adverse events and satisfaction with treatment. RESULTS: Of the 353 participants, 176 were assigned to the code-word alarm and 177 to control. At 16 weeks, 54% (95% CI 47% to 61%) in the experimental group and 47% (95% CI 40% to 55%) in the control group had achieved a full response (p=0.22), with 74% and 66%, respectively, attaining a 50% or more reduction in wetting frequency (p=0.14). The experimental group woke more often than the control group (median percentage of waking 88% vs 77%, p=0.003) and had a greater reduction in wet nights (median reduction of 10 vs 9 nights per fortnight). Fewer in the experimental group discontinued therapy before achieving a full response (27% vs 37% discontinued, p=0.04). There were no significant differences in relapse rates at 6 months, adverse events or satisfaction between the two alarms. CONCLUSIONS: Although the code-word alarm increased waking, no difference in full response rates was demonstrated between the two alarms. TRIAL REGISTRATION NUMBER: ACTRN12609000070235. PMID- 26646855 TI - Do the media demonstrate correct inhaler technique in children? PMID- 26646857 TI - Investigating haptic distance-to-break using linear and nonlinear materials in a simulated minimally invasive surgery task. AB - Accurate detection of mediated haptic information in minimally invasive surgery (MIS) is critical for applying appropriate force magnitudes onto soft tissue with the aim of minimising tissue trauma. Force perception in MIS is a dynamic process, with surgeons' administration of force into tissue revealing information about the remote surgical site which further informs the surgeons' haptic interactions. The relationship between applied force and material deformation rate provides biomechanical information specifying the deformation distance remaining until a tissue will fail: which is termed distance-to-break (DTB). The current study demonstrates that observers can detect DTB while deforming simulated tissues and stop before reaching the tissues' failure points. The design of training simulators, control devices and automated robotic systems for applications outside of MIS is discussed. Practitioner Summary: In MIS, haptic information is critical for applying appropriate forces onto soft tissue to minimise tissue trauma. Observers used force information to detect how far they could deform a virtual tissue before it would break. The design of training simulators, control devices and automated robotic systems is discussed. PMID- 26646858 TI - IMPROVING THE EFFECTIVENESS AND EFFICIENCY OF EVIDENCE PRODUCTION FOR HEALTH TECHNOLOGY ASSESSMENT. AB - OBJECTIVES: Health Technology Assessment (HTA) needs to address the challenges posed by high cost, effective technologies, expedited regulatory approaches, and the opportunities provided by collaborative real-world evaluation of technologies. The Health Technology Assessment International (HTAi) Policy Forum met to consider these issues and the implications for evidence production to inform HTA. This paper shares their discussion to stimulate further debate. METHODS: A background paper, presentations, group discussions, and stakeholder role play at the 2015 HTAi Policy Forum meeting informed this paper. RESULTS: HTA has an important role to play in helping improve evidence production and ensuring that the health service is ready to adopt effective technologies. It needs to move from simply informing health system decisions to also working actively to align stakeholder expectations about realistic evidence requirements. Processes to support dialogue over the health technology life cycle need to be developed that are mindful of limited resources, operate across jurisdictions and learn from past processes. Collaborations between health technology developers and health systems in different countries should be encouraged to develop evidence that will inform decision making. New analytical techniques emerging for real world data should be harnessed to support modeling for HTA. CONCLUSIONS: A paradigm shift (to "Health Innovation System 2.0") is suggested where HTA adopts a more central, proactive role to support alignment within and amongst stakeholders over the whole life cycle of the technology. This could help ensure that evidence production is better aligned with patient and health system needs and so is more effective and efficient. PMID- 26646856 TI - Crystal Structure of the Pre-fusion Nipah Virus Fusion Glycoprotein Reveals a Novel Hexamer-of-Trimers Assembly. AB - Nipah virus (NiV) is a paramyxovirus that infects host cells through the coordinated efforts of two envelope glycoproteins. The G glycoprotein attaches to cell receptors, triggering the fusion (F) glycoprotein to execute membrane fusion. Here we report the first crystal structure of the pre-fusion form of the NiV-F glycoprotein ectodomain. Interestingly this structure also revealed a hexamer-of-trimers encircling a central axis. Electron tomography of Nipah virus like particles supported the hexameric pre-fusion model, and biochemical analyses supported the hexamer-of-trimers F assembly in solution. Importantly, structure assisted site-directed mutagenesis of the interfaces between F trimers highlighted the functional relevance of the hexameric assembly. Shown here, in both cell-cell fusion and virus-cell fusion systems, our results suggested that this hexamer-of-trimers assembly was important during fusion pore formation. We propose that this assembly would stabilize the pre-fusion F conformation prior to cell attachment and facilitate the coordinated transition to a post-fusion conformation of all six F trimers upon triggering of a single trimer. Together, our data reveal a novel and functional pre-fusion architecture of a paramyxoviral fusion glycoprotein. PMID- 26646859 TI - MONITORING REGISTRIES AT ITALIAN MEDICINES AGENCY: FOSTERING ACCESS, GUARANTEEING SUSTAINABILITY. AB - OBJECTIVES: The AIFA (Agenzia Italiana del Farmaco--Italian Medicines Agency) Monitoring Registries track the eligibility of patients and the complete flow of treatments, guaranteeing appropriateness in use of pharmaceutical products, according to approved indications. METHODS: This study describes the Italian pharmaceutical context and the aims and functioning of AIFA Monitoring Registries, focusing on the applications to the Managed Entry Agreements (MEAs) and HTA approaches. RESULTS: The AIFA Monitoring Registries System has been operational in Italy since 2005. In 2012, the system became part of the NHS Information Technology system, aiming at enhancing appropriate use of pharmaceuticals and efficiency of the administrative activity. Currently, seventy six medicines are monitored through the system, corresponding to fifty-eight therapeutic indications; individual treatments recorded are more than 515,000, for a population of approximately 505,000 patients. For each monitored product, patients eligible for treatment are registered in the specific therapeutic indication dynamic monitoring database to collect epidemiologic and clinical data, including data on the safety profile, and ex-post information missing at first evaluation stage. CONCLUSIONS: AIFA Monitoring Registries allow the evaluation of the pharmaceuticals' performance in clinical practice and may promote innovation and quicker access to medicines at affordable prices, for the benefit of patients. PMID- 26646860 TI - TOWARD A SHIFTING HEALTH TECHNOLOGY ASSESSMENT PARADIGM: REACTIONS TO POLICY FORUM DISCUSSIONS. AB - Are we in a period of significant change? Is health technology assessment (HTA) undergoing a fundamental transformation? Or should it be? Are we in the middle of a paradigm shift? These are some of the questions the paper by Facey et al in this journal (1) raises about the future of HTA, based on discussions at the HTAi Policy Forum in February 2015. To further share the deliberations of the Forum and with a view to opening this debate among the wider HTA community, a panel within the HTAi 2015 Annual Meeting in Oslo was organized. Presentations at the panel included a summary of the HTAi Policy Forum deliberations and perspectives from a patient, a clinician, and representatives of an HTA organization, industry, and a health system. This letter presents issues and thoughts raised in the panel session. PMID- 26646861 TI - Communication: Memory effects and active Brownian diffusion. AB - A self-propelled artificial microswimmer is often modeled as a ballistic Brownian particle moving with constant speed aligned along one of its axis, but changing direction due to random collisions with the environment. Similarly to thermal noise, its angular randomization is described as a memoryless stochastic process. Here, we speculate that finite-time correlations in the orientational dynamics can affect the swimmer's diffusivity. To this purpose, we propose and solve two alternative models. In the first one, we simply assume that the environmental fluctuations governing the swimmer's propulsion are exponentially correlated in time, whereas in the second one, we account for possible damped fluctuations of the propulsion velocity around the swimmer's axis. The corresponding swimmer's diffusion constants are predicted to get, respectively, enhanced or suppressed upon increasing the model memory time. Possible consequences of this effect on the interpretation of the experimental data are discussed. PMID- 26646862 TI - Communication: Investigation of the electron momentum density distribution of nanodiamonds by electron energy-loss spectroscopy. AB - The electron momentum distribution of detonation nanodiamonds (DND) was investigated by recording electron energy-loss spectra at large momentum transfer in the transmission electron microscope (TEM), which is known as electron Compton scattering from solid (ECOSS). Compton profile of diamond film obtained by ECOSS was found in good agreement with prior photon experimental measurement and theoretical calculation that for bulk diamond. Compared to the diamond film, the valence Compton profile of DND was found to be narrower, which indicates a more delocalization of the ground-state charge density for the latter. Combining with other TEM characterizations such as high-resolution transmission electron spectroscopy, diffraction, and energy dispersive X-ray spectroscopy measurements, ECOSS was shown to be a great potential technique to study ground-state electronic properties of nanomaterials. PMID- 26646863 TI - Robust validation of approximate 1-matrix functionals with few-electron harmonium atoms. AB - A simple comparison between the exact and approximate correlation components U of the electron-electron repulsion energy of several states of few-electron harmonium atoms with varying confinement strengths provides a stringent validation tool for 1-matrix functionals. The robustness of this tool is clearly demonstrated in a survey of 14 known functionals, which reveals their substandard performance within different electron correlation regimes. Unlike spot-testing that employs dissociation curves of diatomic molecules or more extensive benchmarking against experimental atomization energies of molecules comprising some standard set, the present approach not only uncovers the flaws and patent failures of the functionals but, even more importantly, also allows for pinpointing their root causes. Since the approximate values of U are computed at exact 1-densities, the testing requires minimal programming and thus is particularly suitable for rapid screening of new functionals. PMID- 26646864 TI - Combining molecular dynamics with mesoscopic Green's function reaction dynamics simulations. AB - In many reaction-diffusion processes, ranging from biochemical networks, catalysis, to complex self-assembly, the spatial distribution of the reactants and the stochastic character of their interactions are crucial for the macroscopic behavior. The recently developed mesoscopic Green's Function Reaction Dynamics (GFRD) method enables efficient simulation at the particle level provided the microscopic dynamics can be integrated out. Yet, many processes exhibit non-trivial microscopic dynamics that can qualitatively change the macroscopic behavior, calling for an atomistic, microscopic description. We propose a novel approach that combines GFRD for simulating the system at the mesoscopic scale where particles are far apart, with a microscopic technique such as Langevin dynamics or Molecular Dynamics (MD), for simulating the system at the microscopic scale where reactants are in close proximity. This scheme defines the regions where the particles are close together and simulated with high microscopic resolution and those where they are far apart and simulated with lower mesoscopic resolution, adaptively on the fly. The new multi-scale scheme, called MD-GFRD, is generic and can be used to efficiently simulate reaction diffusion systems at the particle level. PMID- 26646865 TI - Assessing the accuracy of some popular DFT methods for computing harmonic vibrational frequencies of water clusters. AB - A wide range of density functional theory (DFT) methods (37 altogether), including pure, hybrid, range-separated hybrid, double-hybrid, and dispersion corrected functionals, have been employed to compute the harmonic vibrational frequencies of eight small water clusters ranging in size from the dimer to four different isomers of the hexamer. These computed harmonic frequencies have been carefully compared to recently published benchmark values that are expected to be very close to the CCSD(T) complete basis set limit. Of the DFT methods examined here, omegaB97 and omegaB97X are the most consistently accurate, deviating from the reference values by less than 20 cm(-1) on average and never more than 60 cm( 1). The performance of double-hybrid methods including B2PLYP and mPW2-PLYP is only slightly better than more economical approaches, such as the M06-L pure functional and the M06-2X hybrid functional. Additionally, dispersion corrections offer very little improvement in computed frequencies. PMID- 26646866 TI - Modeling molecule-plasmon interactions using quantized radiation fields within time-dependent electronic structure theory. AB - We present a combined cavity quantum electrodynamics/ab initio electronic structure approach for simulating plasmon-molecule interactions in the time domain. The simple Jaynes-Cummings-type model Hamiltonian typically utilized in such simulations is replaced with one in which the molecular component of the coupled system is treated in a fully ab initio way, resulting in a computationally efficient description of general plasmon-molecule interactions. Mutual polarization effects are easily incorporated within a standard ground state Hartree-Fock computation, and time-dependent simulations carry the same formal computational scaling as real-time time-dependent Hartree-Fock theory. As a proof of principle, we apply this generalized method to the emergence of a Fano like resonance in coupled molecule-plasmon systems; this feature is quite sensitive to the nanoparticle-molecule separation and the orientation of the molecule relative to the polarization of the external electric field. PMID- 26646867 TI - Model reduction for stochastic chemical systems with abundant species. AB - Biochemical processes typically involve many chemical species, some in abundance and some in low molecule numbers. We first identify the rate constant limits under which the concentrations of a given set of species will tend to infinity (the abundant species) while the concentrations of all other species remains constant (the non-abundant species). Subsequently, we prove that, in this limit, the fluctuations in the molecule numbers of non-abundant species are accurately described by a hybrid stochastic description consisting of a chemical master equation coupled to deterministic rate equations. This is a reduced description when compared to the conventional chemical master equation which describes the fluctuations in both abundant and non-abundant species. We show that the reduced master equation can be solved exactly for a number of biochemical networks involving gene expression and enzyme catalysis, whose conventional chemical master equation description is analytically impenetrable. We use the linear noise approximation to obtain approximate expressions for the difference between the variance of fluctuations in the non-abundant species as predicted by the hybrid approach and by the conventional chemical master equation. Furthermore, we show that surprisingly, irrespective of any separation in the mean molecule numbers of various species, the conventional and hybrid master equations exactly agree for a class of chemical systems. PMID- 26646869 TI - A study of potential energy curves from the model space quantum Monte Carlo method. AB - We report on the first application of the model space quantum Monte Carlo (MSQMC) to potential energy curves (PECs) for the excited states of C2, N2, and O2 to validate the applicability of the method. A parallel MSQMC code is implemented with the initiator approximation to enable efficient sampling. The PECs of MSQMC for various excited and ionized states are compared with those from the Rydberg Klein-Rees and full configuration interaction methods. The results indicate the usefulness of MSQMC for precise PECs in a wide range obviating problems concerning quasi-degeneracy. PMID- 26646868 TI - Path statistics, memory, and coarse-graining of continuous-time random walks on networks. AB - Continuous-time random walks (CTRWs) on discrete state spaces, ranging from regular lattices to complex networks, are ubiquitous across physics, chemistry, and biology. Models with coarse-grained states (for example, those employed in studies of molecular kinetics) or spatial disorder can give rise to memory and non-exponential distributions of waiting times and first-passage statistics. However, existing methods for analyzing CTRWs on complex energy landscapes do not address these effects. Here we use statistical mechanics of the nonequilibrium path ensemble to characterize first-passage CTRWs on networks with arbitrary connectivity, energy landscape, and waiting time distributions. Our approach can be applied to calculating higher moments (beyond the mean) of path length, time, and action, as well as statistics of any conservative or non-conservative force along a path. For homogeneous networks, we derive exact relations between length and time moments, quantifying the validity of approximating a continuous-time process with its discrete-time projection. For more general models, we obtain recursion relations, reminiscent of transfer matrix and exact enumeration techniques, to efficiently calculate path statistics numerically. We have implemented our algorithm in PathMAN (Path Matrix Algorithm for Networks), a Python script that users can apply to their model of choice. We demonstrate the algorithm on a few representative examples which underscore the importance of non exponential distributions, memory, and coarse-graining in CTRWs. PMID- 26646870 TI - A multi-dimensional Smolyak collocation method in curvilinear coordinates for computing vibrational spectra. AB - In this paper, we improve the collocation method for computing vibrational spectra that was presented in Avila and Carrington, Jr. [J. Chem. Phys. 139, 134114 (2013)]. Using an iterative eigensolver, energy levels and wavefunctions are determined from values of the potential on a Smolyak grid. The kinetic energy matrix-vector product is evaluated by transforming a vector labelled with (nondirect product) grid indices to a vector labelled by (nondirect product) basis indices. Both the transformation and application of the kinetic energy operator (KEO) scale favorably. Collocation facilitates dealing with complicated KEOs because it obviates the need to calculate integrals of coordinate dependent coefficients of differential operators. The ideas are tested by computing energy levels of HONO using a KEO in bond coordinates. PMID- 26646871 TI - Spin-1 Dirac-Weyl fermions protected by bipartite symmetry. AB - We propose that bipartite symmetry allows spin-1 Dirac-Weyl points, a generalization of the spin-1/2 Dirac points in graphene, to appear as topologically protected at the Fermi level. In this spirit, we provide methodology to construct spin-1 Dirac-Weyl points of this kind in a given 2D space group and get the classification of the known spin-1 systems in the literature. We also apply the workflow to predict two new systems, P3m1-9 and P31m-15, to possess spin-1 at K/K' in the Brillouin zone of hexagonal lattice. Their stability under various strains is investigated and compared with that of T3, an extensively studied model of ultracold atoms trapped in optical lattice with spin-1 also at K/K'. PMID- 26646872 TI - Core-core and core-valence correlation energy atomic and molecular benchmarks for Li through Ar. AB - We have established benchmark core-core, core-valence, and valence-valence absolute coupled-cluster single double (triple) correlation energies (+/-0.1%) for 210 species covering the first- and second-rows of the periodic table. These species provide 194 energy differences (+/-0.03 mEh) including ionization potentials, electron affinities, and total atomization energies. These results can be used for calibration of less expensive methodologies for practical routine determination of core-core and core-valence correlation energies. PMID- 26646873 TI - A density functional for core-valence correlation energy. AB - A density functional, epsilonCV-DFT(rhoc, rhov), describing the core-valence correlation energy has been constructed as a linear combination of epsilonLY P (corr)(rhoc), epsilonV WN5 (corr)(rhoc, rhov), epsilonPBE (corr)(rhoc, rhov), epsilonSlater (ex)(rhoc, rhov), epsilonHCTH (ex)(rhoc, rhov), epsilonHF (ex)(rhoc, rhov), and FCV-DFTNi,Zi, a function of the nuclear charges. This functional, with 6 adjustable parameters, reproduces (+/-0.27 kcal/mol rms error) a benchmark set of 194 chemical energy changes including 9 electron affinities, 18 ionization potentials, and 167 total atomization energies covering the first- and second-rows of the periodic table. This is almost twice the rms error (+/ 0.16 kcal/mol) obtained with CCSD(T)/MTsmall calculations, but less than half the rms error (+/-0.65 kcal/mol) obtained with MP2/GTlargeXP calculations, and somewhat smaller than the rms error (+/-0.39 kcal/mol) obtained with CCSD/MTsmall calculations. The largest positive and negative errors from epsilonCV-DFT(rhoc, rhov) were 0.88 and -0.75 kcal/mol with the set of 194 core-valence energy changes ranging from +3.76 kcal/mol for the total atomization energy of propyne to -9.05 kcal/mol for the double ionization of Mg. Evaluation of the epsilonCV DFT(rhoc, rhov) functional requires less time than a single SCF iteration, and the accuracy is adequate for any model chemistry based on the CCSD(T) level of theory. PMID- 26646874 TI - Onsets of hierarchy truncation and self-consistent Born approximation with quantum mechanics prescriptions invariance. AB - The issue of efficient hierarchy truncation is related to many approximate theories. In this paper, we revisit this issue from both the numerical efficiency and quantum mechanics prescription invariance aspects. The latter requires that the truncation approximation made in Schrodinger picture, such as the quantum master equations and their self-consistent-Born-approximation improvements, should be transferable to their Heisenberg-picture correspondences, without further approximations. We address this issue with the dissipaton equation of motion (DEOM), which is a unique theory for the dynamics of not only reduced systems but also hybrid bath environments. We also highlight the DEOM theory is not only about how its dynamical variables evolve in time, but also the underlying dissipaton algebra. We demonstrate this unique feature of DEOM with model systems and report some intriguing nonlinear Fano interferences characteristics that are experimentally measurable. PMID- 26646875 TI - Water dynamics on ice and hydrate lattices studied by second-order central-line stimulated-echo oxygen-17 nuclear magnetic resonance. AB - Oxygen-17 stimulated-echo spectroscopy is a novel nuclear magnetic resonance (NMR) technique that allows one to investigate the time scale and geometry of ultraslow molecular motions in materials containing oxygen. The method is based on detecting orientationally encoded frequency changes within oxygen's central transition NMR line that are caused by second-order quadrupolar interactions. In addition to the latter, the present theoretical analysis of various two-pulse echo and stimulated-echo pulse sequences takes also heteronuclear dipolar interactions into account. As an experimental example, the ultraslow water motion in polycrystals of tetrahydrofuran clathrate hydrate is studied via two-time oxygen-17 stimulated-echo correlation functions. The resulting correlation times and those of hexagonal ice are similar to those from previous deuteron NMR measurements. Calculations of the echo functions' final-state correlations for various motional models are compared with the experimental data of the clathrate hydrate. It is found that a six-site model including the oxygen-proton dipolar interaction describes the present results. PMID- 26646876 TI - Ion-Stockmayer clusters: Minima, classical thermodynamics, and variational ground state estimates of Li(+)(CH3NO2)n (n = 1-20). AB - Structural optimizations, classical NVT ensemble, and variational Monte Carlo simulations of ion Stockmayer clusters parameterized to approximate the Li(+)(CH3NO2)n (n = 1-20) systems are performed. The Metropolis algorithm enhanced by the parallel tempering strategy is used to measure internal energies and heat capacities, and a parallel version of the genetic algorithm is employed to obtain the most important minima. The first solvation sheath is octahedral and this feature remains the dominant theme in the structure of clusters with n >= 6. The first "magic number" is identified using the adiabatic solvent dissociation energy, and it marks the completion of the second solvation layer for the lithium ion-nitromethane clusters. It corresponds to the n = 18 system, a solvated ion with the first sheath having octahedral symmetry, weakly bound to an eight membered and a four-membered ring crowning a vertex of the octahedron. Variational Monte Carlo estimates of the adiabatic solvent dissociation energy reveal that quantum effects further enhance the stability of the n = 18 system relative to its neighbors. PMID- 26646877 TI - Electron transport in molecular junctions with graphene as protecting layer. AB - We present ab initio transport calculations for molecular junctions that include graphene as a protecting layer between a single molecule and gold electrodes. This vertical setup has recently gained significant interest in experiment for the design of particularly stable and reproducible devices. We observe that the signals from the molecule in the electronic transmission are overlayed by the signatures of the graphene sheet, thus raising the need for a reinterpretation of the transmission. On the other hand, we see that our results are stable with respect to various defects in the graphene. For weakly physiosorbed molecules, no signs of interaction with the graphene are evident, so the transport properties are determined by offresonant tunnelling between the gold leads across an extended structure that includes the molecule itself and the additional graphene layer. Compared with pure gold electrodes, calculated conductances are about one order of magnitude lower due to the increased tunnelling distance. Relative differences upon changing the end group and the length of the molecule on the other hand, are similar. PMID- 26646878 TI - Influence of a magnetic field on the viscosity of a dilute gas consisting of linear molecules. AB - The viscomagnetic effect for two linear molecules, N2 and CO2, has been calculated in the dilute-gas limit directly from the most accurate ab initio intermolecular potential energy surfaces presently available. The calculations were performed by means of the classical trajectory method in the temperature range from 70 K to 3000 K for N2 and 100 K to 2000 K for CO2, and agreement with the available experimental data is exceptionally good. Above room temperature, where no experimental data are available, the calculations provide the first quantitative information on the magnitude and the behavior of the viscomagnetic effect for these gases. In the presence of a magnetic field, the viscosities of nitrogen and carbon dioxide decrease by at most 0.3% and 0.7%, respectively. The results demonstrate that the viscomagnetic effect is dominated by the contribution of the jj- polarization at all temperatures, which shows that the alignment of the rotational axes of the molecules in the presence of a magnetic field is primarily responsible for the viscomagnetic effect. PMID- 26646879 TI - Permutationally invariant fitting of intermolecular potential energy surfaces: A case study of the Ne-C2H2 system. AB - The permutation invariant polynomial-neural network (PIP-NN) approach is extended to fit intermolecular potential energy surfaces (PESs). Specifically, three PESs were constructed for the Ne-C2H2 system. PES1 is a full nine-dimensional PIP-NN PES directly fitted to ~42 000 ab initio points calculated at the level of CCSD(T)-F12a/cc-pCVTZ-F12, while the other two consist of the six-dimensional PES for C2H2 [H. Han, A. Li, and H. Guo, J. Chem. Phys. 141, 244312 (2014)] and an intermolecular PES represented in either the PIP (PES2) or PIP-NN (PES3) form. The comparison of fitting errors and their distributions, one-dimensional cuts and two-dimensional contour plots of the PESs, as well as classical trajectory collisional energy transfer dynamics calculations shows that the three PESs are very similar. We conclude that full-dimensional PESs for non-covalent interacting molecular systems can be constructed efficiently and accurately by the PIP-NN approach for both the constituent molecules and intermolecular parts. PMID- 26646880 TI - Quantum control of isomerization by robust navigation in the energy spectrum. AB - In this paper, we present a detailed study on the application of the quantum control technique of navigation in the energy spectrum to chemical isomerization processes, namely, CN-Li? Li-CN. This technique is based on the controlled time variation of a Hamiltonian parameter, an external uniform electric field in our case. The main result of our work establishes that the navigation involved in the method is robust, in the sense that quite sizable deviations from a pre established control parameter time profile can be introduced and still get good final results. This is specially relevant thinking of a experimental implementation of the method. PMID- 26646881 TI - Efficient yet accurate approximations for ab initio calculations of alcohol cluster thermochemistry. AB - We have calculated the binding enthalpies and entropies of gas phase alcohol clusters from ethanol to 1-decanol. In addition to the monomers, we have investigated dimers, tetramers, and pentamers. Geometries have been obtained at the B3LYP/TZVP level and single point energy calculations have been performed with the Resolution of the Identity-MP2 (RIMP2) method and basis set limit extrapolation using aug-cc-pVTZ and aug-cc-pVQZ basis sets. Thermochemistry is calculated with decoupled hindered rotor treatment for large amplitude motions. The results show three points: First, it is more accurate to transfer the rigid rotor harmonic oscillator entropies from propanol to longer alcohols than to compute them with an ultra-fine grid and tight geometry convergence criteria. Second, the computational effort can be reduced considerably by using dimerization energies of longer alcohols at density functional theory (B3LYP) level plus a RIMP2 correction obtained from 1-propanol. This approximation yields results almost with the same accuracy as RIMP2 - both methods differ for 1 decanol only 0.4 kJ/mol. Third, the entropy of dimerization including the hindered rotation contribution is converged at 1-propanol with respect to chain length. This allows for a transfer of hindered rotation contributions from smaller alcohols to longer ones which reduces the required computational and man power considerably. PMID- 26646882 TI - Thermodynamic and kinetic anisotropies in octane thin films. AB - Confinement breaks the translational symmetry of materials, making all thermodynamic and kinetic quantities functions of position. Such symmetry breaking can be used to obtain configurations that are not otherwise accessible in the bulk. Here, we use computer simulations to explore the effect of substrate liquid interactions on thermodynamic and kinetic anisotropies induced by a solid substrate. We consider n-octane nano-films that are in contact with substrates with varying degrees of attraction, parameterized by an interaction parameter epsilonS. Complete freezing of octane nano-films is observed at low temperatures, irrespective of epsilonS, while at intermediate temperatures, a frozen monolayer emerges at solid-liquid and vapor-liquid interfaces. By carefully inspecting the profiles of translational and orientational relaxation times, we confirm that the translational and orientational degrees of freedom are decoupled at these frozen monolayers. At sufficiently high temperatures, however, free interfaces and solid liquid interfaces close to loose (low-epsilonS) substrates undergo "pre freezing," characterized by mild peaks in several thermodynamic quantities. Two distinct dynamic regimes are observed at solid-liquid interfaces. The dynamics is accelerated in the vicinity of loose substrates, while sticky (high-epsilonS) substrates decelerate dynamics, sometimes by as much as two orders of magnitude. These two distinct dynamical regimes have been previously reported by Haji-Akbari and Debenedetti [J. Chem. Phys. 141, 024506 (2014)] for a model atomic glass forming liquid. We also confirm the existence of two correlations-proposed in the above-mentioned work-in solid-liquid subsurface regions of octane thin films, i.e., a correlation between atomic density and normal stress, and between atomic translational relaxation time and lateral stress. Finally, we inspect the ability of different regions of an octane film to explore the potential energy landscape by performing inherent structure calculations, and observe no noticeable difference between the free surface and the bulk in efficiently exploring the potential energy landscape. This is unlike the films of model atomic glass formers that tend to sample their respective landscape more efficiently at free surfaces. We discuss the implications of this finding to the ability of octane and other n-alkanes-to form ultrastable glasses. PMID- 26646883 TI - Forster resonant energy transfer from an inorganic quantum well to a molecular material: Unexplored aspects, losses, and implications to applications. AB - A systematic investigation of Forster resonant energy transfer (FRET) is reported within a hybrid prototype structure based on nitride single quantum well (SQW) donors and light emitting polymer acceptors. Self-consistent Schrodinger-Poisson modeling and steady-state and time-resolved photoluminescence experiments were initially employed to investigate the influence of a wide structural parameter space on the emission quantum yield of the nitride component. The optimized SQW heterostructures were processed into hybrid structures with spin-casted overlayers of polyfluorenes. The influence of important unexplored aspects of the inorganic heterostructure such as SQW confinement, content, and doping on the dipole-dipole coupling was probed. Competing mechanisms to the FRET process associated with interfacial recombination and charge transfer have been studied and their implications to device applications exploiting FRET across heterointerfaces have been discussed. PMID- 26646884 TI - Surface phonon dispersion on hydrogen-terminated Si(110)-(1 * 1) surfaces studied by first-principles calculations. AB - We studied the lattice constants, surface-phonon dispersion curves, spectral densities, and displacement vectors of the hydrogen-terminated Si(110)-(1 * 1) [H:Si(110)-(1 * 1)] surface using the first-principles calculations within the framework of density functional theory (DFT). The symmetry of the H:Si(110)-(1 * 1) surface belongs to the two-dimensional space group p2mg, which has two highly symmetric and orthogonal directions, GammaX- and GammaX(')-, with the glide planes along the GammaX- direction. Because glide symmetry separates the even and odd surface phonon modes, we mapped the even surface modes in the first surface Brillouin zone (SBZ) and the odd surface modes in the second SBZ using the spectral densities and displacement vectors. The surface phonon modes were analyzed with respect to their physical origin, spatial localization properties, polarization, and the charge density of their electronic states. Our calculated surface phonon modes were in good agreement with recent high-resolution electron energy-loss spectroscopy data in the first and second SBZs of the GammaX- direction. In the SBZ of the GammaX(')- direction, our calculated surface phonon modes agree well with the data in the energy region below 65 meV but are not satisfactorily compatible with those in the stretching and bending modes. In addition, we discuss the microscopic nature of the surface phonon dispersion of the H:Si(110)-(1 * 1) surface using the phonon eigen modes. PMID- 26646885 TI - Kinetics of the glass transition of fragile soft colloidal suspensions. AB - Microscopic relaxation time scales are estimated from the autocorrelation functions obtained by dynamic light scattering experiments for Laponite suspensions with different concentrations (CL), added salt concentrations (CS), and temperatures (T). It has been shown in an earlier work [D. Saha, Y. M. Joshi, and R. Bandyopadhyay, Soft Matter 10, 3292 (2014)] that the evolutions of relaxation time scales of colloidal glasses can be compared with molecular glass formers by mapping the waiting time (tw) of the former with the inverse of thermodynamic temperature (1/T) of the latter. In this work, the fragility parameter D, which signifies the deviation from Arrhenius behavior, is obtained from fits to the time evolutions of the structural relaxation time scales. For the Laponite suspensions studied in this work, D is seen to be independent of CL and CS but is weakly dependent on T. Interestingly, the behavior of D corroborates the behavior of fragility in molecular glass formers with respect to equivalent variables. Furthermore, the stretching exponent beta, which quantifies the width w of the spectrum of structural relaxation time scales, is seen to depend on tw. A hypothetical Kauzmann time tk, analogous to the Kauzmann temperature for molecular glasses, is defined as the time scale at which w diverges. Corresponding to the Vogel temperature defined for molecular glasses, a hypothetical Vogel time talpha (infinity) is also defined as the time at which the structural relaxation time diverges. Interestingly, a correlation is observed between tk and talpha (infinity), which is remarkably similar to that known for fragile molecular glass formers. A coupling model that accounts for the tw dependence of the stretching exponent is used to analyse and explain the observed correlation between tk and talpha (infinity). PMID- 26646886 TI - Landscape of kinetically trapped binary assemblies. AB - For two-component assemblies, an inherent structure diagram (ISD) is the relationship between set inter-subunit energies and the types of kinetic traps (inherent structures) one may obtain from those energies. It has recently been shown that two-component ISDs are apportioned into regions or plateaux within which inherent structures display uniform features (e.g., stoichometries and morphologies). Interestingly, structures from one of the plateaux were also found to be robust outcomes of one type of non-equilibrium growth, which indicates the usefulness of the two-component ISD in predicting outcomes of some types of far from-equilibrium growth. However, little is known as to how the ISD is apportioned into distinct plateaux. Also, while each plateau displays classes of structures that are morphologically distinct, little is known about the source of these distinct morphologies. This article outlines an analytic treatment of the two-component ISD and shows that the manner in which any ISD is apportioned arises from a single unitless order parameter. Additionally, the analytical framework allows for the characterization of local properties of the trapped structures within each ISD plateau. This work may prove to be useful in the design of novel classes of robust nonequilibrium assemblies. PMID- 26646887 TI - Deterministic aggregation kinetics of superparamagnetic colloidal particles. AB - We study the irreversible aggregation kinetics of superparamagnetic colloidal particles in two dimensions in the presence of an in-plane magnetic field at low packing fractions. Optical microscopy and image analysis techniques are used to follow the aggregation process and in particular study the packing fraction and field dependence of the mean cluster size. We compare these to the theoretically predicted scalings for diffusion limited and deterministic aggregation. It is shown that the aggregation kinetics for our experimental system is consistent with a deterministic mechanism, which thus shows that the contribution of diffusion is negligible. PMID- 26646888 TI - Dependence of aggregation behavior on concentration in triblock copolymer solutions: The effect of chain architecture. AB - Using the self-consistent field lattice technique, the effects of concentration and hydrophobic middle block length (where the chain length remains constant) on aggregation behavior are studied in amphiphilic symmetric triblock copolymer solutions. The heat capacity peak for the unimer-micelle transition and the distribution peaks for the different degrees of aggregation for micelles and small aggregates (submicelles) are calculated. Analysis of the conducted computer simulations shows that the transition broadness dependence on concentration is determined by the hydrophobic middle block length, and this dependence is distinctly different when the length of the hydrophobic middle block changes. Different size for small aggregates simultaneously appear in the transition region. As temperature decreases, the number of different size small aggregates for the large hydrophobic middle block length first ascends and then descends in aggregation degree order. These results indicate that any transition broadness change with concentration is related to the mechanism of fragmentation and fusion. These results are helpful for interpreting the aggregation process of amphiphilic copolymers at equilibrium. PMID- 26646889 TI - Complete-active-space second-order perturbation theory (CASPT2//CASSCF) study of the dissociative electron attachment in canonical DNA nucleobases caused by low energy electrons (0-3 eV). AB - Low-energy (0-3 eV) ballistic electrons originated during the irradiation of biological material can interact with DNA/RNA nucleobases yielding transient anion species which undergo decompositions. Since the discovery that these reactions can eventually lead to strand breaking of the DNA chains, great efforts have been dedicated to their study. The main fragmentation at the 0-3 eV energy range is the ejection of a hydrogen atom from the specific nitrogen positions. In the present study, the methodological approach introduced in a previous work on uracil [I. Gonzalez-Ramirez et al., J. Chem. Theory Comput. 8, 2769-2776 (2012)] is employed to study the DNA canonical nucleobases fragmentations of N-H bonds induced by low-energy electrons. The approach is based on minimum energy path and linear interpolation of internal coordinates computations along the N-H dissociation channels carried out at the complete-active-space self-consistent field//complete-active-space second-order perturbation theory level. On the basis of the calculated theoretical quantities, new assignations for the adenine and cytosine anion yield curves are provided. In addition, the pi1 (-) and pi2 (-) states of the pyrimidine nucleobases are expected to produce the temporary anions at electron energies close to 1 and 2 eV, respectively. Finally, the present theoretical results do not allow to discard neither the dipole-bound nor the valence-bound mechanisms in the range of energies explored, suggesting that both possibilities may coexist in the experiments carried out with the isolated nucleobases. PMID- 26646890 TI - Effective reaction rates for diffusion-limited reaction cycles. AB - Biological signals in cells are transmitted with the use of reaction cycles, such as the phosphorylation-dephosphorylation cycle, in which substrate is modified by antagonistic enzymes. An appreciable share of such reactions takes place in crowded environments of two-dimensional structures, such as plasma membrane or intracellular membranes, and is expected to be diffusion-controlled. In this work, starting from the microscopic bimolecular reaction rate constants and using estimates of the mean first-passage time for an enzyme-substrate encounter, we derive diffusion-dependent effective macroscopic reaction rate coefficients (EMRRC) for a generic reaction cycle. Each EMRRC was found to be half of the harmonic average of the microscopic rate constant (phosphorylation c or dephosphorylation d), and the effective (crowding-dependent) motility divided by a slowly decreasing logarithmic function of the sum of the enzyme concentrations. This implies that when c and d differ, the two EMRRCs scale differently with the motility, rendering the steady-state fraction of phosphorylated substrate molecules diffusion-dependent. Analytical predictions are verified using kinetic Monte Carlo simulations on the two-dimensional triangular lattice at the single molecule resolution. It is demonstrated that the proposed formulas estimate the steady-state concentrations and effective reaction rates for different sets of microscopic reaction rates and concentrations of reactants, including a non trivial example where with increasing diffusivity the fraction of phosphorylated substrate molecules changes from 10% to 90%. PMID- 26646891 TI - Comment on "Communication: Tolman length and rigidity constants of water and their role in nucleation" [J. Chem. Phys. 142, 171103 (2015)]. PMID- 26646893 TI - Erratum: "Pairwise-additive force fields for selected aqueous monovalent ions from adaptive force matching" [J. Chem. Phys. 143, 194505 (2015)]. PMID- 26646894 TI - Ungulate copiparvovirus 1 (bovine parvovirus 2): characterization of a new genotype and associated viremia in different bovine age groups. AB - A novel bovine parvovirus 2 (BPV2) genotype comprising 5394 nt was identified by next generation sequencing from sera of healthy cattle at different age groups farmed in the state of Rio Grande do Sul, Brazil. The genome organization of new BPV2 genotype retains the two ORFs typical of members of the Parvovirinae with 86.4 % of overall nucleotide sequence identities in comparison to other members of the subfamily. Phylogenetic analysis revealed similar clustering with two previously described bovine BPV2 within the genus Copiparvovirus. No significant differences (P >= 0.05) were detected in the distribution of BPV2 infection in cattle at different age groups. This is the third complete or near complete genome sequence of BPV2 reported to date and may contribute to a better understanding of the biology of copiparvoviruses and its interactions with the host. PMID- 26646895 TI - Controlling and predicting droplet size of nanoemulsions: scaling relations with experimental validation. AB - Nanoemulsions possess powerful nano-scale properties that make them attractive for diverse applications such as drug delivery, food supplements, nanoparticle synthesis and pharmaceutical formulation. However, there is little knowledge in nanoemulsion literature about controlling and predicting droplet size. In this article, we propose a scaling relation to predict the dependence of nanoemulsion droplet size with physical properties such as viscosity of the droplet phase and continuous phase, and process parameters such as input power density. We validate our proposed scaling with a wide range of droplet size data from nanoemulsions prepared with high pressure homogenization and ultrasonication. Our proposed scaling also compares favorably with experimental data from literature. The scaling relation can serve as a guiding principle for rational design of nanoemulsions. PMID- 26646896 TI - The Link between Knowledge, Attitudes and Practices in Relation to Atmospheric Haze Pollution in Peninsular Malaysia. AB - Transboundary haze episodes caused by seasonal forest fires have become a recurrent phenomenon in Southeast Asia, with serious environmental, economic, and public health implications. Here we present a cross-sectional survey conducted among people in Kuala Lumpur and surrounds to assess the links between knowledge, attitudes, and practices in relation to the transboundary haze episodes. Of 305 respondents, 125 were amateur athletes participating in a duathlon event and the remainder were surveyed in an inner-city shopping mall. Across the whole sample, people who possessed more factual information about the haze phenomenon showed significantly higher levels of concern. Duathletes were more knowledgeable than non-duathletes and also more concerned about the negative effects of haze, especially on health. For all people who regularly practice outdoor sports (including people interviewed at the shopping mall), higher levels of knowledge and concerned attitudes translated into a greater likelihood of engaging in protective practices, such as cancelling their outdoor training sessions, while those with greater knowledge were more likely to check the relevant air pollution index on a daily basis. Our results indicate that the provision of accurate and timely information about air quality to residents will translate into beneficial practices, at least among particularly exposed individuals, such as amateur athletes who regularly practice outdoor sports. PMID- 26646897 TI - Protein-protein interactions in plant mitogen-activated protein kinase cascades. AB - Mitogen-activated protein kinases (MAPKs) form tightly controlled signaling cascades that play essential roles in plant growth, development, and defense. However, the molecular mechanisms underlying MAPK cascades are still elusive, due largely to our poor understanding of how they relay the signals. Extensive effort has been devoted to characterization of MAPK-substrate interactions to illustrate phosphorylation-based signaling. The diverse MAPK substrates identified also shed light on how spatiotemporal-specific protein-protein interactions function in distinct MAPK cascade-mediated biological processes. This review surveys various technologies used for characterizing MAPK-substrate interactions and presents case studies of MPK4 and MPK6, highlighting the multiple functions of MAPKs. Mass spectrometry-based approaches in identifying MAPK-interacting proteins are emphasized due to their increasing utility and effectiveness. The potential for using MAPKs and their substrates in enhancing plant stress tolerance is also discussed. PMID- 26646898 TI - Crocetin Activates Foxp3 Through TIPE2 in Asthma-Associated Treg Cells. AB - BACKGROUND/AIMS: Regulatory T cells (Treg) are critical regulators of asthma. Crocetin is isolated from Chinese herb saffron and is a natural carotenoid dicarboxylic acid with anti-inflammatory potential. However, the effects of Crocetin on asthma as well as the underlying mechanisms have not been studied. METHODS: We used Crocetin to treat mice with established ovalbumin (OVA)-induced asthma. We purified CD4+CD25+ Treg cells by flow cytometry and analyzed the levels of two immunoregulatory proteins Foxp3 and tumor necrosis factor (TNF) alpha-induced protein 8-like 2 (TIPE2) in Treg cells. We depleted either Foxp3 or TIPE2 in mouse lung through lentivirus-mediated delivery of shRNA, and analyzed their effects on severity of asthma and Treg cells after Crocetin treatment. RESULTS: Crocetin treatment significantly reduced the severity of an ovalbumin (OVA)-induced asthma in mice. Moreover, Crocetin significantly increased the levels of TIPE2 and Foxp3 in Treg cells and the number of Treg cells. Depletion of Foxp3 abolished the increased in Treg cells, and the effects of Crocetin on the severity of asthma, without affecting TIPE2 levels in Treg cells. On the other hand, depletion of TIPE2 abolished both the increased in Treg cells and the effects of Crocetin on the severity of asthma, through suppressing Foxp3. CONCLUSION: Crocetin may activate Foxp3 through TIPE2 in asthma-associated Treg cells to mitigate the severity of asthma. PMID- 26646899 TI - Genome-wide methylation analysis identifies differentially methylated CpG loci associated with severe obesity in childhood. AB - Childhood obesity is a major public health issue. Here we investigated whether differential DNA methylation was associated with childhood obesity. We studied DNA methylation profiles in whole blood from 78 obese children (mean BMI Z-score: 2.6) and 71 age- and sex-matched controls (mean BMI Z-score: 0.1). DNA samples from obese and control groups were pooled and analyzed using the Infinium HumanMethylation450 BeadChip array. Comparison of the methylation profiles between obese and control subjects revealed 129 differentially methylated CpG (DMCpG) loci associated with 80 unique genes that had a greater than 10% difference in methylation (P-value < 0.05). The top pathways enriched among the DMCpGs included developmental processes, immune system regulation, regulation of cell signaling, and small GTPase-mediated signal transduction. The associations between the methylation of selected DMCpGs with childhood obesity were validated using sodium bisulfite pyrosequencing across loci within the FYN, PIWIL4, and TAOK3 genes in individual subjects. Three CpG loci within FYN were hypermethylated in obese individuals (all P < 0.01), while obesity was associated with lower methylation of CpG loci within PIWIL4 (P = 0.003) and TAOK3 (P = 0.001). After building logistic regression models, we determined that a 1% increase in methylation in TAOK3, multiplicatively decreased the odds of being obese by 0.91 (95% CI: 0.86 - 0.97), and an increase of 1% methylation in FYN CpG3, multiplicatively increased the odds of being obese by 1.03 (95% CI: 0.99 - 1.07). In conclusion, these findings provide evidence that childhood obesity is associated with specific DNA methylation changes in whole blood, which may have utility as biomarkers of obesity risk. PMID- 26646900 TI - High-resolution mapping of H4K16 and H3K23 acetylation reveals conserved and unique distribution patterns in Arabidopsis and rice. AB - Histone acetylation and deacetylation are key epigenetic gene regulatory mechanisms that play critical roles in eukaryotes. Acetylation of histone 4 lysine 16 (H4K16ac) is implicated in many cellular processes. However, its biological function and relationship with transcription are largely unexplored in plants. We generated first genome-wide high-resolution maps of H4K16ac in Arabidopsis thaliana and Oryza sativa. We showed that H4K16ac is preferentially enriched around the transcription start sites and positively correlates with gene expression levels. Co-existence of H4K16ac and H3K23ac is correlated with high gene expression levels, suggesting a potentially combinatorial effect of H4K16ac and H3K23ac histone 3 lysine 23 acetylation on gene expression. Our data further revealed that while genes enriched with both H4K16ac and H3K23ac are ubiquitously expressed, genes enriched with only H4K16ac or H3K23ac showed significantly distinct expression patterns in association with particular developmental stages. Unexpectedly, and unlike in Arabidopsis, there are significant levels of both H4K16ac and H3K23ac in the lowly expressed genes in rice. Furthermore, we found that H4K16ac-enriched genes are associated with different biological processes in Arabidopsis and rice, suggesting a potentially species-specific role of H4K16ac in plants. Together, our genome-wide profiling reveals the conserved and unique distribution patterns of H4K16ac and H3K23ac in Arabidopsis and rice and provides a foundation for further understanding their function in plants. PMID- 26646901 TI - In utero arsenic exposure and epigenome-wide associations in placenta, umbilical artery, and human umbilical vein endothelial cells. AB - Exposure to arsenic early in life has been associated with increased risk of several chronic diseases and is believed to alter epigenetic programming in utero. In the present study, we evaluate the epigenome-wide association of arsenic exposure in utero and DNA methylation in placenta (n = 37), umbilical artery (n = 45) and human umbilical vein endothelial cells (HUVEC) (n = 52) in a birth cohort using the Infinium HumanMethylation450 BeadChip array. Unadjusted and cell mixture adjusted associations for each tissue were examined along with enrichment analyses relative to CpG island location and omnibus permutation tests of association among biological pathways. One CpG in artery (cg26587014) and 4 CpGs in placenta (cg12825509; cg20554753; cg23439277; cg21055948) reached a Bonferroni adjusted level of significance. Several CpGs were differentially methylated in artery and placenta when controlling the false discovery rate (q value<0.05), but none in HUVEC. Enrichment of hypomethylated CpG islands was observed for artery while hypermethylation of open sea regions were present in placenta relative to prenatal arsenic exposure. The melanogenesis pathway was differentially methylated in artery (Max F P < 0.001), placenta (Max F P < 0.001), and HUVEC (Max F P = 0.02). Similarly, the insulin-signaling pathway was differentially methylated in artery (Max F P = 0.02), placenta (Max F P = 0.02), and HUVEC (Max F P = 0.02). Our results show that prenatal arsenic exposure can alter DNA methylation in artery and placenta but not in HUVEC. Further studies are needed to determine if these alterations in DNA methylation mediate the effect of prenatal arsenic exposure and health outcomes later in life. PMID- 26646902 TI - The impact of genetic variation and cigarette smoke on DNA methylation in current and former smokers from the COPDGene study. AB - DNA methylation can be affected by systemic exposures, such as cigarette smoking and genetic sequence variation; however, the relative impact of each on the epigenome is unknown. We aimed to assess if cigarette smoking and genetic variation are associated with overlapping or distinct sets of DNA methylation marks and pathways. We selected 85 Caucasian current and former smokers with genome-wide single nucleotide polymorphism (SNP) genotyping available from the COPDGene study. Genome-wide methylation was obtained on DNA from whole blood using the Illumina HumanMethylation27 platform. To determine the impact of local sequence variation on DNA methylation (mQTL), we examined the association between methylation and SNPs within 50 kb of each CpG site. To examine the impact of cigarette smoking on DNA methylation, we examined the differences in methylation by current cigarette smoking status. We detected 770 CpG sites annotated to 708 genes associated at an FDR < 0.05 in the cis-mQTL analysis and 1,287 CpG sites annotated to 1,242 genes, which were nominally associated in the smoking-CpG association analysis (P(unadjusted) < 0.05). Forty-three CpG sites annotated to 40 genes were associated with both SNP variation and current smoking; this overlap was not greater than that expected by chance. Our results suggest that cigarette smoking and genetic variants impact distinct sets of DNA methylation marks, the further elucidation of which may partially explain the variable susceptibility to the health effects of cigarette smoking. Ascertaining how genetic variation and systemic exposures differentially impact the human epigenome has relevance for both biomarker identification and therapeutic target development for smoking-related diseases. PMID- 26646903 TI - A lincRNA connected to cell mortality and epigenetically-silenced in most common human cancers. AB - Immortality is an essential characteristic of human carcinoma cells. We recently developed an efficient, reproducible method that immortalizes human mammary epithelial cells (HMEC) in the absence of gross genomic changes by targeting 2 critical senescence barriers. Consistent transcriptomic changes associated with immortality were identified using microarray analysis of isogenic normal finite pre-stasis, abnormal finite post-stasis, and immortal HMECs from 4 individuals. A total of 277 genes consistently changed in cells that transitioned from post stasis to immortal. Gene ontology analysis of affected genes revealed biological processes significantly altered in the immortalization process. These immortalization-associated changes showed striking similarity to the gene expression changes seen in The Cancer Genome Atlas (TCGA) clinical breast cancer data. The most dramatic change in gene expression seen during the immortalization step was the downregulation of an unnamed, incompletely annotated transcript that we called MORT, for mortality, since its expression was closely associated with the mortal, finite lifespan phenotype. We show here that MORT (ZNF667-AS1) is expressed in all normal finite lifespan human cells examined to date and is lost in immortalized HMEC. MORT gene silencing at the mortal/immortal boundary was due to DNA hypermethylation of its CpG island promoter. This epigenetic silencing is also seen in human breast cancer cell lines and in a majority of human breast tumor tissues. The functional importance of DNA hypermethylation in MORT gene silencing is supported by the ability of 5-aza-2'-deoxycytidine to reactivate MORT expression. Analysis of TCGA data revealed deregulation of MORT expression due to DNA hypermethylation in 15 out of the 17 most common human cancers. The epigenetic silencing of MORT in a large majority of the common human cancers suggests a potential fundamental role in cellular immortalization during human carcinogenesis. PMID- 26646905 TI - Erratum. PMID- 26646906 TI - Does the presence of siblings affect the results produced by a surveillance system of child mistreatment? Comparisons of several commonly-used statistical methods. AB - BACKGROUND: Over time, the circumstances encountered in case of child mistreatment, can be quite complex and then, can lead to methodological questions for the analysis of the data. Based on data coming from 395 children hospitalized, alone (66.1 %) or in siblings (33.9 %), in a pediatric ward between 2007 and 2012 for mistreatment or because of a severe risk of mistreatment, the aims of this paper were to quantify the degree of similarity between sibling members, to study the differences between children hospitalized alone or with siblings and to compare four statistical methods (logistic regression and GEE, both without and with robust standard error) for the analyses of the associated factors of mistreatment. RESULTS: Almost all intracluster correlation coefficients were large, meaning that the sibling's members have a higher degree of similarity between them. The odds ratios were not exactly the same between the two models and the robust standard errors where almost always higher than the model-based standard errors in both logistic and GEE models leading to wider confidence intervals. CONCLUSION: Because many of the intra-siblings correlations observed were relatively strong, the failure to take this cluster dependency into account had a substantial effect on the statistical analyses. Methods taking into account the cluster dependency are widely available in statistical software and strongly recommended. PMID- 26646904 TI - The many faces of plant chromatin: Meeting summary of the 4th European workshop on plant chromatin 2015, Uppsala, Sweden. AB - In June 2015, the fourth European Workshop on Plant Chromatin took place in Uppsala, Sweden, bringing together 80 researchers studying various aspects of plant chromatin and epigenetics. The intricate relationships between plant chromatin dynamics and gene expression change, chromatin organization within the plant cell nucleus, and the impact of chromatin structure on plant development were discussed. Among the main highlights of the meeting were an ever-growing list of newly identified players in chromatin structure establishment and the development of novel tools and approaches to foster our understanding of chromatin-mediated gene regulation, taking into account the context of the plant cell nucleus and its architecture. In this report, we summarize some of the main advances and prospects of plant chromatin research presented at this meeting. PMID- 26646907 TI - Definition of anatomical zero positions for assessing shoulder pose with 3D motion capture during bilateral abduction of the arms. AB - BACKGROUND: Surgical interventions at the shoulder may alter function of the shoulder complex. Clinically, the outcome can be assessed by universal goniometry. Marker-based motion capture may not resemble these results due to differing angle definitions. METHODS: The clinical inspection of bilateral arm abduction for assessing shoulder dysfunction is performed with a marker based 3D optical measurement method. An anatomical zero position of shoulder pose is proposed to determine absolute angles according to the Neutral-0-Method as used in orthopedic context. Static shoulder positions are documented simultaneously by 3D marker tracking and universal goniometry in 8 young and healthy volunteers. Repetitive bilateral arm abduction movements of at least 150 degrees range of motion are monitored. Similarly a subject with gleno-humeral osteoarthritis is monitored for demonstrating the feasibility of the method and to illustrate possible shoulder dysfunction effects. RESULTS: With mean differences of less than 2 degrees , the proposed anatomical zero position results in good agreement between shoulder elevation/depression angles determined by 3D marker tracking and by universal goniometry in static positions. Lesser agreement is found for shoulder pro-/retraction with systematic deviations of up to 6 degrees . In the bilateral arm abduction movements the volunteers perform a common and specific pattern in clavicula-thoracic and gleno-humeral motion with maximum shoulder angles of 32 degrees elevation, 5 degrees depression and 45 degrees protraction, respectively, whereas retraction is hardly reached. Further, they all show relevant out of (frontal) plane motion with anteversion angles of 30 degrees in overhead position (maximum abduction). With increasing arm anteversion the shoulder is increasingly retroverted, with a maximum of 20 degrees retroversion. The subject with gleno-humeral osteoarthritis shows overall less shoulder abduction range of motion but with increased out-of-plane movement during abduction. CONCLUSIONS: The proposed anatomical zero definition for shoulder pose fills the missing link for determining absolute joint angles for shoulder elevation/depression and pro-/retraction. For elevation-/depression the accuracy suits clinical expectations very well with mean differences less than 2 degrees and limits of agreement of 8.6 degrees whereas for pro /retraction the accuracy in individual cases may be inferior with limits of agreement of up to 24.6 degrees . This has critically to be kept in mind when applying this concept to shoulder intervention studies. PMID- 26646908 TI - Optimization and Dose Estimation of Aerosol Delivery to Non-Human Primates. AB - BACKGROUND: In pre-clinical animal studies, the uniformity of dosing across subjects and routes of administration is a crucial requirement. In preparation for a study in which aerosolized live-attenuated measles virus vaccine was administered to cynomolgus monkeys (Macaca fascicularis) by inhalation, we assessed the percentage of a nebulized dose inhaled under varying conditions. METHODS: Drug delivery varies with breathing parameters. Therefore we determined macaque breathing patterns (tidal volume, breathing frequency, and inspiratory to expiratory (I:E) ratio) across a range of 3.3-6.5 kg body weight, using a pediatric pneumotachometer interfaced either with an endotracheal tube or a facemask. Subsequently, these breathing patterns were reproduced using a breathing simulator attached to a filter to collect the inhaled dose. Albuterol was nebulized using a vibrating mesh nebulizer and the percentage inhaled dose was determined by extraction of drug from the filter and subsequent quantification. RESULTS: Tidal volumes ranged from 24 to 46 mL, breathing frequencies from 19 to 31 breaths per minute and I:E ratios from 0.7 to 1.6. A small pediatric resuscitation mask was identified as the best fitting interface between animal and pneumotachometer. The average efficiency of inhaled dose delivery was 32.1% (standard deviation 7.5, range 24%-48%), with variation in tidal volumes as the most important determinant. CONCLUSIONS: Studies in non human primates aimed at comparing aerosol delivery with other routes of administration should take both the inter-subject variation and relatively low efficiency of delivery to these low body weight mammals into account. PMID- 26646910 TI - [Psychosomatic medicine and psychotherapy as the focus of (health) political and ethical controversies]. PMID- 26646911 TI - [Psychosocial factors in reproductive medicine]. AB - INTRODUCTION: Since the development of assisted reproduction technology in the 1970s, assisted reproduction has become increasingly used by couples for various reasons. Concurrently, the diagnostic possibilities regarding the health of the unborn child have been elaborated. METHODS/RESULTS: The present literature review describes and discusses the possibilities of assisted reproduction (in-vitro fertilization (IVF), intracytoplasmic sperm injection ICSI, cryopreservation, conception of children with the help of a third person) with respect to their psychosocial meaning for those affected and for the children conceived in this manner. The psychological strain pairs experience in the context of prenatal diagnostics and the resulting decisions are illustrated by a case study. CONCLUSIONS: The continued progression in the possibilities and resulting conflicts and decision- making processes in reproductive medicine confronts clinicians and psychosomatic/psychotherapeutic practitioners with many new challenges. In conclusion clinical recommendations for the psychosocial counseling of couples are given. PMID- 26646912 TI - Inpatient and Day-Clinic Experience Scale (IDES) - a Psychometric Evaluation. AB - OBJECTIVES: The Inpatient and Day-Clinic Experience Scale (IDES) was developed to assess common factors in a multimodal psychotherapy setting from the patients' perspective. The questionnaire measures different aspects of therapeutic relationships, a positive self-view and a critical attitude towards therapy. METHODS: Three samples (total N = 821) were used to evaluate the psychometric properties and factor structure of the questionnaire. RESULTS: Confirmatory analyses show a good model fit and support the proposed structure with 25 items and seven scales. In addition, reliability indices were stable throughout multiple assessments over time. Concerning validity, early IDES process measures were moderately associated with symptomatic improvement. CONCLUSIONS: The IDES is a psychometrically reliable questionnaire for the evaluation of process factors in inpatient and day-clinic psychotherapy settings. PMID- 26646913 TI - [How timely are the methods taught in psychotherapy training and practice?]. AB - ISSUES: Even though many psychotherapists consider themselves to be eclectic or integrative, training and reimbursement in the modern healthcare system are clearly oriented toward the model of distinct psychotherapy approaches. Prompted by the proposition to favor general, disorder-oriented psychotherapy, we investigate how timely distinctive methods are that are taught in training and practice. METHODS: We reviewed the pertinent literature regarding general and specific factors, the effectiveness of integrative and eclectic treatments, orientation toward specific disorders, manualization and psychotherapeutic training. RESULTS: There is a lack of systematic studies on the efficacy of combining therapy methods from different approaches. The first empirical findings reveal that a superiority of combined versus single treatmentmethods has yet to be demonstrated. The development of transnosological manuals shows the limits of disorder-specific treatment.General factors such as therapeutic alliance or education about the model of disease and treatment rationale require specific definitions. CONCLUSION: Taking reference to a specific treatment approach provides important consistency of theory, training therapy and supervision, though this does not preclude an openness toward other therapy concepts. Current manualized examples show that methods and techniques can indeed be integrated from other approaches. Integrating different methods can also be seen as a developmental task for practitioners and researchers which may be mastered increasingly better with more experience. PMID- 26646914 TI - [Austrian expenditures on psychopharmaceutical drugs between 2006 and 2013]. AB - OBJECTIVES: Health costs, which are increasing at a yearly rate of 4 %, represent 11% and thus a large share of Austria's gross domestic product (GDP). High expenditures derive frommental health care costs, including medication. In this article we investigate whether the costs and usage of psychopharmaceutic products in Austria are rising. METHOD: We did a descriptive analysis of the sales figures and number for packaging units of pharmaceutical products of ATC-classes N05 and N06 in all Austrian hospitals, pharmacies and medicine chests for the years 2006 2013. All data were provided free of charge by IMSHealth. RESULTS: The sales volume and number of prescribed packaging units of pharmaceuticals of ATC-classes N05 and N06 increased over the time period in question. In 2013, about 25% more packaging units were being sold than in 2006. Among the two ATC-classes, however, the indication subgroups developed differently. Expenditures increased a total of about 31%within the period of consideration. CONCLUSIONS: The increase in psycho pharmaceutical sales exceeds the expansion rates of other health expenditures (17.8 %). During the 9 years of observation, 25% more psychopharmaceutical products were sold. This may result from increased prevalence of mental disorders, higher usage or an increment in prescriptions. PMID- 26646915 TI - [Attachment and psychosomatic health among Catholic pastoral professionals]. AB - OBJECTIVES: The study examines attachment representations and psychosomatic symptoms of Catholic priests and other pastoral professionals in Germany. METHOD: We conducted structured biographical interviews with 83 Catholic pastoral professionals (47 priests, 36 lay pastoral workers). Attachment representations were diagnosed by use of the Adult Attachment Projective Picture System (AAP). Psychosomatic health data (Brief Symptom Inventory - BSI-18) were taken from the associated German Pastoral Ministry Study. RESULTS: In the sample, the proportion of secure attachment representations was 23%, of insecure- dismissing 39%, of insecure-preoccupied 18% and of unresolved attachment status 21%. Individuals with secure attachment representation were associated with lower values of psychosomatic stress, while individuals with insecure-dismissing and unresolved attachment status had higher values. DISCUSSION: The amount of insecure attachment representations and psychosomatic symptoms is higher than in data from the healthy samples, especially in the cohorts between 1933 and 1945. Data from biographical interviews indicate the significant role of institutional attachment to the Church, in many cases possibly compensating for dysfunctional parental relationships in personal history. PMID- 26646916 TI - [Normative-empirical determination of personnel requirements in psychosomatic medicine and psychotherapy]. AB - OBJECTIVES: There is a high degree of misallocated medical care for patients with somatoform disorders and patients with concomitant mental diseases. This complex of problems could be reduced remarkably by integrating psychosomatic departments into hospitals with maximum medical care. Admitting a few big psychosomatic specialist clinics into the calculation basis decreased the Day-Mix Index (DMI). The massive reduction of the calculated costs per day leads to a gap in funding resulting in a loss of the necessary personnel requirements - at least in university psychosomatic departments. The objective of this article is therefore to empirically verify the reference numbers of personnel resources calculated on the basis of the new German lump-sum reimbursement system in psychiatry and psychosomatics (PEPP). METHODS: The minute values of the reference numbers of Heuft (1999) are contrasted with the minute values of the PEPP reimbursement system in the years 2013 and 2014, as calculated by the Institute for Payment Systems in Hospitals (InEK). RESULTS: The minute values derived from the PEPP data show a remarkable convergence with the minute values of Heuft's reference numbers (1999). CONCLUSIONS: A pure pricing system like the PEPP reimbursement system as designed so far threatens empirically verifiable and qualified personnel requirements of psychosomatic departments. In order to ensure the necessary therapy dosage and display it in minute values according to the valid OPS procedure codes, the minimum limit of the reference numbers is mandatory to maintain the substance of psychosomatic care. Based on the present calculation, a base rate of at least 285 e has to be politically demanded. Future developments in personnel costs have to be refinanced at 100 %. PMID- 26646923 TI - Using standardized patients to evaluate medical students' evidence-based medicine skills. AB - OBJECTIVES: To analyze the effectiveness of an Evidence Based Medicine Objective Structured Clinical Examination (EBM OSCE) with standardized patients for end of third year medical students at our institution. METHODS: This was a single-center prospective cross-sectional investigation. As part of the eight-station OSCE exam, the authors developed and implemented a new 25-minute EBM OSCE station with the goal of evaluating evidence based medicine skills necessary for daily clinical encounters. The OSCE case involved a highly educated patient with a history of recurrent debilitating migraines who has brought eight specific questions regarding the use of steroids for migraine headaches. Students were provided computer stations equipped to record a log of the searches performed. RESULTS: One hundred and four third-year medical students participated in this study. The average number of search tools used by the students was 4 (SD = 2). The 104 students performed a total of 896 searches. The two most commonly used websites were uptodate.com and google.com. Sixty-nine percent (95% CI, 60% to 78%) of students were able to find a meta-analysis regarding the use of dexamethasone for the prevention of rebound migraines. Fifty-two percent of students were able to explain that patients who took dexamethasone had a moderate RR (0.68 to 0.78) of having a recurrent migraine, and 71% of students were able to explain to the standardized patient that the NNT for dexamethasone was nine. CONCLUSION: The EBM OSCE was successfully integrated into the existing eight station OSCE and was able to assess student EBM skills. PMID- 26646925 TI - Introduction: Neuroimaging of degenerative and traumatic encephalopathies. PMID- 26646924 TI - Signal sampling for efficient sparse representation of resting state FMRI data. AB - As the size of brain imaging data such as fMRI grows explosively, it provides us with unprecedented and abundant information about the brain. How to reduce the size of fMRI data but not lose much information becomes a more and more pressing issue. Recent literature studies tried to deal with it by dictionary learning and sparse representation methods, however, their computation complexities are still high, which hampers the wider application of sparse representation method to large scale fMRI datasets. To effectively address this problem, this work proposes to represent resting state fMRI (rs-fMRI) signals of a whole brain via a statistical sampling based sparse representation. First we sampled the whole brain's signals via different sampling methods, then the sampled signals were aggregate into an input data matrix to learn a dictionary, finally this dictionary was used to sparsely represent the whole brain's signals and identify the resting state networks. Comparative experiments demonstrate that the proposed signal sampling framework can speed-up by ten times in reconstructing concurrent brain networks without losing much information. The experiments on the 1000 Functional Connectomes Project further demonstrate its effectiveness and superiority. PMID- 26646926 TI - Creutzfeldt-Jakob disease: updated diagnostic criteria, treatment algorithm, and the utility of brain biopsy. AB - Creutzfeldt-Jakob disease (CJD) is a rare neurodegenerative condition with a rapid disease course and a mortality rate of 100%. Several forms of the disease have been described, and the most common is the sporadic type. The most challenging aspect of this disease is its diagnosis-the gold standard for definitive diagnosis is considered to be histopathological confirmation-but newer tests are providing means for an antemortem diagnosis in ways less invasive than brain biopsy. Imaging studies, electroencephalography, and biomarkers are used in conjunction with the clinical picture to try to make the diagnosis of CJD without brain tissue samples, and all of these are reviewed in this article. The current diagnostic criteria are limited; test sensitivity and specificity varies with the genetics of the disease as well as the clinical stage. Physicians may be unsure of all diagnostic testing available, and may order outdated tests or prematurely request a brain biopsy when the diagnostic workup is incomplete. The authors review CJD, discuss the role of brain biopsy in this patient population, provide a diagnostic pathway for the patient presenting with rapidly progressive dementia, and propose newer diagnostic criteria. PMID- 26646927 TI - Role of apolipoprotein E polymorphism as a prognostic marker in traumatic brain injury and neurodegenerative disease: a critical review. AB - OBJECT The difference in course and outcome of several neurodegenerative conditions and traumatic injuries of the nervous system points toward a possible role of genetic and environmental factors as prognostic markers. Apolipoprotein E (Apo-E), a key player in lipid metabolism, is recognized as one of the most powerful genetic risk factors for dementia and other neurodegenerative diseases. In this article, the current understanding of APOE polymorphism in various neurological disorders is discussed. METHODS The English literature was searched for various studies describing the role of APOE polymorphism as a prognostic marker in neurodegenerative diseases and traumatic brain injury. The wide ethnic distribution of APOE polymorphism was discussed, and the recent meta-analyses of role of APOE polymorphism in multiple diseases were analyzed and summarized in tabular form. RESULTS Results from the review of literature revealed that the distribution of APOE is varied in different ethnic populations. APOE polymorphism plays a significant role in pathogenesis of neurodegeneration, particularly in Alzheimer's disease. APOE epsilon4 is considered a marker for poor prognosis in various diseases, but APOE epsilon2 rather than APOE epsilon4 has been associated with cerebral amyloid angiopathy-related bleeding and sporadic Parkinson's disease. The role of APOE polymorphism in various neurological diseases has not been conclusively elucidated. CONCLUSIONS Apo-E is a biomarker for various neurological and systemic diseases. Therefore, while analyzing the role of APOE polymorphism in neurological diseases, the interpretation should be done after adjusting all the confounding factors. A continuous quest to look for associations with various neurological diseases and wide knowledge of available literature are required to improve the understanding of the role of APOE polymorphism in these conditions and identify potential therapeutic targets. PMID- 26646928 TI - Seven-Tesla MRI and neuroimaging biomarkers for Alzheimer's disease. AB - The goal of this paper was to review the effectiveness of using 7-T MRI to study neuroimaging biomarkers for Alzheimer's disease (AD). The authors reviewed the literature for articles published to date on the use of 7-T MRI to study AD. Thus far, there are 3 neuroimaging biomarkers for AD that have been studied using 7-T MRI in AD tissue: 1) neuroanatomical atrophy; 2) molecular characterization of hypointensities; and 3) microinfarcts. Seven-Tesla MRI has had mixed results when used to study the 3 aforementioned neuroimaging biomarkers for AD. First, in the detection of neuroanatomical atrophy, 7-T MRI has exciting potential. Historically, noninvasive imaging of neuroanatomical atrophy during AD has been limited by suboptimal resolution. However, now there is compelling evidence that the high resolution of 7-T MRI may help overcome this hurdle. Second, in detecting the characterization of hypointensities, 7-T MRI has had varied success. PET scans will most likely continue to lead in the noninvasive imaging of amyloid plaques; however, there is emerging evidence that 7-T MRI can accurately detect iron deposits within activated microglia, which may help shed light on the role of the immune system in AD pathogenesis. Finally, in the detection of microinfarcts, 7-T MRI may also play a promising role, which may help further elucidate the relationship between cerebrovascular health and AD progression. PMID- 26646929 TI - Hippocampal and cerebellar atrophy in patients with Cushing's disease. AB - OBJECT Cushing's disease (CD) may cause atrophy of different regions of the human brain, mostly affecting the hippocampus and the cerebellum. This study evaluates the use of 3-T MRI of newly diagnosed patients with CD to detect atrophic degeneration with voxel-based volumetry. METHODS Subjects with newly diagnosed, untreated CD were included and underwent 3-T MRI. Images were analyzed using a voxelwise statistical test to detect reduction of brain parenchyma. In addition, an atlas-based volumetric study for regions likely to be affected by CD was performed. RESULTS Nineteen patients with a mean disease duration of 24 months were included. Tumor markers included adrenocorticotropic hormone (median 17.5 pmol/L), cortisol (949.4 nmol/L), and dehydroepiandrosterone sulfate (5.4 MUmol/L). The following values are expressed as the mean +/- SD. The voxelwise statistical test revealed clusters of significantly reduced gray matter in the hippocampus and cerebellum, with volumes of 2.90 +/- 0.26 ml (right hippocampus), 2.89 +/- 0.28 ml (left hippocampus), 41.95 +/- 4.67 ml (right cerebellar hemisphere), and 42.11 +/- 4.59 ml (left cerebellar hemisphere). Healthy control volunteers showed volumes of 3.22 +/- 0.25 ml for the right hippocampus, 3.23 +/- 0.25 ml for the left hippocampus, 50.87 +/- 4.23 ml for the right cerebellar hemisphere, and 50.42 +/- 3.97 ml for the left cerebellar hemisphere. CONCLUSIONS Patients with untreated CD show significant reduction of gray matter in the cerebellum and hippocampus. These changes can be analyzed and objectified with the quantitative voxel-based method described in this study. PMID- 26646930 TI - Letter to the Editor: Bow hunter's syndrome: surgery or conservative therapy? PMID- 26646933 TI - A luminescent europium(III)-platinum(II) heterometallic complex as a theranostic agent: a proof-of-concept study. AB - A luminescent heterometallic multifunctional theranostic Eu-Pt2 complex [{cis PtCl2(DMSO)}2Eu(L)(H2O)] has been synthesized, possessing two therapeutic Pt centers as covalent DNA binders and one emissive Eu(3+)-center which is sensitized by platinum-based metal-to-ligand charge-transfer excited states. PMID- 26646931 TI - Association of MicroRNAs and YRNAs With Platelet Function. AB - RATIONALE: Platelets shed microRNAs (miRNAs). Plasma miRNAs change on platelet inhibition. It is unclear whether plasma miRNA levels correlate with platelet function. OBJECTIVE: To link small RNAs to platelet reactivity. METHODS AND RESULTS: Next-generation sequencing of small RNAs in plasma revealed 2 peaks at 22 to 23 and 32 to 33 nucleotides corresponding to miRNAs and YRNAs, respectively. Among YRNAs, predominantly, fragments of RNY4 and RNY5 were detected. Plasma miRNAs and YRNAs were measured in 125 patients with a history of acute coronary syndrome who had undergone detailed assessment of platelet function 30 days after the acute event. Using quantitative real-time polymerase chain reactions, 92 miRNAs were assessed in patients with acute coronary syndrome on different antiplatelet therapies. Key platelet-related miRNAs and YRNAs were correlated with platelet function tests. MiR-223 (rp=0.28; n=121; P=0.002), miR 126 (rp=0.22; n=121; P=0.016), and other abundant platelet miRNAs and YRNAs showed significant positive correlations with the vasodilator-stimulated phosphoprotein phosphorylation assay. YRNAs, miR-126, and miR-223 were also among the small RNAs showing the greatest dependency on platelets and strongly correlated with plasma levels of P-selectin, platelet factor 4, and platelet basic protein in the population-based Bruneck study (n=669). A single-nucleotide polymorphism that facilitates processing of pri-miR-126 to mature miR-126 accounted for a rise in circulating platelet activation markers. Inhibition of miR-126 in mice reduced platelet aggregation. MiR-126 directly and indirectly affects ADAM9 and P2Y12 receptor expression. CONCLUSIONS: Levels of platelet related plasma miRNAs and YRNAs correlate with platelet function tests in patients with acute coronary syndrome and platelet activation markers in the general population. Alterations in miR-126 affect platelet reactivity. PMID- 26646932 TI - Compound Heterozygosity for Y Box Proteins Causes Sterility Due to Loss of Translational Repression. AB - The Y-box proteins YBX2 and YBX3 bind RNA and DNA and are required for metazoan development and fertility. However, possible functional redundancy between YBX2 and YBX3 has prevented elucidation of their molecular function as RNA masking proteins and identification of their target RNAs. To investigate possible functional redundancy between YBX2 and YBX3, we attempted to construct Ybx2-/ ;Ybx3-/- double mutants using a previously reported Ybx2-/- model and a newly generated global Ybx3-/- model. Loss of YBX3 resulted in reduced male fertility and defects in spermatid differentiation. However, homozygous double mutants could not be generated as haploinsufficiency of both Ybx2 and Ybx3 caused sterility characterized by extensive defects in spermatid differentiation. RNA sequence analysis of mRNP and polysome occupancy in single and compound Ybx2/3 heterozygotes revealed loss of translational repression almost exclusively in the compound Ybx2/3 heterozygotes. RNAseq analysis also demonstrated that Y-box protein dose-dependent loss of translational regulation was inversely correlated with the presence of a Y box recognition target sequence, suggesting that Y box proteins bind RNA hierarchically to modulate translation in a range of targets. PMID- 26646934 TI - Validation of the Inflammatory Bowel Disease Disability Index in a population based cohort. AB - BACKGROUND: IBDs are chronic destructive disorders that negatively affect the functional status of patients. Recently, the Inflammatory Bowel Disease Disability Index (IBD-DI) was developed according to standard WHO processes. The aims of the current study were to validate the IBD-DI in an independent patient cohort, to develop an index-specific scoring system and to describe the disability status of a well-defined population-based cohort of French patients with IBD. METHODS: From February 2012 to March 2014, the IBD-DI questionnaire was administered to a random sample of adult patients with an established diagnosis of IBD issued from a French population-based registry. The IBD-DI consists of 28 items that evaluate the four domains of body functions, activity participation, body structures and environmental factors. Validation included item reduction and data structure, construct validity, internal consistency, interobserver and intraobserver reliability evaluations. RESULTS: 150 patients with Crohn's disease (CD) and 50 patients with UC completed the IBD-DI validation phase. The intraclass correlation coefficient for interobserver reliability was 0.91 and 0.54 for intraobserver reliability. Cronbach's alpha of internal consistency was 0.86. IBD-DI scores varied from 0 to 100 with a mean of 35.3 (Q1=19.6; Q3=51.8). IBD-DI scores were highly correlated with Inflammatory Bowel Disease Questionnaire (-0.82; p<0.001) and SF-36 (-0.61; p<0.05) scores. Female gender (p<0.001), clinical disease activity (p<0.0001) and disease duration (p=0.02) were associated with higher IBD-DI scores. CONCLUSIONS: The IBD-DI has been validated for use in clinical trials and epidemiological studies. The IBD-DI showed high internal consistency, interobserver reliability and construct validity, and a moderate intraobserver reliability. It comprises 14 questions and ranges from 0 to 100. The mean IBD-DI score was 35.3 and was associated with gender, clinical disease activity and disease duration. Further research is needed to confirm the structural validity and to assess the responsiveness of IBD DI. TRIAL REGISTRATION NUMBER: 2011-A00877-34. PMID- 26646935 TI - Presence of commensal house dust mite allergen in human gastrointestinal tract: a potential contributor to intestinal barrier dysfunction. AB - BACKGROUND: Abnormal gut barrier function is the basis of gut inflammatory disease. It is known that house dust mite (HDM) aero-allergens induce inflammation in respiratory mucosa. We have recently reported allergen from Dermatophagoides pteronyssinus (Der p1) to be present in rodent gut. OBJECTIVE: To examine whether Der p1 is present in human gut and to assess its effect on gut barrier function and inflammation. DESIGN: Colonic biopsies, gut fluid, serum and stool were collected from healthy adults during endoscopy. Der p1 was measured by ELISA. Effect of HDM was assessed on gut permeability, tight-junction and mucin expression, and cytokine production, in presence or absence of cysteine protease inhibitors or serine protease inhibitors. In vivo effect of HDM was examined in mice given oral HDM or protease-neutralised HDM. Role of HDM in low-grade inflammation was studied in patients with IBS. RESULTS: HDM Der p1 was detected in the human gut. In colonic biopsies from healthy patients, HDM increased epithelial permeability (p<0.001), reduced expression of tight-junction proteins and mucus barrier. These effects were associated with increased tumour necrosis factor (TNF)-alpha and interleukin (IL)-10 production and were abolished by cysteine-protease inhibitor (p<0.01). HDM effects did not require Th2 immunity. Results were confirmed in vivo in mice. In patients with IBS, HDM further deteriorated gut barrier function, induced TNF-alpha but failed to induce IL-10 secretion (p<0.001). CONCLUSIONS: HDM, a ubiquitous environmental factor, is present in the human gut where it directly affects gut function through its proteolytic activity. HDM may be an important trigger of gut dysfunction and warrants further investigation. PMID- 26646936 TI - Antidepressants synergize with chemotherapy against cancer stem cells. PMID- 26646937 TI - MECHANISMS IN ENDOCRINOLOGY: Metabolic and inflammatory pathways on the pathogenesis of type 2 diabetes. AB - Obesity is the main risk factor for type 2 diabetes (T2D). Studies performed over the last 20 years have identified inflammation as the most important link between these two diseases. During the development of obesity, there is activation of subclinical inflammatory activity in tissues involved in metabolism and energy homeostasis. Intracellular serine/threonine kinases activated in response to inflammatory factors can catalyse the inhibitory phosphorylation of key proteins of the insulin-signalling pathway, leading to insulin resistance. Moreover, during the progression of obesity and insulin resistance, the pancreatic islets are also affected by inflammation, contributing to beta-cell failure and leading to the onset of T2D. In this review, we will present the main mechanisms involved in the activation of obesity-associated metabolic inflammation and discuss potential therapeutic opportunities that can be developed to treat obesity associated metabolic diseases. PMID- 26646938 TI - GENETICS IN ENDOCRINOLOGY: Gain and loss of function mutations of the calcium sensing receptor and associated proteins: current treatment concepts. AB - The calcium-sensing receptor (CASR) is the main calcium sensor in the maintenance of calcium metabolism. Mutations of the CASR, the G protein alpha 11 (GNA11) and the adaptor-related protein complex 2 sigma 1 subunit (AP2S1) genes can shift the set point for calcium sensing causing hyper- or hypo-calcemic disorders. Therapeutic concepts for these rare diseases range from general therapies of hyper- and hypo-calcemic conditions to more pathophysiology oriented approaches such as parathyroid hormone (PTH) substitution and allosteric CASR modulators. Cinacalcet is a calcimimetic that enhances receptor function and has gained approval for the treatment of hyperparathyroidism. Calcilytics in turn attenuate CASR activity and are currently under investigation for the treatment of various diseases. We conducted a literature search for reports about treatment of patients harboring inactivating or activating CASR, GNA11 or AP2S1 mutants and about in vitro effects of allosteric CASR modulators on mutated CASR. The therapeutic concepts for patients with familial hypocalciuric hypercalcemia (FHH), neonatal hyperparathyroidism (NHPT), neonatal severe hyperparathyroidism (NSHPT) and autosomal dominant hypocalcemia (ADH) are reviewed. FHH is usually benign, but symptomatic patients benefit from cinacalcet. In NSHPT patients pamidronate effectively lowers serum calcium, but most patients require parathyroidectomy. In some patients cinacalcet can obviate the need for surgery, particularly in heterozygous NHPT. Symptomatic ADH patients respond to vitamin D and calcium supplementation but this may increase calciuria and renal complications. PTH treatment can reduce relative hypercalciuria. None of the currently available therapies for ADH, however, prevent tissue calcifications and complications, which may become possible with calcilytics that correct the underlying pathophysiologic defect. PMID- 26646939 TI - Multi-omic profiles of human non-alcoholic fatty liver disease tissue highlight heterogenic phenotypes. AB - Non-alcoholic fatty liver disease (NAFLD) is a consequence of sedentary life style and high fat diets with an estimated prevalence of about 30% in western countries. It is associated with insulin resistance, obesity, glucose intolerance and drug toxicity. Additionally, polymorphisms within, e.g., APOC3, PNPLA3, NCAN, TM6SF2 and PPP1R3B, correlate with NAFLD. Several studies have already investigated later stages of the disease. This study explores the early steatosis stage of NAFLD with the aim of identifying molecular mechanisms underlying the etiology of NAFLD. We analyzed liver biopsies and serum samples from patients with high- and low-grade steatosis (also pre-disease states) employing transcriptomics, ELISA-based serum protein analyses and metabolomics. Here, we provide a detailed description of the various related datasets produced in the course of this study. These datasets may help other researchers find new clues for the etiology of NAFLD and the mechanisms underlying its progression to more severe disease states. PMID- 26646940 TI - Olfactory sensory neurons transiently express multiple olfactory receptors during development. AB - In mammals, each olfactory sensory neuron randomly expresses one, and only one, olfactory receptor (OR)--a phenomenon called the "one-neuron-one-receptor" rule. Although extensively studied, this rule was never proven for all ~1,000 OR genes in one cell at once, and little is known about its dynamics. Here, we directly tested this rule by single-cell transcriptomic sequencing of 178 cells from the main olfactory epithelium of adult and newborn mice. To our surprise, a subset of cells expressed multiple ORs. Most of these cells were developmentally immature. Our results illustrated how the "one-neuron-one-receptor" rule may have been established: At first, a single neuron temporarily expressed multiple ORs- seemingly violating the rule--and then all but one OR were eliminated. This work provided experimental evidence that epigenetic regulation in the olfactory system selects a single OR by suppressing a few transiently expressed ORs in a single cell during development. PMID- 26646941 TI - Methionine restriction fundamentally supports health by tightening epithelial barriers. AB - Dietary methionine restriction (MR) has been found to affect one of the most primary tissue-level functions of an organism: the efficiency with which the epithelial linings of major organs separate the fluid compartments that they border. This process, epithelial barrier function, is basic for proper function of all organs, including the lung, liver, gastrointestinal tract, reproductive tract, blood-brain barrier, and kidney. Specifically, MR has been found to modify the protein composition of tight junctional complexes surrounding individual epithelial cells in a manner that renders the complexes less leaky. This has been observed in both a renal epithelial cell culture model and in gastrointestinal tissue. In both cases, MR increased the transepithelial electrical resistance across the epithelium, while decreasing passive leak of small nonelectrolytes. However, the specific target protein modifications involved were unique to each case. Overall, this provides an example of the primary level on which MR functions to modify, and improve, an organism. PMID- 26646942 TI - Development of the competency scale for primary care managers in Thailand: Scale development. AB - BACKGROUND: The complexity of the primary care system requires a competent manager to achieve high-quality healthcare. The existing literature in the field yields little evidence of the tools to assess the competency of primary care administrators. This study aimed to develop and examine the psychometric properties of the competency scale for primary care managers in Thailand. METHODS: The scale was developed using in-depth interviews and focus group discussions among policy makers, managers, practitioners, village health volunteers, and clients. The specific dimensions were extracted from 35 participants. 123 items were generated from the evidence and qualitative data. Content validity was established through the evaluation of seven experts and the original 123 items were reduced to 84 items. The pilot testing was conducted on a simple random sample of 487 primary care managers. Item analysis, reliability testing, and exploratory factor analysis were applied to establish the scale's reliability and construct validity. RESULTS: Exploratory factor analysis identified nine dimensions with 48 items using a five-point Likert scale. Each dimension accounted for greater than 58.61% of the total variance. The scale had strong content validity (Indices = 0.85). Each dimension of Cronbach's alpha ranged from 0.70 to 0.88. CONCLUSIONS: Based on these analyses, this instrument demonstrated sound psychometric properties and therefore is considered an effective tool for assessment of the primary care manager competencies. The results can be used to improve competency requirements of primary care managers, with implications for health service management workforce development. PMID- 26646944 TI - [Knee joint as a challenge]. PMID- 26646943 TI - Beninese children with cerebral malaria do not develop humoral immunity against the IT4-VAR19-DC8 PfEMP1 variant linked to EPCR and brain endothelial binding. AB - BACKGROUND: Malaria is still one of the most prevalent infectious diseases in the world. Sequestration of infected erythrocytes (IEs) is the prime mediator of disease. Cytoadhesion of IEs is mediated by members of the highly diverse Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1). A restricted sub set of var genes encoding for PfEMP1s possessing the domain cassettes DC8 and DC13 were found to bind to the endothelial protein C receptor (EPCR). These var genes were shown to be highly expressed by parasites from patients with severe malaria clinical outcomes compared to those from patients with uncomplicated symptoms. METHODS: In order to further study the molecular mechanisms underlying DC8/DC13 expressing IEs adhesion to EPCR, a method was developed to produce highly pure recombinant EPCR. The IT4 parasite strain was selected on either anti IT4-VAR19 purified IgG, EPCR or human brain endothelial cell line and their var gene expression profiles as well as their binding phenotypes were compared. The N terminal region of IT4-VAR19 comprising a full-length DC8 cassette as well as the single EPCR binding CIDRalpha1.1 domain were also produced, and their immune recognition (IgG) was assessed using plasma samples from Beninese children presenting acute mild malaria, severe malaria or cerebral malaria at the time of their admission to the clinic, and from convalescent-phase plasma collected 30 days after anti-malarial treatment. RESULTS: The multi-domain VAR19-NTS-DBLgamma6 binds to EPCR with a greater affinity than the CIDRalpha1.1 domain alone and this study also demonstrates that VAR19-NTS-DBLgamma6 binding to the EPCR-expressing endothelial cell line (HBEC5i) is more pronounced than that of the CIDRalpha1.1 domain alone. IT4-VAR19 represents the preferentially expressed-PfEMP1 when FCR3 IEs are selected based on their capability to bind EPCR. Notably, no significant difference in the levels of antibodies towards IT4-VAR19 antigens was observed within all clinical groups between plasma samples collected during the acute malaria phase compared to samples collected 30 days after anti-malaria treatment. CONCLUSIONS: These data indicate that even being the preferentially selected IT4 EPCR-binding variant, the IT4-VAR19-DC8 region does not appear to be associated with the acquisition of antibodies during a single severe paediatric malaria episode in Benin. PMID- 26646945 TI - [Periprosthetic knee fractures]. AB - BACKGROUND: The cumulative incidence of periprosthetic fractures around the knee is increasing further because of an extended indication for knee replacement, previous revision arthroplasty, rising life expectancy and comorbidities. AIM OF THE WORK: The relevance of local parameters such as malalignment, osseous defects, neighbouring implants, aseptic loosening and low-grade infections may sometimes be hidden behind the manifestation of a traumatic fracture. A differentiated diagnostic approach before the treatment of a periprosthetic fracture is of paramount importance, while the physician in-charge should also have particular expertise in fracture treatment and in advanced techniques of revision endoprosthetics. The following work gives an overview of this topic. RESULTS: Valid classifications are available for categorising periprosthetic fractures of the femur, the tibia and the patella respectively, which are helpful for the selection of treatment. CONCLUSIONS: With the wide-ranging modern treatment portfolio bearing in mind the substantial rate of complications and the heterogeneous functional outcome, the adequate analysis of fracture aetiology and the corresponding transformation into an individualised treatment concept offer the chance of an acceptable functional restoration of the patient at early full weight-bearing and prolonged implant survival. The management of complications is crucial to the final outcome. PMID- 26646946 TI - Should ALPPS be Used for Liver Resection in Intermediate-Stage HCC? AB - BACKGROUND: Extended liver resections in patients with hepatocellular carcinoma (HCC) are problematic due to hepatitis, fibrosis, and cirrhosis. Associating liver partition with portal vein ligation for staged hepatectomy (ALPPS) has been promoted as a novel method to induce hypertrophy for patients with extensive colorectal liver metastases, but outcomes in HCC have not been well investigated. METHODS: All patients registered in the international ALPPS Registry ( www.alpps.org ) from 2010 to 2015 were studied. Hypertrophy of the future liver remnant, perioperative morbidity and mortality, age, overall survival, and other parameters were compared between patients with HCC and patients with colorectal liver metastases (CRLM). RESULTS: The study compared 35 patients with HCC and 225 patients with CRLM. The majority of patients undergoing ALPPS for HCC fall into the intermediate-stage category of the Barcelona clinic algorithm. In this study, hypertrophy was rapid and extensive for the HCC patients, albeit lower than for the CRLM patients (47 vs. 76 %; p < 0.002). Hypertrophy showed a linear negative correlation with the degrees of fibrosis. The 90-day mortality for ALPPS used to treat HCC was almost fivefold higher than for CRLM (31 vs. 7 %; p < 0.001). Multivariate analysis showed that patients older than 61 years had a significantly reduced overall survival (p < 0.004). CONCLUSION: The ALPPS approach induces a considerable hypertrophic response in HCC patients and allows resection of intermediate-stage HCC, albeit at the cost of a 31 % perioperative mortality rate. The use of ALPPS for HCC remains prohibitive for most patients and should be performed only for a highly selected patient population younger than 60 years with low-grade fibrosis. PMID- 26646947 TI - Manganese tolerance in yeasts involves polyphosphate, magnesium, and vacuolar alterations. AB - Basidiomycetous and ascomycetous yeast species were tested for manganese tolerance. Basidiomycetous Cryptococcus humicola, Cryptococcus terricola, Cryptococcus curvatus and ascomycetous Candida maltosa, Kluyveromyces marxianus, Kuraishia capsulata, Lindnera fabianii and Sacharomyces cerevisiae were able to grow at manganese excess (2.5 mmol/L), while the growth of basidiomycetous Rhodotorula bogoriensis was completely suppressed. The lag phase duration increased and the exponential growth rate decreased at manganese excess. The increase of cell size and enlargement of vacuoles were characteristics for the cells grown at manganese excess. The alterations in inorganic polyphosphate content and cellular localization were studied. L. fabianii, K. capsulata, C. maltosa, and Cr. humicola accumulated the higher amounts of inorganic polyphosphates, while Cr. terricola and Cr. curvatus demonstrated no such accumulation. The polyphosphate content in the cell wall tested by DAPI staining increased in all species under the study; however, this effect was more pronounced in Cr. terricola and Cr. curvatus. The accumulation of Mg(2+) in the cell wall under Mn(2+) excess was observed in Cr. humicola, Cr. curvatus and Cr. terricola. The accumulation of polyphosphate and magnesium in the cell wall was supposed to be a factor of manganese tolerance in yeasts. PMID- 26646948 TI - Identification of Major Signaling Pathways in Prion Disease Progression Using Network Analysis. AB - Prion diseases are transmissible neurodegenerative diseases that arise due to conformational change of normal, cellular prion protein (PrPC) to protease resistant isofrom (rPrPSc). Deposition of misfolded PrpSc proteins leads to an alteration of many signaling pathways that includes immunological and apoptotic pathways. As a result, this culminates in the dysfunction and death of neuronal cells. Earlier works on transcriptomic studies have revealed some affected pathways, but it is not clear which is (are) the prime network pathway(s) that change during the disease progression and how these pathways are involved in crosstalks with each other from the time of incubation to clinical death. We perform network analysis on large-scale transcriptomic data of differentially expressed genes obtained from whole brain in six different mouse strain-prion strain combination models to determine the pathways involved in prion diseases, and to understand the role of crosstalks in disease propagation. We employ a notion of differential network centrality measures on protein interaction networks to identify the potential biological pathways involved. We also propose a crosstalk ranking method based on dynamic protein interaction networks to identify the core network elements involved in crosstalk with different pathways. We identify 148 DEGs (differentially expressed genes) potentially related to the prion disease progression. Functional association of the identified genes implicates a strong involvement of immunological pathways. We extract a bow-tie structure that is potentially dysregulated in prion disease. We also propose an ODE model for the bow-tie network. Predictions related to diseased condition suggests the downregulation of the core signaling elements (PI3Ks and AKTs) of the bow-tie network. In this work, we show using transcriptomic data that the neuronal dysfunction in prion disease is strongly related to the immunological pathways. We conclude that these immunological pathways occupy influential positions in the PFNs (protein functional networks) that are related to prion disease. Importantly, this functional network involvement is prevalent in all the five different mouse strain-prion strain combinations that we studied. We also conclude that the dysregulation of the core elements of the bow-tie structure, which belongs to PI3K-Akt signaling pathway, leads to dysregulation of the downstream components corresponding to other biological pathways. PMID- 26646949 TI - Graphene stabilized ultra-small CuNi nanocomposite with high activity and recyclability toward catalysing the reduction of aromatic nitro-compounds. AB - Nowadays, it is of great significance and a challenge to design a noble-metal free catalyst with high activity and a long lifetime for the reduction of aromatic nitro-compounds. Here, a 2D structured nanocomposite catalyst with graphene supported CuNi alloy nanoparticles (NPs) is prepared, and is promising for meeting the requirements of green chemistry. In this graphene/CuNi nanocomposite, the ultra-small CuNi nanoparticles (~2 nm) are evenly anchored on graphene sheets, which is not only a breakthrough in the structures, but also brings about an outstanding performance in activity and stability. Combined with a precise optimization of the alloy ratios, the reaction rate constant of graphene/Cu61Ni39 reached a high level of 0.13685 s(-1), with a desirable selectivity as high as 99% for various aromatic nitro-compounds. What's more, the catalyst exhibited a unprecedented long lifetime because it could be recycled over 25 times without obvious performance decay or even a morphology change. This work showed the promise and great potential of noble-metal-free catalysts in green chemistry. PMID- 26646951 TI - Ordered self-assembly of amphipathic graphene nanosheets into three-dimensional layered architectures. AB - A novel layered graphene-based architecture is achieved via an ordered self assembly process. Amphipathic graphene nanosheets are joined horizontally into large sheets via edge splicing, and a cross-linking agent of poly(vinyl alcohol) bridges them into integrated three-dimensional monoliths with tunable interlayer spacing. This layered architecture possesses highly ordered and favorable microchannels for molecular transfer. PMID- 26646952 TI - A fast but accurate excitonic simulation of the electronic circular dichroism of nucleic acids: how can it be achieved? AB - We present and discuss a simple and fast computational approach to the calculation of electronic circular dichroism spectra of nucleic acids. It is based on a exciton model in which the couplings are obtained in terms of the full transition-charge distributions, as resulting from TDDFT methods applied on the individual nucleobases. We validated the method on two systems, a DNA G quadruplex and a RNA beta-hairpin whose solution structures have been accurately determined by means of NMR. We have shown that the different characteristics of composition and structure of the two systems can lead to quite important differences in the dependence of the accuracy of the simulation on the excitonic parameters. The accurate reproduction of the CD spectra together with their interpretation in terms of the excitonic composition suggest that this method may lend itself as a general computational tool to both predict the spectra of hypothetic structures and define clear relationships between structural and ECD properties. PMID- 26646950 TI - Interleukin-21 induces migration and invasion of fibroblast-like synoviocytes from patients with rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by synovial fibroblast hyperplasia and bone erosion. Fibroblast-like synoviocytes (FLS) play a pivotal role in RA pathogenesis through aggressive migration and matrix invasion, and certain proinflammatory cytokines may affect synoviocyte invasion. Whether interleukin (IL)-21 influences this process remains controversial. Here, we evaluated the potential regulatory effect of IL-21 on the migration, invasion and matrix metalloproteinase (MMP) expression in RA-FLS. We found that IL-21 promoted the migration, invasion and MMP (MMP-2, MMP-3, MMP-9, MMP-13) production in RA-FLS. Moreover, IL-21 induced activation of the phosphoinositide 3-kinase (PI3K), signal transducer and activator of transcription-3 (STAT-3) and extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) pathways, and blockage of these pathways [PI3K/protein kinase B (AKT) inhibitor LY294002, STAT-3 inhibitor STA-21 and ERK1/2 inhibitor PD98059] attenuated IL-21-induced migration and secretion of MMP-3 and MMP-9. In conclusion, our results suggest that IL-21 promotes migration and invasion of RA FLS. Therefore, therapeutic strategies targeting IL-21 might be effective for the treatment of RA. PMID- 26646953 TI - Nonstructural protein Pns4 of rice dwarf virus is essential for viral infection in its insect vector. AB - BACKGROUND: Rice dwarf virus (RDV), a plant reovirus, is mainly transmitted by the green rice leafhopper, Nephotettix cincticeps, in a persistent-propagative manner. Plant reoviruses are thought to replicate and assemble within cytoplasmic structures called viroplasms. Nonstructural protein Pns4 of RDV, a phosphoprotein, is localized around the viroplasm matrix and forms minitubules in insect vector cells. However, the functional role of Pns4 minitubules during viral infection in insect vector is still unknown yet. METHODS: RNA interference (RNAi) system targeting Pns4 gene of RDV was conducted. Double-stranded RNA (dsRNA) specific for Pns4 gene was synthesized in vitro, and introduced into cultured leafhopper cells by transfection or into insect body by microinjection. The effects of the knockdown of Pns4 expression due to RNAi induced by synthesized dsRNA from Pns4 gene on viral replication and spread in cultured cells and insect vector were analyzed using immunofluorescence, western blotting or RT-PCR assays. RESULTS: In cultured leafhopper cells, the knockdown of Pns4 expression due to RNAi induced by synthesized dsRNA from Pns4 gene strongly inhibited the formation of minitubules, preventing the accumulation of viroplasms and efficient viral infection in insect vector cells. RNAi induced by microinjection of dsRNA from Pns4 gene significantly reduced the viruliferous rate of N. cincticeps. Furthermore, it also strongly inhibited the formation of minitubules and viroplasms, preventing efficient viral spread from the initially infected site in the filter chamber of intact insect vector. CONCLUSIONS: Pns4 of RDV is essential for viral infection and replication in insect vector. It may directly participate in the functional role of viroplasm for viral replication and assembly of progeny virions during viral infection in leafhopper vector. PMID- 26646954 TI - Ecologic factors relating to firearm injuries and gun violence in Chicago. AB - BACKGROUND: Firearm violence is a major burden on Chicago with greater than 1500 gunshot injuries occurring annually. Identifying ecologic variables related to the incidence of firearm-related injuries and crime could prove useful for developing new strategies for reducing gun-related injuries. METHODS: The Illinois Trauma Registry (ITSR) and the Chicago Police Department's CLEAR (Citizen Law Enforcement Analysis and Reporting) dataset were retrospectively analyzed to investigate group-level factors potentially related to the incidence of gun-related injuries and crime in Chicago from 1999 through 2012. Multivariate linear regression was used to evaluate the effects of day of the week, daily maximum temperature, precipitation, and snow on the incidence of firearm-related injuries and crime. RESULTS: A total of 18,655 gunshot wounds occurred during the study period (ITSR, 1999-2009). There were 156,866 acts of gun violence identified in the CLEAR dataset (2002-2012). Day of the week, daily maximum temperature, and precipitation were associated with differential risks of gun injury and violence. Rain decreased firearm-related injuries by 9.80% [RR: 0.902, 95% CI: 0.854-0.950] and crime by 7.00% [RR: 0.930, 95% CI: 0.910-0.950]. Gunshot wounds were 33% [RR: 1.33, 95% CI: 1.29-1.37] more frequent on Fridays and Saturdays and gun crime was 18% [RR: 1.18, 95% CI: 1.16-1.20] more common on these days. Snow was not associated with firearm-related injuries or crime. CONCLUSIONS: Day of the week, daily maximum temperature, and rain are associated with the incidence of firearm-related injuries and crime. Understanding the effects of these variables may allow for the development of predictive models and for risk-adjusting injury and crime data. PMID- 26646955 TI - Sex determination in a contemporary Mexican population using the scapula. AB - The scapula is useful for sex determination in human skeletons. Muscles provide protection to the scapula making it difficult to fracture, therefore increasing the potential for undamaged scapulae at forensic scenes. The goal of this project is to evaluate the accuracy of discriminant functions, created using an indigenous Guatemalan population when applied to a contemporary Mexican sample for determination of sex from the scapula. The length of the glenoid cavity (LGC) and breadth of the glenoid cavity (BGC) were measured. The sample included 177 individuals (101 males and 76 females) with age ranges from 21 to 100 years old. When the Guatemalan discriminant functions were applied to the Mexican sample they showed high accuracy rates for sexing male scapulae (100%) and low accuracy rates for sexing female scapulae (48.68%-51.32%). Size comparisons were made to an indigenous Guatemalan sample and a contemporary White sample. Overall, LGC and BGC were larger in the Mexican sample than in the Guatemalan sample but LGC and BGC were smaller in the Mexican sample than in the White sample. Population specific discriminant functions were created for the Mexican population with an overall sex classification accuracy rate of 83.6%-89.3%. PMID- 26646956 TI - [Ovarian cancer is in many ways a heterogeneous disease]. AB - Ovarian cancer develops due to a complex interplay between hereditary and environmental factors. Although often described as one disease, ovarian cancer is actually a group of distinct tumor types. Recent research has indicated that a large percentage of ovarian cancers may originate from the fallopian tube epithelium. Although most cancers develop in patients without a known hereditary syndrome, it is clear that the number of familial cancers is larger than previously supposed. The two most common hereditary syndromes where ovarian cancer can develop are hereditary breast ovarian cancer syndrome (HBOC) and Lynch syndrome. PMID- 26646957 TI - [Cervical cancer is a clinical challenge]. AB - Cervical cancer is the third most common female cancer world wide. In Sweden, some 450 cases are diagnosed annually. One out of three affected Swedish women is under the age of 40. Survival for all stages is 73 % in Sweden. Human papilloma virus (HPV) can be detected in the majority of all cervical cancers. Treatment consists of surgery for early stages, and a combination of chemoradiation and brachytherapy for locally advanced disease. For metastatic disease, the treatment is palliative. Late side effects after treatment may have serious impact on the quality of life. There is a strong need for more efficient treatment of metastatic disease. Current lines of research include surgical strategies, optimised radiotherapy, neoadjuvant therapy, targeted therapy, and immunotherapy including therapeutic vaccines. PMID- 26646958 TI - [Early and individualized cancer rehabilitation important]. AB - Survivors of gynecological cancer experience physical, psychological and existential consequences. Late gastrointestinal and urinary bladder symptoms, sexual dysfunction, including underlying physical and relational aspects, as well as lymphedema and fatigue, are common complaints. This may lead to reduced quality of life and social functioning and cancer rehabilitation is needed. Cancer rehabilitation, focusing on the individual cancer survivor and her specific needs, starting at diagnosis and continuing throughout cancer treatment and at follow-ups, is necessary. PMID- 26646959 TI - [Increasingly better diagnosis and treatment of endometrial cancer]. AB - Endometrial cancer is the most common gynecological cancer in developed countries and the observed rise in incidence is mainly caused by life style factors including obesity and diabetes. The management of the disease has undergone major changes in the past 5-10 years. Morphological and genetic studies constitute the basis for the new classification of the disease, and data emerging from the Cancer Genome Atlas suggest that genomic patterns differ within the two types of endometrial cancer. The prognosis seems to be related to occult lymphatic spread but the role of lymphadenectomy is heavily debated. Development of novel biomarkers, sentinel lymph node technique and refined radiological methods may reduce the need of comprehensive staging in the future. The results from the Cancer Genome Atlas suggest that women with endometrial cancer may benefit from "targeted therapies" in the evolving era of personalised medicine. PMID- 26646960 TI - [Individualized treatment for ovarian cancer may become possible]. AB - Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy in developed countries. Several promising steps toward individualized therapy have been taken recently due to increased knowledge of molecular biology. Multidisciplinary conferences for treatment planning and the centralization to tertiary surgical centers improve quality of surgery and survival. The primary treatment of EOC is radical surgery followed by adjuvant chemotherapy with carboplatin and paclitaxel. Bevacizumab added to the chemotherapy and used as maintenance treatment is standard in the primary treatment of patients with residual tumor or inoperable patients. The PARP inhibitor olaparib is recommended as maintenance treatment of women with platinum sensitive relapsed BRCA mutated high-grade serous EOC who have responded to platinum-based chemotherapy. BRCA testing should be offered to women with EOC. In platinum-resistant recurrence addition of bevacizumab to chemotherapy should be considered. PMID- 26646961 TI - [Hope for improvement of survival in ovarian cancer]. AB - Ovarian cancer is the most common cause of death from a gynecologic cancer. Every year around 700 women contracts ovarian cancer in Sweden. The overall survival is among the highest in Europe, but still long term relative survival is only 46%. It is a long-held myth that ovarian cancer is a disease without symptoms. Almost 90% of women have symptoms, even in the early stages. Symptoms that should arise suspicion of ovarian cancer and initiate diagnostic work-up are continuous abdominal extension, early feeling of satiety, pelvic or abdominal pain, urinary urge and postmenopausal bleeding. Women's awareness of symptoms and willingness to seek medical advice and the organization of the health care system are important factors determining cancer survival. Ovarian cancer is a heterogeneous group of diseases with different tumor traits and prognosis. Personalized medicine and preventive measures recognizing recent knowledge about tumor biology will positively affect survival. PMID- 26646962 TI - [Paradigm shift in gynecological cancer]. PMID- 26646963 TI - [Interview instrument provides no reliable assessment of suicide risk. Scientific support is lacking according to report from the Swedish Council on Health Technology Assessment (SBU)]. AB - Identifying individuals at risk of future suicide or suicide attempts is of clinical importance. Instruments have been developed to facilitate the assessment of the risk of future suicidal acts. A systematic review was conducted using the standard methods of the Swedish Council on Health Technology Assessment (SBU). The ability of the instrument to predict risk for future suicide/suicide attempt was assessed at follow up. The methodological quality of eligible studies was assessed; studies with moderate or low risk of bias were analysed in accordance with GRADE. None of the included studies provided scientific evidence to support that any instrument had sufficient accuracy to predict future suicidal behaviour. There is strong evidence to support that the SAD PERSONS Scale has very low sensitivity; most persons who make future suicidal acts are not identified. PMID- 26646965 TI - [Diagnostic errors is a new focus in the IOM report. Diagnostics needs more attention in the work with patient safety]. PMID- 26646964 TI - [The master surgeon Acrel--and treatment of vascular injuries in the 1700s]. PMID- 26646966 TI - [Age discrimination and the shortage of physicians--Stop forcing us to retire]. PMID- 26646967 TI - [Good results from "impossible combination" in child psychiatry]. PMID- 26646968 TI - [Customize inpatient care for patients with autism spectrum disorders]. PMID- 26646969 TI - [The parliamentary ombudsman criticised more than procedural issues]. PMID- 26646971 TI - [Not Available]. PMID- 26646970 TI - [Opioids are not drugs (until they abused)]. PMID- 26646972 TI - [Not Available]. PMID- 26646973 TI - [Age determination is not racism]. PMID- 26646974 TI - Experimental diffuse brain injury results in regional alteration of gross vascular morphology independent of neuropathology. AB - PRIMARY OBJECTIVE: A dynamic relationship exists between diffuse traumatic brain injury and changes to the neurovascular unit. The purpose of this study was to evaluate vascular changes during the first week following diffuse TBI. It was hypothesized that pathology is associated with modification of the vasculature. METHODS: Male Sprague-Dawley rats underwent either midline fluid percussion injury or sham-injury. Brain tissue was collected 1, 2 or 7 days post-injury or sham-injury (n = 3/time point). Tissue was collected and stained by de Olmos amino-cupric silver technique to visualize neuropathology or animals were perfused with AltaBlue casting resin before high-resolution vascular imaging. The average volume, surface area, radius, branching and tortuosity of the vessels were evaluated across three regions of interest. RESULTS: In M2, average vessel volume (p < 0.01) and surface area (p < 0.05) were significantly larger at 1 day relative to 2 days, 7 days and sham. In S1BF and VPM, no significant differences in the average vessel volume or surface area at any of the post-injury time points were observed. No significant changes in average radius, branching or tortuosity were observed. CONCLUSIONS: Preliminary findings suggest gross morphological changes within the vascular network likely represent an acute response to mechanical forces of injury, rather than delayed or chronic pathological processes. PMID- 26646975 TI - Paritaprevir/ritonavir/ombitasvir and dasabuvir for the treatment of chronic hepatitis C virus infection. AB - INTRODUCTION: The use of direct-acting antiviral (DAA) agents against chronic hepatitis C virus (HCV) infections can result in the successful treatment of nearly all patients. Effective antiviral treatments can prevent the progression to cirrhosis and hepatocellular malignancy, and decrease liver-related morbidity and mortality. AREAS COVERED: Paritaprevir-ritonavir-ombitasvir and dasabuvir (PrOD), with or without ribavirin, is an all-oral regimen approved for the treatment of HCV genotype 1 infections, including patients with compensated cirrhosis. Phase 2 and 3 clinical trials demonstrated the safety and efficacy of this regimen in HCV genotype 1-infected patients who are treatment-naive and those who have failed peginterferon/ribavirin therapy. Additional studies evaluated the use of PrOD with or without ribavirin among special populations, including patients co-infected with human immunodeficiency virus-1 and HCV, liver transplant recipients with HCV recurrence, and patients with severe renal impairment. Additionally, the combination of paritaprevir-ritonavir-ombitasvir plus ribavirin is found to be highly efficacious, and is now approved in the US, for the treatment of HCV genotype 4 infections. EXPERT OPINION: The availability and use of interferon-free DAA combination regimens has resulted in a major paradigm shift in the treatment of HCV. PrOD, with or without ribavirin, is an effective, safe and tolerable treatment option. PMID- 26646976 TI - Determination of diethylstilbestrol in seawater by molecularly imprinted solid phase extraction coupled with high-performance liquid chromatography. AB - An effective and highly selective molecularly imprinted material was prepared by suspension polymerization for the isolation and pre-concentration of synthetic estrogen diethylstilbestrol (DES) in seawater. The obtained MIPMs were proved to have more uniform size and porous structure, with maximum adsorption capacity of 8.43 mg g(-1) almost two times more than NIPMs (4.43 mg g(-1)). The MIPMs showed no significant deterioration of the adsorption capacity after five rounds of regeneration. An off-line molecularly imprinted solid phase extraction (MISPE) method followed by HPLC-DAD was proposed for the detection of DES in seawater, and recoveries were satisfactorily higher than 77%. Four seawater samples in aquaculture area were analyzed and 0.61 ng mL(-1) DES was detected in one sample. The result demonstrated that this method can be used for the rapid separation and clean up of trace residual of DES in seawater. PMID- 26646977 TI - Frank Horan 1933-2015. PMID- 26646978 TI - A Quality Improvement Project to Increase Early Detection of Syphilis Infection or Re-infection in HIV-infected Men Who Have Sex With Men. AB - Our quality improvement project evaluated whether testing for syphilis every 3 to 6 months with routine HIV laboratory monitoring had an effect on early detection of asymptomatic syphilis infection/re-infection in HIV-infected men who have sex with men. Retrospective analysis of syphilis testing and infections in a sample of this population (N = 245) was conducted after establishing a change-of practice quality improvement initiative in a not-for-profit, community-based, grant-funded clinic. We compared the clinic's annual rates of syphilis before and after intervention implementation. The detection rate was 6.6% in the preintervention practice change group and 15.5% in the postintervention group. Increased testing identified 27 syphilis cases that would not otherwise have been identified until the annual comprehensive examination. Increased testing frequency led to earlier detection of syphilis, which was clinically significant, showing a potential to decrease the number of new syphilis and HIV infections and to decrease health care expenditures. PMID- 26646979 TI - The urgent need for risk assessment on the antibiotic resistance spread via sewage sludge land application. AB - Sewage sludge is an ever-increasing by-product of the wastewater treatment process frequently used as a soil fertiliser. To control its quality and prevent any possible hazardous impact of fertilisation, some mandatory limits of heavy metal content have been established by the European Commission (Sewage Sludge Directive). However, since the implementation of the limits, new emerging contaminants have been reported worldwide. Regardless of the wastewater treatment process, sewage sludge contains antibiotics, antibiotic-resistant bacteria and antibiotic resistance genes, which can be released into the environment through its land application. Such a practice may even boost the dissemination and further development of antibiotic resistance phenomenon - already a global problem challenging modern medicine. Due to the growing pharmaceutical pollution in the environment, the time is ripe to assess the risk for the human and environmental health of sewage sludge land application in the context of antibiotic resistance spread. In this review we present the current knowledge in the field and we emphasise the necessity for more studies. PMID- 26646980 TI - Application of novel, low-cost, laterite-based adsorbent for removal of lead from water: Equilibrium, kinetic and thermodynamic studies. AB - Contamination of groundwater by carcinogenic heavy metal, e.g., lead is an important issue and possibility of using a natural rock, laterite, is explored in this work to mitigate this problem. Treated laterite (TL- prepared using hydrochloric acid and sodium hydroxide) was successfully utilized for this purpose. The adsorbent was characterized using scanning electron microscopy (SEM), X-ray diffraction (XRD), energy dispersive X-ray (EDX), and Fourier Transform Infrared Spectroscopy (FTIR) to highlight its physical and chemical properties. Optimized equilibrium conditions were 1 g L(-1) adsorbent concentration, 0.26 mm size and a pH of 7 +/- 0.2. Monolayer adsorption capacity of lead on treated laterite was 15 mg/g, 14.5 and 13 mg g(-1) at temperatures of 303 K, 313 K and 323 K, respectively. The adsorption was exothermic and physical in nature. At 303 K, value of effective diffusivity of (De) and mass transfer co efficient (Kf) of lead onto TL were 6.5 * 10(-10) m(2)/s and 3.3 * 10(-4) m/s, respectively (solved from shrinking core model of adsorption kinetics). Magnesium and sulphate show highest interference effect on the adsorption of lead by TL. Efficacy of the adsorbent has been verified using real-life contaminated groundwater. Thus, this work demonstrates performance of a cost-effective media for lead removal. PMID- 26646981 TI - MRI/MRS as a surrogate marker for clinical progression in GM1 gangliosidosis. AB - Background GM1 gangliosidosis is a lysosomal storage disorder caused by mutations in GLB1, encoding beta-galactosidase. The range of severity is from type I infantile disease, lethal in early childhood, to type III adult onset, resulting in gradually progressive neurological symptoms in adulthood. The intermediate group of patients has been recently classified as having type II late infantile subtype with onset of symptoms at one to three years of age or type II juvenile subtype with symptom onset at 2-10 years. To characterize disease severity and progression, six Late infantile and nine juvenile patients were evaluated using magnetic resonance imaging (MRI), and MR spectroscopy (MRS). Since difficulties with ambulation (gross motor function) and speech (expressive language) are often the first reported symptoms in type II GM1, patients were also scored in these domains. Deterioration of expressive language and ambulation was more rapid in the late infantile patients. Fourteen MRI scans in six Late infantile patients identified progressive atrophy in the cerebrum and cerebellum. Twenty-six MRI scans in nine juvenile patients revealed greater variability in extent and progression of atrophy. Quantitative MRS demonstrated a deficit of N acetylaspartate in both the late infantile and juvenile patients with greater in the late infantile patients. This correlates with clinical measures of ambulation and expressive language. The two subtypes of type II GM1 gangliosidosis have different clinical trajectories. MRI scoring, quantitative MRS and brain volume correlate with clinical disease progression and may serve as important minimally invasive outcome measures for clinical trials. PMID- 26646982 TI - A critical hybrid realist-outcomes systematic review of relationships between medical education programmes and communities: BEME Guide No. 35. AB - BACKGROUND: The relationships between medical schools and communities have long inspired and troubled medical education programmes. Successive models of community-oriented, community-based and community-engaged medical education have promised much and delivered to varying degrees. A two-armed realist systematic review was undertaken to explore and synthesize the evidence on medical school community relationships. METHOD: One arm used standard outcomes criteria (Kirkpatrick levels), the other a realist approach seeking out the underlying contexts, mechanisms and outcomes. 38 reviewers completed 489 realist reviews and 271 outcomes reviews; 334 articles were reviewed in the realist arm and 181 in the outcomes arm. Analyses were based on: descriptive statistics on both articles and reviews; the outcomes involved; the quality of the evidence presented; realist contexts, mechanisms, and outcomes; and an analysis of underlying discursive themes. FINDINGS: The literature on medical school-community relationships is heterogeneous and largely idiographic, with no common standards for what a community is, who represents communities, what a relationship is based on, or whose needs are or should be being addressed or considered. CONCLUSIONS: Community relationships can benefit medical education, even if it is not always clear why or how. There is much opportunity to improve the quality and precision of scholarship in this area. PMID- 26646983 TI - Problematic cybersex: Conceptualization, assessment, and treatment. AB - Problematic involvement in cybersex is generally considered to be an excessive and uncontrolled use of online sexual activities associated with tangible negative outcomes and functional impairment. To date, there is no consensus in the literature regarding the conceptualization and labeling of this disorder, or of its diagnosis and assessment (e.g., screening questionnaires and diagnostic criteria). Through a systematic examination of the literature, we emphasize that problematic cybersex is an umbrella construct that regroups various types of distinct dysfunctional online behaviors. Despite a considerable increase in studies on problematic cybersex, no clear diagnostic guidelines exist for clinicians and researchers. Moreover, the factors involved in the development and maintenance of the disorder remain poorly examined, and the evidence regarding valid assessment and treatment are lacking. PMID- 26646984 TI - Effect of Flavourzyme((r)) on Angiotensin-Converting Enzyme Inhibitory Peptides Formed in Skim Milk and Whey Protein Concentrate during Fermentation by Lactobacillus helveticus. AB - Angiotensin-converting enzyme inhibitory (ACE-I) activity as affected by Lactobacillus helveticus strains (881315, 881188, 880474, and 880953), and supplementation with a proteolytic enzyme was studied. Reconstituted skim milk (12% RSM) or whey protein concentrate (4% WPC), with and without Flavourzyme((r)) (0.14% w/w), were fermented with 4 different L. helveticus strains at 37 degrees C for 0, 4, 8, and 12 h. Proteolytic and in vitro ACE-I activities, and growth were significantly affected (P < 0.05) by strains, media, and with enzyme supplementation. RSM supported higher growth and produced higher proteolysis and ACE-I compared to WPC without enzyme supplementation. The strains L. helveticus 881315 and 881188 were able to increase ACE-I to >80% after 8 h of fermentation when combined with Flavourzyme((r)) in RSM compared to the same strains without enzyme supplementation. Supplementation of media by Flavourzyme((r)) was beneficial in increasing ACE-I peptides in both media. The best media to release more ACE-I peptides was RSM with enzyme supplementation. The L. helveticus 881315 outperformed all strains as indicated by highest proteolytic and ACE-I activities. PMID- 26646985 TI - Correction: One-pot atom-efficient synthesis of bio-renewable polyesters and cyclic carbonates through tandem catalysis. AB - Correction for 'One-pot atom-efficient synthesis of bio-renewable polyesters and cyclic carbonates through tandem catalysis' by Fan Jia et al., Chem. Commun., 2015, 51, 8504-8507. PMID- 26646987 TI - Rupture of renal artery aneurysm during late pregnancy: clinical features and diagnosis. AB - PURPOSE: Rupture of renal artery aneurysm during pregnancy is a severe complication with high mortality and morbidity for mother and fetus, and diagnosis is difficult. The clinical presentation is easily confused with more common conditions like placental abruption, and most of the cases are diagnosed with timely delay. METHODS: We present the case of a patient with spontaneous rupture of an aneurysm of the left renal artery during late pregnancy and summarize the previous reports of ruptured renal artery aneurysm during pregnancy and early postpartum period. RESULTS: Regarding all published cases up to now (n = 32), 65.6% of mothers and 40.6% of fetuses survived. The rupture occurred in 68.7% in the third trimester and in 6.3% shortly postpartum. In our case, the increase of maternal serum lactate in a hemodynamically stable patient lead to diagnosis. CONCLUSIONS: Ruptured renal artery aneurysm should be included in the differential diagnosis for pregnant or peripartum patients presenting with flank pain. Early diagnosis and immediate intervention are important for achieving better outcomes for mother and fetus. Careful surveillance and laboratory results like serum lactate may lead to diagnosis even in hemodynamically stable patients. PMID- 26646986 TI - Characterization of a Novel Human-Specific STING Agonist that Elicits Antiviral Activity Against Emerging Alphaviruses. AB - Pharmacologic stimulation of innate immune processes represents an attractive strategy to achieve multiple therapeutic outcomes including inhibition of virus replication, boosting antitumor immunity, and enhancing vaccine immunogenicity. In light of this we sought to identify small molecules capable of activating the type I interferon (IFN) response by way of the transcription factor IFN regulatory factor 3 (IRF3). A high throughput in vitro screen yielded 4-(2-chloro 6-fluorobenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6 carboxamide (referred to herein as G10), which was found to trigger IRF3/IFN associated transcription in human fibroblasts. Further examination of the cellular response to this molecule revealed expression of multiple IRF3-dependent antiviral effector genes as well as type I and III IFN subtypes. This led to the establishment of a cellular state that prevented replication of emerging Alphavirus species including Chikungunya virus, Venezuelan Equine Encephalitis virus, and Sindbis virus. To define cellular proteins essential to elicitation of the antiviral activity by the compound we employed a reverse genetics approach that utilized genome editing via CRISPR/Cas9 technology. This allowed the identification of IRF3, the IRF3-activating adaptor molecule STING, and the IFN associated transcription factor STAT1 as required for observed gene induction and antiviral effects. Biochemical analysis indicates that G10 does not bind to STING directly, however. Thus the compound may represent the first synthetic small molecule characterized as an indirect activator of human STING-dependent phenotypes. In vivo stimulation of STING-dependent activity by an unrelated small molecule in a mouse model of Chikungunya virus infection blocked viremia demonstrating that pharmacologic activation of this signaling pathway may represent a feasible strategy for combating emerging Alphaviruses. PMID- 26646988 TI - Maternal bereavement and the risk of preterm delivery: the importance of gestational age and of the precursor of preterm birth. AB - BACKGROUND: Maternal stress during pregnancy may increase the risk of preterm delivery (PD), but the associations between stress and subtypes of PD are not clear. We investigated maternal loss of a close relative and risks of very and moderately PD (<32 and 32-36 weeks, respectively) and spontaneous and medically indicated PD. METHOD: We studied 4 940 764 live singleton births in Denmark (1978 2008) and Sweden (1973-2006). We retrieved information on death of women's family members (children, partner, siblings, parents), birth outcomes and maternal characteristics from nationwide registries. RESULTS: Overall, the death of a close family member the year before pregnancy or in the first 36 weeks of pregnancy was associated with a 7% increased risk of PD [95% confidence interval (CI) 1.04-1.10]. The highest hazard ratios (HR) for PD were found for death of an older child [HR (95% CI) 1.20 (1.10-1.31)] and for death of a partner [HR (95% CI) 1.31 (1.03-1.66)]. These losses were associated with higher risks of very preterm [HR (95% CI) 1.61 (1.29-2.01) and 2.07 (1.15-3.74), respectively] than of moderately preterm [HR (95% CI) 1.14 (1.03-1.26) and 1.22 (0.94-1.58), respectively] delivery. There were no substantial differences in the association between death of a child or partner and the risk of spontaneous v. medically indicated PD. CONCLUSIONS: Death of a close family member the year before or during pregnancy was associated with an increased risk of PD, especially very PD. Possible mechanisms include both spontaneous and medically indicated preterm birth. PMID- 26646989 TI - High Yield Production and Radiochemical Isolation of Isotopically Pure Arsenic-72 and Novel Radioarsenic Labeling Strategies for the Development of Theranostic Radiopharmaceuticals. AB - Radioisotopes of arsenic are of considerable interest to the field of nuclear medicine with unique nuclear and chemical properties making them well-suited for use in novel theranostic radiopharmaceuticals. However, progress must still be made in the production of isotopically pure radioarsenic and in its stable conjugation to biological targeting vectors. This work presents the production and irradiation of isotopically enriched (72)Ge(m) discs in an irrigation-cooled target system allowing for the production of isotopically pure (72)As with capability on the order of 10 GBq. A radiochemical separation procedure isolated the reactive trivalent radioarsenic in a small volume buffered aqueous solution, while reclaiming (72)Ge target material. The direct thiol-labeling of a monoclonal antibody resulted in a conjugate exhibiting exceptionally poor in vivo stability in a mouse model. This prompted further investigations to alternative radioarsenic labeling strategies, including the labeling of the dithiol containing chelator dihydrolipoic acid, and thiol-modified mesoporous silica nanoparticles (MSN-SH). Radioarsenic-labeled MSN-SH showed exceptional in vivo stability toward dearsenylation. PMID- 26646990 TI - How hematopoietic stem/progenitors and their niche sense and respond to infectious stress. AB - Hematopoietic stem/progenitor cells (HSPCs) play important roles in fighting systemic infection as they supply immune cells in a demand-adapted manner. Various mechanisms govern HSPC responses to infection, including cytokine signaling, niche function, and direct sensing of pathogen-derived molecules by HSPCs themselves. Here we review recent advances in our understanding of HSPC responses to infection and also consider newly identified STING-mediated machinery recognizing bacteria-derived cyclic dinucleotides. PMID- 26646992 TI - Tracking erythroid progenitor cells in times of need and times of plenty. AB - Red blood cell production rates increase rapidly following blood loss or hemolysis, but the expansion of erythropoiesis in these anemic states is tightly regulated such that rebound polycythemia does not occur. The erythroid cells that respond to erythropoietic stimulation or suppression are the progenitor stages of burst-forming units-erythroid (BFU-Es) and colony-forming units-erythroid (CFU Es). Results from an early study of the changes in the size, location, and cell cycling status of BFU-E and CFU-E populations in mice under normal conditions, erythropoietic stimulation, and erythropoietic suppression are used as reference points to review subsequent developments related to erythroid progenitor populations and regulation of their size. The review concerns development of erythroid progenitor populations mainly in mice and humans, with a focus on the mechanisms related to the rapid but highly regulated expansion of erythropoiesis in spleens of erythropoietically stimulated mice. Current knowledge is used as a model of erythroid progenitor populations in mice under normal, erythropoietically suppressed, and erythropoietically stimulated conditions. Clinical applications of information learned from studies of erythropoietic expansion, in terms of current therapies for anemia, are reviewed. PMID- 26646991 TI - Acquired uniparental disomy of chromosome 9p in hematologic malignancies. AB - Acquired uniparental disomy (aUPD) is a common and recurrent molecular event in human cancers that leads to homozygosity for tumor suppressor genes as well as oncogenes, while retaining the diploid chromosomal complement. Because of the lack of copy number change, aUPD is undetectable by comparative genome hybridization, so the magnitude of this genetic change was underappreciated in the past. 9p aUPD was first described in 2002 in patients with polycythemia vera (PV). Since then, systematic application of genomewide single-nucleotide polymorphism arrays has indicated that 9p aUPD is the most common chromosomal aberration in myeloproliferative neoplasms (MPNs), contributing to discovery of the PV-defining mutation JAK2V617F21. It was also found in other myeloid and lymphoid malignancies, though at a relatively lower frequency. By leading to JAK2V617F 23 homozygosity, 9p aUPD plays a causal role in the development of PV and is also associated with less favorable clinical outcomes. It is also possible that new targets other than JAK2V617F 25 are present within 9p aUPD that may contribute to diversity of PV outcome and phenotype. This review summarizes recent discoveries on 9p aUPD in hematologic malignancies and discusses possible underlying mechanisms and potential roles of 9p aUPD in the pathogenesis of PV, the relationship between 9p aUPD and JAK2V617F29, and possible new cancer-related targets within the 9p aUPD region. PMID- 26646993 TI - ACR Practice Parameter for the Performance of Therapy With Unsealed Radiopharmaceutical Sources. AB - This practice parameter is intended to guide appropriately trained and licensed physicians performing therapy with unsealed radiopharmaceutical sources. Such therapy requires close cooperation and communication between the physicians who are responsible for the clinical management of the patient and those who administer radiopharmaceutical therapy and manage the attendant side effects. Adherence to this practice parameter should help to maximize the efficacious use of these procedures, maintain safe conditions, and ensure compliance with applicable regulations. The goal of therapy with unsealed radiopharmaceutical sources is to provide either cure or effective palliation of disease while minimizing untoward side effects and complications. PMID- 26646994 TI - ACR-ASNR Practice Parameter for Brain PET/CT Imaging Dementia. AB - This practice parameter is for both FDG and amyloid brain PET or PET/computed tomography (CT) for patients with cognitive decline, and has been developed collaboratively by the American College of Radiology (ACR) and the American Society for Neuroradiology (ASNR). It is estimated that the number of people with dementia, 36.5 million worldwide in 2010, will increase to 65.7 million in 2030 and to 115 million in 2050. Four primary neurodegenerative etiologies of dementia have been defined: Alzheimer disease (AD), vascular dementia, frontotemporal dementia (FTD), and dementia with Lewy bodies (DLB). Alzheimer disease is the most common form of dementia, accounting for approximately 60%-80% of all cases. Indications for FDG and amyloid brain PET and qualifications for personnel are discussed in this practice parameter. PMID- 26646995 TI - Impact of Patient Preparation on the Diagnostic Performance of 18F-FDG PET in Cardiac Sarcoidosis: A Systematic Review and Meta-analysis. AB - PURPOSE: F-FDG PET/CT is a valuable diagnostic tool in the evaluation of cardiac sarcoidosis. Appropriate patient preparation is important because the diagnostic accuracy of this procedure depends on adequate suppression of physiologic glucose uptake. This systematic review and meta-analysis aims to assess the effect of different patient preparations on the diagnostic accuracy of F-FDG PET/CT in cardiac sarcoidosis. PATIENTS AND METHODS: We searched the PubMed/MEDLINE, Embase, and Cinicaltrials.gov databases. Sixteen studies (n = 559) were identified to be suitable for this systemic review. Studies were stratified according to fasting duration and means of physiologic suppression of F-FDG by cardiac tissue, which involves the use of heparin infusion or high-fat, low carbohydrate diet before imaging. Study quality was assessed using the QUADAS-2 tool. Forest plots of sensitivity and specificity were calculated in Review Manager 5.3, and a random-effects hierarchical summary receiver operating characteristic model was created using MetaDiSc. Meta-regression was performed to investigate sources of heterogeneity. RESULTS: PET/CT had an overall Specificity of 0.75 (95% confidence interval [CI], 0.69-0.80) and specificity of 0.81 (95% CI, 0.76-0.85) for the diagnosis of cardiac sarcoidosis. This modest diagnostic accuracy was attributed to the inclusion of large single study in which a short fasting duration before scanning likely influenced its sensitivity. Its exclusion resulted in an overall sensitivity of 0.81 (95% CI, 0.76-0.86) and specificity of 0.82 (95% CI, 0.77-0.86). Meta-regression showed that the diagnostic odds ratio was significantly affected by fasting time and heparin administration before scanning (P = 0.01, 0.02) but not with high-fat, low-carbohydrate diet (P = 0.17). CONCLUSIONS: F-FDG PET/CT plays an integral role in the diagnosis of cardiac sarcoidosis. Diagnostic accuracy is affected by fasting duration and means of cardiomyocyte glucose uptake suppression before scanning. PMID- 26646996 TI - Malignant Jugular Paraganglioma: Unusual Presentation on 68Ga DOTANOC PET/CT. AB - Metastatic jugular paraganglioma are rare tumors and account for less than 1% of the cases of head and neck tumors. We report a 40-year-old woman of jugular paraganglioma, presenting with right-sided neck swelling, hearing loss, and pulsatile tinnitus. Contrast-enhanced CT temporal bone revealed a mass in the right jugular foramina and extending inferiorly to internal jugular vein. Ga DOTANOC PET/CT was performed, which revealed somatostatin receptor expressing lesion in the right internal jugular vein and extension into sigmoid sinus and additional metastatic focus in the sacrum. PMID- 26646997 TI - Conjunctival Melanoma on 18F-FDG PET/CT as a Second Primary Cancer. AB - Herein we present the F-FDG PET/CT findings in conjunctival melanoma as a second primary cancer in a 56-year-old Taiwanese man with a history of small lymphocytic lymphoma/chronic lymphocytic leukemia and nasal cavity carcinoma under remission. The right eye lesion slowly progressed since noted by the patient himself 2 years ago, but he refused biopsy and further treatment including surgery. Either small lymphocytic lymphoma/chronic lymphocytic leukemia or conjunctival melanoma is extremely rare in Asians, left alone in combination with a third malignancy of nasal cavity carcinoma. FDG PET/CT could effectively evaluate malignancies with multiple primary origins. PMID- 26646998 TI - Utility of 11C-Methionine and 18F-FDG PET/CT in Patients With Functioning Pituitary Adenomas. AB - PURPOSE: MRI is commonly used in the evaluation of pituitary adenomas (PAs). However, it has difficulty to locate the lesions sometimes, especially microadenomas and/or postoperative recurrent tumors. We aimed to evaluate the role of combined C-methionine (MET) and F-FDG PET/CT in patients with functioning PAs. PATIENTS AND METHODS: This study included 43 patients: 15 had Cushing disease, 16 had acromegaly, and 12 had a prolactinoma. F-FDG PET/CT was performed on all of the patients; C-MET PET/CT was performed on 39 of the patients. The PET images and surgical findings were analyzed. RESULTS: On F-FDG PET/CT, 29 (67%) of 43 cases had positive results, all of which were true positives, including 2 cases with equivocal MRI results. On C-MET PET/CT, 37 (95%) of 39 cases had positive results, of which 2 were false positives. All patients underwent surgery, and the results of PET/CT scans were confirmed by surgery and pathological examination. All F-FDG PET/CT results were negative when C-MET PET/CT results were negative. However, 12 patients with positive C-MET PET/CT results had negative F-FDG PET/CT results. The positive rate of F-FDG PET/CT in patients with somatostatin analog treatment, radiosurgery, transsphenoidal surgery, and microadenoma was 63% (5/8), 50% (1/2), 33% (4/12), and 48%(10/21), respectively, while that of C-MET PET/CT was 86% (6/7), 50% (1/2), 100% (12/12), and 100% (21/21), respectively. In the 9 patients with a recurrent microadenoma, the positive rate of F-FDG PET/CT was as low as 22% while that of C-MET PET/CT was 100%. There was no significant difference in the positive rate of C-MET and F FDG PET/CT between the 3 types of PA. CONCLUSIONS: PET/CT may be useful to detect tumors in patients with equivocal MRI results. C-MET PET/CT can provide valuable diagnostic information when F-FDG PET/CT yields negative results, especially in patients with recurrent microadenomas. PMID- 26646999 TI - Follicular Thyroid Adenoma Showing Avid Uptake on 68Ga PSMA-HBED-CC PET/CT. AB - 68Ga-prostate-specific membrane antigen (PSMA) PET/CT imaging is a relatively new imaging technique used to evaluate the extent of disease in prostate carcinoma. Various other neoplasms may also express PSMA and show uptake on PSMA PET/CT scan. We report a case of a 62-year-old man who had a PSMA PET/CT scan for restaging of prostate carcinoma. A PSMA-avid thyroid lesion was identified, and subsequent tissue sampling confirmed the diagnosis of follicular thyroid adenoma. It is important to be aware of this possibility to avoid scan misinterpretation. Tissue biopsy of PSMA-avid thyroid lesions should be considered to exclude a primary thyroid neoplasm. PMID- 26647000 TI - False-Positive 18F-FDG PET/CT Imaging: Dramatic "Flare Response" After Rituximab Administration. AB - We report the case of a 45-year-old woman diagnosed with non-Hodgkin lymphoma. Six months after completion of R-CHOP, she relapsed, and 2 cycles of R-ESHAP were given, with a view to allograft transplant. One month later, F-FDG PET/CT revealed disease progression. Biopsy of lymph nodes showed reactive changes, without evidence of lymphoma. Rituximab, a monoclonal antibody, is used for treatment of non-Hodgkin lymphoma, but its addition may result in an extensive inflammatory response. It is important to be aware of the potential for false positive F-FDG PET/CT imaging after rituximab therapy. Unexpected findings should be confirmed by biopsy. PMID- 26647001 TI - 68Ga-NOTA-Exendin-4 PET/CT in Localization of an Occult Insulinoma and Appearance of Coexisting Esophageal Carcinoma. AB - A 61-year-old woman with biochemically proven endogenous hyperinsulinemic hypoglycemia and negative conventional imaging underwent 68Ga-NOTA-exendin-4 PET/CT for localization of insulinoma. Focal intense radioactivity in the tail of the pancreas was observed that was subsequently confirmed as insulinoma pathologically after surgical resection. In addition, esophageal carcinoma with lymph node and hepatic metastases was found by FDG PET/CT in the same patient. Neither the primary carcinoma nor the metastases showed increased radioactivity on 68Ga-NOTA-exendin-4 PET/CT. PMID- 26647002 TI - Early speech perception in Mandarin-speaking children at one-year post cochlear implantation. AB - PURPOSE: The aim in this study was to examine early speech perception outcomes in Mandarin-speaking children during the first year of cochlear implant (CI) use. METHOD: A hierarchical early speech perception battery was administered to 80 children before and 3, 6, and 12 months after implantation. Demographic information was obtained to evaluate its relationship with these outcomes. RESULTS: Regardless of dialect exposure and whether a hearing aid was trialed before implantation, implant recipients were able to attain similar pre-lingual auditory skills after 12 months of CI use. Children speaking Mandarin developed early Mandarin speech perception faster than those with greater exposure to other Chinese dialects. In addition, children with better pre-implant hearing levels and younger age at implantation attained significantly better speech perception scores after 12 months of CI use. Better pre-implant hearing levels and higher maternal education level were also associated with a significantly steeper growth in early speech perception ability. CONCLUSIONS: Mandarin-speaking children with CIs are able to attain early speech perception results comparable to those of their English-speaking counterparts. In addition, consistent single language input via CI probably enhances early speech perception development at least during the first-year of CI use. PMID- 26647003 TI - Adverse events and the relation with quality of life in adults with intellectual disability and challenging behaviour using psychotropic drugs. AB - BACKGROUND: Psychotropic drugs are prescribed to approximately 30-40% of adults with intellectual disability (ID) and challenging behaviour, despite the limited evidence of effectiveness and the potential of adverse events. AIMS: To assess the prevalence of adverse events in association with psychotropic drug use in adults with ID and challenging behaviour and to examine the relation of these adverse events with the person's quality of life. METHOD: The presence of adverse events was measured with a questionnaire that had to be filled in by the physicians of the participants. Movement disorders were measured separately with a standardised protocol. The strength of the association between adverse events and Intellectual Disability Quality of Life-16 (IDQOL-16), and daily functioning was investigated using linear regression analyses, taking into account the severity of disease (CGI-S) as potential confounder. RESULTS: Virtually all of 103 adults with ID and challenging behaviour had at least one adverse event (84.4%) and almost half had >=3 adverse events (45.6%) across different subclasses. Using psychotropic drugs increased the prevalence of adverse events significantly. Respectively 13% of the patients without psychotropic drugs and 61% of the patients with >=2 psychotropic drugs had >=3 adverse events. Having adverse events had a significantly negative influence on the quality of life. CONCLUSIONS: A large majority of all patients had at least one adverse event associated with psychotropic drug use. More attention is needed for these adverse events and their negative influence on the quality of life of these patients, taking into account the lack of evidence of effectiveness of psychotropic drugs for challenging behaviour. PMID- 26647004 TI - Event-based prospective memory in mildly and severely autistic children. AB - BACKGROUND: There is a growing body of research into the development of prospective memory (PM) in typically developing children but research is limited in autistic children (Aut) and rarely includes children with more severe symptoms. AIMS: This study is the first to specifically compare event-based PM in severely autistic children to mildly autistic and typically developing children. METHODS AND PROCEDURES: Fourteen mildly autistic children and 14 severely autistic children, aged 5-13 years, were matched for educational attainment with 26 typically developing children aged 5-6 years. Three PM tasks and a retrospective memory task were administered. OUTCOMES AND RESULTS: Results showed that severely autistic children performed less well than typically developing children on two PM tasks but mildly autistic children did not differ from either group. No group differences were found on the most motivating (a toy reward) task. CONCLUSIONS AND IMPLICATIONS: The findings suggest naturalistic tasks and motivation are important factors in PM success in severely autistic children and highlights the need to consider the heterogeneity of autism and symptom severity in relation to performance on event-based PM tasks. PMID- 26647005 TI - Synthesis and Evaluation of 131I-Skyrin as a Necrosis Avid Agent for Potential Targeted Radionuclide Therapy of Solid Tumors. AB - An innovative anticancer approach targeted to necrotic tissues, which serves as a noncancerous and generic anchor, may present a breakthrough. Necrosis avid agents with a flat conjugate aromatic structure selectively accumulate in necrotic tissues, but they easily form aggregates that undesirably distribute to normal tissues. In this study, skyrin, a dianthraquinone compound with smaller and distorted pi-cores and thus decreased aggregates as compared with hypericin (Hyp), was designed to target necrosis for tumor therapy. Aggregation studies of skyrin by UV/vis spectroscopy showed a smaller self-association constant with skyrin than with Hyp. Skyrin was labeled by iodine-131 with a radiochemical purity of 98% and exhibited good stability in rat serum for 72 h. In vitro cell uptake studies showed significant difference in the uptake of 131I-skyrin by necrotic cells compared to normal cells (P < 0.05). Compared in rats with liver and muscle necrosis, radiobiodistribution, whole-body autoradiography, and SPECT/CT studies revealed higher accumulation of 131I-skyrin in necrotic liver and muscle (p < 0.05), but lower uptake in normal organs, relative to that of 131I-Hyp. In mice bearing H22 tumor xenografts treated with combretastatin A4 disodium phosphate, the highest uptake of 131I-skyrin was found in necrotic tumor. In conclusion, 131I-skyrin appears a promising agent with reduced accumulation in nontarget organs for targeted radionuclide therapy of solid tumors. PMID- 26647006 TI - Natalizumab Discontinuation and Treatment Strategies in Patients with Multiple Sclerosis (MS): A Retrospective Study from Two Italian MS Centers. AB - INTRODUCTION: Natalizumab (NTZ) discontinuation can be followed by multiple sclerosis (MS) disease reactivation. Currently no disease-modifying drug (DMD) has been shown to be able to abolish disease reactivation. The aims of the current study were: (1) to determine the frequency of MS reactivation after NTZ discontinuation; (2) to evaluate predictors of reactivation risk, and (3) to compare the effect of different treatments in reducing this risk. METHODS: Data from 132 patients with MS followed-up for 2 years before NTZ treatment and 1 year after interruption were collected from two Italian MS centers and retrospectively evaluated. RESULTS: Overall, 72 of 132 patients (54.5%) had relapses after NTZ discontinuation and 60 of 125 patients (48%), who had magnetic resonance imaging, had radiological reactivation. Rebound was observed in 28 of 132 patients (21.2%). A higher number of relapses in the 2 years before NTZ treatment, a longer washout period, and a lower number NTZ infusions correlated with reactivation and rebound. Untreated patients (n = 37) had higher clinical and radiological activity and rebound in comparison to patients receiving DMDs. Moreover, a lower risk of relapses was found in patients treated with second-line therapies (NTZ and fingolimod) than in those treated with first-line therapies (interferon beta, glatiramer acetate, teriflunomide, azathioprine). Interestingly, no disease reactivation in off-label treatment (rituximab, autologous hematopoietic stem cell transplantation) was observed. CONCLUSION: NTZ discontinuation is a risk for MS reactivation and rebound. An alternative treatment should be promptly resumed mainly in patients with a previous very active disease course and with a shorter NTZ therapy. Second-line therapies demonstrate superiority in preventing relapses after NTZ discontinuation. PMID- 26647007 TI - Estimation of Radiative Efficiency of Chemicals with Potentially Significant Global Warming Potential. AB - Halogenated chemical substances are used in a broad array of applications, and new chemical substances are continually being developed and introduced into commerce. While recent research has considerably increased our understanding of the global warming potentials (GWPs) of multiple individual chemical substances, this research inevitably lags behind the development of new chemical substances. There are currently over 200 substances known to have high GWP. Evaluation of schemes to estimate radiative efficiency (RE) based on computational chemistry are useful where no measured IR spectrum is available. This study assesses the reliability of values of RE calculated using computational chemistry techniques for 235 chemical substances against the best available values. Computed vibrational frequency data is used to estimate RE values using several Pinnock type models, and reasonable agreement with reported values is found. Significant improvement is obtained through scaling of both vibrational frequencies and intensities. The effect of varying the computational method and basis set used to calculate the frequency data is discussed. It is found that the vibrational intensities have a strong dependence on basis set and are largely responsible for differences in computed RE values. PMID- 26647009 TI - An evidence-based medicine field guide to new and current psychotropic medications and related drugs: a virtual issue of the International Journal of Clinical Practice. PMID- 26647008 TI - Selective attrition and intraindividual variability in response time moderate cognitive change. AB - OBJECTIVES: Selection of a developmental time metric is useful for understanding causal processes that underlie aging-related cognitive change and for the identification of potential moderators of cognitive decline. Building on research suggesting that time to attrition is a metric sensitive to non-normative influences of aging (e.g., subclinical health conditions), we examined reason for attrition and intraindividual variability (IIV) in reaction time as predictors of cognitive performance. METHOD: Three hundred and four community dwelling older adults (64-92 years) completed annual assessments in a longitudinal study. IIV was calculated from baseline performance on reaction time tasks. Multilevel models were fit to examine patterns and predictors of cognitive change. RESULTS: We show that time to attrition was associated with cognitive decline. Greater IIV was associated with declines on executive functioning and episodic memory measures. Attrition due to personal health reasons was also associated with decreased executive functioning compared to that of individuals who remained in the study. DISCUSSION: These findings suggest that time to attrition is a useful metric for representing cognitive change, and reason for attrition and IIV are predictive of non-normative influences that may underlie instances of cognitive loss in older adults. PMID- 26647010 TI - Proton pump inhibitors and hypomagnesemia in patients with arrhythmias. PMID- 26647011 TI - Anemia should not be the reason for consideration of heavy menstrual bleeding. PMID- 26647012 TI - Neuregulin 1 Attenuates Neuronal Apoptosis Induced by Deep Hypothermic Circulatory Arrest Through ErbB4 Signaling in Rats. AB - Mounting evidence suggests that neurological injury occurs after deep hypothermic circulatory arrest (DHCA), a protocol widely used in surgery for congenital heart diseases and aortic repair. Neuregulin 1 (NRG1), a neurotrophic factor highly expressed in the central nervous system, is crucial for neuronal survival. However, whether NRG1 is protective against apoptosis induced by DHCA is still unclear, as are the putative mechanisms involved. In this study, exogenous human NRG1 pretreatment (2.5 and 3.75 ng/kg, intracarotid injection) significantly inhibited neuronal apoptosis in DHCA-treated male rats, and notably, endogenous NRG1 expression was also increased. Bcl-2, as well as phosphorylated phosphatidylinositol-3-kinase, Akt, and cAMP-response element binding protein, were all increased, resulting in phosphorylation and subsequent activation of the ErbB4 receptor. Finally, expression of the apoptosis-related protein cleaved caspase-3 was decreased, resulting in the inhibition of neuronal apoptosis induced by DHCA. Thus, our data indicate that NRG1 treatment inhibited DHCA induced neuronal apoptosis by activating ErbB4 signaling, providing a potential therapeutic pathway for the prevention of neurological injury induced by DHCA. PMID- 26647013 TI - Asiatic Acid Attenuates the Progression of Left Ventricular Hypertrophy and Heart Failure Induced by Pressure Overload by Inhibiting Myocardial Remodeling in Mice. AB - Cardiac structural remodeling, including cardiomyocyte apoptosis, interstitial fibrosis, and inflammation, appears to be a key event associated with the progression of left ventricular hypertrophy and heart failure. Asiatic acid (AA) is a triterpenoid compound extracted from Centella asiatica that exhibits antiapoptotic, antifibrotic, and anti-inflammatory activities. In the present study, a transverse aortic constriction (TAC) model was created in mice to mimic the progression of hypertrophy (2 weeks post-TAC) and heart failure (4 weeks post TAC) to investigate whether the potential therapeutic drug AA ameliorates hypertrophy progression and which mechanisms are involved in this amelioration. Our results demonstrated that AA markedly inhibited the process of progression induced by pressure overload. The increases cardiomyocyte apoptosis and interstitial fibrosis, and inflammatory responses were significantly suppressed by AA. Our investigation revealed that this inhibitory effect was mediated by blocking the activation of both mitochondrial and death receptor-dependent apoptotic signaling pathways. Additional experiments demonstrated that AA attenuated fibrosis by blocking both transforming growth factor-beta1/Smad and interleukin-6, signaling activation. Consequently, these findings indicated that AA attenuated pathological cardiac structural remodeling and preserved cardiac function via multiple intracellular signaling pathways in response to cardiac stimuli. PMID- 26647014 TI - Absence of the Adenosine A2A Receptor Confers Pulmonary Arterial Hypertension Through RhoA/ROCK Signaling Pathway in Mice. AB - Numerous evidence suggests that RhoA/Rho kinase (ROCK) signaling pathway plays an important role in the pathogenesis of pulmonary arterial hypertension (PAH), but little is known about its effects on the development of PAH in mice with absence of the adenosine A2A receptor (A2AR). Eight A2AR knockout (KO) and 8 wild-type mice were used. Morphometric analysis of pulmonary arterioles included right ventricle/left ventricle plus ventricular septum (Fulton index), vessel wall thickness/total vascular diameter (WT%), and vessel wall area/total vascular area (WA%). The expression of RhoA and ROCK1 mRNA was determined by real-time polymerase chain reaction. The expression of RhoA, ROCK1, and phosphorylation of myosin phosphatase target subunit 1 proteins in pulmonary tissue was tested by Western blot. The position of ROCK1 protein was evaluated by immunohistochemistry. Compared with wild-type mice, A2AR KO mice displayed (1) increased Fulton index, WT%, and WA% (P < 0.01); (2) increased mRNA expression of RhoA and ROCK1 (each P < 0.05); (3) increased protein expression of RhoA, ROCK1, and phosphorylation of myosin phosphatase target subunit 1 (each P < 0.01); (4) increased location of ROCK1 protein in endothelial and smooth muscle cells of pulmonary artery, bronchial, and alveolar epithelial cells. Activation of RhoA/ROCK signaling pathway may cause pulmonary vascular constriction, pulmonary artery remodeling, and PAH in adenosine A2A receptor KO mice. PMID- 26647015 TI - The dilemma of re-licensing DWI offenders: The offenders' point of view. AB - In many jurisdictions, drivers convicted for the first-time of driving while impaired by alcohol undertake a risk assessment that will determine the severity of sanctions and the remedial measures they must follow as requisites for re licensing. There is uncertainty inherent in the assessment of risk for recidivism, however, many offenders feel unfairly assessed and discommoded by the decision-making process and its consequences. The objective of this qualitative study was to gain insight into the perspectives of offenders regarding re licensing decision making and sanctioning. Specifically, in focus groups first time offenders and recidivists were probed as to whether they favoured erring on the side of road safety in decision making, with its consequent greater risk of false positive assessments, or erring on the side of maintaining driving privileges, with its consequent greater risk of false negative assessments. In general, participants preferred a higher probability of false negative vs. false positive assessments. Most cited the consequences of sanctions and remedial measures as too severe to impose them on potentially low-risk drivers, as the assessment and monitoring protocols' limitations could lead to non-equitable treatment. At the same time, recidivists evoked a greater preference for a higher probability of false positive assessments compared to first-time offenders, as they believed that recidivism was more likely to follow a first conviction than did first-time offenders. This information can be useful for a more comprehensive and societally coherent exercise of DWI prevention policies. PMID- 26647016 TI - Potential risk and its influencing factors for separated bicycle paths. AB - In this paper, we propose two potential risk indicators to define and evaluate the safety of bicycle path at the microscopic level. Field bicycle data were collected from three survey sites under different traffic conditions. These two risk indicators based on speed dispersion were proposed and calculated during each 5-min interval. The risk influences of various widths of bicycle path and traffic conditions were analyzed by using one-way ANOVA. We further proposed a generalized linear model (GLM) for modeling and analyzing the relationships between bicycle risks and v/c ratio and percentages of electric bicycles, male cyclists, young cyclists, and loaded cyclists. The stepwise regression models were applied for determination of coefficients. The results show that the influences of gender and age of cyclists on potential risks are not significant. The risks increase with the width of bicycle path and percentage of electric bicycles, while only for wider bicycle path (4-lane case in this study), the risks are associated with whether or not cyclists are loaded. The findings could contribute for analysis and evaluation of the safety for bicycle path. PMID- 26647017 TI - Measuring situational avoidance in older drivers: An application of Rasch analysis. AB - Situational avoidance is a form of driving self-regulation at the strategic level of driving behaviour. It has typically been defined as the purposeful avoidance of driving situations perceived as challenging or potentially hazardous. To date, assessment of the psychometric properties of existing scales that measure situational avoidance has been sparse. This study examined the contribution of Rasch analysis to the situational avoidance construct. Three hundred and ninety nine Australian drivers (M=66.75, SD=10.14, range: 48-91 years) completed the Situational Avoidance Questionnaire (SAQ). Following removal of the item Parallel Parking, the scale conformed to a Rasch model, showing good person separation, sufficient reliability, little disordering of thresholds, and no evidence of differential item functioning by age or gender. The residuals were independent supporting the assumption of unidimensionality and in conforming to a Rasch model, SAQ items were found to be hierarchical or cumulative. Increased avoidance was associated with factors known to be related to driving self-regulation more broadly, including older age, female gender, reduced driving space and frequency, reporting a change in driving in the past five years and poorer indices of health (i.e., self-rated mood, vision and cognitive function). Overall, these results support the use of the SAQ as a psychometrically sound measure of situational avoidance. Application of Rasch analysis to this area of research advances understanding of the driving self-regulation construct and its practice by drivers in baby boomer and older adult generations. PMID- 26647018 TI - Exploration of the labeling of [11C]tubastatin A at the hydroxamic acid site with [11C]carbon monoxide. AB - We aimed to label tubastatin A (1) with carbon-11 (t1/2 = 20.4 min) in the hydroxamic acid site to provide a potential radiotracer for imaging histone deacetylase 6 in vivo with positron emission tomography. Initial attempts at a one-pot Pd-mediated insertion of [(11)C]carbon monoxide between the aryl iodide (2) and hydroxylamine gave low radiochemical yields (<5%) of [(11) C]1. Labeling was achieved in useful radiochemical yields (16.1 +/- 5.6%, n = 4) through a two step process based on Pd-mediated insertion of [(11)C]carbon monoxide between the aryl iodide (2) and p-nitrophenol to give the [(11)C]p-nitrophenyl ester ([(11)C]5), followed by ultrasound-assisted hydroxyaminolysis of the activated ester with excess hydroxylamine in a DMSO/THF mixture in the presence of a strong phosphazene base P1-t-Bu. However, success in labeling the hydroxamic acid group of [(11)C]tubastatin A was not transferable to the labeling of three other model hydroxamic acids. PMID- 26647019 TI - Scalable Production of a Few-Layer MoS2/WS2 Vertical Heterojunction Array and Its Application for Photodetectors. AB - Vertical heterojunctions of two two-dimensional (2D) transition metal dichalcogenides (TMDs) have attracted considerable attention recently. A variety of heterojunctions can be constructed by stacking different TMDs to form fundamental building blocks in different optoelectronic devices such as photodetectors, solar cells, and light-emitting diodes. However, these applications are significantly hampered by the challenges of large-scale production of van der Waals stacks of atomically thin materials. Here, we demonstrate scalable production of periodic patterns of few-layer WS2, MoS2, and their vertical heterojunction arrays by a thermal reduction sulfurization process. In this method, a two-step chemical vapor deposition approach was developed to effectively prevent the phase mixing of TMDs in an unpredicted manner, thus affording a well-defined interface between WS2 and MoS2 in the vertical dimension. As a result, large-scale, periodic arrays of few-layer WS2, MoS2, and their vertical heterojunctions can be produced with desired size and density. Photodetectors based on the as-produced MoS2/WS2 vertical heterojunction arrays were fabricated, and a high photoresponsivity of 2.3 A.W(-1) at an excitation wavelength of 450 nm was demonstrated. Flexible photodetector devices using MoS2/WS2 heterojunction arrays were also demonstrated with reasonable signal/noise ratio. The approach in this work is also applicable to other TMD materials and can open up the possibilities of producing a variety of vertical van der Waals heterojunctions in a large scale toward optoelectronic applications. PMID- 26647022 TI - The experiences of adolescents with osteosarcoma during the one-year of treatment in Taiwan. AB - Osteosarcoma (OS) typically occurs during puberty. The one-year treatment for OS can be very challenging. However, little empirical research has explored the experiences of adolescents with OS. This research explored the experiences of Taiwanese adolescents with OS, utilizing a qualitative inductive content analysis with in-depth interviews and field notes that captured interviewer observations. In total, 20 participants-aged between 10 and 19 years and being treated for OS were recruited. Ten categories were extracted: disbelief, hope for recovery and maintaining body integrity, experience with physical symptoms, inappropriate sleep hygiene, experience of psychosocial distress, use of spirituality to recover from misfortune, information acquisition, preparation to return to school, interdependence, and dedication to hope of recovery. This is the first empirical qualitative study to explore the experiences of Taiwanese adolescents with OS during treatment since being diagnosed. Close surveillance of the compliance in rehabilitation and physical function is needed. Providing age appropriate and culture-oriented support systems would be helpful for addressing their psychosocial difficulties. Social networking sites closely moderated by health professionals may be a feasible way enhancing psychosocial well-being. Conducting a descriptive exploratory qualitative study for further development of psychosocial supportive care interventions is recommended. PMID- 26647021 TI - A vacuum-annealing strategy for improving near-infrared super long persistent luminescence in Cr(3+) doped zinc gallogermanate nanoparticles for bio-imaging. AB - Novel Cr(3+) doped zinc gallogermanate (ZGGO) nanoparticles with 697 nm near infrared (NIR) super long afterglow were prepared via a hydrothermal method. Subsequently, a vacuum-annealing strategy was adopted to improve NIR afterglow in ZGGO:Cr(3+) nanoparticles. For the sample annealed at 800 degrees C, no variation in the particle size is observed, the persistent luminescence increases by an order of magnitude (~14 times) and the NIR afterglow time reaches more than 15 hours relative to the as-prepared sample. After annealing at temperatures higher than 880 degrees C, the persistent luminescence of the nanoparticles is enhanced, but they show aggregated-surface behavior. Meanwhile, shallow and deep traps are generated, related to the antisite defects and VGe-Cr(3+)-VO defect clusters, respectively. Finally, we apply ZGGO:Cr(3+) persistent luminescence nanoparticles (PLNPs) to a human serum albumin (HSA) colloid solution, and more than 1 h of NIR persistent luminescence is detected under 320 nm excitation. The quenching effect of NIR luminescence by OH(-) in the HSA solution is observed based on the reduced contribution of surface Cr(3+) in PLNPs to NIR luminescence. Our results suggest that ZGGO:Cr(3+) PLNPs have potential applications for in vivo bio-imaging. PMID- 26647020 TI - Repeatability of (31) P MRSI in the human brain at 7 T with and without the nuclear Overhauser effect. AB - An often-employed strategy to enhance signals in (31) P MRS is the generation of the nuclear Overhauser effect (NOE) by saturation of the water resonance. However, NOE allegedly increases the variability of the (31) P data, because variation is reported in NOE enhancements. This would negate the signal-to-noise (SNR) gain it generates. We hypothesized that the variation in NOE enhancement values is not caused by the variability in NOE itself, but is attributable to measurement uncertainties in the values used to calculate the enhancement. If true, the expected increase in SNR with NOE would improve the repeatability of (31) P MRS measurements. To verify this hypothesis, a repeatability study of native and NOE-enhanced (31) P MRSI was performed in the brains of seven healthy volunteers at 7 T. The repeatability coefficient (RC) and the coefficient of variation in repeated measurements (CoVrepeat ) were determined for each method, and the 95% limits of agreement (LoAs) between native and NOE-enhanced signals were calculated. The variation between the methods, defined by the LoA, is at least as great as that predicted by the RC of each method. The sources of variation in NOE enhancements were determined using variance component analysis. In the seven metabolites with a positive NOE enhancement (nine metabolite resonances assessed), CoVrepeat improved, on average, by 15%. The LoAs could be explained by the RCs of the individual methods for the majority of the metabolites, generally confirming our hypothesis. Variation in NOE enhancement was mainly attributable to the factor repeat, but between-voxel effects were also present for phosphoethanolamine and (glycero)phosphocholine. CoVrepeat and fitting error were strongly correlated and improved with positive NOE. Our findings generally indicate that NOE enhances the signal of metabolites, improving the repeatability of metabolite measurements. Additional variability as a result of NOE was minimal. These findings encourage the use of NOE-enhanced (31) P MRSI. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26647039 TI - Streptosporangium algeriense sp. nov., an actinobacterium isolated from desert soil. AB - The taxonomic position of a novel actinobacterium, strain 169T, isolated from a sample of Algerian Saharan soil, was determined using a polyphasic taxonomic approach. The aerial mycelium produced non-motile, round- to oval-shaped spores, with a smooth surface, which were sessile or carried by short sporophores. Chemotaxonomically, isolate 169T showed the same results as members of the genus Streptosporangium, but madurose, the so far diagnostic sugar of the genus, was not detected in the whole-cell hydrolysate. Despite the absence of sporangia, the 16S rRNA gene sequence analysis confirmed that strain 169T was a member of the genus Streptosporangium. Strain 169T was most closely related to Streptosporangium jomthongense NBRC 110047T (99.3 % 16S rRNA gene sequence similarity), which is the only non-sporangia-forming species reported among the genus. However, DNA-DNA hybridization studies with this species showed 60 % relatedness. Based upon genotypic and phenotypic data, a novel species, Streptosporangium algeriense sp. nov., is proposed, with 169T ( = DSM 45455T = MTCC 11561T = CCUG 62974T) as the type strain. PMID- 26647041 TI - Testing the mean magnetization approximation, dimensionless and scaling numbers in magnetorheology. AB - The mean magnetization (MM) approximation is undoubtedly the most widely used approximation in magnetorheology both from theoretical and simulation perspectives. According to this, spherical magnetizable particles under field can be replaced by effective dipole moments m placed at their center with strength m = V(p)?M(p)?. Here V(p) and ?M(p)? are the volume and mean (average) magnetization of the particles, respectively. In spite of being extensively used, there is not a mathematical justification to do so in most cases. In this manuscript, we test this approximation using experiments, theories and simulations, for a wide range of magnetic field strengths and particle loadings, in both conventional magnetorheological fluids (CMRFs) and inverse ferrofluids (IFFs). Results demonstrate that the MM approximation is applicable in IFFs for a very wide range of field strengths (up to external fields of 265 kA m(-1)) and particle loadings (up to 20 vol%). For CMRFs, the MM approximation is only applicable in two particular circumstances; in magnetic saturation or in infinite dilution. PMID- 26647040 TI - Scintillation proximity assay (SPA) as a new approach to determine a ligand's kinetic profile. A case in point for the adenosine A1 receptor. AB - Scintillation proximity assay (SPA) is a radio-isotopic technology format used to measure a wide range of biological interactions, including drug-target binding affinity studies. The assay is homogeneous in nature, as it relies on a "mix and measure" format. It does not involve a filtration step to separate bound from free ligand as is the case in a traditional receptor-binding assay. For G protein coupled receptors (GPCRs), it has been shown that optimal binding kinetics, next to a high affinity of a ligand, can result in more desirable pharmacological profiles. However, traditional techniques to assess kinetic parameters tend to be cumbersome and laborious. We thus aimed to evaluate whether SPA can be an alternative platform for real-time receptor-binding kinetic measurements on GPCRs. To do so, we first validated the SPA technology for equilibrium binding studies on a prototypic class A GPCR, the human adenosine A1 receptor (hA1R). Differently to classic kinetic studies, the SPA technology allowed us to study binding kinetic processes almost real time, which is impossible in the filtration assay. To demonstrate the reliability of this technology for kinetic purposes, we performed the so-called competition association experiments. The association and dissociation rate constants (k on and k off) of unlabeled hA1R ligands were reliably and quickly determined and agreed very well with the same parameters from a traditional filtration assay performed simultaneously. In conclusion, SPA is a very promising technique to determine the kinetic profile of the drug-target interaction. Its robustness and potential for high-throughput may render this technology a preferred choice for further kinetic studies. PMID- 26647042 TI - Considerations and recommendations for conducting qualitative research interviews with palliative and end-of-life care patients in the home setting: a consensus paper. AB - OBJECTIVES: To present and discuss the views of researchers at an academic palliative care research centre on research encounters with terminally ill patients in the home setting and to generate a list of recommendations for qualitative researchers working in palliative and end-of-life care. METHODS: Eight researchers took part in a consensus meeting to discuss their experiences of undertaking qualitative interviews. The researchers were of varying backgrounds and all reported having experience in interviewing terminally ill patients, and all but one had experience of interviewing patients in their home environment. RESULTS: The main areas discussed by researchers included: whether participation in end-of-life research unintentionally becomes a therapeutic experience or an ethical concern; power relationships between terminally ill patients and researchers; researcher reflexivity and reciprocity; researchers' training needs. Qualitative methods can complement the home environment; however, it can raise ethical and practical challenges, which can be more acute in the case of research undertaken with palliative and patients at the end-of-life. CONCLUSIONS: The ethical and practical challenges researchers face in this context has the potential to place both participant and researcher at risk for their physical and psychological well-being. We present a set of recommendations for researchers to consider prior to embarking on qualitative research in this context and advocate researchers in this field carefully consider the issues presented on a study-by-study basis. PMID- 26647043 TI - Building a taxonomy of integrated palliative care initiatives: results from a focus group. AB - BACKGROUND: Empirical evidence suggests that integrated palliative care (IPC) increases the quality of care for palliative patients and supports professional caregivers. Existing IPC initiatives in Europe vary in their design and are hardly comparable. InSuP-C, a European Union research project, aimed to build a taxonomy of IPC initiatives applicable across diseases, healthcare sectors and systems. METHODS: The taxonomy of IPC initiatives was developed in cooperation with an international and multidisciplinary focus group of 18 experts. Subsequently, a consensus meeting of 10 experts revised a preliminary taxonomy and adopted the final classification system. RESULTS: Consisting of eight categories, with two to four items each, the taxonomy covers the process and structure of IPC initiatives. If two items in at least one category apply to an initiative, a minimum level of integration is assumed to have been reached. Categories range from the type of initiative (items: pathway, model or guideline) to patients' key contact (items: non-pc specialist, pc specialist, general practitioner). Experts recommended the inclusion of two new categories: level of care (items: primary, secondary or tertiary) indicating at which stage palliative care is integrated and primary focus of intervention describing IPC givers' different roles (items: treating function, advising/consulting or training) in the care process. CONCLUSIONS: Empirical studies are required to investigate how the taxonomy is used in practice and whether it covers the reality of patients in need of palliative care. The InSuP-C project will test this taxonomy empirically in selected initiatives using IPC. PMID- 26647045 TI - Application of Low- and Mid-Frequency Raman Spectroscopy to Characterize the Amorphous-Crystalline Transformation of Indomethacin. AB - Raman spectroscopy using the mid-frequency (1800-1500 cm(-1)) and low-frequency (200-8 cm(-1)) spectral regions is used to study the transformation of amorphous indomethacin (IND) to the gamma-crystalline form. The low-frequency spectral region provides access to collective vibrations of molecules in the crystalline and amorphous state, while the mid-frequency spectral region provides access to the molecular vibrations that are sensitive to the local functional group environment. Both spectral regions provide distinct Raman bands for the amorphous and crystalline forms of IND. The more intense low-frequency Raman bands provide greater sensitivity for detecting the onset of crystallization in an amorphous matrix. Subtle differences in the behavior of the initial crystalline process of IND are observed between the low-frequency and mid-frequency Raman bands. These observations suggest that different responses for mid- and low-frequency Raman bands occur for the microcrystalline domains present during the initial crystallization process. The suitability of low-frequency Raman spectroscopy to monitor IND in a suspension was demonstrated. This suggests that the technique will be a valuable tool for at-line and on-line monitoring of active pharmaceutical ingredient crystallization. PMID- 26647046 TI - Design of a New Concentration Series for the Orthogonal Sample Design Approach and Estimation of the Number of Reactions in Chemical Systems. AB - A new concentration series is proposed for the construction of a two-dimensional (2D) synchronous spectrum for orthogonal sample design analysis to probe intermolecular interaction between solutes dissolved in the same solutions. The obtained 2D synchronous spectrum possesses the following two properties: (1) cross peaks in the 2D synchronous spectra can be used to reflect intermolecular interaction reliably, since interference portions that have nothing to do with intermolecular interaction are completely removed, and (2) the two-dimensional synchronous spectrum produced can effectively avoid accidental collinearity. Hence, the correct number of nonzero eigenvalues can be obtained so that the number of chemical reactions can be estimated. In a real chemical system, noise present in one-dimensional spectra may also produce nonzero eigenvalues. To get the correct number of chemical reactions, we classified nonzero eigenvalues into significant nonzero eigenvalues and insignificant nonzero eigenvalues. Significant nonzero eigenvalues can be identified by inspecting the pattern of the corresponding eigenvector with help of the Durbin-Watson statistic. As a result, the correct number of chemical reactions can be obtained from significant nonzero eigenvalues. This approach provides a solid basis to obtain insight into subtle spectral variations caused by intermolecular interaction. PMID- 26647047 TI - Attenuated Total Reflection Mid-Infrared (ATR-MIR) Spectroscopy and Chemometrics for the Identification and Classification of Commercial Tannins. AB - Attenuated total reflection Fourier transform infrared (FT-IR) spectroscopy was used to characterize 40 commercial tannins, including condensed and hydrolyzable chemical classes, provided as powder extracts from suppliers. Spectral data were processed to detect typical molecular vibrations of tannins bearing different chemical groups and of varying botanical origin (univariate qualitative analysis). The mid-infrared region between 4000 and 520 cm(-1) was analyzed, with a particular emphasis on the vibrational modes in the fingerprint region (1800 520 cm(-1)), which provide detailed information about skeletal structures and specific substituents. The region 1800-1500 cm(-1) contained signals due to hydrolyzable structures, while bands due to condensed tannins appeared at 1300 900 cm(-1) and exhibited specific hydroxylation patterns useful to elucidate the structure of the flavonoid monomeric units. The spectra were investigated further using principal component analysis for discriminative purposes, to enhance the ability of infrared spectroscopy in the classification and quality control of commercial dried extracts and to enhance their industrial exploitation. PMID- 26647048 TI - Imaging of Hydrophilicity and its Inhomogeneity on a Titanium Dioxide Film Exposed to Ultraviolet Irradiation Using a Newly Developed Near-Infrared Camera. AB - This study has investigated hydrophilicity changes and their inhomogeneity of TiO2 films on Pyrex glasses by near-infrared (NIR) spectral imaging. Near infrared spectra of TiO2 films in the 9000-4000 cm(-1) region were measured using a newly developed NIR camera named Compovision. A band in the 5400-4800 cm(-1) region, which is assigned to a combination (nu2 + nu3) mode of bending (nu2) and antisymmetric stretching (nu3) modes of the H2O molecule, was clearly identified and its intensity increased with time in the air. It is interesting that the increased rate rose with ultraviolet (UV) light irradiation (300-400 nm, 1 mW cm( 2)) compared to without UV light irradiation. This result suggested that the hydrophilicity of TiO2 was enhanced about twice upon the UV light irradiation. Moreover, the NIR images clarified spatial distributions of the hydrophilicity on the TiO2 surface with a significantly wide area (20 * 40 mm) and a high speed (within 5 s for one image). This rapid imaging system enabled us to detect the hydrophilicity change during only 1 min. The potential of this camera is quite superior, not only for basic research, but also for diverse industrial applications. PMID- 26647049 TI - Application of Multivariate Strategies to the Classification of Pharmaceutical Excipient Manufacturers Based on Near-Infrared (NIR) Spectra. AB - Using partial least square discriminate analysis (PLSDA), we studied the spectroscopic differences between the commonly used filler-binder microcrystalline cellulose (MCC) from five manufactures. These samples had subtle differences in the chemical and physical properties, which are often the cause of differences in excipient performance. Studying these differences allowed us to build and validate a model to classify five manufacturers of MCC using near infrared (NIR) spectra. The sample training set includes 39 MCC samples collected from five manufactures with regions spanning the United States of America, Japan, Taiwan, Germany, and Brazil. The samples from individual manufacturers include diverse grades that differ in moisture content, particle size, and bulk density. Optimized pretreatment methods were identified as standard normal variate normalization, followed by Savitzky-Golay second derivative, mean centering, and orthogonal signal correction. The model was optimized with cross-validation and validated with an independent sample set comprising nine samples collected from those five manufacturers. The results showed that none of the samples in the independent validation set was misclassified. The score and loading plots revealed that the differences in content of oxidized cellulose group, water content and states, hydrogen bonding, and degree of polymerization of the MCC samples are responsible for the class differentiation. Permutation test demonstrated that the outcome of the PLSDA model was significantly different from that of the randomly generated model. The advantages and limitations of the method in this type of application were discussed. PMID- 26647050 TI - High-Throughput Raman Spectroscopy Screening of Excipients for the Stabilization of Amorphous Drugs. AB - Low aqueous solubility of active pharmaceutical ingredients (APIs) is an enduring problem in pharmaceutical development, and it is becoming increasingly prevalent among new drug candidates. It is estimated that about 40% of drugs in the development pipeline and approximately 60% of the drugs coming directly from discovery suffer from poor aqueous solubility and slow dissolution, thereby reducing their bioavailability and efficacy and thus preventing their commercialization. It is well known that utilizing the amorphous form of a drug can be a useful approach to improve the dissolution rate and solubility of poorly water-soluble APIs. Amorphous compounds are thermodynamically unstable, but they can be stabilized by combining them with a carrier polymer (excipient) to form a solid dispersion. High-throughput Raman spectroscopy was used in this study to identify excipients that promote formation and stabilization of the amorphous drug form in solid dispersions. Four model APIs were used as poorly soluble drug candidates: ketoprofen, danazol, griseofulvin, and probucol. The Raman signals of excipients were generally negligible, and therefore Raman bands from the drugs were used with minimal spectral pre-processing. By comparing Raman spectra collected from the APIs in the crystalline and molten state, appropriate spectral features and regions were identified for the development of semi-quantitative methods to determine the amorphous content for each API. It is demonstrated that methods based on peak intensity ratio, peak width, peak distance, and classical least squares can all be effective methods for the screening of excipients. Interesting excipient-dependent phase transformation behavior was also observed for probucol. PMID- 26647051 TI - Determination of Spectroscopic Band Shapes by Second Derivatives, Part II: Infrared Spectra of Liquid Light and Heavy Water. AB - Second derivative and band simulation techniques are used in a synergetic relationship to identify components in the infrared (IR) spectra of liquid light and heavy water. Nine Gaussian components are retrieved in massive OH and OD stretch absorption. In this context, nu1 and nu3 are the principal components along with satellites derived from harmonic and combination bands. The Raman spectrum of light water matches the IR components with intensity variations as expected. PMID- 26647052 TI - Combination of a Copper-Ion Selective Electrode and Fluorometric Titration for the Determination of Copper(II) Ion Conditional Stability Constants of Humic Substances. AB - A fluorescence quenching model using copper(II) ion (Cu(2+)) ion selective electrode (Cu-ISE) is developed. It uses parallel factor analysis (PARAFAC) to model fluorescence excitation-emission matrices (EEMs) of humic acid (HA) samples titrated with Cu(2+) to resolve fluorescence response of fluorescent components to Cu(2+) titration. Meanwhile, Cu-ISE is employed to monitor free Cu(2+) concentration ([Cu]) at each titration step. The fluorescence response of each component is fit individually to a nonlinear function of [Cu] to find the Cu(2+) conditional stability constant for that component. This approach differs from other fluorescence quenching models, including the most up-to-date multi-response model that has a problematic assumption on Cu(2+) speciation, i.e., an assumption that total Cu(2+) present in samples is a sum of [Cu] and those bound by fluorescent components without taking into consideration the contribution of non fluorescent organic ligands and inorganic ligands to speciation of Cu(2+). This paper employs the new approach to investigate Cu(2+) binding by Pahokee peat HA (PPHA) at pH values of 6.0, 7.0, and 8.0 buffered by phosphate or without buffer. Two fluorescent components (C1 and C2) were identified by PARAFAC. For the new quenching model, the conditional stability constants (logK1 and logK2) of the two components all increased with increasing pH. In buffered solutions, the new quenching model reported logK1 = 7.11, 7.89, 8.04 for C1 and logK2 = 7.04, 7.64, 8.11 for C2 at pH 6.0, 7.0, and 8.0, respectively, nearly two log units higher than the results of the multi-response model. Without buffer, logK1 and logK2 decreased but were still high (>7) at pH 8.0 (logK1 = 7.54, logK2 = 7.95), and all the values were at least 0.5 log unit higher than those (4.83 ~ 5.55) of the multi-response model. These observations indicate that the new quenching model is more intrinsically sensitive than the multi-response model in revealing strong fluorescent binding sites of PPHA in different experimental conditions. The new model was validated by testing it with a mixture of two fluorescing Cu(2+) chelating organic compounds, i.e., l-tryptophan and salicylic acid mixed with one non-fluorescent binding compound oxalic acid titrated with Cu(2+) at pH 5.0. PMID- 26647053 TI - Evaluation of Lignocellulosic Biomass Degradation by Combining Mid- and Near Infrared Spectra by the Outer Product and Selecting Discriminant Wavenumbers Using a Genetic Algorithm. AB - Mid-infrared (MIR) and near-infrared (NIR) spectroscopy provide useful information on the molecular composition of biological systems. Because they are sensitive to organic and mineral components, there is a growing interest in these techniques for the development of biomarkers that reflect intrinsic characteristics of plants and their mode of degradation. Due to their complexity and complementary nature, an important challenge is the combining of MIR and NIR information to identify discriminating wavenumbers in each wavenumber region, with the ultimate goal of assessing the biodegradation process of a lignocellulosic biomass at different time scales. This work investigates the potential of using the outer product to combine MIR and NIR spectra to highlight the connections between fundamental molecular vibrations and their combinations and bonds. Because this operation yields high-dimensional spectra, we propose to use a genetic algorithm to select the most discriminant wavenumbers within the degradation process. The results from two lignocellulosic biomasses with different biodegradation kinetics, miscanthus aerial parts and maize roots, confirm that the outer product combination of MIR and NIR spectral information allows a better discrimination of the biodegradation kinetic compared with the simple concatenation of MIR and NIR spectra or with the use of MIR or MIR spectral information separately. We show that the genetic algorithm selects wavenumbers that correspond to principal vibrations of chemical functional groups of compounds that undergo degradation/conversion during the biodegradation of the lignocellulosic biomass. PMID- 26647054 TI - Accuracy of Noninvasive Glucose Sensing Based on Near-Infrared Spectroscopy. AB - The noninvasive sensing of the blood glucose concentration is usually based on optical, electrical, or acoustical signals induced by blood glucose; these signals are extremely weak and subject to fluctuations caused by the variation in the body or surroundings. Therefore, it is challenging to detect blood glucose noninvasively with high accuracy, and no successful accurate and noninvasive clinical application has been reported. We found that there are two key measurement issues to be addressed: systematic errors, such as the errors induced by the drifts of devices or by variations in body temperature, among others, are too large to guarantee the trueness of measurement at present; and random disturbances in repeated tests, such as disturbances associated with variations in the human-machine interface, pulses, and the thermal noise of the devices, cause larger repeated measurement errors and compromise precision. Recent novel reference measurements based on differential near-infrared (NIR) spectroscopy are considered promising for solving the systematic error issue by establishing matched references, collected at another detection site or at another time, and subsequently differencing to remove the common systematic errors. However, differencing weakens the signal of interest itself and enlarges the effects of the second issue, random disturbances affecting the precision. It is understood that only reference measurements that can meet the precision requirement will be promising for future applications. Therefore, this study quantitatively evaluates the precision of the main differential NIR spectroscopy measurements considering similar conditions and minimized random disturbances. The precision of the measurements under these conditions should represent their optimal precision levels. After the evaluation, noninvasive glucose-sensing methods that hold promise for future clinical application are proposed. Finally, the evaluation criteria could be a reference for the noninvasive detection of other physiological components. PMID- 26647055 TI - Attenuated Total Reflection Fourier Transform Infrared Spectroscopy (ATR FT-IR) Mapping Coupled with Multivariate Curve Resolution (MCR) for Studying the Miscibility of Chlorobutyl Rubber/Polyamide-12 Blends. AB - A series of chlorobutyl rubber/polyamide-12 (CIIR/PA-12) blends compatibilized by different amounts of maleic anhydride (MAH) grafted polypropylene (PP-g-MAH) were investigated by attenuated total reflection Fourier transform infrared spectroscopy (ATR FT-IR) mapping. Multivariate curve resolution (MCR) was used to process the FT-IR images. Both the spectra of pure components in the blends and their concentration distributions in a micro-region were acquired. Our results demonstrated that the blend with 15 parts per hundred rubber PP-g-MAH showed the best miscibility. An amide interphase and an imide interphase were inferred by analyzing the spectra of MCR component 3 of the blends with and without PP-g-MAH, respectively. Correspondingly, two different compatibilizing mechanisms were proposed for these blends. PMID- 26647056 TI - Optical Emission Spectroscopy of an Atmospheric Pressure Plasma Jet During Tooth Bleaching Gel Treatment. AB - Optical emission spectroscopy was performed during atmospheric pressure plasma needle helium jet treatment of various tooth-bleaching gels. When the gel sample was inserted under the plasma plume, the intensity of all the spectral features increased approximately two times near the plasma needle tip and up to two orders of magnitude near the sample surface. The color change of the hydroxylapatite pastille treated with bleaching gels in conjunction with the atmospheric pressure plasma jet was found to be in correlation with the intensity of OH emission band (309 nm). Using argon as an additive to helium flow (2 L/min), a linear increase (up to four times) of OH intensity and, consequently, whitening (up to 10%) of the pastilles was achieved. An atmospheric pressure plasma jet activates bleaching gel, accelerates OH production, and accelerates tooth bleaching (up to six times faster). PMID- 26647057 TI - Detecting Esophageal Cancer Using Surface-Enhanced Raman Spectroscopy (SERS) of Serum Coupled with Hierarchical Cluster Analysis and Principal Component Analysis. AB - Serum samples taken from healthy individuals and pre- and post-operative esophageal cancer patients were analyzed using surface-enhanced Raman spectroscopy (SERS) to explore the feasibility of diagnosing esophageal cancer using the technique. The serum spectrum data were collected using a He-Ne laser of wavelength 632.8 nm. Differences in peaks assigned to nucleic acids, lipids, and proteins were found to be statistically significant between groups, which implies that corresponding serum alterations occur with the development of esophageal diseases. For quantitative analysis, the chemometric methods of hierarchical clustering analysis and principal component analysis were utilized on the obtained SERS spectra for classification with good results. PMID- 26647058 TI - Femtosecond Laser-Induced Breakdown Spectroscopy Studies of Nitropyrazoles: The Effect of Varying Nitro Groups. AB - The technique of femtosecond laser-induced breakdown spectroscopy (FLIBS) was employed to investigate seven explosive molecules of nitropyrazole in three different atmospheres: ambient air, nitrogen, and argon. The FLIBS data illustrated the presence of molecular emissions of cyanide (CN) violet bands, diatomic carbon (C2) Swan bands, and atomic emission lines of C, H, O, and N. To understand the plasma dynamics, the decay times of molecular and atomic emissions were determined from time-resolved spectral data obtained in three atmospheres: air, argon, and nitrogen. The CN decay time was observed to be longest in air, compared to nitrogen and argon atmospheres, for the molecules pyrazole (PY) and 4 nitropyrazole (4-NPY). In the case of C2 emission, the decay time was observed to be the longest in argon, compared to the air and nitrogen environments, for the molecules PY, 4-NPY, and 1-methyl-3,4,5-trinitropyrazole. The intensities of the CN, C2, C, H, O, and N emission lines and various molecular/atomic intensity ratios such as CN/C2, CN(sum)/C2(sum), CN/C, CN(sum)/C, C2/C, C2(sum)/C, (C2 + C) / CN, (C2(sum) + C)/CN(sum), O/H, O/N, and N/H were also deduced from the LIBS spectra obtained in argon atmosphere. A correlation between the observed decay times and molecular emission intensities with respect to the number of nitro groups, the atmospheric nitrogen content, and the oxygen balance of the molecules was investigated. The relationship among the LIBS signal intensity, the molecular/atomic intensity ratios, and the oxygen balance of these organic explosives was also explored. PMID- 26647059 TI - Tudor-domain containing proteins act to make the piRNA pathways more robust in Drosophila. AB - PIWI-interacting RNAs (piRNAs), a subset of small non-coding RNAs enriched in animal gonads, repress transposons by assembling with PIWI proteins to form potent gene-silencing RNP complexes, piRISCs. Accumulating evidence suggests that piRNAs are produced through three interdependent pathways; the de novo primary pathway, the ping-pong pathway, and the phased primary pathway. The de novo primary pathway in Drosophila ovaries produces primary piRNAs for two PIWI members, Piwi and Aub. Aub then initiates the ping-pong pathway to produce secondary piRNAs for AGO3. AGO3-slicer dependent cleavage subsequently produces secondary piRNAs for Aub. Trailer products of AGO3-slicer activity are consumed by the phased primary pathway to increase the Piwi-bound piRNA population. All these pathways are regulated by a number of piRNA factors in a highly coordinated fashion. Recent studies show that two Tudor-domain containing piRNA factors, Krimper (Krimp) and Qin/Kumo, play crucial roles in making Aub-AGO3 heterotypic ping-pong robust. This maintains the levels of piRNAs loaded onto Piwi and Aub to efficiently repress transposons at transcriptional and post-transcriptional levels, respectively. PMID- 26647060 TI - Development of Emotion Word Comprehension in Chinese Children from 2 to 13 Years Old: Relationships with Valence and Empathy. AB - Children's emotion word comprehension (EWC) has constantly received a great deal of attention in developmental science. However, since previous reports focused on only English emotion vocabulary, researchers thus far remained unclear as to the developmental trajectories of EWC (to Chinese emotion words) in Chinese children, let alone the cross-cultural difference of EWC in different languages (i.e., English V.S. Chinese). Furthermore, the influence of valence on EWC, as well as the interaction mechanism between EWC and empathy, has not been fully investigated. Finding answers to these research gaps has become the main motivation of the current study. For this purpose, a Chinese emotion vocabulary was first constructed to estimate EWC of Chinese children (ages 2-13 years old). Then, the valence of each emotion word was evaluated using the standard 9-point scale approach. After that, the Chinese children's EWC and empathy were measured in terms of parental ratings. Finally, all data collected were statistically analyzed to reveal the influence of the valence of EWC, the relation between EWC and empathy, and the cross-cultural difference of children's EWC between China and UK from the viewpoint of developmental science. The main results of the current study included the following: (i) EWC in general increased with age for Chinese children ages 2-13 years old, however, there was a dramatic increase during ages 6-8 years old; (ii) EWC of positive emotion words in general developed better than that of negative and neutral ones for Chinese children (ages 2-13 years old); and the disadvantage of EWC to negative emotion words over neutral ones was gradually observed with the increase of age, even though there were no significant differences between them from the beginning; (iii) EWC completely mediated the effect of age on empathy; and (iv) EWC of children in UK developed better than Chinese counterparts during the early childhood period (ages 4-6 years old), then Chinese counterparts developed better during the middle childhood period (ages 7-10 years old), however, there was no significant difference of EWC between both groups during the late childhood period (ages 11 12 years old). PMID- 26647061 TI - The Effect of Perinatal Hypoxic/Ischemic Injury on Tyrosine Hydroxylase Expression in the Locus Coeruleus of the Human Neonate. AB - We have previously shown that perinatal hypoxic/ischemic injury (HII) may cause selective vulnerability of the mesencephalic dopaminergic neurons of human neonate. In the present study, we investigated the effect of perinatal HII on the noradrenergic neurons of the locus coeruleus (LC) of the same sample. We studied immunohistochemically the expression of tyrosine hydroxylase (TH, first limiting enzyme for catecholamine synthesis) in LC neurons of 15 autopsied infants (brains collected from the Greek Brain Bank) in relation to the neuropathological changes of acute or chronic HII of the neonatal brain. Our results showed that perinatal HII appears to affect the expression of TH and the size of LC neurons of the human neonate. In subjects with neuropathological lesions consistent with abrupt/severe HII, intense TH immunoreactivity was found in almost all neurons of the LC. In most of the neonates with neuropathological changes of prolonged or older injury, however, reduction in cell size and a decrease or absence of TH staining were observed in the LC. Intense TH immunoreactivity was found in the LC of 3 infants of the latter group, who interestingly had a longer survival time and had been treated with anticonvulsant drugs. Based on our observations and in view of experimental evidence indicating that the reduction of TH-immunoreactive neurons occurring in the LC after perinatal hypoxic insults persists into adulthood, we suggest that a dysregulation of monoaminergic neurotransmission in critical periods of brain development in humans is likely to predispose the survivors of perinatal HII, in combination with genetic susceptibility, to psychiatric and/or neurological disorders later in life. PMID- 26647062 TI - Patterning hypoxic multicellular spheroids in a 3D matrix - a promising method for anti-tumor drug screening. AB - 3D multicellular spheroid models are of great value in the investigation of tumor biology and tumor responses to chemotherapy and radiation. To establish a mimicking tumor microenvironment in vitro, we developed a straightforward method by patterning hypoxic multicellular spheroids in a 3D matrix. The efficacy of this approach was evaluated by characterizing spheroid formation, invasive capability and phenotypic transition in aggressive human glioma cells. We observed enhanced cell proliferation, spheroid formation and invasive capability in U87 glioma cells transfected with hypoxia-inducible factors (HIFs) compared with non-treated cells. We also demonstrated that the overexpression of HIFs in hypoxic glioma cells may promote cell migration by epithelial-mesenchymal transition within the 3D matrix. Compared with conventional 3D culturing techniques, the simple operation, rapid prototyping, low cost and high throughput format of the micro-patterning method facilitates the characterization of cell proliferation, migration, phenotypic function and drug evaluation in physiologically relevant 3D microenvironments. This in vitro 3D system can recapitulate the physiologically relevant tumor microenvironment and is a promising method for 3D anti-tumor drug screening and the identification of novel targets for tumor invasion and angiogenesis. PMID- 26647063 TI - The Population Origins and Expansion of Feral Cats in Australia. AB - The historical literature suggests that in Australia, the domestic cat (Felis catus) had a European origin [~200 years before present (ybp)], but it is unclear if cats arrived from across the Asian land bridge contemporaneously with the dingo (4000 ybp), or perhaps immigrated ~40000 ybp in association with Aboriginal settlement from Asia. The origin of cats in Australia is important because the continent has a complex and ancient faunal assemblage that is dominated by endemic rodents and marsupials and lacks the large placental carnivores found on other large continents. Cats are now ubiquitous across the entire Australian continent and have been implicit in the range contraction or extinction of its small to medium sized (<3.5kg) mammals. We analyzed the population structure of 830 cats using 15 short tandem repeat (STR) genomic markers. Their origin appears to come exclusively from European founders. Feral cats in continental Australia exhibit high genetic diversity in comparison with the low diversity found in populations of feral cats living on islands. The genetic structure is consistent with a rapid westerly expansion from eastern Australia and a limited expansion in coastal Western Australia. Australian cats show modest if any population structure and a close genetic alignment with European feral cats as compared to cats from Asia, the Christmas and Cocos (Keeling) Islands (Indian Ocean), and European wildcats (F. silvestris silvestris). PMID- 26647064 TI - Enabling surface dependent diffusion in spatial simulations using Smoldyn. AB - BACKGROUND: Spatial computer simulations are becoming more feasible and relevant for studies of signaling pathways due to technical advances in experimental techniques yielding better high resolution data. However, many common single particle simulation environments used in computational systems biology lack the functionality to easily implement spatially heterogeneous membrane environments. RESULTS: We introduce an extension to the single particle simulator Smoldyn that allows modeling of surface-dependent diffusion, without unnecessarily increasing molecular states or numbers, hence avoiding explosion of molecule and reaction definitions. CONCLUSIONS: We demonstrate the usefulness of this approach studying AMPA receptor diffusion at the postsynaptic density and its spatial trapping without introducing hypothetical scaffold elements or membrane barriers. PMID- 26647065 TI - Assessing the Awareness of Egyptian Medical Students about Responsible Conduct of Research and Research Ethics: Impact of an Educational Campaign. AB - This is a quasi-experimental pre-post assessment study utilizing an anonymous self-administered questionnaire to assess Egyptian medical students' awareness about responsible conduct of research (RCR) and research ethics. Students' were assessed before and after an RCR awareness campaign. Our results showed that most of the pre-campaign respondents were not familiar with the basic principles and terms of RCR. An increase in the awareness about RCR across all discussed topics was noted following the campaign. We concluded that an educational awareness campaign is effective in increasing medical students' awareness about RCR and should be incorporated into current medical school curricula in Egypt. PMID- 26647067 TI - Geochemical behaviour of palladium in soils and Pd/PdO model substances in the presence of the organic complexing agents L-methionine and citric acid. AB - Risk assessments of platinum group metal (PGE) emissions, notably those of platinum (Pt), palladium (Pd) and rhodium (Rh), have been mostly based on data regarding the metallic forms used in vehicular exhaust converters, known to be virtually biologically inert and immobile. To adequately assess the potential impacts of PGE, however, data on the chemical behaviour of these metals under ambient conditions post-emission is needed. Complexing agents with a high affinity for metals in the environment are hypothesized to contribute to an increased bioaccessibility of PGE. The purpose of this study is to examine the modulating effects of the organic complexing agents, L-methionine and citric acid, on the geochemical behavior of Pd in soils and model substances (Pd black and PdO). Batch experimental tests were conducted with soils and model substances to examine the impacts of the concentration of complexing agents, pH and length of extraction period on Pd solubility and its chemical transformation. Particle surface chemistry was examined using X-ray photoelectron spectroscopy (XPS) on samples treated with solutions under various conditions, including low and high O2 levels. Pd was observed to be more soluble in the presence of organic complexing agents, compared to Pt and Rh. Pd in soils was more readily solubilized with organic complexing agents compared to the model substances. After 7 days of extraction, L-methionine (0.1 M) treated soil and Pd black samples, for instance, had mean soluble Pd fractions of 12.4 +/- 5.9% and 0.554 +/- 0.024%, respectively. Surface chemistry analyses (XPS) confirmed the oxidation of metallic Pd surfaces when treated with organic complexing agents. The type of organic complexing agent used for experimental purposes was observed to be the most important factor influencing solubility, followed by solution pH and time of extraction. The results demonstrate that metallic Pd can be transformed into more bioaccessible species in the presence of organic complexing agents which are ubiquitous in the environment. PMID- 26647066 TI - Cellular dynamics underlying regeneration of appropriate segment number during axolotl tail regeneration. AB - BACKGROUND: Salamanders regenerate their tails after amputation anywhere along their length. How the system faithfully reconstitutes the original number of segments and length is not yet known. METHODS: To gain quantitative insight into how the system regenerates the appropriate length, we amputated tails at 4 or 16 myotomes post-cloaca and measured blastema size, cell cycle kinetics via cumulative Bromodeoxyuridine (BrdU) incorporation and the method of Nowakowski, and myotome differentiation rate. RESULTS: In early stages until day 15, blastema cells were all proliferative and divided at the same rate at both amputation levels. A larger blastema was formed in 4th versus 16th myotome amputations indicating a larger founding population. Myotome differentiation started at the same timepoint in the 4th and 16 th level blastemas. The rate of myotome formation was more rapid in 4th myotome blastemas so that by day 21 the residual blastema from the two amputation levels achieved equivalent size. At that time point, only a fraction of blastema cells remain in cycle, with the 4th myotome blastema harboring double the number of cycling cells as the 16th myotome blastema allowing it to grow faster and further reconstitute the larger number of missing myotomes. CONCLUSIONS: These data suggest that there are two separable phases of blastema growth. The first is level-independent, with cells displaying unrestrained proliferation. In the second phase, the level-specific growth is revealed, where differing fractions of cells remain in the cell cycle over time. PMID- 26647068 TI - Early Postoperative Outcomes of Primary Bariatric Surgery in Patients on Chronic Steroid or Immunosuppressive Therapy. AB - BACKGROUND: Previous research suggests that patients on chronic steroids may be at an increased risk of postoperative morbidity after major surgery. We aimed to evaluate the prognostic impact of chronic use of steroid or immunosuppression on 30-day morbidity and mortality rates after primary bariatric surgery. METHODS: From American College of Surgeons-National Surgical Quality Improvement Program (ACS-NSQIP) database, we identified patients who underwent primary bariatric surgery between 2005 and 2013. Logistic regression was used to determine the prognostic impact of chronic use of steroid or immunosuppression on the 30-day postoperative outcomes. RESULTS: One thousand two hundred seventy seven steroid/immunosuppressant-dependent (SD) and 112,892 non-dependent (ND) patients were analyzed. SD patients had a higher baseline risk profile compared to ND patients. Thirty-day mortality rates for SD and ND patients were 0.55 and 0.11 %, respectively (P < 0.001) which corresponds to an adjusted odds ration (OR) of 6.85 (95 % confidence interval (CI) 1.95-24.12). SD patients had a higher 30-day major morbidity compared to ND patients (5.01 versus 2.54 %; P < 0.001, respectively). After adjustment, this translated into an OR of 2.21 (95 % CI 1.29 3.79). Among SD patients, there was no significant difference in 30-day major morbidity after gastric bypass compared to sleeve gastrectomy (OR = 0.36; 95 % CI 0.08-1.66). CONCLUSIONS: Chronic and active use of steroid or immunosuppressant medications is a strong predictor of 30-day postoperative morbidity and mortality following primary bariatric surgery. Among the steroid/immunosuppressant users, complication rates were similar for gastric bypass and sleeve gastrectomy patients. Further studies are needed to help guide the management or discontinuation of such medications in the perioperative period. PMID- 26647070 TI - Neuroprotective potential of the group III mGlu receptor agonist ACPT-I in animal models of ischemic stroke: In vitro and in vivo studies. AB - In the present study, we investigated the effect of ACPT-I [(1S, 3R,4S)-1 aminocyclopentane-1,2,4-tricarboxylic acid], a blood-brain-barrier permeable agonist of group III mGlu receptor, against oxygen-glucose deprivation (OGD) evoked neuronal cell death in primary neuronal cell cultures and in the model of transient middle cerebral artery occlusion (MCAO) in rats. We found that ACPT-I (1-200 MUM) in a concentration- and time-dependent way attenuated the OGD-induced neuronal cell damage, being also effective after a delayed application (30 min after OGD). The neuroprotective effects of ACPT-I were blocked by the group III mGlu receptor antagonist, (RS)-alpha-cyclopropyl-4-phosphonophenyl glycine (CPPG), and by the activator of cAMP-dependent PKA, 8-Bromo-cAMP, but not by an inhibitor of PI-3-K signaling pathway. Moreover, ACPT-I attenuated the OGD induced calpain activity and glutamate release. In the in vitro study, we also demonstrated the neuroprotective potential of mGluR4 positive allosteric modulators (PAMs), PHCCC (30 MUM) and VU0155041 (10 and 30 MUM) and synergism in neuroprotective action of low concentrations of ACPT-I and mGluR4 PAMs suggesting an important role of mGluR4 activation in prevention of ischemic neuronal cell death. In the rat MCAO model, we demonstrated that ACPT-I (30 mg/kg) injected intraperitoneally either 30 min after starting MCAO or 30 min after beginning reperfusion not only diminished the infarction volume by about 30%, but also improved selected gait parameters (CatWalk analysis) and the mobility of animals in the open field test. In conclusion, our results indicate that ACPT-I may be not only neuroprotective against ischemic neuronal damage but may also diminish the postischemic functional deficits. PMID- 26647069 TI - Age-related neuroinflammation and changes in AKT-GSK-3beta and WNT/ beta-CATENIN signaling in rat hippocampus. AB - Aging is a multifactorial process associated with an increased susceptibility to neurodegenerative disorders which can be related to chronic inflammation. Chronic inflammation, however, can be characterized by the persistent elevated glucocorticoid (GCs) levels, activation of the proinflammatory transcription factor NF-kB, as well as an increase in cytokines. Interestingly, both NF-kB and cytokines can be even modulated by Glycogen Synthase Kinase 3 beta (GSK-3beta) activity, which is a key protein that can intermediate inflammation and metabolism, once it has a critical role in AKT signaling pathway, and can also intermediate WNT/beta-CATENIN signaling pathway. The aim of this study was to verify age-related changes in inflammatory status, as well as in the AKT and WNT signaling pathways. Results showed an age-related increase in neuroinflammation as indicated by NF-kB activation, TNF-alpha and GCs increased levels, a decrease in AKT activation and an increase in GSK-3beta activity in both 12- and 24- month old animals. Aging also seems to induce a progressive decrease in canonical WNT/beta-CATENIN signaling pathway once there is a decrease in DVL-2 levels and in the transcription of Axin2 gene. Little is known about the DVL-2 regulation as well as its roles in WNT signaling pathway, but for the first time it was suggested that DVL-2 expression can be changed along aging. PMID- 26647071 TI - Risk factors for noncontact anterior cruciate ligament injury: Analysis of parameters in proximal tibia using anteroposterior radiography. AB - OBJECTIVE: To investigate the relationship between the proximal tibial parameters of tibia width (TW), eminence width (EW), and eminence width index (EWI), and noncontact anterior cruciate ligament (ACL) injury, in a Chinese population. METHODS: A retrospective case-control study was conducted of all ACL reconstructions (ACL group) and meniscal surgeries (control group) undertaken at two Chinese hospitals. Patients in the ACL group were age- and sex-matched with controls. Anteroposterior knee radiographs were used to measure the TW, EW and EWI. RESULTS: A total of 73 pairs of patients who were verified by knee arthroscopy, magnetic resonance imaging and physical examination were included in the study. There was no significant difference between the ACL group and the control group in terms of TW in the total population and in the two sex subgroups. The ACL group had a significantly smaller EW and EWI compared with the control group in the total population and in the two sex subgroups. CONCLUSION: Decreased EW and EWI are associated with increased risk of noncontact ACL injury in a Chinese population. PMID- 26647072 TI - Effect of treatment guidance using a retrospective continuous glucose monitoring system on glycaemic control in outpatients with type 2 diabetes mellitus: A randomized controlled trial. AB - OBJECTIVES: To assess the effect of treatment guidance based on data from a continuous glucose monitoring (CGM) device on glycaemic control, and patient satisfaction, in patients with type 2 diabetes mellitus (T2DM). METHODS: Patients with poorly-controlled T2DM treated with insulin were randomly assigned to the intervention or nonintervention group. Continuous blood-glucose levels were recorded for 4-5 days using a CGM device on three separate occasions during the 8 month study period. The intervention group received treatment guidance based on the CGM data; the nonintervention group received advice based on blood glucose and glycosylated haemoglobin (HbA1c) levels. RESULTS: A total of 34 patients were enrolled in the study. The mean +/- SD baseline HbA1c was 8.2 +/- 1.2% in the intervention group and 8.2 +/- 0.9% in the nonintervention group. At the study end, there was no significant difference in the change from baseline of HbA1c between the two groups. There was also no significant difference in the change from baseline in the Diabetes Treatment Satisfaction Questionnaire score between the two groups. CONCLUSIONS: The present study did not demonstrate that treatment guidance using retrospective CGM data was effective for improving glycaemic control and therapeutic satisfaction in Japanese patients with T2DM. PMID- 26647073 TI - Brucellosis-related acute pancreatitis: A rare complication of a universal disease. AB - OBJECTIVES: To determine the prevalence and determinants of acute pancreatitis in patients with acute brucellosis. METHODS: Adult patients with brucellosis were retrospectively recruited. Brucellosis and acute pancreatitis were diagnosed according to standard criteria. Laboratory analyses included Wright agglutination titre, serum biochemical parameters and blood count. RESULTS: Patients with acute pancreatitis (n = 21) had significantly higher Wright agglutination titres, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma glutamyl transpeptidase, amylase, lipase and serum glucose concentrations, and significantly lower haemoglobin concentrations and haematocrit than patients with brucellosis alone (n = 326). CONCLUSIONS: Hyperglycaemia, anaemia, and liver transaminase and cholestatic enzyme concentrations may represent new approaches for assessing disease severity in patients with brucellosis and acute pancreatitis. PMID- 26647074 TI - Relevance of radiological and clinical measurements in predicting difficult intubation using light wand (Surch-liteTM) in adult patients. AB - OBJECTIVE: To determine the correlation between anatomical features of the upper airway (evaluated via computed tomography imaging) and the ease of light wand assisted endotracheal intubation in patients undergoing ear, nose and throat surgery under general anaesthesia. METHODS: Mallampati class, laryngoscopic grade, thyromental distance, neck circumference, body mass index, mouth opening and upper lip bite class were assessed. Epiglottis length and angle, tongue size and narrowest pharyngeal distance were determined using computed tomography imaging. Intubation success rate, time to successful intubation (intubating time) and postoperative throat symptoms were documented. RESULTS: Of 152 patients, 148 (97.4%) were successfully intubated on the first attempt (mean intubating time 11.5 +/- 6.7 s). Intubating time was positively correlated with laryngoscopic grade and body mass index in both male and female patients, and Mallampati class and neck circumference in male patients. Epiglottis length was positively correlated with intubating time. CONCLUSIONS: Ease of intubation was influenced by epiglottis length. Radiological evaluation may be useful for preoperative assessment of patients undergoing endotracheal intubation with light wand. PMID- 26647075 TI - Diffusion tensor tractography measurement of the distance between corticospinal tracts in patients with spontaneous intraventricular haemorrhage. AB - OBJECTIVE: The difference in the widest distance between corticospinal tracts (CST) on diffusion tensor tractography (DTT) in stroke patients with hydrocephalus was investigated retrospectively. METHODS: Distances were measured on an axial slice of the corona radiata, which provided the widest distance between CSTs. Two distances were measured, the absolute distance - the distance between the most medial point of the CSTs and the relative distance - calculated as a percentage of the absolute distance. RESULTS: The absolute distances of CSTs were 55.34 mm for the patient group and 46.75 mm for the control group. The relative distances of the CSTs were 44.12% and 35.96% for the patient group and the control group. Significant differences in the absolute and relative distances of CSTs were observed between the patient and the control group. CONCLUSION: These results suggest that the absolute and relative distances between CSTs might be used to diagnose hydrocephalus in stroke patients. PMID- 26647076 TI - Clinical, demographic and psychological characteristics of infertile male smokers in Northeast China. AB - OBJECTIVES: To investigate clinical, demographic and psychological characteristics of infertile male smokers in northeast China. METHODS: Serum and semen samples were collected from infertile men. Semen analysis was performed according to conventional procedures. Serum follicle-stimulating hormone, luteinizing hormone and testosterone levels were quantified. Psychological anxiety and depression were evaluated by the self-rating anxiety scale (SAS) and self-rating depression scale (SDS), respectively. RESULTS: Both SDS and SAS scores were significantly higher in smokers (n = 704) than in nonsmokers (n = 372); in addition, sperm viability and motility were significantly lower in smokers than in nonsmokers. Spearman's correlation coefficient analysis revealed significant positive correlations between duration of smoking and SDS and SAS scores, and between cigarettes smoked per day and SDS and SAS scores. CONCLUSIONS: Cigarette smoking has a negative effect on sperm viability and motility, and is associated with increased SDS and SAS scores. PMID- 26647077 TI - Multifactorial Competition and Resistance in a Two-Species Bacterial System. AB - Microorganisms exist almost exclusively in interactive multispecies communities, but genetic determinants of the fitness of interacting bacteria, and accessible adaptive pathways, remain uncharacterized. Here, using a two-species system, we studied the antagonism of Pseudomonas aeruginosa against Escherichia coli. Our unbiased genome-scale approach enabled us to identify multiple factors that explained the entire antagonism observed. We discovered both forms of ecological competition-sequestration of iron led to exploitative competition, while phenazine exposure engendered interference competition. We used laboratory evolution to discover adaptive evolutionary trajectories in our system. In the presence of P. aeruginosa toxins, E. coli populations showed parallel molecular evolution and adaptive convergence at the gene-level. The multiple resistance pathways discovered provide novel insights into mechanisms of toxin entry and activity. Our study reveals the molecular complexity of a simple two-species interaction, an important first-step in the application of systems biology to detailed molecular dissection of interactions within native microbiomes. PMID- 26647079 TI - CT coronary angiographic evaluation of suspected anginal chest pain. AB - Non-invasive imaging plays a critical role in the assessment of patients presenting with suspected angina chest pain. However, wide variations in practice across Europe and North America highlight the lack of consensus in selecting the appropriate first-line test for the investigation of coronary artery disease (CAD). CT coronary angiography (CTCA) has a high negative predictive value for excluding the presence of CAD. As such, it serves as a potential 'gatekeeper' to downstream testing by reducing the rate of inappropriate invasive coronary angiography. Two recent large multicentre randomised control trials have provided insights into whether CTCA can be incorporated into chest pain care pathways to improve risk stratification of CAD. They demonstrate that using CTCA enhances diagnostic certainty and improves the targeting of appropriate invasive investigations and therapeutic interventions. Importantly, reductions in cardiac death and non-fatal myocardial infarction appear to be attained through the more appropriate use of preventative therapy and coronary revascularisation when guided by CTCA. With this increasing portfolio of evidence, CTCA should be considered the non-invasive investigation of choice in the evaluation of patients with suspected angina pectoris due to coronary heart disease. CLINICAL TRIAL NUMBER: NCT01149590, post-results. PMID- 26647078 TI - One-carbon metabolism and epigenetics: understanding the specificity. AB - One-carbon metabolism is a metabolic network that integrates nutrient status from the environment to yield multiple biological functions. The folate and methionine cycles generate S-adenosylmethionine (SAM), which is the universal methyl donor for methylation reactions, including histone and DNA methylation. Histone methylation is a crucial part of the epigenetic code and plays diverse roles in the establishment of chromatin states that mediate the regulation of gene expression. The activities of histone methyltransferases (HMTs) are dependent on intracellular levels of SAM, which fluctuate based on cellular nutrient availability, providing a link between cell metabolism and histone methylation. Here we discuss the biochemical properties of HMTs, their role in gene regulation, and the connection to cellular metabolism. Our emphasis is on understanding the specificity of this intriguing link. PMID- 26647080 TI - New speckle-tracking algorithm for right ventricular volume analysis from three dimensional echocardiographic data sets: validation with cardiac magnetic resonance and comparison with the previous analysis tool. AB - AIMS: (i) To validate a new software for right ventricular (RV) analysis by 3D echocardiography (3DE) against cardiac magnetic resonance (CMR); (ii) to assess the accuracy of different measurement approaches; and (iii) to explore any benefits vs. the previous software. METHODS AND RESULTS: We prospectively studied with 3DE and CMR 47 patients (14-82 years, 28 men) having a wide range of RV end diastolic volumes (EDV 82-354 mL at CMR) and ejection fractions (EF 34-81%). Multi-beat RV 3DE data sets were independently analysed with the new software using both automated and manual editing options, as well as with the previous software. RV volume reproducibility was tested in 15 random patients. RV volumes and EF measurements by the new software had an excellent accuracy (bias +/- SD: 15 +/- 24 mL for EDV; 1.4 +/- 4.9% for EF) and reproducibility compared with CMR, provided that the RV borders automatically tracked by software were systematically edited by operator. The automated analysis option underestimated the EDV, overestimated the ESV, and largely underestimated the EF (bias +/- SD: 17 +/- 10%). RV volumes measured with the new software using manual editing showed similar accuracy, but lower inter-observer variability and shorter analysis time (3-5') in comparison with the previous software. CONCLUSION: Novel vendor-independent 3DE software enables an accurate, reproducible and faster quantitation of RV volumes and ejection fraction. Rather than optional, systematic verification of border tracking quality and manual editing are mandatory to ensure accurate 3DE measurements. These findings are relevant for echocardiography laboratories aiming to implement 3DE for RV analysis for both research and clinical purposes. PMID- 26647081 TI - Should Coronary Artery Bypass Grafting Be Performed in Patients With Moderate Stenosis of the Left Anterior Descending Coronary Artery? PMID- 26647082 TI - Frequency and Predictors of Internal Mammary Artery Graft Failure and Subsequent Clinical Outcomes: Insights From the Project of Ex-vivo Vein Graft Engineering via Transfection (PREVENT) IV Trial. AB - BACKGROUND: The internal mammary artery (IMA) is the preferred conduit for bypassing the left anterior descending (LAD) artery in patients undergoing coronary artery bypass grafting. Systematic evaluation of the frequency and predictors of IMA failure and long-term outcomes is lacking. METHODS AND RESULTS: The Project of Ex-vivo Vein Graft Engineering via Transfection (PREVENT) IV trial participants who underwent IMA-LAD revascularization and had 12- to 18-month angiographic follow-up (n=1539) were included. Logistic regression with fast false selection rate methods was used to identify characteristics associated with IMA failure (>=75% stenosis). The relationship between IMA failure and long-term outcomes, including death, myocardial infarction, and repeat revascularization, was assessed with Cox regression. IMA failure occurred in 132 participants (8.6%). Predictors of IMA graft failure were LAD stenosis <75% (odds ratio, 1.76; 95% confidence interval, 1.19-2.59), additional bypass graft to diagonal branch (odds ratio, 1.92; 95% confidence interval, 1.33-2.76), and not having diabetes mellitus (odds ratio, 1.82; 95% confidence interval, 1.20-2.78). LAD stenosis and additional diagonal graft remained predictive of IMA failure in an alternative model that included angiographic failure or death before angiography as the outcome. IMA failure was associated with a significantly higher incidence of subsequent acute (<14 days of angiography) clinical events, mostly as a result of a higher rate of repeat revascularization. CONCLUSIONS: IMA failure was common and associated with higher rates of repeat revascularization, and patients with intermediate LAD stenosis or with an additional bypass graft to the diagonal branch had increased risk for IMA failure. These findings raise concerns about competitive flow and the benefit of coronary artery bypass grafting in intermediate LAD stenosis without functional evidence of ischemia. CLINICAL TRIAL REGISTRATION: URL: http:/www.clinicaltrials.gov. Unique identifier: NCT00042081. PMID- 26647083 TI - Functional advantage of educated KIR2DL1(+) natural killer cells for anti-HIV-1 antibody-dependent activation. AB - Evidence from the RV144 HIV-1 vaccine trial implicates anti-HIV-1 antibody dependent cellular cytotoxicity (ADCC) in vaccine-conferred protection from infection. Among effector cells that mediate ADCC are natural killer (NK) cells. The ability of NK cells to be activated in an antibody-dependent manner is reliant upon several factors. In general, NK cell-mediated antibody-dependent activation is most robust in terminally differentiated CD57(+) NK cells, as well as NK cells educated through ontological interactions between inhibitory killer immunoglobulin-like receptors (KIR) and their major histocompatibility complex class I [MHC-I or human leucocyte antigen (HLA-I)] ligands. With regard to anti HIV-1 antibody-dependent NK cell activation, previous research has demonstrated that the epidemiologically relevant KIR3DL1/HLA-Bw4 receptor/ligand combination confers enhanced activation potential. In the present study we assessed the ability of the KIR2DL1/HLA-C2 receptor/ligand combination to confer enhanced activation upon direct stimulation with HLA-I-devoid target cells or antibody dependent stimulation with HIV-1 gp140-pulsed CEM.NKr-CCR5 target cells in the presence of an anti-HIV-1 antibody source. Among donors carrying the HLA-C2 ligand for KIR2DL1, higher interferon (IFN)-gamma production was observed within KIR2DL1(+) NK cells than in KIR2DL1(-) NK cells upon both direct and antibody dependent stimulation. No differences in KIR2DL1(+) and KIR2DL1(-) NK cell activation were observed in HLA-C1 homozygous donors. Additionally, higher activation in KIR2DL1(+) than KIR2DL1(-) NK cells from HLA-C2 carrying donors was observed within less differentiated CD57(-) NK cells, demonstrating that the observed differences were due to education and not an overabundance of KIR2DL1(+) NK cells within differentiated CD57(+) NK cells. These observations are relevant for understanding the regulation of anti-HIV-1 antibody-dependent NK cell responses. PMID- 26647085 TI - Long-term monitoring dataset of fish assemblages impinged at nuclear power plants in northern Taiwan. AB - The long-term species diversity patterns in marine fish communities are garnering increasing attention from ecologists and conservation biologists. However, current databases on quantitative abundance information lack consistent long-term time series, which are particularly important in exploring the possible underlying mechanism of community changes and evaluating the effectiveness of biodiversity conservation measures. Here we describe an impinged fish assemblage dataset containing 1, 283, 707 individuals from 439 taxa. Once a month over 19 years (1987-1990 and 2000-2014), we systematically collected the fish killed by impingement upon cooling water intake screens at two nuclear power plants on the northern coast of Taiwan. Because impingement surveys have low sampling errors and can be carried out over many years, they serve as an ideal sampling tool for monitoring how fish diversity and community structure vary over an extended period of time. PMID- 26647086 TI - Ru(II)-polypyridyl surface functionalised gold nanoparticles as DNA targeting supramolecular structures and luminescent cellular imaging agents. AB - The development of Ru(II) functionalized gold nanoparticles 1-3.AuNP is described. These systems were found to be mono-disperse with a hydrodynamic radius of ca. 15 nm in water but gave rise to the formation of higher order structures in buffered solution. The interaction of 1-3.AuNP with DNA was also studied by spectroscopic and microscopic methods and suggested the formation of large self-assembly structures in solution. The uptake of 1-3.AuNP by cancer cells was studied using both confocal fluorescence as well as transmission electron microscopy (TEM), with the aim of investigating their potential as tools for cellular biology. These systems displaying a non-toxic profile with favourable photophysical properties may have application across various biological fields including diagnostics and therapeutics. PMID- 26647087 TI - Towards high-efficiency nanoelectrocatalysts for oxygen reduction through engineering advanced carbon nanomaterials. AB - One of the critical issues in the industrial development of fuel cells (e.g., proton exchange membrane fuel cells, direct methanol fuel cells and biofuel cells) is the high cost, serious intermediate tolerance, anode crossover, sluggish kinetics, and poor stability of the platinum (Pt) as the preferred electrocatalysts for the oxygen reduction reaction (ORR) at the cathode. The development of novel noble-metal-free electrocatalysts with low cost, high activity and practical durability for ORR has been considered as one of the most active and competitive fields in chemistry and materials science. In this critical review, we will summarize recent advances on engineering advanced carbon nanomaterials with different dimensions for the rational design and synthesis of noble-metal-free oxygen reduction electrocatalysts including heteroatom-doped carbon nanomaterials, transition metal-based nanoparticle (NP)-carbon nanomaterial composites and especially the stable iron carbide (Fe3C)-based NP carbon nanomaterial composites. Introducing advanced carbon nanomaterials with high specific surface area and stable structure into the noble-metal-free ORR field has not only led to a maximized electrocatalyst surface area for the electron transfer but also resulted in enhanced electrocatalyst stability for long-term operation. Therefore, the rational design and synthesis of noble-metal free electrocatalysts based on heteroatoms, transition metal-based NPs and Fe3C based NP functionalized carbon nanomaterials are of special relevance for their ORR applications, and represents a rapidly growing branch of research. The demonstrated examples in this review will open new directions on designing and optimizing advanced carbon nanomaterials for the development of extremely active and durable earth-abundant cathodic catalysts for fuel cell applications. PMID- 26647088 TI - Novel insights into the effects of diabetes on gastric motility. AB - Recent data from the Diabetes Control and Complications Trial/Epidemiology of Diabetic Interventions and Complications cohort indicate that the disease burden of gastroparesis in diabetes remains high, consistent with the outcome of cross sectional studies in type 1 and 2 diabetes. An improved understanding of the pathogenesis of diabetic gastroparesis at the cellular level has emerged in the last decade, particularly as a result of initiatives such as the National Institute of Health funded Gastroparesis Clinical Research Consortium in the US. Management of diabetic gastroparesis involves dietary and psychological support, attention to glycaemic control, and the use of prokinetic agents. Given that the relationship between upper gastrointestinal symptoms and the rate of gastric emptying is weak, therapies targeted specifically at symptoms, such as nausea or pain, are important. The relationship between gastric emptying and postprandial glycaemia is complex and inter-dependent. Short-acting glucagon-like peptide-1 agonists, that slow gastric emptying, can be used to reduce postprandial glycaemic excursions and, in combination with basal insulin, result in substantial reductions in glycated haemoglobin in type 2 patients. PMID- 26647084 TI - Clinical Factors and Disease Course Related to Diagnostic Delay in Korean Crohn's Disease Patients: Results from the CONNECT Study. AB - Diagnostic delay frequently occurs in Crohn's disease (CD) patients because of diagnostic limitations. However, diagnostic delay and its related factors remain poorly defined. Therefore, we aimed to identify the predictors associated with diagnostic delay and to evaluate the impact of diagnostic delay on clinical course in a Korean CD patient cohort. We performed a multicenter retrospective analysis of 1,047 CD patients registered in the Crohn's Disease Clinical Network and Cohort study in Korea. The mean interval of diagnostic delay was 16.0 +/- 33.1 months. Multivariate analysis showed that older age at diagnosis (>=40 years) (p = 0.014), concomitant upper gastrointestinal (UGI) disease (p = 0.012) and penetrating disease behavior at diagnosis (p = 0.001) were positively associated with long diagnostic delay (>=18 months). During the longitudinal follow-up, long diagnostic delay was independently predictive of further development of intestinal stenosis (hazard ratio [HR], 1.43; 95% confidence interval [CI], 1.07-1.93; p = 0.017), internal fistulas (HR, 1.62; 95% CI, 1.12 2.33; p = 0.011), and perianal fistulas (HR, 1.38; 95% CI, 1.06-1.80; p = 0.016). However, as for the risk of abscess formation, bowel perforation, and CD-related abdominal surgery, no significant association with diagnostic delay was observed. Older age at diagnosis, UGI involvement, and penetrating behavior are associated with long diagnostic delay in Korean CD patients. Moreover, diagnostic delay is associated with an increased risk of CD-related complications such as intestinal stenosis, internal fistulas, and perianal fistulas. PMID- 26647089 TI - [Comparison of tramadol and lornoxicam in intravenous regional anesthesia: a randomized controlled trial]. AB - BACKGROUND AND OBJECTIVES: Tourniquet pain is one of the major obstacles for intravenous regional anesthesia. We aimed to compare tramadol and lornoxicam used in intravenous regional anesthesia as regards their effects on the quality of anesthesia, tourniquet pain and postoperative pain as well. METHODS: After the ethics committee approval 51 patients of ASA physical status I-II aged 18-65 years were enrolled. The patients were divided into three groups. Group P (n=17) received 3mg/kg 0.5% prilocaine; group PT (n=17) 3mg/kg 0.5% prilocaine+2mL (100mg) tramadol and group PL (n=17) 3mg/kg 0.5% prilocaine+2mL (8mg) lornoxicam for intravenous regional anesthesia. Sensory and motor block onset and recovery times were noted, as well as tourniquet pains and postoperative analgesic consumptions. RESULTS: Sensory block onset times in the groups PT and PL were shorter, whereas the corresponding recovery times were longer than those in the group P. Motor block onset times in the groups PT and PL were shorter than that in the group P, whereas recovery time in the group PL was longer than those in the groups P and PT. Tourniquet pain onset time was shortest in the group P and longest in the group PL. There was no difference regarding tourniquet pain among the groups. Group PL displayed the lowest analgesic consumption postoperatively. CONCLUSION: Adding tramadol and lornoxicam to prilocaine for intravenous regional anesthesia produces favorable effects on sensory and motor blockade. Postoperative analgesic consumption can be decreased by adding tramadol and lornoxicam to prilocaine in intravenous regional anesthesia. PMID- 26647090 TI - [Comparison of sevoflurane concentration for insertion of proseal laryngeal mask airway and tracheal intubation in children (correlation with BIS)]. AB - BACKGROUND: Sevoflurane is an inhalational agent of choice in paediatric anaesthesia. For management of airways in children a suitable alternative to ETT is a paediatric proseal laryngeal mask airway (benchmark second generation SAD). Various studies have shown that less sevoflurane concentration is required for LMA insertion in comparison to TI. BIS is a useful monitor of depth of anaesthesia. AIMS: To compare concentration of sevoflurane (end tidal and MAC value) required for proseal laryngeal mask airway insertion and tracheal intubation in correlation with BIS index. METHOD: The prospective randomised single blind study was done in children between 2 and 9 years of ASA I and II and they were randomly allocated to Group P (proseal laryngeal mask airway insertion) and Group TI (tracheal intubation). No sedative premedication was given. Induction was done with 8% sevoflurane and then predetermined concentration was maintained for 10min. Airway was secured either by proseal laryngeal mask airway or endotracheal tube without using muscle relaxant. End tidal sevoflurane concentration, MAC, BIS, and other vital parameters were monitored every minute till insertion of an airway device. Insertion conditions were observed. Statistical analysis was done by Anova and Student's t test. RESULTS: Difference between ETLMI (2.49+/-0.44) and ETTI (2.81+/-0.65) as well as MACLMI (1.67+/ 0.13) and MACTI (1.77+/-0.43) was statistically very significant, while BISLMI (49.05+/-10.76) and BISTI (41.25+/-3.25) was significant. Insertion conditions were comparable in both the groups. CONCLUSION: We can conclude that in children airway can be secured safely with proseal laryngeal mask airway using less sevoflurane concentration in comparison to tracheal intubation and this was supported by BIS index. PMID- 26647091 TI - Serum leptin and adiponectin levels in children with type 1 diabetes mellitus - Relation to body fat mass and disease course. AB - PURPOSE: Leptin and adiponectin are adipokines presenting a wide range of impacts, including glycemic balance regulations. Insulin is one of the main regulators of adipose tissue function. In type 1 diabetes mellitus (T1DM) endogenous insulin secretion is replaced by the exogenous supply, which is not regulated naturally. The aim of the study was to establish serum leptin and adiponectin levels, and their relations to body fat mass and disease course in children with T1DM. MATERIAL/METHODS: The study included 75 children with T1DM and the control group of 20 healthy coevals. All children had estimated serum leptin and adiponectin concentrations, lipid profile, and bioelectrical impedance analysis. RESULTS: Serum leptin concentrations in children with T1DM were not significantly different from the control group (p=0.067, mean values+/-SD: 3.11+/ 2.98 vs. 5.29+/-5.06MUg/l, respectively), and related positively to body fat mass in both groups. Adiponectin serum concentrations were significantly higher in children with T1DM than in the control group (p<0.001; mean values: 18.82+/-9.31 vs. 12.10+/-5.53MUg/ml, respectively), and were not related to the body fat content in the study group. Both, leptin and adiponectin, showed no relation to any of the analyzed parameters of the disease course. CONCLUSIONS: Differences observed between children with T1DM and their healthy coevals, when similar in terms of age, body weight, and body fat mass, seem not to depend directly on the disease duration, its metabolic control or insulin supply. PMID- 26647092 TI - Intracellular degradation of chemically functionalized carbon nanotubes using a long-term primary microglial culture model. AB - Chemically functionalized carbon nanotubes (f-CNTs) have been used in proof-of concept studies to alleviate debilitating neurological conditions. Previous in vivo observations in brain tissue have suggested that microglia - acting as resident macrophages of the brain - play a critical role in the internalization of f-CNTs and their partial in situ biodegradation following a stereotactic administration in the cortex. At the same time, several reports have indicated that immune cells such as neutrophils, eosinophils and even macrophages could participate in the processing of carbon nanomaterials via oxidation processes leading to degradation, with surface properties acting as modulators of CNT biodegradability. In this study we questioned whether degradability of f-CNTs within microglia could be modulated depending on the type of surface functionalization used. We investigated the kinetics of degradation of multi walled carbon nanotubes (MWNTs) functionalized via different chemical strategies that were internalized within isolated primary microglia over three months. A cellular model of rat primary microglia that can be maintained in cell culture for a long period of time was first developed. The Raman structural signature of the internalized f-CNTs was then studied directly in cells over a period of up to three months, following a single exposure to a non-cytotoxic concentration of three different f-CNTs (carboxylated, aminated and both carboxylated and aminated). Structural modifications suggesting partial but continuous degradation were observed for all nanotubes irrespective of their surface functionalization. Carboxylation was shown to promote more pronounced structural changes inside microglia over the first two weeks of the study. PMID- 26647093 TI - Neuropsychological changes and cranioplasty: A group analysis. AB - BACKGROUND: Cranioplasty is the surgical answer to cranial defect due to decompressive craniectomy in order to increase patient's safety and for cosmetic reasons. Two main neurological sequelae of skull breaches have been described and cranioplasty has been suggested as a way to treat these neurological symptoms, but its effects on cognitive and motor functions are still unclear. MATERIALS AND METHODS: In order to better elucidate if and to what extent the cranioplasty affects the whole array of cognitive functions or just some specific domains, 29 patients were studied pre- and post-cranioplasty, with structured assessments of memory, attention, language and executive functioning performed ~ 4 months and 1 month before cranioplasty and 1 month and 6 months after surgery. RESULTS AND CONCLUSION: Cranioplasty affects the cognitive profile with a non-specific pattern of change. Timing of the cranioplasty plays a key role to enucleate cognitive improvement, indeed greater cognitive changes were seen in patients who had cranioplasty within 6 months following the injury. Thus, cranioplasty must be considered a key factor in neuropsychological recovery and should be performed as soon as possible following the injury in order to take advantage of the window of opportunity for rehabilitation. PMID- 26647094 TI - Pain among older adults from a gender perspective: findings from the Swedish National Study on Aging and Care (SNAC-Blekinge). AB - BACKGROUND AND AIMS: Pain is common in the elderly population and its prevalence varies according to the studied disease, clinical setting, sex and age. This study examines pain in an aging population from a gender perspective. METHODS: The Swedish National study on Aging and Care (SNAC) is conducted at four research centres. Participants were recruited from the baseline sample (n=1402) at one of the research centres, SNAC-Blekinge. Individuals aged 60 years and older were included and non-participation was documented. Research personnel conducted the medical examination on two occasions. RESULTS: The prevalence of pain was 769/1402 (54.8%), distributed as 496/817 (64.5%) women and 273/585 (35.5%) men,p<0.01. Women reported more pain located in the vertebral column,p<0.01. The most common pain location was the legs and feet. About 84% reported pain intensity as 4 or higher on the visual analogue scale (VAS). Pain intensity declines with age among men,p<0.01. The most frequent treatment was painkillers. A total of 128/263 (48.7%) of the men received no pain treatment compared with 177/478 (37.0%) of the women,p<0.01. In a multivariate logistic regression model, women yielded the highest OR [OR 1.94 (C.I. 1.51-2.49)] for pain. CONCLUSIONS: Pain is common among older adults and there are significant differences between the sexes. Almost 55% of participants reported pain, predominantly women. In the majority of cases the intensity was rated as moderate or severe (VAS >4) and women rated higher than men p<002. Almost half of the men (48.7%) did not receive any treatment compared to 37% of the women, p<001. PMID- 26647095 TI - Theory and interpretation in qualitative studies from general practice: Why and how? AB - OBJECTIVE: In this article, I want to promote theoretical awareness and commitment among qualitative researchers in general practice and suggest adequate and feasible theoretical approaches. APPROACH: I discuss different theoretical aspects of qualitative research and present the basic foundations of the interpretative paradigm. Associations between paradigms, philosophies, methodologies and methods are examined and different strategies for theoretical commitment presented. Finally, I discuss the impact of theory for interpretation and the development of general practice knowledge. MAIN POINTS: A scientific theory is a consistent and soundly based set of assumptions about a specific aspect of the world, predicting or explaining a phenomenon. Qualitative research is situated in an interpretative paradigm where notions about particular human experiences in context are recognized from different subject positions. Basic theoretical features from the philosophy of science explain why and how this is different from positivism. Reflexivity, including theoretical awareness and consistency, demonstrates interpretative assumptions, accounting for situated knowledge. Different types of theoretical commitment in qualitative analysis are presented, emphasizing substantive theories to sharpen the interpretative focus. Such approaches are clearly within reach for a general practice researcher contributing to clinical practice by doing more than summarizing what the participants talked about, without trying to become a philosopher. CONCLUSIONS: Qualitative studies from general practice deserve stronger theoretical awareness and commitment than what is currently established. Persistent attention to and respect for the distinctive domain of knowledge and practice where the research deliveries are targeted is necessary to choose adequate theoretical endeavours. PMID- 26647096 TI - The ethnic gap in mental health: A population-based study of Russian, Somali and Kurdish origin migrants in Finland. AB - AIMS: Research demonstrates that migrants are more vulnerable to poor mental health than general populations, but population-based studies with distinct migrant groups are scarce. We aim to (1) assess the prevalence of mental health symptoms in Russian, Somali and Kurdish origin migrants in Finland; (2) compare the prevalence of mental health symptoms in these migrant groups to the Finnish population; (3) determine which socio-demographic factors are associated with mental health symptoms. METHODS: We used data from the Finnish Migrant Health and Wellbeing Study and Health 2011 Survey. Depressive and anxiety symptoms were measured using the Hopkins Symptom Checklist-25 (HSCL-25), and 1.75 was used as cut-off for clinically significant symptoms. Somatization was measured using the Symptom Checklist-90 (SCL-90) somatization scale. The age-adjusted prevalence of mental health symptoms in the studied groups was calculated by gender using predicted margins. Logistic regression analysis was used to determine which socio demographic factors are associated with mental health symptoms in the studied population groups. RESULTS: The prevalence of depressive and anxiety symptoms was higher in Russian women (24%) and Kurdish men (23%) and women (49%) than in the Finnish population (9-10%). These differences were statistically significant (p<.001). Socioeconomic disadvantage (e.g. unemployment and poor economic situation) and migration-related factors (e.g. poor language proficiency and short time since migration) significantly increased the odds for depressive and anxiety symptoms. CONCLUSIONS: Mental health symptoms are highly prevalent particularly in Kurdish migrants in Finland. Holistic interventions and co operation between integration and mental health services are acutely needed. PMID- 26647097 TI - Sex differences in health care consumption in Sweden: A register-based cross sectional study. AB - BACKGROUND: Generally, health care consumption, especially primary care, is greater among women than men. The extent to which this sex difference is explained by reproduction and sex-specific morbidity is unclear. METHODS: We examined age- and sex-specific health care service utilization and costs in the western region of Sweden. Data were retrieved from a regional health care database of information on total health care consumption in the population. Use of health care resources was divided into the following diagnosis categories: health care associated with reproduction; health care received for sex-specific morbidity; and health care provided for all other conditions. RESULTS: Total per capita cost for health care was 20% higher for women than for men. When adjusted for reproduction and sex-specific morbidity, the cost-difference decreased to 8%. The remaining cost-difference could be explained by women's substantially higher costs for mental and behavioral disorders and diseases of the musculoskeletal system. Women were more likely to receive more accessible, less expensive primary care, while men were more likely to receive specialist inpatient care. CONCLUSIONS: The substantially greater use of reproduction-associated care among women, which largely occurs within primary care, might make it easier to also seek health care for other reasons. Efforts to eliminate barriers that prevent men from investing in their health and seeking primary care could reduce future morbidity and costs for specialist care. More studies and appropriate actions are needed to determine why women are overrepresented in mental, behavioral and musculoskeletal disorders. PMID- 26647098 TI - Conflicts, political leadership and public health. PMID- 26647099 TI - Triplication of 16p12.1p12.3 associated with developmental and growth delay and distinctive facial features. AB - The 16p12 region is particularly prone to genomic disorders due to the large number of low copy repeats [Martin et al., 2004; Nature 432:988-994]. We report two unrelated patients with de novo triplication of 16p12.1p12.3 who had developmental delay and similar facial features. Patient 1 is a 4-year-old male with a congenital heart anomaly, bilateral cryptorchidism, chronic constipation, and developmental delay. Patient 2 is a 12-year-old female with prenatally diagnosed hydronephrosis, hepatobiliary disease, failure to thrive, and developmental delay. Distinctive facial features common to both patients include short palpebral fissures, bulbous nose, thin upper vermillion border, apparently lowset ears, and large ear lobes. We compare the clinical manifestations of our patients with a previously reported patient with triplication of 16p12.2. PMID- 26647100 TI - Occupational Needs and Goals of Survivors of Domestic Violence. AB - This study's purpose was to describe the occupational needs and goals of women residing in a domestic violence shelter and their self-perceived changes in satisfaction and occupational performance. Using a retrospective design, data from 68 occupational therapy evaluations from two domestic violence shelter settings were examined. Data were analyzed by coding problem areas and occupational goals and calculating frequencies for these variables. Where data were available, we also analyzed changes in pre- and postscores for self perceived satisfaction and occupational performance (n = 25). The most common problem areas were leisure, education, work, child rearing, and health management. The most common goals were in the areas of education, work, health management, child rearing, and home management. Retrospective pre- and postchange scores in performance and satisfaction for 25 women were statistically significant. Findings provide direction for, and highlight the importance of occupational therapy services within domestic violence shelters as women regain their life skills. PMID- 26647101 TI - Analysis of Naturally Occurring Fluoride in Commercial Teas and Estimation of Its Daily Intake through Tea Consumption. AB - The aim of this study was to determine the levels of fluoride in commercial teas and to estimate the contribution of tea consumption to the fluoride recommended daily allowance. A total of 558 tea products in 6 categories, green tea, black tea, oolong tea, pu'er tea, white tea, and reprocessed tea, were collected in the period from 2010 to 2013. The levels of fluoride in infusions of these teas were determined by a fluoride-ion selective electrode. The mean fluoride level in all of the tea samples was 85.16 mg/kg. For each category of tea, the mean fluoride levels were 63.04, 99.74, 52.19, 101.67, 159.78, and 110.54 mg/kg for green tea, black tea, white tea, pu'er tea, oolong tea, and reprocessed tea, respectively. The fluoride content of tea from 4 tea zones in descending order were Southern tea zone (111.39 mg/kg) > Southwest tea zone (78.78 mg/kg) > Jiangnan tea zone (71.73 mg/kg) > Jiangbei tea zone (64.63 mg/kg). These areas produced teas with lower fluoride levels than available foreign-produced tea (161.11 mg/kg). The mean chronic daily intake (CDI) was 0.02 mg/(kg*day) or 1.27 mg/kg. Generally, consuming tea from these 6 categories does not result in the intake of excessive amounts of fluoride for the general population. PMID- 26647103 TI - Exposure to the Tips From Former Smokers Campaign Among Adolescents in the United States. AB - INTRODUCTION: Evaluation of the Tips from Former Smokers (Tips) campaign in the United States so far has focused exclusively on adult smokers. This study provides evidence on the level of exposure to Tips among adolescents in the United States, an important secondary audience for the campaign. METHODS: Data came from the 2013 National Youth Tobacco Survey (N = 18 406). Exposure to Tips was measured by ad recall. Characteristics of adolescents reporting exposure versus no exposure were examined through a series of bivariate analysis linking exposure to smoking status, demographics, and important risk factors. RESULTS: Most adolescents in the United States (63%, 95% confidence interval [CI] = 60.6%, 65.3%) were exposed to at least one Tips ad. Current smokers (70.6%, 95% CI = 67.7%, 73.4%), noncurrent smokers (67.7%, 95% CI = 65.5%, 69.7%), and high-risk never-smokers (63.8%, 95% CI = 60.2%, 67.2%) reported greater exposure than low risk never-smokers (60.7%, 95% CI = 57.8%, 63.5%; all P < .05). Those who reported exposure were more likely to be female; be older in age; be white (vs. Hispanic); live with a smoker; have less firm smoking rules in the family; have one or more friends using tobacco or are not sure; have been exposed to tobacco advertising from one or more sources; and have skipped classes in the past 30 days. CONCLUSIONS: Tips has significant reach among adolescents in the United States, particularly among those with smoking experience and those whose life environments include more pro-smoking influences. Close monitoring of the Tips' impact on this important population is needed. IMPLICATIONS: This study shows substantial adolescent awareness of the Tips campaign in the United States. This evidence has important implications for the comprehensive evaluation of the public health impact of Tips. So far research on Tips has focused almost entirely on adult smokers. Findings of this study suggest that the potential impact of Tips on adolescents, particularly those at high risk of smoking, should become an integral part of the evaluation research agenda. PMID- 26647102 TI - Altered expression profile of apoptosis-related molecules correlated with clinicopathological factors in non-small-cell lung cancer. AB - Apoptosis-related molecules can be abnormally expressed in cancers and underscore the hallmark of resisting cell death in cancer cells. This study was aimed to observe the expression patterns of apoptosis-related molecules in lung cancer and paired non-cancerous tissues, and to observe if there is a correlation between the expression of these apoptotic molecules and clinicopathologic parameters. Immunohistochemistry (IHC) was performed to analyze the expression level of CASP3, CASP8, CASP9, PARP1, Cleaved CASP3 (C-CASP3), Cleaved PARP1 (C-PARP1), XIAP, BIRC5 (Survivin) and BCL2 in lung cancer and paired non-cancerous tissues. We found that apoptosis-related molecules CASP3, CASP9, BCL2, BIRC5 and PARP1 are abnormally expressed in lung cancer cells and their expression were correlated with histology. BCL2, BIRC5 and PARP1 are expressed at higher levels in SCC than in non-SCC. C-PARP1 expression might be an independent prognostic factor for NSCLC. PMID- 26647104 TI - Feasibility and Smokers' Evaluation of Self-Generated Text Messages to Promote Quitting. AB - INTRODUCTION: Cigarette smoking is a leading cause of preventable mortality. Mobile technologies, including text messaging, provide opportunities to promote quitting. Many text messaging-based cessation interventions contain content created by experts. However, smokers may be best persuaded by receipt of text messages they created based on their reasons for quitting, assisted or not by a motivational facilitator. This study assessed the feasibility and participants' evaluation of two ways to self-generate smoking cessation messages delivered via cell-phone. METHODS: We enrolled smokers (N = 24) and randomized them to: (1) behavioral counseling assistance plus self-generated messages, or (2) self generated messages only. Both groups wrote: (1) their reasons for wanting to quit and then (2) text messages related to their reason(s) for quitting, Messages were delivered as text messages as well as with a link to verbatim self-recorded audio message for 10 days. At follow-up, participants evaluated the intervention. RESULTS: Participants composed and recorded messages and evaluated them and the intervention favorably. The counseling+message group wrote an average of 7.66 (SD = 4.86) text messages while the message-only wrote an average of 6.66 (SD = 2.93) messages. Most participants felt that the messages were of appropriate length, including the frequency and timing of message delivery. CONCLUSION: It is feasible for smokers to self-generate motivational text and audio messages concerning reasons for quitting, even among smokers without an immediate desire to quit. Participants evaluated the messages and intervention favorably. Future research should test self-generated messages in larger trials of self- versus expert-generated message. IMPLICATIONS: This study assessed the feasibility and participants' evaluation of two ways to self-generate smoking cessation messages delivered via cell-phone. It is feasible for smokers to self-generate motivational text and audio messages concerning reasons for quitting, even among smokers without an immediate desire to quit. Participants evaluated the messages and intervention favorable. Future research should test self-generated messages in larger trials of self- versus expert-generated messages. PMID- 26647105 TI - Effects of resveratrol on collagen type II protein in the superficial and middle zone chondrocytes of porcine articular cartilage. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Resveratrol (RSV) was first isolated in 1940 from the roots of white hellebore (Veratrum grandiflorum (Maxim. ex Miq) O. Loes) and in 1963 from the roots of Japanese knotweed (Polygonum cuspidatum Siebold & Zucc.). These species have been used traditionally to treat arthritis, gout or inflammation. RSV (3,5,4-trihydroxystilbene) is a polyphenolic phytoalexin compound found in various plants, such as grape vines, berries, peanuts, seeds and roots; the highest concentration is in the skin of red grapes. This component of red wine has potent anti-inflammatory properties and may reduce the side effects of non-steroidal anti-inflammatory drugs that are currently used for pain amelioration in osteoarthritis (OA). In early degeneration of articular cartilage, which may lead to OA there is a loss of the tensile properties, indicative of damage to the fibrillar network. Damage to this fibrillar meshwork, made up of primarily collagen type II (90-95%), may be a critical event in the pathology of many arthritides, due in part to the very slow rate of collagen turnover within the cartilage. Collagen type II is the pre-dominant protein of the cartilage middle zone matrix mainly responsible for tensile strength of articular cartilage. The aim of the study was to investigate the effects of RSV on the expression of collagen type II from the superficial and middle zone chondrocytes of porcine articular cartilage. MATERIALS AND METHODS: Porcine articular chondrocytes were isolated from the superficial and middle zone of articular cartilage, cultured as monolayers in serum-free chemically defined medium for four days. Effects of RSV on porcine articular chondrocytes were studied by assessing expression of collagen type II mRNA by RT-PCR and protein levels of collagen type II by ELISA; as well as localisation of collagen type II on cartilage tissue sections using immunohistochemistry. RESULTS: RSV significantly stimulated the expression of collagen type II at the mRNA and protein levels in the superficial and middle zone. Immunohistochemistry revealed that collagen type II was present along the whole cartilage tissue sections. The staining was strong in the superficial zone, mild in the middle zone and less around hypertrophic chondrocytes in the deep zone. Histological analysis confirmed that cartilage slices were obtained from specific articular cartilage zones. CONCLUSION: This study revealed the importance of RSV in the regulation of collagen type II protein in different zones of articular cartilage. PMID- 26647106 TI - Cissampelos pareira Linn. ameliorates thyroxin-induced cardiac hypertrophy in rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Cissampelos pareira extract has been traditionally used in ayruveda as cardiotonic, diuretics and in heart complains but its pharmacological evaluation in thyroxin-induced cardiac hypertrophy has not yet been explored. AIM OF THE STUDY: The aim of this study was to assess the cardioprotective effect of C. pareira root extract in experimentally induced hyperthyroidism in rats. MATERIALS AND METHODS: Male Wistar rats were treated with (i) thyroxin (0.1 mg/kg/day, i.p.) for 30 days, (ii) C. pareira extract (200 mg/kg/day, p.o.) alone for 60 days, (iii) C. pareira extract (100 and 200 mg/kg/day, p.o., respectively) for 30 days then with thyroxin for another 30 days, (iv) thyroxin for 30 days then C. pareira extract (100 and 200 mg/kg/day, p.o., respectively) for another 30 days. At the end of experiment, serum calcineurin, nitric oxide, lactate dehydrogenase, and thiobarbituric acid reactive substance as well as serum and/or myocardial antioxidant enzymes activity were estimated. RESULTS: Hyperthyroid induced cardiotoxicity was characterized by a significant (P<0.001) increase in heart weight/body weight ratio, serum calcineurin, nitric oxide, lactate dehydrogenase and thiobarbituric acid reactive substance levels as well as a significant decrease in serum reduced glutathione, myocardial glutathione peroxidase, glutathione reductase and glutathione-S-transferase levels, which were significantly (P<0.05 and P<0.01) reverted by C. pareira extract treatment. Reversal of histological changes on treatment with C. pareira extract was also supported the biochemical parameters. These results were quite comparable with amlodipine, the standard drug taken in this study. CONCLUSIONS: Treatment with C. pareira extract ameliorates thyroxin induced oxidative stress and cardiac hypertrophy, probably through amelioration of calcineurin activity and augmentation of antioxidant enzyme activities. PMID- 26647107 TI - The Intestinal Microbiome and the Liver Transplant Recipient: What We Know and What We Need to Know. AB - The intestinal microbiome and immune system are in close symbiotic relationship in health. Gut microbiota plays a role in many chronic liver diseases and cirrhosis. However, alterations in the gut microbiome after liver transplantation and the implications for liver transplant recipients are not well understood and rely mainly on experimental animal studies. Recent advances in molecular techniques have identified that increased intestinal permeability, decreased beneficial bacteria, and increased pathogenic species may play important roles in the early posttransplant period. The associations between microbiota perturbation and postliver transplant infections and acute rejection are evolving. The link with metabolic syndrome, obesity, and cardiac disease in the general population require translation into the transplant recipient. This review focuses on our current knowledge of the known and potential interaction of the microbiome in the liver transplant recipient. Future human studies focused on microbiota changes in liver transplant patients are warranted and expected. PMID- 26647108 TI - Killing Two Birds With One Stone: Antineoplastic Immunosuppression. PMID- 26647109 TI - Young adults' experiences of seeking online information about diabetes and mental health in the age of social media. AB - BACKGROUND: The Internet is a primary source of health information for many. Since the widespread adoption of social media, user-generated health-related content has proliferated, particularly around long-term health issues such as diabetes and common mental health disorders (CMHDs). OBJECTIVE: To explore perceptions and experiences of engaging with health information online in a sample of young adults familiar with social media environments and variously engaged in consuming user-generated content. METHODS: Forty semi-structured interviews were conducted with young adults, aged 18-30, with experience of diabetes or CMHDs. Data were analysed following a thematic networks approach to explore key themes around online information-seeking and content consumption practices. RESULTS: Although participants primarily discussed well-rehearsed approaches to health information-seeking online, particularly reliance on search engines, their accounts also reflected active engagement with health-related content on social media sites. Navigating between professionally produced websites and user-generated content, many of the young adults seemed to appreciate different forms of health knowledge emanating from varied sources. Participants described negotiating health content based on social media practices and features and assessing content heuristically. Some also discussed habitual consumption of content related to their condition as integrated into their everyday social media use. CONCLUSION: Technologies such as Facebook, Twitter and YouTube offer opportunities to consume and assess content which users deem relevant and useful. As users and organizations continue to colonize social media platforms, opportunities are increasing for health communication and intervention. However, how such innovations are adopted is dependent on their alignment with users' expectations and consumption practices. PMID- 26647110 TI - 3D surface-based registration of ultrasound and histology in prostate cancer imaging. AB - Several transrectal ultrasound (TRUS)-based techniques aiming at accurate localization of prostate cancer are emerging to improve diagnostics or to assist with focal therapy. However, precise validation prior to introduction into clinical practice is required. Histopathology after radical prostatectomy provides an excellent ground truth, but needs accurate registration with imaging. In this work, a 3D, surface-based, elastic registration method was developed to fuse TRUS images with histopathologic results. To maximize the applicability in clinical practice, no auxiliary sensors or dedicated hardware were used for the registration. The mean registration errors, measured in vitro and in vivo, were 1.5+/-0.2 and 2.1+/-0.5mm, respectively. PMID- 26647111 TI - Screening for new brewing yeasts in the non-Saccharomyces sector with Torulaspora delbrueckii as model. AB - This study describes a screening system for future brewing yeasts focusing on non Saccharomyces yeasts. The aim was to find new yeast strains that can ferment beer wort into a respectable beer. Ten Torulaspora delbrueckii strains were put through the screening system, which included sugar utilization tests, hop resistance tests, ethanol resistance tests, polymerase chain reaction fingerprinting, propagation tests, amino acid catabolism and anabolism, phenolic off-flavour tests and trial fermentations. Trial fermentations were analysed for extract reduction, pH drop, yeast concentration in bulk fluid and fermentation by products. All investigated strains were able to partly ferment wort sugars and showed high tolerance to hop compounds and ethanol. One of the investigated yeast strains fermented all the wort sugars and produced a respectable fruity flavour and a beer of average ethanol content with a high volatile flavour compound concentration. Two other strains could possibly be used for pre-fermentation as a bio-flavouring agent for beers that have been post-fermented by Saccharomyces strains as a consequence of their low sugar utilization but good flavour-forming properties. PMID- 26647113 TI - Confirmatory factor analysis of the Spanish version of the California Verbal Learning Test in a sample of middle-aged and older adults with subjective memory complaints. AB - INTRODUCTION: Assessment of the ability to retain new information is of special interest in the second half of life because of age-related changes, especially in those individuals at risk of cognitive impairment. The California Verbal Learning Test (CVLT) is one of the most common auditory-verbal learning tests used to test episodic memory. The objective of this paper is to study the stability of the factorial structure of the Spanish version of CVLT in a sample of adults aged 50 87 years with subjective memory complaints (SMCs). METHOD: Performance at baseline and follow-up assessment (about 18 months later) was analyzed in 301 participants. Models including one, two, three, and four factors were tested, by comparing the results of confirmatory factor analysis and structural equation models of relations between the factors at baseline and follow-up. RESULTS: The two-factor models (accurate and inaccurate memory) yielded the best fit. The model establishing a relationship between these two factors at baseline and follow-up provided a good fit. CONCLUSION: CVLT performance in a sample of middle aged and old adults with SMCs was separated into two factors differentiating accurate recollection and errors. A structural equation modeling (SEM) model relating data from both assessments replicated these findings. PMID- 26647112 TI - Response trajectories capture the continuous dynamics of the size congruity effect. AB - In a comparison task involving numbers, the size congruity effect refers to the general finding that responses are usually faster when there is a match between numerical size and physical size (e.g., 2-8) than when there is a mismatch (e.g., 2-8). In the present study, we used computer mouse tracking to test two competing models of the size congruity effect: an early interaction model, where interference occurs at an early representational stage, and a late interaction model, where interference occurs as dynamic competition between response options. In three experiments, we found that the curvature of responses for incongruent trials was greater than for congruent trials. In Experiment 2 we showed that this curvature effect was reliably modulated by the numerical distance between the two stimulus numbers, with large distance pairs exhibiting a larger curvature effect than small distance pairs. In Experiment 3 we demonstrated that the congruity effects persist into response execution. These findings indicate that incongruities between numerical and physical sizes are carried throughout the response process and result from competition between parallel and partially active response options, lending further support to a late interaction model of the size congruity effect. PMID- 26647114 TI - Kinetics and Mechanisms of Cr(VI) Formation via the Oxidation of Cr(III) Solid Phases by Chlorine in Drinking Water. AB - Hexavalent chromium Cr(VI), typically existing as the oxyanion form of CrO4(2-), is being considered for more stringent drinking water standards by regulatory agencies. Cr(VI) can be inadvertently produced via the oxidation of trivalent chromium Cr(III) solids. This study investigated the kinetics and mechanisms of Cr(III) solids oxidation by chlorine in drinking water and associated Cr(VI) formation. Batch experiments were carried out with three Cr(III) solids of environmental relevance, i.e., chromium hydroxide Cr(OH)3(s), chromium oxide Cr2O3(s), and copper chromite Cu2Cr2O5(s). Impacts of water chemical parameters including pH (6.0-8.5) and bromide concentration (0-5 mg/L) were examined. Results showed that the rapid oxidation of Cr(III) solid phases by chlorine was accompanied by Cr(VI) formation and an unexpected production of dissolved oxygen. Analysis of reaction stoichiometry indicated the existence of Cr intermediate species that promoted the autocatalytic decay of chlorine. An increase in pH modestly enhanced Cr(VI) formation due to changes of reactive Cr(III) surface hydroxo species. Bromide, a trace chemical constituent in source waters, exhibited a catalytic effect on Cr(VI) formation due to an electron shuttle mechanism between Cr(III) and chlorine and the bypass of Cr intermediate formation. The kinetics data obtained from this study suggest that the oxidation of Cr(III) solids by chlorine in water distribution systems can contribute to Cr(VI) occurrence in tap water, especially in the presence of a trace level of bromide. PMID- 26647115 TI - Copper mediated decarboxylative direct C-H arylation of heteroarenes with benzoic acids. AB - Decarboxylative coupling reactions to date require a stoichiometric oxidant (such as copper and silver salts) for decarboxylation purposes along with a metal catalyst (e.g. palladium) for cross-coupling. In this communication, an economic and sustainable approach by using a simple copper salt was developed in the presence of molecular oxygen as the sole oxidant. A wide range of 5-membered heteroarenes undergo aryl-heteroaryl cross-coupling with electron deficient aryl carboxylic acids. PMID- 26647116 TI - Thickness and material selection of polymeric passive samplers for polycyclic aromatic hydrocarbons in water: Which more strongly affects sampler properties? AB - Three configurations of single-phase polymer passive samplers made of polyoxymethylene (POM), silicone rubber, and polyethylene (PE) were simultaneously calibrated in laboratory experiments by determining their partitioning coefficients and the POM diffusion coefficients and by validating a kinetic accumulation model. In addition, the performance of each device was evaluated under field conditions. With the support of the developed model, the device properties are discussed with regard to material selection and polymer thickness. The results show that a sampler's properties, such as its concentration-averaging period and ability to sample a large amount of polycyclic aromatic hydrocarbons, are widely affected by material selection. Sampler thickness also allows modulation of the properties of the device but with a much lower magnitude. Selection of the appropriate polymer and/or thickness allows samplers to be adapted either for quick equilibration or for the kinetic accumulation regime and promotes either membrane or water boundary layer control of the kinetic accumulation. In addition, membrane-controlled or equilibrated compounds are quantified with greater accuracy because they are not corrected by the performance reference compounds approach. However, the averaged concentrations cannot be assessed when compounds reach equilibrium in the sampler, whereas membrane-controlled devices remaining in the kinetic accumulation regime provide averaged concentrations without requiring performance reference compound correction; detection limits are then increased because of the higher mass transfer resistance of the membrane. Environ Toxicol Chem 2016;35:1708-1717. (c) 2015 SETAC. PMID- 26647117 TI - Structural Phase Transitions by Design in Monolayer Alloys. AB - Two-dimensional monolayer materials are a highly anomalous class of materials under vigorous exploration. Mo- and W-dichalcogenides are especially unusual two dimensional materials because they exhibit at least three different monolayer crystal structures with strongly differing electronic properties. This intriguing yet poorly understood feature, which is not present in graphene, may support monolayer phase engineering, phase change memory and other applications. However, knowledge of the relevant phase boundaries and how to engineer them is lacking. Here we show using alloy models and state-of-the-art density functional theory calculations that alloyed MoTe2-WTe2 monolayers support structural phase transitions, with phase transition temperatures tunable over a large range from 0 to 933 K. We map temperature-composition phase diagrams of alloys between pure MoTe2 and pure WTe2, and benchmark our methods to analogous experiments on bulk materials. Our results suggest applications for two-dimensional materials as phase change materials that may provide scale, flexibility, and energy consumption advantages. PMID- 26647118 TI - Hg/Pt-catalyzed conversion of bromo alkynamines/alkynols to saturated and unsaturated gamma-butyrolactams/lactones via intramolecular electrophilic cyclization. AB - Convenient and general Hg(ii)/Pt(iv) catalyzed syntheses of gamma-butyrolactams and alpha,beta-unsaturated gamma-butyrolactones/lactams are described via intramolecular electrophilic cyclizations of bromoalkynes with tosylamino and hydroxyl tethers. The reaction features the use of wet solvents, the exclusion of any base and additive, mild conditions and practical yields. We also synthesised few chiral lactams through this pathway. Additionally, it is shown that the NHTs group distanced further from the homopropargylic position assists regioselective bromoalkyne hydration to yield useful alpha-bromoketones. Furthermore, Boc protected bromo homo propargyl amines undergo 6-endo-dig cyclization through Boc oxygen to give bromomethylene substituted oxazinones. PMID- 26647120 TI - Cortical speech and non-speech discrimination in relation to cognitive measures in preschool children. AB - Effective speech sound discrimination at preschool age is known to be a prerequisite for the development of language skills and later literacy acquisition. However, the speech specificity of cortical discrimination skills in small children is currently not known, as previous research has either studied speech functions without comparison with non-speech sounds, or used much simpler sounds such as harmonic or sinusoidal tones as control stimuli. We investigated the cortical discrimination of five syllable features (consonant, vowel, vowel duration, fundamental frequency, and intensity), covering both segmental and prosodic phonetic changes, and their acoustically matched non-speech counterparts in 63 6-year-old typically developed children, by using a multi-feature mismatch negativity (MMN) paradigm. Each of the five investigated features elicited a unique pattern of differentiating negativities: an early differentiating negativity, MMN, and a late differentiating negativity. All five studied features showed speech-related enhancement of at least one of these responses, suggesting experience-related neural commitment in both phonetic and prosodic speech processing. In addition, the cognitive performance and language skills of the children were tested extensively. The speech-related neural enhancement was positively associated with the level of performance in several neurocognitive tasks, indicating a relationship between successful establishment of cortical memory traces for speech and enhanced cognitive functioning. The results contribute to the understanding of typical developmental trajectories of linguistic vs. non-linguistic auditory skills, and provide a reference for future studies investigating deficits in language-related disorders at preschool age. PMID- 26647119 TI - Diverse Functions of Endothelial NO Synthases System: NO and EDH. AB - Endothelium-dependent relaxations are predominantly regulated by nitric oxide (NO) in large conduit arteries and by endothelium-dependent hyperpolarization (EDH) in small resistance vessels. Although the nature of EDH factors varies depending on species and vascular beds, we have previously demonstrated that endothelial NO synthases (eNOS)-derived hydrogen peroxide (H2O2) is an EDH factor in animals and humans. This vessel size-dependent contribution of NO and EDH is, at least in part, attributable to the diverse roles of endothelial NOSs system; in large conduit arteries, eNOS mainly serves as a NO-generating system to elicit soluble guanylate cyclase-cyclic guanosine monophosphate-mediated relaxations, whereas in small resistance vessels, it serves as a superoxide-generating system to cause EDH/H2O2-mediated relaxations. Endothelial caveolin-1 may play an important role for the diverse roles of NOSs. Although reactive oxygen species are generally regarded harmful, the physiological roles of H2O2 have attracted much attention as accumulating evidence has shown that endothelium-derived H2O2 contributes to cardiovascular homeostasis. The diverse functions of endothelial NOSs system with NO and EDH/H2O2 could account for a compensatory mechanism in the setting of endothelial dysfunction. In this review, we will briefly summarize the current knowledge on the diverse functions of endothelial NOSs system: NO and EDH/H2O2. PMID- 26647121 TI - A zwitterionic triphosphenium compound as a tunable multifunctional donor. AB - The preparation of a novel triphosphenium zwitterion featuring di-, tri-, and tetra-coordinate phosphorus centres derived from a 1,2,4-tris (diphenylphoshinyl)cyclopentadienyl framework is described. The reactivity of this potentially multidentate donor with protons, elemental sulfur and gold(i) chloride is examined, and the preferential reactivity of the pendant phosphine group over the P(i) centre is rationalized on the basis of density functional theory investigations. PMID- 26647134 TI - Commentary on: Abdominal Subcutaneous Mass After Laser-Assisted Lipolysis and Immediate Multiple Treatments with a Dual-Wavelength Laser, Vacuum, and Massage Device. PMID- 26647135 TI - Commentary on: Asymmetry of Inframammary Folds in Patients Undergoing Augmentation Mammaplasty. PMID- 26647136 TI - Postoperative Granulomas at Liposuction Incision Sites. AB - Since most liposuction incisions heal uneventfully, difficult healing in such incisions must be investigated. In the cases of two gynecomastia liposuction patients in which a water-based lubricating gel was used on the liposuction incisions, the incisions failed to heal. For both patients, workup uncovered palisading granulomas at the lateral inframammary fold incision sites several months after otherwise successful surgeries. These two cases are presented and the previous literature is reviewed, with consideration given to the etiology and prevention of such granulomas. LEVEL OF EVIDENCE 5: Risk. PMID- 26647137 TI - Abdominal Subcutaneous Mass After Laser-Assisted Lipolysis and Immediate Multiple Treatments with a Dual-Wavelength Laser, Vacuum and Massage Device. AB - Body contouring by means of minimally invasive procedures is a growing trend. Current approaches to body contouring often involve a combination of surgical techniques (eg, laser-assisted liposuction) and a series of noninvasive device based treatments aimed at accelerating recovery and improving aesthetic outcomes. In this case study, we describe a 38-year-old woman who presented with an abdominal-wall mass that resembled a tumor when assessed with magnetic resonance imaging. Twenty-six months before presenting to our office, the patient had undergone laser lipolysis and a series of treatments with a device that delivered dual-wavelength laser energy and vacuum-assisted massage. To address the patient's concerns, we removed the mass and performed abdominal dermolipectomy. No postoperative complications occurred, and the patient was highly satisfied with the aesthetic outcome. The results of histologic studies indicated that the mass was pseudocystic and fluid-filled, surrounded by a fibrous capsule, and characterized as a foreign-body granuloma. Further analysis is warranted regarding the safety of laser lipolysis without aspiration combined with a device delivering dual-wavelength laser energy and vacuum-assisted massage. LEVEL OF EVIDENCE: 5 Risk. PMID- 26647138 TI - The Reliability of Anthropometric Measurements Used Preoperatively in Aesthetic Breast Surgery. AB - BACKGROUND: Patient outcomes in aesthetic breast surgery are highly dependent on breast measurements used in preoperative planning. OBJECTIVES: The purpose of this study is to determine the reliability of anthropometric breast measurements. METHODS: Four raters measured 28 women using 7 measurements: sternal notch to nipple distance (Sn-N), nipple to midline (N-M), nipple to inframammary-fold distance under maximal stretch (N-IMF), breast base width (BW), soft tissue pinch thickness of the upper pole (STPT:UP), STPT at the inframammary fold (STPT:IMF), and anterior pull skin stretch (APSS). Reliability was assessed using intra-class correlation coefficients (ICCs). RESULTS: Inter-rater reliability was excellent for Sn-N, N-M, and BW (ICC = 0.94, 0.90, and 0.76, respectively) and was good for N-IMF (ICC = 0.70). The STPT:UP, STPT:IMF, and APSS measurements were not reliable between raters (ICC < 0.2). Intra-rater reliability was excellent for Sn N, N-M, and BW for all raters (all ICC > 0.75). The N-IMF intra-rater reliability was excellent in senior raters (ICC > 0.75) and good in junior raters (ICC > 0.6). The STPT:UP, STPT:IMF, and APSS measurements showed fair or poor reliability for most raters (ICC < 0.6). CONCLUSIONS: The Sn-N, N-M, and BW measurements are very reliable. Dynamic measurements including APSS, STPT:UP, and STUP:IMF are unreliable. N-IMF is the only reliable dynamic measurement, and its reliability improves with increasing clinical experience. The variable reliability of preoperative measurements must be considered in the planning of aesthetic breast surgery. LEVEL OF EVIDENCE: 4 Diagnostic. PMID- 26647139 TI - Commentary on: The Reliability of Anthropometric Measurements Used Preoperatively in Aesthetic Breast Surgery. PMID- 26647140 TI - On the stability of foams made with surfactant bilayer phases. AB - The stability of foams made with sponge phases (L3 phases) and lamellar phases (L(alpha) phases), both containing surfactant bilayers, has been investigated. The extreme stability of foams made with lamellar phases seems essentially due to the high viscosity of the foaming solution, which slows down gravity drainage. Moreover, the foams start draining only when the buoyancy stress overcomes the yield stress of the L(alpha) phase. The bubble growth associated with gas transfer is unusual: it follows a power law with an exponent smaller than those corresponding to Ostwald ripening (wet foams) and to coarsening (dry foams). The foams made with sponge phases are in turn very unstable, even less stable than pure surfactant foams made with glycerol solutions having the same viscosity. The fact that the surfactant bilayers in the sponge phase have a negative Gaussian curvature could facilitate bubble coalescence. PMID- 26647141 TI - Kocuria arsenatis sp. nov., an arsenic-resistant endophytic actinobacterium associated with Prosopis laegivata grown on high-arsenic-polluted mine tailing. AB - A Gram-stain-positive, aerobic, non-motile, coccoid, arsenic-resistant actinobacterial strain, designated CM1E1T, was isolated from the lateral root tissue of Prosopis laegivata grown on a mine tailing in San Luis Potosi, Mexico. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain CM1E1T was clustered closely with species of the genus Kocuria, and showed the highest sequence similarity of 98.7 % to Kocuria rhizophila TA68T. The DNA G+C content of strain CM1E1T was 74.5 mol% (Tm). The major fatty acids were anteiso C15 : 0, anteiso-C17 : 0 and iso-C15 : 0. The peptidoglycan of the cell wall contained lysine and alanine. The major respiratory quinones were MK-7(H2) and MK 8(H2). On the basis of the phenotypic characterization, phylogenetic relationships and chemotaxonomic analyses, strain CM1E1T represents a novel species of the genus Kocuria, for which the name Kocuria arsenatis sp. nov. is proposed. The type strain is CM1E1T ( = CCBAU 101092T = HAMBI 3625T = LMG 28671T). PMID- 26647143 TI - Implicit-Solvent Coarse-Grained Simulation with a Fluctuating Interface Reveals a Molecular Mechanism for Peptoid Monolayer Buckling. AB - Peptoid polymers form extended two-dimensional nanostructures via an interface mediated assembly process: the amphiphilic peptoids first adsorb to an air-water interface as a monolayer, then buckle and collapse into free-floating bilayer nanosheets when the interface is compressed. Here, we investigate the molecular mechanism of monolayer buckling by developing a method for incorporating interface fluctuations into an implicit-solvent coarse-grained model. Representing the interface with a triangular mesh controlled by surface tension and surfactant adsorption, we predict the direction of buckling for peptoids with a segregated arrangement of charged side chains and predict that peptoids with with an alternating charge pattern should buckle less easily than peptoids with a segregated charge pattern. PMID- 26647142 TI - Advancing the use of Lactobacillus acidophilus surface layer protein A for the treatment of intestinal disorders in humans. AB - Intestinal immunity is subject to complex and fine-tuned regulation dictated by interactions of the resident microbial community and their gene products with host innate cells. Deterioration of this delicate process may result in devastating autoinflammatory diseases, including inflammatory bowel disease (IBD), which primarily comprises Crohn's disease (CD) and ulcerative colitis (UC). Efficacious interventions to regulate proinflammatory signals, which play critical roles in IBD, require further scientific investigation. We recently demonstrated that rebalancing intestinal immunity via the surface layer protein A (SlpA) from Lactobacillus acidophilus NCFM potentially represents a feasible therapeutic approach to restore intestinal homeostasis. To expand on these findings, we established a new method of purifying bacterial SlpA, a new SlpA specific monoclonal antibody, and found no SlpA-associated toxicity in mice. Thus, these data may assist in our efforts to determine the immune regulatory efficacy of SlpA in humans. PMID- 26647146 TI - President's Letter to the Membership. PMID- 26647144 TI - Accurate Prediction of One-Electron Reduction Potentials in Aqueous Solution by Variable-Temperature H-Atom Addition/Abstraction Methodology. AB - A robust and efficient theoretical approach for calculation of the reduction potentials of charged species in aqueous solution is presented. Within this approach, the reduction potential of a charged complex (with a charge |n| >= 2) is probed by means of the reduction potential of its neutralized (protonated/deprotonated) cognate, employing one or several H-atom addition/abstraction thermodynamic cycles. This includes a separation of one electron reduction from protonation/deprotonation through the temperature dependence. The accuracy of the method has been assessed for the set of 15 transition-metal complexes that are considered as highly challenging systems for computational electrochemistry. Unlike the standard computational protocol(s), the presented approach yields results that are in excellent agreement with experimental electrochemical data. Last but not least, the applicability and limitations of the approach are thoroughly discussed. PMID- 26647147 TI - Variable Temperature Infrared Spectroscopy Investigations of Benzoic Acid Desorption from Sodium and Calcium Montmorillonite Clays. AB - Processes involved in thermal desorption of benzoic acid from sodium and calcium montmorillonite clays are investigated by using variable temperature diffuse reflection Fourier transform infrared spectroscopy (DRIFTS). By monitoring the temperature dependence of infrared absorbance bands while heating samples, subtle changes in molecular vibrations are detected and employed to characterize specific benzoic acid adsorption sites. Abrupt changes in benzoic acid adsorption site properties occur for both clay samples at about 125 degrees C. Difference spectra absorbance band frequency variations indicate that adsorbed benzoic acid interacts with interlayer cations through water bridges and that these interactions can be disrupted by the presence of organic anions, in particular, benzoate. PMID- 26647148 TI - Enhancing Textile Fiber Identification with Detergent Fluorescence. AB - Discovering common origins of trace evidential textile fibers can be a challenging task when fiber structure or dye composition does not provide exclusive identifying information. Introduction of new chemical species after mass production and distribution of a textile may be exploited to trace its history and identify the origin of its fibers. In this article, fluorescence microscopy is used to examine the alteration in the fluorescence spectral fingerprint of single fibers resulting from exposure to commonly used detergents that contain fluorescent whitening agents. Dyed acrylic, cotton, and nylon fibers were laundered and the spectral contribution of the detergent on single fibers was quantified and shown to reach a maximum after five sequential washes; some detergents showed statistically meaningful differences to fiber spectra after only a single wash. Principal component cluster analysis was used to determine that the spectra of laundered fibers are distinct from the spectra of dyed, unwashed cotton or nylon, but not acrylic, fibers. PMID- 26647149 TI - Identifying Raman and Infrared Vibrational Motions of Erythritol Tetranitrate. AB - The vibrational bands of erythritol tetranitrate (ETN) were measured experimentally with both Raman spectroscopy and attenuated total reflectance Fourier transform infrared (ATR FT-IR) spectroscopy. Seventy-two (3N-6) vibrational modes were predicted for ETN using density functional theory calculations performed using the B3LYP/6-31G* density functional basis set and geometry optimization. Raman spectroscopy and ATR FT-IR were used to measure observable Raman and IR signatures between 140 and 3100 wavenumbers (cm(-1)). Within this spectral range, 32 Raman bands and 21 IR bands were measured and identified by their predicted vibrational motion. The spectroscopic and theoretical analysis of ETN performed will advance the detection and identification capabilities of field measuring instruments for this explosive. PMID- 26647150 TI - Cosyntropin-Stimulated Serum Free Cortisol in Healthy, Adrenally Insufficient, and Mildly Cirrhotic Populations. AB - CONTEXT: Serum free cortisol (SFF) responses to cosyntropin simulation test (CST) may more accurately assess adrenal function than total cortisol (TF). OBJECTIVE: The objective of the study was to evaluate the diagnostic utility of SFF responses during a 250-MUg CST. DESIGN: We recruited healthy volunteers (HV; n = 27), patients with primary and secondary adrenal insufficiency (n = 19 and n = 24, respectively), and subjects with Child-Pugh class A cirrhosis (CH; n = 15). Each received 250 MUg cosyntropin with measurement of ACTH and corticosteroid binding globulin (CBG) at time 0 and TF and SFF at 0, 30, and 60 minutes. Salivary cortisol was measured at all time points in CH subjects. RESULTS: Peak SFF and TF were significantly higher in HVs vs both AI groups (P < .05). Peak SFF and TF (6.8 MUg/dL vs 2.2 MUg/dL; [188 nmol/L vs 62 nmol/L]; P < .01) were significantly higher in the secondary adrenal insufficiency vs primary adrenal insufficiency patients. The optimal peak SFF criterion to identify adrenal insufficiency patients vs HV was 0.9 MUg/dL (25 nmol/L) (sensitivity of 95%, specificity of 100%). Mean CBG and albumin levels were similar among all four groups. CH patients had a higher peak SFF than HV (2.4 vs 2.0 MUg/dL; P = .02. In the CH patients, peak salivary cortisol levels correlated well with peak SFF (rs = 0.84, P = .005). CBG levels were similar among the groups. CONCLUSION: We provide normative data for SFF values in HV and AI during the CST. Normal CBG levels in mild cirrhosis did not affect the interpretation of the CST. PMID- 26647151 TI - Diurnal Cortisol Patterns, Future Diabetes, and Impaired Glucose Metabolism in the Whitehall II Cohort Study. AB - CONTEXT: The hypothalamic pituitary-adrenal axis is thought to play a role in type 2 diabetes (T2D). However, evidence for an association between cortisol and future glucose disturbance is sparse. OBJECTIVE: The aim was to examine the association of diurnal cortisol secretion with future T2D and impaired glucose metabolism in a community-dwelling population. DESIGN: This is a prospective cohort study of salivary cortisol measured at the 2002-2004 clinical examination of the Whitehall II study, United Kingdom. We measured cortisol (nmol/l) from six saliva samples obtained over the course of a day: at waking, +30 minutes, +2.5 hours, +8 hours, +12 hours, and bedtime. Participants who were normoglycemic in 2002-2004 (phase 7) were reexamined in 2012-2013 (phase 11). SETTING: The occupational cohort was originally recruited in 1985-1988. PARTICIPANTS: A total of 3270 men and women with an average age of 60.85 years at phase 7 (2002-2004). OUTCOME MEASURES: Incident T2D and impaired fasting glucose in 2012-2013 were measured. RESULTS: Raised evening cortisol at phase 7 was predictive of new-onset T2D at phase 11 (odds ratio [OR], 1.18; 95% confidence interval [CI], 1.01-1.37) with a trend for a flatter slope in participants with incident T2D (odds ratio, 1.15; 95% CI, 0.99-1.33). When expanding this analysis to a broader category of glucose disturbance we found that a flattened diurnal cortisol slope at phase 7 was predictive of future impaired fasting glucose or T2D at phase 11 (OR, 1.12; 95% CI, 1.02-1.22), as was high bedtime cortisol (OR, 1.10; 95% CI, 1.01-1.20). CONCLUSIONS: In this nonclinical population, alterations in diurnal cortisol patterns were predictive of future glucose disturbance. PMID- 26647152 TI - Macrocalcitonin Is a Novel Pitfall in the Routine of Serum Calcitonin Immunoassay. AB - CONTEXT: Calcitonin (CT) is a sensitive marker of medullary thyroid carcinoma (MTC) and is used for primary diagnosis and follow-up after thyroidectomy. However, persistently elevated CT is observed even after complete surgical removal without evidence of a recurrent or persistent tumor. OBJECTIVE: To investigate the presence of assay interference in the serum CT of MTC patients who are apparently without a structural disease. PATIENTS AND METHODS: We studied three index MTC cases for CT assay interference and 14 patients with metastatic MTC. The CT level was measured using an immunofluorometric assay. Screening for assay interference was performed by determination of CT levels before and after serum treatment with polyethylene glycol. Additionally, samples were analyzed by chromatography on ultra-performance liquid chromatography and protein A Sepharose. RESULTS: Patients with biochemical and structural disease showed CT mean recovery of 84.1% after polyethylene glycol treatment, whereas patients suspected of interference showed recovery from 2-7%. The elution profile on UPLC showed that the immunometric CT from these three patients behaved like a high molecular mass aggregate (>300 kDa). Additionally, when these samples were applied to the protein A-Sepharose, CT immunoreactivity was retained on the column and was only released after lowering the pH. CONCLUSIONS: For the first time, our results show the presence of a novel pitfall in the CT immunoassay: "macrocalcitonin." Its etiology, frequency, and meaning remain to be defined, but its recognition is of interest and can help clinicians avoid unnecessary diagnostic investigations and treatment during the follow-up of MTC. PMID- 26647153 TI - Successful Live Birth in a Woman With 17alpha-Hydroxylase Deficiency Through IVF Frozen-Thawed Embryo Transfer. AB - CONTEXT: Congenital adrenal hyperplasia (CAH) due to 17alpha-hydroxylase deficiency in 46,XX patients is characterized by primary amenorrhea, absent or incomplete sexual maturation, infertility, low serum levels of estradiol, and elevated progesterone (P). There were no previous reports of singleton live births from such women. OBJECTIVE: To describe the first successful singleton live birth in a female with CAH due to 17alpha-hydroxylase deficiency. CASE DESCRIPTION: A 26-year-old Brazilian woman with CAH associated with 17alpha hydroxylase deficiency due to the compound heterozygote mutation (p.W406R/P428L) in the CYP17A1 gene expressed the desire to conceive. In vitro fertilization (IVF) was recommended due to the complexity of the disorder. The first attempt of treatment failed despite the production of viable embryos. At the second IVF attempt, all viable embryos were frozen due to inadequate endometrial development associated with prematurely elevated serum P during ovarian stimulation. Subsequently, a long-acting GnRH agonist and oral dexamethasone were used to lower ovarian and adrenal P overproduction. Once serum levels of P were < 1 ng/mL, endometrial preparation with estradiol valerate and frozen-thawed embryo transfer were performed, resulting in a singleton pregnancy. Estradiol supplementation was completely suspended by 14 weeks of gestation. She delivered at 30 weeks and 4 days due to acute fetal distress. The puerperium was uneventful; the newborn was discharged in good conditions 5 weeks after birth. CONCLUSION: A successful live birth was achieved in a woman with 17-hydroxylase deficiency through IVF, cryopreservation of all embryos, and frozen-thawed embryo transfer after adequate endometrial preparation. PMID- 26647154 TI - Sleep duration modifies effects of free ad libitum school meals on adiposity and blood pressure. AB - Insufficient sleep can potentially affect both energy intake and energy expenditure, resulting in obesity and reduced cardiometabolic health. The objective of the study was to investigate if habitual sleep duration of 8- to 11 year-olds modifies the effect of free ad libitum school meals on cardiometabolic markers, body composition, dietary intake, and physical activity. For 2 consecutive 3-month periods, this cluster-randomized, controlled, cross-over trial provided 530 children with school meals or usual lunch brought from home. Dietary intake, activity, and sleep were measured simultaneously for 7 consecutive days using dietary records and accelerometers. Short- and long sleeping children were defined as lower and upper tertile of sleep duration. Body composition, blood pressure, blood lipids, and homeostatic model assessment of insulin resistance (HOMAIR) were measured/calculated. Overall, school meals compared with lunch from home had positive effects on physical activity and blood pressure in long-sleeping children and negative effects on body fat in short sleeping children. Short-sleeping children increased fat mass compared with long sleeping children by 0.21 (95% confidence interval 0.03-0.38) kg, android fat mass by 0.02 (0.001-0.04) kg, waist circumference by 0.73 (0.23-1.24) cm, blood pressure by 1.5 (0.4-2.6) mm Hg, fat intake by 1.1 (0.2-2.0) percentage of energy, and decreased total physical activity by 7.2 (1.6-12.7) % (all P <= 0.04), while HOMAIR and blood lipids were not modified by sleep duration (all P >= 0.32). In conclusion, the susceptibility to increase abdominal adiposity and blood pressure when exposed to dietary changes can potentially be explained by too little sleep, which results in increased caloric intake and reduced physical activity. PMID- 26647155 TI - Growth signalobody selects functional intrabodies in the mammalian cytoplasm. AB - A versatile strategy to inhibit protein functions in the cytoplasmic environment is eagerly anticipated for drug discovery. In this study, we demonstrate a novel system to directly select functional intrabodies from a library in the mammalian cytoplasm. In this system, a target homo-oligomeric antigen is expressed together with a single-chain Fv (scFv) library that is linked to the cytoplasmic domain of a receptor tyrosine kinase (RTK) in the cytoplasm of murine interleukin-3 (IL-3) dependent cells. As the tyrosine kinase is activated by dimerization, only scFv RTK clones that can bind to the target antigen would be oligomerized and transduce a growth signal under the IL-3-deprived condition, which leads to selection of functional intrabodies. To demonstrate this system, we used rabies virus phosphoprotein (RV-P) that forms dimers in the cytoplasm as a target antigen. As a result, functional intrabodies were selected using our system from a naive scFv library as well as from a pre-selected anti-RV-P library generated by phage display. This system may be applied for screening intrabodies that can prevent progression of various severe diseases. PMID- 26647157 TI - Particulate Organic Matter Affects Soil Nitrogen Mineralization under Two Crop Rotation Systems. AB - Changes in the quantity and/or quality of soil labile organic matter between and after different types of cultivation system could play a dominant role in soil nitrogen (N) mineralization. The quantity and quality of particulate organic matter (POM) and potentially mineralizable-N (PMN) contents were measured in soils from 16 paired rice-rapeseed (RR)/cotton-rapeseed (CR) rotations sites in Hubei province, central China. Then four paired soils encompassing low (10th percentile), intermediate (25th and 75th percentiles), and high (90th percentile) levels of soil PMN were selected to further study the effects of POM on soil N mineralization by quantifying the net N mineralization in original soils and soils from which POM was removed. Both soil POM carbon (POM-C) and N (POM-N) contents were 45.8% and 55.8% higher under the RR rotation compared to the CR rotation, respectively. The PMN contents were highly correlated with the POM contents. The PMN and microbial biomass N (MBN) contents concurrently and significantly decreased when POM was removed. The reduction rate of PMN was positively correlated with changes in MBN after the removal of POM. The reduction rates of PMN and MBN after POM removal are lower under RR rotations (38.0% and 16.3%, respectively) than CR rotations (45.6% and 19.5%, respectively). Furthermore, infrared spectroscopy indicated that compounds with low bioavailability accumulated (e.g., aromatic recalcitrant materials) in the soil POM fraction under the RR rotation but not under the CR rotation. The results of the present study demonstrated that POM plays a vital role in soil N mineralization under different rotation systems. The discrepancy between POM content and composition resulting from different crop rotation systems caused differences in N mineralization in soils. PMID- 26647156 TI - Induction of alpha-synuclein aggregate formation by CSF exosomes from patients with Parkinson's disease and dementia with Lewy bodies. AB - Extracellular alpha-synuclein has been proposed as a crucial mechanism for induction of pathological aggregate formation in previously healthy cells. In vitro, extracellular alpha-synuclein is partially associated with exosomal vesicles. Recently, we have provided evidence that exosomal alpha-synuclein is present in the central nervous system in vivo. We hypothesized that exosomal alpha-synuclein species from patients with alpha-synuclein related neurodegeneration serve as carriers for interneuronal disease transmission. We isolated exosomes from cerebrospinal fluid from patients with Parkinson's disease, dementia with Lewy bodies, progressive supranuclear palsy as a non-alpha synuclein related disorder that clinically overlaps with Parkinson's disease, and neurological controls. Cerebrospinal fluid exosome numbers, alpha-synuclein protein content of cerebrospinal fluid exosomes and their potential to induce oligomerization of alpha-synuclein were analysed. The quantification of cerebrospinal fluid exosomal alpha-synuclein showed distinct differences between patients with Parkinson's disease and dementia with Lewy bodies. In addition, exosomal alpha-synuclein levels correlated with the severity of cognitive impairment in cross-sectional samples from patients with dementia with Lewy bodies. Importantly, cerebrospinal fluid exosomes derived from Parkinson's disease and dementia with Lewy bodies induce oligomerization of alpha-synuclein in a reporter cell line in a dose-dependent manner. Our data suggest that cerebrospinal fluid exosomes from patients with Parkinson's disease and dementia with Lewy bodies contain a pathogenic species of alpha-synuclein, which could initiate oligomerization of soluble alpha-synuclein in target cells and confer disease pathology. PMID- 26647158 TI - Formation of environmentally persistent free radical (EPFR) in iron(III) cation exchanged smectite clay. AB - Environmentally persistent free radicals (EPFRs) have been found at a number of Superfund sites, with EPFRs being formed via a proposed redox process at ambient environmental conditions. The possibility of such a redox process taking place at ambient environmental conditions is studied utilizing a surrogate soil system of phenol and iron(III)-exchanged calcium montmorillonite clay, Fe(III)CaM. Sorption of phenol by the Fe(III)CaM is demonstrated by Fourier-transformed infra-red (FT IR) spectroscopy, as evidenced by the peaks between 1345 cm(-1) and 1595 cm(-1), and at lower frequencies between 694 cm(-1) and 806 cm(-1), as well as X-ray diffraction (XRD) spectroscopy, as shown by an increase in interlayer spacing within Fe(III)CaM. The formation and characterization of the EPFRs is determined by electron paramagnetic resonance (EPR) spectroscopy, showing phenoxyl-type radical with a g-factor of 2.0034 and DeltaHP-P of 6.1 G at an average concentration of 7.5 * 10(17) spins per g. EPFRs lifetime data are indicative of oxygen and water molecules being responsible for EPFR decay. The change in the oxidation state of the iron redox center is studied by X-ray absorption near-edge structure (XANES) spectroscopy, showing that 23% of the Fe(III) is reduced to Fe(II). X-ray photoemission spectroscopy (XPS) results confirm the XANES results. These findings, when combined with the EPFR concentration data, demonstrate that the stoichiometry of the EPFR formation under the conditions of this study is 1.5 * 10(-2) spins per Fe(II) atom. PMID- 26647159 TI - Integrating Environmental Management of Asthma into Pediatric Health Care: What Worked and What Still Needs Improvement? AB - The National Environmental Education Foundation (NEEF) launched an initiative in 2005 to integrate environmental management of asthma into pediatric health care. This study, a follow-up to a 2013 study, evaluated the program's impact and assessed training results by 5 new faculty champions. We surveyed attendees at training sessions to measure knowledge and the likelihood of asking about and managing environmental triggers of asthma. To conduct the program evaluation, a workshop was held with the faculty champions and NEEF staff in which we identified major program benefits, as well as challenges and suggestions for the future. Trainee baseline knowledge of environmental triggers was low, but they reported robust improvement in environmental triggers knowledge and intention to recommend environmental management. The program has a broad, national scope, reaching more than 12 000 physicians, health care providers, and students, and some faculty champions successfully integrated materials into health record. Program barriers and future endeavors were identified. PMID- 26647161 TI - Matrix metalloproteinase 14 modulates signal transduction and angiogenesis in the cornea. AB - The cornea is transparent and avascular, and retention of these characteristics is critical to maintaining vision clarity. Under normal conditions, wound healing in response to corneal injury occurs without the formation of new blood vessels; however, neovascularization may be induced during corneal wound healing when the balance between proangiogenic and antiangiogenic mediators is disrupted to favor angiogenesis. Matrix metalloproteinases (MMPs), which are key factors in extracellular matrix remodeling and angiogenesis, contribute to the maintenance of this balance, and in pathologic instances, can contribute to its disruption. Here, we elaborate on the facilitative role of MMPs, specifically MMP-14, in corneal neovascularization. MMP-14 is a transmembrane MMP that is critically involved in extracellular matrix proteolysis, exosome transport, and cellular migration and invasion, processes that are critical for angiogenesis. To aid in developing efficacious therapies that promote healing without neovascularization, it is important to understand and further investigate the complex pathways related to MMP-14 signaling, which can also involve vascular endothelial growth factor, basic fibroblast growth factor, Wnt/beta-catenin, transforming growth factor, platelet-derived growth factor, hepatocyte growth factor or chemokines, epidermal growth factor, prostaglandin E2, thrombin, integrins, Notch, Toll-like receptors, PI3k/Akt, Src, RhoA/RhoA kinase, and extracellular signal-related kinase. The involvement and potential contribution of these signaling molecules or proteins in neovascularization are the focus of the present review. PMID- 26647160 TI - Prevention of diet-induced hepatic steatosis and hepatic insulin resistance by second generation antisense oligonucleotides targeted to the longevity gene mIndy (Slc13a5). AB - Reducing the expression of the Indy (I'm Not Dead Yet) gene in lower organisms extends life span by mechanisms resembling caloric restriction. Similarly, deletion of the mammalian homolog, mIndy (Slc13a5), encoding for a plasma membrane tricarboxylate transporter, protects from aging- and diet-induced adiposity and insulin resistance in mice. The organ specific contribution to this phenotype is unknown. We examined the impact of selective inducible hepatic knockdown of mIndy on whole body lipid and glucose metabolism using 2'-O methoxyethyl chimeric anti-sense oligonucleotides (ASOs) in high-fat fed rats. 4 week treatment with 2'-O-methoxyethyl chimeric ASO reduced mIndy mRNA expression by 91% (P=0.001) compared to control ASO. Besides similar body weights between both groups, mIndy-ASO treatment lead to a 74% reduction in fasting plasma insulin concentrations as well as a 35% reduction in plasma triglycerides. Moreover, hepatic triglyceride content was significantly reduced by the knockdown of mIndy, likely mediating a trend to decreased basal rates of endogenous glucose production as well as an increased suppression of hepatic glucose production by 25% during a hyperinsulinemic-euglycemic clamp. Together, these data suggest that inducible liver-selective reduction of mIndy in rats is able to ameliorate hepatic steatosis and insulin resistance, conditions occurring with high calorie diets and during aging. PMID- 26647163 TI - Obesity: recent insights. PMID- 26647162 TI - iRDA: a new filter towards predictive, stable, and enriched candidate genes. AB - BACKGROUND: Gene expression profiling using high-throughput screening (HTS) technologies allows clinical researchers to find prognosis gene signatures that could better discriminate between different phenotypes and serve as potential biological markers in disease diagnoses. In recent years, many feature selection methods have been devised for finding such discriminative genes, and more recently information theoretic filters have also been introduced for capturing feature-to-class relevance and feature-to-feature correlations in microarray based classification. METHODS: In this paper, we present and fully formulate a new multivariate filter, iRDA, for the discovery of HTS gene-expression candidate genes. The filter constitutes a four-step framework and includes feature relevance, feature redundancy, and feature interdependence in the context of feature-pairs. The method is based upon approximate Markov blankets, information theory, several heuristic search strategies with forward, backward and insertion phases, and the method is aiming at higher order gene interactions. RESULTS: To show the strengths of iRDA, three performance measures, two evaluation schemes, two stability index sets, and the gene set enrichment analysis (GSEA) are all employed in our experimental studies. Its effectiveness has been validated by using seven well-known cancer gene-expression benchmarks and four other disease experiments, including a comparison to three popular information theoretic filters. In terms of classification performance, candidate genes selected by iRDA perform better than the sets discovered by the other three filters. Two stability measures indicate that iRDA is the most robust with the least variance. GSEA shows that iRDA produces more statistically enriched gene sets on five out of the six benchmark datasets. CONCLUSIONS: Through the classification performance, the stability performance, and the enrichment analysis, iRDA is a promising filter to find predictive, stable, and enriched gene-expression candidate genes. PMID- 26647165 TI - Coherent transport through spin-crossover magnet Fe2 complexes. AB - As one of the most promising building blocks in molecular spintronics, spin crossover (SCO) complexes have attracted increasing attention due to their magnetic bistability between the high-spin (HS) and low-spin (LS) states. Here, we explore the electronic structures and transport properties of SCO magnet Fe2 complexes with three different spin-pair configurations, namely [LS-LS], [LS-HS], and [HS-HS], by performing extensive density functional theory calculations combined with the non-equilibrium Green's function technique. Our calculations clearly reveal that the SCO magnet Fe2 complexes should display two-step spin transitions triggered by external stimuli, i.e. temperature or light, which confirm the previous phenomenological model and agree well with previous experimental measurements. Based on the calculated transport results, we observe a nearly perfect spin-filtering effect and negative differential resistance (NDR) behavior integrated in the SCO magnet Fe2 junction with the [HS-HS] configuration. The current through the [HS-HS] SCO magnet Fe2 complex under a small bias voltage is mainly contributed by the spin-down electrons, which is significantly larger than those of the [LS-LS] and [LS-HS] cases. The bias dependent transmissions are responsible for the observed NDR effect. These theoretical findings suggest that SCO Fe2 complexes hold potential applications in molecular spintronic devices. PMID- 26647164 TI - Molecular correlates of fat mass expansion in C57BL/6J mice after short-term exposure to dietary fat. AB - Heterogeneity of obesity within a population of inbred mice fed an obesogenic high-fat diet (HFD) is associated with changes of gene expression in white adipose tissue (WAT). One gene in particular with large variations among mice, mesoderm-specific transcript (Mest), has been shown to be highly inducible after being fed a short-term HFD, and its expression in WAT before HFD feeding is predictive for susceptibility to the development of obesity. To gain further insight into the association of Mest with rapid changes in body composition, 96 individually housed C57BL/6J mice were fed an HFD for only 2 weeks, resulting in a 12-fold and 90-fold variation in Mest mRNA in visceral epididymal and subcutaneous inguinal WAT, respectively. WAT Mest mRNA was positively associated with interindividual variation of fat mass. Surprisingly, there was only a slight association of WAT Mest with food intake when normalized by body weight or lean mass. In addition, WAT Mest expression coincided highly with the expression of the transcription factor Kruppel-like factor 14 (Klf14), an imprinted gene that regulates lipid metabolism in WAT. Our data suggest that KLF14 transcriptional activity may partially mediate, or act in concert with, MEST as part of an epigenetic mechanism that promotes fat mass accumulation in mice fed an obesogenic diet. PMID- 26647166 TI - Species-wide genome sequence and nucleotide polymorphisms from the model allopolyploid plant Brassica napus. AB - Brassica napus (oilseed rape, canola) is one of the world's most important sources of vegetable oil for human nutrition and biofuel, and also a model species for studies investigating the evolutionary consequences of polyploidisation. Strong bottlenecks during its recent origin from interspecific hybridisation, and subsequently through intensive artificial selection, have severely depleted the genetic diversity available for breeding. On the other hand, high-throughput genome profiling technologies today provide unprecedented scope to identify, characterise and utilise genetic diversity in primary and secondary crop gene pools. Such methods also enable implementation of genomic selection strategies to accelerate breeding progress. The key prerequisite is availability of high-quality sequence data and identification of high-quality, genome-wide sequence polymorphisms representing relevant gene pools. We present comprehensive genome resequencing data from a panel of 52 highly diverse natural and synthetic B. napus accessions, along with a stringently selected panel of 4.3 million high-confidence, genome-wide SNPs. The data is of great interest for genomics-assisted breeding and for evolutionary studies on the origins and consequences in allopolyploidisation in plants. PMID- 26647167 TI - Prucalopride succinate for the treatment of constipation: an update. AB - Constipation is a disorder frequently complained about by patients in daily clinical practice. However, to date, its treatment is still commonly unsatisfactory, especially concerning patients' quality of life, when using conventional measures. Prucalopride, a selective 5-hydroxytryptamine receptor 4 agonist, was introduced to the market in 2009 and has been commercially available in Europe since 2010. The main effect of prucalopride is to stimulate colonic motility, which explains its efficacy to treat constipated patients unresponsive to other regimens. Literature search was carried out to look for effects of prucalopride on constipated patients. Several papers were found demonstrating that prucalopride is effective in treatment of constipated patients. Due to its few side effects, the lack of cardiovascular effects and interactions with other drugs, prucalopride may be safely used in elderly people as well. PMID- 26647169 TI - Comparison of windowing effects on elastography images: Simulation, phantom and in vivo studies. AB - In this paper, we have evaluated the use of smooth windows for ultrasound elastography. In ultrasound elastography, local tissue strain is estimated using operations such as cross-correlation on local segments of RF data. In this process, local data segments are selected by multiplying the RF data by a rectangular window. Such data truncation causes non-ideal spectral behavior, which can be mitigated by using smooth windows. Accordingly, we hypothesize that the use of smooth windows may improve the elastographic signal-to-noise ratio (SNRe) and contrast-to-noise ratio (CNRe) of strain images. The effects of using smooth windows have not been fully characterized for time-domain strain estimators. Thus, we have compared the elastographic performance of rectangular, Hanning, Gaussian, and Chebyshev windows used in conjunction with cross correlation based algorithm and adaptive stretching algorithm using finite element method (FEM) simulation, experimental phantom, and in vivo data. Smooth windows are found to improve the SNRe by up to 3.94 for FEM data and by up to 1.76 for phantom data which represent 76% and 60.52% improvements, respectively. CNRe improves by up to 12.23 for FEM simulated data and by up to 4.28 for phantom data which represent 213.07% and 248.2% improvements, respectively. Mean structural similarity (MSSIM) was used for assessing the image perceptual quality and smooth windows improved it by up to 0.22 (85.98% improvement) for simulated data. We have evaluated these parameters at 1-6% applied strains for the experimental phantom and at 1%, 2%, 4%, 6%, 8%, and 12% applied strains for FEM simulation. We observed a maximum deterioration in axial resolution of 0.375 mm (which is on the order of the wavelength, 0.3mm) due to smooth windows. "Salt-and pepper" noise from false-peak errors has also been reduced. Smooth windows increased the lesion-to-background contrast (by increasing the CNRe by 213.07%) of a low contrast lesion (10-dB). For the in vivo cases, use of smooth windows resulted in better depiction of lesions, which is important for lesion classification. In this work, we have used an ATL Ultramark 9 scanner with an L10 5 (7.5 MHz) probe for the phantom experiment and a Sonix SP500 scanner with an L14-5/38 probe (10 MHz) for in vivo data collection. PMID- 26647168 TI - Estimating Information Processing in a Memory System: The Utility of Meta analytic Methods for Genetics. AB - Genetic studies in Drosophila reveal that olfactory memory relies on a brain structure called the mushroom body. The mainstream view is that each of the three lobes of the mushroom body play specialized roles in short-term aversive olfactory memory, but a number of studies have made divergent conclusions based on their varying experimental findings. Like many fields, neurogenetics uses null hypothesis significance testing for data analysis. Critics of significance testing claim that this method promotes discrepancies by using arbitrary thresholds (alpha) to apply reject/accept dichotomies to continuous data, which is not reflective of the biological reality of quantitative phenotypes. We explored using estimation statistics, an alternative data analysis framework, to examine published fly short-term memory data. Systematic review was used to identify behavioral experiments examining the physiological basis of olfactory memory and meta-analytic approaches were applied to assess the role of lobular specialization. Multivariate meta-regression models revealed that short-term memory lobular specialization is not supported by the data; it identified the cellular extent of a transgenic driver as the major predictor of its effect on short-term memory. These findings demonstrate that effect sizes, meta-analysis, meta-regression, hierarchical models and estimation methods in general can be successfully harnessed to identify knowledge gaps, synthesize divergent results, accommodate heterogeneous experimental design and quantify genetic mechanisms. PMID- 26647170 TI - Reduced salinity increases susceptibility of zooxanthellate jellyfish to herbicide toxicity during a simulated rainfall event. AB - Accurately predicting how marine biota are likely to respond to changing ocean conditions requires accurate simulation of interacting stressors, exposure regimes and recovery periods. Jellyfish populations have increased in some parts of the world and, despite few direct empirical tests, are hypothesised to be increasing because they are robust to a range of environmental stressors. Here, we investigated the effects of contaminated runoff on a zooxanthellate jellyfish by exposing juvenile Cassiopea sp. medusae to a photosystem II (PSII) herbicide, atrazine and reduced salinity conditions that occur following rainfall. Four levels of atrazine (0ngL(-1), 10ngL(-1), 2MUgL(-1), 20MUgL(-1)) and three levels of salinity (35 ppt, 25 ppt, 17 ppt) were varied, mimicking the timeline of light, moderate and heavy rainfall events. Normal conditions were then slowly re established over four days to mimic the recovery of the ecosystem post-rain and the experiment continued for a further 7 days to observe potential recovery of the medusae. Pulse-amplitude modulated (PAM) chlorophyll fluorescence, growth and bell contraction rates of medusae were measured. Medusae exposed to the combination of high atrazine and lowest salinity died. After 3 days of exposure, bell contraction rates were reduced by 88% and medusae were 16% smaller in the lowest salinity treatments. By Day 5 of the experiment, all medusae that survived the initial pulse event began to recover quickly. Although atrazine decreased YII under normal salinity conditions, YII was further reduced when medusae were exposed to both low salinity and atrazine simultaneously. Atrazine breakdown products were more concentrated in jellyfish tissues than atrazine at the end of the experiment, suggesting that although bioaccumulation occurred, atrazine was metabolised. Our results suggest that reduced salinity may increase the susceptibility of medusae to herbicide exposure during heavy rainfall events. PMID- 26647171 TI - Integrative transcriptomic and protein analysis of human bronchial BEAS-2B exposed to seasonal urban particulate matter. AB - BACKGROUND: Exposure to particulate matter (PM) is associated with various health effects. Physico-chemical properties influence the toxicological impact of PM, nonetheless the mechanisms underlying PM-induced effects are not completely understood. OBJECTIVES: Human bronchial epithelial cells were used to analyse the pathways activated after exposure to summer and winter urban PM and to identify possible markers of exposure. METHODS: BEAS-2B cells were exposed for 24 h to 10 MUg/cm(2) of winter PM2.5 (wPM) and summer PM10 (sPM) sampled in Milan. A microarray technology was used to profile the cells gene expression. Genes and microRNAs were analyzed by bioinformatics technique to identify pathways involved in cellular responses. Selected genes and pathways were validated at protein level (western blot, membrane protein arrays and ELISA). RESULTS: The molecular networks activated by the two PM evidenced a correlation among oxidative stress, inflammation and DNA damage responses. sPM induced the release of pro inflammatory mediators, although miR-146a and genes related to inflammation resulted up-regulated by both PM. Moreover both PM affected a set of genes, proteins and miRNAs related to antioxidant responses, cancer development, extracellular matrix remodeling and cytoskeleton organization, while miR-29c, implicated in epigenetic modification, resulted up-regulated only by wPM. sPM effects may be related to biological and inorganic components, while wPM apparently related to the high content of organic compounds. CONCLUSIONS: These results may be helpful for the individuation of biomarkers for PM exposure, linked to the specific PM physico-chemical properties. PMID- 26647172 TI - Effects of coastal managed retreat on mercury biogeochemistry. AB - We investigated the impact of managed retreat on mercury (Hg) biogeochemistry at a site subject to diffuse contamination with Hg. We collected sediment cores from an area of land behind a dyke one year before and one year after it was intentionally breached. These sediments were compared to those of an adjacent mudflat and a salt marsh. The concentration of total mercury (THg) in the sediment doubled after the dyke was breached due to the deposition of fresh sediment that had a smaller particle size, and higher pH. The concentration of methylmercury (MeHg) was 27% lower in the sediments after the dyke was breached. We conclude that coastal flooding during managed retreat of coastal flood defences at this site has not increased the risk of Hg methylation or bioavailability during the first year. As the sediment becomes vegetated, increased activity of Hg-methylating bacteria may accelerate Hg-methylation rate. PMID- 26647173 TI - Charge transfer effects on the chemical reactivity of Pd(x)Cu(1-x) nanoalloys. AB - This work reports on the synthesis and characterization of PdxCu1-x (x = 0.7, 0.5 and 0.3) nanoalloys obtained via an eco-friendly chemical reduction method based on ascorbic acid and trisodium citrate. The average size of the quasi-spherical nanoparticles (NPs) obtained by this method was about 4 nm, as observed by TEM. The colloids containing different NPs were then supported on carbon in order to produce powder samples (PdxCu1-x/C) whose electronic and structural properties were probed by different techniques. XRD analysis indicated the formation of crystalline PdCu alloys with a nanoscaled crystallite size. Core-level XPS results provided a fingerprint of a charge transfer process between Pd and Cu and its dependency on the nanoalloy composition. Additionally, it was verified that alloying was able to change the NP's reactivity towards oxidation and reduction. Indeed, the higher the amount of Pd in the nanoalloy, less oxidized are both the Pd and the Cu atoms in the as-prepared samples. Also, in situ XANES experiments during thermal treatment under a reducing atmosphere showed that the temperature required for a complete reduction of the nanoalloys depends on their composition. These results envisage the control at the atomic level of novel catalytic properties of such nanoalloys. PMID- 26647174 TI - Correlation between tibial measurements using peripheral quantitative computed tomography and hip areal bone density measurements in ambulatory chronic stroke patients. AB - OBJECTIVE: Peripheral quantitative computed tomography (pQCT) has been increasingly used in stroke research. The correlations between tibial bone measurements by pQCT and hip areal bone mineral density (aBMD) measurements by dual-energy x-ray absorptiometry (DXA) (gold standard for diagnosing osteoporosis) in chronic stroke patients were examined in this study. If the correlations were strong, there may be potential for further pursuit of clinical use of pQCT. METHODS: Seventy-four chronic stroke patients who are household ambulators (22 women, 52 men; >= 6 months after onset) underwent pQCT scanning of the tibial distal epiphysis (4% site) and diaphysis (66% site) and DXA hip scans on both sides. Pearson's correlation coefficients were used to investigate the correlations between the pQCT-derived variables and the DXA-derived total hip and femoral neck aBMD. RESULTS: All pQCT tibial variables, except the total area, were significantly associated with total hip and femoral neck aBMD. Cortical bone mineral content (66% site) was the only variable that yielded good-to-excellent correlations with total hip and femoral neck aBMD on both sides (r = 0.750 0.833). CONCLUSIONS: Based on the good correlations between tibial pQCT variables and hip aBMD, the clinical use of pQCT in assessing bone health in this population should be further pursued. PMID- 26647175 TI - Secondary neurotransmitter deficiencies in epilepsy caused by voltage-gated sodium channelopathies: A potential treatment target? AB - We describe neurotransmitter abnormalities in two patients with drug-resistant epilepsy resulting from deleterious de novo mutations in sodium channel genes. Whole exome sequencing identified a de novo SCN2A splice-site mutation (c.2379+1G>A, p.Glu717Gly.fs*30) resulting in deletion of exon 14, in a 10-year old male with early onset global developmental delay, intermittent ataxia, autism, hypotonia, epileptic encephalopathy and cerebral/cerebellar atrophy. In the cerebrospinal fluid both homovanillic acid and 5-hydroxyindoleacetic acid were significantly decreased; extensive biochemical and genetic investigations ruled out primary neurotransmitter deficiencies and other known inborn errors of metabolism. In an 8-year old female with an early onset intractable epileptic encephalopathy, developmental regression, and progressive cerebellar atrophy, a previously unreported de novo missense mutation was identified in SCN8A (c.5615G>A; p.Arg1872Gln), affecting a highly conserved residue located in the C terminal of the Nav1.6 protein. Aside from decreased homovanillic acid and 5 hydroxyindoleacetic acid, 5-methyltetrahydrofolate was also found to be low. We hypothesize that these channelopathies cause abnormal synaptic mono-amine metabolite secretion/uptake via impaired vesicular release and imbalance in electrochemical ion gradients, which in turn aggravate the seizures. Treatment with oral 5-hydroxytryptophan, l-Dopa/Carbidopa, and a dopa agonist resulted in mild improvement of seizure control in the male case, most likely via dopamine and serotonin receptor activated signal transduction and modulation of glutamatergic, GABA-ergic and glycinergic neurotransmission. Neurotransmitter analysis in other sodium channelopathy patients will help validate our findings, potentially yielding novel treatment opportunities. PMID- 26647176 TI - Fulminant Ocular Toxoplasmosis: The Hazards of Corticosteroid Monotherapy. AB - PURPOSE: To describe fulminant toxoplasma retinochoroiditis induced by corticosteroid monotherapy. METHODS: Clinical records of nine patients were reviewed. RESULTS: All patients (five female, four male; aged 15-64 years) had been misdiagnosed as unilateral non-infectious uveitis and given systemic and/or local corticosteroid injections elsewhere. Mean disease duration before referral was 105.6 +/- 71 (45-240) days. Visual acuity at presentation was <20/200 in six eyes. Average lesion size was 6.6 disc areas in eight eyes and all four quadrants were involved in one. Toxoplasma DNA was detected in eight tested eyes. Mean duration of anti-toxoplasmic therapy was 92.5 +/- 37.1 days. Three eyes developed rhegmatogenous retinal detachment. Four patients underwent pars plana vitrectomy. Final visual acuity was <20/200 in five eyes. CONCLUSIONS: Iatrogenic immunosuppression due to initial misdiagnosis may lead to an aggressive course and serious complications of ocular toxoplasmosis, a potentially self-limiting infection. PMID- 26647177 TI - Appearance of cytomegalovirus-specific T-cells predicts fast resolution of viremia post hematopoietic stem cell transplantation. AB - BACKGROUND: Cytomegalovirus (CMV) specific T-cells are known to provide long-term control of CMV reactivation, which is a frequent complication of hematopoietic stem cell transplantation. We have studied 58 pediatric patients after hematopoietic stem cell transplantation who suffered from CMV reactivation to reveal which functional T cell subset is best correlating with successful reactivation resolution and which protects from reactivation episode. METHODS: Detection of 30 combinatorial subsets of four types of response to ex vivo CMV stimulation (IFNgamma secretion, IL-2 secretion, CD40L upregulation and degranulation) that were detectable on either CD8+ or CD4+ T cells through flow cytometry intracellular cytokine staining was used. RESULTS: We found that the presence of CD8+ dual positive (IFNgamma+ and IL-2+) cells is the most accurate functional parameter that can predict fast resolution of CMV reactivation. Next, we show that the presence of CD8+ dual positive (IFNgamma+ and IL-2+) and CD8+ IFNgamma+ cells provides a protective effect (a hazard risk of 0.28 (confidence interval 0.18 - 0.43) and 0.45 (CI 0.27 - 0.75), respectively) and the presence of corticotherapy increases the risk of reactivation (HR 2.47 (CI 1.82-3.36)). Thus, a patient without corticotherapy and with both of the critical T cell subsets present has a cumulative 19.6 times lower risk of developing CMV reactivation than a patient on corticotherapy and without CD8+ dual positive (IFNgamma+ and IL-2+) or CD8+ IFNgamma+ cells. CONCLUSIONS: We have established parameters of CMV specific functional response ex vivo that can be used in assisting clinical management of patients with CMV reactivation. (c) 2015 International Clinical Cytometry Society. PMID- 26647178 TI - Reply to Volker and Steenbeek: Multiple indicators point toward gender disparities in grant funding success in The Netherlands. PMID- 26647179 TI - No evidence that gender contributes to personal research funding success in The Netherlands: A reaction to van der Lee and Ellemers. PMID- 26647180 TI - Increasing aridity reduces soil microbial diversity and abundance in global drylands. AB - Soil bacteria and fungi play key roles in the functioning of terrestrial ecosystems, yet our understanding of their responses to climate change lags significantly behind that of other organisms. This gap in our understanding is particularly true for drylands, which occupy ~41% of Earth's surface, because no global, systematic assessments of the joint diversity of soil bacteria and fungi have been conducted in these environments to date. Here we present results from a study conducted across 80 dryland sites from all continents, except Antarctica, to assess how changes in aridity affect the composition, abundance, and diversity of soil bacteria and fungi. The diversity and abundance of soil bacteria and fungi was reduced as aridity increased. These results were largely driven by the negative impacts of aridity on soil organic carbon content, which positively affected the abundance and diversity of both bacteria and fungi. Aridity promoted shifts in the composition of soil bacteria, with increases in the relative abundance of Chloroflexi and alpha-Proteobacteria and decreases in Acidobacteria and Verrucomicrobia. Contrary to what has been reported by previous continental and global-scale studies, soil pH was not a major driver of bacterial diversity, and fungal communities were dominated by Ascomycota. Our results fill a critical gap in our understanding of soil microbial communities in terrestrial ecosystems. They suggest that changes in aridity, such as those predicted by climate-change models, may reduce microbial abundance and diversity, a response that will likely impact the provision of key ecosystem services by global drylands. PMID- 26647181 TI - Ketamine produces antidepressant-like effects through phosphorylation-dependent nuclear export of histone deacetylase 5 (HDAC5) in rats. AB - Ketamine produces rapid antidepressant-like effects in animal assays for depression, although the molecular mechanisms underlying these behavioral actions remain incomplete. Here, we demonstrate that ketamine rapidly stimulates histone deacetylase 5 (HDAC5) phosphorylation and nuclear export in rat hippocampal neurons through calcium/calmodulin kinase II- and protein kinase D-dependent pathways. Consequently, ketamine enhanced the transcriptional activity of myocyte enhancer factor 2 (MEF2), which leads to regulation of MEF2 target genes. Transfection of a HDAC5 phosphorylation-defective mutant (Ser259/Ser498 replaced by Ala259/Ala498, HDAC5-S/A), resulted in resistance to ketamine-induced nuclear export, suppression of ketamine-mediated MEF2 transcriptional activity, and decreased expression of MEF2 target genes. Behaviorally, viral-mediated hippocampal knockdown of HDAC5 blocked or occluded the antidepressant effects of ketamine both in unstressed and stressed animals. Taken together, our results reveal a novel role of HDAC5 in the actions of ketamine and suggest that HDAC5 could be a potential mechanism contributing to the therapeutic actions of ketamine. PMID- 26647182 TI - Signatures and control of strong-field dynamics in a complex system. AB - Controlling chemical reactions by light, i.e., the selective making and breaking of chemical bonds in a desired way with strong-field lasers, is a long-held dream in science. An essential step toward achieving this goal is to understand the interactions of atomic and molecular systems with intense laser light. The main focus of experiments that were performed thus far was on quantum-state population changes. Phase-shaped laser pulses were used to control the population of final states, also, by making use of quantum interference of different pathways. However, the quantum-mechanical phase of these final states, governing the system's response and thus the subsequent temporal evolution and dynamics of the system, was not systematically analyzed. Here, we demonstrate a generalized phase control concept for complex systems in the liquid phase. In this scheme, the intensity of a control laser pulse acts as a control knob to manipulate the quantum-mechanical phase evolution of excited states. This control manifests itself in the phase of the molecule's dipole response accessible via its absorption spectrum. As reported here, the shape of a broad molecular absorption band is significantly modified for laser pulse intensities ranging from the weak perturbative to the strong-field regime. This generalized phase-control concept provides a powerful tool to interpret and understand the strong-field dynamics and control of large molecules in external pulsed laser fields. PMID- 26647183 TI - Directed and persistent movement arises from mechanochemistry of the ParA/ParB system. AB - The segregation of DNA before cell division is essential for faithful genetic inheritance. In many bacteria, segregation of low-copy number plasmids involves an active partition system composed of a nonspecific DNA-binding ATPase, ParA, and its stimulator protein ParB. The ParA/ParB system drives directed and persistent movement of DNA cargo both in vivo and in vitro. Filament-based models akin to actin/microtubule-driven motility were proposed for plasmid segregation mediated by ParA. Recent experiments challenge this view and suggest that ParA/ParB system motility is driven by a diffusion ratchet mechanism in which ParB-coated plasmid both creates and follows a ParA gradient on the nucleoid surface. However, the detailed mechanism of ParA/ParB-mediated directed and persistent movement remains unknown. Here, we develop a theoretical model describing ParA/ParB-mediated motility. We show that the ParA/ParB system can work as a Brownian ratchet, which effectively couples the ATPase-dependent cycling of ParA-nucleoid affinity to the motion of the ParB-bound cargo. Paradoxically, this resulting processive motion relies on quenching diffusive plasmid motion through a large number of transient ParA/ParB-mediated tethers to the nucleoid surface. Our work thus sheds light on an emergent phenomenon in which nonmotor proteins work collectively via mechanochemical coupling to propel cargos-an ingenious solution shaped by evolution to cope with the lack of processive motor proteins in bacteria. PMID- 26647184 TI - period-1 encodes an ATP-dependent RNA helicase that influences nutritional compensation of the Neurospora circadian clock. AB - Mutants in the period-1 (prd-1) gene, characterized by a recessive allele, display a reduced growth rate and period lengthening of the developmental cycle controlled by the circadian clock. We refined the genetic location of prd-1 and used whole genome sequencing to find the mutation defining it, confirming the identity of prd-1 by rescuing the mutant circadian phenotype via transformation. PRD-1 is an RNA helicase whose orthologs, DDX5 [DEAD (Asp-Glu-Ala-Asp) Box Helicase 5] and DDX17 in humans and DBP2 (Dead Box Protein 2) in yeast, are implicated in various processes, including transcriptional regulation, elongation, and termination, ribosome biogenesis, and mRNA decay. Although prd-1 mutants display a long period (~25 h) circadian developmental cycle, they interestingly display a WT period when the core circadian oscillator is tracked using a frq-luciferase transcriptional fusion under conditions of limiting nutritional carbon; the core oscillator in the prd-1 mutant strain runs with a long period under glucose-sufficient conditions. Thus, PRD-1 clearly impacts the circadian oscillator and is not only part of a metabolic oscillator ancillary to the core clock. PRD-1 is an essential protein, and its expression is neither light-regulated nor clock-regulated. However, it is transiently induced by glucose; in the presence of sufficient glucose, PRD-1 is in the nucleus until glucose runs out, which elicits its disappearance from the nucleus. Because circadian period length is carbon concentration-dependent, prd-1 may be formally viewed as a clock mutant with defective nutritional compensation of circadian period length. PMID- 26647185 TI - Inositol phosphate kinase 2 is required for imaginal disc development in Drosophila. AB - Inositol phosphate kinase 2 (Ipk2), also known as IP multikinase IPMK, is an evolutionarily conserved protein that initiates production of inositol phosphate intracellular messengers (IPs), which are critical for regulating nuclear and cytoplasmic processes. Here we report that Ipk2 kinase activity is required for the development of the adult fruit fly epidermis. Ipk2 mutants show impaired development of their imaginal discs, the primordial tissues that form the adult epidermis. Although disk tissue seems to specify normally during early embryogenesis, loss of Ipk2 activity results in increased apoptosis and impairment of proliferation during larval and pupal development. The proliferation defect is in part attributed to a reduction in JAK/STAT signaling, possibly by controlling production or secretion of the pathway's activating ligand, Unpaired. Constitutive activation of the JAK/STAT pathway downstream of Unpaired partially rescues the disk growth defects in Ipk2 mutants. Thus, IP production is essential for proliferation of the imaginal discs, in part, by regulating JAK/STAT signaling. Our work demonstrates an essential role for Ipk2 in producing inositide messengers required for imaginal disk tissue maturation and subsequent formation of adult body structures and provides molecular insights to signaling pathways involved in tissue growth and stability during development. PMID- 26647186 TI - MHC-mismatched mixed chimerism augments thymic regulatory T-cell production and prevents relapse of EAE in mice. AB - Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system with demyelination, axon damage, and paralysis. Induction of mixed chimerism with allogeneic donors has been shown to not cause graft-versus-host disease (GVHD) in animal models and humans. We have reported that induction of MHC-mismatched mixed chimerism can cure autoimmunity in autoimmune NOD mice, but this approach has not yet been tested in animal models of MS, such as experimental autoimmune encephalomyelitis (EAE). Here, we report that MHC mismatched mixed chimerism with C57BL/6 (H-2(b)) donor in SJL/J (H-2(s)) EAE recipients eliminates clinical symptoms and prevents relapse. This cure is demonstrated by not only disappearance of clinical signs but also reversal of autoimmunity; elimination of infiltrating T, B, and macrophage cells in the spinal cord; and regeneration of myelin sheath. The reversal of autoimmunity is associated with a marked reduction of autoreactivity of CD4(+) T cells and significant increase in the percentage of Foxp3(+) Treg among host-type CD4(+) T cells in the spleen and lymph nodes. The latter is associated with a marked reduction of the percentage of host-type CD4(+)CD8(+) thymocytes and an increase of Treg percentage among the CD4(+)CD8(+) and CD4(+)CD8(-) thymocytes. Thymectomy leads to loss of prevention of EAE relapse by induction of mixed chimerism, although there is a dramatic expansion of host-type Treg cells in the lymph nodes. These results indicate that induction of MHC-mismatched mixed chimerism can restore thymic negative selection of autoreactive CD4(+) T cells, augment production of Foxp3(+) Treg, and cure EAE. PMID- 26647208 TI - Quantification of nanoparticle release from polymer nanocomposite coatings due to environmental stressing. AB - Certain engineered nanoparticles (ENP) reduce the flammability of components used in soft furnishings (mattresses and upholstered furniture). However, because of the ENP's small size and ability to interact with biological molecules, these fire retardant ENPs may pose a health and environmental risks, if they are released sometime during the life cycle of the soft furnishing. Quantifying the released amount of these ENPs under normal end-use circumstances provides a basis for assessing their potential health and environmental impact. In this article, we report on efforts to identify suitable methodologies for quantifying the release of carbon nanofibers, carbon nanotubes, and sodium montmorillonites from coatings applied to the surfaces of barrier fabric and polyurethane foam. The ENPs released in simulated chewing and mechanical stressing experiments were collected in aqueous solution and quantified using Ultraviolet-Visible and inductively coupled plasma-optical emission spectroscopy. The microstructures of the released ENPs were characterized using scanning electron microscopy. The reported methodology and results provide important milestones to estimate the impact and toxicity of the ENP release during the life cycle of the nanocomposites. To our knowledge, this is the first study of ENP release from the soft furnishing coating, something that can be important application area for fire safety. PMID- 26647187 TI - AMPA receptor inhibition by synaptically released zinc. AB - The vast amount of fast excitatory neurotransmission in the mammalian central nervous system is mediated by AMPA-subtype glutamate receptors (AMPARs). As a result, AMPAR-mediated synaptic transmission is implicated in nearly all aspects of brain development, function, and plasticity. Despite the central role of AMPARs in neurobiology, the fine-tuning of synaptic AMPA responses by endogenous modulators remains poorly understood. Here we provide evidence that endogenous zinc, released by single presynaptic action potentials, inhibits synaptic AMPA currents in the dorsal cochlear nucleus (DCN) and hippocampus. Exposure to loud sound reduces presynaptic zinc levels in the DCN and abolishes zinc inhibition, implicating zinc in experience-dependent AMPAR synaptic plasticity. Our results establish zinc as an activity-dependent, endogenous modulator of AMPARs that tunes fast excitatory neurotransmission and plasticity in glutamatergic synapses. PMID- 26647209 TI - Open Treatment of Blunt Injuries of Supra-Aortic Branches: Case Series. AB - BACKGROUND: Blunt injuries of the supra-aortic branches are rare entity, and majority of patients die before arrival at the hospital. Those who arrive alive require complex and fast procedure that requires sternotomy. We report 3 successfully managed cases. CASE REPORTS: We report 3 patients with injury of supra-aortic branches. One was treated urgently due to longitudinal rupture on the posterior wall of innominate artery after car accident, and another 2 had chronic false aneurysm located at the very orifice of the right subclavian and left common carotid artery. In first and second patient bypass grafting with a hand-made, Y-shaped, 8-mm Dacron graft from the ascending aorta to the right common carotid and proximal right subclavian artery were performed, whereas in last 1 bypass grafting from the ascending aorta to the cervical part of the left common carotid artery was performed. In our facility, there were no possibilities for any endovascular treatment. CONCLUSIONS: When endovascular technology is not available, open surgical repair of blunt injuries of supra-aortic vessels can be performed without complications. No matter to that, endovascular and hybrid procedures should be considered whenever possible. PMID- 26647210 TI - Endovascular Treatment of Basilar Artery Thrombosis Secondary to Bilateral Vertebral Artery Dissection with Symptom Onset Following Cervical Spine Manipulation Therapy. AB - BACKGROUND: Vertebral artery (VA) dissection (VAD) has been described following neck injury and can be associated with stroke, but the causal association with cervical spine manipulation therapy (cSMT) is controversial. The standard treatment for VAD is antithrombotic medical therapy. To highlight the considerations of an endovascular approach to VAD, we present a critical case of bilateral VAD causing embolic occlusion of the basilar artery (BA) in a patient with symptom debut following cSMT. CASE REPORT: A 37-year-old woman presented with acute onset of neurological symptoms immediately following cSMT in a chiropractic facility. Acute magnetic resonance imaging (MRI) showed ischemic lesions in the right cerebellar hemisphere and occlusion of the cranial part of the BA. Angiography depicted bilateral VAD. Symptoms remitted after endovascular therapy, which included dilatation of the left VA and extraction of thrombus from the BA. After 6 months, the patient had minor sensory and cognitive deficits. CONCLUSIONS: In severe cases, VAD may be complicated by BA thrombosis, and this case highlights the importance of a fast diagnostic approach and advanced intravascular procedure to obtain good long-term neurological outcome. Furthermore, this case underlines the need to suspect VAD in patients presenting with neurological symptoms following cSMT. PMID- 26647211 TI - Negative Cooperativity and High Affinity in Chitooligosaccharide Binding by a Mycobacterium smegmatis Protein Containing LysM and Lectin Domains. AB - LysM domains have been recognized in bacteria and eukaryotes as carbohydrate binding protein modules, but the mechanism of their binding to chitooligosaccharides has been underexplored. Binding of a Mycobacterium smegmatis protein containing a lectin (MSL) and one LysM domain to chitooligosaccharides has been studied using isothermal titration calorimetry and fluorescence titration that demonstrate the presence of two binding sites of nonidentical affinities per dimeric MSL-LysM molecule. The affinity of the molecule for chitooligosaccharides correlates with the length of the carbohydrate chain. Its binding to chitooligosaccharides is characterized by negative cooperativity in the interactions of the two domains. Apparently, the flexibility of the long linker that connects the LysM and MSL domains plays a facilitating role in this recognition. The LysM domain in the MSL-LysM molecule, like other bacterial domains but unlike plant LysM domains, recognizes equally well peptidoglycan fragments as well as chitin polymers. Interestingly, in the case presented here, two LysM domains are enough for binding to peptidoglycan in contrast to the three reportedly required by the LysM domains of Bacillus subtilis and Lactococcus lactis. Also, the affinity of the MSL-LysM molecule for chitooligosaccharides is higher than that of LysM-chitooligosaccharide interactions reported so far. PMID- 26647212 TI - Introduction. December 2015 at a glance. PMID- 26647213 TI - Latent ischaemia as a trigger for a circulus vitiosus of inflammation, fibrosis, and stiffness in HFPEF. PMID- 26647214 TI - Neuromuscular junction fragmentation and muscle wasting in heart failure: a sharp cut from a Sica sword? PMID- 26647216 TI - Corrigendum to 'Heart failure at the crossroads: moving beyond blaming stakeholders to targeting the heart' [Eur J Heart Fail] 2015 August;17(8): 760 763. doi:10.1002/ejhf.315. PMID- 26647215 TI - Sleep-disordered breathing and chronic heart failure: changing position may be important. PMID- 26647217 TI - An Immunogenetic Signature of Ongoing Antigen Interactions in Splenic Marginal Zone Lymphoma Expressing IGHV1-2*04 Receptors. AB - PURPOSE: Prompted by the extensive biases in the immunoglobulin (IG) gene repertoire of splenic marginal-zone lymphoma (SMZL), supporting antigen selection in SMZL ontogeny, we sought to investigate whether antigen involvement is also relevant post-transformation. EXPERIMENTAL DESIGN: We conducted a large-scale subcloning study of the IG rearrangements of 40 SMZL cases aimed at assessing intraclonal diversification (ID) due to ongoing somatic hypermutation (SHM). RESULTS: ID was identified in 17 of 21 (81%) rearrangements using the immunoglobulin heavy variable (IGHV)1-2*04 gene versus 8 of 19 (40%) rearrangements utilizing other IGHV genes (P= 0.001). ID was also evident in most analyzed IG light chain gene rearrangements, albeit was more limited compared with IG heavy chains. Identical sequence changes were shared by subclones from different patients utilizing the IGHV1-2*04 gene, confirming restricted ongoing SHM profiles. Non-IGHV1-2*04 cases displayed both a lower number of ongoing SHMs and a lack of shared mutations (per group of cases utilizing the same IGHV gene). CONCLUSIONS: These findings support ongoing antigen involvement in a sizable portion of SMZL and further argue that IGHV1-2*04 SMZL may represent a distinct molecular subtype of the disease. PMID- 26647220 TI - Symmetry Breaking in the Supramolecular Gels of an Achiral Gelator Exclusively Driven by pi-pi Stacking. AB - Supramolecular symmetry breaking, in which chiral assemblies with imbalanced right- and left-handedness emerge from achiral molecular building blocks, has been achieved in the organogels of a C3-symmetric molecule only via pi-pi stacking. Specifically, an achiral C3-symmetric benzene-1,3,5-tricarboxylate substituted with methyl cinnamate through ester bond was found to form organogels in various organic solvents. More interestingly, when gels formed in cyclohexane, symmetry breaking occurred; i.e., optically active organogels together with the helical nanofibers with predominant handedness were obtained. Furthermore, the stochastically appeared imbalanced helicity could be driven to desired handedness by utilizing slight chiral solvents such as (R)- or (S)-terpinen-4-ol. Remarkably, the handedness of supramolecular assemblies thus formed could be kept even when the chiral solvents were removed. For the first time, we show that symmetry breaking can occur in supramolecular gel system driven exclusively through pi-pi stacking. PMID- 26647219 TI - Usefulness of albumin-bilirubin grade for evaluation of prognosis of 2584 Japanese patients with hepatocellular carcinoma. AB - BACKGROUND AND AIM: The Child-Pugh classification has some non-objective factors, with chronic hepatitis indistinguishable from early liver cirrhosis in Child-Pugh A. We retrospectively evaluated the efficacy of albumin-bilirubin (ALBI) grade, which has been proposed as a new classification for hepatic function, for grading hepatocellular carcinoma (HCC) patients based on hepatic function and predicting their prognosis. METHOD: From 2000 to 2014, 2584 naive HCC [69.0 +/- 9.8 years old, 1850 men, 734 female, Child-Pugh class A:B:C = 1871:558:155] were enrolled. TNM staging was determined using the classification of the Liver Cancer Study Group of Japan and ALBI grade, instead of Child-Pugh classification (ALBI with TNM score: ALBI-T score) (Table 1), and is similar to the Japan Integrated Staging (JIS) score. We retrospectively compared ALBI-T and JIS scores in these patients. RESULTS: Of patients classified as Child-Pugh A (n = 1871), 1285 with 5 points were divided into 858 with ALBI grade 1 and 427 with grade 2, while 586 with 6 points were divided into 53 with grade 1 and 533 with grade 2. The ratio of ALBI grade 2 patients with a Child-Pugh score of 6 points (91.0%) was similar to that of those with 7 points (91.8%). Patients with a lower ALBI-T score (0-5 points) showed a better median survival time than those with a corresponding lower JIS score [137.7:83.2:53.4:27.4:5.0:1.4 vs 97.6:74.9:39.7:15.0:4.0:1.0 months]. CONCLUSION: Albumin-bilirubin grade was found to be superior for distinguishing patients with better hepatic function. ALBI-T scoring may be a better total prognostic scoring system for predicting survival of Japanese patients with HCC. PMID- 26647218 TI - Genetic Landscapes of Relapsed and Refractory Diffuse Large B-Cell Lymphomas. AB - PURPOSE: Relapsed or refractory diffuse large B-cell lymphoma (rrDLBCL) is fatal in 90% of patients, and yet little is known about its biology. EXPERIMENTAL DESIGN: Using exome sequencing, we characterized the mutation profiles of 38 rrDLBCL biopsies obtained at the time of progression after immunochemotherapy. To identify genes that may be associated with relapse, we compared the mutation frequency in samples obtained at relapse to an unrelated cohort of 138 diagnostic DLBCLs and separately amplified specific mutations in their matched diagnostic samples to identify clonal expansions. RESULTS: On the basis of a higher frequency at relapse and evidence for clonal selection, TP53, FOXO1, MLL3 (KMT2C), CCND3, NFKBIZ, and STAT6 emerged as top candidate genes implicated in therapeutic resistance. We observed individual examples of clonal expansions affecting genes whose mutations had not been previously associated with DLBCL including two regulators of NF-kappaB: NFKBIE and NFKBIZ We detected mutations that may be affect sensitivity to novel therapeutics, such as MYD88 and CD79B mutations, in 31% and 23% of patients with activated B-cell-type of rrDLBCL, respectively. We also identified recurrent STAT6 mutations affecting D419 in 36% of patients with the germinal center B (GCB) cell rrDLBCL. These were associated with activated JAK/STAT signaling, increased phospho-STAT6 protein expression and increased expression of STAT6 target genes. CONCLUSIONS: This work improves our understanding of therapeutic resistance in rrDLBCL and has identified novel therapeutic opportunities especially for the high-risk patients with GCB-type rrDLBCL. Clin Cancer Res; 22(9); 2290-300. (c)2015 AACR. PMID- 26647221 TI - A novel approach to sports concussion assessment: Computerized multilimb reaction times and balance control testing. AB - INTRODUCTION: Mild traumatic brain injuries (MTBI) or concussions often result in problems with attention, executive functions, and motor control. For better identification of these diverse problems, novel approaches integrating tests of cognitive and motor functioning are needed. The aim was to characterize minor changes in motor and cognitive performance after sports-related concussions with a novel test battery, including balance tests and a computerized multilimb reaction time test. The cognitive demands of the battery gradually increase from a simple stimulus response to a complex task requiring executive attention. METHOD: A total of 113 male ice hockey players (mean age = 24.6 years, SD = 5.7) were assessed before a season. During the season, nine concussed players were retested within 36 hours, four to six days after the concussion, and after the season. A control group of seven nonconcussed players from the same pool of players with comparable demographics were retested after the season. Performance was measured using a balance test and the Motor Cognitive Test battery (MotCoTe) with multilimb responses in simple reaction, choice reaction, inhibition, and conflict resolution conditions. RESULTS: The performance of the concussed group declined at the postconcussion assessment compared to both the baseline measurement and the nonconcussed controls. Significant changes were observed in the concussed group for the multilimb choice reaction and inhibition tests. Tapping and balance showed a similar trend, but no statistically significant difference in performance. CONCLUSION: In sports-related concussions, complex motor tests can be valuable additions in assessing the outcome and recovery. In the current study, using subtasks with varying cognitive demands, it was shown that while simple motor performance was largely unaffected, the more complex tasks induced impaired reaction times for the concussed subjects. The increased reaction times may reflect the disruption of complex and integrative cognitive function in concussions. PMID- 26647222 TI - Endocrine-Disrupting Effects of Pesticides through Interference with Human Glucocorticoid Receptor. AB - Many pesticides have been identified as endocrine-disrupting chemicals (EDCs) due to their ability to bind sex-steroid hormone receptors. However, little attention has been paid to the ability of pesticides to interfere with other steroid hormone receptors such as glucocorticoid receptor (GR) that plays a critical role in metabolic, endocrine, immune, and nervous systems. In this study, the glucocorticoidic and antiglucocorticoidic effects of 34 pesticides on human GR were investigated using luciferase reporter gene assay. Surprisingly, none of the test chemicals showed GR agonistic activity, but 12 chemicals exhibited apparent antagonistic effects. Bifenthrin, lambda-cyhalothrin, cypermethrin, resmethrin, o,p'-DDT, p,p'-DDT, methoxychlor, ethiofencarb, and tolylfluanid showed remarkable GR antagonistic properties with RIC20 values lower than 10(-6) M. The disruption of glucocorticoid-responsive genes in H4IIE and J774A.1 cells was further evaluated on these 12 GR antagonists. In H4IIEcells, four organochlorine insecticides, bifenthrin, and 3-PBA decreased cortisol-induced PEPCK gene expression, while o,p'-DDT and methoxychlor inhibited cortisol-stimulated Arg and TAT gene expression. Cypermethrin and tolyfluanid attenuated cortisol-induced TAT expression. In J774A.1 cells, lambda-cyhalothrin, resmethrin, 3-PBA, o,p'-DDT, p,p'-DDT, p,p'-DDE, methoxychlor- and tolylfluanid-reduced cortisol-stimulated GILZ expression. Furthermore, molecular docking simulation indicated that different interactions may stabilize the binding between molecules and GR. Our findings suggest that comprehensive screening and evaluation of GR antagonists and agonists should be considered to better understand the health and ecological risks of man-made chemicals such as pesticides. PMID- 26647223 TI - Pillowcase Baby: A Laser Teaching Tool for Dermatology Residents. AB - Laser therapy is an important treatment modality in pediatric dermatology, and its efficacy relies on the provider's proper use of the laser device. We describe a simple yet effective teaching tool that can be used to train dermatology residents prior to their using lasers on actual patients. PMID- 26647224 TI - Controlled formation of uniform CeO2 nanoshells in a buffer solution. AB - Uniform CeO2 nanoshells were successfully prepared by using buffer solution as a unique growth medium. The application of this methodology to construct a yolk shell structured Au@CeO2 nanocatalyst shows improved performance for the catalytic CO oxidation. PMID- 26647225 TI - Graphene-Li2S-Carbon Nanocomposite for Lithium-Sulfur Batteries. AB - Lithium sulfide (Li2S) with a high theoretical specific capacity of 1166mAh g(-1) is a promising cathode material for next-generation Li-S batteries with high specific energy. However, low conductivity of Li2S and polysulfide dissolution during cycling are known to limit the rate performance and cycle life of these batteries. Here, we report on the successful development and application of a nanocomposite cathode comprising graphene covered by Li2S nanoparticles and protected from undesirable interactions with electrolytes. We used a modification of our previously reported low cost, scalable, and high-throughput solution-based method to deposit Li2S on graphene. A dropwise infiltration allowed us to keep the size of the heterogeneously nucleated Li2S particles smaller and more uniform than what we previously achieved. This, in turn, increased capacity utilization and contributed to improved rate performance and stability. The use of a highly conductive graphene backbone further increased cell rate performance. A synergetic combination of a protective layer vapor-deposited on the material during synthesis and in situ formed protective surface layer allowed us to retain ~97% of the initial capacity of ~1040 mAh gs(-1) at C/2 after over 700 cycles in the assembled cells. The achieved combination of high rate performance and ultrahigh stability is very promising. PMID- 26647226 TI - Synthesis of the copper chelator TGTA and evaluation of its ability to protect biomolecules from copper induced degradation during copper catalyzed azide-alkyne bioconjugation reactions. AB - One of the most successful bioconjugation strategies to date is the copper(I) catalyzed cycloaddition reaction (CuAAC), however, the typically applied reaction conditions have been found to degrade sensitive biomolecules. Herein, we present a water soluble copper chelator which can be utilized to protect biomolecules from copper induced degradation. PMID- 26647227 TI - Endovascular revascularization of symptomatic chronic middle cerebral artery occlusions: Two case reports. AB - For patients with chronic middle cerebral artery occlusions who have recurrent ischemic symptoms despite antiplatelet therapy and vascular risk factor control, treatment options are limited. Because of concerns about the safety of endovascular revascularization of these occlusions and the technical skills required, these procedures have not been widely performed. We report on two patients with successful endovascular revascularization of the chronic middle cerebral artery occlusion with impaired cerebral hemodynamics, with vessel patency maintained on follow-up imaging and no recurrence of stroke. A literature review of treatment options for such patients was performed. Revascularization is technically feasible and can be considered an option for carefully selected chronic middle cerebral artery occlusion patients with recurrent ischemic symptoms despite medical therapy. PMID- 26647228 TI - A case of two pial arteriovenous fistulas with giant venous pouches treated by endovascular coil embolization: Therapy with and without anticoagulation. AB - BACKGROUND: Endovascular coil embolization of pial arteriovenous fistulas (AVF) has been reported as an effective treatment. However, venous thrombosis and intracranial hemorrhage developing after endovascular occlusion of a pial AVF have not been adequately reported. CASE DESCRIPTION: A 37-year-old man presented with left middle cerebral artery (MCA) AVF and right posterior cerebral artery (PCA) AVF with giant venous pouches. Staged endovascular coil embolization was performed. The MCA AVF was completely occluded by coils at the first stage. Intravenous heparin (3000 IU) was administered during the procedure, and then low molecular weight heparin (subcutaneous injection, 0.4 mL/12 hours) was administered for two days. The PCA AVF was near completely occluded by coils without anticoagulation therapy at the second stage. Rapid progressive venous thrombosis and intracranial hemorrhage were confirmed by computerized tomography brain scan postoperatively, and the patient was then transferred to the neurological intensive care unit for further treatment. Finally, the patient recovered well at the five-month follow-up. CONCLUSIONS: Endovascular occlusion of a high-flow pial AVF with a giant venous pouch resulting in significant blood stasis could precipitate thrombosis in the venous system. Further studies are required to establish whether anticoagulation therapy is necessary. PMID- 26647229 TI - Embolic stroke secondary to spontaneous thrombosis of unruptured intracranial aneurysm: Report of three cases. AB - Intracranial aneurysms uncommonly present with ischemic stroke. Parent artery occlusion due to local extension of the luminal thrombus, aneurysms ejecting emboli to distal arteries, or increased mass effect have been described as possible pathogenic mechanisms. Guidelines for the management of these patients are absent. We present the clinical outcome and radiological characteristics of three patients with spontaneous thrombosis of intracranial aneurysms as a cause of ischemic stroke. This information is relevant given the possible benign history in terms of stroke recurrence and risk of bleeding. PMID- 26647230 TI - NMR characterization of a 72 kDa transcription factor using differential isotopic labeling. AB - NF-kappaB is a major transcription factor that mediates a number of cellular signaling pathways. Crystal structure analysis gives an incomplete picture of the behavior of the protein, particularly in the free state; free monomers or dimers of NF-kappaB have never been crystallized. NMR analysis gives insights into the structure and dynamics of the protein in solution, but a necessary first step is the assignment of resonances. The size of the heterodimer of the Rel homology regions of the NF-kappaB monomers p65 and p50 (72 kDa) prohibits the straightforward use of triple-resonance spectroscopy to obtain the assignments. However, the dynamic nature of the free heterodimer, in particular the independence of the DNA-binding and dimerization domains of each monomer, allows the assignments made on differentially labeled smaller domains to be mapped successfully onto the spectrum of the larger full-length RHR. Problematic areas such as the p65 nuclear localization sequence, which is disordered in the free protein, can be approached by residue-specific labeling and comparison with previously-published spectra of a short peptide with the same sequence. Overall, this NMR analysis of NF-kappaB has given valuable insights into the highly dynamic nature of the free state, which is likely to play an important role in the functional cycle of NF-kappaB in the cell. PMID- 26647231 TI - Does Insight Affect the Efficacy of Antipsychotics in Acute Mania?: An Individual Patient Data Regression Meta-Analysis. AB - Patients having an acute manic episode of bipolar disorder often lack insight into their condition. Because little is known about the possible effect of insight on treatment efficacy, we examined whether insight at the start of treatment affects the efficacy of antipsychotic treatment in patients with acute mania. We used individual patient data from 7 randomized, double-blind, placebo controlled registration studies of 4 antipsychotics in patients with acute mania (N = 1904). Insight was measured with item 11 of the Young Mania Rating Scale (YMRS) at baseline and study endpoint 3 weeks later. Treatment outcome was defined by (a) mean change score, (b) response defined as 50% or more improvement on YMRS, and (c) remission defined as YMRS score less than 8 at study endpoint. We used multilevel mixed effect linear (or logistic) regression analyses of individual patient data to assess the interaction between baseline insight and treatment outcomes. At treatment initiation, 1207 (63.5%) patients had impaired or no insight into their condition. Level of insight significantly modified the efficacy of treatment by mean change score (P = 0.039), response rate (P = 0.033), and remission rate (P = 0.043), with greater improvement in patients with more impaired insight. We therefore recommend that patients experiencing acute mania should be treated immediately and not be delayed until patients regain insight. PMID- 26647232 TI - Analysis of the influence of synthetic paramaters on the structure and physico chemical properties of non-spherical iron oxide nanocrystals and their biological stability and compatibility. AB - In this work, we analyzed the effects of subtle changes in the synthetic conditions and synthetic parameters on the resulting size, shape, monodispersity, crystallinity and magnetic properties of iron oxide nanocrystals (IONCs) obtained through a modified one pot method for the production of mainly cubic-shaped nanoparticles (NPs). Cubic, octahedral and cuboctahedral shapes with different sizes and monodispersity could be obtained by slightly changing the stabilizer/precursor molar ratio, the precursor concentration, the reaction time and temperature and/or the heating rate. Their physical properties were evaluated using high-resolution transmission electron microscopy (HRTEM), X-ray powder diffraction (XRD), selected-area electron diffraction (SAED) and a superconducting quantum interference (SQUID) device. It was found that monodisperse cubic nanocrystals from ca. 25 to 94 nm could be obtained either by changing the precursor concentration, the heating rate or the reaction time. These cubic nanocrystals were ferrimagnetic in the whole temperature rage analyzed, with saturation magnetization values even larger than those of bulk magnetite. In addition, slightly truncated octahedral NPs could be achieved at relatively large heating ramp rates, whereas cubooctahedral NPs were derived by simply increasing the stabilizer/precursor molar ratio. The saturation magnetization of both types of NPs was slightly lower than the cubic ones, but they were still ferrimagnetic in the whole temperature range analyzed. Moreover, transfer to aqueous solution was possible by a ligand exchange with dimercaptosuccinic acid (DMSA) providing, at the same time, chemical groups for additional functionalization if required. The DMSA-coated cubic IONCs were fairly stable in culture medium, allowing their internalization by different cell types. The NPs inside the cells were located in the cytoplasm and most of them showed a perinuclear distribution. Moreover, a great cytocompatibility in a large range of particle concentrations was observed without the induction of morphological changes in the cultured cells. PMID- 26647245 TI - Modulation of the Phosphate-Deficient Responses by MicroRNA156 and its Targeted SQUAMOSA PROMOTER BINDING PROTEIN-LIKE 3 in Arabidopsis. AB - The microRNA156 (miR156)-modulated SQUAMOSA PROMOTER BINDING PROTEIN-LIKE (SPL) is involved in diverse biological processes that include growth, development and metabolism. Here, we report that the Arabidopsis miR156 and SPL3 as regulators play important roles in phosphate (Pi) deficiency response. MiR156 was induced during Pi starvation whereas SPL3 expression was repressed. Phenotypes of reduced rhizosphere acidification and decreased anthocyanin accumulation were observed in 35S:MIM156 (via target mimicry) transgenic plants under Pi deficiency. The content and uptake of Pi in 35S:MIM156 Arabidopsis plants were increased compared with wild-type (Col-0 ecotype) plants. 35S:rSPL3 seedlings showed similar anthocyanin accumulation and Pi content phenotypes to those of 35S:MIM156 plants. Chromatin immunoprecipitation and an electrophoretic mobility shift assay indicated that the SPL3 protein directly bound to GTAC motifs in the PLDZ2, Pht1;5 and miR399f promoters. The expression of several Pi starvation-induced genes was increased in 35S:MIM156 and 35S:rSPL3 plants, including high-affinity Pi transporters, Mt4/TPS1-like genes and phosphatases. Collectively, our results suggest that the miR156-SPL3-Pht1;5 (-PLDZ2 and -miR399f) pathways constitute a component of the Pi deficiency-induced regulatory mechanism of Arabidopsis. PMID- 26647248 TI - Liber Divinorum Operum (Book of Divine Works): Hildegard von Bingen. PMID- 26647249 TI - Lessons Learned From Comics Produced by Medical Students: Art of Darkness. PMID- 26647250 TI - Pimping in Medical Education: Lacking Evidence and Under Threat. PMID- 26647251 TI - Merging the Health System and Education Silos to Better Educate Future Physicians. PMID- 26647252 TI - Incorporating a New Technology While Doing No Harm, Virtually. PMID- 26647253 TI - A PIECE OF MY MIND. The Greatest Generation. PMID- 26647254 TI - The Pedagogy of Pimping: Educational Rigor or Mistreatment? PMID- 26647255 TI - Resident Depression: The Tip of a Graduate Medical Education Iceberg. PMID- 26647256 TI - Charting the Route to High-Value Care: The Role of Medical Education. PMID- 26647257 TI - At What Cost?: Medical Education 2016. PMID- 26647258 TI - Comparison of Intended Scope of Practice for Family Medicine Residents With Reported Scope of Practice Among Practicing Family Physicians. AB - IMPORTANCE: Narrowing of the scope of practice of US family physicians has been well documented. Proposed reasons include changing practice patterns as physicians age, employer restrictions, or generational choices. Determining components of care that remain integral to the practice of family medicine may be informed by assessing gaps between the intended scope of practice of residents and actual scope of practice of family physicians. OBJECTIVE: To compare intended scope of practice for American Board of Family Medicine (ABFM) initial certifiers at residency completion with self-reported actual scope of practice of recertifying family physicians. DESIGN AND PARTICIPANTS: Cross-sectional data were collected from a practice demographic questionnaire completed by all individuals applying to take the ABFM Maintenance of Certification for Family Physicians examination. Initial certifiers reported intentions and recertifiers reported actual provision of specific clinical activities. All physicians who registered for the 2014 ABFM Maintenance of Certification for Family Physicians examination were included: 3038 initial certifiers and 10,846 recertifiers. EXPOSURES: Initially certifying physicians vs recertifying physicians. MAIN OUTCOMES AND MEASURES: The Scope of Practice for Primary Care score (scope score), a psychometric scale, was calculated for each physician and ranged from 0 to 30, with higher numbers equating to broader scope of practice. Recertifiers were categorized by decades in practice. RESULTS: The final sample included 13,884 family physicians and, because the questionnaire was a required component of the examination application, there was a 100% response rate. Mean scope score was significantly higher for initial certifier intended practice compared with recertifying physicians' reported actual practices (17.7 vs 15.5; difference, 2.2 [95% CI, 2.1-2.3]; P < .001). Compared with recertifiers, initial certifiers were more likely to report intending to provide all clinical services asked except pain management; this included obstetric care (23.7% vs 7.7%; difference, 16.0% [95% CI, 14.4%-17.6%]; P < .001), inpatient care (54.9% vs 33.5%; difference, 21.4% [95% CI, 19.4%-23.4%]; P < .001), and prenatal care (50.2% vs 9.9%; difference, 40.3 [95% CI, 38.5%-42.2%]; P < .001). Similar differences from initial certifiers were present when comparisons were limited to recertifiers in practice for only 1 to 10 years. CONCLUSIONS AND RELEVANCE: In this study of family physicians taking ABFM examinations, graduating family medicine residents reported an intention to provide a broader scope of practice than that reported by current practitioners. This pattern suggests that these differences are not generational, but whether they are due to limited practice support, employer constraints, or other causes remains to be determined. PMID- 26647260 TI - Training Physicians to Provide High-Value, Cost-Conscious Care: A Systematic Review. AB - IMPORTANCE: Increasing health care expenditures are taxing the sustainability of the health care system. Physicians should be prepared to deliver high-value, cost conscious care. OBJECTIVE: To understand the circumstances in which the delivery of high-value, cost-conscious care is learned, with a goal of informing development of effective educational interventions. DATA SOURCES: PubMed, EMBASE, ERIC, and Cochrane databases were searched from inception until September 5, 2015, to identify learners and cost-related topics. STUDY SELECTION: Studies were included on the basis of topic relevance, implementation of intervention, evaluation of intervention, educational components in intervention, and appropriate target group. There was no restriction on study design. DATA EXTRACTION AND SYNTHESIS: Data extraction was guided by a merged and modified version of a Best Evidence in Medical Education abstraction form and a Cochrane data coding sheet. Articles were analyzed using the realist review method, a narrative review technique that focuses on understanding the underlying mechanisms in interventions. Recurrent patterns were identified in the data through thematic analyses. Resulting themes were discussed within the research team until consensus was reached. MAIN OUTCOMES AND MEASURES: Main outcomes were factors that promote education in delivering high-value, cost-conscious care. FINDINGS: The initial search identified 2650 articles; 79 met the inclusion criteria, of which 14 were randomized clinical trials. The majority of the studies were conducted in North America (78.5%) using a pre-post interventional design (58.2%; at least 1619 participants); they focused on practicing physicians (36.7%; at least 3448 participants), resident physicians (6.3%; n = 516), and medical students (15.2%; n = 275). Among the 14 randomized clinical trials, 12 addressed knowledge transmission, 7 reflective practice, and 1 supportive environment; 10 (71%) concluded that the intervention was effective. The data analysis suggested that 3 factors aid successful learning: (1) effective transmission of knowledge, related, for example, to general health economics and prices of health services, to scientific evidence regarding guidelines and the benefits and harms of health care, and to patient preferences and personal values (67 articles); (2) facilitation of reflective practice, such as providing feedback or asking reflective questions regarding decisions related to laboratory ordering or prescribing to give trainees insight into their past and current behavior (56 articles); and (3) creation of a supportive environment in which the organization of the health care system, the presence of role models of delivering high-value, cost-conscious care, and a culture of high-value, cost-conscious care reinforce the desired training goals (27 articles). CONCLUSIONS AND RELEVANCE: Research on educating physicians to deliver high-value, cost-conscious care suggests that learning by practicing physicians, resident physicians, and medical students is promoted by combining specific knowledge transmission, reflective practice, and a supportive environment. These factors should be considered when educational interventions are being developed. PMID- 26647261 TI - Integrating Addiction Services Into General Medicine. PMID- 26647259 TI - Prevalence of Depression and Depressive Symptoms Among Resident Physicians: A Systematic Review and Meta-analysis. AB - IMPORTANCE: Physicians in training are at high risk for depression. However, the estimated prevalence of this disorder varies substantially between studies. OBJECTIVE: To provide a summary estimate of depression or depressive symptom prevalence among resident physicians. DATA SOURCES AND STUDY SELECTION: Systematic search of EMBASE, ERIC, MEDLINE, and PsycINFO for studies with information on the prevalence of depression or depressive symptoms among resident physicians published between January 1963 and September 2015. Studies were eligible for inclusion if they were published in the peer-reviewed literature and used a validated method to assess for depression or depressive symptoms. DATA EXTRACTION AND SYNTHESIS: Information on study characteristics and depression or depressive symptom prevalence was extracted independently by 2 trained investigators. Estimates were pooled using random-effects meta-analysis. Differences by study-level characteristics were estimated using meta-regression. MAIN OUTCOMES AND MEASURES: Point or period prevalence of depression or depressive symptoms as assessed by structured interview or validated questionnaire. RESULTS: Data were extracted from 31 cross-sectional studies (9447 individuals) and 23 longitudinal studies (8113 individuals). Three studies used clinical interviews and 51 used self-report instruments. The overall pooled prevalence of depression or depressive symptoms was 28.8% (4969/17,560 individuals, 95% CI, 25.3%-32.5%), with high between-study heterogeneity (Q = 1247, tau2 = 0.39, I2 = 95.8%, P < .001). Prevalence estimates ranged from 20.9% for the 9-item Patient Health Questionnaire with a cutoff of 10 or more (741/3577 individuals, 95% CI, 17.5%-24.7%, Q = 14.4, tau2 = 0.04, I2 = 79.2%) to 43.2% for the 2-item PRIME-MD (1349/2891 individuals, 95% CI, 37.6%-49.0%, Q = 45.6, tau2 = 0.09, I2 = 84.6%). There was an increased prevalence with increasing calendar year (slope = 0.5% increase per year, adjusted for assessment modality; 95% CI, 0.03%-0.9%, P = .04). In a secondary analysis of 7 longitudinal studies, the median absolute increase in depressive symptoms with the onset of residency training was 15.8% (range, 0.3%-26.3%; relative risk, 4.5). No statistically significant differences were observed between cross-sectional vs longitudinal studies, studies of only interns vs only upper-level residents, or studies of nonsurgical vs both nonsurgical and surgical residents. CONCLUSIONS AND RELEVANCE: In this systematic review, the summary estimate of the prevalence of depression or depressive symptoms among resident physicians was 28.8%, ranging from 20.9% to 43.2% depending on the instrument used, and increased with calendar year. Further research is needed to identify effective strategies for preventing and treating depression among physicians in training. PMID- 26647262 TI - Interventions for Rosacea. AB - CLINICAL QUESTION: Which interventions are associated with highest efficacy and fewest adverse events for treating rosacea? BOTTOM LINE: There is high-quality evidence that topical brimonidine, azelaic acid, and ivermectin, as well as oral doxycycline and isotretinoin, are associated with improvements in rosacea. Lower quality evidence is available for topical metronidazole, oral tetracycline, laser and light-based therapy, and topical cyclosporine for ocular rosacea. Most treatments are not associated with higher adverse event rates than placebo. PMID- 26647263 TI - Hyperkalemia. PMID- 26647264 TI - Placement of US Medical School Graduates Into Graduate Medical Education, 2005 Through 2015. PMID- 26647265 TI - Medical Students in the Emergency Department and Patient Length of Stay. PMID- 26647266 TI - Initial Interventions for Out-of-Hospital Cardiac Arrest. PMID- 26647267 TI - Network Adequacy Standards and Health Insurance. PMID- 26647268 TI - Initial Interventions for Out-of-Hospital Cardiac Arrest--Reply. PMID- 26647269 TI - Incorrect P Value. PMID- 26647270 TI - Missing Article. PMID- 26647271 TI - Network Adequacy Standards and Health Insurance--Reply. PMID- 26647273 TI - To the Young Doctors of 1895. PMID- 26647274 TI - Medical Schools in the United States, 2014-2015. PMID- 26647275 TI - Graduate Medical Education, 2014-2015. PMID- 26647276 TI - JAMA PATIENT PAGE. High-Value Care. PMID- 26647278 TI - Experimental Detection of Branching at a Conical Intersection in a Highly Fluorescent Molecule. AB - Conical intersections are molecular configurations at which adiabatic potential energy surfaces touch. They are predicted to be ubiquitous, yet condensed-phase experiments have focused on the few systems with clear spectroscopic signatures of negligible fluorescence, high photoactivity, or femtosecond electronic kinetics. Although rare, these signatures have become diagnostic for conical intersections. Here we detect a coherent surface-crossing event nearly two picoseconds after optical excitation in a highly fluorescent molecule that has no photoactivity and nanosecond electronic kinetics. Time-frequency analysis of high sensitivity measurements acquired using sub-8 fs pulses reveals phase shifts of the signal due to branching of the wavepacket through a conical intersection. The time-frequency analysis methodology demonstrated here on a model compound will enable studies of conical intersections in molecules that do not exhibit their diagnostic signatures. Improving the ability to detect conical intersections will enrich the understanding of their mechanistic role in molecular photochemistry. PMID- 26647277 TI - Pneumococcal serotype distribution in adults with invasive disease and in carrier children in Italy: Should we expect herd protection of adults through infants' vaccination? AB - The 7-valent pneumococcal conjugate vaccine (PCV7) produced a significant herd protection in unvaccinated adult population mostly because of pneumococcus carriage decrease in vaccinated children. It is not known if the 13-valent pneumococcal vaccine can give similar effect on adults. Aims of the work were to evaluate whether the 6 additional serotypes are present in nasopharynx of children and serotype distribution in invasive pneumococcal infections (IPD) in adults. Realtime-PCR was used to evaluate pneumococcal serotypes in adults with confirmed IPD and in nasopharyngeal swabs (NP) from 629 children not vaccinated or vaccinated with PCV7 and resident in the same geographical areas. Two hundred twenty-one patients (116 males, median 67.9 years) with IPD were studied (pneumonia n = 103, meningitis n = 61 sepsis n = 50, other n = 7). Two hundred twelve were serotyped. The most frequent serotypes were 3, (31/212; 14.6%), 19A, (19/212; 9.0%), 12 (17/212; 8.0%), 7F, (14/212; 6.6%). In NP of children, the frequency of those serotypes causing over 50% of IPD in adults was very low, ranging from 0.48% for serotype 7F to 7.9% for serotype 19A. On the other side serotype 5, very frequent in NP (18.7%) caused <1% IPD. In conclusion serotypes causing IPD in adults are very rarely found in children NP. We suggest that herd protection obtainable with the additional 6 serotypes included in PCV13 may be more limited than that demonstrated with PCV7 in the past. In order to reduce the burden of disease in adults, adults should be offered a specific vaccination program with highly immunogenic PCV. PMID- 26647279 TI - Cryptotanshinone inhibits oxidized LDL-induced adhesion molecule expression via ROS dependent NF-kappaB pathways. AB - Adhesion molecules, such as intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin, play important roles in the initial stage of atherosclerosis. Cryptotanshinone (CPT), a natural compound isolated from Salvia miltiorrhiza Bunge, exhibits anti-atherosclerotic activity although the underlying mechanisms remain elusive. In this study, the protective effect of CPT against oxidized low-density lipoprotein (ox-LDL)-induced adhesion molecule expression was investigated in human umbilical vein endothelial cells. Ox-LDL significantly induced ICAM-1, VCAM-1, and E-selectin expression at the mRNA and protein levels but reduced eNOS phosphorylation and NO generation, which were reversed by CPT pretreatment. Sodium nitroprusside, a NO donor, N-acetyl-L cysteine (NAC), a reactive oxygen species (ROS) scavenger, and BAY117082, a NF kappaB inhibitor, inhibited ox-LDL-induced ICAM-1, VCAM-1, and E-selectin expression. Ox-LDL-induced ROS production was significantly inhibited by CPT and NAC. Furthermore, ox-LDL activated the NF-kappaB signaling pathway by inducing phosphorylation of IKKbeta and IkappaBalpha, promoting the interaction of IKKbeta and IkappaBalpha, and increasing p65 nuclear translocation, which were significantly inhibited by CPT. In addition, CPT, NAC, and BAY117082 inhibited ox LDL-induced membrane expression of ICAM-1, VCAM-1, E-selectin, and endothelial monocyte adhesion and restored eNOS phosphorylation and NO generation. Results suggested that CPT inhibited ox-LDL-induced adhesion molecule expression by decreasing ROS and inhibiting the NF-kappaB pathways, which provides new insight into the anti-atherosclerotic mechanism of CPT. PMID- 26647280 TI - Solubilization of myofibrillar proteins in water or low ionic strength media: Classical techniques, basic principles, and novel functionalities. AB - The qualitative characteristics of meat products are closely related to the functionality of muscle proteins. Myofibrillar proteins (MPs), comprising approximately 50% of total muscle proteins, are generally considered to be insoluble in solutions of low ionic strength (< 0.2 M), requiring high concentrations of salt (> 0.3 M) for solubilization. These soluble proteins are the ones which determine many functional properties of meat products, including emulsification and thermal gelation. In order to increase the utilization of meat and meat products, many studies have investigated the solubilization of MPs in water or low ionic strength media and determining their functionality. However, there still remains a lack of systematic information on the functional properties of MPs solubilized in this manner. Hence, this review will explore some typical techniques that have been used. The main procedures used for their solubilization, the fundamental principles and their functionalities in water (low ionic strength medium) are comprehensively discussed. In addition, advantages and disadvantages of each technique are summarized. Finally, future considerations are presented to facilitate progress in this new area and to enable water soluble muscle MPs to be utilized as novel meat ingredients in the food industry. PMID- 26647281 TI - Therapeutic Vaccination With Dendritic Cells Loaded With Autologous HIV Type 1 Infected Apoptotic Cells. AB - BACKGROUND: We report the results of a phase I/II, open-label, single-arm clinical trial to evaluate the safety and anti-human immunodeficiency virus type 1 (HIV-1) efficacy of an autologous dendritic cell (DC)-based HIV-1 vaccine loaded with autologous HIV-1-infected apoptotic cells. METHODS: Antiretroviral therapy (ART)-naive individuals were enrolled, and viremia was suppressed by ART prior to delivery of 4 doses of DC-based vaccine. Participants underwent treatment interruption 6 weeks after the third vaccine dose. The plasma HIV-1 RNA level 12 weeks after treatment interruption was compared to the pre-ART (ie, baseline) level. RESULTS: The vaccine was safe and well tolerated but did not prevent viral rebound during treatment interruption. Vaccination resulted in a modest but significant decrease in plasma viremia from the baseline level (from 4.53 log10 copies/mL to 4.27 log10 copies/mL;P= .05). Four of 10 participants had a >0.70 log10 increase in the HIV-1 RNA load in plasma following vaccination, despite continuous ART. Single-molecule sequencing of HIV-1 RNA in plasma before and after vaccination revealed increases in G>A hypermutants in gag and pol after vaccination, which suggests cytolysis of infected cells. CONCLUSIONS: A therapeutic HIV-1 vaccine based on DCs loaded with apoptotic bodies was safe and induced T-cell activation and cytolysis, including HIV-1-infected cells, in a subset of study participants. CLINICAL TRIALS REGISTRATION: NCT00510497. PMID- 26647282 TI - Impaired antiviral response of adenovirus-transformed cell lines supports virus replication. AB - Activation of the innate immune response represents one of the most important cellular mechanisms to limit virus replication and spread in cell culture. Here, we examined the effect of adenoviral gene expression on the antiviral response in adenovirus-transformed cell lines; HEK293, HEK293SF and AGE1.HN. We demonstrate that the expression of the early region protein 1A in these cell lines impairs their ability to activate antiviral genes by the IFN pathway. This property may help in the isolation of newly emerging viruses and the propagation of interferon sensitive virus strains. PMID- 26647283 TI - Noncoding RNAs and their functional involvement in regulation of chronic myeloid leukemia. AB - Noncoding RNAs (ncRNAs) comprise multiple classes of transcripts that have no protein-coding ability but play critical roles as RNA regulators in various cellular processes. To date, the well-studied ncRNAs are microRNAs (miRs) that generally act as regulators of gene expression through binding to target mRNAs. Recent advances in high-throughput sequencing technologies have led to the discovery of thousands of unannotated noncoding transcripts, especially long noncoding RNAs (lncRNAs). These lncRNAs are being increasingly recognized as key regulators in diverse biological processes via a variety of mechanisms. Aberrant expression of miRs and lncRNAs has been shown to be associated with many human diseases and cancers. Increasing ncRNAs have been identified as biomarkers for patient prognosis and potential therapeutic agents for cancers. Furthermore, it is worth noting that progresses have been made in understanding the functional involvement of ncRNAs in Bcr-Abl-induced chronic myeloid leukemia (CML). Here, we highlight the pathogenesis of CML, functional significance of miRs and lncRNAs in regulation of CML development and involved mechanisms underlying their action. PMID- 26647284 TI - AIE-Active Fluorene Derivatives for Solution-Processable Nondoped Blue Organic Light-Emitting Devices (OLEDs). AB - A series of fluorene derivatives end-capped with diphenylamino and oxadiazolyl were synthesized, and their photophysical and electrochemical properties are reported. Aggregation-induced emission (AIE) effects were observed for the materials, and bipolar characteristics of the molecules are favored with measurement of carrier mobility and calculation of molecular orbitals using density functional theory (DFT). Using the fluorene derivatives as emitting layer, nondoped organic light-emitting devices (OLEDs) have been fabricated by spin-coating in the configuration ITO/PEDOT:PSS(35 nm)/PVK(15 nm)/PhN-OF(n) Oxa(80 nm)/SPPO13(30 nm)/Ca(8 nm)/Al(100 nm) (n = 2-4). The best device with PhN OF(2)-Oxa exhibits a maximum luminance of 14 747 cd/m(2), a maximum current efficiency of 4.61 cd/A, and an external quantum efficiency (EQE) of 3.09% in the blue region. Investigation of the correlation between structures and properties indicates that there is no intramolecular charge transfer (ICT) increase in these molecules with the increase of conjugation length. The device using material of the shortest conjugation length as emitting-layer gives the best electroluminescent (EL) performances in this series of oligofluorenes. PMID- 26647285 TI - Bridging the gap between PAT concepts and implementation: An integrated software platform for fermentation. AB - Bioreactor control significantly impacts both the amount and quality of the product being manufactured. The complexity of the control strategy that is implemented increases with reactor size, which may vary from thousands to tens of thousands of litres in commercial manufacturing. The Process Analytical Technology (PAT) initiative has highlighted the need for having robust monitoring tools and effective control schemes that are capable of taking real time information about the critical quality attributes (CQA) and the critical process parameters (CPP) and executing immediate response as soon as a deviation occurs. However, the limited flexibility that present commercial software packages offer creates a hurdle. Visual programming environments have gradually emerged as potential alternatives to the available text based languages. This paper showcases development of an integrated programme using a visual programming environment for a Sartorius BIOSTAT(r) B Plus 5L bioreactor through which various peripheral devices are interfaced. The proposed programme facilitates real-time access to data and allows for execution of control actions to follow the desired trajectory. Major benefits of such integrated software system include: (i) improved real time monitoring and control; (ii) reduced variability; (iii) improved performance; (iv) reduced operator-training time; (v) enhanced knowledge management; and (vi) easier PAT implementation. PMID- 26647286 TI - A new phenolic derivative with soluble epoxide hydrolase and nuclear factor kappaB inhibitory activity from the aqueous extract of Acacia catechu. AB - One novel phenolic compound, (4S,5R)-4-(3,4-dihydroxyphenyl)-5-(3 oxobutyl)dihydrofuran-2(3H)-one (1), as well as 12 known compounds (2-13) was obtained from the aqueous extract of Acacia catechu and their chemical structures were determined by spectroscopic analysis. Compounds 8 and 9 exhibited significant soluble epoxide hydrolase (sEH) inhibitory activities with IC50 values of 26.6 +/- 0.5 and 24.4 +/- 5.6 MUM, respectively. Compounds 7-10 showed significant inhibitory effects on TNFalpha-induced nuclear factor kappa B (NF kappaB) transcriptional activity in a dose-dependent manner, with IC50 values ranging from 11.15 to 19.45 MUM. PMID- 26647287 TI - Determination of multiple toxins in whelk and clam samples collected from the Chukchi and Bering seas. AB - Buccinidae whelk Neptunea varicifera (Dall), Cardiidae clam Serripes laperousii (Deshayes), and two unknown species of whelk and clam were collected from the Arctic Chukchi Sea and sub-Arctic Bering Sea in July 2014. In this study, the mollusk samples were analyzed by different liquid chromatography-tandem quadrupole mass spectrometry (LC-MS/MS) methods for multiple shellfish toxins, including okadaic acid (OA), pectenotoxin (PTX), yessotoxin (YTX), azaspiracid (AZA), cyclic imines (CI), and saxitoxin (STX) groups. PTX2 (~2.0 MUg kg(-1) whole tissues) was detected exclusively in the clam S. laperousii collected from the Chukchi Sea. OA and dinophysistoxin-1 (DTX1) were restricted to mollusk samples collected from the Bering Sea, and OA was the dominant component of the whelk N. varicifera (63 MUg kg(-1) digestive gland) and an unknown species of whelk (6.8 MUg kg(-1) digestive gland). Spirolide-1 (SPX1) was confirmed in most samples except for the whelk N. varicifera collected from the Bering Sea. The highest content of SPX1 (~18.5 MUg kg(-1) digestive gland) occurred in the whelk N. varicifera collected from the Chukchi Sea, along with the suspected presence of SPX-C, SPX-D and didesMe-SPX-C. YTX, as well as its derivatives 45-OH-YTX and 45,46,47-Trinor-YTX, were found in all samples, with the highest YTX content (66 MUg kg(-1) digestive gland) present in the whelk N. varicifera collected from the Chukchi Sea. Interestingly, STX and dcSTX were measured only in the whelk N. varicifera and unknown species of clam collected from the Chukchi Sea. No AZA group toxins, gymnodimine (GYM), or pinnatoxin G were found in any samples analyzed. Results demonstrated that the mollusk samples were contaminated by multiple shellfish toxins in the Chukchi and Bering seas. This study highlights the need to monitor potentially toxic microalgae in the Arctic and sub-Arctic regions, as well as species of mollusk that may be included in future commercial or subsistence harvests. PMID- 26647288 TI - Potential impacts of blooms of the toxic dinoflagellate Karenia brevis on the growth, survival and juvenile recruitment of the non-native green mussel Perna viridis in southeastern United States. AB - Red tide blooms formed by Karenia brevis are frequent along the Gulf coast of Florida and it is unclear what tolerance the green mussel Perna viridis, a recently introduced species to coastal waters, has toward these events. Established populations of P. viridis were monitored along the coastal waters of Estero Bay, Florida before, during and following two consecutive red tide blooms to assess the potential effects on growth, survival and juvenile recruitment. Upon onset of the bloom, growth rates fell from 6 to 10 mm month(-1) (March 2011 November 2011) to less than 3 mm month(-1). In the succeeding years, K. brevis blooms were present, and average growth of individually tagged mussels remained below 3 mm month(-1). During growth monitoring the use of calcein as an internal marker was tested with positive staining results and no observed effect on growth or survival. In March 2012, following the first red tide bloom, a population-wide mortality event was observed. Following this event, increased mortality rates were observed with peaks during onset of the bloom in the fall of 2012 and 2013. Juvenile recruitment was also limited during years in which blooms persisted into the spring spawning period suggesting gamete and/or larval sensitivity to K. brevis. Although it cannot be conclusively determined that the cause of reduced growth and survival is due to red tide events, the parallels observed suggest that K. brevis is a factor in the observed changes in population structure. PMID- 26647289 TI - Risk and outcomes of invasive pneumococcal disease in adults with underlying conditions in the post-PCV7 era, The Netherlands. AB - BACKGROUND: Immunocompromising conditions and advanced age (>=65 years) are associated with a high risk for invasive pneumococcal disease (IPD). We investigated the risk and outcomes of IPD in adults with underlying conditions in the post-PCV7 era in The Netherlands. METHODS: IPD data from 2008 to 2012 was obtained from the national pneumococcal surveillance system, covering 25% of the Dutch population. Population estimates of underlying conditions were derived from the primary care data (2012). IPD incidence in adults with immunocompromising conditions (high risk group) and non-immunocompromising comorbidities (medium risk group) were compared to the "normal risk group" without diagnosed comorbidities. Case-fatality and ICU admission in the different risk groups was analyzed by logistic regression. Serotype specific propensities to affect high risk group IPD patients were calculated. RESULTS: Adults with a high risk condition have a 18-fold (95% CI 15.6-21.2) and 3-fold (95% CI 2.6-3.9) higher risk compared to the normal risk group for IPD at age 18-64 years and 65 years and older, respectively. In case of a medium risk condition, the risk is 5-fold (95% CI 4.3-5.7) and 2-fold (95% CI 1.9-2.6) higher in age groups 18-64 and >=65 years old. Likewise, IPD patients with a high or medium risk condition have a higher case-fatality (after adjustment for age, odds ratio: 2-fold (95% CI 1.5 3.5) and 1.4-fold (95% CI 1.0-2.1), respectively). Several serotypes (e.g. 6A, 6B, 23A and 23B) are associated with a significantly higher propensity to cause disease in high risk patients. CONCLUSIONS: The risk for IPD and death in the post-PCV7 era has remained considerably high in adults and elderly with underlying conditions. The identification of serotypes with a high propensity to affect risk groups can be important for selecting (future) vaccine serotypes. PMID- 26647290 TI - Use of mobile phones for improving vaccination coverage among children living in rural hard-to-reach areas and urban streets of Bangladesh. AB - In Bangladesh, full vaccination rates among children living in rural hard-to reach areas and urban streets are low. We conducted a quasi-experimental pre-post study of a 12-month mobile phone intervention to improve vaccination among 0-11 months old children in rural hard-to-reach and urban street dweller areas. Software named "mTika" was employed within the existing public health system to electronically register each child's birth and remind mothers about upcoming vaccination dates with text messages. Android smart phones with mTika were provided to all health assistants/vaccinators and supervisors in intervention areas, while mothers used plain cell phones already owned by themselves or their families. Pre and post-intervention vaccination coverage was surveyed in intervention and control areas. Among children over 298 days old, full vaccination coverage actually decreased in control areas--rural baseline 65.9% to endline 55.2% and urban baseline 44.5% to endline 33.9%--while increasing in intervention areas from rural baseline 58.9% to endline 76*8%, difference +18.8% (95% CI 5.7-31.9) and urban baseline 40.7% to endline 57.1%, difference +16.5% (95% CI 3.9-29.0). Difference-in-difference (DID) estimates were +29.5% for rural intervention versus control areas and +27.1% for urban areas for full vaccination in children over 298 days old, and logistic regression adjusting for maternal education, mobile phone ownership, and sex of child showed intervention effect odds ratio (OR) of 3.8 (95% CI 1.5-9.2) in rural areas and 3.0 (95% CI 1.4-6.4) in urban areas. Among all age groups, intervention effects on age-appropriate vaccination coverage were positive: DIDs +13.1-30.5% and ORs 2.5-4.6 (p<0.001 in all comparisons). Qualitative data showed the intervention was well-accepted. Our study demonstrated that a mobile phone intervention can improve vaccination coverage in rural hard-to-reach and urban street dweller communities in Bangladesh. This small-scale successful demonstration should serve as an example to other low-income countries with high mobile phone usage. PMID- 26647292 TI - Continuous manufacturing and process analytical tools. PMID- 26647291 TI - RPD3 histone deacetylase and nutrition have distinct but interacting effects on Drosophila longevity. AB - Single-gene mutations that extend longevity have revealed regulatory pathways related to aging and longevity. RPD3 is a conserved histone deacetylase (Class I HDAC). Previously we showed that Drosophila rpd3 mutations increase longevity. Here we tested the longevity effects of RPD3 on multiple nutrient levels. Dietary restriction (DR) has additive effects on RPD3-mediated longevity extension, but the effect may be modestly attenuated relative to controls. RPD3 and DR therefore appear to operate by distinct but interacting mechanisms. Since RPD3 regulates transcription, the mRNA levels for two proteins involved in nutrient signaling, 4E-BP and Tor, were examined in rpd3 mutant flies. 4E-BP mRNA was reduced under longevity-increasing conditions. Epistasis between RPD3 and 4E-BP with regard to longevity was then tested. Flies only heterozygous for a mutation in Thor, the 4E BP gene, have modestly decreased life spans. Flies mutant for both rpd3 and Thor show a superposition of a large RPD3-mediated increase and a small Thor-mediated decrease in longevity at all food levels, consistent with each gene product having distinct effects on life span. However, DR-mediated extension was absent in males carrying both mutations and lessened in females. Our results support the view that multiple discrete but interacting mechanisms regulate longevity. PMID- 26647293 TI - Sulfur amino acids and atherosclerosis: a role for excess dietary methionine. AB - The homocysteine theory of arteriosclerosis received credence when it was shown that after a methionine load, circulating homocysteine-cysteine concentrations were higher in cardiovascular disease patients than in healthy controls. Subsequent studies showing associations between homocysteine and coronary artery disease, stroke and cognitive impairment, relied on small increases in homocysteine concentration unlike the very high homocysteine seen in the rare genetic disorders that lead to homocystinuria and much higher homocysteine levels. Subsequent studies in cell culture, animals, and humans showed that a variety of cardiovascular adverse effects of "high homocysteine" introduced either as a nonphysiological bolus or as a methionine load led to high homocysteine. We fed apolipoprotein E-deficient mice diets designed to achieve three conditions: (1) high methionine intake with normal blood homocysteine, (2) high methionine intake with B vitamin deficiency and hyperhomocysteinemia, and (3) normal methionine intake with both B vitamin deficiency and hyperhomocysteinemia. We found that the mice fed methionine-rich diets had significant atheromatous pathology in the aortic arch even with normal plasma homocysteine levels. Mice fed B vitamin-deficient diets developed severe hyperhomocysteinemia but without any increase in vascular pathology. Our findings suggest that even moderate increases in methionine intake are atherogenic in susceptible mice while high plasma homocysteine is not. PMID- 26647295 TI - A high-quality round-shaped monolayer MoS2 domain and its transformation. AB - MoS2 is widely used in many fields including spin-valleytronics, logic transistors, light emitting devices, clean energy and biology. However, controllable synthesis of two-dimensional MoS2 sheets remains a great challenge. We report the formation of round-shaped monolayer MoS2 domains with a tunable size and the shape transformation from triangle to round. A qualitative interpretation of the formation mechanism is presented and the process can be controlled by either a thermodynamic or a kinetic growth regime depending on the growth rate. The round-shaped MoS2 domains show a high electron mobility of 1.39 cm(2) V(-1) s(-1), comparable to the mechanically exfoliated counterparts. Our study reveals the dominant factors that influence the synthesis of MoS2 and improves our understanding of the nucleation and growth mechanisms of MoS2, towards fine control over the synthesis of MoS2 and other TMDs. PMID- 26647294 TI - High-density genetic map construction and gene mapping of pericarp color in wax gourd using specific-locus amplified fragment (SLAF) sequencing. AB - BACKGROUND: High-density map is a valuable tool for genetic and genomic analysis. Although wax gourd is a widely distributed vegetable of Cucurbitaceae and has important medicinal and health value, no genetic map has been constructed because of the lack of efficient markers. Specific-locus amplified fragment sequencing (SLAF-seq) is a newly developed high-throughput strategy for large-scale single nucleotide polymorphism (SNP) discovery and genotyping. RESULTS: In our present study, we constructed a high-density genetic map by using SLAF-seq and identified a locus controlling pericarp color in wax gourd. An F2 population of 140 individuals and their two parents were subjected to SLAF-seq. A total of 143.38 M pair-end reads were generated. The average sequencing depth was 26.51 in the maternal line (B214), 27.01 in the parental line (B227), and 5.11 in each F2 individual. When filtering low-depth SLAF tags, a total of 142,653 high-quality SLAFs were detected, and 22,151 of them were polymorphic, with a polymorphism rate of 15.42 %. And finally, 4,607 of the polymorphic markers were selected for genetic map construction, and 12 linkage groups (LGs) were generated. The map spanned 2,172.86 cM with an average distance between adjacent markers for 0.49 cM. The inheritance of pericarp color was also studied, which showed that the pericarp color was controlled by one single gene. And based on the newly constructed high-density map, a single locus locating on chromosome 5 was identified for controlling the pericarp color of wax gourd. CONCLUSIONS: This is the first report of high-density genetic map construction and gene mapping in wax gourd, which will be served as an invaluable tool for gene mapping, marker assisted breeding, map-based gene cloning, comparative mapping and draft genome assembling of wax gourd. PMID- 26647296 TI - Near-global freshwater-specific environmental variables for biodiversity analyses in 1 km resolution. AB - The lack of freshwater-specific environmental information at sufficiently fine spatial grain hampers broad-scale analyses in aquatic biology, biogeography, conservation, and ecology. Here we present a near-global, spatially continuous, and freshwater-specific set of environmental variables in a standardized 1 km grid. We delineate the sub-catchment for each grid cell along the HydroSHEDS river network and summarize the upstream climate, topography, land cover, surface geology and soil to each grid cell using various metrics (average, minimum, maximum, range, sum, inverse distance-weighted average and sum). All variables were subsequently averaged across single lakes and reservoirs of the Global lakes and Wetlands Database that are connected to the river network. Monthly climate variables were summarized into 19 long-term climatic variables following the 'bioclim' framework. This new set of variables provides a basis for spatial ecological and biodiversity analyses in freshwater ecosystems at near global extent, yet fine spatial grain. To facilitate the generation of freshwater variables for custom study areas and spatial grains, we provide the 'r.stream.watersheds' and 'r.stream.variables' add-ons for the GRASS GIS software. PMID- 26647297 TI - Comment on "Thermo activated persulfate oxidation of antibiotic sulfamethoxazole and structurally related compounds" by Yuefei Ji et al. [Water Res. 87 (2015) 1 9]. PMID- 26647298 TI - Management of eutrophication in Lake De Kuil (The Netherlands) using combined flocculant - Lanthanum modified bentonite treatment. AB - Eutrophication of Lake De Kuil (The Netherlands, 6.7 ha, maximum depth 9 m) has frequently caused cyanobacterial blooms resulting in swimming bans or the issue of water quality warnings during summer. The eutrophication was mainly driven by sediment phosphorus (P)-release. The external P-loading was in the range of the critical loading for phytoplankton blooms. Hence, the reduction of the internal P loading provided a promising way to reduce cyanobacterial blooms. To mitigate the cyanobacterial blooms, the combination of a low dose flocculant (iron(III)chloride; Flock) and a solid phase phosphate fixative (lanthanum modified bentonite; Lock) was applied in May 2009. This combined approach both removed cyanobacterial biomass from the water column and also intercepted P released from the bottom sediments. Immediately after treatment, the Secchi depth increased from 1.5 m up to 5 m. Sediment P-release decreased from 5.2 mg P m(-2) d(-1) (2009) to 0.4 mg P m(-2) d(-1) (2010) but increased in later years. Mean summer concentrations of total P decreased from 0.05 mg L(-1) (1992-2008) to 0.02 mg L(-1) (2009-2014) and chlorophyll-a from 16 MUg L(-1) (1992-2008) to 6 MUg L( 1) (2009-2014). Mean summer Secchi depth increased from 2.31 m (1992-2008) to 3.12 m (2009-2014). The coverage of macrophytes tripled from 2009 to 2011. In the winter of 2010/2011 Planktothrix rubescens bloomed, but cyanobacterial biomass decreased during the summers after the Flock and Lock treatment in comparison to prior years. After the Flock & Lock the bathing water requirements have been fulfilled for six consecutive summers. As the sediment P-release has gradually increased in recent years, there is a risk of a reversion from the present mesotrophic state to a eutrophic state. PMID- 26647300 TI - Secukinumab (AIN-457) for the treatment of Psoriasis. AB - Secukinumab (also known as AIN-457) is a human monoclonal antibody targeting IL 17A, which has been recently FDA-approved for the treatment of moderate to severe psoriasis and psoriatic arthritis with coexistent moderate to severe plaque psoriasis based on clinical trials demonstrating excellent efficacy. This review will address the rationale for targeting the IL-23/Th17/IL-17 axis, the role of IL-17 and Th17 cells in psoriasis and other chronic inflammatory diseases, and will examine pre-clinical studies, pharmacologic properties, clinical efficacy, and the safety profile of secukinumab. PMID- 26647299 TI - Escape from Lethal Bacterial Competition through Coupled Activation of Antibiotic Resistance and a Mobilized Subpopulation. AB - Bacteria have diverse mechanisms for competition that include biosynthesis of extracellular enzymes and antibiotic metabolites, as well as changes in community physiology, such as biofilm formation or motility. Considered collectively, networks of competitive functions for any organism determine success or failure in competition. How bacteria integrate different mechanisms to optimize competitive fitness is not well studied. Here we study a model competitive interaction between two soil bacteria: Bacillus subtilis and Streptomyces sp. Mg1 (S. Mg1). On an agar surface, colonies of B. subtilis suffer cellular lysis and progressive degradation caused by S. Mg1 cultured at a distance. We identify the lytic and degradative activity (LDA) as linearmycins, which are produced by S. Mg1 and are sufficient to cause lysis of B. subtilis. We obtained B. subtilis mutants spontaneously resistant to LDA (LDAR) that have visibly distinctive morphology and spread across the agar surface. Every LDAR mutant identified had a missense mutation in yfiJK, which encodes a previously uncharacterized two component signaling system. We confirmed that gain-of-function alleles in yfiJK cause a combination of LDAR, changes in colony morphology, and motility. Downstream of yfiJK are the yfiLMN genes, which encode an ATP-binding cassette transporter. We show that yfiLMN genes are necessary for LDA resistance. The developmental phenotypes of LDAR mutants are genetically separable from LDA resistance, suggesting that the two competitive functions are distinct, but regulated by a single two-component system. Our findings suggest that a subpopulation of B. subtilis activate an array of defensive responses to counter lytic stress imposed by competition. Coordinated regulation of development and antibiotic resistance is a streamlined mechanism to promote competitive fitness of bacteria. PMID- 26647302 TI - Endometrial cancer in elderly women: Which disease, which surgical management? A systematic review of the literature. AB - OBJECTIVE: Endometrial cancer primarily affects elderly women. The aim of the present literature review is to define the population of elderly women with this disease and to define the characteristics of this cancer in elderly people as well as its surgical treatment. MATERIALS AND METHODS: A systematic review of the English-language literature of the last 20 years indexed in the PubMed database. RESULTS: Endometrial cancer is more aggressive in elderly women. However, surgical staging performed in elderly patients is often not concomitant with the disease's aggressiveness in this group. Mini-invasive surgery is performed less often, for no obvious reason. Of note, oncogeriatric evaluation was not usually ruled out to determine the most appropriate surgical modality. CONCLUSION: Studies are needed to evaluate surgical management of endometrial cancer in elderly women, notably with the aid of oncogeriatric scores to predict surgical morbidity. PMID- 26647301 TI - A LUHMES 3D dopaminergic neuronal model for neurotoxicity testing allowing long term exposure and cellular resilience analysis. AB - Several shortcomings of current Parkinson's disease (PD) models limit progress in identification of environmental contributions to disease pathogenesis. The conditionally immortalized cell line LUHMES promises to make human dopaminergic neuronal cultures more easily available, but these cells are difficult to culture for extended periods of time. We overcame this problem by culturing them in 3D with minor medium modifications. The 3D neuronal aggregates allowed penetration by small molecules and sufficient oxygen and nutrient supply for survival of the innermost cells. Using confocal microscopy, gene expression, and flow cytometry, we characterized the 3D model and observed a highly reproducible differentiation process. Visualization and quantification of neurites in aggregates was achieved by adding 2 % red fluorescent protein-transfected LUHMES cells. The mitochondrial toxicants and established experimental PD agents, rotenone and MPP+, perturbed genes involved in one-carbon metabolism and transsulfuration pathways (ASS1, CTH, and SHTM2) as in 2D cultures. We showed, for the first time in LUHMES, down regulation of mir-7, a miRNA known to target alpha-synuclein and to be involved in PD. This was observed as early as 12 h after rotenone exposure, when pro apoptotic mir-16 and rotenone-sensitive mir-210 were not yet significantly perturbed. Finally, washout experiments demonstrated that withdrawal of rotenone led to counter-regulation of mir-7 and ASS1, CTH, and SHTM2 genes. This suggests a possible role of these genes in direct cellular response to the toxicant, and the model appears to be suitable to address the processes of resilience and recovery in neurotoxicology and Parkinson's disease in future studies. PMID- 26647303 TI - Design, synthesis, and evaluation of potent Wnt signaling inhibitors featuring a fused 3-ring system. AB - The Wnt signaling pathway is a critical developmental pathway which operates through control of cellular functions such as proliferation and differentiation. Aberrant Wnt signaling has been linked to the formation and metastasis of tumors. Porcupine, a member of the membrane-bound O-acyltransferase family of proteins, is an important component of the Wnt pathway. Porcupine catalyzes the palmitoylation of Wnt proteins, a process needed for their secretion and activity. Here we report a novel series of compounds obtained by a scaffold hybridization strategy from a known porcupine inhibitor class. The leading compound 59 demonstrated subnanomolar inhibition of Wnt signaling in a paracrine cellular assay. Compound 59 also showed excellent chemical, plasma and liver microsomal stabilities. Furthermore, compound 59 exhibited good pharmacokinetic profiles with 30% oral bioavailability in rat. Collectively, these results strongly support further optimization of this novel scaffold to develop better Wnt pathway inhibitors. PMID- 26647304 TI - Synthesis and biological evaluation of novel phosphoramidate derivatives of coumarin as chitin synthase inhibitors and antifungal agents. AB - A series of novel phosphoramidate derivatives of coumarin have been designed and synthesized as chitin synthase (CHS) inhibitors. All the synthesized compounds have been screened for their chitin synthase inhibition activity and antimicrobial activity in vitro. The bioactive assay manifested that most of the target compounds exhibited good efficacy against CHS and a variety of clinically important fungal pathogens. In particular, compound 7t with IC50 of 0.08 mM against CHS displayed stronger efficiency than the reference Polyoxin B with IC50 of 0.16 mM. In addition, the apparent Ki values of compound 7t was 0.096 mM while the Km of Chitin synthase prepared from Candida tropicalis was 3.86 mM for UDP-N acetylglucosamine, and the result of the Ki showed that the compounds was a non competitive inhibitor of the CHS. As far as the antifungal activity is concerned, compounds 7o, 7r and 7t were highly active against Aspergillus flavus with MIC values in the range of 1 MUg/mL to 2 MUg/Ml while the results of antibacterial screening showed that these compounds have negligible actions to the tested bacteria. These results indicated that the design of these compounds as antifungal agents was rational. PMID- 26647305 TI - Imaging of the heart: historical perspective and recent advances. AB - Correct diagnosis must be made before appropriate treatment can be given. The aim of cardiac imaging is to establish cardiac diagnosis as accurate as possible and to avert unnecessary invasive procedures. There are many different modalities of cardiac imaging and each of them has advanced tremendously throughout the past decades. Echocardiography, as the first-line modality in most clinical circumstances, has progressed from two-dimensional, single-planed M-mode in the 1960s to three-dimensional speckle tracking echocardiography nowadays. Cardiac computed tomography angiogram (CCTA) has revolutionised the management of coronary artery disease as it allows clinicians to visualise the coronary arteries without performing an invasive angiogram. Because of the high negative predictive value, CCTA plays an important reassuring role in acute chest pain management. The greatest strength of cardiovascular magnetic resonance (CMR) is that it provides information in tissue characterization. It is the modality of choice in assessing myocardial viability and myocardial infiltration such as haemochromatosis or amyloidosis. Each of these modalities has its own strengths and limitations. In fact, they are complementing each other in different clinical settings. Cardiac imaging will continue to advance and, not long from now, we will not need invasive procedures to make an accurate cardiac diagnosis. PMID- 26647306 TI - Depositing CdS nanoclusters on carbon-modified NaYF4:Yb,Tm upconversion nanocrystals for NIR-light enhanced photocatalysis. AB - High-quality hexagonal NaYF4:Yb,Tm upconversion nanocrystals (UCNs) prepared in organic solutions display uniform sizes and strong UC emissions, but they possess a hydrophobic surface which hinders combining them with various semiconductor nanocrystals (NCs) to form a hybrid NIR-activated photocatalyst. Herein we present a facile approach to modify hydrophobic UCNs with a uniform carbon layer and enable them with hydrophilicity and surface functionalization. The carbon shell provides a good substrate for enriching with metal ions and in situ generation of CdS nanoclusters on the particle surface which can utilize both the upconverted UV and visible emissions. The developed NaYF4:Yb,Tm@C@CdS nanoparticles are characterized with TEM, SEM, XRD, PL and UV-Vis spectra and their formation mechanism is elucidated. The products display good photocatalytic activity under visible light and obviously enhanced performance under Vis-NIR light, due to the efficient utilization of UC emissions and the strong adsorption capacity of the carbon shell. The working mechanism of the hybrid photocatalysts is also proposed. PMID- 26647307 TI - ACTG2 variants impair actin polymerization in sporadic Megacystis Microcolon Intestinal Hypoperistalsis Syndrome. AB - Megacystis Microcolon Intestinal Hypoperistalsis Syndrome (MMIHS) is a rare congenital disorder, in which heterozygous missense variants in the Enteric Smooth Muscle actin gamma-2 (ACTG2) gene have been recently identified. To investigate the mechanism by which ACTG2 variants lead to MMIHS, we screened a cohort of eleven MMIHS patients, eight sporadic and three familial cases, and performed immunohistochemistry, molecular modeling and molecular dynamics (MD) simulations, and in vitro assays. In all sporadic cases, a heterozygous missense variant in ACTG2 was identified. ACTG2 expression was detected in all intestinal layers where smooth muscle cells are present in different stages of human development. No histopathological abnormalities were found in the patients. Using molecular modeling and MD simulations, we predicted that ACTG2 variants lead to significant changes to the protein function. This was confirmed by in vitro studies, which showed that the identified variants not only impair ACTG2 polymerization, but also contribute to reduced cell contractility. Taken together, our results confirm the involvement of ACTG2 in sporadic MMIHS, and bring new insights to MMIHS pathogenesis. PMID- 26647308 TI - Identification and functional characterization of de novo FOXP1 variants provides novel insights into the etiology of neurodevelopmental disorder. AB - De novo disruptions of the neural transcription factor FOXP1 are a recently discovered, rare cause of sporadic intellectual disability (ID). We report three new cases of FOXP1-related disorder identified through clinical whole-exome sequencing. Detailed phenotypic assessment confirmed that global developmental delay, autistic features, speech/language deficits, hypotonia and mild dysmorphic features are core features of the disorder. We expand the phenotypic spectrum to include sensory integration disorder and hypertelorism. Notably, the etiological variants in these cases include two missense variants within the DNA-binding domain of FOXP1. Only one such variant has been reported previously. The third patient carries a stop-gain variant. We performed functional characterization of the three missense variants alongside our stop-gain and two previously described truncating/frameshift variants. All variants severely disrupted multiple aspects of protein function. Strikingly, the missense variants had similarly severe effects on protein function as the truncating/frameshift variants. Our findings indicate that a loss of transcriptional repression activity of FOXP1 underlies the neurodevelopmental phenotype in FOXP1-related disorder. Interestingly, the three novel variants retained the ability to interact with wild-type FOXP1, suggesting these variants could exert a dominant-negative effect by interfering with the normal FOXP1 protein. These variants also retained the ability to interact with FOXP2, a paralogous transcription factor disrupted in rare cases of speech and language disorder. Thus, speech/language deficits in these individuals might be worsened through deleterious effects on FOXP2 function. Our findings highlight that de novo FOXP1 variants are a cause of sporadic ID and emphasize the importance of this transcription factor in neurodevelopment. PMID- 26647309 TI - Hypothermia improves disease manifestations in SMA mice via SMN augmentation. AB - Spinal muscular atrophy (SMA) is a progressive motor neuron disease caused by a deficiency of survival motor neuron (SMN) protein. In this study, we evaluated the efficacy of intermittent transient hypothermia in a mouse model of SMA. SMA mice were exposed to ice for 50 s to achieve transient hypothermia (below 25 degrees C) daily beginning on postnatal day 1. Neonatal SMA mice (Smn(-/-)SMN2(+/ )) who received daily transient hypothermia exhibited reduced motor neuron degeneration and muscle atrophy and preserved the architecture of neuromuscular junction when compared with untreated controls at day 8 post-treatment. Daily hypothermia also prolonged the lifespan, increased body weight and improved motor coordination in SMA mice. Quantitative polymerase chain reaction and western blot analyses showed that transient hypothermia led to an increase in SMN transcript and protein levels in the spinal cord and brain. In in vitro studies using an SMN knockdown motor neuron-like cell-line, transient hypothermia increased intracellular SMN protein expression and length of neurites, confirming the direct effect of hypothermia on motor neurons. These data indicate that the efficacy of intermittent transient hypothermia in improving outcome in an SMA mouse model may be mediated, in part, via an upregulation of SMN levels in the motor neurons. PMID- 26647310 TI - The exome sequencing identified the mutation in YARS2 encoding the mitochondrial tyrosyl-tRNA synthetase as a nuclear modifier for the phenotypic manifestation of Leber's hereditary optic neuropathy-associated mitochondrial DNA mutation. AB - Leber's hereditary optic neuropathy (LHON) is the most common mitochondrial disorder. Nuclear modifier genes are proposed to modify the phenotypic expression of LHON-associated mitochondrial DNA (mtDNA) mutations. By using an exome sequencing approach, we identified a LHON susceptibility allele (c.572G>T, p.191Gly>Val) in YARS2 gene encoding mitochondrial tyrosyl-tRNA synthetase, which interacts with m.11778G>A mutation to cause visual failure. We performed functional assays by using lymphoblastoid cell lines derived from members of Chinese families (asymptomatic individuals carrying m.11778G>A mutation, or both m.11778G>A and heterozygous p.191Gly>Val mutations and symptomatic subjects harboring m.11778G>A and homozygous p.191Gly>Val mutations) and controls lacking these mutations. The 191Gly>Val mutation reduced the YARS2 protein level in the mutant cells. The aminoacylated efficiency and steady-state level of tRNA(Tyr) were markedly decreased in the cell lines derived from patients both carrying homozygous YARS2 p.191Gly>Val and m.11778G>A mutations. The failure in tRNA(Tyr) metabolism impaired mitochondrial translation, especially for polypeptides with high content of tyrosine codon such as ND4, ND5, ND6 and COX2 in cells lines carrying homozygous YARS2 p.191Gly>Val and m.11778G>A mutations. The YARS2 p.191Gly>Val mutation worsened the respiratory phenotypes associated with m.11778G>A mutation, especially reducing activities of complexes I and IV. The respiratory deficiency altered the efficiency of mitochondrial ATP synthesis and increased the production of reactive oxygen species. Thus, mutated YARS2 aggravates mitochondrial dysfunctions associated with the m.11778G>A mutation, exceeding the threshold for the expression of blindness phenotype. Our findings provided new insights into the pathophysiology of LHON that were manifested by interaction between mtDNA mutation and mutated nuclear-modifier YARS2. PMID- 26647311 TI - The molecular basis of variable phenotypic severity among common missense mutations causing Rett syndrome. AB - Rett syndrome is caused by mutations in the X-linked MECP2 gene, which encodes a chromosomal protein that binds to methylated DNA. Mouse models mirror the human disorder and therefore allow investigation of phenotypes at a molecular level. We describe an Mecp2 allelic series representing the three most common missense Rett syndrome (RTT) mutations, including first reports of Mecp2[R133C] and Mecp2[T158M] knock-in mice, in addition to Mecp2[R306C] mutant mice. Together these three alleles comprise ~25% of all RTT mutations in humans, but they vary significantly in average severity. This spectrum is mimicked in the mouse models; R133C being least severe, T158M most severe and R306C of intermediate severity. Both R133C and T158M mutations cause compound phenotypes at the molecular level, combining compromised DNA binding with reduced stability, the destabilizing effect of T158M being more severe. Our findings contradict the hypothesis that the R133C mutation exclusively abolishes binding to hydroxymethylated DNA, as interactions with DNA containing methyl-CG, methyl-CA and hydroxymethyl-CA are all reduced in vivo. We find that MeCP2[T158M] is significantly less stable than MeCP2[R133C], which may account for the divergent clinical impact of the mutations. Overall, this allelic series recapitulates human RTT severity, reveals compound molecular aetiologies and provides a valuable resource in the search for personalized therapeutic interventions. PMID- 26647313 TI - Aberrant disulphide bonding contributes to the ER retention of alpha1-antitrypsin deficiency variants. AB - Mutations in alpha1-antitrypsin (AAT) can cause the protein to polymerise and be retained in the endoplasmic reticulum (ER) of hepatocytes. The ensuing systemic AAT deficiency leads to pulmonary emphysema, while intracellular polymers are toxic and cause chronic liver disease. The severity of this process varies considerably between individuals, suggesting the involvement of mechanistic co factors and potential for therapeutically beneficial interventions. We show in Hepa1.6 cells that the mildly polymerogenic I (Arg39Cys) AAT mutant forms aberrant inter- and intra-molecular disulphide bonds involving the acquired Cys39 and the only cysteine residue in the wild-type (M) sequence (Cys232). Substitution of Cys39 to serine partially restores secretion, showing that disulphide bonding contributes to the intracellular retention of I AAT. Covalent homodimers mediated by inter-Cys232 bonding alone are also observed in cells expressing the common Z and other polymerising AAT variants where conformational behaviour is abnormal, but not in those expressing M AAT. Prevention of such disulphide linkage through the introduction of the Cys232Ser mutation or by treatment of cells with reducing agents increases Z AAT secretion. Our results reveal that disulphide interactions enhance intracellular accumulation of AAT mutants and implicate the oxidative ER state as a pathogenic co-factor. Redox modulation, e.g. by anti-oxidant strategies, may therefore be beneficial in AAT deficiency-associated liver disease. PMID- 26647312 TI - De novo dominant ASXL3 mutations alter H2A deubiquitination and transcription in Bainbridge-Ropers syndrome. AB - De novo truncating mutations in Additional sex combs-like 3 (ASXL3) have been identified in individuals with Bainbridge-Ropers syndrome (BRS), characterized by failure to thrive, global developmental delay, feeding problems, hypotonia, dysmorphic features, profound speech delays and intellectual disability. We identified three novel de novo heterozygous truncating variants distributed across ASXL3, outside the original cluster of ASXL3 mutations previously described for BRS. Primary skin fibroblasts established from a BRS patient were used to investigate the functional impact of pathogenic variants. ASXL3 mRNA transcripts from the mutated allele are prone to nonsense-mediated decay, and expression of ASXL3 is reduced. We found that ASXL3 interacts with BAP1, a hydrolase that removes mono-ubiquitin from histone H2A lysine 119 (H2AK119Ub1) as a component of the Polycomb repressive deubiquitination (PR-DUB) complex. A significant increase in H2AK119Ub1 was observed in ASXL3 patient fibroblasts, highlighting an important functional role for ASXL3 in PR-DUB mediated deubiquitination. Transcriptomes of ASXL3 patient and control fibroblasts were compared to investigate the impact of chromatin changes on transcriptional regulation. Out of 564 significantly differentially expressed genes (DEGs) in ASXL3 patient fibroblasts, 52% were upregulated and 48% downregulated. DEGs were enriched in molecular processes impacting transcriptional regulation, development and proliferation, consistent with the features of BRS. This is the first single gene disorder linked to defects in deubiquitination of H2AK119Ub1 and suggests an important role for dynamic regulation of H2A mono-ubiquitination in transcriptional regulation and the pathophysiology of BRS. PMID- 26647314 TI - Effect of Dried Blood Spot Quality on Newborn Screening Analyte Concentrations and Recommendations for Minimum Acceptance Criteria for Sample Analysis. AB - BACKGROUND: The analysis of dried blood spots has been used routinely for newborn screening since the early 1970s, and the number of disorders screened has expanded substantially in recent years. However, there is a lack of evidence regarding minimum blood spot quality acceptance criteria for sample analysis. METHODS: Blood pools were spiked with phenylalanine, tyrosine, leucine, methionine, octanoylcarnitine, decanoylcarnitine, isovalerylcarnitine, glutarylcarnitine, thyroid-stimulating hormone, and immunoreactive trypsinogen to concentrations at the analytical cutoffs used in UK screening protocols. We evaluated the effect of sample volume applied to the card (10, 20, 50, 75, and 100 MUL), punch location (central vs peripheral), and sample quality (double layering, applying blood to both sides of the filter paper, multispotting, applying insufficient sample, and compressing the sample after application). RESULTS: Compression of blood spots produced significantly lower results (14% 44%) for all analytes measured (P < 0.001). Smaller blood spots produced significantly lower results (15%-24% for 10-MUL vs 50-MUL sample size) for all analytes at all concentrations measured (P < 0.001). Results obtained from peripheral punches were higher than those from a central punch, although this did not reach statistical significance for all analytes. Insufficient and multispotted samples demonstrated heterogeneous results. CONCLUSIONS: All blood spots containing <=20 MUL (blood spot diameter <8 mm), those in which blood has not fully penetrated the filter paper, and all samples with evidence of compression should be rejected, since there is a risk of producing false-negative results. PMID- 26647315 TI - Correction to Stimuli-Triggered Activity of Nanoreactors by Biomimetic Engineering Polymer Membranes. PMID- 26647316 TI - Glycocalyx Engineering with a Recycling Glycopolymer that Increases Cell Survival In Vivo. AB - Synthetic glycopolymers that emulate cell-surface mucins have been used to elucidate the role of mucin overexpression in cancer. However, because they are internalized within hours, these glycopolymers could not be employed to probe processes that occur on longer time scales. In this work, we tested a panel of glycopolymers bearing a variety of lipids to identify those that persist on cell membranes. Strikingly, we found that cholesterylamine (CholA) anchored glycopolymers are internalized into vesicles that serve as depots for delivery back to the cell surface, allowing for the display of cell-surface glycopolymers for at least ten days, even while the cells are dividing. As with native mucins, the cell-surface display of CholA-anchored glycopolymers influenced the focal adhesion distribution. Furthermore, we show that these mimetics enhance the survival of nonmalignant cells in a zebrafish model of metastasis. CholA-anchored glycopolymers therefore expand the application of glycocalyx engineering in glycobiology. PMID- 26647347 TI - Expression of Cntnap2 (Caspr2) in multiple levels of sensory systems. AB - Genome-wide association studies and copy number variation analyses have linked contactin associated protein 2 (Caspr2, gene name Cntnap2) with autism spectrum disorder (ASD). In line with these findings, mice lacking Caspr2 (Cntnap2(-/-)) were shown to have core autism-like deficits including abnormal social behavior and communication, and behavior inflexibility. However the role of Caspr2 in ASD pathogenicity remains unclear. Here we have generated a new Caspr2:tau-LacZ knock in reporter line (Cntnap2(tlacz/tlacz)), which enabled us to monitor the neuronal circuits in the brain expressing Caspr2. We show that Caspr2 is expressed in many brain regions and produced a comprehensive report of Caspr2 expression. Moreover, we found that Caspr2 marks all sensory modalities: it is expressed in distinct brain regions involved in different sensory processings and is present in all primary sensory organs. Olfaction-based behavioral tests revealed that mice lacking Caspr2 exhibit abnormal response to sensory stimuli and lack preference for novel odors. These results suggest that loss of Caspr2 throughout the sensory system may contribute to the sensory manifestations frequently observed in ASD. PMID- 26647348 TI - Conjunctival Sensation in Scleritis. AB - PURPOSE: To investigate conjunctival sensation in patients with scleritis. METHODS: Retrospective cross-sectional study of patients with scleritis. Conjunctival sensation was tested by Cochet-Bonnet aesthesiometer in four quadrants of the bulbar conjunctiva plus the area(s) of active or previously active inflammation; sensation was compared with the contralateral eye. RESULTS: Of 28 patients with scleritis, nine had active scleritis and 19 had inactive scleritis. Eleven patients had a systemic autoimmune condition and five had infectious scleritis. The mean conjunctival sensation score of areas of inactive scleritis was significantly less than that of corresponding normal areas in the contralateral eye (p<0.001). Among patients with presumed herpetic scleritis, conjunctival sensation was significantly lower in the affected eye than in the unaffected eye (p<0.001). CONCLUSIONS: Conjunctival sensation is decreased in areas of previously active inflammation from scleritis. Eyes with herpetic scleritis had reduced conjunctival sensation, even in areas without previous active inflammation. PMID- 26647349 TI - Magnetite loaded Polypeptide-PLGA multifunctional microbubbles for dual-mode US/MR imaging. AB - Magnetite loaded Polypeptide-PLGA multifunctional microbubbles (Fe3O4 /Polypeptide-PLGA MMBs) that show superparamagnetic properties were prepared by a modified double emulsion method and employed as imaging agent for dual-mode Ultrasound/Magnetic resonance (US/MR) imaging of prostatic cancer. The successful synthesis of MMBs was determined by Fourier Transform Infrared Spectrometer (FTIR), X-ray diffraction (XRD), Transmission Electron Microscope (TEM), Scanning Electron Microscope (SEM), Atomic Absorption Spectroscopy (AAS) and vibrating sample magnetometer (VSM). The as-prepared MMBs had a diameter of 700 nm and were quite safe as confirmed by MTT assays. Prussian Blue Staining showed that targeted Fe3O4 /Polypeptide-PLGA MMBs enhanced the cellular uptake efficiency. In cell attachment study, adherence of MMBs was significantly higher to LNCaP cells compared with negative control PC3 cells. The in vitro results demonstrated that these MMBs could enhance both US and MR imaging of prostatic cancer. PMID- 26647350 TI - The Associations Between Pre- and Postnatal Maternal Symptoms of Distress and Preschooler's Symptoms of ADHD, Oppositional Defiant Disorder, Conduct Disorder, and Anxiety. AB - OBJECTIVE: The objective of this article is to examine the associations between pre- and postnatal maternal distress and preschooler's symptoms of ADHD, Oppositional Defiant Disorder (ODD), Conduct Disorder (CD), and anxiety, by timing and gender. METHOD: Children, aged 3.5 years (N = 1,195), recruited from the Norwegian Mother and Child Cohort Study, were assessed with a semistructured parental psychiatric interview. Perinatal maternal symptoms of distress were assessed by Symptom Checklist (SCL-5); Poisson regression was used to examine the associations. RESULTS: Mid-gestational maternal distress significantly increased the average number of child symptoms, ranging between 3.8% for ADHD hyperactive impulsive (ADHD-HI) and 8.7% for anxiety. The combination of high maternal scores of distress both pre- and postnatally were associated with increased risk of child symptoms of anxiety (relative risk [RR] = 2.10; 95% confidence interval [CI] = [1.43, 3.07]), CD (RR = 1.83; 95% CI = [1.33, 2.51]), and ODD (RR = 1.30; 95% CI = [1.03, 1.64]), with minor sex differences. CONCLUSION: Maternal distress during mid-gestation was associated with ADHD, behavioral, and emotional symptoms in preschool children. Continued exposure into the postnatal period may further increase these risk associations . PMID- 26647352 TI - Linear Morphea Mimicking Lichen Striatus in Its Early Presentation. AB - Linear morphea and lichen striatus are distinct conditions that have been linked in only one previous case report. We describe two patients with facial lichen striatus preceding linear morphea at the same site. A possible pathogenic relationship is discussed. PMID- 26647351 TI - Studying polyglutamine aggregation in Caenorhabditis elegans using an analytical ultracentrifuge equipped with fluorescence detection. AB - This work explores the heterogeneity of aggregation of polyglutamine fusion constructs in crude extracts of transgenic Caenorhabditis elegans animals. The work takes advantage of the recent technical advances in fluorescence detection for the analytical ultracentrifuge. Further, new sedimentation velocity methods, such as the multi-speed method for data capture and wide distribution analysis for data analysis, are applied to improve the resolution of the measures of heterogeneity over a wide range of sizes. The focus here is to test the ability to measure sedimentation of polyglutamine aggregates in complex mixtures as a prelude to future studies that will explore the effects of genetic manipulation and environment on aggregation and toxicity. Using sedimentation velocity methods, we can detect a wide range of aggregates, ranging from robust analysis of the monomer species through an intermediate and quite heterogeneous population of oligomeric species, and all the way up to detecting species that likely represent intact inclusion bodies based on comparison to an analysis of fluorescent puncta in living worms by confocal microscopy. Our results support the hypothesis that misfolding of expanded polyglutamine tracts into insoluble aggregates involves transitions through a number of stable intermediate structures, a model that accounts for how an aggregation pathway can lead to intermediates that can have varying toxic or protective attributes. An understanding of the details of intermediate and large-scale aggregation for polyglutamine sequences, as found in neurodegenerative diseases such as Huntington's Disease, will help to more precisely identify which aggregated species may be involved in toxicity and disease. PMID- 26647353 TI - Improvement of platelets after SVR among patients with chronic HCV infection and advanced hepatic fibrosis. AB - BACKGROUND AND AIMS: Patients with chronic hepatitis C virus (HCV) infection may develop cirrhosis with portal hypertension, reflected by decreased platelet count and splenomegaly. This retrospective cohort study aimed to assess changes in platelet counts after antiviral therapy among chronic HCV-infected patients with advanced fibrosis. METHODS: Platelet counts and spleen sizes were recorded in an international cohort of patients with Ishak 4-6 fibrosis who started antiviral therapy between 1990 and 2003. Last measured platelet counts and spleen sizes were compared with their pre-treatment values (within 6 months prior to the start of therapy). All registered platelet count measurements from 24-week following cessation of antiviral therapy were included in repeated measurement analyses. RESULTS: This study included 464 patients; 353 (76%) had cirrhosis and 187 (40%) attained sustained virological response (SVR). Among patients with SVR, median platelet count, increased by 35 * 10(9) /L (IQR 7-62, P < 0.001). In comparison, patients without SVR showed a median decline of 17 * 10(9) /L (IQR -5-47, P < 0.001). In a subgroup of 209 patients, median decrease in spleen size was 1.0 cm (IQR 0.3-2.0) for patients with SVR, while median spleen size increased with 0.6 cm (IQR -0.1-2.0, P < 0.001) among those without SVR. The changes in spleen size and platelet count were significantly correlated (R = -0.41, P < 0.001). CONCLUSIONS: Among chronic HCV-infected patients with advanced hepatic fibrosis, the platelet counts improved following SVR and the change in platelets correlated with the change in spleen size following antiviral therapy. These results suggest that HCV eradication leads to reduced portal pressure. PMID- 26647354 TI - Early Intervention Before Autism Diagnosis in Children Referred to a Regional Autism Clinic. AB - OBJECTIVE: To determine the prevalence of receipt of early intervention and therapeutic services in children suspected of having possible autism spectrum disorder (ASD) before their diagnostic ASD evaluations. METHODS: The electronic medical records of all children <=5 years of age evaluated at a single regional ASD clinic between September 2012 and June 2014 were reviewed. Information regarding type of services, clinical diagnoses, and demographic information was abstracted for each patient. RESULTS: Five hundred sixty-one children (mean age = 44 mo [SD, 10 mo]; 80% [N = 450] male; 20% [N = 111] female) completed a diagnostic ASD evaluation. Of these children, 497 (89%) were already receiving early intervention services, and only 64 (11%) were not receiving any services. Receipt of services did not vary based on race, ethnicity, insurance type, or primary language. Children who were already receiving services were more likely to receive an ASD diagnosis (67%, N = 332) than those not receiving services (44% [N = 28]; p <= .001). CONCLUSION: Despite concerns that long wait lists for diagnostic ASD evaluations may delay initiation of critical early interventions, our data indicate that most children are receiving early intervention services before their diagnostic ASD evaluations, particularly if an ASD diagnosis is confirmed. This may be attributable to increased awareness among primary care providers and families of the importance of early interventions. Further investigation into access to more intensive interventions (such as applied behavioral analysis) once an ASD diagnosis is established is warranted. PMID- 26647355 TI - Agomelatine Protection in an LPS-Induced Psychosis-Relevant Behavior Model. AB - BACKGROUND The aim of this study was to investigate the effect of agomelatine in a psychosis-relevant behavior model. MATERIAL AND METHODS We used 18 adult male Wistar rats in this study. Twelve rats given LPS for endotoxemia were randomly divided into 2 groups (n=6). Group I was treated with 1 mL/kg 0.9% NaCl i.p. and Group II was treated with 40 mg/kg agomelatine. Six normal rats served as the control group and were not given LPS for endotoxemia. Cylindrical steel cages containing vertical and horizontal metal bars with top cover were used. Rats were put in these cages for the purpose of orientation for 10 min. Apomorphine was given to rats removed from cages, and then they were immediately put back in the cages for the purpose of observing stereotyped conduct. Brain HVA levels and plasma TNF-a levels were evaluated in tissue homogenates using ELISA. The proportion of malondialdehyde (MDA) was measured in samples taken from plasma for detection of lipid peroxidation similar to thiobarbituric acid reactive substances. RESULTS LPS induced-plasma TNF-alpha, brain TNF-alpha, and plasma MDA levels were significantly lower in the LPS+agomelatine group compared to the LPS+saline group (p<0.05). HVA levels and stereotype scores were significantly lower in the LPS+agomelatine group compared to the LPS+saline group (p <0.001). CONCLUSIONS Agomelatine reduced TNF-alpha, HVA, MDA levels, and the stereotype score in relevant models of psychosis. Our results suggest that the anti inflammatory effect of agomelatine involved oxidant cleansing properties and that its effects on the metabolism of dopamine can play an important role in the model of psychosis. PMID- 26647356 TI - Contribution of the interaction between the rabies virus P protein and I-kappa B kinase epsilon to the inhibition of type I IFN induction signalling. AB - The P protein of rabies virus (RABV) is known to interfere with the phosphorylation of the host IFN regulatory factor 3 (IRF-3) and to consequently inhibit type I IFN induction. Previous studies, however, have only tested P proteins from laboratory-adapted fixed virus strains, and to the best of our knowledge there is no report about the effect of P proteins from street RABV strains or other lyssaviruses on the IRF-3-mediated type I IFN induction system. In this study, we evaluated the inhibitory effect of P proteins from several RABV strains, including fixed and street virus strains and other lyssaviruses (Lagos bat, Mokola and Duvenhage viruses), on IRF-3 signalling. All P proteins tested inhibited retinoic acid-inducible gene-1 (RIG-I)- and TANK binding kinase 1 (TBK1)-mediated IRF-3-dependent IFN-beta promoter activities. On the other hand, the P proteins from the RABV street strains 1088 and HCM-9, but not from fixed strains Nishigahara (Ni) and CVS-11 and other lyssaviruses tested, significantly inhibited I-kappa B kinase epsilon (IKKepsilon)-inducible IRF-3-dependent IFN beta promoter activity. Importantly, we revealed that the P proteins from the 1088 and HCM-9 strains, but not from the remaining viruses, interacted with IKKepsilon. By using expression plasmids encoding chimeric P proteins from the 1088 strain and Ni strain, we found that the C-terminal region of the P protein is important for the interaction with IKKepsilon. These findings suggest that the P protein of RABV street strains may contribute to efficient evasion of host innate immunity. PMID- 26647357 TI - Divergent synthetic route to new cyclopenta[c]pyran iridoids: syntheses of jatamanin A, F, G and J, gastrolactone and nepetalactone. AB - Six natural iridoids including jatamanin A, F, G and J, gastrolactone and nepetalactone have been synthesized via the efficient transformation of a core cyclopenta[c]pyran intermediate. Key features of the syntheses include the stereoselective construction of the core cyclopenta[c]pyran skeleton of the iridoid lactones via a Pd(0)-catalyzed intramolecular allylic alkylation, and the facile transformation of the common intermediate into natural iridoids. PMID- 26647359 TI - Compensating arithmetic ability with derived fact strategies in Broca's aphasia: a case report. AB - We investigated derived fact strategy use in RR, an aphasic patient with severely impaired working memory (no phonological loop), and 16 neurologically healthy matched controls. Participants were tested on derived fact strategy use in multi digit addition, subtraction, multiplication, and division. RR's accuracy only differed from controls in multiplication. He was as quick as controls in addition and subtraction when able to use the strategies, though significantly slower in addition, division, and multiplication without strategies. Our findings suggest the phonological loop is non-essential for multi-digit arithmetic, and derived fact strategies can help speed up arithmetic in individuals with impaired working memory. PMID- 26647358 TI - Lipoprotein (a): truly a direct prothrombotic factor in cardiovascular disease? AB - Elevated plasma concentrations of lipoprotein (a) [Lp(a)] have been determined to be a causal risk factor for coronary heart disease, and may similarly play a role in other atherothrombotic disorders. Lp(a) consists of a lipoprotein moiety indistinguishable from LDL, as well as the plasminogen-related glycoprotein, apo(a). Therefore, the pathogenic role for Lp(a) has traditionally been considered to reflect a dual function of its similarity to LDL, causing atherosclerosis, and its similarity to plasminogen, causing thrombosis through inhibition of fibrinolysis. This postulate remains highly speculative, however, because it has been difficult to separate the prothrombotic/antifibrinolytic functions of Lp(a) from its proatherosclerotic functions. This review surveys the current landscape surrounding these issues: the biochemical basis for procoagulant and antifibrinolytic effects of Lp(a) is summarized and the evidence addressing the role of Lp(a) in both arterial and venous thrombosis is discussed. While elevated Lp(a) appears to be primarily predisposing to thrombotic events in the arterial tree, the fact that most of these are precipitated by underlying atherosclerosis continues to confound our understanding of the true pathogenic roles of Lp(a) and, therefore, the most appropriate therapeutic target through which to mitigate the harmful effects of this lipoprotein. PMID- 26647361 TI - Ionogels of a Sugar Surfactant in Ionic Liquids. AB - Green and environmentally friendly ionogels formed by a sugar surfactant were prepared in two kinds of imidazolium-based ionic liquids. The phase transition from ribbon structures to lamellar structures induced by temperature and the transition mechanism were investigated in detail by means of freeze-fracture TEM and field-emission SEM observations, as well as small-angle X-ray scattering measurements. The rheological properties and tribological properties of two kinds of ionogels were systematically investigated. The difference in the lubricating properties and antiwear capability can be explained well by the mechanical and viscoelastic properties, as well as the different microstructures of samples destroyed by shear forces. This work provides a better understanding of the relationship between the structures, rheological properties, and tribological properties of ionogels. PMID- 26647362 TI - Antidepressant-like activity of aroxyalkyl derivatives of 2 methoxyphenylpiperazine and evidence for the involvement of serotonin receptor subtypes in their mechanism of action. AB - Since serotonin (5-HT) is strongly involved in the etiology and pathophysiology of depression, the development of new antidepressants is still based on the serotonergic system. The complexity of serotonergic system provides an opportunity for the development of compounds with multiple and complementary mechanism of action. This study describes serotonin receptor profile, functional characterization, and pharmacological in vivo evaluation of new aroxyalkyl derivatives of 2-methoxyphenylpiperazine. The obtained results allowed for the identification of compound 3, (1-[3-(2,6-dimethylphenoxy)propyl]-4-(2 methoxyphenyl)piperazine hydrochloride), a partial 5-HT1A receptor agonist, and 5 HT2A receptor antagonist, with high affinity toward 5-HT7 receptors, showing antidepressant- and anxiolytic-like properties. Moreover, 5-HT1A receptor activation is crucial for the antidepressant-like activity of compound 3. The rest of the compounds (except compounds 1 and 9) showed antidepressant but not anxiolytic-like properties, which did not result from 5-HT1A receptors activation. Furthermore, the compounds are 5-HT1A and weak 5-HT3 receptors antagonists, and some of them 5-HT2A antagonists. Moreover, none of the studied compounds impaired motor coordination at antidepressant-like doses. Since the studied compounds exhibited activity in behavioral assays and interacted with various receptors, the results of our experiments are very promising and require further studies. PMID- 26647360 TI - HPA AXIS RELATED GENES AND RESPONSE TO PSYCHOLOGICAL THERAPIES: GENETICS AND EPIGENETICS. AB - BACKGROUND: Hypothalamic-pituitary-adrenal (HPA) axis functioning has been implicated in the development of stress-related psychiatric diagnoses and response to adverse life experiences. This study aimed to investigate the association between genetic and epigenetics in HPA axis and response to cognitive behavior therapy (CBT). METHODS: Children with anxiety disorders were recruited into the Genes for Treatment project (GxT, N = 1,152). Polymorphisms of FKBP5 and GR were analyzed for association with response to CBT. Percentage DNA methylation at the FKBP5 and GR promoter regions was measured before and after CBT in a subset (n = 98). Linear mixed effect models were used to investigate the relationship between genotype, DNA methylation, and change in primary anxiety disorder severity (treatment response). RESULTS: Treatment response was not associated with FKBP5 and GR polymorphisms, or pretreatment percentage DNA methylation. However, change in FKBP5 DNA methylation was nominally significantly associated with treatment response. Participants who demonstrated the greatest reduction in severity decreased in percentage DNA methylation during treatment, whereas those with little/no reduction in severity increased in percentage DNA methylation. This effect was driven by those with one or more FKBP5 risk alleles, with no association seen in those with no FKBP5 risk alleles. No significant association was found between GR methylation and response. CONCLUSIONS: Allele specific change in FKBP5 methylation was associated with treatment response. This is the largest study to date investigating the role of HPA axis related genes in response to a psychological therapy. Furthermore, this is the first study to demonstrate that DNA methylation changes may be associated with response to psychological therapies in a genotype-dependent manner. PMID- 26647363 TI - Diazepam effects on aversive memory retrieval and extinction: Role of anxiety levels. AB - Benzodiazepines (BDZs) are anxiolytic drugs that impair memory acquisition. Previous studies using the plus-maze discriminative avoidance task (PMDAT, which assesses memory and anxiety concomitantly) indicated that the effects of BDZs on anxiety and acquisition are related to each other. The possible influence of the anxiolytic action of BDZs on their effects on memory retrieval and extinction are poorly understood. This is relevant considering the relationship between aversive memories and anxiety disorders. We designed a modified protocol of PMDAT that evaluates anxiety during retrieval and extinction of the task. Male Wistar rats were trained in the PMDAT (plus-maze with two open and two enclosed arms) using a standard or a modified protocol. In the standard protocol, the aversive stimuli were presented in one of the enclosed arms during training, and the animal had free access to the whole apparatus. In the modified protocol, the open arms were blocked with glass walls. Twenty-four hours after training, the animals subjected to each of the protocols were treated with saline or 2.0mg/kg of diazepam (DZP) 30min before the test. There was a third session in the maze (retest) 24h after the test. During the test, DZP impaired and improved retrieval in rats that had been trained in the standard and the modified protocol when compared to the respective saline-treated groups. In addition, treatment with DZP prior to the test induced anxiolysis, but only in the animals that were not pre-exposed to the open arms of the apparatus (modified protocol). In these animals, DZP impaired extinction, which was evaluated during retest session. The impairing effect of DZP on extinction seems to be related to its anxiolytic action during the test (extinction learning). Further, we suggest that aversive memory retrieval depends on both the treatment and the arousal elicited by exposure to the apparatus. PMID- 26647364 TI - Examining a conceptual model of parental nurturance, parenting practices and physical activity among 5-6 year olds. AB - RATIONALE: Parenting is an often-studied correlate of children's physical activity, however there is little research examining the associations between parenting styles, practices and the physical activity of younger children. OBJECTIVE: This study aimed to investigate whether physical activity-based parenting practices mediate the association between parenting styles and 5-6 year old children's objectively-assessed physical activity. METHODS: 770 parents self reported parenting style (nurturance and control) and physical activity-based parenting practices (logistic and modeling support). Their 5-6 year old child wore an accelerometer for five days to measure moderate-to-vigorous physical activity (MVPA). Linear regression was used to examine direct and indirect (mediation) associations. Data were collected in the United Kingdom in 2012/13 and analyzed in 2014. RESULTS: Parent nurturance was positively associated with provision of modeling (adjusted unstandardized coefficient, beta = 0.11; 95% CI = 0.02, 0.21) and logistic support (beta = 0.14; 0.07, 0.21). Modeling support was associated with greater child MVPA (beta = 2.41; 0.23, 4.60) and a small indirect path from parent nurturance to child's MVPA was identified (beta = 0.27; 0.04, 0.70). CONCLUSIONS: Physical activity-based parenting practices are more strongly associated with 5-6 year old children's MVPA than parenting styles. Further research examining conceptual models of parenting is needed to understand in more depth the possible antecedents to adaptive parenting practices beyond parenting styles. PMID- 26647365 TI - Cultural consensus modeling to measure transactional sex in Swaziland: Scale building and validation. AB - Transactional sex is associated with increased risk of HIV and gender based violence in southern Africa and around the world. However the typical quantitative operationalization, "the exchange of gifts or money for sex," can be at odds with a wide array of relationship types and motivations described in qualitative explorations. To build on the strengths of both qualitative and quantitative research streams, we used cultural consensus models to identify distinct models of transactional sex in Swaziland. The process allowed us to build and validate emic scales of transactional sex, while identifying key informants for qualitative interviews within each model to contextualize women's experiences and risk perceptions. We used logistic and multinomial logistic regression models to measure associations with condom use and social status outcomes. Fieldwork was conducted between November 2013 and December 2014 in the Hhohho and Manzini regions. We identified three distinct models of transactional sex in Swaziland based on 124 Swazi women's emic valuation of what they hoped to receive in exchange for sex with their partners. In a clinic-based survey (n = 406), consensus model scales were more sensitive to condom use than the etic definition. Model consonance had distinct effects on social status for the three different models. Transactional sex is better measured as an emic spectrum of expectations within a relationship, rather than an etic binary relationship type. Cultural consensus models allowed us to blend qualitative and quantitative approaches to create an emicly valid quantitative scale grounded in qualitative context. PMID- 26647366 TI - A Time-Stratified Case-Crossover Study of Ambient Ozone Exposure and Emergency Department Visits for Specific Respiratory Diagnoses in California (2005-2008). AB - BACKGROUND: Studies have explored ozone's connection to asthma and total respiratory emergency department visits (EDVs) but have neglected other specific respiratory diagnoses despite hypotheses relating ozone to respiratory infections and allergic responses. OBJECTIVE: We examined relationships between ozone and EDVs for respiratory visits, including specifically acute respiratory infections (ARI), asthma, pneumonia, chronic obstructive pulmonary disease (COPD), and upper respiratory tract inflammation (URTI). METHODS: We conducted a multi-site time stratified case-crossover study of ozone exposures for approximately 3.7 million respiratory EDVs from 2005 through 2008 among California residents living within 20 km of an ozone monitor. Conditional logistic regression was used to estimate associations by climate zone. Random effects meta-analysis was then applied to estimate pooled excess risks (ER). Effect modification by season, distance from the monitor and individual demographic characteristics (i.e., age, race/ethnicity, sex, and payment method), and confounding by other gaseous air pollutants were also investigated. Meta-regression was utilized to explore how climate zone-level meteorological, demographic, and regional differences influenced estimates. RESULTS: We observed ozone-associated increases in all respiratory, asthma, and ARI visits, which were slightly larger in the warm season [asthma ER per 10-ppb increase in mean of same and previous 3 days ozone exposure (lag03) = 2.7%, 95% CI: 1.5, 3.9; ARI ERlag03 = 1.4%, 95% CI: 0.8, 1.9]. EDVs for pneumonia, COPD, and URTI were also significantly associated with ozone exposure over the whole year, but typically more consistently so during the warm season. CONCLUSIONS: Short-term ozone exposures among California residents living near an ozone monitor were positively associated with EDVs for asthma, ARI, pneumonia, COPD, and URTI from 2005 through 2008. Those associations were typically larger and more consistent during the warm season. Our findings suggest that these outcomes should be considered when evaluating the potential health benefits of reducing ozone concentrations. CITATION: Malig BJ, Pearson DL, Chang YB, Broadwin R, Basu R, Green RS, Ostro B. 2016. A time-stratified case-crossover study of ambient ozone exposure and emergency department visits for specific respiratory diagnoses in California (2005-2008). Environ Health Perspect 124:745 753; http://dx.doi.org/10.1289/ehp.1409495. PMID- 26647367 TI - Simultaneous uncoupled expression and purification of the Dengue virus NS3 protease and NS2B co-factor domain. AB - Dengue Virus (DENV) infection is responsible for the world's most significant insect-borne viral disease. Despite an increasing global impact, there are neither prophylactic nor therapeutic options available for the effective treatment of DENV infection. An attractive target for antiviral drugs is the virally encoded trypsin-like serine protease (NS3pro) and its associated cofactor (NS2B). The NS2B-NS3pro complex is responsible for cleaving the viral polyprotein into separate functional viral proteins, and is therefore essential for replication. Recombinant expression of an active NS2B-NS3 protease has primarily been based on constructs linking the C-terminus of the approximately 40 amino acid hydrophilic cofactor domain of NS2B to the N-terminus of NS3pro via a flexible glycine linker. The resulting complex can be expressed in high yield, is soluble and catalytically active and has been used for most in vitro screening, inhibitor, and X-ray crystallographic studies over the last 15 years. Despite extensive analysis, no inhibitor drug candidates have been identified yet. Moreover, the effect of the artificial linker introduced between the protease and its cofactor is unknown. Two alternate methods for bacterial expression of non covalently linked, catalytically active, NS2B-NS3pro complex are described here along with a comparison of the kinetics of substrate proteolysis and binding affinities of substrate-based aldehyde inhibitors. Both expression methods produced high yields of soluble protein with improved substrate proteolysis kinetics and inhibitor binding compared to their glycine-linked equivalent. The non-covalent association between NS2B and NS3pro is predicted to be more relevant for examining inhibitors that target cofactor-protease interactions rather than the protease active site. Furthermore, these approaches offer alternative strategies for the high yield co-expression of other protein assemblies. PMID- 26647368 TI - Sex, health and behaviour: Sexual reproduction might have emerged to provide better immunity against pathogens and further evolved to select for behaviour. PMID- 26647369 TI - Mapping proteome-wide interactions of reactive chemicals using chemoproteomic platforms. AB - A large number of pharmaceuticals, endogenous metabolites, and environmental chemicals act through covalent mechanisms with protein targets. Yet, their specific interactions with the proteome still remain poorly defined for most of these reactive chemicals. Deciphering direct protein targets of reactive small molecules is critical in understanding their biological action, off-target effects, potential toxicological liabilities, and development of safer and more selective agents. Chemoproteomic technologies have arisen as a powerful strategy that enable the assessment of proteome-wide interactions of these irreversible agents directly in complex biological systems. We review here several chemoproteomic strategies that have facilitated our understanding of specific protein interactions of irreversibly-acting pharmaceuticals, endogenous metabolites, and environmental electrophiles to reveal novel pharmacological, biological, and toxicological mechanisms. PMID- 26647370 TI - SBMDb: first whole genome putative microsatellite DNA marker database of sugarbeet for bioenergy and industrial applications. AB - DNA marker plays important role as valuable tools to increase crop productivity by finding plausible answers to genetic variations and linking the Quantitative Trait Loci (QTL) of beneficial trait. Prior approaches in development of Short Tandem Repeats (STR) markers were time consuming and inefficient. Recent methods invoking the development of STR markers using whole genomic or transcriptomics data has gained wide importance with immense potential in developing breeding and cultivator improvement approaches. Availability of whole genome sequences and in silico approaches has revolutionized bulk marker discovery. We report world's first sugarbeet whole genome marker discovery having 145 K markers along with 5 K functional domain markers unified in common platform using MySQL, Apache and PHP in SBMDb. Embedded markers and corresponding location information can be selected for desired chromosome, location/interval and primers can be generated using Primer3 core, integrated at backend. Our analyses revealed abundance of 'mono' repeat (76.82%) over 'di' repeats (13.68%). Highest density (671.05 markers/Mb) was found in chromosome 1 and lowest density (341.27 markers/Mb) in chromosome 6. Current investigation of sugarbeet genome marker density has direct implications in increasing mapping marker density. This will enable present linkage map having marker distance of ~2 cM, i.e. from 200 to 2.6 Kb, thus facilitating QTL/gene mapping. We also report e-PCR-based detection of 2027 polymorphic markers in panel of five genotypes. These markers can be used for DUS test of variety identification and MAS/GAS in variety improvement program. The present database presents wide source of potential markers for developing and implementing new approaches for molecular breeding required to accelerate industrious use of this crop, especially for sugar, health care products, medicines and color dye. Identified markers will also help in improvement of bioenergy trait of bioethanol and biogas production along with reaping advantage of crop efficiency in terms of low water and carbon footprint especially in era of climate change. Database URL: http://webapp.cabgrid.res.in/sbmdb/. PMID- 26647371 TI - Subclinical atherosclerotic risk in endurance-trained premenopausal amenorrheic women. AB - PURPOSE: In premenopausal women, amenorrhea contributes to endothelial dysfunction. It is unknown whether this vascular functional change is associated with vascular structural change. METHODS: This study examined regional and systemic vascular structure and function to gain insight into subclinical atherosclerotic risk in 10 amenorrheic athletes, 18 eumenorrheic athletes, and 15 recreationally active controls. Brachial flow-mediated dilation (FMD) and low flow mediated constriction (L-FMC) were used to measure global endothelial function. Carotid-femoral pulse wave velocity (PWV) was used to measure aortic stiffness. Doppler-ultrasound of the superficial femoral artery (SFA) was used to assess intima-media thickness (IMT) and vessel diameter as indicators of vascular remodeling. RESULTS: Amenorrheic athletes had significantly lower brachial FMD adjusted for shear stimulus (6.9 +/- 1.3%) compared with eumenorrheic athletes (11.0 +/- 1.0%) and controls (11.0 +/- 1.1%, p = 0.05). Brachial L-FMC (-1.8 +/- 4.3%) and aortic PWV (5.0 +/- 1.0 m/s) of amenorrheic athletes were similar to those of eumenorrheic athletes (L-FMC, -1.6 +/- 4.6%; PWV, 4.6 +/- 0.5 m/s) and controls (L-FMC, -1.5 +/- 2.8%, p = 0.98; PWV, 5.4 +/- 0.7 m/s, p = 0.15). SFA diameters were similar in amenorrheic athletes (5.7 +/- 0.7 mm) and eumenorrheic athletes (5.7 +/- 0.7 mm), but amenorrheic athletes had larger SFA diameters compared with controls (5.1 +/- 0.6 mm, p = 0.04). In amenorrheic athletes, SFA IMT (0.31 +/- 0.03 mm) was similar to that of eumenorrheic athletes (0.35 +/- 0.07 mm) but significantly thinner compared to that of controls (0.38 +/- 0.06, p = 0.01). CONCLUSION: Vascular dysfunction in female amenorrheic athletes is not systemic. Parenthetically, amenorrhea may not prevent favorable peripheral vascular structural adaptations to habitual exercise training. PMID- 26647372 TI - Contribution of vitamin D deficiency to the risk of coronary heart disease in subjects with essential hypertension. AB - BACKGROUND: Vitamin D deficiency is proposed as a risk factor for coronary heart disease (CHD). An inverse relation was observed between serum 25-Hydroxy-Vitamin D level and incidence of hypertension. This study aimed to evaluate the predictive value of serum 25-Hydroxy-Vitamin-D in improvement of CHD risk stratification in patients with hypertension. METHODS: In this cohort, we followed 1586 patients with essential hypertension (1078 diabetic and 508 non diabetic) for 8.5 years. Physician-adjudicated first hard CHD event was the primary outcome. Cox regression analysis was used to investigate the association between 25-Hydroxy-Vitamin-D quartiles and incident CHD. 25-Hydroxy-Vitamin-D was also added to the Framingham Risk Score (FRS) and Net-Reclassification Improvement (NRI) and Integrated-Discriminant-Improvement (IDI) were used to examine improved reclassification. RESULTS: During follow-up, 176 events were recorded. Patients in the lowest quartile of 25-Hydroxy-Vitamin-D experienced the most number of hard CHD events. A significant linear trend was observed in hazard ratios (HR) of incident hard CHD events in 25-Hydroxy-Vitamin-D quartiles which remained significant after multiple adjustments for conventional CHD risk-factors (HRs in full-adjusted model: 2.87 [1.76-4.70] for 1st quartile, 2.31 [1.39-3.83] for 2nd quartile and 1.87 [1.15-3.03] for 3rd quartile, compared with the highest quartile; p-for-trend<0.001). Addition of 25-Hydroxy-Vitamin-D to FRS could improve CHD risk-estimation (relative-IDI = 15%, p-value<0.001). Addition of 25 Hydroxy-Vitamin-D to FRS successfully reclassified 33% [18-49] of patients with hypertension among CHD risk groups (p-value<0.001). CONCLUSION: We observed that serum 25-Hydroxy-Vitamin-D is independently associated with future hard CHD events and improves its prediction in patients with essential hypertension. Addition of serum 25-Hydroxy-Vitamin-D to CHD risk-estimation models may have additive values. PMID- 26647373 TI - Serum- and HDL3-serum amyloid A and HDL3-LCAT activity are influenced by increased CVD-burden. AB - BACKGROUND: High density lipoproteins (HDL) protect against cardiovascular disease (CVD). However, increased serum amyloid-A (SAA) related inflammation may negate this property. This study investigated if SAA was related to CVD-burden. METHODS: Subjects referred to the rapid chest pain clinic (n = 240) had atherosclerotic burden assessed by cardiac computerised tomography angiography. Subjects were classified as: no-CVD (n = 106), non-obstructive-CVD, stenosis<50% (n = 58) or moderate/significant-CVD, stenosis >=50% (n = 76). HDL was subfractionated into HDL2 and HDL3 by rapid-ultracentrifugation. SAA concentration was measured by ELISA and lecithin cholesterol acyltransferase (LCAT) activity measured by a fluorimetric assay. RESULTS: We illustrated that serum-SAA and HDL3-SAA-concentration were higher and HDL3-LCAT-activity lower in the moderate/significant-CVD-group, compared to the no-CVD and non-obstructive CVD-groups (percent differences: serum-SAA, +33% & +30%: HDL3-SAA, +65% and +39%: HDL3-LCAT, -6% & -3%; p < 0.05 for all comparisons). We also identified a positive correlation between serum-SAA and HDL3-SAA (r = 0.698; p < 0.001) and a negative correlation between HDL3-SAA and HDL3-LCAT-activity (r = -0.295; p = 0.003), while CVD-burden positively correlated with serum-SAA (r = 0.150; p < 0.05) and HDL3-SAA (r = 0.252; p < 0.001) and negatively correlated with HDL3 LCAT-activity (r = -0.182; p = 0.006). Additionally, multivariate regression analysis adjusted for age, gender, CRP and serum-SAA illustrated that HDL3-SAA was significantly associated with modifying CVD-risk of moderate/significant CVD risk (p < 0.05). CONCLUSION: This study has demonstrated increased SAA-related inflammation in subjects with moderate/significant CVD-burden, which appeared to impact on the antiatherogenic potential of HDL. We suggest that SAA may be a useful biomarker to illustrate increased CVD-burden, although this requires further investigation. PMID- 26647374 TI - Oral Health Prevention and Toddler Well-Child Care: Routine Integration in a Safety Net System. AB - BACKGROUND AND OBJECTIVE: Applying topical fluoride varnish (FV) to young children's teeth is an effective therapeutic strategy for preventing early childhood caries (ECC). In 2008, the pediatricians at Contra Costa Regional Medical Center and Health Centers became concerned that our low-income pediatric patients had high rates of ECC and very limited access to dental care. We formed an interdisciplinary safety net-academic partnership with the University of California San Francisco to implement routine FV applications, along with oral health education, screening, and referral during well-child exams for children aged 1 to 5 years. METHODS: Over 3 years, the team developed clinical policies, educational materials, billing, and support systems to facilitate implementation in the primary care setting. A pilot study was performed in 2 health centers; improvements to the implementation plan were made. A team of local providers and academic partners performed system-wide didactic and hands-on trainings and spread this intervention to the remaining 6 health centers. Continued improvement strategies and provider feedback were pursued with each measurement cycle. RESULTS: In August 2012, 95% of all children aged 1 to 5 years who were seen for well-child checkups received a FV application and oral health education during their primary care well visit. Repeat measurement in April 2014 showed a sustained rate of 97% application of FV for children in this age group seen for well-child visits. CONCLUSIONS: With institutional commitment and an academic partnership, a safety net institution can integrate routine FV applications and oral health interventions into well-child visits to reduce ECC. PMID- 26647375 TI - Locations of Physical Activity as Assessed by GPS in Young Adolescents. AB - OBJECTIVES: To compare adolescents' physical activity at home, near home, at school, near school, and at other locations. METHODS: Adolescents (N = 549) were ages 12 to 16 years (49.9% girls, 31.3% nonwhite or Hispanic) from 447 census block groups in 2 US regions. Accelerometers and Global Positioning System devices assessed minutes of and proportion of time spent in moderate to vigorous physical activity (MVPA) in each of the 5 locations. Mixed-effects regression compared MVPA across locations and demographic factors. RESULTS: Forty-two percent of adolescents' overall MVPA occurred at school, 18.7% at home, 18.3% in other (nonhome, nonschool) locations, and 20.6% near home or school. Youth had 10 more minutes (30% more) of overall MVPA on school days than on nonschool days. However, the percentage of location time spent in MVPA was lowest at school (4.8% on school days) and highest near home and near school (9.5%-10.4%). Girls had 2.6 to 5.5 fewer minutes per day of MVPA than boys in all locations except near school. CONCLUSIONS: Although a majority of adolescents' physical activity occurred at school, the low proportion of active time relative to the large amount of time spent at school suggests potential for increasing school-based activity. Increasing time spent in the neighborhood appears promising for increasing overall physical activity, because a high proportion of neighborhood time was active. Increasing youth physical activity to support metabolic health requires strategies for increasing use of physical activity-supportive locations (eg, neighborhoods) and environmental and program improvements in unsupportive locations (eg, schools, homes). PMID- 26647376 TI - Recurrent Urinary Tract Infections in Children With Bladder and Bowel Dysfunction. AB - BACKGROUND: Little generalizable information is available on the outcomes of children diagnosed with bladder and bowel dysfunction (BBD) after a urinary tract infection (UTI). Our objectives were to describe the clinical characteristics of children with BBD and to examine the effects of BBD on patient outcomes in children with and without vesicoureteral reflux (VUR). METHODS: We combined data from 2 longitudinal studies (Randomized Intervention for Children With Vesicoureteral Reflux and Careful Urinary Tract Infection Evaluation) in which children <6 years of age with a first or second UTI were followed for 2 years. We compared outcomes for children with and without BBD, children with and without VUR, and children with VUR randomly assigned to prophylaxis or placebo. The outcomes examined were incidence of recurrent UTIs, renal scarring, surgical intervention, resolution of VUR, and treatment failure. RESULTS: BBD was present at baseline in 54% of the 181 toilet-trained children included; 94% of children with BBD reported daytime wetting, withholding maneuvers, or constipation. In children not on antimicrobial prophylaxis, 51% of those with both BBD and VUR experienced recurrent UTIs, compared with 20% of those with VUR alone, 35% with BBD alone, and 32% with neither BBD nor VUR. BBD was not associated with any of the other outcomes investigated. CONCLUSIONS: Among toilet-trained children, those with both BBD and VUR are at higher risk of developing recurrent UTIs than children with isolated VUR or children with isolated BBD and, accordingly, exhibit the greatest benefit from antimicrobial prophylaxis. PMID- 26647377 TI - Manta: rapid detection of structural variants and indels for germline and cancer sequencing applications. AB - : We describe Manta, a method to discover structural variants and indels from next generation sequencing data. Manta is optimized for rapid germline and somatic analysis, calling structural variants, medium-sized indels and large insertions on standard compute hardware in less than a tenth of the time that comparable methods require to identify only subsets of these variant types: for example NA12878 at 50* genomic coverage is analyzed in less than 20 min. Manta can discover and score variants based on supporting paired and split-read evidence, with scoring models optimized for germline analysis of diploid individuals and somatic analysis of tumor-normal sample pairs. Call quality is similar to or better than comparable methods, as determined by pedigree consistency of germline calls and comparison of somatic calls to COSMIC database variants. Manta consistently assembles a higher fraction of its calls to base pair resolution, allowing for improved downstream annotation and analysis of clinical significance. We provide Manta as a community resource to facilitate practical and routine structural variant analysis in clinical and research sequencing scenarios. AVAILABILITY AND IMPLEMENTATION: Manta is released under the open-source GPLv3 license. Source code, documentation and Linux binaries are available from https://github.com/Illumina/manta. CONTACT: csaunders@illumina.com SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26647379 TI - Simultaneous evaluation of substrate-dependent oxygen consumption rates and mitochondrial membrane potential by TMRM and safranin in cortical mitochondria. AB - Mitochondrial membrane potential (mtMP) is critical for maintaining the physiological function of the respiratory chain to generate ATP. The present study characterized the inter-relationship between mtMP, using safranin and tetramethyl rhodamine methyl ester (TMRM), and mitochondrial respiratory activity and established a protocol for functional analysis of mitochondrial bioenergetics in a multi-sensor system. Coupled respiration was decreased by 27 and 30-35% in the presence of TMRM and safranin respectively. Maximal respiration was higher than coupled with Complex I- and II-linked substrates in the presence of both dyes. Safranin showed decreased maximal respiration at a higher concentration of carbonyl cyanide-4-(trifluoromethoxy)phenylhydrazone (FCCP) compared with TMRM. FCCP titration revealed that maximal respiration in the presence of glutamate and malate was not sustainable at higher FCCP concentrations as compared with pyruvate and malate. Oxygen consumption rate (OCR) and mtMP in response to mitochondrial substrates were higher in isolated mitochondria compared with tissue homogenates. Safranin exhibited higher sensitivity to changes in mtMP than TMRM. This multi-sensor system measured mitochondrial parameters in the brain of transgenic mice that model Alzheimer's disease (AD), because mitochondrial dysfunction is believed to be a primary event in the pathogenesis of AD. The coupled and maximal respiration of electron transport chain were decreased in the cortex of AD mice along with the mtMP compared with age-matched controls. Overall, these data demonstrate that safranin and TMRM are suitable for the simultaneous evaluation of mtMP and respiratory chain activity using isolated mitochondria and tissue homogenate. However, certain care should be taken concerning the selection of appropriate substrates and dyes for specific experimental circumstances. PMID- 26647380 TI - Prospective Study on Salivary Evening Melatonin and Sleep before and after Pinealectomy in Humans. AB - Melatonin is secreted systemically from the pineal gland maximally at night but is also produced locally in many tissues. Its chronobiological function is mainly exerted by pineal melatonin. It is a feedback regulator of the main circadian pacemaker in the hypothalamic suprachiasmatic nuclei and of many peripheral oscillators. Although exogenous melatonin is approved for circadian rhythm sleep disorders and old-age insomnia, research on endogenous melatonin in humans is hindered by the great interindividual variability of its amount and circadian rhythm. Single case studies on pinealectomized patients report on disrupted but also hypersomnic sleep. This is the first systematic prospective report on sleep with respect to pinealectomy due to pinealocytoma World Health Organization grade I without chemo- or radiotherapy. Before and after pinealectomy, 8 patients completed questionnaires on sleep quality and circadian rhythm (Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale, and Morningness-Eveningness Questionnaire), 2 nights of polysomnography, salivary evening melatonin profiles, and qualitative assessment of 2 weeks of actigraphy and sleep logs. Six patients were assessed retrospectively up to 4 years after pinealectomy. Before pinealectomy, all but 1 patient showed an evening melatonin rise typical for indifferent chronotypes. After pinealectomy, evening saliva melatonin was markedly diminished, mostly below the detection limit of the assay (0.09 pg/mL). No systematic change in subjective sleep quality or standard measures of polysomnography was found. Mean pre- and postoperative sleep efficiency was 94% and 95%, and mean sleep-onset latency was 21 and 17 min, respectively. Sleep-wake rhythm during normal daily life did not change. Retrospective patients had a reduced sleep efficiency (90%) and more stage changes, although this was not significantly different from prospective patients. In conclusion, melatonin does seem to have a modulatory, not a regulatory, effect on standard measures of sleep. Study output is limited by small sample size and because only evening melatonin profiles were assessed. PMID- 26647378 TI - Yeast mitochondrial HMG proteins: DNA-binding properties of the most evolutionarily divergent component of mitochondrial nucleoids. AB - Yeast mtDNA is compacted into nucleoprotein structures called mitochondrial nucleoids (mt-nucleoids). The principal mediators of nucleoid formation are mitochondrial high-mobility group (HMG)-box containing (mtHMG) proteins. Although these proteins are some of the fastest evolving components of mt-nucleoids, it is not known whether the divergence of mtHMG proteins on the level of their amino acid sequences is accompanied by diversification of their biochemical properties. In the present study we performed a comparative biochemical analysis of yeast mtHMG proteins from Saccharomyces cerevisiae (ScAbf2p), Yarrowia lipolytica (YlMhb1p) and Candida parapsilosis (CpGcf1p). We found that all three proteins exhibit relatively weak binding to intact dsDNA. In fact, ScAbf2p and YlMhb1p bind quantitatively to this substrate only at very high protein to DNA ratios and CpGcf1p shows only negligible binding to dsDNA. In contrast, the proteins exhibit much higher preference for recombination intermediates such as Holliday junctions (HJ) and replication forks (RF). Therefore, we hypothesize that the roles of the yeast mtHMG proteins in maintenance and compaction of mtDNA in vivo are in large part mediated by their binding to recombination/replication intermediates. We also speculate that the distinct biochemical properties of CpGcf1p may represent one of the prerequisites for frequent evolutionary tinkering with the form of the mitochondrial genome in the CTG-clade of hemiascomycetous yeast species. PMID- 26647381 TI - Neurobiological Insights from mGlu Receptor Allosteric Modulation. AB - Allosteric modulation of metabotropic glutamate (mGlu) receptors offers a promising pharmacological approach to normalize neural circuit dysfunction associated with various psychiatric and neurological disorders. As mGlu receptor allosteric modulators progress through discovery and clinical development, both technical advances and novel tool compounds are providing opportunities to better understand mGlu receptor pharmacology and neurobiology. Recent advances in structural biology are elucidating the structural determinants of mGlu receptor negative allosteric modulation and supplying the means to resolve active, allosteric modulator-bound mGlu receptors. The discovery and characterization of allosteric modulators with novel pharmacological profiles is uncovering the biological significance of their intrinsic agonist activity, biased mGlu receptor modulation, and novel mGlu receptor heterodimers. The development and exploitation of optogenetic and optopharmacological tools is permitting a refined spatial and temporal understanding of both mGlu receptor functions and their allosteric modulation in intact brain circuits. Together, these lines of research promise to provide a more refined understanding of mGlu receptors and their allosteric modulation that will inform the development of mGlu receptor allosteric modulators as neurotherapeutics in the years to come. PMID- 26647382 TI - Serotonin 5-HT7 Receptor in the Ventral Hippocampus Modulates the Retrieval of Fear Memory and Stress-Induced Defecation. AB - BACKGROUND: Patients with posttraumatic stress disorder or panic disorder are often troubled by inappropriate retrieval of fear memory. Moreover, these disorders are often comorbid with irritable bowel syndrome. The main aim of the present study is to elucidate the involvement of hippocampal serotonergic systems in fear memory retrieval and stress-induced defecation. METHODS AND RESULTS: Microinjection of serotonin7 receptor antagonist, but not other serotonin receptor antagonists (serotonin 1A, 2A, 2C, 3, 4, and 6), into the rat ventral hippocampus significantly suppressed the expression of freezing behavior, an index of fear memory retrieval, and decreased the amount of feces, an index of stress-induced defecation, in the contextual fear conditioning test. Electrophysiological data indicated that the serotonin7 receptor agonist increased the frequency of action potentials in the ventral hippocampal CA3 pyramidal neuron via the activation of the hyperpolarization-activated nonselective cation current Ih. Moreover, in situ hybridization demonstrated that Htr7 mRNA was abundantly expressed in the CA3 compared with other subregions of the hippocampus and that these Htr7 mRNA-positive cells coexpressed hyperpolarization-activated cyclic nucleotide-gated channel 2 and 4 mRNAs, which are components of the Ih channel. CONCLUSIONS: These results indicated that the released serotonin activates the serotonin7 receptor in the CA3 ventral hippocampus subregion, enhances the sensitivity to inputs via hyperpolarization activated cyclic nucleotide 2 and 4 channels, and thereby facilitates fear memory retrieval. The serotonin7 receptor might be a target of drug development for the treatment of mental disorders involving fear memory and gastrointestinal problems. PMID- 26647383 TI - Hyperglycaemia-induced chemoresistance in breast cancer cells: role of the estrogen receptor. AB - Breast cancer patients with diabetes respond less well to chemotherapy; in keeping with this we determined previously that hyperglycaemia-induced chemoresistance in estrogen receptor (ERalpha) positive breast cancer cells and showed that this was mediated by fatty acid synthase (FASN). More recent evidence suggests that the effect of metabolic syndrome and diabetes is not the same for all subtypes of breast cancer with inferior disease-free survival and worse overall survival only found in women with ERalpha positive breast cancer and not for other subtypes. Here we examined the impact of hyperglycaemia on ERalpha negative breast cancer cells and further investigated the mechanism underlying chemoresistance in ERalpha with a view to identifying strategies to alleviate hyperglycaemia-induced chemoresistance. We found that hyperglycaemia-induced chemoresistance was only observed in ERalpha breast cancer cells and was dependent upon the expression of ERalpha as chemoresistance was negated when the ERalpha was silenced. Hyperglycaemia-induced an increase in activation and nuclear localisation of the ERalpha that was downstream of FASN and dependent on the activation of MAPK. We found that fulvestrant successfully negated the hyperglycaemia-induced chemoresistance, whereas tamoxifen had no effect. In summary our data suggests that the ERalpha may be a predictive marker of poor response to chemotherapy in breast cancer patients with diabetes. It further indicates that anti-estrogens could be an effective adjuvant to chemotherapy in such patients and indicates the importance for the personalised management of breast cancer patients with diabetes highlighting the need for clinical trials of tailored chemotherapy for diabetic patients diagnosed with ERalpha positive breast cancers. PMID- 26647384 TI - TGFbeta signaling regulates epithelial-mesenchymal plasticity in ovarian cancer ascites-derived spheroids. AB - Epithelial-mesenchymal transition (EMT) serves as a key mechanism driving tumor cell migration, invasion, and metastasis in many carcinomas. Transforming growth factor-beta (TGFbeta) signaling is implicated in several steps during cancer pathogenesis and acts as a classical inducer of EMT. Since epithelial ovarian cancer (EOC) cells have the potential to switch between epithelial and mesenchymal states during metastasis, we predicted that modulation of TGFbeta signaling would significantly impact EMT and the malignant potential of EOC spheroid cells. Ovarian cancer patient ascites-derived cells naturally underwent an EMT response when aggregating into spheroids, and this was reversed upon spheroid re-attachment to a substratum. CDH1/E-cadherin expression was markedly reduced in spheroids compared with adherent cells, in concert with an up regulation of several transcriptional repressors, i.e., SNAI1/Snail, TWIST1/2, and ZEB2. Treatment of EOC spheroids with the TGFbeta type I receptor inhibitor, SB-431542, potently blocked the endogenous activation of EMT in spheroids. Furthermore, treatment of spheroids with SB-431542 upon re-attachment enhanced the epithelial phenotype of dispersing cells and significantly decreased cell motility and Transwell migration. Spheroid formation was significantly compromised by exposure to SB-431542 that correlated with a reduction in cell viability particularly in combination with carboplatin treatment. Thus, our findings are the first to demonstrate that intact TGFbeta signaling is required to control EMT in EOC ascites-derived cell spheroids, and it promotes the malignant characteristics of these structures. As such, we show the therapeutic potential for targeted inhibition of this pathway in ovarian cancer patients with late-stage disease. PMID- 26647385 TI - Restoration of Nrf2 Signaling Normalizes the Regenerative Niche. AB - Chronic hyperglycemia impairs intracellular redox homeostasis and contributes to impaired diabetic tissue regeneration. The Keap1/Nrf2 pathway is a critical regulator of the endogenous antioxidant response system, and its dysfunction has been implicated in numerous pathologies. Here we characterize the effect of chronic hyperglycemia on Nrf2 signaling within a diabetic cutaneous regeneration model. We characterized the effects of chronic hyperglycemia on the Keap1/Nrf2 pathway within models of diabetic cutaneous wound regeneration. We assessed reactive oxygen species (ROS) production and antioxidant gene expression following alterations in the Nrf2 suppressor Keap1 and the subsequent changes in Nrf2 signaling. We also developed a topical small interfering RNA (siRNA)-based therapy to restore redox homeostasis within diabetic wounds. Western blotting demonstrated that chronic hyperglycemia-associated oxidative stress inhibits nuclear translocation of Nrf2 and impairs activation of antioxidant genes, thus contributing to ROS accumulation. Keap1 inhibition increased Nrf2 nuclear translocation, increased antioxidant gene expression, and reduced ROS production to normoglycemic levels, both in vitro and in vivo. Topical siKeap1 therapy resulted in improved regenerative capacity of diabetic wounds and accelerated closure. We report that chronic hyperglycemia weakens the endogenous antioxidant response, and the consequences of this defect are manifested by intracellular redox dysregulation, which can be restored by Keap1 inhibition. Targeted siRNA based therapy represents a novel, efficacious strategy to reestablish redox homeostasis and accelerate diabetic cutaneous tissue regeneration. PMID- 26647387 TI - System-L amino acid transporters play a key role in pancreatic beta-cell signalling and function. AB - The branched-chain amino acids (BCAA) leucine, isoleucine and valine, are essential amino acids that play a critical role in cellular signalling and metabolism. They acutely stimulate insulin secretion and activate the regulatory serine/threonine kinase mammalian target of rapamycin complex 1 (mTORC1), a kinase that promotes increased beta-cell mass and function. The effects of BCAA on cellular function are dependent on their active transport into the mammalian cells via amino acid transporters and thus the expression and activity of these transporters likely influence beta-cell signalling and function. In this report, we show that the System-L transporters are required for BCAA uptake into clonal beta-cell lines and pancreatic islets, and that these are essential for signalling to mTORC1. Further investigation revealed that the System-L amino acid transporter 1 (LAT1) is abundantly expressed in the islets, and that knockdown of LAT1 using siRNA inhibits mTORC1 signalling, leucine-stimulated insulin secretion and islet cell proliferation. In summary, we show that the LAT1 is required for regulating beta-cell signalling and function in islets and thus may be a novel pharmacological/nutritional target for the treatment and prevention of type 2 diabetes. PMID- 26647386 TI - Monitoring C-Peptide Storage and Secretion in Islet beta-Cells In Vitro and In Vivo. AB - Human proinsulin with C-peptide-bearing Superfolder Green Fluorescent Protein (CpepSfGFP) has been expressed in transgenic mice, driven by the Ins1 promoter. The protein, expressed exclusively in beta-cells, is processed and stored as CpepSfGFP and human insulin comprising only ~0.04% of total islet proinsulin plus insulin, exerting no metabolic impact. The kinetics of the release of insulin and CpepSfGFP from isolated islets appear identical. Upon a single acute stimulatory challenge in vitro, fractional release of insulin does not detectably deplete islet fluorescence. In vivo, fluorescence imaging of the pancreatic surface allows, for the first time, visual assessment of pancreatic islet insulin content, and we demonstrate that CpepSfGFP visibly declines upon diabetes progression in live lepR(db/db) mice. In anesthetized mice, after intragastric or intravenous saline delivery, pancreatic CpepSfGFP (insulin) content remains undiminished. Remarkably, however, within 20 min after acute intragastric or intravenous glucose delivery (with blood glucose concentrations reaching >15 mmol/L), a small subset of islets shows rapid dispossession of a major fraction of their stored CpepSfGFP (insulin) content, whereas most islets exhibit no demonstrable loss of CpepSfGFP (insulin). These studies strongly suggest that there are "first responder" islets to an in vivo glycemic challenge, which cannot be replicated by islets in vitro. PMID- 26647388 TI - Calcium-dependent Nr4a1 expression in mouse Leydig cells requires distinct AP1/CRE and MEF2 elements. AB - The nuclear receptor NR4A1 is expressed in steroidogenic Leydig cells where it plays pivotal roles by regulating the expression of several genes involved in steroidogenesis and male sex differentiation including Star, HSD3B2, and Insl3 Activation of the cAMP and Ca(2+) signaling pathways in response to LH stimulation leads to a rapid and robust activation of Nr4a1 gene expression that requires the Ca(2+)/CAMKI pathway. However, the downstream transcription factor(s) have yet to be characterized. To identify potential Ca(2+)/CaM effectors responsible for hormone-induced Nr4a1 expression, MA-10 Leydig cells were treated with forskolin to increase endogenous cAMP levels, dantrolene to inhibit endoplasmic reticulum Ca(2+) release, and W7 to inhibit CaM activity. We identified Ca(2+)-responsive elements located in the discrete regions of the Nr4a1 promoter, which contain binding sites for several transcription factors such as AP1, CREB, and MEF2. We found that one of the three AP1/CRE sites located at -255 bp is the most responsive to the Ca(2+) signaling pathway as are the two MEF2 binding sites at -315 and -285 bp. Furthermore, we found that the hormone induced recruitment of phospho-CREB and of the co-activator p300 to the Nr4a1 promoter requires the Ca(2+) pathway. Lastly, siRNA-mediated knockdown of CREB impaired NR4A1 expression and steroidogenesis. Together, our data indicate that the Ca(2+) signaling pathway increases Nr4a1 expression in MA-10 Leydig cells, at least in part, by enhancing the recruitment of coactivator most likely through the MEF2, AP1, and CREB transcription factors thus demonstrating an important interplay between the Ca(2+) and cAMP pathways in regulating Nr4a1 expression. PMID- 26647389 TI - Exendin-4 promotes proliferation and differentiation of MC3T3-E1 osteoblasts by MAPKs activation. AB - Glucagon-like peptide-1 (GLP1) and its receptor agonist have been previously reported to play a positive role in bone metabolism in aged ovariectomized rats and insulin-resistant models. However, whether GLP1 has a direct effect on the proliferation and differentiation of osteoblasts or any cellular mechanism for this potential role is unknown. We examined the effects of the GLP1 receptor agonist exendin-4 on the proliferation, differentiation, and mineralization of mouse osteoblastic MC3T3-E1 cells. GLP1 receptor was detected in MC3T3-E1 cells by polymerase chain reaction (PCR) and Western blot assay. Cell proliferation was assessed using MTT assay, revealing that exendin-4 increased cell proliferation at effective concentrations between 10(-10) and 10(-5) M. Quantitative PCR analysis showed that exendin-4 increased the mRNA expression of the differentiation markers alkaline phosphatase (ALP), collagen-1 (COL1), osteocalcin (OC), and runt-related transcription factor 2 (RUNX2) under osteogenic conditions. Alizarin red staining confirmed that 10(-7) M exendin-4 increased osteoblast mineralization by 18.7%. Exendin-4 upregulated the phosphorylation of ERK1/2, p38, and JNK, with the peak effect at 1.5 h in the Western blot analysis. The use of selective MAPK inhibitors, namely PD98059, SB203580, and SP600125, blocked the effects of exendin-4 on kinase activation (ERK1/2, p38, and JNK), as well as cell proliferation and differentiation in MC3T3-E1 cells. These findings demonstrate that exendin-4 promotes both the proliferation and differentiation of preosteoblasts MC3T3-E1 via activation of the MAPK pathway. PMID- 26647390 TI - FT-Raman Spectroscopy Study of the Remineralization of Microwave-Exposed Artificial Caries. AB - Dental caries is a microbially mediated disease that can result in significant tooth structure degradation. Although the preponderance of lesions is treated by surgical intervention, various strategies have been developed for its noninvasive management. Here, we use a novel approach for noninvasive treatment based on killing Streptococcus mutans with high-frequency microwave energy (ME). The rationale for this approach is based on modulating the pH of caries to a physiological state to enable spontaneous tooth remineralization from exogenous sources. In the present study, after demonstrating that ME kills >99% of S. mutans in planktonic cultures, 8 enamel slabs were harvested from a single tooth. Baseline mineral concentration at each of 12 points per slab was obtained using Fourier transform (FT)-Raman spectroscopy. Surface demineralization was subsequently promoted by subjecting all samples to an S. mutans acidic biofilm for 6 d. Half of the samples were then exposed to high-frequency ME, and the other half were used as controls. All samples were next subjected to a remineralization protocol consisting of two 45-min exposures per 24-h period in tryptic soy broth followed by immersion in a remineralizing solution for the remaining period. After 10 d, samples were removed and cleaned. FT-Raman spectra were again obtained at the same 12 points per sample, and the mineral concentration was determined. The effect of the remineralization protocol on the demineralized slabs was expressed as a percentage of mineral loss or gain relative to baseline. The mineral concentration of the microwave-exposed group collectively approached 100% of baseline values, while that of the control group was in the order of 40%. Differences between groups were significant (P = 0.001, Mann-Whitney U test). We concluded that killing of S. mutans by ME promotes effective remineralization of S. mutans-demineralized enamel compared with controls. PMID- 26647391 TI - Predicting Dental Caries Outcomes in Children: A "Risky" Concept. AB - In recent years, unprecedented gains in the understanding of the biology and mechanisms underlying human health and disease have been made. In the domain of oral health, although much remains to be learned, the complex interactions between different systems in play have begun to unravel: host genome, oral microbiome with its transcriptome, proteome and metabolome, and more distal influences, including relevant behaviors and environmental exposures. A reasonable expectation is that this emerging body of knowledge can help improve the oral health and optimize care for individuals and populations. These goals are articulated by the National Institutes of Health as "precision medicine" and the elimination of health disparities. Key processes in these efforts are the discovery of causal factors or mechanistic pathways and the identification of individuals or population segments that are most likely to develop (any or severe forms of) oral disease. This article critically reviews the fundamental concepts of risk assessment and outcome prediction, as they relate to early childhood caries (ECC)-a common complex disease with significant negative impacts on children, their families, and the health system. The article highlights recent work and advances in methods available to estimate caries risk and derive person level caries propensities. It further discusses the reasons for their limited utility in predicting individual ECC outcomes and informing clinical decision making. Critical issues identified include the misconception of defining dental caries as a tooth or surface-level condition versus a person-level disease; the fallacy of applying population-level parameters to individuals, termed privatization of risk; and the inadequacy of using frequentist versus Bayesian modeling approaches to derive individual disease propensity estimates. The article concludes with the notion that accurate caries risk assessment at the population level and "precision dentistry" at the person level are both desirable and achievable but must be based on high-quality longitudinal data and rigorous methodology. PMID- 26647392 TI - ICAM-1-expressing neutrophils exhibit enhanced effector functions in murine models of endotoxemia. AB - Intracellular adhesion molecule-1 (ICAM-1) is a transmembrane glycoprotein expressed on the cell surface of numerous cell types such as endothelial and epithelial cells, vascular smooth muscle cells, and certain leukocyte subsets. With respect to the latter, ICAM-1 has been detected on neutrophils in several clinical and experimental settings, but little is known about the regulation of expression or function of neutrophil ICAM-1. In this study, we report on the de novo induction of ICAM-1 on the cell surface of murine neutrophils by lipopolysaccharide (LPS), tumor necrosis factor, and zymosan particles in vitro. The induction of neutrophil ICAM-1 was associated with enhanced phagocytosis of zymosan particles and reactive oxygen species (ROS) generation. Conversely, neutrophils from ICAM-1-deficient mice were defective in these effector functions. Mechanistically, ICAM-1-mediated intracellular signaling appeared to support neutrophil ROS generation and phagocytosis. In vivo, LPS-induced inflammation in the mouse cremaster muscle and peritoneal cavity led to ICAM-1 expression on intravascular and locally transmigrated neutrophils. The use of chimeric mice deficient in ICAM-1 on myeloid cells demonstrated that neutrophil ICAM-1 was not required for local neutrophil transmigration, but supported optimal intravascular and extravascular phagocytosis of zymosan particles. Collectively, the present results shed light on regulation of expression and function of ICAM-1 on neutrophils and identify it as an additional regulator of neutrophil effector responses in host defense. PMID- 26647393 TI - A CCR2 macrophage endocytic pathway mediates extravascular fibrin clearance in vivo. AB - Extravascular fibrin deposition accompanies many human diseases and causes chronic inflammation and organ damage, unless removed in a timely manner. Here, we used intravital microscopy to investigate how fibrin is removed from extravascular space. Fibrin placed into the dermis of mice underwent cellular endocytosis and lysosomal targeting, revealing a novel intracellular pathway for extravascular fibrin degradation. A C-C chemokine receptor type 2 (CCR2)-positive macrophage subpopulation constituted the majority of fibrin-uptaking cells. Consequently, cellular fibrin uptake was diminished by elimination of CCR2 expressing cells. The CCR2-positive macrophage subtype was different from collagen-internalizing M2-like macrophages. Cellular fibrin uptake was strictly dependent on plasminogen and plasminogen activator. Surprisingly, however, fibrin endocytosis was unimpeded by the absence of the fibrin(ogen) receptors, alphaMbeta2 and ICAM-1, the myeloid cell integrin-binding site on fibrin or the endocytic collagen receptor, the mannose receptor. The study identifies a novel fibrin endocytic pathway engaged in extravascular fibrin clearance and shows that interstitial fibrin and collagen are cleared by different subsets of macrophages employing distinct molecular pathways. PMID- 26647394 TI - CCL5 derived from platelets increases megakaryocyte proplatelet formation. AB - In times of physiological stress, platelet count can transiently rise. What initiates this reactive thrombocytosis is poorly understood. Intriguingly, we found that treating megakaryocytes (MKs) with the releasate from activated platelets increased proplatelet production by 47%. Platelets store inflammatory cytokines, including the chemokine ligand 5 (CCL5, RANTES); after TRAP activation, platelets release over 25 ng/mL CCL5. We hypothesized that CCL5 could regulate platelet production by binding to its receptor, CCR5, on MKs. Maraviroc (CCR5 antagonist) or CCL5 immunodepletion diminished 95% and 70% of the effect of platelet releasate, respectively, suggesting CCL5 derived from platelets is sufficient to drive increased platelet production through MK CCR5. MKs cultured with recombinant CCL5 increased proplatelet production by 50% and had significantly higher ploidy. Pretreating the MK cultures with maraviroc prior to exposure to CCL5 reversed the augmented proplatelet formation and ploidy, suggesting that CCL5 increases MK ploidy and proplatelet formation in a CCR5 dependent manner. Interrogation of the Akt signaling pathway suggested that CCL5/CCR5 may influence proplatelet production by suppressing apoptosis. In an in vivo murine acute colitis model, platelet count significantly correlated with inflammation whereas maraviroc treatment abolished this correlation. We propose that CCL5 signaling through CCR5 may increase platelet counts during physiological stress. PMID- 26647395 TI - Ischemic heart disease among the general Mongolian population: a review of epidemiological studies. AB - Ischemic heart disease (IHD) is considered to be a pivotal health problem in Mongolia. To summarize the existing epidemiology of IHD in the general Mongolian population is crucial for primary prevention. The present review summarized population-based epidemiological data of IHD in Mongolia. When epidemiological studies were extracted from databases, very limited studies were available. The frequencies of IHD and IHD-attributable death rates appeared to be high and have an increased tendency in Mongolia. This could to be due to a gradually worsening state of potential IHD-related risk factors, such as smoking, hypertension, hypercholesterolemia, obesity and diabetes mellitus. This might indicate an urgent need of strategies for IHD and related risk factors. Anti-IHD strategies, such as more epidemiological studies and campaigns to increase awareness of IHD, at nationwide public health levels would be required in Mongolia for more effective prevention. PMID- 26647396 TI - Are school-level factors associated with primary school students' experience of physical violence from school staff in Uganda? AB - BACKGROUND: The nature and structure of the school environment has the potential to shape children's health and well being. Few studies have explored the importance of school-level factors in explaining a child's likelihood of experiencing violence from school staff, particularly in low-resource settings such as Uganda. METHODS: To quantify to what extent a student's risk of violence is determined by school-level factors we fitted multilevel logistic regression models to investigate associations and present between-school variance partition coefficients. School structural factors, academic and supportive environment are explored. RESULTS: 53% of students reported physical violence from staff. Only 6% of variation in students' experience of violence was due to differences between schools and half the variation was explained by the school-level factors modelled. Schools with a higher proportion of girls are associated with increased odds of physical violence from staff. Students in schools with a high level of student perceptions of school connectedness have a 36% reduced odds of experiencing physical violence from staff, but no other school-level factor was significantly associated. CONCLUSION: Our findings suggest that physical violence by school staff is widespread across different types of schools in this setting, but interventions that improve students' school connectedness should be considered. PMID- 26647397 TI - Acral necrosis induced by sodium morrhuate sclerotherapy in infantile haemangioma: a case report. PMID- 26647398 TI - Toscana virus encephalitis following a holiday in Sicily. AB - We report a case of Toscana virus encephalitis. This emerging pathogen is among the three most common causes of meningoencephalitis in Europe during the warm season, yet remains under-recognised. Doctors should consider Toscana virus infection in patients presenting with neurological symptoms who have a relevant exposure history during the summer months. PMID- 26647399 TI - Mental health problems contribute to a quarter of "later" maternal deaths after childbirth. PMID- 26647401 TI - European guideline for managing sexually acquired reactive arthritis. PMID- 26647400 TI - Structural features determining thermal adaptation of esterases. AB - The adaptation of microorganisms to extreme living temperatures requires the evolution of enzymes with a high catalytic efficiency under these conditions. Such extremophilic enzymes represent valuable tools to study the relationship between protein stability, dynamics and function. Nevertheless, the multiple effects of temperature on the structure and function of enzymes are still poorly understood at the molecular level. Our analysis of four homologous esterases isolated from bacteria living at temperatures ranging from 10 degrees C to 70 degrees C suggested an adaptation route for the modulation of protein thermal properties through the optimization of local flexibility at the protein surface. While the biochemical properties of the recombinant esterases are conserved, their thermal properties have evolved to resemble those of the respective bacterial habitats. Molecular dynamics simulations at temperatures around the optimal temperatures for enzyme catalysis revealed temperature-dependent flexibility of four surface-exposed loops. While the flexibility of some loops increased with raising the temperature and decreased with lowering the temperature, as expected for those loops contributing to the protein stability, other loops showed an increment of flexibility upon lowering and raising the temperature. Preserved flexibility in these regions seems to be important for proper enzyme function. The structural differences of these four loops, distant from the active site, are substantially larger than for the overall protein structure, indicating that amino acid exchanges within these loops occurred more frequently thereby allowing the bacteria to tune atomic interactions for different temperature requirements without interfering with the overall enzyme function. PMID- 26647402 TI - Music Therapy Assessment Tool for Awareness in Disorders of Consciousness (MATADOC): Reliability and Validity of a Measure to Assess Awareness in Patients with Disorders of Consciousness. AB - BACKGROUND: Prolonged Disorders of Consciousness (PDOC) describes a population where a consciousness disorder has persisted for at least four weeks post injury but is still under investigation. Complex motor, sensory, communication, and cognitive impairments cause challenges with diagnosis, assessment, and intervention planning. Developing sensitive, reliable, and valid measures is a central concern. The auditory modality is the most sensitive for identifying awareness; however, the current standardized behavioral measures fail to provide adequate screening and measurement of auditory responsiveness. The Music Therapy Assessment Tool for Awareness in Disorders of Consciousness (MATADOC) is a recently standardized measure for assessment with PDOC; however, psychometric values for two of its subscales require examination. OBJECTIVE: To determine the measurement characteristics and properties of the MATADOC subscales two and three. METHODS: In a convenience sample of 21participants with PDOC, a prospective repeated measures study examined inter-rater reliability (IRR) and test-retest reliability (TRR) for both subscales and internal consistency of subscale two. RESULTS: Overall, the items from the MATADOC subscales two and three demonstrated good agreement across and within assessors, with some variability on two identified items. CONCLUSIONS: The MATADOC is a standardized measure for assessment of auditory responsiveness in PDOC. Psychometric limitations for the two identified items may have resulted from variations in music therapist clinical experience and training, leading to variations in the administration and interpretation of PDOC patient responses to these two MATADOC assessment items. Although its psychometric properties could be improved, the MATADOC's clinimetric properties make it a valuable assessment to guide clinical work for patients with PDOC. PMID- 26647403 TI - Getting Messy: Playing, and Engaging the Creative, within Research Inquiry. PMID- 26647404 TI - Parents and Young Children with Disabilities: The Effects of a Home-Based Music Therapy Program on Parent-Child Interactions. AB - BACKGROUND: Responsive parenting style and synchronous parent-child interactions have a positive impact on children in terms of language, cognitive, and social emotional development. Despite widely documented benefits of music therapy on parent-child interactions, empirical evidence for the effects of music therapy on parent-child synchrony is lacking. OBJECTIVE: To examine effects of parent-child dyads' participation in a six-week home-based music therapy program on parent response, child initiation, and parent-child synchrony, as well as parents' daily use of musical activities with their child. METHODS: Twenty-six parent-child dyads participated in this pretest-posttest within-subject single-group design study. Participating dyads included parents and their child with disabilities or developmental delays (ages 1-3 years inclusive). Parent-child dyads participated in a home-based music therapy program that included six weekly 40-minute sessions, and incorporated five responsive teaching strategies (i.e., affect, match, reciprocity, shared control, and contingency). Observational data were recorded for parent-child interactions and parent-child synchrony. RESULTS: Parents' positive physical and verbal responses, as well as children's positive verbal initiations, increased significantly pre- to post-intervention; however, children's positive physical initiations did not increase significantly. Parent child synchrony also improved significantly pre- to post-intervention. CONCLUSIONS: Findings support the use of home-based music therapy programs to facilitate parent-child interactions in the areas of parental responsiveness and child-initiated communication, as well as parent-child synchrony. PMID- 26647405 TI - Innate-like function of memory Th17 cells for enhancing endotoxin-induced acute lung inflammation through IL-22. AB - Lipopolysaccharide (LPS)-induced acute lung injury (ALI) is known as a mouse model of acute respiratory distress syndrome; however, the function of T-cell derived cytokines in ALI has not yet been established. We found that LPS challenge in one lung resulted in a rapid induction of innate-type pro inflammatory cytokines such as IL-6 and TNF-alpha, followed by the expression of T-cell-type cytokines, including IL-17, IL-22 and IFN-gamma. We discovered that IL-23 is important for ALI, since blockage of IL-23 by gene disruption or anti-IL 12/23p40 antibody treatment reduced neutrophil infiltration and inflammatory cytokine secretion into the bronchoalveolar lavage fluid (BALF). IL-23 was mostly produced from F4/80(+)CD11c(+) alveolar macrophages, and IL-23 expression was markedly reduced by the pre-treatment of mice with antibiotics, suggesting that the development of IL-23-producing macrophages required commensal bacteria. Unexpectedly, among T-cell-derived cytokines, IL-22 rather than IL-17 or IFN gamma played a major role in LPS-induced ALI. IL-22 protein levels were higher than IL-17 in the BALF after LPS instillation, and the major source of IL-22 was memory Th17 cells. Lung memory CD4(+) T cells had a potential to produce IL-22 at higher levels than IL-17 in response to IL-1beta plus IL-23 without TCR stimulation. Our study revealed an innate-like function of the lung memory Th17 cells that produce IL-22 in response to IL-23 and are involved in exaggeration of ALI. PMID- 26647407 TI - Ketamine for Analgosedation in the Intensive Care Unit: A Systematic Review. AB - OBJECTIVE: To evaluate the evidence for the use of intravenous ketamine for analgosedation in the intensive care unit. METHODS: MEDLINE and EMBASE were queried from inception until July 2015. Search terms used included ketamine, intensive care, and critical care. The search retrieved 584 articles to be screened for inclusion. The intent was to include randomized controlled studies using sustained intravenous infusions (>24 hours) of ketamine in the critically ill patients. RESULTS: One trial evaluated opioid consumption as an outcome in postoperative critically ill patients who were randomized to ketamine or saline infusions. The mean cumulative morphine consumption at 48 hours was significantly lower in the ketamine group (58 +/- 35 mg) compared to the morphine-only group (80 +/- 37 mg; P < .05). Other trials showed the potential safety of ketamine in terms of cerebral hemodynamics in patients with traumatic brain injury, improved gastrointestinal motility, and decreased vasopressor requirements. The observational study and case reports suggest that ketamine is safe and effective and may have a role in patients who are refractory to other therapies. CONCLUSION: Ketamine use may decrease analgesic consumption in the intensive care unit. Additional trials are needed to further delineate the role of ketamine for analgosedation. PMID- 26647406 TI - Therapeutic potential of regulatory cytokines that target B cells. AB - Autoreactive B cells play a crucial role in the pathogenesis of autoimmune diseases by producing auto-antibodies and presenting antigens. Regulatory cytokines that simultaneously suppress multiple pathways have the potential to control autoreactive B cells. The generally inhibitory cytokine IL-10 may have a stimulatory effect on human B-cell survival and antibody production. TGF-beta family cytokines can decrease or increase antibody production and can suppress B cell proliferation and differentiation. In contrast to TGF-beta1, which induces extensive fibrosis, TGF-beta3 and bone morphogenetic protein 6 (BMP-6)/BMP-7 induce non-scarring wound healing and counteract tissue fibrosis. Therefore, TGF beta3 and BMP-6/BMP-7 may be clinically applicable as therapeutic cytokines that target B cells. Recent progress in protein engineering may enable us to generate novel biologic therapies based on TGF-beta family cytokines. PMID- 26647408 TI - Critical Care Management of Cerebral Edema in Brain Tumors. AB - Cerebral edema associated with brain tumors is extremely common and can occur in both primary and metastatic tumors. The edema surrounding brain tumors results from leakage of plasma across the vessel wall into the parenchyma secondary to disruption of the blood-brain barrier. The clinical signs of brain tumor edema depend on the location of the tumor as well as the extent of the edema, which often exceeds the mass effect induced by the tumor itself. Uncontrolled cerebral edema may result in increased intracranial pressure and acute herniation syndromes that can result in permanent neurological dysfunction and potentially fatal herniation. Treatment strategies for elevated intracranial pressure consist of general measures, medical interventions, and surgery. Alhough the definitive treatment for the edema may ultimately be surgical resection of the tumor, the impact of the critical care management cannot be underestimated and thus patients must be vigilantly monitored in the intensive care unit. In this review, we discuss the pathology, pathophysiology, and clinical features of patients presenting with cerebral edema. Imaging findings and treatment modalities used in the intensive care unit are also discussed. PMID- 26647409 TI - HIF-1alpha Inhibition Sensitized Pituitary Adenoma Cells to Temozolomide by Regulating Presenilin 1 Expression and Autophagy. AB - Pituitary adenomas usually develop temozolomide resistance, which could compromise the anticancer effects of temozolomide. Suppression of hypoxia inducible factor 1alpha has been shown to sensitize glioblastoma cells to temozolomide treatment according to previous reports. However, whether and how the suppression of hypoxia-inducible factor 1alpha could sensitize pituitary adenomas to temozolomide treatment are still poorly understood. In the present study, using hypoxia-inducible factor 1alpha knockdown strategy, we demonstrated for the first time that hypoxia-inducible factor 1alpha knockdown could inhibit temozolomide-induced autophagy in rat pituitary adenoma GH3 cells and thus increase antitumor efficacy of temozolomide. Furthermore, we found hypoxia inducible factor 1alpha knockdown could block autophagy process through neutralizing lysosomal pH value but not inhibiting autophagy induction. Finally, we found hypoxia-inducible factor 1alpha could regulate lysosomal pH value through regulating full length presenilin 1 expression, and exogenous reexpression of presenilin 1could restore lysosome acidic levels. Our data indicated hypoxia-inducible factor 1alpha knockdown could be a potential approach to improve the efficacy of temozolomide therapy for pituitary adenomas. PMID- 26647410 TI - Characteristics of Homicide-Suicide in Australia: A Comparison With Homicide-Only and Suicide-Only Cases. AB - Homicide-suicide represents one of the rarest forms of lethal violence but often precipitates calls to revise social, health, and justice policies. However, there is little empirical information about this type of violence. The current study uses two unique data sets to examine a wide range of individual and situational characteristics of homicide-suicide, with particular emphasis on establishing whether and how homicide-suicide differs from homicide-only and suicide-only. Findings suggest homicide-suicide may have unique characteristics that set it apart from both homicide-only and suicide-only, as well as sharing certain other characteristics with those two types of events. PMID- 26647411 TI - Beyond clinical engagement: a pragmatic model for quality improvement interventions, aligning clinical and managerial priorities. AB - Despite taking advantage of established learning from other industries, quality improvement initiatives in healthcare may struggle to outperform secular trends. The reasons for this are rarely explored in detail, and are often attributed merely to difficulties in engaging clinicians in quality improvement work. In a narrative review of the literature, we argue that this focus on clinicians, at the relative expense of managerial staff, has proven counterproductive. Clinical engagement is not a universal challenge; moreover, there is evidence that managers-particularly middle managers-also have a role to play in quality improvement. Yet managerial participation in quality improvement interventions is often assumed, rather than proven. We identify specific factors that influence the coordination of front-line staff and managers in quality improvement, and integrate these factors into a novel model: the model of alignment. We use this model to explore the implementation of an interdisciplinary intervention in a recent trial, describing different participation incentives and barriers for different staff groups. The extent to which clinical and managerial interests align may be an important determinant of the ultimate success of quality improvement interventions. PMID- 26647412 TI - Supporting adherence for people starting a new medication for a long-term condition through community pharmacies: a pragmatic randomised controlled trial of the New Medicine Service. AB - OBJECTIVE: To examine the effectiveness of the New Medicine Service (NMS), a national community pharmacy service to support medicines-taking in people starting a new medicine for a long-term condition, compared with normal practice. METHODS: Pragmatic patient-level parallel randomised controlled trial, in 46 community pharmacies in England. Patients 1:1 block randomisation stratified by drug/disease group within each pharmacy. 504 participants (NMS: 251) aged 14 years and over, identified in the pharmacy on presentation of a prescription for asthma/chronic obstructive pulmonary disease, hypertension, type 2 diabetes or an anticoagulant/antiplatelet agent. NMS intervention: One consultation 7-14 days after presentation of prescription followed by another 14-21 days thereafter to identify problems with treatment and provide support if needed. Controls received normal practice. Adherence, defined as missing no doses without the advice of a medical professional in the previous 7 days, was assessed through patient self report at 10 weeks. Intention-to-treat analysis was employed, with outcome adjusted for recruiting pharmacy, NMS disease category, age, sex and medication count. Cost to the National Health Service (NHS) was collected. RESULTS: At 10 weeks, 53 patients had withdrawn and 443 (85%) patients were contacted successfully by telephone. In the unadjusted analysis of 378 patients still taking the initial medicine, 61% (95% CI 54% to 67%) and 71% (95% CI 64% to 77%) patients were adherent in the normal practice and NMS arms, respectively (p=0.04 for difference). In the adjusted intention-to-treat analysis, the OR for increased adherence was 1.67 (95% CI 1.06 to 2.62; p=0.027) in favour of the NMS arm. There was a general trend to reduced NHS costs, albeit, statistically non significant, for the NMS intervention: saving L21 (95% CI -L59 to L100, p=0.128) per patient. CONCLUSIONS: The NMS significantly increased the proportion of patients adhering to their new medicine by about 10%, compared with normal practice. TRIAL REGISTRATION NUMBERS: ClinicalTrials.gov trial reference number NCT01635361 (http://clinicaltrials.gov/ct2/show/NCT01635361). Current Controlled trials: trial reference number ISRCTN 23560818 (http://www.controlled trials.com/ISRCTN23560818/; DOI 10.1186/ISRCTN23560818). UK Clinical Research Network (UKCRN) study 12494 (http://public.ukcrn.org.uk/Search/StudyDetail.aspx?StudyID=12494). PMID- 26647413 TI - In vivo exposure to 17beta-estradiol triggers premature sperm capacitation in cauda epididymis. PMID- 26647414 TI - The PRIDE (Partnership to Improve Diabetes Education) Toolkit: Development and Evaluation of Novel Literacy and Culturally Sensitive Diabetes Education Materials. AB - PURPOSE: Patients with low literacy, low numeracy, and/or linguistic needs can experience challenges understanding diabetes information and applying concepts to their self-management. The authors designed a toolkit of education materials that are sensitive to patients' literacy and numeracy levels, language preferences, and cultural norms and that encourage shared goal setting to improve diabetes self-management and health outcomes. The Partnership to Improve Diabetes Education (PRIDE) toolkit was developed to facilitate diabetes self-management education and support. METHODS: The PRIDE toolkit includes a comprehensive set of 30 interactive education modules in English and Spanish to support diabetes self management activities. The toolkit builds upon the authors' previously validated Diabetes Literacy and Numeracy Education Toolkit (DLNET) by adding a focus on shared goal setting, addressing the needs of Spanish-speaking patients, and including a broader range of diabetes management topics. Each PRIDE module was evaluated using the Suitability Assessment of Materials (SAM) instrument to determine the material's cultural appropriateness and its sensitivity to the needs of patients with low literacy and low numeracy. Reading grade level was also assessed using the Automated Readability Index (ARI), Coleman-Liau, Flesch Kincaid, Fry, and SMOG formulas. CONCLUSIONS: The average reading grade level of the materials was 5.3 (SD 1.0), with a mean SAM of 91.2 (SD 5.4). All of the 30 modules received a "superior" score (SAM >70%) when evaluated by 2 independent raters. The PRIDE toolkit modules can be used by all members of a multidisciplinary team to assist patients with low literacy and low numeracy in managing their diabetes. PMID- 26647415 TI - Imbedding Interdisciplinary Diabetes Group Visits Into a Community-Based Medical Setting. AB - PURPOSE: The purpose of this study was to evaluate an interdisciplinary approach and test the efficacy of diabetes group visits tailored to low-income patients in a community-based medical practice. METHODS: A randomized repeated measures design was used with 40 patients in the experimental group and 40 patients in the control group. The diabetes group visit consisted of individualized sessions with a physician or nurse practitioner to review medications and conduct a medical examination and group sessions to deliver diabetes self-management education. Data collected included clinical data and questionnaires. A control group shared comparable demographic characteristics, medication regimens, and baseline A1C levels. RESULTS: The patients in the experimental group decreased their A1C, triglycerides, and heart rate from time 1 to time 5 and maintained their high density lipoprotein significantly more than the control group. In exit interviews, the patients said that the group diabetes visits helped them be more accountable about their diabetes self-management goals. CONCLUSIONS: Diabetes group visits that combined diabetes self-management education and a medical visit with a health care provider improved A1C and were well received by the patients. The study provided patients with a quality program in an environment in which they felt safe to learn and that met them where they were in their diabetes self management behaviors. This approach could be widely disseminated into other clinic settings that serve patients with type 2 diabetes. PMID- 26647416 TI - Erectile dysfunction in COPD patients. AB - Sexual dysfunction is a common problem in chronic obstructive pulmonary disease (COPD). We aimed to assess the presence of erectile dysfunction (ED) in COPD patients. Ninety-three outpatients who had been diagnosed as COPD and followed in Bolvadin State Hospital, Afyon, Turkey, were included in the study. All patients underwent pulmonary function tests and arterial blood gas analysis. They completed International Physical Activity Questionnaire (IPAQ), Medical Research Council (MRC) Dyspnea Scale, Short Form 36-item Scale (SF-36), and International Index of Erectile Function (IIEF) Questionnaire. The mean age of 10 (10.8%) mild, 46 (49.5%) moderate, 28 (30.1%) severe, and 9 (9.7%) very severe COPD patients was 61.4 +/- 9.8 years. Varying degrees of ED were detected in 67.7% of COPD patients. All patients with hypoxemia had ED. IPAQ score and all SF-36 parameters were low in patients with ED, while MRC score was high. Forced expiratory volume in one second, forced vital capacity, partial pressure of oxygen in blood, oxygen (O2) saturation, IPAQ score, and role-physical parameters were statistically low in ED patients (p = 0.04, 0.02, <0.01, <0.01, 0.02, and 0.04, respectively); MRC score was statistically higher in patients with ED (p = 0.02). Patients with moderate and severe ED had statistically lower score of mental health (p < 0.01 and p = 0.02, respectively). There was a positive correlation between IIEF score and IPAQ scores (p < 0.01), MRC scores (p = 0.01), general health (p < 0.01), role-physical (p < 0.01), role-emotional (p < 0.01), physical functioning (p < 0.01), and mental health (p < 0.01) parameters in SF-36. ED is frequently seen in COPD patients. Hypoxemia, smoking, and limitation of physical activity are thought to be associated with ED in COPD as mechanisms. Quality of life and the functional capacity are negatively affected with the presence of ED. It is important for a physician to question the sexual functions in patients with COPD. The presence of ED may be routinely considered in the daily practice of pulmonologists in COPD patients. PMID- 26647417 TI - Relations Between the Intelligibility of Speech in Noise and Psychophysical Measures of Hearing Measured in Four Languages Using the Auditory Profile Test Battery. AB - The aim of the present study was to determine the relations between the intelligibility of speech in noise and measures of auditory resolution, loudness recruitment, and cognitive function. The analyses were based on data published earlier as part of the presentation of the Auditory Profile, a test battery implemented in four languages. Tests of the intelligibility of speech, resolution, loudness recruitment, and lexical decision making were measured using headphones in five centers: in Germany, the Netherlands, Sweden, and the United Kingdom. Correlations and stepwise linear regression models were calculated. In sum, 72 hearing-impaired listeners aged 22 to 91 years with a broad range of hearing losses were included in the study. Several significant correlations were found with the intelligibility of speech in noise. Stepwise linear regression analyses showed that pure-tone average, age, spectral and temporal resolution, and loudness recruitment were significant predictors of the intelligibility of speech in fluctuating noise. Complex interrelationships between auditory factors and the intelligibility of speech in noise were revealed using the Auditory Profile data set in four languages. After taking into account the effects of pure tone average and age, spectral and temporal resolution and loudness recruitment had an added value in the prediction of variation among listeners with respect to the intelligibility of speech in noise. The results of the lexical decision making test were not related to the intelligibility of speech in noise, in the population studied. PMID- 26647418 TI - The mare as a model for luteinized unruptured follicle syndrome: intrafollicular endocrine milieu. AB - Luteinized unruptured follicle (LUF) syndrome is a recurrent anovulatory dysfunction that affects up to 23% of women with normal menstrual cycles and up to 73% with endometriosis. Mechanisms underlying the development of LUF syndrome in mares were studied to provide a potential model for human anovulation. The effect of extended increase in circulating LH achieved by administration of recombinant equine LH (reLH) or a short surge of LH and decrease in progesterone induced by prostaglandin F2alpha (PGF2alpha) on LUF formation (Experiment 1), identification of an optimal dose of COX-2 inhibitor (flunixin meglumine, FM; to block the effect of prostaglandins) for inducing LUFs (Experiment 2), and evaluation of intrafollicular endocrine milieu in LUFs (Experiment 3) were investigated. In Experiment 1, mares were treated with reLH from Day 7 to Day 15 (Day 0=ovulation), PGF2alpha on Day 7, or in combination. In Experiment 2, FM at doses of 2.0 or 3.0 mg/kg every 12 h and human chorionic gonadotropin (hCG) (1500 IU) were administered after a follicle >=32 mm was detected. In Experiment 3, FM at a dose of 2.0 mg/kg every 12 h plus hCG was used to induce LUFs and investigate the intrafollicular endocrine milieu. No LUFs were induced by reLH or PGF2alpha treatment; however, LUFs were induced in 100% of mares using FM. Intrafollicular PGF2alpha metabolite, PGF2alpha, and PGE2 were lower and the ratio of PGE2:PGF2alpha was higher in the induced LUF group. Higher levels of intrafollicular E2 and total primary sex steroids were observed in the induced LUF group along with a tendency for higher levels of GH, cortisol, and T; however, LH, PRL, VEGF-A, and NO did not differ between groups. In conclusion, this study reveals part of the intrafollicular endocrine milieu and the association of prostaglandins in LUF formation, and indicates that the mare might be an appropriate model for studying the poorly understood LUF syndrome. PMID- 26647419 TI - Protein profile screening: reduced expression of Sord in the mouse epididymis induced by nicotine inhibits tyrosine phosphorylation level in capacitated spermatozoa. AB - Many studies have revealed the hazardous effects of cigarette smoking and nicotine exposure on male fertility, but the actual, underlying molecular mechanism remains relatively unclear. To evaluate the detrimental effects of nicotine exposure on the sperm maturation process, two-dimensional gel electrophoresis and mass spectrometry analyses were performed to screen and identify differentially expressed proteins from the epididymal tissue of mice exposed to nicotine. Data mining analysis indicated that 15 identified proteins were mainly involved in the molecular transportation process and the polyol pathway, indicating impaired epididymal secretory functions. Experiments in vitro confirmed that nicotine inhibited tyrosine phosphorylation levels in capacitated spermatozoa via the downregulated seminal fructose concentration. Sord, a key gene encoding sorbitol dehydrogenase, was further investigated to reveal that nicotine induced hyper-methylation of the promoter region of this gene. Nicotine induced reduced expression of Sord could be involved in impaired secretory functions of the epididymis and thus prevent the sperm from undergoing proper maturation and capacitation, although further experiments are needed to confirm this hypothesis. PMID- 26647420 TI - Treatment of aortic graft infection by in situ reconstruction with Omniflow II biosynthetic prosthesis. AB - Currently available conduits for in situ reconstruction after excision of infected aortic grafts have significant limitations. The Omniflow II vascular prosthesis is a biosynthetic graft associated with a low incidence of infection that has succesfully been used in the treatment of infected infrainguinal bypass. We report on the first use of the Omniflow II prosthesis for in situ reconstruction after aortic graft infection.A bifurcated biosynthetic bypass was created by spatulating and anastomosing two 8-mm tubular Omniflow II grafts. This bypass was used for in situ reconstruction after excision of infected aortic grafts in three cases. After a mean follow-up of 2.2 years, no occlusion, degeneration, or rupture of the Omniflow II grafts was observed. Although one patient suffered from graft reinfection, the bypass retained structural integrity and no anastomotic dehiscence was observed.Treatment of aortic graft infection by in situ reconstruction with the Omniflow II vascular prosthesis is feasible. Its resistance to infection and off-the-shelf availability make this graft a promising conduit for aortoiliac reconstruction. PMID- 26647422 TI - A study of the validity and the reliability of the Geriatric Anxiety Inventory in screening for anxiety after stroke in older inpatients. AB - OBJECTIVES: To investigate the validity and reliability of the Geriatric Anxiety Inventory in screening for anxiety in older inpatients post-stroke. DESIGN: Longitudinal. SUBJECTS: A total of 81 inpatients with stroke aged 65 years or older were recruited at four centres in England. MAIN MEASURES: At phase 1 the Geriatric Anxiety Inventory and the Hospital Anxiety and Depression Scale were administered and then the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders 4th edition (phase 2). The Geriatric Anxiety Inventory was repeated a median of seven days later (phase 3). RESULTS: Internal reliability of the Geriatric Anxiety Inventory was high (alpha = 0.95) and test-retest reliability acceptable (tauB = 0.53). Construct validity was evident relative to the Hospital Anxiety and Depression Scale - Anxiety subscale (tauB = 0.61). At a cut off of 6/7, sensitivity of the Geriatric Anxiety Inventory was 0.88, specificity 0.84, with respect to the Structured Clinical Interview anxiety diagnosis. Hospital Anxiety and Depressions Scale - Anxiety subscale sensitivity was 0.88, specificity 0.54 at the optimum cut off of 5/6. A comparison of the areas under the curve of the Receiver Operating Characteristics for the two instruments indicated that the area under the curve of the Geriatric Anxiety Inventory was significantly larger than that of the Hospital Anxiety and Depressions Scale - Anxiety subscale, supporting its superiority. CONCLUSIONS: The Geriatric Anxiety Inventory is an internally consistent, reliable (stable) and valid instrument with acceptable sensitivity and specificity to screen for anxiety in older inpatients with stroke. PMID- 26647421 TI - Training in client-centeredness enhances occupational therapist documentation on goal setting and client participation in goal setting in the medical records of people with stroke. AB - OBJECTIVE: The aim of the present study was to compare client-centeredness as it was documented by the occupational therapists in the units randomized to the intervention clusters with documentation by occupational therapists in the control clusters. DESIGN: Comparison of medical records. SETTING: The study is conducted in a context of a randomized controlled trial in Sweden, with 16 post stroke rehabilitation units cluster randomized to intervention or control group. SUBJECTS: Occupational therapist documentation in medical records of 279 clients with stroke. MAIN MEASURES: The medical records were reviewed for their level of client-centeredness using a protocol developed from the Stewart et al model. The occupational therapists in the intervention groups participated in a workshop training to enhance their client-centeredness. RESULTS: Occupational therapists with training in client-centeredness documented significantly more on goal setting (OR = 4.1; 95% CI, 1.87-8.81), on client participation in goal setting (OR=11.34; 95% CI, 5.97-21.57), on how the goals could be reached (OR=2.8; 95% CI, 1.7-4.62), on client participation in how goals could be reached (OR=4.56; 95% CI, 2.73-7.64), on the follow-up on goals (OR=5.77; 95% CI, 2.78-11-98) and on client participation in follow-up on goals (OR=7.44, 95% CI, 4.33-12.8). This association remained after adjustment for healthcare setting, client socio demographic variables, and stroke severity. CONCLUSION: Documentation of goal setting and client participation in goal setting can be influenced by training. PMID- 26647423 TI - Anti-Inflammatory Role of MicroRNA-146a in the Pathogenesis of Diabetic Nephropathy. AB - Inflammation has a critical role in the pathogenesis of diabetic complications, including diabetic nephropathy (DN). MicroRNAs have recently emerged as important regulators of DN. However, the role of microRNAs in the regulation of inflammation during DN is poorly understood. Here, we examined the in vivo role of microRNA-146a (miR-146a), a known anti-inflammatory microRNA, in the pathogenesis of DN. In a model of streptozotocin-induced diabetes, miR-146a(-/-) mice showed significantly exacerbated proteinuria, renal macrophage infiltration, glomerular hypertrophy, and fibrosis relative to the respective levels in control wild-type mice. Diabetes-induced upregulation of proinflammatory and profibrotic genes was significantly greater in the kidneys of miR-146a(-/-) than in the kidneys of wild-type mice. Notably, miR-146a expression increased in both peritoneal and intrarenal macrophages in diabetic wild-type mice. Mechanistically, miR-146a deficiency during diabetes led to increased expression of M1 activation markers and suppression of M2 markers in macrophages. Concomitant with increased expression of proinflammatory cytokines, such as IL 1beta and IL-18, markers of inflammasome activation also increased in the macrophages of diabetic miR-146a(-/-) mice. These studies suggest that in early DN, miR-146a upregulation exerts a protective effect by downregulating target inflammation-related genes, resulting in suppression of proinflammatory and inflammasome gene activation. Loss of this protective mechanism in miR-146a(-/-) mice leads to accelerated DN. Taken together, these results identify miR-146a as a novel anti-inflammatory noncoding RNA modulator of DN. PMID- 26647424 TI - A Randomized Study Comparing Parathyroidectomy with Cinacalcet for Treating Hypercalcemia in Kidney Allograft Recipients with Hyperparathyroidism. AB - Tertiary hyperparathyroidism is a common cause of hypercalcemia after kidney transplant. We designed this 12-month, prospective, multicenter, open-label, randomized study to evaluate whether subtotal parathyroidectomy is more effective than cinacalcet for controlling hypercalcemia caused by persistent hyperparathyroidism after kidney transplant. Kidney allograft recipients with hypercalcemia and elevated intact parathyroid hormone (iPTH) concentration were eligible if they had received a transplant >=6 months before the study and had an eGFR>30 ml/min per 1.73 m(2) The primary end point was the proportion of patients with normocalcemia at 12 months. Secondary end points were serum iPTH concentration, serum phosphate concentration, bone mineral density, vascular calcification, renal function, patient and graft survival, and economic cost. In total, 30 patients were randomized to receive cinacalcet (n=15) or subtotal parathyroidectomy (n=15). At 12 months, ten of 15 patients in the cinacalcet group and 15 of 15 patients in the parathyroidectomy group (P=0.04) achieved normocalcemia. Normalization of serum phosphate concentration occurred in almost all patients. Subtotal parathyroidectomy induced greater reduction of iPTH and associated with a significant increase in femoral neck bone mineral density; vascular calcification remained unchanged in both groups. The most frequent adverse events were digestive intolerance in the cinacalcet group and hypocalcemia in the parathyroidectomy group. Surgery would be more cost effective than cinacalcet if cinacalcet duration reached 14 months. All patients were alive with a functioning graft at the end of follow-up. In conclusion, subtotal parathyroidectomy was superior to cinacalcet in controlling hypercalcemia in these patients with kidney transplants and persistent hyperparathyroidism. PMID- 26647425 TI - Genetic and Pharmacologic Targeting of Glycogen Synthase Kinase 3beta Reinforces the Nrf2 Antioxidant Defense against Podocytopathy. AB - Evidence suggests that the glycogen synthase kinase 3 (GSK3)-dictated nuclear exclusion and degradation of Nrf2 is pivotal in switching off the self-protective antioxidant stress response after injury. Here, we examined the mechanisms underlying this regulation in glomerular disease. In primary podocytes, doxorubicin elicited cell death and actin cytoskeleton disorganization, concomitant with overactivation of GSK3beta (the predominant GSK3 isoform expressed in glomerular podocytes) and minimal Nrf2 activation. SB216763, a highly selective small molecule inhibitor of GSK3, exerted a protective effect that depended on the potentiated Nrf2 antioxidant response, marked by increased Nrf2 expression and nuclear accumulation and augmented production of the Nrf2 target heme oxygenase-1. Ectopic expression of the kinase-dead mutant of GSK3beta in cultured podocytes reinforced the doxorubicin-induced Nrf2 activation and prevented podocyte injury. Conversely, a constitutively active GSK3beta mutant blunted the doxorubicin-induced Nrf2 response and exacerbated podocyte injury, which could be abolished by treatment with SB216763. In murine models of doxorubicin nephropathy or nephrotoxic serum nephritis, genetic targeting of GSK3beta by doxycycline-inducible podocyte-specific knockout or pharmacologic targeting by SB216763 significantly attenuated albuminuria and ameliorated histologic signs of podocyte injury, including podocytopenia, loss of podocyte markers, podocyte de novo expression of desmin, and ultrastructural lesions of podocytopathy (such as foot process effacement). This beneficial outcome was likely attributable to an enhanced Nrf2 antioxidant response in glomerular podocytes because the selective Nrf2 antagonist trigonelline abolished the proteinuria-reducing and podocyte-protective effect. Collectively, our results suggest the GSK3beta-regulated Nrf2 antioxidant response as a novel therapeutic target for protecting podocytes and treating proteinuric glomerulopathies. PMID- 26647427 TI - Giant Abdominal Aortic Aneurysms: A Case Series and Review of the Literature. AB - INTRODUCTION: Giant abdominal aortic aneurysms (AAAs), defined as those measuring greater than 13.0 cm in transverse diameter, represent a rare clinical entity and present unique anatomic challenges. METHODS: A retrospective review of a prospectively maintained aneurysm database from 2000 to 2013 was performed at a single academic referral center. Preoperative comorbid status, aneurysm characteristics, procedural details, and perioperative course were recorded for all patients. RESULTS: Four patients (male, n = 3) with a mean age of 75.2 years (range, 71-80 years) underwent open repair of giant AAAs. The mean AAA size was 14.4 cm (range, 13.2-15.5 cm). All giant AAAs were associated with neck length <10 mm and/or severe neck angulation. At a mean follow-up of 22 months, there has been 1 late death due to nonaneurysm-related causes. CONCLUSION: Due to anatomic limitation with currently available aortic endografts, giant AAAs have been traditionally repaired using a standard open surgical approach. The feasibility of endovascular aortic aneurysm repair (EVAR) with or without the use of adjunct techniques, including snorkel/chimney or fenestrated EVAR, has yet to be elucidated. PMID- 26647428 TI - Management of Lateral Plantar Artery Pseudoaneurysm After Penetrating Injury in Children. AB - A case of lateral plantar artery pseudoaneurysm following a penetrating injury in a 10-year-old male is presented. Only a handful of such cases have been reported in the literature, and as such, a defined treatment algorithm is lacking. Our case and a review of the literature suggest that these injuries involve vessel transection, making them unsuitable for ultrasound-guided thrombin injection. In addition, the presence of bacterial contamination of the wound makes attempts at endovascular coiling prohibitive. Direct surgical exploration and ligation should remain the mainstay of therapy in most patients. PMID- 26647426 TI - Macula Densa Nitric Oxide Synthase 1beta Protects against Salt-Sensitive Hypertension. AB - Nitric oxide (NO) is an important negative modulator of tubuloglomerular feedback responsiveness. We recently found that macula densa expresses alpha-, beta-, and gamma-splice variants of neuronal nitric oxide synthase 1 (NOS1), and NOS1beta expression in the macula densa increases on a high-salt diet. This study tested whether upregulation of NOS1beta expression in the macula densa affects sodium excretion and salt-sensitive hypertension by decreasing tubuloglomerular feedback responsiveness. Expression levels of NOS1beta mRNA and protein were 30- and five fold higher, respectively, than those of NOS1alpha in the renal cortex of C57BL/6 mice. Furthermore, macula densa NO production was similar in the isolated perfused juxtaglomerular apparatus of wild-type (WT) and nitric oxide synthase 1alpha-knockout (NOS1alphaKO) mice. Compared with control mice, mice with macula densa-specific knockout of all nitric oxide synthase 1 isoforms (MD-NOS1KO) had a significantly enhanced tubuloglomerular feedback response and after acute volume expansion, significantly reduced GFR, urine flow, and sodium excretion. Mean arterial pressure increased significantly in MD-NOS1KO mice (P<0.01) but not NOS1flox/flox mice fed a high-salt diet. After infusion of angiotensin II, mean arterial pressure increased by 61.6 mmHg in MD-NOS1KO mice versus 32.0 mmHg in WT mice (P<0.01) fed a high-salt diet. These results indicate that NOS1beta is a primary NOS1 isoform expressed in the macula densa and regulates the tubuloglomerular feedback response, the natriuretic response to acute volume expansion, and the development of salt-sensitive hypertension. These findings show a novel mechanism for salt sensitivity of BP and the significance of tubuloglomerular feedback response in long-term control of sodium excretion and BP. PMID- 26647429 TI - Single-Center Experience With Remote Endarterectomy for the Treatment of Long Segment Superficial Femoral Artery Occlusion: Long-Term Results. AB - OBJECTIVES: Remote endarterectomy (RE) is a relatively minimally invasive procedure as an alternative to femoropopliteal above-knee bypass for the treatment of long-segment superficial femoral artery (SFA) occlusion. The objective of this study was to report our experience and to evaluate the long term outcome. DESIGN: Single-center nonrandomized retrospective study with prospective collection of patients' data. METHODS: Twelve patients (11 men; mean age 72 years, range 55-81 years) with long (>10 cm) SFA occlusion underwent RE followed by stent (aSpire) placement at the distal end of the endarterectomy. All patients had at least 2 tibial vessels outflow. Indications were severe claudication in 9 (75%), rest pain in 1(8%), and gangrene in 2 (17%) cases. Technical, hemodynamic success rates and clinical improvement were recorded. Assessment of patency and limb loss was made at a mean follow-up of 50 months (range 12-66 months). RESULTS: Technical success rate was 100%. Immediate hemodynamic and clinical improvement were 92% and 75%, respectively. The mean increase in the Ankle-Brachial pressure index was 0.24. The primary, primary assisted, and secondary patency rates were 50%, 83%, and 100%, respectively. The perioperative mortality rate was 8% (one death due to myocardial infarction). There was no early (30-day) reocclusion. During the follow-up, 5 (41.6%) cases underwent 7 reinterventions, all by endovascular means. The amputation rate was 16% (2 of 12). CONCLUSIONS: The RE for long SFA occlusion is a feasible procedure with acceptable short- and long-term outcomes in the presence of distal arterial outflow. Good long-term patency and limb salvage can be achieved with close surveillance and with the compensation of endovascular reintervention procedures. PMID- 26647430 TI - Light-emitting diode fluorescence microscopy for tuberculosis diagnosis: a meta analysis. AB - Light-emitting diode fluorescence microscopy (LED-FM) is recommended by the World Health Organization to replace conventional Ziehl-Neelsen microscopy for pulmonary tuberculosis diagnosis. Uptake of LED-FM has been slow. One reason is its reported loss of specificity compared with Ziehl-Neelsen microscopy. We aimed to determine the diagnostic accuracy of LED-FM for tuberculosis detection and explore potential factors that might affect its performance.A comprehensive search strategy based on pre-specified criteria was employed to identify eligible studies between January 1, 2000 and April 1, 2014 in 11 databases. Standardised study selection, data extraction and quality assessment were conducted. Pooled sensitivity and specificity of LED-FM using culture as the reference standard were estimated through meta-analyses using a bivariate random-effects model. Investigation of heterogeneity was performed by subgroup analyses.We identified 12 unique studies, half of which were from peripheral healthcare facilities. LED FM achieved a pooled sensitivity of 66.9% (95% CI 60.5-72.7%) and pooled specificity of 96.8% (95% CI 93.1-98.6%). A pooled sensitivity of 53.0% (95% CI 42.8-63.0%) and pooled specificity of 96.1% (95% CI 86.0-99.0%) were obtained by LED-FM among HIV-infected patients. Study methodology factors and differences in the LED-FM procedure or device could also affect the performance.LED-FM specificity is high and should not be a barrier to device introduction, particularly among peripheral healthcare settings where this technology is meant to be used. Sensitivity is reduced in HIV-infected patients. PMID- 26647431 TI - Bedaquiline in the treatment of multidrug- and extensively drug-resistant tuberculosis. AB - Bedaquiline, a diarylquinoline, improved cure rates when added to a multidrug resistant tuberculosis (MDR-TB) treatment regimen in a previous placebo controlled, phase 2 trial (TMC207-C208; NCT00449644). The current phase 2, multicenter, open-label, single-arm trial (TMC207-C209; NCT00910871) reported here was conducted to confirm the safety and efficacy of bedaquiline.Newly diagnosed or previously treated patients with MDR-TB (including pre-extensively drug-resistant (pre-XDR)-TB or extensively drug-resistant (XDR)-TB) received bedaquiline for 24 weeks with a background regimen of anti-TB drugs continued according to National TB Programme treatment guidelines. Patients were assessed during and up to 120 weeks after starting bedaquiline.Of 233 enrolled patients, 63.5% had MDR-TB, 18.9% had pre-XDR-TB and 16.3% had XDR-TB, with 87.1% having taken second-line drugs prior to enrolment. 16 patients (6.9%) died. 20 patients (8.6%) discontinued before week 24, most commonly due to adverse events or MDR-TB related events. Adverse events were generally those commonly associated with MDR TB treatment. In the efficacy population (n=205), culture conversion (missing outcome classified as failure) was 72.2% at 120 weeks, and 73.1%, 70.5% and 62.2% in MDR-TB, pre-XDR-TB and XDR-TB patients, respectively.Addition of bedaquiline to a background regimen was well tolerated and led to good outcomes in this clinically relevant patient cohort with MDR-TB. PMID- 26647432 TI - Pirfenidone for idiopathic pulmonary fibrosis: analysis of pooled data from three multinational phase 3 trials. AB - Pirfenidone is an antifibrotic agent that has been evaluated in three multinational phase 3 trials in patients with idiopathic pulmonary fibrosis (IPF). We analysed pooled data from the multinational trials to obtain the most precise estimates of the magnitude of treatment effect on measures of disease progression.All patients randomised to pirfenidone 2403 mg.day(-1) or placebo in the CAPACITY or ASCEND studies were included in the analysis. Pooled analyses of outcomes at 1 year were based on the pre-specified end-points and analytic methods described in the ASCEND study protocol.A total of 1247 patients were included in the analysis. At 1 year, pirfenidone reduced the proportion of patients with a >=10% decline in per cent predicted forced vital capacity or death by 43.8% (95% CI 29.3-55.4%) and increased the proportion of patients with no decline by 59.3% (95% CI 29.0-96.8%). A treatment benefit was also observed for progression-free survival, 6-min walk distance and dyspnoea. Gastrointestinal and skin-related adverse events were more common in the pirfenidone group, but rarely led to discontinuation.Analysis of data from three phase 3 trials demonstrated that treatment with pirfenidone for 1 year resulted in clinically meaningful reductions in disease progression in patients with IPF. PMID- 26647433 TI - Regimens for nontuberculous mycobacterial lung disease lack early bactericidal activity. PMID- 26647434 TI - Improving end-of-life communication between primary and secondary care within respiratory medicine. PMID- 26647435 TI - Recruitment challenges for clinical trials with novel regimens for drug-resistant tuberculosis. PMID- 26647436 TI - Prenatal exposure to antibiotics and wheezing in infancy: a birth cohort study. AB - The role of prenatal antibiotic exposure in the development of childhood wheezing is debated. We evaluated whether this association could potentially be explained by confounding factors.Antibiotic use in the first and third trimester of pregnancy, wheezing in children aged <=18 months and confounding factors were assessed in singletons participating in the NINFEA (Nascita e Infanzia: gli Effetti dell'Ambiente) birth cohort (n=3530 for first-trimester exposure and n=3985 for third-trimester exposure).There was no evidence of an association between antibiotic exposure in the first trimester of pregnancy and ever-wheezing (adjusted risk ratio (RR) 1.02, 95% CI 0.80-1.30) or recurrent wheezing (RR 0.99, 95% CI 0.54-1.82). For the third-trimester exposure, the crude RRs (95% CI) of ever-wheezing and recurrent wheezing were 1.34 (1.10-1.64) and 2.72 (1.80-4.11), respectively, which decreased to 1.12 (0.90-1.39) and 2.09 (1.32-3.29) after adjustment. The RRs of wheezing after genitourinary infections during pregnancy were increased independently of antibiotic treatment.In conclusion, the association between prenatal antibiotic exposure and infant wheezing could be largely explained by confounding factors, in particular respiratory infections during pregnancy. An excess risk of wheezing after antibiotic exposure during the third trimester of pregnancy remains after adjustment. PMID- 26647437 TI - Trends and predictors of asthma costs: results from a 10-year longitudinal study. AB - Research on asthma costs often focuses on estimating average asthma costs. Trends in asthma costs and patterns of medication use, especially for those who have been followed up and under treatment, have received much less attention. This study's objective was to document asthma costs over time for asthma patients who are enrolled in an asthma care programme in Singapore and to identify its predictors, using a 10-year longitudinal dataset.The study population comprised different cohorts of 939 asthma patients entering the programme at different times during 2004-2013. Average asthma costs were estimated and the trends over time examined graphically, within and across patient cohorts. Regression analyses were conducted to examine cost predictors, with a focus on the relationship between risk factors at programme enrolment and subsequent asthma costs.The results indicate that 10-year average annual asthma cost was GBP 341 per patient. The main drivers of costs were asthma medications and consultation fees. Use of combined inhaled corticosteroid/long-acting beta-agonist medications increased over time, but this was accompanied by declines in controller drug use, doctor visits and total asthma drug costs. Obesity, smoking and asthma severity were the main predictors of subsequent asthma costs, especially for females. PMID- 26647438 TI - Impact of sleep disturbances on kidney function decline in the elderly. AB - While sleep disturbances are frequent in renal disease patients, no studies have examined prospectively the associations between sleep disturbances and kidney function decline in community-dwelling elderly subjects.Glomerular filtration rates (eGFRs) were estimated at baseline and at 11-year follow-up. A glomerular filtration decline over the follow-up period was defined as a percentage decline greater than or equal to the cut-off value of the highest tertile of kidney function decline (22%) in 1105 subjects. Excessive daytime sleepiness (EDS) and insomnia complaints were self-rated at baseline. Restless legs syndrome (RLS) and its age at onset were assessed at study end-point. An ambulatory polysomnography recording was performed during the follow-up in 277 subjects. Apnoea-hypopnoea index (AHI), periodic limb movements during sleep (PLMS) and total sleep time were analysed.An increased risk of eGFR decline was associated with EDS (OR 1.67, 95% CI 1.18-2.34) and RLS (OR 1.98, 95% CI 1.18-3.30) independently of potential confounders including cardiovascular risk factors. Among insomnia complaints, a borderline association with eGFR decline was found for early morning awakening only. High AHI (>=30 events.h(-1)) and short total sleep time (<6 h), but not PLMS were linked to eGFR decline in crude associations, but only AHI remained significantly associated after multi-adjustments.EDS, RLS and AHI constitute independent risk factors for kidney glomerular function decline. PMID- 26647439 TI - Childhood wheezing phenotypes influence asthma, lung function and exhaled nitric oxide fraction in adolescence. AB - The objective of this study was to examine the associations of childhood wheezing phenotypes with asthma, lung function and exhaled nitric oxide fraction (FeNO) in adolescence.In a population-based, prospective cohort study of 6841 children, we used latent class analysis to identify wheezing phenotypes during the first 7 years of life. Physician-diagnosed asthma, spirometry and FeNO were assessed at 14-15 years.Compared with never/infrequent wheeze, intermediate-onset and persistent wheeze were consistently strongest associated with higher risk of asthma (risk ratio (95% CI) 10.9 (8.97-13.16) and 9.13 (7.74-10.77), respectively), lower forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio (mean difference in standard deviation units (SDU) (95% CI) -0.34 ( 0.54- -0.14) and -0.50 (-0.62- -0.38), respectively), lower forced expiratory flow at 25-75% of FVC (FEF25-75%) (mean difference in SDU (95% CI) -0.30 (-0.49- 0.10) and -0.42 (-0.54- -0.30), respectively) and increased FEV1 bronchodilator reversibility (mean difference in SDU (95% CI) 0.12 (0.02-0.22) and 0.13 (0.06 0.19), respectively). Prolonged early and persistent wheeze were associated with a decline in FEV1/FVC ratio and FEF25-75% between 8-9 and 14-15 years. Intermediate-onset, late-onset and persistent wheeze were associated with higher FeNO ratios (ratio of geometric means (95% CI) 1.90 (1.59-2.29), 1.57 (1.39-1.77) and 1.37 (1.22-1.53), respectively, compared with never/infrequent wheeze).Early onset wheezing phenotypes persisting after 18 months of age show the strongest associations with asthma, lower lung function, even worsening from mid-childhood, and higher FeNO levels in adolescence. PMID- 26647440 TI - Cost-benefit analysis of Xpert MTB/RIF for tuberculosis suspects in German hospitals. AB - Our objective was to assess the cost-benefit of enhancing or replacing the conventional sputum smear with the real-time PCR Xpert MTB/RIF method in the inpatient diagnostic schema for tuberculosis (TB).Recent data from published per case cost studies for TB/multidrug-resistant (MDR)-TB and from comparative analyses of sputum microscopy, mycobacterial culture, Xpert MTB/RIF and drug susceptibility testing, performed at the German National Reference Center for Mycobacteria, were used. Potential cost savings of Xpert MTB/RIF, based on test accuracy and multiple cost drivers, were calculated for diagnosing TB/MDR-TB suspects from the hospital perspective.Implementing Xpert MTB/RIF as an add-on in smear-positive and smear-negative TB suspects saves on average ?48.72 and ?503, respectively, per admitted patient as compared with the conventional approach. In smear-positive and smear-negative MDR-TB suspects, cost savings amount to ?189.56 and ?515.25 per person, respectively. Full replacement of microscopy by Xpert MTB/RIF saves ?449.98. In probabilistic Monte-Carlo simulation, adding Xpert MTB/RIF is less costly in 46.4% and 76.2% of smear-positive TB and MDR-TB suspects, respectively, but 100% less expensive in all smear-negative suspects. Full replacement by Xpert MTB/RIF is also consistently cost-saving.Using Xpert MTB/RIF as an add-on to and even as a replacement for sputum smear examination may significantly reduce expenditures in TB suspects. PMID- 26647442 TI - Towards the standardisation of lung sound nomenclature. AB - Auscultation of the lung remains an essential part of physical examination even though its limitations, particularly with regard to communicating subjective findings, are well recognised. The European Respiratory Society (ERS) Task Force on Respiratory Sounds was established to build a reference collection of audiovisual recordings of lung sounds that should aid in the standardisation of nomenclature. Five centres contributed recordings from paediatric and adult subjects. Based on pre-defined quality criteria, 20 of these recordings were selected to form the initial reference collection. All recordings were assessed by six observers and their agreement on classification, using currently recommended nomenclature, was noted for each case. Acoustical analysis was added as supplementary information. The audiovisual recordings and related data can be accessed online in the ERS e-learning resources. The Task Force also investigated the current nomenclature to describe lung sounds in 29 languages in 33 European countries. Recommendations for terminology in this report take into account the results from this survey. PMID- 26647441 TI - Oestradiol metabolism and androgen receptor genotypes are associated with right ventricular function. AB - Sex hormones are linked to right ventricular (RV) function, but the relationship between genetic variation in these pathways and RV function is unknown.We performed a cross-sectional study of 2761 genotyped adults without cardiovascular disease. The relationships between RV measures and single nucleotide polymorphisms (SNPs) in 10 candidate genes were assessed. Urinary oestradiol (E2) metabolites produced by cytochrome P4501B1 (CYP1B1) and serum testosterone were measured in women and men respectively.In African-American (AA) women, the CYP1B1 SNP rs162561 was associated with RV ejection fraction (RVEF), such that each copy of the A allele was associated with a 2.0% increase in RVEF. Haplotype analysis revealed associations with RVEF in AA (global p<7.2*10(-6)) and white (global p=0.05) women. In white subjects, higher E2 metabolite levels were associated with significantly higher RVEF. In men, androgen receptors SNPs (rs1337080; rs5918764) were significantly associated with all RV measures and modified the relationship between testosterone and RVEF.Genetic variation in E2 metabolism and androgen signalling was associated with RV morphology in a sex-specific manner. The CYP1B1 SNP identified is in tight linkage disequilibrium with SNPs associated with pulmonary hypertension and oncogenesis, suggesting these pathways may underpin sexual dimorphism in RV failure. PMID- 26647443 TI - Lung function, forced expiratory volume in 1 s decline and COPD hospitalisations over 44 years of follow-up. AB - The use of baseline lung function in the prediction of chronic obstructive pulmonary disease (COPD) hospitalisations, all-cause mortality and lung function decline was assessed in the population-based "Men Born in 1914" cohort.Spirometry was assessed at age 55 years in 689 subjects, of whom 392 had spirometry reassessed at age 68 years. The cohort was divided into three groups using fixed ratio (FR) and lower limit of normal (LLN) criterion: forced expiratory volume in 1 s (FEV1)/vital capacity (VC) >=70%, FEV1/VC <70% but >=LLN (FR(+)LLN(-)), and FEV1/VC <70% and =70%). Hazard ratios for death were 1.30 (0.98 1.72) for FR(+)LLN(-) and 1.58 (1.25-2.00) for FR(+)LLN(+). The adjusted FEV1 decline between 55 and 68 years of age was higher for FR(+)LLN(-) and FR(+)LLN(+) relative to the reference. Of those with FR(+)LLN(-) at 55 years, 53% had progressed to the FR(+)LLN(+) group at 68 years.Airflow obstruction at age 55 years is a powerful risk factor for future COPD hospitalisations. The FR(+)LLN(-) group should be carefully evaluated in clinical practice in relation to future risks and potential benefit from early intervention. This is reinforced by the increased FEV1 decline in this group. PMID- 26647445 TI - Airway dysbiosis: Haemophilus influenzae and Tropheryma in poorly controlled asthma. AB - Asthma is a chronic inflammatory disorder of the airways where bacteria may act as protagonists of chronic inflammation. Little is known about the relation of airway inflammation to the presence of specific bacterial taxa. We sought to describe the sputum microbiome in adults with poorly controlled asthma.DNA was extracted from induced sputum and microbial communities were profiled using 16S rRNA pyrosequencing. Bacterial species were characterised, and the relationship between microbial populations, asthma inflammatory subtypes and other covariates was explored. Real-time PCR was used to identify Tropheryma whipplei and Haemophilus influenzae in sputum.Adults with neutrophilic asthma had reduced bacterial diversity and species richness. Tropheryma was identified and confirmed with real-time PCR in 12 (40%) participants. Haemophilus occurred most often in a group of younger atopic males with an increased proportion of neutrophils. PCR confirmed the presence of H. influenzae in 35 (76%) participants with poorly controlled asthma.There are phenotype-specific alterations to the airway microbiome in asthma. Reduced bacterial diversity combined with a high prevalence of H. influenzae was observed in neutrophilic asthma, whereas eosinophilic asthma had abundant T. whipplei. PMID- 26647444 TI - Accuracy of diagnostic testing in primary ciliary dyskinesia. AB - Diagnosis of primary ciliary dyskinesia (PCD) lacks a "gold standard" test and is therefore based on combinations of tests including nasal nitric oxide (nNO), high speed video microscopy analysis (HSVMA), genotyping and transmission electron microscopy (TEM). There are few published data on the accuracy of this approach.Using prospectively collected data from 654 consecutive patients referred for PCD diagnostics we calculated sensitivity and specificity for individual and combination testing strategies. Not all patients underwent all tests.HSVMA had excellent sensitivity and specificity (100% and 93%, respectively). TEM was 100% specific, but 21% of PCD patients had normal ultrastructure. nNO (30 nL.min(-1) cut-off) had good sensitivity and specificity (91% and 96%, respectively). Simultaneous testing using HSVMA and TEM was 100% sensitive and 92% specific.In conclusion, combination testing was found to be a highly accurate approach for diagnosing PCD. HSVMA alone has excellent accuracy, but requires significant expertise, and repeated sampling or cell culture is often needed. TEM alone is specific but misses 21% of cases. nNO (<=30 nL.min( 1)) contributes well to the diagnostic process. In isolation nNO screening at this cut-off would miss ~10% of cases, but in combination with HSVMA could reduce unnecessary further testing. Standardisation of testing between centres is a future priority. PMID- 26647446 TI - Changes in D-dimer and inflammatory biomarkers before ischemic events in patients with peripheral artery disease: The BRAVO Study. AB - Whether circulating biomarker levels increase shortly before an ischemic heart disease (IHD) event is unknown. We studied whether levels of D-dimer, C-reactive protein (CRP), and serum amyloid A (SAA) are higher within 2 months of an IHD event compared to time periods more than 2 months before the IHD event. We assembled 595 participants with peripheral artery disease (PAD) and followed them for up to 3 years. Blood samples were obtained every 2 months. The primary outcome was IHD events: myocardial infarctions, unstable angina, or IHD death. We used a nested case-control design. Fifty participants (cases) had events and were each matched by age, sex, duration in the study, and number of blood draws to two controls without events. Among cases, the mean D-dimer value of 1.105 obtained within 2 months of the event was higher than values obtained 10 months (0.68 mg/L, p<0.001), 12 months (0.71 mg/L, p=0.001), 16 months (0.65 mg/L, p=0.008), 20 months (p=0.032), 22 months (p=0.033), 26 months (p=0.038), and 32 months (p=0.04) before the event. Compared to controls, median D-dimer levels in cases were higher 4 months (p=0.017), 6 months (p=0.005), and 8 months (p=0.028) before the event. Values of CRP and SAA obtained within two months of an IHD event not consistently higher than values obtained during the prior months. In PAD participants with an IHD event, D-dimer was higher within 2 months of the event, compared to most values obtained 10 to 32 months previously. D-dimer was also higher in cases as compared to controls during most visits within 8 months of the IHD event. PMID- 26647447 TI - Regional differences in referral, procedures, and outcome after ablation for atrial fibrillation in Europe: a report from the Atrial Fibrillation Ablation Pilot Registry of the European Society of Cardiology. AB - AIMS: Ablation is an effective treatment of symptomatic and drug refractory atrial fibrillation (AF). Using data from the European AF Ablation Pilot Registry comprising 1410 patients from 10 European countries, we prospectively investigated regional differences in AF ablation regarding patient selection, ablation strategy, and outcome. METHODS AND RESULTS: Countries were divided into three regions: South (Greece, Italy, Spain), East (Czech Republic, Poland), and West/North (Belgium, Denmark, France, Germany, and the Netherlands). One-year success was defined as patient survival free from atrial arrhythmia, with or without antiarrhythmic drugs (AAD). In all regions, patients were symptomatic and treated extensively with beta-blockers and AAD pre-ablation. Patients in East had more co-morbidity, increased thromboembolic risk, were more likely to have paroxysmal AF, and they underwent more left atrial linear ablations. Adverse events remained within expected levels, albeit with a significantly higher reporting of adverse cardiovascular events in the West/North (4.7 vs. 1.4 and 1.5% in South and East, P = 0.0032). There was no significant difference in peripheral/vascular, neurological, pulmonary, gastrointestinal, or general adverse events. The 1-year success rate after ablation differed non-statistically between regions ranging from 69.1 to 74.7%. A second ablation was performed in 23.2% in West/North compared with 10.5 and 16.5% in South and East. The proportion of patients still on AADs was highest in the South region (51.6 vs. 42.3 and 38.8% in East and West/North). CONCLUSION: This study with all-comer patients shows that patient selection for ablation follows current guidelines but reveals significant differences regarding co-morbidity, medication, and ablation strategy. Despite this, 1-year outcomes are without significant differences and in line with previously published clinical trials. PMID- 26647448 TI - A Comparative Effectiveness Study of Rescue Strategies in 1,000 Subjects With Severe Hypoxemic Respiratory Failure. AB - BACKGROUND: Subjects with severe hypoxemic respiratory failure have shown a high mortality in previous studies. METHODS: All adult ICU patients requiring mechanical ventilation from 2005 to 2010 at Mayo Clinic were screened for severe hypoxemia (Murray lung injury score of >= 3). Extracorporeal membrane oxygenation, prone positioning, high-frequency oscillatory ventilation (HFOV), and inhaled vasodilators were considered as rescue strategies. A propensity-based scoring was created for the indication or predilection to use each strategy. A model was created to evaluate the association of each rescue strategy with hospital mortality. RESULTS: Among 1,032 subjects with severe hypoxemia, 239 subjects received some form of rescue strategy (59 received a combination of therapies, and 180 received individual therapies). Inhaled vasodilators were the most common, followed by HFOV. Rescue strategies were used in younger subjects with severe oxygenation deficits. Subjects receiving rescue strategies had higher mortality and longer ICU stays. None of the strategies individually or in combination showed a significant association with hospital mortality after adjusting covariates by propensity scoring. Adjusted Odds ratios and respective 95% CI were as follows: HFOV 0.67 (0.35-1.27), extracorporeal membrane oxygenation 0.63 (0.18-1.92), prone position 1.07 (0.49-2.28), and inhaled vasodilators 1.17 (0.78-1.77). CONCLUSIONS: In this retrospective comparative effectiveness study, there was no association of rescue strategies with hospital mortality in subjects with severe hypoxemia. PMID- 26647449 TI - A Novel Method for Sensitive Determination of Subclinical Left-Ventricular Systolic Dysfunction in Subjects With Obstructive Sleep Apnea. AB - BACKGROUND: This study was to evaluate the subclinical left-ventricular (LV) systolic dysfunction with 2-dimensional speckle-tracking echocardiography in subjects with obstructive sleep apnea (OSA) with normal left ventricular ejection fraction and without any confounding disease that can cause myocardial dysfunction. METHODS: Nineteen healthy individuals and 60 subjects with OSA were included in this study. According to the severity of disease, OSA subjects were examined in 3 groups: mild, moderate, and severe OSA. LV apical views (for longitudinal strain) and short-axis views (for circumferential strain) were acquired for evaluation. Three-layer longitudinal strain values and circumferential strain values were determined for each view, and averages of these were used in comparison with other groups. RESULTS: Three-layer longitudinal strain values of the subjects with OSA were lower than those of the healthy individuals, and these values were decreased along with the OSA severity. The difference was significant between severe OSA and all other groups. Three layer circumferential strain values of the OSA subjects were lower than those of the healthy individuals, and the difference was significant between the control group and all other groups. The apnea hypopnea index was found to be correlated with the 3-layer longitudinal strain (r = -0.74, P < .001; r = -0.72, P < .001; r = -0.69, P = <.001). CONCLUSIONS: Three-layer longitudinal and circumferential LV systolic functions in OSA subjects with normal left ventricular ejection fraction are deteriorated in the subclinical stage. Two-dimensional speckle-tracking echocardiography can be used as an effective method in the determination of subclinical myocardial dysfunction in subjects with OSA. PMID- 26647450 TI - Value of Plethysmographic Pulse Amplitude Ratio With Valsalva Maneuver in Identifying Left Ventricular Dysfunction During COPD Exacerbation. AB - BACKGROUND: Left-ventricular dysfunction associated with COPD exacerbation is frequently underestimated. We tested whether finger plethysmography waveform change during the Valsalva maneuver could aid in the distinction between patients with COPD exacerbation with and without left-ventricular dysfunction. METHODS: We included 102 subjects with COPD exacerbation and 51 subjects with acute heart failure admitted to the emergency department for acute dyspnea. Measurements of the plethysmographic pulse amplitude ratio under the Valsalva maneuver were obtained. The value of the plethysmographic pulse amplitude ratio in diagnosing left-ventricular dysfunction in COPD exacerbation subjects was quantified using the area under the receiver operating characteristic curves. Diagnostic performance of the plethysmographic pulse amplitude ratio was compared with the Boston score, and the net reclassification improvement was calculated to determine the incremental value in detecting left-ventricular dysfunction. RESULTS: Values of the plethysmographic pulse amplitude ratio were higher in COPD exacerbation subjects with left-ventricular dysfunction compared with those without left-ventricular dysfunction (0.78 vs. 0.38, P = .01) but not significantly different from those of the acute heart failure group (0.78). There was a significant correlation between plethysmographic pulse amplitude ratio values and brain natriuretic peptide serum levels. The area under the receiver operating characteristic curve for the plethysmographic pulse amplitude ratio to detect left-ventricular dysfunction among subjects with COPD exacerbation was significantly higher compared with that of the Boston score (0.92 vs. 0.76, P = .02). Exposure to plethysmographic pulse amplitude ratio values increased the overall accuracy from Boston score-based predictions of left-ventricular dysfunction and provided a net reclassification improvement of 17.3%. CONCLUSIONS: An increased plethysmographic pulse amplitude ratio associated with COPD exacerbation is a good predictor of left-ventricular dysfunction. This simple and noninvasive index could help emergency department physicians to detect or rule out left-ventricular dysfunction in patients with COPD exacerbation who are able to perform the Valsalva maneuver. (ClinicalTrials.gov registration NCT01619540.). PMID- 26647451 TI - CORRECTION. PMID- 26647452 TI - The Challenging Diagnosis of Non-Community-Acquired Pneumonia in Non-Mechanically Ventilated Subjects: Value of Microbiological Investigation. AB - BACKGROUND: Early recognition and an attempt at obtaining microbiological documentation are recommended in patients with non-community-acquired pneumonia (NCAP), whether hospital-acquired (HAP) or health care-associated (HCAP). We aimed to characterize the clinical features and microbial etiologies of NCAP to assess the impact of microbiological investigation on their management. METHODS: This was a prospective 1-y study in a university hospital with 141 non mechanically ventilated subjects suspected of having HAP (n = 110) or HCAP (n = 31). RESULTS: Clinical criteria alone poorly identified pneumonia (misdiagnosis in 50% of cases). Microbiological confirmation was achievable in 80 subjects (57%). Among 79 microorganisms isolated, 28 were multidrug-resistant aerobic Gram negative bacilli and group III Enterobacteriaceae and 6 were methicillin resistant Staphylococcus aureus. Multidrug-resistant aerobic Gram-negative bacilli accounted for one third of the microorganisms in early-onset HAP and for 50% in late-onset HAP. Methicillin-resistant S. aureus was most often recovered from subjects with HCAP. Inappropriate empirical antibiotics were administered to 36% of subjects with confirmed pneumonia. Forty subjects were admitted to the ICU, 13 (33%) of whom died. Overall, 39 subjects (28%) died in the hospital. CONCLUSIONS: Integrating the microbiological investigation in the complex clinical diagnostic workup of patients suspected of having NCAP is mandatory. Respiratory tract specimens should be obtained whenever possible for appropriate management. PMID- 26647453 TI - Value of Computed Tomography of the Chest in Subjects With ARDS: A Retrospective Observational Study. AB - BACKGROUND: The value of computed tomography (CT) of the chest in the management of patients with ARDS is poorly defined. The aim of this study was to assess the clinical utility of thoracic CT scans in subjects with ARDS using the Berlin definition. METHODS: This was a retrospective, observational study in a university hospital ARDS center on all subjects with ARDS in whom a CT scan of the chest was performed immediately before or during an ICU stay between January 1, 2007 and June 30, 2013. RESULTS: During the study period, a total of 1,781 thoracic CT scans were performed, of which 204 cases met inclusion criteria. The most common pathologic findings of the lung parenchyma were consolidations (94.1% of cases) and ground glass opacities (85.3%). Furthermore, CT scans showed pleural effusions (80.4%), mediastinal lymphadenopathy (66.7%), signs of right ventricular strain and pulmonary hypertension (53.9%), pericardial effusion (37.3%), emphysema of the chest wall (12.3%), pneumothorax (11.8%), emphysema of the mediastinum (7.4%), and pulmonary embolism (2.5%). Results of CT scans led to changes in management in 26.5% of cases. Mortality was significantly increased in subjects with involvement of lung parenchyma of >80% (P = .004). Intrahospital transport was associated with critical incidents in 8.3% of cases. CONCLUSIONS: Systematic evaluation of thoracic CT scans yielded information useful for making a diagnosis, predicting prognosis, and recognizing concomitant disorders requiring therapeutic interventions. Results obtained from CT scans led to changes in management in 26.5% of cases. PMID- 26647455 TI - Inspiratory Tube Condensation During High-Flow Nasal Cannula Therapy: A Bench Study. AB - BACKGROUND: High-flow nasal cannula (HFNC) therapy provides better humidification than conventional oxygen therapy. To allay loss of vapor as condensation, a servo controlled heating wire is incorporated in the inspiratory tube, but condensation is not completely avoidable. We investigated factors that might affect condensation: thermal characteristics of the inspiratory tube, HFNC flow, and ambient temperature. METHODS: We evaluated 2 types of HFNC tubes, SLH Flex 22-mm single tube and RT202. Both tubes were connected to a heated humidifier with water reservoir. HFNC flow was set at 20, 40, and 60 L/min, and FIO2 was set at 0.21. Air conditioning was used maintain ambient temperature at close to either 20 or 25 degrees C. We weighed the tubes on a digital scale before (0 h) and at 3, 6, and 24 h after, turning on the heated humidifier, and calculated the amount of condensation by simple subtraction. The amount of distilled water used during 24 h was also recorded. RESULTS: At 25 degrees C, there was little condensation, but at 20 degrees C and HFNC flow of 20, 40, and 60 L/min for 24 h, the amount of condensation with the SLH was 50.2 +/- 10.7, 44.3 +/- 17.7, and 56.6 +/- 13.9 mg, and the amount with the RT202 was 96.0 +/- 35.1, 72.8 +/- 8.2, and 64.9 +/- 0.8 mg. When ambient temperature was set to 20 degrees C, condensation with the RT202 was statistically significantly greater than with the SLH at all flow settings (P < .001). CONCLUSIONS: Ambient temperature statistically significantly influenced the amount of condensation in the tubes. PMID- 26647454 TI - Applying the Transtheoretical Model to Physical Activity Behavior in Individuals With Non-Cystic Fibrosis Bronchiectasis. AB - BACKGROUND: The transtheoretical model has been successful in promoting health behavior change in general and clinical populations. However, there is little knowledge about the application of the transtheoretical model to explain physical activity behavior in individuals with non-cystic fibrosis bronchiectasis. The aim was to examine patterns of (1) physical activity and (2) mediators of behavior change (self-efficacy, decisional balance, and processes of change) across stages of change in individuals with non-cystic fibrosis bronchiectasis. METHODS: Fifty five subjects with non-cystic fibrosis bronchiectasis (mean age +/- SD = 63 +/- 10 y) had physical activity assessed over 7 d using an accelerometer. Each component of the transtheoretical model was assessed using validated questionnaires. Subjects were divided into groups depending on stage of change: Group 1 (pre-contemplation and contemplation; n = 10), Group 2 (preparation; n = 20), and Group 3 (action and maintenance; n = 25). Statistical analyses included one-way analysis of variance and Tukey-Kramer post hoc tests. RESULTS: Physical activity variables were significantly (P < .05) higher in Group 3 (action and maintenance) compared with Group 2 (preparation) and Group 1 (pre-contemplation and contemplation). For self-efficacy, there were no significant differences between groups for mean scores (P = .14). Decisional balance cons (barriers to being physically active) were significantly lower in Group 3 versus Group 2 (P = .032). For processes of change, substituting alternatives (substituting inactive options for active options) was significantly higher in Group 3 versus Group 1 (P = .01), and enlisting social support (seeking out social support to increase and maintain physical activity) was significantly lower in Group 3 versus Group 2 (P = .038). CONCLUSIONS: The pattern of physical activity across stages of change is consistent with the theoretical predictions of the transtheoretical model. Constructs of the transtheoretical model that appear to be important at different stages of change include decisional balance cons, substituting alternatives, and enlisting social support. This study provides support to explore transtheoretical model-based physical activity interventions in individuals with non-cystic fibrosis bronchiectasis. (ClinicalTrials.gov registration NCT01569009.). PMID- 26647457 TI - Variability in Mechanical Ventilation: What's All the Noise About? PMID- 26647456 TI - Telemedicine Versus Face-to-Face Evaluations by Respiratory Therapists of Mechanically Ventilated Neonates and Children: A Pilot Study. AB - BACKGROUND: Mechanical ventilation is one of the most important therapeutic interventions in neonatal and pediatric ICUs. Telemedicine has been shown to reliably extend pediatric intensivist expertise to facilities where expertise is limited. If reliable, telemedicine may extend the reach of pediatric respiratory therapists (RTs) to facilities where expertise does not exist or free up existing RT resources for important face-to-face activities in facilities where expertise is limited. The aim of this study was to determine how well respiratory assessments for ventilated neonates and children correlated when performed simultaneously by 2 RTs face-to-face and via telemedicine. METHODS: We conducted a pilot study including 40 assessments by 16 RTs on 11 subjects (5 neonatal ICU; 6 pediatric ICU). Anonymously completed intake forms by 2 different RTs concurrently assessing 14 ventilator-derived and patient-based respiratory variables were used to determine correlations. RESULTS: Forty paired assessments were performed. Median telemedicine assessment time was 8 min. The Pearson correlation coefficient (r) was used to determine agreement between continuous data, and the Cohen kappa statistics were used for binary variables. Pressure control, PEEP, breathing frequency, and FIO2 perfectly correlated (r = 1, all P < .001) as did the presence of a CO2 monitor and need for increased ventilatory support (kappa = 1). The Pearson correlation coefficient for VT, minute ventilation, mean airway pressure, and oxygen saturation ranged from 0.84 to 0.97 (all P < .001). kappa = 0.41 (95% CI 0.02-0.80) for patient-triggered breaths, and kappa = 0.57 (95% CI 0.19-0.94) for breathing frequency higher than set frequency. kappa = -0.25 (95% CI -0.46 to -0.04) for need for suctioning. CONCLUSIONS: Telemedicine technology was acceptable to RTs. Telemedicine evaluations highly correlated with face-to-face for 10 of 14 aspects of standard bedside respiratory assessment. Poor correlation was noted for more complex, patient-generated parameters, highlighting the importance of further investigation incorporating a virtual stethoscope. PMID- 26647458 TI - Osteoprotegerin as biomarker for persistence of rheumatoid arthritis. PMID- 26647459 TI - Comment on: First report of FIP1L1-PDGFRalpha-positive eosinophilic granulomatosis with polyangiitis: reply. PMID- 26647460 TI - Comment on: First report of FIP1L1-PDGFRalpha-positive eosinophilic granulomatosis with polyangiitis. PMID- 26647461 TI - The CRISPR-associated Csx1 protein of Pyrococcus furiosus is an adenosine specific endoribonuclease. AB - Prokaryotes are frequently exposed to potentially harmful invasive nucleic acids from phages, plasmids, and transposons. One method of defense is the CRISPR-Cas adaptive immune system. Diverse CRISPR-Cas systems form distinct ribonucleoprotein effector complexes that target and cleave invasive nucleic acids to provide immunity. The Type III-B Cmr effector complex has been found to target the RNA and DNA of the invader in the various bacterial and archaeal organisms where it has been characterized. Interestingly, the gene encoding the Csx1 protein is frequently located in close proximity to the Cmr1-6 genes in many genomes, implicating a role for Csx1 in Cmr function. However, evidence suggests that Csx1 is not a stably associated component of the Cmr effector complex, but is necessary for DNA silencing by the Cmr system in Sulfolobus islandicus. To investigate the function of the Csx1 protein, we characterized the activity of recombinant Pyrococcus furiosus Csx1 against various nucleic acid substrates. We show that Csx1 is a metal-independent, endoribonuclease that acts selectively on single-stranded RNA and cleaves specifically after adenosines. The RNA cleavage activity of Csx1 is dependent upon a conserved HEPN motif located within the C terminal domain of the protein. This motif is also key for activity in other known ribonucleases. Collectively, the findings indicate that invader silencing by Type III-B CRISPR-Cas systems relies both on RNA and DNA nuclease activities from the Cmr effector complex as well as on the affiliated, trans-acting Csx1 endoribonuclease. PMID- 26647462 TI - Reproducible features of small RNAs in C. elegans reveal NU RNAs and provide insights into 22G RNAs and 26G RNAs. AB - Small RNAs regulate gene expression and most genes in the worm Caenorhabditis elegans are subject to their regulation. Here, we analyze small RNA data sets and use reproducible features of RNAs present in multiple data sets to discover a new class of small RNAs and to reveal insights into two known classes of small RNAs- 22G RNAs and 26G RNAs. We found that reproducibly detected 22-nt RNAs, although are predominantly RNAs with a G at the 5' end, also include RNAs with A, C, or U at the 5' end. These RNAs are synthesized downstream from characteristic sequence motifs on mRNA and have U-tailed derivatives. Analysis of 26G RNAs revealed that they are processed from a blunt end of double-stranded RNAs and that production of one 26G RNA generates a hotspot immediately downstream for production of another. To our surprise, analysis of RNAs shorter than 18 nt revealed a new class of RNAs, which we call NU RNAs (pronounced "new RNAs") because they have a NU bias at the 5' end, where N is any nucleotide. NU RNAs are antisense to genes and originate downstream from U bases on mRNA. Although many genes have complementary NU RNAs, their genome-wide distribution is distinct from that of previously known classes of small RNAs. Our results suggest that current approaches underestimate reproducibly detected RNAs that are shorter than 18 nt, and theoretical considerations suggest that such shorter RNAs could be used for sequence-specific gene regulation in organisms like C. elegans that have small genomes. PMID- 26647464 TI - Nairobi sheep disease virus/Ganjam virus. AB - Nairobi sheep disease virus (NSDV) is a tick-borne virus which causes a severe disease in sheep and goats, and has been responsible for several outbreaks of disease in East Africa. The virus is also found in the Indian subcontinent, where it is known as Ganjam virus. The virus only spreads through the feeding of competent infected ticks, and is therefore limited in its geographic distribution by the distribution of those ticks, Rhipicephalus appendiculata in Africa and Haemaphysalis intermedia in India. Animals bred in endemic areas do not normally develop disease, and the impact is therefore primarily on animals being moved for trade or breeding purposes. The disease caused by NSDV has similarities to several other ruminant diseases, and laboratory diagnosis is necessary for confirmation. There are published methods for diagnosis based on polymerase chain reaction, for virus growth in cell culture and for other simple diagnostic tests, though none has been commercialised. There is no established vaccine against NSDV, although cell-culture attenuated strains have been developed which show promise and could be put into field trials if it were deemed necessary. The virus is closely related to Crimean-Congo haemorrhagic fever virus, and studies on NSDV may therefore be useful in understanding this important human pathogen. PMID- 26647463 TI - Sequencing of lariat termini in S. cerevisiae reveals 5' splice sites, branch points, and novel splicing events. AB - Pre-mRNA splicing is a central step in the shaping of the eukaryotic transcriptome and in the regulation of gene expression. Yet, due to a focus on fully processed mRNA, common approaches for defining pre-mRNA splicing genome wide are suboptimal-especially with respect to defining the branch point sequence, a key cis-element that initiates the chemistry of splicing. Here, we report a complementary intron-centered approach designed to more efficiently, simply, and directly define splicing events genome-wide. Specifically, we developed a method distinguished by deep sequencing of lariat intron termini (LIT seq). In a test of LIT-seq using the budding yeast Saccharomyces cerevisiae, we not only successfully captured the majority of annotated, expressed splicing events but also uncovered 45 novel splicing events, establishing the sensitivity of LIT-seq. Moreover, our libraries were highly enriched with reads that reported on splice sites; by a simple and direct inspection of sequencing reads, we empirically defined both 5' splice sites and branch sites, as well as their consensus sequences, with nucleotide resolution. Additionally, our study revealed that the 3' termini of lariat introns are subject to nontemplated addition of adenosines, characteristic of signals sensed by 3' to 5' RNA turnover machinery. Collectively, this work defines a novel, genome-wide approach for analyzing splicing with unprecedented depth, specificity, and resolution. PMID- 26647465 TI - Preface. PMID- 26647466 TI - An Interview with MARK FEINBERG. PMID- 26647467 TI - VACCINATING the World's Poorest. PMID- 26647469 TI - New Global Goals and Guidelines Aim to Eliminate AIDS. PMID- 26647468 TI - (How) Can NHP MODELS ACCELERATE Vaccine Development? PMID- 26647470 TI - "The time to consider revalidation is now". PMID- 26647471 TI - Crunch decision on revalidation. PMID- 26647472 TI - Huge variation in predicted cost of regulator's plan. PMID- 26647473 TI - New checks process may take nurses much longer than PREP. PMID- 26647474 TI - Ignorance about new system is 'concern', says NMC. PMID- 26647475 TI - Updated vaccination standards issued for healthcare assistants. PMID- 26647476 TI - "A bad CQC report can help to improve a suboptimal service". PMID- 26647477 TI - "A patient's perspective made me see nursing differently". PMID- 26647478 TI - The importance of assessing pain in adults. AB - Pain affects patients physically and emotionally, so successfully managing the pain they experience is a key component of their recovery. This third article in a series on pain looks at why it is important to assess pain in adults and how this can best be done. The causes and symptoms of chronic and acute pain are detailed, along with the different assessment tools that can be used and for which patients they are suitable. PMID- 26647479 TI - Can sociology help to improve nursing practice? AB - The first in a five-part series on sociology offers an overview of the debate about the relationship between sociology and nursing. Although sociological education is currently limited within nurse education, there is a long-held argument for its relevance. With a growing emphasis on preventative and public healthcare, sociology may yet prove its usefulness. Subsequent articles cover four of the key social factors affecting health. PMID- 26647480 TI - Helping nurses reconnect with their compassion. AB - Recent national reports on NHS care failings highlight the need to support, develop and provide evidence of compassion in practice. This article describes a nurse training and leadership programme that teaches nurses to become champions of compassionate care, delivering cultural change across their teams and areas of practice. PMID- 26647481 TI - A dementia first aid course for family carers. AB - Many people with dementia are cared for by family members, who may receive little advice or support. This article describes a course developed to help carers deal with frustrating and challenging behaviour. PMID- 26647482 TI - 60 seconds with Sue Smith. PMID- 26647483 TI - A mission to prevent suicide. PMID- 26647484 TI - What makes a good nurse mentor? PMID- 26647485 TI - Low BACK PAIN BELIEFS AND THEIR RELATIONSHIPS WITH Low BACK PAIN-RELATED DISABILITY IN NURSES WORKING IN MAINLAND CHINA AND IN AUSTRALIA. AB - Beliefs held about low back pain (LBP) can influence treatment outcomes and the development of LBP-related disability. Beliefs are shaped by cultural norms but few cross-cultural studies have been done. This cross-sectional study investigated the back pain beliefs and their associations with disability in 109 Chinese nurses and 165 Australian Caucasian nurses. Chinese nurses held more pessimistic views about the consequences of LBP than the Australian and those with LBP held higher level of fear avoidance beliefs and had higher disability than the Australian nurses with LBP. In both groups, more negativeback pain beliefs were significantly associated with higher disability. PMID- 26647486 TI - OVERCOMING BARRIERS To DIVERSITY IN CHIROPRACTIC PATIENT AND PRACTITIONER POPULATIONS: A COMMENTARY. AB - Increasing the diversity of practitioner and patient populations has been identified as a worthy goal in the chiropractic profession, which has predominantly white male practitioners and white female patients in the USA. Toward that end, 'diversity' has been the topic of several papers and was the theme of a 2012 conference of chiropractic educators. However, generally just the microcosm of the interactions of practitioners with patients or teachers with students has been discussed. The macrocosm of larger societal issues and government policies has not been broached. Examples of issues and policies that affect diversity within a profession include portrayals of, and value judgements on diversity by the media and politicians, as well as public funding for healthcare and education. Diversity was defined in this paper to mean differences in race, sex, sexual orientation, economic status, ethnicity, religion and other life circumstances in a population. The purpose of this paper is to raise awareness of evidence that social issues and government policy affect the diversity of practitioners and patients, and to suggest that the barriers to diversity present in these realms be addressed with a cogent, profession-wide effort in order to help increase the diversity of people involved with chiropractic. PMID- 26647487 TI - PROMOTING CANCER SCREENING AMONG RURAL AFRICAN AMERICANS: A SOCIAL NETWORK APPROACH. AB - Obstacles that prevent rural African Americans (AAs) from regularly engaging in cancer screening were explored, and a theoretical approach was formulated utilizing social networks as a culturally sensitive form of health promotion. Disparities in cancer morbidity and mortality continue to exist between AAs and Caucasians in the United States. Often rural dwellers are further disadvantaged because of a potential lack of medical and financial resources and low health literacy. Social networks provide an existing framework where health concerns are discussed and health interventions in cancer screening can strengthen or encourage relevant health behaviors in rural AAs and other disadvantaged populations. PMID- 26647488 TI - Hapag Kainan: Dietary Consumption of Fat, Sugar, Fruits and Vegetables Among Filipino Americans. AB - The purpose of this study was to explore the relationships among the variables of the dietary consumption and the anthropometric measurements of Filipino Americans (FAs). The study sample consisted of 128 participants residing in the US who completed two questionnaires and biometric measurements. Strong positive correlations between the consumption of fat and sugar and body mass index (BM) among the participants were found. In contrast, the correlations between the consumption of fruits and vegetables and BMI were strongly negative. This study advances the limited body of knowledge on the dietary practices of FAs in the US. PMID- 26647489 TI - DEVELOPING AND IMPLEMENTING A CULTURAL AWARENESS WORKSHOP FOR NURSE PRACTITIONERS. AB - The results of a needs assessment showed that nurse practitioners want additional education on culture and related concepts. Subsequently, a 3-hour cultural education workshop was developed to address this need. The purpose of this study is to determine the impact and effectiveness of a cultural education workshop on the participant's cultural knowledge and cultural competency resulting from the application of that knowledge. Eighteen nurse practitioners and 45 graduate students participated in the study. The results of the study revealed that the cultural awareness workshop had a positive effect on the participants' cultural knowledge and cultural competence. PMID- 26647490 TI - Aggressive surgical interventions for severe stroke: Impact on quality of life, caregiver burden and family outcomes. AB - INTRODUCTION: Decompressive hemicraniectomy, clot evacuation, and aneurysmal interventions are considered aggressive surgical therapeutic options for treatment of massive cerebral artery infarction (MCA), intracerebral hemorrhage (ICH), and severe subarachnoid hemorrhage (SAH) respectively. Although these procedures are saving lives, little is actually known about the impact on outcomes other than short-term survival and functional status. The purpose of this study was to gain a better understanding of personal and social consequences of surviving these aggressive surgical interventions in order to aid acute care clinicians in helping family members make difficult decisions about undertaking such interventions. METHODS: An exploratory mixed method study using a convergent parallel design was conducted to examine functional recovery (NIHSS, mRS & BI), cognitive status (Montreal Cognitive Assessment Scale, MoCA), quality of life (Euroqol 5-D), and caregiver outcomes (Bakas Caregiver Outcome Scale, BCOS) in a cohort of patients and families who had undergone aggressive surgical intervention for severe stroke between the years 2000-2007 Data were analyzed using descriptive statistics, univariate and multivariate analysis of variance, and multivariate logistic regression. Content analysis was used to analyze the qualitative interviews conducted with stroke survivors and family members. RESULTS: Twenty-seven patients and 13 spouses participated in this study. Based on patient MOCA scores, overall cognitive status was 25.18 (range 23.4-26.9); current functional outcomes scores: NIHSS 2.22, mRS 1.74, and BI 88.5. EQ-5D scores revealed no significant differences between patients and caregivers (p = 0.585) and caregiver outcomes revealed no significant diferences between male/female caregivers or patient diagnostic group (MCA, SAH, ICH; p = 0.103). DISCUSSION: Overall, patients and families were satisfied with quality of life and decisions made at the time of the initial stroke. There was consensus among study participants that formal community-based support (e.g., handibus, caregiving relief, rehabilitation assessments) should be continued for extended periods (e.g, years)post-stroke. Ongoing contact with health care professionals is valuable to help them navigate in the community as needs change over time. PMID- 26647491 TI - Factors that influence the decision-making of an interdisciplinary rehabilitation team when choosing a discharge destination for stroke survivors. AB - This study explored the culture of one interdisciplinary rehabilitation team in British Columbia (BC), Canada, to identify the specific client, clinical, and family factors considered by team members when determining post-hospital discharge placement. The study took the form of an ethnography of a health care team on a stroke unit of a Canadian hospital using observations of the interdisciplinary rehabilitation team meetings and follow-up interviews with team members. The findings from the study indicate post-hospital discharge destination decisions were influenced by specific social, economic, and policy factors; specific types of interactions among members of the team; and the condition of stroke survivors, and the ability and willingness of the patient's family to contribute to home care. PMID- 26647492 TI - Collaborative research teams: It is amazing what you can accomplish if you do not care who gets the credit. AB - This article focuses on working as a collaborative in conducting research. A common recommendation for those who want to get started in scholarly work is to collaborate with a team of like-minded individuals as part of an interest group. As researchers, we all have personal agendas in undertaking research. We need to reflect on the following: our own agendas; being honest with ourselves, and our research teammates; ensuring that our aims are not mutually exclusive or detrimental to the aspirations of our colleagues and students; and on the ethical conduct of the research work itself. PMID- 26647493 TI - Pseudoprogression: Patient experience and nursing in uncertainty. AB - Glioblastoma Multiforme (GBM) is the most common primary brain malignancy in humans and has a limited survival (median of 14.6 months). The goal of treatment is supportive rather than curative. Patients with a GBM struggle with uncertainty related to the illness trajectory. This uncertainty is compounded when possible progression is noted on imaging. Pseudoprogression (PsP) is an early treatment related effect where there are apparent imaging changes suggesting progression, which then improve or stabilize through time. This paper provides a review of the literature on PsP in patients with high-grade gliomas. Insights in the patient and family experience of PsP will be informed by Mishel's Uncertainty in Illness Theory, research on patients' and families' neuro-oncology experience, and the author's nursing practice. Nursing implications will be proposed. PMID- 26647494 TI - Early detection of cognitive disorders: Follow-up study. AB - BACKGROUND: Recently, a new test (Cuetos-Vega) was developed to detect patients with early symptoms of Alzheimer's disease (AD). This test is rapid, simple and could diagnose patients at early phases of cognitive disorders. The aim of our follow-up study is to evaluate the sensitivity, specificity and predictive values of this test in primary health care (PHC) facilities. METHODS: We obtained from our database of La Rambla (village with +/- 8,000 habitants at South Cordoba Health District) the list of asymptomatic independent patients between 66 and 75 years old. A pilot study was conducted with 20 users of La Rambla PHC Centre. This test was modified and adapted for application to our study population. All participants were selected randomly and assigned a date by telephone for the nursing outpatient clinic where the nurse proceeded to administer the screening test. All participants were invited to repeat the same test, together with Pfeiffer test (a short mental status questionnaire), 32 months after the pilot study. RESULTS: The average age of participants was 71.5 +/- 2.9 years and 10 (50%) were men. The sensitivity of the new test after 32 months was 50% and the specificity 90.9%. The test had a positive predictive value of 75% and a negative predictive value of 76.9%. The overall accuracy of the test was 76.4%. CONCLUSION: We present a new test designed to detect patients with mild cognitive impairment and/or early symptoms of AD. A larger cohort is needed to improve the internal validity. PMID- 26647495 TI - Security planning for public health emergencies. AB - In this article the author identifies the security sensitive areas of a hospital during a public health emergency event, and the need to have processes and plans in place to mitigate the security and traffic related problems that accompany such events. He describes a number of specialized security and safety guidelines and tools that have been designed by and provided to healthcare security professionals free of charge. PMID- 26647496 TI - Infectious disease protection for healthcare security officers. AB - Healthcare Security should be considered an active component in an infectious disease event, the authors maintain, and security officers must be included in an Employee Health screening and N95 fit testing initiative to safely welcome the incoming infected patients. In this article, they spell out the different levels of precautions officers should become familiar with in order to protect themselves. PMID- 26647497 TI - How to use security risk assessments to manage risks, prevent violence and deal with new threats. AB - With a growing number of healthcare security requirements from states as well as regulators like FEMA, CMS, and DHS, the need to conduct comprehensive Security Risk Assessments has become essential, according to the author. In this article, she provides the basic elements of such assessments as well as guidance on how to apply them to a facility report and how to present the report to management. PMID- 26647498 TI - Boosting fire drill participation in hospital settings. AB - In a health system with over 100 sites in a geographically dispersed region, boosting fire drill participation to meet government requirements, according to the author, is a constant effort, both to achieve and to maintain. In this article, he describes a comprehensive approach that entails engagement of executive, site committees and local fire authorities, as well as comprehensive training and awareness campaigns. PMID- 26647499 TI - Hospital emergency preparedness and response during Superstorm Sandy. AB - This article presents the findings of a report by the HHS Office of Inspector General (OIG) on the performance of 172 Medicare-certified hospitals in the New York Metropolitan Area before, during, and after Sandy. It makes recommendations on how to close gaps that were found in emergency planning and execution for a disaster of this magnitude. To download the complete 40-page report and a Podcast based on it, go to http://oig.hhs.gov/oei/ reports/oei-06-13-00260. asp. PMID- 26647500 TI - A data-driven model for estimating industry average numbers of hospital security staff. AB - In this article the authors report the results of an expanded survey, financed by the International Healthcare Security and Safety Foundation (IHSSF), applied to the development of a model for determining the number of security officers required by a hospital. PMID- 26647501 TI - Violence throughout the healthcare continuum. AB - In this review of a broad range of reports and studies of workplace violence in healthcare, the authors find that such violence extends through the entire continuum of the industry affecting all health care employees in settings that include Paramedics and EMTs, Emergency Department staff acute care staff, long term care staff and Home Care staff. Knowing the risks and the data is the first step in developing strategies to prevent and minimize its impact, they conclude. PMID- 26647502 TI - Use of force in the healthcare setting. AB - Failure to train security officers in the use of safe and effective physical control techniques to address combative patients, the author claims, exposes the healthcare facility to greater legal risk as well greater danger to the patient, other patients, visitors, and staff In this article he outlines a physical training program for security officers that should be part of a complete "response to aggression" package that should also include extensive training in verbal de-escalation skills for everyone who works in the healthcare environment. PMID- 26647503 TI - Security basics for long-term care facilities. AB - The need for Long-Term Care (LTC) facilities is growing, the author reports, and along with it the need for programs to address the major security concerns of such facilities. In this article he explains how to apply the IAHSS Healthcare Security Industry Guidelines and the Design Guidelines to achieve a safer LTC facility. PMID- 26647504 TI - Three training tenets. AB - If officers are trained to recognize that it is not enough just to observe and report something occurring, but to anticipate its impact, respond appropriately and/or make a recommendation, leaders will obtain a higher level of performance from their security staffs, according to the author who describes three training tenets he has followed over the years to achieve those higher results. PMID- 26647505 TI - Managing a security contract: the LMIPS way. AB - The key to successfully managing a security contract is to develop and maintain a positive working relationship with the security vendor(s), according to the author. In this article he describes how experienced security professionals representing both clients and the contractor, working together in a clearly defined program, are successfully providing security for a large and geographically dispersed health care entity. PMID- 26647506 TI - Incident reporting: the bureau investigation. AB - The Bureau Investigation (BI) is a type of report that lends itself to the internal complaints often generated within a bureaucracy, the author reports, and ranges from discourtesy complaints on a single shift or a single officer to the more complex, sensitive inquiries called for by the senior administration. In this article he explores the many facets of the BI which must be mastered. PMID- 26647507 TI - Putting security in the spotlight. AB - In this article the author provides instructions and advice about getting the word out about Security via an in-house newsletter, security workshops, and special programs. PMID- 26647508 TI - Difficult conversations: the kind thing to do. AB - The author discusses what she believes are the right and wrong ways to handle a customer complaint about the behavior of one of your officers. PMID- 26647509 TI - Dealing with difficult people. AB - The number ofpeople security officers deal with and the number of challenges they present, are increasing every day, the author reports. Developing verbal skills to handle those challenges is not easy, but is essential in helping them and the facility you work for, he says. A veteran of 400 plus hours in training healthcare workers in crisis prevention, he provides in this article a number of effective ways to achieve tension reduction. PMID- 26647510 TI - Change agents among us. PMID- 26647511 TI - Final 2015 Medicare physician fee schedule rule includes quality reporting program changes, CCM service and more. PMID- 26647512 TI - Tenacity in the face of adversity: Recognizing the problems ahead and identifying workable solutions. PMID- 26647513 TI - HIT update: What to watch for in 2015. PMID- 26647514 TI - Price transparency: A useful tool for successful practices. PMID- 26647515 TI - To join or not to join. PMID- 26647516 TI - Integration, independence or employment? Or can you have it all? PMID- 26647517 TI - Better-performing groups use NPPs to extend physician productivity. PMID- 26647518 TI - To boldly go: MGMA member envisions the future of medical group practice. PMID- 26647519 TI - Data, data everywhere and no information to use. PMID- 26647520 TI - Jump-start your 2015 ICD-10 efforts. PMID- 26647521 TI - Game-changer: How do HDHPs affect medical groups? PMID- 26647522 TI - Of particular interest: Available data about medical practices. PMID- 26647523 TI - Health system uses UV robots to kill Ebola and other germs. PMID- 26647525 TI - What's the best advice for physicians at the start of their careers? PMID- 26647524 TI - Nutrition tools for your practice to use. PMID- 26647526 TI - Top 3 strategies to survive--and thrive--as a private practice. PMID- 26647527 TI - Proving your worth: The value of experience in physician groups. PMID- 26647528 TI - [Flap reconstruction of the surgical defects of hypopharyngeal cancer]. PMID- 26647529 TI - [Principles in reconstruction of major defects after tumor ablation in head and neck cancers]. PMID- 26647530 TI - [Anterolateral thigh flap, a better flap for reconstruction of hypopharyngeal and cervical esophageal defects]. AB - Because of minimal donor site morbidity, adequate tissue, excellent clinical and functional results, the anterolateral thigh flap has become one of the most important tissue flaps which are used to repair the defects of head and neck. Generally, anterolateral thigh flap is mainly used to repair the maxillofacial defects in head and neck surgery. However, the anterolateral thigh flap is a better tissue flap for reconstruction of hypopharyngeal and cervical esophageal defects. PMID- 26647531 TI - [Repair surgical defect of squamous cell carcinoma of tongue base with advanced patients]. AB - OBJECTIVE: To repair the postoperative tissue detect of the base of tongue cancer in advanced patients. METHOD: There were 30 patients of medium-high differentiation squamous cell carcinoma(SCC) included in this study. According to the TNM staging of AJCC 2002, there were 4 cases of T2N1M0, 7 of T3N1M0, 10 of T3N2M0, 4 of T4N1M0 and 5 of T4N2M0. Surgical approach of the primary lesion: 12 with transhyoidpharyngotomy approach and 18 with mandibulotomy approach. All cases accepted radiotherapy 4-6 weeks after surgery. RESULT: Twenty-five cases were reconstructed with pedicle pectoralis major myocutaneous flaps, and all them survived. Among them, 1 flap was partial split with surrounding tissue spontaneously, and another flap had partial tissue necrosis, however, both flaps grew well with dressing and other local treatment. Other 5 cases were reconstructed with free anterolateral myocutaneous flaps. Among them, 1 flap had partial tissue necrosis, but had a secondary healing after removing necrotic tissue via mouth approach. All 18 patients of larynx-preservation had tracheal tube pulled out. The 3-year survival rate was 68% and the local control rate was 87%. CONCLUSION: Pedicle pectoralis major myocutaneous flaps and free anterolateral myocutaneous flaps were alternative donor area for repairing postoperative tissue defect of the base of tongue; The former was preferred, and the latter was concealed so as to be a kind of effective method, which need adept technique of microsurgery. PMID- 26647532 TI - [Postoperatively repair methods of head and facial skin malignancies in the advanced ages]. AB - OBJECTIVE: To investigate postoperatively repairing methods and their clinical effects of the olders over 80 years old with head and facial skin malignancies. METHOD: Eighteen cases of skin cancers in the head and face, whose malignancies were resected with Mohs microscopic surgery, according to the local or systemic condition of patients after surgery we choose different repairing methods: free skin flap grafting in 2 cases, local skin flap transferring 12 cases; including rotation skin flap grafting 6 cases, sliding flap 4 cases, nasolabial flap 2 cases; transposition flap 4 cases. RESULT: Operations of the 18 cases went well without special complications. All of the flaps were alive with partial flap necrosis in 1 case, which was cured 1 month later by dressing changes. During the follow-up period ranged from 6 months to 2 years,no tumor recurred,the functional recovery and appearance were satisfactory. CONCLUSION: Choosing operating methods in head and facial skin malignancies should consider patients' age, disease state and general condition. Reparing methods of Head and facial skin malignancies in the advanced ages should be selected according to their specific circumstances, especially the simple, convenient and rapid with less trauma way. PMID- 26647533 TI - [Analysis of correlated factors of cervical lymphatic metastasis of T3 and T4 glottic carcinoma]. AB - OBJECTIVE: To analyze the correlated factors of cervical lymphatic metastasis of T3 and T4 glottic carcinoma. METHOD: We did a retrospective analysis of 91 glottic carcinoma patients' clinical data to analyze cervical lymph node metastasis on different T stage, pathologic degree and the tumor sites. RESULT: The cervical lymph node metastasis rate of 91 cases of T3 and T4 glottic carcinoma was 21.98%. T3 group's metastasis rate was 18.06% (13/72), T4 group's metastasis rate was 36.84% (7/19), P > 0.05. Grouped according to the degree of pathological differentiation, well-differentiated squamous cell carcinoma metastasis rate is 13.89% (5/36), middle-differentiated squamous cell carcinoma metastasis rate is 26.00% (13/50), and poorly-differentiated squamous cell carcinoma metastasis rate is 40.00% (2/5), P > 0.05. Cervical lymph node metastasis rate was 16.22%, when the tumor invading supraglottic region. Cervical lymph node metastasis rate was 15.38%, when the tumor invading subraglottic region. Cervical lymph node metastasis rate was 46.15%, when the tumor invading supraglottic and subraglottic region (P < 0.01). CONCLUSION: Cervical lymph node metastasis in cN0 patient with supraglottic carcinoma is effected by T classification, cervical lymphatic metastasis of T3 and T4 glottic carcinoma is not entirely effected by T stage and pathologic degree. When the tumor invades supraglottic and subraglottic region, cervical lymph node metastasis is significantly higher. Therefore, the area of tumor invasion is an important factor for lymph node metastasis. PMID- 26647534 TI - [The related factors analysis of difficult laryngeal exposure under retaining laryngoscope]. AB - OBJECTIVE: To analyze the related factors of difficult laryngeal exposure under retaining laryngoscope. METHOD: We did a retrospective analysis of 287 retaining laryngoscope surgery patients' clinical datas to observe the relationship between difficult glottis exposure and patients' gender, degree of mouth opening, BMI, neck circumference, head and neck flexion, TMD, HMD and SMD. RESULT: By ROC curve analysis, we determine the optimal threshold for TMD was 7.35 cm, HMD was 6.33 cm, SMD was 14.75 cm. Univariate analysis showed that gender, and glottis exposure had no significant correlation with difficult laryngeal exposure under retaining laryngoscope. Degree of mouth opening, BMI, neck circumference, head and neck flexion, TMD, HMD and SMD had correlation with difficult laryngeal exposure. Multivariate analysis showed that neck circumference, head and neck flexion, TMD, SMD were independent factors of difficult laryngeal exposure under retaining laryngoscope. CONCLUSION: Measurement of neck circumference, head and neck flexion, TMD, SMD before the operation is important for the prediction of difficult laryngeal exposure under retaining laryngoscope. PMID- 26647535 TI - [Comparison of methods for isolating exosomes derived from laryngocarcinoma Hep-2 cells]. AB - OBJECTIVE: To provide a reference about choosing the methods of isolating exosomes derived from tumor cells including laryngocarcinima Hep-2 cells by comparing advantages and defects of two methods of isolation and extraction exosomes. METHOD: Previously, laryngocarcinoma Hep-2 cells were cultivated massively, then the cells were processed with hot shock in 42 degrees C for 1 h. Sucrose density gradient centrifugation ultrafiltration (method 1): cells culture supernatant 90 ml was gathered, the supernatant was clarified through a 3/0.8 MUm small filter to remove impurities and fragments which in larger diameter. Then the filtering fluid was concentrated and purified through sucrose density gradient centrifugation and ultrafiltration, the concentrated fluid was obtained. Exosome Isolation Kit (method 2): cells culture supernatant 4 ml was gathered, the solutions of the kit were added into the supernatant in proper sequence, then filtered by the special column, the concentrated fluid was obtained. Both products are observed by high resolution transmission electron microscopy. RESULT: Both methods could isolate and extract exosomes feasibly. In single high power view of transmission electron microscopy, exosomes of method 1 disperse better, but lower density, and more impurity in background, exosomes of method 2 arrange closer, higher density, and less impurity. CONCLUSION: Exosome isolation Kit require less supernatant, cost less time, process procedure briefly, harvest higher yield. It may become a new option of isolating exosomes derived from Laryngocarcinoma Hep-2 cells. PMID- 26647536 TI - [Clinical profile analysis of laryngeal nonsquamous cell malignancies]. AB - OBJECTIVE: To observe clinical characteristics of 15 cases of laryngeal nonsquamous malignancies. METHOD: The clinical data of 15 patients with laryngeal nonsquamous malignancies were collected. Details about pathology, CT, treatment and follow-up results were carefully taken into account. RESULT: There were more male patients than females while the sex ratio was 4:1. Supraglottic malignancies accounting for 53.33% seemed to be the most common type. In all the 15 patients, 1 patient gave up other treatment except tracheotomy to relieve laryngeal obstruction. Three patients took radiotherapy and chemotherapy. The rest patients underwent surgical procedure after strict endoscopic, radiologic staging. Radiotherapy and (or) chemotherapy were chosen after operation. The follow-up results show that 1 year survival rate was 79.4% and the 3 year survival rate was 57.8%, 5 year survival rate was 27.5% which was not optimistic. CONCLUSION: Being a kind of rare type laryngeal nonsquamous malignancies have difference clinical characteristics with laryngeal squamous cell carcinoma. Laryngeal nonsquamous cell carcinoma have much lower 5 year survival rate and are easier to suffer recurrence and metastasis compared with laryngeal squamous cell carcinoma. PMID- 26647537 TI - [Correlation of osteopontin expression and laryngeal squamous cell carcinoma infiltration and metastasis]. AB - OBJECTIVE: To investigate osteopontin (OPN) expression in plasma and tissue of patients with layngeal squamous cell carcinoma and analyze its role in invasion, metastasis, and clinical significance in laryngeal quamous cell carcinoma. METHOD: Enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry were used to detect expression of OPN in plasma and tissue of 60 cases of laryngeal squamous cell carcinoma, 20 cases of adjacent normal laryngeal tissue and 20 cases of plasma from healthy subjects. RESULT: The expression of plasma OPN was closely correlated with clinical stage and cervical lymphatic metastasis in laryngeal squamous cell carcinoma (P < 0.05), but no significant correlation with the tumor location, pathological grade, gender and age (P > 0.05). The expression of OPN increased in plasma during cancer development: laryngeal squamous cell carcinoma (38.089 +/- 9.225) ng/ml, healthy subjects (18.563 +/- 9.308) ng/ml. There was a significant difference between the groups (P < 0.05). The expression of OPN in tissue was closely correlated with clinical stage (P < 0.05), pathological grade (P < 0.05) and cervical lymphatic metastasis (P < 0.05) in laryngeal squamous cell carcinoma adjacent atypical hyperplastic epithelium and carcinoma. The expression of OPN increased in tissue during cancer development: laryngeal squamous cell carcinoma (56.67%), adjacent normal laryngeal tissue (15.00%). There was a significant difference between the groups (P < 0.05). Elevated expression of plasma OPN is positively correlated with the expression of OPN in tissue in laryngeal squamous cell carcinoma patients (r = 0. 871, P < 0.05). CONCLUSION: OPN plays an important role in the infiltration, metastasis and carcinogenesis in laryngeal squamous cell carcinoma. Combination of serum OPN, tissue OPN detection can be used as diagnostic and surveillance indicators for laryngeal squamous cell carcinoma infiltration and metastasis. PMID- 26647538 TI - [The anatomical structure similarity research on auricular cartilage and nasal alar cartilage]. AB - OBJECTIVE: There are many scaffold materials of repairing nasal alar cartilage defects. Auricuiar cartilage was used extensively in terms of its abundant tissues, good elasticity, little donor-site malformation, good plasticity etc. The authors dissected auricular cartilage and nasal alar cartilage, measured cartilage's morphous data and found some similar territories with nasal alar cartilage in the structure of auricular cartilage. METHOD: An anatomical study was performed using 10 adult cadavers acquired through Plastic Surgery Hospital, Peking Union Medical College, Beijing, China. Seven male and three female cadav ers were included in the study. Harvest 20 auricular cartilage specimens and 20 nasal alar cartilage specimens. Then, Computed Tomography Scan on the auricular cartilage and nasal alar cartilage were performed. The datas were imported into mimics and three-dimensional reconstructions of the auricular cartilage and nasal alar cartilage were carried on. RESULT: Parts of the auricular cartilage, such as conchal fossa, tragus, intertragic notch, and cymba of auricular concha, curs of helix and curs of helix, triangular fossa, are ana-tomically similar to nasal alar cartilage. CONCLUSION: This study reports the anatomy of auricular cartilage and nasal alar cartilage, found some territories in the auricular cartilage, such as conchal fossa, tragus, intertragic notch, and cymba of auricular concha, curs of helix and curs of helix, triangular fossa, are anatomically similar to nasal alar cartilage. This research provides the anatomical basis that auricular cartilage was used to repair the nasal cartilage defect. PMID- 26647539 TI - [Lexical tone perception in sensorineural hearing-impaired and auditory neuropathy spectrum disorder]. AB - OBJECTIVE: This study was aimed at investigating the ability of lexical tone perception in listeners with sensorineural hearing impairment and auditory. neuropathy spectrum disorder. METHOD: Three groups of subjects were recruited in this study, including 11 subjects with normal hearing, 14 subjects with sensorineural hearing impairment, and 25 subjects with auditory neuropathy spectrum disorder. Ten monosyllabic syllables were selected, and combined with four lexical tones which were made up of 40 tone tokens as the original test materials. Then, these original words were recorded using one adult male and one adult female native Beijing Mandarin speaker. The speakers were asked to record these 40 monosyllabic words multiple times, and the 80 tokens in which the durations of four tones in each monosyllabic word were within 5ms precision were chosen as the test tone tokens. The subjects were asked to perform a four alternative forced-choice study and select which tone they had heard. RESULT: The mean and standard deviation of the tone perception correct scores for normal hearing subjects, subjects with sensorineural hearing impairment, and subjects with auditory neuropathy spectrum disorder were (97.3 +/- 2.8)%, (88.0 +/- 9.9)%, and (65.7 +/- 17.1)%, respectively. Significant differences in tone perception scores were found to be between subjects with normal hearing and subjects with sensorineural hearing impairment (P < 0.01) and between subjects with auditory neuropathy spectrum disorder (P < 0.01). In addition, a significant difference was found to be between subjects with sensorineural hearing impairment and auditory neuropathy spectrum disorder (P < 0.05). A significantly negative correlation was observed between tone perception score and pure tone hearing thresholds for both subjects with sensorineural hearing loss (r = -0.756, P < 0.01) and subjects with auditory neuropathy spectrum disorder (r = -0.546, P < 0.01). CONCLUSION: As the hearing loss became more severe, the ability to perceive lexical tone for both subjects with sensorineural hearing loss and auditory neuropathy spectrum disorder reduced. Subjects with auditory neuropathy spectrum disorder had more degraded ability to perceive lexical tone and a larger individual difference, in comparison with subjects with sensorineural hearing loss. PMID- 26647540 TI - [Psychiatric disorders in pharyngitis patients and its associated factor analysis]. AB - OBJECTIVE: To investigate the characteristics of psychiatric comorbidity in pharyngitis patients. METHOD: The psychological investigation and evaluation were done in 100 pharyngitis patients by using self-reporting inventory 90 (SCL-90). All the results were compared with healthy Chinese population, including factors of gender, age, course of disease and education level, using rank-sum test analysis, SPSS 19.0. RESULT: Mild and moderate levels of psychosis were respectively noted in 65% and 14%, with high score of somatization (P < 0.05), obsession (P < 0.05), interpersonal sensitivity (P < 0.05), anxiety (P < 0.05) and other (sleep, diet, P < 0.05) compared with control group. The factor scores of obsession (P < 0.05), anxiety (P < 0.05) in male group were higher than female group. The factor scores of somatization (P < 0.05) and obsession (P < 0.05) in junior group were higher than senior group. The factor scores of somatization (P < 0.05), interpersonal sensitivity (P < 0.05) and anxiety (P < 0.05) in long course group were higher than short course group. The factor score of interpersonal sensitivity (P < 0.05) in low educated group was higher than highly educated group. CONCLUSION: Psychiatric disorders are prevalent in pharyngitis patients, especially upon the factors of somatization, obsession, interpersonal sensitivity, anxiety and other (sleep, diet). Male, junior, long course patients and low educated are in high risk group. PMID- 26647541 TI - [Expressions and correlations of Survivin, Ki67 and p53 in laryngeal squmous cell carcinoma]. AB - OBJECTIVE: To investigate the expression of Survivin, p53 and Ki67 in laryngeal carcinoma and the relation with clinical data. METHOD: Immunohistochemical staining (SP) was used to detect expression of Survivin, p53 and Ki67 of 64 cases with laryngeal carcinoma, 26 cases with precancerosis, 34 cases with vocal polyps. RESULT: The positive expression rates of Survivin, p53 and Ki67 were 59.4%, 68.8%, 65.6% respectively in laryngeal carcinoma, which were significantly higher than those in precancerosis and vocal polyps (P < 0.01). The expression of Survivin, p53 and Ki67 in laryngeal carcinoma were significantly statistical different in TNM stage and lymph node metastasis (P < 0.05), but were not correlated with patients' ages, the pathological grades, 3 years and 5 years surviving rates (P > 0.05). The expression of Survivin, Ki-67 and p53 was positively correlated (r = 0.607, 0.541, 0.648, P < 0.01) in laryngeal carcinoma. CONCLUSION: Survivin, p53 and Ki-67 may play an important role in the carcinogenesis and progress of laryngeal carcinoma. They may play synergetic roles in the process of carcinogenesis of laryngeal carcinoma. PMID- 26647542 TI - [Subtype analysis and clinical significance of HPV infection in laryngeal squamous cell carcinoma and precancerous lesions]. AB - OBJECTIVE: To investigate the correlation of laryngeal squamous cell carcinoma (LSCC) and precancerous lesion with HPV infection subtypes and possible clinical relationship. METHOD: Eighty-three cases in paraffin embedded tissues were detected with thirty seven HPV subtypes by flow-through hybridization and gene chip (HybriMax), including 31 cases of laryngeal squamous cell carcinoma, 52 cases of precancerous lesions (29 cases of vocal cord leukoplakia and 23 cases of laryngeal papilloma), and 36 cases of vocal cord polyp as normal vocal mucosa were used as control. RESULT: The total positive rate of HPV was 19.4% in the group of laryngeal squamous cell carcinoma (6/31), 0 in vocal cord leukoplakia, 65.2% in laryngeal papilloma (15/23), and the control group were all negative, HPV virus subtype of HPV-positive laryngeal squamous cell carcinoma were all high risk HPV16; and there were 6 HPV virus subtypes in laryngeal papilloma (8: HPV6,4: HPV52, 1: HPV11, 1: HPV18, 2: HPV45, 3: HPV16), individual mixing two or more subtypes infection. HPV infection of laryngeal squamous cell carcinoma and precancerous lesions has no statistically significant difference according to gender, high low-risk subtypes. CONCLUSION: HPV infection related to laryngeal squamous cell carcinoma and precancerous lesions, but no significant correlation with the subtype distribution of high and low risk; HPV detection is making positive sense to clinical diagnosis of laryngeal carcinoma and precancerous lesions as well as the development of specific HPV subtype vaccine. PMID- 26647543 TI - [Analysis of the characteristic of pharyngeal paraesthesia patients by high resolution manometry]. AB - OBJECTIVE: To discuss the pressure changing characteristics of upper esophageal sphincter (UES), lower esophageal sphincter (LES) and the esophagus kinetic characteristics of pharyngeal paraesthesia patients. METHOD: To take high resolution manometry in 44 cases of pharyngeal paraesthesia patients and 23 normal subjects separately. According to the RSI score,the 44 patients were divided into group A (the group without reflux, RSI < 13, n = 25) and group B (the group with reflux, RSI >= 13, n = 19). RESULT: The UES average resting pressure and average residual pressure of patients group were higher than the control group (P < 0.05); The UES average resting pressure and average residual pressure of group B were higher than group A (P < 0.05); The LES average resting pressure and average residual pressure of group B were lower than group A and the control group (P < 0.05); The comparison of LES average resting pressure and average residual pressure between group A and the control group was not statistically significant (P > 0.05). The esophagus DCI of group B was lower than that of group A and control group (P < 0.05). The esophagus DCI comparison between group A and control group was not statistically significant (P > 0.05). CONCLUSION: The pharyngeal paresthesia symptoms of'patients was associated with the increasing of UES pressure. The pharyngeal paresthesia symptoms of group with reflux was related to low pressure of LES and high pressure of UES. The last part of esophagus of group with reflux had obstacles in powers, which weaken the peristalsis and declined the ability to clear the bolus and gastric reflux material. PMID- 26647544 TI - [The experimental study on repair of noise-induced hearing loss in guinea pigs by bone marrow NTCSCs transplantation]. AB - OBJECTIVE: To observe the repairing effects of bone marrow transplantation with nerve tissue committed stem cell (NTCSCs) on experimental rats with injury of noise-induced hearing loss. METHOD: Guinea pigs were randomly divided into control group, noise exposure group and the transplanting group. A week after white noise exposure of 110 dB, NTCSCs and PBS were injected into guinea pigs of the noise exposure group and the transplanting group respectively. One week after noise exposure to four weeks continuous administration. ABR thresholds were measured respectively prior to the experiment, 1 week post-noise,1, 2 and 4 weeks post-drugs, The changes of cochlea hair cells were also observed by a scan electron microscope (SEM). RESULT: The ABR threshold shifts in the transplanting group were significantly fewer than that in the noise exposure group. SEM showed that hear hair of the inner and outer hair cells in noise exposure group displayed mess, fusion and imperfections. In the transplanting treatment group, the hair cells displayed slight pathological changes, there wasn't significant differents comparied with normal group. The number of OHCs were relatively stable in the normal group, while the obvious OHC loss was observed in other groups. There was significant difference among the three groups, however, the OHC loss in the transplanting group was no significantly different to that in the noise exposure (P > 0.05). CONCLUSION: The bone marrow NTCSCs which had been transplanted to rat cochlea could reduce the damage of the noise on the hair cell, and thus played a role in repairing the damage of auditory nerve. PMID- 26647545 TI - [Multi-function electric ion fenestration combined with anisodamine and other drugs in the treatment of pseudocyst of auricle]. PMID- 26647546 TI - [Two nasal endoscopic nasal septum diorthosis tamping observation]. PMID- 26647547 TI - [Atypical carcinoid of larynx: a case report]. AB - An 70-year-old male come for swallowing pain 5 years, turning worse 10 months. Laryngoscopy showed a tumor with rough surface at the laryngeal surface of epiglottic. Outpatient pathology: poorly differentiated carcinoma of the larynx. CT: the root of epiglottic is slightly thickened. He accepted the partial laryngectomy, tracheotomy, bilateral functional neck dissection. Pathology: atypical carcinoid of larynx. PMID- 26647548 TI - [The very severe sensorineural deafness patients caused by rubella virus infection: two cases report]. AB - To explore the audiological features in children who were sever sensorineural hearing loss infected with rubella virus. There were two cases of rubella virus infection in children who were deaf, they conducted the distortion product otoacoustic emission, ABR and auditory steady-state evoked response (ASSR) examination, then analyzed the results comprehensively. Two patients' mothers were prompted to have infected rubella virus during the early three months pregnant period by history and laboratory tests. The two patients were not detected deafness gene mutation. Audiology results implied the two patients were very severe binaural sensorineural deafness, so they were recommended to equipped with hearing aids and cochlear implant surgery. Early pregnancy women infected with rubella virus can cause very severe offspring sensorineural deafness. The crowd whose mother were suspected to infect with rubella virus in early pregnancy, that should be tracked and detected hearing in order to achieve early detection, early intervention and early treatment. PMID- 26647549 TI - [Adult onset Still's disease with the initial symptom of pharyngalgia: a case report]. AB - Adult onset Still's disease is a rare inflammatory disease characterized by spiking fevers, arthritis/ arthralgias, typical salmon-colored bumpy rash, pharyngalgia, myalgia and possible involvement of visceral organs. The diagnosis is exclusively based on clinical symptoms, according to the criteria, after the exclusion of well-known infectious, neoplastic, or other autoimmune/autoinflammatory disorders. This report includes one case of adult onset Still's disease with the initial symptom of pharyngalgia. PMID- 26647550 TI - [Through the canal metal crochet embedding operation to remove the stylomastoid foramen for facial paralysis: a case report]. AB - One case with metal crochet through external auditory meatus embedded stylomastoid foramen, preoperative found no paralysis, underwent temporal bone CT examination to assess the illness after emergency surgery to remove the foreign body, postoperative patients of peripheral facial paralysis, explore and summarize the clinical experience. PMID- 26647551 TI - [Eustachian tube dysfunction misdiagnosed: a case report]. AB - The patient has complained of fullness in her right ear since she took a flight 5 years ago. Pure tone audiometry indicated normal hearing threshold and acoustic immitance proved type A tympanogram in both ears. She visited different doctors over and over again, with every doctor diagnosed her with psychogenic ear fullness. The patient was treated with vasodilative and neurotrophic medicine, together with psychotherapy, but her ear fullness didn't relieve. Three months ago she visited our department. Tubomanometry (TMM) can't find R value under 50mBar and ETS-7 score was zero in her right ear. Eustachian tube dysfunction was diagnosed and the patient was then given nasal decongestants, intranasal corticosteroids and myrtol for treatment. A month later the patient's symptom relieved and TMM showed R value less than 1 under 30mBar and EST-7 score was 14 in the right ear. PMID- 26647552 TI - [Research on radiation sensitization effect of microRNA and clinical perspectives in nasopharyngeal carcinoma]. AB - Radiotherapy is the primary treatment for nasopharyngeal carcinoma, and the disease control rate and survival time are able to be greatly improved by enhancing the radiosensitivity. Via mechanisms such as binding to target genes mRNA 3'untranslated region (3'UTR), microRNA (miRNA) inhibits translation, which therefore regulates transcription of target genes and thus affect target protein expression. Recent research showed that miRNAs play significant roles in improvement of radiosensitivity in nasopharyngeal carcinoma. This article reviews mechanism of miRNA action to strengthen radiosensitivity of nasopharyngeal carcinoma and the future of clinical practice of miRNA in this disease. PMID- 26647553 TI - [The eosinophilic otitis media's research progress]. AB - The eosinophilic otitis media(EOM) is an intractable disease characterized by the presence of a highly viscous yellow effusion with extensive accumulation of eosinophils in the middle ear; granulation tissue can been discovered in the middle ear cavity; most of patients have association with bronchial asthma; resist to conventional treatment for otitis media; EOM patients show gradual deterioration of hearing and sometimes become deaf suddenly; effective treatment involves use of topical and oral steroids. This article summarizes the progress of the EOM's diagnosis and treatment. PMID- 26647554 TI - [Tracheostomy]. AB - Tracheostomy is to establish an artificial airway by making an opening at anterior tracheal wall. Due to the blossom of mechanical ventilation and intensive care unit after 1950s, tracheostomy is the most favorable surgical method to access airway at present. In addition to traditional surgical tracheostomy, percutaneous dilational tracheostomy have gained increasing popularity and become an alternative procedure because of its merits such as easier manipulation, shorter operative duration and less complications. This review summarized tracheostomy from definition, history and current status, anatomy and physiology, indications, contraindications, timing, complications and management. We also elaborate our understanding of current contraercy and give some suggestions based on our clinical experience. PMID- 26647555 TI - [Selection strategy and progress on the treatment of femoral neck fractures]. PMID- 26647556 TI - [Hip arthroplasty for failed internal fixation of femoral neck fractures]. AB - OBJECTIVE: To investigate the result of hip arthroplasty for failed internal fixation of femoral neck fractures. METHODS: From June 2007 to January 2014, 29 cases who underwent hip arthroplasty for failed of internal fixation of femoral neck fractures were reviewed. There were 12 males and 17 females. The mean age was 60.3 years (ranged 43 to 83 years) at the time of the fracture. Left hip was in 16 cases, right hip was in 13 cases. The average interval from fracture to arthroplasty was 23.3 months (ranged, 3 to 48 months). RESULTS: All of 29 cases were performed total hip arthroplasty. There were 20 cases of cementless cup,7 cases of cementless cup with bone graft, 2 cases of cemented cup with bone graft; 13 cases of cementless stem, 16 cases of cemented stem. There were no complications occurred such as intraoperative fracture of the greater trochanter. The average operative time was (115 +/- 38) minutes,the mean intraoperative blood loss was (420 +/- 175) ml, the average postoperative drainage volume (240 +/- 119) ml, intraoperative blood transfusion was (200 +/- 220) ml, intraoperative fluid volume was (2,200 +/- 400) ml, the average postoperative blood transfusion was (300 +/- 200) ml. There was 1 case get postoperative dislocation. All patients were followed up for 14.7 months in average (ranged, 5 to 24 months). There was no revision for mechanical failure. Harris Hip Score significantly was improved from 51.1 +/- 7.5 before the conversion to 88.5 +/- 6.4 points at the final follow-up. CONCLUSION: The effect of the hip replacement for patients with failed internal fixation of femoral neck fractures was confirmed. This method can shorten the time on the bed and reduce the complications. It benefits the patients earlier functional recovery, but it must control operation indication. The long term efficacy is necessary to further observation. PMID- 26647557 TI - [Proximal femoral geometry changes after femoral neck fracture treated with total hip arthroplasty]. AB - OBJECTIVE: To observe the changes of proximal femoral geometry after femoral neck fracture treated with THA, analyze the existent of differences and their manifestation. METHODS: All patients of femoral neck fracture (FNF) and osteonecrosis of femoral head (ONFH) were treated with THA by the same operating team from January to December of 2014, including 22 patients with FNF (11 males and 11 females,with age from 44 to 83 years old (means 66.18 +/- 11.47) and 23 patients with ONFH (12 males and 11 females, with age from 19 to 68 years old (means 51.91 +/- 11.76). After THA, height of femorals, offsets, osteotomy position and adjusting modes were measured and the statistic analysis was done. RESULTS: After THA, all patients were measured. Decreased femoral height, offsets and lower osteotomy positions were found in patients with FNF than those with ONFH, and 3 kinds of adjustments because of lower-positional osteotomy were found. CONCLUSION: After THA, lower-positional osteotomy and decreased femoral offsets may occur on patients with FNF. The adjustments caused by lower positional osteotomy may lead to negative results. PMID- 26647558 TI - [Comparison of different diameter hollow screw for the treatment of femoral neck fractures]. AB - OBJECTIVE: To evaluate and compare the outcome of two kinds of diameter hollow screws for the treatment of femoral neck fractures. METHODS: From June 2008 to June 2013, 117 patients with femoral neck fractures were treated by closed reduction and hollow screws fixation. Among them,48 patients were fixed by 6.5 mm screw including 30 males and 18 females with an average age of (45.61 +/- 11.99) years old ranging from 19 to 60 years old, involving 17 cases in Garden I/II and 31 cases in Garden III/IV; 69 patients were fixed by 8.0 mm screw including 40 males and 29 females with an average age of (45.17 +/- 9.95) years old ranging from 18 to 60 years old, involving 31 cases in Garden I/II and 38 cases in Garden III/IV. The general information, operative time, hospital stay time, reduction quality, diameter of femoral head and neck, fracture healing time, the rate of fracture healing, postoperative complications were recorded and evaluated. Harris scoring was used to evaluate the hip joint function. RESULTS: All patients were followed up for 19.6 months (18 to 24 months). The difference of operative time, duration of hospitalization, quality of reduction were not statistically significant (P > 0.05). There was no difference between two groups about the average diameter of the femoral head and neck, the fracture healing time, the rate of healing and the postoperative complications (P > 0.05). There were no difference between two groups about Harris scale. There were significant difference between Garden III/IV and I /II (P > 0.05). CONCLUSION: Closed reduction and internal fixation with hollow screw in treating the young adult patients with femoral neck fracture is the first choice, both different diameters hollow screws could meet the requirements of fixation of femoral neck fracture, and not affect on fracture healing time and postoperative complications. PMID- 26647559 TI - [Comparison among three cannulated screws and dynamic hip screw combined with antirotation screw for comminut- ed fractures of femoral neck]. AB - OBJECTIVE: To compare the effect of three cannulated screws and dynamic hip screw (DHS) combined with antirotation screw in treating patients with comminuted fractures of femoral neck. METHODS: From January 2008 to December 2012,67 patients with comminuted fractures of femoral neck were treated with three cannulated screws or DHS combined with antirotation screw. Among them, 36 patients were treated with DHS combined with antirotation screw including 24 males and 12 females with an average of 43.7 years old ranging from 22 to 58 years old; 31 patients were treated with three cannulated screws including 22 males and 9 females with an average of 43.0 years old ranging from 24 to 56 years old. The incision size, operation time, blood loss, blood transfusion rate, postoperative hospital stay, walking time, weight-bearing time, union time, incidence of complication were recorded and compared between two groups, and functional outcomes were evaluated by Harris scoring. RESULTS: All incision healed at stage I. The differences in operation time, blood loss, blood transfusion rate and postoperative hospital stay between two groups were not significant (P > 0.05). Incision size of DHS group (5.00 +/- 0.86) cm was larger than that of cannulated screw group (3.30 +/- 0.57) cm (P < 0.01). All patients were followed up more than one year, and the follow-up time showed no significant difference between two groups (P > 0.05). Walking time of DHS group (19.0 +/- 3.5) d was less than that of cannulated screw group (37.0 +/- 6.3) d (P < 0.01. Partial and full weight-bearing time of DHS group (23.0 +/- 7.0) d and (138.0 +/- 13.0) d was less than that of cannulated screw group (38.0 +/- 5.7) d and (164.0 +/- 12.0) d (P < 0.01). Union time of DHS group (151 +/- 11) d was less than that of cannulated screw group (162 +/- 11) d (P < 0.01). Harris hip score of DHS group (91.0 +/- 5.7) was higher than that of cannulated screw group (85.0 +/- 12.0) (P < 0.01). No significant differences were found in the incidence of postoperative complications between two groups (P > 0.05). CONCLUSION: The DHS combined with antirotation screw is superior to three cannulated screws for treatment of comminuted fractures of femoral neck due to earlier weight-bearing, faster fracture healing and better hip function PMID- 26647560 TI - [Case-control study on the iliac bone flap transplantation with deep circumflex iliac artery and quadratus femoris bone flap transplantation for the treatment of Garden III/IV femoral neck fracture of young and middle-aged patients]. AB - OBJECTIVE: To compare the clinical effects between hip anterior S-P approach combined with iliac bone flap transplantation with deep circumflex iliac artery and posterior K-L approach combined with quadratus femoris bone flap transplantation for the treatment of femoral neck fracture of Garden III-IV in young and middle-aged patients. METHODS: From January 2004 to January 2011,46 patients with femoral neck fractures were treated by two kinds of operation. Among them, 20 cases were treated with anterior S-P approach combined with iliac bone flap transplantation with deep circumflex iliac artery, included 12 males and 8 females with an average age of (32.1 +/- 7.3) years old, involved 12 cases of Garden III and 8 cases of Garden IV. The other 26 cases were treated with posterior K-L approach combined with quadratus femoris bone flap transplantation, included 20 males and 6 females with an average age of (37.8 +/- 6.9) years old, involved 16 cases of Garden III and 10 cases of Garden IV. The index of hospitalization (hospitalization time, total cost, operative time, intraoperative blood loss, postoperative complications), the quality index of operation (fracture reduction, position of internal fixation, fracture healing time, nonunion and femoral head necrosis) of two groups were observed and compared. Hip joint function were evaluated by Harris score. RESULTS: All patients were followed up from 28 to 41 months with an average of 36 months. The intraoperative blood loss of group S-P (92.3 +/- 10.4) ml was less than that of group K-L (132.4 +/- 11.2) ml, there was significant difference between two groups (P < 0.05). The operation time of group S-P (81.4 +/- 9.2) min was more than that of group K-L (67.1 +/- 4.5) min, the difference was statistically significant (P < 0.05). One case in group S-P and 9 cases in group K-L appeared postoperative complications, there was significant difference between two groups (P < 0.05). The fracture healing time of S-P group (83.5 +/- 7.3) d was shorter than that of group K-L (103.2 +/- 12.6) d, there was significant difference between two groups (P < 0.05). At 30 months after operation, there were significant difference in Harris scoring between two groups (P < 0.05). CONCLUSION: Anterior S-P approach combined with iliac bone flap transplantation with deep circumflex iliac artery for treatment of femoral neck fracture of Garden III-IV of young and middle-aged patients, it has characteristics in clear anatomic and easy to operate. As compared with K-L approach, S-P approach can better reserve residual blood supply of femoral neck. While combining with the iliac bone flap transplantation with deep circumflex iliac artery, it could better reconstruct the blood supply of femoral neck to promote fracture healing. PMID- 26647561 TI - [Reconstruction intramedullary nailing for treatment of ispsilateral femoral neck and shaft fractures]. AB - OBJECTIVE: To evaluate the curative effect and surigical skills of reconstruction intramedullary nailing in the treatment of ipsilateral femoral neck and shaft fractures. METHODS: From January 2007 to January 2013, 13 patients with ipsilateral femoral neck and shaft fractures were treated by reconstruction intramedullary nailing including 11 males and 2 females with an average age of 38.9 yeas old ranging from 25 to 53 years old. For femoral neck fractures,10 cases were basilar neck fracture, 3 were transcervical fractures and according to Garden classification,10 were type II, 2 were type III and 1 was type IV. For feormal shaft fracture, 5 were type I, 4 were type II, 3 were type III and 1 was type IV according to Winquist classification. The location of all 13 feormal shaft fractures were all in the uper 3/4 of the feormal shaft. Complications and postoperative function were recorded and evaluated. RESULTS: Eleven patients were followed up for 23.45 months (12 to 36 months). Time from injury to operation was 5.9 days in average. Malunion of femoral neck fracture happened in 1 patient, nonunion of femoral shaft fracture happened in 2 patients. NO femoral head osteonecrosis, infection and malunion of femoral shaft fracture happened. According to Friedman-Wyman classification, 8 cases get good result, 2 get faii and 1 get poor. CONCLUSION: Reconstruction intramedullary nailing is a good choice for the ipsilateral femoral neck and shaft fractures with the advantages of less soft-tissue trauma and complications. PMID- 26647562 TI - [Application of damage control concept in severe limbs fractures combining with multiple trauma]. AB - OBJECTIVE: To discuss the application and clinical effect of damage control concept in the treatment of severe limbs fractures combining with multiple trauma. METHODS: From July 2009 to July 2012, 30 patients with severe limbs fractures combining with multiple trauma were treated with the damage control concept, included 20 males and 10 females with an average age of (34.03 +/- 12.81) years old ranging from 20 to 60 years old; the ISS averaged (35.00 +/- 12.81) points (ranged from 26 to 54 points). And the control group also contained 30 patients with severe limbs fractures combining with multiple trauma treated by the traditional operation from June 2006 to June 2009, there were 23 males and 7 females with an average age of (34.23 +/- 11.04) years old ranging from 18 to 65 years old. The ISS averaged (35.56 +/- 11.04) points (ranged from 26 to 51 points). The age, gender, ISS, Gustilo classification, operation time, intraoperative blood loss, blood transfusion,postoperative complications and mortality rate were observed and compared. RESULTS: In the damage control concept group,there were 28 cases surviving and 2 cases (6.7%) death; 6 cases of postoperative complication included 2 cases of adult respiratory distress syndrome, 1 case of multiple organ failure, 1 case of disseminated intravascular coagulation and 2 cases of wound infection. In the control group, there were 22 cases surviving and 8 cases death(26.7%); 13 cases of postoperative complication included 4 cases of adult respiratory distress syndrome,2 cases of multiple organ failure, 2 cases of disseminated intravascular coagulation and 3 cases of wound infection. There were no statistically significant differences between two groups in age, gender, ISS, Gustilo classfication and complication (P > 0.05), however there were statistically significant differences in mortality rate, operation time, blodd loss, blodd transfusion between two groups (P < 0.05). CONCLUSION: Damage control concept is used to treat severe limbs fractures combining with multiple trauma which has the rapid and effective therapy, can improve survival rate and reduce complication. PMID- 26647563 TI - [Application of the expanding forming under the plate through cervical spatium intermusculare approach in treating multi-segmental myelopathic cervical spondylosis]. AB - OBJECTIVE: To investigate the application of the expanding forming under the plate through cervical spatium intermusculare approach to treat multi-segmental myelopathic cervical spondylosis. METHODS: From July 2005 to June 2013, 25 patients with multi-segmental myelopathic cervical spondylosis were treated by the expanding forming under the plate through cervical spatium intermusculare approach including 16 males and 9 females with an average age of 56.5 years old ranging from 35 to 78 years old. Among them, 10 cases were onset without causes slowly, 7 cases were onset without causes suddenly, 8 cases were onset after mild trauma or tired. JOA scoring, incidence of postoperative axial symptoms and imaging studies were used to evaluate the effect. RESULTS: Twenty-five cases were followed up for 6 months to 7 years and 6 months with an average of 2 years and 9 months. There were no infection, cerebrospinal fluid leakage after the operation, and complications such as nerve damage were occurred. The operation time was 120 to 150 min, the bleeding was 300 to 500 ml. Imaging examination showed vertebral canal sagittal diameter increased, the vertebral canal increased significantly in the cross sectional area of the spinal cord, cervical curvature was straighten in 4 cases (2 cases of them became normal sequence). There were no more cases of cervical protruding and segmental instability increased. Postoperative walking ability enhanced, the finger activity of majority of patients improved on flexibility, grip strength, and accuracy of using chopsticks improved, numbness and chest waist band feeling had different degree of reduce, preoperative urine impairment were improved to varying degrees. Preoperative JOA scores were 3 to 13 points with an average of (8.86 +/- 4.25) points; Postoperative 12 months' JOA scores were 7 to 17 points with an average of (13.76 +/- 3.56) points, period was 60.19% in average, JOA score had statistically difference between before and after operation (P < 0.05). The result were excellent in 14 cases, good in 6 cases, and fair in 4 cases and poor in 1 case. CONCLUSION: Application of the expanding forming under the plate through cervical spatium intermusculare approach to treat multi-segmental myelopathic cervical spondylosis, through muscular clearance, can retain complete cervical back muscle, maintain stability of cervical spine, and vertebral canal can get effective decompression at the same time. PMID- 26647564 TI - [Double minimally invasive incisions for surgical repair of the acute closed Achilles tendon rupture]. AB - OBJECTIVE: To evaluate the clinical effect of a new surgical approaches for repairing the acute Achilles tendon rupture. METHODS: From January 2009 to January 2014, 21 patients with Achilles tendon rupture were treated by 2 minimally invasive incisions and remaining skin bridge of achilles tendon end including 16 males and 5 females with an average age of 44.3 years old ranging from 21 to 57 years old. Postoperative complications, the range of movement of affected ankle joint, the circumference calf and ankle on both side, time of reture to work and sports activity were observed and recorded. The American Orthopaedic Foot and Ankle Society (AOFAS) score was used to evaluate the functional recovery. RESULTS: All patients were followed up for 6 to 36 months with an average of 13.5 months. No skin necrosis, wound infection, deep vein thrombosis,re-rupture and sensory disturbance with the ankle or foot in the sural nerve distribution were found. At 1 year after operation, there was no significant difference in the range of movement between affected foot (55.4 +/- 6.5) degrees and unaffected foot (56.3 +/- 3.7) degrees (t = 0.872, P = 0.325). There was significant difference in AOFAS between preoperative (65.1 +/- 6.9) and postoperative (94.3 +/- 5.5) (t = 7.672, P = 0.013). All patients returned to work and study at an average of 10 weeks (ranged from 6 to 15 weeks) and 15 patients returned to normal sports activities at 21 weeks (ranged from 18 to 24 weeks). Calf and ankle circumferences decreased by 0.45 cm (0.3 to 0.8 cm) and increased by 0.4 cm (0.2 to 0.7 cm), respectively in the injured leg as compared with the contralateral leg. CONCLUSION: The simplicity of the technique of minimally invasive incision and skin bridge for acute closed Achilles tendon reconstruction is an effective and reliable method with low complication. PMID- 26647565 TI - [Changes of nucleus pulposus after in vitro culture of rabbit whole intervertebral disc and spinal motion segment]. AB - OBJECTIVE: To compare the changes of nucleus pulposus after in vitro culture of rabbit whole intervertebral disc and spinal motion segment. METHODS: Twenty-one New Zealand white rabbits which were randomly divided into organ group with 8 rabbits and segment group with 13 rabbits. Fifty intervertebral discs and 50 spinal motion segments were harvested respectively under aseptic conditions from two groups. These specimens were maintained in organ culture with hyperosmotic media (410 mOsm/kg), then 10 discs of the two groups were observed respectively by HE staining, immunohistochemistry of collagen type III, proteoglycan content and cells viability of nucleus pulposus before culture and at 3, 7, 14, 21 days after culture. RESULTS: HE staining showed the intervertebral disc tissue structure remained intact after culture of 21 days organ group and 14 days segment group,but there was severely degenerated of 21 days segment group. The intensity value of type II collagen immunohistochemical staining in the nucleus pulposus were not changed significantly between 21 days organ group and 14 days segment group (P > 0.05), but the staining of segment group at 21 days became shallower, there was significant difference compared with before each time points and organ group at 21 days (P < 0.05). PAS/AB staining of proteoglycan of nucleus pulposus showed that there were not decrease of tinting strength of two groups within 7 days, but the strength weakened slightly of two groups at 14 days, and the tinting strength became weaker at 21 days segment group, the change is more obvious than the organ group. The intensity value of fluorescence staining of nucleus pulposus cells was not changed significantly within 7 days of two groups (P > 0.05), the intensity value decreased slightly at 21 days organ group and 14 days segment group, but there were no significant difference compared with before time points (P > 0.05) however at 21 days segment group the intensity decreased as cells viability of nucleus pulposus decreased,and there was a significant difference compared with before each time points and organ group at 21 days (P < 0.05). CONCLUSION: It is not obviously degenerated of the discs of organ group cultured within 21 days and segment group cultured within 14 days, but there was significant degeneration of the intervertebral disc of segment group after cultured 21 days, so the rabbit spinal motion segment can be used on research about the biomechanics of intervertebral disc as a vitro experimental model within 14 days. PMID- 26647566 TI - [Inhibition of osthole for resorption of rats femur tissue in vitro]. AB - OBJECTIVE: To investigate osthole effect on femoral tissue resorption activity of rat in vitro. METHODS: Six SD rats weighted (80 +/- 5) g were used to isolate and culture femoral tissue (diaphyses and metaphysis) in vitro. The cultured tissue were devided into control group, estradiol group and osthole group. The femoral tissue was treated with final concentration of 1 x 10(-5) mol/L osthole and 1 x 10(-8) mol/L estradiol culture in vitro at 48 hours after cultured. Tartrate resistant acid phosphatase (StrACP) activity, glucose and Lactic acid content, StrACP, MCSF (Macrophage colony stimulating factor) and CTSK (Cathepsin K) mRNA was detected by Real-Time RT-PCR were detected. RESULTS: Concetration of Alkaline phosphatase activity were 2226 and 2498 in 1 x 10(-5) mol/L osthole and 1 x 10( 8) mol/L estradiol respectively. As compared with control group, the activity of StrACP of 1 x 10(-5) mol/L osthole and 1 x 10(-8) mol/L estradiol were inhibited at 6, 9, 12 days (P < 0.05); under treatment of in l x 10(-5) mol/L osthole, the content of Lactic acid were increased and the content of glucose were decreased at 3, 6, 9 days (P < 0.05); StrACP, MCSF and CTSK mRNA expression level were inhibited at 6, 9 days (P < 0.05). CONCLUSION: Osthole can inhibit bone resorption and raise the level of nutrition metabolism of femurs tissue. PMID- 26647567 TI - [Effect of preoperative cyclooxygenase-2 inhibitor for postoperative pain in patients after total knee arthroplasty: a meta-analysis]. AB - OBJECTIVE: To systematically evaluate the efficacy and safety of preoperative administration of cyclooxygenase-2 (COX-2) inhibitor on pain occurring with total knee arthroplasty (TKA). METHODS: We electronically searched PubMed, Cochrane Library, EMBASE, CNKI, CBM, Wanfang data from inception to March 15, 2014 and manual searched journal of library collection to identify randomized controlled trials (RCTs) about preoperative administration of COX-2 inhibitor on pain occurring with TKA. The methodological quality of the included RCTs was assessed and the data were extracted according to the Cochrane Handbook 5.1.0. Meta analysis was performed by using RevMan 5.2 software. RESULTS: A total of 6 RCTs involving 228 patients were included. The results of meta-analyses showed that: (1) Efficacy: The visual analog scale (VAS) of post-operation at 12-hour (WMD = 0.60, 95% CI -0.83 to -0.37, P < 0.000 01) and 24-hour (WMD = -0.74, 95% CI -1.29 to - 0.19, P = 0.008) was decreased when COX-2 inhibitor was used before operation. And compared with control group, experimental group decreased the modified numerical pain rating scale (MNPRS) at 24-hour (WMD = -0.50, 95% CI 0.70 to -0.30, P < 0.000 01), 48-hour (WMD = -0.55,95% CI -0.65 to -0.45,P < 0.000 01) under quiescent conditions, and the same result at 24-hour (WMD = 0.82, 95% CI -1.26 to -0.38, P <0.000 01), 48-hour (WMD = -0.71, 95% CI -0.82 to 0.60, P < 0.000 01) under active conditions. The morphine consumption postoperatively were fewer in experimental group at the first day (WMD = - 1.35, 95% CI -1.92 to -0.79, P < 0.000 01) and the second day (WMD = -1.60, 95% CI 2.68 to -0.52, P = 0.004). (2) Safety: COX-2 inhibitor could lessen the incidence of postoperative pruritus (RR = 0.35, 95% CI 0.15 to 0.84, P = 0.02), but not statistically decrease of nausea and vomiting (RR = 0.83, 95% CI 0.54 to 1.28, P = 0.40) and exhaustion (RR = 0.63, 95% CI 0.05 to 7.67, P = 0.72). CONCLUSION: The current evidence indicated that preoperative administration of COX-2inhibitor can effectively improve the effect of postoperative analgesia, reduce the consumption of morphine and lessen the incidence of pruritus. Due to the limited quantity of the included studies and the evidence with limited strength,further high-quality RCTs are needed to verify the aforementioned conclusion. PMID- 26647568 TI - [Treatment and analysis of the early postoperative complications of tibial plateau fractures]. AB - OBJECTIVE: To analysis the early complications of tibial fracture and its related factors, and propose a solution. METHODS: From December 2003 to December 2013,38 patients with early complications of tibial plateau fracture after operation were retrospectively analyzed. There were 35 males and 3 females, aged from 37 to 69 years old (averaged 42.3 years). According to Schatzker classification, 3 cases were classified as type II, 2 cases as type III, 2 cases as type IV, 19 cases as type V, 12 cases as type VI. The intervals between injury and operation ranged from 9 hours to 9 days, 26 cases within 3 days. Fifteen cases were treated with internal fixation of plates and 23 were treated by plate fixation and bone transplantation. Early complications included skin necrosis in 15 cases, infection in 6 cases, osteofascial compartment syndrome in 3 cases, common peroneal nerve injury in 2 cases, the superficial peroneal nerve injury in 3 cases, popliteal artery injury in 2 cases, loss of reduction in 7 cases. RESULTS: The wound of 14 cases healed at the first stage and 24 cases healed delay. Hospitalization days ranged from 7 to 67 days (averaged 25.6 days). All patients were followed up for 12 to 36 months with an average of 16.4 months. The fracture healing time ranged from 3 to 9 months (averaged 6.9 months). According to Merchant knee function evaluation criteria, the results were excellent in 19 cases, good in 12, fair in 5 and poor in 2. CONCLUSION: Early complications of tibial fracture after operation is closely associated with the severe fracture complexity and related with preoperative preparation, surgical timing, operation incision selection and surgical technique. Early detection and timely processing reduce damage. PMID- 26647569 TI - [Treatment of osteomyelitis and bone defect of femoral shaft by external fixation and bone transport]. AB - OBJECTIVE: To discuss the clinical effects and superiority of applying external fixation and bone transport to treat osteomyelitis and bone defect of femoral bone. METHODS: From August 2008 to December 2013,16 patients with osteomyelitis and bone defect of femoral bone were treated including 11 males and 5 females with an average age of 42 years old ranging from 13 to 62 years old. The average course of disease was 18 months ranging from 2 months to 4.5 years, and the average length of bone defect was 7.8 cm ranging from 4.5 to 15 cm. The bone defect of all cases were treated by external fixation and bone transport, the bone transport began at 1 week after operation, 1 mm per day and 4 times per day. RESULTS: All patients were followed up for 10 to 36 months (means 22.5 months). One patient did not cooperate with treatment leads to the failure, then took the amputation. The remaining 15 cases of osteomyelitis were under control, including 12 cases of bone transport achieved one stage bone union, 3 cases achieved bone union via bone graft from iliac bone. The bone union time was 5 to 13 months(means 7.9 months). Thirteen patients almost obtained the same length of two lower extremities,2 patients had shortening of 1.5 to 2 cm. The time of moving the external fixation was from 6 to 16 months (means 9.3 months). CONCLUSION: Application of external fixation and bone transport is an effective method in treating the osteomyelitis and bone defect that can control the infection, eradicate wounds, and be the equalization of limb length. PMID- 26647570 TI - [Advance on genetic mechanism of adolescent idiopathic scoliosis and genetic relationship map]. AB - Identification of genetic risk factors is the hotspot of adolescent idiopathic scoliosis (AIS). Through candidate gene approach and genome-wide association studies (GWAS), some genes were preliminary identified. To review AIS related genes,and construct the gene network map of AIS gene. We searched on NCBI PubMed and Web of Science database using search terms "adolescent idiopathic scoliosis" and "gene", to classify induction genes. We then constructed gene diagram using string-db. We found 35 AIS genes relating to connective tissue, nervous system active substances, melatonin synthesis and metabolism, puberty and growth, and genes whose function is unknown. Gene diagram shows that a network relationship between gene and other genes,in which IL6, ESR1, ESR2, VDR, TGFB1, IGF1 gene may as the key gene about AIS' genetic mechanism. Two sites of 3 GWAS results outside the network, it is suggesting new pathway that need to be explored. The study about AIS susceptibility gene is still preliminary, requiring in-depth research to identify the new networks. PMID- 26647571 TI - [A case report of surgical treatment for giant cell tumor of patella]. PMID- 26647572 TI - [Roof folding and rotary pushing for the treatment of back to back fractures of distal radius and ulna in children]. AB - OBJECTIVE: To evaluate the technique and the clinical effect of folding roof and rotary pushing in treatment of children with distal radius and ulna fracture of "back to back". METHODS: From January 2012 to February 2014,38 children with distal radius and ulna fracture of "back to back" were treated by using the technique of folding roof and rotary pushing to reset and splint fixation including 23 males and 15 females with an average age of 9.5 years old ranging from 6 to 14 years old. Injury time was from 45 min to 3 days (averaged 1.3 days). All cases was unilateral closed fracture without symptoms of nerve injury occurred. The wrist joint anteroposterior and lateral radiographs showed double fracture of radius and ulna, and the broken end of radius was typical "back to back" displacement. The quality of reduction was assessed according to Dienst recommendation on the combination of Aro measurement, and the therapeutic effect was evaluated using standard of Anderson function. RESULTS: All patients were followed up from 3 to 13 months with an average of 6 months. There were no iatrogenic nerve injury. Thirty cases were treated successfully for the first time, 8 cases were again reset successfully; 28 cases were anatomical reduction, 7 cases were near anatomic reduction, 3 cases were functional reduction. At the second day 7 cases with hand and finger swelling appeared in multiple reset patients. Quality results of reduction were excellent in 33 cases, good in 5 cases. According to the standard of Anderson function evaluation, 35 cases were excellent, 3 cases were good. All fractures were healed with of deformity of wrist. CONCLUSION: Using the technique of folding roof and rotary pushing in treatment of children with distal radius and ulna fracture of "back to back" is very successful, the patient's limb function recovered well, the whole operation process is simple. PMID- 26647573 TI - [L1-L2 complete traumatic fracture-dislocation of the lumbar spine: a case report]. PMID- 26647574 TI - [Clinical diagnosis and treatment of chronic osteomyelitis]. AB - Chronic osteomyelitis is one of the most common disorder in clinic. In recent years due to diabetes, peripheral vascular disease and trauma induced disease increased, the prevalence rate increased. With the development of magnetic resonance imaging and CT imaging technology, it greatly improved the accuracy of clinical diagnosis of chronic osteomyclitis and ability to describe the infection characteristics, and provide a reliable basis for clinical treatment. The current research on chronic osteomyelitis mainly concentrated on the aspects of imaging applications and ways of using antibiotic optimization control inflammation, defect restoration and reconstruction of blood supply and treatment. But the best time to the antibiotic therapy and the use of program is still uncertain, for after debridement, bone grafting time and defect repair function of fast recovery still need further research. PMID- 26647575 TI - [Causes of perioperative pain and the pain management in total knee arthroplasty]. AB - Total knee arthroplasty has become one of the effective operation methods on end stage knee osteoarthritis. However,the postoperative pain has been plaguing the clinicians. The cause of postoperative pain can be divided into iatrogenic, prosthesis and patient. Pain treatment in perioperative period includes preoperative education, analgesia in advance, and the selection and design of reinforcement; during operation mainly includes the appropriate surgical approach, keep the balance of soft tissue around the knee joint, cocktail analgesia pain around the knee joint; after operation mainly includes oral analgesic drugs, femoral nerve tissue and patient controlled analgesia. And the multimodal analgesi.a which is the analgesic methods combined application in perioperative period raised in resent years fully intervene the pain in perioperative period,so that it can effectively reduce the pain of patients after knee replacement, promote the patients do functional exercise more better and get better operation result. PMID- 26647576 TI - [Preface for special issue on industrial bioprocess technique front (2015)]. AB - Industrial bioprocess is one of the most important research fields supports the promoting of biological manufacturing industry in China, and guarantees the implementation of bioscience and biotechnology research results into the industrial applications. For improving the interconnection between academic researchers and industrial stuffs and pushing research achievement into industrial implementation, bioprocess modelling and control committee of Chinese Society for Microbiology organized two tandem conferences separately in 2012 and 2014 on the topic of "Industrial bioprocess technology", focusing mainly technique front of industrial bioprocess. A special session on industrial technique applications was hold to stimulate cooperation. The conference received many good submissions from academic and industrial sectors. This special issue is based on selected excellent papers from the submissions, together with free submissions. The special issue consists of reviews and original papers, mainly involving the aspects closely related to the bio-industrial sectors including, i) high yield strain constructing and high throughput screening; ii) optimization and modification of industrial enzymes, and iii) bioprocess modelling and high efficient scale-up method. PMID- 26647577 TI - [Advances in biomolecular machine: methane monooxygenases]. AB - Methane monooxygenases (MMO), regarded as "an amazing biomolecular machine", catalyze the oxidation of methane to methanol under aerobic conditions. MMO catalyze the oxidation of methane elaborately, which is a novel way to catalyze methane to methanol. Furthermore, MMO can inspire the biomolecular machine design. In this review, we introduced MMO including structure, gene and catalytic mechanism. The history and the taxonomy of MMO were also introduced. PMID- 26647578 TI - [Advances in transcription activator-like effectors--a review]. AB - As a protein originally found in plant pathogenic bacteria, transcription activator-like effectors (TALEs) can be fused with the cleaving domain of restriction endonuclease (For example Fok I) to form artificial nucleases named TALENs. These proteins are dependent on variable numbers of tandem Repeats of TALEs to recognize and bind DNA sequences. Each of these repeats consists of a set of approximately 34 amino acids, composed of about 32 conserved amino acids and 2 highly variable amino acids called repeat variant di-residues (RVDs). RVDs distinguish one TALE from another and can make TALEs have a simple cipher for the one-to-one recognition for proteins and DNA bases. Based on this, in theory, artificially constructed TALENs could recognize and break DNA sites specifically and arbitrarily to perform gene knockout, insertion or modification. We reviewed the development of this technology in multi-level and multi species, and its advantages and disadvantages compared with ZFNs and CRISPR/Cas technology. We also address its special advantages in industrial microbe breeding, vector construction, targeting precision, high efficiency of editing and biological safety. PMID- 26647579 TI - [Enhancing erythromycin precursor 6-dEB production by using synthetic small regulatory RNAs in Escherichia coli]. AB - Although heterologous biosynthesis of polyketide erythromycin has been successfully achieved in Escherichia coli, the titer remains at a very low level (-10 mg/L). In this study, based on genome-scale metabolic model of E. coli, in silico method flux distribution comparison analysis was used to discover novel potential targets for heterologous 6-dEB biosynthesis. Synthetic small regulatory RNAs (sRNAs) was used to experimentally test 12 down-regulated targets. The results showed that repression of each of these target genes e.g. lsrC and ackA led to significantly improve heterologous 6-dEB biosynthesis. Using co-repression of lsrC and ackA, 6-dEB titer was improved by 59.9% in shake-flask with a maximum yield of 22.8 mg/L. This study indicates that combined flux distribution comparison analysis and synthetic small regulatory RNAs is an effective strategy to improve 6-dEB production in E. coli. PMID- 26647580 TI - [Construction and optimization of Escherichia coli for producing rhamnolipid biosurfactant]. AB - Rhamnolipid biosurfactant is mainly produced by Pseudomonas aeruginosa that is the opportunistic pathogenic strain and not suitable for future industrial development. In order to develop a relatively safe microbial strain for the production of rhamnolipid biosurfactant, we constructed engineered Escherichia coli strains for rhamnolipid production by expressing different copy numbers of rhamnosyltransferase (rhlAB) gene with the constitutive synthetic promoters of different strengths in E. coli ATCC 8739. We further studied the combinatorial regulation of rhlAB gene and rhaBDAC gene cluster for dTDP-1-rhamnose biosynthesis with different synthetic promoters, and obtained the best engineered strain-E. coli TIB-RAB226. Through the optimization of culture temperature, the titer of rhamnolipd reached 124.3 mg/L, 1.17 fold higher than that under the original condition. Fed-batch fermentation further improved the production of rhamnolipid and the titer reached the highest 209.2 mg/L within 12 h. High performance liquid chromatography-mass spectrometry (LC-MS) analysis showed that there are total 5 mono-rhamnolipid congeners with different nuclear mass ratio and relative abundance. This study laid foundation for heterologous biosynthesis of rhanomilipd. PMID- 26647581 TI - [Agrobacterium tumefaciens-mediated transformation of Aureobasidium pullulans and high-efficient screening for polymalic acid producing strain]. AB - To develop a genetic transformation method of Aureobasidium pullulans and T-DNA insertion for high-efficient screening of polymalic acid (PMA) producing strain. Agrobacterium tumefaciens-AGL1, containing the selection genes encoding hygromycin B phosphotase or phosphinothricin acetyltranferase, was used to transform Aureobasidium pullulans CCTCC M2012223 and transformants were confirmed by colony PCR method. Transferred DNA (T-DNA) insertional mutants were cultured in microwell plate, and screened for high-titer PMA producing strain according to the pH response model. DNA walking was used to detect the insertion sites in the mutant. Results show that the selection markers could stably generated in the transformants, and 80 to 120 transformants could be found per 10(7) single cells. A high-titer PMA mutant H27 was obtained, giving a good PMA production caused by the disruption of phosphoglycerate mutase, that increased by 24.5% compared with the control. Agrobacterium tumefaciens-mediated transformation and high-efficient screening method were successfully developed, which will be helpful for genetic transformation of Aureobasidium pullulans and its functional genes discovery. PMID- 26647582 TI - [Improving isoprene production by engineered heterologous mevalonate pathway in Escherichia coli]. AB - Isoprene is an important precursor of synthetic rubber material. In our previous study, metabolic engineered Escherichia coli strain (BW-01) was constructed and used to produce isoprene. Based on the theory of protein budget, using synthetic biology strategies including the increased copy number of genes and rare codons, we regulated the expression of key enzyme to improve isoprene production in Escherichia coli strain. Under shake-flask conditions, isoprene productivity of the engineered strain (BW-07) increased by 73% compared with BW-01, reached 761.1 mg/L. It provides a reference for further studies. PMID- 26647583 TI - [Effect of microparticles on echinocandin B production by Aspergillus nidulans]. AB - Anidulafungin is an effective antifungal medicine, which can inhibit activities of candida in vitro and in vivo. Echinocandin B (ECB) is the key precursor of Anidulafungin, thus the price and market prospect of Anidulafungin is directly due to the fermentation titer of ECB. In this study, Aspergillus nidulans was used for ECB fermentation, and the influence of adding microparticles on ECB fermentation was studied, such as talcum powder, Al2O3, and glass beads. The particle size and concentration were the key factors for mycelium morphology and ECB production, and ECB production could reach 1 262.9 mg/L and 1 344.1 mg/L by adding talcum powder of 20 g/L (d50 = 14.2 MUm) and 7 glass beads (6 mm), an increase by 33.2% and 41.7%, respectively. The results indicated that the mycelium morphology of filamentous microorganisms and the product yield of fermentation could be improved by adding microparticles remarkably, and it provide an important method for the fermentative optimization of filamentous microorganisms. PMID- 26647584 TI - [Construction and application of black-box model for glucoamylase production by Aspergillus niger]. AB - Carbon-limited continuous culture was used to study the relationship between the growth of Aspergillus niger and the production of glucoamylase. The result showed that when the specific growth rate was lower than 0.068 h(-1), the production of glucoamylase was growth-associated, when the specific growth rate was higher than 0.068 h(-1), the production of glucoamylase was not growth-associated. Based on the result of continuous culture, the Monod dynamics model of glucose consumption of A. niger was constructed, Combining Herbert-Pirt equation of glucose and oxygen consumption with Luedeking-Piret equation of enzyme production, the black box model of Aspergillus niger for enzyme production was established. The exponential fed-batch culture was designed to control the specific growth rate at 0.05 h(-1) by using this model and the highest yield for glucoamylase production by A. niger reached 0.127 g glucoamylase/g glucose. The black-box model constructed in this study successfully described the glucoamylase production by A. niger and the result of the model fitted the measured value well. The black box model could guide the design and optimization of glucoamylase production by A. niger. PMID- 26647585 TI - [Computational fluid dynamics simulation of different impeller combinations in high viscosity fermentation and its application]. AB - Agitator is one of the essential factors to realize high efficient fermentation for high aerobic and viscous microorganisms, and the influence of different impeller combination on the fermentation process is very important. Welan gum is a microbial exopolysaccharide produced by Alcaligenes sp. under high aerobic and high viscos conditions. Computational fluid dynamics (CFD) numerical simulation was used for analyzing the distribution of velocity, shear rate and gas holdup in the welan fermentation reactor under six different impeller combinations. The best three combinations of impellers were applied to the fermentation of welan. By analyzing the fermentation performance, the MB-4-6 combination had better effect on dissolved oxygen and velocity. The content of welan was increased by 13%. Furthermore, the viscosity of production were also increased. PMID- 26647586 TI - [Effect of residue Y76 on co-enzyme specificity of meso-diaminopimelate dehydrogenase from Symbiobacterium thermophilum]. AB - In industrial application of NAD(P)H-dependent dehydrogenases, NAD(H) has the advantages over NADP(H) in higher stability, lower price and wider recycling system. Recently, a meso-2,6-diaminopimelate dehydrogenase from Symbiobacterium thermophilum (StDAPDH) has been found to be a useful biocatalyst for the production of D-amino acids, but it requires NADP(H) as co-enzyme. To switch the co-enzyme specificity from NADP(H) to NAD(H), we studied the effect of Y76 on the co-enzyme specificity of StDAPDH, because the crystal structural analysis indicated that residue Y76 is near the adenine ring. The mutation of Y76 exerted significant effect on the co-enzyme specificity. Furthermore, the double mutant R35S/R36V significantly lowered the specific activity toward NADP+, and the combination of R35S/R36V with some of the Y76 mutants resulted in mutant enzymes favorable NAD+ over NADP+. This study should provide useful guidance for the further development of highly active NAD(+)-dependent StDAPDH by enzyme engineering. PMID- 26647587 TI - [Semi-rational modification for improving bond selectivity of recombinant beta glucuronidase]. AB - To improve bond selectivity of recombinant beta-glucuronidase in Escherichia coli (PGUS-E), based on the PGUS-E structure guidance, three key points R329, T369 and N467 were identified to be responsible for the bond selectivity of PGUS-E, and further saturation mutagenesis was conducted. Two positive mutants R329K and T369V were obtained by a combined selection technique of thin-layer chromatography and high performance liquid chromatography. Compared to PGUS-E, the bond selectivity of mutants R329K and T369V increased by 26.9% and 34.3%, respectively; whereas the biochemical properties such as pH and temperature profile were unchanged. Nevertheless, the activity was decreased compared to PGUS E. These results further confirmed that sites R329 and T369 played important roles for the bond selectivity and activity. In summary, this study significantly increased the bond selectivity of PGUS-E by structure guided saturation mutagenesis, providing experimental support for elucidating the relationship between the structure and function of PGUS-E. PMID- 26647588 TI - [Laboratory evaluation and field trial of activation indigenous microbial displacements in the reservoirs after polymer flooding]. AB - Most main oilfields in China have already entered a "double high" development stage (high water cut, high recovery degree). To further enhance oil recovery in reservoirs after polymer flooding (RAPFs), an efficient activator formulation for promoting metabolism of endogenous microorganism was studied by aerogenic experiments, physical simulation experiments, electron microscopy scanning and pyrophosphate sequencing. Results show that the activator could activate the endogenous microorganisms in the injected water and make the pressurized gas reach 2 MPa after 60 d static culture of the activator in a high pressure vessel. The oil recovery efficiency of natural core physical simulation flooding can be improved by more than 3.0% (OOIP) in RAPFs when injected 0.35 PV activator with 1.8% mass concentration, and a lot of growth and reproduction of activated endogenous microorganism in the core was observed by electron microscopy scanning. Field trial with 1 injector and 4 producers was carried out in the east of south II block of Sa Nan in December 2011. By monitoring four effective production wells, changes of carbon isotope delta13C (PDB) content of methane and carbon dioxide were -45 per thousand to -54 per thousand and 7 per thousand to 12 per thousand. Compared with east II of Sa Nan block, the oil amount increased by 35.9%, water cut stabled at 94%. The incremental oil was 5 957 t during the three and a half years, which provides an alternative approach for further improving oil recovery in similar reservoirs. PMID- 26647589 TI - Mastering the Inbox Information Era. PMID- 26647590 TI - Patient Engagement Roles Emerging in Healthcare. PMID- 26647591 TI - BREAKING DOWN HEALTHCARE'S SILOS. PMID- 26647592 TI - Lighting the Mobile Information FHIR. PMID- 26647593 TI - Consumer Health Information Bill of Rights Advancing Public Good. PMID- 26647595 TI - Informatics and HIM: Enabling Semantic Interoperability and the Learning Health System. PMID- 26647594 TI - Best Practices in mHealth for Consumer Engagement. PMID- 26647596 TI - Evaluating the Information Governance Principles for Healthcare: Retention and Disposition. PMID- 26647597 TI - HIM Best Practices for Engaging Consumers in Their Overall Healthcare. PMID- 26647598 TI - Sepsis Under the LCD-10-CM Microscope. PMID- 26647599 TI - ICD-10-PCS From the Heart: Cardiovascular Procedures. PMID- 26647600 TI - "Let's hope common sense is contagious". PMID- 26647601 TI - Senior HCA 'bridging' role will be piloted next year. PMID- 26647603 TI - Lack of staff common theme across sectors, warns CQC. PMID- 26647602 TI - NHS failing to make most of support staff. PMID- 26647604 TI - Home secretary orders nurses be put on shortage occupation list. PMID- 26647605 TI - Letter sparks concern over nursing ratio. PMID- 26647606 TI - NHS to cap agency pay at 55% above permanent staff. PMID- 26647607 TI - Urgent cancer referral pathway does save lives. PMID- 26647608 TI - Gap between falls prevention policies and practice revealed. PMID- 26647609 TI - "We must bridge the gap between health and social care nursing". PMID- 26647610 TI - "The right environment will create leaders in the NHS". PMID- 26647611 TI - Developing a dependency and capacity staffing tool. AB - Policy drivers to move care out of hospital and into the community also emphasise the need to ensure resources are used effectively. However, there is a paucity of information and processes to support successful management of demand and capacity in community nursing services. With the current emphasis on achieving safe staffing, a solution had to be developed in Solihull that can assess the anticipated demand in terms of individual patient needs, to inform the required nursing capacity on a day-to-day basis. This article describes how involving staff helped create an effective dependency and capacity tool operated through the clinical recording system. PMID- 26647612 TI - Revalidation: benefits for the profession and patients. AB - From April 2016 nurses and midwives will undertake a process of revalidation every three years. This has created some anxiety among practitioners. However, the Nursing and Midwifery Council pilot sites have shown that many nurses and midwives have found the process beneficial. This first article in a series of eight outlines why nurses need to revalidate, the potential benefits for patients and the profession and how revalidation links to the NMC Code. Subsequent articles will explore how revalidation works in practice. PMID- 26647613 TI - Using e-learning to enhance nurse education. AB - Technology-enhanced learning can be used creatively in education and is especially useful for students entering nurse training through the widening participation route. This article reviews previous technologies and teaching methods, and details those that are emerging and being debated in the educational press. PMID- 26647614 TI - Using case management to support people with dementia. PMID- 26647615 TI - How gender influences health inequalities. AB - This third article in a five-part series on the relationship between sociology and nursing practice discusses the issue of gender as a social determinant. Health inequalities between men and women are the result of the interaction between biology and society in terms of how society structures and influences our lives. Men and women have different expectations and roles imposed on them by society and this has a significant impact on health. PMID- 26647616 TI - 60 seconds with Sam Matthews. PMID- 26647617 TI - Raising cardiac awareness. PMID- 26647618 TI - METABOLOMICS IN MEDICAL SCIENCES--TRENDS, CHALLENGES AND PERSPECTIVES. AB - Metabolomics is the latest of the "omic" technologies that involves comprehensive analysis of small molecule metabolites of an organism or a specific biological sample. Metabolomics provides an insight into the cell status and describes an actual health condition of organisms. Analysis of metabolome offers a unique opportunity to study the influence of genetic variation, disease, applied treatment or diet on endogenous metabolic state of organisms. There are many areas that might benefit from metabolomic research. In the article some applications of this novel "omic" technology in the field of medical sciences are presented. One of the most popular aims of metabolomic studies is biomarker discovery. Despite using the state-of-art analytical techniques along with advanced bioinformatic tools, metabolomic experiments encounter numerous difficulties and pitfalls. Challenges that researchers in the field of analysis of metabolome have to face include i.a., technical limitations, bioinformatic challenges and integration with other "omic" sciences. One of the grand challenges for studies in the field of metabolomics is to tackle the problem of data analysis, which is probably the most time consuming stage of metabolomic workflow and requires close collaboration between analysts, clinicians and experts in chemometric analysis. Implementation of metabolomics into clinical practice will be dependent on establishment of standardized protocols in analytical performance and data analysis and development of fit-for-purpose biomarker method validation. Metabolomics allows to achieve a sophisticated level of information about biological systems and opens up new perspectives in many fields of medicine, especially in oncology. Apart from its extensive cognitive significance, metabolomics manifests also a practical importance as it may lead to design of new non-invasive, sensitive and specific diagnostic techniques and development of new therapies. PMID- 26647619 TI - PHARMACOLOGICAL ACTIVITIES OF PROTOCATECHUIC ACID. AB - Protocatechuic acid (3,4-dihydroxybenzoic acid, PCA) is a simple phenolic acid. It is found in a large variety of edible plants and possesses various pharmacological activities. This article aims to review the modern trends in phytochemical isolation and extraction of PCA from plants and other natural resources. Moreover, this article also encompasses pharmacological and biological activities of PCA. It is well known to have anti-inflammatory, antioxidant, anti hyperglycemia, antibacterial, anticancer, anti-ageing, anti-athro- genic, anti tumoral, anti-asthma, antiulcer, antispasmodic and neurological properties. PMID- 26647620 TI - A PROSPECTIVE PHARMACOLOGICAL REVIEW OF MEDICINAL HERBS, CUCUMIS MELO AND BERBERIS VULGARIS, COMMONLY USED IN THE TREATMENT OF RENAL DISEASES IN PAKISTAN. AB - The kidneys are important organs which have many functions in the body, including the production of hormones, absorbtion of minerals and the filtration of blood, producing urine. Their failure can be fatal, therefore, to focus the study of such herbs which may be useful in treating renal disease is the need of hour. In Pakistan, Cucumis melo and Berberis vulgaris has been commonly used for renal problems. In both of these plants were found flavonoids, alkaloids and terpenes, which may stand for their renal protective properties. Their reported vitamin E contents and antioxidant potentials also provide a base for their defensive mechanism, may be due to their free radical scavenging properties. Further, their diuretic and urinary tract anti-ulcer properties also support their traditional use in renal diseases. Their anti-histaminic and anti-cholinergic properties also provide symptomatic treatment by decreasing prostaglandin level and due to antispasmodic properties. Concluding, both of these plants can be used for renal problems, especially Cucumis melo, which have both the nutritive and medicinal properties. Therefore, the renal disease patients are advised to take much of this particular fruit, especially their seeds to make their kidneys healthy. PMID- 26647621 TI - ELECTROCHEMICAL FINGERPRINT STUDIES OF SELECTED MEDICINAL PLANTS RICH IN FLAVONOIDS. AB - The combination of a size-exclusion column (SEC) with electrochemical (voltammetric) detection at a boron-doped diamond electrode (BDDE) was applied for studying the correlations between electroactive Cu and Fe species with phenolic groups of flavonoids. For comparison with electrochemical results, SEC HPLC-DAD detection was used. The studied plant material comprised of: Betula verrucosa Ehrh., Equisetun arvense L., Polygonum aviculare L., Viola tricolor L., Crataegus oxyacantha L., Sambucus nigra L. and Helichrysum arenarium (L.) Moench. Based upon the results, high negative correlation was found for the chromatographic peak currents at 45 min with the sum of Cu and Fe for the aqueous extracts of Sambucus, Crataegus and Betula species, and for the peak currents at 65 min of the aqueous extracts of Sambucus, Crataegus, Helichrysum and Betula botanical species. This behavior confirms that it is mainly the flavonoids with easily oxidizable phenolic groups which are strongly influenced by the presence of Cu and Fe. Moreover, the electrochemical profiles obtained thanks to the use of HPLC hyphenated with voltammetric detection can be potentially applied for fingerprint studies of the plant materials used in medicine. PMID- 26647622 TI - REVERSED-PHASE HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY STUDY OF LIPOPHILICITY OF IMIDAZO[2,1-F]THEOPHYLLINE DERIVATIVES. AB - The present study is a part of our physicochemical and pharmacological studies in a group of tricyclic theophylline derivatives. The investigated compounds exhibit different pharmacological profiles in comparison to theophylline and have been tested as potential antidepressant and/or antipsychotic agents. The differences in pharmacological action between theophylline and their tricyclic derivatives can be explained by their various physicochemical properties, especially lipophilicity. The chromatographic behavior of twenty three derivatives of imidazo[2,1-f]theophylline was investigated, using reversed-phase high performance liquid chromatography (RP-HPLC) method. Moreover, partition coefficients and selected pharmacokinetic parameters were calculated computationally. Principal component analysis (PCA) method was used to establish the relationship between obtained experimental and computational parameters. PMID- 26647623 TI - EVALUATION OF LIPOPHILIC PROPERTIES OF BETAMETHASONE AND RELATED COMPOUNDS. AB - The lipophilicity (R(MW)) of betamethasone and its four related compounds: betamethasone-17,21-dipropionate, betamethasone-17-valerate, betamethasone-21 valerate and also betamethasone disodium phosphate was determined by reversed phase HPTLC and various mobile phase systems (methanol-water, dioxane-water and acetonitrile-water). The chromatographic lipophilicity parameters obtained for all examined compounds using abovementioned mobile phases onto three chromatographic plates (RP-2F254, RP-8F254, RP-18WF254) were compared with the theoretical partition coefficients which have been calculated by different computing programs: AlogPs, AClogP, AlogP, MlogP, KOWWIN, xlogP2, xlogP3, logP(ChemDraw) as well as with logP measured by shake-flask method. The results of this work demonstrate that regardless of applied method the greatest similarity in lipophilic properties show betamethasone-17-valerate, betamethasone 21-valerate and also betamethasone 17,21-dipropionate. The influence of solvent system as mobile phase on R(MW) values of examined compounds was observed. Among different mobile phases (organic modifier-water) proposed in this study, which allowed obtaining the reliable chromatographic lipophilicity parameters for all studied compounds is methanol-water mixture. The performance investigations showed that RP-HPTLC method has proved to be a rapid and cost effective analytical tool for describing the lipophilic properties of betamethasone and its related compounds. PMID- 26647624 TI - FREE RADICALS IN THERMALLY STERILIZED ACIDUM BORICUM AND OPTIMIZATION OF THIS PROCESS. AB - Free radicals formation in the acidum boricum (AB) during thermal sterilization process was examined by an X-band (9.3 GHz) electron paramagnetic resonance (EPR) spectroscopy. Acidum boricum was sterilized according to the pharmacopea norms at temperatures 160 degrees C (120 min), 170 degrees C (60 min), and 180 degrees C (30 min). Free radicals (~10(17) spin/g) were thermally formed in these drug. The free radicals system revealed complex character, and the asymmetrical EPR spectra were measured. Mainly oxygen free radicals exist in the tested heated AB. Slower spin-lattice relaxation processes exist in AB sterilized at 160, 170 and 180 degrees C. AB may be sterilized at temperatures 160, 170 and 180 degrees C. For AB thermal sterilization at temperature 170 degrees C is recommended. Free radicals concentrations changes during storage of the examined AB, and probably interactions with oxygen molecules may be responsible for this effect. PMID- 26647625 TI - EPR STUDIES OF THERMALLY STERILIZED VASELINUM ALBUM. AB - Electron paramagnetic resonance (EPR) spectroscopy was used for examination of free radicals in thermally treated vaselinum album (VA). Thermal treatment in hot air as sterilization process was tested. Conditions of thermal sterilization were chosen according to the pharmaceutical norms. Vaselinum album was heated at the following conditions (T--temperature, t--time): T = 160 degrees C and t = 120 min, T = 170 degrees C and t = 60 min and T = 180 degrees C and t = 30 min. The aim of this work was to determine concentration and free radical properties of thermally sterilized VA. EPR analysis for VA was done 15 min after sterilization. EPR measurements were done at room temperature. EPR spectra were recorded in the range of microwave power of 2.2-70 mW. g-Factor, amplitudes (A) and line width (DeltaBpp) of the spectra were determined. The shape of the EPR spectra was analyzed. Free radical concentration (N) in the heated samples was determined. EPR spectra were not obtained for the non heated VA. EPR spectra were detected for all thermally sterilized samples. The spectra revealed complex character, their asymmetry depends on microwave power. The lowest free radicals concentration was found for the VA sterilized at 180 degrees C during 30 min. EPR spectroscopy is proposed as the method useful for optimization of sterilization process of drugs. PMID- 26647626 TI - ANTIPROLIFERATIVE ACTIVITY OF NOVEL ACETYLENIC DERIVATIVES OF BETULIN AGAINST G 361 HUMAN MELANOMA CELLS. AB - Acetylenic derivatives of betulin were tested in vitro for their antiproliferative activity against G-361 human melanoma cells. Two types of betulin derivatives were studied: monoesters, obtained by modification of the hydroxyl group at C-28 position, and diesters modified at both C-28 and C-3 positions. To assess cell proliferation, a colorimetric sulforhodamine B based method was used. All the tested monoesters inhibited cellular growth and 28-O propynoylbetulin showed the strongest cytotoxic effect. Esterification of the C-3 hydroxyl group of the molecule abolished its growth inhibitory activity. PMID- 26647627 TI - DOWN-REGULATION OF INDUCIBLE NITRIC OXIDE SYNTHASE EXPRESSION BY INOSITOL HEXAPHOSPHATE IN HUMAN COLON CANCER CELLS. AB - Inflammatory bowel disease (IBD) is chronic inflammatory condition associated with increased risk of developing colorectal cancer. A number of mediators of inflammation, such as pro-inflammatory cytokines, prostaglandins and nitric oxide have been involved in carcinogenesis, especially in the promotion and progression stages. NO is synthesized from L-arginine by constitutively expressed endothelial and neuronal nitric oxide synthases (eNOS and nNOS, respectively) and an inducible NOS (iNOS) isoform expressed under inflammatory conditions. A selective inhibitors of iNOS could be, therefore, considered to be good candidates as chemopreventive agents against colon cancer. In this study, the effect of inositol hexaphosphate (IP6), dietary phytochemical, on the mRNA expression of iNOS stimulated with bacterial lipopolysaccharides (Escherichia coli and Salmonella typhimurium) and IL-1beta in intestinal cells Caco-2 for 6 and 12 h was investigated. A transcription level of iNOS with the use real time QRT-PCR technique was determined in cells treated with 1 and 2.5 mM IP6. Stimulation of Caco-2 with pro-inflammatory factors (LPS and IL-1beta) resulted in an up expression of iNOS mRNA at 6 and 12 h. Cells exposed to IP6 only revealed significant reduction in iNOS gene transcription after 12 h. A decrease in iNOS transcription by IP6 following the gene induction by proinflammatory agents in 6 and 12 h lasting cultures was also determined. The findings of this study suggest that one of the anti-cancer and anti-inflammatory abilities of IP6 can be realized by suppressing the expression of gene encoding inducible nitric oxide synthase isoform at the transcriptional level. PMID- 26647628 TI - EFFECTS OF 300 mT STATIC MAGNETIC FIELD ON IL-8 SECRETION IN NORMAL HUMAN COLON MYOFIBROBLASTS. AB - Intestinal subepithelial myofibroblasts play a crucial role in the growth and development of the intestine. Colitis, small bowel injury, gastric ulcer disease and inflammatory bowel disease (IBD) accompany the increase in the count of activated myofibroblasts. In the last few years, the increasing production of electromagnetic (EMF) and static magnetic (SMF) fields due to the expanding use of electronic devices in everyday life, has led to a number of studies on the effects of these fields on living organisms. Because of its anti-inflammatory properties, EMF therapy may be of medical use as an IBD treatment. This mechanism has not been elucidated yet. In the present work normal human colon myofibroblasts were exposed to SMF with a flux density of 300 mT for 96 h and then the cells were cultured for 24 and 48 h with 25 mM sodium butyrate (NaB) and 10 mM 5-aminosalicylic acid (5-ASA) in either the presence or absence of SMF. Tumor necrosis factor alpha (TNF-alpha)--dependent IL-8 secretion was determined with ELISA kit. Cell viability was determined with XTT assay. It was shown that SMF has no effect on TNF-alpha--dependent IL-8 secretion in control cells and in cells cultured in the presence of 5-ASA and NaB. PMID- 26647629 TI - IMPACT OF GENISTEIN AND PHYTIC ACID ON THE VIABILITY AND PROLIFERATION ACTIVITY OF NASAL POLYPS' CELLS IN AN IN VITRO MODEL. AB - In developed countries, chronic rhinosinusitis with nasal polyps is one of the diseases that diminish patients' quality of life most significantly. Treatment of that often incurable disease is based on the steroids and surgery in patients who had failed thorough conservative management. It appears that the introduction of new treatment agents suppressing inflammation process and inhibiting cells' proliferation would be a valuable therapeutic option. The aim of the present study was to evaluate the in vitro effect of genistein and phytic acid on the viability and growth rate of fibroblasts derived from nasal polyps. Cells were incubated with various concentrations of genistein (5-500 MUM) and phytic acid (100-20,000 MUM). After 72 h incubation, cells survivability and cells' growth rate were estimated by combination of WST-1 and LDH methods. QRT-PCR technique was used to determine the expression of histone H3, BCL-2, BAX and P53 genes. Caspase-8 and -9 expressions were evaluated by ELISA assay. Genistein and phytic acid significantly and in dose-specific manner decreased nasal polyps fibroblasts survivability and growth rate. Both agents in similar way decreased cell proliferation as measured by the expression of histone H3. They induce apoptotic machinery by modulating the expression of BCL-2, BAX and caspase-8 activity. Genistein and phytic acid have significant potential for a therapeutic role in the treatment of chronic rhinosinusitis. PMID- 26647630 TI - SYNTHESIS AND ANTIBACTERIAL ACTIVITY OF NEW SULFONAMIDE ISOXAZOLO[5,4-b]PYRIDINE DERIVATIVES. AB - A series of novel sulfonamide isoxazolo[5,4-b]pyridines were synthesized. The substrates for their synthesis were 3-aminoisoxazolo[5,4-b]pyridine and selected aryl sulfonic chlorides, chlorosulfonic acid and selected amines. Reactions were carried out using the classical and microwave methods. Selected compounds were tested towards antibacterial and antiproliferative activity. The structure of the obtained new derivatives was determined by elemental analysis and acquired IR and 1H NMR spectra. Among the tested compounds: N- isoxazolo[5,4-b]pyridine-3-yl benzenesulfonamide (2) and N-isoxazolo[5,4-b]pyridine-3-yl-4-methylbenzene sulfonamide (5) showed antimicrobial activity towards Pseudomonas aeruginosa (ATCC 27853) and Escherichia coli (ATCC 25922) at doses: 125, 250 and 500 ug. Both compounds showed a 50% inhibition of proliferation of breast carcinoma cell line MCF7 at concentrations of 152.56 ug/mL and 160 161.08 ug/mL, respectively. PMID- 26647631 TI - SEARCH FOR POTENTIAL CHOLINESTERASE INHIBITORS FROM THE ZINC DATABASE BY VIRTUAL SCREENING METHOD. AB - A virtual screening of the ZINC database was applied for the identification of novel cholinesterase inhibitors. The first step allowed to select compounds with favorable physicochemical properties. Then, the compounds were screened with the pharmacophore models built using crystal structures of donepezil, tacrine, decamethonium and bis-7-tacrine with acetylcholinesterase and well characterized interactions of bis-nor-meptazinol with butyrylcholinesterase. The selected compounds from the group of donepezil were docked to acetyl-cholinesterase giving 7 structures for further studies. These compounds were tested against cholinesterases and two of them, 1-[4-(1H-indol-3-ylmethyl)piperazin-1-yl]-2 phenoxyethanone 2 and 2-[(1-benzylpiperidine-4- yl)amino]-1-phenylethanol 4 displayed, respectively, 50.1% and 79.5% of inhibition against butyryl- cholinesterase at the concentration of 100 uM. PMID- 26647632 TI - IDENTIFICATION CHALLENGES IN EXAMINATION OF COMMERCIAL PLANT MATERIAL OF PSYCHOTRIA VIRIDIS. AB - Psychoria viridis (chacruna) is a hallucinogenic plant with psychoactive properties associated with the presence of N,N-dimethyltryptamine (DMT). This species is primarily known as an ingredient of the beverage Ayahuasca, but dry leaves are also smoked by recreational users. The plant is controlled in Poland and France and its proper identification poses many challenges due to the fact that genus Psychotria is relatively large and there are other species that are easily confused with chacruna. The aim of the present work was to develop an effective authentication procedure for the dried and shredded leaves of P. viridis, to be used in comparison of chemical and botanical characteristics of its commercial products. Dried leaves of P. viridis originating from Brazil, Peru and Hawaii were purchased from Internet providers. For DMT identification, thin layer chromatography (TLC) and high performance liquid chromatography (HPLC) methods have been elaborated, validated and applied. In order to clarify the existing differences among samples, chemometric methods have been used. Botanical features and the gas chromatography tandem mass spectrometry (GC-MS) chromatograms have been analyzed using hierarchical cluster analysis (HCA). Our studies revealed significant variety among plant material marketed as P. viridis. Grouping of samples based on their micromorphology features and GC-MS results did not correspond well with the presence of DMT. Based on our results an indisputable identification of dried specimens as P. viridis is very problematic. It is necessary to postulate changes in legislation regarding regulation of P. viridis and replace it with DMT as controlled substance. PMID- 26647633 TI - CHEMICAL COMPOSITION AND ANTIBACTERIAL ACTIVITY OF SOME MEDICINAL PLANTS FROM LAMIACEAE FAMILY. AB - Chemical composition and antibacterial activity of aqueous (ethanolic and methanolic) extracts from herbs often used in Polish cuisine and traditional herbal medicine including thyme (Thymus vulgaris L.), rosemary (Rosmarinus officinalis L.), oregano (Origanum vulgare L.), peppermint (Mentha piperita L.) and sage (Salvia officinalis L.) were compared. The aqueous ethanolic extracts contained slightly higher levels of phenolics compared to the aqueous methanolic extracts. In turn, GC-MS analysis showed that the aqueous methanolic extracts of thyme, rosemary and sage contained several additional compounds such as eugenol or ledol. The present studies also indicated that the bacterial species applied in the experiment exhibited different sensitivities towards tested extracts. Staphylococcus aureus strains were found to be the most sensitive bacteria to aqueous (ethanolic and methanolic) rosemary and sage extracts and aqueous methanolic thyme extract. Klebsiella pneumoniae ATCC 13883 and Proteus vulgaris NCTC 4635 were more susceptible to the aqueous methanolic thyme extract. However, Listeria monocytogenes 1043S was the most sensitive to the aqueous ethanolic rosemary extract. Gram-positive bacteria were generally more sensitive to the tested extracts than Gram-negative ones. PMID- 26647634 TI - ANTIOXIDANT ACTIVITY OF TISSUE CULTURE-RAISED BALLOTA NIGRA L. PLANTS GROWN EX VITRO. AB - Antioxidant properties and total phenolic and flavonoid contents were evaluated in methanolic extracts of shoots from Ballota nigra plants initiated in vitro (from nodal explants) and in vivo (from seeds). The plants were grown in greenhouse and in the field, and were analyzed at the vegetative and flowering stages. The shoot extract of wild-grown plants of B. nigra was also investigated. The results indicate that antioxidant potential of the B. nigra extracts seems to be due to their scavenging of free radicals (DPPH assay) and metal reducing (FRAP test), while they were less effective at the prevention of linoleic acid peroxidation (LPO test). The extracts from shoots of in vitro derived plants were found to exhibit the greatest antioxidant properties. The extracts were also characterized by the highest content of phenolic compounds and their level was affected by plant developmental stage. The extracts of shoots collected at the flowering period exhibited higher amounts of phenolics and flavonoids than in the extracts of immature plants. A close correlation between the total phenolic content and flavonoid content and antioxidant activity using the DPPH and FRAP assays was obtained. The results of the present study suggest the use in vitro derived plants of B. nigra instead of using wild plants for pharmaceutical purposes. PMID- 26647635 TI - EVALUATION OF ANTIOXIDANT PROPERTIES OF METHANOLIC EXTRACTS FROM LEAVES AND ROOTS OF REHMANNIA GLUTINOSA LIBOSCH. IN HUMAN BLOOD. AB - Compounds with antioxidant activity may protect different elements of blood from damaging effects of oxidative stress. The present in vitro study was designed to examine the antioxidant activity of methanolic extracts from leaves and roots of R. glutinosa plants against damages induced by oxidative stress. Oxidative stress was stimulated in human plasma and human blood platelet samples by the strong biological oxidant--hydrogen peroxide (H2O2) or H2O2/Fe (the donor of hydroxyl radicals). In experimental trials, the level of biomarker of lipid peroxidation- TBARS was significantly decreased by the action of methanolic extracts from R. glutinosa leaves. Therefore, it seems that the methanolic extract from leaves of the plants may be a new source of bioactive antioxidant natural compounds. It may be also an active pharmacological agent or a food supplement for healthy subjects and for people with different diseases (cardiovascular diseases and cancer) induced by oxidative stress. PMID- 26647636 TI - EFFECT OF STARCH HYDROLYSATES IN THE PROCESS OF DISSOLUTION OF SOLIDS. AB - The purpose of this work was to investigate the influence of starch hydrolysates in the dissolution process of the substance practically insoluble in water. Progesterone and ibuprofen were chosen as model substances. The study was conducted with a constant amount of the drug (25 mg/mL) or constant amount of starch hydrolysate (50 mg/mL). Next, the influence of ethanolic solutions (10-30% v/v) on solubility of drug was tested. The results confirm the possibility of using starch hydrolysate as a cheap and safe addition to increase the solubility of practically insoluble drugs. PMID- 26647637 TI - THE INFLUENCE OF EXCIPIENTS ON PHYSICAL PROPERTIES OF TABLETS AND DISSOLUTION OF CAFFEINE. AB - Caffeine is a common component of everyday diet but also a popular ingredient of some analgesics. Before it is administered to a patient, it has to be properly prepared using appropriate procedures to get the suitable drug form with various excipients. The tablets with caffeine were obtained using a wet granulation method. Three groups with four series of tablets were obtained with the constant concentration of caffeine but with different combinations of excipients, including potato starch and lactose, microcrystalline cellulose and lactose and D mannitol alone. The binder solution of polyvinylpyrrolidone was added in all series of granules used in tabletting but in different quantities. A number of pharmacopoeial tests were conducted to determine the properties of the obtained tablets. All series of tablets positively passed physical tests. More than 80% of caffeine dissolved after 45 min from most series. Only two of 12 series of tablets did not meet pharmacopoeial requirements in a dissolution test. The results of the study indicated that proposed compositions of the tablets are suitable for administration of caffeine in that drug form. PMID- 26647638 TI - PHARMACODYNAMICAL EVALUATION OF MATRIX TYPE TRANSDERMAL THERAPEUTIC SYSTEMS CONTAINING CAPTOPRIL. AB - The objective of this study was to evaluate pharmacodynamical properties of transdermal therapeutic systems (TTS) containing captopril together with synthetic and pH independent polymers, Eudragit RL 100 and RS 100. Optimum formulation was chosen according to the results of our previous study regarding in vitro dissolution and ex vivo diffusion rate studies through excised human skin by using Franz Diffusion Cell. Control group, hypertension group (HT) and TTS containing captopril hypertension group (HT-CAP) were assessed for the pharmacodynamic activity of the study. Pharmacodynamic activity of transdermal patches containing captopril was evaluated in rats by the measurement of systolic blood pressure for 24 h with the use of the tail cuff method. Blood pressure, heart rate, body and heart weight, heart and body weight ratio were determined. Lactate dehydrogenase (LDH), creatinine phosphokinase (CPK), glutathione (GSH), malondialdehyde (MDA), myeloperoxidase (MPO) and Na+, K(+)-ATPase were measured in the serum of rats. Histopathological evaluation of the heart tissue was conducted in order to determine any tissue damage. Blood pressure values of the TTS containing captopril hypertension group were decreased significantly and became almost similar with the blood pressure values of the control group. These results indicated that matrix type transdermal patches prepared with Eudragit RL 100 and RS 100 polymers containing captopril can be considered as transdermal therapeutic systems for chronical treatment of hypertension and congestive heart failure. However, further in vivo pharmacokinetic studies should be performed in order to determine the blood level of the drug. PMID- 26647639 TI - KNOWLEDGE, ATTITUDE AND PERCEPTION REGARDING ANTIBIOTICS AMONG POLISH PATIENTS. AB - Antibiotics are drugs often used. This drugs used without legitimate indications or incorrectly may cause not satisfactory clinical results. It is therefore important for the society members to be aware of what is an antibiotic and which benefits and risks its use may bring. The survey was conducted in 2010. Objective of the study was to obtain information on the current knowledge and beliefs about antibiotic therapy of Poles. The research material consisted of 609 questionnaires and interviews, conducted among the adult population residing in the Lublin voivodeship. The study shows that rural inhabitants don't know the term herbal medicine or antibiotic more often than inhabitants in the city. Similarly, they more often don't know the action of antibiotics as well as use them less frequently. Poles treat them as an emergency exit if they are not helped by home treatments. There was a problem of overuse of antibiotics, related to young people, which were busy and have no time for illness. Self-medication in the antibiotic therapy also occurs and is caused, among others, by undisciplined patients. The respondents admited that they have antibiotics from the previous treatment, from pharmacy, or from family or friends. However, residents of rural areas using an antibiotic most frequently, cited a pharmacy as the source of this drug. Other issues dealt within this study generally doesn't differ for rural inhabitants from the data obtained among the urban population. PMID- 26647640 TI - DNAzyme-Based Logic Gate-Mediated DNA Self-Assembly. AB - Controlling DNA self-assembly processes using rationally designed logic gates is a major goal of DNA-based nanotechnology and programming. Such controls could facilitate the hierarchical engineering of complex nanopatterns responding to various molecular triggers or inputs. Here, we demonstrate the use of a series of DNAzyme-based logic gates to control DNA tile self-assembly onto a prescribed DNA origami frame. Logic systems such as "YES," "OR," "AND," and "logic switch" are implemented based on DNAzyme-mediated tile recognition with the DNA origami frame. DNAzyme is designed to play two roles: (1) as an intermediate messenger to motivate downstream reactions and (2) as a final trigger to report fluorescent signals, enabling information relay between the DNA origami-framed tile assembly and fluorescent signaling. The results of this study demonstrate the plausibility of DNAzyme-mediated hierarchical self-assembly and provide new tools for generating dynamic and responsive self-assembly systems. PMID- 26647641 TI - Never blame the umpire - a review of Situation Awareness models and methods for examining the performance of officials in sport. AB - As sport becomes more complex, there is potential for ergonomics concepts to help enhance the performance of sports officials. The concept of Situation Awareness (SA) appears pertinent given the requirement for officials to understand what is going on in order to make decisions. Although numerous models exist, none have been applied to examine officials, and only several recent examples have been applied to sport. This paper examines SA models and methods to identify if any have applicability to officials in sport (OiS). Evaluation of the models and methods identified potential applications of individual, team and systems models of SA. The paper further demonstrates that the Distributed Situation Awareness model is suitable for studying officials in fastball sports. It is concluded that the study of SA represents a key area of multidisciplinary research for both ergonomics and sports science in the context of OiS. Practitioner Summary: Despite obvious synergies, applications of cognitive ergonomics concepts in sport are sparse. This is especially so for Officials in Sport (OiS). This article presents an evaluation of Situation Awareness models and methods, providing practitioners with guidance on which are the most suitable for OiS system design and evaluation. PMID- 26647642 TI - Anhydrous Tetramethylammonium Fluoride for Room-Temperature S(N)Ar Fluorination. AB - This paper describes the room-temperature S(N)Ar fluorination of aryl halides and nitroarenes using anhydrous tetramethylammonium fluoride (NMe4F). This reagent effectively converts aryl-X (X = Cl, Br, I, NO2, OTf) to aryl-F under mild conditions (often room temperature). Substrates for this reaction include electron-deficient heteroaromatics (22 examples) and arenes (5 examples). The relative rates of the reactions vary with X as well as with the structure of the substrate. However, in general, substrates bearing X = NO2 or Br react fastest. In all cases examined, the yields of these reactions are comparable to or better than those obtained with CsF at elevated temperatures (i.e., more traditional halex fluorination conditions). The reactions also afford comparable yields on scales ranging from 100 mg to 10 g. A cost analysis is presented, which shows that fluorination with NMe4F is generally more cost-effective than fluorination with CsF. PMID- 26647643 TI - Does self-efficacy mediate the cross-sectional relationship between perceived quality of health care and self-management of diabetes? Results from Diabetes MILES - Australia. AB - OBJECTIVE: Quality of health care (QoC) and self-efficacy may affect self management of diabetes, but such effects are not well understood. We examined the indirect role of diabetes-specific self-efficacy (DSE) and generalised self efficacy (GSE) in mediating the cross-sectional relationship between self reported QoC and diabetes self-management. DESIGN: Diabetes MILES-Australia was a national survey of 3,338 adults with diabetes. We analysed data from 1,624 respondents (age: M = 52.1, SD = 13.9) with type 1 (T1D; n = 680) or type 2 diabetes (T2D; n = 944), who responded to a version of the survey containing key measures. MAIN OUTCOME MEASURES: self-reported healthy eating, physical activity, self-monitoring of blood glucose frequency, HbA1c, medication/insulin adherence. RESULTS: We used Preacher and Hayes' bootstrapping method, controlling for age, gender and diabetes duration, to test mediation of DSE and GSE on the relationship of QoC with each self-management variable. We found statistically significant but trivial mediation effects of DSE and of GSE on most, but not all, variables (all effect sizes < .06). CONCLUSION: Support for mediation was weak, suggesting that relationships amongst these variables are small and that future research might explore other aspects of self-management in diabetes. PMID- 26647644 TI - Phosphorus Concentrations in Sequentially Fractionated Soil Samples as Affected by Digestion Methods. AB - Sequential fractionation has helped improving our understanding of the lability and bioavailability of P in soil. Nevertheless, there have been no reports on how manipulation of the different fractions prior to analyses affects the total P (TP) concentrations measured. This study investigated the effects of sample digestion, filtration, and acidification on the TP concentrations determined by ICP-OES in 20 soil samples. Total P in extracts were either determined without digestion by ICP-OES, or ICP-OES following block digestion, or autoclave digestion. The effects of sample filtration, and acidification on undigested alkaline extracts prior to ICP-OES were also evaluated. Results showed that, TP concentrations were greatest in the block-digested extracts, though the variability introduced by the block-digestion was the highest. Acidification of NaHCO3 extracts resulted in lower TP concentrations, while acidification of NaOH randomly increased or decreased TP concentrations. The precision observed with ICP-OES of undigested extracts suggests this should be the preferred method for TP determination in sequentially extracted samples. Thus, observations reported in this work would be helpful in appropriate sample handling for P determination, thereby improving the precision of P determination. The results are also useful for literature data comparison and discussion when there are differences in sample treatments. PMID- 26647645 TI - A combined proteomics and metabolomics approach to assess the effects of gold nanoparticles in vitro. AB - Omics technologies, such as proteomics or metabolomics, have to date been applied in the field of nanomaterial safety assessment to a limited extent. To address this dearth, we developed an integrated approach combining the two techniques to study the effects of two sizes, 5 and 30 nm, of gold nanoparticles (AuNPs) in Caco-2 cells. We observed differences in cells exposed for 72 h to each size of AuNPs: 61 responsive (up/down-regulated) proteins were identified and 35 metabolites in the cell extract were tentatively annotated. Several altered biological pathways were highlighted by integrating the obtained multi-omics data with bioinformatic tools. This provided a unique set of molecular information on the effects of nanomaterials at cellular level. This information was supported by complementary data obtained by immunochemistry, microscopic analysis, and multiplexed assays. A part from increasing our knowledge on how the cellular processes and pathways are affected by nanomaterials (NMs), these findings could be used to identify specific biomarkers of toxicity or to support the safe-by design concept in the development of new nanomedicines. PMID- 26647646 TI - Absolute quantification of 35 plasma biomarkers in human saliva using targeted MS. AB - BACKGROUND: Although the use of human saliva for diagnosing disease has been known to be of great clinical potential, few attempts have been made so far to develop its use. In this work, we developed an MRM-MS approach for 35 plasma biomarkers using human saliva in a clinical environment. METHODS & RESULTS: A 30 min micro LC-MS/MS run in MRM mode was conducted in order to quantify the 35 plasma proteins in human saliva. Sample preparation procedures were performed in quadruplicate and analyzed in duplicate. Results show that 32 of the 35 plasma proteins were quantified in human saliva using calibration curves in the 2- log10 dynamic ranges with excellent linearity. DISCUSSION/CONCLUSION: Our MRM method is compatible with routine measurements in daily clinical practice. PMID- 26647647 TI - PLK1 regulation of PCNT cleavage ensures fidelity of centriole separation during mitotic exit. AB - Centrioles are duplicated and segregated in close link to the cell cycle. During mitosis, daughter centrioles are disengaged and eventually separated from mother centrioles. New daughter centrioles may be generated only after centriole separation. Therefore, centriole separation is considered a licensing step for centriole duplication. It was previously known that separase specifically cleaves pericentrin (PCNT) during mitotic exit. Here we report that PCNT has to be phosphorylated by PLK1 to be a suitable substrate of separase. Phospho-resistant mutants of PCNT are not cleaved by separase and eventually inhibit centriole separation. Furthermore, phospho-mimetic PCNT mutants rescue centriole separation even in the presence of a PLK1 inhibitor. On the basis on these results, we propose that PLK1 phosphorylation is a priming step for separase-mediated cleavage of PCNT and eventually for centriole separation. PLK1 phosphorylation of PCNT provides an additional layer of regulatory mechanism to ensure the fidelity of centriole separation during mitotic exit. PMID- 26647648 TI - Discrimination between bacterial species by ratiometric analysis of their carbohydrate binding profile. AB - Antibiotic resistance is a global health concern meaning there is an urgent need for new treatments and diagnostics. Here glycosylated surfaces are used to profile the binding patterns of a range of Gram-negative, Gram-positive and mycobacteria. This enables the creation of 'barcodes' to enable identification and discrimination between the strains, which could not be achieved by single point glycan binding and offers a new concept in bacteria detection. PMID- 26647649 TI - Ligand effects in a heteroleptic bis-tridentate iron(iii) spin crossover complex showing a very high T1/2 value. AB - We describe the first example of a bis-tridentate heteroleptic iron(iii) spin crossover (SCO) complex, [Fe(3-OMe-SalEen)(thsa)]. Compared to the parent homoleptic compounds, the spin crossover features in the heteroleptic species are enhanced with a gradual-abrupt spin transition at 344 K. Clear correlations between pi-pi interactions and the T1/2 value have been revealed. PMID- 26647650 TI - Identifying early-warning signals of critical transitions with strong noise by dynamical network markers. AB - Identifying early-warning signals of a critical transition for a complex system is difficult, especially when the target system is constantly perturbed by big noise, which makes the traditional methods fail due to the strong fluctuations of the observed data. In this work, we show that the critical transition is not traditional state-transition but probability distribution-transition when the noise is not sufficiently small, which, however, is a ubiquitous case in real systems. We present a model-free computational method to detect the warning signals before such transitions. The key idea behind is a strategy: "making big noise smaller" by a distribution-embedding scheme, which transforms the data from the observed state-variables with big noise to their distribution-variables with small noise, and thus makes the traditional criteria effective because of the significantly reduced fluctuations. Specifically, increasing the dimension of the observed data by moment expansion that changes the system from state-dynamics to probability distribution-dynamics, we derive new data in a higher-dimensional space but with much smaller noise. Then, we develop a criterion based on the dynamical network marker (DNM) to signal the impending critical transition using the transformed higher-dimensional data. We also demonstrate the effectiveness of our method in biological, ecological and financial systems. PMID- 26647651 TI - MHD Stagnation-Point Flow and Heat Transfer with Effects of Viscous Dissipation, Joule Heating and Partial Velocity Slip. AB - The steady two-dimensional stagnation-point flow and heat transfer past a permeable stretching/shrinking sheet with effects of viscous dissipation, Joule heating and partial velocity slip in the presence of a magnetic field is investigated. The partial differential equations are reduced to nonlinear ordinary differential equations by using a similarity transformation, before being solved numerically by shooting technique. Results indicate that the skin friction coefficient and the local Nusselt number increase as magnetic parameter increases. It is found that for the stretching sheet the solution is unique while for the shrinking sheet there exist nonunique solutions (dual solutions) in certain range of parameters. The stability analysis shows that the upper branch solution is stable while the lower branch solution is unstable. PMID- 26647652 TI - Phylogeographic pattern of range expansion provides evidence for cryptic species lineages in Silene nutans in Western Europe. AB - As a result of recent or past evolutionary processes, a single species might consist of distinct Evolutionary Significant Units (ESUs), even corresponding to cryptic species. Determining the underlying mechanisms of range shifts and the processes at work in the build-up of divergent ESUs requires elucidating the factors that contribute to population genetic divergence across a species' range. We investigated the large-scale patterns of genetic structure in the perennial herbaceous plant species Silene nutans (Caryophyllaceae) in Western Europe. We sampled and genotyped 111 populations using 13 nuclear microsatellite loci and 6 plastid single-nucleotide polymorphisms. Broad-scale spatial population genetic structure was examined using Bayesian clustering, spatial multivariate analyses and measures of hierarchical genetic differentiation. The genotypic structure of S. nutans was typical of a predominantly allogamous mating system. We also identified plastid lineages with no intra-population polymorphism, mirroring two genetically differentiated nuclear lineages. No evidence of admixture was found. Spatial trends in genetic diversity further suggested independent leading-edge expansion associated with founding events and subsequent genetic erosion. Overall, our findings suggested speciation processes in S. nutans and highlighted striking patterns of distinct stepwise recolonisation of Western Europe shaped by Quaternary climate oscillations. Two main potential ESUs can be defined in Western Europe, corresponding to Eastern and Western nuclear-plastid lineages. In situ preservation of populations and genetic rescue implying ex situ conservation techniques should take the lineage identity into account. This is particularly true in Great Britain, northern France and Belgium, where S. nutans is rare and where distinct lineages co-occur in close contact. PMID- 26647654 TI - Simple diagrammatic approach to delineate duodenum on a radiotherapy planning CT scan. AB - In recent years, there has been increasing application of intensity-modulated radiotherapy and stereotactic body radiotherapy for the treatment of abdominal malignancies (stomach, pancreas, liver, spinal metastases). This warrants accurate delineation of organs at risk, especially the duodenum. The tortuous and curvy anatomy of duodenum often indistinguishable from adjoining organs is a practical challenge. Radiation Therapy Oncology Group (RTOG) has already published upper abdominal normal structure contouring guidelines to ease the delineation process. This pictorial essay following the RTOG guideline elaborates the step-by-step identification of the different parts of duodenum in relation to the adjoining important structures. PMID- 26647653 TI - On the importance of being structured: instantaneous coalescence rates and human evolution--lessons for ancestral population size inference? AB - Most species are structured and influenced by processes that either increased or reduced gene flow between populations. However, most population genetic inference methods assume panmixia and reconstruct a history characterized by population size changes. This is potentially problematic as population structure can generate spurious signals of population size change through time. Moreover, when the model assumed for demographic inference is misspecified, genomic data will likely increase the precision of misleading if not meaningless parameters. For instance, if data were generated under an n-island model (characterized by the number of islands and migrants exchanged) inference based on a model of population size change would produce precise estimates of a bottleneck that would be meaningless. In addition, archaeological or climatic events around the bottleneck's timing might provide a reasonable but potentially misleading scenario. In a context of model uncertainty (panmixia versus structure) genomic data may thus not necessarily lead to improved statistical inference. We consider two haploid genomes and develop a theory that explains why any demographic model with structure will necessarily be interpreted as a series of changes in population size by inference methods ignoring structure. We formalize a parameter, the inverse instantaneous coalescence rate, and show that it is equivalent to a population size only in panmictic models, and is mostly misleading for structured models. We argue that this issue affects all population genetics methods ignoring population structure which may thus infer population size changes that never took place. We apply our approach to human genomic data. PMID- 26647655 TI - Efficient Structure Resonance Energy Transfer from Microwaves to Confined Acoustic Vibrations in Viruses. AB - Virus is known to resonate in the confined-acoustic dipolar mode with microwave of the same frequency. However this effect was not considered in previous virus microwave interaction studies and microwave-based virus epidemic prevention. Here we show that this structure-resonant energy transfer effect from microwaves to virus can be efficient enough so that airborne virus was inactivated with reasonable microwave power density safe for the open public. We demonstrate this effect by measuring the residual viral infectivity of influenza A virus after illuminating microwaves with different frequencies and powers. We also established a theoretical model to estimate the microwaves power threshold for virus inactivation and good agreement with experiments was obtained. Such structure-resonant energy transfer induced inactivation is mainly through physically fracturing the virus structure, which was confirmed by real-time reverse transcription polymerase chain reaction. These results provide a pathway toward establishing a new epidemic prevention strategy in open public for airborne virus. PMID- 26647657 TI - Bursary-v-loans battle is a chance for change. PMID- 26647656 TI - CD44v3+/CD24- cells possess cancer stem cell-like properties in human oral squamous cell carcinoma. AB - Cancer stem cells (CSCs) or cancer stem cell-like cells (CSC-LCs) are a minority population of cells that relate to tumor progression, metastasis and drug resistance. To identify CSC-LCs in oral squamous cell carcinoma (OSCC), we used two OSCC cell lines, SAS and OSC20, and cell surface markers, CD44v3 and CD24. In addition, we examined CD44v3 and CD24 expression immunohistochemically and evaluated the relationship between the expression and clinicopathological parameters in 50 OSCC tissues. In SAS and OSC20, CD44v3+/CD24- cells showed a higher sphere forming ability than the other fractions, i.e., CD44v3+/CD24+, CD44v3-/CD24- and CD44v3-/CD24+ cells. The proportion of CD44v3+/CD24- cells in SAS and OSC20 was 10.7 and 24.1%, respectively. Regarding SAS, CD44v3+/CD24- cells also showed a higher drug resistance for CDDP, 5-FU and cetuximab and expressed higher mRNA levels of CSC property-related genes than the other cell fractions. The tumorigenicity of CD44v3+/CD24- cells was not significantly different from the other fractions in SAS. An immunohistochemical study revealed a significant correlation between CD44v3 expression in the invasive portion and lymph node metastasis. Kaplan Meier analysis revealed cases with CD44v3 expression in the invasive portion tended to show poor overall survival (OS) compared with those without CD44v3, and there was a significant difference in OS between CD44v3+/CD24- and CD44v3-/CD24- immunophenotypes in the invasive portion. In conclusion, the results suggest that the CD44v3+/CD24- cell population displays CSC-LC properties in a human OSCC cell line. Additionally, we present evidence that CD44v3 immunoexpression and CD44v3+/CD24- immunophenotypes could give prognostic information associated with unfavorable clinical outcomes. PMID- 26647658 TI - Plans for associate nurse role move ahead despite warnings from RCN. PMID- 26647659 TI - RCN weighs in on Northern Ireland pay dispute. PMID- 26647660 TI - Foreign nurses need help to adapt to UK hospitals. PMID- 26647662 TI - Hunt admits it was wrong to slash nurse training. PMID- 26647661 TI - Anger at plans to scrap bursaries grows as protests secure debate. PMID- 26647663 TI - How the kindness of a nurse can change a life. PMID- 26647664 TI - NHS England chief calls for more 'flexible' permanent nursing roles. PMID- 26647665 TI - Scale of FGM shows importance of safeguarding. PMID- 26647666 TI - CNO uses summit to share vision for profession's new 'triple aim'. PMID- 26647667 TI - 'Take a hard look at your trust's equality record'. PMID- 26647668 TI - Lung cancer specialist nurses 'too much of a luxury' for some trusts. PMID- 26647669 TI - Healthcare staff praised for their efforts after severe floods. PMID- 26647671 TI - Lack of dysphagia knowledge among stroke-trained nurses. PMID- 26647670 TI - Safety alert over risks in restraint. PMID- 26647673 TI - New self-screening tool aims to put patients in control of their nutrition. PMID- 26647679 TI - Childhood arthritis. PMID- 26647680 TI - Use staff wisely to save NHS money. AB - The NHS could save up to L 2 billion a year by improving workflow and containing workforce costs, according to Labour peer Lord Carter's review of NHS efficiency. Changes in areas such as rostering and management of annual leave must avoid increasing the pressure on staff. PMID- 26647681 TI - From out of reach to back in the loop. AB - A pioneering project to address mental health problems in young men from African Caribbean backgrounds is being piloted in Birmingham. Up My Street uses 'street therapy' to help mental health professionals and lay workers engage with young people. PMID- 26647682 TI - Blowing the whistle on bad practice. AB - Delilah Hesling, the UK's first patient safety ombudsman, says she found supporting staff a struggle, despite having her chief executive's support. Managers could be obstructive and staff were initially reluctant to come forward. The new guardian roles being introduced need to have 'teeth' if they are to be effective, she warns. PMID- 26647693 TI - Beat Panic app. PMID- 26647695 TI - Food for thought, but we won't fix climate while meat is on the menu. PMID- 26647697 TI - Opponents of funding changes are fighting for a failing system. PMID- 26647696 TI - Bursary means more to nursing students than just money. PMID- 26647698 TI - A photo of an empty classroom might sum up nursing's future. PMID- 26647701 TI - Revalidation rules are clear for most, but not for the exceptions. PMID- 26647702 TI - All-graduate profession ignores the talent that is available to us. PMID- 26647704 TI - How to perform basic life support. PMID- 26647705 TI - Education for healthcare clinical support workers. AB - This article reviews the current situation regarding the provision of education and training for healthcare clinical support workers (HCSWs). In the UK, there has been an increasing reliance on unqualified clinical support staff to provide a significant proportion of the direct patient care in all healthcare settings. HCSWs routinely undertake several nursing activities that were traditionally the responsibility of nursing students or junior staff nurses. There is a need for an urgent review of the training of healthcare support staff. A 'tick box' approach to training, with an emphasis on classroom-based or on-the-job learning, makes it difficult for HCSWs to integrate theory into practice, and supports a transactional approach to caring rather than a relational approach to caregiving. Lessons from the educational experiences of other healthcare groups should be applied to the training of HCSWs. An immersive, participatory teaching and learning strategy is one approach that could be used. PMID- 26647706 TI - Enabling sexual expression in people with dementia. AB - Dementia remains a significant health and social care concern in the UK. Cases of dementia are expected to increase exponentially because more people are living longer. In response, the government has issued a set of policies and guidance to better meet the needs of those living with dementia. However, one important relational aspect is notably absent from most policy documents: sexuality. This can be a complicated issue in relationships affected by dementia. This article analyses the literature and uses case studies to provide practical guidance to nurses in relation to sexual expression in people with dementia. PMID- 26647707 TI - Understanding attitudes and their effects on nursing practice. AB - Attitudes are of crucial importance in nursing. Attitudes help us to understand how people perceive issues and processes in care and determine what they deem important, good, relevant and appropriate. We should understand attitudes if we are to provide collaborative, patient-centred care; however, they are poorly understood. This article enables the reader to examine attitudes and their constituent beliefs and values. It explores the function of attitudes, considers how they are formed and reflects on the process of attitude change, examining how persuasion can be used to enable individuals to revisit behaviours that seem problematic or less effective. PMID- 26647708 TI - Stigma. PMID- 26647709 TI - Make yourself heard. PMID- 26647710 TI - Working towards independence. PMID- 26647712 TI - In the ReD: diabetes and renal specialists. PMID- 26647713 TI - The way we used to be. PMID- 26647714 TI - Ca-alpha1T, a fly T-type Ca2+ channel, negatively modulates sleep. AB - Mammalian T-type Ca(2+) channels are encoded by three separate genes (Cav3.1, 3.2, 3.3). These channels are reported to be sleep stabilizers important in the generation of the delta rhythms of deep sleep, but controversy remains. The identification of precise physiological functions for the T-type channels has been hindered, at least in part, by the potential for compensation between the products of these three genes and a lack of specific pharmacological inhibitors. Invertebrates have only one T-type channel gene, but its functions are even less well-studied. We cloned Ca-alpha1T, the only Cav3 channel gene in Drosophila melanogaster, expressed it in Xenopus oocytes and HEK-293 cells, and confirmed it passes typical T-type currents. Voltage-clamp analysis revealed the biophysical properties of Ca-alpha1T show mixed similarity, sometimes falling closer to Cav3.1, sometimes to Cav3.2, and sometimes to Cav3.3. We found Ca-alpha1T is broadly expressed across the adult fly brain in a pattern vaguely reminiscent of mammalian T-type channels. In addition, flies lacking Ca-alpha1T show an abnormal increase in sleep duration most pronounced during subjective day under continuous dark conditions despite normal oscillations of the circadian clock. Thus, our study suggests invertebrate T-type Ca(2+) channels promote wakefulness rather than stabilizing sleep. PMID- 26647715 TI - Bovine parathyroid hormone enhances osteoclast bone resorption by modulating V ATPase through PTH1R. AB - The vacuolar-type H+ adenosine triphosphatase (V-ATPase) plays an important role in cellular acidification and bone resorption by osteoclasts. However, the direct effect of bovine parathyroid hormone (bPTH) on V-ATPase has not yet been elucidated. The aim of the present study was to assess the effects of bPTH on V ATPase and osteoclasts. Osteoclasts from bone marrow (BM)-derived monocytes of C57BL/6 mice were cultured with or without bPTH. The mRNA and protein expression levels of the V-ATPase a3-subunit and d2-subunit (by RT-qPCR and western blot analysis), V-ATPase activity (using the V type ATPase Activity Assay kit) and the bone resorption function of osteoclasts (by bone resorption assay) were examined following treatment with various concentrations of bPTH (0.1, 1.0, 10 and 100 ng/ml) alone or with bPTH and its inhibitor, bafilomycin A1. Furthermore, the expression of parathyroid hormone (PTH) receptors in osteoclasts was also detected. The results revealed that the mRNA and protein expression levels of V ATPase a3-subunit and d2-subunit increased in a dose-dependent manner, paralleling the level of bPTH present. In addition, an increase in the concentration of bPTH was accompanied by the increased resorption capability of osteoclasts, whereas bone resorption was inhibited in the presence of bafilomycin A1. In addition, we confirmed the existence of parathyroid hormone 1 receptor (PTH1R) in osteoclasts using three different methods (RT-qPCR, western blot analysis and immunofluorescence staining). We found that bPTH enhanced the bone resorption capability of osteoclasts by modulating the expression of V-ATPase subunits, intracellular acidification and V-ATPase activity. Thus, we propose that PTH has a direct effect on osteoblasts and osteoclasts, and that this effect is mediated through PTH1R, thus contributing to bone remodeling. PMID- 26647716 TI - Aspirin-triggered resolvin D1 is produced during self-resolving gram-negative bacterial pneumonia and regulates host immune responses for the resolution of lung inflammation. AB - Bacterial pneumonia is a leading cause of morbidity and mortality worldwide. Host responses to contain infection and mitigate pathogen-mediated lung inflammation are critical for pneumonia resolution. Aspirin-triggered resolvin D1 (AT-RvD1; 7S,8R,17R-trihydroxy-4Z,9E,11E,13Z,15E,19Z-docosahexaenoic acid) is a lipid mediator (LM) that displays organ-protective actions in sterile lung inflammation, and regulates pathogen-initiated cellular responses. Here, in a self-resolving murine model of Escherichia coli pneumonia, LM metabololipidomics performed on lungs obtained at baseline, 24, and 72 h after infection uncovered temporal regulation of endogenous AT-RvD1 production. Early treatment with exogenous AT-RvD1 (1 h post infection) enhanced clearance of E. coli and Pseudomonas aeruginosa in vivo, and lung macrophage phagocytosis of fluorescent bacterial particles ex vivo. Characterization of macrophage subsets in the alveolar compartment during pneumonia identified efferocytosis by infiltrating macrophages (CD11b(Hi) CD11c(Low)) and exudative macrophages (CD11b(Hi) CD11c(Hi)). AT-RvD1 increased efferocytosis by these cells ex vivo, and accelerated neutrophil clearance during pneumonia in vivo. These anti-bacterial and pro-resolving actions of AT-RvD1 were additive to antibiotic therapy. Taken together, these findings suggest that the pro-resolving actions of AT-RvD1 during pneumonia represent a novel host-directed therapeutic strategy to complement the current antibiotic-centered approach for combatting infections. PMID- 26647717 TI - Induction of partial immunity in both males and females is sufficient to protect females against sexual transmission of Chlamydia. AB - Sexually transmitted Chlamydia trachomatis causes infertility, and because almost 90% of infections are asymptomatic, a vaccine is required for its eradication. Mathematical modeling studies have indicated that a vaccine eliciting partial protection (non-sterilizing) may prevent Chlamydia infection transmission, if administered to both sexes before an infection. However, reducing chlamydial inoculum transmitted by males and increasing infection resistance in females through vaccination to elicit sterilizing immunity has yet to be investigated experimentally. Here we show that a partially protective vaccine (chlamydial major outer membrane protein (MOMP) and ISCOMATRIX (IMX) provided sterilizing immunity against sexual transmission between immunized mice. Immunizing male or female mice before an infection reduced chlamydial burden and disease development, but did not prevent infection. However, infection and inflammatory disease responsible for infertility were absent in 100% of immunized female mice challenged intravaginally with ejaculate collected from infected immunized males. In contrast to the sterilizing immunity generated following recovery from a previous chlamydial infection, protective immunity conferred by MOMP/IMX occurred independent of resident memory T cells. Our results demonstrate that vaccination of males or females can further protect the opposing sex, whereas vaccination of both sexes can synergize to elicit sterilizing immunity against Chlamydia sexual transmission. PMID- 26647718 TI - Spatiotemporal interplay of severe acute respiratory syndrome coronavirus and respiratory mucosal cells drives viral dissemination in rhesus macaques. AB - Innate immune responses have a critical role in the control of early virus replication and dissemination. It remains unknown, however, how severe acute respiratory syndrome coronavirus (SARS-CoV) evades respiratory innate immunity to establish a systemic infection. Here we show in Chinese macaques that SARS-CoV traversed the mucosa through the respiratory tract within 2 days, resulting in extensive mucosal infiltration by T cells, MAC387(+), and CD163(+) monocytes/macrophages followed by limited viral replication in the lung but persistent viral shedding into the upper airway. Mucosal monocytes/macrophages sequestered virions in intracellular vesicles together with infected Langerhans cells and migrated into the tonsils and/or draining lymph nodes within 2 days. In lymphoid tissues, viral RNA and proteins were detected in infected monocytes upon differentiation into dendritic cells (DCs) within 3 days. Systemic viral dissemination was observed within 7 days. This study provides a comprehensive overview of the spatiotemporal interactions of SARS-CoV, monocytes/macrophages, and the DC network in mucosal tissues and highlights the fact that, while these innate cells contribute to viral clearance, they probably also serve as shelters and vehicles to provide a mechanism for the virus to escape host mucosal innate immunity and disseminate systemically. PMID- 26647719 TI - Simple surface engineering of polydimethylsiloxane with polydopamine for stabilized mesenchymal stem cell adhesion and multipotency. AB - Polydimethylsiloxane (PDMS) has been extensively exploited to study stem cell physiology in the field of mechanobiology and microfluidic chips due to their transparency, low cost and ease of fabrication. However, its intrinsic high hydrophobicity renders a surface incompatible for prolonged cell adhesion and proliferation. Plasma-treated or protein-coated PDMS shows some improvement but these strategies are often short-lived with either cell aggregates formation or cell sheet dissociation. Recently, chemical functionalization of PDMS surfaces has proved to be able to stabilize long-term culture but the chemicals and procedures involved are not user- and eco-friendly. Herein, we aim to tailor greener and biocompatible PDMS surfaces by developing a one-step bio-inspired polydopamine coating strategy to stabilize long-term bone marrow stromal cell culture on PDMS substrates. Characterization of the polydopamine-coated PDMS surfaces has revealed changes in surface wettability and presence of hydroxyl and secondary amines as compared to uncoated surfaces. These changes in PDMS surface profile contribute to the stability in BMSCs adhesion, proliferation and multipotency. This simple methodology can significantly enhance the biocompatibility of PDMS-based microfluidic devices for long-term cell analysis or mechanobiological studies. PMID- 26647720 TI - Validation of a Brazilian Portuguese Version of the Walking Estimated-Limitation Calculated by History (WELCH). AB - BACKGROUND: The Walking Estimated-Limitation Calculated by History (WELCH) questionnaire has been proposed to evaluate walking impairment in patients with intermittent claudication (IC), presenting satisfactory psychometric properties. However, a Brazilian Portuguese version of the questionnaire is unavailable, limiting its application in Brazilian patients. OBJECTIVE: To analyze the psychometric properties of a translated Brazilian Portuguese version of the WELCH in Brazilian patients with IC. METHODS: Eighty-four patients with IC participated in the study. After translation and back-translation, carried out by two independent translators, the concurrent validity of the WELCH was analyzed by correlating the questionnaire scores with the walking capacity assessed with the Gardner treadmill test. To determine the reliability of the WELCH, internal consistency and test-retest reliability with a seven-day interval between the two questionnaire applications were calculated. RESULTS: There were significant correlations between the WELCH score and the claudication onset distance (r = 0.64, p = 0.01) and total walking distance (r = 0.61, p = 0.01). The internal consistency was 0.84 and the intraclass correlation coefficient between questionnaire evaluations was 0.84. There were no differences in WELCH scores between the two questionnaire applications. CONCLUSION: The Brazilian Portuguese version of the WELCH presents adequate validity and reliability indicators, which support its application to Brazilian patients with IC. PMID- 26647721 TI - Cardiac Remodeling: Concepts, Clinical Impact, Pathophysiological Mechanisms and Pharmacologic Treatment. AB - Cardiac remodeling is defined as a group of molecular, cellular and interstitial changes that manifest clinically as changes in size, mass, geometry and function of the heart after injury. The process results in poor prognosis because of its association with ventricular dysfunction and malignant arrhythmias. Here, we discuss the concepts and clinical implications of cardiac remodeling, and the pathophysiological role of different factors, including cell death, energy metabolism, oxidative stress, inflammation, collagen, contractile proteins, calcium transport, geometry and neurohormonal activation. Finally, the article describes the pharmacological treatment of cardiac remodeling, which can be divided into three different stages of strategies: consolidated, promising and potential strategies. PMID- 26647722 TI - Effects of Growth Hormone on Cardiac Remodeling During Resistance Training in Rats. AB - BACKGROUND: Although the beneficial effects of resistance training (RT) on the cardiovascular system are well established, few studies have investigated the effects of the chronic growth hormone (GH) administration on cardiac remodeling during an RT program. OBJECTIVE: To evaluate the effects of GH on the morphological features of cardiac remodeling and Ca2+ transport gene expression in rats submitted to RT. METHODS: Male Wistar rats were divided into 4 groups (n = 7 per group): control (CT), GH, RT and RT with GH (RTGH). The dose of GH was 0.2 IU/kg every other day for 30 days. The RT model used was the vertical jump in water (4 sets of 10 jumps, 3 bouts/wk) for 30 consecutive days. After the experimental period, the following variables were analyzed: final body weight (FBW), left ventricular weight (LVW), LVW/FBW ratio, cardiomyocyte cross sectional area (CSA), collagen fraction, creatine kinase muscle-brain fraction (CK-MB) and gene expressions of SERCA2a, phospholamban (PLB) and ryanodine (RyR). RESULTS: There was no significant (p > 0.05) difference among groups for FBW, LVW, LVW/FBW ratio, cardiomyocyte CSA, and SERCA2a, PLB and RyR gene expressions. The RT group showed a significant (p < 0.05) increase in collagen fraction compared to the other groups. Additionally, the trained groups (RT and RTGH) had greater CK-MB levels compared to the untrained groups (CT and GH). CONCLUSION: GH may attenuate the negative effects of RT on cardiac remodeling by counteracting the increased collagen synthesis, without affecting the gene expression that regulates cardiac Ca2+ transport. PMID- 26647723 TI - Downregulation of transient receptor potential cation channel, subfamily C, member 1 contributes to drug resistance and high histological grade in ovarian cancer. AB - Transient receptor potential cation channel, subfamily C, member 1 (TRPC1) participates in many physiological functions but has also been implicated in cancer development. However, little is known about the role of TRPC1 in ovarian cancer (OC), including the drug resistance of these tumors. In the present study, a significant and consistent downregulation of TRPC1 in drug-resistant OC tissues/cells was determined using real-time quantitative polymerase chain reaction assays and the microarrays deposited in Oncomine and Gene Expression Omnibus (GEO) profiles. Protein/gene-protein/gene and protein-chemical interactions indicated that TRPC1 interacts with 14 proteins/genes and 6 chemicals, all of which are involved in the regulation of drug resistance in OC. Biological process annotation of TRPC1, OC, and drug resistance indicated a role for TRPC1 in drug-resistance-related functions in OC, mainly via the cell cycle, gene expression and cell growth and cell death. Analysis of mRNA-microRNA interactions showed that 8 out of 11 major pathways enriched from 38 predominant microRNAs targeting TRPC1 were involved in the regulation of drug resistance in OC, and 8 out of these top 10 microRNAs were implicated in the drug resistance in ovarian and other cancers. In a clinical analysis using data obtained from The Cancer Genome Atlas project (TCGA) cohort on 341 OC patients, TRPC1 expression was found to differ significantly between grade 2 and grade 3 tumors, with low level expression correlating with higher tumor grade. This is the first report to show a potential association between the downregulation of TRPC1 and both drug resistance and high histological tumor grade in OC. Our results provide the basis for further investigations of the drug-resistance-related functions of TRPC1 in OC and other forms of cancer. PMID- 26647724 TI - Comment on Luiten et al.'s paper: 'Ultra-processed foods have the worst nutrient profile, yet they are the most available packaged products in a sample of New Zealand supermarkets'. PMID- 26647725 TI - Influence of host diet and phylogeny on parasite sharing by fish in a diverse tropical floodplain. AB - The patterns of parasite sharing among hosts have important implications for ecosystem structure and functioning, and are influenced by several ecological and evolutionary factors associated with both hosts and parasites. Here we evaluated the influence of fish diet and phylogenetic relatedness on the pattern of infection by parasites with contrasting life history strategies in a freshwater ecosystem of key ecological importance in South America. The studied network of interactions included 52 fish species, which consumed 58 food types and were infected with 303 parasite taxa. Our results show that both diet and evolutionary history of hosts significantly explained parasite sharing; phylogenetically close fish species and/or species sharing food types tend to share more parasites. However, the effect of diet was observed only for endoparasites in contrast to ectoparasites. These results are consistent with the different life history strategies and selective pressures imposed on these groups: endoparasites are in general acquired via ingestion by their intermediate hosts, whereas ectoparasites actively seek and attach to the gills, body surface or nostrils of its sole host, thus not depending directly on its feeding habits. PMID- 26647726 TI - Liver epithelial cells inhibit proliferation and invasiveness of hepatoma cells. AB - Hepatocellular carcinoma (HCC) is a worldwide malignancy with poor prognosis. Liver progenitors or stem cells could be a potential therapy for HCC treatment since they migrate toward tumors. Rat liver epithelial (RLE) cells have both progenitor and stem cell-like properties. Therefore, our study elucidated the therapeutic effect of RLE cells in rat hepatoma cells. RLE cells were isolated from 10-day old rats and characterized for stem cell marker expression. RLE cells and rat hepatoma cells (H4-IIE-C3 cells) were co-cultured and divided into four groups with different ratios of RLE and hepatoma cells. Group A had only rat hepatoma cells as a control group. The ratios of rat hepatoma and RLE cells in group B, C and D were 5:1, 1:1 and 1:5, respectively. Effective inhibition of cell proliferation and migration was found in group D when compared to group A. There was a significant decrease in Bcl2 expression and increase in late apoptosis of rat hepatoma cells when adding more RLE cells. RLE cells reduced cell proliferation and migration of rat hepatoma cells. These results suggested that RLE cells could be used as a potential cell therapy. PMID- 26647727 TI - PI3K/Akt signaling pathway is involved in the neurotrophic effect of senegenin. AB - Neurodegenerative diseases are frequently associated with the loss of synapses and neurons. Senegenin, extracted from the Chinese herb Polygala tenuifolia Willd, was previously found to promote neurite outgrowth and neuronal survival in primary cultured rat cortical neurons. The aim of the present study was to investigate the underlying mechanisms of senegenin-induced neurotrophic effects on rat cortical neurons. Primary cortical rat neurons were treated with various pharmacological antagonists and with or without senegenin, and subjected to MTT and western blot analysis to explore the effects of senegenin on cell survival as well as the activation of signaling pathways. Neurite outgrowth and neuronal survival induced by senegenin were significantly inhibited by A2A receptor antagonist ZM241385 and specific phosphoinositide-3 kinase (PI3K) inhibitor LY294002, but not by tropomyosin receptor kinase A receptor inhibitor K252a, mitogen-activated protein kinase kinase inhibitor PD98059 or protein kinase C inhibitor GO6976. Furthermore, senegenin enhanced the phosphorylation of Akt, which was blocked by LY294002. The present study revealed that the PI3K/Akt signaling pathway may be involved in the neurotrophic effects of senegenin. PMID- 26647729 TI - CCNE1 amplification is associated with aggressive potential in endometrioid endometrial carcinomas. AB - The clinicopathological significance of amplification was investigated of the gene encoding cyclin E (CCNE1) and we assessed whether CCNE1 was a potential target in endometrioid endometrial carcinomas. CCNE1 amplification and CCNE1 or F box and WD repeat domain-containing 7 (FBXW7) expression in endometrial endometrioid carcinoma was assessed by immunohistochemistry and fluorescence in situ hybridization. CCNE1 knockdown by small interfering RNA (siRNA) was used to assess the CCNE1 function. The results showed that CCNE1 amplification was present in 9 (8.3%) of 108 endometrial carcinomas. CCNE1 amplification was correlated with high histological grade (Grade 3; p=0.0087) and lymphovascular space invasion (p=0.0258). No significant association was observed between CCNE1 amplification and FIGO stage (p=0.851), lymph node metastasis (p=0.078), body mass index (p=0.265), deep myometrial invasion (p=0.256), menopausal status (p=0.289) or patient age (p=0.0817). CCNE1 amplification was significantly correlated with shorter progression-free and overall survival (p=0.0081 and 0.0073, respectively). CCNE1 protein expression or loss of FBXW7 expression in endometrial endometrioid carcinoma tended to be correlated with shorter progression-free and overall survival; however, this difference was not statistically significant. Multivariate analysis showed that CCNE1 amplification was an independent prognostic factor for overall survival but not for progression free survival (P=0.0454 and 0.2175, respectively). Profound growth inhibition was observed in siRNA-transfected cancer cells with endogenous CCNE1 overexpression compared with that in cancer cells having low CCNE1 expression. CCNE1 amplification was independent of p53, HER2, MLH1 and ARID1A expression but dependent on PTEN expression in endometrial carcinomas. These findings indicated that CCNE1 amplification was critical for the survival of endometrial endometrioid carcinomas. Furthermore, the effects of CCNE1 knockdown were dependent on the CCNE1 expression status, suggesting that CCNE1-targeted therapy may be beneficial for patients with endometrial endometrioid carcinoma having CCNE1 amplification. PMID- 26647730 TI - Effects of human vascular endothelial growth factor on reparative dentin formation. AB - It is a challenge for dentists to save dental pulp in patients with pulp disease without resorting to root canal therapy. Formation of tertiary dentin to maintain pulp vitality is a key odontoblast response to dental pulp injury. Vascular endothelial growth factor (VEGF) is the most potent angiogenic and vasculogenic factor involved in tertiary dentin formation. It was hypothesized that VEGF may be used to treat pulp diseases such as pulpitis. To explore this hypothesis, the first step was to assess whether VEGF affects dental pulp cells to promote reparative dentin formation. In the current study, an AdCMV-hVEGF vector was constructed to deliver hVEGF into dental pulp cells of exfoliated deciduous teeth (hDPCs) in vitro and dental pulp cells in a rat model in vivo. The collected data clearly demonstrated that hVEGF increased alkaline phosphatase and mineralization by enzymatic activity. RT-qPCR data demonstrated that hVEGF significantly increased the expression levels of genes commonly involved in osteogenesis/odontogenesis. Data from the in vivo assays indicated that hVEGF enhanced pulp cell proliferation and neovascularization, and markedly increased formation of reparative dentin in dental pulp. The in vitro and in vivo data suggest that hVEGF may have potential clinical applications, thus may aid in the development of novel treatment strategies for dental pulpitis. PMID- 26647731 TI - Trichostatin A inhibits inflammation in phorbol myristate acetate-induced macrophages by regulating the acetylation of histone and/or non-histone proteins. AB - Histone deacetylase inhibitors (HDACi) are currently used in the routine clinical treatment of cancer. Alongside the antitumor activity of HDACi, increased attention has been paid to their anti-inflammatory effects. The present study aimed to analyze the inhibitory effects of the HDACi Trichostatin A (TSA), on the release of inflammatory mediators from macrophages differentiated from U-937 cells. A low dose of TSA (50 nM) was able to effectively decrease the levels of inflammatory cytokines in the cell supernatants, independent of apoptosis. In addition, the potential underlying mechanisms were explored, and TSA was shown to promote, rather than inhibit, the acetylation of histones. Furthermore, the inflammation-induced enhanced expression of class I HDACs was effectively inhibited by TSA. In addition, TSA enhanced the lipopolysaccharide (LPS)-induced expression of cyclooxygenase-2, but suppressed the LPS-induced expression of chemokine (C-C motif) ligand 7. The acetylation level of nuclear factor-kappaB p65 was decreased by LPS, but increased following treatment with TSA. In conclusion, TSA was able to inhibit inflammation in macrophages. However, whether the mechanism by which TSA inhibits inflammation is through significantly enhancing histone acetylation, in order to selectively suppress the expression of proinflammatory genes, and/or through regulating non-histone acetylation requires further research. PMID- 26647728 TI - Frequent alterations in cytoskeleton remodelling genes in primary and metastatic lung adenocarcinomas. AB - The landscape of genetic alterations in lung adenocarcinoma derived from Asian patients is largely uncharacterized. Here we present an integrated genomic and transcriptomic analysis of 335 primary lung adenocarcinomas and 35 corresponding lymph node metastases from Chinese patients. Altogether 13 significantly mutated genes are identified, including the most commonly mutated gene TP53 and novel mutation targets such as RHPN2, GLI3 and MRC2. TP53 mutations are furthermore significantly enriched in tumours from patients harbouring metastases. Genes regulating cytoskeleton remodelling processes are also frequently altered, especially in metastatic samples, of which the high expression level of IQGAP3 is identified as a marker for poor prognosis. Our study represents the first large scale sequencing effort on lung adenocarcinoma in Asian patients and provides a comprehensive mutational landscape for both primary and metastatic tumours. This may thus form a basis for personalized medical care and shed light on the molecular pathogenesis of metastatic lung adenocarcinoma. PMID- 26647732 TI - Measurement of tremor transmission during microsurgery. AB - BACKGROUND: Tremor is a major impediment to performing fine motor tasks, as in microsurgery. However, conventional measurements do not involve tasks representative of microsurgery. METHOD: We developed a low-cost surgical simulator incorporating a force transducer capable of detecting and quantifying the effects of tremor upon high-fidelity silicone replicas of cardiac vessels and substrate muscle. Experienced and trainee surgeons performed simulated anastomoses on this rig. We characterized procedures in terms of tremor intensity, based on Lomb-Scargle periodograms. RESULTS: Distinctive force oscillations occurred at 8-12 Hz, characteristic of enhanced physiological tremor, yielding peaks in power spectral density. These early results suggest a significantly lower transmission of tremor to the operative field by the experienced surgeon in comparison to the trainees. CONCLUSIONS: This new device quantifies the action of tremor upon a manipulandum during a complex task, which may be used for assessment and providing feedback to trainee surgeons. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26647733 TI - Extreme decay of meteoric beryllium-10 as a proxy for persistent aridity. AB - The modern Antarctic Dry Valleys are locked in a hyper-arid, polar climate that enables the East Antarctic Ice Sheet (EAIS) to remain stable, frozen to underlying bedrock. The duration of these dry, cold conditions is a critical prerequisite when modeling the long-term mass balance of the EAIS during past warm climates and is best examined using terrestrial paleoclimatic proxies. Unfortunately, deposits containing such proxies are extremely rare and often difficult to date. Here, we apply a unique dating approach to tundra deposits using concentrations of meteoric beryllium-10 ((10)Be) adhered to paleolake sediments from the Friis Hills, central Dry Valleys. We show that lake sediments were emplaced between 14-17.5 My and have remained untouched by meteoric waters since that time. Our results support the notion that the onset of Dry Valleys aridification occurred ~14 My, precluding the possibility of EAIS collapse during Pliocene warming events. Lake fossils indicate that >14 My ago the Dry Valleys hosted a moist tundra that flourished in elevated atmospheric CO2 (>400 ppm). Thus, Dry Valleys tundra deposits record regional climatic transitions that affect EAIS mass balance, and, in a global paleoclimatic context, these deposits demonstrate how warming induced by 400 ppm CO2 manifests at high latitudes. PMID- 26647734 TI - Doubly robust multiple imputation using kernel-based techniques. AB - We consider the problem of estimating the marginal mean of an incompletely observed variable and develop a multiple imputation approach. Using fully observed predictors, we first establish two working models: one predicts the missing outcome variable, and the other predicts the probability of missingness. The predictive scores from the two models are used to measure the similarity between the incomplete and observed cases. Based on the predictive scores, we construct a set of kernel weights for the observed cases, with higher weights indicating more similarity. Missing data are imputed by sampling from the observed cases with probability proportional to their kernel weights. The proposed approach can produce reasonable estimates for the marginal mean and has a double robustness property, provided that one of the two working models is correctly specified. It also shows some robustness against misspecification of both models. We demonstrate these patterns in a simulation study. In a real-data example, we analyze the total helicopter response time from injury in the Arizona emergency medical service data. PMID- 26647735 TI - Correction: Surface group modification and carrier transport properties of layered transition metal carbides (Ti2CT(x), T: -OH, -F and -O). AB - Correction for 'Surface group modification and carrier transport properties of layered transition metal carbides (Ti2CTx, T: -OH, -F and -O)' by Shen Lai, et al., Nanoscale, 2015, DOI: 10.1039/c5nr06513e. PMID- 26647736 TI - Establishment of a dual-color fluorescence tracing orthotopic transplantation model of hepatocellular carcinoma. AB - Different experimental models of hepatocellular carcinoma (HCC) have been used to investigate the biological mechanisms of hepatocarcinogenesis and its progression. However, previous studies have highlighted the difficulty of distinguishing between the tumor cells and stroma in experimental models of HCC. Therefore the aim of the present study was to establish a red-green dual-color fluorescence tracing orthotopic transplantation model of HCC, and investigate its practical values. Stable high red fluorescent protein (RFP)-expressing HepG2 human hepatoma cells and Hepa1-6 mice hepatoma cells were injected into the right liver lobe of green fluorescent protein-expressing nude mice. The growth and metastasis of the tumors were visualized using a whole-body in vivo fluorescence imaging system in real time. HCC tissues were extracted from tumor-bearing mice, and cut into 5-um serial frozen slices. The organizational structure of the transplanted tumors was observed under a microscope. A dual-color fluorescence tracing orthotopic transplantation tumor model of HCC was successfully established with a success rate of 100%. The growth and metastasis of the tumors were visualized at each stage of development in the tumor-bearing mice. Tumor cells with red fluorescence and host cells with green fluorescence were identified to merge in the reconstruction region of tumor tissue. The invasion, migration, and cell fusion between tumor and host cells was observed clearly. The dual-color fluorescence tracing orthotopic transplantation model of HCC was determined to be a stable and reliable method for tracking tumor progression. Mutual interactions between hepatoma cells and host tissues may be observed directly using this model, further elucidating the development of the tumor microenvironment. PMID- 26647738 TI - Pain hurts worldwide: non-verbal children and adolescents with cerebral palsy. PMID- 26647737 TI - Deep sequencing of hepatitis B virus basal core promoter and precore mutants in HBeAg-positive chronic hepatitis B patients. AB - Mutants in the basal core promoter (BCP) and precore (PC) regions of hepatitis B virus (HBV) genome are associated with the progression of chronic hepatitis B (CHB) infection. However, quasispecies characteristics of naturally occurring mutants in those regions in HBeAg-positive CHB patients has not been well described, partly limited by quantitative assay. This study aimed to develop an Ion Torrent deep sequencing assay to determine BCP and PC mutant percentages in HBeAg-positive CHB patients who were treatment naive and correlate them with different viral and host factors. Our results showed that Ion Torrent deep sequencing could achieve high accuracy (R(2)>0.99) within a dynamic range between 1% and 100%. Twelve hotspots with prevalence of greater than 20% were observed in EnhII/BCP/PC regions. G1719T, T1753V, A1762T and G1764A were genotype C related. BCP A1762T/G1764A double mutants were generally accompanied with PC 1896 wild type or lower PC G1896A mutant percentage. Lower serum HBeAg and HBsAg levels were associated with higher BCP A1762T/G1764A mutant percentages (>= 50%). ALT levels were higher in patients with PC G1896A mutant percentage greater than 10%. In conclusion, deep sequencing such as Ion Torrent sequencing could accurately quantify HBV mutants for providing clinical relevant information during HBV infection. PMID- 26647739 TI - Resurrecting complexity: the interplay of plasticity and rapid evolution in the multiple trait response to strong changes in predation pressure in the water flea Daphnia magna. AB - A resurrection ecology reconstruction of 14 morphological, life history and behavioural traits revealed that a natural Daphnia magna population rapidly tracked changes in fish predation by integrating phenotypic plasticity and widespread evolutionary changes both in mean trait values and in trait plasticity. Increased fish predation mainly generated rapid adaptive evolution of plasticity (especially in the presence of maladaptive ancestral plasticity) resulting in an important change in the magnitude and direction of the multivariate reaction norm. Subsequent relaxation of the fish predation pressure resulted in reversed phenotypic plasticity and mainly caused evolution of the trait means towards the ancestral pre-fish means. Relaxation from fish predation did, however, not result in a complete reversal to the ancestral fishless multivariate phenotype. Our study emphasises that the study population rapidly tracked environmental changes through a mosaic of plasticity, evolution of trait means and evolution of plasticity to generate integrated phenotypic changes in multiple traits. PMID- 26647740 TI - Emotional mimicry signals pain empathy as evidenced by facial electromyography. AB - Facial mimicry has been suggested to be a behavioral index for emotional empathy. The present study is the first to investigate the link between facial muscle activity and empathy for pain by facial electromyographic (EMG) recording while observers watched videos depicting real-life painful events. Three types of visual stimulus were used: an intact painful scene and arm-only (needle injection) and face only (painful expression) scenes. Enhanced EMG activity of the corrugator supercilii (CS) and zygomaticus major (ZM) muscles was found when observers viewed others in pain, supporting a unique pain expression that is distinct from the expression of basic emotions. In the intact video stimulus condition, CS activity was correlated positively with the empathic concern score and ZM activity, suggesting facial mimicry mediated empathy for pain. Cluster analysis of facial EMG responses revealed markedly different patterns among stimulus types, including response category, ratio, and temporal dynamics, indicating greater ecological validity of the intact scene in eliciting pain empathy as compared with partial scenes. This study is the first to quantitatively describe pain empathy in terms of facial EMG data. It may provide important evidence for facial mimicry as a behavioral indicator of pain empathy. PMID- 26647741 TI - Activation of pancreatic stellate cells involves an EMT-like process. AB - Pancreatic adenocarcinoma (PDAC) and chronic pancreatitis (CP) are characterized by a desmoplastic reaction involving activated pancreatic stellate cells (PSCs). However, the mechanisms of PSC activation remain poorly understood. We examined whether the epithelial-mesenchymal transition (EMT) process might play a role in PSC activation. PSCs were isolated from a rat pancreas and characterized using immunofluorescence and immunocytochemistry. We evaluated changes in cell motility and in the expression levels of a panel of EMT-related genes during the PSC activation process. Activation of PSCs occurred after 48 h of in vitro culture, as indicated by a morphological change to a myofibroblastic shape and a decrease in the number of cytoplasmic lipid droplets. After activation, PSCs showed enhanced cell migration ability compared to quiescent cells. In addition, the expression of epithelial markers (E-cadherin, BMP7 and desmoplakin) decreased, while expression of mesenchymal markers (N-cadherin, vimentin, fibronectin1, collagen1alpha1 and S100A4) increased in activated PSCs. EMT-related transcription factors (Snail and Slug) were also upregulated after PSC activation. The concurrent increase in cell migration ability and alterations in EMT-related gene expression suggests that the activation of PSCs involves an EMT like process. The knowledge that PSC activation involves an EMT-like process may help to identify potential new therapeutic targets to alleviate pancreatic fibrosis in diseases like CP and PDAC. PMID- 26647742 TI - MicroRNA-425-5p regulates chemoresistance in colorectal cancer cells via regulation of Programmed Cell Death 10. AB - Acquired chemoresistance represents a major obstacle in cancer treatment, the underlying mechanism of which is complex and not well understood. MiR-425-5p has been reported to be implicated tumorigenesis in a few cancer types. However, its role in regulating chemoresistance has not been investigated in colorectal cancer (CRC) cells. Microarray analysis was performed in isogenic chemosensitive and chemoresistant HCT116 cell lines to identify differentially expressed miRNAs. miRNA quantitative real-time PCR was used to detect miR-425-5p expression levels between drug resistant and parental cancer cells. MiR-425-5p mimic and inhibitor were transfected, followed by CellTiter-Glo((r)) assay to examine drug sensitivity in these two cell lines. Western Blot and luciferase assay were performed to investigate the direct target of miR-425-5p. Xenograft mouse models were used to examine in vivo function of miR-425-5p. Our data showed that expression of miR-425-5p was significantly up-regulated in HCT116-R compared with parental HCT116 cells. Inhibition of miR-425-5p reversed chemoresistance in HCT116-R cells. Programmed cell death 10 (PDCD10) is the direct target of miR-425 5p which is required for the regulatory role of miR-425-5p in chemoresistance. MiR-425-5p inhibitor sensitized HCT116-R xenografts to chemo drugs in vivo. Our study demonstrated that miR-425-5p regulates chemoresistance of CRC cells by modulating PDCD10 expression level both in vitro and in vivo. MiR-425-5p may represent a new therapeutic target for the intervention of CRC. PMID- 26647743 TI - Perceptions of family-centred services in a paediatric rehabilitation programme: strengths and complexities from multiple stakeholders. AB - BACKGROUND: Family-centred services (FCS) are best practice in paediatric rehabilitation and describe philosophies and approaches to medical care that emphasize the partnership and involvement of parents. While evidence supports FCS, there are complexities to its successful implementation. This mixed-methods study aimed to measure the extent to which parents and the healthcare provider (HCP) perceive service provision as being family centred, and to describe barriers and facilitators to the delivery of FCS. METHODS: Parents of children participating in a rehabilitation programme and HCPs providing services participated in this study. Parents completed the measure of processes of care-20 and participated in interviews, while HCPs completed the measure of processes of care-service providers and participated in a focus group. RESULTS: Quantitative analysis revealed that parents were mostly satisfied with features of FCS, which included communication and support between parents and HCPs, respect of diversity and parental collaboration and participation. Parents identified communication methods and psychosocial needs as areas that facilitated but sometimes detracted from FCS. Institutional barriers led to the identification of areas for improvement identified by multiple stakeholders. HCPs identified more areas for improvement than parents. CONCLUSION: When considering these barriers, it is evident that implementation is a complex process, impacted by institutional barriers. FCS needs to be investigated further, and systemic interventions should be used to facilitate its implementation. PMID- 26647744 TI - Can transcutaneous electrical nerve stimulation improve achilles tendon healing in rats? AB - BACKGROUND: Tendon injury is one of the most frequent injuries in sports activities. TENS is a physical agent used in the treatment of pain but its influence on the tendon's healing process is unclear. OBJECTIVE: To evaluate the influence of TENS on the healing of partial rupture of the Achilles tendon in rats. METHOD: Sixty Wistar rats were submitted to a partial rupture of the Achilles tendon by direct trauma and randomized into six groups (TENS or Sham stimulation) and the time of evaluation (7, 14, and 21 days post-injury). Burst TENS was applied for 30 minutes, 6 days, 100 Hz frequency, 2 Hz burst frequency, 200 us pulse duration, and 300 ms pulse train duration. Microscopic analyses were performed to quantify the blood vessels and mast cells, birefringence to quantify collagen fiber alignment, and immunohistochemistry to quantify types I and III collagen fibers. RESULTS: A significant interaction was observed for collagen type I (p=0.020) where the TENS group presented lower percentage in 14 days after the lesion (p=0.33). The main group effect showed that the TENS group presented worse collagen fiber alignment (p=0.001) and lower percentage of collagen III (p=0.001) and the main time effect (p=0.001) showed decreased percentage of collagen III at 7 days (p=0.001) and 14 days (p=0.001) after lesion when compared to 21 days. CONCLUSIONS: Burst TENS inhibited collagen I and III production and impaired its alignment during healing of partial rupture of the Achilles tendon in rats. PMID- 26647745 TI - Interval training based on ventilatory anaerobic threshold increases cardiac vagal modulation and decreases high-sensitivity c-reative protein: randomized clinical trial in coronary artery disease. AB - BACKGROUND: Autonomic dysfunction and inflammatory activity are involved in the development and progression of coronary artery disease (CAD), and exercise training has been shown to confer a cardiovascular benefit. OBJECTIVE: To evaluate the effects that interval training (IT) based on ventilatory anaerobic threshold (VAT) has on heart rate variability (HRV) and high-sensitivity C reactive protein (hs-CRP) levels, as well as the relationship between both levels, in patients with CAD and/or cardiovascular risk factors (RF). METHOD: Forty-two men (aged 57.88+/-6.20 years) were divided into two training groups, CAD-T (n= 12) and RF-T (n= 10), and two control groups, CAD-C (n= 10) and RF-C (n=10). Heart rate and RR intervals in the supine position, cardiopulmonary exercise tests, and hs-CRP levels were measured before and after IT. HRV was analyzed by spectral and symbolic analysis. The CAD-T and RF-T underwent a 16 week IT program of three weekly sessions at training intensities based on the VAT. RESULTS: In the RF-T, cardiac sympathetic modulation index and hs-CRP decreased (p<0.02), while cardiac parasympathetic modulation index increased (p<0.02). In the CAD-T, cardiac parasympathetic modulation index increased, while hs-CRP, systolic, and diastolic blood pressures decreased (p<0.02). Both control groups showed increase in hs-CRP parameters (p<0.02). There was a strong and significant association between parasympathetic and sympathetic modulations with hs-CRP. CONCLUSION: The IT program based on the VAT promoted a decrease in hs-CRP associated with improvement in cardiac autonomic modulation. PMID- 26647746 TI - Benefit of educational feedback for the use of positive expiratory pressure device. AB - BACKGROUND: Positive expiratory pressure (PEP) is regularly used as a self administered airway clearance technique. OBJECTIVE: The aim of this study was to evaluate the need to teach the correct use of the PEP device and to measure the progress of the success rate of the maneuver after training. METHOD: A PEP system (PariPEP-S Sytem) was used to generate PEP in 30 healthy volunteers. They were instructed by a qualified physical therapist to breathe correctly through the PEP device. Then they were evaluated during a set of ten expirations. Two other evaluations were performed at day 2 and day 8 (before and after feedback). The mean PEP and the success rate were calculated for each set of expirations. The number of maneuvers needed to obtain a correct use was calculated on the first session. RESULTS: An optimal PEP was reached after 7.5 SD 2.7 attempts by all subjects. Success rates and mean pressures were similar between the different sets of expirations (p=0.720 and p=0.326, respectively). Pressure variability was around 10%. After one week, 30% of subjects generated more than two non-optimal pressures in the set of ten expirations. No difference in success rate was observed depending on the evaluations. CONCLUSION: This study demonstrates that good initial training on the use of the PEP device and regular follow-up are required for the subject to reach optimal expiratory pressure. PMID- 26647747 TI - Effect of low-level laser therapy (808 nm) on skeletal muscle after endurance exercise training in rats. AB - BACKGROUND: Low-level laser therapy (LLLT) has been demonstrated to be effective in optimizing skeletal muscle performance in animal experiments and in clinical trials. However, little is known about the effects of LLLT on muscle recovery after endurance training. OBJECTIVE: This study evaluates the effects of low level laser therapy (LLLT) applied after an endurance training protocol on biochemical markers and morphology of skeletal muscle in rats. METHOD: Wistar rats were divided into control group (CG), trained group (TG), and trained and laser irradiated group (TLG). The endurance training was performed on a treadmill, 1 h/day, 5 days/wk, for 8 wk at 60% of the maximal speed reached during the maximal effort test (Tmax) and laser irradiation was applied after training. RESULTS: Both trained groups showed significant increase in speed compared to the CG. The TLG demonstrated a significantly reduced lactate level, increased tibialis anterior (TA) fiber cross-section area, and decreased TA fiber density. Myogenin expression was higher in soleus and TA muscles in both trained groups. In addition, LLLT produced myogenin downregulation in the TA muscle of trained animals. CONCLUSION: These results suggest that LLLT could be an effective therapeutic approach for stimulating recovery during an endurance exercise protocol. PMID- 26647748 TI - Skinfold thickness affects the isometric knee extension torque evoked by Neuromuscular Electrical Stimulation. AB - BACKGROUND: Subcutaneous adipose tissue may influence the transmission of electrical stimuli through to the skin, thus affecting both evoked torque and comfort perception associated with neuromuscular electrical stimulation (NMES). This could seriously affect the effectiveness of NMES for either rehabilitation or sports purposes. OBJECTIVE: To investigate the effects of skinfold thickness (SFT) on maximal NMES current intensity, NMES-evoked torque, and NMES-induced discomfort. METHOD: First, we compared NMES current intensity, NMES-induced discomfort, and NMES-evoked torque between two subgroups of subjects with thicker (n=10; 20.7 mm) vs. thinner (n=10; 29.4 mm) SFT. Second, we correlated SFT to NMES current intensity, NMES-induced discomfort, and NMES-evoked knee extension torque in 20 healthy women. The NMES-evoked torque was normalized to the maximal voluntary contraction (MVC) torque. The discomfort induced by NMES was assessed with a visual analog scale (VAS). RESULTS: NMES-evoked torque was 27.5% lower in subjects with thicker SFT (p=0.01) while maximal current intensity was 24.2% lower in subjects with thinner SFT (p=0.01). A positive correlation was found between current intensity and SFT (r=0.540, p=0.017). A negative correlation was found between NMES-evoked torque and SFT (r=-0.563, p=0.012). No significant correlation was observed between discomfort scores and SFT (rs=0.15, p=0.53). CONCLUSION: These results suggest that the amount of subcutaneous adipose tissue (as reflected by skinfold thickness) affected NMES current intensity and NMES evoked torque, but had no effect on discomfort perception. Our findings may help physical therapists to better understand the impact of SFT on NMES and to design more rational stimulation strategies. PMID- 26647749 TI - The use of evidence-based practices for the management of shoulder impingement syndrome among Indian physical therapists: a cross-sectional survey. AB - BACKGROUND: The understanding of the pathomechanics of shoulder impingement has evolved over the years. Likewise, assessment techniques and effective treatment strategies have also been developed. Physical therapists should keep up-to-date on the current evidence. OBJECTIVE: This study explored the practices currently used by Indian physical therapists for the assessment and management of shoulder impingement syndrome (SIS). METHOD: Using an online questionnaire, therapists were asked to declare the causes, methods of assessment and their choices of physical therapy techniques for the management of SIS. The proportions of therapists using different techniques were analyzed descriptively, and comparisons across gender, experience level, and training were made. Data were analyzed to see if the choices of respondents compared with their responses for etiology. RESULTS: A total of 211 responses were analyzed. Most respondents (>75%) believed that overuse and abnormal motion/posture are the most significant causes of SIS. However, fewer respondents reported assessing posture (60.2%) and dyskinesis, especially in women (24.2%). Ninety-four percent of the respondents reported using exercises, but exercise prescription was rather generic. Therapists additionally trained in the techniques of joint mobilization or taping declared using these techniques more frequently. The use of interferential therapy and ultrasound was reported by 89.5% and 98.4% of respondents, respectively CONCLUSION: Most therapists declared awareness of current recommended practices, but patient assessment, exercise prescription, and use of electrotherapy modalities were only partially based on current evidence. The study helps to identify gaps in current physical therapy approaches to SIS in India. PMID- 26647750 TI - Kinesio Taping(r) is not better than placebo in reducing pain and disability in patients with chronic non-specific low back pain: a randomized controlled trial. AB - BACKGROUND: Kinesio Taping(r) has been widely used in clinical practice. However, it is unknown whether this type of tape is more effective than placebo taping in patients with chronic lower back pain. OBJECTIVE: To compare the effectiveness of Kinesio Taping(r) in patients with chronic non-specific low back pain against a placebo tape and a control group. METHOD: This is a 3-arm, randomized controlled trial with a blinded assessor. Sixty patients with chronic non-specific low back pain were randomized into one of the three groups: Kinesio Taping(r) group (n=20), Micropore(r) (placebo) group (n=20) and control group (n=20). Patients allocated to both the Kinesio Taping(r) group and the placebo group used the different types of tape for a period of 48 hours. The control group did not receive any intervention. The outcomes measured were pain intensity (measured by an 11-point numerical rating scale) and disability (measured by the 24-item Roland Morris Disability Questionnaire). A blinded assessor measured the outcomes at baseline, 48 hours and 7 days after randomization. RESULTS: After 48 hours, there was a statistically significant difference between the Kinesio Taping(r) group versus the control group (mean between-group difference = -3.1 points, 95% CI=-5.2 to -1.1, p=0.003), but no difference when compared to the placebo group (mean between-group difference= 1.9 points, 95% CI=-0.2 to 3.9, p=0.08). For the other outcomes no differences were observed. CONCLUSIONS: The Kinesio Taping(r) is not better than placebo (Micropore(r)) in patients with chronic low back pain. PMID- 26647751 TI - Assessment of intensity effort of middle-aged adults practicing regular walking. AB - BACKGROUND: Walking is one of the most commonly recommended activities for sedentary individuals. When performed at the correct intensity, it can provide cardiovascular, respiratory, metabolic, and other benefits by providing a training effect in addition to reducing the risk of death from cardiovascular diseases and other chronic health conditions. OBJECTIVES: The primary aim of this study was to assess whether individuals who practiced regular unsupervised walking carry out the activity safely and with sufficient effort intensity parameters to have a positive physiological (training) effect. The secondary objective was to compare the training heart rate (HR) and the stability of the HR within the ideal range of training between the sexes. METHOD: Individuals were selected from walking tracks within the city of Belo Horizonte, Brazil. The study included subjects from 40 to 60 years of age who had practiced walking for at least two months prior to the study, walking at least three times a week. Individuals who agreed to participate in the survey were asked to walk 15 minutes at their usual pace with their HR measured every 5 minutes using a heart rate monitor. Their average walking HR was compared to the average training HR based on the formula: (220 - age) * 70 to 80% that would result in a positive physiological training effect. RESULTS: Of the 142 individuals evaluated, 25.4% achieved the average training HR. This result was significantly lower than those who did not achieve the average training HR while walking (p=0.002). There were significant differences between men and women who had reached the training HR (p=0.0001). CONCLUSION: The authors found that individuals who walk regularly performed outside the range of the ideal HR intensity that would cause a positive physiological effect and therefore would probably not achieve a beneficial training effect while walking. PMID- 26647752 TI - Assessment of grip strength with the modified sphygmomanometer test: association between upper limb global strength and motor function. AB - BACKGROUND: Grip strength, commonly evaluated with the handgrip dynamometer, is a good indicator of upper limb (UL) function in stroke subjects and may reflect the global strength deficits of the whole paretic UL. The Modified Sphygmomanometer Test (MST) also provides objective and adequate measures at low-cost. OBJECTIVE: To assess whether grip strength values obtained by using the MST and those obtained by using a handgrip dynamometer would present similar correlations with the global strength and motor function of the paretic UL in subjects with stroke, both in the subacute and chronic phases. METHOD: Measures of grip strength (MST and handgrip dynamometer), UL global strength (MST and hand-held dynamometer), and UL motor function (Fugl-Meyer motor assessment scale) were obtained with 33 subacute and 44 chronic stroke subjects. Pearson and Spearman correlation coefficients were calculated and Stepwise multiple regression analyses were performed to investigate predictor variables of grip strength (alpha=0.05). RESULTS: Significant correlations of similar magnitude were found between measures of global strength of the paretic UL and grip strength assessed with both the MST (0.66<=r<=0.78) and handgrip dynamometer (0.66<=r<=0.78) and between UL motor function and grip strength assessed with both the MST (0.50<=rs<=0.51) and hand-held dynamometer (0.50<=rs<=0.63) in subacute and chronic stroke subjects. Only global strength remained as a significant predictor variable of grip strength for the MST (0.43<=R2<=0.61) and for the handgrip dynamometer (0.44<=R2<=0.61) for both stroke subgroups. CONCLUSION: Grip strength assessed with the MST could be used to report paretic UL global strength. PMID- 26647753 TI - The new affordances in the home environment for motor development - infant scale (AHEMD-IS): Versions in English and Portuguese languages. AB - The home environment has been established as a crucial factor for motor development, especially in infants. Exploring the home environment can have significant implications for intervention, as it is common practice in physical therapy to have professionals advise patients on home activities. Since 2010, our group has been working on the development of the Affordances in the Home Environment for Motor Development - Infant Scale (AHEMD-IS), a parental self reporting instrument designed to assess the quality and quantity of factors (affordances) in the home environment. In Brazil, the instrument has been translated as "Affordances no Ambiente Domiciliar para o Desenvolvimento Motor - Escala Bebe", and it has been extensively used in several studies that address infant development. These studies in Brazil and other parts of the world highly recommended the need for a normative sample and standardized scoring system. A description of the study that addressed that need, along with the English version of the questionnaire and score sheets, was recently published in the well-known and respected journal Physical Therapy. Our intent with the present short communication is to notify Brazilian investigators and clinicians of this latest update so they can download the new instrument, as well as present the Brazilian (Portuguese) version of the AHEMD-IS along with its scoring system. PMID- 26647754 TI - Can live weight be used as a proxy for enteric methane emissions from pasture-fed sheep? AB - To test the hypothesis that sheep live weight (LW) could be used to improve enteric methane (CH4) emission calculations, mature ewes of 4 different breeds representative of the UK sheep industry were studied: Welsh Mountain, Scottish Blackface, Welsh Mule and Texel (n = 8 per breed). The ewes were housed and offered ad libitum access to fresh cut pasture of three different types, varying in digestibility: (a) a relatively high digestibility monoculture of perennial ryegrass (Lolium perenne), (b) a medium digestibility permanent pasture comprising a range of grass species, and (c) a relatively low digestibility native grassland pasture comprising mainly Molinia caerulea. Individual LW, feed dry matter intake (DMI), and CH4 emissions in chambers were measured. The linear functional relationship between DMI and CH4 emissions was positive (r = 0.77) with little breed effect. The relationships between LW and DMI, and LW and CH4 emissions were also positive but weaker, regardless of pasture type. It is concluded that change to LW was a poor indicator of DMI and has limited value in the prediction of enteric CH4 emissions from mature ewes. PMID- 26647755 TI - Should stimulation parameters be individualized to stop seizures: Evidence in support of this approach. AB - OBJECTIVE: Deep-brain electrical stimulation (DBS) is a treatment modality being explored for many neurologic diseases and is a potentially potent means of disrupting the aberrant rhythms that arise during the epileptic seizures that afflict >1% of the population. However, current DBS protocols typically employed are formulated a priori and do not reflect the electrophysiologic dynamics within the brain as seizures arise, which may underlie their limited efficacy. This study investigates how the efficacy of DBS could be improved using endogenous dynamics to inform stimulation protocols. METHODS: Multisite brain dynamics within the circuit of Papez were calculated in a chronic rat limbic epilepsy model induced via lithium chloride/pilocarpine intraperitoneal injections. Stimulation/recording electrodes were placed in the CA3 region of the left and right hippocampi and the anteromedial nucleus of the left thalamus. Deconvolution of local field potentials using empirical mode decomposition (EMD) and phase synchrony analysis revealed multisite coherence as seizures approached natural termination that could not be detected with Fourier analysis. Multisite stimulation used charge-neutral biphasic square waves at frequencies observed during natural termination. RESULTS: Synchronization of electrical activity across sites occurred as both spontaneous and evoked seizures naturally terminated. Furthermore, the location and frequency of the synchrony varied between subjects but was stable in time within each animal. DBS protocols were significantly more effective at rapidly stopping seizures when the frequency and location of multisite stimulation reflected the endogenous synchrony dynamics observed in each subject as seizures naturally terminated. SIGNIFICANCE: These results strongly support the approach of tailoring DBS protocols to individual endogenous rhythms that may represent how brains naturally resolve epileptic seizures. This approach may significantly improve the overall efficacy of this potentially important therapy. PMID- 26647756 TI - Sports-related eye and adnexal injuries in the Western Australian paediatric population. AB - PURPOSE: To identify the causes of sports-related eye and adnexal injuries in children in Perth, Western Australia, to determine which sporting activities pose the highest risk of eye and adnexal injury to children. METHODS: We performed a 12-year retrospective review of children admitted to hospital from 2002 to 2013 with sports-related ocular and adnexal eye injuries. The main outcome measures were the cause and type of ocular and adnexal injuries, age and gender risk factors. RESULTS: A total of 93 cases of sports-related ocular and adnexal injury were identified in the 12-year time period. A peak in injuries occurred for 12- to 14-year-olds with a second peak in 6- to 8-year-olds; the median age was 8.82 years (range = 1.59-16.47). Cycling, football (including soccer and Australian Rules Football), tennis, trampolining, fishing and swimming were the sports responsible for the greatest number of injuries, a total of 63%. More than one third (35%) of injuries resulted from being struck by a blunt object, and more than a quarter (26%) were as a result of contact with a blunt projectile. CONCLUSION: Serious ocular and adnexal injuries have occurred in children as a result of participating in sports, with cycling and football being the largest contributors in the 12-year period we assessed. As we continue to encourage children to spend more time participating in sports and recreational activities, identifying associated risk factors will help us develop injury prevention strategies to promote eye safety for children. PMID- 26647758 TI - A simple and fast method to study the hydrodynamic size difference of protein disulfide isomerase in oxidized and reduced form using gold nanoparticles and dynamic light scattering. AB - The hydrodynamic dimension of a protein is a reflection of both its molecular weight and its tertiary structures. Studying the hydrodynamic dimensions of proteins in solutions can help elucidate the structural properties of proteins. Here we report a simple and fast method to measure the hydrodyamic size of a relatively small protein, protein disulfide isomerase (PDI), using gold nanoparticle probes combined with dynamic light scattering. Proteins can readily adsorb to citrate-capped gold nanoparticles to form a protein corona. By measuring the average diameter of the gold nanoparticles before and after protein corona formation, the hydrodynamic diameter of the protein can be deduced from the net particle size increase of the assay solution. This study found that when the disulfide bonds in PDI are reduced to thiols, the reduced PDI exhibits a smaller hydrodynamic diameter than the oxided PDI. This finding is in good agreement with the X-ray diffraction analysis of PDI in single crystals. In comparison with other techniques that are used for protein hydrodynamic size analysis, the current method is easy to use, requires a trace amount of protein samples, with results obtained in minutes instead of hours. PMID- 26647757 TI - Valproate attenuates diabetic nephropathy through inhibition of endoplasmic reticulum stress-induced apoptosis. AB - Previous studies have suggested that endoplasmic reticulum stress (ERS) is one of the mechanisms responsible for the pathogenesis of diabetic nephropathy (DN). Histone acetylation modification can regulate the transcription of genes and is involved in the regulation of ERS. Valproate (VPA), a nonselective histone deacetylase inhibitor, has been reported to have a protective role in kidney tissue injury, however, whether VPA can prevent DN remains to be elucidated. In the present study, it was found that VPA increases the expression of glucose regulated protein (GRP78) and reduces the protein expression of C/EBP-homologous protein (CHOP), growth arrest and DNA-damage-inducible gene 153 and caspase-12 in a rat model of DN. VPA can reduce renal cell apoptosis and alleviate proteinuria and alterations in serum creatinine. VPA also upregulates the acetylation level of histone H4 in the promoter of GRP78 and downregulates the acetylation level of histone H4 in the promoter of CHOP. Collectively, the data indicate that VPA can relieve ERS and reduce renal cell apoptosis, and thus attenuate renal injury in a rat model of DN by regulating the acetylation level of histone H4 in ERS associated protein promoters. PMID- 26647759 TI - Dynamic regulation of effector IFN-gamma-producing and IL-17-producing T cell subsets in the development of acute graft-versus-host disease. AB - Graft-versus-host disease (GVHD) as the predominant complication of allogeneic hematopoietic stem cell transplantation remains to be fully understood. It is known that the cytokines produced by allogeneic reactive effector CD4+ and CD8+ T cells are involved in GVHD. However, the regulation and coordination of IFN-gamma producing and IL-17-producing effector T cells remain unclear. The present study aimed to investigate the dynamic changes of alloantigen-specific effector CD4+ T and CD8+ T cell subsets by flow cytometry, which produce inflammatory cytokines involved in the multistep GVHD pathogenesis progress. The results demonstrated that IL-17-producing CD8+ T (Tc17) cells and IFN-gamma+CD8+ T (Tc1) cells were detected in the early stage of GVHD. The differentiation of CD4+ T cells into Th1 cell (IFN-gamma+CD4+ T) and Th17 (IL-17+CD4+ T) cells was later than that of the Tc1 and Tc17 cells. The effector CD4+ T and CD8+ T cell subsets either became exhausted or became memory cells, exhibiting a CD62L-CD44+ phenotype following marked expansion during GVHD. Furthermore, T cell-associated type I (IL-2 and IFN gamma) and type II (IL-4 and IL-10) classical cytokines exhibited coordinated dynamic regulation. It was concluded that the differentiation of cytokine producing Tc1 and Tc17 cells may be the key step in the initiation of GVHD, whereas CD4+ effector Th1 and Th17 cells are considered to be pathophysiological factors leading to the continuous aggravation of GVHD. PMID- 26647760 TI - Cyclic stretch enhances bone morphogenetic protein-2-induced osteoblastic differentiation through the inhibition of Hey1. AB - Substantial evidence has indicated that osteoblastic differentiation may be regulated by mechanical loads or bone morphogenetic protein-2 (BMP-2). BMP-2 induced in vivo osteogenesis can be significantly enhanced in the presence of mechanical stimuli, revealing the therapeutic potential of the combined application of BMP-2 and mechanical loads in clinical bone diseases (e.g., bone fractures and osteoporosis); however, the underlying mechanisms remain elusive. In this study, we found that cyclic stretch or BMP-2 alone increased the expression of osteoblastic differentiation markers, including alkaline phosphatase (ALP) and runt-related transcription factor 2 (Runx2), as shown by RT qPCR, western blot analysis and ALP activity test. Furthermore, our results revealed that cyclic mechanical stretch with 10% elongation at 0.1 Hz significantly enhanced the BMP-2-induced upregulation of ALP and Runx2 expression in osteoblast-like MC3T3-E1 cells. Cyclic stretch also inhibited the BMP-2 induced upregulation of Hes-related family bHLH transcription factor with YRPW motif 1 (Hey1, measured by RT-qPCR and immunofluorescence staining), a potent negative regulator of osteogenesis. Moreover, the transient transfection of a Hey1 expression plasmid (pcDNA3.1-Hey1) significantly reversed the effects of cyclic stretch on the BMP-2-induced upregulation of differentiation markers in the MC3T3-E1 cells. This revealed the importance of Hey1 in modulating BMP-2 induced osteoblastic differentiation in response to cyclic stretch. Taken together, our results demonstrated that cyclic stretch enhanced the BMP-2-induced osteoblastic differentiation through the inhibition of Hey1. The present study broadens our fundamental knowledge of osteoblastic mechanotransduction and also sheds new insight into the mechanisms through which the combined application of BMP-2 and mechanical load promotes osteogenesis. PMID- 26647761 TI - Molecular epidemiology of enteric viruses in patients with acute gastroenteritis in Aichi prefecture, Japan, 2008/09-2013/14. AB - Acute gastroenteritis is a critical infectious disease that affects infants and young children throughout the world, including Japan. This retrospective study was conducted from September 2008 to August 2014 (six seasons: 2008/09-2013/14) to investigate the incidence of enteric viruses responsible for 1,871 cases of acute gastroenteritis in Aichi prefecture, Japan. Of the 1,871 cases, 1,100 enteric viruses were detected in 978 samples, of which strains from norovirus (NoV) genogroup II (60.9%) were the most commonly detected, followed by strains of rotavirus A (RVA) (23.2%), adenovirus (AdV) type 41 (8.2%), sapovirus (SaV) (3.6%), human astrovirus (HAstV) (2.8%), and NoV genogroup I (1.3%). Sequencing of the NoV genogroup II (GII) strains revealed that GII.4 was the most common genotype, although four different GII.4 variants were also identified. The most common G-genotype of RVA was G1 (63.9%), followed by G3 (27.1%), G2 (4.7%) and G9 (4.3%). Three genogroups of SaV strains were found: GI (80.0%), GII (15.0%), and GV (5.0%). HAstV strains were genotyped as HAstV-1 (80.6%), HAstV-8 (16.1%), and HAstV-3 (3.2%). These results show that NoV GII was the leading cause of sporadic acute viral gastroenteritis, although a variety of enteric viruses were detected during the six-season surveillance period. PMID- 26647762 TI - Expression of arginase I and inducible nitric oxide synthase in the peripheral blood and lymph nodes of HIV-positive patients. AB - Arginase I (Arg I) and inducible nitric oxide synthase (iNOS) are important in regulating immune functions through their metabolites. Previous studies have revealed that the expression of Arg I is increased and the expression of iNOS is reduced in the serum and peripheral blood mononuclear cells of human immunodeficiency virus (HIV)-infected patients. As one of the most important immune organs and HIV replication sites, whether similar changes are present in the lymph nodes following HIV infection remains to be elucidated. To investigate this, the present study collected lymph node and blood specimens from 52 HIV infected patients to measure the expression levels of Arg I and iNOS by immunohistochemistry and fluoresence-based flow cytometry. Compared with control subjects without HIV infection, the patients with HIV had significantly higher expression levels of Arg I in the lymph nodes and higher frequencies of Arg I+ CD4+ T cells and CD8+ T cells in the blood and lymph nodes, and these results were contrary the those of iNOS in the corresponding compartments. The expression levels of Arg I in the lymph nodes and blood were negatively associated with peripheral CD4+ T cell count and positively associated with viral load. However, the expression levels of iNOS in the lymph nodes and blood were positively associated with peripheral CD4+ T cell count and negatively associated with viral load. These results showed that alterations in the expression levels of Arg I and iNOS in the peripheral T cells and peripheral nodes of HIV infected patients are associated with disease progression in these patients. These results indicate a potential to therapeutic strategy for delaying disease progression through regulating and manipulating the expression levels of Arg I and iNOS in patients infected with HIV. PMID- 26647763 TI - Peroxiredoxin 6 attenuates ischemia- and hypoxia-induced liver damage of brain dead donors. AB - Oxidative stress induced by ischemia and hypoxia in the livers of donors after brain death (DBD) is associated with poor organ function and low patient survival rates in those receiving DBD liver transplants. Peroxiredoxin 6 (Prdx6) can defend cells against liver damage induced by oxidative stress. The present study aimed to investigate the role of Prdx6 in ischemia- and hypoxia-induced liver damage in DBD livers. Liver tissue samples from ten DBD patients were collected. The control group constituted of six liver samples from patients with liver hemangioma that had accepted tumor excision surgery. Protein expression levels were determined by western blotting, cell viability was assessed using a CCK-8 assay, intracellular reactive oxygen species (ROS) levels were measured using a ROS assay kit, and phospholipase A2 (PLA2) activity was measured using a PLA2 assay kit. In DBD liver samples, Prdx6 expression was downregulated and the nuclear factor-kappaB (NF-kappaB) signaling pathway was activated. Furthermore, when human liver L02 cells were exposed to ischemia and hypoxia, the expression of Prdx6 was reduced, causing an increase in reactive oxygen species (ROS); this in turn activated NF-kappaB signaling and lowered cell viability (P<0.01). In agreement, overexpression of Prdx6 reduced ROS levels and improved cell viability. It was also demonstrated that inhibition of NF-kappaB increased Prdx6 expression, while inhibition of Prdx6 limited PLA2 activity, exacerbating ischemia- and hypoxia-induced cell damage. This data suggests that Prdx6 and its PLA2 activity have a protective role in DBD livers, the expression of which is regulated by NF-kappaB. Thus, Prdx6 may be a novel target to alleviate liver damage in DBD. PMID- 26647764 TI - (1) H-NMR relaxometric studies of interaction between apoptosis specific MRI paramagnetic contrast agents and micellar models of apoptotic cells. AB - (1) H-NMR was previously used to analyze the interaction between peptides (E3 and R826) selected by phage display to target apoptotic cells and phospholipidic models of these cells. In order to avoid the use of apoptotic cells and to obtain a fast evaluation of the efficiency of the potential MRI contrast agents obtained by grafting these peptides and their scramble analogs on a paramagnetic gadolinium complex, their proton relaxometric behavior was investigated in the presence of micelles mimicking healthy and apoptotic cells. Their preferential interaction with 1,2-dipalmitoyl-sn-glycero-3-phospho-l-serine micelles mimicking apoptotic cells as compared with 1,2-dipalmitoyl-sn-glycero-3-phosphocholine micelles modeling healthy cells was shown by nuclear magnetic relaxation dispersion profiles and the enhancement of the transverse proton relaxation rates at 60 MHz. The association constant values confirm the stronger interaction of the selected conjugated peptides (Ka Gd-PMN-E3(gadolinium 2,2',2'',2'''-[((4 carboxy)pyridine-2,6-diyl)bis(methylenenitrilo)]-tetrakis acetate) grafted with E3 peptide): 2.43 10(4) m(-1) ; Ka Gd-DTPA-R826(gadolinium ((1-p isothiocyanatobenzyl)-diethylenetriaminepentaacetate) grafted with R826 peptide): 2.91 10(4) m(-1) ) as compared with their conjugated scrambles (Ka Gd-PMN E3sc(gadolinium 2,2',2'',2'''-[((4-carboxy)pyridine-2,6 diyl)bis(methylenenitrilo)]-tetrakis acetate) grafted with E3 scramble peptide): 0.18 10(4) m(-1) ; Ka Gd-DTPA-R826sc(gadolinium ((1-p-isothiocyanatobenzyl) diethylenetriaminepentaacetate) grafted with R826 scramble peptide): 0.32 10(4) m(-1) ) even if the conjugation of E3 and R826 seems to decrease their interaction. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26647765 TI - (68) Ga-labeled Ciprofloxacin Conjugates as Radiotracers for Targeting Bacterial Infection. AB - With an aim of developing a bacteria-specific molecular imaging agent, ciprofloxacin has been modified with a propylamine spacer and linked to two common bifunctional chelators, p-SCN-Bz-DOTA and p-SCN-Bz-NOTA. The two ciprofloxacin conjugates, CP-PA-SCN-Bz-DOTA (1) and CP-PA-SCN-Bz-NOTA (2), were radiolabeled with (68)Ga in >90% radiochemical yield and were moderately stable in vitro for 4 h. The efficacy of (68)Ga-1 and (68)Ga-2 has been investigated in vitro in Staphylococcus aureus cells where bacterial binding of the radiotracers (0.9-1.0% for (68)Ga-1 and 1.6-2.3% for (68)Ga-2) could not be blocked in the presence of excess amount of unlabeled ciprofloxacin. However, uptake of radiotracers in live bacterial cells was significantly higher (p < 0.01) than that in non-viable bacterial cells. Bacterial infection targeting efficacy of (68)Ga-1 and (68)Ga-2 was tested in vivo in rats where the infected muscle-to inflamed muscle ((68)Ga-1: 2 +/- 0.2, (68)Ga-2: 3 +/- 0.5) and infected muscle-to normal muscle ratios ((68)Ga-1: 3 +/- 0.4, (68)Ga-2: 6.6 +/- 0.8) were found to improve at 120 min p.i. Fast blood clearance and renal excretion was observed for both the radiotracers. The two (68)Ga-labeled infection targeting radiotracers could discriminate between bacterial infection and inflammation in vivo and are worthy of further detailed investigation as infection imaging agents at the clinical level. PMID- 26647766 TI - (Cost-)effectiveness of self-treatment of exacerbations in patients with COPD: 2 years follow-up of a RCT. AB - BACKGROUND AND OBJECTIVE: Long-term effectiveness of action plans in patients with chronic obstructive pulmonary disease (COPD) is minimally investigated. We have evaluated the (cost-)effectiveness of a self-management programme with or without self-treatment of exacerbations after 2 years follow-up. METHODS: Self management with or without self-treatment of exacerbations was randomly assigned to patients. All patients participated in four self-management meetings. Patients in the self-treatment group (STG) also learned to use an action plan to start a course of prednisolone and/or antibiotics in case of worsening of symptoms. Primary outcome was the duration and severity of exacerbations. RESULTS: Data of 70 COPD patients in the STG and 72 patients in the control group (CG) were analysed. Over 2 years, the median number of exacerbation days was significantly lower in the STG (50, IQR: 32-115) compared with the CG (82, IQR: 22-186) (P = 0.047), as was the mean symptom score of an exacerbation (STG: 43.4, IQR 27.2 68.6 vs CG: 55.9, IQR: 31.2-96.8) (P = 0.029). Also, patients in the STG visited the respiratory physician and emergency department less frequently than patients in the CG with incidence rate ratios of 1.52 (95% CI: 1.28-1.79) and 2.27 (95% CI: 1.11-4.62), respectively. Direct medical costs per patient over 2 years were ?1078 lower in the STG. CONCLUSION: Self-treatment of exacerbations is beneficial in COPD patients without significant comorbidities because it reduces exacerbation duration, exacerbation severity and health-care utilization leading to considerable cost savings. PMID- 26647767 TI - ALK, ROS1 and NTRK3 gene rearrangements in inflammatory myofibroblastic tumours. AB - AIMS: The aim of this study was to elucidate the pathological features of inflammatory myofibroblastic tumour (IMT) with gene rearrangement other than ALK. METHODS AND RESULTS: We investigated anaplastic lymphoma kinase (ALK), ROS1, ETV6, NTRK3 and RET in 36 cases of IMT by using immunohistochemical (IHC) staining, fluorescence in-situ hybridization, and reverse transcription polymerase chain reaction (RT-PCR). IHC staining showed ALK and ROS1 to be positive in 22 of 36 (61.1%) and two of 36 (5.6%) cases, respectively. In one case with ROS1 positivity, IHC staining showed cytoplasmic and dot-like ROS1 expression, and RT-PCR showed the presence of the TFG-ROS1 fusion transcript. Two cases of pulmonary IMT, in a 7-year-old patient and a 23-year-old patient, had ETV6 rearrangement, and the presence of the ETV6-NTRK3 fusion transcript was confirmed in one case. These tumours were composed of hypocellular myxoid areas and highly cellular areas with rich plasmacytic infiltration; the histological features were different from those of infantile fibrosarcoma. RET rearrangement was not detected. CONCLUSIONS: These results suggest that a subset of ALK negative IMTs have rearrangement of ROS1, ETV6 or NTRK3 as a possible oncogenic mechanism, and that the detection of these alterations may be of diagnostic value and helpful for determining promising therapeutic strategies. PMID- 26647768 TI - Heterophyllin B inhibits the adhesion and invasion of ECA-109 human esophageal carcinoma cells by targeting PI3K/AKT/beta-catenin signaling. AB - The present study aimed to measure the effect of heterophyllin B (HB) on the adhesion and invasion of ECA-109 human esophageal carcinoma cells, and examine the possible mechanism involved. A Cell Counting kit 8 assay was performed to determine the cell viability. Cell adhesion and invasion were determined following treatment of the ECA-109 cells with HB (0, 10, 25 and 50 uM) for 24 h. The levels of phosphorylated (p-)ATK and p-phosphoinositide 3-kinase (PI3K), and the protein levels of beta-catenin were measured using western blot analysis. The mRNA and protein expression levels of E-cadherin, vimentin, snail, matrix metalloproteinase (MMP)2 and MMP9 were detected using reverse transcription quantitative polymerase chain reaction and western blot analyses, respectively. HB (10, 25 and 50 uM) significantly suppressed the adhesion and invasion of the ECA-109 human esophageal carcinoma cells in a dose-dependant manner. The expression levels of p-ATK, p-PI3K and beta-catenin were markedly decreased. The expression of E-cadherin was promoted, whereas the expression levels of snail, vimentin, MMP 2 and MMP 9 were decreased significantly in the ECA-109 cells treated with HB. In addition, HB inhibited the adhesion and invasion induced by PI3K activating peptide in the ECA-109 cells, and the protein expression levels were also adjusted. These results suggested that HB effectively suppressed the adhesion and invasion of the human esophageal carcinoma cells by mediating the PI3K/AKT/beta-catenin pathways and regulating the expression levels of adhesion- and invasion-associated genes. PMID- 26647769 TI - Effect of Sleep Extension on the Subsequent Testosterone, Cortisol and Prolactin Responses to Total Sleep Deprivation and Recovery. AB - Total sleep deprivation (TSD) in humans is associated with altered hormonal levels, which may have clinical relevance. Less is known about the effect of an extended sleep period before TSD on these hormonal changes. Fourteen subjects participated in two experimental counterbalanced conditions (randomised cross over design): extended sleep (21.00-07.00 h time in bed, EXT) and habitual sleep (22.30-07.00 h time in bed, HAB). For each condition, subjects performed two consecutive phases: six nights of either EXT or HAB. These nights were followed by 3 days in the sleep laboratory with blood sampling at 07.00 and 17.00 h at baseline (B-07.00 and B-17.00), after 24 and 34 h of continuous awakening (24 h CA, 34 h-CA) and after one night of recovery sleep (R-07.00 and R-17.00) to assess testosterone, cortisol, prolactin and catecholamines concentrations. At 24 h of awakening, testosterone, cortisol and prolactin concentrations were significantly lower compared to B-07.00 and recovered basal levels after recovery sleep at R-07.00 (P < 0.001 for all). However, no change was observed at 34 h of awakening compared to B-17.00. No effect of sleep extension was observed on testosterone, cortisol and catecholamines concentrations at 24 and 34 h of awakening. However, prolactin concentration was significantly lower in EXT at B 07.00 and R-07.00 compared to HAB (P < 0.05, P < 0.001, respectively). In conclusion, 24 h of awakening inhibited gonadal and adrenal responses in healthy young subjects and this was not observed at 34 h of awakening. Six nights of sleep extension is not sufficient to limit decreased concentrations of testosterone and cortisol at 24 h of awakening but may have an impact on prolactin concentration. PMID- 26647770 TI - Forged Under the Sun: Life and Art of Extremophiles from Andean Lakes. AB - High-altitude Andean lakes (HAAL) are a treasure chest for microbiological research in South America. Their indigenous microbial communities are exposed to extremely high UV irradiation and to multiple chemical extremes (Arsenic, high salt content, alkalinity). Microbes are found both, free-living or associated into microbial mats with different degrees of mineralization and lithification, including unique modern stromatolites located at 3570 m above sea level. Characterization of these polyextremophilic microbes began only recently, employing morphological and phylogenetic methods as well as high-throughput sequencing and proteomics approach. Aside from providing a general overview on microbial communities, special attention is given to various survival strategies; HAAL's microbes present a complex system of shared genetic and physiological mechanisms (UV-resistome) based on UV photoreceptors and stress sensors with their corresponding response regulators, UV avoidance and protection strategies, damage tolerance and UV damage repair. Molecular information will be provided for what is, so far the most studied HAAL molecule, a CPD-Class I photolyase from Acinetobacter Ver3 (Laguna Verde, 4400 m). This work further proposes some strategies that make an appeal for the preservation of HAAL, a highly fragile environment that offers promising and ample research possibilities. PMID- 26647772 TI - Broad self-trapped and slow light bands based on negative refraction and interference of magnetic coupled modes. AB - We propose a new mechanism to achieve light localization and slow light. Through the study on the coupling of two magnetic surface modes, we find a special convex band that takes on a negative refraction effect. The negative refraction results in an energy flow concellation effect from two degenerated modes on the convex band. The energy flow concellation effect leads to forming of the self-trapped and slow light bands. In the self-trapped band light is localized around the source without reflection wall in the waveguide direction, whereas in the slow light band, light becomes the standing-waves and moving standing-waves at the center and the two sides of the waveguide, respectively. PMID- 26647771 TI - SIRT2 mediates multidrug resistance in acute myelogenous leukemia cells via ERK1/2 signaling pathway. AB - SIRT2, one of nicotinamide adenine dinucleotide (NAD+)-dependent class III histone deacetylase family proteins, has been found to be involved in the proliferation and survival of acute myeloid leukemia (AML) cells. However, its effect on drug resistance on chemoresistant AML cells is unclear. In the present study, we first found that SIRT2 was expressed at higher level in the relapsed AML patients than the newly diagnosed patients. Consistent with this observation, the expression level of SIRT2 was higher in HL60/A cells than that in HL60 cells. Depletion of SIRT2 by shRNAs in HL60/A cells resulted in decreased MRP1 level, enhanced drug accumulation and triggered more apoptosis. By contrast, overexpression of SIRT2 in HL60 cells led to increased MRP1 level, drug efflux and attenuated drug sensitivity. Moreover, the decreased expression of phosphorylated ERK1/2 was detected in SIRT2-depleted HL60/A cells and increased expression of phosphorylated ERK1/2 was observed in SIRT2 overexpressed HL60 cells. Furthermore, blockage of ERK1/2 signaling pathway with the chemical inhibitor PD98059, further induced apoptosis of HL60/A cells conferred by SIRT2 depletion. Importantly, ERK1/2 inhibition was able to reverse the drug resistance of HL60 conferred by SIRT2 overexpression. Thus, our findings collectively suggested that the expression level of SIRT2 has a positive relationship with DNR/Ara-C resistance and activity of ERK1/2 signaling pathway. SIRT2 might regulate DNR/Ara-C sensitivity in AML cells at least partially through the ERK1/2 pathway. PMID- 26647774 TI - Mechanical Robust and Self-Healable Supramolecular Hydrogel. AB - Development of self-healing polymers with spontaneous self-healing capability and good mechanical performance is highly desired and remains a great challenge. Here, mechanical robust and self-healable supramolecular hydrogels have been fabricated by using poly(2-dimethylaminoethyl methacrylate) brushes modified silica nanoparticles (SiO2 @PDMAEMA) as multifunctional macrocrosslinkers in a poly(acrylic acid) (PAA) network structure. The SiO2 nanoparticles serve as noncovalent crosslinkers, dissipating energy, whereas the electrostatic interactions between cationic PDMAEMA and anionic PAA render the hydrogel self healing property. This process provides a simple and broadly applicable strategy to produce mechanical strong and self-healable materials. PMID- 26647773 TI - Growth differentiation factor 15 may protect the myocardium from no-reflow by inhibiting the inflammatory-like response that predominantly involves neutrophil infiltration. AB - The aim of the current study was to investigate the time course of the expression of growth differentiation factor-15 (GDF-15) in rat ischemic myocardium with increasing durations of reperfusion, and to elucidate its physiopathological role in the no-reflow phenomenon. Wistar rats were randomly divided into ischemia reperfusion (I/R) and sham groups, and myocardial I/R was established by ligation of the left anterior descending coronary artery for 1 h followed by reperfusion for 2, 4, 6, 12, 24 h and 7 days whilst rats in the sham group were subjected to a sham operation. The expression levels of GDF-15 and ICAM-1 were measured, in addition to myeloperoxidase (MPO) activity. The myocardial anatomical no-reflow and infarction areas were assessed. The area at risk was not significantly different following various periods of reperfusion, while the infarct area and no reflow area were significantly greater following 6 h of reperfusion (P<0.05). The mRNA and protein expression levels of GDF-15 were increased during the onset and development of no-reflow, and peaked following 24 h of reperfusion. MPO activity was reduced with increasing reperfusion duration, while ICAM-1 levels were increased. Hematoxylin and eosin staining demonstrated that myocardial neutrophil infiltration was significantly increased by I/R injury, in particular following 2, 4 and 6 h of reperfusion. GDF-15 expression levels were negatively correlated with MPO activity (r=-0.55, P<0.001), and the MPO activity was negatively correlated with the area of no-reflow (r=-0.46, P<0.01). By contrast, GDF-15 was significantly positively correlated with ICAM-1 levels (r=0.52, P<0.01), which additionally were demonstrated to be significantly positively associated with the size of the no-reflow area (r=0.39, P<0.05). The current study demonstrated the time course effect of reperfusion on the expression of GDF-15 in the myocardial I/R rat model, with the shorter reperfusion times (6 h) resulting in significant no-reflow in ischemic myocardium. GDF-15 may protect the I/R myocardium from no reflow by inhibiting the inflammatory-like response, which involves neutrophil infiltration and transendothelial migration. PMID- 26647775 TI - Influence of an oxygen-inhibited layer on enamel bonding of dental adhesive systems: surface free-energy perspectives. AB - The influence of an oxygen-inhibited layer (OIL) on the shear bond strength (SBS) to enamel and surface free-energy (SFE) of adhesive systems was investigated. The adhesive systems tested were Scotchbond Multipurpose (SM), Clearfil SE Bond (CS), and Scotchbond Universal (SU). Resin composite was bonded to bovine enamel surfaces to determine the SBS, with and without an OIL, of adhesives. The SFE of cured adhesives with and without an OIL were determined by measuring the contact angles of three test liquids. There were no significant differences in the mean SBS of SM and CS specimens with or without an OIL; however, the mean SBS of SU specimens with an OIL was significantly higher than that of SU specimens without an OIL. For all three systems, the mean total SFE (gammaS), polarity force (gammaSp), and hydrogen bonding force (gammaSh) values of cured adhesives with an OIL were significantly higher than those of cured adhesives without an OIL. The results of this study indicate that the presence of an OIL promotes higher SBS of a single-step self-etch adhesive system, but not of a three-step or a two-step self-etch primer system. The SFE values of cured adhesives with an OIL were significantly higher than those without an OIL. The SFE characteristics of the OIL of adhesives differed depending on the type of adhesive. PMID- 26647776 TI - Lefty1 alleviates renal tubulointerstitial injury in mice with unilateral ureteral obstruction. AB - Lefty is a member of the transforming growth factor (TGF) beta superfamily, which is implicated in left-right patterning during embryogenesis. Previous studies revealed that lefty attenuates the epithelial-mesenchymal transition in tubular epithelial cells. In the present study, the protective effect of lefty1 on renal interstitial injury was further assessed. Mice with a unilateral ureteral obstruction (UUO) were sacrificed on days 3, 5 and 7 following surgery, and the association between the expression of lefty1 and the degree of interstitial fibrosis was investigated. Subsequently, mice with a UUO were administered recombinant lefty1 (300 ug/kg body weight) or vehicle (0.9% saline solution; 100 ul) through tail-vein injection every other day for 6 days. The effects of lefty1 were assessed by measuring the degree of tubulointerstitial fibrosis, tubular injury and atrophy, and also by monitoring the expression levels of alpha-smooth muscle actin (alpha-SMA), TGF-beta1, phosphorylated (p)-Smad2/3, kidney injury molecular-1 and endogenous lefty1. The expression of lefty1 in the kidney decreased in a time-dependent manner in mice with a UUO, which was inversely correlated with the degree of renal interstitial fibrosis. Furthermore, compared with vehicle treatment, lefty1 attenuated renal interstitial fibrosis. Ureteral ligation induced increased expression levels of alpha-SMA, TGF-beta1 and p Smad2/3. However, these effects were reduced following treatment with lefty1. The UUO also induced tubular injury and atrophy, whereas lefty1 treatment exerted a marked suppressive effect on tubular injury. In addition, exogenous lefty1 administered to mice restored the endogenous expression levels of lefty1. The present study demonstrated that lefty1 attenuated renal interstitial injury by inhibiting the Smad-dependent TGF-beta1 signaling pathway. Lefty1 may therefore by a putative therapeutic agent in the treatment of renal injury. PMID- 26647777 TI - Diallyl trisulfide induces apoptosis by suppressing NF-kappaB signaling through destabilization of TRAF6 in primary effusion lymphoma. AB - The allyl sulfides, including diallyl sulfide (DAS), diallyl disulfide (DAD), and diallyl trisulfide (DAT), contained in garlic and members of the Allium family, have a variety of pharmacological activities. Therefore, allyl sulfides have been evaluated as potential novel chemotherapeutic agents. Here, we found that DAT inhibited nuclear factor-kappaB (NF-kappaB) signaling and induced apoptosis in primary effusion lymphoma (PEL), a subtype of non-Hodgkin's B-cell lymphoma caused by Kaposi's sarcoma-associated herpesvirus (KSHV). We examined the cytotoxic effects of DAS, DAD and DAT on PEL cells. DAT significantly reduced the viability of PEL cells compared with uninfected B-lymphoma cells, and induced the apoptosis of PEL cells by activating caspase-9. DAT induced stabilization of IkappaBalpha, and suppressed NF-kappaB transcriptional activity in PEL cells. We examined the mechanism underlying DAT-mediated IkappaBalpha stabilization. The results indicated that DAT stabilized IkappaBalpha by inhibiting the phosphorylation of IkappaBalpha by the IkappaB kinase (IKK) complex. Furthermore, DAT induced proteasomal degradation of TRAF6, and DAT suppressed IKKbeta phosphorylation through downregulation of TRAF6. It is known that activation of NF-kappaB is essential for survival of PEL cells. In fact, the NF-kappaB inhibitor BAY11-7082 induced apoptosis in PEL cells. In addition, DAT suppressed the production of progeny virus from PEL cells. The administration of DAT suppressed the development of PEL cells and ascites in SCID mice xenografted with PEL cells. These findings provide evidence that DAT has antitumor activity against PEL cells in vitro and in vivo, suggesting it to be a novel therapeutic agent for the treatment of PEL. PMID- 26647778 TI - TGF-beta2 induces epithelial-mesenchymal transition in cultured human lens epithelial cells through activation of the PI3K/Akt/mTOR signaling pathway. AB - The present study aimed to investigate whether the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway is involved in the transforming growth factor beta2 (TGF-beta2)-induced epithelial-mesenchymal transition (EMT) in human lens epithelial (HLE) cells. HLEB-3 cells were cultured and stimulated with 10 ng/ml TGF-beta2 for 24 h. Western blotting was then performed to analyze the expression levels of connexin 43 and fibronectin, and the activities of Akt and mTOR. Confocal cell immunofluorescence was used to observe the expression of phosphorylated (p)-Akt. The toxicity of 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002) was assessed using a Cell Counting Kit-8 assay, and inhibition investigations were performed using a PI3K inhibitor. The expression of connexin 43 was suppressed and the expression of fibronectin was increased when the cells were stimulated with 10 ng/ml TGF-beta2 for 24 h. In addition, Akt and mTOR were activated during TGF-beta2-induced EMT. Treatment of with LY294002 (20 uM) inhibited the activation of Akt and mTOR and effectively prevented TGF-beta2-induced EMT in the HLECs. Therefore, the results of the present study indicated that TGF-beta2 induces EMT by activating the PI3K/Akt/mTOR signaling pathway in cultured HLECs. PMID- 26647779 TI - Reduction-Sensitive Polymeric Micelles Based on Docetaxel-Polymer Conjugates Via Disulfide Linker for Efficient Cancer Therapy. AB - In this article, the low-molecular weight biodegradable methoxy poly (ethylene glycol)-poly (D,L-lactide-co-glycolide) (PP) is chosen as polymeric skeleton to be conjugated with docetaxel (DTX) by disulfide bond (PP-SS-DTX) to construct the reduction-sensitive drug delivery system. The conjugates are synthesized via three steps and are further employed to physically load free DTX to develop the PP-SS-DTX/DTX micelles which exhibit many merits including high drug loading content, good stability, and stimuli-sensitive release of drugs. The hydrodynamic diameter of PP-SS-DTX/DTX micelles determined by DLS is 112.3 nm. The hemolysis assay reveals the good blood compatibility of PP-SS-DTX/DTX micelles. In order to investigate the reductive sensitivity of PP-SS-DTX/DTX micelles, dithiothreitol (DTT) is added into the release medium and a programmed drug release mode is observed in the conjugated micelles. In vitro cytotoxity assay shows that the PP SS-DTX/DTX micelles are more cytotoxic than that of free DTX solution for both MCF-7 and B16F10 cancer cells. In addition, the PP-SS-DTX/DTX micelles also show a higher cellular uptake rate than that of free DTX. Hence, the prepared reduction-sensitive PP-SS-DTX/DTX micelles are effective on inhibiting cancer cells compared with the free DTX which would be a promising carrier in cancer therapy. PMID- 26647780 TI - Energetics of Endotoxin Recognition in the Toll-Like Receptor 4 Innate Immune Response. AB - Bacterial outer membrane lipopolysaccharide (LPS) potently stimulates the mammalian innate immune system, and can lead to sepsis, the primary cause of death from infections. LPS is sensed by Toll-like receptor 4 (TLR4) in complex with its lipid-binding coreceptor MD-2, but subtle structural variations in LPS can profoundly modulate the response. To better understand the mechanism of LPS induced stimulation and bacterial evasion, we have calculated the binding affinity to MD-2 of agonistic and antagonistic LPS variants including lipid A, lipid IVa, and synthetic antagonist Eritoran, and provide evidence that the coreceptor is a molecular switch that undergoes ligand-induced conformational changes to appropriately activate or inhibit the receptor complex. The plasticity of the coreceptor binding cavity is shown to be essential for distinguishing between ligands, whilst similar calculations for a model bacterial LPS bilayer reveal the "membrane-like" nature of the protein cavity. The ability to predict the activity of LPS variants should facilitate the rational design of TLR4 therapeutics. PMID- 26647781 TI - Sodium orthovanadate induces the apoptosis of SH-SY5Y cells by inhibiting PIWIL2. AB - PIWIs have been shown to be abnormally expressed in a variety of cancers and may be important in the maintenance and invasion of cancer cells. The high expression of PIWIL2 contributed to the resistance effect of cisplatin in colon cancer cells, and the knockout of the PIWIL2 gene reduced the aggressive nature and malignant degree of colon cancer cells. Sodium orthovanadate (SOV) is a vanadium compound, and exhibited antineoplastic activity in certain types of human cancer cells, including lung, kidney and prostate cancer cells. However, its effects in human neuroblastoma (NB) cells have not yet been reported. The objective of this study was to investigate the effect of SOV on the apoptosis of NB cells and to explore how PIWIL2 is involved in the mechanism underlying this effect. In the present study, SH-SY5Y cells were treated with SOV and the optimal concentration was determined for further assays. Cell apoptosis, cell count, viability, the cell cycle, and the expression of PIWIL2 mRNA and protein were then determined. The results showed that SOV could induce cell apoptosis, reduce the percentage of viable cells, induce accumulation of SH-SY5Y cells at the G2/M and S phase of the cell cycle, and inhibit the expression of PIWIL2 and Bcl-2 mRNA and protein. The results suggested that the underlying mechanisms may be, at least in part, due to SOV inhibiting the expression of PIWIL2. These findings demonstrated the effect of SOV and supported its further evaluation as a treatment for human NB. PMID- 26647782 TI - Critical Challenges in Making Health Services Research Relevant to Decision Makers. PMID- 26647783 TI - Atrial Fibrillation in Eight New World Camelids. AB - BACKGROUND: There is limited information on the incidence of clinical signs, concurrent illness and treatment options for atrial fibrillation (AF) in New World Camelids (NWC). OBJECTIVE: Describe clinical signs and outcome of AF in NWC. ANIMALS: Eight New World Camelids admitted with AF. METHODS: A retrospective observational study of camelids diagnosed with AF based on characteristic findings on electrocardiogram (ECG). RESULTS: All animals had an irregularly irregular heart rhythm detected on physical examination and 4 cases had obtunded mentation on admission. Three camelids were diagnosed with AF secondary to oleander intoxication, 3 animals had underlying cardiovascular disease, 1 was diagnosed with lone AF and 1 had AF diagnosed on examination for a urethral obstruction. Five of eight animals survived to discharge and nonsurvivors consisted of animals which died or were euthanized as a result of cardiovascular disease (2/8) or extra-cardiac disease unrelated to the AF (1/8). CONCLUSIONS AND CLINICAL IMPORTANCE: Atrial fibrillation occurs in NWC in association with cardiovascular disease, extra-cardiac disease or as lone AF. Amiodarone and transthoracic cardioversion were attempted in one llama with lone AF, but were unsuccessful. Atrial fibrillation was recorded in 0.1% of admissions. PMID- 26647784 TI - Social Inequality and Substance Use and Problematic Gambling Among Adolescents and Young Adults: A Review of Epidemiological Surveys in Germany. AB - The current review provides an overview of socioepidemiological research in Germany about the prevalence of addictive behaviours (smoking, binge and hazardous drinking, consumption of cannabis and other illegal drugs, the non medical use of prescription drugs and problematic gambling) among adolescents (11 17 years) and young adults (18-25 years), also differentiating between different socioeconomic status (SES) indicators (attended school type, family affluence, parental occupational status, parental SES, employment status) and migration background. The authors evaluated data from ten national surveys and one regional survey conducted between 2002 and 2012, which included different samples. The trends over this time frame reveal that the proportion of adolescents who smoke tobacco, show problematic patterns of alcohol consumption, use cannabis or other illegal drugs has generally declined over the investigated time span in Germany. The results nevertheless suggest that some strong associations still exist between social inequalities and the prevalence of substance use. The detailed results are summarised in twelve tables. The main results are as follows: 1) Low SES (school type, employment status) was consistently associated with more cigarette smoking, and, where such data was available, this pattern was observed in both males and females. 2) With regard to family affluence, two surveys show that boys with low and middle FAS are significantly less likely to have binge drinking experience compared to boys with high FAS. There were no significant associations between problematic alcohol use and parental SES, and not all results of the surveys show that binge drinking is more prevalent among HS students. Employment status was associated with gender differences; problematic patterns of alcohol consumption were significantly more prevalent among young unemployed males compared to GY-students (secondary high school/grammar school) of the same age. The opposite was true for females. Another consistent finding was that among adolescents and young adults with a Turkish/Asian migration background, a problematic use of alcohol was significantly less common compared to adolescents and young adults of the same age without a migration background. 3) In terms of the consumption of cannabis, the unemployed and students with low educational level ('Hauptschule') emerge as high-risk groups. 4) The results concerning problematic gambling significantly overlap with and reflect the findings of international research: being male, of low educational attainment, unemployed, receiving social welfare, and having a migration background significantly increased the risk of problematic gambling habits. 5) The highest lifetime prevalence rates for the consumption of illegal drugs (other than cannabis) were observed among students with low educational level. It should be noted that other SES indicators, in addition to school type, have not been examined to date. The review concludes by outlining gaps and future research areas, as well as presenting several implications for prevention initiatives. PMID- 26647785 TI - Combining Stress and Dopamine Based Models of Addiction: Towards a Psycho-Neuro Endocrinological Theory of Addiction. AB - The literature on the two main models of addiction (dopamine-based positive reinforcement and stress-based negative reinforcement models) have made many important contributions to understanding this brain disorder. However, rarely has there been a comprehensive critique of the limitations of both models. This article seeks to resolve theoretical issues inherent to each model, as well as propose a more comprehensive psycho-neuro-endocrinological theory of addiction which reconciles important elements of both. We suggest that there is not only direct interaction of dopaminergic and stress systems throughout the addiction cycle, from initial use, via the abusing stage, to the endpoint of addiction, but that this interaction is present prior to initial use. A combination of genetic factors and/or experiences of adversity may result in a stress-triggered sensitisation of dopaminergic networks which is present before the onset of substance use, which cannot be explained solely in terms of dopaminergic (positive) reinforcement. Rather these processes are best explained by an allostatic model which reconciles aspects of both models of addiction and shows how dopamine/stress interactions become increasingly pathological in the addiction cycle. Our model suggests that chronic stress eventually creates baseline hypodopaminergic activity, but also prompts dopaminergic hyperactivity in cue reactivity. This is the neural marker of allostatic mechanisms observed at endpoint addiction. We propose a multi-circuit explanation of how this cumulative effect of stress increasingly impacts on dopaminergic networks of reward, affect, attention, memory and behavioural control. This revised model provides a useful frame of reference for further research and ultimately clinical practice. PMID- 26647786 TI - Controllable Synthesis of Formaldehyde Modified Manganese Oxide Based on Gas Liquid Interfacial Reaction and Its Application of Electrochemical Sensing. AB - Controllable synthesis of manganese oxides was performed via a simple one-step synthetic method. Then obtained manganese oxides which exhibit flower-like, cloud like, hexagon-like, and rod-like morphologies were modified by formaldehyde based on a simple self-made gas-liquid reaction device respectively and the modified manganese oxides with coral-like, scallop-like and rod-like morphology were synthesized accordingly. The obtained materials were characterized and the formation mechanism was also researched. Then the modified manganese oxides were used to fabricate electrochemical sensors to detect H2O2. Comparison of electrochemical properties between three kinds of modified manganese oxides was investigated and the best one has been successfully employed as H2O2 sensor which shows a low detection limit of 0.01 MUM, high sensitivity of 162.69 MUA mM(-1) cm(-2), and wide linear range of 0.05 MUM-12.78 mM. The study provides a new method for controllable synthesis of metal oxides, and electrochemical application of formaldehyde modified manganese oxides will provides a new strategy for electrochemical sensing with high performance, low cost, and simple fabrication. PMID- 26647787 TI - Understanding the On-Off Switching Mechanism in Cationic Tetravalent Group-V Based Fluoride Molecular Sensors Using Orbital Analysis. AB - The precise control of on-off switching is essential to the design of ideal molecular sensors. To understand the switching mechanism theoretically, we selected as representative example a 9-anthryltriphenylstibonium cation, which was reported as a fluoride ion sensor. In this molecule, the first excited singlet state exhibits two minimum geometries, where one of them is emissive and the other one dark. The excited state at the geometry with bright emission is of pi-pi* character, whereas it is of pi-sigma* character at the "dark" geometry. Geometry changes in the excited state were identified by geometry optimization and partial potential energy surface (PES) mapping. We also studied Group V homologues of this molecule. A barrierless relaxation pathway after vertical excitation to the "dark" geometry was found for the Sb-containing compound on the excited-states PES, whereas barriers appear in the case of P and As. Molecular orbital analysis suggests that the sigma* orbital of the antimony compound is stabilized along such relaxation and that the excited state changes its nature correspondingly. Our results indicate that the size of the central atom is crucial for the design of fluoride sensors with this ligand framework. PMID- 26647788 TI - A fraction from Dojuksan 30% ethanol extract exerts its anti-inflammatory effects through Nrf2-dependent heme oxygenase-1 expression. AB - Dojuksan is a traditional herbal medicine used in Korea and China to treat urinary diseases. In the present study, we aimed to examine the anti-inflammatory effects of an ethanol solvent extract of Dojuksan and a fraction (by bioassay guided fractionation) derived from this extract, and to elucidate the specific mechanisms involved. The Dojuksan 30% ethanol extract (DEE) had a more significant and potent anti-inflammatory effect than the Dojuksan water extract (DWE). DEE markedly inhibited the production of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), nitric oxide (NO), prostaglandin E2 (PGE2), tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta), as well as nuclear factor-kappaB (NF-kappaB) binding activity. We found that the anti inflammatory effects of DEE were mediated by the induction of nuclear factor E2 related factor 2 (Nrf2)-dependent heme oxygenase-1 (HO-1). To further explore the anti-inflammatory effects of DEE, we generated 6 different fractions of DEE. Of these, DEE-5 decreased the production of NO more significantly than the other fractions. DEE-5 also significantly decreased the expression of iNOS and COX-2, and the production of NO, PGE2, TNF-alpha and IL-1beta. In addition, DEE-5 also significantly increased HO-1 levels; HO-1 significanlty contributed to the inhibitory effects of DEE-5 on the production of pro-inflammatory mediators. In this study, we determined whether the choice of extraction solvent affects the biological activity of Dojuksan, a traditional herbal formula. Our findings demonstrate that DEE and a fraction derived from this extract exerts anti inflammatory effects through Nrf2-dependent HO-1 expression, and that DEE may thus have greater potential therapeutic application than DWE. PMID- 26647789 TI - Differential regulation and synthetic lethality of exclusive RB1 and CDKN2A mutations in lung cancer. AB - Genetic alterations in lung cancer are distinctly represented in non-small cell lung carcinoma (NSCLC) and small cell lung carcinoma (SCLC). Mutation of the RB1 and CDKN2A genes, which are tightly associated with cell cycle regulation, is exclusive to SCLC and NSCLC cells, respectively. Through the systematic analysis of transcriptome and proteome datasets for 318 cancer cell lines, we characterized differential gene expression and protein regulation in RB1-mutant SCLC and CDKN2A-mutant NSCLC. Many of the genes and proteins associated with RB1 mutant SCLC cell lines belong to functional categories of gene expression and transcription, whereas those associated with CDKN2A-mutant NSCLC cell lines were enriched in gene sets of the extracellular matrix and focal adhesion. These results indicate that the loss of RB1 and CDKN2A function induces distinctively different signaling cascades in SCLC and NSCLC cells. In addition, knockdown of the RB1 gene in CKDN2A-mutant cell lines (and vice versa) synergistically inhibits cancer cell proliferation. The present study on the exclusive role of RB1 and CDKN2A mutations in lung cancer subtypes demonstrates a synthetic lethal strategy for cancer regulation. PMID- 26647790 TI - Hemodynamic changes with high infusion rates of lipid emulsion. Experimental study in swine. AB - PURPOSE: To evaluate hemodynamic changes caused by sole intravenous infusion of lipid emulsion with doses recommended for treatment of drug-related toxicity. METHODS: Large White pigs underwent general anesthesia, tracheal intubation was performed, and mechanical ventilation was instituted. Hemodynamic variables were recorded using invasive blood pressure and pulmonary artery catheterization. Baseline hemodynamic measurements were obtained after a 30-minute stabilization period. An intravenous bolus injection of 20% lipid emulsion at 1.5 ml/kg was administered. Additional hemodynamic measurements were made after 1 minute, followed by a continuous intravenous lipid infusion of 0.25 ml/kg/min. Further measurements were carried out at 10, 20 and 30 minutes, when the infusion was doubled to 0.5 ml/kg/min. Assessment of hemodynamic changes were then made at 40, 50 and 60 minutes. RESULTS: Lipid infusion did not influence cardiac output or heart rate, but caused an increase in arterial blood pressure, mainly pulmonary blood pressure due to increased vascular resistance. Ventricular systolic stroke work consequently increased with greater repercussions on the right ventricle. CONCLUSION: In doses used for drug-related toxicity, lipid emulsion cause significant hemodynamic changes with hypertension, particularly in the pulmonary circulation and increase in vascular resistance, which is a factor to consider prior to use of these solutions. PMID- 26647791 TI - Whole-body vibration improves fracture healing and bone quality in rats with ovariectomy-induced osteoporosis. AB - PURPOSE: To investigate the effect of vibration therapy on the bone callus of fractured femurs and the bone quality of intact femurs in ovariectomized rats. METHODS: Fifty-six rats aged seven weeks were divided into four groups: control with femoral fracture (CON, n=14), ovariectomized with femoral fracture (OVX, n=14), control with femoral fracture plus vibration therapy (CON+VT, n=14), and ovariectomized with femoral fracture plus vibration therapy (OVX+VT, n=14). Three months after ovariectomy or sham surgery, a complete fracture was produced at the femoral mid-diaphysis and stabilized with a 1-mm-diameter intramedullary Kirschner wire. X-rays confirmed the fracture alignment and fixation. Three days later, the VT groups underwent vibration therapy (1 mm, 60 Hz for 20 minutes, three times per week for 14 or 28 days). The bone and callus quality were assessed by densitometry, three-dimensional microstructure, and mechanical test. RESULTS: Ovariectomized rats exhibited a substantial loss of bone mass and severe impairment in bone microarchitecture, both in the non-fractured femur and the bone callus. Whole-body vibration therapy exerted an important role in ameliorating the bone and fracture callus parameters in the osteoporotic bone. CONCLUSION: Vibration therapy improved bone quality and the quality of the fracture bone callus in ovariectomized rats. PMID- 26647792 TI - Effect of alpha-7 nicotinic acetylcholine receptor activation on beta-amyloid induced recognition memory impairment. Possible role of neurovascular function. AB - PURPOSE: To evaluate the effects of PHA-543613 (alpha7-nAChR agonist) and galantamine (acetylcholinesterase inhibitor (AChEI)) on recognition memory and neurovascular coupling (NVC) response in beta-amyloid (Abeta) 25-35-treated mice. METHODS: PHA-543613 (1 mg/kg, i.p.), and galantamine (3 mg/kg, s.c.), effects were tested in Abeta25-35 mice model of AD. alpha7-nAChR antagonist, methyllycaconitine (MLA) (1 mg/kg, i.p.), was used for evaluation of receptor blockade effects. Recognition memory in animals was assessed by the novel object recognition (NOR) task. NVC response was analyzed by laser-doppler flow meter in barrel cortex by whisker stimulation method. RESULTS: Both, PHA-543613 and galantamine improve recognition memory in Abeta-treated animals. However, the advantageous effects of PHA-543613 were significantly higher than galantamine. Also, pretreatment with MLA reversed both galantamine and PHA-543613 effects on NOR. Impaired NVC response in AD animals was improved by PHA-543613 and galantamine. However, MLA pretreatment disrupts this function. CONCLUSION: Activation of alpha7-nAChR improved recognition memory possible through enhancement of neurovascular response in Alzheimer's disease in animals. PMID- 26647793 TI - Allometric relationships among body mass, MUZZLE-tail length, and tibia length during the growth of Wistar rats. AB - PURPOSE: To investigate allometric relationships among body mass (BM), muzzle tail length (MTL), and tibia length (TL) in Wistar rats and establish their growth rate change parameters. METHODS: Eighteen male and 18 female Wistar rats were studied from the 3rd to the 21st week of age. BM, MTL, and TL were measured daily, and relative growth was compared using allometry. RESULTS: A positive correlation between BM and MTL (p<0.05) and BM and TL (p<0.05) was observed. Males and females showed comparable curves; however, females had turning points at a younger age. The allometric relationship between BM and MTL presented a regular increase until reaching a mass of 351 g (males) and 405 g (females). BM and TL showed an initial increase until 185 g (males) and 182 g (females), and then reached a plateau that finished at 412 g (males) and 334 g (females), to display another increase. CONCLUSIONS: The allometric relationship of body mass with animal length and tibia length was comparable for male and female rats, with female rats maturing earlier. Animal longitudinal growth occurred in a single stage. In contrast, tibia length depicted two stages of accelerated growth with an intermediate period of deceleration. PMID- 26647794 TI - Mechanisms of the beneficial effect of sevoflurane in liver ischemia/reperfusion injury. AB - PURPOSE: To evaluate the underlying mechanisms by which sevoflurane protects the liver against ischemia/reperfusion injury evaluate the mechanism by which sevoflurane exerts this protective effect. METHODS: Twenty-six rats were subjected to partial ischemia/reperfusion injury for 1h: one group received no treatment, one group received sevoflurane, and sham group of animals received laparotomy only. Four hours after reperfusion, levels of alanine and aspartate aminotransferases, tumor necrosis factor-a, and interleukins 6 and 10 were measured. Analyses of mitochondrial oxidation and phosphorylation, malondialdehyde content, histology, and pulmonary vascular permeability were performed. RESULTS: Serum levels of alanine and aspartate aminotransferases were significantly lower in the sevoflurane group compared to untreated controls (p<0.05). The sevoflurane group also showed preservation of liver mitochondrial function compared to untreated controls (p<0.05). Sevoflurane administration did not alter increases in serum levels of tumor necrosis factor-a, and interleukins 6 and 10. Sevoflurane treatment significantly reduced the coagulative necrosis induced by ischemia/reperfusion (p<0.05). Pulmonary vascular permeability was preserved in the sevoflurane group compared to untreated controls. CONCLUSION: Sevoflurane administration protects the liver against ischemia/reperfusion injury, via preservation of mitochondrial function, and also preserves lung vascular permeability. PMID- 26647795 TI - Remifentanil protects uterus against ischemia-reperfusion injury in rats. AB - PURPOSE: To investigate the effects of remifentanil as an antioxidant and analyze the histopathologic, biochemical changes in experimental ischemia-reperfusion (I/R) exposed rat uteri. METHODS: Wistar albino rats were assigned to three groups (n = 7). 2h period of ischemia was followed by 1h of reperfusion in the I/R and the I/R-remifentanil groups. After ischemia, no drug was administered in the sham and I/R groups. In the I/R-remifentanil group, remifentanil infusion (2 MUg/kg/min) was started in the ischemia period, and continued until the end of reperfusion. After the ischemic and reperfusion period, the ischemic uterine horns were removed surgically for biochemical and histopathologic examination. Tissue damage scores (endometrial epithelial glandular leukocytosis, degeneration, and endometrial stromal changes) were examined. Malondialdehyde levels and catalase, superoxide dismutase enzyme activities in tissue were measured. RESULTS: We found significantly lower epithelial leukocytosis and cell degeneration in the I/R-remifentanil group (p<0.05). Remifentanil administration significantly decreased concentrations of malondialdehyde, and increased catalase and superoxide dismutase enzyme activities (p<0.05). CONCLUSION: Remifentanil appears to protect the uterine tissue against ischemia-reperfusion and can be used safely in uterus transplantation. PMID- 26647796 TI - Effects of metoclopramide on the expression of metalloproteinases and interleukins in left colonic anastomoses. An experimental study. AB - PURPOSE: To evaluate the effects of metoclopramide on metalloproteinases (MMP) and interleukins (IL) gene expression in colonic anastomoses in rats. METHODS: Eighty rats were divided into two groups for euthanasia on the 3rd or 7th postoperative day (POD), then into two subgroups for sepsis induction or not, and then into subgroups to receive either metoclopramide or saline solution. Left colonic anastomosis were performed and then analyzed. RESULTS: On the 3rd POD, metoclopramide was associated with increased expression of MMP-1a, MMP-13, and TNF-alpha. On the 7th POD, the transcripts of all MMPs, TNF-alpha, IL-1beta, IFN gamma, and IL-10 of the treated animals became negatively modulated. In the presence of sepsis, metoclopramide did not change MMPs and decreased IL-6, IL 1beta, IFN-gamma and IL-10 gene expression on the 3rd POD. On the 7th POD, increased expression of all MMPs, IFN-gamma and IL-10 and negative modulated TNF alpha and IL-6 gene expression. CONCLUSION: Administration of metoclopramide increased metalloproteinases and interleukins gene expression on the 3rd postoperative day and negatively modulated them on the 7th POD. In the presence of abdominal sepsis, metoclopramide did not change MMPs and decreased ILs gene expression on the 3rd POD. On the 7th POD, the drug increased expression of all MMPs. PMID- 26647797 TI - A comparative study of the areas of osteochondral defects produced in femoral condyles of rabbits treated with sugar cane biopolymer gel. AB - PURPOSE: To assess the histological response of damaged osteochondral tissue in the femoral condyles of rabbits after repairing the wounds with sugar cane biopolymer gel - compared to the control group. METHODS: The study investigated 16 New Zealand rabbits, at 90, 120 and 180 days after surgery. In all the animals, a lesion of 3.2 mm in diameter and 4 mm deep was induced in each right and left femoral condyle. Each animal has provided both knees, divided into medial and lateral condyle, resulting in 64 samples. 32 knees were divided into two groups: Right knee, medial and lateral condyles, filled with biopolymer; Left knee, medial and lateral condyles, unfilled. The anatomical specimens were removed, and subjected to histological techniques and morphometric and statistical analysis. RESULTS: In all the periods of the group under study an inflammatory reaction mediated by giant cells and mononuclear cells was found, while in the control group there was early healing produced by fibroblasts and few mononuclear cells with statistical significance between groups. CONCLUSION: The biopolymer gel caused an inflammatory reaction mediated by giant cells and mononuclear cells while the control group there was cicatrization mediated by fibroblasts. PMID- 26647798 TI - Rutin ameliorates methotrexate induced hepatic injury in rats. AB - PURPOSE: To investigate the possible protective effect of rutin on methotrexate induced hepatotoxicity in rats. METHODS: Twenty-two rats were divided into three experimental groups; Control-saline, Mtx, Mtx+Rutin. Hepatic tissue was taken for histological assessment and biochemical assays. Oxidative stress parameters malondialdehyde (MDA), glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) were investigated. Liver markers aspartate aminotransferase (AST), alanine aminotransferase (ALT) were analyzed in serum. RESULTS: Mtx+Rutin group showed lower histological injury compared to Mtx group, MDA and ALT levels were increased, while SOD and GSH-Px were decreased in Mtx group compared with Control saline group. MDA and ALT levels were increased, while SOD and GSH-Px were decreased in Mtx group, compared with Mtx +Rutin group. Serum AST levels were similar among the groups. CONCLUSION: Rutin may be a potential adjuvant drug to reduce the hepatic side effects observed during Mtx therapy for various clinical conditions. PMID- 26647799 TI - Comparison between hemosiderin and Technetium-99 in sentinel lymph node biopsy in human breast cancer. AB - PURPOSE: To assess the safety and potential equivalence of the use of hemosiderin compared to the Technetium-99 in sentinel lymph node biopsy in human breast cancer. METHODS: Non-random sample of 14 volunteer women diagnosed with breast cancer with primary tumors (T1/T2) and clinically tumor-free axilla were submitted to the identification of sentinel lymph node using hemosiderin obtained from autologous blood injected in the periareolar region 24h before surgery on an outpatient basis. Patients received preoperative subareolar intradermal injection of Technetium-99 in the immediate preoperative period. Patients were submitted to sentinel lymph node biopsy, with incision in the axillary fold guided by Gamma Probe, dissection by planes until the identification of the point of maximum uptake of Technetium-99, identifying the marked nodes and their colors. All surgical specimens were sent for pathological and immunohistochemical study. RESULTS: The results showed no evidence of side effects and/or allergic and non allergic reactions in patients submitted to SLNB with hemosiderin. The SLN identification rate per patient was 100%. SLNB identification rate per patient with hemosiderin was the same as that of Technetium, with a concordance rate of 100% between the methods. CONCLUSION: Hemosiderin is a safe dye that is equivalent to Technetium in breast sentinel lymph node biopsy. PMID- 26647800 TI - Learning to fear a second-order stimulus following vicarious learning. AB - Vicarious fear learning refers to the acquisition of fear via observation of the fearful responses of others. The present study aims to extend current knowledge by exploring whether second-order vicarious fear learning can be demonstrated in children. That is, whether vicariously learnt fear responses for one stimulus can be elicited in a second stimulus associated with that initial stimulus. Results demonstrated that children's (5-11 years) fear responses for marsupials and caterpillars increased when they were seen with fearful faces compared to no faces. Additionally, the results indicated a second-order effect in which fear related learning occurred for other animals seen together with the fear-paired animal, even though the animals were never observed with fearful faces themselves. Overall, the findings indicate that for children in this age group vicariously learnt fear-related responses for one stimulus can subsequently be observed for a second stimulus without it being experienced in a fear-related vicarious learning event. These findings may help to explain why some individuals do not recall involvement of a traumatic learning episode in the development of their fear of a specific stimulus. PMID- 26647801 TI - Antibody-conjugated drug assay for protease-cleavable antibody-drug conjugates. AB - BACKGROUND: Antibody-drug conjugates (ADCs) require multiple assays to characterize their PK. These assays can separately evaluate the ADC by quantifying the antibody or the conjugated drug and may give different answers due to assay measurement differences, heterogeneous nature of ADCs and potential biotransformations that occur in vivo. RESULTS: We present a new version of the antibody-conjugated drug assay for valine-citrulline-linked monomethylauristatin E (vcMMAE) ADCs. A stable isotope-labeled internal standard, protein A affinity capture and solid-phase cleavage of MMAE using papain was used prior to LC-MS/MS analysis. CONCLUSION: The assay was used to assess the difference in ex vivo drug linker stability of native-cysteine versus engineered cysteine ADCs and to determine the number of drugs per antibody of a native-cysteine ADC in vivo. PMID- 26647802 TI - Transmission of vibration through gloves: effects of material thickness. AB - It might be assumed that increasing the thickness of a glove would reduce the vibration transmitted to the hand. Three material samples from an anti-vibration glove were stacked to produce three thicknesses: 6.4, 12.8 and 19.2 mm. The dynamic stiffnesses of all three thicknesses, the apparent mass at the palm and the finger and the transmission of vibration to the palm and finger were measured. At frequencies from 20 to 350 Hz, the material reduced vibration at the palm but increased vibration at the finger. Increased thickness reduced vibration at the palm but increased vibration at the finger. The measured transmissibilities could be predicted from the material dynamic stiffness and the apparent mass of the palm and finger. Reducing the dynamic stiffness of glove material may increase or decrease the transmission of vibration, depending on the material, the frequency of vibration and the location of measurement (palm or finger). Practitioner Summary: Transmission of vibration through gloves depends on the dynamic response of the hand and the dynamic stiffness of glove material, which depends on material thickness. Measuring the transmission of vibration through gloves to the palm of the hand gives a misleading indication of the transmission of vibration to the fingers. PMID- 26647803 TI - Forensic-paternity effectiveness and genetics population analysis of six non CODIS mini-STR loci (D1S1656, D2S441, D6S1043, D10S1248, D12S391, D22S1045) and SE33 in Mestizo and Amerindian populations from Mexico. AB - BACKGROUND: STRs are powerful tools intensively used in forensic and kinship studies. AIM: In order to assess the effectiveness of non-CODIS genetic markers in forensic and paternity tests, the genetic composition of six mini short tandem repeats-mini-STRs-(D1S1656, D2S441, D6S1043, D10S1248, D12S391, D22S1045) and the microsatellite SE33 in Mestizo and Amerindian populations from Mexico were studied. SUBJECTS AND METHODS: Using multiplex polymerase chain reactions and capillary electrophoresis, this study genotyped all loci from 870 chromosomes and evaluated the statistical genetic parameters. RESULTS: All mini-STRs studied were in agreement with HW and linkage equilibrium; however, an important HW departure for SE33 was found in the Mestizo population (p <= 0.0001). Regarding paternity and forensic statistical parameters, high values of combined power discrimination and mean power of exclusion were found using these seven markers. The principal co-ordinate analysis based on allele frequencies of three mini-STRs showed the complex genetic architecture of the Mestizo population. CONCLUSION: The results indicate that this set of loci is suitable to genetically identify individuals in the Mexican population, supporting its effectiveness in human identification casework. In addition, these findings add new statistical values and emphasise the importance of the use of non-CODIS markers in complex populations in order to avoid erroneous assumptions. PMID- 26647804 TI - Effective radiation doses of CT examinations in Japan: a nationwide questionnaire based study. AB - OBJECTIVE: The aims of this study were to estimate the effective radiation doses from CT examinations of both adults and children in Japan and to study the impact of various scan parameters on the effective doses. METHODS: A questionnaire, which contained detailed questions on the CT scan parameters employed, was distributed to 3000 facilities throughout Japan. For each scanner protocol, the effective doses for head (non-helical and helical), chest and upper abdomen acquisitions were estimated using ImPACT CT Patient Dosimetry Calculator software v. 1.0.4 (St George's Hospital, London, UK). RESULTS: The mean effective doses for chest and abdominal examinations using 80-110 kV were significantly lower than those using 120 kV. However, there was no statistically significant difference in the mean effective doses for head scans between facilities employing 80-110 kV and 120 kV. In chest and abdominal examinations, the mean effective doses using CT scanners from Western manufacturers [Siemens (Forchheim, Germany), Philips (Eindhoven, Netherlands) and GE Medical Systems (Milwaukee, WI)] were significantly lower than those of examinations using Japanese scanners [Hitachi (Kashiwa, Japan) and Toshiba (Otawara, Tochigi, Japan)], except for in paediatric chest examinations. CONCLUSION: The mean effective doses for adult head, chest and abdominal CT examinations were 2.9, 7.7 and 10.0 mSv, respectively, whereas the corresponding mean effective doses for paediatric examinations were 2.6, 7.1 and 7.7 mSv, respectively. ADVANCES IN KNOWLEDGE: Facilities using CT scanners by Western manufacturers commonly adopt low-tube voltage techniques, and low-tube-voltage CT may be useful for reducing the radiation doses to the patients, particularly for the body region. PMID- 26647805 TI - Exosomes derived from SW480 colorectal cancer cells promote cell migration in HepG2 hepatocellular cancer cells via the mitogen-activated protein kinase pathway. AB - Exosomes are membrane-derived extracellular vesicles that have recently been recognized as important mediators of intercellular communication. In the present study, we investigated the effects of exosomes derived from SW480 colorectal cancer cells in recipient HepG2 hepatocellular cancer cells. We demonstrated that SW480-derived exosomes were taken up by the recipient HepG2 cells via dynamin dependent endocytosis and were localized to the HepG2 lysosomes. In addition, SW480-derived exosomes induced the phosphorylation of extracellular signal regulated kinase (ERK)1/2 following their uptake into HepG2 cells. Of note, these changes occurred during the early phase after exosome treatment. Furthermore, SW480-derived exosomes promoted the migration of recipient HepG2 cells in a wound healing assay, which was suppressed by pretreatment with U0126, an upstream inhibitor of ERK1/2. These results indicated that SW480-derived exosomes activated a classical mitogen-activated protein kinase pathway in recipient HepG2 cells via dynamin-dependent endocytosis and subsequently enhanced cell migration by ERK1/2 activation. Our results provide new insights into the regulation of cellular functions by exosomes. PMID- 26647807 TI - Green synthesis of silver nanoparticles for selective toxicity towards cancer cells. AB - Therapeutic applications of nanoparticles (NPs) are rapidly increasing for their utility in medicine, especially cancer therapy. The present study investigated the green synthesis of silver NPs (Ag NPs) of 10 nm size using Sargassum vulgare and its preferential ability to kill cancerous human myeloblastic leukemic cells HL60 and cervical cancer cells HeLa as compared with normal peripheral blood mononuclear cells. DNA fragmentation study and annexin V marker fluorescence activated cell sorting (FACS) analysis revealed the Ag NP-induced cell death is through apoptosis. Transmission electron micrographs have showed the endocytosis of Ag NPs into the nucleus. Ag NPs inhibited the lipid peroxidation-induced reactive oxygen species generation, thus preventing the irradiation-related carcinogenesis. This study suggested that a mechanism underlying the toxicity of Ag NPs towards cancer cells is due to DNA damage and apoptosis. The authors' findings revealed the potential utility of as-prepared Ag NPs in the treatment of cancer as prophylactic agent with antioxidant property and chemotherapeutic agent for their selective toxicity to cancer cells. PMID- 26647808 TI - Framework for single input single output nanonetwork-based realistic molecular communication. AB - Mobile ad hoc molecular nanonetwork (MAMNET) is a new paradigm for the realisation of future nanonetworks. In MAMNET, transmission of nanoscale information from nanomachine to infostation is based on collision and adhesion. In this study, the authors develop a realistic framework for encompassing the electronic structure of the neurotransmitter in the process of transmitting nanoscale information at a single input single output nanonetwork. Nanonetwork performance is evaluated in terms of average packet delay, throughput and incurred traffic rate. Numerical results demonstrate the influence of the neurotransmitter's electronic structure over the performance of nanonetworks. PMID- 26647806 TI - Smad4 sensitizes colorectal cancer to 5-fluorouracil through cell cycle arrest by inhibiting the PI3K/Akt/CDC2/survivin cascade. AB - 5-Fluorouracil (5-FU), a cell cycle-specific antimetabolite, is one of the most commonly used chemotherapeutic agents for colorectal cancer (CRC). Yet, resistance to 5-FU-based chemotherapy is still an obstacle to the treatment of this malignancy. Mutation or loss of Smad4 in CRC is pivotal for chemoresistance. However, the mechanism by which Smad4 regulates the chemosensitivity of CRC remains unclear. In the present study, we investigated the role of Smad4 in the chemosensitivity of CRC to 5-FU, and whether Smad4-regulated cell cycle arrest is involved in 5-FU chemoresistance. We used Smad4-expressing CT26 and Smad4-null SW620 cell lines as experimental models, by knockdown or transgenic overexpression. Cells or tumors were treated with 5-FU to determine chemosensitivity by cell growth, tumorigenicity assay and a mouse model. Cell cycle distribution was examined with flow cytometric analysis, and cell cycle related proteins were examined by western blotting. Smad4 deficiency in CT26 and SW620 cells induced chemoresistance to 5-FU both in vitro and in vivo. Smad4 deficiency attenuated G1 or G2 cell cycle arrest by activating the PI3K/Akt/CDC2/survivin pathway. The PI3K inhibitor, LY294002, reversed the activation of the Akt/CDC2/survivin cascade in the Smad4-deficient cells, while it had little effect on cells with high Smad4 expression. In conclusion, we discovered a novel mechanism mediated by Smad4 to trigger 5-FU chemosensitivity through cell cycle arrest by inhibiting the PI3K/Akt/CDC2/survivin cascade. The present study also implies that LY294002 has potential therapeutic value to reverse the chemosensitivity of CRC with low Smad4 expression. PMID- 26647809 TI - Antimicrobial evaluation of quaternary ammonium polyethyleneimine nanoparticles against clinical isolates of pathogenic bacteria. AB - Peritonitis is a disease caused by bacterial strains that have become increasingly resistant to many antibiotics. The development of alternative therapeutic compounds is the focus of extensive research, so novel nanoparticles (NPs) with activity against antibiotic-resistant bacteria should be developed. In this study, the antibacterial activity of quaternary ammonium polyethyleneimine (QA-PEI) NPs was evaluated against Streptococcus viridans, Stenotrophomonas maltophilia and Escherichia coli. To appraise the antibacterial activity, minimal inhibitory concentration (MIC), minimal bactericidal concentration and bactericidal assays were utilised with different concentrations (1.56-100 ug/ml) of QA-PEI NPs. Moreover, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) and annexin V/propidium iodide toxicity assays were performed in cell cultures. MICs for S. maltophilia and E. coli isolates were 12.5 and 25 ug/ml, respectively, whereas the MIC for S. viridans was 100 ug/ml. Furthermore, the growth curve assays revealed that these QA-PEI NPs at a concentration of 12.5 ug/ml significantly inhibited bacterial growth for the bacterial isolates studied. On the other hand, QA-PEI NPs lacked significant toxicity for cells when used at concentrations up to 50 MUg/ml for 48 h. The present findings reveal the potential therapeutic value of this QA-PEI NPs as alternative antibacterial agents for peritonitis, especially against Gram-negative bacteria. PMID- 26647810 TI - Biosynthesised palladium nanoparticles using Eucommia ulmoides bark aqueous extract and their catalytic activity. AB - Palladium nanoparticles (PdNPs) are of great importance as catalytic materials. Their synthesis has been widely studied and interest in their properties is growing. Bio-based methods might be a greener option for designing the PdNPs with reduced environmental impacts. This study reports the synthesis of PdNPs by utilising the aqueous extract of medicinally important Eucommia ulmoides (E. Ulmoides) bark which functions as both reducing and capping agent in moderate reaction conditions. Reduction potential of E. Ulmoides bark aqueous extract was about -0.08 V vs. saturated calomel electrode by open-circuit voltage method and the rich polyphenolics was confirmed by cyclic voltammetry, which helps to reduce palladium ions to PdNPs. The characterisation through high-resolution transmission electron microscopic, energy dispersive X-ray spectroscopy and X-ray diffraction infer that the as-synthesised PdNPs were spherical in shape with a face cubic crystal structure. The results from dynamic light scattering suggest the PdNPs have the narrow size distribution with an average size of 12.6 nm. The lower zeta potential (-25.3 mV) and the Fourier transform infrared spectra indicate that the as-synthesised PdNPs keep remarkably stable for a long period due to the capped biomolecules on the nanoparticle surface. This method for synthesis of PdNPs is simple, economic, non-toxic and efficient. The PdNPs show excellent catalytic activity for the electro-catalytic oxidation of hydrazine and the catalytic reducing degradation of p-aminoazobenzene, a model compound of azo dyes. PMID- 26647811 TI - Preparation, characterisation and antibacterial activity of a florfenicol-loaded solid lipid nanoparticle suspension. AB - A florfenicol-loaded solid lipid nanoparticle (FFC-SLN) suspension was prepared by hot homogenisation and ultrasonic technique. The suspension was characterised for its release profile, stability, toxicity, and the physicochemical properties of the nanoparticles. Antibacterial activity of the suspension was evaluated in vitro and in vivo. The results showed that the mean diameter, polydispersity index and zeta potential of the nanoparticles were 253 +/- 3 nm, 0.409 +/- 0.022 and 47.5 +/- 0.21 mV, respectively. In vitro release profile showed the FFC-SLN suspension had sustained release effect. The minimum inhibition concentration values of the FFC-SLN suspension were 6 and 3 ug/mL against Staphylococcus aureus and Escherichia coli respectively, compared with 3.5 and 2 ug/mL of native florfenicol. The suspension was relatively stable at 4 degrees C and less stable at room temperature during 9 months storage. Although the nanoparticle carriers exhibited cytotoxicity in cell cultures, the LD50 of the lyophilised dry power of the suspension was higher than 5 g/kg body weight. Mortality protection against E. coli lethal infection in mice showed that the nanoparticle suspension had much better efficacy (6/10) than native drug (1/10). These results indicate that FFC SLN suspension could be a promising formulation in veterinary medicine. PMID- 26647812 TI - Facile synthesis of palladium nanocatalyst using gum kondagogu (Cochlospermum gossypium): a natural biopolymer. AB - Palladium nanoparticles (Pd NPs) were synthesised by using gum kondagogu (GK), a non-toxic ecofriendly biopolymer. GK acted as both reducing and stabilising agent for the synthesis of Pd NPs. Various reaction parameters, such as concentration of gum, Pd chloride and reaction pH were standardised for the stable synthesis of GK reduced stabilised Pd NPs (GK-Pd NPs). The nanoparticles have been characterised using ultraviolet-visible spectroscopy, transmission electron microscopy and X-ray diffraction. Physical characterisation revealed that the gum synthesised Pd NPs were in the size range of 6.5 +/- 2.3 nm and crystallised in face centred cubic (FCC) symmetry. Fourier transform infrared spectroscopy implicated the role of carboxyl, amine and hydroxyl groups in the synthesis. The synthesised Pd NPs were found to be highly stable in nature. The synthesised nanoparticles were found to function as an effective green catalyst (k = 0.182 min-1) in the reduction of 4-nitrophenol by sodium borohydride, which was evident from the colour change of bright yellow (nitrophenolate; lambda(max) - 400 nm) to colourless (4-AP; lambda(max) - 294 nm) solution. The overall objectives of the current communication were: (i) to synthesize the Pd NPs using a green reducing/capping agent; GK and (ii) to determine the catalytic performance of the synthesised Pd NPs. PMID- 26647813 TI - In vivo evaluation of the biodistribution of intravenously administered naked and functionalised silver nanoparticles in rabbit. AB - Water-based suspension of silver nanoparticles (AgNPs) and dextran coated AgNPs (dextran-AgNPs) are fabricated and characterised for intravenous administration. A simple method for radiolabelling of nanoparticles with (99m)Tc was used. Labelling efficiency for AgNPs and dextran-AgNPs was found to be more than 80 and 88%, respectively. In vivo tissue uptake of nanoparticles during dynamic phase, after systematic administration by biodistribution analysis with single-photon emission computed tomography imaging has been evaluated. Biodistribution analysis revealed that (99m)Tc-AgNPs and (99m)Tc-dextran-AgNPs are mainly accumulated in liver/spleen region but (99m)Tc-dextran-AgNPs delayed recognition and uptake by liver. Results indicate that dextran-AgNPs are able to evade reticuloendothelum system with enhanced blood retention time. Accumulation of nanoparticles in liver/spleen region implicates the utilisation of AgNPs for liver cancer treatment. PMID- 26647814 TI - Elucidation on enhanced application of synthesised kojic acid immobilised magnetic and chitosan tri-polyphosphate nanoparticles as antibacterial agents. AB - Kojic acid (KA) is a secondary metabolite which is secreted by several aspergillus species. It is a multi-functional skeleton from which many derivatives can be synthesised and applied in various areas of biotechnology. KA grafting on synthesised magnetic nanoparticles (MNPs) and chitosan tri polyphosphate (chitosan-TPP) nanoparticles was successfully done and characterised by Fourier transformation infrared spectroscopy. It was observed that amino propyl triethoxy silane-coated MNPs and chitosan-TPP nanoparticles enhanced the antibacterial activity of KA against both Gram-positive (Staphylococcus aureus) and Gram-negative (Pseudomonas aeruginosa). The organic constitution and significant antibacterial activity of KA-chitosan-TPP nanoparticles can be applicable in the field of medical biotechnology. PMID- 26647815 TI - Encapsulation efficacy of natural and synthetic photosensitizers by silica nanoparticles for photodynamic applications. AB - This study analysed the physical effects of Cichorium Pumilum (CP), as a natural photosensitizer (PS), and Protoporphyrin IX (PpIX), as a synthetic PS, encapsulated with silica nanoparticles (SiNPs) in photodynamic therapy. The optimum concentrations of CP and PpIX, needed to destroy Red Blood Cells (RBC), were determined and the efficacy of encapsulated CP and PpIX were compared with naked CP and PpIX was verified. The results confirmed the applicability of CP and PpIX encapsulated in SiNPs on RBCs, and established a relationship between the encapsulated CP and PpIX concentration and the time required to rupture 50% of the RBCs (t50). The CP and PpIX encapsulated in SiNPs exhibited higher efficacy compared with that of naked CP and PpIX, respectively, and CP had less efficacy compared with PpIX. PMID- 26647816 TI - Short interfering RNA therapeutics: nanocarriers, prospects and limitations. AB - Since the first experiment depicting gene inhibition using RNA interference mechanism, extensive research has been carried out to design targeted delivery systems that use short interfering RNAs (siRNAs) for gene expression regulation. Although several siRNAs loaded nanoparticle systems have reached clinical trial stage, cellular uptake, reticuloendothelial entrapment and endosomal escape still limit the efficacy of these drugs considerably. This review discusses about the RNA interference mechanism, nanostructures being used as non-viral vectors for targeted delivery, limitations of the common delivery systems and the current siRNA-loaded nanoparticle formulations undergoing clinical testing. PMID- 26647817 TI - Nanobiotechnology and its applications in drug delivery system: a review. AB - Nanobiotechnology holds great potential in various regimes of life sciences. In this review, the potential applications of nanobiotechnology in various sectors of nanotechnologies, including nanomedicine and nanobiopharmaceuticals, are highlighted. To overcome the problems associated with drug delivery, nanotechnology has gained increasing interest in recent years. Nanosystems with different biological properties and compositions have been extensively investigated for drug delivery applications. Nanoparticles fabricated through various techniques have elevated therapeutic efficacy, provided stability to the drugs and proved capable of targeting the cells and controlled release inside the cell. Polymeric nanoparticles have shown increased development and usage in drug delivery as well as in diagnostics in recent decades. PMID- 26647818 TI - Tumor suppressive microRNA-429 regulates cellular function by targeting VEGF in clear cell renal cell carcinoma. AB - Clear cell renal cell carcinoma (ccRCC) is the predominant and most aggressive type of kidney malignancy, however, the mechanism underlying its carcinogenesis remains to be elucidated. The present study aimed to determine the expression and function of microRNA (miR)-429 in ccRCC carcinogenesis. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) was used to detect the expression of miR-429 in ccRCC specimens. Following transfection of miR-429 synthetic mimics, the expression of miR-429 was examined and cell proliferation, cell migration, apoptosis and luciferase assays were conducted in ccRCC cell lines. The results demonstrated that expression of miR-429 was decreased in ccRCC cells. In addition, upregulation of miR-429 by transfection of mimics reduced cellular proliferation and migration, and induced apoptosis in ACHN and 786-0 cell lines. Furthermore, miR-429 decreased the 3'UTR luciferase activity of vascular endothelial growth factor (VEGF) and c-MYC, and RT-qPCR analysis demonstrated that the cancer cells transfected with miR-429 mimics exhibited decreased expression of VEGF, but not c-MYC. To the best of our knowledge, the present study was the first to reveal that downregulated miR-429 functioned as a tumor suppressor by restraining cellular proliferation and migration, and inducing apoptosis, as well as targeting VEGF in ccRCC cells. PMID- 26647819 TI - REST mediates resolution of HIF-dependent gene expression in prolonged hypoxia. AB - The hypoxia-inducible factor (HIF) is a key regulator of the cellular response to hypoxia which promotes oxygen delivery and metabolic adaptation to oxygen deprivation. However, the degree and duration of HIF-1alpha expression in hypoxia must be carefully balanced within cells in order to avoid unwanted side effects associated with excessive activity. The expression of HIF-1alpha mRNA is suppressed in prolonged hypoxia, suggesting that the control of HIF1A gene transcription is tightly regulated by negative feedback mechanisms. Little is known about the resolution of the HIF-1alpha protein response and the suppression of HIF-1alpha mRNA in prolonged hypoxia. Here, we demonstrate that the Repressor Element 1-Silencing Transcription factor (REST) binds to the HIF-1alpha promoter in a hypoxia-dependent manner. Knockdown of REST using RNAi increases the expression of HIF-1alpha mRNA, protein and transcriptional activity. Furthermore REST knockdown increases glucose consumption and lactate production in a HIF 1alpha- (but not HIF-2alpha-) dependent manner. Finally, REST promotes the resolution of HIF-1alpha protein expression in prolonged hypoxia. In conclusion, we hypothesize that REST represses transcription of HIF-1alpha in prolonged hypoxia, thus contributing to the resolution of the HIF-1alpha response. PMID- 26647820 TI - Quantifying replicative senescence as a tumor suppressor pathway and a target for cancer therapy. AB - To study quantitatively replicative senescence as a tumor suppressor mechanism, we investigate the distribution of a growing clonal cell population restricted by Hayflick's limit. We find that in the biologically relevant range of parameters, if the imbalance between cell division and death is moderate or low (high death to-birth ratio), senescence offers significant protection against cancer by halting abnormal cell proliferation at early pre-diagnostic stages of tumor development. We also find that by the time tumors are typically detected, there is a high probability that telomerase is activated, even if the cell of origin was telomerase negative. Hence, the fact that most cancers are positive for telomerase is not necessarily an indication that cancer originated in a telomerase positive cell. Finally, we discuss how the population dynamics of cells can determine the outcomes of anti-telomerase cancer therapies, and provide guidelines on how the model could potentially be applied to develop clinically useful tools to predict the response to treatment by telomerase inhibitors in individual patients. PMID- 26647821 TI - Quantum metrology with spin cat states under dissipation. AB - Quantum metrology aims to yield higher measurement precisions via quantum techniques such as entanglement. It is of great importance for both fundamental sciences and practical technologies, from testing equivalence principle to designing high-precision atomic clocks. However, due to environment effects, highly entangled states become fragile and the achieved precisions may even be worse than the standard quantum limit (SQL). Here we present a high-precision measurement scheme via spin cat states (a kind of non-Gaussian entangled states in superposition of two quasi-orthogonal spin coherent states) under dissipation. In comparison to maximally entangled states, spin cat states with modest entanglement are more robust against losses and their achievable precisions may still beat the SQL. Even if the detector is imperfect, the achieved precisions of the parity measurement are higher than the ones of the population measurement. Our scheme provides a realizable way to achieve high-precision measurements via dissipative quantum systems of Bose atoms. PMID- 26647822 TI - Specific quorum sensing-disrupting activity (A QSI) of thiophenones and their therapeutic potential. AB - Disease caused by antibiotic resistant pathogens is becoming a serious problem, both in human and veterinary medicine. The inhibition of quorum sensing, bacterial cell-to-cell communication, is a promising alternative strategy to control disease. In this study, we determined the quorum sensing-disrupting activity of 20 thiophenones towards the quorum sensing model bacterium V. harveyi. In order to exclude false positives, we propose a new parameter (AQSI) to describe specific quorum sensing activity. AQSI is defined as the ratio between inhibition of quorum sensing-regulated activity in a reporter strain and inhibition of the same activity when it is independent of quorum sensing. Calculation of AQSI allowed to exclude five false positives, whereas the six most active thiophenones (TF203, TF307, TF319, TF339, TF342 and TF403) inhibited quorum sensing at 0.25 MUM, with AQSI higher than 10. Further, we determined the protective effect and toxicity of the thiophenones in a highly controlled gnotobiotic model system with brine shrimp larvae. There was a strong positive correlation between the specific quorum sensing-disrupting activity of the thiophenones and the protection of brine shrimp larvae against pathogenic V. harveyi. Four of the most active quorum sensing-disrupting thiophenones (TF 203, TF319, TF339 and TF342) were considered to be promising since they have a therapeutic potential of at least 10. PMID- 26647823 TI - Polygamy and an absence of fine-scale structure in Dendroctonus ponderosae (Hopk.) (Coleoptera: Curcilionidae) confirmed using molecular markers. PMID- 26647824 TI - Stochastic Micro-Pattern for Automated Correlative Fluorescence - Scanning Electron Microscopy. AB - Studies of cellular surface features gain from correlative approaches, where live cell information acquired by fluorescence light microscopy is complemented by ultrastructural information from scanning electron micrographs. Current approaches to spatially align fluorescence images with scanning electron micrographs are technically challenging and often cost or time-intensive. Relying exclusively on open-source software and equipment available in a standard lab, we have developed a method for rapid, software-assisted alignment of fluorescence images with the corresponding scanning electron micrographs via a stochastic gold micro-pattern. Here, we provide detailed instructions for micro-pattern production and image processing, troubleshooting for critical intermediate steps, and examples of membrane ultra-structures aligned with the fluorescence signal of proteins enriched at such sites. Together, the presented method for correlative fluorescence - scanning electron microscopy is versatile, robust and easily integrated into existing workflows, permitting image alignment with accuracy comparable to existing approaches with negligible investment of time or capital. PMID- 26647825 TI - Perfusion Pressure Is a Critical Determinant of the Intratumoral Extravasation of Oncolytic Viruses. AB - Antitumor efficacy of oncolytic virotherapy is determined by the density and distribution of infectious centers within the tumor, which may be heavily influenced by the permeability and blood flow in tumor microvessels. Here, we investigated whether systemic perfusion pressure, a key driver of tumor blood flow, could influence the intratumoral extravasation of systemically administered oncolytic vesicular stomatitis virus (VSV) in myeloma tumor-bearing mice. Exercise was used to increase mean arterial pressure, and general anesthesia to decrease it. A recombinant VSV expressing the sodium iodide symporter (NIS), which concentrates radiotracers at sites of infection, was administered intravenously to exercising or anesthetized mice, and nuclear NIS reporter gene imaging was used to noninvasively track the density and spatial distribution of intratumoral infectious centers. Anesthesia resulted in decreased intratumoral infection density, while exercise increased the density and uniformity of infectious centers. Perfusion state also had a significant impact on the antitumor efficacy of the VSV therapy. In conclusion, quantitative dynamic radiohistologic imaging was used to noninvasively interrogate delivery of oncolytic virotherapy, highlighting the critical importance of perfusion pressure as a driver of intratumoral delivery and efficacy of oncolytic viruses. PMID- 26647827 TI - In vitro antitumor effects of two novel oligostilbenes, cis- and trans suffruticosol D, isolated from Paeonia suffruticosa seeds. AB - Naturally derived stilbenes have been shown to elicit cytotoxic, anti-steroidal, anti-mutagenic, anti-oxidative, anti-inflammatory, and antitumor bioactivities. Previous phytochemical studies revealed that the seeds of Paeonia suffruticosa are rich in natural stilbenes. In this study the antitumor effects and mechanism of action of the oligostilbene isomers, cis- and trans-suffruticosol D, isolated from the seeds of P. suffruticosa were examined. cis- and trans-suffruticosol D exhibited remarkable cytotoxicity against the human cancer cell lines A549 (lung), BT20 (breast), MCF-7 (breast), and U2OS (osteosarcoma), but showed significantly less toxicity to the normal human cell lines HMEC (breast) and HPL1A (lung). We also demonstrated that cis- and trans-suffruticosol D exerted their antitumor effects by provoking oxidative stress, stimulating apoptosis, decreasing the mitochondrial membrane potential, inhibiting cell motility, and blocking the NF-kappaB pathway in human lung cancer cells. In addition, we evaluated their respective bioefficacy and found that trans-suffruticosol D is more potent than cis-suffruticosol D. Collectively, our results suggest that cis- and trans-suffruticosol D could be promising chemotherapeutic agents against cancer. PMID- 26647828 TI - Host-guest chemistry for tuning colloidal solubility, self-organization and photoconductivity of inorganic-capped nanocrystals. AB - Colloidal inorganic nanocrystals (NCs), functionalized with inorganic capping ligands, such as metal chalcogenide complexes (MCCs), have recently emerged as versatile optoelectronic materials. As-prepared, highly charged MCC-capped NCs are dispersible only in highly polar solvents, and lack the ability to form long range ordered NC superlattices. Here we report a simple and general methodology, based on host-guest coordination of MCC-capped NCs with macrocyclic ethers (crown ethers and cryptands), enabling the solubilization of inorganic-capped NCs in solvents of any polarity and improving the ability to form NC superlattices. The corona of organic molecules can also serve as a convenient knob for the fine adjustment of charge transport and photoconductivity in films of NCs. In particular, high-infrared-photon detectivities of up to 3.3 * 10(11) Jones with a fast response (3 dB cut-off at 3 kHz) at the wavelength of 1,200 nm were obtained with films of PbS/K3AsS4/decyl-18-crown-6 NCs. PMID- 26647826 TI - Profiles of microRNA networks in intestinal epithelial cells in a mouse model of colitis. AB - Inflammatory bowel diseases (IBDs) accompany a critical loss of the frontline barrier function that is achieved primarily by intestinal epithelial cells (IECs). Although the gene-regulation pathways underlying these host-defense roles of IECs presumably are deranged during IBD pathogenesis, the quantitative and qualitative alterations of posttranscriptional regulators such as microRNAs (miRNAs) within the cells largely remain to be defined. We aimed to uncover the regulatory miRNA-target gene relationships that arise differentially in inflamed small- compared with large-IECs. Whereas IBD significantly increased the expression of only a few miRNA candidates in small-IECs, numerous miRNAs were upregulated in inflamed large-IECs. These marked alterations might explain why the large, as compared with small, intestine is more sensitive to colitis and shows more severe pathology in this experimental model of IBD. Our in-depth assessment of the miRNA-mRNA expression profiles and the resulting networks prompts us to suggest that miRNAs such as miR-1224, miR-3473a, and miR-5128 represent biomarkers that appear in large-IECs upon IBD development and co operatively repress the expression of key anti-inflammatory factors. The current study provides insight into gene-regulatory networks in IECs through which dynamic rearrangement of the involved miRNAs modulates the gene expression regulation machinery between maintaining and disrupting gastrointestinal homeostasis. PMID- 26647829 TI - MicroRNA-145 inhibits the malignant phenotypes of gastric carcinoma cells via downregulation of fascin 1 expression. AB - MicroRNA (miR)-145 has been demonstrated to act as a tumor suppressor, and deregulation of fascin 1 (FSCN1) has been observed in several types of human malignancy, including gastric carcinoma. However, the molecular mechanism underlying the function of miR-145, specifically its targets in gastric carcinoma have yet to be fully elucidated. In the present study, downregulation of miR-145 and upregulation of FSCN1 was identified in gastric carcinoma cell lines, compared with normal gastric mucosal epithelial cells. A luciferase reporter assay demonstrated that miR-145 was able to bind to the 3'-untranslated region of FSCN1 mRNA. Overexpression of miR-145 led to a significant decrease in FSCN1 expression levels, whereas knockdown of miR-145 resulted in increased FSCN1 expression levels in gastric carcinoma cells. Furthermore, overexpression of miR 145 inhibited proliferation, migration and invasion in gastric carcinoma cells. Similar effects were also observed in gastric carcinoma cells transfected with FSCN1 small interfering RNA. In addition, overexpression of FSCN1 reversed the suppressive effects of miR-145 upregulation on proliferation, migration and invasion in gastric carcinoma cells, suggesting that FSCN1 is indeed involved in the miR-145-mediated malignant phenotype of gastric carcinoma cells. The present study revealed an anti-oncogenic role of miR-145 in gastric carcinoma via inhibition of FSCN1, and suggested that miR-145 may be used for the treatment of gastric carcinoma. PMID- 26647831 TI - Preparation and crystal structure of K2Ce(PO4)2: a new complex phosphate of Ce(iv) having structure with one-dimensional channels. AB - In this manuscript we report crystal structure of a new complex binary phosphate K2Ce(4+)(PO4)2 in K2O-P2O5-CeO2 system prepared by solid state reaction at moderate temperature conditions. The prepared material was characterized by powder X-ray diffraction using lab source and synchrotron radiation as well as thermal analyses, Raman scattering, FTIR, and X-ray photoelectron spectroscopic studies. The crystal structure of the compound has been determined from powder XRD data by ab initio structure solution in direct space followed by Rietveld refinements. K2Ce(PO4)2 crystallizes in a monoclinic (P21/n) lattice with unit cell parameters: a = 9.1060(4), b = 10.8160(5), c = 7.6263(4) A, beta = 111.155(2) degrees , V = 700.50(6) A(3). The unit cell contains two distinguishable PO4 tetrahedra and one CeO8 distorted square anti-prism. Raman spectroscopy confirmed the presence of isolated PO4(3-) groups in the structure. These PO4 tetrahedra are connected to one CeO8 polyhedra by sharing one edge and three other CeO8 polyhedra by sharing corners to form the three dimensional structure and empty channels parallel to a-axis. The channels are occupied by two crystallographically distinguishable K(+) ions which maintain the charge neutrality. Contrast to the earlier reported composition K4Ce2P4O15, this study revealed the composition in actual is K4Ce2P4O16 with Ce in 4+ oxidation state and is also supported by X-ray photoelectron spectroscopic and X-ray absorption near edge structure studies. Differential scanning calorimetric studies revealed a structural transition around 525 degrees C which reverts on cooling with a large thermal hysteresis. At higher temperature it undergoes a loss of oxygen atom and subsequently loss of phosphorus as P2O5. These thermal effects are also supported by in situ high temperature XRD studies. Finally the crystal chemistry of complex phosphates with tetravalent cations is also discussed. PMID- 26647830 TI - Indoleamine 2,3-dioxygenase downregulates T-cell receptor complex zeta-chain and c-Myc, and reduces proliferation, lactate dehydrogenase levels and mitochondrial glutaminase in human T-cells. AB - Indoleamine 2,3-dioxygenase (IDO), through L-tryptophan depletion, activates general control non-derepressible (GCN) 2 kinase and suppresses T-cell proliferation, in addition to suppressing aerobic glycolysis and glutaminolysis, which are required for these rapidly proliferating cells. A number of, however not all of these alterations, are partially mediated through IDO-induced p53 upregulation. In two-way mixed lymphocyte reactions (MLRs), IDO reduced cellular proliferation. In MLR-derived T-cells, IDO induced the expression levels of p53 and p21, however concurrently reduced the levels of zeta-chain, c-Myc, lactate dehydrogenase A (LDH-A) and glutaminase (GLS)2. However, p53 had no effect on the expression of the above proteins. These results were recapitulated in T-cells activated with anti-CD2, anti-CD3 and anti-CD28 by direct activation of the GCN2 kinase with tryptophanol. In conclusion, IDO, through GCN2 kinase activation, downregulates the levels of TCR-complex zeta-chain and c-Myc, resulting in the suppression of T-cell proliferation and a reduction in the levels of LDH-A and GLS2, which are key enzymes involved in aerobic glycolysis and glutaminolysis, respectively. PMID- 26647832 TI - Halogen dependent symmetry change in two series of wheel cluster organic frameworks built from La18 tertiary building units. AB - Two series of wheel cluster organic frameworks (WCOFs) built from La18 tertiary building units are hydrothermally made, which show halogen-dependent structural symmetry, and demonstrate different chiral performances. PMID- 26647833 TI - New tools for reconstruction and heterologous expression of natural product biosynthetic gene clusters. AB - Natural product scaffolds remain a major source and inspiration for human therapeutics. However, generation of a natural product in the post-genomic era often requires reconstruction of the corresponding biosynthetic gene cluster in a heterologous host. In the burgeoning fields of synthetic biology and metabolic engineering, a significant amount of efforts has been devoted to develop DNA assembly techniques with higher efficiency, fidelity, and modularity, and heterologous expression systems with higher productivity and yield. Here we describe recent advances in DNA assembly and host engineering and highlight their applications in natural product discovery and engineering. PMID- 26647835 TI - Pd(0)-catalyzed domino C-N coupling/hydroamination/C-H arylation reactions: efficient synthesis and photophysical properties of azaindolo[1,2 f]phenanthridines. AB - A series of new 7- and 4-azaindolo[1,2-f]phenanthridines were synthesized by a domino Pd(0)-catalyzed reaction, which involves three sequential steps: C-N coupling, hydroamination, and intramolecular C-H arylation. The products show promising fluorescence properties with high quantum yields (12-65%). PMID- 26647834 TI - Loss of synaptic Zn2+ transporter function increases risk of febrile seizures. AB - Febrile seizures (FS) are the most common seizure syndrome and are potentially a prelude to more severe epilepsy. Although zinc (Zn(2+)) metabolism has previously been implicated in FS, whether or not variation in proteins essential for Zn(2+) homeostasis contributes to susceptibility is unknown. Synaptic Zn(2+) is co released with glutamate and modulates neuronal excitability. SLC30A3 encodes the zinc transporter 3 (ZNT3), which is primarily responsible for moving Zn(2+) into synaptic vesicles. Here we sequenced SLC30A3 and discovered a rare variant (c.892C > T; p.R298C) enriched in FS populations but absent in population-matched controls. Functional analysis revealed a significant loss-of-function of the mutated protein resulting from a trafficking deficit. Furthermore, mice null for ZnT3 were more sensitive than wild-type to hyperthermia-induced seizures that model FS. Together our data suggest that reduced synaptic Zn(2+) increases the risk of FS and more broadly support the idea that impaired synaptic Zn(2+) homeostasis can contribute to neuronal hyperexcitability. PMID- 26647836 TI - Effects of hesperetin on platelet-derived growth factor-BB-induced pulmonary artery smooth muscle cell proliferation. AB - Hesperetin is a natural flavonoid, which has been reported to exert various biological activities and positive health effects on mammalian cells. The present study aimed to investigate the effects of hesperetin on the proliferation of primary cultured rat pulmonary artery smooth muscle cells (PASMCs), and to elucidate the possible underlying molecular mechanisms. The results of the present study indicated that hesperetin was able to inhibit the proliferation and DNA synthesis of platelet-derived growth factor-BB (PDGF-BB)-induced PASMCs in a dose- and time-dependent manner, without exerting cell cytotoxicity. In addition, hesperetin blocked the progression of the cell cycle from G0/G1 to S phase, which was correlated with the decreased mRNA expression levels of cyclin D1, cyclin E, cyclin-dependent kinase (CDK)2 and CDK4, and the increased mRNA expression levels of p27. Furthermore, the anti-proliferative effects of hesperetin were associated with suppression of the AKT/glycogen synthase kinase (GSK)3beta and p38 signaling pathway, but were not associated with the extracellular signal-regulated kinases 1/2 and c-Jun N-terminal kinases signaling pathways. These results suggested that hesperetin may inhibit PDGFa-BB-induced PASMC proliferation via the AKT/GSK3beta signaling pathway, and that it may possess therapeutic potential for the treatment of pulmonary vascular remodeling diseases. PMID- 26647837 TI - The long-term fate of permafrost peatlands under rapid climate warming. AB - Permafrost peatlands contain globally important amounts of soil organic carbon, owing to cold conditions which suppress anaerobic decomposition. However, climate warming and permafrost thaw threaten the stability of this carbon store. The ultimate fate of permafrost peatlands and their carbon stores is unclear because of complex feedbacks between peat accumulation, hydrology and vegetation. Field monitoring campaigns only span the last few decades and therefore provide an incomplete picture of permafrost peatland response to recent rapid warming. Here we use a high-resolution palaeoecological approach to understand the longer-term response of peatlands in contrasting states of permafrost degradation to recent rapid warming. At all sites we identify a drying trend until the late-twentieth century; however, two sites subsequently experienced a rapid shift to wetter conditions as permafrost thawed in response to climatic warming, culminating in collapse of the peat domes. Commonalities between study sites lead us to propose a five-phase model for permafrost peatland response to climatic warming. This model suggests a shared ecohydrological trajectory towards a common end point: inundated Arctic fen. Although carbon accumulation is rapid in such sites, saturated soil conditions are likely to cause elevated methane emissions that have implications for climate-feedback mechanisms. PMID- 26647838 TI - Capturing complex tumour biology in vitro: histological and molecular characterisation of precision cut slices. AB - Precision-cut slices of in vivo tumours permit interrogation in vitro of heterogeneous cells from solid tumours together with their native microenvironment. They offer a low throughput but high content in vitro experimental platform. Using mouse models as surrogates for three common human solid tumours, we describe a standardised workflow for systematic comparison of tumour slice cultivation methods and a tissue microarray-based method to archive them. Cultivated slices were compared to their in vivo source tissue using immunohistochemical and transcriptional biomarkers, particularly of cellular stress. Mechanical slicing induced minimal stress. Cultivation of tumour slices required organotypic support materials and atmospheric oxygen for maintenance of integrity and was associated with significant temporal and loco-regional changes in protein expression, for example HIF-1alpha. We recommend adherence to the robust workflow described, with recognition of temporal-spatial changes in protein expression before interrogation of tumour slices by pharmacological or other means. PMID- 26647840 TI - Sensitive detection of vortex-core resonance using amplitude-modulated magnetic field. AB - Understanding and manipulating the dynamic properties of the magnetic vortices stabilized in patterned ferromagnetic structures are of great interest owing to the superior resonant features with the high thermal stability and their flexible tunability. So far, numerous methods for investigating the dynamic properties of the magnetic vortex have been proposed and demonstrated. However, those techniques have some regulations such as spatial resolution, experimental facility and sensitivity. Here, we develop a simple and sensitive method for investigating the vortex-core dynamics by using the electrically separated excitation and detection circuits. We demonstrate that the resonant oscillation of the magnetic vortex induced by the amplitude- modulated alternating-sign magnetic field is efficiently picked up by the lock-in detection with the modulated frequency. By extending this method, we also investigate the size dependence and the influence of the magneto-static interaction in the resonant property of the magnetic vortex. PMID- 26647839 TI - Protection against ischemia/reperfusion-induced renal injury by co-treatment with erythropoietin and sodium selenite. AB - Ischemia/reperfusion injury (IRI) has lzong been an area of concern and focus of investigations. Erythropoietin (EPO) exhibits multiple protective effects, and selenium is an antioxidant trace element in the body, however, there have been no reports concerning the effects of EPO combined with sodium selenite on IRI. In the present study, a mouse model of renal IRI (RIRI) was pre-treated with EPO and sodium selenite to determine the most appropriate combination ratio of the two for further investigation. The results revealed that EPO and sodium selenite had synergistic protective effects in RIRI. EPO was identified as the predominant treatment component, with sodium selenite serving as an adjuvant, and combination treatment was markedly more effective, compared with treatment with either drug alone. The optimal ratio of treatment was 10:1 (10 IU EPO: 1 ug sodium selenite). The results indicated that RIRI markedly induced renal injury, as evidenced by elevated levels of blood urea nitrogen (BUN), as well as higher pathological scores, based on hematoxylin and eosin staining. Pre-treatment with EPO and sodium selenite significantly decreased serum expression levels of BUN and malonaldehyde, and increased the expression levels of superoxide dismutase, glutathione peroxidase and nitric oxide (NO), compared with the model group. Furthermore, co-treatment with EPO and sodium selenite upregulated the protein expression levels of phosphatidylinositol-3 kinase (PI3K) in renal tissue samples. Together, the results suggested that co-administration of EPO and sodium selenite effectively ameliorates IRI-induced renal injury by reducing oxidative stress and activating the PI3K/NO signaling pathway. PMID- 26647841 TI - Natural attenuation processes of arsenic in the groundwater of the Brahmaputra floodplain of Assam, India. AB - Natural attenuation of higher arsenic (As) concentration in the groundwater of the Brahmaputra valley of Assam can be a viable option for its remediation. The assessment of attenuation capacities in aquifers was done using three sediment core samples (namely C_50, C_70 and C_150) representing the commonly found sediments and characterized as viz. reduced, oxidized and moderately oxidized sediments, respectively. The feasability of aquifers to release low As water depends on the sorption capacity of the sediments to directly adsorbed as As(III) and/or oxidation to As(V) on oxidative sites. The various batch sorption experiments along with competition of other anions for adsorption sites at different concentrations were investigated. The sediments were observed to adsorb both As(III) and As(V) with varying magnitudes depending on the species of As, pH and concentrations of competing anions. The Elovich kinetic model best described kinetic test data. The oxidized sediment (C_70) with the highest Fe and Mn content has the highest adsorption capacity. The competition for adsorption sites with As(V) in the sediment samples followed the order PO4(3-) > SiO2 > HCO3(-). The oxidation of As(III) to As(V) by the sediments was analyzed as it is also the most effective pathway to reduce the toxicity as well as the mobility of As in the subsurface environment. Sediment C_70 showed the highest potential to oxidize As(III) to As(V) in the oxidative sites of the sediments. The removal of As(III) in the oxidative site via As(V) was the dominant As removal mechanism for the oxidized sediment (C_70) and moderately oxidized sediment (C_150) than the direct adsorption of As(III) on the adsorptive sites as on reduced sediment sample C_50. Therefore, targeting the oxidized sediment with a high concentration of Fe-oxides and Mn-oxides might make natural attenuation of As viable in the study areas. PMID- 26647842 TI - [Maternal mortality and the new objectives of sustainable development (2016 2030)]. PMID- 26647843 TI - Sexual dysfunction in obese women is more affected by psychological domains than that of non-obese. AB - PURPOSE: To compare differences in the occurrence and changed domains of sexual dysfunction in obese and non-obese Brazilian women. METHODS: Female Sexual Function Index, based on six domains, to investigate 31 sexual dysfunction incidence for obese compared to 32 non-obese women, was used. Statistical analysis using ANOVA and MANOVA were performed to compare total scores of Female Sexual Function Index among groups and to identify the differences among domains, Student t -test was used. Statistical significant level was established for all tests for p<0.05. RESULTS: No difference in female sexual dysfunction frequency between obese (25.8%) and non-obese women (22.5%) was found. However, an important distinction in which aspects of sexual life were affected was found. While the obese group was impaired in three domains of sexual life (desire, orgasm, and arousal), in the control group five aspects were dysfunctional (desire, orgasm, arousal, pain and lubrication). Future research exploring psychological outcomes in obese females, such as body image and measures of positive and negative effect, might better characterize the female sexual dysfunction in this group. CONCLUSIONS: Obesity does not appear to be an independent factor for allow quality of female sexual life. However, disturbance associated to obesity indicates a low frequency of disorder in physical domains, suggesting that psychological factors seem to be mainly involved in the sexual dysfunction in obese women. PMID- 26647844 TI - Telomerase activity associated with progression of cervical lesions in a group of Colombian patients. AB - PURPOSE To analyze the relation between the cytological findings and telomerase activity (TA). METHODS Cervical samples were evaluated and classified according to the Bethesda System. Telomerase activity was measured total product generated values (TPG) using the TRAP assay (telomeric repeat amplification protocol); data were analyzed statistically using the chi2 test, with the level of significance set at p<0.05. RESULTS The study was conducted on 102 patients. Of these, 3.9% showed normal cytological findings, 8.8% showed cervicitis; 2% showed Atypical Squamous Cells of Undetermined Significance (ASCUS); 67.6% showed Low Grade Squamous Intraepithelial Lesion (LSIL); 11.8% showed High Grade Squamous Intraepithelial Lesion (H-SIL) and 5.9% showed Squamous Carcinoma. Among telomerase-positive samples, the TPG values were cervicitis 0.5) with the age in the female monkeys. On the contrary in the male monkeys, only 45% of parameters correlated positively with the age (R(2) > 0.5). CONCLUSIONS: Thus, authors believe that results of this study are important for assisting researchers in the assessment of health status of captive housed African green monkeys for preclinical studies. PMID- 26647918 TI - Dissociation between systemic and pulmonary anti-inflammatory effects of dexamethasone in humans. AB - AIMS: The local pulmonary inflammatory response has a different temporal and qualitative profile compared with the systemic inflammatory response. Although glucocorticoids substantially downregulate the systemic release of acute-phase mediators, it is not clear whether they have comparable inhibitory effects in the human lung compartment. Therefore, we compared the anti-inflammatory effects of a pure glucocorticoid agonist, dexamethasone, on bronchoalveolar lavage and blood cytokine concentrations in response to bronchially instilled endotoxin. METHODS: In this randomized, double-blind and placebo-controlled trial, 24 volunteers received dexamethasone or placebo and had endotoxin instilled into a lung segment and saline instilled into a contralateral segment, followed by bronchoalveolar lavage. RESULTS: Bronchially instilled endotoxin induced a local and systemic inflammatory response. Dexamethasone strongly blunted the systemic interleukin (IL) 6 and C-reactive protein release. In sharp contrast, dexamethasone left the local release of acute-phase mediators in the lungs virtually unchanged: bronchoalveolar lavage levels of IL-6 were only 18% lower and levels of IL-8 were even higher with dexamethasone compared with placebo, although the differences between treatments were not statistically significant (P = 0.07 and P = 0.08, respectively). However, dexamethasone had inhibitory effects on pulmonary protein extravasation and neutrophil migration. CONCLUSIONS: The present study demonstrated a remarkable dissociation between the systemic anti-inflammatory effects of glucocorticoids and its protective effects on capillary leak on the one hand and surprisingly low anti-inflammatory effects in the lungs on the other. PMID- 26647921 TI - Effects of obesity on weight-bearing versus weight-supported exercise testing in patients with COPD. AB - BACKGROUND AND OBJECTIVE: Obesity is associated with increased dyspnoea and reduced health status in patients with chronic obstructive pulmonary disease (COPD). Studies on the effects of obesity on exercise capacity showed divergent results. The objective of this study is to investigate the impact of obesity on weight-bearing versus weight-supported exercise tolerance in obese and normal weight patients, matched for age, gender and degree of airflow limitation. METHODS: Retrospective analyses of data obtained during pre-pulmonary rehabilitation assessment in 108 obese COPD patients (OB) (age: 61.2 +/- 5.3y, FEV1 : 43.2 +/- 7.4%, BMI: 34.1 +/- 3.9 kg/m(2) ,) and 108 age and FEV1 -matched normal weight COPD patients (NW) (age: 61.7 +/- 3.6y, FEV1 : 41.5 +/- 8.4%, BMI: 22.9 +/- 1.2 kg/m(2) ,). Cardiopulmonary exercise test (CPET) and 6 min walk test (6MWT) were performed, Borg scores for dyspnoea and leg fatigue were recorded, before and after the tests. RESULTS: Six-minute walk distance differed between OB (398 +/- 107 m) and NW patients (446 +/- 109 m, P < 0.05), while peak cycling exercise load was comparable (OB: 75 +/- 29 W, NW: 70 +/- 25 W, ns). Dyspnoea (OB 3.2 +/- 2.0 vs NW 3.1 +/- 1.7, ns) and leg fatigue (OB 2.4 +/- 2.3 vs NW 1.9 +/- 1.7, ns) were not significantly different in OB compared with NW after 6MWT, or after CPET (dyspnoea: OB 5.1 +/- 2.4 vs NW 5.4 +/- 2.2, ns; leg fatigue: OB 4.0 +/- 2.3 vs NW 4.0 +/- 2.7, ns). CONCLUSION: In contrast to weight-supported exercise, obesity has a negative impact on weight-bearing exercise capacity, despite comparable exercise-related symptoms. The results of this study enhance the understanding of the impact of obesity on physical performance in COPD. PMID- 26647922 TI - Nonuniform Growth of Composite Layer-by-Layer Assembled Coatings via Three Dimensional Expansion of Hydrophobic Magnetite Nanoparticles. AB - Nanocomposite coatings are promising for a range of practical applications, and layer-by-layer assembly (LbL) is a versatile tool for nanocomposite formation. However, conventional LbL is a quite laborious procedure taking a lot of time to reach a sufficient thickness of the coatings required for practical applications. Herein, we proposed a novel variant of the LbL approach based on the deposition of hydrophilic polyelectrolyte molecules from a polar solvent and hydrophobic magnetite nanoparticles (NPs) from a nonpolar dispersion medium with an intermediate washing in the same polar solvent. The composite multilayers formed in this way exhibit exponential growth of the thickness and mass. On the basis of quartz crystal microbalance (QCM), Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), atomic force microscopy (AFM), and surface profile measurements, we propose a model describing the driving force of multilayer formation and the factors leading to nonlinear growth of their mass and thickness. The results allow one to expand the understanding of the mechanism of the LbL assembly in order to form multifunctional nanocomposites in a more efficient way. PMID- 26647923 TI - A shuttle vector series for precise genetic engineering of Saccharomyces cerevisiae. AB - Shuttle vectors allow for an efficient transfer of recombinant DNA into yeast cells and are widely used in fundamental research and biotechnology. While available shuttle vectors are applicable in many experimental settings, their use in quantitative biology is hampered by insufficient copy number control. Moreover, they often have practical constraints, such as limited modularity and few unique restriction sites. We constructed the pRG shuttle vector series, consisting of single- and multi-copy integrative, centromeric and episomal plasmids with marker genes for the selection in all commonly used auxotrophic yeast strains. The vectors feature a modular design and a large number of unique restriction sites, enabling an efficient exchange of every vector part and expansion of the series. Integration into the host genome is achieved using a double-crossover recombination mechanism, resulting in stable single- and multi copy modifications. As centromeric and episomal plasmids give rise to a heterogeneous cell population, an analysis of their copy number distribution and loss behaviour was performed. Overall, the shuttle vector series supports the efficient cloning of genes and their maintenance in yeast cells with improved copy number control. PMID- 26647924 TI - Amodiaquine-induced reproductive toxicity in adult male rats. AB - Amodiaquine (AQ) is routinely prescribed as an anti-malarial drug. Here, we evaluated AQ-induced toxicity in the male reproductive system. Eighty adult male Sprague-Dawley rats were randomly divided into four groups that received distilled water (control) or daily doses of 5 mg/kg body weight, 10 mg/kg, or 15 mg/kg AQ for 2 weeks. Testes morphology was analyzed using hematoxylin-and-eosin staining, terminal dUTP nicked-end labeling (TUNEL), and immunostaining whereas protein expression was determined by Western blotting. AQ dose-dependently led to abnormal spermatogenesis. Disruption of the blood-testis barrier and increased germ cell apoptosis were observed in all three AQ-treated groups. Interestingly, AQ-induced damage of spermatogenesis recovered over time, based on the survival of promyelocytic leukemia zinc-finger (PLZF)-positive, undifferentiated spermatogonia. Serum levels of luteinizing hormone and testosterone, as well as testicular testosterone levels, were not significantly altered in AQ-treated groups compared with controls. Collectively, our study suggests that AQ exerts substantial acute side effects on the reproductive systems of adult male rats by inducing the apoptosis of differentiating spermatogenic cells and disruption of blood-testis barrier function. PMID- 26647925 TI - Identifying molecular subtypes in human colon cancer using gene expression and DNA methylation microarray data. AB - Identifying colon cancer subtypes based on molecular signatures may allow for a more rational, patient-specific approach to therapy in the future. Classifications using gene expression data have been attempted before with little concordance between the different studies carried out. In this study we aimed to uncover subtypes of colon cancer that have distinct biological characteristics and identify a set of novel biomarkers which could best reflect the clinical and/or biological characteristics of each subtype. Clustering analysis and discriminant analysis were utilized to discover the subtypes in two different molecular levels on 153 colon cancer samples from The Cancer Genome Atlas (TCGA) Data Portal. At gene expression level, we identified two major subtypes, ECL1 (expression cluster 1) and ECL2 (expression cluster 2) and a list of signature genes. Due to the heterogeneity of colon cancer, the subtype ECL1 can be further subdivided into three nested subclasses, and HOTAIR were found upregulated in subclass 2. At DNA methylation level, we uncovered three major subtypes, MCL1 (methylation cluster 1), MCL2 (methylation cluster 2) and MCL3 (methylation cluster 3). We found only three subtypes of CpG island methylator phenotype (CIMP) in colon cancer instead of the four subtypes in the previous reports, and we found no sufficient evidence to subdivide MCL3 into two distinct subgroups. PMID- 26647926 TI - A Randomized Comparative Study of Two Techniques to Optimize the Root Coverage Using a Porcine Collagen Matrix. AB - The aim of this randomized controlled clinical study was to compare the extended flap technique (EFT) with the coronally advanced flap technique (CAF) using a porcine collagen matrix (PCM) for root coverage. Twenty patients with two bilateral gingival recessions, Miller class I or II on non-molar teeth were treated with CAF+PCM (control group) or EFT+PCM (test group). Clinical measurements of probing pocket depth (PPD), clinical attachment level (CAL), recession height (RH), keratinized tissue height (KTH), keratinized mucosa thickness (KMT) were determined at baseline, 3 and 6 months post-surgery. At 6 months, the mean root coverage for test group was 81.89%, and for control group it was 62.80% (p<0.01). The change of recession depth from baseline was statistically significant between test and control groups, with an mean of 2.21 mm gained at the control sites and 2.84 mm gained at the test sites (p=0.02). There were no statistically significant differences for KTH, PPD or CAL comparing the two therapies. The extended flap technique presented better root coverage than the coronally advanced flap technique when PCM was used. PMID- 26647927 TI - Influence of Implant Surfaces on Osseointegration: A Histomorphometric and Implant Stability Study in Rabbits. AB - The aim of this study was to evaluate the stability and osseointegration of implant with different wettability using resonance frequency analysis (RFA) and histomorphometric analysis (bone implant contact, BIC; and bone area fraction occupied, BAFO) after 2 and 4 weeks in rabbit tibiae. Thirty-two Morse taper implants (length 7 mm, diameter 3.5 mm) were divided according to surface characteristics (n=8): Neo, sandblasted and dual acid-etched; and Aq, sandblasted followed by dual acid-etched and maintained in an isotonic solution of 0.9% sodium chloride. Sixteen New Zealand rabbits were used. Two implants of each group were installed in the right and left tibiae according to the experimental periods. The RFA (Ostell(r)) was obtained immediately and after the sacrifice (2 and 4 weeks). The bone/implant blocks were processed for histomorphometric analysis. Data were analyzed using two-way ANOVA followed by Tukey's test and Pearson's correlation for ISQ, BIC and BAFO parameters (p=0.05). No significant effect of implant, period of evaluation or interaction between implant and period of evaluation was found for BIC and BAFO values (p>0.05). Only period of evaluation had significant effect for RFA values at 4 weeks (p=0.001), and at 2 weeks (p<0.001). RFA values were significantly higher at the final period of evaluation compared with those obtained at early periods. There was a significant correlation between BIC values and BAFO values (p=0.009). Both implant surfaces, Aq and Neo, were able to produce similar implant bone integration when normal cortical bone instrumentation was performed. PMID- 26647928 TI - Use of Silver Nanoparticles Reduces Internal Contamination of External Hexagon Implants by Candida albicans. AB - Since the dental implant/abutment interface cannot totally seal the passage of microorganisms, the interior of implant becomes a reservoir of pathogenic microorganisms that produce and maintain chronic inflammation in the tissues around implants. Silver nanoparticles (nano-Ag) are potent and broad-spectrum antimicrobial agents. The aim of this study was to evaluate the capacity of the nano-Ag to prevent the contamination of the implant internal surface by Candida albicans, caused by the implant/abutment microgap infiltration. Thirty-six implants were used in this experiment. Three study groups were performed: experimental group (implants receiving an application of nano-Ag in their inner cavity before installation of the abutment); positive-control group (implants receiving sterile phosphate buffer saline application instead of nano-Ag) and negative-control group (implants receiving the application of nano-Ag in the inner cavity and immersed in a sterile medium). In the positive-control and experimental groups, the implants were immersed in a Candida albicans suspension. The abutments of all three groups were screwed with a 10 N torque. After 72 h of immersion inC. albicans suspension or sterile medium, the abutments were removed and the inner surface of the implants was sampled with absorbent paper cone for fungal detection. No C. albicans contamination was observed in the negative control group. The positive-control group showed statistically higher values of colony forming units (CFUs) of C. albicans compared with the experimental group. In conclusion, silver nanoparticles reduced C. albicans colonization inside the implants, even with low torque screw abutment. PMID- 26647929 TI - Implant-Supported Removable Partial Denture Improves the Quality of Life of Patients with Extreme Tooth Loss. AB - This study aimed to evaluate oral health-related quality of life (OHRQoL) in partially dentate subjects, presenting extreme tooth loss in posterior region with missing post-canines, comparing the use of conventional removable partial dentures (RPDs) and implant-supported RPDs. OHRQoL was measured using the Brazilian version of the Oral Health Impact Profile. Twelve subjects presenting maxillary total and mandibular Kennedy Class I edentulism (mean age 62.6+/-7.8 years) first received complete maxillary dentures and conventional mandibular free-end RPDs. After two months, the subjects had their OHRQoL assessed. Osseointegrated implants were inserted bilaterally in the mandibular first molar regions, and after four months ball abutments were placed to support the free-end RPD. Two months later, the patients had their OHRQoL reassessed. Wilcoxon signed rank test was used to evaluate differences in OHRQoL (alpha=0.05). Results showed improvement in all OHIP-49 domains (p<0.05) after associating implants to the RPD. The mandibular implant-supported free-end RPD significantly improved OHRQoL. PMID- 26647930 TI - In Vitro Fit and Cementation Resistance of Provisional Crowns for Single Implant Supported Restorations. AB - This study aimed to verify marginal fit and the effect of cement film thickness standardization on retention of provisional crowns made with prefabricated acrylic cylinders on abutments, using two temporary luting agents subjected or not to mechanical cycling. Provisional crowns were made from bis-acryl (Luxatemp Fluorescence) or methyl methacrylate (Duralay) resins on acrylic cylinders and marginal fit and cement film thickness were evaluated. For retention evaluation, crowns were cemented with two temporary luting agents: non-eugenol zinc oxide (Tempbond NE) or calcium hydroxide-based (Hydcal) cements and subjected to tensile strength in a universal testing machine. After cleaning, debonded crowns were cemented again, subjected to mechanical cycling and retention was reassessed. The results of marginal fit and cement film thickness were analyzed by Student's t-test while retention of cements before and after mechanical cycling was analyzed using a mixed linear model. Methyl methacrylate crowns presented greater marginal misfit (p=0.001) and occlusal cement film thickness (p=0.003) than the bis-acryl ones. No difference was observed at axial cement film thickness (p=0.606). Resins (p=0.281) did not affect crown retention, but luting agents (p=0.029) and mechanical cycling (p=0.027) showed significant effects. The only significant interaction was mechanical cycling*luting agents, which means that luting agents were differently affected by mechanical cycling (p=0.002). In conclusion, the results showed that bis-acryl resin associated to calcium-hydroxide luting agent provided the best retention and lower cement thickness. PMID- 26647931 TI - Silanated Surface Treatment: Effects on the Bond Strength to Lithium Disilicate Glass-Ceramic. AB - The aim of this study was to evaluate the effect of silanization protocols on the bond strength of two resin cements to a lithium disilicate glass-ceramic. Thirty two ceramic discs were assigned to 2 groups (n=16): G1 - dual-cured resin cement and G2 - light-cured resin cement. Four subgroups were evaluated according to the used silanization protocol. The glass-ceramic was etched with 10% hydrofluoric acid for 20 s and silane was applied for 1 min, as follows: CTL - according to the manufacturer's instructions; HA - dried with hot air; NWA - washed and dried with water and air at room temperature; HWA - washed and dried with hot water and hot air. Thereafter, adhesive was applied and light-cured for 20 s. Silicon molds were used to prepare resin cement cylinders (1x1 mm) on the ceramic surface. The specimens were stored in deionized water at 37 degrees C for 48 h and subjected to a micro-shear test. The data were submitted to statistical analysis (?#61537;=0.05). Group G1 showed higher bond strengths than G2, except for the CTL and NWA subgroups. Differences as function of the silanization protocol were only observed in G1: HWA (25.13+/-6.83)>=HA (22.95+/-7.78)>=CTL(17.44+/-7.24) >=NWA(14.63+/-8.76). For G2 there was no difference among the subgroups. In conclusion, the silanization protocol affected the resin cement/ceramic bond strengths, depending on the material. Washing/drying with hot water and/or hot air increased only the bond strength of the dual-cured resin cement. PMID- 26647932 TI - Effects of Different Polishing Protocols on Lithium Disilicate Ceramics. AB - The aim of this study was to evaluate the effect of different polishing protocols on surface roughness and morphology of lithium disilicate ceramics (IPS e.max CAD). Fifty ceramic bars (2.0x3.0x2.5 mm) were produced and randomly divided into five groups (n=10), according to surface treatments: C: Control; Cer: Ceramaster (60 s); CW: cloth wheel with large-grit diamond (30 s) + cloth wheel with fine grit diamond paste (30 s); E: grey Exa-Cerapol (20 s) + pink Exa-Cerapol (20 s) + Cerapol Super (20 s); F: Felt wheel with large-grit diamond paste (30 s) + Felt wheel with fine-grit diamond paste (30 s). The samples were evaluated quantitatively for surface roughness (Ra) and qualitatively by SEM, at different moments: initial (prior to roughening), after roughening and after polishing procedures. Ra means were submitted to two-way ANOVA and Tukey test (p<0.05). After the different polishing protocols, no statistically significant differences were observed between the Cer and E groups (p=0.6347), E and CW groups (p=0.1366), and CW and FW groups (p=0.5433). Comparing different stages in the same group, it was possible to observe that CW (p<0.0001) and FW groups (p<0.0001) showed significant differences. SEM analysis revealed that both Cer and E groups exhibited a surface morphological pattern similar to that of control group. All polishing systems were effective in reducing the surface roughness of the studied ceramic type. PMID- 26647933 TI - Degree of Conversion and Mechanical Properties of Resin Cements Cured Through Different All-Ceramic Systems. AB - The aim of this study was to verify the degree of conversion (DC), Vickers microhardness (VH) and elastic modulus (E) of resin cements cured through different ceramic systems. One 1.5-mm-thick disc of each ceramic system (feldspathic, lithium dissilicate and zirconia veneered with feldspathic) was used. Three dual-cured (Allcem, Variolink II and RelyX U200) and one chemically cured (Multilink) resin cements were activated through ceramic discs. For dual cured resin cements was used a conventional halogen light-curing unit (Optilux 501 at 650 mW/cm2 for 120 s). Samples cured without the ceramic disc were used as control. The samples were stored at 37 degrees C for 24 h. ATR/FTIR spectrometry was used to evaluate the extent of polymerization in the samples (n=5). Micromechanical properties - VH and E - of the resin cements (n=5) were measured with a dynamic indentation test. Data were statistically analyzed with two-way ANOVA, Tukey's test and Pearson's correlation (alpha=0.05). DC was affected only by the type of resin cement (p=0.001). For VH, significant interaction was detected between resin cement and ceramic (p=0.045). The dual-cured resin cements showed no significant differences in mean values for E and significantly higher values than the chemically-cured resin cement. The degree of conversion and the mechanical properties of the evaluated resin cements depend on their activation mode and the type of ceramics used in 1.5 mm thickness. The dual-cured resin cements performed better than the chemically-cured resin cement in all studied properties. PMID- 26647934 TI - Effect of Plasma and Fiber Position on Flexural Properties of a Polyethylene Fiber-Reinforced Composite. AB - The aim of this study was to evaluate the effect of plasma treatment using argon and oxygen gases, combined with fiber position on flexural properties of a fiber reinforced composite. Eleven groups were evaluated, a non-reinforced control group and 10 groups reinforced with InFibra, a woven polyethylene fiber, varying according to the plasma treatment and fiber position. The samples were prepared using a stainless steel two-piece matrix. The three point bending test was performed in an EMIC testing machine. Flexural strength (FS) and flexural deflection (FD) were calculated from initial (IF) and final (FF) failure. Data were evaluated statistically using Kruskal-Wallis and Mann-Whitney tests (p<0.05). For IF, in all groups with fibers placed on the base, the FS and FD values were significantly higher than those positioned away from the base. The highest value of FS was obtained in the group treated with O 3 min (296.2 MPa) and the highest value of FD was obtained in the group treated with 1 min (0.109 mm). For FF the FS and FD values obtained for the groups with fibers positioned away from the base were similar or higher than those placed on the base. The highest FS value was obtained in the group treated with 1 min (317.5 MPa) and the highest FD value was obtained in the group treated with O 3 min (0.177 mm). Plasma treatment influenced FS and FD. Fiber position and plasma treatment affected the flexural properties of a fiber-reinforced composite. PMID- 26647935 TI - Influence of Organic Acids from the Oral Biofilm on the Bond Strength of Self Etch Adhesives to Dentin. AB - The aim of this study was to evaluate the microtensile bond strength of self-etch adhesive systems to dentin after storage in acids from oral biofilm. Three adhesive systems were used in the study: a two-step self-etch adhesive for use with a silorane-based resin composite (Filtek P90 adhesive system - P90), a two step self-etch adhesive (Clearfil SE Bond - CSE) and a one-step self-etch adhesive (Adper Easy One - AEO). The bond strength of these products was evaluated by bonding resin composite (Filtek Z350 for CSE and AEO; and Filtek P90 for P90) to 90 bovine dentin tooth fragments, according to the manufacturer's instructions. After 24 h of water storage at 37 degrees C, the specimens were sectioned into beams (1 mm2) divided and stored in distilled water, lactic acid and propionic acid, for 7 and 30 days. After storage, the specimens were tested for microtensile bond strength. Data were analyzed by three-way ANOVA and Tukey's test (alpha=0.05). CSE presented the highest microtensile bond strength after storage in distilled water for 7 and 30 days. The microtensile bond strength of all adhesive systems was lower after storage in lactic acid and propionic acid than after water storage. Significant difference was not found between storage times. PMID- 26647936 TI - Influence of Water Storage and Bonding Material on Bond Strength of Metallic Brackets to Ceramic. AB - This study investigated the influence of water storage (24 h and 6 months), and Transbond XT and Fuji Ortho LC bonding materials on the bond strength of metallic brackets bonded to feldspathic ceramic. Four cylinders of feldspathic ceramic were etched with 10% hydrofluoric acid for 60 s. Each cylinder received two layers of silane. Metallic brackets were bonded to the cylinders using Transbond XT or Fuji Ortho LC. Light-activation was carried out with 40 s total exposure time using Bluephase G2. Half the specimens for each bonding materials (n=20) were stored in distilled water at 37 degrees C for 24 h and the other half for 6 months. Shear bond strength testing was performed after storage times at a crosshead speed of 1 mm/min. The adhesive remnant index (ARI) was used to evaluate the amount of adhesive remaining on the ceramic surface at *8 magnification. Data were subjected to two-way ANOVA and Tukey's test (p<0.05). Transbond XT showed significantly higher bond strength (p<0.05) than Fuji Ortho LC. Significant differences in bond strength (p<0.05) were found when 24 h and 6 months storage times were compared between materials. ARI showed a predominance of score 0 for all groups, and higher scores at 1, 2 and 3 for 24 h storage time. In conclusion, storage time and bonding materials showed significant influence on the bond strength of brackets to ceramic. PMID- 26647937 TI - Effect of Brushing Time and Dentifrice Abrasiveness on Color Change and Surface Roughness of Resin Composites. AB - Dentifrice abrasiveness and brushing time may increase color change (?E) and surface roughness (?Ra) of resin composites. This study aimed to evaluate the effect of mechanical brushing time of dentifrices with different abrasiveness on ?E and ?Ra of nanofilled (Z350, 3M ESPE) and nanohybrid (Tetric N-Ceram, Ivoclar Vivadent) resin composites. Sixteen specimens (12 mm diameter x 2 mm thick) were fabricated using a white Teflon matrix of each resin composite and a ceramic (IPS e.max Ceram, Ivoclar Vivadent), used as control. After initial color readouts on white backgrounds (Spectrophotometer PCB 6807, Byk Gardner), with D65 standard illuminant, and surface roughness (Rugosimeter Surfcorder SE 1700, Kosalab) with cut-off=0.8 mm and speed=0.25 mm/s, specimens were assigned (n=8) according to the abrasiveness of the dentifrices: RDA* 68 (Colgate) and RDA* 180 (Colgate Total Plus Whitening). Specimens were submitted to mechanical brushing (58,400 cycles) and after every 14,600 cycles (1 year of brushing by a healthy individual), new color and surface roughness readouts were taken. Color stability was calculated by CIEDE2000. Data were analyzed by 3-way repeated measures ANOVA and Bonferroni test (p<0.05), and demonstrated that the dentifrice abrasiveness (p=0.02) and brushing time (p<0.0001) affected the ?E of nanofilled resin composite. There was no difference on surface roughness of materials (p=0.6752) or brushing time (p=0.7997). In conclusion, the longer the brushing time and dentifrice abrasiveness, the greater the color change of the nanofilled resin composite. The surface roughness was not influenced by dentifrice abrasiveness. PMID- 26647938 TI - Analysis of the Color and Fluorescence Alterations of Enamel and Dentin Treated With Hydrogen Peroxide. AB - The aim of this study was to evaluate the effect of hydrogen peroxide whitening on fluorescence and color of bovine enamel and dentin. Twenty five dentin discs and 25 enamel discs, with 6 mm diameter and 1 mm thick, were obtained. Direct fluorescence (spectrofluorophotometry) and color (spectrophotometry) were assessed. After fluorescence and color baseline measurements, specimens were immersed in a 35% hydrogen peroxide (HP) solution for 1 h. This procedure was repeated after 7 days. Final fluorescence and color measurements were performed after the second immersion. Chemical characterization of 5 additional specimens was also performed. Data were submitted to repeated analysis of variance and Tukey's test for fluorescence and unpaired t-test for color and chemical components (p<0.05). Fluorescence decreased significantly in dentin specimens after whitening. Enamel presented lower fluorescence than dentin at baseline, but this parameter did not decrease after whitening. Color changes were observed for both substrates, with significantly greater whitening effect in dentin (DeltaE=10.37) (p<0.001). Whitening by hydrogen peroxide induced significant decrease in fluorescence of tooth dentin and promoted significant color changes in dentin and enamel with more accentuated outcomes in dentin. PMID- 26647939 TI - Viability and Effects on Bacterial Proteins by Oral Rinses with Hypochlorous Acid as Active Ingredient. AB - This study investigated the effect of hypochlorous acid (HOCl) rinses and chlorhexidine (CHX) on the bacterial viability of S. mutans, A. israelii, P. gingivalis, A. actinomycetemcomitans, E. corrodens, C. rectus, K. oxytoca, K. pneumoniae and E. cloacae. The percentage of live bacteria was tested by fluorescence method using Live/Dead kit(r) and BacLight (Molecular Probes(r)) and compared between groups by the Kruskal-Wallis and U Mann-Whitney tests with Bonferroni correction (p value<0.012). The effect of HOCl and CHX on total proteins of P. gingivalis and S. mutans was determined by SDS-PAGE. CHX showed a higher efficacy than HOCl against S. mutans, A. israelii, E. corrodens and E. cloacae (p<0.001) while HOCl was more effective than CHX against P. gingivalis, A. actinomycetemcomitans, C. rectus and K. oxytoca (p=0.001). CHX and HOCl had similar efficacy against K. pneumoniae. Proteins of P. gingivalis and S. mutans were affected similarly by HOCl and CHX. HOCl reduced the bacterial viability especially in periodontopathic bacteria, which may support its use in the control of subgingival biofilm in periodontal patients. PMID- 26647940 TI - Morphology of Mesiobuccal Root Canals of Maxillary First Molars: a comparison of CBCT scanning and Cross-sectioning. AB - The aim of this study was to evaluate the mesiobuccal root of maxillary first molars, according to the root canal configuration, prevalence and location of isthmuses at 3 and 6 mm from the apex, comparing cone-beam computed tomography (CBCT) analysis and cross sectioning of roots by thirds. Images of the mesiobuccal root of 100 maxillary first molars were acquired by CBCT and then roots were cross-sectioned into two parts, starting at 3 mm from the apex. Data were recorded and analyzed according to Weine's classification for root canal configuration, and Hsu and Kim's classification for isthmuses. In the analysis of CBCT images, 8 root canals were classified as type I, 57 as type II, 35 as type III. In the cross-sectioning technique, 19 root canals were classified as type I, 60 as type II, 20 as type III and 1 as type IV. The classification of isthmuses was predominantly type I in both CBCT and cross-sectioning evaluations for sections at 3 mm from the apex, while for sections at 6 mm from the apex, the classification of isthmuses was predominantly types V and II in CBCT and cross sectioning evaluations, respectively. The cross-sectioning technique showed better results in detection of the internal morphology of root canals than CBCT scanning. PMID- 26647941 TI - Study of Root Canal Anatomy in Human Permanent Teeth in A Subpopulation of Brazil's Center Region Using Cone-Beam Computed Tomography - Part 1. AB - The aim of this study was to evaluate the frequency of roots, root canals and apical foramina in human permanent teeth using cone beam computed tomography (CBCT). CBCT images of 1,400 teeth from database previously evaluated were used to determine the frequency of number of roots, root canals and apical foramina. All teeth were evaluated by preview of the planes sagittal, axial, and coronal. Navigation in axial slices of 0.1 mm/0.1 mm followed the coronal to apical direction, as well as the apical to coronal direction. Two examiners assessed all CBCT images. Statistical data were analyzed including frequency distribution and cross-tabulation. The highest frequency of four root canals and four apical foramina was found in maxillary first molars (76%, 33%, respectively), followed by maxillary second molars (41%, 25%, respectively). The frequency of four root canals in mandibular first molars was 51%. Mandibular first premolars had two root canals and two apical foramina in 29% and 20% of the cases, respectively. Mandibular central and lateral incisors and canines presented two root canals in 35%, 42% and 22% of the cases, respectively. The navigation strategy in CBCT images favors a better identification of frequency and position of roots, root canals and apical foramina in human permanent teeth. PMID- 26647942 TI - Bovine Pulp Tissue Dissolution Ability of Irrigants Associated or Not to Ultrasonic Agitation. AB - The aim of this study was to evaluate the tissue dissolution ability of different irrigating solutions associated or not to ultrasonic agitation. Ninety bovine pulp fragments (n=10 per group) were weighed and then placed individually in Eppendorf test tubes containing the following irrigants: G1- 2.5% sodium hypochlorite (NaOCl); G2- 2.5% NaOCl + ultrasonic agitation (US); G3- 2.5% NaOCl + 0.2% cetrimide (CTR); G4- 2.5% NaOCl + 0.2% CTR + US; G5- 400 ppm Sterilox (SX); G6- SX + US; G7- 0.2% CTR; G8- 0.2% CTR + US; G9- saline solution. Two blinded observers assessed the samples continuously for the first 4 h, and then every hour for the next 12 h. Dissolution speed was calculated by dividing the initial pulp weight (mg) by the period of time until complete dissolution (min). Data were compared by ANOVA and Tukey post hoc test with a 5% significance level. G1 to G4 dissolved pulp fragments completely and G2 was significantly faster than the other groups. G5 to G9 did not exhibit dissolving activity. In conclusion, only groups containing NaOCl were capable of pulp tissue dissolution, which was enhanced by ultrasonic agitation, but did not alter when 0.2% cetrimide was associated. This isolated solution and Sterilox showed no dissolving capacity, regardless the use of ultrasound. PMID- 26647943 TI - Filling Effectiveness and Dentinal Penetration of Endodontic Sealers: A Stereo and Confocal Laser Scanning Microscopy Study. AB - The aim of this study was to evaluate the filling effectiveness and dentinal penetration of the sealers AH Plus, Pulp Canal Sealer EWT, Sealapex and MTA Fillapex applied according to the vertical condensation technique using thermoplastic gutta-percha. Forty single-rooted teeth were selected. After chemical-mechanical preparation and root-canal filling, sections of the root (2, 4 and 6 mm from the apex) were obtained and analyzed by stereo microscopy and confocal laser scanning microscopy. Data were tabulated and statistically analyzed. With regard to the assessment of void spaces in the filling material at 2 mm from the apex, the sealers showed similar results, but at 4 and 6 mm from the apex, MTA Fillapex had inferior performance compared to AH Plus (at 4 mm), Pulp Canal Sealer EWT (at 4 and 6 mm) and Sealapex (at 6 mm) (p<0.05). With regard to the penetration into dentinal tubules at 2 mm from the apex, the sealers also showed similar results, but at 4 and 6 mm Pulp Canal Sealer EWT had an inferior performance compared to MTA Fillapex and AH Plus, respectively (p<0.05). All four sealers were found to be similar regarding adaptation of the filling material to the root canal walls, except the MTA Fillapex, which showed failures at 4 and 6 mm from the root apex. With regard to the ability to penetrate into the dentinal tubules, the sealers were found to be equivalent, except for the Pulp Canal Sealer EWT as it had poorer results at 4 and 6 mm compared to MTA Fillapex and AH Plus, respectively. PMID- 26647944 TI - Efficacy of Electronic Foramen Locators in Controlling Root Canal Working Length during Rotary Instrumentation. AB - The present study evaluated the efficacy of electronic foramen locators (EFLs) to control root canal working length during rotary instrumentation and to assess possible reliability variations of different working lengths. Forty-eight human mandibular bicuspids were randomly divided in 2 groups according to the used device, Root ZX II (RZX) and Propex II (PRO). They were further subdivided in 2 subgroups according to the root canal preparation level (0.0 and -1.0). Preparation was performed with the Protaper rotary system using a crown-down technique. RZX was employed on its automatic auto-reverse mode (AAR) and PRO was used with the MPAS-10R contra-angle to monitor the preparation. The last used file (F3) was fixed, and the apical portion of the teeth was worn buccolingually, allowing to measure the extent between the file tip and the apical foramen (AF). The precision values of 0.0 mm and -1.0 mm were 100% and 0.0% for RZX, and 100% and 66.7% for PRO, respectively, with a range of +/-0.5 mm. Statistical analysis showed no differences between the groups at 0.0 mm. However, at -1.0 mm, RZX showed the poorest results (0.96+/-0.11 mm), followed by PRO (0.43+/-0.23 mm). The difference between RZX and PRO was statistically significant. The EFLs were precise in maintaining the working length during rotary preparation when reaching the AF, but when their penetration was limited, both devices showed decreased precision; the RZX AAR failed in all instances. PMID- 26647945 TI - Regenerative Endodontic Treatment as a Retreatment Option for a Tooth with Open Apex - A Case Report. AB - Treatment of non-vital immature teeth with apical periodontitis has always been a challenge in Endodontics. Regenerative endodontic treatment (RET) has been successfully used for the management of these cases. The aim of this study is to present a case of RET used for the retreatment of a previously endodontically treated permanent tooth with an open apex. A 14-year-old boy with a poor endodontic treatment done on his maxillary right central incisor developed symptomatic apical periodontitis. Radiographically, incomplete root development with thin dentinal walls and an open apex were evident. After accessing and removing previous filling materials, the canal was copiously irrigated with 2.5% sodium hypochlorite. A triple antibiotic paste was placed inside the canal and left for 15 days. After removal of the antibiotic mixture, bleeding was induced into the canal by passing a hand file out of the apex. A collagen membrane barrier was placed over the blood clot, followed by sealing with mineral trioxide aggregate. Access was sealed with permanent filling materials. Clinical examination at 12, 24 and 36 months revealed no symptoms. Radiographic examination showed resolution of the periapical lesion and apical closure. Sensitivity tests with cold and an electric pulp test elicited a negative response at all recall periods. On the basis of long-term results, RET may be an effective option for the retreatment of an immature permanent tooth with a failed previous treatment and periapical periodontitis. PMID- 26647946 TI - Adaptive modes of rumination: the role of subjective anger. AB - Rumination has been demonstrated to have negative consequences on affect, behaviour, and physiological markers. Recent studies, however, suggest that distinct "modes" of anger-associated rumination may lead to several positive consequences. Previous research primarily used recall procedures of anger episodes to elicit anger. By contrast, the present study focused on the effect of subjective anger on the process of rumination and tested its effects in a "staged" social interaction where a confederate provoked participants. Subsequently, participants engaged in rumination about the anger-eliciting event either in an abstract-distanced or a concrete-immersed rumination mode. Results showed an adaptive effect of abstract-distanced rumination on subjective anger primarily if anger is high prior to rumination. The findings also suggest different self-reported anger-related coping strategies in response to subjective anger intensity. These findings highlight that an abstract-distanced rumination may have differential effects on affective outcomes and anger-related coping strategies. PMID- 26647947 TI - Effects of carrying handles, postures, materials and distances on carrying capability. AB - This study recruited 14 industrial workers to examine the effects of carrying handles, postures, materials and distances on maximum acceptable weights of carrying (MAWC), and resulting heart rate and body rating of perceived exertion (RPE) for a 20 min intensive carrying task. This study showed that MAWC of carrying with bar handles, carrying with hands-and-body posture, solid materials and 4 m distance were significantly higher than that of carrying with groove handles, carrying with hands posture, liquid materials and 8 m distance, respectively. The resulting heart rates while carrying MAWCs of groove handles, hands-and-body carrying posture, solid materials and 4 m distance were lower than the resulting heart rates while carrying MAWCs of bar handles, hands carrying posture, liquid materials and 8 m distance, respectively. Most pair levels of independent variables resulted in similar body's RPEs except for the pair levels of carrying distance. PMID- 26647948 TI - Selected aspects of absence at work and work-related health problems in Polish enterprises. AB - Workers' working conditions, work-related health problems and sickness absence are interdependent factors. Both workers' health problems and their absence are adverse events which generate significant costs for both Poland's Social Insurance Institution (ZUS) and employers. Despite the related burdens, it is difficult to assess the number of workers who experience work-related health problems, to indicate the share of those workers who have been unfit for work owing to such disorders and to indicate the types of workers' disorders which are caused by factors the workers are exposed to in the working environment. This article presents the findings of surveys carried out in selected production and service-providing companies, assessing the scale and nature of work-related health problems and their links with workers' sickness absence. PMID- 26647949 TI - Using lagging and leading indicators for the evaluation of occupational safety and health performance in industry. AB - Improvement of occupational safety and health (OSH) management is closely related to the development of OSH performance measurement, which should include OSH outcomes (e.g., occupational accidents), OSH inputs (including working conditions) and OSH-related activities. The indicators used to measure the OSH outcomes are often called lagging indicators, and the indicators of inputs and OSH activities are leading indicators. A study was conducted in 60 companies in order to determine what kinds of indicators were used for OSH performance measurement by companies with different levels of OSH performance. The results reveal that the indicators most commonly used in all of the companies are those related to ensuring compliance with the statutory requirements. At the same time, the leading indicators are much more often adopted in companies with a higher performance level. These companies also much more often monitor on a regular basis the indicators adopted for the evaluation of their OSH performance. PMID- 26647950 TI - Corrosion of connectors used in equipment protecting against falls from a height. AB - Connectors are commonly found in personal equipment protecting against falls from a height. They are typically used outdoors and exposed to atmospheric factors, which can result in corrosion. This article presents the results of a study involving exposure of connectors to experimental corrosive media - neutral salt spray (NSS), acid salt spray (ASS), and seawater mist (for elements made of carbon steel and non-ferrous metals) - and to experimental conditions simulating the processes of pitting, stress, and intercrystalline corrosion (for equipment made of s'tainless steel). The results indicate that the main effects of corrosion on connectors include impaired operation and reduced strength of their mobile elements. The article presents methods of testing connector operation developed for this purpose. Corrosive damage to connectors has been presented in relation to potential hazards for their users. PMID- 26647951 TI - A comparison of neck bending and flexion measurement methods for assessment of ergonomic risk. AB - Head movements of workers were measured in the sagittal plane in order to establish a precise and accurate assessment method to be used in real work situations. Measurements were performed using two inclinometers connected to an embedded recording system. Two quantitative analysis methods were tested, i.e., measurement of bending with an inclinometer attached to the head, and measurement of flexion/extension by using an additional inclinometer located at C7/T1. The results were also compared with a video observation method (qualitative). The results showed that bending measurements were significantly different from those of flexion/extension for angles between 0 degrees and 20 degrees , and angles >45 degrees . There were also significant differences between workers for flexion >45 degrees , reflecting individual variability. Additionally, several limitations of observational methods were revealed by this study. PMID- 26647952 TI - Establishment of an Associate Degree in Safety Technology. AB - Various types of hazards are present in all aspects of the economy. Training is an essential ingredient in the reduction and elimination of these hazards. The development of qualified safety professionals is necessary for solving the main problems facing and organizing a safe work environment. This paper presents the development of an Associate of Applied Science Degree in Safety Technology. The paper includes the rational for the development of the proposed program, a literature review on the need for safety education, the main features of the developed program, a program need analysis, program educational objectives, program outcomes, a degree plan and course description. The developed program should provide a guide to training institutes worldwide for the development of a safety program at any educational level, including an associate, bachelor or graduate education in safety. The level of presentation of such a program would depend on the availability of qualified staff and resources. PMID- 26647953 TI - Exposure of farm workers to electromagnetic radiation from cellular network radio base stations situated on rural agricultural land. AB - The electromagnetic field (EMF) levels generated by mobile telephone radio base stations (RBS) situated on rural-agricultural lands were assessed in order to evaluate the exposure of farm workers in the surrounding area. The expected EMF at various distances from a mobile telephone RBS was calculated using an ad hoc numerical forecast model. Subsequently, the electric fields around some RBS on agricultural lands were measured, in order to obtain a good approximation of the effective conditions at the investigated sites. The viability of this study was tested according to the Italian Regulations concerning general and occupational public exposure to time-varying EMFs. The calculated E-field values were obtained with the RBS working constantly at full power, but during the in situ measurements the actual power emitted by RBS antennas was lower than the maximum level, and the E-field values actually registered were much lower than the calculated values. PMID- 26647955 TI - Erratum. PMID- 26647954 TI - White LED compared with other light sources: age-dependent photobiological effects and parameters for evaluation. AB - Ergonomic science at work and living places should appraise human factors concerning the photobiological effects of lighting. Thorough knowledge on this subject has been gained in the past; however, few attempts have been made to propose suitable evaluation parameters. The blue light hazard and its influence on melatonin secretion in age-dependent observers is considered in this paper and parameters for its evaluation are proposed. New parameters were applied to analyse the effects of white light-emitting diode (LED) light sources and to compare them with the currently applied light sources. The photobiological effects of light sources with the same illuminance but different spectral power distribution were determined for healthy 4-76-year-old observers. The suitability of new parameters is discussed. Correlated colour temperature, the only parameter currently used to assess photobiological effects, is evaluated and compared to new parameters. PMID- 26647956 TI - Generic method approaches for monoclonal antibody therapeutics analysis using both ligand binding and LC-MS/MS techniques. AB - Monoclonal antibody (mAb) and mAb-derived biotherapeutics are being developed to interact with specific target molecule(s) to intervene disease formation or progression. LC-MS/MS methods have emerged to compensate for the limitations of conventional ligand-binding assays. Application of a generic LC-MS/MS method to multiple mAb candidates can save method development time as most mAb biotherapeutics are IgG 1, 2 and 4 isotypes. Three common components are essential to a generic LC-MS/MS method: a common workflow, a common surrogate peptide and the corresponding stable isotope-labeled internal standard. The generic LC-MS/MS method is translatable from a single- into a multiple-analyte method, and from a generic into a specific method. Strategies and caveats on method applications are discussed in this chapter. PMID- 26647957 TI - Shrunken Pore Syndrome is associated with a sharp rise in mortality in patients undergoing elective coronary artery bypass grafting. AB - Shrunken Pore Syndrome was recently suggested for the pathophysiologic state in patients characterized by an estimation of their glomerular filtration rate (GFR) based upon cystatin C, which is lower or equal to 60% of their estimated GFR based upon creatinine, i.e. when eGFR cystatin C <= 60% of eGFR creatinine. Not only the cystatin C level, but also the levels of other low molecular mass proteins are increased in this condition. The preoperative plasma levels of cystatin C and creatinine were measured in 1638 patients undergoing elective coronary artery bypass grafting. eGFR cystatin C and eGFR creatinine were calculated using two pairs of estimating equations, CAPA and LMrev, and CKD-EPI cystatin C and CKD-EPI creatinine, respectively. The Shrunken Pore Syndrome was present in 2.1% of the patients as defined by the CAPA and LMrev equations and in 5.7% of the patients as defined by the CKD-EPI cystatin C and CKD-EPI creatinine equations. The patients were studied over a median follow-up time of 3.5 years (2.0-5.0 years) and the mortality determined. Shrunken Pore Syndrome defined by both pairs of equations was a strong, independent, predictor of long-term mortality as evaluated by Cox analysis and as illustrated by Kaplan-Meier curves. Increased mortality was observed also for the subgroups of patients with GFR above or below 60 mL/min/1.73 m(2). Changing the cut-off level from 60 to 70% for the CAPA and LMrev equations increased the number of patients with Shrunken Pore Syndrome to 6.5%, still displaying increased mortality. PMID- 26647958 TI - Communicating radiation risk to patients and referring physicians in the emergency department setting. AB - Heightened awareness about the radiation risks associated with CT imaging has increased patients' wishes to be informed of these risks, and has motivated efforts to reduce radiation dose and eliminate unnecessary imaging. However, many ordering providers, including emergency physicians, are ill prepared to have an informed discussion with patients about the cancer risks related to medical imaging. Radiologists, who generally have greater training in radiation biology and the risks of radiation, often do not have a face-to-face relationship with the patients who are being imaged. A collaborative approach between emergency physicians and radiologists is suggested to help explain these risks to patients who may have concerns about getting medical imaging. PMID- 26647959 TI - NF-kappaB signaling plays irreplaceable roles in cisplatin-induced bladder cancer chemoresistance and tumor progression. AB - Bladder cancer (BCa) is the most vital urogenital malignant disease worldwide, bringing huge economic and social burden every year. Clinically, BCa is subdivided into superficial type and invasive type according to clinic-pathology, accompanied with different strategy of therapy. Number of reports indicate that 10-30% of superficial BCa will inevitable progress into invasive type, manifesting enhanced malignant behavior compared to original invasive type. Regardless of the original being an original invasive type or invasive type that progressed from superficial type of BCa, chemotherapy (including adjuvant or neo adjuvant chemotherapy) in line with radiotherapy is the final regimen for BCa patients. Previous reports pointed out the high efficiency of cisplatin containing chemotherapeutic regimen for BCa patients, leading to wide use of this regimen in BCa therapeutics. However, cisplatin-resistance inevitably appear, resulting in the failure of the BCa chemotherapy, the mechanism of which is still unknown. In the present study, parental BCa cell lines T24/J82 were used to obtain stable-cisplatin-resistance cell lines T24R/J82R, which showed enhanced capacity of malignancy, tumorigenesis and drug resistance, accompanied by elevated expression of EMT markers. The further mechanism investigation suggested that prolonged time of cisplatin-treatment contributed to the activation of the NF-kappaB signal, resulting in the upregulation of EMT markers, the maintenance of stem cell marker and the elevated expression of ABCB1. Thus, our study provides us a new view of the role of NF-kappaB signaling in BCa therapeutics. PMID- 26647960 TI - Hepatitis B virus induces hypoxia-inducible factor-2alpha expression through hepatitis B virus X protein. AB - A growing number of studies suggest that the hepatitis B virus X protein (HBx) enhances the protein stability of the hypoxia-inducible factor-1alpha (HIF 1alpha). However, the relationship between hepatitis B virus (HBV), HBx and hypoxia-inducible factor-2alpha (HIF-2alpha) has not yet been fully elucidated. Immunohistochemical analysis was employed to detect the expression of HIF-2alpha in normal liver, HBV-related chronic hepatitis, and HBV-related and non-HBV related hepatocellular carcinoma (HCC) tissues. Quantitative real-time PCR (qPCR) and western blotting were used to investigate the impact of HBV and HBx on the expression of HIF-2alpha. Immunoprecipitation and immunofluorescence were applied to explore the underlying mechanisms. The HIF-2alpha expression was found to be higher in HBV-related chronic hepatitis tissues than in normal liver tissues. Furthermore, it was higher in HBV-related HCC tissues and HBV-integrated HepG2 cells than in the corresponding non-HBV-related HCC tissues and HepG2 cells. Both HBV and HBx enhanced the protein stability of HIF-2alpha. HBx-mediated upregulation of HIF-2alpha resulted mainly from an inhibition of the degradation of HIF-2alpha due to the binding of HBx to the von Hippel-Lindau protein (pVHL). In addition, HBx upregulated the expression of HIF-2alpha by activating the NF kappaB signaling pathway. Thus, the present study identified that HBV induces the HIF-2alpha expression through its encoded protein HBx. This upregulates the HIF 2alpha expression by binding to the pVHL activating the NF-kappaB signaling pathway. PMID- 26647961 TI - Dendritic cells pulsed with Hsp70 and HBxAg induce specific antitumor immune responses in hepatitis B virus-associated hepatocellular carcinoma. AB - Previous studies have drawn attention to dendritic cell (DC) vaccines; particularly the application of the tumor-associated antigen-targeted DC vaccine. The present study analyzed DCs derived from a normal individual and pulsed the cells with heat shock protein 70 peptide (Hsp70) and/or hepatitis B virus x antigen (HBxAg), a hepatocellular carcinoma (HCC)-associated antigen. It was then investigated whether this method of vaccination induced strong therapeutic antitumor immunity. The results revealed that the Hsp70/HBxAg complex-activated phenotype improves the functional maturation of DCs compared with using Hsp70 or HBxAg alone. Compared with either Hsp70 or HBxAg alone, matured DCs pulsed with the Hsp70/HBxAg complex stimulated a high level of autologous T-cell proliferation and induced HCC-specific cytotoxic T lymphocytes, which specifically killed HCC cells through a major histocompatibility complex class I mechanism. These results indicated that a vaccination therapy using DCs co-pulsed with the Hsp70/HBxAg complex is an effective strategy for immunotherapy and may offer a useful approach to protect against HCC. PMID- 26647962 TI - Nonlinear Generation of Electromagnetic Waves through Induced Scattering by Thermal Plasma. AB - We demonstrate the conversion of electrostatic pump waves into electromagnetic waves through nonlinear induced scattering by thermal particles in a laboratory plasma. Electrostatic waves in the whistler branch are launched that propagate near the resonance cone. When the amplitude exceeds a threshold ~5 * 10(-6) times the background magnetic field, wave power is scattered below the pump frequency with wave normal angles (~59 degrees ), where the scattered wavelength reaches the limits of the plasma column. The scattered wave has a perpendicular wavelength that is an order of magnitude larger than the pump wave and longer than the electron skin depth. The amplitude threshold, scattered frequency spectrum, and scattered wave normal angles are in good agreement with theory. The results may affect the analysis and interpretation of space observations and lead to a comprehensive understanding of the nature of the Earth's plasma environment. PMID- 26647963 TI - A 3-day EGCG-supplementation reduces interstitial lactate concentration in skeletal muscle of overweight subjects. AB - Green tea, particularly epigallocatechin-3-gallate (EGCG), may affect body weight and composition, possibly by enhancing fat oxidation. The aim of this double blind, randomized placebo-controlled cross-over study was to investigate whether 3-day supplementation with EGCG (282 mg/day) stimulates fat oxidation and lipolysis in 24 overweight subjects (age = 30 +/- 2 yrs, BMI = 27.7 +/- 0.3 kg/m(2)). Energy expenditure, substrate metabolism and circulating metabolites were determined during fasting and postprandial conditions. After 6 h, a fat biopsy was collected to examine gene expression. In 12 subjects, skeletal muscle glycerol, glucose and lactate concentrations were determined using microdialysis. EGCG-supplementation did not alter energy expenditure and substrate oxidation compared to placebo. Although EGCG reduced postprandial circulating glycerol concentrations (P = 0.015), no difference in skeletal muscle lipolysis was observed. Fasting (P = 0.001) and postprandial (P = 0.003) skeletal muscle lactate concentrations were reduced after EGCG-supplementation compared to placebo, despite similar tissue blood flow. Adipose tissue leptin (P = 0.05) and FAT/CD36 expression (P = 0.08) were increased after EGCG compared to placebo. In conclusion, 3-day EGCG-supplementation decreased postprandial plasma glycerol concentrations, but had no significant effects on skeletal muscle lipolysis and whole-body fat oxidation in overweight individuals. Furthermore, EGCG decreased skeletal muscle lactate concentrations, which suggest a shift towards a more oxidative muscle phenotype. PMID- 26647965 TI - Magnetic fluctuations driven insulator-to-metal transition in Ca(Ir(1-x)Rux)O3. AB - Magnetic fluctuations in transition metal oxides are a subject of intensive research because of the key role they are expected to play in the transition from the Mott insulator to the unconventional metallic phase of these materials, and also as drivers of superconductivity. Despite much effort, a clear link between magnetic fluctuations and the insulator-to-metal transition has not yet been established. Here we report the discovery of a compelling link between magnetic fluctuations and the insulator-to-metal transition in Ca(Ir1-xRux)O3 perovskites as a function of the substitution coefficient x. We show that when the material turns from insulator to metal, at a critical value of x ~ 0.3, magnetic fluctuations tend to change their character from antiferromagnetic, a Mott insulator phase, to ferromagnetic, an itinerant electron state with Hund's orbital coupling. These results are expected to have wide-ranging implications for our understanding of the unconventional properties of strongly correlated electrons systems. PMID- 26647964 TI - Suppression of established hepatocarcinoma in adjuvant only immunotherapy: alum triggers anti-tumor CD8+ T cell response. AB - Dendritic cell-based immunotherapy is a new weapon in our battle against malignancies in human. Recent trials in human and research work in model animals have shown various degrees of success, suggesting its great potential for clinical use. While protocols vary, a common scheme in this category of treatment involves activation of dendritic cells, with the purpose of increasing antigen presentation and cellular immunity. Therefore, proper use of immune adjuvant is a central subject of study. We report here an unexpected finding that injection of alum, the most widely used human adjuvant, into mice carrying H22 hepatocarcinoma resulted in a significant reduction of tumor growth with extended animal survival. This effect was associated with an increased specific CD8(+) T cell activation and an inflammatory environment, yet with minimal overt side effects. Our finding suggests that use of adjuvant alone in certain established tumors can invoke protective host immune activation against the same target, which may be of value in our development of new cancer immunotherapies. PMID- 26647966 TI - Distinct immune signatures in the colon of Crohn's disease and ankylosing spondylitis patients in the absence of inflammation. AB - Crohn's disease (CD) is an inflammatory bowel disease characterized by patchy inflammation of the gastrointestinal tract. Ankylosing spondylitis (AS) is primarily characterized by inflammation of the lower vertebral column, and many patients with AS present with inflammatory gut symptoms. Genome-wide association studies have highlighted significant overlap in short nucleotide polymorphisms for both diseases. We hypothesized that patients with CD and AS have a common intestinal immune signature, characterized by inflammatory T cells, compared with healthy people. We designed a pilot study to determine both the feasibility of defining complex immune signatures from primary tissue, and differences in the local immune signature of people with inflammatory diseases compared with healthy people. Intestinal biopsies were obtained by colonoscopy from healthy patients, non-inflamed regions of CD patients and AS patients with inflammatory gut symptoms. A flow cytometry platform was developed measuring polyfunctional T-cell populations based on cytokines, surface molecules and transcription factors. There was overlap in the immune signature of people with CD or AS, characterized by changes in the frequency of regulatory T cells, compared with healthy people. There were significant differences in frequencies of other polyfunctional T-cell populations-CD patients had an increased frequency of T cells producing interleukin-22 (IL-22) and interferon-gamma, whereas AS patients had an increased frequency of T cells producing IL-2; compared with healthy people. These data indicate that the local immune signature could be described in these patients and that distinct immune mechanisms may underlie disease progression. PMID- 26647967 TI - Early-life exercise may promote lasting brain and metabolic health through gut bacterial metabolites. AB - The 100 trillion microorganisms residing within our intestines contribute roughly 5 million additional genes to our genetic gestalt, thus posing the potential to influence many aspects of our physiology. Microbial colonization of the gut shortly after birth is vital for the proper development of immune, neural and metabolic systems, while sustaining a balanced, diverse gut flora populated with beneficial bacteria is necessary for maintaining optimal function of these systems. Although symbiotic host-microbial interactions are important throughout the lifespan, these interactions can have greater and longer lasting impacts during certain critical developmental periods. A better understanding of these sensitive periods is necessary to improve the impact and effectiveness of health promoting interventions that target the microbial ecosystem. We have recently reported that exercise initiated in early life increases gut bacterial species involved in promoting psychological and metabolic health. In this review, we emphasize the ability of exercise during this developmentally receptive time to promote optimal brain and metabolic function across the lifespan through microbial signals. PMID- 26647968 TI - The CD169 sialoadhesin molecule mediates cytotoxic T-cell responses to tumour apoptotic vesicles. AB - Apoptosis leads to the fragmentation and packaging of cellular contents into discrete vesicles, a process known as 'blebbing'. Extracellular vesicles express membrane-bound sialic acids, which enable their capture by CD169 (sialoadhesin; Siglec-1) expressing macrophages in the lymph node and spleen. Furthermore, CD169 mediates vesicle trafficking and suppresses the immune response to exosomes-a type of extracellular vesicle released from living cells. In this study, we found that CD169(+) macrophages were the predominant splenic macrophage subset responsible for the capture of EL4 lymphoma-derived apoptotic vesicles (ApoVs) from circulation. CD169(-/-) mice had significantly enhanced in vivo cytotoxic T lymphocyte responses to antigen-pulsed ApoVs, indicating a suppressive role for CD169(+) macrophages to ApoV-associated antigen. In contrast to the observed immunogenic role of ApoVs, the co-administration of unpulsed ApoVs with antigen pulsed dendritic cells (DCs) significantly suppressed DC-mediated cytotoxic response in vivo; however, this occurred independent of CD169 expression. Overall, our results confirm that apoptosis contributes to both tolerance and immunity, as well as establishing CD169 as a critical mediator of the immune response to extracellular vesicles. PMID- 26647969 TI - Observation of stimulated emission from a single Fe-doped AlN triangular fiber at room temperature. AB - Aluminum nitride (AlN) is a well known wide-band gap semiconductor that has been widely used in fabricating various ultraviolet photo-electronic devices. Herein, we demonstrate that a fiber laser can be achieved in Fe-doped AlN fiber where Fe is the active ion and AlN fiber is used as the gain medium. Fe-doped single crystal AlN fibers with a diameter of 20-50 MUm and a length of 0.5-1 mm were preparated successfully. Stimulated emission (peak at about 607 nm and FWHM ~0.2 nm) and a long luminescence lifetime (2.5 ms) were observed in the fibers by a 532 nm laser excitation at room temperature. The high quality long AlN fibers are also found to be good optical waveguides. This kind of fiber lasers may possess potential advantages over traditional fiber lasers in enhancing power output and extending laser wavelengths from infrared to visible regime. PMID- 26647971 TI - Cannabinoid Modulation of Frontolimbic Activation and Connectivity During Volitional Regulation of Negative Affect. AB - Behavioral and brain research indicates that administration of Delta(9) tetrahydrocannabinol (THC) alters threat perception and enhances the suppression of conditioned fear responses via modulation of the frontolimbic circuit. No prior studies, however, have examined whether THC also affects volitional forms of emotion processing such as cognitive reappraisal. The aim of the current study was therefore to examine the effects of THC on frontolimbic activation and functional connectivity during cognitive reappraisal in a sample of healthy adults. The study was a randomized, double-blind, placebo-controlled, between subject design and all participants ingested either an oral dose of synthetic THC (n=41) or placebo (n=37) before completion of an emotion regulation task during functional magnetic resonance imaging (fMRI). Functional connectivity was assessed using generalized psychophysiological interaction (gPPI) analyses. Results indicated that although there were no group differences in self-reported attenuation of negative affect during cognitive reappraisal, relative to placebo, THC increased amygdala activation and reduced amygdala and dorsolateral prefrontal cortex (dlPFC) functional coupling during cognitive reappraisal of emotionally negative pictures. This suggests that in addition to automatic emotional processes, THC affects frontolimbic functioning during cognitive reappraisal. PMID- 26647970 TI - A comprehensive assessment of somatic mutation detection in cancer using whole genome sequencing. AB - As whole-genome sequencing for cancer genome analysis becomes a clinical tool, a full understanding of the variables affecting sequencing analysis output is required. Here using tumour-normal sample pairs from two different types of cancer, chronic lymphocytic leukaemia and medulloblastoma, we conduct a benchmarking exercise within the context of the International Cancer Genome Consortium. We compare sequencing methods, analysis pipelines and validation methods. We show that using PCR-free methods and increasing sequencing depth to ~ 100 * shows benefits, as long as the tumour:control coverage ratio remains balanced. We observe widely varying mutation call rates and low concordance among analysis pipelines, reflecting the artefact-prone nature of the raw data and lack of standards for dealing with the artefacts. However, we show that, using the benchmark mutation set we have created, many issues are in fact easy to remedy and have an immediate positive impact on mutation detection accuracy. PMID- 26647972 TI - Estradiol in the Preoptic Area Regulates the Dopaminergic Response to Cocaine in the Nucleus Accumbens. AB - The sex-steroid hormone estradiol (E2) enhances the psychoactive effects of cocaine, as evidenced by clinical and preclinical studies. The medial preoptic area (mPOA), a region in the hypothalamus, is a primary neural locus for neuroendocrine integration, containing one of the richest concentrations of estrogen receptors in the CNS and also has a key role in the regulation of naturally rewarding behaviors. However, whether estradiol enhances the neurochemical response to cocaine by acting in the mPOA is still unclear. Using neurotoxic lesions and microdialysis, we examined whether the mPOA modulates cocaine-induced neurochemical activity in the nucleus accumbens. Tract tracing and immunohistochemical staining were used to determine whether projections from the mPOA to the ventral tegmental area (VTA) are sensitive to estrogen signaling. Finally, estradiol microinjections followed by microdialysis were used to determine whether estrogenic signaling in the mPOA modulates cocaine-induced changes of dopamine in the nucleus accumbens. Results showed that lesions of the mPOA or microinjections of estradiol directly into the mPOA increased cocaine induced release of dopamine in the nucleus accumbens. Immunohistochemical analyses revealed that the mPOA modulates cocaine responsiveness via projections to both dopaminergic and GABAergic neurons in the VTA, and that these projections are sensitive to estrogenic stimulation. Taken together, these findings point to a novel estradiol-dependent pathway that modulates cocaine-induced neurochemical activity in the mesolimbic system. PMID- 26647974 TI - AMPK Signaling in the Dorsal Hippocampus Negatively Regulates Contextual Fear Memory Formation. AB - Both the formation of long-term memory (LTM) and dendritic spine growth that serves as a physical basis for the long-term storage of information require de novo protein synthesis. Memory formation also critically depends on transcription. Adenosine monophosphate-activated protein kinase (AMPK) is a transcriptional regulator that has emerged as a major energy sensor that maintains cellular energy homeostasis. However, still unknown is its role in memory formation. In the present study, we found that AMPK is primarily expressed in neurons in the hippocampus, and then we demonstrated a time-dependent decrease in AMPK activity and increase in mammalian target of rapamycin complex 1 (mTORC1) activity after contextual fear conditioning in the CA1 but not CA3 area of the dorsal hippocampus. Using pharmacological methods and adenovirus gene transfer to bidirectionally regulate AMPK activity, we found that increasing AMPK activity in the CA1 impaired the formation of long-term fear memory, and decreasing AMPK activity enhanced fear memory formation. These findings were associated with changes in the phosphorylation of AMPK and p70s6 kinase (p70s6k) and expression of BDNF and membrane GluR1 and GluR2 in the CA1. Furthermore, the prior administration of an mTORC1 inhibitor blocked the enhancing effect of AMPK inhibition on fear memory formation, suggesting that this negative regulation of contextual fear memory by AMPK in the CA1 depends on the mTORC1 signaling pathway. Finally, we found that AMPK activity regulated hippocampal spine growth associated with memory formation. In summary, our results indicate that AMPK is a key negative regulator of plasticity and fear memory formation. PMID- 26647975 TI - Altered White Matter Microstructure in Adolescents and Adults with Bulimia Nervosa. AB - Previous data suggest structural and functional deficits in frontal control circuits in adolescents and adults with bulimia nervosa (BN), but less is known about the microstructure of white matter in these circuits early in the course of the disorder. Diffusion tensor imaging (DTI) data were acquired from 28 female adolescents and adults with BN and 28 age- and BMI-matched healthy female participants. Tract-based spatial statistics (TBSS) was used to detect group differences in white matter microstructure and explore the differential effects of age on white matter microstructure across groups. Significant reductions in fractional anisotropy (FA) were detected in the BN compared with healthy control group in multiple tracts including forceps minor and major, superior longitudinal, inferior fronto-occipital, and uncinate fasciculi, anterior thalamic radiation, cingulum, and corticospinal tract. FA reductions in forceps and frontotemporal tracts correlated inversely with symptom severity and Stroop interference in the BN group. These findings suggest that white matter microstructure is abnormal in BN in tracts extending through frontal and temporoparietal cortices, especially in those with the most severe symptoms. Age related differences in both FA and RD in these tracts in BN compared with healthy individuals may represent an abnormal trajectory of white matter development that contributes to the persistence of functional impairments in self-regulation in BN. PMID- 26647976 TI - Double Dissociation of Monoacylglycerol Lipase Inhibition and CB1 Antagonism in the Central Amygdala, Basolateral Amygdala, and the Interoceptive Insular Cortex on the Affective Properties of Acute Naloxone-Precipitated Morphine Withdrawal in Rats. AB - Both CB1 receptor antagonism and agonism, in particular by 2-arachidonyl glycerol (2-AG), have been shown to reduce somatic symptoms of morphine withdrawal (MWD). Here we evaluated the effects of both systemic pretreatment with the monoacylglycerol lipase (MAGL) inhibitor MJN110 (which selectively elevates 2-AG) and central administration of both MJN110 and the CB1 antagonist (AM251) on the affective properties of MWD. Acute MWD induced place aversion occurs when naloxone is administered 24 h following a single exposure to a high dose of morphine. Systemic pretreatment with the MAGL inhibitor, MJN110, prevented the aversive effects of acute MWD by a CB1 receptor-dependent mechanism. Furthermore, in a double dissociation, AM251 infusions into the central amygdala, but MJN110 infusions into the basolateral amygdala, interfered with the naloxone precipitated MWD induced place aversion. As well, MJN110, but not AM251, infusions into the interoceptive insular cortex (a region known to be activated in acute MWD) also prevented the establishment of the place aversion by a CB1 mechanism of action. These findings reveal the respective sites of action of systemically administered MJN110 and AM251 in regulating the aversive effects of MWD. PMID- 26647978 TI - Nanoscale origins of the damage tolerance of the high-entropy alloy CrMnFeCoNi. AB - Damage tolerance can be an elusive characteristic of structural materials requiring both high strength and ductility, properties that are often mutually exclusive. High-entropy alloys are of interest in this regard. Specifically, the single-phase CrMnFeCoNi alloy displays tensile strength levels of ~ 1 GPa, excellent ductility (~ 60-70%) and exceptional fracture toughness (KJIc>200 MPa?m). Here through the use of in situ straining in an aberration-corrected transmission electron microscope, we report on the salient atomistic to micro scale mechanisms underlying the origin of these properties. We identify a synergy of multiple deformation mechanisms, rarely achieved in metallic alloys, which generates high strength, work hardening and ductility, including the easy motion of Shockley partials, their interactions to form stacking-fault parallelepipeds, and arrest at planar slip bands of undissociated dislocations. We further show that crack propagation is impeded by twinned, nanoscale bridges that form between the near-tip crack faces and delay fracture by shielding the crack tip. PMID- 26647977 TI - Downregulation of caveolin-1 upregulates the expression of growth factors and regulators in co-culture of fibroblasts with cancer cells. AB - Reduced expression levels of caveolin-1 (Cav-1) in tumor stromal fibroblasts influences the occurrence and progression of tumors, particularly in breast cancer, but the relevant molecular mechanism is unclear. The present study aimed to clarify the potential mechanism underlying the promotion of tumor growth by reduced Cav-1 expression levels, by investigating Cav-1-targeted molecules in fibroblasts and breast cancer cells. The expression of growth factors in the ESF fibroblast cell line transfected with Cav-1 small interfering RNA (siRNA) was examined. The expression of apoptotic regulators in the BT474 breast cancer cell line that was co-cultured with the fibroblasts, was also investigated. The transfection of Cav-1-targeting siRNA in ESF cells resulted in efficient and specific inhibition of Cav-1 expression. The downregulation of Cav-1 increased the expression and secretion of stromal cell-derived factor-1 (SDF-1), epidermal growth factor (EGF) and fibroblast-specific protein-1 (FSP-1) in ESF cells. This resulted in the accelerated proliferation of the breast cancer cells. Tumor protein 53-induced glycolysis and apoptosis regulator (TIGAR) was upregulated in the BT474 cells under the condition of co-culture with Cav-1 siRNA fibroblasts, while levels of reactive oxygen species (ROS) were decreased, resulting in apoptosis inhibition in the breast cancer cells. These results demonstrated that the downregulation of Cav-1 promoted the growth of breast cancer cells through increasing SDF-1, EGF and FSP-1 in tumor stromal fibroblasts, and TIGAR levels in breast cancer cells. To the best of our knowledge, the present study supports the hypothesis that Cav-1 possesses tumor-suppressor properties, with the mechanism of Cav-1-dependent signaling involving the regulation of SDF-1, EGF, FSP-1 and TIGAR. PMID- 26647979 TI - Why do employees follow their superiors' instructions? Identification of the reasons to comply with superiors' will in a group of Polish employees. AB - BACKGROUND: Managers influence the way organization works as well as the functioning of subordinates - in the context of their work life but non professional functioning as well e.g., attitude towards work-life balance or taking care of health. We focused on the superior-subordinate relation, referring to social power bases theory by Raven. We identified the reasons why subordinates decide to follow their superiors' orders and determined specific styles of compliance with superiors' will. Understanding why employees listen to their superiors may be valuable in the context of supporting healthy organizational climate and atmosphere of co-operation or communicating values - for example, as regards taking care of own health. We discussed the results referring to the issue of influencing employees in the context of their health behavior. MATERIAL AND METHODS: The research involved 100 Polish employees, aged 28 years old on average, who filled in the Interpersonal Power Inventory by Raven et al. for subordinates in a Polish adaptation by Zaleski. The questionnaire includes 11 subscales referring to power bases. RESULTS: Based on the cluster analysis results, we recognized people who complied because of: all kinds of power bases (typical for 46% of the respondents); the respect for superiors' professionalism (34%); and formal/objective reasons (20%). CONCLUSIONS: Employees differ in terms of their styles of compliance. Their motives to comply with superiors' instructions constitute compilations of power bases. The superiors' awareness of the reasons why their employees decide to follow orders is necessary for successful management. It may motivate employees to work but also to take care of their own health. PMID- 26647973 TI - Architectural Representation of Valence in the Limbic System. AB - In order to thrive, animals must be able to recognize aversive and appetitive stimuli within the environment and subsequently initiate appropriate behavioral responses. This assignment of positive or negative valence to a stimulus is a key feature of emotional processing, the neural substrates of which have been a topic of study for several decades. Until recently, the result of this work has been the identification of specific brain regions, such as the basolateral amygdala (BLA) and nucleus accumbens (NAc), as important to valence encoding. The advent of modern tools in neuroscience has allowed further dissection of these regions to identify specific populations of neurons signaling the valence of environmental stimuli. In this review, we focus upon recent work examining the mechanisms of valence encoding, and provide a model for the systematic investigation of valence within anatomically-, genetically-, and functionally defined populations of neurons. PMID- 26647980 TI - Influence of selected sociodemographic factors on psychosocial workload of nurses and association of this burden with absenteeism at work. AB - BACKGROUND: The aim of this study has been to determine if sociodemographic factors: age, sex and duration of employment as well as the presence of chronic comorbidities exert significant effect on subjective assessment of psychosocial working conditions of nurses. Moreover, we analyzed whether the abovementioned variables influenced the level of absenteeism at work during a year preceding the study. MATERIAL AND METHODS: The study, conducted between December 2012 and January 2013, included 789 nurses employed at public and private healthcare institutions in Bialystok. The participants were surveyed by means of the "Psychosocial Working Conditions" questionnaire. RESULTS: Women accounted for significantly higher scores of the Desired Changes Scale and significantly lower values of the Well-being Scale as compared to men. Respondents' age and duration of employment correlated significantly with the scores of the Demands and Desired Changes Scales. Moreover, we documented significant inverse correlations between the age and tenure and the scores of the Social Support and Well-being Scales. Furthermore, duration of employment was inversely correlated with the results of the Control Scale. The respondents with chronic conditions showed significantly higher scores of the Desired Changes Scale and significantly lower values of the Control and Well-being Scales. We found an inverse correlation between the number of sick leave days and the value of the Well-being Scale, which was also the case with a subset of nurses without chronic conditions. CONCLUSIONS: Similar to other professional groups, a nursing team management requires the use of human resources management techniques and identification of a person being responsible for coordination of the group and diagnosis of its psychosocial needs. PMID- 26647981 TI - Cooperation within physician-nurse team in occupational medicine service in Poland - Knowledge about professional activities performed by the team-partner. AB - BACKGROUND: The goal of the study has been to learn about physicians' and nurses' awareness of the professional activities that are being performed by their colleague in the physician-nurse team. MATERIAL AND METHODS: Postal questionnaires were sent out to occupational physicians and nurses in Poland. The analysis includes responses from 232 pairs of physician-nurse teams. RESULTS: The knowledge among occupational professionals about tasks performed by their colleagues in the physician-nurse team seems to be poor. Respondents were asked about who performs tasks from each of 21 groups mentioned in the Occupational Medicine Service Act. In the case of only 3 out of 21 groups of tasks, the rate of non-consistence in answers was lower than 30%. A specified number of professionals performed their tasks on the individual basis. Although in many cases their team colleagues knew about those activities, there was a major proportion of those who had no awareness of such actions. CONCLUSIONS: Polish occupational physicians and nurses perform a variety of tasks. Occupational nurses, besides medical role, also play important organizational roles in their units. The cooperation between the two professional groups is, however, slightly disturbed by the deficits in communication. This issue needs to be improved for the betterment of operations within the whole system. PMID- 26647982 TI - [Toxicological consultation data management system based on experience of Pomeranian Center of Toxicology]. AB - BACKGROUND: In this paper the structure of poisonings is described, based on the material collected from tele-toxicology consults by the Pomeranian Center of Toxicology in Gdansk and harvested from its Electronic Poison Information Management System. In addition, we analyzed conclusions drawn from a 27-month operation of the system. MATERIAL AND METHODS: Data were harvested from the Electronic Poison Information Management System developed in 2012 and used by the Pomeranian Center of Toxicology since then. The research was based on 2550 tele toxicology consults between January 1 and December 31, 2014. Subsequently the data were electronically cleaned and presented using R programming language. RESULTS: The Pomeranian voivodeship was the prevalent localisation of calls (N = 1879; 73.7%). Most of the calls came from emergency rooms (N = 1495; 58.63%). In the case of 1396 (54.7%) patients the time-lag between intoxication and the consult was less than 6 h. There were no differences in the age distribution between genders. Mean age was 26.3 years. Young people predominated among intoxicated individuals. The majority of intoxications were incidental (N = 888; 34.8%) or suicidal (N = 814; 31.9%) and the most of them took place in the patient's home. CONCLUSIONS: Information about Poison Control Center consultations access should be better spread among medical service providers. The extent of poison information collected by Polish Poison Control Centers should be limited and unified. This should contribute to the increased percentage of properly documented consultations. Additional duties stemming from the need of digital archiving of consults provided, require the involvement of additional staff, leading to the increased operation costs incurred by Poison Control Centers. PMID- 26647983 TI - [Monoinfections caused by Borrelia burgdorferi and Borrelia burgdorferi / Anaplasma phagocytophilum co-infections in forestry workers and farmers]. AB - BACKGROUND: The presence of co-infections induced by tick-borne pathogens in humans is an important epidemiological phenomenon. This issue has attracted growing attention of doctors and people working under conditions of an increased risk of being exposed to tick bites. MATERIAL AND METHODS: The research group consisted of 93 individuals with current anti-immunoglobulin M/G (IgM/ IgG) Borrelia burgdorferi or IgG anti-Anaplasma phagocytophilum. The respondents were identified during the screening survey in a group of farmers and foresters occupationally exposed to tick bites. The aim of the work was to analyse the frequency of antibodies to specific antigens of B. burgdorferi and the levels of cytokines in forestry workers and farmers with B. burgdorferi monoinfections and B. burgdorferi / A. phagocytophilum co-infections. Statistical analysis was performed using the Chi2, Mann-Whitney U and Kruskal-Wallis tests. RESULTS: There is a stronger generation of IgG antibodies to B. burgdorferi antigens in patients with B. burgdorferi / A. phagocytophilum co-infections, such as variable major protein-like sequence expressed (VlsE) (p < 0.05), p19 (p < 0.02), p17 (p < 0.05) and complement regulator-acquiring surface protein 3 (CRASP3) (p < 0.02) compared to persons with B. burgdorferi monoinfections. The discrepancies in the synthesis of cytokines interleukin 6 (IL-6), IL-10, and tumor necrosis factor alpha (TNF alpha) have not been found in persons with B. burgdorferi monoinfections and B. burgdorferi / A. phagocytophilum co-infection. CONCLUSIONS: The immune response directed against B. burgdorferi is stronger in patients co-infected with B. burgdorferi and A. phagocytophilum than in those with monoinfection. PMID- 26647984 TI - [The prevalence of overweight and obesity vs. the level of physical activity of aviation military academy students]. AB - BACKGROUND: The aim of the study was to evaluate overweight, obesity and the level of physical activity in the study group of 100 cadets of the Air Force Military Academy in Deblin (WSOSP). MATERIAL AND METHODS: Evaluation of overweight and obesity was based on body mass index (BMI) and body fat content. An accelerometer AiperMotion 500TM was used to measure the level of physical activity. There were marked such parameters as the average daily energy consumption, the average distance covered during the day and the whole week and the indicator of physical activity level (PAL). RESULTS: Based on BMI indicators, 71.3% of the cadets had normal body weight, 25.3% were overweight and 3.4% were obese. Assessment of nutritional status showed significant differences between the 1st and 2nd vs. the 4th and 5th years of study. Normal BMI values showed 88% of the 1st and 2nd year students, while of the 4th and 5th years - only 48.6% (p < 0.05). Based on the body fat content, obesity was found only in a group of older students (16.2%) and overweight was 10 times higher in the 4th and 5th years (21.6%) in comparison to younger students (2%). The average distance covered during the day or during the whole week was significantly higher in the 1st and 2nd year students. CONCLUSIONS: It is necessary to implement appropriate measures in the field of nutrition and physical activity to prevent the development of excessive body weight during studies among the military cadets of the Air Force Military Academy in Deblin. PMID- 26647985 TI - [Work fatigue in urban bus drivers]. AB - BACKGROUND: Bus drivers are a special group of professional drivers who are at a very high risk of fatigue. The aim of the study was to examine whether the driver's subjective assessment of fatigue allows for the determination of its level and identification of its causes. MATERIAL AND METHODS: The study group comprised 45 randomly selected bus drivers (mean age - 43.7 +/- 7.9 years, period of employment as drivers - 14.7 +/- 8.6 years). Examinations were performed in all subjects four times - before and after work on the "easy" route (outside the city center, small traffic intensity) and before and after work on the "difficult" route (city center, heavy traffic). The fatigue test questionnaire, based on the list of symptoms of fatigue prepared by the Japan Research Committee of Fatigue, was used in the study. RESULTS: The rating of fatigue after the work was significantly higher than that before the work. The profile of fatigue after work was not influenced by the type of route, but the assessment of most symptoms of fatigue reached a higher level after the "difficult" routes and the differences were statistically significant for 7 symptoms. Only the ratings of leg fatigue, feeling of heaviness, and the necessity to squint eyes and gaze with effort reached the higher levels after driving the "easy" routes. It has been found that the level of fatigue was significantly correlated with the job characteristics (driving time, the length of the route, number of stops, etc.) and with the abundance of food ingested and type of beverage (coffee vs. others) drunk prior to driving. CONCLUSIONS: The questionnaire used in our study to assess the subjective feeling of fatigue has proved to be a sensitive and useful tool for indicating the level and causes of fatigue. The relationship between the symptoms of fatigue and the characteristics of job and lifestyle shows that actions must be taken by both the employers and employees to prevent fatigue in bus drivers. PMID- 26647986 TI - [Excessive daytime sleepiness and risk for obstructive sleep apnea in the public transport drivers]. AB - BACKGROUND: Obstructive sleep apnea (OSA) is a set of symptoms related to the increased upper airways resistance during sleep (due to pharyngeal walls collapse) leading to intermittent airflow obstruction in the lungs. One of the most severe OSA symptoms is excessive daytime sleepiness. Sustained daytime sleepiness may impair cognitive functions and thus influence the everyday functioning of affected person. MATERIAL AND METHODS: The aim of the study was to prospectively assess excessive daytime sleepiness and the risk for OSA in municipal bus drivers. The study was performed in a group of 103 men. The anonymous survey comprised Epworth Sleepiness Scale (ESS) for daytime sleepiness assessment and STOP-Bang Questionnaire (SBQ) for OSA risk assessment. RESULTS: In 43 (42%) respondents OSA risk was assessed as low, while moderate and high risk was observed in 55 (53%) and 5 (5%) drivers, respectively. Severe daytime sleepiness correlated positively with ESS results (r = 0.32; p < 0.05). In drivers with high OSA risk revealed in SBQ no correlation with high ESS was observed. CONCLUSIONS: In drivers with moderate and high OSA risk a sleep medicine specialist consultation with a consecutive diagnostic procedures is necessary. STOP-Bang Questionnaire and ESS are the fast tools to identify patients at increased risk for OSA. PMID- 26647987 TI - [Crisis in the valuation, emotional labor and occupational burnout among teachers of religion]. AB - BACKGROUND: This article presents an analysis of the relationship between the crisis of values and in the valuation, the strategy of emotional labor, and occupational burnout in the group of lay teachers of religion. In addition, the role of emotional labor as a mediator of the relationship between the crisis of values and burnout was analyzed. Three strategies of emotional labor were considered in the study: surface acting, deep acting, and expression of naturally felt emotions. MATERIAL AND METHODS: The study was conducted in a group of 169 lay teachers of religion (males - 24%, females - 76%), using the Questionnaire for Investigating Crisis in Valuation developed by Oles, the Maslach Burnout Inventory, and the Emotional Labour Scale developed by Diefendorff, Croyle and Gosserand. RESULTS: The crisis of values and in the valuation is an important factor responsible for occupational burnout in the group of lay teachers of religion. Surface acting and expression of naturally felt emotions mediate the relationship between crisis in the valuation and emotional exhaustion, depersonalization and lack of personal accomplishment. Surface acting increases, while the expression of naturally felt emotions decreases occupational burnout. Deep acting is not related with occupational burnout. CONCLUSIONS: It is justified to seek factors favoring the expression of naturally felt emotions, and also those reducing surface acting. PMID- 26647988 TI - [Optimization of measurement methods for a multi-frequency electromagnetic field from mobile phone base station using broadband EMF meter]. AB - BACKGROUND: This paper presents the characteristics of the mobile phone base station (BS) as an electromagnetic field (EMF) source. The most common system configurations with their construction are described. The parameters of radiated EMF in the context of the access to methods and other parameters of the radio transmission are discussed. Attention was also paid to antennas that are used in this technology. MATERIAL AND METHODS: The influence of individual components of a multi-frequency EMF, most commonly found in the BS surroundings, on the resultant EMF strength value indicated by popular broadband EMF meters was analyzed. The examples of metrological characteristics of the most common EMF probes and 2 measurement scenarios of the multisystem base station, with and without microwave relays, are shown. RESULTS: The presented method for measuring the multi-frequency EMF using 2 broadband probes allows for the significant minimization of measurement uncertainty. Equations and formulas that can be used to calculate the actual EMF intensity from multi-frequency sources are shown. They have been verified in the laboratory conditions on a specific standard setup as well as in real conditions in a survey of the existing base station with microwave relays. CONCLUSIONS: Presented measurement methodology of multi frequency EMF from BS with microwave relays, validated both in laboratory and real conditions. It has been proven that the described measurement methodology is the optimal approach to the evaluation of EMF exposure in BS surrounding. Alternative approaches with much greater uncertainty (precaution method) or more complex measuring procedure (sources exclusion method) are also presented). PMID- 26647989 TI - [Good practice in occupational health services - The influence of hazardous conditions and nuisance coexisting in the work environment and at home on the course and outcome of pregnancy]. AB - The key activity in good practice of occupational medicine is to control, on a regular basis, the workers' health and how it is affected by the work environment and - consequently - to provide the employers and employees with advice regarding the organization, ergonomics, physiology and psychology of work. Occupational medicine practitioners should remember that certain duties are performed both at work and at home. This issue is particularly important in preventive healthcare of pregnant working women. Taking the above into consideration, we reviewed the literature with respect to nuisance and occupational risk factors, which might be associated with professional and household duties. The research indicates the need to reduce activities that require frequent bending or lifting, put a women at risk of falling or cause excess occupational stress for pregnant women. We would like to draw the doctors' attention to the possibility of exceeding a 4 hour limit of work at video display terminals and negative effects of low physical exercise and sitting for a long time both at work and at home. Since long working hours (over 40 h/week) affect the course of pregnancy negatively, total working time at work (including any additional jobs) and at home must be taken into account in the occupational risk assessment. To sum up, we emphasize that preventive healthcare of pregnant working women should mainly include education programmes. Women need to know how to perform their work safely and pay attention to the scope and frequency of household tasks (duties). PMID- 26647990 TI - [Ethylene glycol and propylene glycol ethers - Reproductive and developmental toxicity]. AB - Both ethylene and propylene glycol alkyl ethers (EGAEs and PGAEs, respectively) are widely used, mainly as solvents, in industrial and household products. Some EGAEs demonstrate gonadotoxic, embriotoxic, fetotoxic and teratogenic effects in both humans and experimental animals. Due to the noxious impact of these ethers on reproduction and development of organisms EGAEs are replaced for considerably less toxic PGAEs. The data on the mechanisms of testicular, embriotoxic, fetotoxic and teratogenic effects of EGAEs are presented in this paper. Our particular attention was focused on the metabolism of some EGAEs and their organ specific toxicities, apoptosis of spermatocytes associated with changes in the expression of various genes that code for oxidative stress factors, protein kinases and nuclear hormone receptors. PMID- 26647991 TI - Lung fibrosis and exposure to wood dusts: Two case reports and review of the literature. AB - INTRODUCTION: Increasing evidence suggests that idiopathic pulmonary fibrosis (IPF) occurs more often in subjects previously exposed to wood dusts than in non exposed subjects. Here we report 2 cases of the IPF among workers prolongedly exposed to high levels of hardwood dusts. CASE REPORT: The case No. 1: An 83 year old male former smoker, retired joiner developed mild dyspnoea and chronic dry cough over the period preceding the examination. Pulmonary function tests (PFT) identified a mild restrictive pattern and diffusion capacity for carbon dioxide (CO2) that was severely impaired (57% of predicted value). High resolution computer tomography (HRCT) identified bilateral, subpleural basal reticular opacities in honeycombing, without any nodules or ground-glass opacities. The case No. 2: A 73 year-old male retired jointer, never smoker, presented a 3-year history of progressive breathlessness and non-productive cough in mild hypoxemia. Pulmonary function tests suggested a moderate restrictive pattern in severely impaired diffusion capacity for CO2(54% of predicted value). High resolution computer tomography identified diffuse peripheral reticular opacities and honeycombing of lower fields, with apico-basilar gradient. Both cases received diagnosis of the idiopathic pulmonary fibrosis. DISCUSSION: The pulmonary fibrosis is a common feature of several diseases and may be induced by inflammatory disorders following inhalation of organic and inorganic dusts (e.g., asbestos, silica), and several reports suggest that many cases of the IPF may be in fact secondary to occupational dust exposure as in the case reports we present here. CONCLUSIONS: Occupational exposure to wood dusts may be a risk factor for the IPF. Unfortunately, exposure reconstruction is frequently inconsistent and anamnesis often misses other causes of the pulmonary fibrosis (e.g., extrinsic allergic alveolitis). PMID- 26647992 TI - N-cadherin promotes epithelial-mesenchymal transition and cancer stem cell-like traits via ErbB signaling in prostate cancer cells. AB - N-cadherin has been reported to be upregulated and associated with metastasis and poor prognosis in prostate cancer patients, however the underlying mechanism still remains puzzling. In the present study, we found that upregulation of N cadherin enhanced, while downregulation of N-cadherin impaired the invasion, migration, and epithelial to mesenchymal transition (EMT) of prostate cancer (PCa) cells. Overexpression of N-cadherin increased the efficiency of colony and tumor spheroid formation and the stemness factor expression (including c-Myc, Klf4, Sox2 and Oct4), and vice versa. Furthermore, microarray analysis and western blot analysis mechanistically proved that N-cadherin activated ErbB signaling pathway by upregulating the expression of Grb2, pShc and pERK1/2. Importantly, the regulation of N-cadherin on EMT and stemness was counteracted by lapatinib, a specific ErbB signaling pathway inhibitor. Collectively, these findings demonstrate that N-cadherin regulates EMT and stemness of PCa cells via activating ErbB signaling pathway, which indicates the pivotal role of N cadherin/ErbB axis in the metastasis of prostate cancer. PMID- 26647993 TI - Modulation of transforming growth factor-beta signaling transducers in colon adenocarcinoma cells induced by staphylococcal enterotoxin B. AB - Colorectal cancer (CRC) is a notable cause of cancer-associated mortality worldwide, making it a pertinent topic for the study of cancer and its treatment. Staphylococcal enterotoxin B (SEB), an enterotoxin produced by Staphylococcus aureus, has been demonstrated to exert anticancer and antimetastatic effects due to its ability to modify cell immunity and cellular signaling pathways. In the current study, SEB was investigated, including whether it exerts its growth inhibitory effects on colon adenocarcinoma cells. This may occur through the manipulation of a key tumor growth factor, termed transforming growth factor-beta (TGF-beta), and its signaling pathway transducer, Smad2/3. The human colon adenocarcinoma HCT116 cell line was treated with different concentrations of SEB, and cell number was measured using MTT assay at different treatment times. Smad2/3 RNA expression level was analyzed in untreated or SEB-treated cells using quantitative polymerase chain reaction, which indicated significant differences between cell viability and Smad2/3 expression levels. SEB effectively downregulated Smad2/3 expression in the HCT116 cells at concentrations of 1 and 2 ug/ml (P=0.0021 and P=0.0017, respectively). SEB concentrations that were effective at inhibiting Smad2/3 expression were correlated with those able to inhibit the proliferation of the cancer cells. SEB inhibited Smad2/3 expression at the mRNA level in a concentration- and time-dependent manner. The present study thus proposed SEB as an agent able to significantly reduce Smad2/3 expression in colon cancer cells, provoking moderate TGF-beta growth signaling and the reduction of tumor cell proliferation. PMID- 26647994 TI - Vibrational circular dichroism and chiroptical properties of chiral Ir(iii) luminescent complexes. AB - The octahedral ionic Ir(iii) complex with a dual stereogenic centre of general formula Delta,Lambda-(R,S)-[(ppy)2Ir(Me-Campy)]X, where ppy = 2-phenylpyridine and Me-Campy = 2-methyl-5,6,7,8-tetrahydroquinolin-8-amine, and the complex Lambda-(R,S)-[(ppy)2Ir(H-Campy)]X, where ppy = 2-phenylpyridine, H-Campy = 8 amino-5,6,7,8-tetrahydroquinolines and X(-) = Cl(-) as a counterion in both cases, have been characterized by vibrational circular dichroism (VCD), which turns out to be efficacious in diastereomeric discrimination. Moreover, the single crystal X-ray structure of the complex Delta-(R)-[(ppy)2Ir(Me-Campy)]Cl is reported here. Density functional theory (DFT) calculations allow us to conclude that the most important doublet feature in the VCD spectra is associated with a clear vibrational exciton structure located on the two dissymmetrically disposed phenylpyridine ligands. The features in the VCD spectra associated with the (R) or (S)-central chirality configuration are identified and commented on. DFT calculations provide also the interpretation of electronic circular dichroism (ECD) spectra. Finally, circularly polarized luminescence (CPL) spectra are presented as an additional chiroptical characterization of these luminescent iridium complexes. PMID- 26647995 TI - Highlights from Faraday Discussion 178: Nanoplasmonics, London, UK, February 2015. PMID- 26647996 TI - Confined lattice dynamics of single and quadruple SnSe bilayers in [(SnSe)(1.04)](m)[MoSe2](n) ferecrystals. AB - The Sn specific densities of phonon states in the SnSe subunits of [(SnSe)1.04]m[MoSe2]n ferecrystals with (m,n) = (1,1), (4,1) and in bulk SnSe were derived from nuclear inelastic scattering by the (119)Sn Mossbauer resonance. Using different measurement configurations, phonons with polarization parallel and perpendicular to the ferecrystal plane were specifically probed. Vibrational properties and phonon spectral weight are found to strongly depend on the phonon polarization and layer count m. A highly peculiar feature of these ferecrystal densities of phonon states is the emergence of rather sharp high energy vibrational modes polarized perpendicular to the ferecrystal plane, which contrasts with usual findings in thin layered structures and nanostructured materials in general, and a depletion of modes with a gap appearing between acoustic and high energy modes. The spectral weight of these phonons depends on the overall SnSe content, m, but cannot be unambiguously attributed to SnSe-MoSe2 interfaces. Considering the low energy part of lattice dynamics, ferecrystals exhibit rather low average phonon group velocities as compared to the speed of sound in the long wavelength limit. For the (1,1) ferecrystal, this effect is most pronounced for vibrations polarized in the ferecrystal plane. Thus, an experimental microscopic origin for the vibrational and bonding anisotropy in subunits of ferecrystals is provided. PMID- 26647997 TI - Solvent effect in beta-phosphorylated nitroxides. Part 4: detection of traces of water by electron paramagnetic resonance. AB - For decades, the nitrogene hyperfine coupling constant aN of nitroxides has been applied to probe their environment using EPR. However, the small changes observed (~2 G from n-pentane to water) with the solvent polarity allow only a qualitative discussion. A stable beta-phosphorylated nitroxide exhibiting a small change in aN (~3 G from n-pentane to water) and a striking change (~25 G from n-pentane to water) in phosphorus hyperfine coupling constant aP with the polarity of solvent was prepared and used to develop the first procedure for the titration of water in THF by EPR, down to 0.1% v/v. PMID- 26647998 TI - Association between DNMT3L polymorphic variants and the risk of endometriosis associated infertility. AB - Endometriosis is considered to be an epigenetic disease. It has previously been reported that the DNA methyltransferase 3-like (DNMT3L) rs8129776 single nucleotide polymorphism (SNP) contributes to endometrioma. In the present study, high-resolution melting curve analysis was used to investigate the risks associated with the DNMT3L c.910-635A/G (rs8129776), c.832C/T (rs7354779), c.812C/T (rs113593938) and c.344+62C/T (rs2276248) SNPs on stage I-II endometriosis-associated infertility. Included in the present study were patients presenting with stage I-II endometriosis-associated infertility (n=154) and a control cohort of healthy patients with confirmed fertility (n=383). No significant association between the above-listed DNMT3L SNPs and the development of endometriosis-associated infertility was identified. The lowest P-values generated from trend analysis were observed in the DNMT3L c.832C/T (rs7354779) SNP (Ptrend=0.114). Furthermore, haplotype analyses of the DNMT3L SNPs failed to reveal any risk association between the development of endometriosis-associated infertility and the above-listed polymorphisms, even when the SNPs were present in combinations. Finally, a meta-analysis was performed to examine the association between the DNMT3L rs8129776 SNP and the development of endometrioma, from which no association between the two was identified. On the basis of these results, the present study has demonstrated that variations in the DNMT3L gene do not contribute to stage I-II endometriosis-associated infertility. PMID- 26647999 TI - Erratum: Disadvantageous associations: Reversible spatial cueing effects in a discrimination task. PMID- 26648000 TI - Role of innate immunity-triggered pathways in the pathogenesis of Sickle Cell Disease: a meta-analysis of gene expression studies. AB - Despite the detailed characterization of the inflammatory and endothelial changes observed in Sickle Cell Disease (SCD), the hierarchical relationship between elements involved in the pathogenesis of this complex disease is yet to be described. Meta-analyses of gene expression studies from public repositories represent a novel strategy, capable to identify key mediators in complex diseases. We performed several meta-analyses of gene expression studies involving SCD, including studies with patient samples, as well as in-vitro models of the disease. Meta-analyses were performed with the Inmex bioinformatics tool, based on the RankProd package, using raw gene expression data. Functional gene set analysis was performed using more than 60 gene-set libraries. Our results demonstrate that the well-characterized association between innate immunity, hemostasis, angiogenesis and heme metabolism with SCD is also consistently observed at the transcriptomic level, across independent studies. The enrichment of genes and pathways associated with innate immunity and damage repair associated pathways supports the model of erythroid danger-associated molecular patterns (DAMPs) as key mediators of the pathogenesis of SCD. Our study also generated a novel database of candidate genes, pathways and transcription factors not previously associated with the pathogenesis of SCD that warrant further investigation in models and patients of SCD. PMID- 26648001 TI - Unexpected diversity of Anopheles species in Eastern Zambia: implications for evaluating vector behavior and interventions using molecular tools. AB - The understanding of malaria vector species in association with their bionomic traits is vital for targeting malaria interventions and measuring effectiveness. Many entomological studies rely on morphological identification of mosquitoes, limiting recognition to visually distinct species/species groups. Anopheles species assignments based on ribosomal DNA ITS2 and mitochondrial DNA COI were compared to morphological identifications from Luangwa and Nyimba districts in Zambia. The comparison of morphological and molecular identifications determined that interpretations of species compositions, insecticide resistance assays, host preference studies, trap efficacy, and Plasmodium infections were incorrect when using morphological identification alone. Morphological identifications recognized eight Anopheles species while 18 distinct sequence groups or species were identified from molecular analyses. Of these 18, seven could not be identified through comparison to published sequences. Twelve of 18 molecularly identified species (including unidentifiable species and species not thought to be vectors) were found by PCR to carry Plasmodium sporozoites - compared to four of eight morphological species. Up to 15% of morphologically identified Anopheles funestus mosquitoes in insecticide resistance tests were found to be other species molecularly. The comprehension of primary and secondary malaria vectors and bionomic characteristics that impact malaria transmission and intervention effectiveness are fundamental in achieving malaria elimination. PMID- 26648002 TI - Phase separation enhanced magneto-electric coupling in La0.7Ca0.3MnO3/BaTiO3 ultra-thin films. AB - We study the origin of the magnetoelectric coupling in manganite films on ferroelectric substrates. We find large magnetoelectric coupling in La0.7Ca0.3MnO3/BaTiO3 ultra-thin films in experiments based on the converse magnetoelectric effect. The magnetization changes by around 30-40% upon applying electric fields on the order of 1 kV/cm to the BaTiO3 substrate, corresponding to magnetoelectric coupling constants on the order of alpha = (2-5) . 10(-7) s/m. Magnetic anisotropy is also affected by the electric field induced strain, resulting in a considerable reduction of coercive fields. We compare the magnetoelectric effect in pre-poled and unpoled BaTiO3 substrates. Polarized neutron reflectometry reveals a two-layer behavior with a depressed magnetic layer of around 30 A at the interface. Magnetic force microscopy (MFM) shows a granular magnetic structure of the La0.7Ca0.3MnO3. The magnetic granularity of the La0.7Ca0.3MnO3 film and the robust magnetoelastic coupling at the La0.7Ca0.3MnO3/BaTiO3 interface are at the origin of the large magnetoelectric coupling, which is enhanced by phase separation in the manganite. PMID- 26648003 TI - Effect of Hath1 on the proliferation and apoptosis of cutaneous squamous cell carcinoma in vitro. AB - Increasing evidence has demonstrated that the tumor suppressor gene Hath1 is implicated in the development and progression of tumors and is verified to be downregulated in several types of tumor. However, the roles and precise molecular mechanisms of Hath1 in cutaneous squamous cell carcinoma (SCC) remain to be elucidated. In the present study, two approaches were used to investigate the tumor-suppressing effect of Hath1 in cutaneous SCC. Firstly, the effect of inhibiting Hath1 expression with short hairpin RNA (shRNA) on tumor growth and apoptosis was investigated. KUMA5 cells were stably transfected with a plasmid expressing Hath1 shRNA (pGenesil-1-Hath1). Secondly, the anti-tumor effect of Hath1 was investigated in KUMA5 cells following transfection with pcDNA3.1-Hath1. The mRNA and protein expression of Hath1 was detected by reverse transcription quantitative polymerase chain reaction and western blot analysis, respectively. Cell proliferation in vitro was assessed using an MTT assay. Flow cytometry was used to detect cell apoptosis. The results demonstrated that compared with the control groups, the expression of Hath1 was significantly reduced in the KUMA5/pGenesil-1-Hath1 cells and markedly increased in the KUMA5/pcDNA3.1-Hath1 cells. Cell proliferation was markedly increased in the KUMA5/pGenesil-1-Hath1 cells in a time-dependent manner; however, it was markedly inhibited in the KUMA5/pcDNA3.1-Hath1 cells. Flow cytometry revealed that apoptosis decreased in KUMA5/pGenesil-1-Hath1 cells and increased in KUMA5/pcDNA3.1-Hath1 cells. Downregulation of Hath1 expression promoted the proliferation and reduced the apoptosis of KUMA5 cells. By contrast, overexpression of Hath1 inhibited proliferation and induced the apoptosis of KUMA5 cells. These findings provide possible new strategies and therapeutic targets for the treatment and diagnosis of cutaneous SCC. PMID- 26648005 TI - Genetic and Environmental Influences on Disability Pension Due To Mental Diagnoses: Limited Importance of Major Depression, Generalized Anxiety, and Chronic Fatigue. AB - BACKGROUND: Previous research indicates that liability to disability pension (DP) due to mental diagnoses is moderately influenced by genetic factors. This study investigates whether genetic contributions to the liability to DP due to mood and neurotic diagnoses overlap with the genetic influences on major depression (MD), generalized anxiety disorder (GAD), or chronic fatigue (CF). METHOD: A prospective cohort study including 9,985 female twins born in Sweden 1933-1958. The presence of MD, GAD, and CF was assessed by computer-assisted telephone interviews conducted in 1998-2002. Data on DP due to mood and neurotic diagnoses were obtained from nationwide registers for the years 1998-2010. Common genetic and environmental influences on the phenotypes were estimated by applying structural equation modeling. RESULTS: The prevalence of MD/GAD was 30%, CF 8%, and DP due to mood and neurotic diagnoses 3% in 2010. Genetic effects on MD/GAD explained 31% of the total genetic variation in DP, whereas genetic contributions in common with CF were small and not significant. The majority of the total non shared environmental variance in DP (85%) was explained by the factors that were unique to DP. CONCLUSIONS: Large proportions of genetic and non-shared environmental influences in DP due to mood and neurotic diagnoses were not explained by the contributions from MD/GAD or CF. The results suggest that the process leading to DP is complex and influenced by factors other than those related to the disorder underlying DP. PMID- 26648004 TI - Witnessing substance use increases same-day antisocial behavior among at-risk adolescents: Gene-environment interaction in a 30-day ecological momentary assessment study. AB - Many young adolescents are embedded in neighborhoods, schools, and homes where alcohol and drugs are frequently used. However, little is known about (a) how witnessing others' substance use affects adolescents in their daily lives and (b) which adolescents will be most affected. The current study used ecological momentary assessment with 151 young adolescents (ages 11-15) to examine the daily association between witnessing substance use and antisocial behavior across 38 consecutive days. Results from multilevel logistic regression models indicated that adolescents were more likely to engage in antisocial behavior on days when they witnessed others using substances, an association that held when substance use was witnessed inside the home as well as outside the home (e.g., at school or in their neighborhoods). A significant Gene * Environment interaction suggested that the same-day association between witnessing substance use and antisocial behavior was significantly stronger among adolescents with, versus without, the dopamine receptor D4 seven repeat (DRD4-7R) allele. The implications of the findings for theory and research related to adolescent antisocial behavior are discussed. PMID- 26648006 TI - Application of different techniques to detect Toxoplasma gondii in slaughtered sheep for human consumption. AB - The aim of this study was to investigate occurrence of Toxoplasma gondii in sheep slaughtered in the state of Alagoas, Brazil, by means of different diagnosis techniques. Serum samples and tissues from 100 slaughtered sheep were used. To detect antibodies, the indirect immunofluorescence antibody test (IFAT) was used, and tissues from seropositive animals (cut-off >=1:64) were submitted to Polymerase Chain Reaction (PCR) and immunohistochemistry (IHC). To assess the concordance between the direct techniques, the kappa test was used. In the IFAT, it was observed that 14% (14/100) of the ovine samples were serum-positive. In the PCR, 21.43% (3/14) of the animals were positive and in IHC, it was observed that 7.14% (1/14) were positively stained for T. gondii in cerebral tissue. Histopathologically, the predominant finding was the presence of mononuclear cell infiltrate in the heart and a perivascular cuff in the cerebrum and cerebellum. The concordance between the direct diagnosis techniques was moderate (k=0.44). Thus, it is important to use different direct techniques in diagnosing toxoplasmosis in naturally infected sheep. PMID- 26648007 TI - Epidemiology of Eimeria infections in sheep raised extensively in a semiarid region of Brazil. AB - The aim of this study was to identify and determine the prevalence of Eimeria species affecting sheep raised extensively in a semiarid region of Brazil. Fecal samples of native sheep were collected during the rainy and dry seasons. The degree of infection was determined by counting oocysts per gram (OPG) of feces, and the morphometric method was used for species identification. Oocysts were found in all the properties assessed, in which 68.3% of the animals were infected. The prevalence of oocysts was influenced by the season and animal category (P<0.05). It was higher during the rainy season than the dry season (80.2% vs. 55.8%) and highest in young animals than the adults animals (68.2% vs. 39.6%). The OPG was lower during the dry season (1,269 +/- 312 vs. 4,400 +/- 1,122). Ten species were found; of these, E. ovinoidalis, E. granulosa, E. faurei, and E. crandallis were the most frequent. E. ovinoidalis and E. crandallis were found in all properties, with their prevalences being 19.4% and 13.6% respectively. The high prevalence of pathogenic species shows that eimeriosis is a risk for animals raised extensively in the semiarid region. PMID- 26648008 TI - Gastrointestinal and external parasites of Enicognathus ferrugineus and Enicognathus leptorhynchus (Aves, Psittacidae) in Chile. AB - Parasite species are important components of biodiversity, as they provide valuable information about host health, evolutionary relationships, population structures, trophic interactions, the existence of environmental stresses, and climatic conditions. With the aim of describing the parasites associated with parrots of the genus Enicognathus Gray 1840 from central Chile, thirteen austral parakeets, Enicognathus ferrugineus, and five slender-billed parakeets, E. leptorhynchus, were examined between September 2007 and March 2014. The prevalence of ectoparasites and endoparasites was 88.9% and 22.2%, respectively. On eleven of the E. ferrugineus (84.6%) analyzed, and on all of the E. leptorhynchus analyzed (100%), five feather mite species (Pararalichus hastifolia, Genoprotolichus major, Protonyssus sp., Fainalges sp., and Eurydiscalges sp.) were collected. On ten E. ferrugineus (76.9%) and two E. leptorhynchus (40%), the chewing lice Heteromenopon macrurum, Psittacobrossus patagoni, and Paragoniocotes enicognathidis were collected. The nematode Capillaria plagiaticia was collected from three E. ferrugineus (23.1%), and the nematode Ascaridia hermaphrodita was found in one E. leptorhynchus (20%). The presence of C. plagiaticia, Protonyssus sp., Fainalges sp., and Eurydiscalges sp. from the two Enicognathus spp. are new records for Chile and represent new parasite-host associations. PMID- 26648009 TI - Outbreak of anaplasmosis associated with the presence of different Anaplasma marginale strains in dairy cattle in the states of Sao Paulo and Goias, Brazil. AB - The present study reports the genetic diversity of Anaplasma marginale during anaplasmosis outbreaks in rural properties of the states of Goias and Sao Paulo, Brazil. Mortality rates of 3.5% (37/1,050) in calves, 4.7% (45/954) in heifers and 1.1% (25/2,200) in lactating cows were observed in a cattle herd of the municipality of Mambai, state of Goias, central-western Brazil. In a cattle herd from the municipality of Lins, state of Sao Paulo, in southeastern Brazil, none of the animals died, despite presenting clinical signs suggestive of bovine anaplasmosis and exhibiting a drastic decrease in milk production. Thus, blood samples were collected from 100 animals with clinical signs suggestive of bovine anaplasmosis in the municipalities of Mambai and Lins. Based on the microsatellite structure of the MSP1a of A. marginale, the genotypes E and H were observed in Lins, and the C, D and E genotypes were found in Mambai. The analysis of the tandem repeat structures of the MSP1a showed nine different strains (tau 10 -15, alpha-beta2, alpha-beta3-13, alpha-beta2 192, tau-beta-100, alpha-beta2 Gamma, 193-beta-100, 191-13-Gamma and 191-13-18) in Lins and two (alpha-beta3 Gamma and E-F-phi2-F2) in Mambai. Three new tandem repeats of MSP1a (191, 192 and 193) were described. The tau-10-15 and alpha-beta3-Gamma strains were predominantly associated with the occurrence of clinical anaplasmosis and mortality in calves, heifers and lactating cows. PMID- 26648010 TI - Metazoan parasites of Geophagus brasiliensis (Perciformes: Cichlidae) in Patos Lagoon, extreme south of Brazil. AB - This study has evaluated the parasitic fauna of 79 pearl cichlids (Geophagus brasiliensis) from the estuary of Patos Lagoon (31 degrees 57' S and 52 degrees 06' W), Rio Grande do Sul, Brazil, during the months of May and June in 2011 and 2012. All the hosts analyzed were infected with at least one species of parasite. A total of eleven metazoa were identified in 459 specimens collected. The trematode Austrodiplostomum compactum (34.2%) and ergasilids Ergasilus lizae (32.9%) and Gauchergasilus lizae (32.9%) were the most prevalent species. The trematodes Thometrema overstreeti and Posthodiplostomum sp. had significantly higher prevalence in fish longer than 20 cm. The sex of the host had no effect on parasite prevalence and abundance. Pearl cichlids are registered as a new host for the trematodes Lobatostoma sp., Homalometron pseudopallidum and Thometrema overstreeti, for the ergasilids Ergasilus lizae and Gauchergasilus euripedesi and for the argulid Argulus spinolosus. The crustacean E. lizae is recorded in Rio Grande do Sul for the first time. PMID- 26648011 TI - Prevalence of gastrointestinal parasites in domestic dogs in Tabasco, southeastern Mexico. AB - The overall goal of this study was to estimate the prevalence of gastrointestinal (GI) parasites in dogs in the city of Villahermosa in Tabasco, Mexico. The study population consisted of 302 owned dogs that had limited access to public areas. A fecal sample was collected from each animal and examined for GI parasites by conventional macroscopic analysis and centrifugal flotation. Fecal samples from 80 (26.5%) dogs contained GI parasites. Of these, 58 (19.2%) were positive for helminths and 22 (7.3%) were positive for protozoan parasites. At least seven parasitic species were identified. The most common parasite was Ancylostoma caninum which was detected in 48 (15.9%) dogs. Other parasites detected on multiple occasions were Cystoisospora spp. (n = 19), Toxocara canis (n = 7) and Giardia spp. (n = 3). Three additional parasites, Dipylidium caninum, Trichuris vulpis and Uncinaria spp., were each detected in a single dog. No mixed parasitic infections were identified. In summary, we report a moderately high prevalence of GI parasites in owned dogs in Villahermosa, Tabasco. Several parasitic species identified in this study are recognized zoonotic pathogens which illustrates the important need to routinely monitor and treat dogs that live in close proximity to humans for parasitic infections. PMID- 26648012 TI - Neuroprotective effects of piperine on the 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine-induced Parkinson's disease mouse model. AB - Parkinson's disease (PD) is second only to Alzheimer's disease as the most common and debilitating age-associated neurodegenerative disorder. Currently, no therapy has been shown to unequivocally retard or arrest the progression of the disease. The aim of the present study was to investigate the protective effect of piperine on the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's mouse model. For MPTP treatment, the animals received repeated intraperitoneal injections (i.p.) of MPTP (30 mg/kg) solution for 7 days. Piperine (10 mg/kg) was administered orally for 15 days including 8 days of pretreatment. Motor behavior analysis was conducted with the rotarod test. The Morris water maze (MWM) was used to assess the cognitive learning ability of the mice. A histological examination was subsequently conducted. The results ddemonstrate that piperine treatment attenuated MPTP-induced deficits in motor coordination and cognitive functioning. Piperine also prevented MPTP-induced decreases in the number of tyrosine hydroxylase-positive cells in the substantia nigra. Additionally, piperine reduced the number of activated microglia, expression of cytokine IL 1beta, and oxidative stress following MPTP treatment. An anti-apoptotic property of piperine was identified by maintaining the balance of Bcl-2/Bax. In conclusion, the results show that piperine exerts a protective effect on dopaminergic neurons via antioxidant, anti-apoptotic, and anti-inflammatory mechanisms in an MPTP-induced mouse model of PD. Thus, piperine is a potential therapeutic treatment for PD. PMID- 26648013 TI - Inhibitor of DNA binding 4 functions as a tumor suppressor and is targetable by 5 aza-2'-deoxycytosine with potential therapeutic significance in Burkitt's lymphoma. AB - Epigenetic gene silencing due to promoter methylation is observed in human neoplasia, including lymphoma and certain cancer types. One important target for gene methylation analysis in non-Hodgkin lymphoma (NHL) is inhibitor of DNA binding 4 (ID4). The present study aimed to investigate the gene methylation status of ID4, the expression of ID4 protein and the effect of demethylating agent 5-aza-2'-deoxycytosine (CdR) in the Raji human Burkitt's lymphoma cell line in vitro. Following assessment of the inhibition of Raji cell growth by various concentrations of CdR, the effects of CdR on the expression of ID4 protein were assessed using the immunocytochemical streptavidin-peroxidase method and semi quantitative analysis, while apoptosis and cell cycle were determined by flow cytometry. The ID4 gene methylation status of Raji cells was tested using methylation-specific polymerase chain reaction analysis. ID4 was methylated and its protein expression was low in the control group, while ID4 was partly or completely demethylated and its protein expression was upregulated in Raji cells treated with CdR. In addition, CdR induced apoptosis and cell cycle arrest in Raji cells in a dose- and time-dependent manner. These results demonstrated that ID4 is hypermethylated and its protein expression is low in Burkitt's lymphoma cells, while CdR reversed the abnormal DNA methylation and induced re-expression of ID4 protein. Hypermethylation of ID4 promotes the proliferation of Burkitt's lymphoma cells; ID4 may function as a tumor suppressor and can be targeted with demethylating compounds such as CdR for the treatment of Burkitt's lymphoma. PMID- 26648015 TI - The role of bifurcation angles on collective smooth muscle cell biomechanics and the implication in atherosclerosis development. AB - Vascular smooth muscle cells (SMCs) are located in the middle of the tunica media and regulate the vasodilation and vasoconstriction of the blood vessels. SMCs also play a critical role during the development of atherosclerotic lesions, which are mainly found at sites of disturbed blood flow such as arterial branch points and bifurcations. Although the migratory and proliferative activities of SMCs and their phenotypic switch have been widely studied, the mechanotransduction of the SMC layer underlying atherosclerotic plaques remains unclear. In this study, bifurcate micropatterns with different angles were fabricated with polydimethylsiloxane and polyacrylamide gel for SMC culture and characterization of cell traction force. The cellular morphology, density and orientation-specific adaptation during branched cell layer formation on this platform were monitored until they became confluence. The results indicated that the characteristic cell traction forces and the von Mises stresses were dependent on bifurcation angles, which might provide important geometrical cues associated with the development of atherosclerosis. Immunofluorescence staining and gene analysis further revealed the proliferative and migratory states of SMCs in response to different bifurcation angles, which might elucidate the localization and progression of atherosclerotic lesions. PMID- 26648014 TI - Multi-transgenic minipig models exhibiting potential for hepatic insulin resistance and pancreatic apoptosis. AB - There are currently no multi-transgenic minipig models of diabetes for the regulation of multiple genes involved in its pathogenesis. The foot and mouth disease virus 2A (F2A)-mediated polycistronic system possesses several advantages, and the present study developed a novel multi-transgenic minipig model associated with diabetes using this system. The tissue-specific polycistronic system used in the present study consisted of two expression cassettes, separated by an insulator: (i) 11-beta-hydroxysteroid dehydrogenase 1 (11beta-HSD1), driven by the porcine liver-specific apolipoprotein E promoter; (ii) human islet amyloid polypeptide (hIAPP) and C/EBP homologous protein (CHOP), linked to the furin digested site and F-2A, driven by the porcine pancreas specific insulin promoter. In the present study, porcine fetal fibroblasts were transfected with this vector. Following somatic cell nuclear transfer using 10 cell clones and the transplantation of 1,459 embryos in total, three Landrace x Yorkshire surrogates became pregnant and delivered three Wuzhishan piglets. Genomic polymerase chain reaction (PCR) demonstrated that the piglets were multi transgenic. Reverse transcription-quantitative PCR confirmed that 11beta-HSD1 transcription was upregulated in the targeted liver. Similarly, hIAPP and CHOP were expressed at high levels, compared with the control (P<0.05 and P<0.01) in the pancreas, consistent with the western blotting and immunohistochemistry results. The primary results also showed that overexpression of 11beta-HSD1 in the liver increased the liver fat lipid parameters; and the levels of hIAPP and CHOP in the pancreatic islet cells, leading to delayed beta-cell development and apoptosis. This novel tissue-specific polycistronic system offers a promising starting point for efficiently mimicking multigenic metabolic disease. PMID- 26648016 TI - Polymorphisms in the PE35 and PPE68 antigens in Mycobacterium tuberculosis strains may affect strain virulence and reflect ongoing immune evasion. AB - Previous studies have demonstrated that the Pro-Glu/Pro-Pro-Glu (PE/PPE) genes in strains of Mycobacterium tuberculosis exhibit high sequence variation and may be involved in antigenic variation and immune evasion. Region of Difference 1 (RD1), encoding genes from Rv3871 to Rv3879, was observed to be lost during the original derivation of Bacillus Calmette-Guerin between 1908 and 1921. It has been previously demonstrated that two PE/PPE proteins, PE35 (Rv3872) and PPE68 (Rv3873), are encoded by RD1 and exhibit immunodominance. To explore the genetic diversity of PE35 and PPE68, and to evaluate the impact of sequence variation on the immune recognition of these proteins, 161 clinical M. tuberculosis strains were selected from China and comparative sequence analysis of PE35 and PPE68 was performed. The results indicated that polymorphisms in PE35 and PPE68 may lead to alterations in the function of these proteins, which may potentially affect strain virulence. In addition, the human T-cell epitopes of PE35 and PPE68 were highly variable, suggesting that the two antigens may be involved in diversifying selection to evade host immunity. The prevalence of strains with PE35 mutations in the non-Beijing family was significantly greater compared with the Beijing family, indicating that Beijing strains may be more conservative than non-Beijing strains in this gene. PMID- 26648017 TI - Methylsulfonylmethane inhibits HER2 expression through STAT5b in breast cancer cells. AB - Breast cancer is the most common cancer in women globally. The factors that increase risk include: late age at first birth, alcohol, radiation exposure, family history of breast cancer, and postmenopausal hormone therapy. Numerous drugs are being developed to treat breast cancer. Among them, Herceptin is used for the treatment of human epidermal growth factor receptor 2 (HER2)-positive cases and targets HER2 effectively and efficiently, but it is very expensive. Methylsulfonylmethane (MSM) is an organic sulfur-containing natural compound having no reported toxicity. We examined MSM in breast cancer cell lines and found it inhibited the proliferation of estrogen receptor-positive and HER2 positive breast cancer cells in a dose-dependent manner. It also suppressed the activation of STAT5b and expression of HER2 in breast cancer cells. We determined the STAT5b binding site (GAS element) in the HER2 gene. Detailed analysis showed that MSM decreased the ability of STAT5b to bind the promoter of the HER2 gene and a luciferase assay demonstrated reduced activity. We confirmed that MSM can effectively regulate STAT5b, and thereby decrease HER2 expression. Therefore, we recommend the use of MSM as an inhibitor for the management of HER2-positive breast cancers. PMID- 26648018 TI - Electronic and transport properties of PSi@MoS2 nanocables. AB - Electronic structures and transport properties of prototype MoS2 nanotube (15, 0) nanocables, including undoped PSi@MoS2 and B- and P-doped PSi@MoS2 (where PSi refers to polysilane), are investigated using the density functional theory (DFT) and the non-equilibrium Green's function (NEGF) methods. It is found that transport properties of two-probe systems by sandwiching finite long nanocables between two Au electrodes are basically in agreement with the electronic structures of their corresponding infinitely long systems. Encapsulating undoped and doped PSi nanowires inside the MoS2 nanotubes could not significantly affect the electronic and transport properties. B-doping and P-doping upon PSi play different roles in the electronic and transport properties. B-doping may exert constructive and destructive effects on electron transport depending on its position and applied bias direction, while P-doping displays a negligible effect. In addition, we found that bi-doping by two adjacent B atoms could slightly enhance the conductivity. These results could offer some clues for conducting experiments to achieve nanoelectronic devices with intrinsic transport properties of MoS2 nanotubes. PMID- 26648019 TI - Bioinformatic prediction of the antigenic epitopes of recombinant ferritin of Echinococcus granulosus. AB - Echinococcosis is a zoonotic parasitic disease affecting humans and other mammals, which is mainly caused Echinococcus at larval stages. It is predominantly endemic in Chinese pasture regions, including Xinjiang, Qinghai, Gansu and Ningxia. The aim of the present study was to predict the T- and B combined epitopes of Echinococcus granulosus (Eg). ferritin, and to analyze its secondary structure using online software. Prediction of the T- and B-combined epitopes of Eg. ferritin was performed using IEDB, SYFPEITHI and LEPS software, which are used to identify common areas of T- and B-cells. The results of the present study identified several potential antigenic epitopes of Eg. ferritin, including seven B-cell antigen epitope amino acid sequences with high values: 8 16, 54-61, 70-75, 80-90, 103-109, 117-124 and 167-173; and four T-cell antigen epitope amino acid sequences with high values: 85-93, 105-113, 133-141 and 157 165. Furthermore, a combined epitope region comprising an 105-109 amino acid sequence was identified. In conclusion, using bioinformatic methods, the present study confirmed the existence of Eg. ferritin on four T-cell antigen epitopes, seven B-cell antigen epitopes, and one T- and B-combined epitope region. These findings provide significant information for further investigation of the antigenicity of Eg. ferritin and the development of highly efficient epitope vaccines. PMID- 26648020 TI - Rhus javanica Linn protects against hydrogen peroxide-induced toxicity in human Chang liver cells via attenuation of oxidative stress and apoptosis signaling. AB - Rhus javanica Linn, a traditional medicinal herb from the family Anacardiaceae, has been used in the treatment of liver diseases, cancer, parasitic infections, malaria and respiratory diseases in China, Korea and other Asian countries for centuries. In the present study, the protective effects of R. javanica ethanolic extract (RJE) on hydrogen peroxide (H2O2)-induced oxidative stress in human Chang liver cells was investigated. The cell cytotoxicity and viability were assessed using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The activities of superoxide dismutase (SOD) and catalase (CAT) were measured using respective enzymatic kits. Cell cycle analysis was performed using flow cytometric analysis. The protein expression levels of p53, B-cell lymphoma (Bcl) 2, Bcl-2-associated X protein (Bax) and caspase-3 were assessed by western blotting. Human Chang liver cells were treated with different concentrations (0.1, 0.3 or 0.5 mg/ml) of RJE, and were subsequently exposed to H2O2 (30 uM). Treatment with H2O2 (30 uM) significantly induced cytotoxicity (P<0.05) and reduced the viability of the Chang liver cells. However, pretreatment of the cells with RJE (0.1, 0.3 or 0.5 mg/ml) significantly increased the cell viability (P<0.001 at 0.5 mg/ml) in a concentration-dependent manner following H2O2 treatment. Furthermore, pretreatment with RJE increased the enzyme activities of SOD and CAT, and decreased the sub-G1 growth phase of the cell cycle in response to H2O2-induced oxidative stress (P<0.001 at 0.3 and 0.5 mg/ml H2O2). RJE also regulated the protein expression levels of p53, Bax, caspase-3 and Bcl-2. These results suggested that RJE may protect human Chang liver cells against oxidative damage by increasing the levels of antioxidant enzymes and regulating antiapoptotic oxidative stress mechanisms, thereby providing insights into the mechanism which underpins the traditional claims made for RJE in the treatment of liver diseases. PMID- 26648021 TI - Selective and augmented beta-glucuronidase expression combined with DOX-GA3 application elicits the potent suppression of prostate cancer. AB - The present study was carried out to evaluate the specific and amplified beta glucuronidase (betaG) expression in prostate cancer cells by using a prostate specific antigen (PSA) promoter-controlled bicistronic adenovirus and to evaluate the specific killing of prostate cancer cells after the application of the prodrug DOX-GA3. Bicistronic adenoviral expression vectors were constructed, and the effectiveness of specific and amplified expression was evaluated using luciferase and EGFP as reporter genes. betaG expression was detected in LNCaP cells after they were infected with the betaG-expressing PSA promoter-controlled bicistronic adenovirus. MTT assays were conducted to evaluate the cytoxicity on the infected cells after the application of the prodrug DOX-GA3. Tumor growth inhibition was also evaluated in nude mice after treatment with the betaG expressing adenovirus and DOX-GA3. Selective and amplified expression was observed in the PSA-producing LNCaP cells, but not in the PSA-non-producing DU145 cells. Potent cytotoxity and a strong bystander effect were observed in the LNCaP cells after infection with the betaG-expressing adenovirus and the application of DOX-GA3. Intravenous injection of a GAL4 regulated bicistronic adenovirus vector constructed to express betaG under the control of the PSA promoter (Ad/PSAP-GV16 betaG) and the application of DOX-GA3 strongly inhibited tumor growth and prolonged the survival time of tumor-bearing nude mice. Selective and amplified betaG expression together with the prodrug DOX-GA3 had an increased antitumor effect, showing great potential for prostate cancer therapy. PMID- 26648022 TI - Characteristics and correlates of stealing in college students. AB - BACKGROUND: Stealing is a fairly common behaviour among young adults. Understanding the potential associations and characteristics of individuals who steal may help educational institutions, health services and young people themselves resolve difficulties before the behaviour impacts on their academic performance and health. AIMS: We aim to test the hypothesis that desires to steal among students would be associated with worse academic achievements and higher rates of mood and impulse control disorders. METHODS: One thousand eight hundred and five students completed the College Student Computer User Survey online and were included in this analysis at a large Midwestern United States University. Responders were grouped according to self-reported stealing urges and behaviours and were compared on measures of psychosocial function, mental health disorders and impulsivity. RESULTS: Urges to steal were associated with worse depressive symptoms, higher levels of perceived stress and a number of psychiatric disorders including bipolar disorder and multiple disorders of impulse control (kleptomania, compulsive sexual behaviour, skin picking, trichotillomania and compulsive buying). CONCLUSIONS AND IMPLICATIONS FOR PRACTICE AND/OR FUTURE RESEARCH: These following data indicate that stealing for many college students may be considered within a spectrum of impulsive behaviours. * Illegal behaviours among students point to mental health difficulties among them. * Our findings may provide clinicians, researchers and health professionals with a clearer picture of a range of impulsive behaviours among college students and promote treatment for this group. * Our findings could also inform preventative approaches to impulsive problems in young adults. PMID- 26648023 TI - Gambogic acid induces apoptosis and sensitizes TRAIL-mediated apoptosis through downregulation of cFLIPL in renal carcinoma Caki cells. AB - Gambogic acid (GA) is a natural compound derived from brownish gamboge resin that shows a range of bioactivity, such as antitumor and antimicrobial properties. Although, GA is already known to induce cell death in a variety of cancer cells, the molecular basis for GA-induced cell death in renal cancer cells is unclear. In this study, a treatment with GA induced cell death in human renal carcinoma Caki cells in a dose-dependent manner. Treatment of Caki cells with GA decreased the levels of antiapoptotic proteins, such as Bcl-2 and XIAP in a dose-dependent manner. In addition, GA decreased the expression of the cFLIPL protein, which was downregulated at the transcriptional level without any change in the levels of cFLIPs expression. z-VAD (pan-caspase inhibitor) partially blocked GA-mediated cell death. GA-induced apoptotic cell death in Caki cells is mediated partly by the AIF translocation from the mitochondria into the nucleus via a caspase independent pathway. In contrast, N-acetylcysteine (NAC), a ROS scavenger, had no effect on GA-induced cell death. The restoration of cFLIPL attenuated GA-induced cell death in Caki cells. Furthermore, a sub-toxic dose of GA sensitized TRAIL mediated apoptosis in Caki cells. Pretreatment with z-VAD completely blocked GA plus TRAIL-mediated apoptosis. On the contrary, pretreatment with NAC partially inhibited GA plus TRAIL-induced apoptosis. Our findings suggested that GA induces apoptosis via the downregulation of cFLIPL and sensitized TRAIL-mediated apoptosis in Caki cells. PMID- 26648024 TI - Monomeric Garnet, a far-red fluorescent protein for live-cell STED imaging. AB - The advancement of far-red emitting variants of the green fluorescent protein (GFP) is crucially important for imaging live cells, tissues and organisms. Despite notable efforts, far-red marker proteins still need further optimization to match the performance of their green counterparts. Here we present mGarnet, a robust monomeric marker protein with far-red fluorescence peaking at 670 nm. Thanks to its large extinction coefficient of 95,000 M(-1)cm(-1), mGarnet can be efficiently excited with 640-nm light on the red edge of its 598-nm excitation band. A large Stokes shift allows essentially the entire fluorescence emission to be collected even with 640-nm excitation, counterbalancing the lower fluorescence quantum yield of mGarnet, 9.1%, that is typical of far-red FPs. We demonstrate an excellent performance as a live-cell fusion marker in STED microscopy, using 640 nm excitation and 780 nm depletion wavelengths. PMID- 26648025 TI - Detection and preliminary screening of the human gene expression profile for Hirschsprung's disease. AB - The present study investigated a genome microarray of colorectal lesions (spasm segments) in children with Hirschsprung's disease (HSCR), and analyzed the results. In addition, the present study screened for differentially expressed genes in children with HSCR. Microarray technology was used to examine the human gene expression profiles of the colorectal lesions (spasm segments) of six children with HSCR, and three normal colon tissue samples. The data were analyzed be determining P-values of significance and absolute fold changes. Preliminary screening was performed to identify genes exhibiting significant differential expression in children with HSCR, and these target genes were analyzed in subsequent verification and analytical investigations. Of >20,000 detected human genes, the preliminary screenings demonstrated that 3,850 genes were differentially expressed and upregulated, with P<0.05 and >2-fold absolute changes in expression. In addition, 645 differentially expressed genes with P<0.05 and >2-fold absolute changes were downregulated. Of the upregulated genes, 118 were involved in classic signaling pathways, compared with 11 of the downregulated genes (P<0.001; absolute fold change >2-fold). HSCR etiology is complex and often involves multiple gene changes. Microarray technology can produce large quantities of gene expression data simultaneously, and analyzing this data using various techniques may provide a fast and efficient method for identifying novel gene targets and for investigating the mechanisms underlying HSCR pathogenesis. PMID- 26648026 TI - Correlation between Th17 and nTreg cell frequencies and the stages of progression in chronic hepatitis B. AB - Several studies have suggested that the balance of T helper 17 (Th17) and natural regulatory T (nTreg) cells in the Th17-mediated immune response are critical in the pathogenesis of viral hepatitis. The aim of the present study was to examine the role of circulating Th17 and nTreg cells in the disease progression of hepatitis B virus (HBV) infection. A total of 40 patients with chronic HBV (CHB), 27 patients with HBV-associated cirrhosis, 20 patients with HBV-associated liver failure and 20 healthy controls were enrolled in the present study. The frequencies of Th17 and nTreg cells in the peripheral blood were examined using flow cytometry. Th17-associated serum cytokine levels were measured using an enzyme-linked immunosorbent assay. The results revealed a significantly higher frequency of circulating Th17 cells in the patients with CHB, cirrhosis and liver failure compared, with the normal controls, particularly in the patients with liver failure. The same trend was observed in the serum levels of interleukin (IL)-17. The frequency of Th17 cells and the serum levels of IL-17 were positively correlated with the levels of alanine aminotransferase and the prothrombin times. There was a significantly higher frequency of circulating nTreg cells in the patients with CHB, compared with the normal controls. The nTreg cell frequencies were significantly and positively correlated with plasma HBV DNA load, and were negatively correlated with Th17 frequencies in the cohort of patients with HBV. Taken together, the results suggested that Th17 cell mediated inflammation is associated with progression from CHB to cirrhosis, and to liver failure. Peripheral Th17 cell frequency and serum levels of IL-17 may assisting in predicting the severity of liver damage and fibrosis. PMID- 26648027 TI - Role of nitric oxide synthase in the development of bone cancer pain and effect of L-NMMA. AB - Spinal nitric oxide is involved in the mechanisms of pain generation and transmission during inflammatory and neuropathic pain. The aim of the present study was to explore the role of spinal nitric oxide in the development of bone cancer pain. 2 x 10(5) osteosarcoma cells were implanted into the intramedullary space of right femurs of C3H/HeJ mice to induce a model of ongoing bone cancer. Polymerase chain reaction and immunohistochemical analyses were performed to assess the expression of neuronal nitric oxide synthase (nNOS) and inducible (i)NOS in the spinal cord following inoculation. The results showed that inoculation of osteosarcoma cells induced progressive bone cancer, accompanied with pain-associated behavior. The levels of nNOS mRNA in the spinal cord of tumor mice began to increase at day 10 and then decreased to the level in sham mice at day 14, while iNOS mRNA markedly increased in the tumor group at days 10 and 14. Immunohistochemical analysis showed that nNOS- and iNOS-positive neurons were mainly located in the superficial dorsal horn and around the central canal of the L3-L5 spinal cord. Intrathecal injection of 50 ug NOS inhibitor NG monomethyl-L-arginine (L-NMMA) attenuated cancer-evoked pain behaviors at day 14. These findings indicated that an upregulation of nNOS and iNOS in the spinal cord is associated with bone cancer pain and suggests that exogenously administered L NMMA may have beneficial effects to alleviate bone cancer pain. PMID- 26648028 TI - What history tells us XXXIX. CRISPR-Cas: From a prokaryotic immune system to a universal genome editing tool. PMID- 26648029 TI - Topoisomerase IB of Deinococcus radiodurans resolves guanine quadruplex DNA structures in vitro. AB - Deinococcus radiodurans genome contains a large number of guanine repeats interrupted by a few non-guanine bases, termed G motifs. Some of these G motifs were shown forming guanine quadruplex (G4) DNA structure in vitro. How is the formation and relaxation of G4 DNA regulated in the genome of D. radiodurans is not known and is worth investigating. Here, we showed that the topoisomerase Ib of D. radiodurans (DraTopoIB) could change the electrophoretic mobility of fast migrating intramolecular recF-G4 DNA into the slow migrating species. DraTopoIB also reduced the positive ellipticity in circular diachroism (CD) spectra of intramolecular recF-G4 DNA structures stabilized by K+. On the contrary, when DraTopoIB is incubated with G-motifs annealed without K+, it showed neither any change in electrophoretic mobility nor was ellipticity of the CD spectra affected. DNA synthesis by Taq DNA polymerase through G4 DNA structure was attenuated in the presence of G4 DNA binding drugs, which was abrogated by DraTopoIB. This implies that DraTopoIB could destabilize the G4 DNA structure, which is required for G4 drugs binding and stabilization. Camptothecin treatment inhibited DraTopoIB activity on intramolecular G4 DNA structures. These results suggested that DraTopoIB can relax intramolecular G4 DNA structure in vitro and it may be one such protein that could resolve G4 DNA under normal growth conditions in D. radiodurans. PMID- 26648030 TI - Chromosomal context and replication properties of ARS plasmids in Schizosaccharomyces pombe. AB - Short, specific DNA sequences called as Autonomously Replicating Sequence (ARS) elements function as plasmid as well as chromosomal replication origins in yeasts. As compared to ARSs, different chromosomal origins vary greatly in their efficiency and timing of replication probably due to their wider chromosomal context. The two Schizosaccharomyces pombe ARS elements, ars727 and ars2004, represent two extremities in their chromosomal origin activity - ars727 is inactive and late replicating, while ars2004 is a highly active, early-firing origin. To determine the effect of chromosomal context on the activity of these ARS elements, we have cloned them with their extended chromosomal context as well as in the context of each other in both orientations and analysed their replication efficiency by ARS and plasmid stability assays. We found that these ARS elements retain their origin activity in their extended/altered context. However, deletion of a 133-bp region of the previously reported ars727- associated late replication enforcing element (LRE) caused advancement in replication timing of the resulting plasmid. These results confirm the role of LRE in directing plasmid replication timing and suggest that the plasmid origin efficiency of ars2004 or ars727 remains unaltered by the extended chromosomal context. PMID- 26648031 TI - Semaphorin 4A enhances lung fibrosis through activation of Akt via PlexinD1 receptor. AB - Semaphorin 4A plays a regulatory role in immune function and angiogenesis. However, its specific involvement in controlling lung fibrosis, a process that is closely related to angiogenesis and inflammation is still poorly understood. In the present study, we show that treatment of Sema4A on normal lung fibroblasts induces expression of proteins that contribute to a contractile phenotype, including alpha-smooth muscle actin (alpha-SMA), ezrin, moesin, and paxillin. We confirm that Sema4A enhances the ability of lung fibroblasts to contract collagen gel. Sema4A treatment led to resistance to apoptosis in normal lung fibroblasts. Relative to normal lung fibroblasts, fibroblasts cultured from scars of patients with the fibrotic disease Systemic Sclerosis (SSc) showed elevated Sema4A secretion, enhanced alpha-SMA, ezrin, moesin, and paxillin expression, and high ability to induce collagen gel contraction. Using neutralizing antibody against Sema4A receptor, PlexinD1, we found that endogenous Sema4A signalling in SSc fibroblast was through PlexinD1 receptor. We then identified the signalling mechanism through which Sema4A-PlexinD1 promotes the ability of normal fibroblasts to contract a collagen gel matrix. Western blot analysis showed that Sema4A activated the Akt pathway in lung fibroblasts, and the specific inhibitor of Akt pathway, Akt inhibitor III, blocked the ability of Sema4A to promote the ability of lung fibroblasts to contract a collagen gel matrix. Thus, blocking Sema4APlexinD1- Akt cascades might be beneficial in reducing pulmonary fibrosis. PMID- 26648032 TI - Interdependence of laforin and malin proteins for their stability and functions could underlie the molecular basis of locus heterogeneity in Lafora disease. AB - Lafora disease (LD), an autosomal recessive and fatal form of neurodegenerative disorder, is characterized by the presence of polyglucosan inclusions in the affected tissues including the brain. LD can be caused by defects either in the EPM2A gene coding for the laforin protein phosphatase or the NHLRC1 gene coding for the malin ubiquitin ligase. Since the clinical symptoms of LD patients representing the two genetic groups are very similar and since malin is known to interact with laforin, we were curious to examine the possibility that the two proteins regulate each other's function. Using cell biological assays we demonstrate here that (i) malin promotes its own degradation via autoubiquitination, (ii) laforin prevents the auto-degradation of malin by presenting itself as a substrate and (iii) malin preferentially degrades the phosphatase-inactive laforin monomer. Our results that laforin and malin regulate each other's stability and activity offers a novel and attractive model to explain the molecular basis of locus heterogeneity observed in LD. PMID- 26648033 TI - Regulatory single nucleotide polymorphisms at the beginning of intron 2 of the human KRAS gene. AB - There are two regulatory single nucleotide polymorphisms (rSNPs) at the beginning of the second intron of the mouse K-ras gene that are strongly associated with lung cancer susceptibility. We performed functional analysis of three SNPs (rs12228277: T greater than A, rs12226937: G greater than A, and rs61761074: T greater than G) located in the same region of human KRAS. We found that rs12228277 and rs61761074 result in differential binding patterns of lung nuclear proteins to oligonucleotide probes corresponding two alternative alleles; in both cases, the transcription factor NF-Y is involved. G greater than A substitution (rs12226937) had no effect on the binding of lung nuclear proteins. However, all the nucleotide substitutions under study showed functional effects in a luciferase reporter assay. Among them, rs61761074 demonstrated a significant correlation with allele frequency in non-small-cell lung cancer (NSCLC). Taken together, the results of our study suggest that a T greater than G substitution at nucleotide position 615 in the second intron of the KRAS gene (rs61761074) may represent a promising genetic marker of NSCLC. PMID- 26648034 TI - Signatures of positive selection at hemopexin (PEX) domain of matrix metalloproteinase-9 (MMP-9) gene. AB - Matrix metalloproteinases-9 (MMP-9) is an important cancer-associated, zinc dependent endopeptidase. To investigate the natural selection hypothesis of MMP 9, the orthologous sequences from 12 vertebrates were compared and a molecular evolution analysis was performed. Results suggest that amino acid residues present in the middle region of the protein are more selectively constrained, whereas amino acid residues in the C-terminal region of the MMP-9 protein including exon 13 showed lowest conservation level in non-primate species, suggesting that it is an exon with fast evolving rate compared to the others analyzed. InterProScan analysis shows that exon 13 was located in hemopexin (PEX) domain of MMP-9. Positive selection was detected in PEX domain of MMP-9 protein between human and other species, which indicates that selective pressure may play a role in shaping the function of MMP-9 in the course of evolution. PMID- 26648035 TI - Comparative sequence analyses of genome and transcriptome reveal novel transcripts and variants in the Asian elephant Elephas maximus. AB - The Asian elephant Elephas maximus and the African elephant Loxodonta africana that diverged 5-7 million years ago exhibit differences in their physiology, behaviour and morphology. A comparative genomics approach would be useful and necessary for evolutionary and functional genetic studies of elephants. We performed sequencing of E. maximus and map to L. africana at ~15X coverage. Through comparative sequence analyses, we have identified Asian elephant specific homozygous, non-synonymous single nucleotide variants (SNVs) that map to 1514 protein coding genes, many of which are involved in olfaction. We also present the first report of a high-coverage transcriptome sequence in E. maximus from peripheral blood lymphocytes. We have identified 103 novel protein coding transcripts and 66-long non-coding (lnc)RNAs. We also report the presence of 181 protein domains unique to elephants when compared to other Afrotheria species. Each of these findings can be further investigated to gain a better understanding of functional differences unique to elephant species, as well as those unique to elephantids in comparison with other mammals. This work therefore provides a valuable resource to explore the immense research potential of comparative analyses of transcriptome and genome sequences in the Asian elephant. PMID- 26648036 TI - Differential neural activation for camouflage detection task in Field-Independent and Field-Dependent individuals: Evidence from fMRI. AB - It is not clearly known as to why some people identify camouflaged objects with ease compared with others. The literature suggests that Field-Independent individuals detect camouflaged object better than their Field-Dependent counterparts, without having evidence at the neural activation level. A paradigm was designed to obtain neural correlates of camouflage detection, with real-life photographs, using functional magnetic resonance imaging. Twenty-three healthy human subjects were stratified as Field-Independent (FI) and Field-Dependent (FD), with Witkin's Embedded Figure Test. FIs performed better than FDs (marginal significance; p=0.054) during camouflage detection task. fMRI revealed differential activation pattern between FI and FD subjects for this task. One sample T-test showed greater activation in terms of cluster size in FDs, whereas FIs showed additional areas for the same task. On direct comparison of the two groups, FI subjects showed additional activation in parts of primary visual cortex, thalamus, cerebellum, inferior and middle frontal gyrus. Conversely, FDs showed greater activation in inferior frontal gyrus, precentral gyrus, putamen, caudate nucleus and superior parietal lobule as compared to FIs. The results give preliminary evidence to the differential neural activation underlying the variances in cognitive styles of the two groups. PMID- 26648037 TI - Asymmetric cell division and its role in cell fate determination in the green alga Tetraselmis indica. AB - The prasinophytes (early diverging Chlorophyta), consisting of simple unicellular green algae, occupy a critical position at the base of the green algal tree of life, with some of its representatives viewed as the cell form most similar to the first green alga, the 'ancestral green flagellate'. Relatively large-celled unicellular eukaryotic phytoflagellates (such as Tetraselmis and Scherffelia), traditionally placed in Prasinophyceae but now considered as members of Chlorodendrophyceae (core Chlorophyta), have retained some primitive characteristics of prasinophytes. These organisms share several ultrastructural features with the other core chlorophytes (Trebouxiophyceae, Ulvophyceae and Chlorophyceae). However, the role of Chlorodendrophycean algae as the evolutionary link between cellular individuality and cellular cooperation has been largely unstudied. Here, we show that clonal populations of a unicellular chlorophyte, Tetraselmis indica, consist of morphologically and ultrastructurally variant cells which arise through asymmetric cell division. These cells also differ in their physiological properties. The structural and physiological differences in the clonal cell population correlate to a certain extent with the longevity and function of cells. PMID- 26648038 TI - Structural studies on a non-toxic homologue of type II RIPs from bitter gourd: Molecular basis of non-toxicity, conformational selection and glycan structure. AB - The structures of nine independent crystals of bitter gourd seed lectin (BGSL), a non-toxic homologue of type II RIPs, and its sugar complexes have been determined. The four-chain, two-fold symmetric, protein is made up of two identical two-chain modules, each consisting of a catalytic chain and a lectin chain, connected by a disulphide bridge. The lectin chain is made up of two domains. Each domain carries a carbohydrate binding site in type II RIPs of known structure. BGSL has a sugar binding site only on one domain, thus impairing its interaction at the cell surface. The adenine binding site in the catalytic chain is defective. Thus, defects in sugar binding as well as adenine binding appear to contribute to the non-toxicity of the lectin. The plasticity of the molecule is mainly caused by the presence of two possible well defined conformations of a surface loop in the lectin chain. One of them is chosen in the sugar complexes, in a case of conformational selection, as the chosen conformation facilitates an additional interaction with the sugar, involving an arginyl residue in the loop. The N-glycosylation of the lectin involves a plant-specific glycan while that in toxic type II RIPs of known structure involves a glycan which is animal as well as plant specific. PMID- 26648040 TI - In search of principles for a Theory of Organisms. AB - Lacking an operational theory to explain the organization and behaviour of matter in unicellular and multicellular organisms hinders progress in biology. Such a theory should address life cycles from ontogenesis to death. This theory would complement the theory of evolution that addresses phylogenesis, and would posit theoretical extensions to accepted physical principles and default states in order to grasp the living state of matter and define proper biological observables. Thus, we favour adopting the default state implicit in Darwin's theory, namely, cell proliferation with variation plus motility, and a framing principle, namely, life phenomena manifest themselves as non-identical iterations of morphogenetic processes. From this perspective, organisms become a consequence of the inherent variability generated by proliferation, motility and self organization. Morphogenesis would then be the result of the default state plus physical constraints, like gravity, and those present in living organisms, like muscular tension. PMID- 26648039 TI - Occurrence, detection and detoxification of mycotoxins. AB - Mycotoxins have been identified as important toxins affecting animal species and humans ever since the discovery of aflatoxin B1 in 1960. Mycotoxigenic fungi are ubiquitous in nature and are held responsible for economic loss as they decrease crop yield and quality of food. The presence of fungi and their mycotoxins are reported not only in food grains but also in medicinal herbs and processed foods. Since prevention is not always possible, detoxification of mycotoxins have been attempted using several means; however, only few have been accepted for practical use, e.g. ammonia in the corn industry. Organizations such as the World Health Organization, US Food and Drug Administration and European Union have set regulations and safety limits of important mycotoxins, viz. aflatoxins, fusarium toxins, ochratoxin, patulin zearalenone, etc., to ensure the safety of the consumers. This review article is a brief and up-to-date account of the occurrence, detection and detoxification of mycotoxins for those interested in and considering research in this area. PMID- 26648041 TI - The Montreal Cognitive Assessment-Basic: A Screening Tool for Mild Cognitive Impairment in Illiterate and Low-Educated Elderly Adults. AB - OBJECTIVES: To assess the validity of a newly developed cognitive screening tool, the Montreal Cognitive Assessment-Basic (MoCA-B), in screening for mild cognitive impairment (MCI) in elderly adults with low education and varying literacy. DESIGN: Cross-sectional. SETTING: Community hospital in Bangkok, Thailand. PARTICIPANTS: Cognitively normal controls (n = 43) and individuals with MCI according to the National Institute on Aging-Alzheimer's Association work group criteria (n = 42) aged 55 to 80 with less than 5 years of education. MEASUREMENTS: MoCA-B scores. RESULTS: Mean MoCA-B scores were 26.3 +/- 1.6 for illiterate controls and 21.3 +/- 3.8 for illiterate participants with MCI (P < .001) and 26.6 +/- 2.0 for literate controls and 23.0 +/- 2.1 for literate participants with MCI (P < .001). MoCA-B scores did not differ significantly according to literacy, and multiple regression suggested no association with age or education. The optimal cutoff score of 24 out of 25 yielded 81% sensitivity and 86% specificity for MCI (area under the receiver operating characteristic curve = 0.90, P < .001). Test-retest reliability was 0.91 (P < .001), and internal consistency was 0.82. Administration time was 15 to 21 minutes. CONCLUSION: The MoCA-B appears to have excellent validity and addresses an unmet need by accurately screening for MCI in poorly educated older adults regardless of literacy. PMID- 26648043 TI - Utilizing enzymatic digestion procedures in the bioanalytical laboratory. AB - In recent years, the use of LC-MS technologies in the bioanlytical laboratory for quantitation of peptide/protein biomarkers and biotherapeutics has increased dramatically. The increased interest is due to the improvement in sensitivity of MS instruments over the last 5-10 years, as well as its proven ability to overcome some common issues associated with immunoassay, namely selectivity and reagent availability. However, large proteins (>10 kDa) chromatograph and ionize poorly. To overcome this challenge, LC-MS/MS workflows for proteins larger than 10 kDa utilize enzymatic digestion procedures with subsequent quantitation of one or more of these enzymatically derived peptides to act as a surrogate for the intact protein. Here, recommendations of digestion technique and potential internal standards are summarized. PMID- 26648042 TI - Reducing Timp3 or vitronectin ameliorates disease manifestations in CADASIL mice. AB - OBJECTIVE: CADASIL is a genetic paradigm of cerebral small vessel disease caused by NOTCH3 mutations that stereotypically lead to the extracellular deposition of NOTCH3 ectodomain (Notch3(ECD) ) on the vessels. TIMP3 and vitronectin are 2 extracellular matrix proteins that abnormally accumulate in Notch3(ECD) containing deposits on brain vessels of mice and patients with CADASIL. Herein, we investigated whether increased levels of TIMP3 and vitronectin are responsible for aspects of CADASIL disease phenotypes. METHODS: Timp3 and vitronectin expression were genetically reduced in TgNotch3(R169C) mice, a well-established preclinical model of CADASIL. A mouse overexpressing human TIMP3 (TgBAC-TIMP3) was developed. Disease-related phenotypes, including cerebral blood flow (CBF) deficits, white matter lesions, and Notch3(ECD) deposition, were evaluated between 6 and 20 months of age. RESULTS: CBF responses to neural activity (functional hyperemia), topical application of vasodilators, and decreases in blood pressure (CBF autoregulation) were similarly reduced in TgNotch3(R169C) and TgBAC-TIMP3 mice, and myogenic responses of brain arteries were likewise attenuated. These defects were rescued in TgNotch3(R169C) mice by haploinsufficiency of Timp3, although the number of white matter lesions was unaffected. In contrast, haploinsufficiency or loss of vitronectin in TgNotch3(R169C) mice ameliorated white matter lesions, although CBF responses were unchanged. Amelioration of cerebrovascular reactivity or white matter lesions in these mice was not associated with reduced Notch3(ECD) deposition in brain vessels. INTERPRETATION: Elevated levels of TIMP3 and vitronectin, acting downstream of Notch3(ECD) deposition, play a role in CADASIL, producing divergent influences on early CBF deficits and later white matter lesions. PMID- 26648044 TI - Scaffold-cell bone engineering in a validated preclinical animal model: precursors vs differentiated cell source. AB - The properties of osteoblasts (OBs) isolated from the axial skeleton (tOBs) differ from OBs of the orofacial skeleton (mOBs) due to the different embryological origins of the bones. The aim of the study was to assess and compare the regenerative potential of allogenic bone marrow-derived mesenchymal progenitor cells with allogenic tOBs and allogenic mOBs in combination with a mPCL-TCP scaffold in critical-sized segmental bone defects in sheep tibiae. After 6 months, the tibiae were explanted and underwent biomechanical testing, micro computed tomography (microCT) and histological and immunohistochemical analyses. Allogenic MPCs demonstrated a trend towards a better outcome in biomechanical testing and the mean values of newly formed bone. Biomechanical, microCT and histological analysis showed no significant differences in the bone regeneration potential of tOBs and mOBs in our in vitro study, as well as in the bone regeneration potential of different cell types in vivo. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26648046 TI - Tissue-specific variation in nonsense mutant transcript level and drug-induced read-through efficiency in the Cln1(R151X) mouse model of INCL. AB - About 10% of inherited diseases are caused by nonsense mutations [Trends Mol Med 18 (2012) 688], and nonsense suppression drug therapy promoting translation through premature stop codons is an emerging therapeutic approach. Infantile neuronal ceroid lipofuscinosis (INCL), a childhood neurodegenerative disease, results from mutations in the CLN1 gene encoding the lysosomal enzyme, palmitoyl protein thioesterase 1 (PPT1) [Biochim Biophys Acta 1832 (2013) 1806, Hum Mutat (2012) 63, Biochim Biophys Acta 1832 (2013) 1881]. The nonsense mutation p.R151X is the most common disease-causing CLN1 mutation Hum Mutat (2012) 63. In the novel Cln1(R151X) mouse model of INCL, we found large, tissue-specific variations in Cln1(R151X) mRNA level and PPT1 residual enzyme activity. These tissue specific differences strongly influenced the read-through efficiency of ataluren (PTC124), a well-known nonsense suppression drug. A two-day treatment with ataluren (10 mg/kg) increased PPT1 enzyme activity in the liver and muscle, but not in any other tissue examined. Our study identifies a new challenge/hurdle for read-through drug therapy: variable efficiency of read-through therapy in the different tissues/organs because of tissue-specific variations in nonsense mutant transcript levels. PMID- 26648047 TI - Towards a clinically informed, data-driven definition of elderly onset epilepsy. AB - OBJECTIVE: Elderly onset epilepsy represents a distinct subpopulation that has received considerable attention due to the unique features of the disease in this age group. Research into this particular patient group has been limited by a lack of a standardized definition and understanding of the attributes associated with elderly onset epilepsy. METHODS: We used a prospective cohort database to examine differences in patients stratified according to age of onset. Linear support vector machine learning incorporating all significant variables was used to predict age of onset according to prespecified thresholds. Sensitivity and specificity were calculated and plotted in receiver-operating characteristic (ROC) space. Feature coefficients achieving an absolute value of 0.25 or greater were graphed by age of onset to define how they vary with time. RESULTS: We identified 2,449 patients, of whom 149 (6%) had an age of seizure onset of 65 or older. Fourteen clinical variables had an absolute predictive value of at least 0.25 at some point over the age of epilepsy-onset spectrum. Area under the curve in ROC space was maximized between ages of onset of 65 and 70. Features identified through machine learning were frequently threshold specific and were similar, but not identical, to those revealed through simple univariable and multivariable comparisons. SIGNIFICANCE: This study provides an empirical, clinically informed definition of "elderly onset epilepsy." If validated, an age threshold of 65-70 years can be used for future studies of elderly onset epilepsy and permits targeted interventions according to the patient's age of onset. PMID- 26648048 TI - Molecular mechanisms associated with Fluconazole resistance in clinical Candida albicans isolates from India. AB - Resistance to azole antifungals is a significant problem in Candida albicans. An understanding of resistance at molecular level is essential for the development of strategies to tackle resistance and rationale design of newer antifungals and target-based molecular approaches. This study presents the first evaluation of molecular mechanisms associated with fluconazole resistance in clinical C.albicans isolates from India. Target site (ERG11) alterations were determined by DNA sequencing, whereas real-time PCRs were performed to quantify target and efflux pump genes (CDR1, CDR2, MDR1) in 87 [Fluconazole susceptible (n = 30), susceptible-dose dependent (n = 30) and resistant (n = 27)] C.albicans isolates. Cross-resistance to fluconazole, ketoconazole and itraconazole was observed in 74.1% isolates. Six amino acid substitutions were identified, including 4 (E116D, F145L, E226D, I437V) previously reported ones and 2 (P406L, Q474H) new ones. CDR1 over-expression was seen in 77.7% resistant isolates. CDR2 was exclusively expressed with CDR1 and their concomitant over-expression was associated with azole cross-resistance. MDR1 and ERG11 over-expression did not seem to be associated with resistance. Our results show that drug efflux mediated by Adenosine-5'-triphosphate (ATP)-binding cassette transporters, especially CDR1 is the predominant mechanism of fluconazole resistance and azole cross-resistance in C. albicans and indicate the need for research directed towards developing strategies to tackle efflux mediated resistance to salvage azoles. PMID- 26648049 TI - Evaluation of early anatomical changes following canaloplasty with anterior segment spectral-domain optical coherence tomography and ultrasound biomicroscopy. AB - PURPOSE: To analyse structural changes in conjunctiva, sclera and Schlemm's canal (SC) following canaloplasty with optical coherence tomography (AS-OCT) and ultrasound biomicroscopy (UBM). METHODS: Fifteen patients undergoing canaloplasty were included in this prospective study. AS-OCT images were acquired pre- and 1, 7, 30 and 90 days postoperatively. UBM was performed 3 months postoperatively. The surgical site was evaluated for the presence of SC, transscleral filtration, a scleral lake and the visibility of intra-Schlemm-sutures. The height and width of SC were measured at the 3 and 9 o'clock limbus position. RESULTS: After canaloplasty, SC was detectable with AS-OCT in 93% of the patients on day 1. The increase in height was higher than that in width (height: +369%, p = 0.0004, width: +152%, p = 0.002). IOP was negatively correlated to SC's width 1 week postoperatively (r = -0.63, p = 0.04) and to SC's height until 3 months (r = 0.66, p = 0.02) postoperatively. Using UBM, a reflection of the traction sutures indicated SC's position in all patients. Transscleral filtration was found in all patients using AS-OCT, demonstrating a peak 1 week postoperatively. At 3 months, a scleral lake could be visualized in 50% and 83% of patients using AS-OCT and UBM, respectively. CONCLUSIONS: AS-OCT offers a high resolution for imaging superficial conjunctival areas and SC after canaloplasty, whereas UBM is capable of detecting deeper structures such as scleral lakes or intra-canal-sutures. The results imply a correlation of the dilation of SC with the IOP-lowering effect and an early pronounced transscleral filtration following canaloplasty. PMID- 26648050 TI - An engineered microorganism can simultaneously detoxify cadmium, chlorpyrifos, and gamma-hexachlorocyclohexane. AB - Many ecosystems are currently co-contaminated with heavy metals such as cadmium (Cd(2+) ) and pesticides such as chlorpyrifos (CP) and gamma hexachlorocyclohexane (gamma-HCH). A feasible approach to remediate the combined pollution of heavy metals and pesticides is the use of gamma-HCH degrading bacteria endowed with CP hydrolysis and heavy metal biosorption capabilities. In this work, a recombinant microorganism capable of simultaneously detoxifying Cd(2+) , CP, and gamma-HCH was constructed by display of synthetic phytochelatins (EC20) and methyl parathion hydrolase (MPH) fusion protein on the cell surface of the gamma-HCH degrading Sphingobium japonicum UT26 using the truncated ice nucleation protein (INPNC) as an anchoring motif. The surface localization of INPNC-EC20-MPH was verified by cell fractionation, Western blot analysis, immunofluorescence microscopy, and proteinase accessibility experiment. Expression of EC20 on the cell surface not only improved Cd(2+) binding but also alleviated the cellular toxicity of Cd(2+) . As expected, the rates of CP and gamma-HCH degradation were reduced in the presence of Cd(2+) for cells without EC20 expression. However, expression of EC20 (higher Cd(2+) accumulation) significantly restored the levels of CP and gamma-HCH degradation. These results demonstrated that surface display of EC20 enhanced not only Cd(2+) accumulation but also protected the recombinant strain against the toxic effects of Cd(2+) on CP and gamma-HCH degradation. PMID- 26648051 TI - Expression of CD30 as a biomarker to predict response to brentuximab vedotin. PMID- 26648052 TI - Causes and pathways of cerebral palsy following neonatal encephalopathy in children born at term. PMID- 26648053 TI - Marginal bone level changes and implant stability after loading are not influenced by baseline microstructural bone characteristics: 1-year follow-up. AB - OBJECTIVE: The aim of this study was to investigate the influence of different bone tissue characteristics of implant sites on changes in marginal bone level and implant stability over time. MATERIAL AND METHODS: One hundred and one implants were inserted in 41 patients. Cortical bone thickness of the alveolar ridge was measured on computed tomography (CT) images. Histomorphometric and microtomographic analyses (microCT) were performed in bone specimens obtained by using a trephine bur, at first drilling. Implant stability quotient (ISQ) measured by resonance frequency analysis (RFA) was registered at implant insertion. Implant stability quotient was measured also at the stages of uncovering, loading and at the 1-year follow-up, when standardized periapical radiographs were taken to measure the marginal bone level (MBL). Descriptive statistics, Spearman's rho correlation and multiple linear regression were used for data analysis (P < 0.05). RESULTS: Comparison between groups of higher and lower values of ISQ changes and between groups of higher and lower values of MBL changes revealed no differences in histomorphometric and microtomographic parameters, according to non-parametric comparison tests, (P > 0.05). Bivariate correlation also showed no association among these microstructural parameters and the outcomes evaluated. There was no correlation between cortical thickness and MBL changes (r = -0.029; P = 0.832) and between cortical thickness and ISQ changes (r = 0.145; P = 0.292). CONCLUSION: Microstructural bone characteristics of implant sites have no effect on changes in marginal bone level and implant stability as measured by RFA. Bone morphology cannot predict implant treatment success over time. PMID- 26648054 TI - Vagus nerve stimulator implantation: a UK Otolaryngology Department's 9-year experience of implanting fifty six patients. PMID- 26648056 TI - Common and Distinct Interactions of Chemical Inhibitors with Cytochrome P450 CYP1A2, CYP2A6 and CYP2B6 Enzymes. AB - BACKGROUND: Tobacco smoking is a leading cause of preventable disease and death globally. Nicotine is the main addictive component in tobacco. Nicotine is eliminated from the body by biotransformation in the liver to inactive metabolites. This reaction is catalyzed by the cytochrome P450 2A6 (CYP2A6) enzyme. Administering chemical inhibitors of CYP2A6 has been shown to slow down the elimination of nicotine with consequent reduction in number of cigarettes smoked. We have systematically developed small molecule CYP2A6 inhibitors with good balance between potency and CYP selectivity. OBJECTIVE: During this process we have noticed that many potent CYP2A6 inhibitors also inhibit other human liver CYP forms, most notably CYP1A2 and CYP2B6. This study aimed at defining common and distinct features of ligand binding to CYP1A2, CYP2A6 and CYP2B6 active sites. METHODS: We used our previous chemical inhibitor databases to construct improved 3-dimensional quantitative structureactivity relationship (3D-QSAR) models for CYP1A2, CYP2A6 and CYP2B6. RESULTS: Combined 3D-QSAR and docking procedures yielded precise information about the common and distinct interactions of inhibitors and the enzyme active sites. Positioning of hydrogen bond donor/acceptor atoms and the shape and volume of the compound defined the potency and specificity of inhibition. A novel potent and selective CYP1A2 inhibitor was found. CONCLUSION: This in silico approach will provide a means for very rapid and high throughput prediction of cross-inhibition of these three CYP enzymes. PMID- 26648055 TI - In vivo high-resolution magic angle spinning magnetic and electron paramagnetic resonance spectroscopic analysis of mitochondria-targeted peptide in Drosophila melanogaster with trauma-induced thoracic injury. AB - Trauma is the most common cause of mortality among individuals aged between 1 and 44 years and the third leading cause of mortality overall in the US. In this study, we examined the effects of trauma on the expression of genes in Drosophila melanogaster, a useful model for investigating genetics and physiology. After trauma was induced by a non-lethal needle puncture of the thorax, we observed the differential expression of genes encoding for mitochondrial uncoupling proteins, as well as those encoding for apoptosis-related and insulin signaling-related proteins, thus indicating muscle functional dysregulation. These results prompted us to examine the link between insulin signaling and mitochondrial dysfunction using in vivo nuclear magnetic resonance (NMR) with complementary electron paramagnetic resonance (EPR) spectroscopy. Trauma significantly increased insulin resistance biomarkers, and the NMR spectral profile of the aged flies with trauma induced thoracic injury resembled that of insulin-resistant chico mutant flies. In addition, the mitochondrial redox status, as measured by EPR, was significantly altered following trauma, indicating mitochondrial uncoupling. A mitochondria-targeted compound, Szeto-Schiller (SS)-31 that promotes adenosine triphosphate (ATP) synthesis normalized the NMR spectral profile, as well as the mitochondrial redox status of the flies with trauma-induced thoracic injury, as assessed by EPR. Based on these findings, we propose a molecular mechanism responsible for trauma-related mortality and also propose that trauma sequelae in aging are linked to insulin signaling and mitochondrial dysfunction. Our findings further suggest that SS-31 attenuates trauma-associated pathological changes. PMID- 26648057 TI - Induction of Haemolysis and DNA Fragmentation in a Normal and Malarial-Infected Blood by Commonly - used Antimalarial Drugs in the North-Western Region of Nigeria. AB - BACKGROUND: Antimalarial drugs are medicines that are used to prevent or treat malaria effectively at different stages in the life cycle of the malarial parasites. In spite of this, a good number of these drugs have the potential to cause harm when they are misused or abused. OBJECTIVE: This study was undertaken to evaluate the effects of commonly-used antimalarial drugs in the North Western region of Nigeria on haemolysis and DNA fragmentation in the blood of normal and malarial infected humans ex vivo. METHOD: The drugs used were artemisinine, artesunate, chloroquine, coartem and quinine (0.5-8.0 mg/ml). Haemolysis, haemoglobin status and DNA fragmentations were assayed for using standard procedures. RESULTS: It was observed that all the drugs induced a remarkable dose dependent haemolysis with more pronounced effects on apparently healthy humans. There was a significant (P < 0.05) decrease in the level of haemoglobin in normal blood samples when compared with control samples. Contrariwise, in the malaria infected blood, the haemoglobin level significantly (P < 0.05) increased as compared with control. The drugs caused an exceptional significant (P < 0.05) induction of DNA fragmentation when compared with control. CONCLUSION: Commonly used antimalarial drugs induced haemolysis and altered haemoglobin status which may spontaneously increases the cellular iron levels; a substrate for Fenton and Haber Weiss reactions, and eventually induces DNA fragmentation. Hence, adequate care should be taken during prescription with total avoidance for self medications and/or drugs abuse as a result of their adverse effects within the red blood cells and its immediate microenvironment. PMID- 26648059 TI - Diabetes and Complications: Cellular Signaling Pathways, Current Understanding and Targeted Therapies. AB - Diabetes is a metabolic disorder and over the past decades, it has become a major cause of morbidity and mortality affecting the youth and middle-aged as it is the fourth leading cause of disease related to death. In both type 1 and type 2 diabetes the severe pathogenesis cause micro vascular complications: nephropathy, retinopathy, neuropathy and macro vascular complications: cardiovascular disease, heart attacks and stroke. Under hyperglycemia, activation of different signaling mechanisms such as an increased polyol pathway, advanced-glycation end product formation, activation of Protein Kinase C and hexosamine pathway leads to the over expression of reactive oxygen species and causes pathogenesis of diabetic complications. It is necessary to understand these pathways in diabetic complications causing damage to the secondary system of the body. In the past decade the understanding of these biochemical changes has increased tremendously and various molecules have been exploited as therapeutic targets for diabetic complications as better therapeutic approach. In this review, a brief overview about diabetes mellitus and chronic complications with their current understandings of cellular/molecular mechanisms and targeted therapies along with novel therapeutic strategies is discussed. PMID- 26648058 TI - PTSD in solid organ transplant recipients: Current understanding and future implications. AB - PTSS are quite prevalent in transplant recipients, although full-scale PTSD may not be that common. Those symptoms have been linked to poor transplant outcomes, perhaps owing to non-adherence to medications and other recommendations, brought about by the avoidance dimension of the PTSD/PTSS construct (patients may avoid taking their medications because they serve as reminder of the emotionally traumatic event--the transplant). It is possible to treat PTSD via specific psychotherapeutic techniques, and the treatment has been shown to be safe and likely effective in other populations. Therefore, practitioners who treat transplant recipients should be familiar with the presentation and treatment of those symptoms. This manuscript provides a systematic literature review of the PTSD/PTSS presentation in the pediatric transplant setting, a synthesis of available research findings, and suggestions for current care and future research. PMID- 26648060 TI - Maintaining Plasma Fibrinogen Levels and Fibrinogen Replacement Therapies for Treatment of Intracranial Hemorrhage. AB - BACKGROUND: Intracranial hemorrhage is characterized by the blood vessel rupture and subsequent hematoma expansion. It is the least treatable stroke subtype, resulting in higher morbidity and mortality per incidence than ischemic stroke. Recent studies have observed lower than normal levels of plasma fibrinogen in patients of intracerebral hemorrhage. Furthermore, in other cases of severe hemorrhage, plasma fibrinogen levels have been identified as an indicator of prognosis. Current clinical management of cerebral hemorrhage includes adjunctive therapies and possible surgical evacuation. However, a possible therapeutic target for intracranial hemorrhage is fibrinogen. During intracranial hemorrhage with hematoma expansion, fibrinogen levels are rapidly depleted and thus are in need of replacement. Maintaining high levels of fibrinogen can promote rapid clotting and reduction of hematoma expansion. OBJECTIVES: Within this review, we examine the role of fibrinogen in intracranial hemorrhage and evaluate the use of fibrinogen replacement therapies for maintaining normal levels of this key hemostatic protein. The pros and cons are discussed and an opinion of the most appropriate fibrinogen replacement therapy for intracranial hemorrhage is made. CONCLUSION: It is concluded that fibrinogen concentrate seems to be the most suitable therapy for elevating plasma fibrinogen for the treatment of intracranial hemorrhage with hematoma expansion. PMID- 26648061 TI - Nucleoside Inhibitors of Hepatitis C Virus NS5B Polymerase: A Systematic Review. AB - Nowadays, a large number of people in the world are suffering from chronic Hepatitis C. HCV NS5B polymerase conserved across the identified 7 HCV genotypes is considered to be the most promising target in combating HCV. During the past decade, significant progress has been made in the discovery of novel nucleoside HCV NS5B polymerase inhibitors. A potent anti-HCV drug, sofosbuvir with high cure rates has been approved. Besides, quite a few nucleoside anti-HCV agents are being evaluated in clinical trials. The purpose of this review is to present recent progress in the development of nucleoside HCV NS5B polymerase inhibitors, focusing on lead compounds that hold great promise for medicinal use and their structure-activity relationships (SARs) in order to provide guidance for future drug design and discovery. PMID- 26648062 TI - HPC Analysis of Multiple Binding Sites Communication and Allosteric Modulations in Drug Design: The HSP Case Study. AB - Allostery is a long-range macromolecular mechanism of internal regulation, in which the binding of a ligand in an allosteric site induces distant conformational changes in a distant portion of the protein, modifying its activity. From the drug design point of view, this mechanism can be exploited to achieve important therapeutic effects, since ligands able to bind allosteric sites may be designed to regulate target proteins. Computational tools are a valid support in this sense, since they allow the characterization of allosteric communications within proteins, which are essential to design modulator ligands. While considering long-range interactions in macromolecules, the principal drug design tool available to researcher is molecular dynamics, and related applications, since it allows the evaluation of conformational changes of a protein bound to a ligand. In particular, all-atoms molecular dynamics is suitable to verify the internal mechanisms that orchestrate allosteric communications, in order to identify key residues and internal pathways that modify the protein behaviour. The problem is that these techniques are heavily time-consuming and computationally intensive, thus high performance computing systems, including parallel computing and GPU-accelerated computations, are necessary to achieve results in a reasonable time. In this review, we will discuss how it is possible to exploit in silico approaches to characterize allosteric modulations and long-range interactions within proteins, describing the case study of the Heat Shock Proteins, a class of chaperons regulated by stress conditions, which is particularly important since it is involved in many cancers and neurodegenerative diseases. PMID- 26648064 TI - A Perspective on Monoamine Oxidase Enzyme as Drug Target: Challenges and Opportunities. AB - The monoamine oxidase (MAO) enzyme is responsible for the deamination of monoamine neurotransmitters and regulates their concentration in the central and peripheral nervous systems. Imbalance in the concentration of neurotransmitters in the brain and central nervous system is linked with the biochemical pathology of various neurogenic disorders. Irreversible MAO inhibitors were the first line drugs developed for the management of severe depression but most of these were withdrawn from the clinical practice due to their fatal side effects including food-drug interactions. New generations of MAO inhibitors were developed which were reversible and selective for one of the enzyme isoform and showed improved pharmacological profile. The discovery of crystal structure of MAO-A & MAO-B isoforms helped in understanding the drug-receptor interactions at the molecular level and designing of ligands with selectivity for either of the isoforms. The current article provides an overview on the MAO enzyme as potential drug target for different disease states. The article describes catalytic mechanism of MAO enzyme, crystal structures of the two MAO isoforms, traditional MAO inhibitors and various problems associated with their use, new developments in the MAO inhibitors and their potential as therapeutic agents especially in neurological disorders. PMID- 26648063 TI - The Challenges of Modeling Drug Resistance to Antiangiogenic Therapy. AB - Drug resistance remains an ongoing challenge for the majority of patients treated with inhibitors of the vascular endothelial growth factor (VEGF) pathway, a key regulator of tumor angiogenesis. Preclinical models have played a significant role in identifying multiple complex mechanisms of antiangiogenic treatment failure. Yet questions remain about the optimal methodology to study resistance that may assist in making clinically relevant choices about alternative or combination treatment strategies. The origins of antiangiogenic treatment failure may stem from the tumor vasculature, the tumor itself, or both together, and preclinical methods that define resistance are diverse and rarely compared. We performed a literature search of the preclinical methodologies used to examine resistance to VEGF pathway inhibitors and identified 109 papers from more than 400 that use treatment failure as the starting point for mechanistic study. We found that definitions of resistance are broad and inconsistent, involve only a small number of reagents, and derive mostly from in vitro and in vivo methodologies that often do not represent clinically relevant disease stages or progression. Together, this literature analysis highlights the challenges of studying inhibitors of the tumor microenvironment in the preclinical setting and the need for improved methodology to assist in qualifying (and quantifying) treatment failure to identify mechanisms that will help predict alternative strategies in patients. PMID- 26648065 TI - Drug Targets for Obesity and Depression: From Serotonin to Leptin. AB - The increasing prevalence of both obesity and depression is becoming a significant health concern throughout the world. Evidence suggests a positive and bidirectional association between obesity and depression. It is now well established that central serotonergic system is involved in the elicitation of satiety signal and elevation of mood. Drugs that increase serotonin neurotransmission are commonly recommended for the treatment of depression. But many patients are not benefitted by these drugs, while remission rate is also not satisfactory. Serotonin based antiobesity drugs have been either withdrawn from the market or disapproved for long term use. In view of critical need for novel therapeutic targets for obesity and depression, the role of leptin is becoming increasingly important. The peptide hormone secreted by adipocytes can cross blood brain barriers to elicit satiety signal via its receptors in the hypothalamus. Emerging evidence suggests that the peptide hormone has a role in responses to stress and produces antidepressant like effects. On the other hand, both obesity and depression are often associated with higher levels of leptin in circulation suggesting insensitivity to leptin. The aim of the present article is to draw research interest towards exploring mechanism involved in leptin resistance. These studies may facilitate the development of alternative treatment strategies, beyond serotonin based drugs, for obesity depression and their comorbid condition. PMID- 26648066 TI - LncRNA HOTAIR as Prognostic Circulating Marker and Potential Therapeutic Target in Patients with Tumor Diseases. AB - In the recent years the importance of the role played by non-coding RNA on the regulation of gene expression was increased by numerous studies. The research mainly focused on small ncRNAs, such as miRNAs, while the functions of long non coding RNA (lncRNA) have been much less studied. lncRNAs can be transcribed from intergenic, intragenic or specific chromosomal regions. Compared to miRNAs, lncRNAs have a complex secondary and tertiary structure which allows to bind proteins, RNA, DNA and to carry out their regulatory functions. Several studies showed that extracellular ncRNAs can circulate in the blood of both healthy and diseased patients. Most of the circulating ncRNAs are included in lipid or lipoprotein vesicles, such as apoptotic bodies, macrovesicles or exosomes, in which they are highly stable. The presence of circulating ncRNAs in the blood of cancer patients versus normal subjects suggested the possibility that these molecules may represent new diagnostic markers. HOTAIR is a HOX transcript antisense RNA, located in the HOXC locus, able to repress transcription in the posterior region of the HOXD locus. HOTAIR has been involved in the evolution of several primary tumors, wherein increase of HOTAIR expression has endorsed invasion and metastasis. In this review, we describe the experimental evidences on the potential role as circulating marker of lncRNA HOTAIR. PMID- 26648067 TI - The Double Roles of the Prostaglandin E2 EP2 Receptor in Intracerebral Hemorrhage. AB - BACKGROUND: Intracerebral hemorrhage (ICH), a subtype of stroke, brings high morbidity and mortality to human beings. Multiple studies indicated that neuroinflammation, excitotoxicity, oxidative stress, cytotoxicity resulted from the degradation products of blood clot play vital roles in ICH-induced secondary brain injury, which contributes to deterioration of neurological outcome. Prostaglandin E2 (PGE2), a type of prostanoids commonly up-regulated in these progresses, is proved to modulate numerous cellular and molecular processes by activating EP2 receptor after ICH. OBJECTIVE: This review aim to discuss the PGE2 biosynthesis, downstream signaling pathway of EP2 receptor and the roles of EP2 receptor in ICH-induced brain damage, targeting to provide a potential effective therapeutic strategy. METHODS: A large number of literatures on EP2receptors and intracerebral hemorrhage were searched in PubMed, Medline, and Ebase. RESULTS: Previous studies showed that EP2 receptor mediated double effects in ICH via activation of different signaling pathway. EP2 receptor could induce neuroprotection, spatial learning, and neuroplasticity via cAMP-PKA signaling pathway, while strengthen inflammation mainly through the cAMP-Epac pathway. In addition, the concentration level of cAMP might be the key factor that decides which downstream signaling pathway would be activated. CONCLUSION: In different phase of cerebral hemorrhage, EP2 receptor plays diverse effects in brain damage through different downstream signaling pathways. PMID- 26648068 TI - GPR40 Agonists for the Treatment of Type 2 Diabetes Mellitus: Benefits and Challenges. AB - Apart from functioning as an energy source and important structural components of biological membranes, Free Fatty acids (FFAs) play a key role in the regulation of metabolic homeostasis. FFAs activate specific G-protein coupled receptors (GPCRs) in pancreatic beta-cells, immune cells adipose, and intestine. GPR40 (also known as FFA receptor 1) is primarily expressed in pancreatic .-cells and is activated by medium-chain and long-chain FFAs. GPR40 has been shown to augment glucose dependent insulin secretion (GDIS) from pancreatic .-cells and is widely studied drug discovery target for the treatment of type 2 diabetes mellitus (T2DM) and other metabolic diseases. Several synthetic agonists of GPR40 augment insulin secretion from pancreatic beta- cells and consequently improve glucose tolerance and restore metabolic homeostasis in various rodent models of T2DM. GPR40 agonists TAK-875 and AMG 837 have reached clinical trials and TAK 875 was shown to improve glycemic control in Type 2 diabetic patients. However, phase III clinical trials involving TAK-875 were recently terminated due to signs of liver toxicity in patients. Despite this setback, therapies based on GPR40 agonism provide an attractive alternative in the discovery of new anti-diabetic drugs. This review summarizes our current understanding of the physiological functions of GPR40, benefits and future prospects of GPR40 agonists to treat patients with T2DM. PMID- 26648069 TI - Biology, Epidemiology, Clinical Aspects of Hepatocellular Carcinoma and the Role of Sorafenib. AB - Sorafenib is a small molecular inhibitor of intracellular tyrosine and serine/threonine protein kinases (VEGFR, PDGFR, CRAF and BRAF), and is thought also to induce autophagy, a chief mechanism influencing tumor growth. Sorafenib shows efficacy in the management of non-resectable hepatocellular carcinoma (HCC), which is refractory to other chemotherapeutic drugs. HCC represents a major end point of chronic liver diseases and the third leading cause of cancer related death. In HCC patients Sorafenib increases overall survival compared to placebo. The most common chronic liver disease affecting up to 30% of the population in Western countries is non-alcoholic fatty liver disease (NAFLD), an intra-hepatic amassing of triglycerides deemed as the hepatic manifestation of insulin resistance and obesity. NAFLD encompasses a range of disorders with grades of liver damage varying from steatosis to non-alcoholic steatohepatitis (NASH), hallmarked by hepatocellular injury/inflammation in the presence or not of fibrosis. NAFLD patients progress to NASH in 10% of cases, which may progress to cirrhosis and HCC. Recent exciting studies uncovered a potential therapeutic role for Sorafenib that goes beyond HCC, and extends to cirrhotic portal hypertensive syndrome during cirrhosis, and to selective anti-fibrotic effects mediated through direct inhibition of activated hepatic stellate cells (HSC), the cellular mediators of intra-hepatic matrix deposition. The aim of this review is to concisely summarize our current knowledge of the biology, epidemiology and clinical aspects of HCC, as well as the previously under-appreciated therapeutic efficacy of Sorafenib beyond HCC. The review therefore utilizes data along the spectrum of liver diseases, including from experimental via pre-clinical to clinical. PMID- 26648071 TI - Dysregulated Chemokine Signaling in Cystic Fibrosis Lung Disease: A Potential Therapeutic Target. AB - CF lung disease is characterized by a chronic and non-resolving activation of the innate immune system with excessive release of chemokines/cytokines including IL 8 and persistent infiltration of immune cells, mainly neutrophils, into the airways. Chronic infection and impaired immune response eventually lead to pulmonary damage characterized by bronchiectasis, emphysema, and lung fibrosis. As a complete knowledge of the pathways responsible for the exaggerated inflammatory response in CF lung disease is lacking, understanding these pathways could reveal new therapeutic targets, and lead to novel treatments. Therefore, there is a strong rationale for the identification of mechanisms and pathways underlying the exaggerated inflammatory response in CF lung disease. This article reviews the role of inflammation in the pathogenesis of CF lung disease, with a focus on the dysregulated signaling involved in the overexpression of chemokine IL-8 and excessive recruitment of neutrophils in CF airways. The findings suggest that targeting the exaggerated IL-8/IL-8 receptor (mainly CXCR2) signaling pathway in immune cells (especially neutrophils) may represent a potential therapeutic strategy for CF lung disease. PMID- 26648070 TI - Adoptive Immunotherapy For Leukemia With Ex vivo Expanded T Cells. AB - The development of novel T cell therapies to target leukemia has facilitated the translation of this approach for hematologic malignancies. Different methods of manufacturing leukemia-specific T cells have evolved, along with additional measures to increase the safety of this therapy. This is an overview of expanded T cell therapeutics with a focus on how the manufacturing strategies have been refined, and where the research is heading. PMID- 26648072 TI - Implications of Palmitoleic Acid (Palmitoleate) On Glucose Homeostasis, Insulin Resistance and Diabetes. AB - Obesity is a metabolic, multifactorial disease that is underpinned by factors such as genetics, epigenetics, as well as high-energy food intake and sedentarism. Obesity is often associated with, and exacerbated by, other metabolic disorders such as type 2 diabetes mellitus (T2DM). A hallmark of T2DM is failure of insulin secretion from pancreatic beta-cell to regulate blood glucose disposal into peripheral tissues, such as skeletal muscle, termed insulin resistance, as well as deregulation of pancreatic alpha-cell function. It has been proposed that insulin resistance is, in part, a consequence of impaired signal transduction of insulin caused by several molecules released from adipose tissue that include (adipo)cytokines and fatty acids. However, not all fatty acids exert a negative impact on insulin sensitivity. In fact, it has been suggested that palmitoleic acid (16:1n-7) has hormone-like properties and improves some metabolic parameters that are impaired in obesity and T2DM. Moreover, in vitro approaches reveal that cis-16:1n-7 can influence pancreatic beta-cell survival, insulin secretion, and skeletal muscle insulin response and adipocyte metabolism. In vivo experiments using animal models show that the ingestion of cis-16:1n-7 or sources of it (e.g., macadamia oil) can partially prevent the metabolic alterations caused by high-fat/carbohydrate diets. In general, studies in humans found positive associations between higher trans-16:1n 7 proportion in plasma phospholipids and improved insulin sensitivity or decreased the onset of T2DM. However, plasma cis-16:1n-7 data are still controversial. In this brief review, we discuss the main studies on 16:1n-7 effects on obesity and T2DM and their potential for clinical application. PMID- 26648073 TI - Delivery of Therapeutic Proteins: Challenges and Strategies. AB - Recent advances in genetic engineering and pharmaceutical biotechnology have made possible to combat life-threatening diseases with efficient delivery of therapeutic proteins. These advancements have increased the significance of therapeutic proteins in pharmaceutical market, but their therapeutic delivery to the targeted site is still a major obstacle to achieve desired therapeutic outcomes. In most cases, majority of the therapeutic proteins are usually administered via oral routes which encounter many problems notably enzymatic degradation, poor solubility and nonlinear pharmacokinetics. Besides this route, many other routes like mucosal, intra-nasal, intra-vaginal, pulmonary and transdermal have also been used for the delivery of therapeutic proteins. In order to keep these therapeutic proteins safe from enzymatic degradation and improve their therapeutic efficacy, several strategies have been designed and investigated various therapeutic delivery routes for efficient delivery of therapeutic proteins to the targeted site with minimal side effects. In this article, we have comprehensively summarized the recent advances and developments that have been adopted for delivery systems of these therapeutic proteins via invasive and/or non-invasive routes. PMID- 26648074 TI - Targeting Transient Receptor Potential Canonical Channels for Diseases of the Nervous System. AB - BACKGROUND: Ca2+ influx plays an essential role in the physiological and pathophysiologic processes of several nervous system diseases. The transient receptor-potential channels (TRPCs) form a family of voltage -sensitive calcium ion channels. OBJECTIVE: In this review, we will discuss the importance of transient receptor potential canonical (TRPC) channels, which is a crucial family of calcium channels. This article reviews the role of TRPC channels in the pathogenesis of diseases such as brain hemorrhage, hemorrhagic transformation after cerebral infarction, subarachnoid hemorrhage, and brain injury. RESULTS: TRPC has especially high expression in the central nervous system (CNS), and was involved in several physiological functions. The TRPC family is associated with cerebral vasospasm after subarachnoid hemorrhage, neuronal damage after intracerebral hemorrhage, NMDA cytotoxicity in cerebral ischemia, nervous system tumors, neurodegenerative diseases, neural addiction and other diseases. CONCLUSION: The TRPC family has rich functionality and is widely distributed, with different functions in various nervous system diseases. PMID- 26648075 TI - Emerging Immunotargets in Metastatic Renal Cell Carcinoma. AB - Renal cell carcinoma (RCC) is one of the most immunoresponsive human cancers. High-dose IL-2 and Interferon-alpha were once the principle therapies for metastatic RCC, however they had harsh-tolerance profiles and limited response rates. In the last decade, targeted therapies have supplanted cytokine therapy due to higher response rates and more favorable toxicity profiles. Emerging immunotherapies targeting the PD-1 receptor and PD-L1 ligand have shown promising results. Likewise, other novel targeted immunotherapies are currently under evaluation. The safety profiles and response rates of new generation immunotherapies are encouraging and justify the progression of clinical trials. However, longer follow-up data are needed to confirm these promising results. In addition, it is still unclear if an optimal sequence or combinations of new immunotherapies paired with current targeted therapies will emerge. PMID- 26648076 TI - Design of Lipophilic Prodrugs to Improve Drug Delivery and Efficacy. AB - Poor absorption, short half-life and resistance development are some of the major factors responsible for reduced drug efficacy. Lipophilic prodrugs can offer certain advantages to overcome these challenges. Chemical derivatization of hydrophilic agents with lipophilic pro-moieties can significantly elevate drug diffusion across absorptive membranes. Moreover, the desired linkage (ester vs. amide) may be selected to improve stability in vivo. Importantly, an appropriate selection of pro-moiety (targeting ligand) may promote drug specificity and selectivity. In this review article, an attempt has been made to summarize lipophilic prodrugs employed to improve delivery and efficacy of a wide range of poorly permeable but highly potent therapeutic agents. In addition, a brief overview on recent application of lipophilic prodrugs to promote encapsulation of hydrophilic agents in nano-sized drug carriers has been provided. PMID- 26648077 TI - Therapeutic Value of an Integrin Antagonist in Prostate Cancer. AB - In recent decades we have seen an exponential interest in the implications of integrin receptors in cancer biology and especially in prostate tumour development. Integrins has been reported to control multiple mechanisms, such as cell survival, proliferation, differentiation, and migration. Here, we report the current understanding of the integrin signalling mechanisms in metastatic prostate tumour development, cross-talks between the primary and metastatic sites on tumour growth, interactions between tumour cells and tissue microenvironment, and epithelial-mesenchymal transition (EMT). Finally, this review presents the integrin-based chemotherapeutic agents currently under clinically consideration and provides an insight into cancer drug development using integrin as a target. PMID- 26648078 TI - Protease-Activated Receptor 2: Are Common Functions in Glial and Immune Cells Linked to Inflammation-Related CNS Disorders? AB - Protease-activated receptors (PARs) are a novel family of G-protein coupled receptors (GPCRs) whose activation requires the cleavage of the N-terminus by a serine protease. However, recent evidence reveals that alternative routes of activation also occur, that PARs signal via multiple pathways and that pathway activation is activator- dependent. Given our increased understanding of PAR function both under physiological and pathophysiological conditions, one aspect that has remained constant is the link between PAR2 and inflammation. PAR2 is expressed in immune cells of both the innate and adaptive immune system and has been shown to play a role in several peripheral inflammatory conditions. PAR2 is similarly expressed on astrocytes and microglia within the CNS and its activation is either protective or detrimental to CNS function depending on the conditions or disease state investigated. With a clear similarity between the function of PAR2 on both immune cells and CNS glial cells, here we have reviewed their roles in both these systems. We suggest that the recent development of novel PAR2 modulators, including those that show biased signalling, will further increase our understanding of PAR2 function and the development of potential therapeutics for CNS disorders in which inflammation is proposed to play a role. PMID- 26648079 TI - An Overview of Emerging Immunotargets of Genitourinary Tumors. AB - Emerging immunotherapies targeting immune checkpoints and tumor associated antigens are leading to important clinical advances and providing a new weapon in patients with prostate (PCa) and bladder cancer (BC) and, in particular, with renal cell carcinoma (RCC). The possibility to integrate these agents in the current therapeutic scenario or genitourinary tumors, both in sequential or combined approaches, relies on a more profound comprehension of the protumorigenic activity of the immune system and of the mechanisms of cancer related immunosuppression. In this regards, neutrophils, T and B lymphocytes and tumor-associated macrophages (TAMs) are implicated in the pathogenesis, progression and development of drug resistance in genitourinary tumors. This review is an overview on the recent insights concerning the role of immune cells in this context. PMID- 26648081 TI - Pharmacological Correction of Cystic Fibrosis: Molecular Mechanisms at the Plasma Membrane to Augment Mutant CFTR Function. AB - In the late 1980s, a loss-of-function mutation in the gene encoding for the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel was identified to be the primary cause of cystic fibrosis (CF); a fatal multiple organ disorder that mostly affects Caucasians. To date, approximately 2000 genetic mutations have been identified in the CFTR gene (http://www.genet.sickkids.on.ca/cftr/app). The most common cause of morbidity and mortality in persons with CF is a progressive deterioration in lung function leading ultimately to respiratory collapse. The median life expectancy of CF patients currently is estimated to be 39 years in the US. The most prevalent CFTR mutation, F508del, accounts for 70% of CF cases and causes a processing defect in the protein leading to premature endoplasmic reticulum-associated degradation (ERAD) and reduced F508del-CFTR delivery to the cell surface. A CF corrector is defined as a chemical chaperone that increases cell-surface levels of F508del CFTR. A series of CF correctors have been developed, and VX-809 (lumacaftor) has been cited as the most effective symptomatic CF corrector to date. VX-809 improves the function of the mutant protein by approximately 15% in in vitro culture systems. However, this effect did not completely translate clinically, with only a marginal improvement observed in lung function of the F508del homozygous patients undergoing the therapy. New studies revealed that even after successful ER retrieval, rescued F508del-CFTR (rF508del-CFTR) once at the cell surface does not function properly, exhibiting poor stability and channel gating and structural abnormalities. This becomes further complicated by the existence of genes termed CFTR modifiers, which can alter CFTR function to be additionally defective and exacerbate the CF phenotype while also alternatively suggested be potentially targeted to improve F508del-CFTR functional outcome. It is necessary to understand the biology of F508del-CFTR post-ER and at the plasma membrane where the protein might also confront the modifiers and how we can incorporate these components into CF therapeutics. Additionally, the notion that CF individuals would eventually benefit from more of a personalized medicine is becoming increasingly accepted. Here, we review how CF therapeutics may be simplified by understanding the complexities of rescued F508del-CFTR biology and eventually move toward more personalized medicine for patients suffering with CF. PMID- 26648080 TI - Ubiquitin and Ubiquitin-like proteins in cardiac disease and protection. AB - Post-translational modification represents an important mechanism to regulate protein function in cardiac cells. Ubiquitin (Ub) and ubiquitin-like proteins (UBLs) are a family of protein modifiers that share a certain extent of sequence and structure similarity. Conjugation of Ub or UBLs to target proteins is dynamically regulated by a set of UBL-specific enzymes and modulates the physical and physiological properties of protein substrates. Ub and UBLs control a strikingly wide spectrum of cellular processes and not surprisingly are involved in the development of multiple human diseases including cardiac diseases. Further identification of novel UBL targets will expand our understanding of the functional diversity of UBL pathways in physiology and pathology. Here we review recent findings on the mechanisms, proteome and functions of a subset of UBLs and highlight their potential impacts on the development and progression of various forms of cardiac diseases. PMID- 26648082 TI - Targeting glycolysis in the malaria parasite Plasmodium falciparum. AB - Glycolysis is the main pathway for ATP production in the malaria parasite Plasmodium falciparum and essential for its survival. Following a sensitivity analysis of a detailed kinetic model for glycolysis in the parasite, the glucose transport reaction was identified as the step whose activity needed to be inhibited to the least extent to result in a 50% reduction in glycolytic flux. In a subsequent inhibitor titration with cytochalasin B, we confirmed the model analysis experimentally and measured a flux control coefficient of 0.3 for the glucose transporter. In addition to the glucose transporter, the glucokinase and phosphofructokinase had high flux control coefficients, while for the ATPase a small negative flux control coefficient was predicted. In a broader comparative analysis of glycolytic models, we identified a weakness in the P. falciparum pathway design with respect to stability towards perturbations in the ATP demand. DATABASE: The mathematical model described here has been submitted to the JWS Online Cellular Systems Modelling Database and can be accessed at http://jjj.bio.vu.nl/database/vanniekerk1. The SEEK-study including the experimental data set is available at DOI 10.15490/seek.1. INVESTIGATION: 56 (http://dx.doi.org/10.15490/seek.1. INVESTIGATION: 56). PMID- 26648083 TI - Chronic spontaneous urticaria and internal parasites--a systematic review. AB - Chronic spontaneous urticaria (CSU) is defined as persistent wheals, angioedema, or both lasting for >6 weeks due to known or unknown causes. Some epidemiological studies and case reports suggest that internal parasite infections (PI) can cause CSU. Here, we provide a systematic overview of published findings on the prevalence and relevance of PI in CSU and we discuss possible pathomechanisms. The prevalence of PI in CSU was investigated by 39 independent studies and comorbidity reportedly ranged from 0 to 75.4% (two-thirds of these studies reported infection rates of 10% or less). The prevalence of PI in adult and pediatric CSU patients ranged from 0% to 75.4% and from 0% to 37.8%, respectively. CSU patients were more often diagnosed with protozoa and had a significantly higher risk of toxocariasis seropositivity and Anisakis simplex sensitization when compared to healthy controls. Patients with chronic urticaria more frequently had seropositivity of fasciolosis, Anisakis simplex sensitization, and the presence of Blastocystis hominis allele 34 (ST3) as compared with control subjects. In 21 studies, efficacy of treatment with antiparasitic drugs ranged from 0 to 100% (35.7% of 269 CSU patients benefitted). In 9 (42.8%) of 21 studies, more than 50% of efficacy was observed. The reported rate of urticaria comorbidity in PI patients in 18 independent studies is 1 66.7%. Urticaria including CSU might be a quite common symptom of strongyloidiasis and blastocystosis. Pathogenic mechanisms in CSU due to PI may include specific IgE, Th2 cytokine skewing, eosinophils, activation of the complement, and the coagulation systems. PMID- 26648084 TI - Pharmacokinetics and safety of single doses of tabalumab in subjects with rheumatoid arthritis or systemic lupus erythematosus. AB - AIMS: Two phase 1 studies evaluated the pharmacokinetics (PK), safety and biological activity of tabalumab, a human monoclonal antibody against B-cell activating factor (BAFF), administered intravenously (i.v.) or subcutaneously (s.c.) in subjects with rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE). METHODS: In study A, subjects with RA (n = 23) or SLE (n = 6) received a single i.v. dose of tabalumab (RA 0.01, 0.04, 0.125, 0.5, 2.0, and 8.0 mg kg(-1) and SLE 0.125 or 2.0 mg kg(-1) ) or placebo. In study B, subjects with RA received a single tabalumab dose i.v. (10 mg) (n = 12) or s.c. (20 mg) (n = 12). Serum tabalumab and CD20+ B cells were evaluated and safety was assessed throughout both studies. RESULTS: Tabalumab PK were non-linear across the 0.01 to 8.0 mg kg(-1) dose range. Clearance (CL) decreased from 2.9 to 0.1 l day(-1) and terminal half-life (t1/2 ) increased from about 1.6 to 25 days. Subjects with RA or SLE had similar PK. After s.c. dosing, tabalumab time to maximal concentration (tmax ) was 5.5 days. Absolute bioavailability (F) was approximately 62%. Following tabalumab dosing, CD20+ B cells transiently increased from baseline followed by a progressive decrease below baseline. CONCLUSION: A single tabalumab dose administered i.v. or s.c. was well tolerated and had non-linear CL over the dose range investigated in subjects with RA and SLE. The non-linearity likely reflects target-mediated CL due to binding to BAFF. Tabalumab showed biological activity based on changes in peripheral CD20+ lymphocyte numbers in both subjects with RA and SLE. PMID- 26648085 TI - Readmissions following an initial hospitalization by COPD exacerbation in Spain from 2006 to 2012. AB - BACKGROUND AND OBJECTIVE: Hospitalizations are not isolated events in COPD patients. A significant percentage of patients are readmitted during the first month after their discharge. The aim of this study was to elucidate changes in the incidence, comorbidity, length of hospital stay (LOHS), costs and in-hospital mortality (IHM) of patients readmitted following an initial hospitalization by acute exacerbation of COPD (AE-COPD). METHODS: We selected all patients >=40 years, hospitalized for AE-COPD between 2006 and 2012 in Spain using the National Hospital Discharge Database. Patient readmissions were defined as inpatient re hospitalization within 30 days of discharge for AE-COPD. RESULTS: We identified 301 794 discharges of patients having hospital admissions for AE-COPD as their primary diagnosis (82.47% first admissions, 17.53% hospital readmissions). The risk of re-hospitalization was higher in patients aged 65 to 84 years, males, with comorbidities, malnutrition, not obese, respiratory acidosis, treated with non-invasive ventilation (NIV) or discharged to a health/social institutions. Factors associated with IHM among patients readmitted were: older age, increased Charlson Index, malnutrition, not being obese, respiratory acidosis and treatment with NIV. The IHM and hospital costs were significantly higher in readmissions compared with first admissions. We observed that the incidence and mortality of readmissions had significantly decreased from 2006 to 2012. CONCLUSION: Hospital readmissions within 30 days of discharge for AE-COPD are common in Spain. They have a high impact for COPD patients and health system. However, we have found a downward trend in incidence and mortality of readmissions from 2006 to 2012. PMID- 26648086 TI - Cloning and evaluation of different constitutive promoters in the oleaginous yeast Rhodosporidium toruloides. AB - The oleaginous yeast Rhodosporidium toruloides is an unconventional yeast species that can accumulate a high content of lipids. Because it belongs to the basidiomycetous group of fungus, limited tools and functional elements are available for genetic engineering of R. toruloides and related red yeasts. Here we report the functional evaluation of five constitutive promoters from this yeast. We assembled a reporter gene expression cassette, consisting of a promoter, the hygromycin gene (HYG) and the nos terminator, and inserted it into the binary vector pZPK. Hygromycin-resistant transformants were obtained when R. toruloides cells were co-cultured with Agrobacterium tumefaciens AGL1 cells harbouring the engineered vector. Genomic integration of the reporter cassette was verified by successful amplification of target DNA fragments. Quantitative PCR analysis suggested that the transformant had only one copy of the reporter cassette. The strength of these promoters was demonstrated at the phenotypic level on the hygromycin-gradient plate and at the transcriptional level by real time quantitative PCR. It was found that the strengths of these promoters varied no more than five-fold and followed a decreasing sequence of PPGI, PPGK, PFBA, PTPI, and PGPD. This study established new genetic elements for the construction of superior R. toruloides strains to produce advanced biofuels and related chemicals. PMID- 26648087 TI - Single-walled carbon nanotubes functionalized with sodium hyaluronate enhance bone mineralization. AB - The aim of this study was to evaluate the effects of sodium hyaluronate (HY), single-walled carbon nanotubes (SWCNTs) and HY-functionalized SWCNTs (HY-SWCNTs) on the behavior of primary osteoblasts, as well as to investigate the deposition of inorganic crystals on titanium surfaces coated with these biocomposites. Primary osteoblasts were obtained from the calvarial bones of male newborn Wistar rats (5 rats for each cell extraction). We assessed cell viability using the 3 (4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide assay and by double-staining with propidium iodide and Hoechst. We also assessed the formation of mineralized bone nodules by von Kossa staining, the mRNA expression of bone repair proteins, and the deposition of inorganic crystals on titanium surfaces coated with HY, SWCNTs, or HY-SWCNTs. The results showed that treatment with these biocomposites did not alter the viability of primary osteoblasts. Furthermore, deposition of mineralized bone nodules was significantly increased by cells treated with HY and HY-SWCNTs. This can be partly explained by an increase in the mRNA expression of type I and III collagen, osteocalcin, and bone morphogenetic proteins 2 and 4. Additionally, the titanium surface treated with HY-SWCNTs showed a significant increase in the deposition of inorganic crystals. Thus, our data indicate that HY, SWCNTs, and HY-SWCNTs are potentially useful for the development of new strategies for bone tissue engineering. PMID- 26648088 TI - beta-Citronellol, an alcoholic monoterpene with inhibitory properties on the contractility of rat trachea. AB - beta-Citronellol is an alcoholic monoterpene found in essential oils such Cymbopogon citratus (a plant with antihypertensive properties). beta-Citronellol can act against pathogenic microorganisms that affect airways and, in virtue of the popular use of beta-citronellol-enriched essential oils in aromatherapy, we assessed its pharmacologic effects on the contractility of rat trachea. Contractions of isolated tracheal rings were recorded isometrically through a force transducer connected to a data-acquisition device. beta-Citronellol relaxed sustained contractions induced by acetylcholine or high extracellular potassium, but half-maximal inhibitory concentrations (IC50) for K(+)-elicited stimuli were smaller than those for cholinergic contractions. It also inhibited contractions induced by electrical field stimulation or sodium orthovanadate with pharmacologic potency equivalent to that seen against acetylcholine-induced contractions. When contractions were evoked by selective recruitment of Ca2+ from the extracellular medium, beta-citronellol preferentially inhibited contractions that involved voltage-operated (but not receptor-operated) pathways. beta Citronellol (but not verapamil) inhibited contractions induced by restoration of external Ca2+ levels after depleting internal Ca2+ stores with the concomitant presence of thapsigargin and recurrent challenge with acetylcholine. Treatment of tracheal rings with L-NAME, indomethacin or tetraethylammonium did not change the relaxing effects of beta-citronellol. Inhibition of transient receptor potential vanilloid subtype 1 (TRPV1) or transient receptor potential ankyrin 1 (TRPA1) receptors with selective antagonists caused no change in the effects of beta citronellol. In conclusion, beta-citronellol exerted inhibitory effects on rat tracheal rings, with predominant effects on contractions that recruit Ca2+ inflow towards the cytosol by voltage-gated pathways, whereas it appears less active against contractions elicited by receptor-operated Ca2+ channels. PMID- 26648089 TI - Acute but not chronic metabolic acidosis potentiates the acetylcholine-induced reduction in blood pressure: an endothelium-dependent effect. AB - Metabolic acidosis has profound effects on vascular tone. This study investigated the in vivo effects of acute metabolic acidosis (AMA) and chronic metabolic acidosis (CMA) on hemodynamic parameters and endothelial function. CMA was induced by ad libitum intake of 1% NH4Cl for 7 days, and AMA was induced by a 3-h infusion of 6 M NH4Cl (1 mL/kg, diluted 1:10). Phenylephrine (Phe) and acetylcholine (Ach) dose-response curves were performed by venous infusion with simultaneous venous and arterial blood pressure monitoring. Plasma nitrite/nitrate (NOx) was measured by chemiluminescence. The CMA group had a blood pH of 7.15+/-0.03, which was associated with reduced bicarbonate (13.8+/ 0.98 mmol/L) and no change in the partial pressure of arterial carbon dioxide (PaCO2). The AMA group had a pH of 7.20+/-0.01, which was associated with decreases in bicarbonate (10.8+/-0.54 mmol/L) and PaCO2 (47.8+/-2.54 to 23.2+/ 0.74 mmHg) and accompanied by hyperventilation. Phe or ACh infusion did not affect arterial or venous blood pressure in the CMA group. However, the ACh infusion decreased the arterial blood pressure (DeltaBP: -28.0+/-2.35 mm Hg [AMA] to -4.5+/-2.89 mmHg [control]) in the AMA group. Plasma NOx was normal after CMA but increased after AMA (25.3+/-0.88 to 31.3+/-0.54 MUM). These results indicate that AMA, but not CMA, potentiated the Ach-induced decrease in blood pressure and led to an increase in plasma NOx, reinforcing the effect of pH imbalance on vascular tone and blood pressure control. PMID- 26648090 TI - Galantamine protects against lipopolysaccharide-induced acute lung injury in rats. AB - Lipopolysaccharide (LPS)-induced endotoxemia triggers the secretion of proinflammatory cytokines and can cause acute lung injury (ALI). The high mobility group box 1 (HMGB1) protein plays an important role as a late mediator of sepsis and ALI. Galantamine (GAL) is a central acetylcholinesterase inhibitor that inhibits the expression of HMGB1. This study evaluated the effects of GAL by measuring levels of inflammatory mediators and observing histopathological features associated with LPS-induced ALI. Sixty 8-10 week old male Sprague-Dawley rats (200-240 g) were randomized into three groups as follows: control group, LPS group (7.5 mg/kg LPS), and LPS+GAL group (5 mg/kg GAL before LPS administration). Histopathological examination of lung specimens obtained 12 h after LPS administration was performed to analyze changes in wet-to-dry (W/D) weight ratio, myeloperoxidase (MPO) activity, and HMGB1 expression level. Additionally, plasma concentrations of tumor necrosis factor-alpha, interleukin-6, and HMGB1 were measured using an enzyme-linked immunosorbent assay at 0 (baseline), 3, 6, 9, and 12 h after LPS administration. Mortality in the three groups was recorded at 72 h. LPS-induced ALI was characterized by distortion of pulmonary architecture and elevation of MPO activity, W/D weight ratio, and levels of pro-inflammatory cytokines, including tumor necrosis factor-alpha, interleukin-6, and HMGB1. Pretreatment with GAL significantly reduced the LPS-induced lung pathological changes, W/D weight ratio, levels of pro-inflammatory cytokines and MPO activity (ANOVA). Moreover, GAL treatment significantly decreased the mortality rate (ANOVA). In conclusion, we demonstrated that GAL exerted a protective effect on LPS-induced ALI in rats. PMID- 26648091 TI - Three days of intermittent stretching after muscle disuse alters the proteins involved in force transmission in muscle fibers in weanling rats. AB - The aim of this study was to determine the effects of intermittent passive manual stretching on various proteins involved in force transmission in skeletal muscle. Female Wistar weanling rats were randomly assigned to 5 groups: 2 control groups containing 21- and 30-day-old rats that received neither immobilization nor stretching, and 3 test groups that received 1) passive stretching over 3 days, 2) immobilization for 7 days and then passive stretching over 3 days, or 3) immobilization for 7 days. Maximal plantar flexion in the right hind limb was imposed, and the stretching protocol of 10 repetitions of 30 s stretches was applied. The soleus muscles were harvested and processed for HE and picrosirius staining; immunohistochemical analysis of collagen types I, III, IV, desmin, and vimentin; and immunofluorescence labeling of dystrophin and CD68. The numbers of desmin- and vimentin-positive cells were significantly decreased compared with those in the control following immobilization, regardless of whether stretching was applied (P<0.05). In addition, the semi-quantitative analysis showed that collagen type I was increased and type IV was decreased in the immobilized animals, regardless of whether the stretching protocol was applied. In conclusion, the largest changes in response to stretching were observed in muscles that had been previously immobilized, and the stretching protocol applied here did not mitigate the immobilization-induced muscle changes. Muscle disuse adversely affected several proteins involved in the transmission of forces between the intracellular and extracellular compartments. Thus, the 3-day rehabilitation period tested here did not provide sufficient time for the muscles to recover from the disuse maladaptations in animals undergoing postnatal development. PMID- 26648093 TI - Cancer/testis antigen NY-SAR-35 enhances cell proliferation, migration, and invasion. AB - The cancer/testis antigen NY-SAR-35 is aberrantly expressed in various cancer tissues and cancer cell lines but not in normal tissues except for the testis. A previous study demonstrated that the expression of NY-SAR-35 is activated by hypomethylation in cancer cells. However, the functions of this antigen remain unexplored. In the present study, we investigated the role of NY-SAR-35 in human embryonic kidney (HEK) 293 cells using exogenous expression system of the gene. NY-SAR-35 was predominantly expressed at the cytoplasm and was mainly observed in spermatogonia and spermatocytes. Expression of NY-SAR-35 in stable HEK293 transfectant clones was 2-fold higher than the control cells promoting cell growth and proliferation. NY-SAR-35 overexpression also enhanced cell migration and invasion ~2-fold and 4-fold more than the control, respectively. In contrast, small interfering RNA-mediated knockdown of NY-SAR-35 suppressed cell proliferation, migration, and invasion in HEK293 stable transfectants. We concluded that NY-SAR-35 as a cancer/testis antigen enhanced cell proliferation and invasion. PMID- 26648092 TI - Lyophilized allografts without pre-treatment with glutaraldehyde are more suitable than cryopreserved allografts for pulmonary artery reconstruction. AB - Various methods are available for preservation of vascular grafts for pulmonary artery (PA) replacement. Lyophilization and cryopreservation reduce antigenicity and prevent thrombosis and calcification in vascular grafts, so both methods can be used to obtain vascular bioprostheses. We evaluated the hemodynamic, gasometric, imaging, and macroscopic and microscopic findings produced by PA reconstruction with lyophilized (LyoPA) grafts and cryopreserved (CryoPA) grafts in dogs. Eighteen healthy crossbred adult dogs of both sexes weighing between 18 and 20 kg were used and divided into three groups of six: group I, PA section and reanastomosis; group II, PA resection and reconstruction with LyoPA allograft; group III, PA resection and reconstruction with CryoPA allograft. Dogs were evaluated 4 weeks after surgery, and the status of the graft and vascular anastomosis were examined macroscopically and microscopically. No clinical, radiologic, or blood-gas abnormalities were observed during the study. The mean pulmonary artery pressure (MPAP) in group III increased significantly at the end of the study compared with baseline (P=0.02) and final [P=0.007, two-way repeat measures analysis of variance (RM ANOVA)] values. Pulmonary vascular resistance of groups II and III increased immediately after reperfusion and also at the end of the study compared to baseline. The increase shown by group III vs group I was significant only if compared with after surgery and study end (P=0.016 and P=0.005, respectively, two-way RM ANOVA). Microscopically, permeability was reduced by <=75% in group III. In conclusion, substitution of PAs with LyoPA grafts is technically feasible and clinically promising. PMID- 26648094 TI - The impact of symptomatic mild traumatic brain injury on complex everyday activities and the link with alterations in cerebral functioning: Exploratory case studies. AB - The objective of the study was to explore the neurophysiological correlates of altered functional independence using functional magnetic resonance imaging (fMRI) and event-related potentials (ERP) after a mild traumatic brain injury (mTBI). The participants consisted of three individuals with symptomatic mTBI (3.9 +/- 3.6 months post-mTBI) and 12 healthy controls. The main measures used were the Instrumental Activities of Daily Living (IADL) Profile observation-based assessment; a visual externally ordered working memory task combined to event related potentials (ERP) and fMRI recordings; neuropsychological tests; post concussion symptoms questionnaires; and the Activities of Daily Living (ADL) Profile interview. Compared to normal controls, all three patients had difficulty with a real-world complex budgeting activity due to deficits in planning, ineffective strategy use and/or a prolonged time to detect and correct errors. Reduced activations in the right mid-dorsolateral prefrontal cortex on fMRI as well as abnormal frontal or parietal components of the ERP occurred alongside these deficits. Results of this exploratory study suggest that reduced independence in complex everyday activities in symptomatic mTBI may be at least partly explained by a decrease in brain activation in the prefrontal cortex, abnormal ERP, or slower reaction times on working memory tasks. The study presents an initial attempt at combining research in neuroscience with ecological real-world evaluation research to further our understanding of the difficulties in complex everyday activities experienced by individuals with mTBI. PMID- 26648095 TI - Circuit Impedance Could Be a Crucial Factor Influencing Radiofrequency Ablation Efficacy and Safety: A Myocardial Phantom Study of the Problem and its Correction. AB - BACKGROUND: Circuit impedance could affect the safety and efficacy of radiofrequency (RF) ablation. AIM: To perform irrigated RF ablations with graded impedance to compare (1) lesion dimensions and overheated dimensions in fixed power ablations (2) and in power corrected ablations. METHODS: Ablations were performed with irrigated Navistar Thermocool catheter and Stockert EP shuttle generator at settings of 40 W power for 60 seconds, in a previously validated myocardial phantom. The impedance of the circuit was set at 60 Omega, 80 Omega, 100 Omega, 120 Omega, 140 Omega, and 160 Omega. The lesion and overheated dimensions were measured at 53 degrees C and 80 degrees C isotherms, respectively. In the second set of ablations, power was corrected according to circuit impedance. RESULTS: In total, 70 ablations were performed. The lesion volume was 72.0 +/- 4.8% and 44.7 +/- 4.6% higher at 80 Omega and 100 Omega, respectively, compared to that at 120 Omega and it was 15.4 +/- 1.2%, 28.1 +/- 2.0%, and 38.0 +/- 1.8% lower at 140 Omega, 160 Omega, and 180 Omega, respectively. The overheated volume was four times larger when impedance was reduced to 80 Omega from 100 Omega. It was absent at 120 Omega and above. In the power corrected ablations, the lesion volumes were similar to that of 40 W/120 Omega ablations and there was no evidence of overheating. CONCLUSION: The lesion and overheated dimensions were significantly larger with lower circuit impedance during irrigated RF ablation and the lesion size was smaller in high impedance ablations. Power delivery adjusted to impedance using a simple equation improved the consistency of lesion formation and prevented overheating. PMID- 26648096 TI - A national audit of standards of care for women with vulval conditions and survey of attitudes to nurse practitioners in vulval services in the UK. AB - This national audit assessed whether UK specialist vulval clinics adhere to the British Society of Vulval Diseases (BSSVD) document 'Standards of care for women with vulval conditions' published in 2013 and benchmarked clinician attitudes towards nurse practitioners in vulval services. Audit standards were based on the BSSVD guidance. All BSSVD and British Society for Colposcopy and Cervical Pathology or BSCCP members were surveyed via two electronic questionnaires. Results demonstrate that the majority of specialist vulval clinics in the UK are non-compliant with the standards set out for specialist vulval services. The majority of clinicians would support the introduction of clinical nurse specialists to vulval services, but there is need for development of a national training programme. In conclusion, significant improvements are required in provision of patient information, guidelines, access to multidisciplinary services, multidisciplinary team or MDT processes and data recording in UK specialist vulval services. PMID- 26648097 TI - In vitro, in vivo and in silico metabolic profiling of alpha pyrrolidinopentiothiophenone, a novel thiophene stimulant. AB - BACKGROUND: Little or no pharmacological or toxicological data are available for novel psychoactive substances when they first emerge, making their identification and interpretation in biological matrices challenging. MATERIALS & METHODS: A new synthetic cathinone, alpha-pyrrolidinopentiothiophenone (alpha-PVT), was incubated with hepatocytes and samples were analyzed using liquid chromatography coupled to a Q ExactiveTM Orbitrap mass spectrometer. Authentic urine specimens from suspected alpha-PVT cases were also analyzed. Scans were data mined with Compound DiscovererTM for identification and structural elucidation of metabolites. RESULTS/CONCLUSION: Seven alpha-PVT metabolites were identified in hepatocyte incubations, and in the authentic urine samples, also with an additional monohydroxylated product and a glucuronide of low intensity. alpha-PVT dihydroxypyrrolidinyl, alpha-PVT 2-ketopyrrolidinyl, alpha-PVT hydroxythiophenyl and alpha-PVT thiophenol had the most intense in vivo signals. PMID- 26648098 TI - Theaflavin-3, 3'-digallate decreases human ovarian carcinoma OVCAR-3 cell-induced angiogenesis via Akt and Notch-1 pathways, not via MAPK pathways. AB - Theaflavin-3, 3'-digallate (TF3) is a black tea polyphenol produced from polymerization and oxidization of the green tea ployphenols epicatechin gallate and (-)-epigallocatechin-3-gallate (EGCG) during fermentation of fresh tea leaves. TF3 has been reported to have anticancer properties. However, the effect of TF3 on tumor angiogenesis and the underlying mechanisms are not clear. In the present study, TF3 was verified to inhibit tumor angiogenesis. Compared with EGCG, TF3 was more potent. TF3 inhibited human ovarian carcinoma OVCAR-3 cell induced angiogenesis in human umbilical vein endothelial cell model and in chick chorioallantoic membrane model. TF3 reduced tumor angiogenesis by downregulating HIF-1alpha and VEGF. One of the mechanisms was TF3 inactivated Akt/mTOR/p70S6K/4E BP1 pathway and Akt/c-Myc pathway. Besides, TF3 suppressed the cleavage of Notch 1, subsequently decreased the expression of c-Myc, HIF-1alpha and VEGF, and finally the impaired cancer cells induced angiogenesis. Nevertheless, TF3 did not have any influence on the MAPK pathways. Taken together, these findings suggest that TF3 might serve as a potential anti-angiogenic agent for cancer treatment. PMID- 26648099 TI - Type II diabetes disparities in diverse women: the potential roles of body composition, diet and physical activity. AB - The rates of diabetes in the USA are rapidly increasing, and vary widely across different racial/ethnic groups. This paper explores the potential contribution of body composition, diet and physical activity in explaining diabetes disparities across women of different racial and ethnic backgrounds. For body composition, racial/ethnic groups differ widely by BMI, distribution of body mass and quantity and type of adipose tissue. Dietary patterns that vary across race/ethnicity include consumption of meat, added sugars, high-glycemic carbohydrates and fast food. Additionally, physical activity patterns of interest include aerobic versus muscle-strengthening exercises, and the purpose of physical activity (leisure, occupation, or transportation). Overall, these variables provide a partial picture of the source of these widening disparities, and could help guide future research in addressing and reducing diabetes disparities. PMID- 26648101 TI - Delayed metamorphosis of amphibian larvae facilitates Batrachochytrium dendrobatidis transmission and persistence. AB - Highly virulent pathogens that cause host population declines confront the risk of fade-out, but if pathogen transmission dynamics are age-structured, pathogens can persist. Among other features of amphibian biology, variable larval developmental rates generate age-structured larval populations, which in theory can facilitate pathogen persistence. We investigated this possibility empirically in a population of Salamandra salamandra in Spain affected by Batrachochytrium dendrobatidis (Bd) at breeding sites that lacked alternative amphibian hosts. None of the adults presented infection by Bd. However, for the larvae, while environmental heterogeneity was the most important predictor of infection, the effect on infection dynamics was mediated by transmission from overwintered larvae to new larval recruits, which occurred only in permanent larval habitats. We suggest that interannual Bd maintenance in a host population that experiences mass mortality associated with infection can occur without an environmental reservoir or direct involvement of an alternative host in our study system. However the 2 aquatic habitat types that support intraspecific reservoirs, permanent streams and ponds, are not ideal habitats for long-term Bd maintenance, either due to poor transmission probability or low host survival, respectively. While intraspecific pathogen maintenance due to larval plasticity might be possible at our study sites, this transmission pattern is not without significant risk to the pathogen. The availability of alternative hosts nearby does indicate that permanent Bd fade-out is unlikely. PMID- 26648100 TI - Mapping the genetic diversity of HLA haplotypes in the Japanese populations. AB - Japan has often been viewed as an Asian country that possesses a genetically homogenous community. The basis for partitioning the country into prefectures has largely been geographical, although cultural and linguistic differences still exist between some of the districts/prefectures, especially between Okinawa and the mainland prefectures. The Major Histocompatibility Complex (MHC) region has consistently emerged as the most polymorphic region in the human genome, harbouring numerous biologically important variants; nevertheless the presence of population-specific long haplotypes hinders the imputation of SNPs and classical HLA alleles. Here, we examined the extent of genetic variation at the MHC between eight Japanese populations sampled from Okinawa, and six other prefectures located in or close to the mainland of Japan, specifically focusing at the haplotypes observed within each population, and what the impact of any variation has on imputation. Our results indicated that Okinawa was genetically farther to the mainland Japanese than were Gujarati Indians from Tamil Indians, while the mainland Japanese from six prefectures were more homogeneous than between northern and southern Han Chinese. The distribution of haplotypes across Japan was similar, although imputation was most accurate for Okinawa and several mainland prefectures when population-specific panels were used as reference. PMID- 26648102 TI - Sturgeon nucleo-cytoplasmic large DNA virus phylogeny and PCR tests. AB - Sturgeon epitheliotropic nucleo-cytoplasmic large DNA viruses (NCLDVs) can cause a lethal disease of the integumentary system. These viruses have not been assigned to any currently recognized family or genus. In this study, phylogenetic analyses using the major capsid protein (MCP) showed that the sturgeon NCLDVs formed a cohesive taxonomic group, could be identified to the species or possibly sub-species level and formed a distinct evolutionary lineage within the Megavirales. The genetic relatedness of the sturgeon virus MCP allowed design of 3 PCR diagnostic tests with analytical specificity (ASp) inclusive of this group of viruses. The conventional PCR test, C1, had broader ASp than the 2 quantitative PCR tests, Q1 and Q2, and was inclusive of the sturgeon viruses as well as some viruses belonging to the families Mimi-, Phycodna-, or Iridoviridae. Q2 had broader specificity than Q1 but both tests recognized the sturgeon NCLDVs and did not cross-react with co-localizing sturgeon herpesviruses. Analytical test performance characteristics evaluated for Q1 and Q2 revealed sensitive assays with observed 50% limits of detection between 3 and 6.25 plasmid copies and high intra- and inter-assay repeatability. Q1 was used to test for sturgeon viruses in endangered populations of lake sturgeon Acipenser fulvescens within the Winnipeg River or Nelson River drainage systems of Manitoba, Canada. Test results indicated that namao virus is endemic in the Nelson River water basin. These tests meet the analytical requirements for diagnostic testing in Canada and are useful tools for disease management in sturgeon conservation stocking programs in North America. PMID- 26648103 TI - Wild juvenile salmonids in Muchalat Inlet, British Columbia, Canada: factors associated with sea lice prevalence. AB - The Muchalat Inlet, British Columbia, is among the most westerly points at which aquaculture is practiced in Canada. In this paper, we summarise data from over 18000 wild fish sampled at 16 sites over an 8 yr period, between 2004 and 2011. The most prevalent wild species was chum salmon Oncorhynchus keta (82.4%), followed by Chinook O. tshawytscha (10%) and coho O. kisutch (4.3%). However, inter-annual and seasonal variation was evident, and smaller numbers of other Pacific salmon and stickleback species were sporadically observed. A high percentage of wild salmon (~95%) had no sea lice parasites present, with less than 1% of the fish hosting a mobile-stage sea louse. Of the data for which sea lice species were recorded, just over 96% of samples were identified as Lepeophtheirus salmonis. Logistic regression models assessed the association between the presence of lice and a range of independent variables. These models indicated a significant degree of spatial variation, much of which could be explained in terms of salinity levels. There were also important variations through time, both over the season within a year and across years. In addition, coho salmon were significantly more likely (odds ratio = 1.65; 95% CI = 1.20-2.3) to be infected than chum salmon. The protective effect of low salinity was most clearly seen at values lower than 15 psu, although this was dependent on fish species. PMID- 26648104 TI - Phylogenetic analysis and serotyping of Vibrio splendidus-related bacteria isolated from salmon farm cleaner fish. AB - Cleaner fish, i.e. various wrasse (Labridae) species and lumpsucker Cyclopterus lumpus, are to an increasing extent used for biocontrol of the salmon louse Lepeophtheirus salmonis in European salmon farming. Although efficient de-licers, cleaner fish mortality levels in salmon farms are often high. Bacterial infections are common, and Vibrio splendidus-related strains are frequently identified during diagnostic investigations. The population structure of 112 V. splendidus-related isolates, derived primarily from wrasse species, was investigated by means of multilocus sequence analysis using 5 housekeeping genes (rpoD, ftsZ, pyrH, rpoA and atpA). Most isolates were found to be closely related to the V. splendidus type strain, yet displayed extensive genetic microdiversity. Slide agglutination testing using polyclonal rabbit antisera further indicated O antigen variability. Intra-outbreak genetic and antigenic diversity suggests direct infection from seawater, rather than fish-to-fish transmission, as the main route of infection. The variable nature of isolates involved complicates qualified selection of representative candidate strains, e.g. for infection and vaccine trials. PMID- 26648105 TI - Shewanella putrefaciens in cultured tilapia detected by a new calcein-loop mediated isothermal amplification (Ca-LAMP) method. AB - Shewanella putrefaciens is being increasingly isolated from a wide variety of sources and is pathogenic to many marine and freshwater fish. For better control of this pathogen, there is a need for the development of simple and inexpensive but highly specific, sensitive, and rapid detection methods suitable for application in field laboratories. Our colorogenic loop-mediated isothermal amplification (LAMP) assay combined with calcein (Ca-LAMP) for unaided visual confirmation of LAMP amplicons is a simple method for fish pathogen detection in cultured tilapia. Here, we describe the detection of S. putrefaciens using the same platform. As before, the method gave positive results (orange to green color change) in 45 min at 63 degrees C with sensitivity 100 times higher than that of a conventional PCR assay, with no cross-amplification of other known fish bacterial pathogens tested. Using the assay with 389 samples of gonads, fertilized eggs, and fry of farmed Nile and red tilapia Oreochromis spp., 35% of samples were positive for S. putrefaciens. The highest prevalence was found in samples of gonads (55%) and fertilized eggs (55%) from adult breeding stocks, indicating that S. putrefaciens could be passed on easily to fry used for stocking production ponds. Tissue tropism assays revealed that the spleen showed the highest colonization by S. putrefaciens in naturally infected tilapia and that it would be the most suitable organ for screening and monitoring fish stocks for presence of the bacteria. PMID- 26648106 TI - White spot disease risk factors associated with shrimp farming practices and geographical location in Chanthaburi province, Thailand. AB - Over the past 2 decades, shrimp aquaculture in Thailand has been impacted by white spot disease (WSD) caused by white spot syndrome virus (WSSV). Described here are results of a survey of 157 intensive shrimp farms in Chanthaburi province, Thailand, to identify potential farm management and location risk factors associated with the occurrence of WSD outbreaks. Logistic regression analysis of the survey responses identified WSD risks to be associated with farms sharing inlet water and culturing shrimp year round and with a single owner operating more than 1 farm. The analysis also showed WSD risks to be reduced at farms that used probiotics and applied lime to pond bottoms when fallow to neutralize acidity and kill microorganisms. Regression modeling identified no association of geographical location with WSD. The data should assist shrimp farms in mitigating the effects of WSD in Thailand. PMID- 26648107 TI - In situ hybridisation detects pro-apoptotic gene expression of a Bcl-2 family member in white syndrome-affected coral. AB - White syndrome has been described as one of the most prolific diseases on the Great Barrier Reef. Previously, apoptotic cell death has been described as the mechanism driving the characteristic rapid tissue loss associated with this disease, but the molecular mechanisms controlling apoptotic cell death in coral disease have yet to be investigated. In situ methods were used to study the expression patterns of 2 distinct regulators of apoptosis in Acropora hyacinthus tissues undergoing white syndrome and apoptotic cell death. Apoptotic genes within the Bcl-2 family were not localized in apparently healthy coral tissues. However, a Bcl-2 family member (bax-like) was found to localize to cells and tissues affected by white syndrome and those with morphological evidence for apoptosis. A potential up-regulation of pro-apoptotic or bax-like gene expression in tissues with apoptotic cell death adjacent to disease lesions is consistent with apoptosis being the primary cause of rapid tissue loss in coral affected by white syndrome. Pro-apoptotic (bax-like) expression in desmocytes and the basal tissue layer, the calicodermis, distant from the disease lesion suggests that apoptosis may also underlie the sloughing of healthy tissues associated with the characteristic, rapid spread of tissue loss, evident of this disease. This study also shows that in situ hybridisation is an effective tool for studying gene expression in adult corals, and wider application of these methods should allow a better understanding of many aspects of coral biology and disease pathology. PMID- 26648108 TI - Panulirus argus virus 1 detected in oceanic postlarvae of Caribbean spiny lobster: implications for disease dispersal. AB - Panulirus argus virus 1 (PaV1), a pathogenic virus that specifically attacks Caribbean spiny lobsters Panulirus argus, was recently detected in newly settled postlarvae of P. argus. As PaV1 appears not to be vertically transmitted, infected postlarvae likely acquire PaV1 from the water, but whether this can occur in oceanic waters where the planktonic larvae (phyllosomata) metamorphose into nektonic postlarvae remains unknown. Late-stage phyllosomata and postlarvae of P. argus were collected at distances of 2 to 100 km from the Caribbean coast of Mexico in 2 oceanographic cruises. Most postlarvae were caught in the upper meter of water, usually along with masses of floating Sargassum algae. A PaV1-PCR assay was used to test 169 phyllosomata (stages VI-X) and 239 postlarvae. All phyllosomata tested negative, but 2 postlarvae, 1 from each cruise, tested positive for PaV1. These postlarvae were collected at 55 and 48 km offshore over depths of 850 and 1800 m, respectively, suggesting that postlarvae can acquire PaV1 in offshore waters. We hypothesize that floating Sargassum may be an environmental reservoir for PaV1. The PaV1 allele (460 pb) found in an infected postlarva was more closely related to PaV1 alleles found in lobsters from Puerto Rico than in lobsters from any other location (including Mexico), suggesting high gene flow and long-distance dispersal of PaV1, consistent with previous studies of high genetic connectivity across the Caribbean. PMID- 26648109 TI - Induction of apoptosis in MCF-7 human breast cancer cells by Khz (fusion of Ganoderma lucidum and Polyporus umbellatus mycelium). AB - Khz (fusion of Ganoderma lucidum and Polyporus umbellatus), isolated from the mycelia of G. lucidum and P. umbellatus, exerts anti-proliferative effects against malignant cells; however, its activity against human breast cancer cells remains to be elucidated. In the present study, cell proliferation was assessed using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and poptosis was examined using annexin V-propidium iodide staining and flow cytometry. The activation of caspases 7, 8 and 9 were detected in the Khz-treated cells using western blotting. The results demonstrated that Khz increased the intracellular calcium concentration and induced the production of reactive oxygen species in MCF-7 breast cancer cells, as determined using flow cytometry. The results also demonstrated that Khz inhibited cell proliferation and induced apoptosis in the MCF-7 cells. In addition, the mechanism by which Khz induces apoptosis in cancer cells was investigated. Khz induced apoptosis preferentially in transformed cells, with a minimal effect on non-transformed cells, suggesting its potential as an anticancer therapeutic agent. Oxidative stress is associated with apoptotic and non-apoptotic cell death, although pro-oxidative conditions are not a pre-requisite for apoptosis. Assessment of the activation status of caspases 7, 8 and 9 revealed that the levels of cleaved caspases were significantly increased in the cells treated with Khz. It is widely accepted that calcium signaling is important in apoptosis, and the present study observed an increase in [Ca2+]i in response to Khz treatment. The anti-proliferative and pro apoptotic effects of Khz suggest that this extract may be developed as a potential anticancer agent. PMID- 26648110 TI - Identification of Genes Associated with Smad3-dependent Renal Injury by RNA-seq based Transcriptome Analysis. AB - Transforming growth factor-beta/Smad3 signaling plays a critical role in the process of chronic kidney disease (CKD), but targeting Smad3 systematically may cause autoimmune disease by impairing immunity. In this study, we used whole transcriptome RNA-sequencing to identify the differential gene expression profile, gene ontology, pathways, and alternative splicing related to TGF beta/Smad3 in CKD. To explore common dysregulation of genes associated with Smad3 dependent renal injury, kidney tissues of Smad3 wild-type and knockout mice with immune (anti-glomerular basement membrane glomerulonephritis) and non-immune (obstructive nephropathy)-mediated CKD were used for RNA-sequencing analysis. Totally 1922 differentially expressed genes (DEGs) were commonly found in these CKD models. The up-regulated genes are inflammatory and immune response associated, while decreased genes are material or electron transportation and metabolism related. Only 9 common DEGs were found to be Smad3-dependent in two models, including 6 immunoglobulin genes (Ighg1, Ighg2c, Igkv12-41, Ighv14-3, Ighv5-6 and Ighg2b) and 3 metabolic genes (Ugt2b37, Slc22a19, and Mfsd2a). Our results identify transcriptomes associated with renal injury may represent a common mechanism for the pathogenesis of CKD and reveal novel Smad3 associated transcriptomes in the development of CKD. PMID- 26648111 TI - Structure of the rat tracheal mucosa after chronic intermittent hypoxia or chronic hyperbaric oxygen therapy. AB - OBJECTIVE: This paper is aimed at identifying putative morphological changes induced in the rat's tracheal mucosa by chronic hyperbaric oxygen (HBO) treatment or chronic intermittent hypoxia (CIH). STUDY DESIGN: Tracheal samples were obtained from three groups of 11, 12 and 13 adult Wistar rats. The first group was submitted to 20 sessions of 100 min-long HBO treatment; the second group was submitted to eucapnic CIH for 35 days; and the third group was not submitted to any CIH or HBO therapy. METHODS: Four proximal tracheal rings were collected after sacrifice and neck dissection of the animals. The samples were processed for both light microscopy and morphometric analysis. Inflammatory leukocyte infiltration was evaluated by a semiquantitative method. Unpaired t test and Bernoulli distribution were applied to evaluate statistical differences in the data collected from the three groups. RESULTS: Both CIH and HBO promote an increase in the thickness of the epithelium and of the basement membrane of the rat tracheal mucosa, as well as an increment in the number of infiltrating leukocytes, when compared with results seen in the untreated group. In the HBO group there was a significant lack of seromucous glands, as opposed to the results obtained in the CIH group. CONCLUSIONS: Chronic HBO and CIH exposure causes only minor changes in the architecture of the tracheal mucosa of the rat. The respiratory tract of the rat showed a mild inflammatory response when subject to variations of pressure and oxygen content. Apparently these effects do not constitute a critical issue on prescribing HBO treatments and in the management of sleep apnea patients. PMID- 26648112 TI - Burst predicting neurons survive an in vitro glutamate injury model of cerebral ischemia. AB - Neuronal activity in vitro exhibits network bursts characterized by brief periods of increased spike rates. Recent work shows that a subpopulation of neurons reliably predicts the occurrence of network bursts. Here, we examined the role of burst predictors in cultures undergoing an in vitro model of cerebral ischemia. Dissociated primary cortical neurons were plated on multielectrode arrays and spontaneous activity was recorded at 17 days in vitro (DIV). This activity was characterized by neuronal avalanches where burst statistics followed a power law. We identified burst predictors as channels that consistently fired immediately prior to network bursts. The timing of these predictors relative to bursts followed a skewed distribution that differed sharply from a null model based on branching ratio. A portion of cultures were subjected to an excitotoxic insult (DIV 18). Propidium iodine and fluorescence imaging confirmed cell death in these cultures. While the insult did not alter the distribution of avalanches, it resulted in alterations in overall spike rates. Burst predictors, however, maintained baseline levels of activity. The resilience of burst predictors following excitotoxic insult suggests a key role of these units in maintaining network activity following injury, with implications for the selective effects of ischemia in the brain. PMID- 26648113 TI - Sensitivity and specificity of Cobas TaqMan MTB real-time polymerase chain reaction for culture-proven Mycobacterium tuberculosis: meta-analysis of 26999 specimens from 17 Studies. AB - Since 2010, studies on the diagnostic accuracy of COBAS TaqMan MTB (CTM) have been frequently reported with an unignorable discrepancy. The key inclusion criterion for this systematic review was original studies that could provide sufficient data for calculating the sensitivity and the specificity of CTM for M tuberculosis (TB) or M tuberculosis complex. The reference test was Mycobacterium culture. We used bivariate model for meta-analyses. Of the 201 candidate articles, we finally identified 17 eligible articles.Concerning the respiratory specimens, 1900 culture positive specimens and 20983 culture negative specimens from 15 studies were assessed. This provided the summary estimate sensitivity of 0.808 (95% CI 0.758-0.850) and the summary estimate specificity of 0.990 (95% CI 0.981-0.994). The area under curve was 0.956. The diagnostic odds ratio was 459 (95% CI 261-805, I(2) 26%). For the smear positive respiratory specimens, the sensitivity was 0.952 (95% CI 0.926-0.969) and the specificity was 0.916 (95% CI 0.797-0.968). For the smear negative respiratory specimens, the sensitivity and the specificity were 0.600 (95% CI 0.459-0.726) and 0.989 (95% CI 0.981-0.993), respectively. The diagnostic accuracy was poorer for the non-respiratory specimens, than for the respiratory specimens, but was acceptable. We believe that the information obtained from this study will aid physicians' decision making. PMID- 26648114 TI - The microscopic structure of charge density waves in underdoped YBa2Cu3O6.54 revealed by X-ray diffraction. AB - Charge density wave (CDW) order appears throughout the underdoped high temperature cuprate superconductors, but the underlying symmetry breaking and the origin of the CDW remain unclear. We use X-ray diffraction to determine the microscopic structure of the CDWs in an archetypical cuprate YBa2Cu3O6.54 at its superconducting transition temperature ~ 60 K. We find that the CDWs in this material break the mirror symmetry of the CuO2 bilayers. The ionic displacements in the CDWs have two components, which are perpendicular and parallel to the CuO2 planes, and are out of phase with each other. The planar oxygen atoms have the largest displacements, perpendicular to the CuO2 planes. Our results allow many electronic properties of the underdoped cuprates to be understood. For instance, the CDWs will lead to local variations in the electronic structure, giving an explicit explanation of density-wave states with broken symmetry observed in scanning tunnelling microscopy and soft X-ray measurements. PMID- 26648115 TI - Unantimycin A, a new neoantimycin analog isolated from a microbial metabolite fraction library. PMID- 26648116 TI - Improvement of the productivity of ecumicin, a novel anti-tuberculosis agent, from new Nonomuraea sp. MJM5123. AB - Ecumicin is a novel anti-tuberculosis agent produced by Nonomuraea sp. MJM5123 as a new strain of actinomycetes. First, in order to increase the cell mass of Nonomuraea sp. MJM5123, we optimized the culture conditions with regard to carbon and nitrogen sources. The cell mass of Nonomuraea sp. MJM5123 increased by approximately twofold when glucose and soybean flour were used as carbon and nitrogen sources, respectively. For maximum production of ecumicin, we optimized the culture conditions by adding amino acids as building blocks for ecumicin, by adding vegetable oils and by controlling the temperature and pH. Ecumicin production was two times higher with the addition of valine as the building blocks for ecumicin compared with the production in the absence of valine. Interestingly, with the addition of 1% corn oil, the production of ecumicin increased by 4.6-fold compared with the production in the absence of corn oil. Finally, by controlling the pH and temperature, we established an optimized culture condition in which Nonomuraea sp. MJM5123 produced 576 mg ecumicin per litre of medium, which is about 50 times higher than in the control medium at 30 degrees C and pH 7.0. PMID- 26648117 TI - Maniwamycins: new quorum-sensing inhibitors against Chromobacterium violaceum CV026 were isolated from Streptomyces sp. TOHO-M025. AB - Quorum sensing is an important microbial signaling system that controls the expression of many virulence genes. Maniwamycins C-F, new compounds and quorum sensing inhibitors, were isolated from the culture broth of Streptomyces sp. TOHO M025 using a silica gel column and preparative HPLC. The structures of maniwamycins were elucidated by spectroscopic analyses, including NMR. The compounds each have an azoxy moiety. All maniwamycins inhibited violacein synthesis, which is controlled by quorum sensing, in Chromobacterium violaceum CV026. PMID- 26648118 TI - Improved antibiotic production and silent gene activation in Streptomyces diastatochromogenes by ribosome engineering. PMID- 26648119 TI - PM100117 and PM100118, new antitumor macrolides produced by a marine Streptomyces caniferus GUA-06-05-006A. AB - Two new bioactive polyhydroxyl macrolide lactones PM100117 (1) and PM100118 (2) were isolated from the culture broth of the marine-derived Streptomyces caniferus GUA-06-05-006A. Their structures were elucidated by a combination of spectroscopic methods, mainly one-dimensional and 2D NMR and HRESI-MS. They consist of 36-membered macrolides with a side chain containing three deoxy sugars and a 1,4-naphthoquinone chromophore. Compounds 1 and 2 displayed potent cytotoxicity against three human tumor cell lines with GI50 values in the micromolar range, as well as slight antifungal activity against Candida albicans ATCC10231. In addition, both compounds alter the plasma membrane of tumor cells, inducing loss of membrane integrity and subsequent cell permeabilization leading to a fast and dramatic necrotic cell death. PMID- 26648120 TI - Application of bacterial cytological profiling to crude natural product extracts reveals the antibacterial arsenal of Bacillus subtilis. AB - Although most clinically used antibiotics are derived from natural products, identifying new antibacterial molecules from natural product extracts is difficult due to the complexity of these extracts and the limited tools to correlate biological activity with specific molecules. Here, we show that bacterial cytological profiling (BCP) provides a rapid method for mechanism of action determination on plates and in complex natural product extracts and for activity-guided purification. We prepared an extract from Bacillus subtilis 3610 that killed the Escherichia coli lptD mutant and used BCP to observe two types of bioactivities in the unfractionated extract: inhibition of translation and permeablization of the cytoplasmic membrane. We used BCP to guide purification of the molecules responsible for each activity, identifying the translation inhibitors bacillaene and bacillaene B (glycosylated bacillaene) and demonstrating that two molecules contribute to cell permeabilitization, the bacteriocin subtilosin and the cyclic peptide sporulation killing factor. Our results suggest that bacillaene mediates translational arrest, and show that bacillaene B has a minimum inhibitory concentration 10 * higher than unmodified bacillaene. Finally, we show that BCP can be used to screen strains on an agar plate without the need for extract preparation, greatly saving time and improving throughput. Thus, BCP simplifies the isolation of novel natural products, by identifying strains, crude extracts and fractions with interesting bioactivities even when multiple activities are present, allowing investigators to focus labor intensive steps on those with desired activities. PMID- 26648121 TI - A simple feature construction method for predicting upstream/downstream signal flow in human protein-protein interaction networks. AB - Signaling pathways play important roles in understanding the underlying mechanism of cell growth, cell apoptosis, organismal development and pathways-aberrant diseases. Protein-protein interaction (PPI) networks are commonly-used infrastructure to infer signaling pathways. However, PPI networks generally carry no information of upstream/downstream relationship between interacting proteins, which retards our inferring the signal flow of signaling pathways. In this work, we propose a simple feature construction method to train a SVM (support vector machine) classifier to predict PPI upstream/downstream relations. The domain based asymmetric feature representation naturally embodies domain-domain upstream/downstream relations, providing an unconventional avenue to predict the directionality between two objects. Moreover, we propose a semantically interpretable decision function and a macro bag-level performance metric to satisfy the need of two-instance depiction of an interacting protein pair. Experimental results show that the proposed method achieves satisfactory cross validation performance and independent test performance. Lastly, we use the trained model to predict the PPIs in HPRD, Reactome and IntAct. Some predictions have been validated against recent literature. PMID- 26648122 TI - Calycosin-7-O-beta-D-glucoside attenuates ischemia-reperfusion injury in vivo via activation of the PI3K/Akt pathway. AB - The aim of the present study was to investigate the effects and mechanisms of calycosin-7-O-beta-D-glucoside (CG) on ischemia-reperfusion (I/R) injury in vivo. Hemodynamic parameters, including ejection fraction (EF), fractional shortening (FS), left ventricular end-systolic pressure (LVESP) and left ventricular end diastolic pressure (LVEDP) were monitored using an ultrasound system, and infarct size was measured using Evans blue/tetrazolium chloride double staining. The activities of serum creatine kinase (CK), lactate dehydrogenase (LDH) and superoxide dismutase (SOD), and the levels of malondialdehyde (MDA) were determined to assess the degree of myocardial injury and oxidative stress-induced damage. The protein expression levels of cleaved-caspase-3, cleaved-caspase-9, phosphorylated (p)-phosphatidylinositol 3-kinase (PI3K) p85, PI3K p85, p-Akt and Akt were determined using western blotting. The results demonstrated that pretreatment with high dose (H)-CG markedly improved cardiac function, as evidenced by upregulated EF, FS and LVESP, and downregulated LVEDP. In addition, administration of CG resulted in significant decreases in infarct size in the I/R+low dose-CG and I/R+H-CG groups, compared with the I/R group. The activities of CK and LDH, and the levels of MDA in the I/R+H-CG group were reduced, compared with those in the I/R group, whereas SOD activity was elevated. Treatment with CG inhibited the cleavage and activity of caspase-3 and caspase-9, and enhanced the phosphorylation of PI3K p85 and Akt. Notably, administration of the PI3K inhibitor, LY294002, markedly lowered the levels of p-PI3K p85/p-Akt, and eradicated the inhibitory effects of H-CG on infarct size, myocardial injury and oxidative stress-induced damage. Taken together, the results suggested that CG may alleviate I/R injury by activating the PI3K/Akt signaling pathway. PMID- 26648123 TI - Sulforaphane reverses chemo-resistance to temozolomide in glioblastoma cells by NF-kappaB-dependent pathway downregulating MGMT expression. AB - The survival benefits of patients with glioblastoma (GBM) remain unsatisfactory due to the intrinsic or acquired resistance to temozolomide (TMZ). We elucidated the mechanisms of sulforaphane (SFN) reverse TMZ resistance in TMZ-inducing cell lines by inhibiting nuclear factor-kappaB (NF-kappaB) transcriptional activity. TMZ-resistant cell lines (U87-R and U373-R) were generated by stepwise (6 months) exposure of parental cells to TMZ. Luciferase reporter assay, biochemical assays and subcutaneous tumor establishment were used to characterize the antitumor effect of SFN. MGMT expression and 50% inhibiting concentration (IC50) values of TMZ in GBM cell lines were assessed. Next, we established that U87-R and U373-R cells presenting high IC50 of TMZ, activated NF-kappaB transcription and significantly increased MGMT expression compared with untreated cells. Furthermore, we revealed that SFN could significantly suppress proliferation of TMZ-resistant GBM cells. In addition, SFN effectively inhibited activity of NF kappaB signaling pathway and then reduced MGMT expression to reverse the chemo resistance to TMZ in T98G, U87-R and U373-R cell lines. Sequential combination with TMZ synergistically inhibited survival capability and increased the induction of apoptosis in TMZ-resistant GBM cells. Finally, a nude mouse model was established with U373-R cell subcutaneous tumor-bearing mice, and results showed that SFN could remarkably suppress cell growth and enhance cell death in chemo-resistant xenografts in the nude mouse model. Collectively, the present study suggests that the clinical efficacy of TMZ-based chemotherapy in TMZ resistant GBM may be improved by combination with SFN. PMID- 26648124 TI - Linker histone H1 and H3K56 acetylation are antagonistic regulators of nucleosome dynamics. AB - H1 linker histones are highly abundant proteins that compact nucleosomes and chromatin to regulate DNA accessibility and transcription. However, the mechanisms that target H1 regulation to specific regions of eukaryotic genomes are unknown. Here we report fluorescence measurements of human H1 regulation of nucleosome dynamics and transcription factor (TF) binding within nucleosomes. H1 does not block TF binding, instead it suppresses nucleosome unwrapping to reduce DNA accessibility within H1-bound nucleosomes. We then investigated H1 regulation by H3K56 and H3K122 acetylation, two transcriptional activating histone post translational modifications (PTMs). Only H3K56 acetylation, which increases nucleosome unwrapping, abolishes H1.0 reduction of TF binding. These findings show that nucleosomes remain dynamic, while H1 is bound and H1 dissociation is not required for TF binding within the nucleosome. Furthermore, our H3K56 acetylation measurements suggest that a single-histone PTM can define regions of the genome that are not regulated by H1. PMID- 26648125 TI - Fibroblast growth factor receptor 1 promotes MG63 cell proliferation and is associated with increased expression of cyclin-dependent kinase 1 in osteosarcoma. AB - Osteosarcoma is the most common type of malignant bone tumor in adolescents and young adults. However, current understanding of osteosarcomagenesis remains limited. In the present study, the role of fibroblast growth factor receptor 1 (FGFR1) in human osteosarcoma cell proliferation was investigated, and the possible pathways that contribute to FGFR1-mediated osteosarcoma cell proliferation were examined using microarray analysis. The expression of FGFR1 in osteosarcoma tissues was assessed by reverse transcription-quantitative polymerase chain reaction and immunohistochemistry. The results demonstrated that FGFR1 was markedly increased in osteosarcoma tissues, and that the overexpression of FGFR1 in MG63 cells significantly promoted cell proliferation, as observed using the cell viability assay. In addition, FGFR1-mediated cell proliferation was closely associated with cell cycle re-distribution, as determined by microarray analysis. Western blotting identified that the expression of cyclin dependent kinase 1 (CDK1) was correspondingly increased in response to the overexpression of FGFR1. These results indicated that FGFR1 contributes to cell proliferation in osteosarcoma MG63 cells, and FGFR1 mediated cell proliferation may be attributed to the regulation of the cell cycle regulator, CDK1. These findings provide evidence to support the potential use of molecule target therapy against FGFR1 as a promising strategy in osteosarcoma treatment and prevention. PMID- 26648126 TI - Consequences of bariatric surgery on oesophageal function in health and disease. AB - Obesity is a continuing epidemic with substantial associated morbidity and mortality. Owing to the limitations of lifestyle modifications and pharmacological options, bariatric surgery has come to the forefront as an efficient method of achieving sustained weight loss and decreasing overall mortality in comparison with nonsurgical interventions. The most frequently performed bariatric operations are either purely restrictive, such as laparoscopic adjustable gastric band (LAGB) and laparoscopic sleeve gastrectomy (LSG), or restrictive-malabsorptive, such as the Roux-en-Y gastric bypass (RYGB). Each operation results in weight loss, but can also have unintended effects on the health of the oesophagus. Specifically, operations might lead to oesophageal dilation or the development of GERD. LAGB is the best-studied procedure with notable evidence for postoperative worsening of GERD and pseudo-achalasia, which increases lower oesophageal pressure and causes aperistalsis. In some studies, LSG initiates not only a worsening of GERD, but also the formation of de novo GERD in patients without preoperative GERD symptoms. RYGB demonstrates the most profound evidence for improvement of GERD symptoms and preservation of oesophageal motility. Future high-quality studies will be required to better understand the interaction between bariatric surgery and oesophageal disease. PMID- 26648131 TI - Colorectal cancer: Targeting the root of colorectal cancer--eliminating cancer stem cells. PMID- 26648132 TI - Crystal structure evolution and luminescence properties of color tunable solid solution phosphors Ca(2+x)La(8-x)(SiO4)(6-x)(PO4)xO2:Eu(2+). AB - A series of apatite solid solution phosphors Ca(2+x)La(8-x)(SiO4)(6 x)(PO4)xO2:Eu(2+) (x = 0,2,4,6) were synthesized by a conventional high temperature solid-state reaction. The phase purity was examined using XRD, XPS and XRF. The crystal structure information, such as the concentration, cell parameters and occupation rate, was analyzed using a Rietveld refinement, demonstrating that the Eu(2+) activated the Ca2La8(SiO4)6O2 and Ca8La2(PO4)6O2 to form continuous solid solution phosphors. Different behaviors of luminescence evolution in response to structural variation were verified among the series of phosphors. Two kinds of Eu(2+) ion sites were proved using low temperature PL spectra (8k) and room temperature decay curves. The substitution of large La(3+) ions by small Ca(2+) ions induced a decreased crystal field splitting of the Eu(2+) ions, which caused an increase in emission energy from the 5d excited state to the 4f ground state and a resultant blue-shift from 508 nm to 460 nm. Therefore, with the crystal structure evolution, the emitted color of the series of phosphors could be tuned from green to blue by adjusting the ratio of Ca/La. PMID- 26648133 TI - Partial Geometric Frustration in Inorganic Supramolecular Spin Systems with One Dimensional Trigonally Aligned Magnetic Chains infinity1(MCl4)2- (M = Fe2+, Co2+). AB - Exploration of new spin systems with low-dimensional subunits have been of great interest in the past decades due to their interesting physical properties and potential applications in molecular spintronics. Two inorganic supramolecular complexes, (Hg3S2)(FeCl4) and (Hg3S2)(CoCl4), with trigonally aligned 1-D infinite magnetic infinity(1)(FeCl4)(2-) or infinity(1)(CoCl4)(2-) chains have been prepared by solid-state reactions. They exhibit 3-D long-range spin order with strong field dependence and field induced metamagnetic behavior. The intrachain and interchain magnetic coupling constants were estimated by DFT+U and DFT+U+SOC calculations and the both complexes can be regarded as partially frustrated spin systems. The spin Hamiltonian was constructed, the ground state is proposed to be incommensurate spiral spin order, which differs from the commensurate 120 degrees spin structure ground state of fully frustrated trigonal case by a little canted angle. This study shows that cooperative magnetic ordering induced by geometric frustration can be realized in inorganic supramolecular systems assembled by weak van der Waals' interactions. PMID- 26648134 TI - Antibacterial Au nanostructured surfaces. AB - We present here a technological platform for engineering Au nanotopographies by templated electrodeposition on antibacterial surfaces. Three different types of nanostructures were fabricated: nanopillars, nanorings and nanonuggets. The nanopillars are the basic structures and are 50 nm in diameter and 100 nm in height. Particular arrangement of the nanopillars in various geometries formed nanorings and nanonuggets. Flat surfaces, rough substrate surfaces, and various nanostructured surfaces were compared for their abilities to attach and kill bacterial cells. Methicillin-resistant Staphylococcus aureus, a Gram-positive bacterial strain responsible for many infections in health care system, was used as the model bacterial strain. It was found that all the Au nanostructures, regardless their shapes, exhibited similar excellent antibacterial properties. A comparison of live cells attached to nanotopographic surfaces showed that the number of live S. aureus cells was <1% of that from flat and rough reference surfaces. Our micro/nanofabrication process is a scalable approach based on cost efficient self-organization and provides potential for further developing functional surfaces to study the behavior of microbes on nanoscale topographies. PMID- 26648135 TI - In Vitro selectivity of an acyclic cucurbit[n]uril molecular container towards neuromuscular blocking agents relative to commonly used drugs. AB - An acyclic cucurbit[n]uril (CB[n]) based molecular container (2, a.k.a. Calabadion 2) binds to both amino-steroidal and benzylisoquinolinium type neuromuscular blocking agents (NMBAs) in vitro, and reverses the effect of these drugs in vivo displaying faster recovery times than placebo and the gamma cyclodextrin (CD) based and clinically used reversal agent Sugammadex. In this study we have assessed the potential for other drugs commonly used during and after surgery (e.g. antibiotics, antihistamines, and antiarrhythmics) to interfere with the ability of 2 to bind NMBAs rocuronium and cisatracurium in vitro. We measured the binding affinities (Ka, M(-1)) of twenty seven commonly used drugs towards 2 and simulated the equilibrium between 2, NMBA, and drug based on their standard clinical dosages to calculate the equilibrium concentration of 2.NMBA in the presence of the various drugs. We found that none of the 27 drugs studied possess the combination of a high enough binding affinity with 2 and a high enough standard dosage to be able to promote the competitive dissociation (a.k.a. displacement interactions) of the 2.NMBA complex with the formation of the 2.drug complex. Finally, we used the simulations to explore how the potential for displacement interactions is affected by a number of factors including the Ka of the 2.NMBA complex, the Ka of the AChR.NMBA complex, the Ka of the 2.drug complex, and the dosage of the drug. PMID- 26648137 TI - P accumulation and physiological responses to different high P regimes in Polygonum hydropiper for understanding a P-phytoremediation strategy. AB - Phosphorus (P) accumulators used for phytoremediation vary in their potential to acquire P from different high P regimes. Growth and P accumulation in Polygonum hydropiper were both dependent on an increasing level of IHP (1-8 mM P) and on a prolonged growth period (3-9 weeks), and those of the mining ecotype (ME) were higher than the non-mining ecotype (NME). Biomass increments in root, stem, and leaf of both ecotypes were significantly greater in IHP relative to other organic P (Po) sources (G1P, AMP, ATP), but lower than those in inorganic P (Pi) treatment (KH2PO4). P accumulation in the ME exceeded the NME from different P regimes. The ME demonstrated higher root activity compared to the NME grown in various P sources. Acid phosphatase (Apase) and phytase activities in root extracts of both ecotypes grown in IHP were comparable to that in Pi, or even higher in IHP. Higher secreted Apase and phytase activities were detected in the ME treated with different P sources relative to the NME. Therefore, the ME demonstrates higher P-uptake efficiency and it is a potential material for phytoextraction from P contaminated areas, irrespective of Pi or Po contamination. PMID- 26648136 TI - Dose-dependent inhibitory effects of zoledronic acid on osteoblast viability and function in vitro. AB - Zoledronic acid (ZA), which is one of the most potent and efficacious bisphosphonates, has been commonly used in clinical practice for the treatment of various bone disorders. The extensive use of ZA has been associated with increasing occurrence of jaw complications, now known as bisphosphonate associated osteonecrosis of the jaw (BRONJ). However, the mechanism underlying BRONJ remains to be fully elucidated. The aim of the present study was to investigate the effects of different concentrations of ZA on the MC3T3-E1 murine preosteoblast cell line cells and examine the possible pathogenesis of BRONJ. In the present study, the effect of ZA on the viability, apoptosis, differentiation and maturation of MC3T3-E1 cells, as well as its relevant molecular mechanism, were examined The results of a Cell Counting Kit 8 assay, a flow cytometric Annexin-V/propidium iodide assay and western blot analysis demonstrated that ZA exhibited a significant inhibition of cell viability and induction of apoptosis at concentrations >10 uM. Subsequently, the effect of ZA on cell differentiation at concentrations <1 uM were investigated. In this condition, ZA inhibited bone nodule formation and decreased the activity of alkaline phosphatase. The results of reverse transcription-quantitative polymerase chain reaction and western blot analyses indicated that ZA downregulated the expression levels of the marker genes and proteins associated with osteogenic differentiation. Further investigation revealed that the suppression of differentiation by ZA was associated with decreased expression of bone morphogenetic protein-2 (BMP-2) and downregulation of the phosphorylation levels in the downstream extracellular signal-regulated kinase 1/2 and p38 pathways. These adverse effects of ZA were observed to be concentration-dependent. The results from the present study suggested that ZA at higher concentrations induces cytotoxicity towards osteoblasts, and ZA at lower concentrations suppresses osteoblast differentiation by downregulation of BMP-2. These results assist in further understanding the mechanisms of BRONJ. PMID- 26648138 TI - Regulation of Shootin1 Gene Expression Involves NGF-induced Alternative Splicing during Neuronal Differentiation of PC12 Cells. AB - Shootin1 is a protein involved in neuronal polarization, and has been shown to be a key molecule for the positive/negative feedback loop for axon induction required during neuronal symmetry breaking. To better understand the molecular basis of shootin1 dynamics, we analysed the regulatory pathways and the expressional status of shootin1 gene during NGF-induced neuronal differentiation. We demonstrated that the isoform-1 and isoform-2 of shootin1 is differentially expressed during neuronal differentiation. By blocking individual downstream pathways of NGF signalling, we found that PI3K/Akt pathway plays a major role in the expression of shootin1 isoform-2. Western blot and RT-PCR results showed that the isoform-1 of shootin1 is constitutively expressed, while the isoform-2 is expressed in a manner that is strictly dependent on NGF-stimulation. Isoform specific RT-PCR results demonstrated that the differential expression of the isoform-1 and isoform-2 of shootin1 is a consequence of alternative splicing of shootin1 pre-mRNA, in response to NGF-signalling. Collectively these findings provide the first information on the molecular mechanisms regulating the expression of shootin1 gene and represent the first example of NGF-induced alternative splicing process that has a regulatory role in neuritogenesis. PMID- 26648139 TI - An optical biosensor assay for rapid dual detection of Botulinum neurotoxins A and E. AB - The enzymatic activity of the pathogenic botulinum neurotoxins type A and E (BoNT/A and E) leads to potentially lethal paralytic symptoms in humans and their prompt detection is of crucial importance. A chip assay based on Surface Plasmon Resonance monitoring of the cleavage products is a simple method that we have previously established to detect BoNT/A activity. We have now developed a similar format assay to measure BoNT/E activity. A monoclonal antibody specifically recognizing SNAP25 cleaved by BoNT/E was generated and used to measure the appearance of the neo-epitope following injection of BoNT/E over SNAP-25 immobilized on a chip. This assay detects BoNT/E activity at 1 LD50/ml within minutes and linear dose-responses curves were obtained using a multiplexed biosensor. A threshold of 0.01 LD50/ml was achieved after 5 h of cleavage. This assay is 10-fold more sensitive than the in vivo assay for direct detection of BoNT/E in serum samples. The SNAP25 chip assay is able to discriminate in an automated manner the presence of BoNT/E, BoNT/A or a combination of both toxins. PMID- 26648141 TI - let-7a and its target, insulin-like growth factor 1 receptor, are differentially expressed in recurrent prostate cancer. AB - Prostate cancer (PCa) is the most common malignancy in males worldwide. Approximately 30% of those patients who received radical prostatectomy developed clinical recurrence accompanied by elevated serum prostate-specific antigen levels. Although knowledge regarding the development of PCa has been significantly improved, the molecular mechanism underlying recurrence remains largely unknown. The objective of the present study was to identify the differentially expressed microRNAs (miRNAs) in recurrent PCa to explore the possible involvement of miRNAs in the relapse. The expression of 6 miRs that have been previously reported to be downregulated in PCa stem cells were examined in a total of 32 recurrent and 36 non-recurrent PCa samples, and let-7a was substantially decreased in the recurrent PCa. Using the online prediction tools, let-7a was identified to virtually target insulin-like growth factor 1 receptor (IGF1R). IGF1R as a target of let-7a was subsequently validated using the luciferase assay. Exogenous expression of let-7a suppressed the expression of IGF1R, and reduced the proliferation of PCa cells by introducing apoptosis to the cells. In conclusion, the present data demonstrated a possible involvement of let 7a in the pathogenesis of recurrent PCa, and it may be a potential target of the disease. PMID- 26648140 TI - The cognitive developmental profile associated with fragile X syndrome: A longitudinal investigation of cognitive strengths and weaknesses through childhood and adolescence. AB - Few studies have investigated developmental strengths and weaknesses within the cognitive profile of children and adolescents with fragile X syndrome (FXS), a single-gene cause of inherited intellectual impairment. With a prospective longitudinal design and using normalized raw scores (Z scores) to circumvent floor effects, we measured cognitive functioning of 184 children and adolescents with FXS (ages 6 to 16) using the Wechsler Scale of Intelligence for Children on one to three occasions for each participant. Participants with FXS received lower raw scores relative to the Wechsler Scale of Intelligence for Children normative sample across the developmental period. Verbal comprehension, perceptual organization, and processing speed Z scores were marked by a widening gap from the normative sample, while freedom from distractibility Z scores showed a narrowing gap. Key findings include a relative strength for verbal skills in comparison with visuospatial-constructive skills arising in adolescence and a discrepancy between working memory (weakness) and processing speed (strength) in childhood that diminishes in adolescence. Results suggest that the cognitive profile associated with FXS develops dynamically from childhood to adolescence. Findings are discussed within the context of aberrant brain morphology in childhood and maturation in adolescence. We argue that assessing disorder specific cognitive developmental profiles will benefit future disorder-specific treatment research. PMID- 26648142 TI - Evidence based case report. PMID- 26648143 TI - Robotic surgery. A reality among us. PMID- 26648144 TI - Chronic subdural hematoma: epidemiological and prognostic analysis of 176 cases. AB - OBJECTIVE: To characterize patients with chronic subdural hematoma undergoing surgery and to identify prognostic indicators. METHODS: We conducted a retrospective analysis of patients diagnosed with chronic subdural hematoma (CSDH) undergoing surgical treatment. We analyzed: age, period from trauma to diagnostic imaging, pre and postoperative Glasgow coma scale, type of surgery, associated comorbidities, use of postoperative drainage and outpatient treatment. RESULTS: The sample consisted of 176 patients, 126 male and 50 female patients (ratio 2.5 : 1), ages ranged from six months to 97 years, with an average of 59.3 years. CSDH was caused by trauma in 52% of patients, with the time from trauma to imaging averaging 25.05 days; 37.7% were hypertensive patients and 20% had a neurological disease. Eighty-five (48.3%) patients were elderly and altered consciousness was present in 63% of cases. Of the 91 (51.7%) non-elderly patients, 44% presented with headache, altered consciousness occurred in 40% and motor abnormalities in 27.5%. The CSDH was located on the right in 41%, left in 43% and bilaterally in 16% of patients. CONCLUSION: the change of consciousness was the most common clinical alteration in the elderly and headache in non elderly. The most associated comorbidity was the arterial hypertension and the most frequent cause, head trauma. The trepanation with two oriffices associated with a closed drainage system was the most used operating, with high efficacy and low complication rate. PMID- 26648145 TI - Correlation between the oropharyngo-laryngoscopic findings and the severity of obstructive sleep apnea. AB - OBJECTIVE: To correlate anatomical and functional changes of the oral cavity, pharynx and larynx to the severity of obstructive sleep apnea syndrome (OSAS). METHODS: We conducted a cross-sectional study of 66 patients of both genders, aged between 21 and 59 years old with complaints of snoring and / or apnea. All underwent full clinical evaluation, including physical examination, nasolarybgoscopy and polisonography. We classified individuals into groups by the value of the apnea-hypopnea index (AHI), calculated measures of association and analyzed differences by the Kruskal-Wallis and chi-square tests. RESULTS: all patients with obesity type 2 had OSAS. We found a relationship between the uvula projection during nasoendoscopy and OSAS (OR: 4.9; p-value: 0.008; CI: 1.25 22.9). In addition, there was a major strength of association between the circular shape of the pharynx and the presence of moderate or severe OSAS (OR: 9.4, p-value: 0.002), although the CI was wide (1.80-53.13). The septal deviation and lower turbinate hypertrophy were the most frequent nasal alterations, however unrelated to gravity. Nasal obstruction was four times more common in patients without daytime sleepiness. The other craniofacial anatomical changes were not predictors for the occurrence of OSAS. CONCLUSION: oral, pharyngeal and laryngeal disorders participate in the pathophysiology of OSAS. The completion of the endoscopic examination is of great value to the evaluation of these patients. PMID- 26648146 TI - Aplication of videothoracoscopy in trauma--experience of a service. AB - OBJECTIVE: To evaluate patients with chest trauma submitted to videothoracoscopy during hospitalization. In 2007, the Trauma Surgery Group was created in the General Surgery Department of the Hospital Municipal Lourenco Jorge of Rio de Janeiro-RJ, and started following all trauma victims who were admitted to the Hospital. METHODS: We conducted a retrospective analysis of patients submitted to thoracoscopy from July 2007 to May 2015, based on a database started at the beginning of this period and on data collection from patients who underwent thoracoscopy. We evaluated the following parameters: procedure effectiveness, indication of the procedure, conversion rate, complications and mortality. We included patients who presented post-traumatic pleural collections, such as retained hemothorax and pleural empyema, and penetrating injury in the thoracoabdominal transition. All patients were hemodynamic stable and signed an informed consent. RESULTS: In the analyzed period 53 patients were submitted to videothoracoscopy; 24 had penetrating trauma (45.3%) and 29, blunt (54.7%), with a predominance of males (75.5%). The procedure was performed in 26 cases of retained hemothorax (49%), 14 cases of empyema (26.5%) and in 13 patients for evaluation of injury in the thoracoabdominal transition (24.5%). The thoracoscopy was effective in resolution of 36 cases (80%), without need for further procedure. There was a conversion rate of 15.5% and 3 procedure complications related (6.6%). Mortality was nil. CONCLUSION: In this series, videothoracoscopy proved that this diagnostic and therapeutic procedure is safe and effective, if performed by a surgeon with appropriate training, especially when it is indicated in cases of retained hemothorax and evaluation of penetrating thoracoabdominal trauma. PMID- 26648147 TI - Esophagectomy with gastroplasty in advanced megaesophagus: late results of omeprazole use. AB - OBJECTIVE: To analyze the late results of advanced Chagasic megaesophagus treatment by esophagectomy associated with the use of proton pump inhibitor (omeprazole) as for the incidence of esophagitis and Barrett's esophagus in the remaining stump. METHODS: We studied patients with advanced megaesophagus undergoing esophagectomy and transmediastinal esophagogastroplasty. Patients were divided into three groups: A (20) with esophageal replacement by full stomach, without the use of omeprazole; B (20) with esophageal replacement by full stomach, with omeprazole 40 mg/day introduced after the first postoperative endoscopy and maintained for six years; and C (30) with esophageal replacement by gastric tube with use of omeprazole. Dysphagia, weight loss and BMI were clinical parameters we analyzed. Upper gastrointestinal endoscopy was performed in all patients, and determined the height of the anastomosis, the aspect of the mucosa, with special attention to possible injuries arising from gastroesophageal reflux, and the patency of the esophagogastric anastomosis. RESULTS: We studied 50 patients, 28 males (56%) and 22 (44%) females. All underwent endoscopy every year. In the first endoscopy, erosive esophagitis was present in nine patients (18%) and Barrett's esophagus, in four (8%); in the last endoscopy, erosive esophagitis was present in five patients (8%) and Barrett's esophagus in one (2%). When comparing groups B and C, there was no evidence that the manufacturing of a gastric tube reduced esophagitis and Barrett's esophagus. However, when comparing groups A and C, omeprazole use was correlated with reduction of reflux complications such as esophagitis and Barrett's esophagus (p <0.005). CONCLUSION: The use of omeprazole (40 mg/day) reduced the onset of erosive esophagitis and Barrett's esophagus during the late postoperative period. PMID- 26648148 TI - Impact of Roux-en-Y gastric bypass on lipid and inflammatory profiles. AB - OBJECTIVE: To evaluate the behavior of acute phase proteins and lipid profile in patients undergoing Roux-en-Y gastric bypass. METHODS: We conducted a prospective study, consisting of three moments: M1 - preoperative (24 hours before surgery); M2 - 30 days after surgery; and M3 - 180 days after surgery. We carried measured height and BMI, as well as determined the concentrations of acute phase proteins (C-reactive protein (CRP), albumin and Alpha-1-acid glycoprotein) and total cholesterol, LDL-c, HDL-c and triacylglycerol. RESULTS: participants comprised 25 individuals, with a mean age of 39.28 +/- 8.07, 72% female. At all times of the study there was statistically significant difference as for weight loss and BMI. We found a significant decrease in CRP concentrations between the moments M1 and M3 (p = 0.041) and between M2 and M3 (p = 0.018). There was decrease in Alpha-1 GA concentrations between M1 and M2 (p = 0.023) and between M1 and M3 (p = 0.028). The albumin values increased, but did not differ between times. Total cholesterol and triacylglycerol decreased significantly ay all times. LDL-c concentrations decreased and differed between M1 and M2 (p = 0.001) and between M1 and M3 (p = 0.001). HDL-c values increased, however only differing between M1 and M2 (p = 0.050). CONCLUSION: Roux-en-Y gastric bypass promoted a decrease in plasma concentrations of CRP and Alpha-1-acid glycoprotein, improving lipid and inflammatory profiles. PMID- 26648149 TI - Predictors of "occult" intra-abdominal injuries in blunt trauma patients. AB - OBJECTIVE: to assess predictors of intra-abdominal injuries in blunt trauma patients admitted without abdominal pain or abnormalities on the abdomen physical examination. METHODS: We conducted a retrospective analysis of trauma registry data, including adult blunt trauma patients admitted from 2008 to 2010 who sustained no abdominal pain or abnormalities on physical examination of the abdomen at admission and were submitted to computed tomography of the abdomen and/or exploratory laparotomy. Patients were assigned into: Group 1 (with intra abdominal injuries) or Group 2 (without intra-abdominal injuries). Variables were compared between groups to identify those significantly associated with the presence of intra-abdominal injuries, adopting p<0.05 as significant. Subsequently, the variables with p<0.20 on bivariate analysis were selected to create a logistic regression model using the forward stepwise method. RESULTS: A total of 268 cases met the inclusion criteria. Patients in Group I were characterized as having significantly (p<0.05) lower mean AIS score for the head segment (1.0 +/- 1.4 vs. 1.8 +/- 1.9), as well as higher mean AIS thorax score (1.6 +/- 1.7 vs. 0.9 +/- 1.5) and ISS (25.7 +/- 14.5 vs. 17,1 +/- 13,1). The rate of abdominal injuries was significantly higher in run-over pedestrians (37.3%) and in motorcyclists (36.0%) (p<0.001). The resultant logistic regression model provided 73.5% accuracy for identifying abdominal injuries. The variables included were: motorcyclist accident as trauma mechanism (p<0.001 - OR 5.51; 95%CI 2.40-12.64), presence of rib fractures (p<0.003 - OR 3.00; 95%CI 1.47 6.14), run-over pedestrian as trauma mechanism (p=0.008 - OR 2.85; 95%CI 1.13 6.22) and abnormal neurological physical exam at admission (p=0.015 - OR 0.44; 95%CI 0.22-0.85). CONCLUSION: Intra-abdominal injuries were predominantly associated with trauma mechanism and presence of chest injuries. PMID- 26648150 TI - Video assisted resections. Increasing access to minimally invasive liver surgery? AB - OBJECTIVE: To evaluate perioperative outcomes, safety and feasibility of video assisted resection for primary and secondary liver lesions. METHODS: From a prospective database, we analyzed the perioperative results (up to 90 days) of 25 consecutive patients undergoing video-assisted resections in the period between June 2007 and June 2013. RESULTS: The mean age was 53.4 years (23-73) and 16 (64%) patients were female. Of the total, 84% were suffering from malignant diseases. We performed 33 resections (1 to 4 nodules per patient). The procedures performed were non-anatomical resections (n = 26), segmentectomy (n = 1), 2/3 bisegmentectomy (n = 1), 6/7 bisegmentectomy (n = 1), left hepatectomy (n = 2) and right hepatectomy (n = 2). The procedures contemplated postero-superior segments in 66.7%, requiring multiple or larger resections. The average operating time was 226 minutes (80-420), and anesthesia time, 360 minutes (200-630). The average size of resected nodes was 3.2 cm (0.8 to 10) and the surgical margins were free in all the analyzed specimens. Eight percent of patients needed blood transfusion and no case was converted to open surgery. The length of stay was 6.5 days (3-16). Postoperative complications occurred in 20% of patients, with no perioperative mortality. CONCLUSION: The video-assisted liver resection is feasible and safe and should be part of the liver surgeon armamentarium for resection of primary and secondary liver lesions. PMID- 26648151 TI - Severity assessment of acute pancreatitis: applying Marshall scoring system. AB - OBJECTIVE: To analyze the effectiveness of the Marshall scoring system to evaluate the severity of acute pancreatitis (AP). METHODS: We performed a prospective, observational study in 39 patients with AP evaluated by the Marshall scoring system and the Ranson criteria (admission and 48 hours). We assessed the progression of the disease for seven days and compared the data of the two criteria. RESULTS: Seven patients died during the observation period and one died afterwards. All deaths had shown failure of at least one system by the Marshall method. CONCLUSION: The Marshall scoring system may be used as an effective and simplified application method to assess the severity of acute pancreatitis. PMID- 26648152 TI - Use of surgical mesh of different compositions in the correction of the abdominal wall defect in rats. AB - OBJECTIVE: To analyze the performance of two surgical meshes of different compositions during the defect healing process of the abdominal wall of rats. METHODS: thirty-three adult Wistar rats were anesthetized and subjected to removal of an area of 1.5 cm x 2 cm of the anterior abdominal wall, except for the skin; 17 animals had the defect corrected by edge-to-edge surgical suture of a mesh made of polypropylene + poliglecaprone (Group U--UltraproTM); 16 animals had the defect corrected with a surgical mesh made of polypropylene + polidioxanone + cellulose (Group P--ProceedTM). Each group was divided into two subgroups, according to the euthanasia moment (seven days or 28 days after the operation). Parameters analyzed were macroscopic (adherence), microscopic (quantification of mature and immature collagen) and tensiometric (maximum tension and maximum rupture strength). RESULTS: there was an increase in collagen type I in the ProceedTM group from seven to 28 days, p = 0.047. Also, there was an increase in the rupture tension on both groups when comparing the two periods. There was a lower rupture tension and tissue deformity with ProceedTM mesh in seven days, becoming equal at day 28. CONCLUSION: the meshes retain similarities in the final result and more studies with larger numbers of animals must be carried for better assessment. PMID- 26648153 TI - Single access laparoscopic cholecystectomy: technique without the need for special materials and with better ergonomics. AB - The authors describe a surgical technique which allows, without increasing costs, to perform laparoscopic cholecystectomy with a single incision, without using specific materials and with better surgical ergonomics. The technique consists of a longitudinal umbilical incision, navel detachment, use of a permanent 10mm trocar and two clamps directly and bilaterally through the aponeurosis without the use of 5mm trocars, transcutaneous gallbladder repair with straight needle cotton suture, ligation with unabsorbable suture and umbilical incision for the specimen extraction. The presented technique enables the procedure with conventional and permanent materials, improving surgical ergonomics, with safety and aesthetic advantages. PMID- 26648154 TI - Basic skills for outpatient surgery in medical graduation. AB - Medical students must have domain of basic surgery skills before starting more advanced stages of surgical learning. The authors present a practical and reproducible system of operative techniques circuit, idealized and often applied to the fourth year medical students of a private educational institution. This method has enabled accurate assessment of students' skills, improving their performance and preparing them for more advanced stages of the surgical learning. PMID- 26648155 TI - Laparoscopy in uterine cervical cancer. Current state and literature review. AB - Cervical cancer remains the most frequent gynecological tumor in Brazil and other developing countries. Minimally invasive techniques, especially laparoscopy, have been increasingly employed in such tumors. This article aims to describe the main applications of laparoscopy in the treatment and staging of cervical cancer. In the early stages, it is possible to provide a fertility-preserving surgery in the form of radical trachelectomy and, in a study protocol, the function-preserving surgery, avoiding parametrectomy and the associated morbidity. A fully laparoscopic radical hysterectomy is fairly standard in the literature and has the tendency to become the standard of care in early cases, for patients who want to bear no more children. In advanced stages, minimally invasive surgery can offer ovarian transposition, with intent to prevent actinic castration, without upsetting the time for the start of radiotherapy and chemotherapy. Staging laparoscopic surgery, including pelvic and para-aortic lymphadenectomy, has been the subject of studies, since it has the potential to modify the extension of radiotherapy depending on the extent of lymph node spread. PMID- 26648156 TI - Agenesis or pseudoagenesis of the dorsal pancreas. AB - The authors present an evidence-based case report of a patient with agenesis or pseudoagenesis of the dorsal pancreas. PMID- 26648157 TI - Prehypertensive treatment with losartan, however not amlodipine, leads to long term effects on blood pressure and reduces the risk of stroke in spontaneously hypertensive stroke-prone rats. AB - The current study investigated the efficacy of losartan and amlodipine in protecting spontaneously hypertensive stroke-prone (SHRSP) rats against the risk of stroke. SHRSP rats were administered losartan, amlodipine or the vehicle for 6 weeks. There were no significant differences in systolic blood pressure (SBP) in rats treated with losartan or amlodipine, however, following drug withdrawal, rats treated with losartan maintained reduced SBP for a longer time compared with rats treated with amlodipine. In addition, rats treated with losartan exhibited thinner vascular walls and improved systolic and diastolic function. Clinical stroke scores in the losartan group were significantly reduced compared with those in the amlodipine and vehicle groups. However, rats treated with losartan exhibited higher levels of angiotensin II and lower levels of aldosterone in the serum and brain cortex compared with the vehicle and amlodipine-treated rats. Furthermore, losartan significantly reduced the abnormal expression of angiotensin II receptors type 1 and 2 in SHRSP rats, whilst amlodipine did not. These results suggest that losartan may be more efficacious than amlodipine in ameliorating blood pressure deterioration and reducing stroke risk in SHRSP rats via regulation of the renin angiotensin system. PMID- 26648158 TI - Bufalin induces apoptosis in the U-2OS human osteosarcoma cell line via triggering the mitochondrial pathway. AB - Bufalin has been shown to induce apoptosis in osteosarcoma cells; however, the underlying mechanism has not been elucidated. The purpose of the present study was to investigate whether mitochondria-mediated signaling pathways trigger the process of apoptosis in the U-2OS osteosarcoma cell line. Bufalin inhibited the proliferation and induced apoptosis in U-2OS cells in a time- and dose-dependent manner. Bufalin-induced apoptosis was accompanied with a significant reduction of the mitochondrial membrane potential, release of mitochondrial cytochrome c into the cytosol, activation of caspase-3, caspase-9 and poly(adenosine diphosphate ribose) polymerase, as well as downregulation of B-cell lymphoma 2 (Bcl-2)/Bcl-2 associated X protein. Cyclosporin A, a specific inhibitor of the mitochondrial permeability transition pore, attenuated bufalin-induced apoptosis. In conclusion, the present study revealed that bufalin induced apoptosis in the U 2OS human osteosarcoma cell line via triggering of the mitochondrial pathway. PMID- 26648159 TI - [Corrigendum] NADPH oxidase 3-associated oxidative stress and caspase 3-dependent apoptosis in the cochleae of D-galactose-induced aged rats. PMID- 26648160 TI - Treatment with cyclophosphamide supported by various dendritic cell-based vaccines induces diversification in CD4+ T cell response against MC38 colon carcinoma. AB - The present study shows that an application of cyclophosphamide (CY) supported by dendritic cell (DC)-based vaccines affected differentiation of the activity of CD4+ T cell subpopulations accompanied by an alteration in CD8+ cell number. Vaccines were composed of bone marrow-derived DCs activated with tumor cell lysate (BM-DC/TAgTNF-alpha) and/or genetically modified DCs of JAWS II line (JAWS II/Neo or JAWS II/IL-2 cells). Compared to untreated or CY-treated mice, the combined treatment of MC38 colon carcinoma-bearing mice resulted in significant tumor growth inhibition associated with an increase in influx of CD4+ and CD8+ T cells into tumor tissue. Whereas, the division of these cell population in spleen was not observed. Depending on the nature of DC-based vaccines and number of their applications, both tumor infiltrating cells and spleen cells were able to produce various amount of IFN-gamma, IL-4 and IL-10 after mitogenic ex vivo stimulation. The administration of CY followed by BM-DC/TAgTNF-alpha and genetically modified JAWS II cells, increased the percentage of CD4+T-bet+ and CD4+GATA3+ cells and decreased the percentage of CD4+RORgammat+ and CD4+FoxP3+ lymphocytes. However, the most intensive response against tumor was noted after the ternary treatment with CY + BM-DC/TAgTNF-alpha + JAWS II/IL-2 cells. Thus, the administration of various DC-based vaccines was responsible for generation of the diversified antitumor response. These findings demonstrate that the determination of the size of particular CD4+ T cell subpopulations may become a prognostic factor and be the basis for future development of anticancer therapy. PMID- 26648161 TI - Chemical and photochemical properties of chloroharmine derivatives in aqueous solutions. AB - Thermal and photochemical stability (Phi(R)), room temperature UV-vis absorption and fluorescence spectra, fluorescence quantum yields (Phi(F)) and lifetimes (tau(F)), quantum yields of hydrogen peroxide (Phi(H2O2)) and singlet oxygen (Phi(Delta)) production, and triplet lifetimes (tau(T)) have been obtained for the neutral and protonated forms of 6-chloroharmine, 8-chloroharmine and 6,8 dichloroharmine, in aqueous media. When it was possible, the effect of pH and oxygen concentration was evaluated. The nature of electronic transitions of protonated and neutral species of the three investigated chloroharmines was established using Time-Dependent Density Functional Theory (TD-DFT) calculations. The impact of all the foregoing observations on the biological role of the studied compounds is discussed. PMID- 26648162 TI - Effects of total flavones from Dendranthema morifolium on vasocontraction and proliferation of vascular smooth muscle cells. AB - Pharmacological studies have shown that the active components in Dendranthema morifolium exhibit protective effects against ischemia/reperfusion injury; however, its pharmacological action on blood vessels has not yet been investigated. The purpose of the present study was to assess the effects of the total flavones extracted from D. morifolium (Ramat.) Tzvel. cv. Hangju (FDM) on the vasocontraction and proliferation of vascular smooth muscle cells (VSMCs). The tension of rat thoracic aortic rings was measured using a mechanical force transducer attached to a recording system. FDM induced a dose-dependent relaxation of rings with endothelium pre-contracted by either phenylephrine (PE; 10(-6) mol/l) or a high concentration of potassium chloride (KCl; 60 mmol/l). FDM did not significantly affect the vasorelaxant effects on mechanically removed endothelium. In endothelium-denuded aortic rings depolarized by 60 mmol/l KCl, FDM inhibited the contraction induced by Ca2+. FDM reduced the transient contraction caused by PE in a Ca2+-free solution, but did not affect the contraction induced by phorbol ester. Furthermore, FDM inhibited the proliferation of VSMCs with or without growth stimulation by insulin. In conclusion, that the vasorelaxation induced by FDM in rat aortic rings is not dependent on the endothelium but is mediated via a reduction of the influx of extracellular Ca2+ through the voltage-dependent and receptor-operated channels and via the inhibition of the release of intracellular Ca2+ in VSMCs. The anti proliferative activity of FDM suggests that it may be beneficial in inhibiting atherosclerosis. PMID- 26648163 TI - Salty and spicy food; are they involved in the pathogenesis of acne vulgaris? A case controlled study. AB - BACKGROUND: Many studies have suggested a strong relation between diet and acne. Many patients with acne believe that spicy and salty foods exacerbate acne. AIM: To assess the relationship between the dietary intake of salty and spicy food and the onset, severity, duration of acne. METHODS: Two hundred patients with acne vulgaris and 200 age- and gender-matched controls were subjected to a detailed questionnaire taking, clinical examination and dietary assessment through using "24 h recall" method. Sodium content of the 24-h food intake was computed by a computer program connecting participants' dietary information to the food composition table of National Nutrition Institute data base. RESULTS: Patients with acne consumed significantly higher daily amounts of sodium chloride (NaCl) (median 3367.54 mg) compared to the controls (median 2271.8 mg) (P < 0.001). A negative correlation between the amount of NaCl in the diet of patients with acne and the age of onset of acne lesions was detected (r = -0.216, P = 0.031). However, neither salty nor spicy food correlated with duration or severity of the disease. CONCLUSION: Consumption of salty foods was significantly higher among patients with acne compared to acne free subjects, making the consumption of salty food a possible participating factor in the development of acne. PMID- 26648164 TI - CK0403, a 9-aminoacridine, is a potent anti-cancer agent in human breast cancer cells. AB - 3-({4-[4-(Acridin-9-ylamino)phenylthio]phenyl}(3-hydroxypropyl)amino)propan-1-ol (CK0403) is a sulfur-containing 9-anilinoacridine analogue of amsacrine and was found to be more potent than its analogue 2-({4-[4-(acridin-9 ylamino)phenylthio]phenyl}(2-hydroxyethyl)amino)ethan-1-ol (CK0402) and amsacrine in the inhibition of the topoisomerase II-catalyzed decatenation reaction. A previous study by our group reported that CK0402 was effective against numerous breast cancer cell lines, and the combination of CK0402 with herceptin enhanced its activity in HER2(+) SKBR-3 cells. In order to identify novel chemotherapeutic agents with enhanced potency, the present study explored the potential of CK0403 in the treatment of breast cancer. First, the growth inhibitory activity of CK0403 in the breast cancer cell lines MCF-7, MDA-MB-231, BT474 and SKBR-3, as well as in the non-cancerous MCF-10A cell line, was examined using a sulforhodamine B assay. The results showed that CK0403 exerted more potent growth inhibitory activity than CK0402 in all of the breast cancer cell lines except MCF 7. SKBR-3 and MDA-MB-231 were the most sensitive cell lines tested, and the combination of CK0403 with herceptin in HER2(+) SKBR-3 cells enhanced the growth inhibitory activity of CK0403. Analysis of cell cycle alterations induced by CK0403 in SKBR-3 cells revealed that, similarly to CK0402, CK0403 induced G2/M phase arrest with a decreased S- and G0/G1-phase ratio. In addition, it was shown that CK0403 induced apoptosis more effectively than CK0402 in SKBR-3 cells. Further analysis of autophagy protein 5 (Atg5) indicated that CK0403 induced more cleaved Atg5 than CK0402 and other chemotherapeutic agents tested. Of note, although still relatively potent, CK0403 exhibited reduced growth inhibitory activity under hypoxic conditions, which can induce autophagy. Collectively, the present results supported that CK0403 is highly potent and more effective than CK0402 against estrogen receptor-negative and HER2-overexpressing breast cancer cell lines, suggesting its future application for chemotherapy in breast cancer. PMID- 26648165 TI - Intrinsic effects of gold nanoparticles on proliferation and invasion activity in SGC-7901 cells. AB - Although biomedical applications of functionalized nanoparticles have taken significant strides, biological characterization of unmodified nanoparticles remains unclear. In the present study, we investigated the cell viability and invasion activity of gastric cancer cells after treatment with gold nanoparticles. The growth of SGC-7901 cells was inhibited significantly after treatment with 5-nm gold nanoparticles, and the cell invasion decreased markedly. These effects were not seen by different size gold nanoparticles (10, 20 and 40 nm). The attenuated invasion activity may be associated with the decreased expression of matrix metalloproteinase 9 and intercellular adhesion molecule-1. These data indicated that the response of SGC-7901 cells to gold nanoparticles was strongly associated with their unique size-dependent physiochemical properties. Therefore, we provided new evidence for the effect of gold nanoparticles on gastric cancer cell proliferation and invasion in vitro, making a contribution to the application of gold nanoparticles to novel therapies in gastric cancer. PMID- 26648166 TI - Replication analysis of 15 susceptibility loci for nonsyndromic cleft lip with or without cleft palate in an italian population. AB - BACKGROUND: Nonsyndromic cleft lip with or without cleft palate (nsCL/P) is one of the most common congenital malformations in humans. Its average global incidence is 1.7 per 1000 live births, with wide variation according to geographical location and ethnicity. Its etiology involves both genetic and environmental factors. The aim of the present study was to confirm genetic association of a selection of 15 candidate nsCL/P loci using an independent sample of the Italian population. METHODS: At least one single-nucleotide polymorphism (SNP) for each locus was genotyped in 380 nuclear trios. RESULTS: Transmission disequilibrium analysis revealed significant associations for three variants at two loci (8q24 and 1p22). Two SNPs at 8q24 showed the strongest level of association, the rs987525 (PTDT = 6.81 * 10(-6) ; homozygous relative risk = 3.60 [95% confidence interval, 2.12-6.13]), and the rs17241253 (PTDT = 1.03 * 10(-5) ; homozygous relative risk = 3.75 [95% confidence interval, 2.10-6.67]). Four additional loci (at 1q32, 3q12, 8q21, and 10q25) achieved nominally significant p-values. Two SNPs at 1p36 achieved p-values of < 0.1. The present data suggest that 6 of the 15 analyzed nsCL/P risk loci contribute significantly to nsCL/P risk in the Italian population. These include the 1p22 locus, which previous research has implicated predominantly in Asian populations. CONCLUSION: Different loci, including 8q24 and 1p22 have been found associated with nsCL/P in multiple populations. Further efforts are needed to identify causative variants and transfer knowledge to clinical application, such as personal genetic risk assessment. PMID- 26648167 TI - The effect of gender on the outcome of forensic psychiatric assessment in Sweden: A case vignette study. AB - BACKGROUND: Previous research suggests that female violent offenders at risk of a prison sentence are more likely than their male counterparts to be assessed as having mental health problems of a nature or degree that would lead to a court requirement for hospital treatment. AIMS/HYPOTHESES: To test the hypothesis that there is bias towards hospital disposal of female compared with male violent offenders with mental disorder. METHODS: In Sweden, the National Board of Forensic Medicine oversees all assessments of mental disorder for the criminal courts. Twenty-six Board appointed forensic psychiatrists, psychologists and social workers each independently assessed six case vignettes for fit with criteria for 'severe mental disorder', a prerequisite for hospital disposal from court. Each gender neutral vignette described a person who had been convicted of serious assault and had a major mental disorder. A gender was then assigned to each offender randomly within a block design, thus varying between sets. Participants were blind to the main aim of the study and the gender variation. RESULTS: There was no significant association between gender of the person assessed and judgement that s/he had a 'severe mental disorder'. An offender depicted as having mental retardation was more likely to be assessed as at high risk of criminal recidivism if portrayed as female, regardless of the sex, place of work or level of experience of the assessor. CONCLUSION: We found no evidence of gender bias in determining appropriateness of a hospital disposal of an offender with mental disorder. The difference in assessment of recidivism according to sex of the patient was only in relation to mental retardation; further research would be needed to able to interpret this. As researchers in other countries have reported gender bias in disposals from court, our findings may provide support for a centralised forensic psychiatric assessment board and formal, on-going training. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26648168 TI - The effect and mechanism of bufalin on regulating hepatocellular carcinoma cell invasion and metastasis via Wnt/beta-catenin signaling pathway. AB - Hepatocellular carcinoma (HCC) is a highly malignant tumor with an extremely poor prognosis. Our preliminary study indicated that bufalin could restrain the proliferation of human hepatoma BEL-7402 cells in a time- and dose-dependent manner. In the present study, the colony formation assay, the Transwell invasion assay, the western blot analysis and the immunofluorescence method were respectively used to investigate the effect and mechanism of bufalin against HCC cell invasion and metastasis. We found that: i) bufalin had significant inhibitory effect on the cell proliferation of BEL-7402 cells; ii) bufalin markedly inhibited the migration and invasion of BEL-7402 cells; iii) bufalin could suppress the phosphorylation of GSK-3beta Ser9 site in BEL-7402 cells, decrease the expression of beta-catenin, cyclin D1, metalloproteinases-7 (MMP-7) and cyclooxygenase-2 (COX-2) in the cytoplasm, and increase the expression of E cadherin and beta-catenin on the cell membrane; and iv) the expression of alpha fetoprotein significantly decreased and the expression of albumin increased in BEL-7402 cells after bufalin was used. Our results indicate that: i) bufalin can regulate the expression of associated factors in Wnt/beta-catenin signaling pathway of BEL-7402 cells through suppressing the phosphorylation of GSK-3beta Ser9 site; ii) bufalin can strengthen intercellular E-cadherin/beta-catenin complex to control epithelial-mesenchymal transition; and iii) bufalin can reverse the malignant phenotype and promote the differentiation and maturation by regulating the AFP and ALB expression in BEL-7402 cells. These are very important mechanisms of bufalin on the inhibition of the invasion and metastasis of HCC cells. PMID- 26648170 TI - 4.1N suppresses hypoxia-induced epithelial-mesenchymal transition in epithelial ovarian cancer cells. AB - Protein 4.1N (4.1N) is a member of the protein 4.1 family and is essential for the regulation of cell adhesion, motility and signaling. Previous studies have suggested that 4.1N may serve a tumor suppressor role. However, the molecular mechanisms remain unclear. In the current study, the role of 4.1N in the downregulation of hypoxia-induced factor 1alpha (HIF-1alpha) under hypoxic conditions and therefore the suppression of hypoxia induced epithelial mesenchymal transition (EMT) was investigated. The data were obtained from overexpressed and knockdown 4.1N epithelial ovarian cancer (EOC) cell lines. It was identified that 4.1N was capable of regulating the sub-cellular localization and expression levels of HIF-1alpha, by which 4.1N served a dominant role in the suppression of hypoxia-induced EMT and associated genes. Collectively, the data of the current study identified 4.1N as an inhibitor of hypoxia-induced tumor progression in EOC cells and highlighted its potential role in EOC therapy. PMID- 26648171 TI - Lentivirus-mediated TNF-alpha gene silencing and overexpression of osteoprotegerin inhibit titanium particle-induced inflammatory response and osteoclastogenesis in vitro. AB - Macrophages and osteoclasts release proinflammatory factors and promote osteoclastogenesis following the phagocytosis of wear particles. During this pathological process, receptor of nuclear factor kappaB ligand (RANKL) and tumor necrosis factor (TNF)-alpha are critical factors contributing to resorption and the inflammatory response. The present study aimed to construct recombination lentivirus vectors carrying TNF-alpha small interfering (si)RNA and osteoprotegerin (OPG) cDNA, and to examine the effects of Lenti-siTNFalpha-OPG on the wear particle-induced inflammatory response and osteoclastogenesis in a titanium (Ti) particle-induced-inflammatory response cell model. Lenti-siTNFalpha OPG vectors were constructed and transnfected into RAW264.7 and MC3T3-E1 cells, respectively, prior to particle stimulation. The protein levels of TNF-alpha, OPG and RANKL were evaluated using western blot analysis and enzyme-linked immunosorbent assays, and the mRNA expression levels of the inflammatory factors, TNF-alpha, interleukin (IL)-1beta and IL-6, as well as OPG and RANKL, were measured using reverse transcription-quantitative polymerase chain reaction analysis. The activity of alkaline phosphatase (ALP) was examined using an ALP kit. In the presence of the Lenti-siTNFalpha-OPG vector, the mRNA expression levels of the inflammatory factors and RANKL were downregulated, as were the protein levels of TNF-alpha. The mRNA expression and protein levels of OPG were upregulated, and ALP activity was increased. These findings suggested that Lenti siTNFalpha-OPG transfection inhibited the wear particle-induced inflammatory response and osteoclastogenesis, which warrants further investigation for the prevention and/or treatment of wear particle-induced osteolysis. PMID- 26648173 TI - A randomised comparison of the Ambu(r) AuraGainTM and the LMA(r) supreme in infants and children. AB - We conducted a randomised trial in 100 children in order to compare the clinical performance of the Ambu((r)) AuraGain(TM) and the LMA((r)) Supreme(*) for airway maintenance during mechanical ventilation. The primary outcomes were initial and 10-min airway leak pressures. Ease, time and success rates for device and gastric tube insertion, fibreoptic grades of view, airway quality during anaesthetic maintenance, and complications were also assessed. There were no differences in the initial and ten min airway leak pressures between the Ambu AuraGain and LMA Supreme, median (IQR [range]) initial: 19 (16-22 [10-34]) vs 18 (14-24 [8-40]) cmH2 O, p = 0.4; and ten min: 22 (18-26 [11-40]) vs 20 (16-26 [12-40]) cmH2 O, p = 0.08, respectively. Ease, time and success rates for device placement, gastric tube insertion and complications were also not significantly different. Children receiving the LMA Supreme required more airway manouevers (7 vs 1 patient, p = 0.06) to maintain a patent airway. Our results suggest that the Ambu AuraGain may be a useful alternative to the LMA Supreme, as demonstrated by comparable overall clinical performance in children. PMID- 26648172 TI - Intravenous high mobility group box 1 upregulates the expression of HIF-1alpha in the myocardium via a protein kinase B-dependent pathway in rats following acute myocardial ischemia. AB - The effects of intravenous high mobility group box 1 (HMGB1) on myocardial ischemia/reperfusion (I/R) injury remains to be elucidated. The purpose of the present study was to investigate the effects of intravenous HMGB1 on the expression of hypoxia inducible factor-1alpha (HIF-1alpha) in the myocardium of rats following acute myocardial ischemia, and to examine the effects of intravenous HMGB1 on myocardial I/R injury. Male Wistar rats were divided into the following groups: Sham operation group (n=10), a group exposed to ischemia for 30 min and reperfusion for 4 h (I/R group) as a control (n=10), an HMGB group, in which 100 ng/kg HMGB was administered intravenously 30 min prior to ischemia (n=10), an LY group, in which LY294002, an inhibitor of phosphoinositide 3-kinase (PI3K), was administered intravenously (0.3 mg/kg) 40 min prior to ischemia (n=10), and the HMGB1+LY group, in which HMGB1 (100 ng/kg) and LY294002 (0.3 mg/kg) were administered intravenously 30 min and 40 min prior to ischemia, respectively (n=10). The serum levels of cardiac troponin I (cTnI) and tumor necrosis factor-alpha (TNF-alpha), and myocardial infarct size were measured. The expression levels of phosphorylated Akt and HIF-1alpha were investigated using western blot analyses. The results showed that pre-treatment with HMGB1 significantly decreased serum levels of cTnI, and TNF-alpha, and reduced myocardial infarct size following 4 h reperfusion (all P<0.05). HMGB1 also increased the expression levels of HIF-1alpha and p-Akt induced by I/R (P<0.05). LY294002 was found to eliminate the effects of intravenous HMGB1 on myocardial I/R injury (P<0.05). These results suggest that intravenous pre-treatment with HMGB1 may exert its cardioprotective effects via the upregulation of the myocardial expression of HIF-1alpha, which may be regulated by the PI3K/Akt signaling pathway, in rats following acute myocardial I/R. PMID- 26648169 TI - A20 regulates IL-1-induced tolerant production of CXC chemokines in human mesangial cells via inhibition of MAPK signaling. AB - Chemokines and chemokine receptors are involved in the resolution or progression of renal diseases. Locally secreted chemokines mediated leukocyte recruitment during the initiation and amplification phase of renal inflammation. However, the regulation of chemokine induction is not fully understood. In this study, we found that IL-1 induced a significant up-regulation of CXC chemokines CXCL1, 2, and 8 at both mRNA and protein levels in human mesangial cells. The induction of chemokines was tolerant, as the pre-treatment of HMC with IL-1 down-regulated the induction of chemokines induced by IL-1 re-stimulation. IL-1 up-regulated the ubiquintin-editing enzyme A20. A20 over-expression down-regulated IL-1-induced up regulation of chemokines, and A20 down-regulation reversed chemokine inhibition induced by IL-1 pre-treatment, suggested that A20 played important roles in the tolerant production of chemokines. Unexpectedly, A20 over- expression inhibited the activation of ERK, JNK, and P38, but did not inhibit the activation of NF kappaB. In addition, both IL-1 treatment and A20 over-expression induced the degradation of IRAK1, an important adaptor for IL-1R1 signaling, and A20 inhibition by RNA interference partly reversed the degradation of IRAK1. Taken together, IL-1-induced A20 negatively regulated chemokine production, suggesting that A20 may be an important target for the prevention and control of kidney inflammation. PMID- 26648174 TI - Assessment and comparison of probiotic potential of four Lactobacillus species isolated from feces samples of Iranian infants. AB - The probiotic potential of Lactobacillus species isolated from infant feces was investigated. For this study, the antibiotic susceptibility, tolerance in gut related conditions, antimicrobial activity, and ability to adhere to a human colorectal adenocarcinoma cell line (Caco-2 cells) of four common Lactobacillus species (Lactobacillus paracasei [n = 15], Lactobacillus rhamnosus [n = 45], Lactobacillus gasseri [n = 20] and Lactobacillus fermentum [n = 18]) were assessed. Most isolates that which were sensitive to imipenem, ampicillin, gentamycin, erythromycin and tetracycline were selected for other tests. L. gasseri isolates had the greatest sensitivity to gastric and intestinal fluids (<10% viability). L. fermentum (FH5, FH13 and FH18) had the highest adhesion to Caco-2 cells. The lowest antibacterial activity against pathogenic bacteria was shown by L. gasseri strains in spot tests. Furthermore, non-adjusted cell-free culture supernatants with low pH had greater antimicrobial activity, which was related to organic acid. The results showed that some isolates of L. rhamnosus and L. fermentum are suitable for use as a probiotic. PMID- 26648176 TI - Fundamentals of large-molecule protein therapeutic bioanalysis using ligand binding assays. AB - This article provides an overview of ligand-binding assays, including the origin and evolution of the primary concepts, in addition to reviewing commonly used assay formats. The birth of ligand-binding assays began with a radioimmunoassay developed to measure insulin in 1960. Fundamental to ligand-binding assay design is the requirement of at least one protein that interacts with the analyte of interest. Enzyme immunoassay has largely supplanted radioimmunoassay as the ligand-binding assay of choice in today's laboratory environment. This article illustrates various assay formats such as competitive, sandwich and bridging, in addition to, describing critical reagents necessary for their design. The utility of ligand-binding assays in therapeutic protein development and comparison to alternative bioanalysis platforms is discussed. PMID- 26648175 TI - Placental endoplasmic reticulum stress negatively regulates transcription of placental growth factor via ATF4 and ATF6beta: implications for the pathophysiology of human pregnancy complications. AB - Low maternal circulating concentrations of placental growth factor (PlGF) are one of the hallmarks of human pregnancy complications, including fetal growth restriction (FGR) and early-onset pre-eclampsia (PE). Currently, PlGF is used clinically with other biomarkers to screen for high-risk cases, although the mechanisms underlying its regulation are largely unknown. Placental endoplasmic reticulum (ER) stress has recently been found to be elevated in cases of FGR, and to an even greater extent in early-onset PE complicated with FGR. ER stress activates the unfolded protein response (UPR); attenuation of protein translation and a reduction in cell growth and proliferation play crucial roles in the pathophysiology of these complications of pregnancy. In this study, we further identified that ER stress regulates release of PlGF. We first observed that down regulation of PlGF protein was associated with nuclear localization of ATF4, ATF6alpha and ATF6beta in the syncytiotrophoblast of placentae from PE patients. Transcript analysis showed a decrease of PlGF mRNA, and an increase from genes encoding those UPR transcription factors in placentae from cases of early-onset PE, but not of late-onset (>34 weeks) PE, compared to term controls. Further investigations indicated a strong correlation between ATF4 and PlGF mRNA levels only (r = - 0.73, p < 0.05). These results could be recapitulated in trophoblast like cells exposed to chemical inducers of ER stress or hypoxia-reoxygenation. The stability of PlGF transcripts was unchanged. The use of small interfering RNA specific for transcription factors in the UPR pathways revealed that ATF4 and ATF6beta, but not ATF6alpha, modulate PlGF transcription. To conclude, ATF4 and ATF6beta act synergistically in the negative regulation of PlGF mRNA expression, resulting in reduced PlGF secretion by the trophoblast in response to stress. Therefore, these results further support the targeting of placental ER stress as a potential new therapeutic intervention for these pregnancy complications. PMID- 26648177 TI - Ultrathin Injectable Sensors of Temperature, Thermal Conductivity, and Heat Capacity for Cardiac Ablation Monitoring. AB - Knowledge of the distributions of temperature in cardiac tissue during and after ablation is important in advancing a basic understanding of this process, and for improving its efficacy in treating arrhythmias. Technologies that enable real time temperature detection and thermal characterization in the transmural direction can help to predict the depths and sizes of lesion that form. Herein, materials and designs for an injectable device platform that supports precision sensors of temperature and thermal transport properties distributed along the length of an ultrathin and flexible needle-type polymer substrate are introduced. The resulting system can insert into the myocardial tissue, in a minimally invasive manner, to monitor both radiofrequency ablation and cryoablation, in a manner that has no measurable effects on the natural mechanical motions of the heart. The measurement results exhibit excellent agreement with thermal simulations, thereby providing improved insights into lesion transmurality. PMID- 26648180 TI - The Problem of Functional. PMID- 26648179 TI - Diagnosis and management of aspergillosis in the Netherlands: a national survey. AB - A survey of diagnosis and treatment of invasive aspergillosis was conducted in eight University Medical Centers (UMCs) and eight non-academic teaching hospitals in the Netherlands. Against a background of emerging azole resistance in Aspergillus fumigatus routine resistance screening of clinical isolates was performed primarily in the UMCs. Azole resistance rates at the hospital level varied between 5% and 10%, although rates up to 30% were reported in high-risk wards. Voriconazole remained first choice for invasive aspergillosis in 13 out of 16 hospitals. In documented azole resistance 14 out of 16 centres treated patients with liposomal amphotericin B. PMID- 26648178 TI - Killing cancer with platycodin D through multiple mechanisms. AB - Cancer is a multi-faceted disease comprised of a combination of genetic, epigenetic, metabolic and signalling aberrations which severely disrupt the normal homoeostasis of cell growth and death. Rational developments of highly selective drugs which specifically block only one of the signalling pathways have been associated with limited therapeutic success. Multi-targeted prevention of cancer has emerged as a new paradigm for effective anti-cancer treatment. Platycodin D, a triterpenoid saponin, is one the major active components of the roots of Platycodon grandiflorum and possesses multiple biological and pharmacological properties including, anti-nociceptive, anti-atherosclerosis, antiviral, anti-inflammatory, anti-obesity, immunoregulatory, hepatoprotective and anti-tumour activities. Recently, the anti-cancer activity of platycodin D has been extensively studied. The purpose of this review was to give our perspectives on the current status of platycodin D and discuss its anti-cancer activity and molecular mechanisms which may help the further design and conduct of pre-clinical and clinical trials to develop it successfully into a potential lead drug for oncological therapy. Platycodin D has been shown to fight cancer by inducing apoptosis, cell cycle arrest, and autophagy and inhibiting angiogenesis, invasion and metastasis by targeting multiple signalling pathways which are frequently deregulated in cancers suggesting that this multi-target activity rather than a single effect may play an important role in developing platycodin D into potential anti-cancer drug. PMID- 26648181 TI - Movement Disorders in Non-Wilsonian Cirrhotic Patients: A Report of the Prevalence and Risk Factors from a Study Done in a Medical School in an Agricultural-Based Community. AB - OBJECTIVE: Parkinsonism and other movement disorders have previously been reported in the acquired hepatocerebral degeneration associated with portosystemic shunting. However, there is no study to date about their prevalence as has been noted in general practice. METHODS: One hundred and forty-three patients with hepatic cirrhosis from the gastroenterology clinic and internal medicine wards were enrolled. Liver data included the diagnoses, etiologies, assessments of complications, and treatments for cirrhosis. Hepatic encephalopathy was classified with regard to the West Haven criteria for semi quantitative grading for mental status. Neurological examination results and abnormal involuntary movements were recorded as primary outcomes. Neuro-radiology was used for the detection of severe brain lesions. RESULTS: Alcoholism was the most common cause of liver cirrhosis. Eighty-three patients (58%) presented with movement disorders. Asterixis was found in one of the cases. The most common movement disorder seen was an intentional tremor at 37.1%, which was followed by bradykinesia, Parkinsonism, and postural tremors at 29.4%, 10.5%, and 6.3%, respectively. The prevalence of movement disorders simultaneously increased with a high Child-Turcotte-Pugh score. The hepatic encephalopathy was grade 1 and 2. With the inclusion of age-range adjustments, we found that alcoholic cirrhosis and hepatic encephalopathy are statistically significant factors [p < 0.05, odds ratio (OR) = 6.41, 95% confidence interval (CI) 1.38-29.71 and p < 0.001, OR = 13.65, 95% CI 4.71-39.54] for the development of movement disorders in non Wilsonian cirrhotic patients. CONCLUSIONS: Intentional tremor is a common abnormal movement. Alcoholic cirrhosis and hepatic encephalopathy are significant risk factors in the development of movement disorders in non-Wilsonian cirrhotic patients. PMID- 26648182 TI - Can Postural Instability Respond to Galvanic Vestibular Stimulation in Patients with Parkinson's Disease? AB - OBJECTIVE: Galvanic vestibular stimulation (GVS) activates the vestibular afferents, and these changes in vestibular input exert a strong influence on the subject's posture or standing balance. In patients with Parkinson's disease (PD), vestibular dysfunction might contribute to postural instability and gait disorders. METHODS: Current intensity was increased to 0.7 mA, and the current was applied to the patients for 20 minutes. To perform a sham stimulation, the current intensity was increased as described and then decreased to 0 mA over the course of 10 seconds. The patient's status was recorded continuously for 20 minutes with the patient in the supine position. RESULTS: Three out of 5 patients diagnosed with PD with postural instability and/or abnormal axial posture showed a reduction in postural instability after GVS. The score for item 12 of the revised Unified Parkinson's Disease Rating Scale part 3 was decreased in these patients. CONCLUSIONS: The mechanism of postural instability is complex and not completely understood. In 2 out of the 5 patients, postural instability was not changed in response to GVS. Nonetheless, the GVS-induced change in postural instability for 3 patients in our study suggests that GVS might be a therapeutic option for postural instability. PMID- 26648183 TI - Clinical impact of BRAF mutation on the diagnosis and prognosis of papillary thyroid carcinoma: a systematic review and meta-analysis. AB - BACKGROUND: The possible role of BRAF(V) (600E) mutation in the diagnosis and prognosis of papillary thyroid carcinoma (PTC) remains controversial. A systematic review to investigate the diagnostic and prognostic role of BRAF(V) (600E) mutation in patients with PTC is urgently needed. METHODS: A systematic review of relevant literatures was performed in PubMed, EMBASE and CENTRAL. The incremental accuracy (IA) of fine needle aspiration biopsy plus BRAF(V) (600E) mutation analysis over fine needle aspiration biopsy alone, and the statistical data about the association of BRAF(V) (600E) mutation and the prognosis of PTC (risk ratios (RR) for dichotomous data, standard mean differences for continuous data and hazard ratios (HRs) for disease-free survival (DFS) were pooled. Subgroup analysis was performed to explain the heterogeneities. RESULTS: A total of 67 studies were included. The pooled IA was 2% (95% confidence interval (CI): 0.5-4%). The pooled RR for gender, multifocality, lymph node metastasis, extrathyroidal invasion and pathological stage was 1.11 (95% CI: 0.98-1.25), 1.17 (95% CI: 1.09-1.24), 1.36 (95% CI: 1.20-1.53), 1.60 (95% CI: 1.41-1.82), and 1.49 (95% CI: 1.33-1.68), respectively. The pooled standard mean differences for age and tumour size were 0.14 (95% CI: 0.04-0.23) and 0.21 (95% CI: 0.1-0.32), respectively. The pooled HR for DFS was 1.96 (95% CI: 1.62-2.37). Subgroup analysis showed that these statistical results were affected by the geographical background of patients, study design and detection methods. CONCLUSIONS: BRAF(V) (600E) mutation analysis can not only be used in the diagnosis of PTC, but can also predict its prognosis. PMID- 26648184 TI - Impact of exclusion criteria for the DASISION and ENESTnd trials in the front line treatment of a 'real-life' patient population with chronic myeloid leukaemia. AB - Both Dasision and ENESTnd trials had many exclusion criteria, with a possible selection bias compared with the real-life. To address the impact of this bias on the first-line treatment in the current clinical practice, we revised 207 unselected newly diagnosed chronic phase chronic myeloid leukaemia (CML) patients [M/F 108/99, median age 58.8 years, interquartile range 42.3-70.2] treated with front-line imatinib from June 2002 to June 2013 at our Institution, and evaluated how many of them would have been excluded from enrolment in the two trials. Twenty-eight patients (13.5%) should have been excluded by both trials because of polycomorbidities (12), severe cardiomyopathy (five), age > 80 with frailty (three), drug abuse (two) or other severe concomitant diseases (six). In addition, eight patients should have been excluded by Dasision due to isolated chronic obstructive broncopulmonar disease, and 19 patients should have been excluded by ENESTnd due to isolated diabetes (10), arrhythmia (four), acute myocardial infarction > 6 months before CML diagnosis (two), chronic pancreatic disease (two) and peripheral arterial obstructive disease (one). On the whole, 36 patients (17.4%) would have been excluded by Dasision trial and 47 (22.7%) by ENESTnd trial. The patients potentially not eligible for both trials were significantly older and with imatinib had a worse outcome compared with patients potentially eligible. Our data highlight that an automatic transposition of results available in clinical controlled trials into the frontline real-life management of CML patients should be regarded with caution. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26648185 TI - Exfoliation syndrome: assembling the puzzle pieces. AB - PURPOSE: To summarize various topics and the cutting edge approaches to refine XFS pathogenesis that were discussed at the 21st annual Glaucoma Foundation Think Tank meeting in New York City, Sept. 19-20, 2014. METHODS: The highlights of three categories of talks on cutting edge research in the field were summarized. RESULTS: Exfoliation syndrome (XFS) is a systemic disorder with a substantial ocular burden, including high rates of cataract, cataract surgery complications, glaucoma and retinal vein occlusion. New information about XFS is akin to puzzle pieces that do not quite join together to reveal a clear picture regarding how exfoliation material (XFM) forms. CONCLUSION: Meeting participants concluded that it is unclear how the mild homocysteinemia seen in XFS might contribute to the disarrayed extracellular aggregates characteristic of this syndrome. Lysyl oxidase-like 1 (LOXL1) variants are unequivocally genetic risk factors for XFS but exactly how these variants contribute to the assembly of exfoliation material (XFM) remains unclear. Variants in a new genomic region, CACNA1A associated with XFS, may alter calcium concentrations at the cell surface and facilitate XFM formation but much more work is needed before we can place this new finding in proper context. It is hoped that various animal model and ex vivo systems will emerge that will allow for proper assembly of the puzzle pieces into a coherent picture of XFS pathogenesis. A clear understanding of XFS pathogenesis may lead to 'upstream solutions' to reduce the ocular morbidity produced by XFS. PMID- 26648186 TI - Echinocandin Susceptibility Profile of Fluconazole Resistant Candida Species Isolated from Blood Stream Infections. AB - BACKGROUND: Over the last two decades, Candida blood stream infections (BSIs) have been increasingly reported from various parts of the world. Recent studies on invasive candidiasis have documented the emergence of non albicans Candida (NAC) species as major pathogens. Candida spp. belonging to NAC group often demonstrate intrinsic or acquired or both resistance to fluconazole which is the most readily available and prescribed cost effective antifungal agent. Echinocandins are recent addition to antifungal armamentarium and are now increasingly used as first line drugs for treatment and management of candidemia. OBJECTIVE: The aim of this study was to determine echinocandin susceptibility profile of fluconazole resistant Candida Spp. isolated from BSIs. RESULTS: Predominance of NAC spp was noted. C. glabrata followed by C. krusei and C. parapsilosis demonstrated high resistance to fluconazole. Echinocandins demonstrated good activity against all Candida spp. CONCLUSION: As species distribution of Candida isolates varies greatly by country and by different health care setups within the country, species identification and antifungal susceptibility results are often useful to guide the selection of empiric treatment and design of local therapeutic guidelines. On the basis of antifungal susceptibility profile of the isolates, caspofungin can be suggested as a useful antifungal drug for the treatment of candidemia due to fluconazole resistant species. PMID- 26648187 TI - Novel outcome measurement tool of the nasal valve surgery: image analysis using endoscopic system for smartphones. PMID- 26648188 TI - PD-L1 expression in tumour buds of colorectal carcinoma. PMID- 26648189 TI - Inhibition of caspase-9 by oridonin, a diterpenoid isolated from Rabdosia rubescens, augments apoptosis in human laryngeal cancer cells. AB - Rabdosia rubescens, a commonly used traditional Chinese medicine, has increasingly gained attention for its use as an antitumor herb. Oridonin, a bioactive diterpenoid isolated from Rabdosia rubescens, has been reported to induce apoptosis in human laryngeal cancer HEp-2 cells by our group. Here, we made unexpected observations that the caspase-9 inhibitor (C9i) enhanced apoptosis in response to selected stimuli, and HEp-2 cells which were made deficient in caspase-9 using siRNA exhibited no resistance to apoptotic signals and actually demonstrated increased apoptotic sensitivity to oridonin. The results were reversed by the transfection of an exogenous caspase-9 expression vector. Caspase-9 reduced sensitivity to apoptotic stimuli through reactive oxygen species (ROS)-suppressing and autophagy-promoting methods. ROS triggered the progression of apoptosis through activation of both the caspase-9-independent mitochondrial pathway and death receptor pathways, and the autophagy had an anti apoptotic function in oridonin-treated HEp-2 cells. These collective results suggest that oridonin targets caspase-9 to alter ROS production and autophagy situation to promote HEp-2 cell apoptosis. Therefore, oridonin has the potential to be developed as an anticancer agent, and the combination of oridonin with those agents leading to reduction of caspase-9 expression in tumor cells could represent a novel approach to human laryngeal cancer treatment. PMID- 26648191 TI - Purchasing better, innovative and integrated health services. PMID- 26648192 TI - Editor's note. PMID- 26648190 TI - Protease signaling in animal and plant-regulated cell death. AB - This review aims to highlight the proteases required for regulated cell death mechanisms in animals and plants. The aim is to be incisive, and not inclusive of all the animal proteases that have been implicated in various publications. The review also aims to focus on instances when several publications from disparate groups have demonstrated the involvement of an animal protease, and also when there is substantial biochemical, mechanistic and genetic evidence. In doing so, the literature can be culled to a handful of proteases, covering most of the known regulated cell death mechanisms: apoptosis, regulated necrosis, necroptosis, pyroptosis and NETosis in animals. In plants, the literature is younger and not as extensive as for mammals, although the molecular drivers of vacuolar death, necrosis and the hypersensitive response in plants are becoming clearer. Each of these death mechanisms has at least one proteolytic component that plays a major role in controlling the pathway, and sometimes they combine in networks to regulate cell death/survival decision nodes. Some similarities are found among animal and plant cell death proteases but, overall, the pathways that they govern are kingdom-specific with very little overlap. PMID- 26648193 TI - Practical management of myelofibrosis with ruxolitinib. AB - Treatment for the majority of patients with myelofibrosis is primarily based on symptom control as curative allogeneic stem cell transplantation is typically offered only to younger patients, especially those with poor prognosis disease. Around 50% of patients with myelofibrosis have the JAK2(V617F) mutation, but almost all patients have aberrant activation of the JAK-STAT signalling pathway. Recent efforts have focussed on the clinical use of JAK2 inhibitors to treat myelofibrosis. In this article, we present our recommendations for the practical management of myelofibrosis with ruxolitinib, a selective inhibitor of both JAK1 and JAK2. Ruxolitinib can significantly improve the quality of life of patients with myelofibrosis. There is also increasing evidence of a positive impact on survival. Consistent with the physiological role of JAK signalling the major toxicity of ruxolitinib is cytopenia. Managing cytopenia is key to maximising the therapeutic benefit of ruxolitinib. Further research into the safety of ruxolitinib in patients with thrombocytopenia is warranted, as is its role in special subgroups of patients, such as those undergoing stem cell transplantation and those experiencing thrombosis as a major manifestation of myelofibrosis. PMID- 26648194 TI - Intravascular large B cell lymphoma with haemophagocytic syndrome: a double lethal masquerade. PMID- 26648195 TI - Cannabis, serotonergic drug use and stroke in a 50-year-old woman. PMID- 26648196 TI - Spontaneous bilateral quadriceps tendon rupture associated with norfloxacin. PMID- 26648197 TI - Genuine open-mindedness. PMID- 26648198 TI - Author reply: To PMID 26134692. PMID- 26648200 TI - Corrigendum. PMID- 26648199 TI - The silent canine--a clarification. PMID- 26648201 TI - Communication skills training enhances nurses' ability to respond with empathy to parents' emotions in a neonatal intensive care unit. AB - AIM: We quantitatively analysed the effect of a course in communication on the content of nurse-parent encounters and the ability of nurses to respond to the empathic needs of parents in a level III neonatal intensive care unit. METHODS: We evaluated 36 and 45 nurse-parent encounters audio recorded before and after 13 neonatal nurses attended a communication course. The number of empathic opportunities, the nurses' responses to these and the ways they involved parents in their infants' care were studied. RESULTS: Both before and after the course, the nurses talked more than the parents during the conversations. This nurse centredness decreased after the course. The use of empathic or exploring responses to empathic opportunities increased from 19.9 +/- 9.0% to 53.8 +/- 8.9% (p = 0.027), whereas ignoring the feelings of the parents or giving inadequate advice decreased from 63.0 +/- 10.0% to 27.5 +/- 8.4% (p = 0.043) after the course. Use of statements expressing caring for the parents and encouragement for parents to participate in the care of their infant increased after the course (p = 0.0034 and p = 0.043, respectively). The nurses felt the course was very useful for their profession. CONCLUSION: A course in communication techniques improved nurses' ability to respond to parents' feelings with empathy. PMID- 26648202 TI - Carbon castles and insect invaders: dissecting physical defences in conifer stems. PMID- 26648203 TI - Functioning in children and adolescents with Down syndrome on a population level: scientific opportunities and community care. PMID- 26648204 TI - Dye-Sensitized and Localized Surface Plasmon Resonance Enhanced Visible-Light Photoelectrochemical Biosensors for Highly Sensitive Analysis of Protein Kinase Activity. AB - A novel visible-light photoelectrochemical (PEC) biosensor based on localized surface plasmon resonance (LSPR) enhancement and dye sensitization was fabricated for highly sensitive analysis of protein kinase activity with ultralow background. In this strategy, DNA conjugated gold nanoparticles (DNA@AuNPs) were assembled on the phosphorylated kemptide modified TiO2/ITO electrode through the chelation between Zr(4+) ions and phosphate groups, then followed by the intercalation of [Ru(bpy)3](2+) into DNA grooves. The adsorbed [Ru(bpy)3](2+) can harvest visible light to produce excited electrons that inject into the TiO2 conduction band to form photocurrent under visible light irradiation. In addition, the photocurrent efficiency was further improved by the LSPR of AuNPs under the irradiation of visible light. Moreover, because of the excellent conductivity and large surface area of AuNPs that facilitate electron-transfer and accommodate large number of [Ru(bpy)3](2+), the photocurrent was significantly amplified, affording an extremely sensitive PEC analysis of kinase activity with ultralow background signals. The detection limit of as-proposed PEC biosensor was 0.005 U mL(-1) (S/N = 3). The biosensor also showed excellent performances for quantitative kinase inhibitor screening and PKA activities detection in MCF-7 cell lysates under forskolin and ellagic acid stimulation. The developed dye-sensitization and LSPR enhancement visible-light PEC biosensor shows great potential in protein kinases-related clinical diagnosis and drug discovery. PMID- 26648205 TI - The anti-obesity drug orlistat promotes sensitivity to TRAIL by two different pathways in hormone-refractory prostate cancer cells. AB - After the publication of the article, the authors noted that in Fig. 5c, the image of beta-actin is incorrect. The corrected version of Fig. 5c is shown below. In Fig. 6a, the histogarms are incorrect, and the corrected Fig. 6a is shown below. In Fig. 7, the figure of PrEC is incorrect, and the corrected Fig. 7 (PrEC) is shown below. The corrected figures demonstrate the same findings as the original figures. These corrections do not alter the interpretation of the results and conclusions. [the original article was published in the International Journal of Oncology 40: 1483-1491, 2012; DOI: 10.3892/ijo.2012.1353]. PMID- 26648206 TI - Long-term radiographic evaluation of risk factors related to implant treatment: suggestion for alternative statistical analysis of marginal bone loss. AB - OBJECTIVE: Secular change in marginal bone loss (MBL), which is the index adopted for implant success criteria, has often been used to evaluate risk factors. However, the need to revise these criteria has recently been indicated due to rapid developments in implant treatment. The purpose of this study was to evaluate risk factors by analyzing MBL with an alternative statistical method. MATERIAL AND METHODS: The analyses were performed on the outcomes of 366 patients with 1,902 implants during an average follow-up period of 84.8 months (with a maximum follow-up of 258 months). Instead of evaluating annual MBL, time was calculated as one of the explanatory variables because the correlation between MBL and time was small (correlation coefficient of 0.09010). Analysis of covariance (ANCOVA) was used for exploratory assessment of each factor, and multiple regression analysis was then utilized to identify risk factors. The multiple regression analysis was performed twice, once among all implants and another in which one implant per patient was randomly selected. RESULTS: As a result of multiple regression analysis, smoking habits showed a significant effect on MBL. Age, sex, diabetes mellitus, implant positions, guided bone regeneration, and sinus floor elevation did not affect MBL. IMZ(r) implants were associated with significantly higher MBL than were ANKYLOS(r) and SPI(r) implants. There was no significant difference between Straumann(r) and other implants. CONCLUSION: Our results showed that another statistical process, which eliminated the effect of time rather than comparing annual MBL, could be applied to evaluate MBL because the correlation between MBL and time was small. PMID- 26648207 TI - Haemorrhagic macules on the palms and soles. PMID- 26648208 TI - Editorial. PMID- 26648209 TI - LITERATURE REVIEW: A REVIEW WITH A FOCUS ON THE SYSTEMATIC REVIEWS. PMID- 26648210 TI - Teleaudiology: efficacy assessment of an online social network as a support tool for parents of children candidates for cochlear implant. AB - PURPOSE: To assess the efficacy of an online social network as a support for parents of children with hearing impairment. METHODS: Twenty-two mothers, randomly divided into experimental (n=11) and control (n=11) groups, filled in an online form containing the Parental Stress Index - Short Form (PSI-SF). Only the experimental group had access to the "Babies' Portal" social network. Both groups filled in the online form once again 3 months after the first assessment, for evaluating the use and participation in the social network. The posts on the social network were rated by two independent raters regarding themes and mechanisms of self-help. RESULTS: No difference was observed in mean PSI-SF scores between the groups for both assessments. Intragroup analysis showed no difference for total and subscale results of PSI-SF between the two data collected for both groups except for the "Defensive Response" subscale, in which a decrease was observed in the score for the control group. The most frequent posting themes were related to personal information and expressions of religious beliefs. Regarding self-help mechanisms, a higher frequency of exchanging experiences and gratitude expressions was observed. Participants in the experimental group stated they would have liked to participate more frequently in the social network as they considered this tool important because of the exchange of information and experience with other mothers and hearing health-care professionals. CONCLUSION: The posts and the assessment of participants indicated the potential of this network to support parents of children with hearing impairment. PMID- 26648211 TI - Figure-background in dichotic task and their relation to skills untrained. AB - PURPOSES: To evaluate the effectiveness of auditory training in dichotic task and to compare the responses of trained skills with the responses of untrained skills, after 4-8 weeks. METHODS: Nineteen subjects, aged 12-15 years, underwent an auditory training based on dichotic interaural intensity difference (DIID), organized in eight sessions, each lasting 50 min. The assessment of auditory processing was conducted in three stages: before the intervention, after the intervention, and in the middle and at the end of the training. Data from this evaluation were analyzed as per group of disorder, according to the changes in the auditory processes evaluated: selective attention and temporal processing. Each of them was named selective attention group (SAG) and temporal processing group (TPG), and, for both the processes, selective attention and temporal processing group (SATPG). RESULTS: The training improved both the trained and untrained closing skill, normalizing all individuals. Untrained solving and temporal ordering skills did not reach normality for SATPG and TPG. CONCLUSIONS: Individuals reached normality for the trained figure-ground skill and for the untrained closing skill. The untrained solving and temporal ordering skills improved in some individuals but failed to reach normality. PMID- 26648212 TI - Interaction between diabetes mellitus and hypertension on hearing of elderly. AB - INTRODUCTION: Chronic diseases and metabolic changes may act as accelerating factor in the degeneration of the auditory system due to age. However, studies involving an association between hearing loss and diabetes mellitus (DM) and hypertension (HA) in the elderly have shown controversial conclusions. Thus, further studies on this topic are needed in order to elucidate the effect of these chronic diseases on the auditory system. AIM: To compare the hearing thresholds of elderly patients with DM, HA and DM + HA with a control group (CG). METHODS: Retrospective study was conducted through survey charts of 80 elderly people with full hearing assessment, between 2008 and 2012. Subjects were divided into four groups: DM, HA, DM + HA and without chronic diseases known (CG). The ANOVA, Tukey and Mauchly tests, with a significance level of 0.05, were used. RESULTS: There was no statistically significant difference between the ears, which are grouped. Comparisons between the means of hearing thresholds of CG and DM or HA showed no statistically significant differences. However, a statistically significant difference in the comparison between these three groups and DM + HA group for several of the frequencies evaluated was observed. CONCLUSION: It was found that older adults with DM and hypertension associated showed greater hearing impairment in comparison with the other groups, suggesting a synergistic effect of the two chronic diseases on hearing. PMID- 26648213 TI - Influence of the educational status on the Dichotic Sentence Identification test in Brazilian Portuguese. AB - PURPOSE: To compare the performance of the Dichotic Sentence Identification (DSI) test in the Brazilian Portuguese version, considering: the right and left ears and the educational status in normal-hearing individuals. METHODS: This investigation assessed 200 individuals who are normal listeners and right-handed and were divided into seven groups according to the years of schooling. All the participants underwent basic audiologic evaluation and behavioral auditory processing assessment (sound localization test, memory test for verbal and nonverbal sounds in sequence, dichotic digits test, and DSI). RESULTS: The evaluated individuals revealed an average educational status of 13.1 years and results within normal limits in the selected tests for the audiologic and auditory processing assessments. Regarding the DSI test, the educational status showed a dependent relationship with the percentages of correct answers in each stage of the test and the evaluated ear. There was a statistically significant positive correlation between the educational status and the percentage of correct answers for all the stages of the DSI test in both the ears. There was also an effect of the educational level on the results obtained in each condition of the DSI test, with the exception of directed attention to the right ear. CONCLUSIONS: Comparing the performance considering the variables studied in the DSI test, we concluded that there is an advantage of the right ear and that, the better the educational level, the better the performance of the individuals. PMID- 26648214 TI - Qualitative and quantitative ultrasound analysis of oropharyngeal swallowing. AB - Purpose To analyze the effect of the age group and food's consistency according to the qualitative and quantitative ultrasonographic parameters in the oropharyngeal swallowing. METHODS: Ultrasonographic evaluations of swallowing were performed in 100 health individuals (divided into four groups, whose age brackets were 20-60 years), using liquid and mashed consistencies. For qualitative analysis, five steps were taken into account during the oropharyngeal swallowing. The following parameters were regarded in the quantitative analysis: duration of the tongue propulsion and maximum displacement of the hyoid bone during swallowing. RESULTS: In the qualitative ultrasonographic analysis, all the participants, independent to age groups, presented the same pattern of the tongue position (1, 2, and 5 phases), whereas in phase 3 there was a great variability within participants of the wavelike movement of the tongue. In phase 4, the displacement of the hyoid bone increased as a consequence of the consistency of the food. In the quantitative ultrasonographic analysis, a significant effect regarding age (p=0.03), consistence (p=0.00), as well as the age*consistency interaction was observed (p=0.03). Overall, the group of individuals between 20 and 30 years (G1) differed from the other groups and pudding consistency increased the measure of duration and displacement. CONCLUSION: The ultrasonography of the movement of the tongue proved itself as a viable instrument to describe the oropharyngeal swallowing. Parameters such as age and food consistency modify the USG images of movement of the tongue in normal subjects should be considered in ultrasound examination of oropharyngeal swallowing. PMID- 26648215 TI - Vocabulary and verbal comprehension of students with Attention Deficit Hyperactivity Disorder. AB - PURPOSE: To compare the receptive vocabulary and the verbal comprehension of schoolchildren with and without Attention Deficit Hyperactivity Disorder (ADHD), as well as to confront their performance with the normative scores from applied tests. METHODS: 40 students, with and without ADHD, were submitted to two receptive language tests, TVfusp and Token Test. Descriptive analysis was made, obtaining the average, median, minimum and maximum values. For the comparative assessment between groups, the t Student test was employed. For the comparison of performance scores obtained by the schoolchildren with the normative values from the tests applied, the Mann-Whitney test (p<0.05) was employed. RESULTS: On all measures assessed, the performance of the children with ADHD was inferior to those without the disorder, which occurred both on TVfusp and Token Test. The comparison between groups showed considerable differences, with 50% and 5% of the ADHD schoolchildren presenting average scores, respectively, on TVfusp and Token Test, in comparison to the normative values of the tests. CONCLUSION: Schoolchildren with ADHD presented more restricted vocabulary and more limited verbal comprehension when compared to their pairs without the disorder. The comparison of the performance obtained by groups with the normative values of the TVfusp and Token Test demonstrates that a portion of the children with ADHD presented performance within the average of the applied tests. This study calls attention to the importance of the language evaluation in children with suspicion of ADHD, going beyond evaluating the presence or absence of nuclear symptoms and their relations with the low academic performance. PMID- 26648216 TI - Depressive signs and cognitive performance in patients with a right hemisphere stroke. AB - PURPOSE: This study investigated the influence of suggestive signs of depression (SSD) in right-hemisphere brain-damaged (RHD) patients following a stroke on their cognitive performance measured by a brief neuropsychological assessment battery. METHODS: Forty-two adults with RHD after a single episode of stroke and 84 matched controls participated in this study. They were assessed by means of the Geriatric Depression Scale and by Brief Neuropsychological Assessment Battery NEUPSILIN. RESULTS: Almost half of the patients showed SSD. The RHD group with SSD (RHD+) showed poorer performance in at least one task among all evaluated cognitive domains (concentrated attention, visual perception, working memory, episodic verbal memory and semantic memory, auditory and written language, constructional praxia and verbal fluency). CONCLUSION: The association of depression and RHD seems to enhance the occurrence and the severity of cognitive deficits. A brief neuropsychological assessment can be useful to identify cognitive impairment caused by this neuropsychiatric disorder. PMID- 26648217 TI - Phonological short-term memory and phonological awareness in students from the Elementary School. AB - OBJECTIVES: To characterize and compare the performance of students at the beginning and at the end of the elementary school in Short-Term Phonological Memory (STPM) and Phonological Awareness (PA). METHODS: We assessed 80 students of both the genders who showed adequate linguistic and academic performance. The sample comprised 40 students in 1st grade and 40 in 5th grade from a public state school with mean age of 6.2 and 9.8 years, respectively. The STPM was assessed using a standardized test of Pseudoword Repetition. PA was assessed through a Sequential Assessment Test (CONFIAS). RESULTS: No difference was found between the students of 1st and 5th years in STPM both in total score and concerning the similarity of the pseudowords. Regarding PA, there was a significant difference among the percentage distribution of correct answers in syllabic and phonemic tasks, and the students from 5th grade presented better performance. CONCLUSION: At the beginning and at the end of the elementary school, there is no difference in STPM performance. On the other hand, there is difference in PA, which highlights the influence of schooling on PA development. The correlation between STPM and PA only in 5th-year students suggests that, at the beginning of literacy, STPM cannot be considered as a predictor to children's performance in PA. Nevertheless, as the schooling advances, there is influence of PA on STPM. PMID- 26648218 TI - Comparative analysis of velopharyngeal activity assessed by acoustic rhinometry and rhinomanometry. AB - PURPOSE: To analyze the velopharyngeal (VP) activity of subjects with velopharyngeal dysfunction (VPD) by acoustic rhinometry, as compared to rhinomanometry. METHODS: This was a prospective clinical study conducted in 41 adults, both genders, with repaired cleft palate, with or without a previously repaired cleft lip, and residual VPD on clinical assessment, without compensatory articulations for [p], [t], and [k]. The outcome measures were as follows: (1) on acoustic rhinometry, nasopharyngeal volumetric change (DeltaV) during [p], [t], and [k], relatively to rest condition (decreases by <3 cm3 considered as absence of VP activity); (2) on modified anterior rhinomanometry, VP orifice area (areas >=0.05 cm2 considered as inadequate closure). The plosive [p] was used when comparing the techniques (n=24). RESULTS: (1) A mean DeltaV decrease of 18% was observed during [k], which was significantly lower (p<0.05) than the decrease reported for individuals without VPD (30%). DeltaV values suggesting VPD were observed in 59% subjects. Similar results were obtained for [p] and [t], which shall be used as stimulus, given that they do not involve the use of the tongue to lift the velum during VP closure, differently from the velar plosive [k]. (2) Inadequate closure was seen in 85% subjects. No correlation was observed between ?V and VP orifice area. Agreement between techniques was observed in 51% cases. CONCLUSION: Acoustic rhinometry had low accuracy as a diagnostic method of VPD when compared to the gold standard method. Nevertheless, the technique shows potential as a method for monitoring the outcomes of clinical and surgical treatment of VPD aimed at increasing velar and pharyngeal activity. PMID- 26648219 TI - Study of the correlation between the linear measurements of the skull and face and palatal wide and length measures. AB - OBJECTIVE: To analyze the relation between the anthropometric linear measurements of the skull and face and the measurements of width and length of the hard palate. METHODS: Twenty-three human skulls were used, and the measurements were collected with the help of a caliper and pelvimeter. The following linear measurements were studied: maximum cranial length, biporion distance, maximum face width, nasal height, palatal length, and palatal width. RESULTS: After a complete descriptive assessment of the variables, we observed homogeneity in the measurements of the skull, face, and palate. There were correlations, with higher significance, between the palatal length and width and the maximum face width and the biporion distance, respectively. The biporion distance was the only measurement that was significant in the explanation, generating formulas to obtain the palatal length and width. CONCLUSION: It is possible to estimate the palatal length and the palatal width using the two models (formulas) through the measurements of the biporion distance. Because in the literature, there is no consensus, there is a need for standardization when obtaining the linear measurements of the palate. PMID- 26648220 TI - Analysis of tongue pressure in Brazilian young adults. AB - PURPOSE: To present the measures for tongue pressure in Brazilian young adults, considering specific tasks, and to verify the differences regarding gender and according to the tasks. METHODS: Fifty-one volunteers aged 18 to 28 years, of both genders with normal occlusion and without speech disorders were evaluated. We used the Iowa Oral Performance Instrument in the evaluation of tongue pressure (kilopascal) during specific tests of elevation, protrusion, swallowing, and lateralization, in addition to the endurance test (seconds). The analysis was conducted using analysis of variance, followed by the Tukey's multiple comparison test, adopting a 5% significance level. RESULTS: The values obtained for men and women in the tests were as follows: elevation, 63.94+/-12.92 and 50.27+/-15.29; protrusion, 60.22+/-13.62 and 44.30+/-12.95; swallowing, 33.94+/-12.06 and 34.27+/-13.25; lateralization on the right, 44.15+/-10.47 and 31.85+/-8.46; lateralization on the left, 43.15+/-10.22 and 29.55+/-8.91; and endurance test: 24.85+/-10.95 and 17.35+/-6.71, respectively. The values were higher in men compared with women for the protrusion and lateralization tasks. The measures of the protrusion and elevation tasks did not differ for men but were higher in both genders than those of the lateralization and the swallowing tests. There was no difference in lateralization according to side in both the genders. CONCLUSION: The measures for the tongue pressure in Brazilian young adults were determined by specific tasks. Gender influenced the pressure of the tongue values for the protrusion and lateralization tasks. Elevation and protrusion tasks measures were higher than those of the lateralization and swallowing tasks. PMID- 26648221 TI - A comparison of vocal parameters in adult bilingual Hebrew-English speakers. AB - PURPOSE: There has been growing research on the effects of language on voice characteristics; however, few studies have examined the impact of language on vocal features within bilinguals. This study aimed to compare vocal parameters among bilingual Hebrew/English speaking individuals when speaking in Hebrew versus English. METHODS: Forty bilingual participants (17 males and 23 females) between the ages of 23-60 years were asked to spontaneously speak about a neutral topic. Voice samples were digitalized into a tablet for perceptual and acoustic analyses of selected parameters. RESULTS: Results show that there are changes in resonance, glottal attack, fundamental frequency variation and speech rate when adult bilingual speakers talk in Hebrew as compared to English. CONCLUSION: These findings provide evidence that language plays a role in affecting vocal characteristics of bilingual individuals when they speak different languages. PMID- 26648222 TI - World Voice Day in news: analysis of reports on the Voice Campaign in Brazil. AB - PURPOSE: To analyze the television reports on the World Voice Day transmitted by Globo(r) TV. METHOD: We researched television reports broadcasted by Globo(r) Network in regional television news programs from March 15 to April 20, 2013. For the data analysis, the Document Analysis technique was used. The analyzed variables were the following: location, broadcasting period, duration, interviewed professional, mention of multiprofessional work, orientation to the population, and the interview approach (health promotion or disease prevention). Through statistical analysis, the interview approach was considered the outcome and associated with the other variables. RESULTS: On the regions where there are news programs for the researched TV station, the majority made reports about the Voice Campaign. Among these, we discovered that the five regions of Brazil were contemplated, in the morning/afternoon periods, with medium duration of 5.3 minutes. The presence of the speech-language pathologist was observed in greater numbers of the interviews, as also the emphasis on the importance of a multiprofessional work. Regarding the content presented, the interviewees focused on diseases caused by habits that impair the voice, with orientation to the public about what negatively interferes in the vocal well-being. CONCLUSION: The approach of the interviews was not, in the majority of times, of the same nature (promoting the vocal well-being or preventing voice disorder), and the interprofessional practice is still seen less frequently as a possible work strategy. PMID- 26648223 TI - Speech language therapy bilingual clinic, a written language therapeutical proposal to deaf people: case report. AB - PURPOSE: This study aimed to analyze the written production of a deaf person who is in the process of written language acquisition. METHODS: One person with hearing disability, called R., participated in this study together with his Speech Language Pathologist. The therapist, proficient in sign language, acted as an interlocutor and interpreter, prioritizing the interactive nature of language and interfering in the written production only when it was requested. RESULTS: During the 3 years of work with R., a change in stance toward written language was observed. In addition, he began to reflect on his texts and utilize written Portuguese in a way that allowed his texts to be more coherent. Writing became an opportunity to show his singularity and to begin reconstructing his relationship with language. CONCLUSION: Speech language pathology and audiology therapy, at a bilingual clinic, can allow people with hearing disability early access to sign language and, consequently, enable the development of the written form of Portuguese. PMID- 26648224 TI - A warning to the Brazilian Speech-Language Pathology and Audiology community about the importance of scientific and clinical activities in primary progressive aphasia. AB - This article aims to warn the Brazilian Speech-Language Pathology and Audiology scientific community about the importance and necessity of scientific and clinical activities regarding Primary Progressive Aphasia. This warning is based on a systematic literature review of the scientific production on Primary Progressive Aphasia, from which nine Brazilian articles were selected. It was observed that there is an obvious lack of studies on the subject, as all the retrieved articles were published in medical journals and much of it consisted of small samples; only two articles described the effectiveness of speech-language therapy in patients with Primary Progressive Aphasia. A perspective for the future in the area and characteristics of Speech-Language Therapy for Primary Progressive Aphasia are discussed. As a conclusion, it is evident the need for greater action by Speech-Language Pathology and Audiology on Primary Progressive Aphasia. PMID- 26648225 TI - Suicide Studies Today. Where Do We Come From? Who Are We? Where Are We Going? PMID- 26648226 TI - Association Between Changes in Risk Factor Status and Suicidal Ideation Incidence and Recovery. AB - BACKGROUND: Little is known about risk factors associated with the incidence of and recovery from suicidal ideation. AIMS: To examine the association between potential risk factors and their change in status over the follow-up period and the incidence of and recovery from suicidal ideation. METHOD: A 12-month follow up survey was conducted among 997 adults aged between 20 and 59 years living in Hong Kong. RESULTS: The incidence rates of suicidal ideation increased in individuals who were divorced, separated, or widowed, in low economic status, had a history of psychiatric treatment, and experienced bereavement at baseline. Experiencing three or more life events and persistent unemployment over the follow-up period was associated with increased incidence of suicidal ideation. Increased levels of depression, anxiety, hopelessness, and irrational beliefs were associated with suicidal ideation incidence in men but not in women (p = .009-.067 for interactions). Among individuals who had suicidal ideation at baseline, those who had increased severity of depression, anxiety, and hopelessness over the follow-up period were less likely to recover from suicidal ideation. CONCLUSION: Life events and persistent unemployment were associated with increased risk of suicidal ideation. Gender differences were detected in the association between changes in the status of psychological factors and the occurrence of suicidal ideation. PMID- 26648227 TI - Predicting Intentions to Read Suicide Awareness Stories. The Role of Depression and Characteristics of the Suicidal Role Model. AB - BACKGROUND: Research on factors that influence the intention to read suicide awareness material is lacking. AIMS: To identify how social and state similarities between the featured protagonist of a suicide awareness story and the audience impact on the intent to read similar stories. METHOD: Laboratory experiment with n = 104 students. Participants were randomly assigned to study groups. In the first group, the role model provided his personal story of crisis and was a student. In the second group, the content was identical but the model was socially dissimilar. The third group read about a topic unrelated to suicide. Depression, identification, and exposure intent were measured after the experiment. Conditional process analysis was carried out. RESULTS: In the group featuring a once-suicidal role model with high social similarity, depression in the audience increased the intention to read similar material in the future via identification with the role model; 82% of individuals wanted to read similar material in the future, but only 50% wanted to do so in the group featuring a dissimilar person. CONCLUSION: Exposure intention increases via identification when role model and audience characteristics align regarding social traits and the experience of depression. These factors are relevant when developing campaigns targeting individuals with stories of recovery. PMID- 26648228 TI - Development and Evaluation of the Telephone Crisis Support Skills Scale. AB - BACKGROUND: Although telephone services continue to play an important role in the delivery of front-line crisis support, published evidence of the standardized assessment of such services does not exist to date. AIMS: To describe the development of the Telephone Crisis Support Skills Scale (TCSSS), an instrument to assess workers' intentions to use recommended skills with callers, and to evaluate its factor structure and reliability. METHOD: TCSSS items were mapped to a national telephone crisis support practice model. A national sample of workers (n = 210) completed the TCSSS as part of a larger online survey. Principal axis factoring was used to evaluate the structure of the instrument. Internal consistency was assessed by Cronbach's alpha values. RESULTS: A single factor accounted for more than 40% of the variance within TCSSS ratings, indicating unidimensional structure. Cronbach's alpha coefficients suggested adequate internal consistency. CONCLUSION: Results indicate that the TCSSS is an internally consistent, unidimensional scale, sufficiently sensitive to detect workers' skill priorities for different caller problem types. Further study is required to confirm the factor structure and reliability of the TCSSS using workers from different organizations. Following further evaluation, the TCSSS may be applied to assessing readiness for and quality of service delivery. PMID- 26648229 TI - Suicide Risk Among College Student. The Intersection of Sexual Orientation and Race. AB - BACKGROUND: Research on young adults in the general population has identified a relationship between sexual minority identification and risk for suicide. Differential rates of suicidal ideation and attempts have also been found across racial and ethnic groups. AIMS: This study examined risk for suicide among university students, based on membership in one or more marginalized groups (sexual minority and racial minority identification). METHOD: Data were collected from first-year college students (N = 4,345) at an urban university. Structural equation modeling was employed to model a suicidality construct, based on which a "risk for suicide" category system was derived. Chi-square and logistic regression analyses were then conducted to estimate the relationship between the background variables of interest and suicide risk. RESULTS: Students who identified as lesbian, gay, or bisexual (LGB) were associated with higher suicide risk than their heterosexual peers. Students of color were slightly less at risk than their heterosexual peers. However, LGB students of color were associated with elevated suicide risk relative to heterosexual peers. CONCLUSION: Results indicate that belonging to multiple marginalized groups may increase one's risk for suicide, though these effects are not simply additive. Findings highlight the complexity of the intersection between marginalized identities and suicidality. PMID- 26648230 TI - Suicidal Ideation of Probationers. Gender Differences. AB - BACKGROUND: Gender is often related to different life stressors and mental health disorders, but a limited amount of research examines risks of suicidal ideation of probationers by gender. AIMS: The aim of this study was to examine gender differences in suicidal ideation of probationers. METHOD: Using a national sample of 3,014 male and 1,306 female probationers with data from the National Survey on Drug Use and Health (2009-2011), multivariate regression analysis was conducted. RESULTS: Male and female probationers display similar demographic characteristics although their life circumstances and experiences seem different. Female probationers in the study were more likely to experience financial, psychological, and residential stressors than male probationers were. Female probationers were also more likely to have received medical and/or psychiatric treatments. Female probationers were exposed to more suicidal ideation risks than male probationers were. Additionally, no protective factors to suicidal ideation were found for female probationers. CONCLUSION: The findings suggest that a gender-specific approach to suicidal ideation of probationers may lessen the prevalence of suicidal ideation of this largely neglected population. PMID- 26648231 TI - Assessing Variability and Implementation Fidelity of Suicide Prevention Safety Planning in a Regional VA Healthcare System. AB - BACKGROUND: In 2008, the Veterans Health Administration (VHA) implemented the use of safety planning for suicide prevention. A safety plan is a list of strategies, developed collaboratively with a provider, for a patient to use when suicide risk is elevated. Despite the use of safety plans in VHA, little is known about implementation fidelity, the extent to which safety plans are delivered as intended, or patient-level outcomes of safety planning. AIMS: This study aimed to explore the implementation fidelity of safety planning in a regional VHA hospital and examine the associations between safety plan quality and completeness with patient outcomes. METHOD: A comprehensive chart review was conducted for patients who were flagged as high risk for suicide (N = 200). Completeness and quality were coded, as well as information about patient and provider interactions regarding safety plan use. RESULTS: Safety plans were mostly complete and of moderate quality, although variability existed, particularly in quality. Limited evidence of follow-up regarding safety planning was found in the medical charts. Higher quality was associated with fewer subsequent psychiatric hospitalizations. CONCLUSION: Variability in implementation fidelity and infrequent follow-up suggest a need for additional training and support regarding the use of safety plans for suicide prevention. PMID- 26648232 TI - Suicide-Related Concerns as a Mediator Between Physical Abuse and Self-Harm Behaviors in College Students. AB - BACKGROUND: Multiple studies have found correlations between history of abuse and self-harm behaviors, but few have examined potential mediators. Studying suicide related concerns as a mediator in this relationship could inform the interpersonal theory of suicide by identifying acquired capability as a necessary component in self-harm behavior. AIMS: This study examined the link between childhood physical abuse, self-injurious behaviors, and suicide-related concerns in young adults. It was hypothesized that more physical abuse and fewer suicide related concerns would predict self-harm behaviors, and that suicide-related concerns would mediate this relationship. METHOD: A sample of 212 university students completed self-report measures that assessed self-harm behavior history, reasons for living, and childhood physical abuse. RESULTS: Results supported the hypothesis that more instances of abuse and less concern about pain and death were significantly associated with greater self-harm history. Suicide-related concerns also mediated the relationship between physical abuse and self-harm behaviors. CONCLUSION: These results support recent theories that habituation to painful and provocative events is an important mechanism in explaining why people engage in self-injurious acts, and provides initial evidence for cognitive mediators between physical abuse and self-harm. PMID- 26648233 TI - Suicidal Behaviors Among Muslim Women. Patterns, Pathways, Meanings, and Prevention. AB - BACKGROUND: The literature on Muslim women's suicidality has been growing. Comprehensive reviews are, however, unavailable, and theory needs development. AIMS: This article reviews and integrates theories and findings about Muslim women's suicidality. METHOD: Two databases (PsycINFO and Web of Science) were searched for publications about Muslim women's suicidality. RESULTS: There is significant variability in Muslim women's patterns of suicidality across Muslim majority communities and countries. Muslim women represent half to nearly all cases of nonfatal suicidal behavior. According to the official records of Muslim majority countries, women's suicide mortality is lower than that of men. Community studies, however, show that in some areas, Muslim women have significantly higher suicide rates than Muslim men. Both nonfatal and fatal suicidal behaviors are most common among uneducated and poor rural young women. Muslim women's typical suicide methods vary by locale, and include self-burning, hanging, and poisoning. With regard to contexts and meanings, a recurring female script is that of suicidality as protest against and desperate escape from the oppressive regulation as well as the abuse many women endure within their families and societies. CONCLUSION: Understanding and preventing Muslim women's suicidality, and the socially sanctioned oppression it is often a response to, require system-level - not just individual-level - analyses and interventions as well as a human rights perspective. PMID- 26648234 TI - Not at Imminent Risk. A Systematic Literature Review. AB - BACKGROUND: Suicide is a pervasive and complex issue that can challenge counselors through the course of their careers. Research and practice focus heavily on crisis management and imminent risk rather than early intervention strategies. Early intervention strategies can assist counselors working with clients who have suicidal ideation, but are not at imminent risk, or with clients whose risk factors identify them as having a stronger trajectory for suicidal ideation. AIMS: This systematic literature review examines the current literature on working with clients with suicidal ideation who are not at imminent risk, to ascertain the types of information and strategies available to counselors working with this client group. METHOD: An initial 622 articles were identified for analysis and from these 24 were included in the final review, which was synthesized using a narrative approach. RESULTS: Results indicate that research into early intervention strategies is extremely limited. CONCLUSION: It was possible to describe emergent themes and practice guidelines to assist counselors working with clients with suicidal ideation but not at imminent risk. PMID- 26648236 TI - Confounding by drug formulary restriction in pharmacoepidemiologic research. AB - PURPOSE: The potential consequences of confounding due to drug formulary restrictions in pharmacoepidemiologic research remain incompletely understood. Our objective was to illustrate this potential bias using the example of fluticasone/salmeterol combination therapy, an oral inhaler used to treat asthma and chronic obstructive pulmonary disease, whose use is restricted in the province of Quebec, Canada. METHODS: We identified all new users of fluticasone/salmeterol in Quebec's administrative databases and classified those who received their initial dispensing of fluticasone/salmeterol between 1 September 1999 and 30 September 2003 as users from the liberal period and those who received it between 1 January 2004 and 31 October 2006 as users from the restricted period. The primary outcome was time to first hospitalization for respiratory causes within 12 months of cohort entry. RESULTS: Our cohort included 72 154 new users from the liberal period and 5058 from the restricted period. Compared with use during the liberal period, use during the restricted period was associated with an increased rate of hospitalization for respiratory causes (crude hazard ratio [HR] = 1.41, 95% confidence interval [CI] = 1.32, 1.51). Subsequent adjustment for age, sex, and hospitalization for respiratory causes in the previous year attenuated the association (HR = 1.05, 95%CI = 0.98, 1.12). Further adjustment for other potential confounders resulted in a lower rate during the restricted period (HR = 0.78, 95%CI = 0.73, 0.83). CONCLUSIONS: Formulary restrictions can result in substantial and unexpected confounding and should be considered during the design and analysis of pharmacoepidemiologic studies. PMID- 26648237 TI - Field monitoring of sprinting power-force-velocity profile before, during and after hamstring injury: two case reports. AB - Very little is currently known about the effects of acute hamstring injury on over-ground sprinting mechanics. The aim of this research was to describe changes in power-force-velocity properties of sprinting in two injury case studies related to hamstring strain management: Case 1: during a repeated sprint task (10 sprints of 40 m) when an injury occurred (5th sprint) in a professional rugby player; and Case 2: prior to (8 days) and after (33 days) an acute hamstring injury in a professional soccer player. A sports radar system was used to measure instantaneous velocity-time data, from which individual mechanical profiles were derived using a recently validated method based on a macroscopic biomechanical model. Variables of interest included: maximum theoretical velocity (V0) and horizontal force (F(H0)), slope of the force-velocity (F-v) relationship, maximal power, and split times over 5 and 20 m. For Case 1, during the injury sprint (sprint 5), there was a clear change in the F-v profile with a 14% greater value of F(H0) (7.6-8.7 N/kg) and a 6% decrease in V0 (10.1 to 9.5 m/s). For Case 2, at return to sport, the F-v profile clearly changed with a 20.5% lower value of F(H0) (8.3 vs. 6.6 N/kg) and no change in V0. The results suggest that the capability to produce horizontal force at low speed (F(H0)) (i.e. first metres of the acceleration phase) is altered both before and after return to sport from a hamstring injury in these two elite athletes with little or no change of maximal velocity capabilities (V0), as evidenced in on-field conditions. Practitioners should consider regularly monitoring horizontal force production during sprint running both from a performance and injury prevention perspective. PMID- 26648238 TI - Contraceptive counseling for adolescents. AB - The majority of adolescents become sexually active during their teenage years, making contraceptive counseling an important aspect of routine adolescent healthcare. However, many healthcare providers express discomfort when it comes to counseling adolescents about contraceptive options. This Special Report highlights the evidence supporting age-appropriate contraceptive counseling for adolescents and focuses on best practices for addressing adolescents' questions and concerns about contraceptive methods. PMID- 26648239 TI - A crucial epithelial to mesenchymal transition regulator, Sox4/Ezh2 axis is closely related to the clinical outcome in pancreatic cancer patients. AB - Pancreatic cancer has a poor prognosis because of its high invasiveness and recurrence, and these properties closely link to the phenomenon of epithelial mesenchymal transition (EMT). Recently, it has been reported that Sox4 is indispensable for EMT in vitro and in vivo and regulates various master regulators of EMT including Zeb, Twist and Snail. Moreover, Sox4 induces the transcription of Ezh2 which is the histone methyltransferase, and reprograms the cancer epigenome to promote EMT and metastasis. Therefore, the present study evaluated the importance of Sox4, Ezh2 and miR-335, which regulate Sox4 expression epigenetically, in clinical samples with pancreatic cancer. This retrospective analysis included data from 36 consecutive patients who underwent complete surgical resection for pancreatic cancer and did not undergo any preoperative therapies. We assessed the clinical significance of Sox4/Ezh2 axis and miR-335 expression, using immunohistochemistry and qRT-PCR with laser captured microdissection (LCM). The Sox4 positive patients had significantly worse prognosis as for disease-free survival (DFS) (P=0.0154) and the Ezh2 positive patients had significantly worse prognosis as for overall survival (OS) (P=0.0347). The miR-335 expression was inversely correlated with Sox4 expression in the identical clinical specimens, but it was not related to the prognosis. Sox4/Ezh2 axis was closely associated with the prognosis in pancreatic cancer patients. PMID- 26648243 TI - Metal-Metal Interactions in Trinuclear Copper(II) Complexes [Cu3(RCOO)4(H2TEA)2] and Binuclear [Cu2(RCOO)2(H2TEA)2]. Syntheses and Combined Structural, Magnetic, High-Field Electron Paramagnetic Resonance, and Theoretical Studies. AB - The trinuclear [Cu3(RCOO)4(H2TEA)2] copper(II) complexes, where RCOO(-) = 2 furoate (1), 2-methoxybenzoate (2), and 3-methoxybenzoate (3, 4), as well as dimeric species [Cu2(H2TEA)2(RCOO)2].2H2O, have been prepared by adding triethanolamine (H3TEA) at ambient conditions to hydrated Cu(RCOO)2 salts. The newly synthesized complexes have been characterized by elemental analyses, spectroscopic techniques (IR and UV-visible), magnetic susceptibility, single crystal X-ray structure determination and theoretical calculations, using a Difference Dedicated Configuration Interaction approach for the evaluation of magnetic coupling constants. In 1 and 2, the central copper atom lies on an inversion center, while in the polymorphs 3 and 4, the three metal centers are crystallographically independent. The zero-field splitting parameters of the trimeric compounds, D and E, were derived from high-field, high-frequency electron paramagnetic resonance spectra at temperatures ranging from 3 to 290 K and were used for the interpretation of the magnetic data. It was found that the dominant interaction between the terminal and central Cu sites J12 is ferromagnetic in nature in all complexes, even though differences have been found between the symmetrical or quasi-symmetrical complexes 1-3 and non-symmetrical complex 4, while the interaction between the terminal centers, J23, is negligible. PMID- 26648244 TI - MicroRNA-106b functions as an oncogene in renal cell carcinoma by affecting cell proliferation, migration and apoptosis. AB - Kidney cancer is the 14th most common cancer in the world and its prognosis remains poor due to difficult early detection and treatment. Therefore, the identification of biomarkers for early-stage renal cell carcinoma (RCC) is important. MicroRNA-106b (miR-106b) has been described as an oncogene in several types of human cancer. Previous microarray studies have suggested that miR-106b was significantly upregulated in RCC tissues compared with paired normal kidney tissues and may be a promising biomarker for the prediction of early metastasis following nephrectomy. The present study aimed to determine the expression and function of miR-106b in RCC. The expression of miR-106b in RCC tissues and cells, and in paired normal tissues and cells was determined by reverse transcription quantitative polymerase chain reaction, based on the previous sequencing results of miRNAs. Furthermore, a wound scratch assay, MTT assay and flow cytometry were performed to examine the functions of miR-106b on cell migration, proliferation and apoptosis. The results demonstrated that miR-106b was upregulated in RCC tissues and cell lines compared with control normal tissues and cell lines. Downregulation of miR-106b with a synthesized inhibitor suppressed cell migration and proliferation and induced renal cancer cell apoptosis, suggesting that miR 106b can be characterized as an oncogene in RCC. To the best of our knowledge, the present study was the first to reveal that miR-106b is upregulated and affects cellular migration, proliferation and apoptosis in RCC. Further studies are required to examine the role and target genes of miR-106b in RCC. PMID- 26648245 TI - Postpartum pneumomediastinum and subcutaneous emphysema (Hamman's syndrome). PMID- 26648246 TI - Atomistic modelling of residual stress at UO2 surfaces. AB - Modelling oxide surface behaviour is of both technological and fundamental interest. In particular, in the case of the UO2 system, which is of major importance in the nuclear industry, it is essential to account for the link between microstructure and macroscopic mechanical properties. Indeed micromechanical models at the mesoscale need to be supplied by the energetic and stress data calculated at the nanoscale. In this framework, we present a theoretical study, coupling an analytical model and thermostatistical simulation to investigate the modifications induced by the presence of a surface regarding atomic relaxation and energetic and stress profiles. In particular, we show that the surface effective thickness as well as the stress profile, which are required by micromechanical approaches, are strongly anisotropic. PMID- 26648247 TI - Associations between metals in residential environmental media and exposure biomarkers over time in infants living near a mining-impacted site. AB - Infant exposures to metals are a concern for mining-impacted communities, although limited information is available to assess residential exposures over the first year of life. We measured lead (Pb), manganese, arsenic, and cadmium in indoor air, house dust, yard soil, and tap water from 53 infants' homes near the Tar Creek Superfund Site (Oklahoma, USA) at two time points representing developmental stages before and during initial ambulation (age 0-6 and 6-12 months). We measured infant metal biomarkers in: umbilical cord blood (n=53); 12- (n=43) and 24- (n=22) month blood; and hair at age 12 months (n=39). We evaluated cross-sectional and longitudinal associations between infant residential and biomarker concentrations. A doubling of mean dust Pb concentration was consistently associated with 36-49% higher 12-month blood Pb adjusting for cord blood Pb (P?0.05). Adjusted dust concentration explained 29-35% of blood Pb variance, and consistent associations with other media were not observed. Although concentrations in dust and blood were generally low, strong and consistent associations between dust and body burden suggest that house dust in mining-impacted communities may impact children's health. These relationships were observed at a young age, typically before blood Pb levels peak and when children's development may be particularly vulnerable to toxic insult. PMID- 26648248 TI - Spatio-temporal models to estimate daily concentrations of fine particulate matter in Montreal: Kriging with external drift and inverse distance-weighted approaches. AB - Air pollution is a major environmental and health problem, especially in urban agglomerations. Estimating personal exposure to fine particulate matter (PM2.5) remains a great challenge because it requires numerous point measurements to explain the daily spatial variation in pollutant levels. Furthermore, meteorological variables have considerable effects on the dispersion and distribution of pollutants, which also depends on spatio-temporal emission patterns. In this study we developed a hybrid interpolation technique that combined the inverse distance-weighted (IDW) method with Kriging with external drift (KED), and applied it to daily PM2.5 levels observed at 10 monitoring stations. This provided us with downscaled high-resolution maps of PM2.5 for the Island of Montreal. For the KED interpolation, we used spatio-temporal daily meteorological estimates and spatial covariates as land use and vegetation density. Different KED and IDW daily estimation models for the year 2010 were developed for each of the six synoptic weather classes. These clusters were developed using principal component analysis and unsupervised hierarchical classification. The results of the interpolation models were assessed with a leave-one-station-out cross-validation. The performance of the hybrid model was better than that of the KED or the IDW alone for all six synoptic weather classes (the daily estimate for R(2) was 0.66-0.93 and for root mean square error (RMSE) 2.54-1.89 MUg/m(3)). PMID- 26648249 TI - PMMA interlayer-modulated memory effects by space charge polarization in resistive switching based on CuSCN-nanopyramids/ZnO-nanorods p-n heterojunction. AB - Resistive switching (RS) devices are commonly believed as a promising candidate for next generation nonvolatile resistance random access memory. Here, polymethylmethacrylate (PMMA) interlayer was introduced at the heterointerface of p-CuSCN hollow nanopyramid arrays and n-ZnO nanorod arrays, resulting in a typical bipolar RS behavior. We propose the mechanism of nanostructure trap induced space charge polarization modulated by PMMA interlayer. At low reverse bias, PMMA insulator can block charges through the heterointerface, and V(-)Cu and V(+)o trapped states are respectively created on both sides of PMMA, resulting in a high resistance state (HRS) due to wider depletion region. At high reverse bias, however, electrons and holes can cross PMMA interlayer by Fowler Nordeim tunneling due to a massive tilt of energy band, and then inject into the traps of ZnO and CuSCN, respectively. V(+)Cu and V(-)O trapped states are created, resulting in the formation of degenerate semiconductors on both sides of PMMA. Therefore, quantum tunneling and space charge polarization lead to a low resistance state (LRS). At relatively high forward bias, subsequently, the trapped states of V(-)Cu and V(+)o are recreated due to the opposite injection of charges, resulting in a recovery of HRS. The introduction of insulating interlayer at heterointerface, point a way to develop next-generation nonvolatile memories. PMID- 26648250 TI - Costs associated with evaluation of incidental breast lesions identified on computed tomography. AB - OBJECTIVE: The purpose of this study was to calculate the costs associated with the evaluation of breast incidentalomas (BI) identified on CT. METHODS: All CT scans of the thorax performed at the radiological department of the University Hospital of the Martin-Luther-University Halle-Wittenberg between the years 2006 and 2014 were reanalysed retrospectively. 111 patients with BI were identified. The radiological and clinical reports of these cases were examined, and the costs of all further diagnostic procedures performed to clarify the detected BI were calculated. RESULTS: In 31 (27.9%) of the 111 patients, BI were not further investigated. Of the remaining 80 (72.1%) cases of BI, primary breast carcinoma was diagnosed in 10 (12.5%) cases, breast involvement by lymphoma in 7 (8.8%) cases, intramammary metastases in 19 (23.7%) cases and different benign findings in 44 (55.0%) cases. The total costs associated with clarification of BI in our institution (n = 53) amounted to ?14,045.71. The costs per BI were ?265.01 and per newly identified breast cancer ?1560.63. CONCLUSION: Breast lesions incidentally detected on CT should be categorized as major incidental findings because of the high frequency of malignancy. The radiologist should carefully evaluate the breast on CT images and all identified BI should be clarified. The clarification of BI is associated with a low economic burden in comparison with screening programmes for primary breast cancer. ADVANCES IN KNOWLEDGE: The radiologist should carefully evaluate the breast on CT and all identified BI should be clarified. The evaluation of BI is associated with a low economic burden. PMID- 26648251 TI - Surgery for Dupuytren's contracture of the fingers. AB - BACKGROUND: Dupuytren's disease is a benign fibroproliferative disorder that causes the fingers to be drawn into the palm via formation of new tissue under the glabrous skin of the hand. This disorder causes functional limitations, but it can be treated through a variety of surgical techniques. As a chronic condition, it tends to recur. OBJECTIVES: To assess the benefits and harms of different surgical procedures for treatment of Dupuytren's contracture of the index, middle, ring and little fingers. SEARCH METHODS: We initially searched the following databases on 17 September 2012, then re-searched them on 10 March 2014 and on 20 May 2015: the Cochrane Central Register of Controlled Trials (CENTRAL), The Cochrane Library, the British Nursing Index and Archive (BNI), the Cumulative Index to Nursing and Allied Health Literature (CINAHL), EMBASE, the Latin American Caribbean Health Sciences Literature (LILACS), Ovid MEDLINE, Ovid MEDLINE-In-Process and Other Non-Indexed Citations, ProQuest (ABI/INFORM Global and Dissertations & Theses), the Institute for Scientific Information (ISI) Web of Science and clinicaltrials.gov. We reviewed the reference lists of short listed articles to identify additional suitable studies. SELECTION CRITERIA: We included randomised clinical trials and controlled clinical trials in which groups received surgical intervention for Dupuytren's disease of the index, middle, ring or little finger versus control, or versus another intervention (surgical or otherwise). We excluded the thumb, as cords form on the radial aspect of the thumb and thus are not readily accessible in terms of angular deformity. Furthermore, thumb disease is rare. DATA COLLECTION AND ANALYSIS: A minimum of two review authors independently reviewed search results to select studies for inclusion by using pre-specified criteria, assessed risk of bias of included studies and extracted data from included studies.We grouped outcomes into the following categories: (1) hand function, (2) other patient-reported outcomes (e.g. satisfaction, pain), (3) early objective outcomes (e.g. correction of angular deformity), (4) late objective outcomes (e.g. recurrence) and (5) adverse effects. MAIN RESULTS: We included 14 articles describing 13 studies, comprising 11 single-centre studies and two multi-centre studies. These studies involved 944 hands of 940 participants; of these, 93 participants were reported twice in separate articles describing early and late outcomes of one trial. Three papers reported the outcomes of two trials comparing different procedures. One trial compared needle fasciotomy versus fasciectomy (125 hands, 121 participants), and the other compared interposition firebreak skin grafting versus z-plasty closure of fasciectomy (79 participants). The other 11 studies reported trials of technical refinements of procedures or rehabilitation adjuncts. Of these, three investigated effects of postoperative splinting on surgical outcomes.Ten studies (11 articles) were randomised controlled trials (RCTs) of varying methodological quality; one was a controlled clinical trial. Trial design was unclear in two studies awaiting classification. All trials had high or unclear risk of at least one type of bias. High risks of performance and detection bias were particularly common. We downgraded the quality of evidence (Grades of Recommendation, Assessment, Development and Evaluation - GRADE) of outcomes to low because of concerns about risk of bias and imprecision.Outcomes measured varied between studies. Five articles assessed recurrence; two defined this as reappearance of palpable disease and two as deterioration in angular deformity; one did not explicitly define recurrence.Hand function on the Disabilities of the Arm, Shoulder and Hand (DASH) Scale (scores between 0 and 100, with higher scores indicating greater impairment) was 5 points lower after needle fasciotomy than after fasciectomy at five weeks. Patient satisfaction was better after fasciotomy at six weeks, but the magnitude of effect was not specified. Fasciectomy improved contractures more effectively in severe disease: Mean percentage reduction in total passive extension deficit at six weeks for Tubiana grades I and II was 11% lower after needle fasciotomy than after fasciectomy, whereas for grades III and IV disease, it was 29% and 32% lower.Paraesthesia (defined as subjective tingling sensation without objective evidence of altered sensation) was more common than needle fasciotomy at one week after fasciectomy (228/1000 vs 67/1000), but reporting of complications was variable.By five years, satisfaction (on a scale from 0 to 10, with higher scores showing greater satisfaction) was 2.1/10 points higher in the fasciectomy group than in the fasciotomy group, and recurrence was greater after fasciotomy (849/1000 vs 209/1000). Firebreak skin grafting did not improve outcomes more than fasciectomy alone, although this procedure took longer to perform.One trial investigated four weeks of day and night splinting followed by two months of night splinting after surgery. The other two trials investigated three months of night splinting after surgery, but participants in 'no splint' groups with early deterioration at one week were issued a splint for use. All three studies demonstrated no benefit from splinting. The two trials investigating postoperative night splinting were suitable for meta-analysis, which demonstrated no benefit from splinting: Mean DASH score in the splint groups was 1.15 points lower (95% confidence interval (CI) -2.32 to 4.62) than in the no splint groups. Mean total active extension in the splint groups was 2.21 degrees greater (95% CI -3.59 to 8.01 degrees) than in the no splint groups. Mean total active flexion in the splint groups was 8.42 degrees less (95% CI 1.78 to 15.07 degrees) than in the no splint groups. AUTHORS' CONCLUSIONS: Currently, insufficient evidence is available to show the relative superiority of different surgical procedures (needle fasciotomy vs fasciectomy, or interposition firebreak skin grafting vs z plasty closure of fasciectomy). Low-quality evidence suggests that postoperative splinting may not improve outcomes and may impair outcomes by reducing active flexion. Further trials on this topic are urgently required. PMID- 26648252 TI - Transcriptome analysis of the key role of GAT2 gene in the hyper-accumulation of copper in the oyster Crassostrea angulata. AB - One paradigm of oysters as the hyper-accumulators of many toxic metals is the inter-individual variation of metals, but the molecular mechanisms remain very elusive. A comprehensive analysis of the transcriptome of Crassostrea angulata was conducted to reveal the relationship between gene expression and differential Cu body burden in oysters. Gene ontology analysis for the differentially expressed genes showed that the neurotransmitter transporter might affect the oyster behavior, which in turn led to difference in Cu accumulation. The ATP binding cassette transporters superfamily played an important role in the maintenance of cell Cu homeostasis, vitellogenin and apolipophorin transport, and elimination of excess Cu. Gill and mantle Cu concentrations were significantly reduced after silencing the GABA transporter 2 (GAT2) gene, but increased after the injection of GABA receptor antagonists, suggesting that the function of GABA transporter 2 gene was strongly related to Cu accumulation. These findings demonstrated that GABA transporter can control the action of transmitter GABA in the nervous system, thereby affecting the Cu accumulation in the gills and mantles. PMID- 26648254 TI - Copper(i) halide clusters based upon ferrocenylchalcogenoether ligands: donors, halides and semi-rigidity effects on the geometry and catalytic activity. AB - Six copper(i) halide clusters based upon ferrocenyltelluroethers or ferrocenylselenoethers, 1-6, have been synthesized and structurally characterized by an X-ray crystallographic study. These structures include a discrete step cubane Cu4I4 cluster, a 1D chain with rhomboid Cu2X2 clusters, a 1D chain with cubane Cu4I4 clusters and a 2D network with Cu2I2 clusters. 1-3 are the first structurally characterized example of copper(i) clusters with telluroethers. Their different nuclearities and geometries can be attributed to the different donor atoms and chain flexibility in the ligands. The catalytic activities of six clusters were then investigated in the Ullmann C-N cross-coupling reaction and 2 displayed the best performance with a target product N-(4-phenyl)imidazole in 91.3% yield. From the viewpoint of structure, the specific steric acceptance around Cu(i) in 2 may allow imidazole and iodobenzene to stepwise coordinate with the copper center and give the target product effectively. PMID- 26648253 TI - Chikusetsu saponin IVa confers cardioprotection via SIRT1/ERK1/2 and Homer1a pathway. AB - Hyperglycemia-induced reactive oxygen species (ROS) generation and Ca(2+) overload contribute to the development of diabetic cardiomyopathy. In this study, we aimed to study the protective effects of Chikusetsu saponin IVa (CHS) from Aralia taibaiensis against hyperglycemia-induced myocardial injuries. Treatment of H9c2 cells with high glucose (HG) for 24 h resulted in a loss of cell viability and increase of ROS, LDH and Ca(2+) levels, and also induced cell apoptosis, and those changes were all markedly reversed by the administration of CHS. In further studies, CHS dose-dependently increased the expression of Homer1a, ERK1/2 and SIRT1 in both H9c2 cells and rat primary cardiomyocytes. However, transfection of Homer1a-specific siRNA abolished the ability of CHS in controlling the ROS and Ca(2+) homeostasis. Moreover, specific SIRT1 inhibitors or siRNA significantly suppressed the enhanced phosphorylation of ERK1/2 and expression of Homer1a induced by CHS as well as its cytoprotective effect. CHS induced Homer1a expression was also suppressed by siERK1/2. Additionally, results in diabetic mice also showed that CHS protected myocardium from I/R-introduced apoptosis by activating the SIRT1/ERK1/2/Homer1a pathway. These results demonstrated that CHS protected against hyperglycemia-induced myocardial injury through SIRT1/ERK1/2 and Homer1a pathway in vivo and in vitro. PMID- 26648255 TI - Corrigendum: Genome-wide association study identifies variants at 16p13 associated with survival in multiple myeloma patients. PMID- 26648256 TI - Signal transduction in light-oxygen-voltage receptors lacking the adduct-forming cysteine residue. AB - Light-oxygen-voltage (LOV) receptors sense blue light through the photochemical generation of a covalent adduct between a flavin-nucleotide chromophore and a strictly conserved cysteine residue. Here we show that, after cysteine removal, the circadian-clock LOV-protein Vivid still undergoes light-induced dimerization and signalling because of flavin photoreduction to the neutral semiquinone (NSQ). Similarly, photoreduction of the engineered LOV histidine kinase YF1 to the NSQ modulates activity and downstream effects on gene expression. Signal transduction in both proteins hence hinges on flavin protonation, which is common to both the cysteinyl adduct and the NSQ. This general mechanism is also conserved by natural cysteine-less, LOV-like regulators that respond to chemical or photoreduction of their flavin cofactors. As LOV proteins can react to light even when devoid of the adduct-forming cysteine, modern LOV photoreceptors may have arisen from ancestral redox-active flavoproteins. The ability to tune LOV reactivity through photoreduction may have important implications for LOV mechanism and optogenetic applications. PMID- 26648257 TI - Altered miRNA Signature of Developing Germ-cells in Infertile Patients Relates to the Severity of Spermatogenic Failure and Persists in Spermatozoa. AB - The aim of this study was to assess the cellular miRNA expression behaviour in testes with spermatogenic failure (SpF). We performed a high-throughput screen of 623 mature miRNAs by a quantitative RT-qPCR-based approach in histologically well defined testicular samples with spermatogenic disruption at different germ-cell stages, which revealed altered patterns of miRNA expression. We focussed on the differentially expressed miRNAs whose expression correlated with the number of testicular mature germ-cells and described the combined expression values of a panel of three miRNAs (miR-449a, miR-34c-5p and miR-122) as a predictive test for the presence of mature germ-cells in testicular biopsy. Additionally, we determined decreased cellular miRNA content in developing germ-cells of SpF testis; this was more noticeable the earlier the stage of germ-cell differentiation was affected by maturation failure. Furthermore, we showed that the miRNA expression profile in mature sperm from mild SpF patients was widely altered. Our results suggest that the cellular miRNA content of developed germ cells depends heavily on the efficacy of the spermatogenic process. What is more, spermatozoa that have fulfilled the differentiation process still retain the dysregulated miRNA pattern observed in the developing SpF germ-cells. This altered miRNA molecular signature may have functional implications for the male gamete. PMID- 26648258 TI - Lung cancer exosomes initiate global long non-coding RNA changes in mesenchymal stem cells. AB - Mesenchymal stem cells (MSCs) can be attracted to tumor sites and become an important component of the tumor microenvironment, thus contributing to tumor development. Emerging evidence suggests that tumor cells could transfer genetic information into MSCs through the release of exosomes. However, the molecular mechanisms by which tumor exosomes contribute to interactions between MSCs and tumor cells remain largely unknown. In this study, we found that lung tumor cell derived exosomes could inhibit MSCs osteogenic and adipogenic differentiation. We then investigated the involvement of long non-coding RNAs, a new class of regulators, in tumor exosome treated MSCs by a comprehensive lncRNA and mRNA profiling. lncRNAs (9.1%) (2775 out of 30586) and 9.3% of protein-coding mRNA (2439 out of 26109) were differentially expressed (fold-change >=2; P-value <=0.05) in lung tumor cell exosome treated MSCs. Furthermore, we characterized the differentially expressed lncRNAs through their classes and length distribution and correlated them with differentially expressed mRNA. Noteworthy, GO analysis of biological process showed that upregulated mRNAs were enriched in mRNA metabolic process, while downregulated ones were enriched in detection of mechanical stimulus involved in sensory perception. Pathway analysis indicated that 32 pathways were upregulated while 7 were downregulated in A549 exosome treated MSCs. Here, we are the first to determine genome-wide lncRNA expression patterns in exosome treated MSCs by microarray and the results will bring new insights into the mechanisms underlying interactions between tumor cells exosomes and its environmental component the MSCs. PMID- 26648260 TI - Lentivirus-mediated knockdown of MeCP2 inhibits the growth of colorectal cancer cells in vitro. AB - Methyl-CpG-binding protein 2 (MeCP2) is a transcriptional repressor that has been implicated in tumor onset and progression. Compared with normal and other tumorous tissue, MeCP2 is highly expressed in well-differentiated adenocarcinoma and mucinous adenocarcinoma tissues, particularly at the invasion site of colorectal cancer tissues. The aim of the present study was to evaluate the potential of MeCP2 for use as a therapeutic target for human colorectal cancer. The DLD-1 colorectal cancer cell line was subjected to lentivirus-mediated short hairpin RNA-induced knockdown of MeCP2 and the effects on cell growth, cell cycle progression and cell migration were assessed. It was confirmed that lentivirus mediated RNA interference successfully suppressed MeCP2 expression in vitro, which was demonstrated to result in reduced cell viability, cell cycle arrest in G0/G1 phase and inhibition of cell migration. These results indicated that MeCP2 may serve as a potential target for gene therapy of colorectal cancer. PMID- 26648259 TI - SMARCAL1 Negatively Regulates C-Myc Transcription By Altering The Conformation Of The Promoter Region. AB - SMARCAL1, a member of the SWI2/SNF2 protein family, stabilizes replication forks during DNA damage. In this manuscript, we provide the first evidence that SMARCAL1 is also a transcriptional co-regulator modulating the expression of c Myc, a transcription factor that regulates 10-15% genes in the human genome. BRG1, SMARCAL1 and RNAPII were found localized onto the c-myc promoter. When HeLa cells were serum starved, the occupancy of SMARCAL1 on the c-myc promoter increased while that of BRG1 and RNAPII decreased correlating with repression of c-myc transcription. Using Active DNA-dependent ATPase A Domain (ADAAD), the bovine homolog of SMARCAL1, we show that the protein can hydrolyze ATP using a specific region upstream of the CT element of the c-myc promoter as a DNA effector. The energy, thereby, released is harnessed to alter the conformation of the promoter DNA. We propose that SMARCAL1 negatively regulates c-myc transcription by altering the conformation of its promoter region during differentiation. PMID- 26648261 TI - Shensongyangxin protects against pressure overload-induced cardiac hypertrophy. AB - Shensongyangxin (SSYX) is a medicinal herb, which has long been used in traditional Chinese medicine. Various pharmacological activities of SSYX have been identified. However, the role of SSYX in cardiac hypertrophy remains to be fully elucidated. In present study, aortic banding (AB) was performed to induce cardiac hypertrophy in mice. SSYX (520 mg/kg) was administered by daily gavage between 1 and 8 weeks following surgery. The extent of cardiac hypertrophy was then evaluated by pathological and molecular analyses of heart tissue samples. In addition, in vitro experiments were performed to confirm the in vivo results. The data of the present study demonstrated that SSYX prevented the cardiac hypertrophy and fibrosis induced by AB, as assessed by measurements of heart weight and gross heart size, hematoxylin and eosin staining, cross-sectional cardiomyocyte area and the mRNA expression levels of hypertrophic markers. SSYX also inhibited collagen deposition and suppressed the expression of transforming growth factor beta (TGFbeta), connective tissue growth factor, fibronectin, collagen Ialpha and collagen IIIalpha, which was mediated by the inhibition of the TGFbeta/small mothers against decapentaplegic (Smad) signaling pathway. The inhibitory action of SSYX on cardiac hypertrophy was mediated by the inhibition of Akt signaling. In vitro investigations in the rat H9c2 cardiac cells also demonstrated that SSYX attenuated angiotensin II-induced cardiomyocyte hypertrophy. These findings suggested that SSYX attenuated cardiac hypertrophy and fibrosis in the pressure overloaded mouse heart. Therefore, the cardioprotective effect of SSYX is associated with inhibition of the Akt and TGFbeta/Smad signaling pathways. PMID- 26648262 TI - Low field photo-CIDNP in the intramolecular electron transfer of naproxen pyrrolidine dyads. AB - Photoinduced processes with partial (exciplex) and full charge transfer in donor acceptor systems are of interest because they are frequently used for modeling drug-protein binding. Low field photo-CIDNP (chemically induced dynamic nuclear polarization) for these processes in dyads, including the drug, (S)- and (R) naproxen and (S)-N-methyl pyrrolidine in solutions with strong and weak permittivity have been measured. The dramatic influence of solvent permittivity on the field dependence of the N-methyl pyrrolidine (1)H CIDNP effects has been found. The field dependences of both (R,S)- and (S,S)-dyads in a polar medium are the curves with a single extremum in the area of the S-T+ terms intersection. Moreover, the CIDNP field dependences of the same protons measured in a low polar medium present curves with several extrema. The shapes of the experimental CIDNP field dependence with two extrema have been described using the Green function approach for the calculation of the CIDNP effects in the system without electron exchange interactions. The article discusses the possible causes of the differences between the CIDNP field dependence detected in a low-permittivity solvent with the strong Coulomb interactions and in a polar solvent. PMID- 26648263 TI - Long-lived Aqueous Rechargeable Lithium Batteries Using Mesoporous LiTi2(PO4)3@C Anode. AB - The instability of anode materials during cycling has been greatly limiting the lifetime of aqueous rechargeable lithium batteries (ARLBs). Here, to tackle this issue, mesoporous LiTi2(PO4)3@C composites with a pore size of 4 nm and a large BET surface area of 165 m(2) g(-1) have been synthesized by a novel two-step approach. The ARLB with this type of LiTi2(PO4)3@C anode, commercial LiMn2O4 cathode and 2 M Li2(SO4) aqueous solution (oxygen was removed) exhibited superior cycling stability (a capacity retention of 88.9% after 1200 cycles at 150 mA g( 1) and 82.7% over 5500 cycles at 750 mA g(-1)) and excellent rate capability (discharge capacities of 121, 110, 90, and 80 mAh g(-1) based on the mass of LiTi2(PO4)3 at 30, 150, 1500, and 3000 mA g(-1), respectively). As verified, the mesoporous structure, large surface area and high-quality carbon coating layer of the LiTi2(PO4)3@C composite contribute to the breakthrough in achieving excellent electrochemical properties for ARLB. PMID- 26648265 TI - DNA replication: Quad-jumping. PMID- 26648266 TI - Cytoskeleton: Centriole maturation to motherhood. PMID- 26648264 TI - A-to-I editing of coding and non-coding RNAs by ADARs. AB - Adenosine deaminases acting on RNA (ADARs) convert adenosine to inosine in double stranded RNA. This A-to-I editing occurs not only in protein-coding regions of mRNAs, but also frequently in non-coding regions that contain inverted Alu repeats. Editing of coding sequences can result in the expression of functionally altered proteins that are not encoded in the genome, whereas the significance of Alu editing remains largely unknown. Certain microRNA (miRNA) precursors are also edited, leading to reduced expression or altered function of mature miRNAs. Conversely, recent studies indicate that ADAR1 forms a complex with Dicer to promote miRNA processing, revealing a new function of ADAR1 in the regulation of RNA interference. PMID- 26648267 TI - Gd-based upconversion nanocarriers with yolk-shell structure for dual-modal imaging and enhanced chemotherapy to overcome multidrug resistance in breast cancer. AB - Multidrug resistance (MDR) of cancers is still a major challenge, and it is very important to develop visualized nanoprobes for the diagnosis and treatment of drug resistant cancers. In this work, we developed a multifunctional delivery system based on DOX-encapsulated NaYF4:Yb/Er@NaGdF4 yolk-shell nanostructures for simultaneous dual-modal imaging and enhanced chemotherapy in drug resistant breast cancer. Using the large pore volume of the nanostructure, the delivery system had a high loading efficiency and excellent stability. Also, an in vitro and in vivo toxicity study showed the good biocompatibility of the as-prepared yolk-shell nanomaterials. Moreover, by nanocarrier delivery, the uptake of DOX could be greatly increased in drug resistant MCF-7/ADR cells. Compared with free DOX, the as-prepared delivery system enhanced the chemotherapy efficacy against MCF-7/ADR cells, indicating the excellent capability for overcoming MDR. Furthermore, core-shell NaYF4:Yb/Er@NaGdF4 improved the upconversion luminescence (UCL) performance, and the designed delivery system could also be applied for simultaneous UCL and magnetic resonance (MR) imaging, which could be a good candidate as a dual-modal imaging nanoprobe. Therefore, we developed a multifunctional yolk-shell delivery system, which could have potential applications as a visualized theranostic nanoprobe to overcome MDR in breast cancer. PMID- 26648268 TI - Safe generation and use of bromine azide under continuous flow conditions- selective 1,2-bromoazidation of olefins. AB - Bromine azide (BrN3), a useful but extremely toxic and explosive reagent for the preparation of vicinal 1,2-bromine azide compounds, was safely generated and reacted in situ with alkenes in a continuous flow photoreactor. BrN3 was generated by a novel procedure from NaBr and NaN3 in water, and efficiently extracted into an organic phase containing the alkene thus avoiding decomposition. The resulting addition products have been used for the preparation of several useful building blocks. PMID- 26648269 TI - Formation of crystal-like structures and branched networks from nonionic spherical micelles. AB - Crystal-like structures at nano and micron scales have promise for purification and confined reactions, and as starting points for fabricating highly ordered crystals for protein engineering and drug discovery applications. However, developing controlled crystallization techniques from batch processes remain challenging. We show that neutrally charged nanoscale spherical micelles from biocompatible nonionic surfactant solutions can evolve into nano- and micro-sized branched networks and crystal-like structures. This occurs under simple combinations of temperature and flow conditions. Our findings not only suggest new opportunities for developing controlled universal crystallization and encapsulation procedures that are sensitive to ionic environments and high temperatures, but also open up new pathways for accelerating drug discovery processes, which are of tremendous interest to pharmaceutical and biotechnological industries. PMID- 26648270 TI - Vasculogenic dynamics in 3D engineered tissue constructs. AB - Implantable 3D engineered vascular tissue constructs can be formed by co culturing endothelial and fibroblast cells on macroporous scaffolds. Here we show that these constructs can be used for studying the dynamics of neovascular formation in-vitro by a combination of live confocal imaging and an array of image processing and analysis tools, revealing multiple distinct stages of morphogenesis. We show that this process involves both vasculogenic and angiogenic elements, including an initial endothelial multicellular cluster formation followed by rapid extensive sprouting, ultimately resulting in a stable interconnected endothelial network morphology. This vascular morphogenesis is time-correlated with the deposition and formation of an extensive extra-cellular matrix environment. We further show that endothelial network junctions are formed by two separate morphogenic mechanisms of anastomosis and cluster thinning. PMID- 26648271 TI - Fructus xanthii improves lipid homeostasis in the epididymal adipose tissue of rats fed a high-fat diet. AB - High fat diet (HFD)-induced obesity triggers common features of human metabolic syndrome in rats. Our previous study showed that Fructus xanthii (FX) attenuates HFD-induced hepatic steatosis. The present study was designed to investigate the effects of FX on lipid metabolism in epididymal fat (EF), and examine its underlying mechanisms. Aqueous extraction fractions of FX or vehicle were orally administered by gavage for 6 weeks to rats fed either a HFD or a normal chow diet (NCD). The levels of circulating free fatty acid (FFA) were determined in plasma, and the expression levels of lipid metabolism- and inflammation-associated genes in the EF were measured using reverse transcription-quantitative polymerase chain reaction analysis. The general morphology, size and number of adipocytes in the EF, and the levels of macrophage infiltration were evaluated using hematoxylin and eosin staining or immunohistochemical staining. FX decreased circulating levels of FFA, increased the expression levels of sterol-regulatory-element binding protein-1c, FAS, acetyl coenzyme A carboxylase, diacylglycerol acyltransferase and lipoprotein lipase lipogenic genes in the EF. FX increased the numbers of adipocytes in the EF, and featured a shift towards smaller adipocyte size. Compared with the vehicle-treated rats, positive staining of F4/80 was more dispersed in the FX-treated rats, and the percentage of F4/80 positive cells was significantly decreased. FX attenuated HFD-induced lipid dyshomeostasis in the epididymal adipose tissue. PMID- 26648272 TI - In vitro assessment of the antimicrobial potentials of Lactobacillus helveticus strains isolated from traditional cheese in Sinkiang China against food-borne pathogens. AB - Lactobacillus helveticus, an obligatory hetero-fermentative LAB, is Generally Recognized as Safe (GRAS) and is gaining popularity for application in dairy products. Lactic acid bacteria (LAB) play a remarkable role in inhibiting the growth of pathogenic bacteria in food products, without disturbing the sensory attributes of the food. In this study, the screening of the antimicrobial potential of Lactobacillus helveticus KLDS 1.8701 against four food-borne pathogens including Listeria monocytogenes ATCC 19115, Salmonella typhimurium ATCC 14028, Staphylococcus aureus ATCC 25923, and Escherichia coli O157:H7 ATCC 43889 in vitro was inspected using the Oxford cup method and mixed culture inhibition assays. The organic acid production and antimicrobial potential of the cell-free supernatants (CFS) have been evaluated via different treatments and analysis using high performance liquid chromatography (HPLC). The analysis results revealed that KLDS 1.8701 exhibited the highest antimicrobial potential compared to other antimicrobial strains. The antimicrobial activity of KLDS 1.8701 resulted from the organic acids in the culture and CFS. From the study, it was found that carbon sources, as well as organic acid production, accelerate the antimicrobial activity of KLDS 1.8701 and the fructooligosaccharides (FOS) were considered the best for improving the proliferation of KLDS 1.8701 and supporting its antimicrobial action. Results of the mixed culture inhibition assays showed that part of the antimicrobial activity resulted from the inhibitory action of the bacteria itself in culture, and this action required cellular contact between the food-borne pathogens and KLDS 1.8701. Conversely, the results of the antimicrobial spectrum assay revealed that some Lactobacilli remained unaffected by KLDS 1.8701. KLDS 1.8701 might also be favorable for use as a supplementary starter in fermented dairy productions. Furthermore, KLDS 1.8701 could survive well under GI tract conditions. Further studies on in vivo inhibition assays and the probiotic effects are recommended. PMID- 26648274 TI - GNRs@SiO2-FA in combination with radiotherapy induces the apoptosis of HepG2 cells by modulating the expression of apoptosis-related proteins. AB - The aim of the present study was to examine the apoptosis of the hepatocellular carcinoma cell line, HepG2, induced by treatment with folic acid-conjugated silica-coated gold nanorods (GNRs@SiO2-FA) in combination with radiotherapy, and to determine the involvement of apoptosis-related proteins. An MTT colorimetric assay was used to assess the biocompatibility of GNRs@SiO2-FA. The distribution of GNRs@SiO2-FA into the cells was observed using transmission electron microscopy (TEM). HepG2 cells cultured in vitro were divided into the following 4 groups: i)the control group (untreated), ii) the GNRs@SiO2-FA group, iii) the radiotherapy group (iodine 125 seeds) and iv) the combination group (treated with GNRs@SiO2-FA and iodine 125 seeds) groups. The apoptosis of the HepG2 cells was detected by flow cytometry. The concentration range of <40 ug/ml GNRs@SiO2-FA was found to be safe for the biological activity of the HepG2 cells. GNRs@SiO2-FA entered the cytoplasm through endocytosis. The apoptotic rates of the HepG2 cells were higher in the GNRs@SiO2-FA and radiotherapy groups than in the control group (P<0.05). The apoptotic rate was also significantly higher in the combination group than the GNRs@SiO2-FA and radiotherapy groups (P<0.05). Taken together, these findings demonstrate that the combination of GNRs@SiO2-FA and radiotherapy more effectively induces the apoptosis of HepG2 cells. These apoptotic effects are achieved by increasing the protein expression of Bax and caspase-3, and inhibiting the protein expression of Bcl-2 and Ki-67. The combination of GNRs@SiO2-FA and radiotherapy may thus prove to be a new approach in the treatment of primary liver cancer. PMID- 26648273 TI - Detrimental role of the EP1 prostanoid receptor in blood-brain barrier damage following experimental ischemic stroke. AB - Cyclooxygenase-2 (COX-2) is activated in response to ischemia and significantly contributes to the neuroinflammatory process. Accumulation of COX-2-derived prostaglandin E2 (PGE2) parallels the substantial increase in stroke-mediated blood-brain barrier (BBB) breakdown. Disruption of the BBB is a serious consequence of ischemic stroke, and is mainly mediated by matrix metalloproteinases (MMPs). This study aimed to investigate the role of PGE2 EP1 receptor in neurovascular injury in stroke. We hypothesized that pharmacological blockade or genetic deletion of EP1 protects against BBB damage and hemorrhagic transformation by decreasing the levels and activity of MMP-3 and MMP-9. We found that post-ischemic treatment with the EP1 antagonist, SC-51089, or EP1 genetic deletion results in a significant reduction in BBB disruption and reduced hemorrhagic transformation in an experimental model of transient focal cerebral ischemia. These neurovascular protective effects of EP1 inactivation are associated with a significant reduction in MMP-9/-3, less peripheral neutrophil infiltration, and a preservation of tight junction proteins (ZO-1 and occludin) composing the BBB. Our study identifies the EP1 signaling pathway as an important link between neuroinflammation and MMP-mediated BBB breakdown in ischemic stroke. Targeting the EP1 receptor could represent a novel approach to diminish the devastating consequences of stroke-induced neurovascular damage. PMID- 26648275 TI - Life after care: psychological adjustment to bereavement in family carers of people with dementia. AB - BACKGROUND: Despite well-documented evidence of the psychological effects of caring for a relative with dementia, little is known about the bereavement experiences of family carers. The aim of this study was to explore the key psychological changes associated with carers' adjustment to bereavement and "life after care." METHODS: All carers taking part were recruited from a day care center, providing specialist services to people with dementia. We asked carers to describe the key changes associated with psychological adjustment to bereavement through semi-structured qualitative in-depth interviews. Strategies carers used to cope with and adapt to their new role were also explored. All data were thematically analysed. RESULTS: Thirty-one carers were interviewed. The most frequent emotional reactions to bereavement were feelings of loneliness, loss, void, sadness, anger, and relief. Most carers were able to adapt to their new role, and engaging in pleasant activities was the most frequent strategy used to cope with loss and "life after care." CONCLUSIONS: Feelings of loneliness and loss are amongst the key emotional reactions shaping carers' adjustment to bereavement. Most carers are able to adapt to loss; however, a minority experience increased psychological distress after the death of their loved one. A small percentage of carers continues caring for other dependants. Further research is required to identify how carers of people with dementia adapt to bereavement and how this increasing number of individuals can be best supported. PMID- 26648276 TI - Elevated gamma glutamyl transferase levels are associated with the location of acute pulmonary embolism. Cross-sectional evaluation in hospital setting. AB - CONTEXT AND OBJECTIVE: The location of embolism is associated with clinical findings and disease severity in cases of acute pulmonary embolism. The level of gamma-glutamyl transferase increases under oxidative stress-related conditions. In this study, we investigated whether gamma-glutamyl transferase levels could predict the location of pulmonary embolism. DESIGN AND SETTING: Hospital-based cross-sectional study at Cumhuriyet University, Sivas, Turkey. METHODS: 120 patients who were diagnosed with acute pulmonary embolism through computed tomography-assisted pulmonary angiography were evaluated. They were divided into two main groups (proximally and distally located), and subsequently into subgroups according to thrombus localization as follows: first group (thrombus in main pulmonary artery; n = 9); second group (thrombus in main pulmonary artery branches; n = 71); third group (thrombus in pulmonary artery segmental branches; n = 34); and fourth group (thrombus in pulmonary artery subsegmental branches; n = 8). RESULTS: Gamma-glutamyl transferase levels on admission, heart rate, oxygen saturation, right ventricular dilatation/hypokinesia, pulmonary artery systolic pressure and cardiopulmonary resuscitation requirement showed prognostic significance in univariate analysis. The multivariate logistic regression model showed that gamma-glutamyl transferase level on admission (odds ratio, OR = 1.044; 95% confidence interval, CI: 1.011-1.079; P = 0.009) and pulmonary artery systolic pressure (OR = 1.063; 95% CI: 1.005-1.124; P = 0.033) remained independently associated with proximally localized thrombus in pulmonary artery. CONCLUSIONS: The findings revealed a significant association between increased existing embolism load in the pulmonary artery and increased serum gamma-glutamyl transferase levels. PMID- 26648277 TI - Personality disorders in medical psychology: medical training and professional creativity. PMID- 26648278 TI - Stress, coping and adherence to immunosuppressive medications in kidney transplantation: a comparative study. AB - CONTEXT AND OBJECTIVE: : Adherence to medication is a key issue relating to outcomes from transplantation and it is influenced by several factors, such as stress and coping strategies. However, these factors have been poorly explored. We aimed to compare stress and coping strategies between adherent and nonadherent renal transplant recipients who were receiving immunosuppression. DESIGN AND SETTING: : We conducted a comparative, cross-sectional and observational study at a university-based transplantation clinic in Juiz de Fora, Brazil. METHODS: :Fifty patients were recruited and classified as adherent or nonadherent following administration of the Basel Assessment of Adherence to Immunosuppressive Medications Scale. Stress was evaluated using the Lipp Stress Symptom Inventory for Adults and coping strategies were assessed using the Ways of Coping Scale. RESULTS: : The study included 25 nonadherent patients and 25 controls with a mean age of 44.1 +/- 12.8 years and median post-transplantation time of 71.8 months. Stress was present in 50% of the patients. Through simple logistic regression, nonadherence was correlated with palliative coping (OR 3.4; CI: 1.02-11.47; P < 0.05) and had a marginal trend toward significance with more advanced phases of stress (OR 4.7; CI: 0.99-22.51; P = 0.053). CONCLUSION: :Stress and coping strategies may have implications for understanding and managing nonadherent behavior among transplantation patients and should be considered among the strategies for reducing nonadherence. PMID- 26648279 TI - Down syndrome: Prevalence and distribution of congenital heart disease in Brazil. AB - CONTEXT AND OBJECTIVE: Down syndrome is the most common genetic disorder, affecting 1/700 live births. Among the clinical findings, one constant concern is the high prevalence of congenital heart disease. The objective of this study was to determine the prevalence and profile of congenital heart disease among patients attended at a Down syndrome outpatient clinic in southern Brazil between 2005 and 2013. DESIGN AND SETTING: Cross-sectional study conducted in a referral center. METHODS: Data were retrospectively gathered from the medical files of 1,207 patients with Down syndrome, among whom 604 (50.0%) had been diagnosed with congenital heart disease. These data were subjected to descriptive analysis using the Statistica software. RESULTS: Among the 604 patients with congenital heart disease, 338 (55.8%) were male and 269 (44.5%) were female. The most common heart diseases were atrial septal defect in 254 patients (42.1%); total atrioventricular septal defect in 91 (15.1%); atrial septal defect and ventricular septal defect in 88 (14.6%); ventricular septal defect in 77 (12.7%); patent ductus arteriosus in 40 (6.6%); patent foramen ovale in 34 (5.6%) patients; tetralogy of Fallot in 12 (2%); and other diseases in 8 (1.3%). Pulmonary hypertension was present in 57 (9.4%). Out of the total, 150 patients (24.8%) underwent cardiac surgery. CONCLUSION: The high prevalence of congenital heart disease among the patients at the Down syndrome outpatient clinic (50%) was similar to findings from other studies and justifies investigation during the neonatal period, so as to decrease mortality and morbidity. PMID- 26648280 TI - Translation, cultural adaptation and reproducibility of the Oxford Shoulder Score questionnaire for Brazil, among patients with rheumatoid arthritis. AB - CONTEXT AND OBJECTIVE Although shoulder questionnaires validated for Brazil do exist, none of them are aimed at populations with rheumatic disease. We believe that the Oxford Shoulder Score (OSS) may be useful in this population. The objective of this study was to translate the OSS, adapt it to Brazilian culture and test its reproducibility. DESIGN AND SETTING Validation study conducted in university outpatient clinics. METHODS The OSS was translated into Portuguese by two English teachers and was then retranslated into English by two native English teachers. These translations were reviewed by a committee to establish the version of OSS-Brazil to be administered to 30 patients with rheumatoid arthritis (RA) and shoulder pain, in order to test the cultural adaptation. The validity and reproducibility was tested among another 30 patients with RA and shoulder pain, of both genders and aged 18 to 65 years. The internal consistency and reproducibility were analyzed. The following instruments were evaluated: OSS Brazil; a numerical scale for shoulder pain; DASH; HAQ and SF-36. RESULTS The internal consistency was 0.957 and the intra and inter-rater reproducibility was 0.917 and 0.861, respectively. A high level of correlation was found between OSS Brazil and the following: HAQ (-0.663), DASH (-0.731) and the SF-36 domains of functional capacity (0.589), physical aspects (0.507), pain (0.624), general state of health (0.444), vitality (0.634) and mental health (0.578). CONCLUSION OSS-Brazil was successfully translated and adapted, and this version exhibited good internal consistency, reliability and construct validity. PMID- 26648281 TI - Development of clinical reasoning in an undergraduate medical program at a Brazilian university. AB - CONTEXT AND OBJECTIVE The cognitive processes relating to the development of clinical reasoning are only partially understood, which explains the difficulties in teaching this skill in medical courses. This study aimed to understand how clinical reasoning develops among undergraduate medical students. DESIGN AND SETTING Quantitative and qualitative exploratory descriptive study conducted at the medical school of Universidade Federal de Goias. METHODS The focus group technique was used among 40 students who participated in five focus groups, with eight students from each year, from the first to fifth year of the medical school program. The material was subjected to content analysis in categories, and was subsequently quantified and subjected to descriptive statistical analysis and chi square test for inferential statistics. RESULTS The content of the students' statements was divided into two categories: clinical reasoning - in the preclinical phase, clinical reasoning was based on knowledge of basic medical science and in the clinical phase, there was a change to pattern recognition; knowledge of basic medical science - 80.6% of the students recognized its use, but they stated that they only used it in difficult cases. CONCLUSION In the preclinical phase, in a medical school with a traditional curriculum, clinical reasoning depends on the knowledge acquired from basic medical science, while in the clinical phase, it becomes based on pattern recognition. PMID- 26648283 TI - Investigation of the antidepressant effects of exopolysaccharides obtained from Marasmius androsaceus fermentation in a mouse model. AB - Marasmius androsaceus, a well-known medical fungus, possesses antihypertensive, analgesic and antioxidant effects. Exopolysaccharide (EPS), produced by microorganism secretion, exerts various types of biological activities. The present study aimed to investigate the antidepressant-like effect of the EPS produced during Marasmius androsaceus submerge fermentation (MEPS). Based on the assessment of acute toxicity and behavior, a forced swimming test (FST), tail suspension test (TST), 5-hydroxytryptophan-induced head-twitch assessment and reserpine-induced hypothermia assessment were performed. The administration of MEPS for 7 days enhanced mouse locomotor and balance ability in the mice. Similar to the results following treatment with fluoxetine, which was used as positive control drug, MEPS significantly decreased the duration of immobility in the FST and TST, increased head twitches in the 5-HTP-induced head-twitch test and enhanced rectal temperature in resperpine-induced hypothermia. MEPS altered the abnormal concentrations of 5-hydroxytryptamine, 5-hydroxyindoleacetic acid, dopamine and norepinephrine in the hypothalamus in the resperine-induced mouse model. Additionally, an increase in the expression of tyrosine hydroxylase and a reduction in the level of dopamine transporter in the hypothalamus were noted following 7 days of MEPS administration. Taken together, the EPS produced during MEPS exhibited antidepressant-like effects, which may be associated with its regulation on the dopaminergic system. The results of the present study provide experimental evidence supporting the clinical use of MEPS as an effective agent against depression. PMID- 26648282 TI - Upregulation of the expression of Wnt5a promotes the proliferation of pancreatic cancer cells in vitro and in a nude mouse model. AB - Wnt proteins are a group of secreted signaling proteins, which function to regulate cell fate and pattern formation during embryogenesis. Altered expression of Wnt5a has been implicated in human carcinogenesis and tumor progression. A previous study identified that Wnt5a is overexpressed in human pancreatic cancer tissues, and that upregulated expression of Wnt5a promotes tumor cell migration and invasion. The present study investigated the role of Wnt5a in pancreatic cancer cell proliferation in vitro and in an orthotopic nude mouse model. Wnt5a cDNA or small interfering RNA were stably transfected into pancreatic cancer cells to assess cell proliferation-associated behaviors, including cell viability, colony formation and apoptosis in vitro, as well as tumor cell growth in an orthotopic nude mouse model. Western blot analysis was used to analyze the expression of Wnt signaling molecules. The data showed that upregulation of the expression of Wnt5a significantly promoted proliferation of the human pancreatic cells, but inhibited tumor cell apoptosis in vitro and promoted tumor growth in an orthotopic nude mouse model. By contrast, knockdown of the expression of Wnt5a inhibited cell growth and promoted apoptosis of the pancreatic cancer cells. The data also revealed that beta-catenin mediated the effects of Wnt5a on the regulation of pancreatic cancer cell apoptosis in vitro. These results suggested that Wnt5a is involved in the modulation of pancreatic cancer cell proliferation, and that Wnt5a may be a potential target for pancreatic cancer therapy. PMID- 26648284 TI - MiR-512-5p induces apoptosis and inhibits glycolysis by targeting p21 in non small cell lung cancer cells. AB - MicroRNAs are a family of small non-coding RNAs that constitute a prevalent gene regulation. In this study, we showed the expression of miR-512-5p is downregulated in non-small cell lung cancer (NSCLC) patient tumor samples compared to its paired normal lung tissues. Moreover, expression of miR-512-5p was increased by retinoic acid treatment. Overexpression of miR-512-5p induced apoptosis of NSCLC cell lines A549 and H1299, and miR-512-5p inhibitor reversed this effect in H1299 cells stably expressing miR-512. miR-512-5p inhibited glycolysis and migration in NSCLC cells, but shows no effect on cell proliferation. We identified p21 as a target gene of miR-512-5p. Overexpression of miR-512-5p led to the decrease of p21 protein and mRNA level. Knockdown of p21 resulted in similar effects on apoptosis and glycolysis as that observed of miR 512-5p overexpression, as well as rescued the effect of miR-512-5p inhibitor on cell apoptosis in H1299 cells stably expressing miR-512. In conclusion, our present study revealed miR-512-5p was able to target p21 to induce apoptosis and inhibit glycolysis in A549 and H1299 cell lines. PMID- 26648285 TI - [Corrigendum] Cannabinoid WIN55, 212-2 induces cell cycle arrest and inhibits the proliferation and migration of human BEL7402 hepatocellular carcinoma cells. PMID- 26648286 TI - [Zinc-dependent metalloprotease 1 promotes apoptosis of RAW264.7 macrophages]. AB - OBJECTIVE: To construct the eukaryotic expression vector of zinc-dependent metalloprotease 1 (zmp1) gene from Bacillus Calmette-Guerin (BCG) and investigate its impact on the apoptosis of RAW264.7 macrophages. METHODS: Zmp1 gene was amplified from the genome of BCG by PCR. The zmp1 gene fragment was inserted into multiple cloning sites of pEGFP-N1 to construct the eukaryotic expression vector pEGFP-N1-zmp1. The constructed pEGFP-N1-zmp1 was transfected into RAW264.7 cells by Lipofectamine(TM) 2000. The expression of green fluorescent protein (GFP) was observed by fluorescence microscopy. The zmp1 mRNA was detected by quantitative real-time PCR (qR-PCR). The effect of Zmp1 protein on the apoptosis of RAW264.7 macrophages was detected by flow cytometry (FCM). RESULTS: With zmp1 gene amplified by PCR, we successfully constructed the recombinant vector pEGFP-N1 zmp1 as demonstrated by restriction enzyme analysis and sequencing. GFP was seen in RAW264.7 cells 24 hours after transfected with the recombinant plasmid. As qRT PCR showed, the expression level of zmp1 mRNA was up-regulated. The early apoptotic rate increased 48 hours after transfection. CONCLUSION: The increased expression of Zmp1 in RAW264.7 cells promotes the apoptosis of RAW264.7 cells. PMID- 26648287 TI - [Expression of Dengue virus type 2 nonstructural protein 3 and isolation of host proteins interacting with it]. AB - OBJECTIVE: To construct the plasmid expressing the fusion protein of Dengue virus type 2 (DENV2) nonstructural protein 3 (NS3) with affinity tag, and isolate the cellular proteins interacting with NS3 protein using tandem affinity purification (TAP) assay. METHODS: Primers for amplifying NS3 gene were designed according to the sequence of DENV2 genome and chemically synthesized. The NS3 fragments, after amplified by PCR with DENV2 cDNA as template, were digested and cloned into the mammalian eukaryotic expression vector pCI-SF with the tandem affinity tag (FLAG StrepII). The recombinant pCI-NS3-SF was transiently transformed by Lipofectamine(TM) 2000 into HEK293T cells, and the expression of the fusion protein was confirmed by Western blotting. Cellular proteins that interacted with NS3 were isolated and purified by TAP assay. RESULTS: The eukaryotic expression vector expressing NS3 protein was successfully constructed. The host proteins interacting with NS3 protein were isolated by TAP system. CONCLUSION: TAP is an efficient method to isolate the cellular proteins interacting with DENV2 NS3. PMID- 26648288 TI - [B cells from streptozotocin-induced mouse diabetic model inhibit insulin secretion of MIN-6 cells and promote production of insulin autoantibody]. AB - OBJECTIVE: To explore the role of B cells in the progression of mouse diabetes induced by streptozotocin (STZ). METHODS: The ICR mouse diabetic model was induced by low-dose STZ injection. Radioimmunoassay was performed to examine the serum levels of insulin, and ELISA was conducted to detect insulin autoantibody (IAA). B cells from STZ-treated mice and control group were sorted by CD19 magnetic activated cell sorting (MACS), and cell purity was verified by flow cytometry. The PBS-treated MIN-6 cells were used as blank control group (group A); the isolated normal mouse B cells were incubated with MIN-6 cells as group B; B cells isolated from normal mice were pre-stimulated with 20 MUg/mL lipopolysaccharides (LPS), then were incubated with MIN-6 cells, as group C; and B cells isolated from STZ-treated mice were incubated with MIN-6 cells, as group D. The mRNA and protein levels of insulin were detected by quantitative real-time PCR (qRT-PCR) and radioimmunoassay, respectively. The levels of IAA and transforming growth factor beta(TGF-beta) were detected by ELISA. RESULTS: Compared with group A, STZ-treated mice showed reduced body mass and serum insulin, but increased blood glucose and IAA levels. Flow cytometry indicated that the proportion of CD19(+) B cells were 98%. Compared with group A or B, group C or D presented with decreased mRNA and protein levels of insulin in MIN-6 cells, simultaneously, increased expressions of IAA and TGF-beta. CONCLUSION: B cells isolated from STZ-treated mice promotes the production of IAA and inhibits the secretion of insulin in MIN-6 cells. PMID- 26648289 TI - [Baicalin increases the antioxidant capacity via promoting the nuclear translocation of NF-E2-related factor 2 (Nrf2) in N2a/APPswe cells]. AB - OBJECTIVE: To investigate the protective effect and related mechanism of baicalin in murine neuroblastoma N2a cells stably expressing human Swedish mutant amyloid precursor protein (APP) (N2a/APPswe cells), a cellular model of Alzheimer' s disease (AD). METHODS: MTT assay was performed to observe the effect of baicalin (0.1, 0.5, 1, 5, 10, 20) MUmol/L on the viability of N2a/APPswe cells. After N2a/APPswe cells were incubated with (1, 5, 10) MUmol/L baicalin for 48 hours, xanthine oxidase assay was used to test superoxide dismutase (SOD) activity and thiobarbituric acid method to detect malondialdehyde (MDA) content in each group. Real-time quantitative PCR was applied to determine nuclear factor erythroid 2 related factor 2 (Nrf2) mRNA, and Western blotting to examine protein levels of total Nrf2, nuclear Nrf2 and nuclear factor kappaB (NF-kappaB) in N2a/APPswe cells exposed to different doses of baicalin. Immunofluorescence staining was also used to observe the distribution of Nrf2. RESULTS: We found that baicalin pretreatment increased cell viability. Compared with the control group (N2a/wt cells), SOD activity in N2a/APPswe cells significantly decreased, and MDA content significantly increased; but SOD activity was improved and MDA production was inhibited after pretreatment with baicalin, especially with 10 MUmol/L bacalin. Both mRNA and total protein expression of Nrf2 were not significantly changed in baicalin treatment group compared with N2a/APPswe group, but the nuclear protein of Nrf2 distinctly increased after treatment with baicalin. In addition, baicalin decreased the level of nuclear NF-kappaB protein. Furthermore, immunofluorescence staining revealed that baicalin promoted the translocation of Nrf2 to the nucleus. CONCLUSION: Baicalin has the protection against oxidative stress via activation of Nrf2 in N2a/APPswe cells. PMID- 26648290 TI - [Up-regulating effect of leptin on Hedgehog signaling pathway in the process of adipocyte differentiation and maturity]. AB - OBJECTIVE: To study the regulating effect of leptin on Hedgehog (Hh) signaling pathway. METHODS: 3T3-L1 cells were used to induce adipocyte differentiation. Real-time quantitative PCR and Western blotting were performed to detect the mRNA and protein levels of Gli, the key molecule in Hh signaling pathway, and investigate the effect of leptin on the levels in the process of adipocyte differentiation. RESULTS: At 0, 4, 7, 10 days of adipose differentiation, mRNA and protein expressions of Gli1, Gli2 and Gli3 in Hh signaling pathway were gradually restrained and the down-regulation of Gli1 mRNA was the most significant. However, 100 ng/mL leptin promoted the mRNA and protein expressions of Gli1, Gli2 and Gli3 during adipose differentiation. CONCLUSION: In the process of adipocyte differentiation and maturity, there is an interaction between leptin and Hh signaling pathway. Leptin can upregulate the expression of Gli in Hh pathway, and leptin may play a role in the inhibition of adipogenesis through activating Hh signaling pathway. PMID- 26648291 TI - [Molecular structural characteristics and the functions of mouse DNA-dependent activator of interferon-regulatory factors]. AB - OBJECTIVE: To study the structural characteristics of the mouse DNA-dependent activator of interferon-regulatory factors (DAI) and its related molecular mechanism in anti-viral innate immune responses and signal transduction. METHODS: The coding sequence of mouse DAI gene was amplified from splenic mononuclear cells by reverse transcription-PCR, and the genetic evolution and molecular structure of the mouse DAI gene were analyzed by bioinformatics softwares. After mouse DAI was stimulated by poly(dA-dT) and poly(dG-dC), the nuclear factor kappaB (NF-kappaB) and interferon-beta (IFN-beta) promoter-driven luciferase activity were detected by dual-luciferase reporter assay system. RESULTS: The open reading frame (ORF) of the cloned mouse DAI sequence was 1236 bp, encoding 411 amino acids, which exhibited identity with the corresponding sequences of cattle, pig, rat and other mammals ranging from 60%, 63.1%, 84%, and it contained two Z-DNA domains (Zalpha and Zbeta), DNA binding region (D3) and signaling domain (SD). The stimulation of poly (dA-dT) increased the expressions of mouse DAI activated transcription factors NF-kappaB and IFN-beta promoter. However, the stimulation of poly(dG-dC) only induced the activation of NF-kappaB but not IFN beta promoter. CONCLUSION: Mouse DAI as an important cytosolic DNA sensor, is responsible for the recognition of A/T or G/C-rich DNA derived from DNA virus. It may play an important role in anti-viral innate immune responses. PMID- 26648292 TI - [Rab23 enhances invasion of Sa3 cutaneous squamous cell carcinoma cells via up regulating the expression of Rac1]. AB - OBJECTIVE: To investigate the effect of Ras-related protein 23 (Rab23) on the invasion capacity of Sa3 cutaneous squamous cell carcinaoma (cSCC) cells and determine whether Rab23 can enhance the invasion of Sa3 cells through regulation of Ras-related C3 botulinum toxin substrate 1 (Rac1). METHODS: Sa3 cells stably expressing exogenous Rab23 or Sa3 cells deprived of endogenous Rab23 were generated using lentivirus transfection. Transwell(TM) invasion assay was used to evaluate the invasion capacity in the above-mentioned cells. The effects of Rab23 overexpression or knockdown on Rac1 expression were assessed using Western blotting. In the last experimental setting, the engineered cells were pretreated with Rac1 inhibitor Z62954982 before being subjected to the assessment of invasion capacity by Transwell(TM) assay. RESULTS: Rab23 overexpression enhanced the invasion ability, whereas ablation of Rab23 attenuated the invasion in Sa3 cells. Rab23 could up-regulate the expression level of Rac1. Finally, using Rac1 inhibitor, we successfully suppressed the invasion capacity of Sa3 cells stably overexpressing Rab23. CONCLUSION: Rab23 may enhance cSCC cell invasion via up regulating Rac1 signaling. PMID- 26648293 TI - [Recombinant influenza A virus NS2 protein inhibits the production of interferon in lung tissues of infected mice]. AB - OBJECTIVE: To obtain non-structural protein 2 (NS2) of influenza A virus (IAV) via the expression system of Escherichia coli, and observe the effect of NS2 on the production of interferon gamma (IFN-gamma) in mouse lung tissues. METHODS: A prokaryotic expression plasmid pET22b(+)/NS2 was constructed and transformed into Rosetta-gami(2) of Escherichia coli. Through the inducible expression and purification, NS2 was prepared. Forty BALB/c mice were divided randomly into 8 groups, normal control group, 200 MUg/kg NS2 joint virus group, 200 MUg/kg NS2 joint RNA group, 100 MUg/kg inactivated virus group, 0.2*lethal dose 50% (LD50) virus group, viral RNA group of 50 MUg/kg, 200 MUg/kg NS2 group, and 100 MUg/kg NS2 group. All mice were subjected to nasal inhalation. Reverse transcription-PCR and Western blotting were respectively performed to detect the mRNA and protein expressions of IFN-gamma in lung tissues. RESULTS: Recombinant NS2 was obtained by the induction of isopropyl-beta-D-thiogalactopyranoside (IPTG) and purification. After the nasal inhalation of NS2 or/and IAV to mice, reverse transcription-PCR and Western blotting showed that the levels of IFN-gamma mRNA and protein in the lung tissues of NS2 joint virus group were lower than those of the virus group. CONCLUSION: NS2 could inhibit the expressions of IFN-gamma mRNA and protein in lung tissues of mice infected by IAV. PMID- 26648294 TI - [Changes of six serum biomarkers of rabbits with experimental osteoarthritis]. AB - OBJECTIVE: To investigate the value and significance of six serum biomarkers to the early diagnosis of osteoarthritis by means of quantitative detection of interleukin-1 beta (IL-1beta), matrix metalloproteinase 13 (MMP-13), IL-6, C terminal telopeptide of collagen type II (CTX2), cyclooxygenase 2 (COX2) and prostaglandin E2 (PGE2) levels with time going on. METHODS: 40 New Zealand white rabbits were divided into experimental group (n=20) and control group (n=20). Injection of collagenase into articular cavity was performed in the experimental group for modeling. No treatment was done in the control group. Pathological observation, X-ray examination and HE staining of knee joints were conducted to verify the establishment of modeling. IL-1, MMP-13, IL-6, CTX2, COX2 and PGE2 levels were detected every two weeks after modeling in the experimental group, and these biomarkers were also detected in the control group at the same time points. RESULTS: Levels of the six serum biomarkers in the experimental group were significantly higher than those in the control group at each time point after modeling and were the most distinguishing at the 4th week. CONCLUSION: Combined detection of IL-1beta, IL-6, CTX2, COX2 and PGE2 in serum is helpful for early diagnosis of osteoarthritis. PMID- 26648295 TI - [Expression and affinity purification of Mycobacterium tuberculosis His-LprG-FLAG in HEK293T cells]. AB - OBJECTIVE: To construct a eukaryotic expressing vector of Mycobacterium tuberculosis lipoprotein G (LprG), and express and purify the recombinant protein in HEK293T cells by affinity chromatography. METHODS: The LprG gene was amplified by PCR from the genome of MTB strain H37Rv. The subsequent PCR product and eukaryotic expressing vector pcDNA3.1 were digested by certain restriction enzymes. The recombinant vector, pcDNA3.1-His-LprG-FLAG, was constructed by ligation of target genes and the vector. After identified by enzymes digestion and DNA sequencing analysis, the correct recombinant vector was applied for transfection of HEK293T cells. The expression of His-LprG-FLAG was examined by Western blotting. The target fusion protein successfully expressed in HEK293T cells was purified by Ni(2+) affinity chromatography, and the purification and concentration of the protein was evaluated by SDS-PAGE and Western blotting. RESULTS: The recombinant vector pcDNA3.1-His-LprG-FLAG was successfully constructed, which was identified by double enzyme digestion and DNA sequencing. Western blotting indicated that the fusion protein was expressed in HEK293T cells transfected with the vector, with the molecular mass (Mr) being 27 000. By Ni2+ affinity chromatography, the fusion protein could be purified to a high concentration, as evaluated by SDS-PAGE and Western blotting. CONCLUSION: Fusion protein His-LprG-FLAG has been successfully prepared and expressed in HEK293T cells. PMID- 26648296 TI - [Expression and purification of human sucrase protein in E.coli]. AB - OBJECTIVE: To construct prokaryotic expression vector pET-28a(+)-human sucrase (hSUC) and express hSUC fusion protein in E.coli. METHODS: The hSUC gene fragment was amplified by reverse transciption PCR (RT-PCR) and cloned into pET-28a(+) vector to construct the prokaryotic expression vector pET-28a(+)-hSUC. The recombinant plasmid was then transformed into E.coli BL21. Hisdidine (His)-tagged fusion proteins were induced by isopropyl-beta-D-thiogalactopyranoside (IPTG) and purified by nitrilotriacetic acid (Ni-NTA) agarose resin. The purified fusion proteins were identified by SDS-PAGE and Western blotting. RESULTS: RT-PCR showed that sub-clone of hSUC was about 1482 bp. The recombinant plasmid was correctly constructed as demonstrated by sequencing and restriction enzyme analysis. The molecular mass of the fusion protein was about 61 240. Western blotting showed that the fusion proteins bound specifically to hSUC antibody. CONCLUSION: The hSUC protein has been successfully expressed and purified in E.coli. PMID- 26648297 TI - [Se-ZnCu-65P enhances mouse peritoneal macrophage phagocytosis and inhibits secretion of NO and H2O2 in vitro]. AB - OBJECTIVE: To investigate the effect of selenopeptide on phagocytosis, NO and H2O2 secretion of mouse peritoneal macrophages. METHODS: Mouse peritoneal macrophages induced by lipopolysaccharide (LPS) were cultured for 24 hours by various concentrations of Se-ZnCu-65P, which is a selenopeptide with double antioxidant activity of superoxide dismutase (SOD) and glutathione peroxidase (GPx). Then, the relative cell activity was determined by methyl thiazolyl tetrazolium (MTT) assays, the phagocytic ability of macrophages was evaluated by neutral red uptake assay, nitric oxide (NO) content was examined by nitrate reductase method, and hydrogen peroxide (H2O2) content was detected by molybdate colorimetric method. RESULTS: When Se-ZnCu-65P acted on macrophages alone, the relative cell viability was enhanced, the phagocytic ability was not affected, H2O2 content was reduced, and NO level was almost unchanged. However, the phagocytic ability of macrophages induced by LPS was raised, meanwhile, secretion of NO and H2O2 was promoted. When Se-ZnCu-65P acted on macrophages induced by LPS, the phagocytic ability were further enhanced, and secretion of NO and H2O2 was inhibited significantly. CONCLUSION: Se-ZnCu-65P can effectively improve the relative cell activity of mouse peritoneal macrophages induced by LPS, enhance the phagocytic ability of macrophages, and reduce the secretion levels of NO and H2O2. PMID- 26648298 TI - [Establishment of a mouse model of acute graft-versus-host disease by busulfan combined with cyclophosphamide]. AB - OBJECTIVE: To develop a stable mouse model of acute graft-versus-host disease (aGVHD) by preconditioning with busulfan (BS)-cyclophospha mide (CP). METHODS: Male BALB/c (H-2kd) as recipients were conditioned with 100 mg/kg BS and 200 mg/kg CP followed by being transplanted with bone marrow cells (2*10(7)) or bone marrow cells (2*10(7))-spleen cells (2*10(7)) from female C57BL/6(H-2Kb) as donors. The general data of the transplanted mice were recorded and the manifestations of aGVHD were evaluated. Histopathological changes were observed using HE staining and chimerism in spleen and bone marrow cells was studied using flow cytometry. RESULTS: Mice transplanted with bone marrow cells-spleen cells developed classic aGVHD manifestations starting from the 7th day after transplantation with full donor chimerism. GVHD histopathological changes were seen in liver, spleen, intestine, skin and lung of these mice. The median survival time of these aGVHD mice was 10 days, and they all died within 30 days. Mice transplanted with only bone marrow cells survived over 45 days without any aGVHD signs. CONCLUSION: We developed a stable and reliable aGVHD murine model successfully, which can be used to study the pathogenesis, prevention and therapeutic effect of aGVHD. PMID- 26648299 TI - [Neuregulin-1 promotes proliferation and migration of human coronary artery smooth muscle cells by enhancing its receptor phosphorylation]. AB - OBJECTIVE: To explore the effect of neuregulin-1 (NRG1) on proliferation and migration of human coronary artery smooth muscle cells (HCASMCs). METHODS: HCASMCs were cultured in vitro. The expressions of human epidermal growth factor receptor 2 (ErbB2), ErbB3 and ErbB4 and the phosphorylation of these receptors in HCASMCs were detected by Western blotting. The proliferation of HCASMCs treated with different concentrations of NRG1 was examined by MTT assay, and the migration ability of HCASMCs treated with different concentrations of NRG1 was tested by Transwell(TM) assay. RESULTS: ErbB2, ErbB3 and ErbB4 were expressed in HCASMCs. Compared with the control group, the phosphorylation levels of three receptors increased significantly in NRG1 treatment groups. The proliferation and migration abilities of HCASMCs treated with different concentrations of NRG1 were different, and 10 ng/mL NRG1 markedly promoted the proliferation and migration of HCASMCs. CONCLUSION: NRG1 can promote the proliferation and migration of HCASMCs by enhancing the phosphorylation of ErbB2, ErbB3 and ErbB4, suggesting NRG1 may have promoting effect on the angiogenesis of HCASMCs. PMID- 26648300 TI - [The expression and significance of hnRNPD in esophageal squamous cell carcinoma cells]. AB - OBJECTIVE: To investigate the expression of heterogeneous nuclear ribonucleoprotein D (hnRNPD) in esophageal squamous cell carcinoma (ESCC) tissues and the relationship between hnRNPD expression and the clinicopathological features of ESCC, and to study the effect of down-regulated hnRNPD on the proliferation of ESCC cells and explore its potential mechanism. METHODS: The expression of hnRNPD protein in ESCC tissues and the normal paracancerous tissues were detected by immunohistochemistry. The siRNA-hnRNPD was transfected into ESCC cells and the silence effect was verified by Western blotting. MTT assay and clone formation assay were used to evaluate the proliferation of ESCC cells after down-regulation of hnRNPD genes. Cell apoptosis was examined by annexin V phycoerythrin/7-aminoactinomycin D (annexin V-PE/7-AAD) staining and flow cytometry. RESULTS: The expression of hnRNPD protein in ESCC tissues was significantly higher than that of the normal paracancerous tissues, and the expression was closely related with neoplasm staging. Down-regulation of hnRNPD inhibited the proliferation and clonality of ESCC cells. Compared with the control group, siRNA targeting hnRNPD significantly promoted cell apoptosis. CONCLUSION: Down-regulation of hnRNPD inhibits the proliferation of ESCC cells by promoting cell apoptosis. PMID- 26648301 TI - [C1q tumor necrosis factor-related protein 6 (CTRP6) inhibits the proliferation and migration of ovarian cancer cells]. AB - OBJECTIVE: To explore the role of C1q tumor necrosis factor-related protein 6 (CTRP6) in the proliferation and migration of ovarian cancer cells. METHODS: ELISA was used to detect the serum CTRP6 contents in ovarian cancer patients and healthy volunteers, and CTRP6 levels in the supernatants of SKOV3, 3AO and HO8910 epithelial ovarian cancer cell lines and IOSE80 normal ovarian epithelial cells. Recombinant human CTRP6 protein was applied to treat HO8910 cells. After incubation for 48 hours, ELISA was used to detect the levels of interleukin-8 (IL 8) and vascular endothelial growth factor (VEGF) in the supernatants. The proliferation of HO8910 cells were detected by CCK-8 assay and the ability of invasion was determined by Transwell(TM) invasion assay. CTRP6 siRNA or anti CTRP6 antibody was used to treat HO8910 cells, and then the ability of proliferation was also detected by CCK-8 assay and the ability of migration was evaluated by wound healing experiment. RESULTS: The level of CTRP6 decreased in the sera of the patients with ovarian cancer and the supernatants of epithelial ovarian cancer cells. The levels of IL-8 and VEGF were reduced by the recombinant CTRP6 protein treatment, and the cell proliferation and invasion were also inhibited. CTRP6 siRNA or anti-CTRP6 antibody treatment promoted cell proliferation and migration. CONCLUSION: The level of CTRP6 dropped in the sera of the patients with ovarian cancer as well as in the supernatants of epithelial ovarian cancer cells. CTRP6 could inhibit the proliferation and migration of ovarian cancer cells via blocking IL-8/VEGF pathway. PMID- 26648302 TI - [Hyperoxia induces reactive oxygen species production and promotes SIRT1 nucleocytoplasmic shuttling of peripheral blood mononuclear cells in premature infants in vitro]. AB - OBJECTIVE: To explore the relationship between deacetylase sirtuin 1 (SIRT1) and reactive oxygen species (ROS) after oxygen therapy in the peripheral blood mononuclear cells (PBMCs) of the premature infants. METHODS: According to the fraction of inspired O2 (FiO2), premature infants diagnosed with respiratory distress syndrome (RDS) (gestational age <32 weeks), were divided into three groups: low dosage oxygen group (FiO2 <300 mL/L), moderate dosage oxygen group (FiO2; 300 mL/L-400 mL/L), high dosage oxygen group (FiO2 >400 mL/L). After 48 hours of oxygen treatment, PBMCs and serum were collected from the peripheral blood. Then the intracellular ROS level was detected by MitoSOX(TM) Red labeling combined with confocal laser scanning microscopy; the malondialdehyde (MDA) content in the serum was determined by the whole spectrum spectrophotometer; the SIRT1 localization was observed by immunofluorescence staining; and the SIRT1 levels in PBMCs were examined by Western blotting. RESULTS: With the increase of FiO2, the ROS, MDA content and the rate of SIRT1 nucleocytoplasmic shuttling of PBMCs gradually increased and SIRT1 protein expression was significantly lowered. CONCLUSION: Hyperoxia induces ROS production in premature infants, promotes SIRT1 to cross from nucleus to cytoplasm, inhibits the resistant ability of SIRT1 to oxidative stress. PMID- 26648303 TI - [An increased level of interleukin 27 in peripheral blood mononuclear cells and fibroblasts like synoviocytes of patients with rheumatoid arthritis or osteoarthritis]. AB - OBJECTIVE: To detect the levels of interleukin 27 (IL-27) and its receptor in peripheral blood mononuclear cells (PBMCs) and fibroblasts like synoviocytes (FLS) of patients with rheumatoid arthritis (RA) or osteoarthritis (OA). METHODS: PBMCs were collected from 20 patients with RA, 20 patients with OA and 20 healthy controls. FLS were cultured from synovial tissues of 4 patients with RA and 4 patients with OA. The levels of IL-27 mRNA in PBMCs and FLS were measured using real-time quantitative PCR. The expression of IL-27Ralpha in FLS was detected using immunocytochemical method. RESULTS: The level of IL-27 mRNA in PBMCs of patients with RA or OA was 1.81 or 2.07 times of the level in the normal subjects, respectively. There was no significant difference in the IL-27 mRNA level between RA and OA. However, IL-27 mRNA level in FLS of the patients with RA was 3.74 times of the level in the patients with OA. IL-27Ralpha expression in FLS of RA group was higher than that in OA group. CONCLUSION: The level of IL-27 in patients with RA and OA increased, and the level of IL-27 in FLS was higher than that in PBMCs in RA patients. PMID- 26648304 TI - [Expression and clinical significance of BCL6 corepressor-like 1 in non-small cell lung cancer]. AB - OBJECTIVE: To detect the expression of BCL6 corepressor-like 1 (BCORL1) in tumor tissues of human non-small cell lung cancer (NSCLC) and determine the effect of BCORL1 on cell migration and invasion in A549 cells by knockdown of BCORL1. METHODS: Sixty-eight pairs of NSCLC and nontumor tissues were collected and the expressions of BCORL1 and E-cadherin in them were detected using immunohistochemical staining. The expression of BCORL1 was knocked down by siRNA in A549 cells. Transwell(TM) assays were performed to test NSCLC cell migration and invasion in vitro. RESULTS: The expression of BCORL1 in NSCLC was significantly higher than that in paired noncancerous tissues, while E-cadherin was down-regulated in NSCLC as compared with nontumor tissues. Pearson correlation coefficient analysis suggested that BCORL1 was negatively correlated with E-cadherin expression in NSCLC tissues. Clinical association analysis suggested that the elevated expression of BCORL1 was evidently associated with the higher incidence of lymph node metastasis and more advanced TNM stage. When the expression of BCORL1 was down-regulated by a specific siRNA, E-cadherin was up-regulated, and BCORL1 knockdown obviously inhibited cell migration and invasion in A549 cells. CONCLUSION: BCORL1 is overexpressed in NSCLC tissues and it is negatively correlated with E-cadherin expression. Its high expression is correlated with poor prognostic features. BCORL1 knockdown up-regulates E cadherin expression and subsequently inhibits cell migration and invasion of lung cancer cells. PMID- 26648305 TI - [Transfected miR-1908 inhibits renal fibrosis via targeting transforming growth factor beta 1]. AB - OBJECTIVE: To explore the regulatory role of miR-1908 in renal fibrosis. METHODS: The level of miR-1908 and transforming growth factor beta 1 (TGF-beta1) mRNA during renal fibrosis were detected with real-time quantitative PCR. Bioinformatics and luciferase reporter gene analyses were applied to determine the targeting relationship between miR-1908 and TGF-beta1 mRNA. After primary human renal interstitial fibroblasts were transfected with miR-1908 adenoviral expression vector in vitro, Western blotting was used to detect the protein levels of TGF-beta1, smad2/3 and matrix metalloproteinase 2 (MMP-2) in the cells. Six weeks after intraperitoneal injection of miR-1908 adenoviral vector, the renal tissue sections of the renal fibrosis mouse models were stained with Masson staining. RESULTS: Human miR-1908 showed a gradually decreasing expression during renal fibrosis process, which was completely contrary to the changes of TGF-beta1 mRNA. Overexpression of miR-1908 suppressed the expressions of TGF-beta1, smad2/3 and MMP-2 in human primary renal interstitial cells. The renal fibrosis was significantly relieved in the mice injected with miR-1908 adenovirus vector injection compared with the ones without injection. CONCLUSION: miR-1908 could inhibit renal fibrosis through targeting TGF-beta1. PMID- 26648306 TI - [Preparation and application of monoclonal antibody against human LOC339524 protein]. AB - OBJECTIVE: To prepare and apply monoclonal antibody (mAb) against human LOC339524 protein. METHODS: The non-glycosylated antigenic gene sequence of the LOC339524 protein was expressed in triplicate to enhance immunogenicity. Then this synthetic gene was connected to pET28a plasmid. Recombinant LOC339524 protein was obtained by E.coli expression system and was administered intraperitoneally as an immunogen to BALB/c mice to obtain mAb. The specificity and titer of the mAb were characterized by ELISA. Recombinant LOC339524 protein was identified through Western blotting. The expression of the LOC339524 protein in human myocardial tissues and H9C2 cells were detected by immunohistochemistry, and its level in the sera of patients with different heart diseases was detected with the antibody. RESULTS: We obtained two hybridoma cell lines, 5-D3 and 4-F8, secreting specific mAbs against LOC339524 protein. The titer of 5-D3 was up to 2*10(6), higher than the titer of 4-F8. Western blotting and immunohistochemistry demonstrated that 5-D3 could specifically recognize LOC339524 protein of Homo sapiens and Rattus norvegicus. With the antibody we obtained, we successfully detected the serum level of LOC339524 protein in patients with different heart diseases. CONCLUSION: The mAb against human LOC339524 protein with good specificity and high titer has been successfully prepared. PMID- 26648307 TI - [Selection and identification of completely humanized anti-IL-4 single-chain antibodies]. AB - OBJECTIVE: To express human interleukin 4 (IL-4), select completely humanized anti-IL-4 single-chain antibodies (scFvs) from the completely humanized scFv library and identify their specificity. METHODS: With IPTG-induced pET102/IL 4/BL21, human IL-4 was synthesized, and then purified and identified. Completely humanized scFvs against IL-4 were expressed from the completely humanized antibody phage library, and positive clones were selected with human IL-4 as antigen. The positive clones were tested by PCR, enzyme cleavage and sequencing. The specificity of the completely humanized anti-IL-4 scFvs was determined by dot blot hybridization. RESULTS: The relative molecular mass (Mr) of IL-4 fusion protein was about 27 000. With IL-4 as antigen, we obtained the positive clones expressing anti-IL-4 antibodies. PCR showed amplified target bands of about 1000 bp. Enzyme cleavage analysis revealed that fingerprint maps of the selected clones were diverse except 2 clones. Among 4 clones expressing scFvs that had different fingerprint maps and strong binding to IL-4, sequencing showed the sequence of 3 was correct. Then, dot blot hybridization demonstrated that the scFvs expressed by the 3 clones were specific. CONCLUSION: Completely humanized scFvs against IL-4 has been obtained successfully. PMID- 26648308 TI - Survivin is expressed in degenerated nucleus pulposus cells and is involved in proliferation and the prevention of apoptosis in vitro. AB - Survivin is a unique inhibitor of apoptosis, which is frequently present within degenerated human nucleus pulposus (NP) cells. Survivin has been extensively investigated using proliferation and apoptosis assays in tumor cells; however, studies conducted on survivin in degenerative NP cells remain limited to date. The aim of the present study was to investigate survivin expression and its effects on the proliferation and apoptosis of degenerated NP cells in vitro. The expression levels of survivin in the NP cells of patients (>45 years) with lumbar disc degenerative disease and the NP cells of patients (<25 years) with lumbar vertebra fracture were assessed by reverse transcription-quantitative polymerase chain reaction. The effects on in vitro proliferation and apoptosis were investigated through transfection with a specific small interfering (si)RNA. The results of the present study demonstrated that survivin was expressed in the degenerated NP cells, but was undetectable in normal NP cells at the mRNA level. Survivin suppression following transfection with a specific survivin-siRNA reduced the proliferation rate of NP cells and enhanced sensitization to pro apoptotic stimuli. Therefore, survivin was shown to be expressed and exhibit an important role in the proliferation and prevention of apoptosis of degenerated NP cells. Studies on survivin in NP cells may aid in increasing the understanding of the complex processes underlying NP cell degeneration, and could provide fundamental information for gene therapy to inhibit this degeneration in vitro. PMID- 26648309 TI - Evaluation of the dynamic pattern of viral evolution in patients with virological breakthrough during treatment with nucleoside/nucleotide analogs by ultra-deep pyrosequencing. AB - Virological breakthrough is a clinical manifestation in patients infected with chronic hepatitis B (CHB), who undergo treatment with nucleoside/nucleotide analogs (NUCs). The current understanding of the underlying mechanism of virological breakthrough is limited. Ultra-deep pyrosequencing (UDPS) is a novel and powerful tool used to investigate minor viral variants and viral evolution. The present study used UDPS to investigate the viral evolution pattern during virological breakthrough in patients with CHB treated with NUCs. A total of 12 patients who experienced virological breakthrough were recruited in the present study. During the treatment with lamivudine, adefovir was added as a rescue therapy when virological breakthrough emerged, and the therapy was continued until week 96. Serum samples from each patient were collected at different time points for UDPS analysis. Treatment with lamivudine resulted in an increased rate of the viral mutations, rtM204V/I, rtL180M and rtL80I. Virological breakthrough was accompanied by significant rtM204I/V substitutions in eight of the patients. A total of three types of rt204 mutation, associated with virological breakthrough, were observed, including YIDD variant-dominated, YVDD variant dominated and YMDD wild-type-dominated virological breakthrough. YVDD variants reverted to the wild-type following the adefovir add-on rescue therapy, although the YIDD variants remained dominant following the combination therapy. The mechanism underlying virological breakthrough was revealed to be complex and associated with the rapid replication of mutated variants. UDPS analysis, therefore, provided a useful tool to investigate the dynamic evolution pattern of hepatitis B virus. PMID- 26648310 TI - Clinical applications of diffusion-weighted magnetic resonance imaging in diagnosis of renal lesions - a systematic review. AB - Diffusion-weighted magnetic resonance imaging (DW-MRI) is an established technique to detect the changes of the diffusion of water in biological tissues and reflect the pathophysiological process on the molecular level. It is a promising non-invasive imaging modality in detection of microstructural and functional changes in pathologies of kidney. To systematically review the research advancement of the DW-MRI in diagnosis of renal lesions, a systematic literature search was performed up to 8 October 2014 using the MEDLINE/PubMed and Embase databases for articles reporting on DW-MRI in diagnosis of renal lesions. Only articles with full data about DW-MRI application with potential implication in solving usually encountered clinical challenges about renal lesions were finally examined. The clinical application of DW-MRI allows a better understanding of some pathologic conditions of the kidney including renal insufficiency, renal artery stenosis, ureteral obstruction, foetal kidney disease, hydronephrosis and pyonephrosis. In addition, DW-MRI can also provide clinicians with the information of function evaluation of renal allograft and curative effect assessment of renal tumour. In summary, performance of renal DW MRI, presuming that measurements are high quality, will further boost this modality, particularly for early detection of diffusion renal conditions, as well as more accurate characterization of renal lesions. PMID- 26648311 TI - A neural coding scheme reproducing foraging trajectories. AB - The movement of many animals may follow Levy patterns. The underlying generating neuronal dynamics of such a behavior is unknown. In this paper we show that a novel discovery of multifractality in winnerless competition (WLC) systems reveals a potential encoding mechanism that is translatable into two dimensional superdiffusive Levy movements. The validity of our approach is tested on a conductance based neuronal model showing WLC and through the extraction of Levy flights inducing fractals from recordings of rat hippocampus during open field foraging. Further insights are gained analyzing mice motor cortex neurons and non motor cell signals. The proposed mechanism provides a plausible explanation for the neuro-dynamical fundamentals of spatial searching patterns observed in animals (including humans) and illustrates an until now unknown way to encode information in neuronal temporal series. PMID- 26648312 TI - Comparing and characterizing transient and steady-state tests of the peripheral chemoreflex in humans. AB - NEW FINDINGS: What is the central question of this study? We aimed to characterize the cardiorespiratory and cerebrovascular responses to transient and steady-state tests of the peripheral chemoreflex and to compare the hypoxic ventilatory responses (HVRs) between these tests. What is the main finding and its importance? The cardiovascular and cerebrovascular responses to transient tests were small in magnitude and short in duration. The steady-state isocapnic hypoxia test elicited a larger HVR than the transient 100% N(2) test, but the response magnitudes were correlated within individuals. The transient test of the HVR elicits fewer systemic effects than steady-state techniques and may have greater experimental utility than previously appreciated. Carotid chemoreceptors detect changes in arterial PO(2) and PCO(2), eliciting a peripheral chemoreflex (PCR). Steady-state (SS) hypoxia tests using dynamic end-tidal forcing (DEF) have been used to assess the hypoxic ventilatory response (HVR) but may be confounded by concomitant systemic effects. Transient tests of the PCR have also been developed but are not widely used, nor have the cardiovascular and cerebrovascular responses been characterized. We characterized the cardiorespiratory and cerebrovascular responses to transient tests of the PCR and compared the HVR between transient and SS-DEF tests. We hypothesized that the cardiovascular and cerebrovascular responses to the transient tests would be minimal and that the respiratory responses elicited from the transient and SS-DEF tests would be different in magnitude and not well correlated within individuals. Participants underwent five consecutive trials of two transient tests [three breath 100% N(2) (TT-N(2)) and a single-breath 13% CO(2), in air] and two 10 min SS-DEF tests [isocapnic (SS-ISO) and poikilocapnic (SS-POI) hypoxia]. In response to the transient tests, heart rate, mean arterial pressure and the middle and posterior cerebral artery blood velocity increased (all P < 0.01), but responses were small (all <10%) and transient. Although the TT-N(2) and SS-POI tests elicited similar HVR magnitudes, they were not well correlated within individuals (r = 0.064, P = 0.79). The TT-N(2) test elicited a smaller HVR than the SS-ISO test, but they were correlated within individuals (r = 0.57, P = 0.008). Given that the transient tests exploit the temporal domain of the peripheral chemoreceptors and have minimal cardiovascular and cerebrovascular confounders, we suggest that they may have broader utility than previously appreciated. PMID- 26648313 TI - Inhibitory effects of tetrandrine on epidermal growth factor-induced invasion and migration in HT29 human colorectal adenocarcinoma cells. AB - Tetrandrine has been shown to reduce cancer cell proliferation and to inhibit metastatic effects in multiple cancer models in vitro and in vivo. However, the effects of tetrandrine on the underlying mechanism of HT29 human colorectal adenocarcinoma cell metastasis remain to be fully elucidated. The aim of the present study was focused on tetrandrine-treated HT29 cells following epidermal growth factor (EGF) treatment, and Transwell, gelatin zymography, gene expression and immunoblotting assays were performed to investigate metastatic effects in vitro. Tetrandrine was observed to dose-dependently inhibit EGF-induced HT29 cell invasion and migration, however, no effect on cell viability occurred following exposure to tetradrine between 0.5 and 2 uM. Tetrandrine treatment inhibited the enzymatic activity of matrix metalloprotease (MMP)-2 and MMP-9 in a concentration dependent manner. The present study also found a reduction in the mRNA expression levels of MMP-2 and MMP-9 in the tetrandrine-treated HT29 cells. Tetrandrine also suppressed the phosphorylation of EGF receptor (EGFR) and its downstream pathway, including phosphoinositide-dependent kinase 1, phosphatidylinositol 3-kinase and phosphorylated AKT, suppressing the gene expression of MMP-2 and MMP-9. Furthermore, tetrandrine triggered mitogen-activated protein kinase signaling through the suppressing the activation of phosphorylated extracellular signal regulated protein kinase. These data suggested that targeting EGFR signaling and its downstream molecules contributed to the inhibition of EGF-induced HT29 cell metastasis caused by tetrandrine, eventually leading to a reduction in the mRNA and gelatinase activities of MMP-2 and MMP-9, respectively. PMID- 26648320 TI - Natural killer cell (NK) subsets and NK-like T-cell populations in acute myeloid leukemias and myelodysplastic syndromes. AB - The impact of the immune microenvironment on the behavior and therapeutic strategies for hematopoietic and lymphoid neoplasms is being increasingly recognized. Many functional studies of natural killer (NK) cell cytotoxic responses in myelodysplasia (MDS) and acute myeloid leukemia (AML) exist, but with limited data on these lymphocyte proportions and related T-cell subsets. The proportions of these cells and their prognostic implications were therefore investigated in 89 AML, 51 MDS, and 20 control marrows by flow cytometry. The median proportion of NK cells (relative to the total lymphocytes) was lower in AML versus controls (P = 0.01). Among AML, a lower proportion of NK cells predicted better survival, whereas a higher NK cell proportion was associated with the poor prognostic AML category (P = 0.002). NK cell proportions were similar in MDS, MDS subgroups, and control marrows. The relative proportion of the mature NK cell subset (CD56(dim) CD16/57(bright) ) was lower in AML and MDS versus controls (P = 0.006, P = 0.0002, respectively). The proportion of mature NK cells was not a prognostic indicator although fewer were seen in poor prognosis AML. In contrast, a lower proportion of mature NK cells correlated with worse survival in MDS (P = 0.027). A higher proportion of NK-like T-cells (of total lymphoid cells) was found in MDS compared to controls (P = 0.01). A lower proportion of NK-like T-cells predicted better survival in AML but not in MDS. Thus, the proportions of NK, NK-cell subsets, and NK-like T-cells vary in myeloid neoplasms, may potentially impact immunomodulatory therapies, and may impact outcome. (c) 2016 International Clinical Cytometry Society. PMID- 26648321 TI - Low skeletal muscle density is associated with poor survival in patients who receive chemotherapy for metastatic gastric cancer. AB - Low skeletal muscle density (SMD) and low skeletal muscle index (SMI) are associated with poor overall survival (OS) in patients with various types of cancer. We retrospectively studied SMD and SMI using computed tomographic (CT) scans in patients with gastric cancer receiving chemotherapy to evaluate its prognostic significance. SMD and SMI were obtained from CT-based analysis using Slice-O-Matic(r) medical imaging software in patients who received S-1 plus cisplatin chemotherapy for metastatic gastric cancer. The CT images taken within 1 month before starting chemotherapy were used. The cut-off values for determining low SMD [<33 Hounsfield units (HU) in obese and <41 HU in non-obese patients] and low SMI (<41 cm2/m2 in females, <43 cm2/m2 in non-obese males and <53 cm2/m2 in obese males) were referenced from a large population based study. The CT images of 53 patients were reviewed. The median SMD was 36.8 HU (range, 19.5-59.3 HU), and the median SMI was 39.8 cm2/m2 (range, 23.7-60.0 cm2/m2). Patients with low SMD had significantly shorter OS compared with patients having normal SMD (8.9 vs. 12.8 months, P=0.03). However, OS did not differ significantly between patients with low and normal SMI (11.1 and 14.3 months, P=0.18). Multivariate analyses confirmed that low SMD was an independent predictor of poor outcomes (P<0.01). SMD is an important prognosticator of survival in patients with metastatic gastric cancer receiving chemotherapy. PMID- 26648322 TI - Overview on biotherapeutic proteins: impact on bioanalysis. AB - This article provides an overview of the information and factors relevant to designing bioanalytical strategies in support of in vivo nonclinical and clinical studies of protein therapeutics. The summarized information includes representative types of the therapeutic proteins, their key structural characteristics, the relationship between post-translational modifications and function, issues during purification and formulation, PK of therapeutic proteins and immunogenicity. The effect of each of those on bioanalysis strategy has been pointed out. The impacts of structural variant and 'free'/'bound' forms on PK assessment have been discussed. PMID- 26648323 TI - Inhibition of Helicobacter pylori and Its Associate Urease by Labdane Diterpenoids Isolated from Andrographis paniculata. AB - The present study was carried out to evaluate anti-Helicobacter pylori and its associated urease activity of labdane diterpenoids isolated from Andrographis paniculata. A molecular docking analysis was performed by using ArgusLab 4.0.1 software. The results obtained indicate that compound A possesses strong inhibition to H. pylori, 28 +/- 2.98 (minimum inhibitory concentration, 9 ug/mL), and its urease, 85.54 +/- 2.62% (IC50 , 20.2 ug/mL). Compounds B, C, and D also showed moderate inhibition to H. pylori and its urease. The obtained results were in agreement with the molecular docking analysis of compounds. The phytochemicals under investigation were found to be promising antibacterial agents. Moreover, the isolated compounds can be considered as a resource for searching novel anti H. pylori agents possessing urease inhibition. PMID- 26648324 TI - Effects of integrin alpha5beta1 on the proliferation and migration of human aortic vascular smooth muscle cells. AB - Integrin (ITG) alpha5beta1 is a dominant fibronectin receptor that is abundantly expressed on the surface of vascular smooth muscle cells (VSMCs). However, the association between integrin alpha5beta1 and the proliferation and migration of VSMCs has yet to be elucidated. The aim of the present study was to characterize the roles of ITGalpha5 and ITGbeta1 in the proliferation and migration of VSMCs, and to determine the effects of ITGalpha5beta1 on integrin-linked kinase (ILK) and focal adhesion kinase (FAK) mRNA expression. Lentiviral expression vectors as well as RNA interference vectors of ITGalpha5 and ITGbeta1 were successfully constructed and transfected into VSMCs to obtain ITGalpha5- and ITGbeta1 overexpressing or -silenced cells, respectively. Cell cycle distribution, proliferation and migration were analyzed in the transfected VSMCs in order to clarify the roles of ITGbeta1 and ITGalpha5 in the proliferation and migration of VSMCs. ITGbeta1 was markedly associated with the proliferation and migration of VSMCs, and FAK was shown to be involved in the signaling pathways of ITGbeta1. ITGalpha5 did not exert any effects on VSMCs. The results of the present study may provide a possible therapeutic target for the prevention and treatment of early vascular disease associated with VSMCs. PMID- 26648325 TI - Extramedullary hematopoiesis: Elucidating the function of the hematopoietic stem cell niche (Review). AB - Extramedullary hematopoiesis (EMH) occurs under various circumstances, including during embryonic/developmental periods, pathological status secondary to insufficient bone marrow function or ineffective hematopoiesis, in hematological disorders, for example malignancies, as well as stromal disorders of the bone. EMH is characterized by hematopoietic cell accumulations in multiple body locations. Common EMH locations observed in clinical and pathological practice include the spleen, liver, lymph nodes and para-vertebral regions. Among the various organs associated with EMH, the spleen offers a unique site for evaluation of hematopoietic stem cell (HSC)/niche interactions, as this organ is one of the most common sites of EMH. However, the spleen does not have a major role in embryonic/developmental hematopoiesis. A recent study by our group revealed that circulating HSCs may be trapped by chemokine (C-X-C motif) ligand 12 (CXCL12)-positive cells at the margin of sinuses near CXCL12-positive endothelial cells, resulting in the initiation of the first step of EMH, which is a similar mechanism to bone marrow hematopoiesis. The present review briefly discusses the environment of EMH in extramedullary spaces in order to investigate the mechanisms underlying HSC maintenance, and aid the elucidation of the niche stem cell interactions that occur in the bone marrow. PMID- 26648326 TI - Macular thickening of uveitic eyes in the absence of macular oedema and epiretinal membranes. PMID- 26648327 TI - Computer-aided design and synthesis of magnetic molecularly imprinted polymers with high selectivity for the removal of phenol from water. AB - A molecular simulation method was introduced to compute the phenol-monomer pre assembled system of a molecularly imprinted polymer. The interaction type and intensity between phenol and monomer were evaluated by combining binding energy and charge transfer with complex conformation. The simulation results indicate that interaction energies are simultaneously affected by the type of monomer and the ratio between phenol and monomers. At the same time, we considered that by increasing the amount of functional monomer is not always better for preparing molecularly imprinter polymers. In this study, three kinds of novel magnetic phenol-imprinted polymers with favorable specific adsorption effects were prepared by the surface imprinting technique combined with atom transfer radical polymerization. Various measures were selected to characterize the structure and morphology to obtain the optimal polymer. The characterization results show that the optimal polymer has suitable features for further adsorption process. A series of static adsorption experiments were conducted to analyze its adsorption performance, which follows the Elovich model from the kinetic analysis and the Sips equation from the isothermal analysis. To further verify the reliability and accuracy of the simulation results, the effects of different monomers on the adsorption selectivity were also determined. They display higher selectivity towards phenol than 4-nitrophenol.The results from the simulation of the pre assembled complexes are in reasonable agreement with those from the experiment. PMID- 26648328 TI - Decreased expression of RASSF1A tumor suppressor gene is associated with worse prognosis in clear cell renal cell carcinoma. AB - Clear-cell renal cell carcinoma (ccRCC) is the most common subtype of RCC (70 80%) and is associated with poor prognosis in 40% of cases mainly due to metastasis in the course of the disease. RASSF1, with its isoforms RASSF1A and RASSF1C, is a tumor suppressor gene which has not been fully analyzed in ccRCC yet. The epigenetic downregulation of RASSF1A is commonly associated with promoter hypermethylation. The aim of the present study was to compare the ccRCC outcomes with the expression of RASSF1A and RASSF1C. Tissues were obtained from 86 ccRCC patients. RASSF1A and RASSF1C mRNA levels were assessed in tumor and matched normal kidney tissue, and in 12 samples of local metastases by quantitative PCR (qPCR). RASSF1A and RASSF1C proteins levels were semi-quantified in 58 samples by western blot analysis and their tissue localization was assessed by immunohistochemistry. Hypermethylation of RASSF1A promoter was measured by high-resolution-melting methylation-specific qPCR. RASSF1A mRNA levels were 4 and 5 times lower in 66% of tumor and 75% metastasized samples. RASSF1A hypermethylation was found in 40% of analyzed T cases. RASSF1A protein expression was 5 or 20 times decreased in 70% tumor and 75% metastatic samples, respectively. RASSF1A hypermethylation, mRNA and protein levels were associated with TNM progression and higher Fuhrman's grading. Decreased RASSF1A expression, hypermethylation, TNM and Fuhrman's grading were associated with poorer overall survival (OS). Cox hazard ratio (HR) analysis revealed predictor role of RASSF1A mRNA levels on OS and progression-free survival (PFS) in relation to Fuhrman's grading (OS HR=2.25, PFS HR=2.93). RASSF1C levels were increased in ccRCC; no correlations with clinicopathological variables were found. We conclude that RASSF1C gene is not involved in ccRCC progression and we propose that the measurements of RASSF1A mRNA levels in paired tumor-normal kidney tissue could serve as a new prognostic factor in ccRCC. PMID- 26648329 TI - The role of oxysterols in vascular ageing. AB - The ageing endothelium progressively loses its remarkable and crucial ability to maintain homeostasis of the vasculature, as it acquires a proinflammatory phenotype. Cellular and structural changes gradually accumulate in the blood vessels, and markedly in artery walls. Most changes in aged arteries are comparable to those occurring during the atherogenic process, the latter being more marked: pro-oxidant and proinflammatory molecules, mainly deriving from or triggered by oxidized low density lipoproteins (oxLDLs), are undoubtedly a major driving force of this process. Oxysterols, quantitatively relevant components of oxLDLs, are likely candidate molecules in the pathogenesis of vascular ageing, because of their marked pro-oxidant, proinflammatory and proapoptotic properties. An increasing bulk of experimental data point to the contribution of a variety of oxysterols of pathophysiological interest, also in the age-related genesis of endothelium dysfunction, intimal thickening due to lipid accumulation, and smooth muscle cell migration and arterial stiffness due to increasing collagen deposition and calcification. This review provides an updated analysis of the molecular mechanisms whereby oxysterols accumulating in the wall of ageing blood vessels may 'activate' endothelial and monocytic cells, through expression of an inflammatory phenotype, and 'convince' smooth muscle cells to proliferate, migrate and, above all, to act as fibroblast-like cells. PMID- 26648330 TI - Intakes of folate, vitamin B6 and B12 and risk of depression in community dwelling older adults: the Quebec Longitudinal Study on Nutrition and Aging. AB - BACKGROUND/OBJECTIVES: Depression can decrease quality of life and affect health outcomes in older population. We investigated whether different intake levels of folate, vitamin B6 and B12 were associated with a 3-year depression incidence among generally healthy, community-dwelling older men and women. SUBJECTS/METHODS: Participants in the Quebec Longitudinal Study on Nutrition and Aging (NuAge), free of depression (that is, 30-item Geriatric Depression Scale (GDS) <11) at baseline (N=1368; 74 +/- 4 years old; 50.5% women), were screened annually for incident depression (GDS ? 11) or antidepressant medication. Tertiles of intakes (food only and food+supplements) were obtained from the mean of three non-consecutive 24-h recalls at baseline. Sex-stratified multiple logistic regression models were adjusted for age, physical activity, physical functioning, stressful life events and total energy intake. RESULTS: Over 3 years, 170 participants were identified as depressed. Women in the highest tertile of B6 intake from food were 43% less likely to become depressed when adjusting for demographic and health factors (multivariate odds ratio (OR) 0.57, 95% confidence interval (CI) 0.39-0.96), but adjustment for energy intake attenuated the effect. Men in the highest tertile of dietary B12 intake had decreased risk of depression (energy-adjusted multivariate OR 0.42, 95% CI 0.20 0.90). No other association was observed. CONCLUSIONS: This study provides some evidence of decreased depression risk among women with higher intakes of vitamin B6 from food, which was dependent on total energy intake, and among men with higher intakes of B12 from food, independently of energy intake. PMID- 26648331 TI - Antimicrobial and Anti-biofilm Activity of Thiourea Derivatives Bearing 3-amino 1H-1,2,4-triazole Scaffold. AB - A set of 21 thiourea derivatives were prepared through reacting 3-amino-1H-1,2,4 triazole with the commercial aliphatic and aromatic isothiocyanates. The aliphatic isothiocyanate was used as reagent leading to substitution on NH atom of 3-aminotriazole ring, whereas the triazole amino group was substituted when isothiocyanate group was bonded to the Csp2 hybridized atom, e.g. an aryl or C=O fragment. All compounds were evaluated in vitro for the antimicrobial activity. The derivatives 1, 2, 4, 8, 9, 10 and 12 showed the highest inhibition against Gram-positive cocci (S. aureus and S. epidermidis). The observed MIC values were in the range of 4-32 MUg/mL. Compounds were also tested for their in vitro antimicrobial activity against the hospital methicillin-resistant strains of S. aureus. The observed MIC values varied from 4 to 64 MUg/mL. The products 4 and 10 effectively inhibited the formation of biofilms of the methicillin-resistant and standard strains of S. epidermidis. The compound 10 was found to be more promising with IC50 values of 2-6 MUg/mL as compared to the control. Moreover, the cytotoxicity against the MT-4 cells of all studied thioureas was evaluated. The compound 18 was significantly cytotoxic (CC50 = 8 MUM). PMID- 26648332 TI - Mining ZINC Database to Discover Potential Phosphodiesterase 9 Inhibitors Using Structure-Based Drug Design Approach. AB - In view of the emerging clinical indications for Phosphodiesterase 9 inhibitors e.g. treatment of Alzheimer, diabetes, cancer, and the limited number of its selective inhibitors which possess a single chemical scaffolds, a structure-based approach was undertaken to mine the ZINC database by virtual screening to identify novel PDE9 inhibitors. The database, which was never reported to have been used before for discovery of PDE9 inhibitors, was screened against the ligand binding pocket of the PDE9 complex (PDB:4GH6) using molecular docking programs, MOE and AutoDock Vina in PyRx. Three different scoring functions were used to evaluate the docking poses and scores of the compounds, and the compounds were selected through consensus selection, thus reducing the margin of error in docking. The highest scoring compounds were then selected and purchased for in vitro testing as PDE9 inhibitors and cancer growth inhibitory agents. This led to the discovery of three previously unreported potent PDE 9 inhibitory compounds with two unique chemical scaffolds. Consistent with the role of PDE9 in cancer cell growth, the compounds also inhibited the growth of breast tumor cell lines, MCF-7 and MDA-468 at concentrations comparable to those that inhibited PDE9. PMID- 26648333 TI - Controlled Cell Growth and Cell Migration in Periodic Mesoporous Organosilica/Alginate Nanocomposite Hydrogels. AB - Nanocomposite (NC) hydrogels with different periodic mesoporous organosilica (PMO) concentrations and a NC hydrogel bilayer with various PMO concentrations inside the layers of the hydrogel matrix are prepared. The effect of the PMO concentration on cell growth and migration of cells is reported. The cells migrate in the bilayer NC hydrogel towards higher PMO concentrations and from cell culture plates to NC hydrogel scaffolds. PMID- 26648334 TI - Lipid droplets are involved in the process of high-grade transformation of adenoid cystic carcinoma. PMID- 26648335 TI - Reproductive toxicity of binary and ternary mixture combinations of nickel, zinc, and lead to Ceriodaphnia dubia is best predicted with the independent action model. AB - Metals occur as mixtures in the environment. Risk assessment procedures for metals currently lack a framework to incorporate chronic metal mixture toxicity. In the present study, the toxicity of binary and ternary mixture combinations of Ni, Zn, and Pb was investigated in 3 large-scale experiments using the standard chronic (7-d) Ceriodaphnia dubia reproductive toxicity test. These metals were selected because of anticipated differences in mode of action. The toxicity of the metals in most mixtures, expressed as either free metal ion activities or as dissolved metal concentrations, were antagonistic relative to the concentration addition model, whereas no significant (p < 0.05) interactive effects were observed relative to the independent action model. The only exception was the binary Pb-Zn mixture, for which mixture effects were noninteractive based on the dissolved concentrations, but antagonistic based on free ion activities all relative to the independent action model. Overall, the independent action model fitted the observed toxicity better than the concentration addition model, which is consistent with the different modes of action of these metals. The concentration addition model mostly overestimated toxicity. Finally, the present study warns against extrapolation of the type of interactive effects between species, even when they are closely related. Environ Toxicol Chem 2016;35:1796 1805. (c) 2015 SETAC. PMID- 26648336 TI - Rituximab plus hyper-CVAD alternating with MTX/Ara-C in patients with newly diagnosed mantle cell lymphoma: 15-year follow-up of a phase II study from the MD Anderson Cancer Center. AB - Intensive chemotherapy regimens containing cytarabine have substantially improved remission durability and overall survival in younger adults with mantle cell lymphoma (MCL). However, there have been no long-term follow-up results for patients treated with these regimens. We present long-term survival outcomes from a pivotal phase II trial of rituximab, hyper-fractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone alternating with methotrexate and cytarabine (R-HCVAD/MA). At 15 years of follow-up (median: 13.4 years), the median failure-free survival (FFS) and overall survival (OS) for all patients was 4.8 years and 10.7 years, respectively. The FFS seems to have plateaued after 10 years, with an estimated 15-year FFS of 30% in younger patients (<=65 years). Patients who achieved complete response (CR) after 2 cycles had a favourable median FFS of 8.8 years. Six patients developed myelodysplastic syndrome/acute myeloid leukaemia (MDS/AML) whilst in first CR. The 10-year cumulative incidence of MDS/AML of patients in first remission was 6.2% (95% confidence interval: 2.5 12.2%). In patients with newly diagnosed MCL, R-HCVAD/MA showed sustained efficacy, with a median OS exceeding 10 years in all patients and freedom from disease recurrence of nearly 15 years in almost one-third of the younger patients (<=65 years). PMID- 26648337 TI - Grapevine petioles are more sensitive to drought induced embolism than stems: evidence from in vivo MRI and microcomputed tomography observations of hydraulic vulnerability segmentation. AB - The 'hydraulic vulnerability segmentation' hypothesis predicts that expendable distal organs are more susceptible to water stress-induced embolism than the main stem of the plant. In the current work, we present the first in vivo visualization of this phenomenon. In two separate experiments, using magnetic resonance imaging or synchrotron-based microcomputed tomography, grapevines (Vitis vinifera) were dehydrated while simultaneously scanning the main stems and petioles for the occurrence of emboli at different xylem pressures (Psix ). Magnetic resonance imaging revealed that 50% of the conductive xylem area of the petioles was embolized at a Psix of -1.54 MPa, whereas the stems did not reach similar losses until -1.9 MPa. Microcomputed tomography confirmed these findings, showing that approximately half the vessels in the petioles were embolized at a Psix of -1.6 MPa, whereas only few were embolized in the stems. Petioles were shown to be more resistant to water stress-induced embolism than previously measured with invasive hydraulic methods. The results provide the first direct evidence for the hydraulic vulnerability segmentation hypothesis and highlight its importance in grapevine responses to severe water stress. Additionally, these data suggest that air entry through the petiole into the stem is unlikely in grapevines during drought. PMID- 26648338 TI - Substituent Effects on Cytotoxic Activity, Spectroscopic Property, and DNA Binding Property of Naphthalimide Derivatives. AB - A series of novel naphthalimide derivatives NI1-5 containing piperazine moieties (N-(2-hydroxyethyl)piperazine and 1-piperazinepropanol) and piperidine moieties (4-piperidinemethanol, 4-hydroxypiperidine and 4-piperidineethanol) have been synthesized and evaluated for their cytotoxic activity, spectroscopic property, and DNA binding behaviors. It was found that substituents at the 4-position remarkably influence the various activities of this series of compound. Compounds NI3-5 modified with piperidines exhibited potent cytotoxic activities against Hela, SGC-7901, and A549 cells with the IC50 values from 0.73 MUm to 6.80 MUm, which are better than NI1-2 functionalized with piperazines. Compounds NI1-2 showed higher binding capacity with Ct-DNA than compounds NI3-5 based on studies of UV-vis, fluorescence and CD spectra. Furthermore, compounds NI3-5, as DNA intercalators, showed fluorescence enhancement upon binding with Ct-DNA. More interestingly, fluorescence imaging studies of compound NI4 with A549 cells showed that the fluorescence predominantly appeared in the cytoplasm. These results provided a potential application of NI3-5 as anticancer therapeutic and cancer cell imaging agents. PMID- 26648339 TI - Alpha-methylacyl-CoA racemase deletion has mutually counteracting effects on T cell responses, associated with unchanged course of EAE. AB - Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. Altering the metabolism of immune cells is an attractive strategy to modify their activity during autoimmunity in MS. We investigated the effect of modulating fatty acid metabolism in an animal model of MS, EAE. Alpha-methylacyl CoA racemase (AMACR) converts R-configuration branched fatty acids into the S configuration, thereby preparing them for beta-oxidation. We observed a significant, disease-dependent elevation of AMACR expression in monocytes and T cells from blood, draining lymph nodes and spleen of EAE mice during the preclinical phase. In vitro analysis revealed that the proliferation of T cells was inhibited in AMACR KO mice, but T-cell polarization was switched toward a pathogenic state involving the production of more IFN-gamma and IL-17, but less IL-4. These opposing effects appeared to cancel out each other in vivo, because AMACR KO EAE mice showed a marginal increase in the severity of early clinical symptoms. AMACR was not regulated in the white blood cells of MS patients. Our data show that AMACR is regulated in immune cells during EAE, but it is not a suitable target for the treatment of MS due to its opposing effects. PMID- 26648340 TI - mTOR expression in human testicular seminoma. AB - The mammalian target of rapamycin (TOR) has been implicated in the control of different stressors, growth factors, nutrients and hormones, participating in the control of key cellular functions. Controlling this many pathways poses mTOR signalling as a potential new target in new treatment strategies for multiple cancer types. mTOR components could potentially mislocated in tumour cells, which could lead to activation of signalling pathway that should not be active. Therefore, we aimed to show localisation of mTOR signal proteins in testicular seminoma. Tumoural testicular tissues were obtained from 10 patients with unilateral classic seminoma undergoing to therapeutic orchidectomy and compared with control human testicular tissues. Upon immunohistochemical evaluation, we detected mTOR and p-mTOR (serine 2448), P70S6K, p-P70S6K, PKCalpha and p PKCalpha, CD36 and MAPLC3 proteins in the cytoplasm of Sertoli cells in the seminiferous tubules. We also showed cytoplasmic perinuclear staining in seminoma cells. This study demonstrated the interaction of mTOR signalling pathway and testicular seminoma by showing intense cytoplasmic mTOR pathway proteins immunoreactivity in the seminoma, for the first time in humans. Therefore, we suggested that mTOR signalling components could create new clinical targets for treatment of testicular seminoma patients and male infertility in the future. PMID- 26648341 TI - Changes in blood monocyte Toll-like receptor and serum surfactant protein A reveal a pathophysiological mechanism for community-acquired pneumonia in patients with type 2 diabetes. AB - BACKGROUND: The lung is one of the target organs of microangiopathy in diabetes mellitus (DM); patients with type 2 diabetes mellitus (T2DM) are vulnerable to pneumonia, and a variety of pathophysiological mechanisms has been described. AIM: This study aimed to determine the pathophysiological mechanism of community acquired pneumonia (CAP) in T2DM patients. METHODS: A total of 90 individuals was included in this study comprised of three groups (n = 30): healthy control, T2DM and T2DM+ CAP groups. Toll-like receptor (TLR)2 and 4 protein and messenger RNA expression in peripheral blood monocytes(PBMC) was assessed by western blot and reverse transcription-polymerase chain reaction, respectively, and surfactant protein A (SP-A) levels were examined in serum samples by enzyme-linked immunosorbent assay. RESULTS: In T2DM and T2DM+CAP groups, levels of both TLR2/4 protein and mRNA in PBMC were decreased compared with controls (P <0.05), with lower levels observed in the T2DM+CAP group in comparison with T2DM patients (P <0.05). The serum SP-A levels in T2DM+CAP individuals were significantly higher than the values obtained for T2DM patients (P <0.05). It also showed apparent increases when compared with that in controls although no statistical significance was detected. CONCLUSION: In T2DM patients with pneumonia, TLR2/4 levels in PBMC and serum SP-A were altered, maybe playing an important role in the susceptibility to pneumonia in T2DM patients. PMID- 26648342 TI - Calcium Channel Blockade and Peroxisome Proliferator Activated Receptor gamma Agonism Diminish Cognitive Loss and Preserve Endothelial Function During Diabetes Mellitus. AB - Diabetes mellitus is considered as a main risk factor for vascular dementia. In the past, we have reported the induction of vascular dementia (VaD) by experimental diabetes. This study investigates the efficacy of a nifedipine, a calcium channel blocker and pioglitazone in the pharmacological interdiction of pancreatectomy diabetes (PaD) induced vascular endothelial dysfunction and subsequent VaD in rats. Attentional set shifting (ASST) and Morris water-maze (MWM) test were used for assessment of learning and memory. Vascular endothelial function, blood brain barrier permeability, serum glucose, serum nitrite/nitrate, oxidative stress (viz. aortic superoxide anion, brain thiobarbituric acid reactive species and brain glutathione), brain calcium and inflammation (myeloperoxidase) were also estimated. PaD rats have shown impairment of endothelial function, blood brain barrier permeability, learning and memory along with an increase in brain inflammation, oxidative stress and calcium. Administration of nifedipine and pioglitazone significantly attenuated PaD induced impairment of learning, memory, blood brain barrier permeability, endothelial function and biochemical parameters. It may be concluded that nifedipine, a calcium channel blocker may be considered as a potent pharmacological agent for the management of PaD induced endothelial dysfunction and subsequent VaD. PMID- 26648343 TI - The impact of national vaccination policy changes on influenza incidence in the Netherlands. AB - BACKGROUND: We assessed the impact of two major modifications of the Dutch National Influenza Prevention Programme--the introduction in 1997 of free-of charge vaccination to persons aged >=65 years and to high-risk groups (previously only advised, and not free of charge), and the lowering of the eligible age to 60 years in 2008--on the estimated incidence of influenza infection leading to influenza-like illness (ILI). METHODS: Additive negative-binomial segmented regression models were fitted to ILI data from GP sentinel surveillance in two eight-season intervals (1993/4 to 2000/1, 2004/5 to 2011/12, comparing pre- and post-policy-change periods within each interval), with laboratory virological reporting of samples positive for influenza or other ILI-causing pathogens as covariates. RESULTS: For the 2008 policy change, there was a significant step decrease in influenza contribution considering all ages (=-111 per 100 positives; 95% CI: -162, -65.0), <60 years and 60-64 years age groups (B = -92.1 per 100; 95% CI: -134, -55.5; B = -5.2; 95% CI: -10.3, -1.2, respectively). There was no evidence for a decrease associated with the 1997 policy change targeting the >=65 years age group. CONCLUSIONS: In the Netherlands, a 56% reduction in influenza contribution was associated with the 2008 policy targeting 60-64 year-olds, but there was no effect of the earlier policy targeting >=65-year-olds, for whom vaccination coverage was already rising before the policy change. PMID- 26648344 TI - Impaired gap junctions in human hepatocellular carcinoma limit intrinsic oxaliplatin chemosensitivity: A key role of connexin 26. AB - Hepatocellular carcinoma (HCC) is generally believed to have low sensitivity to chemotherapeutic agents including oxaliplatin (OXA). Studies have demonstrated that gap junctions (GJs) composed of connexin (Cx) proteins have the potential to modulate drug chemosensitivity in multiple tumor cells. In the present study, we investigated the characteristics of Cx and GJs in HCC at both histologic and cytologic levels, and the effects of GJ and its effective components on OXA cytotoxicity in HCC cells in vitro. Immunohistochemistry was performed in 76 HCCs and 20 normal liver tissues to detect and locate the expression of Cx26, Cx32 and Cx43. At cytologic levels, the expression and localization of Cxs were evaluated by RT-PCR, western blot and immunofluorescence assay, respectively. The GJ function between adjacent cells was detected using dye transfer assay. The role of GJs in the modulation of OXA toxicity in HCC cells was explored using pharmacologic and molecular biologic methods. We found that Cx expression in HCC tissues was significantly lower than in normal liver tissues, and the 'internalization' from cell membrane to cytoplasm was remarkable. In vitro experiments revealed the presence of functional GJs in the SMMC-7721 HCC cells due to a small amount of Cx protein along the plasma membrane at cell-cell contacts. Regulation of this part of GJs positively influenced OXA cytotoxicity. Using RNA interference, only specific inhibition of Cx26 but not Cx32 or Cx43 reduced OXA cytotoxicity. Conversely, Cx26 overexpression by transfection of Cx26 plasmid DNA enhanced OXA cytotoxicity. This study demonstrated that during hepatocarcinogenesis, the reduced expression and internalization of Cx proteins impaired the GJ function, which further attenuated OXA cytotoxicity. Impaired GJ function may contribute to low intrinsic chemosensitivity of HCC cells to OXA, mediated by Cx26. PMID- 26648345 TI - [Neurologic manifestations of sarcoidosis: A study of 18 cases]. AB - INTRODUCTION: Sarcoidosis is a multisystemic granulomatous disease of unknown aetiology. Neurologic manifestations are found in 5 to 10% of cases. PATIENTS AND METHODS: We conducted a retrospective study over 6-year period including 18 patients diagnosed with neurosarcoidosis in the Neurologic department of the Military Hospital of Instruction of Tunis. Clinical, radiological, therapeutic features and outcome were studied. RESULTS: The mean age was 43.44 years. Neurologic signs were the first symptom in 10 cases. Peripheral nervous system impairment was often found. Meningitis was noted in 8 cases. Biological tests are not contributive for the diagnosis. The brain magnetic resonance imaging was pathologic in 10 cases. Corticosteroids were administrated in the majority of cases. Eight patients did not show any sign of improvement. Ten cases improved with treatment. DISCUSSION AND CONCLUSION: Diagnosis of neurosarcoidosis is difficult because of its clinical and radiological polymorphism. It is based on a clinical history suggestive of neurosarcoidosis, laboratory, imaging and histological studies. PMID- 26648346 TI - Helicobacter pylori vacuolating cytotoxin genotypes and preneoplastic lesions or gastric cancer risk: a meta-analysis. AB - BACKGROUND AND AIM: Disease progression to gastric cancer (GC) occurs in only a small proportion of Helicobacter pylori (H. pylori) infected patients. The bacterium vacuolating cytotoxin A (vacA) gene polymorphisms may determine the clinical consequences. We examined the strength of this association in adult infected populations and modeled the impact of mean age-standardized incidence rates (ASRs) of GC as a hypothesized moderator variable. METHODS: Pooled relative risk (RR) estimates were calculated. Subgroup, sensitivity, and meta-regression analyses were conducted. RESULTS: Totally, 33 studies (1446 cases/2697 controls) were analyzed. The vacA-s1 genotype was significantly associated with an increased risk of atrophic gastritis(AG), intestinal metaplasia(IM), and GC (RR = 1.116, 95% CI, 1.019-1.222; RR = 1.418, 95% CI, 1.035-1.942; and RR = 1.333, 95% CI, 1.115-1.593, respectively); however, the vacA m1 genotype strongly increased the risk of IM and GC, but not AG (RR = 1.571, 95% CI, 1.247-1.980 and RR = 1.431, 95% CI, 1.180-1.735, respectively). The vacA s1m1 allelic combination was linked to an increased risk of GC. The m1-type of vacA was more potent than s1 for predicting the risk of GC within the subgroups with the mean ASRs of 11/100,000-19/100,000 and less than 10/100,000. The meta-regression analysis indicated that the ASR of GC modified the association between H. pylori genotypes and GC risk, where the estimated risk was significantly decreased with increasing the mean ASRs of GC (P-values = 0.025, 0.00009, and 0.0005 for s1, m1, and s1m1, respectively). CONCLUSIONS: The H. pylori vacA-s1 and vacA-m1 allelic variants strongly increased susceptibility to IM and GC; however, only s1 showed an association with AG. These associations were largely influenced by geographic variations in the GC incidence rate. PMID- 26648347 TI - Biocompatible Solid-Phase Microextraction Nanoelectrospray Ionization: An Unexploited Tool in Bioanalysis. AB - In recent years, different geometrical configurations of solid-phase microextraction (SPME) have been directly coupled to mass spectrometry, resulting in benefits such as diminishing matrix effects, improvement of detection limits, and considerable enhancement of analysis throughput. Although SPME fibers have been used for years, their potential for quantitative analysis when directly combined with mass spectrometry has not been explored to its full extent. In this study, we present the direct coupling of biocompatible SPME (Bio-SPME) fibers to mass spectrometry via nanoelectrospray ionization (nano-ESI) emitters as a powerful tool for fast quantitative analysis of target analytes in biofluids. Total sample preparation time does not exceed 2 min, and by selecting an appropriate fiber length and sample vessel, sample volumes ranging between 10 and 1500 MUL can be used. Despite the short extraction time of the technique, limits of detection in the subnanogram per milliliter with good accuracy (>=90%) and linearity (R(2) > 0.999) were attained for all the studied probes in phosphate buffered saline (PBS), urine, and whole blood. Given that Bio-SPME-nano-ESI efficiently integrates sampling with analyte extraction/enrichment, sample cleanup (including elimination of matrix effects in the form of particles), and ionization, our results demonstrated that it is an advantageous configuration for bioanalytical applications such as therapeutic drug monitoring, doping in sports, and pharmacological studies in various matrixes. PMID- 26648348 TI - Danish VISA-A questionnaire with validation and reliability testing for Danish speaking Achilles tendinopathy patients. AB - The VISA-A questionnaire has proven to be a valid and reliable tool for assessing severity of Achilles tendinopathy (AT). The aim was to translate and cross culturally adapt the VISA-A questionnaire for a Danish-speaking AT population, and subsequently perform validity and reliability tests. Translation and following cross-cultural adaptation was performed as translation, synthesis, reverse translation, expert review, and pretesting. The final Danish version (VISA-A-DK) was tested for reliability on healthy controls (n = 75) and patients (n = 36). Tests for internal consistency, validity, and structure were performed on 71 patients. VISA-A-DK showed good reliability for patients (r = 0.80 ICC = 0.79) and healthy individuals (r = 0.98 ICC = 0.97). Internal consistency was 0.73 (Cronbach's alpha). The mean VISA-A-DK score in AT patients was 51 [47-55]. This was significantly lower than healthy controls with a score of 93 (90-95). Criterion validity was considered good when comparing the scores of the Danish version with the original version in both healthy individuals and patients. VISA A-DK is a valid and reliable instrument and has shown compatible to the original version in assessment of AT patients. VISA-A-DK is a useful tool in the assessment of AT, both in research and in a clinical setting. PMID- 26648349 TI - Successful treatment of refractory idiopathic angio-oedema with omalizumab: review of the literature and function of IgE in angio-oedema. AB - The management of angio-oedema is quite complicated because of the frequent poor response to usual treatments, including H1 antihistamines, systemic corticosteroids, immunosuppressant drugs, antileucotriene drugs or tranexamic acid. Omalizumab, an anti-immunoglobulin (Ig)-E antibody, has shown good resuts in chronic spontaneous urticaria, and might also be a good option for angio oedema. To our knowledge, there have been eight relevant case reports published in the English literature. We report two further cases (a 55-year-old man and a 36-year-old woman) with severe chronic recurrent angio-oedema affecting the face, pharynx, hands, feet and hips. Both patients were refractory to H1 antihistamines, systemic corticosteroids and tranexamic acid. We decided to start with subcutaneous omalizumab 375 mg every other week and tapering doses up to 375 mg every 4 weeks. Both patients showed a very good response to the therapy, with clinical improvement in the first week. This response remained stable more than 3 years later. PMID- 26648350 TI - Pain as a root of the problem: health-related quality of life in children with cerebral palsy. PMID- 26648351 TI - Urban health: landmarks, dilemmas, prospects, and challenges. PMID- 26648352 TI - A pivotal moment for urban health. PMID- 26648353 TI - Health in cities: is a systems approach needed? AB - This paper reviews the potential utility of using the concepts and tools of systems to understand and act on health in cities. The basic elements of systems approaches and the links between cities as systems and population health as emerging from the functioning of a system are reviewed. The paper also discusses implications of systems thinking for urban health including the development of dynamic conceptual models, the use of new tools, the integration of data in new ways and the identification of data gaps, and the formulation of different kinds of questions and identification of new policies. The paper concludes with a review of caveats and challenges. PMID- 26648354 TI - Debate on the paper by Diez Roux. PMID- 26648355 TI - Debate on the paper by Diez Roux. PMID- 26648356 TI - Debate on the paper by Diez Roux. PMID- 26648357 TI - Debate on the paper by Diez Roux. PMID- 26648358 TI - Debate on the paper by Diez Roux. PMID- 26648359 TI - Debate on the paper by Diez Roux. PMID- 26648361 TI - Urban governance and the systems approaches to health-environment co-benefits in cities. AB - The term "co-benefits" refers to positive outcomes accruing from a policy beyond the intended outcome, often or usually in other sectors. In the urban context, policies implemented in particular sectors (such as transport, energy or waste) often generate multiple co-benefits in other areas. Such benefits may be related to the reduction of local or global environmental impacts and also extend into the area of public health. A key to identifying and realising co-benefits is the adoption of systems approaches to understand inter-sectoral linkages and, in particular, the translation of this understanding to improved sector-specific and city governance. This paper reviews a range of policies which can yield health and climate co-benefits across different urban sectors and illustrates, through a series of cases, how taking a systems approach can lead to innovations in urban governance which aid the development of healthy and sustainable cities. PMID- 26648362 TI - The impact of sports mega-events on health and environmental rights in the city of Rio de Janeiro, Brazil. AB - The aim of this study is to discuss the contradictions of the Olympic Games legacy for health and environment in the city of Rio de Janeiro, Brazil. Public policies for sports mega-events have been criticized for contributing to and deepening the city's historical socio-spatial inequalities. Based on document research and data analysis, the article focused on establishing a proposal for a sustainable city, as provided in Law 10,257/2001, the so-called City's Statute. The article concludes with remarks on Olympic urban planning, its market orientation, and failures to overcome public health and environmental sanitation problems that will persist as a legacy after 2016. PMID- 26648363 TI - Urban upgrading and its impact on health: a "quasi-experimental" mixed-methods study protocol for the BH-Viva Project. AB - There is little scientific evidence that urban upgrading helps improve health or reduce inequities. This article presents the design for the BH-Viva Project, a "quasi-experimental", multiphase, mixed-methods study with quantitative and qualitative components, proposing an analytical model for monitoring the effects that interventions in the urban environment can have on residents' health in slums in Belo Horizonte, Minas Gerais State, Brazil. A preliminary analysis revealed intra-urban differences in age-specific mortality when comparing areas with and without interventions; the mortality rate from 2002 to 2012 was stable in the "formal city", increased in slums without interventions, and decreased in slums with interventions. BH-Viva represents an effort at advancing methodological issues, providing learning and theoretical backing for urban health research and research methods, allowing their application and extension to other urban contexts. PMID- 26648364 TI - Brief introductory guide to agent-based modeling and an illustration from urban health research. AB - There is growing interest among urban health researchers in addressing complex problems using conceptual and computation models from the field of complex systems. Agent-based modeling (ABM) is one computational modeling tool that has received a lot of interest. However, many researchers remain unfamiliar with developing and carrying out an ABM, hindering the understanding and application of it. This paper first presents a brief introductory guide to carrying out a simple agent-based model. Then, the method is illustrated by discussing a previously developed agent-based model, which explored inequalities in diet in the context of urban residential segregation. PMID- 26648365 TI - Association of perceived neighborhood problems and census tract income with poor self-rated health in adults: a multilevel approach. AB - Neighborhood problems constitute sources of chronic stress that may increase the risk of poor self-rated health. The associations of census tract level income and perceived neighborhood problems with self-rated health were examined in Florianopolis, Santa Catarina State, Brazil (1,720 adults). Odds ratios (OR) and their 95% confidence intervals (95%CI) of poor self-rated health were estimated through multilevel models. Residents in census tracts in the lower and intermediate tertiles of income reported poorer health than those in the highest tertile. OR of reporting poorer health was 2.44 (95%CI: 2.35- 2.54) in the higher tertile of social disorder (adjusting for mental health). The chances of reporting the poorer health with neighborhood problems ranged from 1.07 (95%CI: 1.03-1.11) to 2.02 (95%CI: 1.95-2.10) for the higher tertile of social disorder (physical health) and physical problem (health-related variables). Perceived neighborhood problems were independently associated with poor health. The perception of a neighborhood among its residents should be considered by health policymakers. PMID- 26648366 TI - Urban road traffic deaths: data linkage and identification of high-risk population sub-groups. AB - This study analyzes the profile of deaths from road traffic accidents in Belo Horizonte, Minas Gerais State, Brazil, by linking two public databases, the Information System of the Urban Transportation and Transit Company (BH10) and the Mortality Information System (SIM). The linked database (n = 306) identified a 24% under-recording rate for deaths and differed in the age distribution from the BH10 database and in roadway user category when compared to the mortality database. The mortality rate for road traffic accidents within the city limits was 10.2 per 100,000 thousand, and was higher among men, young adults, and the elderly. Poisson multivariate regression showed a higher mean death rate for motorcycle occupants (rate ratio - RR: 1.81); pedestrians (RR: 1.32); males (RR: 1.24); single/divorced (RR: 1.27); young adults 18-29 years of age (RR: 1.75); elderly (RR: 1.59); and deaths at the crash site (RR: 1.39) when compared to the reference categories. The study unveils the city's traffic violence, expressed by the large proportion of deaths at the crash site and within the first 24 hours, and confirms the relevance of database linkage for characterizing vulnerable groups and traffic accident mortality in the urban setting. PMID- 26648367 TI - Disaggregating health inequalities within Rio de Janeiro, Brazil, 2002-2010, by applying an urban health inequality index. AB - An urban health index (UHI) was used to quantify health inequalities within Rio de Janeiro, Brazil, for the years 2002-2010. Eight main health indicators were generated at the ward level using mortality data. The indicators were combined to form the index. The distribution of the rank ordered UHI-values provides information on inequality among wards, using the ratio of the extremes and the gradient of the middle values. Over the decade the ratio of extremes in 2010 declined relative to 2002 (1.57 vs. 1.32) as did the slope of the middle values (0.23 vs. 0.16). A spatial division between the affluent south and the deprived north and east is still visible. The UHI correlated on an ecological ward-level with socioeconomic and urban environment indicators like square meter price of apartments (0.54, p < 0.01), low education of mother (-0.61, p < 0.01), low income (-0.62, p < 0.01) and proportion of black ethnicity (-0.55, p < 0.01). The results suggest that population health and equity have improved in Rio de Janeiro in the last decade though some familiar patterns of spatial inequality remain. PMID- 26648368 TI - Self-rated health in urban adults, perceptions of the physical and social environment, and reported comorbidities: The BH Health Study. AB - This study assesses the prevalence of poor self-rated health and investigates its association with individual and environmental characteristics in adults with and without reported morbidity. A household survey assessed 4,048 adults in two districts of Belo Horizonte, Minas Gerais State, Brazil. We used Poisson regression with robust variance stratified by the presence of reported morbidity. Prevalence of poor self-rated health was 29.9% (42.6% in those with morbidity and 13.1% in the group without morbidity). All assessed domains were associated with self-rated health in subjects with reported morbidity. In the group without reported morbidity, the following were associated with self-rated health: social environment, socio-demographic factors, lifestyle, and psychological health. Perceived problems in the environment were associated with poor self-rated health in both groups, even after hierarchical adjustment. The results suggest the importance of investigating self-rated health stratified by reported morbidity and reinforce the need to include variables that characterize the physical and social environment. PMID- 26648369 TI - Social context of neighborhood and socioeconomic status on leisure-time physical activity in a Brazilian urban center: The BH Health Study. AB - This study aimed to estimate the prevalence of leisure-time physical activity and investigate its association with contextual characteristics of the social and physical environment in different socioeconomic statuses, using a household survey in Belo Horizonte, Minas Gerais State, Brazil (2008-2009). Leisure-time physical activity was measured by the International Physical Activity Questionnaire; and the social and physical environment by scales arising from perception of neighborhood attributes. Multilevel logistic regression analysis was performed separately for each socioeconomic status stratum. The overall prevalence of leisure-time physical activity was 30.2%, being 20.2% amongst participants of low socioeconomic status, 25.4% in the medium and 40.6% in the high socioeconomic status group. A greater perception of social cohesion was associated with increased leisure-time physical activity only amongst participants of the lowest socioeconomic status even after adjusting for individual characteristics. The results demonstrate the importance of social cohesion for the promotion of leisure-time physical activity in economically disadvantaged groups, supporting the need to stimulate interventions for enhancing social relationships in this population. PMID- 26648370 TI - Overweight in men and women among urban area residents: individual factors and socioeconomic context. AB - The present study aimed to evaluate factors associated with overweight among adults living in urban areas, with the income of the census tract as a context variable. The survey assessed individuals from two health districts of Belo Horizonte, Minas Gerais State, Brazil. Excess weight was determined by body mass index > 25kg/m2. Multilevel logistic regression was used. The sample comprised 2,935 individuals aged 20 to 60 years. The prevalence of overweight was 52.3% (95%CI: 49.9-54.8), similar between men and women. Higher schooling proved to be protective against overweight in women and a risk for men. Living in census tracts with higher income was associated with excess weight only in males. Report of the consumption of diet soft drinks was positively associated with overweight in both sexes. The occurrence of this event seems to be influenced by different factors or to interrelate differently in men and women. PMID- 26648371 TI - Food environment of fruits and vegetables in the territory of the Health Academy Program. AB - This study provides a spatial analysis of distribution and access to commercial fruit and vegetable establishments within the territory of a representative sample of public fitness facilities known as the Health Academy Program (HAP) in Belo Horizonte, Minas Gerais State, Brazil. The study evaluated commercial food establishments within a buffer area based on a radius of 1,600 meters around each of 18 randomly selected fitness facilities. Quality of access to fruits and vegetables was assessed by the Healthy Food Store Index (HFSI), consisting of the variables availability, variety, and advertising of fruits, vegetables and ultra processed foods. The analysis was based on calculation of the Kernel intensity estimator, nearest neighbor method, and Ripley K-function. Of the 336 food establishments, 61.3% were green grocers and open-air markets, with a median HFSI of 11 (5 to 16). In only 17% of the territories, the majority of the "hot area" establishments displayed better access to healthy foods, and only three areas showed a clustering pattern. The study showed limited access to commercial establishments supplying healthy fruits and vegetables within the territory of the public fitness program. PMID- 26648372 TI - Social networks of men who have sex with men: a study of recruitment chains using Respondent Driven Sampling in Salvador, Bahia State, Brazil. AB - Social and sexual contact networks between men who have sex with men (MSM) play an important role in understanding the transmission of HIV and other sexually transmitted infections (STIs). In Salvador (Bahia State, Brazil), one of the cities in the survey Behavior, Attitudes, Practices, and Prevalence of HIV and Syphilis among Men Who Have Sex with Men in 10 Brazilian Cities, data were collected in 2008/2009 from a sample of 383 MSM using Respondent Driven Sampling (RDS). Network analysis was used to study friendship networks and sexual partner networks. The study also focused on the association between the number of links (degree) and the number of sexual partners, in addition to socio-demographic characteristics. The networks' structure potentially facilitates HIV transmission. However, the same networks can also be used to spread messages on STI/HIV prevention, since the proximity and similarity of MSM in these networks can encourage behavior change and positive attitudes towards prevention. PMID- 26648373 TI - Association of socioeconomic factors with body mass index, obesity, physical activity, and dietary factors in Belo Horizonte, Minas Gerais State, Brazil: The BH Health Study. AB - Obesity prevalence is rapidly increasing in developing countries. Existing research investigating social patterning of obesity and its risk factors in Latin American urban contexts has inconsistent findings. This study analyzed a multistage household survey in adults in Belo Horizonte, Minas Gerais State, Brazil. Marginal models were used to examine the association of education and household and neighborhood income with body mass index (BMI), obesity, physical inactivity, and low fruit and vegetable intake after adjusting for age and ethnicity and stratifying by sex. BMI and obesity were inversely associated with education in women. BMI was positively associated with household and neighborhood income in men. Additionally, physical inactivity and low fruit and vegetable intake were inversely associated with education and household income in both men and women, and physical inactivity was inversely associated with neighborhood income in men. Understanding the drivers of these patterns will allow for development of appropriate policy and interventions to reduce cardiovascular disease risk in large cities in Latin America. PMID- 26648374 TI - Leisure-time physical activity in the vicinity of Academias da Cidade Program in Belo Horizonte, Minas Gerais State, Brazil: the impact of a health promotion program on the community. AB - This study analyzed leisure-time physical activity among 1,621 adults who were non-users of the Academias da Cidade Program in Belo Horizonte, Minas Gerais State, Brazil, but who lived in the vicinity of a fitness center in operation (exposed Group I) or in the vicinity of two sites reserved for future installation of centers (control Groups II and III). The dependent variable was leisure-time physical activity, and linear distance from the households to the fitness centers was the exposure variable, categorized in radial buffers: < 500m; 500-1,000m; and 1,000-1,500m. Binary logistic regression was performed with the Generalized Estimation Equations method. Residents living within < 500m of the fitness center gave better ratings to the physical environment when compared to those living in the 1,000 and 1,500m buffers and showed higher odds of leisure time physical activity (OR = 1.16; 95%CI: 1.03-1.30), independently of socio demographic factors; the same was not observed in the control groups (II and III). The findings suggests the program's potential for influencing physical activity in the population living closer to the fitness center and thus provide a strategic alternative for mitigating inequalities in leisure-time physical activity. PMID- 26648375 TI - Do speed cameras reduce speeding in urban areas? AB - This observational study aimed to estimate the prevalence of speeding on urban roadways and to analyze associated factors. The sample consisted of 8,565 vehicles circulating in areas with and without fixed speed cameras in operation. We found that 40% of vehicles 200 meters after the fixed cameras and 33.6% of vehicles observed on roadways without speed cameras were moving over the speed limit (p < 0.001). Motorcycles showed the highest recorded speed (126km/h). Most drivers were men (87.6%), 3.3% of all drivers were using their cell phones, and 74.6% of drivers (not counting motorcyclists) were wearing their seatbelts. On roadway stretches without fixed speed cameras, more women drivers were talking on their cell phones and wearing seatbelts when compared to men (p < 0.05 for both comparisons), independently of speed limits. The results suggest that compliance with speed limits requires more than structural interventions. PMID- 26648376 TI - The socio-spatial context as a risk factor for hospitalization due to mental illness in the metropolitan areas of Portugal. AB - This study's aims are: (i) identifying spatial patterns for the risk of hospitalization due to mental illness and for the potential risk resulting from contextual factors with influence on mental health; and (ii) analyzing the spatial association between risk of hospitalization due to mental illness and potential risk resulting from contextual factors in the metropolitan areas of Lisbon and Porto, Portugal. A cross-sectional ecological study was conducted by applying statistical methods for assessing spatial dependency and heterogeneity. Results reveal a spatial association between risk of hospitalization due to mental illness and potential risk resulting from contextual factors with a statistical relevance of moderate intensity. 20% of the population under study lives in areas with a simultaneously high potential risk resulting from contextual factors and risk of hospitalization due to mental illness. Porto Metropolitan Area show the highest percentage of population living in parishes with a significantly high risk of hospitalization due to mental health, which puts forward the need for interventions on territory-adjusted contextual factors influencing mental health. PMID- 26648377 TI - Nutritional status of urban adolescents: individual, household and neighborhood factors based on data from The BH Health Study. AB - The increasing prevalence of overweight in young people suggests that adolescent nutritional status is influenced by environmental factors. Using hierarchical modelling, this study aimed to analyse the association between individual, household and neighborhood factors and adolescent nutritional status and well being. The study used data from a population-based household survey conducted in Belo Horizonte, the capital of the State of Minas Gerais, Brazil, between 2008 and 2009. Data was obtained from an adult and adolescent in each household using a confidential questionnaire and anthropometric measurements. Adolescent nutritional status was evaluated using multinomial regression analysis considering distal and proximal influences. The prevalence of overweight and thinness among the sample of 1,030 adolescents was 21.9% and 4.6%, respectively. Although variables from all blocks remained in the final model, head of household education level, family habits and family nutritional status were shown to strongly influence adolescent nutritional status. New approaches to public health are needed which focus on raising awareness and promoting health education targeting teenagers and their social context. PMID- 26648378 TI - The place where you live and self-rated health in a large urban area. AB - The aim of this study was to determine and quantify the association between one's perception of the place of residence and self-rated health. 4,048 adult residents of Belo Horizonte, Minas Gerais State, Brazil, participated in the study in 2008 and 2009. Ordinal logistic regression was used to estimate the magnitude of the association. Health was rated as good or very good, fair, or poor or very poor by 65.7%, 27.8%, and 6.5% of the subjects, respectively. Better self-rated health was associated with the following neighborhood characteristics: positive evaluation of aesthetics and mobility, better quality of public services, less physical and social disorder. The perception of violence had a borderline statistically significant association with worse self-rated health. These associations persisted after controlling for potential confounding demographic, socioeconomic, health, and health behavior variables. The results indicate that public and health policies should incorporate interventions that address the physical and social environment in addition to policies focused on individuals. PMID- 26648379 TI - Social conditions and urban environment associated with participation in the Ciclovia program among adults from Cali, Colombia. AB - The Ciclovia program (CP) has emerged as an effective initiative to promote active living in urban spaces in Latin America. This study assessed the association between social conditions, the urban environment and participation in the CP among adults living in the city of Cali, Colombia. A cross-sectional study was conducted in 2011 and 2012 among 719 adults aged 18 to 44. Urban environment measures were obtained using Geographic Information Systems. A multilevel logistic regression was used for the analysis. Slightly more than 7% of participants had participated in the CP in the previous four weekends. Being male and having a high school degree were positively associated with participation in the CP. Participation in the CP was positively associated with living in neighborhoods with Ciclovia lanes. In contrast, a negative association was found among those living in neighborhoods with a presence of traffic fatalities. This study provides new insights about a recreational program that has potential health benefits in a region marked by urban inequalities in terms of opportunities for physical activity. PMID- 26648380 TI - Forum: public health observatories and urban health. Introduction. PMID- 26648381 TI - Public Health Observatories in England: recent transformations and continuing the legacy. AB - Public Health Observatories (PHOs) were created in England in 2000 as an important adjunct to the public health system in the country. The observatories were networked together, which allowed pooling of expertise and rapid dissemination of methods and results. The network grew to include the whole of the UK and Ireland and was a very successful force for change until PHOs were subsumed into the new Government Agency Public Health Organization, Public Health England. This paper describes the lessons learnt from their existence in the public health system in England for fourteen years. PMID- 26648382 TI - The Belo Horizonte Observatory for Urban Health: its history and current challenges. AB - The Belo Horizonte Observatory for Urban Health (OSUBH), housed in an academic setting, was founded in 2002 as part of a broader agenda to strengthen local and national health systems. Its mission is to build the capacity of the workforce in research on population health and to conduct studies on urban issues that can guide the planning of activities aimed at improving the health of populations, especially in heavily urbanized areas, associated with intra-urban inequalities. It focuses on the acquisition of advanced knowledge on urban health (metric) through scientific research, to contribute to public policies that may interfere with health, both at individual and community levels. During its lifetime, many partnerships and studies have been developed, but many challenges still exist in order for it to consolidate its position as a legitimate space and as a tool to generate systematic information for governments and populations. PMID- 26648383 TI - Developing an academia-based public health observatory: the new global public health observatory with emphasis on urban health at Johns Hopkins Bloomberg School of Public Health. AB - Health observatories may differ according to their mission, institutional setting, topical emphasis or geographic coverage. This paper discusses the development of a new urban-focused health observatory, and its operational research and training infrastructure under the academic umbrella of the Department of Epidemiology and the Institute of Urban Health at the Johns Hopkins Bloomberg School of Public Health (BSPH) in Baltimore, USA. Recognizing the higher education mission of the BSPH, the development of a new professional training in public health was an important first step for the development of this observatory. This new academia-based observatory is an innovative public health research and training platform offering faculty, investigators, professional epidemiology students and research partners a physical and methodological infrastructure for their operational research and training activities with both a local urban focus and a global reach. The concept of a public health observatory and its role in addressing social health inequalities in local urban settings is discussed. PMID- 26648384 TI - Hepatitis B and C in household and health services solid waste workers. AB - Human contact with solid waste poses biological, chemical, and physical health risks for workers involved in waste collection, transportation, and storage. The potential risk to human health resulting from contact with health services waste or household waste still sparks considerable controversy. The aim of this study was to identify the context of scientific discussions on risk/infection from the hepatitis B and C viruses in workers that collect solid waste from health services or households. The search covered publications up to 2013 in Brazilian and international databases, and 11 articles were selected through a literature review. Of these, six conclude that there is an increased risk of infection in workers that collect household waste when compared to those unexposed to waste, three point to greater risk for workers that collect health services waste as compared to those that collect ordinary waste, and the other two found no difference between exposed and unexposed individuals. PMID- 26648385 TI - Caribbean mesophotic coral ecosystems are unlikely climate change refugia. AB - Deeper coral reefs experience reduced temperatures and light and are often shielded from localized anthropogenic stressors such as pollution and fishing. The deep reef refugia hypothesis posits that light-dependent stony coral species at deeper depths are buffered from thermal stress and will avoid bleaching related mass mortalities caused by increasing sea surface temperatures under climate change. This hypothesis has not been tested because data collection on deeper coral reefs is difficult. Here we show that deeper (mesophotic) reefs, 30 75 m depth, in the Caribbean are not refugia because they have lower bleaching threshold temperatures than shallow reefs. Over two thermal stress events, mesophotic reef bleaching was driven by a bleaching threshold that declines 0.26 degrees C every +10 m depth. Thus, the main premise of the deep reef refugia hypothesis that cooler environments are protective is incorrect; any increase in temperatures above the local mean warmest conditions can lead to thermal stress and bleaching. Thus, relatively cooler temperatures can no longer be considered a de facto refugium for corals and it is likely that many deeper coral reefs are as vulnerable to climate change as shallow water reefs. PMID- 26648386 TI - Neurosensoric disturbances after surgical removal of the mandibular third molar based on either panoramic imaging or cone beam CT scanning: A randomized controlled trial (RCT). AB - OBJECTIVE: Pre-surgical CBCT has been suggested before removal of the mandibular third molar. Currently, the standard-of-care is two-dimensional (2D) panoramic imaging. The aim of this randomized controlled trial was to analyse possible differences in neurosensoric disturbances of the inferior alveolar nerve between patients undergoing either panoramic imaging or CBCT before surgical removal of the mandibular third molar. Furthermore, the aim was to perform a sensitivity analysis to assess the statistical significance of different assumptions related to sample size calculations. METHODS: 230 patients were randomized to a scan group and a non-scan group. All patients were referred from practicing dentists in the Copenhagen area. Inclusion criteria were overlap of the root complex and the mandibular canal on a 2D radiographic image. Central allocation of the randomization code and double blind settings were established. The surgical removal was performed in a specialized surgical practice geographically and personally separated from the study practice. Registration of neurosensoric anomalies was performed with a Semmes-Weinstein test and a visual analogue scale questionnaire pre- and post-surgically. RESULTS: In the scan group (n = 114), 21 episodes of neurosensoric disturbances were registered and in the non-scan group (n = 116), 13 episodes of neurosensoric disturbances were registered. There was no statistically significant difference between the two groups (p = 0.14). Performing a sensitivity analysis confirmed that CBCT was not superior to panoramic imaging in avoiding neurosensoric disturbances. CONCLUSIONS: The use of CBCT before removal of the mandibular third molar does not seem to reduce the number of neurosensoric disturbances. PMID- 26648387 TI - Comparison of different methods to assess alveolar cleft defects in cone beam CT images. AB - OBJECTIVES: This study aimed to evaluate the accuracy of three different methods for assessing the volume of cleft defects in CBCT images. The influence of field of view (FOV) and voxel sizes was also assessed. METHODS: Using three radio opaque plastic skulls, unilateral defects were created to mimic alveolar clefts and were filled with wax following the contralateral side contours. They were scanned in a CBCT unit using four different acquisition protocols, varying FOV and voxel sizes. Using three different methods, the defect/wax volume was evaluated on the images by defining: (1) the width, height and facial-palatal length of the defect in maximum intensity projection; (2) the areas of the defect on axial slices; and (3) the threshold and segmentation of the region of interest. The values obtained from each method using different acquisition protocols were compared with the real volume of the wax (gold standard) using ANOVA and Tukey's test. RESULTS: Methods 2 and 3 did not differ from the gold standard (p > 0.05). Conversely, Method 1 presented statistically significant overestimated values (p < 0.01). No differences were found among the different FOV and voxel sizes (p > 0.05). CONCLUSIONS: CBCT volumes proved reliable for the volumetric assessment of alveolar cleft defects, when using Methods 2 and 3 regardless of FOV and voxel sizes. It may be possible to improve surgical planning and outcomes by knowing the exact volume of grafting material needed prior to the surgical intervention. PMID- 26648388 TI - Dissolved oxygen concentration in the medium during cell culture: Defects and improvements. AB - In vitro cell culture has provided a useful model to study the effects of oxygen on cellular behavior. However, it remains unknown whether the in vitro operations themselves affect the medium oxygen levels and the living states of cells. In addition, a prevailing controversy is whether reactive oxygen species (ROS) production is induced by continuous hypoxia or reoxygenation. In this study, we have measured the effects of different types of cell culture containers and the oxygen environment where medium replacement takes place on the actual oxygen tension in the medium. We found that the deviations of oxygen concentrations in the medium are much greater in 25-cm(2) flasks than in 24-well plates and 35-mm dishes. The dissolved oxygen concentrations in the medium were increased after medium replacement in normoxia, but remained unchanged in glove boxes in which the oxygen tension remained at a low level (11.4, 5.7, and 0.5% O2 ). We also found that medium replacement in normoxia increased the number of ROS-positive cells and reduced the cell viability; meanwhile, medium replacement in a glove box did not produce the above effects. Therefore, we conclude that the use of 25 cm(2) flasks should be avoided and demonstrate that continuous hypoxia does not produce ROS, whereas the reoxygenation that occurs during the harvesting of cells leads to ROS and induces cell death. PMID- 26648389 TI - Suppression of hepatocellular carcinoma cell proliferation by short hairpin RNA of frizzled 2 with Sonazoid-enhanced irradiation. AB - Short-hairpin RNA of frizzled-2 (shRNA-Fz2) is known to suppress the proliferation of hepatocellular carcinoma (HCC) cells; however, its effect on HCC cell motility is unknown. In this study, suppression of HCC cell motility by shRNA-Fz2 was analyzed, and introduction of shRNA-Fz2 into HCC cells was facilitated with ultrasound (US) irradiation generated from a diagnostic US device, which was enhanced by the contrast-enhanced US reagent Sonazoid. The HCC cell lines HLF and PLC/PRF/5 that were transfected with shRNA-Fz2 were plated to form monolayers, following which the cell monolayers were scratched with a sterile razor. After 48 h, the cells were stained with hematoxylin and eosin, and the distance between the growing edge of the cell layer and the scratch lines was measured. Total RNA from the cells was isolated and subjected to real-time quantitative PCR to quantify matrix metalloproteinase 9 expression at 48 h after transfection of shRNA-Fz2. Starch-iodide method was applied to analyze the generation of H2O2 following US irradiation with the addition of Sonazoid in the liquid, and cell proliferation was analyzed 72 h later. The distances between the growing edge of the cell layer and the scratch lines and MMP9 expression levels were significantly decreased with transfection of shRNA-Fz2 (P<0.05). In the starch-iodide method, absorbance significantly decreased with the addition of Sonazoid (P<0.05), which suggested that US irradiation with Sonazoid generated H2O2 and enhanced sonoporation. ShRNA-Fz2 suppressed cell proliferation of both cell lines at a mechanical index of 0.4. Motility of HLF cells and PLC/PRF/5 cells was suppressed by shRNA-FZ2. Sonazoid enhanced sonoporation of the cells with the diagnostic US device and the suppression of proliferation of both HCC cell lines by shRNA-Fz2. PMID- 26648390 TI - Management of female urinary incontinence: A survey of urogynaecologists' view on the NICE guideline. AB - We conducted a survey to obtain the opinions of urogynaecologists regarding the National Institute for Health and Care Excellence or NICE 2013 urinary incontinence guideline and whether it would change their current practice. A closed format questionnaire was sent electronically to all members of the British Society of Urogynaecology or BSUG between January and March 2014. There were three major areas of disagreement. First, 70.2% of respondents disagreed that a multidisciplinary team review was necessary before invasive treatment for urinary incontinence. Second, 53.8% of respondents disagreed that preoperative urodynamic studies were not required in stress urinary incontinence diagnosed clinically. Third, 58.6% of respondents disagreed that oxybutynin, tolterodine and darifenacin should be used as first-line drug therapy for overactive bladder. The questionnaire demonstrates that there are significant concerns leading to more than a third of respondents not altering their current practice in line with the entire guideline. PMID- 26648391 TI - Reductively Cleavable Nanocaplets for siRNA Delivery by Template-Assisted Oxidative Polymerization. AB - A series of water-soluble telechelic dithiol monomers bearing multiple guanidinium ion (Gu(+)) units in their main chains were synthesized for packaging siRNA by template-assisted oxidative polymerization at their thiol termini. In the presence of siRNA, oxidative polymerization of (TEG)Gu4 affords a uniform sized (7 +/- 2 nm) nanocaplet containing siRNA (P(TEG)Gu4?siRNA; P(TEG)Gu4 = polymerized (TEG)Gu4). When this small conjugate is incubated with live cells, cellular uptake occurs, and the nanocaplet undergoes depolymerization in the reductive cytosolic environment to liberate the packaged siRNA. Consequently, gene expression in the live cells is suppressed. PMID- 26648392 TI - Curcumin ameliorates dopaminergic neuronal oxidative damage via activation of the Akt/Nrf2 pathway. AB - Parkinson's disease (PD) is an age-related complex neurodegenerative disease that affects <= 80% of dopaminergic neurons in the substantia nigra pars compacta (SNpc). It has previously been suggested that mitochondrial dysfunction, oxidative stress and oxidative damage underlie the pathogenesis of PD. Curcumin, which is a major active polyphenol component extracted from the rhizomes of Curcuma longa (Zingiberaceae), has been reported to exert neuroprotective effects on an experimental model of PD. The present study conducted a series of in vivo experiments, in order to investigate the effects of curcumin on behavioral deficits, oxidative damage and related mechanisms. The results demonstrated that curcumin was able to significantly alleviate motor dysfunction and increase suppressed tyrosine hydroxylase (TH) activity in the SNpc of rotenone (ROT) injured rats. Biochemical measurements indicated that rats pretreated with curcumin exhibited increased glutathione (GSH) levels, and reduced reactive oxygen species activity and malondialdehyde content. Mechanistic studies demonstrated that curcumin significantly restored the expression levels of heme oxygenase-1 and NAD(P)H: quinone oxidoreductase 1, thus ameliorating ROT-induced damage in vivo, via the phosphorylation of Akt and nuclear factor erythroid 2 related factor 2 (Nrf2). Further studies indicated that the Akt/Nrf2 signaling pathway was associated with the protective role of curcumin in ROT-treated rats. Inhibiting the Akt/Nrf2 pathway using a lentiviral vector containing Nrf2 specific short hairpin RNA, or the phosphoinositide 3-kinase inhibitor LY294002, markedly reduced the expression levels of TH and GSH, ultimately attenuating the neuroprotective effects of curcumin against oxidative damage. These results indicated that curcumin was able to significantly ameliorate ROT-induced dopaminergic neuronal oxidative damage in the SNpc of rats via activation of the Akt/Nrf2 signaling pathway. PMID- 26648394 TI - Vacuum ultraviolet excitation luminescence spectroscopy of few-layered MoS2. AB - We report on vacuum ultraviolet (VUV) excited photoluminescence (PL) spectra emitted from a chemical vapor deposited MoS2 few-layered film. The excitation spectrum was recorded by monitoring intensities of PL spectra at ~1.9 eV. A strong wide excitation band peaking at 7 eV was found in the excitation. The PL excitation band is most intensive at liquid helium temperature and completely quenched at 100 K. Through first-principles calculations of photoabsorption in MoS2, the excitation was explicated and attributed to transitions of electrons from p- and d- type states in the valence band to the d- and p-type states in the conduction band. The obtained photon-in/photon-out results clarify the excitation and emission behavior of the low dimensional MoS2 when interacting with the VUV light sources. PMID- 26648395 TI - Simulation of avascular tumor growth by agent-based game model involving phenotype-phenotype interactions. AB - All tumors, both benign and metastatic, undergo an avascular growth stage with nutrients supplied by the surrounding tissue. This avascular growth process is much easier to carry out in more qualitative and quantitative experiments starting from tumor spheroids in vitro with reliable reproducibility. Essentially, this tumor progression would be described as a sequence of phenotypes. Using agent-based simulation in a two-dimensional spatial lattice, we constructed a composite growth model in which the phenotypic behavior of tumor cells depends on not only the local nutrient concentration and cell count but also the game among cells. Our simulation results demonstrated that in silico tumors are qualitatively similar to those observed in tumor spheroid experiments. We also found that the payoffs in the game between two living cell phenotypes can influence the growth velocity and surface roughness of tumors at the same time. Finally, this current model is flexible and can be easily extended to discuss other situations, such as environmental heterogeneity and mutation. PMID- 26648396 TI - Single Cell Dynamics Causes Pareto-Like Effect in Stimulated T Cell Populations. AB - Cell fate choice during the process of differentiation may obey to deterministic or stochastic rules. In order to discriminate between these two strategies we used time-lapse microscopy of individual murine CD4 + T cells that allows investigating the dynamics of proliferation and fate commitment. We observed highly heterogeneous division and death rates between individual clones resulting in a Pareto-like dominance of a few clones at the end of the experiment. Commitment to the Treg fate was monitored using the expression of a GFP reporter gene under the control of the endogenous Foxp3 promoter. All possible combinations of proliferation and differentiation were observed and resulted in exclusively GFP-, GFP+ or mixed phenotype clones of very different population sizes. We simulated the process of proliferation and differentiation using a simple mathematical model of stochastic decision-making based on the experimentally observed parameters. The simulations show that a stochastic scenario is fully compatible with the observed Pareto-like imbalance in the final population. PMID- 26648397 TI - Nanoporous CuS with excellent photocatalytic property. AB - We present the rational synthesis of nanoporous CuS for the first time by chemical dealloying method. The morphologies of the CuS catalysts are controlled by the composition of the original amorphous alloys. Nanoporous Cu2S is firstly formed during the chemical dealloying process, and then the Cu2S transforms into CuS. The nanoporous CuS exhibits excellent photocatalytic activity for the degradation of the methylene blue (MB), methyl orange (MO) and rhodamine B (RhB). The excellent photocatalytic activity of the nanoporous CuS is mainly attributed to the large specific surface area, high adsorbing capacity of dyes and low recombination of the photo generated electrons and holes. In the photo degradation process, both chemical and photo generated hydroxyl radicals are generated. The hydroxyl radicals are favor in the oxidation of the dye molecules. The present modified dealloying method may be extended for the preparation of other porous metal sulfide nanostructures. PMID- 26648398 TI - Soluble molecules in intravenous immunoglobulin: benefits and limitations. AB - Because of its predominance, the main immunomodulatory function of IVIg is carried out by the IgG molecules; while, based on multiple studies, the immunomodulatory role of other soluble molecules in commercial IVIg products is impossible to ignore. Although the existence of these molecules and their suppressive effects on the immune response may be considered a positive contribution to the treatment of autoimmune disorders, their presence, half-life, accumulation and immunosuppressive actions in immunocompromised patients should be monitored by physicians and manufacturing companies. PMID- 26648399 TI - Contrasting levels of absorption of intense femtosecond laser pulses by solids. AB - The absorption of ultraintense, femtosecond laser pulses by a solid unleashes relativistic electrons, thereby creating a regime of relativistic optics. This has enabled exciting applications of relativistic particle beams and coherent X ray radiation, and fundamental leaps in high energy density science and laboratory astrophysics. Obviously, central to these possibilities lies the basic problem of understanding and if possible, manipulating laser absorption. Surprisingly, the absorption of intense light largely remains an open question, despite the extensive variations in target and laser pulse structures. Moreover, there are only few experimental measurements of laser absorption carried out under very limited parameter ranges. Here we present an extensive investigation of absorption of intense 30 femtosecond laser pulses by solid metal targets. The study, performed under varying laser intensity and contrast ratio over four orders of magnitude, reveals a significant and non-intuitive dependence on these parameters. For contrast ratio of 10(-9) and intensity of 2 * 10(19)W cm(-2), three observations are revealed: preferential acceleration of electrons along the laser axis, a ponderomotive scaling of electron temperature, and red shifting of emitted second-harmonic. These point towards the role of J * B absorption mechanism at relativistic intensity. The experimental results are supported by particle-in-cell simulations. PMID- 26648400 TI - Conformational gating of DNA conductance. AB - DNA is a promising molecule for applications in molecular electronics because of its unique electronic and self-assembly properties. Here we report that the conductance of DNA duplexes increases by approximately one order of magnitude when its conformation is changed from the B-form to the A-form. This large conductance increase is fully reversible, and by controlling the chemical environment, the conductance can be repeatedly switched between the two values. The conductance of the two conformations displays weak length dependencies, as is expected for guanine-rich sequences, and can be fit with a coherence-corrected hopping model. These results are supported by ab initio electronic structure calculations that indicate that the highest occupied molecular orbital is more disperse in the A-form DNA case. These results demonstrate that DNA can behave as a promising molecular switch for molecular electronics applications and also provide additional insights into the huge dispersion of DNA conductance values found in the literature. PMID- 26648401 TI - Orally administered betaine reduces photodamage caused by UVB irradiation through the regulation of matrix metalloproteinase-9 activity in hairless mice. AB - Betaine is widely distributed in plants, microorganisms, in several types of food and in medical herbs, including Lycium chinense. The administration of 100 mg betaine/kg body weight/day is an effective strategy for preventing ultraviolet irradiation-induced skin damage. The present study aimed to determine the preventive effects of betaine on ultraviolet B (UVB) irradiation-induced skin damage in hairless mice. The mice were divided into three groups: Control (n=5), UVB-treated vehicle (n=5) and UVB-treated betaine (n=5) groups. The level of irradiation was progressively increased between 60 mJ/cm2 per exposure at week 1 (one minimal erythematous dose = 60 mJ/cm2) and 90 mJ/cm2 per exposure at week 7. The formation of wrinkles significantly increased following UVB exposure in the UVB-treated vehicle group. However, treatment with betaine suppressed UVB-induced wrinkle formation, as determined by the mean length, mean depth, number, epidermal thickness and collagen damage. Furthermore, oral administration of betaine also inhibited the UVB-induced expression of mitogen-activated protein kinase kinase (MEK), extracellular signal-regulated kinase (ERK), and matrix metalloproteinase-9 (MMP-9). These findings suggested that betaine inhibits UVB induced skin damage by suppressing increased expression of MMP-9 through the inhibition of MEK and ERK. PMID- 26648402 TI - Induction of autophagy by the MG-132 proteasome inhibitor is associated with endoplasmic reticulum stress in MCF-7 cells. AB - The aim of the present study was to investigate whether endoplasmic reticulum (ER) stress is involved in MG-132-induced autophagy, and to determine the effects of the inhibition of autophagy and ER stress on cell viability following MG-132 treatment. The proteasome inhibitor, MG-132, was used to induce autophagy in MCF 7 cells, and 3-methyladenine (3-MA) and salubrinal were used to inhibit autophagy and ER stress, respectively. An MTT assay was used to analyze cell viability. Apoptosis and the cell cycle were analyzed using flow cytometry. The expression levels of apoptosis- and ER stress-associated genes were investigated using western blot and reverse transcription-quantitative polymerase chain reaction analyses. MG-132 inhibited cell proliferation, and induced apoptosis and cell cycle arrest at the G2 phase of the cell cycle. Notably, MG-132 increased the autophagy-associated conversion of microtubule-associated protein 1 light chain 3 (LC3)-I to LC3-II, which was partially attenuated by the ER stress inhibitor, salubrinal. In addition, MG-132 inhibited the protein expression of the anti apoptotic protein, B-cell lymphoma (Bcl)-2, whereas the expression levels of Bcl 2-associated X protein and caspase-3 were upregulated. These effects were enhanced by co-treatment with either 3-MA or salubrinal. Furthermore, the mRNA and protein levels of the ER stress-associated genes, glucose-regulated protein 78, growth arrest and DNA damage induced gene-153, and caspase-12, were upregulated by MG132, and these levels were significantly inhibited by co treatment of the cells with salubrinal. Taken together, the results of the present study indicated that the induction of autophagy by the proteasome inhibitor was associated with ER stress in the MCF-7 cells, and that the inhibition of autophagy or ER stress enhanced MG-132-induced apoptosis. These findings suggest the potential application of inhibitors of ER stress and autophagy, in combination with proteasomal inhibitors, for the development of combinatorial targeted cancer therapy. PMID- 26648403 TI - D5h [PhSiO1.5]10 synthesis via F(-) catalyzed rearrangement of [PhSiO1.5]n. An experimental/computational analysis of likely reaction pathways. AB - We describe here the synthesis and analysis of the reaction pathways leading to formation of the rare D5h decaphenylsilsesquioxane (SQ) [PhSiO1.5]10via F(-) catalyzed rearrangement of [PhSiO1.5]nn = 8, 12, and oligomers initially synthesized from PhSi(OEt)3. Isolated yields of ~50% [PhSiO1.5]10 are obtained via rearrangement of all starting materials. The recovered starting materials can be re-equilibrated using catalytic F(-) to generate similar yields in second batches. These yields arise because [PhSiO1.5]10 exhibits higher solubility and better energy stabilization (10 kcal mol(-1) theory) in CH2Cl2 compared to [PhSiO1.5]8 or [PhSiO1.5]12. Reaction intermediates were identified using time dependent (19)F NMR and MALDI-ToF mass spectrometry eventually equilibrating to form the 8 : 10 : 12 cages in a 1 : 3 : 1.3 equilibrium in CH2Cl2. Experimental results coupled with modeling using the Gamess computational package provide multiple reasonable pathways for SQ rearrangements to [RSiO1.5]10, starting from [RSiO1.5]8. Heats of reaction for interconversion of the model intermediates [HSiO1.5]x determined computationally, were used to select the most reasonable reaction pathways. The findings support a mechanism involving activation and cleavage of a T8 cage corner by F(-) attachment, followed by the corners stepwise removal as [i.e. RSi(OH)3], followed thereafter by reinsertion forming [RSiO1.5]9 OH followed by, insertion of another corner to form [RSiO1.5]10-(OH)2 and finally condensation to give [RSiO1.5]10. The most enthalpically favorable path (-24 kcal mol(-1)) involves a hybrid mechanism. PMID- 26648404 TI - Assessment of serial multi-parametric functional MRI (diffusion-weighted imaging and R2*) with (18)F-FDG-PET in patients with head and neck cancer treated with radiation therapy. AB - OBJECTIVE: To evaluate the serial changes and correlations between readout segmented technique with navigated phase correction diffusion-weighted MRI (DWI), R2*-MRI and (18)F-FDG positron emission tomography (PET) CT performed before and during radiation therapy (RT) in patients with mucosal primary head and neck cancer. METHODS: The mean apparent diffusion coefficient (ADCmean) from DWI (at b = 50 and 800 s mm(-2)), the mean R2* values derived from T2(*)-MRI, and PET metabolic parameters, including maximum standardized uptake value (SUVmax), metabolic tumour volume (MTV) and total lesional glycolysis (TLG) were measured for the primary tumour. Spearman correlation coefficients were calculated to evaluate correlations between ADCmean, R2*, SUVmax, MTV and TLG. A paired t-test was performed to assess the MRI changes and the slope of serial MRI changes during RT. RESULTS: Pre-treatment scans were performed in 28 patients and mid treatment scans in 20 patients. No significant correlation was found between ADCmean and either R2* values or PET parameters. There were significant negative correlations of R2* values with pre-treatment PET parameters but not with mid-RT PET parameters: pre-SUVmax (p = 0.008), pre-MTV (p = 0.006) and pre-TLG (p = 0.008). A significant rise in ADCmean was found during the first half (p < 0.001) of RT but not in the second half (p = 0.215) of the treatment. There was an increase of the ADCmean values of 279.4 [95% confidence interval (95% CI): 210 348] in the first half of the treatment (Weeks 0-3). However, during the second half period of treatment, the mean ADC value (Weeks 3-6) was 24.0 and the 95% CI (-40 to 88) included zero. This suggests that there was no significant change in ADC values during the second half of the treatment. CONCLUSION: A significant negative correlation was found between pre-treatment R2*-MRI and PET parameters. DWI appeared to demonstrate potentially predictable changes during RT. ADVANCES IN KNOWLEDGE: Understanding the correlation and changes that occur with time between potential imaging biomarkers may help us establish the most appropriate biomarkers to consider in future research. PMID- 26648405 TI - Correlation between levels of expression of minichromosome maintenance proteins, Ki-67 proliferation antigen and metallothionein I/II in laryngeal squamous cell cancer. AB - MCM2, MCM3 and MCM7 are minichromosome maintenance proteins found in dividing cells and they play a role in DNA synthesis. Increased MCM expression level is observed in cells of different cancer types. Additionally, metallothioneins (MT I/II) are involved in control of cell proliferation and differentiation and changes of their expression are observed in many types of cancer. Ki-67 is known cancer cell proliferation antigen currently used in prognostic evaluation. The study material consisted of 83 laryngeal squamous cell cancer (LSCC) cases and 10 benign hypertrophic lesions of larynx epithelium as a control group. For the present study, laryngeal cancer cell line HEp-2 and human keratinocytes were employed, and to evaluate expression of all the markers, immunohistochemical method (IHC), immunofluorescence (IF) and western blot analysis were used. Statistical analysis showed strong positive correlation between expression of MCM2, MCM3, MCM7 and Ki-67 antigen in LSCC. Additionally, moderate positive correlation was observed between MCM3 and MT-I/II expression. In cancer cells, the level of expression of MCM3, MCM2, MCM7 and Ki-67 markers was increasing with the grade of LSCC malignancy. IF and western blot analysis showed higher MCM2, MCM3, MCM7 expression in HEp-2 cells in comparison to their expression in keratinocytes. MCM proteins might be useful markers of cell proliferation in LSCC. PMID- 26648406 TI - Dirk Willem van Bekkum: a pioneer in haematology, transplantation and radiobiology (1925-2015). PMID- 26648407 TI - Extended survival and reduced risk of AML progression in erythroid-responsive lenalidomide-treated patients with lower-risk del(5q) MDS. PMID- 26648408 TI - Giant pH-responsive microgel colloidosomes: preparation, interaction dynamics and stability. AB - The interactions of two oil droplets grown in the presence of swollen, lightly cross-linked cationic poly(tert-butylamino)ethyl methacrylate (PTBAEMA) microgels was monitored using a high-speed video camera. Three oils (n-dodecane, isopropyl myristate and sunflower oil) were investigated, each in the absence and presence of an oil-soluble cross-linker [tolylene 2,4-diisocyanate-terminated poly(propylene glycol), PPG-TDI]. Adsorption of the swollen microgel particles was confirmed by interfacial tension, interfacial elasticity and dilational viscosity measurements on single pendant oil droplets, and assessment of the oscillatory dynamics for coalescing droplet pairs. Like the analogous bulk emulsions, particle adsorption alone did not prevent coalescence of pairs of giant Pickering emulsion droplets. However, prior addition of surface-active PPG TDI cross-linker to the oil phase results in the formation of highly stable microgel colloidosomes via reaction with the secondary amine groups on the PTBAEMA chains. Colloidosome stability depended on the age of the oil-water interface. This reflects a balance between the adsorption kinetics of the PPG-TDI cross-linker and the microgel particles, each of which must be present at the interface to form a stable colloidosome. Colloidosome formation was virtually instantaneous in n-dodecane, but took up to 120 s in the case of isopropyl myristate. The impact of an acid-induced latex-to-microgel transition on the interaction of giant colloidosomes (originally prepared at pH 10 using isopropyl myristate) was also studied. This acid challenge did not result in coalescence, which is consistent with a closely-related study (A. J. Morse et al., Langmuir, 2014, 30(42), 12509-12519). No evidence was observed for inter-colloidosome cross linking, which was attributed to retention of an aqueous film between the adjacent pair of colloidosomes. PMID- 26648409 TI - A competitive photoelectrochemical immunosensor based on a CdS-induced signal amplification strategy for the ultrasensitive detection of dexamethasone. AB - A novel photoelectrochemical immunosensor based on the competitive strategy is proposed for the specific detection of dexamethasone (DXM). Graphitic carbon nitride coupled with bismuth sulfide are used as the sensing matrix for the immobilization of BSA-DXM on the electrode surface, while cadmium sulfide functionalized titanium dioxide (TiO2@CdS) is used as the photoelectric active labels of anti-DXM. Due to the perfect matching of energy levels between TiO2 and CdS, the in situ prepared composite labels show excellent photocurrent response under visible lights. The competitive binding of DXM in sample solutions and BSA DXM on the electrode surface reduces the specific attachment of labels to the electrode, resulting in a decrease of the photocurrent intensity. Greatly enhanced sensitivity is achieved after the optimization of the detection conditions. Under the optimal detection condition, the well-designed immunosensor for DXM exhibits a low detection limit of 2 pg ? mL(-1). Additionally, the proposed immunoassay system shows high specificity, good reproducibility and acceptable stability, which is also expected to become a promising platform for the detection of other small molecules. PMID- 26648410 TI - Cold-sensing regulates Drosophila growth through insulin-producing cells. AB - Across phyla, body size is linked to climate. For example, rearing fruit flies at lower temperatures results in bigger body sizes than those observed at higher temperatures. The underlying molecular basis of this effect is poorly understood. Here we provide evidence that the temperature-dependent regulation of Drosophila body size depends on a group of cold-sensing neurons and insulin-producing cells (IPCs). Electrically silencing IPCs completely abolishes the body size increase induced by cold temperature. IPCs are directly innervated by cold-sensing neurons. Stimulation of these cold-sensing neurons activates IPCs, promotes synthesis and secretion of Drosophila insulin-like peptides and induces a larger body size, mimicking the effects of rearing the flies in cold temperature. Taken together, these findings reveal a neuronal circuit that mediates the effects of low temperature on fly growth. PMID- 26648411 TI - DNA methylation is stable during replication and cell cycle arrest. AB - DNA methylation is an epigenetic modification with important functions in development. Large-scale loss of DNA methylation is a hallmark of cancer. Recent work has identified large genomic blocks of hypomethylation associated with cancer, EBV transformation and replicative senescence, all of which change the proportion of actively proliferating cells within the population measured. We asked if replication or cell-cycle arrest affects the global levels of methylation or leads to hypomethylated blocks as observed in other settings. We used fluorescence activated cell sorting to isolate primary dermal fibroblasts in G0, G1 and G2 based on DNA content and Ki67 staining. We additionally examined G0 cells arrested by contact inhibition for one week to determine the effects of extended arrest. We analyzed genome wide DNA methylation from sorted cells using whole genome bisulfite sequencing. This analysis demonstrated no global changes or large-scale hypomethylated blocks in any of the examined cell cycle phases, indicating that global levels of methylation are stable with replication and arrest. PMID- 26648412 TI - Nanopatterned polymer brushes: conformation, fabrication and applications. AB - Surfaces with end-grafted, nanopatterned polymer brushes that exhibit well defined feature dimensions and controlled chemical and physical properties provide versatile platforms not only for investigation of nanoscale phenomena at biointerfaces, but also for the development of advanced devices relevant to biotechnology and electronics applications. In this review, we first give a brief introduction of scaling behavior of nanopatterned polymer brushes and then summarize recent progress in fabrication and application of nanopatterned polymer brushes. Specifically, we highlight applications of nanopatterned stimuli responsive polymer brushes in the areas of biomedicine and biotechnology. PMID- 26648413 TI - A Petal-type Chiral NADH Model: Design, Synthesis and its Asymmetric Reduction. AB - A new type of NADH model compound has been synthesized by an efficient and convenient method. This model compound exhibits high reactivity and enantioselectivity in asymmetric reduction reactions. The results show that chiral NADH model S could be effectively combined with Mg(2+) to form ternary complexes. This novel C3 symmetrical NADH model is capable of fluorescence emission at 460 nm when excited at 377 nm. PMID- 26648414 TI - Hydrolysis of Selected Tropical Plant Wastes Catalyzed by a Magnetic Carbonaceous Acid with Microwave. AB - In this study, magnetic carbonaceous acids were synthesized by pyrolysis of the homogeneous mixtures of glucose and magnetic Fe3O4 nanoparticles, and subsequent sulfonation. The synthesis conditions were optimized to obtain a catalyst with both high acid density (0.75 mmol g(-1)) and strong magnetism [magnetic saturation, Ms = 19.5 Am(2) kg(-1)]. The screened catalyst (C-SO3H/Fe3O4) was used to hydrolyze ball-milled cellulose in a microwave reactor with total reducing sugar (TRS) yield of 25.3% under the best conditions at 190 degrees C for 3.5 h. It was cycled for at least seven times with high catalyst recovery rate (92.8%), acid density (0.63 mmol g(-1)) and magnetism (Ms = 12.9 Am(2) kg( 1)), as well as high TRS yield (20.1%) from the hydrolysis of ball-milled cellulose. The catalyst was further successfully tested for the hydrolysis of tropical biomass with high TRS and glucose yields of 79.8% and 58.3% for bagasse, 47.2% and 35.6% for Jatropha hulls, as well as 54.4% and 35.8% for Plukenetia hulls. PMID- 26648415 TI - Morphine-induced delayed pre-conditioning against anoxia/reoxygenation injury in pulmonary artery endothelial cells: The role of mitochondrial KATP channels. AB - Opioids produce delayed pre-conditioning (PC) in vivo and in vitro. Our previous research revealed that opioid-induced delayed PC has an antiapoptotic effect on pulmonary artery endothelial cells (PAECs) suffering from anoxia/reoxygenation (A/R) injury. The present study hypothesized that activation of endothelial mitochondrial ATP-sensitive potassium (KATP) channels may result in antiapoptotic effects and against dysfunction in PAECs. Cultured porcine PAECs underwent 16 h anoxia treatment, followed by 1 h reoxygenation, which occurred 24 h following pretreatment with saline (0.9% NaCl; w/v) or morphine (1 uM). To determine the underlying mechanism, a selective mitochondrial KATP inhibitor, 5-hydroxydecanoic acid (5-HD; 100 uM), and an opioid receptor antagonist, naloxone (Nal; 10 uM), were administered 30 min prior to the A/R load. The percentage of apoptotic cells was assessed by Annexin V-fluorescein isothiocyanate staining, using a fluorescence-activated cell sorter. The mRNA expression of intercellular cell adhesion molecule-1 (ICAM-1) was measured by reverse transcription-quantitative polymerase chain reaction. The endothelin-1 (ET-1) content in the supernatant of PAECs cultures was estimated by radioimmunoassay. Compared with the control, A/R caused the apoptosis of PAECs, release of ET-1 and increased mRNA expression of ICAM-1. Morphine-induced delayed PC significantly reduced PAEC apoptosis, increased the release of ET-1 and reduced the mRNA expression of ICAM-1 by ~1.7 times, compared with A/R. The protective effect of morphine was abolished by pretreatment with 5-HD and Nal, however, the two agents themselves failed to aggravate the A/R injury. These results suggested that morphine-induced delayed PC has a protective effect during A/R injury of PAECs. This effect may be mediated by mitochondrial KATP channels and is opioid receptor-dependent. PMID- 26648416 TI - Programmable v-type valve for cell and particle manipulation in microfluidic devices. AB - A new microfluidic valve or a "v-type valve" which can be flexibly actuated to focus a fluid flow and block a specific area of a microchannel is demonstrated. Valves with different design parameters were fabricated by multilayer soft lithography and characterized at various operating pressures. To evaluate the functionality of the valve, single microparticles (? 7 MUm and ? 15 MUm) and single cells were trapped from flowing suspensions. Continuous processes of particle capture and release were achieved by controlling the actuation and deactuation of the valve. Integration of the v-type valve with poly(dimethyl siloxane) (PDMS) monolithic valves in microfluidic devices was demonstrated to illustrate the potential of the system in various applications such as the creation of a solid phase column, the isolation of a specific number of particles in reactors, and the capture and release of particles or cells in the flow of two immiscible liquids. We believe that this new valve system will be suitable for manipulating particles and cells in a broad range of applications. PMID- 26648417 TI - Maggot Debridement Therapy in Disaster Medicine. AB - BACKGROUND: When disaster strikes, the number of patients requiring treatment can be overwhelming. In low-income countries, resources to assist the injured in a timely fashion may be limited. As a consequence, necrosis and wound infection in disaster patients is common and frequently leads to adverse health outcomes such as amputations, chronic wounds, and loss of life. In such compromised health care environments, low-tech and cheap wound care options are required that are in ready supply, easy to use, and have multiple therapeutic benefits. Maggot debridement therapy (MDT) is one such wound care option and may prove to be an invaluable tool in the treatment of wounds post-disaster. DISCUSSION: This report provides an overview of the wound burden experienced in various types of disaster, followed by a discussion of current treatment approaches, and the role MDT may play in the treatment of complex wounds in challenging health care conditions. Maggot debridement therapy removes necrotic and devitalized tissue, controls wound infection, and stimulates wound healing. These properties suggest that medicinal maggots could assist health care professionals in the debridement of disaster wounds, to control or prevent infection, and to prepare the wound bed for reconstructive surgery. Maggot debridement therapy-assisted wound care would be led by health care workers rather than physicians, which would allow the latter to focus on reconstructive and other surgical interventions. Moreover, MDT could provide a larger window for time-critical interventions, such as fasciotomies to treat compartment syndrome and amputations in case of life threatening wound infection. RECOMMENDATIONS: There are social, medical, and logistic hurdles to overcome before MDT can become widely available in disaster medical aid. Thus, research is needed to further demonstrate the utility of MDT in Disaster Medicine. There is also a need for reliable MDT logistics and supply chain networks. Integration with other disaster management activities will also be essential. CONCLUSIONS: In the aftermath of disasters, MDT could play an important role facilitating timely and efficient medical treatment and improving patient outcomes. Existing social, medical, and logistic barriers will need to be overcome for MDT to be mainstreamed in Disaster Medicine. PMID- 26648418 TI - Remote Manipulation of Droplets on a Flexible Magnetically Responsive Film. AB - The manipulation of droplets is used in a wide range of applications, from lab-on a-chip devices to bioinspired functional surfaces. Although a variety of droplet manipulation techniques have been proposed, active, fast and reversible manipulation of pure discrete droplets remains elusive due to the technical limitations of previous techniques. Here, we describe a novel technique that enables active, fast, precise and reversible control over the position and motion of a pure discrete droplet with only a permanent magnet by utilizing a magnetically responsive flexible film possessing actuating hierarchical pillars on the surface. This magnetically responsive surface shows reliable actuating capabilities with immediate field responses and maximum tilting angles of ~90 degrees . Furthermore, the magnetic responsive film exhibits superhydrophobicity regardless of tilting angles of the actuating pillars. Using this magnetically responsive film, we demonstrate active and reversible manipulation of droplets with a remote magnetic force. PMID- 26648420 TI - Low temperature solution process-based defect-induced orange-red light emitting diode. AB - We report low-temperature solution-processed p-CuO nanorods (NRs)/n-ZnO NRs heterojunction light emitting diode (LED), exploiting the native point defects of ZnO NRs. ZnO NRs were synthesized at 90 degrees C by using hydrothermal method while CuO NRs were synthesized at 100 degrees C by using microwave reaction system. The electrical properties of newly synthesized CuO NRs revealed a promising p-type nature with a hole concentration of 9.64 * 10(18) cm(-3). The current-voltage characteristic of the heterojunction showed a significantly high rectification ratio of 10(5) at 4 V with a stable current flow. A broad orange red emission was obtained from the forward biased LED with a major peak at 610 nm which was attributed to the electron transition from interstitial zinc to interstitial oxygen point defects in ZnO. A minor shoulder peak was also observed at 710 nm, corresponding to red emission which was ascribed to the transition from conduction band of ZnO to oxygen vacancies in ZnO lattice. This study demonstrates a significant progress toward oxide materials based, defect-induced light emitting device with low-cost, low-temperature methods. PMID- 26648419 TI - SNAIL transcription factor increases the motility and invasive capacity of prostate cancer cells. AB - The incidence and mortality rates of prostate cancer (PCa) are increasing, and PCa is almost the second-leading cause of cancer-associated mortality in men. During tumor progression, epithelial cells decrease the number of adhesion molecules, change their polarity and position, rearrange their cytoskeleton and increase their migratory and invasive capacities. These changes are known under the concept of epithelial-mesenchymal transition (EMT). EMT is characterized by an upregulation of certain transcription factors, including SNAIL1, which represses genes that are characteristic of an epithelial phenotype, including E cadherin, and indirectly increase the expression levels of genes, which are associated with the mesenchymal phenotype. It has been suggested that the transcription factor, SNAIL1, decreases the proliferation and increases the migratory and invasive capacities of PCa cell lines. The present study was performed using LNCaP and PC3 cell lines, in which the expression levels of SNAIL1 were increased or silenced through the use of lentiviral vectors. The expression levels of EMT markers were quantified using reverse transcription quantitative polymerase chain reaction and western blot analysis. In addition, cell survival was analyzed using an MTS assay; cell proliferation was examined using an antibody targeting Ki-67; migration on plates with 8 um pores to allow the passage of cells; and invasiveness was analyzed using a membrane chamber covered in dried basement membrane matrix solution. The levels of apoptosis were determined using a Caspase 3/7 assay containing a substrate modified by caspases 3 and 7. The results demonstrated that the overexpression and silencing of SNAIL1 decreased cell proliferation and survival. However, the overexpression of SNAIL1 decreased apoptosis, compared with cells with the SNAIL1-silenced cells, in which cell apoptosis increased. The migration and invasive capacities increased in the cells overexpressing SNAIL1, and decreased when SNAIL1 was silenced. In conclusion, PCa cells overexpressing SNAIL1 exhibited characteristics of an EMT phenotype, whereas the silencing of the SNAIL1 transcriptional repressor promoted an epithelial-like phenotype, with decreased migration and invasion, characteristic of mesenchymal cells. PMID- 26648421 TI - Notch and Wnt signaling pathway in cancer: Crucial role and potential therapeutic targets (Review). AB - There is no radical cure for all cancer types. The most frequently used therapies are surgical treatment, radiotherapy and chemotherapy. However, recrudescence, radiation resistance and chemotherapy resistance are the most challenging issues in clinical practice. To address these issues, they should be further studied at the molecular level, and the signaling pathways involved represent a promising avenue for this research. In the present review, we mainly discuss the components and mechanisms of activation of the Notch and Wnt signaling pathways, and we summarize the recent research efforts on these two pathways in different cancers. We also evaluate the ideal drugs that could target these two signaling pathways for cancer therapy, summarize alterations in the Notch and Wnt signaling pathways in cancer, and discuss potential signaling inhibitors as effective drugs for cancer therapy. PMID- 26648422 TI - MicroRNA-7 suppresses human colon cancer invasion and proliferation by targeting the expression of focal adhesion kinase. AB - Previous studies have demonstrated that microRNA (miRNA) are essential in tumor development and invasion. The close association between focal adhesion kinase (FAK) and colon cancer (CC) has been previously reported. miRNA-7 (miR-7) inhibits the translation of FAK protein. Therefore, the present study aimed to assess the underlying molecular mechanism of miR-7 in human CC cell lines, to provide a novel therapeutic biomarker of CC in the future. The present study detected the expression of miR-7 in 60 CC tissues by reverse transcription quantitative polymerase chain reaction (RT-qPCR). The association between the expression of miR-7 and clinical pathological factors was analyzed. Overexpression/underexpression of miR-7 were established by transfecting miR 7mimics/inhibitors into HCT-8 and Caco-2 cells. The transfected CC cell lines were used in cell viability and scratching assays. The regulation of FAK by miR-7 was analyzed by western blotting and RT-qPCR. It was demonstrated that the expression of miR-7 negatively correlated with lymph node metastasis and tumor node metastasis staging in CC (P<0.05). Inhibition of miR-7 led to an accelerated ability of proliferation and migration in CC cell lines. Additionally, overexpression of miR-7 inhibited the proliferation and migration of CC cells. In addition, it was also observed that miR-7 regulated the proliferation and migration of CC by regulating the protein expression of FAK, therefore, regulating the expression of matrix metalloproteinase (MMP)-2 and MMP-9. miR-7 inhibited the proliferation and migration of CC cells by regulating FAK. These findings suggested that miR-7 may be a novel therapeutic target for CC. PMID- 26648425 TI - Smoking and cancer: Brazil and the Global Burden of Disease initiative. PMID- 26648424 TI - Two-photon sensitized hollow Gd2O3:Eu(3+) nanocomposites for real-time dual-mode imaging and monitoring of anticancer drug release. AB - New two-photon sensitized multifunctional nanocomposites were designed for dual mode imaging and real-time drug release monitoring by photoluminescence (PL) and magnetic resonance imaging (MRI). By drug loading based on coordination effect, PL signals of Eu(3+) and MRI signals of Gd(3+) can be stabilized and enhanced, respectively, which then display excellent linear decreases on drug release. PMID- 26648423 TI - Crocin exerts anti-inflammatory and anti-catabolic effects on rat intervertebral discs by suppressing the activation of JNK. AB - As intervertebral disc (IVD) degeneration has been proven to contribute to low back pain (LBP), drug treatment aiming at attenuating IVD degeneration may prove to be benefiical. Crocin, a bioactive component of saffron, has been found to exert anti-inflammatory effects on cartilage. In the present study, the anti inflammatory and anti-catabolic effects of crocin on rat IVDs were analyzed in vitro and ex vivo. Nucleus pulposus (NP) cells were isolated from the lumbar IVDs of Sprague-Dawley rats. The NP cells were first treated with various concentrations of crocin, and then stimulated with lipopolysaccharide (LPS) to induce inflammation. Subsequently, RT-qPCR and enzyme-linked immunosorbent assay were carried out to measure the expression levels of catabolic enzymes, pro inflammatory factors and the components of the extracellular matrix (ECM). In addition, western blot analysis was also used to investigate the related signaling pathways. The whole spinal motion segment (vertebra-IVD-vertebra section) of the rats was isolated and cultured in the presence or absence of LPS and crocin for 7 days. The ex vivo effects of crocin on the ECM of the IVD structures were determined by histological and biochemical analysis. In vitro, crocin significantly inhibited the LPS-induced overexpression of catabolic enzymes [matrix metalloproteinase (MMP)-1, MMP-3, MMP-13, a disintegrin-like and metalloprotease (reprolysin type) with thrombospondin type 1 motif (ADAMTS)-4 and ADAMTS-5], pro-inflammatory factors [interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha, IL-6 and inducible nitric oxide synthase (iNOS)] and Toll like receptor (TLR)-2 in a concentration-dependent manner. Notably, crocin partly prevented the downregulation of aggrecan and type II collagen (collagen-II). Moreover, crocin suppressed the LPS-induced activation of the mitogen-activated protein kinase (MAPK) pathway by inhibiting the phosphorylation of c-Jun N terminal kinase (JNK). Ex vivo experiments demonstrated that crocin protected the rat IVDs from the LPS-induced depletion of the ECM components, including proteoglycan and collagen-II. In conclusion, crocin effectively suppressed the degeneration-related inflammation and catabolism in rat IVDs in vitro and ex vivo, suggesting that crocin has potential for use as a therapuetic strategy in the treatment of LBP. PMID- 26648426 TI - Evaluation of lung volumes, vital capacity and respiratory muscle strength after cervical, thoracic and lumbar spinal surgery. AB - CONTEXT AND OBJECTIVE: Studies have shown that physiopathological changes to the respiratory system can occur following thoracic and abdominal surgery. Laminectomy is considered to be a peripheral surgical procedure, but it is possible that thoracic spinal surgery exerts a greater influence on lung function. The aim of this study was to evaluate the pulmonary volumes and maximum respiratory pressures of patients undergoing cervical, thoracic or lumbar spinal surgery. DESIGN AND SETTING: Prospective study in a tertiary-level university hospital. METHODS: Sixty-three patients undergoing laminectomy due to diagnoses of tumors or herniated discs were evaluated. Vital capacity, tidal volume, minute ventilation and maximum respiratory pressures were evaluated preoperatively and on the first and second postoperative days. Possible associations between the respiratory variables and the duration of the operation, surgical diagnosis and smoking status were investigated. RESULTS: Vital capacity and maximum inspiratory pressure presented reductions on the first postoperative day (20.9% and 91.6%, respectively) for thoracic surgery (P = 0.01), and maximum expiratory pressure showed reductions on the first postoperative day in cervical surgery patients (15.3%; P = 0.004). The incidence of pulmonary complications was 3.6%. CONCLUSIONS: There were reductions in vital capacity and maximum respiratory pressures during the postoperative period in patients undergoing laminectomy. Surgery in the thoracic region was associated with greater reductions in vital capacity and maximum inspiratory pressure, compared with cervical and lumbar surgery. Thus, surgical manipulation of the thoracic region appears to have more influence on pulmonary function and respiratory muscle action. PMID- 26648427 TI - Prevalence of lung structure abnormalities in patients with acromegaly and their relationship with gas exchange: cross-sectional analytical study with a control group. AB - CONTEXT AND OBJECTIVE: Different functional respiratory alterations have been described in acromegaly, but their relationship with pulmonary tissue abnormalities is unknown. The objective of this study was to observe possible changes in lung structure and explain their relationship with gas exchange abnormalities. DESIGN AND SETTING: Cross-sectional analytical study with a control group, conducted at a university hospital. METHODS: The study included 36 patients with acromegaly and 24 controls who were all assessed through high resolution computed tomography of the thorax (CT). Arterial blood gas, effort oximetry and serum growth hormone (GH) and insulin-like growth factor I (IGF-1) were also assessed in the patients with acromegaly. RESULTS: The abnormalities found in the CT scan were not statistically different between the acromegaly and control groups: mild cylindrical bronchiectasis (P = 0.59), linear opacity (P = 0.29), nodular opacity (P = 0.28), increased attenuation (frosted glass; P = 0.48) and decreased attenuation (emphysema; P = 0.32). Radiographic abnormalities were not associated with serum GH and IGF-1. Hypoxemia was present in seven patients; however, in six of them, the hypoxemia could be explained by underlying clinical conditions other than acromegaly: chronic obstructive pulmonary disease in two, obesity in two, bronchial infection in one and asthma in one. CONCLUSION: No changes in lung structure were detected through thorax tomography in comparison with the control subjects. The functional respiratory alterations found were largely explained by alternative diagnoses or had subclinical manifestations, without any plausible relationship with lung structural factors. PMID- 26648428 TI - Longitudinal assessment of the lung mechanics of very low birth weight preterm infants with and without bronchopulmonary dysplasia. AB - CONTEXT AND OBJECTIVE: Prematurity has been correlated with altered lung mechanics. Some infants develop lung injury as a consequence of lung immaturity, invasive mechanical ventilation and exposure to oxygen, thus resulting in bronchopulmonary dysplasia. The aim here was to compare the lung mechanics of preterm infants with and without bronchopulmonary dysplasia during the first year of life. DESIGN AND SETTING: Prospective cohort study in a tertiary-level hospital. METHODS: This study included premature infants at a public hospital who underwent two pulmonary function tests: one at discharge and the other at the corrected age of 4 to 8 months. Tidal volume, lung compliance and lung resistance were measured. Statistical tests were used for comparisons between infants with and without bronchopulmonary dysplasia. RESULTS: 102 children with mean gestational age of 29 +/- 2.0 weeks were studied; 17 with bronchopulmonary dysplasia. Lung compliance (0.84 +/- 0.29 versus 1.28 +/- 0.46; P < 0.001) and tidal volume (6.1 +/- 0.94 versus 7.2 +/- 1.43; P < 0.01) at discharge were significant lower in children with bronchopulmonary dysplasia than in those without the disease, but no differences were observed at the second test (compliance: 1.53 +/- 0.77 versus 1.94 +/- 1.01; P = 0.12; and tidal volume: 6.9 +/- 1.4 versus 7.3 +/- 1.6; P = 0.42). CONCLUSION: Differences in lung mechanics were observed between infants with and without bronchopulmonary dysplasia at hospital discharge but these differences were no longer detected at the final follow-up. The lung mechanics of all the infants improved over this period of time. PMID- 26648429 TI - Air pollutants and hospitalization due to pneumonia among children. An ecological time series study. AB - CONTEXT AND OBJECTIVE: Exposure to air pollutants is one of the factors responsible for hospitalizations due to pneumonia among children. This has considerable financial cost, along with social cost. A study to identify the role of this exposure in relation to hospital admissions due to pneumonia among children up to 10 years of age was conducted. DESIGN AND SETTING: Ecological time series study using data from Sao Jose dos Campos, Brazil. METHODS: Daily data on hospitalizations due to pneumonia and on the pollutants CO, O3, PM10 and SO2, temperature and humidity in Sao Jose dos Campos, in 2012, were analyzed. A generalized additive model of Poisson's regression was used. Relative risks for hospitalizations due to pneumonia, according to lags of 0-5 days, were estimated. The population-attributable fraction, number of avoidable hospitalizations and cost savings from avoidable hospitalizations were calculated. RESULTS: There were 539 admissions. Exposure to CO and O3 was seen to be associated with hospitalizations, with risks of 1.10 and 1.15 on the third day after exposure to increased CO concentration of 200 ppb and ozone concentration of 20 ug/m3. Exposure to the pollutants of particulate matter and sulfur dioxide were not shown to be associated with hospitalizations. Decreases in CO and ozone concentrations could lead to 49 fewer hospitalizations and cost reductions of R$ 39,000.00. CONCLUSION: Exposure to certain air pollutants produces harmful effects on children's health, even in a medium-sized city. Public policies to reduce emissions of these pollutants need to be implemented. PMID- 26648430 TI - Comparison of a short version of the Food Frequency Questionnaire with its long version--a cross-sectional analysis in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). AB - CONTEXT AND OBJECTIVE: The food frequency questionnaire (FFQ) is the preferred instrument for obtaining dietary information in epidemiological studies. A short form of the FFQ was compared with the original version that was used in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil), and also with three 24-hour dietary recalls. DESIGN AND SETTING: Cross-sectional study carried out in six Brazilian state capitals. METHODS: Multiple linear regression was used to reduce the original food and drink list of the FFQ, which had contained 114 food items. The frequency of consumption and nutritional composition of the foods were also taken into consideration. To assess the validity of the shortened FFQ, the energy and nutrients values of the 24-hour dietary recalls were deattenuated and log-transformed. RESULTS: The list of the FFQ of ELSA-Brasil was reduced to 76 food items. The intraclass correlation coefficients in the validation study ranged from 0.17 (selenium) to 0.66 (calcium). CONCLUSIONS: The number of items was reduced by 33%, while still maintaining relatively good capacity to measure energy and selected nutrients. PMID- 26648431 TI - The relationship between genotype, psychiatric symptoms and quality of life in adult patients with sickle cell disease in Sao Paulo, Brazil: a cross-sectional study. AB - CONTEXT AND OBJECTIVE: Health-related quality of life (HRQoL) may be worsened in sickle cell patients due to the presence of psychiatric disorders. The aims of this study were to describe the psychiatric symptoms in Brazilian sickle cell patients and to evaluate the relationship of these symptoms to the genotype of the disease and the subject's HRQoL. DESIGN AND SETTING: Cross-sectional study conducted at the hematology outpatient clinic, Hospital Sao Paulo. METHODS: Adult patients with sickle cell disease completed the Medical Outcome Study - Short Form 36 and the Patients' Health Questionnaire. Clinical data were gathered from their medical files. Linear regression models were developed to study the dependency of HRQoL domains on the genotype controlling for psychiatric symptoms. RESULTS: In the study period, 110 patients were evaluated. The most frequent psychiatric symptom was depression (30%), followed by anxiety (12.7%) and alcohol abuse (9.1%). Patients with the more severe genotype (SS and Sbetathal0) showed lower scores for the "general health" and "role-physical" HRQoL domains, without interference from psychiatric symptoms. In the "role-physical" domain, the more severe genotype operated as a protective factor for HRQoL (beta = 0.255; P = 0.007). CONCLUSION: The more severe genotypes worsened HRQoL in two domains of physical health (general health and role-physical), but they did not have any influence on mental health, thus suggesting that physicians should be more attentive to aspects of HRQoL relating to the functionality of sickle cell disease patients, so as to be aware of the limitations that these patient live with. PMID- 26648432 TI - Impact of predictors upon the reduction of lipid parameters in family medicine practice. AB - CONTEXT AND OBJECTIVE: To evaluate predictors of changes in lipid parameters consisting of LDL-C (low-density lipoprotein cholesterol), TC (total cholesterol) and non-HDL-C (non-high density lipoprotein cholesterol) among primary care patients. DESIGN AND SETTING: Retrospective study conducted on family medicine patients. METHODS: Demographic features and other clinically relevant information were abstracted from medical records. The primary outcome was the difference in LDL-C level from initial testing to the index test. Secondary outcomes were the changes in TC and non-HDL-C levels between two measurements. RESULTS: Three hundred and eleven participants were included in the final secondary analysis. Multiple linear regression revealed that male patients (beta = 4.97, P = 0.040), diabetes (beta = 9.75, P = 0.003) and higher LDL-C levels at baseline (beta = 0.35, P < 0.001) were positively associated with LDL variance, whereas longer time period (beta = -0.15, P = 0.045) and familial hypercholesterolemia history (beta = -7.56, P = 0.033) were negatively associated. Male patients (beta = 8.45, P = 0.002), DM (beta = 9.26, P = 0.011), higher TC levels at baseline (beta = 0.35, P < 0.001) and taking statins (beta = 7.31, P = 0.023) were positively associated with TC variance, whilst longer time period (beta = -0.183, P = 0.031) and familial hypercholesterolemia (beta = -10.70, P = 0.008) were negatively associated. CONCLUSION: In the present study, patients who were male, on statin treatment, diagnosed with diabetes and had higher baseline lipid values were more likely associated with better lipid outcomes at future testing. PMID- 26648433 TI - Common psychiatric symptoms among public school teachers in Palmas, Tocantins, Brazil. An observational cross-sectional study. AB - CONTEXT AND OBJECTIVE: Teachers are at great risk of physical and mental stress due to material or psychological difficulties associated with their work. This study aimed to assess the prevalence of common psychiatric symptoms measured on the Self-Reporting Questionnaire (SRQ-20) scale that would suggest a diagnosis of psychiatric disorders among public school teachers in Palmas, Tocantins, Brazil, in 2012. DESIGN AND SETTING: Observational cross-sectional study in Palmas, Tocantins, Brazil. METHOD: We assessed 110 municipal teachers in the city of Palmas, Tocantins, Brazil. They were selected randomly from a list of employees of the Municipal Education Department of Palmas. All of them answered the SRQ-20 questionnaire after giving their consent. RESULTS: Between the years 2008 and 2011, 24 cases of absence from work due to mental disorders were found. We excluded one case and 109 teachers answered the SRQ-20questionnaire. Out of the 109 teachers assessed, 54 had >= 7 points on the SRQ-20 scale. This finding suggests that 49.5% of the teachers had symptoms that were sufficient to consider a diagnosis of mental disorder, with the need for treatment. CONCLUSION: Our study found that the prevalence of mental disorders among teachers is as high as seen in the literature. Our results suggest that recognition of mental disorders is low and that the current statistics fail to reach the occupational health sector. PMID- 26648434 TI - Hemoglobinopathies in newborns in the southern region of the Triangulo Mineiro, Brazil. Cross-sectional study. AB - CONTEXT AND OBJECTIVE: Hemoglobinopathies are among the commonest and most widespread genetic disorders worldwide. Their prevalence varies according to ethnic composition and/or geographical region. The aim of this study was to investigate the presence of hemoglobinopathies and their association with ethnicity among 1,004 newborns, to confirm the guideline of the Brazilian National Neonatal Screening Program. DESIGN AND SETTING: Cross-sectional study conducted in a public referral hospital in the Triangulo Mineiro region, Minas Gerais, Brazil. METHODS: Qualitative assessment of hemoglobin was performed through electrophoresis on cellulose acetate: at alkaline pH to identify the hemoglobin (Hb) profile and at acid pH to differentiate Hb S from Hb D and Hb C from Hb E and others that migrate to similar positions at alkaline pH. Neutral pH was used to detect Hb Bart's identified in alpha thalassemia (alpha-thal). The elution method after electrophoresis was used to quantitatively assess hemoglobins. RESULTS: There was predominance of alpha-thal, with 105 cases (10.46%), followed by Hb S with 61 cases (6.08%, comprising 46 Hb AS, 2 Hb SS and 13 Hb S/alpha-thal), 9 cases (0.9%) of Hb AC and 6 cases (0.6%) suggestive of beta thalassemia (beta-thal). The frequency of hemoglobinopathies was significantly higher among Afro-descendants. CONCLUSIONS: These findings corroborated of the National Neonatal Screening Program for diagnosing sickle cell disease and Hb C, Hb D, Hb E and beta-thal hemoglobinopathies. PMID- 26648435 TI - A case of tumor-like inflammatory demyelinating disease with progressive brain and spinal cord involvement. AB - CONTEXT: Tumor-like inflammatory demyelinating disease (TIDD) usually occurs in the brain and rarely occurs in the spinal cord. TIDD appears to be very similar to tumors such as gliomas on imaging, which may lead to incorrect or delayed diagnosis and treatment. CASE REPORT: Because of headache and incoherent speech, a 24-year-old Chinese male presented to our hospital with a two-week history of respiratory infections. After dexamethasone treatment, his symptoms still got worse and surgery was performed for diagnostic purposes. Histological examination revealed that the lesion was inflammatory. Further lesions appeared in the spine (T3 and T4 levels) after two months and in the right occipital lobe after three months. After intravenous immunoglobulin (IVIG) and methylprednisolone treatment, his symptoms improved. CONCLUSION: Progressive lesions may damage the brain and spinal cord, and long-term prednisolone and IVIG therapy are beneficial in TIDD patients. PMID- 26648436 TI - Staphylococcal scalded skin syndrome in a premature newborn caused by methicillin resistant Staphylococcus aureus: case report. AB - CONTEXT: Staphylococcal scalded skin syndrome is an exfoliative skin disease. Reports of this syndrome in newborns caused by methicillin-resistant Staphylococcus aureus are rare but, when present, rapid diagnosis and treatment is required in order to decrease morbidity and mortality. CASE REPORT: A premature newly born girl weighing 1,520 g, born with a gestational age of 29 weeks and 4 days, developed staphylococcal scalded skin syndrome on the fifth day of life. Cultures on blood samples collected on the first and fourth days were negative, but Pseudomonas aeruginosa and Enterococcus sp. (vancomycin-sensitive) developed in blood cultures performed on the day of death (seventh day), and Pseudomonas aeruginosa and Serratia marcescens were identified in cultures on nasopharyngeal, buttock and abdominal secretions. In addition to these two Gram negative bacilli, methicillin-resistant Staphylococcus aureus was isolated in a culture on the umbilical stump (seventh day). The diagnosis of staphylococcal scalded skin syndrome was based on clinical criteria. PMID- 26648437 TI - Selective serotonin reuptake inhibitors for fibromyalgia syndrome. AB - BACKGROUND: Fibromyalgia is a clinically well-defined chronic condition with a biopsychosocial aetiology. Fibromyalgia is characterized by chronic widespread musculoskeletal pain, sleep problems, cognitive dysfunction, and fatigue. Patients often report high disability levels and poor quality of life. Since there is no specific treatment that alters the pathogenesis of fibromyalgia, drug therapy focuses on pain reduction and improvement of other aversive symptoms. OBJECTIVES: To assess the benefits and harms of selective serotonin reuptake inhibitors (SSRIs) in the treatment of fibromyalgia. METHODS: SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2014, Issue 5), MEDLINE (1966 to June 2014), EMBASE (1946 to June 2014), and the reference lists of reviewed articles. SELECTION CRITERIA: We selected all randomized, double-blind trials of SSRIs used for the treatment of fibromyalgia symptoms in adult participants. We considered the following SSRIs in this review: citalopram, fluoxetine, escitalopram, fluvoxamine, paroxetine, and sertraline. DATA COLLECTION AND ANALYSIS: Three authors extracted the data of all included studies and assessed the risks of bias of the studies. We resolved discrepancies by discussion. MAIN RESULTS: The quality of evidence was very low for each outcome. We downgraded the quality of evidence to very low due to concerns about risk of bias and studies with few participants. We included seven placebo-controlled studies, two with citalopram, three with fluoxetine and two with paroxetine, with a median study duration of eight weeks (4 to 16 weeks) and 383 participants, who were pooled together. All studies had one or more sources of potential major bias. There was a small (10%) difference in patients who reported a 30% pain reduction between SSRIs (56/172 (32.6%)) and placebo (39/171 (22.8%)) risk difference (RD) 0.10, 95% confidence interval (CI) 0.01 to 0.20; number needed to treat for an additional beneficial outcome (NNTB) 10, 95% CI 5 to 100; and in global improvement (proportion of patients who reported to be much or very much improved: 50/168 (29.8%) of patients with SSRIs and 26/162 (16.0%) of patients with placebo) RD 0.14, 95% CI 0.06 to 0.23; NNTB 7, 95% CI 4 to 17. SSRIs did not statistically, or clinically, significantly reduce fatigue: standard mean difference (SMD) -0.26, 95% CI -0.55 to 0.03; 7.0% absolute improvement on a 0 to 10 scale, 95% CI 14.6% relative improvement to 0.8% relative deterioration; nor sleep problems: SMD 0.03, 95 % CI -0.26 to 0.31; 0.8 % absolute deterioration on a 0 to 100 scale, 95% CI 8.3% relative deterioration to 6.9% relative improvement. SSRIs were superior to placebo in the reduction of depression: SMD 0.39, 95% CI -0.65 to -0.14; 7.6% absolute improvement on a 0 to 10 scale, 95% CI 2.7% to 13.8% relative improvement; NNTB 13, 95% CI 7 to 37. The dropout rate due to adverse events was not higher with SSRI use than with placebo use (23/146 (15.8%) of patients with SSRIs and 14/138 (10.1%) of patients with placebo) RD 0.04, 95% CI -0.06 to 0.14. There was no statistically or clinically significant difference in serious adverse events with SSRI use and placebo use (3/84 (3.6%) in patients with SSRIs and 4/84 (4.8%) and patients with placebo) RD -0.01, 95% CI -0.07 to 0.05. AUTHORS' CONCLUSIONS: There is no unbiased evidence that SSRIs are superior to placebo in treating the key symptoms of fibromyalgia, namely pain, fatigue and sleep problems. SSRIs might be considered for treating depression in people with fibromyalgia. The black box warning for increased suicidal tendency in young adults aged 18 to 24, with major depressive disorder, who have taken SSRIs, should be considered when appropriate. PMID- 26648438 TI - Alginate dressings for treating pressure ulcers. AB - BACKGROUND: Pressure ulcers, also known as bedsores, decubitus ulcers and pressure injuries, are localised areas of injury to the skin or the underlying tissue, or both. Dressings are widely used to treat pressure ulcers and there are many options to choose from including alginate dressings. A clear and current overview of current evidence is required to facilitate decision-making regarding dressing use for the treatment of pressure ulcers. This review is part of a suite of Cochrane reviews investigating the use of dressings in the treatment of pressure ulcers. Each review will focus on a particular dressing type. OBJECTIVES: To assess the effects of alginate dressings for treating pressure ulcers in any care setting. METHODS: SEARCH METHODS: For this review, in April 2015 we searched the following databases the Cochrane Wounds Group Specialised Register; The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library); Ovid MEDLINE; Ovid MEDLINE (In-Process & Other Non-Indexed Citations); Ovid EMBASE; and EBSCO CINAHL. There were no restrictions based on language or date of publication. SELECTION CRITERIA: Published or unpublished randomised controlled trials (RCTs) comparing the effects of alginate with alternative wound dressings or no dressing in the treatment of pressure ulcers (stage II or above). DATA COLLECTION AND ANALYSIS: Two review authors independently performed study selection, risk of bias assessment and data extraction. MAIN RESULTS: We included six studies (336 participants) in this review; all studies had two arms. The included studies compared alginate dressings with six other interventions that included: hydrocolloid dressings, silver containing alginate dressings, and radiant heat therapy. Each of the six comparisons included just one study and these had limited participant numbers and short follow-up times. All the evidence was of low or very low quality. Where data were available there was no evidence of a difference between alginate dressings and alternative treatments in terms of complete wound healing or adverse events. AUTHORS' CONCLUSIONS: The relative effects of alginate dressings compared with alternative treatments are unclear. The existing trials are small, of short duration and at risk of bias. Decision makers may wish to consider aspects such as cost of dressings and the wound management properties offered by each dressing type, for example, exudate management. PMID- 26648439 TI - Correction: A structure-activity relationship study of the toxicity of ionic liquids using an adapted Ferreira-Kiralj hydrophobicity parameter. AB - Correction for 'A structure-activity relationship study of the toxicity of ionic liquids using an adapted Ferreira-Kiralj hydrophobicity parameter' by Eduardo Borges de Melo et al., Phys. Chem. Chem. Phys., 2015, 17, 4516-4523. PMID- 26648440 TI - Hypoxia-mediated activation of autophagic flux inhibits apoptosis of keratinocytes via blocking tumor necrosis factor-related apoptosis-inducing ligand. AB - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is toxic against transformed tumor cells. Cornification is the terminal differentiation of keratinocytes and a specific form of programmed cell death caused by TRAIL that occurs in keratinocytes. Apoptosis can also be triggered when TRAIL induces expression of keratinocyte differentiation markers. The present study reported that hypoxia inhibits TRAIL-induced apoptosis due to autophagic flux. It is well known that hypoxia activates autophagy in keratinocytes and reduces p62 protein levels. The present study demonstrated that hypoxia inhibited TRAIL-mediated apoptosis and induced autophagic flux in HaCaT cells. In addition, autophagic flux-inactivating reagents, including 3-methyladenine and chloroquine, increased the TRAIL sensitivity of HaCaT cells exposed to hypoxia. In conclusion, these results indicated that inactivating autophagy increased TRAIL sensitivity in hypoxic HaCaT cells. Autophagy inhibitors may be beneficial in therapies using TRAIL against skin cancers. PMID- 26648441 TI - Effects of miR-590 on oxLDL-induced endothelial cell apoptosis: Roles of p53 and NF-kappaB. AB - Oxidized low-density lipoprotein (oxLDL)-induced endothelial cell apoptosis is considered to be important in atherogenesis. MicroRNA (miR)-590 has been reported to inhibit oxLDL-induced endothelial cell apoptosis. However, the mechanism underlying the inhibition of oxLDL-induced endothelial cell apoptosis by miR-590 remains to be elucidated. In the present study, the expression levels of miR-590 were quantified using reverse transcription-quantitative polymerase chain reaction analysis. Cell apoptosis was investigated using Hoechst staining and flow cytometry, and cell viability was measured using an MTS method. The protein expression levels of p53, B cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), caspase-3, lectin-like low-density lipoprotein receptor 1 (LOX-1), p38 mitogen-activated protein kinase (MAPK) and nuclear factor (NF)-kappaB were quantified using western blot analyses. The results of the present study showed that oxLDL treatment inhibited the expression levels of miR-590 in a time dependent and concentration-dependent manner. The overexpression of miR-590 inhibited oxLDL-induced endothelial cell apoptosis, expression of p53 and Bax, reduction of Bcl-2 and activation of caspase-3. miR-590 also inhibited the oxLDL induced upregulation of the expression of LOX-1, overproduction of reactive oxygen species (ROS), phosphoryation of p38MAPK and translocation of NF-kappaB. These findings demonstrated the anti-apoptotic effects of miR-590 in oxLDL treated endothelial cells, with the mechanisms underlying the effects of miR-590 involved, in part, in the LOX-1-ROS-p38MAPK-NF-kappaB signaling cascade and the p53-Bcl-2/Bax-caspase-3 signaling pathway. The present study may provide novel insights into the protective properties of miR-590 in preventing atherosclerosis. PMID- 26648442 TI - Intramuscular injection of bone marrow mononuclear cells contributes to bone repair following midpalatal expansion in rats. AB - Healing from injury requires the activation and proliferation of stem cells for tissue repair. Previous studies have demonstrated that bone marrow is a central pool of stem cells. The present study aimed to investigate the route undertaken by bone marrow mononuclear cells (BMMCs) following BMMC transplantation by masseter injection in a rat model of midpalatal expansion. The rats were divided into five groups according to the types of midpalatal expansion, incision and BMMC transplantation. Samples of midpalatal bone from the rats in each group were used for histological and immunohistochemical assessments to track and evaluate the differential potentials of the transplanted BMMCs in the masseter muscle and midpalatal bone. Bromodeoxyuridine was used as a BMMC tracing label, and M cadherin was used to detect muscle satellite cells. The BMMCs injected into the masseter were observed, not only in the masseter, but also in the blood vessels and oral mucosa, and enveloped the midpalatal bone. A number of the BMMCs transformed into osteoblasts at the boundary of the neuromuscular bundle, and were embedded in the newly formed bone during midpalatal bone regeneration. The results of the present study suggested that BMMCs entered the circulation and migrated from muscle to the bone tissue, where they were involved in bone repair. Therefore, BMMCs may prove useful in the treatment of various types of cancer. PMID- 26648443 TI - Exhaled particles as markers of small airway inflammation in subjects with asthma. AB - Exhaled breath contains suspended particles of respiratory tract lining fluid from the small airways. The particles are formed when closed airways open during inhalation. We have developed a method called Particles in Exhaled air (PExA(r) ) to measure and sample these particles in the exhaled aerosol. Here, we use the PExA(r) method to study the effects of birch pollen exposure on the small airways of individuals with asthma and birch pollen allergy. We hypothesized that birch pollen-induced inflammation could change the concentrations of surfactant protein A and albumin in the respiratory tract lining fluid of the small airways and influence the amount of exhaled particles. The amount of exhaled particles was reduced after birch pollen exposure in subjects with asthma and birch pollen allergy, but no significant effect on the concentrations of surfactant protein A and albumin in exhaled particles was found. The reduction in the number of exhaled particles may be due to inflammation in the small airways, which would reduce their diameter and potentially reduce the number of small airways that open and close during inhalation and exhalation. PMID- 26648445 TI - Distinct X-chromosome SNVs from some sporadic AD samples. AB - Sporadic Alzheimer disease (SAD) is the most prevalent neurodegenerative disorder. With the development of new generation DNA sequencing technologies, additional genetic risk factors have been described. Here we used various methods to process DNA sequencing data in order to gain further insight into this important disease. We have sequenced the exomes of brain samples from SAD patients and non-demented controls. Using either method, we found a higher number of single nucleotide variants (SNVs), from SAD patients, in genes present at the X chromosome. Using the most stringent method, we validated these variants by Sanger sequencing. Two of these gene variants, were found in loci related to the ubiquitin pathway (UBE2NL and ATXN3L), previously do not described as genetic risk factors for SAD. PMID- 26648446 TI - Tomato fruit carotenoid biosynthesis is adjusted to actual ripening progression by a light-dependent mechanism. AB - Carotenoids are isoprenoid compounds that are essential for plants to protect the photosynthetic apparatus against excess light. They also function as health promoting natural pigments that provide colors to ripe fruit, promoting seed dispersal by animals. Work in Arabidopsis thaliana unveiled that transcription factors of the phytochrome-interacting factor (PIF) family regulate carotenoid gene expression in response to environmental signals (i.e. light and temperature), including those created when sunlight reflects from or passes though nearby vegetation or canopy (referred to as shade). Here we show that PIFs use a virtually identical mechanism to modulate carotenoid biosynthesis during fruit ripening in tomato (Solanum lycopersicum). However, instead of integrating environmental information, PIF-mediated signaling pathways appear to fulfill a completely new function in the fruit. As tomatoes ripen, they turn from green to red due to chlorophyll breakdown and carotenoid accumulation. When sunlight passes through the flesh of green fruit, a self-shading effect within the tissue maintains high levels of PIFs that directly repress the master gene of the fruit carotenoid pathway, preventing undue production of carotenoids. This effect is attenuated as chlorophyll degrades, causing degradation of PIF proteins and boosting carotenoid biosynthesis as ripening progresses. Thus, shade signaling components may have been co-opted in tomato fruit to provide information on the actual stage of ripening (based on the pigment profile of the fruit at each moment) and thus finely coordinate fruit color change. We show how this mechanism may be manipulated to obtain carotenoid-enriched fruits. PMID- 26648447 TI - 4-Phenylbutyrate protects rat skin flaps against ischemia-reperfusion injury and apoptosis by inhibiting endoplasmic reticulum stress. AB - 4-phenylbutyrate (4-PBA) is a low molecular weight fatty acid, which has been demonstrated to regulate endoplasmic reticulum (ER) stress. ER stress-induced cell apoptosis has an important role in skin flap ischemia; however, a pharmacological approach for treating ischemia-induced ER dysfunction has yet to be reported. In the present study, the effects of 4-PBA-induced ER stress inhibition on ischemia-reperfusion injury were investigated in the skin flap of rats, and transcriptional regulation was examined. 4-PBA attenuated ischemia reperfusion injury and inhibited cell apoptosis in the skin flap. Furthermore, 4 PBA reversed the increased expression levels of two ER stress markers: CCAAT/enhancer-binding protein-homologous protein and glucose-regulated protein 78. These results suggested that 4-PBA was able to protect rat skin flaps against ischemia-reperfusion injury and apoptosis by inhibiting ER stress marker expression and ER stress-mediated apoptosis. The beneficial effects of 4-PBA may prove useful in the treatment of skin flap ischemia-reperfusion injury. PMID- 26648448 TI - N-methyl-N-nitro-N'-nitrosoguanidine induces the expression of CCR2 in human gastric epithelial cells promoting CCL2-mediated migration. AB - Chronic inflammation has a decisive role in tumorigenesis, particularly in gastric carcinogenesis. The CC chemokine ligand 2 (CCL2), an important inflammatory cytokine, is involved in the initiation, development and progression of various types of cancer. However, the role of CCL2 in gastric cancer remains to be elucidated. The present study demonstrated that recombinant CCL2 stimulation caused no effect on the morphology, proliferation and migration of human GES-1 gastric mucosa epithelial cells, in which the protein expression of CC-chemokine receptor 2 (CCR2) was markedly low. However, the expression of CCR2 was significantly upregulated in the GES-1 cells following pretreatment with the chemical carcinogen, N-methyl-N-nitro-N'-nitrosoguanidine (MNNG), for 12 h or transformed with MNNG (MC cells). The present study used CCL2 to stimulate MNNG pretreated GES-1 cells and MC cells, and demonstrated that CCL2 clearly promoted their migration and the epithelial-mesenchymal transition (EMT). However, no effect was observed on the proliferative ability of the cells. Taken together, these findings suggested that the CCL2/CCR2 chemokine signaling may regulate the EMT in gastric epithelial cells and resulted in gastric carcinogenesis in response to the intake of the carcinogen, MNNG. PMID- 26648449 TI - Combined mismatch repair and POLE/POLD1 defects explain unresolved suspected Lynch syndrome cancers. AB - Many suspected Lynch Syndrome (sLS) patients who lack mismatch repair (MMR) germline gene variants and MLH1 or MSH2 hypermethylation are currently explained by somatic MMR gene variants or, occasionally, by germline POLE variants. To further investigate unexplained sLS patients, we analyzed leukocyte and tumor DNA of 62 sLS patients using gene panel sequencing including the POLE, POLD1 and MMR genes. Forty tumors showed either one, two or more somatic MMR variants predicted to affect function. Nine sLS tumors showed a likely ultramutated phenotype and were found to carry germline (n=2) or somatic variants (n=7) in the POLE/POLD1 exonuclease domain (EDM). Six of these POLE/POLD1-EDM mutated tumors also carried somatic MMR variants. Our findings suggest that faulty proofreading may result in loss of MMR and thereby in microsatellite instability. PMID- 26648451 TI - Exenatide inhibits the growth of endometrial cancer Ishikawa xenografts in nude mice. AB - Studies have showed that diabetes is one of the high risk factors of endometrial cancer; however, no reports describe the anti- or pro-cancer effect of a new kind of anti-diabetes drug, glucagon-like peptide-1 receptor agonist exenatide (exendin-4), on endometrial cancer. To investigate whether exenatide promotes or inhibits the growth of endometrial cancer, we used the subcutaneous human endometrial cancer cell Ishikawa xenografts in nude mouse model, and divided them into control group and exenatide-treated group. The tumor growth rate in exenatide group was slower than that in control group, and the apoptosis rate of exenatide group was higher than that in control group. In vitro, exendin-4 also attenuated Ishikawa cell viability and clone formation rate, but promoted cell apoptosis. There was an increase of phosphorylated-AMPK protein, a decrease of phosphorylated-mTOR protein both in vivo and in vitro after exenatide or exendin 4 treatment. Moreover, when treated with exendin-4 plus AICAR, an AMPK activator, cell apoptosis increased with higher ratio of phosphorylayed-AMPK/AMPK, lower ratio of phosphorylated-mTOR/mTOR and higher expression of cleaved caspase-3 than those in exendin-4 alone group, and the results were the opposite when treated with exendin-4 plus compound C, an AMPK inhibitor. Our results suggest that exenatide could attenuate the growth of endometrial cancer Ishikawa xenografts in nude mice, and AMPK may be the target of the mechanism. PMID- 26648450 TI - Topical treatment with coenzyme Q10-containing formulas improves skin's Q10 level and provides antioxidative effects. AB - Ubiquinone (coenzyme Q10, Q10) represents an endogenously synthesized lipid soluble antioxidant which is crucial for cellular energy production but is diminished with age and under the influence of external stress factors in human skin. Here, it is shown that topical Q10 treatment is beneficial with regard to effective Q10 replenishment, augmentation of cellular energy metabolism, and antioxidant effects. Application of Q10-containing formulas significantly increased the levels of this quinone on the skin surface. In the deeper layers of the epidermis the ubiquinone level was significantly augmented indicating effective supplementation. Concurrent elevation of ubiquinol levels suggested metabolic transformation of ubiquinone resulting from increased energy metabolism. Incubation of cultured human keratinocytes with Q10 concentrations equivalent to treated skin showed a significant augmentation of energy metabolism. Moreover, the results demonstrated that stressed skin benefits from the topical Q10 treatment by reduction of free radicals and an increase in antioxidant capacity. PMID- 26648453 TI - The efficacy and complications of black diaphragm intra-ocular lens implantation in patients with congenital aniridia. AB - PURPOSE: To evaluate the efficacy and complications of black diaphragm intra ocular (BDI) lens implantation in patients with congenital aniridia. METHODS: Twenty patients underwent BDI lens implantation for the treatment of congenital aniridia from January 1999 to December 2012. Fifteen patients (23 eyes) were enrolled in our study, and the mean follow-up period was 26 months. Patient demographics, clinical evaluations [visual acuity (VA), best-corrected visual acuity (BCVA), intra-ocular pressure measurement (IOP), corneal endothelial cell density (ECD) and ultrasound biomicroscopy (UBM)], complications and treatments were analysed for each patient. RESULTS: Sixteen eyes (70.1%) had a BCVA better than 20/200 after BDI lens implantation, and photophobia obviously decreased in all patients. Six eyes (26.09%) developed secondary glaucoma after BDI lens implantation, and one eye underwent glaucoma surgery. Corneal decompensation occurred in two eyes (8.70%), one of which was complicated by glaucoma. Two eyes (8.70%) developed visual axis opacity (VAO) after surgery. One patient (4.35%) had limbal stem cell failure, and another patient (4.35%) had an eccentric BDI lens. Intra-ocular pressure measurement elevation and ECD reduction were found after BDI lens implantation. CONCLUSIONS: Black diaphragm intra-ocular lens implantation can effectively improve VA, decrease photophobia and resolve cosmetic issues in most congenital aniridia eyes. Glaucoma, corneal decompensation and VAO were the major long-term complications of BDI lens implantation in patients with congenital aniridia. All patients should be managed attentively because of high risk of complications and followed long term to achieve favourable outcomes. PMID- 26648452 TI - miR-212 downregulation contributes to the protective effect of exercise against non-alcoholic fatty liver via targeting FGF-21. AB - Non-alcoholic fatty liver disease (NAFLD) is associated with obesity and lifestyle, while exercise is beneficial for NAFLD. Dysregulated microRNAs (miRs) control the pathogenesis of NAFLD. However, whether exercise could prevent NAFLD via targeting microRNA is unknown. In this study, normal or high-fat diet (HF) mice were either subjected to a 16-week running program or kept sedentary. Exercise attenuated liver steatosis in HF mice. MicroRNA array and qRT-PCR demonstrated that miR-212 was overexpressed in HF liver, while reduced by exercise. Next, we investigated the role of miR-212 in lipogenesis using HepG2 cells with/without long-chain fatty acid treatment (+/- FFA). FFA increased miR 212 in HepG2 cells. Moreover, miR-212 promoted lipogenesis in HepG2 cells (+/- FFA). Fibroblast growth factor (FGF)-21, a key regulator for lipid metabolism, was negatively regulated by miR-212 at protein level in HepG2 cells. Meanwhile, FFA downregulated FGF-21 both at mRNA and protein levels in HepG2 cells. Also, FGF-21 protein level was reduced in HF liver, while reversed by exercise in vivo. Furthermore, siRNA-FGF-21 abolished the lipogenesis-reducing effect of miR-212 inhibitor in HepG2 cells (+/- FFA), validating FGF-21 as a target gene of miR 212. These data link the benefit of exercise and miR-212 downregulation in preventing NAFLD via targeting FGF-21. PMID- 26648455 TI - Gene analysis of multiple oral bacteria by the polymerase chain reaction coupled with capillary polymer electrophoresis. AB - Capillary polymer electrophoresis is identified as a promising technology for the analysis of DNA from bacteria, virus and cell samples. In this paper, we propose an innovative capillary polymer electrophoresis protocol for the quantification of polymerase chain reaction products. The internal standard method was modified and applied to capillary polymer electrophoresis. The precision of our modified internal standard protocol was evaluated by measuring the relative standard deviation of intermediate capillary polymer electrophoresis experiments. Results showed that the relative standard deviation was reduced from 12.4-15.1 to 0.6 2.3%. Linear regression tests were also implemented to validate our protocol. The modified internal standard method showed good linearity and robust properties. Finally, the ease of our method was illustrated by analyzing a real clinical oral sample using a one-run capillary polymer electrophoresis experiment. PMID- 26648454 TI - Effect of P2X4R on airway inflammation and airway remodeling in allergic airway challenge in mice. AB - P2X4 receptor (P2X4R) is the most widely expressed subtype of the P2XRs in the purinergic receptor family. Adenosine triphosphate (ATP), a ligand for this receptor, has been implicated in the pathogenesis of asthma. ATP-P2X4R signaling is involved in pulmonary vascular remodeling, and in the proliferation and differentiation of airway and alveolar epithelial cell lines. However, the role of P2X4R in asthma remains to be elucidated. This aim of the present study was to investigate the effects of P2X4R in a murine experimental asthma model. The asthmatic model was established by the inhalation of ovalbumin (OVA) in BALB/c mice. The mice were treated with P2X4R-specific agonists and antagonists to investigate the role of this receptor in vivo. Pathological changes in the bronchi and lung tissues were examined using hematoxylin and eosin staining, Masson's trichrome staining and Alcian blue staining. The inflammatory cells in the bronchoalveolar lavage fluid were counted, and the expression levels of P2X4R, alpha-smooth muscle actin (alpha-SMA) and proliferating cell nuclear antigen (PCNA) were detected using western blotting. In the OVA-challenged mice, inflammation, infiltration, collagen deposition, mucus production, and the expression levels of P2X4R and PCNA were all increased; however, the expression of alpha-SMA was decreased, compared with the mice in the control group. Whereas treatment with the P2X4R agonist, ATP, enhanced the allergic reaction, treatment with the P2X4R antagonist, 5-BDBD, attenuated the allergic reaction. The results suggested that ATP-P2X4R signaling may not only contribute to airway inflammation, but it may also contribute to airway remodeling in allergic asthma in mice. PMID- 26648456 TI - Interindividual anatomical variations affect the plate-to-bone fit during osteosynthesis of distal radius fractures. AB - We hypothesized that interindividual variations in the teardrop, which represents the volar projection of the lunate facet of the distal radius, cause unsatisfactory fitting of the volar locking plate to the bone. This can cause flexor tendon ruptures. Herein, we conducted a cross-sectional study and measured the ratio of teardrop height and the teardrop inclination angle as parameters of teardrop configuration for 200 standardized lateral radiographs (average age of the patients, 51 years). We also quantified the influence of the teardrop morphology by analyzing the fit of three locking plates to three radii with differing teardrop inclination angles using a three-dimensional computer-aided design system. The average ratios of the teardrop height and teardrop inclination angle were 0.42 degrees (0.30-0.56 degrees ) and 28.8 degrees (9.9-44.9 degrees ), respectively. The teardrop inclination angle was moderately correlated with age in men but not in women. In the plate-to-bone fit analyses, the fit of all the plates was significantly different between bones, with the configuration of the radius with the lowest teardrop inclination angle being the closest approximation to that of each plate. We demonstrated the interindividual variation in the shape of the teardrop and its influence on the fit of the volar plate, highlighting the importance of careful plate selection for achieving osteosynthesis of bones with a high teardrop inclination angle. (c) 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:953-960, 2016. PMID- 26648457 TI - The importance of optimal extraction to insure the reliable MS-based assays of endogenous compounds. PMID- 26648458 TI - Expression of the voltage-gated potassium channel Kv3.4 in oral leucoplakias and oral squamous cell carcinomas. AB - AIMS: The expression of the voltage-gated potassium channel Kv3.4 was investigated in both oral squamous cell carcinomas (OSCC) and oral leucoplakias to establish its clinical significance during the development and progression of OSCC. MATERIALS AND METHODS: Tissue specimens from 62 patients with oral leucoplakia were collected prospectively and 100 patients with OSCC who underwent surgical treatment were collected retrospectively, and Kv3.4 expression was analysed by immunohistochemistry. RESULTS: Thirty-nine of 100 tumours exhibited Kv3.4-positive expression, and staining was associated with the degree of differentiation (P = 0.05) but showed no impact on patient prognosis. Abnormal Kv3.4 expression was detected in 16% (7 of 43) hyperplastic lesions and at a significantly higher proportion in oral dysplasias (50%, 8 of 16 cases; P = 0.008), whereas expression was negligible in normal adjacent epithelia. Furthermore, patients carrying Kv3.4-positive lesions exhibited a higher progression risk than those with Kv3.4-negative lesions; however, histology but not Kv3.4 expression predicted oral cancer development significantly in this prospective cohort. CONCLUSION: This study provides original evidence to demonstrate the early occurrence and high prevalence of abnormal Kv3.4 expression in oral leucoplakias. Our results support a role for Kv3.4 potassium channel in OSCC tumorigenesis rather than tumour progression and disease outcome. PMID- 26648459 TI - A novel curcumin derivative increases the cytotoxicity of raloxifene in estrogen receptor-negative breast cancer cell lines. AB - There is a need for new, safe and efficacious drug therapies for the treatment of estrogen receptor (ER)-negative breast cancers. Raloxifene and the 2nd generation curcumin derivative 2,6-bis(pyridin-4-ylmethylene)-cyclohexanone (RL91) have been shown to inhibit the growth of ER-negative breast cancer cells in vitro and in vivo. We investigated whether RL91 could enhance the growth-suppressive effects mediated by raloxifene in MDA-MB-231, MDA-MB-468, Hs578t and SkBr3 human breast cancer cell lines. The cytotoxicity was consistent across the cell lines but RL91 was more potent. EC50 values for RL91 were 1.2-2 uM while EC50 values for raloxifene were 9.6-11.2 uM. When the cells were treated with raloxifene (15 uM), RL91 (1 uM) or a combination of the two for 6-72 h, the combination treatment consistently elicited significantly greater cytotoxicity compared to all other treatments. In SkBr3 cells the combination treatment caused significantly more cells to undergo G1 arrest compared to raloxifene. In all cell lines apoptosis was synergistically induced by the combination treatment, as shown by both flow cytometery and cleaved caspase-3. Furthermore, the stress kinase p38 was increased and EFGR isoforms were decreased by both raloxifene and raloxifene + RL91. The anti-angiogenic anti-metastatic potential of raloxifene was not increased by RL91, as MDA-MB-231 cell migration and invasion as well as endothelial tube formation by HUVEC cells was not different between raloxifene (10 uM) and the combination of raloxifene + RL91. Thus, our findings provide evidence that RL91 increases the ability of raloxifene to suppress ER-negative cancer cell growth by increasing the number of apoptotic cells. The broad effect of this drug combination across a range of ER-negative breast cancer cell lines indicates that this drug combination should be explored further in order to find a safe and efficacious therapy for ER-negative breast cancer. PMID- 26648460 TI - Combined Treatment Fkt-Botulinum Toxin Type A (Btx-A) in Patients with Strumpell Lorrain Disease. AB - The Hereditary Spastic Paraparesis (HSP) or Strumpell-Lorrain disease is a heterogeneous neurodegenerative disease of the spinal cord. It is genetically transmitted and characterized by a progressive muscle weakness, spasticity of the lower limbs and awkward gain. There is no specific pharmacological treatment. The pharmacological therapy decreases the muscle tone and prevents stiffening). Physiotherapy restrains the progression of muscle atrophy, delays contraction of the tendons and gives greater mobility to people affected by the disease. The aim of this study is to demonstrate the efficacy of the combined treatment Fkt and Btx-A in patients with HSP. Retrospective study was conducted recruiting ten patients with spasticity according to Asworth modified scale of at least 2 and with gait deficit. They received treatment for 5 years with incobotulinumtoxinA and physiokinesiotherapy for addressing spasticity in the lower limbs. We evaluated muscle tone with miometric measurement both at the first visit (T0), and at subsequent ones (T1 after 30 days, T2 after 3 months from the first infiltration, T3 after 4 months up to the date of the following infiltration, T4 after 5 months). Baropodometric examination has proven essential for the study of the distribution of loads in statics and dynamics. The data analysis regarding tone assessment through measurements with Myoton highlighted hypertonus reduction in all the three muscle groups examined at T1 and the maintenance of constant values up to 5 months after the first infiltration. It also showed an increase in the percentage of back foot loading in both feet up to T4 (new inoculation, p<0, 05%). Baropodometric examination in dynamics (in particular the speed of the step) showed a gradual increase in this parameter which reaches a peak at 5 months (p<0, 05%) and then declines again in conjunction with the next infiltration treatment. This study showed the benefit of combined treatment with Btx and Fkt. The use of a local muscle relaxant drug with a physical targeted exercise guarantees better mobility of the treated segments, reducing tendon retractions as much as possible, and guarantees an adequate postural alignment. Baropodometric examination highlights a more advantageous distribution load, quite essential for avoiding tendinitis due to overload. Our data observation in the 5 years study shows how the curve relative to the speed of step and the graphics related to the variations of muscle tone remain almost constant with detectable improvement. PMID- 26648461 TI - Cardiovascular disease management through restrained inflammatory responses. AB - Cardio vascular disease (CVD) is the end result of the accumulation of atheromatous plaques within the walls of the coronary arteries and remains the leading cause of death worldwide. Vascular inflammation and associated ongoing inflammatory responses have been considered as the critical culprits in the pathogenesis of CVD. Moreover, the activation of inflammatory pathways is not confined to coronary lesions only but involves the activation of neutrophils, monocytes and lymphocytes in peripheral blood. In view of high mortality rate associated with this devastated disease, it is essential that CVD and related complications should be taken care off at its earliest. To achieve that goal, some inflammatory mediators could be potentially targeted. In the current article, we will highlight targeting some inflammatory mediators viz. IL-1, IL-6, TNF-alpha etc for CVD management. As far as our knowledge goes, we are for the first time reporting the targeting inflammatory mediators especially IL-1, IL-6 and TNF-alpha together in a single article. Based on our review, we believe that scientific community will come up with certain anti-inflammatory agents against atherosclerosis in near future and hopefully that will be used for the successful management of CVD patients. PMID- 26648462 TI - MicroRNA-34a and its target genes: Key factors in cancer multidrug resistance. AB - Following the first small non-coding RNA identification in 1993, accumulated knowledge on the biogenesis, homeostasis and functional roles of microRNAs in different physiological and pathophysiological conditions has been discovered. MicroRNAs act through epigenetic regulation of gene expression. MiR-34a is a member of the MiR-34 family that is involved in p53 pathways, and is implicated in cell death/survival signaling. MiR-34a is associated with G1 cell cycle arrest, senescence and apoptosis, thereby possessing a tumor suppressor activity. Deregulation of MiR-34a has been reported in several types of cancers. MiR-34a downregulation has been correlated with cancer multidrug resistance (MDR), which is a major challenge for successful cancer chemotherapy. MiR-34a mimetic agents have been shown to attenuate drug resistance in different cancer cell lines. This review focuses on the in vitro, experimental and clinical findings dealing with the role of miR-34a downregulation in MDR, and potential therapeutic opportunities arising from this role of miR-34a. PMID- 26648463 TI - RGD-based Therapy: Principles of Selectivity. AB - Design of selective anticancer drugs that are targeting RGD-binding integrin receptors which are known to be one of the perspective directions in the field of oncology. Significant progress in the development and application of these types compounds is already demonstrated. The accumulating body of basic and clinical evidence demonstrates potential significant effects on both in vitro and in vivo experimental models. However, the specific mechanism of action of these compounds is generally not a fully elucidated or the exact target responsible for the achievement of stated effects hasn't yet been defined sufficiently. To date eight types of integrin receptors, which are capable to recognize RGD-motif in natural ligands, has in fact been identified as (namely alphaIIbbeta3, alphavbeta1, alphavbeta3, alphavbeta5, alphavbeta6, alphavbeta8, alpha5beta1, alpha8beta1). Even so, the estimation of the affinity of one particular RGD-bearing anticancer agent is often based on the determination of the binding efficacy to only one or rarely two integrin receptors. Traditionally the range of targets is restricted by the integrins, which are known to be highly expressed in a particular model system. While potential interactions of such an agent with other RGD-recognizing receptors usually remain beyond the research. Nonetheless, such interactions may also affect the viability and behavior of cancer cells. In this review we attempt to critically analyze the principles of selectivity achievement in the case of RGD-bearing natural ligands and the applicability of these principles in the context of the anticancer drug design. PMID- 26648464 TI - Rheumatoid Arthritis: Notable Biomarkers Linking to Chronic Systemic Conditions and Cancer. AB - Adult rheumatoid arthritis (RA) is an autoimmune disorder affecting joints and frequently characterised by initial local and later systemic inflammation. Researchers have, for many years, traced its cause to diverse genetic, environmental and especially immunological responses that work against the body's own cells and tissues. Investigation into several of these biomarkers reveals interconnections that exist between multiple factors, which ultimately lead to specific pathologies. The goal of this paper is to highlight connections present between the major biological players long identified by researchers including more recently uncovered biomarkers in the RA repertoire and some of the pathophysiologies typically affiliated with the disease. Biomarkers reviewed, and becoming more clearly defined for RA include genetic, cytokines like tumor necrosis factor-alpha (TNF-alpha), lymphocytes, nuclear antigens, antibodies to citrullinated peptides (anti-CPs), acute-phase proteins (APPs), microRNA, S100 proteins, platelets and erythrocytes. Some of the disease manifestations that have been connected are bone erosion, diabetes, metabolic syndrome, anemia, synovitis, felty's syndrome, extra-articular manifestations (EAMs) such as atherosclerosis, rheumatoid nodules and cardiovascular (CV) events. Several RA markers associated with malignancy have been identified in literature although there is insufficient evidence of cancer in patients. Due to the complex nature of the disease, the appearance of symptoms and markers vary amongst individuals and the connections may manifest only in part. This manuscript addresses defining factors relevant to rapid identification of pathological influences these biomolecules could exert and to the management of the disease. Each of these biological players may have its place in connecting to symptomatic pathologies and help to highlight potential targets for therapy. PMID- 26648465 TI - Can Probiotics Cure Inflammatory Bowel Diseases? AB - Gastrointestinal (GI) disorders, especially microbial dysbiosis play role in several GI ailments such as irritable bowel syndrome, colorectal cancer, inflammatory bowel diseases, and antibiotic-associated diarrhoea. Role of inflammatory bowel disease (IBD) is multifactorial as it involves loss of maintaining intestinal epithelial barrier integrity, increased release of pro inflammatory molecules, and microbial dysbiosis in gut microflora. Some specific pathogens also play a key role in the IBD development. The origin and causation are still in unfathomable condition and the exact root cause is unknown. Recently probiotic studies have been gaining importance because of their positive responses in their IBD experimental results. According to joint Food and Agricultural Organisation/World Health Organisation working group, probiotics are defined as live microorganisms which when administered in adequate amount confer health benefit on the host. These live beneficial microorganisms are considered helpful in improving gut colonization and perseverance thereby improves prophylactic effect. In the direction of IBD research, a number of studies are needed to standardize its methodology and its applicability on human usage. The particular review presents an overview of gut microflora and its impact on host health, types of IBD and existing therapies to treat this disorder, mechanism of several probiotic actions, role of probiotics in IBD prevention with their supporting evidences. PMID- 26648466 TI - Approaches for the Development of Drugs for Treatment of Obesity and Metabolic Syndrome. AB - Obesity and metabolic syndrome (MS) are risk factors for diabetes, cancer, some cardiovascular and musculoskeletal diseases. Pharmacotherapy should be used when the body mass index (BMI) exceeds 30 kg/m2 or 27 kg/m2 with comorbidity. Efficacy and safety of pharmacotherapy depend on the mechanism of action of drugs. In this context, drugs affecting the central and peripheral mediator systems such as cannabinoid receptor antagonists (Rimonabant), neuronal reuptake inhibitor of NE and 5 HT (Sibutramine), neuronal reuptake inhibitor of NE 5-HT DA (Tesofensine), agonist of 5 HT 2C receptors (Lorcaserin) have a high risk of side effects on the central nervous and cardiovascular systems when used for a long period. Apparently, the drugs design targeting obesity should screen safer drugs that affect fat absorption (Orlistat), activate energy metabolism (Adipokines), inhibit MetAP2 (Beloranib) and other peripheral metabolic processes. The use of synergies of anti-obesity drugs with different mechanisms of action is an effective approach for developing new combined pharmaceutical compositions (Contrave(r), EmpaticTM, Qsymia et al). The purpose of this article is to review the currently available anti-obesity drugs and some new promising trends in development of anti-obesity therapy. PMID- 26648467 TI - Benzofuran Small Molecules as Potential Inhibitors of Human Protein Kinases. A Review. AB - Kinases are known to regulate the majority of human cellular processes such as communication, division, metabolism, survival and apoptosis therefore they can be promising targets in cancer diseases, viral infection and in other disorders. Small molecules acting as selective human protein kinase inhibitors are very attractive pharmacological targets. This review presents a number of examples of biologically active natural and synthetic benzo[b]furans and their derivatives, such as benzo[b]furan-2- and 3-ones, benzo[b]furan-2- and 3-carboxylic acids, as well as benzo[c]furans as potential inhibitors of various human protein kinases. The pathways of function and implication of the inhibitors in cancer and other diseases are discussed. PMID- 26648468 TI - The potential role of antioxidants in metabolic syndrome. AB - Metabolic syndrome (MS) is a constellation of risk factors that raise the risk for heart disease and other health problems, such as obesity. The clustering of metabolic abnormality is closely related to oxidative stress and inflammation, as well as the progression of atherosclerosis. Antioxidants are reducing agents which inhibit the oxidation of other molecules and can be used not only to prevent but also to treat health complications of MS and atherosclerosis. They can be ingested in the normal diet, since they are found in many food sources, or in supplement formulations. Herein, we aim to review the literature concerning the effect of antioxidants on MS. We focus on antioxidants with some evidence of action on this condition, like flavonoids, arginine, vitamin C, vitamin E, carotenoids, resveratrol and selenium. Experimental and clinical studies show that most of the above-mentioned antioxidants exhibit a wide range of effects in protecting the human body, especially in MS patients. However, the underlying mechanisms are not fully elucidated for most of these compounds. Also, some of them should be used with caution because their excess can be toxic to the body. In general, antioxidants (especially those present in foods) can be used by MS individuals because of their direct effect on oxidative stress. Additionally, they should be encouraged as part of a nutritional lifestyle change, since this is part of the therapy for all diseases involved in metabolic disorders. PMID- 26648469 TI - Validating Immunotherapy in Alzheimer's Disease: The EB101 Vaccine. AB - Vaccination has become one of the most promising immunotherapeutic approaches in the prevention and treatment of Alzheimer's disease (AD) and related neuropathological hallmarks. Numerous immunotherapeutic interventions have attempted to achieve adaptive immunity against Abeta with a range of different antigenic designs and immunomodulatory strategies, most of them with great success in AD mouse model studies. Most of these studies have shown that both active and passive immunization can drastically reduce amyloid deposition and prevent the decline in cognitive performance. New approved clinical trials are under investigation to test the effectiveness of those different vaccination approaches, although previous data showed modest clinical success with some adverse inflammatory events in immunized elderly patients. The search for new approaches to overcome these severe side effects has led to novel technical methods such as live vector or DNA vaccines, although the use of innovative adjuvants combined with selected amyloid peptides is among the most auspicious. In this review, we compare and discuss the past and contemporary vaccines and the future strategies that may lead to a viable improvement in AD prevention and treatment. PMID- 26648470 TI - Alterations in Glucose Metabolism on Cognition: A Possible Link Between Diabetes and Dementia. AB - The use of the carbohydrate glucose as an energetic source is essential for an adequate function of the human body. The complex regulation of this molecule involves the coordinated action of various organs such as pancreas, liver and brain. Any disruption of this physiological balance may result in a dangerous compromise of general metabolic activities increasing the possibility of developing T1DM, T2DM and possibly AD. Astrocytes convert glucose into lactate and transfer it to neurons. This lactate is essential for neuronal metabolism and for various processes including the formation of synapses, dendrites and the expression of genes involved in memory. The brain is highly susceptible to variations in glucose blood levels, and both hypoglycemia and hyperglycemia can be dangerous. Pathological hyperglycemia induces changes in plasmatic osmotic pressure, mitochondrial production of free radicals, oxidative stress and activation of neuronal apoptosis, among others. Both AD and diabetes are chronic diseases having age as an important risk factor. As the brain ages, it seems to become much more susceptible to cellular damage induced by excess of circulating glucose and this could explain the appearance of cognitive changes observed in some patients with diabetes. Excessive circulation of pro-inflammatory agents has been observed in insulin resistance and is likely that some of these mediators may cross the bloodbrain barrier and induce abnormal neuroinflammation. GSK-3 is overexpressed in diabetes and also has been reported to regulate tau phosphorylation and production of Abeta peptides in the brain. Currently, diabetes (hyperglycemia) is considered as a risk factor for the development of AD. A novel therapeutic approach, using intranasal insulin and anti-diabetic medications in patients suffering from AD is being explored and is discussed in this review. PMID- 26648471 TI - A proteomics based approach for the identification of gastric cancer related markers. AB - Gastric cancer (GC) is the amongst the most common cancer types causing second largest number of cancer related deaths globally. GC is characterized as an aggressive malignancy which is very tough to be detected at an early stage. GC has been defined as a complex, multistep process involving multiple genetic and epigenetic alterations leading to aberrant expression of key regulating factors. GC according to WHO has been defined as malignant epithelial tumors of the gastric mucosa with glandular differentiation. About one half of the GCs are located in the lower stomach, and remaining is located in the corpus and fundus of the stomach (20%), lesser curvature (20%), cardia (10%) and greater curvature (3%). GC has been classified into intestinal and diffuse types based on epidemiological and clinico- and histopathological features. The etiology of GC is multifactorial and includes dietary as well as non-dietary factors. Despite a lot of research efforts, GC remains to be the cancer without clear symptoms at onset, poor prognosis, with metastasis and recurrence. Thus, there is an urgent need for identifying novel and diagnostic GC biomarkers and techniques with high sensitivity and specificity. In the present review, we provide a synopsis of proteomics based GC biomarkers discovered from various cancerous specimens such as blood, gastric fluid, tissues, cells and H. pylori infected cancer cell lines. The advent of proteomics based GC biomarkers will be a great asset for the early detection and treatment of GC. PMID- 26648472 TI - Super aggregated form of Amphotericin B: a novel way to increase its therapeutic index. AB - Amphotericin B (AmB)-deoxycholate micellar formulation, Fungizone(r), is the drug of choice for the treatment of unidentified mycotic infections. However, it usage has been marred by long therapeutic regimes and severe side effects. The less toxic lipid associated AmB formulations have been limited by their high expense, with some loss in activity. The quest for decreasing AmB cytotoxicity as well as production cost has resulted in the development of AmB super-aggregate as an alternative to its existing lipid formulations. AmB super-aggregate is spectroscopically distinct from the aggregate present in Fungizone, displaying enhanced thermodynamic stability. The poly-aggregated form of AmB exhibits reduced toxicity in mammalian cells in vitro and to mice in vivo, while maintaining its 'gold standard' antifungal activity. Poly-aggregated AmB interacts predominantly with serum albumin and also attenuates its ability to induce potentially harmful cytokines. Bio-distribution studies have demonstrated that the self-associated AmB shows greater accumulation in reticulo-endothelial organs while sparing kidney, one of the principal organs where its toxic effects are seen. The super-aggregated AmB can thus be used to improve the therapeutic index of AmB against a plethora of fungal infections including candidiasis and cryptococcosis, thus providing a fitting solution to growing demand of an active, less toxic substitute of AmB. PMID- 26648473 TI - Male fertility and obesity: are ghrelin, leptin and glucagon-like peptide-1 pharmacologically relevant? AB - Obesity is rising to unprecedented numbers, affecting a growing number of children, adolescents and young adult men. These individuals face innumerous health problems, including subfertility or even infertility. Overweight and obese men present severe alterations in their body composition and hormonal profile, particularly in ghrelin, leptin and glucagon-like peptide-1 (GLP-1) levels. It is well known that male reproductive health is under the control of the individual's nutritional status and also of a tight network of regulatory signals, particularly hormonal signaling. However, few studies have been focused on the effects of ghrelin, leptin and GLP-1 in male reproduction and how energy homeostasis and male reproductive function are linked. These hormones regulate body glucose homeostasis and several studies suggest that they can serve as targets for anti-obesity drugs. In recent years, our understanding of the mechanisms of action of these hormones has grown significantly. Curiously, their effect on male reproductive potential, that is highly dependent of the metabolic cooperation established between testicular cells, remains a matter of debate. Herein, we review general concepts of male fertility and obesity, with a special focus on the effects of ghrelin, leptin and GLP-1 on male reproductive health. We also discuss the possible pharmacological relevance of these hormones to counteract the fertility problems that overweight and obese men face. PMID- 26648474 TI - Neuroimmune Crosstalk in CNS Disorders: The Histamine Connection. AB - The neuroimmune system represents a dense network of biochemical signals associated with neurotransmitters, neuropeptides, neurohormones, cytokines, chemokines, and growth factors synthesized in neurons, glial cells and immune cells, to maintain systemic homeostasis. Endogenous and/or exogenous, noxious stimuli in any tissue are captured by sensor cells to inform the brain; likewise, signals originating at the central nervous system (CNS) level are transmitted to peripheral immune effectors which react to central stimuli. This multidirectional information system makes it possible for the CNS to respond to peripheral damage and for alterations in brain function to be reflected in peripheral immune changes. Different CNS disorders, such as anxiety, depression, psychosis, stroke, Alzheimer's disease, Parkinson's disease, attention-deficit hyperactivity disorder, migraine, epilepsy, vascular dementia, mental retardation, cerebrovascular encephalopathy, multiple sclerosis, brain tumors, cranial nerve neuropathies, mental retardation and post-traumatic brain injury exhibit changes in CD3, CD4, CD7, HLA-DR, CD25, CD28, and CD56 immune markers. Histamine is an important pleiotropic factor in neuroimmune regulation. This biogenic amine shows age-and sex-dependent changes in the CNS, and is significantly altered, together with interleukin- 1beta and TNF-alpha, in Alzheimer's disease and other neurodegenerative disorders in which neuroinflammation appears to be an aggravating phenotype. Therapeutic intervention to halt progression of deleterious neuroinflammatory reactions in CNS disorders is a major challenge for molecular pharmacology in the future. PMID- 26648475 TI - Gp91phox-derived Reactive Oxygen Species/Urocortin 2/Corticotropin-releasing Hormone Receptor Type 2 Play an Important Role in Long-term Ultraviolet A Eye Irradiation-induced Photoaging. AB - Photoaging is induced by long-term ultraviolet A (UVA) eye irradiation. However, the mechanism of skin damage due to UVA eye irradiation is still not well understood. In this study, we used C57BL/6j and gp91phox knockout (gp91phox(-/-) ) mice for the long-term effects of UVA irradiation. The eye or dorsal skin of the mice was locally exposed to UVA for 12 months. The reactive oxygen species (ROS), gp91phox, corticotropin-releasing hormone (CRH), urocortin 2, and CRH receptor (CRHR) type 1 and type 2 levels in the brain and mast cell tryptase and histamine levels in the dorsal skin all increased after UVA irradiation. The levels of CRH, urocortin 2, CRHR type 1 and type 2 in the brain also increased more after UVA eye irradiation than after UVA skin irradiation. Moreover, photoaging of the UVA eye irradiation mice was not induced following the administration of a ROS inhibitor in the brain. In addition, in gp91phox(-/-) mice, photoaging by UVA eye irradiation was not induced. These results indicate that long-term UVA eye irradiation led to increased gp91phox-derived ROS in the brain and the increased expression of urocortin 2 and CRHR type 2, resulting in photoaging; however, further studies are needed to confirm these findings. PMID- 26648476 TI - What if scalp flora was involved in sensitive scalp onset? PMID- 26648477 TI - Observation of a Biexciton Wigner Molecule by Fractional Optical Aharonov-Bohm Oscillations in a Single Quantum Ring. AB - The Aharonov-Bohm effect in ring structures in the presence of electronic correlation and disorder is an open issue. We report novel oscillations of a strongly correlated exciton pair, similar to a Wigner molecule, in a single nanoquantum ring, where the emission energy changes abruptly at the transition magnetic field with a fractional oscillation period compared to that of the exciton, a so-called fractional optical Aharonov-Bohm oscillation. We have also observed modulated optical Aharonov-Bohm oscillations of an electron-hole pair and an anticrossing of the photoluminescence spectrum at the transition magnetic field, which are associated with disorder effects such as localization, built-in electric field, and impurities. PMID- 26648478 TI - Baseline abnormal liver function tests are more important than age in the development of isoniazid-induced hepatoxicity for patients receiving preventive therapy for latent tuberculosis infection. AB - BACKGROUND: One of the cornerstones of Australia's public health programmes to eliminate tuberculosis (TB) is the identification and treatment of latent tuberculosis infection (LTBI). AIMS: The main aim of this study is to determine the demographics, compliance, completion rates and adverse events of patients on preventive therapy (PT) for LTBI at our institution. The secondary aim is to determine the rates of isoniazid (INH) hepatotoxicity and identify any contributory factors. METHODS: The method used was an audit using medical records of 100 consecutive patients (2010-2014) treated with PT for LTBI. RESULTS: Seventy-two patients with confirmed LTBI started 9 months of INH and 22 started 4 months of rifampicin (RIF). The median age was 30 years. Half the patients were born in high TB-prevalence countries. Fifty-six per cent were contacts of index cases with confirmed TB, and 26% were pre-immunosuppression. Seventy-seven per cent completed PT with adequate compliance. Thirty-three per cent on INH and 23% on RIF experienced some liver function test (LFT) abnormality while on treatment. INH was ceased in 3% due to asymptomatic hepatic dysfunction (transaminases >5x upper limit of normal). No patients had permanent liver damage. Significant risk factors for liver dysfunction during PT were risk factors for liver disease (chi(3)(2) = 8.7; P = 0.03) or abnormal pre-therapy LFT (chi(3)(2)= 22.4; P < 0.001). No patients developed active TB. CONCLUSION: The completion rate of 77% and rate of INH-induced hepatic dysfunction of 3% is comparable with the literature. We found no age association with the risk of INH-induced hepatic dysfunction; however, there was a significant and linear association with the degree of liver function abnormality during INH therapy and the presence of abnormal baseline LFT. Routine LFT monitoring allowed early cessation of INH in those with significant but asymptomatic hepatitis who did not meet criteria for ATS/CDC LFT monitoring. PMID- 26648479 TI - Design, Synthesis, and Biological Evaluation of Pyrazole Derivatives. AB - In this in vitro study, a series of novel pyrazole derivatives were designed, synthesized, and evaluated against five human cancer cell lines (PC3, A549, HL60, HCT116, and SW620) for their antiproliferative and p53-MDM2 binding inhibitory activities. Although biological evaluations showed that this series of compounds possessed weak p53-MDM2 inhibitory activities, most of them displayed moderate to potent antiproliferative activities against the tested cells lines. Compound 11c exhibited the best potency for MDM2 (FP-IC50 = 29.22 MUm) and demonstrated antiproliferative activities in response to the five tested cell lines (IC50 = 4.09-16.82 MUm). Compared with the positive control Nutlin-1, there was enhanced antiproliferative activity to p53-mutated or p53-deficient cell lines (SW620, HL60, and PC3). PMID- 26648480 TI - Grancalcin (GCA) modulates Toll-like receptor 9 (TLR9) mediated signaling through its direct interaction with TLR9. AB - Toll-like receptors (TLRs) are playing important roles in stimulating the innate immune response and intensifying adaptive immune response against invading pathogens. Appropriate regulation of TLR activation is important to maintain a balance between preventing tumor activation and inhibiting autoimmunity. Toll like receptor 9 (TLR9) senses microbial DNA in the endosomes of plasmacytoid dendritic cells and triggers myeloid differentiation primary response gene 88 (MyD88) dependent nuclear factor kappa B (NF-kappaB) pathways and type I interferon (IFN) responses. However, mechanisms of how TLR9 signals are mediated and which molecules are involved in controlling TLR9 functions remain poorly understood. Here, we report that penta EF-hand protein grancalcin (GCA) interacts and binds with TLR9 in a yeast two-hybrid system and an overexpression system. Using siRNA-mediated knockdown experiments, we also revealed that GCA positively regulates type I IFN production, cytokine/chemokine production through nuclear localization of interferon regulatory factor 7 (IRF7), NF-kappaB activation, and mitogen-activated protein kinase (MAPK) activation in plasmacytoid dendritic cells. Our results indicate that heterodimerization of GCA and TLR9 is important for TLR9-mediated downstream signaling and might serve to fine tune processes against viral infection. PMID- 26648481 TI - Characterizing the lacrimal punctal region using anterior segment optical coherence tomography. AB - PURPOSE: Abnormalities of lacrimal punctum size and morphology probably contribute to excess tearing, with significant effects on quality-of-life for affected individuals. Our current understanding of normal punctal morphology originates from ex vivo studies, which are unlikely to capture the true nature of the living punctum. This study used enhanced depth anterior segment optical coherence tomography (OCT) to give improved characterization and understanding of lacrimal punctal structure. METHODS: Qualitative and quantitative assessments were performed on spectral domain OCT images collected prospectively from 40 lower puncta of 20 healthy volunteers. RESULTS: The average external lower lid punctal diameter was 0.646 mm (SD 150 MUm) on OCT imaging, measured at the largest diameter, which was in parallel to the mucocutaneous junction. Fifty-five per cent of puncta appeared closed, whilst the eyelids were open. Fluid menisci were visible within 73% of puncta. A postpunctal 'ampulla' was visible within three systems, one of which was imaged through the conjunctival surface. Ampullary dilatation occurred laterally, rather than at the medial wall. CONCLUSION: Optical coherence tomography provides quick and non-invasive assessment of the lacrimal punctum and its neighbouring tissue layers. This assessment of punctal size and morphology has the potential for further investigation of punctal physiology, for aiding diagnosis, and for monitoring the results of treatment. The average external diameter of the punctal opening measured in this study is greater than that recorded in anatomical textbooks. PMID- 26648482 TI - Upper extremity injuries in Danish children aged 6-12, mechanisms, and risk factors. AB - Although injuries to the upper extremity are most costly, the picture of the upper extremity injury problem remains incomplete. This study is the first to describe the etiology and mechanisms of upper extremity injuries in Danish children. A 2.5-year observational prospective cohort study was conducted to record upper extremity injuries in 1048 children. Data were weekly collected by sending a text message. A total of 176 upper extremity injuries were reported (128 acute injuries). Of the acute upper extremity injuries, 55% were sprains, 47% occurred in the hand/wrist, and 53% of cases were caused by a fall. When corrected for exposure to physical activity, this resulted in an acute upper extremity injury incidence density of 0.18 per 1000 h of physical activity. The odds of sustaining an upper extremity injury was higher in the older children (HR: 1.84, 95% CI: 1.10-3.09), a tendency was found suggesting that girls are at increased acute upper extremity risk compared to boys (HR: 1.40 95% CI: 0.97 2.04). The findings that most injuries occur after a fall, that injury risk increases over age and that girls seem to be at increased injury risk provides essential information to guide future childhood injury prevention. PMID- 26648483 TI - Multiple stressors, nonlinear effects and the implications of climate change impacts on marine coastal ecosystems. AB - Global climate change will undoubtedly be a pressure on coastal marine ecosystems, affecting not only species distributions and physiology but also ecosystem functioning. In the coastal zone, the environmental variables that may drive ecological responses to climate change include temperature, wave energy, upwelling events and freshwater inputs, and all act and interact at a variety of spatial and temporal scales. To date, we have a poor understanding of how climate related environmental changes may affect coastal marine ecosystems or which environmental variables are likely to produce priority effects. Here we use time series data (17 years) of coastal benthic macrofauna to investigate responses to a range of climate-influenced variables including sea-surface temperature, southern oscillation indices (SOI, Z4), wind-wave exposure, freshwater inputs and rainfall. We investigate responses from the abundances of individual species to abundances of functional traits and test whether species that are near the edge of their tolerance to another stressor (in this case sedimentation) may exhibit stronger responses. The responses we observed were all nonlinear and some exhibited thresholds. While temperature was most frequently an important predictor, wave exposure and ENSO-related variables were also frequently important and most ecological variables responded to interactions between environmental variables. There were also indications that species sensitive to another stressor responded more strongly to weaker climate-related environmental change at the stressed site than the unstressed site. The observed interactions between climate variables, effects on key species or functional traits, and synergistic effects of additional anthropogenic stressors have important implications for understanding and predicting the ecological consequences of climate change to coastal ecosystems. PMID- 26648484 TI - Novel Synthetic Lethality Approaches for Drug Combinations and Early Drug Development. AB - Preclinical evaluation of drug combinations is challenging. In this mini-review we discuss the concept of synthetic lethality and how this can impact on the evaluation of drug combinations and its clinical development. We will also review novel combinations with immunologic agents and the concept of collateral lethality. We suggest that identification of synthetic lethality interactions including collateral lethality using novel drug combinations can speed up the drug development process. This approach may identify synergistic combinations in tumors with a specific molecular alteration, limiting toxicity to normal tissue. In addition, the combination of an immunotherapy with an agent targeting cancer cells have the potential for acting on different functions with no overlapping of toxicities. Here, we also discuss potential consequences of this approach in the design of early clinical studies. PMID- 26648485 TI - Protein Geranylgeranyltransferase Type 1 as a Target in Cancer. AB - The process of protein prenylation involves the covalent linkage of either farnesyl (15-carbon) or geranylgeranyl (20-carbon) isoprenoid lipds to conserved cysteine residues in the carboxyl-terminus of proteins. Protein geranylgeranyltransferase I (GGTase-I) is the enzyme that catalyzes the addition of the geranylgeranyl moiety from geranylgeranyl pyrophosphate to the target protein, which contains a Cterminal consensus sequence termed a CaaX motif. Geranylgeranylation is important to the function of a number of proteins, including the majority of Rho GTPases, G protein gamma subunits, and several other regulatory proteins. Studies over the past two decades have revealed that many of these proteins contribute to tumor development and metastasis. Blocking Rho GTPase activity through inhibition of GGTase-I in particular has been advanced as a potential strategy for disease therapy. This review will provide an overview of the CaaX prenyltransferases, the rationale for targeting GGTase-I in cancer in particular, and the current status of GGTase-I inhibitor (GGTI) development. PMID- 26648486 TI - Comparative Proteomic Profiling of Extracellular Proteins between Normal and Gastric Cancer Cells. AB - Gastric cancer is the second leading cause of cancer-related deaths worldwide. Gastric cancer is often detected at a late stage when treatment is difficult. Biomarkers for early detection and drug targets for gastric cancer therapy are critical for effective management of gastric cancer. Secreted proteins not only play integral roles in cancer progression and metastasis, they are also easily accessible. Secreted proteins within the tumor microenvironment are therefore an attractive source of biomarkers and drug targets. In this study, iTRAQ-based liquid chromatography/tandem mass spectrometry was used for comparative profiling of the secretomes of 11 gastric cancer cell lines versus a normal gastric epithelial cell line. Of the close to 800 proteins detected, about 600 proteins were detected to display differential expression in one or more gastric cancer cell lines compared to normal cells. These differentially expressed proteins predominantly have binding or enzymatic activities and are largely associated with cellular and metabolic processes. Overexpression of ARPC4 was validated in gastric cell lines and its novel function in gastric cancer cell migration and invasion demonstrated in vitro. The findings support the notion of ARPC4 as a potential biomarker/drug target for metastatic gastric cancer. PMID- 26648487 TI - MicroRNA-200b inhibits the growth and metastasis of glioma cells via targeting ZEB2. AB - MicroRNAs (miRs) have been found to play important roles in mediating a variety of biological processes in human cancers, including tumor cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT). In the present study, we aimed to investigate the putative role of miR-200b in the progression of glioma. Real-time RT-PCR data showed that the miR-200b levels were frequently reduced in primary glioma tissues (n=88) and cell lines, when compared to normal brain tissues (n=25). Moreover, decreased miR-200b level was tightly associated with the malignant progression of glioma. Overexpression of miR-200b significantly suppressed cell proliferation, migration, invasion and EMT in glioma U251 and U87 cells. Luciferase reporter assay data further identified ZEB2 as a direct target of miR-200b, and the protein expression of ZEB2 was markedly reduced after overexpression of miR-200b in U251 and U87 cells. Furthermore, restoration of ZEB2 effectively reversed the reduced expression of ZEB2, as well as the suppressive effects of miR-200b overexpression on the proliferation, migration, invasion and EMT in glioma U251 and U87 cells. Moreover, in vivo study showed that overexpression of miR-200b significantly inhibited tumorigenesis as well as the tumor growth of glioma cells, and effectively protected nude mice from tumor-induced death. Taken together these findings suggest that miR-200b has suppressive effects on the proliferation, migration, invasion and EMT of glioma cells, partly at least, via targeting ZEB2. Therefore, miR-200b acts as a novel tumor suppressor in glioma, and thus may become a promising therapeutic candidate for glioma. PMID- 26648489 TI - Star fruit intoxication in chronic kidney disease patients: from the first clinical description to caramboxin. PMID- 26648488 TI - An active video game intervention does not improve physical activity and sedentary time of children at-risk for developmental coordination disorder: a crossover randomized trial. AB - BACKGROUND: Children with developmental coordination disorder (DCD) are highly inactive and sedentary. The purpose of this study was to assess the impact of a home-based active video game intervention on objectively measured physical activity and sedentary behaviour in children at risk for DCD. METHODS: In a crossover randomized clinical trial, 21 children (mean age 11.0, SD 1.0; n = 11 girls) in Perth, Western Australia participated in two 16-week periods: no active video games (AVGs) control period and AVGs intervention period. Two active input consoles were provided to participants along with a selection of non-violent AVGs for participants to play at home. Participants wore accelerometers at baseline and following each period to determine minutes of sedentary, light, moderate and vigorous times in addition to self-reported types of activities in a diary. Linear mixed models, adjusted for the order of periods, compared physical activity and sedentary time during the last week of each period. RESULTS: There were no significant differences between the intervention and control periods in time spent in sedentary (decrease of -1.0 min/day during the intervention period, 95%CI -12.1, 10.1), light (increase of 2.2 min/day, 95%CI -8.8, 13.2), moderate (decrease of 0.7 min/day, 95%CI -4.6, 3.3) or vigorous (decrease of -0.6 min/day, 95%CI -1.6, 0.4). CONCLUSIONS: Among children at risk for DCD, participating in this AVG intervention did not improve objectively measured physical activity and sedentary time. PMID- 26648490 TI - Kidney disease and calibration of creatinine determination: where are we in Brazil? PMID- 26648491 TI - Troponin I serum levels predict the need of dialysis in incident sepsis patients with acute kidney injury in the intensive care unit. AB - INTRODUCTION: Sepsis, an extremely prevalent condition in the intensive care unit, is usually associated with organ dysfunction, which can affect heart and kidney. OBJECTIVE: To determine whether the cardiac dysfunction and the Troponin I forecast the occurrence of acute renal failure in sepsis. METHODS: Cardiac dysfunction was assessed by echocardiography and by the serum troponin I levels, and renal impairment by AKIN criteria and the need of dialysis. Twenty-nine patients with incident sepsis without previous cardiac or renal dysfunction were enrolled. RESULTS AND DISCUSSION: Patients averaged 75.3 +/- 17.3 years old and 55% were male. Median APACHE II severity score at ICU admission was 16 (9.7 - 24.2) and mortality rate in 30 days was 45%. On the fifth day, 59% had ventricular dysfunction. Troponin serum levels on day 1 in the affected patients were 1.02 +/- 0.6 ng/mL compared with 0.23 +/- 0.18 ng/mL in patients without heart dysfunction (p = 0.01). Eighteen out of 29 patients (62%) underwent renal replacement therapy (RRT) and the percent of patients with ventricular dysfunction who required dialysis was higher (94% vs. 16%, p = 0.0001). Values of troponin at day 1 were used to develop a ROC curve to determine their ability to predict the need of dialysis. The area under the curve was 0.89 and the cutoff value was 0.4 ng/mL. CONCLUSION: We found that an elevation in serum troponin levels, while guarding a relationship with ventricular dysfunction, can be a precious tool to predict the need for dialysis in sepsis patients. PMID- 26648492 TI - Contrast-induced nephropathy after primary angioplasty for acute myocardial infarction. AB - INTRODUCTION: The prevention of contrast-induced nephropathy (CIN) is difficult in emergency situations, making it essential to study CIN in patients submitted to urgent angioplasty. OBJECTIVE: To determine the incidence and associated factors to CIN in patients with myocardial infarction (MI) submitted to primary angioplasty in the first 12 hours after onset of symptoms. METHODS: We studied 201 consecutive cases of MI with ST-segment elevation with less than 12 hours of evolution. All patients were submitted to the same angioplasty protocol. CIN was defined as an absolute increase of creatinine of at least 0.5 mg/dL and/or a relative increase of creatinine of 25% in relation to baseline in a period between 48 and 72 hours after contrast administration. The variables that differed between patients with and without CIN in univariate analysis were analyzed by logistic regression. RESULTS: The sample was formed by 135 (67.2%) men and 66 (32.8%) women, with mean age of 66.6 +/- 11.7 years. The incidence of CIN was 23.8%. In univariate analysis the patients with CIN were older and had higher frequency of left ventricular ejection fraction <= 40% and Killip classification >= 2. In multivariate analysis, we did not find independent predictors of CIN. CONCLUSION: CIN occurred in 1/4 of the patients with MI submitted to angioplasty without predictor variables. This finding highlights the need for CIN preventive measures after contrast use in emergency angioplasty. PMID- 26648493 TI - Risk factors for acute kidney injury in patients treated with polymyxin B at a Tertiary Care Medical Center. AB - INTRODUCTION: Polimyxins were originally abandoned due to high rates of nephrotoxicity. However they have been recently reintroduced due to activity against carbapenem-resistant Gram-negative organisms. Recent literature suggests a lower rate of nephrotoxicity than historically reported. OBJECTIVE: To determine the rate of polymixins-associated nephrotoxicity as defined by the RIFLE criteria. METHODS: A retrospective cohort of all adult patients who received polymixin B at a terciary hospital from December 2010 to March 2011was performed. RESULTS: 61 patients (43%) fulfilled the RIFLE criteria for renal injury and 28 patients (13.7%) needed dialysis. Independent predictors for nephrotoxicity were hypotension (OR, 2.79; CI 1.14-5.8; p = 0.006) and concomitant use of vancomycin (OR, 2.86; CI, 1.27-6.4; p = 0.011). CONCLUSIONS: In this retrospective cohort, nephrotoxicity (as defined by RIFLE criteria) occurred among 43% of treated patients. The concomitant use of vancomycin and hypotension were independent risk factors of nephropathy. Further studies are needed, particularly with polymyxin B, to clarify if the characteristics of this drug and colistin are overlapping. PMID- 26648494 TI - Impact of hemodialysis session on handgrip strength. AB - INTRODUCTION: Handgrip strength (HGS) is a simple and reliable method with a good predictive clinical value for assessing muscle function of patients undergoing hemodialysis (HD). However, there is no consensus regarding the appropriate moment for performing the HGS measurement since the performance of the HGS can be influenced by fluid, electrolyte and blood pressure changes that affect patients on HD. OBJECTIVE: To investigate the impact of the dialysis session on the HGS in patients undergoing HD. METHODS: This is a cross-sectional study with 156 patients [57.7% male, median age of 56.5 (42-67) years old, 28.8% diabetes, mean BMI of 24.75 +/- 4.5 kg/m2 and HD vintage of 38 (19.25 to 72.75) months]. Measures of HGS were performed with a dynamometer during the initial minutes of the HD session and at the end of the session. The values obtained were compared with a national standard reference. Clinical, demographic and laboratory data were collected from medical records. RESULTS: A significant reduction of HGS was observed after the HD session (28.6 +/- 11.4 kg to 27.7 +/- 11.7 kg; p < 0.01). The prevalence of patients with HGS below the 30th percentile increased from 44.9% to 55.1% (p < 0.01). The decrease in blood pressure during dialysis was the only factor associated with the reduction of HGS. CONCLUSION: These findings show that the HD procedure affects negatively the HGS. PMID- 26648495 TI - Metabolic acidosis and its association with nutritional status in hemodialysis. AB - INTRODUCTION: Metabolic acidosis is a common problem in dialysis patients and plays an important role in the pathogenesis of protein-energy malnutrition in these patients. OBJECTIVES: To assess the prevalence of metabolic acidosis in hemodialysis and search their association with nutritional status. METHODS: A cross-sectional study was performed in hemodialysis patients at a single center. Nutritional status was assessed by anthropometric, biochemical and multifrequency bioelectrical impedance analysis. Metabolic acidosis was defined as serum bicarbonate (BIC) < 22 mEq/L and patients were divided into 3 groups according to BIC (< 15.15 to 21.9 and >= 22). The association between BIC and continuous variables was investigated using the Kruskal Wallis test. The linear correlation between BIC and the variables of the study was also tested. RESULTS: We studied 95 patients, 59% male, mean age 52.3 years. The prevalence of metabolic acidosis was 94.7%. BMI, interdialytic weight gain and PTH were significantly different among the 3 groups of BIC. The BIC was negatively correlated with urea, phosphorus and interdialytic weight gain. There was no significant correlation with albumin, phase angle and lean body mass index. CONCLUSION: The prevalence of metabolic acidosis was high in this population, and a lower BIC correlated with higher levels of urea, PTH, phosphorus, interdialytic weight gain and lower BMI. The evaluation of acid-basic status should be routinely implemented in dialysis patients by considering the negative effects of acidosis on the nutritional status, inflammation and bone disease. PMID- 26648496 TI - Quality of life in chronic renal patients on hemodialysis or peritoneal dialysis: a comparative study in a referral service of Curitiba - PR. AB - INTRODUCTION: Chronic kidney disease (CKD) compromises the health and routine of the patient. On the fifth stage of CKD, the patient becomes eligible to start renal replacement therapy: hemodialysis (HD), peritoneal dialysis (PD) or kidney transplantation. The type of CKD treatment is essential to improving quality of life of the patient. OBJECTIVE: To compare the quality of life of CKD stage 5 patients who perform HD and home PD. METHODS: Cross-sectional study with data collection, by convenience, through the application of socioeconomic and KDQOL SF 36 questionnaires in HD and PD patients of the Pro-Renal Foundation and satellite clinics in Curitiba-PR. RESULTS: The sample was 338 patients, 222 HD and 116 PD. Average age: 54.4 years for HD group (+/- 15.28) and 58.00 for the DP group (+/- 13.99). The variables: work status (p < 0.05), encouragement by dialysis staff (p < 0.01) and patient satisfaction (p < 0.001) were in favor of DP; while physical functioning (p < 0.05) and emotional function (p < 0.01) were to HD. CONCLUSION: Objectively, PD was more favorable regarding quality of life, for the large number of items with significant results when compared to HD. However, the two variables of greatest significance found in HD (physical functioning and emotional functioning) ended up having a much greater impact on well-being and daily-life of the patient in the environment external to the clinic than those who were higher in DP, making HD the most favorable for patient quality of life. PMID- 26648497 TI - Minimal change disease and focal segmental glomerulosclerosis in adults: response to steroids and risk of renal failure. AB - INTRODUCTION: There is scarce data on the clinical profile of adult Brazilian patients with nephrotic syndrome caused by minimal change disease (MCD) and focal segmental glomerulosclerosis. OBJECTIVE: We evaluated the clinical characteristics and response to treatment in adult patients with nephrotic syndrome having a histological diagnosis of MCD or FSGS. METHODS: This is a retrospective analysis of 50 patients with MCD and 120 with FSGS. All patients were initially treated with steroids. The study outcomes were: steroid responsiveness, prevalence of total remission, progression to chronic renal failure and need of renal replacement therapy due to end-stage renal disease (ESRD). RESULTS: Initial serum creatinine level was 24% higher among patients with FSGS (p = 0.02), and proteinuria levels were 36% higher in MCD (p < 0.001). Patients with MCD were sensitive to steroid therapy in 80% of the cases, with total remission in 74%, while patients with FSGS were sensitive in 58% (p = 0.01), with total remission in 30% (p = 0.002). Patients with FSGS had an acute renal failure prevalence of 39% (vs. 12%, p = 0.013) and ESRD of 10% (vs. 0%, p < 0.001). Steroid responsiveness reduced in 83% the risk of ESRD (p < 0.001), while total remission was associated to a reduction in risk of 89% (p < 0.001). CONCLUSION: A positive response to steroid therapy was the most important factor related with preservation of renal function and FSGS was related with less steroid responsiveness. PMID- 26648498 TI - Proteinuria after kidney transplantation - prevalence and risk factors. AB - INTRODUCTION: Proteinuria after kidney transplantation (Tx) has variable incidence and is associated with cardiovascular risk and graft survival. OBJECTIVE: To evaluate the prevalence of proteinuria after kidney Tx and its associated factors. METHODS: The prevalence of PTN was evaluated according to definition >= 500 mg/24 hours. Patients were divided into 3 groups: group A, < 500 mg, B, 500-1000 mg and C, > 1000 mg. We tested the association between PTN and: age/gender of the donor and recipient, type of donor, delayed graft function, acute rejection, hypertension and creatinine. The variables with a p value < 0.20 in the bivariate analysis were included in a multivariate logistic regression analysis. RESULTS: 173 recipients were evaluated, mean age 39 years, 57.2% male and 60.7% deceased donor. The prevalence of PTN after kidney Tx was 24.3%. The distribution of patients according to PTN was 75.7% for group A, 15.6% for group B and 8.7% for group C. The following factors were associated with higher risk of PTN: male recipients, living donor and hypertension. Creatinine at month 12 moths post-Tx was higher among patients with proteinuria. 60% of patients with PTN >= 500 mg/24 hours were treated with ACEI/ARB. CONCLUSION: The prevalence of PTN after kidney Tx varied between 24.3%, according to the definition used. The male gender of the recipient, living donor and hypertension were associated with the occurrence of PTN after kidney Tx. Blockade of the renin angiotensin system must be prescribed to more patients. PMID- 26648499 TI - New insights on diabetes and bone metabolism. AB - Diabetes mellitus is a common chronic metabolic disease worldwide whose prevalence has increased during the last decades. Besides its more commonly recognized complications, such as macrovascular disease, retinopathy, nephropathy and neuropathy, diabetes related bone disease has gained growing attention. Diabetic patients are more prone to fracture than the general population as well as to low turnover bone disease in the chronic kidney disease setting. In this review, we discuss the relationship between diabetes and bone as well as the pathogenesis of bone fragility in T2D. PMID- 26648500 TI - Pheochromocytoma and pregnancy: A case report and review. AB - Pheochromocytoma is a catecholamine-producing adrenal tumor, being a rare cause of hypertension in pregnancy. It's prevalence in hypertensive patients is 0.2%, and 0.002% of pregnancies. We follow hypertensive pregnant 24 year old on her third pregnancy, admitted to 33 weeks with hypertensive emergency cesarean section indicated by fetal distress evolving with acute pulmonary edema in the post-partum period. Indicated laparoscopy after 13 days for acute abdominal pain, with no significant finding. In the postoperative, due a severe and resistant hypertension, suspected of pheochromocytoma and confirmed by biochemical tests and imaging. Performed unilateral adrenelectomia with cure of hypertension. The pathology and immunohistochemistry confirmed the diagnosis. We conclude that atypical cases of hypertension in pregnancy should be investigated early and differentiated pre-eclampsia. Despite the low prevalence, pheochromocytoma in pregnancy increases fetal maternal morbidity and mortality and the early recognition and treatment drastically change their outcome. PMID- 26648501 TI - Takayasu's arteritis with renal artery stenosis diagnosed in a patient with 65 years old. AB - Takayasu arteritis is a rare disease of unknown etiology that affects the aorta and its main branches. It is a condition, geographically more common in Southeast Asia, which mainly affects women of reproductive age. The clinical presentation is nonspecific, with signs and symptoms that vary according to the affected arterial segment. The most commonly affected vessel is the subclavian artery, while renal artery stenosis is relatively uncommon. Cardiac involvement and association with other diseases may also be present. We present in this report the case of an elderly patient with late diagnosis of Takayasu's arteritis and various comorbidities or related complications. PMID- 26648502 TI - Post-Legionellosis Proliferative Glomerulonephritis. PMID- 26648503 TI - Chronic kidney disease in Peru: a challenge for a country with an emerging economy. AB - Coverage of renal replacement therapies (RRT) in Peruvian Ministry of Health is poor. There is an unequal distribution of TRR in the country, and is possible that up to 50% of the population does not have access to any kind of TRR. A multi institutional approach to address this problem is necessary as it has been in consistent with the economic improvement of the country. PMID- 26648504 TI - Revealing text in a complexly rolled silver scroll from Jerash with computed tomography and advanced imaging software. AB - Throughout Antiquity magical amulets written on papyri, lead and silver were used for apotropaic reasons. While papyri often can be unrolled and deciphered, metal scrolls, usually very thin and tightly rolled up, cannot easily be unrolled without damaging the metal. This leaves us with unreadable results due to the damage done or with the decision not to unroll the scroll. The texts vary greatly and tell us about the cultural environment and local as well as individual practices at a variety of locations across the Mediterranean. Here we present the methodology and the results of the digital unfolding of a silver sheet from Jerash in Jordan from the mid-8(th) century CE. The scroll was inscribed with 17 lines in presumed pseudo-Arabic as well as some magical signs. The successful unfolding shows that it is possible to digitally unfold complexly folded scrolls, but that it requires a combination of the know-how of the software and linguistic knowledge. PMID- 26648505 TI - Addendum. PMID- 26648506 TI - A case of longitudinal apparent leuconychia on the left thumbnail with an unexpected aetiology. PMID- 26648507 TI - Characteristics of carbonic anhydrase 9 expressing cells in human intestinal crypt base. AB - Though recent studies have revealed that stem cells of many tissues are harbored in hypoxic microenvironment, little is known about the relationship between hypoxia and intestinal crypt base, where intestinal stem cells are supposed to exist. In this study, we focused on carbonic anhydrase IX (CA9), a hypoxia inducible membrane-tethered protein, in normal intestinal crypt base, adenoma and early colorectal cancer. Using surgically resected human colorectal cancer specimen, we searched for the expression pattern and functional association of CA9 in human adult normal intestinal epithelia, adenoma and early colorectal cancer by immunofluorescent and immunohistochemical staining, flow cytometry, and quantitative real-time-polymerase chain reaction. We demonstrated that almost all crypt base slender cells in ileum and crypt base cells with eosinophilic structure in their basal cytoplasm in right and left colon were CA9+ with the ratio of 25 to 40%, and that adenoma and T1 colorectal cancer showed broad expression of CA9. Flow cytometrically sorted CA9+ population showed increased mRNA level of a Wnt signaling factor AXIN2. In conclusion, these observations indicate that CA9 expression in normal crypt base cells has association with intestinal epithelial stemness and CA9 may be involved in the carcinogenesis of colorectal cancer. PMID- 26648508 TI - Magnetic ordering induced giant optical property change in tetragonal BiFeO3. AB - Magnetic ordering could have significant influence on band structures, spin dependent transport, and other important properties of materials. Its measurement, especially for the case of antiferromagnetic (AFM) ordering, however, is generally difficult to be achieved. Here we demonstrate the feasibility of magnetic ordering detection using a noncontact and nondestructive optical method. Taking the tetragonal BiFeO3 (BFO) as an example and combining density functional theory calculations with tight-binding models, we find that when BFO changes from C1-type to G-type AFM phase, the top of valance band shifts from the Z point to Gamma point, which makes the original direct band gap become indirect. This can be explained by Slater-Koster parameters using the Harrison approach. The impact of magnetic ordering on band dispersion dramatically changes the optical properties. For the linear ones, the energy shift of the optical band gap could be as large as 0.4 eV. As for the nonlinear ones, the change is even larger. The second-harmonic generation coefficient d33 of G-AFM becomes more than 13 times smaller than that of C1-AFM case. Finally, we propose a practical way to distinguish the two AFM phases of BFO using the optical method, which is of great importance in next-generation information storage technologies. PMID- 26648509 TI - A High-Performing Sulfur-Tolerant and Redox-Stable Layered Perovskite Anode for Direct Hydrocarbon Solid Oxide Fuel Cells. AB - Development of alternative ceramic oxide anode materials is a key step for direct hydrocarbon solid oxide fuel cells (SOFCs). Several lanthanide based layered perovskite-structured oxides demonstrate outstanding oxygen diffusion rate, favorable electronic conductivity, and good oxygen surface exchange kinetics, owing to A-site ordered structure in which lanthanide and alkali-earth ions occupy alternate (001) layers and oxygen vacancies are mainly located in [LnOx] planes. Here we report a nickel-free cation deficient layered perovskite, (PrBa)0.95(Fe0.9Mo0.1)2O5 + delta (PBFM), for SOFC anode, and this anode shows an outstanding performance with high resistance against both carbon build-up and sulfur poisoning in hydrocarbon fuels. At 800 degrees C, the layered PBFM showed high electrical conductivity of 59.2 S cm(-1) in 5% H2 and peak power densities of 1.72 and 0.54 W cm(-2) using H2 and CH4 as fuel, respectively. The cell exhibits a very stable performance under a constant current load of 1.0 A cm(-2). To our best knowledge, this is the highest performance of ceramic anodes operated in methane. In addition, the anode is structurally stable at various fuel and temperature conditions, suggesting that it is a feasible material candidate for high-performing SOFC anode. PMID- 26648510 TI - Connecting science, policy, and implementation for landscape-scale habitat connectivity. AB - We examined the links between the science and policy of habitat corridors to better understand how corridors can be implemented effectively. As a case study, we focused on a suite of landscape-scale connectivity plans in tropical and subtropical Asia (Malaysia, Singapore, and Bhutan). The process of corridor designation may be more efficient if the scientific determination of optimal corridor locations and arrangement is synchronized in time with political buy-in and establishment of policies to create corridors. Land tenure and the intactness of existing habitat in the region are also important to consider because optimal connectivity strategies may be very different if there are few, versus many, political jurisdictions (including commercial and traditional land tenures) and intact versus degraded habitat between patches. Novel financing mechanisms for corridors include bed taxes, payments for ecosystem services, and strategic forest certifications. Gaps in knowledge of effective corridor design include an understanding of how corridors, particularly those managed by local communities, can be protected from degradation and unsustainable hunting. There is a critical need for quantitative, data-driven models that can be used to prioritize potential corridors or multicorridor networks based on their relative contributions to long-term metacommunity persistence. PMID- 26648511 TI - Improving response rates and evaluating nonresponse bias in surveys: AMEE Guide No. 102. AB - Robust response rates are essential for effective survey-based strategies. Researchers can improve survey validity by addressing both response rates and nonresponse bias. In this AMEE Guide, we explain response rate calculations and discuss methods for improving response rates to surveys as a whole (unit nonresponse) and to questions within a survey (item nonresponse). Finally, we introduce the concept of nonresponse bias and provide simple methods to measure it. PMID- 26648512 TI - Uncertainty and variability in human exposure limits - a chemical-specific approach for ciprofloxacin and methotrexate. AB - Human exposure limits (HELs) for chemicals with a toxicological threshold are traditionally derived using default assessment factors that account for variations in exposure duration, species sensitivity and individual sensitivity. The present paper elaborates a probabilistic approach for human hazard characterization and the derivation of HELs. It extends the framework for evaluating and expressing uncertainty in hazard characterization recently proposed by WHO-IPCS, i.e. by the incorporation of chemical-specific data on human variability in toxicokinetics. The incorporation of human variability in toxicodynamics was based on the variation between adverse outcome pathways (AOPs). Furthermore, sources of interindividual variability and uncertainty are propagated separately throughout the derivation process. The outcome is a two dimensional human dose distribution that quantifies the population fraction exceeding a pre-selected critical effect level with an estimate of the associated uncertainty. This enables policy makers to set separate standards for the fraction of the population to be protected and the confidence level of the assessment. The main sources of uncertainty in the human dose distribution can be identified in order to plan new research for reducing uncertainty. Additionally, the approach enables quantification of the relative risk for specific subpopulations. The approach is demonstrated for two pharmaceuticals, i.e. the antibiotic ciprofloxacin and the antineoplastic methotrexate. For both substances, the probabilistic HEL is mainly influenced by uncertainty originating from: (1) the point of departure (PoD), (2) extrapolation from sub-acute to chronic toxicity and (3) interspecies extrapolation. However, when assessing the tails of the two-dimensional human dose distributions, i.e. the section relevant for the derivation of human exposure limits, interindividual variability in toxicodynamics also becomes important. PMID- 26648513 TI - Core-resonant double photoemission from palladium films. AB - We studied the core-resonant double photoemission process from palladium films with linearly polarized synchrotron radiation. We excited either the 3d or 4p core level and focused on the Auger transitions which leave two holes in the valence band. We find that the two-dimensional energy distributions are markedly different for the 3d and 4p decay. The 3d decay can be understood by a sequential emission of the two electrons while the 4p decay proceeds in a single step. Despite the large differences in the two-dimensional energy spectra we find the shape of the energy sum spectra rather similar. For the description of the 4p decay we propose a model which uses available single electron spectra, but suggest an alternative interpretation of these data. With this we are able to explain the range over which the available energy is shared. Key assumptions of the model are verified by our experiments on the 3d decay. PMID- 26648516 TI - Altered nociception and morphine tolerance in neuropeptide FF receptor type 2 over-expressing mice. AB - BACKGROUND: The neuropeptide FF system is thought to act as an anti-opioid modulator and plays a role in nociception, morphine antinociception and dependence. Two receptor subtypes, NPFFR1 and NPFFR2, have been identified, but their respective roles in these processes remain uncertain. METHODS: In the present study, the role of NPFFR2 was investigated using transgenic mice over expressing NPFFR2 in addition to a NPFFR2 agonist AC-263093. RESULTS: NPFFR2 Tg mice exhibited increased sensitivity to both mechanical and thermal noxious stimuli compared to the WT mice, while the antinociceptive effects of morphine at three different doses (6.25, 12.5 and 25 mg/kg, s.c.) were similar in both strains. The development of tolerance to morphine antinociception after chronic morphine treatment (12.5 mg/kg, s.c.; twice daily * 5 days) was attenuated in NPFFR2 Tg mice when compared to WT mice. Similarly, WT mice receiving AC-263093 pretreatment (2.5 mg/kg, i.p.) showed attenuated morphine tolerance compared to vehicle controls. Most naloxone-precipitated morphine withdrawal symptoms were not attenuated in NPFFR2 Tg mice, with the exception of wet dog shake that was significantly reduced. Both NPFFR2 Tg and WT mice displayed similar degree of morphine rewarding. CONCLUSIONS: Our results suggest that neuropeptide FF R2 is mainly involved in the modulation of nociception and tolerance to morphine antinociception. PMID- 26648517 TI - Math performance in Turner syndrome: implications for math disability research. PMID- 26648515 TI - Sendai virus as a backbone for vaccines against RSV and other human paramyxoviruses. AB - Human paramyxoviruses are the etiological agents for life-threatening respiratory virus infections of infants and young children. These viruses, including respiratory syncytial virus (RSV), the human parainfluenza viruses (hPIV1-4) and human metapneumovirus (hMPV), are responsible for millions of serious lower respiratory tract infections each year worldwide. There are currently no standard treatments and no licensed vaccines for any of these pathogens. Here we review research with which Sendai virus, a mouse parainfluenza virus type 1, is being advanced as a Jennerian vaccine for hPIV1 and as a backbone for RSV, hMPV and other hPIV vaccines for children. PMID- 26648518 TI - Tanshinone IIA decreases the migratory ability of AGS cells by decreasing the protein expression of matrix metalloproteinases, nuclear factor kappaB-p65 and cyclooxygenase-2. AB - During progression of gastric cancer, degradation of the extracellular matrix by matrix metalloproteinases (MMPs) has been associated with poor prognosis. Tanshinone IIA (Tan-IIA) exerts antitumor activity in a variety of human cancer cells. It is extracted from Danshen (Salviae miltiorrhizae radix), and induces apoptosis and inhibits the proliferation of gastric cancer cells. However, the molecular mechanisms underlying the inhibition of migration in gastric cancer by Tan-IIA have not been fully elucidated. In the present study, AGS cell migration ability was evaluated using a wound-healing assay. The protein expression levels of nuclear factor (NF)-kappaB-p65, cyclooxygenase (COX)-2, MMP-2, -7, and -9 and beta-actin in AGS cells were measured by western blotting. The results demonstrated that AGS cells treated with Tan-IIA exhibit decreased protein expression levels of NF-kappaB-p65, COX-2, and MMP-2, -7 and -9. The results also indicate that Tan-IIA inhibits migration ability in a dose- and time-dependent manner. These findings demonstrate that Tan-IIA inhibits the migration ability of AGS human gastric cancer cells and that decreasing the protein expression of NF kappaB-p65, COX-2, and MMP-2, -7 and -9 may be an underlying molecular mechanism. PMID- 26648519 TI - Cytochrome P450 17A1 inhibitor abiraterone attenuates cellular growth of prostate cancer cells independently from androgen receptor signaling by modulation of oncogenic and apoptotic pathways. AB - Abiraterone provides significant survival advantages in prostate cancer (PC), however, the current understanding of the molecular mechanisms of abiraterone is still limited. Therefore, the abiraterone impact on androgen receptor (AR) positive LNCaP and AR-negative PC-3 cells was assessed by cellular and molecular analyses. The present study demonstrated, that abiraterone treatment significantly decreased cell growth, AR expression, and AR activity of AR positive LNCaP cells. Notably, AR-negative PC-3 cells exhibited comparable reductions in cellular proliferation, associated with DNA fragmentation and pro apoptotic modulation of p21, caspase-3, survivin, and transforming growth factor beta (TGFbeta). Our observations suggest that the attenuation of AR signaling is not the only rationale to explain the abiraterone anticancer activity. Abiraterone efficacy may play a more global role in PC progression control than originally hypothesized. In this regard, abiraterone is not only a promising drug for treatment of AR-negative PC stages, even more, abiraterone may represent an alternative for treatment of other malignancies besides prostate cancer. PMID- 26648520 TI - In Vitro Fermentation of Xylooligosaccharides Produced from Miscanthus * giganteus by Human Fecal Microbiota. AB - Purified xylooligosaccharides from Miscanthus * giganteus (M*G XOS) were used in an in vitro fermentation experiment inoculated with human fecal microbiota. A commercial XOS product and pectin were used as controls. Decreases in pH by 2.3, 2.4, and 2.0 units and production of short-chain fatty acids (SCFA; acetic acid, 7764.2, 6664.1, and 6387.9 MUmol/g; propionic acid, 1006.7, 1089.5, and 661.5 MUmol/g; and butyric acid, 955.5, 1252.9, and 917.7 MUmol/g) were observed in M*G XOS, commercial XOS, and pectin medium after 12 h of fermentation, respectively. Titers of Bifidobacterium spp., Lactobacillus spp., and Escherichia coli increased when fed all three substrates as monitored by qPCR. There was no significant trend for Clostridium perfringens. During fermentation, M*G XOS was statistically equivalent in performance to the commercial XOS sample as measured by culture acidification and growth of health-promoting bacteria and resulted in the highest SCFA production among the three substrates. PMID- 26648522 TI - Rational design of a highly selective fluorescent sensor for L-histidine detection in aqueous solution. AB - Computational studies in combination with experimental research were used to design a new rapid, selective and sensitive "turn-on" fluorescent sensor (H3) for l-histidine, which can be first quenched by Ni(2+) and then recovered upon addition of His. PMID- 26648521 TI - Long-term neural and physiological phenotyping of a single human. AB - Psychiatric disorders are characterized by major fluctuations in psychological function over the course of weeks and months, but the dynamic characteristics of brain function over this timescale in healthy individuals are unknown. Here, as a proof of concept to address this question, we present the MyConnectome project. An intensive phenome-wide assessment of a single human was performed over a period of 18 months, including functional and structural brain connectivity using magnetic resonance imaging, psychological function and physical health, gene expression and metabolomics. A reproducible analysis workflow is provided, along with open access to the data and an online browser for results. We demonstrate dynamic changes in brain connectivity over the timescales of days to months, and relations between brain connectivity, gene expression and metabolites. This resource can serve as a testbed to study the joint dynamics of human brain and metabolic function over time, an approach that is critical for the development of precision medicine strategies for brain disorders. PMID- 26648523 TI - Aflibercept Traps Galectin-1, an Angiogenic Factor Associated with Diabetic Retinopathy. AB - Vascular endothelial growth factor (VEGF)-A-driven angiogenesis contributes to various disorders including cancer and proliferative diabetic retinopathy (PDR). Among several VEGF-A blockers clinically used is aflibercept, a chimeric VEGFR1/VEGFR2-based decoy receptor fused to the Fc fragment of IgG1 (i.e., VEGFR1/VEGFR2-Fc). Here, we revealed a novel anti-angiogenic function for aflibercept beyond its antagonism against VEGF family members. Immunoprecipitation and mass spectrometry analyses identified galectin-1 as an aflibercept-interacting protein. Biolayer interferometry revealed aflibercept binding to galectin-1 with higher affinity than VEGFR1-Fc and VEGFR2-Fc, which was abolished by deglycosylation of aflibercept with peptide:N-glycosidase F. Retinal LGALS1/Galectin-1 mRNA expression was enhanced in vitro by hypoxic stimulation and in vivo by induction of diseases including diabetes. Galectin-1 immunoreactivity co-localized with VEGFR2 in neovascular tissues surgically excised from human eyes with PDR. Compared with non-diabetic controls, intravitreal galectin-1 protein levels were elevated in PDR eyes, showing no correlation with increased VEGF-A levels. Preoperative injection of bevacizumab, a monoclonal antibody to VEGF-A, reduced the VEGF-A, but not galectin-1, levels. Galectin-1 application to human retinal microvascular endothelial cells up regulated VEGFR2 phosphorylation, which was eliminated by aflibercept. Our present findings demonstrated the neutralizing efficacy of aflibercept against galectin-1, an angiogenic factor associated with PDR independently of VEGF-A. PMID- 26648524 TI - Manipulating quantum information with spin torque. AB - The use of spin torque as a substitute for magnetic fields is now well established for classical operations like the switching of a nanomagnet. What we are describing here could be viewed as an application of spin torque like effects to quantum processes involving single qubit rotations as well as two qubit entanglement. A key ingredient of this scheme is the use of a large number of itinerant electrons whose cumulative effect is to produce the desired qubit operations on static spins. Each interaction involves entanglement and collapse of wavefunctions so that the operation is only approximately unitary. However, we show that the non-unitary component of the operations can be kept below tolerable limits with proper design. As a capstone example, we present the implementation of a complete CNOT gate using the proposed spin potential based architecture, and show that the fidelity under ideal conditions can be made acceptably close to one. PMID- 26648525 TI - Zebrafish as a model system for characterization of nanoparticles against cancer. AB - Therapeutic nanoparticles (NPs) have great potential to deliver drugs against human diseases. Encapsulation of drugs in NPs protects them from being metabolized, while they are delivered specifically to a target site, thereby reducing toxicity and other side-effects. However, non-specific tissue accumulation of NPs, for example in macrophages, especially in the spleen and liver is a general problem with many NPs being developed for cancer therapy. To address the problem of non-specific tissue accumulation of NPs we describe the development of the zebrafish embryo as a transparent vertebrate system for characterization of NPs against cancer. We show that injection of human cancer cells results in tumor-like structures, and that subsequently injected fluorescent NPs, either made of polystyrene or liposomes can be imaged in real time. NP biodistribution and general in vivo properties can be easily monitored in embryos having selective fluorescent labeling of specific tissues. We demonstrate in vitro, by using optical tweezer micromanipulation, microscopy and flow cytometry that polyethylene glycol (PEG) coating of NPs decreases the level of adhesion of NPs to macrophages, and also to cancer cells. In vivo in zebrafish embryos, PEG coating resulted in longer NP circulation times, decreased macrophage uptake, and reduced adhesion to the endothelium. Importantly, liposomes were observed to accumulate passively and selectively in tumor-like structures comprised of human cancer cells. These results show that zebrafish embryo is a powerful system for microscopy-based screening of NPs on the route to preclinical testing. PMID- 26648526 TI - Low-Temperature, Dry Transfer-Printing of a Patterned Graphene Monolayer. AB - Graphene has recently attracted much interest as a material for flexible, transparent electrodes or active layers in electronic and photonic devices. However, realization of such graphene-based devices is limited due to difficulties in obtaining patterned graphene monolayers on top of materials that are degraded when exposed to a high-temperature or wet process. We demonstrate a low-temperature, dry process capable of transfer-printing a patterned graphene monolayer grown on Cu foil onto a target substrate using an elastomeric stamp. A challenge in realizing this is to obtain a high-quality graphene layer on a hydrophobic stamp made of poly(dimethylsiloxane), which is overcome by introducing two crucial modifications to the conventional wet-transfer method - the use of a support layer composed of Au and the decrease in surface tension of the liquid bath. Using this technique, patterns of a graphene monolayer were transfer-printed on poly(3,4-ethylenedioxythiophene):polystyrene sulfonate and MoO3, both of which are easily degraded when exposed to an aqueous or aggressive patterning process. We discuss the range of application of this technique, which is currently limited by oligomer contaminants, and possible means to expand it by eliminating the contamination problem. PMID- 26648527 TI - Predicting cancerlectins by the optimal g-gap dipeptides. AB - The cancerlectin plays a key role in the process of tumor cell differentiation. Thus, to fully understand the function of cancerlectin is significant because it sheds light on the future direction for the cancer therapy. However, the traditional wet-experimental methods were money- and time-consuming. It is highly desirable to develop an effective and efficient computational tool to identify cancerlectins. In this study, we developed a sequence-based method to discriminate between cancerlectins and non-cancerlectins. The analysis of variance (ANOVA) was used to choose the optimal feature set derived from the g gap dipeptide composition. The jackknife cross-validated results showed that the proposed method achieved the accuracy of 75.19%, which is superior to other published methods. For the convenience of other researchers, an online web-server CaLecPred was established and can be freely accessed from the website http://lin.uestc.edu.cn/server/CalecPred. We believe that the CaLecPred is a powerful tool to study cancerlectins and to guide the related experimental validations. PMID- 26648528 TI - Intensity-modulated salvage radiotherapy with simultaneous integrated boost for local recurrence of prostate carcinoma: a pilot study on the place of PET-choline for guiding target volume delineation. AB - OBJECTIVE: The aim of this study was to report the first cases of salvage radiotherapy (RT) using the intensity-modulated radiotherapy (IMRT) with simultaneous integrated boost (SIB) targeted on choline positron emission tomography (PET) uptake in a local recurrent prostate cancer, after a radical prostatectomy. METHODS: Four patients received salvage irradiation for biochemical relapse that occurred after the initial radical prostatectomy. The relapse occurred from 10 months to 6 years with PSA levels ranging from 2.35 to 4.86 ng ml(-1). For each patient, an (18)F-choline PET-CT showed a focal choline uptake in prostatic fossa, with standardized uptake value calculated on the basis of predicted lean body mass (SUL) max of 3.3-6.8. No involved lymph node or distant metastases were diagnosed. IMRT doses were of 62.7 Gy (1.9 Gy/fraction, 33 fractions), with a SIB of 69.3 Gy (2.1 Gy/fraction, 33 fractions) to a PET guided target volume. RESULTS: Acute toxicities were limited. We observed no gastrointestinal toxicity >=grade 2 and only one grade 2 genitourinary toxicity. At 1-month follow-up evaluation, no complication and a decrease in PSA level (6.8 43.8% of the pre-therapeutic level) were reported. After 4 months, a decrease in PSA level was obtained for all the patients, ranging from 30% to 70%. At a median follow-up of 15 months, PSA level was controlled for all the patients, but one of them experienced a distant lymph node recurrence. CONCLUSION: Salvage irradiation to the prostate bed with SIB guided by PET-CT is feasible, with biological efficacy and no major acute toxicity. ADVANCES IN KNOWLEDGE: IMRT with PET oriented SIB for salvage treatment of prostate cancer is possible, without major acute toxicity. PMID- 26648529 TI - TAK1 modulates satellite stem cell homeostasis and skeletal muscle repair. AB - Satellite cells are resident adult stem cells that are required for regeneration of skeletal muscle. However, signalling mechanisms that regulate satellite cell function are less understood. Here we demonstrate that transforming growth factor beta-activated kinase 1 (TAK1) is important in satellite stem cell homeostasis and function. Inactivation of TAK1 in satellite cells inhibits muscle regeneration in adult mice. TAK1 is essential for satellite cell proliferation and its inactivation causes precocious differentiation. Moreover, TAK1-deficient satellite cells exhibit increased oxidative stress and undergo spontaneous cell death, primarily through necroptosis. TAK1 is required for the activation of NF kappaB and JNK in satellite cells. Forced activation of NF-kappaB improves survival and proliferation of TAK1-deficient satellite cells. Furthermore, TAK1 mediated activation of JNK is essential to prevent oxidative stress and precocious differentiation of satellite cells. Collectively, our study suggests that TAK1 is required for maintaining the pool of satellite stem cells and for regenerative myogenesis. PMID- 26648530 TI - Can public health registry data improve Emergency Medical Dispatch? AB - BACKGROUND: Emergency Medical Dispatchers make decisions based on limited information. We aimed to investigate if adding demographic and hospitalization history information to the dispatch process improved precision. METHODS: This 30 day follow-up study evaluated time-critical emergencies in contact with the emergency phone number 112 in Denmark during 18 months. 'Time-critical' was defined as suspected First Hour Quintet (FHQ) (cardiac arrest, chest pain, stroke, difficulty breathing, trauma). The association of age, sex, and hospitalization history with adverse outcomes was examined using logistic regression. The predictive ability was assessed via area under the curve (AUC) and Hosmer-Lemeshow tests. RESULTS: Of 59,943 patients (median age 63 years, 45% female), 44-45.5% had at least one chronic condition, 3880 (6.47%) died the day or the day after (primary outcome) calling 112. Age 30-59 was associated with increased adjusted odds ratio (OR) of death on day 1 of 3.59 [2.88-4.47]. Male sex was associated with an increased adjusted OR of death on day 1 of 1.37 [1.28 1.47]. Previous hospitalization with nutritional deficiencies (adjusted OR 2.07 [1.47-2.92]) and severe chronic liver disease (adjusted OR 2.02 [1.57-2.59]) was associated with a higher risk of death. For trauma patients, the discriminative ability of the model showed an AUC of 0.74 for death on day 1. CONCLUSION: Increasing age, male sex, and hospitalization history was associated with increased risk of death on day 1 for FHQ 112 callers. Additional efforts are warranted to clarify the role for risk prediction tools in emergency medical dispatch. PMID- 26648531 TI - Astaxanthin reduces type 2 diabetic-associated cognitive decline in rats via activation of PI3K/Akt and attenuation of oxidative stress. AB - Astaxanthin (AST) is an oxygenated derivative of carotenoid, which possesses a strong antioxidant activity. AST can effectively remove active oxygen from the body, and is thus considered to have an important role in disease prevention and treatment. The present study aimed to determine the effects of AST on type 2 diabetic-associated cognitive decline (DACD) in rats. Rats were intraperitoneally injected with streptozotocin (STZ), in order to establish a model of diabetes mellitus (DM). A total of 40 rats were randomly divided into five groups: The control group, the DM group, the AST (50 mg/kg) group, the AST (100 mg/kg) group, and the AST+LY294002 group (AST, 50 mg/kg and LY, 0.25 ug/100 g). Following a 14 day treatment with AST, the body weight, blood glucose levels and cognitive function were determined. In addition, the protein expression levels of phosphatidylinositol 3-kinase (PI3K)/Akt, glutathione peroxidase and superoxide dismutase activity, glutathione and malondialdehyde content, and inducible nitric oxide synthase (iNOS), caspase-3 and caspase-9 activity were detected in the rats with DM. AST clearly augmented body weight and reduced blood glucose levels in rats with DM. Furthermore, treatment with AST significantly improved the cognitive function of rats with DM. Treatment with AST activated the PI3K/Akt pathway, and suppressed oxidative stress in the DM rats. In the cerebral cortex and hippocampus of the rats with DM, the activities of iNOS, caspase-3 and caspase-9 were markedly reduced. Furthermore, treatment with the Akt inhibitor LY294002 reduced the effectiveness of AST on DACD in rats. In conclusion, AST may reduce type 2 DACD in rats via activation of PI3K/Akt and attenuation of oxidative stress. PMID- 26648532 TI - Effects of trophic status on microcystin production and the dominance of cyanobacteria in the phytoplankton assemblage of Mediterranean reservoirs. AB - The aim of our study was to evaluate the abundance of cyanobacteria and microcystins in four Sardinian reservoirs (Italy) characterised by different trophic status to define a reference picture for future changes. Increasing levels of eutrophication and the abundance of cyanobacteria are expected to occur due to climate change, especially in the southern Mediterranean. Consequently, an in-depth study of the occurrence of harmful cyanobacteria is important to develop appropriate management strategies for water resources at a local scale. Monthly samples were collected at one station in each reservoir over an 18-month period. The Analysis of similarity indicated that cyanobacterial abundance and species composition differed significantly among the reservoirs. The Redundancy analysis highlighted their relationship to trophic, hydrological and seasonal patterns. Spearman's analysis indicated that there were significant correlations among the most important species (Planktothrix agardhii-rubescens group, Aphanizomenon flos aquae and Dolichospermum planctonicum), nutrients and microcystins. We highlighted that the species composition during periods of maximum microcystin concentrations differed from those typically reported for other Mediterranean sites. We found new potential microcystin producers (Aphanizomenon klebahnii, Dolichospermum macrosporum and Dolichospermum viguieri), which emphasised the high diversity of cyanobacteria in the Mediterranean area and the need for detailed research at the local scale. PMID- 26648533 TI - Clinical prevalence (diagnosed cases) of monoclonal gammopathy of undetermined significance in the US: estimating the burden on health care. PMID- 26648535 TI - Whole-body diffusion-weighted MRI: a new gold standard for assessing disease burden in patients with multiple myeloma? PMID- 26648534 TI - FOXM1 is a therapeutic target for high-risk multiple myeloma. AB - The transcription factor forkhead box M1 (FOXM1) is a validated oncoprotein in solid cancers, but its role in malignant plasma cell tumors such as multiple myeloma (MM) is unknown. We analyzed publicly available MM data sets and found that overexpression of FOXM1 prognosticates inferior outcome in a subset (~15%) of newly diagnosed cases, particularly patients with high-risk disease based on global gene expression changes. Follow-up studies using human myeloma cell lines (HMCLs) as the principal experimental model system demonstrated that enforced expression of FOXM1 increased growth, survival and clonogenicity of myeloma cells, whereas knockdown of FOXM1 abolished these features. In agreement with that, constitutive upregulation of FOXM1 promoted HMCL xenografts in laboratory mice, whereas inducible knockdown of FOXM1 led to growth inhibition. Expression of cyclin-dependent kinase 6 (CDK6) and NIMA-related kinase 2 (NEK2) was coregulated with FOXM1 in both HMCLs and myeloma patient samples, suggesting interaction of these three genes in a genetic network that may lend itself to targeting with small-drug inhibitors for new approaches to myeloma therapy and prevention. These results establish FOXM1 as high-risk myeloma gene and provide support for the design and testing of FOXM1-targeted therapies specifically for the FOXM1(High) subset of myeloma. PMID- 26648536 TI - Calcineurin and GSK-3 inhibition sensitizes T-cell acute lymphoblastic leukemia cells to apoptosis through X-linked inhibitor of apoptosis protein degradation. AB - The calcineurin (Cn)-nuclear factor of activated T cells signaling pathway is critically involved in many aspects of normal T-cell physiology; however, its direct implication in leukemogenesis is still ill-defined. Glycogen synthase kinase-3beta (GSK-3beta) has recently been reported to interact with Cn in neuronal cells and is implicated in MLL leukemia. Our biochemical studies clearly demonstrated that Cn was able to interact with GSK-3beta in T-cell acute lymphoblastic leukemia (T-ALL) cells, and that this interaction was direct, leading to an increased catalytic activity of GSK-3beta, possibly through autophosphorylation of Y216. Sensitivity to GSK-3 inhibitor treatment correlated with altered GSK-3beta phosphorylation and was more prominent in T-ALL with Pre/Pro immunophenotype. In addition, dual Cn and GSK-3 inhibitor treatment in T ALL cells promoted sensitization to apoptosis through proteasomal degradation of X-linked inhibitor of apoptosis protein (XIAP). Consistently, resistance to drug treatments in primary samples was strongly associated with higher XIAP protein levels. Finally, we showed that dual Cn and GSK-3 inhibitor treatment in vitro and in vivo is effective against available models of T-ALL, indicating an insofar untapped therapeutic opportunity. PMID- 26648537 TI - A progression-risk score to predict treatment-free survival for early stage chronic lymphocytic leukemia patients. PMID- 26648538 TI - Age-related mutations and chronic myelomonocytic leukemia. AB - Chronic myelomonocytic leukemia (CMML) is a hematologic malignancy nearly confined to the elderly. Previous studies to determine incidence and prognostic significance of somatic mutations in CMML have relied on candidate gene sequencing, although an unbiased mutational search has not been conducted. As many of the genes commonly mutated in CMML were recently associated with age related clonal hematopoiesis (ARCH) and aged hematopoiesis is characterized by a myelomonocytic differentiation bias, we hypothesized that CMML and aged hematopoiesis may be closely related. We initially established the somatic mutation landscape of CMML by whole exome sequencing followed by gene-targeted validation. Genes mutated in ?10% of patients were SRSF2, TET2, ASXL1, RUNX1, SETBP1, KRAS, EZH2, CBL and NRAS, as well as the novel CMML genes FAT4, ARIH1, DNAH2 and CSMD1. Most CMML patients (71%) had mutations in ?2 ARCH genes and 52% had ?7 mutations overall. Higher mutation burden was associated with shorter survival. Age-adjusted population incidence and reported ARCH mutation rates are consistent with a model in which clinical CMML ensues when a sufficient number of stochastically acquired age-related mutations has accumulated, suggesting that CMML represents the leukemic conversion of the myelomonocytic-lineage-biased aged hematopoietic system. PMID- 26648539 TI - Suppression of HSP27 increases the anti-tumor effects of quercetin in human leukemia U937 cells. AB - Quercetin, a natural flavonoid, inhibits the growth of leukemia cells and induces apoptosis. Heat shock protein 27 (HSP27) has been reported to promote the development of leukemia by protecting tumor cells from apoptosis through various mechanisms. The present study investigated the effects of small hairpin (sh)RNA mediated HSP27 knockdown on the anti-cancer effects of quercetin in U937 human leukemia cells. Cells were transfected with recombinant lentiviral vector pCMV-G NR-U6-shHSP27 (shHSP27), which expressed shRNA specifically targeting the HSP27 gene, alone or in combination with quercetin. The results showed that shHSP27 and quercetin synergistically inhibited U937 cell proliferation and induced apoptosis by decreasing the Bcl2-to-Bax ratio. Furthermore, this combined treatment significantly suppressed the infiltration of tumor cells and the expression of angiogenesis-associated proteins HIF1alpha and VEGF. Compared with shHSP27 or quercetin alone, shHSP27 plus quercetin markedly decreased the protein expression of cyclinD1 and thus blocked the cell cycle at G1 phase. The Notch/AKT/mTOR signaling pathway is important in tumor aggressiveness; quercetin plus shHSP27 significantly decreased Notch 1 expression and the phosphorylation levels of the downstream signaling proteins AKT and mTOR. The inhibitory effects of quercetin plus shHSP27 on this pathway may thus have been responsible for the cell cycle arrest, inhibition of proliferations and infiltration as well as enhancement of apoptosis. Therefore, these findings collectively suggested that suppression of HSP27 expression amplified the anti-cancer effects of quercetin in U937 human leukemia cells, and that quercetin in combination with shHSP27 represents a promising therapeutic strategy for human leukemia. PMID- 26648540 TI - Dickkopf Wnt signaling pathway inhibitor 1 regulates the differentiation of mouse embryonic stem cells in vitro and in vivo. AB - Embryonic stem cells (ESCs) are pluripotent stem cells derived from early stage embryos. It remains unclear whether inhibiting the Wnt/beta-catenin signaling pathway using dickkopf Wnt signaling pathway inhibitor 1 (DKK1) impacts on the differentiation potential of mouse ESCs in vitro and in vivo. In the present study, immunohistochemical staining was used to measure the expression of markers of the three germ layers in ESCs and teratomas derived from ESCs. The expression of markers for the Wnt/beta-catenin signaling pathway were detected by reverse transcription-polymerase chain reaction (RT-qPCR). Immunohistochemistry and western blotting indicated that the expression levels of octamer-binding transcription factor 4 in the DKK1-treated ESC group were significantly greater compared with the control ESCs. Reduced expression levels of NeuroD and bone morphogenetic protein 4 were observed in the DKK1-treated ESCs and teratomas derived from DKK1-treated ESCs compared with the control group. Increased expression levels of SOX17 were observed in the DKK1-treated ESCs compared with the control group. RT-qPCR indicated that beta-catenin expression was significantly reduced in DKK1-treated ESCs and teratomas derived from DKK1 treated ESCs compared with the control groups. Western blotting indicated no alterations in the expression of GSK-3beta, however, the levels of phosphorylated GSK-3beta were significantly greater in the DKK1 treatment groups, while cyclin D1 and c-Myc expression levels were significantly reduced in the DKK1 treatment groups compared with the control groups. These results suggest that inhibiting Wnt signaling in ESCs using DKK1 may promote mouse ESCs to differentiate into endoderm in vitro and in vivo, and suppress the tumorigenicity of ESCs. PMID- 26648541 TI - Soil-vegetation relationships on a banded ironstone 'island', Carajas Plateau, Brazilian Eastern Amazonia. AB - Vegetation and soil properties of an iron-rich canga (laterite) island on the largest outcrop of banded-iron formation in Serra de Carajas (eastern Amazonia, Brazil) were studied along a topographic gradient (738-762 m asl), and analyzed to test the hypothesis that soil chemical and physical attributes play a key role in the structure and floristic composition of these plant communities. Soil and vegetation were sampled in eight replicate plots within each of the four vegetation types. Surface (0-10 cm) soil samples from each plot were analyzed for basic cations, N, P and plant species density for all species was recorded. CCA ordination analysis showed a strong separation between forest and non-forest sites on the first axis, and between herbaceous and shrubby campo rupestre on the second axis. The four vegetation types shared few plant species, which was attributed to their distinctive soil environments and filtering of their constituent species by chemical, physical and hydrological constraints. Thus, we can infer that Edaphic (pedological) factors are crucial in explaining the types and distributions of campo rupestre vegetation associated with ferruginous ironstone uplands (Canga) in Carajas, eastern Amazonia, therefore the soil properties are the main drivers of vegetation composition and structure on these ironstone islands. PMID- 26648542 TI - Theoretical approach of the main means of appeals in the European procedural law. AB - Knowledge and understanding the means of appeals lodged before the courts of the European Union, limited only to the points of law, are very important taking into account the modality to control a judgment delivered by an inferior court exists since ancient times, being governed among others, by the Larin principle: res judicata pro veritate accipitur. In the following we will examine, in general, the judicial control of the judgments and orders delivered by the General Court and by the Civil Service Tribunal, as a specialized tribunal on civil servant issues, but also the sui generis means of appeals and the extraordinary means of reviews of the judgments and orders. We shall mention that all of them are exercised in accordance with the Rules of Procedure of the European courts and the Statute of the Court of Justice of the European Union. Another aspect to be mentioned is that the judjments of the Court of Justice cannot be challenged to another court, as they remain final and irrevocable. PMID- 26648543 TI - Campomanesia adamantium (Cambess.) O. Berg seed desiccation: influence on vigor and nucleic acids. AB - The aim of this study was to evaluate the sensitivity of Campomanesia adamantium seeds to desiccation by drying in activated silica gel (fast) and under laboratory conditions (slow). To assess the sensitivity of the seeds to desiccation, we used drying with silica gel and drying under laboratory conditions (25 degrees C), in order to obtain seeds with moisture content of 45, 35, 30, 25, 20, 15, 10 and 5%. The physiological potential of the seeds after desiccation was evaluated by measuring primary root protrusion, percentage of normal seedlings, germination seed index, seedling length, total seedling dry mass, electrical conductivity and DNA and RNA integrities. The C. adamantium seeds were sensitive to desiccation and to a reduction in moisture content to 21.1% or less by desiccation using silica gel, and to 17.2% or less by desiccation under laboratory conditions; impairment of the physiological potential of the seeds was observed at these low moisture content levels. The integrity of the seed genomic DNA was not affected after drying seeds in the two methods. However, drying in silica gel to 4.5% moisture content and drying under laboratory conditions to 5.4% moisture content resulted in the loss of seed RNA integrity. PMID- 26648544 TI - Meniscal allograft transplantation in rabbit. AB - This study evaluated the technique for meniscal allograft transplantation using allografts preserved in glycerin 98% in rabbits. Euthanasia was performed at 70 days to compare the transplanted (TM1 to TM16) versus the contralateral meniscus (OM1 to OM16). Sixteen menisci, 8 transplanted and 8 contralateral, were submitted to gross examination, histomorphometric analysis for identification and quantification of cellular type, and for quantification and distribution of collagen fibers. A revascularization study was conducted in all of the other samples. Lengths of the OM varied from 0.9 to 1.0 cm and two TM were smaller. All TM were completely attached to the synovial membrane, except for one case that presented partial fixation. Both, TM and OM had similar amounts of chondrocytes, fibroblasts and fibrocytes, and at the horns, chondrocytes were predominant. The collagen fibers in TM were well organized throughout the body, and disorganized at the horns. These fibers in OM were organized. The amounts of collagen type I and III, and the vascularization of the perimeniscal tissue and of the edge were similar in OM and TM. These results demonstrated graft integration and thus this transplantation technique and preservation method may be recommended. PMID- 26648545 TI - Periodic solutions of Lienard differential equations via averaging theory of order two. AB - For epsilon ? 0 sufficiently small we provide sufficient conditions for the existence of periodic solutions for the Lienard differential equations of the form x'' + f ?(x)? x' + n2?x + g (x) = epsilon2p1 ?(t) + epsilon3 ?p2(t), where n is a positive integer, f : R -> R is a C 3 function, g : R -> R is a C 4 function, and p i : R -> R for i = 1, 2 are continuous 2pi-periodic function. The main tool used in this paper is the averaging theory of second order. We also provide one application of the main result obtained. PMID- 26648546 TI - Contributions to the Dart versus Arrow Debate: New Data from Holocene Projectile Points from Southeastern and Southern Brazil. AB - Lithic bifacial points are very common in the southern and southeastern regions of the Brazilian territory. Dated from Early to Late Holocene, these artifacts have not been studied in terms of their propulsion system. Given the characteristics of the bow and arrow compared to the atlatl and dart, there are important differences in the size and weight of arrowheads and dart points. Applying the techniques proposed by Shott (1997), Bradbury (1997), Fenenga (1953), Hughes (1998), and Hildebrandt and King (2012) to specimens recovered from eight sites dating from the early to the late Holocene, this work aims to present preliminary results to better understand the potential presence of darts and arrows in southeastern and southern Brazil. There was a variation in the results according to the application of different techniques. At least one set of points, dated from the Early Holocene, presented quite a high proportion of specimens classified as arrows, indicating the presence of points that could be used as arrowheads. PMID- 26648547 TI - RhoA is associated with invasion and poor prognosis in colorectal cancer. AB - Colorectal cancer is one of the most common cancers and is the fourth leading cause of cancer death in Korea. Mortality of colorectal cancer is strongly associated with the metastatic spread of the disease. As such, it is important to find and characterize signaling pathways involved in colon cancer metastasis. We investigated the functional importance of RhoA using human cell lines as well as 150 colorectal cancer patient-derived samples as it remains unclear whether RhoA functions as either an oncogene or a tumor suppressor in colon cancer. RhoA was highly expressed in metastatic cancer cell lines. Although cancer cell proliferation was only moderately impaired after depletion of RhoA, RhoA-depleted cancer cells exhibited markedly reduced migration and invasion ability in vitro. Furthermore, we found that RhoA is associated with the invasion of lymph nodes and blood vessels in the patient colorectal cancer samples. Most notably, patients with higher RhoA expression had a significantly poorer 5-year survival rate after surgery. These results suggest that RhoA is a marker of poor prognosis in colorectal cancer and may be a promising target for cancer treatment. PMID- 26648549 TI - Unfavorable Individuals in Social Gaming Networks. AB - In social gaming networks, the current research focus has been on the origin of widespread reciprocal behaviors when individuals play non-cooperative games. In this paper, we investigate the topological properties of unfavorable individuals in evolutionary games. The unfavorable individuals are defined as the individuals gaining the lowest average payoff in a round of game. Since the average payoff is normally considered as a measure of fitness, the unfavorable individuals are very likely to be eliminated or change their strategy updating rules from a Darwinian perspective. Considering that humans can hardly adopt a unified strategy to play with their neighbors, we propose a divide-and-conquer game model, where individuals can interact with their neighbors in the network with appropriate strategies. We test and compare a series of highly rational strategy updating rules. In the tested scenarios, our analytical and simulation results surprisingly reveal that the less-connected individuals in degree-heterogeneous networks are more likely to become the unfavorable individuals. Our finding suggests that the connectivity of individuals as a social capital fundamentally changes the gaming environment. Our model, therefore, provides a theoretical framework for further understanding the social gaming networks. PMID- 26648550 TI - Correction: HIV microarray for the mapping and characterization of HIV-specific antibody responses. AB - Correction for 'HIV microarray for the mapping and characterization of HIV specific antibody responses' by Daniela Gallerano et al., Lab Chip, 2015, 15, 1574-1589. PMID- 26648551 TI - [Corrigendum] Naotaifang extract treatment results in increased ferroportin expression in the hippocampus of rats subjected to cerebral ischemia. PMID- 26648548 TI - Experience-dependent emergence of beta and gamma band oscillations in the primary visual cortex during the critical period. AB - Neural oscillatory activities have been shown to play important roles in neural information processing and the shaping of circuit connections during development. However, it remains unknown whether and how specific neural oscillations emerge during a postnatal critical period (CP), in which neuronal connections are most substantially modified by neural activity and experience. By recording local field potentials (LFPs) and single unit activity in developing primary visual cortex (V1) of head-fixed awake mice, we here demonstrate an emergence of characteristic oscillatory activities during the CP. From the pre-CP to CP, the peak frequency of spontaneous fast oscillatory activities shifts from the beta band (15-35 Hz) to the gamma band (40-70 Hz), accompanied by a decrease of cross frequency coupling (CFC) and broadband spike-field coherence (SFC). Moreover, visual stimulation induced a large increase of beta-band activity but a reduction of gamma-band activity specifically from the CP onwards. Dark rearing of animals from the birth delayed this emergence of oscillatory activities during the CP, suggesting its dependence on early visual experience. These findings suggest that the characteristic neuronal oscillatory activities emerged specifically during the CP may represent as neural activity trait markers for the experience dependent maturation of developing visual cortical circuits. PMID- 26648552 TI - c-Jun N-terminal kinase inhibitor favors transforming growth factor-beta to antagonize hepatitis B virus X protein-induced cell growth promotion in hepatocellular carcinoma. AB - Transforming growth factor (TGF)-beta induces cell growth arrest in well differentiated hepatocellular carcinoma (HCC) while hepatitis B virus X protein (HBx) minimizes the tumor suppression of TGF-beta signaling in early chronic hepatitis B. However, how to reverse the oncogenic effect of HBx and sustain the tumor-suppressive action of TGF-beta has yet to be investigated. The present study examined the effect of TGF-beta and a c-Jun N-terminal kinase (JNK) inhibitor on cell growth in HCC cells with forced expression of HBx. It was found that HBx promoted cell growth via activation of the JNK/pSMAD3L pathway and inhibition of the transforming growth factor-beta type I receptor (TbetaRI)/pSMAD3C pathway. pSMAD3L/SMAD4 and pSMAD3C/SMAD4 complexes antagonized each other to regulate c-Myc expression. In the absence of HBx, TGF-beta induced cell growth arrest through activation of the TbetaRI/pSMAD3C pathway in well differentiated HCC cells. In the presence of HBx, TGF-beta had no effect on cell growth. JNK inhibitor SP600125 significantly reversed the oncogenic action of HBx and favored TGF-beta to regain the ability to inhibit the cell growth in HBx expressing well-differentiated HCC cells. In conclusion, targeting JNK signaling favors TGF-beta to block HBx-induced cell growth promotion in well-differentiated HCC cells. As an adjunct to anti-viral therapy, the combination of TGF-beta and inhibition of JNK signaling is a potential therapy for HBV-infected HCC. PMID- 26648553 TI - Characterization of mitochondrial NADH dehydrogenase 1alpha subcomplex 10 variants in cardiac muscles from normal Wistar rats and spontaneously hypertensive rats: Implications in the pathogenesis of hypertension. AB - Mitochondrial dysfunction has been increasingly associated with the development of cardiovascular diseases, including hypertension and cardiac hypertrophy. In the present study, NADH dehydrogenase 1alpha subcomplex 10 (Ndufa10) was characterized from the left ventricular muscles of spontaneously hypertensive rats (SHRs) and normal Wistar Kyoto (WKY) rats. Western blot analysis demonstrated that there was a shift in the molecular weight (MW) and in the isoelectric point (pI) of the Ndufa10 protein from SHRs and WKY rats. Mass spectrometric analysis revealed that the replacement of an aspartate residue with asparagine at amino acid position 120 was the biochemical difference between the two Ndufa10 isoforms. Further analysis using the bacterially expressed proteins Ndufa10-120N (WKY) and Ndufa10-120D (SHR) revealed that the shift in the pI and MW of the two Ndufa10 isoforms was solely caused by the amino acid mutation, and not by post-translational modifications. Since deficiencies of the mitochondrial complex I are the most common defects in the oxidative phosphorylation system, further studies are required to study the difference between the activities of the two Ndufa10 variants, and their role in the pathogenesis of hypertension. PMID- 26648554 TI - Hierarchical NiMoO4 nanowire arrays supported on macroporous graphene foam as binder-free 3D anodes for high-performance lithium storage. AB - Novel three-dimensional (3D) NiMoO4 nanowire arrays (NWAs) grown directly onto the surface of macroporous graphene foams (GF) with robust adhesion were synthesized via a facile chemical vapor deposition (CVD) and subsequent hydrothermal route. The as-prepared NiMoO4 nanowires are composed of ultra-small nanoparticles (~5 nm) with a diameter of 70-150 nm and are several micrometers in length. Such as-grown NiMoO4 NWA/3DGF composites are then evaluated as monolithic electrodes for lithium-ion batteries (LIBs) without the need of binders or metal based current collectors. Benefitting from the unique three-dimensional arrayed architecture and characteristics with a high specific surface area and more active sites which facilitate fast electron and ionic transport within the electrode, the NiMoO4 NWA/GF composites deliver a high reversible specific capacity of 1088.02 mA h g(-1) at a current density of 200 mA g(-1) and 867.86 mA h g(-1) after 150 cycles (79.77% retention of the second cycle), and excellent rate capability. With the advantages of excellent electrochemical performance and a facile synthesis method, the NiMoO4 nanowire arrays supported on 3DGF exhibit great potential as anode materials for LIBs. PMID- 26648555 TI - Oceanic source strength of carbon monoxide on the basis of basin-wide observations in the Atlantic. AB - We measured the carbon monoxide (CO) concentrations in the marine boundary layer and the surface waters of the Atlantic Ocean from 50 degrees N to 50 degrees S during the UK Atlantic Meridional Transect expedition (AMT-7) in October 1998, covering the open ocean and coastal regions. Throughout the cruise track, atmospheric CO concentrations continually decreased southwards in the northern hemisphere with sporadic low and high concentrations encountered. South of the intertropical convergence zone (ITCZ) atmospheric CO was enhanced by ~10 ppb compared to north of the ITCZ due likely to biomass burning emissions prevailing in the tropical continents. The remainder of the southern hemisphere remains nearly invariable except for the vicinity of Rio de la Plata. The surface seawater was supersaturated everywhere along the track and its saturation anomaly oscillated up to 90, exhibiting a typical diurnal cycle. The maximal dissolved CO concentration in the diurnal cycle appeared 2-5 hours behind the local maximum of solar insolation in the open ocean and the time lag further increased in the coastal region. The global ocean flux of CO to the atmosphere was estimated to be 14 Tg(CO) a(-1) within the range of 4-24 Tg(CO) a(-1). This is within uncertainty almost identical to what was estimated on the basis of the basin-wide observations in the Pacific and the Atlantic, but more than ~4 times lower than the values appeared in the Intergovernmental Panel on Climate Change (IPCC) reports. PMID- 26648556 TI - Reactive electrospinning of degradable poly(oligoethylene glycol methacrylate) based nanofibrous hydrogel networks. AB - A direct, all-aqueous electrospinning method for fabricating degradable nanofibrous hydrogel networks is reported in which hydrazide and aldehyde functionalized poly(oligoethylene glycol methacrylate) (POEGMA) polymers are simultaneously electrospun and cross-linked. The resulting networks are spatially well-defined, mechanically stable (both dry and wet), and offer extremely fast swelling responses, suggesting potential utility as smart hydrogels and tunable tissue engineering matrices. PMID- 26648557 TI - Quantitative phase imaging in biomedicine. PMID- 26648558 TI - Pre-deployment Heat Acclimatization Guidelines for Disaster Responders. AB - INTRODUCTION: Minimal preparation time is a feature of responding to sudden onset disasters. While equipment and supplies are prepared for deployment at short notice, less is known of the physical preparation of medical responders. With many disaster-prone areas classified as tropical regions, there is potential for responders to endure a combination of high ambient temperatures and relative humidity during deployment. Heat acclimatization, defined as the physiological and perceptual adaptations to frequent elevations of core body temperature (Tc), is a key strategy to improve tolerance of hot conditions by medical responders. METHODS: Pre-deployment heat acclimatization guidelines were developed based upon the duration of physical training and the subjective rate of perceived exertion (session RPE). An objective of individual training sessions was the perception of body temperature as warm to hot. The guidelines were implemented for Team Bravo (2nd rotation) of the Australian Medical Assistance Team (AusMAT) deployed to Tacloban, Philippines following Typhoon Haiyan in November 2013. The guidelines were distributed electronically five to seven days prior to deployment and were followed by a consultation. A group training session in hot conditions was undertaken prior to departure. RESULTS: The AusMAT responders to utilize the guidelines were based in cool or temperate climates that required extra layers of clothing, training during warmer parts of the days, or warm indoor conditions to achieve session objectives. Responders reported the guidelines were simple to use, applicable to their varied training regimens, and had improved their confidence to work in the heat despite not completing the entire 14 day period. CONCLUSION: The pre-deployment heat acclimatization guidelines provided AusMAT responders the ability to quantify their physical training and promoted physiological adaptations to maximize health, safety, and performance during deployment. While maintaining year-round heat acclimatization is considered essential for medical responders, these guidelines may facilitate beneficial adaptations once notified of deployment. PMID- 26648559 TI - Phase transition metal-crown ether coordination compounds tuned by metal ions. AB - Two isostructural metal crown ether coordination compounds, (15-crown-5)(BiCl3) 1 and (15-crown-5)(SbCl3) 2, are discovered to show phase transitions above room temperature, where the phase transition temperature relates to the metal center. Compound 1 crystallizes in the chiral orthorhombic space group P212121 in the low temperature phase and undergoes a reversible phase transition around 365 K to crystallize in the polar orthorhombic space group Pna21 in the high temperature phase, accompanied by thermal and dielectric anomalies. The variable-temperature structure analyses of compound 1 show that the phase transition is rooted in the conformational change of the crown ether and the displacement of the Bi cation and Cl anion. PMID- 26648560 TI - Connexin43 knockdown in bone marrow-derived dendritic cells by small interfering RNA leads to a diminished T-cell stimulation. AB - Dendritic cells, the most powerful type of antigen-presenting cells, have the unique ability to induce primary immune responses. Connexin43 expression is upregulated to increase gap junctions when immune cells are exposed to inflammatory factors. The present study applied small-interfering RNA (siRNA) to decrease connexin43 expression. The results showed that silencing of connexin43 using siRNA resulted in arrest of bone marrow-derived dendritic cell (BM-DC) maturation as evidenced by reduced expression of major histocompatibility complex II, CD40, CD80 and CD86. Functionally, connexin43-silenced BM-DC showed a markedly decreased capability to induce T-cell stimulation. In conclusion, the present study demonstrated that antigens present on BM-DCs can be suppressed by connexin43 knockdown in BM-DCs. The present study therefore presented an effective method to modulate the immunology of BM-DCs. PMID- 26648561 TI - Systematic and comprehensive investigation of the toxicity of curcuminoid essential oil complex: A bioavailable turmeric formulation. AB - Curcumin, the active component present in Curcuma longa of the family Zingiberaceae, has a number of pharmacological effects, including potential anti inflammatory activity. One of the major limitations of curcumin/turmeric extract is its poor absorption through the gastrointestinal tract. Several approaches have been adopted to increase the bioavailability of curcumin, including loading curcumin into liposomes or nanoparticles, complexation with phospholipids, addition of essential oils and synthesizing structural analogues of curcumin. In the present study, the toxicity and safety of one such bioavailable turmeric formulation, curcuminoid-essential oil complex (CEC), the toxicity profile of which has not been reported, were examined using in vivo and in vitro models, as per the guidelines of the Organisation for Economic Co-operation and Development. Investigations of acute toxicity study were performed in rats and mice, and the results revealed no signs and symptoms or toxicity or mortality in any of the animals at the maximum recommended dose level of 5,000 mg/kg body weight. The repeated administration of CEC for 90 days in Wistar rats at a dose of 1,000 mg/kg body weight did not induce any observable toxic effects, compared with corresponding control animals. Mutagenicity/genotoxicity investigations were also performed using a bacterial reverse mutation assay (Ames test), a mammalian bone marrow chromosome aberration test and a mammalian erythrocyte micronucleus test in mice. CEC was found to be non-mutagenic in all three mutagenic investigations. Consequently, the present study indicated that CEC elicited no toxic effects in animals or in vitro. Therefore, following investigations of acute toxicity, repeated dose toxicity and mutagenicity, CEC was deemed a safe, non-toxic pharmacological formulation. PMID- 26648562 TI - EGCG attenuates atherosclerosis through the Jagged-1/Notch pathway. AB - Atherosclerosis is the most common cause of cardiovascular diseases worldwide. Oxidized low-density lipoprotein (ox-LDL) is a particularly important risk factor in the pathogenesis of atherosclerosis. Accumulating evidence has indicated that epigallocatechin-3-gallate (EGCG; a catechin found in the popular beverage, greent tea) protects against ox-LDL-induced atherosclerosis. However, the underlying mechanisms remain unclear. In the present study, ox-LDL (100 mg/l) induced damage to, and the apoptosis of human umbilical vein endothelial cells (HUVECs) by reducing endothelial nitric oxide synthase (eNOS) expression and promoting inducible nitric oxide synthase (iNOS) expression; these effects were abrogated by the addition of 50 uM EGCG. Furthermore, ox-LDL rapidly activated the membrane translocation of p22phox, and altered the protein expression of Jagged-1 and Notch pathway-related proteins [Math1, hairy and enhancer of split (HES)1 and HES5]; these effects were also prevented by pre-treatment with 50 uM EGCG. In addition, Jagged-1 played a significant role in the EGCG-mediated protection against ox-LDL-induced apoptosis and ox-LDL-diminished cell adhesion in the HUVECs. Finally, EGCG inhibited high-fat diet (HFD)-induced atherosclerosis in apolipoprotein E (ApoE) knockout (ApoE-KO) mice through the Jagged-1/Notch pathway. Taken together, these findings demonstrate that 50 uM EGCG protects against ox-LDL-induced endothelial dysfunction through the Jagged 1/Notch signaling pathway. Moreover, our data provide insight into the possible molecular mechanisms through which EGCG attenuates ox-LDL-induced vascular endothelial dysfunction. PMID- 26648563 TI - Task analysis of laparoscopic camera control schemes. AB - BACKGROUND: Minimally invasive surgeries rely on laparoscopic camera views to guide the procedure. Traditionally, an expert surgical assistant operates the camera. In some cases, a robotic system is used to help position the camera, but the surgeon is required to direct all movements of the system. Some prior research has focused on developing automated robotic camera control systems, but that work has been limited to rudimentary control schemes due to a lack of understanding of how the camera should be moved for different surgical tasks. METHODS: This research used task analysis with a sample of eight expert surgeons to discover and document several salient methods of camera control and their related task contexts. RESULTS: Desired camera placements and behaviours were established for two common surgical subtasks (suturing and knot tying). CONCLUSION: The results can be used to develop better robotic control algorithms that will be more responsive to surgeons' needs. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26648564 TI - Emission color-tuned light-emitting diode microarrays of nonpolar In(x)Ga(1 x)N/GaN multishell nanotube heterostructures. AB - Integration of nanostructure lighting source arrays with well-defined emission wavelengths is of great importance for optoelectronic integrated monolithic circuitry. We report on the fabrication and optical properties of GaN-based p-n junction multishell nanotube microarrays with composition-modulated nonpolar m plane InxGa1-xN/GaN multiple quantum wells (MQWs) integrated on c-sapphire or Si substrates. The emission wavelengths were controlled in the visible spectral range of green to violet by varying the indium mole fraction of the InxGa1-xN MQWs in the range 0.13 <= x <= 0.36. Homogeneous emission from the entire area of the nanotube LED arrays was achieved via the formation of MQWs with uniform QW widths and composition by heteroepitaxy on the well-ordered nanotube arrays. Importantly, the wavelength-invariant electroluminescence emission was observed above a turn-on of 3.0 V because both the quantum-confinement Stark effect and band filling were suppressed due to the lack of spontaneous inherent electric field in the m-plane nanotube nonpolar MQWs. The method of fabricating the multishell nanotube LED microarrays with controlled emission colors has potential applications in monolithic nonpolar photonic and optoelectronic devices on commonly used c-sapphire and Si substrates. PMID- 26648565 TI - Knockdown of NogoA prevents MPP+-induced neurotoxicity in PC12 cells via the mTOR/STAT3 signaling pathway. AB - NogoA is a myelin-associated protein, which is important in the inhibition of axonal fiber growth and in regeneration following injury of the mammalian central nervous system. A previous study suggested that NogoA may be key in the process of Parkinson's disease (PD), which is the second most common chronic neurodegenerative disorder worldwide. The regulatory mechanism underlying the effect of NogoA on the process of PD remains to be fully elucidated. The present study aimed to investigate the effect and underlying mechanism of NogoA on cellular viability, apoptosis and autophagy induced by 1-methyl-4 phenylpyridinium (MPP+) in PC12 cells, a commonly used in vitro PD model. PC12 cells were treated with 1 mM MPP+ for 24 h and the cells were harvested for western blotting. The results demonstrated that the protien expression levels of NogoA were increased in the PC12 cells treated with MPP+. Subsequently, NogoA small interfering RNA was synthesized and transfected into PC12 cells to silence the expression of NogoA. NogoA knockdown significantly reduced the MPP+-induced decrease in cell viability and apoptosis, detected using a cell counting kit-8 and flow cytometric analysis, respectively. Interference in the expression of NogoA increased the MPP+-induced decrease in mitochondrial membrane potential, determined quantitatively by flow cytometry using JC-1 dye, and the protein levels of Beclin-1. In addition, MPP+ treatment activated the mammalian target of rapamycin (mTOR)/signal transducer and activator of transcription 3 (STAT3) signaling pathway. Knockdown of NogoA significantly inhibited the expression levels of mTOR and STAT3. Furthermore, overexpression of NogoA had similar neurotoxic effects on the PC12 cells as MPP+ treatment. Treatment with rapamycin, an inhibitor of the mTOR/STAT3 signaling pathway had a similar effect to that of NogoA knockdown in the MPP+-treated PC12 cells. Taken together, the results from the present study demonstrated that NogoA may regulate MPP+-induced neurotoxicity in PC12 cells via the mTOR/STAT3 signaling pathway and provided an explanation regarding the regulatory mechanism of NogoA on the process of PD. PMID- 26648566 TI - The challenges of leading change in health-care delivery from the front-line. AB - AIM: The public sector is facing turbulent times and this challenges nurses, who are expected to serve both patient interests and the efficiency drives of their organisations. In the context of implementing person-centred health policy, this paper explores the evolving role of front-line nurses as leaders and champions of change. BACKGROUND: Nurses can be seen to have some autonomy in health-care delivery. However, they are subject to systems of social control. In implementing person-centred policy, nurses can be seen to be doing the best they can within a constrained environment. METHOD: A survey of nursing practice in person-centred health-policy implementation is presented. FINDINGS: Despite much being written about managing health-professional resistance to policy implementation, there is a gap between what is being asked of nurses and the resources made available to them to deliver. In this milieu, nurses are utilising their discretion and leading from the front-line in championing change. CONCLUSIONS: Empowering nurses who seek to lead patient involvement could be the key to unlocking health-care improvement. IMPLICATIONS FOR NURSING MANAGEMENT: Health services tend to be over managed and under-led and there is a need to harness the potential of front-line nurses by facilitating leadership development through appropriate organisational support. PMID- 26648567 TI - Protective effect of C4a against hyperoxic lung injury via a macrophage-dependent but not a neutrophil/lymphocyte-dependent signaling pathway. AB - Complement anaphylatoxins have been investigated extensively; however, the role of complement anaphylatoxin C4a in hyperoxic lung injury has yet to be investigated. To the best of our knowledge, the present study is the first to demonstrate the role of C4a in hyperoxic lung injury in vitro and in vivo. BALB/c mice were ventilated with 100% oxygen with or without C4a treatment for 36 h. The body weight and the relative lung weight of the mice were determined, along with any morphological changes in the lung. The expression levels of interleukin (IL) 1, IL-6 and tumor necrosis factor-alpha (TNF-alpha) were quantified in the lung tissue and bronchoalveolar lavage fluid (BALF) samples by enzyme-linked immunosorbent assay (ELISA) and western blot analysis. The total cell count and the number of macrophages, neutrophils and lymphocytes in the BALF were determined using cytocentrifuge slides and a hemocytometer. Histamine release from total cells in the BALF was also analyzed. The relative mRNA expression levels of CD68, F4/80, CD64, CD19 and CD3 in the murine lung tissue were assessed by reverse transcription-quantitative polymerase chain reaction. The results revealed that hyperoxia induced lung injury and morphological changes, and increased the expression levels of IL-1, IL-6 and TNF-alpha, histamine release, the number of inflammatory cells, and the expression levels of CD68, F4/80, CD64, CD19 and CD3. The hyperoxia-induced morphological changes and inflammatory reaction were significantly attenuated in mice treated with C4a. Treatment with C4a also attenuated the increase in the total cell count, decreased the number of macrophages in the BALF, and suppressed the elevated mRNA expression levels of CD68 and F4/80 in the lung tissue samples. Conversely, treatment with C4a did not affect the number of neutrophils or lymphocytes in the BALF or the mRNA expression of CD64, CD19 and CD3 in lung tissue. In conclusion, C4a attenuated hyperoxic lung injury via a macrophage-dependent but not a neutrophil/lymphocyte dependent pathway. PMID- 26648568 TI - Rapid Effects of an Aggressive Interaction on Dehydroepiandrosterone, Testosterone and Oestradiol Levels in the Male Song Sparrow Brain: a Seasonal Comparison. AB - Across vertebrates, aggression is robustly expressed during the breeding season when circulating testosterone is elevated, and testosterone activates aggression either directly or after aromatisation into 17beta-oestradiol (E2 ) in the brain. In some species, such as the song sparrow, aggressive behaviour is also expressed at high levels during the nonbreeding season, when circulating testosterone is non-detectable. At this time, the androgen precursor dehydroepiandrosterone (DHEA) is metabolised within the brain into testosterone and/or E2 to promote aggression. In the present study, we used captive male song sparrows to test the hypothesis that an acute agonistic interaction during the nonbreeding season, but not during the breeding season, would alter steroid levels in the brain. Nonbreeding and breeding subjects were exposed to either a laboratory simulated territorial intrusion (L-STI) or an empty cage for only 5 min. Immediately afterwards, the brain was rapidly collected and flash frozen. The Palkovits punch technique was used to microdissect specific brain regions implicated in aggressive behaviour. Solid phase extraction followed by radioimmunoassay was used to quantify DHEA, testosterone and E2 in punches. Overall, levels of DHEA, testosterone and E2 were higher in brain tissue than in plasma. Local testosterone and E2 levels in the preoptic area, anterior hypothalamus and nucleus taeniae of the amygdala were significantly higher in the breeding season than the nonbreeding season and were not affected by the L-STI. Unexpectedly, subjects that were dominant in the L-STI had lower levels of DHEA in the anterior hypothalamus and medial striatum in both seasons and lower levels of DHEA in the nucleus taeniae of the amygdala in the breeding season only. Taken together, these data suggest that local levels of DHEA in the brain are very rapidly modulated by social interactions in a context and region-specific pattern. PMID- 26648569 TI - Aberrant expression of Arpin in human breast cancer and its clinical significance. AB - Arpin (Arp2/3 complex inhibitor), a novel protein found in 2013, plays a pivotal role in cell motility and migration. However, the precise role of Arpin in cancer is unclear. This study investigated the expression of Arpin in breast cancer and evaluated its correlation with the characteristics of clinical pathology and prognosis of breast cancer patients. Immunohistochemistry (IHC) for Arpin protein was performed on formalin-fixed, paraffin-embedded 176 breast cancer tissues and 43 normal breast tissues while qRT-PCR for Arpin mRNA with 104 paired tumour and paratumoural tissues from breast cancer patients respectively. The association of Arpin expression with clinical pathological features and survival was assessed in a retrospective cohort analysis of patients. The results showed that the expression of Arpin protein in cancer tissues was lower compared to that in normal breast and the expression of Arpin mRNA was also lower in cancer tissues than that in the matched paratumoural tissues. Among the 176 breast cancer patients, the lower expression of Arpin was significantly associated with advanced tumour, nodes and metastasis system stage, and the reduced Arpin expression was strongly associated with axillary lymph node metastasis using univariate and multivariate logistic regression analysis [odds ratio: 3.242; 95% confidence interval (CI): 1.526, 6.888; P < 0.05]. Furthermore, Arpin expression was an independent risk factor for recurrence-free survival (HR: 0.373; 95% CI: 0.171, 0.813; P < 0.05). As Arpin expression was first examined in human breast cancer tissues with qRT-PCR and IHC, our results suggest that Arpin downregulation may contribute to the initiation and development of breast cancer metastasis. Therefore, as a potential predictive marker, Arpin deserves future studies. PMID- 26648570 TI - SIRT6 suppresses glioma cell growth via induction of apoptosis, inhibition of oxidative stress and suppression of JAK2/STAT3 signaling pathway activation. AB - Sirtuin 6 (SIRT6) is a member of the mammalian NAD+-dependent deacetylase sirtuin family that acts to maintain genomic stability and to repress genes. SIRT6 has recently been reported to be a tumor suppressor that controls cancer metabolism, although this effect of SIRT6 is still in dispute. Moreover, the role of SIRT6 in glioma is largely unknown. In the present study, we found that overexpression of SIRT6 using an adenovirus inhibited glioma cell growth and induced marked cell injury in two glioma cell lines (U87-MG and T98G). Fluorescent terminal deoxyribonucleotidyl transferase (TdT)-mediated biotin-16-dUTP nick-end labelling (TUNEL) assay showed that SIRT6 overexpression induced obvious apoptosis in the T98G glioma cells. Immunoblotting and immunofluorescent staining demonstrated that SIRT6 overexpression promoted the mitochondrial-to-nuclear translocation of apoptosis-inducing factor (AIF), a potent apoptosis inducer. Moreover, we found that SIRT6 overexpression largely reduced oxidative stress and suppressed the activation of the JAK2/STAT3 signaling pathway in glioma cells. Finally, we showed that SIRT6 mRNA and protein levels in human glioblastoma multiforme tissues were significantly lower than the levels in peritumor tissues. In summary, our data suggest that SIRT6 suppresses glioma cell growth via induction of apoptosis, inhibition of oxidative stress and inhibition of the activation of the JAK2/STAT3 signaling pathway. These results indicate that SIRT6 may be a promising therapeutic target for glioma treatment. PMID- 26648571 TI - Cataract was the principle cause of visual impairment and blindness in Shanghai residents with type 2 diabetes. PMID- 26648572 TI - The proteome targets of intracellular targeting antimicrobial peptides. AB - Antimicrobial peptides have been considered well-deserving candidates to fight the battle against microorganisms due to their broad-spectrum antimicrobial activities. Several studies have suggested that membrane disruption is the basic mechanism of AMPs that leads to killing or inhibiting microorganisms. Also, AMPs have been reported to interact with macromolecules inside the microbial cells such as nucleic acids (DNA/RNA), protein synthesis, essential enzymes, membrane septum formation and cell wall synthesis. Proteins are associated with many intracellular mechanisms of cells, thus protein targets may be specifically involved in mechanisms of action of AMPs. AMPs like pyrrhocoricin, drosocin, apidecin and Bac 7 are documented to have protein targets, DnaK and GroEL. Moreover, the intracellular targeting AMPs are reported to influence more than one protein targets inside the cell, suggesting for the multiple modes of actions. This complex mechanism of intracellular targeting AMPs makes them more difficult for the development of resistance. Herein, we have summarized the current status of AMPs in terms of their mode of actions, entry to cytoplasm and inhibition of macromolecules. To reveal the mechanism of action, we have focused on AMPs with intracellular protein targets. We have also included the use of high throughput proteome microarray to determine the unidentified AMP protein targets in this review. PMID- 26648573 TI - Iatrogenic Necrolytic Migratory Erythema in an Infant with Congenital Hyperinsulinism. AB - Necrolytic migratory erythema (NME) is a rare cutaneous finding characterized by painful, pruritic, scaly red patches and plaques, bullae, and superficial erosions. Typically NME is a paraneoplastic phenomenon associated with glucagonoma. We report the exceptional case of an infant who developed iatrogenic NME arising secondary to glucagon therapy for congenital hyperinsulinism. PMID- 26648574 TI - Capsaicin enhances anti-proliferation efficacy of pirarubicin via activating TRPV1 and inhibiting PCNA nuclear translocation in 5637 cells. AB - The recurrence of bladder cancer after surgery with or without chemotherapy remains a major challenge in bladder cancer treatment. Previous studies have shown that transient receptor potential vanilloid 1 (TRPV1) acts as a tumor suppressor through inducing apoptosis in bladder cancer cells. However, whether activation of TRPV1 has any synergistic effects with pirarubicin (THP), one of main drugs used in urinary bladder instillation chemotherapy to improve chemotherapeutic efficacy has remained elusive. The present study verified that TRPV1 was differentially expressed in bladder cancer cell lines. Furthermore, activation of TRPV1 by capsaicin was shown to induce growth inhibition of 5637 cells in which TRPV1 was highly expressed, while the growth of T24 cells, which express TRPV1 at low levels, was not affected. In addition, the present study demonstrated that activation of TRPV1 enhanced the anti-proliferative effects of pirarubicin using an MTT assay and cell cycle analysis. Finally, immunofluorescent microscopy revealed that activation of TRPV1 prevented the translocation of proliferating cell nuclear antigen to the nucleus. This phenomenon was reversed by pre-treatment with capsazepine, a specific TRPV1 antagonist. In conclusion, the present study confirmed the anti-tumor activity of TRPV1 against bladder cancer. Activation of TRPV1 may be applied as a novel strategy to treat bladder cancer or enhance the therapeutic efficacy of traditional chemotherapeutic drugs. PMID- 26648575 TI - ['Tick-borne' encephalitis in an immunocompromised patient]. AB - BACKGROUND: 'Tick-borne' encephalitis virus (TBEV) is a flavivirus that is transmitted by ticks. TBEV is endemic in East Asia, Russia and a number of other European countries. In the Netherlands it is seen only in travellers who have been to these regions. The clinical picture is variable: from a mild form of meningitis to lethal meningoencephalomyelitis. There are no therapeutic options available, only symptomatic treatments. CASE DESCRIPTION: A 48-year-old woman with a history of systemic lupus erythematosus (SLE) for which she used immunosuppressives, developed meningoradiculoencephalitis following a holiday in Germany. She was initially treated for cerebral SLE vasculitis, but it later became apparent that it was a tick-borne encephalitis. The patient died of abscessing pneumonia following protracted mechanical ventilation. CONCLUSION: Tick-borne encephalitis may have serious consequences. Important is to think of this infection in patients who travelled to endemic areas. Vaccination should be recommended to travellers visiting endemic regions, especially if they are immunocompromised. PMID- 26648576 TI - [Heart transplantation in the 21st century in Netherlands: improved survival in the last decade]. AB - OBJECTIVE: Over the past decades donor and recipient characteristics and medical management of heart transplantations patients have changed markedly. We studied the impact of these changes on long-term clinical outcome. DESIGN AND METHODS: Data of all consecutive heart transplant recipients in our center have been collected prospectively. Cohort A (n = 353 patients) was defined as the patients transplanted between 1984 and 1999, and was compared with cohort B (n = 227 patients) transplanted between 2000 and 2013. RESULTS: Compared to cohort A, recipients in cohort B had older donors (mean age 29 vs. 43 years, donors aged > 50 year: 2% vs. 33%, respectively). One-year survival in cohort A vs. B was 89% vs. 86% and at 10 years 53% vs. 68%, respectively (p = 0.02). Cohort B patients were treated more often with tacrolimus based immunosuppression (77% vs. 22%; p < 0.001), and early statins post-heart transplantation (88% vs. 18%; p = 0.001), while renal function was better conserved at 5 and 10 years (p = 0.001 and 0.02). Multivariate analysis showed significant reduction in 10 years mortality with tacrolimus-based immunosuppression (HR: 0.27 and 95% CI 0.17-0.42), treatment of hypertension (HR: 0.5, 95% CI 0.36-0.72) and revascularization (HR: 0.28, 95% CI 0.15-0.52). CONCLUSION: In spite of the use of much older donors, the long-term outcome after heart transplantation has improved considerably in the last decade, probably due to the introduction of newer treatment modalities. PMID- 26648577 TI - [Blood is not for everyone: the usefulness of erythrocyte transfusion]. AB - Increasing evidence on the limited usefulness and the adverse consequences of erythrocyte transfusion has led to a large drop in the number of blood transfusions over the last 20 years. The results of randomised studies suggest that in most haemodynamically stable patients with acute anaemia an Hb transfusion threshold of 4.4 mmol/l for blood transfusion has the same outcomes as a higher transfusion threshold. The effect of blood transfusion in patients with anaemia is not only dependent on their Hb level, but also on other clinical factors that play a role in the balance between oxygen supply and its consumption. The Dutch '4-5-6' rule for indication for blood transfusion takes a number of important clinical factors into account, however, results of recent research suggest that the strict application of this rule will lead to unnecessary transfusions. New research in this area is focused on the quantification of the effect of blood transfusion in various combinations of relevant patient characteristics. PMID- 26648578 TI - Growing muscles in children with cerebral palsy. PMID- 26648579 TI - The clinical learning environment in nursing education: a concept analysis. AB - AIM: The aim of this study was to report an analysis of the clinical learning environment concept. BACKGROUND: Nursing students are evaluated in clinical learning environments where skills and knowledge are applied to patient care. These environments affect achievement of learning outcomes, and have an impact on preparation for practice and student satisfaction with the nursing profession. Providing clarity of this concept for nursing education will assist in identifying antecedents, attributes and consequences affecting student transition to practice. DESIGN: The clinical learning environment was investigated using Walker and Avant's concept analysis method. DATA SOURCES: A literature search was conducted using WorldCat, MEDLINE and CINAHL databases using the keywords clinical learning environment, clinical environment and clinical education. Articles reviewed were written in English and published in peer-reviewed journals between 1995-2014. METHODS: All data were analysed for recurring themes and terms to determine possible antecedents, attributes and consequences of this concept. RESULTS: The clinical learning environment contains four attribute characteristics affecting student learning experiences. These include: (1) the physical space; (2) psychosocial and interaction factors; (3) the organizational culture and (4) teaching and learning components. These attributes often determine achievement of learning outcomes and student self-confidence. CONCLUSION: With better understanding of attributes comprising the clinical learning environment, nursing education programmes and healthcare agencies can collaborate to create meaningful clinical experiences and enhance student preparation for the professional nurse role. PMID- 26648580 TI - CA IX is upregulated in CoCl2-induced hypoxia and associated with cell invasive potential and a poor prognosis of breast cancer. AB - Hypoxia, a common phenomenon during the development of malignant solid tumors including breast cancer, serves to propagate a cascade of molecular pathways triggered by hypoxia-inducible factor-1alpha (HIF-1alpha). Carbonic anhydrase IX (CA IX), one of the target genes of HIF-1alpha, has been reported to be involved in progression of malignant tumors. The objective of this study was to investigate the expression of HIF-1alpha and CA IX in hypoxia, involvement of CA IX in the regulation of migration and invasion/metastasis and its prognostic significance in breast cancer. We used cobalt chloride (CoCl2) as a hypoxia mimetic agent and found that the expression of HIF-1alpha protein, CA IX mRNA and protein, is effectively upregulated, except for HIF-1alpha mRNA. Data showed that the elevated CA IX expression is closely related to in vitro cell migration and invasion, and the underlying mechanism of this process may be associated with epithelial-mesenchymal transition (EMT). The study of clinical tissue samples also demonstrated that CA IX is an independent prognostic marker that may serve as a useful clinical biomarker for predicting tumor progression and the invasion/metastasis of breast cancer. These results provide further insight into the role of CA IX in tumor progression and put forward further strong evidence as well as new consideration for CA IX target therapy. PMID- 26648581 TI - Improved Photodegradation of Organic Contaminants Using Nano-TiO2 and TiO2 -SiO2 Deposited on Portland Cement Concrete Blocks. AB - The photocatalytic activity of TiO2 nanoparticles (nano-TiO2 ) and its hybrid with SiO2 (nano-TiO2 -SiO2 ) for degradation of some organic dyes on cementitious materials was studied in this work. Nanohybrid photocatalysts were prepared using an inorganic sol-gel precursor and then characterized using XRD, SEM and UV-Vis. The grain sizes were estimated by Scherrer's equation to be around 10 nm. Then, a thin layer was applied to Portland cement concrete (PCC) blocks by dipping them into nano-TiO2 and nano-TiO2 -SiO2 solution. The efficiency of coated PCC blocks for the photocatalytic decomposition of two dyes, Malachite Green oxalate (MG) and Methylene Blue (MB), was examined under UV and visible irradiation and then monitored by the chemical oxygen demand tests. The results showed that more than 80% and 92% of MG and MB were decomposed under UV-Vis irradiation using blocks coated with nano-TiO2 -SiO2 . TiO2 /PCC and TiO2 -SiO2 /PCC blocks showed a significant ability to oxidize dyes under visible and UV lights and TiO2 -SiO2 /PCC blocks require less time for dye degradation. Based on these results, coated blocks have increased photocatalytic activity which can make them commercially accessible photocatalysts. PMID- 26648582 TI - Evaluation of the anti-wrinkle effect of an ascorbic acid-loaded dissolving microneedle patch via a double-blind, placebo-controlled clinical study. AB - OBJECTIVE: Although an ascorbic acid-loaded dissolving microneedle patch has been developed to improve anti-wrinkle effects, an efficacy evaluation with a control group has not yet been performed. In this study, the anti-wrinkle effect of an ascorbic acid-loaded dissolving microneedle patch was evaluated in a double-blind clinical study with a control group. In addition, a cumulative skin irritation and sensitization potential of the ascorbic acid-loaded dissolving microneedle patch was performed. METHODS: Twenty-three subjects were selected for anti wrinkle effect evaluation in a double-blind clinical study. Subjects were divided into two groups. Group I subjects applied an ascorbic acid-loaded dissolving microneedle patch on a crow's feet area on the left side of the face and a control sample on a crow's feet area on the right side of the face every 4 days. Group II subjects placed the same patches on opposite sides of the face. Global Photodamage Score and skin replica analysis were conducted by visual inspection and skin visiometer, respectively. A skin irritation and sensitization assessment was performed on 51 subjects using the modified Shelanski & Shelanski procedure. Cumulative skin irritation potential and skin sensitization of the ascorbic acid loaded dissolving microneedle patch and control sample were evaluated. RESULTS: Skin treated with the ascorbic acid-loaded dissolving microneedle patch showed a statistically significant improvement in both the Global Photodamage Score and visiometer R values (P < 0.05) compared with the control sample. The R2 value (maximum roughness), in particular, showed a highly significant improvement (P < 0.01). The skin irritation and sensitization assessment demonstrated that the ascorbic acid-loaded dissolving microneedle patch did not induce any cumulative skin irritation potential or skin sensitization. CONCLUSIONS: An ascorbic acid loaded dissolving microneedle patch produced a significant anti-wrinkle effect without skin irritation and sensitization problems. This cosmetic dissolving microneedle patch can be used efficiently in the anti-wrinkle cosmetic field with patient convenience. PMID- 26648583 TI - Alcohol use disorder hospitalisations over the last two decades: a population based cohort study. AB - BACKGROUND: Alcohol use disorders are risk factors for almost all health conditions due to heavy alcohol use. The epidemiology of alcohol use disorders can be used to monitor harm from heavy alcohol consumption. AIM: To estimate changes in the risk of alcohol use disorders over the last two decades among the Western Australian adult population. METHODS: This population-based cohort study used hospital separation records for Western Australian residents aged 18 years and older that occurred between 1990 and 2013 with a primary diagnosis of alcohol use disorder and annual estimated residential population to estimate the annual gender- and age-specific incidence rate. A random sample of emergency presentations to public hospitals in Western Australia between 2002 and 2013 was used to account for confounding effects, such as changes in patient access to medical care and overall improvement in healthcare service in the multivariable Poisson regression model. RESULTS: The risk of alcohol use disorder hospitalisations among the Western Australia population has increased considerably since 1998 with a decline in 2012 and 2013. The average rate remained significantly higher from 2010 to 2013 compared with previous years. CONCLUSIONS: The trend of alcohol use disorder hospitalisations is indicative of an increase in harm due to heavy alcohol use in the population. PMID- 26648584 TI - Molecular Modeling on Berberine Derivatives toward BuChE: An Integrated Study with Quantitative Structure-Activity Relationships Models, Molecular Docking, and Molecular Dynamics Simulations. AB - A dataset of 67 berberine derivatives for the inhibition of butyrylcholinesterase (BuChE) was studied based on the combination of quantitative structure-activity relationships models, molecular docking, and molecular dynamics methods. First, a series of berberine derivatives were reported, and their inhibitory activities toward butyrylcholinesterase (BuChE) were evaluated. By 2D- quantitative structure-activity relationships studies, the best model built by partial least square had a conventional correlation coefficient of the training set (R(2)) of 0.883, a cross-validation correlation coefficient (Qcv2) of 0.777, and a conventional correlation coefficient of the test set (Rpred2) of 0.775. The model was also confirmed by Y-randomization examination. In addition, the molecular docking and molecular dynamics simulation were performed to better elucidate the inhibitory mechanism of three typical berberine derivatives (berberine, C2, and C55) toward BuChE. The predicted binding free energy results were consistent with the experimental data and showed that the van der Waals energy term (DeltaEvdw) difference played the most important role in differentiating the activity among the three inhibitors (berberine, C2, and C55). The developed quantitative structure-activity relationships models provide details on the fine relationship linking structure and activity and offer clues for structural modifications, and the molecular simulation helps to understand the inhibitory mechanism of the three typical inhibitors. In conclusion, the results of this study provide useful clues for new drug design and discovery of BuChE inhibitors from berberine derivatives. PMID- 26648585 TI - Increased susceptibility to fungal disease accompanies adaptation to drought in Brassica rapa. AB - Recent studies have demonstrated adaptive evolutionary responses to climate change, but little is known about how these responses may influence ecological interactions with other organisms, including natural enemies. We used a resurrection experiment in the greenhouse to examine the effect of evolutionary responses to drought on the susceptibility of Brassica rapa plants to a fungal pathogen, Alternaria brassicae. In agreement with previous studies in this population, we found an evolutionary shift to earlier flowering postdrought, which was previously shown to be adaptive. Here, we report the novel finding that postdrought descendant plants were also more susceptible to disease, indicating a rapid evolutionary shift to increased susceptibility. This was accompanied by an evolutionary shift to increased specific leaf area (thinner leaves) following drought. We found that flowering time and disease susceptibility displayed plastic responses to experimental drought treatments, but that this plasticity did not match the direction of evolution, indicating that plastic and evolutionary responses to changes in climate can be opposed. The observed evolutionary shift to increased disease susceptibility accompanying adaptation to drought provides evidence that even if populations can rapidly adapt in response to climate change, evolution in other traits may have ecological effects that could make species more vulnerable. PMID- 26648586 TI - Glaucoma drainage device surgery after vitreoretinal surgery: incidence and risk factors. AB - PURPOSE: The initial success of vitreoretinal surgery can be annihilated by an acceleration of preexisting glaucoma or the development of secondary glaucoma. Aim of this study was to determine the incidence of and risk factors for medically uncontrollable glaucoma after vitreoretinal surgery. METHODS: Case control study amongst patients who underwent vitreoretinal surgery at the University Medical Center Groningen between 1991 and 2011 (in total 14,942 interventions). Cases were all patients who received a glaucoma drainage device after vitreoretinal surgery. Controls were a subset of the patients who underwent vitreoretinal surgery without a subsequent drainage device. Cases and controls were matched (three controls per case) with regard to the year of the (first) vitreoretinal intervention. The incidence rate was calculated from the number of cases and the number of person-years corresponding to all vitreoretinal interventions performed in the study period. Risk factors were analysed with logistic regression. RESULTS: Ninety-five cases were identified after a follow-up of 101,961 person-years (one per 1000 person-years). Cases were younger (p = 0.017), were more often men (p = 0.035), underwent more interventions (p < 0.001) or were treated with silicone oil (p = 0.021), had a higher intra-ocular pressure 1 week after the intervention (p < 0.001) and had more often a history of glaucoma or ocular hypertension (p < 0.001). CONCLUSION: Glaucoma after vitreoretinal surgery that requires a glaucoma drainage device is not very common and patients who need a device differ from those who do not. This gives the opportunity to monitor certain subgroups more closely. PMID- 26648587 TI - King-Devick Test reference values and associations with balance measures in high school American football players. AB - The King-Devick test appears to be a promising tool in screening for concussions. However, limited evidence exists on the baseline associations between the K-D test and age and baseline screening tools used after concussion. Additionally, there are no published reference values for the K-D test in high school football players. The K-D test, the Balance Error Scoring System, and the Limits of Stability (LOS) test were administered to 157 high school football players. Additionally, a subsample of 62 participants completed the test twice to examine the reliability of K-D test. There was no relationship between the K-D test and the BESS, or the reaction time and directional control of LOS test. Students aged between 16 and 18 years demonstrated faster K-D test performance compared to students between 13 and 15 years of age. However, there was no association between K-D test and history of concussion. The reliability of the K-D test was (ICC2,1 = 0.89), and the minimal detectable change was 6.10 s. Normative reference values for high school football players are presented in this study. PMID- 26648588 TI - Deportation experiences and depression among U.S. citizen-children with undocumented Mexican parents. AB - BACKGROUND: There is a critical need to document the mental health effects of immigration policies and practices on children vulnerable to parental deportation. Few studies capture the differential experiences produced by U.S. citizen-children's encounters with immigration enforcement, much less in ways that analyse mental health outcomes alongside the psychosocial contexts within which those outcomes arise. METHODS: We explore the psychosocial dimensions of depression in U.S. citizen-children with undocumented Mexican parents to examine differences between citizen-children affected and not affected by parental deportation. An exploratory mixed-method design was used to integrate a quantitative measure of depression symptoms (CDI-2) within qualitative data collected with 48 citizen-children aged 8 to 15 with and without experiences of parental deportation. RESULTS: Stressors elicited by citizen-children in the qualitative interview included an inability to communicate with friends, negative perceptions of Mexico, financial struggles, loss of supportive school networks, stressed relation with parent(s) and violence. Fifty percent of citizen-children with probable depression - regardless of experiences with parental deportation - cited 'stressed relation with parents,' compared to 9% without depression. In contrast, themes of 'loss of supportive school network' and 'violence' were mentioned almost exclusively by citizen-children with probable depression and affected by parental deportation. CONCLUSIONS: While citizen-children who suffer parental deportation experience the most severe consequences associated with immigration enforcement, our findings also suggest that the burden of mental health issues extends to those children concomitantly affected by immigration enforcement policies that target their undocumented parents. PMID- 26648589 TI - Monitoring the response of patients with cutaneous leishmaniasis to treatment with pentamidine isethionate by quantitative real-time PCR, and identification of Leishmania parasites not responding to therapy. AB - BACKGROUND: Leishmania (Viannia) guyanensis is believed to be the principal cause of cutaneous leishmaniasis (CL) in Suriname. This disease is treated with pentamidine isethionate (PI), but treatment failure has increasingly been reported. AIM: To evaluate PI for its clinical efficacy, to compare parasite load, and to assess the possibility of treatment failure due to other infecting Leishmania species. METHODS: Parasite load of patients with CL was determined in skin biopsies using real-time quantitative PCR before treatment and 6 and 12 weeks after treatment. Clinical responses were evaluated at week 12 and compared with parasite load. In parallel, molecular species differentiation was performed. RESULTS: L. (V.) guyanensis was the main infecting species in 129 of 143 patients (about 90%). PI treatment led to a significant decrease (P < 0.001) in parasite counts, and cured about 75% of these patients. Treatment failure was attributable to infections with Leishmania (Viannia) braziliensis, Leishmania (Leishmania) amazonensis and L. (V.) guyanensis (1/92, 1/92 and 22/92 evaluable cases, respectively). There was substantial agreement beyond chance between the parasite load at week 6 and the clinical outcome at week 12, as indicated by the kappa value of 0.61. CONCLUSIONS: L. (V.) guyanensis is the main infecting species of CL in Suriname, followed by L. (V.) braziliensis and L. (L.) amazonensis. Furthermore, patient response to PI can be better anticipated based on the parasite load 6 weeks after the treatment rather than on parasite load before treatment. PMID- 26648591 TI - Unexplained early onset epileptic encephalopathy: Exome screening and phenotype expansion. AB - Early onset epileptic encephalopathies (EOEEs) represent a significant diagnostic challenge. Newer genomic approaches have begun to elucidate an increasing number of responsible single genes as well as emerging diagnostic strategies. In this single-center study, we aimed to investigate a cohort of children with unexplained EOEE. We performed whole-exome sequencing (WES), targeting a list of 137 epilepsy-associated genes on 50 children with unexplained EOEE. We characterized all phenotypes in detail and classified children according to known electroclinical syndromes where possible. Infants with previous genetic diagnoses, causative brain malformations, or inborn errors of metabolism were excluded. We identified disease-causing variants in 11 children (22%) in the following genes: STXBP1 (n = 3), KCNB1 (n = 2), KCNT1, SCN1A, SCN2A, GRIN2A, DNM1, and KCNA2. We also identified two further variants (in GRIA3 and CPA6) in two children requiring further investigation. Eleven variants were de novo, and in one paternal testing was not possible. Phenotypes were broadened for some variants identified. This study demonstrates that WES is a clinically useful screening tool for previously investigated unexplained EOEE and allows for reanalysis of data as new genes are being discovered. Detailed phenotyping allows for expansion of specific gene disorders leading to epileptic encephalopathy and emerging sub-phenotypes. PMID- 26648590 TI - Oral Cobalamin Supplementation in Dogs with Chronic Enteropathies and Hypocobalaminemia. AB - BACKGROUND: Cobalamin deficiency is commonly associated with chronic enteropathies (CE) in dogs and current treatment protocols recommend parenteral supplementation. In humans, several studies have reported equal efficacy of oral and parenteral cobalamin administration of cobalamin. OBJECTIVES: To retrospectively evaluate whether oral cobalamin supplementation can restore normocobalaminemia in dogs with CE and hypocobalaminemia. ANIMALS: Fifty-one client-owned dogs with various signs of CE and hypocobalaminemia. MATERIAL AND METHODS: Retrospective study based on a computerized database search for dogs treated at Evidensia Specialist Animal Hospital, Helsingborg, Sweden during January 2012-March 2014. Inclusion criteria were dogs with signs of CE, an initial serum cobalamin <=270 ng/L (reference interval: 234-811 ng/L) and oral treatment with cobalamin tablets. Serum cobalamin for follow-up was analyzed 20 202 days after continuous oral cobalamin supplementation started. RESULTS: All dogs became normocobalaminemic with oral cobalamin supplementation. The mean increase in serum cobalamin concentration after treatment was 794 +/- 462 ng/L. Serum cobalamin concentrations were significantly higher after supplementation (mean 1017 +/- 460 ng/L; P < .0001) than at baseline (mean 223 +/- 33 ng/L). CONCLUSION AND CLINICAL IMPORTANCE: Our results suggest that oral cobalamin supplementation is effective in normalizing serum cobalamin concentrations in dogs with CE. Prospective studies comparing cellular cobalamin status in dogs being treated with parenteral versus oral cobalamin supplementation are warranted before oral supplementation can be recommended for routine supplementation. PMID- 26648592 TI - Methods in renal research: kidney transplantation in the rat. AB - Kidney transplantation in small animals has been crucial in the development of anti-rejection therapies. While there is no substitute for a skilled microsurgeon, there are many aspects of the transplant procedure that can be modified to optimize the reproducibility and utility of the technique. This article provides a detailed description, including video recording, of orthotopic kidney transplantation in the rat. The key variables in the technique are also discussed. PMID- 26648593 TI - Polarization-sensitive interferometric synthetic aperture microscopy. AB - Three-dimensional optical microscopy suffers from the well-known compromise between transverse resolution and depth-of-field. This is true for both structural imaging methods and their functional extensions. Interferometric synthetic aperture microscopy (ISAM) is a solution to the 3D coherent microscopy inverse problem that provides depth-independent transverse resolution. We demonstrate the extension of ISAM to polarization sensitive imaging, termed polarization-sensitive interferometric synthetic aperture microscopy (PS-ISAM). This technique is the first functionalization of the ISAM method and provides improved depth-of-field for polarization-sensitive imaging. The basic assumptions of polarization-sensitive imaging are explored, and refocusing of birefringent structures is experimentally demonstrated. PS-ISAM enables high-resolution volumetric imaging of birefringent materials and tissue. PMID- 26648594 TI - Imaging interfacial electrical transport in graphene-MoS2 heterostructures with electron-beam-induced-currents. AB - Heterostructure devices with specific and extraordinary properties can be fabricated by stacking two-dimensional crystals. Cleanliness at the inter-crystal interfaces within a heterostructure is crucial for maximizing device performance. However, because these interfaces are buried, characterizing their impact on device function is challenging. Here, we show that electron-beam induced current (EBIC) mapping can be used to image interfacial contamination and to characterize the quality of buried heterostructure interfaces with nanometer-scale spatial resolution. We applied EBIC and photocurrent imaging to map photo-sensitive graphene-MoS2 heterostructures. The EBIC maps, together with concurrently acquired scanning transmission electron microscopy images, reveal how a device's photocurrent collection efficiency is adversely affected by nanoscale debris invisible to optical-resolution photocurrent mapping. PMID- 26648595 TI - Combined Neel and Brown rotational Langevin dynamics in magnetic particle imaging, sensing, and therapy. AB - Magnetic nanoparticles have been studied intensely because of their possible uses in biomedical applications. Biosensing using the rotational freedom of particles has been used to detect biomarkers for cancer, hyperthermia therapy has been used to treat tumors, and magnetic particle imaging is a promising new imaging modality that can spatially resolve the concentration of nanoparticles. There are two mechanisms by which the magnetization of a nanoparticle can rotate, a fact that poses a challenge for applications that rely on precisely one mechanism. The challenge is exacerbated by the high sensitivity of the dominant mechanism to applied fields. Here, we demonstrate stochastic Langevin equation simulations for the combined rotation in magnetic nanoparticles exposed to oscillating applied fields typical to these applications to both highlight the existing relevant theory and quantify which mechanism should occur in various parameter ranges. PMID- 26648596 TI - Dynamic trajectory analysis of superparamagnetic beads driven by on-chip micromagnets. AB - We investigate the non-linear dynamics of superparamagnetic beads moving around the periphery of patterned magnetic disks in the presence of an in-plane rotating magnetic field. Three different dynamical regimes are observed in experiments, including (1) phase-locked motion at low driving frequencies, (2) phase-slipping motion above the first critical frequency fc1, and (3) phase-insulated motion above the second critical frequency fc2. Experiments with Janus particles were used to confirm that the beads move by sliding rather than rolling. The rest of the experiments were conducted on spherical, isotropic magnetic beads, in which automated particle position tracking algorithms were used to analyze the bead dynamics. Experimental results in the phase-locked and phase-slipping regimes correlate well with numerical simulations. Additional assumptions are required to predict the onset of the phase-insulated regime, in which the beads are trapped in closed orbits; however, the origin of the phase-insulated state appears to result from local magnetization defects. These results indicate that these three dynamical states are universal properties of bead motion in non-uniform oscillators. PMID- 26648597 TI - Fast crystallization of amorphous Gd2Zr2O7 induced by thermally activated electron-beam irradiation. AB - We investigate the ionization and displacement effects of an electron-beam (e beam) on amorphous Gd2Zr2O7 synthesized by the co-precipitation and calcination methods. The as-received amorphous specimens were irradiated under electron beams at different energies (80 keV, 120 keV, and 2 MeV) and then characterized by X ray diffraction and transmission electron microscopy. A metastable fluorite phase was observed in nanocrystalline Gd2Zr2O7 and is proposed to arise from the relatively lower surface and interface energy compared with the pyrochlore phase. Fast crystallization could be induced by 120 keV e-beam irradiation (beam current = 0.47 mA/cm2). The crystallization occurred on the nanoscale upon ionization irradiation at 400 degrees C after a dose of less than 1017 electrons/cm2. Under e-beam irradiation, the activation energy for the grain growth process was approximately 10 kJ/mol, but the activation energy was 135 kJ/mol by calcination in a furnace. The thermally activated ionization process was considered the fast crystallization mechanism. PMID- 26648598 TI - Perspective Biological Markers for Autism Spectrum Disorders: Advantages of the Use of Receiver Operating Characteristic Curves in Evaluating Marker Sensitivity and Specificity. AB - Autism Spectrum Disorders (ASD) are a heterogeneous group of neurodevelopmental disorders. Recognized causes of ASD include genetic factors, metabolic diseases, toxic and environmental factors, and a combination of these. Available tests fail to recognize genetic abnormalities in about 70% of ASD children, where diagnosis is solely based on behavioral signs and symptoms, which are difficult to evaluate in very young children. Although it is advisable that specific psychotherapeutic and pedagogic interventions are initiated as early as possible, early diagnosis is hampered by the lack of nongenetic specific biological markers. In the past ten years, the scientific literature has reported dozens of neurophysiological and biochemical alterations in ASD children; however no real biomarker has emerged. Such literature is here reviewed in the light of Receiver Operating Characteristic (ROC) analysis, a very valuable statistical tool, which evaluates the sensitivity and the specificity of biomarkers to be used in diagnostic decision making. We also apply ROC analysis to some of our previously published data and discuss the increased diagnostic value of combining more variables in one ROC curve analysis. We also discuss the use of biomarkers as a tool for advancing our understanding of nonsyndromic ASD. PMID- 26648600 TI - Conflict of interest in medical journals. PMID- 26648599 TI - Tissue Specific Promoters in Colorectal Cancer. AB - Colorectal carcinoma is the third most prevalent cancer in the world. In the most advanced stages, the use of chemotherapy induces a poor response and is usually accompanied by other tissue damage. Significant progress based on suicide gene therapy has demonstrated that it may potentiate the classical cytotoxic effects in colorectal cancer. The inconvenience still rests with the targeting and the specificity efficiency. The main target of gene therapy is to achieve an effective vehicle to hand over therapeutic genes safely into specific cells. One possibility is the use of tumor-specific promoters overexpressed in cancers. They could induce a specific expression of therapeutic genes in a given tumor, increasing their localized activity. Several promoters have been assayed into direct suicide genes to cancer cells. This review discusses the current status of specific tumor-promoters and their great potential in colorectal carcinoma treatment. PMID- 26648601 TI - Janus kinase inhibitors - holistically seeing two faces. PMID- 26648602 TI - Cost shifting and the quality use of medicines. PMID- 26648603 TI - Choosing a combined oral contraceptive pill. AB - The combined oral contraceptive pill is an effective contraceptive method which can also offer other benefits. However, other contraceptive options should be discussed. If the pill is the chosen method, prescribe a pill with the lowest effective dose of oestrogen and progestogen. Pills containing levonorgestrel or norethisterone in combination with ethinyloestradiol 35 microgram or less are considered first-line. They are effective if taken correctly, have a relatively low risk of venous thromboembolism, and are listed on the Pharmaceutical Benefits Scheme. The pill is usually taken in a monthly cycle. Some women may prefer an extended pill regimen with fewer or no inactive pills. PMID- 26648604 TI - Measuring vitamin D. AB - When assessing vitamin D status, measure serum 25-hydroxyvitamin D concentration as this reflects total body vitamin D reserves. Recent Australasian guidelines outline who should be tested for vitamin D deficiency, who should be treated and when repeat testing should be performed. A 25-hydroxyvitamin D threshold of at least 50 nanomol/L at the end of winter is a suitable treatment target. Measurement can be repeated after three months of repletion, and thereafter less frequently unless new risk factors for vitamin D deficiency arise. When interpreting vitamin D pathology reports, practitioners should be aware that some laboratories quote reference limits which are based on overseas rather than Australian guidelines. PMID- 26648605 TI - Home monitoring of blood pressure. AB - Home blood pressure monitoring is the self-measurement of blood pressure by patients. In the diagnosis and management of high blood pressure it is complementary to 24-hour ambulatory blood pressure monitoring and clinic blood pressure measurements. Home monitoring can also help to identify white-coat and masked hypertension. Home monitoring has good reproducibility, is well tolerated and relatively inexpensive. It is superior to blood pressure taken in the clinic in predicting cardiovascular events and mortality. Twice-daily measurements are recommended, usually in the morning and evening for a minimum of five days. The threshold for defining hypertension is an average home blood pressure of 135/85 mmHg or above. Patients are engaged with their management when they monitor their own blood pressure. This results in increased adherence to therapy and lower blood pressure. PMID- 26648606 TI - Risk assessment of drug-induced QT prolongation. AB - Drugs can cause prolongation of the QT interval, alone or in combination, potentially leading to fatal arrhythmias such as torsades de pointes. When prescribing drugs that prolong the QT interval, the balance of benefit versus harm should always be considered. Readouts from automated ECG machines are unreliable. The QT interval should be measured manually. Changes in heart rate influence the absolute QT interval. Heart rate correction formulae are inaccurate, particularly for fast and slow heart rates. The QT nomogram, a plot of QT interval versus heart rate, can be used as a risk assessment tool to detect an abnormal QT interval. PMID- 26648607 TI - Enzalutamide. PMID- 26648609 TI - Pomalidomide. PMID- 26648608 TI - Fluticasone furoate with vilanterol. PMID- 26648610 TI - Retapamulin. PMID- 26648611 TI - Data informs debate. PMID- 26648612 TI - Pharmaceuticals, pharmacists and profits. PMID- 26648613 TI - Smoking and preoperative assessment. PMID- 26648614 TI - Long-term drug treatment of patients with alcohol dependence. AB - Drug therapy for alcohol dependence should only be used in conjunction with a comprehensive treatment plan. Naltrexone and acamprosate have well established efficacy and are first-line treatments. Naltrexone is recommended for patients aiming to cut down their alcohol intake who do not have severe liver disease or an ongoing need for opioids. Acamprosate is recommended for those who have achieved and wish to maintain abstinence. Disulfiram is no longer considered first-line treatment due to difficulties with compliance and toxicity. Although baclofen and topiramate have evidence of benefit, they are not registered for alcohol dependence and should only be considered in specialist practice. PMID- 26648616 TI - Imaging for chronic abdominal pain in adults. AB - Diagnostic imaging is often not indicated in chronic abdominal pain. In particular, undifferentiated abdominal pain is rarely an indication for a CT scan. CT scanning is overused even when imaging is required. Other modalities may be preferable. A normal CT scan does not rule out cancer. Alarm symptoms, including anaemia, blood in the stool, waking at night with gastrointestinal symptoms, and weight loss, should be investigated. The most appropriate modality depends on the symptoms. Clinical information on request forms for CT scans should be specific and include the suspected condition as this helps the radiologist to determine an appropriate imaging protocol. PMID- 26648615 TI - How to manage warfarin therapy. AB - Long-term treatment with warfarin is recommended for patients with atrial fibrillation at risk of stroke and those with recurrent venous thrombosis or prosthetic heart valves. Patient education before commencing warfarin - regarding signs and symptoms of bleeding, the impact of diet, potential drug interactions and the actions to take if a dose is missed - is pivotal to successful use. Scoring systems such as the CHADS2 score are used to determine if patients with atrial fibrillation are suitable for warfarin treatment. To rapidly achieve stable anticoagulation, use an age-adjusted protocol for starting warfarin. Regular monitoring of the anticoagulant effect is required. Evidence suggests that patients who self-monitor using point-of-care testing have better outcomes than other patients. PMID- 26648617 TI - Update on the management of post-traumatic stress disorder. AB - Post-traumatic stress disorder occurs in people exposed to life-threatening trauma. GPs may be seeing more patients with post-traumatic stress disorder as military personnel return from overseas deployments. The condition can present in various ways. To reduce the likelihood of missed or delayed diagnosis GPs can screen at-risk populations. A comprehensive assessment is recommended. Specialist referral may be required, particularly if there are other mental health problems. Trauma-focused psychological therapies should be offered as the first line of treatment for post-traumatic stress disorder. Usually 8-12 sessions are needed for a therapeutic effect. If drug treatment is needed, selective serotonin reuptake inhibitors are the first line. Other drugs used in post-traumatic stress disorder include antipsychotics, anticonvulsants and prazosin. PMID- 26648618 TI - Treatment for Alzheimer's disease: has anything changed? AB - Current therapies for Alzheimer's disease do not modify the course of disease and are not universally beneficial. Clinical trials of drugs targeting amyloid and tau in established Alzheimer's disease have been unsuccessful as it is thought that treating established disease may be too late. Research has moved to the prodromal and pre-symptomatic phases of Alzheimer's disease, with a greater emphasis on the role of biomarkers in defining cases and monitoring response to therapy. Mixed pathologies predominate in the older population. The associations between biomarkers, neuropathology and clinical syndromes are weaker in older people and this is likely to pose a greater challenge in identifying effective therapies. PMID- 26648619 TI - Empagliflozin. PMID- 26648620 TI - Perampanel. PMID- 26648621 TI - Simeprevir. PMID- 26648622 TI - Umeclidinium bromide/with vilanterol. PMID- 26648623 TI - Medical management of malignant melanoma. AB - The treatment and outcomes for people with metastatic melanoma have changed considerably in the past few years with the introduction of targeted anticancer drugs. About half of the patients with metastatic melanoma will have activating mutations in the BRAF gene. These people may benefit from a BRAF inhibitor (vemurafenib or dabrafenib) or a MEK inhibitor (trametinib). Addition of a MEK inhibitor to a BRAF inhibitor improves progression-free survival and alters the adverse effect profile. Ipilimumab is another drug indicated for metastatic melanoma. It works by altering the patient's own immune response to the tumour. Toxicities are common with these drugs and include arthralgias, fatigue, photosensitivity, squamous cell carcinomas, fever, diarrhoea, pruritus and immune related adverse effects. PMID- 26648624 TI - Pharmaceuticals, pharmacists and profits. PMID- 26648625 TI - Conflict of interest in medical journals. PMID- 26648626 TI - Complex regional pain syndrome. AB - Complex regional pain syndrome is an uncommon chronic pain condition. It develops spontaneously or following an injury. The features are limb pain, allodynia, hypersensitivity, hyperalgesia, abnormalities of the vasomotor, sudomotor and motor systems, and trophic changes, with reduced use of the affected limb. The diagnosis is clinical and one of exclusion. The emphasis of therapy is graded rehabilitation and movement of the limb with physiotherapy and occupational therapy. Psychological therapies should be offered if a patient is making no or slow progress in the acute phase, and to all patients in the chronic phase as depression can occur. The goal of pharmacotherapy is to assist functional improvement. The early phase may be managed with simple analgesia. Antineuropathic drugs including tricyclic antidepressants and antiepileptic drugs may be added. Other treatments with some evidence of effectiveness include corticosteroids, calcitonin and bisphosphonates. Vitamin C has been used for primary prevention after wrist fracture and upper and lower limb surgery. There is no evidence that it is effective for treating established complex regional pain syndrome. PMID- 26648627 TI - Prescribing azithromycin. AB - Azithromycin is a broad-spectrum macrolide antibiotic with a long half-life and excellent tissue penetration. It is primarily used for the treatment of respiratory, enteric and genitourinary infections and may be used in preference to other macrolides for some sexually transmitted and enteric infections. Azithromycin has additional immunomodulatory effects and has been used in chronic respiratory inflammatory diseases for this purpose. Potential major adverse effects include cardiovascular arrhythmias and hearing loss. Macrolide resistance is also a problem, as are interactions with commonly prescribed drugs. PMID- 26648628 TI - Safe disposal of prescribed medicines. AB - The National Return and Disposal of Unwanted Medicines Program provides a free and safe method for the disposal of unwanted and expired medicines. This stops drugs being dumped in landfill and waterways. An audit showed that over 600 tonnes of medicines are returned through the program. A substantial proportion of these medicines were still within their expiry dates. Salbutamol, insulin and frusemide are the most commonly discarded medicines. More than $2 million of public money is wasted each year. Hoarding and non-adherence to treatment contribute to waste. Health professionals may be able to help minimise waste by informing patients about the importance of completing prescribed courses of treatment, and discouraging them from hoarding medicines after reaching the safety net threshold on the Pharmaceutical Benefits Scheme. Prescribe no more than the required quantity of medicines. When starting a new therapy, prescribe a minimal quantity in case the drug is unsuitable for the patient. Advise patients to return all unwanted medicines to a pharmacy for disposal. PMID- 26648629 TI - Erythrocyte sedimentation rate and C-reactive protein. AB - C-reactive protein is a better indicator of inflammation than the erythrocyte sedimentation rate. It is more sensitive and responds more quickly to changes in the clinical situation. False negative and false positive results are more common when measuring the erythrocyte sedimentation rate. Renal disease, female sex and older age increase the erythrocyte sedimentation rate. The erythrocyte sedimentation rate has value in detecting low-grade bone infection, and in monitoring some patients with systemic lupus erythematosus. PMID- 26648630 TI - Concerns about quetiapine. AB - Quetiapine is subsidised by the Pharmaceutical Benefits Scheme to treat schizophrenia and bipolar disorder. An extended-release formulation is also approved for use, but not subsidised, for treatment-resistant depression and generalised anxiety disorder. There is increasing off-label prescribing of quetiapine for indications such as insomnia that have little evidence to support them. This prescribing is often for at-risk patients, such as people with personality or social vulnerabilities and those at risk of metabolic complications or cardiovascular events. More evidence is required to support prescribing decisions regarding these off-label indications. In the meantime prescribers should be supported with alternatives to prescribing for these conditions, such as psychological therapies that have a better evidence base and safety record. PMID- 26648631 TI - Acute use of oxygen therapy. AB - A major change is needed in the entrenched culture of routinely administering high-concentration oxygen to acutely ill patients regardless of need. Oxygen is a drug that should be prescribed for specific indications. There should be a documented target range for oxygen saturation, and regular monitoring of the patient's response. There are risks from unrelieved hypoxaemia due to insufficient oxygen therapy, and from provoked hyperoxaemia due to excessive oxygen therapy. Oxygen therapy should therefore be titrated so that the saturation is within a range that avoids these risks. If oxygen requirements are increasing, the clinician should review the patient and consider transfer to a higher level of care. If oxygen requirements are decreasing, consider reducing or discontinuing oxygen therapy. PMID- 26648632 TI - Vortioxetine. PMID- 26648634 TI - Antiplatelet drugs and the smokers' paradox. PMID- 26648633 TI - Update on medicines for smoking cessation. AB - Persistent cigarette smokers usually have a nicotine addiction. This addiction has a chronic relapsing and sometimes remitting course and may persist lifelong. Remission can be facilitated by the use of medication as part of a comprehensive management strategy tailored to the individual patient. Nicotine replacement therapy is a first-line drug treatment. It is available in many formulations. Varenicline is also a first-line drug treatment. It should be started before the patient stops smoking. Bupropion is a second-line therapy. It may be associated with an increased risk of seizures and drug interactions. While there is some evidence that electronic cigarettes might facilitate smoking cessation, quit rates are not yet comparable with those of the drugs approved on the Pharmaceutical Benefits Scheme. PMID- 26648635 TI - Data informs debate. PMID- 26648636 TI - Preoperative investigations. PMID- 26648638 TI - Arthritis Australia. PMID- 26648637 TI - Managing osteoarthritis. AB - Management of osteoarthritis should be based on a combination of non-drug and drug treatments targeted towards prevention, modifying risk and disease progression. Obesity is the most important modifiable risk factor, so losing weight in addition to land- and water-based exercise and strength training is important. While paracetamol can be tried, guidelines recommend non-steroidal anti-inflammatory drugs as first-line treatment for osteoarthritis. If there are concerns about the adverse effects of oral treatment, particularly in older patients or those with comorbidities, topical non-steroidal anti-inflammatory drugs can be used. Glucosamine does not appear to be any better than placebo for pain. Its effect on the structural progression of disease when taken alone or in combination with chondroitin is uncertain. Fish oil has not been found to reduce the structural progression of knee arthritis. Surgical interventions should be avoided in the first instance, with arthroscopic procedures not showing benefit over sham procedures or optimised physical and medical therapy. Joint replacement surgery should be considered for severe osteoarthritis. PMID- 26648639 TI - Managing obsessive compulsive disorder. AB - Unlike obsessive compulsive personality traits or occasional repetitive habits, obsessive compulsive disorder can be highly distressing and associated with significant disability. Treatment should always be offered. Psychological interventions and selective serotonin reuptake inhibitors are first-line treatments for obsessive compulsive disorder. Patients with obsessive compulsive disorder respond to selective serotonin reuptake inhibitors at a slower rate than those with depression. The dose of a selective serotonin reuptake inhibitor can be increased at two-week intervals depending on the patient's response. Aim for doses in the higher therapeutic range. Improvements from treatment usually plateau at 12 weeks. Successful treatment should continue for at least 12 months. There is a significant risk of relapse when treatment is stopped. PMID- 26648640 TI - Minor burn management: potions and lotions. AB - The first aid for burns is to run cold water over the burn for 20 minutes. This is effective for up to three hours after the injury. Assess the affected body surface area using the rule of nines. Consult a burn unit if more than 5% of the total body surface area is burnt in a child or if more than 10% in an adult. Extensive or deep burns and burns to special areas, such as the hands, should be referred. Chemical or electrical burns should also be assessed by a burn unit. For minor burns, antimicrobial dressings are recommended, but oral antibiotics should be avoided unless there are signs of infection. As burns are tetanus prone, check the patient's immunisation status. Burns that become infected or are slow to heal should be discussed with a burn unit. The burn unit can also provide advice if there are uncertainties about how to manage a patient. PMID- 26648641 TI - Blood tests for acute pancreatitis. AB - The diagnosis of acute pancreatitis requires the presence of at least two of the three diagnostic criteria - characteristic abdominal pain, elevated serum amylase or lipase, and radiological evidence of pancreatitis. Serum concentrations of amylase and lipase rise within hours of the pancreatic injury. A threshold concentration 2-4 times the upper limit of normal is recommended for diagnosis. Serum lipase is now the preferred test due to its improved sensitivity, particularly in alcohol-induced pancreatitis. Its prolonged elevation creates a wider diagnostic window than amylase. Neither enzyme is useful in monitoring or predicting the severity of an episode of pancreatitis in adults. New biomarkers including trypsinogen and elastase have no significant advantage over amylase or lipase. PMID- 26648642 TI - Medical management of chronic stable angina. AB - Stable angina pectoris is characterised by typical exertional chest pain that is relieved by rest or nitrates. Risk stratification of patients is important to define prognosis, to guide medical management and to select patients suitable for revascularisation. Medical treatment aims to relieve angina and prevent cardiovascular events. Beta blockers and calcium channel antagonists are first line options for treatment. Short-acting nitrates can be used for symptom relief. Low-dose aspirin and statins are prescribed to prevent cardiovascular events. PMID- 26648643 TI - Dienogest. PMID- 26648644 TI - Febuxostat. PMID- 26648645 TI - Ofatumumab. PMID- 26648646 TI - Forty and forward? PMID- 26648647 TI - The failure of drug prohibition and the future of drug law reform in Australia. PMID- 26648648 TI - Warfarin brands. PMID- 26648649 TI - Warfarin and beetroot. PMID- 26648650 TI - Naltrexone and liver disease. PMID- 26648651 TI - Management of benzodiazepine misuse and dependence. AB - There are well-recognised harms from long-term use of benzodiazepines. These include dependency, cognitive decline and falls. It is important to prevent and recognise benzodiazepine dependence. A thorough risk assessment guides optimal management and the necessity for referral. The management of dependence involves either gradual benzodiazepine withdrawal or maintenance treatment. Prescribing interventions, substitution, psychotherapies and pharmacotherapies can all contribute. Unless the patient is elderly, it is helpful to switch to a long acting benzodiazepine in both withdrawal and maintenance therapy. The dose should be gradually reduced over weeks to lower the risk of seizures. Harms from drugs such as zopiclone and zolpidem are less well characterised. Dependence is managed in the same manner as benzodiazepine dependence. PMID- 26648652 TI - Drugs in breastfeeding. AB - Most commonly used drugs are relatively safe for breastfed babies. The dose received via milk is generally small and much less than the known safe doses of the same drug given directly to neonates and infants. Drugs contraindicated during breastfeeding include anticancer drugs, lithium, oral retinoids, iodine, amiodarone and gold salts. An understanding of the principles underlying the transfer into breast milk is important, as is an awareness of the potential adverse effects on the infant. Discussion with the mother about the possibility of either negative product information or ill-informed advice from others will reduce the confusion and anxiety that may be generated. Good resources about medicines and breastfeeding are available and include state-based medicines information services. PMID- 26648653 TI - Prescribing for people in custody. AB - People who are, or have been, in custody often have multiple morbidities and multi-dimensional disadvantage. A thorough clinical evaluation and multidisciplinary approach will assist in managing these patients. Treatment plans should be pragmatic and simple, and explained in an understandable manner. Caution should be used in the prescription of any medicines that have the potential for abuse. There is also a risk of drug diversion. There is an increase in mortality after prisoners are released into the community. Preparations should therefore be made before release to ensure continuity of care. PMID- 26648654 TI - Drug diversion. AB - Prescription drug diversion has significant health, legal and social implications. Deaths from misuse of prescription drugs account for a significant proportion of overdose deaths. The drugs most commonly involved are analgesics, particularly opioids, and psychoactive drugs, particularly benzodiazepines. Diverted drugs are most often sourced from a family member or friend, but are also sourced from overseas pharmacies or laboratories, or bought from drug dealers. Drug diversion can be mitigated by good prescribing practices. Systems for monitoring the prescribing and dispensing of medicines are being instituted across Australia. PMID- 26648655 TI - The World Anti-Doping Code in sport: Update for 2015. AB - Some athletes cheat by using drugs or medical methods such as transfusion to enhance their performance. However, this may put their health at risk. The World Anti-Doping Agency prohibits certain methods and drugs that may enhance performance, harm the athlete or violate the spirit of sport. Some may be banned only during competitions, but others are banned at all times. Prohibited substances include over-the-counter and prescription medicines. It is therefore important for athletes and health professionals to check what is permitted. There are many resources available through organisations such as the Australian Sports Anti-Doping Authority and the World Anti-Doping Agency. PMID- 26648656 TI - Oral targeted therapy for cancer. AB - Oral targeted therapies are increasingly being used to treat cancer. They work by interfering with specific molecules or pathways involved in tumour growth. It is essential that health professionals managing patients taking these drugs have appropriate training and skills. They should be aware of potential adverse effects and drug interactions, and be able to manage toxicities when they occur. Despite the selectivity of these targeted therapies, they still have serious adverse effects including skin reactions, diarrhoea and altered organ function. PMID- 26648657 TI - Apremilast. PMID- 26648658 TI - Ibrutinib. PMID- 26648659 TI - Pembrolizumab. PMID- 26648660 TI - Biomarkers of Eating Disorders Using Support Vector Machine Analysis of Structural Neuroimaging Data: Preliminary Results. AB - Presently, there are no valid biomarkers to identify individuals with eating disorders (ED). The aim of this work was to assess the feasibility of a machine learning method for extracting reliable neuroimaging features allowing individual categorization of patients with ED. Support Vector Machine (SVM) technique, combined with a pattern recognition method, was employed utilizing structural magnetic resonance images. Seventeen females with ED (six with diagnosis of anorexia nervosa and 11 with bulimia nervosa) were compared against 17 body mass index-matched healthy controls (HC). Machine learning allowed individual diagnosis of ED versus HC with an Accuracy >= 0.80. Voxel-based pattern recognition analysis demonstrated that voxels influencing the classification Accuracy involved the occipital cortex, the posterior cerebellar lobule, precuneus, sensorimotor/premotor cortices, and the medial prefrontal cortex, all critical regions known to be strongly involved in the pathophysiological mechanisms of ED. Although these findings should be considered preliminary given the small size investigated, SVM analysis highlights the role of well-known brain regions as possible biomarkers to distinguish ED from HC at an individual level, thus encouraging the translational implementation of this new multivariate approach in the clinical practice. PMID- 26648661 TI - 3,5,4'-Tri-O-acetylresveratrol Attenuates Lipopolysaccharide-Induced Acute Respiratory Distress Syndrome via MAPK/SIRT1 Pathway. AB - The aim of the present research was to investigate the protecting effects of 3,5,4'-tri-O-acetylresveratrol (AC-Rsv) on LPS-induced acute respiratory distress syndrome (ARDS). Lung injuries have been evaluated by histological examination, wet-to-dry weight ratios, and cell count and protein content in bronchoalveolar lavage fluid. Inflammation was assessed by MPO activities and cytokine secretion in lungs and cells. The results showed that AC-Rsv significantly reduced the mortality of mice stimulated with LPS. Pretreatment of AC-Rsv attenuated LPS induced histological changes, alleviated pulmonary edema, reduced blood vascular leakage, and inhibited the MPO activities in lungs. What was more, AC-Rsv and Rsv treatment reduced the secretion of TNF-alpha, IL-6, and IL-1beta in lungs and NR8383 cells, respectively. Further exploration revealed that AC-Rsv and Rsv treatment relieved LPS-induced inhibition on SIRT1 expression and restrained the activation effects of LPS on MAPKs and NF-kappaB activation both in vitro and in vivo. More importantly, in vivo results have also demonstrated that the protecting effects of Rsv on LPS-induced inflammation would be neutralized when SIRT1 was in-hibited by EX527. Taken together, these results indicated that AC Rsv protected lung tissue against LPS-induced ARDS by attenuating inflammation via p38 MAPK/SIRT1 pathway. PMID- 26648663 TI - Caffeine Mitigates Lung Inflammation Induced by Ischemia-Reperfusion of Lower Limbs in Rats. AB - Reperfusion of ischemic limbs can induce inflammation and subsequently cause acute lung injury. Caffeine, a widely used psychostimulant, possesses potent anti inflammatory capacity. We elucidated whether caffeine can mitigate lung inflammation caused by ischemia-reperfusion (IR) of the lower limbs. Adult male Sprague-Dawley rats were randomly allocated to receive IR, IR plus caffeine (IR + Caf group), sham-operation (Sham), or sham plus caffeine (n = 12 in each group). To induce IR, lower limbs were bilaterally tied by rubber bands high around each thigh for 3 hours followed by reperfusion for 3 hours. Caffeine (50 mg/kg, intraperitoneal injection) was administered immediately after reperfusion. Our histological assay data revealed characteristics of severe lung inflammation in the IR group and mild to moderate characteristic of lung inflammation in the IR + Caf group. Total cells number and protein concentration in bronchoalveolar lavage fluid of the IR group were significantly higher than those of the IR + Caf group (P < 0.001 and P = 0.008, resp.). Similarly, pulmonary concentrations of inflammatory mediators (tumor necrosis factor-alpha, interleukin-1beta, and macrophage inflammatory protein-2) and pulmonary myeloperoxidase activity of the IR group were significantly higher than those of the IR + Caf group (all P < 0.05). These data clearly demonstrate that caffeine could mitigate lung inflammation induced by ischemia-reperfusion of the lower limbs. PMID- 26648662 TI - Plasma Nitration of High-Density and Low-Density Lipoproteins in Chronic Kidney Disease Patients Receiving Kidney Transplants. AB - BACKGROUND: Functional abnormalities of high-density lipoprotein (HDL) could contribute to cardiovascular disease in chronic kidney disease patients. We measured a validated marker of HDL dysfunction, nitrated apolipoprotein A-I, in kidney transplant recipients to test the hypothesis that a functioning kidney transplant reduces serum nitrated apoA-I concentrations. METHODS: Concentrations of nitrated apoA-I and apoB were measured using indirect sandwich ELISA assays on sera collected from each transplant subject before transplantation and at 1, 3, and 12 months after transplantation. Patients were excluded if they have history of diabetes, treatment with lipid-lowering medications or HIV protease inhibitors, prednisone dose > 15 mg/day, nephrotic range proteinuria, serum creatinine > 1.5 mg/dL, or active inflammatory disease. Sera from 18 transplanted patients were analyzed. Four subjects were excluded due to insufficient data. Twelve and eight patients had creatinine < 1.5 mg/dL at 3 and 12 months after transplantation, respectively. RESULTS. Nitrated apoA-I was significantly reduced at 12 months after transplantation (p = 0.039). The decrease in apoA-I nitration was associated with significant reduction in myeloperoxidase (MPO) activity (p = 0.047). In contrast to apoA-I, nitrated apoB was not affected after kidney transplantation. CONCLUSIONS: Patients with well-functioning grafts had significant reduction in nitrated apoA-I 12 months after kidney transplantation. Further studies are needed in a large cohort to determine if nitrated apoA-I can be used as a valuable marker for cardiovascular risk stratification in chronic kidney disease. PMID- 26648664 TI - Sphingolipids in High Fat Diet and Obesity-Related Diseases. AB - Nutrient oversupply associated with a high fat diet (HFD) significantly alters cellular metabolism, and specifically including sphingolipid metabolism. Sphingolipids are emerging as bioactive lipids that play key roles in regulating functions, in addition to their traditional roles as membrane structure. HFD enhances de novo sphingolipid synthesis and turnover of sphingolipids via the salvage pathway, resulting in the generation of ceramide, and more specifically long chain ceramide species. Additionally, HFD elevates sphingomyelin and sphingosine-1 phosphate (S1P) levels in several tissues including liver, skeletal muscle, adipose tissue, and cardiovascular tissues. HFD-stimulated sphingolipid generation contributes to systemic insulin resistance, dysregulated lipid accumulation, and cytokine expression and secretion from skeletal muscle and adipose tissues, exacerbating obesity-related conditions. Furthermore, altered sphingolipid levels, particularly ceramide and sphingomyelin, are involved in obesity-induced endothelial dysfunction and atherosclerosis. In this review, HFD mediated sphingolipid metabolism and its impact on HFD-induced biology and pathobiology will be discussed. PMID- 26648666 TI - Significance of Reflux Abolition at the Saphenofemoral Junction in Connection with Stripping and Ablative Methods. AB - Saphenous reflux interferes with the physiological decrease in pressure and induces ambulatory venous hypertension. Elimination of reflux is achieved by flush ligation at the incompetent saphenofemoral junction and stripping of the great saphenous vein, which is the basis of the conventional surgical therapy. Endovenous ablative methods substitute stripping by thermal of chemical destruction of the saphenous trunk; they usually refrain from saphenofemoral junction ligation. Short-term and medium-term results up to 5 years, achieved after endovenous ablation without high ligation, are comparable with those after conventional surgery, which questioned the necessity to ligate the incompetent saphenofemoral junction. Nevertheless, clinical symptoms caused by recurrent reflux occur as a rule not earlier than 8 to 10 years after efficient abolition of reflux. Consequently, randomized studies with long-term follow-ups exceeding 10 years are necessary for trustworthy assessment whether it is justified to abstain from saphenofemoral junction ligation. PMID- 26648667 TI - Comparison of the Quality of Life after Skeletonized versus Pedicled Grafts in Coronary Artery Bypass Graft Surgery. AB - It remains a controversial issue whether internal thoracic artery (ITA) should be dissected in skeletonized or pedicled manner during coronary artery bypass graft (CABG) surgery. The main objective of this cohort study was to compare skeletonized versus pedicled grafts on the basis of patients' perceptions of their physical and mental well-being. Isolated nonemergent CABG patients were divided into two groups according to the type of graft used; skeletonized or pedicled. The quality of life (QOL) was measured preoperatively, 6 months postoperatively, and 12 months postoperatively for each patient using the 36-Item Short Form Health Survey tool. The main outcome variables were physical component summary (PCS) score and mental component summary (MCS) score. A total of 140 patients were included in the study with 70 patients in each group. The PCS (p value = 0.235) and MCS (p-value = 0.239) scores of patients were similar in both the groups before CABG. The PCS and MCS scores were significantly (p-values < 0.0001) improved after CABG at 6 months in both the groups. However, the PCS and MCS scores in the skeletonized group were significantly higher (p-values < 0.0001) than the scores in the pedicled group at 6 and 12 months post-CABG. Both the harvesting techniques improve QOL significantly after CABG. However, skeletonization results in significantly better PCS and MCS scores compared with pedicled harvesting technique. PMID- 26648665 TI - Distinct Functions of Neutrophil in Cancer and Its Regulation. AB - Neutrophils are the most abundant of all white blood cells in the human circulation and are usually associated with inflammation and with fighting infections. In recent years the role immune cells play in cancer has been a matter of increasing interest. In this context the function of neutrophils is controversial as neutrophils were shown to possess both tumor promoting and tumor limiting properties. Here we provide an up-to-date review of the pro- and antitumor properties neutrophils possess as well as the environmental cues that regulate these distinct functions. PMID- 26648668 TI - A Clinical Comparison of Pycnogenol, Antistax, and Stocking in Chronic Venous Insufficiency. AB - This 8-week registry study was a comparative evaluation of Pycnogenol (French Maritime Pine Bark extract; Horphag Research, Geneva) and Antistax (grape leaf extract [GLE, Boehringer Ingelheim, Germany]) in controlling symptoms of chronic venous insufficiency (CVI). "Standard management" for CVI is compression; a group of comparable subjects was monitored to evaluate the effects of stockings. The registry included 183 patients (166 completing). Supplementation with Antistax (two tablets of 360 mg/d) or Pycnogenol (100 mg/d) was used. The groups were comparable for age, symptoms, venous incompetence, and microcirculation (with increased capillary filtration and skin flux) at inclusion. At 8 weeks, the rate of swelling (p < 0.05) and skin flux decreased toward normal values; changes were more important with Pycnogenol (p < 0.05). Transcutaneous Po 2 was increased more with Pycnogenol (p < 0.05). Ankle circumference was decreased more (p < 0.05) with Pycnogenol. An analog scale quantified symptoms. At 8 weeks, pain and edema were decreased with Pycnogenol and elastic compression (p < 0.05) with prevalence for Pycnogenol (p < 0.05). Edema with Pycnogenol was decreased by 40%. Induration was reduced only in the Pycnogenol group (p < 0.05) with minimal variations in the other groups. Tolerability and compliance were optimal. Elastic compression was correctly used by 80% of the patients indicating that it may be more difficult to use, particularly in warmer days. Costs for Pycnogenol were lower (96; 3.3 Euros) in comparison with the other groups (132;1.4 Euros for GLE and 149; 2.2 Euros for compression). PMID- 26648669 TI - Any Degree of Mitral Regurgitation Found during Invasive Ventriculography is Associated with All-Cause Mortality. AB - Background Using a large database of patients who underwent cardiac catheterization for clinical reasons, we evaluated any association between reported degrees of mitral regurgitation (MR) found during ventriculography, and all-cause mortality. Method Using retrospective angiographic data (collected from the years 1993-1997) from 1,771 patients of the VA Long Beach Health Care System with documented ventriculography, we evaluated any association between various degrees of MR and all-cause mortality. We performed uni- and multivariant analysis, adjusting for age and ejection fraction. Results Any degree of MR was associated with all-cause mortality. Total mortality was 20.2% (296/1,465) in patients with no MR versus 32.7% in patients with mild MR (64/196), p < 0.001. Similar to mild MR, any degree of MR was independently associated with all-cause mortality (all MR, 35.1%, [108/306] vs. no MR, 20.2% [296/1,465], p < 0.001). After adjustment for age and comorbidities, any degree of MR remained independently associated with all-cause mortality (multivariate adjusted odds ratio, 1.7; confidence interval, 1.2-2.3; p < 001). Conclusion The presence of any MR documented on invasive ventriculography is associated with increased total mortality independent of age or ejection fraction. Our finding suggests that even mild MR has negative prognostic significance. PMID- 26648670 TI - Coronary Artery Disease Severity and Cardiovascular Biomarkers in Patients with Peripheral Artery Disease. AB - Cardiovascular mortality in peripheral artery disease (PAD) patients is higher in critical limb ischemia (CLI) than in intermittent claudication (IC). We sought to evaluate differential characteristics of coronary artery disease (CAD) severity and prognostic biomarkers for cardiovascular events between CLI and IC patients. Coronary angiography was performed on 242 PAD patients (age 73 +/- 8 years) with either CLI or IC. High-sensitivity troponin T (hs-TnT), eicosapentaenoic acid arachidonic acid ratio (EPA/AA), and lipoprotein(a), as biomarkers for prognostic factors, were measured from blood samples. The study patients were divided into a CLI-group (n = 42) and IC-group (n = 200). The Gensini score as an indicator of coronary angiographic severity was higher in the CLI-group than in the IC-group (39.1 +/- 31.2 vs. 8.5 +/- 8.3, p < 0.0001). Hs-TnT and lipoprotein(a) values were higher in the CLI-group than in the IC-group (0.152 +/- 0.186 ng/mL vs. 0.046 +/- 0.091, p < 0.0001, 45.9 +/- 23.3 mg/dL vs. 26.2 +/- 27.7, p = 0.0002, respectively) and EPA/AA was lower in the CLI-group than in the IC-group (0.22 +/ 0.11 vs. 0.38 +/- 0.29, p = 0.0049, respectively). Greater CAD severity, higher hs-TnT, and lipoprotein(a), and lower EPA/AA were observed in the CLI-group, which may explain higher cardiovascular events in patients with CLI. PMID- 26648671 TI - Role of Coronary Calcium Scoring in the Assessment of Physiological Ischemia in Patients with Intermediate Stenosis. AB - Although coronary artery calcium (CAC) is an established marker of coronary atherosclerosis, whether it also reflects the physiological significance is unknown. This study aims to evaluate if CAC could indicate physiological ischemia in intermediate stenosis defined by an invasive fractional flow reserve (FFR). CAC score (CACS) derived from either whole coronary arteries or individual arteries was measured by computed tomography among patients with intermediate de novo lesions (percent diameter stenosis from 30% to less than 70%). All stenoses were evaluated by invasive FFR; lesions with an FFR <= 0.80 were considered significant. We enrolled 119 patients with 143 lesions. Of these, 42 lesions (29.4%) demonstrated significant ischemia by FFR measurement. FFR values had modest but significant correlations with CACS in individual arteries with intermediate stenosis (r = - 0.290; p < 0.001). A receiver operating characteristic curve analysis showed that CACS of individual arteries with intermediate stenosis had 71.4% sensitivity and 67.3% specificity as a predictor of significant ischemia at a cut off value of 145.9. Multivariable analysis showed that percent diameter stenosis and CACS in individual arteries with intermediate stenosis were independent predictors for significant ischemia. By net reclassification improvement analysis, CACS in individual arteries with intermediate stenosis provided incremental prediction for significant ischemia over minimum lumen diameter, percent diameter stenosis, and lesion length. CACS measured in each artery, but not the total CACS, provides additional information as to whether an angiographically intermediate stenosis within the artery is significant enough to cause myocardial ischemia. PMID- 26648672 TI - Catheter-Directed Thrombolysis Is a Safe and Alternative Therapeutic Approach in the Management of Postpartum Lower Limb Deep Venous Thrombosis. AB - Deep vein thrombosis (DVT) is a major health problem in pregnancy and postpartum period. Catheter-directed thrombolysis (CDT) is safe and effective in management of symptomatic DVT. Value of CDT in postpartum DVT is not fully evaluated. We describe five patients presenting with acute iliofemoral DVT in their early postpartum period who were treated with mechanical thromboaspiration and CDT. The CDT was done using streptokinase infusion and unfractionated heparin. Percutaneous angioplasty was done in patients with symptomatic residual lesion following thrombolysis. Patients were discharged with oral anticoagulant and compression stockings. This approach was successful in all four cases. Percutaneous endovascular therapy using CDT, mechanical thromboaspiration, and balloon angioplasty is safe and effective in iliofemoral DVT in postpartum period. PMID- 26648674 TI - A Case Report: Successful Management of an Aortic Saddle Embolism in a 28-Year Old Female. AB - The obstruction of blood flow at the aortic bifurcation by an embolus defines aortic saddle embolism (ASE). This rare entity occurs preferentially in individuals with cardiovascular diseases such as the middle aged and the elderly. Conversely, its occurrence is sporadic in younger patients. As a result, the diagnosis of ASE is often overlooked or delayed in this age group; therefore, putting these patients at significant risk of neurologic impairment and potential limb loss. Following an extensive literature review, we have found only one reported case of ASE in a patient younger than 30 years. This patient died within 24 hours of admission and was diagnosed with ASE at autopsy. Here, we report for the first time, a case of a successful management of an ASE in a 28-year-old female who presented at our emergency room with acute weakness and numbness of the lower extremities. After vascular consult, the diagnosis of ASE was made and the patient was treated successfully. A week later, the patient was discharged home in stable condition without complications. The purpose of this report is to raise awareness about this potentially fatal condition and emphasize the importance of rapid assessment and treatment. The treatment options are heparin infusion, thrombolytic therapy, and embolectomy. PMID- 26648673 TI - Axillary Artery Injury Accompanying Humeral Neck Fracture. AB - Injuries to the axillary artery from proximal humeral fractures are uncommon. There are only 66 such injuries reported across the world literature to date. We report an additional case of axillary artery injury. This case highlights the importance of maintaining a high index of suspicion to prevent diagnostic delay. PMID- 26648675 TI - Dr. Fritz Kaindl (April 19, 1922 to September 13, 2015): A Tribute. PMID- 26648678 TI - Robot-Assisted Radical Prostatectomy After Previous Prostate Surgery. AB - BACKGROUND AND OBJECTIVES: Our objective is to clarify the effect of previous transurethral resection of the prostate (TURP) or open prostatectomy (OP) on surgical, oncological, and functional outcomes after robot-assisted radical prostatectomy (RARP). METHODS: Between August 1, 2009, and March 31, 2013, 380 patients underwent RARP. Of these, 25 patients had undergone surgery for primary bladder outlet obstruction (TURP, 20 patients; OP, 5 patents) (group 1). A match paired analysis was performed to identify 36 patients without a history of prostate surgery with equivalent clinicopathologic characteristics to serve as a control group (group 2). Patients followed up for 12 months were assessed. RESULTS: Both groups were similar with respect to preoperative characteristics, as mean age, body mass index, median prostate-specific antigen, prostate volume, clinical stage, the biopsy Gleason score, D'Amico risk, the American Society of Anesthesiologists (ASA) classification score, the International Prostate Symptom Score, continence, and potency status. RARP resulted in longer console and anastomotic time, as well as higher blood loss compared with surgery-naive patients. We noted a greater rate of urinary leakage (pelvic drainage, >4 d) in group 1 (12% vs 2,8%). The anastomotic stricture rate was significantly higher in group 1 (16% vs 2.8%). No difference was found in the pathologic stage, positive surgical margin, and nerve-sparing procedure between the groups. Biochemical recurrence was observed in 12% (group 1) and 11.1% (group 2) of patients, respectively. No significant difference was found in the continence and potency rates. CONCLUSIONS: RARP after TURP or OP is a challenging but oncologically promising procedure with a longer console and anastomosis time, as well as higher blood loss and higher anastomotic stricture rate. PMID- 26648676 TI - Laparoscopic Radiofrequency Thermal Ablation for Uterine Adenomyosis. AB - BACKGROUND AND OBJECTIVES: Symptomatic uterine adenomyosis, unresponsive to medical therapy, is a challenging condition for patients who desire to preserve their uterus. This study was an evaluation of the feasibility and efficacy of laparoscopic radiofrequency thermal ablation of symptomatic nodular uterine adenomyosis. METHODS: Fifteen women with symptomatic nodular adenomyosis, who had no plans for pregnancy but declined hysterectomy, underwent radiofrequency thermal ablation. Ultrasonography was performed at baseline and at postoperative follow-ups at 3, 6, 9, and 12 months. The impact of uterine adenomyosis-related symptoms was assessed according to the visual analog scale. RESULTS: The median number of nodular lesions treated per patient was 1 (range, 1-2). The median baseline volume of the adenomyosis area was 60 cm(3) (range, 18-128). The median reduction in volume was 32, 49.4, 59.6, and 65.4% at 3, 6, 9, and 12 months, respectively. A significant progressive improvement in the symptoms score was observed at the 4 follow-ups. CONCLUSION: In this study, laparoscopic radiofrequency thermal ablation reduced uterine adenomyosis-related symptoms and volume, with significant relief of symptoms. PMID- 26648677 TI - A Technique for Simultaneous Cholecystectomy During Bariatric Surgery. AB - BACKGROUND AND OBJECTIVES: Cholecystectomy performed during bariatric surgery is technically demanding. Herein is described a technique we term the Glissonian approach along with an evaluation of its effectiveness and safety. METHODS: From April 1, 2009, through February 28, 2014, laparoscopic cholecystectomy was performed during laparoscopic Roux-en-Y gastric bypass (LRYGB) or laparoscopic sleeve gastrectomy (LSG) in 38 patients with proven cholecystopathy on diagnostic imaging. Perioperative outcomes were compared between the patients operated on with the Glissonian approach and those who underwent conventional laparoscopic cholecystectomy. RESULTS: The Glissonian approach was adopted in 13 patients-11 during LRYGB and 2 during LSG-and the conventional operation was performed on 16 patients during LRYGB and 9 during LSG. Mean body mass indexes were 40.1 kg/m(2) in the Glissonian-approach group and 37.6 kg/m(2) in the conventional group. Laparoscopic cholecystectomy by the Glissonian approach saved a mean operative time of 7 minutes compared with the operative time of the conventional operation. No surgical complications related to cholecystectomy were noted in either group. CONCLUSION: This simple technique can be performed safely in morbidly obese patients, with low resultant morbidity and acceptable operation times. PMID- 26648679 TI - Upper Tract Urological Laparoendoscopic Single-Site Surgery (LESS). AB - BACKGROUND AND OBJECTIVES: Our objective is to report intermediate-term outcomes for patients who have undergone upper tract urologic laparoendoscopic single-site surgery (LESS) at a single institution. METHODS: From January 1, 2008, through November 30, 2012, 107 cases treated with LESS were identified, including pyeloplasty (n = 30), ureterolithotomy (n = 32), nephrectomy (n = 35; simple = 31, partial = 4), and cyst decortication (n = 10). Perioperative data were reviewed, and conversion and complication rates were noted. RESULTS: The median follow-up was 21.5 months for pyeloplasty, 20.5 for ureterolithotomy, 28.0 for simple nephrectomy, 14.0 for partial nephrectomy, and 19.0 for cyst decortication. Major complications were encountered in 8 patients, including 3 intraoperative complications (2 bowel injury with serosal tearing and 1 intraoperative bleeding), which were recognized and repaired with LESS or conversion to conventional laparoscopy (CL). During the intermediate postoperative period (30-90 days) major complications occurred in 5 patients: 4 ureteral strictures (Clavien-Dindo grade [CG] IIIb) and 1 urinoma formation (CG IIIa). During the early postoperative period (<30 days), the most common minor complications were flank pain (CG I) in 16 patients and urinary tract infection (CG II) in 11, followed by urinary leakage (CG I) in 8. CONCLUSIONS: Intermediate term functional outcomes of this single-center study confirm that upper tract LESS is a challenging procedure that can be safe and effective when performed by an experienced team. Prospective studies with longer follow-up periods are needed to investigate the safety of LESS in the treatment of various upper urinary tract conditions. PMID- 26648680 TI - A Comparison of Single-, Two- and Three-Port Laparoscopic Myomectomy. AB - BACKGROUND AND OBJECTIVE: A recent FDA safety communication has discouraged the use of a power morcellator for myoma extraction and has called for a change in surgical techniques for myomectomy. The objective of this study was to compare surgical outcomes of laparoscopic single-, two-, and conventional three-port myomectomy and to evaluate the feasibility of contained manual morcellation for uterine myoma. METHODS: This retrospective study was a review and analysis of data from 191 consecutive women who underwent single-, two-, or three-port myomectomy for the management of uterine myoma from January 1, 2009, through December 31, 2014. RESULTS: The 3 study groups did not differ demographically. Apart from operative time, the single- and two-port groups showed operative outcomes comparable to those of the multiport group. The single-port group had significantly longer operative times (P = .0053) than the two- and three-port groups. However, in the latter half of the single-port cases, the operative time was similar to those in the three-port group. The two-port surgery group showed a consistent operative time without a learning period. CONCLUSION: Single- or two port myomectomy with transumbilical myoma morcellation is feasible and safe, with outcomes comparable to those of three-port myomectomy. These results suggest the potential for minimally invasive management of symptomatic uterine myoma, without the use of a power morcellator. PMID- 26648681 TI - SUMAC: Constructing Phylogenetic Supermatrices and Assessing Partially Decisive Taxon Coverage. AB - The amount of phylogenetically informative sequence data in GenBank is growing at an exponential rate, and large phylogenetic trees are increasingly used in research. Tools are needed to construct phylogenetic sequence matrices from GenBank data and evaluate the effect of missing data. Supermatrix Constructor (SUMAC) is a tool to data-mine GenBank, construct phylogenetic supermatrices, and assess the phylogenetic decisiveness of a matrix given the pattern of missing sequence data. SUMAC calculates a novel metric, Missing Sequence Decisiveness Scores (MSDS), which measures how much each individual missing sequence contributes to the decisiveness of the matrix. MSDS can be used to compare supermatrices and prioritize the acquisition of new sequence data. SUMAC constructs supermatrices either through an exploratory clustering of all GenBank sequences within a taxonomic group or by using guide sequences to build homologous clusters in a more targeted manner. SUMAC assembles supermatrices for any taxonomic group recognized in GenBank and is optimized to run on multicore computer systems by parallelizing multiple stages of operation. SUMAC is implemented as a Python package that can run as a stand-alone command-line program, or its modules and objects can be incorporated within other programs. SUMAC is released under the open source GPLv3 license and is available at https://github.com/wf8/sumac. PMID- 26648682 TI - High Expression of Three-Gene Signature Improves Prediction of Relapse-Free Survival in Estrogen Receptor-Positive and Node-Positive Breast Tumors. AB - The objective of the present study was to validate prognostic gene signature for estrogen receptor alpha-positive (ER03B1+) and lymph node (+) breast cancer for improved selection of patients for adjuvant therapy. In our previous study, we identified a group of seven genes (GATA3, NTN4, SLC7A8, ENPP1, MLPH, LAMB2, and PLAT) that show elevated messenger RNA (mRNA) expression levels in ERalpha (+) breast cancer patient samples. The prognostic values of these genes were evaluated using gene expression data from three public data sets of breast cancer patients (n = 395). Analysis of ERalpha (+) breast cancer cohort (n = 195) showed high expression of GATA3, NTN4, and MLPH genes significantly associated with longer relapse-free survival (RFS). Next cohort of ERalpha (+) and node (+) samples (n = 109) revealed high mRNA expression of GATA3, SLC7A8, and MLPH significantly associated with longer RFS. Multivariate analysis of combined three gene signature for ERalpha (+) cohort, and ERalpha (+) and node (+) cohorts showed better hazard ratio than individual genes. The validated three-gene signature sets for ERalpha (+) cohort, and ERalpha (+) and node (+) cohort may have potential clinical utility since they demonstrated predictive and prognostic ability in three independent public data sets. PMID- 26648683 TI - Retinitis pigmentosa with concomitant essential iris atrophy and glaucoma - case report. AB - PURPOSE: To report a case of a young patient with retinitis pigmentosa (RP), essential iris atrophy, and glaucoma. CASE REPORT: This report presents a case of a 22-year-old female patient with unilateral glaucoma, increased intraocular pressure, increased cup-disc ratio, iris atrophy, peripheral anterior synechiae, and bilateral RP. DISCUSSION: The patient presented glaucoma due to the iridocorneal endothelial syndrome, despite low age. RP is a bilateral disorder that may be associated with angle-closure glaucoma. PMID- 26648685 TI - Recent advances and future prospects in choroideremia. AB - Choroideremia is a complex and rare disease that is frequently misdiagnosed due to its similar appearance to classic retinitis pigmentosa. Recent advances in genetic testing have identified specific genetic mutations in many retinal dystrophies, and the identification of the mutation of the CHM gene on the X chromosome 25 years ago has paved the way for gene replacement therapy with the first human trials now underway. This article reviews the epidemiological and pathological features of choroideremia and new prospects in imaging to monitor disease progression, as well as potential treatment approaches for choroideremia. PMID- 26648684 TI - Update on genetics and diabetic retinopathy. AB - Clinical risk factors for diabetic retinopathy (DR), such as duration of disease and degree of glucose control, do not adequately predict disease progression in individual patients, suggesting the presence of a genetic component. Multiple smaller studies have investigated genotype-phenotype correlations in genes encoding vascular endothelial growth factor, aldose reductase, the receptor for advanced glycation end products, and many others. In general, reported results have been conflicting, due to factors including small sample sizes, variations in study design, differences in clinical end points, and underlying genetic differences between study groups. At this time, there is no confirmed association with any risk allele reported. As we continue to collect data from additional studies, the role of genetics in DR may become more apparent. PMID- 26648686 TI - Clinical effectiveness of brinzolamide 1%-brimonidine 0.2% fixed combination for primary open-angle glaucoma and ocular hypertension. AB - The main first-line treatment strategy for glaucoma is to reduce intraocular pressure (IOP) by topical ocular hypotensive medications, but many patients require multiple medications for adequate IOP control. Fixed-combination therapies provide several benefits, including simplified treatment regimens, theoretical improved treatment adherence, elimination of the potential for washout of the first drug by the second, and the reduction in ocular exposure to preservatives. beta-Adrenoceptor antagonists (particularly 0.5% timolol) are the most commonly used agents in combination with other classes of drugs as fixed combination eyedrops, but they are contraindicated in many patients, owing to local allergy or systemic side effects. A fixed-combination preparation without a beta-blocker is therefore warranted. This paper reviews the clinical effectiveness of brinzolamide 1% and brimonidine 0.2% fixed combination (BBFC) for use in patients with primary open-angle glaucoma and ocular hypertension. We searched PubMed and the ClinicalTrials.gov registry, and identified three randomized controlled trials comparing BBFC vs its constituents (brimonidine vs brinzolamide), and one comparing BBFC with unfixed brimonidine and brinzolamide. All of the studies demonstrated mean diurnal IOP to be statistically significantly lower in the BBFC group compared with constituent groups and noninferior to that with the concomitant group using two separate bottles. The safety profile of BBFC was consistent with that of its individual components, the most common ocular adverse events being ocular hyperemia, visual disturbances, and ocular allergic reactions. Common systemic adverse effects included altered taste sensation, oral dryness, fatigue, somnolence, and decreased alertness. BBFC seems to be a promising new fixed combination for use in glaucoma patients. However, long-term effects of BBFC on IOP, treatment adherence, and safety need to be determined. PMID- 26648687 TI - Pediatric glaucoma medical therapy: who more accurately reports medication adherence, the caregiver or the child? AB - As they grow older, most children with glaucoma must eventually face the transition to self-administering medications. We previously reported factors associated with better or worse medication adherence in children with glaucoma, using an objective, electronic monitor. Utilizing the same data set, the purpose of the current study was to determine whose report (the caregiver's or the child's) corresponded better with electronically monitored adherence. Of the 46 participants (22 girls), the mean age of children primarily responsible, and caregiver primarily responsible for medication administration was 15+/-2 and 10+/ 2 years, respectively. For the children whose caregiver regularly administered the eyedrops, the caregiver's assessment of drop adherence was associated with measured adherence (P=0.012), but the child's was not (P=0.476). For the children who self-administered eyedrops, neither the child's (P=0.218) nor the caregiver's (P=0.395) assessment was associated with measured percent adherence. This study highlights potential errors when relying on self-reporting of compliance in patients and caregivers with pediatric glaucoma, particularly when the child is responsible for administering their own eyedrops. Frank discussions about the importance of medication adherence and how to improve compliance may help both the child and caregiver better communicate with the treating provider. PMID- 26648688 TI - Argus II retinal prosthesis malrotation and repositioning with intraoperative optical coherence tomography in a posterior staphyloma. AB - INTRODUCTION: The Argus II retinal prosthesis may improve visual function in patients with severe vision loss from retinitis pigmentosa. Optimal centration of the electrode array over the macula is important to achieve optimal visual results. Argus tack malrotation is a novel entity that may be encountered during placement, especially in patients with posterior staphyloma. METHODS: Retrospective case review. RESULTS: During tacking of the electronics array a clockwise rotation occurred resulting in malposition. We hypothesize this was secondary to undue rotation or posterior pressure applied during tack insertion in conjunction with placement over a previously unrecognized posterior staphyloma. Intraoperative optical coherence tomography, because of the cross sectional images provided, was helpful in visualizing the distance between the electronics array and the retina, which was difficult to assess using the surgical microscope alone. Repositioning was achieved by adjusting the tack without removal. The patient experienced an improvement in vision as a result of the surgery. CONCLUSION: Malrotation may occur when tacking the Argus II prosthesis, and the presence of a posterior staphyloma may increase this risk. It is important to differentiate malrotation from tack misplacement - the former may be addressed with array unrotation or partial tack withdrawal and the latter may require tack removal and reinsertion. Also, intraoperative optical coherence tomography may be helpful in characterizing electronics array position during surgery. PMID- 26648689 TI - Relationship between consecutive deterioration of mean deviation value and progression of visual field defect in open-angle glaucoma. AB - PURPOSE: To analyze the relationship between consecutive deterioration of mean deviation (MD) value and glaucomatous visual field (VF) progression in open-angle glaucoma (OAG), including primary OAG and normal tension glaucoma. PATIENTS AND METHODS: The subjects of the study were patients undergoing treatment for OAG who had performed VF tests at least 10 times with a Humphrey field analyzer (SITA standard, C30-2 program). The VF progression was defined by a significantly negative MD slope (MD slope worsening) at the final VF test during the follow-up period. The relationship between the MD slope worsening and the consecutive deterioration of MD value were retrospectively analyzed. RESULTS: A total of 165 eyes of 165 patients were included in the analysis. Significant progression of VF defects was observed in 72 eyes of 72 patients (43.6%), while no significant progression was evident in 93 eyes of 93 patients (56.4%). There was significant relationship between the frequency of consecutive deterioration of MD value and MD slope worsening (P<0.0001, Cochran-Armitage trend test). A significant association was observed for MD slope worsening in the eyes with three (odds ratio: 2.1, P=0.0224) and four (odds ratio: 3.6, P=0.0008) consecutive deterioration of MD value in multiple logistic regression analysis, but no significant association in the eyes with two consecutive deterioration (odds ratio: 1.1, P=0.8282). The eyes with VF progression had significantly lower intraocular pressure reduction rate (P<0.01). CONCLUSION: This retrospective study has shown that three or more consecutive deterioration of MD value might be a predictor to future significant MD slope worsening in OAG. PMID- 26648690 TI - Ocular tuberculosis: current perspectives. AB - The World Health Organization currently estimates that nearly two billion people, or one-third of the world's population, are infected by tuberculosis, and that roughly 10% of the infected people are symptomatic. Tuberculosis affects the lungs in 80% of patients, while in the remaining 20% the disease may affect other organs, including the eye. Uveitis can be seen concurrently with tuberculosis, but a direct association is difficult to prove. Ocular tuberculosis is usually not associated with clinical evidence of pulmonary tuberculosis, as up to 60% of extrapulmonary tuberculosis patients may not have pulmonary disease. The diagnosis of tuberculous uveitis is often problematic and in nearly all reported cases, the diagnosis was only presumptive. Tuberculous uveitis is a great mimicker of various uveitis entities and it can be considered in the differential diagnosis of any type of intraocular inflammation. It is still unknown if ocular manifestations result from a direct mycobacterium infection or hypersensitivity reaction and this is reflected on the management of tuberculous uveitis. Prevalence of tuberculosis as an etiology of uveitis may reach up to 10% in endemic areas. Tuberculous uveitis is a vision-threatening disease that inevitably leads to blindness if not properly diagnosed and treated. The aim of this review is to illustrate the various clinical features and management of presumed tuberculous uveitis. The current review focuses on the diagnostic criteria, significance of tuberculin skin test, and use of systemic corticosteroids in the management of tuberculous uveitis as recommended in recent publications. PMID- 26648691 TI - Use of letrozole and clomiphene citrate combined with gonadotropins in clomiphene resistant infertile women with polycystic ovary syndrome: a prospective study. AB - BACKGROUND: Gonadotropin has been used to stimulate ovulation in clomiphene resistant infertile women with polycystic ovary syndrome (PCOS), but it is associated with overstimulated cycles with the development of many follicles. The aim of the study was to evaluate the effectiveness and efficacy of letrozole and clomiphene citrate (CC) combined with human menopausal gonadotropin (HMG) in CC resistant infertile women with PCOS. METHODS: Ninety-four women received the letrozole + HMG, 90 women received CC + HMG, and 71 women received HMG only. All women received one treatment regimen in one treatment cycle. All patients were given HMG 75 IU on alternate days daily starting on day 3 or day 7 until the day of administration of human chorionic gonadotropin. RESULTS: The rate of monofollicular development was 80.2% in the letrozole + HMG group, 65.3% in the CC + HMG group, and 54.7% in the HMG-only group (P<0.05 for letrozole + HMG vs the other two groups). The number of developing follicles (>=14 mm follicles) and the cycle cancellation rate due to ovarian hyperresponse were the lowest in the letrozole + HMG group, but the difference was not significant. The ovulation and pregnancy rate were similar among the three protocols. The HMG dose needed and the mean duration of treatment were significantly lower in the letrozole + HMG and CC + HMG groups compared with the HMG-only group. CONCLUSION: Letrozole in combination with HMG is an effective protocol for reducing the risks of hyperstimulation for ovarian induction in CC-resistant women with PCOS. This combination may be more appropriate in patients who are particularly sensitive to gonadotropin. PMID- 26648692 TI - Profile of suvorexant in the management of insomnia. AB - Suvorexant, approved in late 2014 in the United States and Japan for the treatment of insomnia characterized by difficulty achieving and/or maintaining sleep, is a dual orexin receptor antagonist and the first drug in its class to reach the market. Its development followed from the 1998 discovery of orexins (also called hypocretins), excitatory neuropeptides originating from neurons in the hypothalamus involved in regulation of sleep and wake, feeding behavior and energy regulation, motor activity, and reward-seeking behavior. Suvorexant objectively improves sleep, shortening the time to achieve persistent sleep and reducing wake after sleep onset, although at approved doses (<=20 mg) the benefit was subjectively assessed as modest. Its half-life of 12 hours is relatively long for a modern hypnotic; however, at approved doses (<=20 mg) next-day sedation and driving impairment were much less apparent than at higher doses. Suvorexant is metabolized by the hepatic CYP3A system and should be avoided in combination with strong CYP3A inhibitors. Drug levels are higher in women and obese people; hence, dosing should be conservative in obese women. Administration with food delays drug absorption and is not advised. No dose adjustment is needed for advanced age, renal impairment, or mild-to-moderate hepatic impairment. Suvorexant in contraindicated in narcolepsy and has not been studied in children. In alignment with the changes begun in 2013 in the labeling of other hypnotics, the United States Food and Drug Administration advises that the lowest dose effective to treat symptoms be used and that patients be advised of the possibility of next day impairment in function, including driving. Infrequent but notable side effects included abnormal dreams, sleep paralysis, and suicidal ideation that were dose-related and reported to be mild. Given its mechanism of action, cataplexy and rapid eye movement (REM) sleep behavior disorder could potentially occur in some patients taking this medication. PMID- 26648694 TI - A single-arm Phase II validation study of preventing oxaliplatin-induced hypersensitivity reactions by dexamethasone: the AVOID trial. AB - BACKGROUND: Patients with colorectal cancer treated with oxaliplatin are at risk of hypersensitivity reactions, with the incidence estimated to be 12%-20%. Coinfusion of dexamethasone and oxaliplatin could potentially reduce the incidence of these reactions, but oxaliplatin is reported to be incompatible with alkaline compounds in solution. However, in a previous retrospective study we found that the pH of a solution of dexamethasone and oxaliplatin was less than 7.4, and that hypersensitivity to oxaliplatin could have been prevented by coinfusion of dexamethasone. We aimed to evaluate the effectiveness of coinfusion of dexamethasone and oxaliplatin to prevent oxaliplatin-induced hypersensitivity reactions. PATIENTS AND METHODS: The AVOID trial was a prospective, multicenter, open-label, single-arm Phase II trial conducted from January to September 2013. The study included 73 patients who received capecitabine plus oxaliplatin (XELOX) or XELOX plus bevacizumab therapy for colorectal cancer. In all patients, oxaliplatin was administered in combination with dexamethasone. The primary outcome measure was the presence of hypersensitivity reactions. RESULTS: Hypersensitivity reactions occurred in three patients (4.1%); all three experienced a cutaneous reaction (grade 1 erythema). None of the 73 patients developed respiratory symptoms, ocular symptoms, or anaphylaxis. Grade 3 or higher hemotoxicity occurred in 13.7% of the patients and grade 3 or higher nonhematological toxicity occurred in 13.7%. The response rate to treatment was 64.4%. CONCLUSION: The coinfusion of dexamethasone and oxaliplatin effectively reduced oxaliplatin-induced hypersensitivity reactions in patients with colorectal cancer. This approach should be considered for all patients treated with oxaliplatin, allowing treatment to be completed as planned. PMID- 26648693 TI - Attenuation of myocardial fibrosis with curcumin is mediated by modulating expression of angiotensin II AT1/AT2 receptors and ACE2 in rats. AB - Curcumin is known to improve cardiac function by balancing degradation and synthesis of collagens after myocardial infarction. This study tested the hypothesis that inhibition of myocardial fibrosis by curcumin is associated with modulating expression of angiotensin II (Ang II) receptors and angiotensin converting enzyme 2 (ACE2). Male Sprague Dawley rats were subjected to Ang II infusion (500 ng/kg/min) using osmotic minipumps for 2 and 4 weeks, respectively, and curcumin (150 mg/kg/day) was fed by gastric gavage during Ang II infusion. Compared to the animals with Ang II infusion, curcumin significantly decreased the mean arterial blood pressure during the course of the observation. The protein level of the Ang II type 1 (AT1) receptor was reduced, and the Ang II type 2 (AT2) receptor was up-regulated, evidenced by an increased ratio of the AT2 receptor over the AT1 receptor in the curcumin group (1.2+/-0.02%) vs in the Ang II group (0.7+/-0.03%, P<0.05). These changes were coincident with less locally expressed AT1 receptor and enhanced AT2 receptor in the intracardiac vessels and intermyocardium. Along with these modulations, curcumin significantly decreased the populations of macrophages and alpha smooth muscle actin-expressing myofibroblasts, which were accompanied by reduced expression of transforming growth factor beta 1 and phosphorylated-Smad2/3. Collagen I synthesis was inhibited, and tissue fibrosis was attenuated, as demonstrated by less extensive collagen-rich fibrosis. Furthermore, curcumin increased protein level of ACE2 and enhanced its expression in the intermyocardium relative to the Ang II group. These results suggest that curcumin could be considered as an add-on therapeutic agent in the treatment of fibrosis-derived heart failure patient who is intolerant of ACE inhibitor therapy. PMID- 26648695 TI - Synthesis, structural characterization, and anticancer activity of a monobenzyltin compound against MCF-7 breast cancer cells. AB - A new monoorganotin Schiff base compound, [N-(3,5-dichloro-2-oxidobenzylidene)-4 chlorobenzyhydrazidato](o-methylbenzyl)aquatin(IV) chloride, (compound C1), was synthesized, and its structural features were investigated by spectroscopic techniques and single-crystal X-ray diffractometry. Compound C1 was exposed to several human cancer cell lines, including breast adenocarcinoma cell lines MCF-7 and MDA-MB-231, ovarian adenocarcinoma cell lines Skov3 and Caov3, and prostate cancer cell line PC3, in order to examine its cytotoxic effect for different forms of cancer. Human hepatic cell line WRL-68 was used as a normal cell line. We concentrated on the MCF-7 cell line to detect possible underlying mechanism involvement of compound C1. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay revealed the strongest cytotoxicity of compound C1 against MCF-7 cells, with a half maximal inhibitory concentration (IC50) value of 2.5+/ 0.50 MUg/mL after 48 hours treatment. The IC50 value was >30 MUg/mL in WRL-68 cells. Induced antiproliferative activity of compound C1 for MCF-7 cells was further confirmed by lactate dehydrogenase, reactive oxygen species, acridine orange/propidium iodide staining, and DNA fragmentation assays. A significant increase of lactate dehydrogenase release in treated cells was observed via fluorescence analysis. Luminescent analysis showed significant growth in intracellular reactive oxygen species production after treatment. Morphological changes of necrosis and early and late apoptosis stages were observed in treated cells after staining with acridine orange/propidium iodide. DNA fragmentation was observed as a characteristic of apoptosis in treated cells. Results of the present study obviously reveal potential cytotoxic effects of compound C1 against human breast cancer MCF-7 cells. PMID- 26648696 TI - Radiotherapy potentiation with weekly cisplatin compared to standard every 3 weeks cisplatin chemotherapy for locoregionally advanced head and neck squamous cell carcinoma. AB - BACKGROUND: Despite its toxicity, cisplatin every 3 weeks (q3w) is the standard potentiation of chemo-radiotherapy for head and neck squamous cell carcinoma. This study aimed to determine whether weekly cisplatin (q1w) could be a safe and effective alternative. PATIENTS AND METHODS: Two hundred and sixty-two patients with head and neck squamous cell carcinoma, irradiated in our institution with cisplatin (q1w or q3w) between January 2004 and December 2008, were retrospectively included. Overall survival (OS) and progression-free survival (PFS) were evaluated. Survival distributions were estimated by Kaplan-Meier method and compared using the log-rank test. Prognostic effect of chemo radiotherapy was explored using Cox model. RESULTS: A total of 165 and 97 patients received q1w and q3w cisplatin, respectively. Median age, stage at diagnosis, alcohol consumption, intensity-modulated radiation therapy use, median weight, and renal failure before radiotherapy were significantly different, showing lower risk in the q3w group. Q3w cisplatin was found to be more toxic in terms of weight loss, renal failure, worse chemotherapy plan completion, and grade 3/4 mucositis and dermatitis, with more patients requiring analgesics, secondary hospitalization, and radiotherapy interruption (>=3 days), and patients affected by long-term toxicities. With a median follow-up of 73 months (95% confidence interval [CI] [68.9-76.2]), OS was found to be significantly better with q3w (5 years OS: 62.3%; 95% CI [51.6-71.3]) than with q1w cisplatin (5 years OS: 52.6%; 95% CI [44.5-60.0]) (log-rank P=0.0146). More number of patients treated according to the q1w schedule experienced a recurrence: 47.3% vs 30.9% (P=0.009). Thus, the PFS for q3w schedule was found to be globally better (5 years PFS: 55.8%; 95% CI [45.0-65.3]) than for q1w schedule (5 years PFS: 43.6%; 95% CI [35.9-51.0]) (log-rank P=0.0161). However, both multivariate analyses, OS and PFS, produce no significant hazard ratio for chemo-radiotherapy modality once adjusted on unbalanced covariates according to the descriptive analysis. CONCLUSION: Though q1w seemed to be safer than q3w according to the descriptive analysis, multivariate analyses failed to conclude about its efficiency. Therefore, we conclude that the q3w schedule should remain the standard and prospective comparisons are needed. PMID- 26648697 TI - Different effects of statins on induction of diabetes mellitus: an experimental study. AB - BACKGROUND: To determine the effect of different statins on the induction of diabetes mellitus. MATERIALS AND METHODS: Four statins (atorvastatin, pravastatin, rosuvastatin, and pitavastatin) were used. Cytotoxicity, insulin secretion, glucose-stimulated insulin secretion, and G0/G1 phase cell cycle arrest were investigated in human pancreas islet beta cells, and glucose uptake and signaling were studied in human skeletal muscle cells (HSkMCs). RESULTS: Human pancreas islet beta cells treated with 100 nM atorvastatin, pravastatin, rosuvastatin, and pitavastatin had reduced cell viability (32.12%, 41.09%, 33.96%, and 29.19%, respectively) compared to controls. Such cytotoxic effect was significantly attenuated by decreasing the dose to 10 and 1 nM, ranged from 1.46% to 17.28%. Cells treated with 100 nM atorvastatin, pravastatin, rosuvastatin, and pitavastatin had a reduction in the rate of insulin secretion rate by 34.07%, 30.06%, 26.78%, and 19.22%, respectively. The inhibitory effect was slightly attenuated by decreasing the dose to 10 and 1 nM, ranging from 10.84% to 29.60%. Insulin secretion stimulated by a high concentration of glucose (28 mmol/L) was significantly higher than a physiologic concentration of glucose (5.6 mmol/L) in all treatment groups. The glucose uptake rates at a concentration of 100 nM were as follows: atorvastatin (58.76%) < pravastatin (60.21%) < rosuvastatin (72.54%) < pitavastatin (89.96%). We also found that atorvastatin and pravastatin decreased glucose transporter (GLUT)-2 expression and induced p-p38 MAPK levels in human pancreas islet beta cells. Atorvastatin, pravastatin, and rosuvastatin inhibited GLUT-4, p-AKT, p-GSK-3beta, and p-p38 MAPK levels in HSkMCs. CONCLUSION: Statins similar but different degree of effects on pancreas islet beta cells damage and induce insulin resistance in HSkMC. PMID- 26648698 TI - Hyaluronic acid abrogates ethanol-dependent inhibition of collagen biosynthesis in cultured human fibroblasts. AB - INTRODUCTION: The aim of the study was to evaluate the effect of ethanol on collagen biosynthesis in cultured human skin fibroblasts, and the role of hyaluronic acid (HA) in this process. Regarding the mechanism of ethanol action on human skin fibroblasts we investigated: expression of beta1 integrin and insulin-like growth factor 1 receptor (IGF-IR), signaling pathway protein expression: mitogen-activated protein kinases (MAPKs), protein kinase B (Akt), nuclear factor kappa B (NF-kappaB) transcription factor, cytotoxicity assay and apoptosis, metalloproteinase activity, as well as the influence of HA on these processes. MATERIALS AND METHODS: Collagen biosynthesis, activity of prolidase, DNA biosynthesis, and cytotoxicity were measured in confluent human skin fibroblast cultures that have been treated with 25, 50, and 100 mM ethanol and with ethanol and 500 ug/mL HA. Western blot analysis and zymography were performed to evaluate expression of collagen type I, beta1 integrin receptor, IGF IR, NF-kappaB protein, phospho-Akt protein, kinase MAPK, caspase 9 activity, and matrix metalloproteinases (MMP-9 and MMP-2). RESULTS: Ethanol in a dose-dependent manner lead to the impairment of collagen biosynthesis in fibroblast cultures through decreasing prolidase activity and expression of beta1 integrin and IGF IR. This was accompanied by an increased cytotoxicity, apoptosis and lowered expression of the signaling pathway proteins induced by beta1 integrin and IGF IR, that is, MAPK (ERK1/2) kinases. The lowered amount of synthesized collagen and prolidase activity disturbance may also be due to the activation of NF-kappaB transcription factor, which inhibits collagen gene expression. It suggests that the decrease in fibroblast collagen production may be caused by the disturbance in its biosynthesis but not degradation. The application of HA has a protective effect on disturbances caused by the examined substances. It seems that regulatory mechanism of ethanol-induced collagen aberration take place at the level of collagen biosynthesis, since no effect of ethanol and HA was found on process of collagen degradation by MMP-2 and MMP-9. CONCLUSION: This study provides evidence that ethanol impairs collagen metabolism in human skin fibroblasts, leading to a significant decrease in the amount of produced protein. This mechanism probably is due to downregulation of prolidase activity, expression of beta1 integrin and IGF-IR receptors, and the signaling pathway proteins induced by these receptors. PMID- 26648699 TI - The antiplasmodial and spleen protective role of crude Indigofera oblongifolia leaf extract traditionally used in the treatment of malaria in Saudi Arabia. AB - Malaria is one of the most serious natural hazards faced by human society. Although plant leaves of Indigofera oblongifolia have been used for the treatment of malaria in Saudi Arabian society, there is no laboratory-based evidence for the effectiveness and safety of the plant. This study therefore was designed to investigate the antimalarial and spleen protective activity of I. oblongifolia leaf extract (IOLE) in mice. Three doses (100, 200 and 300 mg/kg) of IOLE were used to treat mice infected with Plasmodium chabaudi-parasitized erythrocytes. The suppressive effect produced by the 100 mg/kg dose on parasitemia was highly significant compared to the infected nontreated group. This dose was also able to repair the change in the thickness of the mice spleen and significantly lower the number of apoptotic cells in the spleen. Moreover, I. oblongifolia also altered gene expression in the infected spleen. On day 7 postinfection, the mRNA expression of six genes - with immune response functions - was upregulated by more than twofold, while that of 24 other genes was downregulated. Among the differentially up- and downregulated genes under the effect of IOLE, we quantified the expression of Ccl8, Saa3, Cd209a, and Cd209b mRNAs. The expression data, determined by microarrays, were largely consistent with the expression analyses we performed with several arbitrarily selected genes using quantitative polymerase chain reaction (PCR). Based on our results, I. oblongifolia exhibits antimalarial activity and could protect the spleen from P. chabaudi-induced injury. PMID- 26648700 TI - What are judgment skills in health literacy? A psycho-cognitive perspective of judgment and decision-making research. AB - OBJECTIVE: The aim of this review is to summarize current research relating to psychological processes involved in judgment and decision-making (JDM) and identify which processes can be incorporated and used in the construct of health literacy (HL) in order to enrich its conceptualization and to provide more information about people's preferences. METHODS: The literature review was aimed at identifying comprehensive research in the field; therefore appropriate databases were searched for English language articles dated from 1998 to 2015. RESULTS: Several psychological processes have been found to be constituents of JDM and potentially incorporated in the definition of HL: cognition, self regulation, emotion, reasoning-thinking, and social perception. CONCLUSION: HL research can benefit from this JDM literature overview, first, by elaborating on the idea that judgment is multidimensional and constituted by several specific processes, and second, by using the results to implement the definition of "judgment skills". Moreover, this review can favor the development of new instruments that can measure HL. PRACTICAL IMPLICATIONS: Future researchers in HL should work together with researchers in psychological sciences not only to investigate the processes behind JDM in-depth but also to create effective opportunities to improve HL in all patients, to promote good decisions, and orient patients' preferences in all health contexts. PMID- 26648701 TI - Patient and parent preferences for characteristics of prophylactic treatment in hemophilia. AB - INTRODUCTION: New longer-acting factor products will potentially allow for less frequent infusion in prophylactic treatment of hemophilia. However, the role of administration frequency relative to other treatment attributes in determining preferences for prophylactic hemophilia treatment regimens is not well understood. AIM: To identify the relative importance of frequency of administration, efficacy, and other treatment characteristics among candidates for prophylactic treatment for hemophilia A and B. METHOD: An Internet survey was conducted among hemophilia patients and the parents of pediatric hemophilia patients in Australia, Canada, and the US. A monadic conjoint task was included in the survey, which varied frequency of administration (three, two, or one time per week for hemophilia A; twice weekly, weekly, or biweekly for hemophilia B), efficacy (no bleeding or breakthrough bleeding once every 4 months, 6 months, or 12 months), diluent volume (3 mL vs 2.5 mL for hemophilia A; 5 mL vs 3 mL for hemophilia B), vials per infusion (2 vs 1), reconstitution device (assembly required vs not), and manufacturer (established in hemophilia vs not). Respondents were asked their likelihood to switch from their current regimen to the presented treatment. Respondents were told to assume that other aspects of treatment, such as risk of inhibitor development, cost, and method of distribution, would remain the same. RESULTS: A total of 89 patients and/or parents of children with hemophilia A participated; another 32 were included in the exercise for hemophilia B. Relative importance was 47%, 24%, and 18% for frequency of administration, efficacy, and manufacturer, respectively, in hemophilia A; analogous values were 48%, 26%, and 21% in hemophilia B. The remaining attributes had little impact on preferences. CONCLUSION: Patients who are candidates for prophylaxis and their caregivers indicate a preference for reduced frequency of administration and high efficacy, but preferences were more sensitive to administration frequency than small changes in annual bleeding rate. PMID- 26648702 TI - Adherence to oral anticoagulant therapy in secondary stroke prevention - impact of the novel oral anticoagulants. AB - BACKGROUND: Oral anticoagulant therapy (OAT) potently prevents strokes in patients with atrial fibrillation. Vitamin K antagonists (VKA) have been the standard of care for long-term OAT for decades, but non-VKA oral anticoagulants (NOAC) have recently been approved for this indication, and raised many questions, among them their influence on medication adherence. We assessed adherence to VKA and NOAC in secondary stroke prevention. METHODS: All patients treated from October 2011 to September 2012 for ischemic stroke or transient ischemic attack with a subsequent indication for OAT, at three academic hospitals were entered into a prospective registry, and baseline data and antithrombotic treatment at discharge were recorded. At the 1-year follow-up, we assessed the adherence to different OAT strategies and patients' adherence to their respective OAT. We noted OAT changes, reasons to change treatment, and factors that influence persistence to the prescribed OAT. RESULTS: In patients discharged on OAT, we achieved a fatality corrected response rate of 73.3% (n=209). A total of 92% of these patients received OAT at the 1-year follow-up. We observed good adherence to both VKA and NOAC (VKA, 80.9%; NOAC, 74.8%; P=0.243) with a statistically nonsignificant tendency toward a weaker adherence to dabigatran. Disability at 1-year follow-up was an independent predictor of lower adherence to any OAT after multivariate analysis, whereas the choice of OAT did not have a relevant influence. CONCLUSION: One-year adherence to OAT after stroke is strong (>90%) and patients who switch therapy most commonly switch toward another OAT. The 1-year adherence rates to VKA and NOAC in secondary stroke prevention do not differ significantly between both therapeutic strategies. PMID- 26648703 TI - Nurse-led intensive interventions improve adherence to continuous positive airway pressure therapy and quality of life in obstructive sleep apnea patients. AB - BACKGROUND: Continuous positive airway pressure (CPAP) is widely recommended for the treatment of sleep apnea/hypopnea syndrome (SAHS), but its usage by patients is very low. The aim of this study was to assess intensive educational programs and nursing support for the improvement of CPAP use and outcomes in SAHS patients. METHODS: Eighty new SAHS patients were randomized to receive nurse-led intensive interventions or usual support at hospital and home. The main outcome measure was CPAP use; changes in sleeping, symptoms, mood, and quality of life were also assessed after 12 months of treatment. RESULTS: All outcome measures were improved after treatment in both groups. However, patients receiving intensive support with significantly higher CPAP use (higher daily CPAP usage by 2.2 hours/day) had greater improvements in SAHS symptoms and mood (P<0.05). The intervention group further showed an improvement in the Short Form-36 domains of mental and physical health (P<0.05). CONCLUSION: The CPAP usage and quality of life can be significantly improved by nurse-led intensive program in obstructive sleep apnea patients. PMID- 26648704 TI - Visual-spatial perception: a comparison between instruments frequently used in the primary care setting and a computerized cognitive assessment battery. AB - BACKGROUND: The development of screening instruments will help the primary care team to determine when further comprehensive cognitive assessment is necessary. DESIGN: A retrospective analysis based on medical records. PATIENTS AND SETTING: Patients referred to a comprehensive geriatric assessment unit. ANALYSIS: Cognitive screening and assessment included visual-spatial components: the Mini Mental State Examination, the Clock Drawing Test, the Montreal Cognitive Assessment Test, and the Neurotrax (Mindstreams) computerized cognitive assessment battery. RESULTS: The average age of the 190 eligible patients was 81.09+/-5.42 years. Comparing the individual tests with that of the visual spatial index of Neurotrax, we found the Trail Making B test to be most sensitive (72.4%) and the Cube Test to have the highest specificity (72.8%). A combination of tests resulted in higher sensitivity and lower specificity. CONCLUSION: The use of a combination of visual-spatial tests for screening in neurocognitive disorders should be evaluated in further prospective studies. PMID- 26648705 TI - The one repetition maximum test and the sit-to-stand test in the assessment of a specific pulmonary rehabilitation program on peripheral muscle strength in COPD patients. AB - BACKGROUND: Individuals with COPD may present reduced peripheral muscle strength, leading to impaired mobility. Comprehensive pulmonary rehabilitation (PR) should include strength training, in particular to lower limbs. Furthermore, simple tools for the assessment of peripheral muscle performance are required. OBJECTIVES: To assess the peripheral muscle performance of COPD patients by the sit-to-stand test (STST), as compared to the one-repetition maximum (1-RM), considered as the gold standard for assessing muscle strength in non-laboratory situations, and to evaluate the responsiveness of STST to a PR program. METHODS: Sixty moderate-to-severe COPD inpatients were randomly included into either the specific strength training group or into the usual PR program group. Patients were assessed on a 30-second STST and 1-minute STST, 1-RM, and 6-minute walking test (6MWT), before and after PR. Bland-Altman plots were used to evaluate the agreement between 1-RM and STST. RESULTS: The two groups were not different at baseline. In all patients, 1-RM was significantly related to the 30-second STST (r=0.48, P<0.001) and to 1-minute STST (r=0.36, P=0.005). The 30-second STST was better tolerated in terms of the perceived fatigue (P=0.002) and less time consuming (P<0.001) test. In the specific strength training group significant improvements were observed in the 30-second STST (P<0.001), 1-minute STST (P=0.005), 1-RM (P<0.001), and in the 6MWT (P=0.001). In the usual PR program group, significant improvement was observed in the 30-second STST (P=0.042) and in the 6MWT (P=0.001). CONCLUSION: Our study shows that in stable moderate-to severe inpatients with COPD, STST is a valid and reliable tool to assess peripheral muscle performance of lower limbs, and is sensitive to a specific PR program. PMID- 26648706 TI - The EFFECT trial: evaluating exacerbations, biomarkers, and safety outcomes with two dose levels of fluticasone propionate/formoterol in COPD. AB - Inhaled corticosteroid/long-acting beta2-agonist combination therapy is recommended in chronic obstructive pulmonary disease (COPD) patients at high risk of exacerbations. The EFFECT (Efficacy of Fluticasone propionate/FormotErol in COPD Treatment) trial is a Phase III, 52-week, randomized, double-blind study to evaluate the efficacy and safety of two doses of fluticasone propionate/formoterol compared to formoterol monotherapy in COPD patients with FEV1 >=50% predicted and a history of exacerbations. The primary endpoint is the annualized rate of moderate and severe exacerbations. Secondary endpoints include pre-dose FEV1, EXACT-PRO (EXAcerbations of Chronic pulmonary disease Tool - Patient-Reported Outcome)-defined exacerbations, St George's Respiratory Questionnaire for COPD, COPD Assessment Test, and EXACT-Respiratory Symptoms total score. Lung-specific biomarkers (surfactant protein D and CC chemokine ligand-18) will be measured in a subset of patients to explore their relationship to other clinical indices in COPD and their predictive utility. Pneumonia will be diagnosed per criteria defined by the British Thoracic Society community acquired pneumonia guideline, primarily by radiological confirmation and, additionally, using clinical criteria when a chest radiograph cannot be obtained. Serial measurements of serum potassium, vital signs and electrocardiograms, 24-hour Holter monitoring, and 24-hour urinary cortisol measurement will be performed in a subset of patients in addition to conventional safety assessments. PMID- 26648707 TI - COPD: it is time to change! AB - COPD is a common cause of disability, morbidity and mortality worldwide and a major global health problem with enormous direct and indirect health care costs. Different reasons can be advanced to explain it, but among them the possibility that the recommended diagnostic and therapeutic approaches to COPD were less effective than they could be, should be also considered. The pharmacological baseline treatment of stable COPD has been widely based on the severity of airflow obstruction and recently, of chronic symptoms and on the annual number of previous exacerbations. These recommendations do not take into account the underlying prevalent disease that should be treated and the future risk. Our suggestion is that the therapy must be firstly tailored on the prevalent disease leading to COPD, independently from the degree of FEV1 reduction and chronic dyspnea and only after that, according to the severity of the disorder (and age of patient), to establish the level of the treatment in order to freeze, when possible, and not to follow the underlying pathological process, running after it. Moreover, given the relevance of exacerbations in the natural history of COPD, greater effort should be placed on recognition of their prevalent type in frequent exacerbators and to prevent them using more tailored and specific treatment. PMID- 26648708 TI - COPD in Taiwan: a National Epidemiology Survey. AB - OBJECTIVES: To determine the prevalence of COPD in Taiwan and to document the disease characteristics and associated risk factors. METHODS: We conducted a random cross-sectional national survey of adults older than 40 years in Taiwan. Respiratory health screening questions identified subjects with diagnosed COPD or whose reported symptoms also fulfilled an epidemiological case definition; these were eligible to complete the survey, which also included indices of symptom severity and disability and questions on comorbidities, medical treatments, smoking habits, and occupations potentially harmful to respiratory health. Subjects with diagnosed COPD were subdivided by smoking status. Subjects who fulfilled the case definition of COPD and smoked were designated as "possible COPD". Participants who did not fit the case definition of COPD were asked only about their personal circumstances and smoking habits. Data from these groups were analyzed and compared. RESULTS: Of the 6,600 participants who completed the survey, 404 (6.1%) fulfilled the epidemiological case definition of COPD: 137 with diagnosed COPD and 267 possible COPD. The most common comorbidities of COPD were hypertension or cardiovascular diseases (36.1%). Subjects with definite COPD had significantly higher COPD Assessment Test scores than the possible COPD group (14.6+/-8.32 vs 12.6+/-6.49, P=0.01) and significantly more comorbid illnesses (P=0.01). The main risk factors contributing to health care utilization in each COPD cohort were higher COPD Assessment Test scores (odds ratio [OR] 1.15, 95% confidence interval [CI] 1.04-1.26), higher modified Medical Research Council Breathlessness Scale scores (OR 1.97, 95% CI 1.11-3.51), and having more than one comorbidity (OR 5.19, 95% CI 1.05-25.61). CONCLUSION: With estimated prevalence of 6.1% in the general population, COPD in Taiwan has been underdiagnosed. Symptoms and comorbidities were independent risk factors for health care utilization in subjects with definite or possible COPD. There is an urgent need to raise awareness of the importance of early evaluation and prompt treatment for subjects with chronic airway symptoms. PMID- 26648709 TI - The utility of inflammatory markers to predict readmissions and mortality in COPD cases with or without eosinophilia. AB - BACKGROUND: COPD exacerbations requiring hospitalization increase morbidity and mortality. Although most COPD exacerbations are neutrophilic, approximately 10% 25% of exacerbations are eosinophilic. AIM: We aimed to evaluate mortality and outcomes of eosinophilic and non-eosinophilic COPD exacerbations and identify new biomarkers that predict survival. METHODS: A retrospective observational cohort study was carried out in a tertiary teaching hospital from January 1, 2014 to November 1, 2014. All COPD patients hospitalized with exacerbations were enrolled in the study at their initial hospitalization and followed-up for 6 months after discharge. Electronic data were collected from the hospital database. Subjects' characteristics, hemogram parameters, CRP levels, neutrophil-to-lymphocyte ratio (NLR), platelet-to-mean platelet volume ratio on admission and discharge, length of hospital stay (days), readmissions, and mortality were recorded. Patients were grouped according to peripheral blood eosinophil (PBE) levels: Group 1, >2% PBE, eosinophilic; Group 2, non-eosinophilic <=2%. Patient survival after hospital discharge was evaluated by Kaplan-Meier survival analysis. RESULTS: A total of 1,704 patients hospitalized with COPD exacerbation were included. Approximately 20% were classified as eosinophilic. Six-month mortality was similar in eosinophilic and non-eosinophilic groups (14.2% and 15.2%, respectively); however, the hospital stay length and readmission rate were longer and higher in the non-eosinophilic group (P<0.001 and P<0.01, respectively). CRP and NLR were significantly higher in the non-eosinophilic group (both P<0.01). The platelet-to mean platelet volume ratio was not different between the two groups. Cox regression analysis showed that survival was negatively influenced by elevated CRP (P<0.035) and NLR (P<0.001) in the non-eosinophilic group. CONCLUSION: Non eosinophilic patients with COPD exacerbations with high CRP and NLR values had worse outcomes than eosinophilic patients. PBE and NLR can be helpful markers to guide treatment decisions. PMID- 26648710 TI - Hyperuricemia is a biomarker of early mortality in patients with chronic obstructive pulmonary disease. AB - Patients with chronic obstructive pulmonary disease (COPD) are often at high risk of early death. Identification of prognostic biomarkers for COPD may aid in improving their survival by providing early strengthened therapy for high-risk patients. In the present study, we investigated the prognostic role of hyperuricemia at baseline on the prognosis of patients with COPD. Thirty-four patients with COPD with hyperuricemia were matched (1:2) to 68 patients with COPD without hyperuricemia and of similar age and sex. Data from those patients with COPD were evaluated retrospectively. The role of hyperuricemia on mortality was first analyzed using the Kaplan-Meier method, and multivariate Cox regression model was then used to evaluate the prognostic significance of hyperuricemia in patients with COPD. Hyperuricemia was not associated with other baseline characteristics in patients with COPD. Kaplan-Meier survival curve showed that patients with COPD with hyperuricemia had higher risk of mortality compared with patients with normouricemia, and the P-value for log-rank test was 0.005. In univariate analysis, hyperuricemia was associated with higher risk of mortality in patients with COPD (hazard ratio =2.29, 95% CI =1.07-4.88, P=0.032). In the multivariate analysis, hyperuricemia was independently associated with higher risk of mortality in patients with COPD (hazard ratio =2.68, 95% CI =1.18-6.09, P=0.019). In conclusion, hyperuricemia is a promising biomarker of early mortality in patients with COPD. PMID- 26648711 TI - Applying the wisdom of stepping down inhaled corticosteroids in patients with COPD: a proposed algorithm for clinical practice. AB - Current guidelines for the management of chronic obstructive pulmonary disease (COPD) recommend limiting the use of inhaled corticosteroids (ICS) to patients with more severe disease and/or increased exacerbation risk. However, there are discrepancies between guidelines and real-life practice, as ICS are being overprescribed. In light of the increasing concerns about the clinical benefit and long-term risks associated with ICS use, therapy needs to be carefully weighed on a case-by-case basis, including in patients already on ICS. Several studies sought out to determine the effects of withdrawing ICS in patients with COPD. Early studies have deterred clinicians from reducing ICS in patients with COPD as they reported that an abrupt withdrawal of ICS precipitates exacerbations, and results in a deterioration in lung function and symptoms. However, these studies were fraught with numerous methodological limitations. Recently, two randomized controlled trials and a real-life prospective study revealed that ICS can be safely withdrawn in certain patients. Of these, the WISDOM (Withdrawal of Inhaled Steroids During Optimized Bronchodilator Management) trial was the largest and first to examine stepwise withdrawal of ICS in patients with COPD receiving maintenance therapy of long-acting bronchodilators (ie, tiotropium and salmeterol). Even with therapy being in line with the current guidelines, the findings of the WISDOM trial indicate that not all patients benefit from including ICS in their treatment regimen. Indeed, only certain COPD phenotypes seem to benefit from ICS therapy, and validated markers that predict ICS response are urgently warranted in clinical practice. Furthermore, we are now better equipped with a larger armamentarium of novel and more effective long-acting beta2-agonist/long-acting muscarinic antagonist combinations that can be considered by clinicians to optimize bronchodilation and allow for safer ICS withdrawal. In addition to providing a review of the aforementioned, this perspective article proposes an algorithm for the stepwise withdrawal of ICS in real-life clinical practice. PMID- 26648712 TI - Effects of 12 weeks of aerobic training on autonomic modulation, mucociliary clearance, and aerobic parameters in patients with COPD. AB - INTRODUCTION: Patients with chronic obstructive pulmonary disease (COPD) exhibit aerobic function, autonomic nervous system, and mucociliary clearance alterations. These parameters can be attenuated by aerobic training, which can be applied with continuous or interval efforts. However, the possible effects of aerobic training, using progressively both continuous and interval sessions (ie, linear periodization), require further investigation. AIM: To analyze the effects of 12-week aerobic training using continuous and interval sessions on autonomic modulation, mucociliary clearance, and aerobic function in patients with COPD. METHODS: Sixteen patients with COPD were divided into an aerobic (continuous and interval) training group (AT) (n=10) and a control group (CG) (n=6). An incremental test (initial speed of 2.0 km.h(-1), constant slope of 3%, and increments of 0.5 km.h(-1) every 2 minutes) was performed. The training group underwent training for 4 weeks at 60% of the peak velocity reached in the incremental test (vVO2peak) (50 minutes of continuous effort), followed by 4 weeks of sessions at 75% of vVO2peak (30 minutes of continuous effort), and 4 weeks of interval training (5*3-minute effort at vVO2peak, separated by 1 minute of passive recovery). Intensities were adjusted through an incremental test performed at the end of each period. RESULTS: The AT presented an increase in the high frequency index (ms(2)) (P=0.04), peak oxygen uptake (VO2peak) (P=0.01), vVO2peak (P=0.04), and anaerobic threshold (P=0.02). No significant changes were observed in the CG (P>0.21) group. Neither of the groups presented changes in mucociliary clearance after 12 weeks (AT: P=0.94 and CG: P=0.69). CONCLUSION: Twelve weeks of aerobic training (continuous and interval sessions) positively influenced the autonomic modulation and aerobic parameters in patients with COPD. However, mucociliary clearance was not affected by aerobic training. PMID- 26648714 TI - Hypericin-bearing magnetic iron oxide nanoparticles for selective drug delivery in photodynamic therapy. AB - Combining the concept of magnetic drug targeting and photodynamic therapy is a promising approach for the treatment of cancer. A high selectivity as well as significant fewer side effects can be achieved by this method, since the therapeutic treatment only takes place in the area where accumulation of the particles by an external electromagnet and radiation by a laser system overlap. In this article, a novel hypericin-bearing drug delivery system has been developed by synthesis of superparamagnetic iron oxide nanoparticles (SPIONs) with a hypericin-linked functionalized dextran coating. For that, sterically stabilized dextran-coated SPIONs were produced by coprecipitation and crosslinking with epichlorohydrin to enhance stability. Carboxymethylation of the dextran shell provided a functionalized platform for linking hypericin via glutaraldehyde. Particle sizes obtained by dynamic light scattering were in a range of 55-85 nm, whereas investigation of single magnetite or maghemite particle diameter was performed by transmission electron microscopy and X-ray diffraction and resulted in approximately 4.5-5.0 nm. Surface chemistry of those particles was evaluated by Fourier transform infrared spectroscopy and zeta potential measurements, indicating successful functionalization and dispersal stabilization due to a mixture of steric and electrostatic repulsion. Flow cytometry revealed no toxicity of pure nanoparticles as well as hypericin without exposure to light on Jurkat T-cells, whereas the combination of hypericin, alone or loaded on particles, with light-induced cell death in a concentration and exposure time-dependent manner due to the generation of reactive oxygen species. In conclusion, the combination of SPIONs' targeting abilities with hypericin's phototoxic properties represents a promising approach for merging magnetic drug targeting with photodynamic therapy for the treatment of cancer. PMID- 26648715 TI - Phytofabrication of bioinduced silver nanoparticles for biomedical applications. AB - Synthesis of nanomaterials holds infinite possibilities as nanotechnology is revolutionizing the field of medicine by its myriad applications. Green synthesis of nanoparticles has become the need of the hour because of its eco-friendly, nontoxic, and economic nature. In this study, leaf extract of Rosa damascena was used as a bioreductant to reduce silver nitrate, leading to synthesis of silver nanoparticles (AgNPs) in a single step, without the use of any additional reducing or capping agents. The synthesized nanoparticles were characterized by the use of UV-visible spectroscopy, fourier transform infrared spectroscopy, dynamic light scattering, transmission electron microscopy, and field emission scanning electron microscopy. Time-dependent synthesis of AgNPs was studied spectrophotometrically. Synthesized AgNPs were found to possess flower-like spherical structure where individual nanoparticles were of 16 nm in diameter, whereas the agglomerated AgNPs were in the range of 60-80 nm. These biologically synthesized AgNPs exhibited significant antibacterial activity against Gram negative bacterial species but not against Gram-positive ones (Escherichia coli and Bacillus cereus). Anti-inflammatory and analgesic activities were studied on a Wistar rat model to gauge the impact of AgNPs for a probable role in these applications. AgNPs tested positive for both these activities, although the potency was less as compared to the standard drugs. PMID- 26648713 TI - Comparison of exercise capacity in COPD and other etiologies of chronic respiratory failure requiring non-invasive mechanical ventilation at home: retrospective analysis of 1-year follow-up. AB - INTRODUCTION: The objective of this study was to compare the change in 6-minute walking distance (6MWD) in 1 year as an indicator of exercise capacity among patients undergoing home non-invasive mechanical ventilation (NIMV) due to chronic hypercapnic respiratory failure (CHRF) caused by different etiologies. METHODS: This retrospective cohort study was conducted in a tertiary pulmonary disease hospital in patients who had completed 1-year follow-up under home NIMV because of CHRF with different etiologies (ie, chronic obstructive pulmonary disease [COPD], obesity hypoventilation syndrome [OHS], kyphoscoliosis [KS], and diffuse parenchymal lung disease [DPLD]), between January 2011 and January 2012. The results of arterial blood gas (ABG) analyses and spirometry, and 6MWD measurements with 12-month interval were recorded from the patient files, in addition to demographics, comorbidities, and body mass indices. The groups were compared in terms of 6MWD via analysis of variance (ANOVA) and multiple linear regression (MLR) analysis (independent variables: analysis age, sex, baseline 6MWD, baseline forced expiratory volume in 1 second, and baseline partial carbon dioxide pressure, in reference to COPD group). RESULTS: A total of 105 patients with a mean age (+/- standard deviation) of 61+/-12 years of whom 37 had COPD, 34 had OHS, 20 had KS, and 14 had DPLD were included in statistical analysis. There were no significant differences between groups in the baseline and delta values of ABG and spirometry findings. Both univariate ANOVA and MLR showed that the OHS group had the lowest baseline 6MWD and the highest decrease in 1 year (linear regression coefficient -24.48; 95% CI -48.74 to -0.21, P=0.048); while the KS group had the best baseline values and the biggest improvement under home NIMV (linear regression coefficient 26.94; 95% CI -3.79 to 57.66, P=0.085). CONCLUSION: The 6MWD measurements revealed improvement in exercise capacity test in CHRF patients receiving home NIMV treatment on long-term depends on etiological diagnoses. PMID- 26648716 TI - Effect of micro-nano-hybrid structured hydroxyapatite bioceramics on osteogenic and cementogenic differentiation of human periodontal ligament stem cell via Wnt signaling pathway. AB - The surface structure of bioceramic scaffolds is crucial for its bioactivity and osteoinductive ability, and in recent years, human periodontal ligament stem cells have been certified to possess high osteogenic and cementogenic differential ability. In the present study, hydroxyapatite (HA) bioceramics with micro-nano-hybrid surface (mnHA [the hybrid of nanorods and microrods]) were fabricated via hydrothermal reaction of the alpha-tricalcium phosphate granules as precursors in aqueous solution, and the effects of mnHA on the attachment, proliferation, osteogenic and cementogenic differentiations of human periodontal ligament stem cells as well as the related mechanisms were systematically investigated. The results showed that mnHA bioceramics could promote cell adhesion, proliferation, alkaline phosphatase (ALP) activity, and expression of osteogenic/cementogenic-related markers including runt-related transcription factor 2 (Runx2), ALP, osteocalcin (OCN), cementum attachment protein (CAP), and cementum protein (CEMP) as compared to the HA bioceramics with flat and dense surface. Moreover, mnHA bioceramics stimulated gene expression of low-density lipoprotein receptor-related protein 5 (LRP5) and beta-catenin, which are the key genes of canonical Wnt signaling. Moreover, the stimulatory effect on ALP activity and osteogenic and cementogenic gene expression, including that of ALP, OCN, CAP, CEMP, and Runx2 of mnHA bioceramics could be repressed by canonical Wnt signaling inhibitor dickkopf1 (Dkk1). The results suggested that the HA bioceramics with mnHA could act as promising grafts for periodontal tissue regeneration. PMID- 26648717 TI - Intracellular targeted co-delivery of shMDR1 and gefitinib with chitosan nanoparticles for overcoming multidrug resistance. AB - Nowadays, multidrug resistance and side effects of drugs limit the effectiveness of chemotherapies in clinics. P-glycoprotein (P-gp) (MDR1), as a member of the ATP-binding cassette family, acts on transporting drugs into cell plasma across the membrane of cancer cells and leads to the occurrence of multidrug resistance, thus resulting in the failure of chemotherapy in cancer. The main aims of this research were to design a nanodelivery system for accomplishing the effective co delivery of gene and antitumor drug and overcoming multidrug resistance effect. In this study, shMDR1 and gefitinib-encapsulating chitosan nanoparticles with sustained release, small particle size, and high encapsulation efficiency were prepared. The serum stability, protection from nuclease, and transfection efficiency of gene in vitro were investigated. The effects of co-delivery of shMDR1 and gefitinib in nanoparticles on reversing multidrug resistance were also evaluated by investigating the cytotoxicity, cellular uptake mechanism, and cell apoptosis on established gefitinib-resistant cells. The results demonstrated that chitosan nanoparticles entrapping gefitinib and shMDR1 had the potential to overcome the multidrug resistance and improve cancer treatment efficacy, especially toward resistant cells. PMID- 26648718 TI - Assessing the axonal translocation of CeO2 and SiO2 nanoparticles in the sciatic nerve fibers of the frog: an ex vivo electrophysiological study. AB - The axonal translocation of two commonly used nanoparticles in medicine, namely CeO2 and SiO2, is investigated. The study was conducted on frog sciatic nerve fibers in an ex vivo preparation. Nanoparticles were applied at the proximal end of the excised nerve. A nerve stimulation protocol was followed for over 35 hours. Nerve vitality curve comparison between control and exposed nerves showed that CeO2 has no neurotoxic effect at the concentrations tested. After exposure, specimens were fixed and then screen scanned every 1 mm along their length for nanoparticle presence by means of Fourier transform infrared microscopy. We demonstrated that both nanoparticles translocate within the nerve by formation of narrow bands in the Fourier transform infrared spectrum. For the CeO2, we also demonstrated that the translocation depends on both axonal integrity and electrical activity. The speed of translocation for the two species was estimated in the range of 0.45-0.58 mm/h, close to slow axonal transportation rate. Transmission electron microscopy provided direct evidence for the presence of SiO2 in the treated nerves. PMID- 26648719 TI - The diameter of nanotubes formed on Ti-6Al-4V alloy controls the adhesion and differentiation of Saos-2 cells. AB - Ti-6Al-4V-based nanotubes were prepared on a Ti-6Al-4V surface by anodic oxidation on 10 V, 20 V, and 30 V samples. The 10 V, 20 V, and 30 V samples and a control smooth Ti-6Al-4V sample were evaluated in terms of their chemical composition, diameter distribution, and cellular response. The surfaces of the 10 V, 20 V, and 30 V samples consisted of nanotubes of a relatively wide range of diameters that increased with the voltage. Saos-2 cells had a similar initial adhesion on all nanotube samples to the control Ti-6Al-4V sample, but it was lower than on glass. On day 3, the highest concentrations of both vinculin and talin measured by enzyme-linked immunosorbent assay and intensity of immunofluorescence staining were on 30 V nanotubes. On the other hand, the highest concentrations of ALP, type I collagen, and osteopontin were found on 10 V and 20 V samples. The final cellular densities on 10 V, 20 V, and 30 V samples were higher than on glass. Therefore, the controlled anodization of Ti-6Al-4V seems to be a useful tool for preparing nanostructured materials with desirable biological properties. PMID- 26648720 TI - Treatment of a multiple sclerosis animal model by a novel nanodrop formulation of a natural antioxidant. AB - Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system and is associated with demyelination, neurodegeneration, and sensitivity to oxidative stress. In this work, we administered a nanodroplet formulation of pomegranate seed oil (PSO), denominated Nano-PSO, to mice induced for experimental autoimmune encephalomyelitis (EAE), an established model of MS. PSO comprises high levels of punicic acid, a unique polyunsaturated fatty acid considered as one of the strongest natural antioxidants. We show here that while EAE-induced mice treated with natural PSO presented some reduction in disease burden, this beneficial effect increased significantly when EAE mice were treated with Nano-PSO of specific size nanodroplets at much lower concentrations of the oil. Pathological examinations revealed that Nano-PSO administration dramatically reduced demyelination and oxidation of lipids in the brains of the affected animals, which are hallmarks of this severe neurological disease. We propose that novel formulations of natural antioxidants such as Nano-PSO may be considered for the treatment of patients suffering from demyelinating diseases. On the mechanistic side, our results demonstrate that lipid oxidation may be a seminal feature in both demyelination and neurodegeneration. PMID- 26648721 TI - A nanomedicine-promising approach to provide an appropriate colon-targeted drug delivery system for 5-fluorouracil. AB - Targeted drug delivery plays a significant role in disease treatment associated with the colon, affording therapeutic responses for a prolonged period of time with low side effects. Colorectal cancer is the third most common cancer in both men and women with an estimated 102,480 cases of colon cancer and 40,340 cases of rectal cancer in 2013 as reported by the American Cancer Society. In the present investigation, we developed an improved oral delivery system for existing anticancer drugs meant for colon cancer via prebiotic and probiotic approaches. The system comprises three components, namely, nanoparticles of drug coated with natural materials such as guar gum, xanthan gum (that serve as prebiotics), and probiotics. The natural gums play a dual role of protecting the drug in the gastric as well as intestinal conditions to allow its release only in the colon. In vitro results obtained from these experiments indicated the successful targeted delivery of 5-fluorouracil to the colon. Electron microscopy results demonstrated that the prepared nanoparticles were spherical in shape and 200 nm in size. The in vitro release data indicated that the maximum release occurs at pH 7.2 and 7.4 with 93% of the drug released in the presence of 4% (w/v) of rat cecal content. In vivo results conclude a practical mechanism to maintain the integrity and intactness of the intestinal/colonic microflora, in the face of a "chemical attack" by oral colon-targeted drug delivery for colon cancer treatment. PMID- 26648722 TI - Development of polymeric-cationic peptide composite nanoparticles, a nanoparticle in-nanoparticle system for controlled gene delivery. AB - We report the formulation of novel composite nanoparticles that combine the high transfection efficiency of cationic peptide-DNA nanoparticles with the biocompatibility and prolonged delivery of polylactic acid-polyethylene glycol (PLA-PEG). The cationic cell-penetrating peptide RALA was used to condense DNA into nanoparticles that were encapsulated within a range of PLA-PEG copolymers. The composite nanoparticles produced exhibited excellent physicochemical properties including size <200 nm and encapsulation efficiency >80%. Images of the composite nanoparticles obtained with a new transmission electron microscopy staining method revealed the peptide-DNA nanoparticles within the PLA-PEG matrix. Varying the copolymers modulated the DNA release rate >6 weeks in vitro. The best formulation was selected and was able to transfect cells while maintaining viability. The effect of transferrin-appended composite nanoparticles was also studied. Thus, we have demonstrated the manufacture of composite nanoparticles for the controlled delivery of DNA. PMID- 26648723 TI - Enhanced detection of single-cell-secreted proteins using a fluorescent immunoassay on the protein-G-terminated glass substrate. AB - We present an evaluation of protein-G-terminated glass slides that may contain a suitable substrate for aligning the orientation of antibodies to obtain better binding moiety to the target antigen. The results of the protein-G-terminated slides were compared with those obtained with epoxy-based slides to evaluate signal enhancement for human immunoglobulin G (IgG) targets, and an increase in the average fluorescence intensity was observed for the lowest measurable amount of IgG target in the assay using protein-G-terminated slides. Applying this strategy for signal amplification to single-cell assays improves the limits of detection for human IgG protein and cytokines (interleukin-2 and interferon gamma) captured from hybridomas. Our data indicate that protein-G-terminated slides have a higher binding capacity for antigens and have better spot-to-spot consistency than that of traditional epoxy-based slides. These properties would be beneficial in the detection of fine amounts of single-cell-secreted proteins, which may provide key insights into cell-cell communication and immune responses. PMID- 26648724 TI - Memantine for the treatment of frontotemporal dementia: a meta-analysis. AB - BACKGROUND: There is no conclusive evidence supporting the efficacy of memantine in frontotemporal dementia (FTD). We conducted a comprehensive meta-analysis of memantine concerning the efficacy and tolerability of memantine in FTD. METHODS: Studies were identified through searches of PubMed, databases of the Cochrane Library, and PsycINFO citations up to April 10, 2015. Outcomes were Clinical Global Impression (primary), Mini-Mental State Examination, Neuropsychiatric Inventory, and Zarit Burden Interview scores as well as all-cause discontinuation. Standardized mean difference and risk ratio with 95% confidence interval were calculated. RESULTS: Two randomized controlled trials (RCTs) (total n=130) met the inclusion criteria. Memantine was marginally superior to placebo as assessed by the Clinical Global Impression scores (standardized mean difference =-0.34, 95% confidence interval =-0.68-0.01, P=0.06). However, there were no significant differences in Mini-Mental State Examination, Neuropsychiatric Inventory, and Zarit Burden Interview scores as well as all cause discontinuation between memantine and placebo. CONCLUSION: Our results suggest that memantine may benefit FTD patients. However, because only two randomized controlled trials have addressed this issue, further studies using larger samples are needed. PMID- 26648725 TI - The association between the subjective memory complaints scale and depressive state and cognitive impairment: a factor analysis. AB - BACKGROUND: We aimed to discriminate individuals with depressive state from individuals with cognitive impairment among community-dwelling people using the subjective memory complaints (SMC) scale. METHODS: The study group consisted of 289 volunteers (over 60 years old; 104 males and 185 females). Participants' SMCs were assessed using the SMC scale. The Japanese version of the Center for Epidemiologic Studies for Depression scale and the Mini-Mental State Examination were administered. Participants whose Center for Epidemiologic Studies for Depression scores were 16 or higher were defined as the depressive group and participants whose Mini-Mental State Examination scores were less than 24 were defined as the cognitive impairment group. Exploratory factor analysis was performed to identify the factor structure of the items of the SMC scale. A multiple logistic regression analysis of the association between depressive state and cognitive impairment and the score of each factor was performed. RESULTS: In the final factor analysis model, six items of the SMC scale remained, and a two factor structure was adequate. Factor 1 included the items 8, 9, and 10 about thought or the ability to think; thus, Factor 1 was defined as "thought disturbance factor". Factor 2 included the items 1, 2, and 4 about memory or forgetfulness; thus, Factor 2 was defined as "memory disturbance factor". In the multiple logistic regression analysis, Factor 1 was significantly associated with depressive state and Factor 2 was significantly associated with cognitive impairment. CONCLUSION: For individuals with SMCs, we might be able to discriminate depressive state or depression from cognitive impairment or dementia through a detailed investigation using the SMC scale. PMID- 26648726 TI - Comparative efficacy, acceptability, and tolerability of dexmethylphenidate versus placebo in child and adolescent ADHD: a meta-analysis of randomized controlled trials. AB - BACKGROUND: The efficacy of dexmethylphenidate (d-MPH) has been proven in the treatment of children and adolescents with attention-deficit hyperactivity disorder (ADHD). OBJECTIVE: The aim of this systematic review is to determine the efficacy, acceptability, and tolerability of d-MPH in child and adolescent ADHD. METHODS: The searches of SCOPUS, MEDLINE, CINAHL, and Cochrane Controlled Trials Register were performed in February 2015. All randomized controlled trials of d MPH versus placebo that were performed in children and adolescents with ADHD up to 18 years of age were included in the study. The efficacy was measured by using the pooled mean-endpoint or mean-changed scores of ADHD rating scales and the response rate. Acceptability and tolerability were measured by using the pooled rates of overall discontinuation and discontinuation due to adverse events, respectively. RESULTS: A total of 1,124 children and adolescents diagnosed as having ADHD were included in this review. In a laboratory school setting, the pooled mean-change and mean-endpoint scores in the d-MPH-treated group were significantly greater than those of the placebo-treated group with standardized mean difference (95% confidence interval [CI]) of -1.20 (-1.73, -0.67), I (2)=95%. Additionally, the pooled mean-changed scores of the ADHD rating scales for teachers and parents in the d-MPH-treated group were significantly greater than that of the placebo-treated group with weighted mean difference (95% CI) of 13.01 (-15.97, -10.05), I (2)=0% and (95% CI) of -12.99 (-15.57, -10.42), I (2)=0%, respectively. The pooled response rate in the d-MPH-treated groups had a significance higher than that of the placebo-treated group. The rates of pooled overall discontinuation and discontinuation due to adverse events between the two groups were not significantly different. CONCLUSION: Based on the findings in this review, it can be concluded that d-MPH medication is efficacious and tolerable in child and adolescent ADHD. However, the acceptability of d-MPH is no greater than that of the placebo. Further systematic studies may confirm these findings. PMID- 26648727 TI - Japanese version of the Munich Parasomnia Screening: translation and linguistic validation of a screening instrument for parasomnias and nocturnal behaviors. AB - OBJECTIVE: There is no broad screening instrument that can comprehensively assess parasomnias and sleep-related movement disorders listed in the International Classification of Sleep Disorders. The aim of this study was to develop the Japanese version of the Munich Parasomnia Screening (MUPS), a screening instrument for parasomnias and nocturnal behaviors, which was developed and validated at the Max Planck Institute of Psychiatry. METHODS: A multi-step translation methodology consisting of forward translation, back translation, expert review, and cognitive debriefing interviews was performed between June and November 2011. RESULTS: The English version of the MUPS was translated into Japanese, and the original author performed an expert review on the basis of a detailed report on the forward and back translation steps. The cognitive debriefing was carried out in five patients with parasomnia. The mean time to fill out the questionnaire was 8 minutes (ranging from 2 to 17 minutes). The authors reviewed and discussed the results of the cognitive debriefing interviews and modified the Japanese version. The final Japanese version was confirmed to be conceptually equivalent to the original English version. CONCLUSION: The Japanese version of the MUPS is an easy-to-use self-rating instrument for parasomnia and nocturnal behavior screening, consistent with the original version. The usage of this instrument would enable clinicians to quickly screen the past history and current frequency of nocturnal behaviors. PMID- 26648728 TI - Long-term effect of early-life stress from earthquake exposure on working memory in adulthood. AB - OBJECTIVE: The present study aimed to investigate the long-term effect of 1976 Tangshan earthquake exposure in early life on performance of working memory in adulthood. METHODS: A total of 907 study subjects born and raised in Tangshan were enrolled in this study. They were divided into three groups according to the dates of birth: infant exposure (3-12 months, n=274), prenatal exposure (n=269), and no exposure (born at least 1 year after the earthquake, n=364). The prenatal group was further divided into first, second, and third trimester subgroups based on the timing of exposure during pregnancy. Hopkins Verbal Learning Test-Revised and Brief Visuospatial Memory Test-Revised (BVMT-R) were used to measure the performance of working memory. Unconditional logistic regression analysis was used to analyze the influential factors for impaired working memory. RESULTS: The Hopkins Verbal Learning Test-Revised scores did not show significant difference across the three groups. Compared with no exposure group, the BVMT-R scores were slightly lower in the prenatal exposure group and markedly decreased in the infant exposure group. When the BVMT-R scores were analyzed in three subgroups, the results showed that the subjects whose mothers were exposed to earthquake in the second and third trimesters of pregnancy had significantly lower BVMT-R scores compared with those in the first trimester. Education level and early-life earthquake exposure were identified as independent risk factors for reduced performance of visuospatial memory indicated by lower BVMT-R scores. CONCLUSION: Infant exposure to earthquake-related stress impairs visuospatial memory in adulthood. Fetuses in the middle and late stages of development are more vulnerable to stress-induced damage that consequently results in impaired visuospatial memory. Education and early-life trauma can also influence the performance of working memory in adulthood. PMID- 26648729 TI - The limits of oral therapy in pulmonary arterial hypertension management. AB - Pulmonary arterial hypertension (PAH) is a devastating disease in which remodeling of the small pulmonary arteries leads to a progressive increase in pulmonary vascular resistance and right-sided heart failure. Over the past decade, new treatments for PAH, such as the use of ERAs, PDE-5 inhibitors and prostacyclin analogs, have brought about dramatic improvements in clinical outcomes. Epoprostenol infusion therapy has been shown to improve hemodynamics, functional status, and survival, and it remains the gold standard for treatment of patients with severe PAH. Many agents, approved for PAH are always delivered in pill form. Although oral therapy occupies an important position, it has some drawbacks and limitations in PAH management. For patients in World Health Organization functional class IV and with severe right heart failure, there are few data on the long-term survival of patients treated with oral medications. Further research, exploration, and clinical experience with oral therapy in severe PAH and combination therapy will redefine its position in PAH management. PMID- 26648730 TI - Utility of high-sensitivity cardiac troponin T in patients receiving anthracycline chemotherapy. AB - BACKGROUND: Anthracycline chemotherapy remains an integral part of the care for curative intent chemotherapy in breast cancer and non-Hodgkin lymphoma patients. Better tools need to be identified to predict cardiac complications of anthracycline chemotherapy. MATERIALS AND METHODS: We investigated the utility of high-sensitivity cardiac troponin T (hscTnT), N-terminal pro-B-type natriuretic peptide, cardiac troponin T and I, and creatine kinase (CK)-MB in cancer patients receiving anthracycline-based chemotherapy, in order to determine whether baseline levels or changes in these biomarkers may help predict the onset of congestive heart failure. RESULTS: Eighteen consecutive patients with a pathologic diagnosis of breast cancer or non-Hodgkin lymphoma were enrolled. The median dose of doxorubicin exposure was 240 mg/m(2) (range 240-400 mg/m(2)). After treatment with doxorubicin, the hscTnT increased to 19.1 pg/mL (P<0.001). CKMB and N-terminal pro-B-type natriuretic peptide levels increased to 1.1 ng/mL and 88.3 pg/mL, respectively (P=0.02). When subjects who had a decline in left ventricular ejection fraction (LVEF) by equilibrium radionuclide ventriculography were compared to those who did not have a change in LVEF, there was a suggestion that those subjects with an elevated baseline hscTnT were more likely to have a decline in LVEF (2.7 pg/mL and 0.1 pg/mL, respectively; P=0.07). Spearman correlation demonstrated that patients with higher baseline hscTnT and CKMB tended to have a greater decline in LVEF (Spearman correlation -0.54, 95% confidence interval -0.80 to -0.08 [P=0.02], and -0.49, 95% confidence interval 0.77 to -0.01 [P=0.04], respectively). CONCLUSION: Elevations in baseline hscTnT levels are suggestive of an oncology subgroup at high risk of developing cardiac complications from their chemotherapy. Early detection by oncologists with the use of baseline biomarkers may be clinically important in designing interventions to prevent serious anthracycline-based chemotherapy complications. PMID- 26648731 TI - Preseason preparation training and endothelial function in elite professional soccer players. AB - AIM: To examine whether a high volume of soccer-specific training can lead to endothelial activation and/or dysfunction in professional soccer players due to exercise-induced oxidative stress. METHODS: Twenty-three (15 nonsmokers and eight smokers) healthy, elite male professional soccer players (mean age: 25.2+/-4.3 years, BMI: 23.1+/-1.3 kg/m(2), fat: 7.8%+/-2.6%) were selected for this study. All participants had a full clinical and laboratory evaluation. von Willebrand factor antigen (vWf Ag) plasma levels were measured on two different occasions: 1 day before the beginning of the preseason preparation period and after 7 weeks of strenuous exercise. RESULTS: Mean vWf Ag plasma levels were significantly decreased from 95.1%+/-26% to 88.3%+/-27.2% at the end of the experimental period (P=0.018), suggesting a potential beneficial effect on the endothelium of these athletes. Further analysis showed that age greater than 29 years with an age range from 29 to 34 years can not impair this effect (P>0.05). CONCLUSION: Strenuous exercise did not lead to endothelium activation or dysfunction in well trained elite soccer players. On the contrary, it seemed to produce a beneficial effect on the endothelium of these players. PMID- 26648732 TI - The Norwegian Offender Mental Health and Addiction Study - Design and Implementation of a National Survey and Prospective Cohort Study. AB - The Norwegian prison inmates are burdened by problems before they enter prison. Few studies have managed to assess this burden and relate it to what occurs for the inmates once they leave the prison. The Norwegian Offender Mental Health and Addiction (NorMA) study is a large-scale longitudinal cohort study that combines national survey and registry data in order to understand mental health, substance use, and criminal activity before, during, and after custody among prisoners in Norway. The main goal of the study is to describe the criminal and health-related trajectories based on both survey and registry linkage information. Data were collected from 1,499 inmates in Norwegian prison facilities during 2013-2014. Of these, 741 inmates provided a valid personal identification number and constitute a cohort that will be examined retrospectively and prospectively, along with data from nationwide Norwegian registries. This study describes the design, procedures, and implementation of the ongoing NorMA study and provides an outline of the initial data. PMID- 26648733 TI - Transitioning from military medics to registered nurses. AB - The nursing shortage in the USA is expected to reach 260,000 registered nurses (RNs) by 2025. The most profound shortages are expected in California and Florida, translating into 109,779 and 128,364 RN jobs, respectively. Despite a foreseen growth in nursing career opportunities nationwide, the supply of nurses will be insufficient to meet the corresponding demand. Capitalizing on prior education, experience, and skills of military clinical personnel to fill these jobs could significantly reduce the projected nursing shortage. Florida International University's Nicole Wertheim College of Nursing and Health Sciences is circumventing barriers to recruit, retain, and graduate transitioning veteran medics and corpsmen as Bachelor of Science in Nursing prepared RNs who reintegrate into the civilian workforce. The Veteran Bachelor of Science in Nursing (VBSN) program is in the form of a cooperative agreement between Florida International University and the US Health Resources and Services Administration. The VBSN program's main objective is to build upon the unique leadership skills, clinical education, and training of military medics and corpsmen to ensure successful completion of the Bachelor of Science in Nursing curriculum. VBSN students, as veterans themselves, have unique knowledge and exposure to the specific health issues and needs of the veteran population overall. They are poised and best prepared to effectively care for the US population, particularly the current 22 million US veterans and 1.6 million Florida veterans. Additionally, the VBSN program will alleviate the challenges, such as the lack of recognition of military skills, unemployment, the substandard income, and homelessness that many former service members face after separation from the military. PMID- 26648734 TI - Early results of pediatric appendicitis after adoption of diagnosis-related group based payment system in South Korea. AB - PURPOSE: As an alternative to the existing fee-for-service (FFS) system, a diagnosis-related group (DRG)-based payment system has been suggested. The aim of this study was to investigate the early results of pediatric appendicitis treatment under the DRG system, focusing on health care expenditure and quality of health care services. PATIENTS AND METHODS: The medical records of 60 patients, 30 patients before (FFS group), and 30 patients after adoption of the DRG system (DRG), were reviewed retrospectively. RESULTS: Mean hospital stay was shortened, but the complication and readmission rates did not worsen in the DRG. Overall health care expenditure and self-payment decreased from Korean Won (KRW) 2,499,935 and KRW 985,540, respectively, in the FFS group to KRW 2,386,552 and KRW 492,920, respectively, in the DRG. The insurer's payment increased from KRW 1,514,395 in the FFS group to KRW 1,893,632 in the DRG. For patients in the DRG, calculation by the DRG system yielded greater overall expenditure (KRW 2,020,209 vs KRW 2,386,552) but lower self-payment (KRW 577,803 vs KRW 492,920) than calculation by the FFS system. CONCLUSION: The DRG system worked well in pediatric patients with acute appendicitis in terms of cost-effectiveness over the short term. The gradual burden on the national health insurance fund should be taken into consideration. PMID- 26648735 TI - Transient and persistent symptoms in patients with lacunar infarction: results from a prospective cohort study. AB - BACKGROUND: The transient symptoms with lacunar infarction (TSI) and persistent symptoms with lacunar infarction (PSI) are the most common forms of symptomatic lacunar infarction (LI). The aim of this study was to compare the differences in TSI and PSI of symptomatic LI. METHODS: A prospective cohort study was conducted in the neurologic outpatients of the tertiary teaching hospital in Northern China between February 2011 and February 2012. The TSI and PSI in participants aged 35 years or over were assessed. Patients were followed up and their outcomes were compared. RESULTS: Of the 453 symptomatic outpatients, 251 patients with LI were diagnosed by magnetic resonance imaging. Approximately 77.3% (194/251) of the patients with LI at this time had TSI. and the remaining 23.7% had PSI. After the adjusted odds ratios, only middle age (risk ratio [RR], 1.1; 95% confidence interval [CI], 1.157-1.189), lower National Institutes of Health Stroke Scale score (RR, 20.6; 95% CI, 6.705-13.31), smaller lacunae on brain images (RR, 2.9; 95% CI, 1.960-4.245), and LI frequently in the anterior circulation territory (RR, 0.2; 95% CI, 0.079-0.721) were independently associated with TSI. During a mean follow-up of 6 months, survival rate was significantly higher among patients with TSI than among those with PSI (log rank, 6.9; P=0.010); estimated unadjusted incidence of vascular subsequent events (30.9% vs 54.4%, P=0.001) was significantly lower in TSI than in PSI. CONCLUSION: The TSI has a higher prevalence and is associated with a lower risk of vascular subsequent events and death than PSI. The implications of these findings for TSI and PSI may require different interventions. PMID- 26648736 TI - Incidence and clinical significance of ESR1 mutations in heavily pretreated metastatic breast cancer patients. AB - BACKGROUND: ESR1 mutation has recently emerged as one of the important mechanisms involved in endocrine resistance. The incidence and clinical implication of ESR1 mutation has not been well evaluated in heavily pretreated breast cancer patients. METHODS: We conducted a retrospective review of advanced breast cancer patients with tumors who underwent next-generation sequencing genomic profiling using Foundation One test at Cancer Treatment Centers of America((r)) regional hospitals between November 2012 and November 2014. RESULTS: We identified a total of 341 patients including 217 (59%) estrogen receptor (ER)+, 177 (48%) progesterone receptor (PR)+, 30 (8%) hormone receptor+/HER2 positive, and 119 (32%) triple negative patients. ESR1 mutation was noted in 27/222 (12.1%) ER+ or PR+ breast cancer patients. All ER+ patients received at least one line of an aromatase inhibitor. All 28 patients were found to harbor ESR1 mutations affecting ligand-binding domain with the most common mutations affecting Y537 (17/28, 60.7%) and D538 (9/28, 32.1%). In this cohort, 19 (67.9%) patients carried three or more, seven (25%) patients had one or two additional genomic alterations and one (3.6%) patient had an ESR1 mutation only. Of 28 patients, three patients were treated with fulvestrant immediately before and two patients were treated after next-generation sequencing testing; only one patient achieved stable disease for 8 months and the other four patients had progression of disease. In all, 3/3 (100%) patients before testing and 2/4 (50%) after testing treated with exemestane and everolimus achieved stable disease for at least 6 months. CONCLUSION: ESR1 mutation was found in 12.1% of a large cohort of advanced breast cancer patients. Exemestane in combination with everolimus might be a reasonable option. Prospective studies are warranted to validate these findings. PMID- 26648737 TI - Cetuximab could be more effective without prior bevacizumab treatment in metastatic colorectal cancer patients. AB - BACKGROUND: Cetuximab and bevacizumab reportedly improve the survival of patients with metastatic colorectal cancer (mCRC), but their most effective sequence of administration is unknown. The aim of this study was to compare the survival of patients with mCRC treated with cetuximab after bevacizumab failure with that of patients with mCRC without previous bevacizumab therapy. PATIENTS AND METHODS: In total, 190 of 323 patients with mCRC treated with cetuximab from March 2006 to July 2013 were enrolled in our hospital for this retrospective study. Forty-seven patients were treated with cetuximab-based second-line therapy, 21 of whom had received prior bevacizumab; 143 patients were treated with cetuximab-based third line therapy, 109 of whom had received prior bevacizumab. The Kaplan-Meier method with a log-rank test and Cox regression analysis were performed to evaluate the overall survival and progression-free survival (PFS) of each group of patients. RESULTS: The median follow-up time was 11.8 months in patients who received second-line cetuximab-based chemotherapy and 13.7 months in those who received third-line cetuximab-based chemotherapy. Univariate analysis revealed that the median PFS was significantly longer in patients without prior bevacizumab therapy than in patients with prior bevacizumab therapy (second line, P=0.048; third line, P=0.0022). Multivariate analysis adjusted for baseline characteristics showed that third-line cetuximab-based chemotherapy with or without prior bevacizumab was significantly associated with PFS (P=0.014). Neither the presence nor the absence of prior bevacizumab administration was associated with overall survival. CONCLUSION: Cetuximab could be more effective without prior bevacizumab. Prior bevacizumab use may decrease the efficacy of cetuximab. PMID- 26648738 TI - Hormone receptor status predicts the clinical outcome of human epidermal growth factor 2-positive metastatic breast cancer patients receiving trastuzumab therapy: a multicenter retrospective study. AB - OBJECTIVES: Trastuzumab, a humanized monoclonal antibody that binds human epidermal growth factor receptor 2 (HER2), dramatically improves the clinical outcomes of HER2-positive breast cancer. Emerging evidence implied that the clinical behavior and sensitivity to targeted agents in HER2-positive breast cancer differed by hormone receptor (HR) status. The objective of this study was to determine the effect of the HR status on survival benefit of HER2-positive metastatic breast cancer when treated with anti-HER2-targeted therapy in People's Republic of China. METHODS: Metastatic breast cancer patients with HER2-positive diseases across six cancer centers in People's Republic of China were retrospectively analyzed in our study. Patients were classified into four groups according to HR/HER2 status and trastuzumab treatment: HER2+/HR+ patients with first-line trastuzumab treatment, HER2+/HR+ patients with no trastuzumab treatment, HER2+/HR- patients with first-line trastuzumab treatment, and HER2+/HR patients with no trastuzumab treatment. Kaplan-Meier analysis, log-rank test, and multivariate analysis were performed during analysis. RESULTS: A total of 295 patients were included in the final analysis. The median overall survival was 30 months (95% confidence interval: 27.521-32.479). Among patients with HER2+/HR- disease, significant survival benefit was observed when treated with trastuzumab (30 vs 21 months, P=0.000). However, in patients with HER2+/HR+ disease, trastuzumab administration had a survival improvement trend but no significant statistical differences (36 vs 30 months, P=0.258). In the multivariate analysis, HR status was an independent predictor of overall survival and trastuzumab treatment had significantly decreased risk of death in HER2+/HR- patients (hazard ratio =0.330). CONCLUSION: HR status is an independent predictor of overall survival in HER2-positive metastatic breast cancer patients and patients with HER2+/HR- subtype might be associated with more survival benefits when treated with trastuzumab-based regimens. PMID- 26648739 TI - Knockdown of a HIF-2alpha promoter upstream long noncoding RNA impairs colorectal cancer stem cell properties in vitro through HIF-2alpha downregulation. AB - Currently, various long noncoding RNAs (lncRNAs) have been identified as key regulators of multiple cancers. However, cancer stem cell (CSC)-related lncRNAs have rarely been reported. In this study, we found an lncRNA that is a promoter upstream transcript of hypoxia-inducible factor-2alpha (HIF-2alpha), and we named it "lncRNA-HIF2PUT". The function of HIF-2alpha is closely connected with "stem cell-like" properties, and the function of PROMPTs is often associated with the adjacent protein-coding transcripts. Herein, we showed that the expression of lncRNA-HIF2PUT was significantly correlated with HIF-2alpha in colorectal cancer (CRC) tissues. Knockdown of lncRNA-HIF2PUT blocked the HIF-2alpha expression and inhibited the CSC properties in CRC cell lines DLD-1 and HT29. LncRNA HIF2PUTsmall interfering RNA transfection resulted in decreased stemness genes expression, impaired colony formation, and spheroid formation ability, retarded migration, and invasion of the cells. These data suggest that lncRNA-HIF2PUT may be a regulator of HIF-2alpha and a mediator of CSCs in CRC. PMID- 26648740 TI - Effect of gyromagnetic fields on human prostatic adenocarcinoma cells. AB - PURPOSE: To investigate the biological effect of gyromagnetic fields (GMFs) on cell proliferation and apoptosis of human prostatic adenocarcinoma cells and explore the underlying mechanisms. METHODS: PC-3 cells were grouped into normal control (NC) and GMF treatment groups. Cell proliferation was analyzed with kit-8 and Ki67 immunofluorescence staining, while cell apoptosis was analyzed with flow cytometry double staining of Annexin V-PE/7-AAD. The Akt and p38 MAPK/Caspase signaling pathways were analyzed by western blotting and immunofluorescence staining, and cell polarization was analyzed with PARD3. RESULTS: Cell proliferation and activity of the Akt pathway were significantly decreased by the GMF, while cell apoptosis, activity of p38 MAPK, and PARD3-positive cell number were significantly increased in the GMF group compared to the NC group. CONCLUSION: GMFs inhibit cell proliferation, induce apoptosis, and regulate tumor cell polarity conditions, potentially through down-regulating Akt, activating the p38 MAPK/Caspase pathway, and promoting PARD3 expression in PC-3 cells. PMID- 26648741 TI - Expression of CPEB4 in invasive ductal breast carcinoma and its prognostic significance. AB - AIMS: Cytoplasmic polyadenylation element binding proteins (CPEBs) are RNA binding proteins that regulate translation by inducing cytoplasmic polyadenylation. CPEB4 has been reported in association with tumor growth, vascularization, and invasion in several cancers. To date, the expression of CPEB4 with clinical prognosis of breast cancer was never reported before. We aim to investigate the expression of CPEB4 and its prognostic significance in invasive ductal breast carcinoma. METHODS: Immunohistochemical staining of CPEB4 and estrogen receptor, progesterone receptor, and human epidermal growth factor receptor was performed in 107 invasive ductal carcinoma (IDC) samples, and prognostic significance was evaluated. RESULTS: High expression of CPEB4 was observed in 48.6% of IDC samples. Elevated CPEB4 expression was possibly related to increased histological grading (P=0.037) and N stage (P<0.001). Patients with high expression of CPEB4 showed shorter overall survival (P=0.001). High CPEB4 expression was an independent prognostic factor for overall survival (P=0.022, hazard ratio =4.344, 95% confidence interval =1.235-15.283). CONCLUSION: High CPEB4 expression is associated with increased histological grading and N stage, and it can serve as an independent prognostic factor in IDC. PMID- 26648743 TI - The association between osteopontin and survival in non-small-cell lung cancer patients: a meta-analysis of 13 cohorts. AB - In the last decade, osteopontin (OPN) was identified as one of the important proteins that promote the metastasis of tumor. However, the association between OPN overexpression and clinical outcome of non-small-cell lung cancer (NSCLC) was unclear. The purpose of this study is to investigate the role of OPN in NSCLC patients. A total of 13 studies are included to explore the relationship between the OPN elevation and the overall survival (OS) and disease-free survival (DFS) in NSCLC patients. We searched for related articles in PubMed, Web of Science, Google Scholar, and Cochrane Library databases, which were published before January 31, 2015. Hazard ratio (HR), odds ratio (OR), and 95% confidence interval (CI) in the high OPN expression group compared with the low OPN expression group were calculated and analyzed. Primary results were summarized by using a fixed effects model or a random-effects model. The stratified analyses in subgroups were also performed. Thirteen cohort studies, which involved 1,630 patients, were included. Subgroup analyses were performed by area and test method of OPN. We found that OPN was significantly associated with poor OS (HR =2.20, 95% CI 1.71 2.83, P<0.001) and DFS (HR =2.11, 95% CI 1.62-2.74, P<0.001) in NSCLC patients. OPN overexpression tended to be associated with the presence of advanced tumor TNM stage (III and IV) (OR =2.57, 95% CI 1.61-4.11, P<0.001). The Egger's test suggested that there was no publication bias in OS studies (P=0.062) and DFS studies (P=0.740). These data indicate that OPN seems to have a significant predictive potential in estimating survival in NSCLC. PMID- 26648742 TI - Ability of PITX2 methylation to predict survival in patients with prostate cancer. AB - BACKGROUND: The aim of this study was to explore whether candidate gene methylation can effectively predict death from prostate cancer. METHODS: After reviewing the literature to identify likely candidate genes, we assembled a case control cohort (in a 1:2 ratio) to explore the distribution of PITX2, WNT5a, SPARC, EPB41L3, and TPM4 methylation levels. The case group comprised 45 patients with a Gleason score <=7 who had died as a result of prostate cancer, and the control group comprised 90 current prostate cancer patients or those who died of other causes. The methylation possibility of each of the candidate genes were maximized. Univariate conditional logistic was applied for data analysis and to evaluate prediction efficiency of gene methylation on prostate cancer. RESULTS: The results indicated that a raised level of PITX2 methylation increased the likelihood of death due to prostate cancer by 10% (odds ratio 1.56, 95% confidence interval 1.17-2.08; P=0.005). Methylation of SPARC was found to be able to distinguish between benign prostate hyperplasia and prostate cancer. CONCLUSION: Methylation of PITX2 is an effective biomarker to predict death from prostate cancer, particularly in patients with a low Gleason score. PMID- 26648744 TI - Relative cost-effectiveness of using an extensively hydrolyzed casein formula containing the probiotic Lactobacillus rhamnosus GG in managing infants with cow's milk allergy in Spain. AB - OBJECTIVE: To estimate the cost-effectiveness of using an extensively hydrolyzed casein formula containing the probiotic Lactobacillus rhamnosus GG (eHCF + LGG; Nutramigen LGG) as a first-line management for cow's milk allergy compared with eHCF alone, and amino acid formulae in Spain, from the perspective of the Spanish National Health Service (SNS). METHODS: Decision modeling was used to estimate the probability of immunoglobulin E (IgE)-mediated and non-IgE-mediated allergic infants developing tolerance to cow's milk by 18 months. The models also estimated the SNS cost (at 2012/2013 prices) of managing infants over 18 months after starting a formula as well as the relative cost-effectiveness of each of the formulae. RESULTS: The probability of developing tolerance to cow's milk by 18 months was higher among infants with either IgE-mediated or non-IgE-mediated allergy who were fed eHCF + LGG compared with those fed one of the other formulae. The total health care cost of initially feeding infants with eHCF + LGG was less than that of feeding infants with one of the other formulae. Hence, eHCF + LGG affords the greatest value for money to the SNS for managing both IgE mediated and non-IgE-mediated cow's milk allergy. CONCLUSION: Using eHCF + LGG instead of eHCF alone or amino acid formulae for first-line management of newly diagnosed infants with cow's milk allergy affords a cost-effective use of publicly funded resources because it improves outcome for less cost. A randomized controlled study showing faster tolerance development in children receiving a probiotic-containing formula is required before this conclusion can be confirmed. PMID- 26648745 TI - Productivity loss and resource utilization, and associated indirect and direct costs in individuals providing care for adults with schizophrenia in the EU5. AB - OBJECTIVE: This study aimed to understand the impact of providing care for adults with schizophrenia on productivity, resource utilization, and costs in the EU5 (France, Germany, Italy, Spain, and UK). METHODS: Data from the 2010, 2011, and 2013 EU5 National Health and Wellness Survey, an online questionnaire of a nationwide sample of adults, were analyzed. Schizophrenia caregivers (n=398) were matched to noncaregivers (n=158,989) and other caregivers (n=14,341) via propensity scores. Outcome measures included health care utilization, Work Productivity and Activity Impairment questionnaire-based scores, and associated direct and indirect costs (estimated from the literature). Significant differences between schizophrenia caregivers vs noncaregivers and other caregivers (eg, cancer and Alzheimer's disease) were examined. RESULTS: After matching, schizophrenia caregivers reported greater activity impairment (38.4% vs 26.1%), provider visits (8.0 vs 5.7), emergency room visits (0.9 vs 0.2), hospitalizations (0.8 vs 0.1), and direct costs (?2,258 vs ?617) than noncaregivers, all P<0.001. Employed schizophrenia caregivers reported greater absenteeism, presenteeism, overall work impairment (35.0% vs 20.7%), and indirect costs (?6,667 vs ?3,795) than noncaregivers, all P<0.001. Schizophrenia caregivers (vs other caregivers) reported greater activity impairment (38.4% vs 32.3%) and provider visits (8.0 vs 6.6), P<0.05. A greater proportion of schizophrenia caregivers (vs other caregivers) reported at least one emergency room visit (26.1% vs 20.2%) and hospitalization (20.4% vs 14.3%), P<0.05. Employed schizophrenia caregivers incurred greater indirect costs than other caregivers (?6,667 vs ?5,104). DISCUSSION: Schizophrenia caregivers reported greater activity impairment, resource utilization, and costs than noncaregivers and other caregivers. Better support systems for schizophrenia caregivers may help reduce the burden on the health care system and caregivers. PMID- 26648746 TI - Gastrointestinal events and association with initiation of treatment for osteoporosis. AB - BACKGROUND: Preexisting gastrointestinal (GI) events may deter the use of pharmacologic treatment in patients diagnosed with osteoporosis (OP). The objective of this study was to examine the association between preexisting GI events and OP pharmacotherapy initiation among women diagnosed with OP. METHODS: The study utilized claims data from a large US managed care database to identify women aged >=55 years with a diagnosis code for OP (index date) during 2002-2009. Patients with a claim for pharmacologic OP treatment in the 12-month pre-index period (baseline) were excluded. OP treatment initiation in the post-index period was defined as a claim for bisphosphonates (alendronate, ibandronate, risedronate, zoledronic acid), calcitonin, raloxifene, or teriparatide. During the post-index period (up to 12 months), GI events were identified before treatment initiation. A time-dependent Cox regression model was used to investigate the likelihood of initiating any OP treatment. Among patients initiating OP treatment, a discrete choice model was utilized to assess the relationship between post-index GI events and likelihood of initiating with a bisphosphonate versus a non-bisphosphonate. RESULTS: In total, 65,344 patients (mean age 66 years) were included; 23.7% had a GI event post diagnosis and before treatment initiation. Post-index GI events were associated with a 75% lower likelihood of any treatment initiation (hazard ratio 0.25; 95% confidence interval 0.24-0.26). Among treated patients (n=23,311), those with post-index GI events were 39% less likely to receive a bisphosphonate versus a non bisphosphonate (odds ratio 0.61; 95% confidence interval 0.54-0.68). CONCLUSION: GI events after OP diagnosis were associated with a decreased likelihood of OP treatment initiation and an increased likelihood of treatment initiation with a non-bisphosphonate versus a bisphosphonate. PMID- 26648747 TI - Estimating health-state utility values for patients with recurrent ovarian cancer using Functional Assessment of Cancer Therapy - General mapping algorithms. AB - OBJECTIVES: In the absence of EuroQol 5D data, mapping algorithms can be used to predict health-state utility values (HSUVs) for use in economic evaluation. In a placebo-controlled Phase II study of olaparib maintenance therapy (NCT00753545), health-related quality of life was measured using the Functional Assessment of Cancer Therapy - Ovarian (FACT-O) questionnaire. Our objective was to generate HSUVs from the FACT-O data using published mapping algorithms. MATERIALS AND METHODS: Algorithms were identified from a review of the literature. Goodness-of fit and patient characteristics were compared to select the best-performing algorithm, and this was used to generate base-case HSUVs for the intention-to treat population of the olaparib study and for patients with breast cancer antigen mutations. RESULTS: Four FACT - General (the core component of FACT-O) mapping algorithms were identified and compared. Under the preferred algorithm, treatment-related adverse events had no statistically significant effect on HSU (P>0.05). Discontinuation of the study treatment and breast cancer antigen mutation status were both associated with a reduction in HSUVs (-0.06, P=0.0009; and -0.03, P=0.0511, respectively). The mean HSUV recorded at assessment visits was 0.786. CONCLUSION: FACT - General mapping generated credible HSUVs for an economic evaluation of olaparib. As reported in other studies, different algorithms may produce significantly different estimates of HSUV. For this reason, it is important to test whether the choice of a specific algorithm changes the conclusions of an economic evaluation. PMID- 26648748 TI - Trihydroxybenzoic acid glucoside as a global skin color modulator and photo protectant. AB - BACKGROUND: 3,4,5-Trihydroxybenzoic acid glucoside (THBG), a molecule produced by an original biocatalysis-based technology, was assessed in this study with respect to its skin photoprotective capacity and its skin color control property on Asian-type skin at a clinical level and on skin explant culture models. METHODS: The double-blinded clinical study was done in comparison to a vehicle by the determination of objective color parameters thanks to recognized quantitative and qualitative analysis tools, including Chroma-Meter, VISIA-CRTM, and SIAscopeTM. Determination of L* (brightness), a* and b* (green-red and blue yellow chromaticity coordinates), individual typology angle, and C* (chroma) and h* (hue angle) parameters using a Chroma-Meter demonstrated that THBG is able to modify skin color while quantification of ultraviolet (UV) spots by VISIA-CRTM confirmed its photoprotective effect. The mechanism of action of THBG molecule was determined using explant skin culture model coupled to histological analysis (epidermis melanin content staining). RESULTS: We have demonstrated that THBG was able to modulate significantly several critical parameters involved in skin color control such as L* (brightness), a* (redness), individual typology angle (pigmentation), and hue angle (yellowness in this study), whereas no modification occurs on b* and C* parameters. We have demonstrated using histological staining that THBG decrease epidermis melanin content under unirradiated and irradiated condition. We also confirmed that THBG molecule is not a sunscreen agent. CONCLUSION: This study demonstrated that THBG controls skin tone via the inhibition of melanin synthesis as well as the modulation of skin brightness, yellowness, and redness. PMID- 26648749 TI - Optimal management of steroid-dependent ulcerative colitis. AB - Ulcerative colitis (UC) is a chronic inflammatory condition that is variable in both extent and severity of disease as well as response to therapy. Corticosteroids (CSs) were the first drugs used in the management of UC and are still used for induction of remission. However, because of their extensive side effect profile, they are not utilized for maintenance of remission. In view of this, CS-free remission has become an important end point while evaluating therapeutic agents used in the management of UC. This review highlights the results of various studies conducted to evaluate the efficacy of different medications to attain CS-free remission in the setting of active UC. The drugs reviewed include established agents such as thiopurines, methotrexate, infliximab, adalimumab, vedolizumab, golimumab, and newer experimental agents, and if all else fails, colectomy will be performed. The efficacy of these drugs is evaluated individually. Our aim is to provide a synopsis of the work done in this field to date. PMID- 26648751 TI - Sleep is associated with task-negative brain activity in fibromyalgia participants with comorbid chronic insomnia. AB - Patients with chronic pain exhibit altered default mode network (DMN) activity. This preliminary project questioned whether comorbid disease states are associated with further brain alterations. Thirteen women with fibromyalgia (FM) only and 26 women with fibromyalgia with comorbid chronic insomnia (FMI) underwent a single night of ambulatory polysomnography and completed a sleep diary each morning for 14 days prior to performing a neuroimaging protocol. Novel imaging analyses were utilized to identify regions associated with significantly disordered sleep that were more active in task-negative periods than task oriented periods in participants with FMI, when compared to participants with FM. It was hypothesized that core DMN areas (ie, cingulate cortex, inferior parietal lobule, medial prefrontal cortex, medial temporal cortex, precuneus) would exhibit increased activity during task-negative periods. Analyses revealed that significantly disordered sleep significantly contributed to group differences in the right cingulate gyrus, left lentiform nucleus, left anterior cingulate, left superior gyrus, medial frontal gyrus, right caudate, and the left inferior parietal lobules. Results suggest that FMI may alter some brain areas of the DMN, above and beyond FM. However, future work will need to investigate these results further by controlling for chronic insomnia only before conclusions can be made regarding the effect of FMI comorbidity on the DMN. PMID- 26648750 TI - Sanfilippo syndrome: causes, consequences, and treatments. AB - Sanfilippo syndrome, or mucopolysaccharidosis (MPS) type III, refers to one of five autosomal recessive, neurodegenerative lysosomal storage disorders (MPS IIIA to MPS IIIE) whose symptoms are caused by the deficiency of enzymes involved exclusively in heparan sulfate degradation. The primary characteristic of MPS III is the degeneration of the central nervous system, resulting in mental retardation and hyperactivity, typically commencing during childhood. The significance of the order of events leading from heparan sulfate accumulation through to downstream changes in the levels of biomolecules within the cell and ultimately the (predominantly neuropathological) clinical symptoms is not well understood. The genes whose deficiencies cause the MPS III subtypes have been identified, and their gene products, as well as a selection of disease-causing mutations, have been characterized to varying degrees with respect to both frequency and direct biochemical consequences. A number of genetic and biochemical diagnostic methods have been developed and adopted by diagnostic laboratories. However, there is no effective therapy available for any form of MPS III, with treatment currently limited to clinical management of neurological symptoms. The availability of animal models for all forms of MPS III, whether spontaneous or generated via gene targeting, has contributed to improved understanding of the MPS III subtypes, and has provided and will deliver invaluable tools to appraise emerging therapies. Indeed, clinical trials to evaluate intrathecally-delivered enzyme replacement therapy in MPS IIIA patients, and gene therapy for MPS IIIA and MPS IIIB patients are planned or underway. PMID- 26648752 TI - Synergistic Effects of Crizotinib and Temozolomide in Experimental FIG-ROS1 Fusion-Positive Glioblastoma. AB - Glioblastoma (GB) is the most common malignant brain tumor. Drug resistance frequently develops in these tumors during chemotherapy. Therefore, predicting drug response in these patients remains a major challenge in the clinic. Thus, to improve the clinical outcome, more effective and tolerable combination treatment strategies are needed. Robust experimental evidence has shown that the main reason for failure of treatments is signal redundancy due to coactivation of several functionally linked receptor tyrosine kinases (RTKs), including anaplastic lymphoma kinase (ALK), c-Met (hepatocyte growth factor receptor), and oncogenic c-ros oncogene1 (ROS1: RTK class orphan) fusion kinase FIG (fused in GB)-ROS1. As such, these could be attractive targets for GB therapy. The study subjects consisted of 19 patients who underwent neurosurgical resection of GB tissues. Our in vitro and ex vivo models promisingly demonstrated that treatments with crizotinib (PF-02341066: dual ALK/c-Met inhibitor) and temozolomide in combination induced synergistic antitumor activity on FIG-ROS1-positive GB cells. Our results also showed that ex vivo FIG-ROS1+ slices (obtained from GB patients) when cultured were able to preserve tissue architecture, cell viability, and global gene-expression profiles for up to 14 days. Both in vitro and ex vivo studies indicated that combination blockade of FIG, p-ROS1, p-ALK, and p-Met augmented apoptosis, which mechanistically involves activation of Bim and inhibition of survivin, p-Akt, and Mcl-1 expression. However, it is important to note that we did not see any significant synergistic effect of crizotinib and temozolomide on FIG-ROS1-negative GB cells. Thus, these ex vivo culture results will have a significant impact on patient selection for clinical trials and in predicting response to crizotinib and temozolomide therapy. Further studies in different animal models of FIG-ROS1-positive GB cells are warranted to determine useful therapies for the management of human GBs. PMID- 26648753 TI - Imaging Brain Development: Benefiting from Individual Variability. AB - Human brain development is a complex process that evolves from early childhood to young adulthood. Major advances in brain imaging are increasingly being used to characterize the developing brain. These advances have further helped to elucidate the dynamic maturational processes that lead to the emergence of complex cognitive abilities in both typical and atypical development. However, conventional approaches involve categorical group comparison models and tend to disregard the role of widespread interindividual variability in brain development. This review highlights how this variability can inform our understanding of developmental processes. The latest studies in the field of brain development are reviewed, with a particular focus on the role of individual variability and the consequent heterogeneity in brain structural and functional development. This review also highlights how such heterogeneity might be utilized to inform our understanding of complex neuropsychiatric disorders and recommends the use of more dimensional approaches to study brain development. PMID- 26648754 TI - Optimal delivery of male breast cancer follow-up care: improving outcomes. AB - Male breast cancer is a rare disease. There are limited data to inform optimal treatment and follow-up strategies in this population. Currently, most follow-up guidelines are drawn from the vast literature on female breast cancer, despite the fact that male breast cancer has unique biological characteristics. In this review, we discuss clinical characteristics of male breast cancer as well as current best practices for long-term care with a focus on surveillance, screening, and treatment-related symptom management in male breast cancer survivors. PMID- 26648755 TI - Clinical utility of RapidArcTM radiotherapy technology. AB - RapidArcTM is a radiation technique that delivers highly conformal dose distributions through the complete rotation (360 degrees ) and speed variation of the linear accelerator gantry. This technique, called volumetric modulated arc therapy (VMAT), compared with conventional radiotherapy techniques, can achieve high-target volume coverage and sparing damage to normal tissues. RapidArc delivers precise dose distribution and conformity similar to or greater than intensity-modulated radiation therapy in a short time, generally a few minutes, to which image-guided radiation therapy is added. RapidArc has become a currently used technology in many centers, which use RapidArc technology to treat a large number of patients. Large and small hospitals use it to treat the most challenging cases, but more and more frequently for the most common cancers. The clinical use of RapidArc and VMAT technology is constantly growing. At present, a limited number of clinical data are published, mostly concerning planning and feasibility studies. Clinical outcome data are increasing for a few tumor sites, even if only a little. The purpose of this work is to discuss the current status of VMAT techniques in clinical use through a review of the published data of planning systems and clinical outcomes in several tumor sites. The study consisted of a systematic review based on analysis of manuscripts retrieved from the PubMed, BioMed Central, and Scopus databases by searching for the keywords "RapidArc", "Volumetric modulated arc radiotherapy", and "Intensity-modulated radiotherapy". PMID- 26648756 TI - Ethical aspects of registry-based research in the Nordic countries. AB - National health care registries in the Nordic countries share many attributes, but different legal and ethical frameworks represent a challenge to promoting effective joint research. Internationally, there is a lack of knowledge about how ethical matters are considered in Nordic registry-based research, and a lack of knowledge about how Nordic ethics committees operate and what is needed to obtain an approval. In this paper, we review ethical aspects of registry-based research, the legal framework, the role of ethics review boards in the Nordic countries, and the structure of the ethics application. We discuss the role of informed consent in registry-based research and how to safeguard the integrity of study participants, including vulnerable subjects and children. Our review also provides information on the different government agencies that contribute registry-based data, and a list of the major health registries in Denmark, Finland, Iceland, Norway, and Sweden. Both ethical values and conditions for registry-based research are similar in the Nordic countries. While Denmark, Finland, Iceland, Norway, and Sweden have chosen different legal frameworks, these differences can be resolved through mutual recognition of ethical applications and by harmonizing the different systems, likely leading to increased collaboration and enlarged studies. PMID- 26648757 TI - Validity of a hospital-based obstetric register using medical records as reference. AB - BACKGROUND: Data from hospital-based registers and medical records offer valuable sources of information for clinical and epidemiological research purposes. However, conducting high-quality epidemiological research requires valid and complete data sources. OBJECTIVE: To assess completeness and validity of a hospital-based clinical register - the Obstetric Database - using a national register and medical records as references. METHODS: We assessed completeness of a hospital-based clinical register - the Obstetric Database - by linking data from all women registered in the Obstetric Database as having given birth in 2013 to the National Patient Register with coverage of all births in 2013. Validity of eleven selected indicators from the Obstetric Database was assessed using medical records as a golden standard. Using a random sample of 250 medical records, we calculated proportion of agreement, sensitivity, specificity, and positive and negative predictive values for each indicator. Two assessors independently reviewed medical records and inter-rater reliability was calculated as proportion of agreement and Cohen's kappa coefficient. RESULTS: We found 100% completeness of the Obstetric Database when compared to the Danish National Patient Register. Except for one delivery all 6,717 deliveries were present in both registers. Proportion of agreement between the Obstetric Database and medical records ranged from 91.1% to 99.6% for the eleven indicators. The validity measures ranged from 0.70 to 1.00 indicating high validity of the Obstetric Database. kappa coefficients from the inter-rater reliability ranged from 0.71 to 1.00. CONCLUSION: Completeness and validity of the Obstetric Database were found acceptable when using the National Patient Register and medical records as golden standards. The Obstetric Database therefore offers a valuable source for examining clinical, administrative, and research questions. PMID- 26648758 TI - A critical appraisal of the misoprostol removable, controlled-release vaginal delivery system of labor induction. AB - BACKGROUND: Induction of labor is a major issue in pregnancy management. Finding strategies to increase rate and decrease time to vaginal delivery is an important goal, but maternal or neonatal safety must remain the primary objective. Misoprostol is a synthetic analogue of prostaglandin used off label to ripen the cervix and induce labor. The misoprostol vaginal insert (MVI) was designed to allow a controlled-release delivery of misoprostol (from 50 to 200 MUg) with a removal tape. The objective of this review was to make a critical appraisal of this device referring to the literature. METHODS: A literature search was performed in the PubMed and Cochrane databases using the keywords "vaginal misoprostol insert". RESULTS: Several studies compared different doses of MVI (50, 100, 150, and 200 MUg) with the 10 mg dinoprostone insert. The 100 MUg MVI compared with the dinoprostone vaginal insert (DVI) showed similar efficacy and no significant differences in cesarean delivery rate. MVI 200 MUg compared with DVI showed a reduced time to vaginal delivery and oxytocin need but had an increased risk of uterine hyperstimulation. The rate of hyperstimulation syndrome was two to three times more frequent with the 200 MUg MVI than the 100 MUg. CONCLUSION: Current data suggest that the 100 MUg MVI would provide the best balance between efficacy and safety. Further studies should be performed to evaluate this dose, especially in high-risk situations needing induction of labor. PMID- 26648760 TI - Is female circumcision evolving or dissolving in Norway? A qualitative study on attitudes toward the practice among young Somalis in the Oslo area. AB - Female genital mutilation or female circumcision (FC) is increasingly visible on the global health and development agenda - both as a matter of social justice and equality for women and as a research priority. Norway is one of the global nations hosting a large number of immigrants from FC-practicing countries, the majority from Somalia. To help counteract this practice, Norway has adopted a multifaceted policy approach that employs one of the toughest measures against FC in the world. However, little is known about the impact of Norway's approach on the attitudes toward the practice among traditional FC-practicing communities in Norway. Against this background, this qualitative study explores the attitudes toward FC among young Somalis between the ages of 16 to 22 living in the Oslo and Akershus regions of Norway. Findings indicate that young Somalis in the Oslo area have, to a large extent, changed their attitude toward the practice. This was shown by the participants' support and sympathy toward criminalization of FC in Norway, which they believed was an important step toward saving young girls from the harmful consequences of FC. Most of the uncircumcised girls see their uncircumcised status as being normal, whereas they see circumcised girls as survivors of violence and injustice. Moreover, the fact that male participants prefer a marriage to uncircumcised girls is a strong condition for change, since if uncut girls are seen as marriageable then parents are unlikely to want to circumcise them. As newly arrived immigrants continue to have positive attitudes toward the practice, knowledge of FC should be integrated into introduction program classes that immigrants attend shortly after their residence permit is granted. This study adds to the knowledge of the process of the abandonment of FC among immigrants in Western countries. PMID- 26648761 TI - Coincidence of an anterior cerebral artery aneurysm and a glioblastoma: case report and review of literature. AB - BACKGROUND: The association between glioblastoma and intracranial aneurysm is rare. Treatment guidelines do not exist, and operative mortality and morbidity are significantly high. To our knowledge, no prior cases have employed endovascular therapy for the treatment of these intra-tumor intracranial aneurysms followed by tumor resection. CASE PRESENTATION: A 74-year-old male, history of a left A2 aneurysm, presented after a motor vehicle accident at low speeds. Imaging was concerning for a possible traumatic brain contusion, an aneurysmal hemorrhage given history of left A2 aneurysm, or a hemorrhage from an underlying tumor given profound edema. The patient was discussed at the brain tumor board, where the plan was to address the aneurysm followed by resection of the mass versus close monitoring with subsequent imaging. The high risk of rehemorrhage, given the real possibility of an aneurysmal hemorrhage, motivated prompt treatment of the aneurysm. The patient was taken to the angiography suite; an anterosuperiorly projecting azygous A2 aneurysm, measuring 4.5 mm * 5.5 mm with a neck width at 3.5 mm and a small daughter sac, was completely obliterated with primary coiling. The following day, he underwent a left craniotomy along a forehead skin crease for mass excision. Final pathology revealed glioblastoma. The patient recovered well from both procedures, with a baseline neurological exam. The patient subsequently underwent hypofractionated radiation and temodar. CONCLUSION: To our knowledge, no prior cases have employed endovascular therapy for the treatment of these intracranial aneurysms. We emphasize that efforts to introduce less invasive elements may improve the overall outcomes in this rare patient population. PMID- 26648759 TI - The impact of social support on the risk of eating disorders in women exposed to intimate partner violence. AB - BACKGROUND: Eating disorders (EDs) are often found among women exposed to intimate partner violence (IPV). The role of social support (SS) as a protective factor against ED among IPV-exposed women is not firmly established. OBJECTIVE: The objective of this study is to determine the distribution of risk of EDs among women exposed to IPV and to examine the impact of SS on risk of ED among IPV exposed women. METHODS: Women (aged 18-64 years) exposed to IPV during their lifetimes (defined by the Humiliation-Afraid-Rape-Kick instrument) were recruited from primary care and domestic violence service agencies and surveyed on demographics, mood/anxiety disorders, psychosocial/community factors, and strategies used in response to IPV. The Eating Disorder Screen for Primary Care assessed the risk of ED. A modified Medical Outcomes Study Social Support Survey assessed overall functional support (scale range: 0-32; categorized into quartiles). Ordinal logistic regression examined the risk of ED based on SS, controlling for prespecified demographics (age, race/ethnicity, marital status, near-poverty level), and health-related factors significant in bivariate analyses (risky alcohol use). RESULTS: Among 302 women with lifetime IPV, 41 (14%) were at high risk, 127 (42%) were at moderate risk, and 134 (44%) were at low risk of an ED. In bivariate analyses, high risk of an ED was significantly more frequent among women with a low SS score (<19, 24%) versus a high SS score (>=30, 12%) (P=0.03). High risk of an ED was significantly associated with risky alcohol use (18%) versus non-risky alcohol use (13%; P=0.008). In multivariable analysis, a 5 unit increase in overall SS was significantly associated with decreased odds of ED risk (P=0.007). CONCLUSION: Among IPV-exposed women, low SS is associated with an increased risk of ED. SS may protect against ED by reducing anxiety and promoting positive actions, but further study is needed to confirm this. PMID- 26648762 TI - Implant survivorship analysis after minimally invasive sacroiliac joint fusion using the iFuse Implant System((r)). AB - INTRODUCTION: Surgical revision rate is a key outcome with all permanent implants. The iFuse Implant System((r)) is a permanent implant used to perform minimally invasive sacroiliac joint fusion. The purpose of this study is to determine the surgical revision rate after sacroiliac joint fusion surgery with this system. METHODS: Using two internal sources of information, revision surgeries were identified and linked to index surgeries. The likelihood of revision surgery was calculated using the Kaplan-Meier life table approach. Predictors of revision were explored. RESULTS: Four-year survivorship free from implant revision was 96.46%. Revision rate did not differ by sex and was lower for age >65. In all, 24% of revisions occurred within the first 30 days after surgery; 63.5% occurred within year 1. Implant survivorship has improved annually since the device was introduced in 2009. CONCLUSION: The survivorship rate with this implant is high and improving; the rate is somewhat higher than total hip replacement but lower than that of lumbar spine procedures. PMID- 26648763 TI - Novel treatment options for nonmelanoma skin cancer: focus on electronic brachytherapy. AB - Nonmelanoma skin cancer (NMSC) is an increasing health care issue in the United States, significantly affecting quality of life and impacting health care costs. Radiotherapy has a long history in the treatment of NMSC. Shortly after the discovery of X-rays and (226)Radium, physicians cured patients with NMSC using these new treatments. Both X-ray therapy and brachytherapy have evolved over the years, ultimately delivering higher cure rates and lower toxicity. Electronic brachytherapy for NMSC is based on the technical and clinical data obtained from radionuclide skin surface brachytherapy and the small skin surface applicators developed over the past 25 years. The purpose of this review is to introduce electronic brachytherapy in the context of the history, data, and utilization of traditional radiotherapy and brachytherapy. PMID- 26648764 TI - Categorical perception of color: evidence from secondary category boundary. AB - Despite a plethora of behavioral research exploring the phenomenon of color categorical perception (CP) known as "better discrimination between pair of colors stimuli from different categories and pair of colors stimuli from the same category even when the stimulus differences between the pairs of stimuli are equal", most of the evidence for the CP of color was derived from Roman or top-to down script readers and very rarely from right-to-left script readers in primary category. To date, no studies of color CP have been conducted on right-to-left script readers in secondary category boundary to support this theory. Three experiments have been conducted: Experiments 1 and 2 established the Arabic blue purple secondary category boundary, and Experiment 3 tested the CP of color in the blue-purple category boundary. Sixty participants (30 men and 30 women) took part in this study. All spoke Arabic as their first language, and all were undergraduate or postgraduate students at King Saud University. Their ages ranged from 18-35 years with a mean age of 21.9 years (SD =5.2). The result indicated that for Experiments 1 and 2, it appeared that the Arabic blue-purple category boundary was approximately 10PB and it is in the same location as for English. For Experiment 3, reaction times in the between-categories condition were significantly faster than those in the within-category condition; this suggested that CP of color was shown in the Arabic's blue-purple secondary category boundary. PMID- 26648765 TI - Extramedullary Conus Ependymoma Involving a Lumbar Nerve Root with Filum Terminale Attachment. AB - PURPOSE: In the current report, we describe a case of an extramedullary ependymoma involving a lumbar nerve root near conus medullaris. Spinal ependymomas commonly present as intramedullary tumors in the cervical or thoracic cord or as tumors arising from the conus medullaris or the filum terminale. In this case, we showed an extramedullary conus ependymoma involving a lumbar nerve root with filum terminale attachment. CASE PRESENTATION: A 69-year-old woman presented with lower back pain, but without sensory disturbance or motor weakness in her lower extremities. CLINICAL ASSESSMENT: Magnetic resonance imaging revealed an intradural mass at T12-L1 at the conus medullaris, which was totally resected. Histopathology revealed a non-myxopapillary ependymoma (WHO grade 2). Postoperatively, the patient did well and displayed no neurological deficits. Moreover, no radiotherapy was required. CONCLUSIONS: This report documented a rare case of intradural extramedullary ependymoma located at the conus medullaris, involving the lumbar nerve root, and attached to the filum terminale. Although extramedullary ependymomas at this region are more frequently classified as myxopapillary, histopathological examination revealed this tumor as a non myxopapillary ependymoma. PMID- 26648766 TI - Deanery placement and the Situational Judgement Test. PMID- 26648767 TI - Improving the quality of feedback given to medical students. PMID- 26648768 TI - Structure and antigenicity analysis of the IgG gene for Nyctereutes procyonoides. AB - OBJECTIVE: Nyctereutes procyonoides immunoglobulin G (IgG) gene is partially cloned. MATERIAL AND METHODS: In order to obtain a certain length (966bp) of Nyctereutes procyonoides immunoglobulin G (IgG), two pairs of primers are designed according to the conserved nucleotide sequence of canine (GenBank:AF354265, AF354265, AF354266, AF354267) and mink (GenBank: L07789). Using Bioinformatics technology and Western-blot to analyze antigenicity of Nyctereutes procyonoides IgG-B gene. RESULTS: The homology for nucleotide sequence of IgG between Nyctereutes procyonoides and canine (IgG A, IgG B, IgG C, IgG D), mink, Homo sapiens, Oryctolagus cuniculus, Mus musculus, Anas platyrhynchos and gallus were respectively (88.1%, 93.6%, 85.4%, 87.2%), 83.7%, 74.8%, 71.8%, 69.2%, 51.6%, 48.4%. It can be seen that there was high homology of aminoacid sequence between IgG of Nyctereutes procyonoides and IgG (A, B, C, D) of canine. And the serum antibody of Nyctereutes procyonoides had obviously cross reaction with HRP conjugated rabbit anti-dog IgG, compared with those of canine, oryctolagus cuniculus, mus musculus, mink, gallus. CONCLUSIONS: We successfully got Nyctereutes procyonoides immuneglobulin G (IgG) gene (Gen- Bank: KM010191). There is the closest ties of consanguinity of IgG exist between Nyctereutes procyonoides and canine among the mammal through the genetic evolution. The detection and treament of canine distemper can be used on Nyctereutes procyonoides. PMID- 26648769 TI - The p38 MAPK inhibitor SB203580 differentially modulates LPS-induced interleukin 6 expression in macrophages. AB - The p38 mitogen-activated protein kinase (MAPK) plays a key role in lipopolysaccharide (LPS)-induced signal transduction pathways that lead to inflammatory cytokine synthesis in macrophages; however, whether the inhibition of p38 MAPK regulates LPS-induced inflammatory cytokine expression in different types of macrophages remains the subject of debate. Herein, we assessed whether the inhibition of p38 MAPK by SB203580 regulates LPS-induced expression of the inflammatory cytokines tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6) in RAW264.7 and resident peritoneal macrophages. Lipopolysaccharide stimulation of RAW264.7 macrophages or mouse resident peritoneal macrophages significantly increased TNF-alpha and IL-6 production. The addition of SB203580 to cultures dramatically blocked LPS-induced TNF-alpha production in RAW264.7 and mouse resident peritoneal macrophages, and dramatically blocked LPS-induced IL-6 production in RAW264.7 macrophages, but not in mouse resident peritoneal macrophages. Additionally, high concentrations of SB203580 resulted in increased IL-6 production. However, LPS-stimulation significantly up-regulated the mRNA transcript levels of TNF-alpha and IL-6 in RAW264.7 and mouse resident peritoneal macrophages, whereas pretreatment with SB203580 dramatically down-regulated LPS induced mRNA transcript levels of TNF-alpha and IL-6 in these cells. Our data show that SB203580 differentially modulates LPS-induced production of the inflammatory cytokine IL-6 in two different sources of macrophages, and that this course of regulation occurs at the IL-6 mRNA post-transcriptional stage. PMID- 26648770 TI - Seropositive bucks and within-herd prevalence of small ruminant lentivirus infection. AB - Caprine arthritis-encephalitis is an economically important disease of goats. It is evident that horizontal transmission through respiratory secretions and milk plays an important part in the disease spread whereas the role of sexual transmission remains questionable. The cross-sectional study was carried out to investigate the relationship between presence of small ruminant lentivirus (SRL V)-seropositive bucks and seroprevalence of SRL V infection in does in herds. The analysis included 76 goat herds seropositive for SRL V infection. A sample of adult female goats from each herd was selected in a simple random fashion. All males present in a herd were also enrolled in the study. The animals were screened with commercial serological immunoenzymatic tests. Standardized questionnaires were used to gather knowledge of 3 hypothesized herd-level confounding factors: number of years for which a herd had existed until testing, goat replacement from other herds in Poland and use of machine milking. Three level hierarchical linear regression model was developed to evaluate the relationship (alpha = 0.05). Median (interquartile range) within-herd seroprevalence of SRL V was 60.1% (35.7% to 87.9%) and 35.8% (10.1% to 49.6%) in herds where seropositive males were present and absent, respectively. Controlling for possible confounders presence of SRL V-seropositive bucks proved to be an independent factor linked to the higher within-herd seroprevalence of SRL V (p = 0.001). The study indicates that seropositive bucks may facilitate the spread of SRL V infection in goat herds and therefore their presence should be considered as a risk factor. PMID- 26648771 TI - The influence of phytoncides on the immune system of broiler chickens and turkeys. AB - The aim of our study was to investigate the influence of adiSalmoSOL PF dietary supplement, given for 3 days in drinking water, on selected parameters of cell mediated (Experiment I) and humoral (Experiment II) immunity in chicken and turkey broilers. In Experiment I, birds were randomly divided into two groups of 10 birds each. Group 1 comprised control turkeys or chickens, whereas group 2 birds were administered adiSalmo(SOL)PF. In Experiment II, a total of 69 chickens were divided into three groups (1-3) of 23 birds each. At the age of 25 days, group 1 was given adiSalmo(SOL)PF. Birds from groups 1-3 were vaccinated at 28 days of age. Group 2 was given adiSalmo(SOL)PF after vaccination. In Experiment I, a significant increase in percentages of CD4 + T lymphocytes in the bursa of Fabricius, cecal tonsils and spleen, CD8 + T lymphocytes in the thymus and spleen, CD4 + CD8 + T lymphocytes in the bursa of Fabricius and ileal mucosa and IgM + B lymphocyte in the ileal mucosa were observed in group 2 chickens. In Experiment I, a significant increase in percentages of CD4 + T lymphocytes in the thymus and spleen, CD8+ T lymphocytes in the cecal tonsils and blood, and CD4 + CD8 + T lymphocytes in the thymus and ileal mucosa was recorded in group 2 turkeys. No differences in percentages of IgM + B lymphocytes were observed between turkey groups. In Experiment II, the highest post-vaccination titers of anti-IB antibodies were observed in group 2, but it was not statistically significant. The results of our study indicate that adiSalmo(SOL)PF showed immunomodulatory activity in chickens and turkeys. PMID- 26648772 TI - Staphylococcus enterotoxin B-induced T cells can efficaciously protect against type 1 diabetes in non-obese diabetic mice. AB - Type 1 diabetes (T1D), an autoimmune disease, can be protected against by natural killer T (NKT) cells. Several attempts demonstrate that NKT cells also can be produced by inducing with Staphylococcus enterotoxin B (SEB) in addition to its classical activated antigen alpha-galactosylceramide. Here, we examined a potential usage of SEB-induced T (SEB-T) cells for the treatment of T1D. We established the immunophenotypes of SEB-T cells via flow cytometry, and in consequence, enriched in CD8(+)NKT cells after SEB stimulated. A high level of transforming growth factor beta (TGF-beta), detected by RT-PCR and ELISA, was first observed to be expressed and secreted by these SEB-T cells. Mixed lymphocyte reactions indicated that SEB-T cells could not produce a response to mitogens and allogeneic lymphocyte, and can inhibit lymphocytes response to mitogens. In an animal model, our data indicated that infusion of SEB-T cells in non-obese diabetic mice was well tolerated and could ameliorate hyperglycemia and maintain the blood glucose nearly on normal level until sacrifice. Strikingly, infusion of SEB-T cells resulted in an increase in the serum TGF-beta level. These data raise the possibility that SEB-T cells can protect against T1D, which is associated with NKT cells generated in these SEB-induced cells. PMID- 26648773 TI - Humoral responses of broiler chickens challenged with NDV following supplemental treatment with extracts of Aloe vera, Alma millsoni, Ganoderma lucidum and Archachatina marginata. AB - AIM OF THE STUDY: The significance of nutritional supplements for immunity has been documented. Locally sourced extracts used in alternative medicine were studied to determine their potential effects on antibody production and humoral responses in viral challenged birds. METHOD: Three hundred and eighty birds were distributed into 19 groups of 20 birds each. Following acclimatization for 16 days, they were fed with standard broilers feed and water ad libitum. Group A was supplemented with Aloe vera (AV) extract, group B was given Alma millsoni (AM) extract, group C was given Archachatina marginata (AMS) extract and group D was given Ganoderma lucidum (GL) extract, and group E was the control group. Extract concentrations of 50 mg, 100 mg and 150 mg were given to three subsets of each treatment group for 30 days. Birds were then challenged with intramuscular administration of 0.2 ml of 50% Embryo Lethal Dose of saline suspension of the challenge strain of Newcastle Disease Virus (NDV) on the 30(th) day, and were examined for clinical signs and symptoms. Serum from venous blood was used for antibody and immunological assay. RESULTS: Aloe vera at 50 ug and A. millsoni extracts supplementations yielded a significant antibody titre (p < 0.001). The difference within the AMS, GL and AV groups and the control group was not statistically significant (p < 0.05). CONCLUSION: Unlike the extract of Ganoderma and A. marginata, pretreatment with A. millsoni extract and a lower dosage of Aloe vera enhanced the ability to mount humoral responses against viral infection in broiler chickens. PMID- 26648774 TI - Antiphospholipid antibodies in patients with upper-extremity deep vein thrombosis. AB - The levels of antibodies to cardiolipin and beta2-glycoprotein I and polymorphic variants G1691A of Factor V (factor V Leiden, FVL) and G20210A of prothrombin gene (G20210A) were studied in 16 patients with upper-extremity deep vein thrombosis (UEDVT). Most of patients with this syndrome have elevated values of these antibodies. Two of these patients are heterozygous carriers for G20210A and 1 - for FVL. Three patients with UEDVT and systemic lupus erythematosus (SLE) are positive for ANA and two others (one of them with Raynaud syndrome) have border line titre 1: 80 for ANA. All 3 patients with SLE are women and the interval between the development of the UEDVT and the onset of SLE was 1-4 years. We would like to suggest that: 1) UEDVT could be the first clinical symptom of Antiphospholipid syndrome, and 2) UEDVT may be the first clinical manifestation of SLE preceding the development of the systemic autoimmune disease by several years. PMID- 26648776 TI - Influence of glucocorticoid receptor gene NR3C1 646 C>G polymorphism on glucocorticoid resistance in asthmatics: a preliminary study. AB - BACKGROUND: Glucocorticoid receptor gene polymorphism (NR3C1 646 C>G) may play an important role in the development of severe bronchial asthma and resistance to glucocorticoids (GCs). OBJECTIVE: The aim of the present study was to determine the relation between the 646 C>G polymorphism of the glucocorticoid receptor gene (NR3C1) and resistance to GCs with development of severe bronchial asthma. MATERIAL AND METHODS: This case-control study included 40 patients with severe bronchial asthma and 20 apparently healthy controls. Atopic status was determined by skin prick test reaction to the most common locally-encountered allergens. GCs reversibility test was performed to differentiate between GCs sensitive and GCs resistant asthma. For all subjects, analysis of the glucocorticoid receptor gene polymorphism (NR3C1 646 C>G) was done using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). RESULTS: The frequencies of NR3C1 646 C>G genotypes and alleles differed significantly between asthmatic patients and controls. The frequencies of the CC genotype and C allele carriers were significantly higher among asthmatics than among controls, and also among GCs sensitive asthmatics than among GCs resistant asthmatics. However, NR3C1 646 C>G genotypes and alleles frequencies did not differ significantly according to the atopic status in asthmatics. CONCLUSIONS: The too small sized of the investigated groups is a shortcoming of this study. Nevertheless, the observed variations demonstrate a marked association of NR3C1 646 C>G CC genotype with the development of bronchial asthma and a higher frequency of the C allele among GCs sensitive asthmatics. Large-scale studies are required to investigate the association between polymorphisms of the NR3C1 gene and GCs resistance among asthmatic patients. PMID- 26648775 TI - Innate immunity gene expression changes in critically ill patients with sepsis and disease-related malnutrition. AB - The aim of this study was an attempt to determine whether the expression of genes involved in innate antibacterial response (TL R2, NOD 1, TRAF6, HMGB 1 and Hsp70) in peripheral blood leukocytes in critically ill patients, may undergo significant changes depending on the severity of the infection and the degree of malnutrition. The study was performed in a group of 128 patients with infections treated in the intensive care and surgical ward. In 103/80.5% of patients, infections had a severe course (sepsis, severe sepsis, septic shock, mechanical ventilation of the lungs). Clinical monitoring included diagnosis of severe infection (according to the criteria of the ACC P/SCC M), assessment of severity of the patient condition and risk of death (APACHE II and SAPS II), nutritional assessment (NRS 2002 and SGA scales) and the observation of the early results of treatment. Gene expression at the mRNA level was analyzed by real-time PCR. The results of the present study indicate that in critically ill patients treated in the IC U there are significant disturbances in the expression of genes associated with innate antimicrobial immunity, which may have a significant impact on the clinical outcome. The expression of these genes varies depending on the severity of the patient condition, severity of infection and nutritional status. Expression disorders of genes belonging to innate antimicrobial immunity should be diagnosed as early as possible, monitored during the treatment and taken into account during early therapeutic treatment (including early nutrition to support the functions of immune cells). PMID- 26648777 TI - Elevated expression of interleukin-21 and its correlation to T-cell subpopulation in patients with ulcerative colitis. AB - OBJECTIVE: To investigate the expression of interleukin-21 (IL-21) and its correlation to T-cell subpopulation including Th1, Tc1 and Th17 cells in Ulcerative colitis (UC). MATERIAL AND METHODS: We examined the expression of IL 21, IL-17 and IFN-gamma in UC patients and controls by enzyme-linked immunosorbent assay (ELISA) and flow cytometry. RESULTS: We found that IL-21 was expressed on CD3(+)CD8(-)T cells by flow cytometry. Plasma IL-21 level and the percentage of CD3(+)CD8(-)IL-21(+) T cells were significantly elevated in UC patients compared to controls. The percentage of CD3(+)CD8(-)IL-17(+) T (Th17), CD3(+)CD8(-)IFN-gamma(+) T (Th1) and CD3(+)CD8(+) IFN-gamma(+) T (Tc1) cells was also significantly increased in UC patients. Moreover, we found a significant positive correlation between CD3(+)CD8(-)IL-21(+)T cells and Th17 cells. CONCLUSIONS: Elevated IL-21 and its positive correlation to Th17 cells may play a role in the pathogenesis of UC. PMID- 26648778 TI - Cytokines in the blood and semen of infertile patients. AB - Cytokines have been important mediators of the immunity and can be involved in numerous processes in the male genital tract including acting as immunomodulatory elements within the male gonad. The aims of this study were: 1) to detect pro- and anti-inflammatory cytokine levels in the control group and subgroups of infertile men; and 2) to set up the practical recommendations concerning determination of cytokine levels for the male infertility diagnosis. Observations were performed in a group of 82 men: healthy controls (n = 27) and infertile patients (n = 55). The male infertility group was further subdivided into patients with: varicocele (n = 22), idiopathic infertility (n = 13) and partners of couples with recurrent spontaneous abortion (RSA; n = 20). Semen analysis was determined following WHO criteria. The cytokine interleukin 1beta (IL-1beta), IL 6, IL-10, IL-18; tumor necrosis factor alpha (TNF-alpha), interferon g (IFN-g) and transforming growth factor beta1 (TGF-beta1) contents in serum and seminal plasma were determined by quantitative ELISA. An interesting marker of male infertility appears to be TGF-beta1 (blood) significantly elevated in idiopathically infertile males and in the RSA group. Besides elevated TGF-beta1 in a group of idiopathic infertility significantly elevated IL-10, IL-18, IFN-g (blood) and statistically decreased IL-1beta while increased IFN-g were revealed in seminal plasma compared to healthy controls. We may postulate novel cytokine micropatterns for patients with different background of infertility. Therefore, circulating cytokines: IL-1beta, IL-10, IL-18, TGF-beta1, IFN-g and IL-1beta, IFN g and TGF-beta1 in seminal plasma should be extended in evaluation of specific types of male infertility. PMID- 26648779 TI - Original inhibition method of excessive synthesis of pro-inflammatory cytokine of tumour necrosis factor alpha. AB - Influence on pro- and anti-inflammatory cytokines of an ill person is an urgent aspect of treatment of many diseases. For inhibition of synthesis of a high level of pro-inflammatory cytokines, medications which are recombinant monoclonal antibodies, especially to tumour necrosis factor alpha (TNF-alpha), are used. However, these methods of treatment require further improvement by elaborating new approaches with a wider spectrum of influence on the immune system. A completely new method of reduction in high activity of TN F-alpha with the method of intradermal autoleukocyte immunization is presented in the article. Investigation was performed in a group of patients with psoriasis (24) with a high level of TNF-alpha in the blood (over 30 pg/ml). Simultaneously such investigation was performed on patients with psoriasis (9) without TNF-alpha detected (0 pg/ml). As a result of immunization, a significant reduction in TNF alpha occurred in all patients with its high level, in 16 (66.7%) from 24 patients - to 0-5 pg/ml. The level of reduction and duration of the achieved effect was of an individual character and requires further investigation. However, the achieved results prove the expediency of administration of this immunization method for patients requiring reduction of TNF-alpha synthesis. However, the content of TNF-alpha in blood serum could not be detected in most patients with a low level of cytokine (in 6 from 9) after immunization (as well as before immunization), but an increase in its level from 0 to 5-8 pg/ml was observed in 3 patients. On the basis of the conducted research, the authors suggest that the influence of immunization on cytokine synthesis depends on the condition of immune cells and correlation of pro- and anti-inflammatory cytokines in a patient's skin. PMID- 26648780 TI - The immunohistochemical analysis of membrane-bound CD55, CD59 and fluid-phase FH and FH-like complement inhibitors in cancers of ovary and corpus uteri origin. AB - One of the potential therapeutic methods of cancer treatment is the immunotherapy with monoclonal antibodies. This kind of therapy, although devoid of serious side effects, has often insufficient efficacy. The presence of complement inhibitors on the cancer cells, which are able to inactivate complement-mediated immune response represents one of the main reasons for the inefficiency of such therapy. In our studies we investigated the expression of main membrane-bound and fluid phase complement regulators: CD55, CD59 and factor H/factor H-like in tumour samples of ovarian and corpus uteri cancer. Tissue samples were collected from 50 patients and stained immunohistochemically, with the use of peroxidase-based immunodetection system. Immunohistochemical analysis revealed that complement inhibitors are present in examined tumors although their presence is heterogenous. The most prevalent is the presence of factor H/H-like, localized mostly in tumor stroma and within vascular structures. Membrane bound complement inhibitors are less prominently expressed by cancer cells. CD55 was detected in low percentage of cells, predominantly within cancer tubules. CD59 immunoreactivity was more prevalent in cancer cells, and was localized particularly at the margin of cancer cell tubules. Our results demonstrate that the most prominent complement inhibitor in cancer of ovary and corpus uteri origin is factor H/factor H-like. Blocking or downregulation of this inhibitor should be taken into consideration with regards to improving the efficiency of immunotherapy with monoclonal antibodies. PMID- 26648781 TI - Influence of fingolimod on basic lymphocyte subsets frequencies in the peripheral blood of multiple sclerosis patients - preliminary study. AB - BACKGROUND: Fingolimod is a drug administered orally to adult patients treated for relapsing remitting course of multiple sclerosis (MS). Mode of action of fingolimod is based on intense S1P1 receptor stimulation and "arresting" lymphocytes in lymphatic organs. Objective of the research was to assess changes in the frequencies of basic lymphocyte subsets in patients treated for multiple sclerosis with the use of fingolimod. MATERIAL AND METHODS: Study group comprised of 25 previously untreated adult patients with MS. Venous blood samples were collected from each patient before and one month, three months and six months after treatment initiation. Peripheral blood lymphocyte immunophenotype was assessed with a set of monoclonal antibodies bounded to appropriate fluorochromes and flow cytometer FACSC alibur. Statistical analysis of the results was conducted using Statistica 9.0 software. RESULTS: Before fingolimod administration median of lymphocyte subsets percentage in each patient was in reference range. After 1 month of treatment we noticed significant changes in frequencies of following lymphocyte subsets: NK cells - 51.22% (p = 0.016), T CD4+ cells - 11.58% (p = 0.01), T CD4+:T CD8+ cells ratio - 0.61 (p = 0.005). After 3 and 6 months of treatment there was further increase of deviation from normal state. CONCLUSIONS: The use of fingolimod is associated with profound changes in lymphocyte subsets distribution, which might bear a risk of the development of cellular immune deficiency symptoms. PMID- 26648782 TI - Negative correlation between mycological surfaces pollution in hospital emergency departments and blood monocytes phagocytosis of healthcare workers. AB - The aim of the present study was to find a possible relationship between the presence of yeast and filamentous fungi in hospital emergency departments and the activity levels of blood granulocytes and monocytes in emergency personnel. The study of mycological pollution was conducted in winter; the samples were collected from 10 Warsaw hospitals emergency departments (HE D) and in 10 control locations (office spaces) and included air samples and swabbing of floor and walls. The blood for immunological investigation was taken in spring, from 40 men, 26 to 53 years old, healthcare workers of these departments, who have been working for at least 5 years in their current positions, and from 36 corresponding controls, working in control offices. Evaluation of blood leukocyte subpopulations was done by hematological analyzer and cytometry analysis and monocyte and granulocyte phagocytosis by Phagotest. There were no significant differences in the level of mycological contamination between the test and control places. The qualitative analysis of the surfaces and air samples revealed a prevalence of strains belonging to Aspergillus spp. and Penicillium spp. genus. Statistical analysis revealed the existence of negative correlation between the number of phagocytizing blood monocytes and fungi spores content on floor and wall surfaces in hospital emergency departments (r = -0.3282, p < 0.05 and positive correlation between the number of phagocytizing monocytes in the blood of office workers and fungi pollution of control offices (r = 0.4421, p < 0.01). PMID- 26648783 TI - Combined bacterial and viral treatment: a novel anticancer strategy. AB - An idea for a new combination therapy will be described herein. It is a proposition to combine viral and bacterial anticancer therapies and make them fight cancer in concert. We analyzed biological anticancer therapies and found overlapping advantages and disadvantages which led us to the conclusion that the combination therapy has the potential to create a new therapeutic quality. It is surprising how many weaknesses of viral anticancer therapy are the strengths of bacterial anticancer therapies and the other way round. We review the facts behind this concept and try to assess its value. We propose a few strategies how to combine these two therapies but as far as the review can go, final answers will have to come from the experiments. This review is the first attempt to describe a new strategy and understand the means for this idea but also to raise new questions and discuss new ways to look at anti-cancer treatment. PMID- 26648784 TI - Role of alpha7 nicotinic receptor in the immune system and intracellular signaling pathways. AB - Acetylcholine has been well known as one of the most exemplary neurotransmitters. In humans, this versatile molecule and its synthesizing enzyme, choline acetyltransferase, have been found in various non-neural tissues such as the epithelium, endothelium, mesothelium muscle, blood cells and immune cells. The non-neuronal acetylcholine is accompanied by the expression of acetylcholinesterase and nicotinic/muscarinic acetylcholine receptors. Increasing evidence of the non-neuronal acetylcholine system found throughout the last few years has indicated this neurotransmitter as one of the major cellular signaling molecules (associated e.g. with kinases and transcription factors activity). This system is responsible for maintenance and optimization of the cellular function, such as proliferation, differentiation, adhesion, migration, intercellular contact and apoptosis. Additionally, it controls proper activity of immune cells and affects differentiation, antigen presentation or cytokine production (both pro- and anti-inflammatory). The present article reviews recent findings about the non-neuronal cholinergic system in the field of immune system and intracellular signaling pathways. PMID- 26648786 TI - Long-term valacyclovir treatment and immune modulation for Herpes-associated erythema multiforme. AB - OBJECTIVE: Erythema multiforme (EM) is an immune-mediated condition characterized by the appearance of target-like lesions on the skin and often accompanied by erosions or bullae involving the oral, genital, and/or ocular mucosae. 70% of recurrent EM cases are associated with HSV reactivation and it is labelled as herpes-associated erythema multiforme (HAE M). Recurrences are seen in approximately 20-25% of EM cases and managing these conditions are challenging for both the patient and the doctor. The effectiveness of antiviral drugs is proven for Herpes simplex infection, however most patients use a multiplicity of alternative and complementary therapies. CLINICAL PRESENTATION: We present clinical data of 3 patients with recurrent HAE M managed by long-term valacyclovir therapy and immunostimulation with Echinacea or replacement immunoglobulin therapy in the case of IgG1 subclass deficiency. The presented cases have demonstrated that immune mechanisms are relevant for HAEM recurrences. CONCLUSIONS: The immune abnormalities, such as antibody deficiency, in the patients with HSV-associated EM can lead to frequent relapses of disease and should be evaluated. Long-term antiviral therapy with immunomodulation can control the relapses of HAEM. PMID- 26648785 TI - Atherosclerosis: a chronic inflammatory disease mediated by mast cells. AB - Inflammation is a process that plays an important role in the initiation and progression of atherosclerosis and immune disease, involving multiple cell types, including macrophages, T-lymphocytes, endothelial cells, smooth muscle cells and mast cells. The fundamental damage of atherosclerosis is the atheromatous or fibro-fatty plaque which is a lesion that causes several diseases. In atherosclerosis the innate immune response, which involves macrophages, is initiated by the arterial endothelial cells which respond to modified lipoproteins and lead to Th1 cell subset activation and generation of inflammatory cytokines and chemoattractant chemokines. Other immune cells, such as CD4+ T inflammatory cells, which play a critical role in the development and progression of atherosclerosis, and regulatory T cells [Treg], which have a protective effect on the development of atherosclerosis are involved. Considerable evidence indicates that mast cells and their products play a key role in inflammation and atherosclerosis. Activated mast cells can have detrimental effects, provoking matrix degradation, apoptosis, and enhancement as well as recruitment of inflammatory cells, which actively contributes to atherosclerosis and plaque formation. Here we discuss the relationship between atherosclerosis, inflammation and mast cells. PMID- 26648787 TI - Modulation of matrix metalloproteinases MMP-2 and MMP-9 activity by hydrofiber foam hybrid dressing - relevant support in the treatment of chronic wounds. AB - Success in chronic wound therapy requires careful selection of appropriate dressing, which enables effective management of wound exudate. According to current knowledge, exudate may contain large quantities of proteases, including matrix metalloproteinases, MMP-2 and MMP-9, which are responsible for delay in wound healing. Therefore, neutralization of MMPs may be beneficial for treatment efficacy. The aim of the study was to test whether AQUACEL Foam, a novel, technologically advanced hydrofiber-foam hybrid dressing (HFHD), may interfere with proteolytic activity of MMPs in vitro. The assessment included in vitro tests of liquid retention and measurement of human recombinant MMP-2 and MMP-9 activity. The MMPs activity was measured before and after their interaction with HFHD, using a fluorescent gelatinase assay kit and Real-Time PCR device. The in vitro tests have shown that the hydrofiber layer of HFHD revealed significant potential to decrease the activity of MMPs in the experimental system. The mentioned modulatory properties of AQUACEL Foam may contribute to a composed mechanism of its beneficial action. Furthermore, our finding may explain clinical effectiveness of HFHD observed in clinical settings. PMID- 26648789 TI - Global Thrombosis Test - a possible monitoring system for the effects and safety of dabigatran. AB - BACKGROUND: Dabigatran is an alternative to warfarin (WF) for the thromboprophylaxis of stroke in patients with non-valvular atrial fibrillation (NVAF). The advantage of dabigatran over WF is that monitoring is not required; however, a method to monitor the effect and the safety of dabigatran is not currently available. The Global Thrombosis Test (GTT) is a novel method to assess both clot formation and lysis activities under physiological conditions. OBJECTIVE: The aim of this study was to evaluate whether treatment with dabigatran might affect shear-induced thrombi (occlusion time [OT], sec) by the GTT, and to investigate the possibility that the GTT could be useful as a monitoring system for dabigatran. PATIENTS/METHODS: The study population consisted of 50 volunteers and 43 NVAF patients on WF therapy, who were subsequently switched to dabigatran. Using the GTT, the thrombotic status was assessed one day before and 1 month after switching anticoagulation from WF to dabigatran. RESULTS: The OT was 524.9 +/- 17.0 sec in volunteers whereas that of NVAF patients on WF therapy was 581.7 +/- 26.3 sec. The switch from WF to dabigatran significantly prolonged OT (784.5 +/- 19.3 sec). One patient on WF therapy and 12 patients on dabigatran therapy were shown to have OT > 900 sec. CONCLUSION: The GTT could be used to assess the risk of dabigatran-related bleeding complications. PMID- 26648788 TI - High-grade serous ovarian cancer cell lines exhibit heterogeneous responses to growth factor stimulation. AB - BACKGROUND: The factors driving the onset and progression of ovarian cancer are not well understood. Recent reports have identified cell lines that are representative of the genomic pattern of high-grade serous ovarian cancer (HGSOC), in which greater than 90 % of tumors have a mutation in TP53. However, many of these representative cell lines have not been widely used so it is unclear if these cell lines capture the variability that is characteristic of the disease. METHODS: We investigated six TP53-mutant HGSOC cell lines (Caov3, Caov4, OV90, OVCA432, OVCAR3, and OVCAR4) for migration, MMP2 expression, proliferation, and VEGF secretion, behaviors that play critical roles in tumor progression. In addition to comparing baseline variation between the cell lines, we determined how these behaviors changed in response to four growth factors implicated in ovarian cancer progression: HB-EGF, NRG1beta, IGF1, and HGF. RESULTS: Baseline levels of each behavior varied across the cell lines and this variation was comparable to that seen in tumors. All four growth factors impacted cell proliferation or VEGF secretion, and HB-EGF, NRG1beta, and HGF impacted wound closure or MMP2 expression in at least two cell lines. Growth factor-induced responses demonstrated substantial heterogeneity, with cell lines sensitive to all four growth factors, a subset of the growth factors, or none of the growth factors, depending on the response of interest. Principal component analysis demonstrated that the data clustered together based on cell line rather than growth factor identity, suggesting that response is dependent on intrinsic qualities of the tumor cell rather than the growth factor. CONCLUSIONS: Significant variation was seen among the cell lines, consistent with the heterogeneity of HGSOC. PMID- 26648790 TI - The revenue generated from clinical chemistry and hematology laboratory services as determined using activity-based costing (ABC) model. AB - BACKGROUND: The rapid and continuous growth of health care cost aggravates the frequently low priority and less attention given in financing laboratory services. The poorest countries have the highest out-of-pocket spending as a percentage of income. Higher charges might provide a greater potential for revenue. If fees raise quality sufficiently, it can enhance usage. Therefore, estimating the revenue generated from laboratory services could help in capacity building and improved quality service provision. METHODS: Panel study design was used to determine revenue generated from clinical chemistry and hematology services at Tikur Anbessa Specialized Teaching Hospital, Addis Ababa, Ethiopia. Activity-Based Costing (ABC) model was used to determine the true cost of tests performed from October 2011 to December 2011 in the hospital. The principle of Activity-based Costing is that activities consume resources and activities consumed by services which incur the costs and hence service takes the cost of resources. All resources with costs are aggregated with the established casual relationships. The process maps designed was restructured in consultation with the senior staffs working and/or supervising the laboratory and pretested checklists were used for observation. Moreover, office documents, receipts and service bills were used while collecting data. The amount of revenue collected from services was compared with the cost of each subsequent test and the profitability or return on investment (ROI) of services was calculated. Data were collected, entered, cleaned, and analyzed using Microsoft Excel 2007 software program and Statistical Software Package for Social Sciences version 19 (SPSS). Paired sample t test was used to compare the price and cost of each test. P-value less than 0.05 were considered as statistically significant. RESULT: A total of 25,654 specimens were analyzed during 3 months of regular working hours. The total numbers of clinical chemistry and hematology tests performed during the study period were 45,959 (66.1 %) and 23,570 (33.9 %), respectively. Only 274, 386 (25.3 %) Ethiopian Birr (ETB) was recovered from the total cost of 1,086,008.09 ETB incurred on clinical chemistry and hematology laboratory tests. The result showed that, about 133,821 (12.32 %) ETB was revenue not collected from out-of-pocket payments that was paid for the services as a result of under pricing. The result showed that 18 out of 20 laboratory tests were under priced. The cost burden related to free Anti Retro-viral Therapy (ART) services was 285,979.82 (26.3 %) ETB. CONCLUSION: The cost per test estimated was significantly different to the existing price. About 90 % of the tests were under priced. This information could warn the hospital to reconsider resetting prices of these tests profitability ration less than 1. The revenue collected could help to build capacity, upscale quality, and sustainable service delivery. PMID- 26648791 TI - Discussions about Racial and Ethnic Differences in Internationally Adoptive Families: Links with Family Engagement, Warmth, & Control. AB - Discussions about racial and ethnic differences may allow international, transracial adoptive families to construct multiracial and/or multiethnic family identities. However, little is known about the ways family communication influences how discussions about racial and ethnic differences occur. This study examined associations between observed family communication constructs, including engagement, warmth, and control, and how adoptive families discuss racial and ethnic differences using a sample of families with adolescent-aged children adopted internationally from South Korea (N = 111 families, 222 adolescents). Using data collected during mid-adolescence and again during late adolescence, higher levels of maternal control and positive adolescent engagement were independently associated with a greater likelihood that family members acknowledged the importance of racial and ethnic differences and constructed a multiracial and/or multiethnic family identity. Adolescent engagement was also related to a greater likelihood that family members disagreed about the importance of racial and ethnic differences, and did not build a cohesive identity about differences. PMID- 26648792 TI - How Has the Robot Contributed to Colon Cancer Surgery? AB - Robotic surgery is an emerging field in colorectal surgery and may overcome the limitations of conventional laparoscopic surgery, such as rigid instrumentation, poor ergonomics, and assistant-dependent camera movements and retraction. In addition, robotic-assisted colectomy appears to offer comparable outcomes to laparoscopic colectomy with limited long-term outcomes data. Prolonged operating time, increased costs and learning curve are the major drawbacks of robotic colectomy for colon cancer. Although new robotic platforms promise improved ingenuity through developing technology, the role of the robot in colon cancer surgery is still unclear. PMID- 26648793 TI - Surgical Management of Complicated Colon Cancer. AB - The management of complicated colon cancer (locally invasive, obstructed, or perforated cancers) can pose diagnostic and therapeutic challenges to surgical management. Adherence to traditional surgical oncologic principles must often be balanced with the patients' clinical presentation and other parameters. While the goal of an R0 (no residual microscopic disease) resection must always be kept in mind, situations sometimes arise which can make this difficult to achieve. Recognition of complicated disease and availability of varied therapeutic modalities is important to ensure favorable patient outcomes. This review will discuss the surgical management of complicated colon cancer, with special focus on locally advanced disease. PMID- 26648795 TI - Management of Appendix Cancer. AB - Primary cancers of the appendix are rare and are frequently diagnosed after surgery for appendicitis, presumed ovarian primary malignancy, or other indications. Primary appendix cancers are histologically diverse, and classification of these tumors has historically been confusing because of the nonstandardized nomenclature that is used. This review aimed to describe the epidemiology, presentation, workup, staging, and management of primary appendix cancers using current, recommended nomenclature. For this purpose, tumors were broadly classified as colonic-type or mucinous adenocarcinoma, goblet cell adenocarcinoma, or neuroendocrine carcinoma. Signet ring cell carcinoma was not regarded as an individual entity. The presence of signet ring cells is a histologic feature that may or may not be present in colonic-type or mucinous adenocarcinoma. The management of primary appendix cancer is complex and is dependent on the histologic subtype and extent of disease. Randomized, prospective trials do not exist for these rare tumors and management is largely guided by retrospective data expert consensus guidelines, which are summarized here. PMID- 26648794 TI - Peritoneal Carcinomatosis from Colon Cancer: A Systematic Review of the Data for Cytoreduction and Intraperitoneal Chemotherapy. AB - A systematic review of the literature on the management of peritoneal carcinomatosis (PC) from colon cancer with cytoreductive surgery (CRS) and intraperitoneal chemotherapy (IPC) was undertaken using OVID Medline. Forty-six relevant studies were reviewed. Mean weighted overall morbidity following CRS and IPC was 49% (range 22-76%) and mortality was 3.6% (range 0-19%). Median overall survival ranged from 15 to 63 months, and 5-year overall survival ranged from 7 to 100%. This represents an improvement over historical treatment with systemic chemotherapy alone, even in the era of modern chemotherapeutic agents. Quality of life following surgery is initially decreased but improves with time and approaches baseline. Available data appear to support the treatment of PC from colon cancer with CRS and IPC. There is a large amount of variability among studies and few high-quality studies exist. Further studies are needed to standardize techniques. PMID- 26648796 TI - Chemotherapy for Stage II Colon Cancer. AB - The adjuvant treatment of patients with stage II colon cancer is an area of controversy in medical oncology. Adjuvant chemotherapy aims to eradicate micrometastatic disease present at the time of surgery, preventing the development of distant metastatic disease and thereby curing those patients of their cancer. National and international guidelines for the adjuvant treatment of stage II colon cancer recommend a range of treatment options from observation to chemotherapy with single-agent or combination regimens, depending on the presence or absence of high-risk features (poorly differentiated histology, presence of lymphovascular invasion, presence of perineural invasion, report of < 12 lymph nodes, bowel obstruction, localized perforation, or positive margins). In the one prospective study designed to address the role of adjuvant chemotherapy in stage II colon cancer, a small but statistically significant benefit in overall survival was seen for those patients who received adjuvant chemotherapy; however, multiple meta-analyses and retrospective subgroup analyses have called these findings into question. Though there may be a role for adjuvant chemotherapy in the treatment of patients with stage II colon cancer, its incremental benefit is small, at best, and comes with the risks of real and rarely fatal complications of chemotherapy. PMID- 26648798 TI - Anh H. Nguyen, MD. PMID- 26648797 TI - Surveillance and Survivorship after Treatment for Colon Cancer. AB - Colorectal cancer is the third most common cancer diagnosed in the United States. Majority of patients have localized disease that is amenable to curative resection. Disease recurrence remains a major concern after resection. In addition, patients are at an increased risk for developing a second or metachronous colon cancer. The principal goal of surveillance following treatment of colon cancer is to improve disease-free and overall survival. Survivorship is a distinct phase following surveillance to help improve quality of life and promote longevity. PMID- 26648799 TI - Cosmetic Asian Rhinoplasty. PMID- 26648800 TI - Milestones of Asian Rhinoplasty. AB - The field of plastic surgery originally developed out of the necessity to reconstruct the human body after the destruction of war. However, injured soldiers were not the only people who desired a change in appearance. After World War II, many people in Asian countries sought to attain a more Western look through surgery. Along with eyes, the nose was the main focus for these cosmetic procedures. In this article, the authors examine the evolution of Asian rhinoplasty from its original description in 1964 to the present. The characteristic anatomical differences between the Western and Asian nose are identified in relation to the technical challenges for rhinoplasty surgeons. Then the benefits and risks of the two major surgical approaches, autograft versus alloplast, are detailed. Finally, the coevolution of techniques and implant usage is traced from a dorsum-only implant, to an L-shaped implant, a cartilaginous cap graft with a one-piece rhinoplasty, an I-shaped implant, and a two-piece augmentation rhinoplasty. Outlining these changes demonstrates the advancement of the field of plastic surgery and the growing expectations of the patient. These advancements have provided the tools necessary to better align a patient's aesthetic goals and their unique anatomical presentation with a specific surgical approach. PMID- 26648801 TI - Nasal Analysis and Anatomy: Anthropometric Proportional Assessment in Asians Aesthetic Balance from Forehead to Chin, Part I. AB - Asian rhinoplasty patients can be analyzed by the nose's component structures and their relationship to one another. A comprehensive understanding of the underlying anatomical structure including bone, cartilage, and soft tissue contributes to better preoperative planning. To achieve an optimal postoperative result, a thorough preoperative analysis utilizing standardized measurements is essential. Knowledge of the Asian nose facilitates the use of an algorithmic approach to Asian rhinoplasty that increases surgical predictability. PMID- 26648802 TI - Nasal Analysis and Anatomy: Anthropometric Proportional Assessment in Asians Aesthetic Balance from Forehead to Chin, Part II. AB - Caucasians usually have reduction or correction rhinoplasty; however, Asian nasal surgery is mainly for augmentation rhinoplasty. Therefore, an Asian rhinoplasty should start with a precise understanding of ethnic anatomical differences. The authors summarize the anatomical characteristics of Asians to ensure the best results. PMID- 26648803 TI - Asian Rhinoplasty: Preoperative Simulation and Planning Using Adobe Photoshop. AB - A rhinoplasty in Asians differs from a rhinoplasty performed in patients of other ethnicities. Surgeons should understand the concept of Asian beauty, the nasal anatomy of Asians, and common problems encountered while operating on the Asian nose. With this understanding, surgeons can set appropriate goals, choose proper operative procedures, and provide an outcome that satisfies patients. In this article the authors define the concept of an Asian rhinoplasty-a paradigm shift from the traditional on-top augmentation rhinoplasty to a structurally integrated augmentation rhinoplasty-and provide a step-by-step procedure for the use of Adobe Photoshop as a preoperative program to simulate the expected surgical outcome for patients and to develop a preoperative plan for surgeons. PMID- 26648804 TI - Simple Implant Augmentation Rhinoplasty. AB - Augmentation rhinoplasty among Asian patients is often performed to improve the height of the nasal dorsum. As the use of autogenous tissues poses certain limitations, alloplastic materials are a viable alternative with a long history of use in Asia. The superiority of one implant prosthesis over another for augmentation rhinoplasty is a matter of debate, with each material representing varying strengths and weaknesses, indications for use, and precautions to consider in nasal implant placement. An implant prosthesis should be used on a case-by-case basis. Augmentation rhinoplasty requires the consideration of specific anatomical preoperative factors, including the external nose, nasal length, nasofrontal angle, humps, and facial proportions. It is equally important to consider several operative guidelines to appropriately shape implants to minimize the occurrence of adverse effects and postoperative complications. The most common postoperative complications include infection, nasal height change, movement of implant prosthesis, and silicone implant protrusion. In addition, the surgeon should consider the current standards of Asian beauty aesthetics to better understand the patient's desired outcome. PMID- 26648805 TI - Rhinoplasty with Cartilage and Alloplastic Materials, Nasal SMAS Management in Asian Rhinoplasty, Contracture Classification, and Secondary Rhinoplasty with Contracture. AB - Rhinoplasty for Asians is quite different from that of Westerners. Most Asians desire a raised nasal bridge with a projected nasal tip, similar to that of Westerners. Nevertheless, most Asian nasal bones, and upper and lower lateral cartilages are inadequately developed. This largely necessitates the use of a nasal alloplastic material such as a silicone implant, most frequently utilized in nasal cosmetic surgery for Asians. Shaping of the silicone implant is rather easy and its removal is also simple, in the case of a complication or undesired result. The disadvantage of a nasal silicone implant, like that of silicone implants of the breast, is the fibrous capsular formation, which may lead to capsular contracture. The frequently employed types of nasal silicone implant include (1) the boat type in which the silicone implant descends down to the nasal tip, (2) the L-shape in which the silicone implant further extends to the anterior nasal spine (ANS) after passing the tip, and (3) the three-quarter type for which the silicone implant extends down to the upper lateral cartilage. In conjunction with the silicone implant, the cartilages of the ear and the nasal septum are commonly used to create or lengthen tip projection. Asians generally have cartilage with inadequate anatomical development. Instead, they often have an anatomically thick fibrous fatty layer including underdeveloped superficial musculoaponeurotic system (SMAS). Patients with a thick fibrous tissue layer have a bulbous tip. This nasal tip is the area where severe capsular contracture occurs after insertion of a silicone implant. It is imperative that the surgeon properly understands the nasal anatomical characteristics of Asians, and selects an appropriate implant together with a suitable donor cartilage to attain a safe and aesthetically pleasing nose. The same principle should apply to reoperation cases; the fibrofatty layer of SMAS along with the capsular contracture must be removed or released to gain a sufficient soft tissue volume. This provides further stability to the cartilage framework. PMID- 26648806 TI - Asian Rhinoplasty with Rib Cartilage. AB - An Asian rhinoplasty is one of the most popular procedures in plastic surgery. The anatomical characteristics of the Asian nose are quite different from those of other races, including low dorsum height, short columella, a thick soft tissue covering on the tip with flaccid lower lateral cartilage, and a sunken midface with relative protrusion of the mouth due to maxilla or premaxillary retrusion. For augmentation and lengthening of the nose, a silicone implant has been commonly used in Asian countries. However, many patients suffer from silicone related complications, which induce soft tissue contraction and deform the already fragile nasal structure. Additionally, revision surgery is also increasing in frequency due to greater patient sophistication and higher expectation that the end rhinoplasty result to be more harmonious with the patient's overall facial structure. In these circumstances, a rhinoplasty using autologous rib cartilage, giving strong support and enough amount of the cartilage to correct deformed structure and midface skeletal retrusion. If properly performed with enough experience, a rib cartilage rhinoplasty will provide excellent and long-lasting results with low risk. PMID- 26648807 TI - Asian Rhinoplasty: Correction of the Short Nose with a Septal Integration Graft. AB - Correction of the short nose is the most challenging part in a rhinoplasty. It is even more difficult in Asians compared with Caucasians due to the thicker skin soft tissue envelope and weaker cartilaginous frameworks. Additionally, most of the Asian patients need augmentation of the nasal dorsum, and projection of the nasal tip at the same time of short nose surgery, which makes short nose correction more complex. Septal extension grafts can effectively and concomitantly correct a short nose. However, the amount of the septal cartilage is not sufficient as a source for the graft often; therefore, the authors devised a septal integration graft in which a septal cartilage graft was fixed to the caudal septum (columellar L-strut) in an end-to-end position to save an amount of the septal cartilage for correction of the short nose. A septal integration graft application resulted in lengthening of the short nose. In addition, the retracted columella and the acute columellar labial angle were improved aesthetically. Therefore, the authors suggest a septal integration graft, a modification of the septal extension graft, for correction of the short nose in an Asian rhinoplasty. PMID- 26648808 TI - Correction of Alar Retraction Based on Frontal Classification. AB - Among the various types of alar deformations in Asians, alar retraction not only has the highest occurrence rate, but is also very complicated to treat because the ala is supported only by cartilage and its soft tissue envelope cannot be easily stretched. As patients' knowledge of aesthetic procedures is becoming more extensive due to increased information dissemination through various media, doctors must give more accurate, logical explanations of the procedures to be performed and their anticipated results, with an emphasis on relevant anatomical features, accurate diagnoses, detailed classifications, and various appropriate methods of surgery. PMID- 26648809 TI - Chemical composition, antioxidant and antimicrobial activities of essential oil from Wedelia prostrata. AB - The following study deals with the chemical composition, antioxidant and antimicrobial activity of essential oils of Wedelia prostrata and their main constituents in vitro. A total of 70 components representing 99.26 % of the total oil were identified. The main compounds in the oil were limonene (11.38 %) and alpha-pinene (10.74 %). Antioxidant assays (1,1-diphenyl-2-picrylhydrazyl, superoxide anion radical, and reducing power test) demonstrate moderate activities for the essential oil and its main components (limonene and alpha pinene). The essential oil (1000 MUg/disc) exhibited promising antimicrobial activity against 10 strains of test microorganisms as a diameter of zones of inhibition (20.8 to 22.2 mm) and MIC values (125 to 250 ug/ml). The activities of limonene and alpha-pinene were also determined as main components of the oil. alpha-Pinene showed higher antimicrobial activity than the essential oil with a diameter of zones of inhibition (20.7 to 22.3 mm) and MIC values (62.5 to 125 ug/ml). The antioxidant and antimicrobial properties of the essential oil may be attributed to the synergistic effects of its diverse major and minor components. PMID- 26648810 TI - A simple click by click protocol to perform docking: AutoDock 4.2 made easy for non-bioinformaticians. AB - Recently, bioinformatics has advanced to the level that it allows almost accurate prediction of molecular interactions that hold together a protein and a ligand in the bound state. For instance, the program AutoDock has been developed to provide a procedure for predicting the interaction of small molecules with macromolecular targets which can easily separate compounds with micromolar and nanomolar binding constants from those with millimolar binding constants and can often rank molecules with finer differences in affinity. AutoDock can be used to screen a variety of possible compounds, searching for new compounds with specific binding properties or testing a range of modifications of an existing compound. The present work is a detailed outline of the protocol to use AutoDock in a more user friendly manner. The first step is to retrieve required Ligand and Target.pdb files from major databases. The second step is preparing PDBQT format files for Target and Ligand (Target.pdbqt, Ligand.pdbqt) and Grid and Docking Parameter file (a.gpf and a.dpf) using AutoDock 4.2. The third step is to perform molecular docking using Cygwin and finally the results are analyzed. With due confidence, this is our humble claim that a researcher with no previous background in bioinformatics research would be able to perform molecular docking using AutoDock 4.2 program by following stepwise guidelines given in this article. PMID- 26648811 TI - Presence of anti-mitochondrial antibodies and elevated serum immunoglobulin G levels: is this primary biliary cirrhosis-autoimmune hepatitis overlap syndrome? AB - Primary biliary cirrhosis in combination with autoimmune hepatitis has been termed "overlap syndrome", but its diagnosis is challenging. We report a case of a 43-year-old lady who presented with a six-month history of jaundice and pruritus. She subsequently developed gum bleeds. Laboratory investigations revealed hypochromic microcytic anemia, abnormal coagulation profiles, elevated serum alanine transferase and alkaline phosphatase levels, and raised serum IgG and IgM levels. Her serum was also positive for anti-nuclear and anti mitochondrial antibodies. The findings from her abdominal CT scan were suggestive of early liver cirrhosis and the histopathological examination results of her liver biopsy were consistent with primary biliary cirrhosis. The patient was treated with ursodeoxycholic acid and her liver function test parameters normalized after six months. PMID- 26648812 TI - Recent studies on betulinic acid and its biological and pharmacological activity. PMID- 26648813 TI - Obesity pharmacotherapy: current status. PMID- 26648814 TI - Prevalence of measles in vaccinated and non-vaccinated children. PMID- 26648815 TI - An updated review of Cucurbitacins and their biological and pharmacological activities. PMID- 26648816 TI - Effects of Trichostatin A on drug uptake transporters in primary rat hepatocyte cultures. AB - The present study was set up to investigate the effects of Trichostatin A (TSA), a prototypical epigenetic modifier, on the expression and activity of hepatic drug uptake transporters in primary cultured rat hepatocytes. To this end, the expression of the sinusoidal transporters sodium-dependent taurocholate cotransporting polypeptide (Ntcp) and organic anion transporting polypeptide 4 (Oatp4) was monitored by real-time quantitative reverse transcriptase polymerase chain reaction analysis and immunoblotting. The activity of the uptake transporters was analyzed using radiolabeled substrates and chemical inhibitors. Downregulation of the expression and activity of Oatp4 and Ntcp was observed as a function of the cultivation time and could not be counteracted by TSA. In conclusion, the epigenetic modifier TSA does not seem to exert a positive effect on the expression and activity of the investigated uptake transporters in primary rat hepatocyte cultures. PMID- 26648817 TI - MicroRNA-15b target Sall4 and diminish in vitro UCB-derived HSCs expansion. AB - Hematopoietic Stem Cells (HSCs) are cells that have the ability to self-renewal and differentiate into all of hematopoietic lineages. The lack of donors and unavailable efficient protocols for ex vivo expansion of HSCs, are obstacles in successful cell therapies. MicroRNAs (also refer as miRNAs or miRs) have significant roles in hematopoiesis; they can effect on HSCs expansion, maintaining undifferentiated state, self-renewal and differentiation. Recently attentions have been given to these small regulatory molecules to utilize them in order to expand HSCs. Using bioinformatics analysis we identified Sall4 as putative target of miR-15b and miR-219-5p. Relative expression levels of miRNAs and Sall4 were evaluated by qRT-PCR. Here we show 247-fold and 4.2-fold increasing Sall4 expression level compared to control group in CD34(+) cells nucleofected by anti-miR-15b and anti-miR-219-5p, respectively. These data showed that anti-miR-15b can promote clonogenic capacity of HSCs and also we found that miR-15b alone was able to increase the number of CD34(+)HSCs in vitro by more than 2 fold by targeting Sall4. Moreover, level of CD34 marker in HSCs nucleofected by anti-miR-15b increased more than 50 %. Our analysis showed no statistically difference in mRNA level of Sall4 after nucleofection of anti-miR 219-5p. Sall4 is a factor capable of enhancing HSC expansion significantly. We demonstrated that inhibition of miR-15b can enhance ex vivo expansion of UCB derived HSCs and also expression of Sall4 allowed expansion and preserve self- renewal of CD34(+) HSCs. PMID- 26648818 TI - The effect of BLA GABA(A) receptors in anxiolytic-like effect and aversive memory deficit induced by ACPA. AB - The roles of GABAergic receptors of the Basolateral amygdala (BLA) in the cannabinoid CB1 receptor agonist (arachydonilcyclopropylamide; ACPA)-induced anxiolytic-like effect and aversive memory deficit in adult male mice were examined in elevated plus-maze task. Results showed that pre-test intra peritoneal injection of ACPA induced anxiolytic-like effect (at dose of 0.05 mg/kg) and aversive memory deficit (at doses of 0.025 and 0.05 mg/kg). The results revealed that Pre-test intra-BLA infusion of muscimol (GABAA receptor agonist; at doses of 0.1 and 0.2 ug/mouse) or bicuculline (GABAA receptor antagonist; at all doses) impaired and did not alter aversive memory, respectively. All previous GABA agents did not have any effects on anxiety-like behaviors. Interestingly, pretreatment with a sub-threshold dose of muscimol (0.025 ug/mouse) and bicuculline (0.025 ug/mouse) did not alter anxiolytic-like behaviors induced by ACPA, while both drugs restored ACPA-induced amnesia. Moreover, muscimol or bicuculline increased and decreased ACPA-induced locomotor activity, respectively. Finally the data may indicate that BLA GABAA receptors have critical and different roles in anxiolytic-like effect, aversive memory deficit and locomotor activity induced by ACPA. PMID- 26648819 TI - Protective role of taurine in developing offspring affected by maternal alcohol consumption. AB - Maternal alcohol consumption is known to affect offspring growth and development, including growth deficits, physical anomalies, impaired brain functions and behavioral disturbances. Taurine, a sulfur-containing amino acid, is essential during development, and continually found to be protective against neurotoxicity and various tissue damages including those from alcohol exposure. However, it is still unknown whether taurine can exert its protection during development of central nervous system and whether it can reverse alcohol damages on developed brain later in life. This study aims to investigate protective roles of taurine against maternal alcohol consumption on growth and development of offspring. The experimental protocol was conducted using ICR-outbred pregnant mice given 10 % alcohol, with or without maternal taurine supplementation during gestation and lactation. Pregnancy outcomes, offspring mortality and successive bodyweight until adult were monitored. Adult offspring is supplemented taurine to verify its ability to reverse damages on learning and memory through a water maze task performance. Our results demonstrate that offspring of maternal alcohol exposure, together with maternal taurine supplementation show conserved learning and memory, while that of offspring treated taurine later in life are disturbed. Taurine provides neuroprotective effects and preserves learning and memory processes when given together with maternal alcohol consumption, but not shown such effects when given exclusively in offspring. PMID- 26648820 TI - Sleep deprivation-induced multi-organ injury: role of oxidative stress and inflammation. AB - Sleep deprivation affects all aspects of health. Adverse health effects by sleep deviation are still underestimated and undervalued in clinical practice and, to a much greater extent in monitoring human health. We hypothesized that sleep deprivation-induced mild organ injuries; oxidative stress and inflammation might play a crucial role in inducing multi-organ injury. Male C57BL/6J mice (n = 6-7) were sleep-deprived for 0-72 h using a modified multiple platform boxes method. Blood and tissue were collected. Liver, heart, kidney, lung, and pancreatic injuries were evaluated using biochemical and histological analyses. Glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), total billirubin (TBIL), creatine phosphokinase (CPK), creatine phosphokinase myocardial band (CKMB), lactic dehydrogenase (LDH), creatinine (CRE), and blood urea nitrogen (BUN) were assayed in blood. Malondialdehyde (MDA), nitric oxide (NO), tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6 levels were measured. Histology revealed mild-to-moderate liver and lung injury in sleep deprived mice. Sleep-deprived mice had significantly higher GOT, GPT, TBIL, CPK, CKMB, LDH, BUN, and alpha-amylase (AMYL) levels, which indicated liver, heart, kidney, and pancreatic injuries. Serum IL-1beta at 24 h and IL-6 at 72 h were significantly higher in sleep-deprived than in control mice. Hepatic TNF-alpha and IL-1beta were significantly higher, but IL-6 significantly lower in mice that had been sleep-deprived for 72 h. Sleep deprivation-mediated inflammation may be associated with mild to moderate multi-organ damage in mice. The implication of this study indicates sleep deprivation in humans may induce multi-organ injury that negatively affects cardiovascular and gastrointestinal health. PMID- 26648821 TI - Molecular detection of antimicrobial resistance in local isolates of Staphylococcus epidermidis from urinary tract infections in Faisalabad region of Pakistan. AB - Staphylococci are one of the foremost causes of urinary tract infections (UTIs) in humans. The emergence of multiple drug resistance (MDR) among Staphylococci poses serious challenges in antimicrobial therapy for UTIs. Most work has been done on S. aureus while coagulase negative Staphylococci (mainly S. epidermidis) are often neglected. This study was conducted to establish a baseline profile of drug resistance in local S. epidermidis isolates from UTIs. Eighty urine samples were collected from suspected UTIs cases and screened for S. epidermidis. Twenty isolates were suspected as S. epidermidis based on colony morphology and Gram staining. Molecular detection by polymerase chain reaction (PCR) confirmed 13 isolates as S. epidermidis. Using disc diffusion method, phenotypic drug resistance of the isolates was observed towards erythromycin (100 %), gentamycin, azithromycin and tetracycline (92.3 %), ampicillin and oxytetracyclin (84.6 %), amikacin and srteptomycin (76.9 %), methicillin (69.2 %), cephradine, cefaclor and cefazolin (53.8 %) and vancomycin (15.3 %). Eighteen most commonly reported genes responsible for conferring resistance towards these drugs were targeted by PCR: among these tetM gene was found most prevalent (46.1 %) followed by tetK (30.7 %), aac(6')/aph(2") (30.7 %), aacA-aphD (23 %), ermA (23 %), blaZ (23 %), mecA (23 %) blaTEM-1 (23 %), MeccA (23 %) and mecA (15.3 %). No gene fragment for vancomycin resistance was detected. The salient finding was that all S. epidermidis isolates were multiple drugs resistant as they showed resistance against at least three structurally different antimicrobial agents. It is concluded that in addition to the mostly used antimicrobial agent vancomycin, the cephalosporins including cephradine, cefaclor and cefazolin are also the drugs of choice against UTIs caused by S. epidermidis. PMID- 26648822 TI - Anti-inflammatory, antioxidant and antitumor activities of ingredients of Curcuma phaeocaulis Val. AB - Curcuma phaeocaulis Val. is used in Chinese Pharmacopoeia as health food and folk medicine for removing blood stasis, alleviating pain and tumor therapy. This research was aimed to explore and compare three main bioactivities including anti oxidant, antitumor and anti-inflammatory activities between the ethanol extract of C. Phaeocaulis and its fractions using different in vitro models. Firstly, 70 % ethanol was used to extract C. Phaeocaulis, and then the crude extract was re extracted, resulting in petroleum ether (EZ-PE), ethyl acetate (EZ-EA), and water fractions (EZ-W), respectively, and then a series of index was detected. Results showed that all the extracts had medium DPPH radical scavenging activity when the concentration was 200 MUg/ml and their DPPH radical scavenging activity was in a concentration-dependent manner. The extracts except ethanol extract of C. Phaeocaulis had almost no cytotoxicity to the survival of RAW264.7 cell when the concentration reached 80 MUg/ml, and all of them had medium inhibitory effect on nitrite release. Extracts of C. Phaeocaulis had medium intensity antitumor activity, EZ-PE and EZ-EA fractions significantly inhibited the proliferation of four tumor cells (SMMC-7721 cell lines, HepG-2 cell lines, A549 cell lines and Hela cell lines). C. Phaeocaulis had antioxidant and anti-inflammatory activities, which did not carry out centralized phenomenon when re-extracted. EZ PE and EZ-EA were active antitumor sites of C. Phaeocaulis. PMID- 26648824 TI - Efficacy of Caltropis procera and Ficus sycomorus extracts in treating MRSA (methicillin-resistant Staphylococcus aureus)-keratitis in rabbit. AB - MRSA-induced keratitis in rabbit was used to evaluate the therapeutic effect of F. sycomorus leaves and C. procera latex extracts. Within the 6 rabbit groups tested, group 1 received sterilized saline, while other groups (2 to 6) received 100 MUl of intrastromal injections of 1.5*10(3) colony forming unit (cfu) ml(-1) of methicillin-resistant Staphylococcus aureus (MRSA). After 12 hours, groups 3 to 6 also received chloramphenicol, aqueous extract of C. procera latex, aqueous and alcoholic extracts of F. sycomorus leaves, respectively 3 times daily for 12 successive days. The tested extracts inhibited MRSA growth in vitro (i.e. on culture medium). Colony counts in cornea discs from groups 3 to 6 were significantly reduced (P <= 0.001) compared to group 2 (untreated). Clinical signs of keratitis were observed on group 2 until the end of experiment. In groups 3 to 6, gradual recovery was observed and signs disappeared by the 12(th) DPI (days post inoculation). Only mild symptoms persisted in group 5 (aqueous extract of leaves). In group 3 and 5, cornea, iris, ciliary body and conjunctiva showed mild leukocytic infiltration and depigmentation of melanin cells while recovery of cornea and iris was observed in groups 4 and 6. In conclusion, the used extracts have potential therapeutic effects on MRSA-induced keratitis in rabbit. PMID- 26648825 TI - Antihypercholesterolemic effect of Cleome arabica L. on high cholesterol diet induced damage in rats. AB - Dietary cholesterol is known to be one of the main risk factors that accelerate oxidation process leading to hypercholesterolemia and attendant cardiovascular diseases. The purpose of this study, carried out on adult male Wistar rats, was to evaluate the inhibitory effects of supplementation with aqueous of Cleome arabica leaf extract on hypercholesterolemia. After 3 months of treatment, animals were sacrificed by decapitation. Blood serum was obtained by centrifugation. Under our experimental conditions, administration of Cleome arabica leaf extract decreased the total cholesterol (TC), LDL-cholesterol (LDL chol) and triglycerides (TG) levels by 27 %, 52 %, 37 %, respectively, and reduced SGOT SGPT, LDH and PAL levels in blood serum compared to untreated hypercholesterolemic rats. TBARS concentrations decreased by 21 % in liver, 22 % in heart and 30 % in kidney in a group of rats treated with cholesterol and Cleome arabica (Chol C.ar) compared to a Chol-treated group. The same treatment with Cleome arabica leaf extract increased superoxide dismutase and enhanced glutathione peroxidase activity. Catalase activity was found to increase in liver, heart and kidney by 17 %, 16 % and 23 %, respectively, in the C.ar Chol treated group. The protective effect of Cleome arabica on hypercholesterolemia inducing oxidative stress in several organs was mainly attributed to antioxidant properties. The latter were due to the presence of phenolic acids and flavonoids shown by the obtained HPLC profiles. PMID- 26648823 TI - Short-interference RNAs: becoming medicines. AB - RNA interference is a cellular mechanism by which small molecules of double stranded RNA modulate gene expression acting on the concentration and/or availability of a given messenger RNA. Almost 10 years after Fire and Mello received the Nobel Prize for the discovery of this mechanism in flat worms, RNA interference is on the edge of becoming a new class of therapeutics. With various phase III studies underway, the following years will determine whether RNAi therapeutics can rise up to the challenge and become mainstream medicines. The present review gives a thorough overview of the current status of this technology focusing on the path to the clinic of this new class of compounds. PMID- 26648827 TI - Highlight report: Blueprint for stem cell differentiation into liver cells. PMID- 26648826 TI - The erratic antibiotic susceptibility patterns of bacterial pathogens causing urinary tract infections. AB - Increasing trend of antibiotic resistance and expression of Extended Spectrum Beta Lactamases (ESBLs) are serious threats for public health as they render the treatment ineffective. Present study was designed to elucidate the antibiotic susceptibility patterns of ESBL and non-ESBL producing E. coli and K. pneumoniae causing urinary tract infections so that the ineffective antibiotics could be removed from the line of treatment. The bacterial isolates obtained from the urine of patients visiting a tertiary health care facility were cultured for strain identification using API20E. Antimicrobial susceptibility and ESBL detection were done by Kirby-bauer diffusion technique. Almost 53.4 % isolates of E. coli and 24.5 % isolates of K. pneumoniae were found to be ESBL producers. The ESBL producing bacteria were found to be more resistant towards various antibiotics. The most effective drugs against E. coli ESBL isolates were imipenem (99.54 %), ampicillin-sulbactam (97.48 %), piperacillin-tazobactam (96.86 %), fosfomycin (94.51 %), amikacin (92.26 %) and nitrofurantoin (90.68 %). The most effective drugs against K. pneumoniae ESBL isolates were imipenem (97.62 %), piperacillin-tazobactam (95.35 %), ampicillin-sulbactam (90.48 %) and amikacin (88.37 %). The antibiotics having the highest resistance, particularly by the ESBL producers were amoxicillin clavulanic acid, sulphamethoxalzole/ trimethoprim, cefuroxime, cefpirome, ceftriaxone and ciprofloxacin. Most of the isolates showed multi drug resistance (MDR). High frequency of ESBL producing E. coli and K. pneumoniae were observed as compared to previous data. Penicillins, cephalosporins and some representatives of fluoroquinolones were least effective against the common UTIs and are recommended to be removed from the line of treatment. PMID- 26648828 TI - Highlight report: Software for tissue analysis and reconstruction. PMID- 26648829 TI - Primary Hormone Therapy in Elderly Women with Hormone-Sensitive Locoregional Breast Cancer: Endocrine Therapy Alone Is a Reasonable Alternative in Selected Patients. AB - BACKGROUND: Treatment with aromatase inhibitors (AIs) followed by surgery is often recommended for women with locoregional hormone-sensitive breast cancer. However, no study has compared the efficacy of AIs alone versus AIs followed by surgery. METHODS: 33 postmenopausal breast cancer patients were treated with primary hormone therapy. Estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor type 2 receptor (HER2) expression levels were analyzed by immunohistochemistry. After hormone therapy, eligible patients underwent surgery, and those who were not candidates for surgery continued on hormone therapy. We retrospectively analyzed time to progression, overall survival, response, and impact of surgery on outcome. RESULTS: All patients were ER+. HER2 was successfully analyzed in 30 patients, all of whom were HER2-. The median time to progression was 94 months, and the median overall survival was not reached, while the mean overall survival was 123 months. The overall response rate was 63.6%, with 9.1% complete responses. No significant differences in time to progression or survival were observed between patients who underwent surgery and those who did not. CONCLUSIONS: Primary hormone therapy with AIs is effective in elderly breast cancer patients with high levels of hormone receptors and may provide a feasible and tolerable alternative to surgery in selected hormone sensitive breast cancer patients. PMID- 26648830 TI - To NIPT or Not to NIPT. PMID- 26648831 TI - A Novel de novo Mutation in CEACAM16 Associated with Postlingual Hearing Impairment. AB - Mutations in CEACAM16 cause autosomal dominant nonsyndromic hearing loss (DFNA4B). So far, 2 families have been reported with segregating missense mutations, both in the immunoglobulin constant domain A of the CEACAM16 protein. In this study, we used the TruSight One panel to investigate a parent-child trio without familial history of hearing loss and one affected child. When filtering for recessive inheritance and de novo events, we discovered a de novo CEACAM16 mutation (c.1094T>G, p.Leu365Arg) as the sole likely pathogenic variant. The de novo mutation was confirmed by Sanger sequencing and STR analysis. The proband's hearing loss closely matches the described onset and severity for DFNA4B. We present the third CEACAM16 variant and the first de novo mutation in CEACAM16. This de novo mutation is robustly described as a pathogenic mutation according to in silico mutation prediction tools and affects a highly conserved amino acid in the most strongly conserved CEACAM16 N2 domain. Our strategy of screening family trios enhances de novo mutation discovery and the exclusion of other variants of potential interest through pedigree filtering. PMID- 26648832 TI - Clinical and Molecular Characterization of Osteogenesis Imperfecta Type V. AB - Osteogenesis imperfecta type V (OI-V) has a wide clinical variability, with distinct clinical/radiological features, such as calcification of the interosseous membrane (CIM) between the radius-ulna and/or tibia-fibula, hyperplastic callus (HPC) formation, dislocation of the radial head (DRH), and absence of dentinogenesis imperfecta (DI). Recently, a single heterozygous mutation (c.-14C>T) in the 5'UTR of the IFITM5 gene was identified to be causative for OI-V. Here, we describe 7 individuals from 5 unrelated families that carry the c.-14C>T IFITM5 mutation. The clinical findings in these cases are: absence of DI in all patients, presence of blue sclera in 2 cases, and 4 patients with DRH. Radiographic findings revealed HPC in 3 cases. All patients presented CIM between the radius and ulna, while 4 patients presented additional CIM between the tibia and fibula. Spinal fractures by vertebral compression were observed in all individuals. The proportion of cases identified with this mutation represents 4% of OI cases at our institution. The clinical identification of OI-V is crucial, as this mutation has an autosomal dominant inheritance with variable expressivity. PMID- 26648833 TI - Novel KIF7 Mutation in a Tunisian Boy with Acrocallosal Syndrome: Case Report and Review of the Literature. AB - Acrocallosal syndrome (ACLS) is a rare autosomal recessive disorder characterized by agenesis of the corpus callosum, facial dysmorphism, postaxial polydactyly of the hands as well as preaxial polydactyly of the feet, and developmental delay. Mutations in the KIF7 gene, encoding a molecule within the Sonic hedgehog (SHH) pathway, have been identified as causative for ACLS but also for the fatal hydrolethalus syndrome and some cases of Joubert syndrome. We report here on a Tunisian boy who shows the clinical characteristics of ACLS and was found to have a novel homozygous KIF7 nonsense mutation. Further, we summarize the current knowledge about the clinical spectrum associated with KIF7 mutations as well as genetic and/or phenotypic overlap with ciliopathies and other mutations in the SHH pathway. PMID- 26648834 TI - The PHF6 Mutation c.1A>G; pM1V Causes Borjeson-Forsman-Lehmann Syndrome in a Family with Four Affected Young Boys. AB - The family presented with 4 boys, 2 sets of brothers, with unexplained intellectual disability. Numerous analyses had been conducted over more than a decade, without reaching a final clinical or molecular diagnosis. According to the pedigree, an X-linked inheritance pattern was strongly suspected. Whole-exome sequencing (WES) with targeted analysis of the coding regions of the X chromosome was carried out in the 4 boys, their mothers, and their shared grandmother. A filtering process searching for nonsynonymous variants and variants in the exon intron boundaries revealed one variant, c.1A>G; pM1V, in the first codon of the PHF6 gene. The variant was hemizygous in the 4 boys and heterozygous in the 2 mothers and the grandmother. Mutations in the PHF6 gene are known to cause Borjeson-Forsman-Lehmann syndrome (BFLS). The boys were reexamined after the finding of the mutation, and the phenotype fitted perfectly with BFLS. The mutation found in the PHF6 gene is causative for the intellectual disability in this family. We also conclude that WES of the X chromosome is a powerful tool in families where an X-linked inheritance pattern is suspected. PMID- 26648835 TI - Pre- and Postnatal Analysis of Chromosome 1q44 Deletion in Agenesis of Corpus Callosum. AB - Agenesis of corpus callosum (ACC) is one of the common brain abnormalities and also a common finding in children with mental disability. ACC is heterogeneous and can occur as an isolated condition or as part of a syndrome. ACC can be accurately identified by the absence of the cavum septum pallucidum and tear drop effect of the lateral ventricle after 18 weeks of pregnancy in an ultrasound scan. Genetic causes have been attributed to 30-45% of cases with ACC. Submicroscopic deletions of 1q43q44 have been reported in several cases of ACC. The AKT3 gene, mapped to 1q44, is required for the development of the callosum and brain size. It is considered to be a candidate gene for ACC. We studied a total of 22 cases with ACC, in pre- and postnatal samples using FISH probes. None of the samples showed a deletion in 1q44, implying that the AKT3 gene may not be associated with ACC. PMID- 26648836 TI - Cytogenetic and Molecular Findings in Children with Acute Lymphoblastic Leukemia: Experience of a Single Institution in Argentina. AB - The purpose of the current study was to evaluate the cytogenetic findings in 1,057 children with acute lymphoblastic leukemia (ALL) referred to the cytogenetics laboratory at the Hospital de Pediatria Dr. Juan P. Garrahan, between 1991 and 2014. Chromosomal abnormalities were evaluated by G-banding and FISH. Since December 2002, RT-PCR determinations were systematically carried out for BCR-ABL1, KMT2A-AFF1, ETV6-RUNX1, and TCF3-PBX1 rearrangements in children, adding KMT2A-MLLT3 and KMT2A-MLLT1 in infants. The percentage of abnormalities detected by cytogenetics was 70.1%. Four novel abnormalities, t(2;8)(p11.2;p22), inv(4)(p16q25), t(1;7)(q25;q32), and t(5;6)(q21;q21), were found in this cohort. We compared cytogenetic and RT-PCR results for BCR-ABL1, KMT2A-AFF1 and TCF3-PBX1 rearrangements in 497 children evaluated by both methods. The results were highly concordant (p < 0.7), and interestingly, FISH was relevant to confirm G-banding findings that were discordant with RT-PCR studies. This study showed the importance of performing G-banding, FISH and RT-PCR simultaneously to improve the detection of chromosomal abnormalities considering their important value in the diagnosis and prognosis of childhood ALL patients. Finally, to the best of our knowledge, this is the first series of cytogenetic findings in children with ALL reported in Argentina. PMID- 26648837 TI - Mitochondrial Dysfunction in a Patient with 8q21.11 Deletion and Charcot-Marie Tooth Disease Type 2K due to GDAP1 Haploinsufficiency. AB - Unbalanced chromosomal rearrangements typically cause multiple organ system involvement including neurodevelopmental deficits. It is atypical, however, to experience developmental and neurological regression. We describe a female with intellectual disability, failure to thrive, short stature, multiple congenital anomalies, and dysmorphic features and a previously diagnosed de novo 8q21.11 deletion at the age of 7. However, at the age of 11, she experienced neurological and developmental regression. The GDAP1 gene encoding ganglioside-induced differentiation-associated protein 1 was deleted in the patient as a part of the contiguous gene syndrome. We argue that haploinsufficiency of GDAP1 could have contributed to the proband's regression based on its involvement in mitochondrial function and a signal transduction pathway in neuronal development. PMID- 26648838 TI - Altered Hippocampal Neurogenesis and Amygdalar Neuronal Activity in Adult Mice with Repeated Experience of Aggression. AB - Repeated experience of winning in a social conflict setting elevates levels of aggression and may lead to violent behavioral patterns. Here, we use a paradigm of repeated aggression and fighting deprivation to examine changes in behavior, neurogenesis, and neuronal activity in mice with positive fighting experience. We show that for males, repeated positive fighting experience induces persistent demonstration of aggression and stereotypic behaviors in daily agonistic interactions, enhances aggressive motivation, and elevates levels of anxiety. When winning males are deprived of opportunities to engage in further fights, they demonstrate increased levels of aggressiveness. Positive fighting experience results in increased levels of progenitor cell proliferation and production of young neurons in the hippocampus. This increase is not diminished after a fighting deprivation period. Furthermore, repeated winning experience decreases the number of activated (c-fos-positive) cells in the basolateral amygdala and increases the number of activated cells in the hippocampus; a subsequent no-fight period restores the number of c-fos-positive cells. Our results indicate that extended positive fighting experience in a social conflict heightens aggression, increases proliferation of neuronal progenitors and production of young neurons in the hippocampus, and decreases neuronal activity in the amygdala; these changes can be modified by depriving the winners of the opportunity for further fights. PMID- 26648839 TI - Criticality as a Set-Point for Adaptive Behavior in Neuromorphic Hardware. AB - Neuromorphic hardware are designed by drawing inspiration from biology to overcome limitations of current computer architectures while forging the development of a new class of autonomous systems that can exhibit adaptive behaviors. Several designs in the recent past are capable of emulating large scale networks but avoid complexity in network dynamics by minimizing the number of dynamic variables that are supported and tunable in hardware. We believe that this is due to the lack of a clear understanding of how to design self-tuning complex systems. It has been widely demonstrated that criticality appears to be the default state of the brain and manifests in the form of spontaneous scale invariant cascades of neural activity. Experiment, theory and recent models have shown that neuronal networks at criticality demonstrate optimal information transfer, learning and information processing capabilities that affect behavior. In this perspective article, we argue that understanding how large scale neuromorphic electronics can be designed to enable emergent adaptive behavior will require an understanding of how networks emulated by such hardware can self tune local parameters to maintain criticality as a set-point. We believe that such capability will enable the design of truly scalable intelligent systems using neuromorphic hardware that embrace complexity in network dynamics rather than avoiding it. PMID- 26648840 TI - Robust Encoding in the Human Auditory Brainstem: Use It or Lose It? PMID- 26648841 TI - Intact Reflexive but Deficient Voluntary Social Orienting in Autism Spectrum Disorder. AB - Impairment in social interactions is a primary characteristic of people diagnosed with autism spectrum disorder (ASD). Although these individuals tend to orient less to naturalistic social cues than do typically developing (TD) individuals, laboratory experiments testing social orienting in ASD have been inconclusive, possibly because of a failure to fully isolate reflexive (stimulus-driven) and voluntary (goal-directed) social orienting processes. The purpose of the present study was to separately examine potential reflexive and/or voluntary social orienting differences in individuals with ASD relative to TD controls. Subjects (ages 7-14) with high-functioning ASD and a matched control group completed three gaze cueing tasks on an iPad in which individuals briefly saw a face with averted gaze followed by a target after a variable delay. Two tasks were 100% predictive with either all congruent (target appears in gaze direction) or all incongruent (target appears opposite from gaze direction) trials, respectively. Another task was non-predictive with these same trials (half congruent and half incongruent) intermixed randomly. Response times (RTs) to the target were used to calculate reflexive (incongruent condition RT-congruent condition RT) and voluntary (non predictive condition RT-predictive condition RT) gaze cueing effects. Subjects also completed two additional non-social orienting tasks (ProPoint and AntiPoint). Subjects with ASD demonstrate intact reflexive but deficient voluntary gaze following. Similar results were found in a separate test of non social orienting. This suggests problems with using social cues, but only in a goal-directed fashion, in our sample of high-functioning individuals with ASD. Such findings may not only explain inconclusive previous findings but more importantly be critical for understanding social dysfunctions in ASD and for developing future interventions. PMID- 26648842 TI - Autophagy Induction by Endothelial-Monocyte Activating Polypeptide II Contributes to the Inhibition of Malignant Biological Behaviors by the Combination of EMAP II with Rapamycin in Human Glioblastoma. AB - This study aims to investigate the effect of endothelial-monocyte activating polypeptide II (EMAP II) on human glioblastoma (GBM) cells and glioblastoma stem cells (GSCs) as well as its possible mechanisms. In this study, EMAP II inhibited the cell viability and decreased the mitochondrial membrane potential in human GBM cells and GSCs, and autophagy inhibitor 3-methyl adenine (3-MA) blocked these effects. Autophagic vacuoles were formed in these cells after EMAP II treatment and this phenomenon was blocked by 3-MA. In addition, the up-regulation of microtubule-associated protein-1 light chain-3 (LC3)-II and the down-regulation of autophagic degraded substrate p62/SQSTM1 caused by EMAP II were observed. Cells treated with EMAP-II inhibited the PI3K/Akt/mTOR signal pathway, and PI3K/Akt agonist insulin-like growth factor-1 (IGF-1) blocked the effect of EMAP II on the expression of LC3-II and p62/SQSTM1. Cells exposed to EMAP-II experienced mitophagy and ER stress. Furthermore, the inhibition of cell proliferation, migration and invasion of GBM cells and GSCs were more remarkable by the combination of EMAP II and rapamycin than either agent alone in vitro and in vivo. The current study demonstrated that the cytotoxicity of EMAP II in human GBM cells and GSCs was induced by autophagy, accompanied by the inhibition of PI3K/Akt/mTOR signal pathway, mitophagy and ER stress. The combination of EMAP II with rapamycin demonstrated the inhibitory effect on the malignant biological behaviors of human GBM cells and GSCs in vitro and in vivo. PMID- 26648843 TI - tPA Deficiency in Mice Leads to Rearrangement in the Cerebrovascular Tree and Cerebroventricular Malformations. AB - The serine protease tissue-type plasminogen activator (tPA) is used as a thrombolytic agent in the management of ischemic stroke, but concerns for hemorrhagic conversion greatly limits the number of patients that receive this treatment. It has been suggested that the bleeding complications associated with thrombolytic tPA may be due to unanticipated roles of tPA in the brain. Recent work has suggested tPA regulation of neurovascular barrier integrity, mediated via platelet derived growth factor (PDGF)-C/PDGF receptor-alpha (PDGFRalpha) signaling, as a possible molecular mechanism affecting the outcome of stroke. To better understand the role of tPA in neurovascular regulation we conducted a detailed analysis of the cerebrovasculature in brains from adult tPA deficient (tPA(-/-) ) mice. Our analysis demonstrates that life-long deficiency of tPA is associated with rearrangements in the cerebrovascular tree, including a reduction in the number of vascular smooth-muscle cell covered, large diameter, vessels and a decrease in vessel-associated PDGFRalpha expression as compared to wild-type (WT) littermate controls. In addition, we found that ablation of tPA results in an increased number of ERG-positive endothelial cells and increased junctional localization of the tight junction protein ZO1. This is intriguing since ERG is an endothelial transcription factor implicated in regulation of vascular integrity. Based on these results, we propose that the protection of barrier properties seen utilizing these tPA (-/-) mice might be due, at least in part, to these cerebrovascular rearrangements. In addition, we found that tPA (-/-) mice displayed mild cerebral ventricular malformations, a feature previously associated with ablation of PDGF-C, thereby providing an in vivo link between tPA and PDGF signaling in central nervous system (CNS) development. Taken together, the data presented here will advance our understanding of the role of tPA within the CNS and in regulation of cerebrovascular permeability. PMID- 26648844 TI - Endocannabinoids Mediate Muscarinic Acetylcholine Receptor-Dependent Long-Term Depression in the Adult Medial Prefrontal Cortex. AB - Cholinergic inputs into the prefrontal cortex (PFC) are associated with attention and cognition; however there is evidence that acetylcholine also has a role in PFC dependent learning and memory. Muscarinic acetylcholine receptors (mAChR) in the PFC can induce synaptic plasticity, but the underlying mechanisms remain either opaque or unresolved. We have characterized a form of mAChR mediated long term depression (LTD) at glutamatergic synapses of layer 5 principal neurons in the adult medial PFC. This mAChR LTD is induced with the mAChR agonist carbachol and inhibited by selective M1 mAChR antagonists. In contrast to other cortical regions, we find that this M1 mAChR mediated LTD is coupled to endogenous cannabinoid (eCB) signaling. Inhibition of the principal eCB CB1 receptor blocked carbachol induced LTD in both rats and mice. Furthermore, when challenged with a sub-threshold carbachol application, LTD was induced in slices pretreated with the monoacylglycerol lipase (MAGL) inhibitor JZL184, suggesting that the eCB 2 arachidonylglyerol (2-AG) mediates M1 mAChR LTD. Yet, when endogenous acetylcholine was released from local cholinergic afferents in the PFC using optogenetics, it failed to trigger eCB-LTD. However coupling patterned optical and electrical stimulation to generate local synaptic signaling allowed the reliable induction of LTD. The light-electrical pairing induced LTD was M1 mAChR and CB1 receptor mediated. This shows for the first time that connecting excitatory synaptic activity with coincident endogenously released acetylcholine controls synaptic gain via eCB signaling. Together these results shed new light on the mechanisms of synaptic plasticity in the adult PFC and expand on the actions of endogenous cholinergic signaling. PMID- 26648846 TI - Type I Vs. Type II Cytokine Levels as a Function of SOD1 G93A Mouse Amyotrophic Lateral Sclerosis Disease Progression. AB - Amyotrophic Lateral Sclerosis (ALS) is a fatal motoneuron disease that is characterized by the degradation of neurons throughout the central nervous system. Inflammation have been cited a key contributor to ALS neurodegeneration, but the timeline of cytokine upregulation remains unresolved. The goal of this study was to temporally examine the correlation between the varying levels of pro inflammatory type I cytokines (IL-1beta, IL-1alpha, IL-12, TNF-alpha, and GFAP) and anti-inflammatory type II cytokines (IL-4, IL-6, IL-10) throughout the progression of ALS in the SOD1 G93A mouse model. Cytokine level data from high copy SOD1 G93A transgenic mice was collected from 66 peer-reviewed studies. For each corresponding experimental time point, the ratio of transgenic to wild type (TG/WT) cytokine was calculated. One-way ANOVA and t-tests with Bonferonni correction were used to analyze the data. Meta-analysis was performed for four discrete stages: early, pre-onset, post-onset, and end stage. A significant increase in TG cytokine levels was found when compared to WT cytokine levels across the entire SOD1 G93A lifespan for majority of the cytokines. The rates of change of the individual cytokines, and type I and type II were not significantly different; however, the mean fold change of type I was expressed at significantly higher levels than type II levels across all stages with the difference between the means becoming more pronounced at the end stage. An overexpression of cytokines occurred both before and after the onset of ALS symptoms. The trend between pro-inflammatory type I and type II cytokine mean levels indicate a progressive instability of the dynamic balance between pro- and anti-inflammatory cytokines as anti-inflammatory cytokines fail to mediate the pronounced increase in pro-inflammatory cytokines. Very early immunoregulatory treatment is necessary to successfully interrupt ALS-induced neuroinflammation. PMID- 26648847 TI - Muscle Expression of SOD1(G93A) Modulates microRNA and mRNA Transcription Pattern Associated with the Myelination Process in the Spinal Cord of Transgenic Mice. AB - A crucial system severely affected in several neuromuscular diseases is the loss of effective connection between muscle and nerve, leading to a pathological non communication between the two tissues. One of the best examples of impaired interplay between muscle and nerve is Amyotrophic Lateral Sclerosis, a neurodegenerative disease characterized by degeneration of motor neurons and muscle atrophy. Increasing evidences suggest that damage to motor neurons is enhanced by alterations in the neighboring non-neuronal cells and indicate that altered skeletal muscle might be the source of signals that impinge motor neuron activity and survival. Here we investigated whether muscle selective expression of SOD1(G93A) mutant gene modulates mRNAs and miRNAs expression at the level of spinal cord of MLC/SOD1(G93A) mice. Using a Taqman array, the Affymetrix Mouse Gene 2.0 ST approach and the MiRwalk 2.0 database, which provides information on miRNA and their predicted target genes, we revealed that muscle specific expression of SOD1(G93A) modulates relevant molecules of the genetic and epigenetic circuitry of myelin homeostasis in spinal cord of transgenic mice. Our study provides insights into the pathophysiological interplay between muscle and nerve and supports the hypothesis that muscle is a source of signals that can either positively or negatively affect the nervous system. PMID- 26648845 TI - Fatigue in Multiple Sclerosis: Neural Correlates and the Role of Non-Invasive Brain Stimulation. AB - Multiple sclerosis (MS) is a chronic progressive inflammatory disease of the central nervous system (CNS) and the major cause of non-traumatic disability in young adults. Fatigue is a frequent symptom reported by the majority of MS patients during their disease course and drastically affects their quality of life. Despite its significant prevalence and impact, the underlying pathophysiological mechanisms are not well elucidated. MS fatigue is still considered the result of multifactorial and complex constellations, and is commonly classified into "primary" fatigue related to the pathological changes of the disease itself, and "secondary" fatigue attributed to mimicking symptoms, comorbid sleep and mood disorders, and medications side effects. Radiological, physiological, and endocrine data have raised hypotheses regarding the origin of this symptom, some of which have succeeded in identifying an association between MS fatigue and structural or functional abnormalities within various brain networks. Hence, the aim of this work is to reappraise the neural correlates of MS fatigue and to discuss the rationale for the emergent use of noninvasive brain stimulation (NIBS) techniques as potential treatments. This will include a presentation of the various NIBS modalities and a suggestion of their potential mechanisms of action in this context. Specific issues related to the value of transcranial direct current stimulation (tDCS) will be addressed. PMID- 26648848 TI - Postsynaptic Density Protein 95 in the Striosome and Matrix Compartments of the Human Neostriatum. AB - The human neostriatum consists of two functional subdivisions referred to as the striosome (patch) and matrix compartments. The striosome-matrix dopamine systems play a central role in cortico-thalamo-basal ganglia circuits, and their involvement is thought to underlie the genesis of multiple movement and behavioral disorders, and of drug addiction. Human neuropathology also has shown that striosomes and matrix have differential vulnerability patterns in several striatal neurodegenerative diseases. Postsynaptic density protein 95 (PSD-95), also known as disks large homolog 4, is a major scaffolding protein in the postsynaptic densities of dendritic spines. PSD-95 is now known to negatively regulate not only N-methyl-D-aspartate glutamate signaling, but also dopamine D1 signals at sites of postsynaptic transmission. Accordingly, a neuroprotective role for PSD-95 against dopamine D1 receptor (D1R)-mediated neurotoxicity in striatal neurodegeneration also has been suggested. Here, we used a highly sensitive immunohistochemistry technique to show that in the human neostriatum, PSD-95 is differentially concentrated in the striosome and matrix compartments, with a higher density of PSD-95 labeling in the matrix compartment than in the striosomes. This compartment-specific distribution of PSD-95 was strikingly complementary to that of D1R. In addition to the possible involvement of PSD-95 mediated synaptic function in compartment-specific dopamine signals, we suggest that the striosomes might be more susceptible to D1R-mediated neurotoxicity than the matrix compartment. This notion may provide new insight into the compartment specific vulnerability of MSNs in striatal neurodegeneration. PMID- 26648849 TI - Differential Anatomical Expression of Ganglioside GM1 Species Containing d18:1 or d20:1 Sphingosine Detected by MALDI Imaging Mass Spectrometry in Mature Rat Brain. AB - GM1 ganglioside plays a role in essential neuronal processes, including differentiation, survival, and signaling. Yet, little is known about GM1 species with different sphingosine bases, such as the most abundant species containing 18 carbon atoms in the sphingosine chain (GM1d18:1), and the less abundant containing 20 carbon atoms (GM1d20:1). While absent in the early fetal brain, GM1d20:1 continues to increase throughout pre- and postnatal development and into old age, raising questions about the functional relevance of the GM1d18:1 to GM1d20:1 ratio. Matrix-assisted laser desorption/ionization imaging mass spectrometry is a novel technology that allows differentiation between these two GM1 species and quantification of their expression within an anatomical context. Using this technology, we find GM1d18:1/d20:1 expression ratios are highly specific to defined anatomical brain regions in adult rats. Thus, the ratio was significantly different among different thalamic nuclei and between the corpus callosum and internal capsule. Differential GM1d18:1/GM1d20:1 ratios measured in hippocampal subregions in rat brain complement previous studies conducted in mice. Across layers of the sensory cortex, opposing expression gradients were found for GM1d18:1 and GM1d20:1. Superficial layers demonstrated lower GM1d18:1 and higher GM1d20:1 signal than other layers, while in deep layers GM1d18:1 expression was relatively high and GM1d20:1 expression low. By far the highest GM1d18:1/d20:1 ratio was found in the amygdala. Differential expression of GM1 with d18:1- or d20:1-sphingosine bases in the adult rat brain suggests tight regulation of expression and points toward a distinct functional relevance for each of these GM1 species in neuronal processes. PMID- 26648850 TI - Control Capabilities of Myoelectric Robotic Prostheses by Hand Amputees: A Scientific Research and Market Overview. AB - Hand amputation can dramatically affect the capabilities of a person. Cortical reorganization occurs in the brain, but the motor and somatosensorial cortex can interact with the remnant muscles of the missing hand even many years after the amputation, leading to the possibility to restore the capabilities of hand amputees through myoelectric prostheses. Myoelectric hand prostheses with many degrees of freedom are commercially available and recent advances in rehabilitation robotics suggest that their natural control can be performed in real life. The first commercial products exploiting pattern recognition to recognize the movements have recently been released, however the most common control systems are still usually unnatural and must be learned through long training. Dexterous and naturally controlled robotic prostheses can become reality in the everyday life of amputees but the path still requires many steps. This mini-review aims to improve the situation by giving an overview of the advancements in the commercial and scientific domains in order to outline the current and future chances in this field and to foster the integration between market and scientific research. PMID- 26648851 TI - Effects of Floral Scents and Their Dietary Experiences on the Feeding Preference in the Blowfly, Phormia regina. AB - The flowers of different plant species have diverse scents with varied chemical compositions. Hence, every floral scent does not uniformly affect insect feeding preferences. The blowfly, Phormia regina, is a nectar feeder, and when a fly feeds on flower nectar, its olfactory organs, antennae, and maxillary palps are exposed to the scent. Generally, feeding preference is influenced by food flavor, which relies on both taste and odor. Therefore, the flies perceive the sweet taste of nectar and the particular scent of the flower simultaneously, and this olfactory information affects their feeding preference. Here, we show that the floral scents of 50 plant species have various effects on their sucrose feeding motivation, which was evaluated using the proboscis extension reflex (PER). Those floral scents were first categorized into three groups, based on their effects on the PER threshold sucrose concentration, which indicates whether a fly innately dislikes, ignores, or likes the target scent. Moreover, memory of olfactory experience with those floral scents during sugar feeding influenced the PER threshold. After feeding on sucrose solutions flavored with floral scents for 5 days, the scents did not consistently show the previously observed effects. Considering such empirical effects of scents on the PER threshold, we categorized the effects of the 50 tested floral scents on feeding preference into 16 of all possible 27 theoretical types. We then conducted the same experiments with flies whose antennae or maxillary palps were ablated prior to PER test in a fly group naive to floral scents and prior to the olfactory experience during sugar feeding in the other fly group in order to test how these organs were involved in the effect of the floral scent. The results suggested that olfactory inputs through these organs play different roles in forming or modifying feeding preferences. Thus, our study contributes to an understanding of underlying mechanisms associated with the convergent processing of olfactory inputs with taste information, which affects feeding preference or appetite. PMID- 26648852 TI - Inter-Dependent Mechanisms Behind Cognitive Dysfunction, Vascular Biology and Alzheimer's Dementia in Down Syndrome: Multi-Faceted Roles of APP. AB - People with Down syndrome (DS) virtually all develop intellectual disability (ID) of varying degree of severity, and also have a high risk of early Alzheimer's disease (AD). ID prior to the onset of dementia, and its relationship to the onset of dementia in DS is a complex phenomenon influenced by many factors, and scarcely understood. Unraveling the causative factors and modulators of these processes remains a challenge, with potential to be informative for both ID and AD, for the development of early biomarkers and/or therapeutic approaches. We review the potential relative and inter-connected roles of the chromosome 21 gene for amyloid precursor protein (APP), in both pathological conditions. Rare non-DS people with duplication of APP (dupAPP) get familial early onset AD (FEOAD) with virtually 100% penetrance and prominent cerebrovascular pathology, but don't suffer from ID before dementia onset. All of these features appear to be radically different in DS. On the other hand, rare individuals with partial trisomy 21 (T21) (with APP, but not DS-critical region in trisomy) have been described having ID. Likewise, partial T21 DS (without APP trisomy) show a range of ID, but no AD pathology. We review the multi-faceted roles of APP that might affect cognitive functioning. Given the fact that both Abeta secretion and synaptic maturation/plasticity are dependent on neuronal activity, we explore how this conflicting inter-dependency might affect cognitive pathogenesis in a dynamic way in DS, throughout the lifespan of an individual. PMID- 26648853 TI - Impulsivity is Associated with Increased Metabolism in the Fronto-Insular Network in Parkinson's Disease. AB - Various neuroimaging studies demonstrated that the fronto-insular network is implicated in impulsive behavior. We compared glucose metabolism (as a proxy measure of neural activity) among 24 patients with Parkinson's disease (PD) who presented with low or high levels of impulsivity based on the Barratt Impulsiveness Scale 11 (BIS) scores. Subjects underwent 18-fluorodeoxyglucose positron emission tomography (FDG-PET) and the voxel-wise group difference of FDG metabolism was analyzed in Statistical Parametric Mapping (SPM8). Subsequently, we performed a partial correlation analysis between the FDG-metabolism and BIS scores, controlling for covariates (i.e., age, sex, severity of disease and levodopa equivalent daily doses). Voxel-wise group comparison revealed higher FDG metabolism in the orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), and right insula in patients with higher impulsivity scores. Moreover, there was a positive correlation between the FDG-metabolism and BIS scores. Our findings provide evidence that high impulsivity is associated with increased FDG metabolism within the fronto-insular network in PD. PMID- 26648854 TI - Interaction does Count: A Cross-Fostering Study on Transgenerational Effects of Pre-reproductive Maternal Enrichment. AB - Pre-reproductive environmental enrichment of female rats influences sensorimotor development and spatial behavior of the offspring, possibly through the changed maternal nurturing. Nevertheless, maternal care could be not the solely responsible for changing offspring developmental trajectories. To disentangle the specific contribution to the transgenerational inheritance of pre- and post-natal factors, a cross-fostering study was performed. Female rats were reared in an enriched environment from weaning to sexual maturity, while control female rats were reared under standard conditions. Following mating with standard-reared males, all females were housed individually. Immediately after delivery, in- or cross-fostering manipulations were performed so that any foster dams received pups born to another dam of the same (in-fostering) or the opposite (cross fostering) pre-reproductive rearing condition. In lactating dams maternal care and nesting activities were assessed, while in their male pups spatial abilities were assessed through Morris Water Maze (MWM) test at post-natal day 45. Moreover, the expression of Brain-Derived-Neurotrophic-Factor (BDNF) was evaluated in the hippocampus and frontal cortex of dams and pups at weaning. Pre reproductive maternal environmental enrichment, followed by adoption procedures, loosened its potential in modifying maternal care and offspring developmental trajectories, as indicated by the lack of differences between in-fostered groups of dams and pups. In addition, enriched dams rearing standard pups showed the least complex maternal repertoire (the highest sniffing duration and the lowest nest quality), and their pups showed a reduced spatial learning in the MWM. Nevertheless, pre-reproductive maternal enrichment kept influencing neurotrophic pattern, with enriched dams expressing increased frontal BDNF levels (regardless of the kind of fostered pups), and their offspring expressing increased hippocampal BDNF levels. The present findings enlighten the crucial importance of the early mother-pups interactions in influencing maternal care and offspring phenotype, with the enriched dam-standard pups couple resulting in the most maladaptive encounter. Our study thus sustains that the bidirectional interactions between mother and pups are able to deeply shape offspring phenotype. PMID- 26648855 TI - Neural Substrates of Sexual Desire in Individuals with Problematic Hypersexual Behavior. AB - Studies on the characteristics of individuals with hypersexual disorder have been accumulating due to increasing concerns about problematic hypersexual behavior (PHB). Currently, relatively little is known about the underlying behavioral and neural mechanisms of sexual desire. Our study aimed to investigate the neural correlates of sexual desire with event-related functional magnetic resonance imaging (fMRI). Twenty-three individuals with PHB and 22 age-matched healthy controls were scanned while they passively viewed sexual and nonsexual stimuli. The subjects' levels of sexual desire were assessed in response to each sexual stimulus. Relative to controls, individuals with PHB experienced more frequent and enhanced sexual desire during exposure to sexual stimuli. Greater activation was observed in the caudate nucleus, inferior parietal lobe, dorsal anterior cingulate gyrus, thalamus, and dorsolateral prefrontal cortex in the PHB group than in the control group. In addition, the hemodynamic patterns in the activated areas differed between the groups. Consistent with the findings of brain imaging studies of substance and behavior addiction, individuals with the behavioral characteristics of PHB and enhanced desire exhibited altered activation in the prefrontal cortex and subcortical regions. In conclusion, our results will help to characterize the behaviors and associated neural mechanisms of individuals with PHB. PMID- 26648856 TI - Social Facilitation of Cognition in Rhesus Monkeys: Audience Vs. Coaction. AB - Social psychology has long established that the mere presence of a conspecific, be it an active co-performer (coaction effect), or a passive spectator (audience effect) changes behavior in humans. Yet, the process mediating this fundamental social influence has so far eluded us. Brain research and its nonhuman primate animal model, the rhesus macaque, could shed new light on this long debated issue. For this approach to be fruitful, however, we need to improve our patchy knowledge about social presence influence in rhesus macaques. Here, seven adults (two dyads and one triad) performed a simple cognitive task consisting in touching images to obtain food treats, alone vs. in presence of a co-performer or a spectator. As in humans, audience sufficed to enhance performance to the same magnitude as coaction. Effect sizes were however four times larger than those typically reported in humans in similar tasks. Both findings are an encouragement to pursue brain and behavior research in the rhesus macaque to help solve the riddle of social facilitation mechanisms. PMID- 26648857 TI - The Vulnerability to Suicidal Behavior is Associated with Reduced Connectivity Strength. AB - Suicidal behavior constitutes a major public health problem. Based on the stress diathesis model, biological correlates of a diathesis might help to predict risk after stressor-exposure. Structural changes in cortical and subcortical areas and their connections have increasingly been linked with the diathesis. The current study identified structural network changes associated with a diathesis using a whole-brain approach by examining the structural connectivity between regions in euthymic suicide attempters (SA). In addition, the association between connectivity measures, clinical and genetic characteristics was investigated. We hypothesized that SA showed lower connectivity strength, associated with an increased severity of general clinical characteristics and an elevated expression of short alleles in serotonin polymorphisms. Thirteen euthymic SA were compared with fifteen euthymic non-attempters and seventeen healthy controls (HC). Clinical characteristics and three serotonin-related genetic polymorphisms were assessed. Diffusion MRI together with anatomical scans were administered. Preprocessing was performed using Explore DTI. Whole brain tractography of the diffusion-weighted images was followed by a number of streamlines-weighted network analysis using NBS. The network analysis revealed decreased connectivity strength in SA in the connections between the left olfactory cortex and left anterior cingulate gyrus. Furthermore, SA had increased suicidal ideation, hopelessness and self-reported depression, but did not show any differences for the genetic polymorphisms. Finally, lower connectivity strength between the right calcarine fissure and the left middle occipital gyrus was associated with increased trait anxiety severity (rs = -0.78, p < 0.01) and hopelessness (rs = 0.76, p < 0.01). SA showed differences in white matter network connectivity strength associated with clinical characteristics. Together, these variables could play an important role in predicting suicidal behavior. PMID- 26648858 TI - Independent Component Analysis of Gait-Related Movement Artifact Recorded using EEG Electrodes during Treadmill Walking. AB - There has been a recent surge in the use of electroencephalography (EEG) as a tool for mobile brain imaging due to its portability and fine time resolution. When EEG is combined with independent component analysis (ICA) and source localization techniques, it can model electrocortical activity as arising from temporally independent signals located in spatially distinct cortical areas. However, for mobile tasks, it is not clear how movement artifacts influence ICA and source localization. We devised a novel method to collect pure movement artifact data (devoid of any electrophysiological signals) with a 256-channel EEG system. We first blocked true electrocortical activity using a silicone swim cap. Over the silicone layer, we placed a simulated scalp with electrical properties similar to real human scalp. We collected EEG movement artifact signals from ten healthy, young subjects wearing this setup as they walked on a treadmill at speeds from 0.4-1.6 m/s. We performed ICA and dipole fitting on the EEG movement artifact data to quantify how accurately these methods would identify the artifact signals as non-neural. ICA and dipole fitting accurately localized 99% of the independent components in non-neural locations or lacked dipolar characteristics. The remaining 1% of sources had locations within the brain volume and low residual variances, but had topographical maps, power spectra, time courses, and event related spectral perturbations typical of non-neural sources. Caution should be exercised when interpreting ICA for data that includes semi-periodic artifacts including artifact arising from human walking. Alternative methods are needed for the identification and separation of movement artifact in mobile EEG signals, especially methods that can be performed in real time. Separating true brain signals from motion artifact could clear the way for EEG brain computer interfaces for assistance during mobile activities, such as walking. PMID- 26648859 TI - Induction of Long-term Depression-like Plasticity by Pairings of Motor Imagination and Peripheral Electrical Stimulation. AB - Long-term depression (LTD) and long-term potentiation (LTP)-like plasticity are models of synaptic plasticity which have been associated with memory and learning. The induction of LTD and LTP-like plasticity, using different stimulation protocols, has been proposed as a means of addressing abnormalities in cortical excitability associated with conditions such as focal hand dystonia and stroke. The aim of this study was to investigate whether the excitability of the cortical projections to the tibialis anterior (TA) muscle could be decreased when dorsiflexion of the ankle joint was imagined and paired with peripheral electrical stimulation (ES) of the nerve supplying the antagonist soleus muscle. The effect of stimulus timing was evaluated by comparing paired stimulation timed to reach the cortex before, at and after the onset of imagined movement. Fourteen healthy subjects participated in six experimental sessions held on non consecutive days. The timing of stimulation delivery was determined offline based on the contingent negative variation (CNV) of electroencephalography brain data obtained during imagined dorsiflexion. Afferent stimulation was provided via a single pulse ES to the peripheral nerve paired, based on the CNV, with motor imagination of ankle dorsiflexion. A significant decrease (P = 0.001) in the excitability of the cortical projection of TA was observed when the afferent volley from the ES of the tibial nerve (TN) reached the cortex at the onset of motor imagination based on the CNV. When TN stimulation was delivered before (P = 0.62), or after (P = 0.23) imagined movement onset there was no significant effect. Nor was a significant effect found when ES of the TN was applied independent of imagined movement (P = 0.45). Therefore, the excitability of the cortical projection to a muscle can be inhibited when ES of the nerve supplying the antagonist muscle is precisely paired with the onset of imagined movement. PMID- 26648860 TI - Anticipation of Negative Pictures Enhances the P2 and P3 in Their Later Recognition. AB - Anticipation of emotional pictures has been found to be relevant to the encoding of the pictures as well as their later recognition performance. However, it is as yet unknown whether anticipation modulates neural activity in the later recognition of emotional pictures. To address this issue, participants in the present study were asked to view emotional (negative or neutral) pictures. The picture was preceded by a cue which indicated the emotional content of the picture in half of the trials (the anticipated condition) and without any cues in the other half (the unanticipated condition). Subsequently, participants had to perform an unexpected old/new recognition task in which old and novel pictures were presented without any preceding cues. Electroencephalography data was recorded during the recognition phase. Event-related potential results showed that for negative pictures, P2 and P3 amplitudes were larger in the anticipated as compared to the unanticipated condition; whereas this anticipation effect was not shown for neutral pictures. The present findings suggest that anticipation of negative pictures may enhance neural activity in their later recognition. PMID- 26648861 TI - Effects of Material and Non-Material Rewards on Remembering to Do Things for Others. AB - Recent research has shown that pro-social prospective memory, i.e., remembering to do something for others, is negatively affected by the presence of small material rewards. While this competition between pro-social and self-gain motives leads to poor memory for the intention, people do not seem to be aware of the possible collision effects of competing motives (Brandimonte et al., 2010). Extending research on this general topic, in two activity-based prospective memory (PM) experiments, we explored the effects of different types and amount of rewards on pro-social prospective remembering. In Experiment 1, participants could receive no reward, a low material reward (1 euro), or a high material reward (20 euro) for their pro-social PM action. In Experiment 2, their pro social PM performance could be rewarded or not with an image reward (disclosure of their altruistic behavior). Results revealed that introducing a small material reward (Experiment 1) or a non-material reward (Experiment 2) impaired pro-social PM. However, introducing a high material reward eliminated the impairment (Experiment 1). Importantly, in Experiment 1, ongoing task performance in the pro social condition was faster than in the No PM condition. However, in Experiment 2, ongoing task costs emerged in the presence of a non-material reward, as compared to the pro-social condition. Also, results from two independent ratings showed that people's predictions on their future pro-social actions were at odds (Experiment 1) or in line (Experiment 2) with actual PM performance. It is suggested that, according to the nature and amount of rewards, memory for a pro social future action may be modulated by conscious or unconscious motivational mechanisms. PMID- 26648862 TI - Corrigendum: Training Recollection in Healthy Older Adults: Clear Improvements on the Training Task, but Little Evidence of Transfer. AB - [This corrects the article on p. 898 in vol. 8, PMID: 25477801.]. PMID- 26648863 TI - Effects of Spike Anticipation on the Spiking Dynamics of Neural Networks. AB - Synchronization is one of the central phenomena involved in information processing in living systems. It is known that the nervous system requires the coordinated activity of both local and distant neural populations. Such an interplay allows to merge different information modalities in a whole processing supporting high-level mental skills as understanding, memory, abstraction, etc. Though, the biological processes underlying synchronization in the brain are not fully understood there have been reported a variety of mechanisms supporting different types of synchronization both at theoretical and experimental level. One of the more intriguing of these phenomena is the anticipating synchronization, which has been recently reported in a pair of unidirectionally coupled artificial neurons under simple conditions (Pyragiene and Pyragas, 2013), where the slave neuron is able to anticipate in time the behavior of the master one. In this paper, we explore the effect of spike anticipation over the information processing performed by a neural network at functional and structural level. We show that the introduction of intermediary neurons in the network enhances spike anticipation and analyse how these variations in spike anticipation can significantly change the firing regime of the neural network according to its functional and structural properties. In addition we show that the interspike interval (ISI), one of the main features of the neural response associated with the information coding, can be closely related to spike anticipation by each spike, and how synaptic plasticity can be modulated through that relationship. This study has been performed through numerical simulation of a coupled system of Hindmarsh-Rose neurons. PMID- 26648864 TI - Editorial: Emergent Neural Computation from the Interaction of Different Forms of Plasticity. PMID- 26648865 TI - Age-Related Changes in Predictive Capacity Versus Internal Model Adaptability: Electrophysiological Evidence that Individual Differences Outweigh Effects of Age. AB - Hierarchical predictive coding has been identified as a possible unifying principle of brain function, and recent work in cognitive neuroscience has examined how it may be affected by age-related changes. Using language comprehension as a test case, the present study aimed to dissociate age-related changes in prediction generation versus internal model adaptation following a prediction error. Event-related brain potentials (ERPs) were measured in a group of older adults (60-81 years; n = 40) as they read sentences of the form "The opposite of black is white/yellow/nice." Replicating previous work in young adults, results showed a target-related P300 for the expected antonym ("white"; an effect assumed to reflect a prediction match), and a graded N400 effect for the two incongruous conditions (i.e. a larger N400 amplitude for the incongruous continuation not related to the expected antonym, "nice," versus the incongruous associated condition, "yellow"). These effects were followed by a late positivity, again with a larger amplitude in the incongruous non-associated versus incongruous associated condition. Analyses using linear mixed-effects models showed that the target-related P300 effect and the N400 effect for the incongruous non-associated condition were both modulated by age, thus suggesting that age-related changes affect both prediction generation and model adaptation. However, effects of age were outweighed by the interindividual variability of ERP responses, as reflected in the high proportion of variance captured by the inclusion of by-condition random slopes for participants and items. We thus argue that - at both a neurophysiological and a functional level - the notion of general differences between language processing in young and older adults may only be of limited use, and that future research should seek to better understand the causes of interindividual variability in the ERP responses of older adults and its relation to cognitive performance. PMID- 26648866 TI - Cerebral Amyloid and Hypertension are Independently Associated with White Matter Lesions in Elderly. AB - In cognitively normal (CN) elderly individuals, white matter hyperintensities (WMH) are commonly viewed as a marker of cerebral small vessel disease (SVD). SVD is due to exposure to systemic vascular injury processes associated with highly prevalent vascular risk factors (VRFs) such as hypertension, high cholesterol, and diabetes. However, cerebral amyloid accumulation is also prevalent in this population and is associated with WMH accrual. Therefore, we examined the independent associations of amyloid burden and VRFs with WMH burden in CN elderly individuals with low to moderate vascular risk. Participants (n = 150) in the Alzheimer's Disease Neuroimaging Initiative (ADNI) received fluid attenuated inversion recovery (FLAIR) MRI at study entry. Total WMH volume was calculated from FLAIR images co-registered with structural MRI. Amyloid burden was determined by cerebrospinal fluid Abeta1-42 levels. Clinical histories of VRFs, as well as current measurements of vascular status, were recorded during a baseline clinical evaluation. We tested ridge regression models for independent associations and interactions of elevated blood pressure (BP) and amyloid to total WMH volume. We found that greater amyloid burden and a clinical history of hypertension were independently associated with greater WMH volume. In addition, elevated BP modified the association between amyloid and WMH, such that those with either current or past evidence of elevated BP had greater WMH volumes at a given burden of amyloid. These findings are consistent with the hypothesis that cerebral amyloid accumulation and VRFs are independently associated with clinically latent white matter damage represented by WMHs. The potential contribution of amyloid to WMHs should be further explored, even among elderly individuals without cognitive impairment and with limited VRF exposure. PMID- 26648867 TI - Age-Specific Effects of Mirror-Muscle Activity on Cross-Limb Adaptations Under Mirror and Non-Mirror Visual Feedback Conditions. AB - Cross-limb transfer (CLT) describes the observation of bilateral performance gains due to unilateral motor practice. Previous research has suggested that CLT may be reduced, or absent, in older adults, possibly due to age-related structural and functional brain changes. Based on research showing increases in CLT due to the provision of mirror visual feedback (MVF) during task execution in young adults, our study aimed to investigate whether MVF can facilitate CLT in older adults, who are known to be more reliant on visual feedback for accurate motor performance. Participants (N = 53) engaged in a short-term training regime (300 movements) involving a ballistic finger task using their dominant hand, while being provided with either visual feedback of their active limb, or a mirror reflection of their active limb (superimposed over the quiescent limb). Performance in both limbs was examined before, during and following the unilateral training. Furthermore, we measured corticospinal excitability (using TMS) at these time points, and assessed muscle activity bilaterally during the task via EMG; these parameters were used to investigate the mechanisms mediating and predicting CLT. Training resulted in significant bilateral performance gains that did not differ as a result of age or visual feedback (both p > 0.1). Training also elicited bilateral increases in corticospinal excitability (p < 0.05). For younger adults, CLT was significantly predicted by performance gains in the trained hand (beta = 0.47), whereas for older adults it was significantly predicted by mirror activity in the untrained hand during training (beta = 0.60). The present study suggests that older adults are capable of exhibiting CLT to a similar degree to younger adults. The prominent role of mirror activity in the untrained hand for CLT in older adults indicates that bilateral cortical activity during unilateral motor tasks is a compensatory mechanism. In this particular task, MVF did not facilitate the extent of CLT. PMID- 26648868 TI - Age-Related Inter-Region EEG Coupling Changes During the Control of Bottom-Up and Top-Down Attention. AB - We investigated age-related changes in electroencephalographic (EEG) coupling of theta-, alpha-, and beta-frequency bands during bottom-up and top-down attention. Arrays were presented with either automatic "pop-out" (bottom-up) or effortful "search" (top-down) behavior to younger and older participants. The phase-locking value was used to estimate coupling strength between scalp recordings. Behavioral performance decreased with age, with a greater age-related decline in accuracy for the search than for the pop-out condition. Aging was associated with a declined coupling strength of theta and alpha frequency bands, with a greater age related decline in whole-brain coupling values for the search than for the pop out condition. Specifically, prefronto-frontal coupling in theta- and alpha bands, fronto-parietal and parieto-occipital couplings in beta-band for younger group showed a right hemispheric dominance, which was reduced with aging to compensate for the inhibitory dysfunction. While pop-out target detection was mainly associated with greater parieto-occipital beta-coupling strength compared to search condition regardless of aging. Furthermore, prefronto-frontal coupling in theta-, alpha-, and beta-bands, and parieto-occipital coupling in beta-band functioned as predictors of behavior for both groups. Taken together these findings provide evidence that prefronto-frontal coupling of theta-, alpha-, and beta-bands may serve as a possible basis of aging during visual attention, while parieto-occipital coupling in beta-band could serve for a bottom-up function and be vulnerable to top-down attention control for younger and older groups. PMID- 26648869 TI - Corrigendum: Salvinorin A, a kappa-opioid receptor agonist hallucinogen: pharmacology and potential template for novel pharmacotherapeutic agents in neuropsychiatric disorders. AB - [This corrects the article on p. 190 in vol. 6, PMID: 26441647.]. PMID- 26648870 TI - Advances and Challenges of Liposome Assisted Drug Delivery. AB - The application of liposomes to assist drug delivery has already had a major impact on many biomedical areas. They have been shown to be beneficial for stabilizing therapeutic compounds, overcoming obstacles to cellular and tissue uptake, and improving biodistribution of compounds to target sites in vivo. This enables effective delivery of encapsulated compounds to target sites while minimizing systemic toxicity. Liposomes present as an attractive delivery system due to their flexible physicochemical and biophysical properties, which allow easy manipulation to address different delivery considerations. Despite considerable research in the last 50 years and the plethora of positive results in preclinical studies, the clinical translation of liposome assisted drug delivery platforms has progressed incrementally. In this review, we will discuss the advances in liposome assisted drug delivery, biological challenges that still remain, and current clinical and experimental use of liposomes for biomedical applications. The translational obstacles of liposomal technology will also be presented. PMID- 26648872 TI - The Role of MicroRNAs in the Regulation of K(+) Channels in Epithelial Tissue. AB - Our understanding of the modulation of proteins has shifted in direction with the discovery of microRNAs (miRs) over twenty years ago. MiRs are now in the "limelight" as these non-coding pieces of RNA (generally ~22 nucleotides long) result in altered translation and function of proteins. Indeed, miRs are now reported to be potential biomarkers of disease. Epithelial K(+) channels play many roles in electrolyte and fluid homeostasis of the human body and have been suggested to be therapeutic targets of disease. Interestingly, the role of miRs in modulating K(+) channels of epithelial tissues is only emerging now. This minireview focuses on recent novel findings into the role of miRs in the regulation of K(+) channels of epithelia. PMID- 26648871 TI - Neuron-Glia Crosstalk in the Autonomic Nervous System and Its Possible Role in the Progression of Metabolic Syndrome: A New Hypothesis. AB - Metabolic syndrome (MS) is characterized by the following physiological alterations: increase in abdominal fat, insulin resistance, high concentration of triglycerides, low levels of HDL, high blood pressure, and a generalized inflammatory state. One of the pathophysiological hallmarks of this syndrome is the presence of neurohumoral activation, which involve autonomic imbalance associated to hyperactivation of the sympathetic nervous system. Indeed, enhanced sympathetic drive has been linked to the development of endothelial dysfunction, hypertension, stroke, myocardial infarct, and obstructive sleep apnea. Glial cells, the most abundant cells in the central nervous system, control synaptic transmission, and regulate neuronal function by releasing bioactive molecules called gliotransmitters. Recently, a new family of plasma membrane channels called hemichannels has been described to allow the release of gliotransmitters and modulate neuronal firing rate. Moreover, a growing amount of evidence indicates that uncontrolled hemichannel opening could impair glial cell functions, affecting synaptic transmission and neuronal survival. Given that glial cell functions are disturbed in various metabolic diseases, we hypothesize that progression of MS may relies on hemichannel-dependent impairment of glial-to neuron communication by a mechanism related to dysfunction of inflammatory response and mitochondrial metabolism of glial cells. In this manuscript, we discuss how glial cells may contribute to the enhanced sympathetic drive observed in MS, and shed light about the possible role of hemichannels in this process. PMID- 26648874 TI - Changes in Membrane Receptors and Ion Channels as Potential Biomarkers for Osteoarthritis. AB - Osteoarthritis (OA), a degenerative joint condition, is currently difficult to detect early enough for any of the current treatment options to be completely successful. Early diagnosis of this disease could increase the numbers of patients who are able to slow its progression. There are now several diseases where membrane protein biomarkers are used for early diagnosis. The numbers of proteins in the membrane is vast and so it is a rich source of potential biomarkers for OA but we need more knowledge of these before they can be considered practical biomarkers. How are they best measured and are they selective to OA or even certain types of OA? The first step in this process is to identify membrane proteins that change in OA. Here, we summarize several ion channels and receptors that change in OA models and/or OA patients, and may thus be considered candidates as novel membrane biomarkers of OA. PMID- 26648873 TI - Structure and Function of SLC4 Family [Formula: see text] Transporters. AB - The solute carrier SLC4 family consists of 10 members, nine of which are [Formula: see text] transporters, including three Na(+)-independent Cl( )/[Formula: see text] exchangers AE1, AE2, and AE3, five Na(+)-coupled [Formula: see text] transporters NBCe1, NBCe2, NBCn1, NBCn2, and NDCBE, as well as "AE4" whose Na(+)-dependence remains controversial. The SLC4 [Formula: see text] transporters play critical roles in pH regulation and transepithelial movement of electrolytes with a broad range of demonstrated physiological relevances. Dysfunctions of these transporters are associated with a series of human diseases. During the past decades, tremendous amount of effort has been undertaken to investigate the topological organization of the SLC4 transporters in the plasma membrane. Based upon the proposed topology models, mutational and functional studies have identified important structural elements likely involved in the ion translocation by the SLC4 transporters. In the present article, we review the advances during the past decades in understanding the structure and function of the SLC4 transporters. PMID- 26648875 TI - Interactions Between Dyspnea and the Brain Processing of Nociceptive Stimuli: Experimental Air Hunger Attenuates Laser-Evoked Brain Potentials in Humans. AB - Dyspnea and pain share several characteristics and certain neural networks and interact with each other. Dyspnea-pain counter-irritation consists of attenuation of preexisting pain by intercurrent dyspnea and has been shown to have neurophysiological correlates in the form of inhibition of the nociceptive spinal reflex RIII and laser-evoked potentials (LEPs). Experimentally induced exertional dyspnea inhibits RIII and LEPs, while "air hunger" dyspnea does not inhibit RIII despite its documented analgesic effects. We hypothesized that air hunger may act centrally and inhibit LEPs. LEPs were obtained in 12 healthy volunteers (age: 21 29) during spontaneous breathing (FB), ventilator-controlled breathing (VC) tailored to FB, after inducing air hunger by increasing the inspired fraction of carbon dioxide -FiCO2- (VCCO2), and during ventilator-controlled breathing recovery (VCR). VCCO2 induced intense dyspnea (visual analog scale = 63% +/- 6% of full scale, p < 0.001 vs. VC), predominantly of the air hunger type. VC alone reduced the amplitude of the N2-P2 component of LEPs (Delta = 24.0% +/- 21.1%, p < 0.05, effect-size = 0.74) predominantly through a reduction in P2, and the amplitude of this inhibition was further reduced by inducting air hunger (Delta = 22.6% +/- 17.9%, p < 0.05, effect-size = 0.53), predominantly through a reduction in N2. Somatosensory-evoked potentials (SEPs) were not affected by VC or VCCO2, suggesting that the observed effects are specific to pain transmission. We conclude that air hunger interferes with the cortical mechanisms responsible for the cortical response to painful laser skin stimulation, which provides a neurophysiological substrate to the central nature of its otherwise documented analgesic effects. PMID- 26648876 TI - Endocrine and Cognitive Adaptations to Cope with Stress in Immature Common Marmosets (Callithrix jacchus): Sex and Age Matter. AB - Phenotypic sex differences in primates are associated with body differentiation during the early stages of life, expressed in both physiological and behavioral features. Hormones seem to play a pivotal role in creating a range of responses to meet environmental and social demands, resulting in better reactions to cope with challenges to survival and reproduction. Steroid hormones actively participate in neuroplasticity and steroids from both gonads and neurons seem to be involved in behavioral modulation in primates. Indirect evidence suggests the participation of sexual steroids in dimorphism of the stress response in common marmosets. This species is an important experimental model in psychiatry, and we found a dual profile for cortisol in the transition from juvenile to subadult, with females showing higher levels. Immature males and females at 6 and 9 months of age moved alone from the family group to a new cage, over a 21-day period, expressed distinct patterns of cortisol variation with respect to range and duration of response. Additional evidence showed that at 12 months of age, males and females buffered the hypothalamic-pituitary-adrenal axis during chronic stress. Moreover, chronic stressed juvenile marmoset males showed better cognitive performance in working memory tests and motivation when compared to those submitted to short-term stress living in family groups. Thus, as cortisol profile seems to be sexually dimorphic before adulthood, age and sex are critical variables to consider in approaches that require immature marmosets in their experimental protocols. Moreover, available cognitive tests should be scrutinized to allow better investigation of cognitive traits in this species. PMID- 26648877 TI - From Theory to PrACTice: A Cognitive Remediation Program Based on a Neuropsychological Model of Schizophrenia. AB - Cognitive dysfunction is one of the hallmark deficits of schizophrenia. A wide range of studies illustrate how it is strongly interconnected to clinical presentation and daily life functioning [see Ref. (1, 2)]. Hence, cognition is an important treatment target in schizophrenia. To address the challenge of cognitive enhancement in schizophrenia, a large number of cognitive remediation programs have been developed and evaluated over the past several decades. First, an overview of these programs is presented highlighting their specificity to cognitive deficit in schizophrenia using an integrated method. In this case, cognitive training focuses on enhancing several elementary cognitive functions considered as a prerequisite to social skills or vocational training modules. These programs are based on the neurodevelopmental hypothesis of schizophrenia. However, moderate improvement for patients who benefit from these therapies has been observed as described in Wykes et al. review (3). Next, neuropsychological models of schizophrenia are then presented. They highlight the critical role of the internally generated intentions in appropriate willful actions. The cognitive control mechanism deals with this ability. Interestingly, available cognitive remediation programs have not been influenced by these models. Hence, we propose another alternative to set up a specific cognitive remediation program for schizophrenia patients by targeting the cognitive control mechanism. We describe the PrACTice program that is in the process of being validated. PMID- 26648878 TI - The Role of Environmental Factors on Sleep Patterns and School Performance in Adolescents. AB - BACKGROUND: Modern life, with its many distractions, is seeing sleep quantity and quality decline during adolescence. This is a concern as research persuasively demonstrates the negative impact of reduced sleep on academic achievement, both in terms of learning and behavior. AIMS: This study examined the relationship between sleep and school functioning in adolescence, with a focus on environmental factors that might mediate this relationship. SAMPLE AND METHOD: Forty-seven adolescents took part. Sleep was measured using the School Sleep Habits Survey (SSHS) and a sleep diary. School records of year grade point averages provided a measure of academic achievement. Raven's Standard Progressive Matrices gave a measure of general cognitive processing. Environmental sleep factors falling into three groups, namely, stimulant consumption, media use and exercise, were measured using a self-report questionnaire. RESULTS: An average of 7.08 h of sleep was reported. Correlations revealed that Total sleep time (TST) and bedtimes on weekdays were strongly associated with academic achievement. Morning/eveningness and sleep/wake behavior problems had a strong relationship with performance on the Ravens. Stimulant consumption and media use before bed revealed strong relationships with TST and bedtimes on weekdays. Crucially, mediation analyses confirmed that both caffeine consumption and electronic media use before bedtime were negatively associated with academic performance, via the mediating pathway by affecting sleep. Exercise was not associated with any of the sleep variables, but was associated with better academic performance. CONCLUSION: The current findings highlight that, now more than ever, parents, schools and policy makers must be aware of the negative effects of caffeinated substances marketed to students, and electronic media use on their sleep habits. Our findings suggest that targeting caffeine consumption and electronic media use before bed may represent effective routes in alleviating modern teenage sleep debt, and in turn enhancing academic performance. PMID- 26648879 TI - A Note on the Eigensystem of the Covariance Matrix of Dichotomous Guttman Items. AB - We consider the covariance matrix for dichotomous Guttman items under a set of uniformity conditions, and obtain closed-form expressions for the eigenvalues and eigenvectors of the matrix. In particular, we describe the eigenvalues and eigenvectors of the matrix in terms of trigonometric functions of the number of items. Our results parallel those of Zwick (1987) for the correlation matrix under the same uniformity conditions. We provide an explanation for certain properties of principal components under Guttman scalability which have been first reported by Guttman (1950). PMID- 26648881 TI - Thinking Outside the Box: Developing Dynamic Data Visualizations for Psychology with Shiny. AB - The study of human perception has helped psychologists effectively communicate data rich stories by converting numbers into graphical illustrations and data visualization remains a powerful means for psychology to discover, understand, and present results to others. However, despite an exponential rise in computing power, the World Wide Web, and ever more complex data sets, psychologists often limit themselves to static visualizations. While these are often adequate, their application across professional psychology remains limited. This is surprising as it is now possible to build dynamic representations based around simple or complex psychological data sets. Previously, knowledge of HTML, CSS, or Java was essential, but here we develop several interactive visualizations using a simple web application framework that runs under the R statistical platform: Shiny. Shiny can help researchers quickly produce interactive data visualizations that will supplement and support current and future publications. This has clear benefits for researchers, the wider academic community, students, practitioners, and interested members of the public. PMID- 26648880 TI - Does Music Training Enhance Literacy Skills? A Meta-Analysis. AB - Children's engagement in music practice is associated with enhancements in literacy-related language skills, as demonstrated by multiple reports of correlation across these two domains. Training studies have tested whether engaging in music training directly transfers benefit to children's literacy skill development. Results of such studies, however, are mixed. Interpretation of these mixed results is made more complex by the fact that a wide range of literacy-related outcome measures are used across these studies. Here, we address these challenges via a meta-analytic approach. A comprehensive literature review of peer-reviewed music training studies was built around key criteria needed to test the direct transfer hypothesis, including: (a) inclusion of music training vs. control groups; (b) inclusion of pre- vs. post-comparison measures, and (c) indication that reading instruction was held constant across groups. Thirteen studies were identified (n = 901). Two classes of outcome measures emerged with sufficient overlap to support meta-analysis: phonological awareness and reading fluency. Hours of training, age, and type of control intervention were examined as potential moderators. Results supported the hypothesis that music training leads to gains in phonological awareness skills. The effect isolated by contrasting gains in music training vs. gains in control was small relative to the large variance in these skills (d = 0.2). Interestingly, analyses revealed that transfer effects for rhyming skills tended to grow stronger with increased hours of training. In contrast, no significant aggregate transfer effect emerged for reading fluency measures, despite some studies reporting large training effects. The potential influence of other study design factors were considered, including intervention design, IQ, and SES. Results are discussed in the context of emerging findings that music training may enhance literacy development via changes in brain mechanisms that support both music and language cognition. PMID- 26648882 TI - Social Identities as Pathways into and out of Addiction. AB - There exists a predominant identity loss and "redemption" narrative in the addiction literature describing how individuals move from a "substance user" identity to a "recovery" identity. However, other identity related pathways influencing onset, treatment seeking and recovery may exist, and the process through which social identities unrelated to substance use change over time is not well understood. This study was designed to provide a richer understanding of such social identities processes. Semi-structured interviews were conducted with 21 adults residing in a drug and alcohol therapeutic community (TC) and thematic analysis revealed two distinct identity-related pathways leading into and out of addiction. Some individuals experienced a loss of valued identities during addiction onset that were later renewed during recovery (consistent with the existing redemption narrative). However, a distinct identity gain pathway emerged for socially isolated individuals, who described the onset of their addiction in terms of a new valued social identity. Almost all participants described their TC experience in terms of belonging to a recovery community. Participants on the identity loss pathway aimed to renew their pre-addiction identities after treatment while those on the identity gain pathway aimed to build aspirational new identities involving study, work, or family roles. These findings help to explain how social factors are implicated in the course of addiction, and may act as either motivations for or barriers to recovery. The qualitative analysis yielded a testable model for future research in other samples and settings. PMID- 26648883 TI - Punctuation, Prosody, and Discourse: Afterthought Vs. Right Dislocation. AB - In a reading production experiment we investigate the impact of punctuation and discourse structure on the prosodic differentiation of right dislocation (RD) and afterthought (AT). Both discourse structure and punctuation are likely to affect the prosodic marking of these right-peripheral constructions, as certain prosodic markings are appropriate only in certain discourse structures, and punctuation is said to correlate with prosodic phrasing. With RD and AT clearly differing in discourse function (comment-topic structuring vs. disambiguation) and punctuation (comma vs. full stop), critical items in this study were manipulated with regard to the (mis-)match of these parameters. Since RD and AT are said to prosodically differ in pitch range, phrasing, and accentuation patterns, we measured the reduction of pitch range, boundary strength and prominence level. Results show an effect of both punctuation and discourse context (mediated by syntax) on phrasing and accentuation. Interestingly, for pitch range reduction no difference between RDs and ATs could be observed. Our results corroborate a language architecture model in which punctuation, prosody, syntax, and discourse-semantics are independent but interacting domains with correspondence constraints between them. Our findings suggest there are tight correspondence constraints between (i) punctuation (full stop and comma in particular) and syntax, (ii) prosody and syntax as well as (iii) prosody and discourse-semantics. PMID- 26648884 TI - Interacting Effects of Instructions and Presentation Rate on Visual Statistical Learning. AB - The statistical regularities of a sequence of visual shapes can be learned incidentally. Arciuli et al. (2014) recently argued that intentional instructions only improve learning at slow presentation rates as they favor the use of explicit strategies. The aim of the present study was (1) to test this assumption directly by investigating how instructions (incidental vs. intentional) and presentation rate (fast vs. slow) affect the acquisition of knowledge and (2) to examine how these factors influence the conscious vs. unconscious nature of the knowledge acquired. To this aim, we exposed participants to four triplets of shapes, presented sequentially in a pseudo-random order, and assessed their degree of learning in a subsequent completion task that integrated confidence judgments. Supporting Arciuli et al.'s (2014) claim, participant performance only benefited from intentional instructions at slow presentation rates. Moreover, informing participants beforehand about the existence of statistical regularities increased their explicit knowledge of the sequences, an effect that was not modulated by presentation speed. These results support that, although visual statistical learning can take place incidentally and, to some extent, outside conscious awareness, factors such as presentation rate and prior knowledge can boost learning of these regularities, presumably by favoring the acquisition of explicit knowledge. PMID- 26648885 TI - Are Happy Faces Attractive? The Roles of Early vs. Late Processing. AB - Facial attractiveness is closely related to romantic love. To understand if the neural underpinnings of perceived facial attractiveness and facial expression are similar constructs, we recorded neural signals using an event-related potential (ERP) methodology for 20 participants who were viewing faces with varied attractiveness and expressions. We found that attractiveness and expression were reflected by two early components, P2-lateral (P2l) and P2-medial (P2m), respectively; their interaction effect was reflected by LPP, a late component. The findings suggested that facial attractiveness and expression are first processed in parallel for discrimination between stimuli. After the initial processing, more attentional resources are allocated to the faces with the most positive or most negative valence in both the attractiveness and expression dimensions. The findings contribute to the theoretical model of face perception. PMID- 26648886 TI - The Standardization of Linear and Nonlinear Effects in Direct and Indirect Applications of Structural Equation Mixture Models for Normal and Nonnormal Data. AB - The application of mixture models to flexibly estimate linear and nonlinear effects in the SEM framework has received increasing attention (e.g., Jedidi et al., 1997b; Bauer, 2005; Muthen and Asparouhov, 2009; Wall et al., 2012; Kelava and Brandt, 2014; Muthen and Asparouhov, 2014). The advantage of mixture models is that unobserved subgroups with class-specific relationships can be extracted (direct application), or that the mixtures can be used as a statistical tool to approximate nonnormal (latent) distributions (indirect application). Here, we provide a general standardization procedure for linear and nonlinear interaction and quadratic effects in mixture models. The procedure can also be applied to multiple group models or to single class models with nonlinear effects like LMS (Klein and Moosbrugger, 2000). We show that it is necessary to take nonnormality of the data into account for a correct standardization. We present an empirical example from education science applying the proposed procedure. PMID- 26648887 TI - Accuracy of Outcome Anticipation, But Not Gaze Behavior, Differs Against Left- and Right-Handed Penalties in Team-Handball Goalkeeping. AB - Low perceptual familiarity with relatively rarer left-handed as opposed to more common right-handed individuals may result in athletes' poorer ability to anticipate the former's action intentions. Part of such left-right asymmetry in visual anticipation could be due to an inefficient gaze strategy during confrontation with left-handed individuals. To exemplify, observers may not mirror their gaze when viewing left- vs. right-handed actions but preferentially fixate on an opponent's right body side, irrespective of an opponent's handedness, owing to the predominant exposure to right-handed actions. So far empirical verification of such assumption, however, is lacking. Here we report on an experiment where team-handball goalkeepers' and non-goalkeepers' gaze behavior was recorded while they predicted throw direction of left- and right-handed 7-m penalties shown as videos on a computer monitor. As expected, goalkeepers were considerably more accurate than non-goalkeepers and prediction was better against right- than left-handed penalties. However, there was no indication of differences in gaze measures (i.e., number of fixations, overall and final fixation duration, time-course of horizontal or vertical fixation deviation) as a function of skill group or the penalty-takers' handedness. Findings suggest that inferior anticipation of left-handed compared to right-handed individuals' action intentions may not be associated with misalignment in gaze behavior. Rather, albeit looking similarly, accuracy differences could be due to observers' differential ability of picking up and interpreting the visual information provided by left- vs. right-handed movements. PMID- 26648888 TI - Sensitivity of Physiological Emotional Measures to Odors Depends on the Product and the Pleasantness Ranges Used. AB - Emotions are characterized by synchronized changes in several components of an organism. Among them, physiological variations provide energy support for the expression of approach/avoid action tendencies induced by relevant stimuli, while self-reported subjective pleasantness feelings integrate all other emotional components and are plastic. Consequently, emotional responses evoked by odors should be highly differentiated when they are linked to different functions of olfaction (e.g., avoiding environmental hazards). As this differentiation has been observed for contrasted odors (very pleasant or unpleasant), we questioned whether subjective and physiological emotional response indicators could still disentangle subtle affective variations when no clear functional distinction is made (mildly pleasant or unpleasant fragrances). Here, we compared the sensitivity of behavioral and physiological [respiration, skin conductance, facial electromyography (EMG), and heart rate] indicators in differentiating odor elicited emotions in two situations: when a wide range of odor families was presented (e.g., fruity, animal), covering different functional meanings; or in response to a restricted range of products in one particular family (fragrances). Results show clear differences in physiological indicators to odors that display a wide range of reported pleasantness, but these differences almost entirely vanish when fragrances are used even though their subjective pleasantness still differed. Taken together, these results provide valuable information concerning the ability of classic verbal and psychophysiological measures to investigate subtle differences in emotional reactions to a restricted range of similar olfactory stimuli. PMID- 26648889 TI - The Effect of Affective Context on Visuocortical Processing of Neutral Faces in Social Anxiety. AB - It has been demonstrated that verbal context information alters the neural processing of ambiguous faces such as faces with no apparent facial expression. In social anxiety, neutral faces may be implicitly threatening for socially anxious individuals due to their ambiguous nature, but even more so if these neutral faces are put in self-referential negative contexts. Therefore, we measured event-related brain potentials (ERPs) in response to neutral faces which were preceded by affective verbal information (negative, neutral, positive). Participants with low social anxiety (LSA; n = 23) and high social anxiety (HSA; n = 21) were asked to watch and rate valence and arousal of the respective faces while continuous EEG was recorded. ERP analysis revealed that HSA showed elevated P100 amplitudes in response to faces, but reduced structural encoding of faces as indexed by reduced N170 amplitudes. In general, affective context led to an enhanced early posterior negativity (EPN) for negative compared to neutral facial expressions. Moreover, HSA compared to LSA showed enhanced late positive potentials (LPP) to negatively contextualized faces, whereas in LSA this effect was found for faces in positive contexts. Also, HSA rated faces in negative contexts as more negative compared to LSA. These results point at enhanced vigilance for neutral faces regardless of context in HSA, while structural encoding seems to be diminished (avoidance). Interestingly, later components of sustained processing (LPP) indicate that LSA show enhanced visuocortical processing for faces in positive contexts (happy bias), whereas this seems to be the case for negatively contextualized faces in HSA (threat bias). Finally, our results add further new evidence that top-down information in interaction with individual anxiety levels can influence early-stage aspects of visual perception. PMID- 26648890 TI - Absence of Sex-Contingent Gaze Direction Aftereffects Suggests a Limit to Contingencies in Face Aftereffects. AB - Face aftereffects (e.g., expression aftereffects) can be simultaneously induced in opposite directions for different face categories (e.g., male and female faces). Such aftereffects are typically interpreted as indicating that distinct neural populations code the categories on which adaptation is contingent, e.g., male and female faces. Moreover, they suggest that these distinct populations selectively respond to variations in the secondary stimulus dimension, e.g., emotional expression. However, contingent aftereffects have now been reported for so many different combinations of face characteristics, that one might question this interpretation. Instead, the selectivity might be generated during the adaptation procedure, for instance as a result of associative learning, and not indicate pre-existing response selectivity in the face perception system. To alleviate this concern, one would need to demonstrate some limit to contingent aftereffects. Here, we report a clear limit, showing that gaze direction aftereffects are not contingent on face sex. We tested 36 young Caucasian adults in a gaze adaptation paradigm. We initially established their ability to discriminate the gaze direction of male and female test faces in a pre-adaptation phase. Afterwards, half of the participants adapted to female faces looking left and male faces looking right, and half adapted to the reverse pairing. We established the effects of this adaptation on the perception of gaze direction in subsequently presented male and female test faces. We found that adaptation induced pronounced gaze direction aftereffects, i.e., participants were biased to perceive small gaze deviations to both the left and right as direct. Importantly, however, aftereffects were identical for male and female test faces, showing that the contingency of face sex and gaze direction participants experienced during the adaptation procedure had no effect. PMID- 26648892 TI - The Clinical Assessment in the Legal Field: An Empirical Study of Bias and Limitations in Forensic Expertise. AB - According to the literature, psychological assessment in forensic contexts is one of the most controversial application areas for clinical psychology. This paper presents a review of systematic judgment errors in the forensic field. Forty-six psychological reports written by psychologists, court consultants, have been analyzed with content analysis to identify typical judgment errors related to the following areas: (a) distortions in the attribution of causality, (b) inferential errors, and (c) epistemological inconsistencies. Results indicated that systematic errors of judgment, usually referred also as "the man in the street," are widely present in the forensic evaluations of specialist consultants. Clinical and practical implications are taken into account. This article could lead to significant benefits for clinical psychologists who want to deal with this sensitive issue and are interested in improving the quality of their contribution to the justice system. PMID- 26648891 TI - Odor Perception in Children with Autism Spectrum Disorder and its Relationship to Food Neophobia. AB - Atypical sensory functioning in Autism Spectrum Disorder (ASD) has been well documented in the last decade for the visual, tactile and auditory systems, but olfaction in ASD is still understudied. The aim of the present study was to examine whether children with ASD and neuro-typically (NT) developed children differed in odor perception, at the cognitive (familiarity and identification ability), sensorimotor (olfactory exploration) and affective levels (hedonic evaluation). Because an important function of the sense of smell is its involvement in eating, from food selection to appreciation and recognition, a potential link between odor perception and food neophobia was also investigated. To these ends, 10 children between 6 and 13 years old diagnosed with ASD and 10 NT control children were tested. To compare performance, 16 stimuli were used and food neophobia was assessed by the parents on a short food neophobia scale. Results revealed that (i) significant hedonic discrimination between attractive and aversive odors was observed in NT (p = 0.005; d = 2.378) and ASD children (p = 0.042; d = 0.941), and (ii) hedonic discrimination level was negatively correlated with food neophobia scores in ASD (p = 0.007) but not NT children. In conclusion, this study offers new insights into odor perception in ASD children, highlighting a relationship between odor hedonic reactivity and eating behavior. This opens up new perspectives on both (i) the role of olfaction in the construction of eating behavior in ASD children, and (ii) the measurement and meaning of food neophobia in this population. PMID- 26648893 TI - Math Anxiety Assessment with the Abbreviated Math Anxiety Scale: Applicability and Usefulness: Insights from the Polish Adaptation. AB - Math anxiety has an important impact on mathematical development and performance. However, although math anxiety is supposed to be a transcultural trait, assessment instruments are scarce and are validated mainly for Western cultures so far. Therefore, we aimed at examining the transcultural generality of math anxiety by a thorough investigation of the validity of math anxiety assessment in Eastern Europe. We investigated the validity and reliability of a Polish adaptation of the Abbreviated Math Anxiety Scale (AMAS), known to have very good psychometric characteristics in its original, American-English version as well as in its Italian and Iranian adaptations. We also observed high reliability, both for internal consistency and test-retest stability of the AMAS in the Polish sample. The results also show very good construct, convergent and discriminant validity: The factorial structure in Polish adult participants (n = 857) was very similar to the one previously found in other samples; AMAS scores correlated moderately in expected directions with state and trait anxiety, self-assessed math achievement and skill as well temperamental traits of emotional reactivity, briskness, endurance, and perseverance. Average scores obtained by participants as well as gender differences and correlations with external measures were also similar across cultures. Beyond the cultural comparison, we used path model analyses to show that math anxiety relates to math grades and self-competence when controlling for trait anxiety. The current study shows transcultural validity of math anxiety assessment with the AMAS. PMID- 26648894 TI - Perceptual Training in Beach Volleyball Defence: Different Effects of Gaze-Path Cueing on Gaze and Decision-Making. AB - For perceptual-cognitive skill training, a variety of intervention methods has been proposed, including the so-called "color-cueing method" which aims on superior gaze-path learning by applying visual markers. However, recent findings challenge this method, especially, with regards to its actual effects on gaze behavior. Consequently, after a preparatory study on the identification of appropriate visual cues for life-size displays, a perceptual-training experiment on decision-making in beach volleyball was conducted, contrasting two cueing interventions (functional vs. dysfunctional gaze path) with a conservative control condition (anticipation-related instructions). Gaze analyses revealed learning effects for the dysfunctional group only. Regarding decision-making, all groups showed enhanced performance with largest improvements for the control group followed by the functional and the dysfunctional group. Hence, the results confirm cueing effects on gaze behavior, but they also question its benefit for enhancing decision-making. However, before completely denying the method's value, optimisations should be checked regarding, for instance, cueing-pattern characteristics and gaze-related feedback. PMID- 26648895 TI - Egocentric Direction and Position Perceptions are Dissociable Based on Only Static Lane Edge Information. AB - When observers perceive several objects in a space, at the same time, they should effectively perceive their own position as a viewpoint. However, little is known about observers' percepts of their own spatial location based on the visual scene information viewed from them. Previous studies indicate that two distinct visual spatial processes exist in the locomotion situation: the egocentric position perception and egocentric direction perception. Those studies examined such perceptions in information rich visual environments where much dynamic and static visual information was available. This study examined these two perceptions in information of impoverished environments, including only static lane edge information (i.e., limited information). We investigated the visual factors associated with static lane edge information that may affect these perceptions. Especially, we examined the effects of the two factors on egocentric direction and position perceptions. One is the "uprightness factor" that "far" visual information is seen at upper location than "near" visual information. The other is the "central vision factor" that observers usually look at "far" visual information using central vision (i.e., foveal vision) whereas 'near' visual information using peripheral vision. Experiment 1 examined the effect of the "uprightness factor" using normal and inverted road images. Experiment 2 examined the effect of the "central vision factor" using normal and transposed road images where the upper half of the normal image was presented under the lower half. Experiment 3 aimed to replicate the results of Experiments 1 and 2. Results showed that egocentric direction perception is interfered with image inversion or image transposition, whereas egocentric position perception is robust against these image transformations. That is, both "uprightness" and "central vision" factors are important for egocentric direction perception, but not for egocentric position perception. Therefore, the two visual spatial perceptions about observers' own viewpoints are fundamentally dissociable. PMID- 26648896 TI - Commentary: An experimental study of gender and cultural differences in hue preference. PMID- 26648897 TI - Commentary: Oxytocin-Gaze Positive Loop and the Coevolution of Human-Dog Bonds. PMID- 26648898 TI - Heterosexual Rejection and Mate Choice: A Sociometer Perspective. AB - Previous studies about the effects of social rejection on individuals' social behaviors have produced mixed results and tend to study mating behaviors from a static point of view. However, mate selection in essence is a dynamic process, and therefore sociometer theory opens up a new perspective for studying mating and its underlying practices. Based on this theory and using self-perceived mate value in the relationship between heterosexual rejection and mate choice as a mediating role, this current study examined the effects of heterosexual rejection on mate choice in two experiments. Results showed that heterosexual rejection significantly reduced self-perceived mate value, expectation, and behavioral tendencies, while heterosexual acceptance indistinctively increased these measures. Self-perceived mate value did not serve as a mediator in the relationship between heterosexual rejection and mate expectation, but it mediated the relationship between heterosexual rejection and mating behavior tendencies toward potential objects. Moreover, individuals evaded both rejection and irrelevant people when suffering from rejection. PMID- 26648899 TI - Rhythm and Attention: Does the Beat Position of a Visual or Auditory Regular Pulse Modulate T2 Detection in the Attentional Blink? AB - The attentional blink (AB) is one impressive demonstration of limited attentional capacities in time: a second target (T2) is often missed when it should be detected within 200-600 ms after a first target. According to the dynamic attending theory, attention cycles oscillatory. Regular rhythms (i.e., pulses) should evoke expectations regarding the point of the next occurrence of a tone/element in the rhythm. At this point, more attentional resources should be provided. Thus, if rhythmic information can be used to optimize attentional release, we assume a modulation of the AB when an additional rhythm is given. We tested this idea in two experiments with a visual (Experiment 1) or an auditory (Experiment 2) rhythm. We found large AB effects. However, the rhythm did not modulate the AB. If the rhythm had an influence at all, then Experiment 2 showed that an auditory rhythm (or stimulus) falling on T2 might generally boost visual processing, irrespective of attentional resources as indexed by the AB paradigm. Our experiments suggest that oscillatory cycling attention does not affect temporal selection as tapped in the AB paradigm. PMID- 26648900 TI - Teaching About "Brain and Learning" in High School Biology Classes: Effects on Teachers' Knowledge and Students' Theory of Intelligence. AB - This study evaluated a new teaching module about "Brain and Learning" using a controlled design. The module was implemented in high school biology classes and comprised three lessons: (1) brain processes underlying learning; (2) neuropsychological development during adolescence; and (3) lifestyle factors that influence learning performance. Participants were 32 biology teachers who were interested in "Brain and Learning" and 1241 students in grades 8-9. Teachers' knowledge and students' beliefs about learning potential were examined using online questionnaires. Results indicated that before intervention, biology teachers were significantly less familiar with how the brain functions and develops than with its structure and with basic neuroscientific concepts (46 vs. 75% correct answers). After intervention, teachers' knowledge of "Brain and Learning" had significantly increased (64%), and more students believed that intelligence is malleable (incremental theory). This emphasizes the potential value of a short teaching module, both for improving biology teachers' insights into "Brain and Learning," and for changing students' beliefs about intelligence. PMID- 26648901 TI - The Role of Intelligence Quotient and Emotional Intelligence in Cognitive Control Processes. AB - The relationship between intelligence quotient (IQ) and cognitive control processes has been extensively established. Several studies have shown that IQ correlates with cognitive control abilities, such as interference suppression, as measured with experimental tasks like the Stroop and Flanker tasks. By contrast, there is a debate about the role of Emotional Intelligence (EI) in individuals' cognitive control abilities. The aim of this study is to examine the relation between IQ and EI, and cognitive control abilities evaluated by a typical laboratory control cognitive task, the Stroop task. Results show a negative correlation between IQ and the interference suppression index, the ability to inhibit processing of irrelevant information. However, the Managing Emotions dimension of EI measured by the Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT), but not self-reported of EI, negatively correlates with the impulsivity index, the premature execution of the response. These results suggest that not only is IQ crucial, but also competences related to EI are essential to human cognitive control processes. Limitations and implications of these results are also discussed. PMID- 26648902 TI - Individual Uncertainty and the Uncertainty of Science: The Impact of Perceived Conflict and General Self-Efficacy on the Perception of Tentativeness and Credibility of Scientific Information. AB - We examined in two empirical studies how situational and personal aspects of uncertainty influence laypeople's understanding of the uncertainty of scientific information, with focus on the detection of tentativeness and perception of scientific credibility. In the first study (N = 48), we investigated the impact of a perceived conflict due to contradicting information as a situational, text inherent aspect of uncertainty. The aim of the second study (N = 61) was to explore the role of general self-efficacy as an intra-personal uncertainty factor. In Study 1, participants read one of two versions of an introductory text in a between-group design. This text provided them with an overview about the neurosurgical procedure of deep brain stimulation (DBS). The text expressed a positive attitude toward DBS in one experimental condition or focused on the negative aspects of this method in the other condition. Then participants in both conditions read the same text that dealt with a study about DBS as experimental treatment in a small sample of patients with major depression. Perceived conflict between the two texts was found to increase the perception of tentativeness and to decrease the perception of scientific credibility, implicating that text inherent aspects have significant effects on critical appraisal. The results of Study 2 demonstrated that participants with higher general self-efficacy detected the tentativeness to a lesser degree and assumed a higher level of scientific credibility, indicating a more naive understanding of scientific information. This appears to be contradictory to large parts of previous findings that showed positive effects of high self-efficacy on learning. Both studies showed that perceived tentativeness and perceived scientific credibility of medical information contradicted each other. We conclude that there is a need for supporting laypeople in understanding the uncertainty of scientific information and that scientific writers should consider how to present scientific results when compiling pertinent texts. PMID- 26648904 TI - Domain-Specificity of Creativity: A Study on the Relationship Between Visual Creativity and Visual Mental Imagery. AB - Creativity refers to the capability to catch original and valuable ideas and solutions. It involves different processes. In this study the extent to which visual creativity is related to cognitive processes underlying visual mental imagery was investigated. Fifty college students (25 women) carried out: the Creative Synthesis Task, which measures the ability to produce creative objects belonging to a given category (originality, synthesis and transformation scores of pre-inventive forms, and originality and practicality scores of inventions were computed); an adaptation of Clark's Drawing Ability Test, which measures the ability to produce actual creative artworks (graphic ability, esthetic, and creativity scores of drawings were assessed) and three mental imagery tasks that investigate the three main cognitive processes involved in visual mental imagery: generation, inspection and transformation. Vividness of imagery and verbalizer visualizer cognitive style were also measured using questionnaires. Correlation analysis revealed that all measures of the creativity tasks positively correlated with the image transformation imagery ability; practicality of inventions negatively correlated with vividness of imagery; originality of inventions positively correlated with the visualization cognitive style. However, regression analysis confirmed the predictive role of the transformation imagery ability only for the originality score of inventions and for the graphic ability and esthetic scores of artistic drawings; on the other hand, the visualization cognitive style predicted the originality of inventions, whereas the vividness of imagery predicted practicality of inventions. These results are consistent with the notion that visual creativity is domain- and task-specific. PMID- 26648903 TI - Long-Lasting Cortical Reorganization as the Result of Motor Imagery of Throwing a Ball in a Virtual Tennis Court. AB - In order to characterize the neural signature of a motor imagery (MI) task, the present study investigates for the first time the oscillation characteristics including both of the time-frequency measurements, event related spectral perturbation and intertrial coherence (ITC) underlying the variations in the temporal measurements (event related potentials, ERP) directly related to a MI task. We hypothesize that significant variations in both of the time-frequency measurements underlie the specific changes in the ERP directly related to MI. For the MI task, we chose a simple everyday task (throwing a tennis ball), that does not require any particular motor expertise, set within the controlled virtual reality scenario of a tennis court. When compared to the rest condition a consistent, long-lasting negative fronto-central ERP wave was accompanied by significant changes in both time frequency measurements suggesting long-lasting cortical activity reorganization. The ERP wave was characterized by two peaks at about 300 ms (N300) and 1000 ms (N1000). The N300 component was centrally localized on the scalp and was accompanied by significant phase consistency in the delta brain rhythms in the contralateral central scalp areas. The N1000 component spread wider centrally and was accompanied by a significant power decrease (or event related desynchronization) in low beta brain rhythms localized in fronto-precentral and parieto-occipital scalp areas and also by a significant power increase (or event related synchronization) in theta brain rhythms spreading fronto-centrally. During the transition from N300 to N1000, a contralateral alpha (mu) as well as post-central and parieto-theta rhythms occurred. The visual representation of movement formed in the minds of participants might underlie a top-down process from the fronto-central areas which is reflected by the amplitude changes observed in the fronto-central ERPs and by the significant phase synchrony in contralateral fronto-central delta and contralateral central mu to parietal theta presented here. PMID- 26648905 TI - The Cognitive Costs of Context: The Effects of Concreteness and Immersiveness in Instructional Examples. AB - Prior research has established that while the use of concrete, familiar examples can provide many important benefits for learning, it is also associated with some serious disadvantages, particularly in learners' ability to recognize and transfer their knowledge to new analogous situations. However, it is not immediately clear whether this pattern would hold in real world educational contexts, in which the role of such examples in student engagement and ease of processing might be of enough importance to overshadow any potential negative impact. We conducted two experiments in which curriculum-relevant material was presented in natural classroom environments, first with college undergraduates and then with middle-school students. All students in each study received the same relevant content, but the degree of contextualization in these materials was varied between students. In both studies, we found that greater contextualization was associated with poorer transfer performance. We interpret these results as reflecting a greater degree of embeddedness for the knowledge acquired from richer, more concrete materials, such that the underlying principles are represented in a less abstract and generalizable form. PMID- 26648906 TI - The Complexity of Neuroenhancement and the Adoption of a Social Cognitive Perspective. AB - This contribution attempts to provide a broad perspective to the psychological study of neuroenhancement (NE). It departs from the assumption that, as the use of performance enhancing substances in sport, the use of substances with the aim of improving one's cognitive, motivational and affective functioning in academic domains is a goal-directed behavior. As such, its scientific study may very well benefit from an analysis taking into account the psychological processes regulating people's behavioral intentions and decisions. Within this broad framework, this contribution addresses several issues that currently seem to characterize the debate in the literature on neuroenhancement substances (NES) use. The first conceptual issue seeks to determine and define the "boundaries" of the phenomenon. The second issue concerns the empirical evidence on the prevalence of using certain substances for the purpose of NE. Finally, there is a debate around the ethical and moral implications of NE. Along these lines, the existing psychological research on NE has adopted mainly sociological and economic decision-making perspectives, greatly contributing to the psychological discourse about the phenomenon of NE. However, we argue that the existing psychological literature does not offer a common, explicit and integrated theoretical framework. Borrowing from the framework of doping research, we recommend the adoption of a social cognitive model for pursuing a systematic analysis of the psychological processes that dynamically regulate students' use of NES over time. PMID- 26648907 TI - Impaired Autonomic Responses to Emotional Stimuli in Autoimmune Limbic Encephalitis. AB - Limbic encephalitis (LE) is an autoimmune-mediated disorder that affects structures of the limbic system, in particular, the amygdala. The amygdala constitutes a brain area substantial for processing of emotional, especially fear related signals. The amygdala is also involved in neuroendocrine and autonomic functions, including skin conductance responses (SCRs) to emotionally arousing stimuli. This study investigates behavioral and autonomic responses to discrete emotion evoking and neutral film clips in a patient suffering from LE associated with contactin-associated protein-2 (CASPR2) antibodies as compared to a healthy control group. Results show a lack of SCRs in the patient while watching the film clips, with significant differences compared to healthy controls in the case of fear-inducing videos. There was no comparable impairment in behavioral data (emotion report, valence, and arousal ratings). The results point to a defective modulation of sympathetic responses during emotional stimulation in patients with LE, probably due to impaired functioning of the amygdala. PMID- 26648908 TI - Revisiting Antagonist Effects in Hypoglossal Nucleus: Brainstem Circuit for the State-Dependent Control of Hypoglossal Motoneurons: A Hypothesis. AB - We reassessed and provided new insights into the findings that were obtained in our previous experiments that employed the injections of combined adrenergic, serotonergic, GABAergic, and glycinergic antagonists into the hypoglossal nucleus in order to pharmacologically abolish the depression of hypoglossal nerve activity that occurred during carbachol-induced rapid-eye-movement (REM) sleep like state in anesthetized rats. We concluded that noradrenergic disfacilitation is the major mechanism that is responsible for approximately 90% of the depression of hypoglossal motoneurons, whereas the remaining 10% can be explained by serotonergic mechanisms that have net inhibitory effect on hypoglossal nerve activity during REM sleep-like state. We hypothesized that both noradrenergic and serotonergic state-dependent mechanisms indirectly control hypoglossal motoneuron excitability during REM sleep; their activities are integrated and mediated to hypoglossal motoneurons by reticular formation neurons. In addition, we proposed a brainstem neural circuit that can explain the new findings. PMID- 26648909 TI - Postpartum Management of Women Begun on Levothyroxine during Pregnancy. AB - During pregnancy, the thyroid gland must produce 50% more thyroid hormone to maintain the euthyroid state. Women with decreased thyroid reserve preconception, most typically due to Hashimoto's thyroiditis, may develop hypothyroidism during pregnancy. Data over the last 20 years have reported a strong association between subclinical hypothyroidism and adverse maternal/fetal events. As a result of this association, an increasing number of women are being screened for thyroid disease either preconception or at the first prenatal visit. Consequently, an ever increasing number of women are being initiated on levothyroxine for the first time during pregnancy. At present, there are very limited guidelines related to the management of the thyroid disease in these women postpartum. Based on an understanding of the physiology of the thyroid gland during pregnancy and postpartum, and the personal clinical experience of the author, recommendations for the postpartum management of women who were started on levothyroxine during pregnancy are presented. PMID- 26648910 TI - Bacterial Colonies in Solid Media and Foods: A Review on Their Growth and Interactions with the Micro-Environment. AB - Bacteria, either indigenous or added, are immobilized in solid foods where they grow as colonies. Since the 80's, relatively few research groups have explored the implications of bacteria growing as colonies and mostly focused on pathogens in large colonies on agar/gelatine media. It is only recently that high resolution imaging techniques and biophysical characterization techniques increased the understanding of the growth of bacterial colonies, for different sizes of colonies, at the microscopic level and even down to the molecular level. This review covers the studies on bacterial colony growth in agar or gelatine media mimicking the food environment and in model cheese. The following conclusions have been brought to light. Firstly, under unfavorable conditions, mimicking food conditions, the immobilization of bacteria always constrains their growth in comparison with planktonic growth and increases the sensibility of bacteria to environmental stresses. Secondly, the spatial distribution describes both the distance between colonies and the size of the colonies as a function of the initial level of population. By studying the literature, we concluded that there systematically exists a threshold that distinguishes micro-colonies (radius < 100-200 MUm) from macro-colonies (radius >200 MUm). Micro-colonies growth resembles planktonic growth and no pH microgradients could be observed. Macro colonies growth is slower than planktonic growth and pH microgradients could be observed in and around them due to diffusion limitations which occur around, but also inside the macro-colonies. Diffusion limitations of milk proteins have been demonstrated in a model cheese around and in the bacterial colonies. In conclusion, the impact of immobilization is predominant for macro-colonies in comparison with micro-colonies. However, the interaction between the colonies and the food matrix itself remains to be further investigated at the microscopic scale. PMID- 26648911 TI - Particle-Associated Differ from Free-Living Bacteria in Surface Waters of the Baltic Sea. AB - Many studies on bacterial community composition (BCC) do not distinguish between particle-associated (PA) and free-living (FL) bacteria or neglect the PA fraction by pre-filtration removing most particles. Although temporal and spatial gradients in environmental variables are known to shape BCC, it remains unclear how and to what extent PA and FL bacterial diversity responds to such environmental changes. To elucidate the BCC of both bacterial fractions related to different environmental settings, we studied surface samples of three Baltic Sea stations (marine, mesohaline, and oligohaline) in two different seasons (summer and fall/winter). Amplicon sequencing of the 16 S rRNA gene revealed significant differences in BCC of both bacterial fractions among stations and seasons, with a particularly high number of PA operational taxonomic units (OTUs at genus-level) at the marine station in both seasons. "Shannon and Simpson indices" showed a higher diversity of PA than FL bacteria at the marine station in both seasons and at the oligohaline station in fall/winter. In general, a high fraction of bacterial OTUs was found exclusively in the PA fraction (52% of total OTUs). These findings indicate that PA bacteria significantly contribute to overall bacterial richness and that they differ from FL bacteria. Therefore, to gain a deeper understanding on diversity and dynamics of aquatic bacteria, PA and FL bacteria should be generally studied independently. PMID- 26648912 TI - Integrating Ecological and Engineering Concepts of Resilience in Microbial Communities. AB - Many definitions of resilience have been proffered for natural and engineered ecosystems, but a conceptual consensus on resilience in microbial communities is still lacking. We argue that the disconnect largely results from the wide variance in microbial community complexity, which range from compositionally simple synthetic consortia to complex natural communities, and divergence between the typical practical outcomes emphasized by ecologists and engineers. Viewing microbial communities as elasto-plastic systems that undergo both recoverable and unrecoverable transitions, we argue that this gap between the engineering and ecological definitions of resilience stems from their respective emphases on elastic and plastic deformation, respectively. We propose that the two concepts may be fundamentally united around the resilience of function rather than state in microbial communities and the regularity in the relationship between environmental variation and a community's functional response. Furthermore, we posit that functional resilience is an intrinsic property of microbial communities and suggest that state changes in response to environmental variation may be a key mechanism driving functional resilience in microbial communities. PMID- 26648913 TI - A Novel C-Terminal Domain of RecJ is Critical for Interaction with HerA in Deinococcus radiodurans. AB - Homologous recombination (HR) generates error-free repair products, which plays an important role in double strand break repair and replication fork rescue processes. DNA end resection, the critical step in HR, is usually performed by a series of nuclease/helicase. RecJ was identified as a 5'-3' exonuclease involved in bacterial DNA end resection. Typical RecJ possesses a conserved DHH domain, a DHHA1 domain, and an oligonucleotide/oligosaccharide-binding (OB) fold. However, RecJs from Deinococcus-Thermus phylum, such as Deinococcus radiodurans RecJ (DrRecJ), possess an extra C-terminal domain (CTD), of which the function has not been characterized. Here, we showed that a CTD-deletion of DrRecJ (DrRecJDeltaC) could not restore drrecJ mutant growth and mitomycin C (MMC)-sensitive phenotypes, indicating that this domain is essential for DrRecJ in vivo. DrRecJDeltaC displayed reduced DNA nuclease activity and DNA binding ability. Direct interaction was identified between DrRecJ-CTD and DrHerA, which stimulates DrRecJ nuclease activity by enhancing its DNA binding affinity. Moreover, DrNurA nuclease, another partner of DrHerA, inhibited the stimulation of DrHerA on DrRecJ nuclease activity by interaction with DrHerA. Opposing growth and MMC resistance phenotypes between the recJ and nurA mutants were observed. A novel modulation mechanism among DrRecJ, DrHerA, and DrNurA was also suggested. PMID- 26648914 TI - Lamivudine Inhibits the Replication of ALV-J Associated Acutely Transforming Virus and its Helper Virus and Tumor Growth In vitro and In vivo. AB - To study the antiviral effects of lamivudine on avian leukosis virus subgroup J (ALV-J) and its inhibitory effect on the growth of fibrosarcomas caused by acute transforming avian leukosis virus, a series of experiments were performed in chicken embryo fibroblast cultures and 1-day-old chickens inoculated with an acutely transforming viral stock Fu-J (SDAU1005). This stock was prepared from an acutely fibrosarcoma of field cases in chicken farms and contained both the replication-defective virus Fu-J carrying v-fps oncogene and its helper virus ALV J strain SDAU1005. The results from three different assays in cell cultures demonstrated the significant inhibitory effect of lamivudine on the replication of both SDAU1005 and Fu-J viruses. Furthermore, the effect was dose dependent in the concentration range of 1-4 MUg/ml. In chicken experiments, lamivudine could decrease the viral loads of SDAU1005 and Fu-J in the plasma of inoculated chickens, delay the appearance of acute sarcomas, and decrease chicken mortality in the early stage. This model may be used to directly evaluate the inhibitory effects of lamivudine on such tumors and to understand the relationship between the replication-defective virus and its helper virus while also assessing tumor processes. PMID- 26648915 TI - Approval of Raxibacumab for the Treatment of Inhalation Anthrax Under the US Food and Drug Administration "Animal Rule". AB - On December 14, 2012, the FDA approved Raxibacumab, the first monoclonal antibody product developed under Project BioShield to achieve this milestone, and the first biologic product to be approved through the FDA animal efficacy rule (or "Animal Rule"). Raxibacumab is approved for the treatment of adult and pediatric patients with inhalational anthrax due to Bacillus anthracis in combination with appropriate antibiotic drugs and for prophylaxis of inhalational anthrax when alternative therapies are not available or not appropriate. The developmental process required for approval of Raxibacumab illustrates many of the challenges that product developers may encounter when pursuing approval under the Animal Rule and highlights a number of important regulatory and policy issues. PMID- 26648916 TI - Natural Sunlight Shapes Crude Oil-Degrading Bacterial Communities in Northern Gulf of Mexico Surface Waters. AB - Following the Deepwater Horizon (DWH) spill in 2010, an enormous amount of oil was observed in the deep and surface waters of the northern Gulf of Mexico. Surface waters are characterized by intense sunlight and high temperature during summer. While the oil-degrading bacterial communities in the deep-sea plume have been widely investigated, the effect of natural sunlight on those in oil polluted surface waters remains unexplored to date. In this study, we incubated surface water from the DWH site with amendments of crude oil, Corexit dispersant, or both for 36 days under natural sunlight in the northern Gulf of Mexico. The bacterial community was analyzed over time for total abundance, density of alkane and polycyclic aromatic hydrocarbon degraders, and community composition via pyrosequencing. Our results showed that, for treatments with oil and/or Corexit, sunlight significantly reduced bacterial diversity and evenness and was a key driver of shifts in bacterial community structure. In samples containing oil or dispersant, sunlight greatly reduced abundance of the Cyanobacterium Synechococcus but increased the relative abundances of Alteromonas, Marinobacter, Labrenzia, Sandarakinotalea, Bartonella, and Halomonas. Dark samples with oil were represented by members of Thalassobius, Winogradskyella, Alcanivorax, Formosa, Pseudomonas, Eubacterium, Erythrobacter, Natronocella, and Coxiella. Both oil and Corexit inhibited the Candidatus Pelagibacter with or without sunlight exposure. For the first time, we demonstrated the effects of light in structuring microbial communities in water with oil and/or Corexit. Overall, our findings improve understanding of oil pollution in surface water, and provide unequivocal evidence that sunlight is a key factor in determining bacterial community composition and dynamics in oil polluted marine waters. PMID- 26648917 TI - In planta Identification of Putative Pathogenicity Factors from the Chickpea Pathogen Ascochyta rabiei by De novo Transcriptome Sequencing Using RNA-Seq and Massive Analysis of cDNA Ends. AB - The most important foliar diseases in legumes worldwide are ascochyta blights. Up to now, in the Ascochyta-legume pathosystem most studies focused on the identification of resistance genes in the host, while very little is known about the pathogenicity factors of the fungal pathogen. Moreover, available data were often obtained from fungi growing under artificial conditions. Therefore, in this study we aimed at the identification of the pathogenicity factors of Ascochyta rabiei, causing ascochyta blight in chickpea. To identify potential fungal pathogenicity factors, we employed RNA-seq and Massive Analysis of cDNA Ends (MACE) to produce comprehensive expression profiles of A. rabiei genes isolated either from the fungus growing in absence of its host or from fungi infecting chickpea leaves. We further provide a comprehensive de novo assembly of the A. rabiei transcriptome comprising 22,725 contigs with an average length of 1178 bp. Since pathogenicity factors are usually secreted, we predicted the A. rabiei secretome, yielding 550 putatively secreted proteins. MACE identified 596 transcripts that were up-regulated during infection. An analysis of these genes identified a collection of candidate pathogenicity factors and unraveled the pathogen's strategy for infecting its host. PMID- 26648918 TI - Survey and Visual Detection of Zaire ebolavirus in Clinical Samples Targeting the Nucleoprotein Gene in Sierra Leone. AB - Ebola virus (EBOV) can lead to severe hemorrhagic fever with a high risk of death in humans and other primates. To guide treatment and prevent spread of the viral infection, a rapid and sensitive detection method is required for clinical samples. Here, we described and evaluated a reverse transcription loop-mediated isothermal amplification (RT-LAMP) method to detect Zaire ebolavirus using the nucleoprotein gene (NP) as a target sequence. Two different techniques were used, a calcein/Mn(2+) complex chromogenic method and real-time turbidity monitoring. The RT-LAMP assay detected the NP target sequence with a limit of 4.56 copies/MUL within 45 min under 61 degrees C, a similar even or increase in sensitivity than that of real-time reverse transcription-polymerase chain reaction (RT-PCR). Additionally, all pseudoviral particles or non- Zaire EBOV genomes were negative for LAMP detection, indicating that the assay was highly specific for EBOV. To appraise the availability of the RT-LAMP method for use in clinical diagnosis of EBOV, of 417 blood or swab samples collected from patients with clinically suspected infections in Sierra Leone, 307 were identified for RT-LAMP-based surveillance of EBOV. Therefore, the highly specific and sensitive RT-LAMP method allows the rapid detection of EBOV, and is a suitable tool for clinical screening, diagnosis, and primary quarantine purposes. PMID- 26648919 TI - SNF3 as High Affinity Glucose Sensor and Its Function in Supporting the Viability of Candida glabrata under Glucose-Limited Environment. AB - Candida glabrata is an emerging human fungal pathogen that has efficacious nutrient sensing and responsiveness ability. It can be seen through its ability to thrive in diverse range of nutrient limited-human anatomical sites. Therefore, nutrient sensing particularly glucose sensing is thought to be crucial in contributing to the development and fitness of the pathogen. This study aimed to elucidate the role of SNF3 (Sucrose Non Fermenting 3) as a glucose sensor and its possible role in contributing to the fitness and survivability of C. glabrata in glucose-limited environment. The SNF3 knockout strain was constructed and subjected to different glucose concentrations to evaluate its growth, biofilm formation, amphotericin B susceptibility, ex vivo survivability and effects on the transcriptional profiling of the sugar receptor repressor (SRR) pathway related genes. The CgSNF3Delta strain showed a retarded growth in low glucose environments (0.01 and 0.1%) in both fermentation and respiration-preferred conditions but grew well in high glucose concentration environments (1 and 2%). It was also found to be more susceptible to amphotericin B in low glucose environment (0.1%) and macrophage engulfment but showed no difference in the biofilm formation capability. The deletion of SNF3 also resulted in the down regulation of about half of hexose transporters genes (four out of nine). Overall, the deletion of SNF3 causes significant reduction in the ability of C. glabrata to sense limited surrounding glucose and consequently disrupts its competency to transport and perform the uptake of this critical nutrient. This study highlighted the role of SNF3 as a high affinity glucose sensor and its role in aiding the survivability of C. glabrata particularly in glucose limited environment. PMID- 26648921 TI - Substrate Type and Free Ammonia Determine Bacterial Community Structure in Full Scale Mesophilic Anaerobic Digesters Treating Cattle or Swine Manure. AB - The microbial-mediated anaerobic digestion (AD) process represents an efficient biological process for the treatment of organic waste along with biogas harvest. Currently, the key factors structuring bacterial communities and the potential core and unique bacterial populations in manure anaerobic digesters are not completely elucidated yet. In this study, we collected sludge samples from 20 full-scale anaerobic digesters treating cattle or swine manure, and investigated the variations of bacterial community compositions using high-throughput 16S rRNA amplicon sequencing. Clustering and correlation analysis suggested that substrate type and free ammonia (FA) play key roles in determining the bacterial community structure. The COD: [Formula: see text] (C:N) ratio of substrate and FA were the most important available operational parameters correlating to the bacterial communities in cattle and swine manure digesters, respectively. The bacterial populations in all of the digesters were dominated by phylum Firmicutes, followed by Bacteroidetes, Proteobacteria and Chloroflexi. Increased FA content selected Firmicutes, suggesting that they probably play more important roles under high FA content. Syntrophic metabolism by Proteobacteria, Chloroflexi, Synergistetes and Planctomycetes are likely inhibited when FA content is high. Despite the different manure substrates, operational conditions and geographical locations of digesters, core bacterial communities were identified. The core communities were best characterized by phylum Firmicutes, wherein Clostridium predominated overwhelmingly. Substrate-unique and abundant communities may reflect the properties of manure substrate and operational conditions. These findings extend our current understanding of the bacterial assembly in full-scale manure anaerobic digesters. PMID- 26648920 TI - Alternatives to Antibiotics to Prevent Necrotic Enteritis in Broiler Chickens: A Microbiologist's Perspective. AB - Since the 2006 European ban on the use of antibiotics as growth promoters in animal feed, numerous studies have been published describing alternative strategies to prevent diseases in animals. A particular focus has been on prevention of necrotic enteritis in poultry caused by Clostridium perfringens by the use of microbes or microbe-derived products. Microbes produce a plethora of molecules with antimicrobial properties and they can also have beneficial effects through interactions with their host. Here we review recent developments in novel preventive treatments against C. perfringens-induced necrotic enteritis in broiler chickens that employ yeasts, bacteria and bacteriophages or secondary metabolites and other microbial products in disease control. PMID- 26648922 TI - Interferon-gamma from Brain Leukocytes Enhances Meningitis by Type 4 Streptococcus pneumoniae. AB - Streptococcus pneumoniae is the leading cause of bacterial meningitis. Pneumococcal meningitis is a life-threatening disease with high rates of mortality and neurological sequelae. Immune targeting of S. pneumoniae is essential for clearance of infection; however, within the brain, the induced inflammatory response contributes to pathogenesis. In this study we investigate the local inflammatory response and the role of IFN-gamma in a murine model of pneumococcal meningitis induced by intracranial injection of type 4 S. pneumoniae. Lymphoid and myeloid cell populations involved in meningitis, as well as cytokine gene expression, were investigated after infection. Animals were treated with a monoclonal antibody specific for murine IFN-gamma to evaluate its role in animal survival. Intracranial inoculation of 3 * 10(4) colony-forming units of type 4 strain TIGR4 caused 75% of mice to develop meningitis within 4 days. The amount of lymphocytes, NK cells, neutrophils, monocytes and macrophages in the brain increased 48 h post infection. IFN-gamma mRNA levels were about 240 fold higher in brains of infected mice compared to controls. Pro-inflammatory cytokines such as IL-1beta and TNF-alpha, and TLR2 were also upregulated. In vivo treatment with anti-IFN-gamma antibody increased survival of infected mice. This study shows that IFN-gamma produced during meningitis by type 4 S. pneumoniae enhances bacterial pathogenesis exerting a negative effect on the disease outcome. PMID- 26648924 TI - Editorial: Microbiotechnology Based Surfactants and Their Applications. PMID- 26648923 TI - Endophytic Actinobacteria and the Interaction of Micromonospora and Nitrogen Fixing Plants. AB - For a long time, it was believed that a healthy plant did not harbor any microorganisms within its tissues, as these were often considered detrimental for the plant. In the last three decades, the numbers of studies on plant microbe interactions has led to a change in our view and we now know that many of these invisible partners are essential for the overall welfare of the plant. The application of Next Generation Sequencing techniques is a powerful tool that has permitted the detection and identification of microbial communities in healthy plants. Among the new plant microbe interactions recently reported several actinobacteria such as Micromonospora are included. Micromonospora is a Gram positive bacterium with a wide geographical distribution; it can be found in the soil, mangrove sediments, and freshwater and marine ecosistems. In the last years our group has focused on the isolation of Micromonospora strains from nitrogen fixing nodules of both leguminous and actinorhizal plants and reported for the first time its wide distribution in nitrogen fixing nodules of both types of plants. These studies have shown how this microoganism had been largely overlooked in this niche due to its slow growth. Surprisingly, the genetic diversity of Micromonospora strains isolated from nodules is very high and several new species have been described. The current data indicate that Micromonospora saelicesensis is the most frequently isolated species from the nodular tissues of both leguminous and actinorhizal plants. Further studies have also been carried out to confirm the presence of Micromonospora inside the nodule tissues, mainly by specific in situ hybridization. The information derived from the genome of the model strain, Micromonospora lupini, Lupac 08, has provided useful information as to how this bacterium may relate with its host plant. Several strategies potentially necessary for Micromonospora to thrive in the soil, a highly competitive, and rough environment, and as an endophytic bacterium with the capacity to colonize the internal plant tissues which are protected from the invasion of other soil microbes were identified. The genome data also revealed the potential of M. lupini Lupac 08 as a plant growth promoting bacterium. Several loci involved in plant growth promotion features such as the production of siderophores, phytohormones, and the degradation of chitin (biocontrol) were also located on the genome and the functionality of these genes was confirmed in the laboratory. In addition, when several host plants species were inoculated with Micromonospora strains, the plant growth enhancing effect was evident under greenhouse conditions. Unexpectedly, a high number of plant cell wall degrading enzymes were also detected, a trait usually found only in pathogenic bacteria. Thus, Micromonospora can be added to the list of new plant microbe interactions. The current data indicate that this microorganism may have an important application in agriculture and other biotechnological processes. The available information is promising but limited, much research is still needed to determine which is the ecological function of Micromonospora in interaction with nitrogen fixing plants. PMID- 26648925 TI - Actinobacterial Diversity in the Sediments of Five Cold Springs on the Qinghai Tibet Plateau. AB - The actinobacterial diversity was investigated in the sediments of five cold springs in Wuli region on the Qinghai-Tibet Plateau using 16S rRNA gene phylogenetic analysis. The actinobacterial communities of the studied cold springs were diverse and the obtained actinobacterial operational taxonomic units were classified into 12 actinobacterial orders (e.g., Acidimicrobiales, Corynebacteriales, Gaiellales, Geodermatophilales, Jiangellales, Kineosporiales, Micromonosporales, Micrococcales, Nakamurellales, Propionibacteriales, Pseudonocardiales, Streptomycetales) and unclassified Actinobacteria. The actinobacterial composition varied among the investigated cold springs and were significantly correlated (r = 0.748, P = 0.021) to environmental variables. The actinobacterial communities in the cold springs were more diverse than other cold habitats on the Tibetan Plateau, and their compositions showed unique geographical distribution characteristics. Statistical analyses showed that biogeographical isolation and unique environmental conditions might be major factors influencing actinobacterial distribution among the investigated cold springs. PMID- 26648926 TI - Archaeal Ammonia Oxidizers Dominate in Numbers, but Bacteria Drive Gross Nitrification in N-amended Grassland Soil. AB - Both ammonia-oxidizing archaea (AOA) and ammonia-oxidizing bacteria (AOB) play an important role in nitrification in terrestrial environments. Most often AOA outnumber AOB, but the relative contribution of AOA and AOB to nitrification rates remains unclear. The aim of this experiment was to test the hypotheses that high nitrogen availability would favor AOB and result in high gross nitrification rates, while high carbon availability would result in low nitrogen concentrations that favor the activity of AOA. The hypotheses were tested in a microcosm experiment where sugars, ammonium, or amino acids were added regularly to a grassland soil for a period of 33 days. The abundance of amoA genes from AOB increased markedly in treatments that received nitrogen, suggesting that AOB were the main ammonia oxidizers here. However, AOB could not account for the entire ammonia oxidation activity observed in treatments where the soil was deficient in available nitrogen. The findings suggest that AOA are important drivers of nitrification under nitrogen-poor conditions, but that input of easily available nitrogen results in increased abundance, activity, and relative importance of AOB for gross nitrification in grassland soil. PMID- 26648927 TI - Aspergillus terreus Meningitis in Immunocompetent Patient: A Case Report. AB - We present a description of a rare but dangerous case of fungal meningitis caused by Aspergillus terreus in an immunocompetent patient with a history of sinus disease. PMID- 26648929 TI - Fractal Hypothesis of the Pelagic Microbial Ecosystem-Can Simple Ecological Principles Lead to Self-Similar Complexity in the Pelagic Microbial Food Web? AB - Trophic interactions are highly complex and modern sequencing techniques reveal enormous biodiversity across multiple scales in marine microbial communities. Within the chemically and physically relatively homogeneous pelagic environment, this calls for an explanation beyond spatial and temporal heterogeneity. Based on observations of simple parasite-host and predator-prey interactions occurring at different trophic levels and levels of phylogenetic resolution, we present a theoretical perspective on this enormous biodiversity, discussing in particular self-similar aspects of pelagic microbial food web organization. Fractal methods have been used to describe a variety of natural phenomena, with studies of habitat structures being an application in ecology. In contrast to mathematical fractals where pattern generating rules are readily known, however, identifying mechanisms that lead to natural fractals is not straight-forward. Here we put forward the hypothesis that trophic interactions between pelagic microbes may be organized in a fractal-like manner, with the emergent network resembling the structure of the Sierpinski triangle. We discuss a mechanism that could be underlying the formation of repeated patterns at different trophic levels and discuss how this may help understand characteristic biomass size-spectra that hint at scale-invariant properties of the pelagic environment. If the idea of simple underlying principles leading to a fractal-like organization of the pelagic food web could be formalized, this would extend an ecologists mindset on how biological complexity could be accounted for. It may furthermore benefit ecosystem modeling by facilitating adequate model resolution across multiple scales. PMID- 26648928 TI - Prevalence and Characterization of Shiga Toxin-Producing and Enteropathogenic Escherichia coli in Shellfish-Harvesting Areas and Their Watersheds. AB - more strains formed a strong biofilm at 18 than at 30 degrees C. Finally, more than 85% of analyzed strains were found to be sensitive to the 16 tested antibiotics. These data suggest the low risk of human infection by STEC if shellfish from these shellfish-harvesting areas were consumed. PMID- 26648930 TI - Sequence-based Analysis of the Vitis vinifera L. cv Cabernet Sauvignon Grape Must Mycobiome in Three South African Vineyards Employing Distinct Agronomic Systems. AB - Recent microbiomic research of agricultural habitats has highlighted tremendous microbial biodiversity associated with such ecosystems. Data generated in vineyards have furthermore highlighted significant regional differences in vineyard biodiversity, hinting at the possibility that such differences might be responsible for regional differences in wine style and character, a hypothesis referred to as "microbial terroir." The current study further contributes to this body of work by comparing the mycobiome associated with South African (SA) Cabernet Sauvignon grapes in three neighboring vineyards that employ different agronomic approaches, and comparing the outcome with similar data sets from Californian vineyards. The aim of this study was to fully characterize the mycobiomes associated with the grapes from these vineyards. The data revealed approximately 10 times more fungal diversity than what is typically retrieved from culture-based studies. The Biodynamic vineyard was found to harbor a more diverse fungal community (H = 2.6) than the conventional (H = 2.1) and integrated (H = 1.8) vineyards. The data show that ascomycota are the most abundant phylum in the three vineyards, with Aureobasidium pullulans and its close relative Kabatiella microsticta being the most dominant fungi. This is the first report to reveal a high incidence of K. microsticta in the grape/wine ecosystem. Different common wine yeast species, such as Metschnikowia pulcherrima and Starmerella bacillaris dominated the mycobiome in the three vineyards. The data show that the filamentous fungi are the most abundant community in grape must although they are not regarded as relevant during wine fermentation. Comparison of metagenomic datasets from the three SA vineyards and previously published data from Californian vineyards revealed only 25% of the fungi in the SA dataset was also present in the Californian dataset, with greater variation evident amongst ubiquitous epiphytic fungi. PMID- 26648931 TI - Nitrification and Nitrifying Bacteria in a Coastal Microbial Mat. AB - The first step of nitrification, the oxidation of ammonia to nitrite, can be performed by ammonia-oxidizing archaea (AOA) or ammonium-oxidizing bacteria (AOB). We investigated the presence of these two groups in three structurally different types of coastal microbial mats that develop along the tidal gradient on the North Sea beach of the Dutch barrier island Schiermonnikoog. The abundance and transcription of amoA, a gene encoding for the alpha subunit of ammonia monooxygenase that is present in both AOA and AOB, were assessed and the potential nitrification rates in these mats were measured. The potential nitrification rates in the three mat types were highest in autumn and lowest in summer. AOB and AOA amoA genes were present in all three mat types. The composition of the AOA and AOB communities in the mats of the tidal and intertidal stations, based on the diversity of amoA, were similar and clustered separately from the supratidal microbial mat. In all three mats AOB amoA genes were significantly more abundant than AOA amoA genes. The abundance of neither AOB nor AOA amoA genes correlated with the potential nitrification rates, but AOB amoA transcripts were positively correlated with the potential nitrification rate. The composition and abundance of amoA genes seemed to be partly driven by salinity, ammonium, temperature, and the nitrate/nitrite concentration. We conclude that AOB are responsible for the bulk of the ammonium oxidation in these coastal microbial mats. PMID- 26648932 TI - The Scion/Rootstock Genotypes and Habitats Affect Arbuscular Mycorrhizal Fungal Community in Citrus. AB - Citrus roots have rare root hairs and thus heavily depend on arbuscular mycorrhizal fungi (AMF) for mineral nutrient uptake. However, the AMF community structure of citrus is largely unknown. By using 454-pyrosequencing of 18S rRNA gene fragment, we investigated the genetic diversity of AMF colonizing citrus roots, and evaluated the impact of habitats and rootstock and scion genotypes on the AMF community structure. Over 7,40,000 effective sequences were obtained from 77 citrus root samples. These sequences were assigned to 75 AMF virtual taxa, of which 66 belong to Glomus, highlighting an absolute dominance of this AMF genus in symbiosis with citrus roots. The citrus AMF community structure is significantly affected by habitats and host genotypes. Interestingly, our data suggests that the genotype of the scion exerts a greater impact on the AMF community structure than that of the rootstock where the physical root-AMF association occurs. This study not only provides a comprehensive assessment for the community composition of the AMF in citrus roots under different conditions, but also sheds novel insights into how the AMF community might be indirectly influenced by the spatially separated yet metabolically connected partner-the scion-of the grafted citrus tree. PMID- 26648933 TI - Investigating the Antigen Specificity of Multiple Sclerosis Central Nervous System-Derived Immunoglobulins. AB - The central nervous system (CNS) of patients with multiple sclerosis (MS) is the site where disease pathology is evident. Damaged CNS tissue is commonly associated with immune cell infiltration. This infiltrate often includes B cells that are found in multiple locations throughout the CNS, including the cerebrospinal fluid (CSF), parenchyma, and the meninges, frequently forming tertiary lymphoid structures in the latter. Several groups, including our own, have shown that B cells from distinct locations within the MS CNS are clonally related and display the characteristics of an antigen-driven response. However, the antigen(s) driving this response have yet to be conclusively defined. To explore the antigen specificity of the MS B cell response, we produced recombinant human immunoglobulin (rIgG) from a series of expanded B cell clones that we isolated from the CNS tissue of six MS brains. The specificity of these MS-derived rIgG and control rIgG derived from non-MS tissues was then examined using multiple methodologies that included testing individual candidate antigens, screening with high-throughput antigen arrays and evaluating binding to CNS derived cell lines. We report that while several MS-derived rIgG recognized particular antigens, including neurofilament light and a protocadherin isoform, none were unique to MS, as non-MS-derived rIgG used as controls invariably displayed similar binding specificities. We conclude that while MS CNS resident B cells display the characteristics of an antigen-driven B cell response, the antigen(s) driving this response remain at large. PMID- 26648935 TI - DNP-KLH Yields Changes in Leukocyte Populations and Immunoglobulin Isotype Use with Different Immunization Routes in Zebrafish. AB - Distinct methods are required for inducing mucosal versus systemic immunity in mammals for vaccine protection at the tissues most commonly breached by pathogens. Understanding of mucosal immunization in teleost fish is needed to combat aquaculture disease, understand emerging ecological threats, and know how vertebrate adaptive immunity evolved. Here, we quantitatively measured expression levels of IgM as well as the teleost mucosal immunoglobulin, IgZ/IgT, in zebrafish given an antigen systemically via intraperitoneal (i.p.) injection or mucosally via bath immersion. Both immunoglobulin isotypes and the B cell activating factor gene transcription was induced in fish injected with antigen as compared to saline injected or antigen immersed fish, though these failed to reach statistical significance. Here we provide additional reference hematology for this model species. Differential blood counts revealed a greater lymphocyte percentage in both i.p. and immersed fish, with increase in large lymphocyte counts and decrease in neutrophils. These humoral adaptive gene transcription and cytological data should provide a foundation for more studies connecting immunology in this dominant developmental and genetic fish model to other species where mucosal immunization is of greater commercial importance. PMID- 26648936 TI - Subverting Toll-Like Receptor Signaling by Bacterial Pathogens. AB - Pathogenic bacteria are detected by pattern-recognition receptors (PRRs) expressed on innate immune cells, which activate intracellular signal transduction pathways to elicit an immune response. Toll-like receptors are, perhaps, the most studied of the PRRs and can activate the mitogen-activated protein kinase (MAPK) and Nuclear Factor-kappaB (NF-kappaB) pathways. These pathways are critical for mounting an effective immune response. In order to evade detection and promote virulence, many pathogens subvert the host immune response by targeting components of these signal transduction pathways. This mini review highlights the diverse mechanisms that bacterial pathogens have evolved to manipulate the innate immune response, with a particular focus on those that target MAPK and NF-kappaB signaling pathways. Understanding the elaborate strategies that pathogens employ to subvert the immune response not only highlights the importance of these proteins in mounting effective immune responses, but may also identify novel approaches for treatment or prevention of infection. PMID- 26648934 TI - Natural Killer Cell-Based Therapies Targeting Cancer: Possible Strategies to Gain and Sustain Anti-Tumor Activity. AB - Natural killer (NK) cells were discovered 40 years ago, by their ability to recognize and kill tumor cells without the requirement of prior antigen exposure. Since then, NK cells have been seen as promising agents for cell-based cancer therapies. However, NK cells represent only a minor fraction of the human lymphocyte population. Their skewed phenotype and impaired functionality during cancer progression necessitates the development of clinical protocols to activate and expand to high numbers ex vivo to be able to infuse sufficient numbers of functional NK cells to the cancer patients. Initial NK cell-based clinical trials suggested that NK cell-infusion is safe and feasible with almost no NK cell related toxicity, including graft-versus-host disease. Complete remission and increased disease-free survival is shown in a small number of patients with hematological malignances. Furthermore, successful adoptive NK cell-based therapies from haploidentical donors have been demonstrated. Disappointingly, only limited anti-tumor effects have been demonstrated following NK cell infusion in patients with solid tumors. While NK cells have great potential in targeting tumor cells, the efficiency of NK cell functions in the tumor microenvironment is yet unclear. The failure of immune surveillance may in part be due to sustained immunological pressure on tumor cells resulting in the development of tumor escape variants that are invisible to the immune system. Alternatively, this could be due to the complex network of immune-suppressive compartments in the tumor microenvironment, including myeloid-derived suppressor cells, tumor associated macrophages, and regulatory T cells. Although the negative effect of the tumor microenvironment on NK cells can be transiently reverted by ex vivo expansion and long-term activation, the aforementioned NK cell/tumor microenvironment interactions upon reinfusion are not fully elucidated. Within this context, genetic modification of NK cells may provide new possibilities for developing effective cancer immunotherapies by improving NK cell responses and making them less susceptible to the tumor microenvironment. Within this review, we will discuss clinical trials using NK cells with a specific reflection on novel potential strategies, such as genetic modification of NK cells and complementary therapies aimed at improving the clinical outcome of NK cell-based immune therapies. PMID- 26648937 TI - SLE: Another Autoimmune Disorder Influenced by Microbes and Diet? AB - Systemic lupus erythematosus (SLE) is a multi-system autoimmune disease. Despite years of study, the etiology of SLE is still unclear. Both genetic and environmental factors have been implicated in the disease mechanisms. In the past decade, a growing body of evidence has indicated an important role of gut microbes in the development of autoimmune diseases, including type 1 diabetes, rheumatoid arthritis, and multiple sclerosis. However, such knowledge on SLE is little, though we have already known that environmental factors can trigger the development of lupus. Several recent studies have suggested that alterations of the gut microbial composition may be correlated with SLE disease manifestations, while the exact roles of either symbiotic or pathogenic microbes in this disease remain to be explored. Elucidation of the roles of gut microbes - as well as the roles of diet that can modulate the composition of gut microbes - in SLE will shed light on how this autoimmune disorder develops, and provide opportunities for improved biomarkers of the disease and the potential to probe new therapies. In this review, we aim to compile the available evidence on the contributions of diet and gut microbes to SLE occurrence and pathogenesis. PMID- 26648938 TI - The Role of Chemokines in Shaping the Balance Between CD4(+) T Cell Subsets and Its Therapeutic Implications in Autoimmune and Cancer Diseases. AB - Chemokines are the key activators of adhesion molecule and also drivers of leukocyte migration to inflammatory sites and are therefore mostly considered as proinflammatory mediators. Many studies, including ours, imply that targeting the function of several key chemokines, but not many others, could effectively suppress inflammatory responses and inflammatory autoimmunity. Along with this, a single chemokine named CXCL10 could be used to induce antitumor immunity, and thereby suppress myeloma. Our working hypothesis is that some chemokines differ from others as aside from being chemoattractants for leukocytes and effective activators of adhesion receptors that possess additional biological properties making them "driver chemokines." We came up with this notion when studying the interlay between CXCR4 and CXCL12 and between CXCR3 and its three ligands: CXCL9, CXCL10, and CXCL11. The current mini-review focuses on these ligands and their biological properties. First, we elaborate the role of cytokines in directing the polarization of effector and regulatory T cell subset and the plasticity of this process. Then, we extend this notion to chemokines while focusing on CXCL 12 and the CXCR3 ligands. Finally, we elaborate the potential clinical implications of these studies for therapy of autoimmunity, graft-versus-host disease, and cancer. PMID- 26648940 TI - Influence of Chronic Kidney Disease on Physical Function and Quality of Life in Patients after Coronary Artery Bypass Grafting. AB - AIMS: The purposes of this study were (1) to compare body composition, physical function, and quality of life (QOL) between patients after coronary artery bypass grafting (CABG) with and without chronic kidney disease (CKD) and (2) to analyze the factors associated with physical function and QOL domains in these patients. METHODS: Thirty male post-CABG patients with CKD and 30 matched controls were recruited. All subjects underwent dual-energy X-ray absorptiometry for body composition evaluation. Physical function tests included the grip strength test, 30-second chair stand test (30CST), and 6-min walk test (6MWT). Physical activity and QOL were assessed using the long form of the International Physical Activity Questionnaire and the World Health Organization Quality of Life Instrument (WHOQOL)-BREF, respectively. RESULTS: Post-CABG patients with CKD exhibited a lower arm lean mass and higher percent leg fat mass than those without CKD (p < 0.05). The patients with CKD also had lower 30CST scores, 6MWT distances, and QOL domain of social relationships scores than those without CKD after adjusting for covariates (p < 0.05). If NYHA class was considered in the model, NYHA class became the most important factor associated with 6MWT distances (beta = -0.647, p < 0.001) and the QOL domains of psychological health (beta = -0.285, p = 0.027) and environment (beta = -0.406, p = 0.001). CONCLUSION: Post-CABG patients with CKD had worse body composition, physical function, and QOL than those without CKD, and this might be associated with a worse NYHA class. PMID- 26648941 TI - Target Hemoglobin May Be Achieved with Intravenous Iron Alone in Anemic Patients with Cardiorenal Syndrome: An Observational Study. AB - BACKGROUND: The treatment of anemia in patients with cardiorenal syndrome (CRS) is based mainly on intravenous (IV) iron therapy and/or erythropoiesis stimulating agents (ESAs). There are concerns about the safety of ESAs due to a potentially higher risk for stroke and malignancy. OBJECTIVE: We aimed to explore whether IV iron alone is sufficient to improve anemia in CRS patients and to define the predictors of treatment response. METHODS: We retrospectively analyzed data of 81 CRS patient treated for anemia at our clinic. All patients received IV iron for 6 weeks. A subset of patients was additionally given subcutaneous ESAs. The end point was the improvement from baseline in hemoglobin (Hb) and ferritin levels at week 7. RESULTS: We retrieved the files of 81 patients; 34 received IV iron alone and 47 were given IV iron and ESAs (the combination group). The Hb levels significantly increased in both groups (in the IV iron alone group: 10.6 +/- 1.1 to 11.9 +/-1.1 g/dl, p < 0.001; in the combination group: 10.2 +/- 0.9 to 12.4 +/- 1.3 g/dl, p < 0.001), but more pronouncedly in the combination group (2.17 vs. 1.24 g/dl; p = 0.001). The platelet count decreased significantly in the IV iron alone group but was unchanged in the combination group. Eighty percent of patients attained a Hb target of 11 g/dl, with no significant difference between the two groups (73.5 vs. 85.1%; p = 0.197). Low baseline Hb was the only predictor of a favorable outcome to treatment. CONCLUSION: Our observational study suggests that IV iron treatment without ESAs may substantially raise the Hb level to >=11 g/dl in CRS patients. This treatment strategy may reduce the use of ESAs and hence its potential adverse effects. PMID- 26648939 TI - Disturbed T Cell Signaling and Altered Th17 and Regulatory T Cell Subsets in the Pathogenesis of Systemic Lupus Erythematosus. AB - Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the presence of autoantibodies against nuclear components. Circulating immune complexes of chromatin and autoantibodies deposit in various tissues leading to inflammation and tissue damage. It has been well documented that autoimmunity in SLE depends on autoreactive T cells. In this review, we summarize the literature that addresses the roles of T cell signaling, and Th17 and regulatory T cells (Tregs) in the development of SLE. T cell receptor (TCR) signaling appears to be aberrant in T cells of patients with SLE. In particular, defects in the TCRzeta chain, Syk kinase, and calcium signaling molecules have been associated with SLE, which leads to hyperresponsive autoreactive T cells. Furthermore, in patients with SLE increased numbers of autoreactive Th17 cells have been documented, and Th17 cells appear to be responsible for tissue inflammation and damage. In addition, reduced numbers of Tregs as well as Tregs with an impaired regulatory function have been associated with SLE. The altered balance between the number of Tregs and Th17 cells in SLE may result from changes in the cytokine milieu that favors the development of Th17 cells over Tregs. PMID- 26648942 TI - Left Ventricular Hypertrophy in Chronic Kidney Disease Patients: From Pathophysiology to Treatment. AB - Cardiovascular diseases represent the main causes of morbidity and mortality in patients with chronic kidney disease (CKD). According to a well-established classification, cardiovascular involvement in CKD can be set in the context of cardiorenal syndrome type 4. Left ventricular hypertrophy (LVH) represents a key feature to provide an accurate picture of systolic-diastolic left heart involvement in CKD patients. Cardiovascular involvement is present in about 80% of prevalent hemodialysis patients, and it is evident in CKD patients since stage IIIb-IV renal disease (according to the K/DOQI CKD classification). According to the definition of cardiorenal syndrome type 4, kidney disease is detected before the development of heart failure, although timing of the diagnosis is not always possible. The evaluation of LVH is a bit heterogeneous, and few standard imaging methods can provide the accuracy of either CT- or MRI-derived left ventricular mass. Key principles in the treatment of LVH in CKD patients are mainly based on anemia and blood pressure control, together with the management of secondary hyperparathyroidism and sudden cardiac death prevention. This review is mainly focused on the clinical aspects of CKD-related LVH to provide practical guidelines both for cardiologists and nephrologists in the daily clinical approach to CKD patients. PMID- 26648943 TI - Usefulness of an Upright T-Wave in Lead aVR for Predicting the Short-Term Prognosis of Incident Hemodialysis Patients: A Potential Tool for Screening High Risk Hemodialysis Patients. AB - BACKGROUND/AIMS: An upright T-wave in lead aVR (aVRT) has recently been reported to be associated with cardiovascular death and mortality among the general population and patients with prior cardiovascular disease (CVD). However, evidence for the predictive ability of aVRT in patients with chronic kidney disease is lacking. Therefore, a hospital-based, prospective, cohort study was conducted to evaluate the predictive ability of an upright aVRT for the short term prognosis in incident hemodialysis patients. METHODS: Among 208 patients who started maintenance hemodialysis, 79 with preexisting CVD (CVD cohort) and 129 with no history of CVD (non-CVD cohort), were studied. An upright and non-upright aVRT were defined as a wave with a positive deflection in amplitude of >=0 mV and a negative deflection in amplitude of <0 mV, respectively. The endpoint was all cause death. RESULTS: Overall, the prevalence of an upright aVRT was 22.6% at baseline. During the mean follow-up period of 2.1 +/- 1.0 years, 33 deaths occurred. Cumulative survival rates at 3 years after starting dialysis in patients with an upright and non-upright aVRT were 50.0 and 80.7%, respectively, in the CVD cohort and 92.0 and 91.3%, respectively, in the non-CVD cohort. In the CVD cohort, multivariate Cox regression analysis showed that an upright aVRT was an independent predictor of death after adjusting for confounding variables. CONCLUSION: Among Japanese hemodialysis patients at high risk for CVD, an upright aVRT seems to be useful for predicting death. PMID- 26648944 TI - Soluble Tumor Necrosis Factor Receptor 1 Is Associated with Glomerular Filtration Rate Progression and Incidence of Chronic Kidney Disease in Two Community-Based Cohorts of Elderly Individuals. AB - OBJECTIVE: We aimed to explore and validate the longitudinal associations between soluble tumor necrosis factor receptor 1 (sTNFR1), glomerular filtration rate (GFR) progression, and chronic kidney disease (CKD) incidence in two independent community-based cohorts of elderly individuals with prespecified subgroup analyses in individuals without prevalent diabetes. RESEARCH DESIGN AND METHODS: Two community-based cohorts of elderly individuals were used with 5-year follow up data on estimated GFR: the Uppsala Longitudinal Study of Adult Men (ULSAM; n = 437 men; mean age: 78 years) and the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS; n = 703; mean age: 70 years; 51% women). GFR categories were defined as >=60, 30-60, and <30 ml/min/1.73 m(2). RESULTS: In longitudinal multivariable logistic regression models adjusted for inflammatory markers and established cardiovascular risk factors, higher serum sTNFR1 was significantly associated with an increased risk to progress to a lower GFR category in both ULSAM and PIVUS [odds ratio (OR) per standard deviation (SD) increase 1.28 (95% CI 1.03-1.60) and OR 1.56 (95% CI 1.30-1.87), respectively]. Also, in subgroup analyses in individuals with a GFR >=60 ml/min/1.73 m(2) at baseline, higher sTNFRs were associated with incident CKD after 5 years in both cohorts [ULSAM: OR per SD increase 1.49 (95% CI 1.16-1.9) and PIVUS: OR 1.84 (95% CI 1.50-2.26)]. Associations were similar in individuals without diabetes. CONCLUSIONS: Higher circulating sTNFR1 independently predicts the progression to a worse GFR category and CKD incidence in elderly individuals even in the absence of diabetes. Further studies are warranted to investigate the underlying mechanisms, and to evaluate the clinical relevance of our findings. PMID- 26648945 TI - Comparison between Cystatin C- and Creatinine-Estimated Glomerular Filtration Rate in Cardiology Patients. AB - OBJECTIVE: Estimation of the glomerular filtration rate (GFR) is essential for identification, evaluation and risk prediction in patients with kidney disease. Estimated GFR (eGFR) is also needed for the correct dosing of drugs eliminated by the kidneys and to identify high-risk individuals in whom coronary angiography or other procedures may lead to kidney failure. Both cystatin C and creatinine are used for the determination of GFR, and we aimed to investigate if eGFR by the two methods differ in cardiology patients. METHODS: We compared cystatin C and creatinine (CKD-EPI) eGFR calculated from the same request from a cardiology outpatient unit (n = 2,716), a cardiology ward (n = 980), a coronary care unit (n = 1,464), and an advanced coronary care unit (n = 518) in an observational, cross sectional study. RESULTS: The median creatinine eGFR results are approximately 10 ml/min/1.73 m(2) higher than the median cystatin C eGFR that is up to 90 ml/min/1.73 m(2), irrespective of the level of care. Creatinine eGFR resulted in a less advanced eGFR category in the majority of patients with a cystatin C eGFR <60 ml/min/1.73 m(2). CONCLUSIONS: Our study demonstrates a difference between creatinine and cystatin C eGFR in cardiology patients. It is important to be aware of which marker is used for the reported eGFR to minimize erroneous interpretations of the test results, as this could lead to under- or overmedication. Further studies are needed to determine the best method of estimating the GFR in cardiology units. PMID- 26648946 TI - Clinical SYNTAX Score Can Predict Acute Kidney Injury following On-Pump but Not Off-Pump Coronary Artery Bypass Surgery. AB - BACKGROUND: The complexity of coronary artery disease is usually a neglected factor in risk stratification systems. We aimed to analyze the discriminative ability of the clinical SYNTAX score (CSS) for acute kidney injury (AKI) following on- and off-pump coronary artery surgery. METHODS: A total of 193 patients were reviewed in this study. Patients were divided into two groups according to the surgical procedure (group I: off-pump coronary artery bypass grafting, n = 89; group II: on-pump coronary artery bypass grafting, n = 104). Preoperative demographic data, the CSS and postoperative renal functions were evaluated. The postoperative AKI classification was made using the RIFLE (Risk, Injury, Failure, Loss of function, and End-stage renal disease) criteria. RESULTS: Postoperative AKI occurred in 14 of 89 patients (15.7%) in group I and in 29 of 104 patients in group II (27.8%; p = 0.046). The CSS did not vary much between the groups (31.52 +/- 13.08 vs. 29.89 +/- 15.70; p = 0.638). In group I, the CSS was not different between patients with AKI and those without AKI (30.167 +/- 3.93 vs. 31.91+/- 14.75; p = 0.78). In group II, the CSS was 36.85 +/- 18.33 in patients with AKI and 28.02 +/- 12.32 in those without, and the difference was significant (p = 0.02). The discriminative ability of the CSS for postoperative AKI using the AUC analysis was 0.500 in group I and 0.840 in group II. CONCLUSION: The CSS may be a simple and successful means of risk prediction of postoperative AKI in on-pump coronary artery surgery. PMID- 26648947 TI - Cardiorenal Syndrome Type 1: Activation of Dual Apoptotic Pathways. AB - Cardiorenal syndrome type 1 (CRS1) pathophysiology is complex, and immune mediated damage, including alterations in the immune response with monocyte apoptosis and cytokine release, has been reported as a potential mechanism. In this study, we examined the putative role of renal tubular epithelial cell (RTC) apoptosis as a pathogenic mechanism in CRS1. In particular, we investigated the caspase pathways involved in induced apoptosis. We enrolled 29 patients with acute heart failure (AHF), 11 patients with CRS1, and 15 controls (CTR) without AHF or acute kidney injury (AKI). Patients who had AKI prior to the episode of AHF or who had any other potential causes of AKI were excluded. Plasma from different groups was incubated with RTCs for 24 h. Subsequently, cell apoptosis, DNA fragmentation, and caspase-3, -8, and -9 activities were investigated in RTCs incubated with AHF, CRS1, and CTR plasma. A p value <0.5 was considered statistically significant. A quantitative analysis of apoptosis showed significantly higher apoptosis rates in CRS1 patients compared to AHF patients and CTR (p < 0.01). This increase in apoptosis was strongly confirmed by caspase 3 levels (rho = 0.73). Caspase-8 and -9 were significantly higher in CRS1 patients compared to AHF patients and CTR (p < 0.01). Furthermore, caspase-3 levels showed a significantly positive correlation with caspase-8 (rho = 0.57) and -9 (rho = 0.47; p < 0.001). This study demonstrated the significantly heightened presence of dual apoptotic disequilibrium in CRS1. Our findings indicated that apoptosis may have a central role in the mechanism of CRS1, and it could be a potential therapeutic target in this syndrome. PMID- 26648948 TI - Quantitative Trait Locus Analysis of Seed Germination and Seedling Vigor in Brassica rapa Reveals QTL Hotspots and Epistatic Interactions. AB - The genetic basis of seed germination and seedling vigor is largely unknown in Brassica species. We performed a study to evaluate the genetic basis of these important traits in a B. rapa doubled haploid population from a cross of a yellow seeded oil-type yellow sarson and a black-seeded vegetable-type pak choi. We identified 26 QTL regions across all 10 linkage groups for traits related to seed weight, seed germination and seedling vigor under non-stress and salt stress conditions illustrating the polygenic nature of these traits. QTLs for multiple traits co-localized and we identified eight hotspots for quantitative trait loci (QTL) of seed weight, seed germination, and root and shoot lengths. A QTL hotspot for seed germination on A02 mapped at the B. rapa Flowering Locus C (BrFLC2). Another hotspot on A05 with salt stress specific QTLs co-located with the B. rapa Fatty acid desaturase 2 (BrFAD2) locus. Epistatic interactions were observed between QTL hotspots for seed germination on A02 and A10 and with a salt tolerance QTL on A05. These results contribute to the understanding of the genetics of seed quality and seeding vigor in B. rapa and can offer tools for Brassica breeding. PMID- 26648950 TI - Characterisation of Lipid Changes in Ethylene-Promoted Senescence and Its Retardation by Suppression of Phospholipase Ddelta in Arabidopsis Leaves. AB - Ethylene and abscisic acid (ABA) both accelerate senescence of detached Arabidopsis leaves. We previously showed that suppression of Phospholipase Ddelta (PLDdelta) retarded ABA-promoted senescence. Here, we report that ethylene promoted senescence is retarded in detached leaves lacking PLDdelta. We further used lipidomics to comparatively profile the molecular species of membrane lipids between wild-type and PLDdelta-knockout (PLDdelta-KO) Arabidopsis during ethylene promoted senescence. Lipid profiling revealed that ethylene caused a decrease in all lipids levels, except phosphatidic acid (PA), caused increases in the ratios of digalactosyl diglyceride/monogalactosyl diglyceride (MGDG) and phosphatidylcholine (PC)/phosphatidylethanolamine (PE), and caused degradation of plastidic lipids before that of extraplastidic lipids in wild-type plants. The accelerated degradation of plastidic lipids during ethylene-promoted senescence in wild-type plants was attenuated in PLDdelta-KO plants. No obvious differences in substrate and product of PLDdelta-catalyzed phospholipid hydrolysis were detected between wild-type and PLDdelta-KO plants, which indicated that the retardation of ethylene-promoted senescence by suppressing PLDdelta might not be related to the role of PLDdelta in catalyzing phospholipid degradation. In contrast, higher plastidic lipid content, especially of MGDG, in PLDdelta-KO plants was crucial for maintaining photosynthetic activity. The lower relative content of PA and higher PC/PE ratio in PLDdelta-KO plants might contribute to maintaining cell membrane integrity. The integrity of the cell membrane in PLDdelta-KO plants facilitated maintenance of the membrane function and of the proteins associated with the membrane. Taking these findings together, higher plastidic lipid content and the integrity of the cell membrane in PLDdelta-KO plants might contribute to the retardation of ethylene-promoted senescence by the suppression of PLDdelta. PMID- 26648949 TI - Involvement of the Cohesin Cofactor PDS5 (SPO76) During Meiosis and DNA Repair in Arabidopsis thaliana. AB - Maintenance and precise regulation of sister chromatid cohesion is essential for faithful chromosome segregation during mitosis and meiosis. Cohesin cofactors contribute to cohesin dynamics and interact with cohesin complexes during cell cycle. One of these, PDS5, also known as SPO76, is essential during mitosis and meiosis in several organisms and also plays a role in DNA repair. In yeast, the complex Wapl-Pds5 controls cohesion maintenance and colocalizes with cohesin complexes into chromosomes. In Arabidopsis, AtWAPL proteins are essential during meiosis, however, the role of AtPDS5 remains to be ascertained. Here we have isolated mutants for each of the five AtPDS5 genes (A-E) and obtained, after different crosses between them, double, triple, and even quadruple mutants (Atpds5a Atpds5b Atpds5c Atpds5e). Depletion of AtPDS5 proteins has a weak impact on meiosis, but leads to severe effects on development, fertility, somatic homologous recombination (HR) and DNA repair. Furthermore, this cohesin cofactor could be important for the function of the AtSMC5/AtSMC6 complex. Contrarily to its function in other species, our results suggest that AtPDS5 is dispensable during the meiotic division of Arabidopsis, although it plays an important role in DNA repair by HR. PMID- 26648951 TI - Comparison of Thermobifida fusca Cellulases Expressed in Escherichia coli and Nicotiana tabacum Indicates Advantages of the Plant System for the Expression of Bacterial Cellulases. AB - The economic conversion of lignocellulosic biomass to biofuels requires in addition to pretreatment techniques access to large quantities of inexpensive cellulases to be competitive with established first generation processes. A solution to this problem could be achieved by plant based expression of these enzymes. We expressed the complete set of six cellulases and an additional beta glucosidase expressed from Thermobifida fusca in the bacterium Escherichia coli and in tobacco plants (Nicotiana tabacum). This was done to determine whether functional enzyme expression was feasible in these organisms. In extracts of recombinant E. coli cells, five of the proteins were detected by western blot analysis, but exocellulases E3 and E6 were undetectable. In the plant-based expression system we were able to detect all six cellulases but not the beta glucosidase even though activity was detectable. When E. coli was used as the expression system, endocellulase E2 was active, while endocellulases E1 and E5 showed only residual activity. The remaining cellulases appeared completely inactive against the model substrates azo-carboxymethyl-cellulose (Azo-CMC) and 4 methylumbelliferyl-cellobioside (4-MUC). Only the beta-glucosidase showed high activity against 4-MUC. In contrast, all the plant-derived enzymes were active against the respective model substrates. Our data indicate that some enzymes of bacterial origin are more active and more efficiently expressed in plants than in a bacterial host. PMID- 26648953 TI - A Homoploid Hybrid Between Wild Vigna Species Found in a Limestone Karst. AB - Genus Vigna comprise several domesticated species including cowpea and mungbean, and diverse wild species. We found an introgressive hybrid population derived from two wild species, Vigna umbellata and Vigna exilis, in Ratchaburi district, Thailand. The hybrid was morphologically similar to V. umbellata but habituated in a limestone rock mountain, which is usually dominated by V. exilis. Analyzing simple sequence repeat loci indicated the hybrid has undergone at least one round of backcross by V. umbellata. We found the hybrid acquired vigorous growth from V. umbellata and drought tolerance plus early flowering from V. exilis, and thus has taken over some habitats of V. exilis in limestone karsts. Given the wide crossability of V. umbellata, the hybrid can be a valuable genetic resource to improve drought tolerance of some domesticated species. PMID- 26648952 TI - Structure and Function of Centromeric and Pericentromeric Heterochromatin in Arabidopsis thaliana. AB - The centromere is a specific chromosomal region where the kinetochore assembles to ensure the faithful segregation of sister chromatids during mitosis and meiosis. Centromeres are defined by a local enrichment of the specific histone variant CenH3 mostly at repetitive satellite sequences. A larger pericentromeric region containing repetitive sequences and transposable elements surrounds the centromere that adopts a particular chromatin state characterized by specific histone variants and post-translational modifications and forms a transcriptionally repressive chromosomal environment. In the model organism Arabidopsis thaliana centromeric and pericentromeric domains form conspicuous heterochromatin clusters called chromocenters in interphase. Here we discuss, using Arabidopsis as example, recent insight into mechanisms involved in maintenance and establishment of centromeric and pericentromeric chromatin signatures as well as in chromocenter formation. PMID- 26648954 TI - Links Between Ethylene and Sulfur Nutrition-A Regulatory Interplay or Just Metabolite Association? AB - Multiple reports demonstrate associations between ethylene and sulfur metabolisms, however the details of these links have not yet been fully characterized; the links might be at the metabolic and the regulatory levels. First, sulfur-containing metabolite, methionine, is a precursor of ethylene and is a rate limiting metabolite for ethylene synthesis; the methionine cycle contributes to both sulfur and ethylene metabolism. On the other hand, ethylene is involved in the complex response networks to various stresses and it is known that S deficiency leads to photosynthesis and C metabolism disturbances that might be responsible for oxidative stress. In several plant species, ethylene increases during sulfur starvation and might serve signaling purposes to initiate the process of metabolism reprogramming during adjustment to sulfur deficit. An elevated level of ethylene might result from increased activity of enzymes involved in its synthesis. It has been demonstrated that the alleviation of cadmium stress in plants by application of S seems to be mediated by ethylene formation. On the other hand, the ethylene-insensitive Nicotiana attenuata plants are impaired in sulfur uptake, reduction and metabolism, and they invest their already limited S into methionine needed for synthesis of ethylene constitutively emitted in large amounts to the atmosphere. Regulatory links of EIN3 and SLIM1 (both from the same family of transcriptional factors) involved in the regulation of ethylene and sulfur pathway, respectively, is also quite probable as well as the reciprocal modulation of both pathways on the enzyme activity levels. PMID- 26648956 TI - Production of the Main Celiac Disease Autoantigen by Transient Expression in Nicotiana benthamiana. AB - Celiac Disease (CD) is a gluten sensitive enteropathy that remains widely undiagnosed and implementation of massive screening tests is needed to reduce the long term complications associated to untreated CD. The main CD autoantigen, human tissue transglutaminase (TG2), is a challenge for the different expression systems available since its cross-linking activity affects cellular processes. Plant-based transient expression systems can be an alternative for the production of this protein. In this work, a transient expression system for the production of human TG2 in Nicotiana benthamiana leaves was optimized and reactivity of plant-produced TG2 in CD screening test was evaluated. First, a subcellular targeting strategy was tested. Cytosolic, secretory, endoplasmic reticulum (C terminal SEKDEL fusion) and vacuolar (C-terminal KISIA fusion) TG2 versions were transiently expressed in leaves and recombinant protein yields were measured. ER TG2 and vac-TG2 levels were 9- to 16-fold higher than their cytosolic and secretory counterparts. As second strategy, TG2 variants were co-expressed with a hydrophobic elastin-like polymer (ELP) construct encoding for 36 repeats of the pentapeptide VPGXG in which the guest residue X were V and F in ratio 8:1. Protein bodies (PB) were induced by the ELP, with a consequent two-fold-increase in accumulation of both ER-TG2 and vac-TG2. Subsequently, ER-TG2 and vac-TG2 were produced and purified using immobilized metal ion affinity chromatography. Plant purified ER-TG2 and vac-TG2 were recognized by three anti-TG2 monoclonal antibodies that bind different epitopes proving that plant-produced antigen has immunochemical characteristics similar to those of human TG2. Lastly, an ELISA was performed with sera of CD patients and healthy controls. Both vac-TG2 and ER TG2 were positively recognized by IgA of CD patients while they were not recognized by serum from non-celiac controls. These results confirmed the usefulness of plant-produced TG2 to develop screening assays. In conclusion, the combination of subcellular sorting strategy with co-expression with a PB inducing construct was sufficient to increase TG2 protein yields. This type of approach could be extended to other problematic proteins, highlighting the advantages of plant based production platforms. PMID- 26648955 TI - Behavior of Leaf Meristems and Their Modification. AB - A major source of diversity in flowering plant form is the extensive variability of leaf shape and size. Leaf formation is initiated by recruitment of a handful of cells flanking the shoot apical meristem (SAM) to develop into a complex three dimensional structure. Leaf organogenesis depends on activities of several distinct meristems that are established and spatiotemporally differentiated after the initiation of leaf primordia. Here, we review recent findings in the gene regulatory networks that orchestrate leaf meristem activities in a model plant Arabidopsis thaliana. We then discuss recent key studies investigating the natural variation in leaf morphology to understand how the gene regulatory networks modulate leaf meristems to yield a substantial diversity of leaf forms during the course of evolution. PMID- 26648957 TI - Staying Alive or Going to Die During Terminal Senescence-An Enigma Surrounding Yield Stability. AB - Breeding programs with the aim to enhance yield productivity under abiotic stress conditions during the reproductive stage of crops is a top priority in the era of climate change. However, the choice of exploring stay-green or senescence phenotypes, which represent an opposing physiological bearing, are explored in cereal breeding programs for enhanced yield stability to a different extent. Thus, the consideration of stay-green or senescence phenotypes is still an ongoing debate and has not been comprehensively addressed. In this review, we provide arguments for designing a target phenotype to mitigate abiotic stresses during pre- and post-anthesis in cereals with a focus on hormonal balances regulating stay-green phenotype versus remobilization. The two major hypothesis for grain yield improvement are (i) the importance of the stay-green trait to elevate grain number under pre-anthesis and anthesis stress and (ii) fine tuning the regulatory and molecular physiological mechanisms to accelerate nutrient remobilization to optimize grain quality and seed weight under post-anthesis stress. We highlight why a cautious balance in the phenotype design is essential. While stay-green phenotypes promise to be ideal for developing stress-tolerant lines during pre-anthesis and fertilization to enhance grain number and yield per se, fine-tuning efficient remobilizing behavior during seed filling might optimize grain weight, grain quality and nutrient efficiency. The proposed model provides novel and focused directions for cereal stress breeding programs to ensure better seed-set and efficient grain-filling in cereals under terminal drought and heat stress exposure. PMID- 26648958 TI - Modulation of Potassium Channel Activity in the Balance of ROS and ATP Production by Durum Wheat Mitochondria-An Amazing Defense Tool Against Hyperosmotic Stress. AB - In plants, the existence of a mitochondrial potassium channel was firstly demonstrated about 15 years ago in durum wheat as an ATP-dependent potassium channel (PmitoKATP). Since then, both properties of the original PmitoKATP and occurrence of different mitochondrial potassium channels in a number of plant species (monocotyledonous and dicotyledonous) and tissues/organs (etiolated and green) have been shown. Here, an overview of the current knowledge is reported; in particular, the issue of PmitoKATP physiological modulation is addressed. Similarities and differences with other potassium channels, as well as possible cross-regulation with other mitochondrial proteins (Plant Uncoupling Protein, Alternative Oxidase, Plant Inner Membrane Anion Channel) are also described. PmitoKATP is inhibited by ATP and activated by superoxide anion, as well as by free fatty acids (FFAs) and acyl-CoAs. Interestingly, channel activation increases electrophoretic potassium uptake across the inner membrane toward the matrix, so collapsing membrane potential (DeltaPsi), the main component of the protonmotive force (Deltap) in plant mitochondria; moreover, cooperation between PmitoKATP and the K(+)/H(+) antiporter allows a potassium cycle able to dissipate also DeltapH. Interestingly, DeltaPsi collapse matches with an active control of mitochondrial reactive oxygen species (ROS) production. Fully open channel is able to lower superoxide anion up to 35-fold compared to a condition of ATP inhibited channel. On the other hand, DeltaPsi collapse by PmitoKATP was unexpectedly found to not affect ATP synthesis via oxidative phosphorylation. This may probably occur by means of a controlled collapse due to ATP inhibition of PmitoKATP; this brake to the channel activity may allow a loss of the bulk phase Deltap, but may preserve a non-classically detectable localized driving force for ATP synthesis. This ability may become crucial under environmental/oxidative stress. In particular, under moderate hyperosmotic stress (mannitol or NaCl), PmitoKATP was found to be activated by ROS, so inhibiting further large-scale ROS production according to a feedback mechanism; moreover, a stress-activated phospholipase A2 may generate FFAs, further activating the channel. In conclusion, a main property of PmitoKATP is the ability to keep in balance the control of harmful ROS with the mitochondrial/cellular bioenergetics, thus preserving ATP for energetic needs of cell defense under stress. PMID- 26648959 TI - Exploring Jasmonates in the Hormonal Network of Drought and Salinity Responses. AB - Present and future food security is a critical issue compounded by the consequences of climate change on agriculture. Stress perception and signal transduction in plants causes changes in gene or protein expression which lead to metabolic and physiological responses. Phytohormones play a central role in the integration of different upstream signals into different adaptive outputs such as changes in the activity of ion-channels, protein modifications, protein degradation, and gene expression. Phytohormone biosynthesis and signaling, and recently also phytohormone crosstalk have been investigated intensively, but the function of jasmonates under abiotic stress is still only partially understood. Although most aspects of jasmonate biosynthesis, crosstalk and signal transduction appear to be similar for biotic and abiotic stress, novel aspects have emerged that seem to be unique for the abiotic stress response. Here, we review the knowledge on the role of jasmonates under drought and salinity. The crosstalk of jasmonate biosynthesis and signal transduction pathways with those of abscisic acid (ABA) is particularly taken into account due to the well established, central role of ABA under abiotic stress. Likewise, the accumulating evidence of crosstalk of jasmonate signaling with other phytohormones is considered as important element of an integrated phytohormonal response. Finally, protein post-translational modification, which can also occur without de novo transcription, is treated with respect to its implications for phytohormone biosynthesis, signaling and crosstalk. To breed climate-resilient crop varieties, integrated understanding of the molecular processes is required to modulate and tailor particular nodes of the network to positively affect stress tolerance. PMID- 26648960 TI - Zinc-Dependent Protection of Tobacco and Rice Cells From Aluminum-Induced Superoxide-Mediated Cytotoxicity. AB - Al(3+) toxicity in growing plants is considered as one of the major factors limiting the production of crops on acidic soils worldwide. In the last 15 years, it has been proposed that Al(3+) toxicity are mediated with distortion of the cellular signaling mechanisms such as calcium signaling pathways, and production of cytotoxic reactive oxygen species (ROS) causing oxidative damages. On the other hand, zinc is normally present in plants at high concentrations and its deficiency is one of the most widespread micronutrient deficiencies in plants. Earlier studies suggested that lack of zinc often results in ROS-mediated oxidative damage to plant cells. Previously, inhibitory action of Zn(2+) against lanthanide-induced superoxide generation in tobacco cells have been reported, suggesting that Zn(2+) interferes with the cation-induced ROS production via stimulation of NADPH oxidase. In the present study, the effect of Zn(2+) on Al(3+)-induced superoxide generation in the cell suspension cultures of tobacco (Nicotiana tabacum L., cell-line, BY-2) and rice (Oryza sativa L., cv. Nipponbare), was examined. The Zn(2+)-dependent inhibition of the Al(3+)-induced oxidative burst was observed in both model cells selected from the monocots and dicots (rice and tobacco), suggesting that this phenomenon (Al(3+)/Zn(2+) interaction) can be preserved in higher plants. Subsequently induced cell death in tobacco cells was analyzed by lethal cell staining with Evans blue. Obtained results indicated that presence of Zn(2+) at physiological concentrations can protect the cells by preventing the Al(3+)-induced superoxide generation and cell death. Furthermore, the regulation of the Ca(2+) signaling, i.e., change in the cytosolic Ca(2+) ion concentration, and the cross-talks among the elements which participate in the pathway were further explored. PMID- 26648961 TI - Plant-Derived Chimeric Virus Particles for the Diagnosis of Primary Sjogren Syndrome. AB - Plants are ideal for the production of protein-based nanomaterials because they synthesize and assemble complex multimeric proteins that cannot be expressed efficiently using other platforms. Plant viruses can be thought of as self replicating proteinaceous nanomaterials generally stable and easily produced in high titers. We used Potato virus X (PVX), chimeric virus particles, and Cowpea mosaic virus, empty virus-like particles to display a linear peptide (lipo) derived from human lipocalin, which is immunodominant in Sjogren's syndrome (SjS) and is thus recognized by autoantibodies in SjS patient serum. These virus derived nanoparticles were thus used to develop a diagnostic assay for SjS based on a direct enzyme linked immunosorbent assay format. We found that PVX-lipo formulations were more sensitive than the chemically synthesized immunodominant peptide and equally specific when used to distinguish between healthy individuals and SjS patients. Our novel assay therefore allows the diagnosis of SjS using a simple, low-invasive serum test, contrasting with the invasive labial biopsy required for current tests. Our results demonstrate that nanomaterials based on plant viruses can be used as diagnostic reagents for SjS, and could also be developed for the diagnosis of other diseases. PMID- 26648962 TI - Crucial Roles of Abscisic Acid Biogenesis in Virulence of Rice Blast Fungus Magnaporthe oryzae. AB - Rice suffers dramatic yield losses due to blast pathogen Magnaporthe oryzae. Pseudomonas chlororaphis EA105, a bacterium that was isolated from the rice rhizosphere, inhibits M. oryzae. It was shown previously that pre-treatment of rice with EA105 reduced the size of blast lesions through jasmonic acid (JA)- and ethylene (ETH)-mediated ISR. Abscisic acid (ABA) acts antagonistically toward salicylic acid (SA), JA, and ETH signaling, to impede plant defense responses. EA105 may be reducing the virulence of M. oryzae by preventing the pathogen from up-regulating the key ABA biosynthetic gene NCED3 in rice roots, as well as a beta-glucosidase likely involved in activating conjugated inactive forms of ABA. However, changes in total ABA concentrations were not apparent, provoking the question of whether ABA concentration is an indicator of ABA signaling and response. In the rice-M. oryzae interaction, ABA plays a dual role in disease severity by increasing plant susceptibility and accelerating pathogenesis in the fungus itself. ABA is biosynthesized by M. oryzae. Further, exogenous ABA increased spore germination and appressoria formation, distinct from other plant growth regulators. EA105, which inhibits appressoria formation, counteracted the virulence-promoting effects of ABA on M. oryzae. The role of endogenous fungal ABA in blast disease was confirmed through the inability of a knockout mutant impaired in ABA biosynthesis to form lesions on rice. Therefore, it appears that EA105 is invoking multiple strategies in its protection of rice from blast including direct mechanisms as well as those mediated through plant signaling. ABA is a molecule that is likely implicated in both tactics. PMID- 26648963 TI - Periprocedural Risk of Stroke Is Elevated in Patients with End-Stage Renal Disease on Hemodialysis. AB - OBJECTIVE: To describe the most common clinical factors and stroke etiologies in a case series of patients with end-stage renal disease on hemodialysis (ESRD/HD) with transient ischemic attack (TIA) or ischemic stroke (IS). BACKGROUND: Prior studies have shown that patients on HD are at an elevated risk of stroke, but these studies have focused on the overall stroke risk. This case series sought to determine the percentage of acute ischemic events that occur during or immediately after HD. METHODS: ICD-9 codes were used to identify IS and TIA patients with ESRD/HD admitted to the stroke service from August 22, 2011, to June 21, 2014. Charts were reviewed to determine the age, sex, and race/ethnicity of the cohort. TIA/IS diagnosis was confirmed by a vascular neurologist. Clinical factors were assessed, including: onset during or shortly after HD, defined as occurring within 12 h of HD; the presence of a lesion on diffusion-weighted MRI; hypotension, hyponatremia, or hypoglycemia at symptom onset; the stroke etiology; the presence of focal neurologic deficits; whether the patient was in the window period for intravenous tissue plasminogen activator (IVtPA) upon presentation, and whether the patient received IVtPA. RESULTS: We identified 34 ESRD/HD patients with a diagnosis of TIA/stroke in the specified time period. A majority of patients (70.6%) were African American. Patient age ranged from 32 to 84 years, with a median age of 67 years. Twenty-seven patients (79.4%) had confirmed ischemic infarcts on diffusion-weighted MRI. Seven patients (20.6%) were diagnosed with TIA. In 13 patients (38.2%), symptom onset occurred during or shortly after HD. Of these 13 patients, 8 (61.5%) had symptom onset during HD. Three patients (8.8%) had documented hypotension near the time of symptom onset, and 2 (5.9%) were hyponatremic on presentation to the emergency department. The distribution of stroke etiologies was as follows: 4 (11.8%) watershed distribution, 1 (2.9%) large artery atherosclerosis, 2 (20.6%) small vessel disease, 10 (29.4%) cardioembolic, and 9 (26.5%) cryptogenic. In 28 patients (82.4%), focal neurologic deficits were observed on presentation. Nine patients (26.5%) arrived within the window period for IVtPA, and 4 (11.8%) were eligible and received IVtPA. CONCLUSIONS: Of all patients with ESRD on HD admitted to the stroke service over the study period, over one third (38.3%) had the onset of their ischemic event during or shortly after HD, and nearly one quarter (23.5%) had the onset during HD. While clinicians may be tempted to attribute neurologic changes after HD to metabolic etiologies, they should also be aware that HD represents a period of elevated risk for acute ischemia. PMID- 26648964 TI - Sex Differences in Long-Term Survival after a First Stroke with Intravenous Thrombolysis: Ebrictus Study. AB - BACKGROUND: A number of large trials have confirmed the benefits of thrombolysis in acute stroke, but there are gender differences. We sought to examine the relationship between sex and outcome after thrombolysis. METHODS: This was a prospective cohort study including 1,272 incident ischemic strokes (597 in women) from April 1, 2006 to December 31, 2014. Statistical approaches were used for analyzing survival outcomes and their relationship with thrombolysis therapy. RESULTS: The death rates were lower (p = 0.003) in the thrombolysis therapy group with an incidence ratio of 0.57 (95% CI 0.39-0.83). 113 (8.8%) patients (53 women) received thrombolysis. They were significantly younger (69.2 +/- 12.7 vs. 73.9 +/- 12.5 years; p < 0.001), had higher NIHSS score (12.7 +/- 6.3 vs. 7.3 +/- 7.0; p < 0.001), spent more days in hospital (10.4 +/- 8.3 vs. 8.3 +/- 7.9; p < 0.001), and had a higher average Barthel score at discharge (85.5 +/- 24.4 vs. 79.2 +/- 28.6; p = 0.023). The male/female incidence ratio showed a significant decrease (p = 0.01) in the incidence of mortality in women and a better Barthel score. The thrombolysis improved the survival in the overall group with thrombolysis versus without thrombolysis (p = 0.028), in women versus in men with thrombolysis (p = 0.023), and in women with thrombolysis versus in those without thrombolysis (p < 0.001) but not in men with thrombolysis versus in those without thrombolysis (p = 0.743). The protective factors as regards mortality were thrombolysis therapy (95% CI 0.37-0.80; p = 0.002), Barthel score >= 60 (95% CI 0.81-0.94; p = 0.002), and cardiovascular secondary prevention 1 year after stroke (0.13, 95% CI 0.06-0.28). CONCLUSIONS: The stroke death rates were lower in women after thrombolysis treatment and suggest significant benefit for women in this setting. The overall benefit on survival of the patients treated with thrombolysis might be explained by the beneficial effect of the thrombolysis on the women. PMID- 26648965 TI - Functional Outcome of Hemorrhagic Transformation after Thrombolysis for Ischemic Stroke: A Prospective Study. AB - BACKGROUND/AIMS: Hemorrhagic transformation (HT) is usually taken into account when symptomatic, but the role of asymptomatic HT is not well known. The aim of our study was to evaluate the link between HT after thrombolysis for ischemic stroke and functional outcome at 3 months, with particular emphasis on asymptomatic HT. METHODS: Our study was performed prospectively between June 2012 and June 2013 in the Stroke Unit of the University Hospital Center of Tours (France). All patients treated with intravenous thrombolysis were consecutively included. HT was classified on susceptibility-weighted imaging (SWI) with 3-tesla MRI at 7 +/- 3 days after treatment. We evaluated functional outcome at 3 months using the modified Rankin Scale (mRS). Dependency was defined as an mRS score of >= 3. RESULTS: After 1 year, 128 patients had received thrombolytic therapy for ischemic stroke, of whom 90 patients underwent both 3-tesla MRI and SWI at day 7. Fifty-two had HT, including 8 symptomatic cases. At 3 months, 68% of those patients were dependent compared to 31% of patients without HT [OR 4.6 (1.9 11.4), p = 0.001]. In asymptomatic HT, the rate was 62% [OR 3.5 (1.4-8.9), p = 0.007], but did not reach significance after adjustment for stroke severity. DISCUSSION: Our study found no statistically significant effect of HT on outcome after adjustment for initial stroke severity. However, the innocuousness of HT is not certain, and only few studies have already highlighted the increased risk of dependency. Using 3-tesla MRI with SWI allows us to increase the detection rate of small hemorrhage. CONCLUSION: HT after thrombolysis is very frequent on SWI, but the initial stroke severity is an important predictor to assess the role of HT for patient outcome. PMID- 26648967 TI - Erratum. PMID- 26648966 TI - Cancer-Associated Stroke: The Bergen NORSTROKE Study. AB - BACKGROUND: Underlying malignancy can cause ischemic stroke in some patients. Mechanisms include the affection of the coagulation cascade, tumor mucin secretion, infections and nonbacterial endocarditis. The release of necrotizing factor and interleukins may cause inflammation of the endothelial lining, creating a prothrombotic surface that triggers thromboembolic events, including stroke. The aims of this study were to assess the occurrence of cancer in patients who had recently suffered an ischemic stroke and to detect possible associations between stroke and cancer subtypes. METHODS: All ischemic stroke patients registered in the Norwegian Stroke Research Registry (NORSTROKE) as part of the ongoing Bergen NORSTROKE study were included. Blood samples were obtained on admission. Stroke etiology was determined by the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria, and the severity of stroke was defined according to the National Institute of Health Stroke Scale score. Information about cancer disease after stroke was obtained from patient medical records and The Cancer Registry of Norway. RESULTS: From a total of 1,282 ischemic stroke patients with no history of cancer, 55 (4.3%) patients were diagnosed with cancer after stroke. The median time from stroke onset to cancer diagnosis was 14.0 months (interquartile range 6.2-24.5). Twenty-three (41.8%) patients were diagnosed with cancer within 1 year and 13 (23.6%) within 6 months. The most common cancer type was lung cancer (19.0%). By Cox regression analysis, cancer after stroke was associated with elevated D-dimer levels on admittance (p < 0.001), age (p = 0.01) and smoking (p = 0.04). CONCLUSIONS: Cancer-associated stroke is rare, and routine investigation for cancer seems unwarranted in acute ischemic stroke. However, in stroke patients with elevated levels of blood coagulation factors, C-reactive protein, higher age and a history of smoking, underlying malignancy should be considered. Our study suggests that an unknown stroke etiology does not predict malignancy. PMID- 26648968 TI - Clinical, Laboratory, and Imaging Characteristics of Transient Ischemic Attack Caused by Large Artery Lesions: A Comparison between Carotid and Intracranial Arteries. AB - BACKGROUND/AIMS: The aims of this study were to determine the differences in clinical characteristics and the risk of ischemic stroke between patients with transient ischemic attack (TIA) attributable to extracranial carotid and intracranial artery occlusive lesions. METHODS: Among 445 patients admitted to our stroke care unit within 48 h of TIA onset between April 2008 and December 2013, 85 patients (63 men, mean age 69.4 years) with large artery occlusive lesions relevant to symptoms were included in this study. The primary endpoints were ischemic stroke at 2 and 90 days after TIA onset. RESULTS: Twenty-eight patients had carotid artery occlusive lesions (extracranial group), and 57 patients had intracranial artery occlusive lesions (intracranial group). Patients in the intracranial group were significantly younger, had lower levels of fibrinogen, and were less likely to have occlusion when compared with those in the extracranial group. Eleven patients in the extracranial group and none in the intracranial group underwent revascularization procedures within 90 days of TIA onset. The 2-day risk (14.2 vs. 0%, p = 0.044) and the 90-day risk (17.1 vs. 0%, p = 0.020) of ischemic stroke after TIA onset were significantly higher in the intracranial group than in the extracranial group. CONCLUSIONS: Among our patients with TIA caused by large artery disease, patients with intracranial artery occlusive lesions were more frequent and were at higher risk of early ischemic stroke than those with extracranial carotid artery occlusive lesions. These data highlight the importance of prompt assessment of intracranial artery lesions in patients with TIA. PMID- 26648969 TI - The CXCR2 Gene Polymorphism Is Associated with Stroke in Patients with Essential Hypertension. AB - Hypertension is the major risk factor for stroke, and genetic factors contribute to its development. Inflammation has been hypothesized to be the key link between blood pressure elevation and stroke. We performed an analysis of the association between inflammatory mediator gene polymorphisms and the incidence of stroke in patients with essential hypertension (EH). The study group consisted of 625 individuals (296 patients with noncomplicated EH, 71 hypertensive patients with ischemic stroke, and 258 control subjects). Both patients and controls were ethnic Tatars originating from the Republic of Bashkortostan (Russian Federation). The analysis has shown that the risk of ischemic stroke was associated with the CXCR2 rs1126579 polymorphism. Our results indicate that among patients with EH, the heterozygous genotype carriers had a higher risk of stroke (OR = 1.72, 95% CI 1.01-2.92), whereas the CXCR2*C/C genotype was protective against stroke (OR = 0.32, 95% CI 0.12-0.83). As shown by the gene-gene interaction analysis, the CXCR2 rs1126579 polymorphism was also present in all genotype/allele combinations associated with the risk of stroke. Genetic patterns associated with stroke also included polymorphisms in the CCL2, CCL18, CX3CR1, CCR5, and CXCL8 (IL8) genes, although no association between these loci and stroke was detected by individual analysis. PMID- 26648970 TI - Improving Outcomes Achieved by a New Stroke Program in Hungary. AB - BACKGROUND: Stroke is a devastating disease with increasing incidence and prevalence due to population aging. Even with the best care, a proportion of patients dies or is left with significant neurological and cognitive disability. Organization of stroke centers markedly improved outcomes worldwide. We initiated a 'lysis alarm' program in September 2013 at our medical center. METHODS: This is a retrospective review of electronic data from patients with acute ischemic stroke before (October 2012-June 2013) and after (October 2013-June 2014) the 'lysis alarm' program was introduced at our medical center. RESULTS: Prior to the introduction of the stroke program, there were only 19 thrombolysis procedures in 777 acute stroke patients in 9 months, while this figure rose to 32 thrombolysis procedures in 737 acute stroke patients after the initiation of the program. The 'door-to-needle' time decreased from 88 to 71 min when the two study periods were compared. These changes were associated with decreased stroke mortality in patients receiving thrombolytic treatment (16% prior to the program and 9% during the program). In 2013, there were 1,439 thrombolysis procedures, representing 3.2% of all stroke cases throughout Hungary. After the introduction of the 'lysis alarm' program, we have reached a 4% thrombolysis rate at our medical center. CONCLUSIONS: Our thrombolysis rate is higher than the national average, but still low compared to the rates of Western European countries. We are continuously working to enhance our stroke program. Here, we discuss those components that need to be further refined in order to improve stroke intervention and outcome. PMID- 26648971 TI - DWI Lesion Patterns in Cancer-Related Stroke--Specifying the Phenotype. AB - BACKGROUND: Due to the lack of specific diagnostic markers, the diagnosis of cancer-related stroke strongly depends on its phenotype. Distinct DWI lesion patterns with involvement of multiple vascular territories have been reported repeatedly in cancer-related stroke but have not been addressed in detail in a selected cohort of prospectively recruited cancer patients with emphasis on hypercoagulable conditions. PATIENTS AND METHODS: Ischemic stroke patients with known malignant cancer activity, laboratory evidence of strong plasmatic hypercoagulation (D-dimer levels > 3 ug/ml) and without competing stroke etiologies according to the recently introduced ASCOD (A - atherosclerosis, S - small vessel disease, C - cardiac pathology, O - other cause, and D - dissection) classification of evidence-rated etiology of stroke subtypes were included in the analysis. Cerebral MRI on admission was reviewed with respect to ischemic lesion patterns. RESULTS: Thirty-two patients met the inclusion criteria. The mean D dimer levels were 15.39 ug/ml (+/- 10.84). Acute infarction in >= 2 vascular territories was present in 27/32 (84%) patients. (Micro-) embolic scattering of infarction was present in 25/32 (78%) patients. Evidence for previous, potentially oligosymptomatic infarction was found in 16 (50%) patients, demonstrated by the additional presence of subacute or chronic ischemic lesions. CONCLUSION: When excluding competing embolic and nonembolic stroke etiologies, the pattern of scattered DWI lesions in multiple vascular supply territories strongly dominates the phenotype of cancer-related stroke. Additionally, evidence of recurrent infarction is frequent in this cohort of patients. This is not only important for the diagnosis of cancer-related stroke itself but may prove helpful for the identification of cancer-related stroke patients with unknown malignancy at the time of stroke manifestation and evaluation of strategies for secondary prevention. PMID- 26648972 TI - Subarachnoid Haemorrhage and Sports. AB - BACKGROUND: Some cases of subarachnoid haemorrhage (SAH) have been associated with vigorous physical activity, including sports. Our research aimed to describe the association between SAH and sports and to identify the types of sports that were more frequently found as precipitating factors in a tertiary single-centre SAH register. METHODS: We retrieved information from a prospectively collected SAH registry and reviewed discharge notes of acute SAH patients admitted to the Stroke Unit of Hospital de Santa Maria, Lisbon, between 1995 and 2014. RESULTS: Out of 738 patients included in the analysis, 424 (57.5%) cases of SAH were preceded by physical activity. Nine cases (1.2%) were associated with sports, namely running (2 cases), aerobics (2 cases), cycling, body balance, dance, surf and windsurf. Patients with SAH while practicing sports were younger than controls (average age 43.1 vs. 57.0 years; p = 0.007). In 1 patient, there was a report of trauma to the neck. Patients in the sports group only had Hunt and Hess scale grades 1 (11.1%) or 2 (88.9%) at admission, while patients in the control group had a wider distribution in severity. CONCLUSIONS: Our findings indicate that SAH precipitated by sports is not very frequent and is uncommonly related to trauma. Patients who suffered SAH associated with sports were younger and apparently had a milder clinical presentation. PMID- 26648973 TI - Vasoactive Peptide Levels after Change of Dialysis Mode. AB - BACKGROUND/AIMS: Plasma concentrations of the N-terminal fragment of pro-brain natriuretic peptide (NT-proBNP) are increased in end-stage renal disease. Improvement in hemodynamic stability has been reported when switching from hemodialysis (HD) to on-line hemodiafiltration (ol-HDF). The aim of this study was to investigate plasma concentrations of NT-proBNP, BNP and neuropeptide Y (NPY) during a 1-year follow-up, after a change from high-flux HD to postdilution ol-HDF. Additional variables were also studied, e.g. pulse wave velocity and ordinary clinical parameters. METHOD: We conducted a prospective, single-center study including 35 patients who were switched from HD to HDF. Plasma concentrations of NT-proBNP, BNP and NPY before and after dialysis were measured at baseline (i.e. HD) and at 1, 2, 4, 6 and 12 months on HDF. RESULTS: All three peptide levels decreased significantly during HD and HDF when comparing concentrations before and after dialysis. Mean absolute value (before/after) and relative decrease (%) before versus after dialysis was 13.697/9.497 ng/l (31%) for NT-proBNP, 62/40 ng/ml (35%) for BNP and 664/364 pg/l (45%) for NPY. No significant differences were observed when comparing predialysis values over time. However, postdialysis NT-proBNP concentration showed a significant decrease of 48% over time after the switch to HDF. CONCLUSION: The postdialysis plasma levels of NT-proBNP, BNP and NPY decreased significantly during both dialysis modes when compared to before dialysis. The postdialysis lowering of NT-proBNP increased further over time after the switch to ol-HDF; the predialysis levels were unchanged, suggesting no effect on its production in the ventricles of the heart. PMID- 26648974 TI - Factors Contributing to Erythropoietin Hyporesponsiveness in Patients on Long Term Continuous Ambulatory Peritoneal Dialysis: A Cross-Sectional Study. AB - BACKGROUND: Factors contributing to erythropoietin (EPO) hyporesponsiveness in patients on long-term continuous ambulatory peritoneal dialysis are not well understood. Therefore, we investigated the factors contributing to EPO hyporesponsiveness using the EPO resistance index (ERI). METHODS: A total of 14 patients (7 males and 7 females, age 65.0 +/- 11.9 years) were selected for this study. We defined ERI as the weekly dose of EPO per body weight divided by hemoglobin (U/kg/g/dl/week). Bioelectrical impedance analysis was used to assess the patients' body composition and fluid status. We examined associations between ERI and clinical parameters, such as physiological, chemical and nutrition status, by correlation and multiple linear regression analyses. RESULTS: Peritoneal dialysis duration was 95 +/- 23 months, and all patients underwent peritoneal dialysis for >5 years. Hemoglobin, blood pressure and ultrafiltration volume of peritoneal dialysis were 11.5 +/- 1.2 g/dl, 123 +/- 14/72 +/- 8 mm Hg and 834 +/- 317 ml/day, respectively. Renal Kt/V and peritoneal Kt/V, which are indices of dialysis adequacy, were 0.32 +/- 0.31 and 1.70 +/- 0.31, respectively. Age and extracellular water/total body water (ECW/TBW) ratio had significant positive correlations with ERI (both p < 0.05). Levels of C-reactive protein, serum albumin, parathyroid hormone and normalized protein catabolic rate were not significantly correlated with ERI. In a multiple regression analysis, ECW/TBW was independently associated with ERI (p < 0.05). CONCLUSIONS: This study demonstrates that ECW/TBW was a factor contributing to ERI and that appropriate maintenance of body fluid volume could contribute to low EPO dosing. PMID- 26648975 TI - Extent of Linkage Disequilibrium and Effective Population Size in Four South African Sanga Cattle Breeds. AB - Knowledge on the extent of linkage disequilibrium (LD) in livestock populations is essential to determine the minimum distance between markers required for effective coverage when conducting genome-wide association studies (GWAS). This study evaluated the extent of LD, persistence of allelic phase and effective population size (Ne) for four Sanga cattle breeds in South Africa including the Afrikaner (n = 44), Nguni (n = 54), Drakensberger (n = 47), and Bonsmara breeds (n = 46), using Angus (n = 31) and Holstein (n = 29) as reference populations. We found that moderate LD extends up to inter-marker distances of 40-60 kb in Angus (0.21) and Holstein (0.21) and up to 100 kb in Afrikaner (0.20). This suggests that genomic selection and association studies performed within these breeds using an average inter-marker r (2)>= 0.20 would require about 30,000-50,000 SNPs. However, r (2)>= 0.20 extended only up to 10-20 kb in the Nguni and Drakensberger and 20-40 kb in the Bonsmara indicating that 75,000 to 150,000 SNPs would be necessary for GWAS in these breeds. Correlation between alleles at contiguous loci indicated that phase was not strongly preserved between breeds. This suggests the need for breed-specific reference populations in which a much greater density of markers should be scored to identify breed specific haplotypes which may then be imputed into multi-breed commercial populations. Analysis of effective population size based on the extent of LD, revealed Ne = 95 (Nguni), Ne = 87 (Drakensberger), Ne = 77 (Bonsmara), and Ne = 41 (Afrikaner). Results of this study form the basis for implementation of genomic selection programs in the Sanga breeds of South Africa. PMID- 26648976 TI - Overexpression of the Heterochromatinization Factor BAHD1 in HEK293 Cells Differentially Reshapes the DNA Methylome on Autosomes and X Chromosome. AB - BAH domain-containing protein 1 (BAHD1) is involved in heterochromatin formation and gene repression in human cells. BAHD1 also localizes to the inactive X chromosome (Xi), but the functional significance of this targeting is unknown. So far, research on this protein has been hampered by its low endogenous abundance and its role in epigenetic regulation remains poorly explored. In this work, we used whole-genome bisulfite sequencing (BS-seq) to compare the DNA methylation profile of HEK293 cells expressing low levels of BAHD1 (HEK-CT) to that of isogenic cells stably overexpressing BAHD1 (HEK-BAHD1). We show that increasing BAHD1 levels induces de novo DNA methylation on autosomes and a marked hypomethylation on the X chromosome (chrX). We identified 91,358 regions that have different methylation patterns in HEK-BAHD1 compared to HEK-CT cells (termed "BAHD1-DMRs"), of which 83,850 mapped on autosomes and 7508 on the X chromosome (chrX). Autosomal BAHD1-DMRs were predominantly hypermethylated and located to satellites, interspersed repeats, and intergenic regions. In contrast, BAHD1-DMRs on chrX were mainly hypomethylated and located to gene bodies and enhancers. We further found that BAHD1-DMRs display a higher-order organization by being clustered within large chromosomal domains. Half of these "BAHD1-Associated differentially methylated Domains" (BADs) overlapped with lamina-associated domains (LADs). Based on these results, we propose that BAHD1-mediated heterochromatin formation is linked to DNA methylation and may play a role in the spatial architecture of the genome. PMID- 26648978 TI - Illuminating Spatial and Temporal Organization of Protein Interaction Networks by Mass Spectrometry-Based Proteomics. AB - Protein-protein interactions are at the core of all cellular functions and dynamic alterations in protein interactions regulate cellular signaling. In the last decade, mass spectrometry (MS)-based proteomics has delivered unprecedented insights into human protein interaction networks. Affinity purification-MS (AP MS) has been extensively employed for focused and high-throughput studies of steady state protein-protein interactions. Future challenges remain in mapping transient protein interactions after cellular perturbations as well as in resolving the spatial organization of protein interaction networks. AP-MS can be combined with quantitative proteomics approaches to determine the relative abundance of purified proteins in different conditions, thereby enabling the identification of transient protein interactions. In addition to affinity purification, methods based on protein co-fractionation have been combined with quantitative MS to map transient protein interactions during cellular signaling. More recently, approaches based on proximity tagging that preserve the spatial dimension of protein interaction networks have been introduced. Here, we provide an overview of MS-based methods for analyzing protein-protein interactions with a focus on approaches that aim to dissect the temporal and spatial aspects of protein interaction networks. PMID- 26648979 TI - Current trends in treatment of hypertension in Karachi and cost minimization possibilities. AB - OBJECTIVE: This study finds out drug usage trends in Stage I Hypertensive Patients without any compelling indications in Karachi, deviations of current practices from evidence based antihypertensive therapeutic guidelines and looks for cost minimization opportunities. METHODS: In the present study conducted during June 2012 to August 2012, two sets were used. Randomized stratified independent surveys were conducted in doctors and general population - including patients, using pretested questionnaires. Sample sizes for doctors and general population were 100 and 400 respectively. Statistical analysis was conducted on Statistical Package for Social Science (SPSS). Financial impact was also analyzed. RESULTS: On the basis of patients' doctors' feedback, Beta Blockers, and Angiotensin Converting Enzyme Inhibitors were used more frequently than other drugs. Thiazides and low-priced generics were hardly prescribed. Beta blockers were prescribed widely and considered cost effective. This trend increases cost by two to ten times. CONCLUSION: Feedbacks showed that therapeutic guidelines were not followed by the doctors practicing in the community and hospitals in Karachi. Thiazide diuretics were hardly used. Beta blockers were widely prescribed. High priced market leaders or expensive branded generics were commonly prescribed. Therefore, there are great opportunities for cost minimization by using evidence-based clinically effective and safe medicines. PMID- 26648977 TI - Biased Allele Expression and Aggression in Hybrid Honeybees may be Influenced by Inappropriate Nuclear-Cytoplasmic Signaling. AB - Hybrid effects are often exhibited asymmetrically between reciprocal families. One way this could happen is if silencing of one parent's allele occurs in one lineage but not the other, which could affect the phenotypes of the hybrids asymmetrically by silencing that allele in only one of the hybrid families. We have previously tested for allele-specific expression biases in hybrids of European and Africanized honeybees and we found that there was an asymmetric overabundance of genes showing a maternal bias in the family with a European mother. Here, we further analyze allelic bias in these hybrids to ascertain whether they may underlie previously described asymmetries in metabolism and aggression in similar hybrid families and we speculate on what mechanisms may produce this biased allele usage. We find that there are over 500 genes that have some form of biased allele usage and over 200 of these are biased toward the maternal allele but only in the family with European maternity, mirroring the pattern observed for aggression and metabolic rate. This asymmetrically biased set is enriched for genes in loci associated with aggressive behavior and also for mitochondrial-localizing proteins. It contains many genes that play important roles in metabolic regulation. Moreover we find genes relating to the piwi interacting RNA (piRNA) pathway, which is involved in chromatin modifications and epigenetic regulation and may help explain the mechanism underlying this asymmetric allele use. Based on these findings and previous work investigating aggression and metabolism in bees, we propose a novel hypothesis; that the asymmetric pattern of biased allele usage in these hybrids is a result of inappropriate use of piRNA-mediated nuclear-cytoplasmic signaling that is normally used to modulate aggression in honeybees. This is the first report of widespread asymmetric effects on allelic expression in hybrids and may represent a novel mechanism for gene regulation. PMID- 26648980 TI - Cancellation of operations in Saudi Arabian hospitals: Frequency, reasons and suggestions for improvements. AB - OBJECTIVE: To identify the frequency and reasons of operations cancellation in 25 Makkah region hospitals in Saudi Arabia. METHODS: Retrospective evaluation of the rate of surgery cancellation in 25 hospitals of Makkah region was performed in this study. The data of scheduled surgeries from 15 different surgical specialties was collected from January to December 2013. Frequency and reasons of cancellation of elective surgical cases in different specialty were studied with a view to recommend suggestions for improvement. Data was analyzed on SPSS -16. RESULTS: There are 120 operating rooms (OR) in 25 Makkah region hospitals and during the year 2013, a total of 16,211 surgery cases were listed, and 1,238 (7.6%) cases were canceled. Contribution to total cancellation was highest in orthopedic 33.8% followed by general surgery 27.5%, obstetrics 7.7% and ENT 5.2%. According to category, 42.81% rate of cancellation was patient related, 20.03% facility related, 9.45% due to improper work-up, 1.45% associated with anesthesia, 7.19% related to surgeons, and 18.90% other/and not recorded reasons. CONCLUSIONS: Present study found 7.6% cancelation rate in Makkah region hospitals and three most common causes for cancellations were patients related, facility related and improper work-up. PMID- 26648981 TI - Success rates and prognosis of heart valvuloplasty and valve replacement performed for elderly patients. AB - OBJECTIVE: To analyze the success rates and prognosis of heart valvuloplasty and valve replacement for elderly patients, and to provide clinical evidence. METHODS: A total of 1240 patients who received heart valve surgeries in our hospital from June 2004 to October 2014 were selected and retrospectively analyzed. They were divided into two groups based on age (60), and those older than 60 (Group B) suffered from rheumatic valvular heart disease and nonrheumatic valvular heart disease including degenerative valve disease. Mitral valve replacement (MVR), tricuspid valve replacement (TVR), aortic valve replacement (AVR), double valve replacement (DVR), mitral valvuloplasty (MVP) and tricuspid valvuloplasty (TVP) were performed by using bioprosthetic and mechanical valves. Before surgery, coronary angiography, coronary artery bypass grafting (CABG), left atrial thrombectomy, left atrial wall folding and radiofrequency ablation were conducted. For the patients younger than 60 (Group A) who had congenital heart disease, rheumatic valvular heart disease and valvular heart disease, MVR, AVR, DVR, MVP, TVP and closed cuspid commissurotomy were performed with bioprosthetic and mechanical valves. The two groups were then monitored. RESULTS: The mortality rates of Group A and Group B were 2.7% (16 cases) and 3.1% (20 cases) respectively. They died mainly of malignant ventricular arrhythmias, multiple organ failure, left ventricular rupture, low cardiac output syndrome, acute renal failure, respiratory failure, upper gastrointestinal bleeding, mechanical valve failure and cerebrovascular accident. The two groups had significantly different application rates of bioprosthetic valve, times of auxiliary ventilation and hospitalization stay lengths (P<0.05), but left ventricular ejection fractions, left ventricular end-diastolic diameters (LVEDDs), mortality rates as well as times of aortic cross-clamping and cardiopulmonary bypass were similar (P>0.05). LVEDD, complicated coronary artery disease, CABG and grade of the New York Heart Association Functional Classification were independent risk factors for postoperative death. CONCLUSION: When heart valvuloplasty and valve replacement were performed for elderly patients, the success rate and prognosis could only be improved by optimizing preoperative preparation, shortening the times of cardiopulmonary bypass and aortic cross-clamping, and paying particular attention to myocardial protection and postoperative treatment. PMID- 26648982 TI - Comparison of pre-procedural anxiety and depression scores for patients undergoing chorion villus sampling and amniocentesis: An alternative perspective on prenatal invasive techniques. AB - OBJECTIVE: To compare the pre-procedural anxiety and depression levels of patients undergoing chorion villus sampling (CVS) and amniocentesis (AC). METHODS: Patients referred to our department for fetal karyotype analysis with a positive first or second trimester screening test for aneuploidy between January 2013 to June 2015 were included. CVS and AC procedures were performed in patients with gestation periods of between 11-14 and 16-20 weeks, respectively. Anxiety was evaluated using the Spielberger State-Trait Anxiety Inventory (STAI), and depression was assessed using the Beck Depression Inventory II (BDI-II). RESULTS: A total of 1,400 patients were included. Compared to first trimester controls, patients undergoing CVS had significantly higher STAI-state and BDI-II results. Likewise, patients undergoing AC had higher STAI-state and BDI-II scores than controls in the second trimester. In terms of STAI-trait results, no difference was found between the groups. Our results also showed that, compared to AC group, patients undergoing CVS had similar STAI-state, STAI-trait and but higher BDI-II scores. CONCLUSION: We conclude that evaluating the stress and depression levels of these patients should be one of the routine procedures in pregnancy follow-up. PMID- 26648983 TI - Factor analysis of the biochemical markers related to liver cirrhosis. AB - OBJECTIVES: The purpose of this study was to find the correlations between biochemical study and liver cirrhosis. METHODS: The patients had liver biopsy to check the degree of their liver fibrosis, from August 2013 to August 2014 at the current medical center. In order to find the etiology of hepatitis, a research was done on gender, age, weight, and biochemical study through the investigation of subjects' medical record and medical history. For biochemical study, we examined hemoglobin, platelets, albumin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, gamma-glutamyl transferase (GGT), prothrombin time (PT), and international normalised ratio (INR). We also analyzed the factors that are related to liver cirrhosis. RESULTS: As a result, the patients at liver cirrhosis F>=2 stage showed 0.973, which is higher than the patients at FO stage with 0.943. F>=2 stage of hemoglobin was 0.544, which is lower than FO stage of hemoglobin with 0.817. Platelet count in F>=2 stage was 0.417, which is higher than FO stage with 0.074. For Albumin, F>=2 stage was 0.155 when F0 stage was 0.135. ATS's F>=2 stage was 0.665, which is 6 times higher than FO stage with 0.100. Moreover, in the case of GGT, F>=2 stage was higher with 0.492 than FO stage with 0.078. CONCLUSIONS: In conclusion, it was confirmed that there is an increase in liver cirrhosis in the following general characteristics and biochemical factors: increase of age, increase of GGT, decrease of albumin, increase of the total bilirubin, and growth of INR (International Normalized Ratio). PMID- 26648984 TI - Descriptive epidemiology of hereditary musculoskeletal and limb defects in the isolated population of Chitral, North-West Pakistan. AB - OBJECTIVES: Musculoskeletal and limb defects (MLDs) are the major categories in hereditary anomalies and are a significant source of the disabilities. This study aimed at elucidating the nature and pattern of MLDs prevalent in Chitral district, which is an isolated population in the North-West of Pakistan. METHODS: A cross-sectional epidemiological study was conducted in Chitral and subjects/families with MLDs were ascertained from public places, hospitals and door-to-door visits. The phenotypic manifestations, expressivity, sporadic/familial presentations, isolated/syndromic nature, inheritance pattern, and socio-demographic attributes, of MLDs were observed. RESULTS: A total of 153 independent subjects/families with certain types of MLDs were recruited. The MLDs were classified into 9 major and 22 minor entities. In this cohort, polydactyly was observed to be overwhelmingly common (71%), followed by syndactyly and absence limb deformities. The majority of the cases (78%) had sporadic nature, 93% anomalies had isolated presentations; upper limbs were more commonly affected than the lower limbs; and unilateral cases were twice in ratio than bilateral. The majority of the malformations had milder phenotypes, however, 17% of the MLDs were severe in nature and resulted in certain types of disability, compromising the normal life of the subject. CONCLUSION: This research witnesses a distinctive pattern of MLDs in Chitral, which has not been reported for any other population of Pakistan so far. Further studies are required to observe the molecular etiologies of these malformations and to offer rapid diagnosis and genetic counseling. PMID- 26648985 TI - Evaluation of early interventional treatment opportunity of the elderly & high risk patients with non-ST segment elevation acute myocardial infarction. AB - OBJECTIVE: To investigate the effect of treatment on prognosis of patients with different timing of early interventional treatment for non-ST segment elevation acute myocardial infarction (NSTEMI). METHODS: Forty two cases above 75 years old, diagnosed with high-risk on NSTEMI, were selected in cardiology department of Xinxiang central hospital. They were randomly divided into two groups: 22 in group A and 20 in group B. Group A was performed PCI surgery within 12 hours after the onset while group B from 12 to 24 hour after the onset. Major adverse cardiovascular events (including death, heart failure readmission rates after ischemia, malignant arrhythmias, again target vessel revascularization) and bleeding data were recorded at the three terms of hospitalization, one month after the onset and six months after the onset. RESULTS: Angina, malignant arrhythmia and heart failure during hospitalization can be reduced after interventional treatment carried out within 12 hours after the onset. Readmission rates after ischemia, heart failure and the incidence of death can be significantly reduced after interventional treatment carried out during 1-6 month after the onset with no significant increase in bleeding rate. CONCLUSION: In the treatment of elderly patients with NSTEMI, early interventional treatment is safe and effective. PMID- 26648986 TI - The pharmacological protection of renal function in patients undergoing cardiac surgery. AB - OBJECTIVES: To compare the effects of different routes and timings of administration of dopamine and mannitol used to alleviate the adverse effects of prolonged cardiopulmonary bypass (CPB) on renal functions in coronary artery surgery. METHODS: Group I (n: 25 patients): Mannitol 1 g/kg was added into the priming solution for CPB. Group II (n: 25 patients): IV dopamine was administered at a dose of 2 MUg/kg/min during the time period between anesthesia induction and end of surgery. Group III (n: 25 patients): IV dopamine was administered at a dose of 2 MUg/kg/min during the time period between anesthesia induction and end of surgery and mannitol 1 g/kg was added into the priming solution for CPB. Group IV (n: 25 patients) (Controls): Furosemide was given when the urine output was low. RESULTS: There was a significant increase in post operative urine microalbumin/creatinine ratio in all groups (p < 0.05), even increase of cystatin c in Groups I, II and III (p < 0.01). CONCLUSIONS: We believe that concurrent use of dopamine infusion (2 MUg/kg/min) with mannitol (1 g/kg) during CPB may represent a more effective strategy for the prevention of the untoward effects of CPB on renal functions. PMID- 26648987 TI - A comparison of post operative pain and hospital stay between Lichtenstein's repair and Laparoscopic Transabdominal Preperitoneal (TAPP) repair of inguinal hernia: A randomized controlled trial. AB - OBJECTIVE: To compare the open Lichtenstein repair and laparoscopic mesh repair for direct inguinal hernias in terms of immediate post operative pain and length of hospital stay. METHODS: This randomized control trial was conducted at Benazir Bhutto Hospital Rawalpindi from January 2009 to June 2010. All patients presenting in the surgical OPD with direct inguinal hernia, ASA I/II, were randomly divided in two equal groups. Group-I, patients underwent Lichtenstein's repair and Group-II had hernioplasty by laparoscopic method (TAPP). Post operative pain intensity assessed by VAS and hospital stay measured in hours. RESULTS: A total 60 patients of direct inguinal hernia were studied. The mean age was 61.48+/-7. The range of postoperative pain experienced was 5.55 as per VAS among all patients. In group-I (open hernioplasty) majority of patients (53.33%, n=16) experience severe type of pain where as in group-II, moderate severity of pain was reported by large number of patients (63.34%, n=19). The mean post operative pain intensity as per VAS was 6.23 in group-I and 4.43 in group-II patients. The mean length of hospital stay was slightly less (35.10 hrs) in group I as compared to group-II (38.70 hrs). CONCLUSION: There is definitely less post operative pain after laparoscopic repair but hospital stay is same in both the procedures but laparoscopic procedure does increase the cost. PMID- 26648989 TI - Effects of intravenously infused lidocaine on analgesia and gastrointestinal function of patients receiving laparoscopic common bile duct exploration. AB - OBJECTIVE: To evaluate the effects of intravenously infused lidocaine on analgesia and gastrointestinal function of patients receiving laparoscopic common bile duct exploration. METHODS: Seventy-eight patients with cholelithiasis were randomly divided into a treatment group and a control group (n=39) that all had laparoscopic common bile duct exploration. The treatment group was intravenously infused with 1.5 mg/kg lidocaine by using a venous pump under anesthesia induction at the speed of 2 mg.kg(-1) .h(-1) until the end of surgery, while the control group was given normal saline with the same volume. RESULTS: All patients successfully completed the surgery, with similar surgical time, incision length and intraoperative blood loss. The required lidocaine concentrations of the treatment group were 2.64+/-1.23 MUg/ml, 1.14+/-0.4 MUg/ml and 0.93+/-0.32 MUg/ml respectively 2 hour, 12 hour and 48 hour after surgery. Pain score of the treatment group, which was significantly lower than that of the control group at the postoperative 2 hour (P<0.05), was similar to those of the control group at the postoperative 12 hour and 48 hour. With extended time, the pain score significantly decreased (P<0.05). The treatment group had significantly shorter first anal exhaust time and first defecation time than those of the control group (P<0.05). Adverse reactions, such as nausea and vomiting, dizziness, headache, subcutaneous emphysema and fat liquefaction of incision, occurred similarly in the two groups, which were alleviated by symptomatic treatment. CONCLUSION: Laparoscopic common bile duct exploration is a promising minimally invasive surgery for patients with cholelithiasis, during which intravenously infused lidocaine can rapidly recover the gastrointestinal function and exert short-term analgesic effects, with mild adverse reactions also. PMID- 26648988 TI - Molecular epidemiology of quinolon resistant strains of extended spectrum beta lactamase producing Escherichia coli. AB - OBJECTIVE: To determine the clonal relationship of ESBL-producing and quinolone resistant E.coli strains and to investigate the risk factors for infections with these microorganisms. METHODS: A total of 95 ESBL-producing and quinolone resistant E.coli strains isolated from various clinical specimens of inpatients and outpatients in our hospital were included in the study. Risk factors for infections with ESBL-producing E.coli and demographic data of the patients were obtained from hospital records. The rep-PCR method was used for the determination of the genetic relationship of the strains. RESULTS: Of the strains included in the study, 33(34.7%) were isolated from inpatients and 62(65.3%) from outpatients. At least one risk factor has been identified in all patients for infection with ESBL producing E.coli and the mean of the risk factors of patients was 4.2. The most common risk factor was urinary catheter insertion (57.9%). The distribution of the strains in each clone was as fallows: clone A: 9(9.5%), clone B: 10(10.5%), clone C: 38(40%), clone D: 12(12.5%), clone E: 6(6.3%), clone F: 7(7.3%) and clone G 5(5.3%). The clones A, D and C (dominant clone) were isolated from hospital and community acquired infections. Clones E, F and G were identified as nosocomial clones. CONCLUSION: Infections with multidrug resistant bacteria may be related to the hospital although they were isolated from outpatients. Developing a medical record system is vitally important to prevent the occurence and spread of resistant bacterial infections in the community. PMID- 26648990 TI - Prevalence of Atherosclerosis in diabetic and non-diabetic patients with rheumatoid arthritis. AB - OBJECTIVES: (1) To compare the prevalence of preclinical atherosclerosis in diabetic vs. non-diabetic rheumatoid arthritis (RA) patients; (2) to determine the influence of classical and RA-related factors on atherosclerosis; (3) to assess the usefulness of combined carotid and femoral ultrasonography in detecting atherosclerosis. METHODS: The study comprised 42 non-diabetic RA patients, 42 diabetic RA patients and 42 controls. Intima media thickness (IMT) was measured in the common carotid and superficial femoral arteries. These vessels were screened for atherosclerotic plaque. RESULTS: Plaque was more prevalent in diabetic RA patients than in non-diabetic RA patients or controls. Carotid IMT and femoral IMT were higher in diabetic RA patients compared to controls. So was femoral IMT in diabetic compared to non-diabetic RA patients. The prevalence of increased IMT and plaque was comparable in carotid ultrasonography and combined carotid and femoral ultrasonography in all groups. CONCLUSIONS: Subclinical atherosclerosis was found to be higher in diabetic RA patients than in non-diabetic RA patients. The combination of carotid and femoral artery ultrasonography did not improve the detection of atherosclerosis in RA. PMID- 26648991 TI - Regular breakfast consumption associated with high intelligence quotient: Myth or Reality? AB - OBJECTIVE: To find the frequency of regular breakfast consumption among Pakistani teenagers while the other objective was to find out the association between breakfast consumers (BC) and intelligence quotient (IQ). METHODS: This comparative cross sectional study was conducted on 102 students of a Public School Rawalpindi from August 2013 to January 2014. Participants were categorised into two groups i.e. regular breakfast consumers (RBC) and irregular breakfast consumers (IBC) according to their breakfast habits. A standardized questionnaire of Wechsler Intelligence Scale for Childrenwas used for IQ assessment. Data was then entered and analysed in SPSS version 20. RESULT: Out of the 102 individuals with mean age 17.17 +/- 0.631, 58(56.9%) were females and 44 (43.1%) were males. There were 63 (61.8%) RBC while 39 (38.2%) were IBC. Among RBC there were 7 (6.9%) in challenged, 5 (4.9%) were below average, 33 (32.4%) in average group, 14(13.7%) in above average and 4 (3.9%) in gifted group. While among IBC, there was 1 (1%) among the severely challenged, 3 (2.9%) in challenged, 8 (7.8%) in below average, 22 (21.6%) in average group, 4 (3.9%) in above average and 1 (1%) in gifted group. There was no significant association found between breakfast intake and IQ level among students (p=0.98). CONCLUSION: More than half of the students were having regular breakfast. There was no significant association found among breakfast consumers and IQ. However the IQ score was more among RBC as compared to IBC. PMID- 26648992 TI - Cost-Conscious of Anesthesia Physicians: An awareness survey. AB - OBJECTIVE: Increasing competitive pressure and health performance system in the hospitals result in pressure to reduce the resources allocated. The aim of this study was to evaluate the anesthesiology and intensive care physicians awareness of the cost of the materials used and to determine the factors that influence it. METHODS: This survey was conducted between September 2012 and September 2013 after the approval of the local ethics committee. Overall 149 anesthetists were included in the study. Participants were asked to estimate the cost of 30 products used by anesthesiology and intensive care units. RESULTS: One hundred forty nine doctors, 45% female and 55% male, participated in this study. Of the total 30 questions the averages of cost estimations were 5.8% accurate estimation, 35.13% underestimation and 59.16% overestimation. When the participants were divided into the different groups of institution, duration of working in this profession and sex, there were no statistically significant differences regarding accurate estimation. However, there was statistically significant difference in underestimation. In underestimation, there was no significant difference between 16-20 year group and >20 year group but these two groups have more price overestimation than the other groups (p=0.031). Furthermore, when all the participants were evaluated there were no significant difference between age-accurate cost estimation and profession time-accurate cost estimation. CONCLUSION: Anesthesiology and intensive care physicians in this survey have an insufficient awareness of the cost of the drugs and materials that they use. The institution and experience are not effective factors for accurate estimate. Programs for improving the health workers knowledge creating awareness of cost should be planned in order to use the resources more efficiently and cost effectively. PMID- 26648993 TI - Clinical observation of docetaxel or gemcitabine combined with cisplatin in the chemotherapy after surgery for stage II-III non-small cell lung cancer. AB - OBJECTIVE: This study aimed to compare the efficacy and toxicity of docetaxel combined with cisplatin (DP) and gemcitabine combined with cisplatin (GP) in postoperative chemotherapy after surgery of non-small cell lung cancer (NSCLC). METHODS: A total of 92 patients diagnosed with NSCLC after surgery were enrolled, and they were treated with DP (DP group) and GP (GP group). The efficacy and toxicity of the medications were then compared. RESULTS: Approximately 92.4% (85 out of 92) of the patients received chemotherapy for more than three weeks. In DP and GP groups, the incidence rates of grade III-IV thrombocytopenia were 24.4% and 6.38%, respectively, whereas the incidence rates of alopecia were 88.9% and 25.5%, respectively. The difference between the two groups was statistically significant (P < 0.05). Disease-free survival rates in DP group in one and two years were 76.5% and 50.47%, respectively, whereas in GP group were 77.8% and 49.52%, respectively. No significant difference was observed between the two groups (P > 0.05). CONCLUSION: These results showed similar disease-free survival rates of DP and GP therapies in one and two years after surgery for NSCLC. However, DP group exhibited higher incidence of grade III-IV thrombocytopenia and alopecia than GP group. Therefore, we should select a specific treatment for each patient according to individual differences. PMID- 26648994 TI - Pattern of patients and diseases during mass transit: The day of Arafat experience. AB - BACKGROUND AND OBJECTIVE: Every year 2-3 million Muslims gather for a few days around the Holy city of Makkah in Saudi Arabia to perform Hajj. Managing enormous health issues associated with such a mass gathering requires a very vibrant health delivery plan. Related research is part of the strategy. This study was done to assess the pattern of patients and illnesses encountered at one health facility at Arafat on the 2nd day of Hajj, when all the pilgrims move from Mina and stay in Arafat for a few hours. The objective of the study was to provide input so that recommendations can be given for future improvement of health care during this mass transit. METHODS: All patients reporting sick to the Nimra Hospital on the Day of Arafat were included and documented on a detailed Performa and analyzed. RESULTS: We received 211 patients, essentially all of those were in need of acute medical intervention. Acute severe asthma and injuries were the major problems encountered. There were two deaths both related to heat stroke. Patients received were predominantly Arabic speaking. CONCLUSIONS: Only those needing acute intervention seek medical advice during transit. Well equipped and staffed health facilities are, however, needed to cater these and for any mass casualties. Pre Hajj training and mandatory Flu vaccination can help. PMID- 26648995 TI - Salivary detection of human Papilloma virus 16 & 18 in pre-malignant and malignant lesions of oral cavity: Is it feasible in Pakistani context of Socio Cultural Taboos? AB - OBJECTIVE: To evaluate salivary detection of HPV-16 & 18 would be feasible and informative biomarker for oral pre-malignant and malignant lesion in our population. METHODS: This non-interventional, case control study was carried out at department of E.N.T, Head and Neck Surgery, Dow University of Health Sciences, Dow Medical College and Civil Hospital Karachi, Pakistan between July 2011 to December 2012. Total of 105 cases were recruited. These were divided in three groups 'A', 'B' & 'C' having 35 subjects each. Group'A' constitutes patients having strong clinical evidence of oral pre-malignant lesions (PML). Group 'B' includes histologically proven oral squamous cell carcinoma (OSCC) and Group 'C' comprised disease free subjects as controls. After taking informed consent, relevant clinical history was recorded on institutional approved performa. Saliva from all subjects was procured by standard 'drooling method'. Samples were stored at +4 degrees C and later transferred to Laboratory to store at-20 degrees C before further process. Samples were centrifuged at 4500 rpm for 15 minutes at 4 degrees C. Cell pellets sediments were used for identification of HPV-16 & 18 by real-time PCR method. Data was entered and analysed using SPSS version 16. P value of 0.05 was taken as standard. RESULTS: In group 'A', HPV-16 was detected in 3 (8.6%) cases while HPV-18 was not detected in any of the subject. In group 'B', HPV-16 was detected in 07 (20%) while HPV-18 was found in 06 (17.1%) cases. Mixed HPV-16 and HPV-18 were found in 02 (5.7%) cases. In group 'C', HPV-16 was detected in 03(8.6%) while HPV-18 was not detected in any of the subjects. Significant relationship was observed between the groups for HPV-18 detection (P= 0.002) while for HPV-16, no significant association was found (P= 0.245). CONCLUSION: HPV infection for the causation of oral cancer cannot be fully established possibly due to small sample size. More over differences in genetic makeup, environment, indulgence in peculiar risk factor habits, sexual practices and difficult evaluation of the acquisition of viral load due to socio-cultural and religious restrictions could be the reason. PMID- 26648996 TI - Myelin basic protein and ischemia modified albumin levels in acute ischemic stroke cases. AB - OBJECTIVE: To investigate early diagnostic effects of serum myelin basic protein (MBP) and ischemic modified albumin (IMA) levels in patients with ischemic stroke. METHODS: Fifty patients who presented to an emergency service with acute ischemic stroke between June 2013 to March 2014 were evaluated with the National Institute of Health Stroke Scale (NIHSS) and diffusion-weighted magnetic resonance imaging (MRI). Thirty four healthy cases were included as control group. All patients' serum IMA and MBP level were assessed. RESULTS: Mean IMA value was 0.52+/-0.25 cases with acute ischemic stroke and serum IMA levels were significantly higher than the control group (p<0.01). No statistical significance was observed between acute ischemic stroke group and control group related to the MBP serum levels (P>0.05). Statistically significant correlation was detected between the volumes of diffusion restriction on MRI and NIHSS score (P=0.002, r=0.43) and IMA (P=0.015, r=0.344) levels. CONCLUSIONS: We have found that serum IMA levels are elevated in acute ischemic stroke cases and these levels are correlated with the ischemic tissue volume. MBP levels do not increase in early period of stroke cases. PMID- 26648997 TI - Correlation between expression of epidermal growth factor receptor and adverse reactions after chemotherapy of advanced non-small-cell lung cancer. AB - OBJECTIVE: To analyze the correlation between expression of epidermal growth factor receptor (EGFR) and adverse reactions after chemotherapy of advanced non small-cell lung cancer (NSCLC). METHODS: A total of 120 NSCLC patients who were treated in our hospital from August 2009 to September 2011 were selected as an observation group, and another 120 healthy subjects were selected as a control group. EGFR expressions in both groups were detected. The observation group was subjected to combination chemotherapy, and their shorter- and long-term prognostic outcomes, adverse reactions and mortality were recorded. Meanwhile, correlation analysis was performed. RESULTS: The observation group had significantly higher percentage and positive rate in EGFR expression than those of the control group (P<0.05). With increasing stage and lymphatic metastasis, the positive expression rate of EGFR rose significantly (P<0.05). In the observation group, the response rate of treatment was 62.5%, and the incidence rate of adverse reactions after chemotherapy was 28.3% (34/120). The 1-, 2- and 3 year survival rates were 38.3%, 15.0% and 10.0% respectively. Multiple Logistic regression analysis showed that TNM stage, lymphatic metastasis and positive EGFR expression were the main independent risk factors for post-chemotherapy adverse reactions (P<0.05). CONCLUSION: Advanced NSCLC was commonly accompanied by high EGFR expression. Although chemotherapy was able to improve the prognosis and survival rate, adverse reactions were also induced, being associated with the pathological characteristics and EGFR expressions of patients. PMID- 26648998 TI - Clinical spectrum of Posterior Reversible Encephalopathy Syndrome (PRES) in patients with eclampsia. AB - OBJECTIVE: To identify the prevalence, demographic details and clinical features of PRES in women suffering from eclampsia. METHODS: Women admitted in the labor room suite with diagnosis of eclampsia were studied. The study period was from October 15. 2011 to March 15. 2012, in the department of obstetrics & gynecology unit 3, Civil hospital Karachi. Of all patients with diagnosis of eclampsia, 22 underwent neuro imaging by computerized tomography. Demographic details, clinical findings and maternal and perinatal outcome were entered on a predesigned Performa. RESULTS: Thirty four women were identified, with eclampsia. Neuro imaging was done in 22 women. Posterior reversible encephalopathy syndrome was recognized in 9 (22) patients. The mean systolic blood pressure was 161(+/-11) mm Hg, and mean diastolic blood pressure was 111(+/-10) mm Hg. Mean number of fits were three, and the mean gestational age of patients were 35 weeks. Gestational age was found significantly associated with PRES (p <0.3) Mean leukocyte count in patients with eclampsia was 20,083+/-16,165/cu mm. CONCLUSION: Our study shows presence of Posterior reversible encephalopathy syndrome (PRES) in women who are identified with eclampsia. There is need for awareness and long term neurological follow up in this group of women. PMID- 26648999 TI - Serum amyloid a gene polymorphism and its association with lipid profile in Saudi females with osteoporosis. AB - BACKGROUND AND OBJECTIVE: Osteoporosis can be defined as a systemic skeletal disease characterized by low bone mass and micro architectural decline of bone tissue. Serum amyloid A (SAA) is a family of protein that increases up to 1,000 fold in blood during inflammation. In this study, we aimed to study the relationship between SAA1 gene polymorphism (rs12218) and lipid profile and osteoporosis. METHODS: The study was performed on the female students of Taibah University in Al Medina, KSA during June 2014 to April 2015. According to BMD; osteoporosis group (138 students) and control group (128 students). All groups were subjected to; BMI, BMD, calcium, phosphorus, creatinine, lipid profile and SAA. Polymerase chain reaction and Real Time were done to determine the distribution of allele and genotype frequency of SAA (rs12218) C/T polymorphism. RESULTS: This study shows that the TT genotype of rs12218 was more frequent in osteoporosis group than control group (P<0.001). Also, TT genotype and T allel was found to be associated with plasma total cholesterol, TG, LDLc, HDLc, Tscore, Zscore and SAA1 level in osteoporosis group (P=0.000, P=0.05, and P=0.000, P=0.000, P=0.01, P=0.02, P=0.000 respectively). The logistic regression analysis with and without lipid disorders in the osteoporosis group also show that the TT genotype of rs12218 still differed significantly between these two groups (P=0.001, OR=1.814, 95% CI: 0.719-4.577). CONCLUSION: The results of this study shows a significant association between TT genotype of rs12218 and both lipid level and osteoporosis in Saudi female population. PMID- 26649001 TI - Evaluation of the Abbott Real Time HCV genotype II assay for Hepatitis C virus genotyping. AB - OBJECTIVE: The determination of HCV genotypes and subtypes is very important for the selection of antiviral therapy and epidemiological studies. The aim of this study was to evaluate the performance of Abbott Real Time HCV Genotype II assay in HCV genotyping of HCV infected patients in Kayseri, Turkey. METHODS: One hundred patients with chronic hepatitis C admitted to our hospital were evaluated between June 2012 and December 2012, HCV RNA levels were determined by the COBAS(r) AmpliPrep/COBAS(r) TaqMan(r) 48 HCV test. HCV genotyping was investigated by the Abbott Real Time HCV Genotype II assay. With the exception of genotype 1, subtypes of HCV genotypes could not be determined by Abbott assay. Sequencing analysis was used as the reference method. RESULTS: Genotypes 1, 2, 3 and 4 were observed in 70, 4, 2 and 24 of the 100 patients, respectively, by two methods. The concordance between the two systems to determine HCV major genotypes was 100%. Of 70 patients with genotype 1, 66 showed infection with subtype 1b and 4 with subtype 1a by Abbott Real Time HCV Genotype II assay. Using sequence analysis, 61 showed infection with subtype 1b and 9 with subtype 1a. In determining of HCV genotype 1 subtypes, the difference between the two methods was not statistically significant (P>0.05). HCV genotype 4 and 3 samples were found to be subtype 4d and 3a, respectively, by sequence analysis. There were four patients with genotype 2. Sequence analysis revealed that two of these patients had type 2a and the other two had type 2b. CONCLUSION: The Abbott Real Time HCV Genotype II assay yielded results consistent with sequence analysis. However, further optimization of the Abbott Real Time HCV Genotype II assay for subtype identification of HCV is required. PMID- 26649000 TI - Association between codon 399 polymorphism in the X-ray repair cross complementing group 1 gene and risk of prostate cancer in Asians: A study of 4,479 cases and 4,281 controls. AB - OBJECTIVE: The polymorphism in codon 399 of the X-ray repair cross-complementing group 1 (XRCC1) gene may subtly alter structure of DNA repair enzymes and modulate the repair capacity. Impaired DNA repair can lead to the development of cancers such as prostate cancer (PCA). Although the association between the XRCC1 codon 399 polymorphism and PCA risk has been extensively reported, the results have been ambiguous. METHODS: We conducted an updated analysis of 18 case-control studies to determine the association between the XRCC1 codon 399 polymorphism and PCA risk. We performed a literature search of the PubMed database to identify all eligible articles that reported this association. Odds ratios (ORs) with 95% confidence intervals (CI) were evaluated to assess the association. RESULTS: Significant associations between PCA risk and XRCC1 codon 399 polymorphism were found (such as A-allele vs. G-allele: OR = 1.11, 95% CI = 1.01-1.23). Moreover, subgroup analysis based on ethnicity revealed similar significant associations in Asians (such as AA vs. GG: OR = 1.53, 95% CI = 1.19-1.97). Egger's test did not reveal the presence of a publication bias. CONCLUSIONS: Our updated analysis provides evidence for significant association between XRCC1 codon 399 polymorphism and PCA risk. Further carefully designed studies should be performed. PMID- 26649002 TI - Nutritional status of congenital heart disease (CHD) patients: Burden and determinant of malnutrition at university of Nigeria teaching hospital Ituku - Ozalla, Enugu. AB - BACKGROUND AND OBJECTIVES: Children with congenital heart disease (CHD) are prone to malnutrition. This can have a significant effect on the outcome of surgery. Our objective was to determine the burden and determinant of malnutrition in children with several types of congenital heart disease (CHD). METHODS: This is a descriptive cross sectional study of children attending the outpatient clinic of UNTH, Ituku - Ozalla, Enugu State, over a six year period from March 2007 to April 2014. Data analysis was done with Statistical Package for Social Sciences (SPSS) version 19 (Chicago IL). RESULTS: Forty thousand one hundred and twenty three (40,123) children attended the outpatient clinic during the study period. Of these, 50 had congenital heart disease, from which 46 were found to have various degree of malnutrition, giving a prevalence of 92% among children with congenital disease and 0.11% in the general population. Malnutrition showed significant correlation between age in years, age appropriate dietary adequacy and pulmonary hypertension. (r= 0.22, p = 0.01; r = 0.20, p = 0.02; r = 0.15, p = 0.01). CONCLUSION: Children with CHD develop severe malnutrition and growth failure. The significant contributing factors are mean age at presentation and age appropriate dietary adequacy. PMID- 26649003 TI - Use of supravital toluidine blue staining to improve the efficiency of fine needle aspiration cytology reporting in comparison to papanicolaou stain. AB - OBJECTIVE: To see the efficiency, adequacy and accuracy of toluidine blue stained smears of FNAC of Breast thyroid and salivary glands swelling with comparison to conventional stained FNAC smears with Papanicolaou. METHODS: A total of 114 aspirates from various sites were included in the study. The smears were stained with toluidine blue and conventional Papanicolaou stain and the cytomorphology of both the smears were compared. The values were tabulated and statistical tests of significance was applied. RESULTS: Of the 114 aspirates included in our study the diagnostic accuracy by using papanicolaou was 78%, while it was upto 100% with supravital toluidine blue stained smears. The percentage of inadequacy was reduced to just 25%. The observations were statistically significant. Breast 37/48 (77%) and Salivary glands 11/48 (23%) respectively. The most commonly used categorization of a five-tier system was used for reporting of breast cytology, with categories ranging from insufficient materials (C1), benign (C2), atypical (C3), suspicious of malignancy (C4), or (C5) frankly malignant. Most of breast lesions were benign 25 (67.56%). There were only 9 (24.32%) malignant cases followed by 2 cases of C-4 and one case of C-3. Benign thyroid lesion were more frequent comprising of 51 (72.27%) cases. One case (1.5%) of papillary carcinoma was found while 13 case were follicular lesions. There were 4 (36.4%) cases of pleomorphic adenoma and 3 (27.3) cases of non-specific sialadenitis. There was one case (9%) of each lesion for mucoepidermoid carcinoma, adenoidcytic carcinoma and benign cyst. CONCLUSION: Toluidine blue stained study of FNAC improves the diagnostic accuracy by minimizing the smearing and drying artifact, loss of cell sample during fixation and staining which influences the diagnostic accuracy. PMID- 26649004 TI - The value of combined application of ultrasound-guided fine needle aspiration cytology and thyroglobulin measurement for the diagnosis of cervical lymph node metastases from thyroid cancer. AB - OBJECTIVE: The aim of this study was to explore the diagnostic value of ultrasound-guided (US-guided) fine-needle aspiration cytology (FNAC), thyroglobulin measurement on fine-needle aspiration (FNA-Tg), combined US-guided FNAC, and the ratio between FNA-Tg and serum Tg (FNA-Tg/serum Tg) for patients with cervical lymph node (CLN) metastases from thyroid carcinoma. METHODS: We selected 148 patients with thyroid cancer with suspicious CLN metastases who met the inclusion criteria. FNAC findings, FNA-Tg levels, and serum Tg levels were evaluated before surgical treatment. The results of FNAC and FNA-Tg from CLNs were analyzed retrospectively. RESULTS: Ninety-four of 148 cases were metastatic and 54 were benign. The sensitivity, specificity, and accuracy of FNAC were 68.1%, 100.0%, and 79.7%, respectively. The sensitivity, specificity, and accuracy of FNA-Tg/serum Tg were 91.5%, 88.9%, and 90.5%, respectively. The sensitivity, specificity, and accuracy of FNA-Tg [10 ng/mL] were 98.9%, 68.5%, and 87.8%, respectively. The sensitivity, specificity, and accuracy of combined US-guided FNAC and FNA-Tg/serum Tg were 95.7%, 96.3%, and 95.9%, respectively. There was a statistically significant difference between FNAC and combined US guided FNAC and FNA-Tg/serum Tg for sensitivity, specificity, and accuracy (P < 0.05). CONCLUSION: The method of FNA-Tg/serum Tg is sensitive enough for diagnosing CLN metastases from thyroid cancer. The combined application of US guided FNAC and FNA-Tg/serum Tg contributes to improving the accuracy of diagnosing CLN metastases in patients with thyroid cancer. PMID- 26649005 TI - Are we using drugs rationally? A survey study from Turkey. AB - OBJECTIVES: To investigate the rational use of drugs from patient's perspective. METHODS: This study was conducted at the Afyon Kocatepe University Training and Research Hospital between February and March 2013. Data were collected with a questionnaire. Descriptive statistics and Chi-Square test were used. RESULTS: About 54% (n=419) of participants reported that they used drugs without the advice of a physician. The 19-24 age group, secondary and high school graduates, and students used drugs more often without consulting a physician (P < 0.05). Participants that used drugs after consulting a physician did not fully use the drugs as recommended by the physician, and physicians did not give patients adequate information about prescribed drug(s). 72% of participants stored drug(s) at home. CONCLUSIONS: Rational use of drugs is not completely achieved. Certain patient groups and even physicians are closer to being a part of the irrational use of drugs. PMID- 26649006 TI - Association analysis of DISC1 gene polymorphisms with Attention-Deficit Hyperactivity Disorder in Iranian population. AB - BACKGROUND & OBJECTIVES: Attention deficit hyperactivity disorder (ADHD) is a common heritable psychiatric disorder with a worldwide prevalence of 5%. The etiology of ADHD is still incompletely understood, but several studies, consistently indicate the strong role of genetic factors on this disorder. The aim of this study was to determine the effect of three SNPs rs11122319, rs11122330 and rs6675281 in the etiology of ADHD in an Iranian children. METHODS: In this research work, for the first time, we investigated the association of three SNPs (rs11122330, rs6675281 and rs11122319) in the DISC1 gene with ADHD in Iranian population. Two hundred fourthy subjects composed of 120 patients and 120 healthy controls were included and tetra-primer ARMS PCR technique was used for genotyping all selected SNPs. RESULTS: We found differences in genotype and allele distributions of rs 6675281 polymorphism between our patients and controls. The A, T and A alleles were the more frequent alleles in rs11122319, rs6675281 and rs11122330 polymorphisms in both case and control groups respectively. The TT genotype was more frequent in control group compared to patients. (P value = 0.008, OR= 1.5837, 95% CI= 1.1012 to 2.2776). CONCLUSION: Our findings strengthens the role of DISC1 gene as a susceptibility locus for ADHD and indicate that rs6675281 polymorphism is a susceptibility factor for ADHD for the first time in children reported in an Iranian population in this part of the world. PMID- 26649007 TI - To compare the effectiveness of constraint induced movement therapy versus motor relearning programme to improve motor function of hemiplegic upper extremity after stroke. AB - OBJECTIVE: To compare the effectiveness of constraint induced movement therapy versus motor relearning programme to improve motor function of hemiplegic upper extremity after stroke. METHOD: A sample of 42 patients was recruited from the Physiotherapy Department of IPM&R and Neurology OPD of Civil Hospital Karachi through non probability purposive sampling technique. Twenty one patients were placed to each experimental and control groups. Experimental group was treated with Constraint Induced Movement Therapy (CIMT) and control group was treated with motor relearning programme (MRP) for three consecutive weeks. Pre and post treatment measurements were determined by upper arm section of Motor Assessment Scale (MAS) and Self Care item of Functional Independence Measure (FIM) Scale. RESULTS: Intra group analysis showed statistically significant results (p value<0.05) in all items of MAS in both groups. However, advanced hand activities item of MAS in MRP group showed insignificant result (p-value=0.059). Self-care items of FIM Scale also showed significant result (p-value< 0.05) in both groups except dressing upper body item (p-value=0.059) in CIMT group and grooming and dressing upper body items (p-value=0.059 & 0.063) in MRP group showed insignificant p-values. CONCLUSION: CIMT group showed more significant improvement in motor function and self-care performance of hemiplegic upper extremity as compared to MRP group in patients with sub-acute stroke assessed by the MAS and FIM scales. Thus CIMT is proved to be more statistically significant and clinically effective intervention in comparison to motor relearning programme among the patients aged between 35-60 years. Further studies are needed to evaluate CIMT effects in acute and chronic post stroke population. PMID- 26649008 TI - Therapeutic effects of probiotics on neonatal jaundice. AB - OBJECTIVE: To evaluate the therapeutic effects of probiotics on neonatal jaundice and the safety. METHODS: Sixty-eight neonates with jaundice were divided into a control group and a treatment group (n=34) randomly, and treated by blue light phototherapy and that in combination with probiotics. The serum bilirubin levels were detected before and 1, 4, 7 days after treatment. The time when therapy showed effects and jaundice faded, clinical outcomes as well as adverse reactions were recorded. The categorical data were expressed as (+/-s) and compared by t test. The numerical data were expressed as (case, %) and compared by chi2 test. P<0.05 was considered statistically significant. RESULTS: Serum bilirubin levels of the two groups were similar before treatment (P>0.05). The levels significantly decreased 1, 4 and 7 days after treatment (P<0.05), but there was no significant inter-group difference on the post-treatment 1st day (P>0.05). The treatment group underwent more significant decreases on the 4th and 7th days than the control group did (P=0.002, 0.001). In the treatment group, the therapy exerted effects on (1.0+/-0.5) d and jaundice faded on (3.8+/-1.7) d, which were (2.6+/-0.6) d and (5.3+/-2.1) d respectively in the control group (P=0.001, 0.002). The effective rate of the treatment group significantly exceeded that of the control group (P=0.002). There were no obvious adverse reactions in either group. CONCLUSIONS: Probiotics lowered the serum bilirubin levels of neonates with jaundice rapidly, safely and significantly, and accelerated jaundice fading as well. This method is worthy of application in clinical practice. PMID- 26649009 TI - Anxiety levels of mothers with newborns in a Neonatal Intensive Care Unit in Turkey. AB - OBJECTIVE: To compare the anxiety levels of mothers with newborns in a Neonatal Intensive Care Unit (NICU) and mothers with healthy newborns in a postpartum care service (PCS). METHODS: This descriptive study was conducted in state and medical school hospitals located in Eskisehir and Afyon, Turkey. The first 200 mothers, including mothers with newborns in a PCS (n=100) and mothers with newborns in a NICU (n=100); participants were followed starting March 1, 2014. Questionnaires to determine the characteristics of mothers and newborns were used as data collection tools, including the State-Trait Anxiety Inventory Scale (STAI TX-1 - STAI TX-2). RESULTS: Trait anxiety levels were not significantly different between mothers with newborns in the NICU and mothers with newborns in PCS (t=0.588, p=0.557), whereas state anxiety levels were significantly different between the two groups (t=-5.109, p=<0.001). The state anxiety levels of mothers whose infants were in the NICU were determined to be higher compared to those of mothers whose infants were in PCS. CONCLUSION: Being a mother of a sick newborn can elevate anxiety and lead to in mothers. During this challenging time, the support of nurses can increase mothers' abilities to cope with the stress of a sick newborn. PMID- 26649010 TI - Pattern of MRI brain in neuro-psychiatric SLE. Effect of anti-phospholipid antibodies: A study at a tertiary care teaching hospital. AB - OBJECTIVE: To compare the neuro-radiologic findings in Systemic lupus erythematosus (SLE) patients with and without antiphospholipid antibodies (aPL) in different neuro-psychiatric manifestations. METHODS: This cross-sectional comparative study was carried out at King Khalid University Hospital, a tertiary care teaching hospital, Riyadh, Saudi Arabia from June 2012 to January 2015. Ninety seven SLE patients with neuro-psychiatric manifestations were included in the study and divided into two groups. Group I (50 patients) SLE with aPL and group II (47 patients) SLE without aPL. We compared Demographic features, clinical manifestations and magnetic resonance imaging (MRI) brain findings. RESULTS: Demographic and clinical characteristics of two groups were similar. In Group-I, anticardiolipin antibodies (aCL) were most common (86%). In patients with headache, most of the patients in Group-I had white matter hyperintensities (WMHIs) (50% vs 27%) while most of the patients in Group-II had normal MRI brain (38% vs 73%). Similarly WMHIs were found more in Group-I patients with seizures (60% vs 21%), while ischemia/infarction, atrophy and normal MRI were found in Group-II. MRI brain in patients with neurological deficit and psychiatric disorder were not much different in both the groups. CONCLUSION: We found no statistically significant differences in frequencies of MRI brain abnormalities in SLE patients with and without aPL antibodies. Each of the three aPL may have a variable effect on the brain. PMID- 26649011 TI - Hysterosalpingographic evaluation of primary and secondary infertility. AB - OBJECTIVE: To determine the pathological patterns of fallopian tubes and uterus on hysterosalpingogrphy (HSG) examination in cases of infertility. METHODS: Two years retrospective charts review of patients referred to our centre for HSG evaluation of infertility, from July 2008 to July 2010. RESULTS: Four thousand one hundred eight hysterosalpingograms were carried out at our centre during the study period. Out of these, 1999 (48.6%) were primary infertility cases while the 2109 (51.3%) were of secondary infertility. Mean age of presentation for primary infertility was 30 years and 35 years for secondary infertility. Bilateral free peritoneal spill was noted in 60% of cases. Unilateral tubal blockage was present in 15% and bilateral tubal blockage in 10% of patients. Bilateral hydrosalpinx was present in 10% of patients and unilateral loculated spill was found in 5% of patients with primary infertility. Patients with uterine congenital anomalies were also evaluated and the frequency of bicornuate uterus was 4%, unicornuate uterus was 2% and uterine didelphys was 0.2%. CONCLUSIONS: Infertile patients who underwent HSG were mostly in older age group with secondary infertility being slightly more common emphasizing early work up and care. Most of the patients with primary infertility had normal HSG examination. To our knowledge this is the largest data for HSG to be presented from Pakistan. PMID- 26649012 TI - Detection of oral Helicobacter Pylori infection using saliva test cassette. AB - OBJECTIVE: To investigate the incidence of oral infection with Helicobacter pylori (H. pylori) and identify related epidemiological factors among freshmen of four colleges in Yancheng. METHODS: The data, scored positive or negative, were collected on 160 individuals who had been diagnosed by H. pylori Saliva Test Cassette (HPS) during October 2013 to October 2014. H. pylori Saliva Test Cassette (HPS) is to use colloidal gold technique to specifically identify urease in saliva. A standard questionnaire, with variables including sex, educational degree of parents etc., was used in the subjects. Statistical data of diagnostic test were analyzed by SPSS17.0 software. RESULTS: Out of 160, 82 subjects were detected positive and 78 were negative. In univariate analysis, dental plaque, family history of stomach diseases, habit of washing hands before meals and habit of brushing teeth twice daily were associated negatively with H. pylori infection. Multivariate logistic regression analysis showed that dental plaque and family history of stomach diseases were the risk factors which may be associated with H. pylori infection. CONCLUSIONS: Dental plaque and family history of gastric diseases were risk factors of oral H. pylori infection. It is vital for the prevention of H. pylori infection to focus on health education and oral hygiene, and avoid transmission by oral-oral route as well. PMID- 26649013 TI - Visual outcome of 25-gauge microincision vitrectomy surgery in diabetic vitreous haemorrhage. AB - OBJECTIVE: To assess the visual outcome and complications of 25-gauge micro incision vitrectomy surgery (MIVS) in diabetic vitreous haemorrhage. METHODS: This Quasi Experimental study was conducted at LRBT, Tertiary eye care hospital Karachi, from February 2012 to January 2013. Sixty eyes of sixty patients with uncontrolled type II diabetes mellitus (DM) were included. There were 43 (71.7%) males and 17 (28.3%) females. Age range was 40 - 60 years. All randomly selected patients underwent 25-gauge sutureless micro incision vitrectomy surgery for diabetic vitreous haemorrhage. Main outcomes measured were best corrected visual acuity (BCVA) assessed with logMAR and post-operative complications. Follow ups were at one day, one week, one month, three months and six months post operatively. RESULT: Best corrected visual acuity (BCVA) gradually improved in majority of subjects in each subsequent follow up visit. Preoperative visual acuity was 1.023 +/-0.226 logMAR, which was improved after final follow up to 0.457+/-0.256 and P-value was < 0.001. Five patients developed recurrent vitreous haemorrhage during study period, one patient developed cataract (1.7%), one (1.7%) had ocular hypotony defined as intraocular pressure < 5 mmHg and one (1.7%) developed endophthalmitis. CONCLUSION: 25-gauge micro incision vitrectomy surgery (MIVS) is an effective sutureless parsplana vitrectomy surgery which has good visual outcome in diabetic vitreous haemorrhage with minimum manageable complications. PMID- 26649014 TI - Mortality in Sepsis and its relationship with Gender. AB - BACKGROUND AND OBJECTIVE: Sepsis remains a leading cause of death across the world, carrying a mortality rate of 20-50%. Women have been reported to be less likely to suffer from sepsis and to have a lower risk of mortality from sepsis compared to men. The objective of this study was to determine the relationship between gender and mortality in sepsis, and compare cytokine profiles of male and female patients. METHODS: This was a prospective case series on 97 patients admitted with sepsis. Clinical and microbiological data was gathered, blood samples were collected for cytokine (IL-10, IL-6 and TNFalpha) levels and patients were followed up for clinical outcome. RESULTS: There were 54% males and 46% females, with no significant difference of age or comorbids between genders. Respiratory tract infection was the commonest source of sepsis, and was more common in females (60%) compared to males (39%) (p=0.034). Males had a higher mortality (p=0.048, RR 1.73) and plasma IL-6 level(p=0.040) compared to females. Mean IL-6 plasma level was significantly (p<0.01) higher in patients who died vs. who recovered. CONCLUSION: Our study shows that males with sepsis have a 70% greater mortality rate, and mortality is associated with a higher IL-6 plasma level. PMID- 26649015 TI - Analyzing correlation between epicardial fat area and metabolic syndrome risk factor by using low-dose Lung CT. AB - OBJECTIVES: To study about the blood count of a risk factor related to physical measurement and metabolic syndrome, and the area of epicardial fat for medical checkup patients. METHODS: From April 1(st) to November 15(th) in 2014, we measured the area of epicardial fat in the adult out patients under 60 years of age, who are in good health; and the patients took the blood test and low-dose lung CT. In order to identify the relationship between the area of epicardial fat and the risk factor of metabolic syndrome, we conducted correlation analysis. Then, we performed multiple regression analysis to evaluate an independent correlation of epicardial area. In addition, we computed the cut-off value of epicardial fat area by using ROC (Receiver Operating Characteristic) curve to foresee a metabolic syndrome factor that has the most proper sensitivity and specificity. RESULTS: Waist circumference, fasting blood sugar, triglyceride, high-density lipoprotein (HDL) cholesterol, systolic blood pressure, and diastolic blood pressure were shown to be the factors that affect the area of epicardial fat. Therefore, if waist circumference, fasting blood sugar, triglyceride, systolic blood pressure, and diastolic blood pressure were increased, the area of epicardial fat would be significantly increased (P<0.05); and if high-density lipoprotein cholesterol was increased, the area of epicardial fat would be significantly decreased (P<0.05). Out of metabolic syndrome factors, waist circumference's ROC curve area was 0.79 (Confidence Interval 0.73-0.84, P<0.05), which was the highest. The sensitivity was 83.7% when specificity was 70.1%, which proves that they are important factors for the diagnosis. In brief, metabolic syndrome is a disease that mostly appears in obesity patients, so we should try to monitor and cure the disease. CONCLUSION: The risk factors of metabolic syndrome can be managed through health care, and if we try to decrease the risk factors, we will be able to shrink epicardial fat area and decrease metabolic syndrome at the same time. PMID- 26649016 TI - Major dietary patterns and risk of acute myocardial infarction in young, urban Pakistani population. AB - OBJECTIVE: To investigate the role of dietary intake in the development of premature acute myocardial infarction (AMI) in a hospital-based Pakistani population in Karachi. METHODS: In a case control study, 203 consecutive patients (146 males and 57 females) with their first AMI and age below 45 years were enrolled with informed consent. Similarly, 205 gender and age matched (within 3 years) healthy adults were also included as controls. Dietary intake of both cases and controls was assessed by using a simple 14-item food frequency questionnaire. Using factor analysis, 3 major dietary patterns- prudent dietary pattern, combination dietary pattern and western dietary pattern were identified. Fasting plasma/serum of both cases and controls were analyzed for homocysteine, folate, vitamin B12, blood Pb, ferritin, cholesterol, LDL-cholesterol, HDL cholesterol and triglycerides. ANOVA and conditional logistic regression were used to predict the association of dietary patterns with AMI. RESULTS: Consumption of prudent diet, characterized by high consumption of legumes, vegetables, wheat, chicken and fruits, is protective against the risk of premature AMI. Moderate to high consumption of combination diet, characterized by high intake of eggs, fish, fruits, juices and coffee was associated with decreased risk of AMI. No association was observed between western diet, characterized by high intake of meat, fish and tea with milk and risk of AMI. CONCLUSIONS: Consumption of a prudent dietary pattern and a combination dietary pattern is protective against the risk of AMI in a Pakistani population. PMID- 26649017 TI - To determine the frequency of Factor V Leiden in cases of Deep Vein Thrombosis and Healthy controls. AB - OBJECTIVE: To determine the frequency of Factor V Leiden in cases of Deep Vein Thrombosis and Healthy controls. METHODS: This case control study was performed in Armed Forces Institute of Pathology Rawalpindi, From 21(st) March to 25(th) September 2013. One hundred patients with diagnostic evidence of Deep vein thrombosis on Doppler ultrasound/Magnetic resonance imaging (MRI) scan were included in the study through non probability convenient sampling and compared with 100 matched healthy controls. DNA was extracted from the blood sample by kit method. In order to identify Factor V Leiden mutation, the polymerase chain reaction (PCR) method was utilized combined with the Amplification refractory mutation system. Data was analyzed using statistical package for social sciences (SPSS) version 17. RESULTS: In 100 patients of Deep Vein Thrombosis (DVT), frequency of Factor V Leiden (FVL) was 13% and it is was 2% in healthy control group. A significant association was found between FVL and DVT with odds ratio of 7.32 and with P value (P = 0.003). CONCLUSION: FVL was found to be highly prevalent among patients of DVT, Signifying strong association between the two. PMID- 26649018 TI - Effect of wavefront optimized LASIK on higher order aberrations in myopic patients. AB - OBJECTIVE: To determine mean change induced in root mean square value of higher order aberrations in myopic patients undergoing wavefront optimized laser assisted in situ keratomileusis. METHODS: This quasi experimental study was conducted at Armed Forces Institute of Ophthalmology, Rawalpindi, Pakistan from Jan 2014 to Dec 2014. Sixty eyes of 35 myopic patients were included in the study. All patients underwent wavefront optimized (WFO) laser assisted in situ keratomileusis (LASIK) using femtosecond laser (FM 200Wavelight technologies) and excimer laser (Ew 500Wavelight technologies). Higher order aberrations (HOAs) were measured with aberrometer (Wavelight allegro analyzer version 1073) during preoperative assessment and one month after surgery. RESULTS: All 35 patients ranged from 20 to 32 years with a mean age of 24 +/- 3.41 years. Refractive error ranged from -1.00 to -9.50 DS with a mean spherical equivalent (SE) of -3.73 +/- 1.95 before surgery and - 0.36 +/- 1.50DS one month after LASIK. Uncorrected visual acuity (UCVA) was improved to 0.00 or better in all 60 eyes. An increase of 1.56 fold was observed in RMS of total HOAs. Among the HOAs, a statistically significant positive correlation was observed between spherical aberrations (4(th) order aberration) and preoperative spherical equivalent. CONCLUSION: In spite of excellent improvement in refractive error, significant amount of higher order aberrations were induced after WFO LASIK. PMID- 26649019 TI - Use of iron supplements in children aged 1-2 years with iron deficiency anemia: A cross-sectional study. AB - OBJECTIVES: Iron deficiency (ID) is the most common nutritional problem in the world and is the most common cause of childhood anemia. In this study, our aim was to find out about the state of usage of iron preparation, which is distributed free of charge by the Ministry of Health, for the infants between 4 12 months in our country, as well as detecting the awareness degree of families those who are informed about iron-deficiency anemia (IDA), prophylaxis of the drug and to determine the drug's effectiveness. METHODS: It was a cross-sectional survey. The laboratory values from the files of the children aged 1-2 those who visited our hospital's department of pediatrics, between January 2010 to August 2013, were collected. The survey included families who have children diagnosed with IDA. Questions included about families' sociodemographic characteristics, the state of the usage of the iron drug, how much information received in terms of the side effects- consumption period and dosage. RESULTS: A total of 139 children were enrolled in our study. While 77.7% of the families who participated stated that (n = 108) iron medicine was prescribed other 43.2% of families stated (n = 60) was prescribed and they were informed about iron pills and IDA. 25.9% of families had received information about drug's side effects, 74.8% of them had information about period of consumption and 77.7% said they were given information about the drug dose. The average duration of use of iron medicine was 6.98+/-4.52 (min: 1, max: 24) months. It has been noted that; parent's education level, mother's occupation, child's gender, how the child was born and receiving information about how to use the medicine had no effects on usage of the drug in children. Nevertheless, it has been noticed that, when the families were given proper information the drug use increased and the patients compliance with medications also increased. CONCLUSION: We believe that, due to frequent diagnosis of anemia in children, prophylaxis iron supplementation should be continued for up to the age of two years. PMID- 26649020 TI - VAAFT: Video Assisted Anal Fistula Treatment; Bringing revolution in Fistula treatment. AB - OBJECTIVE: To share our findings that the new treatment modality Video Assisted Anal Fistula Treatment (VAAFT) is a better alternate to the conventional treatments of Fistula in Ano in our setup with minor changes in the initial method described by Meinero. METHODS: Karl Storz Video equipment including Meinero Fistuloscope was used. Key steps are visualization of the fistula tract, correct localization of the internal fistula opening under direct vision and endoscopic treatment of the fistula. This is followed by an operative phase of fulguration of the fistula tract using glycine solution mixed with manitol, curetting the tract with curette and fistula brush. Internal opening is closed with a Vicryl 1 suture. RESULT: Total of 40 patients were operated using VAAFT from October 2013 to March 2014. Three were re-operated. The other 37 cases were followed up at 6 weeks, 3 months and 6 months. Primary healing took place in 20 (50%) cases at 6 weeks. In the remaining 17 (42.5%) cases, minor discharge occurred with itching which resolved till the next visit at 8 weeks and 12 weeks. CONCLUSION: As the main aim in treating fistula is proper identification of the internal opening, excision of the tract and sparing the sphincter function, VAAFT achieves all aims with additional benefits of patients' satisfaction and negligible scaring. PMID- 26649021 TI - Hypovitaminosis D and its association with lifestyle factors. AB - OBJECTIVES: The present study was designed to determine the serum vitamin D levels and their relation with demographic features and life style factors in young adults. METHODS: It was an analytical cross-sectional study on 88 subjects aged 18-40 years. Relevant information about physical activity, job place, duration of sun exposure, educational status and socioeconomic conditions was obtained. Serum levels of 25-OH vitamin D were measured by ELISA. Data was analyzed using SPSS 20. RESULTS: Mean serum vitamin D level was 8.44+/-0.49 (Range: 1.00-21.08) ng/ml in participants. Vitamin D deficiency was found in 98.86% of the population. Mean vitamin D levels were significantly lower in females (p=0.0001), physically less active (p=0.006), indoor job holders (p=0.0001), less sun exposed (p=0.001), highly educated (p=0.020) and high socioeconomic status (p=0.007) bearing and in subjects having relatively fair skin complexion (p=0.041). CONCLUSIONS: Serum vitamin D levels of study population were below normal and were associated with female gender, less physical activity, indoor jobs, less sun exposure, higher education and higher socioeconomic class and relatively fair skin complexion. PMID- 26649022 TI - Prevalence and pattern of self-medication in Karachi: A community survey. AB - OBJECTIVE: To study the prevalence and pattern of self-medication among adult males and females in Karachi, Pakistan. METHODS: This cross-sectional community- based survey was carried out at five randomly selected towns of Karachi (Defence, Gulshan-e-Iqbal, North Nazimabad, Malir, Orangi town) over a period of 3 months (October, November & December 2012). A sample size of 500 adult cases (250 males & 250 females), with systemic random selection from different towns of Karachi were inducted in this study. The city was divided in 5 zones and one town from each zone was selected by systemic randomization. First available male and female from each randomly selected house were included in the study. After consent and confidentiality assurance they were interviewed on semi-structured Performa designed for this purpose. Results were analyzed and tabulated through SPSS v14.0. RESULT: The prevalence of self-medication in males and females in Karachi is found to be 84.8% (males 88.4% and females 81.2%). The most frequent symptoms for which self-medication used were headache (32.7%), fever (23.3%) and the medicines used were painkillers (28.8%), fever reducer medicines (19.8%). The most common reason 33.3% was previous experience with similar symptom. CONCLUSION: Self-medication is highly prevalent (84.8%) in Karachi. It was frequently used for headache followed by fever. Predominantly painkillers, fever reducer and cough syrups were used in the form of tablets and syrups. Main source of medicines for males were friends and for females were relatives. PMID- 26649023 TI - The prevalence of HTLV-1 and its Co-Infection with HCV, HBV and HIV in Hemophilic patients. AB - BACKGROUND AND OBJECTIVE: Blood-borne infections, such as the HIV virus and hepatitis B and C, are major problems in patients receiving blood products. Here we examined the prevalence of HTLV-1, HCV, HBV, and HIV in hemophilic patients. METHODS: A cross-sectional study on 108 hemophilic patients (101 males and 7 females) involved detection of HBV, HCV, HIV and HTLV-1 infections using immunoassays for HBsAg, hepatitis B core antibodies (anti-HBc), hepatitis C antibodies (anti-HCV), HIV antibodies (anti-HIV) and Anti-HTLV-1. Real-time PCR was used to measure HCV RNA, and HCV genotyping was performed by direct sequencing of the 5' noncoding region. RESULTS: Hemophilia A was reported in 93 (86%) patients with severe symptoms in 8 cases. The seroprevalence of anti-HCV and anti-HTLV-1 antibodies was 20% and 3% respectively. One patient with severe hemophilia had a HCV/HTLV-1 co-infection. HCV-RNA was detected in 82% of patients. In terms of genotyping prevalence was 56% HCV genotype 3a, 39% HCV genotype 1a, and 6% HCV genotype2. Anti HIV and HBsAg were not detected in any patient. HTLV1 prevalence was higher, HCV lower in South Khorasan than other regions in Iran or elsewhere. CONCLUSION: Management of transfusion of blood and blood products should account for the underlying prevalence of infectious agents. PMID- 26649024 TI - The effect of Ramadan fasting on cardiometabolic risk factors and anthropometrics parameters: A systematic review. AB - Fasting during the month of Ramadan is a religious rituals of all healthy adult Muslims. However, there is no clear agreement on the effects of Ramadan fasting on cardiovascular disease. Comorbidities and factors such as age, gender, health status, daily duration of fasting, food intake before and after fasting may impact on a fasting individual's cardiometabolic risk. This review was undertaken to assess the effects of Ramadan fasting on: the incidence of cardiovascular disease during the month of Ramadan; the clinical status of patients with stable cardiac disease; and any alterations in cardiometabolic risk profile. METHODS: A systematic search was undertaken for studies that investigated the impact of Ramadan fasting on cardiovascular outcomes and risk factors. Electronic databases including MEDLINE, Scopus and Web of Knowledge were searched from 1982 up to 2014. The incidence of acute cardiac illness during Ramadan fasting was similar when compared to non-fasting days. Ramadan fasting is associated with elevations in high-density lipoprotein cholesterol (HDL-c), and reductions in low-density lipoprotein cholesterol (LDL-c) and total cholesterol (T-chol). However, the lipid profile of diabetic patients deteriorated significantly during Ramadan fasting. In addition, Ramadan fasting lowers body weight, body fat percentage and BMI (body mass index). However, the relationship between weight reduction and loss of body fat is not studied. The majority of patients with stable cardiac illness can opt for Ramadan fasting safely. However, the long term effects of Ramadan fasting on cardiovascular outcomes and risk factors remains uncertain, and the apparent discordant effects in individuals with and without diabetes mellitus merits further study. PMID- 26649026 TI - Microsurgery for root coverage: A systematic review. AB - OBJECTIVE: To evaluate whether microsurgery gains better result in root coverage compared to conventional surgical techniques. METHODS: A number of databases were searched to identify eligible studies from January 1992 to January 2015. THE FOLLOWING OUTCOMES WERE EVALUATED: number of sites exhibiting complete root coverage and patients' esthetic satisfaction. RESULTS: Four Randomized Clinical Trials (RCTs) fulfilled the inclusion criteria. A pooled estimate from the two RCTs regarding sub-epithelial connective tissue grafts (SCTG) showed significant achievement in complete root coverage in the microsurgical group [relative risk (RR):1.63; 95% confidence interval (CI): 1.12 to 2.36; P=0.01] with acceptable heterogeneity. The other two studies were about coronal advanced flap (CAF) with enamel matrix derivative or free rotated papilla autograft and did not qualify for meta-analysis. Patients' esthetic satisfaction was analyzed only by one study. CONCLUSIONS: Using microsurgical technique for treating gingival recessions may be effective in achieving complete root coverage for SCTG. PMID- 26649025 TI - "OMIC" tumor markers for breast cancer: A review. AB - Breast cancer is a global health issue, and as the tumor burden increases, we need to come up with newer, better technologies which are convenient, cheap, rapid, sensitive with a high specificity. Technological advancements in the field of cancer biomarker has led to the development of techniques such as mass spectrometric analysis and microarray analysis in which genes, proteins and hundreds and thousands of metabolites can be identified with the emergence of genomics, proteomics and metabolomics. This research is focused on finding biomarkers for diagnosis, prognosis, staging, treatment response and targets for chemotherapy, generating a panel of markers which provide better clinical information compared to a single marker in the panel. This review briefly summarizes application of genomics and proteomics followed by key concepts and applications of metabolomics in breast cancer, with the conclusion that an integration of the three "OMIC" technologies may hold the key to future biomarker discovery. SOURCES OF DATA STUDY SELECTION: The information for this review was collected by searching the Google Scholar and PubMed database for English articles published in the period from 2002 to 2015. The search terms included "biomarkers in breast cancer" along with the following search terms: "genomics", "proteomics", "metabolomics", "breast cancer", "mass spectrometry", "molecular markers" and "cancer biomarker". We have endeavored to quote only the primary sources. Titles and abstracts of retrieved studies were assessed first followed by selection and retrieval of selected full text articles. PMID- 26649027 TI - Antipsychotic Medication and QT Prolongation. AB - The QT interval represents ventricular depolarisation and repolarisation. Prolongation of this interval can lead to life-threatening complications. These can include arrhythmias such as Torsades de Pointes and Ventricular Fibrillation, which may ultimately lead to death. Many risk factors have been identified in prolonging the QT interval, one of which is medication commonly used in the treatment of Psychiatric ailments. This article describes Antipsychotic drugs causing prolonged QT interval and the possible underlying mechanisms alongside the current best practice on the management of this potentially fatal complication. PMID- 26649028 TI - Improving Workplace-Based Learning for Undergraduate Medical Students. AB - Workplace-based learning is considered as one of the most effective way of translating medical theory into clinical practice. Although employed traditionally at postgraduate level, this strategy can be used in undergraduate students coming for clerkships in clinical departments. There are many challenges to workplace learning such as, unfavorable physical environment, lack of interest by clinical staff and teachers, and lack of student motivation. Clinical teachers can help bridge this gap and improve workplace learning through individual and collaborative team effort. Knowledge of various educational theories and principles and their application at workplace can enhance student learning and motivation, for which faculty development is much needed. Different teaching and learning activities can be used and tailored according to the clinical setting. Active reflection by students and constructive feedback from the clinicians forms the backbone of effective workplace learning. PMID- 26649029 TI - Diabetic dermopathy ("shin spots") and diabetic bullae ("bullosis diabeticorum") at the same patient. AB - We present a diabetic patient with associated two diabetic dermatoses: diabetic dermopathy ("shin spots") and diabetic bullae. A 34-year-old man, with long history of diabetes mellitus, hypertension, and moderate obesity presented to Dermatology Unit for diagnosis of his skin lesions. On clinical examination multiple, light brown, irregular patches, with atrophic scars and crusts over large bullae were observed on the anterior aspect of both legs. PMID- 26649030 TI - Neonatal idiopathic primary hypoparathyroidism: A rare cause of neonatal seizures. AB - Etiology of neonatal seizures (NNS) is diverse and hypocalcemia is one of the treatable causes. Neonatal hypocalcemia (NHC) due to congenital hypoparathyroidism, either permanent or transient, is extremely rare. Its biochemical abnormalities include hypocalcemia, hyperphosphatemia and low levels of intact parathyroid hormone (PTH). Isolated congenital hypoparathyroidism in which deficiency of PTH has no association with maternal, syndromic or endocrine defects is a very rare entity. We are reporting a case of a newborn who presented with seizures on the 5th day of life and later on investigations revealed hypocalcaemia due to isolated congenital hypoparathyroidism. PMID- 26649031 TI - Beware Postpartum Shortness of Breath. AB - Peripartum cardiomyopathy (PPCM) is one of the potentially life-threatening complications of pregnancy. We report a case of a 36-year-old female patient who presented with shortness of breath, swelling of feet after giving birth to triplets, and her tests revealed that left ventricle is dilated with its diameter on the borderline and she had EF 35% with advanced systolic dysfunction. Anterior wall and septum were severely hypokinetic. In the presence of these findings, the patient was evaluated as PPCM. PPCM must be considered in the differential diagnosis of a patient presenting with shortness of breath and swelling of feet, which are also common in pregnancy. PMID- 26649032 TI - Spontaneous echo contrast masking thrombus in giant left atrium of mitral stenosis-a dilemma in clinical diagnosis. AB - Spontaneous echo contrast (SEC) and thrombus in enlarged left atrium (LA) are common in mitral valvular disease (MVD) and SEC is considered to be a prethrombotic condition. Reliable exclusion of LA thrombus is important before any definitive curative attempts like percutaneous transluminal mitral commissurotomy (PTMC), closed mitral commissurotomy (CMC) or innovative therapies like pulmonary vein isolation and percutaneous closure of the LA appendage. Echocardiography, particularly the transesophageal echocardiography (TEE) is considered to be the gold standard for the diagnosis and to exclude LA thrombus. However, LA thrombus may remain rarely undetected even by TEE potentially making the interventions a risky job. We present a case of mitral stenosis (MS) with giant LA where profuse, dense SEC masked the underlying thrombus in the LA cavity. PMID- 26649033 TI - Restoration of Endothelial Function in Pparalpha (-/-) Mice by Tempol. AB - Peroxisome proliferator activated receptor alpha (PPARalpha) is one of the PPAR isoforms belonging to the nuclear hormone receptor superfamily that regulates genes involved in lipid and lipoprotein metabolism. PPARalpha is present in the vascular wall and is thought to be involved in protection against vascular disease. To determine if PPARalpha contributes to endothelial function, conduit and cerebral resistance arteries were studied in Pparalpha (-/-) mice using isometric and isobaric tension myography, respectively. Aortic contractions to PGF2alpha and constriction of middle cerebral arteries to phenylephrine were not different between wild type (WT) and Pparalpha (-/-); however, relaxation/dilation to acetylcholine (ACh) was impaired. There was no difference in relaxation between WT and Pparalpha (-/-) aorta to treatment with a nitric oxide (NO) surrogate indicating impairment in endothelial function. Endothelial NO levels as well as NO synthase expression were reduced in Pparalpha (-/-) aortas, while superoxide levels were elevated. Two-week feeding with the reactive oxygen species (ROS) scavenger, tempol, normalized ROS levels and rescued the impaired endothelium-mediated relaxation in Pparalpha (-/-) mice. These results suggest that Pparalpha (-/-) mice have impaired endothelial function caused by decreased NO bioavailability. Therefore, activation of PPARalpha receptors may be a therapeutic target for maintaining endothelial function and protection against cardiovascular disease. PMID- 26649034 TI - AICAR Protects against High Palmitate/High Insulin-Induced Intramyocellular Lipid Accumulation and Insulin Resistance in HL-1 Cardiac Cells by Inducing PPAR-Target Gene Expression. AB - Here we studied the impact of 5-aminoimidazole-4-carboxamide riboside (AICAR), a well-known AMPK activator, on cardiac metabolic adaptation. AMPK activation by AICAR was confirmed by increased phospho-Thr(172)-AMPK and phospho-Ser(79)-ACC protein levels in HL-1 cardiomyocytes. Then, cells were exposed to AICAR stimulation for 24 h in the presence or absence of the AMPK inhibitor Compound C, and the mRNA levels of the three PPARs were analyzed by real-time RT-PCR. Treatment with AICAR induced gene expression of all three PPARs, but only the Ppara and Pparg regulation were dependent on AMPK. Next, we exposed HL-1 cells to high palmitate/high insulin (HP/HI) conditions either in presence or in absence of AICAR, and we evaluated the expression of selected PPAR-targets genes. HP/HI induced insulin resistance and lipid storage was accompanied by increased Cd36, Acot1, and Ucp3 mRNA levels. AICAR treatment induced the expression of Acadvl and Glut4, which correlated to prevention of the HP/HI-induced intramyocellular lipid build-up, and attenuation of the HP/HI-induced impairment of glucose uptake. These data support the hypothesis that AICAR contributes to cardiac metabolic adaptation via regulation of transcriptional mechanisms. PMID- 26649035 TI - Recent Advances in Learning Theory. PMID- 26649036 TI - A Randomized Controlled Trial Evaluating a Low-Volume PEG Solution Plus Ascorbic Acid versus Standard PEG Solution in Bowel Preparation for Colonoscopy. AB - Evaluation of polyethylene glycol electrolyte lavage solution containing ascorbic acid (PEG-ASC) has been controversial in the point of its hyperosmolarity, especially in old population. So we therefore designed the present study to compare the efficacy, acceptability, tolerability, and safety of 1.5 L PEG+ASC and 2 L standard PEG electrolyte solution (PEG-ELS), not only in the general population, but also in patients of advanced age. Randomization was stratified by age (<70 years or 70> years), and hematological and biochemical parameters were compared in each age group, especially with respect to the safety profile of each regimen. As a result, the 1.5-L PEG-ASC regimen had higher patient acceptability than the 2-L PEG-ELS regimen. Tolerability, bowel cleansing, and safety were similar between regimens. However, we demonstrated significant statistical changes in the hematological and biochemical parameters after taking bowel preparation solutions, not only in the PEG+ASC group, but also in the PEG-ELS group. No significant differences in the safety profile were found between subjects aged less than 70 years and those aged 70 years or more; nevertheless, regardless of age, proper hydration is needed throughout the bowel preparation process. PMID- 26649037 TI - Prognostic Value of Metastatic No.8p LNs in Patients with Gastric Cancer. AB - Background. To evaluate prognostic value of metastatic No.8p LNs in patients with gastric cancer. Methods. From August 2002 to December 2011, a total of 284 gastric cancer patients who underwent gastrectomy with No.8p LNs dissection were analyzed retrospectively in this study. Patients were divided into two groups according to the status of No.8p LNs. Clinicopathological features were collected to conduct the correlation analysis. Follow-up was carried out up to December 31st, 2014. Overall survival was analyzed. Results. Out of 284 patients, metastatic No.8p LNs were found in 24 (8.5%) patients. Compared with other 260 cases, these patients suffered morphologically larger tumor (P = 0.003), node stage (P = 0.000), and metastatic stage (P = 0.000). The 3-year overall survival rate was 26% in No.8p-positive group and 53% in No.8p-negative group. No significant difference of cumulative survival rates existed between the No.8p positive group and No.8p-negative stage IV group (26% versus 28%, P = 0.923). Patients with other distant metastasis or not in No.8p+ group had similar cumulative survival rates (24% versus 28%, P = 0.914). Conclusions. Positive No.8p LNs were a poor but not an independent prognostic factor for patients with GC and should be recognized as distant metastasis. PMID- 26649038 TI - Association Analysis of MET Gene Polymorphism with Papillary Thyroid Carcinoma in a Chinese Population. AB - To investigate the association of MET SNPs with gender disparity in thyroid tumors, as well as the metastasis and prognosis of patients, 858 patients with papillary thyroid carcinoma (PTC), 556 patients with nodular goiter, and 896 population-based normal controls were recruited. The genotyping of MET SNPs was carried out using the Sequenom MassARRAY system. The distribution of MET SNPs (rs1621 and rs6566) was different among groups. Gender stratification analysis revealed a significant association between the rs1621 genotype and PTC in female patients (P = 0.037), but not in male patients (P > 0.05). For female patients, the rs1621 AG genotype was significantly higher in patients with PTC than in normal controls (P = 0.01) and revealed an increasing risk of PTC (OR: 1.465, 95% CI: 1.118-1.92). However, association analysis of the rs1621 genotype with metastasis and prognosis revealed no significant correlation in both male and female patients. The findings of our study showed that polymorphism of SNP locus rs1621 in MET gene may be associated with gender disparity in PTC. Higher AG genotypes in rs1621 were correlated with PTC in female patients, but not in male patients. PMID- 26649039 TI - CT Findings of Patients Treated with Irreversible Electroporation for Locally Advanced Pancreatic Cancer. AB - Introduction. In patients with locally advanced pancreatic cancer (LAPC), IRE has been shown to be safe for local disease control and palliation. As IRE continues to gain acceptance it is important to characterize the expected imaging findings. Materials and Methods. A review of our prospective soft tissue ablation registry from July 2010 to June 2013 was performed on patients who had undergone IRE for LAPC. Five masses treated with intraoperative IRE ablation for pancreatic tumors that underwent CT imaging before and after ablation were reviewed. Results and Discussion. Following IRE, the postablation bed is larger than the original ablated tumor. This ablation zone may get smaller in size (due to decreased edema and hyperemia) in the following months and more importantly remains stable provided there is no recurrence. In cases of recurrent disease there is increased size of the ablation bed, mass effect, and new or worsening vascular encasement or occlusion. Conclusion. CT imaging remains the best current imaging modality to assess post-IRE ablation changes. Serial imaging over at least 2-6 months must be employed to detect recurrence by comparing with prior studies in conjunction with clinical and serum studies. Larger imaging studies are underway to evaluate a more ideal imaging modality for this unique patient population. PMID- 26649040 TI - Traditional Dietary Pattern Increases Risk of Prostate Cancer in Argentina: Results of a Multilevel Modeling and Bias Analysis from a Case-Control Study. AB - There is increasing evidence that dietary habits play a role in prostate cancer (PC) occurrence. Argentinean cancer risk studies require additional attention because of the singular dietary pattern of this population. A case-control study (147 PC cases, 300 controls) was conducted in Cordoba (Argentina) throughout 2008 2013. A principal component factor analysis was performed to identify dietary patterns. A mixed logistic regression model was applied, taking into account family history of cancer. Possible bias was evaluated by probabilistic bias analysis. Four dietary patterns were identified: Traditional (fatty red meats, offal, processed meat, starchy vegetables, added sugars and sweets, candies, fats, and vegetable oils), Prudent (nonstarchy vegetables, whole grains), Carbohydrate (sodas/juices and bakery products), and Cheese (cheeses). High adherence to the Traditional (OR 2.82, 95%CI: 1.569-5.099) and Carbohydrate Patterns (OR 2.14, 95%CI: 1.470-3.128) showed a promoting effect for PC, whereas the Prudent and Cheese Patterns were independent factors. PC occurrence was also associated with family history of PC. Bias adjusted ORs indicate that the validity of the present study is acceptable. High adherence to characteristic Argentinean dietary patterns was associated with increased PC risk. Our results incorporate original contributions to knowledge about scenarios in South American dietary patterns and PC occurrence. PMID- 26649041 TI - Cyanoacrylate for Intraoral Wound Closure: A Possibility? AB - Wound closure is a part of any surgical procedure and the objective of laceration repair or incision closure is to approximate the edges of a wound so that natural healing process may occur. Over the years new biomaterials have been discovered as an alternate to conventional suture materials. Cyanoacrylate bioadhesives are one among them. They carry the advantages of rapid application, patient comfort, resistance to infection, hemostatic properties, and no suture removal anxiety. Hence this study was undertaken to study the effect of long chain cyanoacrylate as an adhesive for intraoral wound closure and also to explore its hemostatic and antibacterial effects. Isoamyl-2-cyanoacrylate (AMCRYLATE) was used as the adhesive in the study. In conclusion isoamyl cyanoacrylate can be used for intraoral wound closure, as an alternative to sutures for gluing the mucoperiosteum to bone, for example, after impaction removal, periapical surgeries, and cleft repair. Its hemostatic and antibacterial activity has to be further evaluated. PMID- 26649042 TI - Prediction of Short-Term Outcome in Acute Superior Vestibular Nerve Failure: Three-Dimensional Video-Head-Impulse Test and Caloric Irrigation. AB - This retrospective study examines acute unilateral vestibular failure (up to seven days after onset) with modern vestibular testing (caloric irrigation and video-head-impulse test, vHIT) in 54 patients in order to test if the short-term outcome of the patients depends on the lesion pattern defined by the two tests. Patients were grouped according to a pathological unilateral caloric weakness without a pathological vHIT: group I; additional a pathological vHIT of the lateral semicircular canal (SCC): group II; and an additional pathological vHIT of the anterior SCC: group III. Patients with involvement of the posterior SCC were less frequent and not included in the analysis. Basic parameters, such as age of the subjects, days after symptom onset, gender, side of the lesion, treatment, and dizziness handicap inventory, were not different in groups I to III. The frequency of pathological clinical findings and pathological quantified measurements increased from groups I to III. The outcome parameter "days spent in the hospital" was significantly higher in group III compared to group I. The analysis shows that differential vestibular testing predicts short-term outcome of the patients and might be in future important to treat and coach patients with vestibular failure. PMID- 26649043 TI - A Rare Case of Nonsecretory Multiple Myeloma in Lagos, Nigeria: A Case Report and Literature Review. AB - Multiple myeloma (MM) is a plasma cell disorder associated with clonal proliferation of plasma cells. Nonsecretory multiple myeloma (NSMM) is a rare variant of MM and accounts for approximately 1% to 5% of all cases. It is defined as symptomatic myeloma without detectable monoclonal immunoglobulin on serum or urine electrophoresis. This variant usually poses a diagnostic challenge to the clinician. We present a 60-year-old Nigerian man who was investigated extensively for bone pain, weight loss, and anaemia. He was eventually diagnosed as having nonsecretory multiple myeloma based on histology and immunohistochemistry results of bone marrow trephine biopsy. He is currently being managed with bortezomib, doxorubicin, and thalidomide, as well as zoledronic acid. He is also on anticoagulation. He continues to show remarkable clinical improvement. We describe this case report and literature review for better awareness amongst medical practitioners and pathologists. PMID- 26649045 TI - Delta-Like-1 Changes the Immunomodulatory Property of OP9 Cells. AB - As stromal cells and recently confirmed mesenchymal stem cells, OP9 cells support hematopoiesis stem cell (HSC) differentiation into the B lymphocyte lineage, yet Delta-like-1 (DL1) overexpressing OP9 (OP9DL1) cells promote the development of early T lymphocytes from HSC. However, the immunomodulatory capacity of OP9 or OP9DL1 on mature B and T cell proliferation has not been elucidated. Here, we show that OP9 and OP9DL1 have similar proliferation capacities and immunophenotypes except DL1 expression. Compared with OP9, OP9DL1 displayed more osteogenesis and less adipogenesis when cultured in the respective induction media. Both OP9 and OP9DL1 inhibited mature B and T cell proliferation. Furthermore, OP9 showed stronger inhibition on B cell proliferation and OP9DL1 exhibited stronger inhibition on T cell proliferation. With stimulation, both OP9 and OP9DL1 showed increased nitrate oxide (NO) production. The NO levels of OP9 were higher than that of OP9DL1 when stimulated with TNFalpha/IFNgamma or LPS/IL4. Taken together, our study reveals a previously unrecognized role of OP9 and OP9DL1 in mature B and T cell proliferation. DL1 overexpression alone changed the properties of OP9 cells in addition to their role in early B cell development. PMID- 26649046 TI - Effects on Proliferation and Differentiation of Human Umbilical Cord-Derived Mesenchymal Stem Cells Engineered to Express Neurotrophic Factors. AB - Mesenchymal stem cells (MSCs) are multipotential cells with capability to form colonies in vitro and differentiate into distinctive end-stage cell types. Although MSCs secrete many cytokines, the efficacy can be improved through combination with neurotrophic factors (NTFs). Moreover, MSCs are excellent opportunities for local delivery of NTFs into injured tissues. The aim of this present study is to evaluate the effects of overexpressing NTFs on proliferation and differentiation of human umbilical cord-derived mesenchymal stem cells (HUMSCs). Overexpressing NTFs had no effect on cell proliferation. Overexpressing NT-3, BDNF, and NGF also had no significant effect on the differentiation of HUMSCs. Overexpressing NTFs all promoted the neurite outgrowth of embryonic chick E9 dorsal root ganglion (DRG). The gene expression profiles of the control and NT 3- and BDNF-modified HUMSCs were compared using RNA sequencing and biological processes and activities were revealed. This study provides novel information about the effects of overexpressing NTFs on HUMSCs and insight into the choice of optimal NTFs for combined cell and gene therapy. PMID- 26649044 TI - Extracellular Vesicles: Evolving Factors in Stem Cell Biology. AB - Stem cells are proposed to continuously secrete trophic factors that potentially serve as mediators of autocrine and paracrine activities, associated with reprogramming of the tumor microenvironment, tissue regeneration, and repair. Hitherto, significant efforts have been made to understand the level of underlying paracrine activities influenced by stem cell secreted trophic factors, as little is known about these interactions. Recent findings, however, elucidate this role by reporting the effects of stem cell derived extracellular vesicles (EVs) that mimic the phenotypes of the cells from which they originate. Exchange of genetic information utilizing persistent bidirectional communication mediated by stem cell-EVs could regulate stemness, self-renewal, and differentiation in stem cells and their subpopulations. This review therefore discusses stem cell EVs as evolving communication factors in stem cell biology, focusing on how they regulate cell fates by inducing persistent and prolonged genetic reprogramming of resident cells in a paracrine fashion. In addition, we address the role of stem cell-secreted vesicles in shaping the tumor microenvironment and immunomodulation and in their ability to stimulate endogenous repair processes during tissue damage. Collectively, these functions ensure an enormous potential for future therapies. PMID- 26649047 TI - Effects of Magnetically Guided, SPIO-Labeled, and Neurotrophin-3 Gene-Modified Bone Mesenchymal Stem Cells in a Rat Model of Spinal Cord Injury. AB - Despite advances in our understanding of spinal cord injury (SCI) mechanisms, there are still no effective treatment approaches to restore functionality. Although many studies have demonstrated that transplanting NT3 gene-transfected bone marrow-derived mesenchymal stem cells (BMSCs) is an effective approach to treat SCI, the approach is often low efficient in the delivery of engrafted BMSCs to the site of injury. In this study, we investigated the therapeutic effects of magnetic targeting of NT3 gene-transfected BMSCs via lumbar puncture in a rat model of SCI. With the aid of a magnetic targeting cells delivery system, we can not only deliver the engrafted BMSCs to the site of injury more efficiently, but also perform cells imaging in vivo using MR. In addition, we also found that this composite strategy could significantly improve functional recovery and nerve regeneration compared to transplanting NT3 gene-transfected BMSCs without magnetic targeting system. Our results suggest that this composite strategy could be promising for clinical applications. PMID- 26649048 TI - Encapsulated Whole Bone Marrow Cells Improve Survival in Wistar Rats after 90% Partial Hepatectomy. AB - Background and Aims. The use of bone marrow cells has been suggested as an alternative treatment for acute liver failure. In this study, we investigate the effect of encapsulated whole bone marrow cells in a liver failure model. Methods. Encapsulated cells or empty capsules were implanted in rats submitted to 90% partial hepatectomy. The survival rate was assessed. Another group was euthanized at 6, 12, 24, 48, and 72 hours after hepatectomy to study expression of cytokines and growth factors. Results. Whole bone marrow group showed a higher than 10 days survival rate compared to empty capsules group. Gene expression related to early phase of liver regeneration at 6 hours after hepatectomy was decreased in encapsulated cells group, whereas genes related to regeneration were increased at 12, 24, and 48 hours. Whole bone marrow group showed lower regeneration rate at 72 hours and higher expression and activity of caspase 3. In contrast, lysosomal beta-glucuronidase activity was elevated in empty capsules group. Conclusions. The results show that encapsulated whole bone marrow cells reduce the expression of genes involved in liver regeneration and increase those responsible for ending hepatocyte division. In addition, these cells favor apoptotic cell death and decrease necrosis, thus increasing survival. PMID- 26649049 TI - Bone Marrow-Derived Cells as a Therapeutic Approach to Optic Nerve Diseases. AB - Following optic nerve injury associated with acute or progressive diseases, retinal ganglion cells (RGCs) of adult mammals degenerate and undergo apoptosis. These diseases have limited therapeutic options, due to the low inherent capacity of RGCs to regenerate and due to the inhibitory milieu of the central nervous system. Among the numerous treatment approaches investigated to stimulate neuronal survival and axonal extension, cell transplantation emerges as a promising option. This review focuses on cell therapies with bone marrow mononuclear cells and bone marrow-derived mesenchymal stem cells, which have shown positive therapeutic effects in animal models of optic neuropathies. Different aspects of available preclinical studies are analyzed, including cell distribution, potential doses, routes of administration, and mechanisms of action. Finally, published and ongoing clinical trials are summarized. PMID- 26649050 TI - Adipose-Derived Stem Cells Alleviate Radiation-Induced Muscular Fibrosis by Suppressing the Expression of TGF-beta1. AB - We aim to investigate the effects of adipose-derived stem cells (ASCs) transplantation on irradiation-induced skeletal muscle fibrosis. Sixty-four rabbits were randomly divided into ASCs group and PBS group followed by irradiation at unilateral hip with a single dose of 80 Gy. Nonirradiated side with normal skeletal muscle served as normal control. Skeletal muscle tissues were collected from eight rabbits in each group at 1 w, 4 w, 8 w, and 26 w after irradiation. Migration of ASCs was observed in the peripheral tissues along the needle passage in the injured muscle. The proportion of the area of collagen fibers to the total area in sections of ASCs group was lower than those of PBS groups at 4 w, 8 w, and 26 w after irradiation. Significant decrease was noted in the integrated optimal density of the transforming growth factor beta1 (TGF beta1) in the ASCs group compared with those of PBS group at 4 w, 8 w, and 26 w after irradiation. Moreover, the expression of TGF-beta1 was lower in the ASCs group compared to those of the PBS group at each time point determined by Western blot analysis. ASCs transplantation could alleviate irradiation fibrosis by suppressing the level of TGF-beta1 in the irradiated skeletal muscle. PMID- 26649051 TI - Ciprofloxacin Improves the Stemness of Human Dermal Papilla Cells. AB - Improvement in the expansion method of adult stem cells may augment their use in regenerative therapy. Using human dermal papilla cell line as well as primary dermal papilla cells as model systems, the present study demonstrated that ciprofloxacin treatment could prevent the loss of stemness during culture. Clonogenicity and stem cell markers of dermal papilla cells were shown to gradually decrease in the culture in a time-dependent manner. Treatment of the cells with nontoxic concentrations of ciprofloxacin could maintain both stem cell morphology and clonogenicity, as well as all stem cells markers. We found that ciprofloxacin exerted its effect through ATP-dependent tyrosine kinase/glycogen synthase kinase3beta dependent mechanism which in turn upregulated beta-catenin. Besides, ciprofloxacin was shown to induce epithelial-mesenchymal transition in DPCs as the transcription factors ZEB1 and Snail were significantly increased. Furthermore, the self-renewal proteins of Wnt/beta-catenin pathway, namely, Nanog and Oct-4 were significantly upregulated in the ciprofloxacin-treated cells. The effects of ciprofloxacin in preserving stem cell features were confirmed in the primary dermal papilla cells directly obtained from human hair follicles. Together, these results revealed a novel application of ciprofloxacin for stem cell maintenance and provided the underlying mechanisms that are responsible for the stemness in dermal papilla cells. PMID- 26649052 TI - Expression of Genes Related to Germ Cell Lineage and Pluripotency in Single Cells and Colonies of Human Adult Germ Stem Cells. AB - The aim of this study was to elucidate the molecular status of single human adult germ stem cells (haGSCs) and haGSC colonies, which spontaneously developed from the CD49f MACS and matrix- (collagen-/laminin+ binding-) selected fraction of enriched spermatogonia. Single-cell transcriptional profiling by Fluidigm BioMark system of a long-term cultured haGSCs cluster in comparison to human embryonic stem cells (hESCs) and human fibroblasts (hFibs) revealed that haGSCs showed a characteristic germ- and pluripotency-associated gene expression profile with some similarities to hESCs and with a significant distinction from somatic hFibs. Genome-wide comparisons with microarray analysis confirmed that different haGSC colonies exhibited gene expression heterogeneity with more or less pluripotency. The results of this study confirm that haGSCs are adult stem cells with a specific molecular gene expression profile in vitro, related but not identical to true pluripotent stem cells. Under ES-cell conditions haGSC colonies could be selected and maintained in a partial pluripotent state at the molecular level, which may be related to their cell plasticity and potential to differentiate into cells of all germ layers. PMID- 26649053 TI - Three-Dimensional Aggregates Enhance the Therapeutic Effects of Adipose Mesenchymal Stem Cells for Ischemia-Reperfusion Induced Kidney Injury in Rats. AB - It has been shown that administration of adipose derived mesenchymal stem cells (AdMSCs) enhanced structural and functional recovery of renal ischemia reperfusion (IR) injury. Low engraftment of stem cells, however, limits the therapeutic effects of AdMSCs. The present study was designed to enhance the therapeutic effects of AdMSCs by delivering AdMSCs in a three-dimensional (3D) aggregates form. Microwell was used to produce 3D AdMSCs aggregates. In vitro data indicated that AdMSCs in 3D aggregates were less susceptible to oxidative and hypoxia stress induced by 200 MUM peroxide and hypoxia/reoxygenation, respectively, compared with those cultured in two-dimensional (2D) monolayer. Furthermore, AdMSCs in 3D aggregates secreted more proangiogenic factors than those cultured in 2D monolayer. 2D AdMSCs or 3D AdMSCs aggregates were injected into renal cortex immediately after induction of renal IR injury. In vivo data revealed that 3D aggregates enhanced the effects of AdMSCs in recovering function and structure after renal IR injury. Improved grafted AdMSCs were observed in kidney injected with 3D aggregates compared with AdMSCs cultured in 2D monolayer. Our results demonstrated that 3D AdMSCs aggregated produced by microwell enhanced the retention and therapeutic effects of AdMSCs for renal IR injury. PMID- 26649055 TI - Current Status of Norovirus Infections in Children in Sub-Saharan Africa. AB - Noroviruses are a leading cause of acute sporadic gastroenteritis worldwide. In Sub-Saharan Africa, information regarding norovirus infections in children is scarce. A systematic review of studies performed between 1993 and June 2015 was conducted to establish the genotypic distribution and prevalence of norovirus infections in children (<=17) in Sub-Saharan Africa. Analysis of data from 19 studies involving 8,399 samples from children with symptomatic and nonsymptomatic gastroenteritis revealed prevalence of 12.6% (range 4.6% to 32.4%). The prevalence of norovirus infections was higher in symptomatic children (14.2%) than asymptomatic children (9.2%). Genogroup II (GII) was the most prevalent genogroup accounting for 76.4% of all the reported norovirus infections. The rest of the infections were GI (21.7%) and GI/GII (1.9%). The most common genotypes were GII.4 (65.2%), GI.7 (33.3%), and GI.3 (21.3%). These statistics were calculated from studies carried out in 12 out of 48 Sub-Saharan African countries. Therefore, more studies involving several countries are required to determine fully the epidemiology of noroviruses and their contribution to childhood diarrhoea in Sub-Saharan Africa. PMID- 26649056 TI - Significant Decline of Malaria Incidence in Southwest of Iran (2001-2014). AB - Iran is considered as one of the malaria endemic countries of the Eastern Mediterranean Region (EMR) and is at risk due to neighboring Afghanistan, Pakistan in the east, and Iraq to the west. Therefore the aim of the present investigation is the evaluation of the trend of malaria distribution during the past decade (2001-2014) in Khuzestan province, southwestern Iran. In this retrospective cross-sectional investigation, blood samples were taken from all malaria suspicious cases who were referred to health centers across Khuzestan province. For each positive subject a questionnaire containing demographic information was filled out. Data analysis was performed using SPSS 18. From a total of 541 malaria confirmed cases, 498 (92.05%) were male and 43 (7.95%) were female. The highest number of infections was seen in 2001 with 161 (29.75%) cases and the lowest was in 2014 with 0 (0%). Also, Plasmodium vivax was identified as dominant species in 478 (88.35%) individuals and P. falciparum comprised 63 (11.65%). The highest infection rate was observed in non-Iranian populations with number 459 (84.85%) and imported cases 508 (93.90%). Also, the majority of subjects were over 15 years of age, 458 (84.65%). Due to proximity to endemic countries which has made the malaria campaign difficult, more effort is needed to control the infection in order to achieve malaria elimination. PMID- 26649054 TI - Spheroid Culture of Mesenchymal Stem Cells. AB - Compared with traditional 2D adherent cell culture, 3D spheroidal cell aggregates, or spheroids, are regarded as more physiological, and this technique has been exploited in the field of oncology, stem cell biology, and tissue engineering. Mesenchymal stem cells (MSCs) cultured in spheroids have enhanced anti-inflammatory, angiogenic, and tissue reparative/regenerative effects with improved cell survival after transplantation. Cytoskeletal reorganization and drastic changes in cell morphology in MSC spheroids indicate a major difference in mechanophysical properties compared with 2D culture. Enhanced multidifferentiation potential, upregulated expression of pluripotency marker genes, and delayed replicative senescence indicate enhanced stemness in MSC spheroids. Furthermore, spheroid formation causes drastic changes in the gene expression profile of MSC in microarray analyses. In spite of these significant changes, underlying molecular mechanisms and signaling pathways triggering and sustaining these changes are largely unknown. PMID- 26649057 TI - Neonatal Septicemia in Nepal: Early-Onset versus Late-Onset. AB - Introduction. Neonatal septicemia is defined as infection in the first 28 days of life. Early-onset neonatal septicemia and late-onset neonatal septicemia are defined as illnesses appearing from birth to three days and from four to twenty eight days postnatally, respectively. Methods. In this cross-sectional study, blood samples from the suspected infants were collected and processed in the bacteriology laboratory. The growth was identified by standard microbiological protocol and the antibiotic sensitivity testing was carried out by modified Kirby Bauer disk diffusion method. Results. Among total suspected cases, the septicemia was confirmed in 116 (12.6%) neonates. Early-onset septicemia (EOS) was observed in 82 infants and late-onset septicemia (LOS) in 34 infants. Coagulase-negative staphylococcus (CoNS) (46.6%) was the predominant Gram-positive organism isolated from EOS as well as from LOS cases followed by Staphylococcus aureus (14.6%). Acinetobacter species (9.5%) was the predominant Gram-negative organism followed by Klebsiella pneumoniae (7.7%). Conclusions. The result of our study reveals that the CoNS, Staphylococcus aureus, Acinetobacter spp., and Klebsiella pneumoniae are the most common etiological agents of neonatal septicemia. In particular, since rate of CoNS causing sepsis is alarming, prompting concern to curb the excess burden of CoNS infection is necessary. PMID- 26649058 TI - Ultrasound-Guided Percutaneous Electrolysis and Eccentric Exercises for Subacromial Pain Syndrome: A Randomized Clinical Trial. AB - Objective. To compare effects of ultrasound- (US-) guided percutaneous electrolysis combined with an eccentric exercise program of the rotator cuff muscles in subacromial pain syndrome. Methods. Thirty-six patients were randomized and assigned into US-guided percutaneous electrolysis (n = 17) group or exercise (n = 19) group. Patients were asked to perform an eccentric exercise program of the rotator cuff muscles twice every day for 4 weeks. Participants assigned to US-guided percutaneous electrolysis group also received the application of galvanic current through acupuncture needle on each session once a week (total 4 sessions). Shoulder pain (NPRS) and disability (DASH) were assessed at baseline, after 2 sessions, and 1 week after the last session. Results. The ANOVA revealed significant Group*Time interactions for shoulder pain and disability (all, P < 0.01): individuals receiving US-guided percutaneous electrolysis combined with the eccentric exercises experienced greater improvement than those receiving eccentric exercise alone. Conclusions. US-guided percutaneous electrolysis combined with eccentric exercises resulted in small better outcomes at short term compared to when only eccentric exercises were applied in subacromial pain syndrome. The effect was statistically and clinically significant for shoulder pain but below minimal clinical difference for function. Future studies should investigate the long-term effects and potential placebo effect of this intervention. PMID- 26649059 TI - Effects of a Proprietary Standardized Orthosiphon stamineus Ethanolic Leaf Extract on Enhancing Memory in Sprague Dawley Rats Possibly via Blockade of Adenosine A 2A Receptors. AB - The aim of the study was to explore a propriety standardized ethanolic extract from leaves of Orthosiphon stamineus Benth in improving impairments in short-term social memory in vivo, possibly via blockade of adenosine A2A receptors (A2AR). The ethanolic extract of O. stamineus leaves showed significant in vitro binding activity of A2AR with 74% inhibition at 150 MUg/ml and significant A2AR antagonist activity with 98% inhibition at 300 MUg/mL. A significant adenosine A1 receptor (A1R) antagonist activity with 100% inhibition was observed at 300 MUg/mL. Its effect on learning and memory was assessed via social recognition task using Sprague Dawley rats whereby the ethanolic extract of O. stamineus showed significant (p < 0.001) change in recognition index (RI) at 300 mg/kg and 600 mg/kg p.o and 120 mg/kg i.p., respectively, compared to the vehicle control. In comparison, the ethanolic extract of Polygonum minus aerial parts showed small change in inflexion; however, it remained insignificant in RI at 200 mg/kg p.o. Our findings suggest that the ethanolic extract of O. stamineus leaves improves memory by reversing age-related deficits in short-term social memory and the possible involvement of adenosine A1 and adenosine A2A as a target bioactivity site in the restoration of memory. PMID- 26649060 TI - Barriers to Research Utilization among Registered Nurses in Traditional Chinese Medicine Hospitals: A Cross-Sectional Survey in China. AB - Background. As there might be relevant differences with regard to research utilization in the general hospitals, we aimed to study research utilization among registered nurses working in traditional Chinese medicine hospitals. Methods. A total of 648 registered nurses from 4 tertiary-level hospitals in China were recruited for participation. A modified BARRIERS Scale and self designed questionnaires were used for data collection. Data were analyzed with descriptive statistics, t-tests, and one-way ANOVAs and Spearman correlation analysis. Results. Overall, items which belong to the subscale "Research" were identified as the most important barriers. Among the individual items, the lack of time on the job was ranked as the top barrier, followed by the lack of knowledgeable colleagues and by overwhelming research publications. Clinical experience, working pressure, job satisfaction, and research experience could be identified as associated factors for barriers to research utilization. Conclusions. Registered nurses in traditional Chinese medicine hospitals felt high barriers to research utilization. Reducing registered nurses' working pressure, promoting their positive attitude to nursing, and improving research training might be helpful for increasing research utilization. Close cooperation between clinical and nursing schools or academic research centres might facilitate the necessary change in nursing education and routine. PMID- 26649061 TI - Interferon-gamma-Mediated Natural Killer Cell Activation by an Aqueous Panax ginseng Extract. AB - Panax ginseng extracts are used in traditional herbal medicines, particularly in eastern Asia, but their effect on natural killer (NK) cell activity is not completely understood. This study aimed to examine the effects of P. ginseng extracts on the cytotoxic activity of NK cells. We orally administered P. ginseng extracts or ginsenosides to wild-type (WT) C57BL/6 (B6) and BALB/c mice and to B6 mice deficient in either recombination activating gene 2 (RAG-2) or interferon gamma (IFN-gamma). We then tested the cytotoxic activity of NK cells (of spleen and liver mononuclear cells) against NK-sensitive YAC-1 cells. Oral administration of P. ginseng aqueous extract augmented the cytotoxicity of NK cells in WT B6 and BALB/c mice and in RAG-2-deficient B6 mice, but not in IFN gamma-deficient B6 mice. This effect was only observed with the aqueous extract of P. ginseng. Interestingly, the ginsenosides Rb1 and Rg1 did not augment NK cell cytotoxicity. These results demonstrated that the aqueous P. ginseng extract augmented NK cell activation in vivo via an IFN-gamma-dependent pathway. PMID- 26649062 TI - Association of Sasang Constitutional Type with Sarcopenia. AB - Sasang constitutional medicine (SCM) is a unique Korean traditional medicine that classifies human beings as four distinct types named Sasang constitutional types (SCTs), based on physiologic, physical, and psychological traits. Accumulating evidence has demonstrated that specific constitutional types are associated with chronic diseases, but no study has investigated the relationship between SCTs and sarcopenia. The aim of this study was to examine the association in a large population-based study. Data from 1,204 participants who completed questionnaires for life style, anthropometric evaluation, and biochemical analysis were analyzed. Classification of the SCTs was done using an integrated diagnostic method. Sarcopenia was defined as appendicular skeletal muscle mass/height(2) less than one standard deviation below the gender-specific normal mean of a younger group. Dual-energy X-ray absorptiometry was used to assess whole body composition. The prevalence of sarcopenia was 8.6% in the Tae-eum (TE) type, 44.7% in the So-eum (SE) type, and 20.7% in the So-yang (SY) type. Multivariate analysis revealed that the SE and SY types had 9.22 (5.06-16.81; P < 0.0001) and 2.90 (1.76-4.76; P < 0.0001) greater odds of sarcopenia compared to the TE type, respectively. Our results show that the SE and SY types are significantly associated with increased prevalence of sarcopenia. PMID- 26649063 TI - Evaluation of alpha-Glucosidase Inhibitory Effect of 50% Ethanolic Standardized Extract of Orthosiphon stamineus Benth in Normal and Streptozotocin-Induced Diabetic Rats. AB - In the present study, a 50% ethanolic extract of Orthosiphon stamineus was tested for its alpha-glucosidase inhibitory activity. In vivo assays of the extract (containing 1.02%, 3.76%, and 3.03% of 3'hydroxy-5,6,7,4'-tetramethoxyflavone, sinensetin, and eupatorin, resp.) showed that it possessed an inhibitory activity against alpha-glucosidase in normal rats loaded with starch and sucrose. The results showed that 1000 mg/kg of the 50% ethanolic extract of O. stamineus significantly (P < 0.05) decreased the plasma glucose levels of the experimental animals in a manner resembling the effect of acarbose. In streptozotocin-induced diabetic rats, only the group treated with 1000 mg/kg of the extract showed significantly (P < 0.05) lower plasma glucose levels after starch loading. Hence, alpha-glucosidase inhibition might be one of the mechanisms by which O. stamineus extract exerts its antidiabetic effect. Furthermore, our findings indicated that the 50% ethanolic extract of O. stamineus can be considered as a potential agent for the management of diabetes mellitus. PMID- 26649064 TI - Brain-Gut Axis Modulation of Acupuncture in Functional Dyspepsia: A Preliminary Resting-State fcMRI Study. AB - Objective. To explore acupuncture effects on brain functional connectivity in patients with functional dyspepsia (FD). Methods. Eight patients in an acupuncture treatment group and ten healthy adults in the control group participated in the study. Acupuncture effectiveness was evaluated based on changes of the gastrointestinal symptoms, gastric motility measurements, and gastrin levels and comparisons with the control group when appropriate. To investigate functional connectivity changes related to FD and potential modulation after acupuncture, a set of regions of interest (ROIs) were selected according to previous fMRI reports of acupuncture. Results. Patients showed significant improvements of FD signs and symptoms after acupuncture treatments. For all of the ROIs, we identified subportions of the networks showing reduced connectivity in patients with FD. Connectivity between the ROIs and corresponding disease targets showed significant improvement after acupuncture treatment (P < 0.05) in all ROIs except for right medial temporal lobe-hippocampus and right inferior parietal lobule. Conclusion. Functional connectivity of the brain is changed in patients with FD but approximates that in healthy control after acupuncture treatment. The relief of gastrointestinal signs and symptoms by acupuncture is likely due to the normalization of brain-gut axis associated with FD. PMID- 26649065 TI - The Analgesic and Antineuroinflammatory Effect of Baicalein in Cancer-Induced Bone Pain. AB - Cancer-induced bone pain (CIBP) is a severe type of chronic pain. It is imperative to explore safe and effective analgesic drugs for CIBP treatment. Baicalein (BE), isolated from the traditional Chinese herbal medicine Scutellaria baicalensis Georgi (or Huang Qin), has been demonstrated to have anti inflammatory and neuroprotective effects. In this study, we examined the effect of BE on CIBP and the mechanism of this effect. Intrathecal and oral administration of BE at different doses could alleviate the mechanical allodynia in CIBP rats. Intrathecal 100 MUg BE could inhibit the production of IL-6 and TNF alpha in the spinal cord of CIBP rats. Moreover, intrathecal 100 MUg BE could effectively inhibit the activation of p-p38 and p-JNK MAPK signals in CIBP rats. The analgesic effect of BE may be associated with the inhibition of the expression of the inflammatory cytokines IL-6 and TNF-alpha and through the activation of p-p38 and p-JNK MAPK signals in the spinal cord. These findings suggest that BE is a promising novel analgesic agent for CIBP. PMID- 26649066 TI - Compared to casein, bovine lactoferrin reduces plasma leptin and corticosterone and affects hypothalamic gene expression without altering weight gain or fat mass in high fat diet fed C57/BL6J mice. AB - BACKGROUND: Several studies in both humans and rodents have examined the use of lactoferrin as a dietary solution to weight gain and visceral fat accretion and have shown promising results in the short term (up to 7 weeks). This study examined the effects of giving lactoferrin over a longer period of time. METHODS: For 13 weeks, male C57/BL6J mice were given a diet containing 10 % kJ fat and 20 % kJ casein (LFD) or a diet with 45 % kJ fat and either 20 % kJ casein (HFD) or 20 % kJ lactoferrin (HFD + Lac). Physiological, metabolic, and biochemical parameters were investigated. Gene expression was investigated by Real-Time PCR and microarray. All data was assessed using t-test, ANOVA or ANCOVA. Gene Set Enrichment Analysis was used to interpret microarray data and assess the impact on gene sets with common biological roles. RESULTS: By the end of the trial, HFD + Lac fed mice did not alter energy balance, body composition, bodyweight, or weight gain when compared to the HFD group. Notably, there were no changes in subcutaneous or epididymal adipose leptin mRNA levels between high fat diet groups, however plasma leptin was significantly reduced in the HFD + Lac compared to HFD group (P < 0.05) suggesting reduced leptin secretion. Global microarray analysis of the hypothalamus indicate an overall reduction in gene sets associated with feeding behaviour (P < 0.01) and an up-regulation of gene sets associated with retinol metabolism in the HFD + Lac group compared to the HFD group (P < 0.01). Genes in the latter catergory have been shown to impact on the hypothalamic-pituitary-adrenal axis. Notably, plasma corticosterone levels in the HFD + Lac group were reduced compared to the HFD fed mice (P < 0.05). CONCLUSIONS: The data suggests that prolonged feeding of full-length dietary lactoferrin, as part of a high fat diet, does not have a beneficial impact on weight gain when compared to casein. However, its impact on leptin secretion and accompanying changes in hypothalamic gene expression may underlie how this dietary protein alters plasma corticosterone. The lactoferrin fed mouse model could be used to identify leptin and corticosterone regulated genes in the hypothalamus without the confounding effects of body weight change. PMID- 26649067 TI - SensorDB: a virtual laboratory for the integration, visualization and analysis of varied biological sensor data. AB - BACKGROUND: To our knowledge, there is no software or database solution that supports large volumes of biological time series sensor data efficiently and enables data visualization and analysis in real time. Existing solutions for managing data typically use unstructured file systems or relational databases. These systems are not designed to provide instantaneous response to user queries. Furthermore, they do not support rapid data analysis and visualization to enable interactive experiments. In large scale experiments, this behaviour slows research discovery, discourages the widespread sharing and reuse of data that could otherwise inform critical decisions in a timely manner and encourage effective collaboration between groups. RESULTS: In this paper we present SensorDB, a web based virtual laboratory that can manage large volumes of biological time series sensor data while supporting rapid data queries and real time user interaction. SensorDB is sensor agnostic and uses web-based, state-of the-art cloud and storage technologies to efficiently gather, analyse and visualize data. CONCLUSIONS: Collaboration and data sharing between different agencies and groups is thereby facilitated. SensorDB is available online at http://sensordb.csiro.au. PMID- 26649068 TI - A Hybrid Method for Image Segmentation Based on Artificial Fish Swarm Algorithm and Fuzzy c-Means Clustering. AB - Image segmentation plays an important role in medical image processing. Fuzzy c means (FCM) clustering is one of the popular clustering algorithms for medical image segmentation. However, FCM has the problems of depending on initial clustering centers, falling into local optimal solution easily, and sensitivity to noise disturbance. To solve these problems, this paper proposes a hybrid artificial fish swarm algorithm (HAFSA). The proposed algorithm combines artificial fish swarm algorithm (AFSA) with FCM whose advantages of global optimization searching and parallel computing ability of AFSA are utilized to find a superior result. Meanwhile, Metropolis criterion and noise reduction mechanism are introduced to AFSA for enhancing the convergence rate and antinoise ability. The artificial grid graph and Magnetic Resonance Imaging (MRI) are used in the experiments, and the experimental results show that the proposed algorithm has stronger antinoise ability and higher precision. A number of evaluation indicators also demonstrate that the effect of HAFSA is more excellent than FCM and suppressed FCM (SFCM). PMID- 26649069 TI - The Importance of Stochastic Effects for Explaining Entrainment in the Zebrafish Circadian Clock. AB - The circadian clock plays a pivotal role in modulating physiological processes and has been implicated, either directly or indirectly, in a range of pathological states including cancer. Here we investigate how the circadian clock is entrained by external cues such as light. Working with zebrafish cell lines and combining light pulse experiments with simulation efforts focused on the role of synchronization effects, we find that even very modest doses of light exposure are sufficient to trigger some entrainment, whereby a higher light intensity or duration correlates with strength of the circadian signal. Moreover, we observe in the simulations that stochastic effects may be considered an essential feature of the circadian clock in order to explain the circadian signal decay in prolonged darkness, as well as light initiated resynchronization as a strong component of entrainment. PMID- 26649070 TI - Two 27 MHz Simple Inductive Loops, as Hyperthermia Treatment Applicators: Theoretical Analysis and Development. AB - BACKGROUND: Deep heating is still the main subject for research in hyperthermia treatment. AIM: The purpose of this study was to develop and analyze a simple loop as a heating applicator. METHODS: The performance of two 27 MHz inductive loop antennas as potential applicators in hyperthermia treatment was studied theoretically as well as experimentally in phantoms. Two inductive loop antennas with radii 7 cm and 9 cm were designed, simulated, and constructed. The theoretical analysis was performed by using Green's function and Bessel's function technique. Experiments were performed with phantoms radiated by the aforementioned loop antennas. RESULTS: The specific absorption rate (SAR) distributions were estimated from the respective local phantom temperature measurements. Comparisons of the theoretical, simulation, and experimental studies showed satisfying agreement. The penetration depth was measured theoretically and experimentally in the range of 2-3.5 cm. CONCLUSION: The theoretical and experimental analysis showed that current loops are efficient in the case where the peripheral heating of spherical tumor formation located at 2 3.5 cm depth is required. PMID- 26649071 TI - Dimensionality Reduction in Complex Medical Data: Improved Self-Adaptive Niche Genetic Algorithm. AB - With the development of medical technology, more and more parameters are produced to describe the human physiological condition, forming high-dimensional clinical datasets. In clinical analysis, data are commonly utilized to establish mathematical models and carry out classification. High-dimensional clinical data will increase the complexity of classification, which is often utilized in the models, and thus reduce efficiency. The Niche Genetic Algorithm (NGA) is an excellent algorithm for dimensionality reduction. However, in the conventional NGA, the niche distance parameter is set in advance, which prevents it from adjusting to the environment. In this paper, an Improved Niche Genetic Algorithm (INGA) is introduced. It employs a self-adaptive niche-culling operation in the construction of the niche environment to improve the population diversity and prevent local optimal solutions. The INGA was verified in a stratification model for sepsis patients. The results show that, by applying INGA, the feature dimensionality of datasets was reduced from 77 to 10 and that the model achieved an accuracy of 92% in predicting 28-day death in sepsis patients, which is significantly higher than other methods. PMID- 26649072 TI - Image-Processing Scheme to Detect Superficial Fungal Infections of the Skin. AB - The incidence of superficial fungal infections is assumed to be 20 to 25% of the global human population. Fluorescence microscopy of extracted skin samples is frequently used for a swift assessment of infections. To support the dermatologist, an image-analysis scheme has been developed that evaluates digital microscopic images to detect fungal hyphae. The aim of the study was to increase diagnostic quality and to shorten the time-to-diagnosis. The analysis, consisting of preprocessing, segmentation, parameterization, and classification of identified structures, was performed on digital microscopic images. A test dataset of hyphae and false-positive objects was created to evaluate the algorithm. Additionally, the performance for real clinical images was investigated using 415 images. The results show that the sensitivity for hyphae is 94% and 89% for singular and clustered hyphae, respectively. The mean exclusion rate is 91% for the false-positive objects. The sensitivity for clinical images was 83% and the specificity was 79%. Although the performance is lower for the clinical images than for the test dataset, a reliable and fast diagnosis can be achieved since it is not crucial to detect every hypha to conclude that a sample consisting of several images is infected. The proposed analysis therefore enables a high diagnostic quality and a fast sample assessment to be achieved. PMID- 26649074 TI - Iodine prophylaxis in pregnant women in Poland - where we are? (update 2015). AB - Introduction of the model of iodine prophylaxis based on the consumption of iodized salt in 1997 has eliminated the iodine deficiency in Poland. However, in accordance with the current recommendations, all women who are planning to be pregnant or are pregnant or breastfeeding should receive an additional dose of iodine at 150-200 mcg / day because of the increased body's need for iodine during this period. Studies show that only part of women in Poland conduct a proper iodine prophylaxis and it is often initiated in the second and third trimester of pregnancy. The authors try to analyze the possible causes of this situation, pointing out what could be done to increase the degree of compliance with iodine prophylaxis during pregnancy and physiological lactation in Poland. PMID- 26649073 TI - Transcriptomic analysis of lignocellulosic biomass degradation by the anaerobic fungal isolate Orpinomyces sp. strain C1A. AB - BACKGROUND: Anaerobic fungi reside in the rumen and alimentary tract of herbivores where they play an important role in the digestion of ingested plant biomass. The anaerobic fungal isolate Orpinomyces sp. strain C1A is an efficient biomass degrader, capable of simultaneous saccharification and fermentation of the cellulosic and hemicellulosic fractions in multiple types of lignocellulosic biomass. To understand the mechanistic and regulatory basis of biomass deconstruction in anaerobic fungi, we analyzed the transcriptomic profiles of C1A when grown on four different types of lignocellulosic biomass (alfalfa, energy cane, corn stover, and sorghum) versus a soluble sugar monomer (glucose). RESULTS: A total of 468.2 million reads (70.2 Gb) were generated and assembled into 27,506 distinct transcripts. CAZyme transcripts identified included 385, 246, and 44 transcripts belonging to 44, 13, and 8 different glycoside hydrolases (GH), carbohydrate esterases, and polysaccharide lyases families, respectively. Examination of CAZyme transcriptional patterns indicates that strain C1A constitutively transcribes a high baseline level of CAZyme transcripts on glucose. Although growth on lignocellulosic biomass substrates was associated with a significant increase in transcriptional levels in few GH families, including the highly transcribed GH1 beta-glucosidase, GH6 cellobiohydrolase, and GH9 endoglucanase, the transcriptional levels of the majority of CAZyme families and transcripts were not significantly altered in glucose-grown versus lignocellulosic biomass-grown cultures. Further, strain C1A co-transcribes multiple functionally redundant enzymes for cellulose and hemicellulose saccharification that are mechanistically and structurally distinct. Analysis of fungal dockerin domain-containing transcripts strongly suggests that anaerobic fungal cellulosomes represent distinct catalytic units capable of independently attacking and converting intact plant fibers to sugar monomers. CONCLUSIONS: Collectively, these results demonstrate that strain C1A achieves fast, effective biomass degradation by the simultaneous employment of a wide array of constitutively-transcribed cellulosome-bound and free enzymes with considerable functional overlap. We argue that the utilization of this indiscriminate strategy could be justified by the evolutionary history of anaerobic fungi, as well as their functional role within their natural habitat in the herbivorous gut. PMID- 26649075 TI - Efficacy and Tolerability of a Nutraceutical Combination (Red Yeast Rice, Policosanols, and Berberine) in Patients with Low-Moderate Risk Hypercholesterolemia: A Double-Blind, Placebo-Controlled Study. AB - BACKGROUND: Statins are at the forefront of strategies to manage hypercholesterolemia. However 10% to 15% of patients are intolerant to any statin drugs, even at low daily doses and almost one-third of statin users discontinue therapy within 1 year. Some nutraceuticals are prescribed as lipid-lowering substances, but doubts remain about their efficacy and tolerability. OBJECTIVES: We aimed to investigate the efficacy and the safety of a nutraceutical combination consisting mainly of 200 mg red yeast rice extract (equivalent to 3 mg monacolins), 500 mg berberine, and 10 mg policosanols (MBP-NC) in patients with low-moderate risk hypercholesterolemia. METHODS: In this single centre, randomized, double-blind, placebo-controlled study 60 consecutive outpatients (29 men and 31 women; age range = 18-60 years), with newly diagnosed primary hypercholesterolemia not previously treated, after a run-in period of 3 weeks on a stable hypolipidic diet, were randomized to receive a pill of MBP-NC (n = 30) or placebo (n = 30) once a day after dinner, in addition to the hypolipidic diet. The efficacy and the tolerability of the proposed nutraceutical treatment were fully assessed after 4, 12, and 24 weeks of treatment. RESULTS: In the MBP-NC group both total cholesterol and LDL-C already showed a significant reduction at Week 4 (-30.3% +/- 33.9% and -29.4% +/- 35.3%, respectively) that remained substantially unchanged at Week 12 (-26.7% +/- 33.1% and -25.6% +/- 31.5%, respectively) and at Week 24 (-24.6% +/- 32.1% and -23.7% +/- 32.6%, respectively). The between-groups differences were significant at all time points for both total cholesterol and LDL-C. There were no significant changes in HDL-C, fasting glucose, and triglyceride serum levels in either group. MBP-NC was also safe and well tolerated. CONCLUSIONS: In patients with low- to moderate-risk hypercholesterolemia a nutraceutical combination in association with a hypolipidic diet significantly reduced total cholesterol and LDL-C levels and may favor the reaching the recommended cholesterol targets. ClinicalTrials.gov identifier: NCT02078167. PMID- 26649076 TI - Absorption Kinetics of Subcutaneously Administered Ceftazidime in Hypoperfused Guinea Pigs. AB - BACKGROUND: Pneumonia is the most common cause of death in patients with severe motor and intellectual disabilities (SMID), and intravenous ceftazidime (CAZ) is a widely used treatment for such infections. However, intravenous administration in patients with SMID may be difficult because of insufficient vascular development. OBJECTIVES: The aim of our study was to determine the feasibility of subcutaneous drug administration by mentholated warm compresses (WMCs) as an alternative delivery method for ceftazidime in patients with SMID. METHODS: CAZ was subcutaneously administered to the abdominal region of naphazoline-treated hypoperfused guinea pigs, which were used as a hemodynamic model of patients with SMID. MWCs or warm compresses (WCs) were applied to the injection site to increase blood flow. We calculated the cumulative CAZ absorption over time by using the deconvolution method. RESULTS: Application of MWCs or WCs increased blood flow at the administration site and increased CAZ plasma levels. Application of MWCs or WCs after subcutaneous CAZ injection led to higher CAZ plasma levels than the mutant prevention concentration for a longer period than was observed for CAZ administration without the application of MWCs or WCs. CONCLUSIONS: The application of MWCs or WCs enhanced subcutaneous CAZ absorption by increasing blood flow. MWCs and WCs are considered to be safe and routine methods to induce defecation after surgery on the digestive system; thus, the combination of these methods and subcutaneous CAZ administration is a potential method for treating pneumonia in patients with SMID. PMID- 26649077 TI - Ciprofloxacin-Induced Antibacterial Activity Is Attenuated by Phosphodiesterase Inhibitors. AB - BACKGROUND: Ciprofloxacin is a commonly used antibiotic for urinary tract infection that interacts with bacterial topoisomerases leading to oxidative radicals generation and bacterial cell death. Phosphodiesterase inhibitors (PDEis), on the other hand, are commonly used drugs for the management of erectile dysfunction. The group includes agents such as sildenafil, vardenafil, and tadalafil. OBJECTIVES: We investigated whether PDEi could interfere with the antibacterial activity of ciprofloxacin. METHODS: PDEis were tested in several reference bacteria, including Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Staphylococcus epidermidis, Acinetobacter baumannii, Proteus mirabilis, and Klebsiella pneumoniae utilizing a standard disc diffusion method and measuring both zones of inhibition and MIC. RESULTS: Results from both assays indicated that ciprofloxacin demonstrates potent activity against the tested reference bacteria. Additionally, when bacteria were treated with a combination of ciprofloxacin and sildenafil, tadalafil, or vardenafil, the zones of the combination inhibition were significantly reduced, whereas the MIC values were significantly greater than those of ciprofloxacin alone for all tested bacterial strains. In an attempt to examine the mechanism by which PDEis interfere with the action of ciprofloxacin, we utilized the in vitro E coli DNA gyrase cleavage assay. The results showed that PDEi drugs had no effect on ciprofloxacin's inhibition of E coli gyrase activity. CONCLUSIONS: Pretreatment of various reference bacterial cells with PDEis largely inhibited the antibacterial activity of ciprofloxacin. PMID- 26649078 TI - Recombinant Human Erythropoietin Protects Myocardial Cells from Apoptosis via the Janus-Activated Kinase 2/Signal Transducer and Activator of Transcription 5 Pathway in Rats with Epilepsy. AB - OBJECTIVE: To investigate the potential mechanisms underlying the protective effects of recombinant human erythropoietin (rhEPO) and carbamylated EPO (CEPO) against myocardial cell apoptosis in epilepsy. METHODS: Rats were given an intra amygdala injection of kainic acid to induce epilepsy. Groups of rats were treated with rhEPO or CEPO before induction of epilepsy, whereas additional rats were given a caudal vein injection of AG490, a selective inhibitor of Janus kinase 2 (JAK2). At different time points after seizure onset, electroencephalogram changes were recorded, and myocardium samples were taken for the detection of myocardial cell apoptosis and expression of JAK2, signal transducer and activator of transcription 5 (STAT5), caspase-3, and bcl-xl mRNAs and proteins. RESULTS: Induction of epilepsy significantly enhanced myocardial cell apoptosis and upregulated the expression of caspase-3 and bcl-xl proteins and JAK2 and STAT5a at both the mRNA and protein levels. Pretreatment with either rhEPO or CEPO reduced the number of apoptotic cells, upregulated bcl-xl expression, and downregulated caspase-3 expression in the myocardium of epileptic rats. Both myocardial JAK2 and STAT5a mRNAs, as well as phosphorylated species of JAK2 and STAT5a, were upregulated in epileptic rats in response to rhEPO-but not to CEPO pretreatment. AG490 treatment increased apoptosis, upregulated caspase-3 protein expression, and downregulated bcl-xl protein expression in the myocardium of epileptic rats. CONCLUSIONS: These results indicate that myocardial cell apoptosis may contribute to myocardial injury in epilepsy. EPO protects myocardial cells from apoptosis via the JAK2/STAT5 pathway in rats with experimental epilepsy, whereas CEPO exerts antiapoptotic activity perhaps via a pathway independent of JAK2/STAT5 signaling. PMID- 26649079 TI - Chemical Stability of Telavancin in Elastomeric Pumps. AB - BACKGROUND: VIBATIV is a once-daily, injectable lipoglycopeptide antibiotic approved in the U.S. for the treatment of hospital-acquired and ventilator associated bacterial pneumonia (HABP/VABP) caused by susceptible isolates of Staphylococcus aureus when alternative treatments are not suitable. In addition, VIBATIV is approved in the U.S. for the treatment of adult patients with complicated skin & skin structure infections (cSSSI) caused by susceptible isolates of Gram-positive bacteria, including Staphylococcus aureus, both methicillin-susceptible (MSSA) and methicillin-resistant (MRSA) strains. OBJECTIVE: To evaluate the chemical stability of telavancin (Vibativ; Theravance Biopharma US, Inc, Northbrook, Illinois), a lipoglycopeptide antibiotic with activity against methicillin-resistant Staphylococcus aureus, in 2 types of elastomeric pumps, the Intermate Infusion System (Baxter International Inc) and the Homepump Eclipse (I-Flow Corporation). METHODS: Different sizes of the Baxter (Ontario, Canada) (105 mL and 275 mL) and I-Flow (Stoughton, Massachusetts) (100 mL and 250 mL) pumps were compared with glass controls. The telavancin drug product was reconstituted and diluted to concentrations of 0.6 mg/mL and 8.0 mg/mL using either 0.9% saline, 5% dextrose in water, or sterilized water for injection (0.6 mg/mL telavancin) or saline (8.0 mg/mL telavancin) followed by Ringer's Lactate solution. Pumps were filled and stored at 2 degrees C to 8 degrees C, protected from light. Aliquots from both pump types and for all telavancin reconstitution/dilution schemes and concentrations were taken over a period of 8 days and analyzed for appearance, pH, telavancin concentration and purity, and degradation products. RESULTS: The pH of all pump solutions remained consistent throughout the 8-day analysis period, within a range of 4.6 to 5.7 for the 0.6 mg/mL and 4.4 to 4.9 for the 8.0 mg/mL telavancin solutions. There was no significant change in the chromatographic purity for any of the pump solutions examined. All decreases in telavancin concentration were <=2.7%. Comparison of each test sample solution to the corresponding glass control indicated no loss of active drug due to absorption by the elastomeric material of the pumps. The greatest increase in the amount of total degradants observed over the 8-day period was ~0.7 w/w%. CONCLUSIONS: The results of this study indicate that telavancin remains chemically stable when diluted in the Intermate Infusion System and the Homepump Eclipse elastomeric pumps and stored at 2 degrees C to 8 degrees C for up to 8 days protected from light at the concentration range and dilution schemes evaluated. PMID- 26649080 TI - A numerical scale to assess the outcomes of metabolic/bariatric surgery (NOMS). AB - INTRODUCTION: Absent today is a simple numerical system of outcomes assessment that recognizes that bariatric surgery is metabolic surgery and incorporates weight loss, hypertension control, and type 2 diabetes control. AIM: To introduce a simple, new Numerical Scale to Assess the Outcomes of Metabolic Surgery (NOMS). MATERIAL AND METHODS: For the stratification of weight outcomes, we used the percentage excess weight loss (%EWL); for hypertension, the systolic blood pressure (SBP) and diastolic blood pressure (DBP) combined with medication usage; and for type 2 diabetes, the hemoglobin A1c (HbA1c) value combined with medication usage. RESULTS: Utilizing the guidelines of the American Diabetes Association, the Working Group of the European Society of Hypertension, the European Society of Cardiology, and the American College of Cardiology/American Heart Association, we propose for %EWL: W1 >= 50, W2 > 25 and < 50, and W3 <= 25; for hypertension H1 SBP/DPB < 140/90 mm Hg on no medication, H2 SBP/DBP >= 140/90 mm Hg with improvement of SBP or possible reduction of antihypertensive medication, and H3 no change or SBP higher than before surgery; for diabetes mellitus D1 HbA1c <= 7% and no medication, D2 HbA1c > 7% with a decrease of the HbA1c level or possible reduction of medication, D3 no change in HbA1c or HbA1c higher than before surgery. Designations of H0 and D0 are given if hypertension or diabetes was not present before surgery. Patient examples for numerical scores are provided. CONCLUSIONS: The introduction of our numerical scale (NOMS) can be of benefit in metabolic/bariatric outcomes assessment; communications among metabolic/bariatric surgery centers, physicians, and patients; and for more precise reporting in the evidence-based literature. PMID- 26649081 TI - Endoscopic clipping of the Z-line (CMZL) helps recognize anatomical failures after Nissen fundoplication: technical report of a new method. AB - INTRODUCTION: Nearly 15% of patients after laparoscopic antireflux surgery experience recurrence of symptoms or develop new gastrointestinal symptoms. Some of them require redo procedures. It can be demanding to reveal anatomical failure after previous fundoplication. AIM: To present a method which assists in recognition of anatomical failures after Nissen fundoplication. MATERIAL AND METHODS: Five patients with previous laparoscopic Nissen fundoplication and severe gastrointestinal symptoms were included in this study. During the esophagogastroduodenoscopy (EGDS) two radiopaque metal clips were placed to mark the Z-line ("clips-marked Z-line" - CMZL). It was done to achieve precise visualization of the gastroesophageal junction area in the video contrast investigation. Distinctions between conclusions after the EGDS, ordinary video contrast investigation, video contrast investigation with CMZL and intraoperative findings were analyzed. RESULTS: All patients underwent laparoscopic refundoplication with good postoperative results. There were 4 cases misdiagnosed by contrast investigation without clips and four cases misdiagnosed by EGDS. Endoscopic clipping helped to recognize correctly all anatomical failures. CONCLUSIONS: Applying CMZL as a routine investigation before redo fundoplication can reduce frequency of misdiagnosis and help to perform redo fundoplication in appropriate patients, but it requires further studies on larger cohorts of patients. PMID- 26649082 TI - Micropercutaneous nephrolithotripsy: initial experience. AB - INTRODUCTION: For small renal calculi (< 2 cm) the currently available treatment options include extracorporeal shockwave lithotripsy (ESWL), retrograde intrarenal surgery (RIRS) and standard/mini percutaneous nephrolithotomy (PNL). A new method, microperc, has therefore been developed, in which a smaller tract size and smaller instruments were used. AIM: To present our clinical experiences with micropercutaneous nephrolithotripsy (microperc) in the treatment of small renal calculi. MATERIAL AND METHODS: We retrospectively evaluated patients with small renal calculi who underwent microperc between February and June 2013. A 4.8 Fr 'all-seeing needle' was used to achieve percutaneous renal access with the C arm fluoroscopy guidance in the prone position. Holmium: YAG laser 272 um fiber was used for stone fragmentation. RESULTS: A total of 20 patients underwent the microperc procedure. The mean age of the patients was 46.5 +/-13.8 years. The mean stone size was 13 +/-3 mm. The stone-free rate (SFR) was 90% (18/20). Two patients had clinically significant residual fragments (>= 4 mm). The mean operation and fluoroscopy times were 107.5 +/-37 min and 45 +/-40 s respectively. The mean postoperative drop in hemoglobin was 1.2 +/-0.9 g/dl, and 1 patient required blood transfusion. The patients were discharged after an average hospitalization of 1.4 +/-0.8 days. Two complications, urinary tract infection and blood loss requiring blood transfusion, were observed in 2 patients postoperatively. CONCLUSIONS: We suggest that microperc should be considered for the treatment of small renal stones. PMID- 26649083 TI - Reduction of chronic post-herniotomy pain and recurrence rate. Use of the anatomical self-gripping ProGrip laparoscopic mesh in TAPP hernia repair. Preliminary results of a prospective study. AB - INTRODUCTION: The role of fixation of the mesh is especially important in the endoscopic technique. The fixation of mesh through penetrating techniques using staples, clips or screws is associated with a significantly increased risk of developing a post-herniotomy pain syndrome. AIM: To demonstrate the safety and efficacy of the self-fixating anatomical Parietex ProGrip laparoscopic mesh (Sofradim Production, Trevoux France) used with laparoscopic transabdominal preperitoneal hernia repair. The incidence of chronic post-herniotomy pain and recurrence rate in the follow-up after 12 months were evaluated. MATERIAL AND METHODS: Data analysis included all patients who underwent inguinal hernia surgery at our Surgical Department within the period from 1.05.2013 to 31.12.2014, who fulfilled the inclusion criteria. Standard surgical technique was used. Data were prospectively entered and subsequently analyzed on the Herniamed platform. Herniamed is an internet-based register in German and English language and includes all data of patients who underwent surgery for some types of hernia. RESULTS: There were 95 patients enrolled in the group and there were in total 156 inguinal hernias repaired. The mean follow-up was 15.52 months. At the assessment at 1 year mild discomfort in the groin was reported in 2 patients (3.51%) (1-3 VAS). No recurrence or chronic postoperative pain was reported. CONCLUSIONS: Laparoscopic inguinal hernia repair using the transabdominal preperitoneal technique with implantation of the ProGrip laparoscopic mesh is a fast, effective and reliable method in experienced hands, which according to our results reduces the occurrence of chronic post-operative inguinal pain with simultaneously a low recurrence rate. PMID- 26649084 TI - Preservation of splenic vessels during laparoscopic spleen-preserving distal pancreatectomy via lateral approach. AB - INTRODUCTION: Preserving splenic vessels during laparoscopic distal pancreatectomy (SPDP-LA) is feasible and avoids unnecessary splenectomy. AIM: To present our outcomes for this unique technique. MATERIAL AND METHODS: Between January 1998 and January 2012, 6 patients who underwent SPDP-LA for benign or low malignancy tumors in the pancreatic tail were included. Clinical characteristics as well as perioperative data were retrospectively recorded. RESULTS: All procedures were successful, with an average operative time of 184 min (range: 88 277 min) and average blood loss of 401.7 ml (range: 10-900 ml). The mean hospital stay was 7 days. Pancreatic fistula occurred in 2 patients but was then cured by external drainage. There was no mortality. Follow-ups were available for all patients. CONCLUSIONS: Our experience was characterized by a lack of conversions and by acceptable rates of postoperative fistula and morbidity. The lateral approach showed beneficial results in patients without complications and short post-operative hospital stays. PMID- 26649085 TI - Dynamics of quality of life improvement after floppy Nissen fundoplication for gastroesophageal reflux disease. AB - INTRODUCTION: Gastroesophageal reflux disease (GERD) has a negative impact on global quality of life (QOL) of patients. In patients affected by GERD, laparoscopic Nissen fundoplication is one of the most commonly performed laparoscopic procedures worldwide. AIM: To prospectively analyze the dynamics of QOL as well as severity of pain in patients with GERD, before and after laparoscopic floppy Nissen fundoplication. MATERIAL AND METHODS: The study involved 104 consecutive patients operated on for GERD in whom laparoscopic floppy Nissen fundoplication was performed. QOL was assessed before surgery and 1, 3, 6, 12 and 24 months after. The following instruments were used: FACIT-G, FACIT-TS-G, GIQLI, GERD symptom scale. RESULTS: It was found that symptom relief and quality of life improvement presented different dynamics in the postoperative course. Observations revealed relief of symptoms 1 month after surgery and improvement in QOL related to the gastrointestinal tract and pain 3 months after surgery. Global QOL increased significantly as late as 12 months after surgery. CONCLUSIONS: Gastroesophageal reflux disease is a chronic disease of long duration, leading to impairment of quality of life. Patients, apart from typical symptoms of GERD, suffer from pain of significant severity. QOL improves significantly after surgery. Surgical treatment results in relief of GERD symptoms, which leads to gradual improvement of QOL. PMID- 26649086 TI - Laparoscopic gastric plication and its effect on saccharide and lipid metabolism: a 12-month prospective study. AB - INTRODUCTION: Laparoscopic greater curvature plication (LGCP) is a novel restrictive technique that reduces gastric volume by plication of the greater curvature. The advantage of LGCP is its reversibility in comparison to laparoscopic sleeve gastrectomy. Nowadays, the long-term LGCP efficacy, safety and metabolic effect are being investigated. AIM: To assess body composition, clinical complications and metabolic changes in obese patients 6 and 12 months after laparoscopic greater curvature plication. MATERIAL AND METHODS: A total of 70 subjects underwent LGCP; 52 of them (33 women and 19 men) completed 1-year follow-up study. Anthropometry and biochemical parameters (glucose, glycated haemoglobin, lipids, ghrelin, leptin, adiponectin and fibroblast growth factor 21 [FGF-21]) were assessed before and 3, 6, and 12 months after surgery. RESULTS: All study participants exhibited statistically significant weight loss at both 6 and 12 months following the LGCP compared to baseline, with significant reductions in body composition - body weight, body mass index, percentage excess weight loss (%EWL), and percentage excess BMI loss (%EBL) (p <= 0.001). Moreover, significant lowering of glucose and glycated haemoglobin, triacylglycerols and leptin was observed 12 months after LGCP. On the other hand, plasma concentrations of ghrelin, adiponectin and LDL cholesterol increased significantly. Total cholesterol, LDL cholesterol and FGF-21 levels did not change significantly. CONCLUSIONS: Laparoscopic greater curvature plication appears to be a procedure with good restriction results, which might be mediated through alteration in incretin metabolism. Technical aspects and standardization of the procedure still remain to be worked out. PMID- 26649087 TI - Laparoscopic sentinel lymph node mapping after cervical injection of indocyanine green for endometrial cancer - preliminary report. AB - INTRODUCTION: Endometrial cancer (EC) has an increasing incidence worldwide, with lymph node metastases as the main prognostic factor. Systemic lymphadenectomy is connected with elevated morbidity. Sentinel lymph node (SLN) biopsy is intended to avoid extensive lymphadenectomy and provide significant oncologic information. AIM: To evaluate the accuracy of laparoscopic SLN biopsy guided by indocyanine green (ICG) injection into the cervix in EC patients and to develop ideas to improve this method. The optimal time from dye injection to lymph node visualization was assessed. MATERIAL AND METHODS: This retrospective study was conducted between July 2014 and March 2015 in a group of 9 women with EC, at low and intermediate risk of recurrence, scheduled for total laparoscopic hysterectomy and pelvic lymphadenectomy. All patients underwent cervical ICG injection and SLN biopsy, followed by surgery. Pelvic lymph nodes were located using an ICG endoscopic camera. RESULTS: The following data were collected: There were 9 patients with endometrial cancer at low and intermediate risk of recurrence. Median patient age was 59 years, median body mass index (BMI) 28 kg/m(2), endometrioid adenocarcinoma in 9 cases, grading: G1 - 1 patient, G2 - 8 patients. No intraoperative or postoperative complications were noted. Median time from ICG injection and SLN detection during surgery was 25 min. There were no lymph nodes metastasis, all identified by the SLN protocol using ICG injection. CONCLUSIONS: Sentinel lymph node mapping can play a significant role in lymph node assessment and staging in early-stage EC patients with low risk of recurrence according to the ESMO classification. The use of SLN mapping in EC is much needed and the therapeutic benefit is high. PMID- 26649088 TI - Late outcomes of laparoscopic pyeloplasty: a single institution study with follow up longer than 5 years. AB - INTRODUCTION: Although most urologists agree that failures after laparoscopic pyeloplasty occur usually within a year after the operation, late failures are also reported. AIM: To assess late results of laparoscopic pyeloplasty. MATERIAL AND METHODS: Seventy-eight of ninety-five patients who had been operated on between November 2001 and September 2009 were notified about the possibility of diuretic renography (DR). Excluded from the study were 3 patients who failed within 1 year after surgery, 2 others with late recurrences at 1.5 and 2.5 years postoperatively, 8 patients who were lost to follow-up immediately after the operation, 2 patients with equivocal DR after pyeloplasty and 2 cases with open conversion. Twenty-six (33.3%) patients responded to the notification. Mean follow-up was 89 months. In all patients DR, ultrasound, serum creatinine concentration, estimatated glomerular filtration rate and the assessment of symptoms were carried out. Success was defined as T1/2 <= 12 min and improved or stable differential renal function on DR. RESULTS: Diuretic renography revealed no obstruction in 25/26 (96%) patients. One woman was not appropriately hydrated, which rendered the result of the investigation unreliable. Mean half time to tracer clearance was 6.74 min. Mean split renal function on the operated side was 44.62%. Mean pain strength according to the VAS scale was 1.54. CONCLUSIONS: Our study seems to indicate that recurrence after laparoscopic pyeloplasty in the follow-up period longer than 5 years is very unlikely. However, until more data are available, patients should undergo long-term follow-up to receive the benefit of the operation. PMID- 26649089 TI - C-reactive protein is a predictor of complications after elective laparoscopic colorectal surgery: five-year experience. AB - INTRODUCTION: With the development and improvement of laparoscopic surgery, procedures have become common. However, post-operative complications occur when patients are released from hospital. These complications increase patients' morbidity and mortality. They also lead to re-hospitalization, an extended recovery period, and an increase in the cost of treatment. AIM: To evaluate and determine the prognostic properties of C-reactive protein in the early diagnosis of postoperative complications after a laparoscopic colon resection. MATERIAL AND METHODS: The prospective study included patients who underwent laparoscopic colorectal surgery in 2010-2014. The patients were divided into two groups - uncomplicated ones and those with complications. C-reactive protein concentrations in their blood serum were measured on the 2(nd), 4(th) and 6(th) day after surgery. Logistic regression analysis was used to evaluate the relation between C-reactive protein values measured on the 2(nd), 4(th) and 6(th) postoperative day and related complications. Receiver operating characteristic curves were used to determine the sensitivity and specificity of each C-reactive protein value measured on the 2(nd), 4(th) and 6(th) postoperative day. RESULTS: One hundred and six patients were included in the trial; 14 of them had complications. On the second day, a C-reactive protein cut-off value of 88.6 mmol/l provided the highest sensitivity and specificity for predicting evolving complications, being 71.4% and 84.8% respectively (p = 0.003). The significant predictive cut-off value decreases and becomes more sensitive and specific each post-operative day. CONCLUSIONS: It is possible to detect developing post operative complications early on by monitoring C-reactive protein concentration levels in the blood serum on the 2(nd), 4(th), and 6(th) post-operative days. PMID- 26649090 TI - A new option for endovascular treatment of leg ulcers caused by venous insufficiency with fluoroscopically guided sclerotherapy. AB - INTRODUCTION: Ulcers of lower legs are the most bothersome complication of chronic venous insufficiency (CVI). AIM: To assess the effectiveness of endovascular fluoroscopically guided sclerotherapy for the treatment of venous ulcers. MATERIAL AND METHODS: Thirty-eight limbs in 35 patients with crural venous ulcers were treated with guided sclerotherapy under the control of fluoroscopy. Patients with non-healing ulcers in the course of chronic venous insufficiency, with and without features of past deep vein thrombosis, were qualified for the study. Doppler ultrasound and dynamic venography with mapping of venous flow were performed. Ambulatory venous pressure measurements, leg circumference and varicography were performed just before and following the procedure. RESULTS: In 84% of cases, ulcers were treated successfully and healed. Patients with post-thrombotic syndrome (n = 17) healed in 13 (76.5%) cases, whereas patients without post-thrombotic syndrome (n = 21) healed in 19 (90.5%) cases. The mean time of healing of an ulcer for all patients was 83 days (in the first group it was 121 days and in the second group 67 days). Recurrence of an ulcer was observed in 10 limbs: 6 cases in the first group and 4 cases in the second group. Occurrence of deep vein thrombosis associated with the procedure was not observed. Temporary complications were reported but none giving a serious clinical outcome. CONCLUSIONS: Endovascular fluoroscopically guided sclerotherapy can be an alternative method of treatment of venous ulcers, especially in situations when surgical procedures or other options of treatment are impossible. PMID- 26649091 TI - Changing patterns in the surgical treatment of perforated duodenal ulcer - single centre experience. AB - INTRODUCTION: Although the surgical treatment of patients with perforated duodenal ulcer is the method of choice, the introduction of effective pharmacotherapy has changed the surgical strategy. Nowadays less extensive procedures are chosen more frequently. The introduction of laparoscopic procedures had a significant impact on treatment results. AIM: To present our experience in the treatment of perforated duodenal ulcer in two periods, by comparing open radical anti-ulcer procedures with laparoscopic ulcer repair. MATERIAL AND METHODS: The analysis covered patients operated on for perforated duodenal ulcer. Two groups of patients were compared. Group 1 included 245 patients operated on in the period 1980-1994 with a traditional method (pyloroplasty + vagotomy) before introduction of proton pump inhibitors (PPI). Group 2 included 106 patients treated in the period 2000-2014 with the laparoscopic technique supplemented with PPI therapy. Groups were compared in terms of patients' demographic structure, operative time, complication rate and mortality. RESULTS: The mean operative time in group 1 was shorter than in group 2 (p < 0.0001). Complications were noted in 57 (23.3%) patients in group 1 and 14 (13.5%) patients in group 2 (p = 0.0312). Reoperation was necessary in 13 (5.3%) cases in group 1 and in 5 cases in group 2 (p = 0.8179). The mortality rate in group 1 was significantly higher than in group 2 (10.2% vs. 2.8%, p = 0.0192). In group 1, median length of hospital stay was 9 days and differed significantly from group 2 (6 days, p < 0.0001). CONCLUSIONS: Within the last 30 years, significant changes in treatment of perforated peptic ulcer (PPU) have occurred, mainly related to abandoning routine radical anti-ulcer procedures and replacing the open technique with minimally invasive surgery. Thus it was possible to improve treatment results by reducing complication and mortality rates, and shortening the length of hospital stay. Although the laparoscopic operation is longer, it improves outcomes. In the authors' opinion, in each patient with suspected peptic ulcer perforation, laparoscopy should be the method of choice. PMID- 26649092 TI - Comparison of treatment costs of laparoscopic and open surgery. AB - INTRODUCTION: Laparoscopy has been a standard procedure in most medical centres providing surgical services for many years. Both the range and number of laparoscopic procedures performed are constantly increasing. Over the last decade, laparoscopic procedures have been successfully applied both in emergency and oncological surgery. However, treatment costs have become a more important factor in choosing between open or laparoscopic procedures. AIM: To present the total real costs of open and laparoscopic cholecystectomy, appendectomy and sigmoidectomy. MATERIAL AND METHODS: Between 1 May 2010 and 30 March 2015 in the Department of Thoracic Surgery, General and Oncological Surgery, Medical University of Lodz, and in the Department of General Surgery of the Saint John of God Hospital, Lodz, doctors performed 1404 cholecystectomies, 392 appendectomies and 88 sigmoidectomies. A total of 97% of the cholecystectomy procedures were laparoscopic and 3% were open. Similarly, 22% of total appendectomies were laparoscopic and 78% were open, while 9% of sigmoidectomies were laparoscopic and 91% open. RESULTS: The requirement for single-use equipment in laparoscopic procedures increases the expense. However, after adding up all other costs, surprisingly, differences between the costs of laparoscopic and open procedures ranged from 451 PLN/? 114 for laparoscopic operations to 611 PLN/? 153 for open operations. CONCLUSIONS: Laparoscopic cholecystectomy, considered the standard surgery for treating gallbladder diseases, is cheaper than open cholecystectomy. Laparoscopic appendectomy and sigmoidectomy are safe methods of minimally invasive surgery, slightly more expensive than open operations. Of all the analyzed procedures, one-day laparoscopic cholecystectomy is the most profitable. The costs of both laparoscopic and open sigmoidectomy are greatly underestimated in Poland. PMID- 26649093 TI - Laparoscopic radical prostatectomy and resection of rectum performed together: first experience. AB - INTRODUCTION: Laparoscopy is an increasingly used approach in the surgical treatment of rectal cancer and prostate cancer. The anatomical proximity of the two organs is the main reason to consider performing both procedures simultaneously. AIM: To present our first experience of laparoscopic rectal resection and radical prostatectomy, performed simultaneously, in 3 patients. MATERIAL AND METHODS: The first patient was diagnosed with locally advanced rectal cancer and tumor infiltration of the prostate and seminal vesicles. The other 2 patients were diagnosed with tumor duplicity. The surgery of the first patient started with laparoscopic prostatectomy except division of the prostate from the rectal wall. The next step was resection of the rectum, extralevator amputation of the rectum and vesicourethral anastomosis. In the other patients, resection of the rectum, followed by radical prostatectomy, was performed. RESULTS: The median follow-up was 12 months. The median operation time was 4 h 40 min, with blood loss of 300 ml. The operations and postoperative course were without incident in the case of 2 patients. However, 1 patient had stercoral peritonitis and a vesicorectal fistula in the early postoperative stage. Sigmoidostomy and postponed ureteroileal conduit were carried out. All patients were in oncologic remission. CONCLUSIONS: Combined laparoscopic rectal resection and radical prostatectomy is a viable option for selected patients with locally advanced rectal cancer or tumor duplication. The procedures were completed without complications in 2 out of 3 patients. PMID- 26649094 TI - Tolerance of intragastric balloon and patient's satisfaction in obesity treatment. AB - INTRODUCTION: The dietary management of obesity is associated with a high failure rate. Methods which enable the long-term reduction of food intake have been developed. Patients treated with an intragastric balloon may experience some unwanted symptoms during therapy. The severity of these symptoms may result in poor tolerance of treatment, while patients who do not experience these symptoms may refuse to follow dietary modifications. In these cases, weight reduction at the end of treatment may be below expectations. AIM: To assess the tolerance of intragastric balloon treatment in obese patients as well as their satisfaction with this treatment. MATERIAL AND METHODS: Fifty-seven gastric balloon procedures were performed in 51 females and 6 males aged 17 to 65 years (39.5 +/-10.7 years). Baseline weight was 104 +/-14.5 kg (78-140 kg), body mass index 37.2 +/ 4.1 kg/m(2) (29.8-48.1 kg/m(2)), mean excess body weight 41.2 +/-11.5 kg (20.4 63.1 kg). The balloon was filled with 669 +/-25.8 ml of saline solution (550-700 ml). Upon balloon removal 6 months later, the patients completed a 12-question survey. RESULTS: We obtained 57 surveys. The most common symptoms included vomiting, heartburn, abdominal pain and others. Twenty-two patients reported > 2 symptoms. Two patients were symptom-free. The mean duration of symptoms was 24.8 days. Patients reported better control of hypertension, diabetes and resolution of obstructive sleep apnoea and joint symptoms. Only 14 patients did not observe any significant improvement in their bodily function. Fifty-four patients expressed satisfaction after treatment, 6 patients were dissatisfied with the weight loss, and 5 patients would not opt for balloon re-treatment. CONCLUSIONS: The balloon treatment is a safe and well-tolerated therapy with a low complication rate. PMID- 26649095 TI - Pure laparoscopic pancreatoduodenectomy with initial approach to the superior mesenteric artery. AB - INTRODUCTION: The "artery-first approach" (AFA) to the superior mesenteric artery allows an early assessment of resectability of pancreatic tumours and could improve the benefits of laparoscopy, reducing invasiveness, especially for unresectable tumours. AIM: To describe our technique of pure laparoscopic pancreatoduodenectomy (PLPD) with the AFA, and to report the surgical outcomes of this procedure in a small series of 12 patients through a retrospective analysis of a prospectively collected database. MATERIAL AND METHODS: Twelve selected patients underwent elective full laparoscopic pancreatoduodenectomy with the AFA. The technical aspects of the procedure are described in detail and the included images facilitate the understanding of the procedure. RESULTS: The mean operative time was 300 min (range: 250-540 min). No intraoperative complications were observed. No conversion to laparotomy was necessary. The mean postoperative hospital stay was 18 days (range: 8-42). Mortality was null. There were 3 major complications at the 3rd post-operative month follow-up: 2 patients reporting a grade A pancreatic fistula and one biliary fistula. CONCLUSIONS: Our work shows that pure laparoscopic pancreatoduodenectomy (PLPD) with the AFA is feasible, in selected patients. The AFA could improve on the advantages of laparoscopy in the identification of unresectable patients, and it also allows early control of vascular structures. PMID- 26649096 TI - Changes in levels of selected incretins and appetite-controlling hormones following surgical treatment for morbid obesity. AB - INTRODUCTION: The hormonal brain-gut axis is a crucial element in appetite control and the response to surgical treatment for super obesity. However, mechanisms underlying the metabolic response to surgical treatment for morbid obesity are still not clearly specified. AIM: To evaluate and compare the effects of surgical treatment for super obesity by laparoscopic sleeve gastrectomy (LSG) and by laparoscopic Roux-en-Y gastric bypass (LRYGB) on selected incretins and appetite-controlling hormones. MATERIAL AND METHODS: Thirty-five patients were enrolled in a prospective study. Laparoscopic sleeve gastrectomy was performed in 45.8% of patients, and LRYGB in the remaining 54.2% of patients. Before the procedure fasting blood serum was collected from patients and preserved, to determine levels of selected incretins and brain-gut hormones: glucagon-like peptide 1 (GLP-1), peptide YY (PYY), leptin, and ghrelin. RESULTS: Twenty-eight patients came to a follow-up visit 12 months after the surgery. In these patients selected parameters were determined again. The percentage weight loss was 58.8%. The ghrelin levels had decreased, and no statistically significant difference was observed between the two procedures. After both surgical procedures a statistically significant reduction in the leptin level was also observed. Peptide YY levels statistically significantly increased in the whole studied group. The GLP-1 level increased after the surgical procedure. However, the observed change was not statistically significant. CONCLUSIONS: Both treatment methods result in modification of secretion patterns for selected gastrointestinal hormones, and this was considered to be a beneficial effect of bariatric treatment. The laparoscopic sleeve gastrectomy, being a procedure resulting in a metabolic response, seems to be an equally effective method for treatment of super obesity and comorbidities as the laparoscopic gastric bypass. PMID- 26649098 TI - Intraoperative salvage endoscopy performed during orthotopic liver transplantation due to esophageal bleeding. AB - INTRODUCTION: Liver transplantation (LTx) is a widely accepted method of treatment for end stage liver diseases. There are many reports on the management of gastrointestinal bleeding (GIB) after LTx, however the number of studies concerning salvage endoscopic procedures during LTx are scarce. AIM: We present our material of intraoperative endoscopic procedures due to GIB during LTx. MATERIAL AND METHODS: During this period there were 4 females and 1 male at the mean age of 52.2 (35-65) years who underwent LTx and 1 patient had Re-LTx. All patients were Child-Pugh group C and mean MELD score was 17.75. Esophageal and/or gastric varices were present before surgery in all patients but only 1 female patient didn't experience GIB prior to LTx. Variables such as operating time, cold ischemic time, blood loss, blood transfusion, PLT count, international normalized ratio, albumin levels were similar in all patients thus making it statistically insignificant as the cause of GIB. RESULTS: In all cases a single IOE was necessary and bleeding from ruptured varices succumbed to endoscopic ligation. In 2 patients besides trials of ligating the varix, histoacryl was put in use which proved success. In both these last female patients the endoscopic physician had to insert a Danis stent. A follow up endoscopy was performed on the 7-10 POD. CONCLUSIONS: Intra-operative endoscopy performed during LTx does not interrupt surgery. Performed as soon as possible results in less future endoscopic interventions due to GIB. Intraoperative endoscopy may be considered as a salvage procedure and should be performed in the shortest possible time. PMID- 26649097 TI - Laparoscopic adrenalectomy for pheochromocytoma is more difficult compared to other adrenal tumors. AB - INTRODUCTION: Laparoscopic adrenalectomy is the gold standard for the treatment of benign adrenal tumors. However, some authors raise the problem of differences in surgery for pheochromocytoma in comparison to other lesions. AIM: To compare laparoscopic adrenalectomy for pheochromocytoma and for other tumors. MATERIAL AND METHODS: Four hundred and thirty-seven patients with adrenal tumors were included in the retrospective analysis. Patients were divided into two groups: 1 (124 patients treated for pheochromocytoma) and 2 (313 patients with other types of tumor). The two groups were compared with respect to mean operative time, intraoperative blood loss, conversion rate, complication rate and the relationship of tumor size with operative time. RESULTS: The mean operative time in group 1 was 91 min, and in group 2 it was 82 min (p = 0.016). In both groups 1 and 2, tumor size correlated with operative time (p < 0.0001 and p = 0.0003, respectively). The mean blood loss in groups 1 and 2 was 117 ml and 54 ml, respectively (p = 0.0011). The complication rate in groups 1 and 2 was 4% and 4.2%, respectively (p = 0.9542). In groups 1 and 2, conversion was necessary in 2 (1.6%) and 5 (1.6%) cases, respectively (p = 0.9925). CONCLUSIONS: Longer operative time and higher blood loss after laparoscopic adrenalectomy for pheochromocytoma indicate its greater difficulty. However, despite these drawbacks, minimally invasive surgery still seems to be an effective and safe method. PMID- 26649099 TI - Minimally invasive transnasal approach for primary ectopic meningioma of the paranasal sinuses. AB - Endoscopic sinus surgery is a standard procedure in the treatment of various pathologies such as chronic sinusitis or some types of neoplasms. The transnasal approach to tumours of paranasal sinuses is favourable due to functional and aesthetic reasons. We report a rare case of a large primary ectopic meningioma of the paranasal sinuses in a 48-year-old woman referred to the Otolaryngology Clinic due to the incidental finding of a pathologic mass visualised on the orthopantomography picture. After diagnosis, the patient was successfully treated with radical transnasal surgery performed under endoscopic vision. In a 1-year follow-up there were no signs of tumour recurrence. PMID- 26649100 TI - Laparoscopic Roux-en-Y gastric bypass with ileal transposition - an alternative surgical treatment for type 2 diabetes mellitus and gastroesophageal reflux. AB - Currently, type 2 diabetes mellitus (T2DM) is considered as a gastrointestinal disease. Numerous studies have demonstrated that bariatric operations ameliorate T2DM significantly. The laparoscopic Roux-en-Y gastric bypass (L-RYGB) is considered as the gold standard procedure. We aimed to evaluate the feasibility and impact of L-RYGB with ileal transposition (or interposition) on diabetes resolution in a patient who has not benefited from any medical therapy, with its additional effect on the amelioration of gastroesophageal reflux disease. The patient was a 38-year-old diabetic woman with uncontrolled blood glucose despite medical treatment, with additional gastroesophageal reflux disease. Following the procedure, her biochemical parameters and reflux symptoms improved significantly within 10 months. We think that L-RYGB with ileal transposition may be easily employed to gain a maximum effect in diabetics with adverse prognosis. This technique may be an alternative in the treatment of type 2 diabetic patients with gastroesophageal reflux. PMID- 26649101 TI - Endoscopic treatment of a rectovesical fistula following radical prostatectomy by over-the-scope clip (OTSC). AB - The successful management of a rectovesical fistula after radical prostatectomy is difficult. Minimally invasive treatment by over-the-scope clip (OTSC) is a novel method. The authors present results with the use of OTSC. This method was used in 2 patients. The first patient had a rectovesical fistula detected on the fifth day after a prostatectomy. The second patient experienced rectal perforation during prostatectomy and a recurrent fistula after fistulorrhaphy. Both patients had a small fistula located in the vesicourethral anastomosis. Both patients underwent endoscopic OTSC placement. The median follow-up was 26 months. The success rate was 50%. The first patient healed successfully and the second patient had a relapse. The York-Mason procedure was eventually successful. According to our initial experience, the OTSC is suitable for small fistulas detected shortly after a prostatectomy. A more complex fistula, though small, carries a higher recurrence risk. PMID- 26649102 TI - Transpapillary drainage of pancreatic parenchymal necrosis. AB - In the last two decades the strategy of treatment of necrotizing pancreatitis has changed. Endoscopic therapy of patients with symptomatic walled-off pancreatic necrosis has a high rate of efficiency. Here we present a description of a patient with parenchymal limited necrosis of the pancreas and a disruption of the main pancreatic duct. In the treatment, active transpapillary drainage of the pancreatic necrosis (through the major duodenal papilla) was performed and insertion of an endoprosthesis into the main pancreatic duct (through the minor duodenal papilla) was applied, which enabled a bypass over the infiltration and resulted in complete resolution. PMID- 26649103 TI - Transanal total mesorectal excision (TATME) - preliminary findings. AB - Fifteen years ago, laparoscopic surgery of rectal cancer was considered as radical in terms of oncology as open surgery. A trend to reduce surgical injury may be observed in surgery in recent years. In this paper the first experience in the new minimally invasive method of anterior rectal resection is described - through the transanal way. The procedure duration was 130 min. The use of transanal access in rectal cancer surgery is undoubtedly an alternative method to standard laparoscopic surgery. In patients with a large tumour in the lower rectum, the technique allows a longer rectal stump to be left below the resection border. PMID- 26649104 TI - Laparoscopic approach to distal pancreatectomy in pancreatic cystic neoplasms - report of three cases and literature review. AB - The development of cross-section imaging increased the number of diagnosed pancreatic cystic neoplasms (PCNs). Many of these lesions, located frequently in the body or tail of the organ, require resection. We present three cases of patients undergoing laparoscopic distal pancreatectomy because of PCNs, describing the technique along with the post-operative course. The reviewed literature confirms the benefits of the laparoscopic approach, yet it lacks randomized, controlled trials. We also present two spleen-preserving surgical techniques - with and without ligation of the splenic vessels. Both of these procedures can be performed with laparoscopy or laparotomy, but there is no consensus which should be the method of choice. PMID- 26649105 TI - Buried bumper syndrome: a rare complication of percutaneous endoscopic gastrostomy. AB - Feeding via percutaneous endoscopic gastrostomy (PEG) is the preferred form of alimentation when oral feeding is impossible. Although it is a relatively safe method, some complications may occur. One uncommon PEG complication is buried bumper syndrome. In this paper we report a case of buried bumper syndrome, successfully managed with PEG tube repositioning. PMID- 26649107 TI - Pseudoangiomatous stromal hyperplasia of the breast: a case report of a 12-year old girl. AB - Pseudoangiomatous stromal hyperplasia (PASH) of the breast is a benign lesion, characterized by a dense proliferation of stromal mesenchymal cells of myofibroblastic origin forming empty, slit-like channels. We report PASH in a 12 year-old girl with a huge rapidly enlarged right breast. Biopsy of the mass showed histopathologic features characteristic of PASH. Immunohistochemical studies revealed diffuse positive membranous immunoreactivity to CD34. Although it is a benign lesion, lumpectomy was performed to minimize the damage from developing breast tissue. PMID- 26649106 TI - Patient Perspectives on Quality of Life With Uncontrolled Type 1 Diabetes Mellitus: A Systematic Review and Qualitative Meta-synthesis. AB - BACKGROUND: Patients with uncontrolled type 1 diabetes mellitus may be candidates for pancreatic islet cell transplantation. This report synthesizes qualitative research on how patients with uncontrolled type 1 diabetes perceive their quality of life. OBJECTIVE: The objective of this analysis was to examine the perceptions of patients with uncontrolled type 1 diabetes on how it affects their lived experience and quality of life. DATA SOURCES: This report synthesizes 31 primary qualitative studies to examine quality of life from the perspectives of adult patients with type 1 diabetes mellitus and their families or partners. REVIEW METHODS: We performed a qualitative meta-synthesis to integrate findings across primary research studies. RESULTS: Long- and short-term negative consequences of uncontrolled type 1 diabetes affect all aspects of patients' lives: physical, emotional, practical, and social. The effect on each domain is far-reaching, and effects interact across domains. Uncontrolled blood sugar levels lead to substantial psychological distress, negative moods, cognitive difficulties, irritable or aggressive behaviour, and closely associated problems with relationships, self-image, and confidence. Emotional distress is pervasive and under-addressed by health care providers. Patients live in fear of complications from diabetes over the long term. In the shorter term, they are anxious about the personal, social, and professional consequences of hypoglycemic episodes (e.g., injury, humiliation), and may curtail normal activities such as driving or socializing because they are worried about having an episode. The quality of life for patients' family members is also negatively impacted by uncontrolled type 1 diabetes. CONCLUSIONS: Uncontrolled type 1 diabetes has significant negative impacts on the quality of life of both people with the disease and their families. PMID- 26649108 TI - Interrupted aortic arch with post-interruption aneurysm and bicuspid aortic valve in an adult: a case report and literature review. AB - Interrupted aortic arch in adults is rare with a limited number of reported cases. We describe a case of a 53-year-old woman with interrupted aortic arch, bicuspid aortic valve, and post-interruption saccular aneurysm of the aorta. To our knowledge, this is only the second report of an adult patient with all 3 abnormalities. We also review the literature on this unusual condition and discuss its relationship with coarctation of the aorta. PMID- 26649109 TI - Thromboangiitis obliterans (Buerger disease). AB - Thromboangiitis obliterans (Buerger disease) is an occlusive, nonatherosclerotic, inflammatory vasculitis that causes ischemia in small and medium vessels. Most commonly, Buerger disease is diagnosed in 40- to 45-year-old men with a heavy smoking history. Our case exemplifies the most common presentation, diagnosis, and treatment in a 53-year-old male smoker who presents with arm pain and dusky cool fingers. A Buerger diagnosis requires exclusion of autoimmune, diabetic, and embolic causes. The only recognized treatment for this disease is smoking cessation. PMID- 26649110 TI - Drug injection-related fat necrosis of the breast with FDG PET-CT uptake. AB - A 52-year-old woman was found to have a lung mass and bilateral breast lesions on computed tomography (CT). Subsequent positron emission tomography/CT demonstrated marked uptake in the lung mass and mild uptake within the breast lesions. A diagnostic mammogram and targeted ultrasound were performed to exclude primary breast malignancy or metastases from presumed pulmonary malignancy. A pertinent history of recent intravenous drug use with heroin injection into bilateral breasts, together with imaging features, facilitated diagnosis of fat necrosis. Fat necrosis is a common diagnosis in breast imaging and may be an incidental finding on positron emission tomography/CT in the oncologic setting. The presence of fat along with suggestive clinical history can lead to the diagnosis and appropriate assignment of either benign, breast imaging-reporting and data system (BI-RADS) 2, or probably benign, BI-RADS 3, category with short interval follow up. Appropriate work-up of incidental fluorodeoxyglucose-avid breast masses with diagnostic mammogram +/- ultrasound is warranted to avoid incorrect interpretation as neoplastic processes. PMID- 26649111 TI - Recurrent, giant subcutaneous leiomyosarcoma of the thigh. AB - We present a case of recurrent, massive subcutaneous leiomyosarcoma involving the left thigh in a 29-year-old male from Madagascar. The patient had earlier undergone local resection of subcutaneous leiomyosarcoma a half year before. After surgical intervention, local recurrence developed at this site and was rapidly growing. The patient was surgically treated with a 2-cm-wide margin local excision in our hospital. The patient has remained recurrence free at 1-year follow-up. PMID- 26649112 TI - Demystifying the status of fracture healing using tomosynthesis: A case report. AB - Radiography is the most common imaging method for assessing the progress of fracture healing. However, accurate assessment may be confounded by fracture complexity in which a combination of anatomic overlay and hypertrophic callous can be visually misleading. We present just such an instance in which delayed fracture healing was further elucidated using tomosynthesis. PMID- 26649113 TI - Active herpes zoster infection with cutaneous manifestation and adenopathy on FDG PET/CT. AB - We report a patient with history of Hodgkin lymphoma. Six months after treatment, 2-deoxy-2-[18F]fluoro-d-glucose positron emission tomography and/or computed tomography ([18F] FDG PET/CT) scan showed abnormal uptake in right axillary lymph nodes concerning for recurrence. In addition, PET/CT showed a new hypermetabolic skin lesion overlying the right scapula. Clinical evaluation was consistent with shingles, and the patient was treated with valacyclovir. Subsequent PET/CT scan was normal with no evidence of lymphoma. Although there have been reported cases of abnormal FDG in nodes or in skin due to herpes zoster, our case is unique in the literature in that the PET/CT demonstrates abnormalities involving both the skin and associated lymph nodes. The possibility of false positive uptake, not because of recurrent malignancy, must always be considered when abnormal FDG uptake is noted in the follow-up of oncology patients. Careful review of the scan and correlation with clinical findings can avoid false positive interpretation and facilitate patient management. PMID- 26649114 TI - False positive computed tomographic angiography for Stanford type A aortic dissection. AB - BACKGROUND: Computed tomographic angiography (CTA) has emerged as the defacto imaging test to rule out acute aortic dissection; however, it is not without flaws. We report a case of a false-positive CTA with respect to Stanford Type A aortic dissection. CASE: A 52 year-old male presented with sudden onset shortness of breath. He denied chest pain. Due to severe hypertension and an Emergency Department bedside ultrasound suggesting an intimal flap in the aorta, CTA was requested to better assess the ascending aorta and was interpreted as consistent with Stanford Type A aortic dissection with thrombosis of the false lumen in the ascending aorta. However, intra-operative imaging (TEE and epi-aortic scanning) did not identify an intimal flap or dissection, and neither did definitive surgical inspection of the aorta. The suspected aortic dissection and thrombosed false lumen were not visualized on repeat CTA two days later. DISCUSSION: False positive diagnosis of Stanford Type A aortic dissection on CTA can be the result of technical factors, streak artifacts, motion artifacts, and periaortic structures. In this case, non-uniform arterial contrast enhancement secondary to unrecognized biventricular dysfunction resulted in the false positive CTA appearance of an intimal flap and mural thrombus. Intra-operative TEE and epi aortic scanning were proven correct in excluding aortic dissection by the standard of definitive surgical inspection of the aorta. PMID- 26649115 TI - Crowning achievement: a case of dental aspiration. AB - Aspiration of foreign bodies during dental procedures is a rare but potentially serious complication. We present a case of a 75-year-old man who aspirated a dental crown requiring flexible bronchoscopic retrieval. We discuss the risk factors for aspiration, the radiographic features of diagnosis, and the techniques for management and retrieval. PMID- 26649116 TI - Intraovarian oxidized cellulose (Surgicel) mimicking acute ovarian pathology after recent pelvic surgery. AB - Oxidized regenerated cellulose (Ethicon Surgicel) is often used during surgery to achieve hemostasis. The appearance of Surgicel on postoperative computed tomography (CT) may be mistaken for abscess. Meanwhile, the literature regarding its ultrasound appearance remains scant. We report the CT and sonographic appearances of Surgicel in the right ovary of a 21-year-old woman presenting to the emergency department with pelvic pain 7 days after ovarian cystectomy. The patient was discharged home with only supportive measures, and follow-up ultrasound obtained 26 days later demonstrated resolution of the sonographic abnormality. This case stresses the importance of familiarity with common imaging appearances of topical hemostatic agents and the need to correlate radiologic findings with the patient's clinical condition and prior operative reports to identify patients suitable for conservative management. PMID- 26649117 TI - Portal annular pancreas: the pancreatic duct ring sign on MRCP. AB - Portal annular pancreas is a rare pancreatic variant in which the uncinate process of the pancreas extends and fuses to the dorsal surface of the body of the pancreas by surrounding the portal vein. It is asymptomatic, but it can be mistaken for a pancreatic head mass on imaging and could also have serious consequences during pancreatic surgery, if unrecognized. We report this case of a 53-year-old female patient who was diagnosed to have portal annular pancreas on the basis of an unusual course (ring appearance) of the main pancreatic duct on magnetic resonance cholangiopancreatography, not described earlier in the radiology literature. PMID- 26649118 TI - Adult ileocolic intussusception presenting as small bowel metastatic melanoma. AB - We present a rare case of small bowel intussusception that occurred in a young adult with unsuspected metastatic melanoma, diagnosed by imaging, laparotomy and histological examination. We further discuss the clinical presentation, imaging and surgical findings, and provide a brief discussion of adult intussusception. PMID- 26649119 TI - Lipiduria presenting following right hemicolectomy: A case presentation and brief review of the literature. AB - Lipiduria, also known as lipuria, refers to the presence of lipids within the urine. When lipids are present in macroscopic quantities, lipiduria can be visualized as a fat-fluid level on computed tomography imaging. Although the general differential diagnosis of lipiduria is broad, reported etiologies of lipiduria diagnosed by computed tomography have primarily included chyluria, urine-induced lipolysis, and trauma. We report a case of lipiduria occurring coincidentally with resolution of perivesical fat necrosis in a patient after partial right hemicolectomy for B cell lymphoma. PMID- 26649120 TI - Bilateral spontaneous urinary extravasation shown by computed tomography urography in a patient with benign prostatic hyperplasia. AB - Spontaneous extravasation of urine (SUE) is a rare urologic manifestation. Predisposing conditions of SUE include ureteric calculus, retrograde pyelography, pregnancy, abdominal aorta aneurysm, tumors, or enlargement of the prostate gland. Usually, SUE is a self-limiting condition that mandates differentiaton from other catastrophic conditions of pelviureteric ruptures. Most reported cases of SUE based on urograms are unilateral in presentation. Herein, we report a case of bilateral SUE evident on computed tomography urography in a patient with benign prostatic hyperplasia. We also review the literature briefly. PMID- 26649121 TI - Bilateral pigmented villonodular synovitis of the knee. AB - Pigmented villonodular synovitis is a disorder resulting in a villous, nodular, or villonodular proliferation of the synovium, with pigmentation related to the presence of hemosiderin. These lesions are almost exclusively benign with rare reports of malignancy. Pigmented villonodular synovitis can occur in a variety of joints and at any age but most often occurs within the knee in the young adult. Pigmented villonodular synovitis is a rare disease entity, and bilateral synchronous or metachronous involvement of a joint is even more uncommon, with few reports previously described in the literature. We present a case of pigmented villonodular synovitis involving both the right and left knee in the same patient, with radiographic imaging, magnetic resonance imaging, photograph and video intraoperative imaging, and pathologic correlation. PMID- 26649123 TI - Hemifacial spasm due to vertebrobasilar dolichoectasia: a case report. AB - Hemifacial spasm (HFS) happens because of vascular compression of the facial nerve at the root exit zone. Vertebrobasilar dolichoectasia (VBD) is a very rare cause of HFS. VBD is diagnosed by computed tomography angiography and magnetic resonance imaging. Here, we report a case of 65-year-old female patient with HFS due to VBD. We discuss the complications and the treatment options for the case. PMID- 26649122 TI - Visual and otologic manifestation of Camurati-Engelmann's disease: a case report. AB - Camurati-Engelmann's disease (CED) is a rare disorder worldwide with just over 200 cases reported. No case of CED has been reported in Afghanistan till date. Most patients of CED (also known as progressive diaphyseal dysplasia and oeteopathica hyperostotica multiplex infantalis) present with extremity pain, muscle weakness, and waddling gait. It tends to be bilateral and symmetrical and can affect any bone but has greater affinity for long bones e.g., humerus, femur, tibia, ulna, and radius. Other common sites include skull and pelvis. Symptomatology relating to cranial nerve impingement is secondary to amorphous increase in the density of skull bones resulting in stenosis of various foramina/spaces within skull. PMID- 26649124 TI - Ectopic Pregnancy in caesarean section scar: A case report. AB - We report a rare case of ectopic pregnancy occurring in the scar of a previous caesarean section, diagnosed by ultrasonography and confirmed by 3.0-T magnetic resonance imaging of pelvis. We present the clinical details and imaging findings, followed by discussion of the etiology, pathogenesis, and imaging of this condition. PMID- 26649125 TI - Uterine artery embolization for cervical ectopic pregnancy. AB - A 36-year-old woman with 3 prior C-sections is diagnosed with a caesarean scar ectopic pregnancy. Despite receiving intramuscular and transvaginal methotrexate injection 2 months before presentation, the beta human chorionic gonadotropin was recorded to be 73 mIU/mL at the time of encounter. The patient complained of vaginal bleeding with a significant drop in hematocrit from 40% to 33%. Transvaginal ultrasound confirmed retroplacental hemorrhage and because of the patient's desire to retain fertility, interventional radiology was consulted to perform an uterine artery embolization. The uterine artery embolization was successful in achieving hemostasis and resulted in a decrease of betaHCG to 46 on postprocedure day 1 to <1 mIU/mL by postoperative week 3. PMID- 26649126 TI - Unusual continuous intra-abdominal spread of primary testicular lymphoma along the spermatic cord and gonadal vessels: Report of 2 cases. AB - Primary testicular lymphoma (PTL) is an uncommon neoplasm (<5% of all testicular tumors). Testicular lymphoma presents with homogeneous mass, hyperintense on T1 weighted images, and iso-to-hypointense on T2-weighted images with strong diffusion restriction and homogeneous contrast enhancement. Seminoma testis, a close differential due to T2 hypointensity and homogeneousity, can be differentiated by its lower diffusion restriction and younger age group. Involvement of spermatic cord and epididymis is rare with seminoma. Intra abdominal extension along the gonadal vein is not reported. PTL disseminates to extranodal sites. However, extension of PTL along the spermatic cord and gonadal vein up to the inferior vena cava is a rare phenomenon. We report 2 cases of PTL with involvement of epididymis and spermatic cord and further continuous extension along the gonadal vein up to the inferior vena cava. These findings are very rare and when present may help to differentiate testicular lymphoma from other testicular tumors. PMID- 26649127 TI - Plasmocytoma presented as pancreatic head mass. AB - Multiple myeloma is a malignant tumour characterized by proliferation of a single clone of plasma cells, this cell line will produce large amount of ineffective immunoglobulins that are ineffective at fighting infection resulting in immunosuppression. These are medullary tumours most of the time; however, in rare cases they may arise extra medullary. The incidence of extramedullary plasmocytoma is about 5% and they arise in the chest most of the time; but they can also arise in other body systems like gastrointestinal system, which is involved in 10% of the time. We present a very rare case of primary plasmocytoma involving the pancreas. According to our research, there are only 25 cases of primary pancreatic plasmocytoma reported in english literature. PMID- 26649128 TI - Suprasellar choristoma associated with congenital hydrocephalus, anophthalmia, cleft lip and palate, and clinodactly: a proposed variant of a unique new syndrome. AB - A male infant was born with a bilateral cleft lip and/or palate, absent nasal structures, left anophthalmos, right coloboma, and bilateral fifth digit clinodactly. Brain magnetic resonance imaging revealed severe asymmetric hydrocephalus, absent corpus callosum, a suprasellar mass with a high riding third ventricle, and no pituitary gland. He had a normal male karyotype and normal prenatal laboratory testing. He had no significant family history and no renal, vertebral, gastrointestinal, or cardiac malformations. This combination of central nervous system findings, ocular and craniofacial abnormalities, a normal karyotype, and limited skeletal abnormalities to our knowledge has only been previously described once in the literature in association with a disruption in Pax and Sonic Hedgehog protein pathways, and we conclude this patient represents a variant of this described syndrome. PMID- 26649130 TI - A laminar flow microfluidic fuel cell for detection of hexavalent chromium concentration. AB - An electrochemical hexavalent chromium concentration sensor based on a microfluidic fuel cell is presented. The correlation between current density and chromium concentration is established in this report. Three related operation parameters are investigated, including pH values, temperature, and external resistance on the sensor performance. The results show that the current density increases with increasing temperature and the sensor produces a maximum regression coefficient at the catholyte pH value of 1.0. Moreover, it is found that the external resistance has a great influence on the linearity and current densities of the microfluidic sensor. Owing to the membraneless structure and the steady co-laminar flow inside the microchannel, the microfluidic sensor exhibits short response time to hexavalent chromium concentration. The laminar flow fuel cell sensor provides a new and simple method for detecting hexavalent chromium concentration in the industrial wastewater. PMID- 26649129 TI - Electro-microinjection of fish eggs with an immobile capillary electrode. AB - Microinjection with ultra-fine glass capillaries is widely used to introduce cryoprotective agents and other foreign molecules into animal cells, oocytes, and embryos. The fragility of glass capillaries makes difficult the microinjection of fish eggs and embryos, which are usually protected by a hard outer shell, called the chorion. In this study, we introduce a new electromechanical approach, based on the electropiercing of fish eggs with a stationary needle electrode. The electropiercing setup consists of two asymmetric electrodes, including a MUm scaled nickel needle placed opposite to a mm-scaled planar counter-electrode. A fish egg is immersed in low-conductivity solution and positioned between the electrodes. Upon application of a short electric pulse of sufficient field strength, the chorion is electroporated and the egg is attracted to the needle electrode by positive dielectrophoresis. As a result, the hard chorion and the subjacent yolk membrane are impaled by the sharp electrode tip, thus providing direct access to the egg yolk plasma. Our experiments on early-stage medaka fish embryos showed the applicability of electro-microinjection to fish eggs measuring about 1 mm in diameter. We optimized the electropiercing of medaka eggs with respect to the field strength, pulse duration, and conductivity of bathing medium. We microscopically examined the injection of dye solution into egg yolk and the impact of electropiercing on embryos' viability and development. We also analyzed the mechanisms of electropiercing in comparison with the conventional mechanical microinjection. The new electropiercing method has a high potential for automation, e.g., via integration into microfluidic devices, which would allow a large-scale microinjection of fish eggs for a variety of applications in basic research and aquaculture. PMID- 26649131 TI - Study of flow rate induced measurement error in flow-through nano-hole plasmonic sensor. AB - Flow-through gold film perforated with periodically arrayed sub-wavelength nano holes can cause extraordinary optical transmission (EOT), which has recently emerged as a label-free surface plasmon resonance sensor in biochemical detection by measuring the transmission spectral shift. This paper describes a systematic study of the effect of microfluidic field on the spectrum of EOT associated with the porous gold film. To detect biochemical molecules, the sub-micron-thick film is free-standing in a microfluidic field and thus subject to hydrodynamic deformation. The film deformation alone may cause spectral shift as measurement error, which is coupled with the spectral shift as real signal associated with the molecules. However, this microfluid-induced measurement error has long been overlooked in the field and needs to be identified in order to improve the measurement accuracy. Therefore, we have conducted simulation and analytic analysis to investigate how the microfluidic flow rate affects the EOT spectrum and verified the effect through experiment with a sandwiched device combining Au/Cr/Si3N4 nano-hole film and polydimethylsiloxane microchannels. We found significant spectral blue shift associated with even small flow rates, for example, 12.60 nm for 4.2 MUl/min. This measurement error corresponds to 90 times the optical resolution of the current state-of-the-art commercially available spectrometer or 8400 times the limit of detection. This really severe measurement error suggests that we should pay attention to the microfluidic parameter setting for EOT-based flow-through nano-hole sensors and adopt right scheme to improve the measurement accuracy. PMID- 26649132 TI - On-chip assay of the effect of topographical microenvironment on cell growth and cell-cell interactions during wound healing. AB - Wound healing is an essential physiological process for tissue homeostasis, involving multiple types of cells, extracellular matrices, and growth factor/chemokine interactions. Many in vitro studies have investigated the interactions between cues mentioned above; however, most of them only focused on a single factor. In the present study, we design a wound healing device to recapitulate in vivo complex microenvironments and heterogeneous cell situations to investigate how three types of physiologically related cells interact with their microenvironments around and with each other during a wound healing process. Briefly, a microfluidic device with a micropillar substrate, where diameter and interspacing can be tuned to mimic the topographical features of the 3D extracellular matrix, was designed to perform positional cell loading on the micropillar substrate, co-culture of three types of physiologically related cells, keratinocytes, dermal fibroblasts, and human umbilical vein endothelial cells, as well as an investigation of their interactions during wound healing. The result showed that cell attachment, morphology, cytoskeleton distribution, and nucleus shape were strongly affected by the micropillars, and these cells showed collaborative response to heal the wound. Taken together, these findings highlight the dynamic relationship between cells and their microenvironments. Also, this reproducible device may facilitate the in vitro investigation of numerous physiological and pathological processes such as cancer metastasis, angiogenesis, and tissue engineering. PMID- 26649133 TI - Homogeneous agglutination assay based on micro-chip sheathless flow cytometry. AB - Homogeneous assays possess important advantages that no washing or physical separation is required, contributing to robust protocols and easy implementation which ensures potential point-of-care applications. Optimizing the detection strategy to reduce the number of reagents used and simplify the detection device is desirable. A method of homogeneous bead-agglutination assay based on micro chip sheathless flow cytometry has been developed. The detection processes include mixing the capture-probe conjugated beads with an analyte containing sample, followed by flowing the reaction mixtures through the micro-chip sheathless flow cytometric device. The analyte concentrations were detected by counting the proportion of monomers in the reaction mixtures. Streptavidin-coated magnetic beads and biotinylated bovine serum albumin (bBSA) were used as a model system to verify the method, and detection limits of 0.15 pM and 1.5 pM for bBSA were achieved, using commercial Calibur and the developed micro-chip sheathless flow cytometric device, respectively. The setup of the micro-chip sheathless flow cytometric device is significantly simple; meanwhile, the system maintains relatively high sensitivity, which mainly benefits from the application of forward scattering to distinguish aggregates from monomers. The micro-chip sheathless flow cytometric device for bead agglutination detection provides us with a promising method for versatile immunoassays on microfluidic platforms. PMID- 26649134 TI - Longxuetongluo Capsule Improves Erythrocyte Function against Lipid Peroxidation and Abnormal Hemorheological Parameters in High Fat Diet-Induced ApoE-/- Mice. AB - Chinese dragon's blood, the red resin of Dracaena cochinchinensis, one of the renowned traditional medicines, has been used to facilitate blood circulation and disperse blood stasis for thousands of years. Phenolic compounds are considered to be responsible for its main biological activities. In this study, total phenolic compounds of Chinese dragon's blood were made into capsule (Longxuetongluo Capsule, LTC) and their effects on the abnormal hemorheological properties were examined by high fat diet (HFD) induced ApoE-/- mice. Compared to the model group, LTC recovered the abnormal hemorheological parameters in HFD induced ApoE-/- mice by reducing whole blood viscosity (WBV) at high rate and improving erythrocyte function. In conclusion, LTC could ameliorate erythrocyte deformability and osmotic fragility through the reduction of lipid peroxidation on plasma and erythrocyte membranes in HFD-induced ApoE-/- mice, which supported the traditional uses of Chinese dragon's blood as an effective agent for improving blood microcirculation in hypercholesterolemia. PMID- 26649135 TI - Efficiency of Base Excision Repair of Oxidative DNA Damage and Its Impact on the Risk of Colorectal Cancer in the Polish Population. AB - DNA oxidative lesions are widely considered as a potential risk factor for colorectal cancer development. The aim of this work was to determine the role of the efficiency of base excision repair, both in lymphocytes and in epithelial tissue, in patients with CRC and healthy subjects. SNPs were identified within genes responsible for steps following glycosylase action in BER, and patients and healthy subjects were genotyped. A radioisotopic BER assay was used for assessing repair efficiency and TaqMan for genotyping. Decreased BER activity was observed in lymphocyte extract from CRC patients and in cancer tissue extract, compared to healthy subjects. In addition, polymorphisms of EXO1, LIG3, and PolB may modulate the risk of colorectal cancer by decreasing (PolB) or increasing (LIG3 and EXO1) the chance of malignant transformation. PMID- 26649136 TI - Bioavailability Study of an Innovative Orobuccal Formulation of Glutathione. AB - Alteration of the ubiquitous thiol tripeptide glutathione (GSH) is involved in oxidative stress, which plays a role in ageing; consequently, GSH is closely related to this process characterized by progressive decline in the efficiency of physiological function and increased susceptibility to disease. When circulating GSH decreases, oral administration might be considered a therapeutic benefit. Unfortunately, due to the hydrolysis of the tripeptide by intestinal gamma glutamyltransferase, dietary glutathione is not a major determinant for its increase. Aim of this work was to evaluate improvement of GSH systemic availability testing, in vitro and in vivo, an optimized orobuccal fast-slow release formulation tablet containing pure stabilized GSH. In vitro evaluation of the penetration capability of the innovative GSH-release formulation showed that GSH was well absorbed by the reconstructed oral epithelium and its absorption has features of time-dependence. In addition, in vivo results, obtained from 15 healthy volunteers, were in favor of GSH level improvement in blood showing fast (after 30 and 60 minutes) absorption through oral mucosa. In conclusion, the intake of GSH formulated through optimized orobuccal fast-slow release tablets gave positive results in raising GSH blood concentration. PMID- 26649137 TI - Acetaldehyde Induces Cytotoxicity of SH-SY5Y Cells via Inhibition of Akt Activation and Induction of Oxidative Stress. AB - Excessive alcohol consumption can lead to brain tissue damage and cognitive dysfunction. It has been shown that heavy drinking is associated with an earlier onset of neurodegenerative diseases such as Alzheimer's disease. Acetaldehyde, the most toxic metabolite of ethanol, is speculated to mediate the brain tissue damage and cognitive dysfunction induced by the chronic excessive consumption of alcohol. However, the exact mechanisms by which acetaldehyde induces neurotoxicity are not totally understood. In this study, we investigated the cytotoxic effects of acetaldehyde in SH-SY5Y cells and found that acetaldehyde induced apoptosis of SH-SY5Y cells by downregulating the expression of antiapoptotic Bcl-2 and Bcl-xL and upregulating the expression of proapoptotic Bax. Acetaldehyde treatment led to a significant decrease in the levels of activated Akt and cyclic AMP-responsive element binding protein (CREB). In addition, acetaldehyde induced the activation of p38 mitogen-activated protein kinase (MAPK) while inhibiting the activation of extracellular signal-regulated kinases (ERKs, p44/p42MAPK). Meanwhile, acetaldehyde treatment caused an increase in the production of reactive oxygen species and elevated the oxidative stress in SH-SY5Y cells. Therefore, acetaldehyde induces cytotoxicity of SH-SY5Y cells via promotion of apoptotic signaling, inhibition of cell survival pathway, and induction of oxidative stress. PMID- 26649138 TI - The Cellular Response to Oxidatively Induced DNA Damage and Polymorphism of Some DNA Repair Genes Associated with Clinicopathological Features of Bladder Cancer. AB - Genome instability and impaired DNA repair are hallmarks of carcinogenesis. The study was aimed at evaluating the DNA damage response in H2O2-treated lymphocytes using the alkaline comet assay in bladder cancer (BC) patients as compared to clinically healthy controls, elderly persons, and individuals with chronic inflammations. Polymorphism in DNA repair genes involved in nucleotide excision repair (NER) and base excision repair (BER) was studied using the PCR-RFLP method in the Belarusian population to elucidate the possible association of their variations with both bladder cancer risk and clinicopathological features of tumors. The increased level of H2O2-induced DNA damage and a higher proportion of individuals sensitive to oxidative stress were found among BC patients as compared to other groups under study. Heterozygosity in the XPD gene (codon 751) increased cancer risk: OR (95% CI) = 1.36 (1.03-1.81), p = 0.031. The frequency of the XPD 312Asn allele was significantly higher in T >= 2 high grade than in T >= 2 low grade tumors (p = 0.036); the ERCC6 1097Val/Val genotype was strongly associated with muscle-invasive tumors. Combinations of homozygous wild type alleles occurred with the increased frequency in patients with non-muscle invasive tumors suggesting that the maintenance of normal DNA repair activity may prevent cancer progression. PMID- 26649139 TI - Oxidative Stress and Mitochondrial Activation as the Main Mechanisms Underlying Graphene Toxicity against Human Cancer Cells. AB - Due to the development of nanotechnology graphene and graphene-based nanomaterials have attracted the most attention owing to their unique physical, chemical, and mechanical properties. Graphene can be applied in many fields among which biomedical applications especially diagnostics, cancer therapy, and drug delivery have been arousing a lot of interest. Therefore it is essential to understand better the graphene-cell interactions, especially toxicity and underlying mechanisms for proper use and development. This review presents the recent knowledge concerning graphene cytotoxicity and influence on different cancer cell lines. PMID- 26649140 TI - Redox Stimulation of Human THP-1 Monocytes in Response to Cold Physical Plasma. AB - In plasma medicine, cold physical plasma delivers a delicate mixture of reactive components to cells and tissues. Recent studies suggested a beneficial role of cold plasma in wound healing. Yet, the biological processes related to the redox modulation via plasma are not fully understood. We here used the monocytic cell line THP-1 as a model to test their response to cold plasma in vitro. Intriguingly, short term plasma treatment stimulated cell growth. Longer exposure only modestly compromised cell viability but apparently supported the growth of cells that were enlarged in size and that showed enhanced metabolic activity. A significantly increased mitochondrial content in plasma treated cells supported this notion. On THP-1 cell proteome level, we identified an increase of protein translation with key regulatory proteins being involved in redox regulation (hypoxia inducible factor 2alpha), differentiation (retinoic acid signaling and interferon inducible factors), and cell growth (Yin Yang 1). Regulation of inflammation is a key element in many chronic diseases, and we found a significantly increased expression of the anti-inflammatory heme oxygenase 1 (HMOX1) and of the neutrophil attractant chemokine interleukin-8 (IL-8). Together, these results foster the view that cold physical plasma modulates the redox balance and inflammatory processes in wound related cells. PMID- 26649141 TI - Modulation of RhoA GTPase Activity Sensitizes Human Cervix Carcinoma Cells to gamma-Radiation by Attenuating DNA Repair Pathways. AB - Radiotherapy with gamma-radiation is widely used in cancer treatment to induce DNA damage reducing cell proliferation and to kill tumor cells. Although RhoA GTPase overexpression/hyperactivation is observed in many malignancies, the effect of RhoA activity modulation on cancer radiosensitivity has not been previously investigated. Here, we generated stable HeLa cell clones expressing either the dominant negative RhoA-N19 or the constitutively active RhoA-V14 and compared the responses of these cell lines with those of parental HeLa cells, after treatment with low doses of gamma-radiation. HeLa-RhoA-N19 and HeLa-RhoA V14 clones displayed reduced proliferation and survival compared to parental cells after radiation and became arrested at cell cycle stages correlated with increased cellular senescence and apoptosis. Also, Chk1/Chk2 and histone H2A phosphorylation data, as well as comet assays, suggest that the levels of DNA damage and DNA repair activation and efficiency in HeLa cell lines are correlated with active RhoA. In agreement with these results, RhoA inhibition by C3 toxin expression drastically affected homologous recombination (HR) and nonhomologous end joining (NHEJ). These data suggest that modulation of RhoA GTPase activity impairs DNA damage repair, increasing HeLa cell radiosensitivity. PMID- 26649143 TI - Lipoxin A4 Attenuates Cell Invasion by Inhibiting ROS/ERK/MMP Pathway in Pancreatic Cancer. AB - Lipoxin A4 (LXA4), an endogenous arachidonic acid metabolite, was previously considered an anti-inflammatory lipid mediator. But it also has the potential to inhibit cancer progression. To explore the therapeutic effect of LXA4 in pancreatic cancer, we used Panc-1 cells to investigate the mechanism by which LXA4 can attenuate pancreatic cancer cell invasion. Our data showed that LXA4 significantly inhibited both cell invasion and the expression of matrix metalloproteinase- (MMP-) 9 and MMP-2. Further experiments implied that LXA4 decreased the levels of intracellular reactive oxygen species (ROS) and the activity of the extracellular signal regulated kinases (ERK) pathway to achieve similar outcome to ROS scavenger N-acetyl-L-cysteine (NAC). However, a decreased level of intracellular ROS was not observed in cells treated with the specific ERK pathway inhibitor FR180204. The blocking of either intracellular ROS or ERK pathway caused the downregulation of MMP-9 and MMP-2 expression. Furthermore, tests revealed that LXA4 inhibited MMP-9 and MMP-2 at the mRNA, protein, and functional levels. Finally, LXA4 dramatically limited the invasion of CoCl2-mimic hypoxic cells and abrogated intracellular ROS levels, ERK activity, and MMPs expression. These results suggest that LXA4 attenuates cell invasion in pancreatic cancer by suppressing the ROS/ERK/MMPs pathway, which may be beneficial for preventing the invasion of pancreatic cancer. PMID- 26649144 TI - Mitochondrion-Permeable Antioxidants to Treat ROS-Burst-Mediated Acute Diseases. AB - Reactive oxygen species (ROS) play a crucial role in the inflammatory response and cytokine outbreak, such as during virus infections, diabetes, cancer, cardiovascular diseases, and neurodegenerative diseases. Therefore, antioxidant is an important medicine to ROS-related diseases. For example, ascorbic acid (vitamin C, VC) was suggested as the candidate antioxidant to treat multiple diseases. However, long-term use of high-dose VC causes many side effects. In this review, we compare and analyze all kinds of mitochondrion-permeable antioxidants, including edaravone, idebenone, alpha-Lipoic acid, carotenoids, vitamin E, and coenzyme Q10, and mitochondria-targeted antioxidants MitoQ and SkQ and propose astaxanthin (a special carotenoid) to be the best antioxidant for ROS burst-mediated acute diseases, like avian influenza infection and ischemia reperfusion. Nevertheless, astaxanthins are so unstable that most of them are inactivated after oral administration. Therefore, astaxanthin injection is suggested hypothetically. The drawbacks of the antioxidants are also reviewed, which limit the use of antioxidants as coadjuvants in the treatment of ROS associated disorders. PMID- 26649145 TI - HDAC6 Regulates the Chaperone-Mediated Autophagy to Prevent Oxidative Damage in Injured Neurons after Experimental Spinal Cord Injury. AB - Hypoxia-ischemia- (HI-) induced oxidative stress plays a role in secondary pathocellular processes of acute spinal cord injury (SCI) due to HI from many kinds of mechanical trauma. Increasing evidence suggests that the histone deacetylase-6 (HDAC6) plays an important role in cell homeostasis in both physiological and abnormal, stressful, pathological conditions. This paper found that inhibition of HDAC6 accelerated reactive oxygen species (ROS) generation and cell apoptosis in response to the HI. Deficiency of HDAC6 hindered the chaperone mediated autophagy (CMA) activity to resistance of HI-induced oxidative stress. Furthermore, this study provided the experimental evidence for the potential role of HDAC6 in the regulation of CMA by affecting HSP90 acetylation. Therefore, HDAC6 plays an important role in the function of CMA pathway under the HI stress induced by SCI and it may be a potential therapeutic target in acute SCI model. PMID- 26649142 TI - Polyphenols as Modulator of Oxidative Stress in Cancer Disease: New Therapeutic Strategies. AB - Cancer onset and progression have been linked to oxidative stress by increasing DNA mutations or inducing DNA damage, genome instability, and cell proliferation and therefore antioxidant agents could interfere with carcinogenesis. It is well known that conventional radio-/chemotherapies influence tumour outcome through ROS modulation. Since these antitumour treatments have important side effects, the challenge is to develop new anticancer therapeutic strategies more effective and less toxic for patients. To this purpose, many natural polyphenols have emerged as very promising anticancer bioactive compounds. Beside their well-known antioxidant activities, several polyphenols target epigenetic processes involved in cancer development through the modulation of oxidative stress. An alternative strategy to the cytotoxic treatment is an approach leading to cytostasis through the induction of therapy-induced senescence. Many anticancer polyphenols cause cellular growth arrest through the induction of a ROS-dependent premature senescence and are considered promising antitumour therapeutic tools. Furthermore, one of the most innovative and interesting topics is the evaluation of efficacy of prooxidant therapies on cancer stem cells (CSCs). Several ROS inducers-polyphenols can impact CSCs metabolisms and self-renewal related pathways. Natural polyphenol roles, mainly in chemoprevention and cancer therapies, are described and discussed in the light of the current literature data. PMID- 26649146 TI - Nrf2/ARE Pathway Involved in Oxidative Stress Induced by Paraquat in Human Neural Progenitor Cells. AB - Compelling evidences have shown that diverse environmental insults arising during early life can either directly lead to a reduction in the number of dopaminergic neurons or cause an increased susceptibility to neurons degeneration with subsequent environmental insults or with aging alone. Oxidative stress is considered the main effect of neurotoxins exposure. In this study, we investigated the oxidative stress effect of Paraquat (PQ) on immortalized human embryonic neural progenitor cells by treating them with various concentrations of PQ. We show that PQ can decrease the activity of SOD and CAT but increase MDA and LDH level. Furthermore, the activities of Cyc and caspase-9 were found increased significantly at 10 MUM of PQ treatment. The cytoplasmic Nrf2 protein expressions were upregulated at 10 MUM but fell back at 100 MUM. The nuclear Nrf2 protein expressions were upregulated as well as the downstream mRNA expressions of HO-1 and NQO1 in a dose-dependent manner. In addition, the proteins expression of PKC and CKII was also increased significantly even at 1 MUM. The results suggested that Nrf2/ARE pathway is involved in mild to moderate PQ-induced oxidative stress which is evident from dampened Nrf2 activity and low expression of antioxidant genes in PQ induced oxidative damage. PMID- 26649147 TI - Nr2e1 Deficiency Augments Palmitate-Induced Oxidative Stress in Beta Cells. AB - Nuclear receptor subfamily 2 group E member 1 (Nr2e1) has been regarded as an essential regulator of the growth of neural stem cells. However, its function elsewhere is unknown. In the present study, we generated Nr2e1 knockdown MIN6 cells and studied whether Nr2e1 knockdown affected basal beta cell functions such as proliferation, cell death, and insulin secretion. We showed that knockdown of Nr2e1 in MIN6 cells resulted in increased sensitivity to lipotoxicity, decreased proliferation, a partial G0/G1 cell-cycle arrest, and higher rates of apoptosis. Moreover, Nr2e1 deficiency exaggerates palmitate-induced impairment in insulin secretion. At the molecular level, Nr2e1 deficiency augments palmitate-induced oxidative stress. Nr2e1 deficiency also resulted in decreases in antioxidant enzymes and expression level of Nrf2. Together, this study indicated a potential protective effect of Nr2e1 on beta cells, which may serve as a target for the development of novel therapies for diabetes. PMID- 26649148 TI - Draft genome of Gemmata massiliana sp. nov, a water-borne Planctomycetes species exhibiting two variants. AB - Gemmata massiliana is a new Planctomycetes bacterium isolated from a hospital water network in France, using a new culture medium. It is an aerobic microorganism with optimal growth at pH 8, at 30 degrees C and salinity <= 1.25 % NaCl. G. massiliana is resistant to beta-lactam antibiotics, due to lack of peptidoglycan in its cell wall.G. massiliana shares a 97 % 16S rRNA gene sequence similarity with the nearest species, Gemmata obscuriglobus; and 99 % similarity with unnamed soil isolates. Its 9,249,437-bp genome consists in one chromosome and no detectable plasmid and has a 64.07 % G + C content, 32.94 % of genes encoding for hypothetical proteins. The genome contains an incomplete 19.6-kb phage sequence, 26 CRISPRs, 3 CAS and 15 clusters of secondary metabolites. G. massiliana genome increases knowledge of a poorly known world of bacteria. PMID- 26649149 TI - Genome sequence of the clover symbiont Rhizobium leguminosarum bv. trifolii strain CC275e. AB - Rhizobium leguminosarum bv. trifolii strain CC275e is a highly effective, N2 fixing microsymbiont of white clover (Trifolium repens L.). The bacterium has been widely used in both Australia and New Zealand as a clover seed inoculant and, as such, has delivered the equivalent of millions of dollars of nitrogen into these pastoral systems. R. leguminosarum strain CC275e is a rod-shaped, motile, Gram-negative, non-spore forming bacterium. The genome was sequenced on an Illumina MiSeq instrument using a 2 * 150 bp paired end library and assembled into 29 scaffolds. The genome size is 7,077,367 nucleotides, with a GC content of 60.9 %. The final, high-quality draft genome contains 6693 protein coding genes, close to 85 % of which were assigned to COG categories. This Whole Genome Shotgun project has been deposited at DDBJ/EMBL/GenBank under the accession JRXL00000000. The sequencing of this genome will enable identification of genetic traits associated with host compatibility and high N2 fixation characteristics in Rhizobium leguminosarum. The sequence will also be useful for development of strain-specific markers to assess factors associated with environmental fitness, competiveness for host nodule occupancy, and survival on legume seeds (New Zealand Ministry of Business, Innovation and Employment program, 'Improving forage legume-rhizobia performance' contract C10X1308 and DairyNZ Ltd.). PMID- 26649150 TI - Pelvic radiation therapy: Between delight and disaster. AB - In the last few decades radiotherapy was established as one of the best and most widely used treatment modalities for certain tumours. Unfortunately that came with a price. As more people with cancer survive longer an ever increasing number of patients are living with the complications of radiotherapy and have become, in certain cases, difficult to manage. Pelvic radiation disease (PRD) can result from ionising radiation-induced damage to surrounding non-cancerous tissues resulting in disruption of normal physiological functions and symptoms such as diarrhoea, tenesmus, incontinence and rectal bleeding. The burden of PRD-related symptoms, which impact on a patient's quality of life, has been under appreciated and sub-optimally managed. This article serves to promote awareness of PRD and the vast potential there is to improve current service provision and research activities. PMID- 26649151 TI - Anastomotic leakage in rectal cancer surgery: The role of blood perfusion. AB - Anastomotic leakage after anterior resection for rectal cancer remains a common and often devastating complication. Preoperative risk factors for anastomotic leakage have been studied extensively and are used for patient selection, especially whether to perform a diverting stoma or not. From the current literature, data suggest that perfusion in the rectal stump rather than in the colonic limb may be more important for the integrity of the colorectal anastomosis. Moreover, available research suggests that the mid and upper rectum is considerably more vascularized than the lower part, in which the posterior compartment seems most vulnerable. These data fit neatly with the observation that anastomotic leaks are far more frequent in patients undergoing total compared to partial mesorectal excision, and also that most leaks occur dorsally. Clinical judgment has been shown to ineffectively assess anastomotic viability, while promising methods to measure blood perfusion are evolving. Much interest has recently been turned to near-infrared light technology, enhanced with fluorescent agents, which enables intraoperative perfusion assessment. Preliminary data are promising, but large-scale controlled trials are lacking. With maturation of such technology, perfusion measurements may in the future inform the surgeon whether anastomoses are at risk. In high colorectal anastomoses, anastomotic revision might be feasible, while a diverting stoma could be fashioned selectively instead of routinely for low anastomoses. PMID- 26649153 TI - Watch and wait approach to rectal cancer: A review. AB - In 2014, there were an estimated 136800 new cases of colorectal cancer, making it the most common gastrointestinal malignancy. It is the second leading cause of cancer death in both men and women in the United States and over one-third of newly diagnosed patients have stage III (node-positive) disease. For stage II and III colorectal cancer patients, the mainstay of curative therapy is neoadjuvant therapy, followed by radical surgical resection of the rectum. However, the consequences of a proctectomy, either by low anterior resection or abdominoperineal resection, can lead to very extensive comorbidities, such as the need for a permanent colostomy, fecal incontinence, sexual and urinary dysfunction, and even mortality. Recently, trends of complete regression of the rectal cancer after neoadjuvant chemoradiation therapy have been confirmed by clinical and radiographic evaluation-this is known as complete clinical response (cCR). The "watch and wait" approach was first proposed by Dr. Angelita Habr-Gama in Brazil in 2009. Those patients with cCR are followed with close surveillance physical examinations, endoscopy, and imaging. Here, we review management of rectal cancer, the development of the "watch and wait" approach and its outcomes. PMID- 26649152 TI - Evolution and advances in laparoscopic ventral and incisional hernia repair. AB - Primary ventral hernias and ventral incisional hernias have been a challenge for surgeons throughout the ages. In the current era, incisional hernias have increased in prevalence due to the very high number of laparotomies performed in the 20(th) century. Even though minimally invasive surgery and hernia repair have evolved rapidly, general surgeons have yet to develop the ideal, standardized method that adequately decreases common postoperative complications, such as wound failure, hernia recurrence and pain. The evolution of laparoscopy and ventral hernia repair will be reviewed, from the rectoscopy of the 4(th) century to the advent of laparoscopy, from suture repair to the evolution of mesh reinforcement. The nuances of minimally invasive ventral and incisional hernia repair will be summarized, from preoperative considerations to variations in intraoperative practice. New techniques have become increasingly popular, such as primary defect closure, retrorectus mesh placement, and concomitant component separation. The advent of robotics has made some of these repairs more feasible, but only time and well-designed clinical studies will tell if this will be a durable modality for ventral and incisional hernia repair. PMID- 26649154 TI - Natural history of uncomplicated sigmoid diverticulitis. AB - While diverticular disease is extremely common, the natural history (NH) of its most frequent presentation (i.e., sigmoid diverticulitis) is poorly investigated. Relevant information is mostly restricted to population-based or retrospective studies. This comprehensive review aimed to evaluate the NH of simple sigmoid diverticulitis. While there is a clear lack of uniformity in terminology, which results in difficulties interpreting and comparing findings between studies, this review demonstrates the benign nature of simple sigmoid diverticulitis. The overall recurrence rate is relatively low, ranging from 13% to 47%, depending on the definition used by the authors. Among different risk factors for recurrence, patients with C-reactive protein > 240 mg/L are three times more likely to recur. Other risk factors include: Young age, a history of several episodes of acute diverticulitis, medical vs surgical management, male patients, radiological signs of complicated first episode, higher comorbidity index, family history of diverticulitis, and length of involved colon > 5 cm. The risk of developing a complicated second episode (and its corollary to require an emergency operation) is less than 2%-5%. In fact, the old rationale for elective surgery as a preventive treatment, based mainly on concerns that recurrence would result in a progressively increased risk of sepsis or the need for a colostomy, is not upheld by the current evidence. PMID- 26649157 TI - Application of single-layer mucosa-to-mucosa pancreaticojejunal anastomosis in pancreaticoduodenectomy. AB - AIM: To investigate the simplicity, reliability, and safety of the application of single-layer mucosa-to-mucosa pancreaticojejunal anastomosis in pancreaticoduodenectomy. METHODS: A retrospective analysis was performed on the data of patients who received pancreaticoduodenectomy completed by the same surgical group between January 2011 and April 2014 in the General Hospital of the People's Liberation Army. In total, 51 cases received single-layer mucosa-to mucosa pancreaticojejunal anastomosis and 51 cases received double-layer pancreaticojejunal anastomosis. The diagnoses of pancreatic fistula and clinically relevant pancreatic fistula after pancreaticoduodenectomy were judged strictly by the International Study Group on pancreatic fistula definition. The preoperative and intraoperative data of these two groups were compared. chi(2) test and Fisher's exact test were used to analyze the incidences of pancreatic fistula, peritoneal catheterization, abdominal infection and overall complications between the single-layer anastomosis group and double-layer anastomosis group. Rank sum test were used to analyze the difference in operation time, pancreaticojejunal anastomosis time, postoperative hospitalization time, total hospitalization time and hospitalization expenses between the single-layer anastomosis group and double-layer anastomosis group. RESULTS: Patients with grade A pancreatic fistula accounted for 15.69% (8/51) vs 15.69% (8/51) (P = 1.0000), and patients with grades B and C pancreatic fistula accounted for 9.80% (5/51) vs 52.94% (27/51) (P = 0.0000) in the single-layer and double-layer anastomosis groups. Although there was no significant difference in the percentage of patients with grade A pancreatic fistula, there was a significant difference in the percentage of patients with grades B and C pancreatic fistula between the two groups. The operation time (220.059 +/- 60.602 min vs 379.412 +/- 90.761 min, P = 0.000), pancreaticojejunal anastomosis time (17.922 +/- 5.145 min vs 31.333 +/- 7.776 min, P = 0.000), postoperative hospitalization time (18.588 +/- 5.285 d vs 26.373 +/- 15.815 d, P = 0.003), total hospitalization time (25.627 +/- 6.551 d vs 33.706 +/- 15.899 d, P = 0.002), hospitalization expenses (116787.667 +/- 31900.927 yuan vs 162788.608 +/- 129732.500 yuan, P = 0.001), as well as the incidences of pancreatic fistula [13/51 (25.49%) vs 35/51 (68.63%), P = 0.0000], peritoneal catheterization [0/51 (0%) vs 6/51 (11.76%), P = 0.0354], abdominal infection [1/51 (1.96%) vs 11/51 (21.57%), P = 0.0021], and overall complications [21/51 (41.18%) vs 37/51 (72.55%), P = 0.0014] in the single-layer anastomosis group were all lower than those in the double-layer anastomosis group. CONCLUSION: Single-layer mucosa-to-mucosa pancreaticojejunal anastomosis appears to be a simple, reliable, and safe method. Use of this method could reduce the postoperative incidence of complications. PMID- 26649155 TI - Role of laryngeal mask airway in laparoscopic cholecystectomy. AB - Laparoscopic cholecystectomy is one of the most commonly performed surgical procedures and the laryngeal mask airway (LMA) is the most common supraglottic airway device used by the anesthesiologists to manage airway during general anesthesia. Use of LMA has some advantages when compared to endotracheal intubation, such as quick and ease of placement, a lesser requirement for neuromuscular blockade and a lower incidence of postoperative morbididy. However, the use of the LMA in laparoscopy is controversial, based on a concern about increased risk of regurgitation and pulmonary aspiration. The ability of these devices to provide optimal ventilation during laparoscopic procedures has been also questioned. The most important parameter to secure an adequate ventilation and oxygenation for the LMA under pneumoperitoneum condition is its seal pressure of airway. A good sealing pressure, not only state correct patient ventilation, but it reduces the potential risk of aspiration due to the better seal of airway. In addition, the LMAs incorporating a gastric access, permitting a safe anesthesia based on these commented points. We did a literature search to clarify if the use of LMA in preference to intubation provides inadequate ventilation or increase the risk of aspiration in patients undergoing laparoscopic cholecystectomy. We found evidence stating that LMA with drain channel achieves adequate ventilation for these procedures. Limited evidence was found to consider these devices completely safe against aspiration. However, we observed that the incidence of regurgitation and aspiration associated with the use of the LMA in laparoscopic surgery is very low. PMID- 26649156 TI - Endoscopic surgery - exploring the modalities. AB - The adoption of endoscopic surgery continues to expand in clinical situations with the recent natural orifice transluminal endoscopic surgery technique enabling abdominal organ resection to be performed without necessitating any skin incision. In recent years, the development of numerous devices and platforms have allowed for such procedures to be carried out in a safer and more efficient manner, and in some ways to better simulate triangulation and surgical tasks (e.g., suturing and dissection). Furthermore, new novel techniques such as submucosal tunneling, endoscopic full-thickness resection and hybrid endo laparoscopic approaches have further widened its use in more advanced diseases. Nevertheless, many of these new innovations are still at their pre-clinical stage. This review focuses on the various innovations in endoscopic surgery, with emphasis on devices and techniques that are currently in human use. PMID- 26649158 TI - Gastric remnant twist in the immediate post-operative period following laparoscopic sleeve gastrectomy. AB - Twist of stomach remnant post sleeve gastrectomy is a rare entity and difficult to diagnose pre-operatively. We are reporting a case of gastric volvulus post laparoscopic sleeve gastrectomy, which was managed conservatively. A 38-year-old lady with a body mass index of 54 underwent laparoscopic sleeve gastrectomy. Sleeve gastrectomy was performed over a 32 French bougie using Endo-GIA tri stapler. On post-operative day 1, patient had nausea and non-bilious vomiting. An upper gastrointestinal gastrografin study on post-operative days 1 and 2 revealed collection of contrast in the fundic area of stomach with poor flow distally, and she vomited gastrograffin immediately post procedure. With the suspicion of a stricture in the mid stomach as the cause, the patient was taken back for a exploratory laparoscopy and intra-operative endoscopy. We found a twist in the gastric tube which was too tight for the endoscope to pass through. This was managed conservatively with a long stent to keep the gastric tube straight and patent. The stent was discontinued in 7 d and the patient did well. In laparoscopic sleeve gastrectomy the stomach is converted into a tube and is devoid of its supports. If the staples fired are not aligned appropriately, it can predispose this stomach tube to undergo torsion along its long axis. Such a twist can be avoided by properly aligning the staples and by placing tacking sutures to the omentum and new stomach tube. This twist is a functional obstruction rather than a stricture; thus, it can be managed by endoscopy and stent placement. PMID- 26649159 TI - Affective Visual Stimuli: Characterization of the Picture Sequences Impacts by Means of Nonlinear Approaches. AB - INTRODUCTION: The main objective of the present study was to investigate the effect of preceding pictorial stimulus on the emotional autonomic responses of the subsequent one. METHODS: To this effect, physiological signals, including Electrocardiogram (ECG), Pulse Rate (PR), and Galvanic Skin Response (GSR) were collected. As these signals have random and chaotic nature, nonlinear dynamics of these physiological signals were evaluated with the methods of nonlinear system theory. Considering the hypothesis that emotional responses are usually associated with previous experiences of a subject, the subjective ratings of 4 emotional states were also evaluated. Four nonlinear characteristics (including Detrended Fluctuation Analysis (DFA), based parameters, Lyapunov exponent, and approximate entropy) were implemented. Nine standard features (including mean, standard deviation, minimum, maximum, median, mode, the second, third, and fourth moment) were also extracted. RESULTS: To evaluate the ability of features in discriminating different types of emotions, some classification approaches were appraised, of them, Probabilistic Neural Network (PNN) led to the best classification rate of 100%. The results show that considering the emotional sequences, GSR is the best candidate for the representation of the physiological changes. DISCUSSION: Lower discrimination was attained when the sequence occurred in the diagonal line of valence-arousal coordinates (for instance, positive valence and positive arousal versus negative valence and negative arousal). By employing self-assessment ranks, no obvious improvement was achieved. PMID- 26649160 TI - Evaluation of Attention Bias in Morphine and Methamphetamine Abusers towards Emotional Scenes during Early Abstinence: An Eye-Tracking Study. AB - INTRODUCTION: We hypothesized that inappropriate attention during the period of abstinence in individuals with substance use disorder can result in an inadequate perception of emotion and unsuitable reaction to emotional scenes. The main aim of this research was to evaluate the attentional bias towards emotional images in former substance abusers and compare it to healthy adults. METHODS: Paired images of general scenes consisting of pleasant, unpleasant, and neutral images were presented to subjects for 3 s while their attentional bias and eye movements were measured by eye tracking. The participants were 72 male adults consisting of 23 healthy control, 24 morphine former abusers, and 25 methamphetamine former abusers. The former abusers were recruited from a private addiction quitting center and addiction rehabilitation campus. The healthy individuals were selected from general population. Number and duration of first fixation, duration of first gaze, and sustained attention towards emotional scenes were measured as the main variables and the data were analyzed using the repeated measures ANOVA. RESULTS: A significant difference was observed between former morphine abusers and healthy control in terms of number and duration of first fixations and first gaze duration towards pleasant images. DISCUSSION: Individuals with morphine use disorder have more problems with attending to emotional images compared to methamphetamine abusers and healthy people. PMID- 26649161 TI - Motor Learning and Movement Performance: Older versus Younger Adults. AB - INTRODUCTION: Motor skills play an important role during life span, and older adults need to learn or relearn these skills. The purpose of this study was to investigate how aging affects induction of improved movement performance by motor training. METHODS: Serial Reaction Time Test (SRTT) was used to assess movement performance during 8 blocks of motor training. Participants were tested in two separate dates, 48 hours apart. First session included 8 blocks of training (blocks 1-8) and second session comprised 2 blocks (blocks 9, 10). RESULTS: Analyses of data showed that reaction times in both online and offline learning were significantly shorter in older adults compared to younger adults (P<0.001). Young adults demonstrated both online and offline learning (P<0.001), but older adults only showed online learning (P<0.001) without offline learning (P=0.24). DISCUSSION: The result of the current study provides evidence that the healthy older adults are able to improve their performance with practice and learn motor skill successfully in the form of online learning. PMID- 26649162 TI - Effects of Memantine, an NMDA Antagonist, on Metabolic Syndromes in Female NMRI Mice. AB - INTRODUCTION: The brain glutamate neurotransmitter system and its NMDA (N-methyl D-aspartate) receptors in the nucleus accumbens play an important role in the incidence of sensitivity and addiction. The present study examined the inhibitory effect of glutamate NMDA receptors in the nucleus accumbens in response to chronic stress. METHODS: After the unilateral and bilateral placement of cannula(e) in the nucleus accumbens, one group of the animals received different doses of intra-accumbens memantine (0.1, 0.5 and 1 MUg/mouse) 5 minutes before receiving the electric shock stress at their soles (using a Communication Box) and the other group received intraperitoneal memantine (doses of 0.1, 0.5 and 1mg/kg) 30 minutes before receiving the same shock. Chronic stress increased the animals' weight, plasma corticosterone, food and water intake, but reduced their defecation rates and eating latency. RESULTS: The intraperitoneal administration of memantine increased plasma corticosterone, water intake, fecal weight, and eating latency, but had no effect on food intake or weight. The dose and site dependent intra-accumbens administration of memantine either exacerbated the effects of stress on plasma corticosterone levels, water and food intake, or had no effect on these parameters. Furthermore, the administration of memantine had no effect on animal's weight and inhibited the effects of stress on fecal weight and eating latency. DISCUSSION: The inhibition of glutamate NMDA receptors in the nucleus accumbens can inhibit and/or exacerbate the dose and site-dependent effects of chronic stress, and gender plays a significant role in producing this effect too. PMID- 26649163 TI - Successful Reconstruction of Nerve Defects Using Distraction Neurogenesis with a New Experimental Device. AB - INTRODUCTION: Repair of peripheral nerve injuries is an intensive area of challenge and research in modern reconstructive microsurgery. Intensive research is being carried out to develop effective alternatives to the standard nerve autografting, avoiding its drawbacks. The aim of the study was to evaluate the effectiveness of a newly designed mechanical device for the reconstruction of the sciatic nerve in rats in comparison to nerve autografting and to assess the pain during the period of distraction neurogenesis. METHODS: Fourteen Sprague Dawley rats were used and randomly assigned into 2 groups with 7 rats in each group; group A (Nerve Autografting group) in which a 10-mm segment of the sciatic nerve was resected and rotated 180 degrees, then primary end-to-end neurorrhaphy was performed in the reverse direction; group B (Nerve Lengthening group) in which the mechanical device was inserted after surgical resection of 10 mm of the sciatic nerve, then secondary end-to-end neurorrhaphy was performed after completing the nerve lengthening. Thirteen weeks later, assessment of the functional sciatic nerve recovery using static sciatic index (SSI) was performed. Furthermore, fourteen weeks after the nerve resection, assessment of the nerve regeneration with electrophysiological study and histological analysis were performed. Also, gastrocnemius wet weight was measured. For pain assessment in group B, Rat Grimace Scale (RGS) score was used. RESULTS: Significantly better functional recovery rate (using the SSI) was reported in the nerve lengthening group in comparison to autografting group. Also, a statistically significant higher nerve conduction velocity was detected in the nerve lengthening group. On histological analysis of the distal nerve section at 3 mm distal to the nerve repair site, significant myelin sheath thickness was detected in the nerve lengthening group. DISCUSSION: Distraction neurogenesis with the new experimental device is a reliable therapeutic method for the reconstruction of nerve defects. PMID- 26649164 TI - An fMRI Study of Risky Decision Making: The Role of Mental Preparation and Conflict. AB - INTRODUCTION: The current study aimed to elucidate the role of preparatory cognitive control in decision making and its neural correlates using functional Magnetic Resonance Imaging (fMRI). To this effect, by employing a series of new cognitive tasks, we assessed the role of preparatory cognitive control in monetary (risky) decision making. METHODS: The participants had to decide between a risky and a safe gamble based on their chance of winning (high or low). In the 2-phase gambling task (similar to Cambridge gambling task), the chance and the gamble were presented at the same time (i.e. in a single phase), but in a new 3 phase gambling task, the chance is presented before the gamble. The tasks ended with a feedback phase. RESULTS: In the 3-phase task, holding the chance in memory to guide their decision enabled the participants to have more control on their risk taking behaviors as shown by activation in a network of brain areas involved in the control and conflict, including dorsal Anterior Cingulate Cortex (dACC), indexed by faster reaction times and better performance in the gambling task, and the temporal lobe, which has a role in holding contextual information. DISCUSSION: Holding information in memory to guide decision presumably enables the participants to have more control on their risk taking behaviors. The conflict and uncertainty resulting from this risky decision was indexed by the activation of dACC, known to be activated in conflict and cognitive control. PMID- 26649166 TI - The Antinociceptive Effects of Hydroalcoholic Extract of Borago Officinalis Flower in Male Rats Using Formalin Test. AB - INTRODUCTION: Borago officinalis flower (borage) is a known sedative in herbal medicine; the aim of the present study was to evaluate the antinociceptive effect of borage hydroalcoholic extract in formalin test male rats. METHODS: Fifty-six adult male albino Wistar rats were randomly divided into seven groups: Control groups of A (intact), B (saline), and C (Positive control) plus test groups of D, E, F, and G (n=8). The groups D, E, and F received 6.25, 12.5, and 25 mg/kg, Borago officinalis flower hydroalcholic extract before the test, respectively but group G received 25 mg/kg borage extract and aspirin before the test. A biphasic pain was induced by injection of formalin 1%. The obtained data were analyzed by SPSS software ver. 17 employing statistical tests of Kruskal-Wallis and Mann Whitney. The results were expressed as mean+/-SD. Statistical differences were considered significant at P<0.05. RESULTS: The results revealed that the acute and chronic pain behavior score in test groups of D, E, F, and G significantly decreased compared to groups A and B, but this score did not show any difference compared to group C. Moreover, chronic pain behavior score in group G was significantly lower than all other groups. DISCUSSION: The results indicated that Borago officinalis hydroalcoholic extract affects the acute and chronic pain behavior response in formaline test male rats. PMID- 26649165 TI - Exploring Neural Correlates of Different Dimensions in Drug Craving Self-Reports among Heroin Dependents. AB - INTRODUCTION: Drug craving could be described as a motivational state which drives drug dependents towards drug seeking and use. Different types of self reports such as craving feeling, desire and intention, wanting and need, imagery of use, and negative affect have been attributed to this motivational state. By using subjective self-reports for different correlates of drug craving along with functional neuroimaging with cue exposure paradigm, we investigated the brain regions that could correspond to different dimensions of subjective reports for heroin craving. METHODS: A total of 25 crystalline-heroin smokers underwent functional magnetic resonance imaging (fMRI), while viewing heroin-related and neutral cues presented in a block-design task. During trial intervals, subjects verbally reported their subjective feeling of cue induced craving (CIC). After fMRI procedure, participants reported the intensity of their "need for drug use" and "drug use imagination" on a 0-100 visual analog scale (VAS). Afterwards, they completed positive and negative affect scale (PANAS) and desire for drug questionnaire (DDQ) with 3 components of "desire and intention to drug use," "negative reinforcement," and "loss of control." RESULTS: The study showed significant correlation between "subjective feeling of craving" and activation of the left and right anterior cingulate cortex, as well as right medial frontal gyrus. Furthermore, the "desire and intention to drug use" was correlated with activation of the left precentral gyrus, left superior frontal gyrus, and left middle frontal gyrus. Subjects also exhibited significant correlation between the "need for drug use" and activation of the right inferior temporal gyrus, right middle temporal gyrus, and right parahippocampal gyrus. Correlation between subjective report of "heroin use imagination" and activation of the cerebellar vermis was also observed. Another significant correlation was between the "negative affect" and activation of the left precuneus, right putamen, and right middle temporal gyrus. DISCUSSION: This preliminary study proposes different neural correlates for various dimensions of subjective craving self-reports. It could reflect multidimensionality of cognitive functions corresponding with drug craving. These cognitive functions could represent their motivational and affective outcomes in a single item "subjective craving feeling" or in self reports with multiple dissociable items, such as intention, need, imagination, or negative feeling. The new psychological models of drug craving for covering various dimensions of subjective craving self-reports based on their neurocognitive correspondence could potentially modify craving assessments in addiction medicine. PMID- 26649167 TI - NEuro COgnitive REhabilitation for Disease of Addiction (NECOREDA) Program: From Development to Trial. AB - Despite extensive evidence for cognitive deficits associated with drug use and multiple publications supporting the efficacy of cognitive rehabilitation treatment (CRT) services for drug addictions, there are a few well-structured tools and organized programs to improve cognitive abilities in substance users. Most published studies on cognitive rehabilitation for drug dependent patients used rehabilitation tools, which have been previously designed for other types of brain injuries such as schizophrenia or traumatic brain injuries and not specifically designed for drug dependent patients. These studies also suffer from small sample size, lack of follow-up period assessments and or comprehensive treatment outcome measures. To address these limitations, we decided to develop and investigate the efficacy of a paper and pencil cognitive rehabilitation package called NECOREDA (Neurocognitive Rehabilitation for Disease of Addiction) to improve neurocognitive deficits associated with drug dependence particularly caused by stimulants (e.g. amphetamine type stimulants and cocaine) and opiates. To evaluate the feasibility of NECOREDA program, we conducted a pilot study with 10 opiate and methamphetamine dependent patients for 3 months in outpatient setting. NECOREDA was revised based on qualitative comments received from clients and treatment providers. Final version of NECOREDA is composed of brain training exercises called "Brain Gym" and psychoeducational modules called "Brain Treasures" which is implemented in 16 training sessions interleaved with 16 review and practice sessions. NECOREDA will be evaluated as an add-on intervention to methadone maintenance treatment in a randomized clinical trial among opiate dependent patients starting from August 2015. We discuss methodological features of NECOREDA development and evaluation in this article. PMID- 26649168 TI - Case Report: Combination Therapy with Mesenchymal Stem Cells and Granulocyte Colony Stimulating Factor in a Case of Spinal Cord Injury. AB - INTRODUCTION: Various neuroregenerative procedures have been recently employed along with neurorehabilitation programs to promote neurological function after Spinal Cord Injury (SCI), and recently most of them have focused on the acute stage of spinal cord injury. In this report, we present a case of acute SCI treated with neuroprotective treatments in conjunction with conventional rehabilitation program. METHODS: A case of acute penetrative SCI (gunshot wound), 40 years old, was treated with intrathecal bone marrow derived stem cells and parenteral Granulocyte-Colony Stimulating Factor (G-CSF) along with rehabilitation program. The neurological outcomes as well as safety issues have been reported. RESULTS: Assessment with American Spinal Injury Association (ASIA), showed neurological improvement, meanwhile he reported neuropathic pain, which was amenable to oral medication. DISCUSSION: In the acute setting, combination therapy of G-CSF and intrathecal Mesenchymal Stem Cells (MSCs) was safe in our case as an adjunct to conventional rehabilitation programs. Further controlled studies are needed to find possible side effects, and establish net efficacy. PMID- 26649169 TI - A new design of a lentiviral shRNA vector with inducible co-expression of ARGONAUTE 2 for enhancing gene silencing efficiency. AB - BACKGROUND: RNA interference (RNAi) is a robust tool for inhibiting specific gene expression, but it is limited by the uncertain efficiency of siRNA or shRNA constructs. It has been shown that the overexpression of ARGONAUTE 2 (AGO2) protein increases silencing efficiency. However, the key elements required for AGO2-mediated enhancement of gene silencing in lentiviral vector has not been well studied. RESULTS: To explore the application of AGO2-based shRNA system in mammalian cells, we designed shRNA vectors targeting the EGFP reporter gene and evaluated the effects of various factors on silencing efficiency including stem length, loop sequence, antisense location as well as the ratio between AGO2 and shRNA. We found that 19 ~ 21-bp stem and 6- or 9-nt loop structure in the sense loop-antisense (S-L-AS) orientation was an optimal design in the AGO2-shRNA system. Then, we constructed a single lentiviral vector co-expressing shRNA and AGO2 and demonstrated that the simultaneous expression of shRNA and AGO2 can achieve robust silencing of exogenous DsRed2 and endogenous ID1 and P65 genes. However, the titers of packaged lentivirus from constitutive expression of AGO2 vector were extremely low, severely limiting its broad application. For the first time, we demonstrated that the problem can be significantly improved by using the inducible expression of AGO2 lentiviral system. CONCLUSIONS: We reported a novel lentiviral vector with an optimal design of shRNA and inducible AGO2 overexpression which provides a new tool for RNAi research. PMID- 25949807 TI - Behavioural evidence for self-medication in bumblebees? AB - The presence of antimicrobial secondary metabolites in nectar suggests that pollinators, which are threatened globally by emergent disease, may benefit from the consumption of nectars rich in these metabolites. We tested whether nicotine, a nectar secondary metabolite common in Solanaceae and Tilia species, is used by parasitized bumblebees as a source of self-medication , using a series of toxicological, microbiological and behavioural experiments. Caged bees infected with Crithidia bombi had a slight preference for sucrose solution laced with the alkaloid and behavioural tests showed that the parasite infection induced an increased consumption of nicotine during foraging activity, though nicotine had an appetite-reducing effect overall. When ingested, nicotine delayed the progression of a gut infection in bumblebees by a few days, but dietary nicotine did not clear the infection, and after 10 days the parasite load approached that of control bees. Moreover, when pathogens were exposed to the alkaloid prior to host ingestion, the protozoan's viability was not directly affected, suggesting that anti-parasite effects were relatively weak. Nicotine consumption in a single dose did not impose any cost even in starved bees but the alkaloid had detrimental effects on healthy bees if consistently consumed for weeks. These toxic effects disappeared in infected bees, suggesting that detoxification costs might have been counterbalanced by the advantages in slowing the progression of the infection. Nicotine consumption did not affect bee lifespan but the reduction in the parasite load may have other likely unexplored subtle benefits both for individual bees and their colony. Potential evidence for self-medication is discussed. The contention that secondary metabolites in nectar may be under selection from pollinators, or used by plants to enhance their own reproductive success, remains to be confirmed. PMID- 26649171 TI - Prevalence of schizophrenia in China between 1990 and 2010. AB - BACKGROUND: Dramatic development and changes in lifestyle in many low and middle income countries (LMIC) over the past three decades may have affected mental health of their populations. Being the largest country and having the most striking record of development, industrialization and urbanization, China provides an important opportunity for studying the nature and magnitude of possible effects. METHODS: We reviewed CNKI, WanFang and PubMed databases for epidemiological studies of schizophrenia in mainland China published between 1990 and 2010. We identified 42 studies that reported schizophrenia prevalence using internationally recognized diagnostic criteria, with breakdown by rural and urban residency. The analysis involved a total of 2 284 957 persons, with 10 506 diagnosed with schizophrenia. Bayesian methods were used to estimate the probability of case of schizophrenia ("prevalence") by type of residency in different years. FINDINGS: In urban China, lifetime prevalence was 0.39% (0.37 0.41%) in 1990, 0.57% (0.55-0.59%) in 2000 and 0.83% (0.75-0.91%) in 2010. In rural areas, the corresponding rates were 0.37% (0.34-0.40%), 0.43% (0.42-0.44%) and 0.50% (0.47-0.53%). In 1990 there were 3.09 (2.87-3.32) million people in China affected with schizophrenia during their lifetime. The number of cases rose to 7.16 (6.57-7.75) million in 2010, a 132% increase, while the total population increased by 18%. The contribution of cases from urban areas to the overall burden increased from 27% in 1990 to 62% in 2010. CONCLUSIONS: The prevalence of schizophrenia in China has more than doubled between 1990 and 2010, with rates being particularly high in the most developed areas of modern China. This has broad implications, as the ongoing development in LMIC countries may be increasing the global prevalence of schizophrenia. PMID- 26649172 TI - Evaluation of case definitions for estimation of respiratory syncytial virus associated hospitalizations among children in a rural community of northern India. AB - BACKGROUND: The burden estimation studies for respiratory syncytial virus (RSV) have been based on varied case definitions, including case-definitions designed for influenza surveillance systems. We used all medical admissions among children aged 0-59 months to study the effect of case definitions on estimation of RSV associated hospitalizations rates. METHODS: The hospital-based daily surveillance enrolled children aged 0-59 months admitted with acute medical conditions from July 2009-December 2012, from a well-defined rural population in Ballabgarh in northern India. All study participants were examined and nasal and throat swabs taken for testing by real-time polymerase chain reaction (RT-PCR) for RSV and influenza virus. Clinical data were used to retrospectively evaluate World Health Organization (WHO) case definitions (2011) commonly used for surveillance of respiratory pathogens, ie, acute respiratory illness (WHO-ARI), severe ARI (SARI) and influenza-like illness (ILI), for determination of RSV-associated hospitalization. RSV-associated hospitalization rates adjusted for admissions at non-study hospitals were calculated. FINDINGS: Out of 505 children enrolled, 82 (16.2%) tested positive for RSV. Annual incidence rates of RSV-associated hospitalization per 1000 children were highest among infants aged 0-5 months (15.2; 95% confidence interval (CI) 8.3-26.8), followed by ages 6-23 months (5.3, 95% CI 3.2-8.7) and lowest among children 24-59 months (0.5, 95% CI 0.1-1.5). The RSV positive children were more likely to have signs of respiratory distress like wheeze, chest in-drawing, tachypnea, and crepitation compared to RSV-negative based on bivariate comparisons. Other less commonly seen signs of respiratory distress, ie, nasal flaring, grunting, accessory muscle usage were also significantly associated with being RSV positive. Compared to the estimated RSV hospitalization rate based on all medical hospitalizations, the WHO-ARI case definition captured 86% of the total incidence, while case definitions requiring fever like ILI and SARI underestimated the incidence by 50-80%. CONCLUSIONS: Our study suggests that RSV is a substantial cause of hospitalization among children aged <24months especially those aged <6 months. The WHO-ARI case definition appeared to be the most suitable screening definition for RSV surveillance because of its high sensitivity. PMID- 26649173 TI - Association between depression and diabetes amongst adults in Bangladesh: a hospital based case-control study. AB - METHODS: A matched case-control study was conducted among 591 consecutive patients with diabetes attending a tertiary hospital in Dhaka and 591 controls matched for age, sex and area of residence without diabetes not related with the index-case. Depression was measured using the Patient Health Questionnaire-9. Multivariate logistic regression was performed to examine the association between depression and diabetes. RESULTS: The mean age (+/-standard deviation) of the participants was 50.4 +/- 11.4 years, with a male to female ratio of 43:57. The prevalence of depression was 45.2% and 19.8% among cases and controls, respectively. In the multivariate analysis, mild as well as moderate to severe depression were significantly associated with diabetes and independent of sociodemographic factors and co-morbidity (adjusted odds ratio (OR) = 2.0, 95% confidence interval (CI) = 1.4-2.9 and adjusted OR = 6.4, 95% CI = 3.4-12.3; P < 0.001 for both). CONCLUSION: The high prevalence and strong association of depression in individuals with diabetes in Bangladesh suggests that depression should be routinely screened for patients with diabetes at the clinics and that management strategies adequate for resource-poor settings need to be developed. Further research to determine the pathophysiological role of depression in the development of diabetes is merited. PMID- 26649174 TI - Systematic review of the global epidemiology, clinical and laboratory profile of enteric fever. AB - BACKGROUND: Children suffer the highest burden of enteric fever among populations in South Asian countries. The clinical features are non-specific, vary in populations, and are often difficult to distinguish clinically from other febrile illnesses, leading to delayed or inappropriate diagnosis and treatment. We undertook a systematic review to assess the clinical profile and laboratory features of enteric fever across age groups, economic regions, level of care and antibiotic susceptibility patterns. METHODS: We searched PubMed (January 1964 December 2013) for studies describing clinical features in defined cohorts of patients over varying time periods. Studies with all culture-confirmed cases or those with at least 50% culture-confirmed cases were included. 242 reports were screened out of 4398 relevant articles and 180 reports were included for final review. RESULTS: 96% of studies were from an urban location, 96% were hospital based studies, with 41% of studies were from South Asia. Common clinical features in hospitalized children include high-grade fever, coated tongue, anaemia, nausea/vomiting, diarrhea, constipation, hepatomegaly, splenomegaly neutrophilia, abdominal distension and GI bleeding. In adults' nausea/vomiting, thrombocytopenia and GI perforation predominate. The case-fatality rate in children under 5 years is higher than school aged children and adolescents, and is highest in Sub Saharan Africa and North Africa/Middle East regions. Multi-drug resistant enteric fever has higher rates of complications than drug sensitive enteric fever, but case fatality rates were comparable in both. CONCLUSIONS: Our findings indicate variability in disease presentation in adults compared to children, in different regions and in resistant vs sensitive cases. Majority of studies are from hospitalized cases, and are not disaggregated by age. Despite higher complications in MDR enteric fever, case fatality rate is comparable to sensitive cases, with an overall hospital based CFR of 2%, which is similar to recent global estimates. This review underscores the importance of further epidemiological studies in community settings among children and adults, and the need for further preventable measures to curtail the burden of disease. PMID- 26649175 TI - Adherence to zinc supplementation guidelines for the treatment of diarrhea among children under-five in Uttar Pradesh, India. AB - BACKGROUND: There is limited evidence on adherence to the recommended dose and duration of zinc supplementation for diarrheal episodes in children under five years of age. In selected districts of Uttar Pradesh, India, we sought to assess adherence to the nationally advised zinc treatment regimen (ie, 10 mg/day for ages 2-6 months and 20 mg/day for ages 7-59 months for 14 days) among caregivers of zinc-prescribed children. METHODS: We identified and conducted follow-up visits to children advised zinc for the treatment of diarrhea. At the initial visit, we collected data on the treatment instructions received from providers. Caregivers were asked to record treatments administered on a pictorial tracking form and were asked to retain all packaging for collection at follow-up. We quantified the average dose and duration of zinc therapy and built logistic regression models to assess the factors associated with caregiver adherence to national guidelines. RESULTS: Caregivers administered zinc for an average of 10.7 days (standard deviation (SD) = 3.9 days; median = 13 days), and 47.8% continued treatment for the complete 14 days. Among children receiving zinc syrups and tablets respectively, the age appropriate dose was received by 30.8% and 67.3%. Adherence to age appropriate dose and continuation of zinc for 14 days were highly associated with having received appropriate provider instructions. CONCLUSIONS: Our results indicate moderate-to-good adherence to national zinc treatment guidelines for diarrhea among caregivers in rural India. Our findings also highlight the importance of provider guidance in ensuring adherence to zinc dose and duration. Programs aiming to scale-up zinc treatment for childhood diarrhea should train providers to successfully communicate dosing instructions to caregivers, while also addressing the tendency of caregivers to terminate treatment once a child appears to have recovered from an acute diarrheal episode. PMID- 26649176 TI - Assessment of Malawi's success in child mortality reduction through the lens of the Catalytic Initiative Integrated Health Systems Strengthening programme: Retrospective evaluation. AB - BACKGROUND: Malawi is estimated to have achieved its Millennium Development Goal (MDG) 4 target. This paper explores factors influencing progress in child survival in Malawi including coverage of interventions and the role of key national policies. METHODS: We performed a retrospective evaluation of the Catalytic Initiative (CI) programme of support (2007-2013). We developed estimates of child mortality using four population household surveys undertaken between 2000 and 2010. We recalculated coverage indicators for high impact child health interventions and documented child health programmes and policies. The Lives Saved Tool (LiST) was used to estimate child lives saved in 2013. RESULTS: The mortality rate in children under 5 years decreased rapidly in the 10 CI districts from 219 deaths per 1000 live births (95% confidence interval (CI) 189 to 249) in the period 1991-1995 to 119 deaths (95% CI 105 to 132) in the period 2006-2010. Coverage for all indicators except vitamin A supplementation increased in the 10 CI districts across the time period 2000 to 2013. The LiST analysis estimates that there were 10 800 child deaths averted in the 10 CI districts in 2013, primarily attributable to the introduction of the pneumococcal vaccine (24%) and increased household coverage of insecticide-treated bednets (19%). These improvements have taken place within a context of investment in child health policies and scale up of integrated community case management of childhood illnesses. CONCLUSIONS: Malawi provides a strong example for countries in sub Saharan Africa of how high impact child health interventions implemented within a decentralised health system with an established community-based delivery platform, can lead to significant reductions in child mortality. PMID- 26649177 TI - Effectiveness of mHealth interventions for maternal, newborn and child health in low- and middle-income countries: Systematic review and meta-analysis. AB - OBJECTIVE: To assess the effectiveness of mHealth interventions for maternal, newborn and child health (MNCH) in low- and middle-income countries (LMIC). METHODS: 16 online international databases were searched to identify studies evaluating the impact of mHealth interventions on MNCH outcomes in LMIC, between January 1990 and May 2014. Comparable studies were included in a random-effects meta-analysis. FINDINGS: Of 8593 unique references screened after de-duplication, 15 research articles and two conference abstracts met inclusion criteria, including 12 intervention and three observational studies. Only two studies were graded at low risk of bias. Only one study demonstrated an improvement in morbidity or mortality, specifically decreased risk of perinatal death in children of mothers who received SMS support during pregnancy, compared with routine prenatal care. Meta-analysis of three studies on infant feeding showed that prenatal interventions using SMS/cell phone (vs routine care) improved rates of breastfeeding (BF) within one hour after birth (odds ratio (OR) 2.01, 95% confidence interval (CI) 1.27-2.75, I(2) = 80.9%) and exclusive BF for three/four months (OR 1.88, 95% CI 1.26-2.50, I(2) = 52.8%) and for six months (OR 2.57, 95% CI 1.46-3.68, I(2) = 0.0%). Included studies encompassed interventions designed for health information delivery (n = 6); reminders (n = 3); communication (n = 2); data collection (n = 2); test result turnaround (n = 2); peer group support (n = 2) and psychological intervention (n = 1). CONCLUSIONS: Most studies of mHealth for MNCH in LMIC are of poor methodological quality and few have evaluated impacts on patient outcomes. Improvements in intermediate outcomes have nevertheless been reported in many studies and there is modest evidence that interventions delivered via SMS messaging can improve infant feeding. Ambiguous descriptions of interventions and their mechanisms of impact present difficulties for interpretation and replication. Rigorous studies with potential to offer clearer evidence are underway. PMID- 26649178 TI - Implicitly assessed attitudes toward body shape and food: the moderating roles of dietary restraint and disinhibition. AB - BACKGROUND: Attitudes toward body shape and food play a role in the development and maintenance of dysfunctional eating behaviors. Nevertheless, they are rarely investigated together. Therefore, this study aimed to explore the interrelationships between implicitly assessed attitudes toward body shape and food and to investigate the moderating effect on these associations of interindividual differences in problematic and nonproblematic eating behaviors (i.e., flexible versus rigid cognitive control dimension of restraint, disinhibition). METHODS: One hundred and twenty-one young women from the community completed two adapted versions of the Affect Misattribution Procedure to implicitly assess attitudes toward body shape (i.e., thin and overweight bodies) and food (i.e., "permitted" and "forbidden" foods), as well as the Three Factor Eating Questionnaire to evaluate restraint and disinhibition. RESULTS: The results revealed that an implicit preference for thinness was positively associated with a positive attitude toward permitted (i.e., low-calorie) foods. This congruence between implicitly assessed attitudes toward body shape and food was significant at average and high levels of flexible control (i.e., functional component of eating). Moreover, an implicit preference for thinness was also positively associated with a positive attitude toward forbidden (i.e., high calorie) foods. This discordance between implicitly assessed attitudes was significant at average and high levels of rigid control and disinhibition (i.e., dysfunctional components of eating). CONCLUSIONS: These findings shed new light on the influence of congruent or discordant implicitly assessed attitudes toward body shape and food on normal and problematic eating behaviors; clinical implications are discussed. PMID- 26649179 TI - A case of severe ectopic ACTH syndrome from an occult primary - diagnostic and management dilemmas. AB - Resection of primary tumour is the management of choice in patients with ectopic ACTH syndrome. However, tumours may remain unidentified or occult in spite of extensive efforts at trying to locate them. This can, therefore, pose a major management issue as uncontrolled hypercortisolaemia can lead to life-threatening infections. We present the case of a 66-year-old gentleman with ectopic ACTH syndrome from an occult primary tumour with multiple significant complications from hypercortisolaemia. Ectopic nature of his ACTH-dependent Cushing's syndrome was confirmed by non-suppression with high-dose dexamethasone suppression test and bilateral inferior petrosal sinus sampling. The primary ectopic source remained unidentified in spite of extensive anatomical and functional imaging studies, including CT scans and Dotatate-PET scan. Medical adrenolytic treatment at maximum tolerated doses failed to control his hypercortisolaemia, which led to recurrent intra-abdominal and pelvic abscesses, requiring multiple surgical interventions. Laparoscopic bilateral adrenalectomy was considered but decided against given concerns of technical difficulties due to recurrent intra-abdominal infections and his moribund state. Eventually, alcohol ablation of adrenal glands by retrograde adrenal vein approach was attempted, which resulted in biochemical remission of Cushing's syndrome. Our case emphasizes the importance of aggressive management of hypercortisolaemia in order to reduce the associated morbidity and mortality and also demonstrates that techniques like percutaneous adrenal ablation using a retrograde venous approach may be extremely helpful in patients who are otherwise unable to undergo bilateral adrenalectomy. LEARNING POINTS: Evaluation and management of patients with ectopic ACTH syndrome from an unidentified primary tumour can be very challenging.Persisting hypercortisolaemia in this setting can lead to debilitating and even life-threatening complications and hence needs to be managed aggressively.Bilateral adrenalectomy should be considered when medical treatment is ineffective or poorly tolerated.Percutaneous adrenal ablation may be considered in patients who are otherwise unable to undergo bilateral adrenalectomy. PMID- 26649180 TI - First case of Francisella bacteraemia in Western Australia. AB - Francisella species are Gram-negative, nonmotile, pleomorphic coccobacilli, facultative intracellular fastidious bacteria. We report the isolation of a Francisella-like species from a blood culture collected from a 44-year-old bacteraemic patient in Perth, Western Australia. The organism was identified to species level by 16S rRNA sequencing and by fatty acid methyl esters analysis. The strain genotypically resembled Francisella hispaniensis, a species previously isolated from human blood in Spain. PMID- 26649181 TI - Noncontiguous finished genome sequence and description of Virgibacillus massiliensis sp. nov., a moderately halophilic bacterium isolated from human gut. AB - Strain Vm-5(T) was isolated from the stool specimen of a 10-year-old Amazonian boy. This bacterium is a Gram-positive, strictly aerobic rod, motile by a polar flagellum. Here we describe its phenotypic characteristics and complete genome sequence. The 4 353 177 bp long genome exhibits a G + C content of 36.87% and contains 4394 protein-coding and 125 predicted RNA genes. Phylogenetically and genetically, strain Vm-c is a member of the genus Virgibacillus but is distinct enough to be classified as a new species. We propose the creation of V. massiliensis sp. nov., whose type strain is strain Vm-5(T) (CSUR P971 = DSM 28587). PMID- 26649182 TI - Noncontiguous finished genome sequence and description of Weeksella massiliensis sp. nov. AB - Strain FF8(T) (= CSUR P860 = DSM 28259) was isolated in Dakar, Senegal, from the urine of a 65-year-old man with acute cystitis. This strain shows a similarity of sequence of 16S rRNA of 98.38% with Weeksella virosa, and its GenBank accession numbers are HG931340 and CCMH00000000. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry analysis had a poor score, ranging from 1.32 to 1.56, that did not allow identification of the bacterium. Using a polyphasic study made of phenotypic and genomic analyses, strain FF8(T) was a Gram-negative, aerobic rod and a member of the family Flavobacteriaceae. The sequenced genome is 2 562 781 bp with one chromosome but no plasmid. It exhibits a G + C content of 35.9% and contains 2390 protein-coding and 56 RNA genes, including a complete rRNA operon. On the basis of these data, we propose the creation of Weeksella massiliensis sp. nov. PMID- 26649183 TI - Clostridium difficile infections among adults and children in Mwanza/Tanzania: is it an underappreciated pathogen among immunocompromised patients in sub-Saharan Africa? AB - Little is known regarding the epidemiology Clostridium difficile in developing countries. Fresh stool samples from patients with diarrhoea were cultured anaerobically. C. difficile was detected in nine (6.4%) of 141 (95% confidence interval 4.2-13.1), of which seven (77.8%) were from children. HIV infection, prolonged hospitalization and antibiotic use were independent factors associated with the occurrence of C. difficile in the gastrointestinal tract. Two of the toxigenic isolates were typed as ribotype 045, and the other two had unknown ribotype. All C. difficile isolates were susceptible to metronidazole, moxifloxacin and clarithromycin, while three isolates were resistant to clarithromycin. C. difficile may be an important pathogen causing diarrhoea in sub-Saharan Africa among immunocompromised patients. PMID- 26649184 TI - Resistance and integron characterization of Acinetobacter baumannii in a teaching hospital in Chongqing, China. AB - A total of 189 Acinetobacter baumannii isolates were collected in 2011 from a teaching hospital in Chongqing, China. Susceptibility data showed strains carrying integrons were significantly more resistant to all tested antibiotics that strains lacking integrons. Five types of gene cassettes belonging to class I integrons were identified in this study, and for the first time two types of gene cassettes belonging to class II integrons are reported. Most of the cassettes belong to a class I integron (136/144) encoding arr3, aacA4, dfrA17, aadA5, aadB, cat, blaOXA10 , aadA1, aadA2, dfrA and aacC1. Isolates contained a class I gene cassette; AadA2-HP-dfrA was the prevalent strain in this hospital. A class II integron was detected in eight strains, which contained the type IV fimbriae expression regulatory gene pilR and sulfate adenylyltransferase, suggesting a possible role in multidrug resistance. The major epidemic strains from intensive care unit patients belong to international clone 2. In conclusion, the presence of integrons was significantly associated with multiple drug resistance of A. baumannii in this hospital, and class I integron isolates bearing AadA2-HP-dfrA were the prevalent strain in this hospital. PMID- 26649185 TI - Complementary therapy and survival in glioblastoma. AB - BACKGROUND: Complementary therapy (CAM) is common in cancer patients. We undertook this study to assess the association of complementary therapy usage with mortality in glioblastoma (GBM) patients. METHODS: The analysis was based on 470 patients. Information on current use of CAM was collected in structured interviews conducted a median of 6 weeks following GBM diagnosis. Proportional hazards regression was used to estimate hazard ratios (HRs) for GBM-related death according to the use of individual supplements with multivariate adjustment for known prognostic factors including age, KPS, and extent of tumor resection (ESR). RESULTS: Use of CAM agents was common, with 77% of the cohort reporting CAM usage. No mortality association was observed with the use of multivitamins (HR = 0.91; P = .40) or omega-3 fatty acids (HR = 1.07; P = .69). Patients taking vitamin D as an individual supplement (containing higher dosages than in a multivitamin) had reduced mortality when compared with nonusers (age-adjusted HR = 0.68; P = .02). However, the association was diminished after adjustment for KPS and ESR (HR = 0.74; P = .09). Use of herbal supplements was also associated with reduced mortality (HR = 0.58; P = .04). Vitamin E users had a nonsignificantly higher mortality when compared with nonusers (HR = 1.54; P = .09). CONCLUSIONS: Use of CAM is common in GBM patients. These exploratory analyses suggest no mortality association with the use of multivitamins or omega 3 fatty acids. Associations observed with vitamins D and E merit further investigation. PMID- 26649186 TI - Glycemic modulation in neuro-oncology: experience and future directions using a modified Atkins diet for high-grade brain tumors. AB - Dietary glycemic modulation through high-fat, low-carbohydrate diets, which induce a state of systemic ketosis and alter systemic metabolic signaling, have been incorporated into the clinical management of patients with neurological disease for more than a century. Mounting preclinical evidence supports the antitumor, proapoptotic, and antiangiogenic effects of disrupting glycolytic metabolism through dietary intervention. In recent years, interest in incorporating such novel therapeutic strategies in neuro-oncology has increased. To date, 3 published studies incorporating novel dietary therapies in oncology have been reported, including one phase I study in neuro-oncology, and have set the stage for further study in this field. In this article, we review the biochemical pathways, preclinical data, and early clinical translation of dietary interventions that modulate systemic glycolytic metabolism in the management of primary malignant brain tumors. We introduce the modified Atkins diet (MAD), a novel dietary alternative to the classic ketogenic diet, and discuss the critical issues facing future study. PMID- 26649187 TI - A model for germ cell development in a fully segmented worm. AB - INTRODUCTION: Polychaetes are segmented marine worms with body segments separated by a complete or incomplete septum. In most polychaetes the whole body cavity is filled with gametes during the breeding season. Platynereis dumerilii (Pl. dumerilii), which has an incomplete septum was shown to develop a single gonadal structure for gamete production located in the neck region. However, in Perinereis nuntia (Pe. nuntia), which has a complete septum separating each segment, the developmental feature of gametes remains unknown. To clarify this, the marker gene vasa was used to trace the development of germ cells throughout the life stages of Pe. nuntia. RESULTS: In three-segmented juveniles, Pn-vasa was expressed in the parapodia and in the two cells localized in the pygidium. During the addition of a new segment, Pn-vasa positive cells in the pygidium increased from two to four and two new Pn-vasa positive cells were found in the newly generated segment. In adults, Pn-vasa was expressed in a large cell cluster at the distal end of the parapodia, in smaller cell clusters (which had an elongated form in the trunk area of the parapodia), and in oocytes in the coelomic cavity. This may suggest that germ cells settle in the parapodia and later translocate into the coelomic cavity to develop into oocytes. CONCLUSION: Our observations will help in understanding the mechanism of germ cell development in all body segments of Pe. nuntia. We hypothesize that primordial germ cells are supplied from the pygidium to every newly-generating segment which later settle in the parapodium. This will explain how polychaetes can generate gametes in each body segment, even those that are independently separated with a complete septum. PMID- 26649188 TI - Suppressive effects of dRYamides on feeding behavior of the blowfly, Phormia regina. AB - Recently, dRYamides-1 and -2 have been identified as ligands of the neuropeptide Y-like receptor CG5811 in Drosophila melanogaster. It has also been reported in brief that injection of dRYamide-1suppresses the early feeding behavior called proboscis extension reflex (PER) in the blowfly Phormia regina. Immunohistochemical analyses by our group using anti-dRYamide-1 antiserum indicated symmetrical localization of 32 immunoreactive cells in the brain of P. regina. In order to analyze the mechanism of feeding regulation, we further investigated the effects of dRYamide-1 and -2 on intake volume, PER exhibition, and activity of the sugar receptor neuron. After injection of dRYamide-1 or -2, flies showed little change in the intake volume of sucrose solution, but a significant depression of PER to sucrose. Injection of dRYamide-1 revealed a significant decrease in the responsiveness of the sugar receptor neuron, although the injection of dRYamide-2 did not. These results suggest that the dRYamide peptides decrease feeding motivation in flies, as evaluated by PER threshold, through a mechanism that partially involves desensitization of the sugar receptor neuron. PMID- 26649189 TI - Psychosocial Status of Liver Transplant Candidates in Iran and Its Correlation with Health-Related Quality of Life and Depression and Anxiety. AB - Objectives. The study was aimed at providing a psychosocial profile for Iranian liver transplant candidates referred to an established liver transplantation program. Material and Methods. Patients assessed for liver transplant candidacy in Imam Khomeini Hospital (Tehran, Iran) between March 2013 and September 2014 were included. The following battery of tests were administered: Psychosocial Assessment of Candidates for Transplant (PACT), the Short-Form health survey (SF 36), and Hospital Anxiety and Depression Scale (HADS). Results. Psychosocial assessment in 205 liver transplant candidates revealed significant impairments in several SF-36 domains; social functioning was the least and physical functioning was the most impaired domains. The prevalence of cases with probable anxiety and depressive disorders, according to HADS, was 13.8% and 5.6%, respectively. According to PACT, 24.3% of the assessed individuals were considered good or excellent candidates. In 11.2%, transplantation seemed poor candidate due to at least one major psychosocial or lifestyle risk factor. Poor candidate quality was associated with impaired health-related quality of life and higher scores on anxiety and depression scales (p < 0.05). Conclusions. Transplant programs could implement specific intervention programs based on normative databases to address the psychosocial issues in patients in order to improve patient care, quality of life, and transplant outcomes. PMID- 26649190 TI - Dry Eye Disease following Refractive Surgery: A 12-Month Follow-Up of SMILE versus FS-LASIK in High Myopia. AB - Purpose. To compare dry eye disease following SMILE versus FS-LASIK. Design. Prospective, nonrandomised, observational study. Patients. 90 patients undergoing refractive surgery for myopia were included. 47 eyes underwent SMILE and 43 eyes underwent FS-LASIK. Methods. Evaluation of dry eye disease was conducted preoperatively and at 1, 3, 6, and 12 months postoperatively, using the Salisbury Eye Evaluation Questionnaire (SEEQ) and TBUT. Results. TBUT reduced following SMILE at 1 and 3 months (p < 0.001) and at 1, 3, and 6 months following FS-LASIK (p < 0.001). TBUT was greater following SMILE than FS-LASIK at 3, 6, and 12 months (p < 0.001, p < 0.001, and p = 0.009, resp.). SEEQ scores increased (greater symptoms) following SMILE at 1 month (p < 0.001) and 3 months (p = 0.003) and at 1, 3, and 6 months following FS-LASIK (p < 0.001). SMILE produced lower SEEQ scores (fewer symptoms) than FS-LASIK at 1, 3, and 6 months (p < 0.001). Conclusion. SMILE produces less dry eye disease than FS-LASIK at 6 months postoperatively but demonstrates similar degrees of dry eye disease at 12 months. PMID- 26649191 TI - Evaluation of Retinal Nerve Fiber Layer and Ganglion Cell Complex in Patients with Optic Neuritis or Neuromyelitis Optica Spectrum Disorders Using Optical Coherence Tomography in a Chinese Cohort. AB - We evaluate a cohort of optic neuritis and neuromyelitis optica (NMO) spectrum disorders patients in a territory hospital in China. The peripapillary retinal nerve fiber layer (RNFL) and macular ganglion cell complex (GCC) were measured using spectral-domain OCT after 6 months of acute onset. The results showed that both the peripapillary RNFL and macular GCC were significantly thinner in all optic neuritis subtypes compared to controls. In addition, the recurrent optic neuritis and NMO groups showed more severe damage on the RNFL and GCC pattern. PMID- 26649193 TI - Pregnant and Postpartum Women's Experiences and Perspectives on the Acceptability and Feasibility of Copackaged Medicine for Antenatal Care and PMTCT in Lesotho. AB - Objective. To improve PMTCT and antenatal care-related service delivery, a pack with centrally prepackaged medicine was rolled out to all pregnant women in Lesotho in 2011. This study assessed acceptability and feasibility of this copackaging mechanism for drug delivery among pregnant and postpartum women. Methods. Acceptability and feasibility were assessed in a mixed method, cross sectional study through structured interviews (SI) and semistructured interviews (SSI) conducted in 2012 and 2013. Results. 290 HIV-negative women and 437 HIV positive women (n = 727) participated. Nearly all SI participants found prepackaged medicines acceptable, though modifications such as size reduction of the pack were suggested. Positive experiences included that the pack helped women take pills as instructed and contents promoted healthy pregnancies. Negative experiences included inadvertent pregnancy disclosure and discomfort carrying the pack in communities. Implementation was also feasible; 85.2% of SI participants reported adequate counseling time, though 37.8% felt pack use caused clinic delays. SSI participants reported improvement in service quality following pack introduction, due to more comprehensive counseling. Conclusions. A prepackaged drug delivery mechanism for ANC/PMTCT medicines was acceptable and feasible. Findings support continued use of this approach in Lesotho with improved design modifications to reflect the current PMTCT program of lifelong treatment for all HIV-positive pregnant women. PMID- 26649192 TI - Determinants of Weight Loss following Laparoscopic Sleeve Gastrectomy: The Role of Psychological Burden, Coping Style, and Motivation to Undergo Surgery. AB - BACKGROUND: The amount of excess weight loss (%EWL) among obese patients after bariatric surgery varies greatly. However, reliable predictors have not been established yet. The present study evaluated the preoperative psychological burden, coping style, and motivation to lose weight as factors determining postoperative treatment success. METHODS: The sample included 64 morbidly obese patients with a preoperative BMI of 51 +/- 8 kg/m(2) who had undergone laparoscopic sleeve gastrectomy (LSG). Well-established questionnaires were applied before surgery to assess the psychological burden in terms of "perceived stress" (PSQ-20), "depression" (PHQ-9), "anxiety" (GAD-7), and "mental impairment" (ISR) as well as coping style (Brief COPE) and motivation to lose weight. %EWL as an indicator for treatment success was assessed on average 20 months after surgery. RESULTS: Based on the %EWL distribution, patients were classified into three %EWL groups: low (14-39%), moderate (40-59%), and high (60 115%). LSG patients with high %EWL reported significantly more "active coping" behavior prior to surgery than patients with moderate and low %EWL. Patients' preoperative psychological burden and motivation to lose weight were not associated with %EWL. CONCLUSION: An "active coping" style might be of predictive value for better weight loss outcomes in patients following LSG intervention. PMID- 26649194 TI - Sex Differences in Genetic and Environmental Influences on Adolescent Depressive Symptoms: A Meta-Analytic Review. AB - Although sex difference in the mean level of depressive symptoms has been well established, the sex difference in genetic and environmental influences on adolescent depressive symptoms is unclear. The current study conducted a meta analysis of twin studies on sex differences in self- and parent-reported adolescent depressive symptoms. For self-reports, genetic factors influenced adolescent depressive symptoms equally for boys and girls, accounting for 46% of variation, but shared environmental factors had stronger impacts on adolescent girls' versus boys' depressive symptoms (13% versus 1% of the variance). For parent-reports, genetic, shared, and nonshared environmental factors influenced adolescent depressive symptoms equally, with separate estimates of 34%, 35%, and 31%. The implications of sex difference in genetic and environmental etiologies of depressive symptoms are discussed. PMID- 26649196 TI - Association of Genetic Polymorphisms of IFNGR1 with the Risk of Pulmonary Tuberculosis in Zahedan, Southeast Iran. AB - Aim. The present study was undertaken to find out the possible association between interferon-gamma (IFN-gamma) receptor 1 (IFNGR1) gene polymorphisms and risk of pulmonary tuberculosis (PTB) in a sample of Iranian population. Methods. Polymorphisms of IFNGR1 rs1327474 (-611 A/G), rs11914 (+189 T/G), rs7749390 (+95 C/T), and rs137854905 (27-bp ins/del) were determined in 173 PTB patients and 164 healthy subjects. Results. Our findings showed that rs11914 TG genotypes decreased the risk of PTB in comparison with TT (OR = 0.36, 95% CI = 0.21-0.62, and p = 0.0002). The rs11914 G allele decreased the risk of PTB compared with T allele (OR = 0.41, 95% CI = 0.25-0.68, and p = 0.0006). IFNGR1 rs7749390 CT genotype decreased the risk of PTB in comparison with CC genotype (OR = 0.55, 95% CI = 0.32-0.95, and p = 0.038). No significant association was found between IFNGR1 rs1327474 A/G polymorphism and risk/protective of PTB. The rs137854905 (27 bp I/D) variant was not polymorphic in our population. Conclusion. Our findings showed that IFNGR1 rs11914 and rs7749390 variants decreased the risk of PTB susceptibility in our population. PMID- 26649195 TI - Stem Cell-Based Therapeutics to Improve Wound Healing. AB - Issues surrounding wound healing have garnered deep scientific interest as well as booming financial markets invested in novel wound therapies. Much progress has been made in the field, but it is unsurprising to find that recent successes reveal new challenges to be addressed. With regard to wound healing, large tissue deficits, recalcitrant wounds, and pathological scar formation remain but a few of our most pressing challenges. Stem cell-based therapies have been heralded as a promising means by which to surpass current limitations in wound management. The wide differentiation potential of stem cells allows for the possibility of restoring lost or damaged tissue, while their ability to immunomodulate the wound bed from afar suggests that their clinical applications need not be restricted to direct tissue formation. The clinical utility of stem cells has been demonstrated across dozens of clinical trials in chronic wound therapy, but there is hope that other aspects of wound care will inherit similar benefit. Scientific inquiry into stem cell-based wound therapy abounds in research labs around the world. While their clinical applications remain in their infancy, the heavy investment in their potential makes it a worthwhile subject to review for plastic surgeons, in terms of both their current and future applications. PMID- 26649197 TI - Characteristics of Two-Year College Students on the Autism Spectrum and Their Support Services Experiences. AB - Approximately 80% of college-going youth with autism in the US attend a 2-year college at some point. These community-based, universally accessible institutions offer both academic and vocational courses and have experience in teaching diverse learners. This study used nationally representative survey data from the National Longitudinal Transition Study-2 to describe the characteristics and services experiences of adults with autism who attended postsecondary education after high school, focusing on those who attended a 2-year college. Over 60% of those who attended 2-year colleges had little to no trouble conversing or performing functional skills like counting change during high school, and extracurricular participation was common (93.8%). Most 2-year college attenders (85.7%) were able to navigate to places outside the home versus 43.9% of those with no postsecondary education. Over half took vocational courses at 2-year colleges, while one-quarter pursued academic study. Less than half (48.6%) of those who disclosed their disability to the school reported receiving services, accommodations, or other help. Most (87.3%) felt they received enough help, but fewer (68.0%) felt the services they received were useful. Future research should delineate specific needs of students with autism in 2-year college settings and identify what supports are needed to improve persistence and completion rates. PMID- 26649198 TI - Total Phenolic Content and Antioxidant Activity of Different Types of Chocolate, Milk, Semisweet, Dark, and Soy, in Cerebral Cortex, Hippocampus, and Cerebellum of Wistar Rats. AB - Chocolate is a product consumed worldwide and it stands out for presenting an important amount of phenolic compounds. In this study, the total phenolic content and antioxidant activity in the cerebral cortex, hippocampus, and cerebellum of male Wistar rats when consuming different types of chocolate, including milk, semisweet, dark, and soy, was evaluated. The total polyphenols concentration and antioxidant activity in vitro by the method of DPPH radical-scavenging test were evaluated in chocolate samples. Lipid peroxidation (TBARS), protein oxidation (carbonyl), sulfhydryl groups, and activity of SOD enzyme in cerebral cortex, hippocampus, and cerebellum of rats treated or not with hydrogen peroxide and/or chocolate were also evaluated. The dark chocolate demonstrated higher phenolic content and antioxidant activity, followed by semisweet, soy, and milk chocolates. The addition of chocolate in the diet of the rats reduced lipid peroxidation and protein oxidation caused by hydrogen peroxide. In the sulfhydryl assay, we observed that the levels of nonenzymatic defenses only increased with the chocolate treatments The SOD enzyme activity was modulated in the tissues treated with the chocolates. We observed in the samples of chocolate a significant polyphenol content and an important antioxidant activity; however, additional studies with different chocolates and other tissues are necessary to further such findings. PMID- 26649199 TI - Endovascular Stent Placement for Hemodialysis Arteriovenous Access Stenosis. AB - This study aims to report the outcomes of nitinol and polytetrafluoroethylene covered stent placement to treat hemodialysis arteriovenous access stenosis at a single center over a five-year period. Clinical and radiological information was reviewed retrospectively. Poststent primary and secondary patency rates were determined using Kaplan-Meier analysis. Ten clinical variables were subjected to multivariate Cox regression analysis to determine predictors of patency after stent placement. During the study period 60 stents were deployed in 45 patients, with a mean follow-up of 24.5 months. The clinical and anatomical success rate was 98.3% (59/60). Poststent primary patency rates at 6, 12, and 24 months were 64%, 46%, and 35%, respectively. Poststent secondary patency rates at 6, 12, and 24 months were 95%, 89%, and 85%, respectively. Stent placement for upper arm lesions and in access less than 12 months of age was associated with reduced primary patency (adjusted hazards ratio [HR] 5.1, p = 0.0084, and HR 3.5, p = 0.0029, resp.). Resistant or recurrent stenosis can be successfully treated by endovascular stent placement with durable long-term patency, although multiple procedures are often required. Stent placement for upper arm lesions and in arteriovenous access less than 12 months of age was associated with increased risk of patency loss. PMID- 26649200 TI - Validation of EGSYS Score in Prediction of Cardiogenic Syncope. AB - Introduction. Evaluation of Guidelines in Syncope Study (EGSYS) is designed to differentiate between cardiac and noncardiac causes of syncope. The present study aimed to evaluate the accuracy of this predictive model. Methods. In this prospective cross-sectional study, screening performance characteristics of EGSYS U (univariate) and EGSYS-M (multivariate) in prediction of cardiac syncope were calculated for syncope patients who were referred to the emergency department (ED). Results. 198 patients with mean age of 59.26 +/- 19.5 years were evaluated (62.3% male). 115 (58.4%) patients were diagnosed with cardiac syncope. Area under the ROC curve was 0.818 (95% CI: 0.75-0.87) for EGSYS-U and 0.805 (CI 95%: 0.74-0.86) for EGSYS-M (p = 0.53). Best cut-off point for both models was >=3. Sensitivity and specificity were 86.08% (95% CI: 78.09-91.59) and 68.29% (95% CI: 56.97-77.86) for EGSYS-U and 91.30% (95% CI: 84.20-95.52) and 57.32% (95% CI: 45.92-68.02) for EGSYS-M, respectively. Conclusion. The results of this study demonstrated the acceptable accuracy of EGSYS score in predicting cardiogenic causes of syncope at the >=3 cut-off point. It seems that using this model in daily practice can help physicians select at risk patients and properly triage them. PMID- 26649201 TI - Investigation of Fatty Acid Ketohydrazone Modified Liposome's Properties as a Drug Carrier. AB - pH-responsive liposomes were prepared by modifying the liposome with acid cleaving amphiphiles. Palmitic ketohydrazone (P-KH) or stearic ketohydrazone (S KH), composed of hydrophilic sugar headgroup and hydrophobic acyl chain, was used as a modifier of the DMPC liposome. Because the ketohydrazone group of P-KH or S KH was cleaved at low pH conditions ( 0.05). Salivary nitrite levels exhibited a significant correlation with PD, GBTI, severity of gingival overgrowth (%GO), and GCF volume (p < 0.05). Additionally, a strong positive correlation was detected between saliva and plasma nitrate levels (p < 0.005). However, both nitrite and nitrate levels in GCF and plasma demonstrated no significant correlation with clinical parameters, GO severity, and GCF volume (p > 0.05). CONCLUSION: Salivary nitrite and nitrate levels could be used as periodontal disease biomarkers in phenytoin induced gingival overgrowth, and that saliva seems to have a better diagnostic potential than GCF and plasma for the evaluation of drug-induced gingival overgrowth risk. However, when all drug groups were considered, saliva nitrite and nitrate levels could not be used as a biomarker for drug-induced gingival overgrowth. PMID- 26649283 TI - Vinculin Interacts with the Chlamydia Effector TarP Via a Tripartite Vinculin Binding Domain to Mediate Actin Recruitment and Assembly at the Plasma Membrane. AB - The mammalian protein vinculin is often a target of bacterial pathogens to subvert locally host cell actin dynamics. In Chlamydia infection, vinculin has been implicated in RNA interference screens, but the molecular basis for vinculin requirement has not been characterized. In this report, we show that vinculin was involved in the actin recruitment and F-actin assembly at the plasma membrane to facilitate invasion. Vinculin was recruited to the plasma membrane via its interaction with a specific tripartite motif within TarP that resembles the vinculin-binding domain (VBD) found in the Shigella invasion factor IpaA. The TarP-mediated plasma membrane recruitment of vinculin resulted in the localized recruitment of actin. In vitro pulldown assays for protein-protein interaction and imaging-based evaluation of recruitment to the plasma membrane demonstrated the essential role of the vinculin-binding site 1 (VBS1), and the dispensability of VBS2 and VBS3. As further support for the functionality of VBD-vinculin interaction, VBD-mediated actin recruitment required vinculin. Interestingly, while both vinculin and the focal adhesion kinase (FAK) colocalized at the sites of adhesion, the recruitment of one was independent of the other; and the actin recruitment function of the VBD/vinculin signaling axis was independent of the LD/FAK pathway. PMID- 26649284 TI - Editorial: LuxR Solos are Becoming Major Players in Cell-Cell Communication in Bacteria. PMID- 26649285 TI - Erratum to: The association between periodontal disease and metabolic syndrome among outpatients with diabetes in Jordan. AB - [This corrects the article DOI: 10.1186/s40200-015-0192-8.]. PMID- 26649287 TI - Editorial: Pediatric Pulmonary Hypertension. PMID- 26649286 TI - Novel targeted bladder drug-delivery systems: a review. AB - The objective of pharmaceutics is the development of drugs with increased efficacy and reduced side effects. Prolonged exposure of the diseased tissue to the drug is of crucial importance. Drug-delivery systems (DDSs) have been introduced to control rate, time, and place of release. Drugs can easily reach the bladder through a catheter, while systemically administered agents may undergo extensive metabolism. Continuous urine filling and subsequent washout hinder intravesical drug delivery (IDD). Moreover, the low permeability of the urothelium, also described as the bladder permeability barrier, poses a major challenge in the development of the IDD. DDSs increase bioavailability of drugs, therefore improving therapeutic effect and patient compliance. This review focuses on novel DDSs to treat bladder conditions such as overactive bladder, interstitial cystitis, bladder cancer, and recurrent urinary tract infections. The rationale and strategies for both systemic and local delivery methods are discussed, with emphasis on new formulations of well-known drugs (oxybutynin), nanocarriers, polymeric hydrogels, intravesical devices, encapsulated DDSs, and gene therapy. We give an overview of current and future prospects of DDSs for bladder disorders, including nanotechnology and gene therapy. PMID- 26649288 TI - Review of Simulation in Pediatrics: The Evolution of a Revolution. AB - Recent changes in medical education have highlighted the importance of experiential learning. Simulation is one model that has gained significant attention in the last decade and has been widely adopted as a training and assessment tool in medical education. Pediatric simulation has been utilized to teach various skills including resuscitation and trauma management, procedural skills, and team training. It is also a valuable tool for health care educators, as it allows learners to achieve competence without putting patients at risk. Recent literature demonstrates increased retention of knowledge and skills after simulation-based training. Further research is required to improve current simulation curriculums, develop validated assessment tools, and to demonstrate improved clinical outcomes after simulation-based training. We conducted an online search of original and review articles related to simulation and pediatric medical education and provide an overview of the role and utility of simulation in pediatrics. Key PointsSimulation in pediatrics has been widely accepted and adapted as a training and assessment tool in medical education.Simulation in pediatrics has been utilized to teach various skills including resuscitation and trauma management, procedural skills, and team training.Further research is required to improve current simulation curriculums, to develop validated assessment tools, and to demonstrate improved clinical outcomes after simulation based training. PMID- 26649289 TI - Reassessing Biological Threats: Implications for Cooperative Mitigation Strategies. AB - Multiple factors ranging from globalization to ecosystem disruption are presenting the global community with evolving biological threats to local, national, and global security that reach beyond the realm of traditional bioweapon threats. As a result, mitigation strategies have adapted necessarily to the increased diversity of biological threats. In general, response and preparedness strategies have largely shifted from being primarily reactive to traditional biological weapons to more proactive in nature. In this review, we briefly explore biological threats through a wider aperture, to embrace a greater appreciation of viral pathogens, antimicrobial resistance, and agricultural pathogens, and their potential to cause civil, economic, and political devastation. In addition, we discuss current mitigation strategies codified by the Global Health Security Agenda and the One Health paradigm as well as some of the available tools to assist with their sustainable implementation. PMID- 26649290 TI - Bioactive Glasses: Frontiers and Challenges. AB - Bioactive glasses were discovered in 1969 and provided for the first time an alternative to nearly inert implant materials. Bioglass formed a rapid, strong, and stable bond with host tissues. This article examines the frontiers of research crossed to achieve clinical use of bioactive glasses and glass-ceramics. In the 1980s, it was discovered that bioactive glasses could be used in particulate form to stimulate osteogenesis, which thereby led to the concept of regeneration of tissues. Later, it was discovered that the dissolution ions from the glasses behaved like growth factors, providing signals to the cells. This article summarizes the frontiers of knowledge crossed during four eras of development of bioactive glasses that have led from concept of bioactivity to widespread clinical and commercial use, with emphasis on the first composition, 45S5 Bioglass((r)). The four eras are (a) discovery, (b) clinical application, (c) tissue regeneration, and (d) innovation. Questions still to be answered for the fourth era are included to stimulate innovation in the field and exploration of new frontiers that can be the basis for a general theory of bioactive stimulation of regeneration of tissues and application to numerous clinical needs. PMID- 26649291 TI - Prevalence of Cam Morphology in Females with Femoroacetabular Impingement. AB - Cam and pincer are two common morphologies responsible for femoroacetabular impingement (FAI). Previous literature has reported that cam deformity is predominantly a male morphology, while being significantly less common in females. Cam morphology is commonly assessed with the alpha angle, measured on radiographs. The purpose of this study is to determine the prevalence of cam morphology utilizing the alpha angle in female subjects diagnosed with symptomatic FAI. All females presenting to the senior author's clinic diagnosed with symptomatic FAI between December 2006 and January 2013 were retrospectively reviewed. Alpha (alpha) angles were measured on anteroposterior and lateral (Dunn 90 degrees , cross-table lateral, and/or frog-leg lateral) plain radiographs by two blinded physicians, and the largest measured angle was used. Using Gosvig et al.'s classification, alpha angle was characterized as (pathologic > 57 degrees ), borderline (51-56 degrees ), subtle (46-50 degrees ), very subtle (43-45 degrees ), or normal (<=42 degrees ). Three hundred and ninety-one patients (438 hips) were analyzed (age 36.2 +/- 12.3 years). Among the hips included, 35.6% were normal, 14.6% pathologic, 15.1% borderline, 14.6% subtle, and 20.1% very subtle. There was no correlation between alpha angle and patient age (R = 0.17) or body mass index (R = 0.05). The intraclass correlation coefficient for alpha angle measurements was 0.84. Sixty-four percent of females in this cohort had an alpha angle >42 degrees . Subtle cam deformity plays a significant role in the pathoanatomy of female patients with symptomatic FAI. As the majority of revision hip arthroscopies are performed due to incomplete cam correction, hip arthroscopists need to be cognizant of and potentially surgically address these subtle lesions. PMID- 26649292 TI - Techniques and Results for Open Hip Preservation. AB - While hip arthroscopy grows in popularity, there are still many circumstances under which open hip preservation is the most appropriately indicated. This article specifically reviews open hip preservation procedures for a variety of hip conditions. Femoral acetabular impingement may be corrected using an open surgical hip dislocation. Acetabular dysplasia may be corrected using a periacetabular osteotomy. Acetabular protrusio may require surgical hip dislocation with rim trimming and a possible valgus intertrochanteric osteotomy. Legg-Calve-Perthes disease produces complex deformities that may be better served with osteotomies of the proximal femur and/or acetabulum. Chronic slipped capital femoral epiphysis may also benefit from a surgical hip dislocation and/or proximal femoral osteotomy. PMID- 26649293 TI - De Novo Transcriptome Sequencing of the Orange-Fleshed Sweet Potato and Analysis of Differentially Expressed Genes Related to Carotenoid Biosynthesis. AB - Sweet potato, Ipomoea batatas (L.) Lam., is an important food crop worldwide. The orange-fleshed sweet potato is considered to be an important source of beta carotene. In this study, the transcriptome profiles of an orange-fleshed sweet potato cultivar "Weiduoli" and its mutant "HVB-3" with high carotenoid content were determined by using the high-throughput sequencing technology. A total of 13,767,387 and 9,837,090 high-quality reads were produced from Weiduoli and HVB 3, respectively. These reads were de novo assembled into 58,277 transcripts and 35,909 unigenes with an average length of 596 bp and 533 bp, respectively. In all, 874 differentially expressed genes (DEGs) were obtained between Weiduoli and HVB-3, 401 of which were upregulated and 473 were downregulated in HVB-3 compared to Weiduoli. Of the 697 DEGs annotated, 316 DEGs had GO terms and 62 DEGs were mapped onto 50 pathways. The 22 DEGs and 31 transcription factors involved in carotenoid biosynthesis were identified between Weiduoli and HVB-3. In addition, 1,725 SSR markers were detected. This study provides the genomic resources for discovering the genes involved in carotenoid biosynthesis of sweet potato and other plants. PMID- 26649294 TI - Copper-64 Dichloride as Theranostic Agent for Glioblastoma Multiforme: A Preclinical Study. AB - Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults with a median survival time less than one year. To date, there are only a limited number of effective agents available for GBM therapy and this does not seem to add much survival advantage over the conventional approach based on surgery and radiotherapy. Therefore, the development of novel therapeutic approaches to GBM is essential and those based on radionuclide therapy could be of significant clinical impact. Experimental evidence has clearly demonstrated that cancer cells have a particularly high fractional content of copper inside the nucleus compared to normal cells. This behavior can be conveniently exploited both for diagnosis and for delivering therapeutic payloads (theranostic) of the radionuclide copper-64 into the nucleus of cancerous cells by intravenous administration of its simplest chemical form as dichloride salt [(64)Cu]CuCl2. To evaluate the potential theranostic role of [(64)Cu]CuCl2 in GBM, the present work reports results from a preclinical study carried out in a xenografted GBM tumor mouse model. Biodistribution data of this new agent were collected using a small animal PET tomograph. Subsequently, groups of tumor implanted nude mice were treated with [(64)Cu]CuCl2 to simulate single- and multiple-dose therapy protocols, and results were analyzed to estimate therapeutic efficacy. PMID- 26649295 TI - The Effect of Body Weight Support Treadmill Training on Gait Recovery, Proximal Lower Limb Motor Pattern, and Balance in Patients with Subacute Stroke. AB - OBJECTIVE: Gait performance is an indicator of mobility impairment after stroke. This study evaluated changes in balance, lower extremity motor function, and spatiotemporal gait parameters after receiving body weight supported treadmill training (BWSTT) and conventional overground walking training (CT) in patients with subacute stroke using 3D motion analysis. SETTING: Inpatient department of rehabilitation medicine at a university-affiliated hospital. PARTICIPANTS: 24 subjects with unilateral hemiplegia in the subacute stage were randomized to the BWSTT (n = 12) and CT (n = 12) groups. Parameters were compared between the two groups. Data from twelve age matched healthy subjects were recorded as reference. INTERVENTIONS: Patients received gait training with BWSTT or CT for an average of 30 minutes/day, 5 days/week, for 3 weeks. MAIN OUTCOME MEASURES: Balance was measured by the Brunel balance assessment. Lower extremity motor function was evaluated by the Fugl-Meyer assessment scale. Kinematic data were collected and analyzed using a gait capture system before and after the interventions. RESULTS: Both groups improved on balance and lower extremity motor function measures (P < 0.05), with no significant difference between the two groups after intervention. However, kinematic data were significantly improved (P < 0.05) after BWSTT but not after CT. Maximum hip extension and flexion angles were significantly improved (P < 0.05) for the BWSTT group during the stance and swing phases compared to baseline. CONCLUSION: In subacute patients with stroke, BWSTT can lead to improved gait quality when compared with conventional gait training. Both methods can improve balance and motor function. PMID- 26649296 TI - Animal Models in Studying Cerebral Arteriovenous Malformation. AB - Brain arteriovenous malformation (AVM) is an important cause of hemorrhagic stroke. The etiology is largely unknown and the therapeutics are controversial. A review of AVM-associated animal models may be helpful in order to understand the up-to-date knowledge and promote further research about the disease. We searched PubMed till December 31, 2014, with the term "arteriovenous malformation," limiting results to animals and English language. Publications that described creations of AVM animal models or investigated AVM-related mechanisms and treatments using these models were reviewed. More than 100 articles fulfilling our inclusion criteria were identified, and from them eight different types of the original models were summarized. The backgrounds and procedures of these models, their applications, and research findings were demonstrated. Animal models are useful in studying the pathogenesis of AVM formation, growth, and rupture, as well as in developing and testing new treatments. Creations of preferable models are expected. PMID- 26649297 TI - A Novel Murine Anti-Lactoferrin Monoclonal Antibody Activates Human Polymorphonuclear Leukocytes through Membrane-Bound Lactoferrin and TLR4. AB - Soluble lactoferrin (LTF) is a versatile molecule that not only regulates the iron homeostasis, but also harbors direct microbicidal and immunomodulating abilities in mammalian body fluids. In contrast, little is known about the function of membrane-bound LTF (mbLTF), although its expression on human polymorphonuclear leukocytes (huPMNs) has been reported for decades. Given that LTF/anti-LTF antibodies represent a potential diagnostic/prognostic biomarker and a therapeutic target in patients with immune disorders, we wished, in the present study, to generate a novel human LTF- (huLTF-) specific mAb suitable for detailed analyses on the expression and function of mbLTF as well as for deciphering the underlying mechanisms. By using the traditional hybridoma cell fusion technology, we obtained a murine IgG1 (kappa) mAb, M-860, against huLTF. M-860 recognizes a conformational epitope of huLTF as it binds to natural, but not denatured, huLTF in ELISA. Moreover, M-860 detects mbLTF by FACS and captures endogenous huLTF in total cell lysates of huPMNs. Functionally, M-860 induces the activation of huPMNs partially through TLR4 but independently of phagocytosis. M-860 is thus a powerful tool to analyze the expression and function of human mbLTF, which will further our understanding of the roles of LTF in health and disease. PMID- 26649298 TI - PFOS Disturbs BDNF-ERK-CREB Signalling in Association with Increased MicroRNA-22 in SH-SY5Y Cells. AB - Perfluorooctane sulfonate (PFOS), a ubiquitous environmental pollutant, is neurotoxic to mammalian species. However, the underlying mechanism of its neurotoxicity was unclear. We hypothesized that PFOS suppresses BDNF expression to produce its neurotoxic effects by inhibiting the ERK-CREB pathway. SH-SY5Y human neuroblastoma cells were exposed to various concentrations of PFOS to examine the role of the BDNF-ERK-CREB signalling pathway in PFOS-induced apoptosis and cytotoxicity. Furthermore, to ascertain the mechanism by which PFOS reduces BDNF signalling, we examined the expression levels of miR-16 and miR-22, which potentially regulate BDNF mRNA translation at the posttranscriptional level. Results indicated that PFOS significantly decreased cell viability and induced apoptosis in SH-SY5Y cells. In addition, BDNF and pERK protein levels decreased after PFOS treatment; however, pCREB protein levels were significantly elevated in PFOS treated groups. TrkB protein expression increased in the 10 MUM and 50 MUM PFOS groups and significantly decreased in the 100 MUM PFOS group. Our results demonstrated that PFOS exposure decreased miR-16 expression and increased miR-22 expression, which may represent a possible mechanism by which PFOS decreases BDNF protein levels. PFOS may inhibit BDNF-ERK-CREB signalling by increasing miR-22 levels, which may, in part, explain the mechanism of PFOS neurotoxicity. PMID- 26649299 TI - Mechanisms of Drug Resistance in Relapse and Refractory Multiple Myeloma. AB - Multiple myeloma (MM) is a hematological malignancy that remains incurable because most patients eventually relapse or become refractory to current treatments. Although the treatments have improved, the major problem in MM is resistance to therapy. Clonal evolution of MM cells and bone marrow microenvironment changes contribute to drug resistance. Some mechanisms affect both MM cells and microenvironment, including the up- and downregulation of microRNAs and programmed death factor 1 (PD-1)/PD-L1 interaction. Here, we review the pathogenesis of MM cells and bone marrow microenvironment and highlight possible drug resistance mechanisms. We also review a potential molecular targeting treatment and immunotherapy for patients with refractory or relapse MM. PMID- 26649302 TI - Black Rice Anthocyanins Suppress Metastasis of Breast Cancer Cells by Targeting RAS/RAF/MAPK Pathway. AB - Overexpression of human epidermal growth factor receptor 2 (HER2) drives the biology of 30% of breast cancer cases. As a transducer of HER2 signaling, RAS/RAF/MAPK pathway plays a pivotal role in the development of breast cancer. In this study, we examined the molecular mechanisms underlying the chemopreventive effects of black rice anthocyanins (BRACs) extract and identified their molecular targets in HER2(+) breast cancer cells. Treatment of MDA-MB-453 cells (HER2(+)) with BRACs inhibited cell migration and invasion, suppressed the activation of mitogen-activated protein kinase kinase kinase (RAF), mitogen-activated protein kinase kinase (MEK), and c-Jun N-terminal kinase (JNK), and downregulated the secretion of matrix metalloproteinase 2 (MMP2) and MMP9. BRACs also weakened the interactions of HER2 with RAF, MEK, and JNK proteins, respectively, and decreased the mRNA expression of raf, mek, and jnk. Further, we found combined treatment with BRACs and RAF, MEK, or JNK inhibitors could enhance the antimetastatic activity, compared with that of each treatment. Transient transfection with small interfering RNAs (siRNAs) specific for raf, mek, and jnk inhibited their mRNA expression in MDA-MB-453 cells. Moreover, cotreatment with BRACs and siRNA induces a more remarkable inhibitory effect than that by either substance alone. In summary, our study suggested that BRACs suppress metastasis in breast cancer cells by targeting the RAS/RAF/MAPK pathway. PMID- 26649301 TI - Current Status of Research on Osteoporosis after Solid Organ Transplantation: Pathogenesis and Management. AB - Improved survival following organ transplantation has brought to the forefront some long-term complications, among which osteoporosis and associated fractures are the major ones that adversely affect the quality of life in recipients. The pathogenesis of osteoporosis in transplant recipients is complex and multifactorial which may be related to increased bone resorption, decreased bone formation, or both. Studies have shown that the preexisting underlying metabolic bone disorders and the use of immunosuppressive agents are the major risk factors for osteoporosis and fractures after organ transplantation. And rapid bone loss usually occurs in the first 6-12 months with a significant increase in fracture risk. This paper will provide an updated review on the possible pathogenesis of posttransplant osteoporosis and fractures, the natural history, and the current prevention and treatment strategies concerning different types of organ transplantation. PMID- 26649300 TI - Ordinary and Activated Bone Grafts: Applied Classification and the Main Features. AB - Bone grafts are medical devices that are in high demand in clinical practice for substitution of bone defects and recovery of atrophic bone regions. Based on the analysis of the modern groups of bone grafts, the particularities of their composition, the mechanisms of their biological effects, and their therapeutic indications, applicable classification was proposed that separates the bone substitutes into "ordinary" and "activated." The main differential criterion is the presence of biologically active components in the material that are standardized by qualitative and quantitative parameters: growth factors, cells, or gene constructions encoding growth factors. The pronounced osteoinductive and (or) osteogenic properties of activated osteoplastic materials allow drawing upon their efficacy in the substitution of large bone defects. PMID- 26649303 TI - Simultaneous Lateral Interbody Fusion and Posterior Percutaneous Instrumentation: Early Experience and Technical Considerations. AB - Lumbar fusion surgery involving lateral lumbar interbody graft insertion with posterior instrumentation is traditionally performed in two stages requiring repositioning. We describe a novel technique to complete the circumferential procedure simultaneously without patient repositioning. Twenty patients diagnosed with worsening back pain with/without radiculopathy who failed exhaustive conservative management were retrospectively reviewed. Ten patients with both procedures simultaneously from a single lateral approach and 10 control patients with lateral lumbar interbody fusion followed by repositioning and posterior percutaneous instrumentation were analyzed. Pars fractures, mobile grade 2 spondylolisthesis, and severe one-level degenerative disk disease were matched between the two groups. In the simultaneous group, avoiding repositioning leads to lower mean operative times: 130 minutes (versus control 190 minutes; p = 0.009) and lower intraoperative blood loss: 108 mL (versus 93 mL; NS). Nonrepositioned patients were hospitalized for an average of 4.1 days (versus 3.8 days; NS). There was one complication in the control group requiring screw revision. Lateral interbody fusion and percutaneous posterior instrumentation are both readily accomplished in a single lateral decubitus position. In select patients with adequately sized pedicles, performing simultaneous procedures decreases operative time over sequential repositioning. Patient outcomes were excellent in the simultaneous group and comparable to procedures done sequentially. PMID- 26649304 TI - In Vitro Propagation, Phytochemical Analysis, and Evaluation of Free Radical Scavenging Property of Scrophularia kakudensis Franch Tissue Extracts. AB - The current study deals with in vitro propagation, antioxidant property estimation, and assessment of acacetin content in Scrophularia kakudensis Franch. Adventitious shoot induction was achieved from the nodal explant with the highest number of adventitious shoots per explant (17.4) on Murashige and Skoog's (MS) medium fortified with 2.0 mg.L(-1) 6-benzyladenine (BA) and 0.5 mg L(-1) indole-3 acetic acid (IAA). Maximum number of roots per plant (16.5) was noted in half strength MS medium supplemented with 0.5 mg.L(-1) IAA. The regenerated plants displayed successful survival ratio (95%) in the greenhouse. The highest content of acacetin, a pharmaceutically important flavonoid, was observed in the shoot extracts (in vitro: 32.83 ug.g(-1) FW; in vivo: 30.05 ug.g(-1) FW) followed by root extracts. Total phenol and flavonoid contents along with free radical scavenging assays revealed the occurrence of larger amount of antioxidants in shoot extract in comparison with callus and root extracts of S. kakudensis. Thus, the outcome of the present study can be highly beneficial for the germplasm conservation and commercial cultivation of S. kakudensis for therapeutic purposes. PMID- 26649305 TI - Minimally Invasive Scoliosis Surgery: A Novel Technique in Patients with Neuromuscular Scoliosis. AB - Minimally invasive surgery (MIS) has been described in the treatment of adolescent idiopathic scoliosis (AIS) and adult scoliosis. The advantages of this approach include less blood loss, shorter hospital stay, earlier mobilization, less tissue disruption, and relatively less pain. However, despite these significant benefits, MIS approach has not been reported in neuromuscular scoliosis patients. This is possibly due to concerns with longer surgery time, which is further increased due to more levels fused and instrumented, challenges of pelvic fixation, size and number of incisions, and prolonged anesthesia. We modified the MIS approach utilized in our AIS patients to be implemented in our neuromuscular patients. Our technique allows easy passage of contoured rods, placement of pedicle screws without image guidance, partial/complete facet resection, and all standard reduction maneuvers. Operative time needed to complete this surgery is comparable to the standard procedure and the majority of our patients have been extubated at the end of procedure, spending 1 day in the PICU and 5-6 days in the hospital. We feel that MIS is not only a feasible but also a superior option in patients with neuromuscular scoliosis. Long-term results are unavailable; however, short-term results have shown multiple benefits of this approach and fewer limitations. PMID- 26649306 TI - Roles of Hsp70s in Stress Responses of Microorganisms, Plants, and Animals. AB - Hsp70s (heat shock protein 70s) are a class of molecular chaperones that are highly conserved and ubiquitous in organisms ranging from microorganisms to plants and humans. Most research on Hsp70s has focused on the mechanisms of their functions as molecular chaperones, but recently, studies on stress responses are coming to the forefront. Hsp70s play key roles in cellular development and protecting living organisms from environmental stresses such as heat, drought, salinity, acidity, and cold. Moreover, functions of human Hsp70s are related to diseases including neurological disorders, cancer, and virus infection. In this review, we provide an overview of the specific roles of Hsp70s in response to stress, particularly abiotic stress, in all living organisms. PMID- 26649307 TI - Using Theory of Planned Behavior to Predict the Physical Activity of Children: Probing Gender Differences. AB - OBJECTIVES: The primary objective of this study was to use the theory of planned behavior (TPB) to examine the association between TPB variables and the moderate to-vigorous physical activity (MVPA) of children in Shanghai, China. Gender differences were also explored. METHODS: The participants were 353 children (180 boys and 173 girls) aged 9 to 13 years from three primary schools in Shanghai. Accelerometers were used to measure the MVPA duration of the children. Questionnaires that focused on attitude, subjective norms, and perceived behavioral control (PBC) related to MVPA engagement were completed by the participants. RESULTS: Regression analyses revealed that intention, and not PBC, accounted for 9% of the variance in MVPA. Meanwhile, attitude and PBC explained 33% of the variance in intentions to engage in MVPA. In terms of gender differences, TPB performed better in the physical activity (PA) domain for boys than for girls. Furthermore, attitude and PBC were significantly associated with intention among boys, whereas only PBC was significantly related to intention among girls. CONCLUSION: Practitioners should consider tailoring intervention to address gender differences to increase leisure-time PA participation of children. PMID- 26649309 TI - Epidemiology, Detection, and Control of Foodborne Microbial Pathogens. PMID- 26649308 TI - Global Gene Expression Profiling and Alternative Splicing Events during the Chondrogenic Differentiation of Human Cartilage Endplate-Derived Stem Cells. AB - Low back pain (LBP) is a very prevalent disease and degenerative disc diseases (DDDs) usually account for the LBP. However, the pathogenesis of DDDs is complicated and difficult to elucidate. Alternative splicing is a sophisticated regulatory process which greatly increases cellular complexity and phenotypic diversity of eukaryotic organisms. In addition, the cartilage endplate-derived stem cells have been discovered and identified by our research group. In this paper, we continue to investigate gene expression profiling and alternative splicing events during chondrogenic differentiation of cartilage endplate-derived stem cells. We adopted Affymetrix Human Transcriptome Array 2.0 (HTA 2.0) to compare the transcriptional and splicing changes between the control and differentiated samples. RT-PCR and quantitative PCR are used to validate the microarray results. The GO and KEGG pathway analysis was also performed. After bioinformatics analysis of the data, we detected 1953 differentially expressed genes. In terms of alternative splicing, the Splicing Index algorithm was used to select alternatively spliced genes. We detected 4411 alternatively spliced genes. GO and KEGG pathway analysis also revealed several functionally involved biological processes and signaling pathways. To our knowledge, this is the first study to investigate the alternative splicing mechanisms in chondrogenic differentiation of stem cells on a genome-wide scale. PMID- 26649310 TI - Overcoming Multidrug Resistance in Cancer Stem Cells. AB - The principle mechanism of protection of stem cells is through the expression of ATP-binding cassette (ABC) transporters. These transporters serve as the guardians of the stem cell population in the body. Unfortunately these very same ABC efflux pumps afford protection to cancer stem cells in tumors, shielding them from the adverse effects of chemotherapy. A number of strategies to circumvent the function of these transporters in cancer stem cells are currently under investigation. These strategies include the development of competitive and allosteric modulators, nanoparticle mediated delivery of inhibitors, targeted transcriptional regulation of ABC transporters, miRNA mediated inhibition, and targeting of signaling pathways that modulate ABC transporters. The role of ABC transporters in cancer stem cells will be explored in this paper and strategies aimed at overcoming drug resistance caused by these particular transporters will also be discussed. PMID- 26649311 TI - Minimal Invasive Circumferential Management of Thoracolumbar Spine Fractures. AB - INTRODUCTION: While thoracolumbar fractures are common lesions, no strong consensus is available at the moment. OBJECTIVES: The aim of this study was to evaluate the results of a minimal invasive strategy using percutaneous instrumentation and anterior approach in the management of thoracolumbar unstable fractures. METHODS: 39 patients were included in this retrospective study. Radiologic evaluation was based on vertebral and regional kyphosis, vertebral body height restoration, and fusion rate. Clinical evaluation was based on Visual Analogic Score (VAS). All evaluations were done preoperatively and at 1-year follow-up. RESULTS: Both vertebral and regional kyphoses were significantly improved on postoperative evaluation (13 degrees and 7 degrees versus -1 degrees and -9 degrees P < 0.05, resp.) as well as vertebral body height (0.92 versus 1.16, P < 0.05). At 1-year follow-up, mean loss of correction was 1 degrees . A solid fusion was visible in all the cases, and mean VAS was significantly reduced form 8/10 preoperatively to 1/10 at the last follow-up. CONCLUSION: Management of thoracolumbar fractures using percutaneous osteosynthesis and minimal invasive anterior approach (telescopic vertebral body prosthesis) is a valuable strategy. Results of this strategy offer satisfactory and stable results in time. PMID- 26649312 TI - One-Stage Reconstruction of Scalp after Full-Thickness Oncologic Defects Using a Dermal Regeneration Template (Integra). AB - The use of Dermal Regeneration Template (DRT) can be a valid alternative for scalp reconstruction, especially in elderly patients where a rapid procedure with an acceptable aesthetic and reliable functional outcome is required. We reviewed the surgical outcome of 20 patients, 14 (70%) males and 6 (30%) females, who underwent application of DRT for scalp reconstruction for small defects (group A: mean defect size of 12.51 cm(2)) and for large defects (group B: mean defect size of 28.7 cm(2)) after wide excision of scalp neoplasm (basal cell carcinoma and squamous cell carcinoma). In group A, the excisions were performed to the galeal layer avoiding pericranium, and in group B the excisions were performed including pericranium layer with subsequent coverage of the exposed bone with local pericranial flap. In both the groups (A and B) after the excision of the tumor, the wound bed was covered with Dermal Regeneration Template. In 3 weeks we observed the complete healing of the wound bed by secondary intention with acceptable cosmetic results and stable scars. Scalp reconstruction using a DRT is a valid coverage technique for minor and major scalp defects and it can be conducted with good results in elderly patients with multiple comorbidities. PMID- 26649313 TI - One-Step Recovery of scFv Clones from High-Throughput Sequencing-Based Screening of Phage Display Libraries Challenged to Cells Expressing Native Claudin-1. AB - Expanding the availability of monoclonal antibodies interfering with hepatitis C virus infection of hepatocytes is an active field of investigation within medical biotechnologies, to prevent graft reinfection in patients subjected to liver transplantation and to overcome resistances elicited by novel antiviral drugs. In this paper, we describe a complete pipeline for screening of phage display libraries of human scFvs against native Claudin-1, a tight-junction protein involved in hepatitis C virus infection, expressed on the cell surface of human hepatocytes. To this aim, we implemented a high-throughput sequencing approach for library screening, followed by a simple and effective strategy to recover active binder clones from enriched sublibraries. The recovered clones were successfully converted to active immunoglobulins, thus demonstrating the effectiveness of the whole procedure. This novel approach can guarantee rapid and cheap isolation of antibodies for virtually any native antigen involved in human diseases, for therapeutic and/or diagnostic applications. PMID- 26649314 TI - Psychosocial Predictors of Weight Loss among American Indian and Alaska Native Participants in a Diabetes Prevention Translational Project. AB - The association of psychosocial factors (psychological distress, coping skills, family support, trauma exposure, and spirituality) with initial weight and weight loss among American Indians and Alaska Natives (AI/ANs) in a diabetes prevention translational project was investigated. Participants (n = 3,135) were confirmed as prediabetic and subsequently enrolled in the Special Diabetes Program for Indians Diabetes Prevention (SDPI-DP) demonstration project implemented at 36 Indian health care programs. Measures were obtained at baseline and after completing a 16-session educational curriculum focusing on weight loss through behavioral changes. At baseline, psychological distress and negative family support were linked to greater weight, whereas cultural spirituality was correlated with lower weight. Furthermore, psychological distress and negative family support predicted less weight loss, and positive family support predicted greater weight loss, over the course of the intervention. These bivariate relationships between psychosocial factors and weight remained statistically significant within a multivariate model, after controlling for sociodemographic characteristics. Conversely, coping skills and trauma exposure were not significantly associated with baseline weight or change in weight. These findings demonstrate the influence of psychosocial factors on weight loss in AI/AN communities and have substantial implications for incorporating adjunctive intervention components. PMID- 26649315 TI - Gliptins and Cardiovascular Outcomes: A Comparative and Critical Analysis after TECOS. AB - The issue related to macrovascular outcomes and intensive glycemic control was hotly debated after the publication of landmark trials like ACCORD, ADVANCE, and VADT. The only benefits seem to come from intervening early on in the disease process as indicated by the 10-year UKPDS follow-up. To complicate matters USFDA made it mandatory for modern drugs to conduct cardiovascular safety trials in high-risk populations after the 2008 rosiglitazone scare. This led to all the modern group of drugs designing cardiovascular safety trials (gliptins, GLP-1 agonists, and SGLT-2 inhibitors) to meet USFDA regulatory requirements. We saw publication of the first 2 randomized trials with gliptins published a year and a half back. On the face value SAVOR TIMI and EXAMINE satisfied the primary composite CV end-points. However, issues related to significant increase in heart failure and all-cause 7-day on-treatment mortality created a lot of confusion. FDA reanalysis of these data (especially SAVOR) raises a lot of doubts as far as CV safety of these groups of drugs was concerned. Hence, all eyes were on TECOS, which was published this year. We take a microscopic look at these trials trying to understand where we stand as from now on this issue. PMID- 26649316 TI - Binding Orientations and Lipid Interactions of Human Amylin at Zwitterionic and Anionic Lipid Bilayers. AB - Increasing evidence suggests that the interaction of human islet amyloid polypeptide (hIAPP) with lipids may facilitate hIAPP aggregation and cause the death of pancreatic islet beta-cells. However, the detailed hIAPP-membrane interactions and the influences of lipid compositions are unclear. In this study, as a first step to understand the mechanism of membrane-mediated hIAPP aggregation, we investigate the binding behaviors of hIAPP monomer at zwitterionic palmitoyloleoyl-phosphatidylcholine (POPC) bilayer by performing atomistic molecular dynamics simulations. The results are compared with those of hIAPP at anionic palmitoyloleoyl-phosphatidylglycerol (POPG) bilayers. We find that the adsorption of hIAPP to POPC bilayer is mainly initiated from the C terminal region and the peptide adopts a helical structure with multiple binding orientations, while the adsorption to POPG bilayer is mostly initiated from the N terminal region and hIAPP displays one preferential binding orientation, with its hydrophobic residues exposed to water. hIAPP monomer inserts into POPC lipid bilayers more readily than into POPG bilayers. Peptide-lipid interaction analyses show that the different binding features of hIAPP at POPC and POPG bilayers are attributed to different magnitudes of electrostatic and hydrogen-bonding interactions with lipids. This study provides mechanistic insights into the different interaction behaviors of hIAPP with zwitterionic and anionic lipid bilayers. PMID- 26649317 TI - Inhibition of IAPP Aggregation and Toxicity by Natural Products and Derivatives. AB - Fibrillar aggregates of human islet amyloid polypeptide, hIAPP, a pathological feature seen in some diabetes patients, are a likely causative agent for pancreatic beta-cell toxicity, leading to a transition from a state of insulin resistance to type II diabetes through the loss of insulin producing beta-cells by hIAPP induced toxicity. Because of the probable link between hIAPP and the development of type II diabetes, there has been strong interest in developing reagents to study the aggregation of hIAPP and possible therapeutics to block its toxic effects. Natural products are a class of compounds with interesting pharmacological properties against amyloids which have made them interesting targets to study hIAPP. Specifically, the ability of polyphenolic natural products, EGCG, curcumin, and resveratrol, to modulate the aggregation of hIAPP is discussed. Furthermore, we have outlined possible mechanistic discoveries of the interaction of these small molecules with the peptide and how they may mitigate toxicity associated with peptide aggregation. These abundantly found agents have been long used to combat diseases for many years and may serve as useful templates toward developing therapeutics against hIAPP aggregation and toxicity. PMID- 26649318 TI - Circulating Levels of Betatrophin and Irisin Are Not Associated with Pancreatic beta-Cell Function in Previously Diagnosed Type 2 Diabetes Mellitus Patients. AB - Betatrophin and irisin are two recently identified hormones which may participate in regulating pancreatic beta-cell function. However, the associations of these two hormones with beta-cell function remain unclear. The present study aims to demonstrate the associations of circulating betatrophin and irisin levels with beta-cell function, assessed by the area under the curve (AUC) of C-peptide, and the possible correlation between these two hormones in previously diagnosed type 2 diabetes mellitus (T2DM) patients. In total, 20 age-, sex-, and body mass index (BMI-) matched normal glucose tolerance (NGT) subjects and 120 previously diagnosed T2DM patients were included in this study. Partial correlation analysis was used to evaluate the relationships between these two hormones and indexes of beta-cell function and insulin resistance. Our results showed that betatrophin levels were significantly elevated, while irisin levels were significantly decreased, in patients with T2DM compared with NGT subjects. However, partial correlation analysis showed that betatrophin levels did not correlate with beta cell function-related variables or insulin resistance-related variables before or after controlling multiple covariates, while irisin correlated positively with insulin sensitivity but is not associated with beta-cell function-related variables. Besides, no correlation was observed between betatrophin and irisin levels. Hence we concluded that betatrophin and irisin were not associated with beta-cell function in previously diagnosed T2DM patients. PMID- 26649320 TI - Impact of Real-Time Continuous Glucose Monitoring Use on Glucose Variability and Endothelial Function in Adolescents with Type 1 Diabetes: New Technology--New Possibility to Decrease Cardiovascular Risk? AB - Children with type 1 diabetes (T1DM) are the high-risk group of accelerated atherosclerosis. Real-time continuous glucose monitoring (RT-CGM) provides possibilities for the detection of glycaemic variability, newly recognized cardiovascular risk factor. The aim of the study was to assess the usefulness of RT-CGM as an educational tool to find and reduce glycaemic variability in order to improve endothelial function in T1DM adolescents. Forty patients aged 14.6 years were recruited. The study was based on one-month CGM sensors use. Parameters of glycaemic variability were analyzed during first and last sensor use, together with brachial artery flow-mediated dilatation (FMD) to assess endothelial function. In the whole group, FMD improvement was found (10.9% to 16.6%, p < 0.005), together with decrease in all studied glycaemic variability parameters. In patients with HbA1c improvement compared to the group without HbA1c improvement, we found greater increase of FMD (12% to 19%, p < 0.005 versus 8.2% to 11.3%, p = 0.080) and greater improvement of glucose variability. RT-CGM can be considered as an additional tool that offers T1DM adolescents the quick reaction to decrease glycaemic variability in short time observation. Whether such approach might influence improvement in endothelial function and reduction of the risk of future cardiovascular disease remains to be elucidated. PMID- 26649319 TI - Islet Amyloid Polypeptide: Structure, Function, and Pathophysiology. AB - The hormone islet amyloid polypeptide (IAPP, or amylin) plays a role in glucose homeostasis but aggregates to form islet amyloid in type-2 diabetes. Islet amyloid formation contributes to beta-cell dysfunction and death in the disease and to the failure of islet transplants. Recent work suggests a role for IAPP aggregation in cardiovascular complications of type-2 diabetes and hints at a possible role in type-1 diabetes. The mechanisms of IAPP amyloid formation in vivo or in vitro are not understood and the mechanisms of IAPP induced beta-cell death are not fully defined. Activation of the inflammasome, defects in autophagy, ER stress, generation of reactive oxygen species, membrane disruption, and receptor mediated mechanisms have all been proposed to play a role. Open questions in the field include the relative importance of the various mechanisms of beta-cell death, the relevance of reductionist biophysical studies to the situation in vivo, the molecular mechanism of amyloid formation in vitro and in vivo, the factors which trigger amyloid formation in type-2 diabetes, the potential role of IAPP in type-1 diabetes, the development of clinically relevant inhibitors of islet amyloidosis toxicity, and the design of soluble, bioactive variants of IAPP for use as adjuncts to insulin therapy. PMID- 26649322 TI - Review of Herbal Traditional Chinese Medicine for the Treatment of Diabetic Nephropathy. AB - Diabetic nephropathy (DN) is the most serious chronic complications of diabetes; 20-40% of diabetic patients develop into end stage renal disease (ESRD). However, exact pathogenesis of DN is not fully clear and we have great difficulties in curing DN; poor treatment of DN led to high chances of mortality worldwide. A lot of western medicines such as ACEI and ARB have been demonstrated to protect renal function of DN but are not enough to delay or retard the progression of DN; therefore, exploring exact and feasible drug is current research hotspot in medicine. Traditional Chinese medicine (TCM) has been widely used to treat and control diabetes and its complications such as DN in a lot of scientific researches, which will give insights into the mechanism of DN, but they are not enough to reveal all the details. In this paper, we summarize the applications of herbal TCM preparations, single herbal TCM, and/or monomers from herbal TCM in the treatment of DN in the recent 10 years, depicting the renal protective effects and the corresponding mechanism, through which we shed light on the renal protective roles of TCM in DN with a particular focus on the molecular basis of the effect and provide a beneficial supplement to the drug therapy for DN. PMID- 26649323 TI - HERG Protein Plays a Role in Moxifloxacin-Induced Hypoglycemia. AB - The purpose of this study was to investigate the effect of moxifloxacin on HERG channel protein and glucose metabolism. HERG expression was investigated using immunohistochemistry. The whole-cell patch clamp method was used to examine the effect of moxifloxacin on HERG channel currents. A glucose tolerance test was used to analyze the effects of moxifloxacin on blood glucose and insulin concentrations in mice. Results show that HERG protein was expressed in human pancreatic beta-cells. Moxifloxacin inhibited HERG time-dependent and tail currents in HEK293 cells in a concentration-dependent manner. The IC50 of moxifloxacin inhibition was 36.65 MUmol/L. Moxifloxacin (200 mg/kg) reduced blood glucose levels and increased insulin secretion in wild-type mice at 60 min after the start of the glucose tolerance test. In contrast, moxifloxacin did not significantly alter blood glucose and insulin levels in HERG knockout mice. Serum glucose levels increased and insulin concentrations decreased in HERG knockout mice when compared to wild-type mice. The moxifloxacin-induced decrease in blood glucose and increase in insulin secretion occurred via the HERG protein; thus, HERG protein plays a role in insulin secretion. PMID- 26649321 TI - A Multicenter Retrospective Survey regarding Diabetic Ketoacidosis Management in Italian Children with Type 1 Diabetes. AB - We conducted a retrospective survey in pediatric centers belonging to the Italian Society for Pediatric Diabetology and Endocrinology. The following data were collected for all new-onset diabetes patients aged 0-18 years: DKA (pH < 7.30), severe DKA (pH < 7.1), DKA in preschool children, DKA treatment according to ISPAD protocol, type of rehydrating solution used, bicarbonates use, and amount of insulin infused. Records (n = 2453) of children with newly diagnosed diabetes were collected from 68/77 centers (87%), 39 of which are tertiary referral centers, the majority of whom (n = 1536, 89.4%) were diagnosed in the tertiary referral centers. DKA was observed in 38.5% and severe DKA in 10.3%. Considering preschool children, DKA was observed in 72%, and severe DKA in 16.7%. Cerebral edema following DKA treatment was observed in 5 (0.5%). DKA treatment according to ISPAD guidelines was adopted in 68% of the centers. In the first 2 hours, rehydration was started with normal saline in all centers, but with different amount. Bicarbonate was quite never been used. Insulin was infused starting from third hour at the rate of 0.05-0.1 U/kg/h in 72% of centers. Despite prevention campaign, DKA is still observed in Italian children at onset, with significant variability in DKA treatment, underlying the need to share guidelines among centers. PMID- 26649324 TI - Geometry Dynamics of alpha -Helices in Different Class I Major Histocompatibility Complexes. AB - MHC alpha-helices form the antigen-binding cleft and are of particular interest for immunological reactions. To monitor these helices in molecular dynamics simulations, we applied a parsimonious fragment-fitting method to trace the axes of the alpha-helices. Each resulting axis was fitted by polynomials in a least squares sense and the curvature integral was computed. To find the appropriate polynomial degree, the method was tested on two artificially modelled helices, one performing a bending movement and another a hinge movement. We found that second-order polynomials retrieve predefined parameters of helical motion with minimal relative error. From MD simulations we selected those parts of alpha helices that were stable and also close to the TCR/MHC interface. We monitored the curvature integral, generated a ruled surface between the two MHC alpha helices, and computed interhelical area and surface torsion, as they changed over time. We found that MHC alpha-helices undergo rapid but small changes in conformation. The curvature integral of helices proved to be a sensitive measure, which was closely related to changes in shape over time as confirmed by RMSD analysis. We speculate that small changes in the conformation of individual MHC alpha-helices are part of the intrinsic dynamics induced by engagement with the TCR. PMID- 26649326 TI - Dataset for the proteomic inventory and quantitative analysis of the breast cancer hypoxic secretome associated with osteotropism. AB - The cancer secretome includes all of the macromolecules secreted by cells into their microenvironment. Cancer cell secretomes are significantly different to that of normal cells reflecting the changes that normal cells have undergone during their transition to malignancy. More importantly, cancer secretomes are known to be active mediators of both local and distant host cells and play an important role in the progression and dissemination of cancer. Here we have quantitatively profiled both the composition of breast cancer secretomes associated with osteotropism, and their modulation under normoxic and hypoxic conditions. We detect and quantify 162 secretome proteins across all conditions which show differential hypoxic induction and association with osteotropism. Mass Spectrometry proteomics data have been deposited to the ProteomeXchange Consortium with the dataset identifier PXD000397 and the complete proteomic, bioinformatic and biological analyses are reported in Cox et al. (2015) [1]. PMID- 26649325 TI - Chlorophytum borivilianum Polysaccharide Fraction Provokes the Immune Function and Disease Resistance of Labeo rohita against Aeromonas hydrophila. AB - The present study aimed to investigate the effects of Chlorophytum borivilianum polysaccharide (CBP), as a dietary supplement administered at varying concentrations with feed (basal diet), on various cytokine-related responses in Labeo rohita fingerlings. Immune parameters and immune-related gene expressions were measured at 3rd, 4th, and 5th week after feeding. The results revealed that dietary administration of CBP at 0.2% and 0.4% for 4 weeks significantly upregulated serum lysozyme and phagocytic activity. Complement C3 and respiratory burst activity (RBA) were significantly higher after 4 weeks of CBP feeding. The immune related genes IL-8, IL-1beta, TNF-alpha, and iNOS were downregulated (P < 0.05) in groups with 0.2% and 0.4% CBP supplemented diets at week 4. Expression of anti-inflammatory cytokines (IL-10 and TGF-beta) was also downregulated (P < 0.5) after 4 weeks of feeding with 0.2% to 0.8% CBP. However, five weeks of CBP administration had no significant effect on immune gene expression, except TNF alpha and IL-8. Fish fed with 0.4% CBP for 4 weeks showed maximum resistance against Aeromonas hydrophila (73.3% survival) compared to control. From these results, we recommend that CBP administration at 0.4% for 4 weeks could effectively improve immune response and disease resistance in L. rohita. PMID- 26649327 TI - Data in support of the proteomic analysis of plasma membrane and tonoplast from the leaves of mangrove plant Avicennia officinalis. AB - The data provides information in support of the research article, Proteomics 2014, 14, 2545-2557 [1]. Raw data is available from the ProteomeXchange Consortium via the PRIDE partnerRepository [2] with the dataset identifier PXD000837. Plasma membrane and tonoplast proteins from the leaves of Avicennia officinalis were identified using gel electrophoresis (one and two dimensional) combined with LC-MS analysis. Based on GO annotation, identified proteins were predicted to be involved in various biological processes. PMID- 26649328 TI - Protection of Health Imagery by Region Based Lossless Reversible Watermarking Scheme. AB - Providing authentication and integrity in medical images is a problem and this work proposes a new blind fragile region based lossless reversible watermarking technique to improve trustworthiness of medical images. The proposed technique embeds the watermark using a reversible least significant bit embedding scheme. The scheme combines hashing, compression, and digital signature techniques to create a content dependent watermark making use of compressed region of interest (ROI) for recovery of ROI as reported in literature. The experiments were carried out to prove the performance of the scheme and its assessment reveals that ROI is extracted in an intact manner and PSNR values obtained lead to realization that the presented scheme offers greater protection for health imageries. PMID- 26649330 TI - Local Anaesthetic Infiltration and Indwelling Postoperative Wound Catheters for Patients with Hip Fracture Reduce Death Rates and Length of Stay. AB - Background. An analgesic enhanced recovery (ER) protocol for patients with a hip fracture was introduced. It was hypothesised that the ER would reduce pain, length of stay and improve clinical outcomes. The protocol used intraoperative infiltration of levobupivacaine followed by ongoing wound infusions. Methods. Consecutive patients admitted to two hospitals were eligible for the ER protocol. Numerical Reporting Scale pain scores (0-10) were recorded alongside opiate requirements. 434 patients in the ER group (316 full ER, 90 partial ER, and 28 no ER) were compared to a control group (CG) of 100 consecutive patients managed with traditional opiate analgesia. Results. Mean opiate requirement was 49.2 mg (CG) versus 32.5 mg (ER). Pain scores were significantly reduced in the full ER group, p < 0.0001. Direct discharge home and mean acute inpatient stay were significantly reduced (p = 0.0031 and p < 0.0001, resp.). 30-day mortality was 15% (CG) versus 5.5% (ER), p = 0.0024. Conclusions. This analgesic ER protocol for patients with a hip fracture was safe and effective and was associated with reduced inpatient stay and mortality. PMID- 26649329 TI - Live and Heat-Killed Lactobacillus rhamnosus ATCC 7469 May Induce Modulatory Cytokines Profiles on Macrophages RAW 264.7. AB - This study aimed to evaluate the capacity of Lactobacillus rhamnosus and/or its products to induce the synthesis of cytokines (TNF-alpha, IL-1beta, IL-4, IL-6, IL-10, and IL-12) by mouse macrophages (RAW 264.7). Three microorganism preparations were used: live L. rhamnosus (LLR) suspension, heat-killed L. rhamnosus (HKLR) suspension, and the supernatant of a heat-killed L. rhamnosus (SHKLR) suspension, which were cultured with macrophages (37 degrees C, 5% CO2) for 2 h and 30 min. After that, cells were cultured for 16 h. The supernatants were used for the quantitation of cytokines, by ELISA. The results were compared with the synthesis induced by lipopolysaccharide (LPS) and analysed, using ANOVA and Tukey test, 5%. LLR and HKLR groups were able to significantly increase the production of TNF-alpha, IL-6, and IL-10 (P < 0.05). SHKLR also significantly increased the production of TNF-alpha and IL-10 (P < 0.05) but not IL-6 (P > 0.05). All the L. rhamnosus suspensions were not able to produce detectable levels of IL-1beta or significant levels of IL-4 and IL-12 (P > 0.05). In conclusion, live and heat-killed L. rhamnosus suspensions were able to induce the synthesis of different cytokines with proinflammatory (TNF-alpha and IL-6) or regulatory (IL-10) functions, suggesting the role of strain L. rhamnosus ATCC 7469 in the modulation or in the stimulation of immune responses. PMID- 26649331 TI - Patient Satisfaction and Quality of Life in DIEAP Flap versus Implant Breast Reconstruction. AB - The psychological impact of breast reconstruction has widely been described, and multiple studies show that reconstruction improves the well-being and quality of life of patients. In breast reconstruction, the goal is not only the morphological result, but mainly the patient's perception of it. The objective of our study is to compare the physical and psychosocial well-being and satisfaction concerning the body image of patients who had reconstruction with breast implants to those of patients who had reconstruction with deep inferior epigastric artery perforator flaps. Our results demonstrated a similar quality of life between the two groups, but the satisfaction level was significantly higher in patients who had reconstruction with autologous tissue. Feedback from patients who have already received breast reconstruction may be useful in the decision-making process for future patients and plastic surgeons, enabling both to choose the reconstructive technique with the best long-term satisfaction. PMID- 26649332 TI - Biomechanical Evaluation of a Mandibular Spanning Plate Technique Compared to Standard Plating Techniques to Treat Mandibular Symphyseal Fractures. AB - Purpose. The purpose of this study is to compare the biomechanical behavior of the spanning reconstruction plate compared to standard plating techniques for mandibular symphyseal fractures. Materials and Methods. Twenty-five human mandible replicas were used. Five unaltered synthetic mandibles were used as controls. Four experimental groups of different reconstruction techniques with five in each group were tested. Each synthetic mandible was subjected to a splaying force applied to the mandibular angle by a mechanical testing unit until the construct failed. Peak load and stiffness were recorded. The peak load and stiffness were analyzed using ANOVA and the Tukey test at a confidence level of 95% (P < 0.05). Results. The two parallel plates' group showed statistically significant lower values for peak load and stiffness compared to all other groups. No statistically significant difference was found for peak load and stiffness between the control (C) group, lag screw (LS) group, and the spanning plate (SP1) group. Conclusions. The spanning reconstruction plate technique for fixation of mandibular symphyseal fractures showed similar mechanical behavior to the lag screw technique when subjected to splaying forces between the mandibular gonial angles and may be considered as an alternative technique when increased reconstructive strength is needed. PMID- 26649333 TI - CEUS: what is its role in abdominal aortic diseases? PMID- 26649334 TI - Bowel elastography - a pilot study for developing an elastographic scoring system to evaluate disease activity in pediatric Crohn's disease. AB - The diagnosis and monitoring of Crohn's disease (CD) represents a diagnosis challenge in which imaging plays an important role. AIM: In the present paper we aim to demonstrate the role of sonoelastography (SE), performed in addition to hydrosonography (HS), in the evaluation of CD in children and to propose a scoring system for the appreciation of disease activity. MATERIAL AND METHOD: All the patients included into the study were diagnosed with CD and had underwent HS and SE as part of the imaging evaluation. In selected cases magnetic resonance enterography (MRE) was also performed. SE aspects were classified into three types, each corresponding to a specific bowel wall pattern: normal or remission (type A), inflammation (type B) and fibrosis (type C); this classification represents the basis of the scoring system. For the purpose of statistical analysis each evaluated bowel segment became an individual case. RESULTS: Forty eight bowel segments were evaluated by SE: 21 type A, 20 type B and 7 type C. Statistically significant correlations were found between the intestinal wall HS changes, presence of complications, activity markers and the SE score. The HS assessment of the periintestinal area correlated only partially with SE score, while certain SE scores also proved to be predictors for the presence of complications or for increased values of the disease activity markers. CONCLUSIONS: SE, along with HS, represents a reliable investigation in the correct diagnosis and monitoring of pediatric patients with CD and the SE scoring system may be introduced as a method for the assessment of disease activity. PMID- 26649335 TI - Computerized ultrasound image analysis for noninvasive evaluation of hepatic steatosis. AB - OBJECTIVE: To assess the diagnostic value of a particular set of local intensity parameters extracted from ultrasound liver images in conjunction with support vector machine (SVM) classifiers for liver steatosis grading in respect to the "gold standard" provided by liver biopsy. MATERIAL AND METHODS: We prospectively enrolled in the study 228 patients with chronic hepatopathies. All the patients underwent liver biopsy and abdominal ultrasound examination. For quantitative ultrasound assessment of liver steatosis, an image analysis software was developed, which extracts three local intensity parameters from regions of interest (ROI) in the ultrasound section and analyzes their depth variation: the coefficient of variation of luminance (CVL), the median luminance (ml ), and the hepato-splenic attenuation index (HSAI). For steatosis grading, SVM classifiers were trained on the input feature spaces provided by the above mentioned parameters. The statistical significance of the steatosis grading was assessed on a significant test set using SVM classifiers, in terms of sensibility, specificity and through the ROC curves. RESULTS: A cut-off value of 0.362 of the CVL of the liver performed the liver steatosis grading with an accuracy of 89.17% (p<0.0001). A cut-off value of 0.27 of the HSAI performed the prediction of the moderate-severe liver steatosis with an accuracy of 87%. CONCLUSIONS: The proposed computer analysis method of ultrasound images proved innovative and useful for the initial non-invasive assessment and grading of liver steatosis, with an additional advantage of reduced computational complexity and accessibility. The CVL provided a very good accuracy (89.17%) for an AUROC of 0.923 for the classification of liver steatosis in two severity categories (mild versus moderate-severe). PMID- 26649336 TI - Visualization of liver lesions in standardized video-documented ultrasonography - inter-observer agreement and effect of contrast injection. AB - The AIM of this study was to evaluate the inter-observer agreement and effect of contrast injection on the visibility of liver lesions by radiologists reviewing ultrasound examinations acquired by a radiographer using a standardized examination protocol. MATERIAL AND METHOD: A retrospective review was conducted by two radiologists, independently of each other, of 115 ultrasound examinations of the liver with standardized examination protocols between January 2008 and December 2012. All patients included in the study had undergone surgery for colorectal cancer. Patients attending the two-year follow-up were included. RESULTS: Focal findings, the most common of which were cysts, were seen in 42-43 out of the 115 patients before intravenous contrast and in 46-47 patients after intravenous contrast (p=0.012). The inter-observer agreement for focal findings was 86.1% before contrast, and 90.4% after contrast (n.s.), and the corresponding kappa values were 0.72 and 0.84, respectively. CONCLUSIONS: A good inter-observer agreement between two radiologists reviewing ultrasound examinations (standardized ultrasound cine-loop method acquired by a radiographer) after surgery for colorectal cancer was obtained. Injection of contrast medium increased the visibility of liver lesions. PMID- 26649337 TI - Contrast enhanced ultrasound for the diagnosis of liver hemangiomas - results of a Romanian multicentre study. AB - BACKGROUND AND AIM: Contrast enhanced ultrasound (CEUS) has been proven to be a reliable method for the characterization of focal liver lesions (FLL). The aim of this paper was to evaluate the performance of CEUS for the diagnosis of liver hemangiomas in a large cohort of patients. MATERIAL AND METHOD: We performed a multicentre prospective study which included successive CEUS examinations from fourteen centers from Romania. CEUS examinations were performed in de novo FLL, using low mechanical index ultrasound, following an intravenous bolus of 2.4 ml SonoVue. CEUS was considered conclusive for hemangioma if a typical pattern was present following contrast (centripetal fill in during the arterial phase, hyperenhanced lesion during venous and late phases). In all cases a reference method was available (contrast CT or MRI or biopsy). The trial was registered in clinicaltrials.gov (Identifier NCT01329458). RESULTS: During February 2011 - May 2015, 1153 CEUS examinations were performed for the evaluation of de novo FLL. Out of the 1153 de novo FLL, 238 cases were diagnosed as hemangiomas by CEUS (typical enhancing pattern). Contrast CT/MRI and biopsy diagnosed additional 24 hemangiomas. From the 238 cases diagnosed as hemangiomas by CEUS, in 11 the final diagnosis was different. Considering contrast CT/MRI and biopsy as reference methods, CEUS had 90.4% sensitivity, 98.8% specificity, 95.4% positive predictive value, 97.4% negative predictive value, resulting in 96.9% diagnostic accuracy for the diagnosis of hemangiomas. CONCLUSION: CEUS is a sensitive and very specific method for the diagnosis of hemangiomas. PMID- 26649338 TI - Does Contrast Enhanced Ultrasound improve the management of liver abscesses? A single centre experience. AB - Liver abscess is a potentially lethal condition that requires prompt recognition and adequate treatment for a good outcome. The aim of this study was to assess the value of contrast enhanced ultrasound (CEUS) in the management of liver abscesses in the clinical practice of a single centre. MATERIAL AND METHODS: A retrospective analysis was performed including all patients diagnosed with liver abscesses during 5 years (2010-2014) in a tertiary Department of Gastroenterology and Hepatology. The demographic data, the presence of risk factors, the cause of liver abscess, the B-mode conventional US aspect, the CEUS appearance and the patient's outcome were documented and analyzed. RESULTS: The study group included 41 patients diagnosed with liver abscesses (17 women and 24 men, mean age 63.3+/ 13.2 years), 16/41 (39%) of them with diabetes mellitus. A single lesion was found in 28 (68.3%) patients, and 13 (31.7%) patients had multiple abscesses. The CEUS study was conclusive for the diagnosis of liver abscess in clinical context in 38/41 cases (92.7%). All conclusive cases presented rim enhancement in the arterial phase and no enhancement in the liquid areas. The honeycomb appearance with septa enhancement was present in 17/41 (41.5%) patients. Washout of the marginal rim was found in 22/41 (53.6%) lesions. CONCLUSIONS: In our group the most frequent CEUS features found were the rim enhancement in the arterial phase and the presence of no enhancement areas, followed by the honeycomb appearance. CEUS was able to be conclusive for the diagnosis of liver abscess in almost 93% of cases. PMID- 26649339 TI - Prospective comparison between real time contrast enhanced and conventional ultrasound guidance in percutaneous biopsies of liver tumors. AB - AIMS: The performance of percutaneous echo-guided biopsy in the hepatic tumoral diagnosis is limited (90% sensitivity) by several factors, among which tumor characteristics (type, size, and location) play an important role. Contrast enhanced ultrasound guided percutaneous biopsy (CEUS-PLB) is a new developed technique aimed at increasing the accuracy of percutaneous biopsies. The objective of our study was to evaluate the feasibility and performance of CEUS as a guiding method in performing liver biopsy (PLB). MATERIAL AND METHODS: One hundred and seventy one patients with liver tumors referred to the ultrasound department for LB were prospectively included in the study. PLB was performed with CEUS guidance in 90 patients (46 in patients with and 44 in patients without liver cirrhosis), in the remaining 81 (37 in patients with liver cirrhosis and 44 in patients without) with conventional US guidance. The lesions in the CEUS -PLB group were larger than those in the US-LB group (mean diameter 7.73 cm vs. 6.11 cm, p>0.05). In both groups the lesions were further divided in: a) lesions on cirrhosis; b) poorly visualized tumors; c) large tumors (>6 cm); d) cystic tumors; e) recurrences after ablation; and f) portal vein thrombosis. RESULTS: Real time CEUS-PLB was technically successful in 84 of the 86 procedures (97.6% technical success rate). The rate of successful single puncture attempt in CEUS PLB (43.02%) was higher than in the US-PLB group (23.4%) (p<0.05). The sensitivity of LB was significantly higher in the CEUS-PLB group than in the conventional US-LB group for all lesions (96.5% vs. 81.48%, p<0.05), for lesions on liver cirrhosis (95.2% vs. 75%, p<0.05), for large (> 6 cm) (97.8% vs. 82%, p<0.05), and for poorly visible lesions (100 vs. 66.6%, p=0.029). The patients with inconclusive pathological results after conventional guided LB were then biopsied with CEUS guidance. In all cases the final diagnosis could be established. One major complication occurred in each group (p>0.05). CONCLUSIONS: Percutaneous LB performed with CEUS guidance is a feasible and safe technique. It significantly improves the overall sensitivity of the procedure especially in patients with large lesions and in those poorly visualized on conventional ultrasound. PMID- 26649340 TI - Doppler ultrasound measurements of renal functional reserve in healthy subjects. AB - AIMS: The aim of this study was to calculate the normal values of renal functional reserve in healthy individuals measuring the resistive index and pulsatility index using Doppler ultrasonography. MATERIAL AND METHODS: Forty healthy volunteer adults were included in the study. Their basal resistive index and pulsatility index values were measured and after oral protein load at 30th, 75th and 120th minutes, resistive index and pulsatility index measurements were repeated. The maximum changes in resistive index and pulsatility index from baseline were calculated in each subject which represented the renal functional reserve. RESULTS: The mean values of resistive index and pulsatility index decreased significantly starting with 30 minutes and consecutively at 75 and 120 minutes (for all p<0.05). The highest decrease compared to baseline values was recorded at 75 minutes and renal functional reserve values were calculated as 22.2% for resistive index and 25.4% for pulsatility index. CONCLUSIONS: Renal functional reserve can be calculated through Doppler resistive index and pulsatility index measures. We consider that it may be helpful to know normal values of renal functional reserve in healthy subjects. PMID- 26649341 TI - Variation of safety indices during in the learning curve for color Doppler assessment of the fetal heart at 11+0 to 13+6 weeks' gestation. AB - AIMS: The aim of our study was to analyze the variation of acoustic output, as expressed by the thermal (TI) and mechanical index (MI), during the learning curve for a fetal heart scan at 11-13 gestational weeks, with the introduction of a new ultrasound system. MATERIAL AND METHODS: This was a prospective, observational study on 303 normal fetuses. The fetal heart was examined transabdominally using B-Mode and high definition (HD) color Doppler to obtain standard parameters: four-chamber, outflow tracts and three-vessel-trachea views. Data were analyzed in groups of 20 consecutive examinations and the percentage of successful examinations was calculated. TI and MI were retrieved from HD color Doppler examinations of the fetal heart and from pulsed-wave Doppler assessment of the tricuspid flow and ductus venosus. RESULTS: MI values from the color Doppler examination of the fetal heart showed a continuous decrease (0.81 to 0.75, p<0.001), along the learning phase. TI and MI indices from pulsed-wave Doppler evaluation of the tricuspid flow increased at the beginning of the learning phase and stabilized afterwards (0.34 to 0.36, p<0.05 and 0.37 to 0.4, p<0.001, respectively). TI from color Doppler exam of the heart and indices from ductus venosus assessment were very constant and did not change along the studied periods. The length of Doppler examination of the heart increased after about 80 cases by 25%, to a mean of 4 minutes (p<0.05). CONCLUSIONS: Safety indices from Doppler evaluation of the fetal heart and tricuspid flow vary during the learning curve for fetal heart assessment. Also, the occurrence of constant values suggests the potential for their supplementary active reduction. For a better adaptation to a new ultrasound technology, the sonographer should scan the fetal heart longer in the first trimester and follow displayed safety indices along the first 80 cases. PMID- 26649342 TI - The role of ventricular disproportion, aortic, and ductal isthmus ultrasound measurements for the diagnosis of fetal aortic coarctation, in the third trimester of pregnancy. AB - AIM: To analyze the role of ventricular disproportion, aortic, and ductal isthmus ultrasound measurements for the diagnosis of fetal aortic coarctation (AoCo) and to evaluate the prediction of a needed neonatal surgical intervention in the presence of a diagnosis of AoCo. MATERIAL AND METHODS: We performed a prospective study on 41 fetuses (pregnancy age- 32 to 39 weeks, median 36 weeks) evaluated for left ventricle (LV) < right ventricle (RV) disproportion. Four fetuses were lost from evidence and five fetuses with complex cardiac malformations were excluded. The remaining group of 32 fetuses and newborns were evaluated. RESULTS: AoCo was confirmed in 9 neonates (28.12%), all requiring surgical treatment in the neonatal period. Significant statistical differences were found in Z-score (p=0.0023) and dimensions (p=0.0029) of the aortic isthmus between the neonates with normal aorta and those with AoCo. If the values of RV/LV>1.5, Ductus/Ao isthmus >1.4, and Ao isthmus <4.2 mm are concomitantly accomplished, 83.3% of the fetuses (20 of 23) did not necessitate neonatal surgical intervention. Five of the 9 operated newborns had all three parameters with values over the threshold. The probability for required surgery is 13.87 times higher when the Ao isthmus is <4.2 mm (OR = 13.87 [95% CI = 1.88 - 102.20]). CONCLUSIONS: The use of the combination between the three studied parameters with their cut-off score prediction decreases the false positive diagnosis of AoCo. The fetuses with ventricular disproportion developed only in the last trimester, had reduced chances for AoCo. PMID- 26649343 TI - Venous flow volume measured by duplex ultrasound can be used as an indicator of impaired tissue perfusion in patients with peripheral arterial disease. AB - AIM: In this study, we aimed to investigate the arterial and venous flow volume rate (FV) in order to determine the tissue perfusion using duplex ultrasonography (DU). We hypothesized that FV provides reliable information regarding tissue perfusion in patients with peripheral arterial disease (PAD). MATERIAL AND METHODS: The study comprised 38 patients (72 legs) with PAD. In all patients, common femoral, popliteal, anterior tibial, posterior tibial arteries and veins were examined with DU. Measurements were obtained in the supine position with 15 cm elevation of the foot to neutralise central venous pressure. The diameter, blood flow velocity, and FV of arteries and veins were measured for each patient. RESULTS: The FV of the common femoral artery and vein (p = 0.001), popliteal artery and vein (p=0.003), and posterior tibial artery and vein (p = 0.008) had statistically significant differences. However, there was no statistically significant difference between the FV of the anterior tibial vein and artery (p = 0.408). The mean FV values of all veins were significantly lower than those of homonymous arteries in patients with PAD. CONCLUSIONS: Our study showed that venous FV measured by DU can be used as an indicator of impaired tissue perfusion in patients with PAD. PMID- 26649344 TI - Correlations between echocardiographic parameters of right ventricular dysfunction and Galectin-3 in patients with chronic obstructive pulmonary disease and pulmonary hypertension. AB - AIM: To evaluate the association between echocardiographic right ventricular (RV) structural and functional parameters and galectin-3 levels in patients with chronic obstructive pulmonary disease (COPD) and associated pulmonary hypertension presenting with acutely aggravated dyspnoea. MATERIAL AND METHODS: We conducted a prospective study on forty patients with COPD and forty healthy volunteers matched for age and sex (mean age 59+/-6 years), measuring galectin-3 and NT-proBNP serum levels and specific echocardiographic parameters. RESULTS: Galectin-3 was significantly higher in patients with COPD and elevated systolic pulmonary artery pressure than in healthy volunteers and discriminated better between patients with likely and possible pulmonary hypertension when compared to NT-proBNP. In multivariate analysis, the global model was better related to galectin-3 than to NT-proBNP levels (R2=0.61 vs. 0.31, p<0.001). Moreover, in contrast to NT-proBNP levels, correlations between galectin-3 levels and RV dysfunction, as assessed by the E/E' ratio and RV ejection fraction, persisted after adjustment for cardiovascular risk factors and COPD-induced inflammation. CONCLUSION: In patients with COPD-associated pulmonary hypertension presenting with acutely aggravated dyspnoea, galectin-3 levels are predictive of RV dysfunction and correlate better with RV dysfunction parameters compared to NT proBNP. PMID- 26649345 TI - Evaluation of Trastuzumab-induced early cardiac dysfunction using two-dimensional Strain Echocardiography. AB - AIM: Trastuzumab, a chemotherapeutic agent used in the treatment of breast cancer. has been shown to induce subclinical left ventricular (LV) dysfunction during a three to six month period as evidenced by strain echocardiographic examination without any change occurring in the ejection fraction of LV. The present study evaluated the presence of subclinical LV dysfunction using strain echocardiography 1 day and 7 days after the initiation of trastuzumab therapy. MATERIAL AND METHODS: The patients with breast cancer receiving adjuvant trastuzumab therapy underwent 2-dimensional, tissue Doppler, and strain echocardiographic examination at baseline and 1 day and 7 days after therapy. LV global longitudinal strain (GLS), global circumferential strain (GCS) values, and other echocardiographic parameters were calculated. RESULTS: A total of 40 females, mean age 50+/-10 years, were evaluated. Of these patients, 97% received anthracycline and 73% received radiotherapy before the initiation of trastuzumab therapy. No change was observed in any of the echocardiographic parameters 1 day after the initiation of trastuzumab therapy (p>0.05). The LV ejection fraction, tissue Doppler parameters, and GCS values did not show any changes 7 days after the initiation of therapy, whereas significant decreases were observed in GLS value (19.2+/-4.0% vs. 17.2+/-3.4, p=0.001) and systolic annular velocity of the lateral LV wall (S' velocity) (10.5+/-3.2 vs. 8.6+/-2.2, p=0.002). CONCLUSION: Trastuzumab therapy is associated with subclinical LV dysfunction as early as 7 days after initiation of the therapy as evidenced by the decreases in GLS value of LV and systolic annular velocity of the lateral LV wall. PMID- 26649346 TI - Using dynamic infrared thermography to optimize color Doppler ultrasound mapping of cutaneous perforators. AB - AIMS: The high technical demands associated with perforator flaps demand a precise preoperative identification and evaluation of perforator vessels. Color Doppler Ultrasonography (CDU) and Dynamic Infrared Thermography (DIRT) are currently used for preoperative perforator mapping. Each individual technique has advantages and disadvantages. The purpose of this paper is to analyze the value of combining the two methods in order to optimize the process of preoperative perforator mapping. MATERIAL AND METHODS: CDU and DIRT were used for preoperative perforator mapping in 10 pigs. The results were compared to intraoperative findings. Total number of perforators, localization, and identification of the dominant perforator was analyzed for each method. The examination time was recorded for each procedure. RESULTS: Both methods had a high sensitivity in determining the number and localization of perforators when compared to those identified during surgery. DIRT produced a higher number of false positive results. CDU accurately identified the emergence of the perforators in the fascia in all cases. Both methods correctly identified the dominant perforator. The sensitivity, positive predictive value, and accuracy of CDU were 93.56%, 97%, and 91.30% respectively and for DIRT 95.05%, 80.67%, and 77.41% respectively. The average examination was 39.76 minutes for CDU and 10.24 minutes for DIRT. The average time taken into account for the analysis of a single perforator in order to confirm DIRT findings was 1.83 minutes. CONCLUSIONS: Preoperative perforator mapping has become a compulsory step in nearly all reconstructive procedures. In our study, both CDU and DIRT correctly identified the dominant perforator in all cases. By combining the two examinations overall mapping time can be reduced significantly. A reduced examination time translates into increased patient compliance and a lower procedure cost. The combined mapping technique facilitates the selection of the ideal perforator in all cases. Correctly identifying the dominant perforator preoperatively reduces operative time, lowers complication rates and ensures an overall better result. PMID- 26649349 TI - EFSUMB guidelines 2015 on interventional ultrasound. AB - Ultrasound-guided interventions have revolutionized the everyday clinical practice during recent decades. The new interventional ultrasound (INVUS) guidelines of the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) are an expression of interdisciplinary and multiprofessional viewpoints, some of which represent different approaches; this reflects reality in all its diversity. Particular attention has been given to clinical significance including the level of evidence and the more practical grade of recommendation. The review refers to the history of interventional ultrasound and comments on the current EFSUMB guidelines. PMID- 26649347 TI - Doppler ultrasound and strain elastography in the assessment of cutaneous melanoma: preliminary results. AB - AIM: To study the usefulness of color or power Doppler ultrasound (US) in the pre surgical evaluation of skin melanoma, and to correlate the Doppler characteristics with the appearance on high frequency ultrasound strain elastography (SE) in the preoperative evaluation of cutaneous melanoma. MATERIALS AND METHOD: The study included 42 cutaneous melanoma lesions in 39 adult subjects examined between September 2011 and January 2015. Doppler US features (the presence and aspect of vascularization, and the number of vascular pedicles) and elasticity by strain elastography were evaluated together with the pathological results. RESULTS: The melanoma lesions presented hyper-vascularization, with multiple vascular pedicles and stiff appearance. Significant correlations between the thickness of the tumor, measured histopathologically by the Breslow index, and the degree of vascularization (p=0.0167), and number of vascular pedicles (p=0.0065) were identified. Strong correlations between the SE appearance and vascularization on one hand, and SE and the number of vascular pedicles were also identified (p<0.001). CONCLUSION: Our study demonstrates that Doppler US and SE offer useful information for THE preoperative evaluation of cutaneous melanoma and may contribute to better defining the long term prognosis. PMID- 26649348 TI - Recall strategies for patients found to have a nodule in cirrhosis: is there still a role for CEUS? AB - Development of liver tumors and their evolution to hepatocellular carcinoma (HCC) is a multi-step process in which different HCC-etiologies induce continuous rounds of hepatocyte damage and regeneration. Over an extended time, this triggers cirrhosis which is a pathological state of the liver in which lesions can progress to become dysplastic nodules. Later, these nodules may evolve into HCC and occasionally generate metastatic events. To provide optimal care, patients with liver cancer should be managed using a multidisciplinary approach in specialized centers in which all the diagnostic and therapeutic resources are available. Among the different imaging modalities the introduction on contrast agents for ultrasound use has opened new further applications in different clinical settings. In fact, contrast enhanced ultrasound (CEUS) has been applied for more than ten years and plays increasingly important roles in the management of HCC. Since early 2000, international societies including the American Association for the Study of Liver Diseases (AASLD), the European Association for the Study of the Liver (EASL), the Asian Pacific association for the Study of the Liver (APASL), the Japanese society of Hepatology (JSH), the Italian society for the study of the liver (AISF), the World Federation for Ultrasound in Medicine and Biology (WFUMB), and the European Federation of Societies for Ultrasound in Medicine and Biology (EFUSMB) have discussed the important role of CEUS in the diagnosis of HCC. In the present review an update of the literature and a detailed discussion of the present Guidelines regarding the role of CEUS in the evaluation of nodules in cirrhotic patients is offered. PMID- 26649350 TI - Ultrasound in the evaluation of penetrating thoraco-abdominal trauma: a review of the literature. AB - The use of ultrasound in the evaluation of blunt thoraco-abdominal trauma is well described. Evidence for the use of ultrasound in the evaluation of penetrating cardio-thoracic and abdominal trauma, however, is more limited and varied. Current literature demonstrates that ultrasound is an excellent screening tool for penetrating thoracic and cardiac injuries with a high sensitivity for detecting injury requiring acute intervention. For abdominal injuries, however, the sensitivity for detection of injury is low and thus the utility of ultrasound as a screening tool is limited. This review summarizes the existing literature addressing the clinical utility of ultrasound for penetrating trauma to the pericardium, thorax and abdomen. PMID- 26649351 TI - Musculoskeletal ultrasonography in gout. AB - Gout is a frequent inflammatory disease induced by the deposition of monosodium urate crystals in joints and extra-articular tissues. The natural history of the disease includes four different phases: asymptomatic hyperuricemia, acute attacks, intercritical phase, and chronic tophaceous gout. Imaging techniques have several applications in the diagnosis, clinical monitoring and management of the disease but particularly, musculoskeletal ultrasound is able to detect a wide set of abnormalities in gout. This review reports the most relevant findings detectable by ultrasound and the current available data in the literature regarding the role of musculoskeletal ultrasound in gout.. PMID- 26649352 TI - High frequency ultrasound study of skin tumors in dermatological and aesthetic practice. AB - The accurate measurement of skin tumors and the precise delimitation of its borders are important tools for tumor diagnosis and treatment. In this paper we summarized our practical experience in 'the examination of different skin tumors using high frequency ultrasound (HFU). High-frequency transducers 22 MHz and 75 MHz with resolution of 72 and 21 MUm were used for the examination. HFU characteristics of the most important non-melanoma skin tumors are depicted. PMID- 26649353 TI - Prenatal diagnosis of placenta and umbilical cord pathologies by three dimensional ultrasound: pictorial essay. AB - The authors present their experience in prenatal diagnosis of placental and umbilical cord pathologies, using three-dimensional ultrasound (3DUS) in the rendering and tomography ultrasound imaging (TUI) modes, associated with color Doppler in some cases. Cases of placenta accreta/placenta previa, circumvallate placenta, succenturiate lobe, true knot of the umbilical cord, nuchal cord, and marginal/velamentous umbilical cord insertion are presented. 3DUS can contribute to improve the accuracy of prenatal diagnosis of placenta and umbilical cord pathologies. PMID- 26649354 TI - Is Duplex-Ultrasound a useful tool in defining rejection episodes in composite tissue allograft transplants? AB - Immunologic reactions in transplanted organs are in more or less all allograft patients detectable: clear parameters exist as e.g. in renal transplants where the clearance power reduces by rejection. On the contrary, in composite tissue allografts clear and objective indicators stating a rejection episode lack. We present the case of a hand-transplanted subject with signs of acute transplant rejection diagnosed by means of Duplex Ultrasound and confirmed by biopsy. PMID- 26649356 TI - Doppler ultrasound diagnosis of an unusual variant of median arcuate ligament syndrome: concomitant involvement of celiac and superior mesenteric arteries. A case report. AB - Median arcuate ligament syndrome (MALS), also known as celiac artery compression syndrome is a rare condition characterized by chronic mesenteric ischemia, secondary to the compression of the celiac artery by the median arcuate ligament. Occasionally, in addition to the celiac artery, the superior mesenteric artery may be partially compressed by the median arcuate ligament. We report a case with complaints of chronic abdominal pain from compression of both the celiac artery and the superior mesenteric artery due to MALS, which was primarily detected by Doppler ultrasound. The diagnosis was confirmed with CT-angiography. PMID- 26649355 TI - Villous adenoma of the common hepatic duct: the importance of contrast-enhanced ultrasound and endoscopic retrograde cholangiopancreatography for relevant diagnosis. A case report and review of the literature. AB - Adenomas are frequently encountered in the lower digestive tract but are rarely diagnosed in the biliary tree. We report a case of villous adenoma of the common hepatic duct. A 58-year old male was admitted with a four week history of intermittent upper right quadrant pain. Gray scale and contrast-enhanced abdominal ultrasound showed a mass inside the common hepatic duct with arterial enhancement and slow wash-out during the late venous phase. Subsequent endoscopic retrograde cholangiopancreatography and intraductal ultrasound confirmed the presence of the lesion. The final histopathological examination showed villous adenoma of the common hepatic duct with high-grade dysplasia. Contrast enhanced ultrasonography used in conjecture with endoscopic retrograde cholangiopancreatography can help in differentiating biliary tumors. PMID- 26649357 TI - Sonographic features and management options of uterine arteriovenous malformation. A case report. AB - Uterine arteriovenous malformation (AVM), an extremely rare condition, is defined as an abnormal connection between artery and vein. Although the pelvis is a common site for AVM, the uterus is involved occasionally and the true incidence is unknown. The objective of this study was to discuss diagnostic features and management options of AVMs. In this paper six cases of AVMs have been reported with a review of diagnosis and management options. PMID- 26649358 TI - Identification of carotid artery dissection by contrast enhanced ultrasonograph. A case report. AB - Carotid arterial dissection is an important cause of stroke in young and middle aged patients. Ultrasound (and particularly contrast enhanced ultrasonography) is an important approach in patients with sudden onset of stroke combined with renal failure who are not suitable for angiography. In this report we describe the ultrasound features of carotid arterial dissection and discuss its utility. PMID- 26649359 TI - Ultrasound diagnosis of the phalanx fracture not designated by plain radiographs. PMID- 26649360 TI - Ultrasound assist devices - are they useful for interventions? PMID- 26649361 TI - Education in musculoskeletal ultrasonography: training in interventional procedures on a swine model. PMID- 26649362 TI - A new approach for trace analysis of guanidine compounds in surface water with resorcinarene-based ion chromatography columns. AB - Trace levels of pharmaceuticals have been detected in surface water and may pose a health risk to humans and other organisms. New chromatographic materials will help identify and quantify these contaminants. We introduce a new ion chromatographic (IC) material designed to separate cationic pharmaceuticals and report its ability to separate a group of guanidine compounds. Guanidine moieties are strongly basic and protonated under acid conditions, and therefore can potentially be separated on the newly designed stationary phase and detected by ion exchange chromatography. The new column packing material is based on glutamic acids bonded to resorcinarene moieties that in turn are bound to divinylbenzene macroporous resin. Detection limits in the range of 5-30 MUg L(-1) were achieved using integrated pulsed amperometric detection (IPAD) for guanidine (G), methylguanidine (MG), 1,1-dimethylbiguanide (DMG), agmatine (AGM), guanidinobenzoic acid (GBA) and cimetidine (CIM). Suppressed conductivity (CD) and UV-vis detection resulted in limits of detection similar to IPAD, in the range of 2-66 MUg L(-1), but were not able to detect all of the analytes. Three water sources, river, lake, and marsh, were analyzed and despite matrix effects, sensitivity for guanidine compounds was in the 100 MUg L(-1) range and apparent recoveries were 80-96%. The peak area precision was 0.01-2.89% for IPAD, CD and UV-vis detection. PMID- 26649363 TI - Microchip-based electrochemical detection using a 3-D printed wall-jet electrode device. AB - Three dimensional (3-D) printing technology has evolved dramatically in the last few years, offering the capability of printing objects with a variety of materials. Printing microfluidic devices using this technology offers various advantages such as ease and uniformity of fabrication, file sharing between laboratories, and increased device-to-device reproducibility. One unique aspect of this technology, when used with electrochemical detection, is the ability to produce a microfluidic device as one unit while also allowing the reuse of the device and electrode for multiple analyses. Here we present an alternate electrode configuration for microfluidic devices, a wall-jet electrode (WJE) approach, created by 3-D printing. Using microchip-based flow injection analysis, we compared the WJE design with the conventionally used thin-layer electrode (TLE) design. It was found that the optimized WJE system enhances analytical performance (as compared to the TLE design), with improvements in sensitivity and the limit of detection. Experiments were conducted using two working electrodes - 500 MUm platinum and 1 mm glassy carbon. Using the 500 MUm platinum electrode the calibration sensitivity was 16 times higher for the WJE device (as compared to the TLE design). In addition, use of the 1 mm glassy carbon electrode led to limit of detection of 500 nM for catechol, as compared to 6 MUM for the TLE device. Finally, to demonstrate the versatility and applicability of the 3-D printed WJE approach, the device was used as an inexpensive electrochemical detector for HPLC. The number of theoretical plates was comparable to the use of commercially available UV and MS detectors, with the WJE device being inexpensive to utilize. These results show that 3-D-printing can be a powerful tool to fabricate reusable and integrated microfluidic detectors in configurations that are not easily achieved with more traditional lithographic methods. PMID- 26649365 TI - Reply. PMID- 26649364 TI - [Incidence of head and neck cancers in Belgium: comparison with world wide and French data ]. AB - The squamous cell carcinomas of the upper aerodigestive tracts are frequent neoplasia,with as much as 466,831 and 168,368 cases diagnosed in 2008 among men and women worldwide,respectively. As such, they make up the sixth most frequent neoplasia among men and the eighth among women. Their frequency shows interesting variations covering the last 20 years, with an ascending tendency among women, which is higher in Europe, and a descending tendency in men, maximal in the USA. The comparison with the Belgian official data reveals a striking elevation of incidence of these cancers between both sexes, with important regional differences in Belgium. Finally, when we compare Belgian and French data, these cancers seem more frequent in France in men, but there is an opposite tendency among women, in which the carcinoma of the larynx is most represented in Belgium. Although the limited quality of the data limits the interpretation of these data, they seem to be partly in line with the evolution of the risk factors of these pathologies. PMID- 26649366 TI - Spontaneous coronary artery dissection as a cause of acute coronary syndrome. PMID- 26649367 TI - Intelligent life without bones. PMID- 26649368 TI - Peter Reddien. PMID- 26649370 TI - Nanotechnology and Oral Implants: An Update. PMID- 26649369 TI - Dental Professionalism. PMID- 26649371 TI - Addressing the need for high quality research on autism in adulthood. PMID- 26649372 TI - Unravelling how plants benefit from ROS and NO reactions, while resisting oxidative stress. AB - BACKGROUND AND AIMS: Reactive oxygen species (ROS) and reactive nitrogen species (RNS), such as nitric oxide (NO), play crucial roles in the signal transduction pathways that regulate plant growth, development and defence responses, providing a nexus of reduction/oxidation (redox) control that impacts on nearly every aspect of plant biology. Here we summarize current knowledge and concepts that lay the foundations of a new vision for ROS/RNS functions - particularly through signalling hubs - for the next decade. SCOPE: Plants have mastered the art of redox control using ROS and RNS as secondary messengers to regulate a diverse range of protein functions through redox-based, post-translational modifications that act as regulators of molecular master-switches. Much current focus concerns the impact of this regulation on local and systemic signalling pathways, as well as understanding how such reactive molecules can be effectively used in the control of plant growth and stress responses. CONCLUSIONS: The spectre of oxidative stress still overshadows much of our current philosophy and understanding of ROS and RNS functions. While many questions remain to be addressed - for example regarding inter-organellar regulation and communication, the control of hypoxia and how ROS/RNS signalling is used in plant cells, not only to trigger acclimation responses but also to create molecular memories of stress - it is clear that ROS and RNS function as vital signals of living cells. PMID- 26649373 TI - Reply letter: Mental health of people who have used classical psychedelics and no other illicit drugs. PMID- 26649374 TI - Guest Editorial: Haptic Assistive Technology for Individuals who are Visually Impaired. PMID- 26649375 TI - [Signaling molecules in the brain and epigenetic factors in neurodegenerative and mental disorders]. AB - The literature on a role of signaling molecules in the organization of memory and cognitive functions is analyzed basing on mechanisms of memory physiology determined by a complex of biochemical processes initiated by the transmission of the signal to the synapse and completed by the synthesis of functionally significant molecules in the neuronal genetic apparatus. The center of these processes is a coordinated system of signal transduction, transcription, epigenetic and neurotrophic molecules. The dissonance of signal mechanisms is a prime cause of memory impairment and cognitive dysfunction as social maladaptation factors. The results of experimental and clinical studies of a role of the multilevel signaling system in age-related, neurodegenerative (Alzheimer's disease) and mental (depression) disorders are discussed. At the same time, signaling molecules may be considered as particular targets for new therapeutic approaches. PMID- 26649376 TI - [Perampanel is a new drug for adjunctive treatment of primary generalized tonic clonic seizures]. PMID- 26649377 TI - Are you ready for the evolution from patient to consumer? PMID- 26649378 TI - Positive interactions expand habitat use and the realized niches of sympatric species. AB - Niche theory, the oldest, most established community assembly model, predicts that in sympatry, the realized niche will contract due to negative interspecific interactions, but fails to recognize the effects of positive interactions on community assembly. The stress gradient hypothesis predicts that positive interactions expand realized niches in stressful habitats. We tested the predictions of the stress gradient hypothesis in a cobble beach model system across both physical and biological stress gradients. We transplanted seven common littoral species within, adjacent to, and below Spartina alterniflora cordgrass stands in control, cage control, predator exclusion cage, shade, and shaded predator exclusion cage treatments to test the hypothesis that cordgrass expands intertidal organism habitats. On cobble beaches, cordgrass ameliorates physical and predation stresses, expanding the distribution and realized niches of species to habitats in which they cannot live without facilitation, suggesting that niche theory and species distribution models should be amended to accommodate the role of positive interactions in community assembly. PMID- 26649379 TI - Estimating demographic parameters using a combination of known-fate and open N mixture models. AB - Accurate estimates of demographic parameters are required to infer appropriate ecological relationships and inform management actions. Known-fate data from marked individuals are commonly used to estimate survival rates, whereas N mixture models use count data from unmarked individuals to estimate multiple demographic parameters. However, a joint approach combining the strengths of both analytical tools has not been developed. Here we develop an integrated model combining known-fate and open N-mixture models, allowing the estimation of detection probability, recruitment, and the joint estimation of survival. We demonstrate our approach through both simulations and an applied example using four years of known-fate and pack count data for wolves (Canis lupus). Simulation results indicated that the integrated model reliably recovered parameters with no evidence of bias, and survival estimates were more precise under the joint model. Results from the applied example indicated that the marked sample of wolves was biased toward individuals with higher apparent survival rates than the unmarked pack mates, suggesting that joint estimates may be more representative of the overall population. Our integrated model is a practical approach for reducing bias while increasing precision and the amount of information gained from mark resight data sets. We provide implementations in both the BUGS language and an R package. PMID- 26649380 TI - Animal movement constraints improve resource selection inference in the presence of telemetry error. AB - Multiple factors complicate the analysis of animal telemetry location data. Recent advancements address issues such as temporal autocorrelation and telemetry measurement error, but additional challenges remain. Difficulties introduced by complicated error structures or barriers to animal movement can weaken inference. We propose an approach for obtaining resource selection inference from animal location data that accounts for complicated error structures, movement constraints, and temporally autocorrelated observations. We specify a model for telemetry data observed with error conditional on unobserved true locations that reflects prior knowledge about constraints in the animal movement process. The observed telemetry data are modeled using a flexible distribution that accommodates extreme errors and complicated error structures. Although constraints to movement are often viewed as a nuisance, we use constraints to simultaneously estimate and account for telemetry error. We apply the model to simulated data, showing that it outperforms common ad hoc approaches used when confronted with measurement error and movement constraints. We then apply our framework to an Argos satellite telemetry data set on harbor seals (Phoca vitulina) in the Gulf of Alaska, a species that is constrained to move within the marine environment and adjacent coastlines. PMID- 26649381 TI - Fast fitting of non-Gaussian state-space models to animal movement data via Template Model Builder. AB - State-space models (SSM) are often used for analyzing complex ecological processes that are not observed directly, such as marine animal movement. When outliers are present in the measurements, special care is needed in the analysis to obtain reliable location and process estimates. Here we recommend using the Laplace approximation combined with automatic differentiation (as implemented in the novel R package Template Model Builder; TMB) for the fast fitting of continuous-time multivariate non-Gaussian SSMs. Through Argos satellite tracking data, we demonstrate that the use of continuous-time t-distributed measurement errors for error-prone data is more robust to outliers and improves the location estimation compared to using discretized-time t-distributed errors (implemented with a Gibbs sampler) or using continuous-time Gaussian errors (as with the Kalman filter). Using TMB, we are able to estimate additional parameters compared to previous methods, all without requiring a substantial increase in computational time. The model implementation is made available through the R package argosTrack. PMID- 26649382 TI - Phylogenetic relatedness and leaf functional traits, not introduced status, influence community assembly. AB - Considerable debate focuses on whether invasive species establish and become abundant by being functionally and phylogenetically distinct from native species, leading to a host of invasion-specific hypotheses of community assembly. Few studies, however, have quantitatively assessed whether similar patterns of phylogenetic and functional similarity explain local abundance of both native and introduced species, which would suggest similar assembly mechanisms regardless of origin. Using a chronosequence of invaded temperate forest stands, we tested whether the occurrence and abundance of both introduced and native species were predicted by phylogenetic relatedness, functional overlap, and key environmental characteristics including forest age. Environmental filtering against functionally and phylogenetically distinct species strongly dictated the occurrence and abundance of both introduced and native species, with slight modifications of these patterns according to forest age. Thus, once functional and evolutionary novelty were quantified, introduced status provided little information about species' presence or abundance, indicating largely similar sorting mechanisms for both native and introduced species. PMID- 26649383 TI - A unified approach for quantifying invasibility and degree of invasion. AB - Habitat invasibility is a central focus of invasion biology, with implications for basic ecological patterns and processes and for effective invasion management. "Invasibility" is, however, one of the most elusive metrics and misused terms in ecology. Empirical studies and meta-analyses of invasibility have produced inconsistent and even conflicting results. This lack of consistency, and subsequent difficulty in making broad cross-habitat comparisons, stem in part from (1) the indiscriminant use of a closely related, but fundamentally different concept, that of degree of invasion (DI) or level of invasion; and (2) the lack of common invasibility metrics, as illustrated by our review of all invasibility-related papers published in 2013. To facilitate both cross-habitat comparison and more robust ecological generalizations, we clarify the definitions of invasibility and DI, and for the first time propose a common metric for quantifying invasibility based on a habitat's resource availability as inferred from relative resident species richness and biomass. We demonstrate the feasibility of our metric using empirical data collected from 2475 plots from three forest ecosystems in the eastern United States. We also propose a similar metric for DI. Our unified, resource-based metrics are scaled from 0 to 1, facilitating cross-habitat comparisons. Our proposed metrics clearly distinguish invasibility and DI from each other, which will help to (1) advance invasion ecology by allowing more robust testing of generalizations and (2) facilitate more effective invasive species control and management. PMID- 26649384 TI - Plastic response of fearful prey to the spatiotemporal dynamics of predator distribution. AB - Ecological theory predicts that the intensity of antipredator responses is dependent upon the spatiotemporal context of predation risk (the risk allocation hypothesis). However, most studies to date have been conducted over small spatial extents, and did not fully take into account gradual responses to predator proximity. We simultaneously collected spatially explicit data on predator and prey to investigate acute responses of a threatened forest ungulate, the boreal caribou (Rangifer tarandus), to the spatiotemporal dynamics of wolf (Canis lupus) distribution during spring. Movement analysis of GPS-collared individuals from both species revealed high plasticity in habitat-selection decisions of caribou. Female caribou avoided open areas and deciduous forests and moved relatively fast and toward foraging areas when wolves were closer than 2.5 km. Caribou also avoided food-rich areas only when wolves were within 1 km. Our results bridge the gap between long-term perceived risk and immediate flight responses by revealing dynamic antipredator tactics in response to predator proximity. PMID- 26649385 TI - The importance of plant genotype and contemporary evolution for terrestrial ecosystem processes. AB - Plant genetic variation and evolutionary dynamics are predicted to impact ecosystem processes but these effects are poorly understood. Here we test the hypothesis that plant genotype and contemporary evolution influence the flux of energy and nutrients through soil, which then feedback to affect seedling performance in subsequent generations. We conducted a multiyear field evolution experiment using the native biennial plant Oenothera biennis. This experiment was coupled with experimental assays to address our hypothesis and quantify the relative importance of evolutionary and ecological factors on multiple ecosystem processes. Plant genotype, contemporary evolution, spatial variation, and herbivory affected ecosystem processes (e.g., leaf decay, soil respiration, seedling performance, N cycling), but their relative importance varied between specific ecosystem variables. Insect herbivory and evolution also contributed to a feedback that affected seedling biomass of O. biennis in the next generation. Our results show that heritable variation among plant genotypes can be an important factor affecting local ecosystem processes, and while effects of contemporary evolution were detectable and sometimes strong, they were often contingent on other ecological, factors. PMID- 26649386 TI - Controls over native perennial grass exclusion and persistence in California grasslands invaded by annuals. AB - Despite obvious impacts of nonnative species in many ecosystems, the long-term outcome of competition between native and exotic species often remains unclear. Demographic models can resolve the outcome of competition between native and exotic species and provide insight into conditions favoring exclusion vs. coexistence. California grasslands are one of the most heavily invaded ecosystems in North America. Although California native perennial bunchgrasses are thought to be restricted to a fraction of their original abundance, the eventual outcome of competition with invasive European annual grasses at a local scale (competitive exclusion, stable persistence, or priority effects) remains unresolved. Here, we used a two-species discrete time population growth model to predict the outcome of competition between exotic annual and native perennial grasses in California, and to determine the demographic traits responsible for the outcome. The model is parameterized with empirical data from several field experiments. We found that, once introduced, annual grasses persist stably with little uncertainty. Although perennial grasses are competitively excluded on average, the most likely range of model predictions also includes stable coexistence with annual grasses. As for many other perennial plants, native bunchgrass population growth is highly sensitive to the survival of adults. Management interventions that improve perennial adult survival are likely to be more effective than those that reduce exotic annual seed production or establishment, reduce competition, or increase perennial seedling establishment. Further empirical data on summer survival of bunchgrass adults and competitive effects of annuals on perennials would most improve model predictions because they contribute most to the uncertainty in the predicted outcome for the perennial grass. This work demonstrates how demographic approaches can clarify the outcome of competition between native and exotic species, identify key targets for future empirical work, and predict the effectiveness of management interventions. Such studies are critical both for understanding the impacts of invasion and for targeting management responses that maximize the benefit to native species. PMID- 26649387 TI - Soil processes drive seasonal variation in retention of 15N tracers in a deciduous forest catchment. AB - Seasonal patterns of stream nitrate concentration have long been interpreted as demonstrating the central role of plant uptake in regulating stream nitrogen loss from forested catchments. Soil processes are rarely considered as important drivers of these patterns. We examined seasonal variation in N retention in a deciduous forest using three whole-ecosystem 15N tracer additions: in late April (post-snowmelt, pre-leaf-out), late July (mid-growing- season), and late October (end of leaf-fall). We expected that plant 15N uptake would peak in late spring and midsummer, that immobilization in surface litter and soil would peak the following autumn leaf-fall, and that leaching losses would vary inversely with 15N retention. Similar to most other 15N tracer studies, we found that litter and soils dominated ecosystem retention of added 15N. However, 15N recovery in detrital pools varied tremendously by season, with > 90% retention in spring and autumn and sharply reduced 15N retention in late summer. During spring, over half of the 15N retained in soil occurred within one day in the heavy (mineral associated) soil fraction. During summer, a large decrease in 15N retention one week after addition coincided with increased losses of 15NO3- to soil leachate and seasonal increases in soil and stream NO3- concentrations, although leaching accounted for only a small fraction of the lost 15N (< 0.2%). Uptake of 15N into roots did not vary by season and accounted for < 4% of each tracer addition. Denitrification or other processes that lead to N gas loss may have consumed the rest. These measurements of 15N movement provide strong evidence for the dominant role of soil processes in regulating seasonal N retention and losses in this catchment and perhaps others with similar soils. PMID- 26649388 TI - The influence of habitat fragmentation on multiple plant-animal interactions and plant reproduction. AB - Despite broad recognition that habitat loss represents the greatest threat to the world's biodiyersity, a mechanistic understanding of how habitat loss and associated fragmentation affect ecological systems has proven remarkably challenging. The challenge stems from the multiple interdependent ways that landscapes change following fragmentation and the ensuing complex impacts on populations and communities of interacting species. We confronted these challenges by evaluating how fragmentation affects individual plants through interactions with animals, across five herbaceous species native to longleaf pine savannas. We created a replicated landscape experiment that provides controlled tests of three major fragmentation effects (patch isolation, patch shape [i.e., edge-to-area ratio], and distance to edge), established experimental founder populations of the five species to control for spatial distributions and densities of individual plants, and employed structural equation modeling to evaluate the effects of fragmentation on plant reproductive output and the degree to which these impacts are mediated through altered herbivory, pollination, or pre-dispersal seed predation. Across species, the most consistent response to fragmentation was a reduction in herbivory. Herbivory, however, had little impact.on plant reproductive output, and thus we found little evidence for any resulting benefit to plants in fragments. In contrast, fragmentation rarely impacted pollination or pre-dispersal seed predation, but both of these interactions had strong and consistent impacts on plant reproductive output. As a result, our models robustly predicted plant reproductive output (r2 = 0.52-0.70), yet due to the weak effects of fragmentation on pollination and pre-dispersal seed predation, coupled with the weak effect of herbivory on plant reproduction, the effects of fragmentation on reproductive output were generally small in magnitude and inconsistent. This work provides mechanistic insight into landscape scale variation in plant reproductive success, the relative importance of plant animal interactions for structuring these dynamics, and the nuanced nature of how habitat fragmentation can affect populations and communities of interacting species. PMID- 26649389 TI - Fire ecology of C3 and C4 grasses depends on evolutionary history and frequency of burning but not photosynthetic type. AB - Grasses using the C4 photosynthetic pathway dominate frequently burned savannas, where the pathway is hypothesized to be adaptive. However, independent C4 lineages also sort among different fire environments. Adaptations to fire may thus depend on evolutionary history, which could be as important as the possession of the C4 photosynthetic pathway for life in these environments. Here, using a comparative pot experiment and controlled burn, we examined C3 and C4 grasses belonging to four lineages from the same regional flora, and asked the following questions: Do lineages differ in their responses to fire, are responses consistent between photosynthetic types, and are responses related to fire frequency in natural habitats? We found that in the C4 Andropogoneae lineage, frost killed a large proportion of aboveground biomass and produced a large dry fuel load, which meant that only a small fraction of the living tissue was lost in the fire. C3 species from the Paniceae and Danthonioideae lineages generated smaller fuel loads and lost more living biomass, while species from the C4 lineage Aristida generated the smallest fuel loads and lost the most living tissue. Regrowth after the fire was more rapid and complete in the C4 Andropogoneae and C3 Paniceae, but incomplete and slower in the C3 Danthonioideae and C4 Aristida. Rapid recovery was associated with high photosynthetic rates, high specific leaf area, delayed flowering, and frequent fires in natural habitats. Results demonstrated that phylogenetic lineage was more important than photosynthetic type in determining the fire response of these grasses and that fire responses were related to the frequency that natural habitats burned. PMID- 26649390 TI - Species interactions regulate the collapse of biodiversity and ecosystem function in tropical forest fragments. AB - Competitive interactions among species with similar ecological niches are known to regulate the assembly of biological communities. However, it is not clear whether such forms of competition can predict the collapse of communities and associated shifts in ecosystem function in the face of environmental change. Here, we use phylogenetic and functional trait data to test whether communities of two ecologically important guilds of tropical birds (frugivores and insectivores) are structured by species interactions in a fragmented Amazonian forest landscape. In both guilds, we found that forest patch size, quality, and degree of isolation influence the phylogenetic and functional trait structure of communities, with small, degraded, or isolated forest patches having an increased signature of competition (i.e., phylogenetic and functional trait overdispersion in relation to null models). These results suggest that local extinctions in the context of fragmentation are nonrandom, with a consistent bias toward more densely occupied regions of niche space. We conclude that the loss of biodiversity in fragmented landscapes is mediated by niche-based competitive interactions among species, with potentially far-reaching implications for key ecosystem processes, including seed dispersal and plant damage by phytophagous insects. PMID- 26649391 TI - Recovery of African wild dogs suppresses prey but does not trigger a trophic cascade. AB - Increasingly, the restoration of large carnivores is proposed as a means through which to restore community structure and ecosystem function via trophic cascades. After a decades-long absence, African wild dogs (Lycaon pictus) recolonized the Laikipia Plateau in central Kenya, which we hypothesized would trigger a trophic cascade via suppression of their primary prey (dik-dik, Madoqua guentheri) and the subsequent relaxation of browsing pressure on trees. We tested the trophic cascade hypothesis using (1) a 14-year time series of wild dog abundance; (2) surveys of dik-dik population densities conducted before and after wild dog recovery; and (3) two separate, replicated, herbivore-exclusion experiments initiated before and after wild dog recovery. The dik-dik population declined by 33% following wild dog recovery, which is best explained by wild dog predation. Dik-dik browsing suppressed tree abundance, but the strength of suppression did not differ between before and after wild dog recovery. Despite strong, top-down limitation between adjacent trophic levels (carnivore-herbivore and herbivore plant), a trophic cascade did not occur, possibly because of a time lag in indirect effects, variation in rainfall, and foraging by herbivores other than dik-dik. Our ability to reject the trophic-cascade hypothesis required two important approaches: (1) temporally replicated herbivore exclusions, separately established before and after wild dog recovery; and (2) evaluating multiple drivers of variation in the abundance of dik-dik and trees. While the restoration of large carnivores is often a conservation priority, our results suggest that indirect effects are mediated by ecological context, and that trophic cascades are not a foregone conclusion of such recoveries. PMID- 26649392 TI - Invasive carnivores alter ecological function and enhance complementarity in scavenger assemblages on ocean beaches. AB - Species composition is expected to alter ecological function in assemblages if species traits differ strongly. Such effects are often large and persistent for nonnative carnivores invading islands. Alternatively, high similarity in traits within assemblages creates a degree of functional redundancy in ecosystems. Here we tested whether species turnover results in functional ecological equivalence or complementarity, and whether invasive carnivores on islands significantly alter such ecological function. The model system consisted of vertebrate scavengers (dominated by raptors) foraging on animal carcasses on ocean beaches on two Australian islands, one with and one without invasive red foxes (Vulpes vulpes). Partitioning of scavenging events among species, carcass removal rates, and detection speeds were quantified using camera traps baited with fish carcasses at the dune-beach interface. Complete segregation of temporal foraging niches between mammals (nocturnal) and birds (diurnal) reflects complementarity in carrion utilization. Conversely, functional redundancy exists within the bird guild where several species of raptors dominate carrion removal in a broadly similar way. As predicted, effects of red foxes were large. They substantially changed the nature and rate of the scavenging process in the system: (1) foxes consumed over half (55%) of all carrion available at night, compared with negligible mammalian foraging at night on the fox-free island, and (2) significant shifts in the composition of the scavenger assemblages consuming beach-cast carrion are the consequence of fox invasion at one island. Arguably, in the absence of other mammalian apex predators, the addition of red foxes creates a new dimension of functional complementarity in beach food webs. However, this functional complementarity added by foxes is neither benign nor neutral, as marine carrion subsidies to coastal red fox populations are likely to facilitate their persistence as exotic carnivores. PMID- 26649393 TI - Context dependence of maternal effects: testing assumptions of optimal egg size, differential, and sex allocation models. AB - If offspring develop in adverse conditions, the maternal component of their phenotypic variation might increase due to the stronger dependence of offspring traits on parental investment. This should result in increased parental investment to individual offspring, as assumed by the model of optimal egg size. The opposite pattern, i.e., stronger dependence of offspring fitness on parental investment and consequently larger parental investment under good conditions is assumed by both the theory of differential allocation if attractive males provide material benefits, and reproductive compensation if they invest less into paternal care. Another influential idea is the Trivers-Willard model, which assumes sex-specific dependence of offspring fitness on parental investment. Here we tested these ideas by examining the effects of egg size on offspring fitness across many postnatal contexts in the Collared Flycatcher Ficedula albicollis. We employed a cross-fostering design that generated variation in egg size within nests and used brood means of fledgling mass as a functional measure of the quality of rearing conditions. Effects of egg size on three offspring traits, including lifetime reproductive success of recruits, were more pronounced in low quality broods. These results support the assumption of the model of optimal egg size. Based on female preference for males providing material benefits, this pattern could support differential allocation, if attractive males invest less in paternal care, or reproductive compensation, if they invest more. By comparison, we did not find any evidence for sex specificity of fitness returns that might explain sex monomorphism of egg size in this species. The challenge for future studies will be the integration of components of parental investment and offspring fitness into their global measures and testing how the former affects the latter across gradients of postnatal conditions. PMID- 26649394 TI - Effectiveness of primate seed dispersers for an "oversized" fruit, Garcinia benthamii. AB - The largest fruits found in tropical forests may depend on complementary seed dispersal strategies. These fruits are dispersed most effectively by megafauna, but populations can persist where megafauna are absent or erratic visitors. Smaller animals often consume these large fruits, but their capacity to disperse these seeds effectively has rarely been assessed. We evaluated the contributions of gibbons (Hylobates lar) and other frugivores in the seed dispersal of the megafaunal fruit Garcinia benthamii, using the SDE (seed dispersal effectiveness) landscape. Gibbons preferentially consumed G. benthamii fruits and were the main seed disperser that we observed. However, gibbons became satiated when availability was high, with 57% of fruits falling to the ground unhandled. Recruitment of seedlings from gibbon-dispersed seeds was also very low. Elephants consumed G. benthamii fruit, but occurred at low density and were rare visitors to the trees. We suggest that gibbons might complement the seed dispersal role of elephants for G. benthamii, allowing limited recruitment in areas (such as the study site) where elephants occur at low density. Fruit availability varied between years; when availability was low, gibbons reliably consumed most of the crop and dispersed some seeds that established seedlings, albeit at low numbers (2.5 seedlings per crop). When fruit availability was high, the fruit supply overwhelmed the gibbons and other arboreal frugivores, ensuring a large abundance of fruit available to terrestrial seed dispersers. Although gibbons effectively dispersed more seeds at these times (20.7 seedlings per crop), there was the potential for elephants to move many more seeds. Complementary seed dispersal strategies may be important for megafaunal fruit, because they ensure that very large fruits are able to benefit from megafaunal dispersal but also persist where this dispersal becomes erratic. However, our data suggest that smaller seed dispersers might not be capable of replacing large dispersers, leading to potential changes in landscape-scale dispersal patterns where megafauna are absent. PMID- 26649395 TI - Long-term changes in liana loads and tree dynamics in a Malaysian forest. AB - The importance of lianas through time and their effect on tree reproduction are evaluated for the first time in a Southeast Asian Dipterocarp forest. We quantified flower and seed production by lianas and trees for 13 years, assessed liana loads in the crowns of all trees larger than 30 cm in diameter at breast height (1.3 m) in 2002 and 2014, and assessed levels of reproduction for the same trees during a strong general flowering event in 2014 for the 50-ha forest dynamics plot at the Pasoh Forest Reserve, Malaysia. General flowering refers to synchronous reproduction by hundreds of plant species at irregular, multiyear intervals and only occurs in Southeast Asian Dipterocarp forests. Overall, lianas were present in 50% of tree crowns and comprised 31% of flower production and 46% of seed production. Lianas reduced growth, survival, and reproduction by their host trees. Lianas were less frequent in canopy- emergent trees, Dipterocarps comprised a disproportionately large proportion of canopy emergents, and, as a consequence, lianas were less frequent in Dipterocarps than in trees from other plant families. Lianas infested the crowns of significantly fewer trees in 2014 (47.9%) than in 2002 (52.3%); however, the decrease was restricted to trees with the lightest liana loads and sample sizes and statistical power were enormous. Lianas comprised a stable proportion of flower production and a highly variable proportion of seed production from 2002 through 2013. We conclude lianas have a huge impact on trees in this forest and were a stable component of the forest between 2002 and 2014. The emergent habit and associated ability to avoid lianas might contribute to the success of the Dipterocarpaceae. PMID- 26649396 TI - Can inducible resistance in plants cause herbivore aggregations? Spatial patterns in an inducible plant/herbivore model. AB - Many theories regarding the evolution of inducible resistance in plants have an implicit spatial component, but most relevant population dynamic studies ignore spatial dynamics. We examined a spatially explicit model of plant inducible resistance and herbivore population dynamics to explore how realistic features of resistance and herbivore responses influence spatial patterning. Both transient and persistent spatial patterns developed in all models examined, where patterns manifested as wave-like aggregations of herbivores and variation in induction levels. Patterns arose when herbivores moved away from highly induced plants, there was a lag between damage and deployment of induced resistance, and the relationship between herbivore density and strength of the induction response had a sigmoid shape. These mechanisms influenced pattern formation regardless of the assumed functional relationship between resistance and herbivore recruitment and mortality. However, in models where induction affected herbivore mortality, large scale herbivore population cycles driven by the mortality response often co occurred with smaller scale spatial patterns driven by herbivore movement. When the mortality effect dominated, however, spatial pattern formation was completely replaced by spatially synchronized herbivore population cycles. Our results present a new type of ecological pattern formation driven by induced trait variation, consumer behavior, and time delays that has broad implications for the community and evolutionary ecology of plant defenses. PMID- 26649397 TI - Maternal adjustment of offspring provisioning and the consequences for dispersal. AB - Phenotypic plasticity in seed provisioning is a widespread phenomenon in plant populations that is often manifested as environmentally induced maternal effects. Environmental maternal effects can be beneficial if they influence population dynamic functions of seeds in a way that increases fitness, such as escaping from crowding. Using the winter annual plant, Dithyrea californica, we studied the response of seed provisioning to the maternal competitive environment and the associated seed dispersal consequences. We measured the average size of seeds produced by plants experiencing different competitive environments in order to test the hypothesis that mother plants respond to crowding by providing fewer resources to each offspring. We also hypothesized that smaller seeds produced by crowded mothers would benefit from greater dispersal away from their high-density natal habitat. We marked seeds with fluorescent paint while still attached to the mother plant, recorded seed diameter, and followed them for nine months after dispersal, recording the distance they moved from the mother plant. Plants that experienced more competition produced smaller seeds that dispersed farther from their mother plant. Larger seed diameter was previously shown to be'associated with greater competitive ability in D. californica. Thus the production of smaller seeds in more competitive environments implies a possible trade-off between competitive ability and dispersal arising from an environmentally driven aspect of phenotype. Fitness consequences of this trade-off in the context of the year-to-year variation in rainfall and density are uncertain. PMID- 26649398 TI - A multidimensional functional trait analysis of resource exploitation in European ants. AB - The major factors explaining ecological variation in plants have been widely discussed over the last decade thanks to numerous studies that have examined the covariation that exists between pairs of traits. However, multivariate relationships among traits remain poorly characterized in animals. In this study, we aimed to identify the main multivariate trait dimensions that explain variance in important functional traits related to resource exploitation in ants. To this end, we created a large ant trait database. This database includes information on 11 traits that are important in ant resource exploitation; data were obtained for 150 European species found in different biomes. First, we examined the pairwise correlations between the traits included in the database. Second, we used multivariate analyses to identify potential trait dimensions. Our study shows that, to a great extent, resource exploitation strategies align along two main trait dimensions. The first dimension emerged in both the overall and group specific analyses, where it accounted for the same pairwise trait correlations. The second dimension was more variable, as species were grouped by levels of taxonomy, habitat, and climate. These two dimensions included most of the significant pairwise trait correlations, thus highlighting that complementarity, but also redundancy, exists among different pairs of traits. The first dimension was associated with behavioral dominance: dominance was associated with large colony size, presence of multiple nests per colony, worker polymorphism, and a collective foraging 'strategy. The second dimension was associated with resource partitioning along dietary and microhabitat lines: it ranged from species that consume liquid foods, engage in group foraging, and mainly nest in the vegetation to species that consume insects and seeds, engage in individual foraging, and demonstrate strictly diurnal activity. Our findings establish a proficient ecological trait-based animal research that minimizes the number of traits to be measured while maximizing the number of relevant trait dimensions. Overall, resource exploitation in animals might be framed by behavioral dominance, foraging strategy, diet, and nesting habitat; the position of animal species within this trait space could provide relevant information about their distribution and abundance, for today as well as under future global change scenarios. PMID- 26649399 TI - Trophic mismatch requires seasonal heterogeneity of warming. AB - Climate warming has been shown to advance the phenology of species. Asynchronous changes in phenology between interacting species may disrupt feeding interactions (phenological mismatch), which could have tremendous consequences for ecosystem functioning. Long-term field observations have suggested asynchronous shifts in phenology with warming, whereas experimental studies have not been conclusive. Using proxy-based modeling of three trophic levels (algae, herbivores, and fish), we .show that asynchronous changes in phenology only occur if warming is seasonally heterogeneous, but not if warming is constant throughout the year. If warming is seasonally heterogeneous, the degree and even direction of asynchrony depends on the specific seasonality of the warming. Conclusions about phenological mismatches in food web interactions may therefore produce controversial results if the analyses do not distinguish between seasonally constant and seasonal specific warming. Furthermore, our results suggest that predicting asynchrony between interacting species requires reliable warming predictions that resolve sub-seasonal time scales. PMID- 26649400 TI - Fresh carbon input differentially impacts soil carbon decomposition across natural and managed systems. AB - The amount of fresh carbon input into soil is experiencing substantial changes under global change. It is unclear what will be the consequences of such input changes on native soil carbon decomposition across ecosystems. By synthesizing data from 143 experimental comparisons, we show that, on average, fresh carbon input stimulates soil carbon decomposition by 14%. The response was lower in forest soils (1%) compared with soils from other ecosystems (> 24%), and higher following inputs of plant residue-like substrates (31%) compared to root exudate like substrates (9%). The responses decrease with the baseline soil carbon decomposition rate under no additional carbon input, but increase with the fresh carbon input rate. The rates of these changes vary significantly across ecosystems and with the carbon substrates being added. These findings can be applied to provide robust estimates of soil carbon balance across ecosystems under changing aboveground and belowground inputs as consequence of climate and land management changes. PMID- 26649401 TI - Mammalian phylogenetic diversity-area relationships at a continental scale. AB - In analogy to the species-area relationship (SAR), one of the few laws in ecology, the phylogenetic diversity-area relationship (PDAR) describes the tendency of phylogenetic diversity (PD) to increase with area. Although investigating PDAR has the potential to unravel the underlying processes shaping assemblages across spatial scales and to predict PD loss through habitat reduction, it has been little investigated so far. Focusing on PD has noticeable advantages compared to species richness (SR), since PD also gives insights on processes such as speciation/extinction, assembly rules and ecosystem functioning. Here we investigate the universality and pervasiveness of the PDAR at continental scale using terrestrial mammals as study case. We define the relative robustness of PD (compared to SR) to habitat loss as the area between the standardized PDAR and standardized SAR (i.e., standardized by the diversity of the largest spatial window) divided by the area under the standardized SAR only. This metric quantifies the relative increase of PD robustness compared to SR robustness. We show that PD robustness is higher than SR robustness but that it varies among continents. We further use a null model approach to disentangle the relative effect of phylogenetic tree shape and nonrandom spatial distribution of evolutionary history on the PDAR. We find that, for most spatial scales and for all continents except Eurasia, PDARs are not different from expected by a model using only the observed SAR and the shape of the phylogenetic tree at continental scale. Interestingly, we detect a strong phylogenetic structure of the Eurasian PDAR that can be predicted by a model that specifically account for a finer biogeographical delineation of this continent. In conclusion, the relative robustness of PD to habitat loss compared to species richness is determined by the phylogenetic tree shape but also depends on the spatial structure of PD. PMID- 26649402 TI - Signals of climate, conspecific density, and watershed features in patterns of homing and dispersal by Pacific salmon. AB - It is widely assumed that rates of dispersal in animal populations are plastic in response to intrinsic and extrinsic cues, yet the factors influencing this plasticity are rarely known. This knowledge gap is surprising given the important role of dispersal in facilitating range shifts that may allow populations to persist in a rapidly changing global climate. We used two decades of tagging and recapture data from 19 hatchery populations of Oncorhynchus tshawytscha (Chinook salmon) in the Columbia River, USA, to quantify the effects of regional and local climate conditions, density dependence, watershed features such as area and position on the landscape, and direct anthropogenic influence on dispersal rates by adult salmon during the breeding season. We found that the probability of dispersal, termed "straying" in salmon, is plastic in'response to multiple factors and that populations showed varied responses that were largely idiosyncratic. A regional climate index (Pacific Decadal Oscillation), water temperatures in the mainstem Columbia River that was commonly experience by populations during migration, water temperatures in local subbasins unique to each population during the breeding season, migration distance, and density dependence had the strongest effects on dispersal. Patterns of dispersal plasticity in response to commonly experienced conditions were consistent with gene by environment interactions, though we are tentative about this interpretation given the domesticated history of these populations. Overall, our results warn against attempts to predict future range shifts of migratory species without considering population-specific dispersal plasticity, and also caution against the use of few populations to infer species-level patterns. Ultimately, our results provide evidence that analyses that examine the response of dispersal to single factors may be misleading. PMID- 26649403 TI - Disentangling the cause of a catastrophic population decline in a large marine mammal. AB - Considerable uncertainties often surround the causes of long-term changes in population abundance. One striking example is the precipitous decline of southern sea lions (SSL; Otariaflavescens) at the Falkland Islands, from 80 555 pups in the mid 1930s to just 5506 pups in 1965. Despite an increase in SSL abundance over the past two decades, the population has not recovered, with the number of pups born in 2014 (minimum 4443 pups) less than 6% of the 1930s estimate. The order-of-magnitude decline is primarily attributed to commercial sealing in Argentina. Here, we test this established paradigm and alternative hypotheses by assessing (1) commercial sealing at the Falkland Islands, (2) winter migration of SSL from the Falkland Islands to Argentina, (3) whether the number of SSL in Argentina could have sustained the reported level of exploitation, and (4) environmental change. The most parsimonious hypothesis explaining the SSL population decline was environmental change. Specifically, analysis of 160 years of winter sea surface temperatures revealed marked changes, including a period of warming between 1930 and 1950 that was consistent with the period of SSL decline. Sea surface temperature changes likely influenced the distribution or availability of SSL prey and impacted its population dynamics. We suggest that historical harvesting may not always be the "smoking gun" as is often purported. Rather, our conclusions support the growing evidence for bottom-up forcing on the abundance of species at lower trophic levels (e.g., plankton and fish) and resulting impacts on higher trophic levels across a broad range of ecosystems. PMID- 26649404 TI - Revascularization of the superior mesenteric artery alone for treatment of chronic mesenteric ischemia. AB - BACKGROUND: Symptomatic patients with chronic mesenteric ischemia (CMI) should be treated without much delay because symptoms of CMI are present in 43% patients who present with acute mesenteric ischemia. There are few reported series with large numbers of patients undergoing surgery for CMI, and many controversies persist regarding the optimal surgical treatment. These controversies include the type of surgical repair (antegrade vs. retrograde bypass), and the number of arteries that should be treated (single- vs. multiple-vessel reconstruction). It was the aim of presented study to report our experience and long-term results with single-vessel bypass grafting from infrarenal aorta to superior mesenteric artery. METHODS: Patients who were admitted because of mesenteric ischemia at the surgical clinics of University Clinical Center Maribor between January 1999 and January 2009 were identified with a computerized medical data registry. Patients who underwent revascularization for CMI with retrograde synthetic aortomesenteric bypass were included in the study. Demographics, clinical characteristics, imaging, and operative data were obtained from the medical records. Significant superior mesenteric artery stenosis (> 70% diameter stenosis) was confirmed by spiral computed angiography. All patients underwent retrograde aortomesenteric arterial bypass with synthetic bypass graft originating from the infrarenal aorta. Doppler sonography combined with color Doppler was used to evaluate disease progression in patients at 3-month interval during the first year and from then at 6-month intervals. Endpoints of the study were occlusion of graft or death by any cause. RESULTS: Data are presented for a cohort of 19 women and 8 men with a mean age at admission 73 years (range 56-88 years). The mean duration of follow-up was 71 months (range 1-118 months). There was one early death (4%). Four patients died during the follow-up period, and three were lost for follow up. None of the deaths was connected with mesenteric ischemia. During follow-up period none of the patients developed restenosis, and no occlusions were observed. There were no reinterventions. Symptom improvements were noted in 25 patients (93%). One patient (4%) referred to persistent pain despite successful revascularization, although during follow-up period weight gain was observed. At 71 months, freedom from recurrent symptoms, restenosis, and reinterventions was 78% +/- 13.9%. CONCLUSIONS: Surgery for CMI can be safely performed with retrograde approach and single vessel anastomosis. Mortality rates and long-term survival compare favorably with other surgical approaches to treatment of CMI. PMID- 26649405 TI - [Comparison of tigecycline and vancomycin activities in an in vitro biofilm model generated with methicillin-resistant Staphylococcus aureus]. AB - Today, the most common cause of bloodstream infections, which led to high mortality, prolonged hospitalization and increased costs are the intravenous catheters. Among the microorganisms associated with catheter infections, staphylococci took the first place and because of their biofilm-forming properties they cause serious problems in treatment and management of the patients. Although the drug of choice in the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infection is vancomycin, its effect on the bacterial biofilm is known to be low. Tigecycline, newly used in our country is a well tolerated glycylcycline antibiotic. In this study, we aimed to compare the efficacy of tigecycline and vancomycin in an in vitro MRSA biofilm model. The study consisted of 10 MRSA strains, which were detected as causative agents of catheter-related infections in our hospital. The methicillin resistance of the strains were performed by disk diffusion test with oxacillin (1 MUg) disks and the biofilm forming capacity of the strains was evaluated using the Congo red agar method. The silicone disks with created biofilm layer were exposed to tigecycline (2 mg/ml) and vancomycin (2 mg/ml) for 24 hours and for 5 days 4 hours per day in a model of antibiotic lock therapy. The present study showed that, after incubating the silicon discs in antibiotic solution for 24 hours, colony forming unit counts of MRSA decreased from 10(5) cfu/ml to 510 cfu/ml in the tigecycline group and from 105 cfu/ml to 3.800 cfu/ml in the vancomycin group and remained the same in the control (10(5) cfu/ml) group (p< 0.001). In the antibiotic lock therapy model, incubation with antibiotics for 4 hours per day, yielded that the average growth was 1.800 cfu/ml in the tigecycline group and 8.700 cfu/ml in the vancomycin group, which was statistically significant (p< 0.001). No growth was detected in the tigecycline group (0 cfu/ml) while in vancomycin group number of colonies in second, thirth and fourth days were 2.000, 260, 80 cfu/ml, respectively, no growth was seen in the fifth day. From the first day until the fourth day tigecycline was statistically more effective than vancomycin (p< 0.001, p< 0.001, p< 0.001, p= 0.013, according to days respectively). As a result, it was determined that tigecycline showed a higher effect on MRSA biofilm layer created on silicon discs and the results suggested that tigecycline might be a good alternative in the treatment of catheter infections. PMID- 26649406 TI - [Distribution of nontuberculous mycobacteria isolated from clinical specimens and identified with DNA sequence analysis]. AB - The aims of the study were to perform the identification of nontuberculous mycobacteria (NTM) isolated from different clinical specimens in the Mycobacteriology Laboratory of Celal Bayar University, Manisa (located at Aegean region of Turkey), by DNA sequence analysis, and to discuss the epidemiological aspects of the data obtained. Out of 5122 clinical specimens sent to the laboratory with the initial diagnosis of tuberculosis in the period April 2007 to July 2011, M.tuberculosis complex and NTM were identified in 225 (4.39%) and 126 (2.46%) samples, respectively. DNA sequence analysis by targeting hsp65 and 16S rDNA gene regions was performed on 101 of the NTM strains in Mycobacteriology Laboratory of Ege University, Izmir. DNA sequence analysis data was evaluated using RIDOM and GenBLAST data bases. NTM strains were identified as 40 M.porcinum (39.60%), 36 M.lentiflavum (35.65%), six M.abscessus (5.64%), five M.peregrinum (4.95%), four M.gordonae (3.96%), three M.fortuitum (2.97%), two M.chelonae (1.98%), and one for each M.alvei (0.99%), M.scrofulaceum (0.99%), M.kansasii (0.99%) species. Two strains which were both 95-98% compatible with other mycobacteria in the data bases could not be identified with certainty. Seventy two (94.73%) strains of M.lentiflavum and M.porcinum, which were the most frequent (75.24%) species in the study, were isolated from bronchoalveolar lavage (BAL) specimens. The remaining 99 strains examined could not be proven as the cause of the disease due to absence of patients' clinical data, whereas two M.abscessus strains isolated from the sputum were considered as the cause of the disease according to the ATS/IDSA criteria. The isolation rate of NTM in 2010 was found significantly higher (5.33%) than previous years. Review of the 2010 data showed that all strains of M.porcinum and M.lentiflavum, which were the most frequently identified strains were isolated from BAL specimens. This situation is in line with the start of using of an automatic bronchoscope washing machine in our hospital in the same year. In conclusion, NTM were isolated in 2.46% of the clinical specimens of the patients with the initial diagnosis of tuberculosis and these strains belonged to 10 different NTM species. The two NTM species most frequently isolated in our study were M.lentiflavum and M.porcinum which are known for their potential to cause human infections and antibiotic resistance. As these strains were mostly isolated in BAL specimens, it is concluded that automatic bronchoscope washing machines and water delivery system in the hospitals should be examined in terms of contamination by NTM. The isolated NTM strains could not be distinguished as the cause of the disease or a contaminant, which is the limiting factor in this study. However, knowing that the environmental mycobacteria can cause hospital infections, the data obtained in this study can contribute to epidemiology of NTM infections in Turkey. PMID- 26649407 TI - [The comparison of antibiotic susceptibilities of uropathogenic Escherichia coli isolates in transition from CLSI to EUCAST]. AB - Determination of treatment protocols for infections according to antimicrobial susceptibility test (AST) results is are important for controlling the problem of antibiotic resistance. Two standards are widely used in the world. One of them is Clinical Laboratory Standards Institute (CLSI) standards used in Turkey for many years and the other is the European Committee on Antimicrobial Susceptibility Testing (EUCAST) standards which is used in European Union member countries and came into use in 2015 in Turkey. Since the EUCAST standards had higher clinical sensitivity limits particularly for gram-negative bacilli compared to CLSI (2009) standards, there will be some changes in antibiotic resistance profiles of Turkey with the use of EUCAST. CLSI has changed zone diameters after 2009 versions and the differences between the two standards were brought to a minimum level. Knowledge of local epidemiological data is important to determine empirical therapy which will be used in urinary tract infections (UTI). The aim of this study was to determine the differences of antibiotic susceptibility zone diameters based on our local epidemiological data among uropathogenic Escherichia coli isolates according to EUCAST 2014 and CLSI 2014 standards. A total of 298 E.coli strains isolated from urine samples as the cause of uncomplicated acute UTI agents, were included in the study. Isolates were identified by conventional methods and with BBL Crystal E/NF ID System (Becton Dickinson, USA). AST was performed with Kirby Bauer disk diffusion method and results were evaluated and interpreted according to the CLSI 2014 and EUCAST 2014 standards. According to the results, susceptibility rates of isolates against amikacin (100%) and trimethoprim-sulfamethoxazole (63.09%) were identical in both standards. However, statistically significant differences were observed between CLSI and EUCAST standards in terms of susceptibilities against gentamicin (91.95% and 84.56%, respectively; p= 0.004), cefuroxime axetil (20.13% and 77.18%, respectively; p= 0.000) and levofloxacin (73.83% and 67.11%, respectively; p= 0.044). No statistically differences between two standards for ampicillin (32.89% and 36.24%, respectively; p= 0.219), ampicillin-sulbactam (65.77% and 69.13%, respectively; p= 0.216), ciprofloxacin (72.48% and 71.14%, respectively; p= 0.392) and imipenem (94.63% and 95.30%, respectively; p= 0.426) were determined. In this transitional period, continuity of cooperation between the clinician and microbiology laboratory should be kept forefront and the maintenance of local surveillance studies should be provided by taking into account the changes in antibiotic susceptibility results. PMID- 26649408 TI - [Molecular characterization of Salmonella enterica serovar Typhimurium strains isolated from humans in Turkey]. AB - Multidrug resistant (MDR) Salmonella infections, especially infections due to Salmonella Typhimurium DT104 phage type strains are an important public health issue in many parts of the world. S.Typhimurium is the most common serotype isolated from clinical samples in Turkey but we have limited data about the phage types of these isolates. The aims of this study were to find out whether these MDR S.Typhimurium isolates are DT104 phage type isolates and have class 1 integrons and to investigate the relationships of these characteristics between plasmid and pulsed field gel electrophoresis (PFGE) profiles. A total of 66 S.Typhimurium stock strains selected from Enterobacteria Laboratory culture collections of Ankara University School of Medicine, Department of Medical Microbiology were investigated by plasmid profile analysis (PPA) and PFGE with the use of XbaI and SpeI enzymes. The presence of class 1 integrons and the phage type 104 were investigated by polymerase chain reaction (PCR). The strains used in the study were sporadically isolated cases from seven provinces after year 2000 with ACSSuT (63), ACGSSuTT/S (1), ACSSuTT/S (1) and ASSuTT/S (1) resistance types [ampicillin (A), chloramphenicol (C), gentamicin (G), streptomycin (S), sulphonamide (Su), tetracycline (T), trimethoprim/sulfamethoxazole (T/S)]. Of the isolates 65 were found as DT104 phage type. Forty-three S.Typhimurium DT104 isolates that carry class 1 integrons had five different bands between 350-1600 base pairs (bp); all of the isolates harbored 1-4 plasmids with sizes ranging from 1.0-180 kbp and 62 isolates had 90 kbp plasmid which was serotype specific and virulence related. S.Typhimurium DT104 isolates were grouped into five (X1 X5) and seven (S1-S7) profiles with XbaI and SpeI enzymes, respectively. When the profiles of the two enzymes were evaluated, 58 of the 65 (89.2%) isolates showed similar (X1.S1) profile. The molecular characteristics of the most S.Typhimurium isolates were clustered in similar groups when class 1 integron, plasmid and PFGE types were analyzed together. In this study we showed that nearly all S.Typhimurium isolates with five drug resistance pattern (ACSSuT) were DT104 isolates. PFGE profiles of these sporadic isolates suggested that they were epidemiologically related. PMID- 26649409 TI - [Investigation of pathogenic phenotypes and virulence determinants of food-borne Salmonella enterica strains in Caenorhabditis elegans animal model]. AB - Salmonellosis, caused by non-typhoidal Salmonella enterica serovars with the consumption of contaminated food, is one of the leading food-borne disease that makes microbial food safety an important public health issue. This study was performed in order to determine the antibiotic resistance, serotyping, plasmid profiles and pathogenicity potentials of food-borne Salmonella isolates in Caenorhabditis elegans animal model system in Edirne province, located at Thrace region of Turkey. In this study, 32 Salmonella isolates, of which 26 belonged to Infantis, four to Enteritidis, one to Telaviv and one to Kentucky serovars, isolated from chicken carcasses were used. Antibiotic resistance profiles were determined by disc diffusion and broth microdilution methods. A new C.elegans nematode animal model system was used to determine the pathogenicity potential of the isolates. The antibiotic resistance profiles revealed that one (3.1%) isolate was resistant to gentamicin, two (6.2%) to ciprofloxacin, three (9.4%) to ampicillin, 18 (56.3%) to kanamycin, 19 (60.8%) to neomycin, 25 (78.1%) to tetracycline, 25 (78.1%) to trimethoprim, 26 (81.25%) to nalidixic acid, 27 (84.4%) to streptomycin and 32 (100%) to sulfonamide. All of the 32 strains were susceptible to chloramphenicol and ampicillin/sulbactam. High levels of resistance to streptomycin, nalidixic acid, tetracycline, trimethoprim, sulfonamide, kanamycin and neomycin was determined. According to the plasmid analysis, six isolates (18.75%) harboured 1-3 plasmids with sizes between 1.2 and 42.4 kb. In C.elegans nematode animal model system, the time (in days) required to kill 50% (TD50) of nematodes was calculated for each experimental group. TD50 values of the nematode group fed with S.Typhimurium ATCC 14028 that was used as the positive control and another group fed with E.coli OP50 as the negative control were 4.2 +/- 0.5 days and 8.0 +/- 0.02 days, respectively. TD50 of the groups fed with Salmonella isolates ranged between 3.4 and 7.3 days. The significance of the differences between TD50 values of the positive control and experimental groups was analysed by using Student's t test. Ten of the isolates (31.25%), of which six belonged to Infantis and four to the Enteritidis serotypes were non-pathogenic, and the rest 22 isolates including Infantis, Kentucky and Telaviv serovars (67.75%) were found to be pathogenic for the C.elegans animal system (p< 0.05). Twenty of the isolates (90.9%) which were determined as pathogens showed multiple drug resistance and three of them possessed 1-3 plasmids, sizes between 1.2 - 42.4 kb. The overall results underlined wide distribution of antibiotic-resistant Salmonella enterica strains and provided a practical alternative for studies aiming determination of pathogenic potential of environmental and food-borne strains through new experimental animal infection model. In this study, C.elegans was utilized for the first time to determine the profiles of pathogenicity of food-borne Salmonella serotypes in Turkey. PMID- 26649410 TI - [Evaluation of 10 cases of Lyme disease presenting with erythema migrans in Istanbul, Turkey]. AB - Lyme disease (LD) is a tick-borne, multisystemic infection caused by Borrelia burgdorferi. Although variable rates of seropositivity for B.burgdorferi have been reported between 2% to 44% in Turkey, its actual prevalence is not well understood. The aim of this retrospective study was to evaluate the characteristics of 10 cases of LD presenting as erythema migrans (EM) between 2009 and 2013 from Istanbul which is one of the metropolitan cities of Turkey. Of the patients, five were male and five were female, ages between 9-51 years (mean age: 34.5 years). Five of the patients were admitted in June, three in October, one in November and two in December and all have the history of tick bite in last 1-2 weeks. There were no clinical symptoms for systemic infection among the patients with normal level routine laboratory test (whole blood count and biochemical tests) results. Five of the cases had EM lesions in the trunk, three in the upper extremities, and two in the lower extremities. Four patients presented with annular, three with solitary macular, and three with target-like EM lesions. In all cases, the biopsy specimens were positive for B.burgdorferi sensu lato DNA with polymerase chain reaction and all were also positive in terms of B.burgdorferi IgM antibodies with ELISA. Nine patients were treated with oral doxycycline, 100 mg twice daily and one child patient was treated with oral amoxicillin 500 mg twice daily for 21 days. EM lesions disappeared within 2-4 weeks in all patients. There was no clinical evidence for systemic involvement in any of the patients like neurologic, cardiac, and joint involvement at the follow ups on the third, sixth and 12(th) months. To our best knowledge, 10 patients in this study are the largest EM series reported from Turkey. The increase in the number of LD cases may be associated with increased tick bite and increased awareness due to the emergence of concurrent Crimean-Congo hemorrhagic fever epidemic in Turkey. As a result, when enlarged erythematous lesions on the skin were observed, LH must also be considered in differential diagnosis, history of tick bite should be questioned and etiological diagnostic test should be performed. PMID- 26649411 TI - [Seroprevalence of tularemia in risk groups of humans and animals in Van, eastern Turkey]. AB - Tularemia has become a re-emerging zoonotic disease in Turkey recently. The aims of this study were to determine the seroprevalence of tularemia in humans and their animals living in rural risky areas of our region and to investigate the risk factors. Between January and July 2012, people living in rural areas of Van province (located at eastern part of Turkey) and their domestic animals were included in the study. The sample size was determined by using cluster sampling method like in an event with known prevalence and planned as a cross-sectional epidemiological study. Proportional random sampling method was used to determine which individuals will be included in the study. Presence of tularemia antibodies in the sera of a total 495 voluntary persons (343 female, 152 male; age range: 18 79 years, mean age: 40.61) and their 171 animals (40 cattle, 124 sheep and 7 goats) were screened by microagglutination test using safranin O-stained F.tularensis antigen (Public Health Agency of Turkey). For the evaluation of cross-reactivity between Brucella spp., tularemia positive serum samples were also tested with brucella microagglutination test. Among human and animal samples, 11.9% (59/495) and 44% (76/171) yielded positive results with the titers of >= 1:20 in F.tularensis microagglutination test, respectively. However, 69.5% (41/59) of human sera and 78.9% (60/76) of animal sera demonstrated equal or higher titers in the brucella test, so those sera were considered as cross reactive. After exclusion of these sera, the seroprevalence for F.tularensis were calculated as 3.6% (18/495) for humans and 9.4% (16/171) for animals. Among the 16 animals with positive results, 12 were sheep, three were cattle and one was goat. The difference between seropositivity rates among the domestic animal species was not statistically significant (p> 0.05). In addition, no statistically significant differences were found between risk factors including insect bite, tick bite, contact with rodents, eating the meat of hunted animals (rabbit), having pet (cat) in home (p> 0.05). In this study, the rate of tularemia seropositivity among humans was similar to the results of previous studies which were performed in our country; however the seropositivity rate of tularemia among domestic animals in our study was higher than the results of a few studies which were conducted on domestic animals. In conclusion, preventive procedures and precautions must be taken into consideration to control the transmission of the infection. PMID- 26649412 TI - [Mother-to-child transmisson of HIV: an eight-year experience]. AB - Mother-to-child transmission of human immunodeficiency virus (HIV) can be prevented by prenatal, perinatal and postnatal interventions. Although the incidence of HIV infection in Turkey is low, the number of cases are increasing in years. The aim of this study was to evaluate the characteristics of infants with HIV-positive mothers followed in a pediatric HIV center in Istanbul, Turkey and to describe the vertical transmission of HIV infection among the cases. Clinical and laboratory features of HIV-infected mothers and their exposed infants, followed in our department between June 2007 and February 2015 were retrieved from medical records retrospectively. The data about HIV infection and pregnancy course were confirmed with medical records when possible otherwise based on mothers' self-reports. Clinical and laboratory data about the birth and after birth of the babies in the other centers were obtained from the related centers. A total of 32 HIV-exposed infants (18 female, 14 male) were followed in eight years. HIV infection could be diagnosed in 15 (46.9%) mothers before pregnancy, in 10 (31.3%) during pregnancy and in seven (21.8%) during delivery. Nine of the mothers (28.1%) did not receive antiretroviral therapy during pregnancy. The median age for the patients at the admission were 13.5 days in which the earliest was a day and the latest was 420 (14 months) days. Three of the infants were fed with breast milk. Four infants (12.5%) did not receive antiretroviral prophylaxis. Cotrimoxazol prophylaxis were given approximately to 60% (n= 19) of the infants starting from 4-6 weeks. HIV viral load could be tested within the first 48 hours among 20 infants and except one, all was found as negative. A total of two infants (6.2%) were infected with HIV and their initial viral loads were 89.500 and 87.500 copies/ml, respectively. One of the infant was delivered vaginally and his mother's HIV status was detected during delivery. The mother of other infected infant was diagnosed only three weeks before birth and delivered with cesarean section. Both mothers had high viral loads just before delivery (> 102.000 and 67.000 copies/ml, respectively). One of the infants infected with HIV died in the 4(th) month due to pulmonary infection and sepsis. This study reveals a high rate of perinatally transmitted HIV infection and mortality. The limited number of cases involved in this one-center study should be taken into account while interpreting this result. All pediatric HIV centers in Turkey should work as partners for more precise national results. Nevertheless, our results draw attention to the lack of prenatal follow-up evaluation in women. In particular, the prompt diagnosis of HIV infection in pregnancy should be provided or not to be missed and follow-up of pregnant women with HIV should be carried out by specialist centers. PMID- 26649413 TI - [Investigation of the hepatitis E virus seroprevalence in cases admitted to Hacettepe University Medical Faculty Hospital]. AB - Hepatitis E virus (HEV), classified in Hepeviridae family, Hepevirus genus, is a non-enveloped virus with icosahedral capsid containing single-stranded positive sense RNA genome. HEV infections may be asymptomatic especially in children, however it may present as fulminant hepatitis in pregnant women, as well as chronic hepatitis in immunocompromised patients. There are four well-known genotypes of HEV that infect humans and many mammalian species. Genotype 1 and 2 are frequently responsible for water-borne infections transmitted by fecal-oral way in developing countries, while genotype 3 and 4 cause zoonotic infections in developed countries. Turkey is considered as an endemic country with a total seroprevalence rate of 6.3% for normal population, showing significant variation (0-73%) according to the regions and study groups. The aims of this study were to investigate the HEV seropositivity in cases admitted to Hacettepe University Medical Faculty Hospital (HUMFH), to evaluate the results according to the demographic features of patients, and to determine the current HEV seroprevalence in our region, contributing seroepidemiological data in Turkey. A total of 1043 serum samples (514 female, 529 male; age range: 1-90 years, mean age: 38.03) obtained from 327 blood donors (32 female, 295 male; age range: 19-59 years, mean age: 31.1) who were admitted to HUMFH Blood Center, and 716 sera (482 female, 234 male; age range: 1-90 years, mean age: 41.7) that were sent to HUMFH Central Laboratory from various outpatient/inpatient clinics, between November 2012 to November 2013, were included in the study. The presence of HEV-IgG antibodies in serum samples was detected by a commercial ELISA method (Euroimmun, Germany), and the presence of HEV-IgM antibodies was also investigated in the sera with IgG positive results. The overall HEV-IgG seropositivity rate was determined as 4.4% (46/1043), and the seropositivity rates for blood donors and in/outpatients were as 0.92% (3/327) and 6.0% (43/716), respectively. HEV-IgM antibody was not detected in any of the cases. The HEV-IgG seropositivity was 3.2% among male, and 5.6% among female, yielding no statistically significant difference between the gender (p= 0.056). HEV-IgG antibodies were detected in none (0/118) of the pediatric age group (0-18 years), while the seropositivity rates were 1.9% (14/731) and 16.5% (32/194) in 19-55 and >= 56 years-old groups, respectively. The difference between the age groups was statistically significant (p< 0.001), indicating the age-related pattern of HEV exposure. In conclusion, the total HEV seroprevalence rate found as 4.4% in our study, is comparable to the average results reported from Turkey. Our data is also in agreement with the result of a previous report (3.8%) that performed from Ankara province in 2002 with similar study groups, emphasizing that there was no significant changes for HEV exposure have occured over more than the last decade in Ankara, Cental Anatolia, Turkey. PMID- 26649414 TI - [Evaluation of risk factors for invasive pulmonary aspergillosis and detection of diagnostic values of galactomannan and PCR methods in bronchoalveolar lavage samples from non-neutropenic intensive care unit patients]. AB - Non-neutropenic intensive care unit (ICU) patients are at particular risk for invasive pulmonary aspergillosis. In these cases, radiological and microbiological methods (direct microscopy, culture), which can be used for diagnosis, have quite low sensitivity and specificity. The aims of this study were to evaluate the risk factors for invasive pulmonary aspergillosis (IPA) in non-neutropenic ICU patients and to determine the diagnostic values of galactomannan (GM) antigen and Aspergillus nucleic acid detection methods. A total of 44 patients (13 female, 31 male; age range: 36-96 years) who had been followed at pulmonary ICU with invasive mechanical ventilation and undergone bronchoscopy between January to December 2013, were included in the study. Consecutive bronchoalveolar lavage (BAL) and serum samples were obtained from all of the patients. BAL samples were tested for the presence of Aspergillus DNA by polymerase chain reaction (PCR) and both serum and BAL samples were tested for GM antigen by EIA method (Platelia Aspergillus, BioRad, France). EORTC/MSG criteria were used for the case definition of IPA. Patients were classified as high probable IPA, possible IPA and non-IPA. ROC (receiver operating characteristics) analysis was used to determine the diagnostic values of BAL Aspergillus PCR and BAL GM in the diagnosis of IPA. Five patients were defined as high-probable IPA and six were defined as possible IPA; thus the incidence rate of IPA was estimated as 11.4% (5/44) among non-neutropenic intensive care unit patients. In high-probable IPA patients, BAL GM levels were significantly higher than non-IPA patients (p< 0.05). The prolonged duration in ICU, presence of septic shock and the use of high cumulative doses (> 460 mg) of steroid were found to be risk factors for IPA development. The cut-off value for GM in BAL samples was determined as 0.7, with a sensitivity rate of 100% (95% confidence interval: 47.9 100) and a specificity rate of 87.9% (95% confidence interval: 71.7-96.5), so optimal GM level in BAL was considered as >= 0.7 for the diagnosis of IPA. The specificity rates of serum GM and BAL Aspergillus PCR methods were high (97.1% and 93.9%, respectively), however their sensitivity rates were found quite low (33.3% and 40%, respectively), in the diagnosis of IPA. In conclusion, development of IPA should be assessed in non-neutropenic patients when the stay in ICU extends and high dose cumulative steroids are used. GM antigen detection in BAL can be used effectively for diagnosis of IPA in these patients compared to other diagnostic methods. PMID- 26649415 TI - [Genotyping of Giardia intestinalis isolates in the Thrace Region, Turkey]. AB - Giardia intestinalis is a common protozoon that infects humans and may cause water and food-borne outbreaks. It is regarded as a major public health problem worldwide and in Turkey as well. Molecular techniques are widely used to determine the epidemiology, genetic populations and taxonomy of G.intestinalis. It has two genotypes including genotype A and genotype B in humans. The purpose of the present study is to implement the molecular analysis and genotyping of the isolates of G.intestinalis obtained from human stool samples. A total of 39 isolates obtained from the stool samples of persons (30 male, 9 female; age range: 1-74 years, median age: 20) who have admitted to Trakya University Medical Research and Practice Health Center and Edirne State Hospital between September 2011- April 2013 were included in the study. The average number of cysts were identified both with native and lugol methods among all microscopically detected samples by screening at least 50 field with x400 magnification. The samples were then analyzed through loop-mediated isothermal amplification method (LAMP) for the presence of elongation factor-1 alpha (EF-1alpha) gene, and polymerase chain reaction (PCR) method for the presence of beta-giardin (bg) gene regions. In addition, sequence analysis of bg gene was performed. Of 39 samples, 32 (82%) and 19 (48.7%) were found to be positive for G.intestinalis EF-1alpha and bg genes by LAMP and PCR methods, respectively. Genotyping was implemented in 17 out of 19 samples yielding nine genotype A and eight genotype B strains. The sub-genotypes of these strains were identified as A2 (n= 6), A3 (n= 3), B2 (n= 6), B3 (n= 1) and B4 (n= 1). In eight isolates that could be typed among 21 symptomatic patients, genotype B (n= 5) and in nine isolates that could be typed among 18 asymptomatic patients, genotype A (n= 6) were more frequently observed. There was no significant association between symptomatic or asymptomatic status and genotypic patterns of the cases (p= 0.347). The PCR positivity rate showed a significant difference between patients with higher cyst density and lower cyst density (p= 0.0001). In conclusion, molecular methods such as LAMP and PCR might have the potential to provide a substantial guidance for the analysis of outbreaks. In addition, the determined subtypes of G.intestinalis in our region is expected to contribute to the global epidemiological data. PMID- 26649416 TI - [Evaluation of clinical and laboratory findings of adult visceral leishmaniasis cases]. AB - Visceral leishmaniasis (VL, kala-azar) is a zoonotic infection caused by Leishmania species which are transmitted to humans by the bites of infected female phlebotomine sandflies. Leishmania infantum is the responsible species of VL in Aegean, Mediterranean, and Central Anatolia regions of Turkey mainly observed sporadically in pediatric age groups. The aim of this study was to evaluate the clinical and laboratory findings of adult patients with VL who were admitted to our hospital. A total of 10 patients (3 female, 7 male; age range: 18 67 years, mean age: 39.3 +/- 16.51) followed in the infectious diseases clinic of the hospital between 2000 and 2013 were evaluated retrospectively. The diagnosis of VL was based on the presence of appropriate clinical and physical examination, as well as biochemical findings, positive serological test results (indirect fluorescent antibody test, and rK39 rapid antigen test) and/or detection of amastigote forms of parasite in the bone marrow aspiration samples. Of the cases three were diagnosed with both bone marrow and serology positivity, five with bone marrow positivity and one of each only with liver biopsy and positive serology result. Time interval from onset of the symptoms until the establishment of the specific clinical diagnosis was ranged from 2 to 12 weeks. The most frequent initial symptoms were fever, fatigue and abdominal distension. None of the patients had immunosupressive conditions such as HIV infection, corticosteroid use, immunosupressive treatment, or transplantation. All the patients were from Aegean region and six were living in rural areas. In all cases, hepatosplenomegaly, increased erythrocyte sedimentation rate, albumin/globulin ratio inversion, anemia, leukopenia and among nine cases trombocytopenia were detected. In one case acute renal failure has been developed before treatment and the patient was admitted to dialysis program. Bacterial superinfection occurred in two cases. Patients were treated with either meglumine antimonate (Glucantime((r)), 20 mg/kg/day, intramuscularly for 28 days) or liposomal amphotericin B (3 mg/kg/day, intravenously for the first 5 days, then on 14(th) and 21(st) days) according to the availability of drugs. During one year follow-up period all of the patients improved and no recurrence was seen in any patient. In conclusion, among adult patients with fever uncontrolled within 2 week course of ampiric antibiotic treatment without any infectious focus or malignancy, VL should also be considered. PMID- 26649417 TI - [Investigation of the presence of mecC and Panton-Valentine leukocidin genes in Staphylococcus aureus strains isolated from clinical specimens during seven years period]. AB - Detection and identification of methicillin-resistant Staphylococcus aureus (MRSA) in clinical microbiology laboratories are important for the selection of appropriate treatment and obtaining epidemiological data. mecC gene, is a mecA homologue, showing almost 69% DNA similarity with the mecA gene and the encoded protein by this gene shows almost 63% similarity with the PBP2a/2' protein. Several studies indicated that mecC positive MRSA strains can be transmitted from the livestock to humans by cross contamination. Panton-Valentine leukocidin (PVL), a potent cytotoxin of S.aureus is also considered as an important virulence factor. The aim of this study was to determine the existence and prevalence of mecC and pvl genes among S.aureus strains isolated from clinical specimens. A total of 1700 S.aureus isolates including 1177 methicillin susceptible S.aureus (MSSA) and 523 MRSA, isolated in our hospital between January 2007 to December 2014, were included in the study. The isolates were identified by both conventional methods and BD Phoenix automated system (BD Diagnostic Instrument Systems, USA). Antibiotic susceptibility testing was performed by Kirby-Bauer disk diffusion method with oxacillin (1 MUg) and cefoxitin (30 MUg) according to the CLSI standards. The presence of mecA gene was investigated by the use of real-time PCR, and the presence of pvl and mecC genes were detected by conventional PCR method. Among the patients, 44.6% (759/1700) were outpatients, 65.8% (1119/1700) were male and the mean age of of patients was 39.7 years. Of 1700 isolates evaluated in this study, 523 (30.7%) were positive for mecA gene, however all of them were negative for mecC gene. A total of 32 (1.8%) isolates were positive for pvl gene including 23 (1.9%) out of 1177 MSSA and nine (1.7%) out of 523 MRSA strains. Eighteen (56.2%) of the PVL-positive S.aureus strains were isolated from skin and soft tissue infections. The frequency of PVL detected in this study was similar to the data of previous studies in our country. To the best of our knowledge, this is the first study for the determination of the mecC in our country. Although the mecC gene positive S.aureus has not been detected in our study, it should be kept in mind that the regional epidemiological conditions can vary quickly. In conclusion, multicenter studies are needed for the screening of mecC gene including the animal isolates, in Turkey. PMID- 26649418 TI - [Rapid detection of extended-spectrum beta-lactamases by flow cytometry method]. AB - Extended-spectrum beta-lactamases (ESBL), produced by Enterobacteriaceae members are enzymes that especially cause a resistance to cephalosporin group antibiotics commonly used in clinics. Early and rapid detection of ESBL production is crucial for antimicrobial treatment and infection control; however the methods used for this purpose are time consuming (24 to 48 hours). The aim of this study was to determine a flow cytometry based-test which provides to detect ESBL producing bacteria in a short time. A total of 38 ESBL-producing (29 Escherichia coli, 9 Klebsiella pneumoniae) and 10 non-producing (5 E.coli, 5 K.pneumoniae) Enterobacteriaceae strains isolated between 2012 and 2013 were included in this study. The identification and antibiotic susceptibility tests of the isolates were performed by using Phoenix(TM) 100 automated system (Becton Dickinson, USA). The presence of bla(TEM), bla(SHV), bla(CTX-M1), bla(CTX-M2) and bla(CTX-M9) genes were investigated in ESBL positive isolates via polymerase chain reaction method. At least one of the ESBL genes were detected in 36 out of 38 isolates and no genes were detected in two E.coli isolates. In flow cytometric method, the percentages of death cells exposed to cephalosporin [(ceftazidime (CAZ) or cefotaxime (CTX)] and clavulanic acid (CLA) combination, were compared with death cells exposed only to cephalosporin (CAZ or CTX). CLA index values (CAZ-CLA and CTX-CLA indices) were obtained for CTX and CAZ. Index values which was higher than 1.5 just for one cephalosporin were accepted as GSBL positive. The mean index values for CTX-CLA in ESBL positive strains according to their genotypic characteristics were between 1.14 and 7.22, while those values for CAZ-CLA were between 0.85 and 5.6. When the two groups of 38 ESBL positive and 10 ESBL negative strains were evaluated, statistically significant difference was detected for both CAZ-CLA and CTX-CLA indices (p< 0.005). CTX-CLA indices (p= 0.001) shown a better determination of ESBL when CAZ-CLA and CTX-CLA indices were compared statistically. In conclusion, flow cytometry is a rapid and reliable method for the detection of ESBL in clinical microbiology laboratories when compared with the other methods. PMID- 26649419 TI - [Investigation of mutations in transcription factors of efflux pump genes in fluconazole-resistant Candida albicans strains overexpressing the efflux pumps]. AB - In recent years, a significant rise in the number of immunocompromised patients have been observed due to cancer chemotherapy, organ transplantation and HIV infection. As a result of this, the frequency of Candida albicans infections in the clinics have been increased. Fluconazole, as being a well tolerated, easy to use drug with minor side effects, is often the first choice antifungal agent for this patient group, both for therapy and prophylaxis. Especially the long-term use of this drug, causes the selection of resistant strains and leads to the development of fluconazole resistance. The most frequently observed resistance mechanism against fluconazole in C.albicans strains is the transportation of the drug out of the cell via efflux pumps. The efflux pumps mainly involved are Cdr1, Cdr2 ve Mdr1 encoded by CDR1, CDR2 and MDR1 genes. It has been shown that, the overexpression of these efflux pump genes was caused by functional mutations in TAC1 and MRR1 genes which encode the transcription factors Tac1p and Mrr1p. This study was aimed to analyze TAC1 and MRR1 genes of 15 C.albicans strains which consist of six fluconazole-susceptible, four susceptible with trailing effect and five fluconazole-resistant isolates plus one resistant strain (DSY292), known to overexpress Mdr1 efflux pump due to P683H mutation in MRR1 gene and one fluconazole-sensitive ATCC 14053 C.albicans strain in terms of mutations with polymerase chain reaction and sequence analysis. Two of the fluconazole-resistant isolates which had overexpression of Cdr1 and Cdr2 pumps known to have overexpression of TAC1 gene, revealed R673Q and A736V mutations. A P683H point mutation, that overexpressed the Mdr1 pump was detected in a fluconazole resistant strain, which was known to cause MRR1 overexpression. In conclusion, mutations in the transcription factors of the efflux pump genes may play an important role in the resistance against fluconazole among our selected C.albicans strains. PMID- 26649420 TI - [A recurrent case of adult favus successfully treated with terbinafine]. AB - Favus or tinea capitis favosa, is a chronic inflammatory dermatophytosis of the scalp. The disease is particularly common in children aged 6 to 10 years, more often in boys, and it also occurs in adults. Human-to-human transmission is therefore possible. Anthropophilic Trichophyton schoenleinii is responsible for over 95% of favus cases. In addition, there are rare cases of anthropophilic T.violaceum, zoophilic (T.verrucosum, T.quinckeanum, and Microsporum canis) and geophilic M.gypseum species recorded as agents of favus. It is also reported in mice (T.quinckeanum), poultry (M.gallinae), and cats (M.incurvatum). Favus is common in Iran, Nigeria, and China, however it has been reported rarely in the last two decades in Turkey. Although Turkish records are not sufficient to indicate an accurate incidence rate, favus is still present in Turkey. In this report, a 20-year-old female with favus was presented. She had squames and areas of alopecia on the right frontoparietal area of her scalp. Scalp biopsy and hair follicle samples were taken for histopathological examination and fungal culture. According to the conventional identification by mycological methods and internal transcribed spacer (ITS) sequencing analysis, the pathogen was identified as T.schoenleinii. The patient was treated with oral terbinafine (250 mg/day) for 4 weeks and topical isoconazole and ketoconazole for 6 weeks. Clinical recovery was observed after 6 weeks, however, fungal culture could not be repeated. Six months after the initial presentation, the patient's symptoms recurred due to the poor adherence and T.schoenleinii was repeatedly grown in culture. Antifungal treatment was administered with the same drugs for the same period. There was a clinical and mycological recovery 8 months after initial presentation. Favus, which is not frequently observed in adults, is an uncommon disease. Confusion arises in its diagnosis because other diseases have similar clinical appearances, and asymptomatic carriage have also been reported. For these reasons, and because of improvements in health conditions, treatment might be delayed. With accurate assessment of the patient's medical history, the clinical characteristics of the disease, and results of laboratory analyses, coupled with effective mycologist clinician collaboration, it is possible for the patient to continue a healthy social life. Consequently, favus is still an important health problem encountered in Turkey. PMID- 26649421 TI - [Clinical impact of hepatitis C virus genomic variations]. AB - Hepatitis C virus (HCV) is a globally-dispersed agent of chronic hepatitis with a significant public health threat, affecting over 110 million individuals throughout the world. The increased risk for chronicity after exposure and the lack of a protective vaccine make HCV is a leading infectious cause of cirrhosis, liver failure requiring transplantation and hepatocellular carcinoma. The replicative process and infection dynamics in the host enable HCV to generate an array of closely-related but non-identical genetic variants known as quasispecies in the infected individuals. Pathogenesis and outcome in HCV infections are directly affected by the virus genetic heterogeneity, reflected as the emergence of quasispecies in infected individuals. The evolution of these highly-diverse viral populations in the host directly influences the disease course, via providing a pool of variants capable of resuming viral replication under extrinsic and/or intrinsic selective pressures. Viral quasispecies go through several alterations during the course of the infection, and provide a background for the selection of escape mutants from the host humoral and cell-mediated immune responses and antiviral treatment. Supported by the robust next generation sequencing techniques, recent studies have provided significant insights on the genomic diversity and progression as well as on the origin and the epidemiology of HCV. This review provides an overview of the mechanisms of HCV genetic variability, and the interactions with the host, that affects clinical disease, covering viral and host determinants of humoral and cell-mediated immune responses, alterations during the early and late stages of the infection and disease progression leading to chronicity. In addition, current findings in virus evolution and epidemiology were briefly interpreted from the inter-species and population perspectives. The impact of viral genomic heterogeneity on antiviral treatment in the era of direct-acting agents is also discussed, along with an overview of current methods employed for the characterization of viral diversity. PMID- 26649422 TI - The Risk of Tuberculosis Reinfection Soon after Cure of a First Disease Episode Is Extremely High in a Hyperendemic Community. AB - Elevated rates of reinfection tuberculosis in various hyperendemic regions have been reported and, in particular, it has been shown that in a high-incidence setting near Cape Town, South Africa, the rate of reinfection tuberculosis (TB) disease after cure of a previous TB disease episode is about four times greater than the rate of first-time TB disease. It is not known whether this elevated rate is caused by a high reinfection rate due, for instance, to living circumstances, or a high rate of progress to disease specific to the patients, or both. In order to address that question we analysed an extensive data set from clinics attended by TB patients in the high-incidence setting near Cape Town, South Africa and found that, in fact, the (average) rate of reinfection (as opposed to the rate of reinfection disease) after cure of a previous TB disease episode is initially about 0.85 per annum. This rate diminishes rapidly over time and after about ten years this rate is similar to the rate of infection in the general population. Also, the rate of progress to disease after reinfection is initially high but declines in subsequent years down to the figure typical for the general population. These findings suggest that the first few months after cure of a TB disease episode form a critical period for controlling reinfection disease in a hyperendemic setting and that monitoring such cured patients could pre-empt a reinfection progressing to active disease. PMID- 26649423 TI - Epigenetic Manipulation of Brain-derived Neurotrophic Factor Improves Memory Deficiency Induced by Neonatal Anesthesia in Rats. AB - BACKGROUND: Although neonatal exposure to anesthetic drugs is associated with memory deficiency in rodent models and possibly in pediatric patients, the underlying mechanisms remain elusive. The authors tested their hypothesis that exposure of the developing brain to anesthesia triggers epigenetic modification, involving the enhanced interaction among transcription factors (histone deacetylase 2, methyl-cytosine-phosphate-guanine-binding protein 2, and DNA methyltransferase 1) in Bdnf promoter region(s) that inhibit brain-derived neurotrophic factor (BDNF) expression, resulting in insufficient drive for local translation of synaptic mRNAs. The authors further hypothesized that noninvasive environmental enrichment (EE) will attenuate anesthesia-induced epigenetic inhibition of BDNF signaling and memory loss in rodent models. METHODS: Seven days after birth (P7), neonatal rats were randomly assigned to receive either isoflurane anesthesia for 6 h or sham anesthesia. On P21, pups were weaned, and animals were randomly assigned to EE or a standard cage environment (no EE). Behavioral, molecular, and electrophysiological studies were performed on rats on P65. RESULTS: The authors found a substantial reduction of hippocampal BDNF (n = 6 to 7) resulting from the transcriptional factors-mediated epigenetic modification in the promoter region of Bdnf exon IV in rats exposed postnatally to anesthetic drugs. This BDNF reduction led to the insufficient drive for the synthesis of synaptic proteins (n = 6 to 8), thus contributing to the hippocampal synaptic (n = 8 to 11) and cognitive dysfunction (n = 10) induced by neonatal anesthesia. These effects were mitigated by the exposure to an enriched environment. CONCLUSIONS: The findings of this study elucidated the epigenetic mechanism underlying memory deficiency induced by neonatal anesthesia and propose EE as a potential therapeutic approach. PMID- 26649425 TI - Are Epigenetic Changes the Key to the Elusive Mechanism for the Long-lasting Effects of Anesthetic Drugs that Persist after Emergence? PMID- 26649424 TI - IV and Perineural Dexmedetomidine Similarly Prolong the Duration of Analgesia after Interscalene Brachial Plexus Block: A Randomized, Three-arm, Triple-masked, Placebo-controlled Trial. AB - BACKGROUND: Perineural and IV dexmedetomidine have each been suggested to prolong the duration of analgesia when administered in conjunction with peripheral nerve blocks. In the first randomized, triple-masked, placebo-controlled trial to date, the authors aimed to define and compare the efficacy of perineural and IV dexmedetomidine in prolonging the analgesic duration of single-injection interscalene brachial plexus block (ISB) for outpatient shoulder surgery. METHODS: Ninety-nine patients were randomized to receive ISB using 15 ml ropivacaine, 0.5%, with 0.5 MUg/kg dexmedetomidine administered perineurally (DexP group), intravenously (DexIV group), or none (control group). The authors sequentially tested the joint hypothesis that dexmedetomidine prolongs the duration of analgesia and reduces the 24-h cumulative postoperative morphine consumption. Motor blockade, pain severity, hemodynamic variations, opioid related side effects, postoperative neurologic symptoms, and patient satisfaction were also evaluated. RESULTS: Ninety-nine patients were analyzed. The duration of analgesia was 10.9 h (10.0 to 11.8 h) and 9.8 h (9.0 to 10.6 h) for the DexP and DexIV groups, respectively, compared with 6.7 h (5.6 to 7.8) for the control group (P < 0.001). Dexmedetomidine also reduced the 24-h cumulative morphine consumption to 63.9 mg (58.8 to 69.0 mg) and 66.2 mg (60.6 to 71.8 mg) for the DexP and DexIV groups, respectively, compared with 81.9 mg (75.0 to 88.9 mg) for the control group (P < 0.001). DexIV was noninferior to DexP for these outcomes. Both dexmedetomidine routes reduced the pain and opioid consumption up to 8 h postoperatively and did not prolong the duration of motor blockade. CONCLUSION: Both perineural and IV dexmedetomidine can effectively prolong the ISB analgesic duration and reduce the opioid consumption without prolonging motor blockade. PMID- 26649426 TI - Very Low Population Structure in a Highly Mobile and Wide-Ranging Endangered Bird Species. AB - The loss of biodiversity following fragmentation and degradation of habitat is a major issue in conservation biology. As competition for resources increases following habitat loss and fragmentation, severe population declines may occur even in common, highly mobile species; such demographic decline may cause changes within the population structure of the species. The regent honeyeater, Anthochaera phrygia, is a highly nomadic woodland bird once common in its native southeast Australia. It has experienced a sharp decline in abundance since the late 1970s, following clearing of large areas of its preferred habitat, box ironbark woodland, within the last 200 years. A captive breeding program has been established as part of efforts to restore this species. This study used genetic data to examine the range-wide population structure of regent honeyeaters, including spatial structure, its change through time, sex differences in philopatry and mobility, and genetic differences between the captive and wild populations. There was low genetic differentiation between birds captured in different geographic areas. Despite the recent demographic decline, low spatial structure appears to have some temporal consistency. Both sexes appear to be highly mobile, and there does not seem to be significant genetic differentiation between the captive and wild populations. We conclude that management efforts for survival of this species, including habitat protection, restoration, and release of captive-bred birds into the wild, can treat the species as effectively a single genetic population. PMID- 26649427 TI - No Evidence for Activity Adjustment in Response to Increased Density in Daphnia magna. AB - Increased population density may lead to a decrease in energy available for growth and reproduction via effects on the activity level of individuals. Whilst this may be of particular importance for organisms that compete for defendable resources and/or have a high frequency of social interactions, it is less obvious how individual activity should covary with population density when food resources are not defendable or direct interactions among individuals are negligible. Based on observations that there is a general negative relationship between population density and metabolism it has been suggested that organisms actively reduce activity under increased density to accommodate an expected decrease in food availability. However, in the absence of direct activity measurements the validity of this hypothesis is unclear. Here we test for such anticipatory adjustments of activity levels in the planktonic cladoceran Daphnia magna Straus, a filter feeder whose food resources are not defendable, meaning that density responses can be evaluated in the absence of direct interactions. We tested for changes in activity in response to two separate density cues, one being the direct physical and visual stimuli resulting from being in the vicinity of conspecifics ('direct density experiment'), and the other being the detection of olfactory cues in their environment ('olfactory cue experiment'). Ten genetically distinct clones were used to evaluate the potential for genetic variation in these responses. Our measures of activity were highly repeatable, and there was significant variation in activity among clones. Furthermore, this clonal variation was consistent in the 'direct density' and 'olfactory cue' experiments. The estimated evolvability of the trait (1.3-3.2%) was within the range typically observed in behavioural traits. However, there was no indication that the activity level of individuals respond to population density, either directly to actual density or to olfactory cues representing high density. In this case, the energetic influence of density on population dynamics is sufficiently described by effects on per capita resource availability. PMID- 26649428 TI - Diversity of Phytophthora Species from Declining Mediterranean Maquis Vegetation, including Two New Species, Phytophthora crassamura and P. ornamentata sp. nov. AB - The Mediterranean basin is recognized as a global biodiversity hotspot accounting for more than 25,000 plant species that represent almost 10% of the world's vascular flora. In particular, the maquis vegetation on Mediterranean islands and archipelagos constitutes an important resource of the Mediterranean plant diversity due to its high rate of endemism. Since 2009, a severe and widespread dieback and mortality of Quercus ilex trees and several other plant species of the Mediterranean maquis has been observed in the National Park of La Maddalena archipelago (northeast Sardinia, Italy). Infected plants showed severe decline symptoms and a significant reduction of natural regeneration. First studies revealed the involvement of the highly invasive wide-host range pathogen Phytophthora cinnamomi and several fungal pathogens. Subsequent detailed research led to a better understanding of these epidemics showing that multiple Phytophthora spp. were involved, some of them unknown to science. In total, nine Phytophthora species were isolated from rhizosphere soil samples collected from around symptomatic trees and shrubs including Asparagus albus, Cistus sp., Juniperus phoenicea, J. oxycedrus, Pistacia lentiscus and Rhamnus alaternus. Based on morphological characters, growth-temperature relations and sequence analysis of the ITS and cox1 gene regions, the isolates were identified as Phytophthora asparagi, P. bilorbang, P. cinnamomi, P. cryptogea, P. gonapodyides, P. melonis, P. syringae and two new Clade 6 taxa which are here described as P. crassamura sp. nov. and P. ornamentata sp. nov. Pathogenicity tests supported their possible involvement in the severe decline that is currently threatening the Mediterranean maquis vegetation in the La Maddalena archipelago. PMID- 26649429 TI - Challenges in the Management of Short Stature. AB - Human growth, from fetal life to adolescence, is dynamic and a good marker of health. Growth is a complex process influenced by genetic, hormonal, nutritional and environmental factors, both pre- and postnatally. To date, no international agreement regarding normal height has been established. Auxological parameters are fundamental to investigate potential short stature (SS), either with a known diagnosis, e.g. disproportionate or proportionate, prenatal and/or postnatal onset, or an unknown diagnosis, i.e. idiopathic SS. The incidence/prevalence of SS is difficult to establish. The measurement of choice in children aged <2 years is length, while in those >2 years of age it is height. A number of monogenic diseases that lead to proportionate SS due to either isolated growth hormone deficiency, multiple pituitary hormone deficiency, growth hormone insensitivity, primary acid-labile subunit deficiency, primary IGF-1 deficiency, IGF-1 resistance, primary IGF-2 deficiency or primary protease deficiency have been discovered in the last 30 years. In addition, the Nosology and Classification of Genetic Skeletal Disorders revised in 2015 includes 436 conditions, with a number of genes of 364. A practical algorithm for the evaluation of SS as well as therapeutic options are discussed. PMID- 26649430 TI - Detection of BRAF Mutation in Urine DNA as a Molecular Diagnostic for Canine Urothelial and Prostatic Carcinoma. AB - Urothelial carcinoma (UC) of the lower urinary tract and prostatic carcinoma (PC) are aggressive genitourinary cancers in dogs, characterized by invasion to surrounding tissues and high metastatic potential. Current diagnosis of canine UC and PC requires histopathological examination of a biopsy. Such specimens require specialized medical equipment and are invasive procedures, limiting the availability of diagnosis by histopathology for many canine patients. Access to a non-invasive means to confirm diagnosis is currently an unmet need. Recently, the canine BRAF V595E mutation was detected in ~80% of canine UCs and PCs. In this study, we developed a droplet digital PCR (ddPCR) assay for detection of the canine BRAF V595E mutation in canine urogenital tumors. The assay was evaluated in DNA samples prepared from biopsy specimens of UC (n = 48) and PC (n = 27), as well and non-neoplastic bladder epithelium (n = 38). In addition the assay was assessed for use with DNA isolated from free catch urine samples derived from canine patients with UC (n = 23), PC (n = 3), as well as from dogs with cystitis and healthy controls (n = 37). In all cases the sensitivity to detect the mutant allele was compared with conventional Sanger sequencing. ddPCR had superior sensitivity for detection of the V595E mutation: 75% of UC, 85% of PC, and 0% of control samples were mutation positive, respectively, and the V595E mutation was detected at a level as low as just 1 in 10,000 alleles (~0.01%). Furthermore, the ddPCR assay identified the mutation in free catch urine samples from 83% of canine UC and PC patients, demonstrating its utility as a non-invasive means of diagnosis. We have shown that ddPCR is a sensitive molecular technique with the potential to facilitate accurate and non-invasive means of canine UC and PC diagnosis. PMID- 26649431 TI - Antimicrobial Use-Related Problems and Predictors among Hospitalized Medical In Patients in Southwest Ethiopia: Prospective Observational Study. AB - BACKGROUND: The spread of antimicrobial resistance in developing countries is associated with complex and interconnected factors, such as excessive and unnecessary prescribing of antimicrobials, increased self-prescribing by the people and poor quality of available antimicrobials. Moreover, the failure to implement infection control practices and the dearth of routine susceptibility testing and surveillance magnify the problems. This may spread the inappropriateness of prescribing, ending up with the spread of antimicrobial resistance. OBJECTIVE: The aim of this study was to assess antimicrobial use related problems and associated factors among patients admitted at Jimma University specialized hospital. METHODS: A hospital based prospective observational study design was employed at medical wards of Jimma University specialized hospital, Ethiopia. Data collected from patient medication charts and from the patients was analyzed using SPSS, version 16.0. Logistic regression was used to determine the associations between variables. Statistical significance was considered at p-value <0.05. RESULTS: Out of 152 study participants, at least one antimicrobial use problem was identified among 115(75.7%). Accordingly, additional antimicrobials were needed by 45(29.6%) of the patients, whereas they were unnecessary among 44(28.9%). Similarly, 17% of the patients were noncompliant to at least one antimicrobial therapy, while 8.6% experienced at least one type of adverse drug reaction. On the other hand, the coverage of the infectious medical condition in the national guidelines (AOR = 4.888) and the duration of hospital stay (AOR = 3.086) were the determinants of the antimicrobial use problems. CONCLUSION: Most of the antimicrobial use problems identified were related to delay of initiation of effective antimicrobials and excessive use; use without indication or using duplicates of broad spectrum antimicrobials or use for longer duration than recommended. The coverage of the infectious medical condition in the national treatment guidelines and the duration of hospital stay were the determinants of the antimicrobial use problems. PMID- 26649432 TI - Tolerant Paternalism: Pro-ethical Design as a Resolution of the Dilemma of Toleration. AB - Toleration is one of the fundamental principles that inform the design of a democratic and liberal society. Unfortunately, its adoption seems inconsistent with the adoption of paternalistically benevolent policies, which represent a valuable mechanism to improve individuals' well-being. In this paper, I refer to this tension as the dilemma of toleration. The dilemma is not new. It arises when an agent A would like to be tolerant and respectful towards another agent B's choices but, at the same time, A is altruistically concerned that a particular course of action would harm, or at least not improve, B's well-being, so A would also like to be helpful and seeks to ensure that B does not pursue such course of action, for B's sake and even against B's consent. In the article, I clarify the specific nature of the dilemma and show that several forms of paternalism, including those based on ethics by design and structural nudging, may not be suitable to resolve it. I then argue that one form of paternalism, based on pro ethical design, can be compatible with toleration and hence with the respect for B's choices, by operating only at the informational and not at the structural level of a choice architecture. This provides a successful resolution of the dilemma, showing that tolerant paternalism is not an oxymoron but a viable approach to the design of a democratic and liberal society. PMID- 26649433 TI - Efficacy of postoperative mitomycin-C eye drops on the clinical outcome in endoscopic dacryocystorhinostomy. AB - PURPOSE: To evaluate the effect of postoperative topical mitomycin-C (MMC) eye drops in endoscopic (dacryocystorhinostomy) DCR and compare them with intraoperative MMC soaking. DESIGN: Retrospective, nonrandomized, interventional case series. METHODS: One hundred and sixty cases of endoscopic DCR with a single surgeon for primary nasolacrimal duct obstruction (NLDO) were included. Cases were divided into three groups. Group 1 was treated with intraoperative application of 0.02 % MMC for 5 min. Group 2 was treated with 0.02 % MMC eye drops for 5 days after surgery, without intraoperative application of MMC. Group 3 was the control group of cases without the use of MMC. Each group was evaluated for surgical success, presence of complications including granuloma, synechiae, and tube-induced inflammation, and the adverse effect of the MMC at least 6 months after the surgery. RESULTS: The success rate showed no significant difference among the three groups (P = .122, chi-square analysis). In the analysis between the two groups, although the success rate of Group 2 appeared not to be statistically different compared with that of Group 1 (P = .419, chi square analysis), Group 2 had a statistically higher success rate for surgery than Group 3 (P = .041, chi-square analysis). The presence of granuloma was significantly lower in Group 1 than in the other two groups (P = .022, chi-square analysis). Synechiae and silicone tube-induced inflammation were not significantly different (P = .308, P = .881, chi-square analysis). There were no adverse effects associated with intraoperative or postoperative MMC application. CONCLUSION: Use of postoperative topical 0.02 % MMC is a safe and effective adjunctive modality to increase the success rate of endoscopic DCR. PMID- 26649434 TI - Revisiting a dogma: similar survival of patients with small bowel and gastric GIST. A population-based propensity score SEER analysis. AB - BACKGROUND: The objective of the present analysis was to assess whether small bowel gastrointestinal stromal tumor (GIST) is associated with worse cancer specific survival (CSS) and overall survival (OS) compared with gastric GIST on a population-based level. PATIENTS AND METHODS: Data on patients aged 18 years or older with histologically proven GIST was extracted from the SEER database from 1998 to 2011. OS and CSS for small bowel GIST were compared with OS and CSS for gastric GIST by application of adjusted and unadjusted Cox regression analyses and propensity score analyses. RESULTS: GIST were located in the stomach (n = 3011, 59 %), duodenum (n = 313, 6 %), jejunum/ileum (n = 1288, 25 %), colon (n = 139, 3 %), rectum (n = 172, 3 %), and extraviscerally (n = 173, 3 %). OS and CSS of patients with GIST in the duodenum [OS, HR 0.95, 95 % confidence interval (CI) 0.76-1.19; CSS, HR 0.99, 95 % CI 0.76-1.29] and in the jejunum/ileum (OS, HR 0.97, 95 % CI 0.85-1.10; CSS, HR = 0.95, 95 % CI 0.81-1.10) were similar to those of patients with gastric GIST in multivariate analyses. Conversely, OS and CSS of patients with GIST in the colon (OS, HR 1.40; 95 % CI 1.07-1.83; CSS, HR 1.89, 95 % CI 1.41-2.54) and in an extravisceral location (OS, HR 1.42, 95 % CI 1.14-1.77; CSS, HR = 1.43, 95 % CI 1.11-1.84) were significantly worse than those of patients with gastric GIST. CONCLUSIONS: Contrary to common belief, OS and CSS of patients with small bowel GIST are not statistically different from those of patients with gastric GIST when adjustment is made for confounding variables on a population-based level. The prognosis of patients with nongastric GIST is worse because of a colonic and extravisceral GIST location. These findings have implications regarding adjuvant treatment of GIST patients. Hence, the dogma that small bowel GIST patients have worse prognosis than gastric GIST patients and therefore should receive adjuvant treatment to a greater extent must be revisited. PMID- 26649435 TI - Association of apical rocking with super-response to cardiac resynchronisation therapy. AB - BACKGROUND: Super-responders to cardiac resynchronisation therapy (CRT) show an exceptional improvement in left ventricular ejection fraction (LVEF). Previous studies showed that apical rocking was independently associated with echocardiographic response to CRT. However, little is known about the association between apical rocking and super-response to CRT. OBJECTIVES: To determine the independent association of LV apical rocking with super-response to CRT in a large cohort. METHODS: A cohort of 297 consecutive heart failure patients treated with primary indication for CRT-D were included in an observational registry. Apical rocking was defined as motion of the left ventricular (LV) apical myocardium perpendicular to the LV long axis. 'Super-response' was defined by the top quartile of LVEF response based on change from baseline to follow-up echocardiogram. Best-subset regression analysis identified predictors of LVEF super-response to CRT. RESULTS: Apical rocking was present in 45 % of patients. Super-responders had an absolute mean LVEF increase of 27 % (LVEF 22.0 % +/- 5.7 at baseline and 49.0 % +/- 7.5 at follow-up). Apical rocking was significantly more common in super-responders compared with non-super-responders (76 and 34 %, P < 0.001). In univariate analysis, female gender (OR 2.39, 95 % CI 1.38-4.11), lower LVEF at baseline (OR 0.91 95 % CI 0.87-0.95), non-ischaemic aetiology (OR 4.15, 95 % CI 2.33-7.39) and apical rocking (OR 6.19, 95 % CI 3.40-11.25) were associated with super-response. In multivariate analysis, apical rocking was still strongly associated with super-response (OR 5.82, 95 % CI 2.68-12.61). Super-responders showed an excellent clinical prognosis with a very low incidence of heart failure admission, cardiac mortality and appropriate ICD therapy. CONCLUSION: Apical rocking is independently associated with super-response to CRT. PMID- 26649436 TI - The influence of right ventricular stimulation on acute response to cardiac resynchronisation therapy. AB - BACKGROUND: The contribution of right ventricular (RV) stimulation to cardiac resynchronisation therapy (CRT) remains controversial. RV stimulation might be associated with adverse haemodynamic effects, dependent on intrinsic right bundle branch conduction, presence of scar, RV function and other factors which may partly explain non-response to CRT. This study investigates to what degree RV stimulation modulates response to biventricular (BiV) stimulation in CRT candidates and which baseline factors, assessed by cardiac magnetic resonance imaging, determine this modulation. METHODS AND RESULTS: Forty-one patients (24 (59 %) males, 67 +/- 10 years, QRS 153 +/- 22 ms, 21 (51 %) ischaemic cardiomyopathy, left ventricular (LV) ejection fraction 25 +/- 7 %), who successfully underwent temporary stimulation with pacing leads in the RV apex (RVapex) and left ventricular posterolateral (PL) wall were included. Stroke work, assessed by a conductance catheter, was used to assess acute haemodynamic response during baseline conditions and RVapex, PL (LV) and PL+RVapex (BiV) stimulation. Compared with baseline, stroke work improved similarly during LV and BiV stimulation (?+ 51 +/- 42 % and ?+ 48 +/- 47 %, both p < 0.001), but individual response showed substantial differences between LV and BiV stimulation. Multivariate analysis revealed that RV ejection fraction (beta = 1.01, p = 0.02) was an independent predictor for stroke work response during LV stimulation, but not for BiV stimulation. Other parameters, including atrioventricular delay and scar presence and localisation, did not predict stroke work response in CRT. CONCLUSION: The haemodynamic effect of addition of RVapex stimulation to LV stimulation differs widely among patients receiving CRT. Poor RV function is associated with poor response to LV but not BiV stimulation. PMID- 26649437 TI - Managing the Impact of the ICD-10 Transition on a Data Warehouse. PMID- 26649438 TI - [Tropical ophthalmology : Intraocular inflammation caused by "new" infectious pathogens and travel-related infections]. AB - A number of "new" (emerging) infections that can also cause inflammatory eye changes are appearing and becoming increasingly important. In the past, diseases such as chikungunya, dengue fever or West Nile virus infections were endemic in tropical regions, but are now expanding worldwide and causing significant morbidity and even mortality. "Globalization" and human migration are important factors leading to the import of these infections. Climate changes are probably even more important. Increasing temperatures provide suitable conditions for new vectors, and may lead to autochthonous transmission of infectious pathogens. Diagnosis of these diseases requires not only careful assessment of medical and travel history, but also the application of specific laboratory diagnostic tests. A broad spectrum of ocular involvement has been reported, with frequent posterior segment involvement. Emerging infections should therefore be considered in the differential diagnosis of retinitis, chorioretinitis, retinal vasculitis and optic neuropathy in a patient living in or traveling back from an endemic area. Since these infections are often vector (insect) borne and effective treatments are almost uniformly lacking, prevention is at least as important as prompt diagnosis and initiation of supportive care. Here, we focus on Chikungunya, Dengue fever, Ebola fever, the West Nile virus and Rickettsioses, which frequently demonstrate ocular involvement. PMID- 26649439 TI - Skin Signs of Rheumatoid Arthritis and its Therapy-Induced Cutaneous Side Effects. AB - Rheumatoid arthritis (RA) is a systemic inflammatory disorder that primarily affects the joints, but may exhibit extra-articular, including cutaneous, manifestations such as rheumatoid nodules, rheumatoid vasculitis, granulomatous skin disorders, and neutrophilic dermatoses. A large burden of cutaneous disease may be an indication of RA disease activity and the need for more aggressive treatment. Many of the therapeutic agents used to treat RA can also result in cutaneous adverse effects, which pose their own diagnostic and therapeutic challenges. Anti-TNFalpha agents, in particular, have a wide variety of adverse effects including psoraisiform eruptions, granulomatous conditions, and cutaneous connective tissue disorders. Herein we provide an update on the clinical presentations and management of RA-associated cutaneous findings as well as drug induced cutaneous effects, with particular attention to the adverse effects of biologic disease-modifying agents. PMID- 26649440 TI - Anti-IL-17 Medications Used in the Treatment of Plaque Psoriasis and Psoriatic Arthritis: A Comprehensive Review. AB - Our ability to successfully treat patients with moderate to severe psoriasis has improved significantly over the last several years with the development of more targeted therapies. IL-17A, a member of the IL-17 family of interleukins, is involved in regulating the innate and adaptive immune systems and has been identified as a key cytokine involved in the pathogenesis of psoriasis and psoriatic arthritis. In this review, we summarize our understanding of IL-17 and its role in psoriasis and psoriatic arthritis, as well as key findings from clinical trials using anti-IL-17 medications for the treatment of the aforementioned diseases. Secukinumab, ixekizumab, and brodalumab are three anti IL-17 medications used for treating psoriasis, of which only secukinumab is FDA approved; ixekizumab and brodalumab remain under clinical development. Results from clinical trials show that these three medications are highly effective in treating psoriasis and appear to be as safe as other biologic treatments that are FDA approved. PMID- 26649441 TI - Tuning Emission Responses of a Triphenylamine Derivative in Host-Guest Complexes and an Unusual Dynamic Inclusion Phenomenon. AB - A newly synthesized triphenylamine derivative (1Cl3) shows significant differences in inclusion complex formation with two different macrocyclic hosts, cucurbit[7]uril (CB[7]) and beta-cyclodextrin (beta-CD). Detailed investigations by NMR spectroscopy reveal that CB[7] forms a 1:3 host-guest complex ([1.3{CB[7]}]Cl3) in which three arms of 1Cl3 are bound to three host molecules. On the other hand, beta-CD forms a dynamic 1:1 inclusion complex ([1.{beta CD}]Cl3) by binding to only one of the three arms of 1Cl3 at a given time. The formation of a 1:1 host-guest complex with beta-CD and 1:3 host-guest complex with CB[7] was also confirmed from the results of the isothermal titration calorimetric studies. Interestingly, 1Cl3 exhibits a rare dual emission property in solution at room temperature with the lower and higher energy bands arising from a locally excited state and an intramolecular charge-transfer transition, respectively. The difference in inclusion complex formation behavior of 1Cl3 with the two macrocyclic hosts results in the stabilization of different emission states in the two inclusion complexes. The fundamental difference in the electrostatic surface potentials, cavity polarities, and shapes of the two macrocyclic hosts could account for the formation of the different inclusion complexes with distinct luminescence responses. PMID- 26649442 TI - From linear to cyclic oligoparaphenylenes: electronic and molecular changes traced in the vibrational Raman spectra and reformulation of the bond length alternation pattern. AB - Cyclic paraphenylenes, [n]CPPs, and linear paraphenylenes, [n]LPPs, formed by n benzenes, are investigated by Raman spectroscopy for n = 5 to 12 and density functional theory (DFT) for n = 4 to 20. The information on the experimental Raman frequencies and intensities, combined with DFT computations and reported X ray diffraction structures, provides a consistent interpretation of the Raman spectra and allows establishing relevant structure-property trends. Structural and electronic effects such as benzene ring bending, inter-ring torsions, pi conjugation (aromaticity) and orbital energy gaps as a function of the linear elongation in [n]LPPs versus the macrocyclic curvature in [n]CPPs and of the molecular size (i.e., polymer limit) are systematically analyzed on the basis of the vibrational Raman properties. Changes in the BLA as an indicator of the degree of quinonoid character are analyzed and linked to the Effective Conjugation Coordinate (ECC) model. The BLA patterns involved in twisted and non twisted conformations and in different species (bipolarons, quinonoid tautomers, and ECC active modes) are compared and their differences are discussed. This paper offers a unified interpretation of structural and electronic aspects in relation to the evolution from linear 1D pi-systems to cyclic 2D structures. PMID- 26649443 TI - Presence of Rheumatoid Factor during Chronic HCV Infection Is Associated with Expansion of Mature Activated Memory B-Cells that Are Hypo-Responsive to B-Cell Receptor Stimulation and Persist during the Early Stage of IFN Free Therapy. AB - Approximately half of those with chronic hepatitis C virus (HCV) infection have circulating rheumatoid factor (RF), and a portion of these individuals develop cryoglobulinemic vasculitis. B cell phenotype/function in relation to RF in serum has been unclear. We examined B cell subset distribution, activation state (CD86), cell cycle state (Ki67), and ex-vivo response to BCR, TLR9 and TLR7/8 stimulation, in chronic HCV-infected donors with or without RF, and uninfected donors. Mature-activated B-cells of HCV-infected donors had lower CD86 expression compared to uninfected donors, and in the presence of RF they also showed reduced CD86 expression in response to BCR and TLR9 stimulation. Additionally, mature activated memory B cells of HCV RF+ donors less commonly expressed Ki67+ than HCV RF- donors, and did not proliferate as well in response to BCR stimulation. Proportions of mature-activated B cells were enhanced, while naive B-cells were lower in the peripheral blood of HCV-RF+ compared to RF- and uninfected donors. None of these parameters normalize by week 8 of IFN free direct acting antiviral (DAA) therapy in HCV RF+ donors, while in RF- donors, mature activated B cell proportions did normalize. These data indicate that while chronic HCV infection alone results in a lower state of activation in mature activated memory B cells, the presence of RF in serum is associated with a more pronounced state of unresponsiveness and an overrepresentation of these B cells in the blood. This phenotype persists at least during the early time window after removal of HCV from the host. PMID- 26649444 TI - Development and application of a human PBPK model for bromodichloromethane to investigate the impacts of multi-route exposure. AB - As a result of its presence in water as a volatile disinfection byproduct, bromodichloromethane (BDCM), which is mutagenic, poses a potential health risk from exposure via oral, dermal and inhalation routes. We developed a refined human physiologically based pharmacokinetic (PBPK) model for BDCM (including new chemical-specific human parameters) to evaluate the impact of BDCM exposure during showering and bathing on important measures of internal dose compared with oral exposure. The refined model adequately predicted data from the published literature for oral, dermal and bathing/showering exposures. A liter equivalency approach (L-eq) was used to estimate BDCM concentration in a liter of water consumed by the oral route that would be required to produce the same internal dose of BDCM resulting from a 20-min bath or a 10-min shower in water containing 10 ug l(-1) BDCM. The oral liter equivalent concentrations for the bathing scenario were 605, 803 and 5 ug l(-1) BDCM for maximum venous blood concentration (Cmax), the area under the curve (AUCv) and the amount metabolized in the liver per hour (MBDCM), respectively. For a 10-min showering exposure, the oral L-eq concentrations were 282, 312 and 2.1 ug l(-1) for Cmax, AUC and MBDCM, respectively. These results demonstrate large contributions of dermal and inhalation exposure routes to the internal dose of parent chemical reaching the systemic circulation, which could be transformed to mutagenic metabolites in extrahepatic target tissues. Thus, consideration of the contribution of multiple routes of exposure when evaluating risks from water-borne BDCM is needed, and this refined human model will facilitate improved assessment of internal doses from real-world exposures. Published 2015. This article has been contributed to by US Government employees and their work is in the public domain in the USA. PMID- 26649445 TI - Apixaban-induced hepatotoxicity. PMID- 26649446 TI - Prognostic value of left ventricular reverse remodeling and performance improvement after cardiac resynchronization therapy: A prospective study. AB - BACKGROUND: The present study was designed to evaluate the respective value of left ventricular (LV) reverse remodeling (changes in LV end-systolic volume relative to baseline (DeltaLVESV)) or LV performance improvement (DeltaLV ejection fraction (DeltaLVEF) or DeltaGlobal longitudinal strain (GLS)) to predict long-term outcome in a prospective cohort of consecutive patients receiving routine cardiac resynchronization therapy (CRT). METHODS: One hundred and seventy heart failure patients (NYHA classes II-IV, LVEF <= 35%, QRS width >= 120 ms) underwent echocardiography before and 9 months after CRT. The relationships between DeltaLVESV, DeltaLVEF, DeltaGLS and outcome (all-cause mortality and/or CHF hospitalization, overall mortality, cardiovascular mortality, CHF hospitalization) were investigated. RESULTS: During a median follow-up of 32 months, 20 patients died and 27 were hospitalized for heart failure. DeltaLVESV, DeltaLVEF or DeltaGLS were significantly associated with all cause mortality or CHF hospitalization (adjusted hazard's ratio (HR) per standard deviation 0.58 (0.43-0.77), 0.39 (0.27-0.57) or 0.55 (0.37-0.83) respectively, all p < 0.01) and all other endpoints (all p < 0.01). Patients with DeltaLVESV>=15%, DeltaLVEF >= 10% and DeltaGLS >= 1% had a reduced risk of mortality or CHF hospitalization (adjusted HR=0.25 (0.12-0.51), p < 0.001, adjusted HR = 0.26 (0.13-0.54), p < 0.001 and adjusted HR 0.38 (0.19-0.75), p = 0.006 respectively). Overall performance of multivariate models was better using DeltaLVESV or DeltaLVEF compared with DeltaGLS. Interobserver agreement was excellent for DeltaLVESV (Intraclass correlation coefficient - ICC-0.91) and DeltaGLS (ICC 0.90) but modest for DeltaLVEF (ICC 0.76) in a sample of 20 patients from the study population. CONCLUSIONS: LV reverse remodeling assessed by DeltaLVESV is a strong and reproducible predictor of outcome following CRT. Compared with DeltaLVESV, DeltaLVEF and DeltaGLS have important shortcomings: poorer reproducibility or lower predictive value. PMID- 26649447 TI - Self-assembly of a surfactin nanolayer at solid-liquid and air-liquid interfaces. AB - Surfactin, a sustainable and environmentally friendly surface active agent, is used as a model to study the adsorption of biosurfactants at hydrophobic and hydrophilic solid-liquid interfaces as well as the air-liquid interface. Surfactin adsorption was monitored as a function of time and concentration using surface plasmon resonance (SPR) technique in the case of the solid-liquid interfaces or the drop shape analysis (DSA) technique in the case of the air liquid interface. The results obtained in this study showed that surfactin adsorption at the "hard" hydrophobic (functionalized with octadecanethiol) solid liquid and the "soft" air-liquid interface were 1.12 +/- 0.01 mg m(-2) (area per molecule of 157 +/- 2 A(2)) and 1.11 +/- 0.05 mg m(-2) (area per molecule of 159 +/- 7 A(2)), respectively, demonstrating the negligible effect of the interface "hardness" on surfactin adsorption. The adsorption of surfactin at the hydrophilic (functionalized with beta-mercaptoethanol) solid-liquid interface was about threefold lower than its adsorption at the hydrophobic-liquid interfaces, revealing the importance of hydrophobic interaction in surfactin adsorption process. The affinity constant of surfactin for the investigated interfaces follows the following order: air > octadecanethiol > beta-mercaptoethanol. Biosurfactants, such as surfactin, are expected to replace the conventional fossil-based surfactants in several applications, and therefore the current study is a contribution towards the fundamental understanding of biosurfactant behavior, on a molecular level, at hydrophobic and hydrophilic solid-liquid interfaces in addition to the air-liquid interface. Such understanding might aid further optimization of the utilization of surfactin in a number of industrial applications such as enhanced oil recovery, bioremediation, and detergency. PMID- 26649448 TI - Safety and efficacy of plasmid DNA expressing two isoforms of hepatocyte growth factor in patients with critical limb ischemia. AB - VM202, a plasmid DNA that expresses two isoforms of hepatocyte growth factor, may elicit angiogenic effects that could benefit patients with critical limb ischemia (CLI). In a phase 2, double-blind trial in 52 CLI patients, we examined the safety and potential efficacy of intramuscular injections of low-dose (n=21) or high-dose (n=20) VM202 or placebo (n=11) in the affected limb (days 0, 14, 28 and 42). Adverse events and serious adverse events were similar among the groups; no malignancy or proliferative retinopathy was seen. In exploratory efficacy analyses, we found no differences in ankle or toe-brachial index, VAS, VascuQuol or amputation rate among the groups. Complete ulcer healing was significantly better in high-dose (8/13 ulcers; P<0.01) versus placebo (1/9) patients. Clinically meaningful reductions (>50%) in ulcer area occurred in high-dose (9/13 ulcers) and low-dose (19/27) groups versus placebo (1/9; P<0.05 and P<0.005, respectively). At 12 months, significant differences were seen in TcPO2 between the high-dose and placebo groups (47.5 +/- 17.8 versus 36.6 +/- 24.0 mm Hg, respectively; P<0.05) and in the change from baseline among the groups (P<0.05). These data suggest that VM202 is safe and may provide therapeutic bioactivity in CLI patients. PMID- 26649449 TI - Genetic Testing for Melanoma-Where Are We With Moderate-Penetrance Genes? PMID- 26649450 TI - Photocatalyst-free hypervalent iodine reagent catalyzed decarboxylative acylarylation of acrylamides with alpha-oxocarboxylic acids driven by visible light irradiation. AB - A hypervalent iodine(iii) reagent catalyzed carbonylarylation of acrylamides with alpha-oxocarboxylic acids driven by visible-light without a photoredox catalyst has been developed. The reactions generate the corresponding products in good yields at room temperature. Experiments indicate that a blue LED (450-455 nm) is the most effective energy for the cleavage of the oxygen-iodine bond to initiate the reaction. Mechanistic studies further demonstrate that the reaction undergoes a cascade decarboxylative radical addition/cyclization process along with releasing CO2 and H2. PMID- 26649451 TI - Phenytoin carried by silica core iron oxide nanoparticles reduces the expression of pharmacoresistant seizures in rats. AB - AIM: The present study was focused to evaluate the anticonvulsant effects of phenytoin (PHT) loaded in the silica core of iron oxide nanoparticles (NPs) in an animal model with pharmacoresistant seizures. MATERIALS & METHODS: PHT-loaded NPs were synthesized and characterized. The anticonvulsant effects of PHT-loaded NPs were investigated in rats with pharmacoresistant seizures associated with brain P glycoprotein (P-gp) overexpression. RESULTS & CONCLUSION: In P-gp-overexpressing rats, administration of PHT-loaded NPs resulted in reduced prevalence of clonus (40% p < 0.05) and tonic-clonic seizures (20%; p < 0.02). These effects were not evident when animals were treated with PHT not loaded in the NPs. The results obtained support the notion that NPs can be used as drugs carriers to the brain with pharmacoresistant seizures. PMID- 26649452 TI - General practitioners' attitudes toward follow-up after cancer treatment: A cross sectional questionnaire study. AB - OBJECTIVE: An increasing number of cancer patients place a significant workload on hospital outpatient clinics, and health authorities are considering alternative follow-up regimens. It has been suggested that follow-up of cancer patients could be provided by GPs. This study aimed to explore GPs' experiences with the provision of follow-up care for cancer patients, and their views on assuming greater responsibility in the future. DESIGN: Electronic questionnaire study. SUBJECTS: GPs in seven regions in Norway. RESULTS: A total of 317 GPs responded. Many GPs reported experience in providing follow-up care to cancer patients, during the years following initial diagnosis primarily in collaboration with hospital specialists. More than half of the GPs were satisfied with their collaboration. Most GPs preferred to be involved at an early stage in follow-up care and, generally, GPs felt confident in their skills to provide this type of service. Fewer than 10% were willing to assume responsibility for additional cancer patients, citing potentially increased workload as the main reason. CONCLUSIONS: GPs acknowledged the importance of providing follow-up care to cancer patients, and the majority felt confident in their own ability to provide such care. However, they were hesitant to assume greater responsibility primarily due to fears of increased workload. Key Points It has been suggested that follow up of cancer patients can be provided by general practitioners (GPs). The viewpoints and attitudes of GPs regarding such follow-up were investigated. GPs reported broad experience in providing follow-up care to patients after active cancer treatment. GPs acknowledged the importance of follow-up care, and they felt confident in their own ability to provide such care. Fewer than 10% of GPs were willing to assume responsibility for additional cancer patients, citing potentially increased workload as the main reason. PMID- 26649457 TI - Corrigendum. PMID- 26649453 TI - The benefit of expecting no conflict--Stronger influence of self-generated than cue-induced conflict expectations on Stroop performance. AB - The role of expectations in sequential adaptation to cognitive conflict has been debated controversially in prior studies. On the one hand, a sequential congruency effect (SCE) has been reported for trials in which participants expect a repetition of conflict level. On the other hand, conflict level expectations vs. the SCE have been shown to develop differentially across runs of trials with the same conflict level, arguing against the theory that the SCE is purely driven by expectation. The current verbal Stroop experiment addresses this controversy by two means. First, we tested which specific type of expectation (cue-induced expectations vs. self-generated predictions) might affect the SCE. Second, we assessed the impact of expectation on the SCE as well as the development of SCE and expectation with congruency level run length in one design. We observed a dissociation between expectations and SCE, demonstrating that the SCE is not exclusively driven by expectations. At the same time, we found evidence that (self-generated) expectations do have an impact on the SCE. Our data document especially high performance for one specific combination of task events: congruent trial accompanied by congruent prediction and conflict level repetition. Our results are in line with theories attributing conflict adaptation effects to the "adaption to the lack of conflict". We discuss our results in a broader context of theories about conflict monitoring. PMID- 26649458 TI - A comparison of dexmedetomidine versus propofol during drug-induced sleep endoscopy in sleep apnea patients. AB - OBJECTIVES/HYPOTHESIS: In this study, we compared the effects of propofol and dexmedetomidine on the upper airway collapse pattern and cardiopulmonary parameters of patients with obstructive sleep apnea (OSA) undergoing drug-induced sleep endoscopy (DISE). STUDY DESIGN: Prospective, single center, observational study MATERIALS AND METHODS: The 50 patients with OSA underwent 30 minutes of DISE on 2 different days, the first time with propofol target-controlled infusion (TCI) and the second time with dexmedetomidine TCI. Both the characteristics of upper airway obstruction and cardiopulmonary parameters in response to the depth of sedation achieved with each drug were evaluated. RESULTS: The results obtained with propofol and dexmedetomidine DISE were in excellent agreement for all sites of obstruction irrespective of the depth of sedation. Although partial or total obstruction at all areas was consistently observed using both drugs, the degree of upper airway narrowing was slightly lower with dexmedetomidine than with propofol. However, the percentage of patients with a greater than 20% change in blood pressure and heart rate compared to baseline was significantly higher in response to propofol than to dexmedetomidine (P = 0.003 and P < 0.001, respectively). Minimal oxygen saturation was significantly lower in DISE with propofol than with dexmedetomidine (P = 0.004). The percentage of patients with oxygen saturation less than 90% or 80% during DISE was significantly higher in response to propofol than to dexmedetomidine (P = 0.032 and P < 0.001, respectively). CONCLUSION: The DISE findings achieved with propofol and dexmedetomidine were in excellent agreement. However, during DISE, dexmedetomidine provided greater hemodynamic stability and less respiratory depression than propofol. LEVEL OF EVIDENCE: 4. Laryngoscope, 126:763-767, 2016. PMID- 26649459 TI - Forward Genetic Approach to Uncover Stress Resistance Genes in Mice - A High throughput Screen in ES Cells. AB - Phenotype-driven genetic screens in mice is a powerful technique to uncover gene functions, but are often hampered by extremely high costs, which severely limits its potential. We describe here the use of mouse embryonic stem (ES) cells as surrogate cells to screen for a phenotype of interest and subsequently introduce these cells into a host embryo to develop into a living mouse carrying the phenotype. This method provides (1) a cost effective, high-throughput platform for genetic screen in mammalian cells; (2) a rapid way to identify the mutated genes and verify causality; and (3) a short-cut to develop mouse mutants directly from these selected ES cells for whole animal studies. We demonstrated the use of paraquat (PQ) to select resistant mutants and identify mutations that confer oxidative stress resistance. Other stressors or cytotoxic compounds may also be used to screen for resistant mutants to uncover novel genetic determinants of a variety of cellular stress resistance. PMID- 26649460 TI - A CO2 Concentration Gradient Facility for Testing CO2 Enrichment and Soil Effects on Grassland Ecosystem Function. AB - Continuing increases in atmospheric carbon dioxide concentrations (CA) mandate techniques for examining impacts on terrestrial ecosystems. Most experiments examine only two or a few levels of CA concentration and a single soil type, but if CA can be varied as a gradient from subambient to superambient concentrations on multiple soils, we can discern whether past ecosystem responses may continue linearly in the future and whether responses may vary across the landscape. The Lysimeter Carbon Dioxide Gradient Facility applies a 250 to 500 ul L-1 CA gradient to Blackland prairie plant communities established on lysimeters containing clay, silty clay, and sandy soils. The gradient is created as photosynthesis by vegetation enclosed in in temperature-controlled chambers progressively depletes carbon dioxide from air flowing directionally through the chambers. Maintaining proper air flow rate, adequate photosynthetic capacity, and temperature control are critical to overcome the main limitations of the system, which are declining photosynthetic rates and increased water stress during summer. The facility is an economical alternative to other techniques of CA enrichment, successfully discerns the shape of ecosystem responses to subambient to superambient CA enrichment, and can be adapted to test for interactions of carbon dioxide with other greenhouse gases such as methane or ozone. PMID- 26649461 TI - Chirp-Evoked Auditory Brainstem Response in Children: A Review. AB - PURPOSE: The aim of this study was to assess the use of the chirp stimulus to record auditory brainstem responses in the pediatric population via a traditional review. METHOD: An electronic search of the literature and a hand search of the literature were conducted. Studies that utilized chirp stimuli within the pediatric population that met all of the inclusion criteria were included in this review. Qualitative synthesis and interpretation of the data were completed. RESULTS: Seven studies that met the inclusion criteria were included in the review. Chirp stimuli produce auditory brainstem response (ABR) waveform amplitudes in children similar to those in adults when presented at moderate to low frequency levels. Latency data from chirp stimuli are not consistent when stimulus presentation rates are altered. Test-retest reliability when using the chirp stimulus was found to be good, as were sensitivity and specificity of chirp evoked ABRs utilized in a newborn hearing screening protocol. CONCLUSION: Reviewed studies indicated that when presented at 60 dB nHL or lower, broadband chirp-generated ABRs have larger amplitudes than click-generated ABRs in children with normal hearing. Utilization of chirp stimuli decreases test time because waveforms are easier to detect with increased synchronization. Further research should focus on correlating chirp thresholds with behavioral hearing thresholds. Given the variance of results in these select studies, future research should also evaluate latency findings and focus on developing normative data for infants with hearing impairment and normal hearing. PMID- 26649462 TI - Self-Assembly of Micromachining Systems Powered by Janus Micromotors. AB - Janus particles can self-assemble around microfabricated gears in reproducible configurations with a high degree of spatial and orientational order. The final configuration maximizes the torque applied on the rotor leading to a unidirectional and steady rotating motion. The interplay between geometry and dynamical behavior leads to the self-assembly of Janus micromotors starting from randomly distributed particles. PMID- 26649463 TI - A Cancer Cell Spheroid Assay to Assess Invasion in a 3D Setting. AB - The invasive nature of cancer cell lines is thought to correlate with their metastatic potential. Most traditional assays, however, do not examine these invasive features in a three-dimensional environment and the resulting data suffer from reduced biological applicability. Here an approach is presented to visualize the invasive ability of cell lines in a physiologically relevant setting. The cancer cell spheroid invasion assay first utilizes gravity to generate spheroids within drops of media that hang from the lid of a cell culture dish. Next, these spheroids are embedded in a 3D matrix consisting of a mixture of basement membrane materials and type I collagen. Cancer cell egression from the spheroids into the surrounding matrix is then monitored over time. The method described here can be modified to examine invasion after coculture of different cell types, inclusion of drugs/inhibitors, or alterations in extracellular matrix (ECM) constituents. PMID- 26649465 TI - Internet-delivered cognitive behavioural therapy for children with anxiety disorders: A randomised controlled trial. AB - BACKGROUND: Cognitive behaviour therapy (CBT) has been shown to be an effective treatment for anxiety disorders in children, but few affected seek or receive treatment. Internet-delivered CBT (ICBT) could be a way to increase the availability of empirically supported treatments. AIMS: A randomised controlled trial was conducted to evaluate ICBT for children with anxiety disorders. METHOD: Families (N = 93) with a child aged 8-12 years with a principal diagnosis of generalised anxiety disorder, panic disorder, separation anxiety, social phobia or specific phobia were recruited through media advertisement. Participants were randomised to 10 weeks of ICBT with therapist support, or to a waitlist control condition. The primary outcome measure was the Clinician Severity Rating (CSR) and secondary measures included child- and parent-reported anxiety. Assessments were made at pre-treatment, post-treatment and at three-month follow-up. RESULTS: At post-treatment, there were significant reductions on CSR in the treatment group, with a large between-group effect size (Cohen's d = 1.66). Twenty per cent of children in the treatment group no longer met criteria for their principal diagnosis at post-treatment and at follow-up this number had increased to 50%. Parent-reported child anxiety was significantly lower in the treatment group than in the waitlist group at post-treatment, with a small between-group effect size (Cohen's d = 0.45). There were no significant differences between the groups regarding child-ratings of anxiety at post-treatment. Improvements were maintained at three-month follow-up, although this should be interpreted cautiously due to missing data. CONCLUSIONS: Within the limitations of this study, results suggest that ICBT with therapist support for children with anxiety disorders can reduce clinician- and parent-rated anxiety symptoms. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01533402. PMID- 26649466 TI - Expectancy violation, reduction of food cue reactivity and less eating in the absence of hunger after one food cue exposure session for overweight and obese women. AB - The present study investigated whether a single-session of food cue exposure for overweight women would decrease 'if CS then US' expectancies, cue reactivity and eating in the absence of hunger (EAH). EAH was measured in a behavioural paradigm that enabled to also investigate whether the cue exposure effects were specific for exposed foods or would generalise to food items that were not present during exposure. Overweight women were randomly assigned to either the cue exposure intervention or a control intervention that focused on body image. In line with the hypotheses, results showed that cue exposure induced a significant decrease in 'if CS then US' expectancies, in contrast to the control intervention. It was also found that, compared to the control intervention, desires to eat initially increased during cue exposure while gradual extinction was observed towards the end of the intervention. No extinction of increased salivation responses was found. Regarding EAH, the intake of the exposed food item was significantly less in the exposure condition than in the control condition, whereas total caloric food intake was not different between conditions, indicating that cue exposure was effective in reducing intake but did not generalise to the intake of other food items. PMID- 26649464 TI - Increasing clinicians' EBT exploration and preparation behavior in youth mental health services by changing organizational culture with ARC. AB - OBJECTIVE: Clinician EBT exploration and preparation behavior is essential to the ongoing implementation of new EBTs. This study examined the effect of the ARC organizational intervention on clinician EBT exploration and preparation behavior and assessed the mediating role of organizational culture as a linking mechanism. METHOD: Fourteen community mental health agencies that serve youth in a major Midwestern metropolis along with 475 clinicians who worked in those agencies, were randomly assigned to either the three-year ARC intervention or control condition. Organizational culture was assessed with the Organizational Social Context (OSC) measure at baseline and follow-up. EBT exploration and preparation behavior was measured as clinician participation in nine separate community EBT workshops held over a three-year period. RESULTS: There was 69 percent greater odds (OR = 1.69, p < .003) of clinicians in the ARC condition (versus control) attending each subsequent workshop. Workshop attendance in the control group remained under two percent and declined over three years while attendance in the ARC condition grew from 3.6 percent in the first workshop to 12 percent in the ninth and final workshop. Improvement in proficient organizational culture mediated the positive effect of the ARC intervention on clinicians' workshop attendance (a * b = .21; 95% CI:LL = .05, UL = .40). CONCLUSIONS: Organizational interventions that create proficient mental health agency cultures can increase clinician EBT exploration and preparation behavior that is essential to the ongoing implementation of new EBTs in community youth mental health settings. PMID- 26649467 TI - Evaluation of peripheral blood CD34+ cell count in the acute phase of traumatic brain injury and chest trauma. AB - AIM: To determine the impact of traumatic brain injury (TBI) and chest trauma (CT) on the number of peripheral blood (PB) stem cells in affected patients in comparison to normal controls. Additionally, the aim was to determine the relationship between CD34+ cell counts and TBI-induced hypothalamus-pituitary adrenal axis dysfunction in the acute phase of trauma. PATIENTS AND METHOD: Thirty patients with TBI, 12 patients with CT and 53 healthy subjects were included in the study. RESULTS: CD34+ cell counts within the first 24-48 hours of TBI were found to be lower than those obtained on the 7(th) day of TBI and those in the healthy controls. CD34+ cell counts obtained on the 2(nd) day of CT were lower than those in the healthy group, but did not differ from those measured on the 7(th) day of CT. There was no correlation between CD34+ cell counts and serum total cortisol (STC) levels on the 2(nd) and 7(th) days in the TBI or CT groups. CONCLUSION: An increase in CD34+ cell counts as observed on the 7(th) day in both TBI and CT groups suggested that CD34 changes were not specific to TBI. Moreover, this study showed for the first time that CD34 response was not affected by changes in cortisol levels induced by TBI and severity of TBI. PMID- 26649468 TI - Successful endoscopic vacuum therapy with new open-pore film drainage in a case of iatrogenic duodenal perforation during ERCP. PMID- 26649469 TI - Malignant lymphoid polyp - a new category of disease in the large intestine. PMID- 26649470 TI - Peroral endoscopic pyloromyotomy for delayed postoperative gastroparesis. PMID- 26649471 TI - Liver impaction technique to prevent shearing of the guidewire during endoscopic ultrasound-guided hepaticogastrostomy. PMID- 26649472 TI - Early growth and development impairments in patients with ganglioside GM3 synthase deficiency. AB - Ganglioside GM3 synthase is a key enzyme involved in the biosynthesis of gangliosides. GM3 synthase deficiency (GSD) causes a complete absence of GM3 and all downstream biosynthetic derivatives. The individuals affected by this disorder manifest severe irritability, intractable seizures and profound intellectual disability. However, we have found that most newborns seem symptom free for a period of time after birth. In order to further understand the onset of the disease, we investigated the early growth and development of patients with this condition through this study. We compared 37 affected individuals with their normal siblings and revealed that all children with GSD had relatively normal intrauterine growth and development, as their weight, length and head circumference were similar to their normal siblings at birth. However, the disease progresses quickly after birth and causes significant constitutional impairments of growth and development by 6 months of age. Neither breastfeeding nor gastrostomy tube placement made significant difference on growth and development as all groups of patients showed the similar pattern. We conclude that GSD causes significant postnatal growth and developmental impairments and the amount of gangliosides in breast milk and general nutritional intervention do not seem to alter these outcomes. PMID- 26649473 TI - Atomistic Insights into the Oriented Attachment of Tunnel-Based Oxide Nanostructures. AB - Controlled synthesis of nanomaterials is one of the grand challenges facing materials scientists. In particular, how tunnel-based nanomaterials aggregate during synthesis while maintaining their well-aligned tunneled structure is not fully understood. Here, we describe the atomistic mechanism of oriented attachment (OA) during solution synthesis of tunneled alpha-MnO2 nanowires based on a combination of in situ liquid cell transmission electron microscopy (TEM), aberration-corrected scanning TEM with subangstrom spatial resolution, and first principles calculations. It is found that primary tunnels (1 * 1 and 2 * 2) attach along their common {110} lateral surfaces to form interfaces corresponding to 2 * 3 tunnels that facilitate their short-range ordering. The OA growth of alpha-MnO2 nanowires is driven by the stability gained from elimination of {110} surfaces and saturation of Mn atoms at {110}-edges. During this process, extra [MnOx] radicals in solution link the two adjacent {110} surfaces and bond with the unsaturated Mn atoms from both surface edges to produce stable nanowire interfaces. Our results provide insights into the controlled synthesis and design of nanomaterials in which tunneled structures can be tailored for use in catalysis, ion exchange, and energy storage applications. PMID- 26649474 TI - The Effect of Simulated Microgravity on Differentiation of Porcine Blood-Derived Vascular Stem Cells. AB - The negative effects of space flight on cardiovascular health of astronauts have been demonstrated and documented over many years. Endothelial cells (ECs) play an important role in regulating weightlessness-induced cardiovascular dysfunction. This project seeks to study the effect of microgravity on the differentiation of endothelial progenitor cells (EPCs) into ECs and the downstream functions of the differentiated cells. Initial exposure of EPCs to microgravity indicated an inhibition of migratory, proliferative, and antithrombogenic capacity of the differentiated ECs. However, our results indicate a potential recovery of proliferative and antithrombogenic functions on prolonged exposure to microgravity. PMID- 26649475 TI - Research Misconduct Policies: Rule or Person as a Model? PMID- 26649476 TI - Mechanical strain effects on black phosphorus nanoresonators. AB - We perform classical molecular dynamics simulations to investigate the effects of mechanical strain on single-layer black phosphorus nanoresonators at different temperatures. We find that the resonant frequency is highly anisotropic in black phosphorus due to its intrinsic puckered configuration, and that the quality factor in the armchair direction is higher than in the zigzag direction at room temperature. The quality factors are also found to be intrinsically larger than those in graphene and MoS2 nanoresonators. The quality factors can be increased by more than a factor of two by applying tensile strain, with uniaxial strain in the armchair direction being the most effective. However, there is an upper bound for the quality factor increase due to nonlinear effects at large strains, after which the quality factor decreases. The tension induced nonlinear effect is stronger along the zigzag direction, resulting in a smaller maximum strain for quality factor enhancement. PMID- 26649477 TI - Effect of Head Tilt and Ocular Compensatory Mechanisms on Retinal Nerve Fiber Layer Measurements by Cirrus Spectral Domain and Spectralis Optical Coherence Tomography in Normal Subjects. AB - PURPOSE: To determine the effect of head tilt and ocular compensatory mechanisms on retinal nerve fiber layer (RNFL) thickness measurements using the Cirrus and Spectralis spectral-domain optical coherence tomography (OCT) in healthy eyes. Our secondary objective was to assess the visual influence on ocular compensatory mechanisms during head tilt. MATERIALS AND METHODS: This is a prospective, observational study. A single randomly selected eye was scanned undilated in 3 positions (baseline, right, and left tilt) using both machines. In addition, patching was also done for the contralateral eye during head tilt and RNFL measurements repeated. The paired t test was used to analyze effect on RNFL thickness. One-way repeated-measures analysis of variance was used to compare differences in RNFL measurements. RESULTS: In Cirrus OCT RNFL analysis, ipsilateral head tilt resulted in superior thinning and temporal thickening, whereas contralateral head tilt resulted in inferior thinning, nasal thickening, as well as temporal thickening (all P<0.05). Head tilt did not cause any significant change in RNFL thickness with Spectralis OCT (P>0.05). Patching the contralateral eye also did not alter Cirrus RNFL measurement errors due to head tilt. CONCLUSIONS: Head tilt can affect the measurement of the RNFL thickness in Cirrus OCT, and ocular compensatory mechanisms were not sufficient to prevent this. In contrast, Spectralis OCT RNFL thickness measurements were not affected by head tilt. Patching the contralateral eye during head tilt in Cirrus OCT also did not affect RNFL variability. The visual influence on ocular compensatory mechanisms during head tilt appears insignificant. PMID- 26649479 TI - Reply re: "Anterior Segment Ischemia and Retinochoroidal Vascular Occlusion After Intralesional Steroid Injection". PMID- 26649478 TI - "Freeing" Graphene from Its Substrate: Observing Intrinsic Velocity Saturation with Rapid Electrical Pulsing. AB - Rapid (nanosecond-scale) electrical pulsing is used to study drift-velocity saturation in graphene field-effect devices. In these experiments, high-field pulses are utilized to drive graphene's carriers on time scales much faster than that on which energy loss to the underlying substrate can occur, thereby allowing the observation of the highest saturation velocities reported to date. In a dramatic departure from the behavior exhibited by conventional metals and semiconductors, as the electron or hole density is reduced toward the charge neutrality point, the drift velocity is found to reach values comparable to the Fermi velocity itself. Corresponding current densities are as large as 10(9) A/cm(2), similar to the values reported for carbon nanotubes and for graphene-on diamond transistors. In essence, our approach of rapid pulsing allows us to "free" graphene from the deleterious influence of its substrate, revealing a pathway to achieve the superior electrical performance promised by this material. The usefulness of this approach is not merely limited to graphene but should extend also to a broad variety of two-dimensional semiconductors. PMID- 26649480 TI - Reply re: "Presumed Nasolacrimal Endometriosis". PMID- 26649481 TI - Reply re: "Methods of Antibiotic Instillation in Porous Orbital Implants". PMID- 26649482 TI - Reply re: "Methods of Antibiotic Instillation in Porous Orbital Implants". PMID- 26649483 TI - Ionic Surfactant Binding to pH-Responsive Polyelectrolyte Brush-Grafted Nanoparticles in Suspension and on Charged Surfaces. AB - The interactions between silica nanoparticles grafted with a brush of cationic poly(2-(dimethylamino) ethyl methacrylate) (SiO2-g-PDMAEMA) and anionic surfactant sodium dodecyl sulfate (SDS) is investigated by dynamic light scattering, electrophoretic mobility, quartz crystal microbalance with dissipation, ellipsometry, and atomic force microscopy. SiO2-g-PDMAEMA exhibits pH-dependent charge and size properties which enable the SDS binding to be probed over a range of electrostatic conditions and brush conformations. SDS monomers bind irreversibly to SiO2-g-PDMAEMA at low surfactant concentrations (~10(-4) M) while exhibiting a pH-dependent threshold above which cooperative, partially reversible SDS binding occurs. At pH 5, SDS binding induces collapse of the highly charged and swollen brush as observed in the bulk by DLS and on surfaces by QCM-D. Similar experiments at pH 9 suggest that SDS binds to the periphery of the weakly charged and deswollen brush and produces SiO2-g-PDMAEMA/SDS complexes with a net negative charge. SiO2-g-PDMAEMA brush collapse and charge neutralization is further confirmed by colloidal probe AFM measurements, where reduced electrosteric repulsions and bridging adhesion are attributed to effects of the bound SDS. Additionally, sequential adsorption schemes with SDS and SiO2-g PDMAEMA are used to enhance deposition relative to SiO2-g-PDMAEMA direct adsorption on silica. This work shows that the polyelectrolyte brush configuration responds in a more dramatic fashion to SDS than to pH-induced changes in ionization, and this can be exploited to manipulate the structure of adsorbed layers and the corresponding forces of compression and friction between opposing surfaces. PMID- 26649484 TI - A new method to measure electron density and effective atomic number using dual energy CT images. AB - The purpose of this work is to present a new method to extract the electron density ([Formula: see text]) and the effective atomic number (Z eff) from dual energy CT images, based on a Karhunen-Loeve expansion (KLE) of the atomic cross section per electron. This method was used to calibrate a Siemens Definition CT using the CIRS phantom. The predicted electron density and effective atomic number using 80 kVp and 140 kVp were compared with a calibration phantom and an independent set of samples. The mean absolute deviations between the theoretical and calculated values for all the samples were 1.7 % +/- 0.1 % for [Formula: see text] and 4.1 % +/- 0.3 % for Z eff. Finally, these results were compared with other stoichiometric method. The application of the KLE to represent the atomic cross section per electron is a promising method for calculating [Formula: see text] and Z eff using dual-energy CT images. PMID- 26649485 TI - Conversations in cardiology--Is BVS ready for prime time? More about the absorb study. PMID- 26649487 TI - Synthesis of Fused Carbazoles by Gold-Catalyzed Tricyclization of Conjugated Diynes via Rearrangement of an N-Propargyl Group. AB - Various N-propargylanilines bearing a conjugated diyne moiety at the 2-position were converted to tetracyclic fused carbazoles by treatment with a homogeneous gold(I) catalyst. This cascade reaction proceeds through indole formation with concomitant rearrangement of the N-propargyl group, intramolecular nucleophilic addition toward the resulting allene moiety, and subsequent hydroalkenylation. This transformation enables a one-pot synthesis of fused carbazoles from readily accessible substrates with 100% atom economy. PMID- 26649488 TI - Geomagnetic Field (Gmf) and Plant Evolution: Investigating the Effects of Gmf Reversal on Arabidopsis thaliana Development and Gene Expression. AB - One of the most stimulating observations in plant evolution is a correlation between the occurrence of geomagnetic field (GMF) reversals (or excursions) and the moment of the radiation of Angiosperms. This led to the hypothesis that alterations in GMF polarity may play a role in plant evolution. Here, we describe a method to test this hypothesis by exposing Arabidopsis thaliana to artificially reversed GMF conditions. We used a three-axis magnetometer and the collected data were used to calculate the magnitude of the GMF. Three DC power supplies were connected to three Helmholtz coil pairs and were controlled by a computer to alter the GMF conditions. Plants grown in Petri plates were exposed to both normal and reversed GMF conditions. Sham exposure experiments were also performed. Exposed plants were photographed during the experiment and images were analyzed to calculate root length and leaf areas. Arabidopsis total RNA was extracted and Quantitative Real Time-PCR (qPCR) analyses were performed on gene expression of CRUCIFERIN 3 (CRU3), copper transport protein1 (COTP1), Redox Responsive Transcription Factor1 (RRTF1), Fe Superoxide Dismutase 1, (FSD1), Catalase3 (CAT3), Thylakoidal Ascorbate Peroxidase (TAPX), a cytosolic Ascorbate Peroxidase1 (APX1), and NADPH/respiratory burst oxidase protein D (RbohD). Four different reference genes were analysed to normalize the results of the qPCR. The best of the four genes was selected and the most stable gene for normalization was used. Our data show for the first time that reversing the GMF polarity using triaxial coils has significant effects on plant growth and gene expression. This supports the hypothesis that GMF reversal contributes to inducing changes in plant development that might justify a higher selective pressure, eventually leading to plant evolution. PMID- 26649486 TI - IFN-gamma-Producing T-Helper 17.1 Cells Are Increased in Sarcoidosis and Are More Prevalent than T-Helper Type 1 Cells. AB - RATIONALE: Pulmonary sarcoidosis is classically defined by T-helper (Th) cell type 1 inflammation (e.g., IFN-gamma production by CD4(+) effector T cells). Recently, IL-17A-secreting cells have been found in lung lavage, invoking Th17 immunity in sarcoidosis. Studies also identified IL-17A-secreting cells that expressed IFN-gamma, but their abundance as a percentage of total CD4(+) cells was either low or undetermined. OBJECTIVES: Based on evidence that Th17 cells can be polarized to Th17.1 cells to produce only IFN-gamma, our goal was to determine whether Th17.1 cells are a prominent source of IFN-gamma in sarcoidosis. METHODS: We developed a single-cell approach to define and isolate major Th-cell subsets using combinations of chemokine receptors and fluorescence-activated cell sorting. We subsequently confirmed the accuracy of subset enrichment by measuring cytokine production. MEASUREMENTS AND MAIN RESULTS: Discrimination between Th17 and Th17.1 cells revealed very high percentages of Th17.1 cells in lung lavage in sarcoidosis compared with controls in two separate cohorts. No differences in Th17 or Th1 lavage cells were found compared with controls. Lung lavage Th17.1 cell percentages were also higher than Th1-cell percentages, and approximately 60% of Th17.1-enriched cells produced only IFN-gamma. CONCLUSIONS: Combined use of surface markers and functional assays to study CD4(+) T cells in sarcoidosis revealed a marked expansion of Th17.1 cells that only produce IFN-gamma. These results suggest that Th17.1 cells could be misclassified as Th1 cells and may be the predominant producer of IFN-gamma in pulmonary sarcoidosis, challenging the Th1 paradigm of pathogenesis. PMID- 26649489 TI - A nanohybrid of platinum nanoparticles-porous ZnO-hemin with electrocatalytic activity to construct an amplified immunosensor for detection of influenza. AB - In this work, a nanohybrid of platinum nanoparticles-porous ZnO spheres-hemin (Pt pZnO-hemin) was synthesized for construction of alkaline phosphatase-based immunosensor for detection of influenza. Briefly, porous ZnO spheres (pZnO) were prepared using soluble starches as the capping agent, followed by surface functionalization of platinum nanoparticles via a hydrothermal method (Pt-pZnO). Then, hemin with carboxylic functionality was spontaneously adsorbed onto Pt-pZnO by ester-like binding between carboxylic group of hemin and ZnO. Compared with platinum nanoparticles and hemin, the resulting Pt-pZnO-hemin nanohybrid showed more excellent electrocatalysis activity toward 1-naphthol (1-NP). Taking advantage of the Pt-pZnO-hemin, we have developed an amplified electrochemical immunosensor based on in situ generation of redox probe by alkaline phosphatase (ALP) and Pt-pZnO-hemin as signal enhancer. Herein, electrochemically active 1-NP was generated by enzymatic hydrolysis of inactive 1-naphthyl phosphate by ALP, then Pt-pZnO-hemin was used as catalyst to catalytically oxidize 1-NP, resulting in electrochemical signal amplification. Furthermore, in comparison with other nanomaterials including Au-pZnO, Pt-pZnO and Au-pZnO-hemin, the excellent catalytical property of Pt-pZnO-hemin make it a promising nanohybrid material for ALP-based immunosensor for signal amplification. PMID- 26649490 TI - Sensitive detection of Campylobacter jejuni using nanoparticles enhanced QCM sensor. AB - A quartz crystal microbalance (QCM) sensor platform was used to develop an immunosensor for the detection of food pathogen Campylobacter jejuni. Rabbit polyclonal antibodies and commercially available mouse monoclonal antibodies against C. jejuni were investigated to construct direct, sandwich and gold nanoparticles (AuNPs) amplified sandwich assays. The performance of the QCM immunosensor developed using sandwich assay by utilising the rabbit polyclonal antibody as the capture antibody and conjugated to AuNPs as the detection antibody gave the highest sensitivity. This sensor achieved a limit of detection (LOD) of 150 colony forming unit (CFU)mL(-1) of C. jejuni in solution. The QCM sensor showed excellent sensitivity and specificity for Campylobacter detection with low cross reactivity for other foodborne pathogens such as Salmonella Typhimurium, (7%) Listeria monocytogenes (3%) and Escherichia coli (0%). The development of this biosensor would help in the sensitive detection of Campylobacter which can result in reducing pre-enrichment steps; hence, reducing assay time. This work demonstrates the potential of this technology for the development of a rapid and sensitive detection method for C. jejuni. PMID- 26649491 TI - Enhancement of ethanol-oxygen biofuel cell output using a CNT based nano composite as bioanode. AB - The present research, describes preparation and application of a novel bioanode for ethanol-oxygen biofuel cells. We applied an enzyme based nanocomposite consisting of polymethylene green as electron transfer mediator, carboxylated multiwall carbon nanotubes as electron transfer accelerator, alcohol dehydrogenase as biocatalyst and polydiallyldimethylammonium chloride as supporting agent. In the presence of beta-nicotinamide adenine dinucleotide as cofactor, and ethanol as fuel, the feasibility of the bioanode for increasing the power was evaluated under the ambient conditions. In the optimum conditions the biofuel cell produced the power density of 1.713 mW cm(-2) and open circuit voltage of 0.281 V. PMID- 26649492 TI - Thrombin-mediated ratiometric two-photon fluorescent probe for selective imaging of endogenous ultratrace glutathione in platelet. AB - Ultratrace change of reduced glutathione (GSH) can weaken coagulation function of platelet (PLT). Thus, rapid and sensitive imaging of GSH specific in PLT is beneficial for monitoring coagulation function of PLT. Many fluorescent probes for GSH have been reported, but ratio fluorescent probe with excellent two-photon property for screening PLT from peripheral blood and quantitative imaging of GSH are scarce. In this work, a thrombin-mediated two-photon GSH-specific fluorescent probe (IQDC-L) was reported. Sulfuric diamide, a key group as linker, was introduced into IQDC-L, which resulted in not only specific selectivity for GSH, but also FRET occurring in probe. When IQDC-L encountered GSH, "S-N" in sulfonamide group was cut off, and FRET was inhibited. Furthermore, fluorescence intensities at 520 and 595 nm presented linear change on ratio mode in the range of GSH (2.0-65 nM). The lowest detection for GSH was as low as 0.083 nM. Intriguingly, IQDC-L under thrombin-mediated was able to screen PLT from peripheral blood without any interference. Thus, IQDC-L could be used to screen PLT from peripheral blood, and simultaneously, to in situ image ultratrace GSH. PMID- 26649493 TI - Guanine nanowire based amplification strategy: Enzyme-free biosensing of nucleic acids and proteins. AB - Sensitive and specific detection of nucleic acids and proteins plays a vital role in food, forensic screening, clinical and environmental monitoring. There remains a great challenge in the development of signal amplification method for biomolecules detection. Herein, we describe a novel signal amplification strategy based on the formation of guanine nanowire for quantitative detection of nucleic acids and proteins (thrombin) at room temperature. In the presence of analytes and magnesium ions, the guanine nanowire could be formed within 10 min. Compared to the widely used single G-quadruplex biocatalytic label unit, the detection limits are improved by two orders of magnitude in our assay. The proposed enzyme free method avoids fussy chemical label-ling process, complex programming task, and sophisticated equipment, which might provide an ideal candidate for the fabrication of selective and sensitive biosensing platform. PMID- 26649494 TI - Real-Time Observation of Water-Soluble Mineral Precipitation in Aqueous Solution by In Situ High-Resolution Electron Microscopy. AB - The precipitation and dissolution of water-soluble minerals in aqueous systems is a familiar process occurring commonly in nature. Understanding mineral nucleation and growth during its precipitation is highly desirable, but past in situ techniques have suffered from limited spatial and temporal resolution. Here, by using in situ graphene liquid cell electron microscopy, mineral nucleation and growth processes are demonstrated in high spatial and temporal resolution. We precipitate the mineral thenardite (Na2SO4) from aqueous solution with electron beam-induced radiolysis of water. We demonstrate that minerals nucleate with a two-dimensional island structure on the graphene surfaces. We further reveal that mineral grains grow by grain boundary migration and grain rotation. Our findings provide a direct observation of the dynamics of crystal growth from ionic solutions. PMID- 26649495 TI - May 2010: This Month's Highlights. PMID- 26649496 TI - Correction: Additional Author. PMID- 26649497 TI - Letter. PMID- 26649498 TI - Letter. PMID- 26649499 TI - Letter. PMID- 26649500 TI - Letter. PMID- 26649501 TI - Letter. PMID- 26649502 TI - Letter. PMID- 26649508 TI - John Oldham Is President-Elect, Carol Bernstein Begins APA Presidency. PMID- 26649509 TI - Implications of Health Reform for Mental Health Care. PMID- 26649512 TI - Editorial. PMID- 26649513 TI - The Hearing Aid Expert: Audiologist, Dealer, or Otolaryngologist? AB - Based on available data, audiologists have, by far, the best overall dispensing credentials and, in fact, the best credentials in each area evaluated. Unfortunately, the available data are somewhat limited. Although the data indicate that audiologists are the superior dispenser, that is, the hearing aid expert, the data are not sufficient to conclusively prove that point. What we can state with confidence is that there is no basis in the data to recommend the dealer or the otolaryngologist over the audiologist. If a governmental agency or an insurer is going to restrict dispensing, then, based on current credentials, audiologists should always be one of the groups permitted to dispense. PMID- 26649511 TI - Production of IL-27 in multiple sclerosis lesions by astrocytes and myeloid cells: Modulation of local immune responses. AB - The mechanisms whereby human glial cells modulate local immune responses are not fully understood. Interleukin-27 (IL-27), a pleiotropic cytokine, has been shown to dampen the severity of experimental autoimmune encephalomyelitis, but it is still unresolved whether IL-27 plays a role in the human disease multiple sclerosis (MS). IL-27 contribution to local modulation of immune responses in the brain of MS patients was investigated. The expression of IL-27 subunits (EBI3 and p28) and its cognate receptor IL-27R (the gp130 and TCCR chains) was elevated within post-mortem MS brain lesions compared with normal control brains. Moreover, astrocytes (GFAP(+) cells) as well as microglia and macrophages (Iba1(+) cells) were important sources of IL-27. Brain-infiltrating CD4 and CD8 T lymphocytes expressed the IL-27R specific chain (TCCR) implying that these cells could respond to local IL-27 sources. In primary cultures of human astrocytes inflammatory cytokines increased IL-27 production, whereas myeloid cell inflammatory M1 polarization and inflammatory cytokines enhanced IL-27 expression in microglia and macrophages. Astrocytes in postmortem tissues and in vitro expressed IL-27R. Moreover, IL-27 triggered the phosphorylation of the transcription regulator STAT1, but not STAT3 in human astrocytes; indeed IL-27 up regulated MHC class I expression on astrocytes in a STAT1-dependent manner. These findings demonstrated that IL-27 and its receptor were elevated in MS lesions and that local IL-27 can modulate immune properties of astrocytes and infiltrating immune cells. Thus, therapeutic strategies targeting IL-27 may influence not only peripheral but also local inflammatory responses within the brain of MS patients. PMID- 26649514 TI - Average Speech Levels and Spectra in Various Speaking/Listening Conditions: A Summary of the Pearson, Bennett, & Fidell (1977) Report. AB - The large study undertaken by Pearsons et al. (1977) for the Environmental Protection Agency nicely demonstrates "usual" speech levels in a variety of settings in classrooms, homes, hospitals, department stores, and commercial transportation. In most settings, speech levels were between 55 and 66 dBA at conversation distances in the school, home, hospital, and department store environments. S/N ratios on the order of 5 to 15 dB were maintained.Communication distance in the trains and airplanes was considerably less than the usual 1 m, and the speech levels were higher, 73 to 77 dBA, but still at a -1 or -2 dB S/N ratio in the train and airplanes, respectively. Their measurements in an anechoic chamber further reflected the levels of conversational speech in a quiet environment, as well as the levels and spectra for different vocal efforts by females, males, and children. Speech spectra were generally similar for the groups of talkers for casual conversation through raised vocal efforts. For loud speech, and particularly for shouted speech, male speech levels were greater than the speech levels of the females and children. The maximum one-third octave bands for loud and shouted speech shifted to higher frequencies for all three groups. PMID- 26649515 TI - Experience, Attitudes, and Competencies of Audiologic Support Personnel in a Rehabilitation Hospital. PMID- 26649516 TI - The Effects of Auditory Integration Training for Children With Central Auditory Processing Disorders. PMID- 26649517 TI - Area-Under-the-Curve Measure of the Auditory Middle Latency Response (AMLR) From Birth to Early Adulthood. AB - The area-under-the-curve (AUC) measure of the auditory middle latency response (AMLR) waveform was derived and analyzed from recordings in 50 subjects with normal hearing. The AUC metric is believed to represent the total amount of neural energy contributing to the evoked response. This proposed method of measure, therefore, may provide an alternative method of quantifying the response. The subjects were divided into five age groups (n = 10 for each group): infants, children, preteens, teens, and adults. Ipsilateral and contralateral recordings of the AMLR were obtained at two stimulus levels (70 and 40 dB nHL) and at two stimulus rates (11.3 and 3.3/s). AUC measures were obtained for each recording at 70 and 40 dB nHL and at 3.3 and 11.3 clicks/s. These area measurements were compared among the five age groups for significant differences due to age. According to the results, no significant differences in the AUC of the AMLR waveform existed as a function of age. PMID- 26649518 TI - The Occlusion Effect and Ear Canal Sound Pressure Level. AB - Comparisons were made between changes in the audibility of bone-conduction stimuli to differences in the sound pressure present in the external auditory canal when ears were occluded. Fifteen listeners with normal middle ear function were tested using pure tones of 250, 500, and 1000 Hz, delivered via a bone conduction oscillator placed on the mastoid process and the frontal bone. At all three frequencies, and both sites of stimulation, ear canal sound pressures were greater in the occluded than in the unoccluded conditions. Concurrently, the test signals were detected at lower intensities, although the changes in audibility and external canal sound pressure levels were not unity. The occlusion effect was attenuated slightly when the skull was vibrated from the frontal bone. PMID- 26649519 TI - Tympanometric Screening Norms for Adults. AB - The purpose of this study was to reexamine the Margolis and Heller (1987) normative tympanometric data (also American Speech-Language-Hearing [ASHA], 1990 interim norms) using a strict control over subject age and gender. Normative values for peak, compensated static acoustic admittance (Peak Ytm), acoustic equivalent volume (Vea), and tympanometric width (TW) were determined for 102 young adults with normal hearing. Relative to the Margolis and Heller normative values, significant differences were found for Vea and TW. Although statistically significant, these differences were small and of little clinical importance. However, significant and clinically important gender differences in young adults were observed for each of the tympanometric measures. Compared to males, females had lower Peak Ytm values, smaller Vea values, and higher TW values. PMID- 26649520 TI - A Simplified Method for Calibrating a Sound-Level Meter for Use With a Bruel & Kjaer Artificial Mastoid. AB - The standard method for calibrating a sound-level meter for use with the Bruel & Kjaer Artificial Mastoid for bone vibrator tests entails the use of a signal generator, a precision voltmeter, and possibly a frequency counter. This equipment should be certified annually and traceable to the National Institute of Standards and Technology (NIST), and its use generally restricts calibration to a laboratory environment and requires a considerable amount of time. We have developed a simplified method for calibrating the sound-level meter by using a sound-level calibrator and microphone. Using the known sensitivities of the microphone and the artificial mastoid, the sound-level calibrator used for calibration of the microphone may also be used for calibration of the sound-level meter to measure force levels with the artificial mastoid. PMID- 26649521 TI - Effectiveness of Central Auditory Processing Tests With Children. AB - The purpose of this investigation was to determine central auditory processing (CAP) individual test efficacy and test battery efficacy and to estimate the costs that are associated with the identification of a targeted sample. Ninety one children with normal learning (NL) abilities and 147 children with a classroom learning disability (CLD) and presumed CAP disorders (CAPDs) ranging in age from 7 to 13 years were given a battery of seven CAP tests. The test battery consisted of: (1) Binaural Fusion Test (BFT), (2) Masking Level Difference (MLD) test, (3) Filtered Speech Test (FST), (4) Time Compressed Speech (TCS) test, (5) Dichotic Digits Test (DDT), (6) Staggered Spondaic Word (SSW) test, and (7) Pitch Pattern Test (PPT).We believe that this investigation is the first report regarding the assessment of the utility of CAP tests using clinical decision analysis (CDA). We determined that the BFT separated the two samples most effectively and that the FST was the next most effective. A test protocol with BFT and FST or BFT and MLD represented the best battery approach when hit rate, false positive rate, and cost factors were considered. However, if the intent is to be certain that a child with CLD has CAPD given a positive test result, then the BFT and MLD would be the test battery of choice. PMID- 26649522 TI - A Clinical Trial of the ReSound BT2 Personal Hearing System. AB - The Food and Drug Administration requires that hearing aid manufacturers substantiate benefit claims in advertising with clinical research. Recently, Walden (1997) described a model protocol that might be used to assess hearing aid benefit in manufacturer-sponsored clinical trials. The Walter Reed protocol includes laboratory measures of speech recognition ability using the Continuous Speech Test (CST, Cox, Alexander, & Gilmore, 1987; Cox, Alexander, Gilmore, & Pusakulick, 1988) and the scales and subscales of the Profile of Hearing Aid Benefit (PHAB, Cox & Gilmore, 1990) to assess user benefit in four prototype listening environments.A clinical trial of the ReSound BT2 Personal Hearing System (BT2 PHS) using the Walter Reed protocol is reported here. The results for 40 adult participants with moderate-to-severe acquired sensorineural hearing losses revealed significant benefit from the BT2 PHS as compared to unaided performance on most of the CST and PHAB measures.Compared to performance (unaided) of persons with normal hearing, the individuals with hearing impairments obtained substantially poorer performance on the CST and reported slightly poorer BT2-aided performance on the PHAB. Finally, on average, participants reported significantly more success on the PHAB with the BT2 PHS as compared to their own linear hearing aids, and 70% of the participants preferred the BT2 PHS enough to be willing to purchase it rather than to continue to use their own government-issued linear hearing aids. PMID- 26649523 TI - State of the States: The Status of Universal Newborn Hearing Screening, Assessment, and Intervention Systems in 16 States. AB - This study reports the results of a comprehensive survey of 16 states regarding the coordination and characteristics of universal newborn hearing screening, audiologic assessment, and intervention programs. The survey establishes a baseline assessment that was conducted by states as part of their first year of participation in a Maternal and Child Health Bureau grant on state systems for universal newborn hearing screening, assessment, and intervention. States are making progress toward achieving universal newborn hearing screening. However, several issues continue to impede the establishment of statewide systems for linking screening programs to diagnosis and intervention. PMID- 26649524 TI - Benefit From, Satisfaction With, and Cost-Effectiveness of Three Different Hearing Aid Technologies. AB - Clinical decision-making has become more complex as newer, more costly, hearing aid (HA) technologies become available. The expanding array of more expensive HAs demands that clinical researchers continue to justify the value of these instruments relative to the substantial increase in cost to both the provider and consumer.In the present report, 25 current conventional HA users with adult onset of sensorineural hearing loss were fitted with: (a) a one-channel linear HA; (b) a two-channel, nonlinear HA; and (c) a seven-band, two-channel digital signal processing (DSP) HA. All instruments were mini behind-the-ear units with identifying information removed from the cases. Subjects wore each HA for at least a 1-month period.A set of laboratory (Speech Perception in Noise [SPIN] test; audibility index calculated from real-ear measurements) and self-report (Abbreviated Profile of Hearing Aid Benefit; Hearing Handicap Inventory for the Elderly/Adults; Knowles Hearing Aid Satisfaction Survey; preference ratings) outcome measures were used to evaluate the benefit from, satisfaction with, and cost-effectiveness of each test HA. As expected, there were statistically significant differences between unaided and aided conditions across HAs.Although the DSP instrument yielded significantly higher word recognition scores on the SPIN test, no differences were observed among the test HAs for the standardized self-report measures. In contrast, however, more than 75% of the subjects preferred the "higher end" instruments. Yet, 33% of the subjects changed their preference for the "higher end" instruments after being informed of costs. A cost effectiveness model for evaluating the relationship between HA retail purchase price and improvements in performance/benefit is presented. PMID- 26649525 TI - Using UCST Ionic Liquid as a Draw Solute in Forward Osmosis to Treat High Salinity Water. AB - The concept of using a thermoresponsive ionic liquid (IL) with an upper critical solution temperature (UCST) as a draw solute in forward osmosis (FO) was successfully demonstrated here experimentally. A 3.2 M solution of protonated betaine bis(trifluoromethylsulfonyl)imide ([Hbet][Tf2N]) was obtained by heating and maintaining the temperature above 56 degrees C. This solution successfully drew water from high-salinity water up to 3.0 M through FO. When the IL solution cooled to room temperature, it spontaneously separated into a water-rich phase and an IL-rich phase: the water-rich phase was the produced water that contained a low IL concentration, and the IL-rich phase could be used directly as the draw solution in the next cycle of the FO process. The thermal stability, thermal responsive solubility, and UV-vis absorption spectra of the IL were also studied in detail. PMID- 26649527 TI - Internet and Audiology: A Review of the First International Meeting. AB - PURPOSE: The purpose of this research forum article is to describe the impetus for holding the First International Meeting on Internet and Audiology (October 2014) and to introduce the special research forum that arose from the meeting. METHOD: The rationale for the First International Meeting on Internet and Audiology is described. This is followed by a short description of the research sections and articles appearing in the special issue. Six articles consider the process of health care delivery over the Internet; this includes health care specific to hearing, tinnitus, and balance. Four articles discuss the development of effective Internet-based treatment programs. Six articles describe and evaluate Internet-based interventions specific to adult hearing aid users. CONCLUSION: The fledgling field of Internet and audiology is remarkably broad. The Second International Meeting on Internet and Audiology ocurred in September 2015. PMID- 26649528 TI - An E-Platform for Rehabilitation of Persons With Hearing Problems. AB - PURPOSE: The aim of this research forum article was to describe a feasible web based solution for improving the quality of life of persons with hearing problems, such as hearing loss or tinnitus. The online platform was developed at the Department of Behavioural Sciences and Learning at Linkoping University, Sweden, and has been running for a number of years and used in numerous studies and treatments. METHOD: The security aspects of the platform as well as the process flow for running a study or treatment are described, focusing primarily on the technical and practical considerations. Also presented are the design characteristics and the main features and functions available in the platform. RESULTS: We point out the many advantages of running Internet-assisted intervention treatments, the challenges that we have faced, and some intended developments. Many of our research colleagues, both from Sweden and other countries, have already implemented or intend to implement their own studies on this platform. CONCLUSIONS: Audiological rehabilitation can be delivered via the Internet using a stable online platform. Security and usability are important factors to have in mind for the design as well as adaptability to the patients. A next development step is to implement and test blended treatments using video conferencing inside the platform. PMID- 26649526 TI - Nimbolide-Induced Oxidative Stress Abrogates STAT3 Signaling Cascade and Inhibits Tumor Growth in Transgenic Adenocarcinoma of Mouse Prostate Model. AB - AIMS: Prostate cancer (PCa) is one of the most commonly diagnosed cancers worldwide. Currently available therapies for metastatic PCa are only marginally effective, hence novel treatment modalities are urgently required. Considerable evidence(s) suggest that deregulated activation of oncogenic transcription factor, signal transducer and activator of transcription 3 (STAT3) plays a pivotal role in the development and progression of PCa. Thus, agents that can abrogate STAT3 activation could form the basis of novel therapy for PCa patients. In the present study, we analyzed whether the potential anticancer effects of nimbolide (NL), a limonoid triterpene derived from Azadirachta indica, against PCa cell lines and transgenic adenocarcinoma of mouse prostate (TRAMP) model are mediated through the negative regulation of STAT3 pathway. RESULTS: Data from the in vitro studies indicated that NL could significantly inhibit cell viability, induce apoptosis, and suppress cellular invasion and migration. Interestingly, NL also abrogated STAT3 activation and this effect was found to be mediated via an increased production of reactive oxygen species (ROS) due to GSH/GSSG imbalance. Oral administration of NL significantly suppressed the tumor growth and metastasis in TRAMP mouse model without exhibiting any significant adverse effects. INNOVATION: The present study demonstrates the critical role of GSH/GSSG imbalance-mediated ROS production contributing to the STAT3 inhibitory and tumor suppressive effect of NL in PCa. CONCLUSION: Overall, our findings indicate that NL exhibits significant anticancer effects in PCa that may be primarily mediated through the ROS-regulated inhibition of STAT3 signaling cascade. PMID- 26649529 TI - The Development of Balance Retraining: An Online Intervention for Dizziness in Adults Aged 50 Years and Older. AB - PURPOSE: This article outlines the rationale and development process for an online intervention based on vestibular rehabilitation therapy (VRT). The intervention aims to assist adults aged 50 years and older t o self-manage and reduce dizziness symptoms. METHOD: The intervention was developed according to the person-based approach to digital intervention design focused on accommodating perspectives of target users. A prototype version of the intervention was provided to 18 adults (11 women, 7 men) aged 50 years and older with dizziness. These adults were invited to use the intervention over a 6-week period and, during this time, took part in a think-aloud session. This session sought to understand users' perceptions of how acceptable, engaging, and easy to use they found the online intervention. RESULTS: Users were extremely positive regarding how easy to navigate, visually appealing, and informative they found the intervention. Think-aloud sessions provided valuable data for informing small amendments to further enhance acceptability of the intervention for target users. CONCLUSIONS: Informed by these development-phase data, a finalized version of the intervention is now being investigated in a primary care-based randomized controlled trial. Results should provide an understanding of whether VRT can be effectively-especially, cost-effectively-delivered via an online intervention to adults aged 50 years and older. PMID- 26649530 TI - The Effect of Chronological Age on the Acceptance of Internet-Based Hearing Health Care. AB - PURPOSE: The purpose of this article is to offer design considerations in developing Internet-based hearing health care for older adults by analyzing and discussing the relationship between chronological age, computer skills, and the acceptance of Internet-based hearing health care. METHOD: This article reports baseline data from a training study measuring the acceptance of Internet-based hearing health care. Participants (n = 26; 20 men, 6 women) were aged 55-95 years. All passed a cognitive screen and failed a hearing screen. Participants completed the Patient- Technology Acceptance questionnaire (Or, 2008). Computer literacy was measured using the Northstar Digital Literacy Assessment (Cytron Hysom, Hadley, Vanek, Graif, & Asp, 2012). RESULTS: Computer literacy was negatively correlated with increasing age. Additional negative relationships were seen between computer literacy and computer anxiety and between computer literacy and computer self-efficacy. Finally, there was a negative relationship between computer self-efficacy and computer anxiety. CONCLUSION: These results suggest computer literacy is lower in adults of advanced age than in those who are a few years younger. Indirect relationships were observed between age and computer self efficacy and between age and computer anxiety. Consideration should be given to addressing discrepancies in self-efficacy and computer literacy in older adults to increase the likelihood of acceptance of Internet-based hearing health care. PMID- 26649531 TI - Readability of Internet Information on Hearing: Systematic Literature Review. AB - PURPOSE: This systematic literature review asks the following question: " What is the readability of Internet information on hearing that people with hearing impairment and their significant others can access in the context of their hearing care?" METHOD: Searches were completed in three databases: CINAHL, PubMed, and Scopus. Seventy-eight records were identified and systematically screened for eligibility: 8 records were included that contained data on the readability of Internet information on hearing that people with hear ing impairment and their significant others can access in the context of their hearing care. RESULTS: Records reported mean readability levels from 9 to over 14. In other words, people with hearing impairment and their significant others need 9 to 14 years of education to read and understand Internet information on hearing that they access in the context of their hearing care. CONCLUSION: The poor readability of Internet information on hearing has been well documented; it is time to focus on valid and sustainable initiatives that address this problem. PMID- 26649532 TI - SoundSpace Online: The Development of an Online Resource About Hearing Loss. AB - PURPOSE: The Internet has been a growing source of health information on hearing loss, but the information provided often varies in quality, readability, and usability. Additionally, the information is provided across a wide range of domains, making access challenging to those who need it. This research forum article describes the development of a new website, SoundSpace Online (Ng, Archbold, Mayer, & Mulla, 2014), which aims to tackle these issues and bring together information and resource s f or all those concerned with hearing loss. METHOD: The SoundSpace Online website's current developmental state was reached through the following methods: (a) discussions with a group of individuals that included experts in e-learning, education, research, and hearing loss; (b) interviews with different target groups (e.g., users, families, and professionals); and (c) collaboration with contributors. RESULT: The website is structured to become a g o-to resource on various topics related to hearing loss, providing accurate, comprehensive, and functional information and resources at varying levels of complexity for the intended users. CONCLUSION: The literature and the range of interest have illustrated the need for an up-to-date website providing information and resources on hearing loss. Challenges include monitoring and keeping the website up to date; in this article, a plan of action is discussed. The website is currently in development, with plans for a launch in the near future. PMID- 26649533 TI - Apps for Hearing Science and Care. AB - PURPOSE: Our research aims at the identification and assessment of applications (referred to as apps) in the hearing health care domain. This research forum article presents an overview of the current availability, affordability, and variety of hearing-related apps. METHOD: The available apps were reviewed by searching on the leading platforms (iOS, Android, Windows Phone stores) using the keywords hearing, audiology, audio, auditory, speech, language, tinnitus, hearing loss, hearing aid, hearing sys tem, cochlear implant, implantable device, auditory training, hearing rehabilitation, and assistive technology/tool/device. O n the bas is of the offered services, apps were classified into 4 application domains: (a) screening and assessment, (b) intervention and rehabilitation, (c) education and information, and (d) assistive tools. CONCLUSIONS: A large variety of apps are available in the hearing health care domain. These cover a wide range of services for people with hearing or communication problems as well as for hearing professionals, families, or informal caregivers. This evolution can potentially bring along considerable advantages and improved outcomes in the field of hearing health care. Nevertheless, potential risks and threats (e.g., safety, quality, effectiveness, privacy, and regulation) should not be overlooked. Significant research-particularly in terms of assessment and guidance is still needed for the informed, aware, and safe adoption of hearing-related apps by patients and professionals. PMID- 26649534 TI - Clinician-Supported Internet-Delivered Psychological Treatment of Tinnitus. AB - PURPOSE: Internet-delivered psychological treatments for tinnitus distress have existed for more than 15 years, and there are a slowly growing number of studies. The aim of this brief report is to review the evidence and to comment on the future potentials of Internet treatments for tinnitus. METHOD: Studies were retrieved, and in total 6 controlled studies were included in the review with 9 different comparisons (6 in which the treatment was compared against a control group and 3 in which Internet treatment was compared against group treatment). Moreover, 2 open studies based on clinical samples in regular care were also included in the review. The outcomes for the 2 controlled sets of studies were analyzed using meta-analytic methods. RESULTS: For the 6 studies comparing Internet treatment against a no-treatment control condition, a moderate effect size was found (Hedges's g = 0.58). The 3 studies comparing Internet treatment against face-to-face group treatments showed a small difference of Hedges's g =0.13. CONCLUSIONS: Internet-delivered psychological treatment holds promise as a treatment alternative to other standard forms of treatment delivery, including group treatment. Larger studies are needed as well as ways to blend information technology with regular services. PMID- 26649535 TI - Bridging the Gap Between Hearing Screening and Successful Rehabilitation: Research Protocol of a Randomized Controlled Trial of Motivational Interviewing via Internet. AB - PURPOSE: Studies point to low help-seeking after a failed hearing screening. This research forum article presents the research protocol for a randomized controlled trial of motivational interviewing via the Internet to promote help-seeking in people who have failed an online hearing screening. METHOD: Adults who fail a Swedish online hearing screening, including a speech-in-noise recognition test, will be randomized to either an intervention group (participating in motivational interviewing) or an active control group (reading a book on history of hearing aids). Both of the conditions will be delivered via the Internet. The primary outcome is experience with seeking health care and using hearing aids 9 months after the intervention. Secondary outcomes are changes in before and after measures of self-reported hearing difficulties, anxiety, depression, and quality of life. Stages of change and self-efficacy in hearing help-seeking are measured immediately after intervention and at a 9-month follow-up for the purpose of mediation analysis. RESULTS: The results of this randomized controlled trial may help bridge the gap between hearing screening and successful hearing rehabilitation. CONCLUSION: Although no large instantaneous benefits are expected, a slow change toward healthy behaviors-seeking health care and using hearing aids-would shed light on how to use the Internet to assist people with hearing impairment. PMID- 26649536 TI - Internet-Based Acceptance and Commitment Therapy for Psychological Distress Experienced by People With Hearing Problems: Study Protocol for a Randomized Controlled Trial. AB - PURPOSE: Psychological distress and psychiatric symptoms are prevalent among people with hearing loss or other audiological conditions, but psychological interventions for these groups are rare. This article describes the study protocol for a randomized controlled trial for evaluating the effect of a psychological treatment delivered over the Internet for individuals with hearing problems and concurrent psychological distress. METHOD: Participants who are significantly distressed will be randomized to either an 8-week Internet delivered acceptance-based cognitive behavioral therapy (i.e., acceptance and commitment therapy [ACT]), or wa it-list control. We aim to include measures of distress associated with hearing difficulties, anxiety, and depression. In addition, we aim to measure acceptance associated with hearing difficulties as well as quality of life. CONCLUSION: The results of the trial may further our understanding of how to best treat people who present problems with both psychological distress and hearing in using the Internet. PMID- 26649537 TI - The Application of Intervention Coding Methodology to Describe the Tinnitus E Programme, an Internet-Delivered Self-Help Intervention for Tinnitus. AB - PURPOSE: This article describes the Tinnitus E-Programme, a previously untested Internet-delivered self-help intervention for tinnitus. METHOD: Intervention coding methodology was applied to describe the intervention components, techniques, and mode of delivery. RESULTS: The intervention consists of 5 self management intervention components, 5 behavior change techniques, and 3 modes of Internet delivery, which aim to promote relaxation behavior and reduce tinnitus distress. CONCLUSIONS: The intervention coding provided a reliable method for reporting Internet-delivered self-help interventions. It will be used to facilitate our understanding of the intervention's potential mechanisms of change and will guide future evaluation work. PMID- 26649538 TI - Internet Interventions for Hearing Loss. AB - PURPOSE: The purpose of the two studies presented in this research forum article was to develop audiological rehabilitation programs for experienced hearing aid users and evaluate them in online versions. In this research forum article, the differences between the two studies are discussed. METHOD: Two randomized controlled trials (RCTs) were performed evaluating the efficacy of online rehabilitation, including professional guidance by an audiologist. In each RCT, the effects of the online programs were compared with the effects measured in a control group. RESULTS: The results from the first RCT showed a significant increase in activity and participation for both groups with participants in the intervention group improving more than those in the control group. At the 6-month follow-up, after the study, the significant increase was maintained; however, amounts of increase in the two groups were no longer significantly different. The results from the second RCT showed significant increase in activity and participation for the intervention group, although the control group did not improve. CONCLUSIONS: The results from the RCTs provide evidence that the Internet can be used to deliver rehabilitation to hearing-aid users and that their problems are reduced by the intervention; however, the content of the online rehabilitation program requires further investigation. PMID- 26649539 TI - The Process of Developing an Internet-Based Support System for Audiologists and First-Time Hearing Aid Clients. AB - BACKGROUND: In audiologic practice, complementary information sources and access to the clinician between appointments improve information retention and facilitate adjustment behaviors. An Internet-based support system is a novel way to support information sharing and clinician access. PURPOSE: This research forum article describes the process of developing an Internet-based support system for audiologists and their first-time hearing aid clients. METHOD: The iterative development process, including revisions by 4 research audiologists and 4 clinical audiologists, is described. The final system is exemplified. CONCLUSION: An Internet-based support system was successfully developed for audiologic practice. PMID- 26649540 TI - Implementing Internet-Based Aural Rehabilitation in a General Clinical Practice. AB - PURPOSE: The purpose of this paper is to share the lessons that were learned about the process of implementing an Internet-based, randomized controlled trial (RCT) in general clinical practice (GCP) and to address some of the advantages of using the Internet as a tool to implement a RCT in GCP. The RCT implemented focused on investigating Internet-based aural rehabilitation (AR) in addition to hearing aid (HA)-fitting supplemented with telephone support, and it was applied in a clinical setting. The results of this RCT and the questionnaires chosen will be presented in an article elsewhere. PROCEDURE: Here, the procedure of the implemented trial is presented, and the implementation challenges are presented and discussed. Specifically, we describe the trial research question, recruitment strategy, patient eligibility criteria, the questionnaires, clinician participation, funding and time (for the clinicians), and risks and benefits (for the participants). DISCUSSION: The trial implementation showed that AR in addition to HA-fitting can be carried out in GCP using the Internet. Using an Internet-based RCT overcomes some of the challenges of implementing a trial in GCP. PMID- 26649541 TI - Information Retention and Overload in First-Time Hearing Aid Users: An Interactive Multimedia Educational Solution. AB - PURPOSE: An educational intervention to improve knowledge of hearing aids and communication in first-time hearing aid users was assessed. This intervention was based on the concept of reusable learning objects (RLOs). METHOD: A randomized controlled trial was conducted. One group received the educational intervention, and the other acted as a control group. RLOs were delivered online and through DVD for television and personal computer. Knowledge of both practical and psychosocial aspects of hearing aids and communication was assessed using a free recall method 6 weeks postfitting. RESULTS: Knowledge of both practical and psychosocial issues was significantly higher in the group that received the RLOs than in the control group. Moderate to large effect sizes indicated that these differences were clinically significant. CONCLUSION: An educational intervention that supplements clinical practice results in improved knowledge in first-time hearing aid users. PMID- 26649542 TI - Can a Remotely Delivered Auditory Training Program Improve Speech-in-Noise Understanding? AB - PURPOSE: The aims of this study were to determine if a remotely delivered, Internet-based auditory training (AT) program improved speech-in-noise understanding and if the number of hours spent engaged in the program influenced postintervention speech-in-noise understanding. METHOD: Twenty-nine first-time hearing aid users were randomized into an AT group (hearing aids + 3 week remotely delivered, Internet-based auditory training program) or a control group (hearing aids alone). The Hearing in Noise Test (Nilsson, Soli, & Sullivan, 1994) and the Words-in-Noise test (Wilson, 2003) were administered to both groups at baseline + 1 week and immediately at the completion of the 3 weeks of auditory training. RESULTS: Speech-in-noise understanding improved for both groups at the completion of the study; however, there was not a statistically significant difference in postintervention improvement between the AT and control groups. Although the number of hours the participants engaged in the AT program was far fewer than prescribed, time on task influenced the postintervention Words-in Noise but not Hearing in Noise Test scores. CONCLUSION: Although remotely delivered, Internet-based AT programs represent an attractive alternative to resource-intensive, clinic-based interventions, their demonstrated efficacy continues to remain a challenge due in part to issues associated with compliance. PMID- 26649543 TI - Computer and Internet Interventions to Optimize Listening and Learning for People With Hearing Loss: Accessibility, Use, and Adherence. AB - PURPOSE: The aim of this research forum article was to examine accessibility, use, and adherence to computerized and online interventions for people with hearing loss. METHOD: Four intervention studies of people with hearing loss were examined: 2 auditory training studies, 1 working memory training study, and 1 study of multimedia educational support. RESULTS: A small proportion (approximately 15%) of participants had never used a computer, which may be a barrier to the accessibility of computer and Internet-based interventions. Computer competence was not a factor in intervention use or adherence. Computer skills and Internet access influenced participant preference for the delivery method of the multimedia educational support program. CONCLUSIONS: It is important to be aware of current barriers to computer and Internet-delivered interventions for people with hearing loss. However, there is a clear need to develop and future-proof hearing-related applications for online delivery. PMID- 26649544 TI - Introduction to the Special Session on Intervention and Outcomes of Children With Hearing Loss. AB - PURPOSE: This research forum article introduces the special session on "Intervention and Outcomes of Children with Hearing Loss" presented at the HEaring Across the Lifespan (HEAL) Conference in 2014. METHOD: The method involved a narrative summary of the key findings of two papers presented during the session. RESULTS: Early intervention was effective in improving outcomes of children with significant bilateral hearing loss. Preliminary findings on children with mild or unilateral hearing loss showed communicative development on par with their normal-hearing peers. CONCLUSION: Children with bilateral hearing loss benefited from early detection and intervention. PMID- 26649545 TI - Is Early Intervention Effective in Improving Spoken Language Outcomes of Children With Congenital Hearing Loss? AB - PURPOSE: The purpose of this research forum article was to present research findings on the effectiveness of early intervention for improving outcomes of children with congenital hearing loss. METHOD: The method involved a narrative overview of recent findings from the Longitudinal Outcomes of Children with Hearing Impairment study. RESULTS: Early intervention, either in the form of Results: Early intervention, either in the form of amplification or cochlear implantation, was associated with higher language scores. Maternal education and communication mode used during early intervention were also significant contributors to child outcomes. Early performance predicted later language development. CONCLUSION: Early intervention is effective in improving early language outcomes, at a population level. PMID- 26649546 TI - Communication Development in Early-Identified Children With Mild Bilateral and Unilateral Hearing Loss. AB - PURPOSE: This clinical focus article provides preliminary findings from a multicenter longitudinal study investigating auditory and communication development in children with mild bilateral or unilateral hearing loss of any degree. METHOD: A total of 100 children (55 with mild bilateral or unilateral hearing loss and 45 with normal hearing) underwent 1 or more assessments from a battery of auditory and language measures. RESULTS: Children up to age 4 years demonstrated auditory and language skills similar to those of children with normal hearing. CONCLUSIONS: Factors that affect outcomes in communication development will be explored as additional data are collected in this ongoing study. PMID- 26649547 TI - Effect of Amplification on Speech and Language in Children With Aural Atresia. AB - PURPOSE: There currently is no guideline regarding amplification or verification for children with aural atresia. This population, with the absence of the ear canal, has obvious congenital hearing loss. Research suggests that delayed treatment for hearing loss can result in speech and language impairments, including poor performance in school. In this study we examined the relationship between amplification and emerging speech and language development in children with aural atresia. METHOD: Subjects included children, 3 to 6 years of age, with conductive hearing loss due to atresia. Clinical evaluations were used to determine relationships between amplification and speech and language development. Subjects underwent an audiology exam, including pure-tone or warble tone air and bone conduction using play audiometry techniques, and a speech and language evaluation assessing language and vocabulary skills. RESULTS: Subjects who were fitted before 1 year of age showed better compliance with aid use and exhibited fewer delays in speech and language development. Children with right sided atresia had significantly greater speech and language delays when compared with age norms from standardized tests. CONCLUSION: Our findings highlight a relationship between side of atresia, time of first amplification, compliance in aid use, and speech and language abilities. PMID- 26649548 TI - Evaluation of Performance With an Adaptive Digital Remote Microphone System and a Digital Remote Microphone Audio-Streaming Accessory System. AB - PURPOSE: One purpose of this study was to evaluate the improvement in speech recognition obtained with use of 2 different remote microphone technologies. Another purpose of this study was to determine whether a battery of audiometric measures could predict benefit from use of these technologies. METHOD: Sentence recognition was evaluated while 17 adults used each of 2 different hearing aids. Performance was evaluated with and without 2 different remote microphone systems. A variety of audiologic measures were administered to determine whether prefitting assessment may predict benefit from remote microphone technology. RESULTS: Use of both remote microphone systems resulted in improvement in speech recognition in quiet and in noise. There were no differences in performance obtained with the 2 different remote microphone technologies in quiet and at low competing noise levels, but use of the digital adaptive remote microphone system provided better speech recognition in the presence of moderate- to high-level noise. The Listening in Spatialized Noise-Sentence Test Prescribed Gain Amplifier (Cameron & Dillon, 2010) measure served as a good predictor of benefit from remote microphone technology. CONCLUSIONS: Each remote microphone system improved sentence recognition in noise, but greater improvement was obtained with the digital adaptive system. The Listening in Spatialized Noise-Sentence Test Prescribed Gain Amplifier may serve as a good indicator of benefit from remote microphone technology. PMID- 26649549 TI - Adrenergic blockers and the risk for common solid cancers: a case-control study. AB - Laboratory studies have suggested that adrenergic blockers may inhibit the proliferation and migration of cancer cells, but epidemiological evidence of their effect on cancer incidence has proven inconsistent. We therefore conducted a case-control study using the Clinical Practice Research Datalink to assess the effect of adrenergic blockers on the incidence of prostate, lung, bowel and breast cancers. From among patients aged 18 years or older who contributed at least 2 years of prospectively gathered data between 1 January 1987 and 31 December 2012, we selected incident cases of relevant cancers and controls, frequency matched 10 : 1 by age. Logistic regression was used to adjust effect estimates for age, sex, smoking, alcohol use, and a number of potentially confounding comorbidities and coprescriptions. A total of 18 968 colorectal, 19 082 lung, 21 608 prostate and 29 109 breast cancers were identified. We found no evidence of a protective effect of adrenergic blockade in lung and prostate cancers and found a slightly increased risk for colorectal and breast cancers in users. This was largely explained by the effects of confounding in multivariate analyses, with final odds ratio estimates for lung, colorectal, breast and prostate cancers of 0.99 [95% confidence interval (0.96-1.04)], 1.14 (1.09-1.18), 1.10 (1.06-1.14), and 1.01 (0.98-1.05), respectively, for beta-blocker exposure, and final odds ratio estimates for lung, colorectal and breast cancer of 1.03 (0.97-1.09), 1.13 (1.07-1.20), and 1.08 (1.00-1.17), respectively, for alpha blocker exposure. We found no evidence to suggest that adrenergic blocker use prevents common cancers. Indeed, we found a slightly increased risk for colorectal and breast cancers, which may reflect residual confounding. PMID- 26649550 TI - Do the pre-service education programmes for midwives in India prepare confident 'registered midwives'? A survey from India. AB - Objective The graduates of the diploma and degree programmes of nursing and midwifery in India are considered skilled birth attendants (SBAs). This paper aimed to assess the confidence of final-year students from pre-service education programmes (diploma and bachelor's) in selected midwifery skills from the list of midwifery competencies of the International Confederation of Midwives (ICM). Design A cross-sectional survey was conducted in Gujarat, India, involving 633 final-year students from 25 educational institutions (private or government), randomly selected, stratified by the type of programme (diploma and bachelor's). Students assessed their confidence on a four-point scale, in four midwifery competency domains - antepartum, intrapartum, postpartum, and newborn care. Explorative factor analysis was used to reduce skill statements into separate subscales for each domain. Results Overall, 25-40% of students scored above the 75th percentile and 38-50% below the 50th percentile of confidence in all subscales for antepartum, intrapartum, postpartum, and newborn care. The majority had not attended the required number of births prescribed by the Indian Nursing Council. Conclusions The pre-service education offered in the diploma and bachelor's programmes in Gujarat does not prepare confident SBAs, as measured on selected midwifery competencies of the ICM. One of the underlying reasons was less clinical experience during their education. The duration, content, and pedagogy of midwifery education within the integrated programmes need to be reviewed. PMID- 26649551 TI - 2014 Guideline for Management of Wounds in Patients With Lower-Extremity Arterial Disease (LEAD): An Executive Summary. AB - The purpose of this article is to provide a summary of the recommendations from the 2014 Guideline for Management of Wounds in Patients With Lower-Extremity Arterial Disease (LEAD), published by the Wound, Ostomy and Continence Nurses Society (WOCN). This article provides an overview of the process used to update and develop the guideline, and specific recommendations from the guideline for assessment, referral for further evaluation, interventions (ie, debridement, dressings, infection, antibiotics, nutrition, pain management, compression issues, medications, surgical options, and adjunctive therapies), and patient education and risk-reduction strategies. The LEAD guideline is a resource for physicians, nurses, therapists, and other healthcare professionals who work with adults who have/or are at risk for wounds due to LEAD. The full text of the published guideline, which includes the available evidence supporting the recommendations and a complete reference list, is available from the WOCN Society, 1120 Rt. 73, Suite 200, Mount Laurel, NJ, 08054; Web site: www.wocn.org. Refer to the Supplemental Digital Content (Supplement Digital Content 1, http://links.lww.com/JWOCN/A31) associated with this article for the complete reference list for the guideline. The guideline has been accepted for publication by the National Guideline Clearinghouse (www.guideline.gov/). PMID- 26649552 TI - Is Twice-Daily Skin Moisturizing More Effective Than Routine Care in the Prevention of Skin Tears in the Elderly Population? AB - BACKGROUND: Skin-moisturizing routines are part of a bundle of interventions designed to prevent skin tears. OBJECTIVE: This Evidence-Based Report Card reviews the effect of twice-daily moisturization of the skin on skin tear occurrence versus occurrence rates using routine skin care. SEARCH STRATEGY: The literature was systematically reviewed for studies that evaluated the use of standardized skin moisturizers on the rate of skin tears in the older adults (>60 years of age). A professional librarian performed the literature search, which yielded 446 articles. Following title and abstract reviews, we identified and retrieved 3 studies that met inclusion criteria. FINDINGS: Evidence concerning the effectiveness of routine twice-daily skin moisturizing reducing the rate of skin tears is mixed. Routine twice-daily skin moisturizing did not significantly result in a lower incidence of skin tears in long-term care residents compared to usual care in one study. However, the occurrence of skin tears per 1000 occupied beds was 50% lower when a moisturizer applied twice daily was compared to usual care. CONCLUSION: Routine skin moisturizing is recommended as one component of a prevention program for skin tears among aged adults residing in long-term care facilities. PMID- 26649553 TI - Female reproductive activity and its endocrine correlates in the African lesser bushbaby, Galago moholi. AB - Steroid hormones play an important role in female reproductive physiology and behaviour and are often used to monitor important female reproductive events. However, such studies are often attempted on captive populations alone, delivering limited data. One such example is the African lesser bushbaby, Galago moholi, for which contradicting observational data exist between captive and free ranging populations, while hormonal analyses have only been obtained from a single captive population. To extend and rectify the limited information, we monitored faecal progestagen and oestrogen metabolite levels across various important life history stages of both captive and free-ranging G. moholi. We additionally recorded changes in vaginal state as well as the occurrence of reproductive and aggressive behaviour throughout the study. Data from our captive population revealed an ovarian cycle length of 33.44 +/- 0.59 days (mean +/- SD), with follicular and luteal phases of 14.2 +/- 1.0 and 19.1 +/- 1.5 days, respectively, and an average pregnancy length of 128 +/- 3.3 days. The initiation of female reproductive activity was closely linked to an oestrus-related increase in faecal oestrogen metabolite levels. Four of the seven captive females monitored in our study conceived during the May mating period, with one additional female fertilised in September, supporting the idea that the September mating period functions as a back-up for female G. moholi. Identified benchmark faecal progestagen metabolite levels (non-pregnant: >1 ug/g dry weight (DW), pregnant: >9 ug/g DW) should help researchers to determine pregnancy status of randomly wild-caught females in even a cross-sectional study setup. PMID- 26649554 TI - A rare cause of recalcitrant coccydynia: benign dermoid cyst masquerading as coccygeal pain. AB - PURPOSE: Coccydynia is a common entity in orthopedic practice, and various etiologies have been described for it. However, benign dermoid cyst causing coccydynia has not yet been reported. METHODS: A 20-year-old male presented with typical symptoms of coccydynia recalcitrant to conservative treatment for 2 years. Since pain interfered with his daily activities, magnetic resonance imaging was performed which showed a circumscribed precoccygeal cystic lesion. RESULTS: The patient underwent coccygectomy along with cyst excision. Histological examination revealed features of benign dermoid cyst. After surgery, the patient had excellent relief of his symptoms. CONCLUSION: The case report identifies that the treating surgeon should be aware of benign dermoid cyst as one of the treatable but rare causes of intractable coccydynia, and MRI should be performed in patients with persistent coccygeal pain. PMID- 26649555 TI - An RCT study comparing the clinical and radiological outcomes with the use of PLIF or TLIF after instrumented reduction in adult isthmic spondylolisthesis. AB - OBJECTIVE: We prospectively compared posterior lumbar interbody fusion (PLIF) and transforaminal lumbar interbody fusion (TLIF) used in adult isthmic spondylolisthesis (IS) after surgical reduction with pedicle screws. METHODS: Between January 2009 and December 2010, 66 adult patients with single-level IS were randomly assigned to two groups treated using the PLIF technique (PLIF group, n = 34) and the TLIF technique (TLIF group, n = 32). Both groups were followed up for an average of 30.5 months (range 24-48 months). Clinical outcomes were assessed using the visual analog scale (VAS), Oswestry disability index (ODI) and Japanese orthopedic association (JOA) scores. Radiographic outcomes included percentage of vertebral slippage, focal lordosis and disk height. Clinical and radiographic outcomes were compared between the two groups. RESULTS: The average operative time and blood loss during surgery were significantly more in PLIF group than in TLIF group. Spondylolisthesis, disk height and focal lordosis were significantly improved postoperatively in both groups. There was no obvious difference in clinical outcomes, as assessed using the VAS, ODI and JOA scores, and radiographic outcomes. In PLIF group, there were two cases of neuropathic pain after surgery. CONCLUSIONS: After instrumented reduction of adult IS, either PLIF or TLIF can provide good clinical and radiological outcomes. With a single cage, TLIF was superior to PLIF in terms of surgical time and blood loss, but these differences may not be clinically relevant. PMID- 26649556 TI - Comparison of structural changes in skin and amnion tissue grafts for transplantation induced by gamma and electron beam irradiation for sterilization. AB - Sterilization is an important step in the preparation of biological material for transplantation. The aim of the study is to compare morphological changes in three types of biological tissues induced by different doses of gamma and electron beam radiation. Frozen biological tissues (porcine skin xenografts, human skin allografts and human amnion) were irradiated with different doses of gamma rays (12.5, 25, 35, 50 kGy) and electron beam (15, 25, 50 kGy). Not irradiated specimens served as controls. The tissue samples were then thawn and fixed in 10 % formalin, processed by routine paraffin technique and stained with hematoxylin and eosin, alcian blue at pH 2.5, orcein, periodic acid Schiff reaction, phosphotungstic acid hematoxylin, Sirius red and silver impregnation. The staining with hematoxylin and eosin showed vacuolar cytoplasmic changes of epidermal cells mainly in the samples of xenografts irradiated by the lowest doses of gamma and electron beam radiation. The staining with orcein revealed damage of fine elastic fibers in the xenograft dermis at the dose of 25 kGy of both radiation types. Disintegration of epithelial basement membrane, especially in the xenografts, was induced by the dose of 15 kGy of electron beam radiation. The silver impregnation disclosed nuclear chromatin condensation mainly in human amnion at the lowest doses of both radiation types and disintegration of the fine collagen fibers in the papillary dermis induced by the lowest dose of electron beam and by the higher doses of gamma radiation. Irradiation by both, gamma rays and the electron beam, causes similar changes on cells and extracellular matrix, with significant damage of the basement membrane and of the fine and elastic and collagen fibers in the papillary dermis, the last caused already by low dose electron beam radiation. PMID- 26649557 TI - Depression in children and adolescents: complementary therapies. AB - INTRODUCTION: Depression is the world's leading cause of disability-adjusted life years lost among adolescents. Depression may affect 2% to 8% of children and adolescents, with a peak incidence around puberty. It may be self-limiting, but about 40% of affected children experience a recurrent attack, one third of affected children will make a suicide attempt, and 3% to 4% will die from suicide. METHODS AND OUTCOMES: We conducted a systematic overview, aiming to answer the following clinical question: What are the effects of complementary treatments for depression in children and adolescents? We searched: Medline, Embase, The Cochrane Library, and other important databases up to August 2014 (Clinical Evidence overviews are updated periodically; please check our website for the most up-to-date version of this overview). RESULTS: At this update, searching of electronic databases retrieved 141 studies. After deduplication and removal of conference abstracts, 103 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 60 studies and the further review of 43 full publications. Of the 43 full articles evaluated, two systematic reviews were added at this update. CONCLUSIONS: In this systematic overview, we categorised the efficacy for six interventions based on information about the effectiveness and safety of glutamine, light therapy, omega 3 polyunsaturated fatty acids, s-adenosylmethionine, St John's wort (Hypericum perforatum), and vitamin C. PMID- 26649558 TI - What Are the Long-term Results of MUTARS(r) Modular Endoprostheses for Reconstruction of Tumor Resection of the Distal Femur and Proximal Tibia? AB - BACKGROUND: Modular endoprostheses are commonly used to reconstruct defects of the distal femur and proximal tibia after bone tumor resection. Because limb salvage surgery for bone sarcomas is relatively new, becoming more frequently used since the 1980s, studies focusing on the long-term results of such prostheses in treatment of primary tumors are scarce. QUESTIONS/PURPOSES: (1) What proportion of patients experience a mechanical complication with the MUTARS(r) modular endoprosthesis when used for tumor reconstruction around the knee, and what factors may be associated with mechanical failure? (2) What are the nonmechanical complications? (3) What are the implant failure rates at 5, 10, and 15 years? (4) How often is limb salvage achieved using this prosthesis? METHODS: Between 1995 and 2010, endoprostheses were the preferred method of reconstruction after resection of the knee in adolescents and adults in our centers. During that period, we performed 114 MUTARS(r) knee replacements in 105 patients; no other endoprosthetic systems were used. Four patients (four of 105 [4%]) were lost to followup, leaving 110 reconstructions in 101 patients for review. The reverse Kaplan-Meier method was used to calculate median followup, which was equal to 8.9 years (95% confidence interval [CI], 8.0-9.7). Mean age at surgery was 36 years (range, 13-82 years). Predominant diagnoses were osteosarcoma (n = 56 [55%]), leiomyosarcoma of bone (n = 10 [10%]), and chondrosarcoma (n = 9 [9%]). In the early period of our study, we routinely used uncemented uncoated implants for primary reconstructions. Later, hydroxyapatite (HA)-coated implants were the standard. Eighty-nine reconstructions (89 of 110 [81%]) were distal femoral replacements (78 uncemented [78 of 89 {88%}, 42 of which were HA-coated [42 of 78 {54%}]) and 21 (21 of 110 [19%]) were proximal tibial replacements. In 26 reconstructions (26 of 110 [24%]), the reconstruction was performed for a failed previous reconstruction. We used a competing risk model to estimate the cumulative incidence of implant failure. RESULTS: Complications of soft tissue or instability occurred in seven reconstructions (seven of 110 [6%]). With the numbers we had, for uncemented distal femoral replacements, we could not detect a difference in loosening between revision (five of 17 [29%]) and primary reconstructions (eight of 61 [13%]) (hazard ratio [HR], 1.72; 95% CI, 0.55-5.38; p = 0.354). Hydroxyapatite-coated uncemented implants had a lower risk of loosening (two of 42 [5%]) than uncoated uncemented implants (11 of 36 [31%]) (HR, 0.23; 95% CI, 0.05-1.06; p = 0.060). Structural complications occurred in 15 reconstructions (15 of 110 [14%]). Infections occurred in 14 reconstructions (14 of 110 [13%]). Ten patients had a local recurrence (10 of 101 [10%]). With failure for mechanical reasons as the endpoint, the cumulative incidences of implant failure at 5, 10, and 15 years were 16.9% (95% CI, 9.6-24.2), 20.7% (95% CI, 12.5-28.8%), and 37.9% (95% CI, 16.1-59.7), respectively. We were able to salvage some of the failures so that at followup, 90 patients (90 of 101 [89%]) had a MUTARS(r) in situ. CONCLUSIONS: Although no system has yet proved ideal to restore normal function and demonstrate long-term retention of the implant, MUTARS(r) modular endoprostheses represent a reliable long-term option for knee replacement after tumor resection, which seems to be comparable to other modular implants available to surgeons. Although the number of patients is relatively small, we could demonstrate that with this prosthesis, an uncemented HA-coated implant is useful in achieving durable fixation. LEVEL OF EVIDENCE: Level IV, therapeutic study. PMID- 26649559 TI - Classification and Functional Analyses of Putative Conserved Proteins from Chlamydophila pneumoniae CWL029. AB - Chlamydophila pneumoniae, a Gram-negative bacterium belongs to the family Chlamydiaceae, is known to cause community-acquired pneumonia and bronchitis. There is a need for genomic analyses of C. pneumoniae as its chronic infections result in reactive airway disease, lung cancer and asthma. Recent advancement in the sequencing techniques led to the generation of large genomic data. In order to utilize these data, sequence-based function predictions were used for annotating the uncharacterized genes. The genome of C. pneumoniae encodes 1052 proteins, which include a group of 366 functionally uncharacterized proteins, known as "hypothetical proteins" (HPs). Functions of these HPs were predicted by utilizing an integrated approach that combines varieties of bioinformatics tools. The functions of 142 proteins were successfully predicted and categorized into different classes of enzymes, transport proteins, binding proteins and virulence factors. Among these functionally annotated HPs, we were able to identify 12 virulent HPs. Furthermore, the HP with the highest virulence score was subjected to molecular dynamics (MD) simulations to better understand their dynamical behavior in explicit water conditions. These analyses could be utilized for an in depth understanding of virulence mechanism. The functional knowledge of these proteins could be useful in drug design and discovery process of infections caused by C. pneumoniae. PMID- 26649560 TI - Towards understanding peroxisomal phosphoregulation in Arabidopsis thaliana. AB - MAIN CONCLUSION: This work identifies new protein phosphatases and phosphatase related proteins targeting peroxisomes, and raises the question of a novel protein import pathway from ER to peroxisomes involving peroxisomal targeting signal type 1 (PTS1) Plant peroxisomes are essential for several processes, for example lipid metabolism, free radical detoxification, development, and stress related functions. Although research on peroxisomes has been intensified, reversible phosphorylation as a control mechanism in peroxisomes is barely studied. Therefore, it is crucial to identify all peroxisomal proteins involved in phosphoregulation. We here started with protein phosphatases, and searched the Arabidopsis thaliana genome for phosphatase-related proteins with putative peroxisomal targeting signals (PTS). Five potential peroxisomal candidates were detected, from which four were confirmed to target peroxisomes or have a functional PTS. The highly conserved Ser-Ser-Met> was validated for two protein phosphatase 2C (PP2C) family members (POL like phosphatases, PLL2 and PLL3) as a functional peroxisomal targeting signal type 1 (PTS1). Full-length PLL2 and PLL3 fused with a reporter protein targeted peroxisomes in two plant expression systems. A putative protein phosphatase, purple acid phosphatase 7 (PAP7), was found to be dually targeted to ER and peroxisomes and experiments indicated a possible trafficking to peroxisomes via the ER depending on peroxisomal PTS1. In addition, a protein phosphatase 2A regulator (TIP41) was validated to harbor a functional PTS1 (Ser-Lys-Val>), but the full-length protein targeted cytosol and nucleus. Reverse genetics indicated a role for TIP41 in senescence signaling. Mass spectrometry of whole seedlings and isolated peroxisomes was employed, and identified new putative phosphorylated peroxisomal proteins. Previously, only one protein phosphatase, belonging to the phospho-protein phosphatase (PPP) family, was identified as a peroxisomal protein. The present work implies that members of two other main protein phosphatase families, i.e. PP2C and PAP, are also targeting peroxisomes. PMID- 26649561 TI - Population pharmacokinetics of mizoribine in pediatric patients with kidney disease. AB - BACKGROUND: The present study aimed to obtain information enabling optimisation of the clinical effect of mizoribine (MZR) in pediatric patients with kidney disease. METHODS: A total of 105 pediatric patients with kidney disease treated at our institutions were enrolled. Kidney transplant patients were excluded. Population pharmacokinetic analysis of MZR was performed based on serum concentration data. Area under the curve from time zero to infinity (AUCinfinity) and maximal concentration (C max) were calculated by Bayesian analysis. RESULTS: In children, the appearance of MZR in the blood tended to be slower and the subsequent rise in blood concentration tended to be more sluggish, compared to healthy adults. Apparent volume of distribution and oral clearance were also higher in children compared to adults. A significant positive correlation was observed between patient age and AUCinfinity. There were significant differences of AUCinfinity and C max by age group. No relationship was observed between the administration method of MZR and serum concentration. CONCLUSION: The pharmacokinetics of MZR was different in children compared to adults. To obtain the expected clinical efficacy, the regular MZR dosage schedule (2-3 mg/kg/day) might be insufficient for pediatric patients. In particular, younger patients might require a higher dosage of MZR per unit body weight. PMID- 26649562 TI - Estimation of the 24-h urinary protein excretion based on the estimated urinary creatinine output. AB - BACKGROUND: The urinary protein/creatinine ratio [Up/Ucr (g/gCr)] has been used in the clinical management of patients with chronic kidney disease (CKD). However, a discrepancy is often noted between the Up/Ucr and 24-h urinary protein excretion [24hUp (g/day)] in patients with extremes of muscle mass. We examined devised a method for precise estimation of the 24-h urinary protein excretion (E 24hUp) based on estimation of 24-h urinary creatinine output (E-24hCr). METHODS: Three parameters, spot Up/Ucr, 24hUP and E-24hUp (=Up/Ucr * E-24hCr), were determined in 116 adult patients with CKD. The correlations among the groups were analyzed. RESULTS: There was a significant correlation between the Up/Ucr and 24hUp (p < 0.001). We divided the patients into three groups according to the 24hUp; the low urinary protein group (<1.0 g/day), the intermediate urinary protein group (1.0-3.5 g/day), and the high urinary protein group (>3.5 g/day). There was a significant correlation between the Up/Ucr and 24hUp in the low (p = 0.04) and high urinary protein (p = 0.01) groups, whereas the correlation coefficient was lower in the intermediate urinary protein (p = 0.07) group. Thus, we found a significant correlation between 24hUp and E-24hUp in the study population overall (p < 0.001), in the low (p = 0.01), in the intermediate (p < 0.001), and in the high urinary protein group (p < 0.001). CONCLUSION: We conclude that a poor correlation exists between the Up/Ucr and 24hUp in patients with intermediate urinary protein excretion levels. The recommended parameter for monitoring proteinuria in such patients may be the E-24hUp, which is calculated using the E-24hCr. PMID- 26649563 TI - KIR-HLA profiling shows presence of higher frequencies of strong inhibitory KIR ligands among prognostically poor risk AML patients. AB - The expression and interaction between killer cell immunoglobulin-like receptors (KIRs) and HLA are known to be associated with pathogenesis of diseases, including hematological malignancies. Presence of B haplotype KIR in donors is associated with a lower relapse risk for acute myeloid leukemia (AML) after hematopoietic stem cell transplants (HSCT). However, the association of KIR and HLA repertoire with disease development and other clinical features is not well studied for AML. In this study, 206 Chinese patients with AML were analyzed for their FAB subtypes, risk groups, and chemo-responsiveness to assess possible association with their KIR and HLA profile. The results revealed that a B-content score of 2 was significantly more prevalent in AML patients when compared to normal controls. Notably, there is also a differential frequency in the distribution of B haplotype KIR across distinct FAB subtypes, where the M3 subtype had significantly lower frequencies of B haplotype KIR compared to the M5 subtype (p < 0.05). In addition, the stronger inhibitory KIR ligands HLA-C2 and HLA-Bw4-80I were present in significantly higher frequencies in the prognostically "poor" risk group compared to those with "favourable" risk (p < 0.01). Taken together, these associations with clinical features of AML suggest a role of the KIR-HLA repertoire in the development and biological behavior of AML. PMID- 26649564 TI - A Scoping Review of Healthcare Costs for Patients with Cystic Fibrosis. AB - BACKGROUND: Cystic fibrosis (CF), one of the most common life-shortening genetic diseases, has no cure, but people living with it have seen improvements in their health and survival. The rising life expectancy and increased availability of treatment options has likely increased the lifetime costs of people living with CF. In addition, a recent drug approval for a therapy that targets the cause of the disease is one of the most expensive drugs worldwide. In light of these circumstances, it is important to have an updated understanding of the costs of CF therapy and management. This study aims to determine the extent of available literature that quantifies CF costs. METHODS: We used a scoping review framework to identify the sources and types of evidence available to determine the costs of CF therapy and management compared to the general population or a comparable population of people with other complex chronic conditions. We searched 14 databases for peer-reviewed studies and grey literature published in English since 1998. The search was conducted in August 2013 and updated in October 2014. RESULTS: We identified 28 studies that estimated overall, general CF costs. Of these, three studies compare CF costs to healthcare costs of a general population and only one of those provides a direct comparison of CF costs to the general population in order to calculate the incremental cost associated with CF. We estimate there are 98 systematic reviews that quantify the costs of comparable conditions and potentially provide a comparison group for people with CF. CONCLUSIONS: There is evidence available that attempts to quantify overall, general healthcare costs of people with CF, although much of it is outdated. However, there is much less evidence available that provides a comparison of these costs with either the general population or people with comparable conditions. PMID- 26649565 TI - Spiritual Religious Coping is Associated with Quality of Life in Institutionalized Older Adults. AB - The purpose of this study was to investigate the relationship between spiritual/religious coping (SRCOPE) strategies and quality of life (QoL) in institutionalized older adults. This is a cross-sectional, correlational study, with a sample of 77 older adults in Brazil. The present study found long-term care patients use religious and spiritual coping strategies to deal with their chronic health conditions. Positive SRCOPE and Total SRCOPE have positive correlations with most QoL domains from the WHOQOL-OLD and WHOQOL-BREF. On the other hand, Negative SRCOPE strategies correlated negatively with the facets of "death and dying" from the WHOQOL-OLD. These results suggest the need for an integrative approach for long-term care patients, considering the positive and negative aspects of coping. PMID- 26649566 TI - Phase-Transfer Catalysis via a Proton Sponge: A Bifunctional Role for Biscyclopropenimine. AB - The use of a bis(diisopropylamino)cyclopropenimine-substituted bis-protonated proton sponge as a bifunctional phase-transfer catalyst is reported. Experimental studies and DFT calculations suggest it operates simultaneously as a hydrogen bond donor and a phase-transfer catalyst, facilitating the movement of charged intermediates from the interface to the organic phase via favorable partitioning of hydrophilic/hydrophobic surface areas, resulting in high catalytic activity. PMID- 26649567 TI - Electrophysiology on Isolated Brainstem-spinal Cord Preparations from Newborn Rodents Allows Neural Respiratory Network Output Recording. AB - While it is well known that the central respiratory drive is located in the brainstem, several aspects of its basic function, development, and response to stimuli remain to be fully understood. To overcome the difficulty of accessing the brainstem in the whole animal, isolation of the brainstem and part of the spinal cord is performed. This preparation is maintained in artificial cerebro spinal fluid where gases, concentrations, and temperature are controlled and monitored. The output signal from the respiratory network is recorded by a suction electrode placed on the fourth ventral root. In this manner, stimuli can be directly applied onto the brainstem, and the effect can be recorded directly. The signal recorded is linked to the inspiratory signal sent to the diaphragm via the phrenic nerve, and can be described as bursts (around 8 bursts per minute). Analysis of these bursts (frequency, amplitude, length, and area under the curve) allows precise characterization of the stimulus effect on the respiratory network. The main limitation of this method is the viability of the preparation beyond the early post-natal stages. Thus, this method greatly focuses on the study of the whole network without the peripheral inputs in the newborn rat. PMID- 26649568 TI - Comparing Observed with Predicted Weekly Influenza-Like Illness Rates during the Winter Holiday Break, United States, 2004-2013. AB - In the United States, influenza season typically begins in October or November, peaks in February, and tapers off in April. During the winter holiday break, from the end of December to the beginning of January, changes in social mixing patterns, healthcare-seeking behaviors, and surveillance reporting could affect influenza-like illness (ILI) rates. We compared predicted with observed weekly ILI to examine trends around the winter break period. We examined weekly rates of ILI by region in the United States from influenza season 2003-2004 to 2012-2013. We compared observed and predicted ILI rates from week 44 to week 8 of each influenza season using the auto-regressive integrated moving average (ARIMA) method. Of 1,530 region, week, and year combinations, 64 observed ILI rates were significantly higher than predicted by the model. Of these, 21 occurred during the typical winter holiday break period (weeks 51-52); 12 occurred during influenza season 2012-2013. There were 46 observed ILI rates that were significantly lower than predicted. Of these, 16 occurred after the typical holiday break during week 1, eight of which occurred during season 2012-2013. Of 90 (10 HHS regions x 9 seasons) predictions during the peak week, 78 predicted ILI rates were lower than observed. Out of 73 predictions for the post-peak week, 62 ILI rates were higher than observed. There were 53 out of 73 models that had lower peak and higher post-peak predicted ILI rates than were actually observed. While most regions had ILI rates higher than predicted during winter holiday break and lower than predicted after the break during the 2012-2013 season, overall there was not a consistent relationship between observed and predicted ILI around the winter holiday break during the other influenza seasons. PMID- 26649569 TI - The Increase in Animal Mortality Risk following Exposure to Sparsely Ionizing Radiation Is Not Linear Quadratic with Dose. AB - INTRODUCTION: The US government regulates allowable radiation exposures relying, in large part, on the seventh report from the committee to estimate the Biological Effect of Ionizing Radiation (BEIR VII), which estimated that most contemporary exposures- protracted or low-dose, carry 1.5 fold less risk of carcinogenesis and mortality per Gy than acute exposures of atomic bomb survivors. This correction is known as the dose and dose rate effectiveness factor for the life span study of atomic bomb survivors (DDREFLSS). It was calculated by applying a linear-quadratic dose response model to data from Japanese atomic bomb survivors and a limited number of animal studies. METHODS AND RESULTS: We argue that the linear-quadratic model does not provide appropriate support to estimate the risk of contemporary exposures. In this work, we re-estimated DDREFLSS using 15 animal studies that were not included in BEIR VII's original analysis. Acute exposure data led to a DDREFLSS estimate from 0.9 to 3.0. By contrast, data that included both acute and protracted exposures led to a DDREFLSS estimate from 4.8 to infinity. These two estimates are significantly different, violating the assumptions of the linear-quadratic model, which predicts that DDREFLSS values calculated in either way should be the same. CONCLUSIONS: Therefore, we propose that future estimates of the risk of protracted exposures should be based on direct comparisons of data from acute and protracted exposures, rather than from extrapolations from a linear-quadratic model. The risk of low dose exposures may be extrapolated from these protracted estimates, though we encourage ongoing debate as to whether this is the most valid approach. We also encourage efforts to enlarge the datasets used to estimate the risk of protracted exposures by including both human and animal data, carcinogenesis outcomes, a wider range of exposures, and by making more radiobiology data publicly accessible. We believe that these steps will contribute to better estimates of the risks of contemporary radiation exposures. PMID- 26649570 TI - Celiac Disease Histopathology Recapitulates Hedgehog Downregulation, Consistent with Wound Healing Processes Activation. AB - BACKGROUND: In celiac disease (CD), intestinal epithelium damage occurs secondary to an immune insult and is characterized by blunting of the villi and crypt hyperplasia. Similarities between Hedgehog (Hh)/BMP4 downregulation, as reported in a mouse model, and CD histopathology, suggest mechanistic involvement of Hh/BMP4/WNT pathways in proliferation and differentiation of immature epithelial cells in the context of human intestinal homeostasis and regeneration after damage. Herein we examined the nature of intestinal crypt hyperplasia and involvement of Hh/BMP4 in CD histopathology. METHODS AND FINDINGS: Immunohistochemistry, qPCR and in situ hybridization were used to study a cohort of 24 healthy controls (HC) and 24 patients with diagnosed acute celiac disease (A-CD) intestinal biopsies. In A-CD we observed an increase in cells positive for Leucin-rich repeat-containing G protein-coupled receptor 5 (LGR5), an epithelial stem cell specific marker and expansion of WNT responding compartment. Further, we observed alteration in number and distribution of mesenchymal cells, predicted to be part of the intestinal stem cells niche. At the molecular level we found downregulation of indian hedgehog (IHH) and other components of the Hh pathway, but we did not observe a concurrent downregulation of BMP4. However, we observed upregulation of BMPs antagonists, gremlin 1 and gremlin 2. CONCLUSIONS: Our data suggest that acute CD histopathology partially recapitulates the phenotype reported in Hh knockdown models. Specifically, Hh/BMP4 paradigm appears to be decoupled in CD, as the expansion of the immature cell population does not occur consequent to downregulation of BMP4. Instead, we provide evidence that upregulation of BMP antagonists play a key role in intestinal crypt hyperplasia. This study sheds light on the molecular mechanisms underlying CD histopathology and the limitations in the use of mouse models for celiac disease. PMID- 26649571 TI - Cardiac Usage of Reducible Poly(oligo-D-arginine) As a Gene Carrier for Vascular Endothelial Growth Factor Expression. AB - Developments of non-viral carriers have headed toward reducing cytotoxicity, which results from the use of conventional gene carriers, and enhancing gene delivery efficiency. Cys-(d-R9)-Cys repeated reducible poly(oligo-D-arginine) (rPOA) is one of the most efficient non-viral carriers for gene therapy; however, while its efficiency has been verified in the lung and brain, it is necessary to confirm its activity in each organ or tissue since there are differences of gene carrier susceptibility to among tissue types. We therefore tested the compatibility of rPOA in cardiac tissue by in vitro or in vivo experiments and confirmed its high transfection efficiency and low cytotoxicity. Moreover, substantial regenerative effects were observed following transfection with rPOA/pVEGF expression vector complexes (79% decreased infarct size) compared to polyethyleneimine (PEI) (34% decreased infarct size) in a rat myocardial infarction (MI) model. These findings suggest that rPOA efficiently enables DNA transfection in cardiac tissue and can be used as a useful non-viral therapeutic gene carrier for gene therapy in ischemic heart disease. PMID- 26649572 TI - Interfacial n-Doping Using an Ultrathin TiO2 Layer for Contact Resistance Reduction in MoS2. AB - We demonstrate a low and constant effective Schottky barrier height (PhiB ~ 40 meV) irrespective of the metal work function by introducing an ultrathin TiO2 ALD interfacial layer between various metals (Ti, Ni, Au, and Pd) and MoS2. Transmission line method devices with and without the contact TiO2 interfacial layer on the same MoS2 flake demonstrate reduced (24*) contact resistance (RC) in the presence of TiO2. The insertion of TiO2 at the source-drain contact interface results in significant improvement in the on-current and field effect mobility (up to 10*). The reduction in RC and PhiB has been explained through interfacial doping of MoS2 and validated by first-principles calculations, which indicate metallic behavior of the TiO2-MoS2 interface. Consistent with DFT results of interfacial doping, X-ray photoelectron spectroscopy (XPS) data also exhibit a 0.5 eV shift toward higher binding energies for Mo 3d and S 2p peaks in the presence of TiO2, indicating Fermi level movement toward the conduction band (n type doping). Ultraviolet photoelectron spectroscopy (UPS) further corroborates the interfacial doping model, as MoS2 flakes capped with ultrathin TiO2 exhibit a reduction of 0.3 eV in the effective work function. Finally, a systematic comparison of the impact of selective doping with the TiO2 layer under the source drain metal relative to that on top of the MoS2 channel shows a larger benefit for transistor performance from the reduction in source-drain contact resistance. PMID- 26649573 TI - Analysis of Zebrafish Larvae Skeletal Muscle Integrity with Evans Blue Dye. AB - The zebrafish model is an emerging system for the study of neuromuscular disorders. In the study of neuromuscular diseases, the integrity of the muscle membrane is a critical disease determinant. To date, numerous neuromuscular conditions display degenerating muscle fibers with abnormal membrane integrity; this is most commonly observed in muscular dystrophies. Evans Blue Dye (EBD) is a vital, cell permeable dye that is rapidly taken into degenerating, damaged, or apoptotic cells; in contrast, it is not taken up by cells with an intact membrane. EBD injection is commonly employed to ascertain muscle integrity in mouse models of neuromuscular diseases. However, such EBD experiments require muscle dissection and/or sectioning prior to analysis. In contrast, EBD uptake in zebrafish is visualized in live, intact preparations. Here, we demonstrate a simple and straightforward methodology for performing EBD injections and analysis in live zebrafish. In addition, we demonstrate a co-injection strategy to increase efficacy of EBD analysis. Overall, this video article provides an outline to perform EBD injection and characterization in zebrafish models of neuromuscular disease. PMID- 26649575 TI - Divergent Skull Morphology Supports Two Trophic Specializations in Otters (Lutrinae). AB - Variation in terrestrial mammalian skull morphology is known to constrain feeding performance, which in turn influences dietary habits and ultimately fitness. Among mustelids, otters have evolved two feeding specializations: underwater raptorial capture of prey (mouth-oriented) and capture of prey by hand (hand oriented), both of which have likely associations with morphology and bite performance. However, feeding biomechanics and performance data for otters are sparse. The first goal of this study was to investigate the relationships between feeding morphology and bite performance among two mouth-oriented piscivores (Pteronura brasiliensis and Lontra canadensis) and two hand-oriented invertebrate specialists (Enhydra lutris and Aonyx cinerea). Since other vertebrate taxa that are mouth-oriented piscivores tend to possess longer skulls and mandibles, with jaws designed for increased velocity at the expense of biting capability, we hypothesized that mouth-oriented otters would also possess long, narrow skulls indicative of high velocity jaws. Conversely, hand-oriented otters were expected to possess short, blunt skulls with adaptations to increase bite force and crushing capability. Concomitant with these skull shapes we hypothesized that sea otters would possess a greater mandibular bluntness index, providing for a greater mechanical advantage compared to other otter species investigated. A second goal was to examine morphological variation at a finer scale by assessing variation in cranial morphology among three sea otter subspecies. Since diet varies among these subspecies, and their populations are isolated, we hypothesized that the magnitude of mandibular bluntness and concomitant mechanical advantage, as well as occlusal surface area would also vary within species according to their primary food source (fish versus hard invertebrates). Functional expectations were met for comparisons among and within species. Among species the phylogeny suggests a deeply rooted transition to alternative foraging types. Yet within foraging types alternative species were also strongly variable, suggesting either selective differences in the extent or nature of realized foraging mode, or an accumulation of non-adaptive changes during the long independent evolutionary history. At the finest scale, variation among subspecies indicates that trophic adaptation occurred rapidly, making it interesting that we happened to find both deeply and shallowly-rooted transformations associated with diet type in otter species and subspecies. PMID- 26649574 TI - Newly Characterized Region of CP190 Associates with Microtubules and Mediates Proper Spindle Morphology in Drosophila Stem Cells. AB - CP190 is a large, multi-domain protein, first identified as a centrosome protein with oscillatory localization over the course of the cell cycle. During interphase it has a well-established role within the nucleus as a chromatin insulator. Upon nuclear envelope breakdown, there is a striking redistribution of CP190 to centrosomes and the mitotic spindle, in addition to the population at chromosomes. Here, we investigate CP190 in detail by performing domain analysis in cultured Drosophila S2 cells combined with protein structure determination by X-ray crystallography, in vitro biochemical characterization, and in vivo fixed and live imaging of cp190 mutant flies. Our analysis of CP190 identifies a novel N-terminal centrosome and microtubule (MT) targeting region, sufficient for spindle localization. This region consists of a highly conserved BTB domain and a linker region that serves as the MT binding domain. We present the 2.5 A resolution structure of the CP190 N-terminal 126 amino acids, which adopts a canonical BTB domain fold and exists as a stable dimer in solution. The ability of the linker region to robustly localize to MTs requires BTB domain-mediated dimerization. Deletion of the linker region using CRISPR significantly alters spindle morphology and leads to DNA segregation errors in the developing Drosophila brain neuroblasts. Collectively, we highlight a multivalent MT-binding architecture in CP190, which confers distinct subcellular cytoskeletal localization and function during mitosis. PMID- 26649576 TI - Extraction Optimization, Characterization and Bioactivities of a Major Polysaccharide from Sargassum thunbergii. AB - Sargassum thunbergii is a kind of natural edible algae. STP (S. thunbergii polysaccharides) was considered as the main bioactive compounds in S. thunbergii. To obtain the optimal processing conditions for maximum total sugar yield, single factor investigation and response surface methodology (RSM) were employed. The optimal processing conditions were as follows: liquid to solid ratio 120 mL/g, extraction time 210 min, extraction temperature 97 degrees C. The experimental yield 7.53% under optimized conditions was closely agreed with the predicted yield 7.85% of the model. The major polysaccharide fraction from S. thunbergii (named STP-II) was purified by DEAE-Sepharose CL-6B column chromatography. High performance size-exclusion chromatography (HPSEC), gas chromatography (GC) and high-performance liquid chromatography (HPLC) were used to identify its characterizations, and in vitro antioxidant assays and cytotoxicity assays were used to research its bioactivities. The purified fraction STP-II (63.75%) was a single peak in HPSEC with Sugar KS-804 column, had a molecular weight of 550KD, and comprised mainly of fucose, xylose, galactose, glucose and glucuronic acid. STP-II had higher scavenging activities on hydroxyl radical (76.72% at 0.7 mg/mL) and superoxide radical (95.17% at 2 mg/mL) than Vitamin C (Vc). STP-II also exhibited the capability of anti-proliferation in Caco-2 cells. STP-II possessed good antioxidant and inhibitory activity against human colon cancer Caco-2 cells in vitro and could be explored as novel natural functional food. PMID- 26649577 TI - Effective Heat Dissipation from Color-Converting Plates in High-Power White Light Emitting Diodes by Transparent Graphene Wrapping. AB - We have developed a hybrid phosphor-in-glass plate (PGP) for application in a remote phosphor configuration of high-power white light emitting diodes (WLEDs), in which single-layer graphene was used to modulate the thermal characteristics of the PGP. The degradation of luminescence in the PGP following an increase in temperature could be prevented by applying single-layer graphene. First, it was observed that the emission intensity of the PGP was enhanced by about 20% with graphene wrapping. Notably, the surface temperature of the graphene-wrapped PGP (G-PGP) was found to be higher than that of the bare PGP, implying that the graphene layer effectively acted as a heat dissipation medium on the PGP surface to reduce the thermal quenching of the constituent phosphors. Moreover, these experimental observations were clearly verified through a two-dimensional cellular automata simulation technique and the underlying mechanisms were analyzed. As a result, the proposed G-PGP was found to be efficient in maintaining the luminescence properties of the WLED, and is a promising development in high power WLED applications. This research could be further extended to generate a new class of optical or optoelectronic materials with possible uses in a variety of applications. PMID- 26649578 TI - Metabolic Characterization of Polarized M1 and M2 Bone Marrow-derived Macrophages Using Real-time Extracellular Flux Analysis. AB - Specific metabolic pathways are increasingly being recognized as critical hallmarks of macrophage subsets. While LPS-induced classically activated M1 or M(LPS) macrophages are pro-inflammatory, IL-4 induces alternative macrophage activation and these so-called M2 or M(IL-4) support resolution of inflammation and wound healing. Recent evidence shows the crucial role of metabolic reprogramming in the regulation of M1 and M2 macrophage polarization. In this manuscript, an extracellular flux analyzer is applied to assess the metabolic characteristics of naive, M1 and M2 polarized mouse bone marrow-derived macrophages. This instrument uses pH and oxygen sensors to measure the extracellular acidification rate (ECAR) and oxygen consumption rate (OCR), which can be related to glycolytic and mitochondrial oxidative metabolism. As such, both glycolysis and mitochondrial oxidative metabolism can be measured in real time in one single assay. Using this technique, we demonstrate here that inflammatory M1 macrophages display enhanced glycolytic metabolism and reduced mitochondrial activity. Conversely, anti-inflammatory M2 macrophages show high mitochondrial oxidative phosphorylation (OXPHOS) and are characterized by an enhanced spare respiratory capacity (SRC). The presented functional assay serves as a framework to investigate how particular cytokines, pharmacological compounds, gene knock outs or other interventions affect the macrophage's metabolic phenotype and inflammatory status. PMID- 26649579 TI - Impaired Immune Response in Elderly Burn Patients: New Insights Into the Immune senescence Phenotype. AB - OBJECTIVE: Comparing the inflammatory and immunological trajectories in burned adults versus burned elderly patients to gain novel insights and better understanding why elderly have poor outcomes. SUMMARY BACKGROUND DATA: Despite receiving the same treatment and clinical consideration as all other burn patients, elderly patients continue to have substantially poorer outcomes compared with adults. In light of an aging population, gaining a better understanding of their susceptibility to complications and creating new treatment strategies is imperative. METHODS: We included 130 burn patients (94 adults: <65 years old and 36 elderly: >=65 years old) and 10 healthy controls in this study. Immune activity and expression was assessed using bioplex at various time points. Clinical outcomes such as infection, sepsis, and mortality were prospectively collected. RESULTS: Elderly burn patients had significantly lower burn size but significantly higher Baux scores. Morbidity and mortality was significantly increased in the elderly cohort. Immune biomarkers indicated that elderly are immune compromised and unable to respond with the expected inflammatory response during the early phase after injury. This trajectory changes to a hyperinflammatory pattern during the later phase after burn. These findings are even more pronounced when comparing sepsis versus nonsepsis patients as well as survivors versus nonsurvivors in the elderly. CONCLUSIONS: Elderly burned patients mount a delayed immune and dampened inflammatory response early after burn injury that changes to an augmented response at later time points. Late onset sepsis and nonsurvivors had an immune exhaustion phenotype, which may represent one of the main mediators responsible for the striking mortality in elderly. PMID- 26649580 TI - A Propensity-matched Analysis Comparing Survival After Esophagectomy Followed by Adjuvant Chemoradiation to Surgery Alone for Esophageal Squamous Cell Carcinoma. AB - BACKGROUND: The role of adjuvant chemoradiation in esophageal cancer has been underestimated in the literature. This study was undertaken to determine whether adjuvant chemoradiation improves survival compared with surgery alone. METHODS: Data of 1095 esophageal squamous cell carcinoma (ESCC) patients, including 679 in surgery alone group (group 1) and 416 in surgery followed adjuvant chemoradaition group (group 2), were obtained from the Taiwan Cancer Registry database. Propensity score matching (PSM) analysis was used to identify 147 well-balanced patients in each group for overall survival comparison. RESULTS: After PSM, the 3 year survival rates and median survival were 44.9% and 27.2 (95% confidence interval [CI]: 17.6-40.3) months in group 2, which is significantly higher than that in group 1 (28.1% and 18.2 [95% CI: 14.3-24.5] months, P = 0.0043). In the multivariate survival analysis, pT3/4 stage (Hazard Ratio [HR]: 2.03, 95% CI: 1.38-2.97, P < 0.001), pN+ stage (HR: 1.83, 95% CI: 1.31-2.57, P = 0.0004), tumor length more than 32 mm (HR: 1.93, 95% CI: 1.33-2.79, P < 0.001), R1/2 resection (HR: 1.75, 95% CI: 1.15-2.66, P = 0.009), and adjuvant chemoradiation (HR: 0.57, 95% CI: 0.42-0.78, P < 0.0001) were independent prognostic factors. Subgroup analysis suggested patients with pT3/4 stage, pN+ stage tumors, larger tumor size, poorly differentiated tumors, and R1/2 resections were more likely to demonstrate survival benefit from adjuvant chemoradiation. CONCLUSIONS: Compared with surgery alone, adjuvant chemoradiation provides a survival benefit to ESCC patients, especially those with pT3/4 stage, N+ tumors, larger tumor size, poorly differentiated tumors, and R1/2 resections. PMID- 26649585 TI - Reconceiving the Morbidity and Mortality Conference in an Era of Big Data: An "Unexpected" Outcomes Approach. PMID- 26649581 TI - Salvage Versus Primary Liver Transplantation for Early Hepatocellular Carcinoma: Do Both Strategies Yield Similar Outcomes? AB - BACKGROUND DATA: In compensated cirrhotics with early hepatocellular carcinoma (HCC-cirr), upfront liver resection (LR) and salvage liver transplantation (SLT) in case of recurrence may have outcomes comparable to primary LT (PLT). OBJECTIVE: An intention-to-treat (ITT) analysis comparing PLT and SLT strategies. METHODS: Of 130 HCC-cirr patients who underwent upfront LR (group LR), 90 (69%) recurred, 31 could undergo SLT (group SLT). During the same period, 366 patients were listed for LT (group LLT); 26 dropped-out (7.1%), 340 finally underwent PLT (group PLT). We compared survival between groups LR and LLT, LR and PLT, and PLT and SLT. RESULTS: Feasibility of SLT strategy was 34% (31/90). In an ITT analysis, group LLT had better 5-yr/10-yr overall survival (OS) compared with group LR (68%/58% vs. 58%/35%; P = 0.008). Similarly, 5-yr/10-yr OS and disease free survival (DFS) were better in group PLT versus group LR (OS 73%/63% vs. 58%/35%, P = 0.0007; DFS 69%/61% vs. 27%/21%, P < 0.0001). Upfront resection and microvascular tumor invasion were poor prognostic factors for both OS and DFS, presence of satellite tumor nodules additionally predicted worse DFS. Group SLT had similar postoperative and long-term outcomes compared with group PLT (starting from time of LT) (OS 54%/54% vs. 73%/63%, P = 0.35; DFS 48%/48% vs. 69%/61%, P = 0.18, respectively). CONCLUSIONS: In initially transplantable HCC cirr patients, ITT survival was better in group PLT compared with group LR. SLT was feasible in only a third of patients who recurred after LR. Post SLT, short and long-term outcomes were comparable with PLT. Better patient selection for the "resection first" approach and early detection of recurrence may improve outcomes of the SLT strategy. PMID- 26649586 TI - Individualized Performance Feedback to Surgical Residents Improves Appropriate Venous Thromboembolism Prophylaxis Prescription and Reduces Potentially Preventable VTE: A Prospective Cohort Study. AB - OBJECTIVE: To investigate the effect of providing personal clinical effectiveness performance feedback to general surgery residents regarding prescription of appropriate venous thromboembolism (VTE) prophylaxis. BACKGROUND: Residents are frequently charged with prescribing medications for patients, including VTE prophylaxis, but rarely receive individual performance feedback regarding these practice habits. METHODS: This prospective cohort study at the Johns Hopkins Hospital compared outcomes across 3 study periods: (1) baseline, (2) scorecard alone, and (3) scorecard plus coaching. All general surgery residents (n = 49) and surgical patients (n = 2420) for whom residents wrote admission orders during the first 9 months of the 2013-2014 academic year were included. Outcomes included the proportions of patients prescribed appropriate VTE prophylaxis, patients with preventable VTE, and residents prescribing appropriate VTE prophylaxis for every patient, and results from the Accreditation Council for Graduate Medical Education resident survey. RESULTS: At baseline, 89.4% of patients were prescribed appropriate VTE prophylaxis and only 45% of residents prescribed appropriate prophylaxis for every patient. During the scorecard period, appropriate VTE prophylaxis prescription significantly increased to 95.4% (P < 0.001). For the scorecard plus coaching period, significantly more residents prescribed appropriate prophylaxis for every patient (78% vs 45%, P = 0.0017). Preventable VTE was eliminated in both intervention periods (0% vs 0.35%, P = 0.046). After providing feedback, significantly more residents reported receiving data about practice habits on the Accreditation Council for Graduate Medical Education resident survey (87% vs 38%, P < 0.001). CONCLUSIONS: Providing personal clinical effectiveness feedback including data and peer-to-peer coaching improves resident performance, and results in a significant reduction in harm for patients. PMID- 26649587 TI - Recommendations for Best Communication Practices to Facilitate Goal-concordant Care for Seriously Ill Older Patients With Emergency Surgical Conditions. AB - OBJECTIVE: To address the need for improved communication practices to facilitate goal-concordant care in seriously ill, older patients with surgical emergencies. SUMMARY BACKGROUND DATA: Improved communication is increasingly recognized as a central element in providing goal-concordant care and reducing health care utilization and costs among seriously ill older patients. Given high rates of surgery in the last weeks of life, high risk of poor outcomes after emergency operations in these patients, and barriers to quality communication in the acute setting, we sought to create a framework to support surgeons in communicating with seriously ill, older patients with surgical emergencies. METHODS: An interdisciplinary panel of 23 national leaders was convened for a 1-day conference at Harvard Medical School to provide input on concept, content, format, and usability of a communication framework. A prototype framework was created. RESULTS: Participants supported the concept of a structured approach to communication in these scenarios, and delineated 9 key elements of a framework: (1) formulating prognosis, (2) creating a personal connection, (3) disclosing information regarding the acute problem in the context of the underlying illness, (4) establishing a shared understanding of the patient's condition, (5) allowing silence and dealing with emotion, (6) describing surgical and palliative treatment options, (7) eliciting patient's goals and priorities, (8) making a treatment recommendation, and (9) affirming ongoing support for the patient and family. CONCLUSIONS: Communication with seriously ill patients in the acute setting is difficult. The proposed communication framework may assist surgeons in delivering goal-concordant care for high-risk patients. PMID- 26649588 TI - The Human Pancreas as a Source of Protolerogenic Extracellular Matrix Scaffold for a New-generation Bioartificial Endocrine Pancreas. AB - OBJECTIVES: Our study aims at producing acellular extracellular matrix scaffolds from the human pancreas (hpaECMs) as a first critical step toward the production of a new-generation, fully human-derived bioartificial endocrine pancreas. In this bioartificial endocrine pancreas, the hardware will be represented by hpaECMs, whereas the software will consist in the cellular compartment generated from patient's own cells. BACKGROUND: Extracellular matrix (ECM)-based scaffolds obtained through the decellularization of native organs have become the favored platform in the field of complex organ bioengineering. However, the paradigm is now switching from the porcine to the human model. METHODS: To achieve our goal, human pancreata were decellularized with Triton-based solution and thoroughly characterized. Primary endpoints were complete cell and DNA clearance, preservation of ECM components, growth factors and stiffness, ability to induce angiogenesis, conservation of the framework of the innate vasculature, and immunogenicity. Secondary endpoint was hpaECMs' ability to sustain growth and function of human islet and human primary pancreatic endothelial cells. RESULTS: Results show that hpaECMs can be successfully and consistently produced from human pancreata and maintain their innate molecular and spatial framework and stiffness, and vital growth factors. Importantly, hpaECMs inhibit human naive CD4 T-cell expansion in response to polyclonal stimuli by inducing their apoptosis and promoting their conversion into regulatory T cells. hpaECMs are cytocompatible and supportive of representative pancreatic cell types. DISCUSSION: We, therefore, conclude that hpaECMs has the potential to become an ideal platform for investigations aiming at the manufacturing of a regenerative medicine-inspired bioartificial endocrine pancreas. PMID- 26649589 TI - Identification and Resection of Clipped Node Decreases the False-negative Rate of Sentinel Lymph Node Surgery in Patients Presenting With Node-positive Breast Cancer (T0-T4, N1-N2) Who Receive Neoadjuvant Chemotherapy: Results From ACOSOG Z1071 (Alliance). AB - BACKGROUND: The American College of Surgeons Oncology Group Z1071 trial reported a false-negative rate (FNR) of 12.6% with sentinel lymph node (SLN) surgery after neoadjuvant chemotherapy in women presenting with node-positive breast cancer. One proposed method to decrease the FNR is clip placement in the positive node at initial diagnosis with confirmation of clipped node resection at surgery. METHODS: Z1071 was a multi-institutional trial wherein women with clinical T0 T4,N1-N2,M0 breast cancer underwent SLN surgery and axillary dissection (ALND) after neoadjuvant chemotherapy. In cases with a clip placed in the node, the clip location at surgery (SLN or ALND) was evaluated. RESULTS: A clip was placed at initial node biopsy in 203 patients. In the 170 (83.7%) patients with cN1 disease and at least 2 SLNs resected, clip location was confirmed in 141 cases. In 107 (75.9%) patients where the clipped node was within the SLN specimen, the FNR was 6.8% (confidence interval [CI]: 1.9%-16.5%). In 34 (24.1%) cases where the clipped node was in the ALND specimen, the FNR was 19.0% (CI: 5.4%-41.9%). In cases without a clip placed (n = 355) and in those where clipped node location was not confirmed at surgery (n = 29), the FNR was 13.4% and 14.3%, respectively. CONCLUSIONS: Clip placement at diagnosis of node-positive disease with removal of the clipped node during SLN surgery reduces the FNR of SLN surgery after neoadjuvant chemotherapy. Clip placement in the biopsy-proven node at diagnosis and evaluation of resected specimens for the clipped node should be considered when conducting SLN surgery in this setting. PMID- 26649593 TI - Quality of Follow-up: Systematic Review of the Research in Bariatric Surgery. AB - OBJECTIVE: We aim to systematically review the bariatric surgery literature with regards to adequacy of patient follow-up, meeting the McMaster criteria of >=80% follow-up. BACKGROUND: Loss to follow-up is a major concern and can potentially bias the outcome and interpretation of a study. The quality of follow-up in bariatric surgery is quite variable with recent systematic reviews criticizing the field for its lack of overall follow-up. METHODS: A complete search of PubMed was performed. Literature was restricted to a range of 5 years (2007-2012), English language, and publications listed in PubMed. The McMaster Evidence-based Criteria for High Quality Studies was used to assess the follow-up data adequacy and a logistic meta-regression was performed to identify factors associated with high quality follow-up studies. RESULTS: Ninety-nine published manuscripts were included. For follow-up at study end, only 40/99 (40.4%) of papers had adequate patient follow-up, 42/99 (42.4%) failed to meet the McMaster criteria and 17/99 (17.2%) failed to report any follow-up results. On average, 31% were lost to follow-up at the study's end. Only shorter study duration, and if the study was performed in the US, were associated with studies meeting the McMaster criteria. CONCLUSIONS: Only 40% of studies in the bariatric surgery literature meet criteria for adequate follow-up. On average, studies have 30% of patients lost to follow-up at the stated end-point. Identified study characteristics associated with high quality follow-up included shorter study duration and studies performed in the US. PMID- 26649595 TI - [New Series: Translational Research in Pneumology]. PMID- 26649592 TI - Linked Hospital and Primary Care Database Analysis of the Incidence and Impact of Psychiatric Morbidity Following Gastrointestinal Cancer Surgery in England. AB - OBJECTIVE: To evaluate risk of psychiatric morbidity and its impact on survival in gastrointestinal surgery. BACKGROUND: Psychiatric morbidity related to surgery is poorly understood, and may be evaluated using linked hospital and primary care data. METHODS: Patients undergoing gastrointestinal surgery from 2000 to 2011 with linkage of Clinical Practice Research Datalink (CPRD), Hospital Episodes Statistics (HES), Office of National Statistics (ONS), and National Cancer Intelligence Network (NCIN) databases were studied. Psychiatric morbidity was defined as a diagnosis code in CPRD or HES, or a prescription code for psychiatric medication in the 36 months before (preoperative) or 12 months after (postoperative) surgery. Newly diagnosed psychiatric morbidity was measured in patients without preoperative psychiatric morbidity. RESULTS: In our study, 14,797 (23.8%) and 47,279 (76.2%) patients had surgery for cancer and benign disease, respectively. Postoperative psychiatric morbidity was observed in 10.1% (1500/14797) of patients undergoing cancer surgery. Logistic regression revealed that when adjusted for other factors, cancer diagnosis [odds ratio (OR) = 1.19] independently predicted postoperative psychiatric morbidity (P < 0.05). Hepatopancreaticobiliary resection (OR = 2.40) and esophagogastrectomy (OR = 2.55) carried the highest risks of postoperative psychiatric morbidity (P < 0.05). Preoperative psychiatric morbidity (OR = 1.16) and newly diagnosed psychiatric morbidity (OR = 1.87) were associated with increased 1-year mortality in cancer patients only (P < 0.05). CONCLUSIONS: Postoperative psychiatric morbidity affected a tenth of patients who underwent gastrointestinal cancer surgery and was associated with increased mortality. Strategies to identify patients at risk preoperatively and to reduce the observed adverse impact of postoperative psychiatric morbidity should be part of perioperative care in complex cancer patients. PMID- 26649596 TI - [COPD Update 2015: Cell Biology goes Clinic? - Important Research Findings for Clinicians]. AB - The COPD is a very common, chronic, non-contagious disease causing high mortality as well as high socio-economical costs worldwide. Its clinical assessment progressively becomes more comprehensive including the lung function, the rate of exacerbations, the physical capacity, the sensation of dyspnoea, and comorbidities. On the other hand, our therapeutic options are very limited: Although there are several well-tolerated and effective combinable bronchodilators of the group of long-acting beta2-mimetics and anticholinergics, drugs causally affecting pathophysiology are barely available. As anti inflammatory principles only inhaled glucocorticoids as well as one orally available inhibitor of phosphodiesterase 4 are approved, each improving the course of disease in a subgroup of patients. This lack of effective causative therapeutic principles on the one hand and of biomarkers clearly stratifying patients on the other hand to a large extend are caused by our limited understanding of the pathophysiology. Therefore, this review presents the current progress in clinical and experimental research on COPD with regard to clinical practice. PMID- 26649597 TI - Horse Allergy: Curly Horses Allow Horse Allergic Riders To Ride Again. AB - To test the hypothesis that so called hypoallergenic horses (Curly horses) allow horse allergic riders to ride again, we investigated 40 horse allergic riders in a period of 37 months. Methods: We tested these patients (pts.) by skin prick test (SPT) with different non-curly and Curly horses and studied the riding hours and horse brushing by measurements of peak expiratory flow (PEF) and Tiffeneau tests (FEV1) as well as peak nasal inspiratory flow (PNIF) over 12 months. The results in 37/40 pts. showed no relevant reactions of the lower airways or nasal flow. Only in 3/40 patients an initial significant fall of FEV1 was observed, reversed by a single inhalation of salbutamol and not repeated despite further riding contact. In contrast to other allergic events (e. g. baker's asthma) a further and regular contact with these horses abolished the mild allergic reactions of the start period of contact. This may be due to hypoallergenic properties of these horses, whose test material produces weaker reactions in the SPT than that of normal horses. After a period of three years, a loss of reactivity to normal horses could be confirmed in some of the riders. Conclusion: The tested purebreed Curly horses may be a suitable alternative for horse allergic riders if the methodological precautions of this study are followed. PMID- 26649598 TI - [Noninvasive Mechanical Ventilation in Acute Respiratory Failure]. AB - The non-invasive ventilation (NIV) is widespread in the clinical medicine and has attained meanwhile a high value in the clinical daily routine. The application of NIV reduces the length of ICU stay and hospitalization as well as mortality of patients with hypercapnic acute respiratory failure. Patients with acute respiratory failure in context of a cardiopulmonary edema should be treated in addition to necessary cardiological interventions with continuous positive airway pressure (CPAP) or NIV. In case of other forms of acute hypoxaemic respiratory failure it is recommended the application of NIV to be limited to mild forms of ARDS as the application of NIV in severe forms of ARDS is associated with higher rates of treatment failure and mortality. In weaning process from invasive ventilation the NIV reduces the risk of reintubation essentially in hypercapnic patients. A delayed intubation of patients with NIV failure leads to an increase of mortality and should therefore be avoided. With appropriate monitoring in intensive care NIV can also be successfully applied in pediatric patients with acute respiratory insufficiency. Furthermore NIV can be useful within palliative care for reduction of dyspnea and improving quality of life. The aim of the guideline update is, taking into account the growing scientific evidence, to outline the advantages as well as the limitations of NIV in the treatment of acute respiratory failure in daily clinical practice and in different indications. PMID- 26649599 TI - Pd-Catalyzed Asymmetric Decarboxylative Cycloaddition of Vinylethylene Carbonates with Imines. AB - An efficient method for the enantioselective synthesis of beta-tertiary beta amino alcohol derivatives through Pd-catalyzed decarboxylative cycloaddition of vinylethylene carbonates with imines was developed. By using a palladium complex generated in situ from [Pd2(dba)3].CHCl3 and phosphoramidite L2 as a catalyst under mild reaction conditions, the process provided 4-substituted-4 vinyloxazolidines in good to high yields with high levels of enantio- and diastereoselectivities. PMID- 26649600 TI - Quantifying the Sensitivity of Multipolar (Dipolar, Quadrupolar, and Octapolar) Surface Plasmon Resonances in Silver Nanoparticles: The Effect of Size, Composition, and Surface Coating. AB - The effect of composition, size, and surface coating on the sensitivity of localized multipolar surface plasmon resonances has been spectroscopically investigated in high-quality silver colloidal solutions with precisely controlled sizes from 10 to 220 nm and well-defined surface chemistry. Surface plasmon resonance modes have been intensively characterized, identifying the size dependence of dipolar, quadrupolar, and octapolar modes. Modifications of the NP's surface chemistry revealed the higher sensitivity of large sizes, long molecules, thiol groups, and low-order resonance modes. We also extend this study to gold nanoparticles, aiming to compare the sensitivity of both materials, quantifying the higher sensitivity of silver. PMID- 26649601 TI - Systematic Review: Incidence and Course of Hearing Loss Caused by Bacterial Meningitis: In Search of an Optimal Timed Audiological Follow-up. AB - OBJECTIVE: The objective of this study was to clarify the incidence and course of hearing loss after bacterial meningitis to optimize the audiological follow-up. DATA SOURCES: The databases Embase, Medline (OvidSP), Web-of-science, Scopus, Cinahl, Cochrane, PubMed publisher, and Google Scholar were used. Only articles written in English were included. STUDY SELECTION: Articles published from 1985 until March 2015 describing the incidence, risk factors, or course of hearing loss after meningitis were used. DATA EXTRACTION: The quality of the studies was assessed on three aspects: quality of audiometry, number of patients, and methodological quality. DATA SYNTHESIS: For each publication, data were entered in spreadsheet software for analysis. The data were analyzed and interpreted using best evidence synthesis. CONCLUSIONS: The overall quality of the included studies was poor. A major drawback was the quality of the (description of) audiometry, severity, and timing of hearing loss.A systematic review of the literature showed an incidence of hearing loss (>25 +/- 5 dB) of 14% and an incidence of 5% for profound hearing loss (>90 dB). Patients with initial normal hearing after meningitis showed stable normal hearing over time. However, initial hearing loss related to meningitis can improve or deteriorate over time.We therefore recommend early audiological testing of all patients who suffered bacterial meningitis. However, long-term audiological follow-up is only needed for patients with early onset hearing loss and not for patients with normal hearing at the first hearing test. PMID- 26649602 TI - A Systematic Review of the Diagnostic Value of CT Imaging in Diagnosing Otosclerosis. AB - OBJECTIVE: To evaluate the diagnostic value of computed tomography (CT) in detecting otosclerosis in patients with conductive hearing loss and a clinical suspicion of otosclerosis. DATA SOURCES: PubMed, Embase, and the Cochrane Library. STUDY SELECTION: A systematic search was conducted. Studies reporting original study data were included. DATA EXTRACTION: Relevance and risk of bias of the selected articles were assessed. Studies with low relevance, high risk of bias, or both were excluded. Prevalences, sensitivities, specificities, and post test probabilities were extracted from the included articles. DATA SYNTHESIS: Seven studies characterized by a moderate to high relevance and moderate to low risk of bias were included for data extraction. The prevalence of otosclerosis was high (up to 100%) in the majority of the included studies. In those studies with a high prevalence of disease, both positive and negative post-test probabilities were (relatively) high: 99% and between 51% and 67% respectively. In one study with a low prevalence of disease (9%), both positive and negative post-test probabilities were low (23% and 3% respectively). Overall, reported sensitivities ranged between 60% and 95%. CONCLUSION: Preoperative CT has little to add in establishing otosclerosis and may not be necessary to confirm the diagnosis. We would recommend reserving CT for those patients with suspected additional abnormalities, for specific preoperative planning, or out of legal necessity. PMID- 26649603 TI - Relationship Between Electrode-to-Modiolus Distance and Current Levels for Adults With Cochlear Implants. AB - HYPOTHESIS: Electrode-to-modiolus distance is correlated with clinically programmed stimulation levels. BACKGROUND: Conventional wisdom has long supposed a significant relationship between cochlear implant (CI) stimulation levels and electrode-to-modiolus distance; however, to date, no such formal investigation has been completed. Thus, the purpose of this project was to investigate the relationship between stimulation levels and electrode-to-modiolus distance. A strong correlation between the two would suggest that stimulation levels might be used to estimate electrode-to-modiolus geometry. METHODS: Electrode-to-modiolus distance was determined via CT imaging using validated CI position analysis software in 137 implanted ears from the three manufacturers holding FDA approval in the United States. Analysis included 2,365 total electrodes, with 1,472 from precurved arrays. Distances were compared to clinically programmed C/M levels that were converted to charge units. RESULTS: Mean modiolar distance with perimodiolar and lateral wall electrodes was 0.47 and 1.15 mm, respectively. Mean suprathreshold charge values were significantly different between each manufacturer. When combining all data, we found a moderate positive correlation (r = 0.367, p < 0.01) that was driven both by the different charge values across companies, and that the company with the highest mean charge values only offers straight electrode arrays. When grouped by electrode type, however, we found a weak correlation (r = 0.12, p < 0.01) for perimodiolar array electrodes only. When considering a single array type from any one manufacturer, only one was observed where distance mildly predicted charge. CONCLUSION: Our results suggest that electrode distance minimally contributes to the current level required for suprathreshold stimulation. PMID- 26649604 TI - Cost-Utility of Bilateral Versus Unilateral Cochlear Implantation in Adults: A Randomized Controlled Trial. AB - OBJECTIVE: To study the cost-utility of simultaneous bilateral cochlear implantation (CI) versus unilateral CI. STUDY DESIGN: Randomized controlled trial (RCT). SETTING: Five tertiary referral centers. PATIENTS: Thirty-eight postlingually deafened adults eligible for cochlear implantation. INTERVENTIONS: A cost-utility analysis was performed from a health insurance perspective. MAIN OUTCOME MEASURES: Utility was assessed using the HUI3, TTO, VAS on hearing, VAS on general health and EQ-5D. We modeled the incremental cost per quality-adjusted life year (QALY) of unilateral versus bilateral CI over periods of 2, 5, 10, 25 years, and actual life-expectancy. RESULTS: Direct costs for unilateral and bilateral CI were ?43,883 +/- ?11,513(SD) and ?87,765 +/- ?23,027(SD) respectively. Annual costs from the second year onward were ?3,435 +/- ?1,085(SD) and ?6,871 +/- ?2,169(SD), respectively. A cost-utility analysis revealed that a second implant became cost-effective after a 5- to 10-year period, based on the HUI3, TTO, and VAS on hearing. CONCLUSION: This is the first study that describes a cost-utility analysis to compare unilateral with simultaneous bilateral CI in postlingually deafened adults, using a multicenter RCT. Compared with accepted societal willingness-to-pay thresholds, simultaneous bilateral CI is a cost effective treatment for patients with a life expectancy of 5-10 years or longer. PMID- 26649605 TI - Outcomes After Cochlear Implantation in the Very Elderly. AB - OBJECTIVE: To evaluate the outcomes after cochlear implantation (CI) in the elderly population, with a particular emphasis on perioperative complications, dizziness, and speech perception outcomes. STUDY DESIGN: A retrospective cohort study of elderly cochlear implant patients. SETTING: Tertiary referral center (Cochlear Implant Clinic, Royal Victorian Eye and Ear Hospital, Melbourne). PATIENTS: All patients aged 75 and above at the time of first cochlear implant (N = 150). Comparison was made between groups aged 85+ to 80-84, and 75-79. INTERVENTIONS: All patients received Nucleus devices (either CI512 or CI24RE(CA)). MAIN OUTCOME MEASURES: Speech recognition scores both pre- and postimplantation, symptomatic dizziness and effects upon independent living after surgery, and the incidence of perioperative medical and surgical complications. Complications were classified as major (intrinsic device failure, device migration, extracochlear insertion, meningitis, surgical site infection requiring reoperation, wound breakdown, permanent facial nerve paralysis) and minor (tinnitus, transient facial nerve palsy, facial nerve stimulation, taste disturbance, delayed wound healing). RESULTS: All three cohorts had poor preoperative speech perception. There was significant improvement in postoperative word scores at 3 and 12 months across all groups. There was no statistically significant difference between the three cohorts in terms of speech recognition outcomes at 3 and 12 months. After surgery, more than 20% of patients at all ages experienced transient imbalance, although the incidence did not differ significantly between age groups (p = 0.71). In total, there were 13 major complications in 7 patients (4.7%), and 28 minor complications in 25 patients (16.7%). CONCLUSION: Postoperative disequilibrium was commonly observed in this elderly population, yet patients still benefited with improved speech perception after cochlear implantation. Elderly patients can benefit from cochlear implantation, and age should not be a limitation for CI surgery. Cochlear implantation can be done safely and provides significant patient benefits. PMID- 26649606 TI - Lamb Temporal Bone as a Surgical Training Model of Round Window Cochlear Implant Electrode Insertion. AB - OBJECTIVE: The preservation of residual hearing in cochlear implantation opens the door for optimal functional results. This atraumatic surgical technique requires training; however, the traditional human cadaveric temporal bones have become less available or unattainable in some institutions. This study investigates the suitability of an alternative model, using cadaveric lamb temporal bone, for surgical training of atraumatic round window electrode insertion. INTERVENTION: A total of 14 lamb temporal bones were dissected for cochlear implantation by four surgeons. After mastoidectomy, visualization, and drilling of the round window niche, an atraumatic round window insertion of a Medel Flex24 electrode was performed. Electrode insertion depth and position were verified by computed tomography scans. MAIN OUTCOME MEASURE: All cochleas were successfully implanted using the atraumatic round window approach; however, surgical access through the mastoid was substantially different when compared human anatomy. The mean number of intracochlear electrode contacts was 6.5 (range, 4-11) and the mean insertion depth 10.4 mm (range, 4-20 mm), which corresponds to a mean angular perimodiolar insertion depth of 229 degrees (range 67-540 degrees ). Full insertion of the electrode was not possible because of the smaller size of the lamb cochlea in comparison to that of the human. CONCLUSION: The lamb temporal bone model is well suited as a training model for atraumatic cochlear implantation at the level of the round window. The minimally pneumatized mastoid as well as the smaller cochlea can help prepare a surgeon for difficult cochlear implantations. Because of substantial differences to human anatomy, it is not an adequate training model for other surgical techniques such as mastoidectomy and posterior tympanotomy as well as full electrode insertion. PMID- 26649607 TI - Association Between Tegmen Tympani Status and Superior Semicircular Canal Pattern. AB - OBJECTIVE: Detecting and quantifying the possible association between tegmen tympani (TT) status and superior semicircular canal (SSC) pattern. DESIGN: Observational study. SETTING: Study conducted in three tertiary Spanish hospitals. PATIENTS: Nonselected consecutive patients of all ages (607 temporal bones). INTERVENTIONS: Thin-section multidetector row computed axial tomography (CAT scan) of the temporal bones. MAIN OUTCOME MEASURE: Thickness of SSC bone coverture adjacent to the middle fossa, and TT status as a dichotomous variable: dehiscence (TTD) or integrity (TTI). RESULTS: The observed SSC patterns were dehiscence (3.79%), papyraceous or thin (11.20%), normal (76.77%), thick (4.94%), and pneumatized (3.29%). The observed TT statuses were TTD (10.87%) and TTI (89.13%). TTD was associated with SSCD and papyraceous patterns, and TTI percentages were higher in normal and thick patterns (chi2 = 11.102; p = 0.001). The TTD probability was estimated as a function of SSC pattern and age by a multivariate binary logistics regression model (chi2 = 45.939; p < 0.001). CONCLUSION: SSC pattern was significantly associated with TT status. Age influenced this association. The risk for TTD increased by 4.1% per each year of increasing age, did not differ significantly for normal and thick patterns, and increased 12 times and 20 times for papyraceous and SSCD patterns, respectively. PMID- 26649609 TI - Characteristics of Wax Occlusion in the Surgical Repair of Superior Canal Dehiscence in Human Temporal Bone Specimens. AB - HYPOTHESIS: Superior canal dehiscence (SCD) repair using surgical bone wax may result in variable outcomes if large wax volumes are applied. BACKGROUND: SCD is a disorder characterized by a pathologic defect in the bony labyrinth of the superior semicircular canal (SSC), resulting in vestibular and/or auditory symptoms. Repair of SCD using bone wax can provide symptomatic relief, but surgical outcomes are variable. These observations may be associated with the inconsistency in the position and extension of intralabyrinthine bone wax during surgical repair. METHODS: A pathological model of SCD was created using cadaveric human temporal bones and a microdrill. Defects in the arcuate eminence 0.5 to 3.5 mm in length were repaired by surgical occlusion with bone wax. The volume of wax used in the repair was quantified. The position of bone wax was evaluated by direct visualization and imaging (computed tomography [CT]). To visualize wax on CT, specimens were repaired using radiopaque wax. RESULTS: Exceedingly small volumes of bone wax (3.0-5.0 mm2) reliably occluded the canal lumen. Multiple wax applications resulted in extension into the common crus and ampulla. The length of this extension was related to the number of applications. CONCLUSIONS: Repair of SCD with bone wax occludes the bony defect completely in most patients. Wax can extend along the lumen of the superior canal beyond the limits of the dehiscence to reach the sensory neuroepithelium of the vestibular end organs. Limiting the number of wax applications is essential to avoid inadvertent injury to the delicate neurosensory systems. PMID- 26649610 TI - A Neuromonitoring Approach to Facial Nerve Preservation During Image-guided Robotic Cochlear Implantation. AB - HYPOTHESIS: A multielectrode probe in combination with an optimized stimulation protocol could provide sufficient sensitivity and specificity to act as an effective safety mechanism for preservation of the facial nerve in case of an unsafe drill distance during image-guided cochlear implantation. BACKGROUND: A minimally invasive cochlear implantation is enabled by image-guided and robotic assisted drilling of an access tunnel to the middle ear cavity. The approach requires the drill to pass at distances below 1 mm from the facial nerve and thus safety mechanisms for protecting this critical structure are required. Neuromonitoring is currently used to determine facial nerve proximity in mastoidectomy but lacks sensitivity and specificity necessaries to effectively distinguish the close distance ranges experienced in the minimally invasive approach, possibly because of current shunting of uninsulated stimulating drilling tools in the drill tunnel and because of nonoptimized stimulation parameters. To this end, we propose an advanced neuromonitoring approach using varying levels of stimulation parameters together with an integrated bipolar and monopolar stimulating probe. MATERIALS AND METHODS: An in vivo study (sheep model) was conducted in which measurements at specifically planned and navigated lateral distances from the facial nerve were performed to determine if specific sets of stimulation parameters in combination with the proposed neuromonitoring system could reliably detect an imminent collision with the facial nerve. For the accurate positioning of the neuromonitoring probe, a dedicated robotic system for image-guided cochlear implantation was used and drilling accuracy was corrected on postoperative microcomputed tomographic images. RESULTS: From 29 trajectories analyzed in five different subjects, a correlation between stimulus threshold and drill-to-facial nerve distance was found in trajectories colliding with the facial nerve (distance <0.1 mm). The shortest pulse duration that provided the highest linear correlation between stimulation intensity and drill-to-facial nerve distance was 250 MUs. Only at low stimulus intensity values (<=0.3 mA) and with the bipolar configurations of the probe did the neuromonitoring system enable sufficient lateral specificity (>95%) at distances to the facial nerve below 0.5 mm. However, reduction in stimulus threshold to 0.3 mA or lower resulted in a decrease of facial nerve distance detection range below 0.1 mm (>95% sensitivity). Subsequent histopathology follow-up of three representative cases where the neuromonitoring system could reliably detect a collision with the facial nerve (distance <0.1 mm) revealed either mild or inexistent damage to the nerve fascicles. CONCLUSION: Our findings suggest that although no general correlation between facial nerve distance and stimulation threshold existed, possibly because of variances in patient-specific anatomy, correlations at very close distances to the facial nerve and high levels of specificity would enable a binary response warning system to be developed using the proposed probe at low stimulation currents. PMID- 26649608 TI - Longitudinal Cognitive and Neurobehavioral Functional Outcomes Before and After Repairing Otic Capsule Dehiscence. AB - OBJECTIVE: Patients with peripheral vestibular dysfunction because of gravitational receptor asymmetries display signs of cognitive dysfunction and are assumed to have neurobehavioral sequelae. This was tested with pre- and postoperatively quantitative measurements in three cohort groups with superior semicircular canal dehiscence syndrome (SSCDS) symptoms with: 1) superior canal dehiscence (SCD) repaired via a middle cranial fossa craniotomy and canal plugging only; 2) otic capsule defects not visualized with imaging (no-iOCD) repaired with round window reinforcement (RWR) only; or 3) both SCD plugging and subsequent development of no-iOCD followed by RWR. STUDY DESIGN: Prospective patient series. SETTING: Tertiary referral center. PATIENTS: There were 13 adult and 4 pediatric patients with SSCDS who had completion of neuropsychology test batteries pre- and every 3 months postoperatively. Eight patients had no-iOCD and RWR exclusively, 5 had SCD and plugging exclusively, and 4 had both SCD plugging and then development of no-iOCD with RWR. These cohorts included SSCDS with 2 different dehiscence locations. INTERVENTIONS: Completion of a neuropsychology test battery preoperatively and at 3, 6, 9, and 12 months postoperatively that included: Beck Depression Inventory-II (BDI); Wide Range Intelligence Test (WRIT FSIQ) including average verbal (crystallized intelligence) and visual (fluid intelligence); Wide Range Assessment of Memory and Learning (WRAML), including the four domains of verbal memory, visual memory, attention/concentration, and working memory; and Delis-Kaplan Executive Function System (D-KEFS). The Dizziness Handicap Inventory (DHI) and the Headache Impact Test (HIT-6) were also completed to assess the impact of their disease on activities pre- and postoperatively. MAIN OUTCOME MEASURES: Quantitative and statistical analysis of their cognitive and neurobehavioral function. RESULTS: The pattern of differences between the SCD group and the no-iOCD group from WRAML verbal, visual, and attention test performance indicate different postoperative clinical trajectories. For the WRAML, there was a statistically significant improvement for visual memory and verbal memory for the no-iOCD only and both (SCD and subsequent no-iOCD) groups, but no mean improvement for the SCD only group. By contrast, the no-iOCD group had significantly lower scores on the WRAML attention test preoperatively, but they recovered postoperatively to match the other groups. The preoperative findings and postoperative outcomes did not differ significantly among patient groups on the WRAML working memory test, D-KEFS motor scores, D-KEFS number and letter scores, or Wide Range Intelligence Test scores. There was a significant decrease in the BDI for all groups. The IQ scores were unchanged. There was a statistically significant improvement in the DHI and HIT-6 scores postoperatively in all groups. CONCLUSIONS: There was a marked overall improvement in cognitive and neurobehavioral function postoperatively. Variability may result from duration of underlying disease before intervention. The initial decrement or delay in performance improvement measured in several patients may represent brain reorganization. Greater longitudinal data and greater subject numbers are necessary to better understand and optimize cognitive recovery. PMID- 26649611 TI - Birth and Evolution of Chiselling and Drilling Techniques for Removing Ear Canal Exostoses. AB - The main surgical techniques used to remove ear canal exostoses are drilling and/or, chiselling. The aim of this study was to identify the origins and subsequent evolution of, the surgical removal of ear canal exostoses in the 19th century. A critical review and, compilation of primary and secondary historical sources was conducted. Two techniques for removal of exostoses were developed in the latter part of the 19th century and have largely remained unchanged. This demonstrates the importance of that era in the history of ear surgery. PMID- 26649612 TI - Safe Levels of Acoustic Stimulation for Vemps: Comment on "Sudden Bilateral Hearing Loss After Cervical and Ocular Vestibular Evoked Myogenic Potentials". PMID- 26649613 TI - Response to Colebatch and Rosengren: "Safe Levels of Acoustic Stimulation for Vemps" Comment on "Sudden Bilateral Hearing Loss After Cervical and Ocular Vestibular Evoked Myogenic Potentials". PMID- 26649614 TI - Synthesis of 4-Ynamides and Cyclization by the Vilsmeier Reagent to Dihydrofuran 2(3H)-ones. AB - The room-temperature nucleophilic addition of vinyl azides to propargylic alcohols under BF3.Et2O catalysis provides an efficient synthesis of 4-ynamides. The procedure is operationally convenient, shows broad substrate scope, and is viable for the synthesis of multifunctional 4-ynamides. Further, a Vilsmeier intramolecular cyclization of 4-ynamides into dihydrofuran-2(3H)-ones has also been discovered, which represents the first report of alkynes being used as the nucleophiles in Vilsmeier-type reactions. PMID- 26649616 TI - Iron(ii) triflate/N-heterocyclic carbene-catalysed cross-coupling of arylmagnesiums with aryl chlorides and tosylates. AB - In comparison to iron(ii) halides, iron(ii) triflate exhibits a greater resistance towards reduction by p-tolylmagnesium bromide. This knowledge has led to the development of an iron(ii) triflate/N-heterocyclic carbene-catalysed cross coupling system of aryl Grignard reagents with aryl chlorides and tosylates with high efficiency, even surpassing that of previously reported catalyst systems employing strongly coordinating counterions in some cases. PMID- 26649615 TI - Veterans Crisis Line Callers With and Without Prior VHA Service Use. AB - This study examines differences between Veterans with and without prior Veterans Health Administration service use who received a clinical referral from the Veterans' Crisis Line. Differences between groups were identified using data taken from 13,444 calls and medical records. Approximately 91% of Veterans had a history of service use and 9% did not. Callers with prior service use were older, had more mental health disorders, made in-person contact more quickly, and used more outpatient mental healthcare. Those without prior service use were younger, had more mental health problems, and presented for care later. Callers with suicide-related diagnoses had high rates of service contact. These groups represent different subpopulations with unique healthcare needs and practices. PMID- 26649617 TI - ACTH Stimulation Tests for the Diagnosis of Adrenal Insufficiency: Systematic Review and Meta-Analysis. AB - CONTEXT: The diagnosis of adrenal insufficiency is clinically challenging and often requires ACTH stimulation tests. OBJECTIVE: To determine the diagnostic accuracy of the high- (250 mcg) and low- (1 mcg) dose ACTH stimulation tests in the diagnosis of adrenal insufficiency. METHODS: We searched six databases through February 2014. Pairs of independent reviewers selected studies and appraised the risk of bias. Diagnostic association measures were pooled across studies using a bivariate model. DATA SYNTHESIS: For secondary adrenal insufficiency, we included 30 studies enrolling 1209 adults and 228 children. High- and low-dose ACTH stimulation tests had similar diagnostic accuracy in adults and children using different peak serum cortisol cutoffs. In general, both tests had low sensitivity and high specificity resulting in reasonable likelihood ratios for a positive test (adults: high dose, 9.1; low dose, 5.9; children: high dose, 43.5; low dose, 7.7), but a fairly suboptimal likelihood ratio for a negative test (adults: high dose, 0.39; low dose, 0.19; children: high dose, 0.65; low dose, 0.34). For primary adrenal insufficiency, we included five studies enrolling 100 patients. Data were only available to estimate the sensitivity of high dose ACTH stimulation test (92%; 95% confidence interval, 81 97%). CONCLUSION: Both high- and low-dose ACTH stimulation tests had similar diagnostic accuracy. Both tests are adequate to rule in, but not rule out, secondary adrenal insufficiency. Our confidence in these estimates is low to moderate because of the likely risk of bias, heterogeneity, and imprecision. PMID- 26649618 TI - Impact of Antenatal Glucocorticoid Therapy and Risk of Preterm Delivery on Intelligence in Term-Born Children. AB - CONTEXT: Women at risk of preterm delivery are routinely treated with synthetic glucocorticoids (sGCs). Although this therapy substantially reduces neonatal morbidity, concerns remain whether sGC excess may disrupt neurodevelopmental trajectories underlying cognitive functioning. OBJECTIVE: The present study is the first to disentangle direct effects of antenatal sGC treatment on possible long-term cognitive disadvantages from those of pregnancy complications and prematurity. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study included a mixed-sex cohort of 222 term-born children (aged 6-11 years) consisting of three groups: children of mothers admitted to hospital for threatening preterm delivery who had been treated (n = 97) or untreated (n = 36) with sGCs, and controls without pregnancy complications (n = 89). INTERVENTION: Antenatal sGC treatment consisted of single courses with dexamethasone or betamethasone. MAIN OUTCOME MEASURE: Psychometric intelligence was assessed using a German adaption of Cattell's Culture Fair Test. RESULTS: Children born to mothers at risk for preterm delivery scored, on average, 6-7 IQ points below children of mothers without pregnancy complications, irrespective of antenatal sGC treatment. Compared to females, boys were found to be more susceptible to cognitive disadvantages associated with maternal risk for preterm delivery. CONCLUSIONS: Our data indicate that conditions related to a threatening preterm delivery rather than antenatal sGC treatment per se are associated with long-term decreases in the child's intelligence. Although these findings imply that a single course of sGC therapy does not aggravate long-term cognitive deficits, they highlight the need for interventions to reduce the detrimental consequences of distress induced by a threatening preterm delivery. PMID- 26649619 TI - beta-Cell Glucose Sensitivity Is Linked to Insulin/Glucagon Bihormonal Cells in Nondiabetic Humans. AB - CONTEXT: Insulin resistance impacts virtually all tissues, including pancreatic beta cells. Individuals with insulin resistance, but without diabetes, exhibit an increased islet size because of an elevated number of both beta and alpha cells. Neogenesis from duct cells and transdifferentiation of alpha cells have been postulated to contribute to the beta-cell compensatory response to insulin resistance. OBJECTIVE: Our objective was to explore parameters that could potentially predict altered islet morphology. METHODS: We investigated 16 nondiabetic subjects by a 2-hour hyperglycemic clamp to evaluate beta-cell secretory function. We analyzed pancreas samples obtained during pancreatoduodenectomy in the same patients to examine glucagon and insulin double+ cells to assess islet morphology. RESULTS: Among all the functional in vivo parameters of insulin secretion that were explored (basal, first phase and total secretion, glucose sensitivity, arginine-stimulated insulin secretion), beta-cell glucose sensitivity was unique in exhibiting a significant correlation with both islet size and alpha-beta double+ islet cells. CONCLUSIONS: Our data suggest that poor beta-cell glucose sensitivity is linked to islet transdifferentiation, possibly from alpha cells to beta cells, in an attempt to cope with higher demands for insulin secretion. Understanding the mechanism(s) that underlies the adaptive response of the islet cells to insulin resistance is a potential approach to design tools to enhance functional beta-cell mass for diabetes therapy. PMID- 26649620 TI - Evolving Concepts and Translational Relevance of Enteroendocrine Cell Biology. AB - CONTEXT: Classical enteroenteroendocrine cell (EEC) biology evolved historically from identification of scattered hormone-producing endocrine cells within the epithelial mucosa of the stomach, small and large intestine. Purification of functional EEC hormones from intestinal extracts, coupled with molecular cloning of cDNAs and genes expressed within EECs has greatly expanded the complexity of EEC endocrinology, with implications for understanding the contribution of EECs to disease pathophysiology. EVIDENCE ACQUISITION: Pubmed searches identified manuscripts highlighting new concepts illuminating the molecular biology, classification and functional role(s) of EECs and their hormonal products. EVIDENCE SYNTHESIS: Molecular interrogation of EECs has been transformed over the past decade, raising multiple new questions that challenge historical concepts of EEC biology. Evidence for evolution of the EEC from a unihormonal cell type with classical endocrine actions, to a complex plurihormonal dynamic cell with pleiotropic interactive functional networks within the gastrointestinal mucosa is critically assessed. We discuss gaps in understanding how EECs sense and respond to nutrients, cytokines, toxins, pathogens, the microbiota, and the microbial metabolome, and highlight the expanding translational relevance of EECs in the pathophysiology and therapy of metabolic and inflammatory disorders. CONCLUSIONS: The EEC system represents the largest specialized endocrine network in human physiology, integrating environmental and nutrient cues, enabling neural and hormonal control of metabolic homeostasis. Updating EEC classification systems will enable more accurate comparative analyses of EEC subpopulations and endocrine networks in multiple regions of the gastrointestinal tract. PMID- 26649621 TI - Endometrial Expression of Estrogen Receptors and the Androgen Receptor in Women With Polycystic Ovary Syndrome: A Lifestyle Intervention Study. AB - CONTEXT: Polycystic ovary syndrome (PCOS) is a common cause of anovulation. It may also negatively affect the endometrium, which could lead to implantation failure and proliferative aberrations. OBJECTIVE: Our objective was to study sex hormone receptors in the endometrium of women with PCOS. DESIGN: This is a cross sectional study and lifestyle intervention. SETTING: Clinical and laboratory research unit was undertaken at a university hospital. PARTICIPANTS: Twenty overweight/obese women fulfilling all three PCOS criteria (anovulation, hyperandrogenism, and polycystic ovaries), 10 body mass index-matched regularly menstruating controls, 11 normal-weight women with PCOS, and 11 normal-weight controls. INTERVENTION: Intervention for this study included dietary management and physical exercise. MAIN OUTCOME MEASURES: mRNA levels and immunostaining of estrogen receptor alpha (ERalpha) and beta (ERbeta), nongenomic estrogen receptor alpha36 (ERalpha36), and G-protein-coupled estrogen receptor-1 (GPER), and the androgen receptor (AR) on cycle days 6-8 and cycle days 21-23. RESULTS: Before intervention, mRNA levels of ERalpha, ERalpha36, and the ERalpha/ERbeta mRNA ratio were lower in proliferative endometrium of overweight/obese PCOS women compared with controls (P < .05). After intervention, ERalpha protein and the ERalpha/ERbeta protein ratio in proliferative endometrium increased and were higher in PCOS women with improved menstrual function than in those without improvement (P < .05). In the subgroup of PCOS women with restored ovulation, only higher protein levels of GPER were found in secretory endometrium (P < .01). However, PCOS women who remained anovulatory had higher protein levels of ERalpha, GPER, and AR on cycle days 21-23 than controls (P < .05). CONCLUSIONS: Lifestyle intervention alters, but does not fully restore, ER and AR expression in proliferative and secretory endometrium of obese women with PCOS. PMID- 26649624 TI - Suppression of the low spatial frequency effects of scattered radiation in digital radiography. AB - One of the deleterious effects of scattered radiation in the digital radiograph is to add a slowly varying background to the image. This can reduce the ability of the observer to discern low contrast signals if the background gradient over a signal feature prevents the use of a small enough display window to make the signal visible. This paper presents an image processing scheme for suppressing the low spatial frequency effects of scattered radiation in digital radiography and demonstrates it on a range of clinical and phantom images. The approach relies on the approximate separation of high atomic number bony features from the low atomic number soft tissue background, and the use of forward convolution with a scatter kernel to produce an estimate of the scatter distribution arising from the soft tissue background. This is then scaled by an estimate of the soft tissue scatter fraction and subtracted from the original image to produce the final scatter-suppressed image. The implementation employs many approximations in order to make use of information that is readily available in the image headers of current x-ray imaging systems. The performance of the image processing scheme is demonstrated on phantom and clinical images. It is argued that clinical application of the approach could employ a user-controlled scatter subtraction step that would reduce any risk of misinterpretation of the processed image. PMID- 26649625 TI - A chiral lanthanide metal-organic framework for selective sensing of Fe(iii) ions. AB - A new luminescent lanthanide metal-organic framework was synthesized under hydrothermal conditions by introducing the tetracarboxylic acid ligand (H4bptc) as a chromophore to sensitize the luminescence of the Tb(3+) ion. Interestingly, despite the achiral nature of H4bptc, the resulting framework exhibited rare chiral helical channels. The luminescence studies revealed that this material showed a highly selective fluorescence quenching response to Fe(3+) ions in liquid suspension, which can be conveniently observed by the naked eye under UV light. Thus, this material can be potentially used as a chemosensor for sensing Fe(3+) ions and its selective luminescence quenching response can be explained in terms of the competitive absorption mechanism. PMID- 26649626 TI - Isolation of Viral Replication Compartment-enriched Sub-nuclear Fractions from Adenovirus-infected Normal Human Cells. AB - During infection of human cells by adenovirus (Ad), the host cell nucleus is dramatically reorganized, leading to formation of nuclear microenvironments through the recruitment of viral and cellular proteins to sites occupied by the viral genome. These sites, called replication compartments (RC), can be considered viral-induced nuclear domains where the viral genome is localized and viral and cellular proteins that participate in replication, transcription and post-transcriptional processing are recruited. Moreover, cellular proteins involved in the antiviral response, such as tumor suppressor proteins, DNA damage response (DDR) components and innate immune response factors are also co-opted to RC. Although RC seem to play a crucial role to promote an efficient and productive replication cycle, a detailed analysis of their composition and associated activities has not been made. To facilitate the study of adenoviral RC and potentially those from other DNA viruses that replicate in the cell nucleus, we adapted a simple procedure based on velocity gradients to isolate Ad RC and established a cell-free system amenable to conduct morphological, functional and compositional studies of these virus-induced subnuclear structures, as well as to study their impact on host-cell interactions. PMID- 26649627 TI - Field-directed assembly of nanowires: identifying directors, disruptors and indices to maximize the device yield. AB - Individually-addressable nano-electro-mechanical (NEMS) devices have been used to demonstrate sensitive mass detection to the single-proton level, as well as neutral-particle mass spectrometry. The cost of individually securing or patterning such devices is proportional to their number or the chip area covered. This limits statistical support for new research, as well as paths to the commercial availability of extraordinarily sensitive instruments. Field-directed assembly of synthesized nanowires addresses this problem and shows potential for low-cost, large-area coverage with NEMS devices. For positive dielectrophoresis (pDEP) as the main assembly director, the space of field, geometric and material parameters is large, with combinations that can serve either as directors or disruptors for directed assembly. We seek parameter values to obtain the best yield, by introducing a rational framework to reduce trial-and-error. We show that sorting the disruptors by severity and eliminating those weakly coupled to the director, allows reduction of the parameter space. The remaining disruptors are then represented compactly by dimensionless parameters. In the example protocol chosen, a single dimensionless parameter, the yield index, allows minimization of disruptors by the choice of frequency. Following this, the voltage may be selected to maximize the yield. Using this framework, we obtained 94% pre-clamped and 88% post-clamped yield over 57000 nanowire sites. Organizing the parameter space using a director-disruptor framework, with economy introduced by non-dimensional parameters, provides a path to controllably decrease the effort and cost of manufacturing nanoscale devices. This should help in the commercialization of individually addressable nanodevices. PMID- 26649628 TI - Mediastinal Epithelioid Hemangioendothelioma. PMID- 26649630 TI - Dr. Alexopoulos Replies. PMID- 26649629 TI - Active Sites Implanted Carbon Cages in Core-Shell Architecture: Highly Active and Durable Electrocatalyst for Hydrogen Evolution Reaction. AB - Low efficiency and poor stability are two major challenges we encounter in the exploration of non-noble metal electrocatalysts for the hydrogen evolution reaction (HER) in both acidic and alkaline environment. Herein, the hybrid of cobalt encapsulated by N, B codoped ultrathin carbon cages (Co@BCN) is first introduced as a highly active and durable nonprecious metal electrocatalysts for HER, which is constructed by a bottom-up approach using metal organic frameworks (MOFs) as precursor and self-sacrificing template. The optimized catalyst exhibited remarkable electrocatalytic performance for hydrogen production from both both acidic and alkaline media. Stability investigation reveals the overcoating of carbon cages can effectively avoid the corrosion and oxidation of the catalyst under extreme acidic and alkaline environment. Electrochemical active surface area (EASA) evaluation and density functional theory (DFT) calculations revealed that the synergetic effect between the encapsulated cobalt nanoparticle and the N, B codoped carbon shell played the fundamental role in the superior HER catalytic performance. PMID- 26649631 TI - Drs. Leichsenring, Salzer, and Leibing Reply. PMID- 26649632 TI - Correction. PMID- 26649633 TI - Drs. Blazer and Wu Reply. PMID- 26649639 TI - Editor's Disclosures. PMID- 26649637 TI - The Interpersonal Theory of Suicide: Guidance for Working With Suicidal Clientsby Joiner Thomas E. Jr. , Van Orden Kimberly A. , Witte Tracy K. , and Rudd M. David . Washington, D.C. , American Psychological Association , 2009 , 246 pp., $59.95. PMID- 26649641 TI - Biomarkers of oxidative-stress and inflammation in exhaled breath condensate from hospital cleaners. AB - OBJECTIVE: We studied the impact of chlorinated agents exposure on exhaled breath condensate (EBC) biomarkers in cleaners. METHODS: Malondialdehyde (MDA), 4 hydroxynonenal (4-HNE), nitrites (NO2(-)), nitrates (NO3(-)), pH, hydrogen peroxide (H2O2) and ammonium (NH3(+)) were tested in EBC of 40 cleaners and 40 non-exposed controls. Pentraxin-3 (PTX3) and soluble type II receptor of IL-1 (sIL-1RII) were analyzed also in plasma. RESULTS: Levels of MDA-EBC, 4-HNE-EBC and NO3(-)-EBC were higher, while pH-EBC values were lower, in cleaners. MDA-EBC was associated with 4-HNE-EBC, NO3(-)-EBC and pH. 4-HNE-EBC correlated with PTX3. CONCLUSION: Professional exposure to chlorinated agents increases EBC biomarkers of oxidative stress and inflammation. PMID- 26649642 TI - Interactions and Toxicity of Cu-Zn mixtures to Hordeum vulgare in Different Soils Can Be Rationalized with Bioavailability-Based Prediction Models. AB - Soil contamination with copper (Cu) is often associated with zinc (Zn), and the biological response to such mixed contamination is complex. Here, we investigated Cu and Zn mixture toxicity to Hordeum vulgare in three different soils, the premise being that the observed interactions are mainly due to effects on bioavailability. The toxic effect of Cu and Zn mixtures on seedling root elongation was more than additive (i.e., synergism) in soils with high and medium cation-exchange capacity (CEC) but less than additive (antagonism) in a low-CEC soil. This was found when we expressed the dose as the conventional total soil concentration. In contrast, antagonism was found in all soils when we expressed the dose as free-ion activities in soil solution, indicating that there is metal ion competition for binding to the plant roots. Neither a concentration addition nor an independent action model explained mixture effects, irrespective of the dose expressions. In contrast, a multimetal BLM model and a WHAM-Ftox model successfully explained the mixture effects across all soils and showed that bioavailability factors mainly explain the interactions in soils. The WHAM-Ftox model is a promising tool for the risk assessment of mixed-metal contamination in soils. PMID- 26649643 TI - Oxime Catalysis by Freezing. AB - Chemical reaction rates are generally decreased at lower temperatures. Here, we report that an oxime ligation reaction in water at neutral pH is accelerated by freezing. The freezing method and its rate effect on oxime ligation are systematically studied on a peptide model system, and applied to a larger chemokine protein, containing a single acetyl butyrate group, which is conjugated to an aminooxy-labeled ligand. Our improved ligation protocol now makes it possible to efficiently introduce oxime-bond coupled ligands into proteins under aqueous conditions at low concentrations and neutral pH. PMID- 26649644 TI - Non-canonical Stat3 signaling in cancer. AB - Stat3 is a member of the signal transducers and activators of transcription family and is a known regulator of essential biologic processes including angiogenesis, apoptosis, cell cycle progression, and cell migration. Canonical Stat3-mediated signaling involves tyrosine phosphorylation on specific residues that leads to homodimerization and translocation to the nucleus. For many years it was presumed that most, if not all, of the functions of Stat3, both normal and aberrant, were due to the canonical cytokine and growth factor signaling mechanisms. Recent studies suggest that Stat3 functions through alternate non canonical pathways to bring about some of these biological functions both in normal cells as well as during cancer development and progression. A number of studies have now shown that Stat3 has a function in mitochondria and that unphosphorylated Stat3 (uStat3) can also function as a transcription factor broadening the potential mechanisms involved in Stat3 action. In this review article, we discuss these two main non-canonical functions of Stat3 and their potential roles in oncogenesis. Given the many facets of Stat3 signaling, additional comprehensive investigations are required to fully understand the role of non-canonical Stat3 signaling in cancer and whether these pathways can be targeted for cancer prevention and treatment. (c) 2015 Wiley Periodicals, Inc. PMID- 26649645 TI - Relationship between menopausal hormone therapy and mortality after breast cancer The MARIEplus study, a prospective case cohort. AB - Cohort studies of breast cancer (BC) patients, but not of disease-free women at inclusion, have found menopausal hormone therapy (MHT) to be associated with decreased BC specific mortality (BCM). Here, the German population-based MARIEplus BC cohort was analyzed to further elucidate associations of prediagnostic MHT with BCM (and modification by tumor characteristics), recurrence, and secondarily with other cause and overall mortality. Enrolled 2002 2005, incident invasive BC cases (N = 3,321) were followed up for a median of 6.1 years. Cox proportional hazards models adjusted for tumor characteristics, mammography and lifestyle were applied. Compared with never users of MHT, current users at date of diagnosis had significantly lower BCM (Hazard ratio (HR) 0.72, 95% CI 0.53-0.97) and risk of recurrence (HR 0.61, 95% CI 0.46-0.82). The MHT related reduced BCM was confined to patients with low grade tumors (HR 0.44, 95% CI 0.28-0.70; phet = 0.01) and not modified by estrogen receptor or nodal status. BCM decreased with MHT duration in current and increased in past users (phet = 0.015). Mortality due to causes other than BC and overall mortality were also reduced in current MHT users (HR 0.51, 95% CI 0.32-0.81, HR 0.66, 95% CI 0.52-0.86, respectively). Favorable tumor characteristics and mammographic surveillance could not fully explain associations of current MHT use with BCM and recurrence risk. Thus, the study contributes to the evidence that prediagnostic MHT does not have a negative impact on prognosis after BC. The restriction of a reduced BCM to low grade tumors should be confirmed in independent studies. PMID- 26649647 TI - Elevated Whole-Blood Viscosity is Associated with Gallstones. AB - BACKGROUND Gallstones are associated with dyslipidemia, metabolic syndrome, hyperinsulinemia, and carotid intima-media thickness, which all are related to hyperviscosity. Therefore, this study aimed to examine the associations between blood viscosity and gallstones. MATERIAL AND METHODS We investigated the associations between blood viscosity and gallstones in a study conducted in middle-aged subjects. RESULTS Among 849 enrolled patients, 421 (49.6%) had gallstone disease. Compared with control subjects, whole-blood viscosity (WBV) levels were increased in patients with gallstones. The prevalence of gallstones increased as WBV (3 s-1) quartiles increased. Furthermore, logistic regression analysis showed that WBV (3 s-1) was associated with gallstone disease. CONCLUSIONS We found that whole-blood viscosity at low shear rate was independently associated with gallstones. Whether control of hyperviscosity would reduce the risk of developing gallstones deserves further investigation. PMID- 26649648 TI - On the Concept and Definition of Terrorism Risk. AB - In this article, we provide some reflections on how to define and understand the concept of terrorism risk in a professional risk assessment context. As a basis for this discussion we introduce a set of criteria that we believe should apply to any conceptualization of terrorism risk. These criteria are based on both criteria used in other areas of risk analysis and our experience with terrorism risk analysis. That is, these criteria offer our perspective. We show that several of the suggested perspectives and definitions have weaknesses in relation to these criteria. A main problem identified is the idea that terrorism risk can be conceptualized as a function of probability and consequence, not as a function of the interactions between adaptive individuals and organizations. We argue that perspectives based solely on probability and consequence should be used cautiously or not at all because they fail to reflect the essential features of the concept of terrorism risk, the threats and attacks, their consequences, and the uncertainties, all in the context of adaptation by the adversaries. These three elements should in our view constitute the main pillars of the terrorism risk concept. From this concept we can develop methods for assessing the risk by identifying a set of threats, attacks, and consequence measures associated with the possible outcome scenarios together with a description of the uncertainties and interactions between the adversaries. PMID- 26649646 TI - Methionine Sulfoxide Reductase B3-Targeted In Utero Gene Therapy Rescues Hearing Function in a Mouse Model of Congenital Sensorineural Hearing Loss. AB - AIMS: Methionine sulfoxide reductase B3 (MsrB3), which stereospecifically repairs methionine-R-sulfoxide, is an important Msr protein that is associated with auditory function in mammals. MsrB3 deficiency leads to profound congenital hearing loss due to the degeneration of stereociliary bundles and the apoptotic death of cochlear hair cells. In this study, we investigated a fundamental treatment strategy in an MsrB3 deficiency mouse model and confirmed the biological significance of MsrB3 in the inner ear using MsrB3 knockout (MsrB3(-/ )) mice. RESULTS: We delivered a recombinant adeno-associated virus encoding the MsrB3 gene directly into the otocyst at embryonic day 12.5 using a transuterine approach. We observed hearing recovery in the treated ears of MsrB3(-/-) mice at postnatal day 28, and we confirmed MsrB3 mRNA and protein expression in cochlear extracts. Additionally, we demonstrated that the morphology of the stereociliary bundles in the rescued ears of MsrB3(-/-) mice was similar to those in MsrB3(+/+) mice. INNOVATION: To our knowledge, this is the first study to demonstrate functional and morphological rescue of the hair cells of the inner ear in the MsrB3 deficiency mouse model of congenital genetic sensorineural hearing loss using an in utero, virus-mediated gene therapy approach. CONCLUSION: Our results provide insight into the role of MsrB3 in hearing function and bring us one step closer to hearing restoration as a fundamental therapy. PMID- 26649650 TI - Chronic rhinosinusitis identification in administrative databases and health surveys: A systematic review. AB - OBJECTIVES/HYPOTHESIS: Much of the epidemiological data on chronic rhinosinusitis (CRS) are based on large administrative databases and health surveys. The accuracy of CRS identification with these methods is unknown. METHODS: A systematic review was performed to identify studies that measured the accuracy of CRS diagnoses in large administrative databases or within health surveys. The Quality Assessment of Diagnostic Accuracy Studies 2 tool was used to assess study quality. RESULTS: Of 512 abstracts initially identified, 122 were selected for full-text review; only three studies (2.5%) measured the accuracy of CRS patient identification. In a single, large administrative database study with a CRS prevalence of 54.8%, a single International Classification of Diseases-9th Revision diagnostic code for CRS had a positive predictive value (PPV) of only 34%. A diagnostic code algorithm identified CRS patients with a PPV of 91.3% (95% confidence interval [CI], 85.3-95.1); in a population with a CRS prevalence of 5%, this algorithm had a PPV of 31%. In health survey studies having an estimated CRS prevalence of 25% to 46%, self-reported symptom-based CRS diagnosis had a PPV of 62% (95% CI, 50.2-72.1) when nasal endoscopy was the gold standard for CRS diagnosis, and 70% (95% CI, 57.4-80.8) when otolaryngologist-based CRS diagnosis (after interview and nasal endoscopy) was the gold standard. CONCLUSION: Most health administrative data and health surveys examining CRS did not consider the accuracy of case identification. For unselected populations, administrative data and health surveys using self-reported diagnoses inaccurately identify patients with CRS. Epidemiological results based on such data should be interpreted with these results in mind. Laryngoscope, 126:1303-1310, 2016. PMID- 26649649 TI - Quantification of Protein-Induced Membrane Remodeling Kinetics In Vitro with Lipid Multilayer Gratings. AB - The dynamic self-organization of lipids in biological systems is a highly regulated process that enables the compartmentalization of living systems at micro- and nanoscopic scales. Consequently, quantitative methods for assaying the kinetics of supramolecular remodeling such as vesicle formation from planar lipid bilayers or multilayers are needed to understand cellular self-organization. Here, a new nanotechnology-based method for quantitative measurements of lipid protein interactions is presented and its suitability for quantifying the membrane binding, inflation, and budding activity of the membrane-remodeling protein Sar1 is demonstrated. Lipid multilayer gratings are printed onto surfaces using nanointaglio and exposed to Sar1, resulting in the inflation of lipid multilayers into unilamellar structures, which can be observed in a label-free manner by monitoring the diffracted light. Local variations in lipid multilayer volume on the surface is used to vary substrate availability in a microarray format. A quantitative model is developed that allows quantification of binding affinity (K D ) and kinetics (kon and koff ). Importantly, this assay is uniquely capable of quantifying membrane remodeling. Upon Sar1-induced inflation of single bilayers from surface supported multilayers, the semicylindrical grating lines are observed to remodel into semispherical buds when a critical radius of curvature is reached. PMID- 26649652 TI - Dispersal limitation drives successional pathways in Central Siberian forests under current and intensified fire regimes. AB - Fire is a primary driver of boreal forest dynamics. Intensifying fire regimes due to climate change may cause a shift in boreal forest composition toward reduced dominance of conifers and greater abundance of deciduous hardwoods, with potential biogeochemical and biophysical feedbacks to regional and global climate. This shift has already been observed in some North American boreal forests and has been attributed to changes in site conditions. However, it is unknown if the mechanisms controlling fire-induced changes in deciduous hardwood cover are similar among different boreal forests, which differ in the ecological traits of the dominant tree species. To better understand the consequences of intensifying fire regimes in boreal forests, we studied postfire regeneration in five burns in the Central Siberian dark taiga, a vast but poorly studied boreal region. We combined field measurements, dendrochronological analysis, and seed source maps derived from high-resolution satellite images to quantify the importance of site conditions (e.g., organic layer depth) vs. seed availability in shaping postfire regeneration. We show that dispersal limitation of evergreen conifers was the main factor determining postfire regeneration composition and density. Site conditions had significant but weaker effects. We used information on postfire regeneration to develop a classification scheme for successional pathways, representing the dominance of deciduous hardwoods vs. evergreen conifers at different successional stages. We estimated the spatial distribution of different successional pathways under alternative fire regime scenarios. Under intensified fire regimes, dispersal limitation of evergreen conifers is predicted to become more severe, primarily due to reduced abundance of surviving seed sources within burned areas. Increased dispersal limitation of evergreen conifers, in turn, is predicted to increase the prevalence of successional pathways dominated by deciduous hardwoods. The likely fire-induced shift toward greater deciduous hardwood cover may affect climate-vegetation feedbacks via surface albedo, Bowen ratio, and carbon cycling. PMID- 26649654 TI - Global collaboration bears fruit: Tanzania report. PMID- 26649651 TI - First generation versus second generation drug-eluting stents for the treatment of bifurcations: 5-year follow-up of the LEADERS all-comers randomized trial. AB - BACKGROUND: Historically, percutaneous coronary intervention (PCI) of bifurcation lesions was associated with worse procedural and clinical outcomes when compared with PCI of non-bifurcation lesions. Newer generation drug-eluting stents (DES) might improve long-term clinical outcomes after bifurcation PCI. METHODS AND RESULTS: The LEADERS trial was a 10-center, assessor-blind, non-inferiority, all comers trial, randomizing 1,707 patients to treatment with a biolimus A9(TM) eluting stent (BES) with an abluminal biodegradable polymer or a sirolimus eluting stent (SES) with a durable polymer (ClinicalTrials.gov Identifier: NCT00389220). Five-year clinical outcomes were compared between patients with and without bifurcation lesions and between BES and SES in the bifurcation lesion subgroup. There were 497 (29%) patients with at least 1 bifurcation lesion (BES = 258; SES = 239). At 5-year follow-up, the composite endpoint of cardiac death, myocardial infarction (MI) and clinically-indicated (CI) target vessel revascularization (TVR) was observed more frequently in the bifurcation group (26.6% vs. 22.4%, P = 0.049). Within the bifurcation lesion subgroup, no differences were observed in (cardiac) death or MI rates between BES and SES. However, CI target lesion revascularization (TLR) (10.1% vs. 15.9%, P = 0.0495), and CI TVR (12.0% vs. 19.2%, P = 0.023) rates were significantly lower in the BES group. Definite/probable stent thrombosis (ST) rate was numerically lower in the BES group (3.1% vs. 5.9%, P = 0.15). Very late (>1 year) definite/probable ST rates trended to be lower with BES (0.4% vs. 3.1%, P = 0.057). CONCLUSIONS: In the treatment of bifurcation lesions, use of BES led to superior long-term efficacy compared with SES. Safety outcomes were comparable between BES and SES, with an observed trend toward a lower rate of very late definite/probable ST between 1 and 5 years with the BES. (c) 2015 Wiley Periodicals, Inc. PMID- 26649656 TI - Reviving the promise of transcription factor Nrf2-based therapeutics for kidney diseases. AB - The transcription factor Nrf2 plays an important role in many kidney diseases from acute kidney injury to chronic kidney disease, and there have been preliminary Nrf2-based therapeutic trials in humans. Shelton et al. presents an integrated transcriptomic and proteomic analysis of mouse kidney to reveal Nrf2 targets with potentially important roles in kidney homeostasis and pathophysiology. These results can further our understanding of Nrf2-based mechanisms and help in the development of therapeutics for a wide range of kidney diseases. PMID- 26649657 TI - Driving change: kidney proximal tubule CSF-1 polarizes macrophages. AB - Macrophage colony-stimulating factor (CSF-1 or M-CSF) is important for kidney repair after acute kidney injury (AKI). CSF-1 is upregulated in tubule epithelial cells in response to kidney injury stimuli and binds to its sole receptor, CSF1R, in an autocrine and paracrine manner. Wang and colleagues used a genetic approach to constitutively delete Csf1 in proximal tubules to establish that proximal tubule production of CSF-1 is important for polarizing and skewing macrophages toward an M2 phenotype, and for recovery from AKI. PMID- 26649658 TI - Sclerostin levels in CKD patients: an important, but not definitive, step on the way to clinical use. AB - Sclerostin, an inhibitor of the Wnt signaling pathway, inhibits bone formation. In a study of vascular biopsies of patients undergoing kidney transplantation, Qureshi et al. demonstrate that circulating sclerostin levels are associated with vascular calcification (VC). This adds to an emerging body of literature implicating sclerostin as a key link between chronic kidney disease-mineral and bone disorder and cardiovascular disease. Some confounders of this association remain, and the mechanisms by which sclerostin promotes VC have yet to be elucidated. PMID- 26649659 TI - Chinese herbal medicines and chronic kidney disease: a positive outcome in a large patient study in Taiwan. AB - The worth of traditional Chinese herbal medicines for chronic kidney disease (CKD) patients remains in debate. Lin et al. used a research database in Taiwan to identify almost 25,000 stage 3-5 newly diagnosed CKD patients who, after diagnosis, did or did not use prescribed Chinese herbal medicines for CKD. Reduced risk of end-stage kidney disease from specific traditional medicines warrants reflection on a CKD therapy resource that is largely ignored by Western medicine. PMID- 26649660 TI - Finding the safe place between the hammer and the anvil: sounding the depth of therapeutic immunosuppression. AB - Transplanted organs express allogeneic epitopes against which a recipient's immune system mounts a destructive response. In the absence of a reliable strategy for induction of donor-specific tolerance, therapeutic immunosuppression remains the best prospect to prevent rejection, but exposes recipients to increased risks of infection and cancer. Defining the individual upper and lower limits between which the transplanted patient is safe requires the validation of biomarkers able to depth-sound the recipient's immune system. PMID- 26649661 TI - Proteinuria as a surrogate marker for renal outcome: are we there yet? AB - Observational studies in glomerular diseases suggest that proteinuria reduction translates to improved outcomes. Because of a dearth of high-quality studies supporting this association, proteinuria is not universally recognized as a surrogate end point. Barbour et al. report on the longitudinal measure of proteinuria that best predicts hard renal outcomes. Their finding that time varying proteinuria is the most reliable proteinuria metric is a necessary step in establishing proteinuria as a surrogate end point. PMID- 26649662 TI - Gut-kidney kaliuretic signaling: looking forward to feeding. AB - Preston et al. report urinary potassium excretion in healthy subjects in response to an acute potassium load with or without a meal. The investigators show a rapid kaliuretic response that occurs independently of the serum potassium and plasma aldosterone concentration, and that persists in the presence of a mineralocorticoid receptor blocker. This Commentary puts these data in perspective by reviewing the current understanding of the feedback and feedforward systems that regulate renal potassium excretion. PMID- 26649663 TI - Data confusion. PMID- 26649664 TI - New data on the safety of IV iron-but why the discrepancy with FIND-CKD? PMID- 26649665 TI - The Author Replies. PMID- 26649666 TI - A common gene signature in tolerance to renal allograft. PMID- 26649667 TI - The Author Replies. PMID- 26649668 TI - Overlap of ultrastructural findings in C3 glomerulonephritis and dense deposit disease. PMID- 26649669 TI - Can ultrasound kidney length qualify as an early predictor of progression to renal insufficiency in autosomal dominant polycystic kidney disease? PMID- 26649670 TI - Kidney stones are common after bariatric surgery. PMID- 26649671 TI - An animal model of glomerular light-chain-associated amyloidogenesis depicts the crucial role of lysosomes. PMID- 26649672 TI - Long-term risks for kidney donors. PMID- 26649673 TI - Bunches of grapes in renal polyarteritis nodosa. PMID- 26649674 TI - Polymicrobial peritonitis in a peritoneal dialysis patient. PMID- 26649677 TI - Migrated intra-jejunal peritoneal dialysis catheter. PMID- 26649676 TI - An unusual cause of allograft dysfunction. PMID- 26649678 TI - The Case | Azotemia without renal failure. PMID- 26649680 TI - Improvised Neonatal Care-Realizing the Gaps in a Disaster Zone. AB - The treatment of newborns in a disaster zone can be extremely challenging. The effects of the disaster combine with local health care disparity to give these neonates little chance of survival in the event of even minor complications. Rescue teams arriving at such locations must be prepared to handle and to aid these difficult situations using improvisation and ingenuity to overcome many of the unexpected hurdles. A discussion of the difficulties faced in the Philippines following a typhoon and recommendations for future teams are presented. PMID- 26649679 TI - Single exosome study reveals subpopulations distributed among cell lines with variability related to membrane content. AB - Current analysis of exosomes focuses primarily on bulk analysis, where exosome-to exosome variability cannot be assessed. In this study, we used Raman spectroscopy to study the chemical composition of single exosomes. We measured spectra of individual exosomes from 8 cell lines. Cell-line-averaged spectra varied considerably, reflecting the variation in total exosomal protein, lipid, genetic, and cytosolic content. Unexpectedly, single exosomes isolated from the same cell type also exhibited high spectral variability. Subsequent spectral analysis revealed clustering of single exosomes into 4 distinct groups that were not cell line specific. Each group contained exosomes from multiple cell lines, and most cell lines had exosomes in multiple groups. The differences between these groups are related to chemical differences primarily due to differing membrane composition. Through a principal components analysis, we identified that the major sources of spectral variation among the exosomes were in cholesterol content, relative expression of phospholipids to cholesterol, and surface protein expression. For example, exosomes derived from cancerous versus non-cancerous cell lines can be largely separated based on their relative expression of cholesterol and phospholipids. We are the first to indicate that exosome subpopulations are shared among cell types, suggesting distributed exosome functionality. The origins of these differences are likely related to the specific role of extracellular vesicle subpopulations in both normal cell function and carcinogenesis, and they may provide diagnostic potential at the single exosome level. PMID- 26649681 TI - Comparison of Skin Toxic Effects Associated With Gefitinib, Erlotinib, or Afatinib Treatment for Non-Small Cell Lung Cancer. PMID- 26649682 TI - Pseudotumoral hemicerebellitis as a mimicker of Lhermitte-Duclos disease in children: does neuroimaging help to differentiate them? AB - The clinical presentation and neuroimaging findings of children with pseudotumoral hemicerebellitis (PTHC) and Lhermitte-Duclos disease (LDD) may be very similar. The differentiation between these entities, however, is important because their management and prognosis are different. We report on three children with PTHC. For all three children, in the acute situation, the differentiation between PTHC and LDD was challenging. A review of the literature shows that a detailed evaluation of conventional and neuroimaging data may help to differentiate between these two entities. A striated folial pattern, brainstem involvement, and prominent veins surrounding the thickened cerebellar foliae on susceptibility weighted imaging favor LDD, while post-contrast enhancement and an increased choline peak on (1)H-Magnetic resonance spectroscopy suggest PTHC. PMID- 26649684 TI - Editorial. PMID- 26649683 TI - "This Is a Partnership Between All of Us": Audiologists' Perceptions of Family Member Involvement in Hearing Rehabilitation. AB - PURPOSE: The purpose of the study was to explore the perceptions of audiologists about the role of family members in hearing rehabilitation for older adults with hearing impairment (HI), the influence of family member involvement on outcomes, and factors affecting family members' involvement. METHOD: A qualitative descriptive research study was undertaken. Using a purposeful sampling strategy, 9 audiologists were recruited. Audiologists participated in individual semistructured interviews. Interview transcripts were analyzed using thematic analysis, and a process of member checking was used to enhance the trustworthiness of findings reported. RESULTS: The importance of promoting partnership emerged as the overarching theme. Audiologists valued promoting partnership with family members so that a shared understanding could be established, family members could be active participants with distinct roles in hearing rehabilitation, and the rehabilitation outcomes for the person with HI could be improved. Audiologists generally reported low attendance rates of family members to appointments and identified 5 major factors affecting family participation. CONCLUSIONS: There is growing recognition among audiologists of the importance of promoting partnership with family members during the hearing rehabilitation process. More research is needed to develop and evaluate a family centered model of hearing health care that considers the service-level barriers identified by audiologists in the present study. PMID- 26649685 TI - Introduction to the Forum. PMID- 26649687 TI - Editor's Report. PMID- 26649686 TI - Response to Katz and Tillery (2005), Musiek, Bellis, and Chermak (2005), and Rosen (2005). PMID- 26649697 TI - Acoustic Neuroma Case Review: An Audiologist's Self-Portrait. PMID- 26649727 TI - The Chemical Molecule B355252 is Neuroprotective in an In Vitro Model of Parkinson's Disease. AB - 6-Hydroxydopamine (6-OHDA) is a neurotoxin frequently used to create in vitro and in vivo experimental models of Parkinson's disease (PD), a chronic neurodegenerative disorder largely resulting from damage to the nigrostriatal dopaminergic pathway. No effective drugs or therapies have been developed for this devastating disorder, and current regimens of symptomatic therapeutics only alleviate symptoms temporarily. Therefore, effective treatments that reverse or cure this disorder are urgently needed. The aim of the study described in this report was to investigate the therapeutic impact of B355252, an aryl thiophene sulfonamide chemical entity, in the widely recognized in vitro model of PD, and to characterize the molecular signaling pathways. We show here that 6-OHDA induced cell death in HT22, a murine neuronal cell model, through a pathway that involves the mitochondria by increasing the levels of reactive oxygen species (ROS), raising intracellular calcium ([Ca(2+)]i), enhancing the release of cytochrome c to the cytosol, and promoting activation of stress-activated protein kinase/c-Jun NH2-terminal kinase (SAPK/JNK) signaling pathway. More importantly, we found that B355252 protected HT22 neurons against 6-OHDA toxin-induced neuronal cell death by significant attenuation of ROS production, blocking of mitochondrial depolarization, inhibition of cytochrome c release, sequestration of [Ca(2+)]i, modulation of JNK cascade, and strong inhibition of caspase 3/7 cleavage. Overall, this study demonstrates that death of neurons under toxic conditions characteristic of PD can be efficiently halted by B355252 and suggests that further development of the molecule could be potentially beneficial as a therapeutic prevention or treatment option for PD. PMID- 26649728 TI - Downregulation of lncRNA-MALAT1 Affects Proliferation and the Expression of Stemness Markers in Glioma Stem Cell Line SHG139S. AB - Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is among the most abundant and highly conserved lncRNAs, which has been detected in a wide variety of human tumors, including gastric cancer, gallbladder cancer, and so on. Previous research has showed that MALAT1 can activate LTBP3 gene in mesenchymal stem cells. However, the specific roles of MALAT1 in glioma stem cells (GSCs) remain unclear. In this study, we aimed to identify the effects of MALAT1 on proliferation and the expression of stemness markers on glioma stem cell line SHG139S. Our results showed that downregulation of MALAT1 suppressed the expression of Sox2 and Nestin which are related to stemness, while downregulation of MALAT1 promoted the proliferation in SHG139S. Further research on the underlying mechanism showed that the effects of MALAT1 downregulation on SHG139S were through regulating ERK/MAPk signaling activity. And we also found that downregulation of MALAT1 could activate ERK/MAPK signaling and promoted proliferation in SHG139 cells. These findings show that MALAT1 plays an important role in regulating the expression of stemness markers and proliferation of SHG139S, and provide a new research direction to target the progression of GSCs. PMID- 26649729 TI - Adipogenic Mesenchymal Stromal Cells from Bone Marrow and Their Hematopoietic Supportive Role: Towards Understanding the Permissive Marrow Microenvironment in Acute Myeloid Leukemia. AB - PURPOSE: The role of bone marrow-derived mesenchymal stem/stromal cells (MSCs) in creating a permissive microenvironment that supports the emergence and progression of acute myeloid leukemia (AML) is not well established. We investigated the extent to which adipogenic differentiation in normal MSCs alters hematopoietic supportive capacity and we undertook an in-depth comparative study of human bone marrow MSCs derived from newly diagnosed AML patients and healthy donors, including an assessment of adipogenic differentiation capacity. FINDINGS: MSCs from healthy controls with partial induction of adipogenic differentiation, in comparison to MSCs undergoing partial osteogenic differentiation, expressed increased levels of hematopoietic factors and induced greater proliferation, decreased quiescence and reduced in vitro hematopoietic colony forming capacity of CD34(+) hematopoietic stem and progenitor cells (HSPCs). Moreover, we observed that AML-derived MSCs had markedly increased adipogenic potential and delayed osteogenic differentiation, while maintaining normal morphology and viability. AML-derived MSCs, however, possessed reduced proliferative capacity and decreased frequency of subendothelial quiescent MSCs compared to controls. CONCLUSION: Our results support the notion of a bone marrow microenvironment characterized by increased propensity toward adipogenesis in AML, which may negatively impact normal hematopoiesis. Larger confirmatory studies are needed to understand the impact of various clinical factors. Novel leukemia treatments aimed at normalizing bone marrow niches may enhance the competitive advantage of normal hematopoietic progenitors over leukemia cells. PMID- 26649730 TI - Ethyl 3,4-dihydroxybenzoate (EDHB): a prolyl hydroxylase inhibitor attenuates acute hypobaric hypoxia mediated vascular leakage in brain. AB - Sudden exposure to altitude hypoxia is responsible for acute mountain sickness (AMS) in un-acclimatized persons. If not treated in time, AMS can worsen and leads to high altitude cerebral edema, which can be fatal. Present study explores the efficacy of ethyl 3,4-dihydroxybenzoate (EDHB), a prolyl hydroxylase enzyme inhibitor, in modulating adaptive responses to hypobaric hypoxia (HH) in rat brain. Male Sprague-Dawley rats treated with EDHB (75 mg/kg for 3 days), were subjected to acute HH exposure at 9144 m (30,000 ft) for 5 h. Animals were assessed for transvascular leakage and edema formation in brain and role of key inflammatory markers along with hypoxia responsive genes. HH stress increased transvascular permeability and edema formation in conjunction with upregulation of nuclear factor-kappaB (NF-kappaB) and its regulated proteins. There was surge in pro-inflammatory cytokines tumor necrosis factor-alpha, interleukin-6, interferon-gamma, monocyte chemoattractant protein-1 and decrement in anti inflammatory cytokine interleukin-10. Further, upregulation of vascular endothelial growth factor (VEGF), a vascular permeability marker and down regulation of antioxidant and anti-inflammatory proteins hemoxygenase (HO-1) and metallothionein (MT-1) was also observed under hypoxia. EDHB supplementation effectively scaled down HH induced cerebral edema with concomitant downregulation of brain NF-kappaB expression. There was significant curtailment of pro inflammatory cytokines and cell adhesion molecules. There was significant downregulation of permeability factor VEGF by EDHB with concomitant increment in hypoxia inducible factor (HIF1alpha) and anti-inflammatory proteins HO-1 and MT-1 compared to HH control thus accentuating the potential of EDHB as effective hypoxic preconditioning agent in ameliorating HH mediated injury in brain. PMID- 26649731 TI - Syndromic versus non-syndromic sporadic gastrin-producing neuroendocrine tumors of the duodenum: comparison of pathological features and biological behavior. AB - Sporadic gastrin-producing neuroendocrine tumors of the duodenum present either with the Zollinger-Ellison syndrome (ZES) or with unspecific symptoms. While syndromic gastrin-producing neuroendocrine tumors often show metastases at the time of diagnosis, those without a syndrome do not. The aim of the study was to search for clinicopathological features that may distinguish the two categories of gastrin-producing duodenal tumors. In a retrospective study, we analyzed the clinical and pathological data in a series of 41 patients with syndromic (i.e., gastrinomas) or non-syndromic duodenal gastrin-producing neuroendocrine tumors (ns-gas-NETs). Twenty-four (59 %) of the 41 patients had tumors that were associated with a ZES and were classified as gastrinomas. These tumors showed a higher Ki-67 index than that of the ns-gas-NETs (1.74 vs. 0.85 %, p = 0.012). In addition, they had more lymph node metastases (75 vs. 6 %, p < 0.001) and showed liver metastases and thus presented much more frequently in TNM stage >=III (75 vs. 6 %; p < 0.001) than their non-syndromic counterparts. Gastrinomas were removed surgically, ns-gas-NETs endoscopically. We did not observe any significant differences in overall survival or recurrence of disease. Duodenal gastrinomas show no clear morphological features that distinguish them from their non-syndromic counterparts. However, the patients with gastrinomas present in a more advanced stage of disease and need surgical treatment, while non-syndromic gastrin-producing duodenal NETs may be cured by complete endoscopical removal. PMID- 26649732 TI - Renal cell carcinoma with rhabdoid-like features lack intracytoplasmic inclusion bodies and show aggressive behavior. AB - In renal cell carcinoma (RCC), tumor cells with rhabdoid features are characterized by eccentric nuclei, prominent nucleoli, and eosinophilic cytoplasm with intracytoplasmic inclusion bodies. In RCC, tumor cells have also been observed resembling rhabdomyoblasts or rhabdoid but without intracytoplasmic inclusion bodies, and here, we defined these rhabdoid-like features of these cells. To this end, we studied a series of clear cell RCC (ccRCC) with rhabdoid features and compared them with a series of ccRCC with rhabdoid-like features to clarify the differences in the immunohistochemical profile and biological behavior. From 695 cases of ccRCC (80.8 % of all RCCs), 18 cases with rhabdoid features (2.1 % of all RCCs) and 25 cases with rhabdoid-like features (2.9 % of all RCCs) were investigated. The 5-year survival rate for ccRCC with rhabdoid features was 44.7 % and for ccRCC with rhabdoid-like features 30.3 %. Although ccRCC with rhabdoid features showed immunohistochemical co-expression of epithelial markers and vimentin as seen in malignant rhabdoid tumors, ccRCC with rhabdoid-like features showed no such co-expression. Multivariate analyses of cancer-specific survival revealed that perinephric tissues invasion was an independent prognostic factor in ccRCC with rhabdoid features (p = 0.0253) but not in ccRCC with rhabdoid-like features. In summary, although their prognosis is similar, the marker profile and pattern of extension of ccRCC with rhabdoid-like is different from that of ccRCC with rhabdoid features. Therefore, ccRCC with rhabdoid-like features should be distinguished from ccRCC with rhabdoid features. PMID- 26649733 TI - Intermediacy of a Persistent Urazole Radical and an Electrophilic Diazenium Species in the Acid-Catalyzed Reaction of MeTAD with Anisole. AB - The reaction of N-methyl-1,2,4-triazoline-3,5-dione (MeTAD) with anisole in the presence of trifluoroacetic acid affords unexpected disubstituted urazole products instead of the expected monosubstituted urazole as typically observed in the reactions of MeTAD with other substituted benzenes. Our investigation into the mechanism of formation of these disubstituted products suggests that MeTAD is capable of further reaction with the initially formed monosubstituted urazole to afford a persistent urazole radical. The identity of this radical has been established by UV-vis spectroscopy, the nature of its self-dimerization reaction, and via independent generation. Electrochemical oxidation of this radical was carried out, and the resulting diazenium ion was demonstrated to be reactive with added substituted benzenes, including anisole. When oxidation was carried out chemically using thianthrenium perchlorate in the presence of anisole it was shown to produce the same disubstituted products (and in the same ratio) as observed in the acid-catalyzed reaction. A common diazenium species is proposed to be active in both cases. We also report the synthesis and characterization of three interesting tetrazane dimers resulting from unstable urazole radicals. PMID- 26649734 TI - Plasmid-derived DNA Strand Displacement Gates for Implementing Chemical Reaction Networks. AB - DNA nanotechnology requires large amounts of highly pure DNA as an engineering material. Plasmid DNA could meet this need since it is replicated with high fidelity, is readily amplified through bacterial culture and can be stored indefinitely in the form of bacterial glycerol stocks. However, the double stranded nature of plasmid DNA has so far hindered its efficient use for construction of DNA nanostructures or devices that typically contain single stranded or branched domains. In recent work, it was found that nicked double stranded DNA (ndsDNA) strand displacement gates could be sourced from plasmid DNA. The following is a protocol that details how these ndsDNA gates can be efficiently encoded in plasmids and can be derived from the plasmids through a small number of enzymatic processing steps. Also given is a protocol for testing ndsDNA gates using fluorescence kinetics measurements. NdsDNA gates can be used to implement arbitrary chemical reaction networks (CRNs) and thus provide a pathway towards the use of the CRN formalism as a prescriptive molecular programming language. To demonstrate this technology, a multi-step reaction cascade with catalytic kinetics is constructed. Further it is shown that plasmid derived components perform better than identical components assembled from synthetic DNA. PMID- 26649735 TI - Antibiotic resistance in urban aquatic environments: can it be controlled? AB - Over the last decade, numerous evidences have contributed to establish a link between the natural and human-impacted environments and the growing public health threat that is the antimicrobial resistance. In the environment, in particular in areas subjected to strong anthropogenic pressures, water plays a major role on the transformation and transport of contaminants including antibiotic residues, antibiotic-resistant bacteria, and antibiotic resistance genes. Therefore, the urban water cycle, comprising water abstraction, disinfection, and distribution for human consumption, and the collection, treatment, and delivery of wastewater to the environment, is a particularly interesting loop to track the fate of antibiotic resistance in the environment and to assess the risks of its transmission back to humans. In this article, the relevance of different transepts of the urban water cycle on the potential enrichment and spread of antibiotic resistance is reviewed. According to this analysis, some gaps of knowledge, research needs, and control measures are suggested. The critical rationale behind the measures suggested and the desirable involvement of some key action players is also discussed. PMID- 26649736 TI - A small periplasmic protein essential for Cytophaga hutchinsonii cellulose digestion. AB - Cytophaga hutchinsonii is a gliding cellulolytic bacterium that is ubiquitously distributed in soil. The mechanism by which C. hutchinsonii achieves cellulose digestion, however, is still largely unknown. In this study, we obtained a C. hutchinsonii mutant that was defective in utilizing filter paper or Avicel as the sole carbon source by transposon mutagenesis. The interrupted gene locus, CHU_2981, encodes a hypothetical protein with only 130 amino acids. Cell fractionation and western blot detection of CHU_2981 fused with a C-terminal green fluorescence protein (GFP) indicated that CHU_2981 is located in the periplasm. The CHU_2981-disrupted mutant cells exhibited a significant growth defect on Avicel but not on glucose and cellobiose. The absence of CHU_2981 also resulted in a significant defect in colony spreading and individual cell motility compared to wild-type cells. Further analysis demonstrated that the CHU_2981 disrupted mutant cells exhibited a different profile of cellulose-absorbed outer membrane proteins from that of wild-type cells, in which protein varieties and amounts were markedly decreased. Our results showed that CHU_2981, the periplasmic non-cellulolytic protein, plays an important role in both cellulose utilization and cell motility probably by being involved in the appropriate production of outer membrane proteins. PMID- 26649738 TI - [No medical malpractice despite injury of the sphincter muscle during transurethral electroresection]. PMID- 26649737 TI - Rye bran as fermentation matrix boosts in situ dextran production by Weissella confusa compared to wheat bran. AB - The consumption of fiber-rich foods such as cereal bran is highly recommended due to its beneficial health effects. Pre-fermentation of bran with lactic acid bacteria can be used to improve the otherwise impaired flavor and textural qualities of bran-rich products. These positive effects are attributed to enzymatic modification of bran components and the production of functional metabolites like organic acids and exopolysaccharides such as dextrans. The aim of this study was to investigate dextran production in wheat and rye bran by fermentation with two Weissella confusa strains. Bran raw materials were analyzed for their chemical compositions and mineral content. Microbial growth and acidification kinetics were determined from the fermentations. Both strains produced more dextran in rye bran in which the fermentation-induced acidification was slower and the acidification lag phase longer than in wheat bran. Higher dextran production in rye bran is expected to be due to the longer period of optimal pH for dextran synthesis during fermentation. The starch content of wheat bran was higher, which may promote isomaltooligosaccharide formation at the expense of dextran production. W. confusa Cab3 produced slightly higher amounts of dextran than W. confusa VTT E-90392 in all raw materials. Fermentation with W. confusa Cab3 also resulted in lower residual fructose content which has technological relevance. The results indicate that wheat and particularly rye bran are promising matrices for producing technologically significant amounts of dextran, which facilitates the use of nutritionally valuable raw bran in food applications. PMID- 26649739 TI - [Reconstructive methods after Fournier gangrene]. AB - BACKGROUND: Fournier's gangrene is a variant of the necrotizing fasciitis restricted to the perineal and genital region. It presents as an acute life threatening disease and demands rapid surgical debridement, resulting in large soft tissue defects. Various reconstructive methods have to be applied to reconstitute functionality and aesthetics. The objective of this work is to identify different reconstructive methods in the literature and compare them to our current concepts for reconstructing defects caused by Fournier gangrene. METHODS: Analysis of the current literature and our reconstructive methods on Fournier gangrene. RESULTS: The Fournier gangrene is an emergency requiring rapid, calculated antibiotic treatment and radical surgical debridement. After the acute phase of the disease, appropriate reconstructive methods are indicated. The planning of the reconstruction of the defect depends on many factors, especially functional and aesthetic demands. Scrotal reconstruction requires a higher aesthetic and functional reconstructive degree than perineal cutaneous wounds. In general, thorough wound hygiene, proper pre-operative planning, and careful consideration of the patient's demands are essential for successful reconstruction. CONCLUSIONS: In the literature, various methods for reconstruction after Fournier gangrene are described. Reconstruction with a flap is required for a good functional result in complex regions as the scrotum and penis, while cutaneous wounds can be managed through skin grafting. Patient compliance and tissue demand are crucial factors in the decision-making process. PMID- 26649740 TI - The hidden economic burden of air pollution-related morbidity: evidence from the Aphekom project. AB - Public decision-makers commonly use health impact assessments (HIA) to quantify the impacts of various regulation policies. However, standard HIAs do not consider that chronic diseases (CDs) can be both caused and exacerbated by a common factor, and generally focus on exacerbations. As an illustration, exposure to near road traffic-related pollution (NRTP) may affect the onset of CDs, and general ambient or urban background air pollution (BP) may exacerbate these CDs. We propose a comprehensive HIA that explicitly accounts for both the acute effects and the long-term effects, making it possible to compute the overall burden of disease attributable to air pollution. A case study applies the two HIA methods to two CDs-asthma in children and coronary heart disease (CHD) in adults over 65-for ten European cities, totaling 1.89 million 0-17-year-old children and 1.85 million adults aged 65 and over. We compare the current health effects with those that might, hypothetically, be obtained if exposure to NRTP was equally low for those living close to busy roads as it is for those living farther away, and if annual mean concentrations of both PM10 and NO2-taken as markers of general urban air pollution-were no higher than 20 MUg/m3. Returning an assessment of ? 0.55 million (95 % CI 0-0.95), the HIA based on acute effects alone accounts for only about 6.2 % of the annual hospitalization burden computed with the comprehensive method [? 8.81 million (95 % CI 3-14.4)], and for about 0.15 % of the overall economic burden of air pollution-related CDs [? 370 million (95 % CI 106-592)]. Morbidity effects thus impact the health system more directly and strongly than previously believed. These findings may clarify the full extent of benefits from any public health or environmental policy involving CDs due to and exacerbated by a common factor. PMID- 26649741 TI - A Randomized, Phase I Study to Assess the Safety, Tolerability and Pharmacokinetics of Ceftazidime-Avibactam in Healthy Chinese Subjects. AB - BACKGROUND: Avibactam is a non-beta-lactam beta-lactamase inhibitor that restores the in vitro activity of beta-lactams, such as ceftazidime, against bacterial pathogens harboring Ambler class A, C, and some class D beta-lactamases. OBJECTIVE: This randomized, double-blind, placebo-controlled, phase I study (NCT01920399) evaluated the safety, tolerability, and pharmacokinetics of single and repeated doses of avibactam and ceftazidime in healthy Chinese subjects. METHODS: Sixteen healthy Chinese males aged 18-45 years were randomized 3:1 to receive 2000 mg ceftazidime and 500 mg avibactam (n = 12) or matched placebo (n = 4) as a 120-min intravenous infusion, once on Days 1 and 9, and every 8 h on Days 2-8. RESULTS: Avibactam and ceftazidime showed time-independent pharmacokinetics. Plasma exposure to avibactam and ceftazidime was similar following single and multiple dosing and accumulation of either agent was negligible. The majority of the avibactam and ceftazidime dose was recovered in urine. Adverse events were reported in three subjects (25.0%) in the ceftazidime-avibactam group and one subject (25.0%) in the placebo group. Two subjects in the ceftazidime-avibactam group had elevations in transaminases and one subject in the placebo group had elevated serum bilirubin levels that were considered causally related to study treatment. All adverse events were of mild intensity. CONCLUSIONS: Single and multiple doses of 2000 mg ceftazidime and 500 mg avibactam were well tolerated in healthy Chinese subjects, and the observed pharmacokinetics were comparable to previous studies conducted in Western subjects. PMID- 26649742 TI - Domperidone and Risk of Ventricular Arrhythmia and Cardiac Death: A Systematic Review and Meta-analysis. AB - BACKGROUND AND OBJECTIVE: Domperidone is a drug used globally for relieving nausea and vomiting and stimulating breast milk production. Several case reports and studies linked domperidone usage with major cardiovascular adverse events (cardiac arrhythmia and sudden cardiac death). However, multiple randomized controlled efficacy studies failed to detect such adverse events. Our objectives were to systematically review and meta-analyze the association between current domperidone exposure and cardiovascular adverse events. METHODS: The first author performed EMBASE, PubMed and Scopus searches to identify human studies assessing the association between current domperidone exposure and cardiac arrhythmia or sudden death. Thirteen related articles were identified and the first and second authors independently reviewed the articles. Six studies were included in the final analysis. Meta-analysis was performed with a random effect model using the inverse variance approach. Heterogeneity was evaluated using the Q statistic and I(2) test. RESULTS: Five case-control studies and one case-crossover study were included in this meta-analysis. Pooled risk estimates demonstrated that the current use of domperidone increased the risk of ventricular arrhythmia and sudden cardiac death (pooled adjusted odds ratio = 1.70; 95% confidence interval 1.47-1.97; I(2) = 0%). The I(2) test showed that the underlying population was homogeneous. CONCLUSIONS: Evidence from this meta-analysis suggests that current domperidone use increases the risk of cardiac arrhythmia and sudden cardiac death by 70%. Domperidone usage in older populations should be discouraged. Larger observational studies or randomized controlled trials are needed to confirm the findings of this analysis. PMID- 26649743 TI - Relationship Quality Buffers Association Between Co-rumination and Depressive Symptoms Among First Year College Students. AB - Co-rumination, the tendency to dwell on negative events and feelings with a relationship partner, is an aspect of relationships that has been associated with socioemotional adjustment tradeoffs and is found to be associated with depressive symptoms. However, depending on the context in which it occurs, co-rumination is not necessarily associated with detriments to mental well-being. Differences in relationship quality within certain relationships may explain why co-rumination is not always associated with depressive symptoms. In the current study, we utilized self-report measures in an ethnically diverse sample (53.5 % non-White) of 307 first term college students (65 % female) in order to elucidate how co rumination between roommates may be associated with depressive symptoms. We found that the association between co-rumination and depressive symptoms was moderated by relationship quality such that co-rumination in a high quality relationship was not associated with depressive symptoms whereas the opposite was true in low quality relationships. Moreover, we found moderated mediation, such that the variance in the association between co-rumination and depressive symptoms was explained via self-esteem, but only for those co-ruminating within a low quality relationship. These results suggest that relationship quality may impact the extent to which co-rumination is associated with depressive symptoms among first year college students. PMID- 26649744 TI - Direct Aggression and Generalized Anxiety in Adolescence: Heterogeneity in Development and Intra-Individual Change. AB - Co-occurrence of aggression and anxiety might change during adolescence, or stay stable. We studied change and stability of four types of co-occurrence regarding direct aggression and anxiety in adolescence: an anxious and non-aggressive type, an aggressive and non-anxious type, a comorbid aggressive-anxious type and a no problems type. We applied a person-centered approach to assess increases and decreases of these types, and tested various models of intra-individual change of the types: the stability, acting out and failure models. We used data from a five wave study of 923 early-to-middle and 390 middle-to-late adolescents (48.5 % male), thereby covering the ages of 12-20. We observed accelerated development in the older cohort: adolescents tended to grow faster out of the aggressive types in middle-to-late adolescence than in early-to-middle adolescence. We observed one other group-dependent pattern of heterogeneity in development, namely "gender differentiation": gender differences in aggression and generalized anxiety became stronger over time. We found support for two perspectives on intra-individual change of the four types, namely the stability and the acting out perspective. The no problems--and to a lesser extent the anxious--type proved to be stable across time. Acting out was found in early-to-middle adolescents, males, and adolescents with poorer-quality friendships. In all three groups, there were substantial transitions from the anxious type to the aggressive type during 4 years (between 20 and 41 %). Remarkably, acting out was most prevalent in subgroups that, generally speaking, are more vulnerable for aggressive behavior, namely early-to-middle adolescents and males. We interpret acting out as the attempt of adolescents to switch from anxiety to instrumental aggression, in order to become more visible and obtain an autonomous position in the adolescent world. Acting out contributed to the explanation of accelerated development and gender differentiation. We also observed an increase of adolescents with no problems. These findings highlight that the co-occurrence of aggression and anxiety changes considerably during adolescence, but also that the anxious and no problems types are quite stable in this period. PMID- 26649745 TI - Osteological and Soft-Tissue Evidence for Pneumatization in the Cervical Column of the Ostrich (Struthio camelus) and Observations on the Vertebral Columns of Non-Volant, Semi-Volant and Semi-Aquatic Birds. AB - Postcranial skeletal pneumaticity (PSP) is a condition most notably found in birds, but that is also present in other saurischian dinosaurs and pterosaurs. In birds, skeletal pneumatization occurs where bones are penetrated by pneumatic diverticula, membranous extensions that originate from air sacs that serve in the ventilation of the lung. Key questions that remain to be addressed include further characterizing (1) the skeletal features that can be used to infer the presence/absence and extent of PSP in birds and non-avian dinosaurs, and (2) the association between vertebral laminae and specific components of the avian respiratory system. Previous work has used vertebral features such as pneumatic foramina, fossae, and laminae to identify/infer the presence of air sacs and diverticula, and to discuss the range of possible functions of such features. Here, we tabulate pneumatic features in the vertebral column of 11 avian taxa, including the flightless ratites and selected members of semi-volant and semi aquatic Neornithes. We investigate the associations of these osteological features with each other and, in the case of Struthio camelus, with the specific presence of pneumatic diverticula. We find that the mere presence of vertebral laminae does not indicate the presence of skeletal pneumaticity, since laminae are not always associated with pneumatic foramina or fossae. Nevertheless, laminae are more strongly developed when adjacent to foramina or fossae. In addition, membranous air sac extensions and adjacent musculature share the same attachment points on the vertebrae, rendering the use of such features for reconstructing respiratory soft tissue features ambiguous. Finally, pneumatic diverticula attach to the margins of laminae, foramina, and/or fossae prior to their intraosseous course. Similarities in PSP distribution among the examined taxa are concordant with their phylogenetic interrelationships. The possible functions of PSP are discussed in brief, based upon variation in the extent of PSP between taxa with differing ecologies. PMID- 26649746 TI - Creating Two-Dimensional Electron Gas in Nonpolar/Nonpolar Oxide Interface via Polarization Discontinuity: First-Principles Analysis of CaZrO3/SrTiO3 Heterostructure. AB - We studied strain-induced polarization and resulting conductivity in the nonpolar/nonpolar CaZrO3/SrTiO3 (CZO/STO) heterostructure (HS) system by means of first-principles electronic structure calculations. By modeling four types of CZO/STO HS-based slab systems, i.e., TiO2/CaO and SrO/ZrO2 interface models with CaO and ZrO2 surface terminations in each model separately, we found that the lattice-mismatch-induced compressive strain leads to a strong polarization in the CZO film and that as the CZO film thickness increases there exists an insulator to-metal transition. The polarization direction and critical thickness of the CZO film for forming interfacial metallic states depend on the surface termination of CZO film in both types of interface models. In the TiO2/CaO and SrO/ZrO2 interface models with CaO surface termination, the strong polarization drives the charge transfer from the CZO film to the first few TiO2 layers in the STO substrate, leading to the formation of two-dimensional electron gas (2DEG) at the interface. In the HS models with ZrO2 surface termination, two polarization domains with opposite directions are in the CZO film, which results in the charge transfer from the middle CZO layer to the interface and surface, respectively, leading to the coexistence of the 2DEG on the interface and the two-dimensional hole gas (2DHG) at the middle CZO layer. These findings open a new avenue to achieve 2DEG (2DHG) in perovskite-based HS systems via polarization discontinuity. PMID- 26649747 TI - The Herbal Medicine KBH-1 Inhibits Fat Accumulation in 3T3-L1 Adipocytes and Reduces High Fat Diet-Induced Obesity through Regulation of the AMPK Pathway. AB - The aim of this study was to investigate whether a novel formulation of an herbal extract, KBH-1, has an inhibitory effect on obesity. To determine its anti obesity effects and its underlying mechanism, we performed anti-obesity-related experiments in vitro and in vivo. 3T3-L1 preadipocytes were analyzed for lipid accumulation as well as the protein and gene expression of molecular targets involved in fatty acid synthesis. To determine whether KBH-1 oral administration results in a reduction in high-fat diet (HFD)-induced obesity, we examined five groups (n = 9) of C57BL/6 mice as follows: 10% kcal fat diet-fed mice (ND), 60% kcal fat diet-fed mice (HFD), HFD-fed mice treated with orlistat (tetrahydrolipstatin, marketed under the trade name Xenical), HFD-fed mice treated with 150 mg/kg KBH-1 (KBH-1 150) and HFD-fed mice treated with 300 mg/kg KBH-1 (KBH-1 300). During adipogenesis of 3T3-L1 cells in vitro, KBH-1 significantly reduced lipid accumulation and down-regulated the expression of master adipogenic transcription factors, including CCAAT/enhancer binding protein (C/EBP) beta, C/EBP alpha and peroxisome proliferation-activity receptor (PPAR) gamma, which led to the suppression of the expression of several adipocyte specific genes and proteins. KBH-1 also markedly phosphorylated the adenosine monophosphate-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC). In addition, KBH-1-induced the inhibition effect on lipid accumulation and AMPK mediated signal activation were decreased by blocking AMPK phosphorylation using AMPK siRNA. Furthermore, daily oral administration of KBH-1 resulted in dose dependent decreases in body weight, fat pad mass and fat tissue size without systemic toxicity. These results suggest that KBH-1 inhibits lipid accumulation by down-regulating the major transcription factors of the adipogenesis pathway by regulating the AMPK pathway in 3T3-L1 adipocytes and in mice with HFD-induced obesity. These results implicate KBH-1, a safe herbal extract, as a potential anti-obesity therapeutic agent. PMID- 26649748 TI - Working with Human Tissues for Translational Cancer Research. AB - Medical research for human benefit is greatly impeded by the necessity for human tissues and subjects. However, upon obtaining consent for human specimens, precious samples must be handled with the greatest care in order to ensure integrity of organs, tissues, and cells to the highest degree. Unfortunately, tissue processing by definition requires extraction of tissues from the host, a change which can cause great cellular stress and have major repercussions on subsequent analyses. These stresses could result in the specimen being no longer representative of the site from which it was retrieved. Therefore, a strict protocol must be adhered to while processing these specimens to ensure representativeness. The desired assay(s) must also be taken into consideration in order to ensure that an optimal technique is used for sample processing. Outlined here is a protocol for tissue retrieval, processing and various analyses which may be performed on processed tissue in order to maximize downstream production from limited tissue samples. PMID- 26649749 TI - Finite Element Analysis of a New Pedicle Screw-Plate System for Minimally Invasive Transforaminal Lumbar Interbody Fusion. AB - PURPOSE: Minimally invasive transforaminal lumbar interbody fusion (MI-TLIF) is increasingly popular for the surgical treatment of degenerative lumbar disc diseases. The constructs intended for segmental stability are varied in MI-TLIF. We adopted finite element (FE) analysis to compare the stability after different construct fixations using interbody cage with posterior pedicle screw-rod or pedicle screw-plate instrumentation system. METHODS: A L3-S1 FE model was modified to simulate decompression and fusion at L4-L5 segment. Fixation modes included unilateral plate (UP), unilateral rod (UR), bilateral plate (BP), bilateral rod (BR) and UP+UR fixation. The inferior surface of the S1 vertebra remained immobilized throughout the load simulation, and a bending moment of 7.5 Nm with 400N pre-load was applied on the L3 vertebra to recreate flexion, extension, lateral bending, and axial rotation. Range of motion (ROM) and Von Mises stress were evaluated for intact and instrumentation models in all loading planes. RESULTS: All reconstructive conditions displayed decreased motion at L4 L5. The pedicle screw-plate system offered equal ROM to pedicle screw-rod system in unilateral or bilateral fixation modes respectively. Pedicle screw stresses for plate system were 2.2 times greater than those for rod system in left lateral bending under unilateral fixation. Stresses for plate were 3.1 times greater than those for rod in right axial rotation under bilateral fixation. Stresses on intervertebral graft for plate system were similar to rod system in unilateral and bilateral fixation modes respectively. Increased ROM and posterior instrumentation stresses were observed in all loading modes with unilateral fixation compared with bilateral fixation in both systems. CONCLUSIONS: Transforaminal lumbar interbody fusion augmentation with pedicle screw-plate system fixation increases fusion construct stability equally to the pedicle screw rod system. Increased posterior instrumentation stresses are observed in all loading modes with plate fixation, and bilateral fixation could reduce stress concentration. PMID- 26649750 TI - Hypoxia-Targeted Drug Q6 Induces G2-M Arrest and Apoptosis via Poisoning Topoisomerase II under Hypoxia. AB - In spite of the tremendous efforts dedicated to developing hypoxia-activated prodrugs, no agents yet have been approved for clinical therapy. In the present study, the hypoxic selective anti-cancer activity as well as the cellular target of a novel tirapazamine (TPZ) analogue, 7-methyl-3-(3-chlorophenyl)-quinoxaline-2 carbonitrile 1,4-dioxide (Q6) were investigated. Q6 implemented anti-cancer effects via poisoning topoisomerase II (topo II) under hypoxia. Modified trapped in agarose DNA immunostaining (TARDIS) assay showed more topo II-DNA cleavage complexes trapped by Q6 than TPZ at even lower concentration. In addition, by introducing ataxia-telangiectasia-mutated (ATM) kinase inhibitors caffeine and KU 60019, we displayed that Q6-triggered apoptosis was attributed, at least partially, to DNA double-strand breaks generated by the topo II-targeting effect. Collectively, Q6 stood out for its better hypoxia-selectivity and topo II poisoning than the parental compound TPZ. All these data shed light on the research of Q6 as a promising hypoxia-activated prodrug candidate for human hepatocellular carcinoma therapy. PMID- 26649751 TI - Improved Generation of Induced Cardiomyocytes Using a Polycistronic Construct Expressing Optimal Ratio of Gata4, Mef2c and Tbx5. AB - Direct conversion of cardiac fibroblasts (CFs) into induced cardiomyocytes (iCMs) holds great potential for regenerative medicine by offering alternative strategies for treatment of heart disease. This conversion has been achieved by forced expression of defined factors such as Gata4 (G), Mef2c (M) and Tbx5 (T). Traditionally, iCMs are generated by a cocktail of viruses expressing these individual factors. However, reprogramming efficiency is relatively low and most of the in vitro G,M,T-transduced fibroblasts do not become fully reprogrammed, making it difficult to study the reprogramming mechanisms. We recently have shown that the stoichiometry of G,M,T is crucial for efficient iCM reprogramming. An optimal stoichiometry of G,M,T with relative high level of M and low levels of G and T achieved by using our polycistronic MGT vector (hereafter referred to as MGT) significantly increased reprogramming efficiency and improved iCM quality in vitro. Here we provide a detailed description of the methodology used to generate iCMs with MGT construct from cardiac fibroblasts. Isolation of cardiac fibroblasts, generation of virus for reprogramming and evaluation of the reprogramming process are also included to provide a platform for efficient and reproducible generation of iCMs. PMID- 26649752 TI - Characterization and Visualization of Vesicles in the Endo-Lysosomal Pathway with Surface-Enhanced Raman Spectroscopy and Chemometrics. AB - Surface-enhanced Raman spectroscopy (SERS) is an ultrasensitive vibrational fingerprinting technique widely used in analytical and biosensing applications. For intracellular sensing, typically gold nanoparticles (AuNPs) are employed as transducers to enhance the otherwise weak Raman spectroscopy signals. Thus, the signature patterns of the molecular nanoenvironment around intracellular unlabeled AuNPs can be monitored in a reporter-free manner by SERS. The challenge of selectively identifying molecular changes resulting from cellular processes in large and multidimensional data sets and the lack of simple tools for extracting this information has resulted in limited characterization of fundamental cellular processes by SERS. Here, this shortcoming in analysis of SERS data sets is tackled by developing a suitable methodology of reference-based PCA-LDA (principal component analysis-linear discriminant analysis). This method is validated and exemplarily used to extract spectral features characteristic of the endocytic compartment inside cells. The voluntary uptake through vesicular endocytosis is widely used for the internalization of AuNPs into cells, but the characterization of the individual stages of this pathway has not been carried out. Herein, we use reporter-free SERS to identify and visualize the stages of endocytosis of AuNPs in cells and map the molecular changes via the adaptation and advantageous use of chemometric methods in combination with tailored sample preparation. Thus, our study demonstrates the capabilities of reporter-free SERS for intracellular analysis and its ability to provide a way of characterizing intracellular composition. The developed analytical approach is generic and enables the application of reporter-free SERS to identify unknown components in different biological matrices and materials. PMID- 26649753 TI - Mesenchymal Stem Cells Obtained from Synovial Fluid Mesenchymal Stem Cell-Derived Induced Pluripotent Stem Cells on a Matrigel Coating Exhibited Enhanced Proliferation and Differentiation Potential. AB - Induced pluripotent stem cell-derived mesenchymal stem cells (iPSC-MSCs) serve as a promising source for cell-based therapies in regenerative medicine. However, optimal methods for transforming iPSCs into MSCs and the characteristics of iPSC MSCs obtained from different methods remain poorly understood. In this study, we developed a one-step method for obtaining iPSC-MSCs (CD146+STRO-1+ MSCs) from human synovial fluid MSC-derived induced iPSCs (SFMSC-iPSCs). CD146-STRO-1-SFMSCs were reprogrammed into iPSCs by transduction with lentivirus-mediated Sox2, Oct 3/4, klf4, and c-Myc. SFMSC-iPSCs were maintained with mTeSR1 medium in Matrigel coated culture plates. Single dissociated cells were obtained by digesting the SFMSC-iPSCs with trypsin. The dissociated cells were then plated into Matrigel coated culture plate with alpha minimum essential medium supplemented with 10% fetal bovine serum, 1* Glutamax, and the ROCK inhibitor Y-27632. Cells were then passaged in standard cell culture plates with alpha minimum essential medium supplemented with 10% fetal bovine serum and 1* Glutamax. After passaging in vitro, the cells showed a homogenous spindle-shape similar to their ancestor cells (SFMSCs), but with more robust proliferative activity. Flow cytometric analysis revealed typical MSC surface markers, including expression of CD73, CD90, CD105, and CD44 and lack of CD45, CD34, CD11b, CD19, and HLA-DR. However, these cells were positive for CD146 and stro-1, which the ancestor cells were not. Moreover, the cells could also be induced to differentiate in osteogenic, chondrogenic, and adipogenic lineages in vitro. The differentiation potential was improved compared with the ancestor cells in vitro. The cells were not found to exhibit oncogenicity in vivo. Therefore, the method presented herein facilitated the generation of STRO-1+CD146+ MSCs from SFMSC-iPSCs exhibiting enhanced proliferation and differentiation potential. PMID- 26649754 TI - Maternal Occupational Exposure to Noise during Pregnancy and Hearing Dysfunction in Children: A Nationwide Prospective Cohort Study in Sweden. AB - BACKGROUND: Many women of childbearing age are occupationally active, which leads to a large number of pregnancies potentially exposed to occupational exposures. Occupational noise has been identified as a risk factor for hearing impairment in adults. However, very few studies have assessed the effect of occupational noise on the fetus. OBJECTIVES: The aim of this study was to investigate whether occupational exposure to noise during pregnancy is associated with hearing dysfunction in children. METHODS: This population based cohort study included 1,422,333 single births in Sweden 1986-2008. Data on mothers' occupation, smoking habits, age, ethnicity, body mass index, leave of absence, and socioeconomic factors were obtained from interviews performed by prenatal care unit staff at approximately 10 weeks of gestation and from national registers. Occupational noise exposure was classified by a job-exposure-matrix as < 75, 75-84, or >= 85 dBLAeq,8h. Diagnosed cases of hearing dysfunction (ICD-10 codes H90.3-7, 91.0, 91.2-3, 91.8, 93.1-2) were identified from a register of specialized medical care. Cox proportional hazards models were used to estimate associations. RESULTS: In the full sample, containing a mixture of part-time and full-time workers during pregnancy, the adjusted HR for hearing dysfunction associated with maternal occupational noise exposure >= 85 vs. < 75 dBLAeq,8h was 1.27 (95% CI: 0.99, 1.64; 60 exposed cases). When restricted to children whose mothers worked full-time and had < 20 days leave of absence during pregnancy, the corresponding HR was 1.82 (95% CI: 1.08, 3.08; 14 exposed cases). CONCLUSIONS: This study showed an association between occupational noise exposure during pregnancy and hearing dysfunction in children. In view of mechanistic evidence and earlier indicative epidemiological and experimental findings, the results support that pregnant women should not be exposed to high levels of noise at work. CITATION: Selander J, Albin M, Rosenhall U, Rylander L, Lewne M, Gustavsson P. 2016. Maternal occupational exposure to noise during pregnancy and hearing dysfunction in children: a nationwide prospective cohort study in Sweden. Environ Health Perspect 124:855-860; http://dx.doi.org/10.1289/ehp.1509874. PMID- 26649755 TI - An epigenetic toolkit allows for diverse genome architectures in eukaryotes. AB - Genome architecture varies considerably among eukaryotes in terms of both size and structure (e.g. distribution of sequences within the genome, elimination of DNA during formation of somatic nuclei). The diversity in eukaryotic genome architectures and the dynamic processes are only possible due to the well developed epigenetic toolkit, which probably existed in the Last Eukaryotic Common Ancestor (LECA). This toolkit may have arisen as a means of navigating the genomic conflict that arose from the expansion of transposable elements within the ancestral eukaryotic genome. This toolkit has been coopted to support the dynamic nature of genomes in lineages across the eukaryotic tree of life. Here we highlight how the changes in genome architecture in diverse eukaryotes are regulated by epigenetic processes, such as DNA elimination, genome rearrangements, and adaptive changes to genome architecture. The ability to epigenetically modify and regulate genomes has contributed greatly to the diversity of eukaryotes observed today. PMID- 26649757 TI - Importance of Hydrophilic Hydration and Intramolecular Interactions in the Thermodynamics of Helix-Coil Transition and Helix-Helix Assembly in a Deca Alanine Peptide. AB - For a model deca-alanine peptide the cavity (ideal hydrophobic) contribution to hydration favors the helix state over extended states and the paired helix bundle in the assembly of two helices. The energetic contributions of attractive protein solvent interactions are separated into quasi-chemical components consisting of a short-range part arising from interactions with solvent in the first hydration shell and the remaining long-range part that is well described by a Gaussian. In the helix-coil transition, short-range attractive protein-solvent interactions outweigh hydrophobic hydration and favor the extended coil states. Analysis of enthalpic effects shows that it is the favorable hydration of the peptide backbone that favors the unfolded state. Protein intramolecular interactions favor the helix state and are decisive in favoring folding. In the pairing of two helices, the cavity contribution outweighs the short-range attractive protein water interactions. However, long-range, protein-solvent attractive interactions can either enhance or reverse this trend depending on the mutual orientation of the helices. In helix-helix assembly, change in enthalpy arising from change in attractive protein-solvent interactions favors disassembly. In helix pairing as well, favorable protein intramolecular interactions are found to be as important as hydration effects. Overall, hydrophilic protein-solvent interactions and protein intramolecular interactions are found to play a significant role in the thermodynamics of folding and assembly in the system studied. PMID- 26649758 TI - Rational over-imitation: Preschoolers consider material costs and copy causally irrelevant actions selectively. AB - Children's strong tendency to over-imitate - i.e., to reproduce causally irrelevant actions - presents a well-documented, yet puzzling, phenomenon. On first sight this instrumentally inefficient behavior seems maladaptive and different accounts have been put forward to explain it. Causal accounts claim that children are misled by an adult's demonstration, mistake the superfluous actions as causally necessary, and therefore imitate them. Other accounts emphasize cognitive-motivational aspects underlying over-imitation, e.g. social motivations to affiliate with the model, or to adhere to normative conventions. Since all accounts predict the occurrence of over-imitation under typical conditions, different parameters and circumstances have to be considered to distinguish between them. Thus, we investigated children's over-imitation and their spontaneous verbal reactions to a puppet's behavior, in contexts in which a causally irrelevant action either led to the destruction of a valuable object belonging to the experimenter, or not. In addition, children saw the full action sequence being demonstrated either with an instrumental or a conventional focus. Causal accounts predict no flexibility across these contexts, because over imitation is said to occur automatically. Normative accounts claim that different normative considerations affect children's behavior and action parsing, and therefore predict different response patterns across conditions. We found that over-imitation was less frequent in costly and instrumental conditions. Children criticized the puppet for omitting irrelevant actions more often in the non costly condition, but criticized her more often for performing irrelevant actions in the costly condition, often expressing their moral concern. The results support the rational normative action interpretation account of over-imitation. PMID- 26649756 TI - Genomics and the making of yeast biodiversity. AB - Yeasts are unicellular fungi that do not form fruiting bodies. Although the yeast lifestyle has evolved multiple times, most known species belong to the subphylum Saccharomycotina (syn. Hemiascomycota, hereafter yeasts). This diverse group includes the premier eukaryotic model system, Saccharomyces cerevisiae; the common human commensal and opportunistic pathogen, Candida albicans; and over 1000 other known species (with more continuing to be discovered). Yeasts are found in every biome and continent and are more genetically diverse than angiosperms or chordates. Ease of culture, simple life cycles, and small genomes (~10-20Mbp) have made yeasts exceptional models for molecular genetics, biotechnology, and evolutionary genomics. Here we discuss recent developments in understanding the genomic underpinnings of the making of yeast biodiversity, comparing and contrasting natural and human-associated evolutionary processes. Only a tiny fraction of yeast biodiversity and metabolic capabilities has been tapped by industry and science. Expanding the taxonomic breadth of deep genomic investigations will further illuminate how genome function evolves to encode their diverse metabolisms and ecologies. PMID- 26649759 TI - Language familiarity modulates relative attention to the eyes and mouth of a talker. AB - We investigated whether the audiovisual speech cues available in a talker's mouth elicit greater attention when adults have to process speech in an unfamiliar language vs. a familiar language. Participants performed a speech-encoding task while watching and listening to videos of a talker in a familiar language (English) or an unfamiliar language (Spanish or Icelandic). Attention to the mouth increased in monolingual subjects in response to an unfamiliar language condition but did not in bilingual subjects when the task required speech processing. In the absence of an explicit speech-processing task, subjects attended equally to the eyes and mouth in response to both familiar and unfamiliar languages. Overall, these results demonstrate that language familiarity modulates selective attention to the redundant audiovisual speech cues in a talker's mouth in adults. When our findings are considered together with similar findings from infants, they suggest that this attentional strategy emerges very early in life. PMID- 26649760 TI - Intravitreal Injection--Technique and Safety. AB - Intravitreal (IVT) injection of therapeutic agents has become one of the most commonly performed procedures in ophthalmology. Over the past decade, a number of guidelines have been published that recommend proper techniques to increase the safety of IVT injections. Among the various complications of IVT injections, endophthalmitis can be sight threatening. The reported endophthalmitis rates after IVT injection range from 0.020% to 0.085%, which are higher than what would be expected from a simple, fast, and relatively atraumatic procedure. The 2 key issues involved in the prevention of endophthalmitis are pre-IVT injection disinfection using povidone-iodine (PVI) and the use of topical antibiotics as prophylaxis. Whereas 5% PVI for 5 minutes is most commonly used in cataract surgery for disinfection, the duration in IVT injection is much less and can be as short as 30 seconds. Further studies seem warranted to investigate whether longer duration of PVI application in IVT injection can lower the endophthalmitis rate. Recent data suggest that there is inadequate evidence to support the routine use of prophylactic pre-, peri-, or postinjection antibiotics to reduce the risk of endophthalmitis. However, as many confounding factors such as the PVI regimens were not standardized in previous studies, it is too soon to make a concrete conclusion. Despite the availability of published guidelines, considerable variations still exist in real-life clinical situations. In this article, we describe our IVT injection practice protocol and compare it with the most recent international guidelines. Finally, a summary table that shows the clinical features of true, sterile, and pseudoendophthalmitis is presented. PMID- 26649761 TI - Recent Clinical Applications of Laser Speckle Flowgraphy in Eyes with Retinal Disease. AB - Retinal diseases related to ischemia, such as diabetic retinopathy, are the main cause of blindness worldwide. However, the pathogenesis of these diseases remains unclear, as does the time course of associated changes in ocular blood flow. Laser speckle flowgraphy (LSFG), which uses the laser speckle phenomenon to detect and quantify ocular circulation, is a promising candidate for a noninvasive method to measure ocular blood flow in living eyes. A recently developed LSFG measurement parameter, mean blur rate (MBR), can serve as a quantitative and reproducible index of retinal blood cell velocity. Mean blur rate can be used in the study of retinal diseases to evaluate microcirculation in the retinal vessels, choroid, and optic nerve head. In addition to overall MBR (MA), LSFG measurements of optic nerve head microcirculation can be divided into vessel-area MBR (MV) and tissue-area MBR (MT). Absolute values for MT have been shown to be linearly correlated with capillary blood flow, regardless of fundus pigmentation. Recently, there has been an increasing number of reports on the clinical applications of LSFG in retinal disease. PMID- 26649762 TI - Optical Coherence Tomography in Cultivated Limbal Epithelial Stem Cell Transplantation Surgery. AB - PURPOSE: Cultivated limbal epithelial stem cell transplantation (CLET) is a surgical approach reserved for severe stem cell deficiency and anterior segment pathology. The recipient cornea typically displays a highly vascularized pannus that must be dissected before graft placement. Extensive pannus dissection, however, can result in corneal thinning and increase the risk of ectasia and ultimately, of perforation. We aimed to examine the value of anterior segment optical coherence tomography (AS-OCT) intraoperatively during pannus resection and long-term postoperative follow-up of CLET surgery. DESIGN: This was a prospective observational case series. METHODS: This study was performed on 8 eyes of 8 patients who underwent CLET surgery. Intraoperative OCT was performed before dissection and at several time points during dissection and after placement of the ex vivo cultivated graft. During the postoperative follow-up period, OCT was performed to image the graft integration and corneal thickness. RESULTS: Anterior segment optical coherence tomography provided high-resolution images of the corneal pannus, including the blood vessel lumen. Imaging of the pannus depth and cleavage plane was possible intraoperatively, with the patient supine. Postoperative imaging displayed the transplanted graft, temporary amniotic membrane patch, and overlying bandage contact lens. The grafts were also visible after removal of the temporary membrane patch. Four months postoperatively, the grafts were integrated into the cornea, and all 8 participants showed the presence of an epithelial layer. CONCLUSIONS: During CLET surgery, AS-OCT offers a noncontact method for rapid, intraoperative scanning and pachymetry mapping. Intraoperative OCT guidance assists in the removal of the delicate fibrovascular pannus. Sparing the viable corneal stroma can reduce the risk of extreme thinning, iatrogenic ectasia, and wound dehiscence while providing a smooth recipient surface for the composite graft. PMID- 26649763 TI - Visualization of boundaries in CT volumetric data sets using dynamic M-|?f| histogram. AB - Direct volume rendering is widely used for three-dimensional medical data visualization such as computed tomography and magnetic resonance imaging. Distinct visualization of boundaries is able to provide valuable and insightful information in many medical applications. However, it is conventionally challenging to detect boundaries reliably due to limitations of the transfer function design. Meanwhile, the interactive strategy is complicated for new users or even experts. In this paper, we build a generalized boundary model contaminated by noise and prove boundary middle value (M) has a good statistical property. Based on the model we propose a user-friendly strategy for the boundary extraction and transfer function design, using M, boundary height (Deltah), and gradient magnitude (|?f|). In fact, it is a dynamic iterative process. First, potential boundaries are sorted orderly from high to low according to the value of their height. Then, users iteratively extract the boundary with the highest value of Deltah in a newly defined domain, where different boundaries are transformed to disjoint vertical bars using M-|?f| histogram. In this case, the chance of misclassification among different boundaries decreases. PMID- 26649764 TI - Fetal heart rate extraction from abdominal electrocardiograms through multivariate empirical mode decomposition. AB - Assessment of fetal heart rate (FHR) and fetal heart rate variability (fHRV) reveals important information about fetal well-being, specifically in high risk pregnancies. Abdominal electrocardiogram (abdECG) recording is a non-invasive method to capture fetal electrocardiograms. In this paper, we propose a methodology to extract FHR (fetal RR time series) from the abdECG recordings using the recently introduced multivariate empirical mode decomposition (MEMD) technique. MEMD breaks a signal into a finite set of intrinsic mode functions (IMFs). First, elimination of the noisier abdECG channels, based on comparison of similar indexed IMFs that were obtained through the MEMD technique, is conducted. Thereafter, denoising of the remaining abdECG channels is performed by eliminating certain similar indexed IMFs. The unwanted mother QRS complexes are removed from these noise-free abdECG channels, and the candidate fetal R-peaks are detected through a wavelet based approach. The proposed methodology is validated using an open source real-life clinical database. The proposed technique resulted in a high value (0.983) of cross correlation between the detected and true FHR signals. PMID- 26649765 TI - Oral steroids for long-term use in cystic fibrosis. AB - BACKGROUND: In cystic fibrosis (CF) airway obstruction and recurrent respiratory infection lead to inflammation, long-term lung damage, respiratory failure and death. Anti-inflammatory agents, e.g. oral corticosteroids are used since inflammation occurs early in disease. This is an update of a previously published review. OBJECTIVES: To assess the effectiveness of oral corticosteroids in respiratory complications in CF, particularly lung function and adverse events. We examined long-term use (over 30 days) only. SEARCH METHODS: We searched the Cochrane CF and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings.Most recent search: 28 August 2015. SELECTION CRITERIA: Randomised trials comparing oral corticosteroids given for more than 30 days with placebo or no additional therapy in people with CF. DATA COLLECTION AND ANALYSIS: Two authors independently assessed study eligibility and quality. MAIN RESULTS: Of eleven studies identified, three (354 participants) were included: two with four-year follow up and one with 12-weeks follow up. Data were lacking on predefined outcomes; common outcomes were examined at different time-points and presented differently. Meta analyses were not possible.In one study, oral corticosteroids at prednisolone equivalent dose of 1 mg/kg alternate days slowed progression of lung disease; at two and four years, % predicted FEV1 in the 1 mg/kg group changed significantly more than in the placebo group (P < 0.02). During the first two years, the 2 mg/kg group was not significantly different from the placebo group. Linear growth retardation was observed from six months in the 2 mg/kg alternate days prednisolone group and from 24 months in the 1 mg/kg alternate days prednisolone group.Adverse events terminated one four-year study early. Year 10 follow up showed catch-up growth started two years after treatment ceased. Alternate-day treatment with oral corticosteroids may have impaired growth until adulthood in boys. AUTHORS' CONCLUSIONS: Oral corticosteroids at prednisolone-equivalent dose of 1 to 2 mg/kg alternate days appear to slow progression of lung disease in CF; benefit should be weighed against occurrence of adverse events. Risk-benefit analysis of low-dose alternate days corticosteroids is important. No further trials of this intervention are anticipated, and hence the review will no longer be regularly updated. However, if any new data are published, these will be incorporate when available. PMID- 26649767 TI - Comparative Study of the Limitations and Challenges in Atom-Transfer C-H Oxidations. AB - A comparative study is disclosed that seeks to highlight the current limitations and challenges that exist in the field of atom-transfer C-H oxidations. State-of the-art methods are benchmarked in order to showcase clear differences and similarities. A novel Mn-mediated method for C-H oxidation is disclosed that serves as a rapid and simple method for aliphatic C-H hydroxylation. Finally, two methods that allow for C-H oxidation in the presence of pyridine-containing substrates are studied, something that is rare in the field but of great interest to the chemical community. PMID- 26649766 TI - Synthesis and Mechanism Studies of 1,3-Benzoazolyl Substituted Pyrrolo[2,3 b]pyrazine Derivatives as Nonintercalative Topoisomerase II Catalytic Inhibitors. AB - Novel topoisomerase II (Topo II) inhibitors have gained considerable interest for the development of anticancer agents. In this study, a series of 1,3-benzoazolyl substituted pyrrolo[2,3-b]pyrazine derivatives were designed, synthesized, and evaluated as potential Topo II catalytic inhibitors. It was found that some of derivatives had good antiproliferative activity on seven cancer cell lines, especially on HL-60/MX2, a cancer cell line derivative from HL-60 that is resistant to Topo II poison. Topo II mediated DNA relaxation assay results showed that derivatives could significantly inhibit the activity of Topo II, and the structure-activity relationship studies indicated the importance of the alkylamino side chain and the benzoazolyl group. Further mechanism studies revealed that derivatives function as Topo II nonintercalative catalytic inhibitors and may block the ATP binding site of Topo II. Moreover, flow cytometric analysis showed that this class of compounds could induce apoptosis of HL-60 cells. PMID- 26649768 TI - Clinical Association Between Brain MRI Findings With Epidural Blood Patch in Spontaneous Intracranial Hypotension. AB - BACKGROUND: Spontaneous intracranial hypotension (SIH) is characterized by spontaneous postural headache with neck stiffness, nausea, vomiting, tinnitus, and vertigo in patients with low cerebrospinal fluid pressure. Epidural blood patch (EBP) can be a treatment of choice in patients nonresponsive to the initial noninvasive treatments. We compared brain magnetic resonance imaging (MRI) findings and clinical variables between patients with conservative management only and patients with added EBP, to help physicians plan the management modalities for SIH patients. In addition, clinical factors associated with MRI abnormalities in SIH, and the response to EBP between elderly and young patients were assessed. MATERIALS AND METHODS: We retrospectively reviewed the medical records of patients fulfilling the symptomatic diagnostic criteria for SIH between 2001 and 2014. The following data were collected and analyzed by reviewing electronic medical records: demographic variables, initial clinical symptoms (nausea and vomiting, neck stiffness, vertigo, and tinnitus), initial pain score, reports of brain MRI, identified leakage site by cisternography or myelography, finding(s) of spine MRI, and duration of hospital stay. The response to EBP between elderly and young patients based on the age of 45 years, that is, the mean age of EBP in the study, were also compared. RESULTS: The incidence of abnormalities of brain MRI findings did not show significant differences between conservative treatment and EBP. However, the proportion of patients with severe pain was higher in patients who underwent EBP. In multivariate regression analysis, the incidence of positive brain MRI finding(s) for SIH increased in patients with older age, higher weight, and an absence in nausea/vomiting. EBP procedure was effective in both younger and elderly patients. CONCLUSIONS: The results of our study indicated no difference between MRI findings in both conservative treatment and EBP modalities; however, there were differences in initial pain score. Therefore, clinical presentation of SIH patients may be critical and help physicians make a decision of EBP procedure. PMID- 26649769 TI - The Effect of Increased Intracranial Pressure on Pulmonary Compliance in a Neonate. PMID- 26649770 TI - A New Taxon of Basal Ceratopsian from China and the Early Evolution of Ceratopsia. AB - Ceratopsia is one of the best studied herbivorous ornithischian clades, but the early evolution of Ceratopsia, including the placement of Psittacosaurus, is still controversial and unclear. Here, we report a second basal ceratopsian, Hualianceratops wucaiwanensis gen. et sp. nov., from the Upper Jurassic (Oxfordian) Shishugou Formation of the Junggar Basin, northwestern China. This new taxon is characterized by a prominent caudodorsal process on the subtemporal ramus of the jugal, a robust quadrate with an expansive quadratojugal facet, a prominent notch near the ventral region of the quadrate, a deep and short dentary, and strongly rugose texturing on the lateral surface of the dentary. Hualianceratops shares several derived characters with both Psittacosaurus and the basal ceratopsians Yinlong, Chaoyangsaurus, and Xuanhuaceratops. A new comprehensive phylogeny of ceratopsians weakly supports both Yinlong and Hualianceratops as chaoyangsaurids (along with Chaoyangsaurus and Xuanhuaceratops), as well as the monophyly of Chaoyangosauridae + Psittacosaurus. This analysis also weakly supports the novel hypothesis that Chaoyangsauridae + Psittacosaurus is the sister group to the rest of Neoceratopsia, suggesting a basal split between these clades before the Late Jurassic. This phylogeny and the earliest Late Jurassic age of Yinlong and Hualianceratops imply that at least five ceratopsian lineages (Yinlong, Hualianceratops, Chaoyangsaurus + Xuanhuaceratops, Psittacosaurus, Neoceratopsia) were present at the beginning of the Late Jurassic. PMID- 26649771 TI - Expression of Beta-Defensin 131 Promotes an Innate Immune Response in Human Prostate Epithelial Cells. AB - Previously, using the Illumina HumanHT-12 microarray we found that beta-defensin 131 (DEFB131), an antimicrobial peptide, is upregulated in the human prostate epithelial cell line RWPE-1 upon stimulation with lipoteichoic acid (LTA; a gram positive bacterial component), than that in the untreated RWPE-1 cells. In the current study, we aimed to investigate the role of DEFB131 in RWPE-1 cells during bacterial infection. We examined the intracellular signaling pathways and nuclear responses in RWPE-1 cells that contribute to DEFB131 gene induction upon stimulation with LTA. Chromatin immunoprecipitation was performed to determine whether NF-kappaB directly binds to the DEFB131 promoter after LTA stimulation in RWPE-1 cells. We found that DEFB131 expression was induced by LTA stimulation through TLR2 and p38MAPK/NF-kappaB activation, which was evident in the phosphorylation of both p38MAPK and IkappaBalpha. We also found that SB203580 and Bay11-7082, inhibitors of p38MAPK and NF-kappaB, respectively, suppressed LTA induced DEFB131 expression. The chromatin immunoprecipitation assay showed that NF-kappaB directly binds to the DEFB131 promoter, suggesting that NF-kappaB is a direct regulator, and is necessary for LTA-induced DEFB131 expression in RWPE-1 cells. Interestingly, with DEFB131 overexpression in RWPE-1 cells, the accumulation of mRNA and protein secretion of cytokines (IL-1alpha, IL-1beta, IL 6, and IL-12alpha) and chemokines (CCL20, CCL22, and CXCL8) were significantly enhanced. In addition, DEFB131-transfected RWPE-1 cells markedly induced chemotactic activity in THP-1 monocytes. We concluded that DEFB131 induces cytokine and chemokine upregulation through the TLR2/NF-kappaB signaling pathway in RWPE-1 cells during bacterial infection and promotes an innate immune response. PMID- 26649772 TI - 1,3-Dienones and 2H-Pyran-2-ones from Soft alpha-Vinyl Enolization of beta Chlorovinyl Ketones: Defined Roles of Bronsted and Lewis Base. AB - The eliminative reaction pathways of (E)-beta-chlorovinyl ketones were investigated in the presence of both Bronsted and Lewis bases. The Bronsted base, Et3N, effected the soft alpha-vinyl enolization of (E)-beta-chlorovinyl ketones to [3]cumulenol intermediates; in turn, a catalytic amount of Lewis base, PPh3, initiated isomerization to provide 1,3-dienones in high yields. The introduction of a carbon-based nucleophile into the reaction mixture provided the highly efficient synthetic route to 2H-pyran-2-ones in one pot, where the carbon-based nucleophile generated by an extra equivalent of Bronsted base, Et3N, attacked the electrophilic [3]cumulenol intermediates to initiate cyclization to give 2H-pyran 2-ones. PMID- 26649773 TI - Interferences of Silica Nanoparticles in Green Fluorescent Protein Folding Processes. AB - We investigated the relationship between unfolded proteins, silica nanoparticles and chaperonin to determine whether unfolded proteins could stick to silica surfaces and how this process could impair heat shock protein activity. The HSP60 catalyzed green fluorescent protein (GFP) folding was used as a model system. The adsorption isotherms and adsorption kinetics of denatured GFP were measured, showing that denaturation increases GFP affinity for silica surfaces. This affinity is maintained even if the surfaces are covered by a protein corona and allows silica NPs to interfere directly with GFP folding by trapping it in its unstructured state. We determined also the adsorption isotherms of HSP60 and its chaperonin activity once adsorbed, showing that SiO2 NP can interfere also indirectly with protein folding through chaperonin trapping and inhibition. This inhibition is specifically efficient when NPs are covered first with a layer of unfolded proteins. These results highlight for the first time the antichaperonin activity of silica NPs and ask new questions about the toxicity of such misfolded proteins/nanoparticles assembly toward cells. PMID- 26649775 TI - Trends in Self-Harm in Kuala Lumpur, 2005-2011. AB - Acts of self-harm are not routinely tracked in Malaysia. The present study investigates the prevalence of self-harm in Kuala Lumpur, Malaysia, over a 7-year period. The aims were to: (a) assess the prevalence of self-harm; (b) examine any changes over a period of 7 years, and (c) identify correlates of methods of self harm. Data were extracted from the hospital records of Kuala Lumpur Hospital to review trends in self-harm between 2005 and 2011. There were 918 episodes of self harm across the 7-year period, with a significant peak in 2007-2009. The average rate of self-harm (7.7 per 100,000 population per year) was similar or lower than the rate of suicide (6-8 or 8-13 per 100,000) suggesting that genuine cases of self-harm are often attributed to other causes. Nevertheless, over-representation of young people, women and Indians suggest areas in which resources to prevent self-harm might usefully be targeted. Estimating rates of self-harm are fraught with problems and further research is needed to understand the economic and cultural barriers around seeking treatment for self-harm, reporting self-harm and classifying self-harm. PMID- 26649776 TI - An efficient approach for the construction of trifluoromethylated all-carbon quaternary stereocenters: enantioselective Ni(ii)-catalyzed Michael addition of 2 acetyl azaarene to beta,beta-disubstituted nitroalkenes. AB - The first example of a highly enantioselective Michael addition of 2-acetyl azaarenes with beta,beta-disubstituted nitroalkenes was achieved using a Ni(acac)2-bisoxazoline complex as a catalyst, which afforded chiral compounds with an all-carbon quaternary stereocenter bearing a CF3 group in good yields with excellent enantioselectivities (up to >99% ee). This reaction, featuring mild conditions, excellent enantioselectivity and broad generality, provides a new efficient strategy for the construction of trifluoromethylated all-carbon quaternary stereocenters. PMID- 26649774 TI - Circular RNA participates in the carcinogenesis and the malignant behavior of cancer. AB - Circular RNAs (circRNAs) are long, non-coding RNAs that result from the non canonical splicing of linear pre-mRNAs. However, the characteristics and the critical role of circRNA in co-/post-transcriptional regulation were not well recognized until the "microRNA sponge" function of circRNA is discovered. Recent studies have mainly been devoted to the function of the circular RNA sponge for miR-7 (ciRS-7) and sex-determining region Y (SRY) by targeting microRNA-7 (miR-7) and microRNA-138 (miR-138), respectively. In this review, we illustrate the specific role of circRNAs in a wide variety of cancers and in regulating the biological behavior of cancers via miR-7 or miR-138 regulation. Furthermore, circRNA, together with its gene silencing ability, also shows its potential in RNA interference (RNAi) therapy by binding to target RNAs, which provides a novel perspective in cancer treatment. Thus, this review concerns the biogenesis, biological function, oncogenesis, progression and possible therapies for cancer involving circRNAs. PMID- 26649778 TI - Terminal Hemorrhage Preparation and Management #297. PMID- 26649779 TI - Modern Marvels of Children's Palliative Care. PMID- 26649781 TI - Imaging Neutrophils and Monocytes in Mesenteric Veins by Intravital Microscopy on Anaesthetized Mice in Real Time. AB - Efficient immune response is dependent on rapid mobilization of blood leukocytes to the site of infection or injury. Investigating leukocyte migration in vivo is crucial for understanding the molecular basis of leukocyte transendothelial migration and interaction with vascular endothelium. One powerful approach involves intravital microscopy on transgenic mice expressing fluorescent proteins in cells of interest. Here we present a protocol for imaging monocytes and neutrophils in the CX3CR1gfp/wt mouse i.v. injected with orange dye-labeled neutrophils with an inverted confocal microscope. Time-lapse movies gathered from 30 min to several hours of imaging allow the analysis of leukocyte behavior in mesenteric veins under both steady state and inflammatory conditions. We also describe the steps to locally induce blood vessel inflammation with TLR2/TLR1 agonist Pam3SK4 and monitor the subsequent recruitment of neutrophils and monocytes. The presented technique can also be used to monitor other populations of leukocytes and investigate molecules implicated in leukocyte recruitment or trafficking using other stimuli or transgenic mice. PMID- 26649780 TI - Effect of Zhuang Jing Decoction on Learning and Memory Ability in Aging Rats. AB - With the average life span of humans on the rise, aging in the world has drawn considerable attentions. The monoamine neurotransmitters and neurotrophic factors in brain areas are involved in learning and memory processes and are an essential part of normal synaptic neurotransmission and plasticity. In the present study, the effect of Zhuang Jing Decoction (ZJD) on the learning and memory ability in aging rats was examined in vivo using Morris water maze. Furthermore, the levels of monoamine neurotransmitters and neurotrophic factors in brain were detected by high-performance liquid chromatography with a fluorescence detector and enzyme linked immunosorbent assay, respectively. These data showed that oral administration with ZJD at the dose of 30 g.kg(-1) exerted an improved effect on learning and memory ability in aging rats. The results revealed that ZJD could effectively adjust the monoamine neurotransmitters and neurotrophic factors, restore the balance of the level of monoamine neurotransmitters and neurotrophic factors in brain, and finally attenuate the degeneration of learning and memory ability. These findings suggested that ZJD might be a potential agent as cognitive-enhancing drug in improving learning and memory ability. It may exert through regulating the levels of monoamine neurotransmitters and neurotrophic factors in brain, which demonstrated that ZJD had certain antiaging effects. PMID- 26649782 TI - Aluminum borate nanowires from the pyrolysis of polyaminoborane precursors. AB - Polyaminoboranes [N(R)H-BH2]n (1: R = H, 2: R = Me) were pyrolyzed on a range of substrates: silicon, metal foils (stainless steel, nickel, and rhodium), and sapphire wafers, as well as on Al2O3 and AlN powders. The pyrolysis of 2 on a Si wafer resulted in porous nanostructures containing hexagonal-boron nitride (h BN). In the case of 1 or H3N.BH3 as precursor, using rhodium foil as substrate afforded amorphous B and N-containing nanostructures, and polydisperse spherical nanoparticles, respectively. Switching the substrate to sapphire wafers, as well as to Al2O3 or AlN powders, resulted in formation of crystalline Al5BO9 nanostructures (nanowires, nanotubes, and nanoribbons). For sapphire wafers, the size of the resulting nanowires was influenced by modifying the surface defect density. PMID- 26649783 TI - Model-based iterative reconstruction for flat-panel cone-beam CT with focal spot blur, detector blur, and correlated noise. AB - While model-based reconstruction methods have been successfully applied to flat panel cone-beam CT (FP-CBCT) systems, typical implementations ignore both spatial correlations in the projection data as well as system blurs due to the detector and focal spot in the x-ray source. In this work, we develop a forward model for flat-panel-based systems that includes blur and noise correlation associated with finite focal spot size and an indirect detector (e.g. scintillator). This forward model is used to develop a staged reconstruction framework where projection data are deconvolved and log-transformed, followed by a generalized least-squares reconstruction that utilizes a non-diagonal statistical weighting to account for the correlation that arises from the acquisition and data processing chain. We investigate the performance of this novel reconstruction approach in both simulated data and in CBCT test-bench data. In comparison to traditional filtered backprojection and model-based methods that ignore noise correlation, the proposed approach yields a superior noise-resolution tradeoff. For example, for a system with 0.34 mm FWHM scintillator blur and 0.70 FWHM focal spot blur, using the correlated noise model instead of an uncorrelated noise model increased resolution by 42% (with variance matched at 6.9 * 10(-8) mm(-2)). While this advantage holds across a wide range of systems with differing blur characteristics, the improvements are greatest for systems where source blur is larger than detector blur. PMID- 26649784 TI - Evolution, Diversity, and Taxonomy of the Peronosporaceae, with Focus on the Genus Peronospora. AB - Downy mildews are a notorious group of oomycete plant pathogens, causing high economic losses in various crops and ornamentals. The most species-rich genus of oomycetes is the genus Peronospora. This review provides a wide overview of these pathogens, ranging from macro- and micro-evolutionary patterns, their biodiversity and ecology to short overviews for the currently economically most important pathogens and potential emerging diseases. In this overview, the taxonomy of economically relevant species is also discussed, as the application of the correct names and species concepts is a prerequisite for effective quarantine regulations and phytosanitary measures. PMID- 26649786 TI - Alan F. Schatzberg, M.D., 136th President, 2009-2010. PMID- 26649788 TI - Change in Psychotherapy: A Unifying Paradigmby The Boston Change Process Study Group . New York , W.W. Norton and Company , 2010 , 256 pp., $35.00. . PMID- 26649787 TI - Response to Vedeniapin Letter. PMID- 26649785 TI - Myogenic Differentiation of Mouse Embryonic Stem Cells That Lack a Functional Pax7 Gene. AB - The transcription factor Pax7 plays a key role during embryonic myogenesis and sustains the proper function of satellite cells, which serve as adult skeletal muscle stem cells. Overexpression of Pax7 has been shown to promote the myogenic differentiation of pluripotent stem cells. However, the effects of the absence of functional Pax7 in differentiating embryonic stem cells (ESCs) have not yet been directly tested. Herein, we studied mouse stem cells that lacked a functional Pax7 gene and characterized the differentiation of these stem cells under conditions that promoted the derivation of myoblasts in vitro. We analyzed the expression of myogenic factors, such as myogenic regulatory factors and muscle specific microRNAs, in wild-type and mutant cells. Finally, we compared the transcriptome of both types of cells and did not find substantial differences in the expression of genes related to the regulation of myogenesis. As a result, we showed that the absence of functional Pax7 does not prevent the in vitro myogenic differentiation of ESCs. PMID- 26649792 TI - Corrections. PMID- 26649789 TI - Approach to the Psychiatric Patient: Case-Based Essaysedited by Barnhill John W. Washington, DC , American Psychiatric Publishing , 2009 , 565 pp., $67.00 . PMID- 26649795 TI - Interdonato lemon from Nizza di Sicilia (Italy): chemical composition of hexane extract of lemon peel and histochemical investigation. AB - Considering that the determination of authenticity and of the geographical origin of food is a very challenging issue, in this study we studied by means of histological and histochemical analyses the famous Sicilian lemon known as 'Interdonato Lemon of Messina PGI'. Since the protected geographical indication Interdonato lemon of Messina possesses high organoleptic properties, the composition of the hexane extract of lemon peel was determined by HRGC and HRGC MS analyses and compared with that of lemon of different cultivars. The results obtained are informative of the oil's quality and explain the variation of the lemon essential oil composition. Given the fundamental economic implications of any fraud, the aim of this study was to determine a fingerprint able to evaluate the authentication of the geographic origin in such way to prevent frauds in national and international markets. PMID- 26649796 TI - Mutational Analysis in Pediatric Thyroid Cancer and Correlations with Age, Ethnicity, and Clinical Presentation. AB - BACKGROUND: Well-differentiated thyroid cancer (WDTC) incidence in pediatrics is rising, most being papillary thyroid carcinoma (PTC). The objective of the study was to assess the prevalence of different mutations in pediatric WDTC and correlate the genotype with the clinical phenotype. METHODS: This is a single center retrospective study. Thyroid tissue blocks from 42 consecutive pediatric WDTC patients who underwent thyroidectomy between 2001 and 2013 were analyzed at Quest Diagnostics for BRAF(V600E), RAS mutations (N,K,H), and RET/PTC and PAX8/PPARgamma rearrangements, using validated molecular methods. Thyroid carcinomas included PTC, follicular thyroid carcinoma (FTC), and follicular variant of PTC (FVPTC). RESULTS: Thirty-nine samples (29 females) were genotyped. The mean age at diagnosis was 14.7 years (range 7.9-18.4 years), and most were Hispanic (56.4%) or Caucasian (35.9%). The mean follow-up period was 2.9 years. Mutations were noted in 21/39 (53.8%), with both BRAF(V600E) (n = 9), and RET/PTC (n = 6) detected only in PTC. Mutations were detected in 2/5 FTC (PAX8/PPARgamma and NRAS) and 3/6 FVPTC cases (PAX8/PPARgamma). Of 28 PTC patients, 57.1% had mutations: 32.1% with BRAF(V600E), 21.4% with RET/PTC, and 3.6% with NRAS. Of patients with BRAF(V600E), 77.8% were Hispanic and 88.9% were >15 years, while all RET/PTC-positive patients were <=15 years (p = 0.003). Tumor size, lymph node involvement, and distant metastasis at diagnosis (or soon after (131)I ablation) did not vary significantly based on the mutation. CONCLUSIONS: BRAF(V600E) was the most common mutation, especially in older and Hispanic adolescents. A larger, ethnically diverse pediatric cohort followed long term will enable the genotypic variability, clinical presentation, and response to therapy to be better assessed. PMID- 26649799 TI - EAPCCT Abstracts Keyword index. PMID- 26649797 TI - Increased Lung Ischemia-Reperfusion Injury in Aquaporin 1-Null Mice Is Mediated via Decreased Hypoxia-Inducible Factor 2alpha Stability. AB - Aquaporin (AQP) 1, a water channel protein expressed widely in vascular endothelia, has been shown to regulate cell migration, angiogenesis, and organ regeneration. Even though its role in the pathogenesis of lung ischemia reperfusion (IR) injury has been defined, the functional role of AQP1 during long term IR resolution remains to be clarified. Here, we found that AQP1 expression was increased at late time points (7-14 d) after IR and colocalized with endothelial cell (EC) marker CD31. Compared with IR in wild-type mice, IR in Aqp1(-/-) mice had significantly enhanced leukocyte infiltration, collagen deposition, and microvascular permeability, as well as inhibited angiogenic factor expression. AQP1 knockdown repressed hypoxia-inducible factor (HIF)-2alpha protein stability. HIF-2alpha overexpression rescued the angiogenic factor expression in pulmonary microvascular ECs with AQP1 knockdown exposed to hypoxia reoxygenation. Furthermore, AQP1 knockdown suppressed cellular viability and capillary tube formation, and enhanced permeability in pulmonary microvascular ECs, which were partly rescued by HIF-2alpha overexpression. Thus, this study demonstrates that AQP1 deficiency delays long-term IR resolution, partly through repressing angiogenesis mediated by destabilizing HIF-2alpha. These results suggest that AQP1 participates in long-term IR resolution, at least in part by promoting angiogenesis. PMID- 26649800 TI - Observation of Emerging Photoinitiator Additives in Household Environment and Sewage Sludge in China. AB - Photoinitiators (PIs) are widely used additives in industrial polymerization process, the contamination of which through migration into foodstuffs has been subjected to increasing public scrutiny. Nevertheless, little attention has been paid to the PI residue levels and potential exposure pathways from other environmental compartments. In the present study, the occurrence of PI additives with discrete molecular structures, that is, nine benzophenones (BZPs), four thioxanthones (TXs), and eight amine co-initiators (ACIs), was investigated in commercial products, indoor dust and sewage sludge samples. Nine PI compounds were positively detected in ultraviolet curable resins with concentrations of ?PIs (sum of the detected PIs) up to 2.51 * 10(4) ng/g, and 20 PIs can be found in food contact materials with concentrations of ?PIs varying from 65.9 to 6.93 * 10(3) ng/g. The wide usage of PIs in commercial products led to the occurrence of 19 PIs in indoor dust, with concentrations of ?PIs in the range of 245-5.68 * 10(3) ng/g. Meanwhile, all 21 targeted PIs could be identified in the sewage sludge, with concentrations from 67.6 to 2.03 * 10(3) ng/g. Distinct PI composition profiles were observed in different investigated compartments, and BZPs were the dominant homologues in all samples. Most of the target PIs were further identified as class III chemicals by toxic hazard estimation algorithm (Toxtree), which indicates the compounds might be of significant toxicity or have reactive functional groups. PMID- 26649801 TI - Terlipressin versus noradrenaline in the treatment of hepatorenal syndrome: systematic review with meta-analysis and full economic evaluation. AB - OBJECTIVE: The aim of this study was to compare the efficacy and costs of terlipressin and noradrenaline for the treatment of hepatorenal syndrome from the perspective of the Brazilian public health system and that of a major private health insurance. METHODS: Comparison of efficacy was performed through a systematic review with a meta-analysis of randomized-controlled trials using a random-effects model. Economic evaluation was carried out through cost minimization. RESULTS: Four studies (154 patients) were included in the meta analysis. There was no evidence of a difference between treatments with terlipressin or noradrenaline in terms of 30-day survival (risk ratio=1.04, 95% confidence interval=0.84-1.30, P=0.70). From the perspective of the public health system, costs of the treatments with terlipressin or noradrenaline were Int$7437.04 and Int$8406.41, respectively. From the perspective of the private health insurance, costs of treatments with terlipressin and noradrenaline were Int$13,484.57 and Int$15,061.01, respectively. CONCLUSION: There was no evidence of superiority between treatment strategies using terlipressin or noradrenaline in terms of the survival of patients with hepatorenal syndrome, but the strategy using terlipressin was more economical under two different perspectives. PMID- 26649802 TI - Comparison of the ability of the PDD-ICG clearance test, CTP, MELD, and MELD-Na to predict short-term and medium-term mortality in patients with decompensated hepatitis B cirrhosis. AB - OBJECTIVE: Various methods, including the indocyanine green (ICG) clearance test, the Child-Turcotte-Pugh score (CTP), model for end-stage liver disease (MELD), and MELD combined with serum sodium concentration (MELD-Na), have been used widely in liver function evaluation in patients with end-stage liver disease. In this study, we compared the ability of these methods to predict mortality in patients with decompensated hepatitis B cirrhosis. METHODS: A total of 98 patients with decompensated hepatitis B cirrhosis were included in this study and followed up for 12 months. The ICG-derived measurements (ICG-PDR, ICG-R15, EHBF), CTP, MELD, and MELD-Na were obtained within 2 days after patients' admission and patients' survival at 1, 3, 6, and 12 months was recorded. Receiver operating curve was used to evaluate the ability of these methods to predict mortality in these patients with decompensated hepatitis B cirrhosis. RESULTS: At 1 month, 3 months, 6 months and 12 months, the cumulative number of deaths and liver transplant recipients was 12 (12.2%), 17 (17.3%), 21 (21.4%) and 25 (25.5%), respectively. The ICG-derived measurements, CTP, MELD, and MELD-Na of nonsurvivors were significantly different compared with that in survivors. All methods yielded viable values in predicting short-term and medium-term prognosis for patients with decompensated hepatitis B cirrhosis, with most area under the curve exceeding 0.8. Moreover, the ICG-derived measurements showed a significant correlation with that of CTP, MELD, and MELD-Na. CONCLUSION: All four methods, ICG clearance test, CTP, MELD, and MELD-Na, provided reliable prediction of mortality in patients with decompensated hepatitis B cirrhosis for both short term and medium-term prognosis. PMID- 26649803 TI - Short article: Relapsing Whipple's disease: a case report and literature review. AB - Whipple's disease is a rare infection caused by Tropheryma whipplei, a Gram negative Bacillus usually found in macrophages of the lamina propria of the small intestine. The typical clinical manifestations of classic Whipple's disease are diarrhea, weight loss, malabsorption, abdominal pain, and arthralgia. The disease's laboratory diagnosis is currently based on duodenal biopsy. Treatment generally includes primary therapy for 2 weeks with intravenous antibiotics capable of reaching high levels in the cerebrospinal fluid, such as ceftriaxone, usually followed by treatment with oral cotrimoxazole for 1 year. Early diagnosis should enable appropriate treatment and improves the prognosis, and prolonged antibiotic treatment often leads to complete remission. Our case report focuses on a 72-year-old man who had been passing watery stools for 1-2 months, accompanied by low-grade fever. He reported profound asthenia, a weight loss of about 3 kg, and loss of appetite. Thirty years earlier (in 1984), he had been working as a horse keeper at a University Department of Agricultural and Veterinary Studies, where he had contracted Whipple's disease. Laboratory tests and microbiological studies led to a diagnosis of recurrent Whipple's disease. Esophagogastroduodenoscopy was performed under deep sedation. Biopsy samples obtained from the stomach and duodenum were stained with hematoxylin and eosin, Giemsa, and periodic acid-Schiff to identify any accumulation of typical periodic acid-Schiff-positive macrophages in the lamina propria. A specific quantitative real-time PCR assay using specific oligonucleotide probes for targeting repeated sequences of Tropheryma whipplei was also performed to detect its DNA in the duodenum samples. PMID- 26649804 TI - TM4SF3 and AR: A Nuclear Complex that Stabilizes Both Proteins. AB - Transmembrane 4 superfamily 3 (TM4SF3) was identified as a novel androgen regulated gene in prostate cancer (PCa) cells. Our data demonstrate that TM4SF3 exhibits androgen-induced repression of the mRNA but up-regulation of the protein. The androgen positive effect on the TM4SF3 protein is of significant interest in view of the procancer functions of both androgens and tetraspanin proteins. Androgen positively regulates TM4SF3 protein stability by inhibiting its proteasome-dependent degradation. This androgen stabilization of TM4SF3 is involved in promoting PCa cell invasion and migration of both androgen-dependent and androgen-independent PCa cells. Although confirming androgen up-regulation of the TM4SF3 protein, we observed that TM4SF3 is localized not only to the membrane, but also, surprisingly, the nuclei of PCa cells. This novel nuclear localization of TM4SF3 depends on androgen-induced nuclear localization of androgen receptor (AR) in both androgen-dependent and androgen-independent PCa cell lines. TM4SF3 interacts with AR both in PCa cell types and in vitro, strongly suggesting a direct interaction. This direct interaction is required for the stabilization of not only TM4SF3, but also remarkably AR, because down regulation of TM4SF3 resulted in reduced AR protein levels. As expected of an important AR regulator, TM4SF3 regulates androgen-dependent gene expression in and proliferation of PCa cells. Importantly, a direct correlation between AR and TM4SF3 protein levels and nuclear colocalization were also observed in prostate tumors, strongly suggesting that the mutual stabilization resulting from the AR TM4SF3 interaction is found in tumors and that this interaction is important in PCa biology. PMID- 26649806 TI - A precut fistulotomy technique for difficult biliary cannulation. PMID- 26649805 TI - Research Resource: A Dual Proteomic Approach Identifies Regulated Islet Proteins During beta-Cell Mass Expansion In Vivo. AB - Diabetes is characterized by insulin insufficiency due to a relative paucity of functional beta-cell mass. Thus, strategies for increasing beta-cell mass in situ are sought-after for therapeutic purposes. Pregnancy is a physiological state capable of inducing robust beta-cell mass expansion, however, the mechanisms driving this expansion are not fully understood. Thus, the aim of this study was to characterize pregnancy-induced changes in the islet proteome at the peak of beta-cell proliferation in mice. Islets from pregnant and nonpregnant littermates were compared via 2 proteomic strategies. In vivo pulsed stable isotope labeling of amino acids in cell culture was used to monitor de novo protein synthesis during the first 14.5 days of pregnancy. In parallel, protein abundance was determined using ex vivo dimethyl labelling at gestational day 14.5. Comparison of the 2 datasets revealed 170 islet proteins to be up regulated as a response to pregnancy. These included several proteins, not previously associated with pregnancy-induced islet expansion, such as CLIC1, STMN1, MCM6, PPIB, NEDD4, and HLTF. Confirming the validity of our approach, we also identified proteins encoded by genes known to be associated with pregnancy-induced islet expansion, such as CHGB, IGFBP5, MATN2, EHHADH, IVD, and BMP1. Bioinformatic analyses demonstrated enrichment and activation of the biological functions: "protein synthesis" and "proliferation," and predicted the transcription factors HNF4alpha, MYC, MYCN, E2F1, NFE2L2, and HNF1alpha as upstream regulators of the observed expressional changes. As the first characterization of the islet proteome during pregnancy, this study provides novel insight into the mechanisms involved in promoting pregnancy-induced beta-cell mass expansion and function. PMID- 26649807 TI - Multicentric neoadjuvant pilot Phase II study of cetuximab combined with docetaxel in operable triple negative breast cancer. AB - Systemic therapy for triple negative breast cancer (TNBC) is mostly based upon chemotherapy. Epithelial Growth Factor Receptor (EGFR) is overexpressed in around 50% of TNBC and may play a role in its pathogenesis. Consequently, we performed a multicentric pilot Phase II neoadjuvant trial of cetuximab (anti-EGFR antibody) combined with docetaxel for patients with operable, Stage II-III TNBC. Therapy consisted of weekly cetuximab (first infusion: 400 mg/m(2), then 250 mg/m(2)) combined with six cycles of docetaxel (T: 100 mg/m(2)) q.3 weeks. Subsequently, all patients underwent surgery. The primary endpoint was pathological complete response (pCR) while clinical response, toxicity and ancillary studies were secondary endpoints. Paraffin-embedded and frozen tumor samples were systematically collected in order to identify predictive biomarkers of efficacy and resistance. From a total of 35 accrued patients, 25 were assessable for pathologic response. The pCR rate was 24% [95% CI: 7.3-40.7]. Complete clinical response rate (cCR) was observed in 22% of cases. Conservative surgery was performed in 75% of patients. Toxicity, mostly cutaneous and hematologic, was manageable. The pre-therapy ratio between CD8+ and FOXP3+ tumor-infiltrating lymphocytes equal or higher than 2.75 was predictive of pCR: 43% versus 0%, p = 0.047. Cetuximab in combination with docetaxel displays a modest activity, but acceptable toxicity as neoadjuvant therapy of operable TNBC. Similarly to previous observations using panitumumab, another anti-EGFR antibody, the immune component of the tumor microenvironment may play an important role in predicting TNBC response to the neoadjuvant therapy. PMID- 26649809 TI - What is Life-in Everyday Understanding? A Focus Group Study on Lay Perspectives on the Term Life. AB - The philosophical and scientific debate about definitions of life-as-we-know-it and its value is very diverse. How do non-biologists characterize these issues? We held focus groups to shed light on the role of the term life in laypeople's understanding. Results show that features of early childhood cognition dominate the understanding of the term life even in adulthood. Textbook knowledge and definitions derived from specific knowledge systems and beliefs are of minor importance. For an ethical differentiation between life forms the ability to feel and to suffer is seen as the crucial criterion. We conclude that lay perspectives on the concept of life can shape a normative discourse on existing as well as on new life forms in a crucial way. In addition, these perspectives may also strongly influence the expectations towards the life-as-it-could-be that is brought forward by the artificial life community. While some concepts like metabolism exist both in scientific and in everyday reasoning as criteria for life, the normative discussion on life is dominated by such ideas as a hierarchical order of living kinds, which emphasize "easy to think" concepts of a moral differentiation. These can also form a basis for the moral standing of artificial life. PMID- 26649810 TI - On Cellular Darwinism: Mitochondria. AB - The significant role of mitochondria within cells is becoming increasingly clear. This letter uses the NKCS model of coupled fitness landscapes to explore aspects of organelle-nucleus coevolution. The phenomenon of mitochondrial diversity is allowed to emerge under a simple intracellular evolutionary process, including varying the relative rate of evolution by the organelle. It is shown how the conditions for the maintenance of more than one genetic variant of mitochondria are similar to those previously suggested as needed for the original symbiotic origins of the relationship using the NKCS model. PMID- 26649811 TI - Maximizing the Adjacent Possible in Automata Chemistries. AB - Automata chemistries are good vehicles for experimentation in open-ended evolution, but they are by necessity complex systems whose low-level properties require careful design. To aid the process of designing automata chemistries, we develop an abstract model that classifies the features of a chemistry from a physical (bottom up) perspective and from a biological (top down) perspective. There are two levels: things that can evolve, and things that cannot. We equate the evolving level with biology and the non-evolving level with physics. We design our initial organisms in the biology, so they can evolve. We design the physics to facilitate evolvable biologies. This architecture leads to a set of design principles that should be observed when creating an instantiation of the architecture. These principles are Everything Evolves, Everything's Soft, and Everything Dies. To evaluate these ideas, we present experiments in the recently developed Stringmol automata chemistry. We examine the properties of Stringmol with respect to the principles, and so demonstrate the usefulness of the principles in designing automata chemistries. PMID- 26649808 TI - Caged [(18)F]FDG Glycosylamines for Imaging Acidic Tumor Microenvironments Using Positron Emission Tomography. AB - Solid tumors are hypoxic with altered metabolism, resulting in secretion of acids into the extracellular matrix and lower relative pH, a feature associated with local invasion and metastasis. Therapeutic and diagnostic agents responsive to this microenvironment may improve tumor-specific delivery. Therefore, we pursued a general strategy whereby caged small-molecule drugs or imaging agents liberate their parent compounds in regions of low interstitial pH. In this manuscript, we present a new acid-labile prodrug method based on the glycosylamine linkage, and its application to a class of positron emission tomography (PET) imaging tracers, termed [(18)F]FDG amines. [(18)F]FDG amines operate via a proposed two-step mechanism, in which an acid-labile precursor decomposes to form the common radiotracer 2-deoxy-2-[(18)F]fluoro-d-glucose, which is subsequently accumulated by glucose avid cells. The rate of decomposition of [(18)F]FDG amines is tunable in a systematic fashion, tracking the pKa of the parent amine. In vivo, a 4 phenylbenzylamine [(18)F]FDG amine congener showed greater relative accumulation in tumors over benign tissue, which could be attenuated upon tumor alkalinization using previously validated models, including sodium bicarbonate treatment, or overexpression of carbonic anhydrase. This new class of PET tracer represents a viable approach for imaging acidic interstitial pH with potential for clinical translation. PMID- 26649813 TI - Impact of genetic signature on breast cancer therapy: preliminary experience. PMID- 26649812 TI - Focused vs. Broad enhanced cognitive behavioral therapy for bulimia nervosa with comorbid borderline personality: A randomized controlled trial. AB - OBJECTIVE: A subset of individuals with bulimia nervosa (BN) have borderline personality disorder (BPD) symptoms, including chronic negative affect and interpersonal problems. These symptoms predict poor BN treatment outcome in some studies. The broad version of Enhanced Cognitive Behavior Therapy (CBT-E) was developed to address co-occurring problems that interfere with treatment response. The current study investigated the relative effects, predictors, and moderators of CBT-E for BN with BPD and co-occurring mood/anxiety disorders. METHOD: Fifty patients with BN and threshold or sub-threshold BPD and current or recent Axis I mood or anxiety disorders were randomly assigned to receive focused CBT-E (CBT-Ef) or broad CBT-E (CBT-Eb) specifically including an interpersonal module and additional attention to mood intolerance. RESULTS: Forty-two percent of the sample reported remission from binge eating and purging at termination. Significant changes across symptom domains were observed at termination and at 6 month follow-up. Though CBT-Ef predicted good outcomes in multivariate models, the severity of affective/interpersonal problems moderated treatment effects: participants with higher severity showed better ED outcomes in CBT-Eb, whereas those with lower severity showed better outcomes in CBT-Ef. Severity of affective/interpersonal BPD symptoms at baseline predicted negative outcomes overall. Follow-up BPD affective/interpersonal problems were predicted by baseline affective/interpersonal problems and by termination EDE score. DISCUSSION: This study supports the utility of CBT-E for patients with BN and complex comorbidity. CBT-Ef appears to be more efficacious for patients with relatively less severe BPD symptoms, whereas CBT-Eb appears to be more efficacious for patients with more severe BPD symptoms. PMID- 26649814 TI - Self-Assembly of Shaped Nanoparticles into Free-Standing 2D and 3D Superlattices. AB - This article describes a novel supramolecular assembly-mediated strategy for the organization of Au nanoparticles (NPs) with different shapes (e.g., spheres, rods, and cubes) into large-area, free-standing 2D and 3D superlattices. This robust approach involves two major steps: (i) the organization of polymer tethered NPs within the assemblies of supramolecular comblike block copolymers (CBCPs), and (ii) the disassembly of the assembled CBCP structures to produce free-standing NP superlattices. It is demonstrated that the crystal structures and lattice constants of the superlattices can be readily tailored by varying the molecular weight of tethered polymers, the volume fraction of NPs, and the matrix of CBCPs. This template-free approach may open a new avenue for the assembly of NPs into 2D and 3D structures with a wide range of potential applications. PMID- 26649815 TI - Social conversational skills development in early implanted children. AB - OBJECTIVES/HYPOTHESIS: Social conversational skills are a salient aspect of early pragmatic development in young children. These skills include two different abilities, assertiveness and responsiveness. This study investigated the development of these abilities in early implanted children and their relationships with lexical development and some language-sensitive variables. STUDY DESIGN: Prospective, observational, nonrandomized study. METHODS: Participants included 28 children with congenital profound sensorineural hearing loss. The mean age at device activation was 13.3 months (standard deviation [SD] +/-4.2). The Social-Conversational Skills Rating Scale was used to evaluate assertiveness and responsiveness. The MacArthur-Bates Communicative Development Inventory (Words and Sentences form) was used to analyze the lexical development. The device experience was 12 months for each child, and the mean age at testing was 25.9 months (SD +/-4.6). RESULTS: Assertiveness and responsiveness scores were within the normal range of normal-hearing age-matched peers. Age at cochlear implant activation exerted a significant impact, with the highest scores associated to the youngest patients. The residual correlations between assertiveness and responsiveness with the lexical development were positive and strongly significant (r = 0.69 and 0.73, respectively). Preoperative hearing threshold demonstrated an associated significant coefficient on the assertiveness score. Age at diagnosis and maternal education level were not correlated with the social conversational skills. CONCLUSIONS: Early-implanted children developed social conversational skills that are similar to normal-hearing peers matched for age 1 year after device activation. Social conversational skills and lexical development were strongly correlated, but the present study design cannot specify the direction of this relationship. Children with better preoperative residual hearing exhibited better assertive ability. LEVEL OF EVIDENCE: 4 Laryngoscope, 126:2098-2105, 2016. PMID- 26649816 TI - Impact of lesion location on procedural and acute angiographic outcomes in patients with critical limb ischemia treated for peripheral artery disease with orbital atherectomy: A CONFIRM registries subanalysis. AB - OBJECTIVES: This analysis compares the procedural and acute angiographic outcomes in patients with critical limb ischemia (CLI) treated with orbital atherectomy in above-the-knee (ATK)/popliteal (POP) lesions versus below-the-knee (BTK) lesions. BACKGROUND: Lesion location affects the procedural outcomes and the opportunity for limb salvage in patients with CLI suffering from peripheral artery disease (PAD). METHODS: The CONFIRM registry series was analyzed and includes 1109 real world patients (1544 lesions) suffering from CLI treated with orbital atherectomy. The rates of dissection, perforation, slow flow, vessel closure, spasm, embolism, and thrombus formation were compared between CLI patients with ATK/POP lesions and BTK lesions. RESULTS: Patients with ATK/POP lesions had a higher final residual stenosis (10 vs. 9%; P = 0.004) and use of more adjunctive therapies (e.g. balloons and stents; 1.3 vs. 1.1%; P < 0.001) compared to patients with BTK lesions. Patients with BTK had higher incidence of perforation (1.5 vs. 0.2%; P = 0.005), slow flow (7.7 vs. 5.0%; P = 0.03) and spasm (10.3 vs. 4.2%; P < 0.001) but lower incidence of embolism (0.4 vs. 5.1%; P < 0.001). CONCLUSIONS: Plaque modification with orbital atherectomy was successful in CLI patients regardless of lesion location. BTK lesions were associated with increased rates of perforation, slow flow and spasm which may be explained by more challenging procedural characteristics in these patients such as smaller vessel size and tortuosity. The higher incidence of emboli in ATK/POP lesions is most likely attributed to the higher prevalence of severe calcium observed in this cohort. PMID- 26649817 TI - Resource subsidies between stream and terrestrial ecosystems under global change. AB - Streams and adjacent terrestrial ecosystems are characterized by permeable boundaries that are crossed by resource subsidies. Although the importance of these subsidies for riverine ecosystems is increasingly recognized, little is known about how they may be influenced by global environmental change. Drawing from available evidence, in this review we propose a conceptual framework to evaluate the effects of global change on the quality and spatiotemporal dynamics of stream-terrestrial subsidies. We illustrate how changes to hydrological and temperature regimes, atmospheric CO2 concentration, land use and the distribution of nonindigenous species can influence subsidy fluxes by affecting the biology and ecology of donor and recipient systems and the physical characteristics of stream-riparian boundaries. Climate-driven changes in the physiology and phenology of organisms with complex life cycles will influence their development time, body size and emergence patterns, with consequences for adjacent terrestrial consumers. Also, novel species interactions can modify subsidy dynamics via complex bottom-up and top-down effects. Given the seasonality and pulsed nature of subsidies, alterations of the temporal and spatial synchrony of resource availability to consumers across ecosystems are likely to result in ecological mismatches that can scale up from individual responses, to communities, to ecosystems. Similarly, altered hydrology, temperature, CO2 concentration and land use will modify the recruitment and quality of riparian vegetation, the timing of leaf abscission and the establishment of invasive riparian species. Along with morphological changes to stream-terrestrial boundaries, these will alter the use and fluxes of allochthonous subsidies associated with stream ecosystems. Future research should aim to understand how subsidy dynamics will be affected by key drivers of global change, including agricultural intensification, increasing water use and biotic homogenization. Our conceptual framework based on the match-mismatch between donor and recipient organisms may facilitate understanding of the multiple effects of global change and aid in the development of future research questions. PMID- 26649818 TI - Phosphorylation and linear ubiquitin direct A20 inhibition of inflammation. AB - Inactivation of the TNFAIP3 gene, encoding the A20 protein, is associated with critical inflammatory diseases including multiple sclerosis, rheumatoid arthritis and Crohn's disease. However, the role of A20 in attenuating inflammatory signalling is unclear owing to paradoxical in vitro and in vivo findings. Here we utilize genetically engineered mice bearing mutations in the A20 ovarian tumour (OTU)-type deubiquitinase domain or in the zinc finger-4 (ZnF4) ubiquitin-binding motif to investigate these discrepancies. We find that phosphorylation of A20 promotes cleavage of Lys63-linked polyubiquitin chains by the OTU domain and enhances ZnF4-mediated substrate ubiquitination. Additionally, levels of linear ubiquitination dictate whether A20-deficient cells die in response to tumour necrosis factor. Mechanistically, linear ubiquitin chains preserve the architecture of the TNFR1 signalling complex by blocking A20-mediated disassembly of Lys63-linked polyubiquitin scaffolds. Collectively, our studies reveal molecular mechanisms whereby A20 deubiquitinase activity and ubiquitin binding, linear ubiquitination, and cellular kinases cooperate to regulate inflammation and cell death. PMID- 26649819 TI - Interleukin-22 promotes intestinal-stem-cell-mediated epithelial regeneration. AB - Epithelial regeneration is critical for barrier maintenance and organ function after intestinal injury. The intestinal stem cell (ISC) niche provides Wnt, Notch and epidermal growth factor (EGF) signals supporting Lgr5(+) crypt base columnar ISCs for normal epithelial maintenance. However, little is known about the regulation of the ISC compartment after tissue damage. Using ex vivo organoid cultures, here we show that innate lymphoid cells (ILCs), potent producers of interleukin-22 (IL-22) after intestinal injury, increase the growth of mouse small intestine organoids in an IL-22-dependent fashion. Recombinant IL-22 directly targeted ISCs, augmenting the growth of both mouse and human intestinal organoids, increasing proliferation and promoting ISC expansion. IL-22 induced STAT3 phosphorylation in Lgr5(+) ISCs, and STAT3 was crucial for both organoid formation and IL-22-mediated regeneration. Treatment with IL-22 in vivo after mouse allogeneic bone marrow transplantation enhanced the recovery of ISCs, increased epithelial regeneration and reduced intestinal pathology and mortality from graft-versus-host disease. ATOH1-deficient organoid culture demonstrated that IL-22 induced epithelial regeneration independently of the Paneth cell niche. Our findings reveal a fundamental mechanism by which the immune system is able to support the intestinal epithelium, activating ISCs to promote regeneration. PMID- 26649820 TI - A mechanism for the suppression of homologous recombination in G1 cells. AB - DNA repair by homologous recombination is highly suppressed in G1 cells to ensure that mitotic recombination occurs solely between sister chromatids. Although many homologous recombination factors are cell-cycle regulated, the identity of the events that are both necessary and sufficient to suppress recombination in G1 cells is unknown. Here we report that the cell cycle controls the interaction of BRCA1 with PALB2-BRCA2 to constrain BRCA2 function to the S/G2 phases in human cells. We found that the BRCA1-interaction site on PALB2 is targeted by an E3 ubiquitin ligase composed of KEAP1, a PALB2-interacting protein, in complex with cullin-3 (CUL3)-RBX1 (ref. 6). PALB2 ubiquitylation suppresses its interaction with BRCA1 and is counteracted by the deubiquitylase USP11, which is itself under cell cycle control. Restoration of the BRCA1-PALB2 interaction combined with the activation of DNA-end resection is sufficient to induce homologous recombination in G1, as measured by RAD51 recruitment, unscheduled DNA synthesis and a CRISPR Cas9-based gene-targeting assay. We conclude that the mechanism prohibiting homologous recombination in G1 minimally consists of the suppression of DNA-end resection coupled with a multi-step block of the recruitment of BRCA2 to DNA damage sites that involves the inhibition of BRCA1-PALB2-BRCA2 complex assembly. We speculate that the ability to induce homologous recombination in G1 cells with defined factors could spur the development of gene-targeting applications in non dividing cells. PMID- 26649822 TI - Tuberculosis: Autophagy is not the answer. PMID- 26649823 TI - Cosmology: Rare isotopic insight into the Universe. PMID- 26649821 TI - Acute off-target effects of neural circuit manipulations. AB - Rapid and reversible manipulations of neural activity in behaving animals are transforming our understanding of brain function. An important assumption underlying much of this work is that evoked behavioural changes reflect the function of the manipulated circuits. We show that this assumption is problematic because it disregards indirect effects on the independent functions of downstream circuits. Transient inactivations of motor cortex in rats and nucleus interface (Nif) in songbirds severely degraded task-specific movement patterns and courtship songs, respectively, which are learned skills that recover spontaneously after permanent lesions of the same areas. We resolve this discrepancy in songbirds, showing that Nif silencing acutely affects the function of HVC, a downstream song control nucleus. Paralleling song recovery, the off target effects resolved within days of Nif lesions, a recovery consistent with homeostatic regulation of neural activity in HVC. These results have implications for interpreting transient circuit manipulations and for understanding recovery after brain lesions. PMID- 26649824 TI - Self-shaping of oil droplets via the formation of intermediate rotator phases upon cooling. AB - Revealing the chemical and physical mechanisms underlying symmetry breaking and shape transformations is key to understanding morphogenesis. If we are to synthesize artificial structures with similar control and complexity to biological systems, we need energy- and material-efficient bottom-up processes to create building blocks of various shapes that can further assemble into hierarchical structures. Lithographic top-down processing allows a high level of structural control in microparticle production but at the expense of limited productivity. Conversely, bottom-up particle syntheses have higher material and energy efficiency, but are more limited in the shapes achievable. Linear hydrocarbons are known to pass through a series of metastable plastic rotator phases before freezing. Here we show that by using appropriate cooling protocols, we can harness these phase transitions to control the deformation of liquid hydrocarbon droplets and then freeze them into solid particles, permanently preserving their shape. Upon cooling, the droplets spontaneously break their shape symmetry several times, morphing through a series of complex regular shapes owing to the internal phase-transition processes. In this way we produce particles including micrometre-sized octahedra, various polygonal platelets, O shapes, and fibres of submicrometre diameter, which can be selectively frozen into the corresponding solid particles. This mechanism offers insights into achieving complex morphogenesis from a system with a minimal number of molecular components. PMID- 26649825 TI - Reproducibility: Experimental mismatch in neural circuits. PMID- 26649826 TI - Regenerative biology: Innate immunity repairs gut lining. PMID- 26649829 TI - Topical Ruxolitinib for the Treatment of Alopecia Universalis. PMID- 26649828 TI - Neutrophils support lung colonization of metastasis-initiating breast cancer cells. AB - Despite progress in the development of drugs that efficiently target cancer cells, treatments for metastatic tumours are often ineffective. The now well established dependency of cancer cells on their microenvironment suggests that targeting the non-cancer-cell component of the tumour might form a basis for the development of novel therapeutic approaches. However, the as-yet poorly characterized contribution of host responses during tumour growth and metastatic progression represents a limitation to exploiting this approach. Here we identify neutrophils as the main component and driver of metastatic establishment within the (pre-)metastatic lung microenvironment in mouse breast cancer models. Neutrophils have a fundamental role in inflammatory responses and their contribution to tumorigenesis is still controversial. Using various strategies to block neutrophil recruitment to the pre-metastatic site, we demonstrate that neutrophils specifically support metastatic initiation. Importantly, we find that neutrophil-derived leukotrienes aid the colonization of distant tissues by selectively expanding the sub-pool of cancer cells that retain high tumorigenic potential. Genetic or pharmacological inhibition of the leukotriene-generating enzyme arachidonate 5-lipoxygenase (Alox5) abrogates neutrophil pro-metastatic activity and consequently reduces metastasis. Our results reveal the efficacy of using targeted therapy against a specific tumour microenvironment component and indicate that neutrophil Alox5 inhibition may limit metastatic progression. PMID- 26649827 TI - Unique role for ATG5 in neutrophil-mediated immunopathology during M. tuberculosis infection. AB - Mycobacterium tuberculosis, a major global health threat, replicates in macrophages in part by inhibiting phagosome-lysosome fusion, until interferon gamma (IFNgamma) activates the macrophage to traffic M. tuberculosis to the lysosome. How IFNgamma elicits this effect is unknown, but many studies suggest a role for macroautophagy (herein termed autophagy), a process by which cytoplasmic contents are targeted for lysosomal degradation. The involvement of autophagy has been defined based on studies in cultured cells where M. tuberculosis co localizes with autophagy factors ATG5, ATG12, ATG16L1, p62, NDP52, BECN1 and LC3 (refs 2-6), stimulation of autophagy increases bacterial killing, and inhibition of autophagy increases bacterial survival. Notably, these studies reveal modest (~1.5-3-fold change) effects on M. tuberculosis replication. By contrast, mice lacking ATG5 in monocyte-derived cells and neutrophils (polymorponuclear cells, PMNs) succumb to M. tuberculosis within 30 days, an extremely severe phenotype similar to mice lacking IFNgamma signalling. Importantly, ATG5 is the only autophagy factor that has been studied during M. tuberculosis infection in vivo and autophagy-independent functions of ATG5 have been described. For this reason, we used a genetic approach to elucidate the role for multiple autophagy-related genes and the requirement for autophagy in resistance to M. tuberculosis infection in vivo. Here we show that, contrary to expectation, autophagic capacity does not correlate with the outcome of M. tuberculosis infection. Instead, ATG5 plays a unique role in protection against M. tuberculosis by preventing PMN-mediated immunopathology. Furthermore, while Atg5 is dispensable in alveolar macrophages during M. tuberculosis infection, loss of Atg5 in PMNs can sensitize mice to M. tuberculosis. These findings shift our understanding of the role of ATG5 during M. tuberculosis infection, reveal new outcomes of ATG5 activity, and shed light on early events in innate immunity that are required to regulate disease pathology and bacterial replication. PMID- 26649830 TI - The effect of levosimendan on myocardial ischemia-reperfusion injury in streptozotocin-induced diabetic rats. AB - Objective Ischemia/reperfusion (I/R) injury is an important cause of myocardial damage by means of oxidative, inflammatory, and apoptotic mechanisms. The aim of the present study was to examine the potential cardio protective effects of levosimendan in a diabetic rat model of myocardial I/R injury. Methods A total of 18 streptozotocin-induced diabetic Wistar Albino rats (55 mg/kg) were randomly divided into three equal groups as follows: the diabetic I/R group (DIR) in which myocardial I/R was induced following left thoracotomy, by ligating the left anterior descending coronary artery for 60 min, followed by 2 h of reperfusion; the diabetic I/R levosimendan group (DIRL), which underwent I/R by the same method while taking levosimendan intraperitoneal 12 ug kg-1; and the diabetic control group (DC) which underwent sham operations without tightening of the coronary sutures. As a control group (C), six healthy age-matched Wistar Albino rats underwent sham operations similar to the DC group. Two hours after the operation, the rats were sacrificed and the myocardial tissue samples were examined by light microscopy for evidence of myonecrosis and inflammatory cell infiltration. Results Myonecrosis findings were significantly different among groups (p=0.008). Myonecrosis was more pronounced in the DIR group compared with the C, DC, and DIRL groups (p=0.001, p=0.007 and p=0.037, respectively). Similarly, the degree of inflammatory cell infiltration showed significant difference among groups (p<0.0001). Compared with C, DC, and DIRL groups, the inflammatory cell infiltration was significantly higher among the DIR group (p<0.0001, p<0.0001, and p=0.020, respectively). Also, myocardial tissue edema was significantly different among groups (p=0.006). The light microscopic myocardial tissue edema levels were significantly higher in the DIR group than the C, DC, and DIRL groups (p=0.001, p=0.037, and p=0.014, respectively). Conclusion Taken together, our data indicate that levosimendan may be helpful in reducing myocardial necrosis, myocardial inflammation, and myocardial tissue edema resulting from ischemia-reperfusion injury. PMID- 26649831 TI - No Association Between Time of Onset of Hearing Loss (Childhood Versus Adulthood) and Self-Reported Hearing Handicap in Adults. AB - PURPOSE: This study examined the association between time of onset of hearing loss (childhood vs. adulthood) and self-reported hearing handicap in adults. METHODS: This is a population-based cohort study of 2,024 adults (mean = 48 years) with hearing loss (binaural pure-tone average 0.5-4 kHz >= 20 dB HL) who completed a hearing handicap questionnaire. In childhood, the same persons (N = 2,024) underwent audiometry in a school investigation (at ages 7, 10, and 13 years), in which 129 were diagnosed with sensorineural hearing loss (binaural pure-tone average 0.5-4 kHz >= 20 dB HL), whereas 1,895 had normal hearing thresholds. RESULTS: Hearing handicap was measured in adulthood as the sum-score of various speech perception and social impairment items (15 items). The sum score increased with adult hearing threshold level (p < .001). After adjustment for adult hearing threshold level, hearing aid use, adult age, sex, and socioeconomic status, there was no significant difference in hearing handicap sum score between the group with childhood-onset hearing loss (n = 129) and the group with adult-onset hearing loss (n = 1,895; p = .882). CONCLUSION: Self-reported hearing handicap in adults increased with hearing threshold level. After adjustment for adult hearing threshold level, this cohort study revealed no significant association between time of onset of hearing loss (childhood vs. adulthood) and self-reported hearing handicap. PMID- 26649850 TI - Differences Among Patients That Make Their Tinnitus Worse or Better. AB - PURPOSE: Our objective was to identify activities that influence tinnitus and to determine if conditional probabilities exist among such variables. METHOD: Two hundred fifty-eight patients were asked the following two questions: "When you have your tinnitus, which of the following makes it worse?" and "Which of the following reduces your tinnitus?" RESULTS: Things that made tinnitus better included noise (31%) and relaxation (15%). Things that made tinnitus worse included being in a quiet place (48%), stress (36%), being in a noisy place (32%), and lack of sleep (27%). Almost 6% of patients suggested coffee/tea and 4% said certain foods made their tinnitus worse. Conditional probabilities indicated that for those whose tinnitus is not worse in quiet, it is usually not reduced by noise. For those whose tinnitus is not worse in noise, it is usually not reduced in quiet. CONCLUSION: There are dramatic differences among patients. Such differences need to be considered in planning treatments. PMID- 26649851 TI - Multi-wave cohort study of sedentary work and risk of ischemic heart disease. AB - OBJECTIVES: This study aimed to investigate whether sedentary work is a distinct risk factor for ischemic heart disease (IHD) when the effect of occupational sitting is disentangled from that of occupational physical activity. METHODS: Data on occupational sitting time and several covariates were derived from the Danish Work Environment Cohort Study (DWECS) conducted every five years from 1990 2005 among the active Danish population. This study was designed as a multi-wave longitudinal study including participants employed at entry. Respondents were followed in national registers, first for death or hospital treatment due to IHD and second for purchase of medication that may prevent IHD from (re)occurring serving as a proxy for IHD. RESULTS: During 145 850 person-years of follow-up, 510 cases of fatal and non-fatal IHD occurred. After adjustment for age, sex, body mass index (BMI), and socioeconomic status, no difference in risk of IHD was observed between sedentary and non-sedentary employees [hazard ratio (HR) 0.95, 95% confidence interval (95% CI) 0.78-1.16]. During 44 949 and 42 456 person years of follow-up among men and and women, respectively, 1263 men and 1364 women purchased IHD-related medication. No differences in risk were observed between sedentary and non-sedentary participants, either for men or women. A dose response relationship between occupational sitting time and the risk of IHD was also not detected. CONCLUSIONS: This study could not confirm the hypothesis that sedentary work is a distinct risk factor for IHD. Future studies may further investigate the association with objective measures of occupational sitting time. PMID- 26649852 TI - Staged segmental urethroplasty for scrotal/perineal hypospadias: a new concept. AB - PURPOSE: We report the efficacy of staged segmental urethroplasty (SSUP) versus non-staged urethroplasty (NSUP) for treating scrotal/perineal hypospadias (SPH). METHODS: Between 1997 and 2015, 29 SPH patients underwent UP (SSUP: n = 15; NSUP: n = 14). Incidences of urethrocutaneous fistula (UF), stenosis of the neourethra (SNU), diverticula formation, and residual chordee (RC) were compared. Differences were statistically significant if p < 0.05. RESULTS: The difference in mean age at NSUP (3.2 +/- 1.3 years) and at the final stage of SSUP (5.5 +/- 2.4 years) was significant (p < 0.05). Mean operative times for NSUP and SSUP (total for all stages) were not significantly different (231.5 +/- 117.5 versus 272.5 +/- 99.4 min); however, the incidence of postoperative complications was significantly less in SSUP (n = 1; UF) compared with NSUP (n = 6; 2 cases of UF, 3 cases of SNU, and 1 case of RC; (p < 0.05). Mean follow-up was significantly shorter in SSUP; 1.4 +/- 1.2 years versus 7.0 +/- 4.5 years in NSUP (p < 0.05). CONCLUSION: SSUP would appear to be effective for treating SPH because of a significantly lower incidence of UF, SNU and RC during the first postoperative year, the period when complications have been reported to arise most frequently. PMID- 26649854 TI - Editorial. PMID- 26649853 TI - Expression of hepatic lipid droplets is decreased in the nitrofen model of congenital diaphragmatic hernia. AB - BACKGROUND: Prenatal mortality in newborn infants with congenital diaphragmatic hernia (CDH) has been attributed to increased amounts of liver hernia ion through the diaphragmatic defect. Antenatal studies in human and rodent fetus with CDH further demonstrated a contribution of the developing liver in the pathogenesis of CDH. The abnormal hepatic growth in experimental animal models, therefore, indicates a disruption of normal liver development in CDH. However, the underlying structural, histological and functional changes in the liver of animals with CDH remain unclear. We design this study to test the hypothesis that the morphological and cellular liver development is altered in the nitrogen induced CDH model. METHODS: Pregnant rats were exposed to either olive oil or nitrofen on day 9 of gestation (D9). Livers and chest were harvested on D21 and divided into two groups: control (n = 8), nitrofen with CDH (CDH, n = 8). Haematoxylin-eosin (Straub et al. Histopathology 68:617-631, 2013) staining was performed to evaluate underlying morphological changes. Apoptosis was checked by using TUNEL staining and apoptotic cell number was counted on 16-16 slides in 25 fields by two independent viewers. Hepatic lipid droplet expressions were evaluated by hepatic adipose differentiation-related protein (ARDP) expression. RESULTS: Compared to controls markedly increased hypertrophy was seen in CDH group. Significantly increased apoptotic cell numbers were detected in CDH group compared to controls (5.1 +/- 1.5 vs 2.1 +/- 0.6) (p < 0.05). The relative mRNA expression levels of ARDP were significantly reduced in CDH group compared to controls. Immunohistochemistry showed markedly decreased hepatic ADRP immunoreactivity in CDH fetuses compared to controls. CONCLUSIONS: Our findings provide strong evidence of hepatic hypertrophy and increased cell apoptosis in the liver of nitrofen-induced CDH. These morphological changes may affect liver lipid droplet expression function. PMID- 26649855 TI - Synthesis and Rotational Isomerism of 1-Substituted Methyl (S)-[5-(2-Nitrophenyl) 1H-pyrazole-4-carbonyl]alaninates. AB - Seven title compounds 12a-g and the (S)-prolinate analogue 13 were prepared in five steps from 2-nitrobenzoic acid (7). Reduction of the nitro group followed by derivatization of the so formed anilines 14 gave the N-alkyl-(15a-c), N-acyl (16a,b and 19), and N-vinyl derivative 20. NMR spectra of (S)-alanine and (S) proline derived compounds 12, 13, 14-16, 19, and 20 exhibited two sets of signals corresponding to pairs of conformational diastereomers. The free energy barriers of rotation, DeltaG(?)298 = 82-86 kJ mol(-1), were determined by (1)H NMR for 12a, 12d, 12f, and 12g and evaluated by DFT calculations. PMID- 26649856 TI - The Social Dimension of Stress: Experimental Manipulations of Social Support and Social Identity in the Trier Social Stress Test. AB - In many situations humans are influenced by the behavior of other people and their relationships with them. For example, in stressful situations supportive behavior of other people as well as positive social relationships can act as powerful resources to cope with stress. In order to study the interplay between these variables, this protocol describes two effective experimental manipulations of social relationships and supportive behavior in the laboratory. In the present article, these two manipulations are implemented in the Trier Social Stress Test (TSST)-a standard stress induction paradigm in which participants are subjected to a simulated job interview. More precisely, we propose (a) a manipulation of the relationship between different protagonists in the TSST by making a shared social identity salient and (b) a manipulation of the behavior of the TSST selection committee, which acts either supportively or unsupportively. These two experimental manipulations are designed in a modular fashion and can be applied independently of each other but can also be combined. Moreover, these two manipulations can also be integrated into other stress protocols and into other standardized social interactions such as trust games, negotiation tasks, or other group tasks. PMID- 26649857 TI - Sleep and inflammatory markers in different psychiatric disorders. AB - Many psychiatric disorders, like schizophrenia, affective disorders, addictions and different forms of dementia are associated with sleep disturbances. In the etiology and course of those diseases inflammatory processes are regarded to be an increasingly important factor. They are also a frequently discussed element of the pathology of sleep. In this literature review reports on correlations between poor sleep and inflammatory responses in various psychiatric conditions are discussed. The link between schizophrenia, affective disorders and inflammatory cytokines is a complex phenomenon, which has been already confirmed in a number of studies. However, the presence of sleep deficits in those conditions, being a common symptom of depression and psychoses, can be an additional factor having a considerable impact on the immunological processes in mental illnesses. In the analyzed data, a number of studies are presented describing the role of inflammatory markers in sleep disturbances and psychopathological symptoms of affective, psychotic, neurogenerative and other disorders. Also attention is drawn to possible implications for their treatment. Efforts to use, e.g., anti inflammatory agents in psychiatry in the context of their impact on sleep are reported. The aspect of inflammatory markers in the role of sleep deprivation as the treatment method in major depressive disorder is also discussed. A general conclusion is drawn that the improvement of sleep quality plays a crucial role in the care for psychiatric patients. PMID- 26649858 TI - Mothers' Temperament and Personality: Their Relationship to Parenting Behaviors, Locus of Control, and Young Children's Functioning. AB - There appears to be a lack of construct clarity and a dearth of studies that have examined both mothers' temperament and personality in conjunction with parenting behaviors when predicting young children's functioning. As a result, this study examined these constructs jointly so that a further understanding of how mothers' temperament and personality may work together to predict young children's functioning could be gained. As part of this study, 214 diverse mothers with young children who ranged in age from 2- to 6-years rated their own temperament and personality, their parenting characteristics, and their young children's functioning (i.e., temperament and emotional and behavioral functioning). Based on the findings of hierarchical regression analyses completed in this study, both mothers' temperament and personality may be important individual predictors of young children's temperament but may be important joint predictors, along with parenting behaviors, of young children's behavior problems. Consequently, future research should examine the role that mothers' temperament and personality characteristics may play in conjunction with their parenting behaviors when trying to understand young children's functioning. These findings will be particularly helpful for professionals providing parenting interventions to families with young children who have difficult temperament styles and/or emotional and behavioral problems. PMID- 26649859 TI - Premixed insulin regimens for type 2 diabetes. PMID- 26649860 TI - Hashimoto's encephalopathy (HE): an under diagnosed autoimmune-mediated encephalopathy. PMID- 26649861 TI - Upregulation of PTEN suppresses invasion in Tca8113 tongue cancer cells through repression of epithelial-mesenchymal transition (EMT). AB - We previously discovered that the expression of the tumor suppressor phosphatase and tensin homolog (PTEN) was downregulated in the majority patients with tongue squamous cell carcinoma (TSCC). The aim of this study was to investigate the role of PTEN overexpression in the regulation of epithelial-mesenchymal transition (EMT) of the tongue squamous carcinoma cell line Tca8113 as well as explore the underlying mechanism. GV230 (containing the PTEN gene) and empty vectors were transfected into Tca8113 cells. After stable transfection, the messenger RNA (mRNA) and protein levels of PTEN were validated using quantitative real-time PCR (qPCR) and Western blot analysis. The growth and cell cycle were analyzed using Cell Counting Kit-8 (CCK-8) and flow cytometry, respectively. The invasion ability was measured with a transwell assay. The effects of PTEN overexpression on EMT and Hedgehog signaling were assessed by comparing Tca8113-PTEN cells with control and negative control cell groups. We found that PTEN expression was significantly upregulated after transfection. Meanwhile, upregulated PTEN inhibited the proliferation and invasion of Tca8113 cells. In addition, we observed changes in the EMT- and Hedgehog-associated proteins. These data demonstrated that PTEN upregulation could reduce invasion by inhibiting the process of EMT in Tca8113 cells, which might be related to the Hedgehog signaling pathway. PMID- 26649862 TI - Comparative analysis of basaloid and conventional squamous cell carcinomas of the esophagus: prognostic relevance of clinicopathological features and protein expression. AB - Basaloid squamous cell carcinoma (BSCC), a variant of squamous cell carcinoma (SCC), is a rare and aggressive epithelial malignancy which has been reported in only 0.1-11 % of primary esophageal carcinomas. In this study, a comparison of clinicopathological features and protein expression between esophageal BSCC (EBSCC) and conventional esophageal SCC (ESCC) cases from Brazil was performed in order to find factors that can be relevant to better characterize EBSCC. The expression of HER2, epidermal growth factor receptor (EGFR), Ki-67, and cyclins (A, B1, and D1) in 111 cases (95 ESCC and 16 EBSCC) was evaluated by immunohistochemistry using tissue microarray. When the clinicopathological data were compared, no significant difference was found between the two histological types. Although the difference is not significant (p = 0.055), the EGFR expression was more frequent in the conventional ESCC than in the EBSCC group. Our results indicate that the clinicopathological profiles of conventional ESCC and EBSCC are similar and provide no indicators for differences in prognosis between these two groups. PMID- 26649864 TI - Subscapularis Z-lengthening in children with brachial plexus birth palsy loses efficiency at mid-term follow-up: a retrospective cohort study. AB - PURPOSE: The aim of this study was to evaluate early and mid-term clinical outcomes after isolated subscapularis Z-lengthening in children with shoulder internal rotation contractures resulting from brachial plexus birth palsy. METHODS: Children with brachial plexus birth palsy treated with subscapularis tendon Z-lengthening from 2001 to 2011 were retrospectively reviewed. Over this period, 31 patients were identified. Primary outcome was improvement in Mallet score after surgery, and secondary outcome measures were active range of motion and Mallet sub-scores. Clinical outcomes were collected at three time intervals: pre-operatively, one-year post-operative and at latest follow-up. RESULTS: After exclusion, 21 patients remained for further analysis. Mean age at surgery was 3.7 years (range, 1.2-8.7), and mean follow-up length was 6.5 years (2.9-9.7). Moderate improvements were found for mean Mallet score, active external rotation, active abduction and hand-to-mouth movement at one year and latest follow-up. However, improvements in active external rotation and Mallet score were not fully maintained at final follow up. CONCLUSION: Isolated subscapularis Z-lengthening is effective at early follow-up, but results are not maintained at mid-term follow-up. PMID- 26649865 TI - Self-Position of Au NPs in Perovskite Solar Cells: Optical and Electrical Contribution. AB - Metallic nanoparticles (NPs) exhibit a localized surface plasmon resonance (LSPR) and act as scattering centers and subwavelength antennas, so metallic NPs can be incorporated into perovskite solar cells (PSCs) to effectively improve the light absorption of light harvesting devices. Here, we have embedded Au nanoparticles (NPs) into the hole transport layer (HTL) of the PSCs to investigate the photovoltaic effect of the PSCs with Au NPs. Interestingly, it was found that Au NPs dispersed spiro-OMeTAD HTL solution could naturally end up located near the perovskite layer as the result of the spin-coating step. Solar cell performance observations indicate that the LSPR and electrical effects of Au NPs enhance the photovoltaic response of PSCs, in spite of a slight decrease in the open-circuit voltage (VOC), by causing an incredible improvement in the photocurrent density as a dominant factor. PMID- 26649866 TI - Prediction of malting quality traits in barley based on genome-wide marker data to assess the potential of genomic selection. AB - KEY MESSAGE: Genomic prediction of malting quality traits in barley shows the potential of applying genomic selection to improve selection for malting quality and speed up the breeding process. ABSTRACT: Genomic selection has been applied to various plant species, mostly for yield or yield-related traits such as grain dry matter yield or thousand kernel weight, and improvement of resistances against diseases. Quality traits have not been the main scope of analysis for genomic selection, but have rather been addressed by marker-assisted selection. In this study, the potential to apply genomic selection to twelve malting quality traits in two commercial breeding programs of spring and winter barley (Hordeum vulgare L.) was assessed. Phenotypic means were calculated combining multilocational field trial data from 3 or 4 years, depending on the trait investigated. Three to five locations were available in each of these years. Heritabilities for malting traits ranged between 0.50 and 0.98. Predictive abilities (PA), as derived from cross validation, ranged between 0.14 to 0.58 for spring barley and 0.40-0.80 for winter barley. Small training sets were shown to be sufficient to obtain useful PAs, possibly due to the narrow genetic base in this breeding material. Deployment of genomic selection in malting barley breeding clearly has the potential to reduce cost intensive phenotyping for quality traits, increase selection intensity and to shorten breeding cycles. PMID- 26649867 TI - Molecular mapping and marker development for the Triticum dicoccoides-derived stripe rust resistance gene YrSM139-1B in bread wheat cv. Shaanmai 139. AB - KEY MESSAGE: YrSM139-1B maybe a new gene for effective resistance to stripe rust and useful flanking markers for marker-assisted selection were developed. ABSTRACT: Stripe rust, caused by Puccinia striiformis f. sp. tritici, is an important foliar disease of wheat. Two dominant stripe rust resistant genes YrSM139-1B and YrSM139-2D were pyramided in bread wheat cultivar Shaanmai 139; one from wild emmer and the other from Thinopyrum intermedium. Three near isogenic F7:8 line pairs (contrasting RILs), N122-1013R/S, N122-185R/S, and N122 1812R/S, independently derived from different F2 plants and differing at the YrSM139-1B locus were generated from the cross Shaanmai 139 * Hu 901-19 through marker-assisted selection. A large F2:3 population from cross N122-1013R * N122 1013S tested for stripe rust response and subjected to analysis with markers in the 1BS10-0.5 bin region using SSR expressed sequence tags (EST) and site specific sequence markers developed from the 90 K Illumina iSelect SNP array. Five EST-STS markers and four allele-specific PCR markers were mapped to the YrSM139-1B region. The 30.5 cM genetic map for YrSM139-1B consisted of nine markers, two of which were closer to YrSM139-1B than Xgwm273, which was used in producing the contrasting RIL pairs. Race response data and allelism tests showed that YrSM139-1B is different from Yr10, Yr15, and Yr24/26/CH42. PMID- 26649868 TI - Identification of haplotypes at the Rsv4 genomic region in soybean associated with durable resistance to soybean mosaic virus. AB - KEY MESSAGE: Discovery of new germplasm sources and identification of haplotypes for the durable Soybean mosaic virus resistance gene, Rsv 4, provide novel resources for map-based cloning and genetic improvement efforts in soybean. The Soybean mosaic virus (SMV) resistance locus Rsv4 is of interest because it provides a durable type of resistance in soybean [Glycine max (L.) Merr.]. To better understand its molecular basis, we used a population of 309 BC3F2 individuals to fine-map Rsv4 to a ~120 kb interval and leveraged this genetic information in a second study to identify accessions 'Haman' and 'Ilpumgeomjeong' as new sources of Rsv4. These two accessions along with three other Rsv4 and 14 rsv4 accessions were used to examine the patterns of nucleotide diversity at the Rsv4 region based on high-depth resequencing data. Through a targeted association analysis of these 19 accessions within the ~120 kb interval, a cluster of four intergenic single-nucleotide polymorphisms (SNPs) was found to perfectly associate with SMV resistance. Interestingly, this ~120 kb interval did not contain any genes similar to previously characterized dominant disease resistance genes. Therefore, a haplotype analysis was used to further resolve the association signal to a ~94 kb region, which also resulted in the identification of at least two Rsv4 haplotypes. A haplotype phylogenetic analysis of this region suggests that the Rsv4 locus in G. max is recently introgressed from G. soja. This integrated study provides a strong foundation for efforts focused on the cloning of this durable virus resistance gene and marker-assisted selection of Rsv4-mediated SMV resistance in soybean breeding programs. PMID- 26649869 TI - Isolation, expression and evolution of FERTILIZATION INDEPENDENT ENDOSPERM homologs in Podostemaceae. AB - Podostemaceae is an interesting family of angiosperms with unusual development and morphology. Among these, double fertilization, a defining feature of angiosperms is invariably missing in the family. Consequently, embryo development in the seeds takes place without endosperm. In recent years, the role of polycomb genes has garnered much interest because of their crucial role in seed development. Some of these genes have been reported from many unrelated species, underlining their high conservation. Thus, it becomes exciting to know the role of these genes in podostemads, which are devoid of double fertilization and endosperm. Here, we report the isolation, characterization and expression patterns of homologs of Fertilization Independent Endosperm (FIE) in two species of Podostemaceae, Zeylanidium olivaceum and Polypleurum stylosum. FIE like homologs could be identified in Z. olivaceum (ZoFIE) and P. stylosum (PsFIE). The predicted amino acid sequence of FIE homologs showed similarity to other homologs, containing the conserved seven WD40 repeats. Expression studies revealed that ZoFIE and PsFIE transcripts were present in the vegetative tissue (thallus in Podostemaceae) and the seedlings, similar to the model plants. However, the ZoFIE and PsFIE expression disappeared in the flowering stages. This unique pattern of expression suggests that in the absence of double fertilization and endosperm the expression of FIS complex genes perhaps is obliterated in Podostemaceae. PMID- 26649870 TI - Dose Reduction of Caspofungin in Intensive Care Unit Patients with Child Pugh B Will Result in Suboptimal Exposure. AB - BACKGROUND AND OBJECTIVES: Caspofungin is an echinocandin antifungal agent used as first-line therapy for the treatment of invasive candidiasis. The maintenance dose is adapted to body weight (BW) or liver function (Child-Pugh score B or C). We aimed to study the pharmacokinetics of caspofungin and assess pharmacokinetic target attainment for various dosing strategies. METHODS: Caspofungin pharmacokinetic data from 21 intensive care unit (ICU) patients was available. A population pharmacokinetic model was developed. Various dosing regimens (loading dose/maintenance dose) were simulated: licensed regimens (I) 70/50 mg (for BW <80 kg) or 70/70 mg (for BW >80 kg); and (II) 70/35 mg (for Child-Pugh score B); and adapted regimens (III) 100/50 mg (for Child-Pugh score B); (IV) 100/70 mg; and (V) 100/100 mg. Target attainment based on a preclinical pharmacokinetic target for Candida albicans was assessed for relevant minimal inhibitory concentrations (MICs). RESULTS: A two-compartment model best fitted the data. Clearance was 0.55 L/h and the apparent volumes of distribution in the central and peripheral compartments were 8.9 and 5.0 L, respectively. The median area under the plasma concentration-time curve from time zero to 24 h on day 14 for regimens I-V were 105, 65, 93, 130, and 186 mg.h/L, respectively. Pharmacokinetic target attainment was 100 % (MIC 0.03 ug/mL) irrespective of dosing regimen but decreased to (I) 47 %, (II) 14 %, (III) 36 %, (IV) 69 %, and (V) 94 % for MIC 0.125 ug/mL. CONCLUSION: The caspofungin maintenance dose should not be reduced in non cirrhotic ICU patients based on the Child-Pugh score if this classification is driven by hypoalbuminemia as it results in significantly lower exposure. A higher maintenance dose of 70 mg in ICU patients results in target attainment of >90 % of the ICU patients with species with an MIC of up to 0.125 ug/mL. PMID- 26649871 TI - Comment on: "Enzalutamide: A Step Towards Pharmacokinetic-Based Dosing in Men with Metastatic Castration-Resistant Prostate Cancer". PMID- 26649872 TI - Author's Reply to Zheng et al.: A Physiologically Based Pharmacokinetic Drug Disease Model to Predict Carvedilol Exposure in Adult and Paediatric Heart Failure Patients by Incorporating Pathophysiological Changes in Hepatic and Renal Blood Flows. PMID- 26649873 TI - Comment on: "A Physiologically Based Pharmacokinetic Drug-Disease Model to Predict Carvedilol Exposure in Adult and Paediatric Heart Failure Patients by Incorporating Pathophysiological Changes in Hepatic and Renal Blood". PMID- 26649874 TI - Modeling Encephalopathy of Prematurity Using Prenatal Hypoxia-ischemia with Intra amniotic Lipopolysaccharide in Rats. AB - Encephalopathy of prematurity (EoP) is a term that encompasses the central nervous system (CNS) abnormalities associated with preterm birth. To best advance translational objectives and uncover new therapeutic strategies for brain injury associated with preterm birth, preclinical models of EoP must include similar mechanisms of prenatal global injury observed in humans and involve multiple components of the maternal-placental-fetal system. Ideally, models should produce a similar spectrum of functional deficits in the mature animal and recapitulate multiple aspects of the pathophysiology. To mimic human systemic placental perfusion defects, placental underperfusion and/or chorioamnionitis associated with pathogen-induced inflammation in early preterm birth, we developed a model of prenatal transient systemic hypoxia-ischemia (TSHI) combined with intra amniotic lipopolysaccharide (LPS). In pregnant Sprague Dawley rats, TSHI via uterine artery occlusion on embryonic day 18 (E18) induces a graded placental underperfusion defect associated with increasing CNS damage in the fetus. When combined with intra-amniotic LPS injections, placental inflammation is increased and CNS damage is compounded with associated white matter, gait and imaging abnormalities. Prenatal TSHI and TSHI+LPS prenatal insults meet several of the criteria of an EoP model including recapitulating the intrauterine insult, causing loss of neurons, oligodendrocytes and axons, loss of subplate, and functional deficits in adult animals that mimic those observed in children born extremely preterm. Moreover, this model allows for the dissection of inflammation induced by divergent injury types. PMID- 26649876 TI - Cervical Cancer Screening Among Homeless Women of New York City Shelters. AB - Introduction Homeless persons have minimal opportunities to complete recommended cancer screening. The rates and predictors of cervical cancer screening are understudied among homeless women in the US. Methods We enrolled 297 homeless women 21-65 years old residing in 6 major New York City shelters from 2012 to 2014. We used a validated national survey to determine the proportion and predictors of cervical cancer screening using cytology (Pap test). Results Mean age was 44.72 (+/-11.96) years. Majority was Black, heterosexual, single, with high school or lower education; 50.9 % were smokers and 41.7 % were homeless more than a year. Despite a 76.5 % proportion of self-reported Pap test within the past 3 years, 65 % of women assumed their Pap test results were normal or did not get proper follow up after abnormal results. Forty-five-point-nine percent of women did not know about frequency of Pap test or causes of cervical cancer. Lower proportion of up-to-date Pap test was associated with lack of knowledge of recommended Pap test frequency (p < 0.01) and relationship between HPV and an abnormal Pap test (p < 0.01). Conclusions Self-reported Pap testing in homeless women was similar to a national sample. However, the majority of women surveyed were not aware of their results, received limited if any follow up and had significant education gaps about cervical cancer screening. We recommend improved counseling and patient education, patient navigators to close screening loops, and consideration of alternative test-and-treat modalities to improve effective screening. PMID- 26649875 TI - Sleep-Related Infant Deaths in Victoria: A Retrospective Case Series Study. AB - BACKGROUND: There is general agreement that in some circumstances, sharing a sleep surface of any kind with an infant increases the risk of sudden unexpected death in infancy. There is a paucity of research conducted in Australia examining this issue. This study examines the frequency and distribution of sleep-related infant deaths in a defined population, and reports the proportion that occurred in the context of bed-sharing. METHODS: A retrospective population-based case series study was conducted of infants (<=365 days) who died in a sleeping context during the period 1 January 2008 to 31 December 2010 in the state of Victoria, Australia. Information about the infant, caregiver, sleeping environment and bed sharing was collected from a review of the coroner's death investigation record. RESULTS: During the 3-year study period, 72 infant deaths occurred in a sleeping context. Of these, 33 (45.8 %) occurred in the context of bed-sharing: n = 7 in 2008; n = 11 in 2009; and n = 15 in 2010. Further analysis of the 33 deaths occurring in the context of bed-sharing showed that in this group, bed-sharing was largely intentional, habitual and most often involved the mother as one of the parties. CONCLUSIONS: Given the case series nature of the study design, a causal relationship between bed-sharing and infant death could not be inferred. However the fact that nearly half of all sleep-related deaths occurred in the context of bed-sharing, provides strong support for the need to undertake definitive analytic studies in Australia so that evidence-based advice can be provided to families regarding the safety of bed-sharing practices. PMID- 26649877 TI - Pregnancy Intention and Post-partum Depressive Affect in Louisiana Pregnancy Risk Assessment Monitoring System. AB - BACKGROUND: Postpartum depression is associated with negative physical and mental health outcomes for both the mother and infant. This study examines the relationship between a mother and/or her partner's pregnancy intentions and reported post-partum depressive symptoms (PPDs). METHODS: Using Louisiana pregnancy risk assessment monitoring system, 2000-2003, a secondary cross sectional analysis was conducted on 5549 mothers, stratified by race, who delivered a singleton, live birth and whose infant was still alive at the time of the survey. Bivariate and multivariable logistic regressions were conducted, taking into account the complex survey design. RESULTS: In multivariable models, unwanted pregnancies were associated with severe PPDs (aOR 1.76, 95 % CI 1.23 2.53). Furthermore, the association between husbands/partners' who did not want or care about the pregnancy and mild PPDs remained for White women (aOR 1.32, 95 % CI 1.02-1.69); while among Black women, neither parent's pregnancy intention were associated with mild or severe PPDs. CONCLUSIONS: This study supports existing research demonstrating the association between pregnancy intention and PPDs. This study contributes to the limited information on the role that partner pregnancy intention plays on maternal mental health outcomes, however further discussion is needed on the impact of this role across races. Findings can be used in programs aiming to reduce adverse mental health outcomes among high-risk mothers. PMID- 26649878 TI - Parent, Teacher, and Student Perspectives on How Corrective Lenses Improve Child Wellbeing and School Function. AB - OBJECTIVES: Up to 20 % of school-age children have a vision problem identifiable by screening, over 80 % of which can be corrected with glasses. While vision problems are associated with poor school performance, few studies describe whether and how corrective lenses affect academic achievement and health. Further, there are virtually no studies exploring how children with correctable visual deficits, their parents, and teachers perceive the connection between vision care and school function. METHODS: We conducted a qualitative evaluation of Vision to Learn (VTL), a school-based program providing free corrective lenses to low-income students in Los Angeles. Nine focus groups with students, parents, and teachers from three schools served by VTL explored the relationships between poor vision, receipt of corrective lenses, and school performance and health. RESULTS: Twenty parents, 25 teachers, and 21 students from three elementary schools participated. Participants described how uncorrected visual deficits reduced students' focus, perseverance, and class participation, affecting academic functioning and psychosocial stress; how receiving corrective lenses improved classroom attention, task persistence, and willingness to practice academic skills; and how serving students in school rather than in clinics increased both access to and use of corrective lenses. CONCLUSIONS: for Practice Corrective lenses may positively impact families, teachers, and students coping with visual deficits by improving school function and psychosocial wellbeing. Practices that increase ownership and use of glasses, such as serving students in school, may significantly improve both child health and academic performance. PMID- 26649879 TI - mHealth Physical Activity Intervention: A Randomized Pilot Study in Physically Inactive Pregnant Women. AB - INTRODUCTION: Physical inactivity is prevalent in pregnant women, and innovative strategies to promote physical activity are strongly needed. The purpose of the study was to test a 12-week mobile health (mHealth) physical activity intervention for feasibility and potential efficacy. METHODS: Participants were recruited between December 2012 and February 2014 using diverse recruitment methods. Thirty pregnant women between 10 and 20 weeks of gestation were randomized to an intervention (mobile phone app plus Fitbit) or a control (Fitbit) group. Both conditions targeted gradual increases in physical activity. The mHealth intervention included daily messages and a mobile phone activity diary with automated feedback and self-monitoring systems. RESULTS: On monthly average, 4 women were screened for initial eligibility by telephone and 2.5 were randomized. Intervention participants had a 1096 +/- 1898 step increase in daily steps compared to an increase of 259 +/- 1604 steps in control participants at 12 weeks. The change between groups in weekly mean steps per day during the 12-week study period was not statistically significant (p = 0.38). The intervention group reported lower perceived barrier to being active, lack of energy, than the control group at 12-week visit (p = 0.02). The rates of responding to daily messages and using the daily diary through the mobile app declined during the 12 week study period. DISCUSSION: It was difficult to recruit and randomize inactive women who wanted to increase physical activity during pregnancy. Pregnant women who were motivated to increase physical activity might find using mobile technologies in assessing and promoting PA acceptable. Possible reasons for the non-significant treatment effect of the mHealth intervention on physical activity are discussed. Public awareness of safety and benefits of physical activity during pregnancy should be promoted. Clinicaltrials.Gov Identifier NCT01461707. PMID- 26649880 TI - Associations Between Maternal Support and Physical Activity Among 5th Grade Students. AB - BACKGROUND: A large body of research has established an association between parental support for children's physical activity (PA) and children's PA. However, there has been little attention to the relative influences of parent and child perceptions of that parental support. PURPOSE: To examine agreement among parent and child perceptions of parent support for PA and whether these perceptions are associated with objectively-measured moderate-to-vigorous physical activity (MVPA) among those children. METHODS: Cross-sectional associations between PA of children measured via accelerometers and child reported and mother-reported perceptions of parental support for children's PA were assessed via mixed-model regression analyses in a cohort of 693 5th graders. Results Children's perceptions of parental support for PA were consistent with those of their mothers. Nonetheless, in models that included both children's and mothers' perceptions of parental support for PA, mothers' perceptions, but not children's perceptions, were significantly associated with children's PA. Associations were consistent for Total MVPA, After School MVPA, and Evening MVPA, with stronger associations among males than among females. CONCLUSION: Maternal support may influence children's PA. Studies which consider only children's accounts of parental support may overlook important mechanisms. PMID- 26649881 TI - Relationship Between Current Substance Use and Unhealthy Weight Loss Practices Among Adolescents. AB - OBJECTIVES: To determine the relationship between current substance use and unhealthy weight loss practices (UWLP) among 12-to-18 year olds. METHODS: Participants were 12-to-18 year olds who completed the 2013 Youth Risk Behavior Survey in Florida (N = 5620). Current alcohol, tobacco, and marijuana use was self-reported based on last 30-day use. UWLP was defined based on self-report of at least one of three methods to lose weight in last 30-days: (1) >=24 h of fasting, (2) diet pill use, and (3) laxative use/purging. The reference group included those with no reported UWLP. Logistic regression models adjusted for age, gender, race/ethnicity, academic performance, age-sex-specific body mass index percentiles, and perceived weight status were fitted to assess relationships between UWLP and current substance use. RESULTS: About 15 and 41 % of adolescents reported >=1 UWLP and use of >=1 substance in the last 30-days, respectively. Over half (60.1 %) of adolescents who reported substance use engaged in UWLP (p < 0.0001). The prevalence of current alcohol use (50.6 %) was the highest among those who reported UWLP, followed by marijuana (31.9 %), tobacco (19.7 %), and cocaine (10.5 %) use. Adolescents who reported current tobacco [adjusted odds ratio (AOR) 2.7, 95 % confidence interval (CI) 2.1-3.6], alcohol (AOR 2.2, 95 % CI 1.9-2.6), or marijuana (AOR 2.1, 95 % CI 1.7-2.5) use had significantly higher odds of UWLP compared to their non-user counterparts. CONCLUSIONS: This cross-sectional study shows that substance use and UWLP behaviors are likely to co-exist in adolescents. Further studies are necessary to determine the temporal relationship between substance use and UWLP. It is recommended that intervention programs for youth consider targeting these multiple health risk behaviors. PMID- 26649882 TI - Readability and Content Characteristics of Powdered Infant Formula Instructions in the United States. AB - OBJECTIVES: This study aimed to assess readability characteristics and layout features, including reading grade level, text point size, dimensions (length and width), diagrams, key directions (warnings, proper hygiene, preparation and use, and storage), and compliance to International Code provisions of English-language instructions affixed to a representative sample of brand-name and generic powdered, infant formula containers currently available for purchase in the US. METHODS: During June 2014, comprehensive Internet searches were conducted to identify brand-name powdered infant formulas currently available for purchase in the US (n = 10). The English-language instruction section affixed to each formula container was evaluated for readability characteristics and layout features, including reading grade level, text point size, dimensions (length and width), diagrams, key directions (warnings, proper hygiene, preparation and use, and storage), and compliance to International Code. RESULTS: Overall, containers were similar in circumference (50.8 +/- 7.3 cm) and height (14.0 +/- 0.0 cm) and held an average of 656.0 +/- 12.3 g (range 629-663 g) of powdered infant formula. Both Directions for Preparation and Use and Storage Instructions sections had average reading difficulty scores at the college level. Step-by-Step Preparation Directions and Warnings and Safe Handling sections had reading difficulty between the 8th and 9th grade level. All container labels contained three diagrams depicting step-by-step preparation instructions and a feeding chart. Overall, infant formula containers reviewed in our study adhered to compliance to International Code provisions. CONCLUSIONS: As negative health outcomes are associated with inappropriately prepared infant formula feedings, healthcare providers should routinely query infant caregivers regarding their formula preparation and administration practices. PMID- 26649883 TI - The Edinburgh Postnatal Depression Scale: Screening Tool for Postpartum Anxiety as Well? Findings from a Confirmatory Factor Analysis of the Hebrew Version. AB - OBJECTIVES: The Edinburgh Postnatal Depression Scale (EPDS) was originally created as a uni-dimensional scale to screen for postpartum depression (PPD); however, evidence from various studies suggests that it is a multi-dimensional scale measuring mainly anxiety in addition to depression. The factor structure of the EPDS seems to differ across various language translations, raising questions regarding its stability. This study examined the factor structure of the Hebrew version of the EPDS to assess whether it is uni- or multi-dimensional. METHODS: Seven hundred and fifteen (n = 715) women were screened at 6 weeks postpartum using the Hebrew version of the EPDS. Confirmatory factor analysis (CFA) was used to test four models derived from the literature. RESULTS: Of the four CFA models tested, a 9-item two factor model fit the data best, with one factor representing an underlying depression construct and the other representing an underlying anxiety construct. CONCLUSIONS: for Practice The Hebrew version of the EPDS appears to consist of depression and anxiety sub-scales. Given the widespread PPD screening initiatives, anxiety symptoms should be addressed in addition to depressive symptoms, and a short scale, such as the EPDS, assessing both may be efficient. PMID- 26649884 TI - Factors Associated with Early Pregnancy Smoking Status Among Low-Income Smokers. AB - OBJECTIVES: To compare pregnant women who are current smokers at their first prenatal visit with those who recently quit smoking in the 90 days prior to their first prenatal visit (i.e., spontaneous quitters) to identify differences between them and factors that predict their intake smoking status. METHODS: One hundred and thirty participants were enrolled in this cross-sectional research study. The sample was drawn from a population of pregnant women attending their first prenatal visit at a low-income obstetrics clinic in Baltimore, Maryland; the large majority of which have characteristics that previous research has identified as putting them at high-risk of continued smoking during pregnancy. Participants were recruited through referrals from clinical staff. Intake data collection occurred between March and December, 2013. RESULTS: Of the 130 pregnant women enrolled in the study, 126 had complete intake data. The sample included 86 current smokers and 40 recent quitters. The large majority of participants were African American with an average age of 26. Current smokers were significantly more likely than recent quitters to have: more depression symptoms; self-perceived stress; internalizing and externalizing disorder symptoms; substance use disorders; and tobacco dependence. The most significant predictors of smoking status at first prenatal visit were depressive symptoms, readiness to quit, and number of children. CONCLUSIONS: for Practice Differences were identified at intake among this sample of pregnant women already considered to be at high-risk for continued smoking throughout their pregnancy. This study identified relevant factors associated with whether or not a woman had recently quit smoking in early pregnancy or was continuing to smoke at her first prenatal visit. Knowledge of these factors may benefit physicians in understanding and promoting smoking cessation throughout the perinatal period and specifically intervening to decrease depressive symptoms and increasing readiness to quit may improve outcomes. PMID- 26649885 TI - Protocols for Analyzing the Role of Paneth Cells in Regenerating the Murine Intestine using Conditional Cre-lox Mouse Models. AB - The epithelial surface of the mammalian intestine is a dynamic tissue that renews every 3 - 7 days. Understanding this renewal process identified a population of rapidly cycling intestinal stem cells (ISCs) characterized by their expression of the Lgr5 gene. These are supported by a quiescent stem cell population, marked by Bmi-1 expression, capable of replacing them in the event of injury. Investigating the interactions between these populations is crucial to understanding their roles in disease and cancer. The ISCs exist within crypts on the intestinal surface, these niches support the ISC in replenishing the epithelia. The interaction between active and quiescent ISCs likely involves other differentiated cells within the niche, as it has previously been demonstrated that the ''stemness'' of the Lgr5 ISC is closely tied to the presence of their neighboring Paneth cells. Using conditional cre-lox mouse models we tested the effect of deleting the majority of active ISCs in the presence or absence of the Paneth cells. Here we describe the techniques and analysis undertaken to characterize the intestine and demonstrate that the Paneth cells play a crucial role within the ISC niche in aiding recovery following substantial insult. PMID- 26649886 TI - Model-Based Tumor Growth Dynamics and Therapy Response in a Mouse Model of De Novo Carcinogenesis. AB - Tumorigenesis is a complex, multistep process that depends on numerous alterations within the cell and contribution from the surrounding stroma. The ability to model macroscopic tumor evolution with high fidelity may contribute to better predictive tools for designing tumor therapy in the clinic. However, attempts to model tumor growth have mainly been developed and validated using data from xenograft mouse models, which fail to capture important aspects of tumorigenesis including tumor-initiating events and interactions with the immune system. In the present study, we investigate tumor growth and therapy dynamics in a mouse model of de novo carcinogenesis that closely recapitulates tumor initiation, progression and maintenance in vivo. We show that the rate of tumor growth and the effects of therapy are highly variable and mouse specific using a Gompertz model to describe tumor growth and a two-compartment pharmacokinetic/ pharmacodynamic model to describe the effects of therapy in mice treated with 5 FU. We show that inter-mouse growth variability is considerably larger than intra mouse variability and that there is a correlation between tumor growth and drug kill rates. Our results show that in vivo tumor growth and regression in a double transgenic mouse model are highly variable both within and between subjects and that mathematical models can be used to capture the overall characteristics of this variability. In order for these models to become useful tools in the design of optimal therapy strategies and ultimately in clinical practice, a subject specific modelling strategy is necessary, rather than approaches that are based on the average behavior of a given subject population which could provide erroneous results. PMID- 26649888 TI - Peculiar Magnetotransport Features of Ultranarrow Graphene Nanoribbons under High Magnetic Field. AB - Through magnetotransport measurements, we investigate ultrasmooth graphene bilayer nanoribbons obtained by multiwall carbon nanotube unzipping, under a high magnetic field up to 55 T. The high quality of the samples allows us to observe a Hall quantization in ribbons as narrow as 20 nm. The presence, for certain samples, of isolated peaks in the resistance plateau is found to be related to a very moderate long-range disorder, which induces magnetic-field-dependent interedge scattering. Tight-binding numerical simulations of electron transport illustrate and confirm this picture. Our study provides important insights into the quantum Hall effect in quasi-1D systems and indicates possible lines for future investigations of the nonchiral edge states induced by zigzag nanoribbon sections. PMID- 26649887 TI - Complex Evolutionary and Genetic Patterns Characterize the Loss of Scleral Ossification in the Blind Cavefish Astyanax mexicanus. AB - The sclera is the tough outer covering of the eye that provides structural support and helps maintain intraocular pressure. In some fishes, reptiles, and birds, the sclera is reinforced with an additional ring of hyaline cartilage or bone that forms from scleral ossicles. Currently, the evolutionary and genetic basis of scleral ossification is poorly understood, especially in teleost fishes. We assessed scleral ossification among several groups of the Mexican tetra (Astyanax mexicanus), which exhibit both an eyed and eyeless morph. Although eyed Astyanax surface fish have bony sclera similar to other teleosts, the ossicles of blind Astyanax cavefish generally do not form. We first sampled cavefish from multiple independent populations and used ancestral character state reconstructions to determine how many times scleral ossification has been lost. We then confirmed these results by assessing complementation of scleral ossification among the F1 hybrid progeny of two cavefish populations. Finally, we quantified the number of scleral ossicles present among the F2 hybrid progeny of a cross between surface fish and cavefish, and used this information to identify quantitative trait loci (QTL) responsible for this trait. Our results indicate that the loss of scleral ossification is common-but not ubiquitous-among Astyanax cavefish, and that this trait has been convergently lost at least three times. The presence of wild-type, ossified sclera among the F1 hybrid progeny of a cross between different cavefish populations confirms the convergent evolution of this trait. However, a strongly skewed distribution of scleral ossicles found among surface fish x cavefish F2 hybrids suggests that scleral ossification is a threshold trait with a complex genetic basis. Quantitative genetic mapping identified a single QTL for scleral ossification on Astyanax linkage group 1. We estimate that the threshold for this trait is likely determined by at least three genetic factors which may control the severity and onset of lens degeneration in cavefishes. We conclude that complex evolutionary and genetic patterns underlie the loss of scleral ossification in Astyanax cavefish. PMID- 26649889 TI - Mental Health and Service Issues Faced by Older Immigrants in Canada: A Scoping Review. AB - RESUME Une population vieillissante et la croissance de la population sur la base de l'immigration necessitent que la recherche, la pratique et la politique doivent se concentrer sur la sante mentale des immigrants ages, surtout parce que leur sante mentale semble se deteriorer au fil du temps. Cette revue se concentre sur: Qu'est-ce que l'on sait sur les determinants sociaux de la sante mentale chez les immigrants ages, et quels sont les obstacles a l'acces aux services de sante mentale confrontes par les immigrants ages? Les resultats revelent que (1) les determinants sociaux decisifs de la sante mentale sont la culture, le sexe et les services de sante; (2) que les immigrants plus ages utilisent les services de sante mentale de moins que leurs homologues nes au Canada a cause des obstacles tels que, par exemple, les croyances et les valeurs culturelles, un manque de services culturellement et linguistiquement appropriees, des difficultes financieres, et l'agisme; et (3) quelles que soient les sous-categories dans cette population, les immigrants ages eprouvent des inegalites en matiere de la sante mentale. La preuve des recherches disponibles indique que de combler les lacunes des service de sante mentale devrait devenir une priorite pour la politique et la pratique du systeme de soins de sante au Canada. PMID- 26649890 TI - Life History and Risk of Death after 50: A Survival Analysis for Europe. AB - RESUME Dans notre etude nous avons examine l'influence des evenements du passe des individus sur le risque de deces des Europeens ages de plus de 50 ans, en controlant autres variables pertinentes. Notre analyse etait basee sur les donnees d'entretiens biographiques retrospectifs, les donnees d'entretiens reguliers au suivi longitudinal et celles d'entretiens de fin de vie de l'Enquete europeenne SHARE sur la sante, le vieillissement et la retraite en Europe. En particulier, nous relevons l'etat de sante auto-declare pendant l'enfance; les periodes de pauvrete, de faim et de mauvaise sante eprouvees dans le passe; et aussi l'histoire des soins de sante, y compris les soins dentaires, les analyses de sang et les mesures de pression arterielle. Ces informations, avec l'age, le sexe, l'etat de sante subjectif et objectif, et d'autres facteurs socio demographiques, permettent d'expliquer le risque de deces. L'analyse de survie, en controlant des variables pertinentes, montre que les evenements du passe ont un impact significatif sur le risque de deces des Europeens ages de plus de 50 ans. PMID- 26649891 TI - Driving Skills Training for Older Adults: An Assessment of DriveSharp. AB - RESUME Les procedures de formation cognitive informatique visent a augmenter la securite en ameliorant les competences relatives a la conduite, comme la vitesse de-traitement et le Useful Field of View. L'etude actuelle a evalue l'efficacite du DriveSharp dans la formation des conducteurs ages dans un cadre de classe realiste. Les participants (n = 24) ont assiste a 10 heures de cours de DriveSharp pendant 5 semaines. Les seances pre- et post-test ont evalues ameliorations sur un essai dynamique de la perception du risque, Trails A et Trails B. Un groupe de controle (n = 18) a termine seulement les seances pre- et post-test. En classe, les temps de formation etaient plus bas que prevus. L'amelioration des participants aux jeux ont stabilisee apres la premiere evaluation, et le groupe de DriveSharp n'a pas demontre une amelioration significative des performances sur les tests, par rapport au groupe de controle. Parmi plusieurs questions relatives a la facilite d'utilisation, les plus problematiques etaient le malentendudes objectifs de la tache et la difference entre la formation et l'evaluation. Il y a plusieurs implications pour ceux qui utilisent DriveSharp pour ameliorer la securite des conducteurs ages. PMID- 26649892 TI - Not Too Old, Not Too Young: Older Women's Perceptions of Physicians. AB - RESUME Les femmes plus agees interagissent avec les medecins plus souvent que les hommes ages et les personnes plus jeunes; pourtant, la connaissance et la comprehension de leurs experiences avec les medecins sont limitees. Le but de cette etude etait d'etudier les perceptions des femmes agees de leurs interactions avec les medecins et d'identifier ce que les femmes veulent de leurs medecins. Les entrevues en profondeur avec 30 femmes agees montrent que la majorite veulent etre impliquee activement dans leurs propres soins de sante. Dans la relation patient-medecin, les femmes donnent generalement la priorite aux qualites personnelles de medecins et leur comportement a l'egard du patient. Pour de nombreuses femmes, l'age et le sexe du medecin ont aussi leur importance. PMID- 26649893 TI - A Birth Cohort Study of Maternal and Infant Serum PCB-153 and DDE Concentrations and Responses to Infant Tuberculosis Vaccination. AB - BACKGROUND: Reasons for the highly variable and often poor protection conferred by the Mycobacterium bovis bacille Calmette-Guerin (BCG) vaccine are multifaceted and poorly understood. OBJECTIVES: We aimed to determine whether early-life exposure to PCBs (polychlorinated biphenyls) and DDE [1,1-dichloro-2,2-bis(p chlorophenyl)ethylene] reduces 6-month infant BCG vaccine response. METHODS: Data came from families participating in a prospective birth cohort in eastern Slovakia. At birth, maternal and cord blood were collected for chemical analyses, and infants were immunized with BCG. Blood was collected from infants for chemical analyses and to determine 6-month BCG-specific immunoglobulin (Ig) G and IgA levels. Multivariable linear regression models were fit to examine chemical BCG associations among approximately 500 mother-infant pairs, with adjustment for confounders. RESULTS: The median 6-month infant concentration of the prevalent congener PCB-153 was 113 ng/g lipid [interquartile range (IQR): 37-248], and 388 ng/g lipid (IQR: 115-847) for DDE. Higher 6-month infant concentrations of PCB 153 and DDE were strongly associated with lower 6-month BCG-specific antibody levels. For instance, BCG-specific IgG levels were 37% lower for infants with PCB 153 concentrations at the 75th percentile compared to the 25th percentile (95% CI: -42, -32; p < 0.001). Results were similar in magnitude and precision for DDE. There was also evidence of PCB-DDE additivity, where exposure to both compounds reduced anti-BCG levels more than exposure to either compound alone. CONCLUSIONS: The associations observed in this study indicate that environmental exposures may be overlooked contributors to poorer responses to BCG vaccine. The overall association between these exposures and tuberculosis incidence is unknown. CITATION: Jusko TA, De Roos AJ, Lee SY, Thevenet-Morrison K, Schwartz SM, Verner MA, Palkovicova Murinova L, Drobna B, Kocan A, Fabisikova A, Conka K, Trnovec T, Hertz-Picciotto I, Lawrence BP. 2016. A birth cohort study of maternal and infant serum PCB-153 and DDE concentrations and responses to infant tuberculosis vaccination. Environ Health Perspect 124:813-821; http://dx.doi.org/10.1289/ehp.1510101. PMID- 26649894 TI - Time-based prospective memory in adults with developmental dyslexia. AB - Prospective memory (PM) is memory for delayed intentions. Despite its importance to everyday life, the few studies on PM function in adults with dyslexia which exist have relied on self-report measures. To determine whether self-reported PM deficits can be measured objectively, laboratory-based PM tasks were administered to 24 adults with dyslexia and 25 age- and IQ-matched adults without dyslexia. Self-report data indicated that people with dyslexia felt that time-based PM (TBPM; requiring responses at certain times in the future) was most problematic for them and so this form of PM was the focus of investigation. Whilst performing the ongoing task from which they were required to break out every 3 min to make a PM-related response, the participants were allowed to make clock checks whenever they wished. The cognitive demands made on ongoing behaviour were manipulated to determine whether loading executive resources had a mediating role in dyslexia related deficits in PM, resulting in three tasks with varying working memory load. A semi-naturalistic TBPM task was also administered, in which the participants were asked to remind the experimenter to save a data file 40 min after being given this instruction. Dyslexia-related differences were found across all three computerized tasks, regardless of cognitive load. The adults with dyslexia made fewer correct PM responses and also fewer clock checks. On the semi-naturalistic task, the participants with dyslexia were less likely to remember to remind the experimenter to save the file. This is the first study to document PM deficits in dyslexia using objective measures of performance. Since TBPM impairments were found under more naturalistic conditions as well as on computerized tasks, the results have implications for workplace support for adults with dyslexia. PMID- 26649895 TI - A Novel Time-Dependent CENP-E Inhibitor with Potent Antitumor Activity. AB - Centromere-associated protein E (CENP-E) regulates both chromosome congression and the spindle assembly checkpoint (SAC) during mitosis. The loss of CENP-E function causes chromosome misalignment, leading to SAC activation and apoptosis during prolonged mitotic arrest. Here, we describe the biological and antiproliferative activities of a novel small-molecule inhibitor of CENP-E, Compound-A (Cmpd-A). Cmpd-A inhibits the ATPase activity of the CENP-E motor domain, acting as a time-dependent inhibitor with an ATP-competitive-like behavior. Cmpd-A causes chromosome misalignment on the metaphase plate, leading to prolonged mitotic arrest. Treatment with Cmpd-A induces antiproliferation in multiple cancer cell lines. Furthermore, Cmpd-A exhibits antitumor activity in a nude mouse xenograft model, and this antitumor activity is accompanied by the elevation of phosphohistone H3 levels in tumors. These findings demonstrate the potency of the CENP-E inhibitor Cmpd-A and its potential as an anticancer therapeutic agent. PMID- 26649896 TI - Biophysical Characterization of G-Quadruplex Recognition in the PITX1 mRNA by the Specificity Domain of the Helicase RHAU. AB - Nucleic acids rich in guanine are able to fold into unique structures known as G quadruplexes. G-quadruplexes consist of four tracts of guanylates arranged in parallel or antiparallel strands that are aligned in stacked G-quartet planes. The structure is further stabilized by Hoogsteen hydrogen bonds and monovalent cations centered between the planes. RHAU (RNA helicase associated with AU-rich element) is a member of the ATP-dependent DExH/D family of RNA helicases and can bind and resolve G-quadruplexes. RHAU contains a core helicase domain with an N terminal extension that enables recognition and full binding affinity to RNA and DNA G-quadruplexes. PITX1, a member of the bicoid class of homeobox proteins, is a transcriptional activator active during development of vertebrates, chiefly in the anterior pituitary gland and several other organs. We have previously demonstrated that RHAU regulates PITX1 levels through interaction with G quadruplexes at the 3'-end of the PITX1 mRNA. To understand the structural basis of G-quadruplex recognition by RHAU, we characterize a purified minimal PITX1 G quadruplex using a variety of biophysical techniques including electrophoretic mobility shift assays, UV-VIS spectroscopy, circular dichroism, dynamic light scattering, small angle X-ray scattering and nuclear magnetic resonance spectroscopy. Our biophysical analysis provides evidence that the RNA G quadruplex, but not its DNA counterpart, can adopt a parallel orientation, and that only the RNA can interact with N-terminal domain of RHAU via the tetrad face of the G-quadruplex. This work extends our insight into how the N-terminal region of RHAU recognizes parallel G-quadruplexes. PMID- 26649897 TI - Efficiency and bacterial populations related to pollutant removal in an upflow microaerobic sludge reactor treating manure-free piggery wastewater with low COD/TN ratio. AB - A novel upflow microaerobic sludge reactor (UMSR) had proved excellent in nitrogen removal from manure-free piggery wastewater characterized by high concentration of ammonium (NH4(+)-N) and low chemical oxygen demand (COD) to total nitrogen (TN) ratio, but the biological mechanism in the UMSR was still indeterminate. With a constant nitrogen loading rate of 1.10kg/(m(3)d) at hydraulic retention time 8h, the UMSR was kept performing for 67days in the present research and the average load removal of COD, NH4(+)-N and TN was as high as 0.72, 0.76 and 0.94kg/(m(3)d), respectively. Compared with the inoculated sludge, the acclimated sludge was richer in genera responsible for the biological removal of carbon, nitrogen and phosphorus. Ammonium oxidation bacteria, heterotrophic denitrifiers, autotrophic denitrifiers and phosphate accumulating organisms coexisted perfectly in the microaerobic system, and their synergistic action made the UMSR perform well in COD, NH4(+)-N, TN and phosphate removal. PMID- 26649898 TI - Nitrogen removal characteristics of enhanced in situ indigenous aerobic denitrification bacteria for micro-polluted reservoir source water. AB - Indigenous oligotrophic aerobic denitrifiers nitrogen removal characteristics, community metabolic activity and functional genes were analyzed in a micro polluted reservoir. The results showed that the nitrate in the enhanced system decreased from 1.71+/-0.01 to 0.80+/-0.06mg/L, while the control system did little to remove and there was no nitrite accumulation. The total nitrogen (TN) removal rate of the enhanced system reached 38.33+/-1.50% and the TN removal rate of surface sediment in the enhanced system reached 23.85+/-2.52%. TN removal in the control system experienced an 85.48+/-2.37% increase. The densities of aerobic denitrifiers in the enhanced system ranged from 2.24*10(5) to 8.13*10(7)cfu/mL. The abundance of nirS and nirK genes in the enhanced system were higher than those of in the control system. These results suggest that the enhanced in situ indigenous aerobic denitrifiers have potential applications for the bioremediation of micro-polluted reservoir system. PMID- 26649899 TI - Life cycle assessment on biogas production from straw and its sensitivity analysis. AB - This study aims to investigate the synthetically environmental impacts and Global Warming Potentials (GWPs) of straw-based biogas production process via cradle-to gate life cycle assessment (LCA) technique. Eco-indicator 99 (H) and IPCC 2007 GWP with three time horizons are utilized. The results indicate that the biogas production process shows beneficial effect on synthetic environment and is harmful to GWPs. Its harmful effects on GWPs are strengthened with time. Usage of gas-fired power which burns the self-produced natural gas (NG) can create a more sustainable process. Moreover, sensitivity analysis indicated that total electricity consumption and CO2 absorbents in purification unit have the largest sensitivity to the environment. Hence, more efforts should be made on more efficient use of electricity and wiser selection of CO2 absorbent. PMID- 26649900 TI - Isolation and characterization of bacterium producing lipid from short-chain fatty acids. AB - Anaerobic fermentation generates propionic acid, which inhibits microbial growth and accumulates in wastewater containing increased amounts of organic matter. We therefore isolated a propionic acid-assimilating bacterium that could produce triacylglycerol, for use in wastewater treatment. Nitratireductor sp. strain OM-1 can proliferate in medium containing propionic, acetic, butyric, and valeric acids as well as glycerol, and produces triacylglycerol when both propionic and acetic acids or glycerol are present. In composite model wastewater containing acetic acid, propionic acid and glycerol, this strain shows an even higher conversion rate, suggesting that it is suitable for wastewater treatment. Further, nitrogen depletion in medium containing an acetic-propionic acid mixture resulted in the production of the light oil 2-butenoic acid 1-methylethyl ester, but not triacylglycerol. Collectively, our data indicate that strain OM-1 has the potential to reduce accumulation of activated sludge in wastewater treatment and may contribute to the production of biodiesel. PMID- 26649901 TI - Rheological Behavior of Oil-Swollen Wormlike Surfactant Micelles. AB - We study the rheological properties of wormlike micellar aqueous solutions of an anionic surfactant potassium oleate containing solubilized 1-phenyldodecane. We show that upon increasing the amount of absorbed hydrocarbon the rheological behavior of semidilute micellar solutions changes drastically, showing a sequence of different regimes: (i) a "fast-breaking" entangled regime, when very long micellar chains form a network; (ii) an "unbreakable" entangled regime, when the shortening of the micelles leads to the decrease of their reptation time up to the values close to the breaking time; (iii) an unentangled regime (for the first time evidenced for wormlike micelles), where the micelles are so short that they cannot interlace. Within the entangled regime, an unusual rheological behavior has been discovered, probably characterized by the dominant role of end or bond interchange reactions or "breathing" modes, which leads to a novel hypothesis that hydrocarbon is distributed nonuniformly along the micellar length, thus increasing the probability of micellar breakage at certain points. PMID- 26649902 TI - SAP deficiency mitigated atherosclerotic lesions in ApoE(-/-) mice. AB - OBJECTIVE: Serum amyloid P conpoent (SAP), a member of the pentraxin family, interact with pathogens and cell debris to promote their removal by macrophages and neutrophils and is co-localized with atherosclerotic plaques in patients. However, the exact mechanism of SAP in atherogenesis is still unclear. We investigated whether SAP influence macrophage recruitment and foam cell formation and ultimately affect atherosclerotic progression. METHODS: we generated apoE(-/ ); SAP(-/-) (DKO) mice and fed them western diet for 4 and 8 weeks to characterize atherosclerosis development. RESULTS: SAP deficiency effectively reduced plaque size both in the aorta (p = 0.0006 for 4 wks; p = 0.0001 for 8 wks) and the aortic root (p = 0.0061 for 4 wks; p = 0.0079 for 8wks) compared with apoE(-/-) mice. Meanwhile, SAP deficiency inhibited oxLDL-induced foam cell formation (p = 0.0004) compared with apoE(-/-) mice and SAP treatment increases oxLDL-induced foam cell formation (p = 0.002) in RAW cells. Besides, SAP deficiency reduced macrophages recruitment (p = 0.035) in vivo and in vitro (p = 0.026). Furthermore, SAP treatment enhanced CD36 (p = 0.007) and FcgammaRI (p = 0.031) expression induced by oxLDL through upregulating JNK and p38 MAPK phosphorylation whereas specific JNK1/2 inhibitor reduced CD36 (p = 0.0005) and FcgammaRI (P = 0.0007) expression in RAW cell. SAP deficiency also significantly decreased the expression of M1 and M2 macrophage markers and inflammatory cytokines in oxLDL-induced macrophages. CONCLUSION: SAP deficiency mitigated foam cell formation and atherosclerotic development in apoE(-/-) mice, due to reduction in macrophages recruitment, polarization and pro-inflammatory cytokines and inhibition the CD36/FcgammaR-dependent signaling pathway. PMID- 26649903 TI - Soluble CXCL16 and risk of myocardial infarction: The HUNT study in Norway. AB - BACKGROUND AND AIMS: CXCL16 is an interferon-gamma-regulated chemokine and scavenger receptor for oxidized low-density lipoprotein that is expressed in atherosclerotic lesions. High soluble CXCL16 levels during acute cardiovascular events may indicate impaired long-term prognosis, but it is not known if CXCL16 is associated with the risk of developing cardiovascular disease in healthy individuals. We aimed to assess whether soluble CXCL16 is associated with risk of myocardial infarction (MI) in a nested case-control study within a large population-based cohort. METHODS: We conducted a case-control study nested within the population-based HUNT2 cohort in Norway. A total of 58,761 men and women free of known cardiovascular disease were followed for a first myocardial infarction (MI), and during 11.3 years of follow-up, 1587 incident MIs were registered. These cases were compared to 3959 age- and sex-matched controls. RESULTS: Among MI cases, the median CXCL16 concentration was 9.9 ng/ml (interquartile range 7.2 12.6) compared to 9.6 ng/ml (interquartile range 6.9-12.3) among controls (p < 0.001). Although the difference in median value between cases and controls was small, MI risk was twice as high (OR, 2.08; 95% CI: 1.74-2.50) among participants in the highest quartile compared to participants in the lowest quartile of CXCL16 after adjustment for age and sex. Additional adjustment for serum lipids, body mass index, smoking habits, diabetes mellitus, serum creatinine, and high sensitivity C-reactive protein attenuated the excess risk by about half, yielding an odds ratio of 1.46 (95% CI: 1.19-1.79). CONCLUSION: Soluble CXCL16 may provide novel information in clinical cardiovascular risk assessment, but its importance needs to be verified in other prospective population studies. PMID- 26649904 TI - Novel Parallelized Electroporation by Electrostatic Manipulation of a Water-in Oil Droplet as a Microreactor. AB - Electroporation is the most widely used transfection method for delivery of cell impermeable molecules into cells. We developed a novel gene transfection method, water-in-oil (W/O) droplet electroporation, using dielectric oil and an aqueous droplet containing mammalian cells and transgene DNA. When a liquid droplet suspended between a pair of electrodes in dielectric oil is exposed to a DC electric field, the droplet moves between the pair of electrodes periodically and droplet deformation occurs under the intense DC electric field. During electrostatic manipulation of the droplet, the local intense electric field and instantaneous short circuit via the droplet due to droplet deformation facilitate gene transfection. This method has several advantages over conventional transfection techniques, including co-transfection of multiple transgene DNAs into even as few as 103 cells, transfection into differentiated neural cells, and the capable establishment of stable cell lines. In addition, there have been improvements in W/O droplet electroporation electrodes for disposable 96-well plates making them suitable for concurrent performance without thermal loading by a DC electric field. This technique will lead to the development of cell transfection methods for novel regenerative medicine and gene therapy. PMID- 26649905 TI - Human colon cancer targeted pro-apoptotic, anti-metastatic and cytostatic effects of binuclear Silver(I)-N-Heterocyclic carbene (NHC) complexes. AB - The current mechanistic study was conducted to explore the effects of increased lipophilicity of binuclear silver(I)-NHC complexes on cytotoxicity. Two new silver(I)-N-Heterocyclic Carbene (NHC) complexes (3 and 4), having lypophilic terminal alkyl chains (Octyl and Decyl), were derived from meta-xylyl linked bis benzimidazolium salts (1 and 2). Each of the synthesized compounds was characterized by microanalysis and spectroscopic techniques. The complexes were tested for their cytotoxicity against a panel of human cancer c as well normal cell lines using MTT assay. Based on MTT assay results, complex 4 was found to be selectively toxic towards human colorectal carcinoma cell line (HCT 116). Complex 4 was further studied in detail to explore the mechanism of cell death and findings of the study revealed that complex 4 has promising pro-apoptotic and anti-metastatic activities against HCT 116 cells. Furthermore, it showed pronounced cytostatic effects in HCT 116 multicellular spheroid model. Hence, binuclear silver(I)-NHC complexes with longer terminal aliphatic chains have worth to be further studied against human colon cancer for the purpose of drug development. PMID- 26649906 TI - Identification of novel scaffolds for potential anti-Helicobacter pylori agents based on the crystal structure of H. pylori 3-deoxy-d-manno-octulosonate 8 phosphate synthase (HpKDO8PS). AB - The crystal structure of 3-deoxy-d-manno-octulosonate-8-phosphate synthase (KDO8PS) from Helicobacter pylori (HpKDO8PS) was determined alone and within various complexes, revealing an extra helix (HE) that is absent in the structures of KDO8PS from other organisms. In contrast to the metal coordination of the KDO8PS enzyme from Aquifex aeolicus, HpKDO8PS is specifically coordinated with Cd(2+) or Zn(2+) ions, and isothermal titration calorimetry (ITC) and differential scanning fluorimetry (DSF) revealed that Cd(2+) thermally stabilizes the protein structure more efficiently than Zn(2+). In the substrate-bound structure, water molecules play a key role in fixing residues in the proper configuration to achieve a compact structure. Using the structures of HpKDO8PS and API [arabinose 5-phosphate (A5P) and phosphoenolpyruvate (PEP) bisubstrate inhibitor], we generated 21 compounds showing potential HpKDO8PS-binding properties via in silico virtual screening. The capacity of three, avicularin, hyperin, and MC181, to bind to HpKDO8PS was confirmed through saturation transfer difference (STD) experiments, and we identified their specific ligand binding modes by combining competition experiments and docking simulation analysis. Hyperin was confirmed to bind to the A5P binding site, primarily via hydrophilic interaction, whereas MC181 bound to both the PEP and A5P binding sites through hydrophilic and hydrophobic interactions. These results were consistent with the epitope mapping by STD. Our results are expected to provide clues for the development of HpKDO8PS inhibitors. PMID- 26649907 TI - Synthesis and evaluation of antibacterial and antitumor activities of new galactopyranosylated amino alcohols. AB - Three series of d-galactose derivatives linked to a lipophilic aminoalcohol moiety were synthesized and their antibacterial activity was evaluated against Mycobacterium tuberculosis and representative species of Gram positive and Gram negative bacteria. Five out of the thirteen tested compounds displayed activity against M. tuberculosis, with a minimal inhibitory concentration (MIC) of 12.5 MUg/mL and seven compounds were active against the four bacterial strains tested. The best results were obtained for amino alcohols 10 and 11 against Staphylococcus epidermidis (MIC = 2 MUg/mL). The antitumor activity was evaluated against three tumor cell lines (MCF-7, HeLa and MO59J) and compared to the normal cell line GM07492A. The results showed that the lowest IC50 values were observed for the amino alcohol 16 against MCF-7 (11.9 MUM) and MO59J (10.0 MUM). PMID- 26649908 TI - Epidural Blockade Affects the Pharmacokinetics of Propofol in Surgical Patients. AB - BACKGROUND: Neuraxial blockade reduces the dose requirements of sedative agents. It is unclear whether neuraxial blockade affects the pharmacokinetics and/or the pharmacodynamics of IV hypnotics. We therefore studied the influence of epidural blockade on the pharmacokinetics of propofol in patients scheduled for general surgery. METHODS: Twenty-eight patients were randomly divided into 4 groups, in a double-blind manner, to receive 0, 50, 100, or 150 mg epidural ropivacaine. When the epidural blockade had stabilized, a target-controlled infusion of propofol was started at a target concentration of 1, 2.5, 4, and 6 ug/mL at 0, 6, 12, and 18 minutes, respectively. The infusion was terminated at 24 minutes. Arterial blood samples for blood propofol concentration determination were taken during and up to 150-minute postinfusion. The influence of epidural blockade on propofol pharmacokinetics was determined by mixed-effects modeling. RESULTS: With a ropivacaine dose increasing from 0 to 150 mg, the number of blocked segments (median [range]) increased from 0 (0-3) to 16 (6-21). With increasing epidural dose, blood propofol concentration increasingly exceeded target concentration. An epidural blockade of 20 segments reduced propofol's elimination clearance from 2.64 +/- 0.12 to 1.87 +/- 0.08 L/min. Adjusting for weight and sex further improved the propofol pharmacokinetic model. CONCLUSIONS: Epidural blockade affects the pharmacokinetics of propofol and the performance of a target controlled infusion of propofol. At an epidural ropivacaine dose that blocks 20 segments, the propofol dosage or target concentration may be reduced by 30% compared with when no epidural blockade is present. An epidural-induced reduction in hepatic and/or renal blood flow may explain this pharmacokinetic interaction. PMID- 26649909 TI - The Isolated Effect of Adductor Canal Block on Quadriceps Femoris Muscle Strength After Total Knee Arthroplasty: A Triple-Blinded, Randomized, Placebo-Controlled Trial with Individual Patient Analysis. AB - BACKGROUND: Using peripheral nerve block after total knee arthroplasty (TKA), without impeding mobility, is challenging. We hypothesized that the analgesic effect of adductor canal block (ACB) could increase the maximum voluntary isometric contraction (MVIC) of the quadriceps femoris muscle after TKA. METHODS: We included 64 patients on the first postoperative day. Group A received an ACB with 30 mL ropivacaine 0.75% at t0 and with 30 mL saline 60 minutes later (t60). Group B received the treatment in the opposite order. The primary end point was the difference between groups in MVIC at t60, expressed as a percentage of postoperative preblock values. In this manner, the effect of the ACB could be isolated from the detrimental effect on muscle strength caused by the surgery. Secondary end points were differences between groups in mobility and pain scores. We planned a subgroup analysis dividing patients according to preblock pain scores during knee flexion. RESULTS: At t60, MVIC was higher in group A, with a median of 170% (95% confidence interval [CI], 147-231) of preblock values compared with 93% (95% CI, 82-98) in group B (P < 0.0001). No statistically significant differences were found in the Timed Up and Go (TUG) test. Three patients lost the ability to perform the TUG test in group A. At t60, differences in visual analog scale pain were in favor of group A; 12 mm (95% CI, 6-18) at rest, 14 mm (95% CI, 5-22) during knee flexion, and 18 mm (95% CI, 10-26) during the TUG test. CONCLUSIONS: ACB improves quadriceps femoris muscle strength, but whether this translates into enhanced mobility is not clearly supported by this study. PMID- 26649910 TI - A Comparison of Photoplethysmography Versus Esophageal Doppler for the Assessment of Cardiac Index During Major Noncardiac Surgery. AB - BACKGROUND: In this prospective observational study, we compared changes in cardiac index (CI) during fluid challenge using photoplethysmography (PPG; NexfinTM) (CIPPG) versus esophageal Doppler (ED) (CIED) in major noncardiac surgery patients. METHODS: Measurements were obtained when the attending anesthesiologist decided to perform a fluid challenge. Correlations with linear regression, Bland-Altman analysis, and analysis of covariance were performed. Trending ability was studied using 2 different methods: a 4-quadrant plot and a polar plot. RESULTS: Forty-three patients were analyzed with a total of 111 fluid challenges. There was a significant linear relationship between CI PPG and CI ED (r2 = 0.34; P < 0.001). The bias between the ED and the PPG measurements of CI was -0.114 (95% confidence interval [CI95], -1.9 to 1.7) L/min/m2, with a mean percentage error of 55%. The correlation between the changes in CI during a fluid challenge was significant (r2 = 0.25; P = 0.002). The concordance rate of directional changes (increase or decrease) of CI PPG and CI ED during fluid challenge was 67% (CI95, 57-75) for the whole data set and 85% (CI95, 70-94) with an exclusion zone of 15%. When considering ED as a reference, the sensitivity and specificity to give an additional bolus with PPG (increase in CI PPG >= 15%) were 35% (CI95, 19-55) and 90% (CI95, 81-96), respectively, with a positive predictive value of 58% (CI95, 33-80) and a negative predictive value of 78% (CI95, 68-86). CONCLUSIONS: In major noncardiac surgery patients, the evaluation of CI using PPG is not interchangeable with the evaluation of CI using ED. When considering the ED as an accurate device to assess changes in CI, PPG is not appropriate to assess the need for additional fluid administration. These results clearly indicate the limitations of PPG as an accurate device to track changes in CI compared with ED. PMID- 26649911 TI - Attending Handoff Is Correlated with the Decision to Delay Extubation After Surgery. AB - BACKGROUND: Factors including ASA physical status, blood loss, and case length have been described as correlating with the decision to delay tracheal extubation after specific surgical procedures. In this retrospective study, we investigated whether handoffs by anesthesia attendings were associated with delayed extubation after general anesthesia for a broad range of surgical procedures. METHODS: We reviewed the records of 37,824 patients who underwent general anesthesia with an endotracheal tube for surgery (excluding tracheostomy surgery, cardiac surgeries, and liver and lung transplant surgeries) from 2008 to 2013 at Columbia University Medical Center. Our primary outcome was whether the patient was extubated at the end of the surgical case. We hypothesized that attending handoff was a factor that would independently affect the decision of the anesthesiologist to extubate at the end of the surgical case. In addition, we investigated whether the association between handoff and extubation was affected by the timing of the procedure (ending in the daytime versus evening hours) by including an interaction term in the analysis. We adjusted for other variables affecting the decision to delay extubation. RESULTS: Patients (5.4%, n = 2033) were not extubated in the operating room after the completion of their surgery. Cases with an attending handoff appeared to have a greater risk of delayed extubation with an adjusted risk ratio (aRR) of 1.14 (95% confidence interval [CI], 1.03-1.25). Further analysis demonstrated that the attending handoff had a significant effect in daytime cases (aRR, 1.62; 95% CI, 1.29-2.04) but not in evening cases (aRR, 1.07; 95% CI, 0.97-1.19). CONCLUSIONS: Attending handoff was an independent significant factor that increased the risk for the delay of extubation at the end of a surgical case. PMID- 26649912 TI - Discordance in Grading Methods of Aortic Stenosis by Pre-Cardiopulmonary Bypass Transesophageal Echocardiography. AB - BACKGROUND: Current guidelines define severe aortic valve stenosis (AS) as an aortic valve area (AVA) <=1.0 cm by the continuity equation and mean gradient (DeltaPm) >= 40 mm Hg. However, these measurements can be discordant when classifying AS severity. Approximately one-third of patients with normal ejection fraction and severe AS by AVA have nonsevere AS by DeltaPm when measured by preoperative transthoracic echocardiography (TTE). Given the use of positive pressure ventilation and general anesthesia in the pre-cardiopulmonary bypass (pre-CPB) period, we hypothesized that discordance between DeltaPm and AVA during pre-CPB transesophageal echocardiography (TEE) would be higher than previously reported by TTE. METHODS: We retrospectively examined pre-CPB TEE data for patients who had aortic valve replacement, with or without coronary artery bypass grafting, from 2000 to 2012. Patients were excluded if they had ejection fraction <55%, emergency surgery, repeat sternotomy, moderate or severe mitral regurgitation, or severe aortic regurgitation. Only patients with both pre-CPB AVA and DeltaPm measurements were included. Patients were grouped according to severity (mild, moderate, and severe) by AVA or DeltaPm. Discordance was defined as disagreement between severities based on either parameter. RESULTS: A total of 277 patients met inclusion criteria. There were 227 patients with AVA <= 1.0 cm. The proportion of these patients with a DeltaPm < 40 mm Hg was 54% (95% confidence interval, 47%-61%). The rate of discordance was significantly higher than the rate (37%; P < 0.001) found in previously reported analyses using TTE. Of the patients with a DeltaPm >= 40 mm Hg, only 8% (n = 9/113) had a discordant AVA. In contrast, of the patients with DeltaPm < 40 mm Hg, 80% (n = 131/164) had a discordant AVA. CONCLUSIONS: We confirmed our hypothesis that grading AS by DeltaPm and AVA during pre-CPB TEE exhibits higher discordance than reported for TTE by others. It remains unclear whether these discrepancies reflect the effect of general anesthesia, imaging modality (TTE versus TEE) differences, inaccuracies in AS grading cutoffs when applied to pre-CPB TEE, or selection bias of the surgical population. PMID- 26649913 TI - Perceptual face processing in developmental prosopagnosia is not sensitive to the canonical location of face parts. AB - Individuals with developmental prosopagnosia (DP) are strongly impaired in recognizing faces, but it is controversial whether this deficit is linked to atypical visual-perceptual face processing mechanisms. Previous behavioural studies have suggested that face perception in DP might be less sensitive to the canonical spatial configuration of face parts in upright faces. To test this prediction, we recorded event-related brain potentials (ERPs) to intact upright faces and to faces with spatially scrambled parts (eyes, nose, and mouth) in a group of ten participants with DP and a group of ten age-matched control participants with normal face recognition abilities. The face-sensitive N170 component and the vertex positive potential (VPP) were both enhanced and delayed for scrambled as compared to intact faces in the control group. In contrast, N170 and VPP amplitude enhancements to scrambled faces were absent in the DP group. For control participants, the N170 to scrambled faces was also sensitive to feature locations, with larger and delayed N170 components contralateral to the side where all features appeared in a non-canonical position. No such differences were present in the DP group. These findings suggest that spatial templates of the prototypical feature locations within an upright face are selectively impaired in DP. PMID- 26649914 TI - Preserved memory-based orienting of attention with impaired explicit memory in healthy ageing. AB - It is increasingly recognised that spatial contextual long-term memory (LTM) prepares neural activity for guiding visuo-spatial attention in a proactive manner. In the current study, we investigated whether the decline in explicit memory observed in healthy ageing would compromise this mechanism. We compared the behavioural performance of younger and older participants on learning new contextual memories, on orienting visual attention based on these learnt contextual associations, and on explicit recall of contextual memories. We found a striking dissociation between older versus younger participants in the relationship between the ability to retrieve contextual memories versus the ability to use these to guide attention to enhance performance on a target detection task. Older participants showed significant deficits in the explicit retrieval task, but their behavioural benefits from memory-based orienting of attention were equivalent to those in young participants. Furthermore, memory based orienting correlated significantly with explicit contextual LTM in younger adults but not in older adults. These results suggest that explicit memory deficits in ageing might not compromise initial perception and encoding of events. Importantly, the results also shed light on the mechanisms of memory guided attention, suggesting that explicit contextual memories are not necessary. PMID- 26649915 TI - Is less really more: Does a prefrontal efficiency genotype actually confer better performance when working memory becomes difficult? AB - Perhaps the most widely studied effect to emerge from the combination of neuroimaging and human genetics is the association of the COMT-Val(108/158)Met polymorphism with prefrontal activity during working memory. COMT-Val is a putative risk factor in schizophrenia, which is characterized by disordered prefrontal function. Work in healthy populations has sought to characterize mechanisms by which the valine (Val) allele may lead to disadvantaged prefrontal cognition. Lower activity in methionine (Met) carriers has been interpreted as advantageous neural efficiency. Notably, however, studies reporting COMT effects on neural efficiency have generally not reported working memory performance effects. Those studies have employed relatively low/easy working memory loads. Higher loads are known to elicit individual differences in working memory performance that are not visible at lower loads. If COMT-Met confers greater neural efficiency when working memory is easy, a reasonable prediction is that Met carriers will be better able to cope with increasing demand for neural resources when working memory becomes difficult. To our knowledge, this prediction has thus far gone untested. Here, we tested performance on three working memory tasks. Performance on each task was measured at multiple levels of load/difficulty, including loads more demanding than those used in prior studies. We found no genotype-by-load interactions or main effects of COMT genotype on accuracy or reaction time. Indeed, even testing for performance differences at each load of each task failed to find a single significant effect of COMT genotype. Thus, even if COMT genotype has the effects on prefrontal efficiency that prior work has suggested, such effects may not directly impact high-load working memory ability. The present findings accord with previous evidence that behavioral effects of COMT are small or nonexistent and, more broadly, with a growing consensus that substantial effects on phenotype will not emerge from candidate gene studies. PMID- 26649916 TI - Levonorgestrel intrauterine system for endometrial protection in women with breast cancer on adjuvant tamoxifen. AB - BACKGROUND: Adjuvant tamoxifen reduces the risk of breast cancer recurrence in women with oestrogen receptor-positive breast cancer. Tamoxifen also increases the risk of postmenopausal bleeding, endometrial polyps, hyperplasia, and endometrial cancer. The levonorgestrel-releasing intrauterine system (LNG-IUS) causes profound endometrial suppression. This systematic review considered the evidence that the LNG-IUS prevents the development of endometrial pathology in women taking tamoxifen as adjuvant endocrine therapy for breast cancer. OBJECTIVES: To determine the effectiveness and safety of levonorgestrel intrauterine system (LNG-IUS) in pre- and postmenopausal women taking adjuvant tamoxifen following breast cancer for the outcomes of endometrial and uterine pathology including abnormal vaginal bleeding or spotting, and secondary breast cancer events. SEARCH METHODS: We searched the following databases: Cochrane Menstrual Disorders and Subfertility Group Specialised Register (MDSG), Cochrane Breast Cancer Group Specialised Register (CBCG), Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Database of Abstracts of Reviews of Effects (DARE), The Cochrane Library, clinicaltrials.gov, The World Health Organisation International Trials Registry, ProQuest Dissertations & Theses, MEDLINE, EMBASE, CINAHL (Cumulative Index to Nursing and Allied Health Literature), PsycINFO, Web of Science, OpenGrey, LILACS, PubMed, and Google. The final search was performed in October 2015. SELECTION CRITERIA: Randomised controlled trials of women with breast cancer on adjuvant tamoxifen that compared endometrial surveillance alone (control condition) versus the LNG-IUS with endometrial surveillance (experimental condition) on the incidence of endometrial pathology. DATA COLLECTION AND ANALYSIS: Study selection, risk of bias assessment and data extraction were performed independently by two review authors. The primary outcome measure was endometrial pathology (including polyps, endometrial hyperplasia, or endometrial cancer) diagnosed at hysteroscopy or endometrial biopsy. Secondary outcome measures included fibroids, abnormal vaginal bleeding or spotting, breast cancer recurrence, and breast cancer-related deaths. The overall quality of evidence was rated using GRADE methods. MAIN RESULTS: Four randomised controlled trials involving 543 women were identified and are included in this review. In the included studies, the active treatment arm was the 20 MUg/day levonorgestrel-releasing intrauterine system (LNG-IUS) plus endometrial surveillance; the control arm was endometrial surveillance alone. In tamoxifen users, the LNG-IUS led to a reduction in the incidence of endometrial polyps over both a 12-month period (Peto OR 0.22, 95% CI 0.08 to 0.64, 2 studies, n = 212, I2 = 0%) and over a long-term follow-up period (24 to 60 months) (Peto OR 0.22, 95% CI 0.13 to 0.39, 4 studies, n = 417, I2 = 0%, moderate quality evidence). Also the LNG-IUS led to a reduction in the incidence of endometrial hyperplasia over a long-term follow-up period (24 to 60 months) (Peto OR 0.13, 95% CI 0.03 to 0.67, four studies, n = 417, I2 = 0%, moderate quality evidence). However, it should be noted that the number of events of endometrial hyperplasia was low (n = 6). None of the trials were sufficiently powered to detect whether LNG-IUS leads to significant changes in the incidence of endometrial cancer in tamoxifen users. At 12 months of follow-up abnormal vaginal bleeding or spotting was more common in the LNG-IUS treatment group (Peto OR 7.26, 95% CI 3.37 to 15.66, 3 studies, n = 376, I2 = 0%, moderate quality evidence). By 24 months of follow-up, abnormal vaginal bleeding or spotting occurred less frequently compared to 12 months of follow-up in the LNG-IUS treatment group but was still more common than the control group (Peto OR 2.72, 95% CI 1.04 to 7.10, 2 studies, n = 233, I2 = 0%, moderate quality evidence). By 60 months of follow-up, no cases of abnormal vaginal bleeding or spotting were reported in either group. The numbers of events for the following outcomes were low: fibroids (n = 13), breast cancer recurrence (n = 18), and breast cancer-related deaths (n = 16). There was no evidence of a difference between the LNG-IUS treatment group and controls for these outcomes. The quality of the evidence was judged as moderate, due to limited sample sizes and low event rates for the outcome comparisons. AUTHORS' CONCLUSIONS: The LNG IUS reduces the incidence of benign endometrial polyps and endometrial hyperplasia in women with breast cancer taking tamoxifen. At 12 and 24 months of follow-up, the LNG-IUS increased abnormal vaginal bleeding or spotting among women in the treatment group compared to those in the control. There is no clear evidence from the available randomised controlled trials that the LNG-IUS prevents endometrial cancer in these women. There is no clear evidence from the available randomised controlled trials that the LNG-IUS affects the risk of breast cancer recurrence or breast cancer-related deaths. Larger studies are necessary to assess the effects of the LNG-IUS on the incidence of endometrial cancer, and to determine whether the LNG-IUS might have an impact on the risk of secondary breast cancer events. PMID- 26649917 TI - The preliminary study of immune superparamagnetic iron oxide nanoparticles for the detection of lung cancer in magnetic resonance imaging. AB - To improve the sensitive and specific detection of metastasis of lung cancer, this study fabricated immune superparamagnetic iron oxide nanoparticles (SPIONs) used in magnetic resonance (MR) immumoimaging. These SPIONs were coated with oleic acid and carboxymethyl dextran, and then conjugated to mouse anti-CD44v6 monoclonal antibody. The physicochemical properties of magnetic nanoparticles without monoclonal antibody were characterized by X-ray powder diffraction (XRD), thermogravimetric analysis (TGA), and Fourier transform infrared spectroscopy (FTIR). The sizes of the nanoparticles were determined by dynamic light scattering measurements (DLS) and transmission electron microscope (TEM). Coated nanoparticles could well disperse in water with low dosage of CMD as the Fe/CMD ratio is 1/1 and 2/1 (w/w). Importantly, these SPIONs have relatively high saturation magnetization, as measured by vibrating sample magnetometer (VSM). They could efficiently become the transversal relaxation times (T2) contrast agent to improve detection limit through measured in vitro magnetic resonance imaging (MRI) and actively target human lung adenocarcinoma (A549) cells in vitro cell culture. Thus, these immune SPIONs are potentially useful for lung tumor targeting diagnosis. PMID- 26649918 TI - Physicochemical properties of thermotolerant extracellular beta-glucosidase from Talaromyces thermophilus and enzymatic synthesis of cello-oligosaccharides. AB - A thermophilic fungus, Talaromyces thermophilus that produces a novel thermotolerant extra-cellular beta-glucosidase (Bgl.tls), was isolated from Tunisian soil samples. The enzyme was purified from the culture filtrates of T. thermophilus grown on lactose using gel filtration, ion exchange chromatography and FPLC. The monomeric enzyme had a molecular mass of 116.0 kDa and a high specific activity of 1429 UI/mg. Bgl.tls exhibited optimal activity at pH 5.0 and 65 degrees C. It was also stable over a wide range of pH (4.0-10.0) and stable at 50 degrees C for 34 h. Bgl.tls retained about 80% of its initial activity after 1.0 hours of preincubation at 60 degrees C. The Km and Vmax values recorded for pNPG were 0.25 mM and 228.7 umol min(-1), respectively. Bgl.tls was activated by Mn(2+), Mg(2+), Ca(2+) and Co(2+) but obviously inhibited by Fe(2+) and Cu(2+). It was able to hydrolyze a variety of aryl / alkyl -beta-glucosides and disaccharides as well as (1 -> 6) and (1 -> 4)-beta-glucosidic linkages and alpha-glycosidic substrates, thus providing evidence for its broad substrate specificity. The enzyme also displayed high hydrolytic and transglycosylation activities. Overall, this study is the first report on the purification and physicochemical properties of a beta-glucosidase secreted by T. thermophilus. The cello-oligosaccharides synthesized by this enzyme within 2 h were mainly cellotriose, cellotetraose and cellopentaose identified by HPLC and ESI-MS techniques. PMID- 26649919 TI - Defensive Diterpene from the Aeolidoidean Phyllodesmium longicirrum. AB - Phyllodesmium is a tropical marine slug genus with about 30 described species. None of them have a protective shell, and all of them feed on octocorals that are generally known to provide defensive compounds and thus help to defend the naked slugs against sympatric predators, such as fish, crabs, cephalopods, and echinoderms. Phyllodesmium longicirrum is the species that grows the biggest and that is least protected by camouflage on its respective food, usually a soft coral of the genus Sarcophyton. Investigation of the lipophilic extract of a single specimen of P. longicirrum from the Great Barrier Reef (Australia) led to the isolation of four new polycyclic diterpenes. Compound 1 showed significant deterrent activity in a fish feeding assay. PMID- 26649920 TI - NMP and O2 as Radical Initiator: Trifluoromethylation of Alkenes to Tertiary beta Trifluoromethyl Alcohols at Room Temperature. AB - A novel strategy was developed to trigger .CF3 by using in situ generated peroxide in NMP under O2 or air as the radical initiator. Radical trifluoromethylation of alkenes was achieved toward tertiary beta-trifluoromethyl alcohols. Various tertiary beta-trifluoromethyl alcohols can be synthesized in good yields without extra oxidants or transition metal catalysts. Preliminary mechanistic investigation revealed that O2 diffusion can influence the reaction rate. PMID- 26649921 TI - Improvement of Transdermal Delivery of Exendin-4 Using Novel Tip-Loaded Microneedle Arrays Fabricated from Hyaluronic Acid. AB - The purpose of this study was to evaluate the characteristics of exendin-4 tip loaded microneedle arrays and to compare their acute efficacy with subcutaneous injections in type 2 diabetic GK/Slc rats. Fluorescein isothiocyanate labeled dextran with an average molecular weight of 4,000 (FD4) was selected as a model drug, and FD4 tip-loaded microneedle arrays were prepared in this study. In addition, intraperitoneal glucose tolerance tests after application of exendin-4 tip-loaded microneedle arrays were also compared with those after subcutaneous injection in type 2 diabetic GK/Slc rats. The release of FD4 from the tip-loaded microneedle arrays was very rapid, particularly in the initial 30 s, and most of the FD4 was released within 5 min. In addition, glucose tolerance was improved and the insulin secretion was enhanced after application of exendin-4 tip-loaded microneedle arrays, and these effects were comparable to those after subcutaneous injection of exendin-4. Similar plasma concentration profiles were seen after application of exendin-4 tip-loaded microneedle arrays, as was the case with subcutaneous injection in type 2 diabetic GK/Slc rats. These findings indicate that exendin-4 tip-loaded microneedle arrays can be used as an alternative to achieve sufficient delivery of exendin-4 for treatment of type 2 diabetes. To our knowledge, this is the first report of transdermal exendin-4 delivery using tip loaded microneedle arrays. PMID- 26649922 TI - Presenting Different Selves to Different People: Self-Presentation as a Function of Relationship Type and Contingent Self-Esteem. AB - Past work has established a connection between self-esteem and self-presentation; however, research has not explored how self-esteem that is contingent on one's relationship may influence self-presentational tactics in that relationship. Across two studies, undergraduate students reported on the extent to which their self-esteem depended on their friendship and romantic relationship, as well as the extent to which they engaged in self-presentation behaviors in those relationships. The results suggest that relationship-specific contingent self esteem predicts relationship-specific self-presentation; however, friendship contingent self-esteem predicted self-presentation in both friendships and romantic relationships. These results suggest that individuals are keenly and differentially attuned to qualitatively different relationships, and when perceiving potential problems, they attempt to remedy those through their self presentations. Furthermore, results indicate the possibility that self-esteem tied to a particular relationship may not be as important as self-esteem based more generally on one's relationships. PMID- 26649923 TI - The Influence of Confirmation Bias on Memory and Source Monitoring. AB - Two experiments were conducted to examine whether recognition memory for information and/or its source are influenced by confirmation bias. During Phase 1, subjects were shown a summary about the issue of gun control and asked to indicate a position on the issue. During Phase 2, 12 abstracts (Experiment 1) or social media posts (Experiment 2) were shown, one at a time. Posts in Experiment 2 were associated with either friends or strangers. Participants indicated whether they wanted to read a more extensive version of each abstract (Experiment 1) or post (Experiment 2). Phase 3 was the memory phase. Thirty-two abstract titles (Experiment 1) or posts (Experiment 2) were shown one at a time. Participants indicated yes or no, and whether they recognized the titles/posts from the last phase. Recognition memory for information that supported the participants' viewpoint was higher than that for opposing information. PMID- 26649924 TI - Relation Between Emotional Labor and Organizational Citizenship Behavior: An Investigation Among Chinese Teaching Professionals. AB - This study examined the association between emotional labor and organizational citizenship behavior (OCB) and the mediation of work engagement in this relationship. A total of 264 teachers in Mainland China were recruited for this study. Bivariate correlation showed that both deep acting and the expression of naturally felt emotion were positively related to the two dimensions of OCB, namely, OCB toward the individual (OCBI) and OCB toward the organization (OCBO), whereas surface acting was not related to the OCB dimensions. Work engagement was also positively associated with both OCB dimensions. Regression results showed that work engagement partially mediated the relation between deep acting and OCBO, and that between the expression of naturally felt emotion and OCBI. Work engagement also fully mediated the association between deep acting and OCBI, and that between the expression of naturally felt emotion and OCBO. In light of these findings, strategies that encourage employees to display emotions consistent with their inner experience were discussed. PMID- 26649925 TI - Academic Achievement in Early Adolescence: The Influence of Cognitive and Non Cognitive Variables. AB - The present study examined the predictive effects of intellectual ability, self concept, goal orientations, learning strategies, popularity and parent involvement on academic achievement. Hierarchical regression analysis and path analysis were performed among a sample of 1398 high school students (mean age = 12.5; SD =.67) from eight education centers from the province of Alicante (Spain). Cognitive and non-cognitive variables were measured using validated questionnaires, whereas academic achievement was assessed using end-of-term grades obtained by students in nine subjects. The results revealed significant predictive effects of all of the variables. The model proposed had a satisfactory fit, and all of the hypothesized relationships were significant. These findings support the importance of including non-cognitive variables along with cognitive variables when predicting a model of academic achievement. PMID- 26649927 TI - The Impact of the Patient Protection and Affordable Care Act on Mental Health Practices. PMID- 26649928 TI - Impact of the Patient Protection and Affordable Care Act on Emergency Psychiatry. AB - Emergency psychiatry (EP) is an integral component of comprehensive hospital based emergency care. EP developed and grew into a medical subspecialty in response to deinstitutionalization and other large-scale forces, resulting in large numbers of psychiatric patients presenting to emergency departments. The Affordable Care Act (ACA) of 2010 contains several features and provisions that are likely to impact the practice of EP. This article reviews and examines the impact of the ACA on psychiatric emergency care to date and anticipated in the near future. PMID- 26649929 TI - With Additional Insurance Available, Why Are Not More Mental Health Services Being Provided? AB - Among the major objectives of the Mental Health Parity and Addiction Equity Act of 2008 and The Patient Protection and Affordable Care Act of 2010, often referred to today in political discussion as "Obamacare," was to significantly extend more health insurance benefits to those seeking mental health services. This commentary suggests that these recent legislative acts have accomplished little to date to enhance the delivery and the financing of additional mental health services because of the significant delays in rule making and other federal bureaucratic snafus, the numerous difficulties that the newly insured patients will experience in gaining access to qualified mental health personnel, and the cultural factors impinging on the hesitancy of the mentally ill to seek care from mental health professionals. PMID- 26649930 TI - Laughter and Subjective Health Among Community-Dwelling Older People in Japan: Cross-Sectional Analysis of the Japan Gerontological Evaluation Study Cohort Data. AB - The aim of this study was to evaluate the association of laughter with subjective health independent of socioeconomic status and social participation among older people in Japan. We used the data of 26,368 individuals (men, 12,174; women, 14,194) 65 years or older who participated in the Japan Gerontological Evaluation Study (JAGES) in 2013. Participants provided information on laughter and self rated health, depression, socioeconomic, and psychosocial factors. We evaluated laughter from three perspectives: frequency, opportunities, and interpersonal interactions. Even after adjustment for depression, sociodemographic factors, and social participation, the prevalence ratio for poor subjective health among women who never or almost never laugh was 1.78 (95% confidence interval, 1.48-2.15) compared with those who reported laughing every day. Similar associations were observed among men. Laughter may be an important factor for the promotion of general and mental health of older adults. The mechanisms linking laughter and health warrant further study. PMID- 26649931 TI - Parents' and Children's Cognitive Style: The Role of Parents' Practices. AB - Depression among children is a prevalent, distressing phenomenon. Children's hope and negative attributional style are significant precursors for children's depressive symptoms. Thus, the aim of the current study is to examine parents' characteristics that contribute to children's attributional style and hope in a sample of 85 Israeli young elementary school age children (mean [SD] age, 6.70 [0.49] years) and their parents. Results demonstrated positive associations between both mothers' and fathers' positive attributional style and children's hope and positive attributional style; however, parents' hope was not associated with children's hope or with children's positive attributional style. Mothers' overprotectiveness and psychological control were negatively associated with children's hope and positive attributional style, whereas fathers' overprotectiveness was positively associated with these variables. Moreover, few parent and child sex effects were found with fathers' criticism associating negatively with boys' attributional style and hope and positively with girls' attributional style. Finally, our study demonstrated a possible advantage of the fit between mothers' and fathers' practices to children's positive attributional style and hope. Theoretical and clinical implications are discussed. PMID- 26649932 TI - Trichotillomania and Trauma: Dissociation and Alexithymia in a Case of Pregnancy Denial. AB - Pregnancy denial is rare yet reported and is often the result of complex psychosocial circumstances. We present an unusual case of pregnancy denial associated directly with both remote and ongoing trauma. A woman suddenly gave birth to a child in a hospital while visiting her other daughter, resulting in emergent labor and delivery as well as social work and psychiatric evaluation. Various atypical findings were noted, including pathological hair-pulling, alexithymia, indifference, and pregnancy denial. We offer a biopsychosocial conceptualization of the case, commenting on various possible processes including dissociation. The case also explores current states of knowledge regarding the interaction between impulse control disorders such as trichotillomania, dissociation, and trauma, with a call for future clinical and investigational attention to these interactions. PMID- 26649933 TI - Reanalyses of Turkington et al. (2014): Correcting Errors and Clarifying Findings. PMID- 26649936 TI - Restoration of Microtubule Interaction and Cytotoxicity in D-seco Taxanes upon Incorporation of 20-Hydroxymethyl-4-allyloxy Groups. AB - To probe the exact role of the oxetane D ring in both tubulin binding and cytotoxicity of taxanes, novel D-seco taxanes bearing a C4 ether substituent have been prepared from paclitaxel 1a. Among them, 20-hydroxymethyl-4-allyloxy D-seco taxane 5e is the most active in both tubulin and cytotoxicity assays. It is only slightly less potent than 1a on tubulin polymerization promotion in vitro and the most cytotoxic among all D-seco taxanes known to date. The reason for the loss and restoration of bioactivity for these D-seco taxanes is also discussed with the assistance of NMR and molecular modeling studies. From these results, we draw a conclusion that the intact D ring of taxanes is not strictly necessary for their binding to tubulin and cytotoxic effects. PMID- 26649937 TI - A one-pot synthesis of polysulfane-bearing block copolymer nanoparticles with tunable size and refractive index. AB - A one-pot synthesis of sulfur-rich polymer nanoparticles through a ring-opening metathesis polymerization is reported. The nanoparticles are formed in situ from diblock copolymers containing a polynorbornene derivative bearing cyclic polysulfanes. The refractive indices of the resulting nanoparticles are readily controlled in the range from 1.54 to nearly 1.65. PMID- 26649938 TI - High-Dose Magnesium Sulfate Infusion for Severe Asthma in the Emergency Department: Efficacy Study. AB - OBJECTIVE: To assess the efficacy of a high-dose prolonged magnesium sulfate infusion in patients with severe, noninfectious-mediated asthma. DESIGN: Prospective, randomized, open-label study. SETTING: Twenty-nine-bed pediatric emergency department located in a children's hospital in Asuncion, Paraguay. PATIENTS: All patients of 6-16 years old who failed to improve after 2 hours of standard therapy for asthma. INTERVENTIONS: Subjects were randomized to receive magnesium sulfate, 50 mg/kg over 1 hour (bolus) or high-dose prolonged magnesium sulfate infusion of 50 mg/kg/hr for 4 hours (max, 8.000 mg/4 hr). Patients were monitored for cardiorespiratory complications. MEASUREMENTS AND MAIN RESULTS: Asthma severity was assessed via asthma scores and peak expiratory flow rates at 0-2-6 hours. The primary outcome was discharge to home at 24 hours. An analysis of the hospital length of stay and costs was a secondary outcome. Thirty-eight patients were enrolled, 19 in each group. The groups were of similar ages, past medical history of asthma, asthma score, and peak expiratory flow rate. There was a significant difference in the patients discharged at 24 hours: 47% in high-dose prolonged magnesium sulfate infusion (9/19) versus 10% (2/21) in the bolus group (p = 0.032) with an absolute risk reduction 37% (95% CI, 10-63) and a number needed to treat of 2.7 (95% CI, 1.6-9.5) to facilitate a discharge at or before 24 hours. The length of stay was shorter in the high-dose prolonged magnesium sulfate infusion group (mean +/- SD in hr: high-dose prolonged magnesium sulfate infusion, 34.13 +/- 19.54; bolus, 48.05 +/- 18.72; p = 0.013; 95% CI, 1.3-26.5). The cost per patient in the high-dose prolonged magnesium sulfate infusion group was one third lower than the bolus group (mean +/- SD: high-dose prolonged magnesium sulfate infusion, $603.16 +/- 338.47; bolus, $834.37 +/- 306.73; p < 0.016). There were no interventions or discontinuations of magnesium sulfate due to adverse events. CONCLUSIONS: The early utilization of high-dose prolonged magnesium sulfate infusion (50 mg/kg/hr/4 hr), for non-infectious mediated asthma, expedites discharges from the emergency department with significant reduction in healthcare cost. PMID- 26649939 TI - Search of Unknown Fever Focus Using PET in Critically Ill Children With Complicated Underlying Diseases. AB - OBJECTIVES: PET/CT with F-fluorodeoxyglucose can be used to image cellular metabolism and has been used for evaluating fever of unknown origin in adults. However, there are limited studies about the role of F-fluorodeoxyglucose PET/CT in evaluation of fever of unknown origin in critically ill children, especially those presenting with complicated underlying diseases under treatment. Here, we report our preliminary experience using F-fluorodeoxyglucose PET/CT in this specific group of patients. DESIGN: Retrospective observational study. SETTING: PICUs of a university hospital. PATIENTS: Nineteen critically ill children (mean age, 5.7 yr old) with complicated underlying diseases requiring intensive care support underwent F-fluorodeoxyglucose PET/CT to evaluate fever of unknown origin. The median hospitalized stay was 34 days (range, 15-235 d) and fever of at least 7 days (mean, 21.6 d; range, 7-52 d). The PET scan was advocated after all routine microbiology, and conventional imaging showed negative or inconclusive results. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The F fluorodeoxyglucose PET/CT findings (blinded to the final clinical diagnosis) were compared with final histopathology, culture, serology results, or follow-up imaging. A final diagnosis was made in 16 patients (84.2%). F-fluorodeoxyglucose PET/CT accurately localized the source of fever in 14 patients, confers to a sensitivity of 87.5% (14 of 16; 95% CI, 0.604-0.978). A false-positive scan in a patient led to subsequent unnecessary investigations. Two false-negative F fluorodeoxyglucose PET/CT images were later attributed to relapse of underlying disease in the bone marrow and renal abscesses, respectively. In the other two patients where F-fluorodeoxyglucose PET/CT also showed negative findings, fever subsided shortly thereafter without treatment. CONCLUSIONS: Our preliminary experience suggests that F-fluorodeoxyglucose PET/CT may be clinically beneficial in evaluating fever of unknown origin in children with complicated underlying diseases mandating intensive support in ICUs if usual investigative methods are unsuccessful. Further large prospective studies are needed to validate these findings. PMID- 26649940 TI - Tomato HsfA1a plays a critical role in plant drought tolerance by activating ATG genes and inducing autophagy. AB - Autophagy plays critical roles in plant responses to stress. In contrast to the wealth of information concerning the core process of plant autophagosome assembly, our understanding of the regulation of autophagy is limited. In this study, we demonstrated that transcription factor HsfA1a played a critical role in tomato tolerance to drought stress, in part through its positive role in induction of autophagy under drought stress. HsfA1a expression was induced by drought stress. Virus-induced HsfA1a gene silencing reduced while its overexpression increased plant drought tolerance based on both symptoms and membrane integrity. HsfA1a-silenced plants were more sensitive to endogenous ABA mediated stomatal closure, while its overexpression lines were resistant under drought stress, indicating that phytohormone ABA did not play a major role in HsfA1a-induced drought tolerance. On the other hand, HsfA1a-silenced plants increased while its overexpression decreased the levels of insoluble proteins which were highly ubiquitinated under drought stress. Furthermore, drought stress induced numerous ATGs expression and autophagosome formation in wild-type plants. The expression of ATG10 and ATG18f, and the formation of autophagosomes were compromised in HsfA1a-silenced plants but were enhanced in HsfA1a-overexpressing plants. Both electrophoretic mobility shift assay and chromatin immunoprecipitation coupled with qPCR analysis revealed that HsfA1a bound to ATG10 and ATG18f gene promoters. Silencing of ATG10 and ATG18f reduced HsfA1a induced drought tolerance and autophagosome formation in plants overexpressing HsfA1a. These results demonstrate that HsfA1a induces drought tolerance by activating ATG genes and inducing autophagy, which may promote plant survival by degrading ubiquitinated protein aggregates under drought stress. PMID- 26649941 TI - BECN1s, a short splice variant of BECN1, functions in mitophagy. AB - Mitochondria selective autophagy, known as mitophagy, plays a pivotal role in several biological processes, such as elimination of the damaged mitochondria, removal of the mitochondria from immature red blood cells and sperm. The defects in mitophagy are associated with a wide spectrum of human diseases, including neurodegenerative disease, aging, cardiac disease and autoimmune disease. However, the mechanism underlying mitophagy remains largely unclear. Here, we report the characterization of a novel splice variant of BECN1/Beclin 1, BECN1s, which is produced by an alternative splicing mechanism. BECN1s is primarily associated with the outer-membrane of mitochondria. Unlike unspliced BECN1, which is essential for nonselective macroautophagy induction, BECN1s is indispensible for mitochondria-selective autophagy. Furthermore, BECN1s plays an important role in starvation- and membrane depolarization-induced mitophagy. Taken together, our findings broaden the view of BECN1 as an important regulator in autophagy, and implicate BECN1s as a specific mitophagy mediator. PMID- 26649942 TI - A pivotal role of FOS-mediated BECN1/Beclin 1 upregulation in dopamine D2 and D3 receptor agonist-induced autophagy activation. AB - Autophagy dysfunction is implicated in the pathogenesis of Parkinson disease (PD). BECN1/Beclin 1 acts as a critical regulator of autophagy and other cellular processes; yet, little is known about the function and regulation of BECN1 in PD. In this study, we report that dopamine D2 and D3 receptor (DRD2 and DRD3) activation by pramipexole and quinpirole could enhance BECN1 transcription and promote autophagy activation in several cell lines, including PC12, MES23.5 and differentiated SH-SY5Y cells, and also in tyrosine hydroxylase positive primary midbrain neurons. Moreover, we identified a novel FOS (FBJ murine osteosarcoma viral oncogene homolog) binding sequence (5'-TGCCTCA-3') in the rat and human Becn1/BECN1 promoter and uncovered an essential role of FOS binding in the enhancement of Becn1 transcription in PC12 cells in response to the dopamine agonist(s). In addition, we demonstrated a critical role of intracellular Ca2+ elevation, followed by the enhanced phosphorylation of CAMK4 (calcium/calmodulin dependent protein kinase IV) and CREB (cAMP responsive element binding protein) in the increases of FOS expression and autophagy activity. More importantly, pramipexole treatment ameliorated the SNCA/alpha-synuclein accumulation in rotenone-treated PC12 cells that overexpress wild-type or A53T mutant SNCA by promoting autophagy flux. This effect was also demonstrated in the substantia nigra and the striatum of SNCAA53T transgenic mice. The inhibition of SNCA accumulation by pramipexole was attenuated by cotreatment with the DRD2 and DRD3 antagonists and Becn1 siRNAs. Thus, our findings suggest that DRD2 and DRD3 agonist(s) may induce autophagy activation via a BECN1-dependent pathway and have the potential to reduce SNCA accumulation in PD. PMID- 26649944 TI - A molecular switch for selective autophagosome formation. AB - Selective macroautophagy (hereafter autophagy) can eliminate large cytotoxic structures that are designated for degradation by autophagy receptors. In our recent paper, we showed that a key function of target-bound autophagy receptors is to activate the autophagy kinase, Atg1, via interactions with the scaffold protein Atg11. Our work thus reveals a mechanism by which target recognition coordinates the earliest steps in autophagosome biogenesis. PMID- 26649943 TI - A large-scale analysis of autophagy-related gene expression identifies new regulators of autophagy. AB - Autophagy is a pathway mediating vacuolar degradation and recycling of proteins and organelles, which plays crucial roles in cellular physiology. To ensure its proper cytoprotective function, the induction and amplitude of autophagy are tightly regulated, and defects in its regulation are associated with various diseases. Transcriptional control of autophagy is a critical aspect of autophagy regulation, which remains largely unexplored. In particular, very few transcription factors involved in the activation or repression of autophagy related gene expression have been characterized. To identify such regulators, we analyzed the expression of representative ATG genes in a large collection of DNA binding mutant deletion strains in growing conditions as well as after nitrogen or glucose starvation. This analysis identified several proteins involved in the transcriptional control of ATG genes. Further analyses showed a correlation between variations in expression and autophagy magnitude, thus identifying new positive and negative regulators of the autophagy pathway. By providing a detailed analysis of the regulatory network of the ATG genes our study paves the way for future research on autophagy regulation and signaling. PMID- 26649945 TI - Whole-Body Induced Cell Turnover: A Proposed Intervention for Age-Related Damage and Associated Pathology. AB - In both biomedicine in general and biomedical gerontology in particular, cell replacement therapy is traditionally proposed as an intervention for cell loss. This article presents a proposed intervention-whole-body induced cell turnover (WICT)-for use in biomedical gerontology that combines cell replacement therapy with a second therapeutic component (targeted cell ablation) so as to broaden the therapeutic utility of cell therapies and increase the categories of age-related damage that are amenable to cell-based interventions. In particular, WICT may allow cell therapies to serve as an intervention for accumulated cellular and intracellular damage, such as telomere depletion, genomic DNA and mitochondrial DNA damage and mutations, replicative senescence, functionally deleterious age related changes in gene expression, accumulated cellular and intracellular aggregates, and functionally deleterious posttranslationally modified gene products. WICT consists of the gradual ablation and subsequent replacement of a patient's entire set of constituent cells gradually over the course of their adult life span through the quantitative and qualitative coordination of targeted cell ablation with exogenous cell administration. The aim is to remove age associated cellular and intracellular damage present in the patient's endogenous cells. In this study, we outline the underlying techniques and technologies by which WICT can be mediated, describe the mechanisms by which it can serve to negate or prevent age-related cellular and intracellular damage, explicate the unique therapeutic components and utilities that distinguish it as a distinct type of cell-based intervention for use in biomedical gerontology, and address potential complications associated with the therapy. PMID- 26649947 TI - Correction: Insect Biometrics: Optoacoustic Signal Processing and Its Applications to Remote Monitoring of McPhail Type Traps. AB - [This corrects the article DOI: 10.1371/journal.pone.0140474.]. PMID- 26649946 TI - BDNF Methylation and Maternal Brain Activity in a Violence-Related Sample. AB - It is known that increased circulating glucocorticoids in the wake of excessive, chronic, repetitive stress increases anxiety and impairs Brain-Derived Neurotrophic Factor (BDNF) signaling. Recent studies of BDNF gene methylation in relation to maternal care have linked high BDNF methylation levels in the blood of adults to lower quality of received maternal care measured via self-report. Yet the specific mechanisms by which these phenomena occur remain to be established. The present study examines the link between methylation of the BDNF gene promoter region and patterns of neural activity that are associated with maternal response to stressful versus non-stressful child stimuli within a sample that includes mothers with interpersonal violence-related PTSD (IPV-PTSD). 46 mothers underwent fMRI. The contrast of neural activity when watching children including their own-was then correlated to BDNF methylation. Consistent with the existing literature, the present study found that maternal BDNF methylation was associated with higher levels of maternal anxiety and greater childhood exposure to domestic violence. fMRI results showed a positive correlation of BDNF methylation with maternal brain activity in the anterior cingulate (ACC), and ventromedial prefrontal cortex (vmPFC), regions generally credited with a regulatory function toward brain areas that are generating emotions. Furthermore we found a negative correlation of BDNF methylation with the activity of the right hippocampus. Since our stimuli focus on stressful parenting conditions, these data suggest that the correlation between vmPFC/ACC activity and BDNF methylation may be linked to mothers who are at a disadvantage with respect to emotion regulation when facing stressful parenting situations. Overall, this study provides evidence that epigenetic signatures of stress-related genes can be linked to functional brain regions regulating parenting stress, thus advancing our understanding of mothers at risk for stress-related psychopathology. PMID- 26649948 TI - Laser-guided Neuronal Tracing In Brain Explants. AB - We present a technique which combines an in vitro tracer injection protocol, which uses a series of electrical and pressure pulses to increase dye uptake through electroporation in brain explants with targeted laser illumination and matching filter goggles during the procedure. The described technique of in vitro electroporation by itself yields relatively good visual control for targetting certain areas of the brain. By combining it with laser excitation of fluorescent genetic markers and their read-out through band-passing filter goggles, which can pick up the emissions of the genetically labeled cells/nuclei and the fluorescent tracing dye, a researcher can substantially increase the accuracy of injections by finding the area of interest and controlling for the dye-spread/uptake in the injection area much more efficiently. In addition, the laser illumination technique allows to study the functionality of a given neurocircuit by providing information about the type of neurons projecting to a certain area in cases where the GFP expression is linked to the type of transmitter expressed by a subpopulation of neurons. PMID- 26649951 TI - ["Before the therapy the gods have made the diagnosis"]. PMID- 26649949 TI - Theoretical study of the mechanism for the sequential N-O and N-N bond cleavage within N2O adducts of N-heterocyclic carbenes by a vanadium(iii) complex. AB - A theoretical study into the reactions of the N2O adducts of N-heterocyclic carbenes (NHCs) and a V((III)) complex was carried out using DFT calculations. Unlike most transition metal reactions with N2O that simply release N2 following O-atom transfer onto the metal centre, this NHC-based system traps the entire N2O molecule and then cleaves both the N-O and N-N bond in two consecutive reactions. The NHC presence increases the reactivity of N2O by altering the distribution of electron density away from the O-atom towards the two N-atoms. This electronic redistribution enables V-N binding interactions to form a reactive N,O-donor intermediate species. Our results show that bond breaking with concomitant ligand migration occurs via a concerted process for both the N-O and N-N cleavage reactions. PMID- 26649952 TI - [Hyperhidrosis]. PMID- 26649955 TI - [Clinical Practice after Bariatric Surgery: Problems and Complications]. AB - The number of patients undergoing bariatric surgery because of morbid obesity is increasing rapidly. Therefore, it is an important issue to be aware of outcome and complications after bariatric surgery. This mini-review presents a compilation of important gastrointestinal symptoms, as pain, diarrhea and dumping, and includes treatment options. It characterizes possible micronutrient deficiencies, gives instructions concerning the adaptation of drugs and illustrates possible adverse outcomes, such as excessive weight loss, insufficient weight loss and weight gain after bariatric surgery. PMID- 26649954 TI - [Diagnostic Errors in Medicine]. AB - The recognition of diagnostic errors in everyday practice can help improve patient safety. The most common diagnostic errors are the cognitive errors, followed by system-related errors and no fault errors. The cognitive errors often result from mental shortcuts, known as heuristics. The rate of cognitive errors can be reduced by a better understanding of heuristics and the use of checklists. The autopsy as a retrospective quality assessment of clinical diagnosis has a crucial role in learning from diagnostic errors. Diagnostic errors occur more often in primary care in comparison to hospital settings. On the other hand, the inpatient errors are more severe than the outpatient errors. PMID- 26649956 TI - [Suspicion of Dementia but Normal Neuropsychological Screening--What Next?]. AB - Dementia affects more and more people, affects their relatives and results in increasing costs, which is why Switzerland chose to put out a dementia awareness campaign which aims to increase early diagnosis rates for dementia. Thanks to early diagnosis, the frequency of hospitalisations is reduced and transfers to nursing homes are delayed. When screening tests end up being normal by patients with subjective memory disorder, early diagnosis can be difficult. The use of smell identification tests or other clinical signs could help the general practitioner to decide, which patients he has to refer for further investigations. The era of functional brain imaging and biomarkers has not yet come into being. For patients with suspected memory disorder and normal screening tests, the dialogue with the general practitioner is central for a competent and efficient follow-up of the patient. PMID- 26649957 TI - [Update Chronic Viral Hepatitis B and C]. AB - Chronic hepatitis B has a complex natural history. The age at infection, comorbidities, coinfections, and other, yet to be identified factors, determine the probability of developing a chronic infection. The HBV virus can never be completely eliminated and remains in the hepatocytes for life. However, to reach an inactive carrier status is a realistic goal of the therapy. For HBV treatment, pegylated interferon and direct antivirals are available. To screen persons at risk and to vaccinate all of the population are important prophylactic measures. Chronic hepatitis C infection leads, in 30% of cases, to liver cirrhosis. Treatment is recommended from fibrosis stage Metavir 2. New DAA allows short treatment, with a high response rate and very few adverse effects. PMID- 26649958 TI - [Ultrasound for Breast Cancer Screening: an Effective Tool in a Personalized Screening]. AB - Screening mammography is the only imaging modality with proved decrease in breast cancer mortality. Ultrasound has been proposed as additional tool for screening. Controversies remain about the real value of sonography in this setting. In Caucasian women with dense breast, sonography improves significantly breast cancer detection, but also increases the false positive cases, biopsies and costs. A careful selection of women who may benefit from additional screening with sonography is mandatory. PMID- 26649959 TI - [Intensified blood glucose control in type 1 diabetic patients - what are the target levels?]. PMID- 26649961 TI - [Extra calcium in the diet or as a tablet increases bone density only marginally]. PMID- 26649962 TI - [Perioperative bridging passe? Does not apply to every patient]. PMID- 26649964 TI - [Ultrasonography 67. Abdominal pain]. PMID- 26649967 TI - Two Histone Variants TH2A and TH2B Enhance Human Induced Pluripotent Stem Cell Generation. AB - There are two major methods of reprogramming: generation of induced pluripotent stem cells (iPSCs) by overexpressing embryonic stem cell-specific transcription factors (OCT4, SOX2, KLF4, and c-MYC) and somatic cell nuclear transfer by oocyte specific factors. Previously, we reported oocyte-enriched histone variants TH2A, TH2B, and the histone chaperone nucleoplasmin (NPM2) enhance the reprogramming by OSKM in mice by inducing open chromatin structure. In this study, we showed that human TH2A, TH2B, and NPM2 enhance the OSKM-induced reprogramming of adult and neonatal human dermal fibroblasts and umbilical vein endothelial cells. Pluripotency of iPSCs generated by coexpressing OSKM, TH2A, TH2B, and NPM2 was shown by in vitro and in vivo differentiation assays. These iPSCs gave rise to highly differentiated teratomas compared to iPSCs induced by OSKM alone. Genome wide analysis suggests a possibility that TH2A, TH2B, and NPM2 might regulate genes that are involved in naive stem cell stage. Thus, TH2A, TH2B, and NPM2 enhance reprogramming of human somatic cells and improve the quality of human iPSCs. PMID- 26649968 TI - Increasing Awareness of Child and Adolescent Mental Healthedited by Garralda M. Elena and Raynaud Jean-Philippe Lanham, Md. , Jason Aronson , 2010 , 388 338 pp., $80.00 . PMID- 26649970 TI - Clinical Manual of Emergency Psychiatryedited by Riba Michelle B. M.D., M.S. and Ravindranath Divy M.D., M.S. Washington, DC , American Psychiatric Publishing , 2010 , 434 pp., $62.00 . PMID- 26649971 TI - High-Yield Cognitive-Behavior Therapy for Brief Sessions: An Illustrated Guideby Wright Jesse H. Sudak Donna M. Turkington Douglas and Thase Michael E. Washington, DC , American Psychiatric Publishing , 2010 , 383 pp., $74.00 . PMID- 26649973 TI - Corrections. PMID- 26649975 TI - Global and local QSPR models to predict supercooled vapour pressure for organic compounds. AB - In this study, a quantitative structure-property relationship (QSPR) approach was used for estimation of logarithmic values of supercooled liquid vapour pressure (log PL) of a large set of structurally diverse organic compounds. This set includes 12 local sets of aromatic and aliphatic hydrocarbons, polychlorinated biphenyls, ethers, polychlorinated and brominated diphenylethers, polychlorinated naphthalenes and alcohols. Some simple models based on the linear relationship between log PL and VolSurf descriptors were developed as global models, and a general equation as a simple way to calculate the supercooled liquid vapour pressure of organic chemicals was provided. A descriptor representing the hydrophilic regions (WO1) of organic chemicals showed the highest correlation with log PL and resulted in a one-parameter global model characterized by satisfactory statistical performance; calibration (r2c) and prediction (r2p) correlation coefficient of 0.84 and 0.85, respectively. Moreover, local QSPR models were also developed for each subset of organic compounds and, as expected, the statistical results obtained from these models were better than the global one. From the descriptors involved in the models, it is concluded that the hydrophilic and hydrophobic regions at different energy levels and polarizability usually determine the variation of supercooled liquid vapour pressure of organic compounds. PMID- 26649977 TI - Metformin Attenuates 131I-Induced Decrease in Peripheral Blood Cells in Patients with Differentiated Thyroid Cancer. AB - BACKGROUND: 131I treatment (tx) of differentiated thyroid cancer (DTC) is associated with hematopoietic toxicity. It was hypothesized that metformin could have radioprotective effects on bone-marrow function. The objective was to determine whether metformin prevents 131I-induced changes in complete blood counts (CBC) in patients with DTC. METHODS: A retrospective analysis was performed of CBC values in DTC patients who were (40 patients: metformin group) or were not taking metformin (39 patients: control group) at the time of administration of 131I. Repeated measures analysis of variance was used for the analysis of the differences in the averages of CBC that were documented at baseline and at 1, 6, and 12 months post 131I tx. RESULTS: The groups were comparable in terms of age, sex, stage of DTC, 131I dose administered, and baseline CBC values. In the control group, the decrease in white blood cells (WBC) was 35.8% (p < 0.0001) at one month, 21.8% (p < 0.0001) at six months, and 19.4% (p < 0.0001) at 12 months. In the metformin group, the decrease in WBC was 17.1% (p < 0.0001) at one month, and 8.6% at six months (p = 0.01), while at 12 months WBC had returned to baseline values (p = 0.9). Differences between the two groups were highly statistically significant at all time points (p < 0.0001, p = 0.0027, and p < 0.0001, respectively). Lymphocytes were more sensitive to 131I, but metformin's radioprotective properties were more prominent in neutrophils. At 12 months, the decrease in platelets in the control group was 15.5% (p < 0.0001) versus 5.6% (p = 0.056) in the metformin group, while at one and six months the reductions in the two groups were comparable. No statistically significant differences were observed between the two groups in the change from baseline values for hemoglobin. CONCLUSIONS: Metformin attenuated the 131I-induced decrease in CBC parameters, and its radioprotective properties were more prominent in WBC. Patients who were taking metformin during 131I tx also experienced a faster recovery in their blood counts, when compared to the control group. Further study is warranted in order to examine if the radioprotective properties of metformin observed in the current study for 131I tx can also apply to other forms of therapeutic chemo- and radiotherapy. PMID- 26649978 TI - Changes in the oropharyngeal airway of Class II patients treated with the mandibular anterior repositioning appliance. AB - OBJECTIVE: To evaluate the effects of functional appliance treatment on the oropharyngeal airway volume, airway dimensions, and anteroposterior hyoid bone position of growing Class II patients. MATERIALS AND METHODS: Twenty Class II white patients (mean age, 11.7 +/- 1.75 years) treated with the MARA followed by fixed appliances were matched to an untreated control sample by cervical vertebrae maturation stage at pretreatment (T1) and posttreatment (T2) time points. Cone beam computed tomography scans were taken at T1 and T2. Dolphin3D imaging software was used to determine oropharyngeal airway volume, dimensions, and anteroposterior hyoid bone position. RESULTS: Multivariate ANOVA was used to evaluate changes between T1 and T2. Oropharyngeal airway volume, airway dimensions, and A-P position of the hyoid bone increased significantly with functional appliance treatment. SNA and ANB decreased significantly in the experimental group (P <= .05). Changes in SNB and Sn-GoGn failed to reach statistical significance. CONCLUSIONS: Functional appliance therapy increases oropharyngeal airway volume, airway dimensions, and anteroposterior hyoid bone position in growing patients. PMID- 26649980 TI - Molecular design for growth of supramolecular membranes with hierarchical structure. AB - Membranes with hierarchical structure exist in biological systems, and bio inspired building blocks have been used to grow synthetic analogues in the laboratory through self-assembly. The formation of these synthetic membranes is initiated at the interface of two aqueous solutions, one containing cationic peptide amphiphiles (PA) and the other containing the anionic biopolymer hyaluronic acid (HA). The membrane growth process starts within milliseconds of interface formation and continues over much longer timescales to generate robust membranes with supramolecular PA-HA nanofibers oriented orthogonal to the interface. Computer simulation indicates that formation of these hierarchically structured membranes requires strong interactions between molecular components at early time points in order to generate a diffusion barrier between both solutions. Experimental studies using structurally designed PAs confirm simulation results by showing that only PAs with high zeta potential are able to yield hierarchically structured membranes. Furthermore, the chemical structure of such PAs must incorporate residues that form beta-sheets, which facilitates self assembly of long nanofibers. In contrast, PAs that form low aspect ratio nanostructures interact weakly with HA and yield membranes that exhibit non fibrous fingering protrusions. Furthermore, experimental results show that increasing HA molecular weight decreases the growth rate of orthogonal nanofibers. This result is supported by simulation results suggesting that the thickness of the interfacial contact layer generated immediately after initiation of self-assembly increases with polymer molecular weight. PMID- 26649979 TI - Heparan sulfate mimetic PG545-mediated antilymphoma effects require TLR9 dependent NK cell activation. AB - Heparan sulfate (HS) is an essential component of the extracellular matrix (ECM), which serves as a barrier to tumor invasion and metastasis. Heparanase promotes tumor growth by cleaving HS chains of proteoglycan and releasing HS-bound angiogenic growth factors and facilitates tumor invasion and metastasis by degrading the ECM. HS mimetics, such as PG545, have been developed as antitumor agents and are designed to suppress angiogenesis and metastasis by inhibiting heparanase and competing for the HS-binding domain of angiogenic growth factors. However, how PG545 exerts its antitumor effect remains incompletely defined. Here, using murine models of lymphoma, we determined that the antitumor effects of PG545 are critically dependent on NK cell activation and that NK cell activation by PG545 requires TLR9. We demonstrate that PG545 does not activate TLR9 directly but instead enhances TLR9 activation through the elevation of the TLR9 ligand CpG in DCs. Specifically, PG545 treatment resulted in CpG accumulation in the lysosomal compartment of DCs, leading to enhanced production of IL-12, which is essential for PG545-mediated NK cell activation. Overall, these results reveal that PG545 activates NK cells and that this activation is critical for the antitumor effect of PG545. Moreover, our findings may have important implications for improving NK cell-based antitumor therapies. PMID- 26649981 TI - A New Fluorinated Surfactant Contaminant in Biota: Perfluorobutane Sulfonamide in Several Fish Species. AB - Environmental contamination and regulation of longer-chain perfluoroalkyl substances (PFASs) such as perfluorooctanesulfonate (PFOS) has given rise to the increased use of shorter-chain PFASs as alternatives in new products, although confirmation of their presence in the environment remains limited. In this study, the PFAS alternative, perfluoro-1-butane-sulfonamide (FBSA), was identified for the first time in biota in homogenate samples of fish by liquid chromatography quadrupole time-of-flight mass spectrometry (LC-Q-ToF-MS) and quantified by ultra high performance liquid chromatography-triple quadrupole mass spectrometry (UHPLC QQQ-MS/MS). In one flounder (Platichthys flesus) muscle sample from the Western Scheldt, The Netherlands, FBSA concentration was at 80.12 ng/g wet weight (w.w.) and was exceeded only by PFOS. FBSA was also detected in 32 out of 33 samples of freshwater fish collected (2009-2010) from water bodies across Canada. In lake trout (Salvelinus namaycush) from northern Canada (e.g., Lake Kusawa (Yukon Territory), Great Bear Lake (Northwest Territories and in the Arctic), and Lake Athabasca (northern Alberta)), the concentrations of FBSA ranged from below method detection limit (<0.01 ng/g w.w) to 0.44 ng/g w.w. and were much lower than those reported for lake trout from the more urbanized and industrialized Laurentian Great Lakes sites (3.17 +/- 1.53 ng/g w.w.). In three species of fish purchased from a supermarket in Ottawa (ON, Canada), FBSA concentrations were the lowest of all fish and ranged from < MLOD to 0.29 ng/g w.w. and 0.03 to 0.76 ng/g w.w. in muscle and liver, respectively. FBSA is a bioaccumulative contaminant in fish in Canada and possibly in The Netherlands. It is likely sourced from new alternative perfluorobutane-based products, as well as other shorter chain perfluoroalkyl-based products. PMID- 26649982 TI - Complications of Pathologic Myopia. AB - Pathologic myopia (PM) is one of the leading causes of visual impairment worldwide. The pathophysiology of PM is not fully understood, but the axial elongation of the eye followed by chorioretinal thinning is suggested as a key mechanism. Pathologic myopia may lead to many complications such as chorioretinal atrophy, foveoschisis, choroidal neovascularization, rhegmatogenous retinal detachment, cataract, and glaucoma. Some complications affect visual acuity significantly, showing poor visual prognosis. This article aims to review the types, pathophysiology, treatment, and visual outcome of the complications of PM. PMID- 26649984 TI - Acquired Resistance to Bedaquiline and Delamanid in Therapy for Tuberculosis. PMID- 26649985 TI - FDA Approval of Flibanserin--Treating Hypoactive Sexual Desire Disorder. PMID- 26649986 TI - Biallelic NTHL1 Mutations in a Woman with Multiple Primary Tumors. PMID- 26649987 TI - Suspended Planar-Array Chips for Molecular Multiplexing at the Microscale. AB - A novel suspended planar-array chips technology is described, which effectively allows molecular multiplexing using a single suspended chip to analyze extraordinarily small volumes. The suspended chips are fabricated by combining silicon-based technology and polymer-pen lithography, obtaining increased molecular pattern flexibility, and improving miniaturization and parallel production. The chip miniaturization is so dramatic that it permits the intracellular analysis of living cells. PMID- 26649989 TI - Membranes Do Not Tell Proteins How To Fold. AB - Which properties of the membrane environment are essential for the folding and oligomerization of transmembrane proteins? Because the lipids that surround membrane proteins in situ spontaneously organize into bilayers, it may seem intuitive that interactions with the bilayer provide both hydrophobic and topological constraints that help the protein to achieve a stable and functional three-dimensional structure. However, one may wonder whether folding is actually driven by the membrane environment or whether the folded state just reflects an adaptation of integral proteins to the medium in which they function. Also, apart from the overall transmembrane orientation, might the asymmetry inherent in biosynthesis processes cause proteins to fold to out-of-equilibrium, metastable topologies? Which of the features of a bilayer are essential for membrane protein folding, and which are not? To which extent do translocons dictate transmembrane topologies? Recent data show that many membrane proteins fold and oligomerize very efficiently in media that bear little similarity to a membrane, casting doubt on the essentiality of many bilayer constraints. In the following discussion, we argue that some of the features of bilayers may contribute to protein folding, stability and regulation, but they are not required for the basic three-dimensional structure to be achieved. This idea, if correct, would imply that evolution has steered membrane proteins toward an accommodation to biosynthetic pathways and a good fit into their environment, but that their folding is not driven by the latter or dictated by insertion apparatuses. In other words, the three-dimensional structure of membrane proteins is essentially determined by intramolecular interactions and not by bilayer constraints and insertion pathways. Implications are discussed. PMID- 26649988 TI - Sedentary behaviors and light-intensity activities in relation to colorectal cancer risk. AB - A recent meta-analysis found that sedentary behaviors are associated with an increased colorectal cancer (CRC) risk. Yet, the finding on TV viewing time, the most widely used surrogate of sedentary behaviors, was based on only two studies. Furthermore, light-intensity activities (e.g., standing and slow walking), non sedentary by posture but close to sedentary behaviors by Metabolic Equivalent Task values, have not been investigated in relation to CRC risk. Thus, we prospectively analyzed the relationships based on 69,715 women from Nurses' Health Study (1992-2010) and 36,806 men from Health Professionals Follow-Up Study (1988 - 2010). Throughout follow-up, time spent on sedentary behaviors including sitting watching TV and on light-intensity activities were assessed repeatedly; incidence of CRC was ascertained. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models from each cohort. A total of 1,119 and 913 incident cases were documented from women and men, respectively. The multivariable HR comparing >= 21 versus < 7 hr/week of sitting watching TV was 1.21 (95% CI = 1.02 to 1.43, ptrend =.01) in women and 1.06 (95% CI = 0.84 to 1.34, ptrend =.93) in men. In women, those highly sedentary and physically less active had an approximately 41% elevated risk of CRC (95% CI = 1.03 to 1.92) compared with those less sedentary and physically more active. The other sedentary behaviors and light-intensity activities were not related to CRC risk in women or men. In conclusion, we found that prolonged sitting time watching TV was associated with an increased CRC risk in women but not in men. PMID- 26649990 TI - MRI parametric monitoring of biological therapies in primary large vessel vasculitides: a pilot study. AB - OBJECTIVE: To evaluate the development of characteristic MRI changes in patients with primary large-vessel vasculitis (LVV) when treated with biological therapies. METHODS: 12 patients with primary LVV (8 patients with Takayasu arteritis and 4 patients with giant-cell arteritis) received biological therapy with tumour necrosis factor-alpha blockers (n = 9) or an interleukin-6 inhibitor (n = 3). MRI investigations were performed at baseline (pre-treatment) and follow up. All patients underwent the same MRI/MR angiography (MRA) protocol. Laboratory parameters (C-reactive protein and erythrocyte sedimentation rate) and clinical response (Birmingham Vasculitis Activity Score) were assessed. RESULTS: Wall thickness was 4.2 +/- 0.3 mm pre-treatment and significantly decreased to 3.2 +/- 0.3 mm post treatment in 9/12 patients. Mural enhancement was increased in all 12/12 patients with LVV, and subsided with therapy in 5/12 patients. Mural oedema or ill-defined contour were less prevalent but also improved with biological treatment. C-reactive protein and erythrocyte sedimentation rate levels decreased, and clinical assessment revealed a significant improvement from pre treatment to post-treatment. However, the course of imaging characteristics often did not parallel that of laboratory or clinical parameters. In all three patients receiving interleukin-6 blockade, laboratory markers and clinical scores normalized despite persistent vascular inflammation in one patient which was disclosed by MRI. CONCLUSION: Contrast-enhanced MRI/MRA may be useful when evaluating the development of disease activity in primary LVV under biological therapies. A high degree of suspicion and regular imaging follow-up is needed to detect persistent inflammation. ADVANCES IN KNOWLEDGE: This is the first study investigating the applicability of different MRI/MRA parameters for monitoring biological therapy in patients with primary LVV. PMID- 26649991 TI - Increased beta rhythm as an indicator of inhibitory mechanisms in tourette syndrome. AB - BACKGROUND: Inhibitory oscillatory mechanisms subserving tic compensation have been put forward in Tourette syndrome. Modulation of the beta rhythm (15-25 Hz) as the well-established oscillatory movement execution-inhibition indicator was tested during a cognitive-motor task in patients with Tourette syndrome. METHODS: Performing a Go/NoGo task, 12 patients with Tourette syndrome and 12 matched controls were recorded using whole-head magnetoencephalography. RESULTS: Compared to healthy participants, patients showed less beta suppression in the sensorimotor area and enhanced beta power in parieto-occipital brain regions contralaterally to the response hand. Average beta power and power gain correlated negatively with tic severity. CONCLUSIONS: Increased motor inhibitory as well as visuomotor attentional processes are likely to subserve tic compensation. Correlational results suggest that stronger inhibitory compensation accompanies less tic severity. PMID- 26649992 TI - Rapid Fractionation and Isolation of Whole Blood Components in Samples Obtained from a Community-based Setting. AB - Collection and processing of whole blood samples in a non-clinical setting offers a unique opportunity to evaluate community-dwelling individuals both with and without preexisting conditions. Rapid processing of these samples is essential to avoid degradation of key cellular components. Included here are methods for simultaneous peripheral blood mononuclear cell (PBMC), DNA, RNA and serum isolation from a single blood draw performed in the homes of consenting participants across a metropolitan area, with processing initiated within 2 hr of collection. We have used these techniques to process over 1,600 blood specimens yielding consistent, high quality material, which has subsequently been used in successful DNA methylation, genotyping, gene expression and flow cytometry analyses. Some of the methods employed are standard; however, when combined in the described manner, they enable efficient processing of samples from participants of population- and/or community-based studies who would not normally be evaluated in a clinical setting. Therefore, this protocol has the potential to obtain samples (and subsequently data) that are more representative of the general population. PMID- 26649993 TI - Whole-genome resequencing of extreme phenotypes in collared flycatchers highlights the difficulty of detecting quantitative trait loci in natural populations. AB - Dissecting the genetic basis of phenotypic variation in natural populations is a long-standing goal in evolutionary biology. One open question is whether quantitative traits are determined only by large numbers of genes with small effects, or whether variation also exists in large-effect loci. We conducted genomewide association analyses of forehead patch size (a sexually selected trait) on 81 whole-genome-resequenced male collared flycatchers with extreme phenotypes, and on 415 males sampled independent of patch size and genotyped with a 50K SNP chip. No SNPs were genomewide statistically significantly associated with patch size. Simulation-based power analyses suggest that the power to detect large-effect loci responsible for 10% of phenotypic variance was <0.5 in the genome resequencing analysis, and <0.1 in the SNP chip analysis. Reducing the recombination by two-thirds relative to collared flycatchers modestly increased power. Tripling sample size increased power to >0.8 for resequencing of extreme phenotypes (N = 243), but power remained <0.2 for the 50K SNP chip analysis (N = 1245). At least 1 million SNPs were necessary to achieve power >0.8 when analysing 415 randomly sampled phenotypes. However, power of the 50K SNP chip to detect large-effect loci was nearly 0.8 in simulations with a small effective population size of 1500. These results suggest that reliably detecting large effect trait loci in large natural populations will often require thousands of individuals and near complete sampling of the genome. Encouragingly, far fewer individuals and loci will often be sufficient to reliably detect large-effect loci in small populations with widespread strong linkage disequilibrium. PMID- 26649994 TI - Magnetic resonance imaging in a guinea pig model of inner ear decompression sickness and barotrauma. AB - OBJECTIVES/HYPOTHESIS: Scuba diving may cause severe hearing loss and vertigo due to inner ear barotrauma and decompression sickness. These may be difficult to differentiate clinically. Decompression sickness requires costly and potentially dangerous hyperbaric therapy, whereas such treatment may worsen barotrauma. The objective of this study was to assess the potential utility of magnetic resonance imaging to identify and distinguish blood from air in the inner ear, manifestations of barotrauma and decompression sickness, using a guinea pig model. STUDY DESIGN: Prospective animal trial. METHODS: Magnetic resonance of the head was performed at 3 Tesla, pre- and postinjection of 2, 4, or 10 MUL of air or blood through the round window into the perilymph. With this model, 2 MUL has been shown to cause hearing loss. Images were reviewed by a neuroradiologist blinded to the treatment. RESULTS: All 14 normal ears, five of seven blood- and five of seven air-injected ears, were correctly interpreted. Two blood- and one air-injected ear were interpreted as indeterminate. One air-injected ear was incorrectly interpreted as blood. CONCLUSIONS: Magnetic resonance reliably distinguishes small volumes of air and blood in the guinea pig inner ear. Magnetic resonance should be evaluated for its utility in the diagnosis of inner ear barotrauma and decompression sickness in scuba divers. LEVEL OF EVIDENCE: NA Laryngoscope, 126:2106-2109, 2016. PMID- 26649995 TI - Xerostomia Among Older Adults With Low Income: Nuisance or Warning? AB - PURPOSE: The purpose of this study was to identify the prevalence of xerostomia and related factors among low-income older adults in South Korea. STUDY DESIGN: A cross-sectional, population-based study. METHODS: Using data from the Home Healthcare Service Project, a population-based interview survey with home healthcare service, a total of 9,840 adults 65 years of age and older were assessed for the presence of xerostomia in association with aspects of health lifestyles, chronic disease, oral conditions, and oral function. RESULTS: Overall, 40% of participants reported experiencing xerostomia. Multivariate regression analysis indicated xerostomia was more likely to be reported by women having symptoms of gingival bleeding/pain, having difficulty swallowing liquid or chewing solid food, and having multiple chronic diseases. Interestingly, older adults who live alone and drink alcohol (two or more times per week) reported fewer problems with xerostomia. CONCLUSIONS: Increased focus on the detrimental health consequences of xerostomia would make treatment a higher priority. Improved assessment of at-risk populations, particularly among the elderly, could lead to earlier preventative interventions, lessening the negative impact on quality of life. CLINICAL RELEVANCE: Health professionals along with the general public need increased knowledge about the detrimental effects of xerostomia on overall health. There is a need for earlier assessment and treatment to facilitate optimal health promotion and disease prevention. PMID- 26649997 TI - 20 years of bio-lox. PMID- 26649999 TI - Predictive biomarkers for checkpoints, first tests approved. PMID- 26649998 TI - Anti-CD20 antibody wows in multiple sclerosis. PMID- 26649996 TI - Synergistic and antagonistic interactions of future land use and climate change on river fish assemblages. AB - River ecosystems are threatened by future changes in land use and climatic conditions. However, little is known of the influence of interactions of these two dominant global drivers of change on ecosystems. Does the interaction amplify (synergistic interaction) or buffer (antagonistic interaction) the impacts and does their interaction effect differ in magnitude, direction and spatial extent compared to single independent pressures. In this study, we model the impact of single and interacting effects of land use and climate change on the spatial distribution of 33 fish species in the Elbe River. The varying effects were modeled using step-wise boosted regression trees based on 250 m raster grid cells. Species-specific models were built for both 'moderate' and 'extreme' future land use and climate change scenarios to assess synergistic, additive and antagonistic interaction effects on species losses, species gains and diversity indices and to quantify their spatial distribution within the Elbe River network. Our results revealed species richness is predicted to increase by 0.7-2.9 species by 2050 across the entire river network. Changes in species richness are likely to be spatially variable with significant changes predicted for 56-85% of the river network. Antagonistic interactions would dominate species losses and gains in up to 75% of the river network. In contrast, synergistic and additive effects would occur in only 20% and 16% of the river network, respectively. The magnitude of the interaction was negatively correlated with the magnitudes of the single independent effects of land use and climate change. Evidence is provided to show that future land use and climate change effects are highly interactive resulting in species range shifts that would be spatially variable in size and characteristic. These findings emphasize the importance of adaptive river management and the design of spatially connected conservation areas to compensate for these high species turnovers and range shifts. PMID- 26650000 TI - IBM debuts hyped 'cognitive cloud' biotech HQ in Cambridge. PMID- 26650001 TI - 23andMe protects consumers' data. PMID- 26650003 TI - Tumor macrophage target fuels $1.7-billion deal. PMID- 26650002 TI - A face-lift for biotech rules begins. PMID- 26650004 TI - Trade pact blow for innovative drug developers. PMID- 26650005 TI - Share and share alike. PMID- 26650006 TI - Trade-sale exits in different biotech sectors. PMID- 26650007 TI - Patenting parthenotes in the US and Europe. PMID- 26650008 TI - Recent patents in antibody engineering. PMID- 26650009 TI - Patching up hematopoietic stem cells. PMID- 26650010 TI - Your gut microbiome, deconstructed. PMID- 26650011 TI - Cas9 gets a classmate. PMID- 26650014 TI - Acute Generalized Pustular Psoriasis Treated With the IL-17A Antibody Secukinumab. PMID- 26650015 TI - Biometabolic Distribution of 99mTc-3PRGD2 and Its Potential Value in Monitoring Chemotherapeutic Effects. AB - Previous studies have reported that 99mTc-3PRGD2 is an excellent tumor imaging agent that showed a good correlation with integrin alphavbeta3, a main factor of tumor-induced angiogenesis. In this study, we investigated the biometabolic distribution characteristics of 99mTc-3PRGD2 with a continuous dynamic acquisition mode to explore the potential value of 99mTc-3PRGD2 in monitoring chemotherapeutic effects in VX2 tumor models. Eighteen rabbits with 27 implanted VX2 squamous cell tumors were randomly divided into a nontreated control group (NTG, n = 8; 12 tumors) and a treatment group (TG, n = 10; 15 tumors). 99mTc 3PRGD2 imaging was performed prior to cisplatin injection and repeated on days 0, 1, 7, and 14 postinjection. Continuous dynamic scanning up to 30 minutes; static imaging at 0.5 hours, 1 hour, and 3 hours; and single-photon emission computed tomography/computed tomography (SPECT/CT)-integrated imaging at 3 hours post 99mTc-3PRGD2 injection were performed. The peak time (time to reach peak in dynamic curve), tumor to normal (T/N) ratios, and their change rates relative to pretherapy were calculated. Autoradiography, hematoxylin-eosin (H&E) staining, and CD31 and integrin alphav immunohistochemical staining were examined. VX2 tumors were clearly visualized at 3 hours post-99mTc-3PRGD2 injection. Tumors in the TG shrank significantly on day 7 after cisplatin administration (p < .05). The half-life (t1/2) of the radiotracer in heart, liver, and tumor in the NTG were 3.43 +/- 0.94 minutes, 13.41 +/- 9.17 minutes, and 70.83 +/- 33.37 minutes, respectively. The peak time was delayed in the TG immediately and continuously after cisplatin administration compared to the peak time in the NTG. The T/N values and their change rates decreased significantly in the TG compared to the NTG after therapy (p < .05). The immunostained areas were significantly decreased in the TG (p < .05) compared to the NTG. 99mTc-3PRGD2 was an excellent imaging agent for demonstrating tumor angiogenesis. The peak time, T/N values, and their change rates were sensitive parameters to monitor early chemotherapeutic effects. Due to the specific target mechanism and the cost-effective value of 99mTc 3PRGD2, 99mTc-3PRGD2 SPECT imaging may have potential in detecting the therapeutic effects of anticancer therapy. PMID- 26650016 TI - Reduction in High-Frequency Hearing Aid Gain Can Improve Performance in Patients With Contralateral Cochlear Implant: A Pilot Study. AB - PURPOSE: The purpose of this study was to determine whether an alternate fitting strategy, specifically adjustment to gains in a hearing aid (HA), would improve performance in patients who experienced poorer performance in the bimodal condition when the HA was fit to traditional targets. METHOD: This study was a retrospective chart review from a local clinic population seen during a 6-month period. Participants included 6 users of bimodal stimulation. Two performed poorer in the cochlear implant (CI) + HA condition than in the CI-only condition. One individual performed higher in the bimodal condition, but the overall performance was low. Three age range-matched users whose performance increased when the HA was used in conjunction with a CI were also included. The HA gain was reduced beyond 2000 Hz. Speech perception scores were obtained pre- and postmodification to the HA fitting. RESULTS: All listeners whose HA was programmed using the modified approach demonstrated improved speech perception scores with the modified HA fit in the bimodal condition when compared with the traditional HA fit in the bimodal condition. CONCLUSION: Modifications to gains above 2000 Hz in the HA may improve performance for bimodal listeners who perform more poorly in the bimodal condition when the HA is fit to traditional targets. PMID- 26650018 TI - Frequency Importance Functions in Quiet and Noise for Adults With Cochlear Implants. AB - PURPOSE: Several studies have been devoted to understanding the frequency information available to adult users of cochlear implants when listening in quiet. The objective of this study was to construct frequency importance functions for a group of adults with cochlear implants and a group of adults with normal hearing both in quiet and in a +10 dB signal-to-noise ratio. METHOD: Two groups of adults, 1 with cochlear implants and 1 with normal hearing, were asked to identify nonsense syllables in quiet and in the presence of 6-talker babble while "holes" were systematically created in the speech spectrum. Frequency importance functions were constructed. RESULTS: Results showed that adults with normal hearing placed greater weight on bands 1, 3, and 4 than on bands 2, 5, and 6, whereas adults with cochlear implants placed equal weight on all bands. The frequency importance functions for each group did not differ between listening in quiet and listening in noise. CONCLUSIONS: Adults with cochlear implants assign perceptual weight toward different frequency bands, though the weight assignment does not differ between quiet and noisy conditions. Generalizing these results to the broader population of adults with implants is constrained by a small sample size. PMID- 26650028 TI - Formal Synthesis of Anticoagulant Drug Fondaparinux Sodium. AB - The practical formal synthesis of the anticoagulant drug fondaparinux sodium 1 was accomplished using an optimized modular synthetic strategy. The important pentasaccharide 2, a precursor for the synthesis of fondaparinux sodium, was synthesized on a 10 g scale in 14 collective steps with 3.5% overall yield from well-functionalized monosaccharide building blocks. The strategy involved a convergent [3 + 2] coupling approach, with excellent stereoselectivity in every step of glycosylation from the monosaccharide building blocks. Efficient routes to the syntheses of these fully functionalized building blocks were developed, minimizing oligosaccharide stage functional-group modifications. The syntheses of all building blocks avoided rigorous reaction conditions and the use of expensive reagents. In addition, common intermediates and a series of one-pot reactions were employed to enhance synthetic efficiency, improving the yield considerably. In the monosaccharide-to-oligosaccharide assembly reactions, cheaper activators (e.g., NIS/TfOH, TESOTf, and TfOH) were used to facilitate highly efficient glycosylations. Furthermore, crystallization of several monosaccharide and oligosaccharide intermediates significantly simplified purification procedures, which would be greatly beneficial to the scalable synthesis of fondaparinux sodium. PMID- 26650029 TI - "Universal Reimbursement" for "Universal Newborn Hearing Screening"? PMID- 26650030 TI - Year 2000 Position Statement: Principles and Guidelines for Early Hearing Detection and Intervention Programs. PMID- 26650031 TI - Does dienogest influence the inflammatory response of endometriotic cells? A systematic review. AB - OBJECTIVE AND DESIGN: A systematic review of all literature was done to assess the ability of the progestin dienogest (DNG) to influence the inflammatory response of endometriotic cells. MAIN OUTCOME MEASURES: In vitro and in vivo studies report an influence of DNG on the inflammatory response in eutopic or ectopic endometrial tissue (animal or human). RESULTS: After strict inclusion criteria were satisfied, 15 studies were identified that reported a DNG influence on the inflammatory response in endometrial tissue. These studies identified a modulation of prostaglandin (PG) production and metabolism (PGE2, PGE2 synthase, cyclo-oxygenase-2 and microsomal PGE synthase-1), pro-inflammatory cytokine and chemokine production [interleukin (IL)-1beta, IL-6, IL-8, tumor necrosis factor alpha, monocyte chemoattractant protein-1 and stromal cell-derived factor-1], growth factor biosynthesis (vascular endothelial growth factor and nerve growth factor) and signaling kinases, responsible for the control of inflammation. Evidence supports a progesterone receptor-mediated inhibition of the inflammatory response in PR-expressing epithelial cells. It also indicated that DNG inhibited the inflammatory response in stromal cells, however, whether this was via a PR mediated mechanism is not clear. CONCLUSIONS: DNG has a significant effect on the inflammatory microenvironment of endometriotic lesions that may contribute to its clinical efficacy. A better understanding of the specific anti-inflammatory activity of DNG and whether this contributes to its clinical efficacy can help develop treatments that focus on the inhibition of inflammation while minimizing hormonal modulation. PMID- 26650032 TI - High sugar and butter (HSB) diet induces obesity and metabolic syndrome with decrease in regulatory T cells in adipose tissue of mice. AB - OBJECTIVE: The purpose of the study was to develop a novel diet based on standard AIN93G diet that would be able to induce experimental obesity and impair immune regulation with high concentrations of both carbohydrate and lipids. METHODS: To compare the effects of this high sugar and butter (HSB) diet with other modified diets, male C57BL/6 mice were fed either mouse chow, or AIN93G diet, or high sugar (HS) diet, or high-fat (HF) diet, or high sugar and butter (HSB) diet for 11 weeks ad libitum. HSB diet induced higher weight gain. Therefore, control AIN93G and HSB groups were chosen for additional analysis. Regulatory T cells were studied by flow cytometry, and cytokine levels were measured by ELISA. RESULTS: Although HF and HSB diets were able to induce a higher weight gain compatible with obesity in treated mice, HSB-fed mice presented the higher levels of serum glucose after fasting and the lowest frequency of regulatory T cells in adipose tissue. In addition, mice that were fed HSB diet presented higher levels of cholesterol and triglycerides, hyperleptinemia, increased resistin and leptin levels as well as reduced adiponectin serum levels. Importantly, we found increased frequency of CD4(+)CD44(+) effector T cells, reduction of CD4(+)CD25(+)Foxp3(+) and Th3 regulatory T cells as well as decreased levels of IL-10 and TGF-beta in adipose tissue of HSB-fed mice. CONCLUSION: Therefore, HSB represents a novel model of obesity-inducing diet that was efficient in triggering alterations compatible with metabolic syndrome as well as impairment in immune regulatory parameters. PMID- 26650034 TI - [Care preferences and spatial mobility : Factors influencing care-related willingness to move of elderly people in partnerships in a rural area]. AB - The availability of local support and care infrastructures at the place of residence is an important issue for the elderly living in rural areas. Spatial mobility can be seen as a strategy to cope with a lack of local care facilities. This study analyzes the preferences of older people living in long-term relationships concerning support and care arrangements. Furthermore, it is analyzed how far and under which circumstances older couples are willing to relocate their place of residence in response to regional care infrastructures. Using a quasi-experimental survey design, inhabitants of a small rural community aged over 50 years were interviewed and confronted with descriptions of fictitious situations with randomized options for moving residence. A Tobit model estimation method is applied to examine the determinants of older couples' care related willingness to move their residence.The results show that most people prefer either the support of their own partner or outpatient care. Residential care is especially preferred by people aged 75 years and above, whereas new forms of support, such as senior cooperatives, are evaluated as attractive especially by younger age groups. Thus, information and advisory campaigns should address the target group in question even at an early stage in older peoples' life course. Care-related willingness to move home of couples aged 50 years and more is significantly determined by local provision of support and care infrastructures. The expansion of any care infrastructure at older peoples' place of residence can significantly reduce their willingness to move. In particular an increased availability of outpatient care is associated with a comparatively large reduction in couples' likelihood to move. In this way local commitment to rural areas can be sustained and rural depopulation can be prevented. At an alternative place of residence assisted living and residential care in particular can significantly enhance the willingness to relocate and can thus generate incentives to move for older couples. PMID- 26650035 TI - [Management of older patients following solid organ transplantation]. AB - Due to a continuous expansion of transplantation registers, such as the old-for old program in Europe, the number of older patients treated with transplantation is increasing. At the same time the perioperative survival rates show a clear increase even in this patient collective (older than 65 years); therefore, the probability that the care of older patients after organ transplantation will be undertaken in the routine practice increases. This article describes the medical characteristics of older patients following organ transplantation. Special emphasis is placed on the management of accompanying diseases as well as possible side effects and interactions of immunosuppressive therapy. PMID- 26650036 TI - Solid Lipid Nanoparticles (SLNs) for Intracellular Targeting Applications. AB - Nanoparticle-based delivery vehicles have shown great promise for intracellular targeting applications, providing a mechanism to specifically alter cellular signaling and gene expression. In a previous investigation, the synthesis of ultra-small solid lipid nanoparticles (SLNs) for topical drug delivery and biomarker detection applications was demonstrated. SLNs are a well-studied example of a nanoparticle delivery system that has emerged as a promising drug delivery vehicle. In this study, SLNs were loaded with a fluorescent dye and used as a model to investigate particle-cell interactions. The phase inversion temperature (PIT) method was used for the synthesis of ultra-small populations of biocompatible nanoparticles. A 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenylphenyltetrazolium bromide (MTT) assay was utilized in order to establish appropriate dosing levels prior to the nanoparticle-cell interaction studies. Furthermore, primary human dermal fibroblasts and mouse dendritic cells were exposed to dye-loaded SLN over time and the interactions with respect to toxicity and particle uptake were characterized using fluorescence microscopy and flow cytometry. This study demonstrated that ultra-small SLNs, as a nanoparticle delivery system, are suitable for intracellular targeting of different cell types. PMID- 26650037 TI - Evidence for genetic variation of Eurasian avian influenza viruses of subtype H15: the first report of an H15N7 virus. AB - Since the first detection of H15 avian influenza viruses (AIVs) in Australia in 1979, only seven H15 strains have been reported. A new H15 AIV was detected in Ukraine in 2010, carrying the unique HA-NA subtype combination H15N7. This virus replicated efficiently in chicken eggs, and antisera against it reacted strongly with the homologous antigen, but with lower titers when using the reference Australian antigen. The amino acid motifs of the HA cleavage site and receptor binding site were different from those in the Australian viruses. The new virus, together with an H15 virus from Siberia from 2008, constitutes a new clade of H15 AIV isolates. PMID- 26650038 TI - A novel single-stranded RNA virus isolated from the rice-pathogenic fungus Magnaporthe oryzae with similarity to members of the family Tombusviridae. AB - Here, we report a novel virus isolated from rice blast fungus, Magnaporthe oryzae, an important plant pathogen. This virus has an RNA genome of 3246 nucleotides. Its genome possesses two in-frame open reading frames (ORFs). The smaller ORF1 encodes a protein with significant similarity to a protein encoded by the ssRNA mycovirus Diaporthe ambigua RNA virus 1 (DaRV1). The larger ORF2 encodes a protein with similarity to RNA-dependent RNA polymerases (RdRp) of DaRV1 and other plant viruses of the family Tombusviridae. In silico analysis and comparisons with DaRV1 genome expression suggest that ORF2 is translated via a readthrough mechanism together with ORF1. Based upon results of this study, this virus, for which the provisional name Magnaporthe oryzae virus A (MoVA) is proposed, belongs to a new virus species. Furthermore, MoVA along with DaRV1 belong to a new taxon of mycoviruses that are evolutionarily related to plant viruses belonging to the family Tombusviridae. PMID- 26650039 TI - Immunoenhancement with flagellin as an adjuvant to whole-killed rabies vaccine in mice. AB - Vaccination is the most effective method for preventing rabies virus (RABV) infection in both humans and animals; however, no satisfactory vaccine has been developed for use worldwide. In the present study, we investigated the immunoadjuvant properties of Salmonella Typhimurium flagellin (FljB, FliC, and FljB'-FliC) to improve immune responses against the rabies vaccine (RV) and the protective efficacy of the whole-killed rabies vaccine (WKRV) with or without flagellins in BALB/c mice. We also compared the differences among the three flagellins in terms of immunoadjuvant properties to RV. FljB can cause the WKRV to induce stronger humoral and cellular immune responses than WKRV alone or WKRV with FliC or FljB'-FliC can. Mice immunized with WKRV and FljB produced higher levels of virus-neutralizing antibody (VNA) against RABV than those in the other groups did. Although mice in all treatment groups survived RABV challenge, the body weight loss in the group immunized with WKRV and FljB was lower than in the other groups. These results indicate that FljB is a promising adjuvant for use in the development of effective rabies vaccines. PMID- 26650040 TI - Alcelaphine herpesvirus 1 glycoprotein B: recombinant expression and antibody recognition. AB - The gammaherpesvirus alcelaphine herpesvirus 1 (AlHV-1) causes fatal malignant catarrhal fever (MCF) in susceptible species including cattle, but infects its reservoir host, wildebeest, without causing disease. Pathology in cattle may be influenced by virus-host cell interactions mediated by the virus glycoproteins. Cloning and expression of a haemagglutinin-tagged version of the AlHV-1 glycoprotein B (gB) was used to demonstrate that the AlHV-1-specific monoclonal antibody 12B5 recognised gB and that gB was the main component of the gp115 complex of AlHV-1, a glycoprotein complex of five components identified on the surface of AlHV-1 by immunoprecipitation and radiolabelling. Analysis of AlHV-1 virus particles showed that the native form of gB was detected by mAb 12B5 as a band of about 70 kDa, whilst recombinant gB expressed by transfected HEK293T cells appeared to be subject to additional cleavage and incomplete post translational processing. Antibody 12B5 recognised an epitope on the N-terminal furin-cleaved fragment of gB on AlHV-1 virus particles. It could be used to detect recombinant and virus-expressed gB on western blots and on the surface of infected cells by flow cytometry, whilst recombinant gB was detected on the surface of transfected cells by immunofluorescence. Recombinant gB has potential as an antigen for ELISA detection of MCF virus infection and as a candidate vaccine antigen. PMID- 26650041 TI - Graphene/3C-SiC Hybrid Nanolaminate. AB - In this work, we demonstrate a one-step approach to create graphene/3C-SiC nanolaminate structure using microwave plasma chemical vapor deposition technique. Layer-by-layer arrangement of thin 3C-SiC layers and graphene sheets is obtained with the thicknesses of the individual 3C-SiC layers and graphene sheets being 5-10 nm and 2-5 nm, respectively. An intimate contact between 3C-SiC and the graphene sheets is achieved and the nanolaminate film shows a high room temperature conductivity of 96.1 S/cm. A dedicated structural analysis of the nanolaminates by means of high-resolution transmission electron microscopy (HRTEM) reveals that the growth of the nanolaminates follows an iterative process: preferential graphene nucleation around the planar defects at the central region of the SiC layer, leading to the "splitting" of the SiC layer; and the thickening of the SiC layer after being "split". A growth mechanism based on both kinetics and thermodynamics is proposed. Following the proposed mechanism, it is possible to control the layer thickness of the graphene/3C-SiC hybrid nanolaminate by manipulating the carbon concentration in the gas phase, which is further experimentally verified. The high electrical conductivity, large surface area porous structure, feasible integration on different substrates (metal, Mo; semiconductor, Si and 2H-SiC; insulator, diamond) of the graphene/3C-SiC hybrid nanolaminate as well as other unprecedented advantages of the nanolaminate structure make it very promising for applications in mechanical, energy, and sensor-related areas. PMID- 26650043 TI - NOX2 Mediated-Parvalbumin Interneuron Loss Might Contribute to Anxiety-Like and Enhanced Fear Learning Behavior in a Rat Model of Post-Traumatic Stress Disorder. AB - Post-traumatic stress disorder (PTSD) is a common psychiatric disease following exposure to a severe traumatic event or physiological stress, yet the precise mechanisms underlying PTSD remains largely to be determined. Using an animal model of PTSD induced by a single prolonged stress (SPS), we assessed the role of hippocampal nicotinamide adenosine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) and parvalbumin (PV) interneurons in the development of PTSD symptoms. In the present study, behavioral tests were performed by the open field (day 13 after SPS) and fear conditioning tests (days 13 and 14 after SPS). For the interventional study, rats were chronically treated with a NADPH oxidase inhibitor apocynin either by early or delayed administration. The levels of tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-6, IL-10, malondialdehyde, superoxide dismutase, NOX2, 4-hydroxynonenal, and PV in the hippocampus were measured at the indicated time points. In the present study, we showed that SPS rats displayed anxiety-like and enhanced fear learning behavior, which was accompanied by the increased expressions of malondialdehyde, IL-6, NOX2, 4 hydroxynonenal, and decreased PV expression. Notably, early but not delayed treatment with apocynin reversed all these abnormalities after SPS. In conclusion, our results provided evidence that NOX2 activation in the hippocampus, at least in part, contributes to oxidative stress and neuroinflammation, which further results in PV interneuron loss and consequent PTSD symptoms in a rat model of PTSD induced by SPS. PMID- 26650042 TI - The Rotterdam Scan Study: design update 2016 and main findings. AB - Imaging plays an essential role in research on neurological diseases in the elderly. The Rotterdam Scan Study was initiated as part of the ongoing Rotterdam Study with the aim to elucidate the causes of neurological disease by performing imaging of the brain in a prospective population-based setting. Initially, in 1995 and 1999, random subsamples of participants from the Rotterdam Study underwent neuroimaging, whereas from 2005 onwards MRI has been implemented into the core protocol of the Rotterdam Study. In this paper, we discuss the background and rationale of the Rotterdam Scan Study. Moreover, we describe the imaging protocol, image post-processing techniques, and the main findings to date. Finally, we provide recommendations for future research, which will also be topics of investigation in the Rotterdam Scan Study. PMID- 26650046 TI - In Vitro Generation of Murine Plasmacytoid Dendritic Cells from Common Lymphoid Progenitors using the AC-6 Feeder System. AB - Plasmacytoid dendritic cells (pDCs) are powerful type I interferon (IFN-I) producing cells that are activated in response to infection or during inflammatory responses. Unfortunately, study of pDC function is hindered by their low frequency in lymphoid organs, and existing methods for in vitro DC generation predominantly favor the production of cDCs over pDCs. Here we present a unique approach to efficiently generate pDCs from common lymphoid progenitors (CLPs) in vitro. Specifically, the protocol described details how to purify CLPs from bone marrow and generate pDCs by coculturing with gamma-irradiated AC-6 feeder cells in the presence of Flt3 ligand. A unique characteristic of this culture system is that the CLPs migrate underneath the AC-6 cells and become cobblestone area forming cells, a critical step for expanding pDCs. Morphologically distinct DCs, namely pDCs and cDCs, were generated after approximately 2 weeks with a composition of 70-90% pDCs under optimal conditions. Typically, the number of pDCs generated by this method is roughly 100-fold of the number of CLPs seeded. Therefore, this is a novel system with which to robustly generate the large numbers of pDCs required to facilitate further studies into the development and function of these cells. PMID- 26650044 TI - Pro-Resolving Lipid Mediators Improve Neuronal Survival and Increase Abeta42 Phagocytosis. AB - Inflammation in the brain is a prominent feature in Alzheimer's disease (AD). Recent studies suggest that chronic inflammation can be a consequence of failure to resolve the inflammation. Resolution of inflammation is mediated by a family of lipid mediators (LMs), and the levels of these specialized pro-resolving mediators (SPMs) are reduced in the hippocampus of those with AD. In the present study, we combined analysis of LMs in the entorhinal cortex (ENT) from AD patients with in vitro analysis of their direct effects on neurons and microglia. We probed ENT, an area affected early in AD pathogenesis, by liquid chromatography-tandem mass spectrometry (LC-MS-MS), and found that the levels of the SPMs maresin 1 (MaR1), protectin D1 (PD1), and resolvin (Rv) D5, were lower in ENT of AD patients as compared to age-matched controls, while levels of the pro-inflammatory prostaglandin D2 (PGD2) were higher in AD. In vitro studies showed that lipoxin A4 (LXA4), MaR1, resolvin D1 (RvD1), and protectin DX (PDX) exerted neuroprotective activity, and that MaR1 and RvD1 down-regulated beta amyloid (Abeta)42-induced inflammation in human microglia. MaR1 exerted a stimulatory effect on microglial uptake of Abeta42. Our findings give further evidence for a disturbance of the resolution pathway in AD, and indicate that stimulating this pathway is a promising treatment strategy for AD. PMID- 26650045 TI - NMR-Based Metabolomics Reveal a Recovery from Metabolic Changes in the Striatum of 6-OHDA-Induced Rats Treated with Basic Fibroblast Growth Factor. AB - Basic fibroblast growth factor (bFGF) has a potential role in the treatment of Parkinson's disease (PD) due to its neurotrophic effect on dopaminergic neurons. To address the metabolic mechanisms of bFGF administration on PD, we have analyzed the metabolic profiles in the striatum of 6-hydroxydopamine (6-OHDA) induced PD rats after the treatment with bFGF using 1H NMR spectroscopy and partial least squares-discriminant analysis (PLS-DA). In the present study, we found that bFGF treatment can effectively recover PD-induced loss of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra. Metabolomic analyses reveal that PLS-DA failed to discriminate between the control and bFGF groups, indicating that the metabolic difference between these two groups was negligible. However, reliable PLS-DA models can be developed between control and PD groups as well as between PD and bFGF groups, which is attributed to changes in a series of metabolites including GABA, glutamate (Glu), glutamine (Gln), lactate, N acetylaspartate, creatine, taurine, and myo-inositol. ANOVA results show that the levels of all these metabolites were significantly increased in PD rats relative to normal rats, while PD-induced increase can be significantly reduced to normal levels after bFGF administration. In conclusion, our results suggest that a recovery from PD-induced metabolic disorders may be achieved by bFGF treatment, involving Gln/Glu-GABA cycle, energy metabolism, osmoregulation, and inflammation. PMID- 26650047 TI - Deep brain stimulation of the nucleus ventralis intermedius: a thalamic site of graviceptive modulation. AB - Based on animal studies, it has been shown that the nucleus ventralis intermedius (VIM) of the thalamus plays an important role within the vestibular system. A few human studies support the vestibular role of the VIM. In this study, we aimed to test the hypothesis whether changing the stimulation status in patients with unilateral deep brain stimulation in the VIM causally modulates the vestibular system, i.e., the graviceptive vertical perception. We tested six tremor patients for tilt of subjective visual vertical (SVV) with unilateral DBS in the VIM (mean age 67 years; mean time since electrode implantation 55 months). The mean tilt of the patients during the stimulator "on" condition was 1.4 degrees to the contraversive side [standard deviation (SD) +/- 0.4 degrees ] whereas during the "off" period a mean contraversive tilt of 4.4 degrees (SD +/- 3.0 degrees ) was obtained (p = 0.02). Thus, we were able to show that otolith-dominated graviceptive vertical perception can be directly modulated by changing the status of DBS VIM stimulation, indicating that the VIM is directly involved in (contraversive) vertical perception and its thalamic pathways. PMID- 26650048 TI - Deep sleep divides the cortex into opposite modes of anatomical-functional coupling. AB - The coupling of anatomical and functional connectivity at rest suggests that anatomy is essential for wake-typical activity patterns. Here, we study the development of this coupling from wakefulness to deep sleep. Globally, similarity between whole-brain anatomical and functional connectivity networks increased during deep sleep. Regionally, we found differential coupling: during sleep, functional connectivity of primary cortices resembled more the underlying anatomical connectivity, while we observed the opposite in associative cortices. Increased anatomical-functional similarity in sensory areas is consistent with their stereotypical, cross-modal response to the environment during sleep. In distinction, looser coupling-relative to wakeful rest-in higher order integrative cortices suggests that sleep actively disrupts default patterns of functional connectivity in regions essential for the conscious access of information and that anatomical connectivity acts as an anchor for the restoration of their functionality upon awakening. PMID- 26650049 TI - Anatomical study of the motor branches of the median nerve to the forearm and guidelines for selective neurectomy. AB - PURPOSE: The median nerve is responsible for the motor innervation of most of the muscles usually involved in upper limb spasticity. Selective neurectomy is one of the treatments utilized to reduce spasticity. The purpose of this study was to describe the variations of the motor branches of the median nerve in the forearm and draw recommendations for an appropriate planning of selective neurectomy. MATERIALS AND METHODS: The median nerve was dissected in the forearm of 20 fresh cadaver upper limbs. Measurements included number, origin, division, and entry point of each motor branch into the muscles. RESULTS: One branch for the pronator teres was the most common pattern. In 9/20 cases, it arose as a common trunk with other branches. A single trunk innervated the flexor carpi radialis with a common origin with other branches in 17/20 cases. Two, three or four branches innervated the flexor digitorum superficialis, the first one frequently through a common trunk with other branches. They were very difficult to identify unless insertions of pronator teres and flexor digitorum superficialis were detached. The flexor digitorum profundus received one to five branches and flexor pollicis longus one to two branches from the anterior interosseous nerve. CONCLUSIONS: There is no regular pattern of the motor branches of the median nerve in the forearm. Our findings differ in many points from the classical literature. Because of the frequency of common trunks for different muscles, we recommend the use of peroperative electrical stimulation. Selective neurotomy of flexor digitorum superficialis is technically difficult, because the entry point of some of their terminal branches occurs just below the arch and deep to the muscle belly. PMID- 26650050 TI - Superior mesenteric origin of the proper hepatic artery: embryological and clinical implications. AB - The hepatic arteries are subject to a great deal of anatomical variation, potentially complicating hepatobiliary surgical procedures as well as general gastrointestinal procedures that involve foregut and midgut structures. We report a case of a rare variant of the proper hepatic artery discovered during dissection of an 84-year-old male cadaver. In this individual, the common hepatic artery was absent and the proper hepatic artery was replaced directly to the superior mesenteric artery. The gastroduodenal artery and the right inferior phrenic artery took origin from the celiac trunk. In addition, there was no identifiable right gastric artery. The celiac trunk gave off three branches: the splenic, left gastric, and gastroduodenal arteries. The entire arterial blood supply to the liver, therefore, was derived from the superior mesenteric artery. Patterns of regression of the ventral branches and the partial disappearance of the ventral anastomotic arteries during embryonic development play a major role in the variations of the gut arteries. An intraoperative encounter with this particular variant carries a significant risk of iatrogenic injury with potentially devastating ischemia and necrotic results. Accurate depiction and definition of the hepatic arterial anatomy are crucial. Variations like the one described here underscore the importance of pre-operative imaging and knowledge of the embryological origins of variation. PMID- 26650051 TI - SSVEP-based Experimental Procedure for Brain-Robot Interaction with Humanoid Robots. AB - Brain-Robot Interaction (BRI), which provides an innovative communication pathway between human and a robotic device via brain signals, is prospective in helping the disabled in their daily lives. The overall goal of our method is to establish an SSVEP-based experimental procedure by integrating multiple software programs, such as OpenViBE, Choregraph, and Central software as well as user developed programs written in C++ and MATLAB, to enable the study of brain-robot interaction with humanoid robots. This is achieved by first placing EEG electrodes on a human subject to measure the brain responses through an EEG data acquisition system. A user interface is used to elicit SSVEP responses and to display video feedback in the closed-loop control experiments. The second step is to record the EEG signals of first-time subjects, to analyze their SSVEP features offline, and to train the classifier for each subject. Next, the Online Signal Processor and the Robot Controller are configured for the online control of a humanoid robot. As the final step, the subject completes three specific closed loop control experiments within different environments to evaluate the brain robot interaction performance. The advantage of this approach is its reliability and flexibility because it is developed by integrating multiple software programs. The results show that using this approach, the subject is capable of interacting with the humanoid robot via brain signals. This allows the mind controlled humanoid robot to perform typical tasks that are popular in robotic research and are helpful in assisting the disabled. PMID- 26650052 TI - Erratum to: European Resuscitation Council and European Society of Intensive Care Medicine 2015 guidelines for post-resuscitation care. PMID- 26650053 TI - An ultrasonographic sign of intrapulmonary shunt. PMID- 26650054 TI - Long-term survival after extracorporeal life support in children with neutropenic sepsis. PMID- 26650055 TI - Acute cor pulmonale during protective ventilation for acute respiratory distress syndrome: prevalence, predictors, and clinical impact. AB - RATIONALE: Increased right ventricle (RV) afterload during acute respiratory distress syndrome (ARDS) may induce acute cor pulmonale (ACP). OBJECTIVES: To determine the prevalence and prognosis of ACP and build a clinical risk score for the early detection of ACP. METHODS: This was a prospective study in which 752 patients with moderate-to-severe ARDS receiving protective ventilation were assessed using transesophageal echocardiography in 11 intensive care units. The study cohort was randomly split in a derivation (n = 502) and a validation (n = 250) cohort. MEASUREMENTS AND MAIN RESULTS: ACP was defined as septal dyskinesia with a dilated RV [end-diastolic RV/left ventricle (LV) area ratio >0.6 (>=1 for severe dilatation)]. ACP was found in 164 of the 752 patients (prevalence of 22 %; 95 % confidence interval 19-25 %). In the derivation cohort, the ACP risk score included four variables [pneumonia as a cause of ARDS, driving pressure >=18 cm H2O, arterial oxygen partial pressure to fractional inspired oxygen (PaO2/FiO2) ratio <150 mmHg, and arterial carbon dioxide partial pressure >=48 mmHg]. The ACP risk score had a reasonable discrimination and a good calibration. Hospital mortality did not differ between patients with or without ACP, but it was significantly higher in patients with severe ACP than in the other patients [31/54 (57 %) vs. 291/698 (42 %); p = 0.03]. Independent risk factors for hospital mortality included severe ACP along with male gender, age, SAPS II, shock, PaO2/FiO2 ratio, respiratory rate, and driving pressure, while prone position was protective. CONCLUSIONS: We report a 22 % prevalence of ACP and a poor outcome of severe ACP. We propose a simple clinical risk score for early identification of ACP that could trigger specific therapeutic strategies to reduce RV afterload. PMID- 26650056 TI - Night shift and cognitive performance: response to comments by Zijlstra. PMID- 26650057 TI - Systematic review including re-analyses of 1148 individual data sets of central venous pressure as a predictor of fluid responsiveness. AB - PURPOSE: Central venous pressure (CVP) has been shown to have poor predictive value for fluid responsiveness in critically ill patients. We aimed to re evaluate this in a larger sample subgrouped by baseline CVP values. METHODS: In April 2015, we systematically searched and included all clinical studies evaluating the value of CVP in predicting fluid responsiveness. We contacted investigators for patient data sets. We subgrouped data as lower (<8 mmHg), intermediate (8-12 mmHg) and higher (>12 mmHg) baseline CVP. RESULTS: We included 51 studies; in the majority, mean/median CVP values were in the intermediate range (8-12 mmHg) in both fluid responders and non-responders. In an analysis of patient data sets (n = 1148) from 22 studies, the area under the receiver operating curve was above 0.50 in the <8 mmHg CVP group [0.57 (95% CI 0.52-0.62)] in contrast to the 8-12 mmHg and >12 mmHg CVP groups in which the lower 95% CI crossed 0.50. We identified some positive and negative predictive value for fluid responsiveness for specific low and high values of CVP, respectively, but none of the predictive values were above 66% for any CVPs from 0 to 20 mmHg. There were less data on higher CVPs, in particular >15 mmHg, making the estimates on predictive values less precise for higher CVP. CONCLUSIONS: Most studies evaluating fluid responsiveness reported mean/median CVP values in the intermediate range of 8-12 mmHg both in responders and non-responders. In a re analysis of 1148 patient data sets, specific lower and higher CVP values had some positive and negative predictive value for fluid responsiveness, respectively, but predictive values were low for all specific CVP values assessed. PMID- 26650058 TI - Practical assessment in patients suffering from musculoskeletal disorders. AB - Short review of exemplary clinical assessment methods to describe clinical evidence-based assessment for patients suffering from symptoms of musculoskeletal pain.History and physical examination are the primary evidence-based assessment instruments for pain patients. Pain scales and questionnaire might allow assessment of different aspects of pain in order to perform an individualized therapy for pain patients. PMID- 26650060 TI - [Epidemiology of obesity in Austria]. AB - The purpose of this article was to compile all existing data regarding the prevalence of obesity in Austria in all age groups, and to perform additional analyses. Prevalence of obesity in the adult Austrian population varies between 8.3 and 19.9% in men, and 9.0 and 19.8% in women with increasing trends over time. Prevalence of obesity in children and adolescents in Austria varies between 3.1 and 9.0% in boys and between 2.2 and 7.3% in girls. Factors associated with obesity include higher age, lower educational level, profession, migration background, living in eastern parts of Austria, lack of social support, and psycho-social pressure. In women, socio-economic parameters are stronger associated with obesity compared to men. Obesity is associated with hypertension, diabetes mellitus, osteoarthritis, and low back pain, and deteriorated quality of live, in both sexes, and in men additionally with a history of heart attack, and in women additionally with anxiety/depression. PMID- 26650059 TI - [Gender Obesity Report--Influence of obesity on Reproduction and Pregnancy]. AB - Obesity influences reproduction in men and women at all ages. The increasing prevalence of obesity is associated with rising numbers of reproductive disorders in both sexes. Obesity influences menstrual cycle and ovulation irregularities, increases pregnancy complications and complication rates in assisted reproductive technologies in women and in men obesity is associated with lower semen parameters. Weight loss through lifestyle changes or bariatric surgery has positive effects on hormonal parameters and fertility in both men and women. PMID- 26650061 TI - Age estimation in children by measurement of open apices in teeth with Bayesian calibration approach. AB - Age estimation from teeth by radiological analysis, in both children and adolescents, has wide applications in several scientific and forensic fields. In 2006, Cameriere et al. proposed a regression method to estimate chronological age in children, according to measurements of open apices of permanent teeth. Although several regression models are used to analyze the relationship between age and dental development, one serious limitation is the unavoidable bias in age estimation when regression models are used. The aim of this paper is to develop a full Bayesian calibration method for age estimation in children according to the sum of open apices, S, of the seven left permanent mandibular teeth. This cross sectional study included 2630 orthopantomographs (OPGs) from healthy living Italian subjects, aged between 4 and 17 years and with no obvious developmental abnormalities. All radiographs were in digital format and were processed by the ImageJ computer-aided drawing program. The distance between the inner side of the open apex was measured for each tooth. Dental maturity was then evaluated according to the sum of normalized open apices (S). Intra- and inter-observer agreement was satisfactory, according to an intra-class correlation coefficient of S on 50 randomly selected OPGs. Mean absolute errors were 0.72 years (standard deviation 0.60) and 0.73 years (standard deviation 0.61) in boys and girls, respectively. The mean interquartile range (MIQR) of the calibrating distribution was 1.37 years (standard deviation 0.46) and 1.51 years (standard deviation 0.52) in boys and girls, respectively. Estimate bias was betaERR=-0.005 and 0.003 for boys and girls, corresponding to a bias of a few days for all individuals in the sample. Neither of the betaERR values was significantly different from 0 (p>0.682). In conclusion, the Bayesian calibration method overcomes problems of bias in age estimation when regression models are used, and appears to be suitable for assessing both age and age distribution in children according to tooth maturity. PMID- 26650063 TI - Risk of Seizures Associated with Antidepressant Use in Patients with Depressive Disorder: Follow-up Study with a Nested Case-Control Analysis Using the Clinical Practice Research Datalink. AB - INTRODUCTION: Antidepressant use has been associated with an increased risk of seizures. Evidence on the association between antidepressant use at therapeutic doses and seizures mainly comes from clinical trials that were not designed to investigate this potential relationship. OBJECTIVE: The objective of this study was to assess the risk of first-time seizures in association with exposure to antidepressants in patients with depressive disorders. METHODS: We conducted a retrospective follow-up study with a nested case-control analysis between 1998 and 2012, using data from the UK-based Clinical Practice Research Datalink (CPRD). We estimated crude incidence rates with 95 % confidence intervals (CIs) of seizures in depressed patients who used selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), 'other antidepressants', no antidepressants, or who had used antidepressants in the past. To adjust for potential confounding, we estimated odds ratios of antidepressant drug use among cases with seizures and matched controls in a nested case-control analysis. RESULTS: Of 151,005 depressed patients, 619 had an incident seizure during follow-up. Incidence rates per 10,000 person-years were 12.44 (95 % CI 10.67-14.21) in SSRI users, 15.44 (95 % CI 8.99-21.89) in SNRI users, 8.33 (95 % CI 4.68-11.98) in TCA users, 9.33 (95 % CI 6.19-12.46) in non-users of antidepressants, and 5.05 (95 % CI 4.49-5.62) in past users of antidepressants. In the case-control analysis, relative risk estimates for seizures were increased in current users of SSRIs (adjusted odds ratio 1.98, 95 % CI 1.48-2.66) and SNRIs (adjusted odds ratio 1.99, 95 % CI 1.20 3.29), but not TCAs (adjusted odds ratio 0.99, 95 % CI 0.63-1.53), compared with non-users. CONCLUSION: Current use of SSRIs or SNRIs was associated with a twofold increased risk of first-time seizures compared with non-use, while current use of TCAs (mostly low dose) was not associated with seizures. Treatment initiation in SSRI and SNRI users was associated with a higher risk of seizures than longer-term treatment. PMID- 26650062 TI - Advances in the Pharmacogenomics of Adverse Drug Reactions. AB - Rapid developments in pharmacogenomics have been noticeable in recent years, and much of this knowledge has improved understanding of adverse drug reactions. This improved knowledge has largely been the result of improved sequencing technologies and falling costs in this area, as well as improved statistical techniques to analyse the data derived from studies. While the genetic reasons behind adverse drug reactions are becoming better understood, translation of this knowledge, particularly in terms of biomarkers that might be clinically applicable at the bedside, has been more difficult. Understanding of the technologies and their application is limited among practising clinicians. The cost of some of the technologies available may also be prohibitive in stretched healthcare economies. As education about the potential for applying pharmacogenomics improves and costs fall, understanding of adverse drug reactions and application of this knowledge in a clinical setting should improve. PMID- 26650065 TI - Bioconjugated Manganese Dioxide Nanoparticles Enhance Chemotherapy Response by Priming Tumor-Associated Macrophages toward M1-like Phenotype and Attenuating Tumor Hypoxia. AB - Hypoxia promotes not only the invasiveness of tumor cells, but also chemoresistance in cancer. Tumor associated macrophages (TAMs) residing at the site of hypoxic region of tumors have been known to cooperate with tumor cells, and promote proliferation and chemoresistance. Therefore, there is an urgent need for new strategies to alleviate tumor hypoxia and enhance chemotherapy response in solid tumors. Herein, we have taken advantage of high accumulation of TAMs in hypoxic regions of tumor and high reactivity of manganese dioxide nanoparticles (MnO2 NPs) toward hydrogen peroxide (H2O2) for the simultaneous production of O2 and regulation of pH to effectively alleviate tumor hypoxia by targeted delivery of MnO2 NPs to the hypoxic area. Furthermore, we also utilized the ability of hyaluronic acid (HA) modification in reprogramming anti-inflammatory, pro-tumoral M2 TAMs to pro-inflammatory, antitumor M1 macrophages to further enhance the ability of MnO2 NPs to lessen tumor hypoxia and modulate chemoresistance. The HA coated, mannan-conjugated MnO2 particle (Man-HA-MnO2) treatment significantly increased tumor oxygenation and down-regulated hypoxia-inducible factor-1 alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF) in the tumor. Combination treatment of the tumors with Man-HA-MnO2 NPs and doxorubicin significantly increased apparent diffusion coefficient (ADC) values of breast tumor, inhibited tumor growth and tumor cell proliferation as compared with chemotherapy alone. In addition, the reaction of Man-HA-MnO2 NPs toward endogenous H2O2 highly enhanced T1- and T2-MRI performance for tumor imaging and detection. PMID- 26650064 TI - Tools for Assessing Potential Significance of Pharmacist Interventions: A Systematic Review. AB - INTRODUCTION: Assessing the significance of pharmacist interventions (PIs) is essential to demonstrate the added value of pharmacists. Methods and tools for assessing the potential significance of PIs are diverse and their properties are questionable. OBJECTIVES: We aimed to systematically review the tools available to assess the potential significance of PIs. METHODS: We conducted a systematic search for English- or French-language publications from 1986 to 2013 in PubMed, PsycINFO, PASCAL, and CINAHL. Studies were screened by two independent reviewers based on inclusion/exclusion criteria and were abstracted for content, structure of tools, and validation process. RESULTS: Of 873 citations screened, 82 distinct tools were identified from 133 studies. While clinical aspects were often defined quite clearly, terminology regarding humanistic, economic, and process-related aspects of PIs was omitted, incomplete, or ambiguous in most tools. The probabilities of consequences of PIs/drug-related problems were evaluated in 20/82 tools. Few tools simultaneously measured economic, clinical, humanistic, and process-related variables. Structure of the tools varied from an implicit, mono-dimensional tool to an explicit, multi-dimensional algorithm. Validation processes were diverse in terms of quantification and number of raters, rating method, and psychometric parameters. Of 133 identified studies, there was limited evidence of validity (8/133, 6.0%), inter-rater reliability (49/133, 36.8%), and intra-rater reliability (2/133, 1.5%). CONCLUSIONS: The majority of tools focused primarily on assessing clinical aspects and failed to detect comprehensive impacts. The heterogeneity of tools and assessment processes hindered our ability to synthesize the results of evaluations. Limited results for their validity and reliability cast doubt on the credibility of this methodology for justification of the value of PIs. Recommendations for development of tools with optimal theoretical, pragmatic, and psychometric properties are proposed. PMID- 26650068 TI - Development of Functional Surfaces on High-Density Polyethylene (HDPE) via Gas Assisted Etching (GAE) Using Focused Ion Beams. AB - Irradiation damage, caused by the use of beams in electron and ion microscopes, leads to undesired physical/chemical material property changes or uncontrollable modification of structures. Particularly, soft matter such as polymers or biological materials is highly susceptible and very much prone to react on electron/ion beam irradiation. Nevertheless, it is possible to turn degradation dependent physical/chemical changes from negative to positive use when materials are intentionally exposed to beams. Especially, controllable surface modification allows tuning of surface properties for targeted purposes and thus provides the use of ultimate materials and their systems at the micro/nanoscale for creating functional surfaces. In this work, XeF2 and I2 gases were used in the focused ion beam scanning electron microscope instrument in combination with gallium ion etching of high-density polyethylene surfaces with different beam currents and accordingly different gas exposure times resulting at the same ion dose to optimize and develop new polymer surface properties and to create functional polymer surfaces. Alterations in the surface morphologies and surface chemistry due to gas-assisted etching-based nanostructuring with various processing parameters were tracked using high-resolution SEM imaging, complementary energy dispersive spectroscopic analyses, and atomic force microscopic investigations. PMID- 26650067 TI - Neurocognitive function and quality of life in patients with newly diagnosed brain metastasis after treatment with intra-operative cesium-131 brachytherapy: a prospective trial. AB - Intraoperative permanent Cesium-131 (Cs-131) brachytherapy can provide a viable alternative to WBRT with excellent response rates and minimal toxicity. This study reports the results of the prospective trial of the impact of intraoperative Cs-131 on neurocognitive function and quality of life (QoL) in patients with resected brain metastases. Between 2010 and 2012, 24 patients with newly diagnosed metastasis to the brain were accrued on a prospective protocol and treated with Cs-131 brachytherapy seeds after surgical resection. Physicians administered the mini-mental status examination (MMSE) and functional assessment of cancer therapy-brain (FACT-Br) questionnaire to all patients before treatment and again every 2 months for the duration of 6 months with additional follow-up again at 12 months. Wilcoxon rank sum test was used to analyze statistically significant changes in MMSE over time and paired t test was used to analyze changes in FACT-BR. There was a statistical improvement in overall FACT-BR score at 4 and 6 months of follow-up when compared to baseline (162 vs. 143, P = 0.004; 164 vs. 143, P = 0.005 respectively) with a non-significant trend toward improvement at 2 and 12 months (154 vs. 143, P = 0.067; 159 vs. 149, P = 0.4). MMSE score was statistically improved at 4 and up to 12 months compared to pre treatment MMSE (30 vs. 29, P = 0.017; 30 vs. 29, P = 0.001 respectively). Patients with brain metastasis who received intra-operative permanent Cs-131 brachytherapy implants saw an improvement of their neurocognitive status and self assessment of QoL. In addition to the excellent local control of metastasis, this approach may contribute to the improvements in cognitive function and QOL. PMID- 26650069 TI - Effect of Focused Ion Beam Imaging on the Crystallinity of InAs. AB - We investigated the effect of focused ion beam (FIB) imaging on the crystallinity of InAs using Raman scattering. A spatial correlation model was used to fit the broad band induced by FIB imaging. The fitting gives a correlation length of ~42 A for the noisiest image condition (with an ion fluence of 7.4*1010 cm-2), implying severe damage in the surface layer of InAs. However, further increasing the fluence by several orders of magnitude only decreases the correlation length from 42 to 35 A. We attribute the severe damage to the high beam current density and the low scanning speed of the FIB imaging process. These process conditions, along with low InAs thermal conductivity, also leads to a high local temperature in the exposed region that largely annihilated the defects and resulted in the nearly fluence-independent behavior. PMID- 26650070 TI - Microscopy Techniques for Analysis of Nickel Metal Hydride Batteries Constituents. AB - With the need for improvements in the performance of rechargeable batteries has come the necessity to better characterize cell electrodes and their component materials. Electron microscopy has been shown to reveal many important features of microstructure that are becoming increasingly important for understanding the behavior of the components during the many charge/discharge cycles required in modern applications. The aim of this paper is to present an overview of how the full suite of techniques available using transmission electron microscopy (TEM) and scanning transmission electron microscopy was applied to the case of materials for the positive electrode in nickel metal hydride rechargeable battery electrodes. Embedding and sectioning of battery-grade powders with an ultramicrotome was used to produce specimens that could be readily characterized by TEM. Complete electrodes were embedded after drying, and also after dehydration from the original wet state, for examination by optical microscopy and using focused ion beam techniques. Results of these studies are summarized to illustrate the significance of the microstructural information obtained. PMID- 26650066 TI - AshwaMAX and Withaferin A inhibits gliomas in cellular and murine orthotopic models. AB - Glioblastoma multiforme (GBM) is an aggressive, malignant cancer Johnson and O'Neill (J Neurooncol 107: 359-364, 2012). An extract from the winter cherry plant (Withania somnifera ), AshwaMAX, is concentrated (4.3 %) for Withaferin A; a steroidal lactone that inhibits cancer cells Vanden Berghe et al. (Cancer Epidemiol Biomark Prev 23: 1985-1996, 2014). We hypothesized that AshwaMAX could treat GBM and that bioluminescence imaging (BLI) could track oral therapy in orthotopic murine models of glioblastoma. Human parietal-cortical glioblastoma cells (GBM2, GBM39) were isolated from primary tumors while U87-MG was obtained commercially. GBM2 was transduced with lentiviral vectors that express Green Fluorescent Protein (GFP)/firefly luciferase fusion proteins. Mutational, expression and proliferative status of GBMs were studied. Intracranial xenografts of glioblastomas were grown in the right frontal regions of female, nude mice (n = 3-5 per experiment). Tumor growth was followed through BLI. Neurosphere cultures (U87-MG, GBM2 and GBM39) were inhibited by AshwaMAX at IC50 of 1.4, 0.19 and 0.22 uM equivalent respectively and by Withaferin A with IC50 of 0.31, 0.28 and 0.25 uM respectively. Oral gavage, every other day, of AshwaMAX (40 mg/kg per day) significantly reduced bioluminescence signal (n = 3 mice, p < 0.02, four parameter non-linear regression analysis) in preclinical models. After 30 days of treatment, bioluminescent signal increased suggesting onset of resistance. BLI signal for control, vehicle-treated mice increased and then plateaued. Bioluminescent imaging revealed diffuse growth of GBM2 xenografts. With AshwaMAX, GBM neurospheres collapsed at nanomolar concentrations. Oral treatment studies on murine models confirmed that AshwaMAX is effective against orthotopic GBM. AshwaMAX is thus a promising candidate for future clinical translation in patients with GBM. PMID- 26650071 TI - Speckle Suppression by Decoherence in Fluctuation Electron Microscopy. AB - We compare experimental fluctuation electron microscopy (FEM) speckle data with electron diffraction simulations for thin amorphous carbon and silicon samples. We find that the experimental speckle intensity variance is generally more than an order of magnitude lower than kinematical scattering theory predicts for spatially coherent illumination. We hypothesize that decoherence, which randomizes the phase relationship between scattered waves, is responsible for the anomaly. Specifically, displacement decoherence can contribute strongly to speckle suppression, particularly at higher beam energies. Displacement decoherence arises when the local structure is rearranged significantly by interactions with the beam during the exposure. Such motions cause diffraction speckle to twinkle, some of it at observable time scales. We also find that the continuous random network model of amorphous silicon can explain the experimental variance data if displacement decoherence and multiple scattering is included in the modeling. This may resolve the longstanding discrepancy between X-ray and electron diffraction studies of radial distribution functions, and conclusions reached from previous FEM studies. Decoherence likely affects all quantitative electron imaging and diffraction studies. It likely contributes to the so-called Stobbs factor, where high-resolution atomic-column image intensities are anomalously lower than predicted by a similar factor to that observed here. PMID- 26650072 TI - High-Resolution Imaging and Spectroscopy at High Pressure: A Novel Liquid Cell for the Transmission Electron Microscope. AB - We demonstrate quantitative core-loss electron energy-loss spectroscopy of iron oxide nanoparticles and imaging resolution of Ag nanoparticles in liquid down to 0.24 nm, in both transmission and scanning transmission modes, in a novel, monolithic liquid cell developed for the transmission electron microscope (TEM). At typical SiN membrane thicknesses of 50 nm the liquid-layer thickness has a maximum change of only 30 nm for the entire TEM viewing area of 200*200 um. PMID- 26650073 TI - Seed Removal Increased by Scramble Competition with an Invasive Species. AB - Competition for seeds has a major influence on the evolution of granivores and the plants on which they rely. The complexity of interactions and coevolutionary relationships vary across forest types. The introduction of non-native granivores has considerable potential to alter seed dispersal dynamics. Non-native species are a major cause of endangerment for native species, but the mechanisms are often unclear. As biological invasions continue to rise, it is important to understand mechanisms to build up strategies to mitigate the threat. Our field experiment quantified the impact of introduced Abert's squirrels (Sciurus aberti) on rates of seed removal within the range of critically endangered Mount Graham red squirrels (Tamiasciurus hudsonicus grahamensis), which consumes similar foods. In the presence of invasive Abert's squirrels, the time cones were removed was faster than when the invasive was excluded, accounting for a median removal time of cones available to red and Abert's squirrels that is 32.8% less than that of cones available only to the rare native red squirrels. Moreover, in the presence of Abert's squirrels, removal rates are higher at great distance from a territorial red squirrel larderhoard and in more open portions of the forest, which suggests differential patterns of seed dispersal. The impact on food availability as a result of cone removal by Abert's squirrels suggests the potential of food competition as a mechanism of endangerment for the Mount Graham red squirrel. Furthermore, the magnitude and differential spatial patterns of seed removal suggest that non-native granivores may have impacts on forest regeneration and structure. PMID- 26650074 TI - Hacking the hospital environment: young adults designing youth-friendly hospital rooms together with young people with cancer experiences. AB - BACKGROUND: There is a need for youth-friendly hospital environments as the ward environment may affect both patient satisfaction and health outcomes. OBJECTIVE: To involve young people in designing youth-friendly ward environment. METHODS: We arranged a design competition lasting 42 h (Hackathon). Students in architecture, design, engineering, communication and anthropology participated (27 young adults) - forming eight groups. Adolescents and young adults (AYA) with current or former cancer experience participated as sparring partners. We provided workspace and food during the weekend. The groups presented their products to a jury and relevant stakeholders. RESULTS: The groups created eight unique design concepts. The young designers were extremely flexible listening to ideas and experiences from the young patients, which led to common features including individual and flexible design, privacy in two-bed wardrooms and social contact with other hospitalized AYA. The winning project included an integrated concept for both wardrooms and the AYA day room, including logos and names for the rooms and an 'energy wall' in the day room. CONCLUSION: A hackathon event was an effective mode of youth participation. The design concepts and ideas were in line with current evidence regarding pleasing hospital environment and youth-friendly inpatient facilities and may be applicable to other young patients. PMID- 26650075 TI - High level of oxysterols in neonatal cholestasis: a pitfall in analysis of biochemical markers for Niemann-Pick type C disease. AB - BACKGROUND: Niemann-Pick disease type C (NPC) is a rare lipid storage disorder characterized by progressive neurological deterioration. Diagnosing NPC is challenging as clinical signs and symptoms are variable and non-specific. Two oxysterols, cholestane-3beta,5alpha,6beta-triol (triol) and 7-ketocholesterol (7KC), have been proposed as biomarkers for aiding diagnosis of NPC. This study evaluated the use of triol and 7KC as biomarkers in cholestatic neonates with suspected NPC. METHODS: Plasma triol and 7KC were analysed as dimethylglycine esters using an liquid chromatography - tandem mass spectrometry (LC-MS/MS) assay in selected neonates with severe cholestasis and suspected NPC (n=7), adults with cholestasis (n=15), patients with confirmed NPC (positive controls; n=11 [one child and 10 adults]), healthy subjects (negative controls; n=40 [20 children and 20 adults]), and cholestatic adults (comparative reference; n=15). The LC-MS/MS method was subjected to a number of tests for accuracy and consistency. RESULTS: Triol and 7KC levels were substantially and significantly increased in NPC positive patients compared with healthy controls (p<0.001). However, positive results (markedly increased levels of both oxysterols) were identified in 6/7 (86%) neonates with cholestasis. Genetic testing confirmed NPC only in one neonate who had increased triol and 7KC, and increased oxysterol levels among neonates with no identified NPC gene mutations were considered likely due to biliary atresia (BA). CONCLUSIONS: While the potential of oxysterols as NPC biomarkers has been well evaluated in older patient populations (without cholestasis), our data suggest that cholestasis might represent a pitfall in oxysterol measurements intended to aid diagnosis of NPC in affected patients. PMID- 26650076 TI - Why are clinical practice guidelines not followed? AB - Clinical practice guidelines (CPG) are written with the aim of collating the most up to date information into a single document that will aid clinicians in providing the best practice for their patients. There is evidence to suggest that those clinicians who adhere to CPG deliver better outcomes for their patients. Why, therefore, are clinicians so poor at adhering to CPG? The main barriers include awareness, familiarity and agreement with the contents. Secondly, clinicians must feel that they have the skills and are therefore able to deliver on the CPG. Clinicians also need to be able to overcome the inertia of "normal practice" and understand the need for change. Thirdly, the goals of clinicians and patients are not always the same as each other (or the guidelines). Finally, there are a multitude of external barriers including equipment, space, educational materials, time, staff, and financial resource. In view of the considerable energy that has been placed on guidelines, there has been extensive research into their uptake. Laboratory medicine specialists are not immune from these barriers. Most CPG that include laboratory tests do not have sufficient detail for laboratories to provide any added value. However, where appropriate recommendations are made, then it appears that laboratory specialist express the same difficulties in compliance as front-line clinicians. PMID- 26650077 TI - Assessing quality from an accuracy-based HbA1c proficiency survey. PMID- 26650078 TI - Health Gains and Financial Protection from Pneumococcal Vaccination and Pneumonia Treatment in Ethiopia: Results from an Extended Cost-Effectiveness Analysis. AB - BACKGROUND: Pneumonia and pneumococcal disease cause a large disease burden in resource-constrained settings. We pursue an extended cost-effectiveness analysis (ECEA) of two fully publicly financed interventions in Ethiopia: pneumococcal vaccination for newborns and pneumonia treatment for under-five children in Ethiopia. METHODS: We apply ECEA methods and estimate the program impact on: (1) government program costs; (2) pneumonia and pneumococcal deaths averted; (3) household expenses related to pneumonia/pneumococcal disease treatment averted; (4) prevention of household medical impoverishment measured by an imputed money metric value of financial risk protection; and (5) distributional consequences across the wealth strata of the country population. Available epidemiological and cost data from Ethiopia are applied and the two interventions are assessed separately at various incremental coverage levels. RESULTS: Scaling-up pneumococcal vaccines at around 40% coverage would cost about $11.5 million and avert about 2090 child deaths annually, while a 10% increase of pneumonia treatment to all children under 5 years of age would cost about $13.9 million and avert 2610 deaths annually. Health benefits of the two interventions publicly financed would be concentrated among the bottom income quintile, where 30-40% of all deaths averted would be expected to occur in the poorest quintile. In sum, the two interventions would eliminate a total of $2.4 million of private household expenditures annually, where the richest quintile benefits from around 30% of the total private expenditures averted. The financial risk protection benefits would be largely concentrated among the bottom income quintile. The results are most sensitive to variations in vaccine price, population size, number of deaths due to pneumonia, efficacy of interventions and out-of-pocket copayment share. CONCLUSIONS: Vaccine and treatment interventions for children, as shown with the illustrative examples of pneumococcal vaccine and pneumonia treatment, can bring large health and financial benefits to households in Ethiopia, most particularly among the poorest socio-economic groups. PMID- 26650080 TI - Correction: Usage of Complementary Medicine in Switzerland: Results of the Swiss Health Survey 2012 and Development Since 2007. AB - [This corrects the article DOI: 10.1371/journal.pone.0141985.]. PMID- 26650079 TI - Influence of the covalent immobilization of graphene oxide in poly(vinyl alcohol) on human osteoblast response. AB - The differences in the response of human Saos-2 osteoblasts to nanocomposites of poly(vinyl alcohol) (PVA) and 1.5wt.% graphene oxide (GO) prepared by covalent linking (PVA/GO-c) and simple blending (PVA/GO-m) have been evaluated through different biocompatibility parameters. The effects produced on osteoblasts by these two nanocomposites were analysed in parallel and compared with the direct action of GO and with the effect of PVA films without GO. The intracellular content of reactive oxygen species (ROS) and the levels of interleukin-6 (IL-6) were measured to evaluate oxidative stress induction and protective response, respectively. The results demonstrate that the combination of GO with PVA reduces both the proliferation delay and the internal cell complexity alterations induced by GO on human osteoblasts. Moreover, the covalent attachment of GO to the PVA chains increases both cell viability and IL-6 levels, reducing both apoptosis and intracellular ROS content when compared to simple blending of both materials. The use of this strategy to modulate the biointerface reduces the toxic effects of graphene while preserving the reinforcement characteristics for application in tissue engineering scaffolds, and has enormous interest for polymer/graphene biomaterials development. PMID- 26650081 TI - The Consequences of Precipitation Seasonality for Mediterranean-Ecosystem Vegetation of South Africa. AB - Globally, mediterranean-climate ecosystem vegetation has converged on an evergreen, sclerophyllous and shrubby growth form. The particular aspects of mediterranean-climate regions that contribute to this convergence include summer droughts and relatively nutrient-poor soils. We hypothesised that winter precipitation implies stressful summer droughts and leaches soils due to greater water availability (i.e. balance between precipitation and potential evapotranspiration; P-PET) during cold periods. We conducted a comparative analysis of normalised difference vegetation indices (NDVI) and edaphic and climate properties across the biomes of South Africa. NDVI was strongly correlated with both precipitation and P-PET (r2 = 0.8). There was no evidence, however, that winter-precipitation reduces NDVI in comparison to similar amounts of summer-precipitation. Base saturation (BS), a measure of soil leaching was, however, negatively related to P-PET (r2 = 0.64). This led to an interaction between P-PET and BS in determining NDVI, indicating the existence of a trade-off between water availability and soil nutrients that enables NDVI to increase with precipitation, despite negative consequences for soil nutrient availability. The mechanism of this trade-off is suggested to be that water increases nutrient accessibility. This implies that along with nutrient-depauperate geologies and long periods of time since glaciation, the winter-precipitation may have contributed to the highly leached status of the soils. Since many of the ecophysiological characteristics of mediterranean-ecosystem flora are associated with low nutrient availabilities (e.g. evergreen foliage, sclerophylly, cluster roots), we conclude that mediterranean-climates promote convergence of growth forms in these regions through high leaching capacity. PMID- 26650082 TI - Estimate of sulfur, arsenic, mercury, fluorine emissions due to spontaneous combustion of coal gangue: An important part of Chinese emission inventories. AB - A rough estimate of the annual amount of sulfur, arsenic, mercury and fluoride emission from spontaneous combustion of coal gangue in China was determined. The weighted mean concentrations of S, As, Hg, and F in coal gangue are 1.01%, 7.98, 0.18, and 365.54 mg/kg, respectively. Amounts of S, As, Hg, and F emissions from coal gangue spontaneous combustion show approximately 1.13 Mt, and 246, 45, and 63,298 tons in 2013, respectively. The atmospheric release amount of sulfur from coal gangue is more than one tenth of this from coal combustion, and the amounts of As, Hg, and F are close to or even exceed those from coal combustion. China's coal gangue production growth from 1992 to 2013 show an obvious growth since 2002. It may indicate that Chinese coal gangue has become a potential source of air pollution, which should be included in emission inventories. PMID- 26650083 TI - Multivariate calibration-assisted high-performance liquid chromatography with dual UV and fluorimetric detection for the analysis of natural and synthetic sex hormones in environmental waters and sediments. AB - A green method is reported based on non-sophisticated instrumental for the quantification of seven natural and synthetic estrogens, three progestagens and one androgen in the presence of real interferences. The method takes advantage of: (1) chromatography, allowing total or partial resolution of a large number of compounds, (2) dual detection, permitting selection of the most appropriate signal for each analyte and, (3) second-order calibration, enabling mathematical resolution of incompletely resolved chromatographic bands and analyte determination in the presence of interferents. Consumption of organic solvents for cleaning, extraction and separation are markedly decreased because of the coupling with MCR-ALS (multivariate curve resolution/alternating least-squares) which allows the successful resolution in the presence of other co-eluting matrix constituents. Rigorous IUPAC detection limits were obtained: 6-24 ng L(-1) in water, and 0.1-0.9 ng g(-1) in sediments. Relative prediction errors were 2-10% (water) and 1-8% (sediments). PMID- 26650084 TI - Changes in metal availability, desorption kinetics and speciation in contaminated soils during repeated phytoextraction with the Zn/Cd hyperaccumulator Sedum plumbizincicola. AB - Phytoextraction is one of the most promising technologies for the remediation of metal contaminated soils. Changes in soil metal availability during phytoremediation have direct effects on removal efficiency and can also illustrate the interactive mechanisms between hyperaccumulators and metal contaminated soils. In the present study the changes in metal availability, desorption kinetics and speciation in four metal-contaminated soils during repeated phytoextraction by the zinc/cadmium hyperaccumulator Sedum plumbizincicola (S. plumbizincicola) over three years were investigated by chemical extraction and the DGT-induced fluxes in soils (DIFS) model. The available metal fractions (i.e. metal in the soil solution extracted by CaCl2 and by EDTA) decreased greatly by >84% after phytoextraction in acid soils and the deceases were dramatic at the initial stages of phytoextraction. However, the decreases in metal extractable by CaCl2 and EDTA in calcareous soils were not significant or quite low. Large decreases in metal desorption rate constants evaluated by DIFS were found in calcareous soils. Sequential extraction indicated that the acid-soluble metal fraction was easily removed by S. plumbizincicola from acid soils but not from calcareous soils. Reducible and oxidisable metal fractions showed discernible decreases in acid and calcareous soils, indicating that S. plumbizincicola can mobilize non-labile metal for uptake but the residual metal cannot be removed. The results indicate that phytoextraction significantly decreases metal availability by reducing metal pool sizes and/or desorption rates and that S. plumbizincicola plays an important role in the mobilization of less active metal fractions during repeated phytoextraction. PMID- 26650085 TI - Levels and patterns of DDTs in maternal colostrum from an island population and exposure of neonates. AB - Dichlorodiphenyltrichloroethane (DDT) was heavily used in the past in many regions of the world. The occurrence of DDTs in island populations may be elevated if the island is adjacent to major DDT consumption estuaries, such as the Yangtze River Delta. In this study, colostrum samples were collected from maternal-neonate pairs (n = 106) from the Shengsi Island, located directly downstream from the Yangtze River outlet. DDT isomers and enantiomer compositions were analyzed by gas chromatography equipped with mass spectrometer (GC/MS) and GC/MS-MS. The average levels of p,p'-DDE, o,p'-DDD, p,p'-DDD, o,p'-DDT, p,p'-DDT and total DDTs were 1.32, 0.03, 0.09, 0.08, 0.48, and 1.93 MUg g(-1) lipid weight, respectively. Maternal age and pregnancy body mass index (BMI) were positively associated with levels of DDTs (p < 0.05). High (DDE+DDD)/DDT and p,p' DDE/p,p'-DDT ratios suggested that current DDT residues originated primarily from historical use of DDT products, but new sources may also contribute partially to some high o,p'-DDT/p,p'-DDT ratios. Enantiomeric enrichment was found for the (-) enantiomer of o,p'-DDD and the (+)-enantiomer of o,p'-DDT, suggesting stereoselective attenuation. Based on breast milk consumption, the average daily intake of DDTs by neonates was 8.33 +/- 7.34 MUg kg(-1)bw per day, which exceeded the WHO's tolerable daily intake guideline of 0.01 mg kg(-1) bw per day by 25%, implying some neonates in the Yangtze River region are potentially at high risk from exposure to DDTs. PMID- 26650087 TI - Addressing the Educational Needs of Wound Care Professionals. PMID- 26650086 TI - Delphi: From Mythology to Research. PMID- 26650088 TI - FROM THE EDITOR'S DESK. PMID- 26650091 TI - Proceed with Caution: Wound Care-Related Items Are on the 2016 Office of Inspector General Work Plan. PMID- 26650092 TI - Outcomes of Radiation Injuries Using Hyperbaric Oxygen Therapy: An Observational Cohort Study. AB - BACKGROUND: The late effects of radiation therapy following the treatment of cancer are a well-known consequence. Evidence increasingly supports the use of hyperbaric oxygen (HBO) as an adjunctive treatment in a variety of radiation injuries. OBJECTIVE: To present the findings of a new registry of radiation injuries that was developed to evaluate the outcomes and treatment parameters of HBO treatment (HBOT) when applied to patients experiencing the late effects of radiation therapy. DESIGN: Observational cohort. SETTING: Hyperbaric oxygen clinical treatment facilities in the United States. PATIENTS: A total of 2538 patients with radiation-induced injuries. MEASUREMENTS: Injury type, patient age, gender, diabetes, end-stage renal disease, collagen vascular disease, coronary artery disease/peripheral vascular disease, on anticoagulant medication, on systemic steroid medication, patient is current smoker, patient abuses alcohol, symptoms reported, duration of symptoms, symptom progression prior to HBOT, transfusion units, HBOT time, HBOT count, HBO chamber pressure, HBO time in chamber, and patient outcomes. RESULTS: A total of 2538 patient entries with 10 types of radiation injuries were analyzed. The 5 most common injuries were osteoradionecrosis (33.4%), dermal soft tissue radionecrosis (27.5%), radiation cystitis (18.6%), radiation proctitis (9.2%), and laryngeal radionecrosis (4.8%). Clinical outcomes following HBOT were positive with symptoms that improved or resolved varying from 76.7% to 92.6%, depending on injury type. Overall, although the mean symptom improvement score between some groups is statistically significant, the differences are probably not clinically meaningful. Patients with osteoradionecrosis had the highest mean symptom improvement score (3.24) compared with a mean of 3.04 for laryngeal radionecrosis. LIMITATIONS: Limited data were available on patient comorbidities and symptom severity. CONCLUSIONS: Outcomes from a large patient registry of radiation-induced injuries support the continued therapeutic use of HBOT for radiation injuries. PMID- 26650093 TI - Vitamin and Trace Element Loss from Negative-Pressure Wound Therapy. AB - OBJECTIVE: This study investigated select vitamin and trace element loss from wound exudates in burn and trauma patients treated with negative-pressure wound therapy (NPWT). DESIGN: A prospective observational study was performed using wound exudate samples. SETTING: A level I trauma center acute care hospital. PARTICIPANTS: The study was composed of 8 patients with open abdomens and 9 patients with 12 soft-tissue wounds. MAIN OUTCOME MEASURES: The goal was to collect wound exudate samples daily for 3 days, then every other day to day 9 or until NPWT was discontinued, and to analyze for vitamins A (retinol), C, and E and zinc (Zn), iron (Fe), and copper (Cu). Daily loss of each micronutrient was calculated from their concentration and 24-hour volumes of the exudates. MAIN RESULTS: Exudate loss in the open-abdomen group was significantly higher than in the patients with soft-tissue wounds (900 +/- 547 vs 359 +/- 246 mL/d). The mean 24-hour loss of vitamins A, C, and E were 0.3, 2.8, and 11 mg, respectively, in the open-abdomen group. Over the same period, the losses of Zn, Fe, and Cu were 0.5, 0.4, and 0.25 mg, respectively, in these patients. Micronutrient 24-hour loss was significantly lower in the soft-tissue wound patients than in the open abdomen group. CONCLUSIONS: The data support the concept that significant amounts of micronutrients can be lost from NPWT wound exudates, particularly in open abdomens. These losses should be considered in the nutritional support of these patients who typically are in a hypermetabolic and catabolic state. PMID- 26650094 TI - Wound Care: Multicenter Feasibility Study. AB - OBJECTIVES: The aims of this study were to determine a sound recruitment strategy for multisite wound studies to address the rising prevalence and incidence of chronic wounds and to identify appropriate adult patient populations with wounds of interest and establish partnerships with their clinicians and clinical services as a model for a multisite wound care feasibility study. DESIGN: A pilot multisite recruitment feasibility study. SETTING: Three wound clinics located in a large, Midwestern metropolitan area. PARTICIPANTS AND INTERVENTION: A convenience sample of 3 staff and 3 patients with lower-extremity wounds from each clinic was interviewed. Medical records of all patients with lower-extremity wounds seen during 1 week at each clinic were reviewed. Outcome measures included characteristics of patients being treated at the 3 wound care clinics (patient demographics and wound characteristics) and wound treatments used. Barriers and opportunities that could be addressed in recruitment and other research strategies were identified. MAIN RESULTS: Barriers and facilitators for future research were identified and varied within and between clinics. Patients reported they were willing to participate in future research, although fewer were willing if the study was blinded. Patients received a variety of treatments within and across clinics. Medical record reviews provided further information about wound clinic patients, wound characteristics, and barriers and facilitators for future study. CONCLUSIONS: Characteristics of wound clinic patients and their wounds were found to vary by site, suggesting tailored recruitment methods by site within multisite wound care studies may be most productive. This study suggests successful recruitment strategies for future wound care intervention research. PMID- 26650096 TI - The Strategic View of Modified Stage 2 Meaningful Use: Part 1. PMID- 26650097 TI - The Art of Dressing Selection: A Consensus Statement on Skin Tears and Best Practice. PMID- 26650095 TI - The Art of Dressing Selection: A Consensus Statement on Skin Tears and Best Practice. AB - PURPOSE: To provide information about product selection for the management of skin tears. TARGET AUDIENCE: This continuing education activity is intended for physicians and nurses with an interest in skin and wound care. OBJECTIVES: After participating in this educational activity, the participant should be better able to:1. Explain skin tear (ST) risk factors and assessment guidelines.2. Identify best practice treatments for STs, including the appropriate dressings for each ST type. ABSTRACT: To aid healthcare professionals in product selection specific for skin tears, the International Skin Tear Advisory Panel conducted a systematic literature review and 3-phase Delphi consensus with a panel of international reviewers to provide the best available evidence for product selection related to the treatment of skin tears. PMID- 26650098 TI - Shared Genetic Factors of Anxiety and Depression Symptoms in a Brazilian Family Based Cohort, the Baependi Heart Study. AB - To investigate the phenotypic and genetic overlap between anxiety and depression symptoms in an admixed population from extended family pedigrees. Participants (n = 1,375) were recruited from a cohort of 93 families (mean age+/-SD 42+/-16.3, 57% female) in the rural town of Baependi, Brazil. The Hospital Anxiety and Depression Scale (HADS) was used to assess depression and anxiety symptoms. Heritability estimates were obtained by an adjusted variance component model. Bivariate analyses were performed to obtain the partition of the covariance of anxiety and depression into genetic and environmental components, and to calculate the genetic contribution modulating both sets of symptoms. Anxiety and depression scores were 7.49+/-4.01 and 5.70+/-3.82, respectively. Mean scores were affected by age and were significantly higher in women. Heritability for depression and anxiety, corrected for age and sex, were 0.30 and 0.32, respectively. Significant genetic correlations (rhog = 0.81) were found between anxiety and depression scores; thus, nearly 66% of the total genetic variance in one set of symptoms was shared with the other set. Our results provided strong evidence for a genetic overlap between anxiety and depression symptoms, which has relevance for our understanding of the biological basis of these constructs and could be exploited in genome-wide association studies. PMID- 26650099 TI - Magnification devices for endodontic therapy. AB - BACKGROUND: After the introduction of microsurgical principles in endodontics involving new techniques for root canal treatment, there has been a drive to enhance the visualisation of the surgical field. It is important to know if the technical advantages for the operator brought in by magnification devices such as surgical microscopes, endoscopes and magnifying loupes, are also associated with advantages for the patient in terms of improvement of clinical and radiographic outcomes. This version updates the review published in 2009. OBJECTIVES: To evaluate and compare the effects of endodontic treatment performed with the aid of magnification devices versus endodontic treatment without magnification devices. We also aimed to compare the different magnification devices used in endodontics with one another. SEARCH METHODS: The following electronic databases were searched: the Cochrane Oral Health Group Trials Register (to 13 October 2015), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2015, Issue 9), MEDLINE via OVID (1946 to 13 October 2015) and EMBASE via OVID (1980 to 13 October 2015). We searched the US National Institutes of Health Trials Register (http://clinicaltrials.gov) and the WHO Clinical Trials Registry Platform for ongoing trials. No restrictions were placed on the language or date of publication when searching the electronic databases. SELECTION CRITERIA: We considered all randomised controlled trials (RCTs) and quasi randomised controlled trials comparing endodontic therapy performed with versus without one or more magnification devices, as well as randomised and quasi randomised trials comparing two or more magnification devices used as an adjunct to endodontic therapy. DATA COLLECTION AND ANALYSIS: We conducted screening of search results independently and in duplicate. We obtained full papers for potentially relevant trials. The Cochrane Collaboration statistical guidelines were to be followed for data synthesis. MAIN RESULTS: No trials met the inclusion criteria for this review. AUTHORS' CONCLUSIONS: No article was identified in the current literature that satisfied the criteria for inclusion. It is unknown if and how the type of magnification device affects the treatment outcome, considering the high number of factors that may have a significant impact on the success of endodontic surgical procedure. This should be investigated by further long-term, well-designed RCTs that conform to the CONSORT statement (www.consort statement.org/). PMID- 26650100 TI - Total Synthesis of the Oxopolyene Macrolide (-)-Marinisporolide C. AB - The first total synthesis of (-)-marinisporolide C was performed in 25 steps (longest linear sequence) and an overall yield of 1%. Due to the high degree of convergence and robustness, the C9-C35 fragment that corresponds to the polyol portion was obtained in gram quantity. Highlights of this synthesis include five highly stereoselective aldol reactions responsible for the construction of five C C bonds and six stereogenic centers. Additionally, a very efficient Julia Kocienski reaction was used to install a C22-C23 double bond, and the macrocyclic ring was closed using an intramolecular Horner-Wadsworth-Emmons olefination. PMID- 26650101 TI - Combined Atomistic Molecular Calculations and Experimental Investigations for the Architecture, Screening, Optimization, and Characterization of Pyrazinamide Containing Oral Film Formulations for Tuberculosis Management. AB - To date, effective treatment, prophylaxis, and control of tuberculosis (TB) infection is mainly dependent on the use of drugs. However, patient noncompliance with prescribed anti-TB treatment schemes remains a major problem confronting successful pharmacotherapeutic outcomes. Thus, the development of alternative delivery systems that can improve adherence for the existing anti-TB bioactives has been intensified in recent times. The aim of this investigation was to engineer an optimal, thermodynamically stable oral film (OF) formulation containing a key anti-TB agent, pyrazinamide (PYZ), employing molecular modeling and experimental tools. Four PYZ-loaded film variants (OF 1, OF 2, OF 3, OF 4) were constructed in silico and then prepared in vitro using the Accelrys Materials Studio software and solvent casting method, respectively. Screening and selection of the optimal OF was based on the computation of the total interaction energy (ET), kinetic energy (EK), solubility parameter (S), and cohesive energy density (CED) as well as determining mass, thickness, dissolution and disintegration times, dissolution pH, drug loading capacity, and surface morphology in vitro. OF 2 was selected as the optimal formulation as it displayed the lowest ET (-8006.28 kcal/mol), dissolution time (9.96 min), disintegration time (56.49 s), and weight (39.33 mg); moderate EK (1052.98 kcal/mol); highest S (44.55 (J/cm(3))(0.5)) and CED (1.99 * 10(9) J/m(3)), slim dimension (166 MUm), good and unvarying drug loading capacity (98.04%), acceptable dissolution pH (6.70), and well-layered surface topography. The drug release behavior of the optimal OF 2 was best elucidated with the zero order (R(2) = 0.97) and Korsmeyer Peppas (R(2) = 0.99) models. X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), and differential scanning calorimetry (DSC) analyses showed that OF 2 was made of physically mixed multiple component polymeric and nonpolymeric compounds. OF 2 was semicrystalline in nature and displayed a dual phased ex vivo mucosal permeation pattern. In silico and in vitro physicomechanical quantities revealed OF 2's flexibility, robustness, and compressibility. OF 2 was most stable under controlled environmental humidity, pressure, and temperature conditions in silico and in vitro. OF 2 was potentially non-cytotoxic and biocompatible. Succinctly, this work demonstrated the applicability of a combination of atomistic molecular mechanics and dynamics calculations as well as experimental analyses to the fabrication, screening, optimization, and characterization of drug formulations. Lastly, the fabricated OF 2 formulation can function as a potential alternative for the effective loading and delivery of PYZ. PMID- 26650102 TI - Authors' Response. PMID- 26650103 TI - Same Quality but Not the Same Impact: Citations Related to Publications About Celiac Disease in JPGN and AJG. PMID- 26650104 TI - Recurrent Pancreatitis in Children-More Data Still Needed. PMID- 26650105 TI - Does Gastrostomy Placement With Concurrent Fundoplication Increase the Risk of Gastrostomy-related Complications? AB - OBJECTIVE: To compare the incidence of complications with a primary gastrostomy versus gastrostomy with concurrent fundoplication and evaluating the impact of the method of gastrostomy tube placement. Neurologically impaired children were compared with neurologically normal children. Two low profile devices were compared for longevity. METHODS: Ninety-eight patients (58 boys, mean age 4.66 years) with 107 gastrostomies inserted between April 2004 and May 2008 were included in this retrospective, single institution audit. Minimum follow-up period was 1 year. Specific complications reviewed were tube and site related. Logistic regression analysis examined the relationship between complications, type of procedure, method of placement, and neurological status. Survival analysis with log-rank test was used to compare the duration of the low-profile devices. RESULTS: There were 63 primary gastrostomies and 44 with concurrent fundoplication, 71 children were neurologically impaired. Mean (+/-SD) follow-up time was 35.6 +/- 1.4 months. There was a significant association between concurrent gastrostomy insertion with fundoplication and incidence of infection (odds ratio = 2.4, 95% confidence interval (CI) 1.02-5.56, P = 0.02) and excoriation (odds ratio = 2.5, 95% CI 1.09-5.71, P = 0.015). There were no associations between the complications with gastrostomy placement and neurological status. Failure rate of the balloon device was significantly greater than the fixed bolster device with a Hazard Ratio for survival of 3.2 (95% CI 2.2 4.6). CONCLUSIONS: Gastrostomy site-related problems were more common than generally reported. There was a higher incidence of site infection and skin excoriation for gastrostomy placement with concurrent fundoplication. There was no significant difference in complications between the method of gastrostomy placement or neurological status. Balloon devices were changed 3 times more often than bolster retention devices. PMID- 26650106 TI - VASOSPASM OF THE FLAP PEDICLE--MAGNESIUM SULPHATE RELIEVES VASOSPASM OF AXIAL FLAP PEDICLE IN PORCINE MODEL. AB - BACKGROUND: The effect of magnesium sulphate on mechanically provoked vasospasm of the flap pedicle on porcine model was not studied yet. Positive effect of magnesium sulphate on vasospasm was proved in previous studies on rat. METHODS: The bilateral pedicled flaps based on the caudal superficial epigastric arteries were raised on 8 pigs. Flaps on the right side were the treatment group; flaps on the left side were the control group. The vasospasm was provoked by the tension applied on the pedicle in the axial direction using 160g weight. The blood perfusion of the flap was monitored using laser-Doppler. The duration of the vasospasm was defined as the time from the release of the tension until the blood flow began to rise. These times were detected using an automated computerized detection. In the treatment group, magnesium sulphate was given topically on the vessel; saline was used in the control group. RESULTS: The duration of the vasospasm in the treatment group was significantly shorter than in the control group (P = 0.024). CONCLUSION: Magnesium sulphate 10% shortened significantly the mechanically provoked vasospasm on caudal superficial epigastric flap in a porcine model. Further clinical studies are needed to prove the effect in humans. PMID- 26650107 TI - A NOVEL MODEL TO EVALUATE THE LEARNING CURVE IN MICROSURGERY: SERIAL ANASTOMOSIS OF THE RAT FEMORAL ARTERY. AB - The rat's femoral artery is definitely the most frequently used model in microsurgical training for its easy dissection. Our model, consisting in the creation of several anastomoses in a row, helps the novice surgeon to assess his microsurgical level and to improve his capacity. Indeed, this leads to an amplification of the trainee surgeon's mistakes, which add up to each other as the anastomoses are performed. We propose a simple method to evaluate the surgeon microsurgical skills during the training. PMID- 26650108 TI - TWISTED DISTAL LATERAL ARM FLAP FOR IMMEDIATE RECONSTRUCTION OF THUMB AVULSION INJURY. AB - BACKGROUND: Replantation is a complicated procedure in avulsion injuries in majority of the cases. When replantation of an avulsed thumb is not feasible, it is mandatory to find an appropriate reconstruction choice as soon as possible due to the importance of the thumb function in the dynamics of the handgrip. MATERIALS AND METHODS: Three patients with skin avulsion injury underwent immediate reconstruction by twisted lateral arm flap in our department since 2004. RESULTS: No infection, hematoma, partial or complete flap necrosis were observed after the procedure. All of the flaps healed without complications. CONCLUSION: Although the gold standard in reconstruction of these trauma defects is the use of local skin flaps or distant inguinal flap, these reconstructive choices have multiple drawbacks such as the loss of sensibility and they are thicker. In thispaper we propose a modification of distally planned lateral arm flap design and a new technique of its spiral shaping for immediate thumb reconstruction. PMID- 26650109 TI - PIP IMPLANTS--CURRENT KNOWLEDGE AND LITERATURE REVIEW. AB - Non-compliance with the production process and use of non-certified materials du- ring production of PIP implants opened an extensive debate regarding regulation and control mechanisms during their production, but the question of health safety of breast implants in general was also reopened. Production of breast implants is subject to various control mechanisms in each country and it is necessary to unify and coordinate such mechanisms. PIP implants were on the market for more than 15 years and in this period the production process and used materials were being changed purposely and without control, which resulted in production of implants with poor quality capsule filled with non-certified silicon gel. There were around 600,000 of these erroneous implants produced. Despite demonstrable harmfulness of the PIP implants, the current studies were not able to reliably confirm health hazard of these implants. Financial costs together with the inability to demonstrate health risk of PIP implants is the reason why the question to widely replace these implants was not solved and each state has a different opinion on this issue. PMID- 26650110 TI - DELAY PROCEDURE IN THE PERFORASOME ERA: A CASE IN A DIEAP FLAP. AB - The deep inferior epigastric artery perforator (DIEAp) flap is becoming a widely used method of autologous breast reconstruction. Despite the huge use of the DIEAp flap in reconstructive field, an evidenced based approach in perforator selection has not yet been developed. Unfortunately there is no clear evidence about the relation between the number and dimension of the perforator vessel and the prediction of flap survival in a living model. An old technique like the vascular delay could be extremely useful as a lifeboat procedure when the vascularization of the flap after the dissection is inadequate. PMID- 26650111 TI - Silver- versus gold-catalyzed sequential oxidative cyclization of unprotected 2 alkynylanilines with oxone. AB - Unprecedented domino oxidative cyclization reactions of unprotected 2 alkynylanilines to give functionalized 4H-benzo[d][1,3]oxazin-4-one or benzisoxazole derivatives in moderate to good yields are achieved by silver vs. gold selective catalysis. The search for the optimal reaction conditions revealed the divergent catalytic activity of NaAuCl4.H2O and AgNO3. PMID- 26650112 TI - Voriconazole Concentrations in Cerebrospinal Fluid During Prophylactic Use in Children with Acute Myelogenous Leukemia. AB - We report analysis of voriconazole (VRCZ) concentration of cerebrospinal fluid (CSF) during prophylactic use in children and adolescents with acute myelogenous leukemia. The median CSF/plasma ratio was 0.57 (range, 0.35-1.04). There was a significant positive correlation between the VRCZ concentrations in CSF and plasma. The CSF/blood ratio negatively correlated with age, body weight and VRCZ concentration in plasma and CSF. VRCZ is more highly transferred to CSF at low plasma concentrations, and the rate is lower at high plasma concentrations. The exact mechanism of VRCZ penetration though blood-brain barrier is not known. PMID- 26650113 TI - Prolonged Breastfeeding Is Associated With Lower Risk Of Severe Hand, Foot And Mouth Disease In Chinese Children. AB - To assess whether breastfeeding duration can affect risk of severe hand, foot and mouth disease (HFMD) later in childhood, we retrospectively analyzed demographic, environmental and breastfeeding data on 603 children with severe HFMD and 1036 children with mild HFMD. Multivariate analysis showed that breastfeeding for 6-12 months significantly reduced the risk of severe HFMD, as did breastfeeding for >12 months. PMID- 26650114 TI - Clinical Significance of Clostridium difficile in Children Less Than 2 Years Old: A Case-Control Study. AB - BACKGROUND: The significance of Clostridium difficile (CD) in the stools of children 2 years old or younger remains unclear. The aim of this study was to investigate risk factors and clinical evolution of diarrheic children <=2 years old with or without CD in their stools. METHODS: From January 1, 2012 to December 31, 2013, all diarrheic stool samples received in our laboratory were screened for CD. We randomly selected diarrheic children <=2 years old (n = 100) with an isolation of toxigenic CD in the stools and compared them with diarrheic children (n = 100) without isolation of CD. RESULTS: Cases and controls were appropriately matched for age and sex. We found no significant differences between children with or without CD. Of the CD cases, we compared the patients receiving treatment with metronidazole (19%) versus those that were not prescribed treatment (81%), and found that patients in the first group had used more gastric acid suppressants (P = 0.02), had surgery in the last month (P = 0.03) and also presented with more days with diarrhea (P = 0.03). All the patients, including CD cases, independently of the administration of metronidazole, were cured of the diarrheic episode. Polymerase chain reaction-ribotyping performed in all CD cases showed that the most prevalent ribotype was 014 (25%). CONCLUSIONS: Our study reinforces the nonsignificance of CD in neonates and infants younger than 2 years old. Informing clinicians of CD isolates in this population promotes the use of antibiotics against CD, without evidence of a different outcome than those not receiving treatment. PMID- 26650115 TI - A case report of primary cardiac capillary hemangioma. AB - BACKGROUND: Hemangioma of the heart, presenting as a primary cardiac tumor is extremely rare. METHODS: We present a 20-year-old male with a cardiac tumor which was incidentally discovered during routine clinical examination. RESULTS: Echocardiography showed a large intramyocardial mass attached to the left ventricle, close to the apex. A tumor was shown near the apex of the left ventricle by Cardiac CT. We performed a total resection surgery of the tumor one week after admission and the patient recovered well and discharged from hospital 7 d after surgery. CONCLUSION: The pathological diagnosis was primary cardiac capillary hemangioma. No tumor recurrence was shown by echocardiography after 20 months follow-up visits. PMID- 26650116 TI - Site-Specific Characteristics of Bone Marrow Mesenchymal Stromal Cells Modify the Effect of Aging on the Skeleton. AB - Bone is a self-renewing tissue. Bone marrow mesenchymal stromal cells (BMSCs) are located in the adult skeleton and are believed to be involved in the maintenance of skeletal homeostasis throughout life. With increasing age, the ability of the skeleton to repair itself decreases, possibly due to the reduced functional capacity of BMSCs. Recent evidence has suggested the existence of at least two populations of BMSCs with different embryonic origins that cannot be interchanged during stem cell recruitment: craniofacial BMSCs (neural crest origin) and appendicular BMSCs (mesoderm origin). Questions arise as to whether the site specific characteristics alter the effect of aging on the skeleton. In this study, the effects of biological aging on human BMSCs were compared with BMSCs derived from the craniofacial bone versus those derived from the appendicular skeleton. The phenotype, proliferation, and functional characteristics (osteogenic differentiation, cytokine secretion, and bone formation in vivo) of the BMSCs were investigated. The results demonstrated that the proliferative capacity and osteogenic differentiation of the BMSCs decrease significantly with age both in vitro and in vivo. For age-matched groups, the osteogenic differentiation capacity of alveolar BMSCs was higher than that of femoral BMSCs in the middle-aged and old groups, while there was no significant difference for the young groups. Compared with old alveolar BMSCs, old femoral BMSCs had a significantly longer population doubling time, a smaller colony-forming population, and less bone formation in vivo, while there was no significant difference for the young and middle-aged groups. Distinct differences in the expression of cytokine factors were also found. In conclusion, human BMSCs display an age-related decrease in functional capacity, and embryonic origins may play a critical role in mediating the aging rate of BMSCs. These data provide novel insights into the skeletal site-specific characteristics of aged BMSCs. PMID- 26650117 TI - Simultaneous Thermoelectric Property Measurement and Incoherent Phonon Transport in Holey Silicon. AB - Block copolymer patterned holey silicon (HS) was successfully integrated into a microdevice for simultaneous measurements of Seebeck coefficient, electrical conductivity, and thermal conductivity of the same HS microribbon. These fully integrated HS microdevices provided excellent platforms for the systematic investigation of thermoelectric transport properties tailored by the dimensions of the periodic hole array, that is, neck and pitch size, and the doping concentrations. Specifically, thermoelectric transport properties of HS with a neck size in the range of 16-34 nm and a fixed pitch size of 60 nm were characterized, and a clear neck size dependency was shown in the doping range of 3.1 * 10(18) to 6.5 * 10(19) cm(-3). At 300 K, thermal conductivity as low as 1.8 +/- 0.2 W/mK was found in HS with a neck size of 16 nm, while optimized zT values were shown in HS with a neck size of 24 nm. The controllable effects of holey array dimensions and doping concentrations on HS thermoelectric performance could aid in improving the understanding of the phonon scattering process in a holey structure and also in facilitating the development of silicon-based thermoelectric devices. PMID- 26650118 TI - Easy and Accurate Mechano-profiling on Micropost Arrays. AB - Cell culture substrates with integrated flexible microposts enable a user to study the mechanical interactions between cells and their immediate surroundings. Particularly, cell-substrate interactions are the main interest. Today micropost arrays are a well-characterized and established method with a broad range of applications that have been published over the last decade. However, there seems to be a reservation among biologists to adapt the technique due to the lengthy and challenging process of micropost manufacture along with the lack of easily approachable software for analyzing images of cells interacting with microposts. The force read-out from microposts is surprisingly easy. A micropost acts like a spring with the cell ideally attached at its tip. Depending on size a cell applies force from its cytoskeleton through one or multiple focal adhesion points to the micropost, thus deflecting the micropost. The amount of deflection correlates directly to the applied force in direction and in magnitude. The number of microposts covered by a cell and the post deflection patterns are characteristic and allow determination of values like force per post and many biologically relevant parameters that allow "mechano-profiling" of cell phenotypes. A convenient method for mechano-profiling is described here combining the first generation of ready-to-use commercially available microposts with an in house developed software package that is now accessible to all researchers. As a demonstration of typical application, single images of bone cancer cells were taken in bright-field microscopy for mechano-profiling of cell line models of metastasis. This combination of commercial traction force sensors and open source software for analysis allows for the first time a rapid implementation of the micropost array technique into routine lab work done by non-expert users. Furthermore, a robust and streamlined analysis process enables a user to analyze a large number of micropost images in a highly time-efficient manner. PMID- 26650120 TI - B(C6F5)3-catalyzed metal-free hydrogenation of 3,6-diarylpyridazines. AB - This paper describes the first metal-free hydrogenation of 3,6-diarylpyridazines, which was successfully realized using B(C6F5)3 as a catalyst. A variety of 1,4,5,6-tetrahydropyridazine derivatives were furnished in 85-95% yields. PMID- 26650119 TI - Mono-ubiquitylated ORF45 Mediates Association of KSHV Particles with Internal Lipid Rafts for Viral Assembly and Egress. AB - Herpesviruses acquire their envelope by budding into the lumen of cytoplasmic membrane vesicles. This process is initiated by component(s) on viral particles, which recognize the budding site where the viral glycoproteins are present and recruit cellular cargo transport and sorting machinery to the site to complete the budding process. Proteins in the tegument layer, connecting capsid and envelope, are candidates for the recognition of budding sites on vesicle membrane and induction of budding and final envelopment. We examined several outer and matrix tegument proteins of Kaposi's sarcoma-associated herpesvirus (KSHV) and found that ORF45 associates with lipid rafts (LRs) of cellular membrane. LRs are membrane micro-domains, which have been implicated as relay stations in intracellular signaling and transport including viral entry and virion assembly. The ability of ORF45 to target LR is dependent on the mono-ubiquitylation of ORF45 at Lys297 as the mutation at Lys297 (K297R) abolished LR-association of ORF45. The K297R mutation also impairs ORF45 and viral particle co-localization with trans-Golgi network and endosomes, but facilitates ORF45 and viral particles co-localizing with lysosomes. More importantly, the recombinant KSHV carrying ORF45 K297R mutant (BAC-K297R) was found severely defective in producing mature and infectious virion particles in comparison to wild type KSHV (BAC16). Taken together, our results reveal a new function of KSHV tegument protein ORF45 in targeting LR of host cell membrane, promoting viral particles co-localization with trans-Golgi and endosome vesicles and facilitating the maturation and release of virion particles, suggesting that ORF45 plays a role in bringing KSHV particles to the budding site on cytoplasmic vesicle membrane and triggering the viral budding process for final envelopment and virion maturation. PMID- 26650122 TI - October 2009: This Month's Highlights. PMID- 26650123 TI - Letter. PMID- 26650121 TI - Nonrandom Composition of Flower Colors in a Plant Community: Mutually Different Co-Flowering Natives and Disturbance by Aliens. AB - When pollinators use flower color to locate food sources, a distinct color can serve as a reproductive barrier against co-flowering species. This anti interference function of flower color may result in a community assembly of plant species displaying mutually different flower colors. However, such color dispersion is not ubiquitous, suggesting a variable selection across communities and existence of some opposing factors. We conducted a 30-week study in a plant community and measured the floral reflectances of 244 species. The reflectances were evaluated in insect color spaces (bees, swallowtails, and flies), and the dispersion was compared with random expectations. We found that co-existing colors were overdispersed for each analyzed pollinator type, and this overdispersion was statistically significant for bees. Furthermore, we showed that exclusion of 32 aliens from the analysis significantly increased the color dispersion of native flowers in every color space. This result indicated that aliens disturbed a native plant-pollinator network via similarly colored flowers. Our results demonstrate the masking effects of aliens in the detection of color dispersion of native flowers and that variations in pollinator vision yield different outcomes. Our results also support the hypothesis that co-flowering species are one of the drivers of color diversification and affect the community assembly. PMID- 26650130 TI - Kaiser Foundation Reports Aimed at Informing Debate on Health Care Reform. PMID- 26650124 TI - Letter. PMID- 26650132 TI - Between chemistry, medicine and leisure: Antonio Casares and the study of mineral waters and Spanish spas in the nineteenth century. AB - This article considers how chemical analyses were employed not only to study and describe mineral waters, but also to promote new spas, and to reinforce the scientific authority of experts. Scientists, jointly with bath owners, visitors and local authorities, created a significant spa market by transforming rural spaces into social and economic sites. The paper analyses the role developed by the chemist Antonio Casares in the commodification of mineral water in mid-19(th) century Spain. His scientific publications and water analyses put a new economic value on some Spanish mineral waters and rural springs. First the paper explores the relationship between geographic factors, regulation, and spa development in 19(th) century Spain, and considers how scientific work improved the economy of some rural areas. Then the transformation of numerous country springs into spas, and the commodification of baths as places between science and leisure is examined. Finally the location of spas across the borders of medicine and chemistry is shown, together with the complex field operations required to study mineral waters. This paper reveals an intense circulation of knowledge between the field, laboratories and scientific publications, as well as the essential role developed by experts like Casares, who not only contributed to the study of rural springs but also to their economic transformation. PMID- 26650134 TI - 2010 in Review. PMID- 26650133 TI - Neurodevelopmental Outcomes at 2 and 3.5 Years for Very Preterm Babies Enrolled in a Randomized Trial of Milking the Umbilical Cord versus Delayed Cord Clamping. AB - BACKGROUND: Guidelines published by the International Liaison Committee for Resuscitation and by the World Health Organization recommend delaying cord clamping at birth as part of routine care for infants. OBJECTIVE: To study the use of milking of the cord 4 times as an alternative to enhance the redistribution of placental blood into the baby. METHODS: This is a prospective cohort study of neurodevelopmental assessment by the Bayley III method of very preterm infants who had participated in a trial of delayed cord clamping versus cord milking at birth that was conducted in a neonatal tertiary care hospital. The primary outcomes were differences in cognitive, motor and language development at 2 and 3.5 years. Two-tailed analyses were performed with the x03C7;2 test, Fisher's exact test, t test, Mann-Whitney U test and ANCOVA. RESULTS: Out of the 58 infants enrolled in the original study, 39 infants (67%) were assessed at 2 years and 29 (50%) at 3.5 years of age. Neurodevelopmental outcomes at 2 and 3.5 years did not significantly differ between the two groups for the three Bayley III composite scores. At 3.5 years there was a trend towards higher scores for girls in the language composite scores (girls: mean = 121.6, SD = 15.22; boys: mean = 101.07, SD = 19.84) and on the motor scale (girls: mean = 124.60, SD = 18.15; boys: mean = 97.86, SD = 17.23). CONCLUSIONS: In this small number of participants followed up at 2 and 3.5 years of age, milking of the cord 4 times did not have any long-term adverse effect on neurodevelopmental outcome, suggesting that cord milking could be used as an alternative to delayed cord clamping. PMID- 26650135 TI - Reply to Fleisch et al. Letter. PMID- 26650136 TI - Stonerby Williams John , Introduction by McGahern John . New York , New York Review of Books , 2006 , 288 pp., $14.95 . PMID- 26650137 TI - Every Man Dies Alone/Berlin at War: Life and Death in Hitler's Capital. 1939-45 Every Man Dies Alone , by Fallada Hans , Translated by Hofmann Michael . Brooklyn, N.Y. , Melville House , 2010 , 544 pp., $29.95 . Berlin at War: Life and Death in Hitler's Capital. 1939-45 , by Moorhouse Roger . London, United Kingdom , Bodley Head , 2010 , 448 pp., L25.00 . PMID- 26650138 TI - Asylum: Inside the Closed World of State Mental Hospitalsby Payne Christopher , Introduction by Sacks Oliver . Cambridge, Mass. , MIT Press , 2009 , 219 pp., $45.00 . PMID- 26650139 TI - Wolf Hall: A Novelby Mantel Hilary . New York , Henry Holt and Company , 2009 , 532 pp., $27.00 . PMID- 26650140 TI - The Rest Is Noise: Listening to the Twentieth Centuryby Ross Alex . New York, Farrar , Straus and Giroux , 2008 , 704 pp., $30.00 . PMID- 26650144 TI - Personality Shapes the Experience of Insomnia in Women: Commentary on Dorheim et al., Personality and Perinatal Maternal Insomnia: A Study across Childbirth. PMID- 26650143 TI - L-Arginine Derivatives Are Associated with the Hyperthyroid State in the General Population. AB - BACKGROUND: Arginine (ARG) derivatives and thyroid function independently influence atherosclerotic processes. Since thyroid hormones may mediate the association between ARG derivatives and atherosclerosis, this study investigated whether asymmetric and symmetric dimethylarginines (ADMA and SDMA, respectively) as well as homoarginine (hARG) are associated with parameters of thyroid function in the general population. METHODS: Cross-sectional data from 3689 individuals aged 20-81 years from the population-based Study of Health in Pomerania (SHIP-0) were analyzed. Thyroid function was defined according to serum concentrations of thyrotropin (TSH), free triiodothyronine (fT3), and free thyroxine (fT4). Low and high serum TSH were defined by the cutoffs 0.3 mIU/L and 3 mIU/L, respectively. Serum concentrations of ARG, ADMA, SDMA, and hARG were measured using liquid chromatography-tandem mass spectrometry. ARG, ADMA, SDMA, and hARG were associated with serum concentrations of TSH, fT3, and fT4 by median regression and with categorized TSH values by multinomial logistic regression adjusted for age, sex, smoking status, physical activity, body mass index, and estimated glomerular filtration rate. RESULTS: Levels of ADMA (relative risk [RR] = 5.40 [confidence interval (CI) 1.96-14.86]) and SDMA (RR = 3.55 [CI 1.01-12.70]) were associated with low TSH. In addition, ADMA (beta = 0.38 [CI 0.23-0.45]) was positively associated with fT3, while both ADMA (beta = 0.98 [CI 0.43-1.54]) and SDMA (beta = 1.19 [CI 0.50-1.88]) were positively associated with fT4. No consistent associations of ARG and hARG with thyroid function were detected. CONCLUSIONS: The positive associations of ADMA and SDMA with low TSH, fT3, and fT4 argue for a relationship of arginine derivatives with increased thyroid function. This suggests that the atherogenic properties of ADMA and SDMA may be partially mediated by thyroid function. PMID- 26650145 TI - Tiotropium Respimat Is Effective for the Treatment of Asthma at a Dose Lower Than That for Chronic Obstructive Pulmonary Disease. AB - Anticholinergic drug products are not part of the current treatment paradigm for asthma, despite their widespread availability for chronic obstructive pulmonary disease (COPD) and interest in their use for asthma. Published study results, mostly of short duration and primarily with ipratropium and tiotropium, have revealed inconsistent efficacy results. Consequently, the role of inhaled anticholinergic drugs in the treatment of asthma has been unclear. This commentary discusses and comments on data from five clinical trials in adults that were submitted by Boehringer Ingelheim to the U.S. Food and Drug Administration to support approval of tiotropium delivered by the Respimat device (Spiriva Respimat) for the treatment of asthma. These trials provided substantial evidence that supported the approval of Spiriva Respimat at a recommended dose of 2.5 MUg once daily for asthma. Notably, in trials that evaluated two doses of tiotropium, 2.5 MUg and 5 MUg (the dose approved for COPD), pulmonary function measures for Spiriva Respimat 2.5 MUg once daily were better overall than those obtained for the 5-MUg once-daily dose, thus justifying selection of the lower dose for asthma. Spiriva Respimat represents the first new class of drug approved by the U.S. Food and Drug Administration for the treatment of asthma in more than a decade. The availability of Spiriva Respimat for asthma along with other novel therapies currently under development has the potential to impact asthma treatment guidelines. PMID- 26650146 TI - Pharmacotherapy in epilepsy - does gender affect safety? AB - Drug safety and gender issues in the treatment with antiepileptic drugs (AEDs) involve considerations to reach an optimal balance between efficacy and adverse effects or toxicity. In this commentary safety issues relevant to AED therapy in women regarding drug interactions and teratogenic effects, and interactions between drugs and endogenous molecules in both genders are highlighted. Gender and safety issues are closely related. Careful clinical and pharmacological considerations are important and need close attention also in future studies and surveillance of existing AEDs and drugs in development. PMID- 26650147 TI - High Phosphate Concentrations Accelerate Bacterial Peptide Decomposition in Hypoxic Bottom Waters of the Northern Gulf of Mexico. AB - Despite extensive studies of the development and dynamics of hypoxia in coastal oceans, factors controlling the decomposition rates and pathways of labile organic matter (OM) in hypoxic waters are not well understood. Here we investigate peptide decomposition in a stratified water column in the hypoxic region of the northern Gulf of Mexico by conducting on-deck incubation experiments amended with tetrapeptide ala-val-phe-ala (AVFA), a fragment of RuBisCO. Our results show that decomposition efficiency of AVFA was limited by the availability of soluble reactive phosphorus (Pi) in the surface water (<0.3 MUM), as it was greatly enhanced after Pi addition to the incubation water. In contrast, peptide decomposition rate in the subsurface water, enriched with Pi (0.4-1.2 MUM), was twice as high as that in the surface water, concomitant with the development of fast-growing bacteria during the incubation. Consistent with the Growth Rate Hypothesis, these results indicate that a high level of Pi is crucial in stimulating the growth of bacterial strains with high RNA contents and thus faster OM decomposition in marine environments. This high decomposition potential of OM in subsurface hypoxic waters presents a positive feedback on hypoxia formation in Pi-enriched coastal subsurface waters, as a higher OM decomposition rate leads to rapid consumption of dissolved oxygen (DO). PMID- 26650148 TI - Clostridium difficile Infection: A Rarity in Patients Receiving Chronic Antibiotic Treatment for Crohn's Disease. AB - BACKGROUND: Prolonged antibiotic use is limited by several adverse effects, one of which is Clostridium difficile infection (CDI). The aim of this study was to determine the incidence of CDI in patients receiving chronic antibiotic treatment for Crohn's disease (CD). METHODS: We conducted a retrospective review of 100 patients with CD for which >=6 months of outpatient antibiotic therapy was prescribed. Data were collected regarding demographics, CD phenotype, treatment history, and CDI. The incidence of CDI in our patient population was calculated and compared with historical controls. RESULTS: 100 patients were studied-60% of men, mean age 23.9 years at CD diagnosis. Eighty-two percent had disease involving the ileum, and 33% had disease involving the colon. The mean duration of antibiotic therapy was 39.6 months (range, 6-217 months). The most commonly prescribed classes of antibiotics were fluoroquinolones (84%), penicillins (57%), and cephalosporins (32%). Forty-nine percent of patients were treated with concomitant thiopurines, 45% with budesonide, and 41% with biologics. The overall incidence of CDI was 2%. This incidence of CDI was lower than previously reported for non-CD patients receiving chronic antibiotics for continuous-flow left ventricular assist device infections (12.5%) and orthopedic prosthesis infections (22.2%). CONCLUSIONS: The incidence of CDI is rare in patients receiving chronic antibiotic treatment for CD, and it seems significantly lower than for non-CD populations reported in the literature. PMID- 26650149 TI - Postoperative Use of Anti-TNF-alpha Agents in Patients with Crohn's Disease and Risk of Reoperation-A Nationwide Cohort Study. AB - BACKGROUND: Approximately 80% of patients with Crohn's disease will require surgery. Surgery for Crohn's disease is not curative, and recurrence is typical. In this cohort study, based on nationwide Danish registries, we examined the association between postoperative treatment with anti-tumor necrosis factor alpha (anti-TNF-alpha) agents and reoperation. METHODS: The association was examined in cohort 1 = patients not treated with anti-TNF-alpha agents within 6 months before operation, cohort 2 = patients treated with anti-TNF-alpha agents within 6 months before operation. Within both cohorts, we defined postoperative exposure to anti TNF-alpha agents as at least 1 treatment within 6 months after the first operation and the reference cohorts were those not treated. Patients were followed from 6 months after operation and until 5 years. We used Cox proportional-hazards regression to compute adjusted hazard ratios with 95% confidence intervals. RESULTS: In cohort 1, 31 (1.3%) were treated with anti-TNF alpha agents within 6 months after operation and compared with those not treated, the adjusted hazard ratio of reoperation among those treated with anti-TNF-alpha agents was 3.53 (95% confidence interval: 1.61-7.72). In cohort 2, 63 (16.3%) were treated with anti-TNF-alpha agents within 6 months after operation, and the corresponding adjusted hazard ratio of reoperation was 2.16 (95% confidence interval: 1.11-4.18). CONCLUSIONS: Our data suggest that anti-TNF-alpha treatment within 6 months after the first operation is not associated with a reduction in the need for subsequent operation. Uncontrolled confounding might have influenced our results, and, furthermore, future studies are warranted to clarify whether our study population is different from populations most often associated with postoperative anti-TNF-alpha treatment. PMID- 26650150 TI - Are sTWEAK and IL-17A Levels in Inflammatory Bowel Disease Associated with Disease Activity and Etiopathogenesis? AB - BACKGROUND: We aimed to identify the levels of soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) and interleukin 17A (IL-17A) in inflammatory bowel disease (IBD) and to examine their relationship with disease activity. METHODS: A total of 92 patients with IBD, in which 54 patients were diagnosed with ulcerative colitis and 38 patients with Crohn's disease (CD), and 104 healthy controls were included in the study. The Rachmilewitz endoscopic activity index was calculated in ulcerative colitis, and the CD activity index was calculated in CD. RESULTS: sTWEAK (P < 0.001) and IL-17A (P = 0.006) levels were higher in the IBD group than in the control group. Both in the IBD group and ulcerative colitis and CD subgroups, in active patients, sTWEAK and IL-17A levels were found to be higher than in inactive and control groups. In the IBD group, a positive correlation was determined between sTWEAK and IL-17A, and C-reactive protein, endoscopic activity index, and CD activity index. In multivariable regression analysis, C-reactive protein and sTWEAK levels were determined to be an independent risk factor for both endoscopic activity index and CD activity index. In receiver operating curve analysis, the sTWEAK level was determined to predict IBD with high sensitivity and specificity with a value of >588.34 pg/mL and activity with a value of >669.28 pg/mL. CONCLUSION: Based on these results, we ascertain that sTWEAK has a role in etiopathogenesis of IBD. In addition, we believe that sTWEAK could be used as a marker for both disease activity criteria and treatment monitoring. PMID- 26650151 TI - My Life as a (Fake) Patient. PMID- 26650152 TI - Mass Drug Administration for Scabies Control in a Population with Endemic Disease. AB - BACKGROUND: Scabies is an underrecognized cause of illness in many developing countries. It is associated with impetigo, which can lead to serious systemic complications. We conducted a trial of mass drug administration for scabies control in Fiji. METHODS: We randomly assigned three island communities to one of three different interventions for scabies control: standard care involving the administration of permethrin to affected persons and their contacts (standard care group), mass administration of permethrin (permethrin group), or mass administration of ivermectin (ivermectin group). The primary outcome was the change in the prevalence of scabies and of impetigo from baseline to 12 months. RESULTS: A total of 2051 participants were enrolled; 803 were in the standard care group, 532 in the permethrin group, and 716 in the ivermectin group. From baseline to 12 months, the prevalence of scabies declined significantly in all groups, with the greatest reduction seen in the ivermectin group. The prevalence declined from 36.6% to 18.8% in the standard-care group (relative reduction in prevalence, 49%; 95% confidence interval [CI], 37 to 60), from 41.7% to 15.8% in the permethrin group (relative reduction, 62%; 95% CI, 49 to 75), and from 32.1% to 1.9% in the ivermectin group (relative reduction, 94%; 95% CI, 83 to 100). The prevalence of impetigo also declined in all groups, with the greatest reduction seen in the ivermectin group. The prevalence declined from 21.4% to 14.6% in the standard-care group (relative reduction, 32%; 95% CI, 14 to 50), from 24.6% to 11.4% in the permethrin group (relative reduction, 54%; 95% CI, 35 to 73), and from 24.6% to 8.0% in the ivermectin group (relative reduction, 67%; 95% CI, 52 to 83). Adverse events were mild and were reported more frequently in the ivermectin group than in the permethrin group (15.6% vs. 6.8%). CONCLUSIONS: Mass drug administration, particularly the administration of ivermectin, was efficacious for the control of scabies and impetigo. (Funded by the Australian National Health and Medical Research Council; Australian New Zealand Clinical Trials Registry number, ACTRN12613000474752.). PMID- 26650153 TI - Endobronchial Valves for Emphysema without Interlobar Collateral Ventilation. AB - BACKGROUND: Bronchoscopic lung-volume reduction with the use of one-way endobronchial valves is a potential treatment for patients with severe emphysema. To date, the benefits have been modest but have been hypothesized to be much larger in patients without interlobar collateral ventilation than in those with collateral ventilation. METHODS: We randomly assigned patients with severe emphysema and a confirmed absence of collateral ventilation to bronchoscopic endobronchial-valve treatment (EBV group) or to continued standard medical care (control group). Primary outcomes were changes from baseline to 6 months in forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and 6 minute walk distance. RESULTS: Eighty-four patients were recruited, of whom 16 were excluded because they had collateral ventilation (13 patients) or because lobar segments were inaccessible to the endobronchial valves (3 patients). The remaining 68 patients (mean [+/-SD] age, 59+/-9 years; 46 were women) were randomly assigned to the EBV group (34 patients) or the control group (34). At baseline, the FEV1 and FVC were 29+/-7% and 77+/-18% of the predicted values, respectively, and the 6-minute walk distance was 374+/-86 m. Intention-to-treat analyses showed significantly greater improvements in the EBV group than in the control group from baseline to 6 months: the increase in FEV1 was greater in the EBV group than in the control group by 140 ml (95% confidence interval [CI], 55 to 225), the increase in FVC was greater by 347 ml (95% CI, 107 to 588), and the increase in the 6-minute walk distance was greater by 74 m (95% CI, 47 to 100) (P<0.01 for all comparisons). By 6 months, 23 serious adverse events had been reported in the EBV group, as compared with 5 in the control group (P<0.001). One patient in the EBV group died. Serious treatment-related adverse events in this group included pneumothorax (18% of patients) and events requiring valve replacement (12%) or removal (15%). CONCLUSIONS: Endobronchial-valve treatment significantly improved pulmonary function and exercise capacity in patients with severe emphysema characterized by an absence of interlobar collateral ventilation. (Funded by the Netherlands Organization for Health Research and Development and the University Medical Center Groningen; Netherlands Trial Register number, NTR2876.). PMID- 26650155 TI - IMAGES IN CLINICAL MEDICINE. Squamous-Cell Carcinoma of the Nail Bed. PMID- 26650154 TI - CLINICAL PRACTICE. Thyroid Nodules. PMID- 26650156 TI - CASE RECORDS of the MASSACHUSETTS GENERAL HOSPITAL. Case 38-2015. A 21-Year-Old Man with Fatigue and Weight Loss. PMID- 26650157 TI - Scabies and Global Control of Neglected Tropical Diseases. PMID- 26650158 TI - The Immune Response--Learning to Leave Well Enough Alone. PMID- 26650159 TI - Community-Acquired Pneumonia Requiring Hospitalization. PMID- 26650160 TI - Community-Acquired Pneumonia Requiring Hospitalization. PMID- 26650161 TI - Community-Acquired Pneumonia Requiring Hospitalization. PMID- 26650162 TI - Community-Acquired Pneumonia Requiring Hospitalization. PMID- 26650163 TI - Community-Acquired Pneumonia Requiring Hospitalization. PMID- 26650164 TI - Outcomes of Procedures Performed by Attending Surgeons after Night Work. PMID- 26650165 TI - Outcomes of Procedures Performed by Attending Surgeons after Night Work. PMID- 26650166 TI - Outcomes of Procedures Performed by Attending Surgeons after Night Work. PMID- 26650167 TI - Outcomes of Procedures Performed by Attending Surgeons after Night Work. PMID- 26650168 TI - Ischemic Limb Gangrene with Pulses. PMID- 26650169 TI - Ischemic Limb Gangrene with Pulses. PMID- 26650170 TI - Ischemic Limb Gangrene with Pulses. PMID- 26650172 TI - More on SUPPORT. PMID- 26650174 TI - Ischemic Optic Neuropathies. PMID- 26650173 TI - South Korea's Thyroid-Cancer "Epidemic"--Turning the Tide. PMID- 26650175 TI - IMAGES IN CLINICAL MEDICINE. Cullen's and Grey Turner's Signs in Acute Pancreatitis. PMID- 26650176 TI - Combinatorial Biomolecular Nanopatterning for High-Throughput Screening of Stem Cell Behavior. AB - A novel combinatorial biomolecular nanopatterning method is reported, in which multiple biomolecular ligands can be patterned in multiple nanoscale dimensions on a single surface. The applicability of the combinatorial platform toward cell biology applications is demonstrated by screening the adhesion behavior of a population of human dental pulp stem cell (hDPSC) on 64 combinations of nanopatterned extracellular matrix (ECM) proteins in parallel. PMID- 26650178 TI - Design of a New Bimetallic Catalyst for Asymmetric Epoxidation and Sulfoxidation. AB - A new chiral tethered 8-quinolinol-based ligand class is developed. The binuclear titanium complex of the ligand operates through a novel mechanism allowing for the regio- and stereoselective epoxidation of primary and tertiary homoallylic alcohols (up to 98% ee), as well as first examples of 2-allylic phenols (up to 92% ee). The new catalyst system also promotes the asymmetric oxidation of gamma hydroxypropyl sulfides giving an important class of chiral sulfoxides that have been inaccessible to date (up to 95% ee). PMID- 26650177 TI - Genetic variations in vitamin D-related pathways and breast cancer risk in African American women in the AMBER consortium. AB - Studies of genetic variations in vitamin D-related pathways and breast cancer risk have been conducted mostly in populations of European ancestry, and only sparsely in African Americans (AA), who are known for a high prevalence of vitamin D deficiency. We analyzed 24,445 germline variants in 63 genes from vitamin D-related pathways in the African American Breast Cancer Epidemiology and Risk (AMBER) consortium, including 3,663 breast cancer cases and 4,687 controls. Odds ratios (OR) were derived from logistic regression models for overall breast cancer, by estrogen receptor (ER) status (1,983 ER positive and 1,098 ER negative), and for case-only analyses of ER status. None of the three vitamin D related pathways were associated with breast cancer risk overall or by ER status. Gene-level analyses identified associations with risk for several genes at a nominal p <= 0.05, particularly for ER- breast cancer, including rs4647707 in DDB2. In case-only analyses, vitamin D metabolism and signaling pathways were associated with ER- cancer (pathway-level p = 0.02), driven by a single gene CASR (gene-level p = 0.001). The top SNP in CASR was rs112594756 (p = 7 * 10(-5), gene wide corrected p = 0.01), followed by a second signal from a nearby SNP rs6799828 (p = 1 * 10(-4), corrected p = 0.03). In summary, several variants in vitamin D pathways were associated with breast cancer risk in AA women. In addition, CASR may be related to tumor ER status, supporting a role of vitamin D or calcium in modifying breast cancer phenotypes. PMID- 26650180 TI - Chemical Inhibitors of Epigenetic Methyllysine Reader Proteins. AB - Protein methylation is a common post-translational modification with diverse biological functions. Methyllysine reader proteins are increasingly a focus of epigenetics research and play important roles in regulating many cellular processes. These reader proteins are vital players in development, cell cycle regulation, stress responses, oncogenesis, and other disease pathways. The recent emergence of a small number of chemical inhibitors for methyllysine reader proteins supports the viability of these proteins as targets for drug development. This article introduces the biochemistry and biology of methyllysine reader proteins, provides an overview of functions for those families of readers that have been targeted to date (MBT, PHD, tudor, and chromodomains), and reviews the development of synthetic agents that directly block their methyllysine reading functions. PMID- 26650181 TI - Synergistic formation of sulfate and ammonium resulting from reaction between SO2 and NH3 on typical mineral dust. AB - The heterogeneous reactions of SO2 and NH3 on typical mineral oxides were investigated using in situ diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS). A new sulfate formation pathway was proposed where NH3 accelerated the formation of sulfate species. The results revealed that surface hydroxyls and oxygen played principal roles in the conversion of SO2 to sulfate. It was proposed that NH3 adsorbed onto Lewis acid sites, and hydroxyls and water molecules adsorbed on the surfaces of mineral dust. The enhancement of surface Lewis basicity by NH3 induced more SO2 molecules to adsorb on the surface, which were further oxidized to sulfate by interacting with surface hydroxyls and oxygen atoms. The formation of sulfate, in turn, contributed to the adsorption of NH3, mainly as NH4(+) due to enhanced Bronsted acid sites. The IC results showed that the synergistic effect between SO2 and NH3 was more significant on acidic oxides like gamma-Al2O3 and alpha-Fe2O3 compared to basic oxides like MgO. PMID- 26650179 TI - Targeting ceramide synthase 6-dependent metastasis-prone phenotype in lung cancer cells. AB - Sphingolipids make up a family of molecules associated with an array of biological functions, including cell death and migration. Sphingolipids are often altered in cancer, though how these alterations lead to tumor formation and progression is largely unknown. Here, we analyzed non-small-cell lung cancer (NSCLC) specimens and cell lines and determined that ceramide synthase 6 (CERS6) is markedly overexpressed compared with controls. Elevated CERS6 expression was due in part to reduction of microRNA-101 (miR-101) and was associated with increased invasion and poor prognosis. CERS6 knockdown in NSCLC cells altered the ceramide profile, resulting in decreased cell migration and invasion in vitro, and decreased the frequency of RAC1-positive lamellipodia formation while CERS6 overexpression promoted it. In murine models, CERS6 knockdown in transplanted NSCLC cells attenuated lung metastasis. Furthermore, combined treatment with l alpha-dimyristoylphosphatidylcholine liposome and the glucosylceramide synthase inhibitor D-PDMP induced cell death in association with ceramide accumulation and promoted cancer cell apoptosis and tumor regression in murine models. Together, these results indicate that CERS6-dependent ceramide synthesis and maintenance of ceramide in the cellular membrane are essential for lamellipodia formation and metastasis. Moreover, these results suggest that targeting this homeostasis has potential as a therapeutic strategy for CERS6-overexpressing NSCLC. PMID- 26650182 TI - Failing as doorman and disc jockey at the same time: Amygdalar dysfunction in Parkinson's disease. AB - In Braak's model of ascending degeneration in Parkinson's disease (PD), involvement of the amygdala occurs simultaneously with substantia nigra degeneration. However, the clinical manifestations of amygdalar involvement in PD have not been fully delineated. Considered a multitask manager, the amygdala is a densely connected "hub," coordinating and integrating tasks ranging from prompt, multisensorial emotion recognition to adequate emotional responses and emotional tuning of memories. Although phylogenetically predisposed to handle fear, the amygdala handles both aversive and positive emotional inputs. In PD, neuropathological and in vivo studies suggest primarily amygdalar hypofunction. However, as dopamine acts as an inverted U-shaped amygdalar modulator, medication induced hyperactivity of the amygdala can occur. We propose that amygdalar (network) dysfunction contributes to reduced recognition of negative emotional face expressions, impaired theory of mind, reactive hypomimia, and impaired decision making. Similarly, impulse control disorders in predisposed individuals, hallucinations, anxiety, and panic attacks may be related to amygdalar dysfunction. When available, we discuss amygdala-independent trigger mechanisms of these symptoms. Although dopaminergic agents have mostly an activation effect on amygdalar function, adaptive and compensatory network changes may occur as well, but these have not been sufficiently explored. In conclusion, our model of amygdalar involvement brings together several elements of Parkinson's disease phenomenology heretofore left unexplained and provides a framework for testable hypotheses in patients during life and in autopsy analyses. PMID- 26650184 TI - A note on the use of multiple linear regression in molecular ecology. AB - Multiple linear regression analyses (also often referred to as generalized linear models--GLMs, or generalized linear mixed models--GLMMs) are widely used in the analysis of data in molecular ecology, often to assess the relative effects of genetic characteristics on individual fitness or traits, or how environmental characteristics influence patterns of genetic differentiation. However, the coefficients resulting from multiple regression analyses are sometimes misinterpreted, which can lead to incorrect interpretations and conclusions within individual studies, and can propagate to wider-spread errors in the general understanding of a topic. The primary issue revolves around the interpretation of coefficients for independent variables when interaction terms are also included in the analyses. In this scenario, the coefficients associated with each independent variable are often interpreted as the independent effect of each predictor variable on the predicted variable. However, this interpretation is incorrect. The correct interpretation is that these coefficients represent the effect of each predictor variable on the predicted variable when all other predictor variables are zero. This difference may sound subtle, but the ramifications cannot be overstated. Here, my goals are to raise awareness of this issue, to demonstrate and emphasize the problems that can result and to provide alternative approaches for obtaining the desired information. PMID- 26650183 TI - Propofol-Induced Frontal Cortex Disconnection: A Study of Resting-State Networks, Total Brain Connectivity, and Mean BOLD Signal Oscillation Frequencies. AB - Propofol is one of the most commonly used anesthetics in the world, but much remains unknown about the mechanisms by which it induces loss of consciousness. In this resting-state functional magnetic resonance imaging study, we examined qualitative and quantitative changes of resting-state networks (RSNs), total brain connectivity, and mean oscillation frequencies of the regional blood oxygenation level-dependent (BOLD) signal, associated with propofol-induced mild sedation and loss of responsiveness in healthy subjects. We found that detectability of RSNs diminished significantly with loss of responsiveness, and total brain connectivity decreased strongly in the frontal cortex, which was associated with increased mean oscillation frequencies of the BOLD signal. Our results suggest a pivotal role of the frontal cortex in propofol-induced loss of responsiveness. PMID- 26650185 TI - Herbs are different: clonal and bud bank traits can matter more than leaf-height seed traits. PMID- 26650186 TI - GPR84 and TREM-1 Signaling Contribute to the Pathogenesis of Reflux Esophagitis. AB - Gastro-esophageal reflux disease (GERD) is one of the most common disorders in gastroenterology. Patients present with or without increased acid exposure indicating a nonuniform etiology. Thus, the common treatment with proton pump inhibitors (PPIs) fails to control symptoms in up to 40% of patients. To further elucidate the pathophysiology of the condition and explore new treatment targets, transcriptomics, proteomics and histological methods were applied to a surgically induced subchronic reflux esophagitis model in Wistar rats after treatment with either omeprazole (PPI) or STW5, a herbal preparation shown to ameliorate esophagitis without affecting refluxate pH. The normal human esophageal squamous cell line HET-1A and human endoscopic biopsies were used to confirm our findings to the G-protein-coupled receptor (GPR) 84 in human tissue. Both treatments reduced reflux-induced macroscopic and microscopic lesions of the esophagi as well as known proinflammatory cytokines. Proteomic and transcriptomic analyses identified CINC1-3, MIP-1/3alpha, MIG, RANTES and interleukin (IL)-1beta as prominent mediators in GERD. Most regulated cyto-/chemokines are linked to the TREM-1 signaling pathway. The fatty acid receptor GPR84 was upregulated in esophagitis but significantly decreased in treated groups, a finding supported by Western blot and immunohistochemistry in both rat tissue and HET-1A cells. GPR84 was also found to be significantly upregulated in patients with grade B reflux esophagitis. The expression of GPR84 in esophageal tissue and its potential involvement in GERD are reported for the first time. IL-8 (CINC1-3) and the TREM 1 signaling pathway are proposed, besides GPR84, to play an important role in the pathogenesis of GERD.org. PMID- 26650187 TI - AMP-Activated Protein Kinase and Glycogen Synthase Kinase 3beta Modulate the Severity of Sepsis-Induced Lung Injury. AB - Alterations in metabolic and bioenergetic homeostasis contribute to sepsis mediated organ injury. However, how AMP-activated protein kinase (AMPK), a major sensor and regulator of energy expenditure and production, affects development of organ injury and loss of innate capacity during polymicrobial sepsis remains unclear. In the present experiments, we found that cross-talk between the AMPK and GSK3beta signaling pathways controls chemotaxis and the ability of neutrophils and macrophages to kill bacteria ex vivo. In mice with polymicrobial abdominal sepsis or more severe sepsis induced by the combination of hemorrhage and intraabdominal infection, administration of the AMPK activator metformin or the GSK3beta inhibitor SB216763 reduced the severity of acute lung injury (ALI). Improved survival in metformin-treated septic mice was correlated with preservation of mitochondrial complex V (ATP synthase) function and increased amounts of ETC complex III and IV. Although immunosuppression is a consequence of sepsis, metformin effectively increased innate immune capacity to eradicate P. aeruginosa in the lungs of septic mice. We also found that AMPK activation diminished accumulation of the immunosuppressive transcriptional factor HIF 1alpha as well as the development of endotoxin tolerance in LPS-treated macrophages. Furthermore, AMPK-dependent preservation of mitochondrial membrane potential also prevented LPS-mediated dysfunction of neutrophil chemotaxis. These results indicate that AMPK activation reduces the severity of polymicrobial sepsis-induced lung injury and prevents the development of sepsis-associated immunosuppression. PMID- 26650188 TI - Disaster Preparedness in Philippine Nurses. AB - PURPOSE: This study examined the perceived level of disaster preparedness in Philippine nurses. DESIGN: A descriptive, cross-sectional research design was used in this study. METHODS: Two hundred nurses were invited to participate in the study, with 170 responses (105 hospital nurses and 65 community nurses) or an 85% response rate, during the months of April 2014 through July 2014. Data collection was based on interviews using a standardized instrument, the Disaster Preparedness Questionnaire. Descriptive statistics such as frequencies, means, percentages, and standard deviations were utilized to quantify the responses. RESULTS: Three fourths of the respondents (n = 136, 80%) indicated that they were not fully prepared to respond to disasters, while only 20% (n = 34) acknowledged that they felt they were adequately prepared. Respondents believed that they could function in the primary roles of educator (n = 107, 62.94%), caregiver (n = 104, 61.17%), and counselor (n = 82, 48.24%). More than half of the respondents (n = 98, 57.7%) were not aware of existing protocols of disaster management in the workplace. Courses taken in such areas as first aid (n = 79, 46.4%), field triage (n = 43, 25.29%), and basic cardiac life support (n = 57, 33.53%) were cited as important in preparing for disasters. CONCLUSIONS: Nurses in the study revealed that they were not sufficiently prepared for disasters nor were they aware of disaster management protocols in the workplace. CLINICAL RELEVANCE: Hospital administrators should consider the development and formulation of disaster management protocols and provide appropriate disaster nursing education and training. Nursing curricula should incorporate basic principles of disaster management into nursing courses as a framework for addressing this critical deficit. PMID- 26650189 TI - Prevalence of MITF p.E318K in Patients With Melanoma Independent of the Presence of CDKN2A Causative Mutations. AB - IMPORTANCE: The main high-penetrance melanoma susceptibility gene is CDKN2A, encoding p16INK4A and p14ARF. The gene MITF variant p.E318K also predisposes to melanoma and renal cell carcinoma. To date, the prevalence of MITF p.E318K and its clinical and phenotypical implications has not been previously assessed in a single cohort of Spanish patients with melanoma or in p16INK4A mutation carriers. OBJECTIVES: To evaluate the prevalence of MITF p.E318K in Spanish patients with melanoma and assess the association with clinical and phenotypic features. DESIGN, SETTING, AND PARTICIPANTS: A hospital-based, case-control study was conducted at the Melanoma Unit of Hospital Clinic of Barcelona, with MITF p.E318K genotyped in all patients using TaqMan probes. We included 531 patients: 271 patients with multiple primary melanoma (MPM) without mutations affecting p16INK4A (wild-type p16INK4A); 191 probands from melanoma-prone families with a single melanoma diagnosis and without mutations affecting p16INK4A, and 69 probands from different families carrying CDKN2A mutations affecting p16INK4A. A population-based series of 499 age- and sex-matched cancer-free individuals from the Spanish National Bank of DNA were included as controls. Patients were recruited between January 1, 1992, and June 30, 2014; data analysis was conducted from September 1 to November 30, 2014. MAIN OUTCOMES AND MEASURES: The genetic results of the MITF p.E318K variant were correlated with clinical and phenotypic features. RESULTS: Among the 531 patients, the prevalence of the MITF p.E318K variant was calculated among the different subsets of patients included and was 1.9% (9 of 462) in all melanoma patients with wild-type p16INK4A, 2.6% (7 of 271) in those with MPM, and 2.9% (2 of 69) in the probands of families with p16INK4A mutations. With results reported as odds ratio (95% CI), the MITF p.E318K was associated with an increased melanoma risk (3.3 [1.43-7.43]; P < .01), especially in MPM (4.5 [1.83-11.01]; P < .01) and high nevi count (>200 nevi) (8.4 [2.14 33.19]; P < .01). Two fast-growing melanomas were detected among 2 MITF p.E318K carriers during dermatologic digital follow-up. CONCLUSIONS AND RELEVANCE: In addition to melanoma risk, MITF p.E318K is associated with a high nevi count and could play a role in fast-growing melanomas. Testing for MITF p.E318K should not exclude patients with known mutations in p16INK4A. Strict dermatologic surveillance, periodic self-examination, and renal cell carcinoma surveillance should be encouraged in this context. PMID- 26650190 TI - Real-time Monitoring of Reactions Performed Using Continuous-flow Processing: The Preparation of 3-Acetylcoumarin as an Example. AB - By using inline monitoring, it is possible to optimize reactions performed using continuous-flow processing in a simple and rapid way. It is also possible to ensure consistent product quality over time using this technique. We here show how to interface a commercially available flow unit with a Raman spectrometer. The Raman flow cell is placed after the back-pressure regulator, meaning that it can be operated at atmospheric pressure. In addition, the fact that the product stream passes through a length of tubing before entering the flow cell means that the material is at RT. It is important that the spectra are acquired under isothermal conditions since Raman signal intensity is temperature dependent. Having assembled the apparatus, we then show how to monitor a chemical reaction, the piperidine-catalyzed synthesis of 3-acetylcoumarin from salicylaldehyde and ethyl acetoacetate being used as an example. The reaction can be performed over a range of flow rates and temperatures, the in-situ monitoring tool being used to optimize conditions simply and easily. PMID- 26650191 TI - Investing in Audiology Futures: How Diversified Should Our Portfolio Be? PMID- 26650192 TI - Transsaccadic integration and perceptual continuity. AB - Our perception of the visual world seems continuous despite the fact that visual information is sampled in discrete fixations interrupted by saccadic eye movements. Two new behavioral studies show that perceptual continuity may be partly achieved by combining feature information of saccade target objects across saccades in a close-to-statistically optimal fashion. PMID- 26650193 TI - Near-optimal integration of orientation information across saccades. AB - We perceive a stable environment despite the fact that visual information is essentially acquired in a sequence of snapshots separated by saccadic eye movements. The resolution of these snapshots varies-high in the fovea and lower in the periphery-and thus the formation of a stable percept presumably relies on the fusion of information acquired at different resolutions. To test if, and to what extent, foveal and peripheral information are integrated, we examined human orientation-discrimination performance across saccadic eye movements. We found that humans perform best when an oriented target is visible both before (peripherally) and after a saccade (foveally), suggesting that humans integrate the two views. Integration relied on eye movements, as we found no evidence of integration when the target was artificially moved during stationary viewing. Perturbation analysis revealed that humans combine the two views using a weighted sum, with weights assigned based on the relative precision of foveal and peripheral representations, as predicted by ideal observer models. However, our subjects displayed a systematic overweighting of the fovea, relative to the ideal observer, indicating that human integration across saccades is slightly suboptimal. PMID- 26650196 TI - Retraction Note to: In vitro derivation of mammalian germ cells from stem cells and their potential therapeutic application. PMID- 26650194 TI - Lebanese children are iodine deficient and urinary sodium and fluoride excretion are weak positive predictors of urinary iodine. AB - PURPOSE: To assess iodine and fluoride status among Lebanese children. METHODS: A nationally representative cross-sectional study of 6- to 10-year-old schoolchildren was conducted using multistage cluster sampling. Spot urine samples were collected from 1403 children, and urinary iodine, fluoride, creatinine and sodium levels were measured. Salt samples from markets (n = 30) were tested for iodine concentration by titration. RESULTS: Median urinary iodine concentration was 66.0 ug/l, indicating mild deficiency, and almost 75 % of Lebanese children had a urinary iodine concentration (UIC) <100 ug/l. UIC was higher among children from private schools and in areas of higher socioeconomic status. Most salt samples were fortified at levels far below the legislated requirement, and 56 % of samples contained less than 15 ppm iodine. Fluoride-to creatinine ratio (F/Cr) was 0.250 (0.159-0.448) mg/g. There were weak positive correlations between UIC and urinary sodium (r 2 = 0.039, P value <0.001) and UIC and urinary fluoride (r 2 = 0.009, P value <0.001). CONCLUSIONS: Lebanese elementary school children are iodine deficient due to inadequately iodized salt. The weak correlation between UIC and urinary sodium suggests most dietary iodine does not come from iodized salt. The poor correlation between UIC and urinary fluoride suggests that fluoride intake is not affecting iodine metabolism. Efforts are needed in Lebanon to improve industry compliance with salt fortification through improved monitoring and enforcement of legislation. PMID- 26650197 TI - Impact of Dopant Compensation on Graded p-n Junctions in Si Nanowires. AB - The modulation between different doping species required to produce a diode in VLS-grown nanowires (NWs) yields a complex doping profile, both axially and radially, and a gradual junction at the interface. We present a detailed analysis of the dopant distribution around the junction. By combining surface potential measurements, performed by KPFM, with finite element simulations, we show that the highly doped (5 * 10(19) cm(-3)) shell surrounding the NW can screen the junction's built in voltage at shell thickness as low as 3 nm. By comparing NWs with high and low doping contrast at the junction, we show that dopant compensation dramatically decreases the electrostatic width of the junction and results in relatively low leakage currents. PMID- 26650195 TI - Controlling the response to DNA damage by the APC/C-Cdh1. AB - Proper cell cycle progression is safeguarded by the oscillating activities of cyclin/cyclin-dependent kinase complexes. An important player in the regulation of mitotic cyclins is the anaphase-promoting complex/cyclosome (APC/C), a multi subunit E3 ubiquitin ligase. Prior to entry into mitosis, the APC/C remains inactive, which allows the accumulation of mitotic regulators. APC/C activation requires binding to either the Cdc20 or Cdh1 adaptor protein, which sequentially bind the APC/C and facilitate targeting of multiple mitotic regulators for proteasomal destruction, including Securin and Cyclin B, to ensure proper chromosome segregation and mitotic exit. Emerging data have indicated that the APC/C, particularly in association with Cdh1, also functions prior to mitotic entry. Specifically, the APC/C-Cdh1 is activated in response to DNA damage in G2 phase cells. These observations are in line with in vitro and in vivo genetic studies, in which cells lacking Cdh1 expression display various defects, including impaired DNA repair and aberrant cell cycle checkpoints. In this review, we summarize the current literature on APC/C regulation in response to DNA damage, the functions of APC/C-Cdh1 activation upon DNA damage, and speculate how APC/C-Cdh1 can control cell fate in the context of persistent DNA damage. PMID- 26650199 TI - Cancer is associated with intraoperative and postprocedural complications and disorders. AB - OBJECTIVES: To analyze the impact of cancer on intraoperative and postprocedural complications (IPCs) in Germany. METHODS: Patients with first diagnosis of IPCs between 2010 and 2015 were identified in 982 general practitioners in the IMS Disease Analyzer database. Controls were included after individual matching (1:1) to IPC cases by age, gender, type of health insurance (private or statutory) and the physician. Demographic data included: age, sex and health insurance type (private or statutory). Clinical data included: cancer, diabetes, coronary heart disease including myocardial infarction, stroke including TIA, heart failure, chronic respiratory diseases, fractures and depression. A multivariate logistic model was used to calculate the risk of IPC on the basis of patient characteristics. RESULTS: A total of 5817 IPC patients and 5817 controls were included in this study. The mean age was 63.9 years, the proportion of people with private health insurance coverage was equal to 3.0 %, and the proportion of men was equal to 36.0 % in both groups; 21.5 % of IPC patients and 5.8 % of controls had cancer (p value <0.0001). Moreover, diabetes, coronary heart disease, stroke, heart failure, chronic respiratory disease, fractures and depression were also significantly more common in IPC patients than in controls. Cancer had a negative impact on the risk of IPC (OR 4.27, 95 % CI 3.76-4.85 and p value <0.0001). Coronary heart diseases, depression, fractures and chronic respiratory diseases were also significantly associated with an increased risk of IPC. CONCLUSION: The present study indicates that cancer increases the risk of IPCs and may reduce the clinical benefits of surgery. PMID- 26650198 TI - In vivo evaluation of neutron capture therapy effectivity using calcium phosphate based nanoparticles as Gd-DTPA delivery agent. AB - PURPOSE: A more immediate impact for therapeutic approaches of current clinical research efforts is of major interest, which might be obtained by developing a noninvasive radiation dose-escalation strategy, and neutron capture therapy represents one such novel approach. Furthermore, some recent researches on neutron capture therapy have focused on using gadolinium as an alternative or complementary for currently used boron, taking into account several advantages that gadolinium offers. Therefore, in this study, we carried out feasibility evaluation for both single and multiple injections of gadolinium-based MRI contrast agent incorporated in calcium phosphate nanoparticles as neutron capture therapy agent. METHODS: In vivo evaluation was performed on colon carcinoma Col 26 tumor-bearing mice irradiated at nuclear reactor facility of Kyoto University Research Reactor Institute with average neutron fluence of 1.8 * 10(12) n/cm(2). Antitumor effectivity was evaluated based on tumor growth suppression assessed until 27 days after neutron irradiation, followed by histopathological analysis on tumor slice. RESULTS: The experimental results showed that the tumor growth of irradiated mice injected beforehand with Gd-DTPA-incorporating calcium phosphate based nanoparticles was suppressed up to four times higher compared to the non treated group, supported by the results of histopathological analysis. CONCLUSION: The results of antitumor effectivity observed on tumor-bearing mice after neutron irradiation indicated possible effectivity of gadolinium-based neutron capture therapy treatment. PMID- 26650200 TI - Retraction Note to: Structure-based development and optimization of therapy antibody drugs against TNFalpha. PMID- 26650201 TI - The Umwelt of an embodied agent--a measure-theoretic definition. AB - We consider a general model of the sensorimotor loop of an agent interacting with the world. This formalises Uexkull's notion of a function-circle. Here, we assume a particular causal structure, mechanistically described in terms of Markov kernels. In this generality, we define two sigma-algebras of events in the world that describe two respective perspectives: (1) the perspective of an external observer, (2) the intrinsic perspective of the agent. Not all aspects of the world, seen from the external perspective, are accessible to the agent. This is expressed by the fact that the second sigma-algebra is a subalgebra of the first one. We propose the smaller one as formalisation of Uexkull's Umwelt concept. We show that, under continuity and compactness assumptions, the global dynamics of the world can be simplified without changing the internal process. This simplification can serve as a minimal world model that the system must have in order to be consistent with the internal process. PMID- 26650202 TI - Consequences of defensive medicine, second victims, and clinical-judicial syndrome on surgeons' medical practice and on health service. AB - Increased knowledge in disease causes and progression, along with technological and technical advancements in their diagnosis and treatment, have led to increased expectations from physicians by patients and their relatives. The condition of "second victim" is known to affect caregivers that commit an error, and seriously impairs private life and subsequent practice. Besides, a condition has been described, the clinical-judicial syndrome, affecting caregivers at any moment during a medical litigation. In this scenario, physicians have started to practice "defensive medicine", aimed at protect themselves from liability rather than actually advancing care of patients. This paper represents the first review on defensive medicine with specific focus on surgery in an Italian setting. We reviewed the literature on the topic, with particular focus on surgeons and Italian current status, and provide the readers with a snapshot on these relevant issues, proposing strategies to prevent and reduce the practice of defensive medicine, and to support patients and physicians suffering from medical errors. PMID- 26650203 TI - Multi-element composition of soils of seasonal wetlands across North Dakota, USA. AB - The main goal of this study was to assess if the soils of wetlands of different condition varied in terms of element composition. The rationale was that compared to wetlands of good condition, wetlands of poor condition-which in the region have typically been disturbed by agricultural activities, are lower in biodiversity and have fewer native species-would have been altered in their physical and chemical soil characteristics. This in turn would have altered the element composition of the soils. The concentrations of about 50 elements in the topsoil of 43 seasonal wetlands of varying condition, as measured by plant community based assessments, across North Dakota were determined. Organic matter content of the soils increased as condition increased, and it was the most important variable explaining 40 % of variation in the concentrations of elements. This can be partly explained by binding of elements to organic matter (S, Se) and for most other elements (that bind mostly to the inorganic fraction) by displacement by organic matter. The biogeochemistry of S is further implicated in the distribution of Ca, most likely via formation of insoluble gypsum (calcium sulfate). PMID- 26650204 TI - Wastewater analysis: the mean of the monitoring of frequently prescribed pharmaceuticals in Slovakia. AB - The estimation of medication use is based on the statistical data from pharmacies and hospitals. Excessive use or misuse of some compounds, especially psychoactive medications, has not yet been monitored in Slovakia. Wastewater analysis provides useful data about the medication use and misuse in individual regions. This study is focused on the analysis of 23 substances in the wastewaters of Slovakia. The monitoring programme has included stimulants, opioid and morphine derivatives, benzodiazepines, antidepressants, drug precursors and their metabolites. Urinary markers of these compounds were analysed at WWTP influent in seven regions (Bratislava, Kosice, Zvolen, Banska Bystrica, Trencin, Presov a Piestany) using LC-MS/MS technique. The analysis was performed from March to October 2013. The pattern in use of these compounds was also monitored. Tramadol and venlafaxine were found to be the most concentrated compounds among of all studied psychoactive pharmaceuticals. The highest specific loads of tramadol were detected in Piestany (409 mg/day/1000 inhabitants) and Zvolen (366 mg/day/1000 inhabitants). There is a considerable number of spa facilities (hotels) situated in these cities and this fact contributes to a higher occurrence of these psychoactive compounds in respective wastewaters. PMID- 26650205 TI - Groundwater vulnerability assessment in agricultural areas using a modified DRASTIC model. AB - Groundwater contamination is a major concern for groundwater resource managers worldwide. We evaluated groundwater pollution potential by producing a vulnerability map of an aquifer using a modified Depth to water, Net recharge, Aquifer media, Soil media, Topography, Impact of vadose zone, and Hydraulic conductivity (DRASTIC) model within a Geographic Information System (GIS) environment. The proposed modification which incorporated the use of statistical techniques optimizes the rating function of the DRASTIC model parameters, to obtain a more accurate vulnerability map. The new rates were computed using the relationships between the parameters and point data chloride concentrations in groundwater. The model was applied on Saveh-Nobaran plain in central Iran, and results showed that the coefficient of determination (R (2)) between the point data and the relevant vulnerability map increased significantly from 0.52 to 0.78 after modification. As compared to the original DRASTIC model, the modified version produced better vulnerability zonation. Additionally, single-parameter and parameter removal sensitivity analyses were performed to evaluate the relative importance of each DRASTIC parameter. The results from both analyses revealed that the vadose zone is the most sensitive parameter influencing the variability of the aquifers' vulnerability index. Based on the results, for non point source pollution in agricultural areas, using the modified DRASTIC model is efficient compared to the original model. The proposed method can be effective for future groundwater assessment and plain-land management where agricultural activities are dominant. PMID- 26650206 TI - Digital Microfluidics: A New Paradigm for Radiochemistry. AB - The emerging technology of digital microfluidics is opening up the possibility of performing radiochemistry at the microliter scale to produce tracers for positron emission tomography (PET) labeled with fluorine-18 or other isotopes. Working at this volume scale not only reduces reagent costs but also improves specific activity (SA) by reducing contamination by the stable isotope. This technology could provide a practical means to routinely prepare high-SA tracers for applications such as neuroimaging and could make it possible to routinely achieve high SA using synthesis strategies such as isotopic exchange. Reagent droplets are controlled electronically, providing high reliability, a compact control system, and flexibility for diverse syntheses with a single-chip design. The compact size may enable the development of a self-shielded synthesizer that does not require a hot cell. This article reviews the progress of this technology and its application to the synthesis of PET tracers. PMID- 26650224 TI - Is the levator-urethra gap helpful for diagnosing avulsion? AB - INTRODUCTION AND HYPOTHESIS: Levator avulsion is a risk factor for female pelvic organ prolapse (POP) and recurrence after POP surgery. Imaging diagnosis requires the observation of an abnormal muscle insertion on tomographic ultrasound imaging (TUI). This study was designed to compare the diagnostic performance of the qualitative diagnosis (visual qualitative assessment) to measurement of the distance between muscle insertion and urethra [levator-urethra gap; (LUG)]. METHODS: This was a retrospective analysis of data obtained in a tertiary urogynecological unit. All patients presented with symptoms of pelvic floor dysfunction and underwent 4D translabial pelvic floor ultrasound (US), supine, and after voiding. Avulsion was defined qualitatively as abnormal muscle insertion and quantitatively as LUG >=25 mm on at least three consecutive central axial plane slices, with one examiner using both methods. We examined the correlation between both methods and validated them against clinical prolapse, significant organ descent on US, and hiatal ballooning. RESULTS: Between January and July 2013, 233 patients were seen, of whom 202 had complete volume data sets. The qualitative method diagnosed avulsion in 22 % and the quantitative method in 24.3 %. Agreement was good, with a kappa of 0.79 (0.70-0.87). Avulsion diagnosed by either method was associated with clinical and sonographic prolapse and hiatal ballooning, with odds ratios nonsignificantly higher for the quantitative method. CONCLUSION: Qualitative analysis of slices on TUI and a method using LUG measurement show good agreement for the diagnosis of avulsion. The LUG method is at least equally as valid in its capacity to predict significant prolapse on clinical examination and US, as well as ballooning of the levator hiatus. PMID- 26650225 TI - Mid-urethral slings on YouTube: quality information on the internet? AB - INTRODUCTION AND HYPOTHESIS: Scant literature exists about the quality of urogynecological content on social media. Our objective was to measure the accuracy and comprehensiveness of YouTube videos related to mid-urethral sling (MUS) procedures. METHODS: YouTube was searched using the terms "mid-urethral sling," "vaginal tape," "TVT," "TOT," "TVT surgery," and "TOT surgery." Duplicates and videos with less than 1,000 views were excluded. We developed a standardized questionnaire for this project, assessing each video's target audience, main purpose, relevance, informed consent elements, surgical steps, and bias. The primary outcome was the presence of all elements of informed consent. Inter-rater reliability (IRR) was calculated using the Fleiss' kappa statistic. Descriptive statistics were also obtained. RESULTS: Five reviewers each rated 56 videos. Mean IRR was moderate (Fleiss' kappa 0.58 +/- 0.24). Video content was classified as physician educational material (67.9 %), patient information (16.1 %), advertisement (10.7 %), lawsuit recruitment (1.8 %), and unclear (3.6 %). MUS was the primary topic for 82.1 % of the videos. The remainder discussed other types of anti-incontinence procedures or prolapse surgery. None of the videos mentioned all four elements of informed consent. Of 32 videos demonstrating surgical technique, none showed the complete list of pre-determined surgical steps. The mean number of listed steps was 7.6/16. Only four videos mentioned at least one post-operative patient instruction. A marketing element was shown in 26.8 % of videos. CONCLUSIONS: Patient information about MUS on YouTube is lacking and often biased. Physicians and students viewing YouTube videos for educational purposes should be cognizant of the variability in the surgical steps demonstrated. PMID- 26650226 TI - Time efficiency of a web-based questionnaire in urogynecology: a randomized study. AB - INTRODUCTION AND HYPOTHESIS: Based on nationwide recommended questionnaires for women with pelvic floor dysfunction (PFD), we developed a web-based questionnaire (WBQ) that can be sent to women prior to their first visit. We hypothesized that using this WBQ would contribute to a more efficient first visit. Furthermore, we were interested in the satisfaction of patients who used the WBQ. METHODS: Women referred for PFD were randomized between WBQ and no questionnaire. Time spent per consultation was recorded in total and in split times for history taking, physical examination, counseling, and administration. Patient experience was evaluated by a standardized telephone interview. RESULTS: One hundred and twenty eight women were randomized: 64 in the WBQ group and 64 in the control group. History taking was significantly shorter in the WBQ group [mean difference (MD) 1 m 32 s; 95 % confidence interval (CI) -2:41 to -0:23], and time for counseling was significantly longer (MD 1 m 21 s; 95 % CI 0:06-2:37). Overall time of the consultation was equal. The need for an additional visit tended to be less frequent in the WBQ group [53 % versus 64 %; relative risk (RR) 1.3, 95 % CI 0.8 2.0]. Forty-nine percent of women considered the WBQ time consuming without adding value. CONCLUSIONS: The WBQ contributed to a slightly more efficient use of the first consultation. While differences were small and patient satisfaction was low, other benefits of the WBQ should define whether the WBQ will be introduced. PMID- 26650227 TI - A phase I study of two dosing schedules of oral BI 847325 in patients with advanced solid tumors. AB - PURPOSE: This study determined the safety, maximum tolerated dose (MTD), pharmacokinetics, and preliminary efficacy of BI 847325, an oral dual MEK and Aurora kinase inhibitor, in patients with refractory solid tumors. METHODS: This trial recruited patients with an advanced non-resectable and/or metastatic solid tumor following failure of conventional treatment (NCT01324830; 1287.1). BI 847325 was administered orally, once daily (starting at 6 mg in the first cohort) using two dosing schedules: Schedule A (2 weeks on, 1 week off) and Schedule B (three periods of 5 days on, 2 days off). The primary objective was to identify the MTD of BI 847325 for both dosing schedules. RESULTS: Sixty-nine patients (Schedule A, n = 47; Schedule B, n = 22) were treated. The MTD was 120 mg per day for Schedule A (cumulative dose of 1680 mg per 3-week cycle) and 150 mg per day for Schedule B (cumulative dose of 2250 mg per 3-week cycle). Reversible hematologic and gastrointestinal toxicities were the most common dose-limiting toxicities. One patient with esophageal cancer (receiving 160 mg BI 847325, Schedule A) experienced a partial response for 67 days, and 21 patients (n = 11 [23.4%], Schedule A; n = 10 [45.5%], Schedule B) had stable disease. Pharmacokinetic analyses showed at least bi-exponential disposition, with high inter-subject variability. There was no obvious relationship between markers of MEK or Aurora kinase inhibition and exposure to BI 847325 (exploratory analysis). CONCLUSIONS: This first-in-human trial suggests that BI 847325 has an acceptable safety profile. However, due to insufficient drug exposure at the MTD to achieve relevant MEK inhibition, a decision was taken to halt the development of BI 847325. PMID- 26650228 TI - Functional characterization of a VEGF-A-targeting Anticalin, prototype of a novel therapeutic human protein class. AB - Human tear lipocalin (Tlc) was utilized as a protein scaffold to engineer an Anticalin that specifically binds and functionally blocks vascular endothelial growth factor A (VEGF-A), a pivotal inducer of physiological angiogenesis that also plays a crucial role in several neovascular diseases. Starting from a naive combinatorial library where residues that form the natural ligand-binding site of Tlc were randomized, followed by affinity maturation, the final Anticalin PRS-050 was selected to bind all major splice forms of VEGF-A with picomolar affinity. Moreover, this Anticalin cross-reacts with the murine ortholog. PRS-050 efficiently antagonizes the interaction between VEGF-A and its cellular receptors, and it inhibits VEGF-induced mitogenic signaling as well as proliferation of primary human endothelial cells with subnanomolar IC50 values. Intravitreal administration of the Anticalin suppressed VEGF-induced blood retinal barrier breakdown in a rabbit model. To allow lasting systemic neutralization of VEGF-A in vivo, the plasma half-life of the Anticalin was extended by site-directed PEGylation. The modified Anticalin efficiently blocked VEGF-mediated vascular permeability as well as growth of tumor xenografts in nude mice, concomitantly with reduction in microvessel density. In contrast to bevacizumab, the Anticalin did not trigger platelet aggregation and thrombosis in human FcgammaRIIa transgenic mice, thus suggesting an improved safety profile. Since neutralization of VEGF-A activity is well known to exert beneficial effects in cancer and other neovascular diseases, including wet age-related macular degeneration, this Anticalin offers a novel potent small protein antagonist for differentiated therapeutic intervention in oncology and ophthalmology. PMID- 26650229 TI - International conference on "Photosynthesis research for sustainability-2015" in honor of George C. Papageorgiou", September 21-26, 2015, Crete, Greece. AB - During September 21-26, 2015, an international conference entitled ''Photosynthesis Research for Sustainability-2015'' was held in honor of George C. Papageorgiou at the Conference Center of the Orthodox Academy of Crete, an exceptionally beautiful location right on the Mediterranean Sea coast, Kolymvari, Chania, Crete, (Greece) (see http://photosynthesis2015.cellreg.org/ ). The meeting was held under the auspices of the Greek "General Secretariat for Research and Technology" (GSRT). We first provide a brief introduction and key contributions of George C. Papageorgiou, the honored scientist, and then information on the conference, on the speakers, and the program. A special feature of this conference was awards given to 13 young investigators, who are recognized in this Report. Several photographs are also included; they show the pleasant ambience at this conference. We invite the readers to the next conference on "Photosynthesis Research for Sustainability-2016," which will honor Nathan Nelson and T. Nejat Veziroglu; it will be held during June 19-25, 2016, in Pushchino, Moscow Region, Russia (see http://photosynthesis2016.cellreg.org/ ). PMID- 26650230 TI - Photosystem II cycle activity and alternative electron transport in the diatom Phaeodactylum tricornutum under dynamic light conditions and nitrogen limitation. AB - Alternative electron sinks are an important regulatory mechanism to dissipate excessively absorbed light energy particularly under fast changing dynamic light conditions. In diatoms, the cyclic electron transport (CET) around Photosystem II (PS II) is an alternative electron transport pathway (AET) that contributes to avoidance of overexcitation under high light illumination. The combination of nitrogen limitation and high-intensity irradiance regularly occurs under natural conditions and is expected to force the imbalance between light absorption and the metabolic use of light energy. The present study demonstrates that under N limitation, the amount of AET and the activity of CETPSII in the diatom Phaeodactylum tricornutum were increased. Thereby, the activity of CETPSII was linearly correlated with the amount of AET rates. It is concluded that CETPSII significantly contributes to AET in P. tricornutum. Surprisingly, CETPSII was found to be activated already at the end of the dark period under N-limited conditions. This coincided with a significantly increased degree of reduction of the plastoquinone (PQ) pool. The analysis of the macromolecular composition of cells of P. tricornutum under N-limited conditions revealed a carbon allocation in favor of carbohydrates during the light period and their degradation during the dark phase. A possible linkage between the activity of CETPSII and degree of reduction of the PQ pool on the one side and the macromolecular changes on the other is discussed. PMID- 26650231 TI - Factors Influencing Hearing Aid Use in the Classroom: A Pilot Study. AB - PURPOSE: This pilot study examined factors influencing classroom hearing aid use in school-age children with hearing loss. METHOD: The research team visited classrooms of 38 children with mild-to-moderate hearing loss (Grades 1-7) on 2 typical school days, twice per day, to document hearing aid use. In addition, parents reported the number of hours their children used hearing aids at school. RESULTS: Nearly 24% of children were observed not wearing their hearing aids in the classroom on either observation day. Both grade level and degree of hearing loss appeared to affect hearing aid use. Children in Grades 5-7 and those with milder hearing losses were less likely to wear hearing aids. Overall, parents accurately reported classroom hearing aid use; however, those with children in Grades 5-7 were less accurate than those with children in earlier grades. CONCLUSIONS: These preliminary results suggest that children with milder hearing loss and those in Grades 5-7 are at increased risk for reduced hearing aid use in the classroom. Also, parents of school-age children in these later grades are less accurate reporters of classroom hearing aid use compared to parents of children in earlier grades. PMID- 26650233 TI - Isolation and Flow Cytometric Analysis of Glioma-infiltrating Peripheral Blood Mononuclear Cells. AB - Our laboratory has recently demonstrated that natural killer (NK) cells are capable of eradicating orthotopically implanted mouse GL26 and rat CNS-1 malignant gliomas soon after intracranial engraftment if the cancer cells are rendered deficient in their expression of the beta-galactoside-binding lectin galectin-1 (gal-1). More recent work now shows that a population of Gr-1+/CD11b+ myeloid cells is critical to this effect. To better understand the mechanisms by which NK and myeloid cells cooperate to confer gal-1-deficient tumor rejection we have developed a comprehensive protocol for the isolation and analysis of glioma infiltrating peripheral blood mononuclear cells (PBMC). The method is demonstrated here by comparing PBMC infiltration into the tumor microenvironment of gal-1-expressing GL26 gliomas with those rendered gal-1-deficient via shRNA knockdown. The protocol begins with a description of how to culture and prepare GL26 cells for inoculation into the syngeneic C57BL/6J mouse brain. It then explains the steps involved in the isolation and flow cytometric analysis of glioma-infiltrating PBMCs from the early brain tumor microenvironment. The method is adaptable to a number of in vivo experimental designs in which temporal data on immune infiltration into the brain is required. The method is sensitive and highly reproducible, as glioma-infiltrating PBMCs can be isolated from intracranial tumors as soon as 24 hr post-tumor engraftment with similar cell counts observed from time point matched tumors throughout independent experiments. A single experimentalist can perform the method from brain harvesting to flow cytometric analysis of glioma-infiltrating PBMCs in roughly 4 6 hr depending on the number of samples to be analyzed. Alternative glioma models and/or cell-specific detection antibodies may also be used at the experimentalists' discretion to assess the infiltration of several other immune cell types of interest without the need for alterations to the overall procedure. PMID- 26650232 TI - The Na(+)-Taurocholate Cotransporting Polypeptide Traffics with the Epidermal Growth Factor Receptor. AB - Na(+)-taurocholate cotransporting polypeptide (ntcp) mediates bile acid transport, also serving as the hepatitis B virus receptor. It traffics in vesicles along microtubules, requiring activity of protein kinase C (PKC)zeta for motility. We have now found that the epidermal growth factor receptor (EGFR) is the target of PKCzeta activity and that EGFR and ntcp colocalize in vesicles. ntcp-containing vesicles that are not associated with EGFR have reduced microtubule-based motility, consistent with intracellular accumulation and reduced surface expression of ntcp in cells following EGFR knockdown. PMID- 26650234 TI - Live Births from Domestic Dog (Canis familiaris) Embryos Produced by In Vitro Fertilization. AB - Development of assisted reproductive technologies (ART) in the dog has resisted progress for decades, due to their unique reproductive physiology. This lack of progress is remarkable given the critical role ART could play in conserving endangered canid species or eradicating heritable disease through gene-editing technologies-an approach that would also advance the dog as a biomedical model. Over 350 heritable disorders/traits in dogs are homologous with human conditions, almost twice the number of any other species. Here we report the first live births from in vitro fertilized embryos in the dog. Adding to the practical significance, these embryos had also been cryopreserved. Changes in handling of both gametes enabled this progress. The medium previously used to capacitate sperm excluded magnesium because it delayed spontaneous acrosome exocytosis. We found that magnesium significantly enhanced sperm hyperactivation and ability to undergo physiologically-induced acrosome exocytosis, two functions essential to fertilize an egg. Unlike other mammals, dogs ovulate a primary oocyte, which reaches metaphase II on Days 4-5 after the luteinizing hormone (LH) surge. We found that only on Day 6 are oocytes consistently able to be fertilized. In vitro fertilization of Day 6 oocytes with sperm capacitated in medium supplemented with magnesium resulted in high rates of embryo development (78.8%, n = 146). Intra oviductal transfer of nineteen cryopreserved, in vitro fertilization (IVF) derived embryos resulted in seven live, healthy puppies. Development of IVF enables modern genetic approaches to be applied more efficiently in dogs, and for gamete rescue to conserve endangered canid species. PMID- 26650236 TI - Design and Fabrication of an Elastomeric Unit for Soft Modular Robots in Minimally Invasive Surgery. AB - In recent years, soft robotics technologies have aroused increasing interest in the medical field due to their intrinsically safe interaction in unstructured environments. At the same time, new procedures and techniques have been developed to reduce the invasiveness of surgical operations. Minimally Invasive Surgery (MIS) has been successfully employed for abdominal interventions, however standard MIS procedures are mainly based on rigid or semi-rigid tools that limit the dexterity of the clinician. This paper presents a soft and high dexterous manipulator for MIS. The manipulator was inspired by the biological capabilities of the octopus arm, and is designed with a modular approach. Each module presents the same functional characteristics, thus achieving high dexterity and versatility when more modules are integrated. The paper details the design, fabrication process and the materials necessary for the development of a single unit, which is fabricated by casting silicone inside specific molds. The result consists in an elastomeric cylinder including three flexible pneumatic actuators that enable elongation and omni-directional bending of the unit. An external braided sheath improves the motion of the module. In the center of each module a granular jamming-based mechanism varies the stiffness of the structure during the tasks. Tests demonstrate that the module is able to bend up to 120 degrees and to elongate up to 66% of the initial length. The module generates a maximum force of 47 N, and its stiffness can increase up to 36%. PMID- 26650235 TI - Intra-Articular Therapies in the Treatment of Hand Osteoarthritis: A Systematic Literature Review. AB - BACKGROUND: Local treatments to alleviate symptoms in hand osteoarthritis (OA) are preferred, especially in elderly patients with comorbidities. Therefore, we have summarized the benefits and harms of intra-articular (IA) therapies. METHODS: We conducted a systematic literature review until May 2015, including all controlled trials investigating efficacy or safety of any IA therapy in carpometacarpal (CMC) and interphalangeal (IP) OA compared with placebo or other treatments. Two authors independently selected trials and assessed risk of bias using the Cochrane tool. The main efficacy outcome was pain. We performed meta analysis where appropriate. RESULTS: A total of 13 trials (864 patients) studying CMC (n = 11) and IP OA (n = 2) were included, comparing corticosteroids or hyaluronic acid (HA) versus placebo (n = 4 and n = 3), and corticosteroids versus HA (n = 6). Single studies investigated infliximab, dextrose, and different HAs. The overall risk of bias was unclear or high in most trials. Meta-analysis of two trials comparing corticosteroids with placebo in CMC OA showed no improvement in pain [mean difference -3.56, 95 % confidence interval (CI) -13.87 to 6.75, scale 0-100). HA also appeared not efficacious compared with placebo in CMC OA. One trial comparing corticosteroids with placebo in IP OA demonstrated significantly improved pain during movement. No convincing evidence for efficacy of corticosteroids or HA over the other or alternative therapies was found. Only local adverse events were reported. No specific IA therapy appeared more harmful than another. CONCLUSION: Despite a beneficial short-term safety profile, IA corticosteroids or HA do not appear more effective than placebo in CMC OA. The suggestion that IA corticosteroids might be efficacious in IP OA requires confirmation. PMID- 26650237 TI - The Novel New Jersey Eyewitness Instruction Induces Skepticism but Not Sensitivity. AB - In recent decades, social scientists have shown that the reliability of eyewitness identifications is much worse than laypersons tend to believe. Although courts have only recently begun to react to this evidence, the New Jersey judiciary has reformed its jury instructions to notify jurors about the frailties of human memory, the potential for lineup administrators to nudge witnesses towards suspects that they police have already identified, and the advantages of alternative lineup procedures, including blinding of the administrator. This experiment tested the efficacy of New Jersey's jury instruction. In a 2*2 between-subjects design, mock jurors (N = 335) watched a 35 minute murder trial, wherein identification quality was either "weak" or "strong" and either the New Jersey or a "standard" instruction was delivered. Jurors were more than twice as likely to convict when the standard instruction was used (OR = 2.55; 95% CI = 1.37-4.89, p < 0.001). The New Jersey instruction, however, did not improve juror's ability to discern quality; rather, jurors receiving those instructions indiscriminatingly discounted "weak" and "strong" testimony in equal measure. PMID- 26650238 TI - Expression of the Foraging Gene Is Associated with Age Polyethism, Not Task Preference, in the Ant Cardiocondyla obscurior. AB - One of the fundamental principles of social organization, age polyethism, describes behavioral maturation of workers leading to switches in task preference. Here we present a system that allows for studying division of labor (DOL) by taking advantage of the relative short life of Cardiocondyla obscurior workers and thereby the pace of behavioral transitions. By challenging same-age young and older age cohorts to de novo establish DOL into nurse and foraging tasks and by forcing nurses to precociously become foragers and vice versa we studied expression patterns of one of the best known candidates for social insect worker behavior, the foraging gene. Contrary to our expectations we found that foraging gene expression correlates with age, but not with the task foraging per se. This suggests that this nutrition-related gene, and the pathways it is embedded in, correlates with physiological changes over time and potentially primes, but not determines task preference of individual workers. PMID- 26650239 TI - Prevalence of Salmonella Isolates from Chicken and Pig Slaughterhouses and Emergence of Ciprofloxacin and Cefotaxime Co-Resistant S. enterica Serovar Indiana in Henan, China. AB - The prevalence of Salmonella from chicken and pig slaughterhouses in Henan, China and antimicrobial susceptibility of these isolates to antibiotics was determined. From 283 chicken samples and 240 pig samples collected, 128 and 70 Salmonella isolates were recovered with an isolation rate of 45.2 and 29.2% respectively. The predominant serovars in chicken samples were S. enterica serovar Enteritidis, S. enterica serovar Hadar and S. enterica serovar Indiana, while those in pig samples were S. enterica serovar Typhimurium, S. enterica serovar Derby and S. enterica serovar Enteritidis. Resistance to ciprofloxacin was 8.6 and 10.0% for isolates from chickens and pigs respectively, whereas resistance to cefotaxime was 5.5 and 8.6%, respectively. Multidrug resistance (resistance to three or more classes of antimicrobial agent) was markedly higher in pig isolates (57.1%) than in chicken isolates (39.8%). Of particular concern was the detection of ciprofloxacin and cefotaxime co-resistant S. enterica serovar Indiana isolates, which pose risk to public health. All 16 S. enterica serovar Indiana isolates detected were resistant to ciprofloxacin, among which 11 were co-resistant to cefotaxime. The S. enterica serovar Indiana isolates accumulated point mutations in quinolone resistance determination regions of gyrA (S83F/D87G or S83F/D87N) and parC (T57S/S80R). Two plasmid mediated quinolone resistant determinants were found with aac (6')-Ib-cr and oqxAB in 16 and 12 S. enterica serovar Indiana isolates respectively. Cefotaxime-resistance of S. enterica serovar Indiana was associated with the acquisition of a blaCTX-M-65 gene. The potential risk of ciprofloxacin and cefotaxime co-resistant S. enterica serovar Indiana infection is a significant concern due to limited alternative treatment options. Reduction of Salmonella in chicken and pig slaughterhouses, in particular, ciprofloxacin and cefotaxime co-resistant S. enterica serovar Indiana will be an important measure to reduce the public health burden of Salmonella infections. PMID- 26650240 TI - Ethylene Polymerizations Using Parallel Pressure Reactors and a Kinetic Analysis of Chain Transfer Polymerization. AB - We demonstrate a method for high-throughput catalyst screening using a parallel pressure reactor starting from the initial synthesis of a nickel alpha-diimine ethylene polymerization catalyst. Initial polymerizations with the catalyst lead to optimized reaction conditions, including catalyst concentration, ethylene pressure and reaction time. Using gas-uptake data for these reactions, a procedure to calculate the initial rate of propagation (kp) is presented. Using the optimized conditions, the ability of the nickel alpha-diimine polymerization catalyst to undergo chain transfer with diethylzinc (ZnEt2) during ethylene polymerization was investigated. A procedure to assess the ability of the catalyst to undergo chain transfer (from molecular weight and 13C NMR data), calculate the degree of chain transfer, and calculate chain transfer rates (ke) is presented. PMID- 26650242 TI - Obesity and diabetes: the link between adipose tissue dysfunction and glucose homeostasis. AB - Obesity and type 2 diabetes mellitus (T2DM) epidemics, which have already spread, imply the possibility of both conditions being closely related. Thus, the goal of the present review was to draw a parallel between obesity, adipose tissue (AT) changes, and T2DM development. To this end, a search was conducted in PubMed, MEDLINE and SciELO databases, using the following key words and their combinations: obesity; diabetes; insulin resistance; diet; weight loss; adipocin; inflammation markers; and interleukins. Based on a literature review, AT dysfunction observed in obesity is characterised by adipocyte hypertrophy, macrophage infiltration, impaired insulin signalling and insulin resistance. In addition, there is release of inflammatory adipokines and an excessive amount of NEFA promoting ectopic fat deposition and lipotoxicity in muscle, liver and pancreas. Recent evidence supports the hypothesis that the conception of AT as a passive energy storage organ should be replaced by a dynamic endocrine organ, which regulates metabolism through a complex adipocyte communication with the surrounding microenvironment. The present review demonstrates how glucose homeostasis is changed by AT dysfunction. A better understanding of this relationship enables performing nutritional intervention strategies with the goal of preventing T2DM. PMID- 26650241 TI - Hes1 Increases the Invasion Ability of Colorectal Cancer Cells via the STAT3 MMP14 Pathway. AB - The Notch pathway contributes to self-renewal of tumor-initiating cell and inhibition of normal colonic epithelial cell differentiation. Deregulated expression of Notch1 and Jagged1 is observed in colorectal cancer. Hairy/enhancer of split (HES) family, the most characterized targets of Notch, involved in the development of many cancers. In this study, we explored the role of Hes1 in the tumorigenesis of colorectal cancer. Knocking down Hes1 induced CRC cell senescence and decreased the invasion ability, whereas over-expression of Hes1 increased STAT3 phosphorylation activity and up-regulated MMP14 protein level. We further explored the expression of Hes1 in human colorectal cancer and found high Hes1 mRNA expression is associated with poor prognosis in CRC patients. These findings suggest that Hes1 regulates the invasion ability through the STAT3-MMP14 pathway in CRC cells and high Hes1 expression is a predictor of poor prognosis of CRC. PMID- 26650243 TI - Dietary and lifestyle habits and the associated health risks in shift workers. AB - Traditionally only a small proportion of the workforce was engaged in shift work. Changing economic pressures have resulted in increased engagement in shift work, with approximately 17 % of the workforce in Europe engaged in this work pattern. The present narrative review aimed to summarise the data on the effects of shift work on the diet, lifestyle and health of employees, while addressing the barriers to, and opportunities for, improving health among shift workers. Shift work can result in low-quality diet and irregular eating patterns. Adverse health behaviours are also reported; particularly increased smoking and poor sleep patterns. These altered lifestyle habits, in conjunction with disruption to circadian rhythms, can create an unfavourable metabolic phenotype which facilitates the development and progression of chronic disease. Although the data are inconclusive due to issues such as poor study design and inadequate control for confounding factors; shift workers appear to be at increased mental and physical health risk, particularly with regard to non-communicable diseases. Information is lacking on the obstacles to leading a healthier lifestyle while working shifts, and where opportunities lie for intervention and health promotion among this group. In order to provide an informed evidence base to assist shift workers in overcoming associated occupational hazards, this gap must be addressed. This review highlights the unique nutritional issues faced by shift workers, and the subsequent effect on health. In societies already burdened with increased incidence of non-communicable chronic diseases, there is a clear need for education and behaviour change interventions among this group. PMID- 26650244 TI - The role of nutrition on cognition and brain health in ageing: a targeted approach. AB - Animal experiments and cross-sectional or prospective longitudinal research in human subjects suggest a role for nutrition in cognitive ageing. However, data from randomised controlled trials (RCT) that seek causal evidence for the impact of nutrients on cognitive ageing in humans often produce null results. Given that RCT test hypotheses in a rigorous fashion, one conclusion could be that the positive effects of nutrition on the aged brain observed in other study designs are spurious. On the other hand, it may be that the design of many clinical trials conducted thus far has been less than optimal. In the present review, we offer a blueprint for a more targeted approach to the design of RCT in nutrition, cognition and brain health in ageing that focuses on three key areas. First, the role of nutrition is more suited for the maintenance of health rather than the treatment of disease. Second, given that cognitive functions and brain regions vary in their susceptibility to ageing, those that especially deteriorate in senescence should be focal points in evaluating the efficacy of an intervention. Third, the outcome measures that assess change due to nutrition, especially in the cognitive domain, should not necessarily be the same neuropsychological tests used to assess gross brain damage or major pathological conditions. By addressing these three areas, we expect that clinical trials of nutrition, cognition and brain health in ageing will align more closely with other research in this field, and aid in revealing the true nature of nutrition's impact on the aged brain. PMID- 26650245 TI - Correction: LprG-Mediated Surface Expression of Lipoarabinomannan Is Essential for Virulence of Mycobacterium tuberculosis. AB - [This corrects the article DOI: 10.1371/journal.ppat.1004376.]. PMID- 26650246 TI - Sleep-related movement disorder symptoms in SHR are attenuated by physical exercise and an angiotensin-converting enzyme inhibitor. AB - The relationship between hypertension and sleep-related movement disorders has been hypothesized for humans, but the causes and mechanisms have not been elucidated. We investigated whether an alteration in blood pressure (BP) induced by physical exercise and/or an angiotensin-converting enzyme inhibitor (enalapril) could affect locomotor activity in spontaneously hypertensive rats, with emphasis on the dopaminergic system. We used SHR and normotensive Wistar rats distributed into 4 groups for each strain: control, physical exercise, enalapril and physical exercise+enalapril. Physical exercise was performed on a treadmill, and enalapril was administered by gavage, both for 8weeks. During this period, locomotor activity was evaluated in an open field test, and BP was evaluated by tail plethysmography. Dopaminergic receptors, dopamine transporter and tyrosine hydroxylase levels at the striatum were evaluated by Western blotting. The control group of spontaneously hypertensive rats showed higher BP, increased activity in the open field test and lower levels of D2 receptors and tyrosine hydroxylase compared with all other groups throughout the experimental period. In general, physical exercise and enalapril attenuated these alterations. This study suggested the existence of comorbidity between hypertension and sleep related movement disorders in spontaneously hypertensive rats. Physical exercise and enalapril conferred protection for both hypertension and the observed behavioral changes. In addition, these treatments led to changes in dopaminergic signaling in the striatal region (i.e., D2 receptor, TH and DAT). PMID- 26650247 TI - Optimizing Population Variability to Maximize Benefit. AB - Variability is inherent in any population, regardless whether the population comprises humans, plants, biological cells, or manufactured parts. Is the variability beneficial, detrimental, or inconsequential? This question is of fundamental importance in manufacturing, agriculture, and bioengineering. This question has no simple categorical answer because research shows that variability in a population can have both beneficial and detrimental effects. Here we ask whether there is a certain level of variability that can maximize benefit to the population as a whole. We answer this question by using a model composed of a population of individuals who independently make binary decisions; individuals vary in making a yes or no decision, and the aggregated effect of these decisions on the population is quantified by a benefit function (e.g. accuracy of the measurement using binary rulers, aggregate income of a town of farmers). Here we show that an optimal variance exists for maximizing the population benefit function; this optimal variance quantifies what is often called the "right mix" of individuals in a population. PMID- 26650248 TI - Review on Dynamic Contour Tonometry and Ocular Pulse Amplitude. AB - Intraocular pressure (IOP) measurement is the cornerstone of the management of glaucoma patients. The gold standard for assessing IOP is Goldmann applanation tonometry (GAT). Recently, the dynamic contour tonometer (DCT) has become available. While both devices provide reliable IOP measurements, the results are not interchangeable. DCT has the advantage of measuring an additional parameter: ocular pulse amplitude (OPA). OPA is defined as the difference between systolic and diastolic IOP and represents the pulsatile wave front produced by the varying amount of blood in the eye during the cardiac cycle. It has been shown to vary with ocular structural parameters, such as axial length, corneal thickness, and ocular rigidity, as well as with systemic variables like heart rate, blood pressure, and left ventricular ejection fraction. Although the existence of some of these associations is still controversial, the clinical relevance of OPA has been consistently suggested, especially in glaucoma. Further research on this intriguing parameter could not only provide insight into glaucoma pathophysiology but also help integrate this variable into clinical practice. PMID- 26650249 TI - Long-term Erythrocytapheresis Is Associated With Reduced Liver Iron Concentration in Sickle Cell Disease. AB - BACKGROUND: Erythrocytapheresis procedures are increasingly used in sickle cell disease. Serum ferritin and noninvasive magnetic resonance imaging measurements of liver iron concentration (LIC) are frequently used to monitor iron overload secondary to hypertransfusion. There is a paucity of data describing the impact of long-term erythrocytapheresis (LTE) on LIC. MATERIALS AND METHODS: We measured magnetic resonance imaging liver and cardiac iron on LTE subjects and stratified them into 2 groups: higher LIC (>3 mg/g) and lower LIC (<3 mg/g). chi(2) and t test were used to test for differences between the 2 groups. Logistic regression and generalized linear mixed-effects models were used to test what impacted LIC. RESULTS: None of 29 sickle cell disease subjects maintained on LTE had high cardiac iron concentration. LIC was associated with serum ferritin (r=0.697, P<0.001) but was not associated with the total number of LTE procedures (r= 0.088, P=0.656) or total number of simple transfusions (r=0.316, P=0.108). The total number of LTE procedures was not associated with serum ferritin (r=0.040, P=0.838), the total number of simple transfusions (r=-0.258, P=0.184), or LIC group (r=-0.111, P=0.566). CONCLUSION: There was no significant correlation between duration of LTE maintenance and LIC. PMID- 26650250 TI - Parathyroid Cancer in the Pediatric Patient. AB - CONTEXT: Parathyroid carcinoma is exceedingly rare in children. We describe a case of parathyroid cancer in a young female who was originally classified as benign and managed surgically. Upon her diagnosis with malignancy, concurrent with metastatic lung involvement, she was referred for medical and surgical palliation to control her symptomatic hypercalcemia. We briefly review published childhood cases, consider the challenges in differentiating malignant from benign hyperparathyroidism in this age group, and discuss the association of CDC73 mutations with parathyroid carcinoma. CASE PRESENTATION: A 13-year-old African American girl with a history of parathyroid adenoma, diagnosed at 8 years of age with multiple recurrences, presented with hypercalcemia and elevated parathyroid hormone when her disease had been reclassified as malignant. Germline gene analysis revealed a heterozygous partial deletion of CDC73. The patient underwent palliative surgery for disease metastatic to her lungs. She continues with medical management of her hypercalcemia. CONCLUSIONS: A case of pediatric parathyroid carcinoma associated with haploinsufficiency of CDC73 is discussed. We review all published cases of pediatric parathyroid carcinoma and offer diagnostic considerations for a parathyroid mass in a child. PMID- 26650251 TI - The prevalence of actinic keratosis in patients visiting dermatologists in two hospitals in China. AB - BACKGROUND: Actinic keratosis (AK) is one of the most common conditions treated by dermatologists in western countries. Studies have shown that AK prevalence in Europe, the U.S.A. and Australia is 4.5-60%. No data of AK prevalence in China has been reported. OBJECTIVES: This study aimed to explore the prevalence of AK in patients visiting dermatologists in two hospitals in China. METHODS: This study was conducted in the dermatology departments of two teaching hospitals (Peking University First Hospital, Beijing, and Fourth Military Medical University, Xi'an). All records for 5 years between 2008 and 2012 with clinically or pathologically diagnosed AKs were collected from the pathological databases of both hospitals. Data from these records were used to calculate the prevalence of AKs among patients who were seen by dermatologists in these hospitals. To estimate the reliability of data from the previous database, a cross-sectional study was conducted simultaneously in the two hospitals from 15 October to 8 December in 2012 after all dermatologists in the two departments were retrained through intensive courses on recognizing AK clinically. RESULTS: The prevalence of total clinical AKs through 2008-2012 was 0.52% in 1 590 817 patient visits in the two hospitals. The yearly prevalence of clinical AKs was 0.30-1.20%. In the cross-sectional study, 72 437 clinical patients were screened and 76 patients (1.05%) were identified to have clinically recognized AK. CONCLUSIONS: The overall prevalence of AKs in patients visiting dermatologists in the two hospitals in China was 0.52%, which is much lower than the prevalence in western countries. PMID- 26650252 TI - Chronic atomoxetine treatment during adolescence does not influence decision making on a rodent gambling task, but does modulate amphetamine's effect on impulsive action in adulthood. AB - In addition to the symptoms of inattention, hyperactivity, and impulsivity, individuals with attention deficit hyperactivity disorder exhibit impaired performance on tests of real-world cost/benefit decision-making. Atomoxetine, a nonstimulant drug approved for the treatment of attention deficit hyperactivity disorder, is a selective norepinephrine reuptake inhibitor administered chronically during adolescence, a time during which the frontal brain regions necessary for executive function undergo extensive maturation. This treatment protocol can affect behavior well into adulthood, but whether it produces long term changes in complex decision-making has not been investigated. Twenty-four Long-Evans rats were administered saline or 1.0 mg/kg atomoxetine daily from postnatal day 40 to 54. Two weeks after treatment, the adult rats were trained and assessed on the rodent gambling task, in which the animals chose from four options varying in reward, punishment, and uncertainty. Impulsive action was also measured by recording the number of premature responses made. Regardless of the treatment administered during adolescence, rats learned to favor the advantageous options characterized by small, low-penalty rewards in lieu of the larger, higher penalty reward options. Rodent gambling task performance was then assessed following acute treatment with atomoxetine (0.1-1.0 mg/kg) and amphetamine (0.3 1.5 mg/kg). Across groups, the highest dose of atomoxetine impaired decision making and decreased premature responding at all doses tested. Amphetamine also impaired choice performance, but selectively increased impulsive action in rats that had previously received atomoxetine treatment during adolescence. These findings contribute to our understanding of the long-term effects associated with chronic adolescent atomoxetine exposure and suggest that this treatment does not alter decision-making under conditions of risk and uncertainty in adulthood. PMID- 26650254 TI - Neurochemical substrates of the rewarding effects of MDMA: implications for the development of pharmacotherapies to MDMA dependence. AB - In recent years, studies with animal models of reward, such as the intracranial self-stimulation, self-administration, and conditioned place preference paradigms, have increased our knowledge on the neurochemical substrates of the rewarding effects of 3,4-methylenedioxymetamphetamine (MDMA) in rodents. However, pharmacological and neuroimaging studies with human participants are scarce. Serotonin [5-hydroxytryptamine (5-HT)], dopamine (DA), endocannabinoids, and endogenous opiates are the main neurotransmitter systems involved in the rewarding effects of MDMA in rodents, but other neurotransmitters such as glutamate, acetylcholine, adenosine, and neurotensin are also involved. The most important finding of recent research is the demonstration of differential involvement of specific neurotransmitter receptor subtypes (5-HT2, 5-HT3, DA D1, DA D2, CB1, MU and delta opioid, etc.) and extracellular proteins (DA and 5-HT transporters) in the acquisition, expression, extinction, and reinstatement of MDMA self-administration and conditioned place preference. It is important to extend the research on the effects of different compounds acting on these receptors/transporters in animal models of reward, especially in priming-induced, cue-induced, and stress-induced reinstatement. Increase in knowledge of the neurochemical substrates of the rewarding effects of MDMA may contribute to the design of new pharmacological treatments for individuals who develop MDMA dependence. PMID- 26650255 TI - The Effect of Aging and the High-Frequency Auditory Threshold on Speech-Evoked Mismatch Negativity in a Noisy Background. AB - Mismatch negativity (MMN) has been widely used to study the function of central auditory processing in the elderly. However, current research has not yet considered the effect of noise and high-frequency hearing threshold on MMN in the elderly. The aim of this study was to evaluate the effect of aging and high frequency hearing loss on speech-related MMN in noisy backgrounds. Additionally, the possible mechanisms of central auditory processing dysfunction in the elderly were investigated. Fifty people aged 61-80 (70 +/- 5.8) years were recruited for this study. They were divided into a 61- to 70-year-old group and a 71- to 80 year-old group. Fifty younger adults aged 21-40 (31 +/- 5.3) years were recruited as healthy controls. Pure-tone hearing thresholds were recorded. A speech discrimination score (SDS) and a speech-evoked MMN under white noise with a bandwidth from 125 to 8,000 Hz background condition were recorded. The relationships between SDS and MMN latency and amplitude were analyzed. The effects of age and binaural 2,000-, 4,000- and 8,000-Hz pure-tone hearing thresholds on MMN latency and amplitude were analyzed. We found that the hearing thresholds of 2,000, 4,000 and 8,000 Hz in the 61- to 70-year-old and 71- to 80 year-old groups were higher than those in the control group. The SDS in a noisy background in the 61- to 70-year-old and 71- to 80-year-old groups were lower than those in the control group. Speech-evoked MMN latency was longer in the 61- to 70-year-old and in the 71- to 80-year-old groups than in the control group (215.8 +/- 14.2 ms). SDS and speech-evoked MMN latency were negatively correlated. Age and speech-evoked MMN latency were positively correlated, as were the binaural 4,000- to 8,000-Hz pure-tone hearing thresholds and speech-evoked MMN. This study suggests that in elderly subjects, the function of preattentive central auditory processing changes. Additionally, increasing age and high frequency hearing thresholds create a synergy in neurons that is weakened in the MMN time window, which may be a cause of central auditory processing disorders in elderly subjects in noisy background conditions. PMID- 26650253 TI - A role for sigma receptors in stimulant self-administration and addiction. AB - Sigma-1 receptors (sigma1Rs) are structurally unique intracellular proteins that function as chaperones. sigma1Rs translocate from the mitochondria-associated membrane to other subcellular compartments, and can influence a host of targets, including ion channels, G-protein-coupled receptors, lipids, and other signaling proteins. Drugs binding to sigmaRs can induce or block the actions of sigmaRs. Studies indicate that stimulant self-administration induces the reinforcing effects of sigmaR agonists, because of dopamine transporter actions. Once established, the reinforcing effects of sigmaR agonists are independent of dopaminergic mechanisms traditionally thought to be critical to the reinforcing effects of stimulants. Self-administered doses of sigmaR agonists do not increase dopamine concentrations in the nucleus accumbens shell, a transmitter and brain region considered important for the reinforcing effects of abused drugs. However, self-administration of sigmaR agonists is blocked by sigmaR antagonists. Several effects of stimulants have been blocked by sigmaR antagonists, including the reinforcing effects, assessed by a place-conditioning procedure. However, the self-administration of stimulants is largely unaffected by sigmaR antagonists, indicating fundamental differences in the mechanisms underlying these two procedures used to assess the reinforcing effects. When sigmaR antagonists are administered in combination with dopamine uptake inhibitors, an effective and specific blockade of stimulant self-administration is obtained. Actions of stimulant drugs related to their abuse induce unique changes in sigmaR activity and the changes induced potentially create redundant and, once established, independent reinforcement pathways. Concomitant targeting of both dopaminergic pathways and sigmaR proteins produces a selective antagonism of stimulant self administration, suggesting new avenues for combination chemotherapies to specifically combat stimulant abuse. PMID- 26650257 TI - Activation of Si-H bonds across the nickel carbene bond in electron rich nickel PC(carbene)P pincer complexes. AB - Silicon-hydrogen bonds are shown to add to a nickel carbon double bond to yield nickel alpha-silylalkyl hydrido complexes. Kinetic and isotope labeling studies suggest that a concerted 4-centred addition across the Ni=C bond is operative rather than a mechanism involving Si-H oxidative addition. This constitutes an example of Si-H bond activation via ligand cooperativity. PMID- 26650256 TI - Transketolase-like protein 1 expression predicts poor prognosis in colorectal cancer. AB - BACKGROUND: Transketolase-like protein 1 (TKTL1) is an isoform of tranketolase, a key protein in a cancer cell's glucose metabolism that causes rapid cell growth and controls the non-oxidative part of the pentose phosphate pathway (PPP). Its overexpression occurs in several human cancer types. Our purpose was to study whether TKTL1 expression in colorectal cancer tissue associates with these patients' prognosis. METHODS: We collected retrospectively patient data and tissue samples from 840 colorectal cancer patients treated at Helsinki University Hospital, then stained tumor tissue microarrays for TKTL1 by immunohistochemistry, and compared immunohistochemical tissue expression with clinico-pathological parameters and survival. RESULTS: High expression of TKTL1 associated with high Dukes stage, non-mucinous adenocarcinoma, and left-sided disease. Patients with high TKTL1 expression had poorer prognosis than those with low expression, with a 5-year disease-specific survival of 55.7% vs. 62.7%. CONCLUSION: We show that high TKTL1 in tumor tissue can lead to poor survival in colorectal cancer. TKTL1 thus can serve as a candidate marker for identifying patients at risk of recurrent disease. PMID- 26650258 TI - Asymmetric Synthesis of Heterocyclic Analogues of a CGRP Receptor Antagonist for Treating Migraine. AB - An asymmetric synthesis of novel heterocyclic analogue of the CGRP receptor antagonist rimegepant (BMS-927711, 3) is reported. The cycloheptane ring was constructed by an intramolecular Heck reaction. The application of Hayashi Miyaura and Ellman reactions furnished the aryl and the amine chiral centers, while the separable diastereomeric third chiral center alcohols led to both carbamate and urea analogues. This synthetic approach was applicable to both 6- and 5-membered heterocycles as exemplified by pyrazine and thiazole derivatives. PMID- 26650259 TI - Neural Stem Cell Properties of an Astrocyte Subpopulation Sorted by Sedimentation Field-Flow Fractionation. AB - Astrocytes encompass a heterogeneous cell population. Using sedimentation field flow fractionation (SdFFF) method, different, almost pure, astrocyte subpopulations were isolated. Cells were collected from cortex of newborn rats and sorted by SdFFF to obtain different fractions, which were subjected to protein analysis and characterized by immunocytofluorescence. The behavior of the cells was analyzed in vitro, under culture conditions used for neural stem cells. These culture conditions were also applied to cells derived from an adult cortical tissue after traumatic brain injury (TBI). Finally, the astrocytic neural stem-like cells were transplanted in damaged sciatic nerve. Protein analysis indicated a high expression of glial fibrillary acidic protein (GFAP) and vimentin in fraction F3-derived cells. These cells formed neurospheres when cultured with epidermal growth factor and large colonies in a collagen-containing semi-solid matrix. Neurospheres expressed GFAP and nestin and were able in addition to generate neurons expressing MAP2 and oligodendrocytes expressing Olig2. When transplanted in a damaged nerve, cells of F3-derived neurospheres colonized the damaged area. Finally, after TBI in adult rats, cells able to form neurospheres containing a subpopulation of astrocytes expressing vimentin were obtained. Using the SdFFF method, an astrocyte subpopulation presenting stem cell properties was isolated from a newborn rat cortex and from an injured adult rat cortex. The specific activation of this astrocyte subpopulation may provide a potential therapeutic approach to restore lost neuronal function in injured or diseased brain. PMID- 26650260 TI - Rat Model of Photochemically-Induced Posterior Ischemic Optic Neuropathy. AB - Posterior Ischemic optic neuropathy (PION) is a sight-devastating disease in clinical practice. However, its pathogenesis and natural history have remained poorly understood. Recently, we developed a reliable, reproducible animal model of PION and tested the treatment effect of some neurotrophic factors in this model1. The purpose of this video is to demonstrate our photochemically induced model of posterior ischemic optic neuropathy, and to evaluate its effects with retrograde labeling of retinal ganglion cells. Following surgical exposure of the posterior optic nerve, a photosensitizing dye, erythrosin B, is intravenously injected and a laser beam is focused onto the optic nerve surface. Photochemical interaction of erythrosin B and the laser during irradiation damages the vascular endothelium, prompting microvascular occlusion mediated by platelet thrombosis and edematous compression. The resulting ischemic injury yields a gradual but pronounced retinal ganglion cell dieback, owing to a loss of axonal input - a remote, injury-induced and clinically relevant outcome. Thus, this model provides a novel platform to study the pathophysiologic course of PION, and can be further optimized for testing therapeutic approaches for optic neuropathies as well as other CNS ischemic diseases. PMID- 26650261 TI - Sex- and Age-Specific Reference Values and Cutoff Points for TPOAb: Tehran Thyroid Study. AB - BACKGROUND: Current guidelines used for establishing reference intervals for thyroid peroxidase antibodies (TPOAb), recommended by the National Academy of Clinical Biochemistry, have been a matter of controversy. The present study sought to determine TPOAb reference intervals for different age and sex groups, as well as the TPOAb cutoff points for subclinical and overt hypothyroidism in an iodine-sufficient population. METHODS: This cross-sectional study was conducted within the framework of the prospective Tehran Thyroid Study (TTS), in which 4174 healthy euthyroid individuals were followed for 10 years. Thyroid function tests and TPOAb were assessed. RESULTS: The mean age +/- standard deviation of participants was 39.3 +/- 15.2 years. Estimated reference intervals for TPOAb corresponding to the 2.5th and 97.5th percentiles were 1.5-32.8 and 2.1-35 IU/mL in males and females, respectively. There were no significant variations in the different age groups in either sex. The optimal cutoff points for TPOAb were 18.38 and 14.77 IU/mL for predicting clinical and subclinical hypothyroidism, respectively. CONCLUSIONS: This study establishes the reference intervals and the optimal cutoff points for TPOAb in an iodine-sufficient population. PMID- 26650263 TI - December 2009: This Month's Highlights. PMID- 26650276 TI - Bazelon Center's Blueprint for Community Reentry of Inmates With Mental Illnesses. PMID- 26650262 TI - Prion-like propagation of mutant SOD1 misfolding and motor neuron disease spread along neuroanatomical pathways. AB - A hallmark feature of amyotrophic lateral sclerosis (ALS) is that symptoms appear to spread along neuroanatomical pathways to engulf the motor nervous system, suggesting a propagative toxic entity could be involved in disease pathogenesis. Evidence for such a propagative entity emerged recently in studies using mice that express G85R-SOD1 mutant protein fused to YFP (G85R-SOD1:YFP). Heterozygous G85R-SOD1:YFP transgenic mice do not develop ALS symptoms out to 20 months of age. However, when newborns are injected with spinal homogenates from paralyzed mutant SOD1 mice, the G85R-SOD1:YFP mice develop paralysis as early as 6 months of age. We now demonstrate that injecting spinal homogenates from paralyzed mutant SOD1 mice into the sciatic nerves of adult G85R-SOD1:YFP mice produces a spreading motor neuron disease within 3.0 +/- 0.2 months of injection. The formation of G85R-SOD1:YFP inclusion pathology spreads slowly in this model system; first appearing in the ipsilateral DRG, then lumbar spinal cord, before spreading rostrally up to the cervical cord by the time mice develop paralysis. Reactive astrogliosis mirrors the spread of inclusion pathology and motor neuron loss is most severe in lumbar cord. G85R-SOD1:YFP inclusion pathology quickly spreads to discrete neurons in the brainstem and midbrain that are synaptically connected to spinal neurons, suggesting a trans-synaptic propagation of misfolded protein. Taken together, the data presented here describe the first animal model that recapitulates the spreading phenotype observed in patients with ALS, and implicates the propagation of misfolded protein as a potential mechanism for the spreading of motor neuron disease. PMID- 26650277 TI - Federal Action Plan for Improving Responses to Children of Incarcerated Parents. PMID- 26650279 TI - Organoids as Model for Infectious Diseases: Culture of Human and Murine Stomach Organoids and Microinjection of Helicobacter Pylori. AB - Recently infection biologists have employed stem cell derived cultures to answer the need for new and better models to study host-pathogen interactions. Three cellular sources have been used: Embryonic stem cells (ESC), induced pluripotent stem cells (iPSC) or adult stem cells. Here, culture of mouse and human gastric organoids derived from adult stem cells is described and used for infection with the gastric pathogen Helicobacter pylori. Human gastric glands are isolated from resection material, seeded in a basement matrix and embedded in medium containing growth factors epidermal growth factor (EGF), R-spondin, Noggin, Wnt, fibroblast growth factor (FGF) 10, gastrin and transforming growth factor (TGF) beta inhibitor. In these conditions, gastric glands grow into 3-dimensional organoids containing 4 lineages of the stomach. The organoids expand indefinitely and can be frozen and thawed similarly as cell lines. For infection studies, bacteria are microinjected into the lumen of the organoids. Infected organoids are processed for imaging. The described methods can be adapted to other organoids and infections with other bacteria, viruses or parasites. This allows the study of infection-induced changes in primary cells. PMID- 26650280 TI - Low temperature isolation of a dinuclear silver complex of the cyclotetraphosphane [ClP(MU-PMes*)]2. AB - The reaction of the cyclotetraphosphane [ClP(MU-PMes*)]2 (, Mes* = 2,4,6-tri-tert butylphenyl) with Ag[Al(OR(F))4] (R(F) = CH(CF3)2) resulted in a labile, dinuclear silver complex of , which eliminates AgCl above -30 degrees C. Its properties were investigated by spectroscopic methods, single crystal X-ray diffraction and DFT calculations. PMID- 26650281 TI - Necessity of Eigenstate Thermalization. AB - Under the eigenstate thermalization hypothesis (ETH), quantum-quenched systems equilibrate towards canonical, thermal ensembles. While at first glance the ETH might seem a very strong hypothesis, we show that it is indeed not only sufficient but also necessary for thermalization. More specifically, we consider systems coupled to baths with well-defined macroscopic temperature and show that whenever all product states thermalize then the ETH must hold. Our result definitively settles the question of determining whether a quantum system has a thermal behavior, reducing it to checking whether its Hamiltonian satisfies the ETH. PMID- 26650282 TI - Testing Nonassociative Quantum Mechanics. AB - The familiar concepts of state vectors and operators in quantum mechanics rely on associative products of observables. However, these notions do not apply to some exotic systems such as magnetic monopoles, which have long been known to lead to nonassociative algebras. Their quantum physics has remained obscure. This Letter presents the first derivation of potentially testable physical results in nonassociative quantum mechanics, based on effective potentials. They imply new effects which cannot be mimicked in usual quantum mechanics with standard magnetic fields. PMID- 26650283 TI - Revealing Hidden Coherence in Partially Coherent Light. AB - Coherence and correlations represent two related properties of a compound system. The system can be, for instance, the polarization of a photon, which forms part of a polarization-entangled two-photon state, or the spatial shape of a coherent beam, where each spatial mode bears different polarizations. Whereas a local unitary transformation of the system does not affect its coherence, global unitary transformations modifying both the system and its surroundings can enhance its coherence, transforming mutual correlations into coherence. The question naturally arises of what is the best measure that quantifies the correlations that can be turned into coherence, and how much coherence can be extracted. We answer both questions, and illustrate its application for some typical simple systems, with the aim at illuminating the general concept of enhancing coherence by modifying correlations. PMID- 26650284 TI - Verifiable Measurement-Only Blind Quantum Computing with Stabilizer Testing. AB - We introduce a simple protocol for verifiable measurement-only blind quantum computing. Alice, a client, can perform only single-qubit measurements, whereas Bob, a server, can generate and store entangled many-qubit states. Bob generates copies of a graph state, which is a universal resource state for measurement based quantum computing, and sends Alice each qubit of them one by one. Alice adaptively measures each qubit according to her program. If Bob is honest, he generates the correct graph state, and, therefore, Alice can obtain the correct computation result. Regarding the security, whatever Bob does, Bob cannot get any information about Alice's computation because of the no-signaling principle. Furthermore, malicious Bob does not necessarily send the copies of the correct graph state, but Alice can check the correctness of Bob's state by directly verifying the stabilizers of some copies. PMID- 26650285 TI - Diffusion and Subdiffusion of Interacting Particles on Comblike Structures. AB - We study the dynamics of a tracer particle (TP) on a comb lattice populated by randomly moving hard-core particles in the dense limit. We first consider the case where the TP is constrained to move on the backbone of the comb only. In the limit of high density of the particles, we present exact analytical results for the cumulants of the TP position, showing a subdiffusive behavior ~t^{3/4}. At longer times, a second regime is observed where standard diffusion is recovered, with a surprising nonanalytical dependence of the diffusion coefficient on the particle density. When the TP is allowed to visit the teeth of the comb, based on a mean-field-like continuous time random walk description, we unveil a rich and complex scenario with several successive subdiffusive regimes, resulting from the coupling between the geometrical constraints of the comb lattice and particle interactions. In this case, remarkably, the presence of hard-core interactions asymptotically speeds up the TP motion along the backbone of the structure. PMID- 26650286 TI - Steady-State Dynamics and Effective Temperature for a Model of Quantum Criticality in an Open System. AB - We study the thermal and nonthermal steady-state scaling functions and the steady state dynamics of a model of local quantum criticality. The model we consider, i.e., the pseudogap Kondo model, allows us to study the concept of effective temperatures near fully interacting as well as weak-coupling fixed points. In the vicinity of each fixed point we establish the existence of an effective temperature-different at each fixed point-such that the equilibrium fluctuation dissipation theorem is recovered. Most notably, steady-state scaling functions in terms of the effective temperatures coincide with the equilibrium scaling functions. This result extends to higher correlation functions as is explicitly demonstrated for the Kondo singlet strength. The nonlinear charge transport is also studied and analyzed in terms of the effective temperature. PMID- 26650287 TI - Tomographic Constraints on High-Energy Neutrinos of Hadronuclear Origin. AB - Mounting evidence suggests that the TeV-PeV neutrino flux detected by the IceCube telescope has mainly an extragalactic origin. If such neutrinos are primarily produced by a single class of astrophysical sources via hadronuclear (pp) interactions, a similar flux of gamma-ray photons is expected. For the first time, we employ tomographic constraints to pinpoint the origin of the IceCube neutrino events by analyzing recent measurements of the cross correlation between the distribution of GeV gamma rays, detected by the Fermi satellite, and several galaxy catalogs in different redshift ranges. We find that the corresponding bounds on the neutrino luminosity density are up to 1 order of magnitude tighter than those obtained by using only the spectrum of the gamma-ray background, especially for sources with mild redshift evolution. In particular, our method excludes any hadronuclear source with a spectrum softer than E^{-2.1} as a main component of the neutrino background, if its evolution is slower than (1+z)^{3}. Starburst galaxies, if able to accelerate and confine cosmic rays efficiently, satisfy both spectral and tomographic constraints. PMID- 26650288 TI - Absence of Disorder-Driven Metal-Insulator Transitions in Simple Holographic Models. AB - We study electrical transport in a strongly coupled strange metal in two spatial dimensions at finite temperature and charge density, holographically dual to the Einstein-Maxwell theory in an asymptotically four-dimensional anti-de Sitter space spacetime, with arbitrary spatial inhomogeneity, up to mild assumptions including emergent isotropy. In condensed matter, these are candidate models for exotic strange metals without long-lived quasiparticles. We prove that the electrical conductivity is bounded from below by a universal minimal conductance: the quantum critical conductivity of a clean, charge-neutral plasma. Beyond nonperturbatively justifying mean-field approximations to disorder, our work demonstrates the practicality of new hydrodynamic insight into holographic transport. PMID- 26650289 TI - Cosmological Relaxation of the Electroweak Scale. AB - A new class of solutions to the electroweak hierarchy problem is presented that does not require either weak-scale dynamics or anthropics. Dynamical evolution during the early Universe drives the Higgs boson mass to a value much smaller than the cutoff. The simplest model has the particle content of the standard model plus a QCD axion and an inflation sector. The highest cutoff achieved in any technically natural model is 10^{8} GeV. PMID- 26650290 TI - Composite Heavy Vector Triplet in the ATLAS Diboson Excess. AB - Vector triplets of the standard model SU(2)_{L} group are a universal prediction of "natural" new physics models involving a new composite sector and are therefore among the most plausible new particles that the LHC could discover. We consider the possibility that one such triplet could account for the ATLAS excess in the boson-tagged jets analysis and we assess the compatibility of this hypothesis with all other relevant searches. We find that the hypothesis is not excluded and that the predicted signal is close to the expected sensitivity of several channels, some of which show an upper fluctuation of the observed limit while others do not. An accurate study of the signal compatibility with these fluctuations could only be performed by the experimental collaborations. PMID- 26650292 TI - Lepton Universality Test in the Photoproduction of e^{-}e^{+} Versus MU^{-}MU^{+} Pairs on a Proton Target. AB - In view of the significantly different proton charge radius extracted from muonic hydrogen Lamb shift measurements as compared to electronic hydrogen spectroscopy or electron-scattering experiments, we study in this Letter the photoproduction of a lepton pair on a proton target in the limit of very small momentum transfer as a way to provide a test of the lepton universality when extracting the proton charge form factor. By detecting the recoiling proton in the gammap->l^{-}l^{+}p reaction, we show that a measurement of a ratio of e^{-}e^{+}+MU^{-}MU^{+} over e^{-}e^{+} cross sections with an absolute precision of 7*10^{-4} would allow for a test to distinguish, at the 3sigma level, between the two different proton charge radii currently extracted from muonic and electronic observables. PMID- 26650294 TI - Can Nonrelativistic QCD Explain the gammagamma^{*}->eta_{c} Transition Form Factor Data? AB - Unlike the bewildering situation in the gammagamma^{*}->pi form factor, a widespread view is that perturbative QCD can decently account for the recent BABAR measurement of the gammagamma^{*}->eta_{c} transition form factor. The next to-next-to-leading-order perturbative correction to the gammagamma^{*}->eta_{c,b} form factor, is investigated in the nonrelativistic QCD (NRQCD) factorization framework for the first time. As a byproduct, we obtain, by far, the most precise order-alpha_{s}^{2} NRQCD matching coefficient for the eta_{c,b}->gammagamma process. After including the substantial negative order-alpha_{s}^{2} correction, the good agreement between NRQCD prediction and the measured gammagamma^{*} >eta_{c} form factor is completely ruined over a wide range of momentum transfer squared. This eminent discrepancy casts some doubts on the applicability of the NRQCD approach to hard exclusive reactions involving charmonium. PMID- 26650296 TI - Lattice QCD Calculation of Hadronic Light-by-Light Scattering. AB - We perform a lattice QCD calculation of the hadronic light-by-light scattering amplitude in a broad kinematical range. At forward kinematics, the results are compared to a phenomenological analysis based on dispersive sum rules for light by-light scattering. The size of the pion pole contribution is investigated for momenta of typical hadronic size. The presented numerical methods can be used to compute the hadronic light-by-light contribution to the anomalous magnetic moment of the muon. Our calculations are carried out in two-flavor QCD with the pion mass in the range of 270-450 MeV and contain so far only the diagrams with fully connected quark lines. PMID- 26650291 TI - Observation of B^{0}->pLambda[over -]D^{(*)-}. AB - We report the first observation of the decays B^{0}->pLambda[over -]D^{(*)-}. The data sample of 711 fb^{-1} used in this analysis corresponds to 772*10^{6} BB[over -] pairs, collected at the Upsilon(4S) resonance by the Belle detector at the KEKB asymmetric-energy e^{+}e^{-} collider. We observe 19.8sigma and 10.8sigma excesses of events for the two decay modes and measure the branching fractions of B^{0}->pLambda[over -]D^{-} and B^{0}->pLambda[over -]D^{*-} to be (25.1+/-2.6+/-3.5)*10^{-6} and (33.6+/-6.3+/-4.4)*10^{-6}, respectively, where the first uncertainties are statistical and the second are systematic. These results are not compatible with the predictions based on the generalized factorization approach. In addition, a threshold enhancement in the dibaryon (pLambda[over -]) system is observed, consistent with that observed in similar B decays. PMID- 26650300 TI - New Sum Rule for the Nuclear Magnetic Polarizability. AB - The well-known Levinger-Bethe photonuclear sum rule relates the strength of the photoexcitation of the giant dipole resonance in a nucleus to the number of nucleons in that nucleus. I extend this sum rule to the case of virtual photons and relate the size of the magnetic polarizability of a nucleus to the Q^{2} slope of the transverse virtual photoabsorption cross section integrated over the energy in the nuclear range. I check this sum rule for the deuteron where necessary data is available, discuss possible applications and connection with other sum rules postulated in the literature. PMID- 26650298 TI - Observation of Spin-Dependent Charge Symmetry Breaking in LambdaN Interaction: Gamma-Ray Spectroscopy of _{Lambda}^{4}He. AB - The energy spacing between the spin-doublet bound state of _{Lambda}^{4}He(1^{+},0^{+}) was determined to be 1406+/-2+/-2 keV, by measuring gamma rays for the 1^{+}->0^{+} transition with a high efficiency germanium detector array in coincidence with the ^{4}He(K^{-},pi^{-})_{Lambda}^{4}He reaction at J-PARC. In comparison to the corresponding energy spacing in the mirror hypernucleus _{Lambda}^{4}H, the present result clearly indicates the existence of charge symmetry breaking (CSB) in LambdaN interaction. By combining the energy spacings with the known ground-state binding energies, it is also found that the CSB effect is large in the 0^{+} ground state but is vanishingly small in the 1^{+} excited state, demonstrating that the LambdaN CSB interaction has spin dependence. PMID- 26650301 TI - Rotational-State-Dependent Dispersion of Molecules by Pulsed Optical Standing Waves. AB - We report on the rotational-state-dependent, transverse acceleration of CS_{2} molecules affected by pulsed optical standing waves. The steep gradient of the standing wave potential imparts far stronger dipole forces on the molecules than propagating pulses do. Moreover, large changes in the transverse velocities (i.e., up to 80 m/s) obtained with the standing waves are well reproduced in numerical simulations using the effective polarizability that depends on the molecular rotational states. Our analysis based on the rotational-state-dependent effective polarizability can therefore serve as a basis for developing a new technique of state selection for both polar and nonpolar molecules. PMID- 26650302 TI - Positronium Production and Scattering below Its Breakup Threshold. AB - Recent findings on the similarity between electron and positronium scattering at the same velocity [Brawley et al., Science 330, 789 (2010)] have guided us towards the realization of a detectable flux of positronium atoms at beam energies five times lower than previously obtained, enabling total cross sections to be measured in the energy range ~(1-7) eV for the first time. In collision with Ar and Xe, the total cross sections of positronium are found to be smallest at the lowest energy probed, approaching those of the Ramsauer-Townsend minima for electron projectiles. Additional structure has been observed in the case of positronium scattering at incident energies around 5 eV. PMID- 26650299 TI - Isospin Mixing in ^{80}Zr: From Finite to Zero Temperature. AB - The isospin mixing was deduced in the compound nucleus ^{80}Zr at an excitation energy of E^{*}=54 MeV from the gamma decay of the giant dipole resonance. The reaction ^{40}Ca+^{40}Ca at E_{beam}=136 MeV was used to form the compound nucleus in the isospin I=0 channel, while the reaction ^{37}Cl+^{44}Ca at E_{beam}=95 MeV was used as the reference reaction. The gamma rays were detected with the AGATA demonstrator array coupled with LaBr_{3}:Ce detectors. The temperature dependence of the isospin mixing was obtained and the zero temperature value deduced. The isospin-symmetry-breaking correction delta_{C} used for the Fermi superallowed transitions was extracted and found to be consistent with beta-decay data. PMID- 26650303 TI - Cooperative Emission of a Pulse Train in an Optically Thick Scattering Medium. AB - An optically thick cold atomic cloud emits a coherent flash of light in the forward direction when the phase of an incident probe field is abruptly changed. Because of cooperativity, the duration of this phenomena can be much shorter than the excited lifetime of a single atom. Repeating periodically the abrupt phase jump, we generate a train of pulses with short repetition time, high intensity contrast, and high efficiency. In this regime, the emission is fully governed by cooperativity even if the cloud is dilute. PMID- 26650304 TI - Phonon Cooling by an Optomechanical Heat Pump. AB - We propose and analyze theoretically a cavity optomechanical analog of a heat pump that uses a polariton fluid to cool mechanical modes coupled to a single precooled phonon mode via external modulation of the substrate of the mechanical resonator. This approach permits us to cool phonon modes of arbitrary frequencies not limited by the cavity-optical field detuning deep into the quantum regime from room temperature. PMID- 26650305 TI - Correlated Emission Lasing in Harmonic Oscillators Coupled via a Single Three Level Artificial Atom. AB - A single superconducting artificial atom can be used for coupling electromagnetic fields up to the single-photon level due to an easily achieved strong coupling regime. Bringing a pair of harmonic oscillators into resonance with the transitions of a three-level atom converts atomic spontaneous processes into correlated emission dynamics. We present the experimental demonstration of two mode correlated emission lasing in harmonic oscillators coupled via a fully controllable three-level superconducting quantum system (artificial atom). The correlation of emissions with two different colors reveals itself as equally narrowed linewidths and quenching of their mutual phase diffusion. The mutual linewidth is more than 4 orders of magnitude narrower than the Schawlow-Townes limit. The interference between the different color lasing fields demonstrates that the two-mode fields are strongly correlated. PMID- 26650306 TI - Broadband Coherent Enhancement of Transmission and Absorption in Disordered Media. AB - Spatial modulation of the incident wave front has become a powerful method for controlling the diffusive transport of light in disordered media; however, such interference-based control is intrinsically sensitive to frequency detuning. Here, we show analytically and numerically that certain wave fronts can exhibit strongly enhanced total transmission or absorption across bandwidths that are orders of magnitude broader than the spectral correlation width of the speckles. Such broadband enhancement is possible due to long-range correlations in coherent diffusion, which cause the spectral degrees of freedom to scale as the square root of the bandwidth rather than the bandwidth itself. PMID- 26650307 TI - Ultrabroadband Dispersive Radiation by Spatiotemporal Oscillation of Multimode Waves. AB - In nonlinear dynamical systems, qualitatively distinct phenomena occur depending continuously on the size of the bounded domain containing the system. For nonlinear waves, a multimode waveguide is a bounded three-dimensional domain, allowing observation of dynamics impossible in open settings. Here we study radiation emitted by bounded nonlinear waves: the spatiotemporal oscillations of solitons in multimode fiber generate multimode dispersive waves over an ultrabroadband spectral range. This work suggests routes to sources of coherent electromagnetic waves with unprecedented spectral range. PMID- 26650308 TI - Absorption of an Electron by a Dielectric Wall. AB - We introduce a method for calculating the probability with which a low-energy electron hitting the wall of a bounded plasma gets stuck in it and apply the method to a dielectric wall with positive electron affinity smaller than the band gap using MgO as an example. In accordance with electron beam scattering data we obtain energy-dependent sticking probabilities significantly less than unity and question thereby for electrons the perfect absorber assumption used in plasma modeling. PMID- 26650309 TI - Chiral d-Wave Superfluid in Periodically Driven Lattices. AB - A chiral d-wave superfluid is a preliminary example of interacting topological matter. However, unlike s-wave superfluids prevalent in nature, its existence requires a strong d-wave interaction, a criterion that is difficult to access in ordinary systems. There is no experimental observation of such unconventional superfluid at the moment. Here, we present a new principle for creating a two dimensional (2D) chiral d-wave superfluid using periodically driven lattices. Because of an imprinted 2D pseudospin-orbit coupling, where the sublattice index serves as the pseudospin, the s-wave interaction between two hyperfine spin states naturally creates a chiral d-wave superfluid. This scheme can be directly implemented in current experiments. PMID- 26650310 TI - Crossover from beta to alpha Relaxation in Cooperative Facilitation Dynamics. AB - beta and alpha relaxation processes are dynamical scaling regimes of glassy systems occurring on two separate time scales which both diverge as the glass state is approached. We study here the crossover scaling from beta to alpha relaxation in the cooperative facilitation scenario (CFS) and show that it is quantitatively described, with no adjustable parameter, by the leading order asymptotic formulas for scaling predicted by the mode-coupling theory (MCT). These results establish (i) the mutual universality of the MCT and CFS, and (ii) the existence of a purely dynamic realization of MCT, which is distinct from the well-established random first order transition scenario for disordered systems. Some implications of the emerging kinetic-static duality are discussed. PMID- 26650311 TI - Angular-Dependent Phase Factor of Shubnikov-de Haas Oscillations in the Dirac Semimetal Cd_{3}As_{2}. AB - We measure the magnetotransport properties of the three-dimensional Dirac semimetal Cd_{3}As_{2} single crystal under magnetic fields up to 36 T. Shubnikov de Haas (SdH) oscillations are clearly resolved and the n=1 Landau level is reached. A detailed analysis on the intercept of the Landau index plot reveals a significant dependence of the SdH phase factor on the orientation of the applied magnetic field. When the magnetic field is applied in the [001] direction, i.e., along the fourfold screw axis of the tetragonal crystal structure, a nontrivial pi Berry phase, as predicted for the Dirac fermions, is observed. However, in a magnetic field tilted away from the [001] direction, the pi Berry phase is evidently reduced, and a considerable enhancement of the effective mass is also revealed. Our observations demonstrate that the Dirac dispersion in Cd_{3}As_{2} is effectively modified in a tilted magnetic field, whereas the preserved pi Berry phase in a magnetic field along the [001] direction can be related to the realization of the Weyl fermions. The sudden change of the SdH phase also indicates a possible topological phase transition induced by the symmetry breaking effect. PMID- 26650312 TI - Suppression of Three-Dimensional Charge Density Wave Ordering via Thickness Control. AB - Barium bismuth oxide (BaBiO_{3}) is the end member of two families of high-T_{c} superconductors, i.e., BaPb_{1-x}Bi_{x}O_{3} and Ba_{1-x}K_{x}BiO_{3}. The undoped parent compound is an insulator, exhibiting a charge density wave that is strongly linked to a static breathing distortion in the oxygen sublattice of the perovskite structure. We report a comprehensive spectroscopic and x-ray diffraction study of BaBiO_{3} thin films, showing that the minimum film thickness required to stabilize the breathing distortion and charge density wave is ~11 unit cells, and that both phenomena are suppressed in thinner films. Our results constitute the first experimental observation of charge density wave suppression in bismuthate compounds without intentionally introducing dopants. PMID- 26650293 TI - Measurement of the Absolute Branching Fraction for Lambda_{c}^{+} >Lambdae^{+}nu_{e}. AB - We report the first measurement of the absolute branching fraction for Lambda_{c}^{+}->Lambdae^{+}nu_{e}. This measurement is based on 567 pb^{-1} of e^{+}e^{-} annihilation data produced at sqrt[s]=4.599 GeV, which is just above the Lambda_{c}^{+}Lambda[over -]_{c}^{-} threshold. The data were collected with the BESIII detector at the BEPCII storage rings. The branching fraction is determined to be B(Lambda_{c}^{+}->Lambdae^{+}nu_{e})=[3.63+/-0.38(stat)+/ 0.20(syst)]%, representing a significant improvement in precision over the current indirect determination. As the branching fraction for Lambda_{c}^{+} >Lambdae^{+}nu_{e} is the benchmark for those of other Lambda_{c}^{+} semileptonic channels, our result provides a unique test of different theoretical models, which is the most stringent to date. PMID- 26650313 TI - Spin-Current to Charge-Current Conversion and Magnetoresistance in a Hybrid Structure of Graphene and Yttrium Iron Garnet. AB - The use of graphene in spintronic devices depends, among other things, on its ability to convert a spin excitation into an electric charge signal, a phenomenon that requires a spin-orbit coupling (SOC). Here we report the observation of two effects that show the existence of SOC in large-area CVD grown single-layer graphene deposited on a single crystal film of the ferrimagnetic insulator yttrium iron garnet (YIG). The first is a magnetoresistance of graphene induced by the magnetic proximity effect with YIG. The second is the detection of a dc voltage along the graphene layer resulting from the conversion of the spin current generated by spin pumping from microwave driven ferromagnetic resonance into a charge current, which is attributed to the inverse Rashba-Edelstein effect. PMID- 26650297 TI - Azimuthal Anisotropy in U+U and Au+Au Collisions at RHIC. AB - Collisions between prolate uranium nuclei are used to study how particle production and azimuthal anisotropies depend on initial geometry in heavy-ion collisions. We report the two- and four-particle cumulants, v_{2}{2} and v_{2}{4}, for charged hadrons from U+U collisions at sqrt[s_{NN}]=193 GeV and Au+Au collisions at sqrt[s_{NN}]=200 GeV. Nearly fully overlapping collisions are selected based on the energy deposited by spectators in zero degree calorimeters (ZDCs). Within this sample, the observed dependence of v_{2}{2} on multiplicity demonstrates that ZDC information combined with multiplicity can preferentially select different overlap configurations in U+U collisions. We also show that v_{2} vs multiplicity can be better described by models, such as gluon saturation or quark participant models, that eliminate the dependence of the multiplicity on the number of binary nucleon-nucleon collisions. PMID- 26650314 TI - Selective Amplification of the Primary Exciton in a MoS_{2} Monolayer. AB - Optoelectronics applications for transition-metal dichalcogenides are still limited by weak light absorption and their complex exciton modes are easily perturbed by varying excitation conditions because they are inherent in atomically thin layers. Here, we propose a method of selectively amplifying the primary exciton (A^{0}) among the exciton complexes in monolayer MoS_{2} via cyclic reexcitation of cavity-free exciton-coupled plasmon propagation. This was implemented by partially overlapping a Ag nanowire on a MoS_{2} monolayer separated by a thin SiO_{2} spacer. Exciton-coupled plasmons in the nanowire enhance the A^{0} radiation in MoS_{2}. The cumulative amplification of emission enhancement by cyclic plasmon traveling reaches approximately twentyfold selectively for the A^{0}, while excluding other B exciton and multiexciton by significantly reduced band filling, without oscillatory spectra implying plasmonic cavity effects. PMID- 26650315 TI - Formation of Molecular-Orbital Bands in a Twisted Hubbard Tube: Implications for Unconventional Superconductivity in K_{2}Cr_{3}As_{3}. AB - We study a twisted Hubbard tube modeling the [CrAs]_{infinity} structure of quasi one-dimensional superconductors A_{2}Cr_{3}As_{3} (A=K, Rb, Cs). The molecular orbital bands emerging from the quasi-degenerate atomic orbitals are exactly solved. An effective Hamiltonian is derived for a region where three partially filled bands intersect the Fermi energy. The deduced local interactions among these active bands show a significant reduction compared to the original atomic interactions. The resulting three-channel Luttinger liquid shows various interaction-induced instabilities including two kinds of spin-triplet superconducting instabilities due to gapless spin excitations, with one of them being superseded by the spin-density-wave phase in the intermediate Hund's coupling regime. The implications of these results for the alkali chromium arsenides are discussed. PMID- 26650316 TI - Leggett Modes and the Anderson-Higgs Mechanism in Superconductors without Inversion Symmetry. AB - We develop a microscopic and gauge-invariant theory for collective modes resulting from the phase of the superconducting order parameter in noncentrosymmetric superconductors. Considering various crystal symmetries, we derive the corresponding gauge mode omega_{G}(q) and find, in particular, new Leggett modes omega_{L}(q) with characteristic properties that are unique to noncentrosymmetric superconductors. We calculate their mass and dispersion that reflect the underlying spin-orbit coupling and thus the balance between triplet and singlet superconductivity occurring simultaneously. Finally, we demonstrate the role of the Anderson-Higgs mechanism: while the long-range Coulomb interaction shifts omega_{G}(q) to the condensate plasma mode omega_{P}(q), it leaves the mass Lambda_{0} of the new Leggett mode unaffected and only slightly modifies its dispersion. PMID- 26650317 TI - Magnetic Field Tuning and Quantum Interference in a Cooper Pair Splitter. AB - Cooper pair splitting (CPS) is a process in which the electrons of the naturally occurring spin-singlet pairs in a superconductor are spatially separated using two quantum dots. Here, we investigate the evolution of the conductance correlations in an InAs CPS device in the presence of an external magnetic field. In our experiments the gate dependence of the signal that depends on both quantum dots continuously evolves from a slightly asymmetric Lorentzian to a strongly asymmetric Fano-type resonance with increasing field. These experiments can be understood in a simple three-site model, which shows that the nonlocal CPS leads to symmetric line shapes, while the local transport processes can exhibit an asymmetric shape due to quantum interference. These findings demonstrate that the electrons from a Cooper pair splitter can propagate coherently after their emission from the superconductor and how a magnetic field can be used to optimize the performance of a CPS device. In addition, the model calculations suggest that the estimate of the CPS efficiency in the experiments is a lower bound for the actual efficiency. PMID- 26650295 TI - Observation of a Neutral Structure near the DD[over -]^{*} Mass Threshold in e^{+}e^{-}->(DD[over -]^{*})^{0}pi^{0} at sqrt[s]=4.226 and 4.257 GeV. AB - A neutral structure in the DD[over -]^{*} system around the DD[over -]^{*} mass threshold is observed with a statistical significance greater than 10sigma in the processes e^{+}e^{-}->D^{+}D^{*-}pi^{0}+c.c. and e^{+}e^{-}->D^{0}D[over ]^{*0}pi^{0}+c.c. at sqrt[s]=4.226 and 4.257 GeV in the BESIII experiment. The structure is denoted as Z_{c}(3885)^{0}. Assuming the presence of a resonance, its pole mass and width are determined to be [3885.7_{-5.7}^{+4.3}(stat)+/ 8.4(syst)] MeV/c^{2} and [35_{-12}^{+11}(stat)+/-15(syst)] MeV, respectively. The Born cross sections are measured to be sigma[e^{+}e^{-} >Z_{c}(3885)^{0}pi^{0},Z_{c}(3885)^{0}->DD[over -]^{*}]=[77+/-13(stat)+/ 17(syst)] pb at 4.226 GeV and [47+/-9(stat)+/-10(syst)] pb at 4.257 GeV. The ratio of decay rates B[Z_{c}(3885)^{0}->D^{+}D^{*-}+c.c.]/B[Z_{c}(3885)^{0} >D^{0}D[over -]^{*0}+c.c.] is determined to be 0.96+/-0.18(stat)+/-0.12(syst), consistent with no isospin violation in the process, Z_{c}(3885)^{0}->DD[over ]^{*}. PMID- 26650318 TI - Alignment of Copolymer Morphology by Planar Step Elongation during Spinodal Self Assembly. AB - Using simulation and numerical self-consistent field theory of an unentangled diblock copolymer melt, we study the interplay between relaxation of molecular conformations from a highly stretched, nonequilibrium state and structure formation of the local, conserved density during self-assembly from a disordered state. We observe that the planar elongation of molecular conformations in the initial, disordered state results in an alignment of lamella normals perpendicular to the stretch direction during the subsequent self-assembly. Although thermodynamically the parallel orientation is favored, the alignment of the lamella normal perpendicular to the stretch direction is characterized by the larger growth rate of composition fluctuations during the spinodal ordering process. PMID- 26650319 TI - Short-Time Glassy Dynamics in Viscous Protein Solutions with Competing Interactions. AB - The glass transition of colloidal dispersions interacting with both a short ranged attraction and long-ranged repulsion is studied using highly purified lysozyme solutions. Newtonian liquid behavior is observed at all conditions while measurements of the dynamics in the short-time limit show features typical of glassy colloidal systems at high protein concentrations. This interesting behavior is due to the competition of the attraction and repulsion that produces a heterogeneous microstructure only at intermediate range length scales. The results demonstrate that theories for the macroscopic properties of systems with competing interactions need to include intermediate range order. PMID- 26650320 TI - Topological Constraints in Directed Polymer Melts. AB - Polymers in a melt may be subject to topological constraints, as in the example of unlinked polymer rings. How to do statistical mechanics in the presence of such constraints remains a fundamental open problem. We study the effect of topological constraints on a melt of directed polymers, using simulations of a simple quasi-2D model. We find that fixing the global topology of the melt to be trivial changes the polymer conformations drastically. Polymers of length L wander in the transverse direction only by a distance of order (lnL)^{zeta} with zeta?1.5. This is strongly suppressed in comparison with the Brownian L^{1/2} scaling which holds in the absence of the topological constraint. It is also much smaller than the predictions of standard heuristic approaches-in particular the L^{1/4} of a mean-field-like "array of obstacles" model-so our results present a sharp challenge to theory. Dynamics are also strongly affected by the constraints, and a tagged monomer in an infinite system performs logarithmically slow subdiffusion in the transverse direction. To cast light on the suppression of the strands' wandering, we analyze the topological complexity of subregions of the melt: the complexity is also logarithmically small, and is related to the wandering by a power law. We comment on insights the results give for 3D melts, directed and nondirected. PMID- 26650321 TI - Hydrodynamic and Contact Contributions to Continuous Shear Thickening in Colloidal Suspensions. AB - Shear thickening is a widespread phenomenon in suspension flow that, despite sustained study, is still the subject of much debate. The longstanding view that shear thickening is due to hydrodynamic clusters has been challenged by recent theory and simulations suggesting that contact forces dominate, not only in discontinuous, but also in continuous shear thickening. Here, we settle this dispute using shear reversal experiments on micron-sized silica and latex particles to measure directly the hydrodynamic and contact force contributions to shear thickening. We find that contact forces dominate even continuous shear thickening. Computer simulations show that these forces most likely arise from frictional interactions. PMID- 26650322 TI - Reproductive outcome in pregnant women with recurrent pregnancy loss. AB - PURPOSE: To estimate the future pregnancy success rate in women with a history of recurrent pregnancy loss. METHODS: A retrospective cohort study including 103 women seen at a clinic for recurrent pregnancy loss (loss group) between January 2006 and December 2010 and a control group including 204 pregnant women seen at a low-risk prenatal care unit between May 2007 and April 2008. Both groups were seen in the university teaching hospital the Maternidade Climerio de Oliveira, Salvador, Bahia, Brazil. Reproductive success rate was defined as an alive-birth, independent of gestational age at birth and survival after the neonatal period. Continuous variables Means and standard deviations (SD) were compared using Student's t-test and nominal variables proportions by Pearson chi2test. RESULTS: Out of 90 who conceived, 83 (91.2%) had reproductive success rate. There were more full-term pregnancies in the control than in the loss group (174/187; 92.1 versus 51/90; 56.7%; p<0.01). The prenatal visits number was satisfactory for 76 (85.4%) women in the loss group and 125 (61.3%) in the control (p<0.01). In this, the beginning of prenatal care was earlier (13.3; 4.2 versus 19.6; 6.9 weeks). During pregnancy, the loss group women increased the weight more than those in the control group (58.1 versus 46.6%; p=0.04). Although cervix cerclage was performed in 32/90 women in the loss group, the pregnancy duration mean was smaller (34.8 weeks; SD=5.6 versus 39.3 weeks; SD=1.6; p<0.01) than in the control group. Due to gestational complications, cesarean delivery predominated in the loss group (55/83; 64.7 versus 73/183; 39.5%; p<0.01). CONCLUSION: A very good reproductive success rate can be attributed to greater availability of healthcare services to receive pregnant women, through prenatal visits (scheduled or not), cervical cerclage performed on time, and available hospital care for the mother and newborn. PMID- 26650323 TI - Psychiatric Journals in China. PMID- 26650324 TI - Dr. Kent Replies. PMID- 26650325 TI - Psychiatrist on the Road: Encounters in Healing and Healthcareby Climo Lawrence H. . Point Richmond, Calif. Bay Tree Publishing , 2009 , 208 pp., $18.00. PMID- 26650330 TI - APA Council Reports. PMID- 26650327 TI - Cognitive Dysfunction in Bipolar Disorder: A Guide for Cliniciansedited by Goldberg Joseph F. and Burdick Katherine E. . Foreword by Goodwin Frederick K. . Washington, D.C. American Psychiatric Publishing, Inc. , 2008 , 316 pp., $45.00. PMID- 26650332 TI - Review of the Experience with Re-Operation After Laparoscopic Nissen Fundoplication. AB - INTRODUCTION: The risk of redo fundoplication has been demonstrated to be significantly higher in patients of younger age, those with ongoing retching, and those who underwent more extensive dissection of the esophageal hiatus at the initial operation. The purpose of this study was to review the management and outcomes of patients who required one or more re-operations for recurrence after laparoscopic fundoplication. MATERIALS AND METHODS: After obtaining Institutional Review Board approval, we performed a retrospective review of all patients who underwent laparoscopic Nissen fundoplication from 2000 to 2013 and subsequently required a redo operation for recurrence. Patient demographics, neurologic impairment, interval time between re-operations, operative approach, use of mesh, and length of follow-up were analyzed. Two-tailed independent Student's t test was used to compare continuous variables, and two-tailed chi-squared test with Yates's correction (Fisher's exact test where appropriate) was used for discrete variables. RESULTS: Eighty-two patients (10.3% of the sample) required re operation during the study period. The mean age at initial surgery was 1.8 +/- 3.6 years. Fifteen patients (18.3%) required more than one re-operation. Of the 102 re-operations performed, 68 were successfully managed laparoscopically, 3 required conversion to an open procedure, and 31 were performed open from the outset. Of those patients requiring more than one re-operation, there was no difference in age, weight, use of mesh, or time to subsequent re-operations compared with patients that only required one redo fundoplication. CONCLUSIONS: The incidence of patients requiring another operation after a redo operation after an initial laparoscopic fundoplication is 18%. Patient demographics and time to re-operation have not been found to be predictive of which patient will require multiple re-operations for recurrence. However, younger patients and those with a shorter time to re-operation may increase the likelihood of failure. PMID- 26650333 TI - The safety of drug treatments for cervical cancer. AB - INTRODUCTION: The treatment of some early-stage and most locally advanced disease cervical cancer patients consists of concurrent chemoradiation, while almost all with advanced disease require palliative chemotherapy. AREAS COVERED: This review is aimed to analyze the safety issues emerging from trials of chemoradiation for early-stage high-risk disease and locally advanced stages, as well as safety issues of trials of palliative chemotherapy for advanced disease. Safety issues on fertility preservation are also discussed. EXPERT OPINION: Cisplatin chemoradiation produces higher toxicity as compared to radiation alone, yet it is well-tolerated. Further advances would require (i) the development of more effective and tolerated combination chemoradiation regimens, (ii) demonstration of the efficacy and tolerability of adjuvant chemotherapy after cisplatin chemoradiation, and (iii) incorporation of targeted therapies into radiosensitizing regimens. A major problem continues to be the population of patients with advanced disease. The recent incorporation of bevacizumab into chemotherapy regimens represents a step forward; however, toxicity as well as economic issues may impede its wide acceptance worldwide. Preserving fertility in young women with cervical cancer is an issue that must be fully addressed. In this setting, neoadjuvant chemotherapy seems to increase fertlity rate without compromising oncological outcomes. PMID- 26650334 TI - Metagenomic Assembly Reveals Hosts of Antibiotic Resistance Genes and the Shared Resistome in Pig, Chicken, and Human Feces. AB - The risk associated with antibiotic resistance disseminating from animal and human feces is an urgent public issue. In the present study, we sought to establish a pipeline for annotating antibiotic resistance genes (ARGs) based on metagenomic assembly to investigate ARGs and their co-occurrence with associated genetic elements. Genetic elements found on the assembled genomic fragments include mobile genetic elements (MGEs) and metal resistance genes (MRGs). We then explored the hosts of these resistance genes and the shared resistome of pig, chicken and human fecal samples. High levels of tetracycline, multidrug, erythromycin, and aminoglycoside resistance genes were discovered in these fecal samples. In particular, significantly high level of ARGs (7762 */Gb) was detected in adult chicken feces, indicating higher ARG contamination level than other fecal samples. Many ARGs arrangements (e.g., macA-macB and tetA-tetR) were discovered shared by chicken, pig and human feces. In addition, MGEs such as the aadA5-dfrA17-carrying class 1 integron were identified on an assembled scaffold of chicken feces, and are carried by human pathogens. Differential coverage binning analysis revealed significant ARG enrichment in adult chicken feces. A draft genome, annotated as multidrug resistant Escherichia coli, was retrieved from chicken feces metagenomes and was determined to carry diverse ARGs (multidrug, acriflavine, and macrolide). The present study demonstrates the determination of ARG hosts and the shared resistome from metagenomic data sets and successfully establishes the relationship between ARGs, hosts, and environments. This ARG annotation pipeline based on metagenomic assembly will help to bridge the knowledge gaps regarding ARG-associated genes and ARG hosts with metagenomic data sets. Moreover, this pipeline will facilitate the evaluation of environmental risks in the genetic context of ARGs. PMID- 26650335 TI - Space-time clustering of childhood cancers in Switzerland: A nationwide study. AB - The aetiology of childhood cancers remains largely unknown. It has been hypothesized that infections may be involved and that mini-epidemics thereof could result in space-time clustering of incident cases. Most previous studies support spatio-temporal clustering for leukaemia, while results for other diagnostic groups remain mixed. Few studies have corrected for uneven regional population shifts which can lead to spurious detection of clustering. We examined whether there is space-time clustering of childhood cancers in Switzerland identifying cases diagnosed at age <16 years between 1985 and 2010 from the Swiss Childhood Cancer Registry. Knox tests were performed on geocoded residence at birth and diagnosis separately for leukaemia, acute lymphoid leukaemia (ALL), lymphomas, tumours of the central nervous system, neuroblastomas and soft tissue sarcomas. We used Baker's Max statistic to correct for multiple testing and randomly sampled time-, sex- and age-matched controls from the resident population to correct for uneven regional population shifts. We observed space time clustering of childhood leukaemia at birth (Baker's Max p = 0.045) but not at diagnosis (p = 0.98). Clustering was strongest for a spatial lag of <1 km and a temporal lag of <2 years (Observed/expected close pairs: 124/98; p Knox test = 0.003). A similar clustering pattern was observed for ALL though overall evidence was weaker (Baker's Max p = 0.13). Little evidence of clustering was found for other diagnostic groups (p > 0.2). Our study suggests that childhood leukaemia tends to cluster in space-time due to an etiologic factor present in early life. PMID- 26650336 TI - Validation of a Method to Identify Immunocompromised Patients with Severe Sepsis in Administrative Databases. AB - RATIONALE: Immunocompromised patients are at high risk for developing severe sepsis. Currently, there are no validated strategies for identifying this group of patients in large administrative databases. OBJECTIVES: We set out to define and validate a method that could be used to identify immunocompromised patients with severe sepsis in administrative databases. METHODS: Patients were categorized as immunocompromised based on the presence of International Classification of Diseases, 9th revision discharge diagnosis codes and medication data. We validated this strategy by comparing the discriminatory ability of the search algorithm to that of manual chart review. MEASUREMENTS AND MAIN RESULTS: We identified 4,438 patients at a single academic center with severe sepsis using a definition applied to administrative data described by Angus and colleagues. There were 1,185 (26.7%) who were categorized as immunocompromised based on our novel administrative data search strategy. Compared with identification by medical record review, the new administrative data search strategy had positive and negative predictive values of 94.4% (95% confidence interval [CI], 88.8 97.7%) and 94.3% (95% CI, 91.0-96.6%). The sensitivity and specificity were 87.4% (95% CI, 80.6-92.5%) and 97.6% (95% CI, 95.0-99.9%). CONCLUSIONS: Patients who are immunosuppressed are a large subgroup of those with severe sepsis. Following its validation as a search strategy using other large databases, and its adaptation for International Classification of Diseases, 10th revision, this novel method may allow researchers to account for a patient's immune state when examining outcomes. PMID- 26650337 TI - Thinking About a Task Is Associated with Increased Connectivity in Regions Activated by Task Performance. AB - We investigated whether functional neuroimaging of quiet "rest" can reveal the neural correlates of conscious thought. Using resting-state functional MRI, we measured functional connectivity during a resting scan that immediately followed performance of a finger tapping motor sequence task. Self-reports of the amount of time spent thinking about the task during the resting scan correlated with connectivity between regions of the motor network activated during task performance. Thus, thinking about a task is associated with coordinated activity in brain regions responsible for that task's performance. More generally, this study demonstrates the feasibility of using the combination of functional connectivity MRI and self-reports to examine the neural correlates of thought. PMID- 26650338 TI - Video-Based Surgical Coaching: An Emerging Approach to Performance Improvement. PMID- 26650339 TI - Nurse Burnout, Nurse-Reported Quality of Care, and Patient Outcomes in Thai Hospitals. AB - PURPOSE: The purpose of this study was to investigate the effect of nurse burnout on nurse-reported quality of care and patient adverse events and outcomes in Thai hospitals. METHODS: Cross-sectional analysis of data from 2,084 registered nurses working in 94 community hospitals across Thailand. Data were collected through survey questionnaire, including the Maslach Burnout Inventory (MBI), which measures of nurse perceived quality of care and patient outcomes. Multiple logistic regression modeling was performed to explore associations between nurse burnout on quality of care and patient outcomes. FINDINGS: Thirty-two percent of nurses reported high emotional exhaustion, 18% high depersonalization, and 35% low personal accomplishment. In addition, 16% of nurses rated quality of care on their work unit as fair or poor, 5% reported patient falls, 11% reported medication errors, and 14% reported infections. All three subscales of the MBI were associated with increased reporting of fair or poor quality of care, patient falls, medication errors, and infections. Every unit of increasing emotional exhaustion score was associated with a 2.63 times rise in reporting fair or poor quality of care, a 30% increase in patient falls, a 47% increase in medication errors, and a 32% increase in infection. CONCLUSIONS: Findings clearly indicate that nurse burnout is associated with increased odds of reporting negative patient outcomes. Implementing interventions to reduce nurse burnout is critical to improving patient care in Thai hospitals. CLINICAL RELEVANCE: Hospital administrators, nurse managers, and health leaders urgently need to create favorable work environments supporting nursing practice in order to reduce burnout and improve quality of care. PMID- 26650340 TI - Characterization of the transcriptome and gene expression of four different tissues in the ecologically relevant sea urchin Arbacia lixula using RNA-seq. AB - The sea urchin Arbacia lixula is a keystone species in Mediterranean ecosystems that drive landscape changes in littoral communities. However, genomic information available for the whole order Arbacioida is very limited. Using RNA seq techniques, we have characterized the transcriptome of four different tissue types in A. lixula: the 'somatic' tissues (coelomocytes and digestive tissue) and the 'reproductive' tissues (ovary and testis), from two replicated cDNA libraries for each sample. Additionally, we performed a de novo assembly to build the 'reference' transcriptome, pooling reads of the four tissues, to analyse the differential expression (DE) in pairwise comparisons between tissues. The complete de novo assembly yielded 186,084 transcripts, with a sequence size limit of 100 nt, being 31% of them spliced isoforms. Approximately 21% of the transcripts had blast hits against proteins of metazoans (E < 10(-5) ), being less than 2.2% functionally annotated. Between coelomocytes and digestive, 30,794 transcripts showed DE (~11.8% of them with blast hit), and 19,567 transcripts did so between testis and ovary (~28.5% of them with blast hit). Major GO-term categories upregulated in somatic tissues were those related to muscle contraction and energy generation in digestive, and lipid metabolism associated with immune response in coelomocytes. Between reproductive tissues, the major upregulated GO categories were related to energy generation in testis, and negative regulation of nucleotide metabolism in ovary. We particularly screened for a collection of target genes in each tissue because of their relevance for further studies on evolution and adaptation of echinoids. PMID- 26650341 TI - The Bioluminescence Resonance Energy Transfer from Firefly Luciferase to a Synthetic Dye and its Application for the Rapid Homogeneous Immunoassay of Progesterone. AB - The sensitive BRET system for the homogeneous immunoassay of a low-molecular weight antigen was developed using progesterone as an example. Two thermostable mutants of the Luciola mingrelica firefly luciferase (Luc)-the "red" mutant with lambdamax.em = 590 nm (RedLuc) and the "green" mutant with lambdamax.em = 550 nm (GreenLuc)-were tested as the donors. The water-soluble Alexa Fluor 610* (AF) dye was selected as the acceptor because its two absorption maxima, located at 550 and 610 nm, are close to the bioluminescence maxima of the GreenLuc and RedLuc, respectively. The methods for the synthesis of the luciferase-progesterone (Luc Pg) conjugate and the conjugate of the dye and the polyclonal antiprogesterone antibody (AF-Ab) were developed. Both conjugates retained their functional properties, had high antigen-antibody binding activity, and demonstrated a high BRET signal. The homogeneous immunoassay system based on the BRET from the firefly luciferase to the synthetic dye was established to assay progesterone as a model antigen. Optimization of the assay conditions, the composition of the reaction mixture, and the concentrations of the donor and the acceptor made it possible to reach the minimum detectable progesterone concentration of 0.5 ng mL( 1) . PMID- 26650342 TI - Growth references for Japanese individuals with Noonan syndrome. AB - BACKGROUND: Noonan syndrome (NS) is a clinically and genetically heterogeneous syndrome characterized by distinctive facial features, short stature, congenital heart diseases, and other comorbidities. NS-specific growth charts are essential for NS care, but currently no such charts are available for Asian populations. METHODS: We conducted a nationwide survey by collaborating with three academic societies in Japan. We obtained the data of 356 clinically diagnosed NS subjects from 20 hospitals. The Lambda-Mu-Sigma method was used for establishing growth charts. RESULTS: A total of 308 subjects (males: 159 and females: 149) were analyzed after excluding 48 subjects because of missing auxological data (26 subjects), presence of complications affecting growth (5 subjects), and extreme longitudinal growth aberrations which lay more than three standard deviation scores from the mean in this population (17 subjects). Genetic analyses were performed in 150 patients (48.7%); 103 (68.7%) were reported to have some abnormalities in the known causative genes. Cardiovascular diseases were found in 256 patients (83.1%). The NS-specific height, weight, and BMI charts were constructed with 3,249 mixed longitudinal and cross-sectional measurements. CONCLUSION: Growth standards for Japanese individuals with NS were established. These charts are expected to be used in various clinical settings. PMID- 26650344 TI - Special article: 2014 Pediatric Clinical Trials Forum. AB - In November 2014, the American Academy of Pediatrics convened key stakeholders to discuss the feasibility of accelerating children's medical advances by creating an independent global Pediatric Clinical Trials Network. The Forum identified challenges posed by the U.S. and global clinical trial systems regarding testing and disseminating drugs and devices for pediatric patients. Stakeholders mapped a vision to improve the safety and efficacy of pediatric drugs, biological products, and medical devices by creating a global Pediatric Clinical Trials Network. Such a Network would act as a central infrastructure for pediatric subspecialties and enable dedicated staff to provide clinical research sites with scientific, medical, and operational support. A Network would facilitate development and availability of innovative, high-quality therapies to extend and enhance the lives of neonates, infants, children, adolescents, and young adults. Participants expressed strong interest in forming such a Network, since drugs and devices still come to market without adequate pediatric indications-particularly in neonatology and rare diseases. Participants developed a Consensus Statement expressing their shared vision for a Network: Attendees of the Pediatric Clinical Trials Stakeholder Forum resolved to establish a Global Pediatric Clinical Trials Network and are committed to engage in the work to create and sustain it. PMID- 26650343 TI - Inverse association between maternal 25OHD level and cord GLP-1/GIP concentrations. AB - BACKGROUND: Because vitamin D may have beneficial effects on glucose metabolism in pregnant women with gestational diabetes mellitus, we explored whether maternal 25-hydroxyvitamin D (25OHD) levels in normal pregnancy have association with diabetes-related hormone levels and glycated albumin (GA). METHODS: A prospective cohort study was performed to collect serum samples from 612 pairs of pregnant women and cord blood of their offspring. Levels of 25OHD and GA in maternal and cord blood were measured by radioimmunoassay and enzyme assay, respectively. Using cord serum, 12 diabetes-related hormones were assayed. Spearman's rank correlation coefficient was used to quantify the strength of association between biomarkers. RESULTS: A prominent association between maternal and cord 25OHD levels (r = 0.76, 95% confidence intervals (CIs): 0.73-0.79, P < 0.0001) and weak association between maternal and cord GA (r = 0.22, 95% CIs: 0.14-0.30, P < 0.0001) were shown. Among the 12 diabetes-related hormones, both maternal and cord 25OHD levels showed prominent negative associations with glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). CONCLUSIONS: These results suggest that decreased maternal 25OHD may be associated with decreased cord 25OHD and increased cord GLP-1 and GIP levels, which may be involved with the transfer of maternal glucose to the fetus. PMID- 26650345 TI - Three-spined stickleback Gasterosteus aculeatus, as a possible paratenic host for salmonid nematodes in a subarctic lake. AB - In Takvatn, a subarctic lake in northern Norway, 35 of 162 three-spined sticklebacks examined were infected with 106 specimens of third-stage larvae of Philonema oncorhynchi. The prevalence and mean intensity of P. oncorhynchi were 10 % and 2.0 in 2013 and 24 % and 3.0 in 2014, respectively. A single specimen of Cystidicola farionis was found in an additional sample. While the latter is considered an accidental infection, three-spined sticklebacks may function as paratenic hosts of P. oncorhynchi, potentially enhancing its transmission to salmonids due to their central role in the lacustrine food web of this subarctic lake. PMID- 26650346 TI - Hydrolytically Stable Thiol-ene Networks for Flexible Bioelectronics. AB - Hydrolytically stable, tunable modulus polymer networks are demonstrated to survive harsh alkaline environments and offer promise for use in long-term implantable bioelectronic medicines known as electroceuticals. Today's polymer networks (such as polyimides or polysiloxanes) succeed in providing either stiff or soft substrates for bioelectronics devices; however, the capability to significantly tune the modulus of such materials is lacking. Within the space of materials with easily modified elastic moduli, thiol-ene copolymers are a subset of materials that offer a promising solution to build next generation flexible bioelectronics but have typically been susceptible to hydrolytic degradation chronically. In this inquiry, we demonstrate a materials space capable of tuning the substrate modulus and explore the mechanical behavior of such networks. Furthermore, we fabricate an array of microelectrodes that can withstand accelerated aging environments shown to destroy conventional flexible bioelectronics. PMID- 26650347 TI - Fast assessment of structural models of ion channels based on their predicted current-voltage characteristics. AB - Computational prediction of protein structures is a difficult task, which involves fast and accurate evaluation of candidate model structures. We propose to enhance single-model quality assessment with a functionality evaluation phase for proteins whose quantitative functional characteristics are known. In particular, this idea can be applied to evaluation of structural models of ion channels, whose main function - conducting ions - can be quantitatively measured with the patch-clamp technique providing the current-voltage characteristics. The study was performed on a set of KcsA channel models obtained from complete and incomplete contact maps. A fast continuous electrodiffusion model was used for calculating the current-voltage characteristics of structural models. We found that the computed charge selectivity and total current were sensitive to structural and electrostatic quality of models. In practical terms, we show that evaluating predicted conductance values is an appropriate method to eliminate models with an occluded pore or with multiple erroneously created pores. Moreover, filtering models on the basis of their predicted charge selectivity results in a substantial enrichment of the candidate set in highly accurate models. Tests on three other ion channels indicate that, in addition to being a proof of the concept, our function-oriented single-model quality assessment method can be directly applied to evaluation of structural models of some classes of protein channels. Finally, our work raises an important question whether a computational validation of functionality should be included in the evaluation process of structural models, whenever possible. PMID- 26650348 TI - An outstanding Journal requires exceptional reviewers. PMID- 26650350 TI - Transiently Responsive Block Copolymer Micelles Based on N-(2 Hydroxypropyl)methacrylamide Engineered with Hydrolyzable Ethylcarbonate Side Chains. AB - The lack of selectivity and low solubility of many chemotherapeutics impels the development of different biocompatible nanosized drug carriers. Amphiphilic block copolymers, composed of a hydrophilic and hydrophobic domain, show great potential because of their small size, large solubilizing power and loading capacity. In this paper, we introduce a new class of degradable temperature responsive block copolymers based on the modification of N-(2 hydroxypropyl)methacrylamide (HPMA) with an ethyl group via a hydrolytically sensitive carbonate ester, polymerized by radical polymerization using a PEG based macroinitiatior. The micellization and temperature-responsive behavior of the PEG-poly(HPMA-EC) block copolymer were investigated by dynamic light scattering (DLS). We observed that the polymer exhibits lower critical solution temperature (LCST) behavior and that above the cloud point (cp) of 17 degrees C the block copolymer self-assembles in micelles with a diameter of 40 nm. Flow cytometry analysis and confocal microscopy show a dose-dependent cellular uptake of the micelles loaded with a hydrophobic dye. The block copolymer nanoparticles were capable of delivering the hydrophobic payload into cancer cells in both 2D and 3D in vitro cultures. The block copolymer has excellent cytocompatibility, whereas loading the particles with the hydrophobic anticancer drug paclitaxel results in a dose-dependent decrease in cell viability. PMID- 26650351 TI - GGGGCC microsatellite RNA is neuritically localized, induces branching defects, and perturbs transport granule function. AB - Microsatellite expansions are the leading cause of numerous neurodegenerative disorders. Here we demonstrate that GGGGCC and CAG microsatellite repeat RNAs associated with C9orf72 in amyotrophic lateral sclerosis/frontotemporal dementia and with polyglutamine diseases, respectively, localize to neuritic granules that undergo active transport into distal neuritic segments. In cultured mammalian spinal cord neurons, the presence of neuritic GGGGCC repeat RNA correlates with neuronal branching defects, and the repeat RNA localizes to granules that label with fragile X mental retardation protein (FMRP), a transport granule component. Using a Drosophila GGGGCC expansion disease model, we characterize dendritic branching defects that are modulated by FMRP and Orb2. The human orthologs of these modifiers are misregulated in induced pluripotent stem cell-differentiated neurons (iPSNs) from GGGGCC expansion carriers. These data suggest that expanded repeat RNAs interact with the messenger RNA transport and translation machinery, causing transport granule dysfunction. This could be a novel mechanism contributing to the neuronal defects associated with C9orf72 and other microsatellite expansion diseases. PMID- 26650352 TI - Extracellular space preservation aids the connectomic analysis of neural circuits. AB - Dense connectomic mapping of neuronal circuits is limited by the time and effort required to analyze 3D electron microscopy (EM) datasets. Algorithms designed to automate image segmentation suffer from substantial error rates and require significant manual error correction. Any improvement in segmentation error rates would therefore directly reduce the time required to analyze 3D EM data. We explored preserving extracellular space (ECS) during chemical tissue fixation to improve the ability to segment neurites and to identify synaptic contacts. ECS preserved tissue is easier to segment using machine learning algorithms, leading to significantly reduced error rates. In addition, we observed that electrical synapses are readily identified in ECS preserved tissue. Finally, we determined that antibodies penetrate deep into ECS preserved tissue with only minimal permeabilization, thereby enabling correlated light microscopy (LM) and EM studies. We conclude that preservation of ECS benefits multiple aspects of the connectomic analysis of neural circuits. PMID- 26650353 TI - Bordetella adenylate cyclase toxin is a unique ligand of the integrin complement receptor 3. AB - Integrins are heterodimeric cell surface adhesion and signaling receptors that are essential for metazoan existence. Some integrins contain an I-domain that is a major ligand binding site. The ligands preferentially engage the active forms of the integrins and trigger signaling cascades that alter numerous cell functions. Here we found that the adenylate cyclase toxin (CyaA), a key virulence factor of the whooping cough agent Bordetella pertussis, preferentially binds an inactive form of the integrin complement receptor 3 (CR3), using a site outside of its I-domain. CyaA binding did not trigger downstream signaling of CR3 in human monocytes and CyaA-catalyzed elevation of cAMP effectively blocked CR3 signaling initiated by a natural ligand. This unprecedented type of integrin ligand interaction distinguishes CyaA from all other known ligands of the I domain-containing integrins and provides a mechanistic insight into the previously observed central role of CyaA in the pathogenesis of B. pertussis. PMID- 26650354 TI - Rate and timing of cortical responses driven by separate sensory channels. AB - The sense of touch comprises multiple sensory channels that each conveys characteristic signals during interactions with objects. These neural signals must then be integrated in such a way that behaviorally relevant information about the objects is preserved. To understand the process of integration, we implement a simple computational model that describes how the responses of neurons in somatosensory cortex-recorded from awake, behaving monkeys-are shaped by the peripheral input, reconstructed using simulations of neuronal populations that reproduce natural spiking responses in the nerve with millisecond precision. First, we find that the strength of cortical responses is driven by one population of nerve fibers (rapidly adapting) whereas the timing of cortical responses is shaped by the other (Pacinian). Second, we show that input from these sensory channels is integrated in an optimal fashion that exploits the disparate response behaviors of different fiber types. PMID- 26650355 TI - Muscle niche-driven Insulin-Notch-Myc cascade reactivates dormant Adult Muscle Precursors in Drosophila. AB - How stem cells specified during development keep their non-differentiated quiescent state, and how they are reactivated, remain poorly understood. Here, we applied a Drosophila model to follow in vivo behavior of adult muscle precursors (AMPs), the transient fruit fly muscle stem cells. We report that emerging AMPs send out thin filopodia that make contact with neighboring muscles. AMPs keep their filopodia-based association with muscles throughout their dormant state but also when they start to proliferate, suggesting that muscles could play a role in AMP reactivation. Indeed, our genetic analyses indicate that muscles send inductive dIlp6 signals that switch the Insulin pathway ON in closely associated AMPs. This leads to the activation of Notch, which regulates AMP proliferation via dMyc. Altogether, we report that Drosophila AMPs display homing behavior to muscle niche and that the niche-driven Insulin-Notch-dMyc cascade plays a key role in setting the activated state of AMPs. PMID- 26650356 TI - A K(+)-selective CNG channel orchestrates Ca(2+) signalling in zebrafish sperm. AB - Calcium in the flagellum controls sperm navigation. In sperm of marine invertebrates and mammals, Ca(2+) signalling has been intensely studied, whereas for fish little is known. In sea urchin sperm, a cyclic nucleotide-gated K(+) channel (CNGK) mediates a cGMP-induced hyperpolarization that evokes Ca(2+) influx. Here, we identify in sperm of the freshwater fish Danio rerio a novel CNGK family member featuring non-canonical properties. It is located in the sperm head rather than the flagellum and is controlled by intracellular pH, but not cyclic nucleotides. Alkalization hyperpolarizes sperm and produces Ca(2+) entry. Ca(2+) induces spinning-like swimming, different from swimming of sperm from other species. The "spinning" mode probably guides sperm into the micropyle, a narrow entrance on the surface of fish eggs. A picture is emerging of sperm channel orthologues that employ different activation mechanisms and serve different functions. The channel inventories probably reflect adaptations to species-specific challenges during fertilization. PMID- 26650357 TI - Precise assembly of complex beta sheet topologies from de novo designed building blocks. AB - Design of complex alpha-beta protein topologies poses a challenge because of the large number of alternative packing arrangements. A similar challenge presumably limited the emergence of large and complex protein topologies in evolution. Here, we demonstrate that protein topologies with six and seven-stranded beta sheets can be designed by insertion of one de novo designed beta sheet containing protein into another such that the two beta sheets are merged to form a single extended sheet, followed by amino acid sequence optimization at the newly formed strand-strand, strand-helix, and helix-helix interfaces. Crystal structures of two such designs closely match the computational design models. Searches for similar structures in the SCOP protein domain database yield only weak matches with different beta sheet connectivities. A similar beta sheet fusion mechanism may have contributed to the emergence of complex beta sheets during natural protein evolution. PMID- 26650374 TI - Effect of Ginkgo Leaf Tablets on the Pharmacokinetics of Amlodipine in Rats. AB - BACKGROUND AND OBJECTIVE: Ginkgo leaf tablet (GLT) is an effective traditional Chinese multi-herbal formula, which is often combined with amlodipine for treating senile hypertension in clinic. The aim of this study was to study the pharmacokinetics of amlodipine after oral administration of amlodipine and GLT and to investigate the potential for pharmacokinetic herb-drug interactions between GLT and amlodipine in rats. METHODS: A liquid chromatography-tandem mass spectrometry (LC-MS/MS) analytical method was developed for quantification of amlodipine in rat plasma. The accuracy, precision, linearity, selectivity and recovery were all within an acceptable range. Male Sprague-Dawley rats were randomly assigned to two groups: amlodipine group and amlodipine + GLT group. Plasma concentrations of amlodipine were determined at the designated time points after oral administration by using the developed LC-MS/MS method, and the main pharmacokinetic parameters were calculated and compared. As ginkgolides A, ginkgolides B, bilobalide, quercetin and kaempferol were the main components of GLT, the effects of these ingredients in GLT on metabolism of amlodipine were further investigated in rat liver microsomes. RESULTS: The pharmacokinetic parameters, maximum plasma concentration (C max), time to reach C max (T max), area under the concentration-time curve (AUC), area under the first moment plasma concentration-time curve (AUMC) and elimination half-life (t 1/2), of amlodipine were significantly increased in amlodipine + GLT group, which suggested that GLT may influence the pharmacokinetic behavior after oral co-administration with amlodipine. Amlodipine is metabolized by cytochrome P450 (CYP) 3A4, so it was speculated that GLT may change the pharmacokinetic parameters of amlodipine through modulating the metabolism of CYP3A4 enzymes. When ginkgolides B, bilobalide, or quercetin and amlodipine were co-incubated in the rat liver microsomes, the metabolic rate of amlodipine was prolonged to 533.1, 216.1 and 407.6 min, respectively, from 73.7 min. CONCLUSIONS: These results suggested that these components in GLT inhibit the metabolism of amlodipine. So it can be speculated that the herb-drug interactions between GLT and amlodipine resulted from inhibiting the metabolism of amlodipine by GLT when they were co administered. PMID- 26650375 TI - Intra-generic and interspecific karyotype patterns of Leptodactylus and Adenomera (Anura, Leptodactylidae) with inclusion of five species from Central Amazonia. AB - The genera Leptodactylus and Adenomera comprise 92 species distributed throughout the Neotropical region. These species have a modal diploid chromosome number 2n = 22. However, chromosome rearrangements are evident in the differentiation of five intra-generic groups in the genus Leptodactylus (L. fuscus, L. latrans, L. marmoratus (formally composed by the species of the genus Adenomera), L. melanonotus, L. pentadactylus), yet it is not clear if there is a karyotype pattern for each group. Aiming to understand the intra-generic and interspecific karyotype patterns of Leptodactylus and Adenomera, cytogenetic analyses were performed in A. andreae, L. macrosternum, L. pentadactylus, L. petersii, and L. riveroi using conventional staining, C-banding, nucleolus organizer region (NOR) and hybridization in situ fluorescent (FISH). The karyotype of Leptodactylus riveroi was described for the first time. Adenomera andreae had 2n = 26, while the remaining species 2n = 22. The NOR was found on pair No. 8 of A. andreae, L. macrosternum, L. pentadactylus, and L. riveroi, whereas L. petersii had it on pairs Nos. 6 and 10. These locations were confirmed by the FISH with 18S rDNA probe, except for pair No. 10 of L. petersii. The C-banding pattern was evident at the centromeres of chromosomes of all species and some interspecific variations were also observed. 2n = 22 was observed in the species of the L. latrans group, as well as in the intra-generic groups L. fuscus and L. pentadactylus; in the L. melanonotus group there were three diploid chromosome numbers 2n = 20, 22 and 24; and a larger variation in 2n was also evident in the L. marmoratus group. PMID- 26650376 TI - Audiometric Thresholds: Stimulus Considerations in Sound Field and Under Earphones. AB - PURPOSE: This study evaluates a new stimulus, FREquency Specific Hearing assessment (FRESH) noise, to obtain hearing thresholds and reviews the potential pitfalls of using narrow band noise. METHOD: Twelve adults with simulated gradually sloping hearing loss and 12 adults with steeply sloping hearing loss participated. Hearing thresholds were measured in sound field and under a supraaural earphone for FRESH noise, warbled tones, and narrowband noise. Pure tone thresholds were also measured under the supraaural earphone. RESULTS: FRESH noise thresholds were similar to pure-tone and warbled-tone thresholds regardless of audiometric configuration. For the group with gradually sloping hearing loss, thresholds obtained with narrowband noise were approximately 4 dB better than those obtained with the other test stimuli. For the group with steeply sloping hearing loss, narrowband noise significantly underestimated hearing thresholds the steeper the hearing loss, the greater the underestimation. CONCLUSIONS: When hearing loss is suspected, FRESH noise is appropriate for accurately determining audiometric thresholds in sound field and under earphones. A wider band, attention-getting stimulus such as narrowband noise can result in thresholds that are inaccurate. Clinical decision making regarding choice of test stimulus is discussed. PMID- 26650377 TI - Evidence of effectiveness of a fracture liaison service to reduce the re-fracture rate. AB - SUMMARY: We assessed the ability of a fracture liaison service (FLS) to directly reduce re-fracture risk. Having a FLS is associated with a ~40% reduction in the 3-year risk of major bone and ~30% of any bone re-fracture. The number needed to treat to prevent a re-fracture is 20. INTRODUCTION: FLS have been promoted as the most effective interventions for secondary fracture prevention, and while there is evidence of increased rate of investigation and treatment at institutions with a FLS, only a few studies have considered fracture outcomes directly. We therefore sought to evaluate the ability of our FLS to reduce re-fracture risk. METHODS: Historical cohort study of all patients >=50 years presenting over a 6 month period with a minimal trauma fracture (MTF) to the emergency departments of a tertiary hospital with a FLS, and one without a FLS. Baseline characteristics, mortality and MTFs over a 3-year follow-up were recorded. RESULTS: Five hundred fifteen patients at the FLS hospital and 416 patients at the non-FLS hospital were studied. Over 3 years, 63/515 (12%) patients at the FLS hospital and 70/416 (17%) at the non-FLS hospital had a MTF. All patients were analysed in an intention-to-treat analysis regardless of whether they were seen in the FLS follow-up clinic. Statistical analysis using Cox proportional hazard models in the presence of a competing risk of death from any cause was used. After adjustment for baseline characteristics, there was a ~30% reduction in rate of any re-fracture at the FLS hospital (hazard ratio (HR) 0.67, confidence interval (CI) 0.47-0.95, p value 0.025) and a ~40% reduction in major re-fractures (hip, spine, femur, pelvis or humerus) (HR 0.59, CI 0.39-0.90, p value 0.013). CONCLUSIONS: We found a ~30% reduction in any re-fractures and a ~40% reduction in major re-fractures at the FLS hospital compared with a similar non-FLS hospital. The number of patients needed to treat to prevent one new fracture over 3 years is 20. PMID- 26650378 TI - Bone matrix mineralization is preserved during early perimenopausal stage in healthy women: a paired biopsy study. AB - Bone matrix mineralization based on quantitative backscatter electron imaging remained unchanged during the first year of menopause in paired transiliac biopsy samples from healthy women. This suggests that the reported early perimenopausal reductions in bone mineral density are caused by factors other than decreases in the degree of mineralization. INTRODUCTION: It is unknown whether perimenopausal loss of bone mass is associated with a drop in bone matrix mineralization. METHODS: For this purpose, we measured the bone mineralization density distribution (BMDD) by quantitative backscatter electron imaging (qBEI) in n = 17 paired transiliac bone biopsy samples at premenopausal baseline and 12 months after last menses (obtained at average ages of 49 +/- 2 and 55 +/- 2 years, respectively) in healthy women. For interpretation of BMDD outcomes, previously measured bone mineral density (BMD) and biochemical and histomorphometric markers of bone turnover were revisited for the present biopsy cohort. RESULTS: Menopause significantly decreased BMD at the lumbar spine (-4.5 %) and femoral neck (-3.8 %), increased the fasting urinary hydroxyproline/creatinine ratio (+60 %, all p < 0.01) and histomorphometric bone formation rate (+25 %, p < 0.05), but affected neither cancellous nor cortical BMDD variables (paired comparison p > 0.05). Mean calcium concentrations of cancellous (Cn.CaMean) and cortical bone (Ct.CaMean) were within normal range (p > 0.05 compared to established reference data). Ct.CaMean was significantly correlated with Cn.CaMean before (R = 0.81, p < 0.001) and after menopause (R = 0.80, p < 0.001) and to cortical porosity of mineralized tissue (Ct.Po.) after menopause (R = -0.57, p = 0.02). CONCLUSIONS: Surprisingly, the BMDD was found not affected by the changes in bone turnover rates in this cohort. This suggests that the substantial increase in bone formation rates took place shortly before the second biopsy, and the bone mineralization changes lag behind. We conclude that during the first year after the last menses, the degree of bone matrix mineralization is preserved and does not contribute to the observed reductions in BMD. PMID- 26650379 TI - Polycythemia is associated with bone loss and reduced osteoblast activity in mice. AB - Increased fragility has been described in humans with polycythemia vera (PV). Herein, we describe an osteoporotic phenotype associated with decreased osteoblast activity in a mouse model of PV and another mouse of polycythemia and elevated circulating erythropoietin (EPO). Our results are important for patients with PV or those treated with recombinant EPO (rEPO). INTRODUCTION: PV and other myeloproliferative syndromes have been recently associated with an increased risk for fractures. However, the presence of osteoporosis in these patients has not been well documented. EPO, a hormone primarily known to stimulate erythropoiesis, has been shown recently to regulate bone homeostasis in mice. The aim of this study was to examine the bone phenotype of a mouse model of PV and compare it to that of animals with polycythemia caused by elevated circulating EPO. METHODS: Bone mass and remodeling were evaluated by micro-computed tomography and histomorphometry. The JAK2(V617F) knock-in mouse, a model of human PV, manifests polycythemia and low circulating EPO levels. Results from this mouse were compared to wild type (wt) controls and the tg6 transgenic mouse that shows polycythemia caused by increased constitutive expression of EPO. RESULTS: Compared to wt, both JAK2(V617F) and tg6 mice had a decrease in trabecular bone mass. Tg6 mice showed an additional modest decrease in cortical thickness and cortical bone volume per tissue volume (P < 0.01) suggesting a more severe bone phenotype than JAK2(V617F). Decreased osteoblast numbers and bone formation along with normal osteoclast numbers and activity were found in both mice. CONCLUSIONS: This study indicates that PV is associated with low bone mass and decreased osteoblast activity in mice. Our results support future studies of osteoporosis in affected humans. Polycythemia caused by chronically elevated circulating EPO also results in bone loss, and implications on patients treated with rEPO should be evaluated. PMID- 26650380 TI - Central and peripheral fat body mass have a protective effect on osteopenia or osteoporosis in adults and elderly? AB - This cross-sectional study involves randomly selected men aged 50 to 99 years and postmenopausal women. Either central fat mass or peripheral fat mass were associated to osteoporosis or osteopenia independently from fat-free body mass and other confounding factors. INTRODUCTION: Obesity and osteoporosis are public health problems that probably share common pathophysiological mechanisms. The question if body fat mass, central or peripheral, is protective or harmful for osteoporosis or osteopenia is not completely resolved. This study aims to investigate the association between osteoporosis or osteopenia, and fat body mass (central and peripheral) independently from fat-free body mass, in men aged 50 to 99 years old and postmenopausal women randomly selected in the community. METHODS: This is a cross-sectional investigation with a random sample of registered population in Niteroi Family Doctor Program (FDP), State of Rio de Janeiro, Brazil. Bone mineral density (BMD) and fat-free mass were assessed by dual X-ray absorptiometry (DXA). RESULTS: There was statistically significant bivariate association between bone loss with gender, age, skin color, alcohol consumption at risk dose, use of thiazide, fat-free body mass, and fat body mass (central and peripheral). In the multiple analysis of fat-free body mass, central and peripheral fat body mass showed an independent and protective effect on the presence of osteoporosis or osteopenia (p value <0.001). CONCLUSION: Since both obesity and osteoporosis are public health problems worldwide, strategies aimed at preventing both conditions should be encouraged during aging. PMID- 26650381 TI - Detection of Multiple Resistances, Biofilm Formation and Conjugative Transfer of Bacillus cereus from Contaminated Soils. AB - The purpose of this study was to detect microbial resistances to a set of antibiotics/pesticides (multi-resistance) within pesticide and antibiotic contaminated alluvial soils and to identify the corresponding antibiotic resistance genes (ARGs). To assess whether identified multi-resistant isolates are able to construct biofilms, several biofilm formation and conjugation experiments were conducted. Out of 35 isolates, six strains were used for filter mating experiments. Nine strains were identified by 16S rDNA gene sequence analyses and those were closely related to Pseudomonas sp., Citrobacter sp., Acinetobacter sp., Enterobacter sp., and in addition, Bacillus cereus was chosen for multi-resistant and pesticide-tolerant studies. Antibiotic-resistant and pesticide-tolerant bacterial strains were tested for the presence of ARGs. All nine strains were containing multiple ARGs (ampC, ermB, ermD, ermG, mecA, tetM) in different combinations. Interestingly, only strain WR34 (strongly related to Bacillus cereus) exhibited a high biofilm forming capacity on glass beads. Results obtained by filter mating experiments demonstrated gene transfer frequencies from 10(-5) to 10(-8). This study provides evidence that alluvial soils are hot spots for the accumulation of antibiotics, pesticides and biofilm formation. Particularly high resistances to tetracycline, ampicillin, amoxicillin and methicillin were proved. Apparently, isolate WR34 strongly correlated to a pathogenic organism had high potential to deploy biofilms in alluvial soils. Thus, we assume that loosened and unconsolidated soils investigated pose a high risk of an enhanced ARG prevalence. PMID- 26650382 TI - Action Tweets Linked to Reduced County-Level HIV Prevalence in the United States: Online Messages and Structural Determinants. AB - HIV is uncommon in most US counties but travels quickly through vulnerable communities when it strikes. Tracking behavior through social media may provide an unobtrusive, naturalistic means of predicting HIV outbreaks and understanding the behavioral and psychological factors that increase communities' risk. General action goals, or the motivation to engage in cognitive and motor activity, may support protective health behavior (e.g., using condoms) or encourage activity indiscriminately (e.g., risky sex), resulting in mixed health effects. We explored these opposing hypotheses by regressing county-level HIV prevalence on action language (e.g., work, plan) in over 150 million tweets mapped to US counties. Controlling for demographic and structural predictors of HIV, more active language was associated with lower HIV rates. By leveraging language used on social media to improve existing predictive models of geographic variation in HIV, future targeted HIV-prevention interventions may have a better chance of reaching high-risk communities before outbreaks occur. PMID- 26650383 TI - HIV-Related Stigma Among Healthcare Providers in the Deep South. AB - Stigma towards people living with HIV (PLWH) in healthcare settings is a barrier to optimal treatment. However, our understanding of attitudes towards PLWH from healthcare providers' perspective in the United States is limited and out-of date. We assessed HIV-related stigma among healthcare staff in Alabama and Mississippi, using online questionnaires. Participants included 651 health workers (60 % White race; 83 % female). Multivariate regression suggests that several factors independently predict stigmatizing attitudes: Protestant compared to other religions (beta = 0.129, p <= 0.05), White race compared to other races (beta = 0.162, p <= 0.001), type of clinic (HIV/STI clinic: beta = 0.112, p <= 0.01), availability of post-exposure prophylaxis (yes: beta = -0.107, p <= 0.05), and perceptions of policy enforcement (policies not enforced: beta = 0.058, p = p <= 0.05). These findings may assist providers wishing to improve the quality care for PLWH. Enforcement of policies prohibiting discrimination may be a useful strategy for reducing HIV-related stigma among healthcare workers. PMID- 26650384 TI - Stevia rebaudiana Leaves: Effect of Drying Process Temperature on Bioactive Components, Antioxidant Capacity and Natural Sweeteners. AB - Stevia leaves are usually used in dried state and undergo the inevitable effect of drying process that changes the quality characteristics of the final product. The aim of this study was to assess temperature effect on Stevia leaves through analysis of relevant bioactive components, antioxidant capacity and content of natural sweeteners and minerals. The drying process was performed in a convective dryer at constant temperatures ranging from 30 to 80 degrees C. Vitamin C was determined in the leaves and as expected showed a decrease during drying proportional to temperature. Phenolics and flavonoids were also determined and were found to increase during drying below 50 degrees C. Antioxidant activity was determined by DPPH and ORAC assays, and the latter showed the highest value at 40 degrees C, with a better correlation with the phenolics and flavonoids content. The content of eight natural sweeteners found in Stevia leaves was also determined and an increase in the content of seven of the sweeteners, excluding steviol bioside, was found at drying temperature up to 50 degrees C. At temperatures between 60 and 80 degrees C the increase in sweeteners content was not significant. Stevia leaves proved to be an excellent source of antioxidants and natural sweeteners. PMID- 26650385 TI - HCMV Induces Macropinocytosis for Host Cell Entry in Fibroblasts. AB - Human cytomegalovirus (HCMV) is an important and widespread pathogen in the human population. While infection by this beta-herpesvirus in endothelial, epithelial and dendritic cells depends on endocytosis, its entry into fibroblasts is thought to occur by direct fusion of the viral envelope with the plasma membrane. To characterize individual steps during entry in primary human fibroblasts, we employed quantitative assays as well as electron, fluorescence and live cell microscopy in combination with a variety of inhibitory compounds. Our results showed that while infectious entry was pH- and clathrin-independent, it required multiple, endocytosis-related factors and processes. The virions were found to undergo rapid internalization into large vacuoles containing internalized fluid and endosome markers. The characteristics of the internalization process fulfilled major criteria for macropinocytosis. Moreover, we found that soon after addition to fibroblasts the virus rapidly triggered the formation of circular dorsal ruffles in the host cell followed by the generation of large macropinocytic vacuoles. This distinctive form of macropinocytosis has been observed especially in primary cells but has not previously been reported in response to virus stimulation. PMID- 26650387 TI - Scaling Rules for Vibrational Energy Transport in Globular Proteins. AB - Computational studies of vibrational energy flow in biomolecules have to date mapped out transport pathways on a case-by-case basis. To provide a more general approach, we derive scaling rules for vibrational energy transport in a globular protein, which are identified from extensive nonequilibrium molecular dynamics simulations of vibrational energy flow in the villin headpiece subdomain HP36. We parametrize a master equation based on inter-residue, residue-solvent, and heater residue energy-transfer rates, which closely reproduces the results of the all atom simulations. From that fit, two scaling rules emerge, one for energy transport along the protein backbone which relies on a diffusion model and another for energy transport between tertiary contacts, which is based on a harmonic model. Requiring only the calculation of mean and variance of relatively few atomic distances, the approach holds the potential to predict the pathways and time scales of vibrational energy flow in large proteins. PMID- 26650386 TI - Towards Prebiotic Catalytic Amyloids Using High Throughput Screening. AB - Enzymes are capable of directing complex stereospecific transformations and of accelerating reaction rates many orders of magnitude. As even the simplest known enzymes comprise thousands of atoms, the question arises as to how such exquisite catalysts evolved. A logical predecessor would be shorter peptides, but they lack the defined structure and size that are apparently necessary for enzyme functions. However, some very short peptides are able to assemble into amyloids, thereby forming a well-defined tertiary structure called the cross-beta-sheet, which bestows unique properties upon the peptides. We have hypothesized that amyloids could have been the catalytically active precursor to modern enzymes. To test this hypothesis, we designed an amyloid peptide library that could be screened for catalytic activity. Our approach, amenable to high-throughput methodologies, allowed us to find several peptides and peptide mixtures that form amyloids with esterase activity. These results indicate that amyloids, with their stability in a wide range of conditions and their potential as catalysts with low sequence specificity, would indeed be fitting precursors to modern enzymes. Furthermore, our approach can be efficiently expanded upon in library size, screening conditions, and target activity to yield novel amyloid catalysts with potential applications in aqueous-organic mixtures, at high temperature and in other extreme conditions that could be advantageous for industrial applications. PMID- 26650388 TI - Continuum of Care in a Maternal, Newborn and Child Health Program in Ghana: Low Completion Rate and Multiple Obstacle Factors. AB - BACKGROUND: Slow progress has been made in achieving the Millennium Development Goals 4 and 5 in Ghana. Ensuring continuum of care (at least four antenatal visits; skilled birth attendance; postnatal care within 48 hours, at two weeks, and six weeks) for mother and newborn is crucial in helping Ghana achieve these goals and beyond. This study examined the levels and factors associated with continuum of care (CoC) completion among Ghanaian women aged 15-49. METHODS: A retrospective cross-sectional survey was conducted among women who experienced live births between January 2011 and April 2013 in three regions of Ghana. In a two-stage random sampling method, 1,500 women with infants were selected and interviewed about maternal and newborn service usage in line with CoC. Multiple logistic regression models were used to assess factors associated with CoC completion. RESULTS: Only 8.0% had CoC completion; the greatest gap and contributor to the low CoC was detected between delivery and postnatal care within 48 hours postpartum. About 95% of women had a minimum of four antenatal visits and postnatal care at six weeks postpartum. A total of 75% had skilled assisted delivery and 25% received postnatal care within 48 hours. Factors associated with CoC completion at 95% CI were geographical location (OR = 0.35, CI 0.13-0.39), marital status (OR = 0.45; CI 0.22-0.95), education (OR = 2.71; CI 1.11-6.57), transportation (OR = 1.97; CI 1.07-3.62), and beliefs about childhood illnesses (OR = 0.34; CI0.21-0.61). CONCLUSION: The continuum of care completion rate is low in the study site. Efforts should focus on increasing postnatal care within 48 hours and overcoming the known obstacles to increasing the continuum of care completion rate. PMID- 26650389 TI - Will mania survive DSM-5 and ICD-11? AB - As a natural phenomenon, mania without major depression will of course survive DSM-5 and ICD-11, but following its integration as a diagnosis into bipolar-I disorder (BP-I) in those manuals, BP-I will be more heterogeneous and, paradoxically, will include a unipolar disorder. Furthermore, unipolar mania will no longer be adequately identified and coded as an independent disorder in public health statistics. Mania without major depression, with prevalence rates of 1.7 1.8 %, is even more common than schizophrenia. This brief review of our current, still insufficient, knowledge suggests strongly that pure unipolar mania, as well as mania with minor depressive disorders, should remain important elements of the three-dimensional mood spectrum. Research should focus on dimensional and not on simplified categorical models, which entail a considerable loss of information. PMID- 26650390 TI - Three Different Protocols of Corneal Collagen Crosslinking in Keratoconus: Conventional, Accelerated and Iontophoresis. AB - Keratoconus is a bilateral and progressive corneal ectasia. In order to slow down its progression, corneal collagen cross-linking (CXL) has recently been introduced as an efficient treatment option. In biological and chemical sciences, crosslinking refers to new chemical bonds formed between reactive molecules. Hence, the aim of corneal collagen CXL is to synthetically increase the formation of crosslinks between collagen fibrils in the corneal stroma. Despite the fact that the efficiency of the conventional CXL (C-CXL) protocol has already been shown in several clinical studies, it might benefit from improvements in duration of the procedure and removal of corneal epithelium. Hence, in order to provide a coherent evaluation of two new and optimized CXL protocols, we studied keratoconus patients who had undergone one of the three CXL treatments: iontophoresis (I-CXL), accelerated CXL (A-CXL), and conventional CXL (C-CXL). A CXL is a 6 time faster CXL procedure using a ten time higher UVA irradiance but still including an epithelium removal. Iontophoresis is a transepithelial non invasive technique in which a small electric current is applied to improve riboflavin penetration throughout the cornea. Using anterior segment optical coherence tomography (AS OCT) and in vivo confocal microscopy (IVCM), we conclude that regarding the depth of treatment penetration, conventional CXL protocol remains the standard for treating progressive keratoconus. Accelerated CXL seems to be a quick, effective and safe alternative to treat thin corneas. The use of iontophoresis is still being investigated and should be considered with greater caution. PMID- 26650392 TI - Measurement of Fronto-limbic Activity Using an Emotional Oddball Task in Children with Familial High Risk for Schizophrenia. AB - Adolescence is a critical developmental period where the early symptoms of schizophrenia frequently emerge. First-degree relatives of people with schizophrenia who are at familial high risk (FHR) may show similar cognitive and emotional changes. However, the neurological changes underlying the emergence of these symptoms remain unclear. This study sought to identify differences in frontal, striatal, and limbic regions in children and adolescents with FHR using functional magnetic resonance imaging. Groups of 21 children and adolescents at FHR and 21 healthy controls completed an emotional oddball task that relied on selective attention and the suppression of task-irrelevant emotional information. The standard oddball task was modified to include aversive and neutral distractors in order to examine potential group differences in both emotional and executive processing. This task was designed specifically to allow for children and adolescents to complete by keeping the difficulty and emotional image content age-appropriate. Furthermore, we demonstrate a technique for suitable fMRI registration for children and adolescent participants. This paradigm may also be applied in future studies to measure changes in neural activity in other populations with hypothesized developmental changes in executive and emotional processing. PMID- 26650394 TI - Exploring Australian health promotion and environmental sustainability initiatives. AB - Issue addressed Health promotion practitioners have important roles in applying ecosystem approaches to health and actively promoting environmental sustainability within community-level practice. The present study identified the nature and scope of health promotion activities across Australia that tackle environmental sustainability. Methods A mixed-method approach was used, with 82 participants undertaking a quantitative survey and 11 undertaking a qualitative interview. Purposeful sampling strategies were used to recruit practitioners who were delivering community-level health promotion and sustainability programs in Australia. The data were analysed thematically and interpretation was guided by the principles of triangulation. Results Study participants were at various stages of linking health promotion and environmental sustainability. Initiatives focused on healthy and sustainable food, active transport, energy efficiency, contact with nature and capacity building. Conclusion Capacity building approaches were perceived as essential to strengthening this field of practice. Healthy and sustainable food and active transport were suitable platforms for simultaneously promoting community health and sustainability. There was potential for expansion of programs that emphasise contact with nature and energy issues, as well as interventions that emphasise systems thinking and interdisciplinary approaches. So what? It was promising that Australian health promotion programs have started to address complexity rather than single issues, as evidenced by explicit engagement with environmental sustainability. However, more effort is required to enable a shift towards ecosystem approaches to health. PMID- 26650395 TI - Corruption and the Other(s): Scope of Superordinate Identity Matters for Corruption Permissibility. AB - The decision to engage in corruption-public and private corruption, nepotism, and embezzlement-is often attributed to rational actors maximizing benefits to themselves. However, the importance of reciprocal relationships in humans suggests that an actor may weigh the costs of harms of her corrupt behavior to individuals who may generate future benefits for her. We hypothesize that actors who have a larger circle of actual and potential social partners will have more individuals to consider when generating harms and will thus be less likely to find corrupt acts permissible than actors with smaller circles of valued others. Using data from the World Values Survey and European Values Study (WVS), we explore whether participants with a larger geographic identity or a greater number of group memberships (i.e. a larger scope of actual and potential social partners) are less likely to find accepting bribes permissible. We find mixed support for our hypotheses, but consistently find that WVS participants with local, country, continent, or world geographic identities are less likely to find accepting a bribe permissible than those with regional identities-that is, actors whose primary identities that encompass more than their region find corruption less permissible. We discuss the importance of considering an actor's valuation of others when modeling corruption persistence, noting that establishing scopes of positive valuation is a precursor to predicting where actors will target benefits and shunt costs. PMID- 26650391 TI - PTX3, a humoral pattern recognition molecule at the interface between microbe and matrix recognition. AB - Innate immunity consists of a cellular and a humoral arm. PTX3 is a fluid patter recognition molecule (PRM) with antibody-like properties. Gene targeted mice and genetic associations in humans suggest that PTX3 plays a non-redundant role in resistance against selected pathogens (e.g. Aspergillus fumigatus, Pseudomonas aeruginosa, uropathogenic Escherichia coli) and in the regulation of inflammation. PTX3 acts as an extrinsic oncosuppressor by taming complement elicited tumor-promoting inflammation. Recent results indicate that, by interacting with provisional matrix components, PTX3 contributes to the orchestration of tissue repair. An acidic pH sets PTX3 in a tissue repair mode, while retaining anti-microbial recognition. Based on these data and scattered information on humoral PRM and matrix components, we surmise that matrix and microbial recognition are related functions in evolution. PMID- 26650396 TI - Merging Visible-Light Photocatalysis and Palladium Catalysis for C-H Acylation of Azo- and Azoxybenzenes with alpha-Keto Acids. AB - An efficient C-H acylation of azo- and azoxybenzenes with alpha-keto acids has been developed by a combination of palladium catalysis and visible-light photoredox catalysis at room temperature under 1.5 W blue LED irradiation. This method tolerates a variety of disubstituted azo- and azoxybenzenes, as well as alpha-keto acids regardless of the nature of the substituents. A number of aryl ketones were obtained in good yields under mild reaction conditions. PMID- 26650393 TI - Gag-Specific CD4 and CD8 T-Cell Proliferation in Adolescents and Young Adults with Perinatally Acquired HIV-1 Infection Is Associated with Ethnicity - The ANRS EP38-IMMIP Study. AB - The ANRS-EP38-IMMIP study aimed to provide a detailed assessment of the immune status of perinatally infected youths living in France. We studied Gag-specific CD4 and CD8 T-cell proliferation and the association between the proliferation of these cells, demographic factors and HIV disease history. We included 93 youths aged between 15 and 24 years who had been perinatally infected with HIV. Sixty nine had undergone valid CFSE-based T-cell proliferation assays. Gag-specific proliferation of CD4 and CD8 T cells was detected in 12 (16%) and 30 (38%) patients, respectively. The Gag-specific proliferation of CD4 and CD8 T cells was more frequently observed in black patients than in patients from other ethnic groups (CD4: 32% vs. 4%, P = 0.001; CD8: 55% vs. 26%, P = 0.02). Among aviremic patients, the duration of viral suppression was shorter in CD8 responders than in CD8 nonresponders (medians: 54 vs. 20 months, P = 0.04). Among viremic patients, CD8 responders had significantly lower plasma HIV RNA levels than CD8 nonresponders (2.7 vs. 3.7 log10 HIV-RNA copies/ml, P = 0.02). In multivariate analyses including sex and HIV-1 subtype as covariables, Gag-specific CD4 T-cell proliferation was associated only with ethnicity, whereas Gag-specific CD8 T-cell proliferation was associated with both ethnicity and the duration of viral suppression. Both CD4 and CD8 responders reached their nadir CD4 T-cell percentages at younger ages than their nonresponder counterparts (6 vs. 8 years, P = 0.04 for both CD4 and CD8 T-cell proliferation). However, these associations were not significant in multivariate analysis. In conclusion, after at least 15 years of HIV infection, Gag-specific T-cell proliferation was found to be more frequent in black youths than in patients of other ethnic groups, despite all the patients being born in the same country, with similar access to care. PMID- 26650397 TI - Topical Administration Is a Promising Inoculating Route versus Intramuscular Inoculation for the Nanoparticle-Carried DNA Vaccine to Prevent Corneal Infections. AB - PURPOSE: To evaluate the comparative effect of topical versus intramuscular administration of nanoparticle-carried DNA vaccine in preventing corneal herpes simplex virus type 1 (HSV-1) infection. METHODS: Nanoparticle [polyethylenimine (PEI)-Fe3O4]-carried DNA vaccine (PEI-Fe3O4-pRSC-gD-IL-21) or DNA vaccine (pRSC gD-IL-21) alone were topically versus intramuscularly inoculated into one eye each of mice on days 0, 14 and 28. Three weeks after the final immunization, the specific immune responses and clinical degrees of primary herpes simplex keratitis were evaluated. RESULTS: Topical inoculation of nanoparticle-carried DNA vaccine induced mice to generate similar levels of specific HSV-1 neutralizing antibody, IFN-gamma and IL-4 in serum and specific killing (cytotoxicity) and proliferative activities of the splenic lymphocytes, but a significantly higher level of secretory IgA in tears compared to those of intramuscular inoculation. More importantly, the mice inoculated topically showed a significantly decreased herpes simplex keratitis severity than the mice inoculated intramuscularly after HSV-1 challenge on the corneas of the mice. CONCLUSIONS: Topical inoculation of nanoparticle-carried DNA vaccine elicits a stronger specific local immune response and more effectively inhibits herpes simplex keratitis as compared to intramuscular inoculation in an HSV-1 ocular challenge mouse model. Thus, topical administration may be a promising inoculating route for the nanoparticle-carried DNA vaccine to prevent corneal infections. PMID- 26650399 TI - Microtubules and Actin Cytoskeleton of Cryptococcus neoformans as Targets for Anticancer Agents to Potentiate a Novel Approach for New Antifungals. AB - BACKGROUND: We investigated the targeting of microtubules (MT) and F-actin cytoskeleton (AC) of the human pathogenic yeast Cryptococcus neoformans with agents for cancer therapy, in order to examine whether this yeast cytoskeleton could become a new antifungal target for the inhibition of cell division. METHODS: Cells treated with 10 cytoskeleton inhibitors in yeast extract peptone dextrose medium were investigated by phase-contrast and fluorescence microscopy, and growth inhibition was estimated by cell counts using a Burker chamber and measuring absorbance for 6 days. RESULTS: Docetaxel, paclitaxel, vinblastine sulfate salt, cytochalasin D and chlorpropham [isopropyl N-(3-chlorophenyl) carbamate] did not inhibit proliferation. The MT inhibitors methyl benzimidazole 2-ylcarbamate (BCM), nocodazole, thiabendazole (TBZ) and vincristine (VINC) disrupted MT and inhibited mitoses, but anucleated buds emerged on cells that increased in size, vacuolated and seemed to die after 2 days. The response of the cells to the presence of the actin inhibitor latrunculin A (LA) included the disappearance of actin patches, actin cables and actin rings; this arrested budding and cell division. However, in 3-4 days, resistant budding cells appeared in all 5 inhibitors. Disruption of the MT and AC and inhibition of cell division and budding persisted only when the MT and AC inhibitors were combined, i.e. VINC + LA, BCM + LA or TBZ + LA. CONCLUSION: The MT and AC of C. neoformans are new antifungal targets for the persistent inhibition of cell division by combined F actin and MT inhibitors. PMID- 26650398 TI - Nature's Palette: Characterization of Shared Pigments in Colorful Avian and Mollusk Shells. AB - Pigment-based coloration is a common trait found in a variety of organisms across the tree of life. For example, calcareous avian eggs are natural structures that vary greatly in color, yet just a handful of tetrapyrrole pigment compounds are responsible for generating this myriad of colors. To fully understand the diversity and constraints shaping nature's palette, it is imperative to characterize the similarities and differences in the types of compounds involved in color production across diverse lineages. Pigment composition was investigated in eggshells of eleven paleognath bird taxa, covering several extinct and extant lineages, and shells of four extant species of mollusks. Birds and mollusks are two distantly related, calcareous shell-building groups, thus characterization of pigments in their calcareous structures would provide insights to whether similar compounds are found in different phyla (Chordata and Mollusca). An ethylenediaminetetraacetic acid (EDTA) extraction protocol was used to analyze the presence and concentration of biliverdin and protoporphyrin, two known and ubiquitous tetrapyrrole avian eggshell pigments, in all avian and molluscan samples. Biliverdin was solely detected in birds, including the colorful eggshells of four tinamou species. In contrast, protoporphyrin was detected in both the eggshells of several avian species and in the shells of all mollusks. These findings support previous hypotheses about the ubiquitous deposition of tetrapyrroles in the eggshells of various bird lineages and provide evidence for its presence also across distantly related animal taxa. PMID- 26650400 TI - A Rat Treated with Mesenchymal Stem Cells Lives to 44 Months of Age. AB - There is a growing interest in the potential of mesenchymal stem cells (MSCs) for implementing regenerative medicine. We assessed the effect of intravenous administration of human bone marrow-derived MSC on the life span of a single Sprague-Dawley female rat. The treatment was started when the rat was 6 months old and the cells were administered every 2 weeks afterward. The treatment did not induce any obvious changes in body growth or behavior and the rat showed the typical age changes for this strain, except that, unlike intact counterparts, the animal did not develop mammary tumors or pituitary gland hyperplasia. The more remarkable effect of the treatment was on life span, which was 44 months compared with an average of 36 months for intact laboratory rats. We conclude that despite the low N value, it is likely that the MSC treatment was responsible for the exceptionally long survival of the rat. The potential rewards of confirming the present findings warrant further studies involving higher N values. PMID- 26650401 TI - Unraveling the origins of conduction band valley degeneracies in Mg2Si(1-x)Sn(x) thermoelectrics. AB - To better understand the thermoelectric efficiency of the Mg-based thermoelectrics, using hybrid density-functional theory, we study the microscopic origins of valley degeneracies in the conduction band of the solid solution Mg2Si(1-x)Sn(x) and its constituent components--namely, Mg2Si and Mg2Sn. In the solid solution of Mg2Si(1-x)Sn(x), the sublattices are expected to undergo either tensile or compressive strain in the light of Vegard's law. Interestingly, we find both tensile strain of Mg2Si and compressive strain of Mg2Sn enhance the conduction band valley degeneracy. We suggest that the optimal sublattice strain as one of the origins of the enhanced Seebeck coefficient in the Mg2Si(1-x)Sn(x) system. In order to visualize the enhanced band valley degeneracy at elevated temperatures, the ground state eigenvalues and weights are projected by convolution functions that account for high temperature effects. Our results provide theoretical evidences for the role of sublattice strain in the band valley degeneracy observed in Mg2Si(1-x)Sn(x). PMID- 26650403 TI - An approach to locate optic disc in retinal images with pathological changes. AB - Automatic optic disc (OD) detection is an essential step for screening of eye diseases. An OD localization method is proposed in this paper, which aims to locate OD robustly in retinal image with pathological changes. There are mainly three steps in this approach: region-of-interest (ROI) detection, candidate pixel detection, and confidence score calculation. The features of vessel direction, intensity, OD edges, and size of bright regions were extracted and employed in the proposed OD locating approach. Compared with the OD locating method based on vessel direction only, the proposed method could handle the following cases better: OD partially appears in retinal image, retinal vessels are not obvious in retinal image, or there are bright lesions in retinal images. Four public databases with total 340 retinal images were tested to evaluate the performance of our method. The proposed method can achieve an accuracy of 100%, 95.8%, 99.2%, 97.8% for DRIVE database, STARE database, DIARETDB0 database, DIARETDB1 database respectively. Comparison studies showed that the proposed approach is especially robust in the retinal images with diseases. PMID- 26650402 TI - Whole Transcriptome Analysis Provides Insights into Molecular Mechanisms for Molting in Litopenaeus vannamei. AB - Molting is one of the most important biological processes in shrimp growth and development. All shrimp undergo cyclic molting periodically to shed and replace their exoskeletons. This process is essential for growth, metamorphosis, and reproduction in shrimp. However, the molecular mechanisms underlying shrimp molting remain poorly understood. In this study, we investigated global expression changes in the transcriptomes of the Pacific white shrimp, Litopenaeus vannamei, the most commonly cultured shrimp species worldwide. The transcriptome of whole L. vannamei was investigated by RNA-sequencing (RNA-seq) throughout the molting cycle, including the inter-molt (C), pre-molt (D0, D1, D2, D3, D4), and post-molt (P1 and P2) stages, and 93,756 unigenes were identified. Among these genes, we identified 5,117 genes differentially expressed (log2ratio >=1 and FDR <=0.001) in adjacent molt stages. The results were compared against the National Center for Biotechnology Information (NCBI) non-redundant protein/nucleotide sequence database, Swiss-Prot, PFAM database, the Gene Ontology database, and the Kyoto Encyclopedia of Genes and Genomes database in order to annotate gene descriptions, associate them with gene ontology terms, and assign them to pathways. The expression patterns for genes involved in several molecular events critical for molting, such as hormone regulation, triggering events, implementation phases, skelemin, immune responses were characterized and considered as mechanisms underlying molting in L. vannamei. Comparisons with transcriptomic analyses in other arthropods were also performed. The characterization of major transcriptional changes in genes involved in the molting cycle provides candidates for future investigation of the molecular mechanisms. The data generated in this study will serve as an important transcriptomic resource for the shrimp research community to facilitate gene and genome annotation and to characterize key molecular processes underlying shrimp development. PMID- 26650404 TI - Assaying Blood Cell Populations of the Drosophila melanogaster Larva. AB - In vertebrates, hematopoiesis is regulated by inductive microenvironments (niches). Likewise, in the invertebrate model organism Drosophila melanogaster, inductive microenvironments known as larval Hematopoietic Pockets (HPs) have been identified as anatomical sites for the development and regulation of blood cells (hemocytes), in particular of the self-renewing macrophage lineage. HPs are segmentally repeated pockets between the epidermis and muscle layers of the larva, which also comprise sensory neurons of the peripheral nervous system. In the larva, resident (sessile) hemocytes are exposed to anti-apoptotic, adhesive and proliferative cues from these sensory neurons and potentially other components of the HPs, such as the lining muscle and epithelial layers. During normal development, gradual release of resident hemocytes from the HPs fuels the population of circulating hemocytes, which culminates in the release of most of the resident hemocytes at the beginning of metamorphosis. Immune assaults, physical injury or mechanical disturbance trigger the premature release of resident hemocytes into circulation. The switch of larval hemocytes between resident locations and circulation raises the need for a common standard/procedure to selectively isolate and quantify these two populations of blood cells from single Drosophila larvae. Accordingly, this protocol describes an automated method to release and quantify the resident and circulating hemocytes from single larvae. The method facilitates ex vivo approaches, and may be adapted to serve a variety of developmental stages of Drosophila and other invertebrate organisms. PMID- 26650405 TI - [CANNABIS: ALTERNATIVE REALITIES (CRA)]. AB - In this cross sectional and descriptive study, secondary school students trom the city of Santa Rosa were questioned about their beliefs about cannabis and their risk perception derived from it. The sample consisted in 83 male and 71 female 17 year-old teenagers. On the one hand, it was found that the highest risk perceptions were related to the legal issues that might arise due to cannabis consumption, and to its effects on neurons. On the other hand, the lowest risk perceptions were associated with the belief/ idea that smoking tobacco affects the lungs more than smoking cannabis, which might create dependence, and its use can cause mental disorders. Several significant differences were found as regards gender, since the female students noticed more risk than male students in that the consumption of cannabis can develop mental disorders, amotivational syndrome, lack of enthusiasm and less satisfaction with life. The teenager's risk perception about cannabis is variable. PMID- 26650406 TI - [RELATIONSHIPS AMONG DRUG ABUSE PATIENTS' CHARACTERISTICS AND WITH THEIR TREATMENT SATISFACTION]. AB - In the last years, studies of patients' satisfaction in drug abuse treatments have become a valuable tool for assessing the quality of treatment and predicting their outcome. However, no previous research has been found that examine patients' conditions that could predict satisfaction. This study analyzes the relationship between patients' characteristics and their degrees of satisfaction in treatment using a probabilistic sample of 216 patients from institutions specializing in addictions within the metropolitan area of Buenos Aires. Participants complete a questionnaire about their satisfaction with different elements of the treatment. Statistical analysis shows that some patients' variables are associated with different levels of satisfaction. Belonging to the male gender, having a significant other, and having lower levels of education were significantly linked with greater satisfaction. Fewer amounts of substances consumed as well as fewer substances that motivated the reason for consultation were associated with a higher degree of satisfaction. The results show the importance of assessing these existing features when designing treatments to suit the specific needs of patients; to seek higher levels of satisfaction, and ultimately, better overall results. PMID- 26650407 TI - [EL GERIATRICO. Coordination]. PMID- 26650408 TI - [IMPACT OF AGING IN PSYCHIATRY]. AB - The changes associated with aging influence the clinical presentation and treatment approach of psychiatric illness. Several psychiatric disorders are common in old age as depression or set of diseases with cognitive impairment requiring geriatric knowledge. In many countries psychiatry of the elderly are called psychogeriatric. Regardless of the name objective of this article is to convey that the psychiatrist who treats patients over 65 years with multiple disorders, with frailty social problems and polypharmacy should have some tools in addition to the thorough understanding of psychiatric illness itself. Teamwork, meet physiological changes of aging and how these affect the response to drugs, atypical presentation of illness and keep in mind the importance of psychosocial and environmental issues both in presentation and in addressing and monitoring of disease. PMID- 26650409 TI - [PERSONALITY DISORDERS AND GERIATRIC INSTITUTION]. AB - Nursing Homes house a large number of residents with some kind of psychiatric disorder. The most complex cases are those involving personality disorders; these, known as difficult residents, often imply a challenge to the institution in every aspect and have a strong impact on the staff and on other residents. The present article considers the relevant aspects of personality disorders in the nursing home, with the nursing home, and from the nursing home, taking into account the difficulties presented by these personalities when faced aging. Moreover, possible approaches to these residents are proposed. PMID- 26650410 TI - [PSYCHOSOCIAL APPROACH OF BEHAVIORAL AND PSYCHOLOGICAL SYMPTOMS OF DEMENTIA IN GERIATRICS INSTITUTIONS]. AB - The psychological and behavioural symptoms of dementia are one of the most important causesof institutionalization. They can, otherwise, go against it: some institutions refuse to accept patients or their staying there. Lattely, this creates difficult situations to deal with that can destabilize the medical team. A psychosocial approach is based in a wide variety of interventions that are designed in the patient himself, to relief the stress that generates dealing people with dementia. The aim of this paper is to analize theoretical issues and to revalue the role of psychosocial approach based on psychosocial interventions. PMID- 26650411 TI - [THE EROTICISM OF PERSONS WITH DEMENTIA IN NURSING HOMES FOR THE ELDERLY]. AB - The objective of this paper is to present the models used by the Residences for Elderly People to organize the eroticism of their residents, especially for people with dementia. It will be shown the different institutional models and their theoretical perspectives over the eroticism of demented people to define the possible interventions with these people. PMID- 26650412 TI - [ELDERLY ADULTS IN NURSING HOMES IN THE PROVINCE OF CORDOBA: OBJECTS OF CARE OR LEGAL SUBJECTS?]. AB - Argentina is among the Ibero-American countries with the greatest old age population, and is going through a process of advanced demographic transition. Elderly adults have long been considered a vulnerable group in need of care. The purpose of this work was to problematize the conceptions underlying the care given to the elderly in nursing homes, and the possible slides this involves from a human rights stance. An approach to this problem was built up by resorting to secondary documentary sources and interviews with key informants located in institutions for the elderly in the Province of Cordoba. This approach revealed a predominantly asylum-oriented conception centered on caring for others as objects, and a noticeable lack of consideration for the elderly as legal subjects, visible in numerous serious infringements of human rights, mostly silenced and rendered invisible. It seems that to overcome these situations it will be necessary not merely to review legal loopholes and current programs but also to reconsider the place given to the elderly in society. Regardless of their age and other social differences, the elderly require the same opportunities to claim full respect and exercise their human rights and fundamental freedoms. PMID- 26650413 TI - [GERIATRIC ETHNOGRAPHY PROCESSES ASSOCIATED WITH SUPERVISION OF GERONTOLOGICAL TEAMS]. AB - In this paper the sociocultural dimensions of residences for seniors are analyzed. The approach to the reality of these institutions has been made across assessment processes and monitoring sustained for more than 15 years in the Buenos Aires area. In this production are recreated and are reviewed the conceptual categories that form the conceptual matrix of research conducted between 2005 and 2007, comparing the experiences of supervision held between 2011 and 2015. Are worked from the idea of that the geriatric ethnography, to come to visualize the studies about what happens in geriatric residence, modes approaches, the expected body shapes, the narratives that they hegemonize senses on service users and workers. PMID- 26650414 TI - [THE OTHER SIDE OF INSTITUTIONALIZATION. ALICE MUNRO'S VERSION]. AB - The aim of this paper is to describe some aspects of the aging process, the Alzheimer and the nursing home starting from the analysis of some fragments of the tale The bear come over the mountain written by Alice Munro. PMID- 26650416 TI - [Klaus Conrad: Beginning Schizophrenia]. PMID- 26650417 TI - [Incipient schizophrenia. Test of a gestalt analysis of delirium. Klaus Conrad (1958). The Rainer case as a typical case of schizophrenic outbreak]. PMID- 26650415 TI - [LIMITATIONS OF THE BIOMEDICAL PARADIGM IN GERIATRICS INSTITUTIONS]. AB - The social perception of ageing related to the loss of both physical and psychological functions that determine in many cases the institutionalization of the elderly in nursing homes, leads to a medical care focused on a biomedical model, centered on organic factors as determinants of the illness. Illness is not an isolated condition in an individual, but has a subjective and social dimension. For this reason the biographic history becomes the main reference point in the care of the elderly. People experiment their disease within a narrative that gives a meaning to their experience; but this is not considered by the biomedical model, where the psychosocial factors that influence the onset or progression of the pathology are disregarded. This article attempts to explore the problem that arises when the care of the elderly that reside in geriatric institutions is centered on the biomedical model. PMID- 26650418 TI - Highly Stereoselective Synthesis of 1,6-Ketoesters Mediated by Ionic Liquids: A Three-component Reaction Enabling Rapid Access to a New Class of Low Molecular Weight Gelators. AB - In organic chemistry ionic liquids (ILs) have emerged as safe and recyclable reaction solvents. In the presence of a base ILs can be deprotonated to form catalytically active N-Heterocyclic Carbenes (NHCs). Here we have used ILs as precatalysts in the addition of alpha,beta-unsaturated aldehydes to chalcones to form 1,6-ketoesters, incorporating an anti-diphenyl moiety in a highly stereoselective fashion. The reaction has a broad substrate scope and several functional groups and heteroaromatics can be integrated into the ketoester backbone in generally good yields with maintained stereoselectivity. The reaction protocol is robust and scalable. The starting materials are inexpensive and the products can be obtained after simple filtration, avoiding solvent-demanding chromatography. Furthermore, the IL can be recycled up to 5 times without any loss of reactivity. Moreover, the 1,6-ketoester end product is a potent gelator in several hydrocarbon based solvents. The method enables rapid access to and evaluation of a new class of low molecular weight gelators (LMWGs) from recyclable and inexpensive starting materials. PMID- 26650419 TI - Acute toxicity of anionic and non-ionic surfactants to aquatic organisms. AB - The environmental risk of surfactants requires toxicity measurements. As different test organisms have different sensitivity to the toxics, it is necessary to establish the most appropriate organism to classify the surfactant as very toxic, toxic, harmful or safe, in order to establish the maximum permissible concentrations in aquatic ecosystems. We have determined the toxicity values of various anionic surfactants ether carboxylic derivatives using four test organisms: the freshwater crustacean Daphnia magna, the luminescent bacterium Vibrio fischeri, the microalgae Selenastrum capricornutum (freshwater algae) and Phaeodactylum tricornutum (seawater algae). In addition, in order to compare and classify the different families of surfactants, we have included a compilation of toxicity data of surfactants collected from literature. The results indicated that V. fischeri was more sensitive to the toxic effects of the surfactants than was D. magna or the microalgae, which was the least sensitive. This result shows that the most suitable toxicity assay for surfactants may be the one using V. fischeri. The toxicity data revealed considerable variation in toxicity responses with the structure of the surfactants regardless of the species tested. The toxicity data have been related to the structure of the surfactants, giving a mathematical relationship that helps to predict the toxic potential of a surfactant from its structure. Model-predicted toxicity agreed well with toxicity values reported in the literature for several surfactants previously studied. Predictive models of toxicity is a handy tool for providing a risk assessment that can be useful to establish the toxicity range for each surfactant and the different test organisms in order to select efficient surfactants with a lower impact on the aquatic environment. PMID- 26650420 TI - Presence, deposition flux and mass burden of persistent organic pollutants (POPs) from Mehmood Booti Drain sediments, Lahore. AB - This study was conducted with the aim of analyzing persistent organic pollutants i.e., PCBs, PBDEs, DPs and OCPs for sediment samples collected from Mehmood Booti Drain, Lahore, Pakistan that receives higher pollution loads from adjacent waste dumping site. Levels of ?PCBs, ?PBDEs, ?DPs and ?OCPs ranged between 5.9-62, 0.36 1.32, n.d.-0.02 and 0.96-18.07ngg(-1,) respectively. These levels were found to be comparable with other studies of local or global origin. Composition, spatial distribution and source profile indicated that Mehmood Booti waste dumping site was the major input source for sedimentary POPs pollution. The highest POPs deposition flux and mass inventory was attributed to PCBs and OCPs. Deposition flux indicated the input of 6E(-04), 5E(-05), 9E(-07) and 4E(-0)(4)t/yr of PCBs, PBDEs, DPs and OCPs into the Mehmood Booti Drain sediments which ultimately discharge into the River Ravi. Mass inventories suggested 1E(-02), 3E(-04), 7E( 06) and 3E(-03) metric tons PCBs, PBDEs, DPs and OCPs burden, respectively in the Mehmood Booti Drain sediments. PMID- 26650421 TI - Electro-kinetic remediation coupled with phytoremediation to remove lead, arsenic and cesium from contaminated paddy soil. AB - The objectives of this study were to investigate distribution and solubility of Pb, Cs and As in soils under electrokinetic field and examine the processes of coupled electrokinetic phytoremediation of polluted soils. The elevated bioavailability and bioaccumulation of Pb, As and Cs in paddy soil under an electro-kinetic field (EKF) were studied. The results show that the EKF treatment is effective on lowering soil pH to around 1.5 near the anode which is beneficial for the dissolution of metal(loid)s, thus increasing their overall solubility. The acidification in the anode soil efficiently increased the water soluble (SOL) and exchangeable (EXC) Pb, As and Cs, implying enhanced solubility and elevated overall potential bioavailability in the anode region while lower solubility in the cathode areas. Bioaccumulations of Pb, As and Cs were largely determined by the nature of elements, loading levels and EKF treatment. The native Pb in soil usually is not bioavailable. However, EKF treatment tends to transfer Pb to the SOL and EXC fractions improving the phytoextraction efficiency. Similarly, EKF transferred more EXC As and Cs to the SOL fraction significantly increasing their bioaccumulation in plant roots and shoots. Pb and As were accumulated more in plant roots than in shoots while Cs was accumulated more in shoots due to its similarity of chemical properties to potassium. Indian mustard, spinach and cabbage are good accumulators for Cs. Translocation of Pb, As and Cs from plant roots to shoots were enhanced by EKF. However, this study indicated the overall low phytoextraction efficiency of these plants. PMID- 26650422 TI - Brevundimonas diminuta mediated alleviation of arsenic toxicity and plant growth promotion in Oryza sativa L. AB - Arsenic (As), a toxic metalloid adversely affects plant growth in polluted areas. In the present study, we investigated the possibility of improving phytostablization of arsenic through application of new isolated strain Brevundimonas diminuta (NBRI012) in rice plant [Oryza sativa (L.) Var. Sarju 52] at two different concentrations [10ppm (low toxic) and 50ppm (high toxic)] of As. The plant growth promoting traits of bacterial strains revealed the inherent ability of siderophores, phosphate solubilisation, indole acetic acid (IAA), 1 aminocyclopropane-1-carboxylic acid (ACC) deaminase production which may be associated with increased biomass, chlorophyll and MDA content of rice and thereby promoting plant growth. The study also revealed the As accumulation property of NBRI012 strain which could play an important role in As removal from contaminated soil. Furthermore, NBRI012 inoculation significantly restored the hampered root epidermal and cortical cell growth of rice plant and root hair elimination. Altogether our study highlights the multifarious role of B. diminuta in mediating stress tolerance and modulating translocation of As in edible part of rice plant. PMID- 26650423 TI - Psychiatric outcomes after childbirth: can posttraumatic growth protect me from disordered eating symptoms? AB - PURPOSE: While many studies on mood disorder and posttraumatic stress disorder (PTSD) following childbirth have been conducted, little is known regarding posttraumatic growth (PTG) and disordered eating in the postpartum period. This study aims to (a) identify the typology of women following childbirth based on anxiety, depressive, PTSD symptoms and level of PTG and (b) evaluate whether these profiles differ on disordered eating symptoms. METHODS: Up to 2 years after childbirth, 306 French-speaking mothers [mean age (SD) = 29.4 (4.6) years] completed questionnaires assessing PTSD, depressive, anxiety and disordered eating symptoms and level of posttraumatic growth. RESULTS: Four profiles were highlighted: a first one labeled growing cluster (22.2 % of the sample, n = 68), a second one labeled low level of symptoms cluster (37.6 % of the sample, n = 115), a third one labeled vulnerable cluster (21.6 % of the sample, n = 66) and a last one labeled anxious-depressed-traumatized cluster (18.6 % of the sample, n = 57). Our findings also highlight an impact of these profiles on disordered eating symptoms, suggesting that disordered eating in postpartum would not be the result of pregnancy. CONCLUSION: Consistent with our expectation, our findings suggest a potential protective role of posttraumatic growth on the development of disordered eating symptoms. Further researches focusing on traumatic experience, disordered eating and posttraumatic growth in postpartum are warranted. PMID- 26650424 TI - Cardiac Arrest and Seizures Caused by Local Anesthetic Systemic Toxicity After Peripheral Nerve Blocks: Should We Still Fear the Reaper? PMID- 26650425 TI - Regional Versus General Anesthesia and the Incidence of Unplanned Health Care Resource Utilization for Postoperative Pain After Wrist Fracture Surgery: Results From a Retrospective Quality Improvement Project. AB - BACKGROUND AND OBJECTIVES: The establishment at our center of a dedicated regional anesthesia service in 2008-2009 has resulted in a marked increase in single-shot brachial plexus blocks (sBPBs) for ambulatory wrist fracture surgery. Despite the documented benefits of regional over general anesthesia (GA), there has been a perceived increase among sBPB patients in postoperative return rates for pain at our institution. We conducted a retrospective quality improvement project to examine this. METHODS: After exemption from human ethics board review, we sought to identify and contact all wrist fracture surgery patients treated at our center between 2003 and 2012. Our primary outcome was the incidence of unplanned physician visits (office/clinic or emergency department) for pain in the first 48 hours after surgery. Other main outcomes included the incidence of seeking any form of medical attention for pain and self-reporting of severe pain in the first 48 hours. RESULTS: Of 1008 identified patients, 419 could be contacted; 195 qualified for analysis. The incidence of unplanned physician visits in the first 48 hours was 12% (13 of 118) among sBPB patients versus 4% (3 of 77) in GA patients (odds ratio [OR], 3.1; 95% confidence interval [95% CI], 0.8-11.1; P = 0.11). More sBPB versus GA patients sought any form of medical attention for pain (20% vs 5%; OR, 4.7; 95% CI, 1.4-10.9; P = 0.003). Similarly, more sBPB patients reported severe postoperative pain (41% vs 10%; OR, 5.9; 95% CI, 2.6-13.4; P < 0.0001). CONCLUSIONS: Patients who received sBPBs for ambulatory wrist fracture surgery had a higher rate of unplanned health care resource utilization caused by pain after hospital discharge than those undergoing GA. These findings warrant confirmation in a prospective trial and emphasize the need for a defined postdischarge analgesic pathway as well as the potential merits of perineural home catheters. PMID- 26650426 TI - A Clinical Comparison of Intravenous and Epidural Local Anesthetic for Major Abdominal Surgery. AB - BACKGROUND: Epidural analgesia provides good pain control after many postoperative procedures, but it can lead to complications, has some contraindications, and occasionally fails. Intravenous lidocaine infusion has been suggested as an alternative. We assessed, in our clinical practice, the effects of perioperative intravenous lidocaine infusion compared with epidural analgesia for major abdominal surgery. METHODS: We conducted a retrospective review of patients who had received intravenous lidocaine (1 mg/kg per hour) perioperatively after a major abdominal surgery. We matched them with patients who had received epidural analgesia. We tested a joint hypothesis of noninferiority of lidocaine infusion to epidural analgesia in postoperative pain scores and opioid consumption. We assigned a noninferiority margin of 1 point (on an 11-point numerical rating scale) difference in pain and a ratio [mean (lidocaine) / mean (epidural)] of 1.2 in opioid consumption, respectively. RESULTS: Two hundred sixteen patients (108 in each group) were analyzed. Intravenous lidocaine was not inferior to epidural analgesia with respect to pain scores. Lidocaine infusion was inferior to epidural analgesia with respect to opioid consumption. Patients in the lidocaine group had fewer episodes of hypotension and less postoperative nausea and vomiting, pruritus, and urinary retention. Patients receiving lidocaine also had earlier urinary catheter removal and earlier first gastrointestinal function. Daily mental status assessment was similar between the 2 groups. CONCLUSIONS: Patients who received systemic lidocaine infusions with the addition of PRN (as needed) opioids administered for breakthrough pain did not have clinically significant differences in pain scores on postoperative day 2 and beyond. Intravenous lidocaine infusion in major abdominal surgery was inferior to epidural analgesia with respect to opioid consumption. However, lidocaine was associated with improvements in several important aspects of recovery. PMID- 26650427 TI - Serum Triamcinolone Levels Following Interlaminar Epidural Injection. AB - BACKGROUND: Lumbar interlaminar epidural steroid injections (ESIs) are one of the most commonly performed procedures in pain medicine, but little is known about the serum levels of steroids following injection into the epidural space. The primary objective of this study was to investigate the pharmacokinetics of fluoroscopy-guided epidural-administered triamcinolone acetonide in a cohort of patients with chronic low-back pain seeking treatment in a pain medicine clinic. METHODS: The study cohort included 10 patients undergoing a fluoroscopically guided L4-L5 or L5-S1 lumbar interlaminar ESI at a pain medicine specialty clinic. Blood was collected prior to the ESI and on days 1, 2, 4, 6, 8, 14, 21, 28, 35, and 42 following the injection. The sample extract was analyzed by tandem mass spectrometry. RESULTS: The terminal elimination half-life of epidural administered triamcinolone in a noncompartmental analysis was 523 hours. In the noncompartmental analysis, peak triamcinolone concentrations of 4.1 ng/mL were detected within 24 hours after administration. CONCLUSIONS: The pharmacokinetics of epidural-administered triamcinolone is consistent with previously observed adverse effects of the drug on endocrine function. The pharmacokinetics of other epidural-administered steroids should be determined and incorporated in clinical trials to investigate the potential associations between serum levels, clinical outcomes, and potential adverse endocrine effects. PMID- 26650428 TI - Comparison of Needle Path, Anesthetic Dispersion, and Quality of Anesthesia in Retrobulbar and Peribulbar Blocks. AB - BACKGROUND AND OBJECTIVES: To compare the needle path during retrobulbar ophthalmic block with that during peribulbar ophthalmic block, its relation with anesthetic spread, and the quality of the anesthesia. METHODS: This is a prospective comparative study in selected candidates of ophthalmic blocks for phacoemulsification. The procedure used a 22-gauge 1 needle in a single lateral inferior transcutaneous puncture with 5 mL of anesthetic solution with radiological contrast. Patients were randomly divided into 2 groups: GI, retrobulbar block; GII, peribulbar block. Computed tomography scans of the orbit were performed at the time of the blockade and 10 minutes after anesthetic injection. The quality of anesthesia was assessed by measurement of ocular motility at 3, 5, and 10 minutes after the block. RESULTS: Twenty eyes per group were included. The needle path was intraconal in 10 cases in GI and in no patient in GII, transfixed the muscle cone in 5 cases in GI and in 4 in GII, and was extraconal in 2 cases in GI and in 13 in GII. The anesthetic dispersion was directly related to the needle path. In all extraconal cases, the block was unsatisfactory. It was satisfactory when the path of the needle was intraconal or the cone was transfixed (P = 1.0). The quality of anesthesia was higher in the retrobulbar block (P < 0.01). CONCLUSIONS: The path of the needle contributed to the orbital anesthetic solution dispersion and the quality of anesthesia. The retrobulbar block technique provided better-quality anesthesia compared with the peribulbar one. PMID- 26650430 TI - Trends in the Use of Regional Anesthesia: Neuraxial and Peripheral Nerve Blocks. AB - BACKGROUND: A growing body of evidence indicates that the use of regional anesthesia offers advantages over general anesthesia, not only in terms of reducing complications but also regarding resource utilization and patient satisfaction. Because of the paucity of data on the nationwide adoption of regional anesthesia techniques, we aimed to elucidate trends in the use of neuraxial anesthesia (NA) and peripheral nerve blocks (PNBs) in orthopedic surgeries. METHODS: We extracted data from N = 959,257 (Premier Perspective database; 2006-2013) total hip and knee arthroplasties (THA, TKA) and assessed NA/PNB use by a 2-year period, stratified by demographics and hospital factors. Cochran-Armitage trend tests assessed significance of trends. RESULTS: Comparing 2006-2007 with 2012-2013, NA utilization decreased slightly from 21.7% to 19.7% for THA patients; this was 24.7% to 21.3% for TKA patients (with the main drop between 2012 and 2013). Conversely, PNB utilization increased from 6.5% to 8.7% for THA patients and 10.3% to 20.4% for TKA patients (all P < 0.001). These general trends did not change when stratified by patient demographics, whereas stratification by hospital factors did show differences: the highest NA utilization was seen in rural, nonteaching, and small hospitals, whereas the highest PNB utilization was seen in large and teaching hospitals. CONCLUSIONS: Our findings provide important insight into the dynamics of the adoption of regional anesthetic techniques. Whereas PNB utilization is significantly increasing, overall, NA and PNBs are performed in the minority of cases. With accumulating evidence in favor of regional anesthesia, promoting the use of NA and a further increase in PNB utilization could have far-reaching medical and economic implications. PMID- 26650429 TI - Efficacy and Safety of Methylnaltrexone for Opioid-Induced Constipation in Patients With Chronic Noncancer Pain: A Placebo Crossover Analysis. AB - BACKGROUND AND OBJECTIVES: In patients with chronic noncancer pain, subcutaneous methylnaltrexone for opioid-induced constipation (OIC) was examined in a randomized controlled trial (RCT) followed by an open-label extension (OLE). This study examined the reproducibility of RCT findings by analyzing data from placebo treated patients who crossed over to methylnaltrexone. METHODS: Adults with less than 3 weekly rescue-free bowel movements (RFBMs), taking 50 mg or more of an oral morphine equivalent per day, were randomized to receive methylnaltrexone 12 mg or placebo for 4 weeks, followed by open-label methylnaltrexone 12 mg as needed for 8 weeks. RESULTS: A total of 134 placebo-treated patients (median morphine equivalent dose, 150 mg/d; mean of 1.1 RFBM per week) crossed over to methylnaltrexone in OLE. During the RCT, 9.7% of placebo-treated patients experienced an RFBM within 4 hours of first dose and 9.0% of all placebo injections resulted in an RFBM within 4 hours compared with 45.9% and 34.5%, respectively, with methylnaltrexone treatment in the OLE. When expressed as percentage of patients experiencing 3 or more RFBMs per week and a 1-RFBM increase over baseline, weekly values ranged from 35% to 40% during placebo treatment; at week 5 of OLE methylnaltrexone, this percentage increased to more than 70% and remained relatively stable throughout the OLE. The most common adverse events during methylnaltrexone treatment were abdominal pain (9.7% vs 1.5% for placebo) and nausea (5.2% vs 6.7%). CONCLUSIONS: Findings during placebo treatment further establish the profile of OIC and support that little or no gastrointestinal tolerance develops across time. Findings under open-label conditions established the reproducibility and durability of methylnaltrexone for OIC. PMID- 26650431 TI - High Opening Injection Pressure Is Associated With Needle-Nerve and Needle-Fascia Contact During Femoral Nerve Block. AB - BACKGROUND AND OBJECTIVES: High opening injection pressures (OIPs) have been shown to predict sustained needle tip contact with the roots of the brachial plexus. Such roots have a uniquely high ratio of fascicular versus connective tissue. It is unknown if this relationship is preserved during multifascicular nerve blockade. We hypothesized that OIP can predict needle-nerve contact during femoral nerve block, as well as detect needle contact with the fascia iliaca. METHODS: Twenty adults scheduled for femoral block were recruited. Using ultrasound, a 22-gauge needle was sequentially placed in 4 locations: indenting the fascia iliaca, advanced through the fascia iliaca while lateral to the nerve, slightly indenting the femoral nerve, and withdrawn from the nerve 1 mm. At each location, the OIP required to initiate an injection of 1 mL D5W (5% dextrose in water) at 10 mL/min was recorded. Blinded investigators performed evaluations and aborted injections when an OIP of 15 psi was reached. RESULTS: Opening injection pressure was 15 psi or greater for 90% and 100% of cases when the needle indented the femoral nerve and fascia iliaca, respectively. Opening injection pressure was less than 15 psi for all 20 patients when the needle was withdrawn 1 mm from the nerve as well as at the subfascial position (McNemar chi2 P < 0.001). CONCLUSIONS: Opening injection pressure greater than 15 psi was associated with a block needle tip position slightly indenting the epineurium of the femoral nerve (90%) and the fascia iliaca (100%). Needle tip positions not indenting these structures were associated with OIP of less than 15 psi (100%). PMID- 26650433 TI - Low-dimensional multiplexing: the magneto-optical Kerr effect in an individual FeCoCu nanowire. AB - Due to their selective and fascinating effects, metallic nanoparticles have become a very significant topic for science. A modification in morphology and structure of low-dimensional materials can result in extraordinary ultrafast physical phenomena. New findings related to electronic, optical and magnetic processes have emerged from surface plasmon resonance excitations in nanoparticles. Moreover, multi-functional systems can be obtained from the integration of different elements in a nanostructured configuration. Recently, Palmero et al (2015 Nanotechnology 26 461001) have reported magneto-optical Kerr effect explorations in individual FeCuCo nanowires; the influence of tailored morphologies exhibited by particular samples was analyzed. An important magnetization reversal action was revealed and it was concluded that the demagnetization may be responsible for vortex domain wall propagation. The report can provide a solid base for future research and immediate applications in modern spintronics or magnetic data storage can be contemplated. PMID- 26650432 TI - Real-Time Captioning for Improving Informed Consent: Patient and Physician Benefits. AB - BACKGROUND AND OBJECTIVES: New methods are needed to improve physicians' skill in communicating information and to enhance patients' ability to recall that information. We evaluated a real-time speech-to-text captioning system that simultaneously provided a speech-to-text record for both patient and anesthesiologist. The goals of the study were to assess hearing-impaired patients' recall of an informed consent discussion about regional anesthesia using real-time captioning and to determine whether the physicians found the system useful for monitoring their own performance. METHODS: We recorded 2 simulated informed consent encounters with hearing-impaired older adults, in which physicians described regional anesthetic procedures. The conversations were conducted with and without real-time captioning. Subsequently, the patient participants, who wore their hearing aids throughout, were tested on the material presented, and video recordings of the encounters were analyzed to determine how effectively physicians communicated with and without the captioning system. RESULTS: The anesthesiology residents provided similar information to the patient participants regardless of whether the real-time captioning system was used. Although the patients retained relatively few details regardless of the informed consent discussion, they could recall significantly more of the key points when provided with real-time captioning. CONCLUSIONS: Real-time speech-to-text captioning improved recall in hearing-impaired patients and proved useful for determining the information provided during an informed consent encounter. Real time speech-to-text captioning could provide a method for assessing physicians' communication that could be used both for self-assessment and as an evaluative approach to training communication skills in practice settings. PMID- 26650434 TI - The Effect of Protein-Enriched Meal Replacement on Waist Circumference Reduction among Overweight and Obese Chinese with Hyperlipidemia. AB - OBJECTIVE: In China, high-fat diets and excessive energy intake have led to an increasing prevalence of obesity which was previously uncommon. The current study examined the effects of meal replacement (MR) on weight control in overweight or obese Chinese individuals with hyperlipidemia. METHODS: Patients, 18-65 years, with body mass index 25-35 kg/m(2) and triglycerides >1.7 and <5.4 mmol/L were enrolled. Major exclusion criteria were: type II diabetes, fasting glucose >=7.0 mmol/L, glycosylated hemoglobin >=6.5%; weight loss surgery or use of weight loss drugs; weight fluctuations >2%; use of cholesterol-lowering drugs. Eligible patients were randomized 1:1 to a high-protein (HP) diet (2.2 g protein/kg/day) or a standard-protein (SP) diet (1.1 g protein/kg/ day) provided twice daily for 3 months. Assessments included body weight, waist-hip ratio, body fat percentage, blood lipids, blood glucose, insulin, liver and kidney function. RESULTS: Although mean weight loss and percent BMI reduction were greater with HP than SP at 12 weeks, the differences were not significant. There was, however, a significantly greater decrease in waist-hip ratio with HP versus SP (-0.03 +/- 0.03 vs. -0.01 +/- 0.04; p < 0.05). Triglycerides decreased from baseline in both groups; however, the difference was not significant. Both HP and SP were well tolerated. This study demonstrated that in obese Chinese patients with hyperlipidemia, a protein-enriched MR diet resulted in significantly reduced waist circumference compared to a standard protein diet. CONCLUSION: This first study of protein-enriched partial meal replacement in a free-living Chinese population suggests a new and promising strategy for reducing abdominal obesity in China. PMID- 26650435 TI - Synthesis and Site-Specific Incorporation of Red-Shifted Azobenzene Amino Acids into Proteins. AB - A series of red-shifted azobenzene amino acids were synthesized in moderate-to excellent yields via a two-step procedure in which tyrosine derivatives were first oxidized to the corresponding quinonoidal spirolactones followed by ceric ammonium nitrate-catalyzed azo formation with the substituted phenylhydrazines. The resulting azobenzene-alanine derivatives exhibited efficient trans/cis photoswitching upon irradiation with a blue (448 nm) or green (530 nm) LED light. Moreover, nine superfolder green fluorescent protein (sfGFP) mutants carrying the azobenzene-alanine analogues were expressed in E. coli in good yields via amber codon suppression with an orthogonal tRNA/PylRS pair, and one of the mutants showed durable photoswitching with the LED light. PMID- 26650436 TI - Role of Laparoscopic Exploration Under Local Anesthesia in the Management of Hemodynamically Stable Patients with Penetrating Abdominal Injury. AB - BACKGROUND: In many trauma centers there is an ongoing controversy over the way of managing patients with penetrating abdominal injuries. This study was constructed to evaluate the role of diagnostic laparoscopy performed with local anesthesia for the management of penetrating abdominal injury. PATIENTS AND METHODS: Thirty hemodynamically stable patients with a penetrating stab wound in the anterior abdominal wall were included in this study after consent was obtained. Laparoscopic explorations were done with the patient having local anesthesia. If there was bleeding or intestinal content in the peritoneal cavity or visible injury to any abdominal organ, the procedure was converted to open exploration. If the peritoneal cavities showed no fluid and there was no injury to the abdominal viscera, the patient was followed up for the next 72 hours. Continuous variables were expressed as mean and standard deviation values. Categorical variables were expressed as frequencies and percentages. Student's t test was used to assess the statistical significance of the difference between the two study groups' means. Fisher's exact test was used to examine the relationship between categorical variables. A significance level of P < .05 was used in all tests. All statistical procedures were carried out using SPSS version 20 for Windows software (IBM, Armonk, NY). RESULTS: From the total of 30 patients who underwent laparoscopic exploration, 13 patients (43.3%) needed open exploration: 11 cases had intrabdominal organ injuries that needed laparotomy, 1 case had intraperitoneal blood collection where the only source of blood was the anterior abdominal wall wound, and 1 case had acute abdominal pain after 48 hours of negative laparoscopic exploration, in which an intestinal tear was found upon re-exploration. For the other 17 (56.7%) cases, 3 cases had no peritoneal penetration, whereas 14 cases had peritoneal penetration without any internal organ injuries, and these patients were followed up and discharged after 2-3 days. CONCLUSIONS: Laparoscopy performed with the patient having local anesthesia is an accurate diagnostic tool in the management of patients with an equivocal penetrating stab wound in the abdominal wall and can reduce the number of patients with negative open exploration. PMID- 26650439 TI - The Concise Guide to PHARMACOLOGY 2015/16: G protein-coupled receptors. AB - The Concise Guide to PHARMACOLOGY 2015/16 provides concise overviews of the key properties of over 1750 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. The full contents can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.13348/full. G protein-coupled receptors are one of the eight major pharmacological targets into which the Guide is divided, with the others being: ligand-gated ion channels, voltage-gated ion channels, other ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The Concise Guide is published in landscape format in order to facilitate comparison of related targets. It is a condensed version of material contemporary to late 2015, which is presented in greater detail and constantly updated on the website www.guidetopharmacology.org, superseding data presented in the previous Guides to Receptors & Channels and the Concise Guide to PHARMACOLOGY 2013/14. It is produced in conjunction with NC IUPHAR and provides the official IUPHAR classification and nomenclature for human drug targets, where appropriate. It consolidates information previously curated and displayed separately in IUPHAR-DB and GRAC and provides a permanent, citable, point-in-time record that will survive database updates. PMID- 26650437 TI - Post-Transplant Diabetes Mellitus: Causes, Treatment, and Impact on Outcomes. AB - Post-transplant diabetes mellitus (PTDM) is a frequent consequence of solid organ transplantation. PTDM has been associated with greater mortality and increased infections in different transplant groups using different diagnostic criteria. An international consensus panel recommended a consistent set of guidelines in 2003 based on American Diabetes Association glucose criteria but did not exclude the immediate post-transplant hospitalization when many patients receive large doses of corticosteroids. Greater glucose monitoring during all hospitalizations has revealed significant glucose intolerance in the majority of recipients immediately after transplant. As a result, the international consensus panel reviewed its earlier guidelines and recommended delaying screening and diagnosis of PTDM until the recipient is on stable doses of immunosuppression after discharge from initial transplant hospitalization. The group cautioned that whereas hemoglobin A1C has been adopted as a diagnostic criterion by many, it is not reliable as the sole diabetes screening method during the first year after transplant. Risk factors for PTDM include many of the immunosuppressant medications themselves as well as those for type 2 diabetes. The provider managing diabetes and associated dyslipidemia and hypertension after transplant must be careful of the greater risk for drug-drug interactions and infections with immunosuppressant medications. Treatment goals and therapies must consider the greater risk for fluctuating and reduced kidney function, which can cause hypoglycemia. Research is actively focused on strategies to prevent PTDM, but until strategies are found, it is imperative that immunosuppression regimens are chosen based on their evidence to prolong graft survival, not to avoid PTDM. PMID- 26650440 TI - The Concise Guide to PHARMACOLOGY 2015/16: Ligand-gated ion channels. AB - The Concise Guide to PHARMACOLOGY 2015/16 provides concise overviews of the key properties of over 1750 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. The full contents can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.13349/full. Ligand-gated ion channels are one of the eight major pharmacological targets into which the Guide is divided, with the others being: ligand-gated ion channels, voltage-gated ion channels, other ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The Concise Guide is published in landscape format in order to facilitate comparison of related targets. It is a condensed version of material contemporary to late 2015, which is presented in greater detail and constantly updated on the website www.guidetopharmacology.org, superseding data presented in the previous Guides to Receptors & Channels and the Concise Guide to PHARMACOLOGY 2013/14. It is produced in conjunction with NC IUPHAR and provides the official IUPHAR classification and nomenclature for human drug targets, where appropriate. It consolidates information previously curated and displayed separately in IUPHAR-DB and GRAC and provides a permanent, citable, point-in-time record that will survive database updates. PMID- 26650438 TI - The Concise Guide to PHARMACOLOGY 2015/16: Overview. AB - The Concise Guide to PHARMACOLOGY 2015/16 provides concise overviews of the key properties of over 1750 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. The full contents can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.13347/full. This compilation of the major pharmacological targets is divided into eight areas of focus: G protein coupled receptors, ligand-gated ion channels, voltage-gated ion channels, other ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The Concise Guide is published in landscape format in order to facilitate comparison of related targets. It is a condensed version of material contemporary to late 2015, which is presented in greater detail and constantly updated on the website www.guidetopharmacology.org, superseding data presented in the previous Guides to Receptors & Channels and the Concise Guide to PHARMACOLOGY 2013/14. It is produced in conjunction with NC IUPHAR and provides the official IUPHAR classification and nomenclature for human drug targets, where appropriate. It consolidates information previously curated and displayed separately in IUPHAR-DB and GRAC and provides a permanent, citable, point-in-time record that will survive database updates. PMID- 26650441 TI - The Concise Guide to PHARMACOLOGY 2015/16: Voltage-gated ion channels. AB - The Concise Guide to PHARMACOLOGY 2015/16 provides concise overviews of the key properties of over 1750 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. The full contents can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.13350/full. Voltage-gated ion channels are one of the eight major pharmacological targets into which the Guide is divided, with the others being: G protein-coupled receptors, ligand-gated ion channels, other ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The Concise Guide is published in landscape format in order to facilitate comparison of related targets. It is a condensed version of material contemporary to late 2015, which is presented in greater detail and constantly updated on the website www.guidetopharmacology.org, superseding data presented in the previous Guides to Receptors & Channels and the Concise Guide to PHARMACOLOGY 2013/14. It is produced in conjunction with NC IUPHAR and provides the official IUPHAR classification and nomenclature for human drug targets, where appropriate. It consolidates information previously curated and displayed separately in IUPHAR-DB and GRAC and provides a permanent, citable, point-in-time record that will survive database updates. PMID- 26650442 TI - The Concise Guide to PHARMACOLOGY 2015/16: Other ion channels. AB - The Concise Guide to PHARMACOLOGY 2015/16 provides concise overviews of the key properties of over 1750 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. The full contents can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.13351/full. Other ion channels are one of the eight major pharmacological targets into which the Guide is divided, with the others being: G protein-coupled receptors, ligand-gated ion channels, voltage-gated ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The Concise Guide is published in landscape format in order to facilitate comparison of related targets. It is a condensed version of material contemporary to late 2015, which is presented in greater detail and constantly updated on the website www.guidetopharmacology.org, superseding data presented in the previous Guides to Receptors & Channels and the Concise Guide to PHARMACOLOGY 2013/14. It is produced in conjunction with NC IUPHAR and provides the official IUPHAR classification and nomenclature for human drug targets, where appropriate. It consolidates information previously curated and displayed separately in IUPHAR-DB and GRAC and provides a permanent, citable, point-in-time record that will survive database updates. PMID- 26650443 TI - The Concise Guide to PHARMACOLOGY 2015/16: Nuclear hormone receptors. AB - The Concise Guide to PHARMACOLOGY 2015/16 provides concise overviews of the key properties of over 1750 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. The full contents can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.13352/full. Nuclear hormone receptors are one of the eight major pharmacological targets into which the Guide is divided, with the others being: G protein-coupled receptors, ligand-gated ion channels, voltage-gated ion channels, other ion channels, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The Concise Guide is published in landscape format in order to facilitate comparison of related targets. It is a condensed version of material contemporary to late 2015, which is presented in greater detail and constantly updated on the website www.guidetopharmacology.org, superseding data presented in the previous Guides to Receptors & Channels and the Concise Guide to PHARMACOLOGY 2013/14. It is produced in conjunction with NC IUPHAR and provides the official IUPHAR classification and nomenclature for human drug targets, where appropriate. It consolidates information previously curated and displayed separately in IUPHAR-DB and GRAC and provides a permanent, citable, point-in-time record that will survive database updates. PMID- 26650444 TI - The Concise Guide to PHARMACOLOGY 2015/16: Catalytic receptors. AB - The Concise Guide to PHARMACOLOGY 2015/16 provides concise overviews of the key properties of over 1750 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. The full contents can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.13353/full. G protein-coupled receptors are one of the eight major pharmacological targets into which the Guide is divided, with the others being: G protein-coupled receptors, ligand-gated ion channels, voltage-gated ion channels, other ion channels, nuclear hormone receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The Concise Guide is published in landscape format in order to facilitate comparison of related targets. It is a condensed version of material contemporary to late 2015, which is presented in greater detail and constantly updated on the website www.guidetopharmacology.org, superseding data presented in the previous Guides to Receptors & Channels and the Concise Guide to PHARMACOLOGY 2013/14. It is produced in conjunction with NC-IUPHAR and provides the official IUPHAR classification and nomenclature for human drug targets, where appropriate. It consolidates information previously curated and displayed separately in IUPHAR-DB and GRAC and provides a permanent, citable, point-in-time record that will survive database updates. PMID- 26650445 TI - The Concise Guide to PHARMACOLOGY 2015/16: Enzymes. AB - The Concise Guide to PHARMACOLOGY 2015/16 provides concise overviews of the key properties of over 1750 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. The full contents can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.13354/full. G protein-coupled receptors are one of the eight major pharmacological targets into which the Guide is divided, with the others being: G protein-coupled receptors, ligand-gated ion channels, voltage-gated ion channels, other ion channels, nuclear hormone receptors, catalytic receptors and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The Concise Guide is published in landscape format in order to facilitate comparison of related targets. It is a condensed version of material contemporary to late 2015, which is presented in greater detail and constantly updated on the website www.guidetopharmacology.org, superseding data presented in the previous Guides to Receptors & Channels and the Concise Guide to PHARMACOLOGY 2013/14. It is produced in conjunction with NC-IUPHAR and provides the official IUPHAR classification and nomenclature for human drug targets, where appropriate. It consolidates information previously curated and displayed separately in IUPHAR DB and GRAC and provides a permanent, citable, point-in-time record that will survive database updates. PMID- 26650446 TI - The Concise Guide to PHARMACOLOGY 2015/16: Transporters. AB - The Concise Guide to PHARMACOLOGY 2015/16 provides concise overviews of the key properties of over 1750 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. The full contents can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.13355/full. G protein-coupled receptors are one of the eight major pharmacological targets into which the Guide is divided, with the others being: G protein-coupled receptors, ligand-gated ion channels, voltage-gated ion channels, other ion channels, nuclear hormone receptors, catalytic receptors and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The Concise Guide is published in landscape format in order to facilitate comparison of related targets. It is a condensed version of material contemporary to late 2015, which is presented in greater detail and constantly updated on the website www.guidetopharmacology.org, superseding data presented in the previous Guides to Receptors & Channels and the Concise Guide to PHARMACOLOGY 2013/14. It is produced in conjunction with NC-IUPHAR and provides the official IUPHAR classification and nomenclature for human drug targets, where appropriate. It consolidates information previously curated and displayed separately in IUPHAR DB and GRAC and provides a permanent, citable, point-in-time record that will survive database updates. PMID- 26650447 TI - Group 6 metal pentacarbonyl complexes of air-stable primary, secondary, and tertiary ferrocenylethylphosphines. AB - The synthesis and characterization of a series of Group 6 metal pentacarbonyl complexes of air stable primary, secondary, and tertiary phosphines containing ferrocenylethyl substituents are reported [M(CO)5L: M = Cr, Mo, W; L = PH2(CH2CH2Fc), PH(CH2CH2Fc)2, P(CH2CH2Fc)3]. The structure and composition of the complexes were confirmed by multinuclear NMR spectroscopy, IR and UV-Vis absorption spectroscopy, mass spectrometry, X-ray crystallography, and elemental analysis. The solid-state structural data reported revealed trends in M-C and M-P bond lengths that mirrored those of the atomic radii of the Group 6 metals involved. UV-Vis absorption spectroscopy and cyclic voltammetry highlighted characteristics consistent with electronically isolated ferrocene units including wavelengths of maximum absorption between 435 and 441 nm and reversible one electron (per ferrocene unit) oxidation waves between 10 and -5 mV relative to the ferrocene/ferrocenium redox couple. IR spectroscopy confirmed that the sigma donating ability of the phosphines increased as ferrocenylethyl substituents were introduced and that the tertiary phosphine ligand described is a stronger sigma donor than PPh3 and a weaker sigma donor than PEt3, respectively. PMID- 26650449 TI - Sulfide and methane production in sewer sediments: Field survey and model evaluation. AB - Sewer sediment processes have been reported to significantly contribute to overall sulfide and methane production in sewers, at a scale comparable to that of sewer biofilms. The physiochemical and biological characteristics of sewer sediments are heterogeneous; however, the variability of in-sediments sulfide and methane production rates among sewers has not been assessed to date. In this study, five sewer sediment samples were collected from two cities in Australia with different climatic conditions. Batch assays were conducted to determine the rates of sulfate reduction and methane production under different flow velocity (shear stress) conditions as well as under completely mixed conditions. The tests showed substantial and variable sulfate reduction and methane production activities among different sediments. Sulfate reduction and methane production from sewer sediments were confirmed to be areal processes, and were dependent on flow velocity/shear stress. Despite of the varying characteristics and reactions kinetics, the sulfate reduction and methane production processes in all sediments could be well described by a one-dimensional sewer sediment model recently developed based on results obtained from a laboratory sewer sediment reactor. Model simulations indicated that the in-situ contribution of sewer sediment emissions could be estimated without the requirement of measuring the specific sediment characteristics or the sediment depths. PMID- 26650448 TI - Poly (ADP) ribose polymerase inhibition: A potential treatment of malignant peripheral nerve sheath tumor. AB - Poly (ADP) ribose polymerase (PARP) inhibitors, first evaluated nearly a decade ago, are primarily used in malignancies with known defects in DNA repair genes, such as alterations in breast cancer, early onset 1/2 (BRCA1/2). While no specific mutations in BRCA1/2 have been reported in malignant peripheral nerve sheath tumors (MPNSTs), MPNST cells could be effectively targeted with a PARP inhibitor to drive cells to synthetic lethality due to their complex karyotype and high level of inherent genomic instability. In this study, we assessed the expression levels of PARP1 and PARP2 in MPNST patient tumor samples and correlated these findings with overall survival. We also determined the level of PARP activity in MPNST cell lines. In addition, we evaluated the efficacy of the PARP inhibitor AZD2281 (Olaparib) in MPNST cell lines. We observed decreased MPNST cell proliferation and enhanced apoptosis in vitro at doses similar to, or less than, the doses used in cell lines with established defective DNA repair genes. Furthermore, AZD2281 significantly reduced local growth of MPNST xenografts, decreased the development of macroscopic lung metastases, and increased survival of mice with metastatic disease. Our results suggest that AZD2281 could be an effective therapeutic option in MPNST and should be further investigated for its potential clinical use in this malignancy. PMID- 26650450 TI - A highly efficient polyampholyte hydrogel sorbent based fixed-bed process for heavy metal removal in actual industrial effluent. AB - High sorption capacity, high sorption rate, and fast separation and regeneration for qualified sorbents used in removing heavy metals from wastewater are urgently needed. In this study, a polyampholyte hydrogel was well designed and prepared via a simple radical polymerization procedure. Due to the remarkable mechanical strength, the three-dimensional polyampholyte hydrogel could be fast separated, easily regenerated and highly reused. The sorption capacities were as high as 216.1 mg/g for Pb(II) and 153.8 mg/g for Cd(II) owing to the existence of the large number of active groups. The adsorption could be conducted in a wide pH range of 3-6 and the equilibrium fast reached in 30 min due to its excellent water penetration for highly accessible to metal ions. The fixed-bed column sorption results indicated that the polyampholyte hydrogel was particularly effective in removing Pb(II) and Cd(II) from actual industrial effluent to meet the regulatory requirements. The treatment volumes of actual smelting effluent using one fixed bed column were as high as 684 bed volumes (BV) (7736 mL) for Pb(II) and 200 BV (2262 mL) for Cd(II). Furthermore, the treatment volumes of actual smelting effluent using tandem three columns reached 924 BV (31,351 mL) for Pb(II) and 250 BV (8483 mL) for Cd(II), producing only 4 BV (136 mL) eluent. Compared with the traditional high density slurry (HDS) process with large amount of sludge, the proposed process would be expected to produce only a small amount of sludge. When the treatment volume was controlled below 209.3 BV (7103 mL), all metal ions in the actual industrial effluent could be effectively removed (<0.01 mg/L). This wok develops a highly practical process based on polyampholyte hydrogel sorbents for the removal of heavy metal ions from practical wastewater. PMID- 26650451 TI - Woodchip-sulfur based heterotrophic and autotrophic denitrification (WSHAD) process for nitrate contaminated water remediation. AB - Nitrate contaminated water can be effectively treated by simultaneous heterotrophic and autotrophic denitrification (HAD). In the present study, woodchips and elemental sulfur were used as co-electron donors for HAD. It was found that ammonium salts could enhance the denitrifying activity of the Thiobacillus bacteria, which utilize the ammonium that is produced by the dissimilatory nitrate reduction to ammonium (DNRA) in the woodchip-sulfur based heterotrophic and autotrophic denitrification (WSHAD) process. The denitrification performance of the WSHAD process (reaction constants range from 0.05485 h(-1) to 0.06637 h(-1)) is better than that of sulfur-based autotrophic denitrification (reaction constants range from 0.01029 h(-1) to 0.01379 h(-1)), and the optimized ratio of woodchips to sulfur is 1:1 (w/w). No sulfate accumulation is observed in the WSHAD process and the alkalinity generated in the heterotrophic denitrification can compensate for alkalinity consumption by the sulfur-based autotrophic denitrification. The symbiotic relationship between the autotrophic and the heterotrophic denitrification processes play a vital role in the mixotrophic environment. PMID- 26650452 TI - Stormwater biofilter treatment model (MPiRe) for selected micro-pollutants. AB - Biofiltration systems, also known as bioretentions or rain-gardens, are widely used for treatment of stormwater. In order to design them well, it is important to improve models that can predict their performance. This paper presents a rare model that can simulate removal of a wide range of micro-pollutants from stormwater by biofilters. The model is based on (1) a bucket approach for water flow simulation, and (2) advection/dispersion transport equations for pollutant transport and fate. The latter includes chemical non-equilibrium two-site model of sorption, first-order decay, and volatilization, thus is a compromise between the limited availability of data (on stormwater micro-pollutants) and the required complexity to accurately describe the nature of the phenomenon. The model was calibrated and independently validated on two field data series collected for different organic micro-pollutants at two biofilters of different design. This included data on triazines (atrazine, prometryn, and simazine), glyphosate, and chloroform during six simulated stormwater events. The data included variable and challenging biofilter operational conditions; e.g. variable inflow volumes, dry and wet period dynamics, and inflow pollutant concentrations. The model was able to simulate water flow well, with slight discrepancies being observed only during long dry periods when, presumably, soil cracking occurred. In general, the agreement between simulated and measured pollutographs was good. As with flows, the long dry periods posed a problem for water quality simulation (e.g. simazine and prometryn were difficult to model in low inflow events that followed prolonged dry periods). However, it was encouraging that pollutant transport and fate parameters estimated by the model calibration were in agreement with available literature data. This suggests that the model could probably be adopted for assessment of biofilter performance of other stormwater micro-pollutants (PAHs, phenols, phthalates, etc.). The model, therefore, could be applied in practice for sizing of biofilter systems and their validation monitoring, when used for stormwater harvesting. PMID- 26650453 TI - Residual forefoot deformity predicts the need for future surgery in clubfeet treated by Ponseti casting. AB - Tibialis anterior tendon transfer (TATT) is performed for treatment of recurrent clubfeet. We investigated the predictability of residual adductus on the future need for TATT. A retrospective review of 143 patients with clubfoot was performed. The patients were divided into two groups: group 1 with a history of TATT and group 2 with no TATT. Heel-forefoot angle (HFA) was measured. HFA was compared between the groups. HFA was significantly different between groups 1 and 2. Residual adductus deformity in clubfeet treated by Ponseti casting is a risk factor for future need for surgical treatment. PMID- 26650454 TI - School life expectancy and risk for tuberculosis in Europe. AB - OBJECTIVE: This study aims to investigate the effect of country-level school life expectancy on Tuberculosis (TB) incidence to gain further understanding of substantial variation in TB incidence across Europe. METHODS: An ecological study examined the prospective association between baseline country-level education in 2000 measured by school life expectancy and TB incidence in 2000-2010 in 40 countries of the WHO European region using quantile regression. Subsequently, to validate the ecological associations between education and TB incidence, an individual-level analysis was performed using case-based data in 29 EU/EEA countries from the European Surveillance System (TESSy) and simulating a theoretical control group. RESULTS: The ecological analysis showed that baseline school life expectancy had a negative prospective association with TB incidence. We observed consistent negative effects of school life expectancy on individuals' TB infections prospectively. CONCLUSIONS: These findings suggests that country level education is an important determinant of individual-level TB infection in the region, and in the absence of a social determinants indicator that is routinely collected for reportable infectious diseases, the adoption of country level education for reportable infectious diseases would significantly advance the field. PMID- 26650455 TI - Adolescents' responses to the promotion and flavouring of e-cigarettes. AB - OBJECTIVES: The purpose of the study is to examine adolescents' awareness of e cigarette marketing and investigate the impact of e-cigarette flavour descriptors on perceptions of product harm and user image. METHODS: Data come from the 2014 Youth Tobacco Policy Survey, a cross-sectional in-home survey conducted with 11 16 year olds across the UK (n = 1205). Adolescents' awareness of e-cigarette promotion, brands, and flavours was assessed. Perceptions of product harm, and likely user of four examples of e-cigarette flavours was also examined. RESULTS: Some participants had tried e-cigarettes (12 %) but regular use was low (2 %) and confined to adolescents who had also smoked tobacco. Most were aware of at least one promotional channel (82 %) and that e-cigarettes came in different flavours (69 %). Brand awareness was low. E-cigarettes were perceived as harmful (M = 3.54, SD = 1.19) but this was moderated by product flavours. Fruit and sweet flavours were perceived as more likely to be tried by young never smokers than adult smokers trying to quit (p < 0.001). CONCLUSIONS: There is a need to monitor the impact of future market and regulatory change on youth uptake and perceptions of e-cigarettes. PMID- 26650456 TI - Hyperhomocysteinemia-induced upper extremity deep vein thrombosis and pulmonary embolism in a patient with methyltetrahydrofolate reductase mutation: a case report and literature review. AB - The study highlights pulmonary embolism and deep vein thrombosis by methylene tetrahydrofolate reductase (MTHFR) deficiency-related hyperhomocysteinemia occurring in rare locations of left veins superior to the heart extensively. A 59 year-old white man with history of leg pain, smoking, weight loss, benign prostatic hyperplasia, lipoma and panic attack presented with shortness of breath and chest pain for 2 days precipitated by not feeling well for months. The diagnostic workup revealed pulmonary embolism and deep vein thrombosis in the left subclavian vein which extended throughout the left brachiocephalic vein to the superior vena cava and left jugular vein. Further workup showed moderate hyperhomocysteinemia with normal levels of vitamin B6, B12 and folic acid. Methylene tetrahydrofolate reductase genetic study found the patient to be homozygous for G677T variant. He was started on low-molecular-weight heparin and was discharged on oral anticoagulant. No recurrent thrombotic episodes were witnessed after 4 months of follow-up after discharge. PMID- 26650457 TI - Postpartum haemorrhage in a woman with essential thrombocythemia carrying calreticulin mutation: a case report. AB - Coagulation disorder associated with essential thrombocythemia may exacerbate the prothrombotic state physiologically occurring during pregnancy. We report a case of a severe postpartum haemorrhage in a 35-year-old woman previously diagnosed with essential thrombocythemia and carrying the somatic calreticulin mutation. She was referred to our Thrombosis and Haemostasis Unit for pregnancy management. A treatment with low-dose aspirin was prescribed until the labour started, as the platelets count raised above 1000 * 10/l. At the time of bleeding, no residual placenta was detected at the revision of the uterine cavity.Although the postpartum is a high-risk period for thrombotic events, we have to carefully evaluate in women with essential thrombocythemia the likelihood of developing a hemorrhagic complication. PMID- 26650458 TI - The effect of the perfluorocarbon emulsion Oxycyte on platelet count and function in the treatment of decompression sickness in a swine model. AB - Decompression from elevated ambient pressure is associated with platelet activation and decreased platelet counts. Standard treatment for decompression sickness (DCS) is hyperbaric oxygen therapy. Intravenous perfluorocarbon (PFC) emulsion is a nonrecompressive therapy being examined that improves mortality in animal models of DCS. However, PFC emulsions are associated with a decreased platelet count. We used a swine model of DCS to study the effect of PFC therapy on platelet count, function, and hemostasis. Castrated male swine (n = 50) were fitted with a vascular port, recovered, randomized, and compressed to 180 feet of sea water (fsw) for 31 min followed by decompression at 30 fsw/min. Animals were observed for DCS, administered 100% oxygen, and treated with either emulsified PFC Oxycyte (DCS-PFC) or isotonic saline (DCS-NS). Controls underwent the same procedures, but were not compressed (Sham-PFC and Sham-NS). Measurements of platelet count, thromboelastometry, and coagulation were obtained 1 h before compression and 1, 24, 48, 96, 168 and 192 h after treatment. No significant changes in normalized platelet counts were observed. Prothrombin time was elevated in DCS-PFC from 48 to 192 h compared with DCS-NS, and from 96 to 192 h compared with Sham-PFC. Normalized activated partial thromboplastin time was also elevated in DCS-PFC from 168 to 192 h compared with Sham-PFC. No bleeding events were noted. DCS treated with PFC (Oxycyte) does not impact platelet numbers, whole blood clotting by thromboelastometry, or clinical bleeding. Late changes in prothrombin time and activated partial thromboplastin time associated with PFC use in both DCS therapy and controls warrant further investigation. PMID- 26650459 TI - Increased fibrin formation and impaired fibrinolytic capacity in severe chronic kidney disease. AB - Chronic kidney disease (CKD) is associated with a concurrent increased risk of thrombosis and bleeding. We aimed to investigate whether CKD is associated with increased fibrin formation, impaired fibrin degradation, or both. Twenty-one patients with CKD stage 4 (CKD 4), 15 haemodialysis patients, and 13 controls (C) without kidney disease were studied. We used a global assay to determine fibrin formation and degradation in plasma. Fibrin turbidity was measured over time to obtain a value of the coagulation activation profile (Cp) and the fibrinolysis activation profile (Fp), and the amount of fibrin formed, termed fibrin optical density sum (fibrin OD-sum). We used scanning electron microscopy (SEM) to visualize the fibrin network. Plasminogen activator inhibitor type-1 antigen, thrombin-activatable fibrinolysis inhibitor activity, fibrinogen, von Willebrand factor, antithrombin, albumin, and C-reactive protein were measured in plasma. Fibrin OD-sum was significantly elevated in haemodialysis patients [312 a.u.; 278 435 (median; interquartile range); P < 0.0013] and in CKD 4 (293 a.u.; 169-434; P = 0.0119) compared with controls (115 a.u.; 82-234). SEM showed a tight fibrin network in haemodialysis and CKD 4 patients. Fp was lower in the haemodialysis group than in controls (P = 0.030). Plasminogen activator inhibitor type-1 was lower in haemodialysis patients (P = 0.034). Thrombin-activatable fibrinolysis inhibitor activity, Cp, antithrombin, and C-reactive protein did not differ between groups. Fibrinogen was significantly elevated and albumin decreased in both haemodialysis and CKD 4 patients compared with controls. Von Willebrand factor was elevated in haemodialysis patients compared with controls (P = 0.010). The prothrombotic state in severe CKD is characterized by impaired fibrinolysis in association with increased fibrin formation despite normal levels of endogenous fibrinolysis inhibitors. PMID- 26650460 TI - Successful use of eltrombopag in a child with refractory immune thrombocytopenia: case study and literature review. AB - Treatment of refractory immune thrombocytopenia (ITP) continues to challenge medical practitioners because of the lack of well tolerated and effective drugs. Eltrombopag is a second-generation thrombopoietin approved to treat adult chronic/refractory ITP in 2008. The use of eltrombopag to treat pediatric refractory ITP remains in the clinical trial stage, and no reports on its use in China are yet available. In this article, we describe a pediatric case of refractory ITP that was successfully treated with eltrombopag. Eltrombopag appears to be well tolerated and effective for treating pediatric refractory ITP with few side-effects. PMID- 26650461 TI - Plasma homocysteine levels, methylene tetrahydrofolate reductase A1298C gene polymorphism and risk of retinal vein thrombosis. AB - There are limited data regarding the role of methylene tetrahydrofolate reductase (MTHFR) A1298C polymorphism and hyperhomocysteinemia as risk factors for retinal vein thrombosis (RVT) in Iranians. This study aimed to examine a possible association between fasting plasma total homocysteine (tHcy) levels, MTHFR A1298C polymorphism and RVT development in Iranian patients. Our study population consisted of 73 patients with a diagnosis of RVT (52.7 +/- 16.2 years) and 73 age and sex-matched healthy controls (49.1 +/- 14.6 years). Genotyping for the MTHFR A1298Cpolymorphism was conducted by PCR-RFLP technique and plasma tHcy levels were measured by an enzyme immunoassay method. Fasting plasma tHcy levels were 20.29 +/- 8.5 MUmol/l in RVT patients and 10.9 +/- 3.1 MUmol/l in control subjects. The number of cases with abnormal tHcy values (hyperhomocysteinemia) was significantly higher in the RVT patients than control subjects (P = 0.0001). The prevalence of MTHFR 1298CC homozygote genotype was similar in RVT patients and controls (17.8 vs.15.1%, P = 0.45). There were no significant differences in genotype distribution of MTHFR A1298C polymorphism between males and females in both RVT patients and controls (P > 0.05). The frequency of the 1298C allele was 39.1 and 35.6% in patients and controls, respectively, and did not differ significantly between them (P = 0.23). Moreover, heterozygote and homozygote genotypes in the RVT patients had significantly higher abnormal tHcy values than corresponding genotypes in control subjects (P < 0.001). Our study demonstrated that hyperhomocysteinemia but not homozygosity for MTHFR A1298C polymorphism is a significant risk factor for RVT in the Iranian population. PMID- 26650462 TI - Torticollis in a haemophilic infant with inhibitor: a case of spinal epidural haematoma. AB - Central nervous system bleeding, which can be a life-threatening complication, is seen in 2.7% of patients with haemophilia. Spinal epidural haematomas represent about one-tenth of such cases. Here, we report on a 10-month-old boy with severe haemophilia A, who presented with torticollis. Although administration of factor VIII at a dose of 50 U/kg, the patient developed flaccid paralysis of the upper extremities. Factor VIII inhibitor screen was positive. Magnetic resonance imaging of the spine revealed spinal epidural haematomas, extending from C-1 to the cauda equina. Treatment was continued with recombinant activated factor VIIa without surgery. After 1 month, complete neurological recovery was achieved and fully resolved haematomas were detected on spinal MRI. A prompt radiological evaluation of the cervical spine with MRI should be made in patients with haemophilia presenting with torticollis. In addition, in the case of life threatening bleeding in patients with haemophilia, the possibility of an inhibitor should be kept in mind. PMID- 26650463 TI - Simple blood tests as predictive markers of disease severity and clinical condition in patients with venous insufficiency. AB - Chronic venous insufficiency (CVI) is a progressive inflammatory disease. Because of its inflammatory nature, several circulating markers were investigated for predicting disease progression. We aimed to investigate simple inflammatory blood markers as predictors of clinical class and disease severity in patients with CVI. Eighty patients with CVI were divided into three groups according to clinical class (grade 1, 2 and 3) and score of disease severity (mild, moderate and severe). The basic inflammatory blood markers [neutrophil, lymphocyte, mean platelet volume (MPV), white blood cell (WBC), platelet, albumin, D-dimer, fibrinogen, fibrinogen to albumin ratio, and neutrophil to lymphocyte ratio] were investigated in each group. Serum neutrophil, lymphocyte, MPV, platelet count, D dimer and neutrophil to lymphocyte ratio levels were similar among the groups (P > 0.05). Although the serum WBC levels were significant in the clinical severity groups (P < 0.05), it was useless to separate each severity class. However, albumin, fibrinogen and the fibrinogen to albumin ratio were significant predictors of clinical class and disease severity. Especially, the fibrinogen to albumin ratio was detected as an independent indicator for a clinical class and disease severity with high sensitivity and specificity (75% sensitivity and 87.5% specificity for clinical class and 90% sensitivity and 88.3% specificity for disease severity). Serum fibrinogen and albumin levels can be useful parameters to determine clinical class and disease severity in patients with CVI. Moreover, the fibrinogen to albumin ratio is a more sensitive and specific predictor of the progression of CVI. PMID- 26650464 TI - Transplantation of mesenchymal stem cells improves type 1 diabetes mellitus. AB - Bone-marrow-derived stem cells can regenerate pancreatic tissue in a model of type 1 diabetes mellitus. Mesenchymal stem cells (MSCs) form the main part of bone marrow. We show that the intrapancreatic transplantation of MSCs elevates serum insulin and C-peptide, while decreasing blood glucose. MSCs engrafted into the damaged rat pancreas become distributed into the blood vessels, acini, ducts, and islets. Renascent islets, islet-like clusters, and a small number of MSCs expressing insulin protein have been observed in the pancreas of diabetic rats. Intrapancreatic transplantation of MSCs triggers a series of molecular and cellular events, including differentiation towards the pancreas directly and the provision of a niche to start endogenous pancreatic regeneration, which ameliorates hypoinsulinemia and hyperglycemia caused by streptozotocin. These data establish the many roles of MSCs in the restoration of the function of an injured organ. PMID- 26650465 TI - Topographies and isoforms of the progesterone receptor in female human, rat and mouse bladder. AB - Steroid hormones such as progesterone are known to influence bladder function. Progesterone effects are mediated by the progesterone receptor (PR) but no detailed studies of PR in bladder exist. We have investigated the presence, topography and subtypes of PR in mouse, rat and human bladder. Fresh tissue samples were obtained from cystectomies in female humans, rats and mice (n = 7 per group). Tissue samples were processed for immunohistochemistry (IHC), immunofluorescence (IF) and western blot (WB) and, for each species, a panel of specific PR antibody clones was used. Interpretation of IHC/IF was carried out by light/fluorescent microscopy and of WB via standard WB software. IHC/IF in female human bladder showed PR on the interstitial cells in the lamina propria and between detrusor smooth muscle cells, whereas in female rat and mouse bladder, PR was only found on the urothelium. WB in human bladder showed a 78-kD and a 60-kDa band, respectively, corresponding to a modified PR isoform A and PR isoform C. WB in rat and mice bladder showed a 60 kDa band and a 37 kDa band, respectively corresponding with PR isoform C and an unknown isoform. This is the first detailed investigation of the precise location and presence of several isoforms of PR in bladder, together with a comparison of these data between human, rat and mouse. Our study has revealed complex PR families in bladders from the various species studied and demonstrates obvious inter-species differences in PR topography and isoforms. PMID- 26650466 TI - Text Mining for Protein Docking. AB - The rapidly growing amount of publicly available information from biomedical research is readily accessible on the Internet, providing a powerful resource for predictive biomolecular modeling. The accumulated data on experimentally determined structures transformed structure prediction of proteins and protein complexes. Instead of exploring the enormous search space, predictive tools can simply proceed to the solution based on similarity to the existing, previously determined structures. A similar major paradigm shift is emerging due to the rapidly expanding amount of information, other than experimentally determined structures, which still can be used as constraints in biomolecular structure prediction. Automated text mining has been widely used in recreating protein interaction networks, as well as in detecting small ligand binding sites on protein structures. Combining and expanding these two well-developed areas of research, we applied the text mining to structural modeling of protein-protein complexes (protein docking). Protein docking can be significantly improved when constraints on the docking mode are available. We developed a procedure that retrieves published abstracts on a specific protein-protein interaction and extracts information relevant to docking. The procedure was assessed on protein complexes from Dockground (http://dockground.compbio.ku.edu). The results show that correct information on binding residues can be extracted for about half of the complexes. The amount of irrelevant information was reduced by conceptual analysis of a subset of the retrieved abstracts, based on the bag-of-words (features) approach. Support Vector Machine models were trained and validated on the subset. The remaining abstracts were filtered by the best-performing models, which decreased the irrelevant information for ~ 25% complexes in the dataset. The extracted constraints were incorporated in the docking protocol and tested on the Dockground unbound benchmark set, significantly increasing the docking success rate. PMID- 26650467 TI - Multifunctional, Micropipette-based Method for Incorporation And Stimulation of Bacterial Mechanosensitive Ion Channels in Droplet Interface Bilayers. AB - MscL, a large conductance mechanosensitive channel (MSC), is a ubiquitous osmolyte release valve that helps bacteria survive abrupt hypo-osmotic shocks. It has been discovered and rigorously studied using the patch-clamp technique for almost three decades. Its basic role of translating tension applied to the cell membrane into permeability response makes it a strong candidate to function as a mechanoelectrical transducer in artificial membrane-based biomolecular devices. Serving as building blocks to such devices, droplet interface bilayers (DIBs) can be used as a new platform for the incorporation and stimulation of MscL channels. Here, we describe a micropipette-based method to form DIBs and measure the activity of the incorporated MscL channels. This method consists of lipid-encased aqueous droplets anchored to the tips of two opposing (coaxially positioned) borosilicate glass micropipettes. When droplets are brought into contact, a lipid bilayer interface is formed. This technique offers control over the chemical composition and the size of each droplet, as well as the dimensions of the bilayer interface. Having one of the micropipettes attached to a harmonic piezoelectric actuator provides the ability to deliver a desired oscillatory stimulus. Through analysis of the shapes of the droplets during deformation, the tension created at the interface can be estimated. Using this technique, the first activity of MscL channels in a DIB system is reported. Besides MS channels, activities of other types of channels can be studied using this method, proving the multi-functionality of this platform. The method presented here enables the measurement of fundamental membrane properties, provides a greater control over the formation of symmetric and asymmetric membranes, and is an alternative way to stimulate and study mechanosensitive channels. PMID- 26650468 TI - [Actions against Inverse Distribution: cooperation is the Key]. PMID- 26650469 TI - [The Reverse Traffic of Drugs Phenomenon: experience in Galicia, Spain]. AB - IInter-state movement of drugs between EU countries by pharmaceutical companies and distribution warehouses is a permitted activity called parallel trade. As Spain is among the states with lower price of these products, its main activity is shipping to other countries; however, a phenomenon has emerged in acquiring drugs for this purpose, called "reverse traffic" that develops without observing the health regulations in the legal distribution channel in our country; in which, the pharmaceutical distribution warehouses, rather than getting drugs from other pharmaceutical companies or pharmaceutical distribution warehouses under the current legislation, obtain them from community pharmacies, thus reversing the legal supply circuit, as this drugs do not end dispensed to the public. This paper studies the risks to public health caused by these practices, detailing the results of health inspections in Galicia, where in relation to the total pharmaceutical establishments sanctioning procedures in the period 2011-2014, were sanctioned for this reason 15 community pharmacies and 5 distribution warehouses, the maximum fines belonging to a network consisting of a pharmaceutical distribution warehouse, with a 1,000,000 ? fine and closure for 3 years, and 4 community pharmacies, with 2,400,000 ? total fine; It also specifies the methodology of action, identifies the scene of illegal acquisition to make this trade with the greatest economic benefits, highlights the strengths of the success and further action to improve its approach. PMID- 26650470 TI - [Compliance with Physical Activity Recommendations and Associated Factors in a Cohort of Spanish Adult Workers]. AB - BACKGROUND: Physical inactivity remains a public health problem worldwide. The purpose of this study was to determine compliance with physical activity (PA) recommendations developed by the World Health Organization (WHO) and to analyze the association with different cardiovascular risk factors (CVRF) and sociodemographic and lifestyle determinants in a sample of Spanish workers. METHODS: A cross sectional analysis was carried out in a sample of 2.651 individuals (2.428 men and 133 women, aged 40-55 years old) from the Aragon Workers' Health Study (AWHS). Sample was divided into two groups depending on whether they met PA recommendations during the last year, including transportation, leisure and occupational PA. Sociodemographic, anthropometric, clinical, pharmacological and lifestyle data were collected during the years 2011 2014. Median and interquartile range for quantitative variables and frequency distribution for categorical variables were used. Crude and adjusted binary logistic regression models were carried out to study the likelihood of meeting with PA recommendations based on the number of CVRF (hypertension, dyslipidemia, diabetes, obesity and smoking) present. RESULTS: 47.0% of workers complied with WHO recommendations for PA. Lower prevalence of compliance was found among those participants presenting some CVRF (39.7% in hypertensive, 38.7% in dyslipidemic and 32.7% in diabetic). Of the total study sample, 51.3% reported not performing PA or practice a light PA, 20.2% moderate and 28.5% vigorous or very vigorous PA. The likelihood of compliance with PA recommendations decreased with increasing the number of CVRF: 1 CVRF (OR: 0.62; 95%IC: 0.49-0.78), 2 CVRF (OR: 0.49; 95% IC: 0.38-0.62), 3 CVRF (OR: 0.34; 95% IC: 0.25-0.46), 4 CVRF (OR: 0.19; 95% IC: 0.11-0.32). CONCLUSIONS: Compliance with recommendations of PA in our population remains insufficient, moreover in those with increased cardiovascular risk. PMID- 26650471 TI - [Risk Factors for Potentially Unsuccessful Results and Mortality during Tuberculosis Treatment in Spain]. AB - BACKGROUND: Successful result of treatment in 85% of cases is the target of a Tuberculosis (TB) Control Programme. The aim of this study is to determine the risk factors for unsuccessful completion of treatment and deaths of TB cases in Spain. METHODS: Data from the National Surveillance Epidemiological Network. Retrospective study including 5,880 TB cases reported in 2012. Outcomes were classified as: successful (S: cured and treatment completed), potentially unsuccessful (PU: failed, transferred, defaulted, still on treatment and unknown) and deaths. Logistic regression analysis was used to explore the association between epidemiological and clinical factors with PU and deaths as outcome variables. Two different models for nationals and foreigners were adjusted. RESULTS: Successful outcome was 81% in nationals and 79% in foreigners. Spanish TB cases had higher mortality rates than foreigners (8% vs. 2%), and lower percentage of transfers (2% vs. 6%). At multivariate level the risk factors for PU in nationals were: HIV coinfection (OR 1.6 CI95% 1.09-2.29) and previous treatment (OR 2.4 CI95% 1.67-3.53); and HIV coinfection (OR 1.7 CI95% 1.15-2.60), male sex (OR 1.4 CI95% 1.11-1.83) and pulmonary TB (OR 1.6 CI95% 1.22-2.09) in foreigners. Risk factors for death in nationals were: HIV coinfection (OR 2.7 CI95% 1.63-4.54), male sex (OR 1.4 CI95% 1.09-1.89), pulmonary TB (OR 1.5 CI95% 1.13-1.95) and an increasing risk with age (OR 8.9 CI95% 5.16-15.67 in over 45 years group.).; and HIV coinfection (OR 3.2 CI95% 1.53-6.76), male sex (OR 2.2 CI95% 1.01-4.60) and older age (OR 3.4 CI95% 1.81-6.48 in over 45 years group.) in foreigners. CONCLUSION: The rate of successful treatment in Spain does not meet the international target, especially in foreigners. To reduce unsuccessful treatment and deaths it is necessary to improve management in TB-HIV co-infected cases, and those with previous treatment story, pulmonary TB, males and older age. PMID- 26650472 TI - [Factors Associated with Sexual Risk Behaviour Among Young People in Catalonia]. AB - BACKGROUND: Sexual behavior in young people is influenced by external factors that may increase their vulnerability. OBJECTIVE: to describe sexual behavior and other indicators of sexual and reproductive health among young people (16 to 24 years) in Catalonia and to identify factors associated with sexual risk behaviors. METHODS: Cross-sectional study in 2012 carried out by an online survey from a panel of population (n=800). Factors associated with not using a condom at last sexual intercourse were evaluated using multivariate logistic regression models. RESULTS: 76.1% of boys and 83.3% of girls reported having had complete sexual intercourse (p=0.012). The proportion of boys and girls who reported casual partners was 39.7% and 22.5%, respectively. 31.4% of boys and 10.3% of girls reported having contacted partners through Internet. Not using a condom at first sexual intercourse showed significant association with reporting not using a condom in the last sexual intercourse, for both, boys (OR= 2.50) and girls (OR= 3.18). Having contacted partners through the Internet (OR=2.29) was associated with this risky sexual behavior in boys, and having used the emergency contraception 3 or more times (OR=3.38) was associated in girls. CONCLUSIONS: There are differences in the sexual behavior of young people by sex, being condom use at first sexual relationship a good predictor of condom use at last sexual intercourse. Boys show a higher number of casual partners than girls, as well as a higher use of the Internet to contact sexual partners. PMID- 26650473 TI - [Economic Appraisal of the Impact of the Ban on the Use of Lead in Gasoline on the Intellectual Quotient of 7-8 Years Old in the Community of Madrid]. AB - BACKGROUND: The repercussions on health of public policies are hard to assess from an economic point of view, which is why this is rarely done. The purpose of this study was to financially quantify the benefits of reducing blood lead levels in children aged 7-8 years in the Community of Madrid (Spain) as a result of the ban on the use of lead in gasoline. METHODS: The decrease the intellectual quotient (IQ) points was calculated through two studies on children aged 7-8 years according to their blood lead levels. A geometric mean of 3.8 MUg/dl was obtained in the 1995 study and of 0.9 MUg/dl in the 2010 study. The net increase in IQ was measured in terms of productivity gained throughout the working life as per the methods of Schwartz and Salkever. RESULTS: The decrease in blood lead levels in these children prevented a loss of between 135,391 and 144,153 IQ points; the current economic valuation of these points in terms of the productivity gained throughout the working life of this cohort of children was estimated to fall within the ?626.4m- ?865.4m range (2009). CONCLUSIONS: The figures of the economic benefits derived from the decision to ban leaded gasoline are very high. PMID- 26650474 TI - [Elaboration of Criteria and Indicators to Develop and Evaluate Programs of Healthy Aging in the Workplace]. AB - BACKGROUND: In the actual context of population ageing and extension of working age, programs for health promotion at the workplace are a key and necessary tool to promote an active and healthy ageing. This work presents the methodological process followed to elaborate a checklist tool, within the framework of the European project Progress, that contributes to orientate planning, implementation and evaluation of good practices in this field, to be applicable to a variety of programs, countries and workplaces. METHODS: A Delphi technique has been applied in three rounds in which experts in the area from five European countries participated. A questionnaire created from a list of criteria and indicators was adapted throughout the rounds, with the use of webmail, to the evaluation of interventions in the field of interest. Through processes of assessment and consensus, criteria and indicators most relevant were prioritized. RESULTS: From the nine starting criteria and after the implementation of the technique, four key criteria were prioritized: relevance: 62, adequacy to objective: 57, innovation: 50 and guarantee of quality: 41. Using this group of criteria and indicators, a checklist was designed containing the key information that should be collected for planning, implementation and evaluation of good practices in interventions in this field. CONCLUSIONS: The checklist tool helps to systematize the global methodology for the implementation of interventions which could be very useful for persons responsible of programmes to promote active and healthy ageing in the workplace. PMID- 26650475 TI - [Contribution of Electronic Health Record in Surveillance of Notifiable Diseases]. AB - BACKGROUND: In 2009 a system was introduced for the automatic import (AI) of cases with suspected notifiable diseases (ND) from electronic medical record (EMR) to RedAlerta, an application for surveillance in Andalusia. At present, the contribution of this system to classical active statement has not been determined enough. The main objective of this study is to evaluate the usefulness of IA in the province of Granada, between 2009 and 2014. METHODS: During the study period (2009-2014), an epidemiologist assessed whether AI met declaration criteria or not. We calculate the contribution of AI to RedAlerta and the percentage of validation of AI, estimating 95% CI. RESULTS: The contribution of AI was 17.3% (95% CI 16.1 to 18.5); and type of statement, 5.2% (95% CI 4.1 to 6.5) for urgent and 24.4% (95% CI 22.7 to 26.2) for ordinary. The contribution was higher (more than 45%) in Lyme disease, congenital hypothyroidism, genital herpes, hepatitis C and other viral hepatitis. 30% (95% CI 28.1 to 32) of AI were validated; 39.9% (95% CI 33 to 47.2) urgent and 29.1% (95% CI 27.2 to 31.2%) ordinary. The percentage of validation was higher than 45% (between 47.5 and 100%) in vaccine preventable diseases, sexually transmitted infections and low incidence. CONCLUSIONS: Although not replace manual reporting and requires verification, the AI system is useful and increases the completeness of the epidemiological surveillance system. PMID- 26650476 TI - [Lifestyles and Styles of Parental Care Related to Childhood Obesity: compare Spain with Northern European Countries: ENERGY-Project]. AB - BACKGROUND: The prevalence of childhood obesity is higher in Spain than in Northern European countries for reasons that are still unknown. The objective was to determine whether variables related to lifestyle habits and styles of parental care related to obesity in children differ between the countries of Northern Europe and Spain. METHODS: Data were obtained from the ENERGY international project using questionnaires. We analyzed data from Spain, the Netherlands, Belgium and Norway including 1937 boys and 2061 girls aged 10-12 years old. We have studied the behavior of parents related to dietary variables, variables related to physical activity and ways of care. We calculated the mean and the proportions of all the variables and then calculated the association between different variables with the country of origin using the beta coefficient and the odds ratio (OR) as a measure of association. RESULTS: Compared with parents in Northern Europe, Spanish parents consume significantly less days a week sugary drinks (Mean: 1.37 vs 2.16) but they consume more fruit juices (Mean: 2,61 vs 2,35). Spanish parents are more active going to their work, they are less sedentary but perform physical activity in their leisure time fewer days per week (Mean days per week they do physical activity in their leisure time: 1.88 vs 2.21). In addition, they are less negotiators with their children (Mean (0-4): 1.26 vs 1.68) and prevent less negative role models (Mean (0-4): 0.90 vs 1.29). However, they pay more attention (Mean (0-4): 3.42 vs 3.04) and encourage more healthy habits (Mean (0-4): 2.38 vs 2.06). CONCLUSIONS: The variables related to lifestyle habits and styles of care related to childhood obesity differ between Spanish parents and those of the countries of Northern Europe but these differences are not statistically significant. Therefore, differences in lifestyles and parenting practices might not explain the significant differences in childhood obesity between the Northern countries and Spain. PMID- 26650477 TI - Chemical-Biological Properties of Zinc Sensors TSQ and Zinquin: Formation of Sensor-Zn-Protein Adducts versus Zn(Sensor)2 Complexes. AB - Fluorescent zinc sensors are the most commonly used tool to study the intracellular mobile zinc status within cellular systems. Previously, we have shown that the quinoline-based sensors Zinquin and 6-methoxy-8-p toluenesulfonamido-quinoline (TSQ) predominantly form ternary adducts with members of the Zn-proteome. Here, the chemistries of these sensors are further characterized, including how Zn(sensor)2 complexes may react in an intracellular environment. We demonstrate that these sensors are typically used in higher concentrations than needed to obtain maximum signal. Exposing cells to either Zn(Zinquin)2 or Zn(TSQ)2 resulted in efficient cellular uptake and the formation of sensor-Zn-protein adducts as evidenced by both a fluorescence spectral shift toward that of ternary adducts and the localization of the fluorescence signal within the proteome after gel filtration of cellular lysates. Likewise, reacting Zn(sensor)2 with the Zn-proteome from LLC-PK1 cells resulted in the formation of sensor-Zn-protein ternary adducts that could be inhibited by first saturating the Zn- proteome with excess sensor. Further, a native SDS-PAGE analysis of the Zn proteome reacted with either the sensor or the Zn(sensor)2 complex revealed that both reactions result in the formation of a similar set of sensor-Zn-protein fluorescent products. The results of this experiment also demonstrated that TSQ and Zinquin react with different members of the Zn-proteome. Reactions with the model apo-Zn-protein bovine serum albumin showed that both Zn(TSQ)2 and Zn(Zinquin)2 reacted to form ternary adducts with its apo-Zn-binding site. Moreover, incubating Zn(sensor)2 complexes with non-zinc binding proteins failed to elicit a spectral shift in the fluorescence spectrum, supporting the premise that blue-shifted emission spectra are due to sensor-Zn-protein ternary adducts. It was concluded that Zn(sensors)2 species do not play a significant role in the overall reaction between these sensors and intact cells. In turn, this study further supports the formation of sensor-Zn-protein adducts as the principal observed fluorescent product during experiments employing these two sensors. PMID- 26650478 TI - Excited-state deactivation in 8-oxo-deoxyguanosine: comparison between anionic and neutral forms. AB - 8-Oxoguanine is the most abundant oxidation product found in oxidatively damaged DNA. The study of the excited-state properties of the corresponding deoxyribonucleoside 8-oxo-deoxyguanosine is thus of important biological relevance. Herein, we present an ADC(2)-s ab initio study of the neutral and the anionic form of 8-oxo-deoxyguanosine, for each of which we have considered the intramolecularly 5'-O-H...N3 hydrogen-bonded syn conformer. We present energy profiles for a radiationless deactivation mechanism via intramolecular excited state proton transfer. This mechanism is accessible in the neutral form, but it is unavailable in the anion. We present optimized structures for the proton transfer conical intersection of the neutral form as well as the ring-puckered conical intersections inherent to the 8-oxoguanine moiety for the neutral and anionic forms. We highlight the possible relevance of the proton-transfer mechanism for the neutral form and discuss our results in light of several recently published computational and spectroscopic studies. Our results provide new insight into the photophysics of this biologically relevant nucleoside and pave the way for future nonadiabatic dynamics studies and for further spectroscopic investigations. PMID- 26650479 TI - Preclinical and preliminary clinical evaluation of genetically transduced dermal tissue implants for the sustained secretion of erythropoietin and interferon alpha. AB - Protein drugs are currently delivered by bolus injection and although treatment frequently is successful, these methods also have major drawbacks, which call for the development of alternative technologies allowing prolonged delivery of these drugs. We developed a new ex vivo gene therapy platform called Transduced Autologous Restorative Gene Therapy (TARGT) for sustained long term production and secretion of autologous therapeutic proteins. A biopsy of dermal tissue taken from the patient is transduced ex vivo with a viral vector encoding the required gene under a constitutive promoter. Following measurement of protein secretion ex vivo, the transduced dermal tissue is implanted back into the patient, where it secretes the therapeutic protein into the circulation for several months or longer. A major hurdle to this approach is potential immunogenicity of the transduced tissue following implantation. In this paper we describe the preclinical and early clinical development of this technology, which allowed overcoming these hurdles. To that end, we have used the helper dependent (HD) adenoviral vector with newly designed expression cassette containing genetic elements to optimize transgene expression. Moreover, we have developed procedures for TARGT tissue implantation, with measures to improve engraftment and reduce inflammation and rejection. Implantation of human TARGT to immune-deficient SCID mice indicated long-term production of active proteins in the blood. Preliminary results of a clinical trial from two anemic end-stage renal disease patients, implanted with TARGTs expressing the human erythropoietin (EPO) gene, demonstrated prolonged secretion with physiologic blood level of the hormone and Hemoglobin maintenance in the desired range, for a period of at least five months without exogenous EPO administration. We believe that the TARGT technology has the potential to become a platform for the sustained delivery of therapeutic proteins in various clinical indications. PMID- 26650480 TI - Variance in saccadic eye movements reflects stable traits. AB - Saccadic tasks are widely used to study cognitive processes, effects of pharmacological treatments, and mechanisms underlying psychiatric disorders. In genetic studies, it is assumed that saccadic endophenotypes are traits. While internal consistency and temporal stability of saccadic performance is high for most of the measures, the magnitude of underlying trait components has not been estimated, and influences of situational aspects and person by situation interactions have not been investigated. To do so, 68 healthy participants performed prosaccades, antisaccades, and memory-guided saccades on three occasions at weekly intervals at the same time of day. Latent state-trait modeling was applied to estimate the proportions of variance reflecting stable trait components, situational influences, and Person * Situation interaction effects. Mean variables for all saccadic tasks showed high to excellent reliabilities. Intraindividual standard deviations were found to be slightly less reliable. Importantly, an average of 60% of variance of a single measurement was explained by trans-situationally stable person effects, while situation aspects and interactions between person and situation were found to play a negligible role. We conclude that saccadic variables, in standard laboratory settings, represent highly reliable measures that are largely unaffected by situational influences. Extending previous reliability studies, these findings clearly demonstrate the trait-like nature of these measures and support their role as endophenotypes. PMID- 26650481 TI - Erratum to: Longitudinal associations between conduct problems and depressive symptoms among girls and boys with early conduct problems. PMID- 26650482 TI - Distinct relationships between social aptitude and dimensions of manic-like symptoms in youth. AB - Difficulties with interpersonal relationships have been reported in children and adolescents with manic symptoms, even if they do not fulfil criteria for a manic episode. The role of social aptitude (SA) in youths with manic symptoms has never been examined in the general population. Moreover, no study has examined whether SA is differentially associated with dimensions of manic symptoms. We hypothesised that youth with predominantly undercontrol manic symptoms (characterised by irritability) would show lower levels of SA; conversely, youth with predominantly exuberant symptoms would show better than average social skills. Our sample comprised 5325 participants from the 2004 British Child and Adolescent Mental Health Survey (B-CAMHS04), mean age 10.3 years, SD = 3.3, 48 % girls. Manic symptoms were assessed with the Development and Wellbeing Assessment by interviewing parents and young people. Children and adolescents with manic symptoms had a lower SA score, compared to the general population by parent report, but not by self-report. SA score was higher in youths with predominantly exuberant manic symptoms compared to the general population; whereas the youths with predominantly undercontrol manic symptoms had lower SA scores by parent and self-report. Our results provide further evidence for the distinction between exuberant and undercontrol manic symptoms and highlight the need to focus on SA in future research. PMID- 26650483 TI - Identification of miR-139-5p as a saliva biomarker for tongue squamous cell carcinoma: a pilot study. AB - BACKGROUND: Of all human oral carcinomas, 41 % are localized to the tongue. Despite considerable improvements in both diagnosis and treatment, tongue squamous cell carcinoma (TSCC) has remained one of the most lethal types of cancer. Here, we aimed at identifying a salivary microRNA (miRNA) expression signature specific for TSCC patients. METHODS: To identify putative diagnostic biomarkers, we compared the miRNA expression profiles of saliva samples from three TSCC patients and four healthy control individuals using an Agilent miRNA microarray platform (V19). Three of the differentially expressed miRNAs identified were selected for further validation using quantitative reverse transcription PCR (qRT-PCR) in saliva samples from 25 TSCC patients and 25 healthy control individuals. RESULTS: Through microarray-based expression profiling, we found that 419 miRNAs were deregulated in the saliva samples from the TSCC patients compared to those from the healthy control individuals tested. Subsequent qRT-PCR analysis revealed that the expression level of miR-139-5p was significantly reduced in the TSCC validation samples compared to the controls. Further analysis of post-operative saliva samples derived from TSCC patients revealed that the miR-139-5p expression levels had turned back to normal again. In addition, we found that miR-139-5p exhibited enough power to discriminate pre operative TSCC patients from both normal individuals (AUC: 0.805) and post operative TSCC patients (AUC: 0.713), thereby underscoring its diagnostic potential. CONCLUSIONS: From our results we conclude that saliva can be used as a feasible source for routine TSCC diagnostics and that miR-139-5p may serve as a potential biomarker for early TSCC detection. PMID- 26650485 TI - Iron-Doped Carbon Nitride-Type Polymers as Homogeneous Organocatalysts for Visible Light-Driven Hydrogen Evolution. AB - Graphitic carbon nitrides have appeared as a new type of photocatalyst for water splitting, but their broader and more practical applications are oftentimes hindered by the insolubility or difficult dispersion of the material in solvents. We herein prepared novel two-dimensional (2D) carbon nitride-type polymers doped by iron under a mild one-pot method through preorganizing formamide and citric acid precursors into supramolecular structures, which eventually polycondensed into a homogeneous organocatalyst for highly efficient visible light-driven hydrogen evolution with a rate of ~16.2 mmol g(-1) h(-1) and a quantum efficiency of 0.8%. Laser photolysis and electrochemical impedance spectroscopic measurements suggested that iron-doping enabled strong electron coupling between the metal and the carbon nitride and formed unique electronic structures favoring electron mobilization along the 2D nanomaterial plane, which might facilitate the electron transfer process in the photocatalytic system and lead to efficient H2 evolution. In combination with electrochemical measurements, the electron transfer dynamics during water reduction were depicted, and the earth-abundant Fe based catalyst may open a sustainable strategy for conversion of sunlight into hydrogen energy and cope with current challenging energy issues worldwide. PMID- 26650484 TI - HepG2 cells acquire stem cell-like characteristics after immune cell stimulation. AB - BACKGROUND: The presence of cancer stem cells (CSCs) is currently regarded as one of the main culprits of tumor formation and therapy failure. It is known that chronic inflammation is associated with CSCs, but it is not clear yet how inflammation affects the development of CSCs. In the present study we aimed to examine the relationship between cancer cell stimulation mediated by immune cells and the acquisition of a CSC-like phenotype. METHODS: Cancer cells derived from single hepatocarcinoma HepG2 cells were treated with mouse splenic B cells (MSBCs) and mouse peritoneal macrophage cells (MPMCs), respectively. The stem cell-like characteristics of the resulting HepG2 cells (MSBC-HepG2 and MPMC HepG2) were evaluated using different assays, including biomarker assays, in vitro tumoroid and colony forming assays, in vivo tumor forming assays and signal transduction pathway activation assays. RESULTS: Various stemness characteristics of HepG2 cells, including self-renewal, proliferation, chemoresistance and tumorigenicity were evaluated. The expression levels of stemness-related genes and its encoded proteins in the MSBC-HepG2 and MPMC-HepG2 cells were assessed using RT-PCR and FACS analyses. We found that MSBC-HepG2 and MPMC-HepG2 cells possess hepatic CSC properties, including persistent self-renewal, extensive proliferation, drug resistance, high tumorigenic capacity and over-expression of CSC-related genes and proteins (i.e., EpCAM, ALDH, CD133 and CD44), compared to the parental cells. We also found that 1x10(3) MSBC-HepG2 and MPMC-HepG2 cells were able to form tumors in NOD/SCID mice and that the Notch and SHH signaling pathways were highly activated in MSBC-HepG2 cells. CONCLUSIONS: We conclude that the immune system may have a double-edge effect on cancer development. On one hand, immune cells such as B lymphocytes and macrophages may recognize, attack and eliminate cancer cells, whereas on the other hand, they may promote a subset of cancer cells to acquire stem cell-like characteristics. PMID- 26650486 TI - The relationship between RRM1 gene polymorphisms and effectiveness of gemcitabine based first-line chemotherapy in advanced NSCLC patient. AB - PURPOSE: Chemotherapy with platinum compounds and gemcitabine is frequently used in first-line treatment of advanced non-small cell lung cancer (NSCLC) patients in which tyrosine kinase inhibitors (EGFR or ALK) cannot be administered. Unfortunately, less than half of the patients achieve the benefit from chemotherapy. Gemcitabine is an analog of deoxycytidine (pyrimidine antimetabolite) with antitumor activity. The excess of deoxycytidine synthesized by RRM1 enzyme activity may be a cause of competitive displacement of gemcitabine, which reduces the efficacy of this cytostatic. The aim of this study was to determine the association between single nucleotide polymorphisms (SNPs) of the RRM1 promoter (-37C>A, -524C>T) and the effectiveness of first-line chemotherapy based on platinum compounds and gemcitabine in NSCLC patients. PATIENTS AND METHODS: SNPs were determined by SNaPshot PCR((r)) in DNA isolated from peripheral blood of 91 NSCLC patients. RESULTS: The median progression-free survival (PFS) was significantly longer in carriers of AA (-37C>A) as well as CC (-524C>T) genotype of RRM1 compared to patients with other genotypes (10.5 vs 3.5 months, p = 0.0437; HR = 2.17, 95 % CI 1.02-4.62 and 10.5 vs 3.5 months, p = 0.0343; HR = 2.12, 95 % CI 1.06-4.27). In addition, the CC genotype carriers ( 37C>A) showed a significant increase in the risk of shortening overall survival (OS) in comparison to patients with AA or AC genotypes (9.5 vs 18 months, p = 0.0193; HR = 2.13, 95 % CI 1.13-4.03). CONCLUSIONS: Presence of rare AA (-37C>A) and CC (-524C>T) genotypes of the RRM1 may be favorable predictive factors for chemotherapy with platinum compounds and gemcitabine in NSCLC patients. PMID- 26650487 TI - SEOM guidelines for cervical cancer. AB - Cervical cancer (CC) is the second most common cancer worldwide, strongly linked to high-risk human papilloma virus infection. Although screening programs have led to a relevant reduction in the incidence and mortality due to CC in developed countries, it is still an important cause of mortality in undeveloped countries. Clinical stage is still the most relevant prognostic factor. In early stages, the primary treatment is surgery or radiotherapy, whereas concomitant chemo radiotherapy is the conventional approach in locally advanced stages. In the setting of recurrent or metastatic CC, for the first time ever, the combination of chemotherapy plus bevacizumab prolongs the overall survival beyond 12 months. Therefore, this regimen is considered by most of the oncologist a new standard of care for metastatic/recurrent CC. PMID- 26650488 TI - Measuring citalopram in blood and cerebrospinal fluid: revealing a distribution pattern that differs from other antidepressants. AB - The aim of this study was to measure blood and cerebrospinal fluid concentrations of citalopram and its weakly active N-demethylated metabolite desmethylcitalopram to account for the distribution between the two compartments. The findings are discussed in the context with own preceding studies on the distribution pattern of different antidepressants. Concentrations of citalopram were measured in blood serum and cerebrospinal fluid of 18 patients treated with daily doses of 10-40 mg. Daily doses were correlated with serum and cerebrospinal fluid concentrations, and serum concentrations were correlated with concentrations in cerebrospinal fluid. Serum concentrations of citalopram and desmethylcitalopram showed no significant correlation to the daily dose, r=0.164, P=0.515, and r=0.174, P=0.505, respectively, whereas citalopram concentrations in serum and cerebrospinal fluid were highly correlated (r=0.763, P<0.001). The cerebrospinal fluid/serum ratio for citalopram (total=bound+unbound concentration) varied between 0.14 and 0.86 (mean 0.35, SD 0.16). By correcting the mean cerebrospinal fluid/serum ratio for 80% plasma protein binding, cerebrospinal fluid concentrations of citalopram were on average 77% higher than the calculated unbound serum concentration with a ratio of 1.77 (SD 0.81, range 0.68-4.29). Findings indicate a very good ability of citalopram to cross the blood-brain and cerebrospinal fluid barrier. High concentrations of citalopram in the cerebrospinal fluid are indicative of active transport of citalopram into or missing active transport out of the cerebrospinal fluid. The results suggest a high ability of citalopram to enter the brain with sufficiently high drug concentrations at the target sites within the brain, contributing toward clinical efficacy. PMID- 26650490 TI - Is the Patient You Anesthetized Yesterday Fully Recovered Today? PMID- 26650489 TI - Activation of alpha7nAChR Promotes Diabetic Wound Healing by Suppressing AGE Induced TNF-alpha Production. AB - Diabetes frequently presents accumulation of advanced glycation end products (AGEs), which might induce excessive TNF-alpha production from macrophages to cause impaired wound healing. Recent studies have shown that activation of alpha7 nicotinic acetylcholine receptor (alpha7nAChR) on macrophages efficiently suppressed TNF-alpha synthesis. The aim of this study was to investigate the accumulation of AGEs in the wounds and determine whether PNU282987, an alpha7nAChR agonist, can improve wound repair by inhibiting AGE-mediated TNF alpha production in a streptozotocin (STZ)-induced diabetic mouse model. Animals were assigned into four groups: wounded control group, wounded diabetic group, wounded diabetic group treated intraperitoneally with PNU282987, or wounded diabetic group treated intraperitoneally with vehicle. Compared with the non diabetic control mice, the diabetic mice exhibited delayed wound healing that was characterized by elevated accumulation of AGEs, increased TNF-alpha level and macrophage infiltration, and decreased fibroblast number and collagen deposition at the late stage of repair. Besides, macrophages of diabetic wounds showed expression of alpha7nAChR. During late repair, PNU282987 treatment of diabetic mice significantly reduced the level of TNF-alpha, accelerated wound healing, and elevated fibroblast number and collagen deposition. To investigate the cellular mechanism of these observations, RAW 264.7 cells, a macrophage cell line, were incubated with AGEs in the presence or absence of PNU282987. TNF-alpha production from AGE-stimulated macrophages was significantly decreased by PNU282987 in a dose-dependent manner. Furthermore, PNU282987 significantly inhibited AGE-induced nuclear factor-kappaB (NF-kappaB) activation and receptor for AGE (RAGE) expression. These results strongly suggest that activating alpha7nAChR can promote diabetic wound healing by suppressing AGE-induced TNF-alpha production, which may be closely associated with the blockage of NF-kappaB activation in macrophages. PMID- 26650491 TI - Effect of Preoperative Pain on Inferior Alveolar Nerve Block. AB - The present study tested the hypothesis that the amount and severity of preoperative pain will affect the anesthetic efficacy of inferior alveolar nerve block (IANB) in patients with symptomatic irreversible pulpitis. One-hundred seventy-seven adult volunteer subjects, actively experiencing pain in a mandibular molar, participated in this prospective double-blind study carried out at 2 different centers. The patients were classified into 3 groups on the basis of severity of preoperative pain: mild, 1-54 mm on the Heft-Parker visual analog scale (HP VAS); moderate, 55-114 mm; and severe, greater than 114 mm. After IANB with 1.8 mL of 2% lidocaine, endodontic access preparation was initiated. Pain during treatment was recorded using the HP VAS. The primary outcome measure was the ability to undertake pulp access and canal instrumentation with no or mild pain. The success rates were statistically analyzed by multiple logistic regression test. There was a significant difference between the mild and severe preoperative pain group (P = .03). There was a positive correlation between the values of preoperative and intraoperative pain (r = .2 and .4 at 2 centers). The amount of preoperative pain can affect the anesthetic success rates of IANB in patients with symptomatic irreversible pulpitis. PMID- 26650492 TI - Postoperative Pain in Children After Dentistry Under General Anesthesia. AB - The objective of this study was to determine the prevalence, severity, and duration of postoperative pain in children undergoing general anesthesia for dentistry. This prospective cross-sectional study included 33 American Society of Anesthesiology (ASA) Class I and II children 4-6 years old requiring multiple dental procedures, including at least 1 extraction, and/or pulpectomy, and/or pulpotomy of the primary dentition. Exclusion criteria were children who were developmentally delayed, cognitively impaired, born prematurely, taking psychotropic medications, or recorded baseline pain or analgesic use. The primary outcome of pain was measured by parents using the validated Faces Pain Scale Revised (FPS-R) and Parents' Postoperative Pain Measure (PPPM) during the first 72 hours at home. The results showed that moderate-to-severe postoperative pain, defined as FPS-R >= 6, was reported in 48.5% of children. The prevalence of moderate-to-severe pain was 29.0% by FPS-R and 40.0% by PPPM at 2 hours after discharge. Pain subsided over 3 days. Postoperative pain scores increased significantly from baseline (P < .001, Wilcoxon matched pairs signed rank test). Moderately good correlation between the 2 pain measures existed 2 and 12 hours from discharge (Spearman rhos correlation coefficients of 0.604 and 0.603, P < .005). In conclusion, children do experience moderate-to-severe pain postoperatively. Although parents successfully used pain scales, they infrequently administered analgesics. PMID- 26650493 TI - The Anesthetic Effect of Anterior Middle Superior Alveolar Technique (AMSA). AB - Anesthesia of the soft and hard tissues of the maxilla may require up to 5 injections. Thus, the aim of this study was to evaluate the anesthetic efficacy of the anterior middle superior alveolar (AMSA) and supraperiosteal injection techniques during subgingival scaling and root planing (SRP). Thirty individuals with periodontitis were scheduled for SRP on the buccal aspect of teeth in the anterior maxilla. Before SRP, on a randomly chosen side of the maxilla, the supraperiosteal injection was performed in 1 session, while the AMSA injection was conducted in the contralateral side of the same patient in another session. Immediately after each SRP session, patients rated their pain perception during the procedure with a visual analog scale. No statistically significant differences in mean pain ratings during SRP were found after both anesthetic techniques (P > .05). This preliminary study demonstrated that the AMSA and supraperiosteal injection techniques provided similar anesthetic comfort during SRP. The AMSA injection could be an alternative to anesthetize the buccal aspect of maxilla, without the undesirable effects on facial structures such as the upper lip, nostrils, and lower eyelids. However, further randomized clinical trials with larger samples are necessary to confirm such results. PMID- 26650494 TI - Case of Vasovagal Syncope With Asystole Associated With Propofol Sedation. AB - Few cases of bradycardic complications occurring under intravenous sedation have been reported. Here, we report a case of vasovagal syncope with asystole (7.2 seconds) associated with propofol sedation. PMID- 26650495 TI - Pulseless Ventricular Tachycardia During Office-Based Anesthetic in a Four-Year Old Child. AB - A 4-year-old 16-kg boy presented for full mouth dental rehabilitation in a private pediatric dental office. The patient had no significant previous medical history. Upon sevoflurane induction by a dentist anesthesiologist, the patient converted from normal sinus rhythm to pulseless ventricular tachycardia. Advanced cardiac life support protocol was initiated. After 2 automatic external defibrillator shocks were delivered in conjunction with epinephrine administration, the patient returned to normal sinus rhythm. The patient was transported via emergency medical service paramedics to a local children's hospital emergency room where he was observed uneventfully for 24 hours prior to discharge. PMID- 26650496 TI - Partially Withdrawn Nasotracheal Tube: An Alternative to the Nasal Trumpet. AB - After 2-jaw surgery, difficulty in breathing through the mouth and the nose is common due to nasal airway obstruction, intraoral bleeding, and sometimes maxillomandibular fixation. A partially withdrawn nasotracheal tube can be used economically with equal efficacy to the nasopharyngeal airway to provide supplemental oxygen after 2-jaw surgery. PMID- 26650497 TI - Intraoperative Fluids and Fluid Management for Ambulatory Dental Sedation and General Anesthesia. AB - Intravenous fluids are administered in virtually every parenteral sedation and general anesthetic. The purpose of this article is to review the physiology of body-water distribution and fluid dynamics at the vascular endothelium, evaluation of fluid status, calculation of fluid requirements, and the clinical rationale for the use of various crystalloid and colloid solutions. In the setting of elective dental outpatient procedures with minor blood loss, isotonic balanced crystalloid solutions are the fluids of choice. Colloids, on the other hand, have no use in outpatient sedation or general anesthesia for dental or minor oral surgery procedures but may have several desirable properties in long and invasive maxillofacial surgical procedures where advanced hemodynamic monitoring may assess the adequacy of intravascular volume. PMID- 26650500 TI - Reaction Rate Constants of CH4(ads) ? CH3(ads) + H(ads) on Ni(111): The Effect of Lattice Motion. AB - Methane dissociation on metal surfaces is of great commercial importance. The dissociation and recombination rate constants of CH4 on Ni(111) are calculated using the quantum instanton approach with the path integral Monte Carlo method. The Ni(111) lattice is treated rigidly, classically, and quantum mechanically to reveal the effects of lattice motion and quantum tunneling. For the dissociation of CH4, the rates have the smallest value on the rigid lattice, while they possess the largest value on the quantum lattice. For instance, at 300 K, the rates on the classical and quantum lattices are 5 and 12 times larger than that on the rigid lattice, respectively. The curve of the Arrhenius plot for the dissociation rates on the rigid lattice demonstrates that the quantum tunneling effect of the ruptured H atom is remarkable, while the nearly invariable dissociation rates at low temperatures on the quantum lattice confirm that the thermally assisted tunneling should be dominant at low temperatures. For the recombination of CH4, the quantum lattice still has rates that are much larger than that of the rigid lattice. For instance, the ratio of the recombination rates on the quantum and rigid lattices is 12 at 300 K. The quantum tunneling effect seems to play a minor role in the recombination rates on the rigid lattice; however, the thermally assisted tunneling is still very significant for the recombination process. PMID- 26650501 TI - The Future of General Surgery Residency Education. PMID- 26650502 TI - Evaluation of anticonvulsant and antinociceptive properties of new N-Mannich bases derived from pyrrolidine-2,5-dione and 3-methylpyrrolidine-2,5-dione. AB - The aim of the present experiments was to examine anticonvulsant activity of new pyrrolidine-2,5-dione and 3-methylpyrrolidine-2,5-dione derivatives in animal models of epilepsy. In addition, the possible collateral antinociceptive activity was assessed. Anticonvulsant activity was investigated in the electroconvulsive threshold (MEST) test and the pilocarpine-induced seizure models in mice. Antinociceptive activity was examined in the hot plate and the formalin tests in mice. Considering the drug safety evaluation, the Vibrio harveyi test was used to estimate anti/mutagenic activity. To determine the plausible mechanism of anticonvulsant action, for two chosen compounds (12 and 23), in vitro binding assays were carried out. All of the tested compounds revealed significant anticonvulsant activity in the MEST test. Compounds 12 and 23 displayed anticonvulsant effect also in pilocarpine-induced seizures. Four of the tested compounds (12, 13, 15, and 24) revealed analgesic activity in the hot plate test as well as in the first phase of the formalin test, and all of them were active in the second phase of the formalin test. The possible mechanism of action of compounds 12 and 23 is the influence on the neuronal voltage-sensitive sodium and L-type calcium channels. The obtained results indicate that in the group of pyrrolidine-2,5-diones, new anticonvulsants with collateral analgesic properties can be found. PMID- 26650505 TI - Support for a Multiple-Factor Model of Auditory Processing. PMID- 26650504 TI - How animals move along? Exactly solvable model of superdiffusive spread resulting from animal's decision making. AB - Patterns of individual animal movement have been a focus of considerable attention recently. Of particular interest is a question how different macroscopic properties of animal dispersal result from the stochastic processes occurring on the microscale of the individual behavior. In this paper, we perform a comprehensive analytical study of a model where the animal changes the movement velocity as a result of its behavioral response to environmental stochasticity. The stochasticity is assumed to manifest itself through certain signals, and the animal modifies its velocity as a response to the signals. We consider two different cases, i.e. where the change in the velocity is or is not correlated to its current value. We show that in both cases the early, transient stage of the animal movement is super-diffusive, i.e. ballistic. The large-time asymptotic behavior appears to be diffusive in the uncorrelated case but super-ballistic in the correlated case. We also calculate analytically the dispersal kernel of the movement and show that, whilst it converge to a normal distribution in the large time limit, it possesses a fatter tail during the transient stage, i.e. at early and intermediate time. Since the transients are known to be highly relevant in ecology, our findings may indicate that the fat tails and superdiffusive spread that are sometimes observed in the movement data may be a feature of the transitional dynamics rather than an inherent property of the animal movement. PMID- 26650506 TI - The Human Auditory Brain-stem Response to High Click Rates: Aging Effects. AB - In the December 2001 issue (Vol. 10, No. 2), "The Human Auditory Brain-stem Response to High Click Rates: Aging Effects" by Robert F. Burkard and Donald Sims was incorrectly classified as a viewpoint. It should have been classified as an article. In addition, the table of contents indicated an incorrect page number for "Neurophysiologic Basis for Cochlear and Auditory Brainstem Implants" by Aage R. Miller. The correct page number is 68. We regret these errors. PMID- 26650503 TI - Natural compounds for pediatric cancer treatment. AB - There is a tremendous need in clinics to impair cancer progression through noninvasive therapeutic approaches. The use of natural compounds to achieve this is of importance to improve the quality of life of young patients during their treatments. This review will address the "status of the art" related to the potential of natural compounds that are undergoing investigation in combination with standard therapeutic protocols in preclinical and clinical studies and their importance for pediatric cancer treatment. The early studies of drug discovery of these natural compounds discussed here include the main targets, the cellular signaling pathways involved, and the potential modes of action. We also focus on some promising natural compounds that have shown excellent results in vitro and in vivo: Chebulagic acid, Apigenin, Norcantharidin, Saffron/Crocin, Parthenolide, Longikaurin E, Lupeol, Spongistatin 1, and Deoxy-variolin B. Additionally, we introduce the effects of several compounds from nutraceutical and functional foods, to underline their potential use as adjuvant therapies to improve therapeutic benefits. For this purpose, we have selected several compounds: Agaritine, Ganoderma and GL6 peptide, Diallyl trisulfide and Ajoene from garlic, Epigallocatechin gallate from green tea, Curcumin, Resveratrol, and Quercetin. PMID- 26650507 TI - Photocrosslinkable and elastomeric hydrogels for bone regeneration. AB - Nanocomposite biomaterials are extensively investigated for cell and tissue engineering applications due their unique physical, chemical and biological characteristics. Here, we investigated the mechanical, rheological, and degradation properties of photocrosslinkable and elastomeric nanocomposite hydrogels from nanohydroxyapatite (nHAp) and gelatin methacryloyl (GelMA). The addition of nHAp resulted in a significant increase in mechanical stiffness and physiological stability. Cells readily adhere and proliferate on the nanocomposite surfaces. Cyclic stretching of cells on the elastomeric nanocomposites revealed that nHAp elicited a stronger alignment response in the direction of strain. In vitro studies highlight enhanced bioactivity of nanocomposites as determined by alkaline phosphate (ALP) activity. Overall, the elastomeric and photocrosslinkable nanocomposite hydrogels can be used for minimally invasive therapy for bone regeneration. PMID- 26650508 TI - Endogenous conversion of omega-6 to omega-3 polyunsaturated fatty acids in fat-1 mice attenuated intestinal polyposis by either inhibiting COX-2/beta-catenin signaling or activating 15-PGDH/IL-18. AB - Omega-3 polyunsaturated fatty acids (omega-3PUFAs) have inhibitory effects in various preclinical cancer models, but their effects in intestinal polyposis have never been examined. As attempts have been made to use nutritional intervention to counteract colon cancer development, in this study we evaluated the effects of omega-3 PUFAs on intestinal polyposis in the Apc(Min/+) mouse model. The experimental groups included wild-type C56BL/6 mice, Apc(Min/+) mice, fat-1 transgenic mice expressing an n-3 desaturase to enable omega-3 PUFA synthesis, and Apc(Min/+) * fat-1 double-transgenic mice; all mice were 20 weeks of age. Small intestines were collected for gross and pathologic evaluation, including assessment of polyp number and size, followed by immunohistochemical staining and Western blotting. After administration of various concentrations of omega-3 PUFAs, PUFA levels were measured in small intestine tissue by GC/MS/MS analysis to compare with PUFA synthesis of between C57BL6 and fat-1mice. As a result, omega-3 PUFAs significantly attenuated Apc mutation-induced intestinal polyposis accompanied with significant inhibition of Wnt/beta-catenin signaling, COX-2 and PGE2, but induced significant levels of 15-PGDH. In addition, significant induction of the inflammasome-related substrates as IL-1beta and IL-18 and activation of caspase-1 was observed in Apc(Min/+) * fat-1 mice. Administration of at least 3 g/60 kg omega-3 PUFAs was equivalent to omega-3 PUFAs produced in fat-1 mice and resulted in significant increase in the expression of IL-1beta, caspase-3 and IL-18, as seen in Apc(Min/+) * fat-1 mice. We conclude that omega 3PUFAs can prevent intestinal polyp formation by inhibition of Wnt/beta-catenin signaling, but increased levels of 15-PGDH and IL-18. PMID- 26650509 TI - Factors That Influence a Mother's Willingness to Preserve Umbilical Cord Blood: A Survey of 5120 Chinese Mothers. AB - BACKGROUND: Umbilical Cord blood (UCB), which contains a substantive number of stem cells, could be widely used in transplants to treat a variety of oncologic, genetic, hematologic, and immunodeficiency disorders. However, only a small portion of mothers preserve or donate their UCB in China. The limited availability of UCB has hampered stem cell research and therapy nowadays. To date, no systemic investigations regarding factors that influence a mother's willingness to preserve UCB have been performed in China. In the current study, we are trying to determine those factors which will provide useful information for national health policy development and will raise awareness of the importance of UCB preservation. METHODS: During 2011 to 2013, 5120 mothers with the average age of 26.1+/-8.4 years were included in this study. Those mothers participated in a standardized survey. The information gathered consisted of delivery time, occupation, level of education, knowledge of preservation of UCB, willingness to store UCB, and related concerns. The results have been analyzed with SPSS 16.0. RESULTS: The results showed that first-time mothers showed a greater willingness to preserve their UCB (73.3%) compared to those having their second (48.9%) or third child (40.3%). Mothers who were employed at Government Agencies and Organizations were more willing to preserve their UCB (87.3%) than those employed at factories (62.0%), and those who were unemployed (27.3%). Mothers holding master's or college degrees were more willing to preserve their UCB (72.5% and 71.1%, respectively) than mothers with high school diplomas (48.7%) or those who only went to preliminary school or middle school (40.7%). The two strongest factors that influenced an unwillingness to preserve UCB were the high cost and concerns regarding the safety of the preservation. CONCLUSIONS: The results showed that mothers with higher education or those having better occupations are more likely to preserve their UCB in China. These mothers have related knowledge and understand the importance of the preservation and they could more readily afford the relatively high cost. The government, clinicians and UCB banks should combine efforts to take measures, such as increasing public knowledge of the importance of UCB preservation and decreasing the high cost for its storage will most likely increase the frequency of UCB preservation which will further benefit stem cell research and therapy. PMID- 26650510 TI - Early Decompression following Cervical Spinal Cord Injury: Examining the Process of Care from Accident Scene to Surgery. AB - Early decompression may improve neurological outcome after spinal cord injury (SCI), but is often difficult to achieve because of logistical issues. The aims of this study were to 1) determine the time to decompression in cases of isolated cervical SCI in Australia and New Zealand and 2) determine where substantial delays occur as patients move from the accident scene to surgery. Data were extracted from medical records of patients aged 15-70 years with C3-T1 traumatic SCI between 2010 and 2013. A total of 192 patients were included. The median time from accident scene to decompression was 21 h, with the fastest times associated with closed reduction (6 h). A significant decrease in the time to decompression occurred from 2010 (31 h) to 2013 (19 h, p = 0.008). Patients undergoing direct surgical hospital admission had a significantly lower time to decompression, compared with patients undergoing pre-surgical hospital admission (12 h vs. 26 h, p < 0.0001). Medical stabilization and radiological investigation appeared not to influence the timing of surgery. The time taken to organize the operating theater following surgical hospital admission was a further factor delaying decompression (12.5 h). There was a relationship between the timing of decompression and the proportion of patients demonstrating substantial recovery (2-3 American Spinal Injury Association Impairment Scale grades). In conclusion, the time of cervical spine decompression markedly improved over the study period. Neurological recovery appeared to be promoted by rapid decompression. Direct surgical hospital admission, rapid organization of theater, and where possible, use of closed reduction, are likely to be effective strategies to reduce the time to decompression. PMID- 26650511 TI - Efficacy and safety of canagliflozin in type 2 diabetes mellitus: systematic review of randomized controlled trials. AB - BACKGROUND: Currently available antihyperglycemic agents (AHAs), despite being effective, do not provide adequate glycemic control in some cases and are associated with side effects. A sodium glucose co-transporter 2 inhibitor, canagliflozin, is a newer AHA, which acts by decreasing the reabsorption of filtered glucose thereby elevating the urinary glucose excretion in diabetics. AREAS COVERED: This systematic review was completed to assess the clinical effectiveness and safety of canagliflozin in T2DM. A literature search in PubMed, MEDLINE, Cochrane and ClinicalTrials.gov was conducted for randomized clinical trials of canagliflozin as an AHA by applying predetermined inclusion and exclusion criteria. Total 13 studies were included in the systematic review. The main outcomes assessed were change in HbA1c and fasting plasma glucose. EXPERT OPINION: Canagliflozin monotherapy or combination therapy has the potential to decrease inadequately controlled hyperglycemia in T2DM. It acts by a novel insulin independent mechanism which complements the action of the existing AHA and improves glycemic control and decreases the body weight. Safety profile of canagliflozin indicates lower number of hypoglycemic episodes. Some manageable adverse events include genital mycotic infections, urinary tract infections, osmotic diuresis-related events etc. These findings affirm the utility of canagliflozin in T2DM; however, data on long-term safety and efficacy are needed. PMID- 26650513 TI - Investigating the Composition and Conductance Distributions on Highly GeSi Mixed Quantum Dots and Inside Oxidation Problem. AB - With the help of a nanoscale trench, the composition and conductance distributions of single GeSi quantum dots (QDs) are obtained by conductive atomic force microscopy combined with selective chemical etching. However, the obtained composition and current distributions are unwonted and inconsistent on the QDs grown at 680 degrees C. With a series of confirmatory experiments, it is suggested that a thick oxide layer is formed and remains on the QDs' surface after etching. Though this selective chemical etching has already been widely applied to investigate the composition distribution of GeSi nanostructures, the oxidation problem has not been concerned yet. Our results indicate that the oxidation problem could not be ignored on highly GeSi mixed QDs. After removing the oxide layer, the composition and conductance distributions as well as their correlation are obtained. The results suggest that QDs' current distribution is mainly determined by the topographic shape, while the absolute current values are influenced by the Ge/Si contents. PMID- 26650512 TI - Investigating the linkage between disease-causing amino acid variants and their effect on protein stability and binding. AB - Single amino acid variations (SAV) occurring in human population result in natural differences between individuals or cause diseases. It is well understood that the molecular effect of SAV can be manifested as changes of the wild type characteristics of the corresponding protein, among which are the protein stability and protein interactions. Typically the effect of SAV on protein stability and interactions was assessed via the changes of the wild type folding and binding free energies. However, in terms of SAV affecting protein functionally and disease susceptibility, one wants to know to what extend the wild type function is perturbed by the SAV. Here it is demonstrated that relative, rather than the absolute, change of the folding and binding free energy serves as a good indicator for SAV association with disease. Using HumVar as a source for disease-causing SAV and experimentally determined free energy changes from ProTherm and SKEMPI databases, correlation coefficients (CC) between the disease index (Pd) and relative folding (Ppr,f) and binding (Ppr,b) probability indexes, respectively, was achieved. The obtained CCs demonstrated the applicability of the proposed approach and it served as good indicator for SAV association with disease. PMID- 26650514 TI - The Nature and Nurture of Melody: A Twin Study of Musical Pitch and Rhythm Perception. AB - Both genetic and environmental factors are known to play a role in our ability to perceive music, but the degree to which they influence different aspects of music cognition is still unclear. We investigated the relative contribution of genetic and environmental effects on melody perception in 384 young adult twins [69 full monozygotic (MZ) twin pairs, 44 full dizygotic (DZ) twin pairs, 70 MZ twins without a co-twin, and 88 DZ twins without a co-twin]. The participants performed three online music tests requiring the detection of pitch changes in a two-melody comparison task (Scale) and key and rhythm incongruities in single-melody perception tasks (Out-of-key, Off-beat). The results showed predominantly additive genetic effects in the Scale task (58 %, 95 % CI 42-70 %), shared environmental effects in the Out-of-key task (61 %, 49-70 %), and non-shared environmental effects in the Off-beat task (82 %, 61-100 %). This highly different pattern of effects suggests that the contribution of genetic and environmental factors on music perception depends on the degree to which it calls for acquired knowledge of musical tonal and metric structures. PMID- 26650515 TI - The First Bromeligenous Species of Dendropsophus (Anura: Hylidae) from Brazil's Atlantic Forest. AB - We describe a new treefrog species of Dendropsophus collected on rocky outcrops in the Brazilian Atlantic Forest. Ecologically, the new species can be distinguished from all known congeners by having a larval phase associated with rainwater accumulated in bromeliad phytotelms instead of temporary or lentic water bodies. Phylogenetic analysis based on molecular data confirms that the new species is a member of Dendropsophus; our analysis does not assign it to any recognized species group in the genus. Morphologically, based on comparison with the 96 known congeners, the new species is diagnosed by its small size, framed dorsal color pattern, and short webbing between toes IV-V. The advertisement call is composed of a moderate-pitched two-note call (~5 kHz). The territorial call contains more notes and pulses than the advertisement call. Field observations suggest that this new bromeligenous species uses a variety of bromeliad species to breed in, and may be both territorial and exhibit male parental care. PMID- 26650516 TI - Exciton Dynamics in InSb Colloidal Quantum Dots. AB - Extraordinarily fast biexciton decay times and unexpectedly large optical gaps are two striking features observed in InSb colloidal quantum dots that have remained so far unexplained. The former, should its origin be identified as an Auger recombination process, would have important implications regarding carrier multiplication efficiency, suggesting these nanostructures as potentially ideal active materials in photovoltaic devices. The latter could offer new insights into the factors that influence the electronic structure and consequently the optical properties of systems with reduced dimensionality and provide additional means to fine-tune them. Using the state-of-the-art atomistic semiempirical pseudopotential method we unveil the surprising origins of these features and show that a comprehensive explanation for these properties requires delving deep into the atomistic detail of these nanostructures and is, therefore, outside the reach of less sophisticated, albeit more popular, theoretical approaches. PMID- 26650517 TI - A Bromo-Functionalized Conjugated Polymer as a Cross-Linkable Anode Interlayer of Polymer Solar Cells. AB - A cross-linkable conjugated polymer with bromo groups on the side chain has been developed and used as an anode interlayer to improve the active layer morphology and consequently enhance the device performance of polymer solar cells (PSCs). The polymer, PCDTBT-Br, has cross-linkable bromo groups attached to the side chain of a widely-used donor polymer, poly[N-9-heptadecanyl-2,7-carbazole-alt-5,5 (4,7-di-2-thienyl-2,1,3-benzothiadiazole)] (PCDTBT). The pendant bromo groups do not significantly change the LUMO/HOMO energy levels and absorption spectrum of the PCDTBT polymer backbone. PDCTBT-Br can crosslink under UV irradiation to give a robust film, which enables multilayer PSC device fabrication. Moreover, the much lower surface energy of PCDTBT-Br (20.4 mJ m(-2) ) compared to PEDOT: PSS (91.6 mJ m(-2) ) is beneficial for achieving optimal active layer morphology. As a result, with PCDTBT:[6,6]-phenyl-C71 butyric acid methyl ester (PC71 BM) as the active layer, the PSC device with PCDTBT-Br as the underlying layer shows a power conversion efficiency (PCE) of 6.59 %, in comparison to a PCE of 5.86 % of the control device. The device performance enhancement is ascribed to the much improved phase separation with a fibrillar nanostructure in the active layer. PMID- 26650521 TI - Stress-Induced and Fear Circuitry Disorders: Advancing the Research Agenda for DSM-Vedited by Andrews Gavin , Charney Dennis S. , Sirovatka Paul J. , Regier Darrel A. . Washington, D.C. American Psychiatric Publishing, Inc. , 2009 , 330 pp., $60.00. PMID- 26650518 TI - The Effect of Advancing Age on Auditory Middle- and Long-Latency Evoked Potentials Using a Steady-State-Response Approach. AB - PURPOSE: The purpose of the study was to objectively detect age-specific changes that occur in equivalent auditory steady-state responses (ASSRs), corresponding to transient middle- and long-latency auditory evoked potentials as a function of repetition rate and advancing age. METHOD: The study included 48 healthy hearing adults who were equally divided into 3 groups by age: 20-39, 40-59, and 60-79 years. ASSRs were recorded at 7 repetition rates from 40 down to 0.75 Hz, elicited by trains of repeated tone burst stimuli. RESULTS: Temporal analysis of middle- and long-latency equivalent ASSRs revealed no appreciable changes in the magnitudes of the response across the age groups. Likewise, the spectral analysis revealed that advancing age did not substantially affect the spectral content of the response at each repetition rate. Furthermore, the harmonic sum was not significantly different across the 3 age groups, between the younger adults versus the combined Older Group Sample 1 and Sample 2, and between the two extreme age groups (i.e., 20-39 vs. 60-79) for the middle- and long-latency equivalent ASSRs. CONCLUSION: Advancing age has no effect on the long-latency equivalent ASSRs; however, aging does affect the middle-latency equivalent ASSRs when the mean age difference is >= 40 years. PMID- 26650522 TI - Treating the "Untreatable": Healing in the Realms of Madnessby Steinman Ira . London Karnac Books , 2009 , 240 pp., $35.00. PMID- 26650535 TI - Supramolecular Assembly of Biobased Graphene Oxide Quantum Dots Controls the Morphology of and Induces Mineralization on Poly(epsilon-caprolactone) Films. AB - Biobased 2D graphene oxide quantum dots (GOQDs) were synthesized from waste paper via carbon nanosphere intermediates and evaluated as property-enhancing additives for poly(epsilon-caprolactone) (PCL). The morphology of PCL films was controlled by supramolecular assembly of the small, 2D GOQDs in the polymer matrix. Phase behavior studies of PCL-GOQD in the solid state indicated concentration-dependent self-association of GOQD sheets, which was confirmed by SEM observations. Depending on the GOQD concentration, the formation of, e.g., spheres and stacked sheets was observed. GOQDs also induced mineralization on the surface of the films. A calcium phosphate (CaP) mineralization test revealed that the density of growing CaP crystals was controlled by the type of GOQD aggregates formed. Thus, utilization of the aggregation behavior of small GOQD sheets in polymeric matrices paves the way for tuning the morphology and properties of nanocomposites. PMID- 26650536 TI - Erratum to: Considerations on self-psychology and eating disorders. PMID- 26650537 TI - Biomembrane Fabrication by the Solvent-assisted Lipid Bilayer (SALB) Method. AB - In order to mimic cell membranes, the supported lipid bilayer (SLB) is an attractive platform which enables in vitro investigation of membrane-related processes while conferring biocompatibility and biofunctionality to solid substrates. The spontaneous adsorption and rupture of phospholipid vesicles is the most commonly used method to form SLBs. However, under physiological conditions, vesicle fusion (VF) is limited to only a subset of lipid compositions and solid supports. Here, we describe a one-step general procedure called the solvent-assisted lipid bilayer (SALB) formation method in order to form SLBs which does not require vesicles. The SALB method involves the deposition of lipid molecules onto a solid surface in the presence of water-miscible organic solvents (e.g., isopropanol) and subsequent solvent-exchange with aqueous buffer solution in order to trigger SLB formation. The continuous solvent exchange step enables application of the method in a flow-through configuration suitable for monitoring bilayer formation and subsequent alterations using a wide range of surface sensitive biosensors. The SALB method can be used to fabricate SLBs on a wide range of hydrophilic solid surfaces, including those which are intractable to vesicle fusion. In addition, it enables fabrication of SLBs composed of lipid compositions which cannot be prepared using the vesicle fusion method. Herein, we compare results obtained with the SALB and conventional vesicle fusion methods on two illustrative hydrophilic surfaces, silicon dioxide and gold. To optimize the experimental conditions for preparation of high quality bilayers prepared via the SALB method, the effect of various parameters, including the type of organic solvent in the deposition step, the rate of solvent exchange, and the lipid concentration is discussed along with troubleshooting tips. Formation of supported membranes containing high fractions of cholesterol is also demonstrated with the SALB method, highlighting the technical capabilities of the SALB technique for a wide range of membrane configurations. PMID- 26650538 TI - Empowerment in healthcare policy making: three domains of substantive controversy. AB - This paper distinguishes between the uses of empowerment across different contexts in healthcare policy and health promotion, providing a model for the ethical and political scrutiny of those uses. We argue that the controversies currently engendered by empowerment are better understood by means of a historical distinction between two concepts of empowerment, namely, what we call the radical empowerment approach and the new wave of empowerment. Building on this distinction, we present a research agenda for ethicists and policy makers, highlighting three domains of controversy raised by the new wave of empowerment, namely: (1) the relationship between empowerment and paternalistic interferences on the part of professionals; (2) the evaluative commitment of empowerment strategies to the achievement of health-related goals; and (3) the problems arising from the emphasis on responsibility for health in recent uses of empowerment. Finally, we encourage the explicit theorisation of these moral controversies as a necessary step for the development and implementation of ethically legitimate empowerment processes. PMID- 26650539 TI - AtNHX5 and AtNHX6 Control Cellular K+ and pH Homeostasis in Arabidopsis: Three Conserved Acidic Residues Are Essential for K+ Transport. AB - AtNHX5 and AtNHX6, the endosomal Na+,K+/H+ antiporters in Arabidopsis, play an important role in plant growth and development. However, their function in K+ and pH homeostasis remains unclear. In this report, we characterized the function of AtNHX5 and AtNHX6 in K+ and H+ homeostasis in Arabidopsis. Using a yeast expression system, we found that AtNHX5 and AtNHX6 recovered tolerance to high K+ or salt. We further found that AtNHX5 and AtNHX6 functioned at high K+ at acidic pH while AtCHXs at low K+ under alkaline conditions. In addition, we showed that the nhx5 nhx6 double mutant contained less K+ and was sensitive to low K+ treatment. Overexpression of AtNHX5 or AtNHX6 gene in nhx5 nhx6 recovered root growth to the wild-type level. Three conserved acidic residues, D164, E188, and D193 in AtNHX5 and D165, E189, and D194 in AtNHX6, were essential for K+ homeostasis and plant growth. nhx5 nhx6 had a reduced vacuolar and cellular pH as measured with the fluorescent pH indicator BCECF or semimicroelectrode. We further show that AtNHX5 and AtNHX6 are localized to Golgi and TGN. Taken together, AtNHX5 and AtNHX6 play an important role in K+ and pH homeostasis in Arabidopsis. Three conserved acidic residues are essential for K+ transport. PMID- 26650541 TI - The Rickettsia Endosymbiont of Ixodes pacificus Contains All the Genes of De Novo Folate Biosynthesis. AB - Ticks and other arthropods often are hosts to nutrient providing bacterial endosymbionts, which contribute to their host's fitness by supplying nutrients such as vitamins and amino acids. It has been detected, in our lab, that Ixodes pacificus is host to Rickettsia species phylotype G021. This endosymbiont is predominantly present, and 100% maternally transmitted in I. pacificus. To study roles of phylotype G021 in I. pacificus, bioinformatic and molecular approaches were carried out. MUMmer genome alignments of whole genome sequence of I. scapularis, a close relative to I. pacificus, against completely sequenced genomes of R. bellii OSU85-389, R. conorii, and R. felis, identified 8,190 unique sequences that are homologous to Rickettsia sequences in the NCBI Trace Archive. MetaCyc metabolic reconstructions revealed that all folate gene orthologues (folA, folC, folE, folKP, ptpS) required for de novo folate biosynthesis are present in the genome of Rickettsia buchneri in I. scapularis. To examine the metabolic capability of phylotype G021 in I. pacificus, genes of the folate biosynthesis pathway of the bacterium were PCR amplified using degenerate primers. BLAST searches identified that nucleotide sequences of the folA, folC, folE, folKP, and ptpS genes possess 98.6%, 98.8%, 98.9%, 98.5% and 99.0% identity respectively to the corresponding genes of Rickettsia buchneri. Phylogenetic tree constructions show that the folate genes of phylotype G021 and homologous genes from various Rickettsia species are monophyletic. This study has shown that all folate genes exist in the genome of Rickettsia species phylotype G021 and that this bacterium has the genetic capability for de novo folate synthesis. PMID- 26650542 TI - A Label-free Technique for the Spatio-temporal Imaging of Single Cell Secretions. AB - Inter-cellular communication is an integral part of a complex system that helps in maintaining basic cellular activities. As a result, the malfunctioning of such signaling can lead to many disorders. To understand cell-to-cell signaling, it is essential to study the spatial and temporal nature of the secreted molecules from the cell without disturbing the local environment. Various assays have been developed to study protein secretion, however, these methods are typically based on fluorescent probes which disrupt the relevant signaling pathways. To overcome this limitation, a label-free technique is required. In this paper, we describe the fabrication and application of a label-free localized surface plasmon resonance imaging (LSPRi) technology capable of detecting protein secretions from a single cell. The plasmonic nanostructures are lithographically patterned onto a standard glass coverslip and can be excited using visible light on commercially available light microscopes. Only a small fraction of the coverslip is covered by the nanostructures and hence this technique is well suited for combining common techniques such as fluorescence and bright-field imaging. A multidisciplinary approach is used in this protocol which incorporates sensor nanofabrication and subsequent biofunctionalization, binding kinetics characterization of ligand and analyte, the integration of the chip and live cells, and the analysis of the measured signal. As a whole, this technology enables a general label-free approach towards mapping cellular secretions and correlating them with the responses of nearby cells. PMID- 26650543 TI - Social Anxiety, Affect, Cortisol Response and Performance on a Speech Task. AB - BACKGROUND: Social anxiety is characterized by increased emotional reactivity to social stimuli, but results of studies focusing on affective reactions of socially anxious subjects in the situation of social exposition are inconclusive, especially in the case of endocrinological measures of affect. SAMPLING AND METHODS: This study was designed to examine individual differences in endocrinological and affective reactions to social exposure as well as in performance on a speech task in a group of students (n = 44) comprising subjects with either high or low levels of social anxiety. Measures of salivary cortisol and positive and negative affect were taken before and after an impromptu speech. Self-ratings and observer ratings of performance were also obtained. RESULTS: Cortisol levels and negative affect increased in both groups after the speech task, and positive affect decreased; however, group * affect interactions were not significant. Assessments conducted after the speech task revealed that highly socially anxious participants had lower observer ratings of performance while cortisol increase and changes in self-reported affect were not related to performance. CONCLUSIONS: Socially anxious individuals do not differ from nonanxious individuals in affective reactions to social exposition, but reveal worse performance at a speech task. PMID- 26650540 TI - Analysis of COPII Vesicles Indicates a Role for the Emp47-Ssp120 Complex in Transport of Cell Surface Glycoproteins. AB - Coat protein complex II (COPII) vesicle formation at the endoplasmic reticulum (ER) transports nascent secretory proteins forward to the Golgi complex. To further define the machinery that packages secretory cargo and targets vesicles to Golgi membranes, we performed a comprehensive proteomic analysis of purified COPII vesicles. In addition to previously known proteins, we identified new vesicle proteins including Coy1, Sly41 and Ssp120, which were efficiently packaged into COPII vesicles for trafficking between the ER and Golgi compartments. Further characterization of the putative calcium-binding Ssp120 protein revealed a tight association with Emp47 and in emp47Delta cells Ssp120 was mislocalized and secreted. Genetic analyses demonstrated that EMP47 and SSP120 display identical synthetic positive interactions with IRE1 and synthetic negative interactions with genes involved in cell wall assembly. Our findings support a model in which the Emp47-Ssp120 complex functions in transport of plasma membrane glycoproteins through the early secretory pathway. PMID- 26650544 TI - Essential Medicines in a High Income Country: Essential to Whom? AB - OBJECTIVE: To explore the perspectives of a diverse group of stakeholders engaged in medicines decision making around what constitutes an "essential" medicine, and how the Essential Medicines List (EML) concept functions in a high income country context. METHODS: In-depth qualitative semi-structured interviews were conducted with 32 Australian stakeholders, recognised as decision makers, leaders or advisors in the area of medicines reimbursement or supply chain management. Participants were recruited from government, pharmaceutical industry, pharmaceutical wholesale/distribution companies, medicines non-profit organisations, academic health disciplines, hospitals, and consumer groups. Perspectives on the definition and application of the EML concept in a high income country context were thematically analysed using grounded theory approach. FINDINGS: Stakeholders found it challenging to describe the EML concept in the Australian context because many perceived it was generally used in resource scarce settings. Stakeholders were unable to distinguish whether nationally reimbursed medicines were essential medicines in Australia. Despite frequent generic drug shortages and high prices paid by consumers, many struggled to describe how the EML concept applied to Australia. Instead, broad inclusion of consumer needs, such as rare and high cost medicines, and consumer involvement in the decision making process, has led to expansive lists of nationally subsidised medicines. Therefore, improved communication and coordination is needed around shared interests between stakeholders regarding how medicines are prioritised and guaranteed in the supply chain. CONCLUSIONS: This study showed that decision making in Australia around reimbursement of medicines has strayed from the fundamental utilitarian concept of essential medicines. Many stakeholders involved in medicine reimbursement decisions and management of the supply chain did not consider the EML concept in their approach. The wide range of views of what stakeholders considered were essential medicines, challenges whether the EML concept is out-dated or underutilised in high income countries. PMID- 26650545 TI - TIPE2 Mediates the Suppressive Effects of Shikonin on MMP13 in Osteosarcoma Cells. AB - BACKGROUND/AIMS: Osteosarcoma (OS) is a primary malignant bone tumor in humans, and is notorious mainly for its distal metastases. We have recently shown that Shikonin, an effective constituent extracted from Chinese medicinal herb, inhibits OS cell invasion through suppression of matrix metalloproteinase 13 (MMP13). However, the underlying mechanisms remain unknown. METHODS: Here, we studied the levels of tumor necrosis factor (TNF)-alpha-induced protein 8-like 2 (TIPE2) in OS cells upon Shikonin treatment. TIPE2 levels were adapted in OS cell lines through transfection with plasmids carrying transgene or short-hairpin interference RNA (shRNA), and the effects of TIPE2 adaptation on MMP13 and cell invasiveness were evaluated by RT-qPCR, Western blot, ELISA and transwell cell migration assay, respectively. TIPE2 levels in OS specimens from patients were examined and correlated with cancer metastases and patient survival. RESULTS: We found that Shikonin dose-dependently decreased MMP13 levels, and increased TIPE2 levels in two OS cell lines, U2OS and SaOS-2. Overexpression of TIPE2 in U2OS significantly suppressed MMP13 levels and cell invasiveness. Depletion of TIPE2 in SaOS-2 cells significantly increased MMP13 levels and cell invasiveness. Moreover, TIPE2 levels in OS specimens were significantly decreased, compared to adjacent non-cancer bone tissue. Lower TIPE2 levels correlated with higher incidence of metastases and worse 5-year survival. CONCLUSION: TIPE2 mediates the suppressive effects of Shikonin on MMP13 in osteosarcoma cells, and TIPE2 may be a novel therapeutic target for OS. PMID- 26650546 TI - A Single-Cell Gene-Expression Profile Reveals Inter-Cellular Heterogeneity within Human Monocyte Subsets. AB - Human monocytes are a heterogeneous cell population classified into three different subsets: Classical CD14++CD16-, intermediate CD14++CD16+, and non classical CD14+CD16++ monocytes. These subsets are distinguished by their differential expression of CD14 and CD16, and unique gene expression profile. So far, the variation in inter-cellular gene expression within the monocyte subsets is largely unknown. In this study, the cellular variation within each human monocyte subset from a single healthy donor was described by using a novel single cell PCR gene-expression analysis tool. We investigated 86 different genes mainly encoding cell surface markers, and proteins involved in immune regulation. Within the three human monocyte subsets, our descriptive findings show multimodal expression of key immune response genes, such as CD40, NF?B1, RELA, TLR4, TLR8 and TLR9. Furthermore, we discovered one subgroup of cells within the classical monocytes, which showed alterations of 22 genes e.g. IRF8, CD40, CSF1R, NF?B1, RELA and TNF. Additionally one subgroup within the intermediate and non-classical monocytes also displayed distinct gene signatures by altered expression of 8 and 6 genes, respectively. Hence the three monocyte subsets can be further subdivided according to activation status and differentiation, independently of the traditional classification based on cell surface markers. Demonstrating the use and the ability to discover cell heterogeneity within defined populations of human monocytes is of great importance, and can be useful in unravelling inter cellular variation in leukocyte populations, identifying subpopulations involved in disease pathogenesis and help tailor new therapies. PMID- 26650547 TI - Racemized and Isomerized Proteins in Aging Rat Teeth and Eye Lens. AB - The quantification of aspartic acid racemization in the proteins of nonmetabolically active tissues can be used as a measure of chronological aging in humans and other long-lived organisms. However, very few studies have been conducted in shorter-lived animals such as rodents, which are increasingly used as genetic and metabolic models of aging. An initial study had reported significant changes in the ratio of d- to l-aspartate in rat molars with age. Using a sensitive HPLC method for the determination of d- and l-aspartate from protein hydrolysates, we found no accumulation of d-aspartate in the molars of 17 rats that ranged in age from 2 to 44 months, and the amount of d-aspartate per molar did not correspond with molar eruption date as had been previously reported. However, developing an alternate approach, we found significant accumulation of isomerized aspartyl residues in eye lens proteins that are also formed by spontaneous degradation processes. In this study, we used the human protein l-isoaspartate/d-aspartate O-methyltransferase (PCMT1) as an analytical reagent in a sensitive and convenient procedure that could be used to rapidly examine multiple samples simultaneously. We found levels of isomerized aspartyl residues to be about 35 times higher in the lens extracts of 18-month-old rats versus 2-month-old rats, suggesting that isomerization may be an effective marker for biological aging in this range of ages. Importantly, we found that the accumulation appeared to plateau in rats of 18 months and older, indicating that potentially novel mechanisms for removing altered proteins may develop with age. PMID- 26650548 TI - Polymeric Microneedle Array Fabrication by Photolithography. AB - This manuscript describes the fabrication of polymeric microneedle (MN) arrays by photolithography. It involves a simple mold-free process by using a photomask consisting of embedded micro-lenses. Embedded micro-lenses were found to influence MN geometry (sharpness). Robust MN arrays with tip diameters ranging between 41.5 um +/- 8.4 um and 71.6 um +/- 13.7 um, with two different lengths (1,336 um +/- 193 um and 957 um +/- 171 um) were fabricated. These MN arrays may provide potential applications in delivery of low molecular and macromolecular therapeutic agents through skin. PMID- 26650549 TI - Analog sensitive chemical inhibition of the DEAD-box protein DDX3. AB - Proper maintenance of RNA structure and dynamics is essential to maintain cellular health. Multiple families of RNA chaperones exist in cells to modulate RNA structure, RNA-protein complexes, and RNA granules. The largest of these families is the DEAD-box proteins, named after their catalytic Asp-Glu-Ala-Asp motif. The human DEAD-box protein DDX3 is implicated in diverse biological processes including translation initiation and is mutated in numerous cancers. Like many DEAD-box proteins, DDX3 is essential to cellular health and exhibits dosage sensitivity, such that both decreases and increases in protein levels can be lethal. Therefore, chemical inhibition would be an ideal tool to probe the function of DDX3. However, most DEAD-box protein active sites are extremely similar, complicating the design of specific inhibitors. Here, we show that a chemical genetic approach best characterized in protein kinases, known as analog sensitive chemical inhibition, is viable for DDX3 and possibly other DEAD-box proteins. We present an expanded active-site mutant that is tolerated in vitro and in vivo, and is sensitive to chemical inhibition by a novel bulky inhibitor. Our results highlight a course towards analog sensitive chemical inhibition of DDX3 and potentially the entire DEAD-box protein family. PMID- 26650550 TI - Otological complications associated with hyperbaric oxygen therapy. AB - The objective of the present study was to clarify the features of otological complications for hyperbaric oxygen therapy (HBOT) and the risk factors for these complications. We enrolled 1115 patients (776 males and 339 females; age 5-89 years) who underwent HBOT. All otological symptoms experienced during HBOT sessions were evaluated, and risk factors were analysed using multivariate logistic regression analysis. Otoscopic findings and interventions for otological complications were assessed in 58 symptomatic patients who visited the Otolaryngology Department. Otological symptoms were experienced by 165 (14.8 %) of the 1115 patients. The multivariate logistic regression analysis identified ages of >60 years and female sex as independent risk factors, whereas patients with sports injuries were at lower risk than those with other primary diseases, except for severe infectious disease. Eighty-two patients (49.7 %) suffered from symptoms at the first HBOT session. The most prevalent symptoms were otalgia (157/165), followed by ear fullness (13/165), hearing loss (12/165) and tinnitus (3/165). One patient experienced vertigo and deterioration of the bone-conduction pure-tone thresholds, suggesting inner ear barotrauma. In 116 ears of the 58 symptomatic patients, abnormal otoscopic findings were recognized in 58 ears (50.0 %). Twenty-seven of the 58 ears required myringotomy or tube insertion, and HBOT was stopped in eight ears in four patients. Of the remaining 58 ears with normal otoscopic findings, 51 received no treatment. Physicians should be aware of both middle and inner ear barotrauma as potential complications of HBOT. PMID- 26650551 TI - Voice deepening under testosterone treatment in female-to-male gender dysphoric individuals. AB - Female-to-male gender dysphoric individuals rarely access medical services for voice problems arising out of hormonal treatment leading to "voice reassignment". The aim of this study was a close monitoring of voice deepening in the first year following the commencement of testosterone treatment. Voice recordings from nine female-to-male (FTM) were analyzed with Praat software and values for speaking fundamental frequency (SFF) were calculated. Audio recordings were made prior to and within the first year (mean 55.2 weeks) of testosterone treatment at a mean of 35.4 different time points. The values for speaking fundamental frequency were compared with values taken from 21 biological men with healthy voices. The 10th to 90th percentile range of FTM overlapped with those of biological men after about 36 weeks. The mean SFF change was a decrease of 8.78 seminotes at week 52 and at this point in time no significant difference between SSF in FTM and biological men was found. Testosterone treatment led to significant voice deepening within the first year with the degree of change decreasing over time. Mean SFF change in the first year was almost a sixth and thus less than one octave but nonetheless reached an SFF comparable with biological men. PMID- 26650552 TI - [EVALUATION OF THE CONTINUITY OF OUTPATIENT TREATMENT IN ADDICTION IN TOXICOLOGY DIVISION, THE HOSPITAL FERNANDEZ, ARGENTINA]. AB - The lack of continuity in the treatment of patients suffering from an addiction is one of the main difficulties faced by professionals working with this problem. The early discontinuation of treatment has been correlated with a higher number of relapses and poor prognosis. The purpose of this study is to evaluate the continuity in the treatment of patients who consult for problematic substance use and smoking in Outpatients Toxicology Division of Hospital J. A. Fernandez. A retrospective review was performed with longitudinal tracking of medical records entered for a year. Continuity in patients with problematic substance use (N=418) was 45% at 1 month, 22% at the 3rd month and 10% at month 6; in patients presenting with smoking (n 211) continuity was lower, 38% at 1 month and 9% at the 3rd month (p<0.001). Within the group of patients with problematic use of substances, consuming only alcohol (N=96) showed greater continuity, being on 1st, 3rd and 6th month, 47%, 33% and 18% respectively (p=0.012). PMID- 26650553 TI - [QUICK INVENTORY OF DEPRESSIVE SYMPTOMATOLOGY SELF-REPORT IN THE CLINICAL PRACTICE OF DEPRESSIVE PATIENTS]. AB - INTRODUCTION: To determine the intensity of depressive disorder is helpful to make treatment decisions. The purpose of this study is to establish the correlation between the Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR16) and Montgomery Asberg Depression Rating Scale (MADRS), in order to measure the depression intensity in outpatients from two urban areas in Argentina. METHOD: Over an 18-month period, 67 outpatients from the current clinical practice were included in the study. They first presented with a diagnosis of nonpsychotic major depressive disorder, according to the DSM-IV-TR criteria. Both the QIDS-SR16 and MADRS were administered. RESULTS: The internal consistency of the QIDS-SR16 was acceptable, with the Cronbach's alpha being 0.74. Criterion validity was estimated through the correlation between both scales and was 0.84 (p<0.0001), while gamma statistics for the ordinal comparison of categories was 0.95, thus showing a high correlation. CONCLUSION: The study findings show that the correlation between the two analyzed questionnaires allows determining depression intensity in patients from our setting. These findings further allow analyzing the usefulness of the scale for several depressive subtypes. As far as training and administration, the QIDS-SR16 is less time consuming. PMID- 26650554 TI - [ATTENUATED PSYCHOSIS SYNDROME: A LITERATURE REVIEW]. AB - Despite recent findings on the treatment of schizophrenia, it is an illness still associated with high morbidity and incapacity in social and work domains. There is a growing interest in examining the phases prior to the development of the illness so as to make early interventions that would potentially change its devastating course. The attenuated psychosis syndrome was included in the section III of the last version of the Diagnostic and Statistical Manual of Mental Disorders as a condition in which a patient exhibits mild psychotic symptoms, an intact reality testing and certain degree of social or occupational impairment. The present work is a review of the available literature on this subject. The main findings were: the risk of conversion to a psychotic disorder is relatively low and there are some variables (social withdrawal, negative symptoms, neurocognitive impairment, poor global functioning and certain neuroimaging findings) that increase this risk. Those people diagnosed with attenuated psychosis syndrome had one or more other current psychiatric comorbid conditions and these are the main reason to warrant medical attention. Regarding to the treatment of this condition, there are available evidence on atypical antipsychotics, cognitive-behavioral therapy and omega 3 fatty acid. PMID- 26650555 TI - [Psychiatry and HIV]. PMID- 26650556 TI - [HIV- DEMENTIA. A REVIEW THIRTY FIVE YEARS AFTER (1981-2015)]. AB - In this review, the intention is to present the four clinical models of HIV-1 brain damage, named with the diffuse category of HIV-encephalopathy. It contains the past three decades, since the first static-infectological model of Snider WD, developed in 1983, based in a great neuropathological trial with AIDS patients. The second one, maybe the most compact of them, was the AIDS-dementia complex, published by the Navia BA group, in two notable papers published in 1986. This resulted in a consistent HIV-neuropsychiatric condition, till 1996, when HAART era begun. In a third early-HAART evolving model, we can find good correlations between the different levels: clinical (mild-moderate/severe forms), neuropsychological (subcortical pattern), neuroimaging, and LCR-markers. In the last-current paradigm, coincident with the advanced HAART treatments, the original HIV-encephalopathy became in a hybrid-complex compartimentalized condition, in contact with other neurodegenerative entities, like Alzheimer disease, Parkinson disease or the CNS-immune reconstitution inflammatory syndrome, with a high prevalence, atypical clinical forms, and with the demand of a specific management, in parallel to the systemic HIV disease. PMID- 26650557 TI - [SSRI AND BONE METABOLISM IN HIV + PATIENTS WITH ANTIRETROVIRAL THERAPY]. AB - We report a series of 9 male HIV + patients, average age of 41.2 years, viral load negative (<50 copies RNA/ml), treated with antiretroviral (nucleoside and non-nucleoside inhibitors of reverse transcriptase) without systemic infections, the CNS diseases or marker or corticoidoterapia in progress. Were evaluated and supported by their infectologists interconsultation during the period October 2008-October 2013 by depressive syndrome. Psychotherapeutic and psychiatric treatment was initiated with SSRIs and clonazepam; Neuroimaging control and biochemical laboratory studies at baseline and 2 months of treatment were conducted. In the course of psychopharmacological treatment not suffer fractures due to falls and alterations were detected in bone metabolism markers and images. He studied with endocrinology and interdisciplinary medical clinic, decided to withdraw the SSRIs with normalization of biochemical values and psychotherapeutic treatment was continued. We will raise the associations between the use of SSRIs, disturbances of bone metabolism with clinical correlation and possible drug interactions between antidepressants and antiretroviral. PMID- 26650558 TI - [COGNITIVE SCREENING IN HIV-1 INFECTED YOUNG ADULTS AT BUENOS AIRES. PRELIMINARY DATA]. AB - Cognitive impairment is highly prevalent in HIV-1 infected patients, even in younger individuals. These symptoms usually are not recognized by health professionals or even patients themselves. However, they can represent a major cause of functional impairment and failure in treatment compliance. In our country we lack both sufficient epidemiological information on the true impact of these symptoms and screening tests with local validation needed to be used by health professionals during the medical assessment. Therefore we designed a prospective study to compare the performance of four brief cognitive tests and a new screening tool with the neuropsychological assessment (gold standard) in a population of young adults infected with HIV-1 in Argentina, in order to assess their sensitivity and specificity in our culture and language. Different confounding conditions were taken into account. Preliminary data were analyzed after the enrollment of 19 subjects. NEURA screening correlated significantly with the neuropsychological assessment (rho = 0.496, p = .031). In terms of sensitivity and specificity, NEURA performance was superior to other screening tests routinely used in our country: IHDS (S 27%/E 5%), MMSE (S/E 0%), ACE (S 9%/E 100%) and IFS (S 36%/E 80%). PMID- 26650559 TI - [MANAGEMENT OF PSYCHOTROPIC DRUGS IN HIV-INFECTED PATIENTS]. AB - Here we make a revision about the rational use of psychopharmacological drugs in HIV/AIDS patients. We revised the clinical use of psychotropic drugs in this setting. In the clinical spectrum, the most frequent clinical pictures are the depression, anxiety disorders, psychosis, delirium, and the cognitive and behavioral neuropsychiatric symptoms associated with the HIV/AIDS dementia and the substance abuse-dependence. Also, we analyzed the most important pharmacological interactions between psychotropic drugs and antiretrovirals. The medical education and the interdisciplinary work are the basic topics to an adequate clinical management of this kind of patients. PMID- 26650560 TI - [DEBATING PSYCHIATRY: A CRITICAL REVIEW OF SOME RECENT DISCUSSIONS]. AB - This paper reviews the principal critiques and reactions stated regarding the launching of DSM-5 up to the present days in Anglo-Saxon's mental health domain. The arguments are gathered as follows: current diagnoses systems; validity of psychiatric diagnoses; limits of the efficacy of psychiatric treatments (especially medications and conflict of interests); the image of psychiatry in user's networks. In the end controversies get polarized between medicalization of ordinary life and antipsychiatry. However, if acknowledged impasses and benevolent distrust are tolerated, it is possible to make a clinical use of the critiques and reactions. PMID- 26650561 TI - [Jean-Pierre Falret: hallucinations as a clinical and semiological problem]. PMID- 26650562 TI - Effects of the Dietary Approaches to Stop Hypertension (DASH) Eating Plan on the Metabolic Side Effects of Corticosteroid Medications. AB - OBJECTIVE: We aimed to determine the effects of the Dietary Approaches to Stop Hypertension (DASH) diet on the metabolic side effects of corticosteroid medication use. DESIGN: A randomized clinical trial was undertaken in 60 patients on corticosteroid therapy for 10 weeks. Patients were randomly assigned to a DASH or control diet. Carbohydrate, protein, and fat in both groups were 50-60%, 15 20%, 30%, respectively. DASH diet was a diet rich in fruits, vegetables, whole grains, low-fat dairy products, and low in total and saturated fat and cholesterol, refined grains, and also sweets. Fasting blood samples were collected to determine blood glucose and lipid profile. Blood pressure and anthropometric measurements were measured based on the standard guidelines. RESULTS: The mean age and body mass index (BMI) were 31.1 +/- 3.6 year and 26.9 +/- 2.6 kg/m(2), respectively. There were no significant differences between age and BMI in two groups at baseline. No significant difference was observed in body weight and waist circumference following the DASH diet compared to control diet. Systolic and diastolic blood pressures were significantly different following the DASH eating pattern (P = 0.04). Serum total cholesterol and fasting blood glucose significantly decreased in those following the DASH diet after adjustment for potential confounders. CONCLUSION: The DASH diet had beneficial effects on several metabolic side effects among patients using corticosteroid medications. PMID- 26650563 TI - CONCURRENT SCLERAL BUCKLE AND INTRAVITREAL BEVACIZUMAB FOR ADVANCED RETINOPATHY OF PREMATURITY-RELATED RETINAL DETACHMENT. AB - BACKGROUND: The preoperative use of intravitreal bevacizumab in Stage 4 or 5 retinopathy of prematurity (ROP) can reduce vascular endothelial growth factor load and bleeding risk; however, it can induce traction and exacerbate a tractional retinal detachment. Concurrent placement of a scleral buckle may reduce these risks and obviate future vitrectomy. METHODS: A retrospective analysis of eyes treated for Stage 4 and 5 ROP with concurrent intravitreal bevacizumab and scleral buckle was performed. Retinal reattachment and need for vitrectomy were studied. RESULTS: Thirteen eyes from 10 infants were treated with concurrent intravitreal bevacizumab and scleral buckle. Nine eyes were Stage 4a, 2 were Stage 4b, and 2 were Stage 5. All eyes with Stage 4 ROP achieved macular attachment at last follow-up. All the eyes with 4a ROP achieved retinal reattachment: 4 (44.4%) with buckle alone and 5 (55.6%) with subsequent vitrectomy. All 4 eyes with Stage 4b or 5 ROP required vitrectomy. CONCLUSION: Concurrent intravitreal bevacizumab and scleral buckle may serve as a bridge to vitrectomy and, in some instances, may obviate the need for subsequent intervention. PMID- 26650564 TI - SEVERE PANUVEITIS, RETINAL VASCULITIS, AND OPTIC DISK GRANULOMA SECONDARY TO SARCOIDOSIS. AB - PURPOSE: To report a case of panuveitis, retinal vasculitis, and optic disk granuloma due to sarcoidosis. METHODS: Case report and literature review. RESULTS: A 26-year-old previously healthy African American male presented with four months of gradual progressive visual decline in the right eye. Clinical examination revealed severe panuveitis, retinal vasculitis, and large optic nerve mass lesion. Diffuse supraclavicular lymphadenopathy was also present. Histopathologic examination of the lymph node biopsy revealed granulomatous inflammation with some areas of caseous necrosis consistent with sarcoidosis. CONCLUSION: Sarcoidosis is a common cause of uveitis and retinal vasculitis. In rare cases, an optic disk granuloma may occur and can be treated with immunosuppressive therapy. PMID- 26650565 TI - Laser sintering of copper nanoparticles on top of silicon substrates. AB - This study examines the sintering of inkjet printed nanoparticle copper ink in a room environment using a laser as a high speed sintering method. Printed patterns were sintered with increasing laser scanning speed up to 400 mm s(-1). The resistivities of the sintered structures were measured and plotted against the scanning speeds. Increased resistivity seems to correlate with increased scanning speed. A selections of analytical methods was used to study the differences in microstructure and composition of the sintered structures. Based on the results, no discernable difference in the microstructure was noticed between the structures sintered using 20 mm s(-1) to 400 mm s(-1) scanning speeds; only the structure scanned using 5 mm s(-1) speed showed a vastly different microstructure and no resistivity was measurable on this structure. Compositional studies revealed that, apart from the structure scanned with 5 mm s(-1) speed which contained the highest oxygen, the rest of the structures showed a steady oxygen increase with increased scanning speed. PMID- 26650566 TI - Isolation of Mitochondria from Minimal Quantities of Mouse Skeletal Muscle for High Throughput Microplate Respiratory Measurements. AB - Dysfunctional skeletal muscle mitochondria play a role in altered metabolism observed with aging, obesity and Type II diabetes. Mitochondrial respirometric assays from isolated mitochondrial preparations allow for the assessment of mitochondrial function, as well as determination of the mechanism(s) of action of drugs and proteins that modulate metabolism. Current isolation procedures often require large quantities of tissue to yield high quality mitochondria necessary for respirometric assays. The methods presented herein describe how high quality purified mitochondria (~ 450 ug) can be isolated from minimal quantities (~75-100 mg) of mouse skeletal muscle for use in high throughput respiratory measurements. We determined that our isolation method yields 92.5+/- 2.0% intact mitochondria by measuring citrate synthase activity spectrophotometrically. In addition, Western blot analysis in isolated mitochondria resulted in the faint expression of the cytosolic protein, GAPDH, and the robust expression of the mitochondrial protein, COXIV. The absence of a prominent GAPDH band in the isolated mitochondria is indicative of little contamination from non-mitochondrial sources during the isolation procedure. Most importantly, the measurement of O2 consumption rate with micro-plate based technology and determining the respiratory control ratio (RCR) for coupled respirometric assays shows highly coupled (RCR; >6 for all assays) and functional mitochondria. In conclusion, the addition of a separate mincing step and significantly reducing motor driven homogenization speed of a previously reported method has allowed the isolation of high quality and purified mitochondria from smaller quantities of mouse skeletal muscle that results in highly coupled mitochondria that respire with high function during microplate based respirometirc assays. PMID- 26650567 TI - A Biomimetic Synthesis of Phaitanthrin E Involving a Fragmentation of sp(3) Carbon-Carbon Bond: Synthesis and Rearrangement of Phaitanthrin D to Phaitanthrin E. AB - A biogenetic type total synthesis of alkaloids phaitanthrin D and phaitanthrin E has been described. The Csp(3)-Csp(3) bond cleavage with the release of several heteroatoms bearing unexpected leaving groups in intramolecular substitution reactions on an iminium double bond in the quinazolinones has been demonstrated using HMDS/ZnCl2 or NaHMDS. The mechanistic aspects have been supported by isolation and characterization of appropriate intermediates. PMID- 26650568 TI - Ferredoxin 1b (Fdx1b) Is the Essential Mitochondrial Redox Partner for Cortisol Biosynthesis in Zebrafish. AB - Mitochondrial cytochrome P450 (CYP) enzymes rely on electron transfer from the redox partner ferredoxin 1 (FDX1) for catalytic activity. Key steps in steroidogenesis require mitochondrial CYP enzymes and FDX1. Over 30 ferredoxin mutations have been explored in vitro; however, no spontaneously occurring mutations have been identified in humans leaving the impact of FDX1 on steroidogenesis in the whole organism largely unknown. Zebrafish are an important model to study human steroidogenesis, because they have similar steroid products and endocrine tissues. This study aimed to characterize the influence of ferredoxin on steroidogenic capacity in vivo by using zebrafish. Zebrafish have duplicate ferredoxin paralogs: fdx1 and fdx1b. Although fdx1 was observed throughout development and in most tissues, fdx1b was expressed after development of the zebrafish interrenal gland (counterpart to the mammalian adrenal gland). Additionally, fdx1b was restricted to adult steroidogenic tissues, such as the interrenal, gonads, and brain, suggesting that fdx1b was interacting with steroidogenic CYP enzymes. By using transcription activator-like effector nucleases, we generated fdx1b mutant zebrafish lines. Larvae with genetic disruption of fdx1b were morphologically inconspicuous. However, steroid hormone analysis by liquid chromatography tandem mass spectrometry revealed fdx1b mutants failed to synthesize glucocorticoids. Additionally, these mutants had an up regulation of the hypothalamus-pituitary-interrenal axis and showed altered dark light adaptation, suggesting impaired cortisol signaling. Antisense morpholino knockdown confirmed Fdx1b is required for de novo cortisol biosynthesis. In summary, by using zebrafish, we generated a ferredoxin knockout model system, which demonstrates for the first time the impact of mitochondrial redox regulation on glucocorticoid biosynthesis in vivo. PMID- 26650569 TI - Developmental Programming: Impact of Gestational Steroid and Metabolic Milieus on Adiposity and Insulin Sensitivity in Prenatal Testosterone-Treated Female Sheep. AB - Prenatally testosterone (T)-treated sheep present metabolic disruptions similar to those seen in women with polycystic ovary syndrome. These females exhibit an increased ratio of small to large adipocytes, which may be the earliest event in the development of adult insulin resistance. Additionally, our longitudinal studies suggest the existence of a period of compensatory adaptation during development. This study tested whether 1) in utero cotreatment of prenatally T treated sheep with androgen antagonist (flutamide) or insulin sensitizer (rosiglitazone) prevents juvenile insulin resistance and adult changes in adipocyte size; and 2) visceral adiposity and insulin sensitivity are both unaltered during early adulthood, confirming the predicted developmental trajectory in this animal model. Insulin sensitivity was tested during juvenile development and adipose tissue distribution, adipocyte size, and concentrations of adipokines were determined during early adulthood. Prenatal T-treated females manifested juvenile insulin resistance, which was prevented by prenatal rosiglitazone cotreatment. Neither visceral adiposity nor insulin sensitivity differed between groups during early adulthood. Prenatal T-treated sheep presented an increase in the relative proportion of small adipocytes, which was not substantially prevented by either prenatal intervention. A large effect size was observed for increased leptin concentrations in prenatal T-treated sheep compared with controls, which was prevented by prenatal rosiglitazone. In conclusion, gestational alterations in insulin-glucose homeostasis likely play a role in programming insulin resistance, but not adipocyte size distribution, in prenatal T-treated sheep. Furthermore, these results support the notion that a period of compensatory adaptation of the metabolic system to prenatal T exposure occurs between puberty and adulthood. PMID- 26650570 TI - Hepatocyte-Specific Disruption of CD36 Attenuates Fatty Liver and Improves Insulin Sensitivity in HFD-Fed Mice. AB - CD36/FAT (fatty acid translocase) is associated with human and murine nonalcoholic fatty liver disease, but it has been unclear whether it is simply a marker or whether it directly contributes to disease pathogenesis. Mice with hepatocyte-specific deletion of Janus kinase 2 (JAK2L mice) have increased circulating free fatty acids (FAs), dramatically increased hepatic CD36 expression and profound fatty liver. To investigate the role of elevated CD36 in the development of fatty liver, we studied two models of hepatic steatosis, a genetic model (JAK2L mice) and a high-fat diet (HFD)-induced steatosis model. We deleted Cd36 specifically in hepatocytes of JAK2L mice to generate double knockouts and from wild-type mice to generate CD36L single-knockout mice. Hepatic Cd36 disruption in JAK2L livers significantly improved steatosis by lowering triglyceride, diacylglycerol, and cholesterol ester content. The largest differences in liver triglycerides were in species comprised of oleic acid (C18:1). Reduction in liver lipids correlated with an improvement in the inflammatory markers that were elevated in JAK2L mice, namely aspartate aminotransferase and alanine transaminase. Cd36 deletion in mice on HFD (CD36L HFD) reduced liver lipid content and decreased hepatic 4,4-difluoro-4-bora-3a,4a diaza-s-indacene-FA uptake as compared with CON-HFD. Additionally, CD36L-HFD mice had improved whole-body insulin sensitivity and reduced liver and serum inflammatory markers. Therefore, CD36 directly contributes to development of fatty liver under conditions of elevated free FAs by modulating the rate of FA uptake by hepatocytes. In HFD-fed animals, disruption of hepatic Cd36 protects against associated systemic inflammation and insulin resistance. PMID- 26650571 TI - What does Medicaid expansion mean for cancer screening and prevention? Results from a randomized trial on the impacts of acquiring Medicaid coverage. AB - BACKGROUND: The Oregon Medicaid lottery provided a unique opportunity to assess the causal impacts of health insurance on cancer screening rates within the framework of a randomized controlled trial. Prior studies regarding the impacts of health insurance have almost always been limited to observational evidence, which cannot be used to make causal inferences. METHODS: The authors prospectively followed a representative panel of 16,204 individuals from the Oregon Medicaid lottery reservation list, collecting data before and after the Medicaid lottery drawings. The study panel was divided into 2 groups: a treatment group of individuals who were selected in the Medicaid lottery (6254 individuals) and a control group who were not (9950 individuals). The authors also created an elevated risk subpanel based on family cancer histories. One year after the lottery drawings, differences in cancer screening rates, preventive behaviors, and health status were compared between the study groups. RESULTS: Medicaid coverage resulted in significantly higher rates of several common cancer screenings, especially among women, as well as better primary care connections and self-reported health outcomes. There was little evidence found that acquiring Medicaid increased the adoption of preventive health behaviors that might reduce cancer risk. CONCLUSIONS: Medicaid coverage did not appear to directly impact lifestyle choices that might reduce cancer risk, but it did provide access to important care and screenings that could help to detect cancers earlier. These findings could have long-term population health implications for states considering or pursuing Medicaid expansion. Cancer 2016;122:791-797. (c) 2015 American Cancer Society. PMID- 26650572 TI - Absence of germline CDKN2A mutation in Sicilian patients with familial malignant melanoma: Could it be a population-specific genetic signature? AB - Germline CDKN2A mutations have been described in 25% to 40% of melanoma families from several countries. Sicilian population is genetically different from the people of Europe and Northern Italy because of its historical background, therefore familial melanoma could be due to genes different from high-penetrance CDKN2A gene. Four hundred patients with cutaneous melanoma were observed in a 6 years period at the Plastic Surgery Unit of the University of Palermo. Forty eight patients have met the criteria of the Italian Society of Human Genetics (SIGU) for the diagnosis of familial melanoma and were screened for CDKN2A and CDK4 mutations. Mutation testing revealed that none of the families carried mutations in CDK4 and only one patient harboured the rare CDKN2A p.R87W mutation. Unlike other studies, we have not found high mutation rate of CDKN2A in patients affected by familial melanoma or multiple melanoma. This difference could be attributed to different factors, including the genetic heterogeneity of the Sicilian population. It is likely that, as in the Australian people, the inheritance of familial melanoma in this island of the Mediterranean Sea is due to intermediate/low-penetrance susceptibility genes, which, together with environmental factors (as latitude and sun exposure), could determine the occurrence of melanoma. PMID- 26650573 TI - Oxidation behavior of Cr(III) during thermal treatment of chromium hydroxide in the presence of alkali and alkaline earth metal chlorides. AB - The oxidation behavior of Cr(III) during the thermal treatment of chromium hydroxide in the presence of alkali and alkaline earth metal chlorides (NaCl, KCl, MgCl2, and CaCl2) was investigated. The amounts of Cr(III) oxidized at various temperatures and heating times were determined, and the Cr-containing species in the residues were characterized. During the transformation of chromium hydroxide to Cr2O3 at 300 degrees C approximately 5% of the Cr(III) was oxidized to form intermediate compounds containing Cr(VI) (i.e., CrO3), but these intermediates were reduced to Cr2O3 when the temperature was above 400 degrees C. Alkali and alkaline earth metals significantly promoted the oxidation of Cr(III) during the thermal drying process. Two pathways were involved in the influences the alkali and alkaline earth metals had on the formation of Cr(VI). In pathway I, the alkali and alkaline earth metals were found to act as electron transfer agents and to interfere with the dehydration process, causing more intermediate Cr(VI)-containing compounds (which were identified as being CrO3 and Cr5O12) to be formed. The reduction of intermediate compounds to Cr2O3 was also found to be hindered in pathway I. In pathway II, the alkali and alkaline earth metals were found to contribute to the oxidation of Cr(III) to form chromates. The results showed that the presence of alkali and alkaline earth metals significantly increases the degree to which Cr(III) is oxidized during the thermal drying of chromium-containing sludge. PMID- 26650574 TI - Comparative study on the migration of di-2-ethylhexyl phthalate (DEHP) and tri-2 ethylhexyl trimellitate (TOTM) into blood from PVC tubing material of a heart lung machine. AB - Medical devices like blood tubing often consist of PVC material that requires the addition of plasticizers. These plasticizers may migrate into the blood leading to an exposure of the patients. In this study the migration behavior of three different blood tubing sets (PVC material with two different plasticizers and silicone as control material) applied on a heart-lung machine standardly used for cardiopulmonary bypass (CPB) in children was studied. We analyzed the total plasticizer migration by analysis of both, the parent compounds as well as their primary degradation products in blood. Additionally, the total mass loss of the tubing over perfusion time was examined. The PVC tubing plasticized with DEHP (di 2-ethylhexyl phthalate) was found to have the highest mass loss over time and showed a high plasticizer migration rate. In comparison, the migration of TOTM (tri-2-ethylhexyl trimellitate) and its primary degradation products was found to be distinctly lower (by a factor of approx. 350). Moreover, it was observed that the storage time of the tubing affects the plasticizer migration rates. In conclusion, the DEHP substitute TOTM promises to be an effective alternative plasticizer for PVC medical devices particularly regarding the decreased migration rate during medical procedures. PMID- 26650575 TI - Effects of dioxin-related compounds on bone mineral density in patients affected by the Yusho incident. AB - Exposure to dioxin-related compounds results in many adverse health effects. Several studies have examined the effects of dioxin-related compounds on human bone metabolism with inconsistent results. In Japan in 1968, accidental human exposure to rice oil contaminated with dioxin-related compounds led to the development of Yusho oil disease. The aim of this study was to determine whether exposure to dioxin-related compounds was associated with bone mineral density in Yusho patients. In 2010, 262 women and 227 men underwent dual-energy X-ray absorptiometry bone scans as part of the nationwide Yusho health examination. Serum levels of polychlorinated dibenzo-p-dioxin, polychlorinated dibenzofurans, and non-ortho polychlorinated biphenyls were measured using high-resolution gas chromatography and high-resolution mass spectrometry. When adjusted for prefecture, 1,2,3,4,7,8-HxCDD and 2,3,7,8-TCDF were significantly positively associated with Z-scores in men. No congeners were positively associated with Z scores in women. After adjustment for prefecture and body mass index, one congener, 1,2,3,4,6,7,8-HpCDD, was negatively associated with Z-scores in women. In contrast, no congeners remained significant in men after adjusting for body mass index. This may suggest that 1,2,3,4,6,7,8-HpCDD has a negative effect on bone mineral density in women; however, the findings should be interpreted carefully, because no increase in the serum level of this congener was observed in patients with Yusho disease. PMID- 26650577 TI - Developments in the Orthopaedic Management of Children With Stuve-Wiedemann Syndrome: Use of the Fassier-Duval Telescopic Rod to Maintain Correction of Deformity. AB - BACKGROUND: Stuve-Wiedemann syndrome is a rare inherited condition, which is frequently fatal in infancy. Those patients who survive into childhood demonstrate a complex progressive deformity of the long bones, with high rates of recurrence after initial successful correction. Because of the rarity of the condition there is, at present, limited evidence on the most appropriate treatment. METHODS: We describe our experience in the management of 4 patients, who underwent correction of deformity and fixation with Fassier-Duval telescopic rods. RESULTS: In this series we have seen good correction of deformity and maintenance of alignment, with improvement in the walking ability of children treated with this technique. CONCLUSION: Fassier-Duval rodding has a role in the prevention of recurrence of deformity and should be considered as a means to reduce the number of operative procedures required. LEVEL OF EVIDENCE: Level IV therapeutic. PMID- 26650576 TI - A Graphic Overlay Method for Selection of Osteotomy Site in Chronic Radial Head Dislocation: An Evaluation of 3D-printed Bone Models. AB - PURPOSE: Three-dimensional (3D) computed tomography imaging is now being used to generate 3D models for planning orthopaedic surgery, but the process remains time consuming and expensive. For chronic radial head dislocation, we have designed a graphic overlay approach that employs selected 3D computer images and widely available software to simplify the process of osteotomy site selection. METHODS: We studied 5 patients (2 traumatic and 3 congenital) with unilateral radial head dislocation. These patients were treated with surgery based on traditional radiographs, but they also had full sets of 3D CT imaging done both before and after their surgery: these 3D CT images form the basis for this study. From the 3D CT images, each patient generated 3 sets of 3D-printed bone models: 2 copies of the preoperative condition, and 1 copy of the postoperative condition. One set of the preoperative models was then actually osteotomized and fixed in the manner suggested by our graphic technique. Arcs of rotation of the 3 sets of 3D-printed bone models were then compared. RESULTS: Arcs of rotation of the 3 groups of bone models were significantly different, with the models osteotomized accordingly to our graphic technique having the widest arcs. CONCLUSIONS: For chronic radial head dislocation, our graphic overlay approach simplifies the selection of the osteotomy site(s). Three-dimensional-printed bone models suggest that this approach could improve range of motion of the forearm in actual surgical practice. LEVEL OF EVIDENCE: Level IV-therapeutic study. PMID- 26650578 TI - Delayed Wound Dehiscence of Anterior Knee Incisions in Patients Aged 20 Years and Younger: A Comparison of Subcutaneous Skin Closure. AB - BACKGROUND: Delayed wound dehiscence (DWD) typically occurs 2 to 7 weeks postoperatively and is characterized by wound gapping and drainage at a surgical site which has initial normal wound healing. This wound problem clinically mimics deep surgical site infection and, after eventual skin healing, leaves a cosmetically unattractive widened, atrophic surgical scar. METHODS: A single center, retrospective analysis was completed of 252 knees, over a 13-year period, in 194 patients (average age, 14.9 y) undergoing patellar realignment surgery. All knees in this study were treated through an anterior midline knee incision from mid-patella to the tibial tubercle. At wound closure either a 2-0 polyglactin 910 (Vicryl) group (V) or polydioxane (PDS) group (P) suture was used for subcutaneous reapproximation and then the skin was closed with a 4-0 subcuticular Poliglecaprone 25 and IRGACARE (Monocryl) suture. Wound complications were recorded and analyzed by subcutaneous suture type, severity, size of involvement, duration, and treatment type. RESULTS: Of the 252 knees, there were 132 knees in the V group and 120 in the P group. A total of 195 surgeries were primary surgeries and 57 knees were through previous surgical scars. Eleven patients had surgeries in which 1 knee was in each study group. Overall there were 6.1% (8/132) of the V group and 1.7% (2/120) of the P group with DWD (P=0.11); hence there was a trend toward more DWD with Vicryl than PDS, but this did not meet statistical significance. Mean time to resolution of wound dehiscence was 26 days for V group and 46 days for the P group. The length of incision was demonstrated to be a statistically significant independent risk factor for the development of DWD, irrespective of suture type. CONCLUSIONS: The frequency of DWD in anterior knee incisions in our study population was 6.1% in the polyglactin 910 (Vicryl) group and 1.7% in the polydioxane (PDS) group. Although this analysis did not achieve statistical significance, a 3.5 times decrease in DWD when PDS was used is considered by the authors to be clinically significant. The authors have definitively switched from Vicryl to PDS for the subcutaneous skin closure at the knee in patients aged 20 years and younger in the push to make wound complications a nonevent. LEVEL OF EVIDENCE: Level IV. PMID- 26650579 TI - Posttraumatic Tibiofibular Synostosis After Treatment of Distal Tibiofibular Fractures in Children. AB - INTRODUCTION: Posttraumatic pediatric distal tibiofibular synostosis is a rare complication following fracture. This is a retrospective, multicenter case series of synostosis of distal tibiofibular fractures in children. The purpose was to evaluate the incidence and pattern of posttraumatic distal tibiofibular synostosis in children. METHODS: Of the 604 pediatric distal tibiofibular fractures, 20 patients (3.3%) with synostosis after treatment of distal tibiofibular fractures were identified at 3 tertiary referral centers. There were 12 boys and 8 girls, with a mean age of 8.4+/-2.0 years (range, 3.7 to 11.5 y) at the time of injury. Medical records were reviewed, and serial radiographs were analyzed to determine fracture configuration, pattern of synostosis, and changes in the relative positions of the proximal and distal tibial and fibular physes and in the alignment of the ankle. RESULTS: The time from the occurrence of fracture until the recognition of the synostosis ranged from 2 to 6 months (mean, 2.8 mo). The most common fracture configuration was oblique tibial fracture combined with comminuted fibular fracture. There were 12 focal types and 8 extensive types. The proximal tibiofibular distance was decreased in 13 patients. Proximal migration of the distal fibular physis developed in all cases. Five patients exhibited ankle valgus of 10 degrees or greater with moderate or severe distal fibular shortening. Eight patients were symptomatic after synostosis and 12 patients were asymptomatic. CONCLUSIONS: We identified 2 patterns of synostosis after the treatment of pediatric distal tibiofibular fracture: focal and extensive. The focal type was more prevalent than the extensive type, which was more likely to occur due to high-energy injury. When a tibiofibular cross union develops, it creates growth abnormalities that warrant observation and potential treatment, as it may lead to progressive deformity or ankle pain. LEVEL OF EVIDENCE: Level IV. PMID- 26650580 TI - Efficacy of the Modified Brostrom Procedure for Adolescent Patients With Chronic Lateral Ankle Instability. AB - BACKGROUND AND PURPOSE: Lateral ankle sprains are very common, representing up to 30% of sports-related injuries. The anterior talofibular ligament (ATFL) and less commonly the calcaneofibular ligament (CFL) are injured. Surgical treatment is reserved for injuries that fail nonoperative treatment with recurrent instability. Anatomic repair using the modified Brostrom technique has been shown to have good clinical outcomes in the adult population. The purpose of this study was to report on the outcomes of the modified Brostrom technique in the pediatric and adolescent population (under 18 y old) for chronic lateral ankle instability. METHODS: Thirty-one patients over an 8-year period were included in the current study after excluding for congenital malformation or underlying connective tissue disease. All patients were treated with a modified Brostrom technique in which the ATFL was repaired anatomically. Twenty-four patients (77%) underwent concomitant arthroscopy for intra-articular pathology. Demographic, surgical, and clinical data were collected and outcome scores were obtained, including the Marx activity scale, University of California, Los Angeles (UCLA) activity score, and modified American Orthopedic Foot and Ankle Society (AOFAS) score. RESULTS: Mean time from initial injury to surgery averaged 27 months with an overall mean clinical postoperative follow-up of 36 months. Of the 24 patients who underwent concomitant arthroscopy, all had thickening of Bassett ligament and 3 (12.5%) had cartilage lesions. Postoperatively, the mean Marx activity score was 9.9+/-4.7, mean UCLA score was 9.3+/-1.3, and mean modified AOFAS score was 83.8+/-11.7. 71% (22 of 31) of patients achieved good-to-excellent results (as defined by a modified AOFAS score of 80 or greater). Two patients had superficial wound infections; no other complications were experienced in this cohort. CONCLUSIONS: Lateral ankle sprains are common injuries that can frequently be treated nonoperatively; chronic instability may result despite appropriate therapy. Surgical treatment with anatomic repair of the ATFL and CFL using the modified Brostrom technique in pediatric and adolescent patients results in improved stability, low complication rate, and good clinical outcome scores. LEVEL OF EVIDENCE: Level IV-prognostic retrospective case series. PMID- 26650581 TI - Prophylactic Intramedullary Rodding Following Femoral Lengthening in Congenital Deficiency of the Femur. AB - INTRODUCTION: Femoral fracture after lengthening of congenital femoral deficiency (CFD) is a common complication with a high incidence, up to 50%. The purpose of this study is to determine whether prophylactic intramedullary Rush rodding after lengthening for CFD is an effective method to prevent femoral fracture and to assess any complications that may result. METHODS: Forty-five femoral lengthenings (43 CFD patients) were performed using external fixation. At the time of frame removal (except for 3 cases, 8 d later), prophylactic intramedullary Rush rods were inserted. Special reaming techniques were developed to pass a Rush rod through the solid regenerate bone and past sclerotic pin sites. Mean age at time of rodding was 6.9 years (range, 2.9 to 14.2 y). Mean duration of treatment with external fixation was 184 days (range, 146 to 461 d). Mean follow-up was 4.2 years (range, 1.3 to 8.2 y). This group of cases was compared with a historical cohort of 95 femoral lengthening procedures for CFD without prophylactic intramedullary rodding after frame removal previously performed at the same institute by the same surgeons. RESULTS: Eight cases (18%) developed fracture despite intramedullary rodding (1 case with relatively high energy trauma, 3 cases during physical therapy, and 4 cases spontaneously). Only 4 of these fractures required intervention. Fractures were more common when a 3.18 mm Rush rod was used (28%) compared with 4.76 mm (8.3%). Patients with prophylactic rodding had a significantly lower incidence of femur fracture rodding than those who did not (18% vs. 34%, respectively; P=0.04). Three out of 45 Rush rods (7%) developed infection that were treated by debridement and removal of the rod, and all healed uneventfully without residual or recurrent infection. There were no cases of avascular necrosis. CONCLUSIONS: Prophylactic intramedullary rodding is a safe and effective method to prevent femoral fractures after CFD lengthening. Use of 4.76 mm rod is preferred. The risk of infection is acceptable, when compared with the risk of fracture, loss of length, and angulation. LEVEL OF EVIDENCE: Level III-a retrospective comparative study. PMID- 26650582 TI - Efficient Isolation Protocol for B and T Lymphocytes from Human Palatine Tonsils. AB - Tonsils form a part of the immune system providing the first line of defense against inhaled pathogens. Usually the term "tonsils" refers to the palatine tonsils situated at the lateral walls of the oral part of the pharynx. Surgically removed palatine tonsils provide a convenient accessible source of B and T lymphocytes to study the interplay between foreign pathogens and the host immune system. This video protocol describes the dissection and processing of surgically removed human palatine tonsils, followed by the isolation of the individual B and T cell populations from the same tissue sample. We present a method, which efficiently separates tonsillar B and T lymphocytes using an antibody-dependent affinity protocol. Further, we use the method to demonstrate that human adenovirus infects specifically the tonsillar T cell fraction. The established protocol is generally applicable to efficiently and rapidly isolate tonsillar B and T cell populations to study the role of different types of pathogens in tonsillar immune responses. PMID- 26650583 TI - Analysis of potential factors allowing coexistence in a sexual/asexual minnow complex. AB - The northern redbelly dace (Chrosomus eos) and the finescale dace (C. neogaeus) have hybridized to produce an all-female, asexual hybrid (C. eos-neogaeus) that reproduces by sperm-limited parthenogenesis (gynogenesis). However, in this system, gynogenesis is not 100 % efficient; triploid females are occasionally formed which reproduce as sexuals, producing nuclear males and females of the paternal species (generally C. eos). Thus, the asexual lineage continually produces occasional males that can serve as a sperm source. Because (almost) all hybrid offspring are females, the hybrid population has the potential to grow more quickly and even outcompete the sexuals, thus eliminating their own sperm source. The current research uses behavioral testing, ovarian analyses, and modeling to examine three hypotheses for the maintenance of the sexual/asexual complex: male discrimination against hybrid females, fecundity differences between sexual and asexual females, and production of nuclear male sexuals from the asexual lineage. Results suggest that males do not discriminate against asexual females, and that both sexual and asexual females have similar fecundities, eliminating these hypotheses as potential coexistence mechanisms. However, computer simulations of population growth support the hypothesis that occasional triploidy within the hybrid population supplies enough breeding males to maintain the sexual/asexual complex. PMID- 26650584 TI - Large-scale pollination experiment demonstrates the importance of insect pollination in winter oilseed rape. AB - Insect pollination, despite its potential to contribute substantially to crop production, is not an integrated part of agronomic planning. A major reason for this are knowledge gaps in the contribution of pollinators to yield, which partly result from difficulties in determining area-based estimates of yield effects from insect pollination under field conditions. We have experimentally manipulated honey bee Apis mellifera densities at 43 oilseed rape Brassica napus fields over 2 years in Scandinavia. Honey bee hives were placed in 22 fields; an additional 21 fields without large apiaries in the surrounding landscape were selected as controls. Depending on the pollination system in the parental generation, the B. napus cultivars in the crop fields are classified as either open-pollinated or first-generation hybrids, with both types being open pollinated in the generation of plants cultivated in the fields. Three cultivars of each type were grown. We measured the activity of flower-visiting insects during flowering and estimated yields by harvesting with small combine harvesters. The addition of honey bee hives to the fields dramatically increased abundance of flower-visiting honey bees in those fields. Honey bees affected yield, but the effect depended on cultivar type (p = 0.04). Post-hoc analysis revealed that open-pollinated cultivars, but not hybrid cultivars, had 11% higher yields in fields with added honey bees than those grown in the control fields (p = 0.07). To our knowledge, this is the first whole-field study in replicated landscapes to assess the benefit of insect pollination in oilseed rape. Our results demonstrate that honey bees have the potential to increase oilseed rape yields, thereby emphasizing the importance of pollinator management for optimal cultivation of oilseed rape. PMID- 26650585 TI - Anxiety-Like Behavioural Inhibition Is Normative under Environmental Threat Reward Correlations. AB - Behavioural inhibition is a key anxiety-like behaviour in rodents and humans, distinct from avoidance of danger, and reduced by anxiolytic drugs. In some situations, it is not clear how behavioural inhibition minimises harm or maximises benefit for the agent, and can even appear counterproductive. Extant explanations of this phenomenon make use of descriptive models but do not provide a formal assessment of its adaptive value. This hampers a better understanding of the neural computations underlying anxiety behaviour. Here, we analyse a standard rodent anxiety model, the operant conflict test. We harvest Bayesian Decision Theory to show that behavioural inhibition normatively arises as cost-minimising strategy in temporally correlated environments. Importantly, only if behavioural inhibition is aimed at minimising cost, it depends on probability and magnitude of threat. Harnessing a virtual computer game, we test model predictions in four experiments with human participants. Humans exhibit behavioural inhibition with a strong linear dependence on threat probability and magnitude. Strikingly, inhibition occurs before motor execution and depends on the virtual environment, thus likely resulting from a neural optimisation process rather than a pre programmed mechanism. Individual trait anxiety scores predict behavioural inhibition, underlining the validity of this anxiety model. These findings put anxiety behaviour into the context of cost-minimisation and optimal inference, and may ultimately pave the way towards a mechanistic understanding of the neural computations gone awry in human anxiety disorder. PMID- 26650586 TI - Association of Bullying Behavior at 8 Years of Age and Use of Specialized Services for Psychiatric Disorders by 29 Years of Age. AB - IMPORTANCE: Bullying and being exposed to bullying among children is prevalent, especially among children with psychiatric symptoms, and constitutes a major concern worldwide. Whether childhood bullying or exposure to bullying in the absence of childhood psychiatric symptoms is associated with psychiatric outcomes in adulthood remains unclear. OBJECTIVE: To study the associations between bullying behavior at 8 years of age and adult psychiatric outcomes by 29 years of age. DESIGN, SETTING, AND PARTICIPANTS: Nationwide birth cohort study of 5034 Finnish children with complete information about childhood bullying behavior was followed up from 8 to 29 years of age. Follow-up was completed on December 31, 2009, and data were analyzed from January 15, 2013, to February 15, 2015. MAIN OUTCOMES AND MEASURES: Information about bullying, exposure to bullying, and psychiatric symptoms were obtained from parents, teachers, and child self-reports when children were 8 years of age. Use of specialized services for psychiatric disorders from 16 to 29 years of age was obtained from a nationwide hospital register, including outpatient and inpatient treatment. RESULTS: Among the 5034 study participants, 4540 (90.2%) did not engage in bullying behavior; of these, 520 (11.5%) had received a psychiatric diagnosis at follow-up; 33 of 166 (19.9%) who engaged in frequent bullying, 58 of 251 (23.1%) frequently exposed to bullying, and 24 of 77 (31.2%) who both frequently engaged in and were frequently exposed to bullying had received psychiatric diagnoses at follow-up. When analyses were adjusted by sex, family factors, and child psychiatric symptoms at 8 years of age, we found independent associations of treatment of any psychiatric disorder with frequent exposure to bullying (hazard ratio [HR], 1.9; 95% CI, 1.4 2.5) and being a bully and exposed to bullying (HR, 2.1; 95% CI, 1.3-3.4). Exposure to bullying was specifically associated with depression (HR, 1.9; 95% CI, 1.2-2.9). Bullying was associated with psychiatric outcomes only in the presence of psychiatric problems at 8 years of age. Participants who were bullies and exposed to bullying at 8 years of age had a high risk for several psychiatric disorders requiring treatment in adulthood. However, the associations with specific psychiatric disorders did not remain significant after controlling for concurrent psychiatric symptoms. CONCLUSIONS AND RELEVANCE: Exposure to bullying, even in the absence of childhood psychiatric symptoms, is associated with severe adulthood psychiatric outcomes that require treatment in specialized services. Early intervention among those involved in bullying can prevent long-term consequences. PMID- 26650588 TI - July 2009: This Month's Highlights. PMID- 26650587 TI - Deep roots and soil structure. PMID- 26650589 TI - Law & Psychiatry: Congress Restores the Americans With Disabilities Act to Its Original Intent. PMID- 26650590 TI - Alcohol & Drug Abuse: What Is "Women-Focused" Treatment for Substance Use Disorders? PMID- 26650591 TI - Letter. PMID- 26650592 TI - Letter. PMID- 26650593 TI - Letter. PMID- 26650600 TI - Annual Government Spending on Substance Abuse and Addiction Nears a Half Trillion Dollars. PMID- 26650594 TI - Letter. PMID- 26650601 TI - IOM Calls for Stronger Protections Against Conflicts of Interest in Research, Education, and Practice. PMID- 26650604 TI - Self-Assembled Sandwich-like Vanadium Oxide/Graphene Mesoporous Composite as High Capacity Anode Material for Lithium Ion Batteries. AB - Sandwich-like V2O5/graphene mesoporous composite has been synthesized by a facile solvothermal approach. The crystalline structure, morphology, and electrochemical performance of the as-prepared materials have been investigated in detail. The results demonstrate that the 30-50 nm V2O5 particles are homogeneously anchored on conducting graphene sheets, which allow the V2O5 nanoparticles to be wired up to a current collector through the underlying conducting graphene layers. As an anode material for lithium ion batteries, the composite exhibits a high reversible capacity of 1006 mAh g(-1) at a current density of 0.5 A g(-1) after 300 cycles. It also exhibits excellent rate performance with a discharge capacity of 500 mAh g(-1) at the current density of 3.0 A g(-1), which is superior to the performance of the vanadium-based materials reported previously. The electrochemical properties demonstrate that the sandwich-like V2O5/graphene mesoporous composite could be a promising candidate material for high-capacity anode in lithium ion batteries. PMID- 26650603 TI - Targeting activated hepatic stellate cells (aHSCs) for liver fibrosis imaging. AB - Following injurious stimuli, quiescent hepatic stellate cells (qHSCs) transdifferentiate into activated HSCs (aHSCs). aHSCs play pivotal roles in the onset and progression of liver fibrosis. Therefore, molecular imaging of aHSCs in liver fibrosis will facilitate early diagnosis, prognosis prediction, and instruction and evaluation of aHSC-targeted treatment. To date, several receptors, such as integrin alphavbeta3, mannose 6-phosphate/insulin-like growth factor II receptor (M6P/IGF-IIR), collagen type VI receptor (CVIR), platelet derived growth factor receptor-beta (PDGFR-beta), vimentin, and desmin, have been identified as biomarkers of aHSCs. Corresponding ligands to these receptors have also been developed. This review will discuss strategies for developing aHSC targeted imaging in liver fibrosis. PMID- 26650605 TI - Sex Differences in Exploration Behavior and the Relationship to Harm Avoidance. AB - Venturing into novel terrain poses physical risks to a female and her offspring. Females have a greater tendency to avoid physical harm, while males tend to have larger range sizes and often outperform females in navigation-related tasks. Given this backdrop, we expected that females would explore a novel environment with more caution than males, and that more-cautious exploration would negatively affect navigation performance. Participants explored a novel, large-scale, virtual environment in search of five objects, pointed in the direction of each object from the origin, and then navigated back to the objects. We found that females demonstrated more caution while exploring as reflected in the increased amounts of pausing and revisiting of previously traversed locations. In addition, more pausing and revisiting behaviors led to degradation in navigation performance. Finally, individual levels of trait harm avoidance were positively associated with the amount of revisiting behavior during exploration. These findings support the idea that the fitness costs associated with long-distance travel may encourage females to take a more cautious approach to spatial exploration, and that this caution may partially explain the sex differences in navigation performance. PMID- 26650606 TI - Mobility and Navigation among the Yucatec Maya: Sex Differences Reflect Parental Investment, Not Mating Competition. AB - Sex differences in range size and navigation are widely reported, with males traveling farther than females, being less spatially anxious, and in many studies navigating more effectively. One explanation holds that these differences are the result of sexual selection, with larger ranges conferring mating benefits on males, while another explanation focuses on greater parenting costs that large ranges impose on reproductive-aged females. We evaluated these arguments with data from a community of highly monogamous Maya farmers. Maya men and women do not differ in distance traveled over the region during the mate-seeking years, suggesting that mating competition does not affect range size in this monogamous population. However, men's regional and daily travel increases after marriage, apparently in pursuit of resources that benefit families, whereas women reduce their daily travel after marriage. This suggests that parental effort is more important than mating effort in this population. Despite the relatively modest overall sex difference in mobility, Maya men were less spatially anxious than women, thought themselves to be better navigators, and pointed more accurately to distant locations. A structural equation model showed that the sex by marital status interaction had a direct effect on mobility, with a weaker indirect effect of sex on mobility mediated by navigational ability. PMID- 26650607 TI - A GLP-compliant toxicology and biodistribution study: systemic delivery of a rAAV9 vector for the treatment of mucopolysaccharidosis IIIB. AB - No treatment is currently available for mucopolysaccharidosis (MPS) IIIB, a neuropathic lysosomal storage disease due to defect in alpha-N acetylglucosaminidase (NAGLU). In preparation for a clinical trial, we performed an IND-enabling GLP-toxicology study to assess systemic rAAV9-CMV-hNAGLU gene delivery in WT C57BL/6 mice at 1x1014vg/kg and 2x1014vg/kg (n=30/group, M:F=1:1), and non-GLP testing in MPS IIIB mice at 2x1014vg/kg. Importantly, no adverse clinical signs or chronic toxicity were observed through the 6 month study duration. The rAAV9-mediated rNAGLU expression was rapid and persistent in virtually all tested CNS and somatic tissues. However, acute liver toxicity occurred in 33% (5/15) WT males in the 2x1014vg/kg cohort, which was dose dependent, sex-associated and genotype-specific, likely due to hepatic rNAGLU over-expression. Interestingly, a significant dose response was observed only in the brain and spinal cord, whereas in the liver at 24-wk pi, NAGLU activity was reduced to endogenous levels in the high dose cohort but remained at supranormal levels in the low dose group. The possibility of rAAV9 germline transmission appears to be minimal. The vector delivery resulted in transient T-cell responses and characteristic acute antibody responses to both AAV9 and rNAGLU in all rAAV9 treated animals, with no detectable impacts on tissue transgene expression. This study demonstrates a generally safe and effective profile, and may have identified the upper dosing limit of rAAV9-CMV-hNAGLU via systemic delivery for the treatment of MPS IIIB. PMID- 26650608 TI - Aberrant expression of long noncoding RNAs in cumulus cells isolated from PCOS patients. AB - PURPOSE: To describe the long noncoding RNA (lncRNA) profiles in cumulus cells isolated from polycystic ovary syndrome (PCOS) patients by employing a microarray and in-depth bioinformatics analysis. This information will help us understand the occurrence and development of PCOS. METHODS: In this study, we used a microarray to describe lncRNA profiles in cumulus cells isolated from ten patients (five PCOS and five normal women). Several differentially expressed lncRNAs were chosen to validate the microarray results by quantitative RT-PCR (qRT-PCR). Then, the differentially expressed lncRNAs were classified into three subgroups (HOX loci lncRNA, enhancer-like lncRNA, and lincRNA) to deduce their potential features. Furthermore, a lncRNA/mRNA co-expression network was constructed by using the Cytoscape software (V2.8.3, http://www.cytoscape.org/ ). RESULTS: We observed that 623 lncRNAs and 260 messenger RNAs (mRNAs) were significantly up- or down-regulated (>=2-fold change), and these differences could be used to discriminate cumulus cells of PCOS from those of normal patients. Five differentially expressed lncRNAs (XLOC_011402, ENST00000454271, ENST00000433673, ENST00000450294, and ENST00000432431) were selected to validate the microarray results using quantitative RT-PCR (qRT-PCR). The qRT-PCR results were consistent with the microarray data. Further analysis indicated that many differentially expressed lncRNAs were transcribed from chromosome 2 and may act as enhancers to regulate their neighboring protein-coding genes. Forty-three lncRNAs and 29 mRNAs were used to construct the coding-non-coding gene co expression network. Most pairs positively correlated, and one mRNA correlated with one or more lncRNAs. CONCLUSIONS: Our study is the first to determine genome wide lncRNA expression patterns in cumulus cells isolated from PCOS patients by microarray. The results show that clusters of lncRNAs were aberrantly expressed in cumulus cells of PCOS patients compared with those of normal women, which revealed that lncRNAs differentially expressed in PCOS and normal women may contribute to the occurrence of PCOS and affect oocyte development. PMID- 26650609 TI - Association of single-nucleotide polymorphisms rs2197076 and rs2241883 of FABP1 gene with polycystic ovary syndrome. AB - PURPOSE: The objective of this study was to evaluate the association between single-nucleotide polymorphisms (SNPs) rs2197076 and rs2241883 in fatty acid binding protein 1 (FABP1) gene and polycystic ovary syndrome (PCOS). METHODS: The two alleles rs2197076 and rs2241883 in FABP1 gene in 221 PCOS women and 198 normal women were amplified and sequenced. Allele frequency comparison was performed between the PCOS and control groups, and genotype-phenotype correlation analysis was performed using dominant and recessive models to assess the association of FABP1 and the main features of PCOS. RESULTS: Allele frequency analyses showed a strong association of SNPs rs2197076 and rs2241883 of FABP1 gene with PCOS (P < 0.001). The additive, dominant, and recessive genotype model analyses further supported this association even after adjusting for age and body mass index (BMI). The minor allele frequency (MAF) of rs2241883 in obese PCOS women was less than that in obese control women. Further genotype-phenotype correlation analysis showed that SNP rs2197076 had a stronger association with the main features of PCOS than SNP rs2241883. CONCLUSION: In the association of SNPs in FABP1 gene with PCOS, rs2197076 was more closely associated with its main features than rs2241883 and seemed to play a more important role in the pathogenesis of PCOS. PMID- 26650610 TI - Hydrogen Evolution from Water Coupled with the Oxidation of As(III) in a Photocatalytic System. AB - A series of heterostructured CdS/Sr2(Nb17/18Zn1/18)2O7-delta composites with excellent photocatalytic ability for simultaneous hydrogen evolution and As(III) oxidation under simulated sunlight were synthesized and characterized. Among them, 30% CdS/Sr2(Nb17/18Zn1/18)2O7-delta (30CSNZO) has the highest in activity, exhibiting a H2 production rate of 1669.1 MUmol.h(-1).g(-1) that is higher than that of many photocatalysts recently reported in the literature. At pH 9, As(III) is completely oxidized to As(V) over 30CSNZO in 30 min of irradiation of simulated sunlight. In the photocatalytic system, H2 production rate decreases with the increase of As(III) concentration, and the recycle experiments show that 30CSNZO exhibits excellent stability, durability, and recyclability for photocatalytic hydrogen evolution and As(III) oxidation. We propose a mechanism in which superoxide radical (.O2(-)) is the active species for As(III) oxidation and the oxidation of As(III) has an effect on hydrogen evolution. For the first time, it is demonstrated that simultaneous hydrogen evolution and arsenite oxidation is possible in a photocatalytic system. PMID- 26650611 TI - Angiogenic and Immunomodulatory Properties of Endothelial and Mesenchymal Stem Cells. AB - It has been suggested that the effect of implanted cells on the local environment is important when selecting the appropriate cell type for tissue regeneration. Our aim was to compare the local tissue response to implanted human mesenchymal stem cells (MSC) and human umbilical vein endothelial cells (EC). MSC and EC were cultured in poly(L-lactide-co-1,5-dioxepan-2-one) scaffolds for 1 week in a bioreactor system, after which they were implanted subcutaneously in NOD/SCID mice. After 3 weeks, scaffolds were retrieved, and the mRNA expression of selected genes involved in hypoxia and inflammation was examined by real-time reverse transcription polymerase chain reaction and correlated with immunofluorescent staining for corresponding proteins. The Toll-like receptor signaling pathway was examined by superarray hybridization. The expression of 53 angiogenesis-related proteins was investigated by a proteome profiler angiogenesis antibody array kit. Vascularization was quantified using immunohistochemistry for CD31. The expression of hypoxia-inducible factors and biomarkers for angiogenesis was more strongly upregulated in response to implanted EC than to MSC, suggesting a higher sensitivity to low oxygen tension among EC. Hypoxic signaling was increased after implantation of EC compared with MSC, leading to a prolonged acute inflammatory phase that promoted ingrowth of vascular cells and establishment of the circulation. Inflammatory cytokines were also differently expressed at the gene and protein levels in the two experimental groups, resulting in altered recruitment of acute and chronic inflammatory cells. The end result of these differences was increased vessel formation within the constructs in the EC group. PMID- 26650612 TI - Effects of D2 or combined D1/D2 receptor antagonism on the methamphetamine induced one-trial and multi-trial behavioral sensitization of preweanling rats. AB - RATIONALE: There is suggestive evidence that the neural mechanisms mediating one trial and multi-trial behavioral sensitization differ, especially when the effects of various classes of dopamine (DA) agonists are examined. OBJECTIVE: The purpose of the present study was to determine the role of the D2 receptor for the induction of one-trial and multi-trial methamphetamine sensitization in preweanling rats. METHODS: In a series of experiments, rats were injected with saline or raclopride (a selective D2 receptor antagonist), either alone or in combination with SCH23390 (a selective D1 receptor antagonist), 15 min prior to treatment with the indirect DA agonist methamphetamine. Acute control groups were given two injections of saline. This pretreatment regimen occurred on either postnatal days (PD) 13-16 (multi-trial) or PD 16 (one-trial). On PD 17, rats were challenged with methamphetamine and locomotor sensitization was determined. RESULTS: Blockade of D2 or D1/D2 receptors reduced or prevented, respectively, the induction of multi-trial methamphetamine sensitization in young rats, while the same manipulations had minimal effects on one-trial behavioral sensitization. CONCLUSIONS: DA antagonist treatment differentially affected the methamphetamine induced sensitized responding of preweanling rats depending on whether a one trial or multi-trial procedure was used. The basis for this effect is uncertain, but there was some evidence that repeated DA antagonist treatment caused nonspecific changes that produced a weakened sensitized response. Importantly, DA antagonist treatment did not prevent the one-trial behavioral sensitization of preweanling rats. The latter result brings into question whether DA receptor stimulation is necessary for the induction of psychostimulant-induced behavioral sensitization during early ontogeny. PMID- 26650613 TI - The linear plastid chromosomes of maize: terminal sequences, structures, and implications for DNA replication. AB - The structure of a chromosomal DNA molecule may influence the way in which it is replicated and inherited. For decades plastid DNA (ptDNA) was believed to be circular, with breakage invoked to explain linear forms found upon extraction from the cell. Recent evidence indicates that ptDNA in vivo consists of linear molecules with discrete termini, although these ends were not characterized. We report the sequences of two terminal regions, End1 and End2, for maize (Zea mays L.) ptDNA. We describe structural features of these terminal regions and similarities found in other plant ptDNAs. The terminal sequences are within inverted repeat regions (leading to four genomic isomers) and adjacent to origins of replication. Conceptually, stem-loop structures may be formed following melting of the double-stranded DNA ends. Exonuclease digestion indicates that the ends in maize are unobstructed, but tobacco (Nicotiana tabacum L.) ends may have a 5'-protein. If the terminal structure of ptDNA molecules influences the retention of ptDNA, the unprotected molecular ends in mature leaves of maize may be more susceptible to degradation in vivo than the protected ends in tobacco. The terminal sequences and cumulative GC skew profiles are nearly identical for maize, wheat (Triticum aestivum L.) and rice (Oryza sativa L.), with less similarity among other plants. The linear structure is now confirmed for maize ptDNA and inferred for other plants and suggests a virus-like recombination dependent replication mechanism for ptDNA. Plastid transformation vectors containing the terminal sequences may increase the chances of success in generating transplastomic cereals. PMID- 26650614 TI - A self-encoded capsid derivative restricts Ty1 retrotransposition in Saccharomyces. AB - Retrotransposons and retroviral insertions have molded the genomes of many eukaryotes. Since retroelements transpose via an RNA intermediate, the additive nature of the replication cycle can result in massive increases in copy number if left unchecked. Host organisms have countered with several defense systems, including domestication of retroelement genes that now act as restriction factors to minimize propagation. We discovered a novel truncated form of the Saccharomyces Ty1 retrotransposon capsid protein, dubbed p22 that inhibits virus like particle (VLP) assembly and function. The p22 restriction factor expands the repertoire of defense proteins targeting the capsid and highlights a novel host parasite strategy. Instead of inhibiting all transposition by domesticating the restriction gene as a distinct locus, Ty1 and budding yeast may have coevolved a relationship that allows high levels of transposition when Ty1 copy numbers are low and progressively less transposition as copy numbers rise. Here, we offer a perspective on p22 restriction, including its mode of expression, effect on VLP functions, interactions with its target, properties as a nucleic acid chaperone, similarities to other restriction factors, and future directions. PMID- 26650615 TI - Probing dimensionality beyond the linear sequence of mRNA. AB - mRNA is a nexus entity between DNA and translating ribosomes. Recent developments in deep sequencing technologies coupled with structural probing have revealed new insights beyond the classic role of mRNA and place it more centrally as a direct effector of a variety of processes, including translation, cellular localization, and mRNA degradation. Here, we highlight emerging approaches to probe mRNA secondary structure on a global transcriptome-wide level and compare their potential and resolution. Combined approaches deliver a richer and more complex picture. While our understanding on the effect of secondary structure for various cellular processes is quite advanced, the next challenge is to unravel more complex mRNA architectures and tertiary interactions. PMID- 26650616 TI - Ideal Hematocrit to Minimize Renal Injury on Cardiopulmonary Bypass. AB - OBJECTIVE: Renal dysfunction after cardiopulmonary bypass (CBP) ranges from subclinical injury to established renal failure requiring dialysis. The pathophysiology is multifactorial, and recently, hemodilution during CBP has been thought to be an important determinant of postoperative renal injury. In this study, we attempted to assess the independent effect of hemodilution on renal function. We also aimed to identify the optimal hematocrit where hemodilution induced renal injury is minimal. METHODS: A prospective observational study was conducted on 200 patients between February 2012 and July 2013. One hundred fifty patients were included in the study group, who were further subdivided on the basis of lowest hemodilution as mild hemodilution (>25%), moderate hemodilution (21%-25%), and severe hemodilution (<21%) categories. The primary outcome of the study was renal outcome measure, which was assessed by comparing the creatinine clearance across the groups. RESULTS: The creatinine clearance decreased over a period in all three groups. When compared with mild or moderate hemodilution, the reduction in creatinine clearance was significantly higher in the group with severe hemodilution (P <= 0.0001). However, there was no significant difference in creatinine clearance reduction between the mild and moderate hemodilution groups (P = 0.813; 95% confidence interval, -8.41 to 10.68). CONCLUSIONS: Based on our observations, we would like to propose that a hematocrit of 21% should be considered the critical threshold. Hematocrit below this value of 21% during CBP is associated with the most significant deterioration in renal function. PMID- 26650617 TI - Prosthetic Valve Escaping During Transcatheter Aortic Valve Implantation. AB - We performed transapical transcatheter aortic valve implantation on an 87-year old woman with severe aortic valve stenosis. Because of the narrow left ventricular outflow tract, annular positioning of the prosthetic valve proved challenging. During positioning, the prosthetic valve was accidentally dislodged from the balloon catheter and dropped into the left ventricle. Attempted catheter retrieval was unsuccessful. We therefore converted to open surgery without delay. After aortotomy, to our surprise, the prosthesis could not be found, neither in the left ventricle nor in the ascending aorta. Transesophageal echocardiography failed to reveal the location of the missing prosthesis. Fluoroscopy finally displayed the prosthesis in the descending aorta at the level of the left atrium. We proceeded with aortic and mitral valve replacement and closed the sternum. Under fluoroscopic guidance, the prosthetic valve was secured to the wall of the abdominal aorta in an infrarenal position by dilatation with a balloon catheter. This case shows that we should be alert to septum hypertrophy or a narrow left ventricular outflow tract during transapical aortic valve implantation. In such anatomical situations, we recommend advancing the sheath of the application system directly below the annular plane and positioning the prosthesis from this point. PMID- 26650619 TI - Introduction to AJA Implantable Hearing Device Symposium Supplement. PMID- 26650618 TI - Reaction Sites of CO on Size-Selected Silicon Oxide Cluster Anions: A Model Study of Chemistry in the Interstellar Environment. AB - We present reactions of size-selected free silicon oxide cluster anions, SinOm(-) (n = 3-7, 2n - 1 <= m <= 2n + 2), with a CO gas. Adsorption of CO on SinOm(-) is observed as a major reaction channel. The rate constant of the adsorption reaction is high for the oxygen-rich clusters with m >= 2n + 1, whereas almost no reaction product is observed for m <= 2n. DFT calculations revealed that a pair of dangling O atoms on 4-fold-coordinated Si atoms plays a key role, which is the adsorption site of CO on SinOm(-). Bond formation between CO and one of the dangling O atoms is associated with electron transfer from the CO molecule to the other dangling O atom. The present findings give molecular-level insights into adsorption of CO molecules on silicates in the interstellar environment. PMID- 26650620 TI - Cell-free scaffolds with different stiffness but same microstructure promote bone regeneration in rabbit large bone defect model. AB - To promote bone healing, bone repair biomaterials are increasingly designed to incorporate growth factors. However, the impact of matrix mechanics of cell-free scaffold independent of microstructure on the osteogenic differentiation of endogenous osteoprogenitor cells orchestrating bone repair and regeneration remains not to be fully understood. In our recent study, three-dimensional (3D) scaffolds with different stiffness but same microstructure have been successfully fabricated by coating decellularized bone with collagen/hydroxyapatite (HA) mixture with different collagen rations. It has been demonstrated that the scaffold with optimal stiffness can induce the osteogenic differentiation of MSCs in vitro and in the subcutaneous tissue. The present in vivo study further investigated the repair efficiency of these scaffolds in a rabbit radius with a critical-sized segmental defect model and its potential mechanism. Micro-computed tomography (MU-CT), X-ray and histological analysis were carried out to evaluate the repair capacity of these scaffolds. The results demonstrated that the cell free scaffold with optimal stiffness incorporation of endogenous osteoprogenitor cells significantly promoted the repair and reconstruction quality of mass bone defect. One of the crucial mechanisms was that hypoxia and stromal cell-derived factor-1alpha (SDF-1alpha) mediated mesenchymal stem cells (MSCs) migration by which matrix mechanics exerted influence on bone fracture healing. These findings suggested that only modulating the matrix stiffness of cell-free scaffold can be one of the most attractive strategies for promoting the progression of bone healing. PMID- 26650621 TI - Hepatopancreatobiliary Surgery Fellowships: How Many Do We Need? PMID- 26650622 TI - 8-Hydroxy-2-Deoxyguanosine Levels and Cardiovascular Disease: A Systematic Review and Meta-Analysis of the Literature. AB - SIGNIFICANCE: 8-Hydroxy-2-deoxyguanosine (8-OHdG) is generated after the repair of ROS-mediated DNA damages and, thus, is one of the most widely recognized biomarkers of oxidative damage of DNA because guanosine is the most oxidized among the DNA nucleobases. In several pathological conditions, high urinary levels of oxidized DNA-derived metabolites have been reported (e.g., cancer, atherosclerosis, hypertension, and diabetes). RECENT ADVANCES: Even if published studies have shown that DNA damage is significantly associated with the development of atherosclerosis, the exact role of this damage in the onset and progression of this pathology is not fully understood, and the association of oxidative damage to DNA with cardiovascular disease (CVD) still needs to be more extensively investigated. We performed a meta-analysis of the literature to investigate the association among 8-OHdG levels and CVD. CRITICAL ISSUES: Fourteen studies (810 CVD patients and 1106 controls) were included in the analysis. We found that CVD patients showed higher 8-OHdG levels than controls (SMD: 1.04, 95%CI: 0.61, 1.47, p < 0.001, I(2) = 94%, p < 0.001). The difference was confirmed both in studies in which 8-OHdG levels were assessed in urine (MD: 4.43, 95%CI: 1.71, 7.15, p = 0.001) and in blood samples (MD: 1.42, 95%CI: 0.64, 2.21, p = 0.0004). Meta-regression models showed that age, hypertension, and male gender significantly impacted on the difference in 8-OHdG levels among CVD patients and controls. FUTURE DIRECTIONS: 8-OHdG levels are higher in patients with CVD than in controls. However, larger prospective studies are needed to test 8-OHdG as a predictor of CVD. PMID- 26650624 TI - Brexpiprazole for the treatment of schizophrenia. AB - Brexpiprazole (OPC-34712) is a novel serotonin-dopamine activity modulator, which has recently been approved by the U.S Food and Drug Administration for the treatment of schizophrenia. The aim of this paper is to systematically synthesize all data of the efficacy, safety and tolerability of Brexpiprazole in treating schizophrenia. The terms 'Brexpiprazole', 'OPC-34712' and 'schizophrenia' were searched. A total of 12 clinical trials with 7 available data records were found. The pooled effect size of Brexpiprazole 1 mg, 2 mg and 4 mg were all superior to placebo in terms of the change from baseline in positive and negative syndrome scale (PANSS) total score at week 6 (weighted mean difference = -3.74, p = 0.044; weighted mean difference = -5.76, p < 0.01 and weighted mean difference = -7.03, p < 0.01, respectively) when compared to that of the placebo in treating acute schizophrenia. Brexpiprazole displays a good safety and tolerability profile. The incidence of akathisia, headache, insomnia, sedation, agitation, diarrhea, weight gained, nausea, and dyspepsia are comparable to placebo. PMID- 26650623 TI - Serial Diffusion Tensor Imaging In Vivo Predicts Long-Term Functional Recovery and Histopathology in Rats following Different Severities of Spinal Cord Injury. AB - The current study demonstrates the feasibility of using serial magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) in vivo to quantify temporally spinal cord injury (SCI) pathology in adult female Sprague-Dawley rats that were scanned prior to a moderate or severe upper lumbar contusion SCI. Injured rats were behaviorally tested for hind limb locomotion (Basso, Beattie, Bresnahan [BBB] scores) weekly for 4 weeks and scanned immediately after each session, ending with terminal gait analyses prior to euthanasia. As a measure of tissue integrity, fractional anisotropy (FA) values were significantly lower throughout the spinal cord in both injury cohorts at all time-points examined versus pre injury. Moreover, FA values were significantly lower following severe versus moderate SCI at all time-points, and FA values at the injury epicenters at all time-points were significantly correlated with both spared white and gray matter volumes, as well as lesion volumes. Critically, quantified FA values at subacute (24 h) and all subsequent time-points were highly predictive of terminal behavior, reflected in significant correlations with both weekly BBB scores and terminal gait parameters. Critically, the finding that clinically relevant subacute (24 h) FA values accurately predict long-term functional recovery may obviate long-term studies to assess the efficacy of therapeutics tested experimentally or clinically. In summary, this study demonstrates a reproducible serial MRI procedure to predict the long-term impact of contusion SCI on both behavior and histopathology using subacute DTI metrics obtained in vivo to accurately predict multiple terminal outcome measures, which can be particularly valuable when comparing experimental interventions. PMID- 26650625 TI - Water and ion permeability of a claudin model: A computational study. AB - At present, the three-dimensional structure of the multimeric paracellular claudin pore is unknown. Using extant biophysical data concerning the size of the pore and permeation of water and cations through it, two three-dimensional models of the pore are constructed in silico. Molecular Dynamics (MD) calculations are then performed to compute water and sodium ion permeation fluxes under the influence of applied hydrostatic pressure. Comparison to experiment is made, under the assumption that the hydrostatic pressure applied in the simulations is equivalent to osmotic pressure induced in experimental measurements of water/ion permeability. One model, in which pore-lining charged is distributed evenly over a selectivity filter section 10-16 A in length, is found to be generally consistent with experimental data concerning the dependence of water and ion permeation on channel pore diameter, pore length, and the sign and magnitude of pore lining charge. The molecular coupling mechanism between water and ion flow under conditions where hydrostatic pressure is applied is computationally elucidated. PMID- 26650626 TI - ITPA Genotypes Predict Anemia but Do Not Affect Virological Response with Interferon-Free Faldaprevir, Deleobuvir, and Ribavirin for HCV Infection. AB - BACKGROUND & AIM: Whether inosine triphosphatase (ITPA) gene polymorphisms predict anemia during interferon-free therapy in chronic hepatitis C virus (HCV) infected patients is unknown. We examined the relationship between two ITPA polymorphisms, anemia, and sustained virological response 12 weeks post-treatment (SVR12) in patients receiving the NS3/4A protease inhibitor faldaprevir, the non nucleoside polymerase inhibitor deleobuvir, and ribavirin. METHODS: HCV genotype 1-infected, treatment-naive patients (N = 362) were randomized and treated in one of five treatment arms with faldaprevir and deleobuvir with or without ribavirin. Two ITPA polymorphisms (rs1127354 and rs6051702) were genotyped and defined as ITPA-deficient (rs1127354 AA or AC; rs6051702 CC or CA) or ITPA-non-deficient (rs1127354 CC; rs6051702 AA) according to their association with ITPA deficiency. Baseline and on-treatment variables associated with anemia and SVR12 were identified using logistic regression. RESULTS: In the pooled ribavirin-containing arms, 10.1% (32/316) of patients experienced on-treatment hemoglobin <10 g/dL, and 32.6% (103/316) experienced on-treatment hemoglobin <10 g/dL or a change from baseline >=3.5 g/dL. Of the latter group, 99% (102/103) had the ITPA-non deficient rs1127354 genotype. Other variables associated with on-treatment hemoglobin <10 g/dL or a decrease >=3.5 g/dL were age, baseline hemoglobin, rs6051702 genotype, and plasma ribavirin concentration. In a multivariate analysis, high plasma ribavirin concentration, low baseline hemoglobin, HCV genotype 1b, and IL28B genotype CC were associated with higher SVR12. CONCLUSIONS: The ITPA rs1127354 CC and rs6051702 AA genotypes may predict ribavirin-induced anemia during treatment with interferon-free, ribavirin containing regimens. With this interferon-free regimen, SVR was associated with ribavirin levels, but not with anemia or ITPA genotypes. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01132313. PMID- 26650628 TI - Homozygous T172T and Heterozygous G135C Variants of Homologous Recombination Repairing Protein RAD51 are Related to Sporadic Breast Cancer Susceptibility. AB - Breast cancer (BC) is the most common cancer and the second leading cause of death among women worldwide. Only 10% of BC cases have been related to genetic predisposition. Rad51, a homologous recombination (HR) protein plays an important role in HR in meiosis and repairing DNA double-strand breaks. Expression of RAD51 may be a predictive biomarker in certain types of cancers. The exact mechanisms involved in the regulation of RAD51 expression are not fully understood, but certain transcription factors have been suggested to be the tuning mechanism of its expression. In this study, we propose that polymorphisms in the 5'-UTR promoter region of the RAD51 gene are prognostic factors for BC development. Direct sequencing of 106 samples from sporadic BC patients and 54 samples from a control group was performed. FFPE samples were the choice of sample collection, which might be a limitation of our study. Homologous variant T172T alone was found to be significantly associated with BC risk (OR 3.717, 95% CI 2.283-6.052, p < 0.0001). On the other hand, heterozygous G135C did not show any significant relationship with risk of sporadic BC (OR 1.598, 95% CI 0.5638-4.528, p > 0.05). Moreover, both variants; homozygous T172T and heterozygous G135C together; showed a significant relationship with sporadic BC susceptibility. PMID- 26650627 TI - Malignant pheochromocytomas/paragangliomas harbor mutations in transport and cell adhesion genes. AB - One out of ten patients with pheochromocytoma (PCC) and paraganglioma (PGL) develop malignant disease. Today there are no reliable pathological methods to predict malignancy at the time of diagnosis. Tumors harboring mutations in the succinate dehydrogenase subunit B (SDHB) gene often metastasize but the sequential genetic events resulting in malignant progression are not fully understood. The aim of this study was to identify somatic mutations that contribute to the malignant transformation of PCC/PGL. We performed pair-wise (tumor-normal) whole-exome sequencing to analyze the somatic mutational landscape in five malignant and four benign primary PCC/sympathetic PGL (sPGL), including two biological replicates from each specimen. In total, 225 unique somatic mutations were identified in 215 genes, with an average mutation rate of 0.54 mutations/megabase. Malignant tumors had a significantly higher number of mutations compared to benign tumors (p < 0.001). Three novel genes were identified as recurrently mutated; MYCN, MYO5B and VCL, and mutations in these genes were exclusively found in malignant sPGL tumors. Mutations in the MYO5B gene could be verified in two publicly available data sets. A gene ontology analysis of mutated genes showed enrichment of cellular functions related to cytoskeletal protein binding, myosin complex and motor activity, many of which had functions in Rab and Rac/Rho GTPase pathways. In conclusion, we have identified recurrent mutations in genes related to intracellular transport and cell adhesion, and we have confirmed MYO5B to be recurrently mutated in PCC/PGL cases with malignant potential. Our study suggests that deregulated Rab and Rac/Rho pathways may be important in PCC/PGL tumorigenesis. PMID- 26650629 TI - Correlating quantitative tractography at 3T MRI and cognitive tests in healthy older adults. AB - This study used diffusion tensor imaging tractography at 3 T MRI to relate cognitive function to white matter tracts in the brain. Brain T2 fluid attenuated inversion recovery-weighted and diffusion tensor 3 T MRI scans were acquired in thirty-three healthy participants without mild cognitive impairment or dementia. They completed a battery of neuropsychological tests including the Montreal Cognitive Assessment, Stroop test, Trail Making Test B, Wechsler Memory Scale-III Longest span forward, Wechsler Memory Scale-III Longest span backward, Mattis Dementia Rating Scale, California Verbal Learning Test Version II Long Delay Free Recall, and Letter Number Sequencing. Tractography was generated by the Fiber Assignment by Continuous Tracking method. The corpus callosum, cingulum, long association fibers, corticospinal/bulbar tracts, thalamic projection fibers, superior cerebellar peduncle, middle cerebellar peduncle and inferior cerebellar peduncle were manually segmented. The fractional anisotropy (FA) and mean diffusivity (MD) of these tracts were quantified. We studied the association between cognitive test scores and the MD and FA of tracts while controlling for age and total white matter hyperintensities volume. Worse scores on the Stroop test was associated with decreased FA of the corpus callosum, corticospinal/bulbar tract, and thalamic projection tracts. Scores on the other cognitive tests were not associated with either the FA or MD of measured tracts. In healthy persons the Stroop test appears to be a better predictor of the microstructural integrity of white matter tracts measured by DTI tractography than other cognitive tests. PMID- 26650631 TI - Drs. Christian Kieling, Renata Kieling, and Rohde Reply. PMID- 26650630 TI - Social Consequences of Ebola Containment Measures in Liberia. AB - INTRODUCTION: In the Ebola Virus Disease (EVD) outbreak in Liberia, two major emergency disease-control measures were cremation of bodies and enforcement of quarantine for asymptomatic individuals suspected of being in contact with a positive case. Enforced by State-related actors, these were promoted as the only method to curtail transmissions as soon as possible. However, as with other harsh measures witnessed by Liberian citizens, in many cases those measures elicited uncontrolled negative reactions within the communities (stigma; fear) that produced, in some cases, the opposite effect of that intended. METHODOLOGY: The research has been conducted in two phases, for a total of 8 weeks. Ethnography of local practices was carried out in 7 neighbourhoods in Monrovia and 5 villages in Grand Cape Mount County in Liberia. 45 Focus Group Discussions (432 participants) and 30 semi-structured interviews sustained the observing participation. Randomly selected people from different social layers were targeted. The principal investigator worked with the help of two local assistants. Perceptions and practices were both analysed. RESULTS: Participants stressed how cremation perpetuated the social breakdown that started with the isolation for the sickness. Socio-economical divides were created by inequitable management of the dead: those who could bribe the burial teams obtained a burial in a private cemetery or the use of Funeral Homes. Conversely, those in economic disadvantage were forced to send their dead for cremation. State-enforced quarantine, with a mandatory prohibition of movement, raised condemnation, strengthened stigmatization and created serious socio-economic distress. Food was distributed intermittently and some houses shared latrines with non-quarantined neighbours. Escapes were also recorded. Study participants narrated how they adopted local measures of containment, through local task forces and socially-rooted control of outsiders. They also stressed how information that was not spread built up rumours and suspicion. CONCLUSIONS: Populations experiencing an epidemic feel a high degree of social insecurity, in addition to the health hazards. Vertical and coercive measures increase mistrust and fear, producing a counter-productive effect in the containment of the epidemic. On the other hand, local communities show a will to be engaged and a high degree of flexibility in participating to the epidemic response. Efforts in the direction of awareness and community involvement could prove to be better strategy to control the epidemic and root the response on social participation. PMID- 26650632 TI - Dr. Keri Replies. PMID- 26650633 TI - Correction. PMID- 26650635 TI - The Anatomy of Evilby Stone Michael H. . New York , Prometheus Books , 2009 , 430 pp., $26.98 . PMID- 26650639 TI - APA Official Actions. PMID- 26650652 TI - Influence of Test Condition on Speech Perception With Electric-Acoustic Stimulation. AB - PURPOSE: The goal of this work was to better understand speech perception for cochlear implant (CI) users with bilateral residual hearing, including consideration of effects related to listening conditions and test measures. Of interest was the role of acoustic hearing for speech perception in a complex background, the role of listening experience for CI-alone conditions, and whether performance with electric-acoustic stimulation (EAS) was improved by a contralateral hearing aid (HA). METHOD: Eleven subjects provided data on Consonant-Nucleus-Consonant (CNC; Peterson & Lehiste, 1962) words in quiet, City University of New York (CUNY; Boothroyd, Hanin, & Hnath, 1985) sentences in steady noise, and Bamford-Kowal-Bench (Bench, Kowal, & Bamford, 1979) sentences in multitalker babble. Listening conditions included: CI with a full-frequency map, CI with a truncated-frequency map, EAS, and EAS+HA (EAS plus contralateral HA). Sounds were presented at 0 degrees azimuth. RESULTS: For CNC words and CUNY sentences, performance was better with the truncated-frequency than the full frequency map, and performance with EAS was better than for either CI-alone condition. For Bench-Kowal-Bamford sentences, EAS+HA was better than EAS. CONCLUSIONS: As demonstrated previously, performance was better in the EAS condition than either CI-alone condition. Better performance in the truncated frequency than full-frequency CI-alone condition suggests that listening experience may be important. A contralateral HA improved performance over unilateral EAS under some conditions. PMID- 26650656 TI - Smallpox, Anthrax, and the Historiography of Cutaneous Diseases. PMID- 26650657 TI - The History of Sunscreen. PMID- 26650653 TI - Self-Assembled Cationic Biodegradable Nanoparticles from pH-Responsive Amino-Acid Based Poly(Ester Urea Urethane)s and Their Application As a Drug Delivery Vehicle. AB - The objective of this study is to develop a new family of biodegradable and biologically active copolymers and their subsequent self-assembled cationic nanoparticles as better delivery vehicles for anticancer drugs to achieve the synergism between the cytotoxicity effects of the loaded drugs and the macrophage inflammatory response of the delivery vehicle. This family of cationic nanoparticles was formulated from a new family of amphiphilic cationic Arginine Leucine (Arg-Leu)-based poly(ester urea urethane) (Arg-Leu PEUU) synthesized from four building blocks (amino acids, diols, glycerol alpha-monoallyl ether, and 1,6 hexamethylene diisocyanate). The chemical, physical, and biological properties of Arg-Leu PEUU biomaterials can be tuned by controlling the feed ratio of the four building blocks. The Arg-Leu PEUU copolymers have weight-average molecular weights from 13.4 to 16.8 kDa and glass-transition temperatures from -3.4 to -4.6 degrees C. The self-assembled cationic nanoparticles (Arg-Leu PEUU NPs) were prepared using a facile dialysis method. Arg-Leu PEUU NPs have average diameters ranging from 187 to 272 nm, show good biocompatibility with 3T3 fibroblasts, and they support bovine aortic endothelial cell (BAEC) proliferation and adhesion. Arg-Leu PEUU NPs also enhanced the macrophages' production of tumor necrosis factor-alpha (TNF-alpha) and nitric oxide (NO), but produced relatively low levels of interleukin-10 (IL-10), and therefore, the antitumor activity of macrophages might be enhanced. Arg-Leu PEUU NPs were taken up by HeLa cells after 4 h of incubation. The in vitro hemolysis assay showed the cationic Arg-Leu PEUU NPs increased their chance of endosomal escape at a more acidic pH. Doxorubicin (DOX) was successfully incorporated into the Arg-Leu PEUU NPs, and the DOX-loaded Arg-Leu PEUU NPs exhibited a pH-dependent drug release profile with accelerated release kinetics in a mild acidic condition. The DOX-loaded 6-Arg-4-Leu-4 A/L-2/1 NPs showed higher HeLa cell toxicity than the free DOX at the same concentration after 24 h of treatment. The results suggest the cationic Arg-Leu PEUU NPs could potentially be a useful carrier family for hydrophobic anticancer drugs and produce a synergistic effect between DOX cytotoxicity and the production of TNF alpha and NO by macrophages. PMID- 26650658 TI - John Templeton Bowen. PMID- 26650659 TI - The Sweetest Specialty. PMID- 26650660 TI - The Magical Field of Dermatology: Real-Life Dermatology in Fairy Tales. PMID- 26650661 TI - Association Between Leukemia and Topical Use of Pimecrolimus. PMID- 26650662 TI - Association Between Leukemia and Topical Use of Pimecrolimus-Reply. PMID- 26650663 TI - Time-Dependent Measurement of Adverse Events. PMID- 26650664 TI - Time-Dependent Measurement of Adverse Events-Reply. PMID- 26650666 TI - Error in Text. PMID- 26650665 TI - Identification of a CAST Mutation in a Cohort Previously Misdiagnosed as Having Autosomal Recessive Pachyonychia Congenita. PMID- 26650667 TI - Raynaud Phenomenon. PMID- 26650668 TI - An Unpredictable Chronic Mild Stress Protocol for Instigating Depressive Symptoms, Behavioral Changes and Negative Health Outcomes in Rodents. AB - Chronic, unresolved stress is a major risk factor for the development of clinical depression. While many preclinical models of stress-induced depression have been reported, the unpredictable chronic mild stress (UCMS) protocol is an established translationally-relevant model for inducing behavioral symptoms commonly associated with clinical depression, such as anhedonia, altered grooming behavior, and learned helplessness in rodents. The UCMS protocol also induces physiological (e.g., hypercortisolemia, hypertension) and neurological (e.g., anhedonia, learned helplessness) changes that are clinically associated with depression. Importantly, UCMS-induced depressive symptoms can be ameliorated through chronic, but not acute, treatment with common SSRIs. As such, the UCMS protocol offers many advantages over acute stress protocols or protocols that utilize more extreme stressors. Our protocol involves randomized, daily exposures to 7 distinct stressors: damp bedding, removal of bedding, cage tilt, alteration of light/dark cycles, social stresses, shallow water bath, and predator sounds/smells. By subjecting rodents 3-4 hr daily to these mild stressors for 8 weeks, we demonstrate both significant behavioral changes and poor health outcomes to the cardiovascular system. This approach allows for in-depth interrogation of the neurological, behavioral, and physiological alterations associated with chronic stress-induced depression, as well as for testing of new potential therapeutic agents or intervention strategies. PMID- 26650669 TI - Spectroscopy and Dynamics of Cryptolepine in the Nanocavity of Cucurbit[7]uril and DNA. AB - Herein, we explored the photophysical properties of the antimalarial, anticancer drug cryptolepine (CRYP) in the presence of the macrocyclic host cucurbit[7]uril (CB7) and DNA with the help of steady-state and time-resolved fluorescence techniques. Ground-state and excited-state calculations based on density functional theory were also performed to obtain insight into the shape, electron density distribution, and energetics of the molecular orbitals of CRYP. CRYP exists in two forms depending on the pH of the medium, namely, a cationic (charge transfer) form and a neutral form, which emit at lambda=540 and 420 nm, respectively. In a buffer solution of pH 7, the drug exists in the cationic form, and upon encapsulation with CB7, it exhibits a huge enhancement in fluorescence intensity due to a decrement in nonradiative decay pathways of the emitting cryptolepine species. Furthermore, docking and quantum chemical calculations were employed to decipher the molecular orientation of the drug in the inclusion complex. Studies with natural DNA indicate that CRYP molecules intercalate into DNA, which leads to a huge quenching of the fluorescence of CRYP. Keeping this in mind, we studied the DNA-assisted release of CRYP molecules from the nanocavity of CB7. Strikingly, DNA alone could not remove the drug from the nanocavity of CB7. However, an external stimulus such as acetylcholine chloride was able to displace CRYP from the nanocavity, and subsequently, the displaced drug could bind to DNA. PMID- 26650670 TI - Satisfaction with transport and enjoyment of the commute by commuting mode in inner Sydney. AB - Issue addressed Travel satisfaction has become an increasingly popular construct for the assessment and monitoring of transport systems and services. However, satisfaction may not adequately assess emotion or mood towards walking and cycling, especially when infrastructure is biased towards motor vehicle modes. In this exploratory study we sought to examine the associations of both satisfaction with transport and enjoyment from the commute to work or study by commute mode in an Australian inner city context where transport mode choices are readily available. Methods As part of the Sydney Transport and Health Study, 675 baseline study participants (2013) were invited to complete an online questionnaire in September/October 2014 and 512 did so (76% response rate). Participants who did not travel to work were removed from analyses, giving complete data for 473. Participants provided data on usual travel mode to work or study, satisfaction with transport, enjoyment from their commute, and demographics and neighbourhood factors. Results The main mode of travel to work or study in this inner city sample was public transport (41%), followed by motor vehicle (27%), walking (21%) and cycling (10%). Most participants were satisfied with their transport (82%), with little variation by mode. Walkers (49%) and cyclists (52%) reported far higher levels of enjoyment from their commute than car drivers (14%) or public transport users (10%), with an adjusted odds ratio of 6.18 (95% confidence interval 3.10-12.29, P<0.001) for walking and an adjusted odds ratio of 6.15 (95% confidence interval 2.68-14.08, P<0.001) for cycling. Conclusions People who walked or cycled to work or study in inner Sydney reported higher levels of enjoyment from their commute compared with those who drove. This suggests enjoyment may be another benefit of active travel. So what? Focusing on 'enjoyment' associated with walking or cycling to work may be a positive motivator to encourage active travel. PMID- 26650671 TI - Assessing Cortical Cerebral Microinfarcts on High Resolution MR Images. AB - Cerebral microinfarcts are frequent findings in the post-mortem human brain, and are related to cognitive decline and dementia. Due to their small sizes it is challenging to study them on clinical MRI scans. It was recently demonstrated that cortical microinfarcts can be depicted with MRI scanners using high magnetic field strengths (7T). Based on this experience, a proportion of these lesions is also visible on lower resolution 3T MRI. These findings were corroborated with ex vivo imaging of post-mortem human brain tissue, accompanied by histopathological verification of possible cortical microinfarcts. Here an ex vivo imaging protocol is presented, for the purpose of validating MR observed cerebral microvascular pathology with histological evaluation. Furthermore, guidelines are provided for the assessment of cortical microinfarcts on both in vivo 7T and 3T MR images. These guidelines provide researchers with a tool to rate cortical microinfarcts on in vivo images of larger patient samples, to further unravel their clinical relevance in cognitive decline and dementia, and establish these lesions as a novel biomarker of cerebral small vessel disease. PMID- 26650672 TI - Niche Partitioning of Feather Mites within a Seabird Host, Calonectris borealis. AB - According to classic niche theory, species can coexist in heterogeneous environments by reducing interspecific competition via niche partitioning, e.g. trophic or spatial partitioning. However, support for the role of competition on niche partitioning remains controversial. Here, we tested for spatial and trophic partitioning in feather mites, a diverse and abundant group of arthropods. We focused on the two dominant mite species, Microspalax brevipes and Zachvatkinia ovata, inhabiting flight feathers of the Cory's shearwater, Calonectris borealis. We performed mite counts across and within primary and tail feathers on free living shearwaters breeding on an oceanic island (Gran Canaria, Canary Islands). We then investigated trophic relationships between the two mite species and the host using stable isotope analyses of carbon and nitrogen on mite tissues and potential host food sources. The distribution of the two mite species showed clear spatial segregation among feathers; M. brevipes showed high preference for the central wing primary feathers, whereas Z. ovata was restricted to the two outermost primaries. Morphological differences between M. brevipes and Z. ovata support an adaptive basis for the spatial segregation of the two mite species. However, the two mites overlap in some central primaries and statistical modeling showed that Z. ovata tends to outcompete M. brevipes. Isotopic analyses indicated similar isotopic values for the two mite species and a strong correlation in carbon signatures between mites inhabiting the same individual host suggesting that diet is mainly based on shared host-associated resources. Among the four candidate tissues examined (blood, feather remains, skin remains and preen gland oil), we conclude that the diet is most likely dominated by preen gland oil, while the contribution of exogenous material to mite diets is less marked. Our results indicate that ongoing competition for space and resources plays a central role in structuring feather mite communities. They also illustrate that symbiotic infracommunities are excellent model systems to study trophic ecology, and can improve our understanding of mechanisms of niche differentiation and species coexistence. PMID- 26650673 TI - Understanding the Leaky Pipeline: Perceived Barriers to Pursuing a Career in Medicine or Dentistry Among Underrepresented-in-Medicine Undergraduate Students. AB - PURPOSE: Representation of persons from diverse backgrounds remains a persistent challenge for medicine and dentistry workforces. Past research has focused on quantifying factors such as markers of educational achievement to explain the difficulty of increasing diversity within the professions. There has been less effort toward understanding the perspectives of undergraduate students on the threshold of applying to medical/dental school about distinct barriers to pursuing a medical or dental career and continuing through the training pipeline. METHOD: In 2012 and 2013, the authors conducted a qualitative study of undergraduate students participating in the Tour for Diversity in Medicine, a program where minority physicians and dentists visit colleges with large fractions of minority students to encourage careers in the health professions. Focus groups were convened during the visits to examine perceived barriers to pursuing careers in medicine and dentistry and challenges identified through thematic content analysis. RESULTS: Eighty-two students participated in discussions at 11 colleges visited between September 2012 and February 2013. Students described challenges including inadequate institutional resources (e.g., sparse clinical opportunities), strained personal resources (e.g., conflict arising from familial pressure), inadequate guidance and mentoring to assist with key career decisions, and societal barriers. For participants, these challenges caused them to question the viability of persisting in the pipeline to a medical or dental career. CONCLUSIONS: Solving the issue of diversity in medicine and dentistry is multifaceted, but elucidated challenges from the undergraduate student perspective offer targeted areas where intervention may help remedy barriers and decrease pipeline leakiness. PMID- 26650674 TI - Toward Independence: Resubmission Rate of Unfunded National Heart, Lung, and Blood Institute R01 Research Grant Applications Among Early Stage Investigators. AB - PURPOSE: The current, budget-driven low rate of National Institutes of Health (NIH) funding for biomedical research has raised concerns about new investigators' ability to become independent scientists and their willingness to persist in efforts to secure funding. The authors sought to determine resubmission rates for unfunded National Heart, Lung, and Blood Institute (NHLBI) early stage investigator (ESI) independent research grant (R01) applications and to identify resubmission predictors. METHOD: The authors used a retrospective cohort study design and retrieved applications submitted in fiscal years 2010 2012 from NIH electronic research administrative sources. They defined ESI applicants as those who have received no prior R01 (or equivalent) funding and are within 10 years of completion of their terminal research degree or medical residency training. ESI applications at the NHLBI were eligible for special funding consideration if they scored above, but within 10 points of, the payline. The primary outcome was application resubmission after failing to secure funding with the first R01 submission. RESULTS: Over half of the unfunded applications were resubmitted. Some of these were discussed and "percentiled." Among percentiled applications, the only significant predictor of resubmission was the percentile score. Over half (59%) of the ESI R01 grants funded by NHLBI in fiscal years 2010-2012 had percentile scores above but within 10 points of the NHLBI payline, and benefited from the special funding considerations. CONCLUSIONS: The only independent predictor of resubmission of NHLBI ESI R01 grant applications was percentile score; applicant demographics and institutional factors were not predictive of resubmission. PMID- 26650675 TI - Teaching Medicine Through the Study of Literature: Implementing a Fourth-Year Distance Learning Elective. AB - PROBLEM: The amount of time medical students must devote to the residency application process has increased, often at the expense of students' education. The fourth year is still a crucial component of medical education, especially for preparing students for the transition to residency. APPROACH: To maintain flexibility during the residency interview season and provide students with the opportunity to hone critical skills, faculty at the Florida State University College of Medicine developed a literature and medicine distance learning elective for fourth-year students. The four-week course was offered five times per academic year from 2012 to 2014. Participating students and faculty chose a topic and reading list, which guided both students' written reflections and the weekly discussions held via video conference. Nineteen students participated, and 13 completed a postcourse survey to gauge their overall impressions of the elective and its effects on their learning. OUTCOMES: Participants valued the course for six principal reasons: It (1) provided the opportunity to consider others' perspectives, (2) improved their ability to think as a physician and examine personal biases, (3) provided the opportunity to discuss nonmedical literature, (4) provided the opportunity to use different cognitive skills, (5) afforded flexibility, and (6) improved their ability to communicate about difficult topics. NEXT STEPS: The long-term value of a distance learning elective in the humanities remains uncertain. The authors have begun to study students' perceptions of the elective's value after entering residency. However, they believe that the initial positive feedback justifies the course's replication at other institutions. PMID- 26650676 TI - A Matrix Mentoring Model That Effectively Supports Clinical and Translational Scientists and Increases Inclusion in Biomedical Research: Lessons From the University of Utah. AB - Physician-scientists and scientists in all the health professions are vital members of the U.S. biomedical workforce, but their numbers at academic health centers are declining. Mentorship has been identified as a key component in retention of faculty members at academic health centers. Effective mentoring may promote the retention of clinician-scientists in the biomedical workforce. The authors describe a holistic institutional mentoring program to support junior faculty members engaged in clinical and translational science at the University of Utah. The clinical and translational scholars (CATS) program leverages the resources of the institution, including the Center for Clinical and Translational Science, to augment departmental resources to support junior faculty investigators and uses a multilevel mentoring matrix that includes self, senior, scientific, peer, and staff mentorship. Begun in the Department of Pediatrics, the program was expanded in 2013 to include all departments in the school of medicine and the health sciences. During the two-year program, scholars learn management essentials and have leadership training designed to develop principal investigators. Of the 86 program participants since fiscal year 2008, 92% have received extramural awards, 99% remain in academic medicine, and 95% remain at the University of Utah. The CATS program has also been associated with increased inclusion of women and underrepresented minorities in the institutional research enterprise. The CATS program manifests institutional collaboration and coordination of resources, which have benefited faculty members and the institution. The model can be applied to other academic health centers to support and sustain the biomedical workforce. PMID- 26650677 TI - Clinical Reasoning Tasks and Resident Physicians: What Do They Reason About? AB - PURPOSE: A framework of clinical reasoning tasks thought to occur in a clinical encounter was recently developed. It proposes that diagnostic and therapeutic reasoning comprise 24 tasks. The authors of this current study used this framework to investigate what internal medicine residents reason about when they approach straightforward clinical cases. METHOD: Participants viewed three video recorded clinical encounters portraying common diagnoses. After each video, participants completed a post encounter form and think-aloud protocol. Two authors analyzed transcripts from the think-aloud protocols using a constant comparative approach. They conducted iterative coding of the utterances, classifying each according to the framework of clinical reasoning tasks. They evaluated the type, number, and sequence of tasks the residents used. RESULTS: Ten residents participated in the study in 2013-2014. Across all three cases, the residents employed 14 clinical reasoning tasks. Nearly all coded tasks were associated with framing the encounter or diagnosis. The order in which residents used specific tasks varied. The average number of tasks used per case was as follows: Case 1, 4.4 (range 1-10); Case 2, 4.6 (range 1-6); and Case 3, 4.7 (range 1-7). The residents used some tasks repeatedly; the average number of task utterances was 11.6, 13.2, and 14.7 for, respectively, Case 1, 2, and 3. CONCLUSIONS: Results suggest that the use of clinical reasoning tasks occurs in a varied, not sequential, process. The authors provide suggestions for strengthening the framework to more fully encompass the spectrum of reasoning tasks that occur in residents' clinical encounters. PMID- 26650678 TI - Correction: The Seroprevalence of Hepatitis C Antibodies in Immigrants and Refugees from Intermediate and High Endemic Countries: A Systematic Review and Meta-Analysis. AB - [This corrects the article DOI: 10.1371/journal.pone.0141715.]. PMID- 26650679 TI - Aging Stem Cells Lose the Capability to Distribute Damaged Proteins Asymmetrically. AB - Understanding the interplay between reversible epigenetic changes and potentially more difficult to reverse accumulation of damaged macromolecules is a central challenge in developing treatments for aging-associated dysfunction. One hypothesis is that epigenetic drift leads to subtle losses of homeostatic maintenance mechanisms, that in turn, lead to the accumulation of damaged macromolecules, which then further degrade homeostasis. A key mechanism of maintaining optimal cell function is asymmetrical division, whereby cellular damage is segregated away from cells that need to undergo further proliferation, such as stem cells. Such asymmetrical distribution of damaged macromolecules has been observed during cell division in many organisms, from yeast to human embryonic stem cells, and depends on diffusion barriers (DBs) in the membrane of the endoplasmic reticulum (ER). In a recent study, these results have been extended to neural stem cells (NSCs), in which the ability of the ER DB to promote asymmetrical distribution of damaged proteins deteriorates with age. NSC function declines with age as proliferative capacity is reduced. The loss of asymmetric protein distribution correlates with the loss of NSC proliferative capacity. Ectopic expression of progerin, an altered form of lamin A, is associated with the premature aging disorder, Hutchinson-Gilford progeria syndrome (HGPS). Progerin's expression also increases with normal aging due to mis-splicing, weakening the ER DB. Recent work suggests that many cell signaling pathway changes associated with HGPS are replicated during normal aging in cultured cells. Moreover, the detrimental changes associated with progerin expression in HGPS are partially reversible experimentally after treatment with statins, a farnesyltransferase inhibitor, a isoprenylcysteine carboxyl methyltransferase inhibitor, or sulforaphane. It will be of great interest if these compounds can also reverse the aging-associated permeability of the ER DB and restore stem cell function. PMID- 26650680 TI - A Mouse Model of Subchronic and Mild Social Defeat Stress for Understanding Stress-induced Behavioral and Physiological Deficits. AB - Stressful life events often increase the incidence of depression in humans. To study the mechanisms of depression, the development of animal models of depression is essential. Because there are several types of depression, various animal models are needed for a deeper understanding of the disorder. Previously, a mouse model of subchronic and mild social defeat stress (sCSDS) using a modified chronic social defeat stress (CSDS) paradigm was established. In the paradigm, to reduce physical injuries from aggressors, the duration of physical contact between the aggressor and a subordinate was reduced compared to in the original CSDS paradigm. sCSDS mice showed increased body weight gain, food intake, and water intake during the stress period, and their social behaviors were suppressed after the stress period. In terms of the face validity of the stress-induced overeating and overdrinking following the increased body weight gain, the sCSDS mice may show some features related to atypical depression in humans. Thus, a mouse model of sCSDS may be useful for studying the pathogenic mechanisms underlying depression. This protocol will help establish the sCSDS mouse model, especially for studying the mechanisms underlying stress-induced weight gain and polydipsia- and hyperphagia-like symptoms. PMID- 26650683 TI - Nonlinear Dynamics Measures for Automated EEG-Based Sleep Stage Detection. AB - BACKGROUND: The brain's continuous neural activity during sleep can be monitored by electroencephalogram (EEG) signals. The EEG wave pattern and frequency vary during five stages of sleep. These subtle variations in sleep EEG signals cannot be easily detected through visual inspection. SUMMARY: A range of time, frequency, time-frequency and nonlinear analysis methods can be applied to understand the complex physiological signals and their chaotic behavior. This paper presents a comprehensive comparative review and analysis of 29 nonlinear dynamics measures for EEG-based sleep stage detection. KEY MESSAGES: The characteristic ranges of these features are reported for the five different sleep stages. All nonlinear measures produce clinically significant results, that is, they can discriminate the individual sleep stages. Feature ranking based on the statistical F-value, however, shows that the third order cumulant of higher order spectra yields the most discriminative result. The distinct value ranges for each sleep stage and the discriminative power of the features can be used for sleep disorder diagnosis, treatment monitoring, and drug efficacy assessment. PMID- 26650682 TI - Lung and Heart Diseases Are Better Predicted by Pack-Years than by Smoking Status or Duration of Smoking Cessation in HIV Patients. AB - BACKGROUND: The objective of this study was to assess the relationship of pack years smoking and time since smoking cessation with risk of lung and heart disease. METHODS: We investigated the history of lung and heart disease in 903 HIV-infected patients who had undergone thoracic computed tomography (CT) imaging stratified by smoking history. Multimorbidity lung and heart disease (MLHD) was defined as the presence of >= 2 clinical or subclinical lung abnormalities and at least one heart abnormality. RESULTS: Among 903 patients, 23.7% had never smoked, 28.7% were former smokers and 47.6% were current smokers. Spirometry indicated chronic obstructive pulmonary disease in 11.4% of patients and MLHD was present in 53.6%. Age, male sex, greater pack-years smoking history and smoking cessation less than 5 years earlier vs. more than 10 years earlier (OR 2.59, 95% CI 1.27 5.29, p = 0.009) were independently associated with CT detected subclinical lung and heart disease. Pack-years smoking history was more strongly associated with MLHD than smoking status (p<0.001). CONCLUSIONS: MLHD is common even among HIV infected patients who never smoked and pack- years smoking history is a stronger predictor than current smoking status of MLHD. A detailed pack-years smoking history should be routinely obtained and smoking cessation strategies implemented. PMID- 26650681 TI - GLUT, SGLT, and SWEET: Structural and mechanistic investigations of the glucose transporters. AB - Glucose is the primary fuel to life on earth. Cellular uptake of glucose is a fundamental process for metabolism, growth, and homeostasis. Three families of secondary glucose transporters have been identified in human, including the major facilitator superfamily glucose facilitators GLUTs, the sodium-driven glucose symporters SGLTs, and the recently identified SWEETs. Structures of representative members or their prokaryotic homologs of all three families were obtained. This review focuses on the recent advances in the structural elucidation of the glucose transporters and the mechanistic insights derived from these structures, including the molecular basis for substrate recognition, alternating access, and stoichiometric coupling of co-transport. PMID- 26650684 TI - The Impact of Cardiac Diseases during Pregnancy on Severe Maternal Morbidity and Mortality in Brazil. AB - BACKGROUND: To evaluate maternal heart disease as a cause or complicating factor for severe morbidity in the setting of the Brazilian Network for Surveillance of Severe Maternal Morbidity. METHODS AND FINDINGS: Secondary data analysis of this multicenter cross-sectional study was implemented in 27 referral obstetric units in Brazil. From July 2009 to June 2010, a prospective surveillance was conducted among all delivery hospitalizations to identify cases of severe maternal morbidity (SMM), including Potentially Life-Threatening Conditions (PLTC) and Maternal Near Miss (MNM), using the new criteria established by the WHO. The variables studied included: sociodemographic characteristics, clinical and obstetric history of the women; perinatal outcome and the occurrence of maternal outcomes (PLTC, MNM, MD) between groups of cardiac and non-cardiac patients. Only heart conditions with hemodynamic impact characterizing severity of maternal morbidity were considered. 9555 women were included in the Network with severe pregnancy-related complications: 770 maternal near miss cases and 140 maternal death cases. A total of 293 (3.6%) cases were related to heart disease and the condition was known before pregnancy in 82.6% of cases. Maternal near miss occurred in 15% of cardiac disease patients (most due to clinical-surgical causes, p<0.001) and 7.7% of non-cardiac patients (hemorrhagic and hypertensive causes, p<0.001). Maternal death occurred in 4.8% of cardiac patients and in 1.2% of non-cardiac patients, respectively. CONCLUSIONS: In this study, heart disease was significantly associated with a higher occurrence of severe maternal outcomes, including maternal death and maternal near miss, among women presenting with any severe maternal morbidity. PMID- 26650685 TI - Modelling the tumour microenvironment in long-term microencapsulated 3D co cultures recapitulates phenotypic features of disease progression. AB - 3D cell tumour models are generated mainly in non-scalable culture systems, using bioactive scaffolds. Many of these models fail to reflect the complex tumour microenvironment and do not allow long-term monitoring of tumour progression. To overcome these limitations, we have combined alginate microencapsulation with agitation-based culture systems, to recapitulate and monitor key aspects of the tumour microenvironment and disease progression. Aggregates of MCF-7 breast cancer cells were microencapsulated in alginate, either alone or in combination with human fibroblasts, then cultured for 15 days. In co-cultures, the fibroblasts arranged themselves around the tumour aggregates creating distinct epithelial and stromal compartments. The presence of fibroblasts resulted in secretion of pro-inflammatory cytokines and deposition of collagen in the stromal compartment. Tumour cells established cell-cell contacts and polarised around small lumina in the interior of the aggregates. Over the culture period, there was a reduction in oestrogen receptor and membranous E-cadherin alongside loss of cell polarity, increased collective cell migration and enhanced angiogenic potential in co-cultures. These phenotypic alterations, typical of advanced stages of cancer, were not observed in the mono-cultures of MCF-7 cells. The proposed model system constitutes a new tool to study tumour-stroma crosstalk, disease progression and drug resistance mechanisms. PMID- 26650686 TI - An in-silico approach aimed to clarify the role of Y181C and K103N HIV-1 reverse transcriptase mutations versus Indole Aryl Sulphones. AB - The emergence of HIV-1 drugs resistant stains remains of pivotal interest in relation to drugs development. Non nucleoside reverse transcriptase inhibitors proven to be very effective versus HIV-1 wild type but, with the only exception of diarylpyrimidines (e.g., etravirine, 1), were featured by high-level resistance versus mutated RT. The effects of two of the most clinically relevant RT mutations (Y181C; K103N) were studied by a computational approach. This involved molecular dynamics, principal components analysis (PCA) and residue interactions networks (RINs). The methodology was applied to 1 and to Indolyl Aryl Sulphones (IASs 2 and 3), a class of potent RT inhibitors active also versus mutated RT forms. The molecular insight from this study was in accordance with the proposed mechanism of resistance for studied mutations and it might be useful in the design of novel RT inhibitors with high ligand efficacy on resistant strains. PMID- 26650687 TI - Morphological and functional alterations in patients with schizophrenia spectrum disorders. PMID- 26650688 TI - Variation at NRG1 genotype related to modulation of small-world properties of the functional cortical network. AB - Functional brain networks possess significant small-world (SW) properties. Genetic variation relevant to both inhibitory and excitatory transmission may contribute to modulate these properties. In healthy controls, genotypic variation in Neuregulin 1 (NRG1) related to the risk of psychosis (risk alleles) would contribute to functional SW modulation of the cortical network. Electroencephalographic activity during an odd-ball task was recorded in 144 healthy controls. Then, small-worldness (SWn) was calculated in five frequency bands (i.e., theta, alpha, beta1, beta2 and gamma) for baseline (from -300 to the stimulus onset) and response (150-450 ms post-target stimulus) windows. The SWn modulation was defined as the difference in SWn between both windows. Association between SWn modulation and carrying the risk allele for three single nucleotide polymorphisms (SNP) of NRG1 (i.e., rs6468119, rs6994992 and rs7005606) was assessed. A significant association between three SNPs of NRG1 and the SWn modulation was found, specifically: NRG1 rs6468119 in alpha and beta1 bands; NRG1 rs6994992 in theta band; and NRG1 rs7005606 in theta and beta1 bands. Genetic variation at NRG1 may influence functional brain connectivity through the modulation of SWn properties of the cortical network. PMID- 26650689 TI - Effect of Different Obesity Phenotypes on Incidence of Chronic Kidney Disease in Tehranian Adults. AB - BACKGROUND: The aim of this community-based study is to ascertain the effect of different obesity phenotypes on the incidence of chronic kidney disease in Iranian adults. STUDY DESIGN: A prospective cohort study, the Tehran Lipid Glucose Study (TLGS). SETTING AND PARTICIPANTS: Adults aged >= 20 years with a mean age of 40.38 years (54.8% female) who were free from chronic kidney disease (CKD) at baseline (phase 1) and were followed up at 3 time stages (phases 2, 3, and 4) for a mean duration of 9.4 years to assess the risk for CKD. PREDICTOR: Obesity phenotypes. OUTCOME: Incidence of chronic kidney disease. MEASUREMENTS: Glomerular filtration rate (GFR) was estimated from the simplified equation developed using data from the Modification of Diet in Renal Disease (MDRD) Study. RESULTS: CKD events occurred in 1162 participants. The prevalence of the 2 known obesity phenotypes (metabolically obese normal weight [MONW] and metabolically healthy but obese [MHO]) in the overall population was 3.5% and 8.8%, respectively. According to Kaplan-Meier curves, rates of freedom from CKD in the MHO and MONW obesity phenotypes were 75.3% and 60.6%, respectively (p < 0.0001). Age- and sex-adjusted (model 1) hazard ratios for participants with MHO or MONW obesity phenotype were 1.14 (95% confidence interval [CI], 0.91-1.43) and 1.43 (95% CI, 1.09-1.88), respectively. After further adjustment for confounder variables (model 2), multivariate-adjusted hazard ratios for CKD for participants with MHO or MONW obesity phenotypes were 1.23 (95% CI, 0.93-1.62) and 1.43 (95% CI, 1.08-1.90), respectively. CONCLUSION: Adults with the MONW obesity phenotype compared to those with MHO obesity phenotype have a higher risk for incidence of CKD. The results indicate that having a normal weight is not the only factor to protect against incidence of CKD. PMID- 26650690 TI - Analysis of human papillomavirus 16 variants and risk for cervical cancer in Chinese population. AB - HPV16 is the most carcinogenic HPV type, but only a minority of HPV16 infections progress to cancer. Intratype genetic variants of HPV16 have been suggested to confer differential carcinogenicity. To investigate risk implications of HPV16 variants among Chinese women, a case-control study was conducted with 298 cervical cancer patients and 85 controls (all HPV16-positive). HPV16 isolates were predominantly of the A variant lineage, and variants of A4 (previously named "Asian") sublineage were common. A4/Asian variants were significantly associated with increased risk of cervical cancer compared to A1-3 (OR=1.72, 95% CI=1.04 2.85). Furthermore, a meta-analysis including 703 cases and 323 controls from East Asia confirmed the association (OR=2.82, 95% CI=1.44-5.52). In conclusion, A4 variants appear to predict higher risk of cervical cancer among HPV16-positive women, which may provide clues to the genetic basis of differences in the carcinogenicity of HPV16 variants. PMID- 26650692 TI - Innate immune system activation by viral RNA: How to predict it? AB - The immune system is able to identify foreign pathogens via different pathways. In the case of viral infection, recognition of the viral RNA is a crucial step, and many efforts have been made to understand which features of viral RNA are detected by the immune system. The biased viral RNA composition, measured as host virus nucleotidic divergence, or CpG enrichment, has been proposed as salient signal. Peculiar structural features of these RNA could also be related to the immune system activation. Here, we gather multiple datasets and proceed to a meta analysis to uncover the best predictors of immune system activation by viral RNA. "A" nucleotide content and Minimum Folding Energy are good predictors, and are more easily generalized than more complex indicators suggested previously. As RNA composition and structure are highly correlated, we suggest further experiments on synthetic sequences to identify the viral RNA sensing mechanisms by immune system receptors. PMID- 26650691 TI - Pseudotyping of lentiviral vector with novel vesiculovirus envelope glycoproteins derived from Chandipura and Piry viruses. AB - While the envelope glycoprotein of vesicular stomatitis virus (VSV-G) is widely used for pseudotyping of lentiviral vectors, sub-optimal gene transfer into certain cell types and its sensitivity to inactivation by human complement hinders its broader applications. To find alternative candidates, here we evaluated two serologically distinct novel viral envelopes derived from Chandipura (CNV-G) and Piry (PRV-G) vesiculoviruses. Both permitted generation of high titer psuedotyped lentiviral vectors with a capacity for high efficiency gene transfer into various cell types from different species. In human lymphoid and hematopoietic stem cells, their transduction efficiency was significantly lower than that of VSV-G. However, both novel envelopes were found to be more resistant to inactivation by human serum complement compared to VSV-G. Thus CNV-G and PRV-G envelopes can be harnessed for multiple uses in the future based on the cell type that needs to be gene transduced and possibly for in vivo gene transfer. PMID- 26650693 TI - White lesions in the oral cavity: clinical presentation, diagnosis, and treatment. AB - White lesions in the oral cavity are common and have multiple etiologies, some of which are also associated with dermatological disease. While most intraoral white lesions are benign, some are premalignant and/or malignant at the time of clinical presentation, making it extremely important to accurately identify and appropriately manage these lesions. Due to their similar clinical appearances, it may be difficult sometimes to differentiate benign white lesions from their premalignant/malignant counterparts. This review will discuss many of the most common intraoral white lesions including their clinical presentation, how to make an accurate diagnosis, and effective treatment and management strategies. PMID- 26650694 TI - Differential diagnosis and management of oral ulcers. AB - The diagnosis and treatment of oral lesions is often challenging due to the clinician's limited exposure to the conditions that may cause the lesions and their similar appearances. While many oral ulcers are the result of chronic trauma, some may indicate an underlying systemic condition such as a gastrointestinal dysfunction, malignancy, immunologic abnormality, or cutaneous disease. Correctly establishing a definitive diagnosis is of major importance to clinicians who manage patients with oral mucosal disease. Some of these diseases are infectious; however, most are chronic, symptomatic, and desquamative. Treatment and management requires an understanding of the immunopathologic nature of the lesion. This review will address how to differentiate and diagnose varying types of oral ulcers and provide a treatment strategy. PMID- 26650695 TI - HPV and oropharyngeal cancer: etiology and prognostic importance. AB - HPV is the most common sexually transmitted disease, but the overwhelming majority of individuals clear the infection. A small percentage of individuals develop persistence of oncogenic HPV types, especially HPV-16; and as a result, squamous cell carcinoma can develop in the tonsils and base of the tongue. Over 70% of oropharyngeal cancers are now thought to be associated with oncogenic HPV infection. Immunohistochemistry for p16 protein is often used as a surrogate marker for oncogenic HPV in the oropharyngeal tissues, although alternative HPV DNA testing methods are under intensive study. The clinical profile of patients with HPV-associated oropharyngeal cancer (OPC) differs quite notably from that of traditional head and neck cancer patients, and the prognosis for HPV-associated OPC is significantly better. As a result, experimental clinical trials are focused on de-intensification of therapies with the hope of preserving an improved long-term quality of life for these patients. PMID- 26650696 TI - Genital lichen planus: update on diagnosis and treatment. AB - Lichen planus (LP) is an inflammatory autoimmune disease that affects both glabrous and mucosal skin. Although pathophysiology has not yet been fully defined, LP is a T-cell mediated disorder that demonstrates an increased Th1 cytokine expression as well as T-cell reactivity against basement membrane zone components. In males, genital LP often takes its more classic form as pink, shiny, flat-topped papules on the glans and coronal sulcus. In women, erosive disease is most common and often leads to significant scarring and sexual dysfunction. Therapeutic management is challenging, and control rather than cure is the goal. Topical corticosteroids remain first-line therapy, but some women will require systemic immunosuppressants to achieve remission. Surgery is less common for women with significant scarring who wish to resume sexual activity. Further research is needed on pathogenesis, and randomized controlled trials are necessary to better define best treatments for this chronic disease. PMID- 26650697 TI - Noninfectious genital ulcers. AB - Noninfectious genital ulcers are much more common than ulcers arising from infections. Still, it is important to take a thorough history of sexual activity and a sexual abuse screen. A physical exam should include skin, oral mucosa, nails, hair, vulva, and vaginal mucosa if needed. The differential diagnosis of noninfectious genital ulcers includes: lipschutz ulcers, complex aphthosis, Behcet's syndrome, vulvar metastatic Crohn's disease, hidradenitis suppurativa, pyoderma gangrenosum, pressure ulcers, and malignancies. It is important to come to the correct diagnosis to avoid undue testing, stress, and anxiety in patients experiencing genital ulcerations. PMID- 26650698 TI - Vulvodynia. AB - Vulvodynia is a pain syndrome affecting the vulva. It occurs in about 16% of women at some time of their lives. The etiology of vulvodynia is still enigmatic and is probably multifactorial-including physiological concerns (eg, pelvic floor muscle dysfunction, neuropathic pain, and psychosocial) and sexual issues (eg, anxiety and sexual dysfunction). Although it is a common syndrome, most patients are neither correctly diagnosed nor treated. A diagnosis of vulvodynia is based upon patient history and lack of physical findings upon careful examination. No clinical or histological findings are present to aid in diagnosis. Most treatment options for vulvodynia are neither well studied nor have an evidence base, relying instead upon expert opinion, care provider experience, and use of data from other pain syndromes. However, many patients show marked improvement after physical therapy for the pelvic floor, medications for neuropathic pain, and psychosexual therapy. PMID- 26650699 TI - Epithelial vulvar neoplasms and their changing classification. AB - In recent years, there have been many changes in the classification scheme for squamous lesions of the vulva; this is primarily due to the assimilation of new scientific information into the diagnostic terminology. For example, over the past 75 years we have realized that precancerous and cancerous lesions of the vulva may be induced by a variety of preconditions, which are typically divided into human papillomavirus (HPV) and non-HPV precursor lesions. The latter include several dermatoses, especially lichen sclerosus and lichen planus. Additionally, we have learned that HPV on extramucosal and nongenital sites does not have the same malignant potential as on mucosal or genital sites. Because of the frequent changes in nomenclature due to these discoveries, both old and new terms continue to be used in clinical practice; a summary of these terms is provided to help prevent a misunderstanding of their scope and significance. Important points for clinicians and pathologists who are involved in the care of these patients are provided. PMID- 26650700 TI - Unlike History, Should a Simulator Not Repeat Itself? PMID- 26650701 TI - An Internal Medicine Simulated Practical Examination for Assessment of Clinical Competency in Third-Year Medical Students. AB - INTRODUCTION: Achieving standardized assessment of medical student competency in patient care is a challenge. Simulation may provide unique contributions to overall assessment. We developed an Internal Medicine Standardized Simulation Based Examination (SSBE) for the third-year clerkship to assess students' medical knowledge, diagnostic skills, and clinical management skills. We assessed convergent and test criterion validity by comparing the relationship of SSBE scores with United States Medical Licensing Examination step 2 clinical knowledge, shelf examination, eQuiz, objective structured clinical examination, ward evaluation scores, and overall clerkship grades. We hypothesize that the use of the SSBE will allow for a more reliable assessment of these competencies and add value to existing assessments. METHODS: A prospective study design was used. The SSBE consisted of a computer-based photo quiz and cases on high-fidelity simulators. Performance on the SSBE was compared with standardized examinations, clinical evaluations, and overall clerkship grades. Students completed an evaluation of the experience. RESULTS: Two hundred seven students completed the SSBE, with a mean (SD) score of 76.69 (7.78). The SSBE performance was positively related to other assessments of medical knowledge eQuiz scores (r203 = 0.33, P < 0.01), shelf examination scores (r158 = 0.53, P < 0.01), and clinical performance (ward scores) (r163 = 0.31, P < 0.01) but not to objective structured clinical examination scores. There was a positive relationship to final class grades (r163 = 0.45, P < 0.01), shelf examination (r158 = 0.52, P < 0.01) and step 2 clinical knowledge scores (r76 = 0.54, P < 0.01). Most students (93%) agreed that it was a fair examination. CONCLUSIONS: Our results provide validity evidence for the SSBE as an additional assessment tool that uses a novel approach for evaluating competency in patient care at the clerkship level. PMID- 26650702 TI - Remotely Versus Locally Facilitated Simulation-based Training in Management of the Deteriorating Patient by Newly Graduated Health Professionals: A Controlled Trial. AB - INTRODUCTION: This study evaluated delivery of immersive simulation-based training (SBT) by distance education. Newly graduated health professionals' experience of and learning outcomes from videoconference-enabled remotely facilitated (RF) were prospectively compared with a locally facilitated (LF) format within a course addressing management of the deteriorating patient. METHODS: Participants were exposed to both RF and LF formats in an intervention course (IC). The primary outcome measure was a questionnaire detailing participants' experience of 1 RF scenario and 1 LF scenario. The 16-item questionnaire measured perceived learning, comfort, interaction with other learners and instructor, as well as quality of instruction, factors that are considered essential in both SBT and distance education. As a secondary outcome measure, learning outcomes, measured as precourse and postcourse scores and pass rates in multiple-choice question tests, were also measured and compared with those of participants completing control courses, in which only the LF format was used. RESULTS: The study was conducted between April 2013 and April 2014. Among the 155 participants who participated in ICs, questionnaire results revealed a small, significantly higher median total score (25-75 interquartile range) for LF versus RF format scenarios [78 (72-80) vs. 76 (68-80), P = 0.01]. Multiple-choice question test scores compared between 155 IC and 150 control course participants showed no significant differences. CONCLUSIONS: Participants' experience of SBT using the RF format was slightly less positive than the LF format; however, it had no measured impact on knowledge. The impact of RF-SBT on more complex training applications remains poorly understood. Instructors could potentially optimize learner comfort and engagement by improving their interactive skills. PMID- 26650703 TI - Simulation in the Executive Suite: Lessons Learned for Building Patient Safety Leadership. AB - INTRODUCTION: Simulation is a powerful learning tool for building individual and team competencies of frontline health care providers with demonstrable impact on performance. This article examines the impact of simulation in building strategic leadership competencies for patient safety and quality among executive leaders in health care organizations. METHODS: We designed, implemented, and evaluated a simulation as part of a larger safety leadership network meeting for executive leaders. This simulation targeted knowledge competencies of governance priority, culture of continuous improvement, and internal transparency and feedback. Eight teams of leaders in health care organizations-a total of 55 participants participated in a 4-hour session. Each team performed collectively as a new chief executive officer (CEO) tasked with a goal of rescuing a hospital with a failing safety record. Teams worked on a modifiable simulation board reflecting the current dysfunctional organizational structure of the simulated hospital. They assessed and redesigned accountability structures based on information acquired in encounter sessions with confederates playing the role of internal staff and external consultants. RESULTS: Data were analyzed, and results are presented as qualitative themes arising from the simulation exercise, participant reaction data, and performance during the simulation. Key findings include high degrees of variability in solutions developed for the dysfunctional hospital system and generally positive learner reactions to the simulation experience. CONCLUSIONS: This study illustrates the potential value of simulation as a mechanism for learning and strategy development for executive leaders grappling with patient safety issues. Future research should explore the cognitive or functional fidelity of organizational simulations and the use of custom scenarios for strategic planning. PMID- 26650704 TI - Addressing Ophthalmology Education for Newly Matriculated Emergency Medicine Residents Using Innovative Models. AB - INTRODUCTION: A majority of newly matriculated emergency medicine residents begin their residencies without any formal ophthalmology training received in medical school. Research on available eye models for procedural education and an eye emergencies curriculum is limited. METHODS: We developed an eye emergencies curriculum that incorporated a series of lectures and case presentations over the academic year with a biannual "ophthalmology day", which included an intense skills laboratory with novel models. RESULTS: From July 2012 to July 2013, 24 newly matriculated interns and 20 upper-level residents participated in the curriculum. The simulations were successfully implemented during multiple sessions. Reasonable material, faculty, and facility resources allowed for continuation of the curriculum. CONCLUSIONS: The eye emergencies curriculum provides a well-received and practical model for residents to gain ophthalmology experience. Novel eye simulation models may be useful for other programs to implement to enhance postgraduate education. PMID- 26650705 TI - The Importance of Deception in Simulation: A Response. PMID- 26650706 TI - Inhibition of ABC transport proteins by oil sands process affected water. AB - The ATP-binding cassette (ABC) superfamily of transporter proteins is important for detoxification of xenobiotics. For example, ABC transporters from the multidrug-resistance protein (MRP) subfamily are important for excretion of polycyclic aromatic hydrocarbons (PAHs) and their metabolites. Effects of chemicals in the water soluble organic fraction of relatively fresh oil sands process affected water (OSPW) from Base Mine Lake (BML-OSPW) and aged OSPW from Pond 9 (P9-OSPW) on the activity of MRP transporters were investigated in vivo by use of Japanese medaka at the fry stage of development. Activities of MRPs were monitored by use of the lipophilic dye calcein, which is transported from cells by ABC proteins, including MRPs. To begin to identify chemicals that might inhibit activity of MRPs, BML-OSPW and P9-OSPW were fractionated into acidic, basic, and neutral fractions by use of mixed-mode sorbents. Chemical compositions of fractions were determined by use of ultrahigh resolution orbitrap mass spectrometry in ESI(+) and ESI(-) mode. Greater amounts of calcein were retained in fry exposed to BML-OSPW at concentration equivalents greater than 1* (i.e., full strength). The neutral and basic fractions of BML-OSPW, but not the acidic fraction, caused greater retention of calcein. Exposure to P9-OSPW did not affect the amount of calcein in fry. Neutral and basic fractions of BML-OSPW contained relatively greater amounts of several oxygen-, sulfur, and nitrogen-containing chemical species that might inhibit MRPs, such as O(+), SO(+), and NO(+) chemical species, although secondary fractionation will be required to conclusively identify the most potent inhibitors. Naphthenic acids (O2(-)), which were dominant in the acidic fraction, did not appear to be the cause of the inhibition. This is the first study to demonstrate that chemicals in the water soluble organic fraction of OSPW inhibit activity of this important class of proteins. However, aging of OSPW attenuates this effect and inhibition of the activity of MRPs by OSPW from Base Mine Lake does not occur at environmentally relevantconcentrations. PMID- 26650707 TI - Adsorption, uptake and distribution of gold nanoparticles in Daphnia magna following long term exposure. AB - Gold nanoparticles (nAu) have recently been studied and developed within the biological and photothermal therapeutic contexts. The major clinical interest is within the application of novel drug delivery systems. Environmental exposure to nanoparticles can occur in different stages of the lifecycle of the product; from their synthesis, applications, product weathering and their disposal. Freshwater Daphnids, specifically Daphnia magna, have been used since the 1960s as a standard species in acute and chronic aquatic toxicity testing. Visualization of the interactions and uptake of nAu by D. magna was related to reproduction and molting patterns. Exposure to nAu was done using a chronic reproduction test performed for 14 days at six concentrations (0.5mg/L, 2mg/L, 5mg/L, 10mg/L, 15mg/L and 20mg/L). Microscopy was used to determine whether there was any uptake or interaction of nAu with daphnia. However the concentration of nAu in the media and the charge of particles played a role in the uptake and surface adsorption. As exposure concentrations of nAu increased it appeared that the nAu aggregated onto the surface and in the gut of the organisms in higher concentrations. There was no evidence of nAu internalization into the body cavity of the daphnia. Aquatic exposure to nAu resulted in increased adhesion of the particles to the carapace of daphnia, ingestion and uptake into the gut of daphnia and had no significant effect on reproduction and molting patterns. PMID- 26650708 TI - Carbon-ionogel supercapacitors for integrated microelectronics. AB - To exceed the performance limits of dielectric capacitors in microelectronic circuit applications, we design and demonstrate on-chip coplanar electric double layer capacitors (EDLCs), or supercapacitors, employing carbon-coated gold electrodes with ionogel electrolyte. The formation of carbon-coated microelectrodes is accomplished by solution processing and results in a ten-fold increase in EDLC capacitance compared to bare gold electrodes without carbon. At frequencies up to 10 Hz, an areal capacitance of 2.1 pF MUm(-2) is achieved for coplanar carbon-ionogel EDLCs with 10 MUm electrode gaps and 0.14 mm(2) electrode area. Our smallest devices, comprised of 5 MUm electrode gaps and 80 MUm(2) of active electrode area, reach areal capacitance values of ~0.3 pF MUm(-2) at frequencies up to 1 kHz, even without carbon. To our knowledge, these are the highest reported values to date for on-chip EDLCs with sub-mm(2) areas. A physical EDLC model is developed through the use of computer-aided simulations for design exploration and optimization of coplanar EDLCs. Through modeling and comparison with experimental data, we highlight the importance of reducing the electrode gap and electrolyte resistance to achieve maximum performance from on chip EDLCs. PMID- 26650709 TI - Generation of Induced Pluripotent Stem Cells from Human Peripheral T Cells Using Sendai Virus in Feeder-free Conditions. AB - Recently, iPSCs have attracted attention as a new source of cells for regenerative therapies. Although the initial method for generating iPSCs relied on dermal fibroblasts obtained by invasive biopsy and retroviral genomic insertion of transgenes, there have been many efforts to avoid these disadvantages. Human peripheral T cells are a unique cell source for generating iPSCs. iPSCs derived from T cells contain rearrangements of the T cell receptor (TCR) genes and are a source of antigen-specific T cells. Additionally, T cell receptor rearrangement in the genome has the potential to label individual cell lines and distinguish between transplanted and donor cells. For safe clinical application of iPSCs, it is important to minimize the risk of exposing newly generated iPSCs to harmful agents. Although fetal bovine serum and feeder cells have been essential for pluripotent stem cell culture, it is preferable to remove them from the culture system to reduce the risk of unpredictable pathogenicity. To address this, we have established a protocol for generating iPSCs from human peripheral T cells using Sendai virus to reduce the risk of exposing iPSCs to undefined pathogens. Although handling Sendai virus requires equipment with the appropriate biosafety level, Sendai virus infects activated T cells without genome insertion, yet with high efficiency. In this protocol, we demonstrate the generation of iPSCs from human peripheral T cells in feeder-free conditions using a combination of activated T cell culture and Sendai virus. PMID- 26650710 TI - Effects of Alpha-Blockade on Ureteral Peristalsis and Intrapelvic Pressure in an In Vivo Stented Porcine Model. AB - INTRODUCTION: Clinical studies have shown beneficial role of oral alpha-blockers for ureteral stent-related morbidity. However, the in vivo effects of oral alpha blockers on a stented ureter are unclear. We evaluated the effects of alpha blockade on ureteral dynamics in a stented porcine ureter. METHODS: Twenty-seven female pigs were used in this study. Fourteen pigs received oral alpha-blocker medication (silodosin, 8 mg daily), and 13 pigs received no medication. Under cystoscopic guidance, a 5F ureteral catheter was positioned in the renal pelvis and attached to a pressure monitor. A Foley catheter was placed in the bladder along with a bladder pressure transducer. A lumbotomy was performed, and the ureter was identified. A magnetic sensor was placed on the extraluminal surface of the ureter to monitor ureteral peristalsis. We measured renal pelvic and bladder pressures, urine output, and ureteral peristalsis every hour for 10 minutes for a total of 5 hours. The pigs were then euthanized. RESULTS: The mean weight was 42.5 kg in the drug group and 45.9 kg in the nondrug group (p = 0.008). Mean hourly urine output was 140 mL in the drug group and 144 mL in the nondrug group (p = 0.76). Mean baseline renal pressure was 13.2 and 13.8 mm Hg (p = 0.69) in the drug and nondrug groups, respectively. Mean peristaltic renal pelvic pressure was 19.1 mm Hg in the drug group and 19.2 mm Hg in the nondrug group (p = 0.97). Mean number of peristalsis was 11/10 and 14/10 minutes (p = 0.03) in the drug and nondrug groups, respectively. CONCLUSIONS: Alpha-blockade in an in vivo stented porcine ureter resulted in no significant effect on renal pelvic pressure but a significant decrease in the number of ureteral peristalsis. Further investigation of the effects of alpha-blocker on ureteral dynamics is required to better understand its effects on stent-related symptoms. PMID- 26650711 TI - Total Synthesis and Structural Confirmation of the Antimalarial Naphthopyrone Lasionectrin. AB - The total synthesis of lasionectrin, a naphthopyrone metabolite of an Acremonium like fungus collected in Equatorial Guinea, is reported. Divergent access to four stereoisomers confirmed the natural product to be the enantiomer of the originally proposed structure. Highlights of the synthesis include ring opening of a chiral oxetane using a thiol, a highly E-selective Julia-Kocienski olefination, and a modified Sharpless/Upjohn dihydroxylation. Palladium-catalyzed carbonylative lactonization was used to assemble the fused naphthopyrone ring system. PMID- 26650712 TI - Event-triggered synchronization strategy for complex dynamical networks with the Markovian switching topologies. AB - This paper concerns the synchronization problem of complex networks with the random switching topologies. By modeling the switching of network topologies as a Markov process, a novel event-triggered synchronization strategy is proposed. Unlike the existing strategies, the event detection of this strategy only works at the network topology switching time instant, which can significantly decrease the communication frequency between nodes and save the network resources. Under this strategy, the synchronization problem of complex network is equivalently converted to the stability of a class of Markovian jump systems with a time varying delay. By using the Lyapunov-Krasovskii functional method and the weak infinitesimal operation, a sufficient condition for the mean square synchronization of the complex networks subject to Markovian switching topologies is established. Finally, a numerical simulation example is provided to demonstrate the theoretical results. PMID- 26650713 TI - Synthesis and structure of the extended phosphazane ligand [(1,4-C6H4){N(MU PN(t)Bu)2N(t)Bu}2](4). AB - The reaction of the phenylene-bridged precursor (1,4-C6H4)[N(PCl2)2]2 with (t)BuNH2 in the presence of Et3N gives the new ligand precursor (1,4-C6H4)[N(MU N(t)Bu)2(PNH(t)Bu)2]2, deprotonation of which with Bu2Mg gives the novel tetraanion [(1,4-C6H4){N(MU-N(t)Bu)2(PN(t)Bu)2}2](4-). PMID- 26650714 TI - Differential interaction of beta2e with phosphoinositides: A comparative study between beta2e and MARCKS. AB - Voltage-gated calcium (CaV) channels are responsible for Ca(2+) influx in excitable cells. As one of the auxiliary subunits, the CaV beta subunit plays a pivotal role in the membrane expression and receptor modulation of CaV channels. In particular, the subcellular localization of the beta subunit is critical for determining the biophysical properties of CaV channels. Recently, we showed that the beta2e isotype is tethered to the plasma membrane. Such a feature of beta2e is due to the reversible electrostatic interaction with anionic membrane phospholipids. Here, we further explored the membrane interaction property of beta2e by comparing it with that of myristoylated alanine-rich C kinase substrate (MARCKS). First, the charge neutralization of the inner leaf of the plasma membrane induced the translocation of both beta2e and MARCKS to the cytosol, while the transient depletion of poly-phosphoinositides (poly-PIs) by translocatable pseudojanin (PJ) systems induced the cytosolic translocation of beta2e but not MARCKS. Second, the activation of protein kinase C (PKC) induced the translocation of MARCKS but not beta2e. We also found that after the cytosolic translocation of MARCKS by receptor activation, depletion of poly-PIs slowed the recovery of MARCKS to the plasma membrane. Together, our data demonstrate that both beta2e and MARCKS bind to the membrane through electrostatic interaction but with different binding affinity, and thus, they are differentially regulated by enzymatic degradation of membrane PIs. PMID- 26650715 TI - Use of posttreatment imaging and biomarkers in survivors of early-stage breast cancer: Inappropriate surveillance or necessary care? AB - BACKGROUND: Advanced imaging and serum biomarkers are commonly used for surveillance in patients with early-stage breast cancer, despite recommendations against this practice. Incentives to perform such low-value testing may be less prominent in integrated health care delivery systems. The purpose of the current study was to evaluate and compare the use of these services within 2 integrated systems: Kaiser Permanente (KP) and Intermountain Healthcare (IH). The authors also sought to distinguish the indication for testing: diagnostic purposes or routine surveillance. METHODS: Patients with American Joint Committee on Cancer stage 0 to II breast cancer diagnosed between 2009 and 2010 were identified and the use of imaging and biomarker tests over an 18-month period were quantified, starting at 1 year after diagnosis. Chart abstraction was performed on a random sample of patients who received testing to identify the indication for testing. Multivariate regression was used to explore associations with the use of nonrecommended care. RESULTS: A total of 6585 patients were identified; 22% had stage 0 disease, 44% had stage I disease, and 34% had stage II disease. Overall, 24% of patients received at least 1 imaging test (25% at KP vs 22% at IH; P = .009) and 28% of patients received at least 1 biomarker (36% at KP vs 13% at IH; P<.001). Chart abstraction revealed that 84% of imaging tests were performed to evaluate symptoms or signs. Virtually all biomarkers were ordered for routine surveillance. Stage of disease, medical center that provided the services, and provider experience were found to be significantly associated with the use of biomarkers. CONCLUSIONS: Advanced imaging was most often performed for appropriate indications, but biomarkers were used for nonrecommended surveillance. Distinguishing between inappropriate use for surveillance and appropriate diagnostic testing is essential when evaluating adherence to recommendations. PMID- 26650717 TI - Nalbuphine for Treatment of Opioid-induced Pruritus: A Systematic Review of Literature. AB - OBJECTIVES: Opioid-induced pruritus is a common side effect of opioid treatment in patients with acute pain associated with surgery or childbirth. There are several options available to treat opioid-induced pruritus, including nalbuphine. However, it is not known whether nalbuphine offers greater efficacy in treating pruritus without attenuation of analgesia and an increase in the incidence of adverse outcomes. METHODS: A systematic search of studies assessing treatment efficacy of nalbuphine was conducted through Medline, PubMed, Cochrane Library, CINAHL, and ProQuest databases. The primary outcome was reduction of pruritus, whereas the secondary outcomes included analgesia and adverse outcomes. RESULTS: Ten studies that met all inclusion criteria were identified, 9 of which were randomized controlled trials and 1 case report. The incidence of pruritus was higher among patients receiving neuraxial opioids than those with the intravenous route. Nalbuphine provided greater efficacy in treating opioid-induced pruritus when compared with placebo, control, or other pharmacologic agents such as diphenhydramine, naloxone, and propofol. There was no attenuation of analgesia or increase in sedation with low-dose nalbuphine treatment-25% to 50% of the dose to treat pain, that is, 2.5 to 5 mg versus 10 mg intravenously. Further, nalbuphine was associated with reduction of nausea or vomiting, and reversal of respiratory depression. CONCLUSIONS: Nalbuphine is superior in treating opioid-induced pruritus when compared with placebo, control, diphenhydramine, naloxone, or propofol in patients receiving neuraxial opioids for acute pain related to surgery or childbirth. Therefore, it is recommended that nalbuphine should be used as a first-line treatment of opioid-induced pruritus. PMID- 26650716 TI - Protocols for massive blood transfusion: when and why, and potential complications. AB - PURPOSE: An update paper on massive bleeding after major trauma. A review of protocols to address massive bleeding, and its possible complications, including coagulation abnormalities, complications related to blood storage, immunosuppression and infection, lung injury associated with transfusion, and hypothermia is carried out. METHODS: Literature review and discussion with authors' experience. RESULTS: Massive bleeding is an acute life-threatening complication of major trauma, and consequently its prompt diagnosis and treatment is of overwhelming importance. Treatment requires rapid surgical management together with the massive infusion of colloid and blood. CONCLUSIONS: Since massive transfusion provokes further problems in patients who are already severely traumatized and anaemic, once this course of action has been decided upon, a profound knowledge of its potential complications, careful monitoring and proper follow-up are all essential. To diagnose this bleeding, most authors favour, as the main first choice tool, a full-body CT scan (head to pelvis), in non-critical severe trauma cases. In addition, focused abdominal sonography for trauma (FAST, an acronym that highlights the necessity of rapid performance) is a very important diagnostic test for abdominal and thoracic bleeding. Furthermore, urgent surgical intervention should be undertaken for patients with significant free intraabdominal fluid and haemodynamic instability. Although the clinical situation and the blood haemoglobin concentration are the key factors considered in this rapid decision-making context, laboratory markers should not be based on a single haematocrit value, as its sensitivity to significant bleeding may be very low. Serum lactate and base deficit are very sensitive markers for detecting and monitoring the extent of bleeding and shock, in conjunction with repeated combined measurements of prothrombin time, activated partial thromboplastin time, fibrinogen and platelets. PMID- 26650718 TI - Autotrophic denitrification by nitrate-dependent Fe(II) oxidation in a continuous up-flow biofilter. AB - A continuous-upflow biofilter packed with sponge iron was constructed for nitrate removal under an anaerobic atmosphere. Microbacterium sp. W5, a nitrate reducing and Fe(II) oxidizing strain, was added to the biofilter as an inoculum. The best results were achieved when NO3 (-)-N concentration was 30 mg/L and Fe(2+) was 800 mg/L. Nitrite in influent would inhibit nitrate removal and aqueous Fe(2+) resulted in encrustation. Fe(II)EDTA would prevent cells from encrustation and the maximum nitrogen removal efficiency was about 90 % with Fe(II)EDTA level of 1100 mg/L. Nitrate reduction followed first-order reaction kinetics. Characteristics of biofilms were analyzed by X-ray fluorescence spectroscopy. PMID- 26650719 TI - Mixing design for enzymatic hydrolysis of sugarcane bagasse: methodology for selection of impeller configuration. AB - One of the major process bottlenecks for viable industrial production of second generation ethanol is related with technical-economic difficulties in the hydrolysis step. The development of a methodology to choose the best configuration of impellers towards improving mass transfer and hydrolysis yield together with a low power consumption is important to make the process cost effective. In this work, four dual impeller configurations (DICs) were evaluated during hydrolysis of sugarcane bagasse (SCB) experiments in a stirred tank reactor (3 L). The systems tested were dual Rushton turbine impellers (DIC1), Rushton and elephant ear (down-pumping) turbines (DIC2), Rushton and elephant ear (up-pumping) turbines (DIC3), and down-pumping and up-pumping elephant ear turbines (DIC4). The experiments were conducted during 96 h, using 10 % (m/v) SCB, pH 4.8, 50 degrees C, 10 FPU/g biomass, 470 rpm. The mixing time was successfully used as the characteristic parameter to select the best impeller configuration. Rheological parameters were determined using a rotational rheometer, and the power consumptions of the four DICs were on-line measured with a dynamometer. The values obtained for the energetic efficiency (the ratio between the cellulose to glucose conversion and the total energy) showed that the proposed methodology was successful in choosing a suitable configuration of impellers, wherein the DIC4 obtained approximately three times higher energetic efficiency than DIC1. Furthermore a scale-up protocol (factor scale-up 1000) for the enzymatic hydrolysis reactor was proposed. PMID- 26650720 TI - In silico analysis of Clostridium acetobutylicum ATCC 824 metabolic response to an external electron supply. AB - The biological production of butanol has become an important research field and thanks to genome sequencing and annotation; genome-scale metabolic reconstructions have been developed for several Clostridium species. This work makes use of the iCAC490 model of Clostridium acetobutylicum ATCC 824 to analyze its metabolic capabilities and response to an external electron supply through a constraint-based approach using the Constraint-Based Reconstruction Analysis Toolbox. Several analyses were conducted, which included sensitivity, production envelope, and phenotypic phase planes. The model showed that the use of an external electron supply, which acts as co-reducing agent along with glucose derived reducing power (electrofermentation), results in an increase in the butanol-specific productivity. However, a proportional increase in the butyrate uptake flux is required. Besides, the uptake of external butyrate leads to the coupling of butanol production and growth, which coincides with results reported in literature. Phenotypic phase planes showed that the reducing capacity becomes more limiting for growth at high butyrate uptake fluxes. An electron uptake flux allows the metabolism to reach the growth optimality line. Although the maximum butanol flux does not coincide with the growth optimality line, a butyrate uptake combined with an electron uptake flux would result in an increased butanol volumetric productivity, being a potential strategy to optimize the production of butanol by C. acetobutylicum ATCC 824. PMID- 26650721 TI - Morphological and Stress Vulnerability Indices for Human Coronary Plaques and Their Correlations with Cap Thickness and Lipid Percent: An IVUS-Based Fluid Structure Interaction Multi-patient Study. AB - Plaque vulnerability, defined as the likelihood that a plaque would rupture, is difficult to quantify due to lack of in vivo plaque rupture data. Morphological and stress-based plaque vulnerability indices were introduced as alternatives to obtain quantitative vulnerability assessment. Correlations between these indices and key plaque features were investigated. In vivo intravascular ultrasound (IVUS) data were acquired from 14 patients and IVUS-based 3D fluid-structure interaction (FSI) coronary plaque models with cyclic bending were constructed to obtain plaque wall stress/strain and flow shear stress for analysis. For the 617 slices from the 14 patients, lipid percentage, min cap thickness, critical plaque wall stress (CPWS), strain (CPWSn) and flow shear stress (CFSS) were recorded, and cap index, lipid index and morphological index were assigned to each slice using methods consistent with American Heart Association (AHA) plaque classification schemes. A stress index was introduced based on CPWS. Linear Mixed Effects (LME) models were used to analyze the correlations between the mechanical and morphological indices and key morphological factors associated with plaque rupture. Our results indicated that for all 617 slices, CPWS correlated with min cap thickness, cap index, morphological index with r = -0.6414, 0.7852, and 0.7411 respectively (p<0.0001). The correlation between CPWS and lipid percentage, lipid index were weaker (r = 0.2445, r = 0.2338, p<0.0001). Stress index correlated with cap index, lipid index, morphological index positively with r = 0.8185, 0.3067, and 0.7715, respectively, all with p<0.0001. For all 617 slices, the stress index has 66.77% agreement with morphological index. Morphological and stress indices may serve as quantitative plaque vulnerability assessment supported by their strong correlations with morphological features associated with plaque rupture. Differences between the two indices may lead to better plaque assessment schemes when both indices were jointly used with further validations from clinical studies. PMID- 26650722 TI - Enrichment of Bruch's Membrane from Human Donor Eyes. AB - Age-related macular degeneration (AMD) is a leading cause of visual impairment in the developed world. The disease manifests itself by the destruction of the center of the retina, called the macula, resulting in the loss of central vision. Early AMD is characterised by the presence of small, yellowish lesions called soft drusen that can progress onto late AMD such as geographic atrophy (dry AMD) or neovascularisation (wet AMD). Although the clinical changes are well described, and the understanding of genetic influences on conferring AMD risk are getting ever more detailed, one area lacking major progress is an understanding of the biochemical consequences of genetic risk. This is partly due to difficulties in understanding the biochemistry of Bruch's membrane, a very thin extracellular matrix that acts as a biological filter of material from the blood supply and a scaffold on which the retinal pigment epithelial (RPE) cell monolayer resides. Drusen form within Bruch's membrane and their presence disrupts nutrient flow to the RPE cells. Only by investigating the protein composition of Bruch's membrane, and indeed how other proteins interact with it, can researchers hope to unravel the biochemical mechanisms underpinning drusen formation, development of AMD and subsequent vision loss. This paper details methodologies for enriching either whole Bruch's membrane, or just from the macula region, so that it can be used for downstream biochemical analysis, and provide examples of how this is already changing the understanding of Bruch's membrane biochemistry. PMID- 26650723 TI - In vitro assessment of a collagen/alginate composite scaffold for regenerative endodontics. AB - AIM: To develop a biological scaffold that could be moulded to reproduce the geometry of a gutta-percha point with precision and allow the differentiation of mesenchymal stem cells into osteoblasts to be used as a regenerative endodontic material. METHODOLOGY: A collagen/alginate composite scaffold was cast into a sodium alginate mould to produce a gutta-percha point-like cone. Prior to gelation, the cone was seeded with human stem cells from the apical papilla (SCAPs) to evaluate cell/scaffold interactions. The reconstructed tissue was characterized after 8 days in culture. Elastic modulus, tissue compaction and cell differentiation were assessed. Student t-tests and the Mann-Whitney U test were performed. RESULTS: The fabrication method developed enabled the shape of a gutta-percha point to be mimicked with great accuracy and reproducibility (P = 0.31). Stem cells seeded into this composite scaffold were able to spread, survive and proliferate (P < 0.001). Moreover, they were able to differentiate into osteoblasts and produce calcified osseous extracellular matrix (P < 0.001). The construct showed no significant contraction after 8 days, preserving its shape and tip diameter (P = 0.58). CONCLUSIONS: The composite scaffold could present substantial benefits compared to synthetic materials. It could provide a favourable healing environment in the root canal conducive for regenerative endodontics and is therefore appropriate to be evaluated in vivo in further studies. PMID- 26650724 TI - Cortical and Subcortical Gray Matter Volume in Youths With Conduct Problems: A Meta-analysis. AB - IMPORTANCE: A large number of structural neuroimaging studies have used voxel based morphometry (VBM) to identify gray matter abnormalities in youths with conduct problems (CP), but the findings have been disparate and few have been replicated. OBJECTIVE: To conduct a meta-analysis of published whole-brain structural neuroimaging studies on youths with CP that used VBM methods to facilitate replication and aid further analyses by researchers. DATA SOURCES: The PubMed, ScienceDirect, Scopus, Google Scholar, and Web of Science databases were searched for VBM studies published from January 1, 2007, through March 31, 2015. Manual searches were conducted using title and citation information. Authors were contacted for additional data. STUDY SELECTION: A literature search identified 28 studies. Studies were excluded if they (1) failed to use VBM, (2) failed to report a voxelwise comparison between youths with CP and typically developing (TD) youths, (3) used different significance or extent thresholds throughout the brain, (4) included duplicated datasets, and (5) did not provide peak coordinates or parametric maps after contact with the authors. Thirteen studies were deemed eligible for inclusion (394 youths with CP and 350 TD youths). DATA EXTRACTION AND SYNTHESIS: Anisotropic effect-size signed differential mapping (SDM) was used for voxel-based meta-analyses. Statistical parametric maps comparing gray matter differences between youths with CP and TD youths were available for 11 of the studies, with peak coordinates available for the remaining studies. MAIN OUTCOMES AND MEASURES: Regional gray matter volume (GMV) differences in youths with CP compared with TD youths. RESULTS: Youths with CP had decreased GMV in the left amygdala (SDM estimate = -0.218; P < .001) (extending into anterior insula), right insula (SDM estimate = -0.174; P < .001) (extending ventrolaterally into the prefrontal cortex and inferiorly into the superior temporal gyrus), left medial superior frontal gyrus (SDM estimate = -0.163; P = .001) (extending into the right anterior cingulate cortex), and left fusiform gyrus (SDM estimate = 0.146; P = .003). Subgroup meta-analysis assessing age-at-onset effects identified reduced GMV in the left anterior insula (SDM estimate = -0.232; P < .001) (extending into amygdala). Meta-regression analyses revealed that greater scores on measures of callous-unemotional traits were associated with a lower reduction in GMV in the left putamen (SDM estimate = -0.911; P < .001). The proportion of male and female youths in the sample was associated with decreased GMV in the left amygdala (SDM estimate = -0.31; P < .001) and increased GMV in the right inferior temporal cortex (SDM estimate = 0.755; P < .001). While there was no association with comorbid attention-deficit/hyperactivity disorder or IQ, age range was associated with gray matter differences in the left amygdala. CONCLUSIONS AND RELEVANCE: We identified gray matter reductions within the insula, amygdala, frontal and temporal regions in youths with CP as well as inconsistencies in sample characteristics across studies that should be addressed in future research. PMID- 26650725 TI - Reply to comment to Long-term outcomes (>5 years follow-up) with porcine acellular dermal matrix (Permacol) in incisional hernias at risk for infection: Negro P, D'Amore L, Ceci F, Gossetti F (DOI 10.1007/s10029-015-1406-1). PMID- 26650727 TI - alpha-Substituted Bis(octabutoxyphthalocyaninato)Terbium(III) Double-Decker Complexes: Preparation and Study of Protonation by NMR and DFT. AB - Synthesis of the anionic, alpha-substituted, bis(phthalocyaninato)Tb(III) complex [Tb(alpha-obPc)2](-) ([1](-)) (obPc = alpha-octabutoxyphthalocyaninato) leads to the isolation of its protonated form [1H](0). This complex was characterized by X ray diffraction (XRD), mass spectroscopy (MS), infrared (IR) and ultraviolet visible-near-infrared (UV-vis-NIR) spectroscopy. Crystal structure analysis did not allow localization of the additional proton, which is probably attached to the meso-N atom or isoindole-N atom of the phthalocyaninato ligand. [1H](0) can easily be deprotonated or protonated, giving the corresponding anionic and cationic complexes. The three compounds [1H](0), [1](-), and [1HH](+) were studied by a combination of paramagnetic NMR experiments ((1)H, (13)C, variable temperature measurements, two-dimensional nuclear magnetic resonance and DFT calculations (done on Y(III) analogues with octamethoxyphthalocyaninato ligands), for the purpose of elucidating the positions of the acidic protons and for understanding the structural changes of the coordination environment of the Tb ion induced by protonation. PMID- 26650726 TI - Chronic pain after TEP inguinal hernia repair, does MRI reveal a cause? AB - PURPOSE: Persistent pain is a known side effect after TEP inguinal repair disabling 2-5% of patients. A standardized diagnostic work-up so far is not available. MRI is a diagnostic tool in the work-up of inguinal hernias. In the present study the yield of MRI in evaluating chronic pain after TEP hernia repair is addressed. METHODS: In our database patients receiving an MRI scan for groin pain lasting more than 3 months after TEP inguinal hernia repair were identified. A checklist with potential pathologic findings was filled out for each groin by two blinded observers. Findings in painful, pain-free and unoperated groins were compared and statistical analysis done based upon their relative incidences. Cohen's kappa coefficients were calculated to determine interobserver agreement. RESULTS: Imaging studies of 53 patients revealed information regarding 106 groins. Fifty-five groins were painful after the initial operation, 12 were pain free postoperatively and 39 groins were not operated. None of the predefined disorders was observed statistically more often in the patients with painful groins. Only fibrosis appeared more prevalent in patients with chronic pain (P = 0.11). Interobserver agreement was excellent for identifying the mesh (kappa = 0.88) and observing bulging or a hernia (kappa = 0.74) and was substantial for detecting fibrosis (kappa = 0.63). In 40% of the patients, MRI showed a correct mesh position and observed nothing else than minor fibrosis. A wait and see policy resolved complaints in the majority of the patients. In 15 % of the patients, MRI revealed treatable findings explanatory for persisting groin pain. CONCLUSION: For patients with post-TEP hernia groin pain, MRI is useful to confirm a correct flat mesh position and to identify possible not operation related causes of groin pain. It is of little help to identify a specific cause of groin repair-related pain. PMID- 26650728 TI - 30th anniversary of Annals of Nuclear Medicine. PMID- 26650729 TI - Suppression of HIV-1 Infectivity by Human Glioma Cells. AB - HIV-1 infection to the central nervous system (CNS) is very common in AIDS patients. The predominant cell types infected in the brain are monocytes and macrophages, which are surrounded by several HIV-1-resistant cell types, such as astrocytes, oligodendrocytes, neurons, and microvascular cells. The effect of these HIV-1-resistant cells on HIV-1 infection is largely unknown. In this study, we examined the stability of HIV-1 cultured with several human glioblastoma cell lines, for example, NP-2, U87MG, T98G, and A172, to determine whether these HIV-1 resistant brain cells could enhance or suppress HIV-1 infection and thus modulate HIV-1 infection in the CNS. The HIV-1 titer was determined using the MAGIC-5A indicator cell line as well as naturally occurring CD4(+) T cells. We found that the stability of HIV-1 incubated with NP-2 or U87MG cells at 37 degrees C was significantly shorter (half-life, 2.5-4 h) compared to that of HIV-1 incubated with T98G or A172 cells or in culture medium without cells (half-life, 8-18 h). The spent culture media (SCM) of NP-2 and U87MG cells had the ability to suppress both R5- and X4-HIV-1 infection by inhibiting HIV-1 attachment to target cells. This inhibitory effect was eliminated by the treatment of the SCM with chondroitinase ABC but not heparinase, suggesting that the inhibitory factor(s) secreted by NP-2 and U87MG cells was chiefly mediated by chondroitin sulfate (CS) or CS-like moiety. Thus, this study reveals that some but not all glioma cells secrete inhibitory molecules to HIV-1 infection that may contribute in lowering HIV-1 infection in the CNS in vivo. PMID- 26650731 TI - Advances in electrospun carbon fiber-based electrochemical sensing platforms for bioanalytical applications. AB - Electrochemical sensing is an efficient and inexpensive method for detection of a range of chemicals of biological, clinical, and environmental interest. Carbon materials-based electrodes are commonly employed for the development of electrochemical sensors because of their low cost, biocompatibility, and facile electron transfer kinetics. Electrospun carbon fibers (ECFs), prepared by electrospinning of a polymeric precursor and subsequent thermal treatment, have emerged as promising carbon systems for biosensing applications since the electrochemical properties of these carbon fibers can be easily modified by processing conditions and post-treatment. This review addresses recent progress in the use of ECFs for sensor fabrication and analyte detection. We focus on the modification strategies of ECFs and identification of the key components that impart the bioelectroanalytical activities, and point out the future challenges that must be addressed in order to advance the fundamental understanding of the ECF electrochemistry and to realize the practical applications of ECF-based sensing devices. PMID- 26650732 TI - Optical sensing and biosensing based on non-spherical noble metal nanoparticles. AB - Non-spherical noble metal nanoparticles (NPs) have widely tunable localized surface plasmon resonance, very high extinction coefficient, and strongly facet dependent adsorption/binding properties. A few non-spherical noble metal NPs have been employed as reporters and/or modulators for various optical sensing. This review summarizes recent progress in the study of design, performance, and application of colorimetric and fluorescent sensing/biosensing systems based on three kinds of non-spherical noble metal NPs with different dimension, namely, one- (or quasi-one) dimensional nanorods, two-dimensional nanoplates, and three dimensional nanodendritics; furthermore, the future developments in this research area are also discussed. PMID- 26650730 TI - Mobile thrombus on cardiac implantable electronic device leads of patients undergoing cardiac ablation: incidence, management, and outcomes. AB - PURPOSE: The rates of cardiovascular implantable electronic device (CIED) implantations and cardiac ablation procedures are increasing worldwide. To date, the management of CIED lead thrombi in the peri-ablation period remains undefined and key clinical management questions remained unanswered. We sought to describe the clinical course and management strategies of patients with a CIED lead thrombus detected in the peri-ablative setting. METHODS: We performed a retrospective analysis of all patients who underwent a cardiac ablation procedure at Mayo Clinic Rochester from 2000 to 2014. Patients were included in our study cohort if they had documented CIED lead thrombus noted on peri-ablation imaging studies. Electronic medical records were reviewed to determine the overall management strategy, outcomes, and embolic complications in these patients. RESULTS: Our overall cohort included 1833 patients, with 27 (1.4 %) having both cardiac ablation procedures as well as CIED lead thrombus detected on imaging. Of these 27 patients, 21 were male (77 %), and the mean age was 59.2 years. The mean duration of follow-up was 16.5 months (range 3 days-48.3 months). Anticoagulation was an effective therapeutic strategy, with 11/14 (78.6 %) patients experiencing either resolution of the thrombus or reduction in size on re-imaging. For atrial fibrillation ablation, the most common management strategy was a deferment in ablation with initiation/intensification of anticoagulation medication. For ventricular tachycardia ablations, most procedures involved a modified approach with the use of a retrograde aortic approach to access the left ventricle. No patient had any documented embolic complications. CONCLUSIONS: The incidence of lead thrombi in patients undergoing an ablation was small in our study cohort (1.4 %). Anticoagulation and deferral of ablation represented successful management strategies for atrial fibrillation ablation. For patients undergoing ventricular tachycardia ablation, a modified approach using retrograde aortic access to the ventricle was successful. In patients who are not on warfarin anticoagulation at the time of thrombus detection, we recommend initiation of this medication, with a goal INR of 2-3. For patients on warfarin at the time of thrombus detection, we recommend an intensification of anticoagulation with a goal INR of 3.0. PMID- 26650733 TI - Development of a southern oceanic air standard reference material. AB - In 2009, the United States Congress charged the National Institute of Standards and Technology (NIST) with supporting climate change research. As part of this effort, the Gas Sensing Metrology Group at NIST began developing new gas standard mixtures for greenhouse gas mixtures relevant to atmospheric measurements. Suites of gravimetrically prepared primary standard mixtures (PSMs) were prepared at ambient concentration levels for carbon dioxide (CO2), methane (CH4), and nitrous oxide (N2O) in a dry-air balance. In parallel, 30 gas cylinders were filled, by the National Institute of Water and Atmospheric Research (NIWA) in Wellington, New Zealand, to high pressure from pristine southern oceanic air at Baring Head, New Zealand, and shipped to NIST. Using spectroscopic instrumentation, NIST analyzed the 30 cylinder samples for mole fractions of CO2, CH4, and N2O. Certified values were assigned to these mixtures by calibrating the instrumentation with the PSM suites that were recently developed at NIST. These mixtures became NIST Standard Reference Material (SRM) 1721 Southern Oceanic Air and are certified for ambient mole fraction, the first of their kind for NIST. The relative expanded uncertainties corresponding to coverage intervals with 95% probability are no larger than 0.06% of the certified values, representing the smallest uncertainties to date ever assigned to an NIST gas SRM. PMID- 26650735 TI - No rheumatoid arthritis in ancient Egypt: a reappraisal. AB - Antiquity of rheumatoid arthritis (RA) remains controversial, and its origins in Americas or in the Old World are disputed. Proponents of the latter frequently refer to RA in ancient Egypt, but validity of those claims has never been examined. Review of all reported RA cases from ancient Egypt revealed that none of them represent real RA, instead being either examples of changing naming conventions or of imprecise diagnostic criteria. Most cases represented osteoarthritis or spondyloarthropathies. Also review of preserved ancient Egyptian medical writings revealed many descriptions of musculoskeletal disorders, but none of them resembled RA. This suggests that RA was absent in ancient Egypt and supports the hypothesis of the New World origin of RA and its subsequent global spread in the last several centuries. PMID- 26650736 TI - Establishment of an Early Vascular Network Promotes the Formation of Ectopic Bone. AB - Vascularization is crucial for the induction of bone formation. In this study, we investigated the application of two subtypes of peripheral blood-derived endothelial progenitor cells (EPCs) to stimulate vessel formation in ectopic bone constructs. Early and late outgrowth EPCs (E-EPC and L-EPC, respectively) were characterized for their ability to form network structures in vitro and perfused vessels subcutaneously in mice. Only L-EPCs showed the formation of fully connected networks on Matrigel two-dimensional (2D) angiogenesis assays. The presence of multipotent stromal cells (MSCs) inhibited network formation in 2D assays, but stimulated network formation in three-dimensional plugs. In vivo studies revealed that at 2 weeks, the highest incidence of formed perfused vessels was reached by implanted E-EPC/MSC constructs and this could be attributed to the presence of E-EPCs. L-EPCs displayed a significantly lower frequency of blood vessel formation than E-EPCs and this was accompanied by a lowering of total luminal area densities. Nevertheless, combined E-EPC/L-EPC application somewhat increased the percentage incidence of perfused vessels. After 6 weeks, differences in vascularization were still obvious as all three EPC based constructs contained higher numbers of perfused vessels than constructs containing MSCs alone. Bone was formed in all constructs at an incidence that coincided with high density of perfused vessels after 2 weeks. Altogether, our findings suggest the differential establishment of vascular networks by E-EPCs and L-EPCs and suggest the importance of early vasculogenesis in ectopic bone formation. PMID- 26650734 TI - Sweet secrets of a therapeutic worm: mass-spectrometric N-glycomic analysis of Trichuris suis. AB - Trichuris suis, a nematode parasite of pigs, has attracted attention as its eggs have been administered to human patients as a potential therapy for inflammatory diseases. The immunomodulatory factors remain molecularly uncharacterised, but in vitro studies suggest that glycans on the parasite's excretory/secretory proteins may play a role. Using an off-line LC-MS approach in combination with chemical and enzymatic treatments, we have examined the N-linked oligosaccharides of T. suis. In addition to the paucimannosidic and oligomannosidic N-glycans typical of many invertebrates, a number of glycans carry N,N'-diacetyllactosamine (LacdiNAc) modified by fucose and/or phosphorylcholine. Such antennal epitopes are similar to ones previously associated with immunomodulation by helminths; here we propose phosphorylcholine modifications predominantly of terminal N-acetylgalactosamine but also of subterminal alpha1,3-fucosylated N-acetylglucosamine. Exact knowledge of the glycome of T. suis will facilitate more targeted studies on glycan receptors in the host as well as the engineering of cell lines to produce correctly glycosylated recombinant forms of candidate proteins for future studies on immunomodulation. PMID- 26650738 TI - Biotransformation of hexavalent chromium into extracellular chromium(III) oxide nanoparticles using Schwanniomyces occidentalis. AB - OBJECTIVES: To demonstrate biotransformation of toxic Cr(VI) ions into Cr2O3 nanoparticles by the yeast Schwanniomyces occidentalis. RESULTS: Reaction mixtures containing S. occidentalis NCIM 3459 and Cr(VI) ions that were initially yellow turned green after 48 h incubation. The coloration was due to the synthesis of chromium (III) oxide nanoparticles (Cr2O3NPs). UV-Visible spectra of the reaction mixtures showed peaks at 445 and 600 nm indicating (4)A2g -> (4)T1g and (4)A2g -> (4)T2g transitions in Cr2O3, respectively. FTIR profiles suggested the involvement of carboxyl and amide groups in nanoparticle synthesis and stabilization. The Cr2O3NPs ranged between 10 and 60 nm. Their crystalline nature was evident from the selective area electron diffraction and X-ray diffraction patterns. Energy dispersive spectra confirmed the chemical composition of the nanoparticles. These biogenic nanoparticles could find applications in different fields. CONCLUSIONS: S. occidentalis mediated biotransformation of toxic Cr(VI) ions into crystalline extracellular Cr2O3NPs under benign conditions. PMID- 26650737 TI - miR-195 Inhibits EMT by Targeting FGF2 in Prostate Cancer Cells. AB - Prostate cancer (PCa) is one of the leading causes of deaths in America. The major cause of mortality can be attributed to metastasis. Cancer metastasis involves sequential and interrelated events. miRNAs and epithelial-mesenchymal transition (EMT) are implicated in this process. miR-195 is downregulated in many human cancers. However, the roles of miR-195 in PCa metastasis and EMT remain unclear. In this study, data from Memorial Sloan Kettering Cancer Center (MSKCC) prostate cancer database were re-analysed to detect miR-195 expression and its roles in PCa. miR-195 was then overexpressed in castration-resistant PCa cell lines, DU-145 and PC-3. The role of miR-195 in migration and invasion in vitro was also investigated, and common markers in EMT were evaluated through Western blot analysis. A luciferase reporter assay was conducted to confirm the target gene of miR-195; were validated in PCa cells. In MSKCC data re-analyses, miR-195 was poorly expressed in metastatic PCa; miR-195 could be used to diagnose metastatic PCa by measuring the corresponding expression. Area under the receiver operating characteristic curve (AUC-ROC) was 0.705 (P = 0.017). Low miR-195 expression was characterised with a shorter relapse-free survival (RFS) time. miR 195 overexpression suppressed cell migration, invasion and EMT. Fibroblast growth factor 2 (FGF2) was confirmed as a direct target of miR-195. FGF2 knockdown also suppressed migration, invasion and EMT; by contrast, increased FGF2 partially reversed the suppressive effect of miR-195. And data from ONCOMINE prostate cancer database showed that PCa patients with high FGF2 expression showed shorter RFS time (P = 0.046). Overall, this study demonstrated that miR-195 suppressed PCa cell metastasis by downregulating FGF2. miR-195 restoration may be considered as a new therapeutic method to treat metastatic PCa. PMID- 26650739 TI - Forecasting the Effects of Fertility Control on Overabundant Ungulates: White Tailed Deer in the National Capital Region. AB - Overabundant populations of ungulates have caused environmental degradation and loss of biological diversity in ecosystems throughout the world. Culling or regulated harvest is often used to control overabundant species. These methods are difficult to implement in national parks, other types of conservation reserves, or in residential areas where public hunting may be forbidden by policy. As a result, fertility control has been recommended as a non-lethal alternative for regulating ungulate populations. We evaluate this alternative using white-tailed deer in national parks in the vicinity of Washington, D.C., USA as a model system. Managers seek to reduce densities of white-tailed deer from the current average (50 deer per km2) to decrease harm to native plant communities caused by deer. We present a Bayesian hierarchical model using 13 years of population estimates from 8 national parks in the National Capital Region Network. We offer a novel way to evaluate management actions relative to goals using short term forecasts. Our approach confirms past analyses that fertility control is incapable of rapidly reducing deer abundance. Fertility control can be combined with culling to maintain a population below carrying capacity with a high probability of success. This gives managers confronted with problematic overabundance a framework for implementing management actions with a realistic assessment of uncertainty. PMID- 26650740 TI - From the Editor. PMID- 26650741 TI - Community Health Worker Integration in Health Care, Public Health, and Policy: A Partnership Model. AB - Health care systems and public health agencies are focusing increased attention on the capacity of community health workers (CHWs) to improve health outcomes for vulnerable populations and to support integration of clinical and community prevention services. This article describes 3 initiatives in Massachusetts in which the state public health department has collaborated with CHW leaders, health providers, and community-based partners to develop innovative policy and services, including state certification of CHWs, integrated chronic disease programs, and a state-funded pilot program to demonstrate return on investment for community-based prevention. Concluding lessons are relevant for implementation of health care reform nation-wide. PMID- 26650742 TI - Community Health Workers-Promotores de Salud in Mexico: History and Potential for Building Effective Community Actions. AB - This article takes a historical perspective combining 3 illustrative examples of the origins of the community health worker (CHW) model in Mexico, as a community based participatory strategy. Three examples were identified from the sparse literature about CHWs in Mexico emphasizing their key roles and functions in various community settings. The CHW models illustrate what is known of training development and planning, implementation, and evaluation of the CHWs model in different settings addressing cardiovascular disease and risk factors. The potential exists for integrating CHW projects to expand the health promotion model with new emphasis on municipality and regional participation. PMID- 26650743 TI - Estimating the Human Resource Costs of Developing and Implementing Shared Medical Appointments in Primary Care. AB - We used activity-based costing to estimate the human resource costs for developing and implementing a program to support shared medical appointments (SMAs) and an additional SMA on cancer survivorship. In-depth, key informant interviews were conducted to determine completed tasks, personnel involved, and time to complete tasks. Introducing new providers or a new type of SMA may require relatively modest incremental organizational resources and provider time (<8% of time and about 15% of the finances required to start the initial SMA). Time and cost could possibly be further decreased by leveraging relevant materials from existing SMAs. PMID- 26650745 TI - Facing Financial Hardship: Patients' Views on Clinical Trade-offs in Exchange for Cost Savings. AB - As more patients enroll in health insurance with high out-of-pocket costs, provider-patient cost discussions are of growing importance. Little is known about how patients want providers to engage in cost conversations. We surveyed 842 chronically ill adults seeking financial help to examine preferences around treatment trade-offs in 3 areas-convenience, side effects, and efficacy and whether preferences changed with different savings. To save money, half of patients were willing to endure inconvenience (increased dosing), with no difference by magnitude of savings ($50 vs $150 per month). Few participants were willing to tolerate side effects or reduced efficacy. PMID- 26650744 TI - Primary Care Experiences of Emergency Department Patients With Limited Health Literacy. AB - It is unclear why patients with limited health literacy have fewer visits with a personal doctor and more emergency department (ED) visits than patients with adequate health literacy. We identified significant differences in perceived access to a personal doctor and high-quality provider interactions among adults with limited compared to adequate health literacy presenting for emergency treatment. Practice and provider strategies to ensure that patients have timely access to care and high-quality provider interactions may address some of the reasons patients with limited health literacy use more emergency department-based and less preventive care than those with adequate health literacy. PMID- 26650746 TI - Universal Health Care Identifiers: The Challenge of Linking Medical Records. AB - Many patients have a primary care physician and an assortment of specialists they might see regularly or even just once. Patients' use of multiple clinicians and clinical organizations increases the need to share health information among providers to reduce the probability of medical errors, improve quality in general, and eliminate unnecessary costs. An obstacle to sharing records is the absence of a common identifier used by all of a patient's providers. This article draws lessons from a demonstration that tested a method to create unique person specific identification numbers that can increase the probability that patient medical records can be linked. PMID- 26650747 TI - Successful Strategies for Reducing Disparities in Quality of Care: Lessons From Dual-Eligible Special Needs Plans. AB - Identifying strategies to reduce health care disparities is a national priority. This study examines factors within higher performing Medicare Advantage dual eligible special needs plans (SNPs) that contribute to improved diabetic control. These structural and process elements include nonprofit status, interdisciplinary care teams, medication management, home visiting clinicians, and motivational interviewing. We suggest further research into the value of requiring all Medicare plans serving duals comply with standards for the SNP Model of Care. Finally, we recommend that all plans with dual and nondual members report scores separately to demonstrate the quality provided to the dual population. PMID- 26650748 TI - "They're Doing Something That Actually No One Else Can Do": A Qualitative Study of Peer Support and Primary Care Integration. AB - Peer support (PS) is a strategy for improving quality of care for people with chronic disease and is increasingly being integrated with primary care. We conducted semistructured qualitative interviews with 18 staff members from 4 practices that have integrated PS and primary care. From these interviews, we identified several benefits of PS and primary care integration as well as challenges to integrating and sustaining PS programs. We also identified key considerations and strategies for facilitating integration. Strategies for developing messaging to promote understanding of the unique role of peer supporters are discussed. PMID- 26650749 TI - The Role of Primary Care Practices in Advancing Population Health. AB - Improving population health requires the contribution of many entities including state and local governments, hospitals, community organizations, health centers, and private practices. Primary care practices have the potential to play a key role in improving population health. While sporadic, primary care practices engage in a spectrum of practice- and community-based population health activities. Community-based activities are largely driven by altruistic motivations of physicians and staff. Patient and disease registries and access to comprehensive patient data are critical to improving population health. Guidance is needed for practices to engage in population health initiatives and appropriate incentives to motivate practices to address population health issues. PMID- 26650750 TI - TROT Line: Live and Direct From the Republic of Texas. PMID- 26650751 TI - Push and stay factors affecting Irish medical student migration intentions. AB - BACKGROUND: A significant proportion of medical students in Ireland have demonstrated strong intentions to migrate following their graduation. Factors influencing these intentions are poorly understood. Our study aimed to investigate 'push' and 'stay' factors that may influence the migration plans of medical students. METHODS: Cross-sectional survey of 2273 medical students in Ireland using a mixed methods approach. Survey was completed by 2273 medical students, of which 263 provided free text data that are analysed in this paper. RESULTS: Identified push factors include negative perception regarding career opportunities, working conditions and lifestyle, while family was the only identified strong stay factor. Qualitative analysis of free text responses revealed themes that included training, career, personal and financial factors. CONCLUSION: This study has provided insight into the factors that influence medical student migration intentions. There is a strong need for all stakeholders to collectively discuss and engage in possible solutions. PMID- 26650752 TI - Therapeutic goals in patients with pheochromocytoma: a guide to perioperative management. AB - INTRODUCTION: Pheochromocytomas are rare neuroendocrine tumors of the adrenal medulla that may present with protean manifestations. Surgical resection is the mainstay of therapy and patients are at risk of significant hemodynamic and circulatory complications mainly attributable to catecholamine excess. The mainstay of medical therapy in order to optimize patients for surgery includes: alpha-blockers, beta-blockers, calcium channel blocker and other agents to achieve normal blood pressure, heart rate, as well as normal volume status. Understanding the pathophysiology of pheochromocytoma, the pharmacology of medications used, and recognizing postoperative complications will impact patient outcomes. CONCLUSION: A multidisciplinary team approach is best throughout the perioperative period to prevent potential complications that arise. The hospital physician, intensivist, anesthetist and cardiovascular specialist play a pivotal role in the management of patients with pheochromocytoma. In addition to the pharmacologic and volume recommendations, a multidisciplinary discussion allows for seamless implementation of an organized plan of care. PMID- 26650753 TI - The Long-Term Consumption of Ginseng Extract Reduces the Susceptibility of Intermediate-Aged Hearts to Acute Ischemia Reperfusion Injury. AB - BACKGROUND: A large number of experimental studies using young adult subjects have shown that ginseng (Panax ginseng C.A. Meyer) protects against ischemia heart disease. However, ginseng has not been explored for its anti-I/R effect and mechanism of action in the aged myocardium. The present study was designed to evaluate the effects of the long-term consumption of ginseng extract on myocardial I/R in an in vivo rat model and explore the potential underlying mechanism. METHODS AND RESULTS: Young (6-mo-old) and intermediate-aged (18-mo old) rats were gavaged with either standardized ginseng extract (RSE) at 80 mg/kg or vehicle for 90 days. The rats were sacrificed after LAD coronary artery ligation was performed to induce 30 min of ischemia, followed by 90 min of reperfusion. The myocardial infarct size was measured. Left ventricular function was evaluated using pressure-volume loops. The levels of survival, apoptotic and longevity protein expression were assessed through Western blot analysis. Myocardial pathology was detected through H&E or Masson's trichrome staining. We observed higher infarct expansion with impairment in the LV functional parameters, such as LVSP and LVEDP, in aged rats compared with young rats. Enhanced Akt phosphorylation and eNOS expression in RSE-treated aged hearts were accompanied with reduced infarct size, improved cardiac performance, and inducted survival signals. In contrast, p-Erk and caspase 7 were significantly downregulated in aged rats, suggesting that cardiomyocyte apoptosis was suppressed after RSE treatment. RSE also inhibited caspase-3/7 activation and decreased Bax/Bcl-2 ratio. Consistent with the results of apoptosis, Sirt1 and Sirt3 were significantly increased in the RSE-treated aged heart compared with vehicle-treated I/R, suggesting that the anti-aging effect was correlated with the anti-apoptotic activity of RSE. CONCLUSION: These findings suggest that the long-term consumption of ginseng extract reduced the susceptibility of intermediate-aged hearts to acute ischemia reperfusion injury in rats. These effects might be mediated through the activation of Akt/eNOS, suppression of Erk/caspase 7 and upregulation of Sirt1 and Sirt3 in intermediate-aged rats. PMID- 26650754 TI - Target the More Druggable Protein States in a Highly Dynamic Protein--Protein Interaction System. AB - The proteins of the Bcl-2 family play key roles in the regulation of programmed cell death by controlling the integrity of the outer mitochondrial membrane and the initiation of the apoptosis process. We performed extensive molecular dynamics simulations to investigate the conformational flexibility of the Bcl-xL protein in both the apo and holo (with Bad peptide and ABT-737) states. The accelerated molecular dynamics method implemented in Amber 14 was used to produce broader conformational sampling of 200 ns simulations. The pocket mining method based on the variational implicit-solvent model tracks the dynamic evolution of the ligand binding site with a druggability score characterizing the maximal affinity achievable by a drug-like molecule. Major movements were observed around the alpha3-helical domain and the loop region connecting the alpha1 and alpha2 helices, reshaping the ligand interaction in the BH3 binding groove. Starting with the apo crystal structure, which is recognized as "closed" and undruggable, the BH3 groove transitioned between the "open" and "closed" states during equilibrium simulation. Further analysis revealed a small percentage of the trajectory frames (~10%) with a moderate degree of druggability that mimic the ligand-bound states. The ability to attain and detect by computer simulation the most suitable conformational states for ligand binding in advance of compound synthesis and crystal structure solution is of immense value to the application and success of structure-based drug design. PMID- 26650756 TI - Editorial. PMID- 26650755 TI - Mycobacterium tuberculosis copper-regulated protein SocB is an intrinsically disordered protein that folds upon interaction with a synthetic phospholipid bilayer. AB - Multiple genes in Mycobacterium tuberculosis (Mtb) are regulated by copper including socAB (small orf induced by copper A and B), which is induced by copper and repressed by RicR (regulated in copper repressor). socA and socB encode hypothetical proteins of 61 and 54 amino acids, respectively. Here, we use biophysical and computational methods to evaluate the SocB structure. We find that SocB lacks evidence for secondary structure, with no thermal cooperative unfolding event, according to circular dichroism measurements. 2D NMR spectra similarly exhibit hallmarks of a disordered structural state, which is also supported by analyzing SocB diffusion. Altogether, these findings suggest that by itself SocB is intrinsically disordered. Interestingly, SocB interacts with a synthetic phospholipid bilayer and becomes helical, which suggests that it may be membrane-associated. PMID- 26650758 TI - Clinical, but Not Laboratory Features Are Predictive of Risk of Subsequent Development of Preeclampsia in Patients With Isolated Proteinuria After Midgestation. AB - OBJECTIVE: The present study aimed to investigate perinatal outcomes and to describe antenatal factors for development of preeclampsia (PE) in patients with isolated proteinuria in pregnancy. METHODS: This retrospective case control study consisted of patients with isolated proteinuria between 2009 and 2014. The patients were considered as gestational proteinuria (GP) (group 1, n: 35) if they remain normotensive. Patients who develop PE after onset of proteinuria were allocated into group 2 (n: 19). Perinatal outcomes of patients in each group were compared. Logistic regression analysis was performed to detect antenatal risk factors for PE. RESULTS: The rate of small for gestational age (SGA) fetuses was higher in patients with isolated proteinuria than control group. In the logistic regression model, maternal age and completed gestational weeks at onset of proteinuria decreased the risk of PE in multivariate analysis (OR: 0.849 (95% CI: 0.731-0.986), OR: 0.732 (95% CI: 0.594-0.902) respectively). Systolic BP at onset of proteinuria, however, was associated with an independently increased risk of PE (OR: 1.181 (95% CI: 1.046-1.333)). CONCLUSION: Maternal clinical characteristics, but not laboratory features may help to predict development of PE. PMID- 26650757 TI - (E)-Caryophyllene and alpha-Humulene: Aedes aegypti Oviposition Deterrents Elucidated by Gas Chromatography-Electrophysiological Assay of Commiphora leptophloeos Leaf Oil. AB - Aedes aegypti is responsible for the transmission of dengue, a disease that infects millions of people each year. Although essential oils are well recognized as sources of compounds with repellent and larvicidal activities against the dengue mosquito, much less is known about their oviposition deterrent effects. Commiphora leptophloeos, a tree native to South America, has important pharmacological properties, but the chemical profile and applicability of its essential oil in controlling the spread of the dengue mosquito have not been investigated. The aim of this study was to determine the composition of C. leptophloeos leaf oil and to evaluate its larvicidal and oviposition deterrent effects against A. aegypti. Fifty-five components of the essential oil were detected by gas chromatography (GC)-mass spectrometry, with alpha-phellandrene (26.3%), (E)-caryophyllene (18.0%) and beta-phellandrene (12.9%) identified as the major constituents. Bioassays showed that the oil exhibited strong oviposition deterrent effects against A. aegypti at concentrations between 25 and 100 ppm, and possessed good larvicidal activity (LC50 = 99.4 ppm). Analysis of the oil by GC coupled with electroantennographic detection established that seven constituents could trigger antennal depolarization in A. aegypti gravid females. Two of these components, namely (E)-caryophyllene and alpha-humulene, were present in substantial proportions in the oil, and oviposition deterrence assays confirmed that both were significantly active at concentrations equivalent to those present in the oil. It is concluded that these sesquiterpenes are responsible, at least in part, for the deterrent effect of the oil. The oviposition deterrent activity of the leaf oil of C. leptophloeos is one of the most potent reported so far, suggesting that it could represent an interesting alternative to synthetic insecticides. The results of this study highlight the importance of integrating chemical and electrophysiological methods for screening natural compounds for their potential in combating vectors of insect-borne diseases. PMID- 26650759 TI - MicroRNA Expression Profile during Aphid Feeding in Chrysanthemum (Chrysanthemum morifolium). AB - MicroRNAs (miRNAs) are important regulators of gene expression, affecting many biological processes. As yet, their roles in the response of chrysanthemum to aphid feeding have not been explored. Here, the identity and abundance of miRNAs induced by aphid infestation have been obtained using high-throughput Illumina sequencing platform. Three leaf small RNA libraries were generated, one from plants infested with the aphid Macrosiphoniella sanbourni (library A), one from plants with mock puncture treatment (library M), and the third from untreated control plants (library CK). A total of 7,944,797, 7,605,251 and 9,244,002 clean unique reads, ranging from 18 to 30 nucleotides (nt) in length, were obtained from library CK, A and M, respectively. As a result, 303 conserved miRNAs belonging to 276 miRNAs families and 234 potential novel miRNAs were detected in chrysanthemum leaf, out of which 80, 100 and 79 significantly differentially expressed miRNAs were identified in the comparison of CK-VS-A, CK-VS-M and M-VS A, respectively. Several of the differentially abundant miRNAs (in particular miR159a, miR160a, miR393a) may be associated with the plant's response to aphid infestation. PMID- 26650761 TI - Understanding Packing Patterns in Crystals by Analysis of Small Aggregates: A Case Study of CS2. AB - The molecular electrostatic potential (MESP) of the CS2 molecule, in conjunction with the cluster building algorithm, is utilized for generating trial geometries of medium-sized (CS2)n (n = 5-8) aggregates. MESP features suggest crossed, parallel stacked, T-shaped and L-shaped geometries for CS2 clusters. These initial geometries are subjected to geometry optimization employing second-order Moller-Plesset (MP2) theory, with correlation consistent aug-cc-pvDZ (aDZ) basis set. Single-point energies at MP2/aTZ levels are calculated for the estimation of binding energies at complete basis set (CBS) limit. The minimal nature of the reported structures is confirmed by doing vibrational frequency run at MP2/aDZ level of theory using the molecular tailoring approach (MTA). The two- and three body interaction energies are computed for clusters with n = 5, 6, and 7 and these are suggestive of change in contact patterns with increasing n. Such an analysis is found to offer a qualitative explanation of the packing pattern found in the crystal structure. PMID- 26650760 TI - Uncovering the Molecular Mechanism of Actions between Pharmaceuticals and Proteins on the AD Network. AB - This study begins with constructing the mini metabolic networks (MMNs) of beta amyloid (Abeta) and acetylcholine (ACh) which stimulate the Alzheimer's Disease (AD). Then we generate the AD network by incorporating MMNs of Abeta and ACh, and other MMNs of stimuli of AD. The panel of proteins contains 49 enzymes/receptors on the AD network which have the 3D-structure in PDB. The panel of drugs is formed by 5 AD drugs and 5 AD nutraceutical drugs, and 20 non-AD drugs. All of these complexes formed by these 30 drugs and 49 proteins are transformed into dyadic arrays. Utilizing the prior knowledge learned from the drug panel, we propose a statistical classification (dry-lab). According to the wet-lab for the complex of amiloride and insulin degrading enzyme, and the complex of amiloride and neutral endopeptidase, we are confident that this dry-lab is reliable. As the consequences of the dry-lab, we discover many interesting implications. Especially, we show that possible causes of Tacrine, donepezil, galantamine and huperzine A cannot improve the level of ACh which is against to their original design purpose but they still prevent AD to be worse as Abeta deposition appeared. On the other hand, we recommend Miglitol and Atenolol as the safe and potent drugs to improve the level of ACh before Abeta deposition appearing. Moreover, some nutrients such as NADH and Vitamin E should be controlled because they may harm health if being used in wrong way and wrong time. Anyway, the insights shown in this study are valuable to be developed further. PMID- 26650762 TI - Modeling of the Temperature Effect on Oxygen Absorption by Iron-Based Oxygen Scavengers. AB - A new engineering-oriented model for prediction of the effect of temperature on the kinetics of oxygen absorption by iron-based oxygen scavengers (IOSs) was developed. The model is based on the physicochemical mechanism of the O2 scavenging process by the active component of the IOS (iron powder). The conclusions of this study are: (1) the iron deposits formed on the iron particles are composed of 2 different layers: an inner layer of Fe3 O4 and an outer layer of FeOOH that vanishes with the depletion of oxygen. (2) The model considers the chemical processes in the heterogeneous closed system "Fe-H2 O-NaCl-O2 " and describes the kinetics of oxygen absorption by the powder, depending on the characteristics of the system. (3) The nonlinear ordinary differential equation (ODE) of the O2 absorption kinetics was derived and a simple approximate solution to this ODE was obtained theoretically that is similar to the empirical exponential formula published in the relevant literature. (4) The temperature dependence of the oxygen absorption rate is more complicated than that described by the Arrhenius equation. PMID- 26650764 TI - A missing ethical competency? A review of critical reflection in health promotion. AB - ISSUE ADDRESSED: There is increasing emphasis in the health promotion literature on the ethical imperative for the profession to move towards critical practice. A key challenge for health promotion is that critical practice appears both under developed and under-practiced. This is evident in the omission of critical reflection from Australian and international competencies for health promotion practitioners. METHODS: A narrative literature review was undertaken to explore the current use of critical reflection in health promotion. Critical reflection models relevant to health promotion were identified and critiqued. RESULTS: There was a dearth of literature on critical reflection within health promotion, despite recognition of its potential to support critical practice. The discipline of critical social work provided literature on the use, effect and outcome of critical reflection in practice. The interdisciplinary critical reflection model was identified as the model most applicable to health promotion. Underpinned by critical theory, this model emphasises both critical and ethical practice. CONCLUSIONS: Critical reflection is a core competency for health promotion practitioners to address the ethical imperative to move towards critical practice. There is a need to explore the application of a critical reflection model in health promotion to determine how it may support critical and ethical practice. So what? If health promotion is to meet its ethical responsibilities, then critical reflection needs to be articulated as a core health promotion competency and a model for its application in health promotion developed. PMID- 26650765 TI - Sports Psychiatry: Strategies for Life Balance and Peak Performanceby McDuff David R. , M.D. Washington, DC , American Psychiatric Publishing , 2012 , 288 pp., $59.00 (paper). PMID- 26650766 TI - The Mental Health Professional in Court: A Survival Guideby Gutheil Thomas G. , M.D., and Drogin Eric Y. , J.D., Ph.D. Washington DC , American Psychiatric Publishing , 2013 , 129 pp., $59.00 (paper). PMID- 26650769 TI - Correction. PMID- 26650771 TI - The Mouse Round-window Approach for Ototoxic Agent Delivery: A Rapid and Reliable Technique for Inducing Cochlear Cell Degeneration. AB - Investigators have utilized a wide array of animal models and investigative techniques to study the mammalian auditory system. Much of the basic research involving the cochlea and its associated neural pathways entails exposure of model cochleae to a variety of ototoxic agents. This allows investigators to study the effects of targeted damage to cochlear structures, and in some cases, the self-repair or regeneration of those structures. Various techniques exist for delivery of ototoxic agents to the cochlea. When selecting a particular technique, investigators must consider a number of factors, including the induction of inadvertent systemic toxicity, the amount of cochlear damage produced by the surgical procedure itself, the type of lesion desired, animal survivability, and reproducibility/reliability of results. Currently established techniques include parenteral injection, intra-peritoneal injection, trans tympanic injection, endolymphatic sac injection, and cochleostomy with perilymphatic perfusion. Each of these methods has been successfully utilized and is well described in the literature; yet, each has various shortcomings. Here, we present a technique for topical application of ototoxic agents directly to the round window niche. This technique is non-invasive to inner ear structures, produces rapid onset of reliably targeted lesions, avoids systemic toxicity, and allows for an intra-animal control (the contra-lateral ear). Results stemming from this approach have helped deeper understanding of auditory pathophysiology, cochlear cell degeneration, and regenerative capacity in response to an acute injury. Future investigations may use this method to conduct interventional studies involving gene therapy and stem cell transplantation to combat hearing loss. PMID- 26650772 TI - A Strategy to Reduce General Surgery Resident Attrition: A Resident's Perspective. PMID- 26650773 TI - The Relationship Between Hearing Aid Self-Efficacy and Hearing Aid Satisfaction. AB - PURPOSE: The purpose of this study was to investigate the relationship between self-efficacy for hearing aids (HAs) and satisfaction with HAs in a group of adult HA owners. METHOD: Forty-seven adults acquiring HAs (new and experienced owners) completed a demographic questionnaire, the Hearing Handicap Questionnaire (Gatehouse & Noble, 2004), and received an audiometric evaluation prior to HA fitting. Twelve weeks following the completion of the HA fitting, they completed the Measure of Audiologic Rehabilitation Self-Efficacy for Hearing Aids (Smith & West, 2006) and the Satisfaction with Amplification in Daily Life (Cox & Alexander, 1999) questionnaires. RESULTS: There were no significant differences between experienced and new HA owners in terms of self-efficacy or HA satisfaction. The majority of participants had adequate self-efficacy for basic HA handling and adjustment to HAs. Fewer participants had adequate self-efficacy for aided listening and advanced handling of HAs. HA self-efficacy was related to HA satisfaction in three domains: positive effect and negative features of HAs and service and cost. CONCLUSION: Many HA owners do not have adequate self efficacy in important HA-related domains. Clinical intervention to improve self efficacy for HAs may help improve HA satisfaction. PMID- 26650774 TI - Videography supported adhesion, and proliferation behavior of MG-63 osteoblastic cells on 2.5D titania nanotube matrices. AB - Human osteosarcoma cells MG-63 were cultured on anodically etched titania nanotubes (TiO2 NT), with diameters ranging from 40-100 nm, to study the correlations between cell proliferation and adhesion on the 2.5 dimensional (2.5D) extracellular matrix (ECM). Unlike other reports, mostly based on mouse stem cells, and 2D cell culture, our studies indicate that the 2.5D NT promote higher proliferation and activity, but less 2D adhesion. Proliferation of the MG 63 cells was significantly higher in the NTs, the best being the 70 nm diameter sample, compared to planar titania (control). This is consistent with previous studies. However, cellular adhesion was stronger on TiO2 NT with increasing diameter, and highest on the control as obtained from shear stress measurement, paxilin imaging, and western blot measurements probing focal adhesion kinase, p130 CAS, and extracellular-regulated kinase, in addition to cell morphology imaging by fluorescence microscopy. We provide direct videography of cell migration, and cell speed data indicating faster filopodial activity on the TiO2 NT surfaces having lower adhesion. This evidence was not available previously. The NT matrices promote cells with smaller surface area, because of less 2D stretching. In contrast, on comparatively planar 2D-like surfaces uniaxial stretching of the cell body with strong anchoring of the filopodia, resulted in larger cell surface area, and demonstrated stronger adhesion. The difference in the results, with those previously published, may be generally attributed to, among others, the use of mouse stem cells (human osteosarcoma used here), and unannealed as-grown TiO2 NTs used previously (annealed ECMs used here). PMID- 26650775 TI - CADRE-SS, an in Silico Tool for Predicting Skin Sensitization Potential Based on Modeling of Molecular Interactions. AB - Using computer models to accurately predict toxicity outcomes is considered to be a major challenge. However, state-of-the-art computational chemistry techniques can now be incorporated in predictive models, supported by advances in mechanistic toxicology and the exponential growth of computing resources witnessed over the past decade. The CADRE (Computer-Aided Discovery and REdesign) platform relies on quantum-mechanical modeling of molecular interactions that represent key biochemical triggers in toxicity pathways. Here, we present an external validation exercise for CADRE-SS, a variant developed to predict the skin sensitization potential of commercial chemicals. CADRE-SS is a hybrid model that evaluates skin permeability using Monte Carlo simulations, assigns reactive centers in a molecule and possible biotransformations via expert rules, and determines reactivity with skin proteins via quantum-mechanical modeling. The results were promising with an overall very good concordance of 93% between experimental and predicted values. Comparison to performance metrics yielded by other tools available for this endpoint suggests that CADRE-SS offers distinct advantages for first-round screenings of chemicals and could be used as an in silico alternative to animal tests where permissible by legislative programs. PMID- 26650776 TI - Tuning Cysteine Reactivity and Sulfenic Acid Stability by Protein Microenvironment in Glyceraldehyde-3-Phosphate Dehydrogenases of Arabidopsis thaliana. AB - AIMS: Cysteines and H2O2 are fundamental players in redox signaling. Cysteine thiol deprotonation favors the reaction with H2O2 that generates sulfenic acids with dual electrophilic/nucleophilic nature. The protein microenvironment surrounding the target cysteine is believed to control whether sulfenic acid can be reversibly regulated by disulfide formation or irreversibly oxidized to sulfinates/sulfonates. In this study, we present experimental oxidation kinetics and a quantum mechanical/molecular mechanical (QM/MM) investigation to elucidate the reaction of H2O2 with glycolytic and photosynthetic glyceraldehyde-3 phosphate dehydrogenase from Arabidopsis thaliana (cytoplasmic AtGAPC1 and chloroplastic AtGAPA, respectively). RESULTS: Although AtGAPC1 and AtGAPA have almost identical 3D structure and similar acidity of their catalytic Cys149, AtGAPC1 is more sensitive to H2O2 and prone to irreversible oxidation than AtGAPA. As a result, sulfenic acid is more stable in AtGAPA. INNOVATION: Based on crystallographic structures of AtGAPC1 and AtGAPA, the reaction potential energy surface for Cys149 oxidation by H2O2 was calculated by QM. In both enzymes, sulfenic acid formation was characterized by a lower energy barrier than sulfinate formation, and sulfonate formation was prevented by very high energy barriers. Activation energies for both oxidation steps were lower in AtGAPC1 than AtGAPA, supporting the higher propensity of AtGAPC1 toward irreversible oxidation. CONCLUSIONS: QM/MM calculations coupled to fingerprinting analyses revealed that two Arg of AtGAPA (substituted by Gly and Val in AtGAPC1), located at 8-15 A distance from Cys149, are the major factors responsible for sulfenic acid stability, underpinning the importance of long-distance polar interactions in tuning sulfenic acid stability in native protein microenvironments. PMID- 26650777 TI - Genetic heterogeneity in synchronous colorectal cancers impacts genotyping approaches and therapeutic strategies. AB - Synchronous colorectal carcinomas (sCRC) are clinically challenging neoplasms. Although the epidemiological characteristics are quite well established, their biological basis is still poorly understood. Hence, we performed comprehensive molecular profiling of 23 sCRC cases comprising 50 synchronous primary tumors, 5 metastases, and corresponding normal tissue by targeted deep sequencing of 30 CRC related genes, microsatellite analysis and analysis for methylated MLH1. We identified a striking inter- and intratumoral genetic heterogeneity of sCRC. Twenty (87%) cases showed genetic heterogeneity leaving only three cases with tumors that had an identical genetic make-up. Intertumoral heterogeneity was frequently observed for clinically actionable genes, including KRAS. Specifically, 44% of the cases harbored tumors of which at least one was KRAS mutated and the other KRAS wildtype. Moreover, 48% of the cases had at least double, sometimes even triple or quadruple mutations in KRAS, APC, TP53, PIK3CA, and TGFBR2, most of them being subclonal events. Lastly, we detected four cases (17%) with microsatellite instable (MSI) tumors with one case harboring one MSI- and a distinct microsatellite stable carcinoma. Our data demonstrate a striking genetic heterogeneity not only between different sCRC of a single case but also within a single tumor. These results contribute to the biological understanding of sCRC and directly impact genotyping strategies and oncological decision making. Testing one tumor or a single metastasis may not suffice in the sCRC setting as clinically relevant and tumor-specific genetic information may be left undetected compromising optimal oncological therapy. (c) 2015 Wiley Periodicals, Inc. PMID- 26650779 TI - Long-term Outcomes After Radiosurgery for Temporal Bone Paragangliomas. AB - OBJECTIVES: To determine the long-term outcome after stereotactic radiosurgery (SRS) for temporal bone paragangliomas. MATERIALS AND METHODS: We retrospectively reviewed the medical records of 11 patients with temporal bone paragangliomas (10 patients with a glomus jugulare tumor and 1 patient with a glomus tympanicum tumor) treated between January 1997 and July 2012 at the University of Florida with SRS to a median dose of 15 Gy in 1 fraction. Ten previously unirradiated patients received SRS as did 1 patient who received prior fractionated radiotherapy (FRT) and then received salvage SRS for a local recurrence. The major outcome endpoint was local control, meaning no further growth or shrinkage on follow-up computed tomography or magnetic resonance imaging scans. RESULTS: The median follow-up time was 5.3 years. Two patients developed a local recurrence after SRS, including the patient who received salvage SRS after prior FRT. The overall local control rates at 5 and 10 years were both 81%. The cause specific survival rates at 5 and 10 years were both 88%. The distant metastasis free survival rates at 5 and 10 years were both 100%. The overall survival rates at 5 and 10 years were both 78%. There were no severe complications. CONCLUSIONS: SRS for benign head and neck paragangliomas is a safe and efficacious treatment associated with minimal morbidity. SRS is suitable for patients with skull base tumors <3 cm when FRT is logistically unsuitable. Surgery is reserved for patients in good health whose risk of associated morbidity is low. Observation is a reasonable option for asymptomatic patients with a limited life expectancy. PMID- 26650780 TI - Early Results From the Implementation of a Lung Cancer Screening Program: The Beaumont Health System Experience. AB - PURPOSE: In 2010, a new study published by the National Lung Screening Trial showed a 20% reduction in mortality for those patients screened with low-dose computed topography (CT) versus x-ray. Recently, the Centers of Medicare and Medicaid have agreed to cover this service for those patients who meet the screening criteria. We compare the outcomes and costs associated with developing and implementing a lung cancer screening program. MATERIALS AND METHODS: One thousand sixty-five patients were screened from January 2014 to December 2014. These patients were screened on a low-dose CT screening protocol throughout Beaumont Health System. The American College of Radiology Lung Imaging Reporting and Data System (Lung-RADS) were used to assign the score for each patient. Screening eligibility criteria were based on the National Comprehensive Cancer Network guidelines. Downstream activity and revenue was determined after initial low-dose CT screening. RESULTS: At 1 year, 20 patients (1.6%) were diagnosed with lung cancer and another 15 patients were diagnosed with another form of cancer after screening. The median age, packs per day, and pack years smoked for all patients was 63, 1.0, and 39.0 years, respectively. Lung-RADS scores for all patients was 18% (1), 24.1% (2), 6.3% (3), and 5.4% (4). The net revenue for all activity after screening was $3.2 million. CONCLUSIONS: The establishment of a low-dose CT lung cancer screening program improved the ability to screen patients as demonstrated by the number of patients screened and those diagnosed with a malignancy. These findings were also consistent with the findings from the National Lung Screening Trial study. PMID- 26650781 TI - Indirect Immunofluorescence on Frozen Sections of Mouse Mammary Gland. AB - Indirect immunofluorescence is used to detect and locate proteins of interest in a tissue. The protocol presented here describes a complete and simple method for the immune detection of proteins, the mouse lactating mammary gland being taken as an example. A protocol for the preparation of the tissue samples, especially concerning the dissection of mouse mammary gland, tissue fixation and frozen tissue sectioning, are detailed. A standard protocol to perform indirect immunofluorescence, including an optional antigen retrieval step, is also presented. The observation of the labeled tissue sections as well as image acquisition and post-treatments are also stated. This procedure gives a full overview, from the collection of animal tissue to the cellular localization of a protein. Although this general method can be applied to other tissue samples, it should be adapted to each tissue/primary antibody couple studied. PMID- 26650778 TI - Electrospun Fibers for Spinal Cord Injury Research and Regeneration. AB - Electrospinning is the process by which a scaffold containing micrometer and nanometer diameter fibers are drawn from a polymer solution or melt using a large voltage gradient between a polymer emitting source and a grounded collector. Ramakrishna and colleagues first investigated electrospun fibers for neural applications in 2004. After this initial study, electrospun fibers are increasingly investigated for neural tissue engineering applications. Electrospun fibers robustly support axonal regeneration within in vivo rodent models of spinal cord injury. These findings suggest the possibility of their eventual use within patients. Indeed, both spinal cord and peripheral nervous system regeneration research over the last several years shows that physical guidance cues induce recovery of limb, respiration, or bladder control in rodent models. Electrospun fibers may be an alternative to the peripheral nerve graft (PNG), because PNG autografts injure the patient and are limited in supply, and allografts risk host rejection. In addition, electrospun fibers can be engineered easily to confront new therapeutic challenges. Fibers can be modified to release therapies locally or can be physically modified to direct neural stem cell differentiation. This review summarizes the major findings and trends in the last decade of research, with a particular focus on spinal cord injury. This review also demonstrates how electrospun fibers can be used to study the central nervous system in vitro. PMID- 26650791 TI - Ion-Current-Based Temporal Proteomic Profiling of Influenza-A-Virus-Infected Mouse Lungs Revealed Underlying Mechanisms of Altered Integrity of the Lung Microvascular Barrier. AB - Investigation of influenza-A-virus (IAV)-infected lung proteomes will greatly promote our understanding on the virus-host crosstalk. Using a detergent-cocktail extraction and digestion procedure and a reproducible ion-current-based method, we performed the first comprehensive temporal analysis of mouse IAV infection. Mouse lung tissues at three time points post-inoculation were compared with controls (n = 4/group), and >1600 proteins were quantified without missing value in any animal. Significantly changed proteins were identified at 4 days (n = 144), 7 days (n = 695), and 10 days (n = 396) after infection, with low false altered protein rates (1.73-8.39%). Functional annotation revealed several key biological processes involved in the systemic host responses. Intriguingly, decreased levels of several cell junction proteins as well as increased levels of tissue metalloproteinase MMP9 were observed, reflecting the IAV-induced structural breakdown of lung epithelial barrier. Supporting evidence of MMP9 activation came from immunoassays examining the abundance and phosphorylation states of all MAPKs and several relevant molecules. Importantly, IAV-induced MMP gelatinase expression was suggested to be specific to MMP9, and p38 MAPK may contribute predominantly to MMP9 elevation. These findings help to resolve the long-lasting debate regarding the signaling pathways of IAV-induced MMP9 expression and shed light on the molecular mechanisms underlying pulmonary capillary-alveolar leak syndrome that can occur during influenza infection. PMID- 26650792 TI - Effects of Effortful Swallow on Cardiac Autonomic Regulation. AB - Swallowing-induced changes in heart rate have been recently reported. However, it is not apparent the responses of heart rate variability (HRV) elicited by effortful swallow maneuver. We investigated the acute effects of effortful swallowing maneuver on HRV. This study was performed on 34 healthy women between 18 and 35 years old. We assessed heart rate variability in the time (SDNN, RMSSD, and pNN50) and frequency (HF, LF, and LF/HF ratio) domains and, visual analysis through the Poincare plot. The subjects remained at rest for 5 min during spontaneous swallowing and then performed effortful swallowing for 5 min. HRV was analyzed during spontaneous and effortful swallowing. We found no significant differences for SDNN, pNN50, RMSSD, HF in absolute units (ms(2)). There is a trend for increase of LF in absolute (p = 0.05) and normalized (p = 0.08) units during effortful swallowing. HF in normalized units reduced (p = 0.02) during effortful swallowing and LF/HF ratio (p = 0.03) increased during effortful swallowing. In conclusion effortful swallow maneuver in healthy women increased sympathetic cardiac modulation, indicating a cardiac overload. PMID- 26650793 TI - Quantifying aflatoxins in peanuts using fluorescence spectroscopy coupled with multi-way methods: Resurrecting second-order advantage in excitation-emission matrices with rank overlap problem. AB - A rapid, simple and inexpensive method using fluorescence spectroscopy coupled with multi-way methods for the determination of aflatoxins B1 and B2 in peanuts has been developed. In this method, aflatoxins are extracted with a mixture of water and methanol (90:10), and then monitored by fluorescence spectroscopy producing EEMs. Although the combination of EEMs and multi-way methods is commonly used to determine analytes in complex chemical systems with unknown interference(s), rank overlap problem in excitation and emission profiles may restrain the application of this strategy. If there is rank overlap in one mode, there are several three-way algorithms such as PARAFAC under some constraints that can resolve this kind of data successfully. However, the analysis of EEM data is impossible when some species have rank overlap in both modes because the information of the data matrix is equivalent to a zero-order data for that species, which is the case in our study. Aflatoxins B1 and B2 have the same shape of spectral profiles in both excitation and emission modes and we propose creating a third order data for each sample using solvent as a new additional selectivity mode. This third order data, in turn, converted to the second order data by augmentation, a fact which resurrects the second order advantage in original EEMs. The three-way data is constructed by stacking augmented data in the third way, and then analyzed by two powerful second order calibration methods (BLLS-RBL and PARAFAC) to quantify the analytes in four kinds of peanut samples. The results of both methods are in good agreement and reasonable recoveries are obtained. PMID- 26650794 TI - A 'Plug and Play' Method to Create Water-dispersible Nanoassemblies Containing an Amphiphilic Polymer, Organic Dyes and Upconverting Nanoparticles. AB - In this protocol, we first describe a procedure to synthesize lanthanide doped upconverting nanoparticles (UCNPs). We then demonstrate how to generate amphiphilic polymers in situ, and describe a protocol to encapsulate the prepared UCNPs and different organic dye molecules (porphyrins and diarylethenes) using polymer shells to form stable water-dispersible nanoassemblies. The nanoassembly samples containing both the UCNPs and the diarylethene organic dyes have interesting photochemical and photophysical properties. Upon 365 nm UV irradiation, the diarylethene group undergoes a visual color change. When the samples are irradiated with visible light of another specific wavelength, the color fades and the samples return to the initial colorless state. The samples also emit visible light from the UCNPs upon irradiation with 980 nm near-infrared light. The emission intensity of the samples can be tuned through alternate irradiation with UV and visible light. Modulation of fluorescence can be performed for many cycles without observable degradation of the samples. This versatile encapsulation procedure allows for the transfer of hydrophobic molecules and nanoparticles from an organic solvent to an aqueous medium. The polymer helps to maintain a lipid-like microenvironment for the organic molecules to aid in preservation of their photochemical behavior in water. Thus this method is ideal to prepare water-dispersible photoresponsive systems. The use of near infrared light to activate upconverting nanoparticles allows for lower energy light to be used to activate photoreactions instead of more harmful ultraviolet light. PMID- 26650795 TI - Antihypertensive and cardioprotective effects of Cerebralcare granule(r) on spontaneously hypertensive rats from the perspective of the gaseous triumvirate NO-CO-H2S system. AB - Cerebralcare granule((r)) (CG) has been reported to have hypotensive effect. However, several pathways involved in the mechanism of hypotension are still unclear. This study was designed to verify the antihypertensive effect of CG and to characterize its mechanism of action, especially from the perspective of gasotrasmmiter NO/cGMP, CO/HO and H2S/CSE systems. By using the widely used in vitro model of rat isolated thoracic aortic rings, the vasorelaxant effect of CG were studied. Furthermore, we assessed the chronic hypotensive effect of CG on spontaneously hypertensive rats (SHRs) and further to explore the potential mechanisms of its antihypertensive activity. Data in the present study demonstrated that oral treatment with CG could induce a potent antihypertensive effect. CG could reduce the intima-media thickness (IMT) of thoracic aorta significantly and increase the serum NO and H2S levels. In addition, the present results indicated that CG played a critical protective role against pressure overload-induced cardiac hypertrophy. CG not only inhibited the development of cardiac hypertrophy but also improved ventricular function. In vitro, the results showed that CG induced relaxation in rat aortic rings through an endothelium dependent pathway mediated by NO/cGMP, CO/HO and H2S/CSE systems. Taken together, the present study demonstrated that CG could induce a potent antihypertensive effect that was partly due to the improvement of endothelial function. Also CG played a critical protective role against pressure overload-induced cardiac hypertrophy. In addition, CG could induce relaxation in rat aortic rings. PMID- 26650796 TI - Acute exposure of mercury chloride stimulates the tissue regeneration program and reactive oxygen species production in the Drosophila midgut. AB - We used Drosophila as an animal model to study the digestive tract in response to the exposure of inorganic mercury (HgCl2). We found that after oral administration, mercury was mainly sequestered within the midgut. This resulted in increased cell death, which in turn stimulated the tissue regeneration program, including accelerated proliferation and differentiation of the intestinal stem cells (ISCs). We further demonstrated that these injuries correlate closely with the excessive production of the reactive oxygen species (ROS), as vitamin E, an antioxidant reagent, efficiently suppressed the HgCl2 induced phenotypes of midgut and improved the viability. We propose that the Drosophila midgut could serve as a suitable model to study the treatment of acute hydrargyrism on the digestive systems. PMID- 26650797 TI - Total saponins isolated from Radix et Rhizoma Leonticis suppresses tumor cells growth by regulation of PI3K/Akt/mTOR and p38 MAPK pathways. AB - Both PI3K/AKT/mTOR and mitogen activated protein kinase (MAPK) signaling cascades played an important role in tumorigenesis, a more complete understanding of these signaling pathways allowed the development of new therapeutic strategies. Total saponins isolated from Radix et Rhizoma Leonticis (RLTS) was recognized with anticancer properties. In a murine hepatocellular carcinoma H22 cell-bearing mouse model, RLTS exhibited significant inhibitory effect on tumor growth. Here, we investigated the role of RLTS on the PI3K/AKT/mTOR signaling pathway and MAPK pathways in liver and lung cancer cells. Results obtained showed RLTS inhibited cell proliferation and induced cell apoptosis in vitro, which attributed to the inhibition on the activation of PI3K/AKT/mTOR cascade and its related signaling molecules, such as activated VEGFR and NF-kappaB, and activation of p38 MAPK in tumor cells. Additional, RLTS inhibited cell migration and downregulated proteins that mediated metastasis including CXCR4, MMP2 and MMP9. Overall, these findings suggested that RLTS interfered with multiple signaling cascades involved in tumorigenesis and had potential in cancer therapy. PMID- 26650798 TI - Inhalation exposure or body burden? Better way of estimating risk--An application of PBPK model. AB - We aim to establish a new way for estimating the risk from internal dose or body burden due to exposure of benzene in human subject utilizing physiologically based pharmacokinetic (PBPK) model. We also intend to verify its applicability on human subjects exposed to different levels of benzene. We estimated personal inhalation exposure of benzene for two occupational groups namely petrol pump workers and car drivers with respect to a control group, only environmentally exposed. Benzene in personal air was pre-concentrated on charcoal followed by chemical desorption and analysis by gas chromatography equipped with flame ionization detector (GC-FID). We selected urinary trans,trans-muconic acid (t,t MA) as biomarker of benzene exposure and measured its concentration using solid phase extraction followed by high performance liquid chromatography (HPLC). Our estimated inhalation exposure of benzene was 137.5, 97.9 and 38.7 MUg/m(3) for petrol pump workers, car drivers and environmentally exposed control groups respectively which resulted in urinary t,t-MA levels of 145.4+/-55.3, 112.6+/ 63.5 and 60.0+/-34.9 MUg g(-1) of creatinine, for the groups in the same order. We deduced a derivation for estimation of body burden from urinary metabolite concentration using PBPK model. Estimation of the internal dose or body burden of benzene in human subject has been made for the first time by the measurement of t,t-MA as a urinary metabolite using physiologically based pharmacokinetic (PBPK) model as a tool. The weight adjusted total body burden of benzene was estimated to be 17.6, 11.1 and 5.0 MUg kg(-1) of body weight for petrol pump workers, drivers and the environmentally exposed control group, respectively using this method. We computed the carcinogenic risk using both the estimated internal benzene body burden and external exposure values using conventional method. Our study result shows that internal dose or body burden is not proportional to level of exposure rather have a non-linear relationship. At a higher exposure level such as for occupational exposure of petrol pump workers and drivers, the conventionally estimated risk is higher than risk estimated from internal body burden. Likewise, for environmental exposure the conventional risk estimation predict lower level than estimated in our study. This emphasizes the importance of body burden and to consider it as a key parameter while estimating health risk at varying level of exposure. PMID- 26650799 TI - Transcriptome profiling and pathway analysis of hepatotoxicity induced by tris (2 ethylhexyl) trimellitate (TOTM) in mice. AB - Tris (2-ethylhexyl) trimellitate (TOTM) is commonly used as an alternative plasticizer for medical devices. But very little information was available on its biological effects. In this study, we investigated toxicity effects of TOTM on hepatic differential gene expression analyzed by using high-throughput sequencing analysis for over-represented functions and phenotypically anchored to complementary histopathologic, and biochemical data in the liver of mice. Among 1668 candidate genes, 694 genes were up-regulated and 974 genes were down regulated after TOTM exposure. Using Gene Ontology analysis, TOTM affected three processes: the cell cycle, metabolic process and oxidative activity. Furthermore, 11 key genes involved in the above processes were validated by real time PCR. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that these genes were involved in the cell cycle pathway, lipid metabolism and oxidative process. It revealed the transcriptome gene expression response to TOTM exposure in mouse, and these data could contribute to provide a clearer understanding of the molecular mechanisms of TOTM-induced hepatotoxicity in human. PMID- 26650800 TI - Magnesium lithospermate B acts against dextran sodiumsulfate-induced ulcerative colitis by inhibiting activation of the NRLP3/ASC/Caspase-1 pathway. AB - This study aimed to observe the therapeutic effects of magnesium lithospermate B on acute and chronic colitis induced by dextran sodiumsulfate (DSS) and the role of inflammasome complex (NOD-like receptor protein, NLRP; apoptosis-associated speck-like protein containing, ASC; caspase-1). Establishment of acute and chronic colitis models were by using 5% DSS oral administration in BALB/C male mice. Magnesium lithospermate B (240 mg/kg body weight) was given by subcutaneous injection. Samples were collected for biomarker assay, histological examination, immunohistochemical evaluation and western blot. There was obvious increase in TNF-alpha level and NLPR3, ASC, and caspase-1 expressions in acute and chronic colitis groups compared with the normal control. Significant decrease of the tumor necrosis factor-alpha level and the expressions of NLPR3, ASC, and caspase 1 were observed after treatment with magnesium lithospermate B. This study showed that magnesium lithospermate B could be used to treat acute and chronic colitis by inhibiting the activation of the NLRP3/ASC/Caspase-1 pathway. PMID- 26650801 TI - Ethylene bisdithiocarbamate pesticides Maneb and Mancozeb cause metal overload in human colon cells. AB - Previous studies in our laboratory have shown that ethylene bisdithiocarbamate (EBDC) fungicides Maneb and Mancozeb are equipotent gastrointestinal toxicants that produce cell loss and metal accumulation within HT-29 and Caco2 colon cells. Nabam, MnCl2, CuCl2 and ZnCl2 exposure produced no loss of viability up to 200 MUM and increases in metal levels were noted but not to the same extent as Maneb and Mancozeb. EBDC exposure caused increases in copper levels (20-200 MUM). Maneb and Mancozeb treatment also caused increases in manganese and zinc concentrations (20-200 MUM). Nabam plus MnCl2 and Nabam and MnCl2 plus ZnCl2 caused decreases in viability and increases in metal levels comparable to Maneb and Mancozeb. Decreases in the ratio of reduced glutathione to glutathione disulfide were observed with Maneb and Mancozeb (20-200 MUM). Maneb and Mancozeb treatment results in intracellular metal accumulation leading to the oxidative stress. The metal moiety and the organic portion of EBDCs contribute to toxicity. PMID- 26650802 TI - Transcranial sonography in movement disorders: an interesting tool for diagnostic perspectives. AB - Transcranial sonography has become an important tool for the diagnosis of various movement disorders. In most patients with idiopathic Parkinson disease, a markedly hyperechogenic substantia nigra (SN) was detected on at least one side. We have highlighted the sonographic features that might help the differential diagnosis of PD and other movement disorders. Our investigation involved 30 patients (age 45-85 years) with idiopathic Parkinson disease, 2 multiple system atrophy, 3 progressive supranuclear palsy and 2 patients with restless legs syndrome. In accordance with several previous studies, we detected hyperechogenicity of the SN by TCS in 90% of patients with idiopathic Parkinson disease. Subjects with a marked severity disease had a larger extent of the hyperechogenic SN signal. All progressive supranuclear palsy patients had an enlarged third ventricle and, in two cases, we observed the presence of hyperechoic areas in the lentiform nucleus. This last ultrasonographic feature was also seen in our patients with multiple system atrophy. TCS abnormalities of the SN, midbrain raphe and basal ganglia are characteristics of several movement and affective disorders. These features are less easily detected by other techniques, such as CT and MRI, which enable the exclusion of structural lesions, such as tumours and multi-infarct disease, because the physical principle differs from other imaging methods. PMID- 26650804 TI - Introduction to Special Issue: Adoptees' Ethnic Identity Within Family and Social Contexts. AB - This special issue focuses on the construction of ethnic identity among international transracial adoptees (ITRAs) in the context of their families and community. These studies represent an emerging focus on identity development in families where parents, as members of the dominant culture, face the task of helping children who are members of minority groups, develop a positive identity. Because the process of identity formation is developmental, the six articles study explore identity from middle childhood through emerging adulthood and feature diverse ITRAs at different ages and adopted into the United States and Italy, as well as different sample sizes and methodologies, including two community-based interventions. PMID- 26650803 TI - Analysis of catechol-O-methyltransferase gene mutation and identification of new pathogenic gene for paroxysmal kinesigenic dyskinesia. AB - We aimed to analyze the mutation site and frequency of catechol-O methyltransferase (COMT) gene, to explore the relationship between COMT genotype and phenotype, and to find new pathogenic genes for paroxysmal kinesigenic dyskinesia (PKD). PKD patients who were treated from December 2011 to January 2014 were selected and subjected to genetic testing in the exon region of COMT. Two patients and one intrafamilial healthy control were subjected to exome sequencing using whole exome capture in combination with high-throughput sequencing to find candidate pathogenic gene sites. The results were verified by Sanger sequencing. A total of 11 familial PKD patients from 4 families and 9 sporadic patients without family history were included. Pathogenic c.634dupC(p.P220fsX7) mutation of COMT gene was found in 7 familial PKD patients and3 sporadic patients. Mutated COMT gene carriers suffered from PKD earlier (average age of onset: 11.61 +/- 2.33 vs 16.21 +/- 2.58, P = 0.001) with symmetric symptoms in most cases, while the mutation-negative group only showed unilateral symptoms (P = 0.001). The mutation-positive group also had more daily attacks (P = 0.038). Carbamazepine worked for all mutation-positive patients (10/10, 100%), but only for a part of mutation-negative patients (3/10, 30.0%). About 90000 single nucleotide polymorphisms and 2000 insertion-deletion polymorphisms were detected in each of the three samples. c.737C -> T(p.T246 M) mutation of POC1B gene was a new pathogenic site for a selected family. COMT gene mutation, which was the pathogenesis of most familial PKD patients and a part of sporadic patients, predicted the response to carbamazepine. POC1B may be a novel pathogenic gene for PKD. PMID- 26650805 TI - "American" or "Multiethnic"? Family Ethnic Identity Among Transracial Adoptive Families, Ethnic-Racial Socialization, and Children's Self-Perception. AB - Drawing on a model of ethnic-racial socialization (E-RS; Pinderhughes, 2013), this study examined hypothesized relations among parents' role variables (family ethnic identity and acknowledgment of cultural and racial differences), cultural socialization (CS) behaviors, and children's self-perceptions (ethnic self-label and feelings about self-label). The sample comprised 44 U.S.-based parents and their daughters ages 6 to 9 who were adopted from China. Correlation analyses revealed that parents' role variables and CS behaviors were related, and children's ethnic self-label was related to family ethnic identity and CS behaviors. Qualitative analyses point to complexities in children's ethnic identity and between family and children's ethnic identities. Together, these findings provide support for the theoretical model and suggest that although ethnic identity among international transracial adoptees (ITRAs) has similarities to that of nonadopted ethnic minority children, their internal experiences are more complex. PMID- 26650806 TI - Culture Camp, Ethnic Identity, and Adoption Socialization for Korean Adoptees: A Pretest and Posttest Study. AB - This study explores the impact of racial-ethnic socialization on adopted South Korean children and adolescents who attended a sleepaway Korean culture camp for one week. This camp provided racial-ethnic socialization experiences via exposure to camp counselors, staff, and teachers who were Korean Americans, Korean nationals, and Korean adult adoptees, and exposure to cultural activities and discussions. Using a pretest-posttest design to control for the lack of a comparison group (McCall & Green, ), 75 Korean adoptee children and adolescents (mean age = 12.96) completed both the Children's Depression Inventory (CDI) and the Revised Children's Manifest Anxiety Scale (RCMAS) surveys at pretest and posttest, and completed the Multigroup Ethnic Identity Measure (MEIM) at posttest. Results indicated that adoptees reported lower levels of depression at the end of camp than at the beginning of camp, but little variance could be attributed to ethnic identity at posttest. The results of this study suggest that scholars investigate the possibility that adoptee culture camps may provide an adoption socialization experience that may be more salient for adoptees than the racial-ethnic socialization that was intended. Implications for research and practice are discussed. PMID- 26650807 TI - Ethnic Identity and Psychological Well-Being of International Transracial Adoptees: A Curvilinear Relationship. AB - Research in general has shown a beneficial effect of ethnic identity on adoptees' psychological well-being. However, studies also indicate that overemphasis on birth culture and racial/ethnic differences may negatively impact adoptees' overall adjustment. Using Rojewski's () and Brodzinsky's () propositions of a balanced approach to adoption and culture issues, this study examines the curvilinear relationship between ethnic identity and psychological well-being of international adoptees (i.e., psychological well-being will be high when ethnic identity is moderate instead of either low or high). Using data from a study on identity development and psychological well-being in international adoptees, the hypothesized relationship was examined among 100 internationally adopted Asian adolescents and young adults placed with White parents in the United States. Results indicated that a moderate level of ethnic identity was associated with positive esteem, whereas low and high levels of ethnic identity were related to low self-esteem. Implications for practice and research are discussed. PMID- 26650808 TI - Korean Adoptee Identity: Adoptive and Ethnic Identity Profiles of Adopted Korean Americans. AB - Adopted Korean adolescents face the task of grappling with their identity as Koreans and coming to terms with their adoptive status. In order to explore these dual identities, the authors conducted a person-centered study of the identity profiles of 189 adopted Korean American adolescents. Using cluster analytic procedures, the study examined patterns of commitment to ethnic and adoptive identities, revealing six conceptually unique identity clusters. Analyzing the association between these identity profiles and psychological adjustment, the study found that the identity profiles were undifferentiated with respect to behavioral development and risk behaviors. However, group differences were found on life satisfaction, school adjustment, and family functioning. Results confirm the importance of considering the collective impact of multiple social identities on a variety of outcomes. The social implications of the results are discussed. PMID- 26650809 TI - Ethnic Identity, Bicultural Identity Integration, and Psychological Well-Being Among Transracial Adoptees: A Longitudinal Study. AB - The ethnic identity development plays a crucial role in adolescence and emerging adulthood and may be more complex for adoptees who do not share their ethnic identity with their adoptive families. Evidence from the studies was mixed, with strong ethnic identity not always found to be indicative of improved psychological adjustment. Recently research carried out on ethnic minorities has highlighted that the relation between ethnic identity and well-being could be influenced by Bicultural Identity Integration (BII) (Benet-Martinez et al., 2002): It reflects how individuals who experience more than one culture organize and combine their dual cultural backgrounds. These results are consistent also among adoptees (Manzi, Ferrari, Rosnati, & Benet-Martinez, 2013) but need to be further explored. A longitudinal study was conducted to investigate whether and the extent to which ethnic identity, national identity, and BII are protective factors for adoptees' psychological well-being. A self-report questionnaire was administered to 79 Italian transracial adoptees, aged between 15 and 25, at two time points, one year apart. In line with predictions, longitudinal analyses showed the crucial role of BII that turned out to increase higher levels of well being one year later. Results are discussed in relation to implications for intervention with adoptive parents and children. PMID- 26650810 TI - Participation in the Adoption Mentoring Partnership: Mentors' Experiences of Ethnic Identity. AB - The Adoption Mentoring Partnership (AMP) matches preadolescent adoptees with adopted college students, prioritizing matches of the same ethnic background. As part of AMP, participants actively discuss issues of ethnicity and adoption with a cohort of mentors over a period of 1 to 3 years in mentor group meetings (MGMs). This study focuses on mentors' perceptions of ethnic identity processes within the context of adoption during their participation in AMP. Thematic analysis is used to analyze two interviews from each of 12 internationally and transracially adopted mentors (8 females, 4 males; average age = 20.4 years; birth countries from Asia or Latin America). Four overarching domains emerged: personal ethnic identity exploration, communication with family members about adoption/ethnicity, social exchanges outside the family, and mentors' perceived personal meanings of ethnicity while participating in AMP. All mentors acknowledged degrees of ambivalence around ethnic identity, yet reported overwhelmingly positive feelings about participating in AMP. PMID- 26650811 TI - New Trends and Directions in Ethnic Identity Among Internationally Transracially Adopted Persons: Summary of Special Issue. AB - The collective findings of the six articles in this special issue highlight the importance of ethnic-racial socialization and ethnic identity among international transracial adoptees (ITRAs). A multidimensional developmental phenomenon, ethnic identity intersects with other identities, notably adoptive identity. Family, peers, community, and host culture are important socialization contexts that engage transracial adoptees in transactional processes that promote ethnic identity development. New directions in research were identified, including developmental processes in navigating ethnic and other identities, similarities and differences in ethnic identity between ITRAs and immigrants, the effectiveness of interventions targeting ethnic identity in ITRAs, and the impact of discrimination on ethnic identity construction and the role of social and national contexts. Implications for policies and practices were discussed, such as pre- and postadoption supports for adoptees and parents that provide developmentally appropriate support for positive ethnic identity; training for professionals working with ITRAs and their families; and intercountry practices that promote connection with cultures of origin. Lessons about ITRAs and their ethnic identity in transaction with multiple social contexts enhance understanding of how all individuals navigate multiple identities. PMID- 26650812 TI - Commentary-Enlarging Concepts, Refining Methods, Improving Interventions. AB - As illustrated by the articles in this special issue, the research into ethnic identity in adoption is making significant progress. At the same time, it faces new challenges in the definition of concepts, the use of appropriate methods of study, and the consideration of implications for professional interventions. This commentary offers additional thoughts about these three areas in an effort to complete the new perspectives opened by the foregoing articles. PMID- 26650813 TI - Expression of Trypanosoma brucei gambiense Antigens in Leishmania tarentolae. Potential for Use in Rapid Serodiagnostic Tests (RDTs). AB - The development of rapid serodiagnostic tests for sleeping sickness and other diseases caused by kinetoplastids relies on the affordable production of parasite specific recombinant antigens. Here, we describe the production of recombinant antigens from Trypanosoma brucei gambiense (T.b. gambiense) in the related species Leishmania tarentolae (L. tarentolae), and compare their diagnostic sensitivity and specificity to native antigens currently used in diagnostic kits against a panel of human sera. A number of T.b. gambiense protein antigen candidates were chosen for recombinant expression in L. tarentolae based on current diagnostics in field use and recent findings on immunodiagnostic antigens found by proteomic profiling. In particular, the extracellular domains of invariant surface glycoprotein 65 (ISG65), variant surface glycoproteins VSG LiTat 1.3 and VSG LiTat 1.5 were fused with C-terminal histidine tags and expressed as soluble proteins in the medium of cultured, recombinant L. tarentolae. Using affinity chromatography, on average 10 mg/L of recombinant protein was purified from cultures and subsequently tested against a panel of sera from sleeping sickness patients from controls, i.e. persons without sleeping sickness living in HAT endemic countries. The evaluation on sera from 172 T.b. gambiense human African trypanosomiasis (HAT) patients and from 119 controls showed very high diagnostic potential of the two recombinant VSG and the rISG65 fragments with areas under the curve between 0.97 and 0.98 compared to 0.98 and 0.99 with native VSG LiTat 1.3 and VSG LiTat 1.5 (statistically not different). Evaluation on sera from 78 T.b. rhodesiense HAT patients and from 100 controls showed an acceptable diagnostic potential of rISG65 with an area under the curve of 0.83. These results indicate that a combination of these recombinant antigens has the potential to be used in next generation rapid serodiagnostic tests. In addition, the L. tarentolae expression system enables simple, cheap and efficient production of recombinant kinetoplatid proteins for use in diagnostic, vaccine and drug discovery research that does not rely on animal use to generate materials. PMID- 26650814 TI - A literature review of the regional implementation of the central Swedish government's health care reforms on choice and privatization. AB - The introduction in 2010 of the Freedom of Choice Act represents one of the most far-reaching reforms of the Swedish health system. While it is mandatory for the regional counties to introduce choice plans for primary care it is voluntary for ambulatory specialist services. The voluntary nature of the regulations for the latter types of care generates a potential gap between the central government's reform attempts and the regional implementation of the plans. We review the regional implementation of this reform with respect to specialist services from a political economy perspective. Data on the scope of implementation show that counties of the same political ideology as the central government have introduced the most choice plans for specialist care. In particular, counties ruled by right wing majorities have introduced the Choice Act to a considerably larger extent than left-wing counties. This creates a highly uneven situation across the various parts of the country, possibly at odds with the basic premises of the country's health law of equal access to care. The introduction of choice plans forms part of a decidedly contentious set of issues that are high on the political agenda of Sweden. The nature and impacts of these reforms are also a concern to the general public and the broader industry. Considerably more rigorous analyses will be needed to assess the impact on key policy parameters such as overall system efficiency and equitable access to services as a result of these changes to the health care markets. PMID- 26650816 TI - Cost Analyses in the US and Japan: A Cross-Country Comparative Analysis Applied to the PRONOUNCE Trial in Non-Squamous Non-Small Cell Lung Cancer. AB - INTRODUCTION: Health technology assessment is not required for regulatory submission or approval in either the United States (US) or Japan. This study was designed as a cross-country evaluation of cost analyses conducted in the US and Japan based on the PRONOUNCE phase III lung cancer trial, which compared pemetrexed plus carboplatin followed by pemetrexed (PemC) versus paclitaxel plus carboplatin plus bevacizumab followed by bevacizumab (PCB). METHODS: Two cost analyses were conducted in accordance with International Society For Pharmacoeconomics and Outcomes Research good research practice standards. Costs were obtained based on local pricing structures; outcomes were considered equivalent based on the PRONOUNCE trial results. Other inputs were included from the trial data (e.g., toxicity rates) or from local practice sources (e.g., toxicity management). The models were compared across key input and transferability factors. RESULTS: Despite differences in local input data, both models demonstrated a similar direction, with the cost of PemC being consistently lower than the cost of PCB. The variation in individual input parameters did affect some of the specific categories, such as toxicity, and impacted sensitivity analyses, with the cost differential between comparators being greater in Japan than in the US. CONCLUSION: When economic models are based on clinical trial data, many inputs and outcomes are held consistent. The alterable inputs were not in and of themselves large enough to significantly impact the results between countries, which were directionally consistent with greater variation seen in sensitivity analyses. The factors that vary across jurisdictions, even when minor, can have an impact on trial-based economic analyses. FUNDING: Eli Lilly and Company. PMID- 26650815 TI - Management of Chronic Kidney Disease: The Relationship Between Serum Uric Acid and Development of Nephropathy. AB - Chronic kidney disease (CKD) is increasingly recognized as a global health problem, and new and effective strategies are needed for the management of this condition. Recently, there has been renewed interest in the relationship between serum uric acid (SUA) levels and CKD, and several recent trials have demonstrated a possible link between SUA and the development and/or progression of CKD in patients with and without diabetes. The identification of key urate transporters such as urate transporter 1 and glucose transporter 9 has provided not only insights into the pathophysiology of hyperuricemia, but also possible links to other processes, such as glucose homeostasis. The renewed interest in the role of SUA in CKD has coincided with the development of sodium glucose co-transporter 2 inhibitors for the treatment of diabetes. In addition to improving glycemic control, these agents, acting via the kidneys in an insulin-independent manner, have also been shown to reduce SUA levels and potentially improve some measures of renal function. This review will discuss the role of uric acid in CKD treatment, and how SUA-lowering therapies may prevent or delay the progression of CKD. FUNDING: Janssen Scientific Affairs. PMID- 26650817 TI - Synthesis, Spectroscopic Characterization and DFT/TD-DFT Calculations of new Fluorescent Derivatives of Imidazo[4',5':3,4]Benzo[c]Isoxazole. AB - An increasingly wide variety of fluorescent compounds is used in biotechnology, genomics, immunoassays, array technologies, imaging, and drug discovery. Therefore, synthesis of fluorophores with novel structural features can be interesting and useful in various fields. In this paper, four new fluorescent heterocyclic compounds with high quantum yields are introduced. These new fluorophores are synthesized in moderate to high yields via regioselective nitration of 3-alkyl-8-(4-chlorophenyl)-3 H-imidazo[4',5':3,4]benzo[c]isoxazoles. The latter compounds are obtained from the reaction of 1-alkyl-5-nitro-1 H benzoimidazoles with (4-chlorophenyl)acetonitrile in basic MeOH solution. Physical spectral (UV-vis, IR, (1)HNMR, (13)C NMR, NOESY and fluorescence) and analytical data have established the structures of synthesized compounds. The fluorescence properties of new fluorescent heterocyclic compounds are studied. The fluorescence of all compounds is very intense and fluorescence quantum yields are high (> 0.52). Density functional theory (DFT) calculations are performed to provide the optimized geometries, relevant frontier orbitals and the prediction of (1)H NMR chemical shifts for confirming the exact structure of fluorescent compounds. Calculated electronic absorption spectra were also obtained by time dependent density functional theory (TD-DFT) method. PMID- 26650818 TI - CD73 Pathway Contributes to the Immunosuppressive Ability of Mesenchymal Stem Cells in Intraocular Autoimmune Responses. AB - Mesenchymal stem cells (MSCs) exhibit a potent immunomodulatory capacity and have been applied to treat diseases such as graft versus host disease and severe autoimmune diseases. However, the mechanism underlying their immunosuppressive effect is not yet completely understood. Here, we investigated the role of the CD73/adenosine pathway in immune modulation by MSCs using a mouse model of experimental autoimmune uveitis (EAU). Moreover, we examined the in vitro modulatory effect of MSCs mediated through the CD73/adenosine pathway in human and mouse T cells. We found that the severity of EAU was significantly attenuated by MSCs; however, most therapeutic effects of MSCs were lost by pretreatment with a CD73 inhibitor. The inhibitory mechanism of MSCs might be contributed by CD73 on MSCs that cooperated with CD39 and CD73 on activated T cells to produce adenosine, resulting in inhibition of T-cell proliferation. Furthermore, MSCs increased the expression of CD73 on CD4(+) T cells, and transforming growth factor-beta1 (TGF-beta1) was the only tested cytokine that contributed to upregulation of CD73. Hence, our study demonstrates that the CD73/adenosine pathway involves the immunomodulatory function of MSCs in autoimmune responses. PMID- 26650819 TI - B Cells Loaded with Synthetic Particulate Antigens: A Versatile Platform To Generate Antigen-Specific Helper T Cells for Cell Therapy. AB - Adoptive cell therapy represents a promising approach for several chronic diseases. This study describes an innovative strategy for biofunctionalization of nanoparticles, allowing the generation of synthetic particulate antigens (SPAg). SPAg activate polyclonal B cells and vectorize noncognate proteins into their endosomes, generating highly efficient stimulators for ex vivo expansion of antigen-specific CD4+ T cells. This method also allows harnessing the ability of B cells to polarize CD4+ T cells into effectors or regulators. PMID- 26650820 TI - Behaviour of human dental pulp cells cultured in a collagen hydrogel scaffold cross-linked with cinnamaldehyde. AB - AIM: To investigate the effects of the cross-linking agent cinnamaldehyde (CA) on differentiation of human dental pulp cells (hDPCs) cultured in a collagen hydrogel, which may be useful as a scaffold for regenerative endodontic therapy. METHODOLOGY: The odontogenic potential of hDPCs exposed to CA was examined using alkaline phosphatase (ALP) activity, Alizarin red S staining and real-time polymerase chain reaction for odontogenic gene expression. The morphological features of hDPCs cultured in CA-treated collagen were evaluated by scanning electron microscopy. Determination of cell numbers for evaluating proliferation was assessed by optical and fluorescence microscopy. To assess the mechanical properties of collagen treated with CA, setting time, compressive strength and surface roughness were measured. Statistical analysis was performed using Student's t-test compared with control (P = 0.05). RESULTS: CA per se did not increase ALP activity, calcium nodule formation and expression of odontogenic related markers (P > 0.05). On the contrary, the proliferation and odontogenic differentiation of hDPCs cultured in a collagen scaffold was promoted in the presence of CA (P < 0.05). The setting time was significantly shortened, and the compressive strength and surface roughness were increased by treatment with CA (P < 0.05). CONCLUSIONS: Cross-linking of collagen scaffolds by CA had beneficial effects with respect to attachment, proliferation and differentiation of hDPCs. Consequently, the application of cross-linking agents such as CA may represent a new strategy for dentine-pulp complex regeneration. PMID- 26650821 TI - Stable Flies (Stomoxys calcitrans L.) from Confined Beef Cattle Do Not Carry Shiga-Toxigenic Escherichia coli (STEC) in the Digestive Tract. AB - BACKGROUND AND OBJECTIVE: Stable flies (Stomoxys calcitrans L.) are very common around confined and pastured cattle, and due to their painful bites they are very important animal pests. Cattle are asymptomatic reservoirs of foodborne pathogens, Escherichia coli O157:H7 and other Shiga-toxigenic E. coli serotypes (STEC). In the present study, the potential of stable flies to carry STEC in a beef cattle feedlot was assessed. METHODS: Stable flies (n = 180) were collected over 3 summer months and processed individually for STEC-8 that included the serotype O157 and seven non-O157 serotypes (O26, O45, O103, O104, O111, O121, and O145). Isolation and detection of STEC was based on direct plating as well as the enrichment/immunomagnetic separation approach. Modified Posse agar (mP) was used for culturing non-O157 serotypes and sorbitol MacConkey agar with cefixime and potassium tellurite (CT-SMAC) for E. coli O157. Multiplex polymerase chain reactions were used for differentiation of individual serotypes and detection of virulence genes (stx1, stx2, eae, and ehxA). RESULTS AND CONCLUSIONS: Of 180 stable flies, 67 (37.2%) carried enterics on mP (mean: 3.6 +/- 1.05 * 10(6) colony-forming units [CFU]/fly) and 55/180 (30.5%) were positive for bacteria on CT-SMAC (mean: 1.2 +/- 1.08 * 10(4) CFU/fly). However, stable flies positive for E. coli serotypes of interest were very rare (prevalence: 1.1%). The three serotype-positive isolates, two E. coli O26 and one E. coli O45, were recovered from two flies and neither of them harbored the virulence genes. We conclude that stable flies likely do not play a role as a biological vector and/or reservoir of STEC-8 in cattle feedlots. PMID- 26650822 TI - SIGN Guidelines for Scotland: BMD Versus FRAX Versus QFracture. AB - Scottish Intercollegiate Guidelines Network (SIGN) recently issued guidance on the management of osteoporosis and the prevention of fragility fractures. The aim of this paper was to critically review the guidance. The SIGN guidance utilises risk factors for fracture as an initial step for assessment, but recommends treatment only in individuals with a T-score of -2.5. There are many problems with the sole use of BMD as the sole gateway to treatment. Moreover, the assessment tools to determine risk (FRAX or QFracture) are not designed to detect osteoporosis but rather fracture risk. Whereas SIGN assumes that FRAX overestimates fracture probability, there are compelling reasons to believe that the disparity is related to the inadequate calibration of QFracture. The disparities make the use of a single threshold for BMD testing problematic. The SIGN guidance for men at high risk of fracture provides a set of confused and inconsistent recommendations that are in direct conflict with regulatory authorizations and is likely to increase further the large treatment gap in men. For women, the number of women eligible for treatment (i.e. with osteoporosis) is 81,700 with the use of FRAX but only 12,300 with QFracture representing 8.2 and 1.2 % of the total population at risk, respectively. We conclude that serious problems with the SIGN guidance preclude its implementation. PMID- 26650823 TI - Can Patient Safety Incident Reports Be Used to Compare Hospital Safety? Results from a Quantitative Analysis of the English National Reporting and Learning System Data. AB - BACKGROUND: The National Reporting and Learning System (NRLS) collects reports about patient safety incidents in England. Government regulators use NRLS data to assess the safety of hospitals. This study aims to examine whether annual hospital incident reporting rates can be used as a surrogate indicator of individual hospital safety. Secondly assesses which hospital characteristics are correlated with high incident reporting rates and whether a high reporting hospital is safer than those lower reporting hospitals. Finally, it assesses which health-care professionals report more incidents of patient harm, which report more near miss incidents and what hospital factors encourage reporting. These findings may suggest methods for increasing the utility of reporting systems. METHODS: This study used a mix methods approach for assessing NRLS data. The data were investigated using Pareto analysis and regression models to establish which patients are most vulnerable to reported harm. Hospital factors were correlated with institutional reporting rates over one year to examine what factors influenced reporting. Staff survey findings regarding hospital safety culture were correlated with reported rates of incidents causing harm; no harm and death to understand what barriers influence error disclosure. FINDINGS: 5,879,954 incident reports were collected from acute hospitals over the decade. 70.3% of incidents produced no harm to the patient and 0.9% were judged by the reporter to have caused severe harm or death. Obstetrics and Gynaecology reported the most no harm events [OR 1.61(95%CI: 1.12 to 2.27), p<0.01] and pharmacy was the hospital location where most near-misses were captured [OR 3.03(95%CI: 2.04 to 4.55), p<0.01]. Clinicians were significantly more likely to report death than other staff [OR 3.04(95%CI: 2.43 to 3.80) p<0.01]. A higher ratio of clinicians to beds correlated with reduced rate of harm reported [RR = -1.78(95%Cl: -3.33 to -0.23), p = 0.03]. Litigation claims per bed were significantly negatively associated with incident reports. Patient satisfaction and mortality outcomes were not significantly associated with reporting rates. Staff survey responses revealed that keeping reports confidential, keeping staff informed about incidents and giving feedback on safety initiatives increased reporting rates [r = 0.26 (p<0.01), r = 0.17 (p = 0.04), r = 0.23 (p = 0.01), r = 0.20 (p = 0.02)]. CONCLUSION: The NRLS is the largest patient safety reporting system in the world. This study did not demonstrate many hospital characteristics to significantly influence overall reporting rate. There were no association between size of hospital, number of staff, mortality outcomes or patient satisfaction outcomes and incident reporting rate. The study did show that hospitals where staff reported more incidents had reduced litigation claims and when clinician staffing is increased fewer incidents reporting patient harm are reported, whilst near misses remain the same. Certain specialties report more near misses than others, and doctors report more harm incidents than near misses. Staff survey results showed that open environments and reduced fear of punitive response increases incident reporting. We suggest that reporting rates should not be used to assess hospital safety. Different healthcare professionals focus on different types of safety incidents and focusing on these areas whilst creating a responsive, confidential learning environment will increase staff engagement with error disclosure. PMID- 26650824 TI - Clinical outcome and global gene expression data support the existence of the estrogen receptor-negative/progesterone receptor-positive invasive breast cancer phenotype. AB - The presence or absence of estrogen and progesterone steroid hormone receptor expression (ER, PR) is an essential feature of invasive breast cancer and determines prognosis and endocrine treatment decisions. Among the four ER/PR receptor phenotypes, the ER-/PR+ is infrequent, and its clinical relevance has been controversially discussed. Thus, we investigated its clinical significance and gene expression pattern in large datasets. In a retrospective clinical study of 15,747 breast cancer patients, we determined the ER/PR subtype survival probabilities using Kaplan-Meier and Cox regression analyses. From The Cancer Genome Atlas (TCGA) breast cancer dataset, PAM50 expression signature and pathway analyses were performed to test for distinct molecular features. In our cohort, the ER-/PR+ phenotype has been observed at a frequency of 4.1 % and was associated with an improved 10-year survival for stage I cancers compared to the ER+/PR+ reference subtype (median; 95 % CI 88.1 %; 83-93 vs. 84.3 %; 82-86 %, P = 0.024) as was confirmed by multivariate analysis over the entire follow-up (HR 0.59, 95 % CI 0.38-0.92, P = 0.021). This association lacked significance when including all stages. ER-/PR+ patients treated with antihormonal agents (34.5 %) had shorter survival compared to their non-treated counterparts (Log-rank P = 0.0001). PAM50 signatures suggest a distinct configuration for the ER-/PR+ phenotype. This specific phenotype has been further separated by a set of 59 uniquely expressed genes. Our study supports the notion of the existence of an ER /PR+ phenotype with clinical and molecular features distinct from the large group of ER+/PR+ patients. PMID- 26650825 TI - Effects of a self-management program on antiemetic-induced constipation during chemotherapy among breast cancer patients: a randomized controlled clinical trial. AB - Research on patient-reported outcomes indicates that constipation is a common adverse effect of chemotherapy, and the use of 5-hydroxytryptamine (serotonin; 5HT3) receptor antagonists aggravates this condition. As cancer patients take multiple drugs as a part of their clinical management, a non-pharmacological self management (SM) of constipation would be recommended. We aimed to evaluate the effectiveness of a SM program on antiemetic-induced constipation in cancer patients. Thirty patients with breast cancer, receiving 5HT3 receptor antagonists to prevent emesis during chemotherapy were randomly assigned to the intervention or control group. The SM program consisted of abdominal massage, abdominal muscle stretching, and education on proper defecation position. The intervention group started the program before the first chemotherapy cycle, whereas patients in the wait-list control group received the program on the day before their second chemotherapy cycle. The primary outcome was constipation severity, assessed by the constipation assessment scale (CAS, sum of eight components). The secondary outcome included each CAS component (0-2 points) and mood states. A self-reported assessment of satisfaction with the program was performed. The program produced a statistically and clinically significant alleviation of constipation severity (mean difference in CAS, -3.00; P = 0.02), decrease in the likelihood of a small volume of stool (P = 0.03), and decrease in depression and dejection (P = 0.02). With regards to program satisfaction, 43.6 and 26.4 % patients rated the program as excellent and good, respectively. Our SM program is effective for mitigating the symptoms of antiemetic-induced constipation during chemotherapy. PMID- 26650826 TI - Polonium behaviour in reservoirs potentially affected by acid mine drainage (AMD) in the Iberian Pyrite Belt (SW of Spain). AB - The province of Huelva is one of the areas most affected by acid mine drainage (AMD) in the world, which can produce big enhancements and fractionations in the waters affected by AMD. There are very few studies on this issue, and none on polonium-210. Twenty-two water reservoirs were sampled, and the (210)Po was measured in both dissolution and particulate phases. The (210)Po concentrations in the waters were in the same order of magnitude to those ones for unperturbed systems, although the data published to particulate matter are very scarce. A mean value and standard uncertainty for (210)Po of 0.25 +/- 0.03 mBq L(-1) in the dissolved matter, and 62 +/- 9 mBq g(-1) in the particulate matter can be established as base line for the reservoirs of the Huelva area. The distribution coefficients (kd) range from 10(4) to 10(6) L kg(-1), in agreement to the found ones by other authors for the case of neutral waters, but being the lowest values for the more acidic reservoirs. It has been also found that (210)Po has a high tendency to be associated to the particulate matter for neutral-alkaline waters, however, under extreme acid conditions (pH < 3), increases the Po tendency to be associated to the dissolved phase. Therefore, the main conclusion obtained in this work is that AMD has no a significant influence on the total activity concentration of (210)Po in the waters of reservoirs, but the acidity has a clear influence on its distribution between both dissolved and the particulate phases. PMID- 26650827 TI - Indication of the radioactive fallout in Riyadh, Saudi Arabia following the Fukushima nuclear accident. AB - On March 2011, a severe damage has occurred to Fukushima Di-iachi nuclear reactor complex in Japan following the huge earthquake and the resulting Tsunami. Consequently, vast amounts of radioactive fallout were released into the atmosphere and contaminated the environment in Japan. Soon after the accident, traces of anthropogenic radionuclides were detected in environmental samples collected in many parts in the northern hemisphere even very far away from Japan creating a global concern. There is no information about radioactive contamination in the Arabian Peninsula caused by the Japanese Fukushima nuclear accident. The first evidence of Fukushima radioactive fallout in Riyadh (24 degrees 43' N, 46 degrees 38' E), Saudi Arabia has been confirmed in April 8, 2011. The airborne fission products (131)I, (134)Cs and (137)Cs were measured in air samples. The radionuclide concentrations were determined by identifying their characteristic gamma rays using a germanium detector. Their activity concentrations were studied as a function of time over a period of 20 days at the end of which they had mostly fallen below our limit of detection. The maximum activity concentration of (131)I, (134)Cs and (137)Cs in air of, respectively, 323.7 +/- 18.5, 17.2 +/- 1.0 and 26.0 +/- 1.8 MUBq m(-3) were observed on April 10-11, 2011. The (131)I/(137)Cs and (134)Cs/(137)Cs activity ratio values in air were presented and discussed. Finally, the effective doses to the public of Riyadh city from inhalation of (131)I, (134)Cs and (137)Cs due to contribution from Fukushima incident was found far below levels of concern. PMID- 26650828 TI - Relationships between ground and airborne gamma-ray spectrometric survey data, North Ras Millan, Southern Sinai Peninsula, Egypt. AB - In the last decades of years, there was considerable growth in the use of airborne gamma-ray spectrometry. With this growth, there was an increasing need to standardize airborne measurements, so that they can be independent of survey parameters. Acceptable procedures were developed for converting airborne to ground gamma-ray spectrometric measurements of total-count intensity as well as, potassium, equivalent uranium and equivalent thorium concentrations, due to natural sources of radiation. The present study aims mainly to establish relationships between ground and airborne gamma-ray spectrometric data, North Ras Millan, Southern Sinai Peninsula, Egypt. The relationships between airborne and ground gamma-ray spectrometric data were deduced for the original and separated rock units in the study area. Various rocks in the study area, represented by Quaternary Wadi sediments, Cambro-Ordovician sandstones, basic dykes and granites, are shown on the detailed geologic map. The structures are displayed, which located on the detailed geologic map, are compiled from the integration of previous geophysical and surface geological studies. PMID- 26650829 TI - Mechanistic interpretation of the varying selectivity of Cesium-137 and potassium uptake by radish (Raphanus sativus L.) under field conditions near Chernobyl. AB - The selectivity of cation uptake by radish (Raphanus sativus L.) growing in the field near Chernobyl varies during the growth season. It is hypothesised that this is a consequence of variation in (137)Cs (Csss) and potassium (Kss) concentrations in the soil solution or the amount of dissolved potassium available to the plants. In the experiments reported here, it was observed that (1) Csss and Kss were positively correlated, (2) the selectivity for uptake of (137)Cs versus potassium (r) increased exponentially with decreasing Csss and Kss, and (3) the (137)Cs concentration, but not the potassium concentration, in plant material, increased abruptly upon the simultaneous reduction of Kss and Csss below about 10 MUg ml(-1) and 6.7 Bq l(-1), respectively. It is thought that potassium enters root cells from the soil solution through constitutively expressed, inward rectifying K(+) channels (KIRC) and K(+)/H(+)-symporters, whose abundance increases when plants become potassium-deficient. Cesium is thought to enter root cells through non-specific cation channels (NSCC) and, in plants lacking sufficient potassium, through K(+)/H(+)-symporters. It is argued that the increase in r, together with the abrupt increase (137)Cs concentration in plant tissues, when Kss and Csss decrease simultaneously cannot be attributed to competition between Cs(+) and K(+) for transport though KIRC, NSCC or K(+)/H(+) symporters and that the most plausible explanation of these phenomena is an increase in the abundance of K(+)/H(+)-symporters in plants exhibiting incipient potassium deficiency. PMID- 26650830 TI - Urinary excretion of uranium in adult inhabitants of the Czech Republic. AB - The main aim of this study was to determine and evaluate urinary excretion of uranium in the general public of the Czech Republic. This value should serve as a baseline for distinguishing possible increase in uranium content in population living near legacy sites of mining and processing uranium ores and also to help to distinguish the proportion of the uranium content in urine among uranium miners resulting from inhaled dust. The geometric mean of the uranium concentration in urine of 74 inhabitants of the Czech Republic was 0.091 mBq/L (7.4 ng/L) with the 95% confidence interval 0.071-0.12 mBq/L (5.7-9.6 ng/L) respectively. The geometric mean of the daily excretion was 0.15 mBq/d (12.4 ng/d) with the 95% confidence interval 0.12-0.20 mBq/d (9.5-16.1 ng/d) respectively. Despite the legacy of uranium mines and plants processing uranium ore in the Czech Republic, the levels of uranium in urine and therefore, also human body content of uranium, is similar to other countries, esp. Germany, Slovenia and USA. Significant difference in the daily urinary excretion of uranium was found between individuals using public supply and private water wells as a source of drinking water. Age dependence of daily urinary excretion of uranium was not found. Mean values and their range are comparable to other countries, esp. Germany, Slovenia and USA. PMID- 26650831 TI - Ultrasound is at least as good as magnetic resonance imaging in predicting tumour size post-neoadjuvant chemotherapy in breast cancer. AB - BACKGROUND: The aim of this study was to evaluate the accuracy of clinical imaging of the primary breast tumour post-neoadjuvant chemotherapy (NAC) related to the post-neoadjuvant histological tumour size (gold standard) and whether this varies with breast cancer subtype. In this study, results of both magnetic resonance imaging (MRI) and ultrasound (US) were reported. METHODS: Patients with invasive breast cancer were enrolled in the INTENS study between 2006 and 2009. We included 182 patients, of whom data were available for post-NAC MRI (n=155), US (n=123), and histopathological tumour size. RESULTS: MRI estimated residual tumour size with <10-mm discordance in 54% of patients, overestimated size in 28% and underestimated size in 18% of patients. With US, this was 63%, 20% and 17%, respectively. The negative predictive value in hormone receptor-positive tumours for both MRI and US was low, 26% and 33%, respectively. The median deviation in clinical tumour size as percentage of pathological tumour was 63% (P25=26, P75=100) and 49% (P25=22, P75=100) for MRI and US, respectively (P=0.06). CONCLUSIONS: In this study, US was at least as good as breast MRI in providing information on residual tumour size post-neoadjuvant chemotherapy. However, both modalities suffered from a substantial percentage of over- and underestimation of tumour size and in addition both showed a low negative predictive value of pathologic complete remission (Gov nr: NCT00314977). PMID- 26650832 TI - Differential Octopaminergic Modulation of Olfactory Receptor Neuron Responses to Sex Pheromones in Heliothis virescens. AB - Octopamine is an important neuromodulator of neural function in invertebrates. Octopamine increases male moth sensitivity to female sex pheromones, however, relatively little is known as to the role of octopamine in the female olfactory system, nor its possible effects on the reception of non-pheromone odorants. The purpose of this study was to determine relative effects of octopamine on the sensitivity of the peripheral olfactory system in male and female Heliothis virescens. Single sensillum recording was conducted in both sexes following injection with octopamine or Ringer solution, and during odorant stimulation with conspecific female sex pheromone or host plant volatiles. Results indicate that octopamine plays a significant modulatory role in female sex pheromone detection in female moths; and that male and female pheromone detection neurons share distinct pharmacological and physiological similarities in H. virescens despite sexual dimorphism at the antennal level. PMID- 26650833 TI - Generation of Aggregates of Mouse Embryonic Stem Cells that Show Symmetry Breaking, Polarization and Emergent Collective Behaviour In Vitro. AB - We have developed a protocol improving current Embryoid Body (EB) culture which allows the study of self-organization, symmetry breaking, axial elongation and cell fate specification using aggregates of mouse embryonic stem cells (mESCs) in suspension culture. Small numbers of mESCs are aggregated in basal medium for 48 hr in non-tissue-culture-treated, U-bottomed 96-well plates, after which they are competent to respond to experimental signals. Following treatment, these aggregates begin to show signs of polarized gene expression and gradually alter their morphology from a spherical mass of cells to an elongated, well organized structure in the absence of external asymmetry cues. These structures are not only able to display markers of the three germ layers, but actively display gastrulation-like movements, evidenced by a directional dislodgement of individual cells from the aggregate, which crucially occurs at one region of the elongated structure. This protocol provides a detailed method for the reproducible formation of these aggregates, their stimulation with signals such as Wnt/beta-Catenin activation and BMP inhibition and their analysis by single time-point or time-lapse fluorescent microscopy. In addition, we describe modifications to current whole-mount mouse embryo staining procedures for immunocytochemical analysis of specific markers within fixed aggregates. The changes in morphology, gene expression and length of the aggregates can be quantitatively measured, providing information on how signals can alter axial fates. It is envisaged that this system can be applied both to the study of early developmental events such as axial development and organization, and more broadly, the processes of self-organization and cellular decision-making. It may also provide a suitable niche for the generation of cell types present in the embryo that are unobtainable from conventional adherent culture such as spinal cord and motor neurones. PMID- 26650834 TI - Identification of potential cargo proteins of transportin protein AtTRN1 in Arabidopsis thaliana. AB - KEY MESSAGE: We identified 23 novel proteins that can interact with At TRN1. These proteins are potential candidates of At TRN1 cargo proteins, which will facilitate our comprehending of At TRN1 functions in Arabidopsis. Tranportin 1 (TRN1) carries out the nucleo-cytoplasmic transport of many proteins, thereby ensuring that each of them is delivered to the right compartment for its proper function. These cargo proteins involved in lots of important processes, such as alternative pre-mRNA splicing, transcriptional regulation, and protein translation. Current understanding of cargo proteins transported by Arabidopsis thaliana transportin 1 (AtTRN1) is limited. Here, first we employed the yeast two hybrid (Y2H) screening to identify proteins that can interact with AtTRN1 in Arabidopsis, and 12 novel proteins were found. Searching for PY-NLS motif in these 12 proteins suggested that no typical PY-NLS motif was present. We next investigated the specific motifs that will mediate the interactions in these sequences, and found that thirteen truncated fragments interacted with AtTRN1, containing 8 acidic and 5 basic fragments, respectively. We also searched the Arabidopsis proteome for homologs of cargo proteins of yeast Kapl04p and mammalian Kapbeta2, and PY-NLS motif-containing proteins. Among these proteins, 11 were identified to interact with AtTRN1. The interactions between all the 23 proteins and AtTRN1 were confirmed by both Y2H and bimolecular fluorescence complementation (BiFC) assays. Our results show that AtTRN1 recognizes a broad spectrum of proteins having diverse functions, which will potentially be the cargoes of AtTRN1. Taken together, these results demonstrate the feasibility and potential power of these methods to identify cargo proteins of AtTRN1, and represent a primary and significant step in interpretation of AtTRN1 functionalities. PMID- 26650835 TI - Cytokinin response factor 4 (CRF4) is induced by cold and involved in freezing tolerance. AB - KEY MESSAGE: Cytokinin response factor 4 (CRF4) shows a short-term induction by cold (4 degrees C) that appears to play a role in non-acclimated freezing tolerance as seen in mutant and overexpression lines. Responses to abiotic stresses, such as cold stress, are critical to plant growth and optimal production. Examination of Arabidopsis cytokinin response factors (CRFs) showed transcriptional induction after exposure to cold (4 degrees C). In particular, CRF4 was strongly induced in both root and shoot tissues. As CRF4 is one of several CRFs not transcriptionally regulated by cytokinin, we further investigated its response to cold. Peak CRF4 induction occurred 6 h post cold exposure, after which expression was maintained at moderately elevated levels during extended cold and subsequent treatment recovery. Examination of CRF4 mutant and overexpression lines under standard (non-cold) conditions revealed little difference from WT. One exception was a small, but significant increase in primary root growth of overexpression plants (CRF4OX). Under cold conditions, the only phenotype observed was a reduction in the rate of germination of CRF4OX seeds. The pattern of CRF4 expression along with the lack of strong phenotype at 4 degrees C led us to hypothesize that cold induction of CRF4 could play a role in short-term cold acclimation leading to increased freeze tolerance. Examination of CRF4OX and crf4 plants exposed to freezing temperatures revealed mutants lacking expression of CRF4 were more sensitive to freezing, while CRF4OXs with increased levels CRF4 levels were more tolerant. Altered transcript expression of CBF and COR15a cold signaling pathway genes in crf4 mutant and overexpression lines suggest that CRF4 may be potentially connected to this pathway. Overall this indicates that CRF4 plays an important role in both cold response and freezing stress. PMID- 26650836 TI - CarNAC4, a NAC-type chickpea transcription factor conferring enhanced drought and salt stress tolerances in Arabidopsis. AB - KEY MESSAGE: CarNAC4 is a typical stress-responsive NAC transcription factor and enhances drought and salt stress tolerances in transgenic Arabidopsis. Chickpea (Cicer arietinum L.) is relatively vulnerable to abiotic stress conditions, but the tolerance mechanisms for such stresses in chickpea are largely unknown. To identify stress-related factors in chickpea, we previously constructed a cDNA library of chickpea leaves exposed to drought stress conditions. A cDNA encoding a putative NAC transcription factor (CarNAC4) was identified as a putative stress responsive gene. Our study indicated that the transcript levels of CarNAC4 were enhanced in response to several abiotic stresses and phytohormones. Promoter analysis demonstrated that multiple stress-related cis-acting elements exist in promoter region of CarNAC4. CarNAC4 is localized in the nucleus and binds to the DNA sequence containing CGT[G/A], while the C-terminal region of CarNAC4 contains a transcriptional activation domain. Over-expression of CarNAC4 in Arabidopsis plants improved tolerance to drought and salt stresses. Transgenic plants exhibited greater reduced rates of water loss and more proline accumulation than Col-0 plants under drought stress and less MDA contents than Col-0 plants under salt stress. In addition, over-expression of CarNAC4 enhanced the expression of stress-responsive genes such as RD29A, ERD10, COR15A, COR47, KIN1 and DREB2A. These results indicated that CarNAC4 functions as a transcription factor involved in the regulation of drought and salt stress response. PMID- 26650837 TI - Constitutive expression of the tzs gene from Agrobacterium tumefaciens virG mutant strains is responsible for improved transgenic plant regeneration in cotton meristem transformation. AB - KEY MESSAGE : virG mutant strains of a nopaline type of Agrobacterium tumefaciens increase the transformation frequency in cotton meristem transformation. Constitutive cytokinin expression from the tzs gene in the virG mutant strains is responsible for the improvement. Strains of Agrobacterium tumefaciens were tested for their ability to improve cotton meristem transformation frequency. Two disarmed A. tumefaciens nopaline strains with either a virGN54D constitutively active mutation or virGI77V hypersensitive induction mutation significantly increased the transformation frequency in a cotton meristem transformation system. The virG mutant strains resulted in greener explants after three days of co-culture in the presence of light, which could be attributed to a cytokinin effect of the mutants. A tzs knockout strain of virGI77V mutant showed more elongated, less green explants and decreased cotton transformation frequency, as compared to a wild type parental strain, suggesting that expression of the tzs gene is required for transformation frequency improvement in cotton meristem transformation. In vitro cytokinin levels in culture media were tenfold higher in the virGN54D strain, and approximately 30-fold higher in the virGI77V strain, in the absence of acetosyringone induction, compared to the wild type strain. The cytokinin level in the virGN54D strain is further increased upon acetosyringone induction, while the cytokinin level in the virGI77V mutant is decreased by induction, suggesting that different tzs gene expression regulation mechanisms are present in the two virG mutant strains. Based on these data, we suggest that the increased cytokinin levels play a major role in increasing Agrobacterium attachment and stimulating localized division of the attached plant cells. PMID- 26650838 TI - The stay-green phenotype of wheat mutant tasg1 is associated with altered cytokinin metabolism. AB - KEY MESSAGE: By measuring the cytokinin content directly and testing the sensitivity to the cytokinin inhibitor lovastatin, we demonstrated that tasg1 cytokinin metabolism is different from wild-type. Our previous studies have indicated that compared with wild-type (WT) plants, a wheat stay-green mutant tasg1 exhibited delayed senescence. In this study, we found that the root development of tasg1 occurred later than that of WT. The number of lateral roots was fewer, but the lateral root length was longer in tasg1 than in WT, which resulted in a lower root to shoot ratio in tasg1 than WT. The levels of cytokinin (CK), CK activity, and expression of CK metabolic genes were measured. We found that the total CK content in the root tips and leaf of tasg1 was greater than in WT. The accumulation of mRNA of the CK synthetic gene (TaIPT) in tasg1 was higher than in WT at 9 and 11 days during seedling growth, but the expression of CK oxidase gene (TaCKX) was significantly lower in tasg1. Furthermore, the CK inhibitor lovastatin was used to inhibit CK activity. When treated with lovastatin, both the chlorophyll content and thylakoid membrane protein stability were significantly lower in tasg1 than WT, consistent with the inhibited expression of senescence-associated genes (TaSAGs) in tasg1. Lovastatin treatment also inhibited the antioxidative capability of wheat seedlings, and tasg1 was more sensitive to lovastatin than WT, as indicated by the MDA content, protein carbonylation, and antioxidant enzyme activity. The decreased antioxidative capability after lovastatin treatment may be related to the down-regulation of some antioxidase genes. These results suggest that the CK metabolism was altered in tasg1, which may play an important role in its ability to delay senescence. PMID- 26650839 TI - Sexual Motivation in the Female and Its Opposition by Stress. AB - A well worked-out motivational system in laboratory animals produces estrogen dependent female sex behavior. Here, we review (a) the logical definition of sexual motivation and (b) the basic neuronal and molecular mechanisms that allow the behavior to occur. Importantly, reproductive mechanisms in the female can be inhibited by stress. This is interesting because, in terms of the specificity of neuroendocrine dynamics in space and time, the two families of phenomena, sex and stress, are the opposite of each other. We cover papers that document stress effects on the underlying processes of reproductive endocrinology in the female. Not all of the mechanisms for such inhibition have been clearly laid out. Finally, as a current topic of investigation, this system offers several avenues for new investigation which we briefly characterize. PMID- 26650840 TI - Quality of life and mood predict posttraumatic stress disorder after hematopoietic stem cell transplantation. AB - BACKGROUND: During hospitalization for hematopoietic stem cell transplantation (HCT), patients experience a steep deterioration in quality of life (QOL) and mood. To our knowledge, the impact of this deterioration on patients' QOL and posttraumatic stress disorder (PTSD) symptoms after HCT is unknown. METHODS: We conducted a prospective longitudinal study of patients hospitalized for HCT. They assessed QOL using the Functional Assessment of Cancer Therapy-Bone Marrow Transplantation (FACT-BMT) and depression and anxiety symptoms were assessed using the Patient Health Questionnaire-9 (PHQ-9) at the time of admission for HCT, during hospitalization, and 6 months after HCT. We also used the Hospital Anxiety and Depression Scale (HADS) to measure patients' anxiety and depression symptoms at baseline and during HCT hospitalization. The PTSD Checklist was used to assess for PTSD symptoms. Multivariable linear regression models were used to identify predictors of QOL and PTSD symptoms at 6 months. RESULTS: We enrolled 90 of 93 consecutively eligible patients (97%) undergoing autologous and allogeneic HCT. Data at 6 months were available for 67 participants. At 6 months, 28.4% of participants met the criteria for PTSD and 43.3% had clinically significant depression. On multivariable regression analyses adjusting for significant covariates, changes in QOL and depression scores from week 2 of HCT hospitalization to baseline predicted worse QOL (changes in scores between week 2 and baseline [Delta] QOL: beta, 0.94 [P<.0001] and Delta PHQ-9: beta, -2.59 [P = 0.001]) and PTSD symptoms (Delta QOL: beta, -0.40 [P<.0001] and Delta PHQ-9: beta, 1.26 [P<.0001]) at 6 months after HCT. CONCLUSIONS: Six months after HCT, a significant percentage of patients met the criteria for PTSD and depression. A decline in QOL and an increase in depressive symptoms during hospitalization for HCT were found to be the most important predictors of 6-month QOL impairment and PTSD symptoms. Therefore, managing symptoms of depression and QOL deterioration during HCT hospitalization may be critical to improving QOL at 6 months and reducing the risk of PTSD. Cancer 2016;122:806-812. (c) 2015 American Cancer Society. PMID- 26650842 TI - The Reputational Consequences of Failed Replications and Wrongness Admission among Scientists. AB - Scientists are dedicating more attention to replication efforts. While the scientific utility of replications is unquestionable, the impact of failed replication efforts and the discussions surrounding them deserve more attention. Specifically, the debates about failed replications on social media have led to worry, in some scientists, regarding reputation. In order to gain data-informed insights into these issues, we collected data from 281 published scientists. We assessed whether scientists overestimate the negative reputational effects of a failed replication in a scenario-based study. Second, we assessed the reputational consequences of admitting wrongness (versus not) as an original scientist of an effect that has failed to replicate. Our data suggests that scientists overestimate the negative reputational impact of a hypothetical failed replication effort. We also show that admitting wrongness about a non-replicated finding is less harmful to one's reputation than not admitting. Finally, we discovered a hint of evidence that feelings about the replication movement can be affected by whether replication efforts are aimed one's own work versus the work of another. Given these findings, we then present potential ways forward in these discussions. PMID- 26650841 TI - Kinetics of Label Retaining Cells in the Developing Rat Kidneys. AB - BACKGROUND: The kidney is a specialized low-regenerative organ with several different types of cellular lineages. The BrdU label-retaining cell (LRCs) approach has been used as part of a strategy to identify tissue-specific stem cells in the kidney; however, because the complementary base pairing in double stranded DNA blocks the access of the anti-BrdU antibody to BrdU subunits, the stem cell marker expression in BrdU-labeled cells are often difficult to detect. In this study, we introduced a new cell labeling and detection method in which BrdU was replaced with 5-ethynyl-2-deoxyuridine (EdU) and examined the time dependent dynamic changes of EdU-labeled cells and potential stem/progenitor markers in the development of kidney. METHODS: Newborn rats were intraperitoneally injected with EdU, and their kidneys were harvested respectively at different time points at 1 day, 3 days, 1 week, 2 weeks, and 6 weeks post-injection. The kidney tissues were processed for EdU and cellular markers by immunofluorescence staining. RESULTS: At the early stage, LRCs labeled by EdU were 2176.0 +/- 355.6 cells at day one in each renal tissue section, but dropped to 168 +/- 48.4 cells by week 6. As time increased, the numbers of LRCs were differentially expressed in the renal cortex and papilla. At the postnatal day one, nearly twice as many cells in the cortex were EdU-labeled as compared to the papilla (28.6 +/- 3.6% vs. 15.6 +/- 3.4%, P<0.05), while there were more LRCs within the renal papilla since the postnatal week one, and at the postnatal week 6, one third as many cells in the cortex were EdU-labeled as compared to the papilla (2.5 +/- 0.1% vs. 7.7 +/- 2.7%, P<0.05). The long-term LRCs at 6-week time point were associated exclusively with the glomeruli in the cortex and the renal tubules in the papilla. At 6 weeks, the EdU-labeled LRCs combined with expression of CD34, RECA-1, Nestin, and Synaptopodin were discretely but widely distributed within the glomeruli; Stro-1 around the glomeruli; and alpha-smooth muscle actin (SMA) in arteries. Conversely, co-expression of CD34, RECA-1, and Nestin with the long term EdU-labeled LRCs was significantly lower in renal tubules (P<0.01), while Stro-1 and Synaptopodin were not detected. CONCLUSION: Our data found that at 6-week time point, EdU-labeled LRCs existing in the glomeruli expressed undifferentiated podocyte and endothelial markers at high rates, while those in the renal tubules expressed Nestin and vascular markers at low rates. To understand the characterization and localization of these EdU-LRCs, further studies will be needed to test cell lineage tracing, clonogenicity and differentiation potency, and the contributions to the regeneration of the kidney in response to renal injury/repair. PMID- 26650843 TI - Silver and Cyanine Staining of Oligonucleotides in Polyacrylamide Gel. AB - To explore why some oligonucleotides in denaturing polyacrylamide gel could not be silver-stained, 134 different oligonucleotides were analyzed using denaturing polyacrylamide gel electrophoresis stained with silver and asymmetric cyanine. As a result, we found that the sensitivity of oligos (dA), (dC), (dG) and (dT) to silver staining could be ranged as (dA) > (dG) > (dC) > (dT) from high to low. It was unexpected that oligo (dT) was hard to be silver-stained. Moreover, the silver staining of an oligonucleotide containing base T could be partially or completely inhibited by base T. The inhibition of silver staining by base T was a competitive inhibition which could be affected by the amounts of the argyrophil nucleobase and base T, the cis-distance between the argyrophil nucleobase and base T, and the gel concentration. The changes of the intensity of an oligonucleotide band caused by the changes of DNA base composition were diverse and interesting. The intensity of some oligonucleotide bands would significantly change when the changes of DNA base composition accumulated to a certain extent (usually >= 4 nt). The sensitivity of cyanine staining of <= 11-nt long oligonucleotides could be enhanced about 250-fold by fixing the gels with methanol fixing solution. PMID- 26650844 TI - The Presence of Thyroid-Stimulation Blocking Antibody Prevents High Bone Turnover in Untreated Premenopausal Patients with Graves' Disease. AB - Osteoporosis-related fractures are one of the complications of Graves' disease. This study hypothesized that the different actions of thyroid-stimulating hormone receptor (TSHR) antibodies, both stimulating and blocking activities in Graves' disease patients might oppositely impact bone turnover. Newly diagnosed premenopausal Graves' disease patients were enrolled (n = 93) and divided into two groups: patients with TSHR antibodies with thyroid-stimulating activity (stimulating activity group, n = 83) and patients with TSHR antibodies with thyroid-stimulating activity combined with blocking activity (blocking activity group, n = 10). From the stimulating activity group, patients who had matched values for free T4 and TSH binding inhibitor immunoglobulin (TBII) to the blocking activity group were further classified as stimulating activity-matched control (n = 11). Bone turnover markers BS-ALP, Osteocalcin, and C-telopeptide were significantly lower in the blocking activity group than in the stimulating activity or stimulating activity-matched control groups. The TBII level showed positive correlations with BS-ALP and osteocalcin levels in the stimulating activity group, while it had a negative correlation with the osteocalcin level in the blocking activity group. In conclusion, the activation of TSHR antibody activated TSH signaling contributes to high bone turnover, independent of the actions of thyroid hormone, and thyroid-stimulation blocking antibody has protective effects against bone metabolism in Graves' disease. PMID- 26650845 TI - Obturator Nerve Transfer to the Branch of the Tibial Nerve Innervating the Gastrocnemius Muscle for the Treatment of Sacral Plexus Nerve Injury. AB - BACKGROUND: Lower-limb function is severely impaired after sacral plexus nerve injury. Nerve transfer is a useful reconstructive technique for proximal nerve injuries. OBJECTIVE: To investigate the clinical effectiveness and safety of transferring the ipsilateral obturator nerve to the branch of the tibial nerve innervating the medial head of the gastrocnemius muscle to recover knee and ankle flexion. METHODS: From 2007 to 2011, 5 patients with sacral plexus nerve injury underwent ipsilateral obturator nerve transfer as part of a strategy for surgical reconstruction of their plexuses. The mean patient age was 31.4 years (range, 19 45 years), and the mean interval from injury to surgery was 5.8 months (range, 3 8 months). The anterior branch of the obturator nerve was coapted to the branch of the tibial nerve innervating the medial head of the gastrocnemius muscle by autogenous nerve grafting. RESULTS: Patient follow-up ranged from 24 to 38 months. There were no complications related to the surgery. Three patients recovered to Medical Research Council grade 3 or better in the medial head of the gastrocnemius muscle. Thigh adduction function was not affected in any patient. CONCLUSION: Knee and ankle flexion can be achieved by transferring the anterior branch of the obturator nerve to the branch of the tibial nerve innervating the medial head of the gastrocnemius muscle, which is useful for balance. This procedure can be used as a new method for treating sacral plexus nerve injury. ABBREVIATION: MRC, Medical Research Council. PMID- 26650846 TI - Isolation and Compositional Analysis of Plant Cuticle Lipid Polyester Monomers. AB - Terrestrial plants produce extracellular aliphatic biopolyesters that modify cell walls of specific tissues. Epidermal cells synthesize cutin, a polyester of glycerol and modified fatty acids that constitutes the framework of the cuticle that covers aerial plant surfaces. Suberin is a related lipid polyester that is deposited on the cell walls of certain tissues, including the root endodermis and the periderm of tubers, tree bark and roots. These lipid polymers are highly variable in composition among plant species, and often differ among tissues within a single species. Here, we describe a detailed protocol to study the monomer composition of cutin in Arabidopsis thaliana leaves by sodium methoxide (NaOMe)-catalyzed depolymerisation, derivatization, and subsequent gas chromatography-mass spectrometry (GC/MS) analysis. This method can be used to investigate the monomers of insoluble polyesters isolated from whole delipidated plant tissues bearing either cutin or suberin. The method can by applied not only to characterize the composition of lipid polymers in species not previously analyzed, but also as an analytical tool in forward and reverse genetic approaches to assess candidate gene function. PMID- 26650848 TI - Ion channels and calcium signaling in motile cilia. AB - The beating of motile cilia generates fluid flow over epithelia in brain ventricles, airways, and Fallopian tubes. Here, we patch clamp single motile cilia of mammalian ependymal cells and examine their potential function as a calcium signaling compartment. Resting motile cilia calcium concentration ([Ca2+] ~170 nM) is only slightly elevated over cytoplasmic [Ca2+] (~100 nM) at steady state. Ca2+ changes that arise in the cytoplasm rapidly equilibrate in motile cilia. We measured CaV1 voltage-gated calcium channels in ependymal cells, but these channels are not specifically enriched in motile cilia. Membrane depolarization increases ciliary [Ca2+], but only marginally alters cilia beating and cilia-driven fluid velocity within short (~1 min) time frames. We conclude that beating of ependymal motile cilia is not tightly regulated by voltage-gated calcium channels, unlike that of well-studied motile cilia and flagella in protists, such as Paramecia and Chlamydomonas. PMID- 26650849 TI - Synthesis of Multiring Fused 2-Pyridones via a Nitrene Insertion Reaction: Fluorescent Modulators of alpha-Synuclein Amyloid Formation. AB - An efficient, straightforward method for the synthesis of thiazolo-2-pyridone embedded peptidomimetic polyheterocycles via a catalyst-free, microwave-assisted, intramolecular C-H amination reaction is reported. All the synthesized polyheterocycles were evaluated for their fluorescent properties and effect on alpha-synuclein amyloid formation. PMID- 26650850 TI - Hydrazine N-N Bond Cleavage over Silica-Supported Tantalum-Hydrides. AB - Hydrazine reacts with silica-supported tantalum-hydrides [(=SiO)2TaHx] (x = 1, 3), 1, under mild conditions (100 degrees C). The IR in situ monitoring of the reaction with N2H4 or (15)N2H4, and the solid-state MAS NMR spectra of the fully (15)N labeled compounds (CP (15)N, (1)H-(15)N HETCOR, (1)H-(1)H double-quantum, and (1)H-(1)H triple-quantum spectra) were used to identify stable intermediates and products. DFT calculations were used for determining the reaction pathway and calculating the (15)N and (1)H NMR chemical shifts. Combining the experimental and computational studies led to the following results. At room temperature, only hydrazine adducts, 1-N2H4, are formed. Upon heating at 100 degrees C, the hydrazine adducts are converted to several species among which [(=SiO)2Ta(?NH)(NH2)], 2, [(=SiO)2TaH(NH2)2], 3, and [(=SiO)2TaH2(NH-NH2)], 4, were identified. The final product 2 is also formed in the reaction of N2 with the same silica-supported tantalum-hydride complexes, and the species identified as 3 and 4 had been previously suggested by DFT studies as intermediates on the reaction pathway for N-N cleavage in N2. The present computational studies (cluster models with M06 functional complemented by selected calculations with periodic calculations) show that 2 is formed via 3 and 4, with either N2 or N2H4. This strengthens the previous proposal of the existence of 3 and 4 as intermediates in the reaction of N2 with the tantalum-hydrides. However, the reaction of N2 does not imply the formation of N2H4 or its hydrazido monoanionic or dianionic ligand as an intermediate. For this reason, this study informs both on the similarities and differences of the reaction pathways involving N2 and N2H4 with tantalum-hydrides. PMID- 26650852 TI - Local muscle oxygen consumption related to external and joint specific power. AB - The purpose of the present study was to examine the effects of external work rate on joint specific power and the relationship between knee extension power and vastus lateralis muscle oxygen consumption (mVO2). We measured kinematics and pedal forces and used inverse dynamics to calculate joint power for the hip, knee and ankle joints during an incremental cycling protocol performed by 21 recreational cyclists. Vastus lateralis mVO2 was estimated using near-infrared spectroscopy with an arterial occlusion. The main finding was a non-linear relationship between vastus lateralis mVO2 and external work rate that was characterised by an increase followed by a tendency for a levelling off (R(2)=0.99 and 0.94 for the quadratic and linear models respectively, p<0.05). When comparing 100W and 225W, there was a ~43W increase in knee extension but still a ~9% decrease in relative contribution of knee extension to external work rate resulting from a ~47W increase in hip extension. When vastus lateralis mVO2 was related to knee extension power, the relationship was still non-linear (R(2)=0.99 and 0.97 for the quadratic and linear models respectively, p<0.05). These results demonstrate a non-linear response in mVO2 relative to a change in external work rate. Relating vastus lateralis mVO2 to knee extension power showed a better fit to a linear equation compared to external work rate, but it is not a straight line. PMID- 26650851 TI - Reduced Arrhythmia Inducibility With Calcium/Calmodulin-dependent Protein Kinase II Inhibition in Heart Failure Rabbits. AB - RATIONALE: Calcium/calmodulin-dependent protein kinase II (CaMKII) is activated in heart failure (HF) and can contribute to arrhythmias induced by beta adrenergic receptor-mediated sarcoplasmic reticulum calcium leak. OBJECTIVE: To evaluate the effect of CaMKII inhibition on ventricular tachycardia (VT) induction in conscious HF and naive rabbits. METHODS AND RESULTS: Nonischemic HF was induced by aortic insufficiency and constriction. Electrocardiograms were recorded in rabbits pretreated with vehicle (saline) or the CaMKII inhibitor KN 93 (300 MUg/kg); VT was induced by infusion of increasing doses of norepinephrine (1.56-25 MUg.kg-1.min-1) in naive (n = 8) and HF (n = 7) rabbits. With saline, median VT dose threshold in HF was 6.25 versus 12.5 MUg.kg-1.min-1 norepinephrine in naive rabbits (P = 0.06). Pretreatment with KN-93 significantly increased VT threshold in HF and naive rabbits (median = 25 MUg.kg-1.min-1, P < 0.05 vs. saline for both groups). Mean cycle length of VT initiation was shorter in HF (221 +/- 20 milliseconds) than naive (296 +/- 23 milliseconds, P < 0.05) rabbits with saline; this difference was not significant after treatment with KN-93. CONCLUSIONS: KN-93 significantly reduced arrhythmia inducibility and slowed initiation of VT, suggesting that CaMKII inhibition may have antiarrhythmic effects in the failing human heart. PMID- 26650853 TI - Occurrence and Recurrence of Attempted Suicide Among People With Epilepsy. AB - IMPORTANCE: People with epilepsy have a 5-fold increased risk of suicide. Less is known about attempted suicide and whether psychiatric disorders and antiepileptic drugs modify the risk of attempted suicide. OBJECTIVES: To estimate the magnitude of the association between attempted suicide and epilepsy by comparing a first suicide attempt and a second suicide attempt (hereafter referred to as a recurrent suicide attempt) among people before they received a diagnosis of epilepsy (case patients) with a first suicide attempt and a recurrent suicide attempt among people without epilepsy (control patients), and to evaluate the effect of comorbid psychiatric disorders and the exclusion of antiepileptic drug prescriptions on this association. DESIGN, SETTING, AND PARTICIPANTS: Population based retrospective cohort study in the United Kingdom of case patients with incident epilepsy and control patients without a history of epilepsy in a general practice setting using Clinical Practice Research Datalink. The case patients with incident epilepsy were identified between 1987 and 2013 and were 10 to 60 years of age. The control patients for each case patient were 4 randomly selected people who did not receive a diagnosis of epilepsy before the case patient's epilepsy was diagnosed (the index date), matched by year of birth, sex, and general practice for a control to case ratio of 4 to 1. MAIN OUTCOMES AND MEASURES: Hazard ratio for incident and recurrent suicide attempts among case patients with epilepsy compared with control patients without. RESULTS: For 14,059 case patients (median age, 36 years [range, 10-60 years]) who later had an onset of epilepsy vs 56,184 control patients (median age, 36 years [range, 10-60 years]), the risk was increased 2.9-fold (95% CI, 2.5- to 3.4-fold) for a first suicide attempt during the time period before the case patients received a diagnosis of epilepsy. For 278 case patients (median age, 37 years [range, 10-61 years]) who later had an onset of epilepsy vs 434 control patients (median age, 35 years [range, 11-61 years]), the risk was increased 1.8-fold (95% CI, 1.3- to 2.5-fold) for a recurrent suicide attempt up to and including the day that epilepsy was diagnosed. Exclusion of antiepileptic drugs prescribed before the index date did not meaningfully alter the findings, nor did separate analyses of patients with and patients without diagnosed psychiatric disorders. CONCLUSIONS AND RELEVANCE: Suicide attempts and recurrent suicide attempts are associated with epilepsy even before epilepsy manifests, suggesting a common underlying biology. Our findings indicate that both incident and recurrent suicide attempts are associated with incident epilepsy in the absence of antiepileptic drugs and in the absence of diagnosed psychiatric disorders, further strengthening the evidence for a common underlying etiology with an as-yet-unknown mechanism. PMID- 26650854 TI - Specialty Fellowships Within General Surgery: How Do We Find the Right Balance? PMID- 26650855 TI - High-throughput realization of an infrared selective absorber/emitter by DUV microsphere projection lithography. AB - In this paper, we present a low-cost and high-throughput nanofabrication method to realize metasurfaces that have selective absorption/emission in the mid infrared region of the electromagnetic spectrum. We have developed DUV projection lithography to produce arbitrary patterns with sub-80 nm feature sizes. As examples of practical applications, we experimentally demonstrate structures with single and double spectral absorption/emission features, and in close agreement with numerical simulation. The fundamental mechanism of perfect absorption is discussed as well. Selective infrared absorbers/emitters are critical elements in realizing efficient thermophotovoltaic cells and high-performance biosensors. PMID- 26650856 TI - Gelatin Scaffolds with Controlled Pore Structure and Mechanical Property for Cartilage Tissue Engineering. AB - Engineering of cartilage tissue in vitro using porous scaffolds and chondrocytes provides a promising approach for cartilage repair. However, nonuniform cell distribution and heterogeneous tissue formation together with weak mechanical property of in vitro engineered cartilage limit their clinical application. In this study, gelatin porous scaffolds with homogeneous and open pores were prepared using ice particulates and freeze-drying. The scaffolds were used to culture bovine articular chondrocytes to engineer cartilage tissue in vitro. The pore structure and mechanical property of gelatin scaffolds could be well controlled by using different ratios of ice particulates to gelatin solution and different concentrations of gelatin. Gelatin scaffolds prepared from >=70% ice particulates enabled homogeneous seeding of bovine articular chondrocytes throughout the scaffolds and formation of homogeneous cartilage extracellular matrix. While soft scaffolds underwent cellular contraction, stiff scaffolds resisted cellular contraction and had significantly higher cell proliferation and synthesis of sulfated glycosaminoglycan. Compared with the gelatin scaffolds prepared without ice particulates, the gelatin scaffolds prepared with ice particulates facilitated formation of homogeneous cartilage tissue with significantly higher compressive modulus. The gelatin scaffolds with highly open pore structure and good mechanical property can be used to improve in vitro tissue-engineered cartilage. PMID- 26650868 TI - [Molecular diagnosis of collagen vascular diseases and vasculitides]. AB - Collagen vascular diseases and vasculitides comprise various diseases, which may affect virtually every organ system. Therefore, their diagnosis and management is often an interdisciplinary challenge. Because of the heterogeneous symptoms, these diseases have significant overlap, which interferes with the clinical diagnosis and may require additional investigation. Therefore, a rational and comprehensive diagnostic work-up should be performed at the initial presentation before initiation of therapy. The detection of antinuclear (ANA) or anticell antibodies by indirect immunofluorescence microscopy on Hep2 cells is used to screen for autoantibodies in collagen vascular diseases. The molecular specificity of autoantibodies should be further characterized using immunoassays with recombinant or purified protein. When systemic autoimmune disease is suspected, the function of the frequently affected organs should be evaluated. The immunopathological findings should always be interpreted in the context of clinical, histological, and imaging data. The detection of autoantibodies is helpful for the initial diagnosis, provides prognostic information, may indicate involvement of organs or systems and some parameters may also be used for disease monitoring. The clinical significance of autoantibodies is emphasized by the fact that their detection constitutes diagnostic criteria for most collagen vascular diseases and several vasculitides. The screening for ANCA may be performed using immunoassays with recombinant myeloperoxidase and proteinase 3 or by indirect immunofluorescence microscopy on granulocytes. In this article, the current diagnostic tools and their relevance for the diagnosis and monitoring of systemic autoimmune diseases with primary skin involvement are reviewed. PMID- 26650869 TI - A special case of recurrent gross hematuria: Answers. AB - Wilson's disease (WD) is an autosomal recessive disorder, and has a variety of presentations. We reported a case of 9-year-old girl who presented with a history of recurrent gross hematuria, renal histological changes of IgA nephropathy, and finally had been confirmed to be Wilson's disease-associated IgA nephropathy. PMID- 26650870 TI - Accelerometer-Determined Physical Activity and Mortality in a National Prospective Cohort Study: Considerations by Hearing Sensitivity. AB - BACKGROUND: Previous work demonstrates that hearing impairment and physical inactivity are associated with premature all-cause mortality. The purpose of this study was to discern whether increased physical activity among those with hearing impairment can produce survival benefits. METHOD: Data from the 2003-2006 National Health and Nutrition Examination Survey were used, with follow-up through 2011. Physical activity was objectively measured over 7 days via accelerometry. Hearing sensitivity was objectively measured using a modified Hughson Westlake procedure. RESULTS: Among the 1,482 participants, 152 died during the follow-up period (10.26%, unweighted); the unweighted median follow-up period was 89 months (interquartile range = 74-98 months). For those with normal hearing and after adjustments, for every 60-min increase in physical activity, adults had a 19% (HR [Hazard Ratio] = 0.81; 95% confidence interval [CI] [0.48 1.35]; p = .40) reduced risk of all-cause mortality; however, this association was not statistically significant. In a similar manner, physical activity was not associated with all-cause mortality among those with mild hearing loss (HR = 0.76; 95% CI [0.51-1.13]; p = .17). However, after adjustments, and for every 60 min increase in physical activity for those with moderate or greater hearing loss, there was a 20% (HR = 0.20; 95% CI [0.67-0.95]; p = .01) reduced risk of all-cause mortality. CONCLUSION: Physical activity may help to prolong survival among those with greater hearing impairment. PMID- 26650871 TI - Influence of T1 Slope on the Cervical Sagittal Balance in Degenerative Cervical Spine: An Analysis Using Kinematic MRI. AB - STUDY DESIGN: A retrospective kinematic magnetic resonance imaging (kMRI) study. OBJECTIVE: To evaluate the utility of kMRI in determining the relationship between cervical sagittal balance and TI alignment. SUMMARY OF BACKGROUND DATA: Thoracic inlet parameters play an important role in cervical spine sagittal balance. However, most of the literature is based on lower resolution cervical X rays or CT scans in the supine position. METHODS: Cervical spine kMRI of 83 patients with degenerative cervical spine conditions (20-68 yr of age) was analyzed for: (1) cervical spine parameters: C2-C7 angle, C2-C7 sagittal vertical axis (SVA), cranial tilt, and cervical tilt; and (2) T1 parameters: thoracic inlet angle (TIA), T1 slope, and neck tilt (NT). Multiple logistic regression analysis and Pearson correlation coefficients were performed. RESULTS: The mean TIA, T1 slope, and NT were 78.0, 33.2, and 44.8 degrees , respectively. The mean C2-7 angle, SVA of C2-C7, cervical tilt, and cranial tilt were -15.4 degrees , 22.0 mm, 18.1 degrees , and 15.1 degrees , respectively. The ratio of cervical:cranial tilt was maintained as 55:45%. A significant correlation was found between the C2-C7 angle and T1 slope (r = 0.731), TIA and C2-C7 angle (r = 0.406), cervical tilt with C2-C7 angle (r = 0.671), T1 slope with TIA (r = 0.429), TIA with neck tilt (r = 0.733), TIA with cervical tilt (r = 0.377), SVA C2-C7 with cervical tilt (r = -0.480), SVA C2-C7 with cranial tilt (r = 0.912), and C2-7 SVA with the ratio of cranial tilt to cervical tilt (r = 0.694). CONCLUSION: An individual with a large T1 slope required large cervical lordosis to preserve physiologic sagittal balance of the cervical spine. Cranial tilt was the cervical parameter most strongly correlated with SVA C2-C7, and thus may be a good parameter to assess decompensation of cervical sagittal balance. LEVEL OF EVIDENCE: 3. PMID- 26650873 TI - Evidence-based Recommendations for Spine Surgery. PMID- 26650874 TI - Influences of Nutrition Supply and Pathways on the Degenerative Patterns in Human Intervertebral Disc. AB - STUDY DESIGN: Investigation of the effects of the impairment of different nutritional pathways on the intervertebral disc degeneration patterns in terms of spatial distributions of cell density, glycosaminoglycan content, and water content. OBJECTIVE: The aim of this study was to test the hypothesis that impairment of different nutritional pathways would result in different degenerative patterns in human discs. SUMMARY OF BACKGROUND DATA: Impairment of nutritional pathways has been found to affect cell viability in the disc. However, details on how impairment of different nutritional pathways affects the disc degeneration patterns are unknown. METHODS: A 3D finite element model was used for this study. This finite element method was based on the cell-activity coupled mechano-electrochemical theory for cartilaginous tissues. Impairment of the nutritional pathways was simulated by lowering the nutrition level at the disc boundaries. Effects of the impartment of cartilaginous endplate-nucleus pulposus (CEP-NP) pathway only (Case 1), annulus fibrosus (AF) pathway only (Case 2), and both pathways (Case 3) on disc degeneration patterns were studied. RESULTS: The predicted critical levels of nutrition for Case 1, Case 2, and Case 3 were around 30%, 20%, and 50% of the reference values, respectively. Below this critical level, the disc degeneration would occur. Disc degeneration appeared mainly in the NP for Case 1, in the outer AF for Case 2, and in both the NP and inner to middle AF for Case 3. For Cases 1 and 3, the loss of water content was primarily located in the mid-axial plane, which is consistent with the horizontal gray band seen in some T2-weighted magnetic resonance imaging (MRI). For the disc geometry used in this study, it was predicted that there existed a high-intensity zone (for Case 3), as seen in some T2-weighted MRI images. CONCLUSION: Impairment of different nutrition pathways results in different degenerative patterns. LEVEL OF EVIDENCE: N/A. PMID- 26650875 TI - The Constellation of Chronic Low Back Pain and Other Subjective Symptoms: Does the View Differ From China? AB - STUDY DESIGN: This was a pilot, cross-sectional study. Its site was West China Hospital in Chengdu, Sichuan Province. OBJECTIVE: An objective was to explore whether, in China, chronic low back pain (cLBP) characteristically is one symptom among co-occurring subjective symptoms. More basic objectives were to test a supplemented list of symptoms and to reconfigure findings from the literature on co-occurrence of symptoms so that they pertain specifically to cLBP. The governing metaphor was a constellation of symptoms in which cLBP is located. SUMMARY OF BACKGROUND DATA: With the exception of small, isolated societies, previous studies of co-occurrence of symptoms were conducted in the affluent West. Although China's population is larger than the combined populations of affluent countries of the West, research on co-occurring symptoms has been neglected in China. Unknown is whether results from studies conducted in the affluent West may be extended to China. METHODS: A survey with the supplemented symptom list was cross-culturally adapted into Chinese and administered to cLBP patients (N = 72) and normal controls (N = 102). Multiple regression analysis was used to determine the effects of covariates (age, gender, education) on symptom reporting. RESULTS: cLBP patients reported higher median numbers of symptoms than normal controls, including total symptoms (9 vs. 3), musculoskeletal symptoms (4 vs. 1), and nonmusculoskeletal symptoms (6 vs. 2.5); differences between cLBP and normal controls were highly significant (p < 0.001). Covariates had a little effect on symptom reporting. CONCLUSION: cLBP characteristically was one symptom in a constellation of symptoms. This finding came from one research site in China. Nevertheless, consistency between studies is notable, with findings from the affluent West supporting the finding from the Chinese site. The tendency to concentrate on a discrete clinical entity, cLBP itself, may obscure the constellation of symptoms. The more expansive view of cLBP has implications for clinical practice and research. LEVEL OF EVIDENCE: N/A. PMID- 26650876 TI - Magnetic Resonance Imaging Biomarker of Axon Loss Reflects Cervical Spondylotic Myelopathy Severity. AB - STUDY DESIGN: A prospective cohort study. OBJECTIVE: In this study, we employed diffusion basis spectrum imaging (DBSI) to quantitatively assess axon/myelin injury, cellular inflammation, and axonal loss of cervical spondylotic myelopathy (CSM) spinal cords. SUMMARY OF BACKGROUND DATA: A major shortcoming in the management of CSM is the lack of an effective diagnostic approach to stratify treatments and to predict outcomes. No current clinical diagnostic imaging approach is capable of accurately reflecting underlying spinal cord pathologies. METHODS: Seven patients with mild (mJOA >=15), five patients with moderate (14>=mJOA >=11), and two patients with severe (mJOA <11) CSM were prospectively enrolled. Given the low number of severe patients, moderate and severe patients were combined for comparison with seven age-matched controls and statistical analysis. We employed the newly developed DBSI to quantitatively measure axon and myelin injury, cellular inflammation, and axonal loss. RESULTS: Median DBSI inflammation volume is similar in control (266 MUL) and mild CSM (171 MUL) subjects, with a significant overlap of the middle 50% of observations (quartile 3 - quartile 1). This was in contrast to moderate CSM subjects that had higher DBSI-inflammation volumes (382 MUL; P = 0.033). DBSI-axon volume shows a strong correlation with clinical measures (r = 0.79 and 0.87, P = 1.9 x 10-5 and 2 x 10 4 for mJOA and MDI, respectively). In addition to axon and myelin injury, our findings suggest that both inflammation and axon loss contribute to neurological impairment. Most strikingly, DBSI-derived axon volume declines as severity of impairment increases. CONCLUSION: DBSI-quantified axonal loss may be an imaging biomarker to predict functional recovery following decompression in CSM. Our results demonstrate an increase of about 60% in the odds of impairment relative to the control for each decrease of 100 MUL in axon volume. LEVEL OF EVIDENCE: 3. PMID- 26650877 TI - Outcomes and Related Factors of C5 Palsy Following Cervical Laminectomy With Instrumented Fusion Compared With Laminoplasty. AB - STUDY DESIGN: A retrospective study. OBJECTIVE: The aim of this study was to analyze the clinical outcomes and related factors of C5 palsy (C5P) following posterior cervical laminectomy with fusion (LF) compared with laminoplasty (LP). SUMMARY OF BACKGROUND DATA: C5P is more common after LF than after LP. There have not been any studies on C5P-LF compared with C5P-LP. METHODS: We retrospectively analyzed consecutive cases that underwent cervical LF for nontraumatic cervical myelopathy or myeloradiculopathy (CMR). To analyze the related factors, C5P-LF and non-C5P-LF groups were compared. To assess the clinical parameters, preoperative diagnosis, clinical symptoms, surgical procedures, and outcome instruments were analyzed. Radiographically, we analyzed preoperative maximal spinal cord compression ratio, presence of C4-5 foraminal stenosis (FS), and correction angles on the sagittal plane. To compare with C5P-LP, we analyzed the incidence, time of onset, grade of muscle weakness, other accompanying cervical nerve root palsies, recovery time, and degree of final recovery in the C5P-LF and the C5P-LP groups of 100 consecutive LPs. RESULTS: A total of 90 LF patients were enrolled (M:F = 54:36, mean age 61.1 yr, mean follow-up 35 months). C5P occurred in 26 patients (28.9%), and 14 cases (53.8%) demonstrated other cervical nerve root palsies. Clinically significant differences were observed between the C5P-LF and non-C5P-LF groups with regard to preoperative clinical diagnosis (CMR 88.5:42.2%, P < 0.001) and presence of preoperative upper extremity weakness (57.7:32.3%, P = 0.02). Comparison between the C5P-LF and C5P-LP groups showed significant differences between incidence (28.9:4%), mean grade of weakness (2.1:3.5), accompanying nerve root symptoms (53.8:0%), recovery time (20.8:10.5 weeks), and incidence of incomplete recovery (15.4:0%). CONCLUSION: C5P-LF patients showed higher incidence, more severe weakness, frequent involvement of multiple cervical nerve roots, and longer recovery time than C5P-LP patients. Preoperative clinical manifestation of CMR and preexisting upper extremity weakness were the related factors of C5 palsy. LEVEL OF EVIDENCE: 3. PMID- 26650879 TI - Aging Stereotypes Must be Taken Into Account for the Diagnosis of Prodromal and Early Alzheimer Disease. AB - Because of a dramatic increase of older people worldwide, screening for prodromal state of Alzheimer disease (AD) is a major societal challenge. Many individuals diagnosed with prodromal AD, do not convert to AD, some remaining stable and others reversing back to normal. We argue that an important source of this overdiagnosis comes from negative aging stereotypes (eg, the culturally shared beliefs that aging inescapably causes severe cognitive decline and diseases). Many laboratory studies show that such stereotypes impair memory performance in healthy older adults, producing inflated age differences. Research is needed to examine how aging stereotypes implicitly permeate neuropsychological testing and contribute to false positives. PMID- 26650878 TI - Mixed chimerism evolution is associated with T regulatory type 1 (Tr1) cells in a beta-thalassemic patient after haploidentical haematopoietic stem cell transplantation. AB - In a cohort of beta-Thalassemia (beta-Thal) transplanted with haploidentical-HSCT we identified one transplanted patient characterized by persistent mixed chimerism (PMC) for several months after HSCT. In this unique beta-Thal patient we assessed the donor engraftment overtime after transplantation, the potential loss of the non-shared HLA haplotype, and the presence of CD49b(+)LAG-3(+) T regulatory type 1 (Tr1) cells, previously demonstrated to be associated with PMC after HLA-related HSCT for beta-Thal. The majority of the patient's erythrocytes were of donor origin, whereas T cells were initially mostly derived from the recipient, no HLA loss, but an increased frequency of circulating Tr1 cells were observed. For the first time, we showed that when the proportion of residual donor cells decreases, the frequency of CD49b(+)LAG-3(+) Tr1 cells declines, reaching the levels present in healthy subjects. These findings confirm previous results obtained in transplant related settings for beta-Thal, and supported the central role of Tr1 cells in promoting and maintaining PMC after allo-HSCT. PMID- 26650883 TI - 99mTc-Macroaggregated Albumin SPECT/CT Perfusion Imaging of Omental Extrahepatic Vascularization. AB - The authors present a case of omental perfusion by an extrahepatic branch of the right hepatic artery depicted during pre-embolization planning with 99mTc macroaggregated albumin SPECT/CT imaging. This omental scintigraphic finding corresponds to an extrahepatic branch of the right hepatic artery demonstrated by selective angiography and related CT angiography. The authors would like to add the omentum to the previously reported sites of extrahepatic vascularization encountered during the hepatic pre-embolization imaging. PMID- 26650880 TI - Diabetic Phenotypes and Late-Life Dementia Risk: A Mechanism-specific Mendelian Randomization Study. AB - BACKGROUND: Mendelian Randomization (MR) studies have reported that type 2 diabetes (T2D) was not associated with Alzheimer disease (AD). We adopted a modified, mechanism-specific MR design to explore this surprising result. METHODS: Using inverse-variance weighted MR analysis, we evaluated the association between T2D and AD using data from 39 single nucleotide polymorphisms (SNPs) significantly associated with T2D in DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) and the corresponding associations of each SNP with AD risk obtained from the International Genomics of Alzheimer's Project (IGAP, n=17,008 AD cases and n=37,154 controls). We evaluated mechanism-specific genetic subscores, including beta-cell function, insulin sensitivity, and adiposity, and repeated analyses in 8501 Health and Retirement Study participants for replication and model validation. RESULTS: In IGAP, the overall T2D polygenic score did not predict AD [odds ratio (OR) for the T2D polygenic score=1.01; 95% confidence interval (CI), 0.96, 1.06] but the insulin sensitivity polygenic score predicted higher AD risk (OR=1.17; 95% CI, 1.02, 1.34). In the Health and Retirement Study, polygenic scores were associated with T2D risk; the associations between insulin sensitivity genetic polygenic score and cognitive phenotypes were not statistically significant. CONCLUSIONS: Evidence from polygenic scores suggests that insulin sensitivity specifically may affect AD risk, more than T2D overall. PMID- 26650884 TI - Ca(2+) ATPase Conformational Transitions in Lipid Bilayers Mapped by Site directed Ethylation and Solid-State NMR. AB - To transmit signals across cellular compartments, many membrane-embedded enzymes undergo extensive conformational rearrangements. Monitoring these events in lipid bilayers by NMR at atomic resolution has been challenging due to the large size of these systems. It is further exacerbated for large mammalian proteins that are difficult to express and label with NMR-active isotopes. Here, we synthesized and engineered (13)C ethyl groups on native cysteines to map the structural transitions of the sarcoplasmic reticulum Ca(2+)-ATPase, a 110 kDa transmembrane enzyme that transports Ca(2+) into the sarcoplasmic reticulum. Using magic angle spinning NMR, we monitored the chemical shifts of the methylene and methyl groups of the derivatized cysteine residues along the major steps of the enzymatic cycle. The methylene chemical shifts are sensitive to the ATPase conformational changes induced upon nucleotide and Ca(2+) ion binding and are ideal probes for active and inactive states of the enzyme. This new approach is extendable to large mammalian enzymes and signaling proteins with native or engineered cysteine residues in their amino acid sequence. PMID- 26650886 TI - Use of the Ramsay Assay to Measure Fluid Secretion and Ion Flux Rates in the Drosophila melanogaster Malpighian Tubule. AB - Modulation of renal epithelial ion transport allows organisms to maintain ionic and osmotic homeostasis in the face of varying external conditions. The Drosophila melanogaster Malpighian (renal) tubule offers an unparalleled opportunity to study the molecular mechanisms of epithelial ion transport, due to the powerful genetics of this organism and the accessibility of its renal tubules to physiological study. Here, we describe the use of the Ramsay assay to measure fluid secretion rates from isolated fly renal tubules, with the use of ion specific electrodes to measure sodium and potassium concentrations in the secreted fluid. This assay allows study of transepithelial fluid and ion fluxes of ~20 tubules at a time, without the need to transfer the secreted fluid to a separate apparatus to measure ion concentrations. Genetically distinct tubules can be analyzed to assess the role of specific genes in transport processes. Additionally, the bathing saline can be modified to examine the effects of its chemical characteristics, or drugs or hormones added. In summary, this technique allows the molecular characterization of basic mechanisms of epithelial ion transport in the Drosophila tubule, as well as regulation of these transport mechanisms. PMID- 26650885 TI - Biomarkers of Cervical Inflammation and Immunity Associated with Cervical Shedding of HIV-1. AB - BACKGROUND: Cervicovaginal HIV shedding is associated with increased female-to male and mother-to-child transmission. Genital inflammation may increase shedding through cytokines/chemokines which recruit and activate HIV target cells. We evaluated whether cervical immune mediators present before seroconversion affected HIV shedding and whether mediators differed between shedders and nonshedders. METHODS: We used cervical samples from 187 African women with documented HIV seroconversion in the Hormonal Contraception and HIV study. Samples were from the two visits before seroconversion (T-2 and/or T-1), and/or at seroconversion (T0), and/or the two visits (T + 1 and/or T + 2) after seroconversion. We measured interleukin (IL)-1beta, IL-1 Receptor Antagonist (IL 1RA), IL-6, IL-8, RANTES (Regulated on Activation, Normal T-Cell Expressed and Secreted), MIP-3alpha, vascular endothelial growth factor (VEGF), Intercellular Adhesion Molecule-1 (ICAM-1), secretory leukocyte protease inhibitor (SLPI), and BD-2 and used the Wilcoxon test and generalized linear models to evaluate the association between mediators and shedding. RESULTS: The only immune mediator that differed at T-1 was RANTES, which was higher among shedders (p <= .05). HIV seroconversion was followed by significant decreases in many mediators, but a significant increase in RANTES. The magnitude of the change was significantly different for shedders versus nonshedders with regard to RANTES (increased in both groups, significantly more so in shedders), SLPI (decreased in both groups, significantly more so in shedders), and MIP-3alpha (decreased in shedders and increased in nonshedders). At T0, shedders had lower levels of SLPI and MIP 3alpha than nonshedders. CONCLUSIONS: In this study, a specific immune mediator profile was associated with risk of cervical HIV shedding. Higher and increasing levels of RANTES and lower and decreasing levels of SLPI and MIP-3alpha were associated with increased risk of HIV shedding. PMID- 26650887 TI - Supramolecular Dimerization and [2 + 2] Photocycloaddition Reactions of Crown Ether Styryl Dyes Containing a Tethered Ammonium Group: Structure-Property Relationships. AB - Molecular self-assembly is an effective strategy for controlling the [2 + 2] photocycloaddition reaction of olefins. The geometrical properties of supramolecular assemblies are proven to have a critical effect on the efficiency and selectivity of this photoreaction both in the solid state and in solution, but the role of other factors remains poorly understood. Convenient supramolecular systems to study the structure-property relationships are pseudocyclic dimers spontaneously formed by styryl dyes containing a crown ether moiety and a remote ammonium group. New dyes of this type were synthesized to investigate the effects of structural and electronic factors on the quantitative characteristics of supramolecular dimerization and [2 + 2] photocycloaddition in solution. Variable structural parameters for the styryl dyes were the size and structure of macrocyclic moiety, the nature of heteroaromatic residue, and the length of the ammonioalkyl group attached to this residue. Quantum chemical calculations of the pseudocyclic dimers were performed in order to interpret the relationships between the structure of the ammonium dyes and the efficiency of the supramolecular photoreaction. One of the dimeric complexes was obtained in the crystalline state and studied by X-ray diffraction. The results obtained demonstrate that the photocycloaddition in the pseudocyclic dimers can be dramatically affected by the electronic structure of the styryl moieties, as dependent on the electron-donating ability of the substituents on the benzene ring, and by the conformational flexibility of the pseudocycle, which determines the mobility of the olefinic bonds. The significance of electronic factors is highlighted by the fact that the photocycloaddition quantum yield in geometrically similar dimeric structures varies from <=10(-4) to 0.38. The latter value is unusually high for olefins in solution. PMID- 26650889 TI - Role of Stem Cells Transplantation in Tissue Regeneration After Acute or Chronic Acetaminophen Induced Liver Injury. AB - PURPOSE: Acetaminophen-induced liver injury (APAP) is recognized as a frequent etiologic factor responsible for hepatic damage in the developed world. Management remains still elusive as treatment options are limited and their results are inconclusive. Consequently new strategies are explored at the experimental level. Mesenchymal stem cells (MSCs) present a promising modality as they can promote liver regeneration (LG) and compensate acute liver injury (ALI). MATERIALS AND METHODS: Our research was focused on articles related to drug induced liver injury, mechanisms of liver regeneration (LG) after Acute Liver Injury (ALI) and recent experimental protocols of Mesenchymal Stem Cells (MSCs) transplantation after chemical insult. All these studies are cited on Pubmed and MedLine. RESULTS: This review has three distinct sections. First recent developments in ALI pathogenesis are presented. The second section covers cellular pathways and histological findings relevant to liver regeneration. The final chapter analyzes MSCs transplantation protocols after ALI and interrelation between liver regeneration and hepatic differentiation of MSCs. CONCLUSION: Adipose tissue stem cells (ADSCs) and (MSCs) transplantation represents a promising modality in severe ALI management although many aspects remain to be clarified. PMID- 26650888 TI - Recurrent somatic loss of TNFRSF14 in classical Hodgkin lymphoma. AB - Investigation of the genetic lesions underlying classical Hodgkin lymphoma (CHL) has been challenging due to the rarity of Hodgkin and Reed-Sternberg (HRS) cells, the pathognomonic neoplastic cells of CHL. In an effort to catalog more comprehensively recurrent copy number alterations occurring during oncogenesis, we investigated somatic alterations involved in CHL using whole-genome sequencing mediated copy number analysis of purified HRS cells. We performed low-coverage sequencing of small numbers of intact HRS cells and paired non-neoplastic B lymphocytes isolated by flow cytometric cell sorting from 19 primary cases, as well as two commonly used HRS-derived cell lines (KM-H2 and L1236). We found that HRS cells contain strikingly fewer copy number abnormalities than CHL cell lines. A subset of cases displayed nonintegral chromosomal copy number states, suggesting internal heterogeneity within the HRS cell population. Recurrent somatic copy number alterations involving known factors in CHL pathogenesis were identified (REL, the PD-1 pathway, and TNFAIP3). In eight cases (42%) we observed recurrent copy number loss of chr1:2,352,236-4,574,271, a region containing the candidate tumor suppressor TNFRSF14. Using flow cytometry, we demonstrated reduced TNFRSF14 expression in HRS cells from 5 of 22 additional cases (23%) and in two of three CHL cell lines. These studies suggest that TNFRSF14 dysregulation may contribute to the pathobiology of CHL in a subset of cases. PMID- 26650890 TI - Editor's Report. PMID- 26650891 TI - The N(2)-Furfuryl-deoxyguanosine Adduct Does Not Alter the Structure of B-DNA. AB - N(2)-Furfuryl-deoxyguanosine (fdG) is carcinogenic DNA adduct that originates from furfuryl alcohol. It is also a stable structural mimic of the damage induced by the nitrofurazone family of antibiotics. For the structural and functional studies of this model N(2)-dG adduct, reliable and rapid access to fdG-modified DNAs are warranted. Toward this end, here we report the synthesis of fdG-modified DNAs using phosphoramidite chemistry involving only three steps. The functional integrity of the modified DNA has been verified by primer extension studies with DNA polymerases I and IV from E. coli. Introduction of fdG into a DNA duplex decreases the Tm by ~1.6 degrees C/modification. Molecular dynamics simulations of a DNA duplex bearing the fdG adduct revealed that though the overall B-DNA structure is maintained, this lesion can disrupt W-C H-bonding, stacking interactions, and minor groove hydrations to some extent at the modified site, and these effects lead to slight variations in the local base pair parameters. Overall, our studies show that fdG is tolerated at the minor groove of the DNA to a better extent compared with other bulky DNA damages, and this property will make it difficult for the DNA repair pathways to detect this adduct. PMID- 26650893 TI - Fluorescence and Bioluminescence Imaging of Subcellular Ca2+ in Aged Hippocampal Neurons. AB - Susceptibility to neuron cell death associated to neurodegeneration and ischemia are exceedingly increased in the aged brain but mechanisms responsible are badly known. Excitotoxicity, a process believed to contribute to neuron damage induced by both insults, is mediated by activation of glutamate receptors that promotes Ca2+ influx and mitochondrial Ca2+ overload. A substantial change in intracellular Ca2+ homeostasis or remodeling of intracellular Ca2+ homeostasis may favor neuron damage in old neurons. For investigating Ca2+ remodeling in aging we have used live cell imaging in long-term cultures of rat hippocampal neurons that resemble in some aspects aged neurons in vivo. For this end, hippocampal cells are, in first place, freshly dispersed from new born rat hippocampi and plated on poli-D-lysine coated, glass coverslips. Then cultures are kept in controlled media for several days or several weeks for investigating young and old neurons, respectively. Second, cultured neurons are loaded with fura2 and subjected to measurements of cytosolic Ca2+ concentration using digital fluorescence ratio imaging. Third, cultured neurons are transfected with plasmids expressing a tandem of low-affinity aequorin and GFP targeted to mitochondria. After 24 hr, aequorin inside cells is reconstituted with coelenterazine and neurons are subjected to bioluminescence imaging for monitoring of mitochondrial Ca2+ concentration. This three-step procedure allows the monitoring of cytosolic and mitochondrial Ca2+ responses to relevant stimuli as for example the glutamate receptor agonist NMDA and compare whether these and other responses are influenced by aging. This procedure may yield new insights as to how aging influence cytosolic and mitochondrial Ca2+ responses to selected stimuli as well as the testing of selected drugs aimed at preventing neuron cell death in age related diseases. PMID- 26650894 TI - Operating from different premises: the ethics of inter-disciplinarity in health promotion. AB - The intersectoral and interdisciplinary nature of health promotion gives rise to ethical questions. This is because health promotion depends upon alliances between people who often have different perspectives on what matters in particular cases or different visions of the good society. This paper draws on the ambivalent relationship that health promoters can have with biomedicine to illustrate and explore the nature of these ethical questions. Examples from everyday life are used to underline the familiar nature of the kinds of coalitions and compromises that are needed to work alongside others with different values to oneself. It is suggested that analogous kinds of compromise are needed in health promotion and that this requires a form of 'diplomatic ethics' for health promoters that, in turn, raises questions about their ethical integrity. PMID- 26650892 TI - Structure and functional characterization of a bile acid 7alpha dehydratase BaiE in secondary bile acid synthesis. AB - Conversion of the primary bile acids cholic acid (CA) and chenodeoxycholic acid (CDCA) to the secondary bile acids deoxycholic acid (DCA) and lithocholic acid (LCA) is performed by a few species of intestinal bacteria in the genus Clostridium through a multistep biochemical pathway that removes a 7alpha hydroxyl group. The rate-determining enzyme in this pathway is bile acid 7alpha dehydratase (baiE). In this study, crystal structures of apo-BaiE and its putative product-bound [3-oxo-Delta(4,6) -lithocholyl-Coenzyme A (CoA)] complex are reported. BaiE is a trimer with a twisted alpha + beta barrel fold with similarity to the Nuclear Transport Factor 2 (NTF2) superfamily. Tyr30, Asp35, and His83 form a catalytic triad that is conserved across this family. Site directed mutagenesis of BaiE from Clostridium scindens VPI 12708 confirm that these residues are essential for catalysis and also the importance of other conserved residues, Tyr54 and Arg146, which are involved in substrate binding and affect catalytic turnover. Steady-state kinetic studies reveal that the BaiE homologs are able to turn over 3-oxo-Delta(4) -bile acid and CoA-conjugated 3-oxo Delta(4) -bile acid substrates with comparable efficiency questioning the role of CoA-conjugation in the bile acid metabolism pathway. PMID- 26650895 TI - Selenium Increases Thyroid-Stimulating Hormone-Induced Sodium/Iodide Symporter Expression Through Thioredoxin/Apurinic/Apyrimidinic Endonuclease 1-Dependent Regulation of Paired Box 8 Binding Activity. AB - AIMS: The sodium-iodide symporter (NIS) mediates the uptake of I(-) by the thyroid follicular cell and is essential for thyroid hormone biosynthesis. Nis expression is stimulated by thyroid-stimulating hormone (TSH) and also requires paired box 8 (Pax8) to bind to its promoter. Pax8 binding activity depends on its redox state by a mechanism involving thioredoxin/thioredoxin reductase-1 (Txn/TxnRd1) reduction of apurinic/apyrimidinic endonuclease 1 (Ape1). In this study, we investigate the role of Se in Nis expression. RESULTS: Selenium increases TSH-induced Nis expression and activity in rat thyroid cells. The stimulatory effect of Se occurs at the transcriptional level and is only observed for Nis promoters containing a Pax8 binding site in the Nis upstream enhancer, suggesting that Pax8 is involved in this effect. In fact, Se increases Pax8 expression and its DNA-binding capacity, and in Pax8-silenced rat thyroid cells, Nis is not Se responsive. By inhibiting Ape1 and TxnRd1 functions, we found that both enzymes are crucial for TSH and TSH plus Se stimulation of Pax8 activity and mediate the Nis response to Se treatment. INNOVATION: We describe that Se increases Nis expression and activity. We demonstrate that this effect is dependent on the redox functions of Ape1 and Txn/TxnRd1 through control of the DNA binding activity of Pax8. CONCLUSION: Nis expression is controlled by Txn/Ape1 through a TSH/Se-dependent mechanism. These findings open a new field of study regarding the regulation of Nis activity in thyroid cells. Antioxid. Redox Signal. 24, 855-866. PMID- 26650896 TI - Electrospun gelatin biopapers as substrate for in vitro bilayer models of blood brain barrier tissue. AB - Gaining a greater understanding of the blood-brain barrier (BBB) is critical for improvement in drug delivery, understanding pathologies that compromise the BBB, and developing therapies to protect the BBB. In vitro human tissue models are valuable tools for studying these issues. The standard in vitro BBB models use commercially available cell culture inserts to generate bilayer co-cultures of astrocytes and endothelial cells (EC). Electrospinning can be used to produce customized cell culture substrates with optimized material composition and mechanical properties with advantages over off-the-shelf materials. Electrospun gelatin is an ideal cell culture substrate because it is a natural polymer that can aid cell attachment and be modified and degraded by cells. Here, we have developed a method to produce cell culture inserts with electrospun gelatin "biopaper" membranes. The electrospun fiber diameter and cross-linking method were optimized for the growth of primary human endothelial cell and primary human astrocyte bilayer co-cultures to model human BBB tissue. BBB co-cultures on biopaper were characterized via cell morphology, trans-endothelial electrical resistance (TEER), and permeability to FITC-labeled dextran and compared to BBB co-cultures on standard cell culture inserts. Over longer culture periods (up to 21 days), cultures on the optimized electrospun gelatin biopapers were found to have improved TEER, decreased permeability, and permitted a smaller separation between co-cultured cells when compared to standard PET inserts. PMID- 26650897 TI - Investigation of Aberrant Splicing Induced by AIPL1 Variations as a Cause of Leber Congenital Amaurosis. AB - Purpose: Biallelic mutations in AIPL1 cause Leber congenital amaurosis (LCA), a devastating retinal degeneration characterized by the loss or severe impairment of vision within the first few years of life. AIPL1 is highly polymorphic with more than 50 mutations and many more polymorphisms of uncertain pathogenicity identified. As such, it can be difficult to assign disease association of AIPL1 variations. In this study, we investigate suspected disease-associated AIPL1 variations, including nonsynonymous missense and intronic variants to validate their pathogenicity. Methods: AIPL1 minigenes harboring missense and intronic variations were constructed by amplification of genomic fragments of the human AIPL1 gene. In vitro splice assays were performed to identify the resultant AIPL1 transcripts. Results: We show that all nine of the suspected disease-associated AIPL1 variations investigated induced aberrant pre-mRNA splicing of the AIPL1 gene, and our study is the first to show that AIPL1 missense mutations alter AIPL1 splicing. We reveal that the presumed rare benign variant c.784G>A [p.(G262S)] alters in vitro AIPL1 splicing, thereby validating the disease association and clarifying the underlying disease mechanism. We also reveal that in-phase exon skipping occurs normally at a low frequency in the retina, but arises abundantly as a consequence of specific AIPL1 variations, suggesting a tolerance threshold for the expression of these alternative transcripts in the retina normally, which is exceeded in LCA. Conclusions: Our data confirm the disease-association of the AIPL1 variations investigated and reveal for the first time that aberrant splicing of AIPL1 is an underlying mechanism of disease in LCA. PMID- 26650898 TI - Optimizing the Detection of Preperimetric Glaucoma by Combining Structural and Functional Tests. AB - Purpose: We evaluated the performance of low contrast achromatic (LLA) multifocal visual evoked potentials (mfVEP) in preperimetric glaucoma and compared its diagnostic performance to other early diagnostic tests. We identified the clinically most useful tests and combinations in preperimetric glaucoma. Methods: We studied 59 patients with at least one glaucomatous disc, with normal, reliable visual fields in that eye, and 17 normal controls. All participants underwent complete ophthalmic examination including Humphrey visual fields (HVF), short wavelength automated perimetry (SWAP), frequency doubling perimetry (FDT Matrix), Spectralis optical coherence tomography (OCT), Heidelberg retinal tomography (HRT 3), and color stereoscopic optic disc photographs. We recorded mfVEPs using LLA stimulation. Results: We studied 85 eyes of 59 patients (64.89 +/- 8.15 years) and 34 eyes of 17 controls (64.28 +/- 13.06 years; P = 0.64). Heidelberg retinal tomography and LLA mfVEP demonstrated the best sensitivities (50.6% and 51.8%, respectively) in identifying preperimetric glaucoma, and were not significantly different from each other. Both tests had significantly better sensitivity than all other tests (P < 0.0001). Of the eyes, 76.5% were identified by the combination of (any one of) LLA mfVEP and HRT. Sensitivity of the combination was significantly better than any of the individual tests (P < 0.05 for all pairs), or any other combinations of tests, with better negative than positive predictive value. Conclusions: The LLA mfVEP test identified approximately 50.6% eyes with preperimetric glaucoma, which was significantly higher than other perimetric methods, and similar to HRT. The combination of LLA mfVEP and HRT had exceptionally high sensitivity of 76.5% for preperimetric glaucoma. PMID- 26650899 TI - Estimating the Usefulness of Humphrey Perimetry Gaze Tracking for Evaluating Structure-Function Relationship in Glaucoma. AB - Purpose: We have previously reported that fixation loss (FL) rates, false positive (FP) rates, and gaze tracking (GT) parameters (average tracking failure frequency per stimulus [TFF], average blinking frequency [BF], average frequency of eye movements between 1 degrees and 2 degrees [move1-2], between 3 degrees and 5 degrees [move3-5], and equal to or more than 6 degrees [move>=6]) are related to the over- or underestimation of visual field (VF) results. The purpose of the current study was to validate these results by investigating the effect of implementing the GT parameters on the relationship between VF results and optical coherence tomography (OCT) measurements. Methods: Two hundred forty-four eyes of 155 open-angle glaucoma patients were included. Vision fixation during VF tests with the Humphrey Field Analyzer (24-2 SITA standard) was evaluated using the gaze fixation chart at the bottom of the VF printout. Mean total deviation (mTD) values were calculated, and their relationship with OCT-determined circumpapillary retinal nerve fiber layer (cp-RNFL), OCT-determined macular ganglion cell complex (GCC) thickness, and axial length was investigated using the corrected Akaike Information Criterion (AICc) in linear mixed modeling. Results: In the best model, average total cpRNFL thickness, average total GCC thickness, axial length, FL, FP, move3-5, move>=6, TFF, and BF were selected as significant predictors (mTD = 2.1 + 0.097 * average total cpRNFL thickness + 0.089 * average total GCC thickness - 0.94 * axial length + 2.7 * FL + 7.2 * FP - 7.0 * move3-5 - 1.8 * move>=6 - 4.2 * TFF - 1.7 * BF). Conclusions: Both GT parameters and classic VF reliability indices had significant influence on the structure-function relationship analysis in glaucoma. PMID- 26650900 TI - Squiggly Lines and Wiggly Data. PMID- 26650901 TI - Lens Position Parameters as Predictors of Intraocular Pressure Reduction After Cataract Surgery in Nonglaucomatous Patients With Open Angles. AB - Purpose: To evaluate the relationship between lens position parameters and intraocular pressure (IOP) reduction after cataract surgery in nonglaucomatous eyes with open angles. Methods: The main outcome of the prospective study was percentage of IOP change, which was calculated using the preoperative IOP and the IOP 4 months after cataract surgery in nonglaucomatous eyes with open angles. Lens position (LP), defined as anterior chamber depth (ACD) + 1/2 lens thickness (LT), was assessed preoperatively using parameters from optical biometry. Preoperative IOP, central corneal thickness, ACD, LT, axial length (AXL), and the ratio of preoperative IOP to ACD (PD ratio) were also evaluated as potential predictors of percentage of IOP change. The predictive values of the parameters we found to be associated with the primary outcome were compared. Results: Four months after cataract surgery, the average IOP reduction was 2.03 +/- 2.42 mm Hg, a 12.74% reduction from the preoperative mean of 14.5 +/- 3.05 mm Hg. Lens position was correlated with IOP reduction percentage after adjusting for confounders (P = 0.002). Higher preoperative IOP, shallower ACD, shorter AXL, and thicker LT were significantly associated with percentage of IOP decrease. Although not statistically significant, LP was a better predictor of percentage of IOP change compared to PD ratio, preoperative IOP, and ACD. Conclusions: The percentage of IOP reduction after cataract surgery in nonglaucomatous eyes with open angles is greater in more anteriorly positioned lenses. Lens position, which is convenient to compute by basic ocular biometric data, is an accessible predictor with considerable predictive value for postoperative IOP change. PMID- 26650902 TI - Spontaneous Cross-linking for Fabrication of Nanohybrids Embedded with Size Controllable Particles. AB - This paper reports a versatile method to fabricate robust carbon/metal hybrids with ultrasmall particle and highly developed porous structure through a scalable and facile way. Alginate is used as the precursor for it could perform cross linking reaction with different polyvalent metal ions to form gels. After simple freeze-drying and carbonization of the alginate-derived gels, we obtained the carbon/metal hybrids with fine nanostructure. Eleven kinds of metal ions were introduced to form gels and five kinds of the gels were carbonized to produce the carbon/metal hybrids. By adjusting the reaction condition, we could tune the size of the nanoparticles in the obtained hybrids. The obtained SnO2/C hybrid shows outstanding specific capacity, rate performance, and long cycle life when it is used as the anode materials of lithium ion batteries. The ultrasmall active nanoparticles were uniformly dispersed within an interconnected pore framework. It ensured a short diffusion and transportation distance of electrolyte ions to the surfaces of active nanoparticles. In addition, the robust carbon framework comprises of quasigraphitic carbon layers. It contributed to the high rate performance by providing excellent conductive pathways for electrons within the electrodes. This work provides a general method for fabrication of carbon/metal (oxide) hybrids with fine nanostructure for application in energy storage. PMID- 26650903 TI - Outcome after Repetitive Mild Traumatic Brain Injury Is Temporally Related to Glucose Uptake Profile at Time of Second Injury. AB - Repeated mild traumatic brain injury (rmTBI) results in worsened outcomes, compared with a single injury, but the mechanism of this phenomenon is unclear. We have previously shown that mild TBI in a rat lateral fluid percussion model results in globally depressed glucose uptake, with a peak depression at 24 h that resolves by 16 days post-injury. The current study investigated the outcomes of a repeat injury conducted at various times during this period of depressed glucose uptake. Adult male rats were therefore subjected to rmTBI with a latency of 24 h, 5 days, or 15 days between injuries, followed by assessment of motor function, histopathology, and glucose uptake using positron emission tomography (PET). Rats that received a 24 h rmTBI showed significant deficits in motor function tasks, as well as significant increases in lesion volume and neuronal damage. The level of microglial and astrocytic activation also was associated with the timing of the second impact. Finally, rmTBI with latencies of 24 h and 5 days showed significant alterations in [(18)F]fluorodeoxyglucose uptake, compared with baseline scans. Therefore, we conclude that the state of the metabolic environment, as indicated by FDG-PET at the time of the repeat injury, significantly influences neurological outcomes. PMID- 26650913 TI - Thin strut bare metal stents in patients with atrial fibrillation: Is there still a need for BMS? AB - OBJECTIVES: This observational study assessed the 9-month clinical outcomes in an " all comers " population with a focus on patients with atrial fibrillation (AF) after thin strut bare metal stenting. BACKGROUND: Drug eluting stent (DES) implantation is the treatment of choice for coronary artery disease (CAD) leaving only marginal indications for the use of bare metal stents (BMS). However, selected treatment populations with DES contraindications such as patients who cannot sustain 6-12 months of dual antiplatelet therapy (DAPT) remain candidates for BMS implantations. METHODS: Thin strut bare metal stenting in a priori defined subgroups were investigated in a non-randomized, international, multicenter "all comers" observational study. Primary endpoint was the 9-month TLR rate whereas secondary endpoints included the 9-month MACE and procedural success rates. RESULTS: A total of 783 patients of whom 98 patients had AF underwent BMS implantation. Patient age was 70.4 +/- 12.8 years. Cardiovascular risk factors in the overall population were male gender (78.2%, 612/783), diabetes (25.2%, 197/783), hypertension (64.1%, 502/783), cardiogenic shock (4.9%, 38/783) and end stage renal disease (4.9%, 38/783). In-hospital MACE was 4.1% (30/783) in the overall population. The 9-month TLR rate was 4.5% (29/645) in the non-AF group and 3.3% (3/90) in the AF group (P = 0.613). At 9 months, the MACE rate in the AF-group and non-AF group was not significantly different either (10.7%, 69/645 vs. 6.7%, 6/90; P = 0.237). Accumulated stroke rates were 0.3% (2/645) in the non-AF subgroup at baseline and 1.1% (1/90) in the AF subgroup (P = 0.264). CONCLUSION: Bare metal stenting in AF patients delivered acceptably low TLR and MACE rates while having the benefit of a significantly shorter DAPT duration in a DES dominated clinical practice. (c) 2015 Wiley Periodicals, Inc. PMID- 26650914 TI - Early deterioration of residual hearing in patients with SLC26A4 mutations. AB - OBJECTIVES/HYPOTHESIS: To compare changes in hearing in patients with SLC26A4 during early and late childhood. STUDY DESIGN: Retrospective chart review. METHODS: A total of 102 patients with biallelic SLC26A4 mutations visited the tertiary referral otolaryngology department between March 2005 and February 2015. Newborn hearing screening tests had been performed on 22 of these patients. We analyzed 26 patients who underwent hearing tests more than twice using the same method (auditory brainstem response/auditory steady state response/play audiometry) before and after 3 years of age. We analyzed changes in hearing levels according to age. RESULTS: Among 22 patients with SLC26A4 mutations who underwent newborn hearing screening tests, seven (31.8%) passed the newborn hearing screening test in both ears, and six (27.3%) passed in one ear. Among 16 patients with SLC26A4 mutations who underwent hearing tests more than twice before age 3 years, the hearing levels of 14 (87.5%) deteriorated rapidly during this time. Among 16 patients with SLC26A4 mutations who underwent hearing tests more than twice after the age of 3 years, two (12.5%) patients' hearing levels deteriorated; the hearing levels of most of the patients were relatively stable. CONCLUSIONS: These data suggest that many patients with SLC26A4 mutations have significant residual hearing at birth, and that the hearing deterioration in these patients occurs before 3 years of age. After age 3 years, the residual hearing was relatively stable and did not tend to deteriorate. Therefore, in patients with a pendrin mutation, early intervention to preserve residual hearing should be a clinical focus. LEVEL OF EVIDENCE: 4. Laryngoscope, 126:E286-E291, 2016. PMID- 26650915 TI - Chemical Gardens as Flow-through Reactors Simulating Natural Hydrothermal Systems. AB - Here we report experimental simulations of hydrothermal chimney growth using injection chemical garden methods. The versatility of this type of experiment allows for testing of various proposed ocean / hydrothermal fluid chemistries that could have driven reactions toward the origin of life in environments on the early Earth, early Mars, or even other worlds such as the icy moons of the outer planets. We show experiments that include growth of chemical garden structures under anoxic conditions simulating the early Earth, inclusion of trace components of phosphates / organics in the injection solution to incorporate them into the structure, a switch of the injection solution to introduce a secondary precipitating anion, and the measurement of membrane potentials generated by chemical gardens. Using this method, self-assembling chemical garden structures were formed that mimic the natural chimneys precipitated at submarine hydrothermal springs, and these precipitates can be used successfully as flow through reactors by feeding through multiple successive "hydrothermal" injections. PMID- 26650917 TI - The effect of smoking habit changes on body weight: Evidence from the UK. AB - This paper evaluates the causal relationship between smoking and body weight through two waves (2004-2006) of the British Household Panel Survey. We model the effect of changes in smoking habits, such as quitting or reducing, and account for the heterogeneous responses of individuals located at different points of the body mass distribution by quantile regression. We test our results by means of a large set of control groups and investigate their robustness by using the changes in-changes estimator and accounting for different thresholds to define smoking reductions. Our results reveal the positive effect of quitting smoking on weight changes, which is also found to increase in the highest quantiles, whereas the decision to reduce smoking does not affect body weight. PMID- 26650916 TI - Cooperation between CD4+ T Cells and Humoral Immunity Is Critical for Protection against Dengue Using a DNA Vaccine Based on the NS1 Antigen. AB - Dengue virus (DENV) is spread through most tropical and subtropical areas of the world and represents a serious public health problem. At present, the control of dengue disease is mainly hampered by the absence of antivirals or a vaccine, which results in an estimated half worldwide population at risk of infection. The immune response against DENV is not yet fully understood and a better knowledge of it is now recognized as one of the main challenge for vaccine development. In previous studies, we reported that a DNA vaccine containing the signal peptide sequence from the human tissue plasminogen activator (t-PA) fused to the DENV2 NS1 gene (pcTPANS1) induced protection against dengue in mice. In the present work, we aimed to elucidate the contribution of cellular and humoral responses elicited by this vaccine candidate for protective immunity. We observed that pcTPANS1 exerts a robust protection against dengue, inducing considerable levels of anti-NS1 antibodies and T cell responses. Passive immunization with anti-NS1 antibodies conferred partial protection in mice infected with low virus load (4 LD50), which was abrogated with the increase of viral dose (40 LD50). The pcTPANS1 also induced activation of CD4+ and CD8+ T cells. We detected production of IFN-gamma and a cytotoxic activity by CD8+ T lymphocytes induced by this vaccine, although its contribution in the protection was not so evident when compared to CD4+ cells. Depletion of CD4+ cells in immunized mice completely abolished protection. Furthermore, transfer experiments revealed that animals receiving CD4+ T cells combined with anti-NS1 antiserum, both obtained from vaccinated mice, survived virus infection with survival rates not significantly different from pcTPANS1-immunized animals. Taken together, results showed that the protective immune response induced by the expression of NS1 antigen mediated by the pcTPANS1 requires a cooperation between CD4+ T cells and the humoral immunity. PMID- 26650918 TI - A comparison of diagnosed and undiagnosed diabetes patients and labor supply. AB - Using data from four waves of the National Health and Nutrition Examination Survey, we examine the difference between individuals with diagnosed and undiagnosed cases of type 2 diabetes and their labor supply decisions. We show that a diagnosis of type 2 diabetes is significantly associated with a reduction in both male and female employment probability by 11 and 19 percentage points, respectively. Additionally, hours worked by individuals with diagnosed type 2 diabetes are 7h lower per week for males and 8h lower per week for females. Further, individuals with undiagnosed type 2 diabetes experience a drop in labor supply somewhat smaller but similar to their diagnosed counterparts. This association may be driven by the similarities between undiagnosed and very recently diagnosed type 2 diabetes. In all estimations, we consistently find that type 1 diabetes has a different effect than either diagnosed or undiagnosed type 2 diabetes. PMID- 26650919 TI - Does obesity influence labour market outcomes among working-age adults? Evidence from Canadian longitudinal data. AB - Although a negative association between obesity and labour market outcomes is commonly reported in many studies, the causal nature of this relationship remains unclear. Using nationally representative longitudinal data from the last six confidential master files (2000/2001-2010/2011) of the National Population Health Survey, we examine the association between obesity and employment participation and earnings among working-age adults in Canada. After controlling for demographic and socioeconomic characteristics, lifestyle factors and time invariant individual heterogeneity, our results show that obesity is not significantly associated with employment participation but is associated with reduced hourly wage rate and annual income among women by about 4% and 4.5%, respectively. The corresponding results for men show that obesity is associated with about 2% reduction in wage rate and income, but significant at 10% level. However, after controlling for the potential reverse causality bias using the lagged measure of obesity, the effect of obesity on wage rate and income became positive or statistically non-significant. Our findings suggest that obesity is not causally associated with negative labour market outcomes among working-age men in Canada. For working-age women, we find limited evidence of negative labour market outcomes. PMID- 26650920 TI - On-Surface Engineering of a Magnetic Organometallic Nanowire. AB - The manipulation of the molecular spin state by atom doping is an attractive strategy to confer desirable magnetic properties to molecules. Here, we present the formation of novel magnetic metallocenes by following this approach. In particular, two different on-surface procedures to build isolated and layer integrated Co-ferrocene (CoFc) molecules on a metallic substrate via atomic manipulation and atom deposition are shown. The structure as well as the electronic properties of the so-formed molecule are investigated combining scanning tunneling microscopy and spectroscopy with density functional theory calculations. It is found that unlike single ferrocene a CoFc molecule possesses a magnetic moment as revealed by the Kondo effect. These results correspond to the first controlled procedure toward the development of tailored metallocene based nanowires with a desired chemical composition, which are predicted to be promising materials for molecular spintronics. PMID- 26650921 TI - Visualizing Human Hematopoietic Stem Cell Trafficking In Vivo Using a Zebrafish Xenograft Model. AB - Zebrafish is gaining increased popularity as a model organism to study stem cell biology. It also is widely used as model system to visualize human leukemic stem cells. However, xenotransplantation of primary human stem/progenitor cells has not been described. Here, we use casper pigmentation mutant fish that are transparent crossed to fli-GFP transgenic fish as recipients of red labeled human CD34(+) cells. We have investigated various conditions and protocols with the aim to monitor and visualize the fate of transplanted human CD34(+) cells. We here report successful use of casper mutant zebrafish embryos for the direct monitoring of human hematopoietic stem cell transplantation, differentiation, and trafficking in vivo. PMID- 26650922 TI - Sleep Hygiene and Sleep Quality of Third-Trimester Pregnant Women. AB - The purpose of this descriptive study was to examine the associations of sleep hygiene and actigraphy measures of sleep with self-reported sleep quality in 197 pregnant women in northern Taiwan. Third-trimester pregnant women completed the Sleep Hygiene Practice Scale (SHPS) and the Pittsburgh Sleep Quality Index (PSQI) as well as the Center for Epidemiologic Studies-Depression Scale (CES-D), and wore an actigraph for 7 consecutive days. Student's t-test was used to compare the SHPS scores and means as well as variability of actigraphy sleep variables between poor sleepers (i.e., PSQI global score >5) and good sleepers (i.e., PSQI global score <=5). Compared to good sleepers, poor sleepers reported significantly worse sleep hygiene, with higher SHPS scores and higher sleep schedule, arousal-related behavior, and sleep environment subscale scores. Poor sleepers had significantly greater intra-individual variability of sleep onset latency, total nighttime sleep, and wake after sleep onset than good sleepers. In stepwise linear regression, older maternal age (p = .01), fewer employment hours per week (p = .01), higher CES-D total score (p < .01), and higher SHPS arousal related behavior subscale scores (p < .01) predicted self-reported global sleep quality. Findings support avoiding physically, physiologically, emotionally, or cognitively arousing activities before bedtime as a target for sleep-hygiene intervention in women during pregnancy. PMID- 26650923 TI - Encephalitozoon cuniculi in Raw Cow's Milk Remains Infectious After Pasteurization. AB - This study describes the prevalence of Encephalitozoon cuniculi in raw cow's milk and evaluates the effect of different milk pasteurization treatments on E. cuniculi infectivity for severe combined immunodeficient (SCID) mice. Using a nested polymerase chain reaction approach, 1 of 50 milking cows was found to repeatedly shed E. cuniculi in its feces and milk. Under experimental conditions, E. cuniculi spores in milk remained infective for SCID mice following pasteurization treatments at 72 degrees C for 15 s or 85 degrees C for 5 s. Based on these findings, pasteurized cow's milk should be considered a potential source of E. cuniculi infection in humans. PMID- 26650924 TI - Meta-Analysis of Oral Anticoagulants with Dual versus Single Antiplatelet Therapy in Patients after Percutaneous Coronary Intervention. AB - BACKGROUND: The combined use of dual antiplatelet therapy with oral anticoagulation (OAC) is required after coronary artery stenting or acute coronary syndromes (ACS). METHODS AND RESULTS: We performed a meta-analysis (Embase and MEDLINE search) of the comparative effects of triple antithrombotic therapy (TT) versus OAC with single antiplatelet therapy (dual therapy [DT]) on all-cause mortality, stroke, cardiovascular death, myocardial infarction (MI), target vessel revascularization, and major bleeding. Three prospective controlled studies and five cohort studies compared TT versus DT. We identified three prospective controlled and five cohort studies with 4564 patients on TT and 1848 on DT with an average follow-up duration of 10.1 months. TT is associated with similar rates of all-cause mortality, stroke, and major bleeding but significantly lower rates of MI compared with DT. CONCLUSIONS: Triple antithrombotic therapy is associated with similar mortality and bleeding rates but fewer MIs compared with OAC and single antiplatelet therapy. PMID- 26650925 TI - Prevalence of adult ADHD in an all-female prison unit. AB - There is increasing evidence suggesting a link between ADHD and criminality, including a strong association between ADHD symptoms and the likelihood of being on probation or in prison. Most studies investigating the prevalence of ADHD in prison populations have focused on adult male offenders. In the current study, 69 female prisoners were screened for both childhood and adult ADHD symptoms using the Barkley Adult ADHD Rating Scale-IV. The results indicate that 41 % of the prisoners met the diagnostic criteria for ADHD in childhood and continued to meet criteria for ADHD as adults. More importantly, young female prisoners (aged 18 25) were significantly more likely to report symptoms of ADHD than older prisoners. Prisoners who reported symptoms of ADHD also reported high levels of impairment associated with these symptoms. A better understanding of the prevalence of ADHD in female prison units can highlight specific areas for intervention during rehabilitation, as well as the management of serious incidents within prison. PMID- 26650926 TI - Regional Brain Glucose Hypometabolism in Young Women with Polycystic Ovary Syndrome: Possible Link to Mild Insulin Resistance. AB - OBJECTIVE: To investigate whether cerebral metabolic rate of glucose (CMRglu) is altered in normal weight young women with polycystic ovary syndrome (PCOS) who exhibit mild insulin resistance. MATERIALS AND METHODS: Seven women with PCOS were compared to eleven healthy female controls of similar age, education and body mass index. Regional brain glucose uptake was quantified using FDG with dynamic positron emission tomography and magnetic resonance imaging, and its potential relationship with insulin resistance assessed using the updated homeostasis model assessment (HOMA2-IR). A battery of cognitive tests was administered to evaluate working memory, attention and executive function. RESULTS: The PCOS group had 10% higher fasting glucose and 40% higher HOMA2-IR (p <= 0.035) compared to the Controls. The PCOS group had 9-14% lower CMRglu in specific regions of the frontal, parietal and temporal cortices (p <= 0.018). A significant negative relation was found between the CMRglu and HOMA2-IR mainly in the frontal, parietal and temporal cortices as well as in the hippocampus and the amygdala (p <= 0.05). Globally, cognitive performance was normal in both groups but scores on the PASAT test of working memory tended to be low in the PCOS group. CONCLUSIONS: The PCOS group exhibited a pattern of low regional CMRglu that correlated inversely with HOMA2-IR in several brain regions and which resembled the pattern seen in aging and early Alzheimer's disease. These results suggest that a direct association between mild insulin resistance and brain glucose hypometabolism independent of overweight or obesity can exist in young adults in their 20s. Further investigation of the influence of insulin resistance on brain glucose metabolism and cognition in younger and middle-aged adults is warranted. PMID- 26650927 TI - Imaging findings of Hoffa's fat pad herniation. AB - BACKGROUND: We report the radiologic findings of herniation of Hoffa's fat pad through a defect in the lateral patellar retinaculum in young children who presented with painless masses visible by ultrasound (US) only with flexion of the knee. MATERIAL AND METHODS: Six children, between the ages of 1-8 years, presented with an anterolateral knee mass that was not tender and was only seen and palpable with knee flexion. An US was performed in all patients, magnetic resonance imaging (MRI) in 2 patients and knee radiographs in 1 patient. RESULTS: US imaging displayed focal herniation of Hoffa's fat pad within the infrapatellar region through a defect of the lateral retinaculum, visible only during dynamic imaging when the knee was in flexion. MRI performed in knee extension did not demonstrate a mass; however, it revealed a focal defect in the lateral retinaculum in the region of the abnormality. Radiographs were normal. CONCLUSION: Focal herniation of Hoffa's fat pad is an uncommon cause of an anterolateral knee mass in young children. When a knee mass is only identified in flexion, focal fat herniation through a defect in the retinaculum should be suspected and a dynamic US should be performed. PMID- 26650928 TI - Economic constraints on taste formation and the true cost of healthy eating. AB - This article shows how an interaction between economic constraints and children's taste preferences shapes low-income families' food decisions. According to studies of eating behavior, children often refuse unfamiliar foods 8 to 15 times before accepting them. Using 80 interviews and 41 grocery-shopping observations with 73 primary caregivers in the Boston area in 2013-2015, I find that many low income respondents minimize the risk of food waste by purchasing what their children like--often calorie-dense, nutrient-poor foods. High-income study participants, who have greater resources to withstand the cost of uneaten food, are more likely to repeatedly introduce foods that their children initially refuse. Several conditions moderate the relationship between children's taste aversion and respondents' risk aversion, including household-level food preferences, respondents' conceptions of adult authority, and children's experiences outside of the home. Low-income participants' risk aversion may affect children's taste acquisition and eating habits, with implications for socioeconomic disparities in diet quality. This article proposes that the cost of providing children a healthy diet may include the possible cost of foods that children waste as they acquire new tastes. PMID- 26650929 TI - Framing health for land-use planning legislation: A qualitative descriptive content analysis. AB - PURPOSE AND SETTING: Framing health as a relevant policy issue for other sectors is not well understood. A recent review of the New South Wales (Australia) land use planning system resulted in the drafting of legislation with an internationally unprecedented focus on human health. We apply a political science approach to investigate the question 'how and to what extent were health and wider issues framed in submissions to the review?' METHODS: We investigated a range of stakeholder submissions including health focussed agencies (n = 31), purposively identified key stakeholders with influence on the review (n = 24), and a random sample of other agencies and individuals (n = 47). Using qualitative descriptive analysis we inductively coded for the term 'health' and sub categories. We deductively coded for 'wider concerns' using a locally endorsed 'Healthy Urban Development Checklist'. Additional inductive analysis uncovered further 'wider concerns'. FINDINGS: Health was explicitly identified as a relevant issue for planning policy only in submissions by health-focussed agencies. This framing concerned the new planning system promoting and protecting health as well as connecting health to wider planning concerns including economic issues, transport, public open space and, to a slightly lesser extent, environmental sustainability. Key stakeholder and other agency submissions focussed on these and other wider planning concerns but did not mention health in detail. Health agency submissions did not emphasise infrastructure, density or housing as explicitly as others. CONCLUSIONS: Framing health as a relevant policy issue has the potential to influence legislative change governing the business of other sectors. Without submissions from health agencies arguing the importance of having health as an objective in the proposed legislation it is unlikely health considerations would have gained prominence in the draft bill. The findings have implications for health agency engagement with legislative change processes and beyond in land use planning. PMID- 26650930 TI - Contribution of health behaviors to the association between area-level socioeconomic status and cancer mortality. AB - Cancer mortality is higher among residents of low-socioeconomic status (SES) areas than those of high-SES areas; however, the contribution of modifiable risk factors to this disparity is not known. We used data from 54,737 participants in the VITamins And Lifestyle (VITAL) Study, aged 50-76 with no history of cancer at baseline (2000-2002). Of these, 1488 died of cancer over an average of 7.7 years of follow-up. Data on modifiable risk factors including body mass index (BMI), physical activity, diet, alcohol, smoking and screening were taken from baseline questionnaires. We constructed a block group-level SES index using data from the 2000 United States Census and fit Cox proportional hazards models estimating the association between area-level SES and total cancer mortality with and without control for modifiable risk factors. All statistical tests are 2-sided. Cancer mortality was 77% (95% CI: 50%, 111%) higher in the lowest-SES areas compared with the highest. Modifiable risk factors accounted for 45% (95% CI: 34%, 62%) of this association. Smoking explained the greatest proportion (29%; 95% CI: 22%, 40%) of the observed association, followed by diet (11%; 95% CI: 7%, 17%), physical activity (10%; 95% CI: 7%, 16%), screening (9%; 6%, 13%), and BMI (5%; 95% CI: 1%, 10%). Results were similar in models controlling for individual education and income. The association between area-level SES and cancer mortality is partially explained by modifiable risk factors, which could suggest the appropriate targets to reduce socioeconomic disparities. PMID- 26650931 TI - Extracellular Vesicles Derived from Adipose Mesenchymal Stem Cells Regulate the Phenotype of Smooth Muscle Cells to Limit Intimal Hyperplasia. AB - PURPOSE: Extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) play important roles in the reduction of inflammation in multiple disease models. However, their role in vein graft (VG) remodeling is undefined. We aimed to investigate the effect of EVs from adipose MSCs (ADMSC-EVs) on VG intimal hyperplasia and to explore the possible mechanisms. METHODS: After generation and characterization of control-EVs and ADMSC-EVs in vitro, we investigated their effect on the proliferation and migration of vascular smooth muscle cells (VSMCs) in vitro. Next, we established a mouse model of VG transplantation. Mice underwent surgery and received control-EVs or ADMSC-EVs by intraperitoneal injection every other day for 20 days. VG remodeling was evaluated after 4 weeks. We also assessed the effect of ADMSC-EVs on macrophage migration and inflammatory cytokine expression. RESULTS: Significant inhibitory effects of ADMSC-EVs on in vitro VSMC proliferation (p < 0.05) and migration (p < 0.05) were observed compared with control-EVs. The extent of intimal hyperplasia was significantly decreased in ADMSC-EV-treated mice compared with control-EV-treated mice (26 +/- 8.4 vs. 45 +/- 9.0 MUm, p < 0.05). A reduced presence of macrophages was observed in ADMSC-EV-treated mice (p < 0.05). Significantly decreased expression of inflammatory cytokines interleukin (IL)-6 and monocyte chemoattractant protein-1 (MCP-1) was also found in the ADMSC-EV-treated group (both p < 0.05). In addition, phosphorylation of Akt, Erk1/2, and p38 in VGs was decreased in the ADMSC-EV-treated group. CONCLUSIONS: We demonstrated that ADMSC-EVs exert an inhibitory effect on VG neointima formation by regulating VSMC proliferation and migration, macrophage migration, inflammatory cytokine expression, and the related signaling pathways. PMID- 26650932 TI - Molecular cloning and identification of a flavanone 3-hydroxylase gene from Lycium chinense, and its overexpression enhances drought stress in tobacco. AB - Flavonoids, as plant secondary metabolites, are widespread throughout the plant kingdom and involved in many physiological and biochemical processes. Drought resistance is attributed to flavonoids with respect to protective functions in the cell wall and membranes. The flavanone 3-hydroxylase (F3H) gene which encodes flavanone 3-hydroxylase, is essential in flavonoids biosynthetic pathway. Lycium chinense (L. chinense) is a deciduous woody perennial halophyte that grows under a large variety of environmental conditions and survives under extreme drought stress. A novel cDNA sequence coding a F3H gene in Lycium chinense (LcF3H, GenBank: KJ636468.1) was isolated. The open reading frame of LcF3H comprised 1101 bp encoding a polypeptide of 366 amino acids with a molecular weight of about 42 kDa and an isoelectric point of 5.32. The deduced LcF3H protein showed high identities with other plant F3Hs, and the conserved motifs were found in LcF3H at similar positions like other F3Hs. The recombinant protein converted naringen into dihydrokaempferol in vitro. Since studies have shown that amongst flavonoids, flavan-3-ols (catechin and epicatechin) have direct free radical scavenging activity to maintain the normal physiological function of cells in vivo, these data support the possible relationship between the oxidative damage and the regulation of LcF3H gene expression in L. chinense under drought stress. In order to better understand the biotechnological potential of LcF3H, gene overexpression was conducted in tobacco. The content of flavan-3-ols and the tolerance to drought stress were increased in LcF3H overexpressing tobacco. Analysis of transgenic tobacco lines also showed that antioxidant enzyme activities were increased meanwhile the malondialdehyde (MDA) content and the content of H2O2 were reduced comparing to nontransformed tobacco plants. Furthermore, the photosynthesis rate was less decreased in the transgenetic plants. These results suggest that LcF3H plays a role in enhancing drought tolerance in L. chinense, and its overexpression increases tolerance to drought stress by improving the antioxidant system in tobacco. PMID- 26650933 TI - Relationship between the Sequencing and Timing of Vocal Motor Elements in Birdsong. AB - Accurate coordination of the sequencing and timing of motor gestures is important for the performance of complex and evolutionarily relevant behaviors. However, the degree to which motor sequencing and timing are related remains largely unknown. Birdsong is a communicative behavior that consists of discrete vocal motor elements ('syllables') that are sequenced and timed in a precise manner. To reveal the relationship between syllable sequencing and timing, we analyzed how variation in the probability of syllable transitions at branch points, nodes in song with variable sequencing across renditions, correlated with variation in the duration of silent gaps between syllable transitions ('gap durations') for adult Bengalese finch song. We observed a significant negative relationship between transition probability and gap duration: more prevalent transitions were produced with shorter gap durations. We then assessed the degree to which long-term age dependent changes and acute context-dependent changes to syllable sequencing and timing followed this inverse relationship. Age- but not context-dependent changes to syllable sequencing and timing were inversely related. On average, gap durations at branch points decreased with age, and the magnitude of this decrease was greater for transitions that increased in prevalence than for transitions that decreased in prevalence. In contrast, there was no systematic relationship between acute context-dependent changes to syllable sequencing and timing. Gap durations at branch points decreased when birds produced female-directed courtship song compared to when they produced undirected song, and the magnitude of this decrease was not related to the direction and magnitude of changes to transition probabilities. These analyses suggest that neural mechanisms that regulate syllable sequencing could similarly control syllable timing but also highlight mechanisms that can independently regulate syllable sequencing and timing. PMID- 26650934 TI - Detection of Intracellular Gene Expression in Live Cells of Murine, Human and Porcine Origin Using Fluorescence-labeled Nanoparticles. AB - The reprogramming of somatic cells to induced pluripotent stem cells (iPS) has successfully been performed in different mammalian species including mouse, rat, human, pig and others. The verification of iPS clones mainly relies on the detection of the endogenous expression of different pluripotency genes. These genes mostly represent transcription factors which are located in the cell nucleus. Traditionally, the proof of their endogenous expression is supplied by immunohistochemical staining after fixation of the cells. This approach requires replicate cultures of each clone at this early stage to preserve validated clones for further experiments. The present protocol describes an approach with gene specific nanoparticles which allows the evaluation of intracellular gene expression directly in live cells by fluorescence. The nanoparticles consist of a central gold particle coupled to a capture strand carrying a sequence complementary to the target mRNA as well as a quenched reporter strand. These nanoparticles are actively endocytosed and the target mRNA displaces the reporter strand which then start to fluoresce. Therefore, specific target gene expression can be detected directly under the microscope. In addition, the emitted fluorescence allows the identification, isolation and enrichment of cells expressing a specific gene by flow cytometry. This method can be applied directly to live cells in culture without any manipulation of the target cells. PMID- 26650935 TI - Quantitative evaluation of beam-hardening artefact correction in dual-energy CT myocardial perfusion imaging. AB - OBJECTIVES: To assess quantitatively the impact of a novel reconstruction algorithm ("kernel") with beam-hardening correction (BHC) on beam-hardening artefacts of the myocardium at dual-energy CT myocardial perfusion imaging (DE CTMPI). METHODS: Rest-series of DE-CTMPI examinations from 14 patients were retrospectively analyzed. Six image series were reconstructed for each patient: a) 100 kV, b) 140 kV, and c) linearly blended MIX0.5, each with BHC (D33f kernel) and without (D30f kernel). Seven hundred and fifty-six myocardial regions were assessed. Seven equal regions of interest divided the myocardium in the axial section. Three subdivisions were created within these regions in areas prone to BHA. Reports of SPECT studies performed within 30 days of CT examination were used to confirm the presence and location of true perfusion defects. Paired student t-test was used for statistical evaluation. RESULTS: Overall mean myocardial attenuation was lower using BHC (D30f: 87.3 +/- 24.1 HU; D33f: 85.5 +/ 21.5 HU; p = 0.009). Overall relative difference from average myocardial attenuation (RDMA) was more homogeneous using BHC (D30f: -0.3 +/- 11.4 %; D33f: 0.1 +/- 10.1 %; p < 0.001). Changes in RDMA were greatest in the posterobasal myocardium (D30f: -16.2 +/- 10.0 %; D33f: 3.4 +/- 10.7 %; p < 0.001). CONCLUSIONS: A dedicated reconstruction algorithm with BHC can significantly reduce beam-hardening artefacts in DE-CTMPI. KEY POINTS: * Beam-hardening artefacts (BHA) cause interference with attenuation-based CT myocardial perfusion assessment (CTMPI). * BHA occur mostly in the posterobasal left ventricular wall. * Beam-hardening correction homogenized and decreased mean myocardial attenuation. * BHC can help avoid false-positive findings and increase specificity of static CTMPI. PMID- 26650937 TI - Mechanism of Prominent Trimethylamine Oxide (TMAO) Accumulation in Hemodialysis Patients. AB - Large size, protein binding and intracellular sequestration are well known to limit dialytic removal of compounds. In studying the normal renal and dialytic handling of trimethylamine oxide (TMAO), a molecule associated with cardiovascular disease in the general population, we discovered two largely unrecognized additional limitations to sustained reduction of a solute by chronic hemodialysis. We measured solute levels and handling in subjects on chronic hemodialysis (ESRD, n = 7) and compared these with levels and clearance in normal controls (NLS, n = 6). The ESRD patients had much higher peak predialysis plasma levels of TMAO than NLS (77 +/- 26 vs 2+/-1 MUM, mean +/- SD, p<0.05). For comparison, predialysis BUN levels in ESRD subjects were 45+/-11 mg/dl and 15+/-3 mg/dl in NLS. Thus TMAO levels in ESRD average about 40 fold those in NLS while BUN is 3 fold NLS. However, the fractional reduction of TMAO concentration during dialysis, was in fact greater than that of urea (86+/-3 vs 74+/-6%, TMAO vs urea, p < 0.05) and its dialytic clearance while somewhat lower than that of urea was comparable to creatinine's. Also production rates were similar (533+/-272 vs 606 +/- 220 MU moles/day, ESRD vs NLS, p>0.05). However, TMAO has a volume of distribution about one half that of urea. Also in NLS the urinary clearance of TMAO was high (219+/-78 ml/min) compared to the urinary urea and creatinine clearances (55+/-14 and 119+/-21 ml/min, respectively). Thus, TMAO levels achieve multiples of normal much greater than those of urea due mainly to 1) TMAO's high clearance by the normal kidney relative to urea and 2) its smaller volume of distribution. Modelling suggests that only much more frequent dialysis would be required to lower levels Thus, additional strategies such as reducing production should be explored. Furthermore, using urea as the sole marker of dialysis adequacy may be misleading since a molecule, TMAO, that is dialyzed readily accumulates to much higher multiples of normal with urea based dialysis prescriptions. PMID- 26650938 TI - The Preventable Admissions Care Team (PACT): A Social Work-Led Model of Transitional Care. AB - In 2010, the Preventable Admissions Care Team (PACT), a social work-led transitional care model, was developed at Mount Sinai to reduce 30-day readmissions among high-risk patients. PACT begins with a comprehensive bedside assessment to identify the psychosocial drivers of readmission. In partnership with the patient and family, a patient-centered action plan is developed and carried out through phone calls, accompaniments, navigations and home visits, as needed, in the first 30 days following discharge. 620 patients were enrolled during the pilot from September 2010-August 2012. Outcomes demonstrated a 43% reduction in inpatient utilization and a 54% reduction in emergency department visits among enrollees. In addition, 93% of patients had a follow-up appointment within 7-10 days of discharge and 90% of patients attended the appointment. The success of PACT has led to additional funding from the Centers for Medicare and Medicaid Services under the Community-based Care Transitions Program and several managed care companies seeking population health management interventions for high risk members. PMID- 26650936 TI - Amiodarone Induces Overexpression of Similar to Versican b to Repress the EGFR/Gsk3b/Snail Signaling Axis during Cardiac Valve Formation of Zebrafish Embryos. AB - Although Amiodarone, a class III antiarrhythmic drug, inhibits zebrafish cardiac valve formation, the detailed molecular pathway is still unclear. Here, we proved that Amiodarone acts as an upstream regulator, stimulating similar to versican b (s-vcanb) overexpression at zebrafish embryonic heart and promoting cdh-5 overexpression by inhibiting snail1b at atrioventricular canal (AVC), thus blocking invagination of endocardial cells and, as a result, preventing the formation of cardiac valves. A closer investigation showed that an intricate set of signaling events ultimately caused the up-regulation of cdh5. In particular, we investigated the role of EGFR signaling and the activity of Gsk3b. It was found that knockdown of EGFR signaling resulted in phenotypes similar to those of Amiodarone-treated embryos. Since the reduced phosphorylation of EGFR was rescued by knockdown of s-vcanb, it was concluded that the inhibition of EGFR activity by Amiodarone is s-vcanb-dependent. Moreover, the activity of Gsk3b, a downstream effector of EGFR, was greatly increased in both Amiodarone-treated embryos and EGFR-inhibited embryos. Therefore, it was concluded that reduced EGFR signaling induced by Amiodarone treatment results in the inhibition of Snail functions through increased Gsk3b activity, which, in turn, reduces snail1b expression, leading to the up-regulation the cdh5 at the AVC, finally resulting in defective formation of valves. This signaling cascade implicates the EGFR/Gsk3b/Snail axis as the molecular basis for the inhibition of cardiac valve formation by Amiodarone. PMID- 26650939 TI - Endoscopic Disease Activity in Inflammatory Bowel Disease. AB - Endoscopic scoring systems in Crohn's disease and ulcerative colitis aim to translate the assessment of mucosal disease activity into a quantified value. This value seeks to provide a clear, objective record of the endoscopic mucosal severity, which can then be used to guide medical management decisions. The primary driver of all endoscopic indices, however, is to define a scale of responsiveness for therapeutic endpoints in clinical trials. Mucosal healing now has widespread acceptance as a therapeutic and clinical endpoint, but despite the development of multiple endoscopic scoring systems, the endoscopic definition has yet to be resolved. This review describes recent advances in endoscopic scoring systems for ulcerative colitis (Mayo Clinic endoscopy subscore, UCEIS, and UCCIS among others) and for Crohn's disease. PMID- 26650940 TI - Retinal Arteriolar Morphometry Based on Full Width at Half Maximum Analysis of Spectral-Domain Optical Coherence Tomography Images. AB - OBJECTIVES: In this study, we develop a microdensitometry method using full width at half maximum (FWHM) analysis of the retinal vascular structure in a spectral domain optical coherence tomography (SD-OCT) image and present the application of this method in the morphometry of arteriolar changes during hypertension. METHODS: Two raters using manual and FWHM methods measured retinal vessel outer and lumen diameters in SD-OCT images. Inter-rater reproducibility was measured using coefficients of variation (CV), intraclass correlation coefficient and a Bland-Altman plot. OCT images from forty-three eyes of 43 hypertensive patients and 40 eyes of 40 controls were analyzed using an FWHM approach; wall thickness, wall cross-sectional area (WCSA) and wall to lumen ratio (WLR) were subsequently calculated. RESULTS: Mean difference in inter-rater agreement ranged from -2.713 to 2.658 MUm when using a manual method, and ranged from -0.008 to 0.131 MUm when using a FWHM approach. The inter-rater CVs were significantly less for the FWHM approach versus the manual method (P < 0.05). Compared with controls, the wall thickness, WCSA and WLR of retinal arterioles were increased in the hypertensive patients, particular in diabetic hypertensive patients. CONCLUSIONS: The microdensitometry method using a FWHM algorithm markedly improved inter-rater reproducibility of arteriolar morphometric analysis, and SD-OCT may represent a promising noninvasive method for in vivo arteriolar morphometry. PMID- 26650941 TI - Puumala Hantavirus-Induced Hemorrhagic Fever with Renal Syndrome Must Be Considered across the Borders of Nephrology to Avoid Unnecessary Diagnostic Procedures. AB - BACKGROUND: Nephropathia epidemica (NE), a milder form of hemorrhagic fever with renal syndrome, is caused by Puumala virus and is characterized by acute kidney injury and thrombocytopenia. METHODS: A cross-sectional prospective survey of 456 adult patients with serologically confirmed NE was performed. RESULTS: Of the 456 investigated patients, 335 had received inpatient treatment. At time of admission to hospital, 72% of the patients had still an AKI and thrombocytopenia was present in 64% of the patients. The 335 patients were treated in 29 different hospitals and 6 of which had nephrology departments. 10 out of 335 patients received treatment in university hospitals and 63% of patients admitted themselves to hospital. Initially, the patients were admitted to 12 different clinical departments (29% of the patients were referred to a nephrology department) and during the course of the disease, 8% of the patients were transferred to another department in the same hospital and 3% were transferred to a nephrology department at another hospital. Regarding diagnostic procedures, in 28% of the inpatients computed tomography to exclude pulmonary embolism or due to severe gastrointestinal symptoms, lumbar puncture to exclude meningitis, magnetic resonance tomography of the brain owing to suspected stroke because of visual disorders, gastroscopy, or colonoscopy due to gastrointestinal symptoms was performed at time of admission to hospital. CONCLUSIONS: NE must be considered by physicians across the borders of nephrology to avoid unnecessary diagnostic procedures especially in areas where NE is endemic. PMID- 26650943 TI - ? PMID- 26650944 TI - ? PMID- 26650942 TI - Primary Adrenocortical Insufficiency Case Series: Genetic Etiologies More Common than Expected. AB - BACKGROUND/AIMS: Primary adrenal insufficiency (AI) is an important cause of morbidity in children. Our objectives were: (1) to describe the clinical presentation of children with new-onset primary AI, and (2) to identify monogenic causes of primary AI in children. METHODS: Chart review and mutation detection in candidate genes were conducted for 11 patients with primary AI. RESULTS: The likely cause of AI was determined in 9 patients. One had a homozygous MC2R mutation associated with familial glucocorticoid deficiency. Two had the same homozygous mutation in the AIRE gene which is associated with type 1 autoimmune polyglandular syndrome. One patient had a heterozygous change in this gene of undetermined significance. Five were homozygous for the previously reported p.R188C STAR mutation causing nonclassic lipoid congenital adrenal hyperplasia, representing the largest cohort of such patients from a single geographic area. In the remaining 2 patients, no clear etiology was identified. CONCLUSIONS: We recommend genetic testing for patients who have negative anti-adrenal antibodies or suggestive family history. Diagnosing a genetic etiology can provide information about prognosis and treatment, and is therefore beneficial for patients. Our high proportion of patients with nonclassic lipoid congenital adrenal hyperplasia likely represents a founder effect. PMID- 26650945 TI - [Transcatheter aortic valve implantation - What does the anaesthetist need to know and pay attention to?]. AB - Recent advancements in the field of cardiovascular surgery have been dominated by 3 aspects that comparably challenge a sophisticated cardiological, surgical and anaesthesiological management of this patient population. The proportion of elderly patients with relevant comorbidities increases steadily, and the number of combined cardiac surgical procedures is rising in this elderly population. A very important innovation in the last decade pertaining to the treatment of elderly patients at high risk suffering from significant aortic stenosis is the minimally invasive transcatheter aortic valve implantation (TAVI). Over the last 7 years this interventional-surgical "hybrid-procedure" has increased in numbers from almost 0 to 10,500 procedures in 2013 in Germany, performed at more than 80 centers. These patients relevant comorbidities accounting for a high risk of perioperative complications and moreover for a high mortality. The combination of a patient at high risk with the specific characteristics of the TAVI procedure necessitates to update the required skills of anaesthetists responsible for providing care for this kind of procedure. PMID- 26650946 TI - [Coagulation factor XIII - Pathophysiology, clinic and therapy of factor XIII deficiency]. AB - The complex activity of the transglutaminase factor XIII (FXIII) comprises central functions in secondary hemostasis. Congenital or acquired FXIII deficiencies may be associated with habitual abortions, impaired wound healing, coagulopathy and fatal hemorrhage. The present review describes physiological functions of FXIII, as well as pathophysiology, diagnostic and therapeutic options of FXIII deficiencies. PMID- 26650947 TI - [Not Available]. PMID- 26650948 TI - [Not Available]. PMID- 26650950 TI - [Analgesia, sedation and delir - Treatment of patients in the neuro intensive care unit]. AB - Analgesia and sedation of patients in the neuro intensive care unit, in particular in case of intracranial hypertension, remains a challenge even today. A goal for analgesia and sedation should be set for each individual patient (RASS -5 in case of intracranial hypertension) and should be re-evaluated repeatedly based on standardized scores (RASS plus EEG monitoring where appropriate, NCS). There are no sufficient evidence-based sedation algorithms in this patient cohort. Remifentanil, sufentanil and fentanyl have been proven safe and effective for continuous application; however, bolus application should be avoided. (S )Ketamin can be considered safe when mechanical ventilation and sedation with GABA receptor agonists are applied. Propofol and benzodiazepines are equally safe and effective with shorter wake up times for propofol. The use of barbitarutes is restricted to intractable intracranial hypertension or status epilepicus. Evidence for alpha-2-adrenoceptoragonists and inhalative sedation is poor and requires further research. PMID- 26650949 TI - ["Symptomatic Treatment of Delirium, Anxiety and Stress, and Protocol Based Analgesia, Sedation and Management of Sleep in Intensive Care Patients"]. AB - Critically ill patients suffer from anxiety, stress, pain, sleep disturbance and delirium. The updated version of the German evidence and consensus based guideline "Analgesia, Sedation and Delirium management in Intensive Care - DAS 2015" contributes an improved therapeutic management and is aimed to improve clinical outcome based on the current state of evidence. The task force members were representatives from 17 national medical societies therefore have consented following guiding principle in common: "Patients in intensive care shall be awake, alert and free of pain, anxiety and delirium, to be able to participate in the healing process actively." PMID- 26650951 TI - [Analgesia, sedation and management of delir in children and neonates]. PMID- 26650952 TI - [Emergency medicine in tactical environments - Support from military medicine?]. PMID- 26650953 TI - [Mind the explosion? The evolution of safety at work in anaesthesiology]. AB - The evolution of safety in anaesthesiology is characterized by 2 aspects: exposure of anaesthetic staff by volatile anaesthetics and fire as well as explosions in combination with those. In the 20th century, the exposure of staff in the operating room became more and more important. Trigger for the fatal complications were gas lights in combination with chloroform. Later oxygen and inhalation anaesthetics caused explosions and fires. Therefore safety rules were implemented in the 1980s in the Federal Republic of Germany. These were valid for application anaesthetics including apparatus and configuration of operating rooms. The only imponderability is still the human factor. PMID- 26650954 TI - ? PMID- 26650956 TI - ? PMID- 26650955 TI - ? PMID- 26650957 TI - ? PMID- 26650958 TI - Skew-t partially linear mixed-effects models for AIDS clinical studies. AB - We propose partially linear mixed-effects models with asymmetry and missingness to investigate the relationship between two biomarkers in clinical studies. The proposed models take into account irregular time effects commonly observed in clinical studies under a semiparametric model framework. In addition, commonly assumed symmetric distributions for model errors are substituted by asymmetric distribution to account for skewness. Further, informative missing data mechanism is accounted for. A Bayesian approach is developed to perform parameter estimation simultaneously. The proposed model and method are applied to an AIDS dataset and comparisons with alternative models are performed. PMID- 26650959 TI - Impact of point spread function reconstruction on quantitative 18F-FDG-PET/CT imaging parameters and inter-reader reproducibility in solid tumors. AB - INTRODUCTION: This study aims to determine the impact of point-spread function (PSF) reconstruction on quantitative PET/computed tomography (CT) indices and the inter-reader reproducibility of these measurements. MATERIALS AND METHODS: The study was approved by the Institutional Review Board under a waiver of informed consent. A total of 42 oncology patients with 85 lesions (all >= 2 cm) were included. The PET/CT images were reconstructed with PSF (OSEM+TOF, 2i, 21s, all pass filter) and without PSF (OSEM+TOF, 2i, 21s, 5 mm Gaussian). For each lesion, the maximum, mean, and peak standardized uptake values (SUV), total lesion glycolysis (TLG), and metabolic tumor volume (MTV) were measured by two readers (R1 and R2) using a semiautomatic gradient segmentation method. Intraclass correlation coefficient (ICC) and Bland-Altman analyses were performed. RESULTS: There was excellent correlation between non-PSF and PSF reconstruction PET/CT values (ICC >= 0.96 for all parameters, P < 0.0001). Comparison of PSF with non PSF images showed a mean bias (percentage change) of +11.97% (R1) and +11.94% (R2) for SUV max, +7.63% (R1) and +7.82% (R2) for SUV mean, +7.45% (R1) and +7.37% (R2) for SUV peak, -0.82% (R1) and -0.1% (R2) for TLG, and -6.68% (R1) and -5.65% (R2) for MTV. PSF reconstruction resulted in a decrease in MTV in 77.6% (R1) and 83.5% (R2) of lesions. Percentage changes in PSF versus non-PSF indices were not related to the site of the lesions (P > 0.05). Close agreement was observed between two readers (ICC ranged between 0.9 and 1.0, P < 0.0001). CONCLUSION: The PSF reconstruction increased the SUV max, SUV mean, and SUV peak, as expected, whereas it tended to produce lower values for MTV and had variable effect on TLG. This can be attributed to the ability of PSF reconstruction to better discern tumor uptake from activity spill-out. PMID- 26650960 TI - Grape seed procyanidin B2 protects podocytes from high glucose-induced mitochondrial dysfunction and apoptosis via the AMPK-SIRT1-PGC-1alpha axis in vitro. AB - Grape seed procyanidin B2 (GSPB2) was reported to have protective effects on diabetic nephropathy (DN) as a strong antioxidant. Our previous studies demonstrated that GSPB2 was effective in ameliorating podocyte injury in rats with DN. However, little is known about the benefits of GSPB2 in protecting against podocyte apoptosis and its molecular mechanisms in vitro. In the present study, we investigated whether GSPB2 could protect podocytes from high glucose induced apoptosis and explored the possible mechanism. Cell viability and apoptosis were detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and flow cytometry, respectively. The intracellular reactive oxygen species (ROS) level was measured using a dichlorofluorescein diacetate (DCFH-DA) fluorescent probe. Real-time reverse transcription-PCR was used to determine the gene expression of nuclear respiratory factor 1 (NRF-1) and mitochondrial transcription factor A (TFAM), and quantitative real-time PCR was used to detect mitochondrial DNA (mtDNA) copy number. Western blots were carried out for the related protein expression in podocytes. Our results showed that GSPB2 significantly inhibited high glucose-induced podocyte apoptosis and increased the expression of nephrin and podocalyxin. GSPB2 treatment also suppressed intracellular ROS production and oxidative stress. The mRNA expressions of NRF-1, TFAM and mtDNA copy number were markedly increased, and mitochondrial swelling was effectively reduced in podocytes cultured under high glucose after GSPB2 treatment. The AMPK-SIRT1-PGC-1alpha axis was also activated by GSPB2 intervention. In conclusion, GSPB2 protected podocytes from high glucose-induced mitochondrial dysfunction and apoptosis via the AMPK-SIRT1-PGC-1alpha axis in vitro, suggesting a potential role of GSPB2 in the treatment of DN. PMID- 26650961 TI - The implementation of evidence-based eating disorder prevention programs. PMID- 26650962 TI - Qubit Control Limited by Spin-Lattice Relaxation in a Nuclear Spin-Free Iron(III) Complex. AB - High-spin transition metal complexes are of interest as candidates for quantum information processing owing to the tunability of the pairs of MS levels for use as quantum bits (qubits). Thus, the design of high-spin systems that afford qubits with stable superposition states is of primary importance. Nuclear spins are a potent instigator of superposition instability; thus, we probed the Ph4P(+) salt of the nuclear spin-free complex [Fe(C5O5)3](3-) (1) to see if long-lived superpositions were possible in such a system. Continuous-wave and pulsed electron paramagnetic resonance (EPR) spectroscopic measurements reveal a strong EPR transition at X-band that can be utilized as a qubit. However, at 5 K the coherent lifetime, T2, for this resonance is 721(3) ns and decreases rapidly with increasing temperature. Simultaneously, the spin-lattice relaxation time is extremely short, 11.33(1) MUs, at 5 K, and also rapidly decreases with increasing temperature. The coincidence of these two temperature-dependent data sets suggests that T2 in 1 is strongly limited by the short T1. Importantly, these results highlight the need for new design parameters in pursuit of high-spin species with appreciable coherence times. PMID- 26650963 TI - Genomic profiling of advanced bladder cancer to guide the use of targeted therapeutics. PMID- 26650964 TI - Biomimetic Materials to Characterize Bacteria-host Interactions. AB - Bacterial attachment to host cells is one of the earliest events during bacterial colonization of host tissues and thus a key step during infection. The biochemical and functional characterization of adhesins mediating these initial bacteria-host interactions is often compromised by the presence of other bacterial factors, such as cell wall components or secreted molecules, which interfere with the analysis. This protocol describes the production and use of biomimetic materials, consisting of pure recombinant adhesins chemically coupled to commercially available, functionalized polystyrene beads, which have been used successfully to dissect the biochemical and functional interactions between individual bacterial adhesins and host cell receptors. Protocols for different coupling chemistries, allowing directional immobilization of recombinant adhesins on polymer scaffolds, and for assessment of the coupling efficiency of the resulting "bacteriomimetic" materials are also discussed. We further describe how these materials can be used as a tool to inhibit pathogen mediated cytotoxicity and discuss scope, limitations and further applications of this approach in studying bacterial - host interactions. PMID- 26650965 TI - Allylic Azide Rearrangement in Tandem with Huisgen Cycloaddition for Stereoselective Annulation: Synthesis of C-Glycosyl Iminosugars. AB - Allylic azide rearrangement is used in tandem with intramolecular azide-alkene cycloaddition to give a triazoline that when subsequently decomposed in the presence of a nucleophile gives piperidines. The tandem reaction gives two stereocenters that are generated with high control. The formation of the piperidines required the presence of innate conformational constraint. The applicability of the annulation reaction is demonstrated by the synthesis of iminosugars. A proposal is included to account for the observed stereoselectivity, which is influenced by the precursor structure. PMID- 26650966 TI - Recombinant Adeno-Associated Virus Vector Genomes Take the Form of Long-Lived, Transcriptionally Competent Episomes in Human Muscle. AB - Gene augmentation therapy as a strategy to treat alpha-1 antitrypsin (AAT) deficiency has reached phase 2 clinical testing in humans. Sustained serum levels of AAT have been observed beyond one year after intramuscular administration of a recombinant adeno-associated virus (rAAV) vector expressing the AAT gene. In this study, sequential muscle biopsies obtained at 3 and 12 months after vector injection were examined for the presence of rAAV vector genomes. Each biopsy sample contained readily detectable vector DNA, the majority of which existed as double-stranded supercoiled and open circular episomes. Episomes persisted through 12 months, although at slightly lower levels than observed at 3 months. There was a clear dose response when comparing the low- and mid-vector-dose groups to the high-dose group. The highest absolute copy numbers were found in a high-dose subject, and serum AAT levels at 12 months confirmed that the high-dose group also had the highest sustained serum AAT levels. Sequence analysis revealed that the vast majority of episomes contained double-D inverted terminal repeats ranging from fully intact to severely deleted. Molecular clones of vector genomes derived directly from the biopsies were transcriptionally active, potentially identifying them as the source of serum AAT in the trial subjects. PMID- 26650967 TI - Longitudinal modelling of theory-based depressive vulnerabilities, depression trajectories and poor outcomes post-ACS. AB - BACKGROUND: Depression is associated with increased mortality in patients with acute coronary syndrome (ACS). However, little is known about the theoretical causes of depression trajectories post-ACS, and whether these trajectories predict subsequent morbidity/mortality. We tested a longitudinal model of depressive vulnerabilities, trajectories and mortality. METHODS: A prospective observational study of 374 ACS patients was conducted. Participants completed questionnaires on theoretical vulnerabilities (interpersonal life events, reinforcing events, cognitive distortions, and Type D personality) during hospitalisation and depression at baseline and 3, 6 and 12 months post hospitalisation. Latent class analysis determined trajectories of depression. Path analysis was used to test relationships among vulnerabilities, depression trajectories and outcomes (combination of 1-year morbidity and 7-year mortality). RESULTS: Vulnerabilities independently predicted persistent and subthreshold depression trajectory categories, with effect sizes significantly highest for persistent depression. Both subthreshold and persistent depression trajectories were significant predictors of morbidity/mortality (e.g. persistent depression OR=2.4, 95% CI=1.8-3.1, relative to never depressed). LIMITATIONS: Causality cannot be inferred from these associations. We had no measures of history of depression or treatments, which may affect associations. CONCLUSIONS: Theoretical vulnerabilities predicted depression trajectories, which in turn predicted increased morbidity/mortality, demonstrating for the first time a potential longitudinal chain of events post-ACS. This longitudinal model has important practical implications as clinicians can use vulnerability measures to identify those at most risk of poor outcomes. PMID- 26650968 TI - Traumatic brain injury and affective disorder: A nationwide cohort study in Taiwan, 2000-2010. AB - BACKGROUND: Studies investigating the relationship between head injury and the subsequent onset of affective disorders often show conflicting results. AIMS: To investigate the risk of affective disorders following traumatic brain injury in a large Taiwanese cohort. METHOD: This retrospective cohort study makes use of the National Health Insurance Research Database. A cohort containing 68,376 individuals who experienced traumatic brain injury (TBI) during 2000-2010 and had no prior history of mental disorders before the injury was identified. Using Cox Proportional Hazards regression, the subsequent risk of affective disorders was determined. RESULTS: TBI was associated with a higher risk of both bipolar disorder (Hazard Ratio [HR]=1.42, 95% Confidence Interval [CI]=[1.26, 1.59]) and major depression (HR=1.41, 95% CI=[1.28, 1.54]). More severe injury was associated with greater risk. The first year following the injury was the highest risk period for major depression, while the highest risk period for bipolar disorder was delayed until two to four years following the injury. LIMITATIONS: Using a claims database, we were unable to assess confounding variables that were not contained in the data set. CONCLUSIONS: The elevated risks of affective disorders after TBI speak to the psychiatric need of individuals who suffer from brain injury. Early detection and timely intervention may help prevent secondary and tertiary disability associated with head trauma. PMID- 26650969 TI - Identifying the women at risk of antenatal anxiety and depression: A systematic review. AB - BACKGROUND: Pregnancy is a time of increased vulnerability for the development of anxiety and depression. This systematic review aims to identify the main risk factors involved in the onset of antenatal anxiety and depression. METHODS: A systematic literature analysis was conducted, using PubMed, PsychINFO, and the Cochrane Library. Original papers were included if they were written in English and published between 1st January 2003 and 31st August 2015, while literature reviews and meta-analyses were consulted regardless of publication date. A final number of 97 papers were selected. RESULTS: The most relevant factors associated with antenatal depression or anxiety were: lack of partner or of social support; history of abuse or of domestic violence; personal history of mental illness; unplanned or unwanted pregnancy; adverse events in life and high perceived stress; present/past pregnancy complications; and pregnancy loss. LIMITATIONS: The review does not include a meta-analysis, which may have added additional information about the differential impact of each risk factor. Moreover, it does not specifically examine factors that may influence different types of anxiety disorders, or the recurrence or persistence of depression or anxiety from pregnancy to the postpartum period. CONCLUSIONS: The results show the complex aetiology of antenatal depression and anxiety. The administration of a screening tool to identify women at risk of anxiety and depression during pregnancy should be universal practice in order to promote the long-term wellbeing of mothers and babies, and the knowledge of specific risk factors may help creating such screening tool targeting women at higher risk. PMID- 26650971 TI - Sustained-Release Buprenorphine (RBP-6000) Blocks the Effects of Opioid Challenge With Hydromorphone in Subjects With Opioid Use Disorder. AB - A major goal for the treatment of opioid use disorder is to reduce or eliminate the use of illicit opioids. Buprenorphine, a MU-opioid receptor partial agonist and kappa opioid receptor antagonist, is now being developed as a monthly, sustained-release formulation (RBP-6000). The objective of this study was to demonstrate that RBP-6000 blocks the subjective effects and reinforcing efficacy of the MU-opioid receptor agonist hydromorphone (intramuscularly administered) in subjects with moderate or severe opioid use disorder. Subjects were first inducted and dose stabilized on sublingual buprenorphine/naloxone (8-24 mg daily; dose expressed as the buprenorphine component), then received two subcutaneous injections of RBP-6000 (300 mg) on Day 1 and Day 29. Hydromorphone challenges (6 mg, 18 mg or placebo administered in randomized order) occurred on 3 consecutive days of each study week before and after receiving RBP-6000. Subjects reported their responses to each challenge on various 100-mm Visual Analogue Scales (VAS). Subjects also completed a choice task to assess the reinforcing efficacy of each hydromorphone dose relative to money. At baseline, mean "drug liking" VAS scores for hydromorphone 18 mg and 6 mg versus placebo were 61 mm (95% confidence interval, 52.3-68.9) and 45 mm (95% confidence interval, 37.2-53.6), respectively. After 300 mg RBP-6000 was administered, mean VAS score differences from placebo were less than 10 mm through week 12. The reinforcing efficacy of hydromorphone decreased in a parallel manner. This study demonstrated that RBP 6000 at a 300 mg dose provides durable and potent blockade of the subjective effects and reinforcing efficacy of hydromorphone in subjects with moderate or severe opioid use disorder. PMID- 26650970 TI - Analytic Models of Oxygen and Nutrient Diffusion, Metabolism Dynamics, and Architecture Optimization in Three-Dimensional Tissue Constructs with Applications and Insights in Cerebral Organoids. AB - Diffusion models are important in tissue engineering as they enable an understanding of gas, nutrient, and signaling molecule delivery to cells in cell cultures and tissue constructs. As three-dimensional (3D) tissue constructs become larger, more intricate, and more clinically applicable, it will be essential to understand internal dynamics and signaling molecule concentrations throughout the tissue and whether cells are receiving appropriate nutrient delivery. Diffusion characteristics present a significant limitation in many engineered tissues, particularly for avascular tissues and for cells whose viability, differentiation, or function are affected by concentrations of oxygen and nutrients. This article seeks to provide novel analytic solutions for certain cases of steady-state and nonsteady-state diffusion and metabolism in basic 3D construct designs (planar, cylindrical, and spherical forms), solutions that would otherwise require mathematical approximations achieved through numerical methods. This model is applied to cerebral organoids, where it is shown that limitations in diffusion and organoid size can be partially overcome by localizing metabolically active cells to an outer layer in a sphere, a regionalization process that is known to occur through neuroglial precursor migration both in organoids and in early brain development. The given prototypical solutions include a review of metabolic information for many cell types and can be broadly applied to many forms of tissue constructs. This work enables researchers to model oxygen and nutrient delivery to cells, predict cell viability, study dynamics of mass transport in 3D tissue constructs, design constructs with improved diffusion capabilities, and accurately control molecular concentrations in tissue constructs that may be used in studying models of development and disease or for conditioning cells to enhance survival after insults like ischemia or implantation into the body, thereby providing a framework for better understanding and exploring the characteristics and behaviors of engineered tissue constructs. PMID- 26650972 TI - An Open Trial of Lurasidone as an Acute and Maintenance Adjunctive Treatment for Outpatients With Treatment-Resistant Bipolar Disorder. PMID- 26650973 TI - Antidepressant Effects of a Single Dose of Ayahuasca in Patients With Recurrent Depression: A SPECT Study. AB - Ayahuasca is an Amazonian botanical hallucinogenic brew which contains dimethyltryptamine, a 5-HT2A receptor agonist, and harmine, a monoamine-oxidase A inhibitor. Our group recently reported that ayahuasca administration was associated with fast-acting antidepressive effects in 6 depressive patients. The objective of the present work was to assess the antidepressive potentials of ayahuasca in a bigger sample and to investigate its effects on regional cerebral blood flow. In an open-label trial conducted in an inpatient psychiatric unit, 17 patients with recurrent depression received an oral dose of ayahuasca (2.2 mL/kg) and were evaluated with the Hamilton Rating Scale for Depression, the Montgomery Asberg Depression Rating Scale, the Brief Psychiatric Rating Scale, the Young Mania Rating Scale, and the Clinician Administered Dissociative States Scale during acute ayahuasca effects and 1, 7, 14, and 21 days after drug intake. Blood perfusion was assessed eight hours after drug administration by means of single photon emission tomography. Ayahuasca administration was associated with increased psychoactivity (Clinician Administered Dissociative States Scale) and significant score decreases in depression-related scales (Hamilton Rating Scale for Depression, Montgomery-Asberg Depression Rating Scale, Brief Psychiatric Rating Scale) from 80 minutes to day 21. Increased blood perfusion in the left nucleus accumbens, right insula and left subgenual area, brain regions implicated in the regulation of mood and emotions, were observed after ayahuasca intake. Ayahuasca was well tolerated. Vomiting was the only adverse effect recorded, being reported by 47% of the volunteers. Our results suggest that ayahuasca may have fast-acting and sustained antidepressive properties. These results should be replicated in randomized, double-blind, placebo-controlled trials. PMID- 26650974 TI - Utilization of Psychopharmacological Treatment Among Patients With Newly Diagnosed Bipolar Disorder From 2001 to 2010. AB - OBJECTIVE: The aim of the study was to examine utilization and patterns of psychopharmacological treatment during a 1-year follow-up period among patients with newly diagnosed bipolar disorder from 2001 to 2010. METHODS: Patients with newly diagnosed bipolar disorder from 2001 to 2010 were identified from the National Health Insurance Research Database in Taiwan. We assessed prescription records related to 4 kinds of psychopharmacological medication, including antipsychotics (APs), antidepressants, mood stabilizers, and benzodiazepines, as well as health care utilization in a 1-year follow-up period among the study subjects. In addition, logistic regressions were applied to test the trends for utilization of psychopharmacological treatment during the 10-year study period. RESULTS: A total of 2703 patients newly diagnosed with bipolar disorder were enrolled. The ratio of good adherence, defined as medications possession ratio greater than 0.8, for use of the examined psychopharmacological medication was relatively low during the study period. The use of first-generation APs, selective serotonin reuptake inhibitors, tricyclic antidepressants, lithium, carbamazepine, and benzodiazepines has declined; however, the use of second generation APs, serotonin and norepinephrine reuptake inhibitors, lamotrigine, and valproate has risen markedly during the 10-year period. CONCLUSIONS: This study presents patterns of pharmacological treatment in patients with newly diagnosed bipolar disorder in Taiwan for a 10-year study period. It would be of importance to further investigate causes and outcomes for polytherapy and nonadherence to psychotropic medications among patients with bipolar disorder. PMID- 26650975 TI - Call to Action for General Surgery-Trained Specialists: Maintain Both Breadth and Depth. PMID- 26650976 TI - Multifaceted and route-controlled "click" reactions based on vapor-deposited coatings. AB - "Click" reactions provide precise and reliable chemical transformations for the preparation of functional architectures for biomaterials and biointerfaces. The emergence of a multiple-click reaction strategy has paved the way for a multifunctional microenvironment with orthogonality and precise multitasking that mimics nature. We demonstrate a multifaceted and route-controlled click interface using vapor-deposited functionalized poly-para-xylylenes. Distinctly clickable moieties of ethynyl and maleimide were introduced into poly-para-xylylenes in one step via a chemical vapor deposition (CVD) copolymerization process. The advanced interface coating allows for a double-click route with concurrent copper(i) catalyzed Huisgen 1,3-dipolar cycloaddition (CuAAC) and the thiol-maleimide click reaction. Additionally, double-click reactions can also be performed in a cascade manner by controlling the initiation route to enable the CuAAC and/or thiol-yne reaction using a mono-functional alkyne-functionalized poly-para-xylylene. The use of multifaceted coatings to create straightforward and orthogonal interface properties with respect to protein adsorption and cell attachment is demonstrated and characterized. PMID- 26650977 TI - Electronic and thermal transport study of sinusoidally corrugated nanowires aiming to improve thermoelectric efficiency. AB - Improvement of thermoelectric efficiency has been very challenging in the solid state industry due to the interplay among transport coefficients which measure the efficiency. In this work, we modulate the geometry of nanowires to interrupt thermal transport with causing only a minimal impact on electronic transport properties, thereby maximizing the thermoelectric power generation. As it is essential to scrutinize comprehensively both electronic and thermal transport behaviors for nano-scale thermoelectric devices, we investigate the Seebeck coefficient, the electrical conductance, and the thermal conductivity of sinusoidally corrugated silicon nanowires and eventually look into an enhancement of the thermoelectric figure-of-merit [Formula: see text] from the modulated nanowires over typical straight nanowires. A loss in the electronic transport coefficient is calculated with the recursive Green function along with the Landauer formalism, and the thermal transport is simulated with the molecular dynamics. In contrast to a small influence on the thermopower and the electrical conductance of the geometry-modulated nanowires, a large reduction of the thermal conductivity yields an enhancement of the efficiency by 10% to 35% from the typical nanowires. We find that this approach can be easily extended to various structures and materials as we consider the geometrical modulation as a sole source of perturbation to the system. PMID- 26650978 TI - Inflexible Ears. PMID- 26650979 TI - February 2010: This Month's Highlights. PMID- 26650986 TI - 4-Phenylaminomethyl-Benzeneboric Acid Modified Tip Extraction for Determination of Brassinosteroids in Plant Tissues by Stable Isotope Labeling-Liquid Chromatography-Mass Spectrometry. AB - Monitoring brassinosteroids (BRs) has been of major interest of researchers as these substances play a crucial role in a variety of phytological processes in plants. However, the determination of endogenous BRs in plant tissue is still a challenging task due to their low abundance and the complex matrix of plant tissues. In this study, a single step strategy by combining tip extraction and in situ derivatization was proposed for BR analysis. In the proposed strategy, a mixed mode sorbent (C8-SO3H) in tip was modified with 4-phenylaminomethyl benzeneboric acid (4-PAMBA) through cation exchange and hydrophobic interactions, and then used as a boronate affinity media to selectively capture and purify BRs from plant extract through the reaction of boric acid groups of 4-PAMBA and cis diol on BRs. The BRs-4-PAMBA derivatives formed were easily eluted from the C8 SO3H tip by nullifying the ion exchange and hydrophobic interactions using ammonia acetonitrile, followed by LC-MS/MS analysis. BR standards, isotopically labeled with d5-4-phenylaminomethyl-benzeneboric acid (4-PAMBA-d5) were introduced to improve the assay precision of LC-MS/MS. Under the optimized conditions, the overall process could be completed within 1 h, which is greatly improved in speed compared with previously reported protocols. In addition, the detection sensitivities of labeled BRs were improved by over 2000-fold compared with unlabeled BRs, thus the consumption of plant materials was reduced to 50 mg. Finally, the proposed method was applied for the investigation of BRs response in rice toward Cd stress. PMID- 26650987 TI - Retrospective Analysis of Decreasing the Use of Anesthesia in Pediatric Audiology: A Preliminary Study. AB - PURPOSE: The purpose of this article is to analyze outcomes of processes aimed at reducing the need for use of anesthesia in evaluating pediatric hearing loss. METHOD: A retrospective chart review was completed to assess how often a pediatric hearing evaluation was successful/not successful and auditory brainstem response (ABR) testing with anesthesia was avoided/required following review of orders for ABR testing with anesthesia. RESULTS: A total of 30% of the patients referred for ABR with anesthesia successfully completed a pediatric hearing evaluation, therefore avoiding anesthesia. Male subjects and subjects with developmental delay were less likely to avoid testing with anesthesia. None of the subjects with a comorbidity of developmental delay completed a pediatric hearing evaluation successfully. Other comorbidities with low success rates were autism spectrum disorder and speech delay. No significant outcome differences were measured as a function of referral source. CONCLUSIONS: Processes implemented in this study resulted in elimination of the need to use anesthesia to evaluate hearing in a large portion of patients referred. Success rates for avoiding anesthesia may vary depending on available resources, physician education, and population tested. Additional benefits of the described process include reduced stress on the health care system and families receiving services. PMID- 26650989 TI - What Data Are Really Needed to Evaluate the Population Impact of Chlamydia Screening Programs? PMID- 26650990 TI - Trends in Chlamydia Screening, Test Positivity, and Treatment Among Females in California Juvenile Detention Facilities, 2003-2014. AB - BACKGROUND: Juvenile detention facilities house adolescents at high risk for sexually transmitted diseases. Collaboration between health departments and juvenile detention authorities can provide routine, cost-efficient chlamydia screening and treatment to females with limited access to care. We describe trends in screening, positivity, treatment, and associated costs in a well established juvenile detention chlamydia screening program. METHODS: In the California Chlamydia Screening Project, juvenile detention facilities in 12 counties collected quarterly aggregate data on female census and line-listed chlamydia test results and treatment data from fiscal year (FY) 2003-2004 to FY 2013-2014. Trends in the proportion of females screened, positivity, and treatment by age, race/ethnicity, and facility volume were evaluated by Cochran Armitage test. The median cost of the program per chlamydia positive identified was compared by facility in FY 2013-2014. RESULTS: Data from 59,518 test records among juvenile females indicated high screening rates (75.1%-79.4%). Chlamydia positivity, although consistently high, decreased from 14.8% in 2003-2004 to 11.5% in 2013-2014 (P < 0.001). Documented treatment decreased (88.8% in 2005 2006 to 79.0% in 2013-2014, P < 0.001); of those treated, treatment within 7 days increased (80.1% in 2005-2006 to 88.8% in 2013-2014, P < 0.001). The median cost per chlamydia positive identified was $708 (interquartile range, $669-$894) and was lowest for facilities with high chlamydia positivity. CONCLUSIONS: The California Chlamydia Screening Project demonstrated consistently high rates of chlamydia screening and positivity among adolescent females while keeping costs low for high-volume facilities. Further improvement in timely treatment rates remains a challenge for extending the impact of screening in this high-risk population. PMID- 26650991 TI - Getting What You Pay For: The Economics of Quality Care for Sexually Transmitted Infections. AB - BACKGROUND: Understanding the relationship between charges, reimbursement, and quality for sexually transmitted infection (STI) care is necessary to evaluate consequences of shifting patients from STI specialty to nonspecialty settings and to inform quality improvement efforts in this area. METHODS: Chart reviews were used to evaluate quality of documented STI care among 450 patients across 5 different clinical settings within a large safety net hospital in Massachusetts for patients presenting with penile discharge/dysuria or vaginal discharge. Charges billed and recouped by the hospital for each visit were extracted from billing records. Univariate methods examined unadjusted differences between quality and other patient and practice characteristics, and charges billed and recouped, whereas a multivariable model predicted the effect of quality on charges and reimbursements after adjusting for potential confounders. RESULTS: Higher documented quality of care was associated with higher charges, with each additional quality point predicting a 9% increase in visit charges. However, these charges were not recouped by the institution, as quality was not associated with higher levels of hospital reimbursement. Among sites of care, the STI clinic had the highest average quality score, as well as the lowest average amount billed and recouped. CONCLUSIONS: The relationship we find between documented quality and charges billed may reflect resource use for patient visits. The hospital, however, did not recoup any more on average from higher-quality visits, thus posing an incentive problem for the institution. Our findings suggest that loss of government funds for STI clinics may not be replaced by hospital billing and may lead to lower quality of care. PMID- 26650992 TI - Quality of Sexually Transmitted Infection Case Management Services in Gauteng Province, South Africa: An Evaluation of Health Providers' Knowledge, Attitudes, and Practices. AB - BACKGROUND: The sexually transmitted infection (STI) clinical encounter is an opportunity to identify current and prevent new HIV and STI infections. We examined knowledge, attitudes, and practices regarding STIs and HIV among public and private providers in a large province in South Africa with a high disease burden. METHODS: From November 2008 to March 2009, 611 doctors and nurses from 120 public and 52 private clinics serving patients with STIs in Gauteng Province completed an anonymous, self-administered survey. Responses were compared by clinic location, provider type, and level of training. RESULTS: Most respondents were nurses (91%) and female (89%), were from public clinics (91%), and had received formal STI training (67%). Most (88%) correctly identified all of the common STI syndromes (i.e., genital ulcer syndrome, urethral discharge syndrome, and vaginal discharge syndrome). However, almost none correctly identified the most common etiologies for all 3 of these syndromes (0.8%), or the recommended first or alternative treatment regimens for all syndromes (0.8%). Very few (6%) providers correctly answered the 14 basic STI knowledge questions. Providers reporting formal STI training were more likely to identify correctly all 3 STI syndromes (P = 0.034) as well as answer correctly all 14 general STI knowledge questions (P = 0.016) compared with those not reporting STI training. In addition, several providers reported negative attitudes about patients with STI that may have affected their ability to practice optimal STI management. CONCLUSIONS: Sexually transmitted infection general knowledge was suboptimal, particularly among providers without STI training. Provider training and brief refresher courses on specific aspects of diagnosis and management may benefit HIV/STI clinical care and prevention in Gauteng Province. PMID- 26650993 TI - Syphilis Time to Treatment at Publicly Funded Sexually Transmitted Disease Clinics Versus Non-Sexually Transmitted Disease Clinics--Maricopa and Pima Counties, Arizona, 2009-2012. AB - Delays in syphilis treatment may contribute to transmission. We evaluated time to treatment for symptomatic patients with syphilis by clinical testing site in 2 Arizona counties. Fewer patients were tested and treated at publicly funded sexually transmitted disease clinics, but received the timeliest treatment; these clinics remain crucial to syphilis disease control. PMID- 26650994 TI - Time From HIV Diagnosis to Viral Load Suppression: 2007-2013. AB - BACKGROUND: US guidelines now recommend that all HIV-infected persons receive antiretroviral therapy). HIV prevention is increasingly focused on ensuring that infected persons are diagnosed soon after HIV acquisition and quickly link to care and initiate antiretroviral therapy. We examined trends in time from HIV diagnosis to viral load suppression in King County, WA, to gauge improvement in our HIV care continuum over time. METHODS: We used HIV surveillance data and Cox proportional hazards to evaluate how the time from diagnosis to viral suppression changed among persons newly diagnosed as having HIV in King County, WA, between 2007 and 2013. RESULTS: A total of 1490 (84%) of 1766 newly diagnosed persons achieved viral suppression in a median time of 213 days (95% confidence interval, 203-229). Thirty-six percent of all persons diagnosed in 2007 and 77% in 2013 were virally suppressed within 12 months of HIV diagnosis (P < 0.0001). Differences in time to suppression by calendar year persisted when stratifying by CD4 count at diagnosis. Race was not significantly associated with time to viral suppression. CONCLUSIONS: Time from HIV diagnosis to viral suppression dramatically declined between 2007 and 2013, and more than three quarters of recently HIV-diagnosed individuals in King County, WA, now achieve viral suppression within a year of diagnosis. This improvement was evident among all persons newly diagnosed as having HIV, regardless of race/ethnicity or CD4 count at time of diagnosis. PMID- 26650995 TI - The Best of Both Worlds: Collaborations Can Improve Epidemiological Analyses of Public Health Data. PMID- 26650996 TI - Hepatitis C Virus Awareness Among Men Who Have Sex With Men in Southwest Switzerland. AB - BACKGROUND: In Switzerland, the incidence of hepatitis C virus (HCV) infection in HIV-positive men who have sex with men (MSM) rose 18-fold between 1998 and 2011. We aimed to evaluate transmission risk factors, awareness, and seroprevalence of HCV among MSM in southwest Switzerland. METHODS: From 1st June 2011 to 31st August 2012, trained health care professionals invited individuals attending (1) MSM screening clinics and (2) indoor and outdoor meeting areas to complete an anonymous questionnaire. Consenting participants were rapid tested for HCV (OraQuick HCV Rapid Antibody Test). RESULTS: Of 918 MSM approached, 654 agreed to participate, most of whom (536, 82%) were enrolled via MSM screening clinics. Of 654 participants, 21 (3.2%) disclosed being HIV positive; 140 (21%) had unknown HIV status. In the preceding 12 months, 357 (55%) of 654 participants reported unprotected anal intercourse (UAI) and 321 (49%) of 654 participants reported UAI with partners of different/unknown HIV status. Not HIV serosorting was reported more frequently among HIV-positive individuals (76%, P < 0.001). Three hundred two participants (46%) were aware of HCV, awareness being higher among clinic than meeting area participants (49% vs. 33%, P = 0.04). One individual (of 654; 0.2%), with a negative HIV test result 18 months previously was newly diagnosed as being HCV positive on rapid testing. CONCLUSIONS: In this sample of predominantly HIV-negative MSM, half the participants were aware of HCV and HCV seroprevalence was low. However, high rates of UAI and of UAI without HIV serosorting were reported. Given the increasing incidence of HCV among HIV positive men, we propose that HCV counseling should be offered to MSM regardless of HIV status, with testing offered to those at high risk. PMID- 26650997 TI - The Impact of a Social Marketing Campaign on HIV and Sexually Transmissible Infection Testing Among Men Who Have Sex With Men in Australia. AB - BACKGROUND: In response to increasing HIV and other sexually transmissible infection (HIV/STI) notifications in Australia, a social marketing campaign Drama Downunder (DDU) was launched in 2008 to promote HIV/STI testing among men who have sex with men (MSM). We analyzed prospective data from (1) an online cohort of MSM and (2) clinic-level HIV/STI testing to evaluate the impact of DDU on HIV, syphilis, gonorrhea, and chlamydia testing. MATERIALS AND METHODS: (1) Cohort participants who completed 3 surveys (2010-2014) contributed to a Poisson regression model examining predictors of recent HIV testing.(2) HIV, syphilis, gonorrhea, and chlamydia tests among MSM attending high caseload primary care clinics (2007-2013) were included in an interrupted time series analysis. RESULTS: (1) Although campaign awareness was high among 242 MSM completing 726 prospective surveys, campaign recall was not associated with self-reported HIV testing. Reporting previous regular HIV testing (adjusted incidence rate ratio, 2.4; 95% confidence interval, 1.3-4.4) and more than 10 partners in the previous 6 months (adjusted incidence rate ratio, 1.2; 95% confidence interval, 1.1-1.4) was associated with recent HIV testing. (2) Analysis of 257,023 tests showed increasing monthly HIV, syphilis, gonorrhea, and chlamydia tests pre-DDU. Post DDU, gonorrhea test rates increased significantly among HIV-negative MSM, with modest and nonsignificant increasing rates of HIV, syphilis, and chlamydia testing. Among HIV-positive MSM, no change in gonorrhea or chlamydia testing occurred and syphilis testing declined significantly. CONCLUSIONS: Increasing HIV/STI testing trends among MSM occurred pre- and post-DDU, coinciding with other plausible drivers of testing. Modest changes in HIV testing post-DDU suggest that structural changes to improve testing access may need to occur alongside health promotion to increase testing frequency. PMID- 26650998 TI - Field Evaluation of a Dual Rapid Immunodiagnostic Test for HIV and Syphilis Infection in Peru. AB - BACKGROUND: Integrated prevention for HIV and syphilis is warranted because both syphilis and HIV infections have evidence-based, scalable interventions using current health care mechanisms. The advent of dual rapid point-of-care tests, single devices that can detect multiple infections using the same specimen, provides the opportunity to integrate the screening of syphilis into HIV prevention programs, potentially increasing the numbers of people tested and allowing for same-day testing and treatment. The aim of our study was to evaluate the MedMira Multiplo Rapid TP/HIV Antibody Test (MedMira Inc, Halifax, Nova Scotia, Canada), a qualitative, rapid immunoassay that detects antibodies to Treponema pallidum and HIV. METHODS: The reference test for comparison to the T. pallidum component of the Multiplo TP/HIV Test was the T. pallidum particle agglutination assay. For the HIV component, the reference test included a fourth generation enzyme immunoassay with a confirmatory Western blot test. RESULTS: The sensitivity and specificity for the HIV antibody component were 93.8% (95% confidence interval [CI], 69.8%-99.8%) and 100% (95% CI, 97.7%-100%), respectively. The T. pallidum component of the test had a sensitivity of 81.0% (95% CI, 68.1%-94.6%) and a specificity of 100% (95% CI, 97.6%-100%). CONCLUSIONS: Our study showed excellent performance of the HIV antibody component of the test and very good performance for the T. pallidum antibody component of the MedMira Multiplo Rapid TP/HIV Antibody Test, which should be considered to improve screening coverage. Use of effective dual tests will create improved access to more comprehensive care by integrating the screening of syphilis into HIV prevention programs. PMID- 26650999 TI - The Program Cost of a Brief Video Intervention Shown in Sexually Transmitted Disease Clinic Waiting Rooms. AB - BACKGROUND: Patients in sexually transmitted disease (STD) clinic waiting rooms represent a potential audience for delivering health messages via video-based interventions. A controlled trial at 3 sites found that patients exposed to one intervention, Safe in the City, had a significantly lower incidence of STDs compared with patients in the control condition. An evaluation of the intervention's cost could help determine whether such interventions are programmatically viable. MATERIALS AND METHODS: The cost of producing the Safe in the City intervention was estimated using study records, including logs, calendars, and contract invoices. Production costs were divided by the 1650 digital video kits initially fabricated to get an estimated cost per digital video. Clinic costs for showing the video in waiting rooms included staff time costs for equipment operation and hardware depreciation and were estimated for the 21-month study observation period retrospectively. RESULTS: The intervention cost an estimated $416,966 to develop, equaling $253 per digital video disk produced. Per-site costs to show the video intervention were estimated to be $2699 during the randomized trial. CONCLUSIONS: The cost of producing and implementing Safe in the City intervention suggests that similar interventions could potentially be produced and made available to end users at a price that would both cover production costs and be low enough that the end users could afford them. PMID- 26651000 TI - Strengthening Sexually Transmitted Disease Services in Detroit, Michigan: A Call to Action. PMID- 26651003 TI - [In memoriam Prof. Dr. med. Klaus Jahnke]. PMID- 26651004 TI - [For expert evaluation of a possible connection: formaldehyde and nasopharyngeal cancer]. PMID- 26651005 TI - [Fluorescence imaging in laryngology: Physical principles, clinical applications and study results]. AB - BACKGROUND: Early detection and adequate preoperative assessment of neoplastic lesions of the larynx allow for voice-preserving therapy concepts. OBJECTIVE: The physical principles, clinical applications and most important study results of fluorescence imaging are presented. MATERIALS AND METHODS: The entire literature on autofluorescence endoscopy of the larynx was analysed and compared to induced fluorescence endoscopy. RESULTS: In detecting malignant and premalignant lesions of the larynx, autofluorescence endoscopy shows a significantly higher sensitivity, specificity and accuracy than white light endoscopy alone. Induced fluorescence endoscopy achieved an even higher sensitivity, albeit at the expense of specificity. CONCLUSION: Autofluorescence endoscopy represents a simple screening procedure for early detection of laryngeal cancer and its precursor lesions, whereas induced fluorescence endoscopy is more suited for the identification of recurrent disease. PMID- 26651006 TI - How do resting state changes in depression translate into psychopathological symptoms? From 'Spatiotemporal correspondence' to 'Spatiotemporal Psychopathology'. AB - PURPOSE OF REVIEW: To review the recent findings in resting-state activity in major depressive disorder (MDD) and link them to psychopathological symptoms. RECENT FINDINGS: MDD shows changes in resting state functional connectivity (rsFC) mainly within the default-mode network with a focus on especially the perigenual anterior cingulate cortex. rsFC in perigenual anterior cingulate cortex is abnormally high in MDD and decreased in the lateral prefrontal cortex with the central executive network (CEN). rsFC in other networks like the salience network, including the insula, amygdala, and supragenual anterior cingulate cortex and the sensorimotor network is also affected in MDD. SUMMARY: Resting-state activity in MDD shows abnormal topographical and spatiotemporal pattern. The spatiotemporal alterations in resting state may translate into corresponding spatiotemporal changes underlying the sensorimotor, affective, and cognitive functions, and thus, the various symptoms. Such spatiotemporal correspondence between resting state changes and psychopathological symptoms may make necessary the development of what I describe as 'Spatiotemporal Psychopathology'. PMID- 26651007 TI - Functional neuroimaging of psychotherapeutic processes in anxiety and depression: from mechanisms to predictions. AB - PURPOSE OF REVIEW: The review provides an update of functional neuroimaging studies that identify neural processes underlying psychotherapy and predict outcomes following psychotherapeutic treatment in anxiety and depressive disorders. Following current developments in this field, studies were classified as 'mechanistic' or 'predictor' studies (i.e., informing neurobiological models about putative mechanisms versus aiming to provide predictive information). RECENT FINDINGS: Mechanistic evidence points toward a dual-process model of psychotherapy in anxiety disorders with abnormally increased limbic activation being decreased, while prefrontal activity is increased. Partly overlapping findings are reported for depression, albeit with a stronger focus on prefrontal activation following treatment. No studies directly comparing neural pathways of psychotherapy between anxiety and depression were detected. Consensus is accumulating for an overarching role of the anterior cingulate cortex in modulating treatment response across disorders. When aiming to quantify clinical utility, the need for single-subject predictions is increasingly recognized and predictions based on machine learning approaches show high translational potential. SUMMARY: Present findings encourage the search for predictors providing clinically meaningful information for single patients. However, independent validation as a crucial prerequisite for clinical use is still needed. Identifying nonresponders a priori creates the need for alternative treatment options that can be developed based on an improved understanding of those neural mechanisms underlying effective interventions. PMID- 26651008 TI - Can anxiety damage the brain? AB - PURPOSE OF REVIEW: Stress exacerbates mental illnesses such as depression but also appears to increase risk of dementia, suggesting a common mechanism for development of stress-induced affective and cognitive impairment. The purpose of this review is to address the question of whether anxiety 'damages' the brain, and to identify potential mechanisms for the link between stress and neuropsychiatric illness. RECENT FINDINGS: Anxiety disorders are associated with alterations in fear neurocircuitry such that 'bottom-up' processes in the amygdala which respond to threat are exaggerated, and regulation of these processes by the prefrontal cortex (PFC) and hippocampus is impaired. Chronic stress exposure similarly alters fear neurocircuitry by enhancing amygdalar functioning while causing structural degeneration in the PFC and hippocampus thereby inhibiting PFC/hippocampus control over the stress response. Pharmacological (e.g., antidepressant medications) and nonpharmacological interventions (cognitive-behavioral therapy, exercise) may reverse stress-induced damage in the brain. SUMMARY: Pathological anxiety and chronic stress lead to structural degeneration and impaired functioning of the hippocampus and the PFC, which may account for the increased risk of developing neuropsychiatric disorders, including depression and dementia. Longitudinal studies are needed to determine whether reversal of stress-induced brain changes by interventions such as cognitive-behavioral therapy can reduce risk of neuropsychiatric illness. PMID- 26651009 TI - Avoidant personality disorder as a social anxiety phenotype: risk factors, associations and treatment. AB - PURPOSE OF REVIEW: This article identifies research trends and synthesizes information from recent studies of avoidant personality disorder (AVPD). RECENT FINDINGS: AVPD and social anxiety disorder (SAD) share genetic vulnerability, but may have distinct environmental risk factors that shape qualitative differences. Negative self-concept, shame proneness, and interpersonal hypersensitivity are characteristic of AVPD and may be predisposed to by heritable traits of high negative affectivity and low positive affectivity, and experiences of neglectful or emotionless parents. The interpersonal difficulties of AVPD may be associated with both anxious and avoidant attachment. Most individuals with AVPD do not also meet criteria for SAD. SUMMARY: Integrative treatments incorporating cognitive behavioral strategies effective in SAD but also targeting shame aversion and avoidance may be most helpful for AVPD. Therapy adapted to both anxious attachment, associated with heightened interpersonal sensitivity and distress, and avoidant attachment, associated with experiential avoidance, may be optimal, though this is yet to be tested. Effective treatment of AVPD may enhance the outcome of comorbid conditions. More research is needed which compares three social anxiety groups (SAD alone, AVPD alone, and SAD plus AVPD) to further explore these disorders which are highly related, but which may have differences that are clinically relevant for individuals. PMID- 26651010 TI - Mindfulness for personality disorders. AB - PURPOSE OF REVIEW: Third-wave cognitive-behaviour therapies such as dialectical behaviour therapy have demonstrated effectiveness in the treatment of personality disorders, which are considered difficult to treat. These therapies typically incorporate some component of mindfulness practice. The current study examines current applications and effectiveness of mindfulness to the treatment of personality disorders. RECENT FINDINGS: The majority of evidence available focuses on borderline personality disorder, and highlights positive associations between mindfulness practice and reduced psychiatric and clinical symptoms, less emotional reactivity, and less impulsivity. Fewer studies examine the other personality disorders, though emerging case studies have applied mindfulness techniques to treatment with antisocial, avoidant, paranoid, and obsessive compulsive personality disorders. SUMMARY: Mindfulness is a promising clinical tool for the treatment of personality disorders, and appears to be adaptable to the unique features of different types of personality disorders. However, further empirical research with greater methodological rigour is required to clarify the effectiveness of mindfulness as a specific skill component, and to identify the underlying mechanisms that contribute to therapeutic change. PMID- 26651011 TI - The complexity of bipolar and borderline personality: an expression of 'emotional frailty'? AB - PURPOSE OF REVIEW: The purpose of this article is to review recent findings regarding the comorbidity of bipolar disorder with borderline personality disorder (BPD). The conceptualization of the comorbid condition is explored in the context of complexity theory. RECENT FINDINGS: Recent studies highlight distinguishing features between the two disorders. The course of illness of the comorbid condition is generally considered to be more debilitating than bipolar disorder alone. SUMMARY: Some of the differentiating features of bipolar disorder and BPD are highlighted. It is also crucial to consider a co-morbid diagnosis as worse outcomes may be anticipated than for bipolar disorder alone. The concept of 'emotional frailty' is introduced and the comorbid bipolar disorder-BPD condition is considered an expression of this syndrome. PMID- 26651013 TI - Synthesis of Thermoresponsive Amphiphilic Polyurethane Gel as a New Cell Printing Material near Body Temperature. AB - Waterborne polyurethane (PU) based on poly(epsilon-caprolactone) (PCL) diol and a second oligodiol containing amphiphilic blocks was synthesized in this study. The microstructure was characterized by dynamic light scattering (DLS), small-angle X ray scattering (SAXS), and rheological measurement of the PU dispersion. The surface hydrophilicity measurement, infrared spectroscopy, wide-angle X-ray diffraction, mechanical and thermal analyses were conducted in solid state. It was observed that the presence of a small amount of amphiphilic blocks in the soft segment resulted in significant changes in microstructure. When 90 mol % PCL diol and 10 mol % amphiphilic blocks of poly(l-lactide)-poly(ethylene oxide) (PLLA-PEO) diol were used as the soft segment, the synthesized PU had a water contact angle of ~24 degrees and degree of crystallinity of ~14%. The dispersion had a low viscosity below room temperature. As the temperature was raised to body temperature (37 degrees C), the dispersion rapidly (~170 s) underwent sol-gel transition with excellent gel modulus (G' ~ 6.5 kPa) in 20 min. PU dispersions with a solid content of 25-30% could be easily mixed with cells in sol state, extruded by a 3D printer, and deposited layer by layer as a gel. Cells remained alive and proliferating in the printed hydrogel scaffold. We expect that the development of novel thermoresponsive PU system can be used as smart injectable hydrogel and applied as a new type of bio-3D printing ink. PMID- 26651014 TI - Synthetic Transformations through Alkynoxy-Palladium Interactions and C-H Activation. AB - Organic synthesis based on straightforward transformations is essential for environmentally benign manufacturing for the invention of novel pharmaceuticals, agrochemicals, and organoelectronic materials in order to ultimately realize a sustainable society. Metal-catalyzed C-H bond-cleaving functionalization has become a promising method for achieving the above goal. For site-selective C-H bond cleavage, so-called directing groups, i.e., ligands attached to substrates, are employed. Commonly utilized directing groups are carbonyls, imines, carboxyls, amides, and pyridyls, which sigma-donate electron pairs to metals. On the other hand, unsaturated substrates such as alkenes and alkynes, which participate largely as reactants in organic synthesis, are prepared readily by a wide variety of synthetic transformations and are also employed as reactants in organometallic chemistry. Moreover, such unsaturated groups form complexes with some metals by ligation of their p orbitals via donation and back-donation. However, the use of unsaturated bonds as directing groups has not been studied extensively. We have been involved in the development of methods for the cleavage of C-H bonds by means of transition-metal catalysts to achieve new carbon-carbon bond-forming reactions and incidentally came to focus on the alkynoxy group ( OC=C-), which shows a ketene-like resonance structure. We expected the alkynoxy group to interact electrophilically with a low-valent transition-metal complex in order to cleave adjacent C-H bonds. In this Account, we summarize our recent achievements on C-H activation based on interactions of palladium with the alkynoxy group in alkynyl aryl ethers. The alkynoxy group plays two roles in the transformation: as a directing group for adjacent C-H bond activation and as an acceptor for the carbon and hydrogen fragments. A typical example is palladium catalyzed ortho-C-H bond activation in alkynoxyarenes followed by sequential insertion/annulation with internal alkynes and the alkynoxy group to produce 2 methylidene-2H-1-benzopyrans. Mechanistic studies have shown that the presence of both oxygen and alkynyl moieties is essential for selective ortho-C-H bond activation and subsequent annulation. In addition to internal alkynes, norbornene, allenes, isocyanates, and ketenes produce the corresponding oxacycles. It is worthy of note that benzoxadinones formed by the reaction with isocyanates exhibit solid-state luminescence. In addition, 2-methylphenyl alkynyl ethers and 2-alkynoxybiaryls undergo intramolecular annulation at the benzylic gamma-position and aryl delta-position via C-H bond activation to give benzofurans and dibenzopyrans, respectively. The disclosed methods allow us to construct useful pi-conjugated systems in a straightforward manner. PMID- 26651016 TI - Reverse Microemulsion-mediated Synthesis of Monometallic and Bimetallic Early Transition Metal Carbide and Nitride Nanoparticles. AB - A reverse microemulsion is used to encapsulate monometallic or bimetallic early transition metal oxide nanoparticles in microporous silica shells. The silica encapsulated metal oxide nanoparticles are then carburized in a methane/hydrogen atmosphere at temperatures over 800 degrees C to form silica-encapsulated early transition metal carbide nanoparticles. During the carburization process, the silica shells prevent the sintering of adjacent carbide nanoparticles while also preventing the deposition of excess surface carbon. Alternatively, the silica encapsulated metal oxide nanoparticles can be nitridized in an ammonia atmosphere at temperatures over 800 degrees C to form silica-encapsulated early transition metal nitride nanoparticles. By adjusting the reverse microemulsion parameters, the thickness of the silica shells, and the carburization/nitridation conditions, the transition metal carbide or nitride nanoparticles can be tuned to various sizes, compositions, and crystal phases. After carburization or nitridation, the silica shells are then removed using either a room-temperature aqueous ammonium bifluoride solution or a 0.1 to 0.5 M NaOH solution at 40-60 degrees C. While the silica shells are dissolving, a high surface area support, such as carbon black, can be added to these solutions to obtain supported early transition metal carbide or nitride nanoparticles. If no high surface area support is added, then the nanoparticles can be stored as a nanodispersion or centrifuged to obtain a nanopowder. PMID- 26651015 TI - Dendritic Cells Enhance HIV Infection of Memory CD4(+) T Cells in Human Lymphoid Tissues. AB - Dendritic cells (DCs) play a key role in controlling infections by coordinating innate and adaptive immune responses to invading pathogens. Paradoxically, DCs can increase HIV-1 dissemination in vitro by binding and transferring infectious virions to CD4(+) T cells, a process called transinfection. Transinfection has been well characterized in cultured cell lines and circulating primary T cells, but it is unknown whether DCs enhance infection of CD4(+) T cells in vivo. In untreated HIV infection, massive CD4(+) T-cell infection and depletion occur in secondary lymphoid tissues long before decline is evident in the peripheral circulation. To study the role of DCs in HIV infection of lymphoid tissues, we utilized human tonsil tissues, cultured either as tissue blocks or as aggregate suspension cultures, in single-round infection experiments. In these experiments, addition of monocyte-derived DCs (MDDCs) to the cultures increased T-cell infection, particularly in CD4(+) T cells expressing lower levels of HLA-DR. Subset analysis demonstrated that MDDCs increased HIV-1 infection of central and effector memory T-cell populations. Depletion of endogenous myeloid DCs (myDCs) from the cultures decreased memory T-cell infection, and readdition of MDDCs restored infection to predepletion levels. Using an HIV-1 fusion assay, we found that MDDCs equally increased HIV delivery into naive, central, and effector memory T cells in the cultures, whereas predepletion of myDCs reduced fusion into memory T cells. Together, these data suggest that resident myDCs facilitate memory T-cell infection in lymphoid tissues, implicating DC-mediated transinfection in driving HIV dissemination within these tissues in untreated HIV/AIDS. PMID- 26651017 TI - Inhibition of Condensation Frosting by Arrays of Hygroscopic Antifreeze Drops. AB - The formation of frost and ice can have negative impacts on travel and a variety of industrial processes and is typically addressed by dispensing antifreeze substances such as salts and glycols. Despite the popularity of this anti-icing approach, some of the intricate underlying physical mechanisms are just being unraveled. For example, recent studies have shown that in addition to suppressing ice formation within its own volume, an individual salt saturated water microdroplet forms a region of inhibited condensation and condensation frosting (RIC) in its surrounding area. This occurs because salt saturated water, like most antifreeze substances, is hygroscopic and has water vapor pressure at its surface lower than water saturation pressure at the substrate. Here, we demonstrate that for macroscopic drops of propylene glycol and salt saturated water, the absolute RIC size can remain essentially unchanged for several hours. Utilizing this observation, we demonstrate that frost formation can be completely inhibited in-between microscopic and macroscopic arrays of propylene glycol and salt saturated water drops with spacing (S) smaller than twice the radius of the RIC (delta). Furthermore, by characterizing condensation frosting dynamics around various hygroscopic drop arrays, we demonstrate that they can delay complete frosting over of the samples 1.6 to 10 times longer than films of the liquids with equivalent volume. The significant delay in onset of ice nucleation achieved by dispensing propylene glycol in drops rather than in films is likely due to uniform dilution of the drops driven by thermocapillary flow. This transport mode is absent in the films, leading to faster dilution, and with that facilitated homogeneous nucleation, near the liquid-air interface. PMID- 26651018 TI - Genetic and epigenetic alterations of microRNAs and implications for human cancers and other diseases. AB - MicroRNAs (miRNAs) are a well-studied group of noncoding RNAs that control gene expression by interacting mainly with messenger RNA. It is known that miRNAs and their biogenesis regulatory machineries have crucial roles in multiple cell processes; thus, alterations in these genes often lead to disease, such as cancer. Disruption of these genes can occur through epigenetic and genetic alterations, resulting in aberrant expression of miRNAs and subsequently of their target genes. This review focuses on the disruption of miRNAs and their key regulatory machineries by genetic alterations, with emphasis on mutations and epigenetic changes in cancer and other diseases. PMID- 26651020 TI - Editorial. PMID- 26651019 TI - Synthesis of alpha-MnO2 nanowires modified by Co3O4 nanoparticles as a high performance catalyst for rechargeable Li-O2 batteries. AB - The alpha-MnO2 nanowires uniformly coated with Co3O4 nanoparticles were prepared as a bi-functional catalyst for rechargeable Li-O2 batteries. The alpha-MnO2 nanowires were 5-20 nm in diameter, ranging between 5 and 10 MUm in length. And the coated Co3O4 nanoparticles were around 5 nm in diameter. The alpha-MnO2/Co3O4 hybrid had a high specific surface area of 329.5 cm(2) g(-1), and showed excellent catalytic property. Both of the charge and discharge overpotentials are effectively reduced and the batteries could stably work for more than 60 cycles. It is demonstrated that the catalytic performance of the alpha-MnO2/Co3O4 hybrid is not only associated with the morphology and size of the catalyst, but also with their synergetic effects and the oxygen vacancies produced at the surface of MnO2. The results of charge-discharge cycling tests demonstrate that this alpha MnO2/Co3O4 hybrid catalyst is a promising candidate for the Li-O2 batteries. PMID- 26651021 TI - P-Arylation of Dialkyl Phosphites and Secondary Phosphine Oxides with Arynes. AB - The novel P-arylation of dialkyl phosphites and secondary phosphine oxides with arynes has been achieved. The reactions produce dialkyl arylphosphonates in 71 99% yield and tertiary phosphine oxides in 68-92% yield under mild conditions. PMID- 26651022 TI - Effect of Sucralfate on the Relative Bioavailability of Enrofloxacin and Ciprofloxacin in Healthy Fed Dogs. AB - BACKGROUND: Sucralfate impairs absorption of ciprofloxacin and other fluoroquinolones in humans, but no sucralfate-fluoroquinolone interaction has been reported in dogs. Veterinary formularies recommend avoiding concurrent administration of these medications, which might impact compliance, therapeutic success, and resistance selection from fluoroquinolones. OBJECTIVES: To determine whether a drug interaction exists when sucralfate is administered to fed dogs concurrently with ciprofloxacin or enrofloxacin, and whether a 2 hour delay between fluoroquinolone and sucralfate affects fluoroquinolone absorption. ANIMALS: Five healthy Greyhounds housed in a research colony. METHODS: This was a randomized crossover study. Treatments included oral ciprofloxacin (C) or oral enrofloxacin (E) alone, each fluoroquinolone concurrently with an oral suspension of sucralfate (CS, ES), and sucralfate suspension 2 hours after each fluoroquinolone (C2S, E2S). Fluoroquinolone concentrations were evaluated using liquid chromatography with mass spectrometry. RESULTS: Drug exposure of ciprofloxacin was highly variable (AUC 5.52-22.47 h MUg/mL) compared to enrofloxacin (AUC 3.86-7.50 h MUg/mL). The mean relative bioavailability for ciprofloxacin and concurrent sucralfate was 48% (range 8-143%) compared to ciprofloxacin alone. Relative bioavailability of ciprofloxacin improved to 87% (range 37-333%) when sucralfate was delayed by 2 hours. By contrast, relative bioavailability for enrofloxacin and concurrent sucralfate was 104% (94-115%). CONCLUSIONS AND CLINICAL IMPORTANCE: A possible clinically relevant drug interaction for the relative bioavailability of ciprofloxacin with sucralfate was found. No significant difference in bioavailability was documented for enrofloxacin with sucralfate. Further research is warranted in fasted dogs and clinical cases requiring enrofloxacin or other approved fluoroquinolones in combination with sucralfate. PMID- 26651023 TI - Pathogenesis mediated by proviral host factors involved in translation and replication of plant positive-strand RNA viruses. AB - Viral pathogenesis comes from complex interactions between viruses and hosts. All the processes of viral infection, including translation of viral factors and replication of viral genomes, define viral pathogenesis; therefore, molecular insights into the mechanisms underlying viral replication strategies unambiguously pave the way for our comprehensive understanding of viral pathogenesis and disease outcome, as well as for developing new antiviral strategies against plant virus disease. Recent studies of plant positive-strand RNA [(+)RNA] viruses have advanced our understanding of co-opted host factors and their roles in viral translation and replication. It is becoming clear that plant (+)RNA viruses harness host factors involved in membrane trafficking and lipid metabolism to establish the viral replication complex (VRC). In this review, we aim to discuss the contribution of co-opted host factors in translation and genome replication of plant (+)RNA viruses mainly focusing on those involved in the biogenesis of the VRC, which may act as a central hub in almost all the processes of viral infection as well as viral pathogenesis. PMID- 26651024 TI - The altered photosynthetic machinery during compatible virus infection. AB - As an organelle only found in plant cells and some protists, the chloroplast is not only the main metabolic energy originator, but also the abiotic/biotic stress sensor and defense signal generator. For a long time, chloroplasts have been recognized as a common target by many plant viruses. Viruses may directly modify chloroplast membranes to assemble their replication complex for viral genome replication. Viruses may downregulate chloroplast-related and photosynthesis related genes via an as yet unknown mechanism to support their infection. Viruses may also interrupt functionality of the photosynthetic machinery through protein protein interactions. This review briefly summarizes current knowledge about modifications of the photosynthetic machinery by plant viruses, highlights the important role of chloroplasts in the infection process and discusses chloroplast associated pathogenesis. PMID- 26651025 TI - Using Fiberless, Wearable fNIRS to Monitor Brain Activity in Real-world Cognitive Tasks. AB - Functional Near Infrared Spectroscopy (fNIRS) is a neuroimaging technique that uses near-infrared light to monitor brain activity. Based on neurovascular coupling, fNIRS is able to measure the haemoglobin concentration changes secondary to neuronal activity. Compared to other neuroimaging techniques, fNIRS represents a good compromise in terms of spatial and temporal resolution. Moreover, it is portable, lightweight, less sensitive to motion artifacts and does not impose significant physical restraints. It is therefore appropriate to monitor a wide range of cognitive tasks (e.g., auditory, gait analysis, social interaction) and different age populations (e.g., new-borns, adults, elderly people). The recent development of fiberless fNIRS devices has opened the way to new applications in neuroscience research. This represents a unique opportunity to study functional activity during real-world tests, which can be more sensitive and accurate in assessing cognitive function and dysfunction than lab-based tests. This study explored the use of fiberless fNIRS to monitor brain activity during a real-world prospective memory task. This protocol is performed outside the lab and brain haemoglobin concentration changes are continuously measured over the prefrontal cortex while the subject walks around in order to accomplish several different tasks. PMID- 26651026 TI - Purcell factor based understanding of enhancements in surface plasmon-coupled emission with DNA architectures. AB - We demonstrate the successful application of DNA thin films as dynamic bio spacers in a surface plasmon-coupled emission platform. Site-directed DNA modification using silver and carbon nanomaterials resulted in an amplified Purcell factor (PF) and >130-fold fluorescence enhancements. We present unique architectures of DNA as a plasmonic spacer in metal-dielectric-metal substrates. PMID- 26651027 TI - Albicetus oxymycterus, a New Generic Name and Redescription of a Basal Physeteroid (Mammalia, Cetacea) from the Miocene of California, and the Evolution of Body Size in Sperm Whales. AB - Living sperm whales are represented by only three species (Physeter macrocephalus, Kogia breviceps and Kogia sima), but their fossil record provides evidence of an ecologically diverse array of different forms, including morphologies and body sizes without analog among living physeteroids. Here we provide a redescription of Ontocetus oxymycterus, a large but incomplete fossil sperm whale specimen from the middle Miocene Monterey Formation of California, described by Remington Kellogg in 1925. The type specimen consists of a partial rostrum, both mandibles, an isolated upper rostrum fragment, and incomplete tooth fragments. Although incomplete, these remains exhibit characteristics that, when combined, set it apart morphologically from all other known physeteroids (e.g., a closed mesorostral groove, and the retention of enameled tooth crowns). Kellogg originally placed this species in the genus Ontocetus, a enigmatic tooth taxon reported from the 19th century, based on similarities between the type specimen Ontocetus emmonsi and the conspicuously large lower dentition of Ontocetus oxymycterus. However, the type of the genus Ontocetus is now known to represent a walrus tusk (belonging to fossil Odobenidae) instead of a cetacean tooth. Thus, we assign this species to the new genus Albicetus, creating the new combination of Albicetus oxymycterus, gen. nov. We provide new morphological observations of the type specimen, including a 3D model. We also calculate a total length of approximately 6 m in life, using cranial proxies of body size for physeteroids. Lastly, a phylogenetic analysis of Albicetus oxymycterus with other fossil and living Physeteroidea resolves its position as a stem physeteroid, implying that large body size and robust dentition in physeteroids evolved multiple times and in distantly related lineages. PMID- 26651029 TI - The Impact of Previous Physical Training on Redox Signaling after Traumatic Brain Injury in Rats: A Behavioral and Neurochemical Approach. AB - Throughout the world, traumatic brain injury (TBI) is one of the major causes of disability, which can include deficits in motor function and memory, as well as acquired epilepsy. Although some studies have shown the beneficial effects of physical exercise after TBI, the prophylactic effects are poorly understood. In the current study, we demonstrated that TBI induced by fluid percussion injury (FPI) in adult male Wistar rats caused early motor impairment (24 h), learning deficit (15 days), spontaneous epileptiform events (SEE), and hilar cell loss in the hippocampus (35 days) after TBI. The hippocampal alterations in the redox status, which were characterized by dichlorofluorescein diacetate oxidation and superoxide dismutase (SOD) activity inhibition, led to the impairment of protein function (Na(+), K(+)-adenosine triphosphatase [ATPase] activity inhibition) and glutamate uptake inhibition 24 h after neuronal injury. The molecular adaptations elicited by previous swim training protected against the glutamate uptake inhibition, oxidative stress, and inhibition of selected targets for free radicals (e.g., Na(+), K(+)-ATPase) 24 h after neuronal injury. Our data indicate that this protocol of exercise protected against FPI-induced motor impairment, learning deficits, and SEE. In addition, the enhancement of the hippocampal phosphorylated nuclear factor erythroid 2-related factor (P-Nrf2)/Nrf2, heat shock protein 70, and brain-derived neurotrophic factor immune content in the trained injured rats suggests that protein expression modulation associated with an antioxidant defense elicited by previous physical exercise can prevent toxicity induced by TBI, which is characterized by cell loss in the dentate gyrus hilus at 35 days after TBI. Therefore, this report suggests that previous physical exercise can decrease lesion progression in this model of brain damage. PMID- 26651030 TI - Raman Radiation Patterns of Graphene. AB - We report the angular distribution of the G and 2D Raman scattering from graphene on glass by detecting back focal plane patterns. The G Raman emission can be described by a superposition of two incoherent orthogonal point dipoles oriented in the graphene plane. Due to double resonant Raman scattering, the 2D emission can be represented by the sum of either three incoherent dipoles oriented 120 degrees with respect to each other, or two orthogonal incoherent ones with a 3:1 weight ratio. Parameter-free calculations of the G and 2D intensities are in excellent agreement with the experimental radiation patterns. We show that the 2D polarization ratio and the 2D/G intensity ratio depend on the numerical aperture of the microscope objective. This is due to the depolarization of the emission and excitation light when graphene is on a dielectric substrate, as well as to tight focusing. The polarization contrast decreases substantially for increasing collection angle, due to polarization mixing caused by the air-dielectric interface. This also influences the intensity ratio I(2D)/I(G), a crucial quantity for estimating the doping in graphene. Our results are thus important for the quantitative analysis of the Raman intensities in confocal microscopy. In addition, they are relevant for understanding the influence of signal enhancing plasmonic antenna structures, which typically modify the sample's radiation pattern. PMID- 26651031 TI - A novel endovascular occlusion device with a steerable introducer for embolization in a porcine model. AB - OBJECTIVES: It has been reported that vascular plugging has become a therapeutic alternative to coil embolization in certain cases that require occlusion. However, the use of a relatively large and rigid delivery sheath may be a limiting factor in vascular plug use. In this study, we aimed to determine the safety and efficacy of a novel transcatheter occlusion device with unique design and delivery system in a pig model. METHODS: The Cera vascular plug was delivered and deployed through the FuStar steerable introducer sheath, which can control tip direction during advancement. Twelve pigs were randomized to undergo an embolization procedure in which the Cera vascular plug was implanted into the left internal iliac artery (IIA) with the FuStar steerable introducer (n = 6) or a control introducer sheath. Another eight pigs were assigned to undergo an embolization procedure in which the test device was implanted into either the splenic artery (SA, n = 4) or the lower segmental branch of left renal artery (LRA, n = 4). Angiography and pathological examinations were performed to evaluate the outcomes. RESULTS: A total of 20 target vessels were embolized with a total of 22 test plugs. Compared with the control introducer, plug embolization through the FuStar steerable introducer was associated with shorter fluoroscopy time (21.50 +/- 3.62 vs. 28.33 +/- 2.16 min, P = 0.003) and less contrast medium (129.17 +/- 22.68 vs. 162.50 +/- 13.69 mL, P = 0.012). At the 2-month follow-up, angiography and pathological examinations did not show any evidence of migration, and persistent occlusion was observed in 18 of the 20 target vessels. Organ ischemia occurred when plugs were deployed within the lower segmental branch of the LRA. CONCLUSION: This novel device is suitable for therapeutic vascular embolization with the use of flexible delivery systems. The different outcomes of SA and LRA plugging suggested that the occluding device should be placed within the appropriate portion of the target vessel to allow the development of collateralization. PMID- 26651028 TI - Pterostilbene Decreases the Antioxidant Defenses of Aggressive Cancer Cells In Vivo: A Physiological Glucocorticoids- and Nrf2-Dependent Mechanism. AB - AIMS: Polyphenolic phytochemicals have anticancer properties. However, in mechanistic studies, lack of correlation with the bioavailable concentrations is a critical issue. Some reports had suggested that these molecules downregulate the stress response, which may affect growth and the antioxidant protection of malignant cells. Initially, we studied this potential underlying mechanism using different human melanomas (with genetic backgrounds correlating with most melanomas), growing in nude mice as xenografts, and pterostilbene (Pter, a natural dimethoxylated analog of resveratrol). RESULTS: Intravenous administration of Pter decreased human melanoma growth in vivo. However, Pter, at levels measured within the tumors, did not affect melanoma growth in vitro. Pter inhibited pituitary production of the adrenocorticotropin hormone (ACTH), decreased plasma levels of corticosterone, and thereby downregulated the glucocorticoid receptor- and nuclear factor (erythroid-derived 2)-like 2 (Nrf2) dependent antioxidant defense system in growing melanomas. Exogenous corticosterone or genetically induced Nrf2 overexpression in melanoma cells prevented the inhibition of tumor growth and decreased antioxidant defenses in these malignant cells. These effects and mechanisms were also found in mice bearing different human pancreatic cancers. Glutathione depletion (selected as an antimelanoma strategy) facilitated the complete elimination by chemotherapy of melanoma cells isolated from mice treated with Pter. INNOVATION: Although bioavailability-related limitations may preclude direct anticancer effects in vivo, natural polyphenols may also interfere with the growth and defense of cancer cells by downregulating the pituitary gland-dependent ACTH synthesis. CONCLUSIONS: Pter downregulates glucocorticoid production, thus decreasing the glucocorticoid receptor and Nrf2-dependent signaling/transcription and the antioxidant protection of melanoma and pancreatic cancer cells. Antioxid. Redox Signal. 24, 974-990. PMID- 26651032 TI - Risk factors for lower extremity amputation in patients with diabetic foot ulcers: a hospital-based case-control study. AB - BACKGROUND: Diabetic foot ulcers (DFU) may cause significant morbidity and lower extremity amputation (LEA) due to diabetic foot problems can occur more often compared to the general population. The purpose of the present study was to use an epidemiological design to determine and to quantify the risk factors of subsequent amputation in hospitalized DFU patients. METHODS: We performed a hospital-based, case-control study of 47 DFU patients with LEA and 47 control DFU patients without LEA. The control subjects were matched to cases in respect to age (+/-5 years), sex, and nutritional status, with ratio of 1:1. This study was conducted in Dr. Kariadi General Hospital Semarang between January 2012 and December 2014. Patients' demographical data and all risk factors-related information were collected from clinical records using a short structural chart. Using LEA as the outcome variable, we calculated odds ratios (ORs) and 95% confidence intervals (CIs) by logistic regression. Univariate and stepwise logistic regression analyses were used to assess the independent effect of selected risk factors associated with LEA. The data were analyzed in SPSS version 21. RESULTS: There were 47 case-control pairs, all of which were diagnosed with type 2 diabetes mellitus. Seven potential independent variables show a promise of influence, the latter being defined as p<=0.15 upon univariate analysis. Multivariable logistic regression identified levels of HbA1c >=8% (OR 20.47, 95% CI 3.12-134.31; p=0.002), presence of peripheral arterial disease (PAD) (OR 12.97, 95% CI 3.44-48.88; p<0.001), hypertriglyceridemia (OR 5.58, 95% CI 1.74 17.91; p=0.004), and hypertension (OR 3.67, 95% CI 1.14-11.79; p=0.028) as the independent risk factors associated with subsequent LEA in DFU. CONCLUSIONS: Several risk factors for LEA were identified. We found that HbA1c >=8%, PAD, hypertriglyceridemia, and hypertension have been recognized as the predictors of LEA in this study. Good glycemic control, active investigation against PAD, and management of comorbidities such as hypertriglyceridemia and hypertension are considered important to reduce amputation risk. PMID- 26651033 TI - Analytical challenges of extracellular vesicle detection: A comparison of different techniques. AB - The interest in extracellular vesicles (EVs) has grown exponentially over the last decade. Evolving evidence is demonstrating that these EVs are playing an important role in health and disease. They are involved in intercellular communication and have been shown to transfer proteins, lipids, and nucleic acids. This review focuses on the most commonly used techniques for detection of EVs, to include microparticles, 100-1,000 nm in size, and exosomes, 50-100 nm in size. Conventional flow cytometry is the most prevalent technique, but nanoparticle tracking analysis (NTA), dynamic light scattering (DLS), and resistive pulse sensing have also been used to detect EVs. The accurate measurement of these vesicles is challenged by size heterogeneity, low refractive index, and the lack of dynamic measurement range for most of the available technologies. Sample handling during the preanalytical phase can also affect the accuracy of measurements. Currently, there is not one single method which allows phenotyping, sizing, and enumerating the whole range of EVs and, therefore, providing all the necessary information to truly understand the biology of these particles. A combination of methods is probably needed which might also include electron and atomic force microscopy and full RNA, lipid, and protein profiling. PMID- 26651054 TI - Development and Validation of a Rex1-RFP Potency Activity Reporter Assay That Quantifies Stress-Forced Potency Loss in Mouse Embryonic Stem Cells. AB - Assays for embryonic stem cells (ESCs) of the blastocyst are needed to quantify stress-induced decreases of potent subpopulations. High-throughput screens (HTSs) of stressed ESCs quantify embryonic stress, diminishing laboratory animal needs. Normal or stress-induced ESC differentiation is marked by Rex1 potency factor loss. Potency reporter ESC assays were developed, using low-stress techniques to create transgenic ESCs. Rex1 and Oct4 promoters drove RFP and green fluorescent protein (GFP) expression, respectively. Lentivirus infection and fluorescence activated cell sorting selection of ESCs obviated the need for stressful electroporation and antibiotic selection, respectively. We showed using immunoblots, microscopic analysis, flow cytometry, and fluorescence microplate reader that the response to stress of potency-reporter ESCs is similar to parental ESCs assayed by biochemical means. Stress caused a dose-dependent decrease in bright Rex1-RFP(+) ESCs and increase in Rex1 dim ESCs. At highest stress, ~ 20% of bright Rex1-RFP cells are lost coinciding with a 2.8-fold increase in Rex1-RFP dim cells that approach 20%. This conversion of bright to dim cells tested by flow cytometry is commensurate with about 60% loss in fluorescence measured by microplate reader. Dose-dependent stress-induced Rex1 RFP and endogenous Rex1 protein decreases are similar. The data show that Rex1 reporter ESCs accurately report stress in a microplate reader-based HTS. The increasing dim Rex1 subpopulation size is balanced by the decreasing total ESC number during culture at multiple sorbitol doses. This is consistent with previous observations that stress forces potency decrease and differentiation increase to compensate for stress-induced diminished stem cell population growth. PMID- 26651055 TI - A Microfluidic Platform for Precision Small-volume Sample Processing and Its Use to Size Separate Biological Particles with an Acoustic Microdevice. AB - A major advantage of microfluidic devices is the ability to manipulate small sample volumes, thus reducing reagent waste and preserving precious sample. However, to achieve robust sample manipulation it is necessary to address device integration with the macroscale environment. To realize repeatable, sensitive particle separation with microfluidic devices, this protocol presents a complete automated and integrated microfluidic platform that enables precise processing of 0.15-1.5 ml samples using microfluidic devices. Important aspects of this system include modular device layout and robust fixtures resulting in reliable and flexible world to chip connections, and fully-automated fluid handling which accomplishes closed-loop sample collection, system cleaning and priming steps to ensure repeatable operation. Different microfluidic devices can be used interchangeably with this architecture. Here we incorporate an acoustofluidic device, detail its characterization, performance optimization, and demonstrate its use for size-separation of biological samples. By using real-time feedback during separation experiments, sample collection is optimized to conserve and concentrate sample. Although requiring the integration of multiple pieces of equipment, advantages of this architecture include the ability to process unknown samples with no additional system optimization, ease of device replacement, and precise, robust sample processing. PMID- 26651056 TI - Incorporation of Nitrogen Defects for Efficient Reduction of CO2 via Two-Electron Pathway on Three-Dimensional Graphene Foam. AB - The practical recycling of carbon dioxide (CO2) by the electrochemical reduction route requires an active, stable, and affordable catalyst system. Although noble metals such as gold and silver have been demonstrated to reduce CO2 into carbon monoxide (CO) efficiently, they suffer from poor durability and scarcity. Here we report three-dimensional (3D) graphene foam incorporated with nitrogen defects as a metal-free catalyst for CO2 reduction. The nitrogen-doped 3D graphene foam requires negligible onset overpotential (-0.19 V) for CO formation, and it exhibits superior activity over Au and Ag, achieving similar maximum Faradaic efficiency for CO production (~85%) at a lower overpotential (-0.47 V) and better stability for at least 5 h. The dependence of catalytic activity on N-defect structures is unraveled by systematic experimental investigations. Indeed, the density functional theory calculations confirm pyridinic N as the most active site for CO2 reduction, consistent with experimental results. PMID- 26651057 TI - Reviewers Continue to Rise to an ''Exceptional" Level. PMID- 26651059 TI - Antibacterial Effects of Pyrolysis Oil Against Salmonella Typhimurium and Escherichia coli. AB - Many issues have been found to be related to food preservation and food contamination caused by various pathogenic bacteria in recent years. Many antibacterial agents act efficiently against Gram-positive foodborne bacteria; however, they are less effective against Gram-negative foodborne bacteria. In the present study, an attempt has been made to evaluate the antibacterial activity of pyrolysis oil manufactured from Pinus densiflora (PLO) against two Gram-negative foodborne pathogenic bacteria, Salmonella Typhimurium and Escherichia coli O157:H7. PLO possessed potent antibacterial activity against both foodborne pathogenic bacteria, as indicated by inhibition zones of 10.33-12.33 mm and minimum inhibitory concentration and minimum bactericidal concentration values of 250-500 MUg/mL and 500-1000 MUg/mL, respectively. PLO at the minimum inhibitory concentration exhibited an inhibitory effect on the viability of the bacterial pathogens with leakage of 260 nm absorbing materials, an increase in the relative electrical conductivity, and loss of salt tolerance capacity. PLO exhibited promising antibacterial activity against both of the Gram-negative foodborne pathogenic bacteria and thus it can be utilized in the food sector and pharmaceutical industries for the development of antibiotics and preservatives. PMID- 26651060 TI - Reconstituted high-density lipoprotein can elevate plasma alanine aminotransferase by transient depletion of hepatic cholesterol: role of the phospholipid component. AB - Human apolipoprotein A-I preparations reconstituted with phospholipids (reconstituted high-density lipoprotein [HDL]) have been used in a large number of animal and human studies to investigate the physiological role of apolipoprotein A-I. Several of these studies observed that intravenous infusion of reconstituted HDL might cause transient elevations in plasma levels of hepatic enzymes. Here we describe the mechanism of this enzyme release. Observations from several animal models and in vitro studies suggest that the extent of hepatic transaminase release (alanine aminotransferase [ALT]) correlates with the movement of hepatic cholesterol into the blood after infusion. Both the amount of ALT release and cholesterol movement were dependent on the amount and type of phospholipid present in the reconstituted HDL. As cholesterol is known to dissolve readily in phospholipid, an HDL preparation was loaded with cholesterol before infusion into rats to assess the role of diffusion of cholesterol out of the liver and into the reconstituted HDL. Cholesterol-loaded HDL failed to withdraw cholesterol from tissues and subsequently failed to cause ALT release. To investigate further the role of cholesterol diffusion, we employed mice deficient in SR-BI, a transporter that facilitates spontaneous movement of cholesterol between cell membranes and HDL. These mice showed substantially lower movement of cholesterol into the blood and markedly lower ALT release. We conclude that initial depletion of hepatic cholesterol initiates transient ALT release in response to infusion of reconstituted HDL. This effect may be controlled by appropriate choice of the type and amount of phospholipid in reconstituted HDL. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26651061 TI - Internal auditory canal meningocele-perilabyrinthine/translabyrinthine fistula: Case report and imaging. AB - The case of a 17-year-old patient with progressive unilateral sensorineural hearing loss and temporal bone malformations concerning for internal auditory canal meningocele with translabyrinthine/perilabyrinthine cerebrospinal fluid fistula is presented with associated computed tomography and magnetic resonance imaging. As the second reported case of an unruptured internal auditory canal meningocele with translabyrinthine/perilabyrinthine fistula, the case presents several clinically relevant points for otologists, neurotologists, and neuroradiologists. Although rare, it is an additional entity to consider as a cause of unilateral sensorineural hearing loss and may pose a risk for developing meningitis and possible "gushing" of cerebrospinal fluid should surgical intervention be attempted. Laryngoscope, 126:1931-1934, 2016. PMID- 26651062 TI - Exploring the shock response of spider webs. AB - Spider orb-webs are designed to allow for quick energy absorption as well as the constraint of drastic oscillations occurring upon prey impact. Studies on spider silk illustrate its impressive mechanical properties and its capacity to be used as technical fibers in composite materials. Models have previously been used to study the mechanical properties of different silk fibers, but not the behavior of the spider web as a whole. Full spider webs have been impacted by a projectile and the transverse displacement was measured by means of a laser interferometer. The damping and stiffness of the entire webs were quantified considering the orb web as a single-degree-of-freedom (SDOF) system. The amplitude, the period duration, and the energy dissipation of the oscillations have also been reported from the experiments. The analysis of the energy dissipation confirmed that the webs of orb-web spiders are optimized for the capture of a single or few large prey, rather than several small prey. The experiments also confirmed that the overall stiffness of the web displayed a non-linear behavior. Such non-linearity was also observed in the damping characteristics of the webs studied. PMID- 26651063 TI - Degradation of Ti-6Al-4V alloy under cyclic loading in a simulated body environment with cell culturing. AB - The present study reports the corrosion fatigue of the Ti-6Al-4V alloy using cyclic deformation test in a simulated body fluid under cell culturing for the first time. Cyclic deformation tests were carried out using three types of specimens to reveal the effects of proteins and cells on the corrosion fatigue of the alloy. For the 1-day-immersed and 1-week-immersed specimens, tensile specimens were soaked in a simulated body fluid for 1 day and 1 week, respectively, before cyclic deformation test, whereas for the cell-cultured specimen, MC3T3-E1 osteoblast-like cells were seeded and then cultured on tensile specimens for 1 week. The incubation period for crack initiation was longer for the cell-cultured and 1-week-immersed specimens compared to that for the 1-day immersed specimen. On the other hand, crack propagation period for the cell cultured and 1-week-immersed specimens was shorter than that for the 1-day immersed specimen. These results indicate that proteins and cells adhered on the alloy surface inhibit metal dissolution at newly created surface emerged by cyclic deformation to suppress crack initiation, whereas they accelerate crack propagation because dissolution at crack tip is accelerated in the occluded space formed under proteins and cells. PMID- 26651064 TI - Water-assisted self-healing and property recovery in a natural dermal armor of pangolin scales. AB - Self-healing capacity, of which the inspiration comes from biological systems, is significant for restoring the mechanical properties of materials by autonomically repairing damages. Clarifying the naturally occurring self-healing behaviors and mechanisms may provide valuable inspiration for designing synthetic self-healing materials. In this study, water-assisted self-healing behavior was revealed in a natural dermal armor of pangolin scales. The indentation damages which imitate the injury caused by predatory attack can be continuously mitigated through hydration. The healing kinetics was characterized according to the variations of indentation crater dimension and quantitatively described in terms of the viscoelastic behavior of biopolymer. The mechanical properties of original, damaged, and recovered scales in both dry and wet states were systematically evaluated by three-point bending and compared through statistical analysis. The hydration effects and mechanisms were explored by examining the dynamic mechanical properties and thermal behaviors. The promoted self-healing process can be attributed to the improved flexibility of macromolecules in the biopolymer. This study may stimulate useful self-healing strategies in bio inspired design and aid in developing high-performance synthetic self-healing materials. PMID- 26651065 TI - Visualizing Hyporheic Flow Through Bedforms Using Dye Experiments and Simulation. AB - Advective exchange between the pore space of sediments and the overlying water column, called hyporheic exchange in fluvial environments, drives solute transport in rivers and many important biogeochemical processes. To improve understanding of these processes through visual demonstration, we created a hyporheic flow simulation in the multi-agent computer modeling platform NetLogo. The simulation shows virtual tracer flowing through a streambed covered with two dimensional bedforms. Sediment, flow, and bedform characteristics are used as input variables for the model. We illustrate how these simulations match experimental observations from laboratory flume experiments based on measured input parameters. Dye is injected into the flume sediments to visualize the porewater flow. For comparison virtual tracer particles are placed at the same locations in the simulation. This coupled simulation and lab experiment has been used successfully in undergraduate and graduate laboratories to directly visualize river-porewater interactions and show how physically-based flow simulations can reproduce environmental phenomena. Students took photographs of the bed through the transparent flume walls and compared them to shapes of the dye at the same times in the simulation. This resulted in very similar trends, which allowed the students to better understand both the flow patterns and the mathematical model. The simulations also allow the user to quickly visualize the impact of each input parameter by running multiple simulations. This process can also be used in research applications to illustrate basic processes, relate interfacial fluxes and porewater transport, and support quantitative process based modeling. PMID- 26651066 TI - Moisture insensitive adsorption of ammonia on resorcinol-formaldehyde resins. AB - Phenolic-formaldehyde resins aged at 85, 90 and 95 degrees C were used as ammonia adsorbents at dynamic conditions in dry and moist air. To avoid pressure drops 10% bentonite was added as a binder. The initial and hybrid materials (before and after ammonia adsorption) were extensively characterized from the point of view of their porosity and surface chemistry. The results showed that the addition of the binder had various effects on materials' properties depending on the chemistry of their surface groups. When the phenolic acidic groups were predominant, the largest increase in surface acidity upon the addition of the binder was found. It was linked to the exfoliation of bentonite by polar moieties of the resins, which made acidic groups from aluminosilicate layers available for ammonia adsorption. On this sample, a relatively high amount of ammonia was strongly adsorbed in dry conditions. Insensitivity to moisture is a significant asset of ammonia adsorbents. PMID- 26651067 TI - Self-heating of dried industrial tannery wastewater sludge induced by pyrophoric iron sulfides formation. AB - Similarly to many powders of solids, dried sludge originated from tannery wastewater may result in a self-heating process, under given circumstances. In most cases, it causes a moderate heating (reaching 70-90 degrees C), but larger, off-design residence times in the drier, in a suboxic atmosphere, extremely reactive solids can be produced. Tannery waste contains several chemicals that mostly end up in the wastewater treatment sludge. Unexpected and uncontrolled self heating could lead to a combustion and even to environmental problems. Elaborating on previous studies, with the addition of several analytical determinations, before and after the self-heating, we attempted to formulate a mechanism for the onset of heating. We demonstrated that the system Fe/S/O has been involved in the process. We proved that the formation of small quantities of pyrophoric iron sulfides is the key. They are converted to sulfated by reaction with water and oxygen with exothermic processes. The pyrite/pyrrhotite production depends on the sludge drying process. The oxidation of sulfides to oxides and sulfates through exothermic steps, reasonably catalyzed by metals in the sludge, occurs preferentially in a moist environment. The mechanism has been proved by reproducing in the laboratory prolonged heating under anoxic/suboxic atmosphere. PMID- 26651068 TI - Osmotic membrane bioreactor for phenol biodegradation under continuous operation. AB - Continuous phenol biodegradation was accomplished in a two-phase partitioning osmotic membrane bioreactor (TPPOMBR) system, using extractant impregnated membranes (EIM) as the partitioning phase. The EIMs alleviated substrate inhibition during prolonged operation at influent phenol concentrations of 600 2000mg/L, and also at spiked concentrations of 2500mg/L phenol restricted to 2 days. Filtration of the effluent through forward osmosis maintained high biomass concentration in the bioreactor and improved effluent quality. Steady state was reached in 5-6 days at removal rates varying between 2000 and 5500mg/L-day under various conditions. Due to biofouling and salt accumulation, the permeate flux varied from 1.2-7.2 LMH during 54 days of operation, while maintaining an average hydraulic retention time of 7.4h. A washing cycle, comprising 1h osmotic backwashing using 0.5M NaCl and 2h washing with water, facilitated biofilm removal from the membranes. Characterization of the extracellular polymeric substances (EPS) through FTIR showed peaks between 1700 and 1500cm(-1), 1450 1450cm(-1) and 1200-1000cm(-1), indicating the presence of proteins, phenols and polysaccharides, respectively. The carbohydrate to protein ratio in the EPS was estimated to be 0.3. These results indicate that TPPOMBR can be promising in continuous treatment of phenolic wastewater. PMID- 26651069 TI - Mechanistic model for interpreting the toxic effects of sulfonamides on nitrification. AB - Antibiotics are categorized as pseudopersistent compounds because of their widespread use and continuous emission into the environment. Biological systems such as active sludge and biofilms are still the principal tools used to remove antibiotics in wastewater treatment plants (WWTPs). Consequently, it is important to determine the relationship between toxic effects in biological WWTPs and the structural characteristics of antibiotics. In the present study, toxic effects of 10 sulfonamides (SAs) on nitrification in an active sludge system were studied. The toxicity results (half-effective concentrations, EC50) indicated that the toxicity of sulfadimethoxine (SDM) is approximately 4 times as large as that of sulfadiazine (SD). Based on the toxicity mechanism and the partial least squares regression (PLS) method, an optimum quantitative structure-activity relationship (QSAR) model was developed for the test system. The mechanistic model showed that the pKa, the binding energies between SAs with dihydropteroate synthetase ( [Formula: see text] ) and the binding energies between SAs with ammonia monooxygenase ( [Formula: see text] ) are the key factors affecting the toxic effects of SAs on nitration process in active sludge system, following an order of importance of [Formula: see text] > [Formula: see text] >pKa. PMID- 26651070 TI - CO gas sensing properties of In4Sn3O12 and TeO2 composite nanoparticle sensors. AB - A simple hydrothermal route was used to synthesize In4Sn3O12 nanoparticles and In4Sn3O12-TeO2 composite nanoparticles, with In(C2H3O2)3, SnCl4, and TeCl4 as the starting materials. The structure and morphology of the synthesized nanoparticles were examined by X-ray diffraction and scanning electron microscopy (SEM), respectively. The gas-sensing properties of the pure and composite nanoparticles toward CO gas were examined at different concentrations (5-100ppm) of CO gas at different temperatures (100-300 degrees C). SEM observation revealed that the composite nanoparticles had a uniform shape and size. The sensor based on the In4Sn3O12-TeO2 composite nanoparticles showed stronger response to CO than its pure In4Sn3O12 counterpart. The response of the In4Sn3O12-TeO2 composite nanoparticle sensor to 100ppm of CO at 200 degrees C was 10.21, whereas the maximum response of the In4Sn3O12 nanoparticle sensor was 2.78 under the same conditions. Furthermore, the response time of the composite sensor was 19.73s under these conditions, which is less than one-third of that of the In4Sn3O12 sensor. The improved sensing performance of the In4Sn3O12-TeO2 nanocomposite sensor is attributed to the enhanced modulation of the potential barrier height at the In4Sn3O12-TeO2 interface, the stronger oxygen adsorption of p-type TeO2, and the formation of preferential adsorption sites. PMID- 26651071 TI - Estimate of uptake and translocation of emerging organic contaminants from irrigation water concentration in lettuce grown under controlled conditions. AB - The widespread distribution of emerging organic contaminants (EOCs) in the water cycle can lead to their incorporation in irrigated crops, posing a potential risk for human consumption. To gain further insight into the processes controlling the uptake of organic microcontaminants, Batavia lettuce (Lactuca sativa) grown under controlled conditions was watered with EOCs (e.g., non-steroidal anti inflammatories, sulfonamides, beta-blockers, phenolic estrogens, anticonvulsants, stimulants, polycyclic musks, biocides) at different concentrations (0-40MUgL( 1)). Linear correlations were obtained between the EOC concentrations in the roots and leaves and the watering concentrations for most of the contaminants investigated. However, large differences were found in the root concentration factors ( [Formula: see text] =0.27-733) and leaf translocation concentration factors ( [Formula: see text] =0-3) depending on the persistence of the target contaminants in the rhizosphere and the specific physicochemical properties of each one. With the obtained dataset, a simple predictive model based on a linear regression and the root bioconcentration and translocation factors can be used to estimate the concentration of the target EOCs in leaves based on the dose supplied in the irrigation water or the soil concentration. Finally, enantiomeric fractionation of racemic ibuprofen from the initial spiking mixture suggests that biodegradation mainly occurs in the rhizosphere. PMID- 26651072 TI - Molecular recognition features (MoRFs) in three domains of life. AB - Intrinsically disordered proteins and protein regions offer numerous advantages in the context of protein-protein interactions when compared to the structured proteins and domains. These advantages include ability to interact with multiple partners, to fold into different conformations when bound to different partners, and to undergo disorder-to-order transitions concomitant with their functional activity. Molecular recognition features (MoRFs) are widespread elements located in disordered regions that undergo disorder-to-order transition upon binding to their protein partners. We characterize abundance, composition, and functions of MoRFs and their association with the disordered regions across 868 species spread across Eukaryota, Bacteria and Archaea. We found that although disorder is substantially elevated in Eukaryota, MoRFs have similar abundance and amino acid composition across the three domains of life. The abundance of MoRFs is highly correlated with the amount of intrinsic disorder in Bacteria and Archaea but only modestly correlated in Eukaryota. Proteins with MoRFs have significantly more disorder and MoRFs are present in many disordered regions, with Eukaryota having more MoRF-free disordered regions. MoRF-containing proteins are enriched in the ribosome, nucleus, nucleolus and microtubule and are involved in translation, protein transport, protein folding, and interactions with DNAs. Our insights into the nature and function of MoRFs enhance our understanding of the mechanisms underlying the disorder-to-order transition and protein-protein recognition and interactions. The fMoRFpred method that we used to annotate MoRFs is available at http://biomine.ece.ualberta.ca/fMoRFpred/. PMID- 26651073 TI - New-onset atrial fibrillation: What's the significance? PMID- 26651074 TI - Building partnerships with prevention experts targeting other mental health problems. PMID- 26651075 TI - Comprehensive genomic profiling of 295 cases of clinically advanced urothelial carcinoma of the urinary bladder reveals a high frequency of clinically relevant genomic alterations. AB - BACKGROUND: In the current study, the authors present a comprehensive genomic profile (CGP)-based study of advanced urothelial carcinoma (UC) designed to detect clinically relevant genomic alterations (CRGAs). METHODS: DNA was extracted from 40 um of formalin-fixed, paraffin-embedded sections from 295 consecutive cases of recurrent/metastatic UC. CGP was performed on hybridization captured, adaptor ligation-based libraries to a mean coverage depth of 688X for all coding exons of 236 cancer-related genes plus 47 introns from 19 genes frequently rearranged in cancer, using process-matched normal control samples as a reference. CRGAs were defined as GAs linked to drugs on the market or currently under evaluation in mechanism-driven clinical trials. RESULTS: All 295 patients assessed were classified with high-grade (International Society of Urological Pathology classification) and advanced stage (stage III/IV American Joint Committee on Cancer) disease, and 294 of 295 patients (99.7%) had at least 1 GA on CGP with a mean of 6.4 GAs per UC (61% substitutions/insertions/deletions, 37% copy number alterations, and 2% fusions). Furthermore, 275 patients (93%) had at least 1 CRGA involving 75 individual genes with a mean of 2.6 CRGAs per UC. The most common CRGAs involved cyclin-dependent kinase inhibitor 2A (CDKN2A) (34%), fibroblast growth factor receptor 3 (FGFR3) (21%), phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) (20%), and ERBB2 (17%). FGFR3 GAs were diverse types and included 10% fusions. ERBB2 GAs were equally divided between amplifications and substitutions. ERBB2 substitutions were predominantly within the extracellular domain and were highly enriched in patients with micropapillary UC (38% of 32 cases vs 5% of 263 nonmicropapillary UC cases; P<.0001). CONCLUSIONS: Using a CGP assay capable of detecting all classes of GA simultaneously, an extraordinarily high frequency of CRGA was identified in a large series of patients with advanced UC. Cancer 2016;122:702-711. (c) 2015 American Cancer Society. PMID- 26651076 TI - Colposcopy combined with dynamic spectral imaging. A prospective clinical study. AB - OBJECTIVE: To analyze the value of dynamic spectral imaging (DSI) compared to, and as an adjunct to, conventional colposcopy (CC) in the diagnosis of cervical intraepithelial neoplasia (CIN). STUDY DESIGN: Four hundred seventy-nine women referred for colposcopy after an abnormal Pap-smear (>=ASC-US) to the Low Genital Tract Unit of the San Carlos Clinical Hospital in Madrid, Spain during the years 2012-2014 were examined simultaneously by CC and DSI. Thirty-six cases (8.1%) were excluded because the DSI map was not calculated. The gold standard for comparisons was the final histological diagnosis performed by punch biopsy or LEEP. RESULTS: Out of the 443 cases, 293 were found to be negative for CIN, 109 had CIN1 and 41 were found with CIN2+. The sensitivity of CC to detect those with CIN2+ lesions was 73.2% and the specificity 92.3%. Using the DSI map as an adjunct, led to a statistically significant increase of the sensitivity to 87.8% with a concomitant drop in specificity to 85.6%. The adjunctive use of DSI increased the sensitivity for CIN2+ also in the high-risk group of the 65 cases with an identified HPV16/18 infection; CC had a sensitivity of 88.9%, which increased to 100%. The specificity dropped from 91.1% to 87.5%. CONCLUSIONS: Combining conventional colposcopy with DSI mapping improves the capability to detect cervical lesions. PMID- 26651077 TI - Effect of the co-sensitization sequence on the performance of dye-sensitized solar cells with porphyrin and organic dyes. AB - To obtain a broad spectral response in the visible region, TiO2 film is co sensitized with a porphyrin dye (FNE57 or FNE59) and an organic dye (FNE46). It is found that the stepwise co-sensitization in one single dye solution followed by in another single dye solution is better than the co-sensitization in a cocktail solution in terms of photovoltaic performance. The stepwise co sensitization first with a porphyrin dye and then with an organic dye outperforms that in a reverse order. DSSC devices based on co-sensitizers FNE57 + FNE46 and FNE59 + FNE46 with a quasi-solid-state gel electrolyte generate power conversion efficiencies of 7.88% and 8.14%, respectively, which exhibits remarkable efficiency improvements of 61% and 35%, as compared with devices sensitized with the porphyrin dyes FNE57 and FNE59, respectively. Co-sensitization brings about a much improved short-circuit photocurrent due to the complementary absorption of the two sensitizers. The observed enhancement of incident monochromatic photon-to electron conversion efficiency from individual dye sensitization to co sensitization is attributed to the improved charge collection efficiency rather than to the light harvesting efficiency. Interestingly, the open-circuit photovoltage for the co-sensitization system comes between the higher voltage for the porphyrin dye (FNE57 or FNE59) and the lower voltage for the organic dye (FNE46), which is well correlated with their electron lifetimes. This finding indicates that not only the spectral complementation but also the electron lifetime should be considered to select dyes for co-sensitization. PMID- 26651078 TI - Laser-capture Microdissection of Human Prostatic Epithelium for RNA Analysis. AB - The prostate gland contains a heterogeneous milieu of stromal, epithelial, neuroendocrine and immune cell types. Healthy prostate is comprised of fibromuscular stroma surrounding discrete epithelial-lined secretory lumens and a very small population of immune and neuroendocrine cells. In contrast, areas of prostate cancer have increased dysplastic luminal epithelium with greatly reduced or absent stromal population. Given the profound difference between stromal and epithelial cell types, it is imperative to separate the cell types for any type of downstream molecular analysis. Despite this knowledge, the bulk of gene expression studies compare benign prostate to cancer without micro-dissection, leading to stromal bias in the benign samples. Laser-capture micro-dissection (LCM) is an effective method to physically separate different cell types from a specimen section. The goal of this protocol is to show that RNA can be successfully isolated from LCM-collected human prostatic epithelium and used for downstream gene expression studies such as RT-qPCR and RNAseq. PMID- 26651079 TI - Catalytic Enantioselective alpha,beta,gamma-Trioxygenation. AB - Applying a catalytic enantioselective aldehyde alpha-oxygenation condition to an enal substrate led to the discovery of the first alpha,beta,gamma trifunctionalization cascade of enals. Under optimal conditions, a tryptophan derived imidazolidinone catalyst in fluorinated aromatic solvents provided alpha,beta,gamma-trioxyaldehydes in up to 51% isolated yield (average of 80% yield per oxygenation step) and 85:15 er. Substitution at the delta position was tolerated, but not at the alpha, beta, or gamma positions. The reaction proceeded through initial TEMPO incorporation at the gamma position, and rapid racemization of this intermediate, reversible conjugate addition of water, followed by TEMPO incorporation at the alpha position to set all three stereocenters with double dynamic kinetic resolution. PMID- 26651080 TI - Management of Microbial Communities through Transient Disturbances Enhances the Functional Resilience of Nitrifying Gas-Biofilters to Future Disturbances. AB - Microbial communities have a key role for the performance of engineered ecosystems such as waste gas biofilters. Maintaining constant performance despite fluctuating environmental conditions is of prime interest, but it is highly challenging because the mechanisms that drive the response of microbial communities to disturbances still have to be disentangled. Here we demonstrate that the bioprocess performance and stability can be improved and reinforced in the face of disturbances, through a rationally predefined strategy of microbial resource management (MRM). This strategy was experimentally validated in replicated pilot-scale nitrifying gas-biofilters, for the two steps of nitrification. The associated biological mechanisms were unraveled through analysis of functions, abundances and community compositions for the major actors of nitrification in these biofilters, that is, ammonia-oxidizing bacteria (AOB) and Nitrobacter-like nitrite-oxidizers (NOB). Our MRM strategy, based on the application of successive, transient perturbations of increasing intensity, enabled to steer the nitrifier community in a favorable way through the selection of more resistant AOB and NOB sharing functional gene sequences close to those of, respectively, Nitrosomonas eutropha and Nitrobacter hamburgensis that are well adapted to high N load. The induced community shifts resulted in significant enhancement of nitrification resilience capacity following the intense perturbation. PMID- 26651082 TI - High-plasticity mesenchymal stem cells isolated from adult-retained primary teeth and autogenous adult tooth pulp--A potential source for regenerative therapies? AB - PURPOSE: The objective of this study was to compare the growth rate, morphology, immunohistology and plasticity of autogenous adult-retained SHEDs (arSHEDs) and adult dental pulp stem cells (DPSCs) obtained from the same donor. METHODS: Expression of the mesenchymal stem cell markers CD44, CD90, CD105, caspase-3 and GAPDH were assessed using RT-PCR. Caspase-3 and CD44 were also evaluated at the protein level by western blotting of cell lysates. Plasticity of DPSCs and arSHEDs were tested by culture in adipogenic, chondrogenic, osteogenic and Schwann cells induction media. RESULTS: DPSCs and arSHEDs were isolated by explant culturing and were similarly positive for growth rate and all tested markers. Furthermore, DPSCs and arSHEDs could be driven to adipocyte, chondrocyte, osteocyte and Schwann cells lineages thus indicating similar plasticity as precursor cells. CONCLUSION: This study demonstrates the similarities between DPSCs and arSHEDs in a unique situation, where both stem cells (SC) types were obtained from a single patient and thus represent an alternative source of SC's for tissue engineering and regeneration. PMID- 26651081 TI - Optimal Seeding Densities for In Vitro Chondrogenesis of Two- and Three Dimensional-Isolated and -Expanded Bone Marrow-Derived Mesenchymal Stromal Stem Cells Within a Porous Collagen Scaffold. AB - Bone marrow-derived mesenchymal stromal stem cells (BMSCs) are a promising cell source for treating articular cartilage defects. The objective of this study was to assess the impact of cell seeding density within a collagen I scaffold on in vitro BMSC chondrogenesis following isolation and expansion in two-dimensional (2D) and three-dimensional (3D) environments. It was hypothesized that both expansion protocols would produce BMSCs capable of hyaline-like chondrogenesis with an optimal seeding density of 10 * 10(6) cells/cm(3). Ovine BMSCs were isolated in a 2D environment by plastic adherence, expanded to passage two in flasks containing an expansion medium, and seeded within collagen I scaffolds at densities of 50, 10, 5, 1, and 0.5 * 10(6) BMSCs/cm(3). For 3D isolation and expansion, aspirates containing known quantities of mononucleated cells (bone marrow-derived mononucleated cells [BMNCs]) were seeded on scaffolds at 50, 10, 5, 1, and 0.5 * 10(6) BMNCs/cm(3) and cultured in the expansion medium for an equivalent duration to 2D expansion. Constructs were differentiated in vitro in the chondrogenic medium for 21 days and assessed with reverse-transcription quantitative polymerase chain reaction, safranin O staining, histological scoring using the Bern Score, collagen immunofluorescence, and glycosaminoglycan (GAG) quantification. Two-dimensional-expanded BMSCs seeded at all densities were capable of proteoglycan production and displayed increased expressions of aggrecan and collagen II messenger RNA (mRNA) relative to predifferentiation controls. Collagen II deposition was apparent in scaffolds seeded at 0.5-10 * 10(6) BMSCs/cm(3). Chondrogenesis of 2D-expanded BMSCs was most pronounced in scaffolds seeded at 5-10 * 10(6) BMSCs/cm(3) based on aggrecan and collagen II mRNA, safranin O staining, Bern Score, total GAG, and GAG/deoxyribonucleic acid (DNA). For 3D-expanded BMSC-seeded scaffolds, increased aggrecan and collagen II mRNA expressions relative to controls were noted with all densities. Proteoglycan deposition was present in scaffolds seeded at 0.5-50 * 10(6) BMNCs/cm(3), while collagen II deposition occurred in scaffolds seeded at 10-50 * 10(6) BMNCs/cm(3). The highest levels of aggrecan and collagen II mRNA, Bern Score, total GAG, and GAG/DNA occurred with seeding at 50 * 10(6) BMNCs/cm(3). Within a collagen I scaffold, 2D- and 3D-expanded BMSCs are capable of hyaline-like chondrogenesis with optimal cell seeding densities of 5-10 * 10(6) BMSCs/cm(3) and 50 * 10(6) BMNCs/cm(3), respectively. PMID- 26651083 TI - Mechanical and chemical dental wear in historical population from the Syrian lower Euphrates valley. AB - OBJECTIVES: The aim of this study was a comprehensive macro- and microanalysis of dental wear observed in the populations inhabiting the Syrian lower Euphrates valley. We may assume that social changes have had an important impact on the dietetic and hygienic habits of the local population. MATERIALS AND METHODS: Six periods were chosen: Early Bronze (2650-2350 BC), Middle Bronze (2200-1700 BC), Neo-Assyrian (900-700 BC), late Roman (AD 200-400), Islamic (AD 600-1200), and modern Islamic (AD 1850-1950). The dental remains belong to 196 individuals, with a total of 3292 teeth. Mechanical dental wear was evaluated according to Smith's and Shykoluk & Lovell's scale. Also, SEM technique was used to select teeth. RESULTS: Individuals from both Bronze Ages were characterized by a large percentage of severe dental wear, contrary to the younger chronological periods. The rate of dental wear slowed down from the Middle Bronze Age. The frequency of deep scratches, punctures, and pits successively decreased with younger periods, while striae became more frequent. The highest number of teeth diagnosed with erosive loss was from the Neo-Assyrian period. DISCUSSION: In the Early and Middle Bronze Ages the diet was rather hard and more contaminated. The diet in the Neo-Assyrian period was rich in products lowering the pH in the oral cavity. The frequency of dental erosion in two consecutive periods--Islamic and late Roman--took place at a similar level. Thus similar alimentary habits in these periods can be suggested. PMID- 26651084 TI - Very preterm adolescents show impaired performance with increasing demands in executive function tasks. AB - BACKGROUND: Very preterm birth is often associated with executive function deficits later in life. The transition to adolescence increases personal autonomy, independence and, in parallel, the demands placed on executive functions at home and in school. AIM: To assess the impact of increasing demands on executive function performance in very preterm children and adolescents with normal intellectual and motor functions. METHODS: Forty-one very preterm children and adolescents with normal intellectual and motor functions and 43 healthy term born peers were assessed at a mean age of 13.0 years (SD: 1.9; range: 10.0-16.9). A comprehensive battery of performance-based executive function measures with different demand levels as well as a parent-rating questionnaire evaluating executive functions relevant for everyday life was applied. Standardized mean differences between groups of d >= .41 were regarded as clinically relevant. RESULTS: No group differences were found at the lowest demand levels of working memory (d=.09), planning (d=-.01), cognitive flexibility (d=-.21) and verbal fluency (d=-.14) tasks, but very preterm participants scored significantly below their term-born peers in the most demanding levels (d=-.50, -.59, -.43 and -.55, respectively). These differences were clinically relevant. Executive functions relevant for everyday life were strongly impaired in very preterm participants, e.g., global executive composite (d=-.66). CONCLUSION: Very preterm children and adolescents with normal intellectual and motor functions are at high risk for executive function deficits that may only become apparent with increasing demands, potentially leading to academic and other deficits. PMID- 26651085 TI - Using cluster analysis to provide new insights into development of very low birthweight (VLBW) premature infants. AB - BACKGROUND: Very low birthweight (VLBW) premature infant follow-up studies report on single developmental outcome variables but do not assess profiles of development. AIMS: To identify developmental profiles of VLBW premature infants based on cognitive and language development and their association with demographic, perinatal, and behavior variables. STUDY DESIGN: Retrospective chart review. SUBJECTS: 117 children<1250 g BW seen at 18 months post-term on the Bayley Scales-III and Child Behavior Checklist 1 1/2-5 (CBCL 1 1/2-5), a behavior problem questionnaire. Demographic and perinatal variables were obtained from medical records. OUTCOME MEASURES: Bayley Cognitive, Expressive Language, and Receptive Language scores were used to cluster the subjects into developmental profiles. Demographic, perinatal, and CBCL variables were analyzed as they related to clusters. RESULTS: Children were clustered into 4 groups based on their Bayley Cognitive, Expressive Language, and Receptive Language scores: Consistently High, Consistently Average, Average with Delayed Expressive Language, and Consistently Low. Socioeconomic status, bronchopulmonary dysplasia, Grades III-IV intraventricular hemorrhage, and summary Behavior Problems and Attention Deficit/Hyperactivity (ADHD) Problems scores were significantly related to clusters. CONCLUSION: Cluster analysis defined distinct outcome groups in VLBW premature children and provides an informative means of identifying factors related to developmental outcome. This approach may be useful in predicting later outcome and determining which groups of children will require early intervention. PMID- 26651086 TI - 2015 Richard Skalak Award. PMID- 26651087 TI - TEM investigations on the local microstructure of electrodeposited galfenol nanowires. AB - The local microstructure of Fe-Ga nanowires is investigated considering dependence on the deposition technique. Using a complexed electrolyte, smooth and homogeneous Fe80Ga20 nanowires are deposited into anodic aluminum oxide templates by either applying pulse potential or potentiostatic deposition technique. At optimized deposition conditions the wires show the desired composition of Fe80+/ 2Ga20+/-2 without a gradient along the growth direction. Composition distribution, structure and microstructure are examined in detail and reveal only minor differences. Line EELS and crystal lattice measurements reveal a negligible oxygen content for both preparation routines. Neither Fe/Ga oxides nor hydroxides were found. Both potentiostatically deposited as well as pulse deposited nanowires exhibit a preferred <110>orientation, the latter with slightly larger crystals. Different contrast patterns were found by TEM that appear more pronounced in the case of pulse deposited wires. High resolution transmission electron microscopy analysis and comparison of differently prepared focused ion beam lamellas reveal that these contrasts are caused by defects in the alternating potential deposition itself and are not induced during the TEM preparation process. The alternating potential mode causes periodic growth thereby inducing different layers with reduced wire thickness/defects at the layer interfaces. PMID- 26651088 TI - Prevalence and Characteristics of Autism Spectrum Disorder Among 4-Year-Old Children in the Autism and Developmental Disabilities Monitoring Network. AB - OBJECTIVE: Early identification of children with autism spectrum disorder (ASD) facilitates timely access to intervention services. Yet, few population-based data exist on ASD identification among preschool-aged children. The authors aimed to describe ASD prevalence and characteristics among 4-year-old children in 5 of 11 sites participating in the 2010 Autism and Developmental Disabilities Monitoring Network. METHOD: Children with ASD were identified through screening of health and education records for ASD indicators, data abstraction and compilation for each child, and clinician review of records. ASD prevalence estimates, ages at first evaluation and ASD diagnosis, cognitive test scores, and demographics were compared for 4-year-old children and 8-year-old children living in the same areas. RESULTS: Among 58,467 children in these 5 sites, 4-year-old ASD prevalence was 13.4 per 1000, which was 30% lower than 8-year-old ASD prevalence. Prevalence of ASD without cognitive impairment was 40% lower among 4 year-olds compared with 8-year-olds, but prevalence of ASD with cognitive impairment was 20% higher among 4-year-olds compared with 8-year-olds. Among 4 year-olds with ASD, female and non-Hispanic white children were more likely to receive their first comprehensive evaluation by age 36 months compared with male and non-Hispanic black children, respectively. Among children diagnosed with ASD by age 48 months, median age at first comprehensive evaluation was 27 months for 4-year-olds compared with 32 months for 8-year-olds. CONCLUSION: Population-based ASD surveillance among 4-year-old children provides valuable information about the early identification of children with ASD and suggests progression toward lowering the age of first ASD evaluation within participating Autism and Developmental Disabilities Monitoring communities. PMID- 26651089 TI - Prevalence Counts: Commentary on "Prevalence and Characteristics of Autism Spectrum Disorder Among 4-Year-Old Children in the Autism and Developmental Disabilities Monitoring Network". PMID- 26651090 TI - Impact of Media Use on Adolescent Sleep Efficiency. AB - OBJECTIVE: In 2010, American youth aged 8 to 18 spent an average of 7.5 hours daily using entertainment media, an increase of more than an hour compared with 2005. Increase in media use is associated with multiple negative outcomes, including decreased sleep time and increased tiredness, but little research has examined whether media use is associated with poorer sleep efficiency when the individual is actually asleep. METHODS: This study assessed relations between adolescent media use and sleep efficiency. Fifty-five adolescents (mean age = 14.89 years; SD = 0.62; 53% African-American and 47% white) completed self-report measures concerning their media use. Sleep quality was measured by actigraphy for 1 week, and both sleep offset and sleep efficiency were extracted from actigraphy data. RESULTS: Sleep efficiency was negatively correlated to daily time spent text messaging (r(52) = -0.29; p < .05), media use after bed (r(52) = -0.32; p < .05), and number of nighttime awakenings by mobile phones (r(52) = -0.33; p < .05). Decreased sleep efficiency was related to sleeping later in the morning, presumably to make up for lost sleep at night (r(52) = -0.33; p < .05). In a regression model, media use accounted for 30% of the variance in sleep efficiency (adjusted R = 0.30; F(6,44) = 3.74; p < .01). CONCLUSION: Media use after bed, awakenings by a mobile phone at night, and sleep offset associated with adolescents' sleep efficiency. Results support the incorporation of media use habits into adolescent sleep health education and sleep dysfunction interventions. Parental education about the effects of media use on sleep could also mitigate negative effects. PMID- 26651093 TI - Incorrect Grant Information. PMID- 26651091 TI - Infant Breastfeeding Duration and Mid-Childhood Executive Function, Behavior, and Social-Emotional Development. AB - OBJECTIVE: The authors aim was to examine associations of breastfeeding duration and exclusivity in infancy with executive function, behavior, and social emotional development in mid-childhood. METHODS: The authors studied 1037 participants in Project Viva, a prebirth cohort that enrolled pregnant mothers from 1999 to 2002 and followed children for 7 to 10 years. Main exposures were: (1) duration of any breastfeeding in the first 12 months and (2) duration of exclusive breastfeeding in the first 6 months. Main outcomes were child executive function, behavior, and social-emotional development, assessed by (1) the Behavior Rating Inventory of Executive Function (BRIEF) and (2) the Strengths and Difficulties Questionnaire (SDQ), completed independently by parents and teachers. Higher scores indicate greater problems. RESULTS: In linear regression models adjusted for sociodemographics, maternal intelligence, home environment, early child care, and maternal depression, longer breastfeeding duration was not associated with substantially better executive function, behavior, or social emotional development. For example, for each additional month of any breastfeeding, the BRIEF Global Executive Composite score (parent) was 0.10 points higher (95% confidence interval, -0.01 to 0.22) and the SDQ total difficulties score was 0.06 points higher (-0.01, 0.12). Breastfeeding duration was also not associated with BRIEF or SDQ subscales, nor was exclusive breastfeeding duration associated with any of the outcomes analyzed. CONCLUSION: Despite beneficial effects on general intelligence, longer duration of any breastfeeding or of exclusive breastfeeding was not associated with better executive function, behavior, or social-emotional development in mid-childhood. PMID- 26651094 TI - A Digital Dermoscopy Follow-up Illustration and a Histopathologic Correlation for Angulated Lines in Extrafacial Lentigo Maligna. AB - IMPORTANCE: The diagnosis of extrafacial lentigo maligna can be a challenge because the dermoscopic features are not well described. These features can share some of the criteria of superficial spreading melanoma and some of facial lentigo maligna; however, these features are often absent. A new dermoscopic pattern has recently been described as forming angulated lines. OBSERVATIONS: We report 4 cases of extrafacial lentiginous lesions in 3 patients in whom straight angulated lines have been observed as the only key for diagnosis. This is the first time, to our knowledge, that these lines were seen in the follow-up by digital dermoscopy during a lapse time of a few months. This morphologic change led to the excision of the lesion. The pathologic diagnosis of lentigo maligna was established in each case. Moreover, a histologic correlation of these straight angulated lines is documented. CONCLUSIONS AND RELEVANCE: Angulated lines could be considered as a new warning sign during the follow-up of extrafacial lentigo. More studies are required to establish the sensitivity and specificity of this newly described dermoscopic feature. PMID- 26651095 TI - April 2010: This Month's Highlights. PMID- 26651096 TI - Letter. PMID- 26651102 TI - Service Learning in Undergraduate Audiology Education. AB - PURPOSE: The purpose of this study was to incorporate a service learning project in an undergraduate audiology course and evaluate how it affected student learning in the class. METHOD: The study involved partnering with a group of students enrolled in a band learning community. Students in the audiology course learned about hearing assessment procedures in class and practiced the procedures on each other in labs. Toward the end of the semester, they assessed the hearing of the band students and provided counseling regarding the importance of hearing protection. Qualitative data were obtained in the form of preflections and final reflection papers completed by the students in the audiology course at the start and conclusion of the semester. Quantitative data included completion of the Community Service Attitudes Scale (CSAS; Shiarella, McCarthy, & Tucker, 2000) prior to and at the conclusion of the course. RESULTS: Results revealed overwhelmingly positive comments from the students in their final reflections, although there were no significant changes in the pre- and post-administration of the CSAS. CONCLUSION: Incorporating service learning projects into undergraduate curricula in speech and hearing has the potential to enhance academic and civic learning while also benefitting the community. PMID- 26651103 TI - External Fixator for Maintaining Reduction Before Volar Plating: A Simple Treatment Method for Association of Osteosynthesis Type C3 Distal Radius Fracture. AB - Volar plating for Association of Osteosynthesis type C3 distal radius fractures involves more time and more radiation exposure because it is extremely difficult to simultaneously maintain the reduction and restore the congruity of the articular surface. The authors present a technique of maintaining the acceptable reduction by using an external fixator followed by open volar plating for restoring articular congruity. A consecutive series of 96 Association of Osteosynthesis type C3 distal radius fractures treated with the technique were retrospectively reviewed between January 2004 and December 2012. The technique makes surgery simpler and more effective, and reduces radiation exposure. PMID- 26651105 TI - Nomogram for Predicting Overall Survival and Salvage Abdominoperineal Resection for Patients with Anal Cancer. AB - BACKGROUND: Anal cancer treatment has evolved from abdominoperineal resection to chemoradiotherapy, which allows for sphincter preservation. OBJECTIVE: The aim of this study was to develop an accurate model and nomogram to predict overall survival and the probability of salvage abdominoperineal resection for anal cancer patients. DESIGN: This is a retrospective cohort study. SETTINGS: Data were gathered from National Cancer Database entries from 1998 to 2010. PATIENTS: Patients with de novo anal cancer were selected from the National Cancer Database in the years 1998 through 2010; 1778 patients were included, and their data were analyzed. MAIN OUTCOME MEASURES: Variables included time to death, censoring indicator, age, race, sex, tumor size, year of diagnosis, surgery status, nodal status, TNM stage, and chemoradiation therapy. A stratified Cox proportional hazards model for overall survival and a logistic regression model for salvage abdominoperineal resection were developed. Our final models were internally validated for discrimination and validation. RESULTS: Statistically significant variables in the salvage surgery model were tumor size and nodal status (p <= 0.001). For overall survival model, statistically significant variables (all with p <= 0.005), fitted across the strata of TNM clinical stage included age, sex, tumor size, nodal status, chemoradiotherapy treatment, and combination salvage surgery and chemoradiotherapy. Nomograms that predict events are based on our final models. LIMITATIONS: Limitations included clerical database errors and nonmeasured variables, such as HIV status. CONCLUSIONS: A nomogram can predict overall survival and salvage surgery for an individual with anal cancer. Such tools may be used as decision support aids to guide therapy and predict whether or not patients may need salvage surgery. PMID- 26651106 TI - Long-term Oncologic Outcome After Transanal Endoscopic Microsurgery for Rectal Carcinoma. AB - BACKGROUND: Transanal endoscopic microsurgery is superior to other methods of local excision of rectal cancer, but few studies report long-term follow-up data. OBJECTIVE: This study investigated the use of transanal endoscopic microsurgery alone as curative and compromise therapy based on long-term disease recurrence and mortality. DESIGN: This was a retrospective review of prospectively collected data. SETTINGS: The study was conducted at a tertiary care university medical center. PATIENTS: The study included 133 patients treated between 1985 and 2007. There were 3 groups, including transanal endoscopic microsurgery in curative intent (low-risk rectal carcinoma, including pT1, G1/2, L0, and LX with clear margins and a minimal distance between tumor and resection margin of >1 mm (N = 64) or clear margins only (N = 18 ))) and as compromise therapy (high-risk or incompletely resected rectal carcinoma; N = 51). MAIN OUTCOME MEASURES: Log-rank tests were used to compare overall and cancer-specific survival. RESULTS: The median follow-up time was 8.6 years (range, 0.2-25.1 years), and a total of 131 of 133 patients (98.5%) were followed >5 years or until death. The preoperative diagnosis of carcinoma was not associated with belonging into 1 of the 3 categories. In patients with low-risk completely (>1 mm) resected carcinoma, the 5- and 10-year local recurrence rates were 6.6% and 11.6%. In patients with high risk or incompletely resected carcinoma, the rates were 32.5% and 35.0% (p = 0.006). The 5- and 10-year cancer-specific survival rates for low-risk patients were 98.0% and 91.0% and 84.3% and 74.3% for high-risk patients (p = 0.05). LIMITATIONS: The study was limited by its retrospective design and small subgroups. CONCLUSIONS: The high cancer-specific survival justifies transanal endoscopic microsurgery alone as curative treatment in low-risk rectal carcinoma. Complete resection is essential to lower the risk of local recurrence. The high local recurrence rate in patients with high-risk rectal carcinoma restricts the use of TEM alone as compromise therapy. PMID- 26651104 TI - Bone Marrow-derived Cells Contribute to the Pathogenesis of Pulmonary Arterial Hypertension. AB - RATIONALE: Pulmonary arterial hypertension (PAH) is a progressive lung disease of the pulmonary microvasculature. Studies suggest that bone marrow (BM)-derived circulating cells may play an important role in its pathogenesis. OBJECTIVES: We used a genetic model of PAH, the Bmpr2 mutant mouse, to study the role of BM derived circulating cells in its pathogenesis. METHODS: Recipient mice, either Bmpr2(R899X) mutant or controls, were lethally irradiated and transplanted with either control or Bmpr2(R899X) BM cells. Donor cells were traced in female recipient mice by Y chromosome painting. Molecular and function insights were provided by expression and cytokine arrays combined with flow cytometry, colony forming assays, and competitive transplant assays. MEASUREMENTS AND MAIN RESULTS: We found that mutant BM cells caused PAH with remodeling and inflammation when transplanted into control mice, whereas control BM cells had a protective effect against the development of disease, when transplanted into mutant mice. Donor BM derived cells were present in the lungs of recipient mice. Functional and molecular analysis identified mutant BM cell dysfunction suggestive of a PAH phenotype soon after activation of the transgene and long before the development of lung pathology. CONCLUSIONS: Our data show that BM cells played a key role in PAH pathogenesis and that the transplanted BM cells were able to drive the lung phenotype in a myeloablative transplant model. Furthermore, the specific cell types involved were derived from hematopoietic stem cells and exhibit dysfunction long before the development of lung pathology. PMID- 26651107 TI - Dynamic Article: Full-Thickness Excision for Benign Colon Polyps Using Combined Endoscopic Laparoscopic Surgery. AB - BACKGROUND: Benign colon polyps are commonly encountered but may not always be amenable to endoscopic excision because of their size, shape, location, or scarring from previous attempts. The addition of laparoscopy allows a greater degree of bowel manipulation, but the current technique is still limited when encountering a polyp with inadequate lifting attributed to polyp morphology or scarring. We describe an extension to the existing combined endoscopic laparoscopic surgery technique using a full-thickness approach to increase polyp maneuverability and local excision of difficult but benign polyps. OBJECTIVE: The purpose of this study was to report the technical details and preliminary results of a new approach for full-thickness excision of difficult colon polyps, combined endoscopic laparoscopic surgery full-thickness excision. DESIGN: This study is a retrospective review of our experience from December 2013 to May 2015. SETTINGS: The study was conducted at a single academic institution. PATIENTS: All of the patients had previous incomplete colonoscopic polypectomy performed at other institutions. Patients were selected for our technique if the polyp had a benign appearance but was unable to be resected by traditional endoscopic or combined endoscopic laparoscopic surgery methods because of polyp morphology or scarring from previous biopsies. MAIN OUTCOME MEASURES: The safety and feasibility of this procedure were measured. RESULTS: Three patients underwent combined endoscopic laparoscopic surgery-full-thickness excision for difficult colon polyps. There were no intraoperative or postoperative complications. The length of stay was 1 day for all of the patients. All 3 of the patients had benign final pathology. LIMITATIONS: This study was limited by the small number of patients in a single institution. CONCLUSIONS: Full-thickness excision for benign colon polyps using combined endoscopic laparoscopic surgery is safe and feasible. Using this technique, difficult polyps not amenable to traditional endoscopic approaches can be removed and colectomy may be avoided. PMID- 26651108 TI - Does CD10 Expression Predict Lymph Node Metastasis in Colorectal Cancer? AB - BACKGROUND: Accurate preoperative prediction of lymph node status would be a revolutionary adjunct in treating colorectal cancer. The immunohistochemical marker CD10 has been suggested recently to have a predictive capacity for lymph node involvement in colorectal cancer. OBJECTIVE: The aim of our study was to evaluate the relationship between the presence of the CD10 molecular marker and lymph node metastasis in a US patient population using previously banked colorectal cancer specimens. DESIGN: This was a retrospective study. SETTINGS: The study was conducted at a single academic institution. PATIENTS: Included were specimens from 191 patients, with cancer stages ranging from T1N0 to T3N2. MAIN OUTCOME MEASURES: The relationship between CD10 and different clinicopathologic parameters was assessed, as well as the ability to predict lymph node metastasis by itself and in conjunction with lymphovascular invasion. RESULTS: CD10 was significantly correlated with left-sided colon cancers (p = 0.01) and the presence of mucinous histology and had a relatively high specificity (75.7%) for lymph node metastasis. CD10 did not correlate with lymph node status (p = 0.33) or enhance the ability of lymphovascular invasion to predict lymphatic metastasis in our patient population. Sensitivity and specificity of lymphovascular invasion alone for lymph node metastasis were 62.8% and 93.6%, whereas adding CD10 status resulted in a sensitivity of 70.6% and specificity of 69.3%. Multivariate analysis revealed only lymphovascular invasion as a predictor of lymph node metastasis in our patient population. LIMITATIONS: This study was primarily limited by its small sample size and retrospective nature. CONCLUSIONS: In our patient population, CD10 status was not significantly associated with lymph node metastasis, and it was no better than lymphovascular invasion alone when predicting lymph node status. PMID- 26651109 TI - Failing to Prepare Is Preparing to Fail: A Single-Blinded, Randomized Controlled Trial to Determine the Impact of a Preoperative Instructional Video on the Ability of Residents to Perform Laparoscopic Right Colectomy. AB - BACKGROUND: Laparoscopic colorectal resection is an index case for advanced skills training, yet many residents struggle to reach proficiency by graduation. Current methods to reduce the learning curve for residents remain expensive, time consuming, and poorly validated. OBJECTIVE: The purpose of this study was to assess the impact of the addition of a preprocedural instructional video to improve the ability of a general surgery resident to perform laparoscopic right colectomy when compared with standard preparation. DESIGN: This was a single blinded, randomized control study. SETTINGS: Four university-affiliated teaching hospitals were included in the study. PARTICIPANTS: General surgery residents in postgraduation years 2 through 5 participated. INTERVENTION: Residents were randomly assigned to preparation with a narrated instructional video versus standard preparation. MAIN OUTCOME MEASURES: Resident performance, scored by a previously validated global assessment scale, was measured. RESULTS: Fifty-four residents were included. Half (n = 27) were randomly assigned to view the training video and half (n = 27) to standard preparation. There were no differences between groups in terms of training level or previous operative experience or in patient demographics (all p > 0.05). Groups were similar in the percentage of the case completed by residents (p = 0.39) and operative time (p = 0.74). Residents in the video group scored significantly higher in total score (mean: 46.8 vs 42.3; p = 0.002), as well as subsections directly measuring laparoscopic skill (vascular control mean: 11.3 vs 9.7, p < 0.001; mobilization mean: 7.6 vs. 7.0, p = 0.03) and overall performance score (mean: 4.0 vs 3.1; p < 0.001). Statistical significance persisted across training levels. LIMITATIONS: There is potential for Hawthorne effect, and the study is underpowered at the individual postgraduate year level. CONCLUSIONS: The simple addition of a brief, narrated preprocedural video to general surgery resident case preparation significantly increased trainee ability to successfully perform a laparoscopic right colectomy. In an era of shortened hours and less exposure to cases, incorporating a brief but effective instructional video before surgery may improve the learning curve of trainees and ultimately improve safety. PMID- 26651110 TI - C-Reactive Protein as a Marker for Postoperative Complications. Are There Differences in Emergency and Elective Colorectal Surgery? AB - BACKGROUND: C-reactive protein levels are frequently raised in patients with major complications following elective colorectal surgery and used as a predictor for complications. The significance of raised C-reactive protein levels to predict outcome in emergency colorectal surgery is unclear, because preoperative C-reactive protein levels are often raised. OBJECTIVE: The aim of this study was to determine whether serum C-reactive protein is an adequate predictive marker for major postoperative complications after colorectal surgery in an acute setting. DESIGN: This is an observational cohort study of all patients undergoing colorectal surgery. PATIENTS: Consecutive patients undergoing colorectal surgery with reconstruction via anastomosis and/or stoma from January 2009 to March 2014 were included. SETTING: This study was conducted at VU University Medical Center, Amsterdam. MAIN OUTCOME MEASURES: Postoperative C-reactive protein levels, operative details, and postoperative complications were recorded to determine the differences in C-reactive protein as a marker for complications in emergency and elective colorectal surgery. RESULTS: A total of 724 patients underwent colorectal resection, 559 elective cases and 165 emergency cases. A major complication was observed in 176 of 724 patients (24.3%). Major complications were observed more often in patients who underwent emergency surgery, 37% versus 20.9% after elective resections. C-reactive protein levels were significantly higher preoperatively in patients operated on in an acute care setting and on the first two postoperative days; from the third postoperative day, no statistically significant differences were found in C-reactive protein levels. LIMITATIONS: This study was limited by its observational nature. CONCLUSIONS: Although acute colorectal surgery is associated with higher C-reactive protein levels in the first 2 postoperative days, this study shows that postoperative C-reactive protein levels may be used as a predictor for complications in both acute and elective surgery from the third postoperative day onward. It is hypothesized that the stimulus for C-reactive protein production is removed during surgery, and, with a short-half-life of 19 hours, C-reactive protein levels drop to similar levels as seen in patients undergoing elective surgery. PMID- 26651111 TI - Health-Related Quality of Life and Sexual Functioning of HIV-Positive Men Who Have Sex With Men Who Are Treated for Anal Intraepithelial Neoplasia. AB - BACKGROUND: The impact of the treatment of precursor lesions of anal cancer (anal intraepithelial neoplasia) on health-related quality of life has not been investigated. OBJECTIVE: This study aimed to evaluate the impact of 3 treatment options for anal intraepithelial neoplasia on health-related quality of life and sexual functioning in HIV-positive men who have sex with men. DESIGN: The prospective cohort was embedded in a randomized clinical trial evaluating the optimal treatment of anal intraepithelial neoplasia. SETTING: This study was performed at the HIV outpatient clinic of the Academic Medical Center, Amsterdam, the Netherlands. PATIENTS: Included in the study were HIV-positive men who have sex with men with anal intraepithelial neoplasia. INTERVENTION: Treatment with imiquimod (n = 54), topical fluorouracil (n = 48), or electrocautery (n = 46) was given for 16 weeks. MAIN OUTCOME MEASURES: Health-related quality of life and sexual functioning were assessed before, during, and 4 weeks after treatment. Health-related quality of life was assessed using the EQ5D, sexual functioning was assessed using items derived from the International Index of Erectile Function, and the female sexual function index adapted for anal intercourse. RESULTS: One hundred forty-five patients (98%) completed at least 1 questionnaire. There was a significant different pattern of change over time in health-related quality of life among the 3 treatment groups. Patients in the imiquimod group were more likely to report pain/discomfort at week 8 than patients in the electrocautery group. Patients in the electrocautery group were more likely to report anxiety/depression and were less satisfied with their overall sex life at week 16 than patients in the imiquimod and fluorouracil groups, and patients in the electrocautery group were also more likely to report pain/discomfort and problems with usual activities at week 20 than patients in the fluorouracil group. LIMITATIONS: The follow-up method differed slightly among treatment groups. There is no standardized, validated sexual functioning questionnaire for HIV-positive men who have sex with men. CONCLUSIONS: All treatment options have a negative impact on aspects of health-related quality of life. Electrocautery has significantly more negative effects on health-related quality of life than imiquimod and fluorouracil and also has a negative effect on sexual functioning. PMID- 26651112 TI - Outcomes of Sacral Neurostimulation Lead Reimplantation for Fecal Incontinence: A Cohort Study. AB - BACKGROUND: Adverse events and complications have been reported after sacral neurostimulation for fecal incontinence, which may result in surgical revision and device explantation. Lead reimplantation may be feasible; however, available data regarding outcomes are less robust. OBJECTIVE: The aim of this study was to determine the outcomes of sacral neurostimulation lead reimplantation for fecal incontinence. DESIGN: This was a retrospective review of prospectively collected data. SETTINGS: The study was conducted at 2 clinical sites from a single institution. PATIENTS: Patients with fecal incontinence who underwent sacral neurostimulation implantation or reimplantation between 2011 and 2014 were included in the study. INTERVENTIONS: Sacral neurostimulation reimplantation was the included intervention. MAIN OUTCOME MEASURES: Change in the Cleveland Clinic Florida Fecal Incontinence Score (0 best; 20 worst) in reimplantation as compared with index implantation controls was the main measure. Secondary outcomes included the frequency and type of adverse events and complications. RESULTS: A total of 112 patients underwent either sacral neurostimulation implantation or reimplantation between 2011 and 2014. Ninety-seven patients underwent an index percutaneous nerve stimulation trial, 93 of whom also underwent a stimulator implantation. Fifteen patients underwent lead reimplantation, with 5 performed before stimulator implantation and 10 after stimulator implantation. The index implanted and reimplanted groups had similar demographics, comorbidities, and complication profiles including explantation rates. The most common reason for reimplantation was lead related (6/15), including 4 lead migrations, 1 lead fracture, and 1 lead erosion. Significant decreases in the incontinence score were achieved in each group (index implantation: p < 0.001; reimplantation: p = 0.006). When comparing the efficacy of sacral neurostimulation therapy in decreasing the fecal incontinence score from baseline in each group, patients with an index implantation were found to have a more significant improvement in their incontinence score as compared with the reimplantation group (p = 0.047). LIMITATIONS: This was a retrospective study. A large number of patients with incomplete functional assessment data were excluded from analysis. CONCLUSIONS: The improvements in fecal incontinence are significantly better after index implantation than after reimplantation. PMID- 26651113 TI - Impact of Rising Grades of Internal Rectal Intussusception on Fecal Continence and Symptoms of Constipation. AB - BACKGROUND: A theory of rectal intussusception has been advanced that intrarectal intussusception, intra-anal intussusception, and external rectal prolapse are points on a continuum and are a cause of fecal incontinence and constipation. OBJECTIVE: This study evaluates the association among rectal intussusception, constipation, fecal incontinence, and anorectal manometry. DESIGN: Patients undergoing defecography were studied from a prospectively maintained database and classified according to the Oxford Rectal Prolapse Grade as normal or having intra-rectal, intra-anal, or external intussusception. Patient symptoms were assessed using the Constipation Severity Index and the Fecal Incontinence Severity Index. Quality-of-life surveys were also used. Patients also underwent anorectal manometry. SETTINGS: The study was conducted at a tertiary care university medical center (Massachusetts General Hospital). PATIENTS: The study included 147 consecutive patients undergoing evaluation for evacuatory dysfunction and involved defecography, symptoms questionnaires, and anorectal physiology testing from January 2011 to December 2013. MAIN OUTCOME MEASURES: Symptom severity and quality-of-life scores were measured, as well as anal manometry results. RESULTS: Increasing Oxford grade was associated with an increase in severity of fecal incontinence (median score: normal = 23.9, intrarectal = 21.0, intra-anal = 30.0, external prolapse = 35.3; beta = 4.71; p = 0.009), which persisted in a multivariable model including age (beta = 2.13; p = 0.03), and decreased sphincter pressures (median mean resting pressure: normal = 75.4, intra-rectal = 69.7, intra-anal = 64.3, external prolapse = 48.3; beta = 8.57; p = 0.003), which did not persist in a multivariable model. Constipation severity did not increase with rising intussusception (mean score: normal = 37.4, intrarectal = 35.0, intra-anal = 41.4, external prolapse = 32.9; p = 0.79), and balloon expulsion improved rather than worsened (normal = 47.1%, intrarectal = 60.5%, intra-anal = 82.9%, external prolapse = 93.1%; p < 0.001). LIMITATIONS: The study was limited because it was an observational study from a single center. CONCLUSIONS: Increasing grades of rectal intussusception are associated with increasing fecal incontinence but not constipation. PMID- 26651114 TI - Patients Prefer Propofol to Midazolam Plus Fentanyl for Sedation for Colonoscopy: Results of a Single-Center Randomized Equivalence Trial. AB - BACKGROUND: Common sedation options for colonoscopy include propofol alone or a combination of midazolam and fentanyl. The former usually requires the presence of an anesthesia caregiver. The strategy that optimizes patient satisfaction has not yet been determined. OBJECTIVE: This study was designed to assess whether patient satisfaction at the time of colonoscopy is equivalent for propofol compared with midazolam and fentanyl. DESIGN: In this prospective, single-center, parallel group, single-blind, randomized, equivalence trial (NCT-01488045), 262 patients blinded to treatment received propofol (n = 126) or midazolam plus fentanyl (n = 136) at the time of colonoscopy. A patient satisfaction survey was administered in the recovery room and 1 to 5 days postprocedure. The endoscopist completed a survey immediately postprocedure. SETTINGS: This study was conducted at a tertiary academic hospital with a dedicated colon and rectal surgery division. PATIENTS: Patients over the age of 18 years who were undergoing elective colonoscopy were included in this study. MAIN OUTCOME MEASURES: The primary outcome was patient satisfaction with the colonoscopy. Secondary outcomes included physician and patient perception of patient pain, physician perception of patient tolerance of and difficulty of procedure, procedure duration, percentage of patients with cecal intubation, recovery time, and adverse events. RESULTS: Patient overall satisfaction scores in the recovery room after using the combination of midazolam and fentanyl (n = 136) during colonoscopy were not equivalent to patient satisfaction scores after using propofol (n = 126) alone (mean = 83.9 and 98.0 visual analog scale points) because the 90% CI (-18.5 to 9.6) for the mean treatment difference (-14.1) was completely outside the prespecified range of equivalence (+/-5 visual analog scale points). Patient pain as reported by the patient and as perceived by the physician and difficulty of the procedure were significantly worse for the midazolam/fentanyl group (n = 136) compared with the propofol group (n = 126). Time in the colonoscopy suite was significantly shorter for the propofol group, but the difference was small (4 minutes). There were no significant differences in percentage with cecal intubation, recovery time, or adverse events. LIMITATIONS: This is a single institution, single-endoscopist study and is limited by the inability to perform blinding of the endoscopist. CONCLUSIONS: The use of propofol for conscious sedation during colonoscopy is associated with greater patient satisfaction and less pain when compared with midazolam/fentanyl, as perceived by the patient and endoscopist. PMID- 26651115 TI - Comparing Mechanical Bowel Preparation With Both Oral and Systemic Antibiotics Versus Mechanical Bowel Preparation and Systemic Antibiotics Alone for the Prevention of Surgical Site Infection After Elective Colorectal Surgery: A Meta Analysis of Randomized Controlled Clinical Trials. AB - BACKGROUND: The discussion on the role of mechanical bowel preparation and oral antibiotics in elective colorectal surgery is still ongoing. OBJECTIVE: This meta analysis aimed to determine whether oral systemic antibiotics with mechanical bowel preparation are superior to systemic antibiotics and mechanical bowel preparation for prophylaxis of bacterial infection during elective colorectal operation. DATA SOURCES: Embase, PubMed, and the Cochrane Library were searched using the terms oral, antibiotics/antimicrobial, colorectal/rectal/colon/rectum, and surgery/operation. STUDY SELECTION: All of the available randomized controlled trials that compared the efficacy of combined oral and systemic antibiotics and mechanical bowel preparation with systemic antibiotics alone and mechanical bowel preparation in colorectal surgery and defined surgical site infection based on Centers for Disease Control and Prevention criteria were included. INTERVENTION: All of the statistical analyses were performed using Review Manager 5.2 software. A fixed model was used if there was no evidence of heterogeneity; otherwise, a random-effects model was used. MAIN OUTCOME MEASURES: We focused on incidence of surgical site infection among the groups. RESULTS: Seven randomized controlled trials that consisted of 1769 cases were eligible for analysis. We found that both total surgical site infection and incisional surgical site infection were significantly reduced in patients who received oral systemic antibiotics and mechanical bowel preparation compared with patients who received systemic antibiotics alone and mechanical bowel preparation (total: 7.2% vs 16.0%, p < 0.00001; incisional: 4.6% vs 12.1%, p < 0.00001). However, no significant difference was detected in the rate of organ/space surgical site infection (4.0% vs 4.8%; p = 0.56) after elective colorectal surgery. LIMITATIONS: The meta-analysis was limited by the risk of bias because a majority of the studies did not use the blinding method. CONCLUSIONS: Oral systemic antibiotics and mechanical bowel preparation significantly lowered the incidence of surgical site infection after elective colorectal surgery compared with systemic antibiotics alone and mechanical bowel preparation. PMID- 26651116 TI - Low Anterior Resection Syndrome: A Treatment Algorithm. PMID- 26651117 TI - Identifying and Treating Patients With Pelvic Organ Dysfunction After Treatment for Pelvic Cancer. PMID- 26651120 TI - Self-Assessment Quiz: Answers, Critiques, and References. PMID- 26651118 TI - Fluorescence Angiography in Colorectal Resection. AB - BACKGROUND: Intraoperative laser fluorescence angiography is a relatively new tool that can be used by colorectal surgeons to ensure adequate perfusion to bowel that remains after resection. It has been used mostly to determine an appropriate point of transection of the proximal bowel, as well as to ensure perfusion after the anastomosis has been constructed. We propose a different use of the technology in complex cases to ensure the ability to safely transect a major vascular pedicle and to ensure that perfusion will remain adequate. OBJECTIVE: The purpose of this article is to describe a new use for fluorescence angiography technology. DESIGN: This is a technical note. SETTINGS: The work was conducted at a tertiary care military medical center. PATIENTS: Patients included individuals requiring oncologic colorectal resection where the status of 1 major vascular pedicle was unknown or impaired. MAIN OUTCOME MEASURES: We assessed perfusion after occlusion of a major vascular pedicle for the short term in hospital outcomes. RESULTS: Adequate studies were obtained, and perfusion was maintained in both patients. Oncologic resections were performed, and short-term outcomes were comparable with any individual undergoing these procedures. LIMITATIONS: This study was limited because it is early experience that was not performed in the setting of a scientific investigation. CONCLUSIONS: Application of intraoperative fluorescence angiography in this setting appears to be safe and may assist the surgeon in estimating reliable vascular perfusion in patients such as these who require oncologic colorectal resection. PMID- 26651121 TI - Residency Programs in Colon and Rectal Surgery. PMID- 26651122 TI - Characterizing the Individual, Social, and Structural Determinants of Condom Use Among Men Who Have Sex with Men in Swaziland. AB - Within the broadly generalized HIV epidemic in Swaziland, men who have sex with men (MSM) have specific HIV acquisition and transmission risks. In the current era of expanding antiretroviral therapy-based prevention and treatment approaches, condom use remains a core component of mitigating these risks. A cross-sectional study characterizing the vulnerabilities for HIV among MSM in Swaziland was analyzed to describe factors associated with condom use at last sex with a male partner. Bivariate and multivariate logistic regression analyses were conducted to assess correlates of condom use at last sex with both casual and regular male partners. Disclosure of sexual practices to a healthcare provider and being able to count on other MSM to support condom use were significantly associated with condom use at last sex with a causal and a regular partner, respectively. Reporting difficulty insisting on condom use was inversely associated with condom use at last sex with both regular and casual partners. In addition, having faced legal discrimination was similarly inversely associated with condom use at last sex with a regular partner. Condom use among MSM in Swaziland may increase with improved partner communication, provider sensitization to encourage sexual disclosure, and the promotion of safer sex norms within MSM communities. These approaches, in combination with existing and emerging evidence of informed and human rights affirming prevention and HIV treatment approaches may reduce the incidence of HIV among MSM in Swaziland and all those in their sexual networks. PMID- 26651124 TI - Editorial. PMID- 26651123 TI - Proinflammatory Cytokines Induce XFG Development. AB - PURPOSE: To reveal the roles of proinflammatory cytokines within the process of pseudoexfoliation (PEX) production. METHODS: Our study included 120 patients referred to cataract surgery (early and late stage of pseudoexfoliation syndrome (XFS), pseudoexfoliation glaucoma (XFG), and control group). Serum and humor levels of cytokines were measured in a sample with high sensitivity enzyme-linked immunosorbent assay (ELISA) kit. RESULTS: Our findings revealed that TNF-alpha and IL-17, overlooked by IL-6 action in the early stage and in the phase of glaucoma, played the main role in the inflammation activation in the tissue in the early and late stage of XFS and in XFG. CONCLUSIONS: Local conditions cause chronic inflammation in the eye, subsequently activating fibrotic process with fibrotic tissue deposits in the eye. PMID- 26651125 TI - Editor's Report. PMID- 26651126 TI - Probabilistic encoding of stimulus strength in astrocyte global calcium signals. AB - Astrocyte calcium signals can range in size from subcellular microdomains to waves that spread through the whole cell (and into connected cells). The differential roles of such local or global calcium signaling are under intense investigation, but the mechanisms by which local signals evolve into global signals in astrocytes are not well understood, nor are the computational rules by which physiological stimuli are transduced into a global signal. To investigate these questions, we transiently applied receptor agonists linked to calcium signaling to primary cultures of cerebellar astrocytes. Astrocytes repetitively tested with the same stimulus responded with global signals intermittently, indicating that each stimulus had a defined probability for triggering a response. The response probability varied between agonists, increased with agonist concentration, and could be positively and negatively modulated by crosstalk with other signaling pathways. To better understand the processes determining the evolution of a global signal, we recorded subcellular calcium "puffs" throughout the whole cell during stimulation. The key requirement for puffs to trigger a global calcium wave following receptor activation appeared to be the synchronous release of calcium from three or more sites, rather than an increasing calcium load accumulating in the cytosol due to increased puff size, amplitude, or frequency. These results suggest that the concentration of transient stimuli will be encoded into a probability of generating a global calcium response, determined by the likelihood of synchronous release from multiple subcellular sites. PMID- 26651127 TI - Assessment of therapeutic options for reducing alkali burn-induced corneal neovascularization and inflammation. AB - This article aims to review and provide the current knowledge of the possibilities of topical treatment of corneal neovascularization due to alkali burns, evidenced by laboratory experiments, in vitro studies, and clinical trials published in the specialized literature. Authors present clinically relevant treatment of corneal neovascularization used in clinical practice, potential antiangiogenic topical therapeutics against corneal neovascularization, which are under investigation, and anti-angiogenic gene-therapy. PMID- 26651128 TI - Evaluation of treatment outcomes and clinical indications for antibiotic prophylaxis in patients undergoing implantation procedures. AB - PURPOSE: The use of antibiotic therapy during implantation to reduce the risk of an early implant failure is widely discussed among clinicists. However, half an hour after the procedure a quarter of patients show bacteremia which could decrease the efficacy of the surgery. Implant failure is associated with destruction of bone tissue within the alveolar process and may lead to an alternative but compromised treatment plan. The aim of the study was to evaluate the influence of perioperative antibiotic protection on success of implantation. MATERIAL AND METHODS: The retrospective study involved 1915 patients (females: 57.3%, males: 42.7%) with no systemic or local diseases, who required antibiotic therapy during surgical procedures. Group 1 comprised 203 patients with diagnosed vertical or horizontal bone atrophy within the alveolar ridge requiring reconstruction procedure before implantation. Group 2 included 1712 patients who did not need any surgical procedures before implantation. All the subjects took three types of antibiotics twice a day for 7 days. The data were statistically analyzed. RESULTS: A total number of 3309 implants were placed. Implantation efficacy in group 1 amounted to 98.53% and in group 2 it was 99.24%. Complications occurred most commonly after administration of cephalosporin which proved to be statistically significant for the patients who underwent augmentation with a bone block before the implant procedure (p 0.0209). CONCLUSIONS: Perioperative use of antibiotic therapy beneficially influences tissue healing, provides safety and success of the surgical procedure, as well as translates into high efficacy of implantation (99.52%). PMID- 26651129 TI - A novel framework for improvement of road accidents considering decision-making styles of drivers in a large metropolitan area. AB - Road accidents can be caused by different factors such as human factors. Quality of the decision-making process of drivers could have a considerable impact on preventing disasters. The main objective of this study is the analysis of factors affecting road accidents by considering the severity of accidents and decision making styles of drivers. To this end, a novel framework is proposed based on data envelopment analysis (DEA) and statistical methods (SMs) to assess the factors affecting road accidents. In this study, for the first time, dominant decision-making styles of drivers with respect to severity of injuries are identified. To show the applicability of the proposed framework, this research employs actual data of more than 500 samples in Tehran, Iran. The empirical results indicate that the flexible decision style is the dominant style for both minor and severe levels of accident injuries. PMID- 26651131 TI - Functionalized protein nanocages as a platform of targeted therapy and immunodetection. AB - To improve the therapeutic/diagnostic potentials of drugs and/or imaging contrast agents, various targeted delivery systems are actively being developed. Especially protein nanocages, hollow and highly symmetrical nanometer-sized cage structures that are self-assembled from multiple protein subunits, are emerging as powerful targeted delivery tools. Their natural abundance, biocompatibility, low toxicity, well defined size and high symmetry are a few of the favorable characteristics which render protein nanocages as near ideal carriers for pharmaceuticals and/or imaging probes. This review aims to highlight current progress in the development and application of protein nanocages in targeted drug delivery approaches with an emphasis on the use of antibodies as targeting motifs to achieve high selectivity toward specific targets. PMID- 26651132 TI - Magnetoelectric Coupling in Well-Ordered Epitaxial BiFeO3/CoFe2O4/SrRuO3 Heterostructured Nanodot Array. AB - Multiferroic magnetoelectric (ME) composites exhibit sizable ME coupling at room temperature, promising applications in a wide range of novel devices. For high density integrated devices, it is indispensable to achieve a well-ordered nanostructured array with reasonable ME coupling. For this purpose, we explored the well-ordered array of isolated epitaxial BiFeO3/CoFe2O4/SrRuO3 heterostructured nanodots fabricated by nanoporous anodic alumina (AAO) template method. The arrayed heterostructured nanodots demonstrate well-established epitaxial structures and coexistence of piezoelectric and ferromagnetic properties, as revealed by transmission electron microscopy (TEM) and peizoeresponse/magnetic force microscopy (PFM/MFM). It was found that the heterostructured nanodots yield apparent ME coupling, likely due to the effective transfer of interface couplings along with the substantial release of substrate clamping. A noticeable change in piezoelectric response of the nanodots can be triggered by magnetic field, indicating a substantial enhancement of ME coupling. Moreover, an electric field induced magnetization switching in these nanodots can be observed, showing a large reverse ME effect. These results offer good opportunities of the nanodots for applications in high-density ME devices, e.g., high density recording (>100 Gbit/in.(2)) or logic devices. PMID- 26651133 TI - Successful retrieval of a firmly stuck rotablator burr by using a modified STAR technique. AB - Rotablator burr entrapment occurring during rotational atherectomy is a rare but serious complication that can lead to coronary occlusion and require emergency cardiac surgery. Although several bailout techniques for stuck burrs have been proposed, no definitive methods for removal have been established. We report here a difficult case of a stuck rotablator burr, in which various techniques failed to retrieve the burr. It was ultimately removed using the subintimal tracking and reentry (STAR) technique with a 3-g tapered tip hydrophilic wire. This modified STAR technique, which was originally developed for percutaneous coronary intervention for chronic total occlusion, may be useful as a bailout technique in patients with a firmly stuck rotablator burr that cannot be removed by using standard procedures. PMID- 26651134 TI - Protein Recognition by Phase Transition of Aptamer-Linked Polythiophene Single Nanowire. AB - A novel protein recognition platform is developed using aptamer-linked polythiophene nanowires. As the aptamer functionalized poly (3-methylthiophene) nanowire is treated by the specific protein, resonance Raman and photoluminescence signals are simultaneously enhanced. Statistical analyses deliver the capability of a single conjugated polymer nanowire with phase transition characteristics in response to selectivity and concentration. PMID- 26651130 TI - Shear-Sensitive Genes in Aortic Valve Endothelium. AB - SIGNIFICANCE: Currently, calcific aortic valve disease (CAVD) is only treatable through surgical intervention because the specific mechanisms leading to the disease remain unclear. In this review, we explore the forces and structure of the valve, as well as the mechanosensors and downstream signaling in the valve endothelium known to contribute to inflammation and valve dysfunction. RECENT ADVANCES: While the valvular structure enables adaptation to dynamic hemodynamic forces, these are impaired during CAVD, resulting in pathological systemic changes. Mechanosensing mechanisms-proteins, sugars, and membrane structures-at the surface of the valve endothelial cell relay mechanical signals to the nucleus. As a result, a large number of mechanosensitive genes are transcribed to alter cellular phenotype and, ultimately, induce inflammation and CAVD. Transforming growth factor-beta signaling and Wnt/beta-catenin have been widely studied in this context. Importantly, NADPH oxidase and reactive oxygen species/reactive nitrogen species signaling has increasingly been recognized to play a key role in the cellular response to mechanical stimuli. In addition, a number of valvular microRNAs are mechanosensitive and may regulate the progression of CAVD. CRITICAL ISSUES: While numerous pathways have been described in the pathology of CAVD, no treatment options are available to avoid surgery for advanced stenosis and calcification of the aortic valve. More work must be focused on this issue to lead to successful therapies for the disease. FUTURE DIRECTIONS: Ultimately, a more complete understanding of the mechanisms within the aortic valve endothelium will lead us to future therapies important for treatment of CAVD without the risks involved with valve replacement or repair. Antioxid. Redox Signal. 25, 401-414. PMID- 26651146 TI - Analysis of laryngoscopic features in patients with unilateral vocal fold paresis. AB - OBJECTIVES/HYPOTHESIS: The diagnosis of paresis in patients with vocal fold motion impairment remains a challenge. More than 27 clinical parameters have been cited that may signify paresis. We hypothesize that some features are more significant than others. STUDY DESIGN: Prospective case series. METHODS: Two laryngologists rated laryngoscopy findings in 19 patients suspected of paresis. The diagnosis was confirmed with laryngeal electromyography. A standard set of 27 ratings was used for each examination that included movement, laryngeal configuration, and stroboscopy signs. A Fisher exact test was completed for each measure. A kappa coefficient was calculated for effectiveness in predicting the laterality of paresis. RESULTS: Left-sided vocal fold paresis (n = 13) was significantly associated with ipsilateral axis deviation, thinner vocal fold, bowing, reduced movement, reduced kinesis, and phase lag (P < .05). Right-sided vocal fold paresis (n = 6) was significantly associated with ipsilateral shorter vocal fold, axis deviation, reduced movement, and reduced kinesis (P < .05). Using these key parameters, the senior author was accurately able to diagnose the side of paresis in 89.5% of cases for a kappa coefficient of 0.78. CONCLUSIONS: Of the multiple features on laryngoscopy, glottic configuration, ipsilateral thin vocal fold, vocal fold bowing, reduced movement, reduced kinesis, and phase lag were more likely to be associated with vocal fold paresis. LEVEL OF EVIDENCE: 4 Laryngoscope, 126:1831-1836, 2016. PMID- 26651147 TI - Reply: To PMID 25974180. PMID- 26651148 TI - Letter to the Editor. PMID- 26651149 TI - A de-novo deletion of dystrophin provoking severe 'peri-partum cardiomyopathy': The importance of genetic testing in peripartum cardiomyopathy to uncover female carriers. PMID- 26651150 TI - Incidence and prognosis implications of long term left ventricular reverse remodeling in patients with dilated cardiomyopathy. AB - BACKGROUND: Left ventricular reverse remodeling (LVRR) in dilated cardiomyopathy is poorly known within the context of current therapeutic approach. Our goal is to describe the present incidence of LVRR, the factors able to predict it and the long term prognosis of these patients. METHODS AND RESULTS: We performed a retrospective analysis of a cohort or 387 consecutive outpatients. Mean follow-up was 50.4 +/- 28.4 months. Sustained LVRR occurred in 57.6% of patients. The number of coronary arteries with severe stenosis (HR 0.69, 95% CI 0.55-0.86; p=0.001), New York Heart Association Functional Class (NYHA FC) (HR 0.39, 95% CI 0.27-0.54; p<0.001) as well as the severity of mitral regurgitation (MR) at the end of follow-up (HR 0.42, 95% CI 0.30-0.58; p<0.001) and the time until first event (HR 1.02, 95% CI 1.01-1.03; p<0.001) were independent predictors of left ventricular ejection fraction improvement. LVRR was tightly related to prognosis due to the fact that both improvement in cardiac function achieving normal or slightly impaired LVEF (HR 0.31, 95% CI 0.17-0.56; p<0.001) and shorter time to achieve LVRR (HR 0.99, 95% CI 0.98-0.99; p=0.017) formed part of the best model for predicting events in DCM. CONCLUSION: More than half of the patients showed sustained LVRR associated with a significantly better prognosis. Fewer numbers of coronary arteries with severe stenosis, milder NYHA FC and the absence of significant MR at the end of follow-up as well as longer event free period formed a simple model to prognosticate LVRR. LVRR and the time to achieve it were strongly related to long term prognosis in patients with DCM. PMID- 26651151 TI - Nanoscale multilevel switching in Ge2Sb2Te5 thin film with conductive atomic force microscopy. AB - We demonstrate three-level data storage in amorphous Ge2Sb2Te5 (GST) thin film by conductive atomic force microscopy (C-AFM). Due to the high resolution and current sensitivity of AFM, the electrical properties of GST are investigated in the nanoscale. By applying an electric field between an AFM probe tip and the GST surface, well-resolved threshold switching and memory switching are obtained successively in a current-voltage sweeping. Correspondingly, three states with high, intermediate and low resistances, which are assigned data values '0', '1' and '2' respectively, are observed in an IV-spectrum. The electrical resistance of GST thin film decreases by over two orders of magnitude in both switching processes, which provides a clear contrast to distinguish the three logical states. We also discuss the threshold electrical field of threshold switching in the amorphous GST thin film. Nanoscale conductive marks in the amorphous ON state and crystalline state are successfully fabricated by applying IV-spectra with different voltage ranges on the GST thin films. PMID- 26651152 TI - CuO-Functionalized Silicon Photoanodes for Photoelectrochemical Water Splitting Devices. AB - One main difficulty for the technological development of photoelectrochemical (PEC) water splitting (WS) devices is the fabrication of active, stable and cost effective photoelectrodes that ensure high performance. Here, we report the development of a CuO/Silicon based photoanode, which shows an onset potential for the water oxidation of 0.53 V vs SCE at pH 9, that is, an overpotential of 75 mV, and high stability above 10 h. These values account for a photovoltage of 420 mV due to the absorbed photons by silicon, as proven by comparing with analogous CuO/FTO electrodes that are not photoactive. The photoanodes have been fabricated by sputtering a thin film of Cu(0) on commercially available n-type Si wafers, followed by a photoelectrochemical treatment in basic pH conditions. The resulting CuO/Cu layer acts as (1) protective layer to avoid the corrosion of nSi, (2) p-type hole conducting layer for efficient charge separation and transportation, and (3) electrocatalyst to reduce the overpotential of the water oxidation reaction. The low cost, low toxicity, and good performance of CuO-based coatings can be an attractive solution to functionalize unstable materials for solar energy conversion. PMID- 26651154 TI - The role of chronotype, gender, test anxiety, and conscientiousness in academic achievement of high school students. AB - Previous findings have demonstrated that chronotype (morningness/intermediate/eveningness) is correlated with cognitive functions, that is, people show higher mental performance when they do a test at their preferred time of day. Empirical studies found a relationship between morningness and higher learning achievement at school and university. However, only a few of them controlled for other moderating and mediating variables. In this study, we included chronotype, gender, conscientiousness and test anxiety in a structural equation model (SEM) with grade point average (GPA) as academic achievement outcome. Participants were 158 high school students and results revealed that boys and girls differed in GPA and test anxiety significantly, with girls reporting better grades and higher test anxiety. Moreover, there was a positive correlation between conscientiousness and GPA (r = 0.17) and morningness (r = 0.29), respectively, and a negative correlation between conscientiousness and test anxiety (r = -0.22). The SEM demonstrated that gender was the strongest predictor of academic achievement. Lower test anxiety predicted higher GPA in girls but not in boys. Additionally, chronotype as moderator revealed a significant association between gender and GPA for evening types and intermediate types, while intermediate types showed a significant relationship between test anxiety and GPA. Our results suggest that gender is an essential predictor of academic achievement even stronger than low or absent test anxiety. Future studies are needed to explore how gender and chronotype act together in a longitudinal panel design and how chronotype is mediated by conscientiousness in the prediction of academic achievement. PMID- 26651155 TI - Effect of long-term using of hormonal contraception on anti-Mullerian hormone secretion. AB - Anti-Mullerian hormone (AMH) is an important factor associated with female fertility and the ovarian reserve. There are several past studies available concerning the influence of hormonal contraception (HC) on serum AMH levels. Recent studies have reported that AMH levels in women using HC can be about 30% lower compared to those not using HC. However, earlier studies showed no reduction in AMH levels in HC users. We decided to evaluate the effects of long term HC use (mean duration of HC use: 11.4 years) on AMH levels in women. To exclude potential shorter and reversible decreasing effects of HC on fertility function, we decided to include women in the study who had stopped using HC 1 year before the AMH sample collection. We examined 105 women who used HC and 44 women who had never used HC. The median concentration of AMH in the group of long term users of HC was 2.89 and 3.37 ng/ml in the group of women who had never used HC. We found no statistically significant difference (p = 0.3261). In conclusion, we observed no negative impact of HC on the AMH serum levels. AMH can be used as an ovarian reserve marker for these women. PMID- 26651153 TI - An Essential Role of Nedd4-2 in the Ubiquitination, Expression, and Function of Organic Anion Transporter-3. AB - Organic anion transporter-3 (OAT3) is a member of the organic anion transporter family that mediates the body disposition of a diverse array of clinically important drugs. We previously demonstrated that activation of protein kinase C (PKC) inhibits OAT3 transport activity by accelerating OAT3 internalization from cell surface into intracellular compartments. In the current study, we established that PKC-induced inhibition of OAT3 transport activity occurred through an enhanced OAT3 ubiquitination, a process catalyzed by an E3 ubiquitin protein ligase Nedd4-2 (neural precursor cell expressed, developmentally downregulated 4-2). Overexpression of Nedd4-2 enhanced OAT3 ubiquitination, decreased OAT3 expression at the cell surface, and inhibited OAT3 transport activity. In contrast, overexpression of the ubiquitin ligase-dead mutant Nedd4 2/C821A or siRNA knockdown of endogenous Nedd4-2 had opposite effects on OAT3. Furthermore, immunoprecipitation experiments conducted both in culture cells and with rat kidney slices showed that there was a physical interaction between OAT3 and Nedd4-2. In conclusion, our results provided the first evidence that Nedd4-2 is an important regulator for OAT3 ubiquitination, expression, and transport activity. PMID- 26651158 TI - CASSCF Computational Study of Pseudopericyclic Character in Electrocyclic Rearrangements Involving Heteroatoms. AB - The Complete Active Space Self-Consistent Field (CASSCF) computational method, with the 6-31G* basis set, was used to examine six electrocyclic rearrangements, each involving a 1,2,4,6-heptatetraene skeleton with two variously located oxygen and/or nitrogen heteroatoms, as a way to determine which, if any, are pseudopericyclic as opposed to pericyclic. Primarily through the close examination of the active space orbitals, but also considering transition structure geometries and activation energies, it was concluded that rearrangements 3 -> 4, 5 -> 6, 7 -> 8, and 9 -> 10 are pseudopericyclic with two orbital disconnections each, whereas the 13 -> 14 and 15 -> 16 rearrangements are pericyclic. Our conclusions agreed with those of others in two of the four cases that had been studied previously by density functional theory (3 -> 4 and 7 -> 8) but ran contrary to the previous conclusions that the 5 -> 6 rearrangement is pericyclic and that the 15 -> 16 rearrangement is pseudopericyclic. Our results are also compared and contrasted to previous similar ones of ours involving the 3 -> 4 electrocyclization (essentially pericyclic), the 11 -> 12 [3,3] sigmatropic rearrangement (pseudopericyclic), and similar [3,3] sigmatropic rearrangements (all pericyclic), and detailed rationales for these latest results are provided. PMID- 26651157 TI - Can trained nurses exclude acute otitis media with tympanometry or acoustic reflectometry in symptomatic children? AB - OBJECTIVE: Since acute otitis media (AOM) is the most prevalent bacterial infection in young children, the reliable exclusion of AOM by nurses might save physicians' time for other duties. The study aim was to determine whether nurses without otoscopic experience can reliably use tympanometry or spectral gradient acoustic reflectometry (SG-AR) to exclude AOM. DESIGN: Three nurses were trained, who performed examinations with tympanometry and SG-AR. Pneumatic otoscopy by the study physician served as the diagnostic standard. SETTING: Study clinic at primary health care level. PATIENTS: 281 children 6-35 months of age. MAIN OUTCOME MEASURES: Predictive values (with 95% confidence interval) for tympanometry and SG-AR, and the clinical usefulness, i.e. the proportion of visits where nurses obtained the exclusive test result from both ears of the child. RESULTS: At 459 visits, the negative predictive value of type A and C1 tympanograms (tympanometric peak pressure >-200 daPa) was 94% (91-97%). Based on type A and C1 tympanograms, the nurse could exclude AOM at 94/459 (20%) of visits. The negative predictive value of SG-AR level 1 result (>95 degrees ) was 94% (89-97%). Based on the SG-AR level 1 result, the nurse could exclude AOM at 36/459 (8%) of visits. CONCLUSION: Type A and C1 tympanograms and SG-AR level 1 results obtained by nurses are reliable test results in excluding AOM. However, the clinical usefulness of these test results is limited by their rarity. Type A and C1 tympanograms were obtained by nurses from both ears of the child only at one-fifth of the symptomatic visits. Key Points Acute otitis media (AOM) is the most prevalent bacterial infection in young children. Nurses' role in excluding AOM is unknown. Type A and C1 tympanograms (tympanometric peak pressure >-200 daPa) obtained by nurses are reliable test results in excluding AOM. With type A and C1 tympanograms, nurses could exclude AOM only at one-fifth of the symptomatic visits. The clinical usefulness of the exclusion of AOM performed by nurses seems to be limited. PMID- 26651159 TI - Utility of diffusion tensor imaging studies linked to neuronavigation and other modalities in repeat hemispherotomy for intractable epilepsy. AB - OBJECT Hemispherectomy for unilateral, medically refractory epilepsy is associated with excellent long-term seizure control. However, for patients with recurrent seizures following disconnection, workup and investigation can be challenging, and surgical options may be limited. Few studies have examined the role of repeat hemispherotomy in these patients. The authors hypothesized that residual fiber connections between the hemispheres could be the underlying cause of recurrent epilepsy in these patients. Diffusion tensor imaging (DTI) was used to test this hypothesis, and to target residual connections at reoperation using neuronavigation. METHODS The authors identified 8 patients with recurrent seizures following hemispherectomy who underwent surgery between 1995 and 2012. Prolonged video electroencephalography recordings documented persistent seizures arising from the affected hemisphere. In all patients, DTI demonstrated residual white matter association fibers connecting the hemispheres. A repeat craniotomy and neuronavigation-guided targeted disconnection of these residual fibers was performed. Engel class was used to determine outcome after surgery at a minimum of 2 years of follow-up. RESULTS Two patients underwent initial hemidecortication and 6 had periinsular hemispherotomy as their first procedures at a median age of 9.7 months. Initial pathologies included hemimegalencephaly (n = 4), multilobar cortical dysplasia (n = 3), and Rasmussen's encephalitis (n = 1). The mean duration of seizure freedom for the group after the initial procedure was 32.5 months (range 6-77 months). In all patients, DTI showed limited but definite residual connections between the 2 hemispheres, primarily across the rostrum/genu of the corpus callosum. The median age at reoperation was 6.8 years (range 1.3-14 years). The average time taken for reoperation was 3 hours (range 1.8-4.3 hours), with a mean blood loss of 150 ml (range 50-250 ml). One patient required a blood transfusion. Five patients are seizure free, and the remaining 3 patients are Engel Class II, with a minimum follow-up of 24 months for the group. CONCLUSIONS Repeat hemispherotomy is an option for consideration in patients with recurrent intractable epilepsy following failed surgery for catastrophic epilepsy. In conjunction with other modalities to establish seizure onset zones, advanced MRI and DTI sequences may be of value in identifying patients with residual connectivity between the affected and unaffected hemispheres. Targeted disconnection of these residual areas of connectivity using neuronavigation may result in improved seizure outcomes, with minimal and acceptable morbidity. PMID- 26651160 TI - Computed tomography morphometric analysis of anterior instrumentation in the pediatric thoracic spine. AB - OBJECT The authors' goal in this paper was to quantify reference data on the dimensions and relationships of the maximum posterior screw angle and the thoracic spinal canal in different pediatric age groups. METHODS One hundred twelve pediatric patients were divided into 4 age groups, and their thoracic vertebrae were studied on CT scans. The width, depth, and maximum posterior screw angles with different screw entrance points were measured on a Philips Brilliance 16 CT. The statistical analysis was performed using the Student t-test and Pearson's correlation analysis. RESULTS The width and depth of the thoracic vertebrae increased from T-5 to T-12. The width ranged from 18.5 to 37.1 mm, while the depth ranged from 16.1 to 28.2 mm. The maximum posterior screw angle decreased from T-5 to T-12 in all groups. The ranges and mean angles at the entrance points were as follows: initial entrance point, 6.9 degrees to 12.3 degrees with a mean angle of 9.1 degrees ; second entrance point, 20.6 degrees to 27.0 degrees with a mean angle of 24.2 degrees ; and third entrance point, 29.2 degrees to 37.5 degrees with a mean angle of 33.7 degrees . There were no significant age-related differences noted for the maximum posterior screw angles. CONCLUSIONS The angle decreased from T-5 to T-12. No significant age-related differences were noted in the maximum posterior screw angles. Screws should be placed between the initial and second points and parallel to the coronal section or at a slight anterior orientation. PMID- 26651161 TI - Letter to the Editor: Changes in the trend of hydrocephalus subtypes in infants. PMID- 26651162 TI - Synthesis of Polysubstituted Pyridines via a One-Pot Metal-Free Strategy. AB - An efficient strategy for the one-pot synthesis of polysubstituted pyridines via a cascade reaction from aldehydes, phosphorus ylides, and propargyl azide is reported. The reaction sequence involves a Wittig reaction, a Staudinger reaction, an aza-Wittig reaction, a 6pi-3-azatriene electrocyclization, and a 1,3 H shift. This protocol provides quick access to the polysubstituted pyridines from readily available substrates in good to excellent yields. PMID- 26651163 TI - Hole-Transporting Materials with a Two-Dimensionally Expanded pi-System around an Azulene Core for Efficient Perovskite Solar Cells. AB - Two-dimensionally expanded pi-systems, consisting of partially oxygen-bridged triarylamine skeletons that are connected to an azulene (1-3) or biphenyl core (4), were synthesized and characterized. When tetra-substituted azulene 1 was used as a hole-transporting material (HTM) in perovskite solar cells, the observed performance (power conversion efficiency = 16.5%) was found to be superior to that of the current HTM standard Spiro-OMeTAD. A comparison of the hole mobility, the ability to control the HOMO and LUMO levels, and the hole collection efficiency at the perovskite/HTM interface in 1 with reference compounds (2-4 and Spiro-OMeTAD) led to the elucidation of key factors required for HTMs to act efficiently in perovskite solar cells. PMID- 26651164 TI - Improvement of a low-level mesurement system used at LNHB. AB - In this new approach, the active shielding of a low level spectrometer is monitored by an extendable dead time used as an "extendable GATE" signal. This concept is directly inspired from the live-timed anti-coincidence system implemented at LNE-LNHB (MTR2 modules). This allows a significant reduction in the cost and complexity of the system since several electronic modules are replaced by only one module dedicated specifically to this type of experiment. Settings of this new approach are detailed and results are discussed. PMID- 26651165 TI - Measurement of partial L fluorescence yields of bismuth using synchrotron radiation. AB - Tunable monochromatic photon radiation was used to measure transmission of a bismuth target in the energy range from 7keV to 20keV. Partial L fluorescence yields of bismuth were obtained by combining measurement of the fluorescence induced by photoionization of the bismuth target and X-rays from the radioactive decay of (210)Pb. Several photon energies have been used to successively ionize the L subshells, which allowed detailed analysis of the rearrangement spectra and determination of the X-ray relative intensities of the L1, L2 and L3 series. PMID- 26651166 TI - Characterisation of the IAEA-375 Soil Reference Material for radioactivity. AB - The Joint Research Centre Institute for Reference Materials and Measurements (JRC IRMM) participated in a research project initiated by the International Atomic Energy Agency (IAEA) to upgrade some of its existing reference materials (RMs). The aim of the work described in this article was to determine the activity concentration of a series of radionuclides in the IAEA-375 soil RM with values traceable to the SI units. The radionuclides (40)K, (134)Cs, (137)Cs, (212)Pb, (212)Bi, (214)Pb and (214)Bi were measured by gamma-ray spectrometry after drying the sample and placing it in a suitable container. The (90)Sr was assessed by liquid scintillation counting after dissolution of the soil by wet digestion and chemical separation of Sr by extraction chromatography. This soil RM was used later as basis for the 2010 EC Interlaboratory Comparison on Radionuclides in Soil. PMID- 26651167 TI - Reference drums used in calibration of a plastic scintillation counter in a 4pi counting geometry. AB - In this study, two kinds of reference drums were developed. One type was constructed with nine layers of large-area sources filled with different materials having five different densities. The other type of reference drums was constructed with nine rod sources filled with the same materials of different densities. The efficiency calibration of a plastic scintillation counter in 4pi counting geometry using these two kinds of drums showed that rod-source drums resulted in higher counting efficiency than layered source drums. The counting rates obtained from rod-source drums were closer to those obtained from a standard drum with water solution than counting rates from drums with layered sources. The results of this study recommend to use reference drums with rod sources to compensate the drawbacks of standard drums with water solution of not being able to adjust the density of material. The proposed reference drums improve the accuracy of radioactivity analysis for waste drums of different densities. PMID- 26651168 TI - Preparation of graphene thin films for radioactive samples. AB - A new method for the preparation of conductive thin films is presented. The metallization of VYNS films guarantees the electrical conductivity but it results in the breaking of a high proportion of them. Graphene, a two-dimensional nanostructure of monolayer or few layers graphite has attracted a great deal of attention because of its excellent properties such as a good chemical stability, mechanical resistance and extraordinary electronic transport properties. In this work, the possibilities of graphene have been explored as a way to produce electrical conductive thin films without an extra metallization process. The procedure starts with preparing homogenous suspensions of reduced graphene oxide (rGO) in conventional VYNS solutions. Ultra-sonication is used to ensure a good dispersibility of rGO. Graphene oxide (GO) is prepared via oxidation of graphite and subsequent exfoliation by sonication. Different chemically rGO were obtained by reaction with hydrazine sulfate, sodium borohydride, ascorbic acid and hydroiodic acid as reducing agents. The preparation of the thin graphene films is done in a similar way as the conventional VYNS foil preparation procedure. Drops of the solution are deposited onto water. The graphene films have been used to prepare sources containing some electron capture radionuclides ((109)Cd, (55)Fe, (139)Ce) with an activity in the order of 3kBq. The samples have been measured to test the attainable low energy electron efficiency and the energy resolution of Auger and conversion electrons by 4pi (electron capture)-gamma coincidence measurements. The 4pi (electron capture)-gamma coincidence setup includes a pressurized proportional counter and a NaI(Tl) detector. Tests with different pressures up to 1000kPa were carried out. All these tests show similar values in both parameters (efficiency and resolution) as those obtained by using the conventional metallized films without the drawback of the high percentage of broken films. PMID- 26651169 TI - Equivalence of computer codes for calculation of coincidence summing correction factors - Part II. AB - The aim of this study was to check for equivalence of computer codes that are capable of performing calculations of true coincidence summing (TCS) correction factors. All calculations were performed for a set of well-defined detector parameters, sample parameters and decay scheme data. The studied geometry was a point source of (133)Ba positioned directly on the detector window of a low energy (n-type) detector. Good agreement was established between the TCS correction factors computed by the different codes. PMID- 26651170 TI - (3)H activity comparison between FTMC, VNIIM and LNE-LNHB. AB - An activity comparison of tritiated water was organized in 2013 between 3 laboratories: FTMC (Lithuania), LNE-LNHB (France) and VNIIM (Russia). The solution was prepared by LNHB and ampoules were sent to the others laboratories. This solution was standardized in terms of activity per unit mass by participant laboratories using the Triple to Double Coincidence Ratio (TDCR) method in liquid scintillation counting (LSC). The tritiated water solution is traceable to the solution prepared by LNHB for the CCRI(II)-K2.H-3 2009 (3)H international comparison. PMID- 26651171 TI - Preparation of (228)Ra standard solution. AB - For the preparation of a standard solution of (228)Ra, (228)Ra was isolated from (232)Th salt. Two simple methods were developed for Th-Ra separation. Both are based on a very good solubility of thorium nitrate in organic solvents. The first one used Ra co-precipitation with Pb in the form of Pb(NO3)2 from acetic acid solution. The second method was based on solvent extraction, remaining Th in the organic phase, while Ra was concentrated in the aqueous phase. The activity of (228)Ra (up to 20kBq) in the standard solution was related to the (232)Th standard by means of gamma ray spectrometry measurement. The obtained uncertainty was less than 0.7% (k=1). The standard solution was free of (232)Th and contained the carrier in the usual concentration (1gL(-1) BaCl2, 10gL(-1) HCl). PMID- 26651172 TI - Comparison of acid leaching and fusion techniques to determine uranium in soil samples by alpha spectrometry. AB - Dissolution of radionuclides of interest is an indispensable first step in the alpha spectrometric analysis of soil samples. In this study a uranium recovery method for the analysis of uranium isotopes in soil samples is presented. Two different soil sample dissolution techniques were used: digestion in open beaker and fusion. The results of these techniques were compared. Two proficiency test samples and one reference material prepared by the IAEA were analyzed. Better results were obtained by fusion dissolution technique but impurities were higher than with acid leaching. Results of two techniques were more or less similar within the uncertainty limits. The detection limit (a(#)) was evaluated as part of the quality control. PMID- 26651173 TI - Determination of X- and gamma-ray emission intensities in the decay of (131)I. AB - The activity per unit mass of an iodine-131 solution was absolutely standardized by both the 4pibeta-gamma coincidence method and the 4pigamma counting technique. The calibrated solution was used to prepare point sources after a preliminary deposit of AgNO3 to prevent the loss of volatile iodine. Relative and absolute photon emission intensities of 15 sgamma-rays and those of the two K X-rays of xenon were determined by gamma-ray spectrometry, with relative uncertainties of 0.8% for the three main emissions. PMID- 26651174 TI - Standardisation and half-life measurements of (111)In. AB - The standardisation of (111)In by 4pi(LS)-gamma coincidence and anticoincidence counting is presented. Absolute measurements were performed for samples with different concentrations of carrier solution and for different window settings in the gamma channel. The radioactive concentration of the master solution determined on the same reference date was consistent for all measurements performed. The evaluated typical uncertainty was 0.43%. The half-life of (111)In was determined using a time series of measurements performed with an ionisation chamber. A least squares fit of the measured data resulted in a half-life of 2.8067 (34) days consistent with Decay Data Evaluation Project recommended value (0.064% higher than the DDEP value). PMID- 26651175 TI - Standardization of the radionuclides (60)Co and (59)Fe by digital 4pibeta(PC) gamma(NaI) coincidence counting. AB - The digital coincidence counting (DCC) technique has been developed at NIM, China to replace the classical analog coincidence units in the 4pibeta-gamma counting system. The detector system comprises two NaI (Tl) gamma-ray detectors and a 4pibeta proportional counter (PC) operated with a mixture of argon and methane at atmospheric pressure in a gas flow arrangement. To update the activity results of radionuclide (60)Co in the KCDB and contribute to the APMP.RI(II)-K2.Fe-59 comparison, (60)Co and (59)Fe dry sources were prepared and measured using the digital 4pibeta(PC)-gamma(NaI) coincidence system by applying the efficiency extrapolation method. For (60)Co nuclide, the activity concentration value equal to 290.6kBqg(-1) with a relative standard uncertainty of 0.26%, is consistent with the result given by the calibrated ionization chamber. For the nuclide (59)Fe, the activity concentration value at the reference date was 471.7kBqg(-1) with a relative standard uncertainty of 0.34%. This value is in good agreement with the result obtained with the HPGe gamma spectrometry, which was calibrated by using a series of standard point sources from PTB. PMID- 26651176 TI - Investigation of the response variability of ionization chambers for the standard transfer of SIR-Spheres((r)). AB - The present paper addresses the calibration of well-type ionization chambers (ICs) used at LNE-LNHB as standard transfer instruments to calibrate hospitals in the case of SIR-Spheres((r))(90)Y resin microspheres (Sirtex, Australia). Developed for interventional oncology, this radiopharmaceutical is directly injected in the liver for cancer treatment via a selective internal radiation therapy. The present work was carried out in the framework of the European project "Metrology for molecular radiotherapy" (MetroMRT). As commonly performed in radionuclide metrology for radiopharmaceuticals, the objective is to ensure the metrological traceability of SIR-Spheres((r)) to hospitals. Preceding studies were focused on primary measurements of SIR-Spheres((r)) based on the TDCR (Triple to Double Coincidence Ratio) method, applied after the dissolution of the (90)Y-labeled resin microspheres. As (90)Y is a high-energy beta(-)-emitter, the IC response strongly depends on the transport of electrons in the radioactive solution and surroundings (vial, chamber liners and materials). The variability of the IC-response due to the geometry dependence is investigated by means of measurements and Monte Carlo simulations in the case of a Vinten IC. The aim of the present study was also to propose a reliable uncertainty for ICs calibrations for the standard transfer of SIR-Spheres((r)) to hospitals. PMID- 26651177 TI - Conversion electron spectrometry of Pu isotopes with a silicon drift detector. AB - An electron spectrometry set-up was built at IRMM consisting of a vacuum chamber with a moveable source holder and windowless Peltier-cooled silicon drift detector (SDD). The SDD is well suited for measuring low-energy x rays and electrons emitted from thin radioactive sources with low self-absorption. The attainable energy resolution is better than 0.5keV for electrons of 30keV. It has been used to measure the conversion electron spectra of three plutonium isotopes, i.e. (238)Pu, (239)Pu, (240)Pu, as well as (241)Am (being a decay product of (241)Pu). The obtained mixed x-ray and electron spectra are compared with spectra obtained with a close-geometry set-up using another SDD in STUK and spectra measured with a Si(Li) detector at IRMM. The potential of conversion electron spectrometry for isotopic analysis of mixed plutonium samples is investigated. With respect to the (240)Pu/(239)Pu isotopic ratio, the conversion electron peaks of both isotopes are more clearly separated than their largely overlapping peaks in alpha spectra. PMID- 26651179 TI - "Wanting," "liking," and their relation to consciousness. AB - Most animal and human behaviors emanate from goal-directedness and pleasure seeking, suggesting that they are primarily under conscious control. However, "wanting" and "liking" are believed to be adaptive core subcortical processes working at an unconscious level and responsible for guiding behavior toward appropriate rewards. Here we examine whether "wanting" is an inherent property of conscious goals and "liking" an intrinsic component of conscious feelings. We argue that "wanting" and "liking" depend on mechanisms acting below the level of consciousness, explaining why individuals often struggle to enhance or refrain their motivations and emotions by means of conscious control. In particular, hyperreactivity of subcortical "wanting" systems has been tied to pathological behaviors such as drug addiction and gambling disorder. In addicts, cognitive processes intended to curb drug-seeking wage a constant battle against subcortical urges to take more drug that often ends in relapse following repeated assaults. Nevertheless, we suggest that in nonpathological contexts, "wanting" and "liking" interact with major cognitive processes to guide goal-directed actions. PMID- 26651178 TI - Taxane anticancer agents: a patent perspective. AB - INTRODUCTION: Paclitaxel and docetaxel were two epoch-making anticancer drugs and have been successfully used in chemotherapy for a variety of cancer types. In the year 2010, a new taxane, cabazitaxel, was approved by FDA for use in combination with prednisone for the treatment of metastatic hormone-refractory prostate cancer. Albumin-bound paclitaxel (nabTM-paclitaxel; abraxane) nanodroplet formulation was another notable invention (FDA approval 2005 for refractory, metastatic, or relapsed breast cancer). Abraxane in combination with gemcitabine for the treatment of pancreatic cancer was approved by FDA in 2013. Accordingly, there have been a huge number of patent applications dealing with taxane anticancer agents in the last 5 years. Thus, it is a good time to review the progress in this area and find the next wave for new developments. AREA COVERED: This review covers the patent literature from the year 2010 to early 2015 on various aspects of taxane-based chemotherapies and drug developments. EXPERT OPINION: Three FDA-approved taxane anticancer drugs will continue to expand their therapeutic applications, especially through drug combinations and new formulations. Inspired by the success of abraxane, new nano-formulations are emerging. Highly potent new-generation taxanes will play a key role in the development of efficacious tumor-targeted drug delivery systems. PMID- 26651180 TI - White matter microstructure in ultra-high risk and first episode schizophrenia: A prospective study. AB - There is increasing evidence of white matter (WM) pathology in schizophrenia, but its role at the very early stage of the disorder remains unclear. In an exploration of WM microstructure in ultra-high risk (UHR) subjects and first episode schizophrenia (FES), 34 FES, 27 UHR and 26 healthy control (HC) subjects underwent a magnetic resonance imaging (MRI) tract based spatial statistics (TBSS) investigation. Whole brain fractional anisotropy (FA), mean diffusivity (MD), radial (RD) and axial diffusivity (AD) values were extracted. UHR subjects who later developed psychosis showed lower FA compared with HC in the corpus callosum (CC), the left superior and inferior longitudinal fasciculus, the left inferior fronto-occipital fasciculs (IFO), and the forceps; RD was significantly higher in the CC, the forceps, the anterior thalamic radiation bilaterally, and the cingulum bundle. FES, compared to HC, showed a significant FA reduction of the CC, the superior and inferior longitudinal fasciculi bilaterally, the IFO bilaterally, the corona radiate bilaterally, and the forceps; while RD was found to be significantly increased in the left superior longitudinal fasciculus. UHR who later developed psychosis had WM abnormalities affecting brain pathways that are crucial for intra- and inter-hemispheric connections. PMID- 26651181 TI - Ecological and morphological characteristics of parasitoids in Phauda flammans (Lepidoptera, Zygaenidae). AB - Phauda flammans Walker (Lepidoptera, Zygaenidae) is one of the notorious defoliators on Ficus spp. trees. In order to avoid environmental pollution, potential biological control agents for P. flammans need to be investigated instead of chemical control. Four species of insect parasitoids were identified from P. flammans, including three hymenopteran species (i.e., Gotra octocinctus, Apanteles sp. and Eurytoma verticillata) and one dipteran species (i.e., Exorista yunnanica). Parasitoid ratios of G. octocinctus, Apanteles sp., Eu. verticillata and Ex. yunnanica were 7.2%, 4.2%, 1.6% and 0.9%. The four species were all larval endoparasitoids of P. flammans larvae. Time of cocoon (pupa) to adult, life span, major axis of cocoon and body length of females were all longer compared to males for G. octocinctus, Apanteles sp. and Ex. yunnanica. Based on the parasitoid ratios, the most abundant parasitoid species was G. octocinctus. PMID- 26651182 TI - In Vitro Systems Toxicology Assessment of a Candidate Modified Risk Tobacco Product Shows Reduced Toxicity Compared to That of a Conventional Cigarette. AB - Cigarette smoke increases the risk for respiratory and other diseases. Although smoking prevalence has declined over the years, millions of adults choose to continue to smoke. Modified risk tobacco products (MRTPs) are potentially valuable tools for adult smokers that are unwilling to quit their habit. Here, we investigated the biological impact of a candidate MRTP, the tobacco-heating system (THS) 2.2, compared to that of the 3R4F reference cigarette in normal primary human bronchial epithelial cells. Chemical characterization of the THS 2.2 aerosol showed reduced levels of harmful constituents compared to those of a combustible cigarette. Multiparametric indicators of cellular toxicity were measured via real-time cellular analysis and high-content screening. The study was complemented by a whole transcriptome analysis, followed by computational approaches to identify and quantify perturbed molecular pathways. Exposure of cells to 3R4F cigarette smoke resulted in a dose-dependent response in most toxicity end points. Moreover, we found a significant level of perturbation in multiple biological pathways, particularly in those related to cellular stress. By contrast, exposure to THS 2.2 resulted in an overall lower biological impact. At 3R4F doses, no toxic effects were observed. A toxic response was observed for THS 2.2 in some functional end points, but the responses occurred at doses between 3 and 15 times higher than those of 3R4F. The level of biological network perturbation was also significantly reduced following THS 2.2 aerosol exposure compared to that of 3R4F cigarette smoke. Taken together, the data suggest that THS 2.2 aerosol is less toxic than combustible cigarette smoke and thus may have the potential to reduce the risk for smoke-related diseases. PMID- 26651183 TI - Evaluation of Asperger Syndrome in Youth Presenting to a Gender Dysphoria Clinic. AB - PURPOSE: There is evolving evidence that children and adolescents with gender dysphoria have higher-than-expected rates of autism spectrum disorder (ASD), yet clinical data on ASD among youth with gender dysphoria remain limited, particularly in North America. This report aims to fill this gap. METHODS: We conducted a retrospective review of patient chart data from 39 consecutive youth ages 8 to 20 years (mean age 15.8 years, natal male: n = 22, natal female: n = 17) presenting for evaluation at a multidisciplinary gender clinic in a large U.S. pediatric hospital from 2007 to 2011 to evaluate the prevalence of ASD in this patient population. RESULTS: Overall, 23.1% of patients (9/39) presenting with gender dysphoria had possible, likely, or very likely Asperger syndrome as measured by the Asperger Syndrome Diagnostic Scale (ASDS). CONCLUSION: These findings are consistent with growing evidence supporting increased prevalence of ASD in gender dysphoric children. To guide provision of optimal clinical care and therapeutic intervention, routine assessment of ASD is recommended in youth presenting for gender dysphoria. PMID- 26651184 TI - A new taraxastane-type triterpenoid glycoside from the roots of Clematis uncinata. AB - A new taraxastane-type triterpenoid glycoside, clematiunicinoside I (1), together with four known ones (2-5), was isolated from the roots of Clematis uncinata. The structure of the new compound was elucidated on the basis of spectroscopic analyses and acid hydrolysis. The cytotoxic activities of all the compounds against caski cervical cancer (Caski) cells were evaluated. This is the first report of the presence of taraxastane-type triterpenoid glycoside in the genus Clematis. PMID- 26651185 TI - The Patient's Turn Roy Porter and Psychiatry's Tales, Thirty Years on. PMID- 26651186 TI - Animal Magnetism, Psychiatry and Subjective Experience in Nineteenth-Century Germany: Friedrich Kraubeta and his Nothschrei. AB - Friedrich Kraubeta (1791-1868) is the author of Nothschrei eines Magnetisch Vergifteten [Cry of Distress by a Victim of Magnetic Poisoning] (1852), which has been considered one of the most comprehensive self-narratives of madness published in the German language. In this 1018-page work Kraubeta documents his acute fears of 'mesmerist' influence and persecution, his detainment in an Antwerp asylum and his encounter with various illustrious physicians across Europe. Though in many ways comparable to other prominent nineteenth-century first-person accounts (eg. John Thomas Perceval's 1838 Narrative of the Treatment Experienced by a Gentleman or Daniel Paul Schreber's 1903 Memoirs of my Nervous Illness), Kraubeta's story has received comparatively little scholarly attention. This is especially the case in the English-speaking world. In this article I reconstruct Kraubeta's biography by emphasising his relationship with physicians and his under-explored stay at the asylum. I then investigate the ways in which Kraubeta appropriated nascent theories about 'animal magnetism' to cope with his disturbing experiences. Finally, I address Kraubeta's recently discovered calligraphic oeuvre, which bears traces of his typical fears all the while showcasing his artistic skills. By moving away from the predominantly clinical perspective that has characterised earlier studies, this article reveals how Friedrich Kraubeta sought to make sense of his experience by selectively appropriating both orthodox and non-orthodox forms of medical knowledge. In so doing, it highlights the mutual interaction of discourses 'from above' and 'from below' as well as the influence of broader cultural forces on conceptions of self and illness during that seminal period. PMID- 26651187 TI - 'No "Sane" Person Would Have Any Idea': Patients' Involvement in Late Nineteenth century British Asylum Psychiatry. AB - In his 1895 textbook, Mental Physiology, Bethlem Royal Hospital physician Theo Hyslop acknowledged the assistance of three fellow hospital residents. One was a junior colleague. The other two were both patients: Walter Abraham Haigh and Henry Francis Harding. Haigh was also thanked in former superintendent George Savage's book Insanity and Allied Neuroses (1884). In neither instance were the patients identified as such. This begs the question: what role did Haigh and Harding play in asylum theory and practice? And how did these two men interpret their experiences, both within and outside the asylum? By focusing on Haigh and Harding's unusual status, this paper argues that the notion of nineteenth-century 'asylum patient' needs to be investigated by paying close attention to specific national and institutional circumstances. Exploring Haigh and Harding's active engagement with their physicians provides insight into this lesser-known aspect of psychiatry's history. Their experience suggests that, in some instances, representations of madness at that period were the product of a two-way process of negotiation between alienist and patient. Patients, in other words, were not always mere victims of 'psychiatric power'; they participated in the construction and circulation of medical notions by serving as active intermediaries between medical and lay perceptions of madness. PMID- 26651188 TI - Making Sense of the 'Chemical Revolution'. Patients' Voices on the Introduction of Neuroleptics in the 1950s. AB - The so-called chemical revolution has produced a vast historiographical corpus. Yet the patient's voice remains surprisingly absent from these stories. Based on the archives of the Institut de Psychiatrie (Brussels), this paper traces the introduction of Largactil as recounted in patient letters, physician records and nurse notes. The paper thus contributes to the history of therapies from below, but also participates in the historiographical debate about whether the introduction of neuroleptics can indeed be considered a revolution. PMID- 26651189 TI - Constructing Patient Stories: 'Dynamic' Case Notes and Clinical Encounters at Glasgow's Gartnavel Mental Hospital, 1921-32. AB - This article contextualises the production of patient records at Glasgow's Gartnavel Mental Hospital between 1921 and 1932. Following his appointment as asylum superintendent in 1921, psychiatrist David Kennedy Henderson sought to introduce a so-called dynamic approach to mental health care. He did so, primarily, by encouraging patients to reveal their inner lives through their own language and own understanding of their illness. To this effect, Henderson implemented several techniques devised to gather as much information as possible about patients. He notably established routine 'staff meetings' in which a psychiatrist directed questions towards a patient while a stenographer recorded word-for-word the conversation that passed between the two parties. As a result, the records compiled at Gartnavel under Henderson's guidance offer a unique window into the various strategies deployed by patients, but also allow physicians and hospital staff to negotiate their place amidst these clinical encounters. In this paper, I analyse the production of patient narratives in these materials. The article begins with Henderson's articulation of his 'dynamic' psychotherapeutic method, before proceeding to an in-depth hermeneutic investigation into samples of Gartnavel's case notes and staff meeting transcripts. In the process, patient-psychiatrist relationships are revealed to be mutually dependent and interrelated subjects of historical enquiry rather than as distinct entities. This study highlights the multi-vocal nature of the construction of stories 'from below' and interrogates their subsequent appropriation by historians. PMID- 26651190 TI - The Moral Career of 'Outmates': Towards a History of Manufactured Mental Disorders in Post-Socialist China. AB - This study focuses on 'manufactured mentally ill' (bei jingshenbing, [symbol in text]) individuals in post-socialist China. In Chinese society, bei jingshenbing is a neologistic catchphrase that refers to someone who has been misidentified as exhibiting symptoms of mental illness and has been admitted to a mental hospital. Specifically, it refers to those individuals who were subjected to unnecessary psychiatric treatment during the first decade of the twenty-first century. Based on archival analysis and ethnographic fieldwork, this study addresses the ways in which the voices of bei jingshenbing victims and those who support them reveal China's experiences with psychiatric modernity. It also discusses the active role of these individuals in knowledge production, medical policymaking, and the implications for reforming the psychiatric and mental health systems in post socialist China. PMID- 26651203 TI - Why Creating a Digital Library for the History of Medicine is Harder than You'd Think! PMID- 26651204 TI - Look Out for 'La Grippe': Using Digital Humanities Tools to Interpret Information Dissemination during the Russian Flu, 1889-90. PMID- 26651207 TI - The authors respond. PMID- 26651208 TI - Clinical experience with systemic cyclosporine A treatment in severe childhood psoriasis. AB - BACKGROUND: Severe forms of psoriasis including erythrodermic or pustular psoriasis, which require a more aggressive therapeutic approach such as phototherapy or systemic therapies, are rarely seen. Systemic toxicity and long term safety of these agents are serious concerns in children. OBJECTIVE: We report our experience on the efficacy and safety of cyclosporine A treatment in 22 patients of childhood psoriasis. METHODS: We retrospectively analyzed the records of all patients less than 18 years of age treated with systemic cyclosporine A therapy at our clinic between January 2000 and March 2009. Demographic features as well as other relevant data including previous therapies, the dosage and duration of cyclosporine A therapy, response to treatment and side effects were retrieved from the patients' records. RESULTS: A total of 22 children were treated with systemic cyclosporine A therapy. Seventeen patients were found to be excellent responders. The mean therapeutic dosage of cyclosporine A was 3.47 +/- 0.62 mg/kg/day. The mean duration of cyclosporine A therapy was 5.68 +/- 3.29 months. The median time to total clearance of the lesions was 4.0 weeks. CONCLUSION: We conclude that cyclosporine A therapy is equally effective and safe in pediatric psoriasis patients as in adults. PMID- 26651209 TI - Effects of Lactobacillus plantarum NCU116 on Intestine Mucosal Immunity in Immunosuppressed Mice. AB - The effects of Lactobacillus plantarum (L. plantarum) NCU116 isolated from pickled vegetables on intestine mucosal immunity in cyclophosphamide treated mice were investigated. Animals were divided into six groups: normal group (NIM), immunosuppression group (IM), immunosuppression plus L. plantarum NCU116 groups with three different doses (NCU-H, NCU-M, and NCU-L), and plus Bifidobacterium BB12 as positive control group (BB12). Results showed that the thymus indexes of the four treatment groups were significantly higher than that of the IM group (2.02 +/- 0.16) (p < 0.05) and close to the index of the NIM group (2.61 +/- 0.37) at 10 days. The level of immune factor IL-2 notably increased (IM, 121 +/- 9.0) (p < 0.05) and was close to 65% of NIM group's level (230 +/- 10.7). The levels of other immune factors (IFN-gamma, IL-10, IL-12p70, and sIgA), the gene expression levels of IL-2 and IFN-gamma, and the number of IgA-secreting cells showed similar patterns (p < 0.05). However, the level of immune factor IL-4 remarkably decreased (IM, 128 +/- 10.2) (p < 0.05) and was only approximately 50% of the NIM group (154 +/- 18.2). The levels of other immune factors (IL-6 and IgE) and the gene expression level of IL-6 at 10 days exhibited similar changes (p < 0.05) but showed a slight recovery at 20 days, accompanied by the altered protein expression levels of T-bet and GATA-3 in the small intestine. These findings suggest that L. plantarum NCU116 enhanced the immunity of the small intestine in the immunosuppressed mice. PMID- 26651210 TI - Challenges of using progress monitoring measures: Insights from practicing clinicians. AB - Although integrating progress monitoring (PM) measures into psychotherapy practice can provide numerous benefits, including improved client outcomes, relatively few clinicians use these measures (e.g., Ionita & Fitzpatrick, 2014). To better understand the reasons for clinicians' reluctance, consensual qualitative research methodology was used to examine the challenges faced by clinicians currently using PM measures. Open-ended, semistructured interviews, with 25 clinicians who chose to use PM measures, revealed that clinicians tended to face challenges involving technical concerns, negative responses from others, and personal barriers such as anxiety. The majority of participants discussed ways to overcome the challenges they experienced, including ensuring the fit of the PM measure, explaining measures to others to help engender a positive response, adapting their own perspective, and increasing their own and others' knowledge of the measures. Implications for practicing psychologists and for knowledge translation efforts are discussed. PMID- 26651211 TI - Authenticity in relationships: Predicting caregiving and attachment in adult romantic relationships. AB - The primary purpose of this research was to examine associations between authenticity in relationships and romantic attachment and caregiving. Authenticity is approached as a relational phenomenon that is facilitated when individuals assume that truthful and open communication with one's partner will be reciprocally valued despite prospective risks. Items from the Authenticity in Relationship Scale (AIRS; Lopez & Rice, 2006) were translated to Portuguese, back translated by a bilingual expert, and then reviewed by other researchers. Four hundred Portuguese participants (23-71 years old) in long-term intimate relationships completed the Portuguese version of the scale (AIRS-P) as well as the Romantic Attachment Questionnaire (Matos, Cabral, & Costa, 2008) and the Caregiving Questionnaire (Torres & Oliveira, 2010). A few items from the original AIRS loaded poorly in the Portuguese sample. However, confirmatory factor analysis of the AIRS-P established the presence of the 2 original underlying factors: unacceptability of deception and intimate risk taking. Structural equation modeling results indicated that authenticity in relationships is linked in expected ways to romantic attachment and caregiving to a partner. The correlates found in this Portuguese sample are similar to those found in previous research with American samples, suggesting cross-cultural consistency in the nature of authenticity. (PsycINFO Database Record PMID- 26651212 TI - Corrective relational experiences in psychodynamic-interpersonal psychotherapy: Antecedents, types, and consequences. AB - In posttherapy interviews with 31 clients who had recently terminated from individual open-ended psychodynamic-interpersonal psychotherapy, 18 reported having had at least 1 corrective relational experience (CRE) during psychotherapy, whereas 13 did not report any CREs. CREs typically occurred in the context of therapeutic relationships that were primarily positive but also had minor difficulties. Therapists typically facilitated CREs by identifying or questioning client behavior patterns and conveying trustworthiness. Corrective shifts for clients typically involved a new understanding of the therapy experience and variantly involved gaining a new understanding of behavior patterns. Consequences generally included improvements in the therapy relationship and intrapersonal well-being. Qualitatively, the 13 non-CRE clients more frequently reported wishing the therapist's theoretical orientation was a better match than did the 18 CRE clients. Quantitatively, the CRE clients rated themselves as having more interpersonal problems at intake on the Inventory of Interpersonal Problems-32 (Barkham, Hardy, & Startup, 1996), had marginally significant improvements in interpersonal functioning over time, rated their therapy alliances higher on the Working Alliance Inventory-Short Revised (Hatcher & Gillaspy, 2006) midtherapy, and rated their therapy alliances higher over time compared with the non-CRE clients. Implications for practice and research are discussed. PMID- 26651213 TI - Moving away from a cultural deficit to a holistic perspective: Traditional gender role values, academic attitudes, and educational goals for Mexican descent adolescents. AB - Latina/o youth lag behind Asian American and non-Latina/o White youth in many academic areas. Previous research has taken a deficit approach to understand the factors that affect academic outcomes for Latina/o youth often neglecting to highlight both the potential positive and negative contributions of gender role values. The present study took a holistic perspective to understand the affect of traditional Latina/o gender role values (i.e., marianismo, machismo, and caballerismo) on the academic attitudes and educational goals of Mexican descent youth. Structural equation models were tested to examine the associations of "positive" and "negative" gender role values on educational goals using 524 Mexican descent adolescents from a mid-sized city in southern Texas. We hypothesized that positive aspects of traditional Latina/o gender role values (i.e., "positive marianismo" and caballerismo) would be associated with more positive attitudes toward academics and higher educational goals. We further expected negative gender role values (i.e., "negative marianismo" and machismo) to have the opposite effect. Additionally, based on the theory of planned behavior and gender schema theory, academic attitudes were hypothesized to mediate the relation between gender role values and educational goals. An alternative model was tested in which educational goals mediated the relation between gender roles and academic attitudes. Results indicated that both models fit the data well, and recommendations are made for future longitudinal research aimed at disentangling the directionality of the relations in the model. Implications for research and practice are discussed. PMID- 26651214 TI - Design of a microfluidic strategy for trapping and screening single cells. AB - Traditionally, in vitro investigations on biology and physiology of cells rely on averaging the responses eliciting from heterogeneous cell populations, thus being unsuitable for assessing individual cell behaviors in response to external stimulations. In the last years, great interest has thus been focused on single cell analysis and screening, which represents a promising tool aiming at pursuing the direct and deterministic control over cause-effect relationships guiding cell behavior. In this regard, a high-throughput microfluidic platform for trapping and culturing adherent single cells was presented. A single cell trapping mechanism was implemented based on dynamic variation of fluidic resistances. A round-shaped culture chamber (Phi = 250 um, h = 25 um) was conceived presenting two connections with a main fluidic path: (i) an upper wide opening, and (ii) a bottom trapping junction which modulates the hydraulic resistance. Starting from eight different layouts, the chamber geometry was computationally optimized for maximizing the single cell trapping efficacy and then integrated in a polydimethylsiloxane (PDMS) microfluidic device. The final platform consists in (i) 288 chambers for trapping single cells organized in six culture units, independently addressable through the lines of (ii) a chaotic-mixer based serial dilution generator (SDG), designed for creating spatio-temporally controlled patterns of both soluble factors and non-diffusive particles. The device was experimentally validated by trapping polystyrene microspheres, featuring diameters comparable to cell size (Phi = 10 um). PMID- 26651215 TI - Microfluidic interactions between red blood cells and drug carriers by image analysis techniques. AB - Blood is a complex biological fluid composed of deformable cells and platelets suspended in plasma, a protein-rich liquid. The peculiar nature of blood needs to be considered when designing a drug delivery strategy based on systemically administered carriers. Here, we report on an in vitro fluid dynamic investigation of the influence of the microcapillary flow of red blood cells (RBCs) on micron sized carriers by high-speed imaging methods. The experiments were carried out in a 50 um diameter glass capillary that mimicked the hydrodynamic conditions of human microcirculation. Spherical MU-particles (MU-Ps), with sizes ranging between 0.5 and 3 um, were tested. Images of the flowing RBCs and MU-Ps were acquired by a high- speed/high-magnification microscopy. The transport and distribution of rigid particles in a suspension of RBCs under shear flow were investigated by analyzing: (i) the velocity profile of both MU-Ps and RBCs in the capillary; (ii) the radial distribution of MU-Ps in the presence of RBCs; (iii) the migration of MU-Ps towards the vessel wall due to their hydrodynamic interactions with RBCs. This study suggests that the therapeutic efficacy of MU Ps could be ultimately affected by their interactions with the flowing RBCs in the vasculature. PMID- 26651216 TI - Small Buccal Fat Pad Cells Have High Osteogenic Differentiation Potential. AB - Dedifferentiated fat (DFAT) cells derived from mature adipocytes have mesenchymal stem cells' (MSCs) characteristics. Generally, mature adipocytes are 60-110 MUm in diameter; however, association between adipocyte size and dedifferentiation efficiency is still unknown. This study, therefore, investigated the dedifferentiation efficiency of adipocytes based on cell diameter. Buccal fat pad was harvested from five human donors and dissociated by collagenase digestion. After exclusion of unwanted stromal cells by centrifugation, floating adipocytes were collected and their size distribution was analyzed. The floating adipocytes were then separated into two groups depending on cell size using 40- and 100-MUm nylon mesh filters: cell diameters less than 40 MUm (small adipocytes: S adipocytes) and cell diameters of 40-100 MUm (large adipocytes: L-adipocytes). Finally, we evaluated the efficiency of adipocyte dedifferentiation and then characterized the resultant DFAT cells. The S-adipocytes showed a higher capacity to dedifferentiate into DFAT cells (S-DFAT cells) compared to the L-adipocytes (L DFAT cells). The S-DFAT cells also showed a relatively higher proportion of CD146 positive cells than L-DFAT cells, and exhibited more osteogenic differentiation ability based on the alkaline phosphatase activity and amount of calcium deposition. These results suggested that the S- and L-DFAT cells had distinct characteristics, and that the higher dedifferentiation potential of S-adipocytes compared to L-adipocytes gives the former group an advantage in yielding DFAT cells. PMID- 26651217 TI - Benchmarking Calculations of Excitonic Couplings between Bacteriochlorophylls. AB - Excitonic couplings between (bacterio)chlorophyll molecules are necessary for simulating energy transport in photosynthetic complexes. Many techniques for calculating the couplings are in use, from the simple (but inaccurate) point dipole approximation to fully quantum-chemical methods. We compared several approximations to determine their range of applicability, noting that the propagation of experimental uncertainties poses a fundamental limit on the achievable accuracy. In particular, the uncertainty in crystallographic coordinates yields an uncertainty of about 20% in the calculated couplings. Because quantum-chemical corrections are smaller than 20% in most biologically relevant cases, their considerable computational cost is rarely justified. We therefore recommend the electrostatic TrEsp method across the entire range of molecular separations and orientations because its cost is minimal and it generally agrees with quantum-chemical calculations to better than the geometric uncertainty. Understanding these uncertainties can guard against striving for unrealistic precision; at the same time, detailed benchmarks can allow important qualitative questions-which do not depend on the precise values of the simulation parameters-to be addressed with greater confidence about the conclusions. PMID- 26651218 TI - Facet-Controlling Agents Free Synthesis of Hematite Crystals with High-Index Planes: Excellent Photodegradation Performance and Mechanism Insight. AB - Hematite (alpha-Fe2O3) crystals with uniform size and structure are synthesized through very facile one-pot hydrothermal methods without any additive. The as synthesized sub-micrometer-sized alpha-Fe2O3 crystals with small surface areas perform superb visible light photodegradation activities, even much better than most other alpha-Fe2O3 nanostructures with large surface areas. Profound mechanism analyses reveal that the microwave-assisted hydrothermal (Mic-H) synthesized alpha-Fe2O3 is enclosed by 12 high-index {2-15} facets. The structure and the low unoccupied molecular orbital (LUMO) of the high-index planes result in the excellent photocatalytic activity. This is the first report on the formation of {2-15} plane group of hematite, and the synthesis of the hematite particles with the {2-15} planes is very simple and no any facet-controlling agent is used. This study may pave the way to further performance enhancement and practical applications of the cheap hematite materials. PMID- 26651219 TI - UV-Induced Charge Transfer States in DNA Promote Sequence Selective Self-Repair. AB - Absorption of UV-radiation in nucleotides initiates a number of photophysical and photochemical processes, which may finally cause DNA damage. One major decay channel of photoexcited DNA leads to reactive charge transfer states. This study shows that these states trigger self-repair of DNA photolesions. The experiments were performed by UV spectroscopy and HPLC on different single and double stranded oligonucleotides containing a cyclobutane pyrimidine dimer (CPD) lesion. In a first experiment we show that photoexcitation of adenine adjacent to a CPD has no influence on this lesion. However, excitation of a guanine (G) adenine (A) sequence leads to reformation of the intact thymine (T) bases. The involvement of two bases for the repair points to a long-living charge transfer state between G and A to be responsible for the repair. The negatively charged A radical anion donates an electron to the CPD, inducing ring splitting and repair. In contrast, a TA sequence, having an inverted charge distribution (T radical anion, A radical cation), is not able to repair the CPD lesion. The investigations show that the presence of an adjacent radical ion is not sufficient for repair. More likely it is the driving power represented by the oxidation potential of the radical ion, which controls the repair. Thus, repair capacities are strongly sequence dependent, creating DNA regions with different tendencies of self-repair. This self-healing activity represents the simplest sequence-dependent DNA repair system. PMID- 26651220 TI - A New Covalent Inhibitor of Class C beta-Lactamases Reveals Extended Active Site Specificity. AB - O-Aryloxycarbonyl hydroxamates have previously been shown to efficiently inactivate class C beta-lactamases by cross-linking serine and lysine residues in the active site. A new analogue of these inhibitors, D-(R)-O-(phenoxycarbonyl)-N [(4-amino-4-carboxy-1-butyl)oxycarbonyl]hydroxylamine, designed to inactivate certain low-molecular mass dd-peptidases, has now been synthesized. Although the new molecule was found to be only a poor inactivator of the latter enzymes, it proved, unexpectedly, to be a very effective inactivator (ki = 3.5 * 10(4) M(-1) s(-1)) of class C beta-lactamases, more so than the original lead compound, O phenoxycarbonyl-N-(benzyloxycarbonyl)hydroxylamine. Furthermore, the mechanism of inactivation is different. Mass spectrometry demonstrated that beta-lactamase inactivation by the new molecule involved formation of an O alkoxycarbonylhydroxamate with the nucleophilic active site serine residue. This acyl-enzyme did not cyclize to cross-link the active site as did that from the lead compound. Model building suggested that the rapid enzyme acylation by the new molecule may occur because of favorable interaction between the polar terminus of its side chain and elements of the Omega loop that abuts the active site, Arg 204 in particular. This interaction should be considered in the design of new covalent beta-lactamase inhibitors. The initially formed acyl-enzyme partitions (ratio of ~ 1) between hydrolysis, which regenerates the active enzyme, and formation of an inert second acyl-enzyme. Structural modeling suggests that the latter intermediate arises from conformational movement of the acyl group away from the reaction center, probably enforced by the inflexibility of the acyl group. The new molecule is thus a mechanism-based inhibitor in which an inert complex is formed by noncovalent rearrangement. Phosphyl analogues of the new molecule were efficient inactivators of neither dd-peptidases nor beta lactamases. PMID- 26651221 TI - Phomanolides A and B from the Fungus Phoma sp.: Meroterpenoids Derived from a Putative Tropolonic Sesquiterpene via Hetero-Diels-Alder Reactions. AB - Phomanolides A (1) and B (2), unique meroterpenoids with new pentacyclic and tetracyclic skeletons, respectively, and phomanoxide (3), the double-epoxidation product of a putative biosynthetic precursor of 1 and 2, were isolated from the solid substrate fermentation cultures of the fungus Phoma sp., along with the known compound eupenifeldin (4). The structures of 1-3 were elucidated based on NMR spectroscopic data and electronic circular dichroism calculations and further secured by X-ray crystallography. Biogenetically, compounds 1 and 2 could be derived from a hypothetical monotropolonic sesquiterpene intermediate via hetero Diels-Alder reactions. Compound 4 showed potent antiproliferative effects against three human glioma cell lines, with IC50 values of 0.08-0.13 MUM. PMID- 26651222 TI - Infecting Pacific Herring with Ichthyophonus sp. in the Laboratory. AB - The protistan parasite Ichthyophonus sp. occurs in coastal populations of Pacific Herring Clupea pallasii throughout the northeast Pacific region, but the route(s) by which these planktivorous fish become infected is unknown. Several methods for establishing Ichthyophonus infections in laboratory challenges were examined. Infections were most effectively established after intraperitoneal (IP) injections with suspended parasite isolates from culture or after repeated feedings with infected fish tissues. Among groups that were offered the infected tissues, infection prevalence was greater after multiple feedings (65%) than after a single feeding (5%). Additionally, among groups that were exposed to parasite suspensions prepared from culture isolates, infection prevalence was greater after exposure by IP injection (74%) than after exposure via gastric intubation (12%); the flushing of parasite suspensions over the gills did not lead to infections in any of the experimental fish. Although the consumption of infected fish tissues is unlikely to be the primary route of Ichthyophonus sp. transmission in wild populations of Pacific Herring, this route may contribute to abnormally high infection prevalence in areas where juveniles have access to infected offal. PMID- 26651223 TI - Testicular germ cell tumours. AB - Testicular germ cell tumours are at the crossroads of developmental and neoplastic processes. Their cause has not been fully elucidated but differences in incidences suggest that a combination of genetic and environment factors are involved, with environmental factors predominating early in life. Substantial progress has been made in understanding genetic susceptibility in the past 5 years on the basis of the results of large genome-wide association studies. Testicular germ cell tumours are highly sensitive to radiotherapy and chemotherapy and hence have among the best outcomes of all tumours. Because the tumours occur mainly in young men, preservation of reproductive function, quality of life after treatment, and late effects are crucial concerns. In this Seminar, we provide an overview of advances in the understanding of the epidemiology, genetics, and biology of testicular germ cell tumours. We also summarise the consensus on how to treat testicular germ cell tumours and focus on a few controversies and improvements in the understanding of late effects of treatment and quality of life for survivors. PMID- 26651224 TI - Interpregnancy weight gain--a modifiable cause of stillbirth? PMID- 26651225 TI - Weight change between successive pregnancies and risks of stillbirth and infant mortality: a nationwide cohort study. AB - BACKGROUND: Maternal overweight and obesity are risk factors for stillbirth and infant mortality. Whether temporal changes in maternal weight affect these risks is not clear. We aimed to assess whether change of BMI between first and second pregnancies affects risks of stillbirth and infant mortality in the second-born offspring. METHODS: In a Swedish population-based cohort of women who gave birth to their first and second child between Jan 1, 1992, and Dec 31, 2012, we investigated associations between change in maternal body-mass index (BMI) during early pregnancy from first to second pregnancies and risks of stillbirth and neonatal, postneonatal, and infant mortality after the second pregnancy. Relative risks (RRs) for each outcome according to BMI change categories were calculated with binomial regression. FINDINGS: Complete information was available for 456,711 (77.7%) of 587,710 women who had their first and second single births in the study period. Compared with women with a stable BMI (change between -1 kg/m(2) and <1 kg/m(2)) between pregnancies, the adjusted RRs for women who gained at least 4 BMI units between pregnancies were 1.55 (95% CI 1.23-1.96) for stillbirth and 1.29 (1.00-1.67) for infant mortality. Stillbirth risks increased linearly with increased BMI gain. Risks of infant mortality in second pregnancy only increased with BMI gain in women with healthy BMI (<25 kg/m(2)) during first pregnancy; the adjusted RR for healthy weight women who gained 2 to less than 4 BMI units was 1.27 (1.01-1.59) and for those who gained 4 BMI units or more the adjusted RR was 1.60 (1.16-2.22). In overweight women (BMI >=25 kg/m(2)), weight loss before pregnancy reduced risk of neonatal mortality. INTERPRETATION: Our findings emphasise the need to prevent weight gain before pregnancy in healthy and overweight women and that weight loss should be promoted in overweight women. FUNDING: Swedish Research Council for Health, Working Life and Welfare, and Karolinska Institutet. PMID- 26651226 TI - Single-stage immediate breast reconstruction with acellular dermal matrix: Experience gained and lessons learnt from patient reported outcome measures. AB - INTRODUCTION: Acellular Dermal Matrix (ADM) assisted breast reconstruction has transformed the single-stage Immediate Breast Reconstruction (IBR) with an impact on the cosmetic outcomes. However, there is limited data available on patient reported outcomes. This study highlights the Patient Reported Outcome Measures (PROMs), post-operative complications and lessons learnt from ADM assisted single stage immediate breast reconstruction. METHODS: This prospective study enrolled consecutive patients from Feb 2012 - May 2015 undergoing mastectomy with direct to-implant ADM assisted breast reconstruction, using StratticeTM (Acelity, San Antonio, TX, USA). Patients were recruited from the beginning of our unit's use of ADMs and completed a post-operative questionnaire at 6 weeks, covering pre operative, operative and post-operative outcomes. Information on tumour biology and post-operative complications was obtained from the medical notes. RESULTS: This study included 49 patients undergoing a total of 53 procedures. Following surgery 93.3% of women reported a high level of body confidence when clothed. 6.7% of patients reported severe post-operative pain during the first week. Mean length of hospital stay was 1.7 days, return to light activities was within 2.5 weeks and normal activities in 5.4 weeks. Implant loss at 3 months occurred in 5.7% of procedures, of which two thirds were smokers. CONCLUSIONS: PROMs for StratticeTM ADM based reconstruction show high levels of satisfaction with cosmetic outcomes, low incidences of severe post-operative pain and a short recovery process. PROMs help us to better describe patients' experience, allowing women to make more informed choices about ADM based breast reconstruction, which reassures and helps to achieve better outcomes. PMID- 26651227 TI - Inhibition of Salmonella-induced apoptosis as a marker of the protective efficacy of virulence gene-deleted live attenuated vaccine. AB - Vaccination is one of the best protection strategies against Salmonella infection in humans and chickens. Salmonella bacteria must induce apoptosis prior to initiating infection, pathogenesis and evasion of host immune responses. In this study, we evaluated the efficacy of vaccinating chickens against Salmonella Enteritidis (SE) using a vaccine candidate strain (JOL919), constructed by deleting the lon and cpxR genes from a wild-type SE using an allelic exchange method. In present study day old chickens were inoculated with 1*10(7)cfu (colony forming unit) of JOL919 per os. We measured cell-mediated immunity, protective efficacy and extent of apoptosis induction in splenocytes. Seven days post immunization, the number of CD3+CD4+ and CD3+ CD8+ T cells was significantly higher in the immunized group compared to the control group, indicating a significant augmentation of systemic immune response. The internal organs of chickens immunized with JOL919 had a significantly lower challenge-strain recovery, indicating effective protection and clearance of the challenge strain. Post-challenge, the number of apoptotic cells in the immunized group was significantly lower than in the control group. Additionally, AV/PI (Annexin V/propidium iodide) staining was performed to differentiate between apoptotic cells and necrotic cells, which corroborated TUNEL-assay (terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick end labeling) results. The proportions of AV+/PI- and AV+/PI+ cells, which represent the proportions of early apoptotic and late apoptotic/early necrotic cells present, respectively, were significantly lower in the immunized group. Our findings suggest that the apoptotic splenocytes in immunized chickens significantly decreased in number, which occurred concomitantly with a significant rise in systemic immune response and bacterial clearance. This suggests that inhibition of apoptosis may be a marker of protection efficacy in immunized chickens. PMID- 26651228 TI - Brachycephalic trunk aneurysm found before percutaneous tracheotomy. PMID- 26651229 TI - Hybrid, Gate-Tunable, van der Waals p-n Heterojunctions from Pentacene and MoS2. AB - The recent emergence of a wide variety of two-dimensional (2D) materials has created new opportunities for device concepts and applications. In particular, the availability of semiconducting transition metal dichalcogenides, in addition to semimetallic graphene and insulating boron nitride, has enabled the fabrication of "all 2D" van der Waals heterostructure devices. Furthermore, the concept of van der Waals heterostructures has the potential to be significantly broadened beyond layered solids. For example, molecular and polymeric organic solids, whose surface atoms possess saturated bonds, are also known to interact via van der Waals forces and thus offer an alternative for scalable integration with 2D materials. Here, we demonstrate the integration of an organic small molecule p-type semiconductor, pentacene, with a 2D n-type semiconductor, MoS2. The resulting p-n heterojunction is gate-tunable and shows asymmetric control over the antiambipolar transfer characteristic. In addition, the pentacene/MoS2 heterojunction exhibits a photovoltaic effect attributable to type II band alignment, which suggests that MoS2 can function as an acceptor in hybrid solar cells. PMID- 26651230 TI - Interventions aimed at improving the ability to use everyday technology in work after brain injury. AB - OBJECTIVE: The aim of this study was to explore and describe how client-centred occupational therapy interventions may support and improve the ability to use everyday technology (ET) in work tasks in people with acquired brain injury (ABI). METHOD: A qualitative, descriptive multiple-case study was designed, and occupation-based interventions were provided to three working-age participants with ABI. Multiple sources were used to collect data throughout the three intervention processes, including assessments, field notes, and interviews. The Canadian Occupational Performance Measure and the Management of Everyday Technology Assessment were administered before the interventions, after the interventions and at a follow-up session 2-3 months subsequent to the interventions. RESULTS: The three intervention processes initially consisted of similar actions, but subsequently the actions took on a different focus and intensity for each case. All of the goals in each of the three case processes were achieved, and both perceived and observed abilities to use ET in work tasks improved. CONCLUSIONS: Client-centred occupational therapy interventions might have the potential to improve the ability to use ET in work tasks in people with ABI. PMID- 26651231 TI - The Supportive Care Needs of Parents With a Child With a Rare Disease: A Qualitative Descriptive Study. AB - There are few studies that exist which focus specifically on parents with a child with a rare disease. The purpose of this study was to better understand the lived experiences and supportive care needs (SCN) of parents caring for a child across a spectrum of rare diseases. A qualitative descriptive approach was used to guide the research, and four semi-structured focus group interviews were conducted with 23 parents (17 mothers and 6 fathers). Participants described 'feeling boxed-in outside the box' due to a number of limitations unique to their child's disease, daily practical challenges in providing care and the various relational impacts of caring for a child with a rare disease were discussed. The results from this study help to give clearer direction for health professionals on where to focus future efforts in better meeting the supportive care needs of parents and their child with a rare disease. PMID- 26651232 TI - Developmental Origins of Health and Disease: A Challenge for Nurses. AB - Prevention of disease is a cornerstone of nursing care. Through our endeavors in research, teaching, and clinical care, nurses consistently seek to change the trajectory of disease development. The theoretical framework known as the Developmental Origins of Health and Disease (DOHaD) offers a new lens that shifts the current disease prevention paradigm upstream, encouraging intensified care of pregnant girls/women, neonates, and infants. This new focus parallels other emerging ecobiodevelopmental, life-course theories, which identify the long-term impact of early environments and stressors on the later risk of chronic adult diseases. Nurses have the potential to influence the health of multiple generations by incorporating DOHaD perspectives and interventions into their research and patient care. PMID- 26651233 TI - The unmet support needs of family members caring for a suicidal person. AB - BACKGROUND: The prevention of suicide is a key aim for health care authorities and society in general and family members have a principal role in caring for suicidal people. However, the support needs of these essential family carers are relatively unknown. AIM: To explore the support needs of family members of suicidal people. METHOD: Eighteen participants were interviewed using a short topic guide. Transcripts were analysed using thematic analysis and confirmed by discussion. FINDINGS: Family members of suicidal people have unmet needs (this was the main theme). Four sub-themes emerged: having practical support, respite and advice; feeling acknowledged and included; having someone to turn-to; and consistency of support. CONCLUSIONS: Family members are perceived to have an important role in suicide prevention; however some carers experience a lack of support which impinges on their ability to undertake this role. Family members need be included in care and require support from healthcare staff. PMID- 26651234 TI - Re: The Use of Resectoscope Combined with Ureteroscope for the Treatment of Bladder stones. (From: Jia Q, Wang K, Jin T, et al. J Endourol 2015;29:455-458). PMID- 26651235 TI - Enhanced Mass Defect Filtering To Simplify and Classify Complex Mixtures of Lignin Degradation Products. AB - High resolution mass spectrometry was utilized to study the highly complex product mixtures resulting from electrochemical breakdown of lignin. As most of the chemical structures of the degradation products were unknown, enhanced mass defect filtering techniques were implemented to simplify the characterization of the mixtures. It was shown that the implemented ionization techniques had a major impact on the range of detectable breakdown products, with atmospheric pressure photoionization in negative ionization mode providing the widest coverage in our experiments. Different modified Kendrick mass plots were used as a basis for mass defect filtering, where Kendrick mass defect and the mass defect of the lignin specific guaiacol (C7H7O2) monomeric unit were utilized, readily allowing class assignments independent of the oligomeric state of the product. The enhanced mass defect filtering strategy therefore provided rapid characterization of the sample composition. In addition, the structural similarities between the compounds within a degradation sequence were determined by comparison to a tentatively identified product of this compound series. In general, our analyses revealed that primarily breakdown products with low oxygen content were formed under electrochemical conditions using protic ionic liquids as solvent for lignin. PMID- 26651237 TI - Clostridium difficile Infection in Texas Hospitals, 2007-2011. PMID- 26651236 TI - Lipid-based nanoformulations of trifluralin analogs in the management of Leishmania infantum infections. AB - AIM: To improve the potential of trifluralin (TFL) in the management of Leishmania infantum infections through the synthesis of analogs (TFLA) and incorporation in nanoparticulate drug delivery systems (NanoDDS), liposomes and solid lipid nanoparticles, for selective targeting to leishmania infection sites. MATERIAL & METHODS: In vitro screening of 18 TFLA was performed by flow cytometry. NanoDDS were loaded with active TFLA and evaluated for antileishmanial efficacy in mice through determination of parasite burden in liver and spleen. RESULTS: The in vitro testing revealed the most active and nontoxic TFLAs, which were selected for the in vivo studies based on high incorporation in liposomes and lipid nanoparticles (>90%). Selected TFLA nanoformulations showed superior antileishmanial activity in mice (parasite burden >80%), over free TFLA and Glucantime. CONCLUSION: The modification of TFL structure to obtain active TFLA, together with their incorporation in NanoDDS, improved their in vivo performance against L. infantum infection. PMID- 26651238 TI - Points for Consideration for dengue vaccine introduction - recommendations by the Dengue Vaccine Initiative. AB - Dengue is a public health problem in the tropics and subtropics. There are several vaccine candidates in clinical development. However, there may be gaps in the new vaccine introduction after vaccine licensure before it becomes available in developing countries. In anticipation of the first dengue vaccine candidate to be licensed, Dengue Vaccine Initiative (DVI) and, its predecessor, Pediatric Dengue Vaccine Initiative (PDVI) have been working on points for consideration to accelerate evidence-based dengue vaccine introduction, once a vaccine becomes available. In this paper, we review the history of PDVI and its successor, the DVI, and elaborate on the points of consideration for dengue vaccine introduction. PMID- 26651239 TI - Darwin and Mendel today: a comment on "Limits of imagination: the 150th Anniversary of Mendel's Laws, and why Mendel failed to see the importance of his discovery for Darwin's theory of evolution". AB - We comment on a recent paper by Rama Singh, who concludes that Mendel deserved to be called the father of genetics, and Darwin would not have understood the significance of Mendel's paper had he read it. We argue that Darwin should have been regarded as the father of genetics not only because he was the first to formulate a unifying theory of heredity, variation, and development -- Pangenesis, but also because he clearly described almost all genetical phenomena of fundamental importance, including what he called "prepotency" and what we now call "dominance" or "Mendelian inheritance". The word "gene" evolved from Darwin's imagined "gemmules", instead of Mendel's so-called "factors". PMID- 26651240 TI - Start hard, finish better: further evidence for the reversal of the RAE advantage. AB - The relative age effect (RAE) has been highlighted extensively within literature as influencing selection and identification within sports. However, this initial bias appears to not be systemic in some talent development systems. Accordingly, we report an investigation into the initial identification, selection and conversion of academy players from professional Rugby Union and Cricket at national level. Reflecting previous studies, data again demonstrated a reversal of RAE advantage whereby relatively young players from both sports were less likely to be selected into their respective national academy systems but were more likely to transition into senior national squads. On the basis of our observations, we further propose a psychological explanation for the mechanism of such a reversal, based on the influence of additional challenge experienced throughout the development journey. As such, we also highlight the need for further qualitative investigation to explore this phenomenon in greater depth. PMID- 26651241 TI - In vitro probiotic profiling of novel Enterococcus faecium and Leuconostoc mesenteroides from Tunisian freshwater fishes. AB - Novel lactic acid bacteria isolated from different organs of freshwater fish were examined for their potential application as probiotics in raw and processed foods. Four isolates of Enterococcus faecium and Leuconostoc mesenteroides were identified at the molecular level by 16S rRNA sequencing and random amplification of polymorphic DNA - polymerase chain reaction, and their antimicrobial activity against a panel of pathogens and food-poisoning bacteria was investigated. The whole bacteriocins of the 4 isolates were characterized by enterobacterial repetitive intergenic consensus sequences in PCR. The isolates exhibited high inhibitory activities against food-borne pathogens and spoilage microbial species and have significant probiotic profiles, since they survived at pH 3.0 and in the presence of bile salts, pancreatin, and pepsin, without any detectable hemolytic activity. Further, moderate heat resistance, adhesion ability to steel surfaces, and sensitivity to clinically relevant antimicrobial agents were revealed for all the isolates. These results highlight the specific probiotic properties of the strains and give evidence for potential application in minimally processed foods subjected to moderate heat processing. PMID- 26651242 TI - Foot model for tracking temperature of safety boot insoles: application to different insole materials in firefighter boots. AB - This research is based on the development of a human foot model to study the temperature conditions of a foot bottom surface under extreme external conditions. This foot model is made by combining different manufacturing techniques to enable the simulation of bones and tissues, allowing the placement of sensors on its surface to track the temperature values of different points inside a shoe. These sensors let researchers capture valuable data during a defined period of time, making it possible to compare the features of different safety boots, socks or soles, among others. In this case, it has been applied to compare different plantar insole materials, placed into safety boots on a high temperature surface. PMID- 26651243 TI - Cell surface heparan sulfate proteoglycans are involved in the binding of Hsp90alpha and Hsp90beta to the cell plasma membrane. AB - Extracellular membrane-bound and secreted heat shock protein 90 (Hsp90) is known to be involved in cell motility and invasion. The mechanism of Hsp90 anchoring to the plasma membrane remains obscure. We showed that treatment of human glioblastoma A-172 and fibrosarcoma HT1080 cells with sodium chlorate, heparinase, and heparin causes a prominent loss of 2 Hsp90 cytosolic isoforms, Hsp90alpha and Hsp90beta, from the cell surface and strongly inhibits the binding of exogenous Hsp90 to cells. We revealed that Hsp90alpha and Hsp90beta are partly colocalized with heparan sulfate proteoglycans (HSPGs) on the cell surface and that this colocalization was sensitive to heparin. The results demonstrate that cell surface HSPGs are involved in the binding/anchoring of Hsp90alpha and Hsp90beta to the plasma membrane. PMID- 26651244 TI - Response to Pickering et al. PMID- 26651245 TI - Turn-taking in Human Communication--Origins and Implications for Language Processing. AB - Most language usage is interactive, involving rapid turn-taking. The turn-taking system has a number of striking properties: turns are short and responses are remarkably rapid, but turns are of varying length and often of very complex construction such that the underlying cognitive processing is highly compressed. Although neglected in cognitive science, the system has deep implications for language processing and acquisition that are only now becoming clear. Appearing earlier in ontogeny than linguistic competence, it is also found across all the major primate clades. This suggests a possible phylogenetic continuity, which may provide key insights into language evolution. PMID- 26651246 TI - Preface. PMID- 26651247 TI - The changing epidemiology of Asian digestive cancers: From etiologies and incidences to preventive strategies. AB - Digestive cancers are a major health burden in Asia. Due to the presence of similar "infection-inflammation-cancer" pathways in the carcinogenesis process, eradicating infective pathogens or attenuating relevant inflammatory signaling pathways may reduce digestive cancer incidences and improve patient outcomes. The aim of this paper is to review the recent evidence regarding the epidemiology of three major digestive cancers in Asia: stomach cancer, liver cancer, and colorectal cancer. We focused on the incidence trends, the major etiologies, and especially the potential preventive strategies. PMID- 26651248 TI - Overview of gastrointestinal cancer prevention in Asia. AB - "War on cancer" was declared through the National Cancer Act by President Richard Nixon in 1971, but cancer statistics from the American Cancer Society and other sources indicated the failure of this war, suggesting instead focus on the message that a "prevention strategy" might be much more effective than cancer treatment. While cancer statistics notoriously showed sharp increases in incidence as well as in mortality concurrent with economic growth in Asia, fortunately Asian countries benefit from plentiful resources of natural compounds, which can prevent cancer. Just like cancer chemotherapeutics targeted to kill cancer cells in Western countries, natural agents activating molecular mechanisms for cancer prevention, reversion of premalignant tumors, and even ablation of cancer stem cells, are very abundant in Asia. Currently, these natural agents are under very active investigations targeting the hallmarks of cancer prevention, including selective induction of apoptosis in cancer cells, suppression of growth factors or their signaling, suppression of cell proliferation and of cancer-promoting angiogenesis, induction of mesenchymal epithelial transition, and disruption of the tumor microenvironment, developing promising cancer preventive agents. However, Asia is the most populous continent in the world and some Asian countries do not have the resources to implement cancer screening programs for early detection or treatment. In addition, despite the excellent cancer preventive screening strategies in some Asian countries, well-designed clinical trials for cancer prevention are somewhat delayed compared to Western countries. In this review article, several phytochemicals/phytoceuticals produced and studied in different Asian countries will be introduced, including Korean red ginseng (pride of Korea), curcumin (Indian spice for life), black or green tea (popular in Japan/Sri Lanka), genistein from tofu (famous Chinese food), diallylsulfide or S-allylcysteine (garlic, popularly consumed as a food ingredient in many Asian countries), capsaicin, 6-gingerol, flavopiridol, and silymarin (abundant in various Asian foods). Whereas in Western countries cancer chemotherapeutics involve strategies not only to block the growth of the primary tumor, but also to inhibit its progression to metastatic disease, the endless pursuit of effective agents for cancer prevention may be a unique and featured strategy in Asia. More active efforts for clinical application of these principles should be supported. PMID- 26651249 TI - Prevention strategies for esophageal cancer: Perspectives of the East vs. West. AB - Esophageal cancer is the eighth most common cancer worldwide. Esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC) are the two major phenotypes in Western and Eastern countries, respectively. Because of different pathways in carcinogenesis, the risk factors and effective steps for prevention of esophageal cancer are different between EAC and ESCC. The carcinogenesis of EAC is initiated by the acid exposure of the esophageal mucosa from stomach while that of the ESCC are related to the chronic irritation of carcinogens mainly by the alcohol, cigarette, betel quid, and hot beverage. To eliminate the burden of esophageal cancer on the global health, the effective strategy should be composed of the primary, secondary, and tertiary prevention. In this article, we perform a systematic review of the preventive strategies for esophageal cancer with special emphasis on the differences from the perspectives of Western and Eastern countries. PMID- 26651250 TI - Early esophageal cancer screening in China. AB - In China, the incidence of esophageal cancer (EC) and its related mortality are high. Screening strategies aiming at early diagnosis can improve the prognosis. Researches on detection of early EC, especially in China are reviewed. Compared to esophageal balloon cytology or routine endoscopy, chromoendoscopy with Lugol's staining and biopsy appears to be the gold standard for early EC diagnosis in China today. Narrow-band imaging endoscopy, Confocal Laser endomicroscopy and other novel diagnostic approaches are more and more widely used in developed urban areas, but cost and lack of essential training to the endoscopists have made their use limited in rural areas. No specific biomarkers or serum markers were strongly commended to be used in screening strategies currently, which need to be evaluated in future. Trials on organized screening have been proposed in some regions of china with high disease prevalence. Screening in these areas has been shown to be cost effective. PMID- 26651251 TI - Screening of gastric cancer in Asia. AB - In North-Eastern Asian countries, where incidence and mortality of gastric cancer remain very high, population-based gastric cancer screenings have been conducted under governmental subsidy in Japan and Korea. Reduction of gastric cancer mortality by the screening was documented in Japan, but the Japanese gastric cancer screening with the X-ray photofluorography is criticized for its high cost and a low uptake rate. Although the Korean program seems to achieve a high-rate of uptake with increasing use of endoscopy, the work load is substantial. In the meantime, more attention in the world turns to primary prevention through eradication of Helicobacter pylori. Indeed, fairly large-scale studies to examine the feasibility of mass-eradication to prevent gastric cancer are underway in China and Taiwan. In the future, gastric cancer screening should incorporate 'screen to treat' of H. pylori infection at younger age followed by endoscopic surveillance for subjects at risk. PMID- 26651252 TI - Hepatitis B vaccination and prevention of hepatocellular carcinoma. AB - Hepatitis B virus (HBV) infection is a global health threat; with 240 million people are chronic carriers of the virus. The infection can cause acute and chronic liver disease including liver cirrhosis and hepatocellular carcinoma (HCC). On the basis of disease burden and the availability of safe and effective vaccines, World Health Organization has recommended that hepatitis B vaccine be incorporated into routine infant and childhood immunization programs for all countries. The efficacy of universal immunization has been proven in many countries, with substantial reductions of the prevalence of HBV carriage in children, adolescents and young adults. Most important, hepatitis B vaccination can protect them from HCC, as has been demonstrated in Taiwan and other countries. Nevertheless, the implementation of worldwide vaccination against HBV indeed requires more effort to overcome the social and economic challenges. To have a global control of HBV infection, we have to continue the universal HBV vaccination, interrupt the possible transmission routes and treat eligible patients with antiviral agents. However, current treatments are still far from ideal as they cannot eradicate intrahepatic HBV cccDNA, and lifelong administration of these agents will pose a major economic burden, especially in the endemic Asia-Pacific region. Thus we need innovative treatment strategies and novel agents with difference modes of action to overcome the unmet medical need for an efficient HBV cure with subsequent global eradication of HBV infection, hopefully by the first half of 21st century. PMID- 26651253 TI - Changing epidemiology of hepatocellular carcinoma in Asia. AB - Hepatocellular carcinoma is a major problem in Asia because of the presence of multiple risk factors in the region such as endemicity of hepatitis B and significant contamination of foodstuff by aflatoxin in some areas. Another risk factor for HCC, chronic hepatitis C infection, in Asia is most significant in Japan, the only Asian country with more HCV than HBV-related hepatocellular carcinoma. As these risk factors can and are being modified by measures such as universal hepatitis B immunisation, successful treatment of HCV infections, reduction and improved surveillance of aflatoxin contamination of foodstuff, it is not surprising that the epidemiology of HCC in Asia is changing. All these are offset by the rising importance of NAFLD and NASH as chronic liver diseases and risk factors for HCC which contributes to the changing epidemiology of HCC in Asia. PMID- 26651254 TI - Effective screening for early diagnosis of pancreatic cancer. AB - Diagnosis of pancreatic cancer (PC) at an early stage with curative surgery should improve long-term patient outcome. At present, improving survival should lie in identifying those cases with high-risk factors or precursor lesions through an effective screening including ultrasonography, some biological markers, or national familial pancreatic cancer registration. Recently, cases with PC < 10 mm with a favorable prognosis have been reported. For the diagnoses of cases with PC < 10 mm, the rate of tumor detection was higher on endoscopic ultrasonography (EUS) than on CT or other modalities, and EUS-guided fine needle aspiration was helpful in confirming the histologic diagnosis. Additionally, for the diagnosis of cases with PC in situ, EUS and magnetic resonance cholangiopancreatography (MRCP) may play important roles in detecting the local irregular stenosis of the pancreatic duct. Cytodiagnosis of pancreatic juice using endoscopic nasopancreatic drainage multiple times may be useful in the final diagnosis. PMID- 26651255 TI - Targeted screening for colorectal cancer in high-risk individuals. AB - The idea of targeted screening for colorectal cancer based on risk profiles originates from its benefits to improve detection yield and optimize screening efficiency. Clinically, it allows individuals to be more aware of their own risk and make informed decisions on screening choice. From a public health perspective, the implementation of risk stratification strategies may better justify utilization of colonoscopic resources, and facilitate resource-planning in the formulation of population-based screening programmes. There are several at risk groups who should receive earlier screening, and colonoscopy is more preferred. This review summarizes the currently recommended CRC screening strategies among subjects with different risk factors, and introduces existing risk scoring systems. Additional genetic, epidemiological, and clinical parameters may be needed to enhance their performance to risk-stratify screening participants. Future research studies should refine these scoring systems, and explore the adaptability, feasibility, acceptability, and user-friendliness of their use in clinical practice among different population groups. PMID- 26651256 TI - Non-invasive screening for colorectal cancer in Asia. AB - There is an increasing trend of colorectal cancer incidence in Asia and nearly 45% of CRC cases worldwide occur in Asia therefore screening for CRC becomes an urgent task. Stool-based tests, including guaiac fecal occult blood test (gFOBT) and fecal immunochemical test (FIT), can select subjects at risk of significant colorectal neoplasms from the large target population thus are currently the most commonly used non-invasive screening tool in large population screening programs. FIT has the advantage over gFOBT in terms of higher sensitivity for early neoplasms, the ability to provide high-throughput automatic analysis, and better public acceptance thus greater effectiveness on reducing CRC mortality and incidence is expected. Owing to the large target population and constrained endoscopic capacity and manpower, FIT is nowadays the most popular CRC screening test in Asia. Some Asian countries have launched nationwide screening program in the past one or two decades but also encountered some challenges such as low screening participation rate, low verification rate after positive stool tests, low public awareness, and insufficient manpower. In addition, some controversial or potential future research issues are also addressed in this review. PMID- 26651257 TI - Chemoprevention trials of GI cancers in Asia. AB - Cancers are among the leading causes of morbidity and mortality worldwide, with gastrointestinal (GI) luminal cancers accounting for a large proportion of cancer incidence. Chemoprevention of GI luminal cancers is important to reduce this cancer burden. Screening for and eradication of Helicobacter pylori (H. pylori) in areas with high gastric cancer incidence is a safe and effective strategy to decrease the incidence of gastric cancer. Eradication of H. pylori also seems to be effective in preventing metachronous cancer development after endoscopic resection of early gastric cancer. For the average risk individual, COX inhibitors may have a role in reducing the incidence of adenoma formation as well as colorectal cancer, bearing in mind its inherent risks. There is currently insufficient evidence to recommend a chemoprevention agent against esophageal and small intestine cancer. PMID- 26651258 TI - Assessment of a cancer screening program. AB - Several Asian countries are implementing nationwide cancer screening programs. Assessment of the effectiveness of these programs is critical to their success as this is the only way to ensure that the benefits of screening outweigh the harms. In this paper we focus on colorectal cancer (CRC) screening to illustrate the principles of screening program assessment. The International Agency for Research on Cancer (IARC) has defined organized screening, distinguishing it from opportunistic screening. The key advantage of organized screening is that it provides greater protection against the possible harms of screening. Since screening is a process, not simply a test, the effectiveness of a program depends on the quality of each step in the cancer screening process. The evaluation of long-term screening program outcomes (CRC incidence and mortality) will not be observable for many years, given the time it takes to plan, pilot and implement a program. However, early performance indicators of the impact of screening should be monitored to give an early indication whether the program is on track. The European Union (EU) has recommended a minimum dataset to be collected and reported regularly by a screening program. Using information from these data tables, early performance indicators can be generated (e.g., participation rate, proportion of screen-detected cancers that are early-stage). Subsequently, modeling the natural history of the disease can be very helpful to estimate long term outcomes, making use of these directly measured early performance indicators. Modeling can also be used to estimate the cost-effectiveness of a screening program and the potential impact of changes in policy, as illustrated by its recent use in the Netherlands to change the definition of a positive fecal immunochemical test (FIT) for the CRC screening program. Programs should consider modeling as an important component of screening program evaluation. PMID- 26651259 TI - In Situ Potentiodynamic Analysis of the Electrolyte/Silicon Electrodes Interface Reactions--A Sum Frequency Generation Vibrational Spectroscopy Study. AB - The key factor in long-term use of batteries is the formation of an electrically insulating solid layer that allows lithium ion transport but stops further electrolyte redox reactions on the electrode surface, hence solid electrolyte interphase (SEI). We have studied a common electrolyte, 1.0 M LiPF6/ethylene carbonate (EC)/diethyl carbonate (DEC), reduction products on crystalline silicon (Si) electrodes in a lithium (Li) half-cell system under reaction conditions. We employed in situ sum frequency generation vibrational spectroscopy (SFG-VS) with interface sensitivity in order to probe the molecular composition of the SEI surface species under various applied potentials where electrolyte reduction is expected. We found that, with a Si(100)-hydrogen terminated wafer, a Si-ethoxy (Si-OC2H5) surface intermediate forms due to DEC decomposition. Our results suggest that the SEI surface composition varies depending on the termination of Si surface, i.e., the acidity of the Si surface. We provide the evidence of specific chemical composition of the SEI on the anode surface under reaction conditions. This supports an electrochemical electrolyte reduction mechanism in which the reduction of the DEC molecule to an ethoxy moiety plays a key role. These findings shed new light on the formation mechanism of SEI on Si anodes in particular and on SEI formation in general. PMID- 26651260 TI - Predictors of improvement and progression of diabetic polyneuropathy following treatment with alpha-lipoic acid for 4 years in the NATHAN 1 trial. AB - AIMS: We aimed to analyze the impact of baseline factors on the efficacy of alpha lipoic acid (ALA) over 4 years in the NATHAN 1 trial. METHODS: This was a post hoc analysis of the NATHAN 1 trial, a 4-year randomized study including 460 diabetic patients with mild-to-moderate polyneuropathy using ALA 600 mg qd or placebo. Amongst others, efficacy measures were the Neuropathy Impairment Score of the lower limbs (NIS-LL) and heart rate during deep breathing (HRDB). RESULTS: Improvement and prevention of progression of NIS-LL (DeltaNIS-LL>=2 points) with ALA vs. placebo after 4 years was predicted by higher age, lower BMI, male sex, normal blood pressure, history of cardiovascular disease (CVD), insulin treatment, longer duration of diabetes and neuropathy, and higher neuropathy stage. Participants treated with ALA who received ACE inhibitors showed a better outcome in HRDB after 4 years. CONCLUSIONS: Better outcome in neuropathic impairments following 4-year treatment with alpha-lipoic acid was predicted by normal BMI and blood pressure and higher burden due to CVD, diabetes, and neuropathy, while improvement in cardiac autonomic function was predicted by ACE inhibitor treatment. Thus, optimal control of CVD risk factors could contribute to improved efficacy of alpha-lipoic acid in patients with higher disease burden. PMID- 26651261 TI - Markers of inflammation and endothelial dysfunction are associated with incident cardiovascular disease, all-cause mortality, and progression of coronary calcification in type 2 diabetic patients with microalbuminuria. AB - BACKGROUND: We evaluated markers of inflammation and endothelial dysfunction and their associations with incident cardiovascular disease (CVD), all-cause mortality and progression of coronary artery calcium (CAC) in patients with type 2 diabetes (T2D) and microalbuminuria but without known coronary artery disease (CAD). METHODS: Prospective study including 200 patients receiving multifactorial treatment. Markers of inflammation (TNF-alpha, sICAM-1, sICAM-3, hsCRP, SAA, IL 1beta, IL-6, IL-8) and endothelial dysfunction (thrombomodulin, sVCAM-1, sICAM-1, sICAM-3, sE-selectin, sP-selectin) were measured at baseline. Adjustment included traditional CVD risk factors, and full adjustment additionally NT-proBNP and CAC. The "SQRT method" assessed CAC progression after 5.8years, and cut-point was an annualised difference >2.5. RESULTS: Occurrence of CVD (n=40) and all-cause mortality (n=26) was traced after 6.1years. In adjusted and fully adjusted Cox models, TNF-alpha was a determinant of CVD and all-cause mortality (p<=0.007). Further, in adjusted and fully adjusted logistic regression, TNF-alpha was related to CAC progression (p<=0.042). Of the other biomarkers, sICAM-3 and thrombomodulin were also associated with both endpoints (p<=0.046), IL-1beta with CVD endpoints (p=0.021), and sVCAM-1 and sICAM-1 with all-cause mortality (p<=0.005). Higher composite z-scores including all markers of inflammation and endothelial dysfunction were associated with CVD and all-cause mortality (p<=0.008). CONCLUSIONS: In patients with T2D and microalbuminuria without known CAD and receiving multifactorial treatment, biomarkers of inflammation and endothelial dysfunction were independently associated with CVD, all-cause mortality and CAC progression. Especially TNF-alpha was a robust determinant, even after adjusting for NT-proBNP and CAC. PMID- 26651262 TI - A sensitive multidimensional method for the detection, characterization, and quantification of trace free drug species in antibody-drug conjugate samples using mass spectral detection. AB - Conjugation processes and stability studies associated with the production and shelf life of antibody-drug conjugates (ADCs) can result in free (non-conjugated) drug species. These free drug species can increase the risk to patients and reduce the efficacy of the ADC. Despite stringent purification steps, trace levels of free drug species may be present in formulated ADCs, reducing the therapeutic window. The reduction of sample preparation steps through the incorporation of multidimensional techniques has afforded analysts more efficient methods to assess trace drug species. Multidimensional methods coupling size exclusion and reversed phase liquid chromatography with ultra-violet detection (SEC-RPLC/UV) have been reported, but offer limited sensitivity and can limit method optimization. The current study addresses these challenges with a multidimensional method that is specific, sensitive, and enables method control in both dimensions via coupling of an on-line solid phase extraction column to RPLC with mass spectral detection (SPE-RPLC/MS). The proposed method was evaluated using an antibody-fluorophore conjugate (AFC) as an ADC surrogate to brentuximab vedotin and its associated parent maleimide-val-cit-DSEA payload and the derived N-acetylcysteine adduct formed during the conjugation process. Assay sensitivity was found to be 2 orders more sensitive using MS detection in comparison to UV-based detection with a nominal limit of quantitation of 0.30 ng/mL (1.5 pg on-column). Free-drug species were present in an unadulterated ADC surrogate sample at concentrations below 7 ng/mL, levels not detectable by UV alone. The proposed SPE-RPLC/MS method provides a high degree of specificity and sensitivity in the assessment of trace free drug species and offers improved control over each dimension, enabling straightforward integration into existing or novel workflows. PMID- 26651263 TI - Microbubble oscillating in a microvessel filled with viscous fluid: A finite element modeling study. AB - Understanding the dynamics of coated-microbubble oscillating in an elastic microvessel is important for effective and safe applications of ultrasound contrast agents (UCAs) in imaging and therapy. Numerical simulations are performed based on a two-dimensional (2D) asymmetric finite element model to investigate the influences of both acoustic driving parameters (e.g., pressure and frequency) and material properties (vessel size, microbubble shell visco elastic parameters and fluid viscosity) on the dynamic interactions in the bubble blood-vessel system. The results show that, the constrained effect of the blood vessel along the radial direction will induce the asymmetric bubble oscillation and vessel deformation, as well as shifting the bubble resonance frequency toward the higher frequency range. For a bubble (1.5-MUm radius) activated by 1-MHz ultrasound pulses in a microvessel with a radius varying between 2 and 6.5 MUm, up to 26.95 kPa shear stress could be generated on the vessel wall at a driving pressure of 0.2 MPa, which should be high enough to damage the vascular endothelial cells. The asymmetrical oscillation ratio of the bubble can be aggravated from 0.12% to 79.94% with the increasing acoustic driving pressure and blood viscosity, or the decreasing vessel size and microbubble shell visco elastic properties. The maximum compression velocity on the bubble shell will be enhanced from 0.19 to 22.79 m/s by the increasing vessel size and acoustic pressure, or the decreasing microbubble shell visco-elasticity and blood viscosity. As the results, the peak values of microstreaming-induced shear stress on the vessel wall increases from 0.003 to 26.95 kPa and the deformation degree of vessel is raised from 1.01 to 1.49, due to the enhanced acoustic amplitude, or the decreasing vessel size, blood viscosity and microbubble shell visco elasticity. Moreover, it also suggests that, among above impact parameters, microbubble resonance frequency and UCA shell elasticity might play more dominant roles in dynamic interactions of the bubble-blood-vessel system. PMID- 26651264 TI - Serological subsets of juvenile idiopathic inflammatory myopathies--an update. AB - In this review we explore the different characteristics of the serological phenotypes identified in juvenile-onset myositis and consider how the serological sub-classification of patients with juvenile myositis can be advantageous both in terms of reaching what can be a difficult diagnosis and informing on prognosis. Recent studies have described the autoantibody associated disease phenotypes and outcome for those with juvenile-onset disease and include analyses of large juvenile-onset myositis cohorts. Here we describe the autoantibody associated disease features for patients within juvenile-onset myositis in detail and discuss the expanding opportunities and strategies for myositis specific autoantibody testing in clinical practice. PMID- 26651265 TI - High-Resolution Remote Sensing of Water Quality in the San Francisco Bay-Delta Estuary. AB - The San Francisco Bay-Delta Estuary watershed is a major source of freshwater for California and a profoundly human-impacted environment. The water quality monitoring that is critical to the management of this important water resource and ecosystem relies primarily on a system of fixed water-quality monitoring stations, but the limited spatial coverage often hinders understanding. Here, we show how the latest technology in visible/near-infrared imaging spectroscopy can facilitate water quality monitoring in this highly dynamic and heterogeneous system by enabling simultaneous depictions of several water quality indicators at very high spatial resolution. The airborne portable remote imaging spectrometer (PRISM) was used to derive high-spatial-resolution (2.6 * 2.6 m) distributions of turbidity, and dissolved organic carbon (DOC) and chlorophyll-a concentrations in a wetland-influenced region of this estuary. A filter-passing methylmercury vs DOC relationship was also developed using in situ samples and enabled the high spatial-resolution depiction of surface methylmercury concentrations in this area. The results illustrate how high-resolution imaging spectroscopy can inform management and policy development in important inland and estuarine water bodies by facilitating the detection of point- and nonpoint-source pollution, and by providing data to help assess the complex impacts of wetland restoration and climate change on water quality and ecosystem productivity. PMID- 26651267 TI - Ultrafast Spectroscopy Evidence for Picosecond Ligand Exchange at the Binding Site of a Heme Protein: Heme-Based Sensor YddV. AB - An important question for the functioning of heme proteins is whether different ligands present within the protein moiety can readily exchange with heme-bound ligands. Studying the dynamics of the heme domain of the Escherichia coli sensor protein YddV upon dissociation of NO from the ferric heme by ultrafast spectroscopy, we demonstrate that when the hydrophobic leucine residue in the distal heme pocket is mutated to glycine, in a substantial fraction of the protein water replaces NO as an internal ligand in as fast as ~4 ps. This process, which is near-barrierless and occurs orders of magnitude faster than the corresponding process in myoglobin, corresponds to a ligand swap of NO with a water molecule present in the heme pocket, as corroborated by molecular dynamics simulations. Our findings provide important new insight into ligand exchange in heme proteins that functionally interact with different external ligands. PMID- 26651266 TI - Sub-Epidemics Explain Localized High Prevalence of Reduced Susceptibility to Rilpivirine in Treatment-Naive HIV-1-Infected Patients: Subtype and Geographic Compartmentalization of Baseline Resistance Mutations. AB - OBJECTIVE: The latest nonnucleoside reverse transcriptase inhibitor (NNRTI) rilpivirine (RPV) is indicated for human immunodeficiency virus type-1 (HIV-1) patients initiating antiretroviral treatment, but the extent of genotypic RPV resistance in treatment-naive patients outside clinical trials is poorly defined. STUDY DESIGN: This retrospective observational study of clinical data from Belgium and Portugal evaluates genotypic information from HIV-1 drug-naive patients obtained for the purpose of drug resistance testing. Rilpivirine resistance-associated mutations (RPV-RAMs) were defined based on clinical trials, phenotypic studies, and expert-based resistance algorithms. Viral susceptibility to RPV alone and to the single-tablet regimen was estimated using expert-based resistance algorithms. RESULTS: In 4,631 HIV-1 treatment-naive patients infected with diverse HIV-1 subtypes, major RPV-RAMs were detected in 4.6%, while complete viral susceptibility to RPV was estimated in 95% of patients. Subtype C- and F1 infected patients displayed the highest levels of reduced viral susceptibility at baseline, respectively 13.2% and 9.3%, mainly due to subtype- and geographic dependent occurrence of RPV-RAMs E138A and A98G as natural polymorphisms. Strikingly, a founder effect in Portugal resulted in a 138A prevalence of 13.2% in local subtype C-infected treatment-naive patients. The presence of transmitted drug resistance did not impact our estimates. CONCLUSION: RPV is the first HIV-1 inhibitor for which, in the absence of transmitted drug resistance, intermediate or high-level genotypic resistance can be detected in treatment-naive patients. The extent of RPV susceptibility in treatment-naive patients differs depending on the HIV-1 subtype and dynamics of local compartmentalized epidemics. The highest prevalence of reduced susceptibility was found to be 15.7% in Portuguese subtype C-infected treatment-naive patients. In this context, even in the absence of transmitted HIV-1 drug resistance (TDR), drug resistance testing at baseline should be considered extremely important before starting treatment with this NNRTI. PMID- 26651277 TI - Copper-Catalyzed Trifluoromethylation of Polysubstituted Alkenes Assisted by Decarboxylation. AB - An efficient copper-catalyzed trifluoromethylation of polysubstituted alkenes assisted by decarboxylation of beta,gamma-unsaturated carboxylic acids has been achieved. The reaction provides a general method to construct allylic and vinylic CF3-substituted compounds under mild conditions. PMID- 26651278 TI - Early Results of a Helmetless-Tackling Intervention to Decrease Head Impacts in Football Players. AB - OBJECTIVE: To test a helmetless-tackling behavioral intervention for reducing head impacts in National Collegiate Athletic Association Division I football players. DESIGN: Randomized controlled clinical trial. SETTING: Football field. PATIENTS OR OTHER PARTICIPANTS: Fifty collegiate football players (intervention = 25, control = 25). INTERVENTION(S): The intervention group participated in a 5 minute tackling drill without their helmets and shoulder pads twice per week in the preseason and once per week through the season. During this time, the control group performed noncontact football skills. MAIN OUTCOME MEASURE(S): Frequency of head impacts was recorded by an impact sensor for each athlete-exposure (AE). Data were tested with a 2 * 3 (group and time) repeated-measures analysis of variance. Significant interactions and main effects (P < .05) were followed with t tests. RESULTS: Head impacts/AE decreased for the intervention group compared with the control group by the end of the season (9.99 +/- 6.10 versus 13.84 +/- 7.27, respectively). The intervention group had 30% fewer impacts/AE than the control group by season's end (9.99 +/- 6.10 versus 14.32 +/- 8.45, respectively). CONCLUSION: A helmetless-tackling training intervention reduced head impacts in collegiate football players within 1 season. PMID- 26651280 TI - Surgical Repair of Imperforate Anus: A Report from Haly Abbas (949-982AD). PMID- 26651279 TI - Asymptomatic Elite Adolescent Tennis Players' Signs of Tendinosis in Their Dominant Shoulder Compared With Their Nondominant Shoulder. AB - CONTEXT: Tennis is an asymmetric overhead sport with specific muscle-activation patterns, especially eccentrically in the rotator cuff. Magnetic resonance imaging (MRI) findings in asymptomatic adolescent elite tennis players have not previously been reported. OBJECTIVE: The first aim of the study was to describe MRI findings regarding adaptations or abnormalities, as well as muscle cross sectional area (CSA), of the rotator cuff. The second aim of the study was to investigate the rotator cuff based on the interpretation of the MRI scans as normal versus abnormal, with the subdivision based on the grade of tendinosis, and its association with eccentric rotator cuff strength in the dominant arm (DA) of the asymptomatic elite adolescent tennis player. SETTING: Testing environment at the radiology department of Medicinsk Rontgen AB. PATIENTS OR OTHER PARTICIPANTS: Thirty-five asymptomatic elite tennis players (age = 17.4 +/- 2.7 years) were selected based on ranking and exposure time. INTERVENTION(S): We assessed MRI scans and measured the CSA of the rotator cuff muscle. The non-DA (NDA) was used as a control. In addition, eccentric testing of the external rotators of the DA was performed with a handheld dynamometer. RESULTS: The DA and NDA displayed different frequencies of infraspinatus tendinosis (grade 1 changes) (P < .05). Rotator cuff measurements revealed larger infraspinatus and teres minor CSA (P < .05) in the DA than in the NDA. Mean eccentric external-rotation strength in the DA stratified by normal tendon and tendinosis was not different between groups (P = .723). CONCLUSIONS: Asymptomatic adolescent elite tennis players demonstrated infraspinatus tendinosis more frequently in the DA than in the NDA. Clinicians must recognize these tendon changes in order to modify conditioning and performance programs appropriately. PMID- 26651281 TI - Laparoscopy-assisted versus transabdominal reoperation in Hirschprung's disease for residual aganglionosis and transition zone pathology after transanal pull through. AB - INTRODUCTION: This study aims to describe laparoscopic reoperation (LSR) and compare its outcomes with transabdominal reoperation (TAR) for treating Hirschsprung's disease (HD). PATIENTS AND METHODS: Eighteen patients with HD underwent reoperation for recurring constipation due to residual aganglionosis and transition zone pathology after an initial transanal procedure (LSR, n=10; TAR, n=8). Preoperative, operative and postoperative data were collected through patient follow-ups ranging from 13 to 75months to compare operative characteristics and postoperative outcomes between the two groups. RESULTS: Ten patients underwent laparoscopic reoperation in our institution without major complications. On average, blood loss was significantly lower in the LSR group (mean+/-standard deviation, 83+/-32.7mL) than in the TAR group (185+/-69mL) (P=0.001). The LSR group had a shorter hospitalization time (12+/-2days) than the TAR group (15+/-2.1days) (P=0.02). There was no statistically significant difference in incidence of postoperative complications between the two groups. CONCLUSIONS: LSR is safe and technically feasible in HD for recurring constipation due to residual aganglionosis and transition zone pathology, when initial transanal procedure fails. Although RA and TZP can be cured by reoperation, great efforts should be made to diminish the necessity of reoperation. PMID- 26651282 TI - Salvage rates after progression of high-risk neuroblastoma with a soft tissue mass. AB - PURPOSE: Treatment of progression in high-risk neuroblastoma remains challenging despite improved survival. We retrospectively evaluated outcomes in children with a first progression that included soft-tissue masses. METHODS: We reviewed records of 903 consecutive children with high-risk neuroblastoma diagnosed between 2004 and 2014, and identified 42 whose first progression included soft tissue masses. Data on demographics, disease characteristics, treatment, and survival were collected. Primary outcome was 5-year overall survival (OS) from time of first progression. Secondary outcomes were local disease-free progression (LDFR) and progression-free survival (PFS) postprogression. We evaluated the prognostic significance of concomitant bone/bone marrow involvement, MYCN status, and multifocality of soft tissue relapse. RESULTS: Median age at diagnosis was 3.0 (range: 1-10.7) years. Median time to first relapse or progression was 1.2 (range: 0.1-4.5) years after complete remission or minimal stable residual disease. Twelve (29%) patients had concomitant bone or marrow involvement at progression/relapse. There were 11 (26%) patients with International Neuroblastoma Staging System stage 3 disease (all with MYCN amplification), and 31 (74%) with stage 4 disease (12 with MYCN amplification). Nine (21%) patients had multifocal soft tissue progression. R1 resection was achieved in 41 children (95%), 38 (95%) of whom also received salvage radiation therapy. Five-year OS postprogression was 35% (95% CI: 19-51%), 5-year LDFS was 52% (95% CI: 32-72%), and 5-year PFS postprogression was 20% (95% CI: 6-34%). CONCLUSION: Among children with high-risk neuroblastoma who underwent aggressive treatment of a first soft-tissue recurrence, 5-year postprogression overall survival was 34%. Multifocality and MYCN amplification were the predominant prognostic correlates for worse survival. PMID- 26651283 TI - Are PEGJs a Risk Factor for the Buried Bumper Syndrome? AB - AIM: Percutaneous endoscopic gastrostomies (PEGs) with or without a jejunal extension (PEGJs) are a well-accepted method of enteral feeding. They are associated with a number of complications, including the buried bumper syndrome (BBS). We aimed to identify risk factors for BBS, our current management strategies, and optimal timing for surgical treatment. METHODS: Hospital coding and a database compiled by our specialist nutrition nurse were used to identify all cases of buried bumpers from January 2012 to December 2014 as well as all PEG/PEGJ devices inserted during this time. A retrospective case note review was performed for each patient with BBS to identify risk factors, management strategies, and outcomes. RESULTS: Two hundred twelve PEGs and 22 PEGJs were inserted. Nine patients were identified with BBS. Patients with PEGJ tubes were significantly more likely to develop BBS (7/22, 32%) than those with PEG tubes (2/212, 0.9%) P<0.01. There was one death in the study group because of abdominal sepsis associated with an intraperitoneal PEG bumper 33days after BBS was diagnosed and before removal was attempted. All other patients underwent laparotomy to remove the bumper. Mean hospital stay was 22days postoperatively. CONCLUSIONS: Buried bumper syndrome is a serious condition which warrants urgent intervention. We have demonstrated a higher than expected rate of BBS associated with PEGJ tubes. We hypothesize that this may be related to the jejunal extensions leading to difficulty in the usual maintenance regimen that all carers are taught after PEG/PEGJ insertion. PMID- 26651284 TI - Iranian pregnant teenage women tell the story of "fast development": A phenomenological study. AB - BACKGROUND: Teenage pregnancy is a major health problem significantly associated with negative impacts on the health of both teenage mothers and their newborn. However, little is known about teenage pregnancy from teenager's perspective, particularly in developing countries including Iran. AIM: This study aimed to explore the experience of pregnancy in Iranian teenage women. METHODS: An interpretive phenomenological study was used as a suitable research design to conduct this research. Data were collected through individual, semi structured and in-depth interview with 11 married teenage women aged between 15 and 19 years old, primigravida with singleton pregnancy. Data were analysed through thematic analysis approach. FINDINGS: "Fast development" was the main theme that emerged from the participants' experiences. It refers to the unexpected development process that occurs simultaneously with other important development events. Fast development consists of three themes, 'unexpected development', 'development within development', and 'struggle with development'. CONCLUSION: Teenage pregnant women simultaneously encounter multiple developmental challenges related to adolescence period, marriage, pregnancy, and mothering responsibilities. According to the results, fast development concept should be considered by healthcare providers in order to offer comprehensive and age-appropriate health services to pregnant teenage women for successful transition from the multiple developmental stages. Moreover, this concept will help health care providers, especially midwives, to understand how to deal with pregnant teenagers. PMID- 26651285 TI - Highly Transparent and Stretchable Conductors Based on a Directional Arrangement of Silver Nanowires by a Microliter-Scale Solution Process. AB - We report an effective method for fabricating highly transparent and stretchable large-area conducting films based on a directional arrangement of silver nanowires (AgNWs) driven by a shear force in a microliter-scale solution process. The thin conducting films with parallel AgNWs or cross-junctions of AgNWs are deposited on the coating substrate by dragging a microliter drop of the coating solution trapped between two plates. The optical and electrical properties of the AgNW thin films are finely tuned by varying the simple systematic parameters in the coating process. The transparent thin films with AgNW cross-junctions exhibit the superior electrical conductivity with a sheet resistance of 10 Omega sq(-1) at a transmittance of 85% (lambda = 550 nm), which is well described by the high ratio of DC to optical conductivity of 276 and percolation theory in a two dimensional matrix model. This simple coating method enables the deposition of AgNW thin films with high optical transparency, flexibility, and stretchability directly on plastic substrates. PMID- 26651286 TI - Heal Thy Cell(f): A Single-Cell View of Regeneration. AB - In this issue of Developmental Cell, Wurtzel et al. (2015) use single-cell transcriptome sequencing on planarian cells to investigate the cell-type specificity and temporal dynamics underlying the regenerative wound response. PMID- 26651287 TI - Autophagy Devours the Nuclear Lamina to Thwart Oncogenic Stress. AB - A recent study by Dou et al. (2015) in Nature extends the functions of autophagy to the nucleus, where it mediates the degradation of the nuclear lamina upon oncogenic insults to reinforce cellular senescence. PMID- 26651288 TI - Liquids, Fibers, and Gels: The Many Phases of Neurodegeneration. AB - Recent advances suggest that phase transitions of proteins into liquid or hydrogel states could underlie pathological protein aggregation associated with neurodegenerative disease. In a recent issue of Neuron, Murakami et al. (2015) demonstrate that ALS-associated FUS mutations abrogate the reversibility of condensed liquids and/or hydrogels, leading to neurotoxicity in C. elegans. PMID- 26651289 TI - Shaping Developing Tissues with Light. AB - Using light to control cell and animal behavior has opened up many avenues of research in neuroscience and cell biology, but applications in developmental biology have been limited thus far. Guglielmi et al. (2015) now apply optogenetic tools to control cortical contractility and tissue morphogenesis in Drosophila embryos. PMID- 26651290 TI - Two Ways to Get Mad at Kinetochores. AB - The spindle assembly checkpoint ensures that mitotic cells only segregate their sister chromatids once all chromosomes are attached via kinetochores by microtubules of the mitotic spindle. Reporting in Developmental Cell, Silio et al. (2015) show that in human cells the signaling cascade controlling the checkpoint operates through two separate branches. PMID- 26651291 TI - Lrig2 Negatively Regulates Ectodomain Shedding of Axon Guidance Receptors by ADAM Proteases. AB - Many guidance receptors are proteolytically cleaved by membrane-associated metalloproteases of the ADAM family, leading to the shedding of their ectodomains. Ectodomain shedding is crucial for receptor signaling and function, but how this process is controlled in neurons remains poorly understood. Here, we show that the transmembrane protein Lrig2 negatively regulates ADAM-mediated guidance receptor proteolysis in neurons. Lrig2 binds Neogenin, a receptor for repulsive guidance molecules (RGMs), and prevents premature Neogenin shedding by ADAM17 (TACE). RGMa reduces Lrig2-Neogenin interactions, providing ADAM17 access to Neogenin and allowing this protease to induce ectodomain shedding. Regulation of ADAM17-mediated Neogenin cleavage by Lrig2 is required for neurite growth inhibition by RGMa in vitro and for cortical neuron migration in vivo. Furthermore, knockdown of Lrig2 significantly improves CNS axon regeneration. Together, our data identify a unique ligand-gated mechanism to control receptor shedding by ADAMs and reveal functions for Lrigs in neuron migration and regenerative failure. PMID- 26651292 TI - A Dynamic Unfolded Protein Response Contributes to the Control of Cortical Neurogenesis. AB - The cerebral cortex contains layers of neurons sequentially generated by distinct lineage-related progenitors. At the onset of corticogenesis, the first-born progenitors are apical progenitors (APs), whose asymmetric division gives birth directly to neurons. Later, they switch to indirect neurogenesis by generating intermediate progenitors (IPs), which give rise to projection neurons of all cortical layers. While a direct lineage relationship between APs and IPs has been established, the molecular mechanism that controls their transition remains elusive. Here we show that interfering with codon translation speed triggers ER stress and the unfolded protein response (UPR), further impairing the generation of IPs and leading to microcephaly. Moreover, we demonstrate that a progressive downregulation of UPR in cortical progenitors acts as a physiological signal to amplify IPs and promotes indirect neurogenesis. Thus, our findings reveal a contribution of UPR to cell fate acquisition during mammalian brain development. PMID- 26651293 TI - Role for Lipid Droplet Biogenesis and Microlipophagy in Adaptation to Lipid Imbalance in Yeast. AB - The immediate responses to inhibition of phosphatidylcholine (PC) biosynthesis in yeast are altered phospholipid levels, slow growth, and defects in the morphology and localization of ER and mitochondria. With chronic lipid imbalance, yeast adapt. Lipid droplet (LD) biogenesis and conversion of phospholipids to triacylglycerol are required for restoring some phospholipids to near-wild-type levels. We confirmed that the unfolded protein response is activated by this lipid stress and find that Hsp104p is recruited to ER aggregates. We also find that LDs form at ER aggregates, contain polyubiquitinated proteins and an ER chaperone, and are degraded in the vacuole by a process resembling microautophagy. This process, microlipophagy, is required for restoration of organelle morphology and cell growth during adaptation to lipid stress. Microlipophagy does not require ATG7 but does requires ESCRT components and a newly identified class E VPS protein that localizes to ER and is upregulated by lipid imbalance. PMID- 26651294 TI - KNL1-Bubs and RZZ Provide Two Separable Pathways for Checkpoint Activation at Human Kinetochores. AB - The spindle assembly checkpoint (SAC) ensures the accurate segregation of sister chromatids during mitosis. Activation of the SAC occurs through a series of ordered molecular events that result in recruitment of Mad1:Mad2 complexes to improperly attached kinetochores. The current model involves sequential phospho dependent recruitment of Bub3:Bub1 to KNL1 followed by binding of Mad1:Mad2 to Bub1. Here, we show in non-transformed diploid human cells that the KNL1-Bub3 Bub1 (KBB) pathway is required during normal mitotic progression when kinetochores are misaligned but is nonessential for SAC activation and Mad2 loading when kinetochores are unattached from microtubules. We provide evidence that the Rod-ZW10-Zwilch (RZZ) complex is necessary to recruit Mad1:Mad2 to, and delay anaphase onset in response to, unattached kinetochores independently of the KBB pathway. These data suggest that the KBB and RZZ complexes provide two distinct kinetochore receptors for Mad1:Mad2 and reveal mechanistic differences between SAC activation by unattached and improperly attached kinetochores. PMID- 26651295 TI - A Generic and Cell-Type-Specific Wound Response Precedes Regeneration in Planarians. AB - Regeneration starts with injury. Yet how injuries affect gene expression in different cell types and how distinct injuries differ in gene expression remain unclear. We defined the transcriptomes of major cell types of planarians- flatworms that regenerate from nearly any injury--and identified 1,214 tissue specific markers across 13 cell types. RNA sequencing on 619 single cells revealed that wound-induced genes were expressed either in nearly all cell types or specifically in one of three cell types (stem cells, muscle, or epidermis). Time course experiments following different injuries indicated that a generic wound response is activated with any injury regardless of the regenerative outcome. Only one gene, notum, was differentially expressed early between anterior- and posterior-facing wounds. Injury-specific transcriptional responses emerged 30 hr after injury, involving context-dependent patterning and stem-cell specialization genes. The regenerative requirement of every injury is different; however, our work demonstrates that all injuries start with a common transcriptional response. PMID- 26651296 TI - In vitro maturation affects chromosome segregation, spindle morphology and acetylation of lysine 16 on histone H4 in horse oocytes. AB - Implantation failure and genetic developmental disabilities in mammals are caused by errors in chromosome segregation originating mainly in the oocyte during meiosis I. Some conditions, like maternal ageing or in vitro maturation (IVM), increase the incidence of oocyte aneuploidy. Here oocytes from adult mares were used to investigate oocyte maturation in a monovulatory species. Experiments were conducted to compare: (1) the incidence of aneuploidy, (2) the morphology of the spindle, (3) the acetylation of lysine 16 on histone H4 (H4K16) and (4) the relative amount of histone acetyltransferase 1 (HAT1), K(lysine) acetyltransferase 8 (KAT8, also known as MYST1), histone deacetylase 1 (HDAC1) and NAD-dependent protein deacetylase sirtuin 1 (SIRT1) mRNA in metaphase II stage oocytes that were in vitro matured or collected from peri-ovulatory follicles. The frequency of aneuploidy and anomalies in spindle morphology was increased following IVM, along with a decrease in H4K16 acetylation that was in agreement with our previous observations. However, differences in the amount of the transcripts investigated were not detected. These results suggest that the degradation of transcripts encoding for histone deacetylases and acetyltransferases is not involved in the changes of H4K16 acetylation observed following IVM, while translational or post-translational mechanisms might have a role. Our study also suggests that epigenetic instabilities introduced by IVM may affect the oocyte and embryo genetic stability. PMID- 26651297 TI - Infantile nystagmus syndrome: clinical characteristics, current theories of pathogenesis, diagnosis, and management. AB - Infantile nystagmus syndrome (INS) is an important clinical diagnosis because it is a common presenting sign of many ocular, neurologic, and systemic diseases. Although INS has been studied for more than a century, its diagnosis and treatment remains a challenge to clinicians because of its varied manifestations and multiple associations, and its pathogenesis continues to rouse considerable scientific debate. Fueled by these challenges, recent basic research and clinical investigations have provided new insights into INS. New genetic discoveries and technological advances in ocular imaging have refined our understanding of INS subtypes and offer new diagnostic possibilities. Unexpected surgical outcomes have led to new understanding of its pathogenesis based on novel hypothesized pathways of ocular motor control. Comparative studies on nonhuman visual systems have also informed models of the neural substrate of INS in humans. This review brings together the classic profile of this disorder with recent research to provide an update on the clinical features of INS, an overview of the current theories on how and why INS develops, and a practical approach to the diagnosis and management of INS. PMID- 26651298 TI - Intravitreal bevacizumab for retinopathy of prematurity: Considerations for informed consent. PMID- 26651299 TI - Fixation pattern analysis with microperimetry in nystagmus patients. AB - OBJECTIVE: To assess the usefulness of microperimetry (MP) as an additional objective method for characterizing the fixation pattern in nystagmus. DESIGN: Prospective study. PARTICIPANTS: Fifteen eyes of 8 subjects (age, 12-80 years) with nystagmus from the Lluis Alcanyis Foundation (University of Valencia, Spain) were included. METHODS: All patients had a comprehensive ophthalmologic examination including a microperimetric examination (MAIA, CenterVue, Padova, Italy). The following microperimetric parameters were evaluated: average threshold (AT), macular integrity index (MI), fixating points within a circle of 1 degrees (P1) and 2 degrees of radius (P2), bivariate contour ellipse area (BCEA) considering 63% and 95% of fixating points, and horizontal and vertical axes of that ellipse. RESULTS: In monocular conditions, 6 eyes showed a fixation classified as stable, 6 eyes showed a relatively unstable fixation, and 3 eyes showed an unstable fixation. Statistically significant differences were found between the horizontal and vertical components of movement (p = 0.001), as well as in their ranges (p < 0.001). Intereye comparison showed differences between eyes in some subjects, but only statistically significant differences were found in the fixation coordinates X and Y (p < 0.001). No significant intereye differences were found between microperimetric parameters. Between monocular and binocular conditions, statistically significant differences in the X and Y coordinates were found in all eyes (p < 0.02) except one. No significant differences were found between MP parameters for monocular or binocular conditions. Strong correlations of corrected distance visual acuity (CDVA) with AT (r = 0.812, p = 0.014), MI (r = -0.812, p = 0.014), P1 (r = 0.729, p = 0.002), horizontal diameter of BCEA (r = -0.700, p = 0.004), and X range (r = -0.722, p = 0.005) were found. CONCLUSIONS: MP seems to be a useful technology for the characterization of the fixation pattern in nystagmus, which seems to be related to the level of visual acuity achieved by the patient. PMID- 26651300 TI - Workforce supply of eye care providers in Canada: optometrists, ophthalmologists, and subspecialty ophthalmologists. AB - OBJECTIVE: To assess the population distribution of optometrists, ophthalmologists, and subspecialist ophthalmologists in Canada. DESIGN: Cross sectional study. PARTICIPANTS: Participants were optometrists listed in optometry associations' databases and Canadian ophthalmologists listed in the Canadian Medical Association (CMA), Canadian Ophthalmological Society (COS), and American Academy of Ophthalmology (AAO) databases. Canadian population data are from Statistics Canada. METHODS: Provincial optometry associations' databases and the CMA database were used to determine the number and location of currently licensed optometrists and ophthalmologists, respectively, in Canada. The COS and AAO databases were used to determine subspecialization, which was further verified by contacting subspecialty organizations. Provider ratios to a 100,000 population were determined. RESULTS: In 2012 there were 5729 optometrists and 1164 ophthalmologists, of which 524 ophthalmologists (45%) were subspecialized, representing 4.92 optometrists per ophthalmologist. For every 100,000 Canadians there were 3.35 ophthalmologists (1.84 comprehensive and 1.51 subspecialists) and 16.48 optometrists. Of the 148 census areas, 1 (0.7%, Yellowknife) had no optometrist and 43 (29%) had no ophthalmologist. The greatest proportions of ophthalmology subspecialists were in surgical retina (20.6%) and the lowest was ocular pathology (1.5%). CONCLUSIONS: Although benchmarks regarding the ideal balance among number of optometrists, ophthalmologists, and subspecialists in relation to population are unknown, we found that all census regions had at least 1 ophthalmologist or optometrist. Forty-five percent of ophthalmologists identified a subspecialty interest, of which the majority was surgical retina. This information may be of value to training ophthalmologists when deciding on a subspecialty and practice location. PMID- 26651301 TI - Effects of malicious ocular laser exposure in commercial airline pilots. AB - OBJECTIVE: Intentional malicious laser strikes on commercial pilots are committed by individuals who target a laser into airplane cockpits during takeoff and landing. Because laser exposure to pilots is a relatively new but growing occurrence, our study investigates the ocular effect of this laser exposure in pilots. DESIGN: Retrospective chart review by a single ophthalmologist. PARTICIPANTS: All commercial airline pilots (58 male, 3 female) who experienced a laser strike while flying between April 2012 and November 2014 who presented to our clinic were included. METHODS: A retrospective chart review was performed in a retinal specialist's practice. Ocular assessment was performed within 3 days of laser exposure. A complete ophthalmic evaluation was conducted, including Early Treatment Diabetic Retinopathy Study visual acuity, colour vision, visual fields, intraocular pressure, slit-lamp examination, dilated fundus examination, colour fundus photographs, and ocular coherence tomography. RESULTS: Sixty-four laser strike incidents involving commercial pilots were included. All pilots in the study experienced some degree of immediate ocular irritation or light sensitivity. No definite cases of ocular damage were attributed to laser strikes. No pilot had any functional ocular deficits. CONCLUSIONS: Our study revealed that laser strikes on aircraft did not result in permanent visual functional or structural deficits. However, laser strikes cause immediate visual effects, including glare, flash blindness, and ocular irritation that can interfere with a pilot's visual function. Given the widespread accessibility of high-power lasers and the rapid increase in incidents, laser strikes threaten to jeopardize aviation safety unless effective preventative measures are put in place. PMID- 26651302 TI - Bacterial endophthalmitis: 10-year review of the culture and sensitivity patterns of bacterial isolates. AB - OBJECTIVE: To examine the spectrum and sensitivity patterns of bacterial isolates derived from all culture-positive aqueous and vitreous samples submitted for culture and sensitivity analysis at our institution over a 10-year period. DESIGN: Retrospective cohort study. PARTICIPANTS: A total of 368 culture-positive aqueous and vitreous samples from 265 patients were reviewed. METHODS: Over a decade extending from January 2000 through December 2009, all culture-positive aqueous and vitreous specimens at our institution were identified. Isolated bacterial pathogens and their in vitro antibiotic sensitivities were analyzed. RESULTS: Approximately 86.4% of patients had positive cultures for either staphylococci (Staphylococcus aureus and coagulase-negative staphylococci [CNS]) or streptococci. Gram-negative bacteria were isolated in only 9.8% of patients. From 2000 to 2004, 81.2% and 55.9% of CNS isolates were sensitive to ciprofloxacin and cefazolin, respectively, compared with 41.2% and 23.5% of isolates in the last 5 years. Over the study period, ceftazidime retained 100% efficacy against the gram-negative isolates tested. Vancomycin was 99.6% effective against the gram-positive isolates tested. CONCLUSIONS: The microbiology of pathogens in endophthalmitis is evolving, with an increase in streptococcal isolates and a decrease in CNS. The apparent lack of efficacy of conventionally used antibiotics and the emergence of increasingly resistant strains of bacteria may have significant implications in the management of bacterial endophthalmitis. PMID- 26651303 TI - Impaired photoreceptor inner segment ellipsoid layer reflectivity in mild diabetic retinopathy. AB - OBJECTIVE: To determine alterations in retinal pigment epithelium (RPE), photoreceptor inner segment ellipsoid layer (ISel), and external limiting membrane (ELM) reflectivities using optical coherence tomography (OCT) image analysis in patients with mild nonproliferative diabetic retinopathy (NPDR). DESIGN: Retrospective, single-centre, controlled clinical study. PARTICIPANTS: The study cohort included 42 eyes of 42 patients with mild NPDR (NPDR group) and 40 eyes of 40 healthy subjects (control group). Eyes with moderate and severe NPDR, proliferative DR, macular edema, and other macular pathologies were excluded. METHODS: The reflectivities of RPE, ISel, and ELM were calculated using a medical image-processing software based on greyscale OCT images. The differences in the reflectivity values between the NPDR and control groups were analyzed. RESULTS: The NPDR group comprised 22 males and 20 females (with a mean age of 61.3 +/- 6.5 years), and the control group consisted of 14 males and 26 females (with a mean age of 63.0 +/- 4.1 years) (p > 0.05). The ISel had significantly lower reflectivity (both absolute and relative) in eyes with mild NPDR compared with that of the control eyes (p < 0.001), whereas the reflectivities of RPE and ELM did not differ between the 2 groups (p = 0.126, p = 0.053 respectively). CONCLUSIONS: Although previous ex vivo studies reported photoreceptor degeneration in diabetic retinopathy, this is the first clinical study to investigate retinal layer reflectivities in NPDR using OCT. In eyes with mild NPDR, ISel seems to have lower reflectivity, and this finding might indicate early photoreceptor degeneration in diabetic retinopathy pathogenesis. PMID- 26651304 TI - Retinal toxicity of high-dose hydroxychloroquine in patients with chronic graft versus-host disease. AB - OBJECTIVE: To evaluate retinal toxicity in patients treated with high-dose hydroxychloroquine (HCQ) (Plaquenil, Sanofi Pharmaceuticals) for chronic graft versus-host disease (GVHD). DESIGN: Cohort study. PARTICIPANTS: Twelve patients with chronic GVHD treated with 800 mg/day HCQ between June 2005 and December 2010. METHODS: Patients in this study underwent ophthalmologic examination yearly and ancillary studies including colour vision, Amsler grid, fundus photographs, Humphrey 10-2 automated perimetry, spectral-domain optical coherence tomography (SD-OCT), and multifocal electroretinography (mfERG). Evidence of HCQ toxicity was determined by the presence of scotomas in the Amsler grid and Humphrey 10-2 automated perimetry, and confirmed by at least 1 objective test including SD-OCT or mfERG. RESULTS: Of the 12 patients, 7 were male and 5 were female. Mean age was 49 years. Mean best corrected visual acuity at baseline was 20/25 and remained 20/25 at final follow-up. Median duration of HCQ treatment was 22.8 months. Median adjusted daily dosage was 11.5 mg/kg/day. Seven patients developed vortex keratopathy. No signs of pigmentary retinopathy or bull's-eye maculopathy were found in any of the patients. Three patients developed retinal toxicity with scotomas in the Amsler grid and Humphrey 10-2 automated perimetry, as well as abnormal mfERG. Retinal structure measured by SD-OCT was abnormal in 2 of the 3 patients with retinal toxicity. Colour vision measured by Ishihara plates, as well as by 100 Hue colour test, was abnormal in 2 of the 3 patients with retinal toxicity. CONCLUSIONS: High-dose HCQ in patients with GVHD was associated with higher incidence and earlier development of retinal toxicity. PMID- 26651305 TI - Association of CX3CR1 (V249I and T280M) polymorphisms with age-related macular degeneration: a meta-analysis. AB - OBJECTIVE: Studies investigating the associations between CX3CR1 genetic polymorphisms and age-related macular degeneration (AMD) have reported controversial results. Therefore, this meta-analysis aims to clarify the effects of CX3CR1 T280M and V249I polymorphisms on AMD risk. DESIGN: Meta-analysis. PARTICIPANTS: Results from six studies were pooled in the meta-analysis. METHODS: Relevant studies were selected through an extensive search of PubMed, EMBASE, and the Web of Science databases. Pooled odds ratio (OR) and 95% confidence interval (CI) were calculated using random-effects model. RESULTS: Six studies with were included in this systematic review and meta-analysis. There was no significant association between CX3CR1 T280M polymorphism and risk of AMD under all genetic models (TT vs CC/CT: OR = 1.57, 95% CI = 0.87-2.84; CC vs TT/CT: OR = 0.75, 95% CI = 0.54-1.06; TT vs CC: OR = 0.58, 95% CI = 0.30-1.144; CT vs CC: OR = 1.25, 95% CI = 0.91-1.70). The CX3CR1 V249I polymorphism also did not significantly affect the AMD risk (AA vs GG/AG: OR = 1.23, 95% CI = 0.98-1.55; AG/AA vs GG: OR = 0.56, 95% CI = 0.29-1.07; AA vs GG: OR = 1.43, 95% CI = 0.97-2.09; AG vs GG: OR = 1.07, 95% CI = 0.85-1.36). CONCLUSIONS: This meta-analysis suggested that CX3CR1 T280M and V249I polymorphisms may not be associated with an increased risk of AMD based on current published data. Given the limited sample size, the finding on CX3CR1 polymorphisms needs further investigation. PMID- 26651306 TI - Total ocular surface amniotic membrane transplantation for paraquat-induced ocular surface injury. AB - OBJECTIVE: To evaluate the therapeutic efficacy of modified amniotic membrane transplantation (MAMT) for paraquat-induced ocular surface injury. DESIGN: Retrospective case series. PARTICIPANTS: Thirty patients (30 eyes) with paraquat induced ocular surface injury. METHODS: Among the patients, 8 underwent MAMT, 14 received conventional amniotic membrane transplantation (AMT), and 8 were treated with simple drug therapy (DT). Features related to the damage, corneal epithelial defect closure time, visual acuity, stromal haze, and complications were recorded. RESULTS: In the MAMT and AMT groups, visual acuity in all eyes recovered to the preinjury level; in the DT group, visual acuity in 3 eyes (37.5%) recovered to the preinjury level. The mean corneal epithelial defect closure time was 7.6 +/- 2.7 days in the MAMT group, 9.8 +/- 3.6 days in the AMT group, and 18.2 +/- 5.2 days in the DT group (p < 0.05). There was a significant difference in the symblepharon rate after treatment among the 3 groups (MAMT: 0%, AMT: 35.7%, DT: 87.5%; p < 0.05). Although the tear secretion was reduced in all groups, it was significantly lower in the DT group compared with the MAMT and AMT groups (p < 0.05). CONCLUSIONS: Paraquat-induced ocular injuries can lead to whole ocular surface damage. MAMT treatment in a timely manner can effectively promote the repair of the ocular surface and reduce the complications from symblepharon. PMID- 26651307 TI - Surgical outcomes of endoscopic dacryocystorhinostomy: analysis of 1083 consecutive cases. AB - OBJECTIVE: We report on the surgical outcome of endoscopic dacryocystorhinostomy (DCR) and analyze factors that influence surgical failure. DESIGN: Retrospective observational cases series. PARTICIPANTS: A total of 1083 cases who underwent endoscopic DCR with bicanalicular lacrimal stent insertion, performed by 1 surgeon between January 2007 and February 2013. METHODS: A retrospective chart review of 1083 cases who underwent endoscopic DCR with bicanalicular lacrimal stent insertion was performed, focusing on factors that were expected to affect the surgical outcomes. Surgical outcomes were recorded as the resolution of symptoms and endoscopic evidence of ostium patency postoperatively. RESULTS: The overall success rate of DCR was 92.7% (1004 cases). Of 79 cases with unsuccessful outcomes, the visualization of anatomical obstruction with endoscopy was possible in 68 cases (86%), whereas no anatomic evidence of obstruction was found in 11 cases (14%). In total, 64 cases underwent additional lacrimal intervention, and 12 cases underwent revision surgery twice after the initial DCR operation. Radioactive iodine ablation was associated with surgery failure by logistic regression analysis. However, other factors, such as sex, age, the presence of earlier accidental tube removal, indications for surgery, and Guardix injection, did not show statistically significant differences. CONCLUSIONS: Endoscopic DCR is a surgical technique that has a predictable, favourable success rate. It could be considered appropriate for the initial treatment of nasolacrimal duct obstruction. PMID- 26651308 TI - Surgical correction of myogenic ptosis using a modified levator resection technique. AB - OBJECTIVE: This report describes our experience using a modified anterior levator resection approach in myogenic ptosis patients and presents the results from a consecutive series of patients treated with this method. DESIGN: This was a retrospective case series study. PARTICIPANTS: Forty-one patients with moderate and severe myogenic ptosis were included. METHODS: All patients underwent a modified anterior levator resection approach under local anesthesia. The procedure involved exposing Whitnall's ligament, dissecting and resecting the underlying levator muscle from Whitnall's ligament, and leaving the aponeurosis intact. All patients underwent pre- and postoperative photography, and final outcomes were assessed after a minimum of 6 months. Outcome measures included pre and post-marginal reflex distance (MRD1), symmetry of height, contour, and complications. RESULTS: Forty-one patients undergoing 56 procedures were included. The mean age of the patients was 15 (13-18) years. The mean postoperative MRD1 was 3.45 mm. Thirty-four patients achieved their desired lid height and contour, and 7 patients had undercorrection, including 1 patient with 2 mm of asymmetry, with a final success rate of 83% (34/41 patients). CONCLUSIONS: Our modified anterior levator resection approach had a high success rate and is particularly suitable for patients with moderate and severe myogenic ptosis. PMID- 26651309 TI - Acute serous macular detachment and edema after uncomplicated phacoemulsification: A case series. AB - OBJECTIVE: To report cases of acute serous macular detachment and edema after uncomplicated phacoemulsification. DESIGN: Retrospective case series. PARTICIPANTS: We reviewed the clinical data of 5 patients who developed an acute serous macular detachment and edema after uncomplicated phacoemulsification with intraocular lens implantation by the same expert surgeon and without any complication during surgery. METHODS: Best corrected visual acuity (BCVA), biomicroscopy, fundus examination, and optical coherence tomography were performed at 1, 3, 7, and 30 postoperative days. RESULTS: On the first postoperative day, all eyes had low visual acuity (median 1.0 logMAR) despite normal postoperative appearance of the anterior segment. Optical coherence tomography showed serous macular detachment with intraretinal fluid accumulation. After treatment with oral indomethacin and acetazolamide, at 7 days, intraretinal and subretinal fluid were fully reabsorbed and BCVA improved (at least 0.1 logMAR). In the following 6 months, no eye had recurrence of macular edema. CONCLUSIONS: Acute serous macular detachment and edema can occur after uncomplicated phacoemulsification. It should be considered in cases of low visual acuity during the early postoperative period. PMID- 26651310 TI - Lens opacities in glycogenoses type I and III. AB - OBJECTIVE: The glycogen storage diseases (GSD) or glycogenoses comprise several inherited diseases caused by abnormalities of the enzymes that regulate the synthesis or degradation of glycogen. This report presents lens opacities not previously described in patients with type I or III GSD. PARTICIPANTS: Eleven patients with type I and III GSD. METHODS: We examined a series of 11 consecutive patients (aged 13-40 years) with type I and III GSD by full ophthalmologic examination. RESULTS: We found changes of the lens on 7 of 11 patients (aged 23 40 years) with glycogenoses I and III. In 6 patients, the lens showed multiple, bilateral, punctate, and peripheral opacities; only 1 patient showed a posterior subcapsular opacity in both eyes. We did not observe changes in the cornea and the posterior pole correlated to the accumulation of glycogen and lipids. CONCLUSIONS: In this series, we found that 60% of patients with type I and III GSD show lens opacities. These opacities are bilateral, peripheral, multiple, and small; they do not give any visual disturbance. Considering that subjects with age ranging from 13 to 23 years had no lens opacities, we postulate that they could progressively develop over time because of exposure to recurrent attacks of hypoglycemia, which lead to a progressive depletion of hexokinase. PMID- 26651311 TI - Sensitivity of multifocal electroretinography (mfERG) in detecting siderosis. AB - OBJECTIVE: To evaluate use of multifocal electroretinography (mfERG) in diagnosing retinal toxicity from siderosis with normal ERG. DESIGN: Prospective case series. PARTICIPANTS: Six patients with retained intraocular foreign body were recruited. METHODS: The affected eye of the patients had no clinical evidence of siderosis, had similar full-field photopic 3.0 ERG compared with the fellow eye, and had subnormal visual acuity. Group averages in each MfERG ring for implicit time and amplitude at P1 wave were compared between affected and fellow eye to look for latent siderosis. RESULTS: On mfERG, no statistical difference in group averaged amplitude was observed; however, a significant difference (p < 0.05) was found in group averaged latency between fellow and affected eye at most tested rings (<2 degree, 2-5 degree, and >15 degree rings). Average latency for overall retinal area mapped also showed significant difference (p = 0.010). CONCLUSIONS: Increased mfERG latency may serve as an early predictor of retinal damage from siderosis when full-field ERG is normal. PMID- 26651312 TI - Rituximab treatment for nonparaneoplastic autoimmune retinopathy. PMID- 26651313 TI - The malignancy masquerader: hyperostosis and bone marrow hypertrophy after pleomorphic adenoma removal. PMID- 26651314 TI - Iris spatula-guided epinuclear cleavage in posterior polar cataracts. PMID- 26651315 TI - Iatrogenic retinal detachment secondary to inadvertent subretinal injection of triamcinolone during cataract surgery. PMID- 26651316 TI - Surgical management of 2 cases with Schwartz-Jampel syndrome. PMID- 26651317 TI - Intraocular pressure rise in the course of peginterferon alpha-2a, ribavirin, and boceprevir therapy for hepatitis C. PMID- 26651318 TI - Spectral-domain optical coherence tomography in mitochondrial encephalopathy, lactic acidosis, and strokelike episodes. PMID- 26651319 TI - A Ghostly OCT. PMID- 26651320 TI - Loss of red reflex due to trypan blue in a cataract operation. PMID- 26651321 TI - Small cell carcinoma of the lung metastatic to the retina: A clinicopathologic case report. PMID- 26651322 TI - Isolated orbital floor fracture lateral to infraorbital nerve: report of 2 pediatric patients. PMID- 26651323 TI - Delusional parasitosis involving the eyelid. PMID- 26651324 TI - Burnout Syndrome and Demotivation Among Health Care Personnel. Managing Stressful Situations: The Importance of Teamwork. AB - Almost one-third of our lives is spent in the workplace, where much of our interaction with others takes place and where we are exposed to stressful situations. Work-related stress has consequences for the individual's physical and mental health. Stress and professional burnout syndrome are the main consequences of work situations characterized by a constant state of tension. Stress is the second leading cause of absenteeism in the European Union, and around 12% of European workers are currently affected by burnout syndrome. It is therefore vital to identify demotivated and stressed staff in both large organizations (hospitals and clinics) and smaller centers (private practices) so as to facilitate preventive measures and ensure early intervention in situations of stress, with a view to improving the performance of work teams. PMID- 26651325 TI - Screening for Latent Tuberculosis in the Patient With Moderate to Severe Psoriasis Who Is a Candidate for Systemic and/or Biologic Therapy. AB - Screening to detect latent tuberculosis infection (LTBI) is essential before patients with moderate to severe psoriasis start treatment with biologics and vigilance will continue to be needed during and after such treatment. The most recently analyzed statistics from the BIOBADADERM registry show a 20.5% prevalence of LTBI in psoriasis patients treated with biologics in Spain. Various screening protocols are in effect in different countries according to their levels of endemic TB and bacillus Calmette-Guerin (BCG) vaccination, and there is no consensus on a gold-standard approach to the diagnosis of LTBI. Tuberculin skin testing (TST) continues to be the diagnostic method of choice in spite of its limited sensitivity, mainly in immunocompromised patients. Additional problems include the TST's well-established lack of specificity, errors in application, subjectivity in the interpretation of results (which must be read during a second visit), and lack of privacy; the main advantages of this test are its low cost and ease of application. Most cost-benefit studies are therefore inclined to favor using interferon-gamma release assays to detect LTBI because they minimize false positives (especially in BCG-vaccinated individuals), thereby eliminating the extra costs and side effects of unnecessary chemoprophylaxis. We review the methods used for LTBI screening in psoriasis patients who are candidates for biologic therapy. Additionally, given the fact that most guidelines do not currently consider it necessary to screen patients about to start conventional systemic therapy, we discuss the reasons underlying the need for such screening. PMID- 26651326 TI - Early Detection of Emotional and Behavioral Disorders in Dermatology. AB - Many skin diseases are associated with mental disorders. When the psychological symptoms are mild, as is often the case in dermatology, it can be difficult to distinguish between normality and the manifestations of a mental disorder. To facilitate the distinction we review the concept of mental disorder in the present article. It is also important to have instruments that can facilitate early detection of psychological disease, i.e. when the symptoms are still mild. Short, simple, self-administered questionnaires have been developed to help dermatologists and other health professionals identify the presence of a mental disorder with a high degree of certainty. In this article, we focus on the questionnaires most often used to detect the 2 most common mental disorders: anxiety and depression. Finally, we describe the circumstances in which it is advisable to refer a dermatological patient to a psychiatrist, who can diagnose and treat the mental disorder in accordance with standard protocols. PMID- 26651327 TI - Annular Lesions on the Head of an Infant. PMID- 26651328 TI - Teaching research methodology to student midwives through a socio-constructivist educational model: The experience of the high school for science and health techniques of Tunis. AB - Since its independence in 1956, Tunisia's maternal health indicators have steadily improved as the result of the implementation of a national holistic strategy that emancipated women and developed midwifery education and maternal health services provision. The last review of the midwifery education programme, occurred in 2008, and was based on evidence based core competencies. This paper describes the implementation process of the socio-constructivist educational model used by to teach research methodology to student midwives, the changes observed among them, the challenges and the lessons learned. PMID- 26651329 TI - On the analysis of movement smoothness. AB - Quantitative measures of smoothness play an important role in the assessment of sensorimotor impairment and motor learning. Traditionally, movement smoothness has been computed mainly for discrete movements, in particular arm, reaching and circle drawing, using kinematic data. There are currently very few studies investigating smoothness of rhythmic movements, and there is no systematic way of analysing the smoothness of such movements. There is also very little work on the smoothness of other movement related variables such as force, impedance etc. In this context, this paper presents the first step towards a unified framework for the analysis of smoothness of arbitrary movements and using various data. It starts with a systematic definition of movement smoothness and the different factors that influence smoothness, followed by a review of existing methods for quantifying the smoothness of discrete movements. A method is then introduced to analyse the smoothness of rhythmic movements by generalising the techniques developed for discrete movements. We finally propose recommendations for analysing smoothness of any general sensorimotor behaviour. PMID- 26651330 TI - Antioxidant and immunomodulatory properties of polysaccharides from Allanblackia floribunda Oliv stem bark and Chromolaena odorata (L.) King and H.E. Robins leaves. AB - BACKGROUND: Many plant polysaccharides have shown high antioxidant and immunostimulating properties and can be explored as novel molecules with biological properties that can potentially improve immune function. The objective of this work was to characterize soluble and cell wall polysaccharides isolated from the stem bark of Allanblackia floribunda and Chromolaena odorata leaves and to evaluate their antioxidant and immunomodulatory properties. METHODS: Three polysaccharide fractions: soluble polysaccharides (PoS), pectins (Pec) and hemicelluloses (Hem) were extracted from A. floribunda stem bark and C. odorata leaves. These samples were analysed for their proteins, phenolic compounds and total sugar contents. The monosaccharide composition was determined by gas chromatography and arabinogalactan proteins content in PoS was evaluated by rocket electrophoresis. The in vitro antioxidant activities were evaluated by 1, 1-diphenyl-2-picryl hydrazyl (DPPH) and 2,2'-azino-bis-3-ethylbenzylthiazoline-6 sulphonic acid (ABTS) radical scavenging assays and ferrous ions chelating activity. Immunomodulatory activities were performed on the peripheral blood mononuclear cells (PBMCs) using proliferation and enzyme linked immunospot (ELISPOT) method to determine the production of an interferon-gamma. RESULTS: The characterization of the various fractions showed varied metabolites in each plant. In PoS fractions, Ara and Gal were the major monosaccharides found, indicating that arabinogalactans are the primary macromolecules. Hem fractions contained predominantly Xyl and GalA for A. floribunda and Xyl (upto 80 %) for and C. odorata. A. floribunda Hem fraction and C. odorata PoS fraction showed significant DPPH and ABTS radical scavenging activities and immunostimulatory activity via stimulation of PBMC and production of IFN-gamma in a dose-dependent manner. CONCLUSION: The results obtained from this study support the ethnomedicinal use of the stem bark of A. floribunda and leaves of C. odorata. Further research is necessary to have supporting evidence that the antioxidative and immunomodulative activities of these fractions are really connected to the polysaccharides and not polyphenols. PMID- 26651331 TI - Seniors managing multiple medications: using mixed methods to view the home care safety lens. AB - BACKGROUND: Patient safety is a national and international priority with medication safety earmarked as both a prevalent and high-risk area of concern. To date, medication safety research has focused overwhelmingly on institutional based care provided by paid healthcare professionals, which often has little applicability to the home care setting. This critical gap in our current understanding of medication safety in the home care sector is particularly evident with the elderly who often manage more than one chronic illness and a complex palette of medications, along with other care needs. This study addresses the medication management issues faced by seniors with chronic illnesses, their family, caregivers, and paid providers within Canadian publicly funded home care programs in Alberta (AB), Ontario (ON), Quebec (QC) and Nova Scotia (NS). METHODS: Informed by a socio-ecological perspective, this study utilized Interpretive Description (ID) methodology and participatory photographic methods to capture and analyze a range of visual and textual data. Three successive phases of data collection and analysis were conducted in a concurrent, iterative fashion in eight urban and/or rural households in each province. A total of 94 participants (i.e., seniors receiving home care services, their family/caregivers, and paid providers) were interviewed individually. In addition, 69 providers took part in focus groups. Analysis was iterative and concurrent with data collection in that each interview was compared with subsequent interviews for converging as well as diverging patterns. RESULTS: Six patterns were identified that provide a rich portrayal of the complexity of medication management safety in home care: vulnerabilities that impact the safe management and storage of medication, sustaining adequate supports, degrees of shared accountability for care, systems of variable effectiveness, poly-literacy required to navigate the system, and systemic challenges to maintaining medication safety in the home. CONCLUSIONS: There is a need for policy makers, health system leaders, care providers, researchers, and educators to work with home care clients and caregivers on three key messages for improvement: adapt care delivery models to the home care landscape; develop a palette of user centered tools to support medication safety in the home; and strengthen health systems integration. PMID- 26651333 TI - The Salford Lung Study protocol: a pragmatic, randomised phase III real-world effectiveness trial in asthma. AB - BACKGROUND: Novel therapies need to be evaluated in normal clinical practice to allow a true representation of the treatment effectiveness in real-world settings. METHODS/DESIGN: The Salford Lung Study is a pragmatic randomised controlled trial in adult asthma, evaluating the clinical effectiveness and safety of once-daily fluticasone furoate (100 MUg or 200 MUg)/vilanterol 25 MUg in a novel dry-powder inhaler, versus existing asthma maintenance therapy. The study was initiated before this investigational treatment was licensed and conducted in real-world clinical practice to consider adherence, co-morbidities, polypharmacy, and real-world factors. PRIMARY ENDPOINT: Asthma Control Test at week 24; safety endpoints include the incidence of serious pneumonias. The study utilises the Salford electronic medical record, which allows near to real-time collection and monitoring of safety data. DISCUSSION: The Salford Lung Study is the world's first pragmatic randomised controlled trial of a pre-licensed medication in asthma. Use of patients' linked electronic health records to collect clinical endpoints offers minimal disruption to patients and investigators, and also ensures patient safety. This highly innovative study will complement standard double-blind randomised controlled trials in order to improve our understanding of the risk/benefit profile of fluticasone furoate/vilanterol in patients with asthma in real-world settings. TRIAL REGISTRATION: Clinicaltrials.gov, NCT01706198; 04 October 2012. PMID- 26651332 TI - Common mental disorder in Nyanza province, Kenya in 2013 and its associated risk factors--an assessment of change since 2004, using a repeat household survey in a demographic surveillance site. AB - BACKGROUND: Repeat household surveys are useful to assess change in prevalence over time, but there have been no repeat surveys of common mental disorder (CMD) in Kenya, or indeed sub-Saharan Africa. Therefore a repeat household survey of CMD and its associated risk factors was conducted in Maseno area, Kisumu county in Kenya, using a demographic surveillance site as the sample frame, in order to test the hypotheses that (a) the prevalence of CMD would increase between 2004 and 2013 due to the intervening political, social and economic pressures; (b) as in 2004, there would be no gender difference in prevalence of CMD. METHODS: One thousand one hundred ninety households were selected, and 1158 adult participants consented to be interviewed with a structured epidemiological assessment while 32 refused to participate in the study interviews, giving a response rate of 97.3%. RESULTS: The study found that the overall prevalence of CMD in 2013 was 10.3%. However, there were significantly higher rates of having any CMD in 2013 if one was female (OR 6.2, p < 0.001), divorced/widowed (OR 2.5, p < 0.003), aged over 60 (OR 2.3, p = 0.052), either self-employed (OR 3.3 p < 0.001) or employed (OR 3.3, p < 0.001), or belonged to the lowest asset quintile (OR 2.5, p = .0.004) after adjusting for other variables significant at the bivariate level. The overall prevalence in 2013 was consistent with that found in 2004, despite intervening political and community turbulence. However, this apparent consistency masks the development of a striking difference in prevalence between the genders. Over the decade 2004-13, the prevalence for men dropped from 10.9 to 3.8% (P = 0.001) and the prevalence for women increased from 10.8 to 17.5% (p = 0.001). CONCLUSION: Common mental disorders continue to pose a significant public health burden in Kenya, and gender related vulnerability merits further research and is relevant for health worker training. PMID- 26651334 TI - Sense of coherence as a mediator of health-related quality of life dimensions in patients with breast cancer: a longitudinal study with prospective design. AB - BACKGROUND: In our previous study, we found that the degree of sense of coherence (SOC) and baseline ratings of several dimensions of health-related quality of life (HRQoL) were the most important predictors of HRQoL changes 6 months after the pre-diagnosis period of breast cancer. To find a way to explain these findings, the aim of this study was to explore the mediating effect of the SOC between ratings of HRQoL dimensions before final diagnosis, and ratings of the same dimensions at the 6 months follow up, within a sample of women with breast cancer. METHODS: A longitudinal study with a prospective design at baseline (T1) and 6 months later (T2) was conducted on 162 women with breast cancer. To measure HRQoL dimensions three different questionnaires, the European Organization for Research and Treatment of Cancer QLQ-30, the SF-12 Health Survey version 2 and the Health Index were applied at T1 and T2 to cover both diagnostic-specific and generic dimensions. Measurement of the SOC as a mediator was done by the SOC-13 scale. RESULTS: Mediational analyses on eight significant pairs of HRQoL dimensions showed that the degree of SOC totally mediated variations of global quality of life (p < 0.001) as well as cognitive and social functioning (p <0.05) scores between T1 to T2. Changes in the scores of emotional functioning (p < 0.01), fatigue (p < 0.05), financial difficulties (p < 0.05), well-being (p < 0.001), and mental health component (p < 0.001) were partially mediated. The degree of SOC explained 16% to 45% of the variances in HRQoL dimensions at T2. CONCLUSIONS: The mediating pathway of the SOC in the context of this study appears to be the key to understanding how a higher sense of coherence as an inner resource may serve as a protective psychological factor in the adaptation process of the patients. Clinicians might consider coherence-oriented structure of the SOC and the connection between the SOC and HRQoL data in intervention plans from the first visit onwards. It may assist the identification of women who are at greater risk for maladaptation to the breast cancer trajectory. PMID- 26651335 TI - Administration of ivermectin to peridomestic cattle: a promising approach to target the residual transmission of human malaria. AB - BACKGROUND: The success of current control tools in combatting malaria vectors is well established. However, sustained residual transmission of Plasmodium parasites persists. Mass drug administration (MDA) to humans of the endectocide ivermectin for vector control is receiving increasing attention. However, vectors feeding upon animals escape this promising approach. Zoophagy of mosquitoes sustains both the vector population and endemic population of vector-borne pathogens. Therefore, only a strategy that will combine ivermectin MDAs targeted at humans and their peridomestic animals could be successful at controlling residual malaria transmission. METHODS: Burkinabe cattle have been treated with injectable therapeutic dose of ivermectin (0.2 mg/kg of body weight) to render blood meals toxic to field representative populations of Anopheles coluzzii carrying the kdr mutation. Direct skin-feeding assays were performed from 2 to 28 days after injection (DAI) and mosquitoes were followed for their survival, ability to become gravid and fecundity. Membrane feeding assays were further performed to test if an ivermectin blood meal taken at 28 DAI impacts gametocyte establishment and development in females fed with infectious blood. RESULTS: The mosquitocidal effect of ivermectin is complete for 2 weeks after injection, whether 12 days cumulative mortalities were of 75 and 45 % the third and fourth weeks, respectively. The third week, a second ivermectin blood meal at sub-lethal concentrations further increased mortality to 100 %. Sub-lethal concentrations of ivermectin also significantly decreased egg production by surviving females, increasing further the detrimental effect of the drug on vector densities. Although females fitness was impaired by sub-lethal ivermectin blood meals, these did not diminish nor increase their susceptibility to infection. CONCLUSION: This study demonstrates the potential of integrated MDA of ivermectin to both human and peridomestic cattle to target vector reservoirs of residual malaria transmission. Such integration lies in 'One-Health' efforts being implemented around the globe, and would be especially relevant in rural communities in Africa where humans are also at risk of common zoonotic diseases. PMID- 26651336 TI - Laparoscopic resection of retroperitoneal lymphangioma around the pancreas: a case report and review of the literature. AB - INTRODUCTION: Lymphangiomas are rare, benign tumors. An intra-abdominal location of these lesions is rarer still and there are only a few reports describing laparoscopic resection for retroperitoneal lymphangiomas, especially in tumors that mimic pancreatic tumors. CASE PRESENTATION: We present the case of an asymptomatic 30-year-old Japanese woman in whom a cystic tumor was found incidentally in close approximation to the pancreas. Because the tumor was located in the retroperitoneal space and the body of the pancreas was compressed, we were unable to distinguish a cystic lymphangioma from cystic pancreatic tumors. We started the procedure laparoscopically with five ports. The tumor was in fact separated from the pancreas and was dissected free from the body of the pancreas using scissors and laparoscopic coagulating shears. The left gastric vessels, which were compressed by the tumor, were preserved. As we realized that the tumor was connected to the retroperitoneal lymphatic tissue, we completed the procedure by performing a cystectomy without rupture. The specimen was extracted using a plastic bag. Our patient was discharged on postoperative day 7 without any complications. There is no evidence of recurrence during a >2-year observation period. CONCLUSIONS: In addition to the therapeutic significance in differentiating between a cystic lymphangioma in close approximation to the body of the pancreas and a pancreatic cystic neoplasm, the laparoscopic approach is feasible and effective. PMID- 26651337 TI - Nephrotoxicity caused by oral antiviral agents in patients with chronic hepatitis B treated in a hospital for tropical diseases in Thailand. AB - BACKGROUND: There is increasing concern about the potential for nephrotoxicity in patients with chronic hepatitis B (CHB) treated long-term with nucleotide analogs. METHODS: We examined renal dysfunction and its associated risk factors in patients with CHB treated with antiviral regimens containing either nucleosides or nucleotide analogs. We undertook a retrospective cohort study from 2006 to 2014 at the Hospital for Tropical Diseases, Bangkok, Thailand, and analyzed the data of 102 patients with a median follow-up time of 44.5 months (range 4-101 months). RESULTS: Seventy-three patients were treated with an antiviral regime containing a nucleoside analog, and 29 with a regime containing a nucleotide analog. Abnormally elevated serum creatinine concentration was observed in 12 patients (11.8 %) after 8 years of treatment. Thirty one percent of patients treated with nucleotide analogs had elevated serum creatinine levels and three of these patients (10.3 %) developed nephrotoxicity. In contrast, serum creatinine concentrations were elevated in three of the 73 patients treated with a nucleoside analog (4.1 %), and none developed nephrotoxicity. The incidence of renal dysfunction by the nucleotide analog regimen was cumulative, with 11.1, 21.0, 26.5 and 47.6 % of patients affected after 2, 4, 6 and 8 years, respectively. Univariate and multivariate analysis indicated that a nucleotide analog-based regimen significantly predicted renal dysfunction (odds ratio 10.5, 95 % confidence intervals 2.6-42.4, P <0.001). CONCLUSION: The long-term use of nucleotide analogs increased the risk of nephrotoxicity in patients with CHB. Thus, the regular assessment of renal function is recommended for all patients with CHB, particularly those treated with a nucleotide analog. PMID- 26651338 TI - AVP modulation of the vestibular nucleus via V1b receptors potentially contributes to the development of motion sickness in rat. AB - BACKGROUND: Arginine vasopressin (AVP) is considered to be an etiologic hormone in motion sickness (MS). The present study was designed to investigate whether individual differences in AVP expression in the paraventricular nucleus (PVN) and in modulation on the vestibular nucleus (VN) are involved in MS. Systemic application or microinjection of AVP into rat VN and rotatory stimulus were used to induce conditioned taste aversion (CTA) to 0.15 % saccharin sodium solution as a model of MS. RESULTS: Intra-VN use of SSR149415, an antagonist of V1b receptors (V1bRs), blunted CTA. AVP inhibited Ca(2+) influxes through L-type Ca(2+) channels and NMDA receptor channels in cultured VN neurones, but antagonised by SSR149415. More AVP and V1bRs were expressed respectively in the PVN and VN after rotatory stimulus, especially in rats susceptible to MS. In the VN, AVP content was low, the AVP mRNA was less expressed, a few AVP-positive fibres were sparsely distributed, and fewer AVP/synaptophysin-positive terminals were identified. Almost no fluoro-ruby-labelled AVP-positive neurones in the PVN were found with retrograde tracing from the VN. SNP analysis of the reported 9 sites of the AVP gene showed significant difference between the groups susceptible and insusceptible to MS at the site rs105235842 in the allele frequencies and genotypes. However, there was not any difference between these two groups in the SNP of the reported 38 sites of V1bR gene. CONCLUSIONS: AVP, through its modulatory, possibly humoral action on the VN neurones via the mediation of V1bR, may contribute to the development of motion sickness in rats; AVP gene polymorphisms may contribute to the individual difference in the responsive expression of AVP in the PVN; and higher expressions of AVP in the PVN and V1bRs in the VN may contribute to the development of motion sickness in rats after vestibular stimulation. PMID- 26651339 TI - Ideonella paludis sp. nov., isolated from a marsh. AB - A bacterial strain, designated KBP-31T, was isolated from a water sample taken from the Banping Lake Wetland Park in Taiwan and characterized using a polyphasic taxonomic approach. Cells of strain KBP-31T were Gram-stain-negative, strictly aerobic, motile, light-yellow rods. Growth occurred at 10-37 degrees C (optimum 25 degrees C), at pH 6-8 (optimum pH 6) and with 0-1 % NaCl (w/v, optimum 0 %). Phylogenetic analyses based on 16S rRNA gene sequences showed that strain KBP-31T belonged to the genus Ideonella and was most closely related to Ideonella dechloratans ATCC 51718T with a sequence similarity of 98.2 %. Strain KBP-31T contained summed feature 3 (comprising C16 : 1omega7c and/or C16 : 1omega6c) and C16 : 0 as the predominant fatty acids. The major hydroxyl fatty acid was C10 : 0 3-OH. The polar lipid profile consisted of phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol, an uncharacterized aminophospholipid and two uncharacterized phospholipids. The DNA G+C content of the genomic DNA was 67.9 mol%. The DNA-DNA relatedness of strain KBP-31T with respect to recognized species of the genus Ideonella was less than 70 %. On the basis of the phylogenetic inference and phenotypic data, strain KBP-31T should be classified as a novel species, for which the name Ideonella paludis sp. nov. is proposed. The type strain is KBP-31T ( = BCRC 80524T = KCTC 32238T). PMID- 26651342 TI - Exploring lesbian, gay, bisexual, and queer (LGBQ) people's experiences with disclosure of sexual identity to primary care physicians: a qualitative study. AB - BACKGROUND: It has been demonstrated that health disparities between lesbian, gay, bisexual and queer (LGBQ) populations and the general population can be improved by disclosure of sexual identity to a health care provider (HCP). However, heteronormative assumptions (that is, assumptions based on a heterosexual identity and experience) may negatively affect communication between patients and HCPs more than has been recognized. The aim of this study was to understand LGBQ patients' perceptions of their experiences related to disclosure of sexual identity to their primary care provider (PCP). METHODS: One-on-one semi structured telephone interviews were conducted, audio-recorded, and transcribed. Participants were self-identified LGBQ adults with experiences of health care by PCPs within the previous five years recruited in Toronto, Canada. A qualitative descriptive analysis was performed using iterative coding and comparing and grouping data into themes. RESULTS: Findings revealed that disclosure of sexual identity to PCPs was related to three main themes: 1) disclosure of sexual identity by LGBQ patients to a PCP was seen to be as challenging as coming out to others; 2) a solid therapeutic relationship can mitigate the difficulty in disclosure of sexual identity; and, 3) purposeful recognition by PCPs of their personal heteronormative value system is key to establishing a strong therapeutic relationship. CONCLUSION: Improving physicians' recognition of their own heteronormative value system and addressing structural heterosexual hegemony will help to make health care settings more inclusive. This will allow LGBQ patients to feel better understood, willing to disclose, subsequently improving their care and health outcomes. PMID- 26651341 TI - Aging in Down Syndrome and the Development of Alzheimer's Disease Neuropathology. AB - Chromosome 21, triplicated in Down Syndrome, contains several genes that are thought to play a critical role in the development of AD neuropathology. The overexpression of the gene for the amyloid precursor protein (APP), on chromosome 21, leads to early onset beta-amyloid (Abeta) plaques in DS. In addition to Abeta accumulation, middle-aged people with DS develop neurofibrillary tangles, cerebrovascular pathology, white matter pathology, oxidative damage, neuroinflammation and neuron loss. There is also evidence of potential compensatory responses in DS that benefit the brain and delay the onset of dementia after there is sufficient neuropathology for a diagnosis of AD. This review describes some of the existing literature and also highlights gaps in our knowledge regarding AD neuropathology in DS. It will be critical in the future to develop networked brain banks with standardized collection procedures to fully characterize the regional and temporal pathological events associated with aging in DS. As more information is acquired regarding AD evolution in DS, there will be opportunities to develop interventions that are age-appropriate to delay AD in DS. PMID- 26651340 TI - Role of Trisomy 21 Mosaicism in Sporadic and Familial Alzheimer's Disease. AB - Trisomy 21 and the consequent extra copy of the amyloid precursor protein (APP) gene and increased beta-amyloid (Abeta) peptide production underlie the universal development of Alzheimer's disease (AD) pathology and high risk of AD dementia in people with Down syndrome (DS). Trisomy 21 and other forms of aneuploidy also arise among neurons and peripheral cells in both sporadic and familial AD and in mouse and cell models thereof, reinforcing the conclusion that AD and DS are two sides of the same coin. The demonstration that 90% of the neurodegeneration in AD can be attributed to the selective loss of aneuploid neurons generated over the course of the disease indicates that aneuploidy is an essential feature of the pathogenic pathway leading to the depletion of neuronal cell populations. Trisomy 21 mosaicism also occurs in neurons and other cells from patients with Niemann Pick C1 disease and from patients with familial or sporadic frontotemporal lobar degeneration (FTLD), as well as in their corresponding mouse and cell models. Biochemical studies have shown that Abeta induces mitotic spindle defects, chromosome mis-segregation, and aneuploidy in cultured cells by inhibiting specific microtubule motors required for mitosis. These data indicate that neuronal trisomy 21 and other types of aneuploidy characterize and likely contribute to multiple neurodegenerative diseases and are a valid target for therapeutic intervention. For example, reducing extracellular calcium or treating cells with lithium chloride (LiCl) blocks the induction of trisomy 21 by Abeta. The latter finding is relevant in light of recent reports of a lowered risk of dementia in bipolar patients treated with LiCl and in the stabilization of cognition in AD patients treated with LiCl. PMID- 26651343 TI - Genome-wide analysis of the basic leucine zipper (bZIP) transcription factor gene family in six legume genomes. AB - BACKGROUND: Plant bZIP proteins characteristically harbor a highly conserved bZIP domain with two structural features: a DNA-binding basic region and a leucine (Leu) zipper dimerization region. They have been shown to be diverse transcriptional regulators, playing crucial roles in plant development, physiological processes, and biotic/abiotic stress responses. Despite the availability of six completely sequenced legume genomes, a comprehensive investigation of bZIP family members in legumes has yet to be presented. RESULTS: In this study, we identified 428 bZIP genes encoding 585 distinct proteins in six legumes, Glycine max, Medicago truncatula, Phaseolus vulgaris, Cicer arietinum, Cajanus cajan, and Lotus japonicus. The legume bZIP genes were categorized into 11 groups according to their phylogenetic relationships with genes from Arabidopsis. Four kinds of intron patterns (a-d) within the basic and hinge regions were defined and additional conserved motifs were identified, both presenting high group specificity and supporting the group classification. We predicted the DNA-binding patterns and the dimerization properties, based on the characteristic features in the basic and hinge regions and the Leu zipper, respectively, which indicated that some highly conserved amino acid residues existed across each major group. The chromosome distribution and analysis for WGD derived duplicated blocks revealed that the legume bZIP genes have expanded mainly by segmental duplication rather than tandem duplication. Expression data further revealed that the legume bZIP genes were expressed constitutively or in an organ-specific, development-dependent manner playing roles in multiple seed developmental stages and tissues. We also detected several key legume bZIP genes involved in drought- and salt-responses by comparing fold changes of expression values in drought-stressed or salt-stressed roots and leaves. CONCLUSIONS: In summary, this genome-wide identification, characterization and expression analysis of legume bZIP genes provides valuable information for understanding the molecular functions and evolution of the legume bZIP transcription factor family, and highlights potential legume bZIP genes involved in regulating tissue development and abiotic stress responses. PMID- 26651344 TI - Urodynamics for Prostate Surgery Trial; Randomised Evaluation of Assessment Methods (UPSTREAM) for diagnosis and management of bladder outlet obstruction in men: study protocol for a randomised controlled trial. AB - BACKGROUND: Lower urinary tract symptoms (LUTS) comprise storage symptoms, voiding symptoms and post-voiding symptoms. Prevalence and severity of LUTS increase with age and the progressive increase in the aged population group has emphasised the importance to our society of appropriate and effective management of male LUTS. Identification of causal mechanisms is needed to optimise treatment and uroflowmetry is the simplest non-invasive test of voiding function. Invasive urodynamics can evaluate storage function and voiding function; however, there is currently insufficient evidence to support urodynamics becoming part of routine practice in the clinical evaluation of male LUTS. DESIGN: A 2-arm trial, set in urology departments of at least 26 National Health Service (NHS) hospitals in the United Kingdom (UK), randomising men with bothersome LUTS for whom surgeons would consider offering surgery, between a care pathway based on urodynamic tests with invasive multichannel cystometry and a care pathway based on non-invasive routine tests. The aim of the trial is to determine whether a care pathway not including invasive urodynamics is no worse for men in terms of symptom outcome than one in which it is included, at 18 months after randomisation. This primary clinical outcome will be measured with the International Prostate Symptom Score (IPSS). We will also establish whether inclusion of invasive urodynamics reduces rates of bladder outlet surgery as a main secondary outcome. DISCUSSION: The general population has an increased life-expectancy and, as men get older, their prostates enlarge and potentially cause benign prostatic obstruction (BPO) which often requires surgery. Furthermore, voiding symptoms become increasingly prevalent, some of which may not be due to BPO. Therefore, as the population ages, more operations will be considered to relieve BPO, some of which may not actually be appropriate. Hence, there is sustained interest in the diagnostic pathway and this trial could improve the chances of an accurate diagnosis and reduce overall numbers of surgical interventions for BPO in the NHS. The morbidity, and therapy costs, of testing must be weighed against the cost saving of surgery reduction. TRIAL REGISTRATION: Controlled-trials.com - ISRCTN56164274 (confirmed registration: 8 April 2014). PMID- 26651345 TI - The atypical two-subunit sigma factor from Bacillus subtilis is regulated by an integral membrane protein and acid stress. AB - Extracytoplasmic function (ECF) sigma factors constitute a major component of the physicochemical sensory apparatus in bacteria. Most ECF sigma factors are co expressed with a negative regulator called an anti-sigma factor that binds to its cognate sigma factor and sequesters it from productive association with core RNA polymerase (RNAP). Anti-sigma factors constitute an important element of signal transduction pathways that mediate an appropriate transcriptional response to changing environmental conditions. The Bacillus subtilis genome encodes seven canonical ECF sigma factors and six of these are co-expressed with experimentally verified anti-sigma factors. B. subtilis also expresses an ECF-like atypical two subunit sigma factor composed of subunits SigO and RsoA that becomes active after exposure to certain cell-wall-acting antibiotics and to growth under acidic conditions. This work describes the identification and preliminary characterization of a protein (RsiO, formerly YvrL) that constitutes the anti sigma factor cognate to SigO-RsoA. Synthesis of RsiO represses SigO-RsoA dependent transcription initiation by binding the N-terminus of SigO under neutral (pH 7) conditions. Reconstitution of the SigO-RsoA-RsiO regulatory system into a heterologous host reveals that the imposition of acid stress (pH 5.4) abolishes the ability of RsiO to repress SigO-RsoA-dependent transcription and this correlates with loss of RsiO binding affinity for SigO. A current model for RsiO function indicates that RsiO responds, either directly or indirectly, to increased extracytoplasmic hydrogen ion concentration and becomes inactivated. This results in the release of SigO into the cytoplasm, where it productively associates with RsoA and core RNAP to initiate transcription from target promoters in the cell. PMID- 26651346 TI - Albuminuria and its associated biomedical factors among indigenous adults in Far North Queensland: a 7-year follow up study. AB - BACKGROUND: To document albuminuria prevalence and its associated factors in Aboriginal and Torres Strait Islander (TSI) adults with high renal and metabolic risks from 19 rural and remote north Queensland communities. METHODS: One thousand nine hundred seventy-one indigenous adults were enrolled in 1998 and 566 completed follow up in 2007 in this population-based study. Measurements included weight, waist circumference (WC), blood pressure (BP), fasting glucose, lipids, gamma-glutamyltransferase (GGT), urinary albumin creatinine ratio (UACR), smoking, alcohol intake and physical activity (PA). Albuminuria was defined as an UACR > =2.5 g/mol in males and > =3.5 g/mol in females. The association between albuminuria and biomedical factors was assessed with generalised linear modelling. RESULTS: Baseline albuminuria prevalence was 19.7 % (95 % CI: 18.0 21.6 %). Follow up prevalence was 42.4 % (95 % CI: 38.4-46.5 %) among the 566 adults having the 2(nd) UACR measurements. Follow-up albuminuria was associated with fasting glucose of 5.4 mmol/L (OR 2.5, 95 % CI 1.5-4.2), GGT tertiles in a dose-response manner (OR 2.0 for 2(nd) and 3.7 for 3(rd) tertile, p for trend <0.001), and abdominal overweight and obesity (OR 2.1, 95 % CI 1.1-3.9 and 5.4, 95 % CI: 2.2-13.5 respectively). Aboriginal people with diabetes were three times more likely of having albuminuria compared to TSI counterparts, while TSI smokers had twice the likelihood (95 % CI 1.2-3.2). At both baseline and follow up, albuminuria was more prevalent among older participants. CONCLUSIONS: Indigenous Australians in north Queensland are at high risk of albuminuria. Overweight and obesity, glycaemia, increased GGT, and smoking were associated with albuminuria at baseline and/or follow up. PMID- 26651347 TI - With practice, keyboard shortcuts become faster than menu selection: A crossover interaction. AB - It is widely believed that a graphical user interface (GUI) is superior to a command line interface (CLI) for novice users, but less efficient than the CLI after practice. However, there appears to be no detailed study of the crossover interaction that this implies. The rate of learning may shed light on the reluctance of experienced users to adopt keyboard shortcuts, even though, when mastered, shortcut use would reduce task completion times. We report 2 experiments examining changes in the efficiency of and preference for keyboard input versus GUI with practice. Experiment 1 had separate groups of subjects make speeded choice responses to words on a 20-item list either by clicking on a tab in a dropdown menu (GUI version) or by entering a preassigned keystroke combination (CLI version). The predicted crossover was observed after approximately 200 responses. Experiment 2 showed that following training all but 1 subject in the CLI-trained group chose to continue using shortcuts. These results suggest that frequency of shortcut use is a function of ease of retrieval, which develops over the course of multiple repetitions of the command. We discuss possible methods for promoting shortcut learning and the practical implications of our results. PMID- 26651348 TI - The influence of framing on clinicians' judgments of the biological basis of behaviors. AB - Practicing clinicians frequently think about behaviors both abstractly (i.e., in terms of symptoms, as in the Diagnostic and Statistical Manual of Mental Disorders, 5th ed., DSM-5; American Psychiatric Association, 2013) and concretely (i.e., in terms of individual clients, as in DSM-5 Clinical Cases; Barnhill, 2013). Does abstract/concrete framing influence clinical judgments about behaviors? Practicing mental health clinicians (N = 74) were presented with hallmark symptoms of 6 disorders framed abstractly versus concretely, and provided ratings of their biological and psychological bases (Experiment 1) and the likely effectiveness of medication and psychotherapy in alleviating them (Experiment 2). Clinicians perceived behavioral symptoms in the abstract to be more biologically and less psychologically based than when concretely described, and medication was viewed as more effective for abstractly than concretely described symptoms. These findings suggest a possible basis for miscommunication and misalignment of views between primarily research-oriented and primarily practice-oriented clinicians; furthermore, clinicians may accept new neuroscience research more strongly in the abstract than for individual clients. PMID- 26651349 TI - The role of siblings in adoption outcomes and experiences from adolescence to emerging adulthood. AB - In many families, siblings play important roles in shaping each other's outcomes and experiences across development. In adoptive families, siblings may affect adoptees' feelings about adoption and birth family contact. Among "target adoptees" (i.e., 1 participating adopted individual within adoptive families) with siblings who may have also been adopted or the biological children of the adoptive parents, we examined how adoption experiences and individual adjustment from adolescence into emerging adulthood were associated with sibling relationship dynamics. We present 3 studies using longitudinal, mixed method data within the same overarching sample of adoptive families. Study 1 was a follow-up to Berge et al.'s (2006) study of adolescent adoptees and their adopted siblings with birth family contact; we found evidence of changes in the status of contact collectively experienced by 26 adopted sibling pairs when target adoptees were emerging adults. In Study 2, we found that target adoptees (n = 91) with siblings (adopted or not) who were more involved with target adoptees' birth family contact demonstrated more favorable behavioral outcomes than target adoptees who had uninvolved siblings. Finally in Study 3, for target adoptees with siblings who were also adopted (n = 51), results showed that target adoptees felt more positively about their own adoption when siblings expressed similar positive feelings about individual adoption experiences. Implications of our findings are discussed in terms of the enduring contributions of sibling relationships from childhood into adulthood and the unique ways in which adoptive siblings are important in shaping one another's experiences of adoption. PMID- 26651350 TI - The intergenerational continuity of socioeconomic status: Effects of parenting, personality, and age at first romantic partnership. AB - Research has indicated that socioeconomic status (SES) is related to individual health and well-being, and may be transmitted across generations. According to the interactionist model, circumstances in the family of origin and individual characteristics both account for social, economic, and developmental outcomes associated with SES. Thus, for the present investigation, we evaluated continuities in SES across 2 generations (G1, G2) as mediated through G1 maternal positive parenting, G2 personality, and G2 age of first committed romantic partnership. Participants were 432 emerging adults from an ongoing longitudinal study. Consistent with the interactionist model, G1 SES was associated with G2 personality indirectly through G1 maternal positive parenting. G1 SES, G2 personality, and G2 first partnership directly predicted G2 SES. G1 maternal positive parenting was also indirectly associated with G2 age at first partnership through G2 personality. Findings were consistent across 2 broad personality domains-negative emotionality and constraint. However, positive emotionality was not associated with G2 age at partnership. (PsycINFO Database Record PMID- 26651351 TI - Marital satisfaction and maternal depressive symptoms among Korean mothers transitioning to parenthood. AB - Although many empirical findings support associations between marital satisfaction and depressive symptoms, gaps remain in our understanding of the magnitude and direction of the associations between marital satisfaction and depressive symptoms as well as the associations in a collectivistic culture. The present study examined autoregressive cross-lagged associations between marital satisfaction and maternal depressive symptoms across a 3-year investigation in a sample of Korean mothers transitioning to parenthood. The sample consisted of 2,078 mothers in the Panel Study of Korean Children. The mothers reported marital satisfaction and maternal depressive symptoms annually for 3 years. The results of an autoregressive cross-lagged model revealed bidirectional associations between marital satisfaction and maternal depressive symptoms. The findings provide evidence of an interactional model of depression in a sample of Korean mothers. (PsycINFO Database Record PMID- 26651352 TI - Cognitive-behavioral conjoint therapy for PTSD improves various PTSD symptoms and trauma-related cognitions: Results from a randomized controlled trial. AB - Numerous studies document an association between posttraumatic stress disorder (PTSD) and impairments in intimate relationship functioning, and there is evidence that PTSD symptoms and associated impairments are improved by cognitive behavioral conjoint therapy for PTSD (CBCT for PTSD; Monson & Fredman, 2012). The present study investigated changes across treatment in clinician-rated PTSD symptom clusters and patient-rated trauma-related cognitions in a randomized controlled trial comparing CBCT for PTSD with waitlist in a sample of 40 individuals with PTSD and their partners (N = 40; Monson et al., 2012). Compared with waitlist, patients who received CBCT for PTSD immediately demonstrated greater improvements in all PTSD symptom clusters, trauma-related beliefs, and guilt cognitions (Hedge's gs -.33 to -1.51). Results suggest that CBCT for PTSD improves all PTSD symptom clusters and trauma-related cognitions among individuals with PTSD and further supports the value of utilizing a couple-based approach to the treatment of PTSD. PMID- 26651353 TI - Pyrene-Oxadiazoles for Organic Light-Emitting Diodes: Triplet to Singlet Energy Transfer and Role of Hole-Injection/Hole-Blocking Materials. AB - Three pyrene-oxadiazole derivatives were synthesized and characterized by optical, electrochemical, thermal, and theoretical investigations to obtain efficient multifunctional organic light emitting diode (OLED) materials. Synthesized molecules were used as emitters and electron transporters in three different device configurations, involving hole-injection/hole-blocking materials that showed good current and power efficiencies. To understand the underlying mechanisms involved in the application of these molecules as emitters and transporters, a detailed photophysical characterization of molecules 4-6 was carried out. The absorption, steady-state fluorescence, phosphorescence, fluorescence lifetime, and phosphorescence lifetime measurements were carried out. The high quantum yield and efficient reverse intersystem crossing leading to delayed fluorescence emission makes the molecule a good emitter, and the charge delocalization properties leading to excimer formation make them efficient electron transporters. Isoenergetic singlet and triplet states of the molecules make the reverse intersystem crossing feasible at room temperature even in the absence of thermal activation. PMID- 26651355 TI - Synthesis of 1,1,1-Tris(boronates) from Vinylarenes by Co-Catalyzed Dehydrogenative Borylations-Hydroboration. AB - The selective preparation of 1,1,1-tris(boronates) from vinylarenes and bis(pinacolato)diboron is described. The reactions occur at ambient temperature with excellent selectivity, high yields, and good functional group tolerance. Mechanistic studies suggest that Co(I)-catalyzed double dehydrogenative borylations generate a 1,1-diborylalkene intermediate, which undergoes hydroboration with pinacolborane formed in situ to yield 1,1,1-tris(boronate). PMID- 26651354 TI - Assembly-Controlled Permeability of Layer-by-Layer Polymeric Microcapsules Using a Tapered Fluidized Bed. AB - Nano- and microcapsules engineered through layer-by-layer (LbL) assembly are finding an increasingly large number of applications as catalysts, electrochemical biosensors, bioreactors, artificial cells and drug delivery vehicles. While centrifugation-based LbL assembly is the most common method for coating template particles and preparing capsules, it is a batch process and requires frequent intervention that renders the system challenging to automate and scale up. Here, we report the use of a tapered fluidized bed (TFB) for the preparation of multilayered polymer capsules. This is a significant improvement over our recent approach of fluidizing particles in cylindrical fluidized beds (CFB) for LbL assembly. We demonstrate that TFB is compatible with particles <3 MUm in diameter (an order-of-magnitude improvement compared with CFB), which can be fluidized with minimal entrainment. Additionally, layering materials were expanded to include both electrostatic and hydrogen-bonding polymer pairs (e.g., poly(allylamine hydrochloride) (PAH) and poly(styrenesulfonate) (PSS), and thiol modified poly(methacrylic acid) (PMASH) and poly(N-vinylpyrrolidone) (PVPON), respectively). Finally, differences between capsules prepared via centrifugation based and TFB LbL assembly were investigated. The obtained TFB microcapsules demonstrate increased film thickness and roughness compared with those prepared using centrifugation-based LbL assembly. Furthermore, PMASH microcapsules exhibit lower swelling and permeability when prepared via TFB LbL assembly compared with centrifugation-based LbL assembly due to enhanced multilayer deposition, entanglement, and cross-linking. Therefore, polymeric capsules fabricated via TFB LbL assembly may be useful for encapsulation and retention of relatively low molecular weight (~20 kDa) hydrophilic biomacromolecules to passively or responsively release the payload for drug delivery applications. PMID- 26651357 TI - Sensitive Water Probing through Nonlinear Photon Upconversion of Lanthanide-Doped Nanoparticles. AB - Lanthanide-doped upconversion nanoparticles have received growing attention in the development of low-background, highly sensitive and selective sensors. Here, we report a water probe based on ligand-free NaYF4:Yb/Er nanoparticles, utilizing their intrinsically nonlinear upconversion process. The water molecule sensing was realized by monitoring the upconversion emission quenching, which is mainly attributed to efficient energy transfer between upconversion nanoparticles and water molecules as well as water-absorption-induced excitation energy attenuation. The nonlinear upconversion process, together with power function relationship between upconversion emission intensity and excitation power density, offers a sensitive detection of water content down to 0.008 vol % (80 ppm) in an organic solvent. As an added benefit, we show that noncontact detection of water can be achieved just by using water attenuation effect. Moreover, these upconversion nanoparticle based recyclable probes should be particularly suitable for real-time and long-term water monitoring, due to their superior chemical and physical stability. These results could provide insights into the design of upconversion nanoparticle based sensors. PMID- 26651356 TI - Kynurenine Signaling Increases DNA Polymerase Kappa Expression and Promotes Genomic Instability in Glioblastoma Cells. AB - Overexpression of the translesion synthesis polymerase hpol kappa in glioblastomas has been linked to poor patient prognosis; however, the mechanism promoting higher expression in these tumors remains unknown. We determined that activation of the aryl hydrocarbon receptor (AhR) pathway in glioblastoma cells leads to increased hpol kappa mRNA and protein levels. We blocked nuclear translocation and DNA binding by AhR in glioblastoma cells using a small-molecule and observed decreased hpol kappa expression. Pharmacological inhibition of tryptophan-2,3-dioxygenase (TDO), the enzyme largely responsible for activating AhR in glioblastoma, led to a decrease in the endogenous AhR agonist kynurenine and a corresponding decrease in hpol kappa protein levels. Importantly, we discovered that inhibiting TDO activity, AhR signaling, or suppressing hpol kappa expression with RNA interference led to decreased chromosomal damage in glioblastoma cells. Epistasis assays further supported the idea that TDO activity, activation of AhR signaling, and the resulting overexpression of hpol kappa function primarily in the same pathway to increase endogenous DNA damage. These findings indicate that upregulation of hpol kappa through glioblastoma specific TDO activity and activation of AhR signaling likely contributes to the high levels of replication stress and genomic instability observed in these tumors. PMID- 26651358 TI - Interaction between Tea Polyphenols and Bile Acid Inhibits Micellar Cholesterol Solubility. AB - The molecular mechanism by which tea polyphenols decrease the micellar solubility of cholesterol is not completely clear. To clarify this mechanism, this study investigated the interaction between tea polyphenols (catechins and oolongtheanins) and cholesterol micelles. A nuclear magnetic resonance (NMR) study was performed on a micellar solution containing taurocholic acid and epigallocatechin gallate (EGCg), and high-performance liquid chromatography (HPLC) analysis was carried out on the precipitate and the supernatant that formed when EGCg was added to a cholesterol-micelle solution. The data indicated a regiospecific interaction of EGCg with taurocholic acid. Therefore, the ability of EGCg to lower the solubility of phosphatidylcholine (PC) and cholesterol in micellar solutions can be attributed to their elimination from the micelles due to interaction between taurocholic acids and EGCg. PMID- 26651359 TI - Ge/GeO2-Ordered Mesoporous Carbon Nanocomposite for Rechargeable Lithium-Ion Batteries with a Long-Term Cycling Performance. AB - Germanium-based nanostructures are receiving intense interest in lithium-ion batteries because they have ultrahigh lithium ion storage ability. However, the Germanium-based anodes undergo the considerably large volume change during the charge/discharge processes, leading to a fast capacity fade. In the present work, a Ge/GeO2-ordered mesoporous carbon (Ge/GeO2-OMC) nanocomposite was successfully fabricated via a facile nanocasting route by using mesoporous carbon as a nanoreactor, and was then used as an anode for lithium-ion batteries. Benefited from its unique three-dimensional "meso-nano" structure, the Ge/GeO2-OMC nanocomposite exhibited large reversible capacity, excellent long-time cycling stability and high rate performance. For instance, a large reversible capacity of 1018 mA h g(-1) was obtained after 100 cycles at a current density of 0.1 A g( 1), which might be attributed to the unique structure of the Ge/GeO2-OMC nanocomposite. In addition, a reversible capacity of 492 mA h g(-1) can be retained when cycled to 500 cycles at a current density of 1 A g(-1). PMID- 26651360 TI - Inner-Shell Water Rearrangement Following Photoexcitation of Tris(2,2' bipyridine)iron(II). AB - The solvent dynamics in Fe-tris-bipyridine [Fe(bpy)3](2+) upon electronic excitation (oxidation) and subsequent relaxation is followed on the picosecond time scale by using atomistic simulations. Starting from the low spin (LS) Fe(II)LS state the transition to the excited Fe(III) (1,3)MLCT (metal-to-ligand charge transfer) state decreases the water coordination in immediate proximity of the central iron atom. This readjustment of the solvent shell occurs on the subpicosecond time scale. Full relaxation of the water environment would occur on the 10 ps time scale which is, however, never reached as the lifetime of the (1,3)MLCT state is only 200 fs. Further relaxation toward the long-lived (665 ps) [Fe(II)HS(bpy)3] high spin (HS) state does not change the degree of solvation. The results support a model in which the change in the degree of solvation is driven by electronic effects (charge redistribution) and not by structural changes (change in bond lengths). Furthermore, the results are consistent with recent combined X-ray emission (XES) and X-ray diffusion (XDS) scattering experiments which provided evidence for a reduced solvent density upon excitation of the [Fe(II)LS(bpy)3] initial state. However, the time scale for water exchange dynamics is faster than that found in the experiments. PMID- 26651361 TI - Copper-Catalyzed Vicinal Oxyazidation and Diazidation of Styrenes under Mild Conditions: Access to Alkyl Azides. AB - A novel and efficient copper-catalyzed oxyazidation and diazidation of styrenes is described. The stable azidoiodine(III) reagent is used as an efficient azide radical source in this reaction. A variety of synthetically useful functional groups are compatible with the mild reaction conditions. This protocol enables the straightforward synthesis of various functionalized azides in good-to excellent yields. PMID- 26651362 TI - IPEC-J2 MDR1, a Novel High-Resistance Cell Line with Functional Expression of Human P-glycoprotein (ABCB1) for Drug Screening Studies. AB - The P-glycoprotein (P-gp) efflux pump has been shown to affect drug distribution and absorption in various organs and to cause drug resistance in cancer therapy. The aim of this work was to develop a cell line to serve as a screening system for potential substrates of P-gp. This requires a cell line with high paracellular tightness, low expression of nonhuman ABC transporters, and high expression of functional human P-gp (ABCB1). The porcine intestinal epithelial cell line, IPEC-J2, was selected as a transfection host, due to its ability to form extremely high-resistance monolayers (>10,000 Omega.cm(2)) and its low endogenous expression of ABC-type efflux transporters. The IPEC-J2 cells were transfected with a plasmid that contained the sequence of the human MDR1 gene, which encodes P-gp, followed by a selection of successfully transfected cells with geneticin and puromycin. The resulting cell line, IPEC-J2 MDR1, retained its high transepithelilal resistance (>15,000 Omega.cm(2)), which translated into low permeability of the small hydrophilic tracer, mannitol (P < 10(-7) cm.s(-1)). The lipophilic compound, diazepam, displayed high permeability resulting in a dynamic range of 1500 (PDiazepam/Pmannitol) to separate high and low permeability compounds. Human P-gp was expressed predominantly in the apical membrane, as demonstrated by immunocytochemistry, Western blots, and a high efflux ratios (Pbasolateral-apical/Papical-basolateral) of known P-gp substrates. P-gp was demonstrated to be responsible for the efflux transport by substrate profiling, combined with application of P-gp and BCRP inhibitors. Furthermore, the compounds atenolol, citalopram, and mitoxantrone were identified as P-gp substrates. Functional P-gp expression was shown to be stable through at least 10 cell passages. In conclusion, the IPEC-J2 MDR1 cell line displays high paracellular tightness combined with high expression of human P-gp and low expression of porcine ABC transporters, and it may serve as a useful tool in drug development studies. PMID- 26651363 TI - Shock-Induced Ordering in a Nano-segregated Network-Forming Ionic Liquid. AB - Understanding shockwave-induced physical and chemical changes of impact-absorbing materials is an important step toward the rational design of materials that mitigate the damage. In this work, we report a series of network-forming ionic liquids (NILs) that possess an intriguing shockwave absorption property upon laser-induced shockwave. Microstructure analysis by X-ray scattering suggests nano-segregation of alkyl side chains and charged head groups in NILs. Further post-shock observations indicate changes in the low-Q region, implying that the soft alkyl domain in NILs plays an important role in absorbing shockwaves. Interestingly, we observe a shock-induced ordering in the NIL with the longest (hexyl) side chain, indicating that both nano-segregated structure and shock induced ordering contribute to NIL's shockwave absorption performance. PMID- 26651364 TI - Mannose-derived FimH antagonists: a promising anti-virulence therapeutic strategy for urinary tract infections and Crohn's disease. AB - INTRODUCTION: Type 1 pili are utilized by Gram-negative bacteria to adhere to host tissue and thus are a key virulence factor in urinary tract infections (UTIs) and Crohn's disease (CD). This adhesion is mediated through specific binding of the terminal adhesin, FimH, to mannosylated host glycoproteins. FimH is essential for UTI pathogenesis and thus is a promising therapeutic target. AREAS COVERED: Herein, we review the structural frameworks of FimH antagonists disclosed in the patent literature. X-ray crystallographic binding studies of D mannose and early FimH antagonists have uncovered key molecular interactions. Exploiting this knowledge, mannosides with extraordinarily high binding affinities have been designed. Structure-activity relationships (SAR) and structure-property relationship (SPR) studies have resulted in the rapid development of orally bioavailable FimH antagonists with promising therapeutic potential for UTI and CD. EXPERT OPINION: It is our opinion that biaryl or 'two ring' mannosides, which represent the largest and most thoroughly tested class of FimH antagonists, also hold the most promise as a novel treatment for UTIs. These antagonists have also been shown to have efficacy in treating CD. Judging from the strong preclinical data, we predict that one or more FimH antagonists will be entering the clinic within the next 1-2 years. PMID- 26651365 TI - Understanding Engagement in HIV Risk and Prevention Research Among Black Young Men Who Have Sex with Men and Transgender Women in the District of Columbia. AB - PURPOSE: To develop optimal methods to study sexual health among black young men who have sex with men and transgender women (BYMSM/TW). METHODS: We conducted a mixed-methods prospective study to identify recruitment and retention strategies for BYMSM/TW (age 16-21) in Washington D.C., and describe HIV risk behaviors and context. RESULTS: Incentivized peer referral was highly productive, and 60% of BYMSM/TW were retained for 3 months. Participants reported high levels of sexual risk, homophobia, racism, and maternal support. CONCLUSION: BYMSM/TW studies should utilize a combination of peer-based, in-person, and technology-based recruiting strategies. Additional research is needed to leverage mobile technology and social media to enhance retention. PMID- 26651366 TI - Dihydroisocoumarin Derivatives from Marine-Derived Fungal Isolates and Their Anti inflammatory Effects in Lipopolysaccharide-Induced BV2 Microglia. AB - Chemical investigation of the EtOAc extracts of marine-derived fungal isolates Aspergillus sp. SF-5974 and Aspergillus sp. SF-5976 yielded a new dihydroisocoumarin derivative (1) and 12 known metabolites. The structures of the isolated metabolites were established by extensive spectroscopic analyses, including 1D and 2D NMR spectra and MS data. Among the metabolites, the absolute configuration of 5'-hydroxyasperentin (6) was determined by single-crystal X-ray diffraction analysis. The in vitro antineuroinflammatory effects of the metabolites were also evaluated in lipopolysaccharide (LPS)-stimulated microglial cells. Among the isolated metabolites, dihydroisocoumarin derivatives 1-6 (10-80 MUM) were shown to inhibit LPS-induced nitric oxide (NO) and prostaglandin E2 (PGE2) production by suppressing the expression of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2), respectively, in LPS-stimulated BV2 microglia. Further, 1 (20-80 MUM) was found to suppress the phosphorylation of the inhibitor of nuclear factor kappa B-alpha (IkappaB-alpha), interrupt the nuclear translocation of nuclear factor kappa B (NF-kappaB), and decrease the activation of p38 mitogen-activated protein kinase (MAPK). PMID- 26651367 TI - Turkish Migrant Women with Recurrent Depression: Results from Community-based Self-help Groups. AB - The study focuses on psychosocial functioning of female Turkish immigrants in Austria with recurrent depressive disorder participating in self-help groups. Self-help groups guided by group leaders of Turkish descent should increase autonomy in participants, providing the opportunity to follow their ethnic health beliefs. Turkish immigrant women (n = 43) with recurrent depressive disorder participated in self-help groups over four months. Qualitative data of participants and group leaders, containing interviews, group protocols and supervision protocols of group leaders were analyzed using the qualitative content analysis for effects on psychosocial function, such as interaction with others, illness beliefs and benefit from self-help group. Women reported feelings of being neglected and violated by their husbands. They stated that they had gained strength and had emancipated themselves from their husbands. Self-help groups functioned as social resources and support for changes in participants' lives. Further interventions should integrate the functional value of depressive symptoms and focus on social support systems and social networks. PMID- 26651368 TI - Management of Sialorrhea in Amyotrophic Lateral Sclerosis #299. PMID- 26651369 TI - Psoriasis: burning down the host. PMID- 26651370 TI - Indole alkaloid glucosides from the roots of Isatis indigotica. AB - Five new indole alkaloid glucosides named isatindigotindolosides A-E (1-5), along with three known analogs (6-8), were isolated from an aqueous extract of the Isatis indigotica roots. Their structures including the absolute configurations were determined based on comprehensive spectroscopic data analysis, combined with chemical methods and electronic circular dichroism spectra calculations. In the preliminary assays, compounds 1, 6 and 7 showed antiviral activity against influenza virus A/Hanfang/359/95 (H3N2) with IC50 values of 14.6-33.3 MUM. Compound 1 also exhibited inhibitory effect against nitric oxide (NO) production in microglial cell BV2 with an inhibition ratio of 93.0% at 10 MUM. PMID- 26651371 TI - Erratum. PMID- 26651372 TI - Composting of wastewater treatment sludge with different bulking agents. AB - The main objectives of this study were to investigate the compostability of wastewater treatment sludge (WTS) containing different bulking agents (BAs) and to determine the most efficient BA. Four different compost trials consisting of mixtures of wheat straw (WS), plane leaf (PL), corncob (CC) and sunflower stalk (SS) with WTS were performed in laboratory reactors. In all experiments, a mixture of 60% WTS and 40% BA (wet basis) was used. The temperature, dry matter (DM), organic matter (OM), pH, electrical conductivity (EC) and C/N ratio were monitored during the composting process. Evaluation of the operational parameters showed that the highest organic matter degradation (i.e. 37.6%), loss of dry matter (i.e. 29.6%) and temperature (i.e. 64 degrees C) were achieved for the WTS-CC mixtures. Results also showed that the WTS-SS mixture was also successful in terms of these operational parameters. Use of bulking agents for the treatment of wastewater treatment sludge in composting process is an important issue with regards to process efficiency, economy and disposal of agricultural waste. Corncob and sunflower stalk that were previously not used for the composting of WTS from food industry were shown to be highly successful BA materials in this study. IMPLICATIONS: The compostability of wastewater treatment sludge from the food industry with different bulking agents was studied. Wheat straw, plane leaf, corncob, and sunflower stalk were used as bulking agents. The required microbial stabilization and degree of mineralization were achieved with corncobs and sunflower stalks. PMID- 26651373 TI - When Thinking Impairs Sleep: Trait, Daytime and Nighttime Repetitive Thinking in Insomnia. AB - We performed two studies in individuals with sleep problems to investigate trait, daytime, and nighttime repetitive thinking as risk factors for insomnia. In Study 1, 139 participants completed questionnaires on worry, rumination, insomnia, anxiety, depression, and a sleep diary. Trait rumination and trait worry were not associated with sleep impairment. In Study 2, 64 participants completed similar measures and a daytime and nighttime sleep-related worry diary. Only nighttime sleep-related worry was consistently associated with sleep impairment. Overall, results indicate that nighttime sleep-related worry is important in the maintenance of insomnia, whereas effects of trait and daytime repetitive thinking are more benign. Treatment for insomnia can potentially be improved by focusing more on nighttime sleep-related worry. PMID- 26651374 TI - Formation of Ideal Rashba States on Layered Semiconductor Surfaces Steered by Strain Engineering. AB - Spin splitting of Rashba states in two-dimensional electron system provides a promising mechanism of spin manipulation for spintronics applications. However, Rashba states realized experimentally to date are often outnumbered by spin degenerated substrate states at the same energy range, hindering their practical applications. Here, by density functional theory calculation, we show that Au one monolayer film deposition on a layered semiconductor surface beta-InSe(0001) can possess "ideal" Rashba states with large spin splitting, which are completely situated inside the large band gap of the substrate. The position of the Rashba bands can be tuned over a wide range with respect to the substrate band edges by experimentally accessible strain. Furthermore, our nonequilibrium Green's function transport calculation shows that this system may give rise to the long sought strong current modulation when made into a device of Datta-Das transistor. Similar systems may be identified with other metal ultrathin films and layered semiconductor substrates to realize ideal Rashba states. PMID- 26651375 TI - Influence of children's oral health promotion on parents' behaviours, attitudes and knowledge. AB - Objective The aim was to compare the changes in parents' oral health-related behaviour, knowledge and attitudes in 2001-2003 and 2003-2005, during a 3.4-year intervention in Pori and in the reference area Rauma, Finland. Materials and methods The study population consisted of parents of children who participated in the oral health promotion programme in Pori (all 5th and 6th graders who started the 2001-2002 school year in the town of Pori, n = 1691) and the parents of same aged children in a reference town (n = 807). In 2001-2003, the promotion was targeted only to the children in Pori. In 2003-2005, the promotion was targeted also to parents, for example via local mass media. The statistical significances of the differences in parents' self-reported behaviour, knowledge and attitudes, and changes in these, were evaluated using Mann-Whitney U-tests and confidence intervals. Results In 2001-2003, the trend in changing behaviours was in favour of parents in Pori. Mothers in Pori also improved their knowledge and the attitude 'importance of brushing for health and appearance'. In 2003-2005, the trend in changing behaviours was rather similar in both towns, which may be due to diffusion of the oral health intervention to Rauma via the media. Conclusions The results suggest that health promotion targeted to children, which in previous studies has been shown to be successful in improving children's behaviours, also helped their parents in mending their habits. PMID- 26651377 TI - "Knowing that I'm not alone": client perspectives on counselling for self-injury. AB - BACKGROUND: Self-injury is an increasingly common phenomenon among clinical and non-clinical populations. Health care providers generally recommend behavioural interventions that address coping skills for people who self-injure despite a lack of a consistent evidence base about their effectiveness. There is limited understanding about experiences of counselling for self-injury from the perspectives of clients. AIM: To understand clients' experiences of counselling for self-injury. METHOD: Ten interviews were conducted, audio-recorded and transcribed. Data were analysed using Grounded Theory (GT). RESULTS: One central category, "Developing a healing reconnection with self and others" and four categories: (i) Building trust; (ii) seeing beyond the cutting; (iii) human contact and (iv) integrating experiences. CONCLUSIONS: Overcoming self-injury is possible within the context of a trusting and accepting therapeutic relationship. Participants perceived counselling to be helpful when counsellors were willing to work with underlying issues rather than focus primarily on the cessation of self injury. Counsellors and mental health practitioners must look beyond the behaviour to meet with the person and facilitate the development of a therapeutic relationship, which promotes a healing reconnection with self and others. PMID- 26651376 TI - A Randomized Trial of an Intensive Physical Therapy Program for Patients with Acute Respiratory Failure. AB - RATIONALE: Early physical therapy (PT) interventions may benefit patients with acute respiratory failure by preventing or attenuating neuromuscular weakness. However, the optimal dosage of these interventions is currently unknown. OBJECTIVES: To determine whether an intensive PT program significantly improves long-term physical functional performance compared with a standard-of-care PT program. METHODS: Patients who required mechanical ventilation for at least 4 days were eligible. Enrolled patients were randomized to receive PT for up to 4 weeks delivered in an intensive or standard-of-care manner. Physical functional performance was assessed at 1, 3, and 6 months in survivors who were not currently in an acute or long-term care facility. The primary outcome was the Continuous Scale Physical Functional Performance Test short form (CS-PFP-10) score at 1 month. MEASUREMENTS AND MAIN RESULTS: A total of 120 patients were enrolled from five hospitals. Patients in the intensive PT group received 12.4 +/ 6.5 sessions for a total of 408 +/- 261 minutes compared with only 6.1 +/- 3.8 sessions for 86 +/- 63 minutes in the standard-of-care group (P < 0.001 for both analyses). Physical function assessments were available for 86% of patients at 1 month, for 76% at 3 months, and for 60% at 6 months. In both groups, physical function was reduced yet significantly improved over time between 1, 3, and 6 months. When we compared the two interventions, we found no differences in the total CS-PFP-10 scores at all three time points (P = 0.73, 0.29, and 0.43, respectively) or in the total CS-PFP-10 score trajectory (P = 0.71). CONCLUSIONS: An intensive PT program did not improve long-term physical functional performance compared with a standard-of-care program. Clinical trial registered with www.clinicaltrials.gov (NCT01058421). PMID- 26651378 TI - Editorial Comment for Sener et al. PMID- 26651379 TI - Integrating Whispering Gallery Mode Refractive Index Sensing with Capillary Electrophoresis Separations Using Phase Sensitive Detection. AB - Whispering gallery mode (WGM) resonators are small, radially symmetric dielectrics that recirculate light through continuous total internal reflection. High-Q resonances are observed that shift in response to changes in surrounding refractive index, leading to many applications in label-free sensing. Surface binding measurements with WGM resonators have demonstrated competitive analytical detection metrics compared to other sensing schemes. Similar figures of merit for detecting bulk refractive index changes, however, have proven more challenging. This has limited their use in applications such as capillary electrophoresis (CE), where their compact footprint and refractive index sensitivity offers advantages in nondestructive, universal detection. Here we couple WGM detection with CE by introducing a modulation scheme to improve detection limits. Phase sensitive WGM (PS-WGM) detection is developed to monitor real-time shifts in the WGM spectrum due to changes in surrounding refractive index. We directly compare phase sensitive detection with spectral measurements normally used to track WGM shifts. We report an improvement in detection limits by almost 300-fold using the PS-WGM method. The integrated CE with PS-WGM approach is demonstrated by detecting the separation of a three-component mixture of cations (Na(+), Li(+), and K(+)). PMID- 26651381 TI - Fabrication of novel GMO/Eudragit E100 nanostructures for enhancing oral bioavailability of carvedilol. AB - In the present work, novel nanostructures comprising of glyceryl monooleate (GMO) and Eudragit E100 were prepared using high intensity ultrasonic homogenization. 3(2) Factorial design approach was used for optimization of nanostructures. Results of regression analysis revealed that the amount of GMO and Eudragit E100 had a drastic effect on particle size and percent entrapment efficiency. Optimized carvedilol-loaded nanostructures (Car-NS) were characterized by FTIR, TEM, DSC, in vitro drug release study. Pharmacokinetic parameters such as Cmax, Tmax, Ke, Ka, Vd and AUC were estimated for Car-NS upon its oral administration in Sprague-Dawley rats. Particle size of Car-NS was found to be 183 +/- 2.43 nm with an entrapment efficiency of 81.4 +/- 0.512%. FTIR studies revealed loading and chemical compatibility of carvedilol with the components of nanostructures. DSC thermograms did not show endothermic peak for melting of carvedilol which could be attributed to solubilization of carvedilol in molten GMO during DSC run. The prepared Car-NS released carvedilol in sustained manner over a period of 10 h as suggested by in vitro drug release study. The pharmacokinetic study of Car-NS showed significant improvement in Cmax (two fold, p < 0.001) and AUC (four folds, p < 0.001) of carvedilol when compared to carvedilol suspension. Car-NS were found to be stable for a period of 3 months. Thus, a stable, floating, multiparticulate GMO/Eudragit E100 nanostructures having ability to release the drug in sustained manner with enhanced oral bioavailability can prove to be a promising carrier system for poorly water soluble drugs. PMID- 26651382 TI - The Impact of Nighttime Intensivists on Medical Intensive Care Unit Infection Related Indicators. AB - In 2013, a before-and-after intervention study was conducted to evaluate the effect 24-hour intensivist coverage on length of stay and rates of catheter associated urinary tract infection, central-line associated blood stream infection, and ventilator-associated events. Intensivist coverage for 24 hours did not decrease length of stay or result in a decrease in any specific infection rate. PMID- 26651380 TI - Routinely vaccinating adolescents against meningococcus: targeting transmission & disease. AB - Adolescents have the highest rates of meningococcal carriage and transmission. Interrupting the adolescent habitat in order to reduce carriage and transmission within adolescents and to other age groups could help to control meningococcal disease at a population level. Compared to immunization strategies restricted to young children, a strategy focused on adolescents may have more profound and long lasting indirect impacts, and may be more cost effective. Despite challenges in reaching this age-group, experience with other vaccines show that high vaccine coverage of adolescents is attainable. PMID- 26651383 TI - Positional group significantly influences the offensive and defensive skill involvements of junior representative rugby league players during match play. AB - This study examined the skill involvements of three positional groups across a junior representative rugby league season. Data were collected from 45 rugby league players (mean +/- SD; age = 16.5 +/- 1.0 years) currently participating in the Harold Matthews and SG Ball Cup. Players were subdivided into hit-up forwards, adjustables and outside backs. The frequency (n . min(-1)) of offensive, defensive and overall involvements was coded for each group using a notation system and a practical coach skill analysis tool. Multivariate analysis of variance (MANOVA) revealed a significant effect of playing position on skill involvements (F = 9.06; P < 0.001; ES = 0.41). Hit-up forwards performed a significantly greater frequency of offensive (0.31 +/- 0.10), defensive (0.42 +/- 0.15) and overall involvements (0.74 +/- 0.19) when compared to adjustables (0.20 +/- 0.08, 0.28 +/- 0.08 and 0.52 +/- 0.15, respectively) and outside backs (0.20 +/- 0.12, 0.11 +/- 0.07 and +/- 0.31 +/- 0.17, respectively). Further, adjustables performed a significantly greater number of defensive (0.28 +/- 0.08) and overall involvements (0.52 +/- 0.15) when compared to outside backs (0.11 +/- 0.07 and 0.31 +/- 0.17, respectively). The findings of this study suggest that it is important to consider a junior player's positional group when analysing their skill involvements. Information gained from this study could assist in the design of specific training methodologies for junior rugby league players in high-level talent development programmes. PMID- 26651384 TI - Effects of customized foot orthoses on manufacturing workers in the metal industry. AB - This 8-week study evaluates the effects of customized foot orthoses on work related musculoskeletal disorders (WMSDs) of metal industry workers. These WMSDs were evaluated applying the Nordic musculoskeletal questionnaire (NMQ) at three different times (start, 4th week and 8th week) and additional questions were also formulated to obtain information about adaptation, fatigue, comfort and possible improvements. According to the NMQ results, statistical significance was found in the improvements after 4 weeks (p < 0.05 in two areas, p < 0.01 in three areas, p < 0.001 in two areas and no significance in the other two) and after 8 weeks (p < 0.01 in three areas, p < 0.001 in four areas and no significance in the other two). The additional questions indicated fatigue reduction (both in general and in lower extremity), comfort level increase (after the adaptation period) and good acceptance, according to workers' answers, suggesting customized orthoses can be effective in reducing and preventing WMSDs in several body regions. PMID- 26651385 TI - Pathophysiology and prevention of sudden cardiac death. AB - Sudden cardiac death (SCD) is known to occur in individuals with diverse diseases. Each disease state has a specific etiology and pathophysiology, and is diagnosed and treated differently. Etiologies for SCD include cardiac arrhythmias, coronary artery disease, congenital coronary artery anomalies, hypertrophic cardiomyopathy, arrhythmogenic right ventricular dysplasia, dilated cardiomyopathy, and aortic valve stenosis. A potential unifying mechanism of SCD in these diseases involves a massive stimulation of the sympathetic nervous system's stress response and the subsequent elevation of circulating catecholamines. The diagnosis of cardiac diseases that contribute to an increased risk for SCD is accomplished by a combination of different techniques including electrocardiography, echocardiography, magnetic resonance imaging, and invasive cardiac catheterization. Several therapies including anti-arrhythmic drugs, beta blockers, and antiplatelet agents may be used as medical treatment in patients for the prevention of SCD. Invasive therapies including percutaneous angioplasty, coronary artery bypass surgery, and implantable cardioverter-defibrillators are also used in the clinical management of SCD. PMID- 26651386 TI - Direct Phenotypic Screening in Mice: Identification of Individual, Novel Antinociceptive Compounds from a Library of 734,821 Pyrrolidine Bis-piperazines. AB - The hypothesis in the current study is that the simultaneous direct in vivo testing of thousands to millions of systematically arranged mixture-based libraries will facilitate the identification of enhanced individual compounds. Individual compounds identified from such libraries may have increased specificity and decreased side effects early in the discovery phase. Testing began by screening ten diverse scaffolds as single mixtures (ranging from 17,340 to 4,879,681 compounds) for analgesia directly in the mouse tail withdrawal model. The "all X" mixture representing the library TPI-1954 was found to produce significant antinociception and lacked respiratory depression and hyperlocomotor effects using the Comprehensive Laboratory Animal Monitoring System (CLAMS). The TPI-1954 library is a pyrrolidine bis-piperazine and totals 738,192 compounds. This library has 26 functionalities at the first three positions of diversity made up of 28,392 compounds each (26 * 26 * 42) and 42 functionalities at the fourth made up of 19,915 compounds each (26 * 26 * 26). The 120 resulting mixtures representing each of the variable four positions were screened directly in vivo in the mouse 55 degrees C warm-water tail-withdrawal assay (ip administration). The 120 samples were then ranked in terms of their antinociceptive activity. The synthesis of 54 individual compounds was then carried out. Nine of the individual compounds produced dose-dependent antinociception equivalent to morphine. In practical terms what this means is that one would not expect multiexponential increases in activity as we move from the all-X mixture, to the positional scanning libraries, to the individual compounds. Actually because of the systematic formatting one would typically anticipate steady increases in activity as the complexity of the mixtures is reduced. This is in fact what we see in the current study. One of the final individual compounds identified, TPI 2213-17, lacked significant respiratory depression, locomotor impairment, or sedation. Our results represent an example of this unique approach for screening large mixture-based libraries directly in vivo to rapidly identify individual compounds. PMID- 26651388 TI - Conserved Hydration Sites in Pin1 Reveal a Distinctive Water Recognition Motif in Proteins. AB - Structurally conserved water molecules are important for biomolecular stability, flexibility, and function. X-ray crystallographic studies of Pin1 have resolved a number of water molecules around the enzyme, including two highly conserved water molecules within the protein. The functional role of these localized water molecules remains unknown and unexplored. Pin1 catalyzes cis/trans isomerizations of peptidyl prolyl bonds that are preceded by a phosphorylated serine or threonine residue. Pin1 is involved in many subcellular signaling processes and is a potential therapeutic target for the treatment of several life threatening diseases. Here, we investigate the significance of these structurally conserved water molecules in the catalytic domain of Pin1 using molecular dynamics (MD) simulations, free energy calculations, analysis of X-ray crystal structures, and circular dichroism (CD) experiments. MD simulations and free energy calculations suggest the tighter binding water molecule plays a crucial role in maintaining the integrity and stability of a critical hydrogen-bonding network in the active site. The second water molecule is exchangeable with bulk solvent and is found in a distinctive helix-turn-coil motif. Structural bioinformatics analysis of nonredundant X-ray crystallographic protein structures in the Protein Data Bank (PDB) suggest this motif is present in several other proteins and can act as a water site, akin to the calcium EF hand. CD experiments suggest the isolated motif is in a distorted PII conformation and requires the protein environment to fully form the alpha-helix-turn-coil motif. This study provides valuable insights into the role of hydration in the structural integrity of Pin1 that can be exploited in protein engineering and drug design. PMID- 26651387 TI - The safety of regorafenib for the treatment of gastrointestinal stromal tumors. AB - INTRODUCTION: The management of gastrointestinal stromal tumors (GIST) evolved due to effective molecularly targeted therapy with imatinib and sunitinib which are used first- and second-line, respectively. However, due to the development of resistance to those drugs in the majority of patients, the need for third-line therapy arose. AREAS COVERED: Regorafenib, an oral multitargeted inhibitor with activity against multiple kinases including KIT, RET, RAF1, BRAF, angiogenesis (VEGFR, TIE-2) and those involved in tumor microenvironment (PDGFR and FGFR) was introduced after the successful Phase III GRID (GIST - Regorafenib In progressive Disease) clinical trial. This study showed significant improvement in progression free survival for patients receiving regorafenib compared to placebo (4.8 months vs 0.9 months). The treatment was reasonably well tolerated, with arterial hypertension, hand-foot syndrome, diarrhea being the most common grade >=3 adverse events, which could be managed by dose reduction and supportive treatment. The aim of this paper is to describe, assess and advise on the safety of regorafenib as third-line therapy in GIST. EXPERT OPINION: Regorafenib has demonstrated clinical benefit in GIST patients after progression on prior treatment with at least imatinib/sunitinib and currently it is the approved standard third-line option in therapy of advanced GIST. The safety profile is similar to other multikinase inhibitors with anti-VEGFR activity and is manageable. PMID- 26651389 TI - Activation of Chiral (Salen)AlCl Complex by Phosphorane for Highly Enantioselective Cyanosilylation of Ketones and Enones. AB - Phosphoranes 2 are identified as a class of effective Lewis bases to activate chiral (salen)AlCl complex 1 to enhance its electrophilicity. Accordingly, a three-component catalyst system consisting of complex 1, phosphorane 2e, and Ph3PO is developed as a powerful tool for asymmetric ketone cyanosilylation. In particular, an unprecedented highly enantioselective cyanosilylation of linear aliphatic ketones is achieved. A tandem Wittig-cyanosilylation sequence starting from phosphorane 2a and enals 10 is further achieved, which internally utilizes the Ph3PO byproduct and remaining phosphorane 2a as cocatalysts for cyanosilylation of alpha,beta,gamma,delta-unsaturated enones, providing atom efficient access to valuable chiral conjugated dienes and enynes. The high efficiency of the cyanosilylation originates from orthogonal activation of both (salen)AlCl complex 1 and cyanotrimethylsilane by the phosphorane and Ph3PO, respectively. This mechanistic insight is supported by NMR, MS, and ReactIR analyses and DFT calculations. Furthermore, the formation of charged complexes through the activation of chiral complex 1 by phosphorane 2a is confirmed by electrical conductivity experiments. PMID- 26651390 TI - The Role of Core-Needle Biopsy as a First-Line Diagnostic Tool for Initially Detected Thyroid Nodules. AB - BACKGROUND: The aim of this study was to evaluate the role of core-needle biopsy (CNB) as a first-line diagnostic tool for initially detected thyroid nodules. METHODS: This observational study evaluated 632 initially detected thyroid nodules in 632 consecutive patients who underwent CNB between October 2008 and December 2011. CNB results were categorized into the six categories of the Bethesda System. A final diagnosis of malignancy was based on surgery or CNB, whereas a final diagnosis of benign nodules was based on surgery, two benign biopsy results, or benign cytology of stable size after one year. The rates of Bethesda category 1 and inconclusive results, diagnostic performance, unnecessary surgery, and complications were evaluated. Subgroup analysis based on nodule size was performed. Risk factors for inconclusive results were evaluated by multivariate logistic regression analysis. RESULTS: The rates of Bethesda category 1 and inconclusive results by CNB were 1.3% and 5.9%, respectively. The diagnostic accuracy, sensitivity, specificity, positive predictive value, and negative predictive value for the diagnosis of malignancy were 97.6%, 90.0%, 100%, 100%, and 92.3%, respectively. The rate of unnecessary surgery was 0.5%, and the complications rate was 0.2%. Based on subgroup analysis, the diagnostic performance was not significantly associated with nodule size. There were no independent risk factors associated with inconclusive results. CONCLUSION: CNB showed low rates of Bethesda category 1 and inconclusive results and a high diagnostic accuracy. CNB also minimized unnecessary surgery. CNB seems to be a promising diagnostic tool for patients with initially detected thyroid nodules. PMID- 26651392 TI - Mortality and Cumulative Exposure to Antipsychotics, Antidepressants, and Benzodiazepines in Patients With Schizophrenia: An Observational Follow-Up Study. AB - OBJECTIVE: Although mortality related to psychotropic medications has received much attention in recent years, little is known about the relationship between risk of death and cumulative antipsychotic load, and even less about the relationship between mortality and cumulative exposure to antidepressants or benzodiazepines. The authors examined these relationships using nationwide databases. METHOD: The authors used prospectively collected nationwide databases to identify all individuals 16-65 years of age with a schizophrenia diagnosis (N=21,492) in Sweden. All-cause and cause-specific mortality rates were calculated as a function of cumulative low, moderate, and high exposure to antipsychotics, antidepressants, and benzodiazepines from 2006 through 2010. RESULTS: Compared with no exposure, both moderate (adjusted hazard ratio=0.59, 95% CI=0.49-0.70) and high (adjusted hazard ratio=0.75, 95% CI=0.63-0.89) antipsychotic exposures were associated with substantially lower overall mortality. Moderate antidepressant exposure was associated with a lower mortality (adjusted hazard ratio=0.85, 95% CI=0.73-0.98), and high exposure, even lower (adjusted hazard ratio=0.71, 95% CI=0.59-0.86). Exposure to benzodiazepines showed a dose-response relationship with mortality (hazard ratios up to 1.74 [95% CI=1.50-2.03]). CONCLUSIONS: Moderate and high-dose antipsychotic and antidepressant use were associated with 15%-40% lower overall mortality, whereas chronic high-dose use of benzodiazepines was associated with up to a 70% higher risk of death compared with no exposure. Since patients with anxiety and depressive symptoms may have a higher intrinsic risk of death, the finding for benzodiazepines may be attributable to some extent to residual confounding. PMID- 26651391 TI - Identification of Distinct Psychosis Biotypes Using Brain-Based Biomarkers. AB - OBJECTIVE: Clinical phenomenology remains the primary means for classifying psychoses despite considerable evidence that this method incompletely captures biologically meaningful differentiations. Rather than relying on clinical diagnoses as the gold standard, this project drew on neurobiological heterogeneity among psychosis cases to delineate subgroups independent of their phenomenological manifestations. METHOD: A large biomarker panel (neuropsychological, stop signal, saccadic control, and auditory stimulation paradigms) characterizing diverse aspects of brain function was collected on individuals with schizophrenia, schizoaffective disorder, and bipolar disorder with psychosis (N=711), their first-degree relatives (N=883), and demographically comparable healthy subjects (N=278). Biomarker variance across paradigms was exploited to create nine integrated variables that were used to capture neurobiological variance among the psychosis cases. Data on external validating measures (social functioning, structural magnetic resonance imaging, family biomarkers, and clinical information) were collected. RESULTS: Multivariate taxometric analyses identified three neurobiologically distinct psychosis biotypes that did not respect clinical diagnosis boundaries. The same analysis procedure using clinical DSM diagnoses as the criteria was best described by a single severity continuum (schizophrenia worse than schizoaffective disorder worse than bipolar psychosis); this was not the case for biotypes. The external validating measures supported the distinctiveness of these subgroups compared with clinical diagnosis, highlighting a possible advantage of neurobiological versus clinical categorization schemes for differentiating psychotic disorders. CONCLUSIONS: These data illustrate how multiple pathways may lead to clinically similar psychosis manifestations, and they provide explanations for the marked heterogeneity observed across laboratories on the same biomarker variables when DSM diagnoses are used as the gold standard. PMID- 26651394 TI - Genetics of attention-deficit/hyperactivity disorder: an update. AB - Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder affecting children, adolescents, and adults. The prevalence is estimated at 5 to 7% of school-aged children and 2.5 to 5% of adults. The phenotype is complex and heterogeneous, presenting variable clinical features, developmental course, and outcome. The genetic susceptibility to ADHD is attributed to both common and rare variants from a broad range of genes related mainly to neurotransmission and neurodevelopment pathways. However, it has been difficult to identify the genetic risk variants that account for the high heritability of this disorder. In this paper, we present recent findings from molecular genetics studies on both child and adult ADHD. Challenges and future directions for ADHD genetic studies are reviewed and discussed. PMID- 26651393 TI - Perinatal Phosphatidylcholine Supplementation and Early Childhood Behavior Problems: Evidence for CHRNA7 Moderation. AB - OBJECTIVE: alpha7-Nicotinic receptors are involved in the final maturation of GABA inhibitory synapses before birth. Choline at levels found in the amniotic fluid is an agonist at alpha7-nicotinic receptors. The authors conducted a double blind placebo-controlled trial to assess whether high-dose oral phosphatidylcholine supplementation during pregnancy to increase maternal amniotic fluid choline levels would enhance fetal development of cerebral inhibition and, as a result, decrease childhood behavior problems associated with later mental illness. METHOD: The authors previously reported that newborns in the phosphatidylcholine treatment group have increased suppression of the cerebral evoked response to repeated auditory stimuli. In this follow-up, they report parental assessments of the children's behavior at 40 months of age, using the Child Behavior Checklist. RESULTS: At 40 months, parent ratings of children in the phosphatidylcholine group (N=23) indicated fewer attention problems and less social withdrawal compared with the placebo group (N=26). The improvement is comparable in magnitude to similar deficits at this age associated with later schizophrenia. The children's behavior is moderated by CHRNA7 variants associated with later mental illness and is related to their enhanced cerebral inhibition as newborns. CONCLUSIONS: CHRNA7, the alpha7-nicotinic acetylcholine receptor gene, has been associated with schizophrenia, autism, and attention deficit hyperactivity disorder. Maternal phosphatidylcholine treatment may, by increasing activation of the alpha7-nicotinic acetylcholine receptor, alter the development of behavior problems in early childhood that can presage later mental illness. PMID- 26651395 TI - Ground State Reactions of nC60 with Free Chlorine in Water. AB - Facile, photoenhanced transformations of water-stable C60 aggregates (nC60) to oxidized, soluble fullerene derivatives, have been described as key processes in understanding the ultimate environmental fate of fullerene based materials. In contrast, fewer studies have evaluated the aqueous reactivity of nC60 during ground-state conditions (i.e., dark conditions). Herein, this study identifies and characterizes the physicochemical transformations of C60 (as nC60 suspensions) in the presence of free chlorine, a globally used chemical oxidant, in the absence of light under environmentally relevant conditions. Results show that nC60 undergoes significant oxidation in the presence of free chlorine and the oxidation reaction rates increase with free chlorine concentration while being inversely related to solution pH. Product characterization by FTIR, XPS, Raman Spectroscopy, TEM, XRD, TOC, collectively demonstrates that oxidized C60 derivatives are readily formed in the presence of free chlorine with extensive covalent oxygen and even chlorine additions, and behave as soft (or loose) clusters in solution. Aggregation kinetics, as a function of pH and ionic strength/type, show a significant increase in product stabilities for all cases evaluated, even at pH values approaching 1. As expected with increased (surface) oxidation, classic Kow partitioning studies indicate that product clusters are relatively more hydrophilic than parent (reactant) nC60. Taken together, this work highlights the importance of understanding nanomaterial reactivity and the identification of corresponding stable daughter products, which are likely to differ significantly from parent material properties and behaviors. PMID- 26651397 TI - Toward an Accurate Estimate of the Exfoliation Energy of Black Phosphorus: A Periodic Quantum Chemical Approach. AB - The black phosphorus (black-P) crystal is formed of covalently bound layers of phosphorene stacked together by weak van der Waals interactions. An experimental measurement of the exfoliation energy of black-P is not available presently, making theoretical studies the most important source of information for the optimization of phosphorene production. Here, we provide an accurate estimate of the exfoliation energy of black-P on the basis of multilevel quantum chemical calculations, which include the periodic local Moller-Plesset perturbation theory of second order, augmented by higher-order corrections, which are evaluated with finite clusters mimicking the crystal. Very similar results are also obtained by density functional theory with the D3-version of Grimme's empirical dispersion correction. Our estimate of the exfoliation energy for black-P of -151 meV/atom is substantially larger than that of graphite, suggesting the need for different strategies to generate isolated layers for these two systems. PMID- 26651398 TI - Rh(III)-Catalyzed C-H Cyclization of Arylnitrones with Diazo Compounds: Access to N-Hydroxyindolines. AB - We have developed the Cp*Rh(III)-catalyzed cyclization reaction of arylnitrones with diazo compounds to obtain N-hydroxyindoline products under mild conditions. The substrate scope and functional group compatibility were examined with the demonstration of synthetic utility. PMID- 26651396 TI - CSL311, a novel, potent, therapeutic monoclonal antibody for the treatment of diseases mediated by the common beta chain of the IL-3, GM-CSF and IL-5 receptors. AB - The beta common-signaling cytokines interleukin (IL)-3, granulocyte-macrophage colony stimulating factor (GM-CSF) and IL-5 stimulate pro-inflammatory activities of haematopoietic cells via a receptor complex incorporating cytokine-specific alpha and shared beta common (betac, CD131) receptor. Evidence from animal models and recent clinical trials demonstrate that these cytokines are critical mediators of the pathogenesis of inflammatory airway disease such as asthma. However, no therapeutic agents, other than steroids, that specifically and effectively target inflammation mediated by all 3 of these cytokines exist. We employed phage display technology to identify and optimize a novel, human monoclonal antibody (CSL311) that binds to a unique epitope that is specific to the cytokine-binding site of the human betac receptor. The binding epitope of CSL311 on the betac receptor was defined by X-ray crystallography and site directed mutagenesis. CSL311 has picomolar binding affinity for the human betac receptor, and at therapeutic concentrations is a highly potent antagonist of the combined activities of IL-3, GM-CSF and IL-5 on primary eosinophil survival in vitro. Importantly, CSL311 inhibited the survival of inflammatory cells present in induced sputum from human allergic asthmatic subjects undergoing allergen bronchoprovocation. Due to its high potency and ability to simultaneously suppress the activity of all 3 beta common cytokines, CSL311 may provide a new strategy for the treatment of chronic inflammatory diseases where the human betac receptor is central to pathogenesis. The coordinates for the betac/CSL311 Fab complex structure have been deposited with the RCSB Protein Data Bank (PDB 5DWU). PMID- 26651412 TI - Effect of triiodothyronine (T3) excess on fatty acid metabolism in the soleus muscle from endurance-trained rats. AB - We studied whether short-term administration of triiodothyronine (T3) for the last 3 days of endurance training would influence the rate of uptake of palmitic acid (PA) as well as metabolism in rat soleus muscle, in vitro. Training per se did not affect the rate of PA uptake by the soleus; however, an excess of T3 increased the rate of this process at 1.5 mmol/L PA, as well as the rate that at which PA was incorporated into intramuscular triacylglycerols (TG). The rate of TG synthesis in trained euthyroid rats was reduced after exercise (1.5 mmol/L PA). The rate of PA oxidation in all of the trained rats immediately after exercise was enhanced by comparison with the sedentary values. Hyperthyroidism additionally increased the rate of this process at 1.5 mmol/L PA. After a recovery period, the rate of PA oxidation returned to the control values in both the euthyroid and the hyperthyroid groups. Examination of the high-energy phosphate levels indicated that elevated PA oxidation after exercise-training in euthyroid rats was associated with stable ATP levels and increased ADP and AMP levels, thus reducing energy cellular potential (ECP). In the hyperthyroid rats, levels of ADP and AMP were increased in the sedentary as well as the exercise trained rats. ECP levels were high as a result of high levels of ATP and decreased levels of ADP and AMP in hyperthyroid rats after the recovery period. In conclusion, short-term hyperthyroidism accelerates PA utilization in well trained soleus muscle. PMID- 26651413 TI - Supramolecular Chirality of the Two-Component Supramolecular Copolymer Gels: Who Determines the Handedness? AB - Natural supramolecular systems typically contain a wide variety of chiral molecules. Studying the chiral conflict within different supramolecular assemblies not only can be very helpful for understanding the inherent principles of supramolecular chirality but also can guide the preparation of many functional chiral soft matters. For assemblies containing only structurally similar molecules, supramolecular chirality is determined by enantiomeric excess of molecular building blocks. For supramolecular systems assembled by structurally different chiral molecules, however, the optical activity of the systems and the chiral conflict among different chiral molecules can be very complex. We found rather unexpected results regarding the chiral conflict within two-component supramolecular copolymer gels in this study. The handedness of the chirality of supramolecular copolymer gels, which were formed by the coassembly of bolaamphiphilic L-histidine derivatives and tartaric acids, was found to be dependent on the ordering molecular packing, instead of the preponderance of certain chiral molecules. PMID- 26651414 TI - Evolving techniques for gastrointestinal endoscopic hemostasis treatment. AB - With mortality due to gastrointestinal (GI) bleeding remaining stable, the focus on endoscopic hemostasis has been on improving other outcomes such as rebleeding rate, need for transfusions, and need for angiographic embolization or surgery. Over the past few years, a number of devices have emerged to help endoscopically assess and treat bleeding GI lesions. These include the Doppler endoscopic probe, hemostatic powder, and over-the-scope clip. Also, new applications have been described for radiofrequency ablation. In this article, we will discuss these evolving tools and techniques that have been developed, including an analysis of their efficacy and limitations. PMID- 26651415 TI - Ciliopathies: Does HDAC6 Represent a New Therapeutic Target? AB - Cilia are cellular appendages with critical roles in sensing and transducing environmental signals and guiding fluid flow. Consistent with these diverse activities, defects in ciliary structure or function have been implicated in a variety of human diseases, collectively known as 'ciliopathies'. Histone deacetylase 6 (HDAC6) is a unique cytoplasmic enzyme that regulates many biological processes through its deacetylase and ubiquitin-binding activities. There is accumulating evidence that HDAC6 is a major driver of ciliary disassembly. Small-molecule compounds that inhibit HDAC6 have been demonstrated to restore ciliary structure and function in several different ciliopathies. Here, we discuss recent findings that highlight the important role for HDAC6 in mediating ciliary disassembly and the potential for HDAC6-selective inhibitors as therapeutics for specific ciliopathies. PMID- 26651417 TI - Solid-State 17O NMR studies of organic and biological molecules: Recent advances and future directions. AB - This Trends article highlights the recent advances published between 2012 and 2015 in solid-state (17)O NMR for organic and biological molecules. New developments in the following areas are described: (1) new oxygen-containing functional groups, (2) metal organic frameworks, (3) pharmaceuticals, (4) probing molecular motion in organic solids, (5) dynamic nuclear polarization, and (6) paramagnetic coordination compounds. For each of these areas, the author offers his personal views on important problems to be solved and possible future directions. PMID- 26651416 TI - Cellular Biomechanics in Drug Screening and Evaluation: Mechanopharmacology. AB - The study of mechanobiology is now widespread. The impact of cell and tissue mechanics on cellular responses is well appreciated. However, knowledge of the impact of cell and tissue mechanics on pharmacological responsiveness, and its application to drug screening and mechanistic investigations, have been very limited in scope. We emphasize the need for a heightened awareness of the important bidirectional influence of drugs and biomechanics in all living systems. We propose that the term 'mechanopharmacology' be applied to approaches that employ in vitro systems, biomechanically appropriate to the relevant (patho)physiology, to identify new drugs and drug targets. This article describes the models and techniques that are being developed to transform drug screening and evaluation, ranging from a 2D environment to the dynamic 3D environment of the target expressed in the disease of interest. PMID- 26651418 TI - TREM2 rare variant p.R47H is not associated with Parkinson's disease. AB - Variant p.R47H of triggering receptor expressed on myeloid cells 2 (TREM2) has been associated with Parkinson's disease (PD). We screened this TREM2-variant in 821 PD patients including 261 demented PD patients (PDD) and in healthy controls (n = 919). Neither the entire PD nor the small PDD sample was associated with p.R47H. PMID- 26651419 TI - Rationale and Design of the Informing Fresh versus Old Red Cell Management (INFORM) Trial: An International Pragmatic Randomized Trial. AB - Although red blood cell transfusion is a potentially lifesaving intervention in severely anemic and acutely bleeding patients, some observational studies have suggested that prolonged red cell storage before transfusion is associated with harm. INFORM is a large, pragmatic, randomized controlled trial comparing the effect of the shorter storage with longer storage red blood cell transfusions on inhospital mortality in hospitalized patients who require a blood transfusion. The trial is being conducted in centers in Australia, Canada, Israel, and the United States and is expected to enroll 31497 patients. If the results of INFORM indicate that shorter storage red blood cell transfusion is associated with superior outcomes compared with standard issue red blood cell transfusion, consideration may be given to shortening blood storage times. If, in contrast, the INFORM trial provides no evidence of harm from longer storage red blood cells, clinicians and patients may be reassured that current blood inventory management strategies are appropriate. PMID- 26651420 TI - [Depression: A predictor of dementia]. AB - Many studies suggest that in 10-25% of cases of Alzheimer's, the most common dementia in our society, can be prevented with the elimination of some risk factors. Barnes and Yaffe found that one-third of Alzheimer's cases are attributable to depression, but in the scientific literature it is not clear if it has a real causal effect on the development of dementia. The purpose of this study is to analyse the scientific evidence on the hypothesis that depression increases the risk of developing dementia. A systematic review and a meta analysis were performed on the scientific literature published up until the present day, searching articles that were published between 1990 and 2014. Ten of the studies found met the selection criteria -similar to a) size and characteristics of the sample (origin, age...), b) process of gathering data c) method of studying the relationship (within and/or between group comparison), and d) statistical analysis of the results- and the previously established quality. The value of odds ratio varied from 1.72 to 3.59, and the hazard ratio from 1,72 to 5.44. This indicates that the subjects with a history of depression have a higher risk of developing dementia than others who did not suffer depression. PMID- 26651421 TI - A new prognostic index to make short-term prognoses in MDS patients treated with azacitidine: A combination of p53 expression and cytogenetics. AB - TP53 mutation is associated with various hematological malignancies and immunohistochemistry of p53 has been used as a simple method to establish the presence of a TP53 mutation. Since the significance of p53 expression is controversial in myelodysplastic syndrome (MDS) patients treated with azacitidine (Aza), we analyzed the prevalence of p53 expression as a prognostic factor in 60 MDS patients treated with Aza. To assess p53 expression, immunohistochemical analyses of bone marrow clot sections were performed. Overall survival (OS) was significantly lower in p53-positive patients compared with p53-negetive patients (59% vs. 85% at 12 months; P=0.006). Multivariate analysis demonstrated that p53 positive was a significant prognostic factor for OS along with poor cytogenetics. Here, we propose a new prognostic index to make short-term prognoses of MDS patients in the era of Aza treatment; high: p53-positive and poor cytogenetics, low: p53-negative and absence of poor cytogenetics, and intermediate: the others. OS was significantly different among the three groups according to this index (Low 92%, Intermediate 65% and High 27% at 12 months; P<0.0001). In conclusion, p53 expression was a significant prognostic factor in MDS patients treated with Aza. In combination with cytogenetic abnormalities, it is possible to make short term prognoses. PMID- 26651422 TI - Disciplinary capture and epistemological obstacles to interdisciplinary research: Lessons from central African conservation disputes. AB - Complex environmental problems require well-researched policies that integrate knowledge from both the natural and social sciences. Epistemic differences can impede interdisciplinary collaboration, as shown by debates between conservation biologists and anthropologists who are working to preserve biological diversity and support economic development in central Africa. Disciplinary differences with regard to 1) facts, 2) rigor, 3) causal explanation, and 4) research goals reinforce each other, such that early decisions about how to define concepts or which methods to adopt may tilt research design and data interpretation toward one discipline's epistemological framework. If one of the contributing fields imposes a solution to an epistemic problem, this sets the stage for what I call disciplinary capture. Avoiding disciplinary capture requires clear communication between collaborators, but beyond this it also requires that collaborators craft research questions and innovate research designs which are different from the inherited epistemological frameworks of contributing disciplines. PMID- 26651423 TI - Precision Lifestyle Medicine: A New Frontier in the Science of Behavior Change and Population Health. PMID- 26651424 TI - State Law and Standing Orders for Immunization Services. AB - INTRODUCTION: This study determined whether state laws permit the implementation of standing orders programs (SOPs) for immunization practice. SOPs are an effective strategy to increase uptake of vaccines. Successful SOPs require a legal foundation authorizing delegation of immunization services performed by a wide range of providers, administered to broad patient populations, in several settings. Without legal permission to administer vaccines, non-physician health professionals (NPHPs) are unable to provide preventive services. METHODS: From 2012 through 2013, researchers analyzed the legal environment in 50 states and the District of Columbia to determine whether NPHPs are authorized to (1) assess patient immunization status; (2) prescribe vaccines; and (3) administer vaccines under their own practice license or delegated authority. Laws governing the following NPHPs were included: (1) medical assistants; (2) midwives; (3) nurses in advanced practice; (4) registered, practical, and vocational nurses; (5) physician assistants; and (6) pharmacists. Additionally, the review determined which vaccines may be administered, permissible patient populations, and allowable practice settings for each category of NPHP. RESULTS: The laws are highly variable, and no state authorizes all NPHPs to conduct all elements of immunization practice for all patients. The laws frequently indicate where NPHPs may or may not administer vaccines and outline permissible vaccines, eligible patients, and required level of supervision. CONCLUSIONS: The variation in the laws could potentially present a challenge to successful implementation of public health goals to improve immunization rates. Expanded authorization of SOPs in all states could increase health practitioners' ability to deliver recommended vaccines. PMID- 26651425 TI - Gene expression analysis in the compartments of the murine uterus. AB - Embryo implantation, a key critical feature of mammalian pregnancy, involves co ordinate interplay between an incoming blastocyst and a receptive uterus. Aberrations in signaling cascades during this process result in pregnancy loss in mammals, including women. Analysis of the complete uterus at any given point either during preparation for implantation or during and after embryo attachment and invasion makes it difficult to assign specific signaling mechanism to the individual cellular compartments of the uterus. Here, we describe methods for the specific isolation of the luminal epithelium (LE) and subsequent analysis of gene expression/signaling pathways during embryo attachment. We further describe the analysis of RNA and proteins by specific techniques of quantitative PCR (qPCR), immunostaining and Western blotting of uterine tissues. These methods can be applied to the other cellular compartments of the uterus and embryo invasion and endometrial development. These techniques will be beneficial to investigators for delineating the mechanisms involved during embryo attachment and female reproduction as well as providing a means to studying highly dynamic changes in gene expression in tissues. PMID- 26651426 TI - Investigation of sexual dimorphisms through mouse models and hormone/hormone disruptor treatments. AB - Sexual dimorphism in mouse reproductive tissues is observable in adult, post natal, and embryonic stages. The development of sexually dimorphic tissues starts with an ambisexual structure. It is followed by sex-specific organogenesis as guided by different signaling pathways that occur from late embryonic stages. The measurement of the anogenital distance (AGD), and the observation of the external genitalia are practical ways to distinguish male and female pups at birth and thereafter. Careful observation of the morphological or histological features and the molecular signatures of the external genitalia and perineum enable identification of sex or feminization/masculinization of embryos. Aberrations in hormone signaling via castration or treatment with hormones or hormone disruptors result in dysmorphogenesis of reproductive tissues. Several hormone disruptors have been used to modulate different aspects of hormone action through competitive inhibition and exogenous hormone treatment. Concomitantly, the vast advancement of conditional mutant mouse analysis leads to the frequent utilization of Cre recombination technology in the study of reproductive/urogenital tissue development. Mouse Cre-lines that are tissue specific and cell-specific are also effective tools in identifying the molecular mechanisms during sexually dimorphic development. Cre-lines applicable to different cell populations in the prostate, seminal vesicles, testis and ovaries, and mammary glands are currently being utilized. In the external genitalia and perineum, Cre lines that examine the signaling pathways of cells of endodermal, ectodermal, and mesenchymal origin reveal the roles of these tissues in the development of the external genitalia. The interaction of hormones and growth factors can be examined further through a variety of techniques available for researchers. Such cumulative information about various technologies is summarized. PMID- 26651427 TI - Health behaviors of young adult heroin injectors in the Seattle area. AB - BACKGROUND: Recent indicators point to substantial increases in the number of young heroin users across much of the United States as well as across Washington State. This study characterizes this younger generation of heroin injectors in order to inform public health responses. METHODS: A cross-sectional analysis was conducted using street-intercept surveys at King County, WA syringe exchange programs in 2013. Survey responses were restricted to heroin injectors (n=389) and then categorized by the participant's age (<30 and >=30) for a descriptive epidemiological analysis. A manual stepwise logistic regression tested the independent relationship of user characteristics with being under the age of 30. RESULTS: In regression analyses, adjusting for other characteristics, young adults were significantly (p<0.05) more likely to: re-use syringes 2-4 times (OR=2.28 compared to those who used a syringe once), share syringes (OR=2.92), report they were "hooked on" prescription-type opioids prior to using heroin (OR=2.54), have had a sexual partner in the prior year (opposite sex OR=7.37, same sex OR=23.29, both genders OR=22.04), and report powder cocaine use in the prior 3 months (OR=2.49) compared to those ages 30 and older. Young adults were significantly less likely to report using pain medicines (OR=0.33), having an abscess in the prior year (OR=0.33) or having tested positive for hepatitis C (OR=0.22) than older adults adjusting for other variables. CONCLUSIONS: Younger heroin injectors engage in risky injection practices more than older heroin injectors. Along with other significant differences, these findings have implications for outreach programs and medical care for younger heroin injectors. PMID- 26651428 TI - The timing of elective shoulder surgery after shoulder injection affects postoperative infection risk in Medicare patients. AB - BACKGROUND: The goal of this study was to employ a national database to evaluate the association of preoperative injection before shoulder arthroscopy and arthroplasty with the incidence of postoperative infection. METHODS: A national database of Medicare patients was queried for patients who underwent shoulder arthroscopy or arthroplasty after ipsilateral shoulder injection. Three arthroscopy cohorts were created: arthroscopy within 3 months of injection (n = 3625), arthroscopy between 3 and 12 months after injection (n = 7069), and matched control arthroscopy without prior injection (n = 186,678). Three arthroplasty cohorts were created: arthroplasty within 3 months of injection (n = 636), arthroplasty between 3 and 12 months after injection (n = 1573), and matched control arthroplasty (n = 6211). Infection rates within 3 and 6 months postoperatively were assessed. RESULTS: The incidence of infection after arthroscopy at 3 months (0.7%; odds ratio [OR], 2.2; P < .0001) and 6 months (1.1%; OR, 1.6; P = .003) was significantly higher in patients who underwent injection within 3 months before arthroscopy compared with controls. The incidence of infection after arthroplasty at 3 months (3.0%; OR, 2.0; P = .007) and 6 months (4.6%; OR, 2.0; P = .001) was significantly higher in patients who underwent injection within 3 months before arthroplasty compared with controls. CONCLUSIONS: There was a significant increase in postoperative infection in Medicare patients who underwent injection within 3 months before shoulder arthroscopy and arthroplasty. This association was not noted when shoulder arthroscopy or arthroplasty occurred >3 months after injection. PMID- 26651429 TI - Kingella kingae Sequence Type 25 Causing Endocarditis with Multiple and Severe Cerebral Complications. PMID- 26651430 TI - Improved Survival in Down Syndrome over the Last 60 Years and the Impact of Perinatal Factors in Recent Decades. AB - OBJECTIVE: To calculate the survival of people with Down syndrome over the past 60 years and the influence of major perinatal factors by using linked population based data. STUDY DESIGN: A data linkage between 2 Western Australian (WA) data sets (the Register for Developmental Anomalies and the Intellectual Disability Exploring Answers database) was used to identify 772 children born with Down syndrome in WA from 1980-2010. Perinatal and mortality data were extracted from the WA Midwives Information System and WA death registrations and compared with the remaining WA population born during that same era. An additional 606 children with Down syndrome living in WA prior to 1980 were available from a disability services database and were used for predicting survival into adulthood. RESULTS: Overall, for cases born 1953-2010, 88% (95% CI 86%, 90%) survived to 5 years of age, 87% (95% CI 85%, 89%) to 10 years, and 83% (95% CI 80%, 85%) to 30 years. Children live-born with Down syndrome were significantly more likely (all P > .001) to have mothers older than 35 years (32.7% vs 13.4%), a gestational age less than 37 weeks (23.8% vs 7.9%), a cesarean delivery (28.9% vs 23.0%), and a birth weight less than 2500 g (20.4% vs 6.1%). Down syndrome survival was reduced in the presence of a cardiovascular defect, younger gestational age, low birth weight, or earlier birth years. CONCLUSIONS: Improved survival for children born with Down syndrome over the last 60 years has occurred incrementally, but disparities still exist for children who are preterm or have low birth weight. PMID- 26651431 TI - Gastrostomy Tube Feeding after Neonatal Complex Cardiac Surgery Identifies the Need for Early Developmental Intervention. AB - OBJECTIVE: To compare the proportion of developmental delay in early complex cardiac surgery (CCS) survivors with and without gastrostomy tube feeding (GTF). To explore acute care predictors of GTF that might help improve care in CCS survivors. STUDY GROUP: This comparison study of 2 groups within an inception cohort included 334 CCS survivors after cardiopulmonary bypass at <=6 weeks of age (2005-2012) who did not require extracorporeal membrane oxygenation or heart transplantation. Children were assessed at 21 +/- 3 months with the Bayley Scales of Infant and Toddler Development-Third Edition and the Adaptive Behavior Assessment System-Second Edition: general adaptive composite score. Delay was determined by scores >2 SD below mean. The chi(2) test compared groups. Predictors of GTF were analyzed using multiple logistic regression analysis, results expressed as OR with 95% CI. RESULTS: Of the survivors, 67/334 (20%) had GTF any time before the 21-month assessment. Developmental delays in children with GTF were cognitive in 16 (24%), motor in 18 (27%), language in 24 (36%) vs without GTF in 7 (3%), 8 (3%), and 32 (12%), respectively (P < .001). Gastrostomy group had almost 8 times the number of children delayed on the general adaptive composite score. Independent OR for GTF are presence of a chromosomal abnormality, OR 4.6 (95% CI 1.8, 12.0) (P = .002), single ventricle anatomy, OR 3.4 (95% CI 1.7, 6.8) (P < .001), total postoperative days of open sternum, OR 1.15 (95% CI 1.1, 1.3) (P = .031), and total number of hospital days at CCS, OR 1.03 (95% CI 1.1, 1.04) (P = .002). CONCLUSIONS: GTF identifies CCS survivors at risk for delay, who would benefit from early developmental intervention. The described mostly nonmodifiable predictors may guide counseling of these children's families. PMID- 26651432 TI - Parental Sources of Support and Guidance When Making Difficult Decisions in the Pediatric Intensive Care Unit. AB - OBJECTIVE: To assess sources of support and guidance on which parents rely when making difficult decisions in the pediatric intensive care unit and to evaluate associations of sources of support and guidance to anxiety, depression, and positive and negative affect. STUDY DESIGN: This was a prospective cohort study of 86 English-speaking parents of 75 children in the pediatric intensive care unit at The Children's Hospital of Philadelphia who were hospitalized greater than 72 hours. Parents completed standardized instruments and a novel sources of support and guidance assessment. RESULTS: Most parents chose physicians, nurses, friends, and extended family as their main sources of support and guidance when making a difficult decision. Descriptive analysis revealed a broad distribution for the sources of support and guidance items related to spirituality. Parents tended to fall into 1 of 2 groups when we used latent class analysis: the more spiritual group (n = 47; 55%) highly ranked "what my child wants" (P = .023), spouses (P = .002), support groups (P = .003), church community (P < .001), spiritual leader (P < .001), higher power (P < .001), and prayer (P < .001) compared with the less-spiritual group (n = 39; 45%). The more-spiritual parents had greater positive affect scores (P = .005). Less-spiritual parents had greater depression scores (P = .043). CONCLUSIONS: Parents rely most on physicians, nurses, and friends and extended family when making difficult decisions for their critically ill child. Respondents tended to fall into 1 of 2 groups where the more-spiritual respondents were associated with greater positive affect and may be more resistant to depression. PMID- 26651433 TI - Maternal transfer of dechloranes and their distribution among tissues in contaminated ducks. AB - The tissue concentrations of dechlorane plus and its analogues were determined in ducks collected from several e-waste recycling villages of Taizhou, China. Compared with the published literature, the relatively high concentrations of these compounds were detected in ducks, indicating serious DP contamination. Since both the duck meat and eggs were important components for diet, this result reminded us of keeping a watchful eye on human dietary exposure to DP and its analogues in this study area. The wet-weight concentrations of DP and its analogues were significantly related to tissue lipid content (p < 0.05), indicating that the lipid pools predominantly impacted the distribution of DPs in ducks. On the basis of lipid adjustment, the significantly lower levels in brain than those in liver and blood, displayed the occurrence of liver sequestration and blood-brain barrier to DP and its analogues in the duck (p < 0.05). The maternal transfer of DP and Mirex was not obviously limited, and the transferring extent of Dec 602 was over one. The stereo-selected accumulation of two DP isomers occurred among tissues with preference to syn-DP in blood, and to anti-DP in brain. The values of lipid-adjusted monodechlorinated products mainly originated from the exterior environment in ducks. PMID- 26651434 TI - Analysis of 17 STR data on 5362 southern Portuguese individuals-an update on reference database. AB - The main objective of this work consisted of the updating of allele frequencies and other relevant forensic parameters for the 17 autosomal STR loci provided by the combination of the two types of kits used routinely in our laboratory casework: AmpF/STR Identifiler((r)) and the Powerplex((r)) 16 Systems. This aim was of significant importance, given that the last study on these kits within the southern Portuguese population dates back to 2006, and, as a consequence, it was necessary to correct the deviation caused by population evolution over the last ten years so that they might be better applied to our forensic casework. For this reason genetic data from 5362 unrelated Caucasian Portuguese individuals from the south of Portugal who were involved in paternity testing casework from 2005 to 2014 was used. Of all the markers, TPOX proved to be the least polymorphic, and Penta E the most. Secondly, this up-to-date southern Portuguese population was compared not only with the northern and central Portuguese populations, but also with that of southern Portugal in 2006, along with populations from Spain, Italy, Greece, Romania, Morocco, Angola and Korea in order to infer information about the relatedness of these respective populations, and the variation of the southern Portuguese population over time. PMID- 26651435 TI - Weighing in on pediatric obesity: Weight screening at the dental visit. AB - BACKGROUND AND OVERVIEW: Pediatric obesity is a public health concern requiring an interprofessional approach to care. Weight screening in the dental office can promote healthy behaviors to improve weight and oral health status and reduce systemic and oral health risks. CONCLUSIONS: Oral health care professionals can perform weight screenings quickly. Routine weight screening of pediatric patients and early intervention through education and referral of patients to a registered dietitian nutritionist and a physician for more in-depth evaluation may help reduce disease risk. PRACTICAL IMPLICATIONS: Oral health care professionals can measure a patient's height and weight and can easily calculate body mass index percentile according to a patient's age and sex to detect weight status that does not fall within the normal range. Oral health care professionals should refer patients who are underweight, overweight, or obese to a registered dietitian nutritionist and the patient's physician for follow-up. PMID- 26651436 TI - [Everyone has the right to peace, integration and universal health coverage]. PMID- 26651437 TI - Adult narcoleptic patients have increased risk of cancer: A nationwide population based study. AB - BACKGROUND: The comorbidity profile, especially cancer risk, of narcoleptic patients has seldom been explored. We used a nationwide database to evaluate the risk of cancer among adult narcoleptic patients. METHODS: We conducted the cohort study using National Health Insurance Research Database from 2000 to 2009. Standardized incidence ratios (SIRs) of cancers were calculated to compare the cancer incidence of the study cohort with that of the general population. RESULTS: 2833 narcoleptic patients were identified after excluding patients with antecedent malignancy and age younger than 18 years old. The study cohort was observed for 15,913 person-years during a 10-year period. The median follow-up interval was 5.6 +/- 3.0 years. Seventy-four cancers occurred in during the follow-up. The risk of all cancers was found significantly increased in adult narcoleptic patients (SIR 1.32; 95% CI, 1.04-1.66, p=0.0248). Regarding sex, the overall cancer risk was increased in female patients (SIR 1.52; 95% CI, 1.05 2.13, p=0.026). Furthermore, females were found to have more head and neck cancers (SIR 6.17; 95% CI, 1.66-15.80, p=0.009) and gastric cancers (SIR 4.87; 95% CI, 1.31-12.48, p=0.02). For males, the incidence of overall and specific cancer types was not significantly increased. CONCLUSIONS: Adult narcoleptic patients had a higher risk for cancer. Further research is warranted to elucidate the mechanism underlying its association. PMID- 26651438 TI - Associations between contextual factors and colorectal cancer screening in a racially and ethnically diverse population in Texas. AB - BACKGROUND: Colorectal cancer is the third most commonly diagnosed cancer and the third leading cause of cancer death in the United States. Increased attention has been given to understanding the role of local contexts on cancer screening behaviors. We examined the associations between multiple tract-level socioeconomic measures and adherence to colorectal cancer screening (CRCS) in Harris County and the City of Houston, Texas. METHODS: We conducted a cross sectional multilevel study linking individual-level data on CRCS from the 2010 Health of Houston Survey with contextual data from the U.S. Census and the U.S. Department of Housing and Urban Development. We examined tract-level poverty, education, employment, income inequality, and foreclosure measures across 543 Census tracts. Analyses were limited to individuals aged 50-74 years (N=1720). RESULTS: Overall, 58.0% of the sample was adherent to any recommended CRCS test. In bivariate analyses, increasing levels of area poverty, low education, unemployment, and foreclosures were associated with lower odds of adherence to CRCS. After controlling for individual-level covariates, only tract-level unemployment remained associated with adherence to CRCS (adjusted OR=0.80; 95% CI: 0.66-0.99; P=.037). CONCLUSIONS: Neighborhood socioeconomic disadvantage is increasingly recognized as a determinant of health, and our study suggests that the contextual effect of area unemployment may extend to cancer screening outcomes. Our finding is important to cancer control planners because we identified a contextual marker of disparity that can be used to target local interventions to promote CRCS and thereby reduce cancer disparities among non adherent individuals who reside in communities with high unemployment rates. PMID- 26651439 TI - Evaluation of a mammography screening program within the population-based Vorarlberg Health Monitoring & Prevention Program (VHM&PP). AB - OBJECTIVES: To describe the mammography screening program from 1989 to 2005 within a population-based prevention program in Austria and to appraise it according to recommended quality indicators. MATERIAL AND METHOD: From 01.01.1989 all women aged 40 years or older participating in the Vorarlberg Health Monitoring & Prevention Program (VHM&PP) was offered to undergo additionally a "screening mammography". Passive follow-up has been performed by record linkages with the Vorarlberg cancer registry and mortality statistics for information on outcome variables. Interval cancer rates have been estimated and the survival after breast cancer has been calculated by life table technique by examination period and age groups (40-49 years, 50-69 years). RESULTS: Between 1989 and 2005 50,100 women aged 40 to 69 years participated in the program, of which 123,652 mammogram results have been collected. In the target population the participation rate was 65.1%. During median follow-up time 13.5 years and 633,342 person-years overall 665 invasive cancer and 87 ductal carcinoma in situ (11.6%) cases have been identified. Between 1996 and 2004 the detection rates were 239.9 per 100.000 among women aged 40-49 years and 543.2 per 100,000 among women aged 50-69 years. The rates for interval cancers were 160.4 and 277.4 per 100 000 negative screens, respectively. During median follow-up of 13.5 years 165 deaths occurred with no difference in survival between patients with interval and screen detected cancers. CONCLUSION: A mammography screening program has been performed between 1989 and 2005 in Vorarlberg. Till 2005 most quality indicators improved and met the EU-recommendations suggesting that alternative approaches to organized mammography screening based on routine data should be explored. PMID- 26651440 TI - Trends in mammography utilization for breast cancer screening in a Middle-Eastern country: Lebanon 2005-2013. AB - INTRODUCTION: In Lebanon, annual national breast awareness campaigns were started in 2002 during the international breast month of October to promote the utilization of mammography for women aged >= 40. The impact of the campaigns has been assessed periodically since 2003. Results of 2003-2005 campaigns have been published previously. OBJECTIVES: To measure the prevalence of two behavioral outcomes of interest: ever-use of mammography, and repeat mammography in the previous 12 months among ever-users. The prevalence was described by region and age group. The aim was to document the effectiveness of the program towards reaching a nationally defined goal of 80% screening coverage. METHODS: The survey's sampling frame was developed incrementally, and since 2005 it has included women aged >= 40 from all areas of Lebanon. The sample size has also increased incrementally from 1200 in 2005 to 2400 in 2013. Results have been tabulated biannually and presented as historical trends with regional and demographic variations covering a 9-year period. RESULTS: In all six consecutive surveys presented here, the mean age of participating women was about 50 years. Year-by-year increases in utilization indicators were detected, with consistent differences in favor of the more urban areas in and around the capital city Beirut and its suburbs (Greater Beirut or GB). By 2013, ever-utilization had reached 43% (41-45) and recent mammography 20% (18-22) nationwide. Utilization was significantly more important in the age group 50-59 compared with the age group 40-49 or >= 60. While recent rates have increased nationwide, they have reached a plateau of about 25% in GB and are tending to the same level in other areas. DISCUSSION AND CONCLUSIONS: While initial progress was slow, it has been accelerating in the last 4-5 years, indicating that the message is being accepted by a larger audience of targeted women at each iteration. However, concern remains that women between 40 and 50 and those >60 are not responding as well as desired to the screening message, for reasons currently under investigation. PMID- 26651441 TI - Prostate cancer trends in Barbados: An analysis of the Barbados Urologic Diseases Survey database. AB - OBJECTIVES: To describe the burden and trend of prostate cancer (CaP) in the Caribbean island of Barbados. METHODS: All urologic pathology reports in Barbados between 1990 and 2009 were entered into the Barbados Urologic Diseases Survey (BUDS) database. All new cases of CaP were identified and the database was used to assess trends in CaP epidemiology over the study period. RESULTS: 3066 new cases of CaP were identified between 1990 and 2009. The world age-standardized rate increased steadily from 71.8 (95% CI 57.8-88.4) per 100,000 in 1990 to 112.4 (95% CI 94.0-133.7) per 100,000 in 2009, with a peak rate of 148.9 (95% CI 127.0 172.8) in 2004. The cumulative risk up to 74 years of age also increased from 11.1% in 1990 to 23.8% in 2009 with a peak of 29.9% in 2004. The mean age at diagnosis decreased from 73.1 years in 1990 to a nadir of 66.2 years in 2009. The rate of high-grade cancer (Gleason score >= 8) and intermediate-grade cancer (Gleason score=7) at presentation rose between 2000 and 2009 while the rate of low-grade cancer (Gleason score <= 6) decreased. CONCLUSIONS: Barbados suffers an unusually high burden of CaP with a trend towards more aggressive disease over the last decade. The results are important as they highlight the utility of the BUDS initiative in epidemiologic evaluation, but should be looked at cautiously due to a lack of specific details regarding screening practices in this population. PMID- 26651442 TI - Breast cancer age at diagnosis patterns in four Latin American Populations: A comparison with North American countries. AB - BACKGROUND: In the Latin America countries (LAC), one in five breast cancer (BC) cases occur in women younger than 45 years, almost twice the frequency seen in developed countries. Most BC cases in younger women are premenopausal and are generally more difficult to detect at early stages and to treat than postmenopausal cancers. We employ data from four high quality population-based registries located in LAC and assess the extent to which the higher frequency of BC occurring in younger women is due to a younger population structure, compared to that of developed countries. Next, we analyze secular and generational trends of incidence rates in search for additional explanations. METHODS: Using data from the International Agency for Research on cancer, between 1988 and 2007, the age distribution of BC incident cases for registries located in Brazil, Colombia, Costa Rica, Ecuador is compared to that of USA and Canadian registries, both before and after removing differences in population age structure. An age-period cohort modelling of incidence rates is also conducted in all compared registries to identify secular and generational effects. RESULTS: BC incident cases in the LAC registries present, on average, at an earlier age than in the USA and Canadian registries and for 2003-2007, between 20 and 27% of cases occur in women aged 20-44. About two thirds of the difference in age distribution between LAC and USA registries is attributable to the younger age distribution in the LAC base populations. The USA registries show the highest age-specific BC incidence rates of all compared aggregated registries, at all ages. However, in all the LAC registries incidence rates are rapidly increasing, fueled by a strong birth cohort effect. This cohort effect may be explained by important reduction in fertility rates occurring during the second half of the 20th century, but also by a greater exposure to other risk factors for BC related to the adoption of life styles more prevalent in developed countries. CONCLUSION: The younger age at presentation of BC incident cases seen in the analyzed LAC registries, and possibly in many Latin American countries, is not only attributable to their relatively young population age structure but also to the low incidence rates in older women. As more recently born cohorts, with greater exposure to risk factors for postmenopausal BC, reach older age, incidence rates will be more similar to the rates seen in the USA and Canadian registries. There is a need for additional research to identify determinants of the higher BC rate among younger women in these countries. PMID- 26651443 TI - A national profile of the impact of parental cancer on their children in Japan. AB - OBJECTIVE: Dependent children under the age of 18 are particularly vulnerable to the stress of parental death from cancer or of having a parent diagnosed and treated for the disease. More and more Japanese couples are postponing parenthood, which increases their chances of developing cancer while they still have a dependent child. However, the problem has not received enough attention from healthcare professionals and policy-makers because the extent and breadth of the problem has never been examined in the Japanese population. Therefore, we aimed to estimate the nationwide incidence of cancer patients who have children under the age of 18 years, as well as the incidence of children who have a parent diagnosed with cancer in Japan. STUDY DESIGN: We calculated the proportion of patients who have children stratified by age, gender and cancer type using electronic medical records of cancer patients (20-59 years old) admitted to the National Cancer Center Hospital (NCCH) for the first time between January 2009 and December 2013. We projected these estimates onto the Japanese population using 2010 population-based cancer registry data, and repeated the projection using 2011 hospital-based cancer registry data so that estimates of patients receiving care at Designated Cancer Care (DCC) hospitals could be obtained. RESULTS: We found that an estimated 56,143 cancer patients who have 87,017 dependent children are diagnosed with cancer every year in Japan. The proportion of children in Japan who had a parent newly diagnosed with cancer in 2010 was approximately 0.38%. We estimated that in 2011 there were on average about 82 cancer patients with minor children and 128 minor children who have at least one parent diagnosed with cancer in every DCC hospital in Japan. CONCLUSION: Parental cancer is common. We have identified that many adults diagnosed with cancer have the double burden of coping with the diagnosis and treatment as well as supporting their children through this experience. Additional data on socioeconomic characteristics and needs assessment of these patients are required to understand how best to help children and families cope with cancer. PMID- 26651444 TI - Trends in incidence and survival for anal cancer in New South Wales, Australia, 1972-2009. AB - INTRODUCTION: Little is known about the incidence and survival of anal cancer in New South Wales (NSW), Australia, as anal cancer cases are often grouped together with other colorectal cancers in descriptive epidemiological analyses. METHODS: We studied patterns and trends in the incidence and survival of people diagnosed with anal cancer in NSW, Australia, 1972-2009 (n=2724). We also predicted anal cancer incidence in NSW during 2010-2032. Given the human papilloma virus associated aetiology for most anal cancers, we quantified these changes over time in incidence and survival by histological subtype: anal squamous cell carcinoma (ASCC); and anal adenocarcinoma (AAC). RESULTS: There was a linear increase in incident anal cancer cases in NSW with an average annual percentage change (AAPC) of 1.6 (95% CI 1.1-2.0) such that, in combination with age-period-cohort modelling, we predict there will be 198 cases of anal cancer in the 2032 calendar year (95% CI 169-236). Almost all of these anal cancer cases are projected to be ASCC (94%). Survival improved over time regardless of histological subtype. However, five-year relative survival was substantially higher for people with ASCC (70% (95% CI 66-74%)) compared to AAC (51% (95% CI 43-59%)), a 37% difference. Survival was also greater for women (69% (95% CI 64-73%)) with ASCC compared to men (55% (95% CI 50-60%)). It was not possible to estimate survival by stage at diagnosis particularly given that 8% of all cases were recorded as having distant stage and 22% had missing stage data. INTERPRETATION: Aetiological explanations, namely exposure to oncogenic types of human papillomavirus, along with demographic changes most likely explain the actual and projected increase in ASCC case numbers. Survival differences by gender and histological subtype point to areas where further research is warranted to improve treatment and outcomes for all anal cancer patients. PMID- 26651445 TI - What is the benefit of treatment with multiple lines of chemotherapy for patients with metastatic breast cancer? A retrospective cohort study. AB - BACKGROUND: Despite the extensive clinical experience, it is still under debate to what extent patients with metastatic breast cancer (MBC) benefit from multiple lines of chemotherapy beyond standard first or second line treatment. Selection of patients with MBC who will benefit from treatment is crucial to improve outcome and reduce unnecessary toxicity. In this retrospective study, systemic treatment outcome for patients with metastatic MBC is being evaluated. We evaluated to what extent the clinical benefit of prior chemotherapy can predict the success of a subsequent treatment line. METHODS: Ninety-one patients treated with chemotherapy for MBC between January 2005 and January 2009 were included in this study. Clinical characteristics of patients, choices of chemotherapy and response at first evaluation of every treatment line was evaluated based on radiologic and clinical data. RESULTS: Patients received multiple systemic cytotoxic and biological (combination) therapies. 30% of these patients received more than five consecutive systemic (combination) treatments. First line chemotherapy was mostly anthracycline-based, followed by taxanes, capecitabine and vinorelbine. The response rate (RR, complete response plus partial response according to RECIST 1.1) decreased from 20% (95% CI 11-28%) upon first line of treatment to 0% upon the fourth line. The clinical benefit rate (combining RR and stable disease) decreased from 85% (95% CI 78-93%) in the first to 54% (95% CI 26 67) upon the fourth line. 24% of the patients with clinical benefit at first evaluation did not receive a subsequent line of treatment when progressive disease occurred, while sixty-one percent of the patients with progressive disease at first evaluation of a treatment did not receive a subsequent line of chemotherapy. When applied, the efficacy of a subsequent line of treatment was similar for patients independent of previous treatment benefit. CONCLUSION: The clinical benefit at first evaluation from systemic treatment in MBC does not predict for subsequent treatment benefit in this retrospective analysis. The fact that 61% of patients did not receive subsequent treatment after previous treatment failure suggests that either clinical judgement is of critical value in selection of patients to prevent them from unnecessary toxicity or, alternatively indicates that based on the assumption that prior treatment failure predicts for lack of benefit undertreatment of patients occurs. Therefore, a more adequate clinical judgement tool or predictive biomarkers for response are urgently needed to improve treatment outcome. PMID- 26651446 TI - Survival after initiation of androgen deprivation therapy for prostate cancer of Australian men. AB - OBJECTIVE: To examine duration of use and survival rates of Australian males who initiated androgen deprivation therapy for prostate cancer, including survival rates stratified by the type of the initial androgen deprivation therapy and age at initiation. METHOD: Cohort study using Australian Government Department of Veterans' Affairs (DVA) data. Males aged 50 and over initiating androgen deprivation therapy (2008-2010) were included in the cohort. Time to death or end of study (31 Dec 2012), duration of therapy and 1 to 5-year relative survival rates stratified by type of initial therapy and age were presented. RESULTS: Of the androgen deprivation therapy initiators (n=3,611, mean age 84), 92% survived 1 year with the relative survival rate decreasing to 79% at 3 years and to 57% at 5 years. Survival outcomes stratified by the type of initial therapy showed slightly higher rates amongst those initiated on gonadotropin releasing hormone analogues or on combined androgen blockage compared to those initiated on anti androgens. Age specific rates were similar amongst the younger groups (under 80 years old) at each single point of time and were slightly higher than in those aged 80 years and over for some points of time. Fifty percent of patients received androgen deprivation therapy for extended periods (30 months). CONCLUSIONS: The 1-year relative survival of veterans was high and similar to that of the general Australian population with prostate cancer. Factors such as tumour stage and grade (not available in the data) could explain differences in survival based on the type of the initial therapy. PMID- 26651447 TI - Trends in ethnic and socioeconomic inequalities in cancer survival, New Zealand, 1991-2004. AB - Improvements in cancer survival may be distributed inequitably throughout populations and across time. We assessed trends in cancer survival inequalities in New Zealand by ethnic and income group. 126,477 people diagnosed with cancer between 1991 and 2004, followed-up to 2006, were included. First, inequalities pooled over time were measured with excess mortality rate ratios (EMRRs). Second, interpretation of changes in inequalities over time can differ depending on whether one uses EMRRs, excess mortality rate differences (EMRD) or absolute differences in relative survival risks (RSRD); we estimated all three by cancer site and (for EMRRs only) pooled across all sites. We found that pooled over time and all sites, Maori had an EMRR of 1.29 (95% CI, 1.24-1.34) compared to non Maori. The low compared to high-income EMRR was 1.12 (95% CI, 1.09-1.15). Pooled over cancers, there was no change in the ethnic EMRR over time but the income EMRR increased by 9% per decade (1-17%). Changes over time in site-specific inequalities were imprecisely measured, but the direction of change was usually consistent across EMRRs, EMRDs and RSRDs. There were persistent ethnic inequalities in cancer survival over time, and slower improvements for low-income people. PMID- 26651448 TI - Determinants in decision making for curative treatment and survival in patients with resectable oesophageal cancer in the Netherlands: a population-based study. AB - BACKGROUND: Preferred treatment for resectable oesophageal cancer is surgery with or without neoadjuvant treatment. However, oesophageal surgery has high morbidity and in vulnerable patients with co-morbidity other treatment modalities can be proposed. We examined determinants in decision making for surgery and factors affecting survival in patients with resectable oesophageal cancer in southern Netherlands. METHODS: All patients with resectable (T1-3, N0-1, M0-1A) oesophageal cancer (n=849) diagnosed between 2003 and 2010 were selected from the population-based data of the Eindhoven Cancer Registry. Logistic regression analysis and multivariable Cox survival analysis were conducted to examine determinants of surgery and survival. RESULTS: Forty-five percent of the patients underwent surgery. In multivariable survival analysis only surgery, chemoradiation alone and tumour stage influenced overall survival (OS). Patients aged >= 70 yrs, a low socioeconomic status (SES), one or more co-morbidities, cT1 tumours, cN1-tumours, a squamous-cell carcinoma, and those with a proximal tumour were significantly less often offered surgical resection. Older patients and patients with cT1 tumours were less likely to receive chemoradiation alone. Patients with clinically positive lymph nodes or a proximal tumour were more likely to receive chemoradiation alone. CONCLUSION: Treatment modalities including surgery and chemoradiation alone as well as stage of disease were independent predictors of a better OS in patients with potentially resectable oesophageal cancer. Therefore, the decision to perform potentially curative treatment is of crucial importance to improve OS for patients with potentially resectable oesophageal cancer. Although age and SES had no significant influence on overall survival, a higher age and low SES negatively influenced the probability to propose potentially curative treatment. PMID- 26651449 TI - Lifestyle and health-related predictors of cervical cancer screening attendance in a Swiss population-based study. AB - BACKGROUND: Since the implementation of cervical cancer (CC) screening, incidence and mortality rates have decreased worldwide. Little is known about lifestyle and health-related predictors of cervical cancer screening attendance in Switzerland. Our aim was to examine the relationship between lifestyle and health-related factors and the attendance to CC screening in Switzerland. METHODS: We analyzed data of 20-69 years old women (n=7319) of the Swiss Health Survey (SHS) 2012. Lifestyle factors included body mass index, smoking status, alcohol consumption, physical activity and attention to diet. Health-related factors of interest were diabetes, hypertension, high cholesterol levels, chronic diseases, self-perceived health, and psychological distress. We performed multivariable logistic regression analyses with the dichotomized CC screening status as outcome measure and adjusted for demographic factors. RESULTS: Obesity, low physical activity, and not paying attention to diet were statistically significantly associated with lower CC screening participation. High cholesterol levels and history of chronic diseases were statistically significantly positively associated with screening participation. CONCLUSION: Being obese, physically inactive and non-attention to diet are risk factors for CC screening attendance. These findings are of importance for improving the CC screening practices of low-user groups. PMID- 26651450 TI - Time to first treatment after colonoscopy in patients suffering from colon or rectum cancer in France. AB - BACKGROUND: Time to treatment of cancer is becoming a serious political and social issue. A greater understanding of the timeframes involved in cancer care is needed to reduce inequalities in access to care caused by delays. OBJECTIVE: To describe indicators of time to first treatment after colonoscopy in colon cancer (CC) and rectum cancer (RC) patients in France. METHOD: Using the international classification of diseases and medical procedures codes, from national hospital discharge and long term illness databases we selected patients newly diagnosed for CC or RC in 2009-2010 who had undergone treatment. RESULTS: We included 15 694 and 6 623 patients for CC and RC, respectively. Median times to surgery in patients with a surgical treatment pathway for CC and RC were 22 (Q1=14; Q3=34) and 97 (Q1=34; Q3=141) days, respectively. Median times to chemotherapy for patients with a non-surgical treatment pathway, for CC and RC were 36 (Q1=21; Q3=59) and 40 (Q1=27; Q3=59) days, respectively. The median time to radiotherapy in RC patients was 53 (Q1=39; Q3=78) days.Time to surgery as first treatment in RC patients (46 days) was twice as long as that in CC patients (22 days). Time to treatment was longer in most northern regions and in overseas districts, and shorter in southern regions, for both CC and RC. CONCLUSION: The findings in this unprecedented study in France will inform decision-making policies on the future implementation of guidelines on timeframes for colorectal cancer treatment access. PMID- 26651451 TI - Comparison of Tricuspid Annular Plane Systolic Excursion in Patients With Atrial Fibrillation Versus Sinus Rhythm. AB - Echocardiography now plays a central guiding role in the management of patients with atrial fibrillation (AF). However, the current guidelines mention little about the presence AF during the assessment of echocardiographic variables in the clinical setting. AF itself may impact on tricuspid annular plane systolic excursion (TAPSE) as a right ventricular systolic function compared with sinus rhythm (SR). The aim of this study was to compare and assess the echocardiographic parameters including TAPSE in patients with AF and SR. From January 1, 2013, to September 30, 2014, patients with AF without any cardiovascular disease were retrospectively evaluated using echocardiography. Age , gender-, and left ventricular ejection fraction-matched patients with SR were selected from our database on the basis of a comprehensive history, physical examination, and echocardiographic findings. During the study period, we identified 239 patients with AF (74 +/- 9 years; 65% men) and without any cardiac disease who underwent echocardiography. We also included 281 patients in the SR group (74 +/- 8 years; 67% men). In all study subjects, TAPSE in AF was smaller than in SR regardless of age (17 +/- 3 vs 20 +/- 3 mm, p <0.001). In the stepwise multiple regression model, TAPSE was strongly associated with the presence of AF (standardized beta = -0.362, p <0.001) and stroke volume index (standardized beta = 0.173, p <0.001) after adjustment for age, gender, heart rate, left ventricular ejection fraction, and tricuspid regurgitant grade. In conclusions, patients with AF had lower TAPSE than those with SR regardless of age. When we assess TAPSE in the clinical setting, we must pay attention to the presence of AF. PMID- 26651452 TI - Relation Between Hospital Length of Stay and Quality of Care in Patients With Acute Coronary Syndromes (from the American Heart Association's Get With the Guidelines--Coronary Artery Disease Data Set). AB - Worries regarding short length of stay (LOS) adversely impacting quality of care prompted us to assess the relation between hospital LOS and inpatient guideline adherence in patients with acute coronary syndrome. We used the American Heart Association's Get with The Guidelines (GWTG)--Coronary Artery Disease data set. Data were collected from January 2, 2000, to March 21, 2010, for patients with acute coronary syndrome from 405 different sites. Of the 119,398 patients in the study, the mean LOS was 5.5 days with a median of 4 days. There was no difference in the LOS on the basis of hospital size, hospital type, or cardiac surgery availability. The population with an LOS <4 days were younger (63.8 +/- 14.1 vs 70 +/- 14.5, p <0.0001), men (63.8% vs 55.3%, p <0.0001) and had fewer clinical co-morbidities. The overall adherence was high in the GWTG participating hospitals. Those with the LOS <4 days were more likely to receive aspirin (adjusted odds ratio [OR] 1.12, 95% CI 1.06 to 1.19; p <0.001), clopidogrel (OR 1.77, 95% CI 1.60 to 1.95; p <0.001), lipid-lowering therapy if indicated (OR 1.13, 95% CI 1.05 to 1.21; p <0.001), angiotensin-converting enzyme inhibitor or angiotensin receptor blocker for left ventricular systolic dysfunction (OR 1.10, 95% CI 1.01 to 1.21; p = 0.04) and smoking cessation counseling (OR 1.17, 95% CI 1.1 to 1.24; p <0.001) compared to those with the LOS >= 4 days. In contrast, those with the LOS <4 days were less likely to receive beta blockers (OR 0.88, 95% CI 0.84 to 0.93; p <0.001). The odds of receiving defect-free care were greater for patients with the LOS <4 days (OR 1.15, 95% CI 1.1 to 1.21; p <0.001). In conclusion, in GWTG participating hospitals, a shorter LOS did not appear to adversely affect adherence to discharge quality of care measures. PMID- 26651453 TI - Effect of Bosentan on Claudication Distance and Endothelium-Dependent Vasodilation in Hispanic Patients With Peripheral Arterial Disease. AB - Endothelin (ET) is involved in the etiopathogenesis of peripheral arterial disease (PAD). We hypothesized that ET antagonism might improve the endothelial function, inflammatory status, and symptoms in PAD. This pilot randomized clinical trial was designed to determine the clinical efficacy, pleiotropic effects, and safety of dual ET-receptor antagonist bosentan in Hispanic patients with PAD presenting intermittent claudication. The Bosentan Population-Based Randomized Trial for Clinical and Endothelial Function Assessment on Endothelin Antagonism Therapy was a 12-month, randomized, controlled, parallel-group, double blind, proof-of-concept pilot study evaluating the effect of bosentan on absolute claudication distance (primary efficacy end point), flow-mediated arterial dilation, and C-reactive protein levels (primary pleiotropic end points) in patients with PAD with Rutherford category 1 to 2 of recent diagnosis. Secondary end points included ankle-brachial index, subjective claudication distance, and safety. Of the 629 screened subjects, 56 patients were randomized 1:1 to receive bosentan for 12 weeks (n = 27) or placebo (n = 29). Six months after the initiation, a significant treatment effect in flow-mediated arterial dilation of 2.43 +/- 0.3% (95% CI 1.75 to 3.12; p = 0.001), absolute claudication distance of 283 +/- 23 m (95% CI 202 to 366; p = 0.01), ankle-brachial index of 0.16 +/- 0.03 (95% CI 0.09 to 0.23; p = 0.001), and a decrease in C-reactive protein levels of 2.0 +/- 0.5 mg/L (95% CI -2.8 to -1.1; p = 0.02) were observed in the bosentan treated group compared to the control group. No severe adverse effects were found in the bosentan group. In conclusion, in Hispanic patients with intermittent claudication, bosentan was well tolerated and improved endothelial function and claudication distance as well as inflammatory and hemodynamic states. PMID- 26651454 TI - Comparison of Percutaneous Mitral Valve Repair Versus Conservative Treatment in Severe Functional Mitral Regurgitation. AB - Percutaneous mitral valve repair (PMVR) using the MitraClip System is feasible and entails clinical improvement even in patients with high surgical risk and severe functional mitral regurgitation (MR). The aim of this study was to assess survival rates and clinical outcome of patients with severe, functional MR treated with optimal medical therapy (OMT) compared with those who received MitraClip device. Sixty patients treated with OMT were compared with a propensity matched cohort of 60 patients who underwent PMVR. Baseline demographics and echocardiographic variables were similar between the 2 groups. The mean age of patients was 75 years, and 67% were men. The median logistic EuroSCORE and EuroSCORE II were 17% and 6%, respectively, because of the presence of several co morbidities. The mechanism of MR was functional in all cases with an ischemic etiology in 52% of patients. Median left ventricle ejection fraction was 34%. All the patients were symptomatic for dyspnea with 63% and 12% in the New York Heart Association class III and IV, respectively. In PMVR group, the procedure was associated with safety and very low incidence of procedural complications with no occurrence of procedural and inhospital mortality. After a median follow-up of 515 days (248 to 828 days), patients treated with PMVR demonstrated overall survival, survival freedom from cardiac death and survival free of readmission due to cardiac disease curves higher than patients treated conservatively (log rank test p = 0.007, p = 0.002, and p = 0.04, respectively). In conclusion, PMVR offers a valid option for selected patients with high surgical risk and severe, functional MR and entails better survival outcomes compared with OMT. PMID- 26651455 TI - Prognostic Utility of Brain Natriuretic Peptide in Asymptomatic Patients With Significant Mitral Regurgitation and Preserved Left Ventricular Ejection Fraction. AB - We sought to study the prognostic utility of serum brain natriuretic peptide (BNP) in patients with significant primary mitral regurgitation (MR) and preserved left ventricular (LV) ejection fraction (EF). Consecutive 548 asymptomatic patients (age 62 +/- 13 years and 66% men) with >= 3 + primary MR and preserved LVEF on echo at rest, evaluated at our center from 2005 to 2008 were studied. Baseline clinical and echo data were recorded and the Society of Thoracic Surgeons (STS) score was calculated. Mean STS score was 4 +/- 1%. Mean LVEF, mitral effective regurgitant orifice, indexed LV end-systolic diameter, and right ventricular systolic pressure (RVSP) were 62 +/- 4%, 0.55 +/- 0.3 cm(2), 1.6 +/- 0.3 cm/m(2), and 38 +/- 15 mm Hg; 43% had flail. Median log-transformed brain natriuretic peptide (lnBNP) was 4.1 (interquartile range 3.30 to 5.0), corresponding to an absolute BNP value of 60 pg/ml (only 13% had an absolute BNP value >250 pg/ml). At 7.4 +/- 2 years, 493 patients (90%) had mitral surgery (92% repair) and nonmalignancy death occurred in 53 patients (10%). On multivariate Cox analysis, higher STS score (hazard ratio [HR] 1.50, 95% CI 1.20 to 1.88), higher baseline RVSP (HR 1.17, 95% CI 1.02 to 1.35), and higher ln BNP (HR 2.51, 95% CI 1.86 to 3.39) predicted death, whereas mitral surgery (HR 0.17, 95% CI 0.09 to 0.30) was associated with improved survival (all p <0.01). Eighty-nine percent of deaths occurred in patients with lnBNP >4.1. Addition of lnBNP to a model of STS score, baseline RVSP, and mitral surgery provided incremental prognostic utility (chi-square for mortality increased from 137 to 162, p <0.001). In conclusion, in asymptomatic patients with >= 3 + primary MR and preserved LVEF, the addition of BNP improved risk stratification and higher BNP independently predicted reduced survival. PMID- 26651456 TI - Risk Factors and Outcomes of Gastrointestinal Bleeding in Left Ventricular Assist Device Recipients. AB - Increasing use of left ventricular assist devices (LVADs) has been accompanied by rising incidence of gastrointestinal bleeding (GIB). Objectives of this study were to determine the yearly incidence of GIB in LVAD recipients, compare outcomes of continuous-flow (CF) and pulsatile-flow LVAD eras, and investigate for risk factors. The Healthcare Cost and Utilization Project-Nationwide Inpatient Sample database from 2005 to 2010 was analyzed. Primary outcome of interest was incidence of GIB in LVAD recipients. Multivariate logistic regression model was used to examine independent associations of GIB with risk factors and outcomes. An estimated 8,879 LVAD index admissions and 8,722 readmissions in LVAD recipients over 6 years were analyzed. The yearly incidence of GIB after LVAD implantation increased from 5% in 2005 to 10% in 2010. On multivariate regression analysis, the odds of GIB was 3.24 times greater (95% confidence interval 1.53 to 6.89) in the era of CF LVADs than in the era of pulsatile-flow LVADs. Compared to their younger counterparts, in LVAD recipients aged >65 years, the adjusted odds of GIB was 20.5 times greater (95% confidence interval 2.24 to 188). GIB did not significantly increase the inhospital mortality but increased the inpatient length of stay. In conclusion, the incidence of GIB in LVAD recipients has increased since the use of CF LVADs has increased, leading to greater inpatient lengths of stay and hospital charges. Older recipients of CF LVADs appear to be at a greater risk of GIB. PMID- 26651457 TI - Suboptimal cytoreduction: the confounding effects of tumor biology. PMID- 26651458 TI - Opinion Paper: A Cognitive-cultural Segregation and the Three Stages of Aging. AB - There is no doubt that the world is divided and unequal, mostly with respect to wealth. However, the true obstacle preventing the progress of humanity is not the divide between the rich and the poor. It is the divide between the cognitive and the physical. Apart from the social and ethical issues associated with this, there are also medical ones. The implications of this divide have direct relevance to aging, both in research and in the clinical sense. We cannot simply apply the same 'healthy aging' guidelines to everybody, but we need to establish if our approach is specifically suited to the individual. Our research endeavours need to have this division in focus. In this Opinion paper I describe three separate groups of humanity, which are divided, not by economic criteria, but by a worldview of intellectual creativity. Each arbitrary group has its own health priorities. If we overlook these priorities we may, at best, give the wrong advice to our patients, or at worst waste resources and exacerbate the rate of age-related degeneration in many individuals. As our society becomes more reliant on technology, what is now considered 'healthy' may not be so, for many millions of people. PMID- 26651459 TI - Promoting Cognitive Flexibility Under Attention-demanding Conditions in Aged Rats. AB - BACKGROUND: Age-related decline in cognitive flexibility and learning contributes to poorer quality of life. Thus, it is important to develop procedures that minimize age-related cognitive decline. Previous research has shown that, when young adult rats were trained in an attention-demanding task with a distracter, they learned a new task more quickly compared with rats trained in the same attention- demanding task without a distracter. OBJECTIVE: The goal of the present experiment was to test whether this beneficial effect of distracter exposure was observed in aged rats. METHOD: Male FBNF hybrid rats (n=20) trained in a two-lever visual sustained attention task that required discrimination of brief illumination of a centrally located panel light compared with trials when the light was not illuminated. At age 20 months, half of the animals received a flashing houselight distracter for the remaining testing sessions and the other animals did not. After 20 sessions, new task trials were interspersed within the sessions, when the rats received water access for pressing the lever under the left or right panel light after that light was illuminated. RESULTS: When 70% of the trials in a session were the new discrimination task, the distracter-exposed animals had higher accuracy in detecting the shortest signal in the remaining attention task trials compared with rats not exposed to the distracter. CONCLUSION: The present results suggest that aged animals' learning can benefit from overcoming distracter exposure, although not to the same extent as younger animals. PMID- 26651460 TI - Does location uncertainty in letter position coding emerge because of literacy training? AB - In the quest to unveil the nature of the orthographic code, a useful strategy is to examine the transposed-letter effect (e.g., JUGDE is more confusable with its base word, JUDGE, than the replacement-letter nonword JUPTE). A leading explanation of this phenomenon, which is line with models of visual attention, is that there is perceptual uncertainty at assigning letters ("objects") to positions. This mechanism would be at work not only with skilled readers but also with preliterate children. An alternative explanation is that the transposed letter effect emerges at an orthographic level of processing as a direct consequence of literacy training. To test these accounts, we conducted a same different matching experiment with preliterate 4-year-old children using same versus different trials (created by letter transposition or replacement). Results showed a significantly larger number of false positives (i.e., "same" responses) to transposed-letter strings than to 1/2 replacement-letter strings. Therefore, the present data favor the view that the visual processing of location information is inherently noisy and rule out an interpretation of confusability in letter position coding as emerging from literacy training. (PsycINFO Database Record PMID- 26651461 TI - Special issue on eHealth and mHealth: Challenges and future directions for assessment, treatment, and dissemination. AB - This special issue is intended to promote a discussion of eHealth and mHealth and its connection with health psychology. "eHealth" generally refers to the use of information technology, including the Internet, digital gaming, virtual reality, and robotics, in the promotion, prevention, treatment, and maintenance of health. "mHealth" refers to mobile and wireless applications, including text messaging, apps, wearable devices, remote sensing, and the use of social media such as Facebook and Twitter, in the delivery of health related services. This special issue includes 11 articles that begin to address the need for more rigorous methodology, valid assessment, innovative interventions, and increased access to evidence-based programs and interventions. PMID- 26651462 TI - Building health behavior models to guide the development of just-in-time adaptive interventions: A pragmatic framework. AB - Advances in wireless devices and mobile technology offer many opportunities for delivering just-in-time adaptive interventions (JITAIs)-suites of interventions that adapt over time to an individual's changing status and circumstances with the goal to address the individual's need for support, whenever this need arises. A major challenge confronting behavioral scientists aiming to develop a JITAI concerns the selection and integration of existing empirical, theoretical and practical evidence into a scientific model that can inform the construction of a JITAI and help identify scientific gaps. The purpose of this paper is to establish a pragmatic framework that can be used to organize existing evidence into a useful model for JITAI construction. This framework involves clarifying the conceptual purpose of a JITAI, namely, the provision of just-in-time support via adaptation, as well as describing the components of a JITAI and articulating a list of concrete questions to guide the establishment of a useful model for JITAI construction. The proposed framework includes an organizing scheme for translating the relatively static scientific models underlying many health behavior interventions into a more dynamic model that better incorporates the element of time. This framework will help to guide the next generation of empirical work to support the creation of effective JITAIs. PMID- 26651463 TI - Microrandomized trials: An experimental design for developing just-in-time adaptive interventions. AB - OBJECTIVE: This article presents an experimental design, the microrandomized trial, developed to support optimization of just-in-time adaptive interventions (JITAIs). JITAIs are mHealth technologies that aim to deliver the right intervention components at the right times and locations to optimally support individuals' health behaviors. Microrandomized trials offer a way to optimize such interventions by enabling modeling of causal effects and time-varying effect moderation for individual intervention components within a JITAI. METHOD: The article describes the microrandomized trial design, enumerates research questions that this experimental design can help answer, and provides an overview of the data analyses that can be used to assess the causal effects of studied intervention components and investigate time-varying moderation of those effects. RESULTS: Microrandomized trials enable causal modeling of proximal effects of the randomized intervention components and assessment of time-varying moderation of those effects. CONCLUSION: Microrandomized trials can help researchers understand whether their interventions are having intended effects, when and for whom they are effective, and what factors moderate the interventions' effects, enabling creation of more effective JITAIs. PMID- 26651464 TI - A pilot randomized, controlled trial of an active video game physical activity intervention. AB - OBJECTIVE: Active video games (AVGs) transform the sedentary screen time of video gaming into active screen time and have great potential to serve as a "gateway" tool to a more active lifestyle for the least active individuals. This pilot randomized trial was conducted to explore the potential of theory-guided active video games in increasing moderate-to-vigorous physical activity (MVPA) among young adults. METHOD: In this pilot 4-week intervention, participants were randomly assigned to 1 of the following groups: an AVG group with all the self determination theory (SDT)-based game features turned off, an AVG group with all the SDT-based game features turned on, a passive gameplay group with all the SDT based game features turned on, and a control group. Physical activity was measured using ActiGraph GT3X accelerometers. Other outcomes included attendance and perceived need satisfaction of autonomy, competence and relatedness. RESULTS: It was found that playing the self-determination theory supported AVG resulted in greater MVPA compared with the control group immediately postintervention. The AVG with the theory-supported features also resulted in greater attendance and psychological need satisfaction than the non-theory-supported one. CONCLUSION: An AVG designed with motivation theory informed features positively impacted attendance and MVPA immediately postintervention, suggesting that including AVG features guided with motivation theory may be a method of addressing common problems with adherence and increasing effectiveness of active gaming. PMID- 26651465 TI - Restoring depleted resources: Efficacy and mechanisms of change of an internet based unguided recovery training for better sleep and psychological detachment from work. AB - OBJECTIVE: This randomized controlled trial evaluated the efficacy of an Internet based intervention, which aimed to improve recovery from work-related strain in teachers with sleeping problems and work-related rumination. In addition, mechanisms of change were also investigated. METHODS: A sample of 128 teachers with elevated symptoms of insomnia (Insomnia Severity Index [ISI] >= 15) and work related rumination (Cognitive Irritation Scale >= 15) was assigned to either an Internet-based recovery training (intervention condition [IC]) or to a waitlist control condition (CC). The IC consisted of 6 Internet-based sessions that aimed to promote healthy restorative behavior. Self-report data were assessed at baseline and again after 8 weeks. Additionally, a sleep diary was used starting 1 week before baseline and ending 1 week after postassessment. The primary outcome was insomnia severity. Secondary outcomes included perseverative cognitions (i.e., work-related rumination and worrying), a range of recovery measures and depression. An extended 6-month follow-up was assessed in the IC only. A serial multiple mediator analysis was carried out to investigate mechanisms of change. RESULTS: IC participants displayed a significantly greater reduction in insomnia severity (d = 1.37, 95% confidence interval: 0.99-1.77) than did participants of the CC. The IC was also superior with regard to changes in all investigated secondary outcomes. Effects were maintained until a naturalistic 6-month follow up. Effects on insomnia severity were mediated by both a reduction in perseverative cognitions and sleep effort. Additionally, a greater increase in number of recovery activities per week was found to be associated with lower perseverative cognitions that in turn led to a greater reduction in insomnia severity. CONCLUSIONS: This study provides evidence for the efficacy of an unguided, Internet-based occupational recovery training and provided first evidence for a number of assumed mechanisms of change. PMID- 26651466 TI - Future-oriented tweets predict lower county-level HIV prevalence in the United States. AB - OBJECTIVE: Future orientation promotes health and well-being at the individual level. Computerized text analysis of a dataset encompassing billions of words used across the United States on Twitter tested whether community-level rates of future-oriented messages correlated with lower human immunodeficiency virus (HIV) rates and moderated the association between behavioral risk indicators and HIV. METHOD: Over 150 million tweets mapped to U.S. counties were analyzed using 2 methods of text analysis. First, county-level HIV rates (cases per 100,000) were regressed on aggregate usage of future-oriented language (e.g., will, gonna). A second data-driven method regressed HIV rates on individual words and phrases. RESULTS: Results showed that counties with higher rates of future tense on Twitter had fewer HIV cases, independent of strong structural predictors of HIV such as population density. Future-oriented messages also appeared to buffer health risk: Sexually transmitted infection rates and references to risky behavior on Twitter were associated with higher HIV prevalence in all counties except those with high rates of future orientation. Data-driven analyses likewise showed that words and phrases referencing the future (e.g., tomorrow, would be) correlated with lower HIV prevalence. CONCLUSION: Integrating big data approaches to text analysis and epidemiology with psychological theory may provide an inexpensive, real-time method of anticipating outbreaks of HIV and etiologically similar diseases. PMID- 26651467 TI - Behavioral response to a just-in-time adaptive intervention (JITAI) to reduce sedentary behavior in obese adults: Implications for JITAI optimization. AB - OBJECTIVE: Just-in-time adaptive interventions (JITAIs) use mobile computers, sensors, and software analytics to automatically detect behavior and deliver tailored treatment. However, little is known about how JITAIs influence patterns of behavior or how best to design JITAIs for maximum effect. METHOD: This study examined prompts and behavioral response to the B-MOBILE JITAI for reducing sedentary behavior (SB) in overweight/obese individuals. Thirty participants (83% women; 67% White, mean +/- SD body mass index = 36.2 kg/m2) tested 3 conditions presented in a randomized counterbalanced order involving smartphone-based prompts for walking breaks of (a) 3 min after 30 SB min, (b) 6 min after 60 SB min, and (c) 12 min after 120 SB min. RESULTS: Participants carried the smartphone an average of 6.90 days during each 7-day condition, for an average of 14.94 hr per day. The 3- and 6-min conditions resulted in the greatest number of prompts, walking breaks, the best adherence to prompts, the greatest amount of daily time spent in walking breaks, and fastest adherence to prompts (ps < .01). Small but statistically significant decreases in the number of daily walking breaks, adherence to prompts, and minutes per day spent in walking breaks were observed as a function of the number of days spent in a condition (ps < .05). CONCLUSIONS: The B-MOBILE JITAI was effective in prompting breaks in sedentary behavior when it was most clinically relevant. Frequent prompts for small change may be an optimal strategy for shaping sedentary behavior, although more research is needed to determine how best to promote long-term adherence. PMID- 26651468 TI - Temporal dynamics of physical activity and affect in depressed and nondepressed individuals. AB - OBJECTIVE: The association between physical activity and affect found in longitudinal observational studies is generally small to moderate. It is unknown how this association generalizes to individuals. The aim of the present study was to investigate interindividual differences in the bidirectional dynamic relationship between physical activity and affect, in depressed and nondepressed individuals, using time-series analysis. METHOD: A pair-matched sample of 10 depressed and 10 nondepressed participants (mean age = 36.6, SD = 8.9, 30% males) wore accelerometers and completed electronic questionnaires 3 times a day for 30 days. Physical activity was operationalized as the total energy expenditure (EE) per day segment (i.e., 6 hr). The multivariate time series (T = 90) of every individual were analyzed using vector autoregressive modeling (VAR), with the aim to assess direct as well as lagged (i.e., over 1 day) effects of EE on positive and negative affect, and vice versa. RESULTS: Large interindividual differences in the strength, direction and temporal aspects of the relationship between physical activity and positive and negative affect were observed. An exception was the direct (but not the lagged) effect of physical activity on positive affect, which was positive in nearly all individuals. CONCLUSION: This study showed that the association between physical activity and affect varied considerably across individuals. Thus, while at the group level the effect of physical activity on affect may be small, in some individuals the effect may be clinically relevant. PMID- 26651469 TI - Randomized controlled trial of a web-based indoor tanning intervention: Acceptability and preliminary outcomes. AB - OBJECTIVE: This article describes the acceptability and preliminary behavioral outcomes of a pilot randomized control trial of a web-based indoor tanning intervention for young adult women. The intervention targets indoor tanning users' perceptions of the benefits and value of tanning and addresses the role of body image-related constructs in indoor tanning. METHOD: Participants were 186 young adult women who reported indoor tanning at least once in the past 12 months. The study design was a 2-arm randomized controlled trial with pre- and postintervention assessments and random assignment to an intervention or control condition. Intervention acceptability was assessed by obtaining participants' evaluation of the intervention. Regression analyses were used to test for intervention condition differences in preliminary behavioral outcomes measured at 6 weeks postintervention. RESULTS: Participants provided favorable evaluations of the intervention on several dimensions and a highly positive overall rating. Intervention participants were more likely to report abstaining from indoor tanning and indicated a lower likelihood of using indoor tanning in the future compared with control participants on the postintervention assessment. No differences were found for sunburns. CONCLUSIONS: The results of this pilot randomized controlled trial provide evidence that the indoor tanning intervention is acceptable to participants and may encourage cessation of indoor tanning behavior. The findings provide preliminary support for an indoor tanning intervention that engages tanners to challenge their beliefs about the benefits of indoor tanning. The use of a web-based indoor tanning intervention is unique and provides strong potential for dissemination. PMID- 26651470 TI - Use of an online smoking cessation community promotes abstinence: Results of propensity score weighting. AB - OBJECTIVE: We estimated the causal effects of use of an online smoking cessation community on 30-day point prevalence abstinence at 3 months. METHODS: Participants (N = 492) were adult current smokers in the enhanced Internet arm of The iQUITT Study, a randomized trial of Internet and telephone treatment for smoking cessation. All participants accessed a Web-based smoking-cessation program that included a large, established online community. Automated tracking metrics of passive (e.g., reading forum posts, viewing member profiles) and active (e.g., writing forum posts, sending private messages) community use were extracted from the site at 3 months. Self-selected community use defines the groups of interest: "None," "Passive," and "Both" (passive + active). Inverse probability of treatment weighting corrected for baseline imbalances on demographic, smoking, psychosocial, and medical history variables. Propensity weights estimated via generalized boosted models were used to calculate Average Treatment Effects (ATE) and Average Treatment effects on the Treated (ATT). RESULTS: Patterns of community use were: None = 198 (40.2%), Passive = 110 (22.4%), and Both = 184 (37.4%). ATE-weighted abstinence rates were: None = 4.2% (95% CI = 1.5-6.9); Passive = 15.1% (95% CI = 8.4-21.9); Both = 20.4% (95% CI = 13.9-26.8). ATT-weighted abstinence rates indicated even greater benefits of community use. CONCLUSIONS: Community users were more likely to quit smoking at 3 months than nonusers. The estimated benefit from use of online community resources was even larger among subjects with high propensity to use them. No differences in abstinence emerged between passive and passive/active users. Results suggest that lurking in online communities confers specific abstinence benefits. Implications of these findings for online cessation communities are discussed. PMID- 26651471 TI - Internet-based physical activity intervention for women with a family history of breast cancer. AB - OBJECTIVE: Physical inactivity is a modifiable risk factor for breast cancer. Physical activity interventions that can be delivered through the Internet have the potential to increase participant reach. The efficacy of an Internet-based physical activity intervention was tested in a sample of women at an elevated risk for breast cancer. METHOD: A total of 55 women with at least 1 first-degree relative with breast cancer (but no personal history of breast cancer) were randomized to a 3-month theoretically grounded Internet-based physical activity intervention or an active control arm. Minutes of moderate to vigorous physical activity, psychosocial mediators of physical activity adoption and maintenance, as well as worry and perceived risk of developing breast cancer were assessed at baseline, 3-month, and 5-month follow up. RESULTS: Participants were on average 46.2 (SD = 11.4) years old with a body mass index of 27.3 (SD = 4.8) kg/m2. The intervention arm significantly increased minutes of moderate to vigorous physical activity compared to the active control arm at 3 months (213 vs. 129 min/week) and 5 months (208 vs. 119 min/week; both ps < .001). Regression models indicated that participants in the intervention had significantly higher self-efficacy for physical activity at 3 months (p < .01) and borderline significantly higher self efficacy at 5 months (p = .05). Baseline breast cancer worry and perceived risk were not associated with physical activity. CONCLUSION: Findings from this study suggest that an Internet-based physical activity intervention may substantially increase physical activity in women with a family history of breast cancer. PMID- 26651473 TI - Solving the Pericyclic-Pseudopericyclic Puzzle in the Ring-Closure Reactions of 1,2,4,6-Heptatetraene Derivatives. AB - The ongoing controversy whether cyclization reactions of conjugated allenes or ketenes follow a pericyclic or a pseudopericyclic mechanism has triggered dozens of investigations, which have led to new valuable synthetic routes. In this work, the mechanism of 10 representative cyclization reactions of hepta-1,2,4,6 tetraenes with different terminal groups is investigated utilizing the unified reaction valley approach that registers all electronic structure changes of the target molecule along the entire reaction pathway. A clear differentiation between a purely pericyclic and a purely pseudopericyclic mechanism is established. Additionally, it is found that, by using suitable functional groups, a pericyclic mechanism can be converted into a pseudopericyclic one, which is associated with a steady decrease of the reaction barrier and a continuous change from one mechanism to the other. The energetics of the reaction are confirmed by coupled cluster calculations of the CCSD(T) type. The mechanistic insight gained is used to design new pseudopericyclic reactions with low or no barrier, which will open new synthetic avenues. PMID- 26651472 TI - Pilot RCT of bidirectional text messaging for ART adherence among nonurban substance users with HIV. AB - OBJECTIVE: This pilot study tested the preliminary efficacy of a theory-based bidirectional text messaging intervention (TEXT) on antiretroviral (ART) adherence, missed care visits, and substance use among people with HIV. METHOD: Participants with recent substance use and ART nonadherence from 2 nonurban HIV clinics were randomized to TEXT or to usual care (UC). The TEXT intervention included daily queries of ART adherence, mood, and substance use. The system sent contingent intervention messages created by participants for reports of adherence/nonadherence, good mood/poor mood, and no substance use/use. Assessments were at preintervention, postintervention, and 3-month postintervention follow-up. Objective primary outcomes were adherence, measured by past 3-month pharmacy refill rate, and proportion of missed visits (PMV), measured by medical records. The rate of substance-using days from the timeline follow-back was a secondary outcome. RESULTS: Sixty-three patients participated, with 33 randomized to TEXT and 30 to UC. At preintervention, adherence was 64.0%, PMV was 26.9%, and proportion of days using substances was 53.0%. At postintervention, adherence in the TEXT condition improved from 66% to 85%, compared with 62% to 71% in UC participants (p = .04). PMV improved from 23% to 9% for TEXT participants and 31% to 28% in UC participants (p = .12). There were no significant differences between conditions in substance-using days at postintervention. At 3-month follow-up, differences were not significant. CONCLUSIONS: Personalized bidirectional text messaging improved adherence and shows promise to improve visit attendance, but did not reduce substance using days. This intervention merits further testing and may be cost-efficient given its automation. PMID- 26651474 TI - Understanding responses to gait instability from plantar pressure measurement and the relationship to balance and mobility in lower-limb amputees. AB - BACKGROUND: Measuring responses to a more unstable walking environment at the point-of-care may reveal clinically relevant strategies, particularly for rehabilitation. This study determined if temporal measures, center of pressure derived measures, and force impulse measures can quantify responses to surface instability and correlate with clinical balance and mobility measures. METHODS: Thirty-one unilateral amputees, 11 transfemoral and 20 transtibial, walked on level and soft ground while wearing pressure-sensing insoles. Foot-strike and foot-off center of pressure, center of pressure path, temporal, and force impulse variables were derived from F-Scan pressure-sensing insoles. FINDINGS: Significant differences (P<0.05) between level and soft ground were found for temporal and center of pressure path measures. Twenty regression models (R(2) <= 0.840), which related plantar-pressure-derived measures with clinical scores, consisted of nine variables. Stride time was in eight models; posterior deviations per stride in six models; mean CoP path velocity in five models; and anterior-posterior center of pressure path coefficient of variation, percent double-support time, and percent stance in four models. INTERPRETATION: Center of pressure-derived parameters, particularly temporal and center of pressure path measures, can differentiate between level and soft ground walking for transfemoral and transtibial amputees. Center of pressure-derived parameters correlated with clinical measures of mobility and balance, explaining up to 84.0% of the variability. The number of posterior deviations per stride, mean CoP path velocity stride time, anterior-posterior center of pressure path coefficient of variation, percent double-support time, and percent stance were frequently related to clinical balance and mobility measures. PMID- 26651475 TI - A patient-specific model of total knee arthroplasty to estimate patellar strain: A case study. AB - BACKGROUND: Inappropriate patellar cut during total knee arthroplasty can lead to patellar complications due to increased bone strain. In this study, we evaluated patellar bone strain of a patient who had a deeper patellar cut than the recommended. METHODS: A patient-specific model based on patient preoperative data was created. The model was decoupled into two levels: knee and patella. The knee model predicted kinematics and forces on the patella during squat movement. The patella model used these values to predict bone strain after total knee arthroplasty. Mechanical properties of the patellar bone were identified with micro-finite element modeling testing of cadaveric samples. The model was validated with a robotic knee simulator and postoperative X-rays. For this patient, we compared the deeper patellar cut depth to the recommended one, and evaluated patellar bone volume with octahedral shear strain above 1%. FINDINGS: Model predictions were consistent with experimental measurements of the robotic knee simulator and postoperative X-rays. Compared to the recommended cut, the deeper cut increased the critical strain bone volume, but by less than 3% of total patellar volume. INTERPRETATION: We thus conclude that the predicted increase in patellar strain should be within an acceptable range, since this patient had no complaints 8 months after surgery. This validated patient-specific model will later be used to address other questions on groups of patients, to eventually improve surgical planning and outcome of total knee arthroplasty. PMID- 26651476 TI - Effects of different heel angles in sleep mode on heel interface pressure in the elderly. AB - BACKGROUND: The heels are one of the most common sites of pressure ulcers, and the incidence rate in the elderly aged 70 years or older is high. Although there is literature on heel interface pressure, the heel interface pressure of the elderly in different postures has not yet been explored, which will be investigated in this study, as well as the effects of different foot positions. Their skin conditions will also be examined. METHODS: Twenty-five females and twenty-six males, 70 years old or older, are evaluated while lying down, with only their naked foot in its natural position on a mattress, as well as placed on a standard or pressure-relieving mattress in different positions. The moisture, sebum content, and elasticity of the skin of the heel are tested. FINDINGS: The heel of most of the participants is positioned at a 60 degrees -69 degrees or 90 degrees -99 degrees angle to the support surface. The heel interface pressure is the greatest when the foot is upright. The age, weight, and body mass index have no significant impacts. The moisture and sebum content are extremely low while elasticity is normal. INTERPRETATION: The relaxed position of the foot is in neutral external rotation and upright positions. A greater amount of pressure is experienced when the foot is upright. The pressure-relieving mattress is more effective for reducing heel pressure but may not apply to all cases. Finally, the skin of the heel is dry and lacks sebum, which implies greater risk of developing heel sores. PMID- 26651477 TI - NephroCheck data compared to serum creatinine in various clinical settings. AB - BACKGROUND: Acute kidney injury is frequently observed at the intensive care unit, after surgery, and after toxic drug administration. A rise in serum creatinine and a fall in urine output are consequences of much earlier injury to the most sensitive part of tubular cells located at the proximal tubule. The aim of the present study was to investigate the course of two cell-cycle arrest urinary biomarkers compared to serum creatinine in four clinical settings: ischemic reperfusion injury, cardiac failure, severe acute kidney injury, and chemotherapy-induced kidney injury. METHODS: A recently developed bedside test known as NephroCheck measures two urinary parameters: insulin-like growth factor binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinase-2 (TIMP-2). The test is based on a sandwich immunoassay technique. The final test output, labeled AKIRisk, is shown as a numeric result. RESULTS: This report revealed that [IGFBP7] . [TIMP-2] in urine rise rapidly prior to any change in serum creatinine. A unique feature of all four clinical settings is that a rapid decline predicts the recovery of kidney function. Besides, a subclinical kidney injury might be detected by the test. CONCLUSION: This bedside test detects biomarkers of renal injury. A rapid decline in AKIRisk was associated with the restoration of kidney function, whereas a prolonged high AKIRisk score was associated with end-stage renal disease. However, the dynamics seem to differ, depending on the cause and the extent of injury. Further studies will be needed to clarify the issue. PMID- 26651478 TI - Cost-effectiveness of blended vs. face-to-face cognitive behavioural therapy for severe anxiety disorders: study protocol of a randomized controlled trial. AB - BACKGROUND: Anxiety disorders are among the most prevalent psychiatric conditions, and are associated with poor quality of life and substantial economic burden. Cognitive behavioural therapy is an effective treatment to reduce anxiety symptoms, but is also costly and labour intensive. Cost-effectiveness could possibly be improved by delivering cognitive behavioural therapy in a blended format, where face-to-face sessions are partially replaced by online sessions. The aim of this trial is to determine the cost-effectiveness of blended cognitive behavioural therapy for adults with anxiety disorders, i.e. panic disorder, social phobia or generalized anxiety disorder, in specialized mental health care settings compared to face-to-face cognitive behavioural therapy. In this paper, we present the study protocol. It is hypothesized that blended cognitive behavioural therapy for anxiety disorders is clinically as effective as face-to face cognitive behavioural therapy, but that intervention costs may be reduced. We thus hypothesize that blended cognitive behavioural therapy is more cost effective than face-to-face cognitive behavioural therapy. METHODS/DESIGN: In a randomised controlled equivalence trial 156 patients will be included (n = 78 in blended cognitive behavioural therapy, n = 78 in face-to-face cognitive behavioural therapy) based on a power of 0.80, calculated by using a formula to estimate the power of a cost-effectiveness analysis: [Formula: see text]. Measurements will take place at baseline, midway treatment (7 weeks), immediately after treatment (15 weeks) and 12-month follow-up. At baseline a diagnostic interview will be administered. Primary clinical outcomes are changes in anxiety symptom severity as measured with the Beck Anxiety Inventory. An incremental cost effectiveness ratio will be calculated to obtain the costs per quality-adjusted life years (QALYs) measured by the EQ-5D (5-level version). Health-economic outcomes will be explored from a societal and health care perspective. DISCUSSION: This trial will be one of the first to provide information on the cost-effectiveness of blended cognitive behavioural therapy for anxiety disorders in routine specialized mental health care settings, both from a societal and a health care perspective. TRIAL REGISTRATION: Netherlands Trial Register NTR4912. Registered 13 November 2014. PMID- 26651479 TI - TMEM106B, a frontotemporal lobar dementia (FTLD) modifier, associates with FTD-3 linked CHMP2B, a complex of ESCRT-III. AB - BACKGROUND: Transmembrane protein 106B (TMEM106B) has been identified as a risk factor for frontotemporal lobar degeneration, which is the second most common form of progressive dementia in people under 65 years of age. Mutations in charged multivesicular body protein 2B (CHMP2B), which is involved in endosomal protein trafficking, have been found in chromosome 3-linked frontotemporal dementia. Despite the number of studies on both CHMP2B and TMEM106B in the endolysosomal pathway, little is known about the relationship between CHMP2B and TMEM106B in the endosomal/autophagy pathway. RESULTS: This study found that endogenous TMEM106B was partially sequestered in CHMP2B-positive structures, suggesting its possible involvement in endosomal sorting complexes required for transport (ESCRT)-associated pathways. The role of single nucleotide polymorphisms of TMEM106B (T185, S185, or S134N) in the ESCRT-associated pathways were characterized. The T185 and S185 variants were more localized to Rab5-/Rab7 positive endosomes compared with S134N, while all of the variants were more localized to Rab7-positive endosomes compared to Rab5-positive endosomes. T185 was more associated with CHMP2B compared to S185. Autophagic flux was slightly reduced in the T185-expressing cells compared to the control or S185-expressing cells. Moreover, T185 slightly enhanced the accumulation of EGFR, impairments in autophagic flux, and neurotoxicity that were caused by CHMP2B(Intron5) compared to S185-expressing cells. CONCLUSIONS: These findings suggest that the T185 variant functions as a risk factor in neurodegeneration with endolysosomal defects. This study provides a better understanding of pathogenic functions of TMEM106B, which is a risk factor for the progression of neurodegenerative diseases that are associated with endosomal defects in the aged brain. PMID- 26651480 TI - Genetic diversity of Plasmodium falciparum parasite by microsatellite markers after scale-up of insecticide-treated bed nets in western Kenya. AB - BACKGROUND: An initial study of genetic diversity of Plasmodium falciparum in Asembo, western Kenya showed that the parasite maintained overall genetic stability 5 years after insecticide-treated bed net (ITN) introduction in 1997. This study investigates further the genetic diversity of P. falciparum 10 years after initial ITN introduction in the same study area and compares this with two other neighbouring areas, where ITNs were introduced in 1998 (Gem) and 2004 (Karemo). METHODS: From a cross-sectional survey conducted in 2007, 235 smear positive blood samples collected from children <=15-year-old in the original study area and two comparison areas were genotyped employing eight neutral microsatellites. Differences in multiple infections, allele frequency, parasite genetic diversity and parasite population structure between the three areas were assessed. Further, molecular data reported previously (1996 and 2001) were compared to the 2007 results in the original study area Asembo. RESULTS: Overall proportion of multiple infections (MA) declined with time in the original study area Asembo (from 95.9 %-2001 to 87.7 %-2007). In the neighbouring areas, MA was lower in the site where ITNs were introduced in 1998 (Gem 83.7 %) compared to where they were introduced in 2004 (Karemo 96.7 %) in 2007. Overall mean allele count (MAC ~ 2.65) and overall unbiased heterozygosity (H e ~ 0.77) remained unchanged in 1996, 2001 and 2007 in Asembo and was the same level across the two neighbouring areas in 2007. Overall parasite population differentiation remained low over time and in the three areas at FST < 0.04. Both pairwise and multilocus linkage disequilibrium showed limited to no significant association between alleles in Asembo (1996, 2001 and 2007) and between three areas. CONCLUSIONS: This study showed the P. falciparum high genetic diversity and parasite population resilience on samples collected 10 years apart and in different areas in western Kenya. The results highlight the need for long-term molecular monitoring after implementation and use of combined and intensive prevention and intervention measures in the region. PMID- 26651481 TI - Interstitial lung disease in clinically amyopathic dermatomyositis with and without anti-MDA-5 antibody: to lump or split? AB - BACKGROUND: Interstitial lung disease (ILD) associated with clinically amyopathic dermatomyositis (CADM-ILD) is often refractory and rapidly progressive. Although the anti-melanoma differentiation-associated gene 5 (anti-MDA-5) antibody is associated with rapidly progressive ILD (RP-ILD), differences in clinical features and prognosis of anti-MDA-5 antibody-positive and -negative CADM-ILD remain unclear. METHODS: To clarify the differences in the clinical features and prognosis between anti-MDA-5 antibody-positive and -negative cases, we retrospectively reviewed the medical records of patients diagnosed with CADM-ILD with and without anti-MDA-5 antibody at Kurashiki Central Hospital from January 2005 to September 2014. RESULTS: Anti-MDA-5 antibody was found in 10 of 16 patients (63%). The levels of Krebs von den Lungen-6 (KL-6) and surfactant protein D (SP-D) at the first visit were significantly lower in positive patients than in negative patients, whereas the levels of aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (gamma-GTP), and the CD4(+)/CD8(+) ratio in the bronchoalveolar lavage (BAL) fluid were significantly higher in positive patients than negative patients. Subpleural ground-glass opacity (GGO) or irregular linear opacity was predominant in positive patients. Peribronchovascular consolidation was predominant in negative patients. Positive patients had significantly lower survival rates than negative patients, with all six fatal cases occurring in positive patients who died of refractory ILD within 92 days from the first visit despite intensive treatment. CONCLUSIONS: There are clear differences in the clinical features and prognosis of anti-MDA-5 antibody positive and -negative CADM-ILD. Low serum KL-6 and SP-D levels, high serum AST and gamma-GTP levels, high CD4(+)/CD8(+) ratio in BAL fluid, and predominance of subpleural GGO or irregular linear opacity in HRCT may help to discriminate anti MDA-5 antibody-positive CADM-ILD with poor prognosis. PMID- 26651482 TI - Exploring transcriptomic diversity in muscle revealed that cellular signaling pathways mainly differentiate five Western porcine breeds. AB - BACKGROUND: Among transcriptomic studies, those comparing species or populations can increase our understanding of the impact of the evolutionary forces on the differentiation of populations. A particular situation is the one of short evolution time with breeds of a domesticated species that underwent strong selective pressures. In this study, the gene expression diversity across five pig breeds has been explored in muscle. Samples came from: 24 Duroc, 33 Landrace, 41 Large White dam line, 10 Large White sire line and 39 Pietrain. From these animals, 147 muscle samples obtained at slaughter were analyzed using the porcine Agilent 44 K v1 microarray. RESULTS: A total of 12,358 genes were identified as expressed in muscle after normalization and 1,703 genes were declared differential for at least one breed (FDR < 0.001). The functional analysis highlighted that gene expression diversity is mainly linked to cellular signaling pathways such as the PI3K (phosphoinositide 3-kinase) pathway. The PI3K pathway is known to be involved in the control of development of the skeletal muscle mass by affecting extracellular matrix - receptor interactions, regulation of actin cytoskeleton pathways and some metabolic functions. This study also highlighted 228 spots (171 unique genes) that differentiate the breeds from each other. A common subgroup of 15 genes selected by three statistical methods was able to differentiate Duroc, Large White and Pietrain breeds. CONCLUSIONS: This study on transcriptomic differentiation across Western pig breeds highlighted a global picture: mainly signaling pathways were affected. This result is consistent with the selection objective of increasing muscle mass. These transcriptional changes may indicate selection pressure or simply breed differences which may be driven by human selection. Further work aiming at comparing genetic and transcriptomic diversities would further increase our understanding of the consequences of human impact on livestock species. PMID- 26651483 TI - Erratum to: Post-mortem brain analyses of the Lothian Birth Cohort 1936: extending lifetime cognitive and brain phenotyping to the level of the synapse. AB - The original version of this article [1] unfortunately contained several mistakes. The presentation of Table 2 and 3 was incorrect, in the HTML and PDF versions of this article. The corrected Tables 2 and 3 are given below. PMID- 26651484 TI - The Italian Diabetes and Exercise Study 2 (IDES-2): a long-term behavioral intervention for adoption and maintenance of a physically active lifestyle. AB - BACKGROUND: Physical activity (PA)/exercise have become an integral part of the management of type 2 diabetes mellitus (T2DM). However, current guidelines are difficult to put into action in this population due to a number of barriers, especially the lack of acceptable, feasible, and validated behavioral intervention strategies. The present manuscript reports the rationale, study design and methods, and design considerations of the Italian Diabetes and Exercise Study (IDES)-2, a randomized controlled trial testing the efficacy of a behavior change strategy in increasing total daily PA and reducing sedentary time (SED-time) in patients with T2DM. METHODS/DESIGN: Starting 7 January 2014, the IDES_2 began enrolling 300 patients with known T2DM of at least 1-year duration in three tertiary referral outpatient Diabetes Clinics in Rome. Additional requirements are age 40 to 80 years, body mass index 27 to 40 kg/m(2), sedentary lifestyle, and physically inactive for at least 6 months, ability to walk 1.6 km without assistance, and eligibility after cardiovascular evaluation. Patients are randomized by center and within each center, by age and type of diabetes treatment to either the intervention or the control group. Patients in the intervention (INT) group (n = 150) receive theoretical and practical exercise counseling consisting of aggregated behavior change techniques (one individual theoretical counseling session plus eight twice-a-week individual theoretical and practical exercise counseling sessions) once a year for 3 years. Patients in the control (CON) group (n = 150), receive standard care, including general physician recommendations for daily PA. The primary outcomes are total daily PA and SED time, as measured objectively by the use of an accelerometer. Secondary outcomes include physical fitness, modifiable cardiovascular risk factors, musculoskeletal disturbances, well-being/depression, and health-related quality of life. DISCUSSION: The behavioral intervention strategy tested in the IDES_2 is based on solid theoretical grounds and uses several behavioral change techniques, two factors which were found to improve effectiveness of behavioral intervention. In addition, physicians and exercise specialists have been specifically trained for counselling/prescribing and supervising PA/exercise, respectively, in subjects suffering from metabolic disorders. Finally, the large sample size, the long study duration, and the objective measurement of PA allow statistically significant and scientifically robust conclusions to be drawn on the feasibility and efficacy of this intervention in T2DM patients. TRIAL REGISTRATION: ClinicalTrials.gov; NCT01600937 ; 10 October 2012. PMID- 26651485 TI - Prevalence of gastrointestinal symptoms in patients with influenza, clinical significance, and pathophysiology of human influenza viruses in faecal samples: what do we know? AB - This review provides for the first time an assessment of the current understanding about the occurrence and the clinical significance of gastrointestinal (GI) symptoms in influenza patients, and their correlation with the presence of human influenza viruses in stools of patients with confirmed influenza virus infection. Studies exploring how human influenza viruses spread to the patient's GI tract after a primary respiratory infection have been summarized. We conducted a systematic search of published peer-reviewed literature up to June 2015 with regard to the above-mentioned aspects, focusing on human influenza viruses (A(H1N1), A(H1N1)pdm09, A(H3N2), and B). Forty-four studies were included in this systematic review and meta-analysis. The pooled prevalence of any digestive symptoms ranged from 30.9% (95% CI, 9.8 to 57.5; I(2) = 97.5%) for A(H1N1)pdm09 to 2.8% (95% CI, 0.6 to 6.5; I(2) = 75.4%) for A(H1N1). The pooled prevalence of influenza viruses in stool was 20.6% (95% CI, 8.9 to 35.5; I(2) = 96.8%), but their correlation with GI symptoms has rarely been explored. The presence of viral RNA in stools because of haematogenous dissemination to organs via infected lymphocytes is likely, but the potential to cause direct intestinal infection and faecal-oral transmission warrants further investigation. This review highlights the gaps in our knowledge, and the high degree of uncertainty about the prevalence and significance of GI symptoms in patients with influenza and their correlation with viral RNA positivity in stool because of the high level of heterogeneity among studies. PMID- 26651486 TI - Oral health-related quality of life before and after crown therapy in young patients with amelogenesis imperfecta. AB - BACKGROUND: Amelogenesis imperfecta (AI) is a rare, genetically determined defect in enamel mineralization associated with poor esthetics and dental sensitivity. Because the condition is associated with negative social outcomes, this study evaluated oral health-related quality of life (OHRQoL), dental fear, and dental beliefs before and after early prosthetic crown therapy for AI during adolescence. METHODS: The study included 69 patients with AI, aged 6-25 yr: 33 males and 36 females (mean age 14.5 +/- 4.3); healthy controls (n = 80), patients with cleft lip and palate (CLP; n = 30), and patients with molar incisor hypomineralization (MIH; n = 39). All matched in age and gender, and all but the CLP group insocioeconomic area. Patients completed three questionnaires measuring OHRQoL (OHIP-14), dental fear (CFSS-DS), and dental beliefs (DBS-R). Twenty-six patients with severe AI between ages 9 and 22 yr received crown therapy and completed the questionnaires twice: before and after therapy. RESULTS: OHIP-14 scores were significantly higher among patients with AI (7.0 +/- 6.7), MIH (6.8 +/- 7.6) and CLP (13.6 +/- 12.1) than healthy controls (1.4 +/- 2.4) (p < 0.001). After crown therapy, quality of life problems in the 26 patients with severe AI decreased significantly, from 7.8 +/- 6.1 to 3.0 +/- 4.8 (p < 0.001). Early prosthetic therapy did not increase dental fear or negative attitudes toward dental treatment. CONCLUSIONS: OHRQoL increased after early crown therapy in patients with severe AI. Therapy did not increase dental fear or negative attitudes toward dental treatment. PMID- 26651487 TI - The provision of NHS health checks in a community setting: an ethnographic account. AB - BACKGROUND: The UK National Health Service Health Checks programme aims to reduce avoidable cardiovascular deaths, disability and health inequalities in England. However, due to the reported lower uptake of screening in specific black and minority ethnic communities who are recognised as being more at risk of cardiovascular disease, there are concerns that NHS Health Checks may increase inequalities in health. This study aimed to examine the feasibility and acceptability of community outreach NHS Health Checks targeted at the Afro Caribbean community. METHODS: This paper reports findings from an ethnographic study including direct observation of four outreach events in four different community venues in inner-city Bristol, England and follow up semi-structured interviews with attendees (n = 16) and staff (n = 4). Interviews and field notes were transcribed, anonymized and analysed thematically using a process of constant comparison. RESULTS: Analysis revealed the value of community assets (community engagement workers, churches, and community centres) to publicise the event and engage community members. People were motivated to attend for preventative reasons, often prompted by familial experience of cardiovascular disease. Attendees valued outreach NHS Health Checks, reinforcing or prompting some to make healthy lifestyle changes. The NHS Health Check provided an opportunity for attendees to raise other health concerns with health staff and to discuss their test results with peers. For some participants, the communication of test results, risk and lifestyle information was confusing and unwelcome. The findings additionally highlight the need to ensure community venues are fit for purpose in terms of assuring confidentiality. CONCLUSIONS: Outreach events provide evidence of how local health partnerships (family practice staff and health trainers) and community assets, including informal networks, can enhance the delivery of outreach NHS Health Checks and in promoting the health of targeted communities. To deliver NHS Health Checks effectively, the location and timing of events needs to be carefully considered and staff need to be provided with the appropriate training to ensure patients are supported and enabled to make lifestyle changes. PMID- 26651488 TI - Improving primary palliative care in Scotland: lessons from a mixed methods study. AB - BACKGROUND: Since 2012, all GP practices across Scotland have been supported to take a systematic approach to end-of-life care, by helping them to identify more patients for palliative care through a Palliative Care Directed Enhanced Service (DES). We aimed to understand the impact of this initiative. METHODS: Routine quantitative data from the 2012/13, and 2013/14 DES were collected from regional health boards, analysed and discussed. Qualitative data were collected from a sample of 2012/13 DES returns and analysed using Thematic Analysis. RESULTS: Data were received from 512 practices in nine Scottish Health boards for the 2012-13 DES and 638 practices in 11 Health boards for 2013-14. A sample of 90 of the returns for 2012-13 was selected for qualitative analysis. In 2012-13, 72 % of patients who died of cancer were listed on the palliative care register (PCR) before death while 27 % of patients who died as a result of non-malignant conditions were listed on the PCR. In 2013-14, cancer identification remained the same but identification of people dying with other long-term conditions had improved to 32.5 %. We identified several key issues needed to improve palliative care in the community. The need for training to identify patients with palliative care needs (particularly non-cancer); communication skills training; improvements in sharing information across the NHS; under-resource of and lack of coordination with district nurses; improvements in information technology; and tools for working with enlarged palliative care registers. CONCLUSIONS: The DES helped more patients with long-term conditions (LTC) receive generalist palliative care. Approaching generalist palliative care as anticipatory care could facilitate communication between GPs and patients/families and remove some barriers to early identification of palliative care needs. Improvement of information technology and use of identification tools like the SPICTTM may improve professionals' communication with each other and help may make identification and management of patients easier. PMID- 26651489 TI - Antenatal care and women's decision making power as determinants of institutional delivery in rural area of Western Ethiopia. AB - BACKGROUND: Delivery by skilled birth attendance serves as an indicator of progress towards reducing maternal mortality. In Ethiopia, the proportions of births attended by skilled personnel were very low 15 % and Oromia region 14.7 %. The current study identified factors associated with utilization of institutional delivery among married women in rural area of Western Ethiopia. METHODS: A community based cross-sectional study was employed from January 2 to January 31, 2015 among mothers who gave birth in the last 2 years in rural area of East Wollega Zone. A multi-stage sampling procedure was used to select 798 study participants. A pre-tested structured questionnaire was used to collect data and female high school graduates data collectors were involved in the data collection process. Bivariate and multivariable logistic regression model was fit and statistical significance was determined through a 95 % confidence level. RESULTS: The study revealed that 39.7 % of the mothers delivered in health facilities. Age 15-24 years (AOR 4.20, 95 % CI 2.07-8.55), 25-34 years (AOR 2.21, 95 % CI 1.32 3.69), women's educational level (AOR 2.00, 95 % CI 1.19-3.34), women's decision making power (AOR 2.11, 95 % CI 1.54-2.89), utilization of antenatal care (ANC) during the index pregnancy (AOR 1.56, 95 % CI 1.08-2.23) and parity one (AOR 2.20, 95 % CI 1.10-4.38) showed significant positive association with utilization of institutional delivery. CONCLUSION AND RECOMMENDATION: In this study proportion of institutional delivery were low (39.7 %). Age, women's literacy status, women's decision making power, ANC practice and numbers of live birth were found important predictors of institutional delivery. The findings of current study highlight the importance of boosting women involvement in formal education and decision making power. Moreover since ANC is big pillar for the remaining maternal health services effort should be there to increase ANC service utilization. PMID- 26651490 TI - Necrotizing crescentic glomerulonephritis related to sarcoidosis: a case report. AB - INTRODUCTION: Renal injury due to sarcoidosis develops in less than a quarter of patients with this systemic disease. In most cases, granulomatous tissue alters the production of vitamin D, which leads to hypercalciuria, nephrocalcinosis, and nephrolithiasis. Granulomatous interstitial nephritis is another well-recognized pathological process associated with sarcoidosis. However, a glomerular pathology is very rarely noted, and only a few cases are reported to have cellular crescentic glomerulonephritis. CASE PRESENTATION: We describe the case of a 26 year-old African American woman with systemic sarcoidosis, with a unique constellation of renal lesions, including noncaseating epithelioid granulomatous necrotizing interstitial nephritis, cellular crescent formation, and necrotizing vasculitis. Immunosuppressive therapy was helpful for alleviating her nephrotic syndrome and maintaining the stability of her renal function over a 30-month period. CONCLUSION: Glomerular involvement of sarcoidosis needs to be considered in the differential diagnosis in cases of rapidly progressive glomerular nephritis. PMID- 26651491 TI - Athalassotoga saccharophila gen. nov., sp. nov., isolated from an acidic terrestrial hot spring, and proposal of Mesoaciditogales ord. nov. and Mesoaciditogaceae fam. nov. in the phylum Thermotogae. AB - A novel moderately thermophilic, weakly acidophilic, heterotrophic, anaerobic, short-rod bacterium having an outer sheath-like structure (toga) was isolated from a low-salt acidic terrestrial hot spring in Oku-Shiobara, Tochigi, Japan. The strain, designated NAS-01T, grew between 30 and 60 degrees C (optimum 55 degrees C), and at pH 4.5 and 7.5 (optimum pH 5.5 to 6.0) and could not grow in media with >= 1 % NaCl (optimum 0 % NaCl). It utilized Fe(III), thiosulfate or l cystine as electron acceptor for growth, and yeast extract, peptone or a variety of sugars as carbon and energy sources. The major cellular fatty acid was C16 : 0, and no lipoquinone was detected. Strain NAS-01T contained phospholipids and glycolipids, but not aminolipids. The DNA G+C content was 41.1 mol%. Phylogenetic analysis based on the 16S rRNA gene sequence revealed that the strain was included in the phylum Thermotogae, and was closely related to Mesoaciditoga lauensis. The 16S rRNA gene sequence similarity between them was 90 %, and they were deeply branched off the rest of the known Thermotogae species. On the basis of the phylogenetic and ecophysiological properties, strain NAS-01T represents a novel species of a new genus in the phylum Thermotogae, for which we propose the name Athalassotoga saccharophila gen. nov., sp. nov. The type strain of the type species is NAS-01T ( = JCM 19762T = DSM 28954T). In addition, we propose a new order and family, Mesoaciditogales ord. nov. and Mesoaciditogaceae fam. nov., respectively, to accommodate the novel genus and the closely related genus Mesoaciditoga. PMID- 26651492 TI - Laser-Induced Dynamics of Peroxodicopper(II) Complexes Vary with the Ligand Architecture. One-Photon Two-Electron O2 Ejection and Formation of Mixed-Valent Cu(I)Cu(II)-Superoxide Intermediates. AB - Photoexcitation of end-on trans-MU-1,2-peroxodicopper(II) complex [(tmpa)2Cu(II)2(O2)](2+) (1) (lambdamax = 525 and 600 nm) and side-on MU eta(2):eta(2)-peroxodicopper(II) complexes [(N5)Cu(II)2(O2)](2+) (2) and [(N3)Cu(II)2(O2)](2+) (3) at -80 degrees C in acetone led to one-photon two electron peroxide-to-dioxygen oxidation chemistry (O2(2-) + hnu -> O2 + 2e(-)). Interestingly, light excitation of 2 and 3 (having side-on MU-eta(2):eta(2) peroxo ligation) led to release of dioxygen, while photoexcitation of 1 (having an end-on trans-1,2-peroxo geometry) did not, even though spectroscopic studies revealed that both reactions proceeded through previously unknown mixed-valent superoxide species: [Cu(II)(O2(*-))Cu(I)](2+) (lambdamax = 685-740 nm). For 1, this intermediate underwent further fast intramolecular electron transfer to yield an "O2-caged" dicopper(I) adduct, Cu(I)2-O2, and a barrierless stepwise back electron transfer to regenerate 1 occurred. Femtosecond laser excitation of 2 and 3 under the same conditions still led to [Cu(II)(O2(*-))Cu(I)](2+) intermediates that, instead, underwent O2 release with a quantum yield of 0.14 +/ 0.1 for 3. Such remarkable differences in reaction pathways likely result from the well-known ligand-derived stability of 2 and 3 vs 1 indicated by ligand Cu(II/I) redox potentials; (N5)Cu(I) and (N3)Cu(I) complexes are far more stable than (tmpa)Cu(I) species. The fast Cu(I)2/O2 rebinding kinetics was also measured after photoexcitation of 2 and 3, with the results closely tracking those known for the dicopper proteins hemocyanin and tyrosinase, for which the synthetic dicopper(I) precursors [(N5)Cu(I)2](2+) and [(N3)Cu(I)2](2+) and their dioxygen adducts serve as models. The biological relevance of the present findings is discussed, including the potential impact on the solar water splitting process. PMID- 26651493 TI - Uncommon dihydropyrimidine dehydrogenase mutations and toxicity by fluoropyrimidines: a lethal case with a new variant. AB - DPD is the rate-limiting enzyme involved in the metabolism of 5-fluorouracil and its prodrugs, capecitabine and tegafur. Many cases of severe toxicities by fluoropyrimidines are reported in the literature, sometimes with lethal outcome, due to a poor or null metabolizer phenotype. The exon 14-skipping mutation IVS14+1G>A and the c.2846A>T are the most common deficient variants. However, many additional variants of the DPYD gene with unclear functional significance have been reported. We describe a patient with metastatic breast cancer who received capecitabine and trastuzumab at standard doses. Six days after beginning capecitabine, the patient developed fever, leucopenia and neutropenia, mucositis, hand-foot syndrome, multiple organ dysfunction and eventually died. Since the toxicity profile was compatible with capecitabine administration, complete exon sequencing of DPYD was carried out and the patient was found to be compound heterozygous for the rare mutation c.257C>T in exon 4, c.496A>G in exon 6, the new variant c.1850C>T in exon 14 and c.2194G>A in exon 18. Given the marginal role of c.496A>G and c.2194G>A in DPD deficiency, the cause of death was suggested to be dependent on the novel c.1850C>T in combination with c.257C>T. The complexity of DPD pharmacogenetics suggests the need to develop cost effective screening approaches to identify patients at risk of severe toxicities. PMID- 26651494 TI - Internal Conversion and Vibrational Energy Redistribution in Chlorophyll A. AB - We have computationally investigated the role of intramolecular vibrational modes in determining nonradiative relaxation pathways of photoexcited electronic states in isolated chlorophyll A (ChlA) molecules. To simulate the excited state relaxation from the initially excited Soret state to the lowest excited state Qy, the approach of nonadiabatic excited state molecular dynamics has been adopted. The intramolecular vibrational energy relaxation and redistribution that accompany the electronic internal conversion process is followed by analyzing the excited state trajectories in terms of the ground state equilibrium normal modes. The time dependence of the normal mode velocities is determined by projecting instantaneous Cartesian velocities onto the normal mode vectors. Our analysis of the time evolution of the average mode energies uncovers that only a small subset of the medium-to-high frequency normal modes actively participate in the electronic relaxation processes. These active modes are characterized by the highest overlap with the nonadiabatic coupling vectors (NACRs) during the electronic transitions. Further statistical analysis of the nonadiabatic transitions reveals that the electronic and vibrational energy relaxation occurs via two distinct pathways with significantly different time scales on which the hopping from Soret to Qx occurs thereby dictating the overall dynamics. Furthermore, the NACRs corresponding to each of the transitions have been consistently found to be predominantly similar to a set of normal modes that vary depending upon the transition and the identified categories. Each pathway exhibits a differential time scale of energy transfer and also a differential set of predominant active modes. Our present analysis can be considered as a general approach allowing identification of a reduced subset of specific vibrational coordinates associated with nonradiative relaxation pathways. Therefore, it represents an adequate prior strategy that can particularly facilitates mixed quantum-classical approaches. PMID- 26651495 TI - Randomized, double-blind, comparative study on efficacy and safety of itraconazole pulse therapy and terbinafine pulse therapy on nondermatophyte mold onychomycosis: A study with 90 patients. AB - BACKGROUND: Nondermatophyte mold (NDM) onychomycosis shows poor response to current topical, oral or device-related antifungal therapies. This study was aimed to determine the efficacy and safety of itraconazole and terbinafine pulse therapy on NDM onychomycosis. METHODS: Mycologically proven subjects were treated with itraconazole 400 mg daily or terbinafine 500 mg daily for 7 days/month; two pulses for fingernails and three pulses for toenails(SLCTR/2013/013). RESULTS: One-hundred seventy-eight patients underwent mycological studies and 148 had positive fungal isolates. NDM were the prevailing fungi, 68.2%, followed by candida species 21.6%, and dermatophytes made up only 10.1%. Out of NDM Aspergillus spp (75.1%) predominated followed by 8.9% Fusarium spp and 4.95% Penicillium spp. The clinical cure at completion of pulse therapy was statistically significant 9.2% versus 2.0% (p < 0.05) in itraconazole group. But no statistically significant difference was detected between the two regimens at the end of 12 months; 65.1% versus 54.64%. Recurrences observed in both groups (6.5% vs. 4.1%) were not statistically significant. With itraconazole pulse 68.22% Aspergillus spp, 50.0% Fusarium spp and 84.6% Penicillium spp showed clinical cure, while terbinafine pulse cured 55.0% Aspergillus spp and 50.0% Fusarium spp. CONCLUSIONS: NDM was the prevailing fungi in onychomycosis in Sri Lanka. Both itraconazole and terbinafine were partially effective on NDM onychomycosis showing a clinical cure of 54-65%. Future research should focus on searching more effective antifungal for NDM onychomycosis. PMID- 26651496 TI - Application of Consistency Criteria To Calculate BET Areas of Micro- And Mesoporous Metal-Organic Frameworks. AB - Metal-organic frameworks (MOFs) can exhibit exceptionally high surface areas, which are experimentally estimated by applying the BET theory to measured nitrogen isotherms. The Brunauer, Emmett, and Teller (BET)-estimated nitrogen monolayer loading is thus converted to a "BET area," but the meaning of MOF BET areas remains under debate. Recent emphasis has been placed on the usage of four so-called "BET consistency criteria." Using these criteria and simulated nitrogen isotherms for perfect crystals, we calculated BET areas for graphene and 25 MOFs having different pore-size distributions. BET areas were compared with their corresponding geometrically calculated, nitrogen-accessible surface areas (NASAs). Analysis of simulation snapshots elucidated the contributions of "pore filling" and "monolayer-formation" to the nitrogen adsorption loadings in different MOF pores, revealing the origin of inaccuracies in BET-calculated monolayer loadings, which largely explain discrepancies between BET areas and NASAs. We also find that even if all consistency criteria are satisfied, the BET calculation can significantly overestimate the true monolayer loading, especially in MOFs combining mesopores (d >= 20 A) and large micropores (d = 10-20 A), due to the overlap of pore-filling and monolayer-formation regimes of these two kinds of pores. While it is not always possible to satisfy all consistency criteria, it is critical to minimize the deviation from these criteria during BET range selection to consistently compare BET areas of different MOFs and for comparing simulated and experimental BET areas of a given MOF. To accurately assess the quality of a MOF sample, it is best to compare experimental BET areas with simulated BET areas rather than with calculated NASAs. PMID- 26651497 TI - It's Never Just HIV: Exposure to an HIV Prevention Media Campaign and Behavior Change Among Men Who Have Sex with Men Participating in the National HIV Behavioral Surveillance System in New York City. AB - PURPOSE: The aim of this study was to assess the exposure to and impact of the It's Never Just HIV mass media campaign aimed at HIV negative men who have sex with men (MSM) in New York City. METHODS: Questions about the campaign were included in the local questionnaire of the Centers for Disease Control and Prevention (CDC)-sponsored National HIV Behavioral Surveillance (NHBS) study of MSM in NYC conducted in 2011. Participants in this cross-sectional study were recruited using venue-based sampling. RESULTS: Among 447 NYC National HIV Behavioral Surveillance study participants who self-reported HIV negative or unknown status and answered questions about the NYC Department of Health and Mental Hygiene's It's Never Just HIV campaign, more than one-third (n = 173, 38.7%) reported having seen the campaign. Latinos (34.8%) and blacks (34.4%) were less likely to report seeing the campaign compared to whites (47.7%). Most of those who reported seeing the campaign saw it on the subway (80.1%). Only 9.4% of those who saw the campaign reported having changed their sexual or health behaviors in response to the campaign. CONCLUSIONS: These data suggest that thousands of HIV-uninfected MSM in NYC have been reached by the campaign and recalled its message. PMID- 26651498 TI - Increased red cell distribution width predicts occlusion of the infarct-related artery in STEMI. AB - OBJECTIVE: Infarct-related artery (IRA) patency yields a better outcome in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). Red cell distribution width (RDW) emerges as a marker of adverse cardiovascular events and mortality in STEMI. Therefore, we aimed to assess the relationship between IRA patency and RDW value on admission in patients with STEMI undergoing primary PCI. METHODS: A total of 564 patients with STEMI undergoing primary PCI were recruited in this study. According to thrombolysis in myocardial infarction (TIMI) flow grade in the IRA before PCI, the study population was divided into two groups as TIMI 0 or 1 group (occluded IRA, n = 398) and TIMI 2 or 3 group (patent IRA, n = 166). RESULTS: RDW was significantly higher in the occluded IRA group (15.1 +/- 1.7 versus 13.4 +/- 1.3, p < 0.001) as compared to the patent IRA group. White blood cell (WBC) count, platelet count, creatine kinase-myocardial band (CK-MB) and troponin-I levels were also significantly higher in the occluded IRA group (p < 0.05). Moreover, RDW showed positive correlations with troponin-I (r = 0.397, p < 0.001), CK-MB (r = 0.344, p < 0.001) and WBC (r = 0.219, p < 0.001). In multivariate regression analysis, RDW (OR: 0.483, 95% CI: 0.412-0.567, p < 0.001) and WBC count were significantly and independently associated with IRA patency. CONCLUSIONS: Our findings suggested that RDW value and WBC count on admission were independent predictors of IRA patency in patients with STEMI. As RDW is an easily available, simple and cheap biomarker, it can be used in daily practice as a novel predictor for IRA patency. PMID- 26651499 TI - Topical drug delivery systems: a patent review. AB - INTRODUCTION: Topical administration is the favored route for local delivery of therapeutic agents due to its convenience and affordability. The specific challenge of designing a therapeutic system is to achieve an optimal concentration of a certain drug at its site of action for an appropriate duration. AREAS COVERED: This review summarizes innovations from the past 3 years (2012-2015) in the field of topical drug delivery for the treatment of local infections of the vagina, nose, eye and skin. The review also throws some light on the anatomy and physiology of these organs and their various defensive barriers which affect the delivery of drugs administered topically. EXPERT OPINION: Topical administration has been gaining attention over the last few years. However, conventional topical drug delivery systems suffer from drawbacks such as poor retention and low bioavailability. The successful formulation of topical delivery products requires the careful manipulation of defensive barriers and selection of a soluble drug carrier. Extensive research is required to develop newer topical drug delivery systems aiming either to improve the efficacy or to reduce side effects compared to current patented systems. PMID- 26651500 TI - Fabrication and Performance of High Energy Li-Ion Battery Based on the Spherical Li[Li(0.2)Ni(0.16)Co(0.1)Mn(0.54)]O2 Cathode and Si Anode. AB - The cathode materials of Li-ion batteries for electric vehicles require not only a large gravimetric capacity but also a high volumetric capacity. A new Li-rich layered oxide cathode with superior capacity, Li[Li0.20Ni0.16Co0.10Mn0.54]O2 (denoted as LNCM), is synthesized from precursor, a coprecipitated spherical metal hydroxide. The preparation technology of precursor such as stirring speed, concentration of metal solution, and reaction time are regulated elaborately. The final product LNCM shows a well-ordered, hexagonal-layer structure, as confirmed by Rietveld refinement of X-ray diffraction pattern. The particle size of the final product has an average diameter of about 10 MUm, and the corresponding tap density is about 2.25 g cm(-3). Electrochemical measurements indicate that as prepared LNCM has great initial columbic efficiency, reversible capacity, and cycling stability, with specific discharge capacities of 278 and 201 mAh g(-1) at 0.03 and 0.5 C rates, respectively. Cycling at 0.1 C, LNCM delivers a discharge capacity of 226 mAh g(-1) with 95% retention capacity after 50 cycles. Si/LNCM cell is fabricated using Si submicroparticle as anode against LNCM. The cell can exhibit a specific energy of 590 Wh kg(-1) based on the total weight of cathode and anode materials. PMID- 26651501 TI - How the kinetochore switches off the spindle assembly checkpoint. PMID- 26651502 TI - "You don't have anorexia, you just want to look like a celebrity": perceived stigma in individuals with anorexia nervosa. AB - BACKGROUND: Minimal research has been conducted on how individuals with Anorexia nervosa (AN) undergoing treatment perceive public stigma. AIM: Explore how affected individuals with AN believe the general public perceives AN. METHOD: Using thematic analysis, 19 participants with AN were interviewed at the beginning of treatment. RESULTS: Three interrelated themes were ascertained: (1) AN is not an illness; (2) eating disorder behaviours are volitional and the public endorses a socio-cultural explanation for the disorder; 3) affected individuals delay disclosing their illness and experience shame engaging in intensive treatment for AN as a result of their perception of stigma. CONCLUSIONS: Individuals with AN viewed the public as trivializing AN by viewing behaviours as within their control and by attributing eating disorder behaviours solely to socio-cultural factors. Participants believed that the public minimizes the challenges associated with treatment. Findings suggest that clinical interventions targeting stigma are required to counteract perceptions held by service users regarding how others view their illness. "Mental health literacy" interventions are needed for health professionals working with high risk groups likely to avoid seeking help due to fears of stigmatization. PMID- 26651505 TI - Do karate fighters use situational probability information to improve decision making performance during on-mat tasks? AB - This study examined the contribution of situational probability information to the perceptual and cognitive processes underlying decision-making behaviour during in situ Karate performance. Experts and novices were required to make decisions about various attacks in different fight scenarios. The order in which the fight situations were presented was modified in order to provide advanced probability information and identify whether fighters were able to use the latter information to make better decisions. Specifically, one of the attacks was repeated every four actions. Results revealed that experts were more accurate and faster than their less skilled counterparts to block and counterattack the opponent. The experts picked up the occurrence of the attack pattern after the fifth repetition whereas novices did not. This enabled experts to improve decision time and decision accuracy. Findings suggest that such superiority could stem from the perceptual and cognitive skills possessed by the experts, thus giving them the opportunity to recognise a situation more easily. This was reinforced by gaze behaviour which demonstrated that experts used a more efficient search strategy involving fewer fixations of longer duration on a lesser number of areas relative to the novices. Moreover, experts generated more refined karate-specific knowledge structures compared with the novices. PMID- 26651503 TI - Development of a schistosomiasis vaccine. AB - Schistosomiasis is a neglected tropical disease (NTD) of public health importance. Despite decades of implementation of mass praziquantel therapy programs and other control measures, schistosomiasis has not been contained and continues to spread to new geographic areas. A schistosomiasis vaccine could play an important role as part of a multifaceted control approach. With regards to vaccine development, many biological bottlenecks still exist: the lack of reliable surrogates of protection in humans; immune interactions in co-infections with other diseases in endemic areas; the potential risk of IgE responses to antigens in endemic populations; and paucity of appropriate vaccine efficacy studies in nonhuman primate models. Research is also needed on the role of modern adjuvants targeting specific parts of the innate immune system to tailor a potent and protective immune response for lead schistosome vaccine candidates with the long-term aim to achieve curative worm reduction. This review summarizes the current status of schistosomiasis vaccine development. PMID- 26651506 TI - Characterization of spent nickel-metal hydride batteries and a preliminary economic evaluation of the recovery processes. AB - Valuable metal materials can be recovered from spent nickel-metal hydride (NiMH) batteries. However, little attention has been paid to the metal compositions of individual components of NiMH batteries, although this is important for the selection of the appropriate recycling process. In this study, NiMH batteries were manually disassembled to identify the components and to characterize the metals in each of these. A preliminary economic analysis was also conducted to evaluate the recovery of valuable metals from spent NiMH batteries using thermal melting versus simple mechanical separation. The results of this study show that metallic components account for more than 60% of battery weight. The contents of Ni, Fe, Co, and rare earth elements (REEs) (i.e., valuable metals of interest for recovery) in a single battery were 17.9%, 15.4%, 4.41%, and 17.3%, respectively. Most of the Fe was in the battery components of the steel cathode collector, cathode cap, and anode metal grid, while Ni (>90%) and Co (>90%) were mainly in the electrode active materials (anode and cathode metal powders). About 1.88 g of REEs (Ce, La, and Y) could be obtained from one spent NiMH battery. The estimated profits from recovering valuable metals from spent NiMH batteries by using thermal melting and mechanical processes are 2,329 and 2,531 USD/ton, respectively, when including a subsidy of 1,710 USD/ton. The findings of this study are very useful for further research related to technical and economic evaluations of the recovery of valuable metals from spent NiMH batteries. IMPLICATIONS: The spent nickel-metal hydride (NiMH) batteries were manually disassembled and their components were identified. The metals account for more than 60% of battery weight, when Ni, Fe, Co, and rare earth elements (REEs) were 17.9%, 15.4%, 4.41%, and 17.3%, respectively, in a single battery. The estimated profits of recovering valuable metals from NiMH batteries by using thermal melting and mechanical processing are 2,329 and 2,531 USD/ton, respectively, when including a subsidy of 1,710 USD/ton. These findings are very useful to develop or select the recovery methods of valuable metals from spent NiMH batteries. PMID- 26651507 TI - Distress Tolerance as a Correlate of Tobacco Dependence and Motivation: Incremental Relations over and above Anxiety and Depressive Symptoms. AB - Distress tolerance-the capacity to withstand distressing states-is implicated in the etiology of regular smoking. The present study extends past research by examining whether relations between perceived distress tolerance and smoking related factors: (1) differ across subdimensions of distress tolerance (Tolerance, Appraisal, Regulation, Absorption); (2) extend across measures of dependence, negative reinforcement smoking, and craving; and (3) are incremental to depressive and anxiety symptoms. Results showed that global distress tolerance was associated with measures of dependence, negative reinforcement, and craving even after controlling for affective symptomatology. Subdimensions of distress tolerance were not uniquely related to smoking outcomes in unadjusted or adjusted models. These findings suggest that: (a) distress tolerance is uniquely implicated in smoking over and above affective symptomatology; and (b) specific subdimensions of distress tolerance do not provide more information about smoking related characteristics than global dimensions; and PMID- 26651504 TI - Higher Estradiol and Lower Dehydroepiandrosterone-Sulfate Levels Are Associated with Pulmonary Arterial Hypertension in Men. AB - RATIONALE: Recent studies have focused on the role of female sex and estradiol (E2) in pulmonary arterial hypertension (PAH), but it is not known whether sex hormones are risk factors for PAH in men. OBJECTIVES: We performed a case-control study to determine whether hormone levels (E2, dehydroepiandrosterone-sulfate [DHEA-S], and testosterone) are associated with PAH in men. METHODS: Plasma sex hormone levels in men with idiopathic, heritable, or connective tissue disease associated PAH were compared with those from age- and body mass index-matched men without clinical cardiovascular disease. MEASUREMENTS AND MAIN RESULTS: There were 23 cases with PAH (70% had idiopathic PAH, 65% were functional class III/IV) and 67 control subjects. Higher E2 and E2/testosterone levels were associated with the risk of PAH (odds ratio per 1 ln[E2:testosterone], 6.0; 95% confidence interval, 2.2-16.4; P = 0.001), whereas higher levels of DHEA-S were associated with a reduced risk (odds ratio per 1 ln[DHEA-S], 0.1; 95% confidence interval, 0.0-0.3; P = 0.001). E2 and DHEA-S levels were strong predictors of case status (C statistic for both, 0.82) but testosterone was not (C statistic, 0.53). Higher levels of E2 were associated with shorter 6-minute-walk distances (P = 0.03), whereas higher levels of DHEA-S were associated with lower right atrial pressure (P = 0.02) and pulmonary vascular resistance (P = 0.01) in men with PAH. CONCLUSIONS: Higher levels of E2 and lower levels of DHEA-S were associated with PAH in men. Sex-based differences in sex hormone processing and signaling may contribute to unique phenotypes in pulmonary vascular disease. PMID- 26651508 TI - Influence of Protein Surface Coverage on Anomalously Strong Adsorption Sites. AB - Serum albumin is commonly used as a blocking agent to reduce nonspecific protein adsorption in bioassays and biodevices; however, the details of this process remain poorly understood. Using single molecule techniques, we investigated the dynamics of human serum albumin (HSA) on four model surfaces as a function of protein concentration. By constructing super-resolution maps, identifying anomalously strong adsorption sites, and quantifying surface heterogeneity, we found that the concentration required for site blocking varied dramatically with surface chemistry. When expressed in terms of protein surface coverage, however, a more consistent picture emerged, where a significant fraction of strong sites were passivated at a fractional coverage of 10(-4). On fused silica (FS), "non fouling" oligo (ethylene glycol) functionalized FS, and hydrophobically modified FS, a modest additional site blocking effect continued at higher coverage. However, on amine-functionalized surfaces, the surface heterogeneity exhibited a minimum at a coverage of ~10(-4). Using intermolecular Forster resonance energy transfer (FRET), we determined that new anomalous strong sites were created at higher coverage on amine surfaces and that adsorption to these sites was associated with protein-protein interactions, i.e., surface-induced aggregation. PMID- 26651509 TI - Converting One-Face alpha-Helix Mimetics into Amphiphilic alpha-Helix Mimetics as Potent Inhibitors of Protein-Protein Interactions. AB - Many biologically active alpha-helical peptides adopt amphiphilic helical structures that contain hydrophobic residues on one side and hydrophilic residues on the other side. Therefore, alpha-helix mimetics capable of mimicking such amphiphilic helical peptides should possess higher binding affinity and specificity to target proteins. Here we describe an efficient method for generating amphiphilic alpha-helix mimetics. One-face alpha-helix mimetics having hydrophobic side chains on one side was readily converted into amphiphilic alpha helix mimetics by introducing appropriate charged residues on the opposite side. We also demonstrate that such two-face amphiphilic alpha-helix mimetics indeed show remarkably improved binding affinity to a target protein, compared to one face hydrophobic alpha-helix mimetics. We believe that generating a large combinatorial library of these amphiphilic alpha-helix mimetics can be valuable for rapid discovery of highly potent and specific modulators of protein-protein interactions. PMID- 26651510 TI - Corrigendum. PMID- 26651511 TI - THE BACTERIA AMONG US. AB - A growing number of studies are linking microbes in our bodies with physiology and disease. Jeffrey Perkel speaks to researchers trying to understand this relationship and, possibly, even use it to improve human health. PMID- 26651512 TI - Heterogeneous catalysis for azide-alkyne bioconjugation in solution via spin column: Attachment of dyes and saccharides to peptides and DNA. AB - Copper-catalyzed azide-alkyne cycloaddition (CuAAC) "click" chemistry is widely used and has demonstrated particular utility for bio-orthogonal conjugation reactions. Here we describe a one-pot, heterogeneous bioconjugation and purification method for selectively activated CuAAC. A Cu(II) precursor, with either the neutral ligand 1,10-phenanthroline-5,6-dione or the anionic ligand 4,7 diphenyl-1,10-phenanthroline-disulfonic acid, is converted to the active Cu(I) species within an ion-exchange matrix using zinc amalgam as the reducing agent. The Cu(I) complexes are then layered on top of a size-exclusion matrix within a commercial microcentrifuge spin column; passing a mixture of an ethynyl-labeled biomolecule and an azide-bearing ligand through the column results in clean and efficient coupling. The methodology is demonstrated by glycosylating a DNA oligonucleotide as well as by labeling a membrane-penetrating peptide (octa arginine) with a coumarin dye. PMID- 26651514 TI - RisaAligner software for aligning fluorescence data between Agilent 2100 Bioanalyzer chips: Application to soil microbial community analysis. AB - Ribosomal Intergenic Spacer Analysis (RISA) is a high-resolution and highly reproducible fingerprinting technique for discriminating between microbial communities. The community profiles can be visualized using the Agilent 2100 Bioanalyzer. Comparison between fingerprints relies upon precise estimation of all amplified DNA fragment lengths; however, size standard computation can vary between gel runs. For complex samples such as soil microbial communities, discrimination by fragment size is not always sufficient. In such cases, the comparison of whole fluorescence data as a function of time (electrophoregrams) is more appropriate. When electrophoregrams [fluorescence = f (time)] are used, and more than one chip is involved, electrophoregram comparisons are challenging due to experimental variations between chips and the lack of correction by the Agilent software in such situations. Here we present RisaAligner software for analyzing and comparing electrophoregrams from Agilent chips using a nonlinear ladder-alignment algorithm. We demonstrate the robustness and substantial improvement of data analysis by analyzing soil microbial profiles obtained with Agilent DNA 1000 and High Sensitivity chips. PMID- 26651513 TI - Karyotyping human and mouse cells using probes from single-sorted chromosomes and open source software. AB - Multispectral karyotyping analyzes all chromosomes in a single cell by labeling them with chromosome-specific probes conjugated to unique combinations of fluorophores. Currently available multispectral karyotyping systems require the purchase of specialized equipment and reagents. However, conventional laser scanning confocal microscopes that are capable of separating multiple overlapping emission spectra through spectral imaging and linear unmixing can be utilized for classifying chromosomes painted with multicolor probes. Here, we generated multicolor chromosome paints from single-sorted human and mouse chromosomes and developed the Karyotype Identification via Spectral Separation (KISS) analysis package, a set of freely available open source ImageJ tools for spectral unmixing and karyotyping. Chromosome spreads painted with our multispectral probe sets can be imaged on widely available spectral laser scanning confocal microscopes and analyzed using our ImageJ tools. Together, our probes and software enable academic labs with access to a laser-scanning spectral microscope to perform multicolor karyotyping in a cost-effective manner. PMID- 26651515 TI - Immunoreactive insulin in diabetes mellitus patient sera detected by ultrasensitive ELISA with thio-NAD cycling. AB - To minimize patient suffering, the smallest possible volume of blood should be collected for diagnosis and disease monitoring. When estimating insulin secretion capacity and resistance to insulin in diabetes mellitus (DM), increasing insulin assay immunosensitivity would reduce the blood sample volume required for testing. Here we present an ultrasensitive ELISA coupled with thio-NAD cycling to measure immunoreactive insulin in blood serum. Only 5 MUL of serum was required for testing, with a limit of detection (LOD) for the assay of 10(-16) moles/assay. Additional recovery tests confirmed this method can detect insulin in sera. Comparisons between a commercially available immunoreactive insulin kit and our ultrasensitive ELISA using the same commercially available reference demonstrated good data correlation, providing further evidence of assay accuracy. Together, these results demonstrate our ultrasensitive ELISA could be a powerful tool in the diagnosis and treatment of not only DM but also many other diseases in the future. PMID- 26651516 TI - New insights on single-stranded versus double-stranded DNA library preparation for ancient DNA. AB - An innovative single-stranded DNA (ssDNA) library preparation method has sparked great interest among ancient DNA (aDNA) researchers, especially after reports of endogenous DNA content increases >20-fold in some samples. To investigate the behavior of this method, we generated ssDNA and conventional double-stranded DNA (dsDNA) libraries from 23 ancient and historic plant and animal specimens. We found ssDNA library preparation substantially increased endogenous content when dsDNA libraries contained <3% endogenous DNA, but this enrichment is less pronounced when dsDNA preparations successfully recover short endogenous DNA fragments (mean size < 70 bp). Our findings can help researchers determine when to utilize the time- and resource-intensive ssDNA library preparation method. PMID- 26651517 TI - C-H Oxidation/Michael Addition/Cyclization Cascade for Enantioselective Synthesis of Functionalized 2-Amino-4H-chromenes. AB - A streamlined method for the enantioselective synthesis of 2-amino-4H-chromenes from readily available 2-alkyl-substituted phenols and active methylene compounds bearing a cyano group with up to 97% ee is presented. This reaction is a cascade procedure including manganese dioxide mediated C-H oxidation for the generation of o-quinone methides and bifunctional squaramide-catalyzed Michael addition/cyclization. PMID- 26651518 TI - Strategy To Fabricate Naked-Eye Readout Ultrasensitive Plasmonic Nanosensor Based on Enzyme Mimetic Gold Nanoclusters. AB - It is broadly interesting but remains a big challenge to explore nanomaterials based methods to enable naked-eye observation and determination of ultratrace biomarkers and drugs. In this study, we developed a straightforward and extendable plasmonic nanosensor to enable visually quantitative determination of ultratrace target molecules through combining the use of enzyme-mimetic gold nanoclusters (AuNCs). Starting from sandwiched antibody-antigen (i.e., an analyte)-antibody structure, we conjugated AuNCs on the outer layer antibody to catalyze the decomposition of hydrogen peroxide used to reduce HAuCl4 into gold nanopartilces (AuNPs) for naked eye readout. This strategy is in theory applicable to all immunoreactions available and the protocol proposed to attach AuNCs onto an antibody is suitable to all proteins. The applicability of this type of nanosensor was validated by the determination of various ultratrace analytes such as protein avidin, breast cancer antigen, thyroid hormone, and even methamphetamine (MA), giving a naked-eye-readout limit of detection (LOD), down to 1.0 * 10(-20) M protein avidin, 7.52 * 10(-14) U/mL breast cancer antigen 15 3, 2.0 * 10(-15) mg/mL 3,5,3'-L-triiodothyronine and 2.3 * 10(-18) mg/mL MA. This strategy is thus considered an ultrasensitive way to fabricate plasmonic nanosensors, having wide and invaluable application potential in clinical, biological, and environmental studies, and in food quality control. PMID- 26651519 TI - Antibodies to watch in 2016. AB - The number of novel antibody therapeutics that received first marketing approvals in 2015 met expectations, with 6 (alirocumab (Praluent(r)), evolocumab (Repatha(r)), daratumumab (Darzalex(r)), dinutuximab (Unituxin(r)), idarucizumab (Praxbind(r)), mepolizumab (Nucala(r))) granted first approvals as of mid November*. Seven novel antibody therapeutics (begelomab, brodalumab, elotuzumab, ixekizumab, necitumumab, obiltoxaximab, reslizumab) are in regulatory review, and thus a similar number, if not more, are projected to gain first approvals in 2016. Commercial late-stage antibody therapeutics development exceeded expectations by increasing from 39 candidates in Phase 3 studies as of late 2014 to 53 as of late 2015. Of the 53 candidates, transitions to regulatory review by the end of 2016 are projected for 8 (atezolizumab, benralizumab, bimagrumab, durvalumab, inotuzumab ozogamicin, lebrikizumab, ocrelizumab, tremelimumab). Other "antibodies to watch" include 15 candidates (bavituximab, bococizumab, dupilumab, fasinumab, fulranumab, gevokizumab, guselkumab, ibalizumab, LY2951742, onartuzumab, REGN2222, roledumab, romosozumab, sirukumab, Xilonix) undergoing evaluation in Phase 3 studies that have estimated primary completion dates in 2016. As evidenced by the antibody therapeutics discussed in this perspective, the biopharmaceutical industry has a highly active late-stage clinical pipeline that may deliver numerous new products to the global market in the near future. *See Note added in proof for updates through December 31, 2015. PMID- 26651520 TI - A Multicenter Longitudinal Study of Hospital-Onset Bacteremia: Time for a New Quality Outcome Measure? - ERRATUM. PMID- 26651521 TI - Interactive and Mediational Etiologic Models of Eating Disorder Onset: Evidence from Prospective Studies. AB - It is vital to elucidate how risk factors work together to predict eating disorder onset because it should improve the yield of prevention efforts. Risk factors that have predicted eating disorder onset in multiple studies include low body mass index (BMI) for anorexia nervosa; thin-ideal internalization, perceived pressure to be thin, body dissatisfaction, dieting, and negative affect for bulimia nervosa; and body dissatisfaction and dieting for purging disorder. No such risk factors have been identified for binge eating disorder. Classification tree analyses have identified several amplifying interactions, mitigating interactions, and alternative pathway interactions between risk factors, such as evidence that elevated BMI amplifies the risk between appearance overvaluation and the future onset of recurrent binge eating. However, there have been no tests of mediational risk factor models in the prediction of eating disorder onset. Gaps in the literature are identified and procedures for providing rigorous tests of interactive and mediational etiologic models are outlined. PMID- 26651522 TI - Bone-tissue engineering: complex tunable structural and biological responses to injury, drug delivery, and cell-based therapies. AB - Bone loss and failure of proper bone healing continues to be a significant medical condition in need of solutions that can be implemented successfully both in human and veterinary medicine. This is particularly true when large segmental defects are present, the bone has failed to return to normal form or function, or the healing process is extremely prolonged. Given the inherent complexity of bone tissue - its unique structural, mechanical, and compositional properties, as well as its ability to support various cells - it is difficult to find ideal candidate materials that could be used as the foundation for tissue regeneration from technological platforms. Recently, important developments have been made in the implementation of complex structures built both at the macro- and the nano-level that have been shown to positively impact bone formation and to have the ability to deliver active biological molecules (drugs, growth factors, proteins, cells) for controlled tissue regeneration and the prevention of infection. These materials are diverse, ranging from polymers to ceramics and various composites. This review presents developments in this area with a focus on the role of scaffold structure and chemistry on the biologic processes that influence bone physiology and regeneration. PMID- 26651523 TI - New sesquiterpene and thiophene derivatives from Artemisia rupestris. AB - A new sesquiterpene, rupestrisin A (1), and three new thiophene derivatives, rupestrienes A-C (2-4), were isolated from Artemisia rupestris. Their structures were determined by analyses of MS and NMR spectroscopic data, and the absolute configuration of 1 was established by calculated ECD spectra using time-dependent density functional theory. In in vitro bioassays, compounds 1-4 showed inhibitory effects on LPS-stimulated NO production in BV-2 microglial cells with IC50 values of 24.3, 20.3, 8.5, and 5.3 MUM, respectively. PMID- 26651524 TI - Do Everything! For the Patient, Their Family, or Ourselves? A Surgical Resident's Experience. PMID- 26651525 TI - Prioritizing HIV comparative effectiveness trials based on value of information: generic versus brand-name ART in the US. AB - BACKGROUND: Value of Information (VOI) analysis examines whether to acquire information before making a decision. We introduced VOI to the HIV audience, using the example of generic antiretroviral therapy (ART) in the US. METHODS AND FINDINGS: We used a mathematical model and probabilistic sensitivity analysis (PSA) to generate probability distributions of survival (in quality-adjusted life years, QALYs) and cost for three potential first-line ART regimens: three-pill generic, two-pill generic, and single-pill branded. These served as input for a comparison of two hypothetical two-arm trials: three-pill generic versus single pill branded; and two-pill generic versus single-pill branded. We modeled pre trial uncertainty by defining probability distributions around key inputs, including 24-week HIV-RNA suppression and subsequent ART failure. We assumed that, without a trial, patients received the single-pill branded strategy. Post trial, we assumed that patients received the most cost-effective strategy. For both trials, we quantified the probability of changing to a generic-based regimen upon trial completion and the expected VOI in terms of improved health outcomes and costs. Assuming a willingness to pay (WTP) threshold of $100 000/QALY, the three-pill trial led to more treatment changes (84%) than the two-pill trial (78%). Estimated VOI was $48 000 (three-pill trial) and $35 700 (two-pill trial) per future patient initiating ART. CONCLUSIONS: A three-pill trial of generic ART is more likely to lead to post-trial treatment changes and to provide more value than a two-pill trial if policy decisions are based on cost-effectiveness. Value of Information analysis can identify trials likely to confer the greatest impact and value for HIV care. PMID- 26651526 TI - Reliability of a field-based drop vertical jump screening test for ACL injury risk assessment. AB - OBJECTIVES: There is an epidemic of anterior cruciate ligament (ACL) injuries in youth athletes. Poor neuromuscular control is an easily modifiable risk factor for ACL injury, and can be screened for by observing dynamic knee valgus on landing in a drop vertical jump test. This study aims to validate a simple, clinically useful population-based screening test to identify at-risk athletes prior to participation in organized sports. We hypothesized that both physicians and allied health professionals would be accurate in subjectively assessing injury risk in real-time field and office conditions without motion analysis data and would be in agreement with each other. METHODS: We evaluated the inter-rater reliability of risk assessment by various observer groups, including physicians and allied health professionals, commonly involved in the care of youth athletes. Fifteen athletes age 11-17 were filmed performing a drop vertical jump test. These videos were viewed by 242 observers including orthopaedic surgeons, orthopaedic residents/fellows, coaches, athletic trainers (ATCs), and physical therapists (PTs), with the observer asked to subjectively estimate the risk level of each jumper. Objective injury risk was calculated using normalized knee separation distance (measured using Dartfish, Alpharetta, GA), based on previously published studies. Risk assessments by observers were compared to each other to determine inter-rater reliability, and to the objectively calculated risk level to determine sensitivity and specificity. Seventy one observers repeated the test at a minimum of 6 weeks later to determine intra-rater reliability. RESULTS: Between groups, the inter-rater reliability was high, kappa = 0.92 (95% CI 0.829-0.969, p < 0.05), indicating that no single group gave better (or worse) assessments, including comparisons between physicians and allied health professionals. With a screening cutoff isolated to subjects identified by observers as "high risk", the sensitivity was 63.06% and specificity 82.81%. Reducing the screening cutoff to also include jumpers identified as "medium risk" increased sensitivity to 95.04% and decreased the specificity to 46.07%. Intra-rater reliability was moderate, kappa = 0.55 (95% CI 0.49-0.61, p < 0.05), indicating that individual observers made reproducible risk assessments. CONCLUSIONS: This study supports the use of a simple, field-based observational drop vertical jump screening test to identify athletes at risk for ACL injury. Our study shows good inter- and intra-rater reliability and high sensitivity and suggests that screening can be performed without significant training by physicians as well as allied health professionals, including: coaches, athletic trainers and physical therapists. Identification of these high risk athletes may play a role in enrollment in appropriate preventative neuromuscular training programs, which have been shown to decrease the incidence of ACL injuries in this population. PMID- 26651527 TI - Inhibitory Effects of 4'-Demethylnobiletin, a Metabolite of Nobiletin, on 12-O Tetradecanoylphorbol-13-acetate (TPA)-Induced Inflammation in Mouse Ears. AB - Nobiletin (NOB) is major citrus flavonoid with many health-promoting benefits. We reported previously that 4'-demethylnobiletin (4DN), a major metabolite of NOB, significantly inhibited lipopolysaccharide (LPS)-stimulated inflammation in RAW 264.7 macrophages. In this study, we further studied the anti-inflammatory effects of 4DN in TPA-induced skin inflammation in mice. We demonstrated that topical application of 4DN decreased TPA-induced ear edema by >88 +/- 4.77% in mice. This inhibitory effect was associated with inhibition on TPA-induced up regulation of pro-inflammatory cytokines IL-1beta, IL-6, and TNF-alpha. Immunoblotting results showed that 4DN resulted in profound effects on multiple proteins related with inflammation and carcinogenesis. 4DN significantly decreased the expression levels of iNOS, COX-2, and MMP-9, suppressed phosphorylation of PI3K/Akt and ERK, and increased the levels of HO-1 and NQO1 in TPA-treated mice. Overall, the results demonstrated that 4DN had strong anti inflammatory effects in vivo, which provided a scientific basis for using NOB to inhibit inflammation-driven diseases. PMID- 26651528 TI - Phosphate Hydrolysis by the Fe2-Ca3-Dependent Alkaline Phosphatase PhoX: Mechanistic Insights from DFT calculations. AB - PhoX is a pentanuclear metalloenzyme that employs two ferric ions and three calcium ions to catalyze the hydrolysis of phosphomonoesters. On the basis of the X-ray structure of PhoX ( Science 2014 , 345 , 1170 - 1173 ), a model of the active site is designed, and quantum chemical calculations are used to investigate the reaction mechanism of this enzyme. The calculations support the experimental suggestion, in which the two high spin ferric ions interact in an antiferromagnetic fashion. The two step mechanism proposed by experimentalists has been investigated. The nucleophilic attack of a trinuclear bridging oxo group on the phosphorus center was calculated to be the first step, which is concomitant with the departure of the phenolate, which is stabilized by a calcium ion. The second step is a reverse attack by a water molecule activated by a calcium-bound hydroxide, leading to the regeneration of the bridging oxo group. The second step was calculated to have a barrier of 27.6 kcal/mol. The high barrier suggests that the alternative mechanism involving phosphate release directly from the active site seems to be more likely. All five metal ions are involved in the catalysis by stabilizing the pentacoordinated trigonal bipyramidal transition states. PMID- 26651529 TI - Plasmon Field Effect Transistor for Plasmon to Electric Conversion and Amplification. AB - Direct coupling of electronic excitations of optical energy via plasmon resonances opens the door to improving gain and selectivity in various optoelectronic applications. We report a new device structure and working mechanisms for plasmon resonance energy detection and electric conversion based on a thin film transistor device with a metal nanostructure incorporated in it. This plasmon field effect transistor collects the plasmonically induced hot electrons from the physically isolated metal nanostructures. These hot electrons contribute to the amplification of the drain current. The internal electric field and quantum tunneling effect at the metal-semiconductor junction enable highly efficient hot electron collection and amplification. Combined with the versatility of plasmonic nanostructures in wavelength tunability, this device architecture offers an ultrawide spectral range that can be used in various applications. PMID- 26651530 TI - Association between resiliency and posttraumatic growth in firefighters: the role of stress appraisal. AB - The purpose of this study was to establish the relation between resiliency and the level of positive changes, comprising posttraumatic growth in a group of firefighters experiencing job-related traumatic events and the mediating role of stress appraisal in this relation. The study was performed on a group of 100 firefighters from firefighting and rescue brigades, out of which 75 admitted to experiencing a traumatic event. Firefighters covered by the study were on average 31.51 years old (SD = 6.34). A Polish version of Posttraumatic Growth Inventory, the Resiliency Assessment Scale and Stress Appraisal Questionnaire were used in the study. The results have shown that 22.7% of firefighters displayed low, 58.6% average and 18.7% high intensity of positive changes resulting from a traumatic event. Resiliency poorly correlates with posttraumatic growth expressed in changes in self-perception, and strongly correlates with stress appraisal, negatively correlates with threat and harm/loss and positively correlates with challenge. Appraisal of stress as a threat and challenge appeared to be mediators of the relationship between resiliency and posttraumatic growth. PMID- 26651531 TI - Distribution of Silica-Coated Silver/Gold Nanostars in Soft- and Hardwood Applying SERS-Based Imaging. AB - Nanoparticles (NPs) in aqueous suspension have just begun to be exploited for the preservative treatment of wood. However, at present, there is very little information available on the distribution of NPs in wood after impregnation, due to associated analytical challenges. In this study, we present the detection of model NPs in softwood and hardwood by surface-enhanced Raman spectroscopy (SERS). SERS is a highly sensitive analytical method requiring no fluorescent labeling. The NP distribution after impregnation is evaluated with one representative species of the two wood types. To show the feasibility of the method, we prepared SERS-active Au/Ag nanostars coated with silica to act as a model NP system. We show herein that NPs can be imaged in very low quantities in both wood types without any matrix interactions. The presence of the NPs in the wood was confirmed by scanning electron microscopy (SEM) imaging and energy dispersive X ray analysis (EDX). The fast detection of NPs in a complex matrix, without complicated sample preparation, marks a huge step forward in the development and application of nanotechnology for wood preservation and the quest to optimize the properties of one of the world's most important raw materials. PMID- 26651532 TI - LEADS-PEP: A Benchmark Data Set for Assessment of Peptide Docking Performance. AB - With increasing interest in peptide-based therapeutics also the application of computational approaches such as peptide docking has gained more and more attention. In order to assess the suitability of docking programs for peptide placement and to support the development of peptide-specific docking tools, an independently constructed benchmark data set is urgently needed. Here we present the LEADS-PEP benchmark data set for assessing peptide docking performance. Using a rational and unbiased workflow, 53 protein-peptide complexes with peptide lengths ranging from 3 to 12 residues were selected. The data set is publicly accessible at www.leads-x.org . In a second step we evaluated several small molecule docking programs for their potential to reproduce peptide conformations as present in LEADS-PEP. While most tested programs were capable to generate native-like binding modes of small peptides, only Surflex-Dock and AutoDock Vina performed reasonably well for peptides consisting of more than five residues. Rescoring of docking poses with scoring functions ChemPLP, ChemScore, and ASP further increased the number of top-ranked near-native conformations. Our results suggest that small molecule docking programs are a good and fast alternative to specialized peptide docking programs. PMID- 26651533 TI - Intranasal Administration of Novel Chitosan Nanoparticle/DNA Complexes Induces Antibody Response to Hepatitis B Surface Antigen in Mice. AB - The generation of strong pathogen-specific immune responses at mucosal surfaces where hepatitis B virus (HBV) transmission can occur is still a major challenge. Therefore, new vaccines are urgently needed in order to overcome the limitations of existing parenteral ones. Recent studies show that this may be achieved by intranasal immunization. Chitosan has gained attention as a nonviral gene delivery system; however, its use in vivo is limited due to low transfection efficiency mostly related to strong interaction between the negatively charged DNA and the positively charged chitosan. We hypothesize that the adsorption of negatively charged human serum albumin (HSA) onto the surface of the chitosan particles would facilitate the intracellular release of DNA, enhancing transfection activity. Here, we demonstrate that a robust systemic immune response was induced after vaccination using HSA-loaded chitosan nanoparticle/DNA (HSA-CH NP/DNA) complexes. Furthermore, intranasal immunization with HSA-CH NP/DNA complexes induced HBV specific IgA in nasal and vaginal secretions; no systemic or mucosal responses were detected after immunization with DNA alone. Overall, our results show that chitosan-based DNA complexes elicited both humoral and mucosal immune response, making them an interesting and valuable gene delivery system for nasal vaccination against HBV. PMID- 26651534 TI - On an Easy Way To Prepare Metal-Nitrogen Doped Carbon with Exclusive Presence of MeN4-type Sites Active for the ORR. AB - Today, most metal and nitrogen doped carbon catalysts for ORR reveal a heterogeneous composition. This can be reasoned by a nonoptimized precursor composition and various steps in the preparation process to get the required active material. The significant presence of inorganic metal species interferes with the assignment of descriptors related to the ORR activity and stability. In this work we present a simple and feasible way to reduce the contribution of inorganic metal species in some cases even down to zero. Such catalysts reveal the desired homogeneous composition of MeN4 (Me = metal) sites in the carbon that is accompanied by a significant enhancement in ORR activity. Among the work of other international groups, our iron-based catalyst comprises the highest density of FeN4 sites ever reported without interference of inorganic metal sites. PMID- 26651535 TI - Decacyclene Trianhydride at Functional Interfaces: An Ideal Electron Acceptor Material for Organic Electronics. AB - We report the interface energetics of decacyclene trianhydride (DTA) monolayers on top of two distinct model surfaces, namely, Au(111) and Ag(111). On the latter, combined valence band photoemission and X-ray absorption measurements that access the occupied and unoccupied molecular orbitals, respectively, reveal that electron transfer from substrate to surface sets in. Density functional theory calculations confirm our experimental findings and provide an understanding not only of the photoemission and X-ray absorption spectral features of this promising organic semiconductor but also of the fingerprints associated with the interface charge transfer. PMID- 26651536 TI - Fe-Catalyzed Olefin Hydroamination with Diazo Compounds for Hydrazone Synthesis. AB - A novel Fe-catalyzed olefin hydroamination with diazo compounds for accessing hydrazones has been developed. Diazo compounds are used as radical acceptors and can be trapped by the in situ generated alkyl radical toward C-N bond formation. The reaction conditions are mild, and the substrate scope is broad. Additionally, this hydroamination protocol is applicable for intramolecular reactions to construct diverse heterocycles. PMID- 26651537 TI - Rotenoids, Flavonoids, and Chalcones from the Root Bark of Millettia usaramensis. AB - Five new compounds, 4-O-geranylisoliquiritigenin (1), 12-dihydrousararotenoid B (2), 12-dihydrousararotenoid C (3), 4'-O-geranyl-7-hydroxyflavanone (4), and 4'-O geranyl-7-hydroxydihydroflavanol (5), along with 12 known natural products (6-17) were isolated from the CH2Cl2/MeOH (1:1) extract of the root bark of Millettia usaramensis ssp. usaramensis by chromatographic separation. The purified metabolites were identified by NMR spectroscopic and mass spectrometric analyses, whereas their absolute configurations were established on the basis of chiroptical data and in some cases also by X-ray crystallography. The crude extract was moderately active (IC50 = 11.63 MUg/mL) against the ER-negative MDB MB-231 human breast cancer cell line, and accordingly compounds 6, 8, 9, 10, 12, and 16 also showed moderate to low cytotoxic activities (IC50 25.7-207.2 MUM). The new natural product 1 exhibited antiplasmodial activity with IC50 values of 3.7 and 5.3 MUM against the chloroquine-sensitive 3D7 and the chloroquine resistant Dd2 Plasmodium falciparum strains, respectively, and was also cytotoxic to the HEK293 cell line. PMID- 26651538 TI - Prevalence, risk surfaces and inter-municipality variations in caries experience in Danish children and adolescents in 2012. AB - OBJECTIVE: The aim of this study was to describe the caries experience, prevalence and distribution related to tooth type and surfaces in the primary and permanent dentition in children and adolescents in Denmark in 2012. In addition, to examine if explanatory factors influence the inter-municipality variation in caries experience. MATERIALS AND METHODS: Data was collected in the public Child Dental Health Service. In total, 5636 caries registrations on 3-, 9-, 15- and 18 year-olds were collected in 35 of the 98 Danish municipalities. Caries experience was expressed by mean def-s/DMF-S and caries prevalence by def-s = 0/DMF-S = 0. Inter-municipality variations were illustrated. Multivariate regression analyses were applied to assess the influence of fluoride concentration in drinking water, proportion of immigrants and personal income on the inter-municipality variation in mean def-s/DMF-S. RESULTS: Only 4.6% of 3-year-olds had def-s (mean = 0.25), compared to 44.9% of 9-year-olds (mean = 3.07), primarily located occlusally and interproximally on the primary molars. Mean DMF-S for the 9-, 15- and 18-year olds were 0.27, 1.97 and 4.40, respectively. Caries were primarily located occlusally and in pits on the permanent molars, which also showed high frequencies of sealings. Mean def-s/DMF-S showed substantial inter-municipality variations, while the caries location in both dentitions was rather stable. The three background factors explained less than 25% of the variation in mean def s/DMF. CONCLUSIONS: The caries distribution within the primary and permanent dentition among 3-, 9-, 15- and 18-year-olds followed definite patterns concerning location on teeth and surfaces. Background factors only explained a minor part of the variation. PMID- 26651539 TI - Comparative Study on the Differentiation of Mesenchymal Stem Cells Between Fetal and Postnatal Rat Spinal Cord Niche. AB - In a previous study, we established a prenatal surgical approach and transplanted mesenchymal stem cells (MSCs) into the fetal rat spinal column to treat neural tube defects (NTDs). We found that the transplanted MSCs survived and differentiated into neural lineage cells. Various cytokines and extracellular signaling systems in the spinal cord niche play an important role in cell differentiation. In this study, we observed the differentiation of transplanted MSCs in different spinal cord niches and further observed the expression of neurotrophic factors and growth factors in the spinal cord at different developmental stages to explore the mechanism of MSC differentiation in different spinal cord niches. The results showed that transplanted MSCs expressed markers of neural precursor cells (nestin), neurogliocytes (GFAP), and neurons (beta tubulin). The percentages of GFP(+)/nestin(+) double-positive cells in transplanted MSCs in E16, P1, and P21 rats were 18.31%, 12.18%, and 5.06%, respectively. The percentages of GFP(+)/GFAP(+) double-positive cells in E16, P1, and P21 rats were 32.01%, 15.35%, and 12.56%, respectively. The percentages of GFP(+)/beta-tubulin(+) double-positive cells in E16, P1, and P21 were 11.76%, 7.62%, and 4.88%, respectively. The differentiation rates of MSCs in embryonic spinal cords were significantly higher than in postnatal spinal cords (p < 0.05). We found that the transplanted MSCs expressed synapsin-1 at different developmental stages. After MSC transplantation, we observed that neurotrophic factor-3 (NT-3), fibroblast growth factor-2 (FGF-2), FGF-8, transforming growth factor-alpha (TGF-alpha), vascular endothelial growth factor (VEGF), and platelet derived growth factor (PDGF) significantly increased in the MSC transplantation group compared with the blank injection group. Furthermore, FGF-2 and VEGF expression were positively correlated with the number of surviving MSCs. In addition, we found that the expression of brain-derived neurotrophic factor (BDNF), NT-3, FGF-8, TGF-beta, epidermal growth factor (EGF), and insulin-like growth factor (IGF) decreased with age, and the expression of FGF-2, FGF-10, FGF 20, TGF-alpha, and PDGF increased with age. Our data suggest that the embryonic spinal cord niche is more conducive to MSC differentiation after transplantation. PMID- 26651540 TI - Workstations for people with disabilities: an example of a virtual reality approach. AB - This article describes a method of adapting workstations for workers with motion disability using computer simulation and virtual reality (VR) techniques. A workstation for grinding spring faces was used as an example. It was adjusted for two people with a disabled right upper extremity. The study had two stages. In the first, a computer human model with a visualization of maximal arm reach and preferred workspace was used to develop a preliminary modification of a virtual workstation. In the second stage, an immersive VR environment was used to assess the virtual workstation and to add further modifications. All modifications were assessed by measuring the efficiency of work and the number of movements involved. The results of the study showed that a computer simulation could be used to determine whether a worker with a disability could access all important areas of a workstation and to propose necessary modifications. PMID- 26651541 TI - ABM Clinical Protocol #19: Breastfeeding Promotion in the Prenatal Setting, Revision 2015. AB - A central goal of the Academy of Breastfeeding Medicine is the development of clinical protocols for managing common medical problems that may impact breastfeeding success. These protocols serve only as guidelines for the care of breastfeeding mothers and infants and do not delineate an exclusive course of treatment or serve as standards of medical care. Variations in treatment may be appropriate according to the needs of an individual patient. PMID- 26651542 TI - Effect of Delayed Cord Clamping Above Versus Below the Perineum on Neonatal Hematocrit: A Randomized Controlled Trial. AB - OBJECTIVE: The purpose of this study was to determine if there is a difference in neonatal hematocrit at 24 hours of life in full-term newborns for which delayed cord clamping is performed above versus below the perineum. MATERIALS AND METHODS: One hundred one patients with singleton pregnancies >37 weeks of gestation presenting for delivery were randomized to delayed cord clamping above or below the perineum. At 24 hours of life, neonatal hematocrit was determined, and the difference was compared using statistical analysis. Secondary outcomes measured were need for phototherapy, transfusion, and neonatal intensive care unit (NICU) admission. RESULTS: Of 101 patients recruited for the study, 53 were randomized to the above group, and 48 were randomized to the below group. Twenty seven patients in the above group and 26 patients in the below group completed the study. The above group had an average neonatal hematocrit of 52.7% (+/- 2.58%). The below group had an average neonatal hematocrit of 55.8% (+/- 2.42%). There was no statistical difference between groups (p = 0.10). Similarly, differences in secondary outcomes did not reach statistical significance. Three infants in the above group and one infant in the below group required phototherapy. None of the infants required blood transfusion. Three infants in the above group and one infant in the below group required NICU admission. CONCLUSIONS: When comparing delayed cord clamping above versus below the perineum, there is no difference in the neonatal hematocrit at 24 hours of life. PMID- 26651543 TI - The Layers of Plant Responses to Insect Herbivores. AB - Plants collectively produce hundreds of thousands of specialized metabolites that are not required for growth or development. Each species has a qualitatively unique profile, with variation among individuals, growth stages, and tissues. By the 1950s, entomologists began to recognize the supreme importance of these metabolites in shaping insect herbivore communities. Plant defense theories arose to address observed patterns of variation, but provided few testable hypotheses because they did not distinguish clearly among proximate and ultimate causes. Molecular plant-insect interaction research has since revealed the sophistication of plant metabolic, developmental, and signaling networks. This understanding at the molecular level, rather than theoretical predictions, has driven the development of new hypotheses and tools and pushed the field forward. We reflect on the utility of the functional perspective provided by the optimal defense theory, and propose a conceptual model of plant defense as a series of layers each at a different level of analysis, illustrated by advances in the molecular ecology of plant-insect interactions. PMID- 26651552 TI - [Clonidine can reduce opioid medication during post-operative pain]. AB - Post-operative pain management can be a challenge, and one of the first choices seems to be opioids. However, opioids have undesirable side effects, and attention may lead to a multimodal analgesia. The use of clonidine is a part of this strategy. We present a study with assessment of routes of administration of clonidine. Overall, there is a good effect of post-operative pain management. Side effects as hypotension and sedation are mentioned but not as a limitation. Many anaesthesiologists do already use clonidine in the management of post operative pain, but more research about intravenous administration of clonidine is needed. PMID- 26651553 TI - [Diabetes increases the risk of fractures]. AB - Diabetes is associated with an increased risk of fracture, however, neither bone mineral density, falls, diabetes complications nor other risk factors can explain why. Among patients with diabetes, hyperglycaemia may have detrimental effects on bone, but also use of anti-diabetic treatment may have an impact on fracture risk. In this article we assess the relationship between diabetes, bone and fracture and the effects of hyperglycaemia and anti-diabetic treatment on bone. Furthermore, fracture preventive measures in patients with diabetes are evaluated. PMID- 26651554 TI - [Endobronchial leiomyoma is a rare cause of recidivating pneumonia]. AB - Leiomyomas arise from the smooth muscle cells of the lung and account for less than 2% of all benign tumours of the lung. Symptomatology is based on the degree of bronchial obstruction. Endobronchial leiomyomas often present with obstructive pneumonia and atelectasis. We present a case report of a 17-year-old woman who had pneumonia of the right lower lobe. The anamnesis revealed three previous hospitalizations over the last one and a half years due to pneumonia of the right lung. A diagnosis of primary endobronchial leiomyoma was made on the basis of histopathology and immunohistochemistry obtained during bronchoscopy. PMID- 26651555 TI - [Amyloidosis presenting as melaena]. AB - Amyloidosis is a disease characterized by abnormal extracellular deposits of protein. The disease may affect the stomach, however, symptoms are rare in this case. Furthermore, the rare symptoms are diffuse and unspecific and the diagnosis relies on biopsy. We report the case of a 79-year-old female presenting with melaena and no history of amyloidosis. Gastroscopy raised suspicion of a malignant process in the stomach, but biopsy revealed gastric amyloidosis. The treatment of gastric involvement is primarily symptomatic, and causal treatment is reserved for the few. PMID- 26651556 TI - [Subcutaneous myxopapillary ependymoma]. AB - Subcutaneous myxopapillary ependymoma is a very rare entity, and to our knowledge this is the first published case from Denmark. A previously healthy 32-year-old male presented with subcutaneous swelling and tenderness located at the top of the intergluteal cleft. The circular soft tumour, measuring 1.7 * 1.7 * 1.2 cm, was removed surgically. After histopathological examination with several immunohistochemical and special stainings, the diagnosis surprisingly was subcutaneous myxopapillary ependymoma. The tumour was removed with free margins and no metastases were found on follow-up CT- and MRI scans. PMID- 26651557 TI - [Pregnancy predispose to higher incidence of venous thromboembolism]. AB - Venous thromboembolism (VTE) is a major cause of maternal morbidity and mortality despite the possibility to prevent and treat the disorder. The hypercoagulability of normal pregnancy predispose to an approximately six-fold higher incidence of VTE in pregnancy. Identification of risk pregnancies and start of prophylaxis is essential, as is early diagnosis of VTE to prevent progression and pulmonary embolism. For anticoagulant treatment and prophylaxis in pregnancy, low molecular weight heparin is the drug of choice and prophylaxis, if indicated, should initiate as soon as pregnancy is confirmed. PMID- 26651558 TI - Evaluation of the Determination of Free Urea in Water-Soluble Liquid Fertilizers Containing Urea and Ureaforms by Urease and HPLC Methods. AB - Currently there are three AOAC Official Methods for the determination of urea in fertilizers. AOAC Official Method 959.03, Urea in Fertilizers, Urease Method, First Action 1959, Final Action 1960, is based on the use of fresh commercial 1% urease solution, or preparation of such solution from urease powder in water, or from jack bean meal in water. AOAC Official Method 983.01, Urea and Methyleneureas (Water-Soluble) in Fertilizers, First Action 1983, Final Action 1984, is based on LC with a refractive index detector using water as the mobile phase and a C18 column. AOAC Official Method 2003.14, Determination of Urea in Water- Soluble Urea-Formaldehyde Fertilizer Products and in Aqueous Urea Solutions, First Action 2003, Final Action 2008, is based on LC with a UV detector using acetonitrile-water (85+15, v/v) mobile phase and a propylamine column. The urea method, AOAC Official Method 959.03, is very much dependent on the nature of the urease enzyme. The method was developed in 1960 and used for simple urea fertilizer solutions. With the advent of complex fertilizer compositions, especially with the class of liquid triazone fertilizers and water soluble urea forms, the analyses of free urea in these fertilizers by the urease method is often inaccurate and inconsistent. AOAC Official Method 983.01 is not always reliable due to the interference of some of the components of these fertilizers, and due to the fact that the use of water as the mobile phase does not always separate the free urea from other components. AOAC Official Method 2003.14 was subjected to ring test studies that showed it could be used for the determination of "free urea" in these classes of fertilizers with good accuracy and precision. PMID- 26651559 TI - Determination of Isoflavone Content in SRM 3238 Using Liquid Chromatography Particle Beam/Electron Ionization Mass Spectrometry. AB - The characterization of marker components in botanical materials is a challenging task, and the increased consumption of botanicals and dietary supplements demands a greater understanding of the associated health benefits and risks. In order to successfully acquire and compare clinical results and correlate health trends, accurate, precise, and validated methods of analysis must be developed. Presented here is the development of a quantitative method for the determination of soy isoflavones (daidzin, glycitin, genistin, daidzein, and genistein) using LC particle beam/electron ionization-MS (LC-PB/EIMS). An internal standard (IS) approach for quantitation with 7-hydroxy-4- chromone as the IS compound was used, with response factors for each individual isoflavone obtained from calibrant solutions. The results from this method were compared with the certified and reference values for National Institute of Standards and Technology (NIST) SRM 3238 Soy-Containing Solid Oral Dosage Form to demonstrate that the method was in control. Results obtained using LC-PB/EIMS were consistent with the NIST certified or reference values and their uncertainties for all five isoflavones, demonstrating that the LC-PB/EIMS approach is both accurate and precise when used for the determination of the target isoflavones in soy-containing dietary supplement finished products while simultaneously providing structural information. PMID- 26651560 TI - Evaluation of Different Light Conditions in the Working Environment for Handling Photosensitive and Thermolabile Compounds. AB - Lighting in the working environment plays a significant role on the degree of degradation of photosensitive, thermolabile compounds and on working efficiency. Light emitting diodes (LEDs) are semiconductor light emitting devices that are promising artificial light sources with easy modulation of light wave signals and are also known for low heat generation. Therefore, the effect of polychromatic LED light was tested in the working environment using the drug compounds montelukast, nifedipine, and clavulanic acid, which are known to be photosensitive or thermolabile. As a control, other lighting sources like a sodium lamp, a classic (incandescent, tungsten) lamp, and indirect sunlight were also used in this study. All the experiments were carried out with methanolic solutions at room temperature. An Acquity UPLC/MS/MS system was used for quantification of the main analytes and degradation products. Under the tested conditions, LED lighting proved to be more suitable for handling photosensitive and thermolabile compounds. PMID- 26651561 TI - Validated HPLC and Ultra-HPLC Methods for Determination of Dronedarone and Amiodarone Application for Counterfeit Drug Analysis. AB - Two simple, accurate, and precise chromatographic methods have been developed and validated for the determination of dronedarone (DRO) HCl and amiodarone (AMI) HCl either alone or in binary mixtures due to the possibility of using AMI as a counterfeit of DRO because of its lower price. First, an RP-HPLC method is described for the simultaneous determination of DRO and AMI. Chromatographic separation was achieved on a BDS Hypersil C18 column (150*4.6 mm, 5 MUm). Isocratic elution based on potassium dihydrogen phosphate buffer with 0.1% triethylamine pH 6-methanol (10+90, v/v) at a flow rate of 2 mL/min with UV detection at 254 nm was performed. The second method is RP ultra-HPLC in which the chromatographic separation was achieved on an AcclaimTM RSLC 120 C18 column (100*2.1 mm, 2.2 MUm) using isocratic elution with potassium dihydrogen phosphate buffer with 0.1% triethylamine pH 6-methanol (5+95, v/v) at a flow rate of 1 mL/min with UV detection at 254 nm. Linearity, accuracy, and precision of the two methods were found to be acceptable over the concentration ranges of 5-80 MUg/mL for both DRO and AMI. The results were statistically compared using one-way analysis of variance. The optimized methods were validated and proved to be specific, robust, precise, and accurate for the QC of the drugs in their pharmaceutical preparations. PMID- 26651562 TI - Development and Validation of a Reliable and Robust Method for the Analysis of Cannabinoids and Terpenes in Cannabis. AB - The requirements for an acceptable cannabis assay have changed dramatically over the years resulting in a large number of laboratories using a diverse array of analytical methodologies that have not been properly validated. Due to the lack of sufficiently validated methods, we conducted a single- laboratory validation study for the determination of cannabinoids and terpenes in a variety of commonly occurring cultivars. The procedure involves high- throughput homogenization to prepare sample extract, which is then profiled for cannabinoids and terpenes by HPLC-diode array detector and GC-flame ionization detector, respectively. Spike recovery studies for terpenes in the range of 0.03-1.5% were carried out with analytical standards, while recovery studies for Delta9-tetrahydrocannabinolic acid, cannabidiolic acid, Delta9-tetrahydrocannabivarinic acid, and cannabigerolic acid and their neutral counterparts in the range of 0.3-35% were carried out using cannabis extracts. In general, accuracy at all levels was within 5%, and RSDs were less than 3%. The interday and intraday repeatabilities of the procedure were evaluated with five different cultivars of varying chemotype, again resulting in acceptable RSDs. As an example of the application of this assay, it was used to illustrate the variability seen in cannabis coming from very advanced indoor cultivation operations. PMID- 26651563 TI - Determination of 11 Cannabinoids in Biomass and Extracts of Different Varieties of Cannabis Using High-Performance Liquid Chromatography. AB - An HPLC single-laboratory validation was performed for the detection and quantification of the 11 major cannabinoids in most cannabis varieties, namely, cannabidiolic acid (CBDA), cannabigerolic acid (CBGA), cannabigerol (CBG), cannabidiol (CBD), tetrahydrocannabivarin (THCV), cannabinol (CBN), Delta9-trans tetrahydrocannabinol (Delta9-THC), Delta8-trans-tetrahydrocannabinol (Delta8 THC), cannabicyclol (CBL), cannabichromene (CBC), and Delta9 tetrahydrocannabinolic acid-A (THCAA). The analysis was carried out on the biomass and extracts of these varieties. Methanol-chloroform (9:1, v/v) was used for extraction, 4-androstene-3,17-dione was used as the internal standard, and separation was achieved in 22.2 min on a C18 column using a two- step gradient elution. The method was validated for the 11 cannabinoids. The concentration response relationship of the method indicated a linear relationship between the concentration and peak area with r2 values of >0.99 for all 11 cannabinoids. Method accuracy was determined through a spike study, and recovery ranged from 89.7 to 105.5% with an RSD of 0.19 to 6.32% for CBDA, CBD, THCV, CBN, Delta9-THC, CBL, CBC, and THCAA; recovery was 84.7, 84.2, and 67.7% for the minor constituents, CBGA, CBG, and Delta8-THC, respectively, with an RSD of 2.58 to 4.96%. The validated method is simple, sensitive, and reproducible and is therefore suitable for the detection and quantification of these cannabinoids in different types of cannabis plant materials. PMID- 26651564 TI - Rapid Enantiomeric Separation and Quantitation of Levetiracetam on alpha-Acid Glycoprotein (AGP) Chiral Stationary Phase by High-Performance Liquid Chromatography. AB - A new, simple, and rapid chiral HPLC method was developed for enantioselective analysis of levetiracetam and its enantiomer [(R)-alpha-ethyl-2- oxo-pyrrolidine acetamide] in a pharmaceutical formulation and bulk material. Enantiomeric separation was achieved on a chiral-alpha1-acid glycoprotein (AGP) column (150*4.0 mm, 5 MUm) using an isocratic mobile phase of phosphate buffer (pH=7) at a flow rate of 0.7 mL/min. The UV detector was set at 210 nm. Calibration curves were linear in the range of 1-100 MUg/mL and 0.4-20 MUg/mL for levetiracetam and the (R)-enantiomer, respectively. LOD and LOQ for the (R)-enantiomer were 0.1 and 0.4 MUg/mL, respectively. The run time of analysis was less than 5.0 min. PMID- 26651565 TI - Rapid Electroanalytical Method for Determination of Nebivolol at a Boron-Doped Diamond Electrode. AB - A boron-doped diamond electrode provided a sensitive and cost-effective sensing platform for detection and quantitative determination of novel beta(1)-adrenergic receptor antagonist nebivolol. The net square-wave voltammetric response at 1.31 V related to the oxidation of nebivolol was obtained in Britton-Robinson buffer solution at pH 8. It increased linearly with the drug concentration in the range of 2.5*10(-7) to 1.5*10(-5) M. The LOD attained was 3.2*10(-8) M. The practical analytical approach was illustrated by high speed quantification of nebivolol in a commercial pharmaceutical formulation. The RP-HPLC was selected as a comparative method for evaluating the proposed electroanalytical method. The newly developed method at the unmodified electrode surface was faster and simpler in comparison with HPLC (the retention time was 17.6 min), and only 6 s was necessary for direct voltammetric measurement in the potential range from 0.5 to 1.7 V with a 2 mV potential step and pulse frequency of 100 Hz. PMID- 26651566 TI - Simultaneous Determination of Eight Hypotensive Drugs of Various Chemical Groups in Pharmaceutical Preparations by HPLC-DAD. AB - A new sensitive, simple, rapid, and precise HPLC method with diode array detection has been developed for separation and simultaneous determination of hydrochlorothiazide, furosemide, torasemide, losartane, quinapril, valsartan, spironolactone, and canrenone in combined pharmaceutical dosage forms. The chromatographic analysis of the tested drugs was performed on an ACE C18, 100 A, 250*4.6 mm, 5 MUm particle size column with 0.0.05 M phosphate buffer (pH=3.00) acetonitrile-methanol (30+20+50 v/v/v) mobile phase at a flow rate of 1.0 mL/min. The column was thermostatted at 25 degrees C. UV detection was performed at 230 nm. Analysis time was 10 min. The elaborated method meets the acceptance criteria for specificity, linearity, sensitivity, accuracy, and precision. The proposed method was successfully applied for the determination of the studied drugs in the selected combined dosage forms. PMID- 26651567 TI - Crystal Diagnostics XpressTM E7 STEC Kit for the Rapid Multiplex Detection of E. coli O157 and non-O157 Shiga toxin-producing E. coli. AB - The Crystal Diagnostics (CDx) Xpress E7 STEC kit is a rapid and sensitive detection assay for the detection of Escherichia coli O157 and six non-O157 Shiga toxin-producing E. coli (serogroups O26, O45, O1O3, O111, O121, and O145, collectively referred to as STEC) at 1 CFU/325 g of raw ground beef and raw beef trim, or 200 g of spinach. The system comprises an automatic Crystal Diagnostics Xpress System Reader that integrates immunochemical and optical processes for the liquid crystal-based detection of microorganisms, a CDx BioCassette that incorporates antibody-coupled microspheres and liquid crystal for selective identification of the intended microbe, and additional commercially available components. The Crystal Diagnostics Xpress System(TM) combines proprietary liquid crystal technology with antibody-coated paramagnetic microspheres to selectively capture and detect STEC from food matrixes. The Xpress System expeditiously (9.5 h enrichment) provides the sensitivity and specificity of the U. S. Department of Agriculture Food Safety and Inspection Service and the U. S. Food and Drug Administration reference methods in screening as low as 1 STEC CFU/test portion. The inclusivity validation demonstrated detection of 53 of 54 STEC test strains. Shelf life testing of the antibody-coated microspheres and other Crystal Diagnostic consumables indicated that all materials were stable for a minimum of 3 months (ongoing), and lot-to-lot testing demonstrated consistent results between lots (data not shown). The internal and independent laboratory tests demonstrate that the method is rapid and sensitive for screening of the target STEC. PMID- 26651568 TI - Determination of beta-N-methylamino-L-alanine, N-(2-aminoethyl)glycine, and 2,4 diaminobutyric acid in Food Products Containing Cyanobacteria by Ultra Performance Liquid Chromatography and Tandem Mass Spectrometry: Single-Laboratory Validation. AB - A single-laboratory validation study was completed for the determination of beta N-methylamino-L-alanine (BMAA), N-(2-aminoethyl)glycine (AEG), and 2,4 diaminobutyric acid (DAB) in bulk natural health product supplements purchased from a health food store in Canada. BMAA and its isomers were extracted with acid hydrolysis to free analytes from protein association. Acid was removed with the residue evaporated to dryness and reconstituted with derivatization using 6 aminoquinolyl-N-hydroxysuccinimidyl carbamate (AccQ-Fluor). Chromatographic separation and detection were achieved using RP ultra-performance LC coupled to a tandem mass spectrometer operated in multiple reaction monitoring mode. Data from biological samples were evaluated for precision and accuracy across different days to ensure repeatability. Accuracy was assessed by spike recovery of biological samples using varying amino acid concentrations, with an average recovery across all samples of 108.6%. The analytical range was found to be 764 0.746 ng/mL prior to derivatization, thereby providing a linear range compatible with potentially widely varying analyte concentrations in commercial health food products. Both the U. S. Food and Drug Administration (FDA) and U. S. Pharmacopeia definitions were evaluated for determining method limits, with the FDA approach found to be most suitable having an LOD of 0.187 ng/mL and LLOQ of 0.746 ng/mL. BMAA in the collected specimens was detected at concentrations lower than 1 MUg/g, while AEG and DAB were found at concentrations as high as 100 MUg/g. Finding these analytes, even at low concentrations, has potential public health significance and suggests a need to screen such products prior to distribution. The method described provides a rapid, accurate, and precise method to facilitate that screening process. PMID- 26651569 TI - Determination of Ochratoxin A in Pig Kidneys by Immunoaffinity Cleanup and Ultra High Performance Liquid Chromatography. AB - An accurate method was developed for determining ochratoxin A (OTA) in pig kidney using an immunoaffinity column for cleanup and ultra-HPLC/MS/MS for identification and quantification. Mean recoveries of OTA from kidney samples fortified at 0.10-5 MUg/kg levels ranged from 74 to 92%, with RSDs of 4.6-7.5%. The LOD was estimated to be 0.03 MUg/kg and the LOQ was 0.10 MUg/kg based on an S/N in kidney of 3:1 and 10:1, respectively. The developed method was used for the determination of OTA in pig kidney. A survey of the OTA content of pig kidneys slaughtered in Chongqing, China, revealed that 35 out of 40 analyzed samples were contaminated; the OTA concentration in kidney ranged from trace level (0.03-0.1) to 0.323 MUg/kg. This method was shown to be useful for accurately evaluating the intake of OTA from pig kidneys. PMID- 26651570 TI - QuickToxTM Kit for QuickScan Aflatoxin FREE. AB - The QuickTox Kit for QuickScan Aflatoxin FREE uses competitive lateral flow technology and a reader based system for quantitative determination of total aflatoxins in varied matrixes. Aqueous based extraction protocols are used for corn and wheat, reducing use of solvents. Fifty percent ethanol (Reagent Alcohol) extraction is used for oats, sorghum, and barley. Eighty percent ethanol (Reagent Alcohol) extraction is used for whole peanut, peanut seed, and peanut hull samples. Matrix specific assay procedures and calibration curves are used to enable analyses across multiple sample types. The performance of this assay was examined using naturally contaminated aflatoxin corn samples and spiked samples of barley, oats, sorghum, wheat, whole peanut, peanut seed, and peanut hull samples. All data were judged against previously established acceptance criteria. Performance was evaluated in linearity, selectivity, matrix, lot consistency, and robustness experiments in the sponsor's laboratory. Results produced in all studies except robustness were within acceptable ranges. Out of range robustness study results reflected simultaneous deviation in sample volume and assay development time compared to the standard assay procedures. Aflatoxin B1, B2, and G1 were detected with approximately equal sensitivity; sensitivity for G2 was 64% that of B1. The presence of other common mycotoxins did not interfere with the assay. Matrix studies in an independent laboratory examined corn and barley to challenge both aqueous and ethanol based extraction procedures. All data points in these studies fell within the ranges defined in the acceptance criteria. The assay exhibited a linear dose response over the range tested, 0-100 ppb, with R(2) values exceeding 0.93 and RSDr values for results ranging from 2.27 to 23.84%. PMID- 26651571 TI - Automated Aflatoxin Analysis Using Inline Reusable Immunoaffinity Column Cleanup and LC-Fluorescence Detection. AB - A novel reusable immunoaffinity cartridge containing monoclonal antibodies to aflatoxins coupled to a pressure resistant polymer has been developed. The cartridge is used in conjunction with a handling system inline to LC with fluorescence detection to provide fully automated aflatoxin analysis for routine monitoring of a variety of food matrixes. The handling system selects an immunoaffinity cartridge from a tray and automatically applies the sample extract. The cartridge is washed, then aflatoxins B1, B2, G1, and G2 are eluted and transferred inline to the LC system for quantitative analysis using fluorescence detection with postcolumn derivatization using a KOBRA(r) cell. Each immunoaffinity cartridge can be used up to 15 times without loss in performance, offering increased sample throughput and reduced costs compared to conventional manual sample preparation and cleanup. The system was validated in two independent laboratories using samples of peanuts and maize spiked at 2, 8, and 40 MUg/kg total aflatoxins, and paprika, nutmeg, and dried figs spiked at 5, 20, and 100 MUg/kg total aflatoxins. Recoveries exceeded 80% for both aflatoxin B1 and total aflatoxins. The between-day repeatability ranged from 2.1 to 9.6% for aflatoxin B1 for the six levels and five matrixes. Satisfactory Z-scores were obtained with this automated system when used for participation in proficiency testing (FAPAS(r)) for samples of chilli powder and hazelnut paste containing aflatoxins. PMID- 26651572 TI - A Rapid Method for Determination of the Main Conjugated Linoleic Acid Precursors (C18:2 n-6 and C18:3 n-3) in Forage by Capillary Zone Electrophoresis with Ultraviolet Detection Using Gas Chromatography with Flame Ionization Detection as a Comparative Method. AB - A rapid method has been proposed for determination of the main conjugated linoleic acid precursors such as linoleic (C18:2 n-6) and linolenic (C18:3 n-3) acids in forages by capillary zone electrophoresis (CZE) with direct UV detection at 200 nm. Among the fatty acids found in forages, C18:2 n-6 and C18:3 n-3 have received particular attention due to their roles as precursors for the synthesis of conjugated linoleic acid, a class of health-enhancing compounds that is predominantly found in dairy products. The electrolyte background consisted of 12.0 mmol/L tetraborate buffer (pH 9.2) added to 12.0 mmol/L Brij 35(r), 17% acetonitrile, and 33% methanol. Under the optimized conditions, the baseline separation of C18:2 n-6 and C18:3 n-3 was achieved within 4 min. The CZE-UV method was compared to GC with a flame ionization detector, which is the American Oil Chemists' Society (AOCS 996.06) official method for fatty acid analysis. The methods did not show any evidence of significant differences within 95% confidence interval (P>0.05). The CZE-UV method was successfully applied to the analysis of 80 genotypes of Brachiaria ruzizienses clones submitted to a genetic improvement program in agricultural research. PMID- 26651573 TI - Lipid Characterization of White, Dark, and Milk Chocolates by FT-Raman Spectroscopy and Capillary Zone Electrophoresis. AB - There are few studies about different types of chocolate and their chemical characterization by Fourier transform (FT)-Raman spectroscopy and capillary zone electrophoresis (CZE). The aim of this study was to evaluate the lipid profile of different types of Brazilian chocolate through characterization by FT-Raman spectroscopy and identification and quantification of major fatty acids (FAs) by CZE to confirm FT-Raman spectrometry results. It was found that the main spectroscopic profile difference of the chocolate samples analyzed was related to the presence of saturated or unsaturated FAs. Well defined bands at approximately 1660, 1267, and 1274 cm(-1) corresponding to vibrational modes of unsaturated FAs (UnFAs) were found only in the spectra of samples with cocoa butter in their composition according to label specifications, mainly in dark chocolate samples. The FA identification and quantification by CZE found the presence of stearic (18:0) and palmitic (16:0) acids as the major saturated FAs in all chocolate samples. Dark chocolate samples showed the highest levels of oleic (cis-9 18:1) and linoleic (cis, cis -9,12 18:2) UnFAs monitored and the lowest levels of 14:0 in their chemical composition. Samples coded as 02 (with not only cocoa butter in their composition according to label) had the highest levels of 14:0 (FA not present in cocoa butter composition) corresponding to label information and inferring the presence of other fat sources, called cocoa butter substitutes, mainly for milk and white chocolate samples. This study suggests FT-Raman spectroscopy is a powerful technique that can be used to chemically characterize the chocolate lipid fraction, and CZE is a tool able to confirm Raman spectroscopy results and identify and quantify the major FAs in chocolate samples. PMID- 26651574 TI - GlutenTox(r) Pro Test for the Detection of Gluten in Select Foods and Surfaces. AB - The GlutenTox(r) Pro Test is an immunochromatographic test for the detection of gluten in foods and on surfaces with varying compositions and levels of processing, from raw foods/ingredients to final product testing. The Method Developer evaluation for the validation of the GlutenTox Pro Test Kit (Biomedal Diagnostics, Sevilla, Spain) for the detection of gluten in foods and on surfaces was conducted at Biomedal, S. L., Camas, Sevilla, Spain. The GlutenTox Pro test method was evaluated by testing the following: cross-reactivity, interference, specificity and sensitivity, robustness, stability, lot-to-lot variation, food matrix, and environmental surface. To evaluate the performance of the GlutenToxPro test for the detection of gluten, 10 matrixes were selected: rice flour, bread/biscuit, rolled oat, pate, and yogurt (and a second bread matrix for incurred sampled testing) for the food matrix study and food-grade painted wood, plastic, rubber, sealed ceramic, and stainless steel for the environmental surface matrix study. For the food matrix study, 30 replicates were evaluated at six spiked levels of gluten (0, 3, 8, 15, 25, and 45 ppm) against four detection thresholds (5, 10, 20, and 40 ppm) for each food matrix. Additionally, 10 replicates were evaluated at a concentration of 10,000 ppm using all four detection thresholds only for rice flour matrix. Three replicates of each concentration level of gluten were analyzed using paired samples by the AOAC OMA 2012.01 reference method for each food matrix. For the environmental surface study, 30 replicates were evaluated at a low spike level of gluten (16 ng/16 cm2), five replicates at a high spike level of gluten (400 ng/16 cm2), and five replicates at an unspiked control level (0 ng/16 cm2) for each surface matrix. Upon completion of testing, the probability of detection values and confidence intervals were calculated and plotted versus the concentration level as determined by the reference method when applicable. An independent laboratory evaluation of the GlutenTox Pro Test Kit with rice flour and stainless steel environmental surface was conducted at Q Laboratories, Inc. (Cincinnati, OH). The GlutenTox Pro Test Kit demonstrated reliability as an effective rapid method for the detection of gluten in food matrixes (LOD 5 ppm gluten; threshold limits 5, 10, 20, and 40 ppm gluten) and on environmental surfaces (amount of detection 16 ng/16 cm2). PMID- 26651575 TI - Rapid Quantification of Four Anthocyanins in Red Grape Wine by Hydrophilic Interaction Liquid Chromatography/Triple Quadrupole Linear Ion Trap Mass Spectrometry. AB - The identification and quantification of four anthocyanins (cyanidin-3-O glucoside, peonidin-3-O-glucoside, delphinidin-3-O-glucoside, and malvidin-3-O glucoside) in red grape wine were carried out by hydrophilic interaction liquid chromatography/triple quadrupole linear ion trap MS (HILIC/QTrap-MS/MS). Samples were diluted directly and separated on a Merck ZIC HILIC column with 20 mM ammonium acetate solution-acetonitrile mobile phase. Quantitative data acquisition was carried out in the multiple reaction monitoring mode. Additional identification and confirmation of target compounds were performed using the enhanced product ion mode of the linear ion trap. The LOQs were in the range 0.05 1.0 ng/mL. The average recoveries were in the range 94.6 to 104.5%. The HILIC/QTrap-MS/MS platform offers the best sensitivity and specificity for characterization and quantitative determination of the four anthocyanins in red grape wines and fulfills the quality criteria for routine laboratory application. PMID- 26651576 TI - A Rapid Method for Analysis of Phenylalanine in Cereal Products by MEKC-UV Using LC/MS/MS as a Comparative Method. AB - The aim of this study was to develop a new and fast micellar electrokinetic chromatography (MEKC) method for the determination of phenylalanine in cereal samples. The background electrolyte was chosen by a factorial design and was composed of 30 mmol/L phosphoric acid, 100 mmol/L sodium dodecyl sulfate, and 25% methanol (v/v) at pH 1.9. A fused silica capillary (48.5 cm total length*8.5 cm effective length*50 MUm id*375 MUm od) was used in a short-end injection configuration, and direct UV detection was at 200 nm. The method was validated following the Eurachem guidelines, and values such as linearity (from 10.1 to 40.4 mg/L); recovery (86.8-103.9%); repeatability (0.06-0.22% for migration time and 1.14-4.82% for peak area); reproducibility (0.04-0.61% for migration time and 2.22-5.72% for peak area); and LOD and LOQ of 20 and 60 mg/100 g, respectively, were obtained. After the comparison involving selectivity and accuracy between capillary electrophoresis and LC/MS/MS method, the MEKC-UV method was successfully applied to analysis of phenylalanine in different cereal products. PMID- 26651577 TI - A Real-Time PCR Method Targeting Camel Ingredient for Food Authentication. AB - The special nutritious value of camel showed high potential for market exploitation. In this paper, a real-time PCR method targeting camel ingredient in camel meat and milk is reported as an approach to fight against adulteration. To understand the impact of processing procedures on the amplifiability of cytb gene, four kinds of processed camel meat were investigated, and the rate of DNA breakage was explored. The method was able to detect 5 fg/MUL camel DNA and highly processed food containing 0.01% camel meat with a high confidence level. PMID- 26651578 TI - Detection of Adulterated Vegetable Oils Containing Waste Cooking Oils Based on the Contents and Ratios of Cholesterol, beta-Sitosterol, and Campesterol by Gas Chromatography/Mass Spectrometry. AB - A simple and accurate authentication method for the detection of adulterated vegetable oils that contain waste cooking oil (WCO) was developed. This method is based on the determination of cholesterol, beta-sitosterol, and campesterol in vegetable oils and WCO by GC/MS without any derivatization. A total of 148 samples involving 12 types of vegetable oil and WCO were analyzed. According to the results, the contents and ratios of cholesterol, beta-sitosterol, and campesterol were found to be criteria for detecting vegetable oils adulterated with WCO. This method could accurately detect adulterated vegetable oils containing 5% refined WCO. The developed method has been successfully applied to multilaboratory analysis of 81 oil samples. Seventy-five samples were analyzed correctly, and only six adulterated samples could not be detected. This method could not yet be used for detection of vegetable oils adulterated with WCO that are used for frying non-animal foods. It provides a quick method for detecting adulterated edible vegetable oils containing WCO. PMID- 26651580 TI - Determination of Myo-Inositol in Infant, Pediatric, and Adult Formulas by Liquid Chromatography-Pulsed Amperometric Detection with Column Switching: Collaborative Study, Final Action 2011.18. AB - AOAC First Action Method 2011.18, Myo-Inositol (Free and Bound as Phosphatidylinositol) in Infant and Pediatric Formulas and Adult Nutritionals, was collaboratively studied. With this method free myo-inositol and phosphatidylinositol bound myo-inositol are extracted using two different sample preparation procedures, separated by ion chromatography using a combination of Dionex Carbo Pac PA1 and MA1 columns with column switching, and detected with pulsed amperometry using a gold electrode. Free myo-inositol is extracted from samples with dilute hydrochloric acid and water. Phosphatidylinositol is extracted from samples with chloroform and separated from other fats with silica SPE cartridges. Myo-inositol is then released from the glycerol backbone with concentrated acetic and hydrochloric acids at 120 degrees C. During this collaborative study, nine laboratories from five different countries analyzed blind duplicates of nine infant and pediatric nutritional formulas for both free and phosphatidylinositol bound myo-inositol, and one additional laboratory only completed the free myo-inositol analyses. The method demonstrated acceptable repeatability and reproducibility and met the AOAC Stakeholder Panel on Infant Formula and Adult Nutritionals (SPIFAN) Standard Method Performance Requirements (SMPRs(r)) for free myo-inositol plus phosphatidylinositol bound myo-inositol for all the matrixes analyzed. SMPRs for repeatability were <=5% RSD at myo-inositol concentrations of 2-68 mg/100 g ready-to-feed (RTF) liquid. SMPRs for reproducibility were <=8% RSD in products with myo-inositol concentrations ranging from 2 to 68 mg/100 g RTF liquid. During this collaborative study, repeatability RSDs ranged from 0.51 to 3.22%, and RSDs ranged from 2.66 to 7.55% for free myo-inositol plus phosphatidylinositol bound myo-inositol. PMID- 26651579 TI - Determination of Vitamin B12 in Infant, Adult, and Pediatric Formulas by HPLC-UV and Column Switching: Collaborative Study, Final Action 2011.10. AB - AOAC First Action Method 2011.10, Vitamin B12 in Infant and Pediatric Formulas and Adult Nutritionals, was collaboratively studied. This method uses a pH 4.5 sodium acetate buffer and potassium cyanide at 105 degrees C to extract and convert all biologically active forms of vitamin B12 present to cyanocobalamin; octylsilyl (C8) or C18 SPE cartridges to purify and concentrate cyanocobalamin; a combination of size-exclusion and RPLC to isolate cyanocobalamin; and visible absorbance at 550 nm to detect and quantitate cyanocobalamin in infant, pediatric, and adult nutritionals with vitamin B12 concentrations greater than 0.025 MUg/100 g ready-to-feed (RTF) liquid. During this collaborative study, nine to 11 laboratories from eight different countries analyzed blind duplicates of 12 infant, pediatric, and adult nutritional formulas. Per the AOAC Expert Review Panel (ERP) on Stakeholder Panel on Infant Formula and Adult Nutritionals (SPIFAN) Nutrient Methods the method demonstrated acceptable repeatability and reproducibility and met SPIFAN Standard Method Performance Requirements (SMPRs(r)) for the majority of product matrixes analyzed. Vitamin B12 SPIFAN SMPRs for repeatability were <=15% RSD at vitamin B12 concentrations of 0.01 MUg/100 g RTF liquid and <=7% RSD at vitamin B12 concentrations of 0.2-5.0 MUg/100 g RTF liquid. Vitamin B12 SPIFAN SMPRs for reproducibility were <=11% RSD in products with vitamin B12 concentrations ranging from 0.3 to 5.0 MUg/100 g RTF liquid. During this collaborative study, the RSDr ranged from 2.98 to 9.77%, and the RSDR ranged from 3.54 to 19.5%. During previous single-laboratory validation studies, the method LOQ was estimated to be 0.025 MUg/100 g RTF liquid. PMID- 26651581 TI - Determination of Labeled Fatty Acids Content in Milk Products, Infant Formula, and Adult/Pediatric Nutritional Formula by Capillary Gas Chromatography: Single Laboratory Validation, First Action 2012.13. AB - The method described is intended for the quantification of all fatty acids, including commercially important groups of fatty acids used for labeling reasons [i. e., trans fatty acids, saturated fatty acids, monounsaturated fatty acids, polyunsaturated fatty acids (PUFA), omega-3, omega-6, and omega-9] and/or individual fatty acids (i. e., linoleic acid, alpha-linolenic acid, arachidonic acid, ecosapentaenoic acid, and docosahexaenoic acid) in milk products, infant formula, and adult/pediatric nutritional formula. These products often contain milk fat and/or vegetable oils and are supplemented or not supplemented with oils rich in long-chain PUFA. The determination is performed by direct transesterification of ready-to-feed (RTF) liquid concentrate or powder products without prior fat extraction. Single-laboratory validation (SLV) data were submitted to the AOAC Expert Review Panel (ERP) on Nutrient Methods for review at the AOAC Annual Meeting held on September 30 to October 3, 2012, in Las Vegas, NV. The ERP determined that the data reviewed met the Standard Method Performance Requirements (SMPR(r) 2012.011) set by the AOAC Stakeholder Panel on Infant Formula and Adult Nutritionals (SPIFAN) and was approved as an AOAC Official First Action method. The analytical range for SPIFAN samples was between 0.001 and 7.94 g/100 g reconstituted product or RTF liquid. LOQ was estimated as 0.001 g/100 g, while repeatability and intermediate precision were both less than 1.8% RSD above 0.05 g/100 g and <3.5% RSD at 0.005 g/100 g. Recovery values based on spiking experiments at two different levels of linoleic and linolenic acids ranged from 100.0 to 102.9% for three different SPIFAN products. All the parameters evaluated during the SLV were well within the values defined in SMPR 2012.011. PMID- 26651582 TI - Pantothenic Acid (Vitamin B5) in Infant Formula and Adult/ Pediatric Nutritional Formula by Ultra-High Pressure Liquid Chromatography/Tandem Mass Spectrometry Method: Collaborative Study, Final Action 2012.16. AB - In order to determine repeatability and reproducibility of AOAC First Action Method 2012.16 [Pantothenic Acid (Vitamin B5) in Infant Formula and Adult/Pediatric Nutritional Formula by Ultra-High Pressure Liquid Chromatography/Tandem Mass Spectrometry], a collaborative study was organized. The study was divided in two parts: method setup and qualification of participants (part 1) and collaborative study participation (part 2). For part 1, each participating laboratory was asked to analyze two practice samples using the aforementioned method. Laboratories that provided results within a range of expected levels were qualified for part 2, during which each laboratory received 10 samples in blind duplicates. Results have been compared to the Standard Method Performance Requirement (SMPR(r)) 2012.009 established for pantothenic acid. Precision results (repeatability and reproducibility) were within the limits stated in the SMPR. Repeatability ranged from 1.3 to 3.3%, and reproducibility ranged from 4.1 to 7.0%. Horwitz ratio (HorRat) values were all <1, ranging from 0.33 to 0.69. The AOAC Expert Review Panel on Stakeholder Panel on Infant Formula and Adult Nutritionals Nutrient Methods determined that the data presented met the SMPR and recommended the method for Final Action status, which was then granted by the AOAC Official Methods Board. PMID- 26651583 TI - Determination of Chromium, Selenium, and Molybdenum in Infant Formula and Adult Nutritional Products by Inductively Coupled Plasma/Mass Spectrometry: Collaborative Study, Final Action 2011.19. AB - AOAC First Action Method 2011.19: Chromium, Selenium, and Molybdenum in Infant Formula and Adult Nutritional Products, was collaboratively studied. This method uses microwave digestion of samples with nitric acid, hydrogen peroxide, and internal standard followed by simultaneous detection of the elements by an inductively coupled plasma (ICP)/MS instrument equipped with a collision/reaction cell. During this collaborative study, nine laboratories from four different countries, using seven different models of ICP/MS instruments, analyzed blind duplicates of seven infant, pediatric, and adult nutritional formulas. One laboratory's set of data was rejected in its entirety. The method demonstrated acceptable repeatability and reproducibility and met the AOAC Stakeholder Panel on Infant Formula and Adult Nutritionals (SPIFAN) Standard Method Performance Requirements (SMPRs(r)) for almost all of the matrixes analyzed. The Cr, Mo, and Se SPIFAN requirement for repeatability was <=5% RSD. The SMPR called for a reproducibility of <=15% RSD for products with ultratrace element concentrations above the targeted LOQ of 20 MUg/kg Cr/Mo and 10 MUg/kg Se (as ready-to-feed). During this collaborative study, RSDr ranged from 1.0 to 7.0% and RSDR ranged from 2.5 to 13.4% across all three ultratrace elements. PMID- 26651584 TI - Determination of Minerals and Trace Elements in Infant Formula and Adult/Pediatric Nutritional Formula by Inductively Coupled Plasma/Mass Spectrometry A Performance Evaluation: Single-Laboratory Validation, First Action 2015.06. AB - A method for determination of 12 minerals and trace elements (Na, Mg, P, K, Ca, Cr, Mn, Fe, Cu, Zn, Se, and Mo) in infant formula and adult/ pediatric nutritional formula was developed and evaluated in a single-laboratory validation. Some additional reproducibility data were obtained from a small interlaboratory study. The method involves microwave digestion of the sample followed by inductively coupled plasma/MS and uses Ge and Te as internal standards. The method is an extension of Official Method(SM) 2011.19 and was compared to AOAC Standard Method Performance Requirements (SMPRs(r)) 2011.009 and 2014.004 developed by the AOAC Stakeholder Panel on Infant Formula and Adult Nutritionals (SPIFAN). Repeatability precision for the 12 elements in 11 SPIFAN matrixes and National Institute of Standards and Technology Standard Reference Material (SRM) 1849a was <5%, meeting the SMPR criterion for repeatability. Intermediate reproducibility (8 days, two analysts, two instruments) in the 11 SPIFAN matrixes was <5% for nine (Na, Mg, P, K, Mn, Fe, Cu, Zn, Se) of the 12 elements in all 11 matrixes. The mean reproducibility across 6-7 laboratories and seven SPIFAN matrixes ranged from 2.5% for Cu to 7.1% for P. Recovery from spiked matrixes varied from 90.1 to 109%, and accuracy of determination using SRM 1849a ranged from 96.2 to 107.7%, meeting the requirement of 90-110% recovery/accuracy. PMID- 26651585 TI - Data Quality in Biofilm High-Throughput Routine Analysis: Intralaboratory Protocol Adaptation and Experiment Reproducibility. AB - Biofilm research is growing more diverse and dependent on high-throughput technologies, and the large-scale production of results aggravates data substantiation. In particular, experimental protocols are often adapted to meet the needs of a particular laboratory, and no statistical validation of the modified method is provided. This paper discusses the impact of intralaboratory adaptation and non-rigorous documentation of experimental protocols on biofilm data interchange and validation. The case study is a non-standard, but widely used, workflow for Pseudomonas aeruginosa biofilm development considering three analysis assays: the crystal violet (CV) assay for biomass quantification, the 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide inner salt (XTT) assay for respiratory activity assessment, and the colony forming units (CFU) assay for determination of cell viability. The ruggedness of the protocol was assessed by introducing small changes in the biofilm growth conditions, which simulate minor protocol adaptations and non- rigorous protocol documentation. Results show that even minor variations in the biofilm growth conditions may affect the results considerably, and that the biofilm analysis assays lack repeatability. Intralaboratory validation of non-standard protocols is found critical to ensure data quality and enable the comparison of results within and among laboratories. PMID- 26651587 TI - Separation and Enrichment of Gold in Water, Geological and Environmental Samples by Solid Phase Extraction on Multiwalled Carbon Nanotubes Prior to its Determination by Flame Atomic Absorption Spectrometry. AB - This study proposes the application of multi-walled carbon nanotubes as a solid sorbent for the preconcentration of gold prior to its flame atomic absorption spectrometry determination. Extraction was achieved by using a glass column (15.0 cm in length and 1.0 cm in diameter). Quantitative recoveries were obtained in the pH range of 2.5-4.0; the elution step was carried out with 5.0 ml of 1.0 mol/L HNO3 in acetone. In the ligand-free study, variables such as pH, eluent type, sample volume, flow rates, and matrix effect were examined for the optimum recovery of gold ions. The gold ions were able to be pre-concentrated by a factor of 150 and their LOD was determined to be 1.71 MUg/L. In order to evaluate the accuracy of the developed method, addition-recovery tests were applied for the tap water, mineral water, and sea water samples. Gold recovery studies were implemented using a wet digestion technique for mine and soil samples taken from various media, and this method was also applied for anodic slime samples taken from the factories located in the Kayseri Industrial Zone of Turkey. PMID- 26651586 TI - A Highly Sensitive Oligonucleotide Hybridization Assay for Klebsiella pneumoniae Carbapenemase with the Probes on a Gold Nanoparticles Modified Glassy Carbon Electrode. AB - To develop a new electrochemical DNA biosensor for determination of Klebsiella pneumoniae carbapenemase, a highly sensitive and selective electrochemical biosensor for DNA detection was constructed based on a glassy carbon electrode (GCE) modified with gold nanoparticles (Au-nano). The Au-nano/GCE was characterized by scanning electromicroscopy, cyclic voltammetry, and electrochemical impedance spectroscopy. The hybridization detection was measured by differential pulse voltammetry using methylene blue as the hybridization indicator. The dynamic range of detection of the sensor for the target DNA sequences was from 1 * 10(-11) to 1 * 10(-8) M, with an LOD of 1 * 10(-12) M. The DNA biosensor had excellent specificity for distinguishing complementary DNA sequence in the presence of non-complementary and mismatched DNA sequence. The Au nano/GCE showed significant improvement in electrochemical characteristics, and this biosensor was successfully applied for determination of K. pneumoniae. PMID- 26651588 TI - Determination of Dufulin Residue in Vegetables, Rice, and Tobacco Using Liquid Chromatography with Tandem Mass Spectrometry. AB - A rapid and accurate LC/MS/MS method using positive electrospray ionization was established for the determination of residues of the novel plant antiviral agent dufulin in samples of tobacco leaf (dry), tomato, cucumber, and rice. Samples were extracted with acetonitrile; cleaned up by dispersive SPE using primary secondary amine, C18, and graphitized carbon black sorbents; separated on a C18 column; and confirmed by multiple reaction monitoring mode MS with a matrix effect of -21.5-19.6%. The method showed satisfactory linearity (R2>=0.9912) for the target compound. The LOD and the LOQ were 0.05 and 0.15 MUg/kg, respectively. The mean recoveries from four matrixes varied from 71.9 to 93.6% with intraday RSD in the range of 2.9 to 9.0% and interday RSD 6.9 to 15.2%. The method was successfully applied for analysis of dufulin in actual trial samples. PMID- 26651589 TI - Ultra-Performance Liquid Chromatographic Determination of Manufacturing Intermediates and Subsidiary Colors in D&C Red No. 6, D&C Red No. 7, and Their Lakes. AB - An ultra-performance LC (UPLC) method was developed to determine the manufacturing intermediates and subsidiary colors in the monosulfo monoazo color additives D&C Red No. 6 and D&C Red No. 7 and their lakes. This method is intended for use in batch certification of the color additives by the U. S. Food and Drug Administration to ensure that each lot meets published specifications for coloring drugs and cosmetics. The intermediates are 2-amino-5 methylbenzenesulfonic acid (PTMS) and 3-hydroxy-2-naphthalenecarboxylic acid (3 hydroxy-2-naphthoic acid). The subsidiary colors are 3-hydroxy-4-[(4 methylphenyl)azo]-2-naphthalenecarboxylic acid (unsulfonated subsidiary color) and 1-[(4-methylphenyl) azo]-2-naphthalenol (4-methyl Sudan I). The analytes were identified by comparing their UPLC retention times and UV-Vis absorption spectra with those of standards. Validation studies showed that calibration curves were linear (average R2=0.9994), and recoveries were 96-106%. Average LOD was 0.0014 0.0061% and average LOQ was 0.0047-0.020%. Results for RSD at the specification levels ranged from 0.67 to 5.79%. Survey analyses of 42 samples from 14 domestic and foreign manufacturers yielded results by the new UPLC method and a previously reported HPLC method that were consistent within experimental error. The new UPLC method provided increased sensitivity, faster analysis times, and improved separations compared to the HPLC method. PMID- 26651590 TI - An Interlaboratory Comparative Study on the Quantitative Determination of Glyphosate at Low Levels in Wheat Flour. AB - In recent years, the use of glyphosate has dramatically increased worldwide, and there is growing concern about contamination of organic products caused by its heavy use on neighboring fields. Glyphosate is found as a residue not only in soil, plants, and groundwater but also in humans and animals. Considering the controversy on glyphosate maximum residue level in foodstuff and the difficulties in its analytical determination, the main purpose of the present paper was to investigate the competence and accuracy of 13 accredited European laboratories in determining glyphosate in wheat flour at a level close to their reporting limit of 10 MUg/kg. According to the results of this performance assessment, the laboratories were not able to quantify glyphosate at trace levels. Therefore, their specified reporting limits of 10 MUg/kg were not supported by their results, and a reporting limit of around 50 MUg/kg of glyphosate in flour seems to be more appropriate to guarantee reliable and robust results. The widespread use of glyphosate and its harmfulness to humans make its detection at trace levels a primary goal for analytical laboratories. This is achievable through the improvement of QA and/or the optimization of the method of analysis used for glyphosate detection. PMID- 26651591 TI - Systematic Robustness Testing of a Liquid Chromatographic Method: A Case Study. AB - Robustness testing of a method plays a crucial role in establishing its reliability. It examines the potential sources of variability in one or more responses of the proposed method. In this study, the robustness testing of a method proposed for simultaneous determination of warfarin and its two process related impurities was evaluated by using two level, fractional factorial design. Factors that are sensitive to a variation during method transfer were selected as independent variables [aqueous content (range: 39-43%, v/v), concentration of acetic acid (range: 0.08-0.12%, v/v), flow rate (range: 0.93-1.33 mL/min), and wavelength (range: 218-222 nm)]. Variables that determine the quality of separation, viz., retention factor of the first peak, resolution between the critical peak pair, tailing factor of warfarin, and total analysis time were selected as responses. Robustness was assessed by graphical (half normal probability and Pareto plots) and statistical (analysis of variance) methods. It was found that, among the studied variables, aqueous content had a significant effect on capacity factor and analysis time. Furthermore, non-significant intervals for significant factors were established by contour profiling. This study demonstrated the significance of experimental design and other statistical tools in understanding the effects of investigating factors of the chromatographic system and in defining their limits. PMID- 26651592 TI - Targeting Insulin-Degrading Enzyme to Treat Type 2 Diabetes Mellitus. AB - Insulin-degrading enzyme (IDE) selectively degrades peptides, such as insulin, amylin, and amyloid beta (Abeta) that form toxic aggregates, to maintain proteostasis. IDE defects are linked to the development of type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD). Structural and biochemical analyses revealed the molecular basis for IDE-mediated destruction of amyloidogenic peptides and this information has been exploited to develop promising inhibitors of IDE to improve glucose homeostasis. However, the inhibition of IDE can also lead to glucose intolerance. In this review, I focus on recent advances regarding our understanding of the structure and function of IDE and the discovery of IDE inhibitors, as well as challenges in developing IDE-based therapy for human diseases, particularly T2DM. PMID- 26651593 TI - Intraoperative electron radiation therapy combined with external beam radiation therapy and limb sparing surgery in extremity soft tissue sarcoma: a retrospective single center analysis of 183 cases. AB - BACKGROUND AND PURPOSE: To report our experience with limb-sparing surgery, IOERT and EBRT in extremity STS. MATERIALS AND METHODS: 183 patients were retrospectively analyzed. 78% presented in primary situation, with 80% located in the lower limb. Stage at presentation was: I: 6%, IIa: 25%, IIb: 21%, III: 42%, IV: 7%. The majority showed high-grade lesions (grade 1: 5%, 2: 31%, 3: 64%). IOERT was applied to the tumor bed (median 15Gy) and preceded (9%) or followed (91%) by EBRT (median 45Gy) in all patients. RESULTS: Median follow-up was 64months (78months in survivors). Surgery was complete in 68%, while 32% had microscopic residual disease. 5- and 10-year-LC was 86% and 84%, respectively. LC was significantly higher in primary compared to recurrent disease and tended to be higher after complete resection. Estimated 5- and 10-year-DC was 68% and 66%, while corresponding OS was 77% and 66%, respectively. OS was significantly affected by grading and stage. Severe postoperative complications and late toxicities were observed in 19% and 20%, respectively. Limb-preservation rate was 95% with good function in 83%. CONCLUSIONS: Combination of limb-sparing surgery, IOERT and EBRT achieved encouraging LC and OS in this unfavorable patient group with acceptable postoperative complications and low rates of late toxicities resulting in a high limb-preservation rate and good functional outcome. PMID- 26651594 TI - Bronchial epithelial cell lines and primary nasal epithelial cells from cystic fibrosis respond differently to cigarette smoke exposure. AB - The effects of cigarette smoke extract (CSE) on airway epithelial cells (AECs) from cystic fibrosis (CF) and non-cystic fibrosis (non-CF) individuals are not fully understood. It has been suggested that CSE modulates inflammatory cytokine release from AECs by modulating the epidermal growth factor receptor (EGFR) pathway; these pathways could reveal novel therapeutic targets. We compared the effect of CSE pre-incubation on IL-8 release from CF and non-CF bronchial epithelial cell lines, and separately, with primary nasal epithelial cells (NECs) retrieved from CF and non-CF individuals. We also determined if the EGFR pathway regulates IL-8 release by LPS or cytomix in non-CF and CF AECs at baseline and following CSE exposure. CF and non-CF cell lines, NECs derived from both CF patients (R117H heterozygous and F508del homozygous), and from healthy subjects, were cultured in the presence or absence of CSE, and subsequently exposed to inflammatory stimuli. In cell lines CSE significantly reduced IL-8 release following inflammatory challenge. Conversely, CSE pre-treatment was pro inflammatory in primary NECs. In NECs from control subjects, CSE increased cytomix and LPS induced IL-8 release, and for the R117H heterozygous NEC cultures, CSE enhanced basal IL-8 release. Cytomix and LPS induced IL-8 release from F508del homozygous NEC cultures was further heightened following CSE pre treatment. EGFR inhibition mitigated IL-8 release from immortalised and primary non-CF and CF AECs, suggesting that constitutive and CSE elicited IL-8 release from AECs is partly regulated via the EGFR pathway. This study demonstrates the importance of the EGFR cascade in the regulation of constitutive and CSE induced inflammatory mediator release from immortalised and primary AECs. Moreover, it clearly highlights the significance of using primary cells to confirm results obtained from immortalised cell studies, as these model systems may respond very differently to the stimuli under investigation. PMID- 26651595 TI - UK guidance opens new therapeutic avenues for patients with moderate-severe ulcerative colitis. PMID- 26651596 TI - Structure-property relationship of quinuclidinium surfactants--Towards multifunctional biologically active molecules. AB - Motivated by diverse biological and pharmacological activity of quinuclidine and oxime compounds we have synthesized and characterized novel class of surfactants, 3-hydroxyimino quinuclidinium bromides with different alkyl chains lengths (CnQNOH; n=12, 14 and 16). The incorporation of non conventional hydroxyimino quinuclidinium headgroup and variation in alkyl chain length affects hydrophilic hydrophobic balance of surfactant molecule and thereby physicochemical properties important for its application. Therefore, newly synthesized surfactants were characterized by the combination of different experimental techniques: X-ray analysis, potentiometry, electrical conductivity, surface tension and dynamic light scattering measurements, as well as antimicrobial susceptibility tests. Comprehensive investigation of CnQNOH surfactants enabled insight into structure property relationship i.e., way in which the arrangement of surfactant molecules in the crystal phase correlates with their solution behavior and biologically activity. The synthesized CnQNOH surfactants exhibited high adsorption efficiency and relatively low critical micelle concentrations. In addition, all investigated compounds showed very potent and promising activity against Gram-positive and clinically relevant Gram-negative bacterial strains compared to conventional antimicrobial agents: tetracycline and gentamicin. The overall results indicate that bicyclic headgroup with oxime moiety, which affects both hydrophilicity and hydrophobicity of CnQNOH molecule in addition to enabling hydrogen bonding, has dominant effect on crystal packing and physicochemical properties. The unique structural features of cationic surfactants with hydroxyimino quinuclidine headgroup along with diverse biological activity have made them promising structures in novel drug discovery. Obtained fundamental understanding how combination of different functionalities in a single surfactant molecule affects its physicochemical properties represents a good starting point for further biological research. PMID- 26651597 TI - BMP-SMAD signaling: From pluripotent stem cells to cardiovascular commitment. AB - Human pluripotent stem cells (hPSCs) can form all somatic cells of the body. They thus offer opportunities for understanding (i) the basic steps of early human development, (ii) the pathophysiology in human degenerative diseases and (iii) approaches to regenerative medicine and drug development. Methods for improving their differentiation to defined mesodermal derivatives in particular will benefit their use in all of these areas but most particularly applications that require cardiac and vascular tissue. However, the molecular mechanisms that regulate mesodermal development in humans are still poorly understood. Gene ablation studies in mice have shown that the signaling pathways activated by the transforming growth factor beta (TGFbeta) superfamily, including the bone morphogenetic proteins (BMP), play crucial roles in mesoderm differentiation and patterning the early embryo. Understanding their interplay and interaction with other signaling pathways, how they activate and inhibit transcription factors and epigenetic regulators during self-renewal, maintenance and exit from pluripotency and differentiation could provide vital information for a range of applications. This includes disease modeling when the hPSCs are derived from patients or drug screens for diseases of mesodermal organs. Here, we review the role of the BMP SMAD signaling pathway in pluripotent stem cells and during mesoderm differentiation with focus on the cells that make up the cardiovascular system. PMID- 26651598 TI - Transcranial magnetic stimulation potentiates glutamatergic neurotransmission in depressed adolescents. AB - Abnormalities in glutamate neurotransmission may have a role in the pathophysiology of adolescent depression. The present pilot study examined changes in cortical glutamine/glutamate ratios in depressed adolescents receiving high-frequency repetitive transcranial magnetic stimulation. Ten adolescents with treatment-refractory major depressive disorder received up to 30 sessions of 10 Hz repetitive transcranial magnetic stimulation at 120% motor threshold with 3000 pulses per session applied to the left dorsolateral prefrontal cortex. Baseline, posttreatment, and 6-month follow-up proton magnetic resonance spectroscopy scans of the anterior cingulate cortex and left dorsolateral prefrontal cortex were collected at 3T with 8-cm(3) voxels. Glutamate metabolites were quantified with 2 distinct proton magnetic resonance spectroscopy sequences in each brain region. After repetitive transcranial magnetic stimulation and at 6 months of follow-up, glutamine/glutamate ratios increased in the anterior cingulate cortex and left dorsolateral prefrontal cortex with both measurements. The increase in the glutamine/glutamate ratio reached statistical significance with the TE-optimized PRESS sequence in the anterior cingulate cortex. Glutamine/glutamate ratios increased in conjunction with depressive symptom improvement. This reached statistical significance with the TE-optimized PRESS sequence in the left dorsolateral prefrontal cortex. High-frequency repetitive transcranial magnetic stimulation applied to the left dorsolateral prefrontal cortex may modulate glutamate neurochemistry in depressed adolescents. PMID- 26651599 TI - Field triage to primary percutaneous coronary intervention: Factors influencing health-related quality of life for patients aged >=70 and <70 years with non complicated ST-elevation myocardial infarction. AB - OBJECTIVE: To examine clinical and health-related quality of life (HRQOL) outcomes and predictors of HRQOL for uncomplicated field triage ST-elevation myocardial infarction (STEMI) patients aged >=70 years and <70 years after primary percutaneous coronary intervention (PPCI). BACKGROUND: Pre-hospital field triage for PPCI is associated with lower mortality but the impact of age and other factors on HRQOL remains unknown. METHODS: 77 field triage STEMI patients were assessed for HRQOL using the Short Form-12 (SF-12) and the Seattle Angina Questionnaire (SAQ) at 4 weeks and 6 months after PPCI. RESULTS: Regression analysis showed improvements in SF-12 domains and angina stability for older people. Age predicted lower physical function (p = 0.001) and better SAQ QOL at 6 months (p = 0.003). CONCLUSION: Age, length of hospitalization, recurrent angina and hypertension were important predictors of HRQOL with PPCI. Assessment of HRQOL combined with increased support for physical and emotional recovery is needed to improve clinical care for field triage PPCI patients. PMID- 26651600 TI - Barakat syndrome or HDR syndrome: Another association of kidney disease and deafness. PMID- 26651601 TI - The Effect of Docetaxel-Loaded Micro-Bubbles Combined with Low-Frequency Ultrasound in H22 Hepatocellular Carcinoma-Bearing Mice. AB - A novel lipid micro-bubble (MB) loaded with docetaxel (DOC-MB) was investigated in a previous study. However, its anti-tumor effects and mechanism of action in combination with low-frequency ultrasound (LFUS) in vivo are still unclear. DOC MBs containing 5.0 mg of DOC were prepared by lyophilization with modification via ultrasonic emulsification. Then, the effects of DOC-MBs combined with LFUS on tumor growth, proliferating cell nuclear antigen (PCNA) expression and cell apoptosis, as well as local DOC delivery, were investigated in H22 hepatocellular carcinoma (HCC)-bearing mice. Compared with the previously prepared DOC-MBs (1.6 mg of DOC loaded), the encapsulation efficiency (81.2% +/- 3.89%) and concentration ([7.94 +/- 0.04] * 10(9) bubbles/mL) of the DOC-MBs containing 5.0 mg of DOC were higher, but the bubble size (1.368 +/- 0.004 MUm) was smaller. After treatment with the DOC-MBs and LFUS, the H22 HCC growth inhibition rate was significantly increased, PCNA expression in tumor tissue was significantly inhibited and local release of DOC was induced. In conclusion, new DOC-MBs containing 5.0 mg of DOC were successfully prepared with a high encapsulation efficiency and superior bubble size and concentration, and their combination with LFUS significantly enhanced the anti-tumor effect of DOC in H22 HCC-bearing mice by inhibiting tumor cell proliferation and increasing local drug delivery. PMID- 26651602 TI - Clinicians' attitude towards changes in Australian National Cervical Screening Program. AB - BACKGROUND: Australian guidelines for cervical cancer screening are being revised under the "renewal program". Physicians' willingness to accept these changes will play a pivotal role in its success. OBJECTIVE: To understand the willingness and acceptance of, as well as barriers and facilitators for Royal Australian and New Zealand College of Obstetricians and Gynaecologists (RANZCOG) affiliates to screening using human papillomavirus (HPV) testing, starting at 25 years of age, every 5 years. STUDY DESIGN: An electronic survey of RANZCOG affiliates was undertaken April-June 2014, while renew was announced April 28th 2014. Responses used a 7 point Likert scale, which was dichotomized as <=4, indicating 'unwilling' and >4, indicating 'willing' to adopt revised practices. RESULTS: Response rate was 22% (n=956): 60% were obstetricians and gynaecologists (OG); 27% general practitioner diplomates; 13% OG trainees. Overall, 60% (n=526/874) were willing to revise their screening practice. This correlated with awareness of new guidelines (p=<0.001). Fifty percent (n=438/869) of respondents were concerned about delaying to 25 years, and 48% (n=421/869) concerned cervical cancers would be missed. Reasons respondents gave for wishing to continue screening from 18 years contrary to guidelines included: women not being vaccinated (65.6%), immunosuppressed women (92.2%) and women who had been victims of childhood sexual assault (73.9%). CONCLUSIONS: The majority of RANZCOG affiliates were willing to change screening practice however, a number of barriers to delaying onset of screening age to age 25 years were reported. Effective change management strategies will need to be implemented to address the concerns raised to ensure best practice for cervical screening. PMID- 26651603 TI - Genomic Analysis Reveals Disruption of Striatal Neuronal Development and Therapeutic Targets in Human Huntington's Disease Neural Stem Cells. AB - We utilized induced pluripotent stem cells (iPSCs) derived from Huntington's disease (HD) patients as a human model of HD and determined that the disease phenotypes only manifest in the differentiated neural stem cell (NSC) stage, not in iPSCs. To understand the molecular basis for the CAG repeat expansion dependent disease phenotypes in NSCs, we performed transcriptomic analysis of HD iPSCs and HD NSCs compared to isogenic controls. Differential gene expression and pathway analysis pointed to transforming growth factor beta (TGF-beta) and netrin 1 as the top dysregulated pathways. Using data-driven gene coexpression network analysis, we identified seven distinct coexpression modules and focused on two that were correlated with changes in gene expression due to the CAG expansion. Our HD NSC model revealed the dysregulation of genes involved in neuronal development and the formation of the dorsal striatum. The striatal and neuronal networks disrupted could be modulated to correct HD phenotypes and provide therapeutic targets. PMID- 26651604 TI - Neurite Aggregation and Calcium Dysfunction in iPSC-Derived Sensory Neurons with Parkinson's Disease-Related LRRK2 G2019S Mutation. AB - Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most-common genetic determinants of Parkinson's disease (PD). The G2019S mutation is detected most frequently and is associated with increased kinase activity. Whereas G2019S mutant dopamine neurons exhibit neurite elongation deficits, the effect of G2019S on other neuronal subtypes is unknown. As PD patients also suffer from non-motor symptoms that may be unrelated to dopamine neuron loss, we used induced pluripotent stem cells (iPSCs) to assess morphological and functional properties of peripheral sensory neurons. LRRK2 G2019S iPSC-derived sensory neurons exhibited normal neurite length but had large microtubule-containing neurite aggregations. Additionally, LRRK2 G2019S iPSC-derived sensory neurons displayed altered calcium dynamics. Treatment with LRRK2 kinase inhibitors resulted in significant, but not complete, morphological and functional rescue. These data indicate a role for LRRK2 kinase activity in sensory neuron structure and function, which when disrupted, may lead to sensory neuron deficits in PD. PMID- 26651605 TI - Canonical MicroRNA Activity Facilitates but May Be Dispensable for Transcription Factor-Mediated Reprogramming. AB - MicroRNAs (miRNAs) are important regulators of reprogramming of somatic cells into induced pluripotent stem cells (iPSCs); however, it is unclear whether miRNAs are required for reprogramming and whether miRNA activity as a whole facilitates reprogramming. Here we report on successful reprogramming of mouse fibroblasts and neural stem cells (NSCs) lacking Dgcr8, a factor required for the biogenesis of canonical miRNAs, by Yamanaka factors, albeit at decreased efficiencies. Though iPSCs derived from Dgcr8-deficient mouse fibroblasts or NSCs were able to self-renew and expressed pluripotency-associated markers, they exhibited poor differentiation potential into mature somatic tissues, similar to Dgcr8(-/-) embryonic stem cells. The differentiation defects could be rescued with expression of DGCR8 cDNA. Our data demonstrate that while miRNA activity as a whole facilitates reprogramming, canonical miRNA may be dispensable in the derivation of iPSCs. PMID- 26651606 TI - A Dynamic Role of TBX3 in the Pluripotency Circuitry. AB - Pluripotency represents a cell state comprising a fine-tuned pattern of transcription factor activity required for embryonic stem cell (ESC) self renewal. TBX3 is the earliest expressed member of the T-box transcription factor family and is involved in maintenance and induction of pluripotency. Hence, TBX3 is believed to be a key member of the pluripotency circuitry, with loss of TBX3 coinciding with loss of pluripotency. We report a dynamic expression of TBX3 in vitro and in vivo using genetic reporter tools tracking TBX3 expression in mouse ESCs (mESCs). Low TBX3 levels are associated with reduced pluripotency, resembling the more mature epiblast. Notably, TBX3-low cells maintain the intrinsic capability to switch to a TBX3-high state and vice versa. Additionally, we show TBX3 to be dispensable for induction and maintenance of naive pluripotency as well as for germ cell development. These data highlight novel facets of TBX3 action in mESCs. PMID- 26651607 TI - Notch-Dependent Pituitary SOX2(+) Stem Cells Exhibit a Timed Functional Extinction in Regulation of the Postnatal Gland. AB - Although SOX2(+) stem cells are present in the postnatal pituitary gland, how they are regulated molecularly and whether they are required for pituitary functions remain unresolved questions. Using a conditional knockout animal model, here we demonstrate that ablation of the canonical Notch signaling in the embryonic pituitary gland leads to progressive depletion of the SOX2(+) stem cells and hypoplastic gland. Furthermore, we show that the SOX2(+) stem cells initially play a significant role in contributing to postnatal pituitary gland expansion by self-renewal and differentiating into distinct lineages in the immediate postnatal period. However, we found that within several weeks postpartum, the SOX2(+) stem cells switch to an essentially dormant state and are no longer required for homeostasis/tissue adaptation. Our results present a dynamic tissue homeostatic model in which stem cells provide an initial contribution to the growth of the neonatal pituitary gland, whereas the mature gland can be maintained in a stem cell-independent fashion. PMID- 26651609 TI - Characterizing the Lower Paleolithic bone industry from Schoningen 12 II: A multi proxy study. AB - Although preservation of Paleolithic faunal assemblages from open-air settings is often poor, the Lower Paleolithic sites of Schoningen provide exceptionally well preserved mammalian faunal material for investigating hominin/animal relationships. Pleistocene fossil assemblages, however, usually reflect a complex taphonomic history in which natural and anthropogenic processes are often superimposed. A number of examples of osseous finds that resemble tools were recently discovered in the MIS 9 deposits of Schoningen 12 II. Non-anthropogenic agents are known to produce surface modifications mimicking human artifacts and the identification of osseous remains used and/or deliberately modified by ancient hominins is often controversial in such old contexts. Multiple lines of evidence are thus useful for distinguishing between osseous artifacts and "eco facts". In this paper, the recognition of the use of bone for different technological purposes by late Middle Pleistocene hominins is addressed through a multi-proxy study combining geoarcheology, bone taphonomy, zooarcheology, and use wear analysis. This allowed the identification of the processes and agents responsible for the formation and modification of the different bone assemblages of Schoningen 12 II. Our analysis points to different types of bones having been likely used as tools. These results expand the diversity of the organic technological repertoire of the Middle Pleistocene hominins, making Schoningen 12 II a remarkable new source of information on osseous technology long before the Upper Paleolithic, the period traditionally viewed as the start of the systematic use of bone tools. Together with other observations of bone tools documented during the Lower and Middle Paleolithic, the results from Schoningen show that archeologists may have underestimated the diversity and importance of osseous technology among archaic hominins. PMID- 26651608 TI - Non-genetic Purification of Ventricular Cardiomyocytes from Differentiating Embryonic Stem Cells through Molecular Beacons Targeting IRX-4. AB - Isolation of ventricular cardiomyocytes (vCMs) has been challenging due to the lack of specific surface markers. Here we show that vCMs can be purified from differentiating mouse embryonic stem cells (mESCs) using molecular beacons (MBs) targeting specific intracellular mRNAs. We designed MBs (IRX4 MBs) to target mRNA encoding Iroquois homeobox protein 4 (Irx4), a transcription factor specific for vCMs. To purify mESC vCMs, IRX4 MBs were delivered into cardiomyogenically differentiating mESCs, and IRX4 MBs-positive cells were FACS-sorted. We found that, of the cells isolated, ~98% displayed vCM-like action potentials by electrophysiological analyses. These MB-purified vCMs continuously maintained their CM characteristics as verified by spontaneous beating, Ca(2+) transient, and expression of vCM-specific proteins. Our study shows the feasibility of isolating pure vCMs via cell sorting without modifying host genes. The homogeneous and functional ventricular CMs generated via the MB-based method can be useful for disease investigation, drug discovery, and cell-based therapies. PMID- 26651610 TI - Immunoglobulin Concentrations in Plasma and Saliva During the Neonatal Period. AB - BACKGROUND: Screening for infectious diseases in newborns using immunoglobulin (Ig)A-, IgM-, and IgE-specific antibodies is expensive and impractical. To determine if total levels of these Igs can be used for screening purposes, thus simplifying the process, their basic levels in the 1(st) month of extrauterine life need to be determined. Additionally, the ability to simplify screening by using saliva also needs to be determined. The aim of this study was to determine IgA, IgM, and IgE concentrations in plasma and saliva in newborns, correlation between the samples, and relationship between Ig levels and newborn age. METHODS: We enrolled 53 apparently healthy newborns, paired samples of plasma and saliva were collected, and total IgA, IgM, and IgE concentrations determined by capture enzyme-linked immunosorbent assay. The correlation between plasma and saliva values was calculated by Spearman's rank correlation coefficient and the IgA, IgM, and IgE distributions were analyzed by the Shapiro-Wilk test. We also determined the level of each Ig concentration according to age. RESULTS: IgA and IgM levels in plasma and IgA levels in saliva increased significantly during 1(st) month of life, especially in the 2(nd) week and 3(rd) week, with a good correlation of IgA between plasma and saliva. IgE levels in both plasma and saliva and IgM levels in saliva were very low or absent. CONCLUSION: These results suggest that Igs in saliva could be good biomarkers for newborn screening programs during the 1(st) week of life. This study established reference values for Igs according to age in the neonatal period. PMID- 26651611 TI - Differential Impact of Pulmonary Regurgitation on Patients With Surgically Repaired Pulmonary Stenosis Versus Tetralogy of Fallot. AB - Patients with repaired pulmonary stenosis (PS) or tetralogy of Fallot (TOF) both develop pulmonary regurgitation (PR) leading to right ventricular (RV) dilatation and dysfunction. We aimed to characterize differential effects of chronic PR in these populations. Patients with surgically repaired PS were matched 1:2 by age and PR fraction with patients with TOF. Patients with previous pulmonary valve replacement were excluded. Cardiovascular magnetic resonance data were compared; peak longitudinal and circumferential systolic strain by feature tracking were compared to evaluate differential contribution of the RV sinus and outflow tract, respectively. PS (n = 24, 41 +/- 13 years old) and TOF (n = 47, 39 +/- 13 years old) patients did not differ in RV end-diastolic volume (153 +/- 45 vs 154 +/- 45 ml/m(2), p = 0.99) or diastolic function. However, patients with PS had preserved RV ejection fraction (54.3 +/- 4.4% vs 48.0 +/- 7.1%, p <0.0001). Differences were greater in RV circumferential (-15.8 +/- 3.3 vs -11.8 +/- 3.4, p <0.0001) than longitudinal strain (-18.0 +/- 3.8 vs -15.9 +/- 3.8, p = 0.04), with particular decrease in the infundibulum (-17.4 +/- 7.5 vs -6.8 +/- 6.3, p <0.0001). Late gadolinium enhancement in the RV outflow tract was more frequent in patients with TOF (70.2% vs 45.8%, p = 0.001). In conclusion, surgical repair of PS leads to similar RV dilatation and diastolic dysfunction compared to patients with TOF, but differential effects on ventricular systolic function, largely related to differences in the outflow tract. With different patterns of scarring and ventricular remodeling, further study is needed to clarify whether criteria for pulmonary valve replacement in patients with PS should differ from those with TOF. PMID- 26651612 TI - Oral Administration of Sustained Release Niacin Inhibits Platelet Aggregation. AB - BACKGROUND: Previous studies have suggested that niacin may have antiplatelet properties, however the effects of niacin on the platelet activity are not well defined. OBJECTIVE: The purpose of this trial was to investigate whether the oral administration of niacin inhibits platelet aggregation. METHOD: This study was run in three segments measuring the inhibitory effect of niacin: 1) 3 mmol/L niacin in vitro, 2) one hour after 1-gram sustained-release (SR) niacin administration, 3) twelve hours after 2-gram SR niacin administration. Platelet aggregation was measured using the VerifyNow-Aspirin and whole blood impedance aggregometry. RESULTS: Preincubation with niacin resulted in a significant inhibition of platelet aggregation. Significant inhibition of platelet aggregation was found one hour following the oral administration of 1 gram of SR niacin while the oral administration of a 2 gram dose of SR niacin did not produce significant platelet inhibition when platelet aggregation was measured 12 hours after the dose. CONCLUSION: Niacin has a small, direct effect on platelet aggregation. Niacin platelet inhibition is transient and may dissipate as it is converted into metabolites. The clinical significance is unknown. PMID- 26651613 TI - Uric acid is associated with microalbuminuria and decreased glomerular filtration rate in the general population during 7 and 13 years of follow-up: The Tromso Study. AB - BACKGROUND: The role of uric acid in development of renal dysfunction (RD) remains controversial. Earlier studies have reported inconsistent results, possibly because of their varying ability to adjust for confounding. The impact of longitudinal change in uric acid on renal outcome has not been assessed previously. We aimed to study the impact of change in serum uric acid (SUA) as well as baseline SUA on the development of RD. METHODS: In a prospective cohort study, we assessed the associations between change in SUA during follow-up, baseline SUA and RD (defined as albumin-creatinine-ratio (ACR) >=1.13 mg albumin/mmol creatinine and/or eGFR < 60 ml/min/1.73 m(2)) in a large cohort from a general population participating in the Tromso Study (n = 2637). Participants were stratified according to tertiles of change in SUA between baseline (1994/95) and follow-up 13 years later. (upper tertile: SUA increasing group, two lower tertiles: SUA non-increasing group). Logistic regression analysis was applied with RD and each component of RD after 7 and 13 years as the dependent variables. Adjustments were made for baseline eGFR, cardiovascular risk factors, and the use of antihypertensive drugs including diuretics. RESULTS: After excluding participants with RD at baseline, SUA increasers, compared to SUA non-increasers, had a doubled risk of RD after 7 years (odds ratio 2.00, (95 % CI 1.45, 2.75)). Odds ratio for RD in SUA increasers after 13 years was 2.18 (95 % CI 1.71, 2.79). The risk of developing ACR >=1.13 mg/mmol alone was not significantly increased after 7 years (odds ratio 1.30 (95 % CI 0.90, 1.89), but after 13 years (odds ratio 1.43 (95 % CI 1.09, 1.86)). An increase in baseline SUA of 59 MUmol/L (1 mg/dL) gave an odds ratio for RD after 13 years of 1.16 (95 % CI 1.04, 1.29). CONCLUSION: An increase in SUA during follow-up was associated with an increased risk of developing RD after 7 and 13 years. PMID- 26651615 TI - Social inequalities in malaria knowledge, prevention and prevalence among children under 5 years old and women aged 15-49 in Madagascar. AB - BACKGROUND: Approximately 15 % of all deaths in Africa among children under five years old are due to malaria, a preventable and treatable disease. A prevailing sociological theory holds that resources (including knowledge, money, power, prestige, or beneficial social connections) are particularly relevant when diseases are susceptible to effective prevention. This study examines the role of socioeconomic inequalities by broadly predicting malaria knowledge and use of preventive technology among women aged 15-49, and malaria among children aged 6 59 months in Madagascar. METHODS: Data came from women aged 15-49 years (N = 8279) interviewed by Madagascar's 2011/2013 Malaria Indicator Studies, and their children aged under five years (N = 7644). Because geographic location may be associated with socioeconomic factors and exposure to malaria, multilevel models were used to account for unobserved geographic and administrative variation. Models also account for observed social, economic, demographic, and seasonal factors. RESULTS: Prevalence among children four years old and younger was 7.8 %. Results showed that both mother's education and household wealth strongly influence knowledge about and efforts to prevent and treat malaria. Analyses also revealed that the prevalence of malaria among children aged 6-59 months was determined by household wealth (richest vs poorest: OR = 0.25, 95 % CI [0.10, 0.64]) and maternal education (secondary vs none: OR = 0.51, 95 % CI [0.28, 0.95]). CONCLUSIONS: Malaria may be subject to socio-economic forces arising from a broad set of behavioural and geographic determinants, even after adjusting for geographic risk factors and seasonality. Nearly 21 % of the sample lacked primary schooling. To improve malaria reduction efforts, broad-based interventions may need to attack inequalities to ensure that knowledge, prevention and treatment are improved among those who are most vulnerable. PMID- 26651614 TI - Chemoprotection of murine hematopoietic cells by combined gene transfer of cytidine deaminase (CDD) and multidrug resistance 1 gene (MDR1). AB - BACKGROUND: Hematologic toxicity represents a major side effect of cytotoxic chemotherapy frequently preventing adequately dosed chemotherapy application and impeding therapeutic success. Transgenic (over)expression of chemotherapy resistance (CTX-R) genes in hematopoietic stem- and progenitor cells represents a potential strategy to overcome this problem. To apply this concept in the context of acute myeloid leukemia and myelodysplasia, we have investigated the overexpression of the multidrug resistance 1 (MDR1) and the cytidine deaminase (CDD) gene conferring resistance to anthracyclines and cytarabine (Ara-C), the two most important drugs in the treatment of these diseases. METHODS: State-of the-art, third generation, self-inactivating (SIN) lentiviral vectors were utilized to overexpress a human CDD-cDNA and a codon-optimized human MDR1-cDNA corrected for cryptic splice sites from a spleen focus forming virus derived internal promoter. Studies were performed in myeloid 32D cells as well as primary lineage marker negative (lin(-)) murine bone marrow cells and flow cytometric analysis of suspension cultures and clonogenic analysis of vector transduced cells following cytotoxic drug challenge were utilized as read outs. RESULTS: Efficient chemoprotection of CDD and MDR1 transduced hematopoietic 32D as well as primary lin(-) cells was proven in the context of Ara-C and anthracycline application. Both, CTX-R transduced 32D as well as primary hematopoietic cells displayed marked resistance at concentrations 5-20 times the LD50 of non transduced control cells. Moreover, simultaneous CDD/MDR1 gene transfer resulted in similar protection levels even when combined Ara-C anthracycline treatment was applied. Furthermore, significant enrichment of transduced cells was observed upon cytotoxic drug administration. CONCLUSIONS: Our data demonstrate efficient chemoprotection as well as enrichment of transduced cells in hematopoietic cell lines as well as primary murine hematopoietic progenitor cells following Ara-C and/or anthracycline application, arguing for the efficacy as well as feasibility of our approach and warranting further evaluation of this concept. PMID- 26651616 TI - Translating group programmes into online formats: establishing the acceptability of a parents' sex and relationships communication serious game. AB - BACKGROUND: With ongoing concerns about the sexual health and wellbeing of young people, there is increasing need to innovate intervention approaches. Engaging parents as agents to support their children, alongside capitalising on increasingly sophisticated technological options could jointly enhance support. Converting existing programmes into interactive game based options has the potential to broaden learning access whilst preserving behaviour change technique fidelity. However the acceptability of this approach and viability of adapting resources in this way is yet to be established. This paper reports on the process of converting an existing group programme ("What Should We Tell the Children?") and tests the acceptability within a community setting. METHODS: Translation of the original programme included selecting exercises and gathering user feedback on character and message framing preferences. For acceptability testing, parents were randomised to either the game (n = 106) or a control (non-interactive webpage) condition (n = 76). At time 1 all participants completed a survey on demographics, computer literacy and Theory of Planned Behaviour (TPB) items. Post intervention (time 2) users repeated the TPB questions in addition to acceptability items. Interviews (n = 17) were conducted 3 months post intervention to gather qualitative feedback on transfer of learning into real life. RESULTS: The process of conversion identified clear preferences for first person role play, home setting and realistic characters alongside positively phrased feedback. Evaluation results show that the game was acceptable to parents on cognitive and emotional dimensions, particularly for parents of younger children. Acceptability was not influenced by baseline demographics, computer skills or baseline TPB variables. MANOVA analysis and qualitative feedback suggest potential for effective translation of learning into real life. However attrition was more likely in the game condition, potentially due to feedback text volume. CONCLUSIONS: A manualised group programme can be viably converted into a serious game format which is both cognitively and emotionally acceptable. The intervention may be more effectively targeted at parents with younger children, and further game developments must particularly address information dosing. Establishing the viability of digitally converting a group programme is a significant step forward for implementation focused research. PMID- 26651618 TI - Modular Synthesis of Aromatic Hydrocarbon Macrocycles for Simplified, Single Layer Organic Light-Emitting Devices. AB - A method for the modular synthesis of aromatic hydrocarbon macrocycles has been developed for base materials in single-layer organic light-emitting devices. The method with Ir-catalyzed direct C-H borylation and Suzuki-Miyaura coupling was concise and scalable, which allowed for a gram-scale preparation of aromatic hydrocarbon macrocycles that have bulky substituents at the periphery. The new arylated hydrocarbon macrocycles enabled a quantitative electro-optical conversion in organic light-emitting devices with a phosphorescent emitter, which is, notably, in a single-layer architecture consisting of two regions of doped and undoped materials. The highest external quantum efficiencies reached 24.8%, surpassing those of previous hydrocarbon base materials. PMID- 26651617 TI - Improved taxonomic assignment of human intestinal 16S rRNA sequences by a dedicated reference database. AB - BACKGROUND: Current sequencing technology enables taxonomic profiling of microbial ecosystems at high resolution and depth by using the 16S rRNA gene as a phylogenetic marker. Taxonomic assignation of newly acquired data is based on sequence comparisons with comprehensive reference databases to find consensus taxonomy for representative sequences. Nevertheless, even with well-characterised ecosystems like the human intestinal microbiota it is challenging to assign genus and species level taxonomy to 16S rRNA amplicon reads. A part of the explanation may lie in the sheer size of the search space where competition from a multitude of highly similar sequences may not allow reliable assignation at low taxonomic levels. However, when studying a particular environment such as the human intestine, it can be argued that a reference database comprising only sequences that are native to the environment would be sufficient, effectively reducing the search space. RESULTS: We constructed a 16S rRNA gene database based on high quality sequences specific for human intestinal microbiota, resulting in curated data set consisting of 2473 unique prokaryotic species-like groups and their taxonomic lineages, and compared its performance against the Greengenes and Silva databases. The results showed that regardless of used assignment algorithm, our database improved taxonomic assignation of 16S rRNA sequencing data by enabling significantly higher species and genus level assignation rate while preserving taxonomic diversity and demanding less computational resources. CONCLUSION: The curated human intestinal 16S rRNA gene taxonomic database of about 2500 species like groups described here provides a practical solution for significantly improved taxonomic assignment for phylogenetic studies of the human intestinal microbiota. PMID- 26651619 TI - Police training in interviewing and interrogation methods: A comparison of techniques used with adult and juvenile suspects. AB - Despite empirical progress in documenting and classifying various interrogation techniques, very little is known about how police are trained in interrogation methods, how frequently they use various techniques, and whether they employ techniques differentially with adult versus juvenile suspects. This study reports the nature and extent of formal (e.g., Reid Technique, PEACE, HUMINT) and informal interrogation training as well as self-reported technique usage in a diverse national sample (N = 340) of experienced American police officers. Officers were trained in a variety of different techniques ranging from comparatively benign pre-interrogation strategies (e.g., building rapport, observing body language or speech patterns) to more psychologically coercive techniques (e.g., blaming the victim, discouraging denials). Over half the sample reported being trained to use psychologically coercive techniques with both adults and juveniles. The majority (91%) receive informal, "on the job" interrogation training. Technique usage patterns indicate a spectrum of psychological intensity where information-gathering approaches were used most frequently and high-pressure tactics less frequently. Reid-trained officers (56%) were significantly more likely than officers without Reid training to use pre interrogation and manipulation techniques. Across all analyses and techniques, usage patterns were identical for adult and juvenile suspects, suggesting that police interrogate youth in the same manner as adults. Overall, results suggest that training in specific interrogation methods is strongly associated with usage. Findings underscore the need for more law enforcement interrogation training in general, especially with juvenile suspects, and highlight the value of training as an avenue for reducing interrogation-induced miscarriages of justice. (PsycINFO Database Record PMID- 26651620 TI - The clinical usefulness of the DSM-5 specifier for conduct disorder outside of a research context. AB - The Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5) specifier 'with Limited Prosocial Emotions' (LPE) is expected to provide information about impairment of adolescents with conduct disorder (CD) and to designate a severe subgroup of antisocial youths. This study is the first to scrutinize the clinical usefulness of this LPE specifier outside of a research context. Standardized questionnaires and diagnostic interviews were administered to 380 detained boys as part of a clinical protocol. Boys with CD that met criteria for the LPE specifier did not significantly differ from CD boys without LPE on any of the variables of interest. When using a CD diagnosis by itself (that is, without linking it to the LPE specifier) boys with CD were significantly more psychiatrically disturbed, rule-breaking, reactively and proactively aggressive, and reported more violent and nonviolent offenses than boys without CD. These differences were also revealed while using the LPE specifier by itself (that is, without linking it to a CD diagnosis). Additional analyses, nevertheless, showed that the magnitude of the group differences was strong when using a CD diagnosis by itself, but weak to moderate when using the LPE specifier by itself, or when incorporating the LPE specifier into a diagnosis of CD as recommended by the DSM-5. Altogether, this study suggests that incorporating the LPE specifier into CD is of restricted usefulness to discriminate between detained boys with varying levels of psychiatric problems and antisocial behavior. Interestingly, a CD diagnosis by itself seems the most clinically useful measure to identify a troubled group of detained boys. (PsycINFO Database Record PMID- 26651621 TI - Psychometric properties of the Hare Psychopathy Checklist-Revised (PCL-R) in a representative sample of Canadian federal offenders. AB - The Hare Psychopathy Checklist-Revised (PCL-R; Hare, 2003) is a commonly used psychological test for assessing traits of psychopathic personality disorder. Despite the abundance of research using the PCL-R, the vast majority of research used samples of convenience rather than systematic methods to minimize sampling bias and maximize the generalizability of findings. This potentially complicates the interpretation of test scores and research findings, including the "norms" for offenders from the United States and Canada included in the PCL-R manual. In the current study, we evaluated the psychometric properties of PCL-R scores for all male offenders admitted to a regional reception center of the Correctional Service of Canada during a 1-year period (n = 375). Because offenders were admitted for assessment prior to institutional classification, they comprise a sample that was heterogeneous with respect to correctional risks and needs yet representative of all offenders in that region of the service. We examined the distribution of PCL-R scores, classical test theory indices of its structural reliability, the factor structure of test items, and the external correlates of test scores. The findings were highly consistent with those typically reported in previous studies. We interpret these results as indicating it is unlikely any sampling limitations of past research using the PCL-R resulted in findings that were, overall, strongly biased or unrepresentative. PMID- 26651622 TI - The dynamic nature of interrogation. AB - Building on a substantial body of literature examining interrogation methods employed by police investigators and their relationship to suspect behaviors, we analyzed a sample of audio and video interrogation recordings of individuals suspected of serious violent crimes. Existing survey research has focused on the tactics reportedly used, at what rate, and under what conditions; observational studies detail which methods are actually employed. With a few notable exceptions, these foundational studies were static examinations of interrogation methods that documented the absence or presence of various approaches. In the present study, we cast interrogation as a dynamic phenomenon and code the recordings in 5-min intervals to examine how interrogation methods and suspect cooperation change over time. Employing the interrogation taxonomy framework, particularly 4 discrete domains-rapport and relationship building, emotion provocation, presentation of evidence, and confrontation/competition-we found that the emphasis of the domains varied across interrogations and were significantly different when suspects confessed versus when they denied involvement. In regression models, suspect cooperation was positively influenced by the rapport and relationship building domain, though it was negatively impacted by presentation of evidence and confrontation/competition. Moreover, we found that the negative effects of confrontation/competition on suspect cooperation lasted for up to 15 min. The implications of the findings for practice and future research include the benefits of a rapport-based approach, the deleterious effects of accusatorial methods, and the importance of studying when, not just if, certain interrogation techniques are employed. (PsycINFO Database Record PMID- 26651623 TI - GOLD: Its Good Points. PMID- 26651624 TI - Comparison of Costs and Clinical Outcomes Between Hospital and Outpatient Administration of Omalizumab in Patients With Severe Uncontrolled Asthma. AB - OBJECTIVES: To compare clinical outcomes and costs between two administration strategies of omalizumab treatment. METHOD: We evaluated two cohorts of patients with uncontrolled severe asthma over a 1-year period. Patients received the treatment in the primary care center in Hospital A and conventional hospital administration in Hospital B. RESULTS: We studied 130 patients, 86 in Hospital A and 44 in Hospital B, 30 men (24%) and 100 women (76%), age 50 +/- 15 years, FEV1% 67 +/- 22%, body mass index (BMI) 28 +/- 6 kg/m(2), 639 +/- 747 UI IgE/mL, followed for 24 +/- 11 months (12-45), Asthma Control Test (ACT) score 12 +/- 4 and Asthma Control Questionnaire (ACQ) 3 +/- 2. There were no significant pretreatment differences between the groups in hospital admissions and emergency room visits in the previous year, nor in proportion of patients receiving oral steroids. Evaluations were performed at baseline and after 12 months of treatment, revealing significant differences in ACT (P<0.001), ACQ (P<0.001), improvement in FEV1% (P<0.001), reduction in total admissions (P<0.001), days of hospitalization (P<0.001), emergency room visits (P<0.001), cycles and doses of oral steroids (P<0.001) compared to the previous year. Hospitalization costs, emergency room visits, unscheduled visits to primary care and to the pulmonologist were significantly reduced in each hospital and on the whole, but administration and travel costs were 35% lower in the ambulatory strategy adopted in Hospital A. CONCLUSION: The administration of omalizumab in ambulatory health centers achieved the same clinical results as a hospital administration strategy, but with lower costs. PMID- 26651626 TI - Gastric cancer: Geographic differences in multidisciplinary management. PMID- 26651625 TI - Utility of Induced Sputum in Routine Clinical Practice. AB - OBJECTIVE: To determine the general and specific utility in diagnosis and/or treatment of induced sputum (IS) inflammatory cell counts in routine clinical practice. METHODS: Retrospective study of 171 patients referred for clinical sputum induction over a 1-year period in the pulmonology department of a referral hospital. Independent observers established whether the information provided by IS inflammatory cell count was useful for making diagnostic and therapeutic decisions. RESULTS: The most frequent reasons for determination of IS inflammatory cell count were: asthma 103 (59.20%); uncontrolled asthma 34 (19.54%); chronic cough 19 (10.9%), and gastroesophageal reflux 15 (8.6%). In 115 patients (67.3%) it was generally useful for diagnosis and/or treatment; in 98 patients (57.3%) it provided diagnostic information and in 85 patients (49.7%) it assisted in therapeutic decision-making. In asthma, uncontrolled asthma, chronic cough and gastroesophageal reflux, the results were useful in 71.8%, 67.6%, 47.4% and 60%, respectively. CONCLUSION: The information provided by IS inflammatory cell count is extremely useful in clinical practice, especially in asthma and chronic cough. These results may justify the inclusion of the IS technique in pulmonology departments and asthma units of referral centers. PMID- 26651627 TI - Attainability of Carnot efficiency with autonomous engines. AB - The maximum efficiency of autonomous engines with a finite chemical potential difference is investigated. We show that, without a particular type of singularity, autonomous engines cannot attain the Carnot efficiency. This singularity is realized in two ways: single particle transports and the thermodynamic limit. We demonstrate that both of these ways actually lead to the Carnot efficiency in concrete setups. Our results clearly illustrate that the singularity plays a crucial role in the maximum efficiency of autonomous engines. PMID- 26651628 TI - Phase behavior near and beyond the thermodynamic stability threshold. AB - The phase behavior of stabilized dispersions of macromolecules is most easily described in terms of the effective interaction between the centers of mass of solute particles. For molecules such as polymer chains, dendrimers, etc., the effective pair potential is finite at the origin, allowing "particles" to freely interpenetrate each other. Using a double-Gaussian model (DGM) for demonstration, we study the behavior of the system as a function of the attraction strength eta. Above a critical strength eta(c), the infinite-size system is Ruelle unstable, in that it collapses to a cluster of finite volume. As eta(c) is approached from below, the liquid-vapor region exhibits an anomalous widening at low temperature, and the liquid density apparently diverges at the stability threshold. Above eta(c), the thermodynamic plane is divided in two regions, differing in the value of the average waiting time for collapse, being finite and small on one side of the boundary line, while large or even infinite in the other region. Upon adding a small hard core to the DGM potential, stability is fully recovered and the boundary line is converted to the spinodal line of a transition between fluid phases. We argue that the destabilization of a colloidal dispersion, as induced by the addition of salt or other flocculant, finds a suggestive analogy in the process by which a strengthening of the attraction pushes a stabilized-DGM system inside the fluid-fluid spinodal region. PMID- 26651629 TI - Kerr effect at high electric field in the isotropic phase of mesogenic materials. AB - The well-known Kerr effect in isotropic fluids consists in the appearance of uniaxial orientational order and birefringence that grows as the square of the applied electric field. We predict and observe that at a high electric field, the Kerr effect displays features caused by the nonlinear dependence of dielectric permittivity on the field-induced orientational order parameter. Namely, the field-induced birefringence grows faster than the square of the electric field and the dynamics of birefringence growth slows down as the field increases. As a function of temperature, the field-induced birefringence is inversely proportional to the departure from an asymptotic critical temperature, but this temperature is no longer a constant (corresponding to the lower limit of the supercooled isotropic phase) and increases proportionally to the square of the electric field. PMID- 26651630 TI - Nanoscale engineering of two-dimensional disordered hyperuniform block-copolymer assemblies. AB - Disordered hyperuniform (DH) media have been recognized as a new state of disordered matter that broadens our vision of material engineering. Here, long range correlated disordered two-dimensional patterns are fabricated by self assembling of spherical diblock-copolymer (BCP) micelles. Control of the self assembling parameters leads to the formation of DH patterns of micelles that can host nanoscale material inclusions, therefore providing an effective strategy for fabricating multimaterial DH structures at molecular scale. Centroidal patterns are accurately determined by virtue of BCP micelles loaded with metal nanoparticles. Our analysis reveals the signature of nearly ideal DH BCP assemblies in the local density fluctuation and a dominant linear scaling in the local number fluctuation. PMID- 26651631 TI - Amoeboid motion in confined geometry. AB - Many eukaryotic cells undergo frequent shape changes (described as amoeboid motion) that enable them to move forward. We investigate the effect of confinement on a minimal model of amoeboid swimmer. A complex picture emerges: (i) The swimmer's nature (i.e., either pusher or puller) can be modified by confinement, thus suggesting that this is not an intrinsic property of the swimmer. This swimming nature transition stems from intricate internal degrees of freedom of membrane deformation. (ii) The swimming speed might increase with increasing confinement before decreasing again for stronger confinements. (iii) A straight amoeoboid swimmer's trajectory in the channel can become unstable, and ample lateral excursions of the swimmer prevail. This happens for both pusher- and puller-type swimmers. For weak confinement, these excursions are symmetric, while they become asymmetric at stronger confinement, whereby the swimmer is located closer to one of the two walls. In this study, we combine numerical and theoretical analyses. PMID- 26651632 TI - Deterministic coherence resonance in coupled chaotic oscillators with frequency mismatch. AB - A small mismatch between natural frequencies of unidirectionally coupled chaotic oscillators can induce coherence resonance in the slave oscillator for a certain coupling strength. This surprising phenomenon resembles "stabilization of chaos by chaos," i.e., the chaotic driving applied to the chaotic system makes its dynamics more regular when the natural frequency of the slave oscillator is a little different than the natural frequency of the master oscillator. The coherence is characterized with the dominant component in the power spectrum of the slave oscillator, normalized standard deviations of both the peak amplitude and the interpeak interval, and Lyapunov exponents. The enhanced coherence is associated with increasing negative both the third and the fourth Lyapunov exponents, while the first and second exponents are always positive and zero, respectively. PMID- 26651633 TI - Recurrent noise-induced phase singularities in drifting patterns. AB - We show that the key ingredients for creating recurrent traveling spatial phase defects in drifting patterns are a noise-sustained structure regime together with the vicinity of a phase transition, that is, a spatial region where the control parameter lies close to the threshold for pattern formation. They both generate specific favorable initial conditions for local spatial gradients, phase, and/or amplitude. Predictions from the stochastic convective Ginzburg-Landau equation with real coefficients agree quite well with experiments carried out on a Kerr medium submitted to shifted optical feedback that evidence noise-induced traveling phase slips and vortex phase-singularities. PMID- 26651634 TI - Scaling laws for the bifurcation escape rate in a nanomechanical resonator. AB - We report on experimental and theoretical studies of the fluctuation-induced escape time from a metastable state of a nanomechanical Duffing resonator in a cryogenic environment. By tuning in situ the nonlinear coefficient gamma we could explore a wide range of the parameter space around the bifurcation point, where the metastable state becomes unstable. We measured in a relaxation process the distribution of the escape times. We have been able to verify its exponential distribution and extract the escape rate Gamma. We investigated the scaling of Gamma with respect to the distance to the bifurcation point and gamma, finding an unprecedented quantitative agreement with the theoretical description of the stochastic problem. Simple power scaling laws turn out to hold in a large region of the parameter space, as anticipated by recent theoretical predictions. These unique findings, implemented in a model dynamical system, are relevant to all systems experiencing underdamped saddle-node bifurcation. PMID- 26651635 TI - Chimeras in networks with purely local coupling. AB - Chimera states in spatially extended networks of oscillators have some oscillators synchronized while the remainder are asynchronous. These states have primarily been studied in networks with nonlocal coupling, and more recently in networks with global coupling. Here, we present three networks with only local coupling (diffusive, to nearest neighbors) which are numerically found to support chimera states. One of the networks is analyzed using a self-consistency argument in the continuum limit, and this is used to find the boundaries of existence of a chimera state in parameter space. PMID- 26651636 TI - Destabilization of rotating flows with positive shear by azimuthal magnetic fields. AB - According to Rayleigh's criterion, rotating flows are linearly stable when their specific angular momentum increases radially outward. The celebrated magnetorotational instability opens a way to destabilize those flows, as long as the angular velocity is decreasing outward. Using a local approximation we demonstrate that even flows with very steep positive shear can be destabilized by azimuthal magnetic fields which are current free within the fluid. We illustrate the transition of this instability to a rotationally enhanced kink-type instability in the case of a homogeneous current in the fluid, and discuss the prospects for observing it in a magnetized Taylor-Couette flow. PMID- 26651637 TI - Role of helicity for large- and small-scale turbulent fluctuations. AB - The effects of the helicity on the dynamics of turbulent flows are investigated. The aim is to disentangle the role of helicity in fixing the direction, the intensity, and the fluctuations of the energy transfer across the inertial range of scales. We introduce an external parameter alpha that controls the mismatch between the number of positive and negative helically polarized Fourier modes. We present direct numerical simulations of Navier-Stokes equations from the fully symmetrical case, alpha=0, to the fully asymmetrical case, alpha=1, when only helical modes of one sign survive. We found a singular dependency of the direction of the energy cascade on alpha, measuring a positive forward flux as soon as only a few modes with different helical polarities are present. Small scale fluctuations are also strongly sensitive to the degree of mode reduction, leading to a vanishing intermittency already for values of alpha~0.1. If the analysis is restricted to sets of modes with the same helicity sign, intermittency is vanishing for the modes belonging to the minority set, and it is close to that measured on the original Navier-Stokes equations for the other set. PMID- 26651638 TI - Observation of Rayleigh-Taylor-instability evolution in a plasma with magnetic and viscous effects. AB - We present time-resolved observations of Rayleigh-Taylor-instability (RTI) evolution at the interface between an unmagnetized plasma jet colliding with a stagnated, magnetized plasma. The observed instability growth time (~10 MUs) is consistent with the estimated linear RTI growth rate calculated using experimentally inferred values of density (~10(14) cm(-3)) and deceleration (~10(9) m/s(2)). The observed mode wavelength (?1 cm) nearly doubles within a linear growth time. Theoretical estimates of magnetic and viscous stabilization and idealized magnetohydrodynamic simulations including a physical viscosity model both suggest that the observed instability evolution is subject to magnetic and/or viscous effects. PMID- 26651639 TI - Electrostatic structure of a magnetized laser-produced plasma. AB - Measurements of the structure of the electrostatic fields produced by the expansion of a laser-produced plasma into a background magnetized plasma are presented. The three-dimensional measurements of the electrostatic field are made using an emissive probe that measures the time-varying plasma potential on two orthogonal planes, one across and one containing the background magnetic field. The inductive electric field is also calculated from probe measurements of the time-varying magnetic fields. Deviations from local charge neutrality at the level of 10(-4) generate a radial electrostatic field with peak strength an order of magnitude larger than the corresponding inductive field. The electrostatic energy density near full expansion is over an order of magnitude larger than that of the induced azimuthal electric field. These measurements show that electrostatic fields must be included in theoretical and computational models of collisionless coupling in magnetized point explosions of laser-produced plasmas and their relation to similar phenomena such as magnetospheric chemical releases. PMID- 26651640 TI - Micrometer-sized negative-ion accelerator based on ultrashort laser pulse interaction with transparent solids. AB - We report here energetic (>100 keV) negative hydrogen ions (H(-)) generated in the interaction of moderately intense (10(18) W cm(-2)) ultrashort laser pulses (45 fs) with transparent hydrogen containing solid targets. An unambiguous and consistent detection of negative hydrogen ions, with a flux of 8*10(11)H(-) ions/sr, has been observed in every single laser shot, using a Thomson parabola ion spectrograph. Simple estimates based on charge transfer cross sections match well with experimental observations. Our method offers the implementation of an intense, ultrashort laser based negative-ion source at a higher repetition rate, which can be important for various applications. PMID- 26651641 TI - Information geometry and the renormalization group. AB - Information theoretic geometry near critical points in classical and quantum systems is well understood for exactly solvable systems. Here, we show that renormalization group flow equations can be used to construct the information metric and its associated quantities near criticality for both classical and quantum systems in a universal manner. We study this metric in various cases and establish its scaling properties in several generic examples. Scaling relations on the parameter manifold involving scalar quantities are studied, and scaling exponents are identified. The meaning of the scalar curvature and the invariant geodesic distance in information geometry is established and substantiated from a renormalization group perspective. PMID- 26651642 TI - Landauer's blowtorch effect as a thermodynamic cross process: Brownian cooling. AB - The local heating of a selected region in a double-well potential alters the relative stability of the two wells and gives rise to an enhancement of population transfer to the cold well. We show that this Landauer's blowtorch effect may be considered in the spirit of a thermodynamic cross process linearly connecting the flux of particles and the thermodynamic force associated with the temperature difference and consequently ensuring the existence of a reverse cross effect. This reverse effect is realized by directing the thermalized particles in a double-well potential by application of an external bias from one well to the other, which suffers cooling. PMID- 26651643 TI - Reentrant disorder-disorder transitions in generalized multicomponent Widom Rowlinson models. AB - In the lattice version of the multicomponent Widom-Rowlinson (WR) model, each site can be either empty or singly occupied by one of M different particles, all species having the same fugacity z. The only nonzero interaction potential is a nearest-neighbor hard-core exclusion between unlike particles. For Mz(d) (M). If M>=M(0), there is an intermediate ordered "crystal phase" (composed of two nonequivalent even and odd sublattices) for z lying between z(c)(M) and z(d)(M) which is driven by entropy. We generalize the multicomponent WR model by replacing the hard-core exclusion between unlike particles by more realistic large (but finite) repulsion. The model is solved exactly on the Bethe lattice with an arbitrary coordination number. The numerical calculations, based on the corner transfer matrix renormalization group, are performed for the two-dimensional square lattice. The results for M=4 indicate that the second-order phase transitions from the disordered gas to the demixed phase become of first order, for an arbitrarily large finite repulsion. The results for M>=M(0) show that, as the repulsion weakens, the region of the crystal phase diminishes itself. For weak enough repulsions, the direct transition between the crystal and demixed phases changes into a separate pair of crystal-gas and gas-demixed transitions; this is an example of a disorder-disorder reentrant transition via an ordered crystal phase. If the repulsion between unlike species is too weak, the crystal phase disappears from the phase diagram. It is shown that the generalized WR model belongs to the Ising universality class. PMID- 26651644 TI - Convergence of large-deviation estimators. AB - We study the convergence of statistical estimators used in the estimation of large-deviation functions describing the fluctuations of equilibrium, nonequilibrium, and manmade stochastic systems. We give conditions for the convergence of these estimators with sample size, based on the boundedness or unboundedness of the quantity sampled, and discuss how statistical errors should be defined in different parts of the convergence region. Our results shed light on previous reports of "phase transitions" in the statistics of free energy estimators and establish a general framework for reliably estimating large deviation functions from simulation and experimental data and identifying parameter regions where this estimation converges. PMID- 26651645 TI - Oscillating hysteresis in the q-neighbor Ising model. AB - We modify the kinetic Ising model with Metropolis dynamics, allowing each spin to interact only with q spins randomly chosen from the whole system, which corresponds to the topology of a complete graph. We show that the model with q>=3 exhibits a phase transition between ferromagnetic and paramagnetic phases at temperature T*, which linearly increases with q. Moreover, we show that for q=3 the phase transition is continuous and that it is discontinuous for larger values of q. For q>3, the hysteresis exhibits oscillatory behavior-expanding for even values of q and shrinking for odd values of q. Due to the mean-field-like nature of the model, we are able to derive the analytical form of transition probabilities and, therefore, calculate not only the probability density function of the order parameter but also precisely determine the hysteresis and the effective potential showing stable, unstable, and metastable steady states. Our results show that a seemingly small modification of the kinetic Ising model leads not only to the switch from a continuous to a discontinuous phase transition, but also to an unexpected oscillating behavior of the hysteresis and a puzzling phenomenon for q=5, which might be taken as evidence for the so-called mixed order phase transition. PMID- 26651646 TI - Identifying the order of a quantum phase transition by means of Wehrl entropy in phase space. AB - We propose a method to identify the order of a quantum phase transition by using area measures of the ground state in phase space. We illustrate our proposal by analyzing the well known example of the quantum cusp and four different paradigmatic boson models: Dicke, Lipkin-Meshkov-Glick, interacting boson model, and vibron model. PMID- 26651647 TI - Additivity property and emergence of power laws in nonequilibrium steady states. AB - We show that an equilibriumlike additivity property can remarkably lead to power law distributions observed frequently in a wide class of out-of-equilibrium systems. The additivity property can determine the full scaling form of the distribution functions and the associated exponents. The asymptotic behavior of these distributions is solely governed by branch-cut singularity in the variance of subsystem mass. To substantiate these claims, we explicitly calculate, using the additivity property, subsystem mass distributions in a wide class of previously studied mass aggregation models as well as in their variants. These results could help in the thermodynamic characterization of nonequilibrium critical phenomena. PMID- 26651648 TI - Nonequilibrium structure in sequential assembly. AB - The assembly of monomeric constituents into molecular superstructures through sequential-arrival processes has been simulated and theoretically characterized. When the energetic interactions allow for complete overlap of the particles, the model is equivalent to that of the sequential absorption of soft particles on a surface. In the present work, we consider more general cases by including arbitrary aggregating geometries and varying prescriptions of the connectivity network. The resulting theory accounts for the evolution and final-state configurations through a system of equations governing structural generation. We find that particle geometries differ significantly from those in equilibrium. In particular, variations of structural rigidity and morphology tune particle energetics and result in significant variation in the nonequilibrium distributions of the assembly in comparison to the corresponding equilibrium case. PMID- 26651649 TI - Recovering a stochastic process from super-resolution noisy ensembles of single particle trajectories. AB - Recovering a stochastic process from noisy ensembles of single-particle trajectories is resolved here using the coarse-grained Langevin equation as a model. The massive redundancy contained in single-particle tracking data allows recovering local parameters of the underlying physical model. We use several parametric and nonparametric estimators to compute the first and second moments of the process, to recover the local drift, its derivative, and the diffusion tensor, and to deconvolve the instrumental from the physical noise. We use numerical simulations to also explore the range of validity for these estimators. The present analysis allows defining what can exactly be recovered from statistics of super-resolution microscopy trajectories used for characterizing molecular trafficking underlying cellular functions. PMID- 26651650 TI - Continuity of the entropy of macroscopic quantum systems. AB - The proper definition of entropy is fundamental to the relationship between statistical mechanics and thermodynamics. It also plays a major role in the recent debate about the validity of the concept of negative temperature. In this paper, I analyze and calculate the thermodynamic entropy for large but finite quantum mechanical systems. A special feature of this analysis is that the thermodynamic energy of a quantum system is shown to be a continuous variable, rather than being associated with discrete energy eigenvalues. Calculations of the entropy as a function of energy can be carried out with a Legendre transform of thermodynamic potentials obtained from a canonical ensemble. The resultant expressions for the entropy are able to describe equilibrium between quantum systems having incommensurate energy-level spacings. This definition of entropy preserves all required thermodynamic properties, including satisfaction of all postulates and laws of thermodynamics. It demonstrates the consistency of the concept of negative temperature with the principles of thermodynamics. PMID- 26651651 TI - Quaternionic R transform and non-Hermitian random matrices. AB - Using the Cayley-Dickson construction we rephrase and review the non-Hermitian diagrammatic formalism [R. A. Janik, M. A. Nowak, G. Papp, and I. Zahed, Nucl. Phys. B 501, 603 (1997)], that generalizes the free probability calculus to asymptotically large non-Hermitian random matrices. The main object in this generalization is a quaternionic extension of the R transform which is a generating function for planar (noncrossing) cumulants. We demonstrate that the quaternionic R transform generates all connected averages of all distinct powers of X and its Hermitian conjugate X?: <<1/NTrX(a)X(?b)X(c)...>> for N->infinity. We show that the R transform for Gaussian elliptic laws is given by a simple linear quaternionic map R(z+wj)=x+sigma(2)(MUe(2iphi)z+wj) where (z,w) is the Cayley-Dickson pair of complex numbers forming a quaternion q=(z,w)=z+wj. This map has five real parameters Rex, Imx, phi, sigma, and MU. We use the R transform to calculate the limiting eigenvalue densities of several products of Gaussian random matrices. PMID- 26651652 TI - Correlation function for generalized Polya urns: Finite-size scaling analysis. AB - We describe a universality class for the transitions of a generalized Polya urn by studying the asymptotic behavior of the normalized correlation function C(t) using finite-size scaling analysis. X(1),X(2),... are the successive additions of a red (blue) ball [X(t)=1(0)] at stage t and C(t)=Cov[X(1),X(t+1)]/Var[X(1)]. Furthermore, z(t)=?(s=1)(t)X(s)/t represents the successive proportions of red balls in an urn to which, at the (t+1)th stage, a red ball is added [X(t+1)=1] with probability q[z(t)]=(tanh{J[2z(t)-1]+h}+1)/2, J>=0, and a blue ball is added [X(t+1)=0] with probability 1-q[z(t)]. A boundary [J(c)(h),h] exists in the (J,h) plane between a region with one stable fixed point and another region with two stable fixed points for q(z). C(t)~c+c'.t(l-1) with c=0(>0) for JJ(c)), and l is the (larger) value of the slope(s) of q(z) at the stable fixed point(s). On the boundary J=J(c)(h),C(t)?c+c'.(lnt)(-alpha')) and c=0(c>0), alpha'=1/2(1) for h=0 (h?0). The system shows a continuous phase transition for h=0 and C(t) behaves as C(t)?(lnt)(-alpha'))g[(1-l)lnt] with a universal function g(x) and a length scale 1/(1-l) with respect to lnt. beta=nu(||).alpha' holds with beta=1/2 and nu(||)=1. PMID- 26651653 TI - Fixed-point structure and effective fractional dimensionality for O(N) models with long-range interactions. AB - We study, by renormalization group methods, O(N) models with interactions decaying as power law with exponent d+sigma. When only the long-range momentum term p(sigma) is considered in the propagator, the critical exponents can be computed from those of the corresponding short-range O(N) models at an effective fractional dimension D(eff). Neglecting wave function renormalization effects the result for the effective dimension is D(eff)=2d/sigma, which turns to be exact in the spherical model limit (N->infinity). Introducing a running wave function renormalization term the effective dimension becomes instead D(eff)=(2 eta(SR))d/sigma. The latter result coincides with the one found using standard scaling arguments. Explicit results in two and three dimensions are given for the exponent nu. We propose an improved method to describe the full theory space of the models where both short- and long-range propagator terms are present and no a priori choice among the two in the renormalization group flow is done. The eigenvalue spectrum of the full theory for all possible fixed points is drawn and a full description of the fixed-point structure is given, including multicritical long-range universality classes. The effective dimension is shown to be only approximate, and the resulting error is estimated. PMID- 26651654 TI - Neutron fluctuations: The importance of being delayed. AB - The neutron population in a nuclear reactor is subject to fluctuations in time and in space due to the competition of diffusion by scattering, births by fission events, and deaths by absorptions. As such, fission chains provide a prototype model for the study of spatial clustering phenomena. In order for the reactor to be operated in stationary conditions at the critical point, the population of prompt neutrons instantaneously emitted at fission must be in equilibrium with the much smaller population of delayed neutrons, emitted after a Poissonian time by nuclear decay of the fissioned nuclei. In this work, we will show that the delayed neutrons, although representing a tiny fraction of the total number of neutrons in the reactor, actually have a key impact on the fluctuations, and their contribution is very effective in quenching the spatial clustering. PMID- 26651655 TI - Dynamical phase transitions in one-dimensional hard-particle systems. AB - We analyze a one-dimensional model of hard particles, within ensembles of trajectories that are conditioned (or biased) to atypical values of the time averaged dynamical activity. We analyze two phenomena that are associated with these large deviations of the activity: phase separation (at low activity) and the formation of hyperuniform states (at high activity). We consider a version of the model which operates at constant volume, and a version at constant pressure. In these nonequilibrium systems, differences arise between the two ensembles, because of the extra freedom available to the constant-pressure system, which can change its total density. We discuss the relationships between different ensembles, mechanical equilibrium, and the probability cost of rare density fluctuations. PMID- 26651656 TI - Anomalous behavior of the energy gap in the one-dimensional quantum XY model. AB - We reexamine the well-studied one-dimensional spin-1/2 XY model to reveal its nontrivial energy spectrum, in particular the energy gap between the ground state and the first excited state. In the case of the isotropic XY model, the XX model, the gap behaves very irregularly as a function of the system size at a second order transition point. This is in stark contrast to the usual power-law decay of the gap and is reminiscent of the similar behavior at the first order phase transition in the infinite-range quantum XY model. The gap also shows nontrivial oscillatory behavior for the phase transitions in the anisotropic model in the incommensurate phase. We observe a close relation between this anomalous behavior of the gap and the correlation functions. These results, those for the isotropic case in particular, are important from the viewpoint of quantum annealing where the efficiency of computation is strongly affected by the size dependence of the energy gap. PMID- 26651657 TI - Entropy production and the geometry of dissipative evolution equations. AB - Purely dissipative evolution equations are often cast as gradient flow structures, z =K(z)DS(z), where the variable z of interest evolves towards the maximum of a functional S according to a metric defined by an operator K. While the functional often follows immediately from physical considerations (e.g., the thermodynamic entropy), the operator K and the associated geometry does not necessarily do so (e.g., Wasserstein geometry for diffusion). In this paper, we present a variational statement in the sense of maximum entropy production that directly delivers a relationship between the operator K and the constraints of the system. In particular, the Wasserstein metric naturally arises here from the conservation of mass or energy, and depends on the Onsager resistivity tensor, which, itself, may be understood as another metric, as in the steepest entropy ascent formalism. This variational principle is exemplified here for the simultaneous evolution of conserved and nonconserved quantities in open systems. It thus extends the classical Onsager flux-force relationships and the associated variational statement to variables that do not have a flux associated to them. We further show that the metric structure K is intimately linked to the celebrated Freidlin-Wentzell theory of stochastically perturbed gradient flows, and that the proposed variational principle encloses an infinite-dimensional fluctuation dissipation statement. PMID- 26651658 TI - Linear response and modified fluctuation-dissipation relation in random potential. AB - In this work, a physical system described by the Hamiltonian H(omega)=H(0)+V(omega)(t) consisting of a solvable model H(0) and external random and time-dependent potential V(omega)(t) is investigated. Under the conditions in which, for each realization, the potential changes smoothly so that the evolution of the system follows the Schrodinger dynamics, and that the average external potential with respect to all realizations is constant in time, an adjusted equilibrium state can be defined as a reference state and the mean dynamics can be derived from taking the average of the equation with respect to the configuration parameter omega. It provides extra contributions from the deviations of the Hamiltonian and evolves the state along the time by the Heisenberg and Liouville-von Neumann equations. Consequently, the Kubo formula and the fluctuation-dissipation relation (FDR) are modified in the sense that the contribution from the information of randomness and memory effects from the time dependence is also present. The modified Kubo formula now has a contribution from two terms. The first term is an antisymmetric cross correlation between two observables measured by a probe as expected, and the latter term is an accumulation of the propagation of the effects from the randomness. When the considered system is in the adjusted equilibrium state at the time the measurement probe interacts, the latter contribution vanishes, and the standard FDR is recovered. PMID- 26651659 TI - Modulated escape from a metastable state driven by colored noise. AB - Many phenomena in nature are described by excitable systems driven by colored noise. The temporal correlations in the fluctuations hinder an analytical treatment. We here present a general method of reduction to a white-noise system, capturing the color of the noise by effective and time-dependent boundary conditions. We apply the formalism to a model of the excitability of neuronal membranes, the leaky integrate-and-fire neuron model, revealing an analytical expression for the linear response of the system valid up to moderate frequencies. The closed form analytical expression enables the characterization of the response properties of such excitable units and the assessment of oscillations emerging in networks thereof. PMID- 26651660 TI - Far-from-equilibrium distribution from near-steady-state work fluctuations. AB - A long-standing goal of nonequilibrium statistical mechanics has been to extend the conceptual power of the Boltzmann distribution to driven systems. We report some new progress towards this goal. Instead of writing the nonequilibrium steady state distribution in terms of perturbations around thermal equilibrium, we start from the linearized driven dynamics of observables about their stable fixed point, and expand in the strength of the nonlinearities encountered during typical fluctuations away from the fixed point. The first terms in this expansion retain the simplicity of known expansions about equilibrium, but can correctly describe the statistics of a certain class of systems even under strong driving. We illustrate this approach by comparison with a numerical simulation of a sheared Brownian colloid, where we find that the first two terms in our expansion are sufficient to account for the shear thinning behavior at high shear rates. PMID- 26651661 TI - Microscopic theory of heat transfer between two fermionic thermal baths mediated by a spin system. AB - In this paper we have presented the heat exchange between the two fermionic thermal reservoirs which are connected by a fermionic system. We have calculated the heat flux using solution of the c-number Langevin equation for the system. Assuming small temperature difference between the baths we have defined the thermal conductivity for the process. It first increases as a nonlinear function of average temperature of the baths to a critical value then decreases to a very low value such that the heat flux almost becomes zero. There is a critical temperature for the fermionic case at which the thermal conductivity is maximum for the given coupling strength and the width of the frequency distribution of bath modes. The critical temperature grows if these quantities become larger. It is a sharp contrast to the Bosonic case where the thermal conductivity monotonically increases to the limiting value. The change of the conductivity with increase in width of the frequency distribution of the bath modes is significant at the low temperature regime for the fermionic case. It is highly contrasting to the Bosonic case where the signature of the enhancement is very prominent at high temperature limit. We have also observed that thermal conductivity monotonically increases as a function of damping strength to the limiting value at the asymptotic limit. There is a crossover between the high and the low temperature results in the variation of the thermal conductivity as a function of the damping strength for the fermionic case. Thus it is apparent here that even at relatively high temperature, the fermionic bath may be an effective one for the strong coupling between system and reservoir. Another interesting observation is that at the low temperature limit, the temperature dependence of the heat flux is the same as the Stefan-Boltzmann law. This is similar to the bosonic case. PMID- 26651662 TI - General response formula and application to topological insulator in quantum open system. AB - It is well-known that the quantum linear response theory is based on the first order perturbation theory for a system in thermal equilibrium. Hence, this theory breaks down when the system is in a steady state far from thermal equilibrium and the response up to higher order in perturbation is not negligible. In this paper, we develop a nonlinear response theory for such quantum open system. We first formulate this theory in terms of general susceptibility, after which we apply it to the derivation of Hall conductance for open system at finite temperature. As an example, the Hall conductance of the two-band model is derived. Then we calculate the Hall conductance for a two-dimensional ferromagnetic electron gas and a two-dimensional lattice model. The calculations show that the transition points of topological phase are robust against the environment. Our results provide a promising platform for the coherent manipulation of the nonlinear response in quantum open system, which has potential applications for quantum information processing and statistical physics. PMID- 26651663 TI - Chaos and relaxation to equilibrium in systems with long-range interactions. AB - In the thermodynamic limit, systems with long-range interactions do not relax to equilibrium, but become trapped in nonequilibrium stationary states. For a finite number of particles a nonequilibrium state has a finite lifetime, so that eventually a system will relax to thermodynamic equilibrium. The time that a system remains trapped in a quasistationary state (QSS) scales with the number of particles as N(delta), with delta>0, and diverges in the thermodynamic limit. In this paper we will explore the role of chaotic dynamics on the time that a system remains trapped in a QSS. We discover that chaos, measured by the Lyapunov exponents, favors faster relaxation to equilibrium. Surprisingly, weak chaos favors faster relaxation than strong chaos. PMID- 26651664 TI - Relaxation dynamics of vortex lines in disordered type-II superconductors following magnetic field and temperature quenches. AB - We study the effects of rapid temperature and magnetic field changes on the nonequilibrium relaxation dynamics of magnetic vortex lines in disordered type-II superconductors by employing an elastic line model and performing Langevin molecular dynamics simulations. In a previously equilibrated system, either the temperature is suddenly changed or the magnetic field is instantaneously altered which is reflected in adding or removing flux lines to or from the system. The subsequent aging properties are investigated in samples with either randomly distributed pointlike or extended columnar defects, which allows us to distinguish the complex relaxation features that result from either type of pinning centers. One-time observables such as the radius of gyration and the fraction of pinned line elements are employed to characterize steady-state properties, and two-time correlation functions such as the vortex line height autocorrelations and their mean-square displacement are analyzed to study the nonlinear stochastic relaxation dynamics in the aging regime. PMID- 26651665 TI - Efficiency at and near maximum power of low-dissipation heat engines. AB - A universality in optimization of trade-off between power and efficiency for low dissipation Carnot cycles is presented. It is shown that any trade-off measure expressible in terms of efficiency and the ratio of power to its maximum value can be optimized independently of most details of the dynamics and of the coupling to thermal reservoirs. The result is demonstrated on two specific trade off measures. The first one is designed for finding optimal efficiency for a given output power and clearly reveals diseconomy of engines working at maximum power. As the second example we derive universal lower and upper bounds on the efficiency at maximum trade-off given by the product of power and efficiency. The results are illustrated on a model of a diffusion-based heat engine. Such engines operate in the low-dissipation regime given that the used driving minimizes the work dissipated during the isothermal branches. The peculiarities of the corresponding optimization procedure are reviewed and thoroughly discussed. PMID- 26651666 TI - Random walk with random resetting to the maximum position. AB - We study analytically a simple random walk model on a one-dimensional lattice, where at each time step the walker resets to the maximum of the already visited positions (to the rightmost visited site) with a probability r, and with probability (1-r), it undergoes symmetric random walk, i.e., it hops to one of its neighboring sites, with equal probability (1-r)/2. For r=0, it reduces to a standard random walk whose typical distance grows as ?n for large n. In the presence of a nonzero resetting rate 0infinity. However, the approach to this stationary distribution is accompanied by a dynamical phase transition, characterized by a weakly singular large deviation function. We also show that r=0 is a special "critical" point, for which the growth laws are different from the r->0 case and we calculate the exact crossover functions that interpolate between the critical (r=0) and the off critical (r->0) behavior for finite but large n. PMID- 26651667 TI - Optimal first-arrival times in Levy flights with resetting. AB - We consider the diffusive motion of a particle performing a random walk with Levy distributed jump lengths and subject to a resetting mechanism, bringing the walker to an initial position at uniformly distributed times. In the limit of an infinite number of steps and for long times, the process converges to superdiffusive motion with replenishment. We derive a formula for the mean first arrival time (MFAT) to a predefined target position reached by a meandering particle and we analyze the efficiency of the proposed searching strategy by investigating criteria for an optimal (a shortest possible) MFAT. PMID- 26651668 TI - Pond fractals in a tidal flat. AB - Studies over the past decade have reported power-law distributions for the areas of terrestrial lakes and Arctic melt ponds, as well as fractal relationships between their areas and coastlines. Here we report similar fractal structure of ponds in a tidal flat, thereby extending the spatial and temporal scales on which such phenomena have been observed in geophysical systems. Images taken during low tide of a tidal flat in Damariscotta, Maine, reveal a well-resolved power-law distribution of pond sizes over three orders of magnitude with a consistent fractal area-perimeter relationship. The data are consistent with the predictions of percolation theory for unscreened perimeters and scale-free cluster size distributions and are robust to alterations of the image processing procedure. The small spatial and temporal scales of these data suggest this easily observable system may serve as a useful model for investigating the evolution of pond geometries, while emphasizing the generality of fractal behavior in geophysical surfaces. PMID- 26651669 TI - Bulk and interfacial liquid water as a transient network. AB - The special macroscopic properties of liquid water stem from its structure as a complex network of molecules connected by hydrogen bonds. While the dynamics of single molecules within this network has been extensively investigated, only little attention has been paid to the closed loops (meshes) of hydrogen-bonded molecules which determine the network topology. Using molecular dynamics simulations we analyze the size, shape, geometrical arrangement, and dynamical stability of loops containing up to 10 hydrogen bonds. We find that six-membered loops in liquid water even at room temperature retain a striking similarity with the well-known structure of ice. Analyzing the network dynamics we find that rings of more than five hydrogen bonds are stabilized compared to a random collection containing the same number of single bonds. We finally show that in the vicinity of hydrophobic and hydrophilic interfaces loops arrange in a preferred orientation. PMID- 26651670 TI - Horizons and free-path distributions in quasiperiodic Lorentz gases. AB - We study the structure of quasiperiodic Lorentz gases, i.e., particles bouncing elastically off fixed obstacles arranged in quasiperiodic lattices. By employing a construction to embed such structures into a higher-dimensional periodic hyperlattice, we give a simple and efficient algorithm for numerical simulation of the dynamics of these systems. This same construction shows that quasiperiodic Lorentz gases generically exhibit a regime with infinite horizon, that is, empty channels through which the particles move without colliding, when the obstacles are small enough; in this case, the distribution of free paths is asymptotically a power law with exponent -3, as expected from infinite-horizon periodic Lorentz gases. For the critical radius at which these channels disappear, however, a new regime with locally finite horizon arises, where this distribution has an unexpected exponent of -5, previously observed only in a Lorentz gas formed by superposing three incommensurable periodic lattices in the Boltzmann-Grad limit where the radius of the obstacles tends to zero. PMID- 26651671 TI - Equivalent Markov processes under gauge group. AB - We have studied Markov processes on denumerable state space and continuous time. We found that all these processes are connected via gauge transformations. We have used this result before as a method to resolve equations, included the case in a previous work in which the sample space is time-dependent [Phys. Rev. E 90, 022125 (2014)]. We found a general solution through dilation of the state space, although the prior probability distribution of the states defined in this new space takes smaller values with respect to that in the initial problem. The gauge (local) group of dilations modifies the distribution on the dilated space to restore the original process. In this work, we show how the Markov process in general could be linked via gauge (local) transformations, and we present some illustrative examples for this result. PMID- 26651672 TI - Landauer's blow-torch effect in systems with entropic potential. AB - We consider local heating of a part of a two-dimensional bilobal enclosure of a varying cross section confining a system of overdamped Brownian particles. Since varying cross section in higher dimension results in an entropic potential in lower dimension, local heating alters the relative stability of the entropic states. We show that this blow-torch effect modifies the entropic potential in a significant way so that the resultant effective entropic potential carries both the features of variation of width of the confinement and variation of temperature along the direction of transport. The reduced probability distribution along the direction of transport calculated by full numerical simulations in two dimensions agrees well with our analytical findings. The extent of population transfer in the steady state quantified in terms of the integrated probability of residence of the particles in either of the two lobes exhibits interesting variation with the mean position of the heated region. Our study reveals that heating around two particular zones of a given lobe maximizes population transfer to the other. PMID- 26651673 TI - Neuromorphic behavior in percolating nanoparticle films. AB - We show that the complex connectivity of percolating networks of nanoparticles provides a natural solid-state system in which bottom-up assembly provides a route to realization of neuromorphic behavior. Below the percolation threshold the networks comprise groups of particles separated by tunnel gaps; an applied voltage causes atomic scale wires to form in the gaps, and we show that the avalanche of switching events that occurs is similar to potentiation in biological neural systems. We characterize the level of potentiation in the percolating system as a function of the surface coverage of nanoparticles and other experimentally relevant variables, and compare our results with those from biological systems. The complex percolating structure and the electric field driven switching mechanism provide several potential advantages in comparison to previously reported solid-state neuromorphic systems. PMID- 26651674 TI - Shot-noise Fano factor. AB - A variability measure of the times of uniform events based on a shot-noise process is proposed and studied. The measure is inspired by the Fano factor, which we generalize by considering the time-weighted influence of the events given by a shot-noise response function. The sequence of events is assumed to be an equilibrium renewal process, and based on this assumption we present formulas describing the behavior of the variability measure. The formulas are derived for a general response function, restricted only by some natural conditions, but the main focus is given to the shot noise with exponential decrease. The proposed measure is analyzed and compared with the Fano factor. PMID- 26651675 TI - Large deviation analysis of a simple information engine. AB - Information thermodynamics provides a framework for studying the effect of feedback loops on entropy production. It has enabled the understanding of novel thermodynamic systems such as the information engine, which can be seen as a modern version of "Maxwell's Daemon," whereby a feedback controller processes information gained by measurements in order to extract work. Here, we analyze a simple model of such an engine that uses feedback control based on measurements to obtain negative entropy production. We focus on the distribution and fluctuations of the information obtained by the feedback controller. Significantly, our model allows an analytic treatment for a two-state system with exact calculation of the large deviation rate function. These results suggest an approximate technique for larger systems, which is corroborated by simulation data. PMID- 26651676 TI - Association-dissociation process with aging subunits: Recursive solution. AB - The coupling of stochastic growth and shrinkage of one-dimensional structures to random aging of the constituting subunits defines the simple association dissociation-aging process which captures the essential features of the nonequilibrium assembly of cytoskeletal filaments. Because of correlations, previously employed mean-field methods fail to correctly describe filament growth. We study an alternative formulation of the full master equation of the stochastic process. An ansatz for the steady-state solution leads to a recursion relation which allows for the calculation of all emergent quantities with increasing accuracy and in excellent agreement with stochastic simulations. PMID- 26651677 TI - General formalism for singly thermostated Hamiltonian dynamics. AB - A general formalism is developed for constructing modified Hamiltonian dynamical systems which preserve a canonical equilibrium distribution by adding a time evolution equation for a single additional thermostat variable. When such systems are ergodic, canonical ensemble averages can be computed as dynamical time averages over a single trajectory. Systems of this type were unknown until their recent discovery by Hoover and colleagues. The present formalism should facilitate the discovery, construction, and classification of other such systems by encompassing a wide class of them within a single unified framework. This formalism includes both canonical and generalized Hamiltonian systems in a state space of arbitrary dimensionality (either even or odd) and therefore encompasses both few- and many-particle systems. Particular attention is devoted to the physical motivation and interpretation of the formalism, which largely determine its structure. An analogy to stochastic thermostats and fluctuation-dissipation theorems is briefly discussed. PMID- 26651678 TI - Generalized fluctuation theorems for classical systems. AB - The fluctuation theorem has a very special place in the study of nonequilibrium dynamics of physical systems. The form in which it is used most extensively is the Gallavoti-Cohen fluctuation theorem which is in terms of the distribution of the work p(W)/p(-W)=exp(alphaW). We derive the general form of the fluctuation theorems for an arbitrary multidimensional Gaussian Markov process. Interestingly, the parameter alpha is by no means universal, hitherto taken for granted in the case of linear Gaussian processes. As a matter of fact, conditions under which alpha does become a universal parameter 1/KT are found to be rather restrictive. As an application we consider fluctuation theorems for classical cyclotron motion of an electron in a parabolic potential. The motion of the electron is described by four coupled Langevin equations and thus is nontrivial. The generalized theorems are equally valid for nonequilibrium steady states and could be especially important in the presence of anisotropic diffusion. PMID- 26651679 TI - Percolation in spatial evolutionary prisoner's dilemma game on two-dimensional lattices. AB - We study the spatial evolutionary prisoner's dilemma game with updates of imitation max on triangular, hexagonal, and square lattices. We use the weak prisoner's dilemma game with a single parameter b. Due to the competition between the temptation value b and the coordination number z of the base lattice, a greater variety of percolation properties is expected to occur on the lattice with the larger z. From the numerical analysis, we find six different regimes on the triangular lattice (z=6). Regardless of the initial densities of cooperators and defectors, cooperators always percolate in the steady state in two regimes for small b. In these two regimes, defectors do not percolate. In two regimes for the intermediate value of b, both cooperators and defectors undergo percolation transitions. The defector always percolates in two regimes for large b. On the hexagonal lattice (z=3), there exist two distinctive regimes. For small b, both the cooperators and the defectors undergo percolation transitions while only defectors always percolate for large b. On the square lattice (z=4), there exist three regimes. Combining with the finite-size scaling analyses, we show that all the observed percolation transitions belong to the universality class of the random percolation. We also show how the detailed growth mechanism of cooperator and defector clusters decides each regime. PMID- 26651680 TI - Cascading blockages in channel bundles. AB - Flow in channel networks may involve a redistribution of flux following the blockage or failure of an individual link. Here we consider a simplified model consisting of N(c) parallel channels conveying a particulate flux. Particles enter these channels according to a homogeneous Poisson process and an individual channel blocks if more than N particles are simultaneously present. The behavior of the composite system depends strongly on how the flux of entering particles is redistributed following a blockage. We consider two cases. In the first, the intensity on each open channel remains constant while in the second the total intensity is evenly redistributed over the open channels. We obtain exact results for arbitrary N(c) and N for a system of independent channels and for arbitrary N(c) and N=1 for coupled channels. For N>1 we present approximate analytical as well as numerical results. Independent channels block at a decreasing rate due to a simple combinatorial effect, while for coupled channels the interval between successive blockages remains constant for N=1 but decreases for N>1. This accelerating cascade is due to the nonlinear dependence of the mean blocking time of a single channel on the entering particle flux that more than compensates for the decrease in the number of active channels. PMID- 26651681 TI - Maximum entropy principle for stationary states underpinned by stochastic thermodynamics. AB - The selection of an equilibrium state by maximizing the entropy of a system, subject to certain constraints, is often powerfully motivated as an exercise in logical inference, a procedure where conclusions are reached on the basis of incomplete information. But such a framework can be more compelling if it is underpinned by dynamical arguments, and we show how this can be provided by stochastic thermodynamics, where an explicit link is made between the production of entropy and the stochastic dynamics of a system coupled to an environment. The separation of entropy production into three components allows us to select a stationary state by maximizing the change, averaged over all realizations of the motion, in the principal relaxational or nonadiabatic component, equivalent to requiring that this contribution to the entropy production should become time independent for all realizations. We show that this recovers the usual equilibrium probability density function (pdf) for a conservative system in an isothermal environment, as well as the stationary nonequilibrium pdf for a particle confined to a potential under nonisothermal conditions, and a particle subject to a constant nonconservative force under isothermal conditions. The two remaining components of entropy production account for a recently discussed thermodynamic anomaly between over- and underdamped treatments of the dynamics in the nonisothermal stationary state. PMID- 26651682 TI - Effect of reorientation statistics on torque response of self-propelled particles. AB - We consider the dynamics of self-propelled particles subject to external torques. Two models for the reorientation of self-propulsion are considered: run-and tumble particles and active Brownian particles. Using the standard tools of nonequilibrium statistical mechanics we show that the run and tumble particles have a more robust response to torques. This macroscopic signature of the underlying reorientation statistics can be used to differentiate between the two types of self-propelled particles. PMID- 26651683 TI - Protocol-independent granular temperature supported by numerical simulations. AB - A possible approach to the statistical description of granular assemblies starts from Edwards's assumption that all blocked states occupying the same volume are equally probable [Edwards and Oakeshott, Physica A 157, 1080 (1989)]. We performed computer simulations using two-dimensional polygonal particles excited periodically according to two different protocols: excitation by pulses of "negative gravity" and excitation by "rotating gravity." The first protocol exhibits a nonmonotonous dependency of the mean volume fraction on the pulse strength. The overlapping histogram method is used in order to test whether the volume distribution is described by a Boltzmann-like distribution and to calculate the inverse compactivity as well as the logarithm of the partition sum. We find that the mean volume is a unique function of the measured granular temperature, independently of the protocol and of the branch in phi(g), and that all determined quantities are in agreement with Edwards's theory. PMID- 26651684 TI - Generalized transport coefficients for inelastic Maxwell mixtures under shear flow. AB - The Boltzmann equation framework for inelastic Maxwell models is considered to determine the transport coefficients associated with the mass, momentum, and heat fluxes of a granular binary mixture in spatially inhomogeneous states close to the simple shear flow. The Boltzmann equation is solved by means of a Chapman Enskog-type expansion around the (local) shear flow distributions f(r)(0) for each species that retain all the hydrodynamic orders in the shear rate. Due to the anisotropy induced by the shear flow, tensorial quantities are required to describe the transport processes instead of the conventional scalar coefficients. These tensors are given in terms of the solutions of a set of coupled equations, which can be analytically solved as functions of the shear rate a, the coefficients of restitution alpha(rs), and the parameters of the mixture (masses, diameters, and composition). Since the reference distribution functions f(r)(0) apply for arbitrary values of the shear rate and are not restricted to weak dissipation, the corresponding generalized coefficients turn out to be nonlinear functions of both a and alpha(rs). The dependence of the relevant elements of the three diffusion tensors on both the shear rate and dissipation is illustrated in the tracer limit case, the results showing that the deviation of the generalized transport coefficients from their forms for vanishing shear rates is in general significant. A comparison with the previous results obtained analytically for inelastic hard spheres by using Grad's moment method is carried out, showing a good agreement over a wide range of values for the coefficients of restitution. Finally, as an application of the theoretical expressions derived here for the transport coefficients, thermal diffusion segregation of an intruder immersed in a granular gas is also studied. PMID- 26651685 TI - Drop formation in shear-thickening granular suspensions. AB - We study droplet formation in granular suspensions by systematically varying the volume fractions (phi) and particle diameters (d). For suspensions with water as the suspending liquid, we find three different regimes. For dilute suspensions (phi<=45%), drop formation follows the predictions for inertial breakup and exhibits identical dynamics to that of pure water. The breakup is strongly asymmetrical in this case. Only for more concentrated suspensions (phi>45%) does the presence of particles change the dynamics and two other regimes, a symmetrical inertial regime and a Bagnoldian regime, are uncovered. We construct and discuss a phase diagram that allows us to understand and predict the breakup behavior in granular suspensions. PMID- 26651686 TI - Granular-front formation in free-surface flow of concentrated suspensions. AB - A granular front emerges whenever the free-surface flow of a concentrated suspension spontaneously alters its internal structure, exhibiting a higher concentration of particles close to its front. This is a common and yet unexplained phenomenon, which is usually believed to be the result of fluid convection in combination with particle size segregation. However, suspensions composed of uniformly sized particles also develop a granular front. Within a large rotating drum, a stationary recirculating avalanche is generated. The flowing material is a mixture of a viscoplastic fluid obtained from a kaolin water dispersion with spherical ceramic particles denser than the fluid. The goal is to mimic the composition of many common granular-fluid materials, such as fresh concrete or debris flow. In these materials, granular and fluid phases have the natural tendency to separate due to particle settling. However, through the shearing caused by the rotation of the drum, a reorganization of the phases is induced, leading to the formation of a granular front. By tuning the particle concentration and the drum velocity, it is possible to control this phenomenon. The setting is reproduced in a numerical environment, where the fluid is solved by a lattice-Boltzmann method, and the particles are explicitly represented using the discrete element method. The simulations confirm the findings of the experiments, and provide insight into the internal mechanisms. Comparing the time scale of particle settling with the one of particle recirculation, a nondimensional number is defined, and is found to be effective in predicting the formation of a granular front. PMID- 26651687 TI - Non-Newtonian hydrodynamics for a dilute granular suspension under uniform shear flow. AB - We study in this work a steady shearing laminar flow with null heat flux (usually called "uniform shear flow") in a gas-solid suspension at low density. The solid particles are modeled as a gas of smooth hard spheres with inelastic collisions while the influence of the surrounding interstitial fluid on the dynamics of grains is modeled by means of a volume drag force, in the context of a rheological model for suspensions. The model is solved by means of three different but complementary routes, two of them being theoretical (Grad's moment method applied to the corresponding Boltzmann equation and an exact solution of a kinetic model adapted to granular suspensions) and the other being computational (Monte Carlo simulations of the Boltzmann equation). Unlike in previous studies on granular sheared suspensions, the collisional moment associated with the momentum transfer is determined in Grad's solution by including all the quadratic terms in the stress tensor. This theoretical enhancement allows for the detection and evaluation of the normal stress differences in the plane normal to the laminar flow. In addition, the exact solution of the kinetic model gives the explicit form of the velocity moments of the velocity distribution function. Comparison between our theoretical and numerical results shows in general a good agreement for the non-Newtonian rheological properties, the kurtosis (fourth velocity moment of the distribution function), and the velocity distribution of the kinetic model for quite strong inelasticity and not too large values of the (scaled) friction coefficient characterizing the viscous drag force. This shows the accuracy of our analytical results that allows us to describe in detail the flow dynamics of the granular sheared suspension. PMID- 26651688 TI - Search for hyperuniformity in mechanically stable packings of frictionless disks above jamming. AB - We numerically simulate mechanically stable packings of soft-core, frictionless, bidisperse disks in two dimensions, above the jamming packing fraction phi(J). For configurations with a fixed isotropic global stress tensor, we investigate the fluctuations of the local packing fraction phi(r) to test whether such configurations display the hyperuniformity that has been claimed to exist exactly at phi(J). For our configurations, generated by a rapid quench protocol, we find that hyperuniformity persists only out to a finite length scale and that this length scale appears to remain finite as the system stress decreases towards zero, i.e., towards the jamming transition. Our result suggests that the presence of hyperuniformity at jamming may be sensitive to the specific protocol used to construct the jammed configurations. PMID- 26651689 TI - Coarse-grained model of conformation-dependent electrophoretic mobility and its influence on DNA dynamics. AB - The electrophoretic mobility of molecules such as lambda-DNA depends on the conformation of the molecule. It has been shown that electrohydrodynamic interactions between parts of the molecule lead to a mobility that depends on conformation and can explain some experimental observations. We have developed a new coarse-grained model that incorporates these changes of mobility into a bead spring chain model. Brownian dynamics simulations have been performed using this model. The model reproduces the cross-stream migration that occurs in capillary electrophoresis when pressure-driven flow is applied parallel or antiparallel to the electric field. The model also reproduces the change of mobility when the molecule is stretched significantly in an extensional field. We find that the conformation-dependent mobility can lead to a new type of unraveling of the molecule in strong fields. This occurs when different parts of the molecule have different mobilities and the electric field is large. PMID- 26651690 TI - Velocity and displacement statistics in a stochastic model of nonlinear friction showing bounded particle speed. AB - Diffusion of colloidal particles in a complex environment such as polymer networks or biological cells is a topic of high complexity with significant biological and medical relevance. In such situations, the interaction between the surroundings and the particle motion has to be taken into account. We analyze a simplified diffusion model that includes some aspects of a complex environment in the framework of a nonlinear friction process: at low particle speeds, friction grows linearly with the particle velocity as for regular viscous friction; it grows more than linearly at higher particle speeds; finally, at a maximum of the possible particle speed, the friction diverges. In addition to bare diffusion, we study the influence of a constant drift force acting on the diffusing particle. While the corresponding stationary velocity distributions can be derived analytically, the displacement statistics generally must be determined numerically. However, as a benefit of our model, analytical progress can be made in one case of a special maximum particle speed. The effect of a drift force in this case is analytically determined by perturbation theory. It will be interesting in the future to compare our results to real experimental systems. One realization could be magnetic colloidal particles diffusing through a shear thickening environment such as starch suspensions, possibly exposed to an external magnetic field gradient. PMID- 26651691 TI - Anisotropy of stress correlation in two-dimensional liquids and a pseudospin model. AB - Liquids are condensed matter in which atoms are strongly correlated in position and momentum. The atomic pair density function (PDF) is used often in describing such correlation. However, elucidation of many properties requires higher degrees of correlation than the pair correlation. For instance, viscosity depends upon the stress correlations in space and time. In this paper, we examine the cross correlation between the stress correlation at the atomic level and the PDF for two-dimensional liquids. We introduce the concept of the stress-resolved pair distribution function (SRPDF) that uses the sign of atomic-level stress as a selection rule to include particles from density correlations. The connection between SRPDFs and stress correlation function is explained through an approximation in which the shear stress is replaced by a pseudospin. We further assess the possibility of interpreting the long-range stress correlation as a consequence of short-range Ising-like pseudospin interactions. PMID- 26651692 TI - Correlated two-particle diffusion in dense colloidal suspensions at early times: Theory and comparison to experiment. AB - The spatially resolved diffusive dynamic cross correlations of a pair of colloids in dense quasi-two-dimensional monolayers of identical particles are studied experimentally and theoretically at early times where motion is Fickian. In very dense systems where strong oscillatory equilibrium packing correlations are present, we find an exponential decay of the dynamic cross correlations on small and intermediate length scales. At large separations where structure becomes random, an apparent power law decay with an exponent of approximately -2.2 is observed. For a moderately dense suspension where local structural correlations are essentially absent, this same apparent power law decay is observed over all probed interparticle separations. A microscopic nonhydrodynamic theory is constructed for the dynamic cross correlations which is based on interparticle frictional effects and effective structural forces. Hydrodynamics enters only via setting the very short-time single-particle self-diffusion constant. No adjustable-parameter quantitative predictions of the theory for the dynamic cross correlations are in good agreement with experiment over all length scales. The origin of the long-range apparent power law is the influence of the constraint of fixed interparticle separation on the amplitude of the mean square force exerted on the two tagged particles by the surrounding fluid. The theory is extended to study high-packing-fraction 3D hard sphere fluids. The same pattern of an oscillatory exponential form of the dynamic cross correlation function is predicted in the structural regime, but the long-range tail decays faster than in monolayers with an exponent of -3. PMID- 26651693 TI - Dynamics of micelle formation from temperature-jump Monte Carlo simulations. AB - In the present work we perform temperature jumps in a surfactant solution by means of Monte Carlo simulations, investigating the dynamics of micelle formation. We use a lattice model that allows orientational freedom and hydrogen bonding for solvent molecules, which can make a connection between the different time scales of hydrogen bond formation and amphiphilic aggregation. When we perform a large jump between a high-temperature nonmicellized state and a micellized state, there is strong hysteresis between the heating and cooling processes, the latter showing the formation of premicelles that act as nucleation centers for the assembly of larger aggregates and the former is a drive for dissociation of the existing aggregates. Hysteresis is not seen when we perform a small jump between two states that can be both micellized or nonmicellized. Looking for a more detailed analysis of the hydrophobic effect that drives aggregation, we compare the time evolution of the solvent hydrogen bonds in our system close and far from micelles and how that is affected by the formation of large clusters at low temperatures. We find a strong connection between them, with the total number of hydrogen bonds in the system always increasing when micelles are formed. To gain insights into the mechanism of premicellar formation and growth, we measure the lifetime of micellized amphiphiles as a function of the aggregate size and the stage of the aggregation process. Our results indicate that the premicelles are always unstable, quickly exchanging amphiphiles with the solution due to their low probabilty in equilibrium. Furthermore, we find that the stability of individual surfactants in micelles increases with the aggregate size, with the lifetime of amphiphiles in large micelles being as much as 35 times longer than in the case of the unstable premicellar region. PMID- 26651694 TI - Role of interfacial friction for flow instabilities in a thin polar-ordered active fluid layer. AB - We construct a generic coarse-grained dynamics of a thin inflexible planar layer of polar-ordered suspension of active particles that is frictionally coupled to an embedding isotropic passive fluid medium with a friction coefficient Gamma. Being controlled by Gamma, our model provides a unified framework to describe the long-wavelength behavior of a variety of thin polar-ordered systems, ranging from wet to dry active matter and free-standing active films. Investigations of the linear instabilities around a chosen orientationally ordered uniform reference state reveal generic moving and static instabilities in the system that can depend sensitively on Gamma. Based on our results, we discuss estimation of bounds on Gamma in experimentally accessible systems. PMID- 26651695 TI - Monodisperse cluster crystals: Classical and quantum dynamics. AB - We study the phases and dynamics of a gas of monodisperse particles interacting via soft-core potentials in two spatial dimensions, which is of interest for soft matter colloidal systems and quantum atomic gases. Using exact theoretical methods, we demonstrate that the equilibrium low-temperature classical phase simultaneously breaks continuous translational symmetry and dynamic space-time homogeneity, whose absence is usually associated with out-of-equilibrium glassy phenomena. This results in an exotic self-assembled cluster crystal with coexisting liquidlike long-time dynamical properties, which corresponds to a classical analog of supersolid behavior. We demonstrate that the effects of quantum fluctuations and bosonic statistics on cluster-glassy crystals are separate and competing: Zero-point motion tends to destabilize crystalline order, which can be restored by bosonic statistics. PMID- 26651696 TI - Correlation between rearrangements and soft modes in polymer glasses during deformation and recovery. AB - We explore the link between soft vibrational modes and local relaxation events in polymer glasses during physical aging, active deformation at constant strain rate, and subsequent recovery. A softness field is constructed out of the superposition of the amplitudes of the lowest energy normal modes, and found to predict up to 70% of the rearrangements. Overlap between softness and rearrangements increases logarithmically during aging and recovery phases as energy barriers rise due to physical aging, while yielding rapidly rejuvenates the overlap to that of a freshly prepared glass. In the strain hardening regime, correlations rise for uniaxial tensile deformation but not for simple shear. These trends can be explained by considering the differing degrees of localization of the soft modes in the two deformation protocols. PMID- 26651697 TI - Mesoscopic turbulence and local order in Janus particles self-propelling under an ac electric field. AB - To elucidate mechanisms of mesoscopic turbulence exhibited by active particles, we experimentally study turbulent states of nonliving self-propelled particles. We realize an experimental system with dense suspensions of asymmetrical colloidal particles (Janus particles) self-propelling on a two-dimensional surface under an ac electric field. Velocity fields of the Janus particles in the crowded situation can be regarded as a sort of turbulence because it contains many vortices and their velocities change abruptly. Correlation functions of their velocity field reveal the coexistence of polar alignment and antiparallel alignment interactions, which is considered to trigger mesoscopic turbulence. Probability distributions of local order parameters for polar and nematic orders indicate the formation of local clusters with particles moving in the same direction. A broad peak in the energy spectrum of the velocity field appears at the spatial scales where the polar alignment and the cluster formation are observed. Energy is injected at the particle scale and conserved quantities such as energy could be cascading toward the larger clusters. PMID- 26651698 TI - Morphological instability during steady electrodeposition at overlimiting currents. AB - We present a linear stability analysis of a planar metal electrode during steady electrodeposition. We extend the previous work of Sundstrom and Bark by accounting for the extended space-charge density, which develops at the cathode once the applied voltage exceeds a few thermal voltages. In accordance with Chazalviel's conjecture, the extended space-charge region is found to greatly affect the morphological stability of the electrode. To supplement the numerical solution of the stability problem, we have derived analytical expressions valid in the limit of low and high voltage, respectively. PMID- 26651699 TI - Nonequilibrium structure of colloidal dumbbells under oscillatory shear. AB - We investigate the nonequilibrium behavior of dense, plastic-crystalline suspensions of mildly anisotropic colloidal hard dumbbells under the action of an oscillatory shear field by employing Brownian dynamics computer simulations. In particular, we extend previous investigations, where we uncovered nonequilibrium phase transitions, to other aspect ratios and to a larger nonequilibrium parameter space, that is, a wider range of strains and shear frequencies. We compare and discuss selected results in the context of scattering and rheological experiments. Both simulations and experiments demonstrate that the previously found transitions from the plastic crystal phase with increasing shear strain also occur at other aspect ratios. We explore the transition behavior in the strain-frequency phase and summarize it in a nonequilibrium phase diagram. Additionally, the experimental rheology results hint at a slowing down of the colloidal dynamics with higher aspect ratio. PMID- 26651700 TI - Phase-transition oscillations induced by a strongly focused laser beam. AB - We report the observation of a surprising phenomenon consisting in a oscillating phase transition which appears in a binary mixture when this is enlightened by a strongly focused infrared laser beam. The mixture is poly-methyl-meth-acrylate (PMMA)-3-octanone, which has an upper critical solution temperature at T(c)=306.6K and volume fraction phi(c)=12.8% [Crauste et al., arXiv:1310.6720, 2013]. We describe the dynamical properties of the oscillations, which are produced by a competition between various effects: the local accumulation of PMMA produced by the laser beam, thermophoresis, and nonlinear diffusion. We show that the main properties of this kind of oscillations can be reproduced in the Landau theory for a binary mixture in which a local driving mechanism, simulating the laser beam, is introduced. PMID- 26651701 TI - Electrorotation of a metal sphere immersed in an electrolyte of finite Debye length. AB - We theoretically study the rotation induced on a metal sphere immersed in an electrolyte and subjected to a rotating electric field. The rotation arises from the interaction of the field with the electric charges induced at the metal electrolyte interface, i.e., the induced electrical double layer (EDL). Particle rotation is due to the torque on the induced dipole, and also from induced-charge electro-osmostic flow (ICEO). The interaction of the electric field with the induced dipole on the system gives rise to counterfield rotation, i.e., the direction opposite to the rotation of the electric field. ICEO generates co-field rotation of the sphere. For thin EDL, ICEO generates negligible rotation. For increasing size of EDL, co-field rotation appears and, in the limit of very thick EDL, it compensates the counter-field rotation induced by the electrical torque. We also report computations of the rotating fluid velocity field around the sphere. PMID- 26651702 TI - Pickering emulsions stabilized by oppositely charged colloids: Stability and pattern formation. AB - A binary mixture of oppositely charged colloids can be used to stabilize water-in oil or oil-in-water emulsions. A Monte Carlo simulation study to address the effect of charge ratio of colloids on the stability of Pickering emulsions is presented. The colloidal particles at the interface are modeled as aligned dipolar hard spheres, with attractive interaction between unlike-charged and repulsive interaction between like-charged particles. The optimum composition (fraction of positively charged particles) required for the stabilization corresponds to a minimum in the interaction energy per particle. In addition, for each charge ratio, there is a range of compositions where emulsions can be stabilized. The structural arrangement of particles or the pattern formation at the emulsion interface is strongly influenced by the charge ratio. We find well mixed isotropic, square, and hexagonal arrangements of particles on the emulsion surface for different compositions at a given charge ratio. The distribution of coordination numbers is calculated to characterize structural features. The simulation study is useful for the rational design of Pickering emulsifications wherein oppositely charged colloids are used, and for the control of pattern formation that can be useful for the synthesis of colloidosomes and porous shells derived thereof. PMID- 26651703 TI - Real-time measurements of crystallization processes in viscoelastic polymeric photonic crystals. AB - We present a study of the dynamic shear ordering of viscoelastic photonic crystals, based on core-shell polymeric composite particles. Using an adapted shear-cell arrangement, the crystalline ordering of the material under conditions of oscillatory shear is interrogated in real time, through both video imaging and from the optical transmission spectra of the cell. In order to gain a deeper understanding of the macroscopic influences of shear on the crystallization process in this solvent-free system, the development of bulk ordering is studied as a function of the key parameters including duty cycle and shear-strain magnitude. In particular, optimal ordering is observed from a prerandomized sample at shear strains of around 160%, for 1-Hz oscillations. This ordering reaches completion over time scales of order 10 s. These observations suggest significant local strains are needed to drive nanoparticles through energy barriers, and that local creep is needed to break temporal symmetry in such high viscosity nanoassemblies. Crystal shear-melting effects are also characterized under conditions of constant shear rate. These quantitative experiments aim to stimulate the development of theoretical models which can deal with the strong local particle interactions in this system. PMID- 26651704 TI - Molecular dynamics study of phase separation in fluids with chemical reactions. AB - We present results from the first d=3 molecular dynamics (MD) study of phase separating fluid mixtures (AB) with simple chemical reactions (A?B). We focus on the case where the rates of forward and backward reactions are equal. The chemical reactions compete with segregation, and the coarsening system settles into a steady-state mesoscale morphology. However, hydrodynamic effects destroy the lamellar morphology which characterizes the diffusive case. This has important consequences for the phase-separating structure, which we study in detail. In particular, the equilibrium length scale (l(eq)) in the steady state suggests a power-law dependence on the reaction rate epsilon:l(eq)~epsilon( theta) with theta?1.0. PMID- 26651705 TI - Electrostatic potential of mean force between two curved surfaces in the presence of counterion connectivity. AB - In this paper, we investigate effects of counterion connectivity (i.e., association of the counterions into a chain molecule) on the electrostatic potential of mean force (EPMF) between two similarly charged cylinder rods in a primitive model electrolyte solution by solving a classical density functional theory. The main findings include the following: (i) The counterion connectivity helps in inducing a like-charge-attractionlike (LCA-like) phenomenology even in a monovalent counterion solution wherein the LCA-like observation generally does not occur without the counterion connectivity. (ii) For divalent counterion solutions, the counterion connectivity can reinforce or weaken the LCA-like observation depending on the chain length N, and simply increases the equilibrium nearest surface separation of the rods corresponding to the minimum EPMF to nearly three times the counterion site diameter, whether N is large or small. (iii) If N is large enough, the LCA-like strength tends to be negatively correlated with the electrolyte concentration c over the entire range of the rod surface charge magnitude |sigma*| considered; whereas if N drops, the correlation tends to become positive with decrease of the |sigma*| value, and particularly for modest |sigma*| values, the correlation relationship exhibits an extreme value phenomenon. (iv) In the case of a 1:1 electrolyte, the EPMF effects of the diameters of counterion and coion sites are similar in both situations with and without the counterion connectivity. All of these findings can be explained self consistently by a recently proposed hydrogen-bonding style mechanism reinforced by one additional concept: flexibility of the counterion chain and the factors affecting it, like N and counterion site valence. PMID- 26651706 TI - Shapeable sheet without plastic deformation. AB - Randomly crumpled sheets have shape memory. In order to understand the basis of this form of memory, we simulate triangular lattices of springs whose lengths are altered to create a topography with multiple potential energy minima. We then deform these lattices into different shapes and investigate their ability to retain the imposed shape when the energy is relaxed. The lattices are able to retain a range of curvatures. Under moderate forcing from a state of local equilibrium, the lattices deform by several percent but return to their retained shape when the forces are removed. By increasing the forcing until an irreversible motion occurs, we find that the transitions between remembered shapes show cooperativity among several springs. For fixed lattice structures, the shape memory tends to decrease as the lattice is enlarged; we propose ways to counter this decrease by modifying the lattice geometry. We survey the energy landscape by displacing individual nodes. An extensive fraction of these nodes proves to be bistable; they retain their displaced position when the energy is relaxed. Bending the lattice to a stable curved state alters the pattern of bistable nodes. We discuss this shapeability in the context of other forms of material memory and contrast it with the shapeability of plastic deformation. We outline the prospects for making real materials based on these principles. PMID- 26651707 TI - Anomalous approach to thermodynamic equilibrium: Structure formation of molecules after vapor deposition. AB - We describe experiments and computer simulations of molecular deposition on a substrate in which the molecules (substituted adenine derivatives) self-assemble into ordered structures. The resulting structures depend strongly on the deposition rate (flux). In particular, there are two competing surface morphologies (alpha and beta), which differ by their topology (interdigitated vs lamellar structure). Experimentally, the alpha phase dominates at both low and high flux, with the beta phase being most important in the intermediate regime. A similar nonmonotonic behavior is observed on varying the substrate temperature. To understand these effects from a theoretical perspective, a lattice model is devised which reproduces qualitatively the topological features of both phases. Via extensive Monte Carlo studies we can, on the one hand, reproduce the experimental results and, on the other hand, obtain a microscopic understanding of the mechanisms behind this anomalous behavior. The results are discussed in terms of an interplay between kinetic trapping and temporal exploration of configuration space. PMID- 26651708 TI - Wetting and evaporation of salt-water nanodroplets: A molecular dynamics investigation. AB - We employ molecular dynamics simulations to study the wetting and evaporation of salt-water nanodroplets on platinum surfaces. Our results show that the contact angle of the droplets increases with the salt concentration. To verify this, a second simulation system of a thin salt-water film on a platinum surface is used to calculate the various surface tensions. We find that both the solid-liquid and liquid-vapor surface tensions increase with salt concentration and as a result these cause an increase in the contact angle. However, the evaporation rate of salt-water droplets decreases as the salt concentration increases, due to the hydration of salt ions. When the water molecules have all evaporated from the droplet, two forms of salt crystals are deposited, clump and ringlike, depending on the solid-liquid interaction strength and the evaporation rate. To form salt crystals in a ring, it is crucial that there is a pinned stage in the evaporation process, during which salt ions can move from the center to the rim of the droplets. With a stronger solid-liquid interaction strength, a slower evaporation rate, and a higher salt concentration, a complete salt crystal ring can be deposited on the surface. PMID- 26651709 TI - Electrochemical characteristics of ideal polarizable interfaces with limited number of charge carriers. AB - Recent progress in material chemistry and surface engineering has led to emergence of new electrode materials with unique physical and electrochemical properties. Here, we introduce a physical model describing charging of ideal polarizable electrode-electrolyte interface where the electrode is characterized by a limited capacity to store charge. The analytical model treats the electrode and electrolyte phases as independent nonlinear capacitors that are eventually coupled through the condition of equality of the total stored electrical charge opposite in sign. Gouy-Chapman and condensed layer theories applied to a general 1:n valent electrolyte are used to predict dependencies of differential capacitance of the electrolyte phase and surface concentration of the electrical charge on the applied potential. The model of the nonlinear capacitor for the electrode phase is described by a theory of electron donors and acceptors present in conductive solids as a result of thermal fluctuations. Both the differential capacitance and the surface concentration of the electrical charge in the electrode are evaluated as functions of the applied potential and related to the capacity of the electrode phase to accumulate charge and its ability to form electron donors and acceptors. The knowledge of capacitive properties of both phases allows to predict electrochemical characteristics of ideal polarizable interfaces, e.g., current responses in linear sweep voltammetry. The coupled model also shows significant potential drops in the electrode comparable to those in the electrolyte phase for materials with low charge carrier concentrations. PMID- 26651710 TI - Smoothening in thin-film deposition on rough substrates. AB - The evolution of the surface roughness W of a thin film deposited on a rough substrate is studied with a model of temperature-activated adatom diffusion, irreversible lateral aggregation, and no step energy barrier, in which the main parameter is the ratio R of diffusion and deposition rates. At sufficiently low temperatures (R?10), the average number of adatom steps after adsorption is very small, thus W monotonically increases with time t due to an approximately uncorrelated deposition at short times. If the temperature is not very low (R~10(3) or larger), smoothening occurs at short times and the Villain-Lai-Das Sarma (VLDS) growth equation governs the long time roughening, which is attained after a crossover time t(c) that increases with the correlation length xi(i) of the substrate. Scaling arguments predict the dependence of t(c) on temperature and on the substrate production time and the scaling relation for the difference between the roughness of films deposited on rough and flat substrates, in good agreement with numerical results. The effect of temperature is not a direct extension of previous results on flat substrates because the short wavelength fluctuations delay the formation of terraces. For this reason, the effective energy obtained from the dependence of t(c) on R is 40% of the energy of activated adatom diffusion. A scaling law for the initial smoothening is proposed as W/W(i)=Psi(t/t(c1)), with a crossover time t(c1)=R(-theta)xi(i)(z), where W(i) is the substrate roughness, theta~0.4, and z is the VLDS dynamical exponent. It provides good data collapse if W is not very small and is suggested to be tested experimentally. PMID- 26651711 TI - Spherical microparticles with Saturn ring defects and their self-assembly across the nematic to smectic-A phase transition. AB - We report experimental studies on the Saturn ring defect associated with a spherical microparticle across the nematic (N) to smectic-A (SmA) phase transition. We observe that the director distortion around the microparticle changes rapidly with temperature. The equilibrium interparticle separation and the angle between two quadrupolar particles in the N phase are larger than those of the SmA phase. They are almost independent of the temperature in both phases, except for a discontinuous jump at the transition. We assembled a few particles using a laser tweezer to form a two-dimensional colloidal crystal in the N phase. The lattice structure of the crystal dissolves irreversibly across the N-SmA phase transition. The results on the pretransitional behavior of the defect are supported by the Landau-de Gennes Q-tensor modeling. PMID- 26651712 TI - Liquid crystals with patterned molecular orientation as an electrolytic active medium. AB - Transport of fluids and particles at the microscale is an important theme in both fundamental and applied science. One of the most successful approaches is to use an electric field, which requires the system to carry or induce electric charges. We describe a versatile approach to generate electrokinetic flows by using a liquid crystal (LC) with surface-patterned molecular orientation as an electrolyte. The surface patterning is produced by photoalignment. In the presence of an electric field, the spatially varying orientation induces space charges that trigger flows of the LC. The active patterned LC electrolyte converts the electric energy into the LC flows and transport of embedded particles of any type (fluid, solid, gaseous) along a predesigned trajectory, posing no limitation on the electric nature (charge, polarizability) of these particles and interfaces. The patterned LC electrolyte exhibits a quadratic field dependence of the flow velocities; it induces persistent vortices of controllable rotation speed and direction that are quintessential for micro- and nanoscale mixing applications. PMID- 26651713 TI - Effect of flip-flop motion on dielectric spectra of highly ordered liquid crystals. AB - This paper presents studies of dielectric response of chosen Schiff bases, which have similar molecular structures with different isomerizations of an azomethine bridging group, alkyloxy chain length with n=5 or n=6 carbon atoms, and a bromine or chlorine halogen terminal atom. Significant differences in the values of the maximum of dielectric absorption related to flip-flop molecular jumps in hexagonal smectic-B(Cry) phases have been found despite small differences of molecular dipole moments in these substances. This phenomenon is discussed in relation to the possibilities of the creation of dimers and to steric factors favoring motions. PMID- 26651714 TI - Geometric phase and o-mode blueshift in a chiral anisotropic medium inside a Fabry-Perot cavity. AB - Anomalous spectral shift of transmission peaks is observed in a Fabry-Perot cavity filled with a chiral anisotropic medium. The effective refractive index value resides out of the interval between the ordinary and the extraordinary refractive indices. The spectral shift is explained by contribution of a geometric phase. The problem is solved analytically using the approximate Jones matrix method, numerically using the accurate Berreman method, and geometrically using the generalized Mauguin-Poincare rolling cone method. The o-mode blueshift is measured for a 4-methoxybenzylidene-4'-n-butylaniline twisted-nematic layer inside the Fabry-Perot cavity. The twist is electrically induced due to the homeoplanar-twisted configuration transition in an ionic-surfactant-doped liquid crystal layer. Experimental evidence confirms the validity of the theoretical model. PMID- 26651715 TI - Entropic effects, shape, and size of mixed micelles formed by copolymers with complex architectures. AB - The entropic effects in the comicellization behavior of amphiphilic AB copolymers differing in the chain size of solvophilic A parts were studied by means of molecular dynamics simulations. In particular, mixtures of miktoarm star copolymers differing in the molecular weight of solvophilic arms were investigated. We found that the critical micelle concentration values show a positive deviation from the analytical predictions of the molecular theory of comicellization for chemically identical copolymers. This can be attributed to the effective interactions between copolymers originated from the arm size asymmetry. The effective interactions induce a very small decrease in the aggregation number of preferential micelles triggering the nonrandom mixing between the solvophilic moieties in the corona. Additionally, in order to specify how the chain architecture affects the size distribution and the shape of mixed micelles we studied star-shaped, H-shaped, and homo-linked-rings-linear mixtures. In the first case the individual constituents form micelles with preferential and wide aggregation numbers and in the latter case the individual constituents form wormlike and spherical micelles. PMID- 26651716 TI - Transition from ballistic to electrodiffusive transport in free-standing nanometer-sized polymer membranes. AB - The transition from ballistic to electrodiffusive transport of ions through thin polymer membranes has been investigated by recording single transport events via time-correlated single-particle detection. At the highest kinetic energies investigated, ballistic transport of potassium ions is observed with no discernible energy loss to the membrane. At the lowest kinetic energies investigated (several 100 eV) ions are demonstrated to lose the entire kinetic energy to the membrane. Transport there occurs by electrodiffusion. A transition regime is observed. The transition energy is shown to depend on the thickness of the membrane. PMID- 26651717 TI - Zipping and entanglement in flagellar bundle of E. coli: Role of motile cell body. AB - The course of a peritrichous bacterium, such as E. coli, crucially depends on the level of synchronization and self-organization of several rotating flagella. However, the rotation of each flagellum generates countermovements of the body which in turn affect the flagellar dynamics. Using a detailed numerical model of an E. coli, we demonstrate that flagellar entanglement, besides fluid flow relative to the moving body, dramatically changes the dynamics of flagella from that compared to anchored flagella. In particular, bundle formation occurs through a zipping motion in a remarkably rapid time, affected little by initial flagellar orientation. A simplified analytical model supports our observations. Finally, we illustrate how entanglement, hydrodynamic interactions, and body movement contribute to zipping and bundling. PMID- 26651718 TI - First-passage times in multiscale random walks: The impact of movement scales on search efficiency. AB - An efficient searcher needs to balance properly the trade-off between the exploration of new spatial areas and the exploitation of nearby resources, an idea which is at the core of scale-free Levy search strategies. Here we study multiscale random walks as an approximation to the scale-free case and derive the exact expressions for their mean-first-passage times in a one-dimensional finite domain. This allows us to provide a complete analytical description of the dynamics driving the situation in which both nearby and faraway targets are available to the searcher, so the exploration-exploitation trade-off does not have a trivial solution. For this situation, we prove that the combination of only two movement scales is able to outperform both ballistic and Levy strategies. This two-scale strategy involves an optimal discrimination between the nearby and faraway targets which is only possible by adjusting the range of values of the two movement scales to the typical distances between encounters. So, this optimization necessarily requires some prior information (albeit crude) about target distances or distributions. Furthermore, we found that the incorporation of additional (three, four, ...) movement scales and its adjustment to target distances does not improve further the search efficiency. This allows us to claim that optimal random search strategies arise through the informed combination of only two walk scales (related to the exploitative and the explorative scales, respectively), expanding on the well-known result that optimal strategies in strictly uninformed scenarios are achieved through Levy paths (or, equivalently, through a hierarchical combination of multiple scales). PMID- 26651719 TI - Theory of bimolecular reactions in a solution with linear traps: Application to the problem of target search on DNA. AB - One-dimensional sliding along DNA as a means to accelerate protein target search is a well-known phenomenon occurring in various biological systems. Using a biomimetic approach, we have recently demonstrated the practical use of DNA sliding peptides to speed up bimolecular reactions more than an order of magnitude by allowing the reactants to associate not only in the solution by three-dimensional (3D) diffusion, but also on DNA via one-dimensional (1D) diffusion [A. Turkin et al., Chem. Sci. (2015)]. Here we present a mean-field kinetic model of a bimolecular reaction in a solution with linear extended sinks (e.g., DNA) that can intermittently trap molecules present in a solution. The model consists of chemical rate equations for mean concentrations of reacting species. Our model demonstrates that addition of linear traps to the solution can significantly accelerate reactant association. We show that at optimum concentrations of linear traps the 1D reaction pathway dominates in the kinetics of the bimolecular reaction; i.e., these 1D traps function as an assembly line of the reaction product. Moreover, we show that the association reaction on linear sinks between trapped reactants exhibits a nonclassical third-order behavior. Predictions of the model agree well with our experimental observations. Our model provides a general description of bimolecular reactions that are controlled by a combined 3D+1D mechanism and can be used to quantitatively describe both naturally occurring as well as biomimetic biochemical systems that reduce the dimensionality of search. PMID- 26651720 TI - Numerical computations of the dynamics of fluidic membranes and vesicles. AB - Vesicles and many biological membranes are made of two monolayers of lipid molecules and form closed lipid bilayers. The dynamical behavior of vesicles is very complex and a variety of forms and shapes appear. Lipid bilayers can be considered as a surface fluid and hence the governing equations for the evolution include the surface (Navier-)Stokes equations, which in particular take the membrane viscosity into account. The evolution is driven by forces stemming from the curvature elasticity of the membrane. In addition, the surface fluid equations are coupled to bulk (Navier-)Stokes equations. We introduce a parametric finite-element method to solve this complex free boundary problem and present the first three-dimensional numerical computations based on the full (Navier-)Stokes system for several different scenarios. For example, the effects of the membrane viscosity, spontaneous curvature, and area difference elasticity (ADE) are studied. In particular, it turns out, that even in the case of no viscosity contrast between the bulk fluids, the tank treading to tumbling transition can be obtained by increasing the membrane viscosity. Besides the classical tank treading and tumbling motions, another mode (called the transition mode in this paper, but originally called the vacillating-breathing mode and subsequently also called trembling, transition, and swinging mode) separating these classical modes appears and is studied by us numerically. We also study how features of equilibrium shapes in the ADE and spontaneous curvature models, like budding behavior or starfish forms, behave in a shear flow. PMID- 26651721 TI - Schelling model of cell segregation based only on local information. AB - While biological studies suggest that motility of cells is involved in cell segregation, few computational models have investigated this mechanism. We apply a simple Schelling model, modified to reflect biological conditions, demonstrating how differences in cell motility arising exclusively from differences in the composition of the local environment can be sufficient to drive segregation. The work presented here demonstrates that the segregation behavior observed in the original Schelling model is robust to a relaxation of the requirement for global information and that the Schelling model may yield insight in the context of biological systems. In the model, the time course of cell segregation follows a power law in accord with experimental observations and previous work. PMID- 26651723 TI - Method for simultaneous localization and parameter estimation in particle tracking experiments. AB - We present a numerical method for the simultaneous localization and parameter estimation of a fluorescent particle undergoing a discrete-time continuous-state Markov process. In particular, implementation of the method proposed in this work yields an approximation to the posterior density of the particle positions over time in addition to maximum likelihood estimates of fixed, unknown parameters. The method employs sequential Monte Carlo methods and can take into account complex, potentially nonlinear noise models, including shot noise and camera specific readout noise, as well as a wide variety of motion models and observation models, including those representing recent engineered point spread functions. We demonstrate the technique by applying it to four scenarios, including a particle undergoing free, confined, and tethered diffusions. PMID- 26651722 TI - Multiscale study of bacterial growth: Experiments and model to understand the impact of gas exchange on global growth. AB - Using a millifluidics and macroscale setup, we study quantitatively the impact of gas exchange on bacterial growth. In millifluidic environments, the permeability of the incubator materials allows an unlimited oxygen supply by diffusion. Moreover, the efficiency of diffusion at small scales makes the supply instantaneous in comparison with the cell division time. In hermetic closed vials, the amount of available oxygen is low. The growth curve has the same trend but is quantitatively different from the millifluidic situation. The analysis of all the data allows us to write a quantitative modeling enabling us to capture the entire growth process. PMID- 26651724 TI - Onset of collective motion in locusts is captured by a minimal model. AB - We present a minimal model to describe the onset of collective motion seen when a population of locusts are placed in an annular arena. At low densities motion is disordered, while at high densities locusts march in a common direction, which may reverse during the experiment. The data are well captured by an individual based model, in which demographic noise leads to the observed density-dependent effects. By fitting the model parameters to equation-free coefficients, we give a quantitative comparison, showing time series, stationary distributions, and the mean switching times between states. PMID- 26651725 TI - Unified analysis of ensemble and single-complex optical spectral data from light harvesting complex-2 chromoproteins for gaining deeper insight into bacterial photosynthesis. AB - Bacterial light-harvesting pigment-protein complexes are very efficient at converting photons into excitons and transferring them to reaction centers, where the energy is stored in a chemical form. Optical properties of the complexes are known to change significantly in time and also vary from one complex to another; therefore, a detailed understanding of the variations on the level of single complexes and how they accumulate into effects that can be seen on the macroscopic scale is required. While experimental and theoretical methods exist to study the spectral properties of light-harvesting complexes on both individual complex and bulk ensemble levels, they have been developed largely independently of each other. To fill this gap, we simultaneously analyze experimental low temperature single-complex and bulk ensemble optical spectra of the light harvesting complex-2 (LH2) chromoproteins from the photosynthetic bacterium Rhodopseudomonas acidophila in order to find a unique theoretical model consistent with both experimental situations. The model, which satisfies most of the observations, combines strong exciton-phonon coupling with significant disorder, characteristic of the proteins. We establish a detailed disorder model that, in addition to containing a C_{2}-symmetrical modulation of the site energies, distinguishes between static intercomplex and slow conformational intracomplex disorders. The model evaluations also verify that, despite best efforts, the single-LH2-complex measurements performed so far may be biased toward complexes with higher Huang-Rhys factors. PMID- 26651726 TI - Learning in neural networks based on a generalized fluctuation theorem. AB - Information maximization has been investigated as a possible mechanism of learning governing the self-organization that occurs within the neural systems of animals. Within the general context of models of neural systems bidirectionally interacting with environments, however, the role of information maximization remains to be elucidated. For bidirectionally interacting physical systems, universal laws describing the fluctuation they exhibit and the information they possess have recently been discovered. These laws are termed fluctuation theorems. In the present study, we formulate a theory of learning in neural networks bidirectionally interacting with environments based on the principle of information maximization. Our formulation begins with the introduction of a generalized fluctuation theorem, employing an interpretation appropriate for the present application, which differs from the original thermodynamic interpretation. We analytically and numerically demonstrate that the learning mechanism presented in our theory allows neural networks to efficiently explore their environments and optimally encode information about them. PMID- 26651727 TI - Effect of sound on gap-junction-based intercellular signaling: Calcium waves under acoustic irradiation. AB - We present a previously unrecognized effect of sound waves on gap-junction-based intercellular signaling such as in biological tissues composed of endothelial cells. We suggest that sound irradiation may, through temporal and spatial modulation of cell-to-cell conductance, create intercellular calcium waves with unidirectional signal propagation associated with nonconventional topologies. Nonreciprocity in calcium wave propagation induced by sound wave irradiation is demonstrated in the case of a linear and a nonlinear reaction-diffusion model. This demonstration should be applicable to other types of gap-junction-based intercellular signals, and it is thought that it should be of help in interpreting a broad range of biological phenomena associated with the beneficial therapeutic effects of sound irradiation and possibly the harmful effects of sound waves on health. PMID- 26651728 TI - Limits to anaerobic energy and cytosolic concentration in the living cell. AB - For many physical systems at any given temperature, the set of all states where the system's free energy reaches its largest value can be determined from the system's constitutive equations of internal energy and entropy, once a state of that set is known. Such an approach is fraught with complications when applied to a living cell, because the cell's cytosol contains thousands of solutes, and thus thousands of state variables, which makes determination of its state impractical. We show here that, when looking for the maximum energy that the cytosol can store and release, detailed information on cytosol composition is redundant. Compatibility with cell's life requires that a single variable that represents the overall concentration of cytosol solutes must fall between defined limits, which can be determined by dehydrating and overhydrating the cell to its maximum capacity. The same limits are shown to determine, in particular, the maximum amount of free energy that a cell can supply in fast anaerobic processes, starting from any given initial state. For a typical skeletal muscle in normal physiological conditions this energy, i.e., the maximum anaerobic capacity to do work, is calculated to be about 960 J per kg of muscular mass. Such energy decreases as the overall concentration of solutes in the cytosol is increased. Similar results apply to any kind of cell. They provide an essential tool to understand and control the macroscopic response of single cells and multicellular cellular tissues alike. The applications include sport physiology, cell aging, disease produced cell damage, drug absorption capacity, to mention the most obvious ones. PMID- 26651729 TI - Theory of epithelial elasticity. AB - We propose an elastic theory of epithelial monolayers based on a two-dimensional discrete model of dropletlike cells characterized by differential surface tensions of their apical, basal, and lateral sides. We show that the effective tissue bending modulus depends on the apicobasal differential tension and changes sign at the transition from the flat to the fold morphology. We discuss three mechanisms that stabilize the finite-wavelength fold structures: Physical constraint on cell geometry, hard-core interaction between non-neighboring cells, and bending elasticity of the basement membrane. We show that the thickness of the monolayer changes along the waveform and thus needs to be considered as a variable rather than a parameter. Next we show that the coupling between the curvature and the thickness is governed by the apicobasal polarity and that the amplitude of thickness modulation along the waveform is proportional to the apicobasal differential tension. This suggests that intracellular stresses can be measured indirectly by observing easily measurable morphometric parameters. We also study the mechanics of three-dimensional structures with cylindrical symmetry. PMID- 26651730 TI - Totally asymmetric simple exclusion process simulations of molecular motor transport on random networks with asymmetric exit rates. AB - Using the totally asymmetric simple-exclusion-process and mean-field transport theory, we investigate the transport in closed random networks with simple crossing topology-two incoming, two outgoing segments, as a model for molecular motor motion along biopolymer networks. Inspired by in vitro observation of molecular motor motion, we model the motor behavior at the intersections by introducing different exit rates for the two outgoing segments. Our simulations of this simple network reveal surprisingly rich behavior of the transport current with respect to the global density and exit rate ratio. For asymmetric exit rates, we find a broad current plateau at intermediate motor densities resulting from the competition of two subnetwork populations. This current plateau leads to stabilization of transport properties within such networks. PMID- 26651731 TI - Role of connectivity and fluctuations in the nucleation of calcium waves in cardiac cells. AB - Spontaneous calcium release (SCR) occurs when ion channel fluctuations lead to the nucleation of calcium waves in cardiac cells. This phenomenon is important since it has been implicated as a cause of various cardiac arrhythmias. However, to date, it is not understood what determines the timing and location of spontaneous calcium waves within cells. Here, we analyze a simplified model of SCR in which calcium release is modeled as a stochastic processes on a two dimensional network of randomly distributed sites. Using this model we identify the essential parameters describing the system and compute the phase diagram. In particular, we identify a critical line which separates pinned and propagating fronts, and show that above this line wave nucleation is governed by fluctuations and the spatial connectivity of calcium release units. Using a mean-field analysis we show that the sites of wave nucleation are predicted by localized eigenvectors of a matrix representing the network connectivity of release sites. This result provides insight on the interplay between connectivity and fluctuations in the genesis of SCR in cardiac myocytes. PMID- 26651732 TI - Effect of intermodular connection on fast sparse synchronization in clustered small-world neural networks. AB - We consider a clustered network with small-world subnetworks of inhibitory fast spiking interneurons and investigate the effect of intermodular connection on the emergence of fast sparsely synchronized rhythms by varying both the intermodular coupling strength J(inter) and the average number of intermodular links per interneuron M(syn)(inter). In contrast to the case of nonclustered networks, two kinds of sparsely synchronized states such as modular and global synchronization are found. For the case of modular sparse synchronization, the population behavior reveals the modular structure, because the intramodular dynamics of subnetworks make some mismatching. On the other hand, in the case of global sparse synchronization, the population behavior is globally identical, independently of the cluster structure, because the intramodular dynamics of subnetworks make perfect matching. We introduce a realistic cross-correlation modularity measure, representing the matching degree between the instantaneous subpopulation spike rates of the subnetworks, and examine whether the sparse synchronization is global or modular. Depending on its magnitude, the intermodular coupling strength J(inter) seems to play "dual" roles for the pacing between spikes in each subnetwork. For large J(inter), due to strong inhibition it plays a destructive role to "spoil" the pacing between spikes, while for small J(inter) it plays a constructive role to "favor" the pacing between spikes. Through competition between the constructive and the destructive roles of J(inter), there exists an intermediate optimal J(inter) at which the pacing degree between spikes becomes maximal. In contrast, the average number of intermodular links per interneuron M(syn)(inter) seems to play a role just to favor the pacing between spikes. With increasing M(syn)(inter), the pacing degree between spikes increases monotonically thanks to the increase in the degree of effectiveness of global communication between spikes. Furthermore, we employ the realistic sub- and whole-population order parameters, based on the instantaneous sub- and whole-population spike rates, to determine the threshold values for the synchronization-unsynchronization transition in the sub- and whole populations, and the degrees of global and modular sparse synchronization are also measured in terms of the realistic sub- and whole-population statistical-mechanical spiking measures defined by considering both the occupation and the pacing degrees of spikes. It is expected that our results could have implications for the role of the brain plasticity in some functional behaviors associated with population synchronization. PMID- 26651733 TI - Spatial interactions in a modified Daisyworld model: Heat diffusivity and greenhouse effects. AB - In this work we investigate a modified version of the Daisyworld model, originally introduced by Lovelock and Watson to describe in a simple way the interactions between an Earth-like planet, its biosphere, and the incoming solar radiation. Here a spatial dependency on latitude is included, and both a variable heat diffusivity along latitudes and a simple greenhouse effect description are introduced in the model. We show that the spatial interactions between the variables of the system can locally stabilize the coexistence of the two vegetation types. The feedback on albedo is able to generate equilibrium solutions which can efficiently self-regulate the planet climate, even for values of the solar luminosity relatively far from the current Earth conditions. PMID- 26651734 TI - Stochastic entrainment of a stochastic oscillator. AB - In this work, we consider a stochastic oscillator described by a discrete-state continuous-time Markov chain, in which the states are arranged in a circle, and there is a constant probability per unit time of jumping from one state to the next in a specified direction around the circle. At each of a sequence of equally spaced times, the oscillator has a specified probability of being reset to a particular state. The focus of this work is the entrainment of the oscillator by this periodic but stochastic stimulus. We consider a distinguished limit, in which (i) the number of states of the oscillator approaches infinity, as does the probability per unit time of jumping from one state to the next, so that the natural mean period of the oscillator remains constant, (ii) the resetting probability approaches zero, and (iii) the period of the resetting signal approaches a multiple, by a ratio of small integers, of the natural mean period of the oscillator. In this distinguished limit, we use analytic and numerical methods to study the extent to which entrainment occurs. PMID- 26651735 TI - Protein-fluctuation-induced water-pore formation in ion channel voltage-sensor translocation across a lipid bilayer membrane. AB - We have applied a combined fluorescence microscopy and single-ion-channel electric current recording approach, correlating with molecular dynamics (MD) simulations, to study the mechanism of voltage-sensor domain translocation across a lipid bilayer. We use the colicin Ia ion channel as a model system, and our experimental and simulation results show the following: (1) The open-close activity of an activated colicin Ia is not necessarily sensitive to the amplitude of the applied cross-membrane voltage when the cross-membrane voltage is around the resting potential of excitable membranes; and (2) there is a significant probability that the activation of colicin Ia occurs by forming a transient and fluctuating water pore of ~15 A diameter in the lipid bilayer membrane. The location of the water-pore formation is nonrandom and highly specific, right at the insertion site of colicin Ia charged residues in the lipid bilayer membrane, and the formation is intrinsically associated with the polypeptide conformational fluctuations and solvation dynamics. Our results suggest an interesting mechanistic pathway for voltage-sensitive ion channel activation, and specifically for translocation of charged polypeptide chains across the lipid membrane under a transmembrane electric field: the charged polypeptide domain facilitates the formation of hydrophilic water pore in the membrane and diffuses through the hydrophilic pathway across the membrane; i.e., the charged polypeptide chain can cross a lipid membrane without entering into the hydrophobic core of the lipid membrane but entirely through the aqueous and hydrophilic environment to achieve a cross-membrane translocation. This mechanism sheds light on the intensive and fundamental debate on how a hydrophilic and charged peptide domain diffuses across the biologically inaccessible high-energy barrier of the hydrophobic core of a lipid bilayer: The peptide domain does not need to cross the hydrophobic core to move across a lipid bilayer. PMID- 26651736 TI - Energy transfer efficiency in the chromophore network strongly coupled to a vibrational mode. AB - Using methods from condensed matter and statistical physics, we examine the transport of excitons through the photosynthetic complex from a receiving antenna to a reaction center. Writing the equations of motion for the exciton creation annihilation operators, we are able to describe the exciton dynamics, even in the regime when the reorganization energy is of the order of the intrasystem couplings. We determine the exciton transfer efficiency in the presence of a quenching field and protein environment. While the majority of the protein vibrational modes are treated as a heat bath, we address the situation when specific modes are strongly coupled to excitons and examine the effects of these modes on the energy transfer efficiency in the steady-state regime. Using the structural parameters of the Fenna-Matthews-Olson complex, we find that, for vibrational frequencies below 16 meV, the exciton transfer is drastically suppressed. We attribute this effect to the formation of a "mixed exciton vibrational mode" where the exciton is transferred back and forth between the two pigments with the absorption or emission of vibrational quanta, instead of proceeding to the reaction center. The same effect suppresses the quantum beating at the vibrational frequency of 25 meV. We also show that the efficiency of the energy transfer can be enhanced when the vibrational mode strongly couples to the third pigment only, instead of coupling to the entire system. PMID- 26651737 TI - Kinetics of symmetry and asymmetry in a phase-separating bilayer membrane. AB - We simulate a phase-separating bilayer in which the leaflets experience a direct coupling favoring local compositional symmetry ("registered" bilayer phases), and an indirect coupling due to hydrophobic mismatch that favors strong local asymmetry ("antiregistered" bilayer phases). For wide ranges of overall leaflet compositions, multiple competing states are possible. For estimated physical parameters, a quenched bilayer may first evolve toward a metastable state more asymmetric than if the leaflets were uncorrelated; subsequently, it must nucleate to reach its equilibrium, more symmetric, state. These phase-transition kinetics exhibit characteristic signatures through which fundamental and opposing interleaflet interactions may be probed. We emphasize how bilayer phase diagrams with a separate axis for each leaflet can account for overall and local symmetry or asymmetry, and capture a range of observations in the experiment and simulation literature. PMID- 26651738 TI - You can run, you can hide: The epidemiology and statistical mechanics of zombies. AB - We use a popular fictional disease, zombies, in order to introduce techniques used in modern epidemiology modeling, and ideas and techniques used in the numerical study of critical phenomena. We consider variants of zombie models, from fully connected continuous time dynamics to a full scale exact stochastic dynamic simulation of a zombie outbreak on the continental United States. Along the way, we offer a closed form analytical expression for the fully connected differential equation, and demonstrate that the single person per site two dimensional square lattice version of zombies lies in the percolation universality class. We end with a quantitative study of the full scale US outbreak, including the average susceptibility of different geographical regions. PMID- 26651739 TI - Hamiltonian mean field model: Effect of network structure on synchronization dynamics. AB - The Hamiltonian mean field model of coupled inertial Hamiltonian rotors is a prototype for conservative dynamics in systems with long-range interactions. We consider the case where the interactions between the rotors are governed by a network described by a weighted adjacency matrix. By studying the linear stability of the incoherent state, we find that the transition to synchrony begins when the coupling constant K is inversely proportional to the largest eigenvalue of the adjacency matrix. We derive a closed system of equations for a set of local order parameters to study the effect of network heterogeneity on the synchronization of the rotors. When K is just beyond the transition to synchronization, we find that the degree of synchronization is highly dependent on the network's heterogeneity, but that for large K the degree of synchronization is robust to changes in the degree distribution. Our results are illustrated with numerical simulations on Erdos-Renyi networks and networks with power-law degree distributions. PMID- 26651740 TI - Analytical solution and scaling of fluctuations in complex networks traversed by damped, interacting random walkers. AB - A general model for random walks (RWs) on networks is proposed. It incorporates damping and time-dependent links, and it includes standard (undamped, noninteracting) RWs (SRWs), coalescing RWs, and coalescing-branching RWs as special cases. The exact, time-dependent solutions for the average numbers of visits (w) to nodes and their fluctuations (sigma2) are given, and the long-term sigma-w relation is studied. Although sigma ? w(1/2) for SRWs, this power law can be fragile when coalescing-branching interaction is present. Damping, however, often strengthens it but with an exponent generally different from 1/2. PMID- 26651741 TI - Structural versus dynamical origins of mean-field behavior in a self-organized critical model of neuronal avalanches. AB - Critical dynamics of cortical neurons have been intensively studied over the past decade. Neuronal avalanches provide the main experimental as well as theoretical tools to consider criticality in such systems. Experimental studies show that critical neuronal avalanches show mean-field behavior. There are structural as well as recently proposed [Phys. Rev. E 89, 052139 (2014)] dynamical mechanisms that can lead to mean-field behavior. In this work we consider a simple model of neuronal dynamics based on threshold self-organized critical models with synaptic noise. We investigate the role of high-average connectivity, random long-range connections, as well as synaptic noise in achieving mean-field behavior. We employ finite-size scaling in order to extract critical exponents with good accuracy. We conclude that relevant structural mechanisms responsible for mean field behavior cannot be justified in realistic models of the cortex. However, strong dynamical noise, which can have realistic justifications, always leads to mean-field behavior regardless of the underlying structure. Our work provides a different (dynamical) origin than the conventionally accepted (structural) mechanisms for mean-field behavior in neuronal avalanches. PMID- 26651742 TI - Spatial game in cellular automaton evacuation model. AB - For numerical simulations of crowd dynamics in an evacuation we need a computationally light environment, such as the cellular automaton model (CA). By choosing the right model parameters, different types of crowd behavior and collective effects can be produced. But the CA does not answer why, when, and how these different behaviors and collective effects occur. In this article, we present a model, where we couple a spatial evacuation game to the CA. In the game, an agent chooses its strategy by observing its neighbors' strategies. The game matrix changes with the distance to the exit as the evacuation conditions develop. In the resulting model, an agent's strategy choice alters the parameters that govern its behavior in the CA. Thus, with our model, we are able to simulate how evacuation conditions affect the behavior of the crowd. Also, we show that some of the collective effects observed in evacuations are a result of the simple game the agents play. PMID- 26651743 TI - Simple and efficient self-healing strategy for damaged complex networks. AB - The process of destroying a complex network through node removal has been the subject of extensive interest and research. Node loss typically leaves the network disintegrated into many small and isolated clusters. Here we show that these clusters typically remain close to each other and we suggest a simple algorithm that is able to reverse the inflicted damage by restoring the network's functionality. After damage, each node decides independently whether to create a new link depending on the fraction of neighbors it has lost. In addition to relying only on local information, where nodes do not need knowledge of the global network status, we impose the additional constraint that new links should be as short as possible (i.e., that the new edge completes a shortest possible new cycle). We demonstrate that this self-healing method operates very efficiently, both in model and real networks. For example, after removing the most connected airports in the USA, the self-healing algorithm rejoined almost 90% of the surviving airports. PMID- 26651744 TI - Zealotry promotes coexistence in the rock-paper-scissors model of cyclic dominance. AB - Cyclic dominance models, such as the classic rock-paper-scissors (RPS) game, have found real-world applications in biology, ecology, and sociology. A key quantity of interest in such models is the coexistence time, i.e., the time until at least one population type goes extinct. Much recent research has considered conditions that lengthen coexistence times in an RPS model. A general finding is that coexistence is promoted by localized spatial interactions (low mobility), while extinction is fostered by global interactions (high mobility). That is, there exists a mobility threshold which separates a regime of long coexistence from a regime of rapid collapse of coexistence. The key finding of our paper is that if zealots (i.e., nodes able to defeat others while themselves being immune to defeat) of even a single type exist, then system coexistence time can be significantly prolonged, even in the presence of global interactions. This work thus highlights a crucial determinant of system survival time in cyclic dominance models. PMID- 26651745 TI - Multiway spectral community detection in networks. AB - One of the most widely used methods for community detection in networks is the maximization of the quality function known as modularity. Of the many maximization techniques that have been used in this context, some of the most conceptually attractive are the spectral methods, which are based on the eigenvectors of the modularity matrix. Spectral algorithms have, however, been limited, by and large, to the division of networks into only two or three communities, with divisions into more than three being achieved by repeated two way division. Here we present a spectral algorithm that can directly divide a network into any number of communities. The algorithm makes use of a mapping from modularity maximization to a vector partitioning problem, combined with a fast heuristic for vector partitioning. We compare the performance of this spectral algorithm with previous approaches and find it to give superior results, particularly in cases where community sizes are unbalanced. We also give demonstrative applications of the algorithm to two real-world networks and find that it produces results in good agreement with expectations for the networks studied. PMID- 26651746 TI - Communicability angles reveal critical edges for network consensus dynamics. AB - We consider the question of determining how the topological structure influences a consensus dynamical processes taking place on a network. By considering a large data set of real-world networks we first determine that the removal of edges according to their communicability angle, an angle between position vectors of the nodes in an Euclidean communicability space, increases the average time of consensus by a factor of 5.68 in real-world networks. The edge betweenness centrality also identifies, in a smaller proportion, those critical edges for the consensus dynamics; i.e., its removal increases the time of consensus by a factor of 3.70. We justify theoretically these findings on the basis of the role played by the algebraic connectivity and the isoperimetric number of networks on the dynamical process studied and their connections with the properties mentioned before. Finally, we study the role played by global topological parameters of networks on the consensus dynamics. We determine that the network density and the average distance-sum, which is analogous of the node degree for shortest-path distances, account for more than 80% of the variance of the average time of consensus in the real-world networks studied. PMID- 26651747 TI - Universality in survivor distributions: Characterizing the winners of competitive dynamics. AB - We investigate the survivor distributions of a spatially extended model of competitive dynamics in different geometries. The model consists of a deterministic dynamical system of individual agents at specified nodes, which might or might not survive the predatory dynamics: all stochasticity is brought in by the initial state. Every such initial state leads to a unique and extended pattern of survivors and nonsurvivors, which is known as an attractor of the dynamics. We show that the number of such attractors grows exponentially with system size, so that their exact characterization is limited to only very small systems. Given this, we construct an analytical approach based on inhomogeneous mean-field theory to calculate survival probabilities for arbitrary networks. This powerful (albeit approximate) approach shows how universality arises in survivor distributions via a key concept-the dynamical fugacity. Remarkably, in the large-mass limit, the survivor probability of a node becomes independent of network geometry and assumes a simple form which depends only on its mass and degree. PMID- 26651748 TI - Phase transitions in Ising models on directed networks. AB - We examine Ising models with heat-bath dynamics on directed networks. Our simulations show that Ising models on directed triangular and simple cubic lattices undergo a phase transition that most likely belongs to the Ising universality class. On the directed square lattice the model remains paramagnetic at any positive temperature as already reported in some previous studies. We also examine random directed graphs and show that contrary to undirected ones, percolation of directed bonds does not guarantee ferromagnetic ordering. Only above a certain threshold can a random directed graph support finite-temperature ferromagnetic ordering. Such behavior is found also for out-homogeneous random graphs, but in this case the analysis of magnetic and percolative properties can be done exactly. Directed random graphs also differ from undirected ones with respect to zero-temperature freezing. Only at low connectivity do they remain trapped in a disordered configuration. Above a certain threshold, however, the zero-temperature dynamics quickly drives the model toward a broken symmetry (magnetized) state. Only above this threshold, which is almost twice as large as the percolation threshold, do we expect the Ising model to have a positive critical temperature. With a very good accuracy, the behavior on directed random graphs is reproduced within a certain approximate scheme. PMID- 26651749 TI - Phase transitions in the q-voter model with noise on a duplex clique. AB - We study a nonlinear q-voter model with stochastic noise, interpreted in the social context as independence, on a duplex network. To study the role of the multilevelness in this model we propose three methods of transferring the model from a mono- to a multiplex network. They take into account two criteria: one related to the status of independence (LOCAL vs GLOBAL) and one related to peer pressure (AND vs OR). In order to examine the influence of the presence of more than one level in the social network, we perform simulations on a particularly simple multiplex: a duplex clique, which consists of two fully overlapped complete graphs (cliques). Solving numerically the rate equation and simultaneously conducting Monte Carlo simulations, we provide evidence that even a simple rearrangement into a duplex topology may lead to significant changes in the observed behavior. However, qualitative changes in the phase transitions can be observed for only one of the considered rules: LOCAL&AND. For this rule the phase transition becomes discontinuous for q=5, whereas for a monoplex such behavior is observed for q=6. Interestingly, only this rule admits construction of realistic variants of the model, in line with recent social experiments. PMID- 26651750 TI - Estimating interevent time distributions from finite observation periods in communication networks. AB - A diverse variety of processes-including recurrent disease episodes, neuron firing, and communication patterns among humans-can be described using interevent time (IET) distributions. Many such processes are ongoing, although event sequences are only available during a finite observation window. Because the observation time window is more likely to begin or end during long IETs than during short ones, the analysis of such data is susceptible to a bias induced by the finite observation period. In this paper, we illustrate how this length bias is born and how it can be corrected without assuming any particular shape for the IET distribution. To do this, we model event sequences using stationary renewal processes, and we formulate simple heuristics for determining the severity of the bias. To illustrate our results, we focus on the example of empirical communication networks, which are temporal networks that are constructed from communication events. The IET distributions of such systems guide efforts to build models of human behavior, and the variance of IETs is very important for estimating the spreading rate of information in networks of temporal interactions. We analyze several well-known data sets from the literature, and we find that the resulting bias can lead to systematic underestimates of the variance in the IET distributions and that correcting for the bias can lead to qualitatively different results for the tails of the IET distributions. PMID- 26651751 TI - Fractional quantum mechanics on networks: Long-range dynamics and quantum transport. AB - In this paper we study the quantum transport on networks with a temporal evolution governed by the fractional Schrodinger equation. We generalize the dynamics based on continuous-time quantum walks, with transitions to nearest neighbors on the network, to the fractional case that allows long-range displacements. By using the fractional Laplacian matrix of a network, we establish a formalism that combines a long-range dynamics with the quantum superposition of states; this general approach applies to any type of connected undirected networks, including regular, random, and complex networks, and can be implemented from the spectral properties of the Laplacian matrix. We study the fractional dynamics and its capacity to explore the network by means of the transition probability, the average probability of return, and global quantities that characterize the efficiency of this quantum process. As a particular case, we explore analytically these quantities for circulant networks such as rings, interacting cycles, and complete graphs. PMID- 26651752 TI - Detrended fluctuation analysis made flexible to detect range of cross-correlated fluctuations. AB - The detrended cross-correlation coefficient rho(DCCA) has recently been proposed to quantify the strength of cross-correlations on different temporal scales in bivariate, nonstationary time series. It is based on the detrended cross correlation and detrended fluctuation analyses (DCCA and DFA, respectively) and can be viewed as an analog of the Pearson coefficient in the case of the fluctuation analysis. The coefficient rho(DCCA) works well in many practical situations but by construction its applicability is limited to detection of whether two signals are generally cross-correlated, without the possibility to obtain information on the amplitude of fluctuations that are responsible for those cross-correlations. In order to introduce some related flexibility, here we propose an extension of rho(DCCA) that exploits the multifractal versions of DFA and DCCA: multifractal detrended fluctuation analysis and multifractal detrended cross-correlation analysis, respectively. The resulting new coefficient rho(q) not only is able to quantify the strength of correlations but also allows one to identify the range of detrended fluctuation amplitudes that are correlated in two signals under study. We show how the coefficient rho(q) works in practical situations by applying it to stochastic time series representing processes with long memory: autoregressive and multiplicative ones. Such processes are often used to model signals recorded from complex systems and complex physical phenomena like turbulence, so we are convinced that this new measure can successfully be applied in time-series analysis. In particular, we present an example of such application to highly complex empirical data from financial markets. The present formulation can straightforwardly be extended to multivariate data in terms of the q-dependent counterpart of the correlation matrices and then to the network representation. PMID- 26651753 TI - Role of adjacency-matrix degeneracy in maximum-entropy-weighted network models. AB - Complex network null models based on entropy maximization are becoming a powerful tool to characterize and analyze data from real systems. However, it is not easy to extract good and unbiased information from these models: A proper understanding of the nature of the underlying events represented in them is crucial. In this paper we emphasize this fact stressing how an accurate counting of configurations compatible with given constraints is fundamental to build good null models for the case of networks with integer-valued adjacency matrices constructed from an aggregation of one or multiple layers. We show how different assumptions about the elements from which the networks are built give rise to distinctively different statistics, even when considering the same observables to match those of real data. We illustrate our findings by applying the formalism to three data sets using an open-source software package accompanying the present work and demonstrate how such differences are clearly seen when measuring network observables. PMID- 26651754 TI - Spike-count distribution in a neuronal population under weak common stimulation. AB - We study the probability distribution of the number of synchronous action potentials (spike count) in a model network consisting of a homogeneous neural population that is driven by a common time-dependent stimulus. We derive two analytical approximations for the count statistics, which are based on linear response theory and hold true for weak input correlations. Comparison to numerical simulations of populations of integrate-and-fire neurons in different parameter regimes reveals that our theory correctly predicts how much a weak common stimulus increases the probability of common firing and of common silence in the neural population. PMID- 26651755 TI - Kinetic models of opinion formation in the presence of personal conviction. AB - We consider a nonlinear kinetic equation of Boltzmann type, which takes into account the influence of conviction during the formation of opinion in a system of agents, which interact through the binary exchanges, introduced by Toscani [G. Toscani, Commun. Math. Sci. 4, 481 (2006)]. The original exchange mechanism, which is based on the human tendency to compromise and change of opinion through self-thinking, is here modified in the parameters of the compromise and diffusion terms, which now are assumed to depend on the personal degree of conviction. The numerical simulations show that the presence of conviction has the potential to break symmetry, and to produce clusters of opinions. The model is partially inspired by the recent work [L. Pareschi and G. Toscani, Phil. Trans. R. Soc. A 372, 20130396 (2014)], in which the role of knowledge in the formation of wealth distribution has been investigated. PMID- 26651756 TI - Systematic variational method for statistical nonlinear state and parameter estimation. AB - In statistical data assimilation one evaluates the conditional expected values, conditioned on measurements, of interesting quantities on the path of a model through observation and prediction windows. This often requires working with very high dimensional integrals in the discrete time descriptions of the observations and model dynamics, which become functional integrals in the continuous-time limit. Two familiar methods for performing these integrals include (1) Monte Carlo calculations and (2) variational approximations using the method of Laplace plus perturbative corrections to the dominant contributions. We attend here to aspects of the Laplace approximation and develop an annealing method for locating the variational path satisfying the Euler-Lagrange equations that comprises the major contribution to the integrals. This begins with the identification of the minimum action path starting with a situation where the model dynamics is totally unresolved in state space, and the consistent minimum of the variational problem is known. We then proceed to slowly increase the model resolution, seeking to remain in the basin of the minimum action path, until a path that gives the dominant contribution to the integral is identified. After a discussion of some general issues, we give examples of the assimilation process for some simple, instructive models from the geophysical literature. Then we explore a slightly richer model of the same type with two distinct time scales. This is followed by a model characterizing the biophysics of individual neurons. PMID- 26651757 TI - Synchronization of nearly identical dynamical systems: Size instability. AB - We study the generalized synchronization and its stability using the master stability function (MSF) in a network of coupled nearly identical dynamical systems. We extend the MSF approach for the case of degenerate eigenvalues of the coupling matrix. Using the MSF we study the size instability in star and ring networks for coupled nearly identical dynamical systems. In the star network of coupled Rossler systems we show that the critical size beyond which synchronization is unstable can be increased by having a larger frequency for the central node of the star. For the ring network we show that the critical size is not significantly affected by parameter variations. The results are verified by explicit numerical calculations. PMID- 26651758 TI - Reversibility of dynamics and multiple-quantum coherences. AB - In spin systems, the decay of the Loschmidt echo in the time-reversal experiment (evolution-perturbation-time-reversed evolution) is linked to the generation of multiple-quantum (MQ) coherences. Unlimited growth of the MQ coherences leads to irreversibility of dynamics. In some cases, one can expect that the deviation of the Loschmidt echo and the second moment of the MQ intensities distribution are linear in time. The criteria of such behavior, called weak irreversibility, are formulated. The proposed approach can be extended beyond spin systems, in order to analyze some general aspects of reversibility of many-body quantum dynamics. PMID- 26651759 TI - Regularly timed events amid chaos. AB - We show rigorously that the solutions of a class of chaotic oscillators are characterized by regularly timed events in which the derivative of the solution is instantaneously zero. The perfect regularity of these events is in stark contrast with the well-known unpredictability of chaos. We explore some consequences of these regularly timed events through experiments using chaotic electronic circuits. First, we show that a feedback loop can be implemented to phase lock the regularly timed events to a periodic external signal. In this arrangement the external signal regulates the timing of the chaotic signal but does not strictly lock its phase. That is, phase slips of the chaotic oscillation persist without disturbing timing of the regular events. Second, we couple the regularly timed events of one chaotic oscillator to those of another. A state of synchronization is observed where the oscillators exhibit synchronized regular events while their chaotic amplitudes and phases evolve independently. Finally, we add additional coupling to synchronize the amplitudes, as well, however in the opposite direction illustrating the independence of the amplitudes from the regularly timed events. PMID- 26651760 TI - Predictability of critical transitions. AB - Critical transitions in multistable systems have been discussed as models for a variety of phenomena ranging from the extinctions of species to socioeconomic changes and climate transitions between ice ages and warm ages. From bifurcation theory we can expect certain critical transitions to be preceded by a decreased recovery from external perturbations. The consequences of this critical slowing down have been observed as an increase in variance and autocorrelation prior to the transition. However, especially in the presence of noise, it is not clear whether these changes in observation variables are statistically relevant such that they could be used as indicators for critical transitions. In this contribution we investigate the predictability of critical transitions in conceptual models. We study the quadratic integrate-and-fire model and the van der Pol model under the influence of external noise. We focus especially on the statistical analysis of the success of predictions and the overall predictability of the system. The performance of different indicator variables turns out to be dependent on the specific model under study and the conditions of accessing it. Furthermore, we study the influence of the magnitude of transitions on the predictive performance. PMID- 26651761 TI - Characterization of degeneration process in combustion instability based on dynamical systems theory. AB - We present a detailed study on the characterization of the degeneration process in combustion instability based on dynamical systems theory. We deal with combustion instability in a lean premixed-type gas-turbine model combustor, one of the fundamentally and practically important combustion systems. The dynamic behavior of combustion instability in close proximity to lean blowout is dominated by a stochastic process and transits to periodic oscillations created by thermoacoustic combustion oscillations via chaos with increasing equivalence ratio [Chaos 21, 013124 (2011); Chaos 22, 043128 (2012)]. Thermoacoustic combustion oscillations degenerate with a further increase in the equivalence ratio, and the dynamic behavior leads to chaotic fluctuations via quasiperiodic oscillations. The concept of dynamical systems theory presented here allows us to clarify the nonlinear characteristics hidden in complex combustion dynamics. PMID- 26651762 TI - Classical to quantum correspondence in dissipative directed transport. AB - We compare the quantum and classical properties of the (quantum) isoperiodic stable structures [(Q)ISSs], which organize the parameter space of a paradigmatic dissipative ratchet model, i.e., the dissipative modified kicked rotator. We study the spectral behavior of the corresponding classical Perron-Frobenius operators with thermal noise and the quantum superoperators without it for small h(eff) values. We find a remarkable similarity between the classical and quantum spectra. This finding significantly extends previous results-obtained for the mean currents and asymptotic distributions only-and, on the other hand, unveils a classical to quantum correspondence mechanism where the classical noise is qualitatively different from the quantum one. This is crucial not only for simple attractors but also for chaotic ones, where just analyzing the asymptotic distribution is revealed as insufficient. Moreover, we provide with a detailed characterization of relevant eigenvectors by means of the corresponding Weyl Wigner distributions, in order to better identify similarities and differences. Finally, this model being generic, it allows us to conjecture that this classical to quantum correspondence mechanism is a universal feature of dissipative systems. PMID- 26651763 TI - Revival of oscillation from mean-field-induced death: Theory and experiment. AB - The revival of oscillation and maintaining rhythmicity in a network of coupled oscillators offer an open challenge to researchers as the cessation of oscillation often leads to a fatal system degradation and an irrecoverable malfunctioning in many physical, biological, and physiological systems. Recently a general technique of restoration of rhythmicity in diffusively coupled networks of nonlinear oscillators has been proposed in Zou et al. [Nat. Commun. 6, 7709 (2015)], where it is shown that a proper feedback parameter that controls the rate of diffusion can effectively revive oscillation from an oscillation suppressed state. In this paper we show that the mean-field diffusive coupling, which can suppress oscillation even in a network of identical oscillators, can be modified in order to revoke the cessation of oscillation induced by it. Using a rigorous bifurcation analysis we show that, unlike other diffusive coupling schemes, here one has two control parameters, namely the density of the mean field and the feedback parameter that can be controlled to revive oscillation from a death state. We demonstrate that an appropriate choice of density of the mean field is capable of inducing rhythmicity even in the presence of complete diffusion, which is a unique feature of this mean-field coupling that is not available in other coupling schemes. Finally, we report the experimental observation of revival of oscillation from the mean-field-induced oscillation suppression state that supports our theoretical results. PMID- 26651764 TI - Toward the Darwinian transition: Switching between distributed and speciated states in a simple model of early life. AB - It has been hypothesized that in the era just before the last universal common ancestor emerged, life on earth was fundamentally collective. Ancient life forms shared their genetic material freely through massive horizontal gene transfer (HGT). At a certain point, however, life made a transition to the modern era of individuality and vertical descent. Here we present a minimal model for stochastic processes potentially contributing to this hypothesized "Darwinian transition." The model suggests that HGT-dominated dynamics may have been intermittently interrupted by selection-driven processes during which genotypes became fitter and decreased their inclination toward HGT. Stochastic switching in the population dynamics with three-point (hypernetwork) interactions may have destabilized the HGT-dominated collective state and essentially contributed to the emergence of vertical descent and the first well-defined species in early evolution. A systematic nonlinear analysis of the stochastic model dynamics covering key features of evolutionary processes (such as selection, mutation, drift and HGT) supports this view. Our findings thus suggest a viable direction out of early collective evolution, potentially enabling the start of individuality and vertical Darwinian evolution. PMID- 26651765 TI - Experimental observation of multistability and dynamic attractors in silicon central pattern generators. AB - We report on the multistability of chaotic networks of silicon neurons and demonstrate how spatiotemporal sequences of voltage oscillations are selected with timed current stimuli. A three neuron central pattern generator was built by interconnecting Hodgkin-Huxley neurons with mutually inhibitory links mimicking gap junctions. By systematically varying the timing of current stimuli applied to individual neurons, we generate the phase lag maps of neuronal oscillators and study their dependence on the network connectivity. We identify up to six attractors consisting of triphasic sequences of unevenly spaced pulses propagating clockwise and anticlockwise. While confirming theoretical predictions, our experiments reveal more complex oscillatory patterns shaped by the ratio of the pulse width to the oscillation period. Our work contributes to validating the command neuron hypothesis. PMID- 26651766 TI - Synchronization of cells with activator-inhibitor pathways through adaptive environment-mediated coupling. AB - In this paper, we report the synchronized dynamics of cells with activator inhibitor pathways via an adaptive environment-mediated coupling scheme with feedbacks and control mechanisms. The adaptive character of the extracellular medium is modeled via its damping parameter as a physiological response aiming at annihilating the cellular differentiation existing between the chaotic biochemical pathways of the cells, in order to preserve homeostasis. We perform an investigation on the existence and stability of the synchronization manifold of the coupled system under the proposed coupling pattern. Both mathematical and computational tools suggest the accessibility of conducive prerequisites (conditions) for the emergence of a robust synchronous regime. The relevance of a phase-synchronized dynamics is appraised and several numerical indicators advocate for the prevalence of this fascinating phenomenon among the interacting cells in the phase space. PMID- 26651767 TI - Experimental study of synchronization of coupled electrical self-oscillators and comparison to the Sakaguchi-Kuramoto model. AB - We explore the collective phase dynamics of Wien-bridge oscillators coupled resistively. We carefully analyze the behavior of two coupled oscillators, obtaining a transformation from voltage to effective phase. From the phase dynamics we show that the coupling can be quantitatively described by Sakaguchi's modification to the Kuramoto model. We also examine an ensemble of oscillators whose frequencies are taken from a flat distribution within a fixed frequency interval. We characterize in detail the synchronized cluster, its initial formation, as well as its effect on unsynchronized oscillators, all as a function of a global coupling strength. PMID- 26651768 TI - Mixed-mode oscillation suppression states in coupled oscillators. AB - We report a collective dynamical state, namely the mixed-mode oscillation suppression state where the steady states of the state variables of a system of coupled oscillators show heterogeneous behaviors. We identify two variants of it: The first one is a mixed-mode death (MMD) state, which is an interesting oscillation death state, where a set of variables show dissimilar values, while the rest arrive at a common value. In the second mixed death state, bistable and monostable nontrivial homogeneous steady states appear simultaneously to a different set of variables (we refer to it as the MNAD state). We find these states in the paradigmatic chaotic Lorenz system and Lorenz-like system under generic coupling schemes. We identify that while the reflection symmetry breaking is responsible for the MNAD state, the breaking of both the reflection and translational symmetries result in the MMD state. Using a rigorous bifurcation analysis we establish the occurrence of the MMD and MNAD states, and map their transition routes in parameter space. Moreover, we report experimental observation of the MMD and MNAD states that supports our theoretical results. We believe that this study will broaden our understanding of oscillation suppression states; subsequently, it may have applications in many real physical systems, such as laser and geomagnetic systems, whose mathematical models mimic the Lorenz system. PMID- 26651769 TI - Flow-induced arrest of spatiotemporal chaos and transition to a stationary pattern in the Gray-Scott model. AB - We examine the prototypical Gray-Scott model, which mimics cubic autocatalytic reaction with linear decay of the autocatalyst, to model the kinetics of a reaction-diffusion system subjected to advective streamline flow. For a proper choice of boundary conditions and parameter space, the system admits wave-induced spatiotemporal chaos in the absence of flow. We show that flow above a critical value leads to an arrest of the spatiotemporal chaos due to a change in the instability from absolute to convective type. Furthermore, stationary spatial structures are borne out of a second successive bifurcation for yet another critical flow value. The theoretical formulations are corroborated by extensive numerical simulation of the full reaction-diffusion-advection system in one dimension. PMID- 26651770 TI - Stable and transient multicluster oscillation death in nonlocally coupled networks. AB - In a network of nonlocally coupled Stuart-Landau oscillators with symmetry breaking coupling, we study numerically, and explain analytically, a family of inhomogeneous steady states (oscillation death). They exhibit multicluster patterns, depending on the cluster distribution prescribed by the initial conditions. Besides stable oscillation death, we also find a regime of long transients asymptotically approaching synchronized oscillations. To explain these phenomena analytically in dependence on the coupling range and the coupling strength, we first use a mean-field approximation, which works well for large coupling ranges but fails for coupling ranges, which are small compared to the cluster size. Going beyond standard mean-field theory, we predict the boundaries of the different stability regimes as well as the transient times analytically in excellent agreement with numerical results. PMID- 26651771 TI - Localized modes in nonlinear binary kagome ribbons. AB - The localized mode propagation in binary nonlinear kagome ribbons is investigated with the premise to ensure controlled light propagation through photonic lattice media. Particularity of the linear system characterized by the dispersionless flat band in the spectrum is the opening of new minigaps due to the "binarism." Together with the presence of nonlinearity, this determines the guiding mode types and properties. Nonlinearity destabilizes the staggered rings found to be nondiffracting in the linear system, but can give rise to dynamically stable ringlike solutions of several types: unstaggered rings, low-power staggered rings, hour-glass-like solutions, and vortex rings with high power. The type of solutions, i.e., the energy and angular momentum circulation through the nonlinear lattice, can be controlled by suitable initial excitation of the ribbon. In addition, by controlling the system "binarism" various localized modes can be generated and guided through the system, owing to the opening of the minigaps in the spectrum. All these findings offer diverse technical possibilities, especially with respect to the high-speed optical communications and high-power lasers. PMID- 26651772 TI - Switching synchronization in one-dimensional memristive networks. AB - We report on a switching synchronization phenomenon in one-dimensional memristive networks, which occurs when several memristive systems with different switching constants are switched from the high- to low-resistance state. Our numerical simulations show that such a collective behavior is especially pronounced when the applied voltage slightly exceeds the combined threshold voltage of memristive systems. Moreover, a finite increase in the network switching time is found compared to the average switching time of individual systems. An analytical model is presented to explain our observations. Using this model, we have derived asymptotic expressions for memory resistances at short and long times, which are in excellent agreement with results of our numerical simulations. PMID- 26651773 TI - Hydrodynamic stability of three-dimensional homogeneous flow topologies. AB - This article examines the hydrodynamic stability of various homogeneous three dimensional flow topologies. The influence of inertial and pressure effects on the stability of flows undergoing strain, rotation, convergence, divergence, and swirl are isolated. In marked contrast to two-dimensional topologies, for three dimensional flows the inertial effects are always destabilizing, whereas pressure effects are always stabilizing. In streamline topologies with a negative velocity gradient third invariant, inertial effects prevail leading to instability. Vortex stretching is identified as the underlying instability mechanism. In flows with positive velocity-gradient third derivative, pressure overcomes inertial effects to stabilize the flow. PMID- 26651775 TI - Energy-decomposition analysis for viscous free-surface flows. AB - This work is dedicated to the energy decomposition analysis of a viscous free surface flow. In the presence of a free surface, the viscous dissipation for a Newtonian liquid can be decomposed into two terms: an enstrophy component and a free-surface deformation component. The latter requires the evaluation of volume and surface integrals in the meshless framework. The analysis is based on the weakly compressible smoothed particle hydrodynamics formalism. The behavior of the energy terms is studied in standing wave problems by changing the viscosity and the wave amplitude. Finally, an analysis of a complex shallow water breaking wave case is provided. It is shown that in presence of intense breaking phenomena the two energy components are always comparable, whereas generally the free surface component is dominant on the viscous dissipation of gravity waves. PMID- 26651774 TI - Hydrodynamic correlations in shear flow: Multiparticle-collision-dynamics simulation study. AB - The nonequilibrium hydrodynamic correlations of a multiparticle-collision dynamics (MPC) fluid in shear flow are studied by analytical calculations and simulations. The Navier-Stokes equations for a MPC fluid are linearized about the shear flow and the hydrodynamic modes are evaluated as an expansion in the wave vector. The shear-rate dependence and anisotropy of the transverse and longitudinal velocity correlations are analyzed. We demonstrate that hydrodynamic correlations in shear flow are anisotropic, specifically, the two transverse modes are no longer identical. In addition, our simulations reveal the directional dependence of the frequency and attenuation of the longitudinal velocity correlation function. Furthermore, the velocity autocorrelation functions of a tagged fluid particle in shear flow are determined. The simulation results for various hydrodynamic correlations agree very well with the theoretical predictions. PMID- 26651776 TI - Impact of the Peterlin approximation on polymer dynamics in turbulent flows. AB - We study the impact of the Peterlin approximation on the statistics of the end-to end separation of polymers in a turbulent flow. The finitely extensible nonlinear elastic (FENE) model and the FENE model with the Peterlin approximation (FENE-P) are numerically integrated along a large number of Lagrangian trajectories resulting from a direct numerical simulation of three-dimensional homogeneous isotropic turbulence. Although the FENE-P model yields results in qualitative agreement with those of the FENE model, quantitative differences emerge. The steady-state probability of large extensions is overestimated by the FENE-P model. The alignment of polymers with the eigenvectors of the rate-of-strain tensor and with the direction of vorticity is weaker when the Peterlin approximation is used. At large Weissenberg numbers, the correlation times of both the extension and of the orientation of polymers are underestimated by the FENE-P model. PMID- 26651777 TI - Impact of a single drop on a flowing liquid film. AB - The impact of a single liquid drop on a flowing liquid film is experimentally and theoretically studied. The drop impact produces a crownlike rising liquid sheet, which radially expands. Small droplets can be formed from the crown sheet, resulting in splash. The present study results in three major contributions. (1) A theoretical model is developed to predict the expansion of the crown base. The model with an introduced energy loss factor is shown to be in satisfactory agreement with our experimental observations of drop impact on both stationary and flowing films. The energy loss factor is correlated to the properties of the film and drop. (2) Analysis is conducted to derive an equation for evaluating the stretching rate of the rising crown sheet, which is the local gradient of the rising velocity at the top edge of the crown sheet. It shows that the highest stretching rate appears where the drop spreading flow is right opposite to the film flow, which helps explain why the same location is most probable for splash to take place. (3) A parameter as a function of modified Weber and Reynolds numbers is defined to predict splash and nonsplash of drop impact on flowing films. The two nondimensional numbers evaluate the competition of the two flows (drop and film) against viscosity and surface tension effects. A threshold value of the parameter is found for the occurrence of splash impact on flowing films. PMID- 26651778 TI - Heat transfer enhancement induced by wall inclination in turbulent thermal convection. AB - We present a series of numerical simulations of turbulent thermal convection of air in an intermediate range or Rayleigh numbers (10(6)<=Ra<=10(9)) with different configurations of a thermally active lower surface. The geometry of the lower surface is designed in such a way that it represents a simplified version of a mountain slope with different inclinations (i.e., "Lambda"- and "V"-shaped geometry). We find that different wall inclinations significantly affect the local heat transfer by imposing local clustering of instantaneous thermal plumes along the inclination peaks. The present results reveal that significant enhancement of the integral heat transfer can be obtained (up to 32%) when compared to a standard Rayleigh-Benard configuration with flat horizontal walls. This is achieved through combined effects of the enlargement of the heated surface and reorganization of the large-scale flow structures. PMID- 26651779 TI - Nonmodal linear stability analysis of miscible viscous fingering in porous media. AB - The nonmodal linear stability of miscible viscous fingering in a two-dimensional homogeneous porous medium has been investigated. The linearized perturbed equations for Darcy's law coupled with a convection-diffusion equation is discretized using a finite difference method. The resultant initial value problem is solved by a fourth-order Runge-Kutta method, followed by a singular value decomposition of the propagator matrix. Particular attention is given to the transient behavior rather than the long-time behavior of eigenmodes predicted by the traditional modal analysis. The transient behaviors of the response to external excitations and the response to initial conditions are studied by examining the epsilon-pseudospectra structures and the largest energy growth function, respectively. With the help of nonmodal stability analysis we demonstrate that at early times the displacement flow is dominated by diffusion and the perturbations decay. At later times, when convection dominates diffusion, perturbations grow. Furthermore, we show that the dominant perturbation that experiences the maximum amplification within the linear regime lead to the transient growth. These two important features were previously unattainable in the existing linear stability methods for miscible viscous fingering. To explore the relevance of the optimal perturbation obtained from nonmodal analysis, we performed direct numerical simulations using a highly accurate pseudospectral method. Furthermore, a comparison of the present stability analysis with existing modal and initial value approach is also presented. It is shown that the nonmodal stability results are in better agreement than the other existing stability analyses, with those obtained from direct numerical simulations. PMID- 26651780 TI - Locomotion of a microorganism in weakly viscoelastic liquids. AB - In the present work we study the motion of microorganisms swimming by an axisymmetric distribution of surface tangential velocity in a weakly viscoelastic fluid. The second-order fluid constitutive equation is used to model the suspending fluid, while the well-known "squirmer model" [M. J. Lighthill, Comm. Pure Appl. Math. 5, 109 (1952); J. R. Blake, J. Fluid Mech. 46, 199 (1971)] is employed to describe the organism propulsion mechanism. A regular perturbation expansion up to first order in the Deborah number is performed, and the generalized reciprocity theorem from Stokes flow theory is then used, to derive analytical formulas for the squirmer velocity. Results show that "neutral" squirmers are unaffected by viscoelasticity, whereas "pullers" and "pushers" are slowed down and hastened, respectively. The power dissipated by the swimming microorganism and the "swimming efficiency" are also analytically quantified. PMID- 26651781 TI - Near-surface viscosity effects on capillary rise of water in nanotubes. AB - In this paper, we present an approach for predicting nanoscale capillary imbibitions using the Lucas-Washburn (LW) theory. Molecular dynamics (MD) simulations were employed to investigate the effects of surface forces on the viscosity of liquid water. This provides an update to the modified LW equation that considered only a nanoscale slip length. An initial water nanodroplet study was performed to properly elucidate the wetting behavior of copper and gold surfaces. Intermolecular interaction strengths between water and corresponding solid surfaces were determined by matching the contact angle values obtained by experimental measurements. The migration of liquid water into copper and gold capillaries was measured by MD simulations and was found to differ from the modified LW equation. We found that the liquid layering in the vicinity of the solid surface induces a higher density and viscosity, leading to a slower MD uptake of fluid into the capillaries than was theoretically predicted. The near surface viscosity for the nanoscale-confined water was defined and calculated for the thin film of water that was sheared between the two solid surfaces, as the ratio of water shear stress to the applied shear rate. Considering the effects of both the interface viscosity and slip length of the fluid, we successfully predicted the MD-measured fluid rise in the nanotubes. PMID- 26651782 TI - Turbulence constitutive modeling of the square root of the Reynolds stress. AB - A methodology for turbulence constitutive modeling is discussed on the basis of the square-root tensor of the Reynolds stress. The present methodology can satisfy the realizability condition for the Reynolds stress proposed by Schumann [Phys. Fluids 20, 721 (1977)] in a more general manner than the conventional methodologies. The definition and uniqueness of the square-root tensor have been discussed, and its boundary condition has been properly obtained consistently with that of the Reynolds stress. Examples of possible constitutive models of both tensor-expansion and transport-equation types have been proposed. PMID- 26651783 TI - Effect of inertia on laminar swimming and flying of an assembly of rigid spheres in an incompressible viscous fluid. AB - A mechanical model of swimming and flying in an incompressible viscous fluid in the absence of gravity is studied on the basis of assumed equations of motion. The system is modeled as an assembly of rigid spheres subject to elastic direct interactions and to periodic actuating forces which sum to zero. Hydrodynamic interactions are taken into account in the virtual mass matrix and in the friction matrix of the assembly. An equation of motion is derived for the velocity of the geometric center of the assembly. The mean power is calculated as the mean rate of dissipation. The full range of viscosity is covered, so that the theory can be applied to the flying of birds, as well as to the swimming of fish or bacteria. As an example a system of three equal spheres moving along a common axis is studied. PMID- 26651784 TI - Collision model for fully resolved simulations of flows laden with finite-size particles. AB - We present a collision model for particle-particle and particle-wall interactions in interface-resolved simulations of particle-laden flows. Three types of interparticle interactions are taken into account: (1) long- and (2) short-range hydrodynamic interactions, and (3) solid-solid contact. Long-range interactions are incorporated through an efficient and second-order-accurate immersed boundary method (IBM). Short-range interactions are also partly reproduced by the IBM. However, since the IBM uses a fixed grid, a lubrication model is needed for an interparticle gap width smaller than the grid spacing. The lubrication model is based on asymptotic expansions of analytical solutions for canonical lubrication interactions between spheres in the Stokes regime. Roughness effects are incorporated by making the lubrication correction independent of the gap width for gap widths smaller than ~1% of the particle radius. This correction is applied until the particles reach solid-solid contact. To model solid-solid contact we use a variant of a linear soft-sphere collision model capable of stretching the collision time. This choice is computationally attractive because it allows us to reduce the number of time steps required for integrating the collision force accurately and is physically realistic, provided that the prescribed collision time is much smaller than the characteristic time scale of particle motion. We verified the numerical implementation of our collision model and validated it against several benchmark cases for immersed head-on particle wall and particle-particle collisions, and oblique particle-wall collisions. The results show good agreement with experimental data. PMID- 26651785 TI - Anomalous scaling in magnetohydrodynamic turbulence: Effects of anisotropy and compressibility in the kinematic approximation. AB - The field-theoretic renormalization group and the operator product expansion are applied to the model of passive vector (magnetic) field advected by a random turbulent velocity field. The latter is governed by the Navier-Stokes equation for compressible fluid, subject to external random force with the covariance ? delta(t-t')k(4-d-y), where d is the dimension of space and y is an arbitrary exponent. From physics viewpoints, the model describes magnetohydrodynamic turbulence in the so-called kinematic approximation, where the effects of the magnetic field on the dynamics of the fluid are neglected. The original stochastic problem is reformulated as a multiplicatively renormalizable field theoretic model; the corresponding renormalization group equations possess an infrared attractive fixed point. It is shown that various correlation functions of the magnetic field and its powers demonstrate anomalous scaling behavior in the inertial-convective range already for small values of y. The corresponding anomalous exponents, identified with scaling (critical) dimensions of certain composite fields ("operators" in the quantum-field terminology), can be systematically calculated as series in y. The practical calculation is performed in the leading one-loop approximation, including exponents in anisotropic contributions. It should be emphasized that, in contrast to Gaussian ensembles with finite correlation time, the model and the perturbation theory presented here are manifestly Galilean covariant. PMID- 26651786 TI - Capillary imbibition of aqueous foams by miscible and nonmiscible liquids. AB - When put in contact with a large liquid drop, dry foams wick owing to surface tension-driven flows until reaching equilibrium. This work is devoted to the dynamics of this imbibition process. We consider imbibition of both wetting or nonwetting liquid, by putting the dry foam into contact either with the foaming solution that constitutes the foam or with organic oils. Indeed, with the appropriate choice of surfactants, oil spontaneously invades the liquid network of the foam without damaging it. Our experiments show an early-time dynamics in t(1/2) followed by a late-time dynamics in t(1/4). These features, which differ from theoretical works predicting a t(1/3) dynamics, are rationalized considering the influence of the initial liquid fraction of the foam in the driving capillary force and the impact of gravity through the capillary-gravity equilibrium. PMID- 26651787 TI - Bifurcations of rotating waves in rotating spherical shell convection. AB - The dynamics and bifurcations of convective waves in rotating and buoyancy-driven spherical Rayleigh-Benard convection are investigated numerically. The solution branches that arise as rotating waves (RWs) are traced by means of path-following methods, by varying the Rayleigh number as a control parameter for different rotation rates. The dependence of the azimuthal drift frequency of the RWs on the Ekman and Rayleigh numbers is determined and discussed. The influence of the rotation rate on the generation and stability of secondary branches is demonstrated. Multistability is typical in the parameter range considered. PMID- 26651788 TI - Model of heap formation in vibrated gravitational suspensions. AB - In vertically vibrated dense suspensions, several localized structures have been discovered, such as heaps, stable holes, expanding holes, and replicating holes. Because an inclined free fluid surface is difficult to maintain because of gravitational pressure, the mechanism of those structures is not understood intuitively. In this paper, as a candidate for the driving mechanism, we focus on the boundary condition on a solid wall: the slip-nonslip switching boundary condition in synchronization with vertical vibration. By applying the lubrication approximation, we derived the time evolution equation of the fluid thickness from the Oldroyd-B fluid model. In our model we show that the initially flat fluid layer becomes unstable in a subcritical manner, and heaps and convectional flow appear. The obtained results are consistent with those observed experimentally. We also find that heaps climb a slope when the bottom is slightly inclined. We show that viscoelasticity enhances heap formation and climbing of a heap on the slope. PMID- 26651789 TI - Current inversions induced by resonant coupling to surface waves in a nanosized water pump. AB - We conducted a molecular dynamics simulation to investigate current inversions in a nanosized water pump based on a single-walled carbon nanotube powered by mechanical vibration. It was found that the water current depended sensitively on the frequency of mechanical vibration. Especially in the resonance region, the nanoscale pump underwent reversals of the water current. This phenomenon was attributed to the dynamics competition of the water molecules in the two sections (the left and right parts) divided by the vibrating atom and the differences in phase and decay between the two mechanical waves generated by mechanical vibration and propagating in opposite directions toward the two ends of the carbon nanotube. Our findings provide an insight into water transportation through nanosized pumps and have potential in the design of high-flux nanofluidic systems and nanoscale energy converters. PMID- 26651790 TI - Ring-bursting behavior en route to turbulence in narrow-gap Taylor-Couette flows. AB - We investigate the Taylor-Couette system where the radius ratio is close to unity. Systematically increasing the Reynolds number, we observe a number of previously known transitions, such as one from the classical Taylor vortex flow (TVF) to wavy vortex flow (WVF) and the transition to fully developed turbulence. Prior to the onset of turbulence, we observe intermittent bursting patterns of localized turbulent patches, confirming the experimentally observed pattern of very short wavelength bursts (VSWBs). A striking finding is that, for a Reynolds number larger than that for the onset of VSWBs, a new type of intermittently bursting behavior emerges: patterns of azimuthally closed rings of various orders. We call them ring-bursting patterns, which surround the cylinder completely but remain localized and separated in the axial direction through nonturbulent wavy structures. We employ a number of quantitative measures including the cross-flow energy to characterize the ring-bursting patterns and to distinguish them from the background flow. These patterns are interesting because they do not occur in the wide-gap Taylor-Couette flow systems. The narrow-gap regime is less studied but certainly deserves further attention to gain deeper insights into complex flow dynamics in fluids. PMID- 26651791 TI - Derivation of the Biot-Savart equation from the nonlinear Schrodinger equation. AB - We present a systematic derivation of the Biot-Savart equation from the nonlinear Schrodinger equation, in the limit when the curvature radius of vortex lines and the intervortex distance are much greater than the vortex healing length, or core radius. We derive the Biot-Savart equations in Hamiltonian form with Hamiltonian expressed in terms of vortex lines,H=kappa(2)/8pi?(|s-s'|>xi(*))(ds.ds')/|s s'|,with cutoff length xi(*)~0.3416293/?(rho(0)), where rho(0) is the background condensate density far from the vortex lines and kappa is the quantum of circulation. PMID- 26651792 TI - Kinetic and dynamic probability-density-function descriptions of disperse turbulent two-phase flows. AB - This article analyzes the status of two classical one-particle probability density function (PDF) descriptions of the dynamics of discrete particles dispersed in turbulent flows. The first PDF formulation considers only the process made up by particle position and velocity Z(p)=(x(p),U(p)) and is represented by its PDF p(t; y(p),V(p)) which is the solution of a kinetic PDF equation obtained through a flux closure based on the Furutsu-Novikov theorem. The second PDF formulation includes fluid variables into the particle state vector, for example, the fluid velocity seen by particles Z(p)=(x(p),U(p),U(s)), and, consequently, handles an extended PDF p(t; y(p),V(p),V(s)) which is the solution of a dynamic PDF equation. For high-Reynolds-number fluid flows, a typical formulation of the latter category relies on a Langevin model for the trajectories of the fluid seen or, conversely, on a Fokker-Planck equation for the extended PDF. In the present work, a new derivation of the kinetic PDF equation is worked out and new physical expressions of the dispersion tensors entering the kinetic PDF equation are obtained by starting from the extended PDF and integrating over the fluid seen. This demonstrates that, under the same assumption of a Gaussian colored noise and irrespective of the specific stochastic model chosen for the fluid seen, the kinetic PDF description is the marginal of a dynamic PDF one. However, a detailed analysis reveals that kinetic PDF models of particle dynamics in turbulent flows described by statistical correlations constitute incomplete stand-alone PDF descriptions and, moreover, that present kinetic-PDF equations are mathematically ill posed. This is shown to be the consequence of the non-Markovian characteristic of the stochastic process retained to describe the system and the use of an external colored noise. Furthermore, developments bring out that well-posed PDF descriptions are essentially due to a proper choice of the variables selected to describe physical systems and guidelines are formulated to emphasize the key role played by the notion of slow and fast variables. PMID- 26651793 TI - Effect of the vertical component of diffusion on passive scalar transport in an isolated vortex model. AB - On the basis of the ellipsoidal vortex model and a Monte-Carlo-type diffusion simulation, we examine the flux and ensuing distribution of passive fluid particles through the boundary of an idealized geophysical vortex. Our focus is on features that the horizontal and vertical diffusion components introduce into the fluid particle transport. We examine the concurrent effect of both components, and we compare it with the only horizontal diffusion impact. We analyze the ellipsoid vortex model in two cases: (i) the steady state when the ellipsoid is motionless, i.e., there is no variation in its axes' lengths, and consequently the exterior fluid is not being stirred; (ii) the perturbed case when the ellipsoid rotates periodically, varying it axes' lengths, which results in the appearance of stirred fluid outside the ellipsoid. Influenced by diffusion, a fluid particle is now permitted to move to another vertical horizon, thus there is an increased possibility that the particle will eventually be located in the exterior stirred region rather than in the ellipsoid vortex with the regular dynamics. This is because the area of the horizontal section of the ellipsoid vortex decreases with depth, but the region of stirred exterior fluid extends significantly deeper. Numerical calculations show that factoring in the vertical component of diffusion significantly affects scalar spreading in the horizontal plane in the perturbed case, while in the steady state the vertical component of diffusion only induces dispersion linear growth according to a Gaussian distribution. PMID- 26651794 TI - Droplet impact on deep liquid pools: Rayleigh jet to formation of secondary droplets. AB - The impact of droplets on a deep pool has applications in cleaning up oil spills, spray cooling, painting, inkjet printing, and forensic analysis, relying on the changes in properties such as viscosity, interfacial tension, and density. Despite the exhaustive research on different aspects of droplet impact, it is not clear how liquid properties can affect the instabilities leading to Rayleigh jet breakup and number of daughter drops formed after its pinch-off. In this article, through systematic experiments we investigate the droplet impact phenomena by varying viscosity and surface tension of liquids as well as impact speeds. Further, using numerical simulations, we show that Rayleigh-Plateau instability is influenced by these parameters, and capillary time scale is the appropriate scale to normalize the breakup time. Based on Ohnesorge number (Oh) and impact Weber number (We), a regime map for no breakup, Rayleigh jet breakup, and crown splash is suggested. Interestingly, crown splash is observed to occur at all Ohnesorge numbers; however, at high Oh, a large portion of kinetic energy is dissipated, and thus the Rayleigh jet is suppressed regardless of high impact velocity. The normalized required time for the Rayleigh jet to reach its peak varies linearly with the critical height of the jet. PMID- 26651795 TI - Onset of dissolution-driven instabilities in fluids with nonmonotonic density profile. AB - Analog systems have recently been used in several experiments in the context of convective mixing of CO(2). We generalize the nonmonotonic density dependence of the growth of instabilities and provide a scaling relation for the onset of instability. The results of linear stability analysis and direct numerical simulations show that these fluids do not resemble the dynamics of CO(2)-water convective instabilities. A typical analog system, such as water-propylene glycol, is found to be less unstable than CO(2)-water. These results provide a basis for further research and proper selection of analog systems and are essential to the interpretation of experiments. PMID- 26651796 TI - Electromotive force due to magnetohydrodynamic fluctuations in sheared rotating turbulence. AB - This article presents a calculation of the mean electromotive force arising from general small-scale magnetohydrodynamical turbulence, within the framework of the second-order correlation approximation. With the goal of improving understanding of the accretion disk dynamo, effects arising through small-scale magnetic fluctuations, velocity gradients, density and turbulence stratification, and rotation, are included. The primary result, which supplements numerical findings, is that an off-diagonal turbulent resistivity due to magnetic fluctuations can produce large-scale dynamo action-the magnetic analog of the "shear-current" effect. In addition, consideration of alpha effects in the stratified regions of disks gives the puzzling result that there is no strong prediction for a sign of alpha, since the effects due to kinetic and magnetic fluctuations, as well as those due to shear and rotation, are each of opposing signs and tend to cancel each other. PMID- 26651797 TI - Quasicollisional magneto-optic effects in collisionless plasmas with sub-Larmor scale electromagnetic fluctuations. AB - High-amplitude, chaotic or turbulent electromagnetic fluctuations are ubiquitous in high-energy-density laboratory and astrophysical plasmas, where they can be excited by various kinetic-streaming and/or anisotropy-driven instabilities, such as the Weibel instability. These fields typically exist on "sub-Larmor scales" scales smaller than the electron Larmor radius. Electrons moving through such magnetic fields undergo small-angle stochastic deflections of their pitch angles, thus establishing diffusive transport on long time scales. We show that this behavior, under certain conditions, is equivalent to Coulomb collisions in collisional plasmas. The magnetic pitch-angle diffusion coefficient, which acts as an effective "collision" frequency, may be substantial in these, otherwise, collisionless environments. We show that this effect, colloquially referred to as the plasma "quasicollisionality," may radically alter the expected radiative transport properties of candidate plasmas. We argue that the modified magneto optic effects in these plasmas provide an attractive, radiative diagnostic tool for the exploration and characterization of small-scale magnetic turbulence, as well as affect inertial confinement fusion and other laser-plasma experiments. PMID- 26651798 TI - Simulation of emission spectra from nonuniform reactive laser-induced plasmas. AB - We demonstrate that chemical reactions leading to the formation of AlO radicals in plasmas produced by ablation of aluminum or Ti-sapphire with ultraviolet nanosecond laser pulses can be predicted by the model of local thermodynamic equilibrium. Therefore, emission spectra recorded with an echelle spectrometer and a gated detector were compared to the spectral radiance computed for uniform and nonuniform equilibrium plasmas. The calculations are based on analytical solutions of the radiation transfer equation. The simulations show that the plasmas produced in argon background gas are almost uniform, whereas temperature and density gradients are evidenced in air. Furthermore, chemical reactions exclusively occur in the cold plume periphery for ablation in air. The formation of AlO is negligible in argon as the plasma temperature is too large in the time interval of interest up to several microseconds. Finally, the validity of local thermodynamic equilibrium is shown to depend on time, space, and on the elemental composition. The presented conclusions are of interest for material analysis via laser-induced breakdown spectroscopy and for laser materials processing. PMID- 26651799 TI - Impact of oxygen on the 300-K isotherm of Laser Megajoule ablator using ab initio simulation. AB - The ablator material for inertial confinement fusion (ICF) capsules on the Laser Megajoule is a glow-discharge polymer (GDP) plastic. Its equation of state (EOS) is of primary importance for the design of such capsules, since it has direct consequences on shock timing and is essential to mitigate hydrodynamic instabilities. Using ab initio molecular dynamics (AIMD), we have investigated the 300-K isotherm of amorphous CH(1.37)O(0.08) plastic, whose structure is close to GDP plastic. The 300-K isotherm, which is often used as a cold curve within tabular EOS, is an important contribution of the EOS in the multimegabar pressure range. AIMD results are compared to analytic models within tabular EOS, pointing out large discrepancies. In addition, we show that the effect of oxygen decreases 300-K isotherm pressure by 10%-15%. The implication of these observations is the ability to improve ICF target performance, which is essential to achieve fusion ignition. PMID- 26651800 TI - Radiative ablation with two ionizing fronts when opacity displays a sharp absorption edge. AB - The interaction of a strong flux of photons with matter through an ionizing front (I-front) is an ubiquitous phenomenon in the context of astrophysics and inertial confinement fusion (ICF) where intense sources of radiation put matter into motion. When the opacity of the irradiated material varies continuously in the radiation spectral domain, only one single I-front is formed. In contrast, as numerical simulations tend to show, when the opacity of the irradiated material presents a sharp edge in the radiation spectral domain, a second I-front (an edge front) can form. A full description of the mechanism behind the formation of this edge front is presented in this article. It allows us to understand extra shocks (edge-shocks), displayed by ICF simulations, that might affect the robustness of the design of fusion capsules in actual experiments. Moreover, it may have consequences in various domains of astrophysics where ablative flows occur. PMID- 26651801 TI - Mitigating the relativistic laser beam filamentation via an elliptical beam profile. AB - It is shown that the filamentation instability of relativistically intense laser pulses in plasmas can be mitigated in the case where the laser beam has an elliptically distributed beam profile. A high-power elliptical Gaussian laser beam would break up into a regular filamentation pattern-in contrast to the randomly distributed filaments of a circularly distributed laser beam-and much more laser power would be concentrated in the central region. A highly elliptically distributed laser beam experiences anisotropic self-focusing and diffraction processes in the plasma channel ensuring that the unstable diffractive rings of the circular case cannot be produced. The azimuthal modulational instability is thereby suppressed. These findings are verified by three-dimensional particle-in-cell simulations. PMID- 26651802 TI - Generation of overdense and high-energy electron-positron-pair plasmas by irradiation of a thin foil with two ultraintense lasers. AB - A scheme for enhanced quantum electrodynamics (QED) production of electron positron-pair plasmas is proposed that uses two ultraintense lasers irradiating a thin solid foil from opposite sides. In the scheme, under a proper matching condition, in addition to the skin-depth emission of gamma-ray photons and Breit Wheeler creation of pairs on each side of the foil, a large number of high-energy electrons and photons from one side can propagate through it and interact with the laser on the other side, leading to much enhanced gamma-ray emission and pair production. More importantly, the created pairs can be collected later and confined to the center by opposite laser radiation pressures when the foil becomes transparent, resulting in the formation of unprecedentedly overdense and high-energy pair plasmas. Two-dimensional QED particle-in-cell simulations show that electron-positron-pair plasmas with overcritical density 10(22) cm(-3) and a high energy of 100s of MeV are obtained with 10 PW lasers at intensities 10(23) W/cm(2), which are of key significance for laboratory astrophysics studies. PMID- 26651803 TI - Self-consistent theory of high-order harmonic generation by relativistic plasma mirror. AB - We present a self-consistent semianalytical model of the relativistic plasma mirror, based on the exact computation of the laser-driven electron surface oscillations within the cold-fluid approximation. Valid for arbitrary solid densities, laser incidence angle, and a large set of laser intensities (10(18) 10(21) W/cm(2)), the model unravels different regimes of harmonic generation. In particular, it is found that efficient conversion of p-polarized laser pulses into high-order harmonics well above the plasma frequency requires either high laser intensities, low plasma densities, or incidence angles larger than a threshold value. This critical angle corresponds to a transition between a regime where the electron surface dynamics is mostly governed by the laser J*B force and a "cyclotron Brunel" regime, where electrons perform many cyclotron gyrations when moving into the vacuum. Under conditions relevant to current laser experiments, the latter regime gives rise to nonmonotonic variations of the harmonic yield with the laser field. Our predictions are supported by an extensive parametric study performed with highly resolved one-dimensional particle-in-cell simulations. PMID- 26651804 TI - Predictions for the energy loss of light ions in laser-generated plasmas at low and medium velocities. AB - The energy loss of light ions in dense plasmas is investigated with special focus on low to medium projectile energies, i.e., at velocities where the maximum of the stopping power occurs. In this region, exceptionally large theoretical uncertainties remain and no conclusive experimental data are available. We perform simulations of beam-plasma configurations well suited for an experimental test of ion energy loss in highly ionized, laser-generated carbon plasmas. The plasma parameters are extracted from two-dimensional hydrodynamic simulations, and a Monte Carlo calculation of the charge-state distribution of the projectile ion beam determines the dynamics of the ion charge state over the whole plasma profile. We show that the discrepancies in the energy loss predicted by different theoretical models are as high as 20-30%, making these theories well distinguishable in suitable experiments. PMID- 26651805 TI - Shear viscosity for dense plasmas by equilibrium molecular dynamics in asymmetric Yukawa ionic mixtures. AB - We present molecular dynamics (MD) calculations of shear viscosity for asymmetric mixed plasma for thermodynamic conditions relevant to astrophysical and inertial confinement fusion plasmas. Specifically, we consider mixtures of deuterium and argon at temperatures of 100-500 eV and a number density of 10^{25} ions/cc. The motion of 30,000-120,000 ions is simulated in which the ions interact via the Yukawa (screened Coulomb) potential. The electric field of the electrons is included in this effective interaction; the electrons are not simulated explicitly. Shear viscosity is calculated using the Green-Kubo approach with an integral of the shear stress autocorrelation function, a quantity calculated in the equilibrium MD simulations. We systematically study different mixtures through a series of simulations with increasing fraction of the minority high-Z element (Ar) in the D-Ar plasma mixture. In the more weakly coupled plasmas, at 500 eV and low Ar fractions, results from MD compare very well with Chapman Enskog kinetic results. In the more strongly coupled plasmas, the kinetic theory does not agree well with the MD results. We develop a simple model that interpolates between classical kinetic theories at weak coupling and the Murillo Yukawa viscosity model at higher coupling. This hybrid kinetics-MD viscosity model agrees well with the MD results over the conditions simulated, ranging from moderately weakly coupled to moderately strongly coupled asymmetric plasma mixtures. PMID- 26651806 TI - Influence of atomic modeling on integrated simulations of laser-produced Au plasmas. AB - Time-integrated x-ray emission spectra of laser-irradiated Au disks were recorded using transmission grating spectrometry, at laser intensities of 10(13) to 10(14) W/cm(2). Radiation-hydrodynamics and atomic physics calculations were used to simulate the emitted spectra. Three major plasma regions can be recognized: the heat wave, the corona, and an intermediate region connecting them. An analysis of the spectral contribution of these three plasma regions to the integrated recorded spectrum is presented. The importance of accurate atomic modeling of the intermediate plasma region, between the corona and the heat wave, is highlighted. The influence of several aspects of the atomic modeling is demonstrated, in particular multiply-excited atomic configurations and departure from local thermal equilibrium. PMID- 26651807 TI - Linear and nonlinear ion-acoustic waves in nonrelativistic quantum plasmas with arbitrary degeneracy. AB - Linear and nonlinear ion-acoustic waves are studied in a fluid model for nonrelativistic, unmagnetized quantum plasma with electrons with an arbitrary degeneracy degree. The equation of state for electrons follows from a local Fermi Dirac distribution function and applies equally well both to fully degenerate and classical, nondegenerate limits. Ions are assumed to be cold. Quantum diffraction effects through the Bohm potential are also taken into account. A general coupling parameter valid for dilute and dense plasmas is proposed. The linear dispersion relation of the ion-acoustic waves is obtained and the ion-acoustic speed is discussed for the limiting cases of extremely dense or dilute systems. In the long-wavelength limit, the results agree with quantum kinetic theory. Using the reductive perturbation method, the appropriate Korteweg-de Vries equation for weakly nonlinear solutions is obtained and the corresponding soliton propagation is analyzed. It is found that soliton hump and dip structures are formed depending on the value of the quantum parameter for the degenerate electrons, which affect the phase velocities in the dispersive medium. PMID- 26651808 TI - Rogue waves in a two-component Manakov system with variable coefficients and an external potential. AB - We construct rogue waves (RWs) in a coupled two-mode system with the self focusing nonlinearity of the Manakov type (equal SPM and XPM coefficients), spatially modulated coefficients, and a specially designed external potential. The system may be realized in nonlinear optics and Bose-Einstein condensates. By means of a similarity transformation, we establish a connection between solutions of the coupled Manakov system with spatially variable coefficients and the basic Manakov model with constant coefficients. Exact solutions in the form of two component Peregrine and dromion waves are obtained. The RW dynamics is analyzed for different choices of parameters in the underlying parameter space. Different classes of RW solutions are categorized by means of a naturally introduced control parameter which takes integer values. PMID- 26651809 TI - Energy invariant for shallow-water waves and the Korteweg-de Vries equation: Doubts about the invariance of energy. AB - It is well known that the Korteweg-de Vries (KdV) equation has an infinite set of conserved quantities. The first three are often considered to represent mass, momentum, and energy. Here we try to answer the question of how this comes about and also how these KdV quantities relate to those of the Euler shallow-water equations. Here Luke's Lagrangian is helpful. We also consider higher-order extensions of KdV. Though in general not integrable, in some sense they are almost so within the accuracy of the expansion. PMID- 26651810 TI - Physics-based statistical learning approach to mesoscopic model selection. AB - In materials science and many other research areas, models are frequently inferred without considering their generalization to unseen data. We apply statistical learning using cross-validation to obtain an optimally predictive coarse-grained description of a two-dimensional kinetic nearest-neighbor Ising model with Glauber dynamics (GD) based on the stochastic Ginzburg-Landau equation (sGLE). The latter is learned from GD "training" data using a log-likelihood analysis, and its predictive ability for various complexities of the model is tested on GD "test" data independent of the data used to train the model on. Using two different error metrics, we perform a detailed analysis of the error between magnetization time trajectories simulated using the learned sGLE coarse grained description and those obtained using the GD model. We show that both for equilibrium and out-of-equilibrium GD training trajectories, the standard phenomenological description using a quartic free energy does not always yield the most predictive coarse-grained model. Moreover, increasing the amount of training data can shift the optimal model complexity to higher values. Our results are promising in that they pave the way for the use of statistical learning as a general tool for materials modeling and discovery. PMID- 26651811 TI - Fluctuating hydrodynamics in periodic domains and heterogeneous adjacent multidomains: Thermal equilibrium. AB - We first study fluctuating hydrodynamics (FH) at equilibrium in periodic domains by use of the smoothed dissipative particle dynamics (SDPD) method. We examine the performance of SDPD by comparing it with the theory of FH. We find that the spatial correlation of particle velocity is always the Dirac delta function, irrespective of numerical resolution, in agreement with the theory. However, the spatial correlation of particle density has a finite range of r(c), which is due to the kernel smoothing procedure for the density. Nevertheless, this finite range of correlation can be reduced to an arbitrarily small value by increasing the resolution, that is, reducing r(c), similarly to how the smoothing kernel converges to the Dirac delta function. Moreover, we consider temporal correlation functions (CFs) of random field variables in Fourier space. For sufficient resolution, the CFs of SDPD simulations agree very well with analytical solutions of the linearized FH equations. This confirms that both the shear and sound modes are modeled accurately and that fluctuations are generated, transported, and dissipated in both thermodynamically and hydrodynamically consistent ways in SDPD. We also show that the CFs of the classical dissipative particle dynamics (DPD) method with proper parameters can recover very well the linearized solutions. As a reverse implication, the measurement of CFs provides an effective means of extracting viscosities and sound speed of a DPD system with a new set of input parameters. Subsequently, we study the FH in truncated domains in the context of multiscale coupling via the domain decomposition method, where a SDPD simulation in one subdomain is coupled with a Navier-Stokes (NS) solver in an adjacent subdomain with an overlapping region. At equilibrium, the mean values of the NS solution are known a priori and do not need to be extracted from actual simulations. To this end, we model a buffer region as an equilibrium boundary condition (EBC) at the truncated side of the SDPD simulation. In the EBC buffer, the velocity of particles is drawn from a known Gaussian distribution, that is, the Maxwell-Boltzmann distribution. Due to the finite range of spatial correlation, the density of particles in the EBC buffer must be drawn from a conditional Gaussian distribution, which takes into account the available density distribution of neighboring interior particles. We introduce a Kriging method to provide such a conditional distribution and hence preserve the spatial correlation of density. Spatial and temporal correlations of SDPD simulations in the truncated domain are compared to that in a single complete domain. We find that a gap region between the buffer and interior is important to reduce the extra dissipation generated by the artificial buffer at equilibrium, rendering more investigations necessary for thermal fluctuations in the multiscale coupling of nonequilibrium flows. PMID- 26651812 TI - Lattice Boltzmann Stokesian dynamics. AB - Lattice Boltzmann Stokesian dynamics (LBSD) is presented for simulation of particle suspension in Stokes flows. This method is developed from Stokesian dynamics (SD) with resistance and mobility matrices calculated using the time independent lattice Boltzmann algorithm (TILBA). TILBA is distinguished from the traditional lattice Boltzmann method (LBM) in that a background matrix is generated prior to the calculation. The background matrix, once generated, can be reused for calculations for different scenarios, thus the computational cost for each such subsequent calculation is significantly reduced. The LBSD inherits the merits of the SD where both near- and far-field interactions are considered. It also inherits the merits of the LBM that the computational cost is almost independent of the particle shape. PMID- 26651813 TI - Simulated quantum annealing of double-well and multiwell potentials. AB - We analyze the performance of quantum annealing as a heuristic optimization method to find the absolute minimum of various continuous models, including landscapes with only two wells and also models with many competing minima and with disorder. The simulations performed using a projective quantum Monte Carlo (QMC) algorithm are compared with those based on the finite-temperature path integral QMC technique and with classical annealing. We show that the projective QMC algorithm is more efficient than the finite-temperature QMC technique, and that both are inferior to classical annealing if this is performed with appropriate long-range moves. However, as the difficulty of the optimization problem increases, classical annealing loses efficiency, while the projective QMC algorithm keeps stable performance and is finally the most effective optimization tool. We discuss the implications of our results for the outstanding problem of testing the efficiency of adiabatic quantum computers using stochastic simulations performed on classical computers. PMID- 26651814 TI - Simulation of two-phase liquid-vapor flows using a high-order compact finite difference lattice Boltzmann method. AB - A high-order compact finite-difference lattice Boltzmann method (CFDLBM) is extended and applied to accurately simulate two-phase liquid-vapor flows with high density ratios. Herein, the He-Shan-Doolen-type lattice Boltzmann multiphase model is used and the spatial derivatives in the resulting equations are discretized by using the fourth-order compact finite-difference scheme and the temporal term is discretized with the fourth-order Runge-Kutta scheme to provide an accurate and efficient two-phase flow solver. A high-order spectral-type low pass compact nonlinear filter is used to regularize the numerical solution and remove spurious waves generated by flow nonlinearities in smooth regions and at the same time to remove the numerical oscillations in the interfacial region between the two phases. Three discontinuity-detecting sensors for properly switching between a second-order and a higher-order filter are applied and assessed. It is shown that the filtering technique used can be conveniently adopted to reduce the spurious numerical effects and improve the numerical stability of the CFDLBM implemented. A sensitivity study is also conducted to evaluate the effects of grid size and the filtering procedure implemented on the accuracy and performance of the solution. The accuracy and efficiency of the proposed solution procedure based on the compact finite-difference LBM are examined by solving different two-phase systems. Five test cases considered herein for validating the results of the two-phase flows are an equilibrium state of a planar interface in a liquid-vapor system, a droplet suspended in the gaseous phase, a liquid droplet located between two parallel wettable surfaces, the coalescence of two droplets, and a phase separation in a liquid-vapor system at different conditions. Numerical results are also presented for the coexistence curve and the verification of the Laplace law. Results obtained are in good agreement with the analytical solutions and also the numerical results reported in the literature. The study shows that the present solution methodology is robust, efficient, and accurate for solving two-phase liquid-vapor flow problems even at high density ratios. PMID- 26651816 TI - Lattice Boltzmann simulation of coalescence of multiple droplets on nonideal surfaces. AB - The interaction dynamics of droplets on a solid surface is a fundamental problem that is important to a wide variety of industrial applications, such as inkjet printing. Most previous research has focused on a single droplet and little research has been reported on the dynamics of multiple-droplet interactions on surfaces. Recently, Zhou et al. [W. Zhou, D. Loney, A. G. Fedorov, F. L. Degertekin, and D. W. Rosen, Lattice Boltzmann simulations of multiple-droplet interaction dynamics, Phys. Rev. E 89, 033311 (2014)] reported an efficient numerical solver based on the lattice Boltzmann method (LBM) that enabled the simulation of the multiple-droplet interaction dynamics on an ideal surface (i.e., smooth and homogeneous). In order to predict the interaction dynamics in the real world, it is necessary to take into consideration the contact angle hysteresis phenomenon on a nonideal surface, which is possibly caused by the surface roughness and chemical inhomogeneity of the surface. In this paper a dynamic contact angle boundary condition is developed to take into account the contact angle hysteresis effect based on the previously reported LBM. The improved LBM is validated with experimental data from the literature. The influence of the droplet impact conditions (e.g., fluid properties and impingement velocity), droplet spacing, and surface conditions on the two-droplet interaction dynamics is investigated with the validated LBM. Interesting phenomena are observed and discussed. The interaction of a line of six droplets on a nonideal surface is simulated to demonstrate the powerful capability of the developed numerical solver in simulating the multiple-droplet interaction dynamics in the real world. PMID- 26651815 TI - Anchored boundary conditions for locally isostatic networks. AB - Finite pieces of locally isostatic networks have a large number of floppy modes because of missing constraints at the surface. Here we show that by imposing suitable boundary conditions at the surface the network can be rendered effectively isostatic. We refer to these as anchored boundary conditions. An important example is formed by a two-dimensional network of corner sharing triangles, which is the focus of this paper. Another way of rendering such networks isostatic is by adding an external wire along which all unpinned vertices can slide (sliding boundary conditions). This approach also allows for the incorporation of boundaries associated with internal holes and complex sample geometries, which are illustrated with examples. The recent synthesis of bilayers of vitreous silica has provided impetus for this work. Experimental results from the imaging of finite pieces at the atomic level need such boundary conditions, if the observed structure is to be computer refined so that the interior atoms have the perception of being in an infinite isostatic environment. PMID- 26651817 TI - Erratum: Role of inertia for the rotation of a nearly spherical particle in a general linear flow [Phys. Rev. E 91, 053023 (2015)]. AB - This corrects the article DOI: 10.1103/PhysRevE.91.053023. PMID- 26651818 TI - Publisher's Note: Dynamic model of target charging by short laser pulse interactions [Phys. Rev. E 92, 043107 (2015)]. AB - This corrects the article DOI: 10.1103/PhysRevE.92.043107. PMID- 26651819 TI - Publisher's Note: Colloidal interactions in a homeotropic nematic cell with different elastic constants [Phys. Rev. E 92, 042505 (2015)]. AB - This corrects the article DOI: 10.1103/PhysRevE.92.042505. PMID- 26651820 TI - Erratum: Criterion for the emergence of explosive synchronization transitions in networks of phase oscillators [Phys. Rev. E 88, 042921 (2013)]. AB - This corrects the article DOI: 10.1103/PhysRevE.88.042921. PMID- 26651821 TI - The domestic cat as a natural animal model of Alzheimer's disease. AB - INTRODUCTION: Alzheimer's disease (AD) is the most dominant neurodegenerative disorder that causes dementia, and no effective treatments are available. To study its pathogenesis and develop therapeutics, animal models representing its pathologies are needed. Although many animal species develop senile plaques (SP) composed of amyloid-beta (Abeta) proteins that are identical to those found in humans, none of them exhibit neurofibrillary tangles (NFT) and subsequent neurodegeneration, which are integral parts of the pathology of AD. RESULTS: The present study shows that Abeta accumulation, NFT formation, and significant neuronal loss all emerge naturally in the hippocampi of aged domestic cats. The NFT that form in the cat brain are identical to those seen in human AD in terms of their spatial distribution, the cells they affect, and the tau isoforms that comprise them. Interestingly, aged cats do not develop mature argyrophilic SP, but instead accumulate intraneuronal Abeta oligomers in their hippocampal pyramidal cells, which might be due to the amino acid sequence of felid Abeta. CONCLUSIONS: These results suggest that Abeta oligomers are more important than SP for NFT formation and the subsequent neurodegeneration. The domestic cat is a unique animal species that naturally replicates various AD pathologies, especially Abeta oligomer accumulation, NFT formation, and neuronal loss. PMID- 26651823 TI - Resting easy with a sleep regulator. PMID- 26651822 TI - Recruitment and retention in obesity prevention and treatment trials targeting minority or low-income children: a review of the clinical trials registration database. AB - BACKGROUND: Efforts to recruit and retain participants in clinical trials are challenging, especially in studies that include minority or low-income children. To date, no studies have systematically examined recruitment and retention strategies and their effectiveness in working successfully with this population. We examined strategies employed to recruit or retain minority or low-income children in trials that included an obesity-related behavior modification component. METHODS: First, completed home-, community-, and school-based trials involving minority or low-income children aged 2-17 years were identified in a search of the ClinicalTrials.gov registry. Second, a PubMed search of identified trials was conducted to locate publications pertinent to identified trials. Recruitment and retention rates were calculated for studies that included relevant information. RESULTS: Our final analytic sample included 43 studies. Of these, 25 studies reported recruitment or retention strategies, with the amount of information varying from a single comment to several pages; 4 published no specific information on recruitment or retention; and 14 had no publications listed in PubMed. The vast majority (92 %) of the 25 studies reported retention rates of, on average, 86 %. Retention rates were lower in studies that: targeted solely Hispanics or African Americans (vs. mixed races of African Americans, whites, and others); involved children and parents (vs. children only); focused on overweight or obese children (vs. general children), lasted >=1 year (vs. <1 year), were home or community-based (vs. school-based), included nutrition and physical activity intervention (vs. either intervention alone), had body mass index or other anthropometrics as primary outcome measures (vs. obesity-related behavior, insulin sensitivity, etc.). Retention rates did not vary based on child age, number of intervention sessions, or sample size. CONCLUSIONS: Variable amounts of information were provided on recruitment and retention strategies in obesity-related trials involving minority or low-income children. Although reported retention rates were fairly high, a lack of reporting limited the available information. More and consistent reporting and systematic cataloging of recruitment and retention methods are needed. In addition, qualitative and quantitative studies to inform evidence-based decisions in the selection of effective recruitment and retention strategies for trials including minority or low-income children are warranted. PMID- 26651824 TI - How to make an oscillator. PMID- 26651826 TI - Survivin polymorphism is associated with disease activity in rheumatoid arthritis patients. AB - AIM: Survivin expression was associated with unfavorable and erosive course of rheumatoid arthritis (RA). This is the first study investigating association between BIRC5 polymorphisms, survivin plasma levels and disease activity in RA. PATIENTS & METHODS: A testing group of 123 and validation group of 150 RA patients initially treated with methotrexate monotherapy were genotyped for three BIRC5 promoter polymorphisms. Survivin plasma levels were determined in testing group. RESULTS: BIRC5 c.-31G>C was marginally associated with treatment response after 6 months of methotrexate treatment (p = 0.046) and with DAS28 at the time of inclusion in testing (p = 0.052) and in validation group (p = 0.057). Survivin plasma levels were not associated with BIRC5 polymorphisms or DAS28. CONCLUSION: BIRC5 -31C>G polymorphism could be useful pharmacogenetic marker for methotrexate treatment response in RA. PMID- 26651825 TI - Clinical implications and characterization of Group A Streptoccoccus infections in adults with cystic fibrosis. AB - BACKGROUND: Persistent airway infection is a hallmark feature of cystic fibrosis (CF). However, increasingly it has been observed that non-classical pathogens may transiently infect CF lower airways. Streptococcus pyogenes (Group A Streptococcus; (GAS)) is an uncommon but potentially dangerous cause of community acquired pneumonia. Our aim was to determine the incidence, natural history, and clinical impact of GAS infections in CF and phenotypically and genotypically characterize the isolates. METHODS: We retrospectively evaluated the Calgary Adult CF Clinic biobank to identify adults with at least one GAS isolate. Patient demographics, medical and pulmonary exacerbation (PEx) histories were evaluated. The primary outcome was PEx occurrence at incident GAS culture. Secondary outcomes evaluated were changes in lung function and PEx frequency following GAS isolation. Isolates were assessed for extra-cellular virulence factor production capacity and ability to produce quorum sensing (AI-2). Isolates were genotyped using pulse-field gel electrophoresis (PFGE). RESULTS: Fifteen individuals who cultured GAS twenty times were identified. At the time of GAS isolation, 47% (7/15) of subjects experienced a PEx and half of these (4/7) were severe. Individuals were more likely to have a PEx at the time of the index GAS isolate compared to the preceding visit (RR = 6.0, 95% CI 0.82-43.0, p = 0.08), particularly if GAS was the numerically dominant sputum pathogen (RR = 6.5, 95% CI 1.00-43.0, p = 0.009). There were no changes in PEx frequency or rate of lung function decline following GAS. None of the patients developed chronic airways infection, bacteremia, necrotizing pneumonia or empyema. Susceptibility was universal to common anti-Streptococcal antibiotics and anti-Pseudomonal antibiotics commonly used in CF, with the exception of azithromycin. GAS isolates varied in their production of protease, DNase, and AI-2 but these did not correlate with PEx, and none produced elastase, chrondrotin sulfatase or H202. One patient had prolonged carriage with the same isolate and two patients had isolates with similar PFGE patterns. CONCLUSIONS: GAS was an uncommon lower respiratory pathogen of adults with CF. Identification of GAS in sputum was frequently associated with PEx, particularly when numerically dominant. However, transient GAS infection did not result in chronic infection nor appreciably change long-term disease trajectory. PMID- 26651827 TI - Construction and immune efficacy of recombinant pseudorabies virus expressing PrM E proteins of Japanese encephalitis virus genotype I. AB - BACKGROUND: Japanese encephalitis (JE) is an arboviral disease with high case fatality rates and neurologic or psychiatric sequelae among survivors in Asia, western Pacific countries and northern Australia. Japanese encephalitis virus (JEV) is the cause of JE and the emergence of genotype I (GI) JEV has displaced genotype III (GIII) as the dominant strains circulating in some Asian regions. The currently available JE vaccines are safe and effective in preventing this disease, but they are developed based on the GIII JEV strains. METHODS: The recombinant virus PRV TK(-)/gE(-)/PrM-E(+) which expressed the premembrane (prM) and envelope (E) proteins of JEV SX09S-01 strain (genotype I, GI) was constructed by homologous recombination between the genome of PRV TK(-)/gE(-)/LacZ(+) digested with EcoRI and plasmid pIE-CAG-PrM-E-BGH. Expression of JEV PrM and E proteins was analyzed by Western blot analysis. Immune efficacy of PRV TK(-)/gE( )/PrM-E(+) was further evaluated in mouse model. RESULTS: A recombinant pseudorabies virus (PRV TK(-)/gE(-)/PrM-E(+)) was successfully constructed. Mice experiments showed that PRV TK(-)/gE(-)/PrM-E(+) could induce a high level of ELISA antibodies against PRV and JEV, as well as high titer of PRV neutralizing antibodies. After challenge with 1 * 10(7) PFU virulent JEV SX09S-01 strain, the time of death was delayed and the survival rate was improved in PRV TK(-)/gE( )/PrM-E(+) vaccinated mice. CONCLUSIONS: PRV TK(-)/gE(-)/PrM-E(+) is a potential vaccine candidate against PRV and JEV GI infection in the future. PMID- 26651828 TI - Is exposure in vivo cost-effective for chronic low back pain? A trial-based economic evaluation. AB - BACKGROUND: Back pain is one of the most expensive health complaints. Comparing the economic aspects of back pain interventions may therefore contribute to a more efficient use of available resources. This study reports on a long-term cost effectiveness analysis (CEA) and cost-utility analysis (CUA) of two treatments as viewed from a societal perspective: 1) exposure in vivo treatment (EXP), a recently developed cognitive behavioral treatment for patients with chronic low back pain who have elevated pain-related fear and 2) the more commonly used graded activity (GA) treatment. METHODS: Sixty-two patients with non-specific chronic low back pain received either EXP or GA. Primary data were collected at four participating treatment centers in the Netherlands. Primary outcomes were self-reported disability (for the CEA) and quality-adjusted life years (for the CUA). Program costs, health care utilization, patient and family costs, and production losses were measured by analyzing therapy records and cost diaries. Data was gathered before, during, and after treatment, and at 6 and 12 months after treatment. Non-parametric bootstrap analyses were used to quantify the uncertainty concerning the cost-effectiveness ratio. In addition, cost effectiveness planes and cost-effectiveness acceptability curves were performed. RESULTS: EXP showed a tendency to reduce disability, increase quality adjusted life years and decrease costs compared to GA. The incremental cost-effectiveness ratios of both the CEA and CUA are in favor of EXP. CONCLUSIONS: Based on these results, implementing EXP for this group of patients seems to be the best decision. TRIAL REGISTRATION: ISRCTN88087718. PMID- 26651829 TI - Psychometric evaluation of the Mental Health Continuum-Short Form (MHC-SF) in Chinese adolescents - a methodological study. AB - BACKGROUND: In epidemiological surveillance of mental health there is good reason to also include scales that measure the presence of well-being rather than merely symptoms of ill health. The Mental Health Continuum-Short Form (MHC-SF) is a self reported scale to measure emotional, psychological and social well-being and conduct categorical diagnosis of positive mental health. This particular instrument includes the three core components of the World Health Organization's definition of mental health and had previously not been psychometrically evaluated on adolescents in China. METHODS: In total 5,399 students (51.1% female) from schools in the urban areas of Weifang in China were included in the study (mean age = 15.13, SD = 1.56). Participants completed a comprehensive questionnaire with several scales, among them the MHC-SF. Statistical analyses to evaluate reliability, structural validity, measurement invariance, presence of floor and ceiling effects and to some extent external validity of the MHC-SF were carried out. RESULTS: The Cronbach's alpha coefficients for sub-scales as well as the total scale were all above 0.80 indicating good reliability. Confirmative factor analysis confirmed the three-dimensional structure of the Chinese version of MHC-SF and supported the configural and metric invariance across gender and age. Noteworthy ceiling effects were observed for single items and sub-scales although not for the total scale. More importantly, observed floor effects were negligible. The stronger correlation found between MHC-SF and Minneapolis Manchester Quality of Life Instrument (as measure of positive mental health) than between MHC-SF and Hospital Anxiety Depression Scale (as measure of mental illness and distress) yielded support for external validity. CONCLUSION: In conclusion, the main findings of this study are in line with studies from other countries that evaluated the psychometric properties of the MHC-SF and show that this instrument, that includes the three core components of the WHO definition of mental health, is useful in assessing positive adolescent mental health also in China. PMID- 26651830 TI - Swiss family physicians' perceptions and attitudes towards knowledge translation practices. AB - BACKGROUND: Several studies have been performed to understand the way family physicians apply knowledge from medical research in practice. However, very little is known concerning family physicians in Switzerland. In an environment in which information constantly accumulates, it is crucial to identify the major sources of scientific information that are used by family physicians to keep their medical knowledge up to date and barriers to use these sources. Our main objective was to examine medical knowledge translation (KT) practices of Swiss family physicians. METHODS: The population consisted of French- and German speaking private practice physicians specialised in family medicine. We conducted four interviews and three focus groups (n = 25). The interview guides of the semi structured interviews and focus groups focused on (a) ways and means used by physicians to keep updated with information relevant to clinical practice; (b) how they consider their role in translating knowledge into practice; (c) potential barriers to KT; (d) solutions proposed by physicians for effective KT. RESULTS: Family physicians find themselves rather ambivalent about the translation of knowledge based on scientific literature, but generally express much interest in KT. They often feel overwhelmed by "information floods" and perceive clinical practice guidelines and other supports to be of limited usefulness for their practice. They often combine various formal and informal information sources to keep their knowledge up to date. Swiss family physicians report considering themselves as artisans, caring for patients with complex needs. CONCLUSION: Improved performance of KT initiatives in family medicine should be tailored to actual needs and based on high quality evidence-based sources. PMID- 26651831 TI - Comprehensive pulmonary rehabilitation in home-based online groups: a mixed method pilot study in COPD. AB - BACKGROUND: Comprehensive multidisciplinary pulmonary rehabilitation is vital in the management of chronic obstructive pulmonary disease (COPD) and is considered for any stage of the disease. Rehabilitation programmes are often centre-based and organised in groups. However, the distance from the patient's home to the centre and lack of transportation may hinder participation. Rehabilitation at home can improve access to care for patients regardless of disease severity. We had previously studied the technology usability and acceptability of a comprehensive home rehabilitation programme designed for patients with very severe COPD receiving long-term oxygen therapy. The acceptability of such comprehensive home programmes for those with less severe COPD, who may be less homebound, is not known. The aims of this feasibility study were to assess patient acceptability of the delivery mode and components of a comprehensive pulmonary rehabilitation programme for any stage of COPD, as well as the technology usability, patient outcomes and economic aspects. METHODS: Ten participants with COPD in the Global Initiative for Chronic Obstructive Lung Disease (GOLD) grade I-IV were enrolled in a 9-week home programme and divided into two rehabilitation groups, with five patients in each group. The programme included exercise training and self-management education in online groups of patients, and individual online consultations. The patients also kept a digital health diary. To assess the acceptability of the programme, the patients were interviewed after the intervention using a semi-structured interview guide. In addition the number of sessions attended was observed. The usability of the technology was assessed using interviews and the System Usability Scale questionnaire. The St George's Respiratory Questionnaire (SGRQ) was used to measure health-related quality of life. RESULTS: The mode of delivery and the components of the programme were well accepted by the patients. The programme provided an environment for learning from both healthcare professionals and peers, for asking questions and discussing disease-related issues and for group exercising. The patients considered that it facilitated health-enhancing behaviours and social interactions with a social group formed among the participants. Even participants who were potentially less homebound appreciated the home group and social aspects of the programme. The participants found the technology easy to learn and use. The acceptability and usability results were consistent with those in our previous study of patients with very severe COPD. Only the mean change in the SGRQ total score of -6.53 (CI 95 % -0.38 to -12.68, p = 0.04) indicates a probable clinically significant effect. Economic calculations indicated that the cost of the programme was feasible. CONCLUSIONS: The results of this study indicate that comprehensive pulmonary rehabilitation delivered in home-based online groups may be feasible in COPD. The mode of delivery and components of the programme appeared to be acceptable across patients with different disease severity. The results in terms of patient outcomes are inconclusive, and further assessment is needed. PMID- 26651833 TI - Streptococcus oricebi sp. nov., isolated from the oral cavity of tufted capuchin. AB - A Gram-stain-positive, catalase-negative, coccus-shaped organism was isolated from the oral cavity of tufted capuchin (Cebus apella). Comparative 16S rRNA gene sequence analysis suggested classification of the organism within the genus Streptococcus. Strain M8T was related most closely to Streptococcus oralis ATCC 35037T (96.17 % similarity) followed by Streptococcus massiliensis CCUG 49690T (95.90 %) based on the 16S rRNA gene. Strain M8T was related most closely to S. massiliensis CCUG 49690T (86.58 %) based on the RNA polymerase beta subunit encoding gene (rpoB), and to Streptococcus tigurinus AZ_3aT (81.26 %) followed by S. massiliensis CCUG 49690T (80.45 %) based on the 60 kDa heat-shock protein gene (groEL). The phylogenetic trees of 16S rRNA, rpoB and groEL gene sequences showed that strain M8T was most closely related to S. massiliensis. Based on phenotypic characterization as well as 16S rRNA gene and housekeeping gene (rpoB and groEL) sequence data, a novel taxon, Streptococcus oricebi sp. nov. (type strain M8T = JCM 30719T = DSM 100101T), is proposed. PMID- 26651834 TI - Theoretical Study on the Noble Gas Exchange Reactions of Ng + HNBNg'(+) -> Ng' + HNBNg(+) (Ng, Ng' = He, Ne, Ar, Kr, and Xe). AB - High-level correlated electronic structure calculation and dual-level variational transition state theory with multidimensional tunneling calculation for rate constants have been performed on four noble gas exchange reactions [(1) He + HNBHe'(+) -> He' + HNBHe(+), (2) He + HNBNe(+) -> Ne + HNBHe(+), (3) Ne + HNBNe'(+) -> Ne' + HNBNe(+), and (4) Ar + HNBAr'(+) -> Ar' + HNBAr(+)] and on three (3)He isotopic analogues (He + HNB(3)He(+), (3)He + HNBHe(+), and (3)He + HNB(3)He(+)) of the first reaction. The classical barrier heights were predicted to be 8.9, 6.8, 5.7, and 5.5 kcal/mol for the four reactions, respectively. The tunneling effects were found to be important below 250 K for the He reactions and below 150 K for the Ne and Ar reactions. Kinetic helium isotope effects as large as 7.8 at 100 K were predicted for the (3)He + HNB(3)He(+) reaction. Additionally, the structures and energies of the Kr + HNBKr'(+) and Xe + HNBXe'(+) systems have also been studied. PMID- 26651832 TI - Human mesenchymal stem cells target adhesion molecules and receptors involved in T cell extravasation. AB - INTRODUCTION: Systemic delivery of bone marrow-derived mesenchymal stem cells (MSC) seems to be of benefit in the treatment of multiple sclerosis (MS), an autoimmune disease of the central nervous system (CNS) sustained by migration of T cells across the brain blood barrier (BBB) and subsequent induction of inflammatory lesions into CNS. MSC have been found to modulate several effector functions of T cells. In this study, we investigated the effects of MSC on adhesion molecules and receptors on T cell surface that sustain their transendothelial migration. METHODS: We used different co-culture methods combined with real-time PCR and flow cytometry to evaluate the expression both at the mRNA and at the plasma-membrane level of alpha4 integrin, beta2 integrin, ICAM-1 and CXCR3. In parallel, we assessed if MSC are able to modulate expression of adhesion molecules on the endothelial cells that interact with T cells during their transendothelial migration. RESULTS: Our in vitro analyses revealed that MSC: (i) inhibit proliferation and activation of both peripheral blood mononuclear cells (PBMC) and CD3(+)-selected lymphocytes through the release of soluble factors; (ii) exert suppressive effects on those surface molecules highly expressed by activated lymphocytes and involved in transendothelial migration; (iii) inhibit CXCL10-driven chemotaxis of CD3(+) cells; (iv) down-regulated expression of adhesion molecules on endothelial cells. CONCLUSIONS: Taken together, these data demonstrate that the immunosuppressive effect of MSC does not exclusively depends on their anti-proliferative activity on T cells, but also on the impairment of leukocyte migratory potential through the inhibition of the adhesion molecules and receptors that are responsible for T cell trafficking across BBB. This could suggest a new mechanism through which MSC modulate T cell responses. PMID- 26651835 TI - Destructive effect of anticancer oxali-palladium on heme degradation through the generation of endogenous hydrogen peroxide. AB - The interaction between human hemoglobin (Hb) and oxali-palladium was studied using different spectroscopic methods of UV-vis, fluorescence, circular dichroism (CD), and chemiluminescence at two temperatures of 25 and 37 degrees C. The experimental results showed that both dynamic and static quenching is occurred simultaneously when oxali-palladium quenches the fluorescence of Hb. According to the fluorescence quenching method, the binding site number, apparent binding constant, and corresponding thermodynamic parameters were measured at two temperatures. The values of DeltaH degrees , DeltaS degrees , and DeltaG degrees indicate that process of the formation of oxali-palladium-Hb complex is a spontaneous interaction procedure in which electrostatic interaction plays a major role. In addition, UV-vis and CD results showed that the addition of oxali palladium changes the conformation of Hb. To evaluate the functional changes of Hb via destruction of the heme structure, fluorescence studies were performed. The results demonstrated that two fluorescent heme degradation products are found during the interaction of oxali-palladium with Hb. Also, the amount of hydrogen peroxide produced in the solution of Hb due to the interaction of oxali-palladium with Hb using chemiluminescence method indicated heme degradation in the protein is occurred. Structural and functional changes induced in Hb via heme degradation are considered as side effects of this synthesized anticancer drug. PMID- 26651836 TI - Solution NMR Spectroscopy Provides an Avenue for the Study of Functionally Dynamic Molecular Machines: The Example of Protein Disaggregation. AB - Solution-based NMR spectroscopy has been an important tool for studying the structure and dynamics of relatively small proteins and protein complexes with aggregate molecular masses under approximately 50 kDa. The development of new experiments and labeling schemes, coupled with continued improvements in hardware, has significantly reduced this size limitation, enabling atomic resolution studies of molecular machines in the 1 MDa range. In this Perspective, some of the important advances are highlighted in the context of studies of molecular chaperones involved in protein disaggregation. New insights into the structural biology of disaggregation obtained from NMR studies are described, focusing on the unique capabilities of the methodology for obtaining atomic resolution descriptions of dynamic systems. PMID- 26651837 TI - Neuroprotective effects of curcumin on endothelin-1 mediated cell death in hippocampal neurons. AB - OBJECTIVES: Alzheimer's disease is a progressive neurodegenerative disease characterized by loss of hippocampal neurons leading to memory deficits and cognitive decline. Studies suggest that levels of the vasoactive peptide endothelin-1 (ET-1) are increased in the brain tissue of Alzheimer's patients. Curcumin, the main ingredient of the spice turmeric, has been shown to have anti inflammatory, anti-cancer, and neuroprotective effects. However, the mechanisms underlying some of these beneficial effects are not completely understood. The objective of this study was to determine if curcumin could protect hippocampal neurons from ET-1 mediated cell death and examine the involvement of c-Jun in this pathway. METHODS: Primary hippocampal neurons from rat pups were isolated using a previously published protocol. Viability of the cells was measured by the live/dead assay. Immunoblot and immunohistochemical analyses were performed to analyze c-Jun levels in hippocampal neurons treated with either ET-1 or a combination of ET-1 and curcumin. Apoptotic changes were evaluated by immunoblot detection of cleaved caspase-3, cleaved fodrin, and a caspase 3/7 activation assay. RESULTS: ET-1 treatment produced a 2-fold increase in the levels of c-Jun as determined by an immunoblot analysis in hippocampal neurons. Co-treatment with curcumin significantly attenuated the ET-1 mediated increase in c-Jun levels. ET 1 caused increased neuronal cell death of hippocampal neurons indicated by elevation of cleaved caspase-3, cleaved fodrin and an increased activity of caspases 3 and 7 which was attenuated by co-treatment with curcumin. Blockade of JNK, an upstream effector of c-Jun by specific inhibitor SP600125 did not fully protect from ET-1 mediated activation of pro-apoptotic enzymes in primary hippocampal cells. DISCUSSION: Our data suggests that one mechanism by which curcumin protects against ET-1-mediated cell death is through blocking an increase in c-Jun levels. Other possible mechanisms include decreasing pro apoptotic signaling activated by ET-1 in primary hippocampal neurons. PMID- 26651838 TI - The electrophysiological correlates of integrated face and body-part perception. AB - Previous studies have suggested that the human visual system processes faces and bodies holistically-that is, the different body parts are integrated into a unified representation. However, the time course of this integrative process is less known. In the present study, we investigated this issue by recording event related potentials evoked by a face and two hands presented simultaneously and in different configurations. When the hands were rotated to obtain a biologically implausible configuration, a reduction of the P2 amplitude was observed relative to the condition in which the face and hands were retained in their veridical configuration and were supplemented with visual cues to highlight further the overall body posture. Our results show that the P2 component is sensitive to manipulations affecting the configuration of face and hand stimuli and suggest that the P2 reflects the operation of perceptual mechanisms responsible for the integrated processing of visually presented body parts. PMID- 26651839 TI - Induction therapy with a combination of fumarates and cyclosporine: A benefit for the patient? AB - Fumarates or fumaric acid esters derivates (FAED) have appeared to be effective and less toxic than other systemic treatments for psoriasis. Due to its safe adverse event profile, FAED can be used as a long-term maintenance therapy. One of the greatest reasons why FAED are not preferred as a first-line treatment is that according to the recommended dosing schedule, clinically meaningful improvement is seen just after 6 to 8 weeks of therapy. In this manuscript, we suppose an alternative induction scheme with a combination therapy of fumarates and cyclosporine for a more rapid improvement and better compliance. PMID- 26651840 TI - Stochastic Optimally Tuned Range-Separated Hybrid Density Functional Theory. AB - We develop a stochastic formulation of the optimally tuned range-separated hybrid density functional theory that enables significant reduction of the computational effort and scaling of the nonlocal exchange operator at the price of introducing a controllable statistical error. Our method is based on stochastic representations of the Coulomb convolution integral and of the generalized Kohn Sham density matrix. The computational cost of the approach is similar to that of usual Kohn-Sham density functional theory, yet it provides a much more accurate description of the quasiparticle energies for the frontier orbitals. This is illustrated for a series of silicon nanocrystals up to sizes exceeding 3000 electrons. Comparison with the stochastic GW many-body perturbation technique indicates excellent agreement for the fundamental band gap energies, good agreement for the band edge quasiparticle excitations, and very low statistical errors in the total energy for large systems. The present approach has a major advantage over one-shot GW by providing a self-consistent Hamiltonian that is central for additional postprocessing, for example, in the stochastic Bethe Salpeter approach. PMID- 26651841 TI - Comparing Samples of Men Who Have Sex with Men Recruited Online and in Venues, Jiangsu Province, China, 2013. AB - PURPOSE: Two common methods to sample men who have sex with men (MSM) for HIV research are venue- and internet-based approaches. However, it is unclear which is best to sample Chinese MSM. METHODS: We conducted side-by-side comparisons of time-location sampling (TLS) and an online sample of MSM in Nanjing, China. RESULTS: TLS-recruited MSM tended to be older and of lower socio-economic status compared to online-recruited MSM, whereas online-recruited MSM reported higher risk behavior and lower frequency of HIV testing. CONCLUSION: Significant differences were observed between the two separate samples. Without a gold standard, the choice of sampling method or recruitment approach should be guided by the segment of the population targeted to be reached. PMID- 26651842 TI - Time on treatment of everolimus and chemotherapy among postmenopausal women with hormone-receptor-positive/human-epidermal-growth-factor-receptor-2-negative metastatic breast cancer: a retrospective claims study in the US. AB - OBJECTIVE: This study aimed to compare time on treatment (TOT) among patients treated with everolimus and chemotherapy, two commonly used treatments for hormone-receptor-positive/human-epidermal-growth-factor-receptor-2-negative (HR+/HER2-) metastatic breast cancer (mBC). METHODS: Postmenopausal women with HR+/HER2- mBC who initiated >=1 new line of therapy for mBC during 20 July 2012 31 March 2014 after a non-steroidal aromatase inhibitor were identified from MarketScan and PharMetrics databases (2002Q1-2014Q2) using a claims-based algorithm. Patients were classified into treatment groups by regimen and line of therapy, and were followed until discontinuation of therapy, end of insurance eligibility, or data cut-off (30 June 2014). Discontinuation was defined as a treatment gap of >=60 days; patients who did not discontinue were censored at the end of follow-up. TOT was compared between everolimus, chemotherapy, and capecitabine monotherapy using Kaplan-Meier analyses and multivariable Cox models adjusting for line of therapy, age, insurance, de novo mBC diagnosis, prior use of chemotherapy for mBC, sites of metastases, and Charlson comorbidity index. RESULTS: Across the first four lines of therapies for mBC, a total of 940 everolimus, 3410 chemotherapy, and 721 capecitabine monotherapy regimens were included. Based on the different lines of therapies, the median TOT ranged from 5.5 to 7.2 months for everolimus, 4.3 to 4.7 months for chemotherapy, and 3.5 to 6.0 months for capecitabine monotherapy. Pooling all lines of therapies, everolimus was associated with significantly longer TOT compared to chemotherapy (multivariable-adjusted hazard ratio [HR] = 0.69, 95% confidence interval [CI]: 0.62-0.76) or capecitabine monotherapy (multivariable-adjusted HR = 0.73, 95% CI: 0.64-0.83). Longer TOT was consistently observed for everolimus for each line of therapy. LIMITATIONS: Proxies used for identifying HR + /HER2- mBC and treatment line, lack of certain clinical factors in claims data, generalizability limited to commercially insured patients in the US. CONCLUSIONS: This study found that HR+/HER2- mBC patients receiving everolimus experienced significantly longer TOT than those receiving chemotherapy overall or capecitabine monotherapy. PMID- 26651843 TI - Physico-Chemical Heterogeneity of Organic-Rich Sediments in the Rifle Aquifer, CO: Impact on Uranium Biogeochemistry. AB - The Rifle alluvial aquifer along the Colorado River in west central Colorado contains fine-grained, diffusion-limited sediment lenses that are substantially enriched in organic carbon and sulfides, as well as uranium, from previous milling operations. These naturally reduced zones (NRZs) coincide spatially with a persistent uranium groundwater plume. There is concern that uranium release from NRZs is contributing to plume persistence or will do so in the future. To better define the physical extent, heterogeneity and biogeochemistry of these NRZs, we investigated sediment cores from five neighboring wells. The main NRZ body exhibited uranium concentrations up to 100 mg/kg U as U(IV) and contains ca. 286 g of U in total. Uranium accumulated only in areas where organic carbon and reduced sulfur (as iron sulfides) were present, emphasizing the importance of sulfate-reducing conditions to uranium retention and the essential role of organic matter. NRZs further exhibited centimeter-scale variations in both redox status and particle size. Mackinawite, greigite, pyrite and sulfate coexist in the sediments, indicating that dynamic redox cycling occurs within NRZs and that their internal portions can be seasonally oxidized. We show that oxidative U(VI) release to the aquifer has the potential to sustain a groundwater contaminant plume for centuries. NRZs, known to exist in other uranium-contaminated aquifers, may be regionally important to uranium persistence. PMID- 26651844 TI - MKRN1: Uncovering function by an unbiased systems approach. PMID- 26651845 TI - Synthesis of Cu2O Octadecahedron/TiO2 Quantum Dot Heterojunctions with High Visible Light Photocatalytic Activity and High Stability. AB - Since p-n heterojunction photocatalysts with higher energy facets exposed usually possess greatly enhanced photocatalytic activities than single-phase catalysts, a novel Cu2O octadecahedron/TiO2 quantum dot (Cu2O-O/TiO2-QD) p-n heterojunctions composite was designed and synthesized in this study. Cu2O octadecahedra (Cu2O-O) with {110} facets and {100} facets exposed were synthesized first, then highly dispersed TiO2 quantum dots (TiO2-QDs) were loaded on Cu2O-O by the precipitation of TiO2-QDs sol in the presence of absolute ethanol. The morphology, crystal structure, chemical composition, optical properties, photocatalytic activity, and stability of Cu2O-O/TiO2-QD heterojunctions were characterized and investigated. It was found that TiO2-QDs were firmly anchored on Cu2O-O single crystals with good dispersibility. The Cu2O-O/TiO2-QD heterojunctions with partial coverage of TiO2-QDs showed a strong absorbance of visible light and exhibited an effective transfer of photoexcited electrons. The degradation of methyl orange (MO) under visible light irradiation indicated that the photocatalytic activity of Cu2O O/TiO2-QD heterojunctions was significantly enhanced compared with that of Cu2O O. This Cu2O-O/TiO2-QD heterojunctions composite exhibited high stability in MO degradation process and after storage in air. The high visible light photocatalytic activity and good stability were attributed to high utilization of light, effective separation of photoexcited electron-hole pairs, and instant scavenging of holes in the unique heterojunction structure. PMID- 26651846 TI - Are professional psychology training programs willing the future to economic illiterates?: a clarion call for pedagogical action. AB - BACKGROUND: The behavioral health care environment in the United States is changing and many experts expect seismic shifts in access, accountability and reimbursement policies. Students in professional psychology training programs will be called upon to administer, manage, supervise and deliver clinically sound as well as cost effective services. While in general, traditional professional psychology training curricula prepare students well for clinical challenges, most students enter the profession naive to the economic, financial and business enterprise crucibles in the behavioral health care marketplace. AIMS: This article examines the problem of such naivete and offers several recommendations for improving graduate students' economic literacy. Moreover, the article argues that increased business and economic acumen may serve to close the research practice gap in professional psychology. METHODS: The article reviews literature pertinent to training psychologists and highlights pedagogical gaps. RESULTS: Several recommendations for curricular development are offered. Specifically, adding courses in health care economics and basic business principles is suggested. Integrating cost-effectiveness analyses across all course content is proposed. The article also emphasizes both didactic and experiential learning opportunities. CONCLUSION: Course work should be augmented with training opportunities at the practicum, internship, and post-doctoral fellowship level. PMID- 26651847 TI - Pneumococcal conjugate vaccine use in adults. AB - Streptococcus pneumoniae is a leading cause of illness and death in adults. A polysaccharide vaccine has been available for over 30 years, but despite significant use, the public health impact of this vaccine has been limited. The 13-valent pneumococcal conjugate vaccine (PCV13) has been licensed by the US Food and Drug Administration and other international regulatory authorities with the assumption that induction of a T cell-dependent immune response and noninferior immunogenicity to vaccine antigens when compared with the polysaccharide vaccine would be important to satisfy a significant unmet medical need. PCV13 efficacy against vaccine-type pneumococcal community-acquired pneumonia was confirmed in a large randomized controlled trial in older adults and its use is now increasingly recommended globally. PMID- 26651849 TI - Football experts versus sports economists: Whose forecasts are better? AB - Given the uncertainty of outcome in sport, predicting the outcome of sporting contests is a major topic in sport sciences. This study examines the accuracy of expert predictions in the German Bundesliga and compares their predictions to those of sports economists. Prior to the start of each season, a set of distinguished experts (head coaches and players) express their subjective evaluations of the teams in school grades. While experts may be driven by irrational sentiments and may therefore systematically over- or underestimate specific teams, sports economists use observable characteristics to predict season outcomes. The latter typically use team wage bills given the positive pay performance relationship as well as other factors (average team age, tenure, appearances on national team, and attendance). Using data from 15 consecutive Bundesliga seasons, the predictive accuracy of expert evaluations and sports economists is analysed. The results of separate estimations show that relative grade and relative wage bill significantly affect relative points, while age, tenure, appearances, and attendance are insignificant. In a joint model, relative grade and relative wage bill are still statistically significant, suggesting that the two types of predictions are complements rather than substitutes. Consequently, football experts and sports economists seem to rely on completely different sources of information when making their predictions. PMID- 26651850 TI - Quantifying external focus of attention in sailing by means of action sport cameras. AB - The aim of the current study was twofold: (1) to validate the use of action sport cameras for quantifying focus of visual attention in sailing and (2) to apply this method to examine whether an external focus of attention is associated with better performance in upwind sailing. To test the validity of this novel quantification method, we first calculated the agreement between gaze location measures and head orientation measures in 13 sailors sailing upwind during training regattas using a head mounted eye tracker. The results confirmed that for measuring visual focus of attention in upwind sailing, the agreement for the two measures was high (intraclass correlation coefficient (ICC) = 0.97) and the 95% limits of agreement were acceptable (between -8.0% and 14.6%). In a next step, we quantified the focus of visual attention in sailing upwind as fast as possible by means of an action sport camera. We captured sailing performance, operationalised as boat speed in the direction of the wind, and environmental conditions using a GPS, compass and wind meter. Four trials, each lasting 1 min, were analysed for 15 sailors each, resulting in a total of 30 upwind speed trials on port tack and 30 upwind speed trials on starboard tack. The results revealed that in sailing - within constantly changing environments - the focus of attention is not a significant predictor for better upwind sailing performances. This implicates that neither external nor internal foci of attention was per se correlated with better performances. Rather, relatively large interindividual differences seem to indicate that different visual attention strategies can lead to similar performance outcomes. PMID- 26651851 TI - Field study of nitrous oxide production with in situ aeration in a closed landfill site. AB - Nitrous oxide (N(2)O) has gained considerable attention as a contributor to global warming and depilation of stratospheric ozone layer. Landfill is one of the high emitters of greenhouse gas such as methane and N(2)O during the biodegradation of solid waste. Landfill aeration has been attracted increasing attention worldwide for fast, controlled and sustainable conversion of landfills into a biological stabilized condition, however landfill aeration impel N(2)O emission with ammonia removal. N(2)O originates from the biodegradation, or the combustion of nitrogen-containing solid waste during the microbial process of nitrification and denitrification. During these two processes, formation of N(2)O as a by-product from nitrification, or as an intermediate product of denitrification. In this study, air was injected into a closed landfill site and investigated the major N(2)O production factors and correlations established between them. The in-situ aeration experiment was carried out by three sets of gas collection pipes along with temperature probes were installed at three different distances of one, two and three meter away from the aeration point; named points A-C, respectively. Each set of pipes consisted of three different pipes at three different depths of 0.0, 0.75 and 1.5 m from the bottom of the cover soil. Landfill gases composition was monitored weekly and gas samples were collected for analysis of nitrous oxide concentrations. It was evaluated that temperatures within the range of 30-40 degrees C with high oxygen content led to higher generation of nitrous oxide with high aeration rate. Lower O(2) content can infuse N(2)O production during nitrification and high O(2) inhibit denitrification which would affect N(2)O production. The findings provide insights concerning the production potentials of N(2)O in an aerated landfill that may help to minimize with appropriate control of the operational parameters and biological reactions of N turnover. IMPLICATIONS: Investigation of nitrous oxide production potential during in situ aeration in an old landfill site revealed that increased temperatures and oxygen content inside the landfill site are potential factors for nitrous oxide production. Temperatures within the range of optimum nitrification process (30-40 degrees C) induce nitrous oxide formation with high oxygen concentration as a by-product of nitrogen turnover. Decrease of oxygen content during nitrification leads increase of nitrous oxide production, while temperatures above 40 degrees C with moderate and/or low oxygen content inhibit nitrous oxide generation. PMID- 26651848 TI - High-Density Genetic Mapping Identifies New Susceptibility Variants in Sarcoidosis Phenotypes and Shows Genomic-driven Phenotypic Differences. AB - RATIONALE: Sarcoidosis is a multisystem disease of unknown cause. Lofgren's syndrome (LS) is a characteristic subgroup of sarcoidosis that is associated with a good prognosis in sarcoidosis. However, little is known about its genetic architecture or its broader phenotype, non-LS sarcoidosis. OBJECTIVES: To address the genetic architecture of sarcoidosis phenotypes, LS and non-LS. METHODS: An association study in a white Swedish cohort of 384 LS, 664 non-LS, and 2,086 control subjects, totaling 3,134 subjects using a fine-mapping genotyping platform was conducted. Replication was performed in four independent cohorts, three of white European descent (Germany, n = 4,975; the Netherlands, n = 613; and Czech Republic, n = 521), and one of black African descent (United States, n = 1,657), totaling 7,766 subjects. MEASUREMENTS AND MAIN RESULTS: A total of 727 LS-associated variants expanding throughout the extended major histocompatibility complex (MHC) region and 68 non-LS-associated variants located in the MHC class II region were identified and confirmed. A shared overlap between LS and non-LS defined by 17 variants located in the MHC class II region was found. Outside the MHC region, two LS-associated loci, in ADCY3 and between CSMD1 and MCPH1, were observed and replicated. CONCLUSIONS: Comprehensive and integrative analyses of genetics, transcription, and pathway modeling on LS and non-LS indicates that these sarcoidosis phenotypes have different genetic susceptibility, genomic distributions, and cellular activities, suggesting distinct molecular mechanisms in pathways related to immune response with a common region. PMID- 26651853 TI - Single-Tailed Lipidoids Enhance the Transfection Activity of Their Double-Tailed Counterparts. AB - Cationic lipid-like molecules (lipidoids) are widely used for in vitro and in vivo gene delivery. Nearly all lipidoids developed to date employ double-tail or multiple-tail structures for transfection. Single-tail lipidoids are seldom considered for transfection as they have low efficiency in gene delivery. So far, there is no detailed study on the contribution to transfection efficiency of single-tail lipidoids when combined with standard double-tail lipidoids. Here, we use combinatorial chemistry to synthesize 17 double-tail and 17 single-tail lipidoids using thiol-yne and thiol-ene click chemistry, respectively. HEK 293T cells were used to analyze transfection efficiency by fluorescence microscopy and calculated based on the percentage of cells transfected. The size and zeta potential of liposomes and lipoplexes were characterized by dynamic light scattering (DLS). Intracellular DNA delivery and trafficking was further examined using confocal microscopy. Our study shows that combining single with double-tail lipidoids increases uptake of lipoplexes, as well as cellular transfection efficiency. PMID- 26651852 TI - A Mixed-Methods Pilot Study of Mindfulness-Based Stress Reduction for HIV Associated Chronic Pain. AB - Treatment guidelines for chronic pain recommend nonpharmacologic modalities as part of a comprehensive management plan. Chronic pain is common among people living with HIV/AIDS, but there is little data to guide the choice of nonpharmacologic therapies in this complex population. We performed a mixed methods feasibility study of Mindfulness-Based Stress Reduction (MBSR) versus health education control with 32 inner city, HIV-infected participants. Outcome measures included: the Brief Pain Inventory, Perceived Stress Scale, HIV Symptoms Index, autonomic function testing, and audiotaped focus groups. Post intervention, participants reported modest improvements in pain measures and perceived stress, but no effect of group assignment was observed. At 3-month follow-up, 79% of MBSR participants were still practicing, and pain intensity was improved, whereas in the control group pain intensity had worsened. Qualitative analysis revealed a strong sense of community in both groups, but only MBSR was perceived as useful for relaxation and pain relief. PMID- 26651854 TI - A Supramolecular Sensor Array Using Lanthanide-Doped Nanoparticles for Sensitive Detection of Glyphosate and Proteins. AB - Lanthanide (Ln(3+))-doped nanoparticles (NPs) are an intensive area of research in chemical and materials sciences. Herein a sensor array of Ln(3+)-doped NPs was developed for the first time toward sensitive molecular sensing based on a novel strategy of the hybridized time-resolved Forster resonance energy transfer (TR FRET) with the indicator displacement assay (IDA) concept (TR-FRET-IDA). The sensor platform was generated in situ by binding a series of negatively charged indicators on the surface of ligand-free LiYF4:Ce/Tb NPs. The TR-FRET between NPs and dyes resulted in indicator emission and was employed as a means of removing undesired short-lived background luminescence from the indicator effectively. Displacement of indicators from the NP/indicator ensembles by glyphosate, a common herbicide, led to turn-off of the indicator emission. The sensor array was able to successfully discriminate 11 biologically relevant anions with high accuracy and sensitivity in pure aqueous buffer both qualitatively and quantitatively. Furthermore, the differentiation of six model proteins in the nM range was achieved with 100% accuracy for the classification, thereby demonstrating the versatility of this simple sensor platform. The study of the mechanism of binding and signal modulation further verified TR-FRET-IDA as a reliable sensing paradigm. PMID- 26651855 TI - Association between the clinical classification of hypothyroidism and reduced TSH in LT4 supplemental replacement treatment for pregnancy in China. AB - The study was aimed to evaluate the effects of levothyroxine (LT4) supplemental replacement treatment for pregnancy and analyze the associations between the clinical classification of hypothyroidism and reduced thyroid-stimulating hormone (TSH) in LT4 therapy. Totally, 195 pregnant women with hypothyroidism receiving routine prenatal care were enrolled. They were categorized into three groups: overt hypothyroidism (OH), subclinical hypothyroidism (SCH) with negative thyroperoxidase antibody (TPOAb), and SCH with positive TPOAb. The association between the clinical classification and reduced TSH in LT4 supplemental replacement treatment was assessed. The results indicated that reduced TSH was significantly different among the groups according to the clinical classifications (p = 0.043). The result was also significantly different between patients with OH and patients with SCH and negative TPOAb (p = 0.036). Similar result was reported for the comparison between patients with OH and patients with SCH and positive TPOAb (p = 0.016). Multiple variable analyses showed that LT4 supplementation, gestational age and the variable of clinical classifications were associated with reduced TSH independently. Our data suggested that the therapeutic effect of substitutive treatment with LT4 was significantly associated with different clinical classifications of hypothyroidism in pregnancy and the treatment should begin as soon as possible after diagnosis. PMID- 26651856 TI - Regenerable Thiophenolic Radical-Trapping Antioxidants. AB - Diphenyl disulfides carrying alkyltelluro groups in the o-, m-, and p-positions were prepared using ortho-lithiation and lithium halogen exchange reactions. The novel antioxidants showed only minimal inhibitory effect on the azo-initiated peroxidation of linoleic acid in chlorobenzene until reduced to the corresponding thiophenols by tris(2-carboxyethyl)phosphine (TCEP). The best in situ generated thiophenol (from 7c) under these conditions quenched peroxyl radicals more efficiently than alpha-tocopherol with an almost 3-fold increase in inhibition time. PMID- 26651857 TI - High-Throughput Metabolic Profiling of Soybean Leaves by Fourier Transform Ion Cyclotron Resonance Mass Spectrometry. AB - As a relatively recent research field, plant metabolomics has gained increasing interest in the past few years and has been applied to answer biological questions through large-scale qualitative and quantitative analyses of the plant metabolome. The combination of sensitivity and selectivity offered by mass spectrometry (MS) for measurement of many metabolites in a single shot makes it an indispensable platform in metabolomics. In this regard, Fourier-transform ion cyclotron resonance (FTICR) has the unique advantage of delivering high mass resolving power and mass accuracy simultaneously, making it ideal for the study of complex mixtures such as plant extracts. Here we optimize soybean leaf extraction methods compatible with high-throughput reproducible MS-based metabolomics. In addition, matrix-assisted laser desorption ionization (MALDI) and direct LDI of soybean leaves are compared for metabolite profiling. The extraction method combined with electrospray (ESI)-FTICR is supported by the significant reduction of chlorophyll and its related metabolites as the growing season moves from midsummer to the autumn harvest day. To our knowledge for the first time, the use of ESI-FTICR MS and MALDI-FTICR MS is described in a complementary manner with the aim of metabolic profiling of plant leaves that have been collected at different time points during the growing season. PMID- 26651858 TI - Discovery and characterization of hydroxylysine in recombinant monoclonal antibodies. AB - Tryptic peptide mapping analysis of a Chinese hamster ovary (CHO)-expressed, recombinant IgG1 monoclonal antibody revealed a previously unreported +16 Da modification. Through a combination of MS(n) experiments, and preparation and analysis of known synthetic peptides, the possibility of a sequence variant (Ala to Ser) was ruled out and the presence of hydroxylysine was confirmed. Post translational hydroxylation of lysine was found in a consensus sequence (XKG) known to be the site of modification in other proteins such as collagen, and was therefore presumed to result from the activity of the CHO homolog of the lysyl hydroxylase complex. Although this consensus sequence was present in several locations in the antibody sequence, only a single site on the heavy-chain Fab was found to be modified. PMID- 26651859 TI - The moderating role of parenting on the relationship between psychopathy and antisocial behavior in adolescence. AB - We aimed to analyze the impact of several parenting factors on the relationship between psychopathy and antisocial behavior. Nine hundred youths and their mothers reported on parent-youth interactions, and youth self-report measures of psychopathy, delinquency and violent behavior were taken. Multiple regression was used to test for the significance of interactions between parenting and psychopathy scores. In terms of delinquency, linear interactions between psychopathy and the level of conflict with parents and parents' knowledge of their youths' whereabouts/youths' willingness to disclose information were found based on the data reported by the youths. Data reported by mothers indicated a linear interaction between psychopathy and parents' knowledge/youth disclosure, and a quadratic interaction of conflict with parents. For violence, we used logistic regression models to analyze moderation. No interaction effects between psychopahy scores and parenting factors were found. Youths' reports of high conflict with parents and parents' knowledge/youth disclosure showed to have an impact on violence regardless of the level of psychopathic traits. Implications for the prevention and treatment are discussed. PMID- 26651860 TI - From the Bedside Chair. PMID- 26651861 TI - Familism and Health Care Provision to Hispanic Older Adults. AB - The Hispanic older adult population's rapid growth calls for an awareness of values that can affect the rendering and receipt of care. Familism, or familismo, a traditional Hispanic value, places importance of family over the self and can potentially affect health care perceptions and practices for Hispanic older adults. The current article discusses familism, which is upheld by some Hispanic older adults, and the potential for underuse of health care services. The traditional feminine role, marianismo, and masculine role, machismo, are considered, as well as implications for how decision making may be made by family members rather than the patient. Clinical implications for the provision of health care to Hispanic older adults are provided, along with the importance of considering acculturation and ethnic heterogeneity. Health care management strategies that reflect recognition and respect of familism, yet emphasize optimization of adherence and self-care, are described. PMID- 26651862 TI - Prevalence of Advance Directives Among Older Adults Admitted to Intensive Care Units and Requiring Mechanical Ventilation. AB - Because older adults are at high risk for hospitalization and potential decisional incapacity, advance directives are important components of pre hospital advanced care planning, as they document individual preferences for future medical care. The prevalence of pre-hospital advance directive completion in 450 critically ill older adults requiring mechanical ventilation from two Mid Atlantic hospitals is described, and demographic and clinical predictors of pre hospital advance directive completion are explored. The overall advance directive completion rate was 42.4%, with those in older age groups (75 to 84 years and 85 and older) having approximately two times the odds of completion. No significant differences in the likelihood of advance directive completion were noted by sex, race, or admitting diagnosis. The relatively low prevalence of advance directive completion among older adults with critical illness and high mortality rate (24%) suggest a need for greater awareness and education. PMID- 26651863 TI - Effects of a Behavioral and Exercise Program on Depression and Quality of Life in Community-Dwelling Older Adults: A Controlled, Quasi-Experimental Study. AB - Sedentary behavior and low participation in exercise among older adults can lead to depression and low quality of life (QOL). The current study investigated the effects of behavioral and exercise programs on depression severity and QOL among Malaysian community-dwelling older adults. A controlled, quasi-experimental, pre posttest design was used. A total of 63 participants were divided into three groups: (a) exercise and behavior group (EBG), (b) exercise only group (EG), and (c) control group (CG). Results showed a significant difference in depression among groups (F(2,58) = 33.49, p < 0.01, eta(2) = 0.54; mean, EBG < EG < CG) and in physical (F(2,58) = 5.33, p < 0.01, eta(2)= 0.16; mean, EBG > EG > CG) and mental (F(2,58) = 4.08, p < 0.01, eta(2) = 0.12; mean, EBG > CG > EG) scores of QOL. A combination of behavioral and exercise programs has superior effects on depression and QOL of older adults. [Journal of Gerontological Nursing, 42(2), 45 54.]. PMID- 26651864 TI - Effects of Staffing and Regional Location on Influenza and Pneumococcal Vaccination Rates in Nursing Home Residents. AB - Vaccinations reduce the risk of hospitalizations and adverse health outcomes in older adult populations, which has led to initiatives such as the Healthy People 2010 goal to vaccinate 90% of all nursing home residents. The current analysis looked at the percentage of residents who received vaccinations in 15,653 nursing homes in the United States and relationships of vaccination to staffing intensity and regional location. Overall, approximately 75% of facilities reached the optimum 90% vaccination levels for long-term residents, but less than 50% reached this goal for short-term residents. Further analyses revealed a consistently lower median rate of vaccination for metropolitan areas and indicated a weak relationship between staffing levels of RNs and short-term resident vaccination. Factors influencing staffing levels, and the possible connection between vaccination and technology, are discussed, as well as suggestions for future research aimed at better understanding mechanisms involved in suboptimal influenza and pneumococcal vaccination in nursing homes. [Journal of Gerontological Nursing, 42(2), 38-44.]. PMID- 26651865 TI - Computerized Adaptive Diagnosis and Testing of Mental Health Disorders. AB - In this review we explore recent developments in computerized adaptive diagnostic screening and computerized adaptive testing for the presence and severity of mental health disorders such as depression, anxiety, and mania. The statistical methodology is unique in that it is based on multidimensional item response theory (severity) and random forests (diagnosis) instead of traditional mental health measurement based on classical test theory (a simple total score) or unidimensional item response theory. We show that the information contained in large item banks consisting of hundreds of symptom items can be efficiently calibrated using multidimensional item response theory, and the information contained in these large item banks can be precisely extracted using adaptive administration of a small set of items for each individual. In terms of diagnosis, computerized adaptive diagnostic screening can accurately track an hour-long face-to-face clinician diagnostic interview for major depressive disorder (as an example) in less than a minute using an average of four questions with unprecedented high sensitivity and specificity. Directions for future research and applications are discussed. PMID- 26651866 TI - Chemical constituents from the roots and stems of Litsea cubeba. AB - A new monoterpene and a new lignan, named litsecols A and B (1 and 2), respectively, together with nine known compounds (3-11), were isolated in a continuous investigation on the roots and stems of Litsea cubeba. Their structures were elucidated on the basis of extensive spectroscopic data analysis, and the absolute configuration of 1 was resolved by X-ray diffraction analysis. Compounds 2-5 and 7-9 showed significant inhibitory activity against nitric oxide (NO) production in lipopolysaccharide (LPS)-induced murine microglial (Bv-2) cell line. Compounds 10 and 11 exhibited significant neuroprotective effect against hydrogen peroxide-induced oxidative damage in rat adrenal pheochromocytoma (PC12) cell line. PMID- 26651867 TI - CXCL1 microspheres: a novel tool to stimulate arteriogenesis. AB - CONTEXT: After arterial occlusion, diametrical growth of pre-existing natural bypasses around the obstruction, i.e. arteriogenesis, is the body's main coping mechanism. We have shown before that continuous infusion of chemokine (C-X-C motif) ligand 1 (CXCL1) promotes arteriogenesis in a rodent hind limb ischemia model. OBJECTIVE: For clinical translation of these positive results, we developed a new administration strategy of local and sustained delivery. Here, we investigate the therapeutic potential of CXCL1 in a drug delivery system based on microspheres. MATERIALS AND METHODS: We generated poly(ester amide) (PEA) microspheres loaded with CXCL1 and evaluated them in vitro for cellular toxicity and chemokine release characteristics. In vivo, murine femoral arteries were ligated and CXCL1 was administered either intra-arterially via osmopump or intramuscularly encapsulated in biodegradable microspheres. Perfusion recovery was measured with Laser-Doppler. RESULTS: The developed microspheres were not cytotoxic and displayed a sustained chemokine release up to 28 d in vitro. The amount of released CXCL1 was 100-fold higher than levels in native ligated hind limb. Also, the CXCL1-loaded microspheres significantly enhanced perfusion recovery at day 7 after ligation compared with both saline and non-loaded conditions (55.4 +/- 5.0% CXCL1-loaded microspheres versus 43.1 +/- 4.5% non loaded microspheres; n = 8-9; p < 0.05). On day 21 after ligation, the CXCL1 loaded microspheres performed even better than continuous CXCL1 administration (102.1 +/- 4.4% CXCL1-loaded microspheres versus 85.7 +/- 4.8% CXCL1 osmopump; n = 9; p < 0.05). CONCLUSION: Our results demonstrate a proof of concept that sustained, local delivery of CXCL1 encapsulated in PEA microspheres provides a new tool to stimulate arteriogenesis in vivo. PMID- 26651868 TI - Palliative Care Consultation in the Emergency Department #298. PMID- 26651869 TI - Pulsed electric field increases reproduction. AB - Purpose To study the effect of pulsed electric field - applied in corona discharge photography - on Drosophila melanogaster reproduction, possible induction of DNA fragmentation, and morphological alterations in the gonads. Materials and methods Animals were exposed to different field intensities (100, 200, 300, and 400 kV/m) during the first 2-5 days of their adult lives, and the effect on reproductive capacity was assessed. DNA fragmentation during early- and mid-oogenesis was investigated by application of the TUNEL (Terminal deoxynucleotide transferase dUTP Nick End Labeling) assay. Sections of follicles after fixation and embedding in resins were observed for possible morphological/developmental abnormalities. Results The field increased reproduction by up to 30% by increasing reproductive capacity in both sexes. The effect increased with increasing field intensities. The rate of increase diminished at the strongest intensities. Slight induction of DNA fragmentation was observed exclusively in the nurse (predominantly) and follicle cells, and exclusively at the two most sensitive developmental stages, i.e., germarium and predominantly stage 7-8. Sections of follicles from exposed females at stages of early and mid-oogennesis other than germarium and stages 7-8 did not reveal abnormalities. Conclusions (1) The specific type of electric field may represent a mild stress factor, inducing DNA fragmentation and cell death in a small percentage of gametes, triggering the reaction of the animal's reproductive system to increase the rate of gametogenesis in order to compensate the loss of a small number of gametes. (2) The nurse cells are the most sensitive from all three types of egg chamber cells. (3) The mid-oogenesis checkpoint (stage 7-8) is more sensitive to this field than the early oogenesis one (germarium) in contrast to microwave exposure. (4) Possible therapeutic applications, or applications in increasing fertility, should be investigated. PMID- 26651870 TI - Multiresidue Method for Determination of 183 Pesticide Residues in Leeks by Rapid Multiplug Filtration Cleanup and Gas Chromatography-Tandem Mass Spectrometry. AB - This study reports the development of a novel multiplug filtration cleanup (m PFC) procedure for analysis of pesticide residues in leek samples followed by gas chromatography-tandem mass spectrometry detection. The leek samples were initially purified following the dispersive solid-phase extraction with different sorbents to determine the most suitable proportioning of sorbent materials; then, the m-PFC method was carried out by applying the streamlined procedure with syringes. Average recoveries of most pesticides were in the range from 70.2 to 126.0% with the relative standard deviation < 20% with the m-PFC process. The limits of detection were 0.03-3.3 MUg kg(-1). The limits of quantification were 0.1-10 MUg kg(-1). The m-PFC process is convenient and time-efficient, taking just a few seconds per sample. Finally, the developed method was successfully applied to the determination of pesticide residues in market samples. In that analysis, 35 pesticides were detected in 29 samples, with values ranging from 2.0 to 9353.1 MUg kg(-1). PMID- 26651871 TI - Structure, Bonding, and Stability of Mercury Complexes with Thiolate and Thioether Ligands from High-Resolution XANES Spectroscopy and First-Principles Calculations. AB - We present results obtained from high energy-resolution L3-edge XANES spectroscopy and first-principles calculations for the structure, bonding, and stability of mercury(II) complexes with thiolate and thioether ligands in crystalline compounds, aqueous solution, and macromolecular natural organic matter (NOM). Core-to-valence XANES features that vary in intensity differentiate with unprecedented sensitivity the number and identity of Hg ligands and the geometry of the ligand environment. Post-Hartree-Fock XANES calculations, coupled with natural population analysis, performed on MP2-optimized Hg[(SR)2...(RSR)n] complexes show that the shape, position, and number of electronic transitions observed at high energy-resolution are directly correlated to the Hg and S (l,m) projected empty densities of states and occupations of the hybridized Hg 6s and 5d valence orbitals. Linear two-coordination, the most common coordination geometry in mercury chemistry, yields a sharp 2p to 6s + 5d electronic transition. This transition varies in intensity for Hg bonded to thiol groups in macromolecular NOM. The intensity variation is explained by contributions from next-nearest, low-charge, thioether-type RSR ligands at 3.0-3.3 A from Hg. Thus, Hg in NOM has two strong bonds to thiol S and k additional weak Hg...S contacts, or 2 + k coordination. The calculated stabilization energy is -5 kcal/mol per RSR ligand. Detection of distant ligands beyond the first coordination shell requires precise measurement of, and comparison to, spectra of reference compounds as well as accurate calculation of spectra for representative molecular models. The combined experimental and theoretical approaches described here for Hg can be applied to other closed-shell atoms, such as Ag(I) and Au(I). To facilitate further calculation of XANES spectra, experimental data, a new crystallographic structure of a key mercury thioether complex, Cartesian coordinates of the computed models, and examples of input files are provided as Supporting Information . PMID- 26651872 TI - Band Gap Engineering in a 2D Material for Solar-to-Chemical Energy Conversion. AB - The electronic structure of 2D semiconductors depends on their thickness, providing new opportunities to engineer semiconductors for energy conversion, electronics, and catalysis. Here we show how a 3D semiconductor, black phosphorus, becomes active for solar-to-chemical energy conversion when it is thinned to a 2D material. The increase in its band gap, from 0.3 eV (3D) to 2.1 eV (2D monolayer), is accompanied by a 40-fold enhancement in the formation of chemical products. Despite this enhancement, smaller flakes also have shorter excited state lifetimes. We deduce a mechanism in which recombination occurs at flake edges, while the "van der Waals" surface of black phosphorus bonds to chemical intermediates and facilitates electron transfer. The unique properties of black phosphorus highlight its potential as a customizable material for solar energy conversion and catalysis, while also allowing us to identify design rules for 2D photocatalysts that will enable further improvements in these materials. PMID- 26651873 TI - Changes in Cell Adhesiveness and Physicochemical Properties of Cross-Linked Albumin Films after Ultraviolet Irradiation. AB - We discovered the unique cell adhesive properties of ultraviolet (UV)-irradiated albumin films. Albumin films prepared using a cross-linking reagent with epoxy groups maintained native albumin properties, such as resistance to cell adhesion. Interestingly, the cell adhesive properties of films varied depending upon the UV irradiation time; specifically, cell adhesiveness increased until 2 h of UV irradiation, when the cell number attached to the film was similar to that of culture dishes, and then cell adhesiveness decreased until 20 h of UV irradiation, after which the surface returned to the initial non-adhesive state. To elucidate the molecular mechanisms underlying this phenomenon, we examined the effect of UV irradiation on albumin film properties. The following changes occurred in response to UV irradiation: decreased alpha-helical structure, cleavage of albumin peptide bonds, and increased hydrophilicity and oxygen content of the albumin film surface. In addition, we found a positive correlation between the degree of cell adhesion and the amount of fibronectin adsorbed on the film. Taken together, UV-induced changes in films highly affect the amount of cell adhesion proteins adsorbed on the films depending upon the irradiation time, which determines cell adhesion behavior. PMID- 26651874 TI - Inexpensive Method for Selecting Receptor Structures for Virtual Screening. AB - This article introduces a screening performance index (SPI) to help select from a number of experimental structures one or a few that are more likely to identify more actives among its top hits from virtual screening of a compound library. It achieved this by docking only known actives to the experimental structures without considering a large number of decoys to reduce computational costs. The SPI is calculated by using the docking energies of the actives to all the receptor structures. We evaluated the performance of the SPI by applying it to study eight protein systems: fatty acid binding protein adipocyte FABP4, serine/threonine-protein kinase BRAF, beta-1 adrenergic receptor ADRB1, TGF-beta receptor type I TGFR1, adenosylhomocysteinase SAHH, thyroid hormone receptor beta 1 THB, phospholipase A2 group IIA PA2GA, and cytochrome P450 3a4 CP3A4. We found that the SPI agreed with the results from other popular performance metrics such as Boltzmann-Enhanced Discrimination Receiver Operator Characteristics (BEDROC), Robust Initial Enhancement (RIE), Area Under Accumulation Curve (AUAC), and Enrichment Factor (EF) but is less expensive to calculate. SPI also performed better than the best docking energy, the molecular volume of the bound ligand, and the resolution of crystal structure in selecting good receptor structures for virtual screening. The implications of these findings were further discussed in the context of ensemble docking, in situations when no experimental structure for the targeted protein was available, or under circumstances when quick choices of receptor structures need to be made before quantitative indexes such as the SPI and BEDROC can be calculated. PMID- 26651875 TI - Charge Transfer Stabilization of Late Transition Metal Oxide Nanoparticles on a Layered Niobate Support. AB - Interfacial interactions between late transition metal/metal oxide nanoparticles and oxide supports impact catalytic activity and stability. Here, we report the use of isothermal titration calorimetry (ITC), electron microscopy and density functional theory (DFT) to explore periodic trends in the heats of nanoparticle support interactions for late transition metal and metal oxide nanoparticles on layered niobate and silicate supports. Data for Co(OH)2, hydroxyiridate-capped IrOx.nH2O, Ni(OH)2, CuO, and Ag2O nanoparticles were added to previously reported data for Rh(OH)3 grown on nanosheets of TBA0.24H0.76Ca2Nb3O10 and a layered silicate. ITC measurements showed stronger bonding energies in the order Ag < Cu ~ Ni ~ Co < Rh < Ir on the niobate support, as expected from trends in M-O bond energies. Nanoparticles with exothermic heats of interaction were stabilized against sintering. In contrast, ITC measurements showed endothermic interactions of Cu, Ni, and Rh oxide/hydroxide nanoparticles with the silicate and poor resistance to sintering. These trends in interfacial energies were corroborated by DFT calculations using single-atom and four-atom cluster models of metal/metal oxide nanoparticles. Density of states and charge density difference calculations reveal that strongly bonded metals (Rh, Ir) transfer d-electron density from the adsorbed cluster to niobium atoms in the support; this mixing is absent in weakly binding metals, such as Ag and Au, and in all metals on the layered silicate support. The large differences between the behavior of nanoparticles on niobate and silicate supports highlight the importance of d-orbital interactions between the nanoparticle and support in controlling the nanoparticles' stability. PMID- 26651877 TI - In Situ Generated Ag(II)-Catalyzed Selective Oxo-Esterification of Alkyne with Alcohol to alpha-Ketoester: Photophysical Study. AB - An expert and easy one-step catalytic method for the multi O-C coupling of alkyne is developed for the synthesis of valuable alpha-ketoesters and their chiral analogues, in contrast to the generation of esters by a noncatalytic method. The in situ generated powerful Ag(II) catalyst from AgOTf is the workhorse in the oxidative grafting of alkyne with PhIO and alcohol. The radical mechanism is confirmed in our controlled experiments and UV-vis study. PMID- 26651876 TI - Pulsed Dynamic Nuclear Polarization with Trityl Radicals. AB - Continuous-wave (CW) dynamic nuclear polarization (DNP) is now established as a method of choice to enhance the sensitivity in a variety of NMR experiments. Nevertheless, there remains a need for the development of more efficient methods to transfer polarization from electrons to nuclei. Of particular interest are pulsed DNP methods because they enable a rapid and efficient polarization transfer that, in contrast with CW DNP methods, is not attenuated at high magnetic fields. Here we report nuclear spin orientation via electron spin locking (NOVEL) experiments using the polarizing agent trityl OX063 in glycerol/water at a temperature of 80 K and a magnetic field of 0.34 T. (1)H NMR signal enhancements up to 430 are observed, and the buildup of the local polarization occurs in a few hundred nanoseconds. Thus, NOVEL can efficiently dynamically polarize (1)H atoms in a system that is of general interest to the solid-state DNP NMR community. This is a first, important step toward the general application of pulsed DNP at higher fields. PMID- 26651878 TI - Drug-diagnostic co-development: challenges and issues. AB - Diagnostic tests have become increasingly important for optimizing drug use. Ideally, a companion diagnostic test is developed concurrently with a corresponding therapeutic product (co-development). However, the diagnostic test may also be developed to optimize treatment with previously approved therapeutic agents (follow-up-development). In co-development, the effectiveness of an agent in marker-defined patients is confirmed by an enrichment trial design. In follow up-development, a biomarker is validated by prospective and/or retrospective analyses of unselected design trials. A prospectively designed trial is the gold standard approach to biomarker validation, but retrospective validation can be used to efficiently determine effective treatments for marker-defined patients. Accumulation and systematization of examples of drug-diagnostic development will aid in the effective development of companion diagnostics. PMID- 26651879 TI - Stelliosphaerols A and B, Sesquiterpene-Polyol Conjugates from an Ecuadorian Fungal Endophyte. AB - Endophytic fungi are plant tissue-associated fungi that represent a rich resource of unexplored biological and chemical diversity. As part of an ongoing effort to characterize Amazon rainforest-derived endophytes, numerous fungi were isolated and cultured from plants collected in the Yasuni National Park in Ecuador. Of these samples, phylogenetic and morphological data revealed a previously undescribed fungus in the order Pleosporales that was cultured from the tropical tree Duroia hirsuta. Extracts from this fungal isolate displayed activity against Staphylococcus aureus and were thus subjected to detailed chemical studies. Two compounds with modest antibacterial activity were isolated, and their structures were elucidated using a combination of NMR spectroscopic analysis, LC-MS studies, and chemical degradation. These efforts led to the identification of stelliosphaerols A (1) and B (2), new sesquiterpene-polyol conjugates that are responsible, at least in part, for the S. aureus inhibitory activity of the fungal extract. PMID- 26651880 TI - Interleukin-10 modulates pulmonary neutrophilic inflammation induced by cigarette smoke exposure. AB - AIM OF THE STUDY: Interleukin (IL)-10 is an anti-inflammatory cytokine, but its role in cigarette smoke (CS)-induced inflammation and chronic obstructive pulmonary disease (COPD) has not been fully elucidated. The purpose of this study was to investigate the effect of IL-10 deficiency on CS-induced pulmonary inflammation in mice in vivo and in vitro. MATERIALS AND METHODS: IL-10-deficient and wild-type control mice with a C57BL6/J genetic background were exposed to CS, and inflammatory cells in bronchoalveolar lavage fluid (BALF) and mRNA of cytokines in lung were evaluated with enzyme-linked immunosorbent assay (ELISA) and reverse transcription polymerase chain reaction (RT-PCR). RESULTS: During 12 days of daily CS exposure to wild-type mice, neutrophil counts in BAL fluid and tumor necrosis factor (TNF)-alpha mRNA expression were increased, peaked at day 8, and then declined on day 12 when the level of IL-10 reached its peak. In IL-10 deficient mice, neutrophil recruitment and TNF-alpha mRNA levels induced by CS exposure were significantly greater than those in wild-type mice. Keratinocyte derived chemokine (KC; murine ortholog of human CXCL8) and granulocyte macrophage colony-stimulating factor (GM-CSF) mRNA levels or matrix metalloproteinase(MMP)-9 protein levels were not correlated with neutrophil count. CONCLUSIONS: IL-10 had a modulatory effect on CS-induced pulmonary neutrophilic inflammation and TNF alpha expression in mice in vivo and therefore appears to be an important endogenous suppressor of airway neutrophilic inflammation. PMID- 26651881 TI - MiR-21 modulates human airway smooth muscle cell proliferation and migration in asthma through regulation of PTEN expression. AB - BACKGROUND: Asthma is characterized by airway remodeling arising from an increase in airway smooth muscle (ASM) mass. This increase is regulated in part by ASM cell proliferation and migration. MicroRNA (miR)-21 also plays a role in asthma, but the molecular mechanisms underlying its effects are not completely understood. This study investigated the effects and mechanism of miR-21 on the human ASM (HASM) cell proliferation and migration. MATERIALS AND METHODS: HASM cells were transduced with a miR-21 vector, and the expression of miR-21 was determined by quantitative real-time polymerase chain reaction (qRT-PCR). The effect of the miR-21 on HASM cell proliferation and migration was analyzed by CCK8 and transwell assay. The expression level of PTEN (phosphatase and tensin homolog deleted on chromosome 10) in HASM cells was assessed by qRT-PCR and Western blot analysis. Meanwhile, the activity of PTEN was measured by PTEN malachite green assay kit. RESULTS: Lentivirus-mediated miR-21 overexpression markedly enhanced the proliferation and migration of HASM cells (P < .05), and ablation of miR-21 by anti-miR-21 inhibitor markedly reduced cell proliferation and migration. We demonstrated that miR-21 overexpression significantly reduced the expression of PTEN (P < .05), while PTEN knock-down markedly increased HASM cell proliferation and migration. Furthermore, we found that overexpression of PTEN led to a decrease of HASM cell proliferation and migration. MiR-21 mediated HASM cell proliferation and migration through activation of the phosphoinositide 3-kinase pathway. CONCLUSIONS: This study provides the first in vitro evidence that overexpression of miR-21 in HASM cells can trigger cell proliferation and migration, and the effects of miR-21 depend on the level of PTEN. PMID- 26651882 TI - Long-term exposure to ultrasonically nebulized distilled water and saline causes cellular influx and oxidative stress in lung tissue of rats. AB - PURPOSE: The aim of this study was to evaluate of the effect of distilled water and saline ultrasonic nebulization on the inflammatory and oxidative stress responses and on the lower airway architecture. MATERIALS AND METHODS: Twenty-one male Fischer rats were distributed into 3 groups of 7 animals each: a control group (CG), exposed to ambient air; a saline group (SG), exposed to 0.9% sodium chloride (NaCl); and a group exposed to distilled water (DWG). The exposure was carried out in a box attached to an ultrasonic inhaler, occurring for 20 min, 3 times a day for 6 months. At 24h after the last exposure, the animals were euthanized. The bronchoalveolar lavage fluid (BALF) and lungs were collected for study. RESULTS: There was an increase of inflammatory cells in the pulmonary tissue BALF in the DWG compared with the CG. The DWG showed an increase of inflammatory cells compared with the SG and CG. The DWG and SG had higher NADPH oxidase activity than the CG. The volume density (Vv) of the alveolar septum was higher in the DWG than in the SG and CG, and the DWG also had a higher Vv of collagen fibers than the other 2 groups. The DWG presented elevated content of thiobarbituric acid reactive substances in lung homogenates relative to the SG and CG. CONCLUSIONS: The ultrasonic nebulization of distilled water increased the influx of inflammatory cells and oxidative damage, and promoted changes in the lung architecture. PMID- 26651883 TI - Post-conditioning with Cyclosporine A after a 24-hour cold ischemia in ex vivo reperfused pig lungs. AB - OBJECTIVE: To evaluate the effects of 1 and 5 MUM of Cyclosporine A (CsA), administered 24 hours after a cold ischemic period, in an ex vivo reperfused pig lung model. METHODS: The experiments were performed in 15 pigs. Each pair of lungs was surgically separated. Extracorporeal perfusion and mechanical ventilation were started after a cold ischemia of 2 hours for one lung and 24 hours for the contralateral. We constituted three groups (n = 5 each): two groups for which the lung underwent a 24-hour ischemia received either 1 or 5 MUM of CsA at the time of reperfusion, and a control group without CsA. For each group, lungs undergoing a 2-hour ischemia did not receive CsA. RESULTS: Reperfusion with either CsA increased the PO2 levels in a dose dependent manner, and reduced concentrations of the receptor for advanced glycation endproducts, compared to the control. The pulmonary arterial pressure, the capillary pressure, and the pulmonary vascular resistances were not increased, even with 5 MUM of CsA. No significant change was shown on cytokines levels. DISCUSSION: Postconditioning with CsA improves lung function, after a 24-hour cold ischemic period. Either 1 or 5 MUM seemed to be safe regarding the pulmonary vascular pressures and resistances. PMID- 26651886 TI - It's not the noise, it's what you do with it. PMID- 26651884 TI - Organotypic lung culture: A new model for studying ischemia and ex vivo perfusion in lung transplantation. AB - AIM: Donors after cardiac death (DCD) in lung transplantation is considered as a solution for organ shortage. However, it is characterized by warm ischemic period, which could be involved in severe Ischemia-Reperfusion lesion (IR) with early graft dysfunction. We describe a new hybrid model combining in vivo ischemia followed by in vitro reoxygenation using organ-specific culture. MATERIAL AND METHODS: A hybrid model using in vivo ischemic period followed by in vitro lung slice reoxygenation was set up in rat to mimic DCD in lung transplantation with in vitro perfusion. Different markers (bioenergetics, oxidant stress assays, and histology) were measured to evaluate the viability of lung tissue after different ischemic times (I-0, I-1, I-2, I-4, I-15 hours) and reoxygenation times (R-0, R-1, R-4, R-24 hours). RESULTS: No differences were found in cell viability, ATP concentrations, extracellular LDH assays or histology, demonstrating extensive viability of up to 4 hours in lung tissue warm ischemia. We found oxidative stress mainly during the ischemic period with no burst at reoxygenation. Cytosolic anti-oxidant system was involved first (I-0,I 1,I-2) followed by mitochondrial anti-oxidant system for extensive ischemia (I 4). Histological features showed differences in this model of ischemia reoxygenation between bronchial epithelium and lung parenchymal cells, with epithelium regeneration after 2 hours of warm ischemia and 24 hours of perfusion. CONCLUSION: The results of our hybrid model experiment suggest extensive lung viability of up to 4 hours ischemia. Our model could be an interesting tool to evaluate ex vivo reconditioning techniques after different in vivo lung insults. PMID- 26651887 TI - Brown tumor of the pelvis. PMID- 26651888 TI - An alerting sign: Enlarged cardiac silhouette. PMID- 26651889 TI - Does allergic conjunctivitis always require prescription eyedrops? PMID- 26651890 TI - A young man with an unusual cause of palpitations. PMID- 26651891 TI - Catheter-based transarterial therapies for hepatocellular cancer. AB - As the prevalence of liver cancer increases, so does the demand for nonsurgical, minimally invasive alternatives to surgery, since many patients have tumors that cannot be surgically resected. Catheter-based hepatic arterial procedures may be an option in patients with primary and metastatic liver cancer. The authors describe four catheter-based hepatic arterial procedures and outline the management of potential complications during the immediate postprocedural period. PMID- 26651892 TI - Insulin pumps: Beyond basal-bolus. AB - Insulin pumps are a major advance in diabetes management, making insulin dosing easier and more accurate and providing great flexibility, safety, and efficacy for people who need basal-bolus insulin therapy. They are the preferred treatment for people with type 1 diabetes and many with type 2 diabetes who require insulin. This article reviews the basics of how insulin pumps work, who benefits from a pump, and how to manage inpatients and outpatients on insulin pumps. PMID- 26651893 TI - Insulin pumps: Great devices, but you still have to press the button. PMID- 26651894 TI - The new oral anticoagulants: Reasonable alternatives to warfarin. AB - Dabigatran (a direct thrombin inhibitor) and rivaroxaban, apixaban, and edoxaban (direct activated factor X inhibitors) are increasingly being used in clinical practice. Compared with vitamin K antagonists, they are more convenient, do not require laboratory monitoring, have limited drug and food interactions, and have fixed dosages suitable for most patients. But the shortcomings of these agents can jeopardize their efficacy and increase the risk of bleeding. Their future role in preventing and treating thromboembolic disease will depend on building clinical experience, but current evidence indicates that they are reasonable alternatives to vitamin K antagonists. PMID- 26651895 TI - Asymptomatic carotid artery disease: A personalized approach to management. AB - Asymptomatic carotid artery disease is relatively common and poses a challenge for internists as well as vascular specialists when deciding whether to pursue surgical endarterectomy, percutaneous stenting, or medical therapy alone. The authors review the management of asymptomatic carotid disease, reflecting the most current data. PMID- 26651896 TI - Multibody model of the human upper extremity for fracture simulation. AB - About 3.8 million people are injured in accidents at work in Europe every year. The resulting high costs are incurred by the victims themselves, their families, employers and society. We have used a numerical simulation to reconstruct accidents at work for several years. To reconstruct these accidents MADYMO R7.5 with a numerical human model (pedestrian model) is used. However, this model is dedicated to the analysis of car-to-pedestrian accidents and thus cannot be fully used for reconstructing accidents at work. Therefore, we started working on the development of a numerical model of the human body for the purpose of simulating accidents at work. Developing a new numerical model which gives an opportunity to simulate fractures of the upper extremity bones is a stage of that work. PMID- 26651897 TI - Capillary zone electrophoresis as a tool for bottom-up protein analysis. PMID- 26651905 TI - Synthesis of Pyrene-Fused Pyrazaacenes on Metal Surfaces: Toward One-Dimensional Conjugated Nanostructures. AB - We investigated the synthesis of one-dimensional nanostructures via Schiff base (imine) formation on three close-packed coinage metal (Au, Ag, and Cu) surfaces under ultrahigh vacuum conditions. We demonstrate the feasibility of forming pyrene-fused pyrazaacene-based oligomers on the Ag(111) surface by thermal annealing of tetraketone and tetraamine molecules, which were designed to afford cyclocondensation products. Direct visualization by scanning tunneling microscopy of reactants, intermediates, and products with submolecular resolution and the analysis of their statistical distribution in dependence of stoichiometry and annealing temperature together with the inspection of complementary X-ray photoelectron spectroscopy signatures provide unique insight in the reaction mechanism, its limitations, and the role of the supporting substrate. In contrast to the reaction on Ag(111), the reactants desorb from the Au(111) surface before reacting, whereas they decompose on the Cu(111) surface during the relevant thermal treatment. PMID- 26651906 TI - [In Process Citation]. PMID- 26651907 TI - [In Process Citation]. PMID- 26651908 TI - [In Process Citation]. PMID- 26651909 TI - [In Process Citation]. PMID- 26651910 TI - [Fracture prevention programmes can reduce the number of subsequent fractures]. AB - Once a fragility fracture has occurred after the age of 50 years, 41-85% of patients will experience another fracture. Patients who present at hospitals with a fragility fracture would benefit from introduction of fracture prevention programmes, as these programmes have been shown to reduce the number of subsequent fractures, reduce mortality, and furthermore are cost-effective. This paper presents the evidence for implementation of fracture prevention programmes and how these can be introduced successfully. PMID- 26651911 TI - [Demyelinating diseases in children with acute neurological symptoms]. AB - Demyelinating diseases in children is a broad group of illnesses, which affect the central nervous system. Demyelinating diseases can be monophasic or chronic and comprise acute disseminated encephalomyelitis, optic neuritis, transverse myelitis, multiple sclerosis and neuromyelitis optica. Demyelinating diseases are rare, but it is important for the physician to recognize these diseases, as well as to understand the differential diagnoses. This review summarizes the current knowledge of demyelinating disorders in children, focusing on an approach to diagnosis and management. PMID- 26651912 TI - [Limited evidence for monitoring and treatment of hypophosphataemia in critically ill patients]. AB - Hypophosphataemia is a potentially hazardous metabolic disturbance which is common in critically ill patients. The condition is reported to be associated with severe complications and increased mortality. It is unknown, whether hypophosphataemia has a causal effect or reflects the severity of illness. There are no randomized clinical trials to support treatment of hypophosphataemia with intravenous phosphate substitution, which has resulted in large variations in monitoring and treatment of hypophosphataemia in the intensive care unit. PMID- 26651913 TI - [Metformin and the obstetric patient]. AB - Polycystic ovary syndrome (PCOS) is associated with insulin resistance, infertility, obesity and gestational complications. Metformin is widely used in fertility treatment of women with PCOS, due to a suggested positive effect of continued metformin treatment beyond the first trimester on pregnancy complications. Larger randomized trials have failed to confirm this. Metformin treatment has not been found to be superior to insulin treatment in women with gestational diabetes and may be associated with long-term consequences in the children in the form of overweight and disturbed glucose metabolism. PMID- 26651914 TI - Intrinsic subtypes and genomic signatures of primary breast cancer and prognosis after systemic relapse. AB - Molecular subtypes and gene expression signatures are widely used in early breast cancer but their role in metastatic disease is less explored. Two hundred-twenty patients diagnosed with primary breast cancer and subsequent relapse in Stockholm, Sweden between 1997 and 2006 were identified and their primary tumor was assessed for immunohistochemistry (IHC)- and PAM50-based subtypes, risk of recurrence (ROR-S) score, 21-gene and 70-gene signatures using research-based microarray expression profiles. Clinical and pathological data were retrospectively collected. Post-relapse survival within intrinsic subtypes and genomic signatures was investigated by Kaplan-Meier and Cox regression methods. ROR weighted for proliferation index (ROR-P) was explored and the prognostic contribution provided when combined to a clinical model estimated as change in LR chi(2). IHC classified 27%, 24%, 36% and 13% of the tumors as luminal A, luminal B, HER2+ and triple negative, respectively. PAM50 categorized 22%, 24%, 26%, 22%, 6% of the tumors as luminal A, luminal B, HER2-enriched, basal-like and normal like. Triple negative and basal tumors had a significantly shorter median post relapse survival in comparison with luminal. Overall, neither IHC nor PAM50 subtypes, 21- and 70- gene profiles were prognostic in multivariable models. Low and medium ROR-S had a longer survival compared with the high-risk group (23 vs 10 months; p = 0.04). ROR-P independently correlated with post-relapse survival (p = 0.002) and provided the most significant prognostic information when added to a clinical model. ROR score from primary tumor represents an independent prognostic factor of post-relapse survival beyond classical clinical and pathological variables. PMID- 26651915 TI - New direct-acting antivirals in hepatitis C therapy: a review of sofosbuvir, ledipasvir, daclatasvir, simeprevir, paritaprevir, ombitasvir and dasabuvir. AB - Hepatitis C is a chronic infection associated with considerable morbidity and mortality. In recent years, there has been a shift in treatment paradigm with the discovery and approval of agents that target specific proteins vital for hepatitis C replication. The NS3/4A inhibitors simeprevir and paritaprevir, the NS5A inhibitors ombitasvir, ledipasvir, and daclatasvir, and the NS5B inhibitors sofosbuvir and dasabuvir have been newly FDA approved and incorporated as first line agents into the latest IDSA-AASLD guidelines for Hepatitis C treatment. Used in combination, these agents produce higher rates of sustained virologic response and less adverse effects than historical options, along with limited rates of resistance. Pertinent clinical data, pharmacology, and pharmacokinetics are reviewed for these new direct acting antiviral agents. PMID- 26651916 TI - Pathophysiological and neurobehavioral injuries in mice experimentally envenomed with Androctonus liouvillei (Pallary, 1928) scorpion venom. AB - The genus Androctonus is represented by 7 scorpion species in Morocco. All studies conducted on the characterization of Androctonus species venom are limited to Androctonus mauritanicus. However, there is other species which arouses also interest of scientists due to their high toxicity. Thus, we chose to assess the toxic effect of Androctonus liouvillei venom by sublethal injection and the effects on some vital organs, by a histological and a biochemical tools. In addition, we aimed to characterize the neurobehavioral impairments, in Swiss mice, 3h, 6h and 12h following envenomation. The LD50 of A. liouvillei scorpion venom was found to be 0.29mg/kg by subcutaneous injection route. Venom administration induced glomerular destruction and disorganization in the Bowman's spac. Examination of lungs showed a remarkable focal rupture of the alveolar structure and intra-alveolar hemorrhage. Concurrently, there was a significant enhancement in the serum enzymes levels of AST, ALT, CPK and LDH, and a high level of glucose and creatinine. Proteinuria was also observed. Regarding the behavioral effects we noted a hypoactivity and anxiogenic-like effect, manifested by an increased time spent in the open arms in groups tested 30min and 12h after the injection. Concomitantly with an increased immobility time in the tail suspension test. The present finding show an obvious profound neuromodulatory effect of A. liouvillei venom manifested by an impaired neurobehavioral and physiological patterns in mice that may in part explain the toxic effect of the venom in human as one of the potent death agents. PMID- 26651917 TI - Structural Biology of Nuclear Auxin Action. AB - Auxin coordinates plant development largely via hierarchical control of gene expression. During the past decades, the study of early auxin genes paired with the power of Arabidopsis genetics have unraveled key nuclear components and molecular interactions that perceive the hormone and activate primary response genes. Recent research in the realm of structural biology allowed unprecedented insight into: (i) the recognition of auxin-responsive DNA elements by auxin transcription factors; (ii) the inactivation of those auxin response factors by early auxin-inducible repressors; and (iii) the activation of target genes by auxin-triggered repressor degradation. The biophysical studies reviewed here provide an impetus for elucidating the molecular determinants of the intricate interactions between core components of the nuclear auxin response module. PMID- 26651918 TI - Machine Learning for High-Throughput Stress Phenotyping in Plants. AB - Advances in automated and high-throughput imaging technologies have resulted in a deluge of high-resolution images and sensor data of plants. However, extracting patterns and features from this large corpus of data requires the use of machine learning (ML) tools to enable data assimilation and feature identification for stress phenotyping. Four stages of the decision cycle in plant stress phenotyping and plant breeding activities where different ML approaches can be deployed are (i) identification, (ii) classification, (iii) quantification, and (iv) prediction (ICQP). We provide here a comprehensive overview and user-friendly taxonomy of ML tools to enable the plant community to correctly and easily apply the appropriate ML tools and best-practice guidelines for various biotic and abiotic stress traits. PMID- 26651919 TI - Analytical and Decision Support Tools for Genomics-Assisted Breeding. AB - To successfully implement genomics-assisted breeding (GAB) in crop improvement programs, efficient and effective analytical and decision support tools (ADSTs) are 'must haves' to evaluate and select plants for developing next-generation crops. Here we review the applications and deployment of appropriate ADSTs for GAB, in the context of next-generation sequencing (NGS), an emerging source of massive genomic information. We discuss suitable software tools and pipelines for marker-based approaches (markers/haplotypes), including large-scale genotypic and phenotypic, data management, and molecular breeding approaches. Although phenotyping remains expensive and time consuming, prediction of allelic effects on phenotypes opens new doors to enhance genetic gain across crop cycles, building on reliable phenotyping approaches and good crop information systems, including pedigree information and target haplotypes. PMID- 26651920 TI - Evolutionary and Epidemiological Implications of Multiple Infection in Plants. AB - Recent methodological advances have uncovered tremendous microbial diversity cohabiting in the same host plant, and many of these microbes cause disease. In this review we highlight how the presence of other pathogen species, or other pathogen genotypes, within a plant can affect key components of host-pathogen interactions: (i) within-plant virulence and pathogen accumulation, through direct and host-mediated mechanisms; (ii) evolutionary trajectories of pathogen populations, through virulence evolution, generation of novel genetic combinations, and maintenance of genetic diversity; and (iii) disease dynamics, with multiple infection likely to render epidemics more devastating. The major future challenges are to couple a community ecology approach with a molecular investigation of the mechanisms operating under coinfection and to evaluate the evolution and effectiveness of resistance within a coinfection framework. PMID- 26651921 TI - Cardiospecific troponin immunoassays: How low is it worth to go? PMID- 26651922 TI - The first Mares Conference on Marine Ecosystem Health and Conservation 2014: Key messages and outcomes. PMID- 26651923 TI - [Therapeutic failure in scabies: An observational study]. AB - BACKGROUND: Several sources suggest an escalation of scabies in France. AIM: To describe a population of patients continuing to present with scabies despite multiple treatments in order to identify factors associated with persistence of infection. PATIENTS AND METHODS: A descriptive cross-sectional study in adults and children consulting for persistent scabies despite at least one previous treatment. A standardized questionnaire explored potential sources of treatment failure. RESULTS: Thirty-one patients were analyzed. Initial symptoms were noted to have started between two and 52 weeks earlier (mean: 19 weeks). The mean number of prior consultations with a general practitioner was 3.1 (0-10) and 1.7 with a dermatologist (0-7). The mean number of patients per household was 3.5 (1 9). At least one dose of oral ivermectin (maximum of 6 doses per household) was prescribed for 84 % of patients (29 % of whom were not fasted at the time). Further, 74 % of patients received at least one local application of esdepallethrin and piperonyl butoxide (maximum: 5 courses), four received benzyl benzoate and two received permethrin; however, 58 % did not reapply the substance after hand washing. All households bought the prescribed treatments despite the costs. Close contacts of patients were treated in 58 % of households. Decontamination of bedding and clothing was carried out properly in 90 % of households. DISCUSSION: Persistence of infection appears to be linked to: (1) insufficient treatment of close contacts; (2) absence of a second treatment between days 7 and 14; (3) insufficient efficacy of the available treatments, doubtless due to multiple factors (intrinsic resistance of Sarcoptes, failure to repeat treatment, poor explanation of methods for dosing and application, and oral intake of treatments). Access to non-reimbursed treatments was not identified as a problem and decontamination of bedding and clothing was correctly performed in most cases. CONCLUSION: Though certain fundamental aspects of scabies treatment must be better known, longer consultations and provision of efficacious treatments are also a priority. PMID- 26651924 TI - [Anatomoclinical study of large-cell acanthoma]. AB - BACKGROUND: Large-cell acanthoma (LCA) is a benign tumour initially described in 1970, since when it has been subject to controversy and remains poorly understood. We carried out a single-centre anatomoclinical study in order to identify the clinical and histological characteristics of the disease. PATIENTS AND METHODS: Slides classed as LCA in our cutaneous histopathology laboratory were re-read and subjected to Melan-A and HMB45 immunohistochemical labelling. Diagnosis was based upon the presence of a clearly delineated epidermal lesion comprising keratinocytes twice as large as cells adjacent to the lesion. Clinical information was obtained through the analysis of existing requests and clinical files. RESULTS: We identified 20 cases of LCA. Mean patient age was 70 years and the sex ratio was 0.25. The mean disease duration was 1.6 years. In most cases, a pigmented macule or papule was seen, sometimes with a verrucous surface. LCA had not been diagnosed by the clinician in any of the cases seen. In terms of histology, all lesions were clearly delineated, with hypergranulosis beneath hyperorthokeratosis, occasionally with accentuation of the papillary outline. An accentuated stratum lucidum was noted in 80% of cases. In the pigmented forms, immunohistochemical labelling showed no increase in melanocyte count. DISCUSSION: LCA is a benign lesion that is most likely underdiagnosed since it is poorly known to clinicians and to certain pathologists. It is seen primarily in adult women and is found on the limbs and on the face. Some debate surrounds the definition of LCA as a separate entity, and some authors assimilate it with solar lentigo, but this hypothesis is countered by the existence of hypopigmented forms and we consider it to be a specific anatomoclinical entity. PMID- 26651925 TI - Shifting Paradigms for High-grade Prostatic Intraepithelial Neoplasia. PMID- 26651927 TI - Active Surveillance Challenges in Men with Prostate Cancer: Role of Imaging Today and Tomorrow. PMID- 26651926 TI - The Proteome of Primary Prostate Cancer. AB - BACKGROUND: Clinical management of the prostate needs improved prognostic tests and treatment strategies. Because proteins are the ultimate effectors of most cellular reactions, are targets for drug actions and constitute potential biomarkers; a quantitative systemic overview of the proteome changes occurring during prostate cancer (PCa) initiation and progression can result in clinically relevant discoveries. OBJECTIVES: To study cellular processes altered in PCa using system-wide quantitative analysis of changes in protein expression in clinical samples and to identify prognostic biomarkers for disease aggressiveness. DESIGN, SETTING, AND PARTICIPANTS: Mass spectrometry was used for genome-scale quantitative proteomic profiling of 28 prostate tumors (Gleason score 6-9) and neighboring nonmalignant tissue in eight cases, obtained from formalin-fixed paraffin-embedded prostatectomy samples. Two independent cohorts of PCa patients (summing 752 cases) managed by expectancy were used for immunohistochemical evaluation of proneuropeptide-Y (pro-NPY) as a prognostic biomarker. RESULTS AND LIMITATIONS: Over 9000 proteins were identified as expressed in the human prostate. Tumor tissue exhibited elevated expression of proteins involved in multiple anabolic processes including fatty acid and protein synthesis, ribosomal biogenesis and protein secretion but no overt evidence of increased proliferation was observed. Tumors also showed increased levels of mitochondrial proteins, which was associated with elevated oxidative phosphorylation capacity measured in situ. Molecular analysis indicated that some of the proteins overexpressed in tumors, such as carnitine palmitoyltransferase 2 (CPT2, fatty acid transporter), coatomer protein complex, subunit alpha (COPA, vesicle secretion), and mitogen- and stress-activated protein kinase 1 and 2 (MSK1/2, protein kinase) regulate the proliferation of PCa cells. Additionally, pro-NPY was found overexpressed in PCa (5-fold, p<0.05), but largely absent in other solid tumor types. Pro-NPY expression, alone or in combination with the ERG status of the tumor, was associated with an increased risk of PCa specific mortality, especially in patients with Gleason score <= 7 tumors. CONCLUSIONS: This study represents the first system-wide quantitative analysis of proteome changes associated to localized prostate cancer and as such constitutes a valuable resource for understanding the complex metabolic changes occurring in this disease. We also demonstrated that pro-NPY, a protein that showed differential expression between high and low risk tumors in our proteomic analysis, is also a PCa specific prognostic biomarker associated with increased risk for disease specific death in patients carrying low risk tumors. PATIENT SUMMARY: The identification of proteins whose expression change in prostate cancer provides novel mechanistic information related to the disease etiology. We hope that future studies will prove the value of this proteome dataset for development of novel therapies and biomarkers. PMID- 26651928 TI - [Residual pleural opacity in patients treated for pleural tuberculosis in Yaounde]. AB - INTRODUCTION: The aim of this study was to evaluate the incidence and risk factors of residual pleural opacity (RPO) at the end and after 6 months (M12) of antituberculosis treatment (ATT) in adults with pleural tuberculosis. METHODS: In this prospective cohort study, all patients admitted for pleural tuberculosis between September 2010 and August 2012 in the pneumology A unit of Yaounde Jamot Hospital were included. Each patient was then followed up for 12 months. RPO was considered significant if it was measured 10mm or more on standard chest X-ray. The logistic regression model was used to investigate the risk factors of significant RPO at the end of antituberculosis treatment. RESULTS: Of the 193 patients included, median (interquartile range) age of 33 (25-42) years, 115 (59.6%) were men. The incidence (95% CI) of significant RPO was 22.0% (14.9-29.1) and 11.0% (4.9-17.1) at the end of ATT and at M12 respectively. In multivariate analysis, the risk factors of the occurrence of a significant RPO at the end of ATT and at M12 were smoking, associated parenchymal lesions, and hypoglycopleuria. CONCLUSION: Cumulative incidence of RPO >= 10 mm was 22% at the end of ATT and 11% after 12 months from the beginning of treatment. Patients with risk factors of RPO >= 10 mm should benefit from greater surveillance and appropriate management. PMID- 26651929 TI - [Mycobacterium avium tumoral infection mimicking a lung adenocarcinoma: A potential diagnostic pitfall]. AB - INTRODUCTION: The incidence of atypical mycobacterial infection in Europe is estimated at one case per 100,000 persons/year. Despite the low incidence of Mycobacterium avium infection, it can result in a nodular lesion simulating lung cancer. We report a case of atypical mycobacteriosis, mimicking lung cancer, which led to a lobectomy. CASE REPORT: It was a right pulmonary upper lobe nodule found in a 63-year-old COPD patient, partially nephrectomized for renal carcinoma, and weekly treated by methotrexate for rheumatoid arthritis. FDG uptake was weakly positive on PET-CT (SUV=2.2) in the upper fissure. Bronchoscopy yielded no lesions and no bacteriological findings. Percutaneous transthoracic lung biopsy revealed lung adenocarcinoma stage T1 (a) N0M0. An upper lobectomy with lymphadenectomy was performed. Histological examination revealed epithelioid granuloma surrounded by giant cells suggestive of tuberculomas. The bronchial washing fluid culture was positive for Mycobacterium avium after 7 weeks. CONCLUSION: In pseudo-neoplastic forms of atypical mycobacteriosis, the presence of alveolar, inflammatory cytonuclear abnormalities can mimic an adenocarcinoma. Making the difference between the cytonuclears defects related to inflammation or neoplasia remains a daily challenge in histopathology. PMID- 26651930 TI - [Dynamic of indicators of ambulatory care of tuberculosis in the antituberculous center of Adjame]. AB - INTRODUCTION: Tuberculosis (TB) remains a real problem of public health in Cote d'Ivoire. The aim of our study is to describe the dynamic of anti-TB fight indicators in anti-TB center (CAT) of Adjame. METHODOLOGY: We realized a retrospective study, comparing the anti-TB activities of two periods (1999-2001 versus 2010-2012) at the CAT of Adjame. Over two periods, 24,520 cases of TB were recorded in the registers of TB declaration. RESULTS: Logistic regression results were the following ones. The proportion of the patients of Adjame municipality increased to detriment of the patients coming from other municipalities. Our study showed an increase of TB contagious forms, a reduction of new cases of TB. The rate of screening of HIV infection increased. We noted a reduction of TB-HIV co-infection prevalence. The proportion of smear positive at the 2nd month decreased. We noted an increase of the rate therapeutic success and a reduction of lost at follow-up. CONCLUSION: Important progresses were realized in the TB fight and TB-HIV co-infection. PMID- 26651931 TI - [Multidrug resistant tuberculosis among health personnel in Cote d'Ivoire]. AB - Multidrug resistance tuberculosis (MDR-TB) of health workers raises the question of hospital-borne transmission of infection. OBSERVATIONS: We report 4 cases of MDR-TB confirmed at the health workers over a period of 8 years (January, 2005 to December 2012), in the 2 services of pulmonology from Abidjan to Cote d'Ivoire). It was about young grown-up patients (aged between 28 and 39 years), all HIV negatives, in a no-win situation of antituberculosis treatment (3 patients/4). The most concerned staffs were the male nurses (2/4). Two agents worked in general hospital and the only one in a pulmonology department at the time of the diagnosis. The tuberculosis was of lung seat with bilateral radiographic hurt (3/4) and multiples excavations (4/4). The case index, when it was identified (2/2), was a family case. Among 3 agents who benefited from a second line treatment, 1 died further to an extensive drug resistance and 2 are declared to be cured. The fourth died before the beginning of the treatment. These cases of cure were in touch with a premature care. CONCLUSION: Multidrug resistant tuberculosis at the health workers could have a negative impact on the antituberculosis fight imposing rigorous measures of infection control and better implication of the occupational medicine. PMID- 26651932 TI - [Epidemiological, clinical and evolutionary peculiarities of interstitial lung disease in systemic sclerosis]. AB - Pulmonary involvement during systemic sclerosis (SS) is dominated by interstitial lung disease and arterial pulmonary hypertension. It is about a retrospective study analyzing 65 cases of SS over a period of 13 years. We compared cases with and without interstitial lung disease. The diagnosis of SS was retained according to American College of Rheumatology (ACR)/EULAR 2013 criteria. The diagnosis of interstitial lung disease was retained in TDM and EFR. Pulmonary hypertension is defined by a pulmonary arterial pression higher than 25 mmHg. The mean delay of diagnosis of interstitial lung disease and the diagnosis was of 48 months (extremes 0-78 months). The comparison between both groups according to average age of the patients, prevalence of pulmonary hypertension, frequency of Raynaud phenomenon and trophic disorders did not find any significant difference. Lung involvement was associated with an esophageal involvement in 71% of the cases (P=0.059). Antibodies anti-Scl 70 were noted more frequently in patient's with interstitial lung disease (79% of the cases, P=0.001). Patients were treated with colchicine and vitamin E. A corticotherapy had been indicated at a single patient. The evolution of SS was marked by the stabilisation of the restrictive syndrome in 71.8% of the cases and a worsening in 25% of the cases. Early and appropriate diagnosis of SS and screening of lung involvement are essential for a early care. PMID- 26651933 TI - [Pulmonary arterial hydatidosis: About three cases]. PMID- 26651934 TI - Insomnia following a mild traumatic brain injury: a missing piece to the work disability puzzle? PMID- 26651935 TI - Baby, It's Cold Outside: Host-Microbiota Relationships Drive Temperature Adaptations. AB - When exposed to cold temperatures, mammals undergo remarkable physiological adaptations including thermogenesis, increased intake of dietary energy, and enhanced capacity for intestinal absorption. In a recent Cell paper, Chevalier, Stojanovic, and colleagues reveal that these key adaptations to life in the cold are facilitated by the intestinal microbiota (Chevalier et al., 2015). PMID- 26651936 TI - Fungal Sex Receptors Recalibrated to Detect Host Plants. AB - Secreted peroxidases are well-known components of damage-induced defense responses in plants. A recent study in Nature (Turra et al., 2015) has revealed that these enzymes can inadvertently serve as reporters of wounded sites and constitute an "Achilles heel," allowing adapted pathogens to track and enter host tissue. PMID- 26651937 TI - Stress Flips a Chromatin Switch to Wake Up Latent Virus. AB - Stress-induced reactivation of latent herpesviruses requires disabling of repression, but the mechanism for converting silenced chromatin into an active state is unknown. In this issue of Cell Host & Microbe, Cliffe et al. (2015) suggest a methyl/phospho switch on histone H3 overcomes repression to facilitate reactivation of latent herpes simplex virus type 1 (HSV-1). PMID- 26651938 TI - Too Much Sugar Puts a Parasite in Jeopardy. AB - Toxoplasma gondii and other coccidian parasites accumulate starch-like amylopectin stores whose functional significance is unclear. In this issue of Cell Host & Microbe, Uboldi et al. (2015) present a pioneering investigation into a signaling cascade with a pivotal role in amylopectin metabolism and transmission of encysted parasites during chronic infection. PMID- 26651939 TI - Gambling with Flu: "All in" to Maximize Reward. AB - In this issue of Cell Host & Microbe, Tripathi et al. (2015) report an in-depth meta-analysis of eight influenza virus siRNA screens combined with viral-host protein interactome data. The integration of the different omics datasets highlights candidate genes and pathways for further investigation and potential therapeutic targeting in the future. PMID- 26651940 TI - Beating Cancer with a Gut Feeling. AB - Blockade of immune checkpoint molecules, a group of molecules normally involved in maintaining self-tolerance and limiting T cell responses, has emerged as a breakthrough in cancer therapy. Two recent studies published in Science show that, in mice, gut commensal microbes promote antitumor immunity and may determine therapy efficacy. PMID- 26651941 TI - Neuronal Stress Pathway Mediating a Histone Methyl/Phospho Switch Is Required for Herpes Simplex Virus Reactivation. AB - Herpes simplex virus (HSV) reactivation from latent neuronal infection requires stimulation of lytic gene expression from promoters associated with repressive heterochromatin. Various neuronal stresses trigger reactivation, but how these stimuli activate silenced promoters remains unknown. We show that a neuronal pathway involving activation of c-Jun N-terminal kinase (JNK), common to many stress responses, is essential for initial HSV gene expression during reactivation. This JNK activation in neurons is mediated by dual leucine zipper kinase (DLK) and JNK-interacting protein 3 (JIP3), which direct JNK toward stress responses instead of other cellular functions. Surprisingly, JNK-mediated viral gene induction occurs independently of histone demethylases that remove repressive lysine modifications. Rather, JNK signaling results in a histone methyl/phospho switch on HSV lytic promoters, a mechanism permitting gene expression in the presence of repressive lysine methylation. JNK is present on viral promoters during reactivation, thereby linking a neuronal-specific stress pathway and HSV reactivation from latency. PMID- 26651943 TI - Regulation of Starch Stores by a Ca(2+)-Dependent Protein Kinase Is Essential for Viable Cyst Development in Toxoplasma gondii. AB - Transmissible stages of Toxoplasma gondii store energy in the form of the carbohydrate amylopectin. Here, we show that the Ca(2+)-dependent protein kinase CDPK2 is a critical regulator of amylopectin metabolism. Increased synthesis and loss of degradation of amylopectin in CDPK2 deficient parasites results in the hyperaccumulation of this sugar polymer. A carbohydrate-binding module 20 (CBM20) targets CDPK2 to amylopectin stores, while the EF-hands regulate CDPK2 kinase activity in response to Ca(2+) to modulate amylopectin levels. We identify enzymes involved in amylopectin turnover whose phosphorylation is dependent on CDPK2 activity. Strikingly, accumulation of massive amylopectin granules in CDPK2 deficient bradyzoite stages leads to gross morphological defects and complete ablation of cyst formation in a mouse model. Together these data show that Ca(2+) signaling regulates carbohydrate metabolism in Toxoplasma and that the post translational control of this pathway is required for normal cyst development. PMID- 26651942 TI - Evolution and Spread of Ebola Virus in Liberia, 2014-2015. AB - The 2013-present Western African Ebola virus disease (EVD) outbreak is the largest ever recorded with >28,000 reported cases. Ebola virus (EBOV) genome sequencing has played an important role throughout this outbreak; however, relatively few sequences have been determined from patients in Liberia, the second worst-affected country. Here, we report 140 EBOV genome sequences from the second wave of the Liberian outbreak and analyze them in combination with 782 previously published sequences from throughout the Western African outbreak. While multiple early introductions of EBOV to Liberia are evident, the majority of Liberian EVD cases are consistent with a single introduction, followed by spread and diversification within the country. Movement of the virus within Liberia was widespread, and reintroductions from Liberia served as an important source for the continuation of the already ongoing EVD outbreak in Guinea. Overall, little evidence was found for incremental adaptation of EBOV to the human host. PMID- 26651944 TI - A Single Bacterial Immune Evasion Strategy Dismantles Both MyD88 and TRIF Signaling Pathways Downstream of TLR4. AB - During bacterial infections, Toll-like receptor 4 (TLR4) signals through the MyD88- and TRIF-dependent pathways to promote pro-inflammatory and interferon (IFN) responses, respectively. Bacteria can inhibit the MyD88 pathway, but if the TRIF pathway is also targeted is unclear. We demonstrate that, in addition to MyD88, Yersinia pseudotuberculosis inhibits TRIF signaling through the type III secretion system effector YopJ. Suppression of TRIF signaling occurs during dendritic cell (DC) and macrophage infection and prevents expression of type I IFN and pro-inflammatory cytokines. YopJ-mediated inhibition of TRIF prevents DCs from inducing natural killer (NK) cell production of antibacterial IFNgamma. During infection of DCs, YopJ potently inhibits MAPK pathways but does not prevent activation of IKK- or TBK1-dependent pathways. This singular YopJ activity efficiently inhibits TLR4 transcription-inducing activities, thus illustrating a simple means by which pathogens impede innate immunity. PMID- 26651945 TI - Group B Streptococcus Evades Host Immunity by Degrading Hyaluronan. AB - In response to tissue injury, hyaluronan (HA) polymers are cleaved by host hyaluronidases, generating small fragments that ligate Toll-like receptors (TLRs) to elicit inflammatory responses. Pathogenic bacteria such as group B Streptococcus (GBS) express and secrete hyaluronidases as a mechanism for tissue invasion, but it is not known how this activity relates to immune detection of HA. We found that bacterial hyaluronidases secreted by GBS and other Gram positive pathogens degrade pro-inflammatory HA fragments to their component disaccharides. In addition, HA disaccharides block TLR2/4 signaling elicited by both host-derived HA fragments and other TLR2/4 ligands, including lipopolysaccharide. Application of GBS hyaluronidase or HA disaccharides reduced pulmonary pathology and pro-inflammatory cytokine levels in an acute lung injury model. We conclude that breakdown of host-generated pro-inflammatory HA fragments to disaccharides allows bacterial pathogens to evade immune detection and could be exploited as a strategy to treat inflammatory diseases. PMID- 26651946 TI - Molecular Basis for Antibody-Mediated Neutralization of New World Hemorrhagic Fever Mammarenaviruses. AB - In the Western hemisphere, at least five mammarenaviruses cause human viral hemorrhagic fevers with high case fatality rates. Junin virus (JUNV) is the only hemorrhagic fever virus for which transfusion of survivor immune plasma that contains neutralizing antibodies ("passive immunity") is an established treatment. Here, we report the structure of the JUNV surface glycoprotein receptor-binding subunit (GP1) bound to a neutralizing monoclonal antibody. The antibody engages the GP1 site that binds transferrin receptor 1 (TfR1)-the host cell surface receptor for all New World hemorrhagic fever mammarenaviruses-and mimics an important receptor contact. We show that survivor immune plasma contains antibodies that bind the same epitope. We propose that viral receptor binding site accessibility explains the success of passive immunity against JUNV and that this functionally conserved epitope is a potential target for therapeutics and vaccines to limit infection by all New World hemorrhagic fever mammarenaviruses. PMID- 26651949 TI - Effect of a long chain n-3 PUFA-enriched diet on production and reproduction variables in Holstein dairy cows. AB - The objective of this study was to determine the effect of a rumen-protected fish oil supplement on the production and reproduction variables in postpartum dairy cows. Holstein cows (n=46) were given a basal total mixed diet plus one PUFA supplement: n-3 (n-3; protected fish oil; 1% dry matter intake (DMI); n=23) or control (n-6; toasted soybeans; 1.8% DMI; n=23), in a switchback design over two consecutive lactations. Supplements were added to the diet between calving and 2 months after calving to assess the effect on growth and maturation of ovarian follicles from which ovulation occurred around the day of insemination. Body weight (BW), milk yield (MY) and composition, dry matter intake (DMI), energy balance (EB), subcutaneous fat thickness, plasma fatty acid composition, plasma nonesterified fatty acids (NEFA), glucose and urea concentrations, follicular activity, embryo mortalities and fertility (conception rate after first AI, AI1) were assessed. BW, MY, DMI, plasma NEFA, glucose and urea were unaffected by the diet. There was a trend of an increased number of large follicles (diameter>=10mm) with the n-3 dietary supplementation (P=0.06) and a decrease in infertility or early embryo mortality rate 21 days after AI, 13.5% in the n-3 compared with 38.8% in the n-6 group (P=0.09), with no effect on the conception rate at 35d or 90d after AI1. These data suggest that the effect seen on ovarian variables is not associated with an effect on production and metabolic variables and is specific to n-3 PUFA supplementation. Further studies are necessary to determine whether DHA or EPA enhances fertility in lactating dairy cattle. PMID- 26651950 TI - Sex determination of ovine embryos by SRY and amelogenin (AMEL) genes using maternal circulating cell free DNA. AB - Simple and precise methods for sex determination in animals are a pre-requisite for a number of applications in animal production and forensics. Some of the existing methods depend only on the detection of Y-chromosome specific sequences. However, the detection of Y and X-chromosome specific sequences is advantageous. In the present study the accuracy of sex determination by SRY (sex-determining region Y) and AMEL (Amelogenin) gene detection was assessed using a polymerase chain reaction (PCR) of DNA extracted from free fetal cells in maternal blood, which is noninvasive for fetus and easier to collect. The PCR amplification of SRY primers produced a single band of 171bp from ewes bearing a male fetus, whereas no band was amplified from the DNA extracted from ewes pregnant to a female fetus. Moreover, two bands of 182 and 242bp in male and a single band of 242 in female fetuses were produced by AMEL gene primers in the PCR reaction. Using this technique 100% of samples were successfully sexed, excluding twins. In conclusion, we demonstrated that sex determination using DNA of free fetal cells in maternal plasma is efficient using both SRY and AMEL gene sequences. It also is evident that this method is not suitable for sex determination of twin pregnancies. PMID- 26651948 TI - Meta- and Orthogonal Integration of Influenza "OMICs" Data Defines a Role for UBR4 in Virus Budding. AB - Several systems-level datasets designed to dissect host-pathogen interactions during influenza A infection have been reported. However, apparent discordance among these data has hampered their full utility toward advancing mechanistic and therapeutic knowledge. To collectively reconcile these datasets, we performed a meta-analysis of data from eight published RNAi screens and integrated these data with three protein interaction datasets, including one generated within the context of this study. Further integration of these data with global virus-host interaction analyses revealed a functionally validated biochemical landscape of the influenza-host interface, which can be queried through a simplified and customizable web portal (http://www.metascape.org/IAV). Follow-up studies revealed that the putative ubiquitin ligase UBR4 associates with the viral M2 protein and promotes apical transport of viral proteins. Taken together, the integrative analysis of influenza OMICs datasets illuminates a viral-host network of high-confidence human proteins that are essential for influenza A virus replication. PMID- 26651951 TI - Dichotomous effects of latent CMV infection on the phenotype and functional properties of CD8+ T-cells and NK-cells. AB - CMV markedly alters the phenotype and function of NK-cells and T-cells and has been linked to immunosenescence. We show here that subjects with effective CMV control (evidenced by low CMV IgG titers) have functional responses to CMV that are driven by either NKG2C+ NK-cells or CMV-specific T-cells (15 of 24 subjects), but not both. These data indicate that people with effective CMV control are either NK-cell or T-cell responders, and corroborates the idea that NK-cells have rheostat-like properties that regulate anti-viral T-cell responses. Whether or not lifelong CMV control through either NK-cell or T-cell responses have implications for immunosenescence remains to be determined. PMID- 26651952 TI - Acute effects of stretching exercise on the soleus muscle of female aged rats. AB - It has been shown that stretching exercises can improve the flexibility and independence of the elderly. However, although these exercises commonly constitute training programs, the morphological adaptations induced by stretching exercises in aged skeletal muscle are still unclear. OBJECTIVE: To assess the acute effects of passive mechanical static stretching on the morphology, sarcomerogenesis and modulation of important components of the extracellular matrix of the soleus muscle of aged female rats. METHODS: Fifteen old female rats with 26 months were divided into two groups: stretching (n=8, SG) and control (n=7, CG): The stretching protocol consisted of 4 repetitions each of 1 min with 30s interval between sets. Stretching was performed on the left soleus muscle, 3 times a week for 1 week. After three sessions, the rats were anesthetized to remove the left soleus muscle, and then euthanized. The following analyses were carried out: muscle fiber cross-sectional area and serial sarcomere number; immunohistochemistry for the quantification of collagen I, III and TGFbeta-1. RESULTS: a decrease in muscle fiber cross-sectional area of the SG was observed when compared to the CG (p=0.0001, Kruskal-Wallis); the percentage of type I collagen was significantly lower in the SG when compared to the CG (p=0.01, Kruskal-Wallis), as well as the percentage of TGFbeta-1 (p=0.04, Kruskal-Wallis); collagen III was significantly higher in the SG than in the CG (7.06+/-6.88% vs 4.92+/-5.30%, p=0.01, Kruskal-Wallis). CONCLUSION: Although the acute stretching induced muscle hypotrophy, an antifibrotic action was detected. PMID- 26651953 TI - The role of CAPE in PI3K/AKT/mTOR activation and oxidative stress on testis torsion. AB - Ischemia reperfusion injury arises from testicular torsion resulting in a loss of spermatogenesis and significant germ cell apoptosis. This study evaluates the prooxidant/antioxidant effects of caffeic acid phenethyl ester (CAPE) through PI3K/AKT/mTOR signal pathways on testis torsion. A total of (28) male Wistar rats were divided randomly into 4 groups (n=7 for each group):group A (sham) group,group B torsion/detorsion group, group C (saturation group, during four days of CAPE, one dose (10 MUmol/kg, i.p)) and group D (a single dose of CAPE 2h after torsion and before detorsion). At the end of the study, unilateral orchiectomies were performed for measurements of MDA and 8OHdG levels, histopathologic and immunohistochemical and TUNEL apoptotic cell examination. Testicular torsion-detorsion led to a significant decrease in the mean values of the Johnsen's scores and a significant increase in the apoptotic cell values of group B. There were no significant differences between group D and group A. In addition, the MDA and 8OHdG levels increased significantly in group B. The MDA and 8OHdG values were lower in group D. However, the 8OHdG levels were higher in group C than the groups A and D. On the other hand, CAPE suppresses mTOR activation and reduces the apoptosis on ischemia/reperfusion damage in rat testis. These results demonstrate that CAPE suppresses mTOR activation and reduces the apoptosis on ischemia/reperfusion damage in rat testis. PMID- 26651954 TI - [Study of parenteral iron use in a health facility and its impact in terms of hospital economics]. AB - INTRODUCTION: Administration of parenteral iron is a mainstay of iron deficiency treatment. Evaluation and control of this element is an issue for healthcare facilities. Study of parenteral iron use is thus to be evaluated in its impact in terms of hospital economics. MATERIALS AND METHODS: Parenteral iron administrations that took place on 2014 in our healthcare facility were retrospectively identified by pharmacists. Following data were extracted from PharmaTM and CrosswayTM softwares: indication, diagnostic coding and total dose of iron received. They were then compared to the summary of product characteristics. RESULTS: Of 198 analyzed prescriptions, iron deficiency was known or suspected for 97% of patients. However, the total dose of iron administered was not in compliance for three quarters of prescriptions. Sixty eight percent of patients appear under-dosed. Administration's traceability was found for two-thirds. Eighty-five hospital discharges did not have the right coding and 34 stays were charged like an external act instead sessions. Financial loss for the hospital is estimated at 49,300 euros. DISCUSSION AND CONCLUSION: As part of improving practice, close pharmaceutical monitoring of parenteral iron prescribed dosing regimen is essential. Effective communication with the medical information department and regular awareness raising of prescribers should also allow to give more value to this act. Hospital economics is a real tool to aid decision-making. PMID- 26651955 TI - Improved outcomes with the comprehensive stage 2 procedure after an initial hybrid stage 1. AB - OBJECTIVE: To report our improving institutional experience with the hybrid alternative surgical strategy for the management of hypoplastic left heart syndrome, in which hybrid stage 1 is followed by a comprehensive stage 2 procedure (removal of patent ductus arteriosus stent and pulmonary artery [PA] bands, aorta and PA reconstruction, Damus-Kaye-Stansel, atrial septectomy, Glenn). METHODS: In this Institutional Review Board-approved retrospective review of all patients undergoing a comprehensive stage 2 procedure between January 2002 and December 2014, data were compared between the pre-protocol group (n = 64; January 2002 to March 2010) and the post-protocol group (n = 55; March 2010 to December 2014). These 2 groups flank the implementation of a perioperative management protocol to prevent PA thrombosis. RESULTS: Pre-protocol mortality was 19% (12 of 64), with the most common mode of death involving PA thrombosis in at least 7 patients, with an urgent indication for surgery and age as contributing factors. Care modifications instituted in March 2010 included avoidance of procedures on an emergent basis or in patients aged <3 months, use of a systemic PA shunt in cases of too-small superior vena cava and/or PA, completion angiogram with a low threshold for intraoperative stenting, and postoperative anticoagulation therapy for 6 weeks. There was a significant decrease in mortality (2 of 55; 4%; P = .01), PA thrombosis (0 of 55; 0%; P = .01), and use of extracorporeal membrane oxygenation (0/55 [0%] compared with 7 of 64 [11%]; P = .01) after protocol implementation. CONCLUSIONS: Despite the technical challenges of the comprehensive stage 2 procedure, excellent outcomes are attainable. Experience coupled with an internal quality review drove the implementation of a successful perioperative management protocol. PMID- 26651956 TI - Successful endoluminal rescue of an endovascular graft unintentionally deployed in the false lumen of Stanford type B aortic dissection. PMID- 26651957 TI - Two roads diverged: Coronary artery bypass grafting versus percutaneous coronary intervention for moderately stenosed coronary arteries. PMID- 26651958 TI - Locally advanced esophageal cancer: What becomes of 5-year survivors? AB - OBJECTIVE: To determine the long-term outcomes of patients with locally advanced esophageal cancer (LAEC) who underwent esophagectomy and survived at least 5 years, and the predictors of disease-free survival (DFS) beyond 5 years. METHODS: This was a retrospective review of a prospective database to identify patients with clinical stage T2N0M0 or higher LAEC. Medical records were reviewed to obtain demographic, clinical, and pathological characteristics, as well as data on recurrence and survival. Multivariable analysis of predictors of DFS beyond 5 years was performed using a Cox regression model. RESULTS: Between 1988 and 2009, 355 of 500 patients underwent esophagectomy for cT2N0M0 or higher disease. Of these 355 patients, 126 were alive and disease-free at the 5-year follow-up, for an actuarial 5-year DFS of 33%. Recurrent esophageal cancer developed in 8 patients after 5 years. Among the 126 surviving patients, the actuarial overall survival was 94% at 7 years and 80% at 10 years. On multivariable analysis, the sole significant predictor of DFS after the 5-year time point was non-en bloc resection at the original operation (P = .006). Pulmonary-related deaths accounted for 10 out of 22 noncancer deaths. A second primary cancer developed in 23 of the 126 surviving patients. CONCLUSIONS: Prolonged survival can be obtained in one-third of patients with LAEC. An en bloc resection at the original operation is the most significant predictor of prolonged survival. Survivors experience a high rate of second primary cancer and an apparently high rate of deaths from pulmonary disease. Careful follow-up is necessary for these patients, even after the 5-year mark. PMID- 26651959 TI - Fate of aortic bioprostheses: An 18-year experience. AB - OBJECTIVE: To report our experience in aortic valve replacement with the Mitroflow (Sorin, Vancouver, Canada) aortic bioprosthesis. METHODS: We retrospectively reviewed all patients who underwent aortic valve replacement with a Mitroflow bioprosthesis at our institution from January 1994 to December 2011. No exclusion criteria were retained. Patients were followed yearly. Echocardiography follow-up was performed systematically before the hospital discharge and annually by patients' cardiologists. RESULTS: Seven hundred twenty eight patients (mean age, 76 +/- 6 years; range, 33-91 years) underwent aortic valve replacement with Mitroflow 12A or LX model and were included in this analysis. 30-day mortality for nonemergent isolated aortic valve replacement was 5.5%. Eight patients (1%) underwent reoperation for structural valve deterioration (SVD) and 30 patients (5.8%) presented echocardiographic signs of SVD. Actuarial freedom from reoperation for SVD was 99% +/- 0.5% and 95% +/- 5% at 10 and 15 years. Actuarial freedom from echocardiographic signs of SVD was 77% +/- 5% and 56% +/- 11% at 10 and 15 years, respectively. At the univariate analysis, only the mean gradient at discharge (P = .0200), the prevalence of size 19 (P = .0273), and severe patient-prosthesis mismatch (P = .0384) were significantly different in patients developing SVD at follow-up. Freedom from echocardiographic signs of SVD at 8 years were 88% +/- 4% and 64% +/- 13% in patients with a Mitroflow > 19 and Mitroflow 19, respectively (log-rank test, P = .0056; Wilcoxon test, P = .0589). CONCLUSIONS: Overall outcomes were satisfactory. However the risk of early SVD seems higher for the Mitroflow size 19. This size should be reserved for applications when annulus enlargement is risky or there is an anatomic contraindication to sutureless or stentless valve. PMID- 26651960 TI - Outcomes of contemporary mechanical circulatory support device configurations in patients with severe biventricular failure. AB - OBJECTIVES: Severe right ventricular failure often is considered a contraindication for left ventricular assist device (LVAD) therapy and necessitates use of biventricular assist devices (BiVADs). Available options for BiVADs are limited, and comparative outcomes are largely unknown. METHODS: Heart transplant candidates who were registered on the United Network for Organ Sharing waitlist and underwent long-term contemporary LVAD (n = 3195) or BiVAD (n = 408) implantation, from January 2010 through June 2014, were retrospectively analyzed. We evaluated clinical characteristics and outcomes of patients requiring a BiVAD, as well as regional differences in utilization of this technology. RESULTS: Patients requiring a BiVAD were younger (48.9 vs 53.3 years), had a higher proportion of nonischemic disease (69.1% vs 58.2%), a higher bilirubin level (0.9 vs 0.7 mg/dL), and a lower 6-month survival rate (68.1% vs 92.7%) after device implantation (all P < .05). Postimplantation and posttransplantation survival was comparable for commonly used BiVAD configurations, including total artificial heart, continuous flow BiVAD, a continuous-flow LVAD coupled with a right-sided device, and pulsatile flow. Significant variation was found in regional utilization of these devices, regardless of differences in transplantation waitlist times. A large body surface area was an independent predictor of mortality on a BiVAD (hazard ratio = 2.12, P = .017). CONCLUSIONS: Outcomes of patients requiring a BiVAD remain poor in the contemporary device era, regardless of the configuration used. Among other clinical factors, body surface area should be incorporated into decision making for device selection in these patients. PMID- 26651961 TI - Hey, pulmonologists and family doctors, please read me and see the data--It is a brave new world. PMID- 26651962 TI - How much is enough to warrant prophylactic tricuspid repair? PMID- 26651963 TI - Discussion. PMID- 26651964 TI - Decisions, decisions: Chocolate, vanilla, or something else? PMID- 26651965 TI - Restoration of sinus rhythm and atrial transport function after the maze procedure: U lesion set versus box lesion set. AB - OBJECTIVE: In a U lesion set, the left atrium (LA) roof between the right and left superior pulmonary veins is not ablated, to allow activation to propagate across the posterior LA and to recruit this segment as a contractile atrial component. In contrast, the box lesion set isolates the entire posterior LA. METHODS: To compare the two lesion sets, postoperative freedom from atrial fibrillation (AF) and LA transport function were examined in 402 patients who underwent surgery for AF with a U lesion (n = 329) or box lesion (n = 73) set. Patients who underwent pulmonary vein isolation alone or other simplified procedures were excluded from the study. LA transport function was quantified at 20 +/- 33 months postoperatively by the ratio of peak velocity of the A wave to the E wave (peak A/E) of the transmitral Doppler flow. RESULTS: In patients with long-standing persistent AF, freedom from AF was 85% with the U lesion set and 77% with the box lesion set at 5 years after the maze procedure, and 82% and 77%, respectively, at 10 years after the procedure. There was no significant difference between the U lesion set and box lesion set in patients with long standing persistent AF (P = .30) and those with paroxysmal or persistent AF (P = .90). Proportional hazards analysis identified increased LA diameter (P = .003) and long-standing persistent AF (P = .03), but not the type of lesion set (P = .51), as predictive of postoperative AF recurrence. The postoperative peak A/E was significantly greater after the U lesion set than after the box lesion set (0.42 +/- 0.22 vs 0.23 +/- 0.17), and multiple regression analysis demonstrated that the type of lesion set and preoperative LA diameter significantly affected postoperative A/E. CONCLUSIONS: The U lesion set restores sinus rhythm frequently as the box lesion set and provides better LA transport function. A dilated LA is a risk factor for postoperative recurrence of AF and poor postoperative LA transport function. PMID- 26651966 TI - The missing piece of the puzzle? PMID- 26651967 TI - "Moving right along" after lung resection, but the data suggest "not so fast". PMID- 26651968 TI - Systematic development of a proctor certification examination for the Fundamentals of Laparoscopic Surgery testing program. AB - BACKGROUND: The fundamentals of laparoscopic surgery (FLS) examination is administered by proctors around the world. Inconsistent administration represents a threat to test validity. We systematically developed a test to assess the FLS proctors knowledge and skills relating to FLS test administration. METHODS: Downing's 12 steps for test development were used. subject matter expert's created a job and/or task analysis inventory of the knowledge and skills of an FLS proctor. Using the weighted blueprint, a 45 question examination was created using online testing software and piloted. RESULTS: The blueprint generated 38 job and/or task analysis items in 4 domains. Items on the test had an average content validity index of .9. The mean score during beta testing was 32 of 45 (71%). Reliability was good at .72. Mean item difficulty and discrimination were .71 and .28, respectively. The cut score was set at 62% resulting in a pass rate of 83%. CONCLUSIONS: We developed a test representing the skills of the FLS proctor that demonstrates considerable validity evidence. Incorporation of this examination into proctor training should reduce the threats to validity for the FLS examination. PMID- 26651969 TI - Rectal cancer in patients under the age of 50 years: the delayed diagnosis. AB - BACKGROUND: The incidence of rectal cancer in younger patients continues to increase. Because most of these patients do not meet criteria for routine colorectal cancer screening, diagnosis may be delayed, potentially resulting in adverse outcomes. The aim of this study was to determine whether patients under the age of 50 years with rectal cancer have a delay in diagnosis and treatment leading to a worse overall prognosis. METHODS: A case control study of patients diagnosed with rectal adenocarcinoma in an academic medical center from 1997 to 2007 under 50 years of age were matched 1:1 to randomly selected patients over the age of 50 years by sex and date of diagnosis. Time to diagnosis, time to treatment, staging of the American Joint Committee on Cancer, and 5-year overall survival were compared. RESULTS: The overall time to treatment from symptom onset was 217 days for patients under the age of 50 years versus 29.5 days if over 50 years of age (P < .0001). The primary delay occurred between the onset of symptoms and presentation to the initial physician. There was no difference in stage at the time of diagnosis or 5-year survival (64% vs 71%, P = .39 and P = .54, respectively). CONCLUSIONS: Patients with rectal cancer under the age of 50 years have symptoms for a considerable period of time before seeking medical care and are referred in less timely manner to specialists. However, the delay in diagnosis did not adversely impact stage on presentation or 5-year survival. PMID- 26651970 TI - Identification of N-Oxide and Sulfoxide Functionalities in Protonated Drug Metabolites by Using Ion-Molecule Reactions Followed by Collisionally Activated Dissociation in a Linear Quadrupole Ion Trap Mass Spectrometer. AB - The in vivo oxidation of sulfur and nitrogen atoms in many drugs into sulfoxide and N-oxide functionalities is a common biotransformation process. Unfortunately, the unambiguous identification of these metabolites can be challenging. In the present study, ion-molecule reactions of tris(dimethylamino)borane followed by collisionally activated dissociation (CAD) in an ion trap mass spectrometer are demonstrated to allow the identification of N-oxide and sulfoxide functionalities in protonated polyfunctional drug metabolites. Only ions with N-oxide or sulfoxide functionality formed diagnostic adducts that had lost dimethyl amine (DMA). This was demonstrated even for an analyte that contains a substantially more basic functionality than the functional group of interest. CAD of the diagnostic product ions (M) resulted mainly in type A (M - DMA) and B fragment ions (M - HO-B(N(CH3)2)2) for N-oxides, but sulfoxides also formed diagnostic C ions (M - O?BN(CH3)2), thus allowing differentiation of the functionalities. Some protonated analytes yielded abundant TDMAB adducts that had lost two DMA molecules instead of just one. This provides information on the environment of the N-oxide and sulfoxide functionalities. Quantum chemical calculations were performed to explore the mechanisms of the above-mentioned reactions. The method can be implemented on HPLC for real drug analysis. PMID- 26651971 TI - Cannabinoids and Cytochrome P450 Interactions. AB - OBJECTIVE: This review consists of three parts, representing three different possibilities of interactions between cannabinoid receptor ligands of both exogenous and endogenous origin and cytochrome P450 enzymes (CYPs). The first part deals with cannabinoids as CYP substrates, the second summarizes current knowledge on the influence of various cannabinoids on the metabolic activity of CYP, and the third outline a possible involvement of the endocannabinoid system and cannabinoid ligands in the regulation of CYP liver activity. METHODS: We performed a structured search of bibliographic and drug databases for peer reviewed literature using focused review questions. RESULTS: Biotransformation via a hydrolytic pathway is the major route of endocannabinoid metabolism and the deactivation of substrates is characteristic, in contrast to the minor oxidative pathway via CYP involved in the bioactivation reactions. Phytocannabinoids are extensively metabolized by CYPs. The enzymes CYP2C9, CYP2C19, and CYP3A4 catalyze most of their hydroxylations. Similarly, CYP represents a major metabolic pathway for both synthetic cannabinoids used therapeutically and drugs that are abused. In vitro experiments document the mostly CYP inhibitory activity of the major phytocannabinoids, with cannabidiol as the most potent inhibitor of many CYPs. The drug-drug interactions between cannabinoids and various drugs at the CYP level are reported, but their clinical relevance remains unclear. The direct activation/inhibition of nuclear receptors in the liver cells by cannabinoids may result in a change of CYP expression and activity. Finally, we hypothesize the interplay of central cannabinoid receptors with numerous nervous systems, resulting in a hormone-mediated signal towards nuclear receptors in hepatocytes. PMID- 26651972 TI - Intracellular Metabolism of Nucleoside/Nucleotide Analogues: a Bottleneck to Reach Active Drugs on HIV Reverse Transcriptase. AB - BACKGROUND: To date, the most effective way to treat HIV is to use a highly active antiretroviral therapy (HAART) that combines three or more different drugs. The usual regimen consists of two nucleoside reverse transcriptase inhibitors and either a protease inhibitor, a non-nucleoside reverse transcriptase inhibitor, or an integrase strand transfer inhibitor. Due to the emerging resistance against the nucleoside analogues in use, there is a continuous need for the development of such therapeutic molecules with different structural features. OBJECTIVES: In this review, we would like to summarize the state of knowledge of the antiretroviral nucleoside analogues intracellular metabolism. Indeed, these molecules have to be phosphorylated in the cell, a process that is often a bottleneck, to produce their pharmacologically active triphosphorylated forms. These forms can be used by the HIV reverse transcriptase. Because they lack a 3'-hydroxyl group, they block further extension of the viral DNA, and finally lead to early chain termination. Several kinases can act on the phosphorylation of these drugs; most of them have low nucleoside/nucleotide specificity. On the other hand, there are also nucleotidases in the cell, which can reverse the phosphorylation process, thus shifting the equilibrium from the active triphosphorylated state to the non active (not-, mono- or di-phosphorylated) states of these analogues. CONCLUSION: Here, we would like to bring to the attention of the medicinal chemists that they have to take into account the limitation of the intracellular phosphorylation machinery when designing new nucleoside analogue drugs. PMID- 26651973 TI - Hydrophilic Interaction Liquid Chromatography/Mass Spectrometry: An Attractive and Prospective Method for the Quantitative Bioanalysis in Drug Metabolism. AB - During the development, dosage optimization and safety evaluation of a drug, rapid and precise monitoring of administered drug and/or its metabolites in biological samples including blood, plasma, serum, tissues and saliva are vital. As drug biotransformation produces more hydrophilic metabolites for the enhancement of drug elimination, which is often a challenge for traditional reversed-phase liquid chromatography (RPLC) separation. Because hydrophilic interaction liquid chromatography (HILIC) is capable of retaining polar compounds and readily compatible with mass spectrometry (MS), HILIC has been used as a complementary separation technique to RPLC for analysis of polar metabolites, especially polar drugs and their metabolites. This review covers core aspects of HILIC-MS/MS method and overall profile of its application in analysis of drug and/or its metabolites. The emphasis of this paper has been placed on the applications of HILIC-MS/MS method in quantitative bioanalysis of drugs alone or along with their metabolites in drug metabolism studies in recent years. As a fundamental and critical step of bioanalytical method, conventional sample preparation techniques of biological matrices for the HILIC-MS/MS analysis of drugs and/or their metabolites are also briefly featured. PMID- 26651974 TI - Smad7 and its Potential as Therapeutic Target in Inflammatory Bowel Diseases. AB - BACKGROUND: The etiology of Crohn's disease (CD) and ulcerative colitis (UC), the two major forms of inflammatory bowel disease (IBD) in humans, is still unknown, but evidence suggests that genetic and environmental factors interact to promote an excessive immune response that leads to tissue damage. Defects in the counter regulatory mechanisms are also supposed to make a major contribution to the amplification and maintenance of the IBD-related inflammatory response. One such a mechanism involves TGF-beta1, a cytokine synthesized by both immune and non immune cells in the gut, which is essential in the maintenance of immune homeostasis. In both CD and UC, active inflammation occurs in areas characterized by enhanced production of TGF-beta1 and reduced ability of this cytokine to activate Smad-associated signaling and suppress inflammatory pathways. The defective TGF-beta1 activity is due to elevated levels of Smad7, an intracellular protein that inhibits TGF-beta1-associated Smad signaling. METHODS: Data from original studies and reviews were selected through an accurate research of the literature using the terms "IBD", "colitis", "Crohn's disease", "Smad7", "TGF beta1", "antisense oligonucleotide" and "Mongersen". RESULTS: Twenty-fours studies describing the most accredited hypothesis about IBD pathogenesis and the role of Smad7 in the negative control of TGF-beta1 were discussed in the review. Additionally, we reported data from original work illustrating the generation and the in vitro and in vivo effect of a specific Smad7 antisense oligonucleotide on intestinal inflammatory signals. We also discussed the results of phase 1 and phase 2 studies assessing the safety profile and clinical efficacy of Mongersen, an oral Smad7 antisense oligonucleotidecontaining drug, in patients with active CD. CONCLUSIONS: Data indicate that, in IBD, high Smad7 contributes to sustain detrimental immune responses and knockdown of this molecule can help attenuate the ongoing mucosal inflammation in patients with such disorders. PMID- 26651975 TI - Cysteine Network (CYSTEINET) Dysregulation in Parkinson's Disease: Role of N acetylcysteine. AB - BACKGROUND: Reactive species have been regarded as by-products of cellular metabolism, which cause oxidative damage contributing to aging and neurodegenerative diseases. However, accumulated evidence support the notion that reactive species mediate intracellular and extracellular signals that regulate physiological functions including posttranslational protein modifications. Cysteine thiol groups of proteins are particularly susceptible to oxidative modifications by oxygen, nitrogen and sulfur species generating different products with critical roles in the cellular redox homeostasis. At physiological conditions, reactive species can function not only as intracellular second messengers with regulatory roles in many cellular metabolic processes but also as part of an ancestral biochemical network that controls cellular survival, regeneration, and death. OBJECTIVE: To propose a biochemical network, called cellular cysteine network (CYSTEINET), which can be dysregulated in Parkinson's disease. Due to the fact that there are many cysteine-bearing proteins and cysteine-dependent enzymes susceptible to oxidative modifications, it is proposed that oxidative-changed proteins at cysteine residues may be critical for Parkinson's disease development. CONCLUSION: In the present review, I advance the concept that "cysteinet" is impaired in Parkinson's disease resulting in a functional and structural dysregulation of the matrix of interconnected cysteine bearing proteins, which in conjunction with reactive species and glutathione regulate the cellular bioenergetic metabolism, the redox homeostasis, and the cellular survival. This network may represent an ancestral down-top system composed of a complex matrix of proteins with very different cellular functions, but bearing the same regulatory thiol radical. Finally, the possible role of N acetylcysteine and derivatives to regulate "cysteinet" and slow down Parkinson's disease development and progression is discussed. PMID- 26651976 TI - Influence of CYP3A5 polymorphism on the pharmacokinetics of psychiatric drugs. AB - BACKGROUND: The contribution of the CYP3A5 enzyme to the metabolism of clinically used drugs has been established only for a few CYP3A substrates, such as the immunosuppressant tacrolimus, while for drugs used in the field of psychiatry its role is still vague. METHODS: We herein discuss all published data on the contribution of CYP3A5 and its polymorphisms to the metabolism of antipsychotics and antidepressants that are known to be metabolized by CYP3A enzymes, as well as of carbamazepine, an antiepileptic drug used as mood stabilizer. Published papers from 1990 to April 2015 were retrieved from PubMed and Scopus by use of the keywords CYP3A5, CYP3A, gene polymorphism, antipsychotics, psychiatry, pharmacogenomics, haloperidol, risperidone, quetiapine, aripiprazole, clozapine, olanzapine, antidepressants, and carbamazepine. RESULTS: Available evidence is only sparse and no firm conclusions can be drawn on whether CYP3A5 enzyme exhibits affinity and metabolic capacity similar to CYP3A4 for these drugs. Nevertheless, the role of CYP3A5 should be studied further, since there is evidence suggesting that CYP3A5 potentially catalyses alternative metabolic pathways that may give rise to intermediate metabolites with yet unknown pharmacologic properties and may also limit drug bioavailability through intestinal first pass metabolism. Additionally, expression of CYP3A5 may overcome CYP3A4 drug-drug interactions. CONCLUSIONS: Overall, CYP3A5 is an overlooked polymorphic enzyme and its potential in improving psychiatric pharmacogenomics remains to be explored. The impact of CYP3A5 pharmacogenetics in the clinical setting merits the attention of both researchers and clinicians. PMID- 26651977 TI - Optimizing DMPK Properties: Experiences from a Big Pharma DMPK Department. AB - BACKGROUND: The disposition of a drug is dependent on interactions between the body and the drug, its molecular properties and the physical and biological barriers presented in the body. In order for a drug to have a desired pharmacological effect it has to have the right properties to be able to reach the target site in sufficient concentration. This review details how drug metabolism and pharmacokinetics (DMPK) and physicochemical deliveries played an important role in data interpretation and compound optimization at AstraZeneca R&D in Sodertalje, Sweden. METHODS: A selection of assays central in the evaluation of the DMPK properties of new chemical entities is presented, with guidance and consideration on assay outcome interpretation. Early in projects, solubility, LogD, permeability and metabolic stability were measured to support effective optimization of DMPK properties. Changes made to facilitate high throughput, efficient bioanalysis and the handling of large amounts of samples are described. Already early in drug discovery, we used an integrated approach for the prediction of the fate of drugs in human (early dose to man) based on data obtained from in vitro experiments. The early dose to man was refined with project progression, which triggered more intricate assays and experiments. At later stages, preclinical in vivo pharmacokinetic (PK) data was integrated with pharmacodynamics (PD) to allow predictions of required dose, dose intervals and exposure profile to achieve the desired effect in man. RESULTS AND CONCLUSIONS: A well-defined work flow of DMPK activities from early lead identification up to the selection of a candidate drug was developed. This resulted in a cost effective and efficient optimization of chemical series, and facilitated informed decision making throughout project progress. PMID- 26651978 TI - Indole-3-Carbinol (I3C) and its Major Derivatives: Their Pharmacokinetics and Important Roles in Hepatic Protection. AB - BACKGROUND: Indoles, including indole-3-carbinol (I3C) and its derivatives, are the products of glucosinolate hydrolysis catalyzed by the enzyme myrosinase. Under acidic conditions, I3C polymerizes into 3, 3- diindolylmethane (DIM), [2 (indol-3-ylmethyl)-indol-3-yl]indol-3-ylmethane (LTr1), 1-(3-hydroxymethyl)- indolyl-3-indolylmethane (HI-IM) and indolo[3,2b]carbazole (ICZ). Recently, I3C and its dimer DIM have shown pleiotropic protective effects on chronic liver injuries, including viral hepatitis, hepatic steatosis, hepatic cirrhosis, hepatocellular carcinoma, and so on. METHODS: We reviewed the published papers about the pharmacokinetics of I3C and its derivatives in vitro and in vivo, and summarized their multiple protective roles in the processes of chronic liver diseases. RESULTS: Indoles not only regulate transcriptional factors and their respective signaling pathways, but also relieve oxidative stress and inhibit the synthesis of DNA to influence the activation, proliferation and apoptosis of target cells. Moreover, indoles modulate the enzymes that are relevant to hepatitis viral replication, lipogenesis, and the metabolism of ethanol and some hepatotoxic substances to protect the liver. Currently, the immunomodulatory biofunction of indoles contributes to improving non-alcoholic steatohepatitis. In addition, indoles also function as the inhibitors of pro-inflammatory cytokines and chemokines to reduce microbial-induced liver injures. CONCLUSION: Indoles, especially I3C and DIM as phytochemicals, exert anti-fibrosis, anti-tumor, anti oxidant, immunomodulatory, detoxification and anti-inflammation effects on hepatic protection through pleiotropic mechanism. PMID- 26651979 TI - Occurrence, Human Intake and Biodegradation of Estrogen-Like Nonylphenols and Octylphenols. AB - BACKGROUND: Long-chain alkylphenols, such as nonylphenols and octylphenols, are man-made compounds with estrogen-like activity and considered to be endocrine disputing chemicals. They are known to influence sexual development and reproduction of humans and other animals, therefore cause health and ecological concerns. OBJECTIVE: This review aims to identify the key findings presented in recent scientific literature with respect to the presence of long-chain alkylphenols in food, intake by different populations and describe the metabolism by human and the mechanisms to disrupt the estrogenic activity of nonylphenols and octylphenols by bacteria and fungi in the environment. METHOD: The current knowledge related to the physicochemical properties, source, occurrence, toxic effects, level in foods, human intake, elimination and metabolism of long-chain alkylphenols was summarized. RESULTS: Long-chain alkylphenols have been detected in soil, surface and ground water, sediments, wastewater effluent, air and in most foods. The daily human intake of 4-nonylphenols and 4-octylphenols has been compared among different population. A comprehensive summary of the major degradation pathways and mechanism in bacteria, fungi, yeasts and vertebrates was described. CONCLUSION: The findings of this review revealed the wide distribution of long-chain alkylphenols in various environments and contamination in foods. Therefore, further investigation of long-term exposure is necessary to comprehensively evaluate the potential health risks to humans. The diverse biodegradation mechanisms can be used in the removal of these compounds before entering food chains. The review provides indication as to how it might be possible to reduce the adverse effects on human health from estrogen-like long chain alkylphenols. PMID- 26651980 TI - Therapeutic Potential of N-Acetylcysteine for Wound Healing, Acute Bronchiolitis, and Congenital Heart Defects. AB - BACKGROUND: Wound healing is a composite and vital process in which devitalized tissue layers and cellular structures repair themselves. Bronchiolitis is generally prompted by respiratory syncytial virus or human metapneumovirus; this condition is an acute inflammatory injury of bronchioles. Heart problems that develop before birth are known as congenital heart defects (CHDs), and pregestational diabetes is considered a major predisposing factor of CHDs. N Acetylcysteine (NAC) is a transformed kind of amino acid cysteine which restores the intracellular levels of the natural antioxidant glutathione when taken internally, thereby assisting the cells' ability to diminish the damaging effects of reactive oxygen species (ROS). OBJECTIVE: In the present communication, NAC's therapeutic potential for wound healing, acute bronchiolitis, and congenital heart defects (CHDs) is critically analyzed by reviewing its effect on the various targets of these diseases. The multifunctional nature of NAC is outlined in a review of evidence from in vitro and in vivo studies. CONCLUSION: In conclusion, NAC could be used as a therapeutic agent in the treatment of wound healing, acute bronchiolitis and congenital heart defects (CHDs). The focus of future research should be the following; (1) to examine NAC clinically to be considered in the treatment of wound healing; (2) to investigate whether NAC could be used alone or with insulin to prevent CHDs in infants with pregestational diabetes; (3) to evaluate the application of NAC as a potential agent for PAH treatment. PMID- 26651981 TI - Fungible weights in logistic regression. AB - In this article we develop methods for assessing parameter sensitivity in logistic regression models. To set the stage for this work, we first review Waller's (2008) equations for computing fungible weights in linear regression. Next, we describe 2 methods for computing fungible weights in logistic regression. To demonstrate the utility of these methods, we compute fungible logistic regression weights using data from the Centers for Disease Control and Prevention's (2010) Youth Risk Behavior Surveillance Survey, and we illustrate how these alternate weights can be used to evaluate parameter sensitivity. To make our work accessible to the research community, we provide R code (R Core Team, 2015) that will generate both kinds of fungible logistic regression weights. (PsycINFO Database Record PMID- 26651982 TI - Multilevel structural equation models for assessing moderation within and across levels of analysis. AB - Social scientists are increasingly interested in multilevel hypotheses, data, and statistical models as well as moderation or interactions among predictors. The result is a focus on hypotheses and tests of multilevel moderation within and across levels of analysis. Unfortunately, existing approaches to multilevel moderation have a variety of shortcomings, including conflated effects across levels of analysis and bias due to using observed cluster averages instead of latent variables (i.e., "random intercepts") to represent higher-level constructs. To overcome these problems and elucidate the nature of multilevel moderation effects, we introduce a multilevel structural equation modeling (MSEM) logic that clarifies the nature of the problems with existing practices and remedies them with latent variable interactions. This remedy uses random coefficients and/or latent moderated structural equations (LMS) for unbiased tests of multilevel moderation. We describe our approach and provide an example using the publicly available High School and Beyond data with Mplus syntax in Appendix. Our MSEM method eliminates problems of conflated multilevel effects and reduces bias in parameter estimates while offering a coherent framework for conceptualizing and testing multilevel moderation effects. (PsycINFO Database Record PMID- 26651983 TI - Are fit indices really fit to estimate the number of factors with categorical variables? Some cautionary findings via Monte Carlo simulation. AB - An early step in the process of construct validation consists of establishing the fit of an unrestricted "exploratory" factorial model for a prespecified number of common factors. For this initial unrestricted model, researchers have often recommended and used fit indices to estimate the number of factors to retain. Despite the logical appeal of this approach, little is known about the actual accuracy of fit indices in the estimation of data dimensionality. The present study aimed to reduce this gap by systematically evaluating the performance of 4 commonly used fit indices-the comparative fit index (CFI), the Tucker-Lewis index (TLI), the root mean square error of approximation (RMSEA), and the standardized root mean square residual (SRMR)-in the estimation of the number of factors with categorical variables, and comparing it with what is arguably the current golden rule, Horn's (1965) parallel analysis. The results indicate that the CFI and TLI provide nearly identical estimations and are the most accurate fit indices, followed at a step below by the RMSEA, and then by the SRMR, which gives notably poor dimensionality estimates. Difficulties in establishing optimal cutoff values for the fit indices and the general superiority of parallel analysis, however, suggest that applied researchers are better served by complementing their theoretical considerations regarding dimensionality with the estimates provided by the latter method. PMID- 26651984 TI - Planning sample sizes when effect sizes are uncertain: The power-calibrated effect size approach. AB - Statistical power and thus the sample size required to achieve some desired level of power depend on the size of the effect of interest. However, effect sizes are seldom known exactly in psychological research. Instead, researchers often possess an estimate of an effect size as well as a measure of its uncertainty (e.g., a standard error or confidence interval). Previous proposals for planning sample sizes either ignore this uncertainty thereby resulting in sample sizes that are too small and thus power that is lower than the desired level or overstate the impact of this uncertainty thereby resulting in sample sizes that are too large and thus power that is higher than the desired level. We propose a power-calibrated effect size (PCES) approach to sample size planning that accounts for the uncertainty associated with an effect size estimate in a properly calibrated manner: sample sizes determined on the basis of the PCES are neither too small nor too large and thus provide the desired level of power. We derive the PCES for comparisons of independent and dependent means, comparisons of independent and dependent proportions, and tests of correlation coefficients. We also provide a tutorial on setting sample sizes for a replication study using data from prior studies and discuss an easy-to-use website and code that implement our PCES approach to sample size planning. PMID- 26651985 TI - A correction factor for the impact of cluster randomized sampling and its applications. AB - Cluster randomized sampling is 1 method for sampling a population. It requires recruiting subgroups of participants from the population of interest (e.g., whole classes from schools) instead of individuals solicited independently. Here, we demonstrate how clusters affect the standard error of the mean. The presence of clusters influences 2 quantities, the variance of the means and the expected variance. Ignoring clustering produces spurious statistical significance and reduces statistical power when effect sizes are moderate to large. Here, we propose a correction factor. It can be used to estimate standard errors and confidence intervals of the mean under cluster randomized sampling. This correction factor is easy to integrate into regular tests of means and effect sizes. It can also be used to determine sample size needed to reach a prespecified power. Finally, this approach is an easy-to-use alternative to linear mixed modeling and hierarchical linear modeling when there are only 2 levels and no covariates. PMID- 26651986 TI - Sequential hypothesis testing with Bayes factors: Efficiently testing mean differences. AB - Unplanned optional stopping rules have been criticized for inflating Type I error rates under the null hypothesis significance testing (NHST) paradigm. Despite these criticisms, this research practice is not uncommon, probably because it appeals to researcher's intuition to collect more data to push an indecisive result into a decisive region. In this contribution, we investigate the properties of a procedure for Bayesian hypothesis testing that allows optional stopping with unlimited multiple testing, even after each participant. In this procedure, which we call Sequential Bayes Factors (SBFs), Bayes factors are computed until an a priori defined level of evidence is reached. This allows flexible sampling plans and is not dependent upon correct effect size guesses in an a priori power analysis. We investigated the long-term rate of misleading evidence, the average expected sample sizes, and the biasedness of effect size estimates when an SBF design is applied to a test of mean differences between 2 groups. Compared with optimal NHST, the SBF design typically needs 50% to 70% smaller samples to reach a conclusion about the presence of an effect, while having the same or lower long-term rate of wrong inference. (PsycINFO Database Record PMID- 26651987 TI - The latent class multitrait-multimethod model. AB - A latent class multitrait-multimethod (MTMM) model is proposed to estimate random and systematic measurement error in categorical survey questions while making fewer assumptions than have been made so far in such evaluations, allowing for possible extreme response behavior and other nonmonotone effects. The method is a combination of the MTMM research design of Campbell and Fiske (1959), the basic response model for survey questions of Saris and Andrews (1991), and the latent class factor model of Vermunt and Magidson (2004, pp. 227-230). The latent class MTMM model thus combines an existing design, model, and method to allow for the estimation of the degree to and manner in which survey questions are affected by systematic measurement error. Starting from a general form of the response function for a survey question, we present the MTMM experimental approach to identification of the response function's parameters. A "trait-method biplot" is introduced as a means of interpreting the estimates of systematic measurement error, whereas the quality of the questions can be evaluated by item information curves and the item information function. An experiment from the European Social Survey is analyzed and the results are discussed, yielding valuable insights into the functioning of a set of example questions on the role of women in society in 2 countries. PMID- 26651988 TI - Modeling missing data in knowledge space theory. AB - Missing data are a well known issue in statistical inference, because some responses may be missing, even when data are collected carefully. The problem that arises in these cases is how to deal with missing data. In this article, the missingness is analyzed in knowledge space theory, and in particular when the basic local independence model (BLIM) is applied to the data. Two extensions of the BLIM to missing data are proposed: The former, called ignorable missing BLIM (IMBLIM), assumes that missing data are missing completely at random; the latter, called missing BLIM (MissBLIM), introduces specific dependencies of the missing data on the knowledge states, thus assuming that the missing data are missing not at random. The IMBLIM and the MissBLIM modeled the missingness in a satisfactory way, in both a simulation study and an empirical application, depending on the process that generates the missingness: If the missing data-generating process is of type missing completely at random, then either IMBLIM or MissBLIM provide adequate fit to the data. However, if the pattern of missingness is functionally dependent upon unobservable features of the data (e.g., missing answers are more likely to be wrong), then only a correctly specified model of the missingness distribution provides an adequate fit to the data. PMID- 26651989 TI - Challenges for Restoration of Lower Urinary Tract Innervation in Patients with Spinal Cord Injury: A European Single-center Retrospective Study with Long-term Follow-up. AB - Xiao and colleagues in China reported successful restoration of bladder control in patients with spinal cord injury (SCI) by establishing a somatic-autonomic reflex pathway through lumbar-to-sacral ventral root nerve rerouting. We evaluated long-term results in eight patients who underwent this procedure at a German university clinic between 2005 and 2007. The primary outcome was the occurrence of voiding upon stimulation of the skin, with normalization of bladder pressure when filling, as assessed with videourodynamics at each visit. Videourodynamic variables, urinary tract infections, and bladder/stool events recorded in a patient diary were stored in a prospective database and reviewed retrospectively. Intraoperative testing indicated successful nerve rerouting in all eight patients. Duration of follow-up was 71 mo (range: 56-86). No patient reached the primary goal of voluntary voiding with normalization of detrusor pressure at any point during follow-up. No improvements in videourodynamic or diary variables regarding bladder function were observed. In view of the lack of short (12-18 mo) and long-term (71 mo) success in our patients and others, the risks of any surgical procedure using general anesthesia, and potential for unmet expectations to wreak havoc on patient emotional well-being, we cannot recommend this procedure for patients with SCI. PATIENT SUMMARY: Although the hope was to improve long-term outcomes of spinal cord injury patients, intraspinal nerve rerouting did not improve or normalize bladder function. In view of the lack of success, we cannot recommend this procedure until proven in clinical studies. PMID- 26651990 TI - Risk-based Patient Selection for Magnetic Resonance Imaging-targeted Prostate Biopsy after Negative Transrectal Ultrasound-guided Random Biopsy Avoids Unnecessary Magnetic Resonance Imaging Scans. AB - BACKGROUND: Multiparametric magnetic resonance imaging (mpMRI) is increasingly used in men with suspicion of prostate cancer (PCa) after negative transrectal ultrasound (TRUS)-guided random biopsy. Risk-based patient selection for mpMRI could help to avoid unnecessary mpMRIs. OBJECTIVE: To study the rate of potentially avoided mpMRIs after negative TRUS-guided random biopsy by risk-based patient selection using the Rotterdam Prostate Cancer Risk Calculator (RPCRC). DESIGN, SETTING, AND PARTICIPANTS: One hundred and twenty two consecutive men received a mpMRI scan and subsequent MRI-TRUS fusion targeted biopsy in case of suspicious lesion(s) (Prostate Imaging Reporting and Data System >= 3) after negative TRUS-guided random biopsy. Men were retrospectively stratified according to the RPCRC biopsy advice to compare targeted biopsy outcomes after risk-based patient selection with standard (prostate specific antigen and/or digital rectal examination-driven) patient selection. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The rate of potentially avoided mpMRIs by RPCRC-based patient selection in relation to the rate of missed high-grade (Gleason >= 3+4) PCa. Receiver operating characteristic curve analysis was performed to determine the area under the curve of the RPCRC for (high-grade) PCa. RESULTS AND LIMITATIONS: Of the 60 men with a positive biopsy advice, six (10%) had low-grade PCa and 28 (47%) had high-grade PCa in targeted biopsy. Of the 62 men with a negative advice, two (3%) had low-grade PCa and three (5%) had high-grade PCa. Upfront RPCRC-based patient selection would have avoided 62 (51%) of 122 mpMRIs and two (25%) of eight low grade PCa diagnoses, missing three (10%) of 31 high-grade PCa. The area under the curve of the RPCRC for PCa and high-grade PCa was respectively 0.76 (95% confidence interval 0.67-0.85) and 0.84 (95% confidence interval 0.76-0.93). CONCLUSIONS: Risk-based patient selection with the RPCRC can avoid half of mpMRIs after a negative prostate specific antigen and/or digital rectal examination driven TRUS-guided random biopsy. Further improvement in risk-based patient selection for mpMRI could be made by adjusting the RPCRC for MRI-targeted biopsy outcome prediction. PATIENT SUMMARY: The suspicion of prostate cancer remains in many men after a negative ultrasound-guided prostate biopsy. These men increasingly receive an often unnecessary magnetic resonance imaging (MRI) scan. We found that patient selection for MRI based on the Rotterdam Prostate Cancer Risk Calculator biopsy advice could avoid half of the MRIs. PMID- 26651991 TI - Gastrointestinal symptoms, inflammation and hypoalbuminemia in chronic kidney disease patients: a cross-sectional study. AB - BACKGROUND: Few studies have focused on investigating hypoalbuminemia in patients during earlier stages of chronic kidney disease (CKD). In particular, little is known about the role of gastrointestinal (GI) symptoms. Our goal in this paper is to study how GI symptoms relate to serum albumin levels in CKD, especially in the context of and compared with inflammation. METHODS: We performed a cross sectional study of 3599 patients with chronic kidney disease enrolled in the Chronic Renal Insufficiency Cohort (CRIC) study. All subjects were asked to complete the Modification of Diet in Renal Disease (MDRD) study patient symptom form. Our main predictor is GI symptom score. Serum level of C-reactive protein (CRP) was measured as well. Main outcome measures are serum albumin levels and prevalence of hypoalbuminemia. RESULTS: Of the participants assessed, mean serum albumin was 3.95 +/- 0.46 g/dL; 12.7 % had hypoalbuminemia. Patients with lower estimated glomerular filtration rate (eGFR) were likely to have more GI symptoms (apparent at an eGFR <45 ml/min/1.73 m(2)). Patients with worse GI symptoms had lower dietary protein intake. GI symptoms, like inflammation, were risk factors for lower serum albumin levels. However, adding GI symptom score or CRP into the multivariable regression analysis, did not attenuate the association between lower eGFR and lower albumin or hypoalbuminemia. CONCLUSIONS: Increased prevalence of GI symptoms become apparent among CKD patients at relatively high eGFR levels (45 ml/min/1.73 m(2)), long before ESRD. Patients with more severe GI symptoms scores are more likely to have hypoalbuminemia. But our data do not support GI symptoms/decreased protein intake or inflammation as being the main determinants of serum albumin level in CKD patients. PMID- 26651992 TI - New progress in understanding the molecular, cellular, and genetic basis of alcohol and poly-substance abuse. PMID- 26651993 TI - Clonal population expansion in an outbreak of Plasmodium falciparum on the northwest coast of Ecuador. AB - BACKGROUND: Determining the source of malaria outbreaks in Ecuador and identifying remaining transmission foci will help in malaria elimination efforts. In this study, the genetic signatures of Plasmodium falciparum isolates, obtained from an outbreak that occurred in northwest Ecuador from 2012 to 2013, were characterized. METHODS: Molecular investigation of the outbreak was performed using neutral microsatellites, drug resistance markers and pfhrp2 and pfhrp3 genotyping. RESULTS: A majority of parasite isolates (31/32) from this outbreak were of a single clonal type that matched a clonal lineage previously described on the northern coast of Peru and a historical isolate from Ecuador. All but one isolate carried a chloroquine-resistant pfcrt genotype and sulfadoxine- and pyrimethamine-sensitive pfdhps and pfdhfr genotypes. Pfmdr1 mutations were identified in codons 184 and 1042. In addition, most samples (97 %) showed presence of pfhrp2 gene. CONCLUSIONS: This study indicates that parasites from a single clonal lineage largely contributed to this outbreak and this lineage was found to be genetically related to a lineage previously reported in the Peruvian coast and historical Ecuadorian parasites. PMID- 26651994 TI - Effects of different types of fluid resuscitation for hemorrhagic shock on splanchnic organ microcirculation and renal reactive oxygen species formation. AB - INTRODUCTION: Fluid resuscitation is an indispensable procedure in the acute management of hemorrhagic shock for restoring tissue perfusion, particularly microcirculation in splanchnic organs. Resuscitation fluids include crystalloids, hypertonic saline (HTS), and synthetic colloids, and their selection affects the recovery of microcirculatory blood flow and reactive oxygen species (ROS) formation, which is often evident in the kidney, following reperfusion. In this study, the effects of acute resuscitation with 0.9% saline (NS), 3% HTS, 4% succinylated gelatin (GEL), and 6% hydroxyethyl starch (HES) 130/0.4 were compared in a hemorrhagic shock rat model to analyze restoration of microcirculation among various splanchnic organs and the gracilis muscle and reperfusion-induced renal ROS formation. METHODS: A total of 96 male Wistar rats were subjected to sham operation (sham group), hemorrhagic shock (control group), and resuscitation with NS, HTS, GEL and HES. Two hours after resuscitation, changes in the mean arterial pressure (MAP), serum lactate level and the microcirculatory blood flow among various splanchnic organs, namely the liver, kidney, and intestine (mucosa, serosal muscular layer, and Peyer's patch), and the gracilis muscle, were compared using laser speckle contrast imaging. Renal ROS formation after reperfusion was investigated using an enhanced in vivo chemiluminescence (CL) method. RESULTS: Microcirculatory blood flow was less severely affected by hemorrhaging in the liver and gracilis muscle. Impairment of microcirculation in the kidney was restored in all resuscitation groups. Resuscitation in the NS group failed to restore intestinal microcirculation. Resuscitation in the HTS, GEL, and HES groups restored intestinal microcirculatory blood flow. By comparison, fluid resuscitation restored hemorrhagic shock-induced hypotension and decreased lactatemia in all resuscitation groups. Reperfusion-induced in vivo renal ROS formation was significantly higher in the GEL and HES groups than in the other groups. CONCLUSION: Although fluid resuscitation with NS restored the MAP and decreased lactatemia following hemorrhagic shock, intestinal microcirculation was restored only by other volume expanders, namely 3% HTS, GEL, and HES. However, reperfusion induced renal ROS formation was significantly higher when synthetic colloids were used. PMID- 26651996 TI - VariantSpark: population scale clustering of genotype information. AB - BACKGROUND: Genomic information is increasingly used in medical practice giving rise to the need for efficient analysis methodology able to cope with thousands of individuals and millions of variants. The widely used Hadoop MapReduce architecture and associated machine learning library, Mahout, provide the means for tackling computationally challenging tasks. However, many genomic analyses do not fit the Map-Reduce paradigm. We therefore utilise the recently developed SPARK engine, along with its associated machine learning library, MLlib, which offers more flexibility in the parallelisation of population-scale bioinformatics tasks. The resulting tool, VARIANTSPARK provides an interface from MLlib to the standard variant format (VCF), offers seamless genome-wide sampling of variants and provides a pipeline for visualising results. RESULTS: To demonstrate the capabilities of VARIANTSPARK, we clustered more than 3,000 individuals with 80 Million variants each to determine the population structure in the dataset. VARIANTSPARK is 80 % faster than the SPARK-based genome clustering approach, ADAM, the comparable implementation using Hadoop/Mahout, as well as ADMIXTURE, a commonly used tool for determining individual ancestries. It is over 90 % faster than traditional implementations using R and Python. CONCLUSION: The benefits of speed, resource consumption and scalability enables VARIANTSPARK to open up the usage of advanced, efficient machine learning algorithms to genomic data. PMID- 26651995 TI - Do discrimination, residential school attendance and cultural disruption add to individual-level diabetes risk among Aboriginal people in Canada? AB - BACKGROUND: Aboriginal peoples in Canada (First Nations, Metis and Inuit) are experiencing an epidemic of diabetes and its complications but little is known about the influence of factors attributed to colonization. The purpose of this study was to investigate the possible role of discrimination, residential school attendance and cultural disruption on diabetes occurrence among First Nations adults. METHODS: This 2012/13 cross sectional survey was conducted in two Saskatchewan First Nations communities comprising 580 households and 1570 adults. In addition to self-reported diabetes, interviewer-administered questionnaires collected information on possible diabetes determinants including widely recognized (e.g. age, sex, lifestyle, social determinants) and colonization related factors. Clustering effect within households was adjusted using Generalized Estimating Equations. RESULTS: Responses were obtained from 874 (55.7 %) men and women aged 18 and older living in 406 (70.0 %) households. Diabetes prevalence was 15.8 % among women and 9.7 % among men. In the final models, increasing age and adiposity were significant risk factors for diabetes (e.g. OR 8.72 [95 % CI 4.62; 16.46] for those 50+, and OR 8.97 [95 % CI 3.58; 22.52] for BMI 30+) as was spending most time on-reserve. Residential school attendance and cultural disruption were not predictive of diabetes at an individual level but those experiencing the most discrimination had a lower prevalence of diabetes compared to those who experienced little discrimination (2.4 % versus 13.6 %; OR 0.11 [95 % CI 0.02; 0.50]). Those experiencing the most discrimination were significantly more likely to be married and to have higher incomes. CONCLUSIONS: Known diabetes risk factors were important determinants of diabetes among First Nations people, but residential school attendance and cultural disruption were not predictive of diabetes on an individual level. In contrast, those experiencing the highest levels of discrimination had a low prevalence of diabetes. Although the reasons underlying this latter finding are unclear, it appears to relate to increased engagement with society off-reserve which may lead to an improvement in the social determinants of health. While this may have physical health benefits for First Nations people due to improved socio-economic status and other undefined influences, our findings suggest that this comes at a high emotional price. PMID- 26651997 TI - Pre-conceptional intake of folic acid supplements is inversely associated with risk of preterm birth and small-for-gestational-age birth: a prospective cohort study. AB - Associations of folic acid supplementation with risk of preterm birth (PTB) and small-for-gestational-age (SGA) birth were unclear for the Chinese populations. The aim of the present study was to investigate the associations in a large Chinese prospective cohort study: the Jiaxing Birth Cohort. In the Jiaxing Birth Cohort, 240 954 pregnant women visited local clinics or hospitals within their first trimester in Southeast China during 1999-2012. Information on anthropometric parameters, folic acid supplementation and other maternal characteristics were collected by in-person interviews during their first visit. Pregnancy outcomes were recorded during the follow-up of these participants. Multinomial logistic regression was used to examine the association of folic acid supplementation with pregnancy outcomes. The prevalence of folic acid supplementation was 24.9% in the cohort. The prevalence of PTB and SGA birth was 3.48 and 9.2%, respectively. Pre-conceptional folic acid supplementation was associated with 8% lower risk of PTB (relative risk (RR) 0.92; 95% CI 0.85, 1.00; P=0.04) and 19% lower risk of SGA birth (RR 0.81; 95% CI 0.70, 0.95; P=0.008), compared with non-users. Higher frequency of pre-conceptional folic acid use was associated with lower risk of PTB (P trend=0.032) and SGA birth (P trend=0.046). No significant association between post-conceptional initiation of folic acid supplementation and either outcome was observed. In conclusion, the present study suggests an association between pre-conceptional, but not post-conceptional, folic acid supplementation and lower risk of PTB and SGA birth in the Jiaxing Birth Cohort. Further research in other cohorts of large sample size is needed to replicate these findings. PMID- 26651998 TI - Ternatin and improved synthetic variants kill cancer cells by targeting the elongation factor-1A ternary complex. AB - Cyclic peptide natural products have evolved to exploit diverse protein targets, many of which control essential cellular processes. Inspired by a series of cyclic peptides with partially elucidated structures, we designed synthetic variants of ternatin, a cytotoxic and anti-adipogenic natural product whose molecular mode of action was unknown. The new ternatin variants are cytotoxic toward cancer cells, with up to 500-fold greater potency than ternatin itself. Using a ternatin photo-affinity probe, we identify the translation elongation factor-1A ternary complex (eEF1A.GTP.aminoacyl-tRNA) as a specific target and demonstrate competitive binding by the unrelated natural products, didemnin and cytotrienin. Mutations in domain III of eEF1A prevent ternatin binding and confer resistance to its cytotoxic effects, implicating the adjacent hydrophobic surface as a functional hot spot for eEF1A modulation. We conclude that the eukaryotic elongation factor-1A and its ternary complex with GTP and aminoacyl-tRNA are common targets for the evolution of cytotoxic natural products. PMID- 26651999 TI - NG2 glia are required for vessel network formation during embryonic development. AB - The NG2(+) glia, also known as polydendrocytes or oligodendrocyte precursor cells, represent a new entity among glial cell populations in the central nervous system. However, the complete repertoire of their roles is not yet identified. The embryonic NG2(+) glia originate from the Nkx2.1(+) progenitors of the ventral telencephalon. Our analysis unravels that, beginning from E12.5 until E16.5, the NG2(+) glia populate the entire dorsal telencephalon. Interestingly, their appearance temporally coincides with the establishment of blood vessel network in the embryonic brain. NG2(+) glia are closely apposed to developing cerebral vessels by being either positioned at the sprouting tip cells or tethered along the vessel walls. Absence of NG2(+) glia drastically affects the vascular development leading to severe reduction of ramifications and connections by E18.5. By revealing a novel and fundamental role for NG2(+) glia, our study brings new perspectives to mechanisms underlying proper vessels network formation in embryonic brains. PMID- 26652000 TI - Population genomics of intrapatient HIV-1 evolution. AB - Many microbial populations rapidly adapt to changing environments with multiple variants competing for survival. To quantify such complex evolutionary dynamics in vivo, time resolved and genome wide data including rare variants are essential. We performed whole-genome deep sequencing of HIV-1 populations in 9 untreated patients, with 6-12 longitudinal samples per patient spanning 5-8 years of infection. The data can be accessed and explored via an interactive web application. We show that patterns of minor diversity are reproducible between patients and mirror global HIV-1 diversity, suggesting a universal landscape of fitness costs that control diversity. Reversions towards the ancestral HIV-1 sequence are observed throughout infection and account for almost one third of all sequence changes. Reversion rates depend strongly on conservation. Frequent recombination limits linkage disequilibrium to about 100 bp in most of the genome, but strong hitch-hiking due to short range linkage limits diversity. PMID- 26652001 TI - Mycolic acid-specific T cells protect against Mycobacterium tuberculosis infection in a humanized transgenic mouse model. AB - Group 1 CD1 molecules, CD1a, CD1b and CD1c, present lipid antigens from Mycobacterium tuberculosis (Mtb) to T cells. Mtb lipid-specific group 1 CD1 restricted T cells have been detected in Mtb-infected individuals. However, their role in protective immunity against Mtb remains unclear due to the absence of group 1 CD1 expression in mice. To overcome the challenge, we generated mice that expressed human group 1 CD1 molecules (hCD1Tg) and a CD1b-restricted, mycolic acid specific TCR (DN1Tg). Using DN1Tg/hCD1Tg mice, we found that activation of DN1 T cells was initiated in the mediastinal lymph nodes and showed faster kinetics compared to Mtb Ag85B-specific CD4(+) T cells after aerosol infection with Mtb. Additionally, activated DN1 T cells exhibited polyfunctional characteristics, accumulated in lung granulomas, and protected against Mtb infection. Therefore, our findings highlight the vaccination potential of targeting group 1 CD1-restricted lipid-specific T cells against Mtb infection. PMID- 26652002 TI - Misaligned feeding impairs memories. AB - Robust sleep/wake rhythms are important for health and cognitive function. Unfortunately, many people are living in an environment where their circadian system is challenged by inappropriate meal- or work-times. Here we scheduled food access to the sleep time and examined the impact on learning and memory in mice. Under these conditions, we demonstrate that the molecular clock in the master pacemaker, the suprachiasmatic nucleus (SCN), is unaltered while the molecular clock in the hippocampus is synchronized by the timing of food availability. This chronic circadian misalignment causes reduced hippocampal long term potentiation and total CREB expression. Importantly this mis-timed feeding resulted in dramatic deficits in hippocampal-dependent learning and memory. Our findings suggest that the timing of meals have far-reaching effects on hippocampal physiology and learned behaviour. PMID- 26652003 TI - The evolution of distributed sensing and collective computation in animal populations. AB - Many animal groups exhibit rapid, coordinated collective motion. Yet, the evolutionary forces that cause such collective responses to evolve are poorly understood. Here, we develop analytical methods and evolutionary simulations based on experimental data from schooling fish. We use these methods to investigate how populations evolve within unpredictable, time-varying resource environments. We show that populations evolve toward a distinctive regime in behavioral phenotype space, where small responses of individuals to local environmental cues cause spontaneous changes in the collective state of groups. These changes resemble phase transitions in physical systems. Through these transitions, individuals evolve the emergent capacity to sense and respond to resource gradients (i.e. individuals perceive gradients via social interactions, rather than sensing gradients directly), and to allocate themselves among distinct, distant resource patches. Our results yield new insight into how natural selection, acting on selfish individuals, results in the highly effective collective responses evident in nature. PMID- 26652004 TI - Discrete spatial organization of TGFbeta receptors couples receptor multimerization and signaling to cellular tension. AB - Cell surface receptors are central to the cell's ability to generate coordinated responses to the multitude of biochemical and physical cues in the microenvironment. However, the mechanisms by which receptors enable this concerted cellular response remain unclear. To investigate the effect of cellular tension on cell surface receptors, we combined novel high-resolution imaging and single particle tracking with established biochemical assays to examine TGFbeta signaling. We find that TGFbeta receptors are discretely organized to segregated spatial domains at the cell surface. Integrin-rich focal adhesions organize TbetaRII around TbetaRI, limiting the integration of TbetaRII while sequestering TbetaRI at these sites. Disruption of cellular tension leads to a collapse of this spatial organization and drives formation of heteromeric TbetaRI/TbetaRII complexes and Smad activation. This work details a novel mechanism by which cellular tension regulates TGFbeta receptor organization, multimerization, and function, providing new insight into the mechanisms that integrate biochemical and physical cues. PMID- 26652006 TI - Photoacoustic Probes for Ratiometric Imaging of Copper(II). AB - Photoacoustic tomography has emerged as a promising alternative to MRI and X-ray scans in the clinical setting due to its ability to afford high-resolution images at depths in the cm range. However, its utility has not been established in the basic research arena owing to a lack of analyte-specific photoacoustic probes. To this end, we have developed acoustogenic probes for copper(II)-1 and -2 (APC-1 and APC-2, a water-soluble congener) for the chemoselective visualization of Cu(II), a metal ion which plays a crucial role in chronic neurological disorders such as Alzheimer's disease. To detect Cu(II), we have equipped both APCs with a 2-picolinic ester sensing module that is readily hydrolyzed in the presence of Cu(II) but not by other divalent metal ions. Additionally, we designed APC-1 and APC-2 explicitly for ratiometric photoacoustic imaging by using an aza-BODIPY dye scaffold exhibiting two spectrally resolved NIR absorbance bands which correspond to the 2-picolinic ester capped and uncapped phenoxide forms. The normalized ratiometric turn-on responses for APC-1 and APC-2 were 89- and 101-fold, respectively. PMID- 26652005 TI - RNA polymerase errors cause splicing defects and can be regulated by differential expression of RNA polymerase subunits. AB - Errors during transcription may play an important role in determining cellular phenotypes: the RNA polymerase error rate is >4 orders of magnitude higher than that of DNA polymerase and errors are amplified >1000-fold due to translation. However, current methods to measure RNA polymerase fidelity are low-throughout, technically challenging, and organism specific. Here I show that changes in RNA polymerase fidelity can be measured using standard RNA sequencing protocols. I find that RNA polymerase is error-prone, and these errors can result in splicing defects. Furthermore, I find that differential expression of RNA polymerase subunits causes changes in RNA polymerase fidelity, and that coding sequences may have evolved to minimize the effect of these errors. These results suggest that errors caused by RNA polymerase may be a major source of stochastic variability at the level of single cells. PMID- 26652007 TI - Functional characterization of CYP2D6 novel allelic variants identified in the Chinese Han population. AB - AIM: This study was aimed to functionally characterize four novel CYP2D6 alleles identified in Chinese Han population. MATERIALS & METHODS: CYP2D6 proteins of wild-type and the four novel variants along with CYP2D6.2 and CYP2D6.10 were heterologously expressed in yeast cells and the kinetic parameters were determined. RESULTS: Compared with CYP2D6.1 (frequency in Chinese 24.65%), CYP2D6.X (1.63%), CYP2D6.Y (1.50%), CYP2D6.Z (0.81%), CYP2D6.10 (52.53%) and CYP2D6.75 (0.13%) exhibited low activity at different degrees, whereas the kinetic parameters of CYP2D6.2 (11.06%) were much the same with CYP2D6.1. The novel allele CYP2D6.75 showed decreased enzyme activity. CONCLUSION: This is the first study to conduct functional analysis of CYP2D6 four novel alleles in Chinese Han population, which might be helpful for optimizing pharmacotherapy and the design of personalized medicine. PMID- 26652008 TI - Segmental pneumatosis cystoides coli: computed tomography-facilitated diagnosis. AB - Intestinal pneumatosis is a rare entity of unclear etiopathogenesis characterized by the presence of gaseous cystic or linear collections within the intestinal wall. Intestinal pneumatosis may be primary and idiopathic in origin or, more frequently, it accompanies various clinical conditions. Rarely, the development of intestinal pneumatosis is attributed to the pharmacotherapy with different drugs. This is a case report of cystic pneumatosis limited to the large intestine with predominant clinical presentation of chronic watery diarrhea in a 64-year old man suffering from diabetes mellitus treated with metformin and acarbose. The patient had been referred to the outpatient gastroenterology clinic for further investigation of numerous polyp-like lesions found on colonoscopy. There was no history of cigarette smoking, drug abuse or extraintestinal complaints. The patient was in a good general condition and his laboratory tests were normal. No relevant abnormalities were found on chest X-ray, esophagogastroduodenoscopy or abdominal ultrasound, but computed tomography showed intramural gas-filled bubbles in the cecum and splenic flexure without signs of perforation or any other significant pathology in the abdominal cavity. The final diagnosis of pneumatosis cystoides coli (PCC), possibly related to treatment with acarbose, was established. On a follow-up visit after discontinuation of acarbose the patient reported no complaints and remained asymptomatic for the next 12 months. To conclude, drug-related PCC should be considered in a differential diagnosis of gastrointestinal symptoms and/or polyp-like lesions disclosed on colonoscopy in diabetic patients treated with acarbose. PMID- 26652009 TI - Preoperative versus postoperative ultrasound-guided rectus sheath block for improving pain, sleep quality and cytokine levels of patients with open midline incisions undergoing transabdominal gynaecological operation: study protocol for a randomised controlled trial. AB - BACKGROUND: Rectus sheath block (RSB) is used for postoperative pain relief in patients undergoing abdominal surgery with midline incision. Preoperative RSB has been shown to be effective, but it has not been compared with postoperative RSB. The aim of the present study is to evaluate postoperative pain, sleep quality and changes in the cytokine levels of patients undergoing gynaecological surgery with RSB performed preoperatively versus postoperatively. METHODS/DESIGN: This study is a prospective, randomised, controlled (randomised, parallel group, concealed allocation), single-blinded trial. All patients undergoing transabdominal gynaecological surgery will be randomised 1:1 to the treatment intervention with general anaesthesia as an adjunct to preoperative or postoperative RSB. The objective of the trial is to evaluate postoperative pain, sleep quality and changes in the cytokine levels of patients undergoing gynaecological surgery with RSB performed preoperatively (n = 32) versus postoperatively (n = 32). All of the patients, irrespective of group allocation, will receive patient-controlled intravenous analgesia (PCIA) with oxycodone. The primary objective is to compare the interval between leaving the post-anaesthesia care unit and receiving the first PCIA bolus injection on the first postoperative night between patients who receive preoperative versus postoperative RSB. The secondary objectives will be to compare (1) cumulative oxycodone consumption at 24 hours after surgery; (2) postoperative sleep quality, as measured using a BIS-Vista monitor during the first night after surgery; and (3) cytokine levels (interleukin-1, interleukin-6, tumour necrosis factor-alpha and interferon-gamma) during surgery and at 24 and 48 hours postoperatively. DISCUSSION: Clinical experience has suggested that RSB is a very effective postoperative analgesic technique, and we will answer the following questions with this trial. Do preoperative block and postoperative block have the same duration of analgesic effects? Can postoperative block extend the analgesic time? The results of this study could have actual clinical applications that could help to reduce postoperative pain and shorten hospital stays. TRIAL REGISTRATION: Current Controlled Trials NCT02477098 15 June 2015. PMID- 26652010 TI - Effects of Charged Cholesterol Derivatives on Abeta40 Amyloid Formation. AB - Understanding of the mechanistic progess of amyloid-beta peptide (Abeta) aggregation is critical for elucidating the underlying pathogenesis of Alzheimer's disease (AD). Herein, we report for the first time the effects of two cholesterol derivatives, negatively charged cholesterol sulfate (cholesterol-SO4) and positively charged 3beta-[N-(dimethylaminoethane)carbamoyl]-cholesterol (DC cholesterol), on the fibrillization of Abeta40. Our results demonstrate that both of the nonvesicular forms of cholesterol-SO4 and DC-cholesterol moderately accelerate the aggregation rate of Abeta40. This effect is similar to that observed for unmodified cholesterol, indicating the importance of hydrophobic interactions in binding of Abeta40 to these steroid molecules. Furthermore, we show that the vesicles formed at higher concentrations of anionic cholesterol-SO4 facilitate Abeta40 aggregation rate markedly. In contrast, the cationic DC cholesterol vesicles show the ability to inhibit Abeta40 fibril formation under appropriate experimental conditions. The results suggest that the electrostatic interactions between Abeta40 and the charged vesicles can be of great importance in regulating Abeta40-vesicle interaction. Our results also indicate that the structural properties of the aggregates of the cholesterol derivatives, including the surface charge and the size of the vesicles, are critical in regulating the effects of these vesicles on Abeta40 aggregation kinetics. PMID- 26652012 TI - Boronic Acid-Catalyzed, Highly Enantioselective Aza-Michael Additions of Hydroxamic Acid to Quinone Imine Ketals. AB - Boronic acid is one of the most versatile organic molecules in chemistry. Its uses include organic reactions, molecular recognition, assembly, and even medicine. While boronic acid catalysis, which utilizes an inherent catalytic property, has become an important research objective, it still lags far behind other boronic acid chemistries. Here, we report our discovery of a new boronic acid catalysis that enables the aza-Michael addition of hydroxamic acid to quinone imine ketals. By using 3-borono-BINOL as a chiral boronic acid catalyst, this reaction could be implemented in a highly enantioselective manner, paving the way to densely functionalized cyclohexanes. PMID- 26652011 TI - Financial obligations and economic barriers to antiretroviral therapy experienced by HIV-positive women who participated in a job-creation programme in northern Uganda. AB - Economic costs are commonly cited as barriers to women's use of antiretroviral therapy (ART) in sub-Saharan Africa; however, little is known about how changes in women's income influence economic barriers to care. We analysed in-depth interviews with 17 HIV-positive women who participated in a job-creation programme in northern Uganda and two key informant interviews with programme staff to examine lingering economic barriers to care experienced after programme enrollment. We found that participants continued to experience economic barriers even after receiving a steady income and improving their economic status. Two themes emerged: first, limited resources in health facilities (e.g. drug and staff shortages) led participants to view ART utilisation as a primarily economic endeavour where clients made informal payments for prompter service or sought treatment in private facilities where ART was readily available; second, increased economic status among participants increased expectations of economic reciprocity among participants' social networks. Financial obligations often manifested themselves in the form of caring for additional dependents, limiting the resources women could allocate toward their HIV treatment. When paired with limited resources in health facilities, increased financial obligations perpetuated the economic barriers experienced by participants. Job-creation programmes should consider how health institutions interact with participants' financial obligations to influence women's access to HIV services. PMID- 26652013 TI - The intrathecal, polyspecific antiviral immune response in neurosarcoidosis, acute disseminated encephalomyelitis and autoimmune encephalitis compared to multiple sclerosis in a tertiary hospital cohort. AB - BACKGROUND: A polyspecific, intrathecal humoral immune response against the neurotropic viruses, measles, rubella and varicella zoster virus, called "MRZ reaction" (MRZR), is present in the majority of patients with multiple sclerosis (MS). Neurosarcoidosis (NS) and acute disseminated encephalomyelitis (ADEM) are important clinical differential diagnoses of MS. Autoimmune encephalitis (AIE) represents a well characterized autoimmune CNS disorder with intrathecal antibody synthesis. The aim of this study was to investigate the specificity of MRZR for MS in patients with NS, ADEM and AIE for the first time, and to compare it with the diagnostic value of oligoclonal bands (OCB). PATIENTS AND METHODS: Twenty-two patients with NS, 17 with AIE, 8 with ADEM and 33 with MS serving as controls were analyzed for OCB and MRZR by calculation of the antibody index (AI) for each virus. MRZR was considered as positive if at least two AIs were >=1.5. RESULTS: A positive MRZR was statistically significantly less frequent in NS (9%), AIE (11%) and ADEM (0%) compared to MS patients (70%; p < 0.001 each). The specificity of MRZR for MS was 92% in the study cohort. In comparison to MRZR, the OCB showed a higher sensitivity (100%), but a lower specificity (69%) for MS. CONCLUSION: These results indicate that MRZR seems to be the most specific available CSF marker of MS. PMID- 26652014 TI - Point-of-care testing in India: missed opportunities to realize the true potential of point-of-care testing programs. AB - BACKGROUND: The core objective of any point-of-care (POC) testing program is to ensure that testing will result in an actionable management decision (e.g. referral, confirmatory test, treatment), within the same clinical encounter (e.g. POC continuum). This can but does not have to involve rapid tests. Most studies on POC testing focus on one specific test and disease in a particular healthcare setting. This paper describes the actors, technologies and practices involved in diagnosing major diseases in five Indian settings - the home, community, clinics, peripheral laboratories and hospitals. The aim was to understand how tests are used and fit into the health system and with what implications for the POC continuum. METHODS: The paper reports on a qualitative study including 78 semi structured interviews and 13 focus group discussions with doctors, nurses, patients, lab technicians, program officers and informal providers, conducted between January and June 2013 in rural and urban Karnataka, South India. Actors, diseases, tests and diagnostic processes were mapped for each of the five settings and analyzed with regard to whether and how POC continuums are being ensured. RESULTS: Successful POC testing hardly occurs in any of the five settings. In hospitals and public clinics, most of the rapid tests are used in laboratories where either the single patient encounter advantage is not realized or the rapidity is compromised. Lab-based testing in a context of manpower and equipment shortages leads to delays. In smaller peripheral laboratories and private clinics with shorter turn-around-times, rapid tests are unavailable or too costly. Here providers find alternative measures to ensure the POC continuum. In the home setting, patients who can afford a test are not/do not feel empowered to use those devices. CONCLUSION: These results show that there is much diagnostic delay that deters the POC continuum. Existing rapid tests are currently not translated into treatment decisions rapidly or are not available where they could ensure shorter turn-around times, thus undermining their full potential. To ensure the success of POC testing programs, test developers, decision-makers and funders need to account for such ground realities and overcome barriers to POC testing programs. PMID- 26652015 TI - Sarcoidosis misdiagnosed as malignant tumors: a case report. AB - BACKGROUND: Sarcoidosis is a rare condition that is often misdiagnosed as malignant tumors due to the similar clinical manifestations and imaging findings. CASE PRESENTATION: We encountered a 56-year-old Chinese woman who had a chief complaint of a persistent cough. The chest computer tomography (CT) revealed mediastinal and bilateral hilar lymph node enlargement, and positron emission tomography-computer tomography (PET-CT) revealed abnormal fluorodeoxyglucose (FDG) uptake in the lymph nodes of the chest and abdomen. To further clarify the diagnosis, a lymph node sampling was performed by video-assisted thoracoscopic surgery (VATS) and the histopathologic diagnosis of sarcoidosis was confirmed. CONCLUSIONS: VATS could be an effective and minimally invasive diagnostic method to discriminate pulmonary sarcoidosis with other malignant tumors. PMID- 26652016 TI - Ceramic Veneers and Direct-Composite Cases of Amelogenesis Imperfecta Rehabilitation. AB - The aim of this article is to present two case reports for the treatment of patients affected with amelogenesis imperfecta. One case was treated with composite resin and the other case with ceramic veneers. Esthetic and functional results were achieved using both treatments, and a review of advantages and disadvantages is presented. PMID- 26652017 TI - Emission Characteristics and Effect of Battery Drain in "Budget" Curing Lights. AB - Recently, "budget" dental light-emitting diode (LED)-based light-curing units (LCUs) have become available over the Internet. These LCUs claim equal features and performance compared to LCUs from major manufacturers, but at a lower cost. This study examined radiant power, spectral emission, beam irradiance profiles, effective emission ratios, and the ability of LCUs to provide sustained output values during the lifetime of a single, fully charged battery. Three examples of each budget LCU were purchased over the Internet (KY-L029A and KY-L036A, Foshan Keyuan Medical Equipment Co, and the Woodpecker LED.B, Guilin Woodpecker Medical Instrument Co). Major dental manufacturers provided three models: Elipar S10 and Paradigm (3M ESPE) and the Bluephase G2 (Ivoclar Vivadent). Radiant power emissions were measured using a laboratory-grade thermopile system, and the spectral emission was captured using a spectroradiometer system. Irradiance profiles at the tip end were measured using a modified laser beam profiler, and the proportion of optical tip area that delivered in excess of 400 mW/cm(2) (termed the effective emission ratio) was displayed using calibrated beam profile images. Emitted power was monitored over sequential exposures from each LCU starting at a fully charged battery state. The results indicated that there was less than a 100-mW/cm(2) difference between manufacturer-stated average tip end irradiance and the measured output. All the budget lights had smaller optical tip areas, and two demonstrated lower effective emission ratios than did the units from the major manufacturers. The budget lights showed discontinuous values of irradiance over their tip ends. One unit delivered extremely high output levels near the center of the light tip. Two of the budget lights were unable to maintain sustained and stable light output as the battery charge decreased with use, whereas those lights from the major manufacturers all provided a sustained light output for at least 100 exposures as well as visual and audible indications that the units required recharging. PMID- 26652018 TI - Evaluation of Bond Strength and Microleakage of a Novel Metal-titanate Antibacterial Agent. AB - OBJECTIVES: To evaluate the effect on both bond strength and microleakage of incorporation of a novel antibacterial nanoparticulate metal-titanate complex (nMT) into a dental adhesive system. MATERIALS AND METHODS: Eighty extracted human molars were prepared to determine whether incorporation of nMT into bonding agents can affect shear bond strength (SBS) and adhesive strength fatigue. SBS was measured with a universal testing machine, and the peak force at failure was recorded. An electromechanical fatigue machine was used for cyclic loading treatment of specimens. Differences in the SBS values among groups were identified using analysis of variance and Tukey post hoc analyses (alpha=0.05). Twenty standard Class V cavities were restored to examine microleakage when the primer/bonding resin was modified with 10 wt% nMT. Microleakage at the enamel and dentin margins was calculated as a percentage of the full length of the cavity. Results of the microleakage experiment were analyzed with paired and independent sample t-tests (alpha=0.05). RESULTS: The mean (+/- standard deviation) shear bond strength values of before fatigue and after fatigue ranged from 21.9 (2.5) MPa to 23.9 (3.8) MPa and from 17.1 (2.5) MPa to 17.7 (2.5) MPa respectively. No statistically significant differences in failure force were observed among groups (p=0.70). Microleakage under all conditions was significantly greater in the dentin margins than in the enamel margins (p<0.05). There was no evidence that microleakage differed between the experimental groups with modified primer and bonding resin. CONCLUSIONS: Incorporating nMT into a dental adhesive system will not compromise the resin composite's tooth bonding and sealing ability. PMID- 26652019 TI - Effects of Surface Treatments on the Bond Strength Between Resin Cement and a New Zirconia-reinforced Lithium Silicate Ceramic. AB - This study evaluated the effects of surface treatments on the bond strength between the new zirconia-reinforced lithium silicate ceramic (ZLS) and resin cement. VITA Suprinity blocks were crystallized according to the manufacturer's instructions and randomly assigned to six groups (N=36; n=6), according to the surface treatment to be performed and aging conditions: HF20, 10% hydrofluoric acid for 20 seconds, baseline (control); HF20tc, 10% hydrofluoric acid for 20 seconds, aging; HF40, 10% hydrofluoric acid for 40 seconds, baseline; HF40tc, 10% hydrofluoric acid for 40 seconds, aging; CJ, CoJet sandblasting (25 seconds, 2.5 bar, 15-mm distance), baseline; and CJtc, CoJet sandblasting (25 seconds, 2.5 bar, 15-mm distance), aging. All specimens were silanized (Monobond S) and cemented with Panavia F to newly polymerized Z250 resin blocks. After specimens were immersed for 24 hours in distilled water at 37 degrees C, 1-mm(2) cross section microbars were obtained by means of a cutting machine under constant cooling. Baseline groups were immediately tested, whereas "tc" groups were used to analyze the effect of aging on bond strength (10,000 thermal cycles, 5/55 degrees C, 30-second bath). The microtensile bond strength test was performed with a universal testing machine (0.5 mm/min), and bond strength (MPa) was calculated when the load-to-failure (N) was divided by the adhesive area (mm(2)). We also evaluated the surface roughness (Sa, average roughness; Str, texture aspect ratio; Sdr, developed interfacial area ratio) and the contact angle resulting from the treatments. Data were statistically analyzed by one- or two way analysis of variance and Tukey's test (all alpha=5%). The failure mode of each specimen was evaluated by stereomicroscopy, and representative specimens were analyzed by scanning electron microscopy. The microtensile bond strength was affected by the surface conditioning (p<0.0001), storage condition (p<0.0001), and the interaction between them (p=0.0012). The adhesion for HF etching was stable, whereas for CJ, aging significantly damaged the adhesion. Most failures were predominantly adhesive between ceramic and cement (52.6%). The roughness of the treated samples was higher compared with that of polished specimens for the three evaluated parameters (Sa, Str, and Sdr; all p<0.0001). Contact angle was also influenced by treatments (p<0.0001), with the CJ group showing values similar to those of control specimens. It can be concluded that the three surface treatment techniques present favorable immediate results, but silica coating was not effective in maintaining the bond strength over the long term. PMID- 26652020 TI - Restoration of Severely Compromised Teeth With Modern Operative Techniques. AB - This case report illustrates how to restore severely compromised teeth with direct composite restorations. The size of the restorations presented is often considered by dentists as being a contraindication for direct composites. Hence, the technique is explained step by step, addressing the crucial points. PMID- 26652021 TI - Influence of Restoration Type on the Cytotoxicity of a 35% Hydrogen Peroxide Bleaching Gel. AB - OBJECTIVES: The tooth/restoration interface may act as a pathway for hydrogen peroxide (H2O2) diffusion into the pulp chamber. Therefore, the influence of resin-modified glass ionomer cement (RMGIC) and resin composite simulated restorations on the cytotoxicity of an in-office bleaching gel was assessed in vitro. MATERIALS AND METHODS: Cavities in enamel/dentin discs restored with RMGIC Vitremer (3M ESPE) or Single Bond/Filtek Z350 (3M ESPE) resin composite (RC) were subjected or not subjected to hydrolytic degradation (HD). A 35%-H2O2 bleaching gel was applied to simulated restored and nonrestored enamel surfaces, and culture medium in contact with the dentin substrate (extract) was collected and applied to MDPC-23 cells. Nonrestored discs subjected or not subjected to bleaching were used as positive and negative controls, respectively. Cell viability, oxidative stress, interleukin (IL)-1beta expression, alkaline phosphatase (ALP) activity, and mineralized nodule deposition were evaluated. The H2O2 in the extracts was quantified. Data were subjected to statistical analysis. RESULTS: Higher oxidative stress associated with reduced cell viability, ALP activity, and mineralized nodule deposition was observed for all bleached groups compared with the negative control group. The RMGIC/HD group, which presented the highest H2O2 diffusion, had the lowest values of cell viability, ALP activity, and mineralized nodule deposition, as well as significantly increased IL-1beta expression. CONCLUSIONS: Dental cavities restored with the RMGIC subjected to hydrolytic degradation allowed for more intense diffusion of H2O2 into the pulp chamber, intensifying the toxicity of a 35%-H2O2 bleaching gel to pulp cells. PMID- 26652022 TI - Switch costs in the self-memory system. AB - Two experiments on undergraduates examined the idea that the working self operates as an executive structure to constrain and co-ordinate the generation of autobiographical memories. A switching task was used, in which participants completed an autobiographical memory fluency task, using either alternating self image cues or the same cue repeatedly. In two experiments, there was a clear switch cost, whereby participants took longer to generate autobiographical memories when alternating between two different self-images. In the second experiment, there was also a similar cost associated with generating names and places from two separate domains, home and university. Taken together, these experiments support the idea that autobiographical memories and personal semantics are organized into a hierarchical structure, which can be probed using executive-function-like tasks. In particular, the task switch cost points to retrieval systems being geared up to retrieving memories according to the current goals of the self. In terms of autobiographical retrieval, the self can thus be thought of as a mental structure that is subject to dynamic patterns of excitation and interference. PMID- 26652023 TI - Lack of association between the CARD10 rs6000782 polymorphism and type 1 autoimmune hepatitis in a Japanese population. AB - BACKGROUND: Previous genome-wide association studies have evaluated the impact of common genetic variants and identified several non-HLA risk loci associated with autoimmune liver diseases. More recent genome-wide association studies and replication analyses reported an association between variants of the CARD10 polymorphism rs6000782 and risk of type 1 autoimmune hepatitis (AIH). In this case-control study, we genotyped 326 Japanese AIH patients and 214 control subjects. RESULTS: Genomic DNA from 540 individuals of Japanese origin, including 326 patients with type-1 AIH and 214 healthy controls, was analyzed for two single nucleotide polymorphisms (SNPs) in the CARD10 gene. We selected CARD10 rs6000782 SNPs and genotyped these using PCR-RFLP method and direct sequencing. The Chi square test revealed that the rs6000782 variant alle (c) was not associated with the susceptibility for AIH in a Japanese population [p = 0.376, odds ratio (OR) 1.271, 95 % confidence interval (CI) 0.747-2.161] in an allele model. Our data also showed that CARD10 rs6000782 variants were not associated with AIH or with the clinical parameters of AIH. CONCLUSIONS: In this study we examined an association between rs6000782 SNPs in the CARD10 gene and type-1 AIH. Results showed no significant association of rs62000782 with type-1 AIH in a Japanese population. This study demonstrated no association between CARD10 rs6000782 variants and AIH in a Japanese population. PMID- 26652024 TI - WNT5A transforms intestinal CD8alphaalpha+ IELs into an unconventional phenotype with pro-inflammatory features. AB - BACKGROUND: Intestinal intraepithelial lymphocytes that reside within the epithelium of the intestine form one of the main branches of the immune system. A majority of IELs express CD8alpha homodimer together with other molecules associated with immune regulation. Growing evidence points to the WNT signaling pathway as a pivotal piece in the immune balance and focuses on its direct regulation in intestinal epithelium. Therefore we decided to investigate its role in IELs' immune status determination. METHOD: DSS colitis was induced in male C57BL mice. IELs were isolated from colon samples using mechanical dissociation followed by percoll gradient purification and Magnetic-activated cell sorting. Phenotype and cytokine production and condition with Wnts were analyzed by flow cytometry, real-time PCR or ELISA. Proliferation of lymphocytes were evaluated using CFSE dilution. Cell responses after WNT pathway interference were also evaluated. RESULTS: Non-canonical WNT pathway elements represented by FZD5, WNT5A and NFATc1 were remarkably elevated in colitis IELs. The non-canonical WNT5A skewed them into a pro-inflammatory category as measured by inhibitory cell surface marker LAG3, LY49E, NKG2A and activated marker CD69 and FASL. Gaining of a pro-inflammatory marker was correlated with increased IFN-gamma production but not TNF whilst decreased TGF-beta and IL-10. Both interrupting WNT5A/PKC pathway and adding canonical WNT stimulants could curtail its immune-activating effect. CONCLUSION: Canonical and non-canonical WNT signals act in opposing manners concerning determining CD8alphaalpha(+) IELs immune status. Targeting non canonical WNT pathway may be promising in tackling inflammatory bowel disease. PMID- 26652025 TI - Genetic modification of human mesenchymal stem cells helps to reduce adiposity and improve glucose tolerance in an obese diabetic mouse model. AB - INTRODUCTION: Human mesenchymal stem cells (MSCs) are multipotent cells that can differentiate into fat, muscle, bone and cartilage cells. Exposure of subcutaneous abdominal adipose tissue derived AD-MSCs to high glucose (HG) leads to superoxide accumulation and up-regulation of inflammatory molecules. Our aim was to inquire how HG exposure affects MSCs differentiation and whether the mechanism is reversible. METHODS: We exposed human adipose tissue derived MSCs to HG (25 mM) and compared it to normal glucose (NG, 5.5 mM) exposed cells at 7, 10 and 14 days. We examined mitochondrial superoxide accumulation (Mitosox-Red), cellular oxygen consumption rate (OCR, Seahorse) and gene expression. RESULTS: HG increased reactive superoxide (ROS) accumulation noted by day 7 both in cytosol and mitochondria. The OCR between the NG and HG exposed groups however did not change until 10 days at which point OCR of HG exposed cells were reduced significantly. We noted that HG exposure upregulated mRNA expression of adipogenic (PPARG, FABP-4, CREBP alpha and beta), inflammatory (IL-6 and TNF alpha) and antioxidant (SOD2 and Catalase) genes. Next, we used AdSOD2 to upregulate SOD2 prior to HG exposure and thereby noted reduction in superoxide generation. SOD2 upregulation helped reduce mRNA over-expression of PPARG, FABP 4, IL-6 and TNFalpha. In a series of separate experiments, we delivered the eGFP and SOD2 upregulated MSCs (5 days post ex-vivo transduction) and saline intra peritoneally (IP) to obese diabetic (db/db) mice. We confirmed homing-in of eGFP labeled MSCs, delivered IP, to different inflamed fat pockets, particularly omental fat. Mice receiving SOD2-MSCs showed progressive reduction in body weight and improved glucose tolerance (GTT) at 4 weeks, post MSCs transplantation compared to the GFP-MSC group (control). CONCLUSIONS: High glucose evokes superoxide generation, OCR reduction and adipogenic differentiation. Mitochondrial superoxide dismutase upregulation quenches excess superoxide and reduces adipocyte inflammation. Delivery of superoxide dismutase (SOD2) using MSCs as a gene delivery vehicle reduces inflammation and improves glucose tolerance in vivo. Suppression of superoxide production and adipocyte inflammation using mitochondrial superoxide dismutase may be a novel and safe therapeutic tool to combat hyperglycemia mediated effects. PMID- 26652027 TI - Cystofilobasidium intermedium sp. nov. and Cystofilobasidium alribaticum f.a. sp. nov., isolated from Mediterranean forest soils. AB - Multiple isolates belonging to the basidiomycetous genus Cystofilobasidium were obtained from forest soils in Serra da Arrabida Natural Park in Portugal. Phylogenetic analyses employing concatenated sequences of the D1/D2 domain and ITS region support the recognition of two novel species: Cystofilobasidium alribaticum f.a., sp. nov. (type strain CBS 14164T = PYCC 6956T = DSM 101473T) and Cystofilobasidium intermedium sp. nov. (type strain CBS 14089T = PYCC 6856T = DSM 101474T). Whereas C. alribaticum f. a. sp. nov. does not form hyphae, even when different strains are crossed, C. intermedium sp. nov. is self-fertile and forms mycelium with teliospores that upon germination give rise to slender basidia. The most remarkable physiological trait of the two novel species is their ability to grow at 35 degrees C, a property not observed for remaining species of the genus. PMID- 26652026 TI - Randomized, controlled, double-blind clinical study evaluating the safety and efficacy of MD2011001 cream in mild-to-moderate atopic dermatitis of the face and neck in children, adolescents and adults. AB - INTRODUCTION: This mono-center randomized, controlled, double-blind study evaluates the safety and efficacy of MD2011001 cream versus placebo, in mild-to moderate atopic dermatitis (AD). MD2011001 is a nonsteroidal topical cream containing vitamin E, epigallocatechin gallate and grape seed procyanidins. METHODS: Patients with AD (corresponding to an IGA score of 2 or 3), involving the face, the perioral/periocular area and/or the neck, were enrolled. Patients were randomized 1:1 ratio to receive MD2011001 or placebo before the start of the study (D0), then evaluated after 7 days, and after 28 days. The study was approved by the Local Independent Ethics Committee and conducted according to the Declaration of Helsinki and local regulations. The statistical tests used were the Wilcoxon test and the Mann-Whitney U-test. RESULTS: Forty-four patients (29F and 15M) were enrolled. The IGA values showed a statistically significant reduction during the treatment period obtaining a favorable safety profile and local tolerance for both the products. The reduction in the surface area affected by AD was significantly faster with MD2011001. DISCUSSION: This study focuses on very sensitive areas known to be particularly susceptible to local complications. CONCLUSIONS: These results suggest the usefulness of an emollient treatment for mild/moderate AD. PMID- 26652028 TI - Broadband Microwave Spectroscopy of Prototypical Amino Alcohols and Polyamines: Competition between H-Bonded Cycles and Chains. AB - The rotational spectra of the amino alcohols d-allo-threoninol, 2-amino-1,3 propanediol, and 1,3-diamino-2-propanol and the triamine analog, propane-1,2,3 triamine, have been investigated under jet-cooled conditions over the 7.5-18.5 GHz frequency range using chirped-pulsed Fourier transform microwave spectroscopy. Microwave transitions due to three conformers of d-allothreoninol, four conformers of 2-amino-1,3-propanediol, four conformers of 1,3-diamino-2 propanol, and four conformers of propane-1,2,3-triamine have been identified and assigned, aided by comparison of the fitted experimental rotational constants with the predictions for candidate structures based on an exhaustive conformational search using force field, ab initio and DFT methods. Distinctions between conformers with similar rotational constants were made on the basis of the observed nuclear quadrupole splittings and relative line strengths, which reflect the direction of the permanent dipole moment of the conformers. With three adjacent H-bonding substituents along the alkyl chain involving a combination of OH and NH2 groups, hydrogen-bonded cycles (3 H-bonds) and chains (2 H-bonds) remain close in energy, no matter what the OH/NH2 composition. Two families of H-bonded chains are possible, with H-bonding substituents forming curved chain or extended chain structures. Percent populations of the observed conformers were extracted from the relative intensities of their microwave spectra, which compare favorably with relative energies calculated at the B2PLYP D3BJ/aug-cc-pVTZ level of theory. In glycerol (3 OH), d-allothreoninol (2 OH, 1 NH2), 2-amino-1,3-propanediol (2 OH, 1 NH2), and 1,3-diamino-2-propanol (1 OH, 2 NH2), H-bonded cycles are most highly populated, followed by curved chains (3 OH or 2 OH/1 NH2) or extended chains (1 OH/2 NH2). In propane-1,2,3-triamine (3 NH2), H-bonded cycles are pushed higher in energy than both curved and extended chains, which carry all the observed population. The NH2 group serves as a better H-bond acceptor than donor, as is evidenced by optimized structures in which H bond lengths fall into the following order: r(OH...N) ~ r(OH...O) < r(NH...N) ~ r(NH...O). PMID- 26652029 TI - A Dyadic Exercise Intervention to Reduce Psychological Distress Among Lesbian, Gay, and Heterosexual Cancer Survivors. AB - PURPOSE: Studies have found disparities in psychological distress between lesbian and gay cancer survivors and their heterosexual counterparts. Exercise and partner support are shown to reduce distress. However, exercise interventions haven't been delivered to lesbian and gay survivors with support by caregivers included. METHODS: In this pilot randomized controlled trial (RCT), ten lesbian and gay and twelve heterosexual survivors and their caregivers were randomized as dyads to: Arm 1, a survivor-only, 6-week, home-based, aerobic and resistance training program (EXCAP(c)(r)); or Arm 2, a dyadic version of the same exercise program involving both the survivor and caregiver. Psychological distress, partner support, and exercise adherence, were measured at baseline and post intervention (6 weeks later). We used t-tests to examine group differences between lesbian/gay and heterosexual survivors and between those randomized to survivor-only or dyadic exercise. RESULTS: Twenty of the twenty-two recruited survivors were retained post-intervention. At baseline, lesbian and gay survivors reported significantly higher depressive symptoms (P = .03) and fewer average steps walked (P = .01) than heterosexual survivors. Post-intervention, these disparities were reduced and we detected no significant differences between lesbian/gay and heterosexual survivors. Participation in dyadic exercise resulted in a significantly greater reduction in depressive symptoms than participation in survivor-only exercise for all survivors (P = .03). No statistically significant differences emerged when looking across arm (survivor-only vs. dyadic) by subgroup (lesbian/gay vs. heterosexual). CONCLUSION: Exercise may be efficacious in ameliorating disparities in psychological distress among lesbian and gay cancer survivors, and dyadic exercise may be efficacious for survivors of diverse sexual orientations. Larger trials are needed to replicate these findings. PMID- 26652030 TI - Impact of weight change on quality of life in adults with overweight/obesity in the United States: a systematic review. AB - OBJECTIVE: To review published evidence on the impact of weight/BMI change on health-related quality of life (HRQoL) in adults from the US with overweight/obesity. METHODS: The systematic review was conducted in accordance with PRISMA guidelines. MEDLINE, Embase, EconLit, and Cochrane Library databases were reviewed using pre-defined eligibility criteria to identify relevant US studies in adults with overweight/obesity, with >=1 year follow-up, quantified weight change, and measured HRQoL. This manuscript focuses on HRQoL derived using the Short-Form 36 (SF-36) and Impact of Weight on Quality of Life-Lite (IWQOL Lite) instruments. RESULTS: In total, 32 of 6793 identified publications reported HRQoL according to SF-36 or IWQOL-Lite; 20 provided adequate data for inclusion in this review. Although study design and outcomes were heterogeneous, improvements in HRQoL were generally observed with weight loss. Bariatric surgery studies provided the most evidence (12 publications) and demonstrated dramatic (>=20%) weight loss and associated HRQoL improvements. Sustained weight loss was associated with maintenance of HRQoL improvements out to 6 years in some studies. In lifestyle and pharmaceutical intervention studies showing weight loss of 5% 10%, some aspects of HRQoL improved, although the association with weight was not typically explored. Across the 20 publications, physical versus mental HRQoL improvements were more commonly statistically significant. CONCLUSION: Overweight/obesity is typically associated with poorer HRQoL than normal weight (BMI 18.5-24.9 kg/m(2)). This systematic review of US literature demonstrated that significant weight loss after bariatric surgery may be associated with improvements in HRQoL. In non-bariatric studies with weight loss of >=5%, improvements in some aspects of HRQoL were noted, although the causal nature of the relationship is uncertain. Although many SF-36 and IWQOL-Lite domain scores increased, improvements were typically only significant for physical, rather than mental, HRQoL. This systematic review provides evidence supporting that weight loss may improve HRQoL in people with overweight/obesity. PMID- 26652032 TI - Performance Boosting of Flexible ZnO UV Sensors with Rational Designed Absorbing Antireflection Layer and Humectant Encapsulation. AB - Flexible ZnO thin film UV sensors with 3 orders of magnitude improvement in sensitivity and 2 orders of magnitude acceleration in speed are realized via light absorption efficiency enhancement and surface encapsulation. Devices are constructed on polyethylene substrate incorporating morphology controlled ZnO nanorod arrays (NRAs) as absorbing antireflection layers. By adjusting the morphology of ZnO NRAs, the light absorptance exceeds 99% through effectively trapping incident photons. As a result, the sensitivity of the UV sensor reaches 109 000. Moreover, a mechanism of competitive chemisorption between O2 and H2O at oxygen vacancy sites is proposed to explain the phenomenon of the speed acceleration in moist environment. A new approach of humectant encapsulation is used to make H2O participant rapid processes dominant for speed acceleration. Two orders of magnitude speed enhancement in reset time is achieved by polyethylene glycol encapsulation. After a total 3000 cycles bending test, the decay in the responsivity of UV sensor is within 20%, indicating good mechanical stability. All these results not only demonstrate a simple, effective and scalable approach to fabricate high sensitive and fast response flexible ZnO UV sensors, but also provide meaningful references for performance boosting of photoelectronic devices based on other oxide semiconductors. PMID- 26652031 TI - The tumor-suppressive and potential therapeutic functions of miR-34a in epithelial carcinomas. AB - INTRODUCTION: Many RNA species have been identified as important players in the development of chronic diseases including cancer. Certain classes of regulatory RNAs such as microRNAs (miRNAs) have been investigated in such detail that bona fide tumor suppressive and oncogenic miRNAs have been identified. Because of this, there has been a major effort to therapeutically target these small RNAs. One in particular, a liposomal formulation of miR-34a (MRX34), has entered Phase I trials. AREAS COVERED: This review aims to summarize miRNA biology, its regulation within normal versus disease states and how it can be targeted therapeutically, with a particular emphasis on miR-34a. Understanding the complexity of a single miRNA will aid in the development of future RNA-based therapeutics for a broader range of chronic diseases. EXPERT OPINION: The potential of miRNAs to be developed into anti-cancer therapeutics has become an increasingly important area of research. miR-34a is a tumor suppressive miRNA across many tumor types through its ability to inhibit cellular proliferation, invasion and tumor sphere formation. miR-34a also shows promise within certain in vivo solid tumor models. Finally, as miR-34a moves into clinical trials it will be important to determine if it can further sensitize tumors to certain chemotherapeutic agents. PMID- 26652034 TI - Lived experience practitioners and the medical model: world's colliding? AB - BACKGROUND: Australian mental health policy requires that mental health services facilitate meaningful and genuine consumer participation in all aspects of mental health services. Roles for practitioners who work from their own experience of significant mental health challenges and mental health service use have been implemented in many services to promote participation and the development of more consumer focused services. AIMS: To enhance understanding of perspectives of individuals working in lived experience roles to more closely understand their experiences and opinions about these roles. METHOD: A grounded theory study interviews were conducted with 13 lived experience practitioners. RESULTS: The medical model was a core category arising from this work. Participants described the medical model as a prevailing culture within mental health services from their personal and professional experiences. This culture imposed a major limitation on the implementation, effectiveness and development of lived experience roles and themselves as individuals. It was also seen as a major limitation to the progress of Recovery orientated reform. CONCLUSIONS: The development of Recovery oriented services requires a strong lived experience practitioner workforce, with appropriate resourcing and support available. The current medical model approach requires critique to facilitate reform and avoid tokenism. PMID- 26652033 TI - Novel therapeutic interventions for p53-altered tumors through manipulation of its family members, p63 and p73. AB - TP53 is highly mutated in human cancers, thus targeting this tumor suppressor pathway is highly desirable and will impact many cancer patients. (1,2) Therapeutic strategies to reactivate the p53-pathway have been challenging, (3,4) and no effective treatment exists. (5) We utilized the p53-family members, p63 and p73, which are not frequently mutated in cancer, to treat p53-defective cancers. The N-terminal splice variants of p63 and p73 are denoted as the TA and DeltaN isoforms. We recently demonstrated that deletion of either DeltaNp63 or DeltaNp73 in p53-deficient mouse tumors results in tumor regression mediated by metabolic programming. Using this strategy, we identified pramlintide, a synthetic analog of amylin, as an effective treatment for p53 deficient and mutant tumors. Here, we show the utility of using pramlintide, as a potential cancer preventive option for p53-deficient tumors in mouse models. Additionally, we found that in vivo inhibition of both DeltaNp63 and DeltaNp73 in combination accelerates tumor regression and increases survival of p53-deficient mice. We report that inhibition of both DeltaNp63 and DeltaNp73 in combination results in upregulation of 3 key metabolic regulators, IAPP, GLS2, and TIGAR resulting in an increase in apoptosis and tumor regression in DeltaNp63/DeltaNp73/p53 deficient thymic lymphomas. These data highlight the value of generating inhibitors that will simultaneously target DeltaNp63 and DeltaNp73 to treat cancer patients with alterations in p53. PMID- 26652035 TI - Prospects and progress of DNA vaccines for treating hepatitis B. AB - The hepatitis B virus (HBV) is a global cause of liver disease. The preventive HBV vaccine has effectively reduced the disease burden. However, an estimated 340 million chronic HBV cases are in need of treatment. Current standard therapy for chronic HBV blocks reverse transcription. As this therapy blocks viral maturation and not viral protein expression, any immune inhibition exerted by these proteins will remain throughout therapy. This may help to explain why these drugs rarely induce off-therapy responses. Albeit some restoration of immune function occurs during therapy, this is clearly insufficient to control replication. Central questions when considering therapeutic DNA vaccination as an addition to blocking virus production are as follows: what does one hope to achieve? What do we think is wrong and how can the vaccination correct this? We here discuss different scenarios with respect to the lack of success of tested DNA vaccines, and suggest strategies for improvement. PMID- 26652036 TI - Comparison of the Mechanisms of Heme Hydroxylation by Heme Oxygenases-1 and -2: Kinetic and Cryoreduction Studies. AB - The two isoforms of human heme oxygenase (HO1 and HO2) catalyze oxidative degradation of heme to biliverdin, Fe, and CO. Unlike HO1, HO2 contains two C terminal heme regulatory motifs (HRMs) centered at Cys265 and Cys282 that act as redox switches and, in their reduced dithiolate state, bind heme (Fleischhacker et al., Biochemistry , 2015 , 54 , 2693 - 2708 ). Here, we describe cryoreduction/annealing and electron paramagnetic resonance spectroscopic experiments to study the structural features of the oxyheme moiety in HO2 and to elucidate the initial steps in heme degradation. We conclude that the same mechanism of heme hydroxylation to alpha-meso-hydroxyheme is employed by both isoforms and that the HRMs do not affect the physicochemical properties of the oxy-Fe(II) and HOO-Fe(III) states of HO2. However, the absorption spectrum of oxy Fe(II)-HO2 is slightly blue-shifted relative to that of HO1. Furthermore, heme hydroxylation proceeds three times more slowly, and the oxy-Fe(II) state is 100 fold less stable in HO2 than in HO1. These distinctions are attributed to slight structural variances in the two proteins, including differences in equilibrium between open versus closed conformations. Kinetic studies revealed that heme oxygenation by HO2 occurs solely at the catalytic core in that a variant of HO2 lacking the C-terminal HRM domain exhibits the same specific activity as one containing both the catalytic core and HRM domain; furthermore, a truncated variant containing only the HRM region binds but cannot oxidize heme. In summary, HO1 and HO2 share similar catalytic mechanisms, and the HRMs do not play a direct role in the HO2 catalytic cycle. PMID- 26652037 TI - The effect of beta-alanine supplementation on cycling time trials of different length. AB - The varying results reported in response to beta-alanine supplementation may be related to the duration and nature of the exercise protocol employed. We investigated the effects of beta-alanine supplementation on a wide range of cycling performance tests in order to produce a clear concise set of criteria for its efficacy. Fourteen trained cyclists (Age = 24.8 +/- 6.7 years; VO2max = 65.4 +/- 10.2 mL.kg.min(-1)) participated in this placebo-controlled, double-blind study. Prior to supplementation, subjects completed two (familiarization and baseline) supramaximal cycling bouts until exhaustion (120% pre-supplementation VO2max) and two 1-, 4- and 10-km cycling time trial (TT). Subjects then supplemented orally for 4 weeks with 6.4 g/d placebo or beta-alanine and repeated the battery of performance tests. Blood lactate was measured pre-exercise, post exercise and 5 min post-exercise. beta-alanine supplementation elicited significant increases in time to exhaustion (TTE) (17.6 +/- 11.5 s; p = 0.013, effect compared with placebo) and was likely to be beneficial to 4-km TT performance time (-7.8 +/- 8.1 s; 94% likelihood), despite not being statistically different (p = 0.060). Performance times in the 1- and 10-km TT were not affected by treatment. For the highly trained cyclists in the current study, beta-alanine supplementation significantly extended supramaximal cycling TTE and may have provided a worthwhile improvement to 4-km TT performance. However, 1- and 10-km cycling TT performance appears to be unaffected by beta alanine supplementation. PMID- 26652038 TI - Enzyme and Thermal Dual Responsive Amphiphilic Polymer Core-Shell Nanoparticle for Doxorubicin Delivery to Cancer Cells. AB - Dual responsive polymer nanoscaffolds for administering anticancer drugs both at the tumor site and intracellular compartments are made for improving treatment in cancers. The present work reports the design and development of new thermo- and enzyme-responsive amphiphilic copolymer core-shell nanoparticles for doxorubicin delivery at extracellular and intracellular compartments, respectively. A hydrophobic acrylate monomer was tailor-made from 3-pentadecylphenol (PDP, a natural resource) and copolymerized with oligoethylene glycol acrylate (as a hydrophilic monomer) to make new classes of thermo and enzyme dual responsive polymeric amphiphiles. Both radical and reversible addition-fragmentation chain transfer (RAFT) methodologies were adapted for making the amphiphilic copolymers. These amphiphilic copolymers were self-assembled to produce spherical core-shell nanoparticles in water. Upon heating, the core-shell nanoparticles underwent segregation to produce larger sized aggregates above the lower critical solution temperature (LCST). The dual responsive polymer scaffold was found to be capable of loading water insoluble drug, such as doxorubicin (DOX), and fluorescent probe like Nile Red. The drug release kinetics revealed that DOX was preserved in the core-shell assemblies at normal body temperature (below LCST, <= 37 degrees C). At closer to cancer tissue temperature (above LCST, ~43 degrees C), the polymeric scaffold underwent burst release to deliver 90% of loaded drugs within 2 h. At the intracellular environment (pH 7.4, 37 degrees C) in the presence of esterase enzyme, the amphiphilic copolymer ruptured in a slow and controlled manner to release >95% of the drugs in 12 h. Thus, both burst release of cargo at the tumor microenvironment and control delivery at intracellular compartments were accomplished in a single polymer scaffold. Cytotoxicity assays of the nascent and DOX-loaded polymer were carried out in breast cancer (MCF-7) and cervical cancer (HeLa) cells. Among the two cell lines, the DOX-loaded polymers showed enhanced killing in breast cancer cells. Furthermore, the cellular uptake of the DOX was studied by confocal and fluorescence microscopes. The present investigation opens a new enzyme and thermal-responsive polymer scaffold approach for DOX delivery in cancer cells. PMID- 26652039 TI - Informational constraints on interceptive actions of elite football goalkeepers in 1v1 dyads during competitive performance. AB - The aim of this study was to examine whether perceptual variables can provide informational constraints for the goalkeepers to intercept the ball successfully in 1v1 dyads. Video images of 42 actions (1v1 in direct shots) were selected randomly from different matches and divided into conceded goals (n = 20) and saved actions (n = 22) to investigate interceptive actions of 20 goalkeepers in the English Premier League in season 2013-2014. Time to Contact (TTC) of the closing distance gap between shooter and goalkeeper was obtained by digitising actions in the 18-yard penalty box. Statistical analyses revealed that, in sequences of play resulting in an intercepted shot at goal, goalkeepers closed down outfield players in the X axis, whereas when a goal was conceded, there was a significantly delayed movement by goalkeepers toward the shooters in this plane. The results of canonical correlations showed that a decreasing distance between a shooter and goalkeeper, and accompanied reduction in relative interpersonal velocity followed a temporal pattern. Findings of this study showed how perception of key informational constraints on dyadic system relations, such as TTC, interpersonal distance and relative velocity, constrain elite goalkeepers' interceptive actions, playing an important role in successful performance. PMID- 26652040 TI - Our critics might have valid concerns: Reducing our propensity to conflate. PMID- 26652041 TI - Association among Emergency Department Volume Changes, Length of Stay, and Leaving Before Treatment Complete. AB - The authors examined the association between the size of an emergency department (ED), volume increases over time, length of stay (LOS), and left before treatment complete (LBTC). EDs participating in the Emergency Department Benchmarking Alliance providing at least two years of data from 2004 to 2011 were included in the analysis. The impact of volume on LOS and LBTC varied depending on annual ED volume. Based on this, EDs can anticipate better how changes in volume will impact patient throughput in the future. PMID- 26652042 TI - Does Quality of Healthcare Service Determine Patient Adherence? Evidence from the Primary Healthcare Sector in India. AB - Patient adherence is extremely important to achieve positive outcome. While quality of healthcare service has been studied as a determinant of patient satisfaction and loyalty, its impact on patient adherence has not been examined. The authors attempt to determine dimensions of quality and their impact on patient adherence in primary healthcare in India. Exploratory factor analysis resulted into seven factors. Factor scores were used for regression to identify the influence of dimensions of service quality on patient adherence. Quality of healthcare emerged as a determinant of patient adherence. PMID- 26652043 TI - Union Density and Hospital Outcomes. AB - The authors address the hospital outcomes of patient satisfaction, healthcare quality, and net income per bed. They define union density as the percentage of a hospital's employees who are in unions, healthcare quality as its 30-day acute myocardial infraction (AMI; heart attack) mortality rate, and patient satisfaction as its overall Hospital Consumer Assessment of Healthcare Providers and Systems score. Using a random sample of 84 union and 84 nonunion hospitals from across the United States, multiple regression analyses show that union density is negatively related to patient satisfaction. Union density is not related to healthcare quality as measured by the AMI mortality rate or to net income per bed. This implies that unions per se are not good or bad for hospitals. The authors suggest that it is better for hospital administrators to take a Balanced Scorecard approach and be concerned about employee satisfaction, patient satisfaction, healthcare quality, and net income. PMID- 26652044 TI - CuAAC: An Efficient Click Chemistry Reaction on Solid Phase. AB - Click chemistry is an approach that uses efficient and reliable reactions, such as Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC), to bind two molecular building blocks. CuAAC has broad applications in medicinal chemistry and other fields of chemistry. This review describes the general features and applications of CuAAC in solid-phase synthesis (CuAAC-SP), highlighting the suitability of this kind of reaction for peptides, nucleotides, small molecules, supramolecular structures, and polymers, among others. This versatile reaction is expected to become pivotal for meeting future challenges in solid-phase chemistry. PMID- 26652045 TI - Platelet Lysate-Modified Porous Silicon Microparticles for Enhanced Cell Proliferation in Wound Healing Applications. AB - The new frontier in the treatment of chronic nonhealing wounds is the use of micro- and nanoparticles to deliver drugs or growth factors into the wound. Here, we used platelet lysate (PL), a hemoderivative of platelets, consisting of a multifactorial cocktail of growth factors, to modify porous silicon (PSi) microparticles and assessed both in vitro and ex vivo the properties of the developed microsystem. PL-modified PSi was assessed for its potential to induce proliferation of fibroblasts. The wound closure-promoting properties of the microsystem were then assessed in an in vitro wound healing assay. Finally, the PL-modified PSi microparticles were evaluated in an ex vivo experiment over human skin. It was shown that PL-modified PSi microparticles were cytocompatible and enhanced the cell proliferation in different experimental settings. In addition, this microsystem promoted the closure of the gap between the fibroblast cells in the wound healing assay, in periods of time comparable with the positive control, and induced a proliferation and regeneration process onto the human skin in an ex vivo experiment. Overall, our results show that PL-modified PSi microparticles are suitable microsystems for further development toward applications in the treatment of chronic nonhealing wounds. PMID- 26652046 TI - Enantioselective Metal-Free Hydrogenations of Disubstituted Quinolines. AB - A metal-free hydrogenation of 2,4-disubstituted quinolines was realized for the first time using chiral diene derived borane catalysts to furnish the corresponding tetrahydroquinolines in 75-98% yields with 95/5-99/1 dr's and 86 98% ee's. This catalytic system was also effective for 2,3-disubstituted quinolines to give moderate to good ee's. PMID- 26652047 TI - FMR6 may play a role in the pathogenesis of fragile X-associated premature ovarian insufficiency. AB - The aim of this study was to evaluate whether long noncoding RNA accumulation play a role in the pathophysiology of fragile X-associated premature ovarian insufficiency (FXPOI). The study population consisted of 22 consecutive fragile X mental retardation 1 (FMR1) premutation carriers (CGGn 55-199 repeats) undergoing in vitro fertilization and pre-implantation genetic diagnosis (IVF-PGD) treatment. The control group consists of 11 patients, with <55 CGG repeats, undergoing IVF-ICSI for male factor infertility, matched by age, treated in the same period. After oocyte retrieval, granulosa cells from follicular fluid were washed and stored at -80 degrees C. RNA was transcribed to generate cDNA and the RNA levels were measured using RT-PCR. Transcripts levels in granulosa cells of long noncoding RNA's FMR4 and FMR6 were measured. In FMR1 premutation carriers there was a significant nonlinear association between the number of CGG repeats and the levels of FMR6 (p = 0.03), but not FMR4. The highest level of FMR6 was seen in women with mid-size CGG repeats (80-120). In addition, a significant negative linear correlation was observed between the number of oocytes retrieved and the RNA levels in granulosa cells of FMR6 (r = -0.53, p = 0.01) but not FMR4. Our study supports previous findings suggesting RNA toxic gain-of-function as one of the possible pathophysiologic mechanisms underlying FXPOI. PMID- 26652049 TI - Characterization of the Axial Jet Separator with a CO2/Helium Mixture: Toward GC AMS Hyphenation. AB - Development of interfaces for sample introduction from high pressures is important for real-time online hyphenation of chromatographic and other separation devices with mass spectrometry (MS) or accelerator mass spectrometry (AMS). Momentum separators can reduce unwanted low-density gases and introduce the analyte into the vacuum. In this work, the axial jet separator, a new momentum interface, is characterized by theory and empirical optimization. The mathematical model describes the different axial penetration of the components of a jet-gas mixture and explains the empirical results for injections of CO2 in helium into MS and AMS instruments. We show that the performance of the new interface is sensitive to the nozzle size, showing good qualitative agreement with the mathematical model. Smaller nozzle sizes are more preferable due to their higher inflow capacity. The CO2 transmission efficiency of the interface into a MS instrument is ~ 14% (CO2/helium separation factor of 2.7). The interface receives and delivers flows of ~ 17.5 mL/min and ~ 0.9 mL/min, respectively. For the interfaced AMS instrument, the ionization and overall efficiencies are 0.7-3% and 0.1-0.4%, respectively, for CO2 amounts of 4-0.6 MUg C, which is only slightly lower compared to conventional systems using intermediate trapping. The ionization efficiency depends on to the carbon mass flow in the injected pulse and is suppressed at high CO2 flows. Relative to a conventional jet separator, the transmission efficiency of the axial jet separator is lower, but its performance is less sensitive to misalignments. PMID- 26652048 TI - Influence of Surrounding Cations on the Surface Degradation of Magnesium Alloy Implants under a Compressive Pressure. AB - The effect of cations in the surrounding solutions on the surface degradation of magnesium alloys, a well-recognized biodegradable biomaterial, has been neglected compared with the effect of anions in the past. To better simulate the compressive environment where magnesium alloys are implanted into the body as a cardiovascular stent, a device is designed and employed in the test so that a pressure, equivalent to the vascular pressure, can be directly applied to the magnesium alloy implants when the alloys are immersed in a medium containing one of the cations (K(+), Na(+), Ca(2+), and Mg(2+)) found in blood plasma. The surface degradation behaviors of the magnesium alloys in the immersion test are then investigated using hydrogen evolution, mass loss determination, electron microscopy, pH value, and potentiodynamic measurements. The cations are found to promote the surface degradation of the magnesium alloys with the degree decreased in the order of K(+) > Na(+) > Ca(2+) > Mg(2+). The possible mechanism of the effects of the cations on the surface degradation is also discussed. This study will allow us to predict the surface degradation of magnesium alloys in the physiological environment and to promote the further development of magnesium alloys as biodegradable biomaterials. PMID- 26652050 TI - Longitudinal phenotypes for alcoholism: Heterogeneity of course, early identifiers, and life course correlates. AB - Alcoholism is a heterogeneous disorder; however, characterization of life-course variations in symptomatology is almost nonexistent, and developmentally early predictors of variations are very poorly characterized. In this study, the course of alcoholic symptomatology over 32 years is differentiated, and predictors and covariates of trajectory class membership are identified. A community sample of alcoholic and neighborhood matched control families, 332 men and 336 women, was recruited based on alcoholism in the men. Symptoms were assessed retrospectively at baseline (mean age = 32) back to age 15 and prospectively from baseline every 3 years for 15 years. Trajectory classes were established using growth mixture modeling. Men and women had very similarly shaped trajectory classes: developmentally limited (men: 29%, women: 42%), developmentally cumulative (men: 26%, women: 38%), young adult onset (men: 31%, women: 21%), and early onset severe (men: 13%). Three factors at age 15 predicted class membership: family history of alcoholism, age 15 symptoms, and level of childhood antisocial behavior. Numerous measures of drinking and other psychopathology were also associated with class membership. The findings suggest that clinical assessments can be crafted where the profile of current and historical information can predict not only severity of prognosis but also future moderation of symptoms and/or remission over intervals as long as decades. PMID- 26652051 TI - External Validation of the International Mission for Prognosis and Analysis of Clinical Trials in Traumatic Brain Injury: Prognostic Models for Traumatic Brain Injury on the Study of the Neuroprotective Activity of Progesterone in Severe Traumatic Brain Injuries Trial. AB - Prediction models for patients with traumatic brain injury (TBI) are important for multiple reasons, including case-mix adjustment, trial design, and benchmarking for quality-of-care evaluation. Models should be generalizable and therefore require regular external validation. We aimed to validate the International Mission for Prognosis and Analysis of Clinical Trials in TBI (IMPACT) prognostic models for moderate and severe TBI in a recent randomized controlled trial. We studied 1124 patients enrolled in the multi-center randomized placebo-controlled Study of the Neuroprotective Activity of Progesterone in Severe Traumatic Brain Injuries (SyNAPSe) trial that evaluated the efficacy of progesterone in TBI. Treatment and placebo groups were combined for analysis. We evaluated the predictive performance of the three prognostic models (core, extended, and lab) from the IMPACT study with regard to discrimination (area under the receiver operating characteristic curve [AUC]) and calibration (comparison of observed to predicted risks). Substantial differences were found in case-mix and outcome distribution between IMPACT and SyNAPSe. In line with the more homogeneous case-mix of a clinical trial, the discriminative performance was reasonable. For the core model, an AUC of 0.677 and 0.684 was obtained for 6-month mortality and unfavorable outcome, respectively. Performance was slightly better for the extended model (0.693 and 0.705) and for the lab model (0.689 and 0.711, respectively). For calibration, we found overestimation of mortality, especially at higher risk predictions, and underestimation of unfavorable outcome, especially at lower risk predictions. This pattern of miscalibration was consistent across all three models. In a contemporary trial setting, the IMPACT models have reasonable discrimination if enrollment restrictions apply. Observed changes in outcome distribution necessitate updating of previously developed prognostic models. PMID- 26652052 TI - Sesquiterpenoids and further diterpenoids from the rare Chloranthaceae plant Chloranthus sessilifolius. AB - Two new dimeric lindenane-type sesquiterpenoids (1 and 2, named chlorasessilifols A and B, resp.), one new ent-podocarpane-type C17 norditerpenoid (3), and one new ent-torarane-type diterpenoid (4), along with seven known terpenoids, were isolated from the whole plant of Chloranthus sessilifolius. The new structures were established by means of spectroscopic methods and/or observed cotton effects in the circular dichroism spectra. Among the isolates, 3alpha,7beta-dihydroxy-ent abieta-8,11,13-triene (11) exhibited significant anti-neuroinflammatory activity by inhibiting the nitric oxide production in lipopolysaccharide-stimulated murine BV-2 microglial cells, with an IC50 value of 4.3 MUM. PMID- 26652054 TI - Internet-Delivered Psychological Treatments. AB - During the past 15 years, much progress has been made in developing and testing Internet-delivered psychological treatments. In particular, therapist-guided Internet treatments have been found to be effective for a wide range of psychiatric and somatic conditions in well over 100 controlled trials. These treatments require (a) a secure web platform, (b) robust assessment procedures, (c) treatment contents that can be text based or offered in other formats, and (d) a therapist role that differs from that in face-to-face therapy. Studies suggest that guided Internet treatments can be as effective as face-to-face treatments, lead to sustained improvements, work in clinically representative conditions, and probably are cost-effective. Despite these research findings, Internet treatment is not yet disseminated in most places, and clinical psychologists should consider using modern information technology and evidence based treatment programs as a complement to their other services, even though there will always be clients for whom face-to-face treatment is the best option. PMID- 26652053 TI - Understanding differences between synthetic and natural antibodies can help improve antibody engineering. AB - Synthetic libraries are a major source of human-like antibody (Ab) drug leads. To assess the similarity between natural Abs and the products of these libraries, we compared large sets of natural and synthetic Abs using "CDRs Analyzer," a tool we introduce for structural analysis of Ab-antigen (Ag) interactions. Natural Abs, we found, recognize their Ags by combining multiple complementarity-determining regions (CDRs) to create an integrated interface. Synthetic Abs, however, rely dominantly, sometimes even exclusively on CDRH3. The increased contribution of CDRH3 to Ag binding in synthetic Abs comes with a substantial decrease in the involvement of CDRH2 and CDRH1. Furthermore, in natural Abs CDRs specialize in specific types of non-covalent interactions with the Ag. CDRH1 accounts for a significant portion of the cation-pi interactions; CDRH2 is the major source of salt-bridges and CDRH3 accounts for most hydrogen bonds. In synthetic Abs this specialization is lost, and CDRH3 becomes the main sources of all types of contacts. The reliance of synthetic Abs on CDRH3 reduces the complexity of their interaction with the Ag: More Ag residues contact only one CDR and fewer contact 3 CDRs or more. We suggest that the focus of engineering attempts on CDRH3 results in libraries enriched with variants that are not natural-like. This may affect not only Ag binding, but also Ab expression, stability and selectivity. Our findings can help guide library design, creating libraries that can bind more epitopes and Abs that better mimic the natural antigenic interactions. PMID- 26652055 TI - Folate-decorated poly(3-hydroxybutyrate-co-3-hydroxyoctanoate) nanoparticles for targeting delivery: optimization and in vivo antitumor activity. AB - CONTEXT: Doxorubicin (DOX)-loaded folate-targeted poly(3-hydroxybutyrate-co-3 hydroxyoctanoate) [P(HB-HO)] nanoparticles [DOX/FA-PEG-P(HB-HO) NPs] have potential application in clinical treatments for cervical cancer due to specific affinity of folate and folate receptor in HeLa cells. OBJECTIVE: The aim of this study was to develop an optimized formulation for DOX/FA-PEG-P(HB-HO) NPs, and investigate the targeting and efficacies of the nanoparticles. MATERIALS AND METHODS: DOX/FA-PEG-P(HB-HO) NPs were prepared by W1/O/W2 solvent extraction/evaporation method, and an orthogonal experimental design [L9 (3(4))] was applied to establish the optimum conditions. The physico-chemical characteristics, microscopic observation and in vivo antitumor study of the nanoparticles were evaluated. RESULTS: The optimum formulation was obtained with DOX 10% (w/v), FA-PEG-P(HB-HO) 6.5% (w/v), PVA 3%(w/v) and oil phase/internal water phase volume ratio of 3/1. The size distribution, drug loading and encapsulation efficiency of the optimized nanoparticles were 150-350 nm, 29.6 +/- 2.9% and 83.5 +/- 5.7%, respectively. In vitro release study demonstrated that 80% of the drug could release from the nanoparticles within 11 days. Furthermore, in vitro microscopic observation and in vivo antitumor study showed that DOX/FA PEG-P(HB-HO) NPs could inhibit HeLa cells effectively, and the tumor inhibition rate (TIR) in vivo was 76.91%. DISCUSSION AND CONCLUSIONS: DOX/FA-PEG-P(HB-HO) NPs have been successfully developed and optimized. In vitro drug release study suggested a sustained release profile. Moreover, DOX/FA-PEG-P(HB-HO) NPs could effectively inhibit HeLa cells with satisfying targeting, and reduce side effects and toxicity to normal tissues. DOX/FA-PEG-P(HB-HO) NPs were superior in terms of inhibiting HeLa tumor over non-targeted formulations therapy. PMID- 26652056 TI - Patient Home Visits: Measuring Outcomes of a Community Model for Palliative Care Education. AB - BACKGROUND: Health care professionals may have limited exposure to home-based care. There is no published literature that has described the experiences and satisfaction of participation in patient home visits (PHV). OBJECTIVE: The objective of this article is to describe the characteristics of PHV, our approach, and evaluation by participants over a nine-year period. METHODS: We conducted a review of surveys completed by participants in PHV from 2005-2013. All participants anonymously completed the evaluation questionnaires at the end of PHVs. Different PHV assessment forms were used for the 2005-2010 and 2011-2013 time periods. RESULTS: A total of 34 PHVs were conducted with 106 patients and approximately 750 participants with a mean of 3 patients and 22 participants per PHV between 2005 and 2013. For 18 PHVs there are 317 surveys completed with 353 participants, making it a 90% response rate. Responding participants were physicians 125/543 (23%) and other professionals 418/543 (77%). In both time periods of 2005-2010 and 2011-2013 a survey with a 1 (completely agree) to 5 (completely disagree) scale was used. Agreeing that PHV was an effective teaching tool during 2005-2010 were 335/341 (98%); during 2011-2013, 191/202 (95%) agreed that PHV provided increased understanding and sharing of best practices in palliative care. CONCLUSIONS: PHV was perceived by participants as an effective way of providing interactive community education. A broad range of themes were addressed, and the participants reported high levels of learning in all domains of palliative care. There were no cases of patient or relative expression of distress as a result of PHV. PMID- 26652057 TI - Successful treatment of FKBP51-expressed multicentric reticulohistiocytosis using combination therapy with low-dose denosumab and tacrolimus. PMID- 26652058 TI - Distribution of Animal Drugs between Skim Milk and Milk Fat Fractions in Spiked Whole Milk: Understanding the Potential Impact on Commercial Milk Products. AB - Seven animal drugs [penicillin G (PENG), sulfadimethoxine (SDMX), oxytetracycline (OTET), erythromycin (ERY), ketoprofen (KETO), thiabendazole (THIA), and ivermectin (IVR)] were used to evaluate the drug distribution between milk fat and skim milk fractions of cow milk. More than 90% of the radioactivity was distributed into the skim milk fraction for ERY, KETO, OTET, PENG, and SDMX, approximately 80% for THIA, and 13% for IVR. The distribution of drug between milk fat and skim milk fractions was significantly correlated to the drug's lipophilicity (partition coefficient, log P, or distribution coefficient, log D, which includes ionization). Data were fit with linear mixed effects models; the best fit was obtained within this data set with log D versus observed drug distribution ratios. These candidate empirical models serve for assisting to predict the distribution and concentration of these drugs in a variety of milk and milk products. PMID- 26652059 TI - Role of Temperature and Pressure on the Multisensitive Multiferroic Dicyanamide Framework [TPrA][Mn(dca)3] with Perovskite-like Structure. AB - A multistimuli response to temperature and pressure is found in the hybrid inorganic-organic perovskite-like [TPrA][Mn(dca)3] compound, which is related to a first-order structural phase transition near room temperature, Tt ~ 330 K. This phase transition involves a transformation from room temperature polymorph I, with the noncentrosymmetric space group P421c, to the high temperature polymorph II, with the centrosymmetric space group I4/mcm, and it implies ionic displacements, order-disorder phenomena, and a large and anisotropic thermal expansion (specially along the c-axis). As a consequence, [TPrA][Mn(dca)3] exhibits a dielectric anomaly, associated with the change from a cooperative to a noncooperative electric behavior (antiferroelectric (AFE)-paraelectric (PE) transition). The former implies an AFE distribution of electric dipoles in polymorph I, related to the described off-shift of the apolar TPrA cations and the order-disorder of the polar dca ligands mechanisms, that are different from those reported, up to now, for others perovskite-type hybrid compounds. Such cooperative electric order, below Tt ~ 330 K, coexisting with long-range antiferromagnetic ordering below T = 2.1 K render the [TPrA][Mn(dca)3] a new type I multiferroic material. In addition, the obtained experimental results reveal that this compound is also a multistimuli-responsive material, with a very large sensitivity toward temperature and applied external pressure, deltaTt/deltaP ~ 24 K kbar(-1), even for small values of pressure (P < 2 kbar). Therefore, this material opens up a potential interest for future technological applications, such as temperature/pressure sensing. PMID- 26652061 TI - Real-Time Observation of Reconstruction Dynamics on TiO2(001) Surface under Oxygen via an Environmental Transmission Electron Microscope. AB - The surface atomic structure has a remarkable impact on the physical and chemical properties of metal oxides and has been studied extensively by scanning tunneling microscopy. However, acquiring real-time information on the formation and evolution of the surface structure remains a great challenge. Here we use environmental transmission electron microscopy to directly observe the stress induced reconstruction dynamics on the (001) surface of anatase TiO2. Our in situ results unravel for the first time how the (1 * 4) reconstruction forms and how the metastable (1 * 3) and (1 * 5) patterns transform into the (1 * 4) surface stable structure. With the support of first-principles calculations, we find that the surface evolution is driven by both low coordinated atoms and surface stress. This work provides a complete picture of the structural evolution of TiO2(001) under oxygen atmosphere and paves the way for future studies of the reconstruction dynamics of other solid surfaces. PMID- 26652060 TI - Parameterizing sequence alignment with an explicit evolutionary model. AB - BACKGROUND: Inference of sequence homology is inherently an evolutionary question, dependent upon evolutionary divergence. However, the insertion and deletion penalties in the most widely used methods for inferring homology by sequence alignment, including BLAST and profile hidden Markov models (profile HMMs), are not based on any explicitly time-dependent evolutionary model. Using one fixed score system (BLOSUM62 with some gap open/extend costs, for example) corresponds to making an unrealistic assumption that all sequence relationships have diverged by the same time. Adoption of explicit time-dependent evolutionary models for scoring insertions and deletions in sequence alignments has been hindered by algorithmic complexity and technical difficulty. RESULTS: We identify and implement several probabilistic evolutionary models compatible with the affine-cost insertion/deletion model used in standard pairwise sequence alignment. Assuming an affine gap cost imposes important restrictions on the realism of the evolutionary models compatible with it, as single insertion events with geometrically distributed lengths do not result in geometrically distributed insert lengths at finite times. Nevertheless, we identify one evolutionary model compatible with symmetric pair HMMs that are the basis for Smith-Waterman pairwise alignment, and two evolutionary models compatible with standard profile based alignment. We test different aspects of the performance of these "optimized branch length" models, including alignment accuracy and homology coverage (discrimination of residues in a homologous region from nonhomologous flanking residues). We test on benchmarks of both global homologies (full length sequence homologs) and local homologies (homologous subsequences embedded in nonhomologous sequence). CONCLUSIONS: Contrary to our expectations, we find that for global homologies a single long branch parameterization suffices both for distant and close homologous relationships. In contrast, we do see an advantage in using explicit evolutionary models for local homologies. Optimal branch parameterization reduces a known artifact called "homologous overextension", in which local alignments erroneously extend through flanking nonhomologous residues. PMID- 26652062 TI - Kinetic and Structural Aspects of the Permeabilization of Biological and Model Membranes by Lichenysin. AB - The various lichenysins produced by Bacillus licheniformis are anionic surfactants with interesting properties. Here it is shown that lichenysin caused hemolysis of human erythrocytes, which varied with lichenysin concentration in a sigmoidal manner. The release of K(+) from red blood cells induced by lichenysin preceded the leakage of hemoglobin, and in addition, hemolysis could be impeded by the presence of compounds in the external medium having a size larger than that of PEG 3350, indicating a colloid-osmotic mechanism for hemolysis. Lichenysin also caused permeabilization of model phospholipid membranes, which was a slow process with an initial lag period of 10-20 s observed for all lichenysin concentrations. A high cholesterol ratio in the membrane decreased the extent of leakage as compared to that of pure POPC, whereas at lower ratios the effect of cholesterol was the opposite, enhancing the extent of leakage. POPE was found to decrease the extent of leakage at all the concentrations assayed, and inclusion of DPPC resulted in a considerable increase in CF leakage extent. From this scenario it was concluded that lipid membrane composition plays a role in the target membrane selectivity of lichenysin. Molecular dynamics simulations indicated that lichenysin is well distributed along the bilayer, and Na(+) ions can penetrate inside the bilayer through the lichenysin molecules. The presence of lichenysin in the membrane increases the permeability of the membrane to hydrophilic molecules facilitating its flux across the lipid palisade. The results presented in this work contribute to understanding the molecular mechanisms that explain the biological actions of lichenysin related to biomembranes. PMID- 26652063 TI - Knowledge, attitudes and practices of occupational risks in Colombian taxi drivers. AB - OBJECTIVE: The objective of this study was to learn about the health and safety strategies in a sample of taxi drivers in Bucaramanga, Colombia. METHODS: A cross sectional study was conducted among 138 taxi drivers. A survey was used to identify the socio-demographic and working characteristics, knowledge, attitudes and practices according to their occupational risk. RESULTS: Eighty-five percent of the workers labored 9-15 h/day. Of those who suffered accidents, 27% were not affiliated to an occupational risk administrator (p = 0.028). Of the workers who had a work-related accident, 58% considered that the use of a cell phone while driving would not always reduce their attention, 50% always used their seat belt and 7% took active breaks and wore their seat belt (p = 0.01). CONCLUSIONS: Within this group of taxi drivers, having or believing to possess knowledge regarding an occupational risk did not ensure that they had a safe attitude or safe working practices. PMID- 26652064 TI - Specific Inhibition of MicroRNA Processing Using L-RNA Aptamers. AB - In vitro selection was used to obtain l-RNA aptamers that bind the distal stem loop of various precursor microRNAs (pre-miRs). These l-aptamers, termed "aptamiRs", bind their corresponding pre-miR target through highly specific tertiary interactions rather than Watson-Crick pairing. Formation of a pre-miR aptamiR complex inhibits Dicer-mediated processing of the pre-miR, which is required to form the mature functional microRNA. One of the aptamiRs, which was selected to bind oncogenic pre-miR-155, inhibits Dicer processing under simulated physiological conditions, with an IC50 of 87 nM. Given that l-RNAs are intrinsically resistant to nuclease degradation, these results suggest that aptamiRs might be pursued as a new class of miR inhibitors. PMID- 26652065 TI - Femtosecond Measurements Of Size-Dependent Spin Crossover In Fe(II)(pyz)Pt(CN)4 Nanocrystals. AB - We report a femtosecond time-resolved spectroscopic study of size-dependent dynamics in nanocrystals (NCs) of Fe(pyz)Pt(CN)4. We observe that smaller NCs (123 or 78 nm cross section and <25 nm thickness) exhibit signatures of spin crossover (SCO) with time constants of ~5-10 ps whereas larger NCs with 375 nm cross section and 43 nm thickness exhibit a weaker SCO signature accompanied by strong spectral shifting on a ~20 ps time scale. For the small NCs, the fast dynamics appear to result from thermal promotion of residual low-spin states to high-spin states following nonradiative decay, and the size dependence is postulated to arise from differing high-spin vs low-spin fractions in domains residing in strained surface regions. The SCO is less efficient in larger NCs owing to their larger size and hence lower residual LS/HS fractions. Our results suggest that size-dependent dynamics can be controlled by tuning surface energy in NCs with dimensions below ~25 nm for use in energy harvesting, spin switching, and other applications. PMID- 26652066 TI - The Hydroxyalkyl Moiety As a Protecting Group for the Stereospecific Alkylation of Masked Secondary Phosphine-Boranes. AB - The synthesis of functionalized tertiary phosphine-boranes has been developed via a chemodivergent approach from readily accessible (hydroxymethyl) phosphine boranes under mild conditions. O-Alkylation or decarbonylative P-alkylation product could be exclusively obtained. The P-alkylation reaction was found to proceed in moderate to very good yields and very high enantiospecificity (es >95%) using a variety of alkyl halides as electrophiles. The configurational stability of the sodium phosphido-borane intermediate was also investigated and allowed a deeper understanding of the reaction mechanism, furnishing secondary phosphine-boranes in moderate yield and enantiopurity. PMID- 26652067 TI - Circulating cell-free nucleic acids as biomarkers in colorectal cancer screening and diagnosis. AB - Screening methods for the most frequent diagnosed malignant tumor, colorectal cancer (CRC), have limitations. Circulating cell-free DNA (cfDNA) analysis came into focus as a potential screening test for CRC. Detection of epigenetic and genetic alterations of cfDNA as DNA methylation or DNA mutations and related ribonucleic acids may improve cancer detection based on unique, CRC-specific patterns. In this review the authors summarize the CRC-specific nucleic acid biomarkers measured in peripheral blood and their potential as screening markers. Detection of DNA mutation has inadequate sensitivity; however, methylated DNA can be established with higher sensitivity from CRC plasma samples. The ribonucleic acid based miRNA studies represented higher sensitivity for CRC as compared with mRNA studies. Recently, isolation of cfDNA has become automated, highly reproducible and a high throughput method. With automated possible diagnostic tools, a new approach may be available for CRC screening as liquid biopsy. PMID- 26652068 TI - Treatment Options for Juvenile Idiopathic Arthritis (JIA) Associated Uveitis. AB - PURPOSE: To summarize the available published data regarding the treatment of JIA associated chronic uveitis. METHODS: Available peer-reviewed publications regarding the treatments of JIA-associated uveitis were read by multiple authors (RMA, EM, JET, and DH) and the data from these reports were synthesized for this review. RESULTS: Juvenile idiopathic arthritis (JIA)-associated chronic uveitis is a significant cause of ocular morbidity and visual impairment in children, often resulting in more frequent complications and worse visual outcomes than other types of pediatric uveitis. Since not all patients respond to the first medication introduced, it is useful to have a wide range of available treatment modalities to address recalcitrant disease. Treatment options for JIA-associated uveitis have increased substantially over the past decade, particularly with the availability of newer biological agents in addition to established medication classes such as anti-inflammatories (including topical and systemic corticosteroids) and antimetabolites. CONCLUSIONS: Although data are increasing regarding biologic agents, definitive randomized prospective clinical trials would be helpful to determine their optimal dose, frequency, treatment duration, and long-term safety in children. PMID- 26652069 TI - Effect of Instructing Care Program Through Group Discussion on the Quality of Life of the Parents of the Children Afflicted With Leukemia. AB - PURPOSE: Children long-term involvement with cancer may have a negative impact on the quality of life their parents. Design and implementation of training programs for parents whose children have been diagnosed with leukemia, as the primary caregivers of children, will have a special significance and can contribute to better taking care of such children. The main purpose of the present study was to examine the impact of conducting group discussion, as care program training, on the quality of life parents whose children were suffering from leukemia. METHODS: This quasi-experimental before-after intervention study encompassed two groups of parents (in total 41) of leukemia children. To collect data, a demographic questionnaire and the shortened version of SF-36 questionnaire were used to determine the quality of life of parents. Both groups completed the quality of life questionnaires before and two months after the intervention. RESULTS: Comparison of the parents' quality of life mean scores, obtained before and two months after training, showed that promotion in 6 domains of bodily pain, general health, emotional health, role limitation due to emotional problems, social functioning, and vitality were occurred. (P <0.05). CONCLUSIONS: Considering the important role of parents in taking care of children suffering from leukemia, introduction of care program training can be a positive step to help these parents and empower them to manage their children's problems more systematically and will ultimately lead to improved quality of life of parents. PMID- 26652070 TI - The Women'S Perceptions About Unwanted Pregnancy: A Qualitative Study in Iran. AB - BACKGROUND: Unwanted pregnancy has affected different aspects of our life. Researchers point out if a child's birth is unwanted, an increase in maternal issues can be observed. The aim of this study was to describe the women's viewpoints regarding unwanted pregnancy. METHOD: This qualitative study using content analysis was employed in Shiraz University in 2013-2014. 20 women with unwanted pregnancy were chosen using purposeful sampling. Data were gathered through semi-structured interviews and trustworthiness of them was evaluated. RESULTS: Findings of this study, according to the participants' experience, revealed maternal emotions like embarrassment for getting pregnant, mother's own negative affection, concerns about missing family and other children, and terminating the pregnancy through illegal abortion, the husband's disagreement about the termination, blaming themselves for thinking about abortion or illegal abortion, and concern about their guilt feeling. Another finding was family problems like husband's behavior and his negative outlook towards his child and fetus. The next category belonged to anxiety about the future of their child, including economic, social and relational problems, and suppression of the children's logical expectations. The last finding was the lack of maternal emotional support. CONCLUSIONS: Unwanted pregnancy's effects on the mothers and infants' health are considerable. A closer observation by family and health care providers for unwanted pregnancies and its results is recommended; therefore, they should be taken care of as high risk pregnancies, requiring family support. PMID- 26651947 TI - microRNA Function Is Limited to Cytokine Control in the Acute Response to Virus Infection. AB - With the capacity to fine-tune protein expression via sequence-specific interactions, microRNAs (miRNAs) help regulate cell maintenance and differentiation. While some studies have also implicated miRNAs as regulators of the antiviral response, others have found that the RISC complex that facilitates miRNA-mediated silencing is rendered nonfunctional during cellular stress, including virus infection. To determine the global role of miRNAs in the cellular response to virus infection, we generated a vector that rapidly eliminates total cellular miRNA populations in terminally differentiated primary cultures. Loss of miRNAs has a negligible impact on both innate sensing of and immediate response to acute viral infection. In contrast, miRNA depletion specifically enhances cytokine expression, providing a posttranslational mechanism for immune cell activation during cellular stress. This work highlights the physiological role of miRNAs during the antiviral response and suggests their contribution is limited to chronic infections and the acute activation of the adaptive immune response. PMID- 26652071 TI - A Retrospective Study of Causes of Low Vision in Saud Arabia, A Case of Eye World Medical Complex in Riyadh. AB - Vision is the ability of seeing with a definite understanding of features, color and contrast, and to distinguish between objects visually. In the year 1999, the World Health Organization (WHO) and the International Agency for the Prevention of Blindness formulated a worldwide project for the eradication of preventable loss of sight with the subject of "Vision 2020: the Right to Sight". This global program aims to eradicate preventable loss of sight by the year 2020. This study was conducted to determine the main causes of low vision in Saudi Arabia and also to assess their visual improvement after using low vision aids (LVD).The study is a retrospective study and was conducted in low vision clinic at Eye World Medical Complex in Riyadh, Saudi Arabia. The file medical record of 280 patients attending low vision clinics from February 2008 to June 2010 was included. A data sheet was filled which include: age, gender, cause of low vision, unassisted visual acuity for long distances and short distances, low vision devices needed for long distances and short distances that provides best visual acuity. The result shows that the main cause of low vision was Optic atrophy (28.9%). Retinitis pigmentosa was the second cause of low vision, accounting for 73 patients (26%) followed by Diabetic retinopathy and Macular degeneration with 44 patients (15.7%) and 16 patients (5.7%) respectively. Inter family marriage could be one of the main causes of low vision. Public awareness should be embarked on for enlightenment on ocular diseases result in consanguineous marriage. Also, it is an important issue to start establishing low vision clinics in order to improve the situation. PMID- 26652072 TI - Iranian Clinical Nurses' Activities for Self-Directed Learning: A Qualitative Study. AB - BACKGROUND: Clinical nurses need lifelong learning skills for responding to the rapid changes of clinical settings. One of the best strategies for lifelong learning is self-directed learning. The aim of this study was to explore Iranian clinical nurses' activities for self-directed learning. METHODS: In this qualitative study, 23 semi-structured personal interviews were conducted with nineteen clinical nurses working in all four hospitals affiliated to Isfahan Social Security Organization, Isfahan, Iran. Study data were analyzed by using the content analysis approach. The study was conducted from June 2013 to October 2014. FINDINGS: Study participants' activities for self-directed learning fell into two main categories of striving for knowledge acquisition and striving for skill development. The main theme of the study was 'Revising personal performance based on intellectual-experiential activities'. CONCLUSIONS: Study findings suggest that Iranian clinical nurses continually revise their personal performance by performing self-directed intellectual and experiential activities to acquire expertise. The process of acquiring expertise is a linear process which includes two key steps of knowledge acquisition and knowledge development. In order to acquire and advance their knowledge, nurses perform mental learning activities such as sensory perception, self-evaluation, and suspended judgment step-by-step. Moreover, they develop their skills through doing activities like apprenticeship, masterly performance, and self-regulation. The absolute prerequisite to expertise acquisition is that a nurse needs to follow these two steps in a sequential manner. PMID- 26652073 TI - The Effect of Health Promoting Programs on Patient's Life Style After Coronary Artery Bypass Graft-Hospitalized in Shiraz Hospitals. AB - BACKGROUND: Health promotion is an essential strategy for reduction of health disparities. Health promotion includes all activities that encourage optimum physical, spiritual, and mental functions. The aim of this study was to determine the impact of a Health Promotion Program (HPP) on behavior in terms of the dimensions of the Health Promoting Lifestyle Profile (HPLP) in patients after Coronary Artery Bypass Graft (CABG). METHODS & MATERIALS: In this clinical trial study, 80 patients who had undergone CABG surgery (2011-2012) were selected and randomly divided in two groups: Experimental and Control that investigated by (HPLP II). Then the experimental group was educated about diet, walking and stress management. The program process was followed up for three months and after tward whole variables were investigated again. The overall score and the scores for the six dimensions of the HPLP (self actualization, health responsibility, exercise, nutrition, interpersonal support and stress management) were measured in the pre- and post-test periods. Data were manually entered into SPSS version 21(IBM Corp, USA) by one the authors. Statistical analysis was performed using Student's t-test and paired t-test. Mean standard deviation and standard error of the mean (with 95% Confidence Interval) were generated for each item. RESULTS: Results showed that score of stress management (p=.036), diet (p=.002), Spiritual Growth (p=.001) and interrelationship (p=002) increase in experimental group after intervention. Average scores after three months in the control group had no significant changes; except responsibility for health (p<.05). Results of the study revealed that comparison the scores of the experimental group were significantly different from the control group in all lifestyle aspects except for spiritual growth. CONCLUSION: This study showed that HPP on lifestyle and health promotion in patients who suffered from Coronary Heart Disease (CAD) could improve the patient's awareness of healthy behaviors and well-being in the quality of life. PMID- 26652074 TI - Acute Kidney Injury Recognition and Management: A Review of the Literature and Current Evidence. AB - Acute renal failure is defined as a rapid decrease in the glomerular filtration rate, occurring over a period of hours to days and by the inability of the kidney to regulate fluid and electrolyte homeostasis appropriately. AKI is a catastrophic, life-threatening event in critically ill patients. AKI can be divided into pre-renal injury, intrinsic kidney disease (including vascular insults) and obstructive uropathies. The prognosis of AKI is highly dependent on the underlying cause of the injury. Children who have AKI as a component of multisystem failure have a much higher mortality rate than children with intrinsic renal disease. Treatment of AKI is subjected to risk stratification and ongoing damage control measures, such as patients with sepsis, exposure to nephrotoxic agents, ischemia, bloody diarrhea, or volume loss, could be helped by optimizing the fluid administrations, antibiotics possessing least nephrotoxic potential, blood transfusion where hemoglobin is dangerously low, limiting the use of nephrotoxic agents including radio contrast use, while maximize the nutrition. Acute kidney injury remains a complex disorder with an apparent differentiation in pathology between septic and nonseptic forms of the disease. Although more studies are still required, progress in this area has been steady over the last decade with purposeful international collaboration. PMID- 26652075 TI - Psychometric Testing of the Greek Version of the Clinical Learning Environment Teacher (CLES+T). AB - Clinical practice is an important part of nursing education, and robust instruments are required to evaluate the effectiveness of the hospital setting as a learning environment. The study aim is the psychometric test of the Clinical Learning Environment+Teacher (CLES+T) scale-Greek version. 463 students practicing in acute care hospitals participated in the study. The reliability of the instrument was estimated with Cronbach's alpha coefficients. The construct validity was evaluated using exploratory factor analysis (EFA) with Varimax rotation. Convergent validity was examined by measuring the bivariate correlations between the scale/subscales. Content, validity and semantic equivalence were examined through reviews by a panel of experts. The total scale showed high internal consistency (alpha=0.95). EFA was identical to the original scale, had eigen values larger than one and explained a total of 67.4% of the variance. The factor with the highest eigen value and the largest percentage of variance explained was "supervisory relationship", with an original eigenvalue of 13.1 (6.8 after Varimax rotation) and an explanation of around 38% of the variance (or 20% after rotation). Convergent validity was examined by measuring the bivariate correlations between the scale and a question that measured the general satisfaction. The Greek version of the CLES+T is a valid and reliable instrument that can be used to examine students' perceptions of the clinical learning environment. PMID- 26652076 TI - Relationship Between Shift Work and Personality Traits of Nurses and Their Coping Strategies. AB - BACKGROUND & OBJECTIVE: Because of social progress, population growth, industrialization, and the requirements of some jobs, a significant percentage of employees are working in shifts. Shift work is considered a threat to health that could have unfavorable effects on various aspects of human life. This study investigated the relationship between shift work and the personality traits of nurses and their coping strategies in a selection of non-governmental hospitals in Tehran in 2014. METHODS: This applied cross-sectional descriptive research employed the Standard Shift work Index and Eysenck Personality Questionnaire (EPQ) which, after confirmation of its validity and reliability (Cronbach's alpha 0.73), were distributed among 305 nurses from 6 non-governmental hospitals in Tehran selected through cluster random sampling. Data was analyzed in two statistical levels: descriptive and inferential. RESULTS: Results revealed that 43.6% of the nurses participating in the study were introverted and 56.4% were extroverted. There are significant relationships between age and physical health (P=0.008), sex and physical health (P=0.015), educational level and physical health (P=0.014), sex and cognitive, somatic anxiety (P=0.006), age and social family status (P=0.001), marital status and social-family status (P=0.001), having a second job and social-family status (P=0.001), educational level and sleep and fatigue (P=0.002), work experience and coping strategies (P=0.044), and sleep and fatigue and personality traits (P=0.032). CONCLUSION: Complying with the standards of working hours for nurses and avoiding overtime when scheduling, especially for nurses with more work experience, can prevent the severe complications of shift work, enhance health, and ultimately enhance the quality of care. By improving the physical, psychological, and social health of nurses, the quality of patient care can be expected to improve, too. PMID- 26652077 TI - Evaluation of the Persian Transcript of the COPD Assessment Test in the Measurement of COPD Health Status in Iranian COPD Patients. AB - AIM: Chronic obstructive pulmonary disease is a completely irreversible obstructive airway disease. The COPD assessment test (CAT) is one of the standard methods for the clinical assessment of the disease, which is translated into Persian. This study investigated the reliability of the test and its relationship with the severity of the disease. METHODS: In this cross-sectional study, 120 patients filled out the Persian transcript of the test. After two weeks, the patients filled out the CAT test again. Obstruction severity was determined for all the patients using spirometry, and the patients were categorized into four groups according to the Global Initiative for Chronic Obstructive Lung Disease criteria. The relationship between the test scores and the disease severity wan validated. RESULTS: The mean age of the patients was 51.5 years. The Cronbach's alpha coefficient of the Persian transcript of the test was 0.872 in the first time, and 0.885 in the second time. Intragroup reliability, test re-test and intragroup correlations were significant for all the questions (<0.001). The relationship between the test mean score and obstruction severity was significant, and the correlation between disease categorization in accordance with obstruction severity and categorization according to the test score was significant as well. CONCLUSION: The Persian transcript of the assessment test for COPD was reliable and is directly related to the disease severity according to airflow limitation. PMID- 26652078 TI - Correlation Between Mothers' Depression and Developmental Delay in Infants Aged 6 18 Months. AB - BACKGROUND: Regarding the importance of children's developmental status and various factors that delay their development, this study was conducted to examine the correlation between mothers' depression levels and the developmental delay in infants. METHODS: This descriptive study was performed on 1053 mothers and their infants' age 6 to18 month-old in medical centers affiliated with Shahid Beheshti University of Medical Sciences, Iran, in 2014-2015. The participants were selected through multi-stage random sampling. The following instruments were used in this study: A demographic and obstetric specification questionnaire, infant specification questionnaire, the Beck Depression Inventory, and the Ages and Stages Questionnaire to determine the status of the children's development. The data were analyzed using SPSS19 software, Mann-Whitney; independent T-test and logistic-Regression tests were used. RESULTS: The results showed that 491 mothers (46.7%) suffered mild to extremely severe depression. The delay in infant development was 11.8%. The Mann-Whitney test showed a correlation between mothers' depression levels and developmental delay in infants (P=0.001). Moreover, there was a significant correlation between mothers' depression and developmental delays in gross-motor and problem-solving skills (P<0/05). In logistic model age of infants showed significant correlation with developmental delay (P=0.004 OR=1.07), but unwanted pregnancy, gender of infants, type of delivery and socioeconomic status had no correlation with developmental delay. CONCLUSION: Given the correlation between mothers' depression and infant development, it is recommended to screen mothers for depression in order to perform early interventions in developmental delay. PMID- 26652079 TI - Factors Associated With Marital Satisfaction in Infertile Couple: A Comprehensive Literature Review. AB - BACKGROUND: Many factors impact on marital satisfaction. Related factors include demographic factors, assisted reproductive techniques, psychological health, quality of life, psychological, socioeconomic and family support, and sexual function. METHODS: This study is a literature review of research studies conducted on factors associated with marital satisfaction in infertile couples. The current literature review search was undertaken using multiple databases selected from articles pertinent to the study. The selection of subjects was undertaken from1990 through 2015. The methodological quality was analyzed based on a checklist adopted from a systematic review. Quality assessment of full text studies was finally carried out by two reviewers. RESULTS: The initial search yielded a list of 445 papers, and then reviewers studied titles and abstracts. Thereafter, 69 papers were incorporated, and researchers reviewed summaries of all of the searched articles. Finally, the researchers utilized the data gained from 64 full articles so as to compile this review paper. Reviewing the studies conducted on marital satisfaction, they classified related findings into 6 categories: demographic factors, using fertility assisting methods, psychological health, life quality, economic, social, and family support, and sexual function. CONCLUSION: The results of this review article depicted that various factors play role in creating marriage life satisfaction in an infertile couple, so that paying attention to them can play an important role in continuing their treatment. Thus, to identify such factors is considered essential in their treatment protocol highly based on culture. Of the drawbacks of this research is that it has tried at best to employ the studies belonging to diverse countries with different cultures. Also, the number of the papers was considerably limited. PMID- 26652080 TI - The Relationship between Sleep Quality and Social Intimacy, and Academic Burn-Out in Students of Medical Sciences. AB - INTRODUCTION: Academic burnout leads to creation of a series of negative and scattered thoughts, loss of hope and emotional and physical exhaustion in carrying out activities. Two factors that affect academic burnout are sleep quality and social intimacy. This study was conducted in order to investigate the relationship between sleep quality and social intimacy, and academic burn-out in the students of Tabriz University of Medical Sciences. MATERIALS & METHODS: This study was descriptive and correlational. The population of this study consisted of the students in Tabriz University of Medical Sciences and 196 medical students were selected. They completed Berso et al. Academic Burnout Questionnaire, Pittsburgh Sleep Quality Index (PSQI) and Miller Social Intimacy Scale (MSIS). The validity of the questionnaires confirmed by experts' views. Their reliability were obtained as 77%, 64% and 85% for academic burnout, sleep quality and social intimacy questionnaires respectively by calculating the internal consistency (Cronbach's alpha). For data analysis, descriptive statistics and Pearson correlation test, Regression, cluster analysis and t-test were used. RESULTS: The results showed that there was a positive and significant relationship between sleep quality and academic burnout at the level p<0.05 (r=0.38). There was a negative and significant relationship between social intimacy and academic burnout at the level p<0.05 (r= -0.40). Also, the regression results showed that sleep quality and social intimacy were able to predict 37% and 39% of academic burnout respectively. Moreover, the students were divided into two clusters of individuals with high social intimacy and individuals with low social intimacy. No significant difference was found between the two types in terms of the variable of academic burn-out. CONCLUSION: Based on the research results, it can be stated that the variables of sleep quality and social intimacy are the predictor factors of academic burn-out. PMID- 26652081 TI - Does Spousal Support Can Decrease Women's Premenstrual Syndrome Symptoms? AB - Premenstrual syndrome is a syndrome that includes behavioral and physical symptoms occurring in the second half of the menstrual cycle and this syndrome affects millions of women universal. With regard to the importance of spouse participation in promoting reproductive and women's health, the aim of this study was to determine the effect of educational intervention for spouse on women's premenstrual syndrome symptoms. This quasi -experimental study was down with the participation of 100 women of reproductive age with PMS were referred to health centers Falavarjan city in 2015. Women were divided randomly into two groups as intervention and control. Educational intervention about supportive behaviors to control premenstrual symptoms was performed for spouses during the three educational sessions in the intervention group. Data was obtained with self administered questionnaire before and three months after educational intervention and were analyzed by SPSS21 and appropriate statistical tests. Three mounts after the intervention the score of spouse's supportive behaviors was increased significantly compare to before of the educational intervention and the control group. As well as significant decrease was occurred in case of physical and psychological-behavioral symptoms of women in the intervention group compare to before the intervention and control groups (p<0.05). Spouse's supportive behaviors can reduce PMS symptoms in women. As a result, it is recommended that the health care system organize the educational intervention to increase spouse supportive behaviors. PMID- 26652082 TI - Research Performance Measures and the Moderating Role of Faculty Characteristics in Epidemiology. AB - Several numeric measures have been proposed to evaluate the individual researchers' scientific performance. Among these measures, h-index is the most common and well recognized measure of research productivity and impact in scientific communities. However, empirical investigations and recent inspections revealed some shortcomings and limitations of this measure. In order to complement these limitations, several variants have been proposed in which g index and ar-index were among the most discussed measures. The aim of this study was to examine h-index, g-index and ar-index across Iranian epidemiologists to identify the moderating characteristics as well as the distribution of these measures in the field. Using Web of Science Database, a list of Iranian epidemiologists was searched and total number of articles, total citations, and citations per paper, h-index, scientific age, g-index and ar-index were extracted and calculated for any epidemiologist. Descriptive statistics and multivariate linear regression models were used to examine research performance measures of Iranian epidemiologists. According to our findings, research performance measures found to be statistically associated with scientific age and academic ranking of Iranian Epidemiologists. Gender differences were not relevant to research performance across different measures. PMID- 26652084 TI - Health Research and Millennium Development Goals: Identifying the Gap From Public Health Perspective. AB - Assessing the research output within the universities could provide an effective means for tracking the Millennium Development Goals (MDGs) progress. This analytical database study was designed to assess the trend of research theses conducted by the Public Health Department (PHD), Faculty of Medicine, Cairo University during the period 1990 to 2014 as related to the: MDGS, Faculty and department research priority plans and to identify the discrepancies between researchers' priorities versus national and international research priorities. A manual search of the theses was done at the Postgraduate Library using a specially designed checklist to chart adherence of each thesis to: MDGs, Faculty and department research plans (RPs). The theses' profile showed that the highest research output was for addressing the MDGS followed by the PHD and Faculty RPs. Compliance to MDGs 5 and 6 was obvious, whereas; MDGs 2, 3, and 7 were not represented at all after year 2000. No significant difference was found between PH theses addressing the Faculty RPs and those which were not before and after 2010. A significantly lower percent of PH theses was fulfilling the PHD research priorities compared to those which were not after 2010. This study showed a definite decline in research output tackling the MDGS and PHD research priorities, with a non-significant increase in the production of theses addressing the Faculty RPs. The present study is a practical model for policy makers within the universities to develop and implement a reliable monitoring and evaluation system for assessment of research output. PMID- 26652083 TI - Prevalence and Risk Factors of Domestic Violence Against Women by Their Husbands in Iran. AB - OBJECTIVE: Domestic violence against women is a health problem. Research on domestic violence in order to clarify the relationship between the different forms of violence and health outcomes is needed. This study aimed to determine the frequency and risk factors of domestic violence in women. It also assessed the association between risk factors and psychological, physical, and sexual violence against women by their intimate partners. MATERIALS & METHODS: This cross-sectional study was done on married women 16-80 years of age living in jahrom south of Iran between August 2013 and December 2014. This research was implemented through questionnaires including the demographic characteristic. The form of partner violence including emotional abuse, physical violence and sexual violence was assessed with a validated questionnaire. Odds ratios and 95% confidence intervals were calculated to measure the association between violence and factors. RESULTS: The prevalence of physical, sexual and emotional domestic violence was respectively 16.4%, 18.6% and 44.4%.and was associated with Age (p=0.002), Husband's Age (p=0.001), Length of marriage (p=0.002), Woman's low educational level women's education (OR=4.67 95%.CI=1.97-11.07), husband's low education (OR=9.22 95%. CI=0.69-12.16), were the most important risk factors for violence. CONCLUSION: Prevalence of physical, emotional or sexual violence was very high. Men's violence against women in intimate relationships is commonly occurring in Iran. Considering the factors contributing to violence against women, raising the level of education of men and women is one of the ways to prevent violence. PMID- 26652085 TI - Suicide Prevention and Follow-Up Services: A Narrative Review. AB - Previous suicide attempt is the most important predictor of death by suicide. Thus preventive interventions after attempting to suicide is essential to prevent reattempts. This paper attempts to determine whether phone preventive interventions or other vehicles (postal cards, email and case management) are effective in reattempt prevention and health promotion after discharge by providing an overview of studies on suicide reattempts. The research investigated in this review conducted from 1995 to 2014. A total of 26 cases related to the aim of this research were derived from 36 English articles with the aforementioned keywords Research shows that providing comprehensive aids, social support, and follow-up after discharge can significantly prevent suicide reattempts. Several studies showed that follow-up support (phone calls, crisis cards, mails, postal cards.) after discharge can significantly decrease the risk of suicide. More randomized controlled trials (RCT) are required to determine what factors of follow-up are more effective than other methods. PMID- 26652086 TI - Pedestrian Road-Crossing Behaviours: A Protocol for an Explanatory Mixed Methods Study. AB - BACKGROUND: Pedestrian crossing is an important traffic safety concern. The aim of this paper is to report the protocol for a sequential explanatory mixed methods study that set out to determine the pedestrians' traffic behaviors, the associated factors and exploring the perception of young people about the traffic risky behaviors in crossing the road. The ultimate purpose of the study is to design a preventive and cultural based strategy to promote young people's health. METHODS: This is a sequential explanatory mixed methods design. The study has two sequential phases. During the first phase, a population-based cross-sectional survey of a sample of young people will be conducted using the proportional random multistage cluster sampling method, in Tehran, Iran. Data will be collected by a questionnaire including items on socio-demographic information, items on measuring social conformity tendency, and questions on subjective norms, attitudes, and perceived behavioral control based on the Theory of Planned behavior. In the second phase, a qualitative study will be conducted. A purposeful sampling strategy will be used and participants who can help to explain the quantitative findings will be selected. Data collection in qualitative phase will be predominately by individual in-depth interviews. A qualitative content analysis approach will be undertaken to develop a detailed understanding of the traffic risky behaviors among young pedestrians. CONCLUSION: The findings of this explanatory mixed methods study will provide information on traffic risky behaviors in young pedestrians. The findings will be implemented to design a cultural based strategy and intervention programs. PMID- 26652087 TI - An Investigation on the Status of Implementation of Communications and Information Management System (MCI) in Khorasan Razavi Hospitals. AB - BACKGROUND & OBJECTIVES: The aim of this investigation is to determine the mean scores of the possibility of implementing the MCI standards in Khorasan Razavi hospitals, from the perspective of Managers, in order to provide a suitable model for evaluating and promoting the system. METHODS: This was a Research and method (R&D) and Survey Research method, which is of the type of Cross- Sectional, descriptive-analytic Studies conducted in two steps in hospitals of Khorasan Razavi from July to December 2014. This study was approved by the Ethical Committee of Tehran University of Medical Sciences (TUMS) in 2013/6/10. About the nature and purpose of the study was explained to the participants. Were used to apply functional assessment, based on Accreditation Model. In order to collect data, two questionnaires were used, all of which were taken from the standards of MCI. The reliability and validity of the questionnaires were approved by experts.Cronbach's alphas for the questionnaires were obtained to be (0.95, 0.86), respectively. In order to analyze information, statistical analyses, including one way ANOVA, and Independent sample t-test were used. RESULTS: The mean scores of the possibility of implementing the MCI standards in Khorasan Razavi hospitals, were (51.6 and 12.27), respectively. CONCLUSIONS: According to half (43.8%) of managers, the MCI standards are applicable in hospitals of Khorasan Razavi; however, their application requires greater efforts by the hospitals. PMID- 26652088 TI - Study of Effect of Household Parental Smoking on Development of Acute Otitis Media in Children Under 12 Years. AB - BACKGROUND & AIM: High prevalence of acute otitis media (AOM) in children represents a combination of the factors developing eustachian tube dysfunction and higher susceptibility to upper respiratory tract infections in children. This disease is relatively prevalent in Iran and much cost is spent annually to treat it. This study investigated the effect of household parental smoking on development of AOM in children under 12 years. METHODS: In this case-control study all patients under the age of 12 years with AOM referring an ENT clinic in Shahrekord, southwest Iran between April 2014 and August 2014 were enrolled by convenience sampling. This study included two groups. Group 1 (G1) was exposed to parental smoking at home and group 2 (G2) was not. For the patients, a questionnaire of demographic data such as age and gender, the disease symptoms, parents' education level, history of respiratory diseases, allergy, surgery (adenoidectomy, tonsillectomy, and tympanostomy), and household smoking was filled out by a specialist through interview. RESULTS: In this study, 250 children 1-12 years with AOM, 145 in G1 and 105 in G2, were investigated. Clinical symptoms including fever (p=0.001) and hearing loss (p=0.014) were significantly more frequent in the children of G1 than G2, and otalgia, discharge, and tinnitus were similarly frequent in the two groups (p>0.05). Also, eardrum inflammation was more frequent in G1 than G2, with no significant difference (p>0.05). AOM was reported 70.3% in G1, which was higher than 26.7% reported in G2 (p=0.001). Also, asthma, recurrent ear pain, enlargement of the tonsils, and respiratory problems were more frequent in G1 than G2 (p<0.05). CONCLUSIONS: Parental smoking was a risk factor for AOM and respiratory problems and therefore the parents are recommended to avoid smoking near children to reduce the likelihood of AOM development and exacerbation in children. PMID- 26652089 TI - Social Consequences of Infertility on Families in Iran. AB - BACKGROUND & OBJECTIVE: Social reactions to infertility are one of the concerns infertile people. This study aimed to investigate the social consequences of infertility among urban and rural population of Shahroud in northeast of Iran. METHOD: This study is a comparative study that was conducted in 2013. In this study, 1,528 women (511 infertile and 1017 fertile ones) were randomly selected. The 36-item questionnaire included 18 items about women's attitude towards infertility and 18 questions about the consequences of infertility was used. Data were analyzed using chi-square test, one-way analysis of variance and t test. FINDINGS: The prevalence of infertility in rural areas was estimated to be 2.23 percent. 42.2% of the participants were living the city (n= 645) and 57.8 % were living in the village (n= 883). 49.2% of the participants had education below high school diploma (n=751), 31.7% had high school diploma (n=484) and 19.2% had university degrees (n=293). 51.9% of the people referred to the infertility problem among distant relatives, 24.9% referred to infertility among the close relatives and 9% reported the infertility among their family members. The mean score of attitude of the fertile was 56.6+/-7.0 and that of the infertile was 56.8+/- 6.6 and there was no statistically significant difference between the two groups (P>0.05). There was a significant association between fertility status and encouraging divorce, encouraging remarriage and encouraging adoption (P = 0.001). CONCLUSION: Infertility causes a negative attitude toward infertile people. But the interference of others leads to further encouragement of divorce and remarriage among the infertile people. PMID- 26652090 TI - The Relationship Between Maternal Periodontal Status of and Preterm and Low Birth Weight Infants in Iran: A Case Control Study. AB - AIM & BACKGROUND: It has been suggested that periodontitis is associated with systemic alterations such as adverse pregnancy outcomes. However, some conflicting results have been reported. This study was conducted to determine the association between periodontitis and preterm birth (PTB), low birth weight (LBW) to obtain information which is necessary for the planning of preventive programs of periodontal disease for pregnant women in this area. MATERIALS & METHODS: This case-control study was performed on 264 mothers. The index used to determine oral hygiene and periodontal diseases is Community Periodontal Index Treatment Needs (CPITN). RESULTS: The mothers in the sample group with single delivery delivered 8 times low birth weight infants more than the mothers in the control group with single delivery. And also the mothers in the sample group with multiple deliveries; delivered 10 times low birth weight infants and 8 times premature infant more than the mothers in the control group. CONCLUSION: More studies should be carried out in through preventing and treating periodontal diseases, expenses incurred due to preterm labor and low birth weight decrease and the society will witness fewer mental problems suffered by such children as they grow up. So we can emphasize the importance of periodontal care in prenatal health programs. And we may suggest that a special program of periodontal disease prevention for pregnant women is very necessary. PMID- 26652091 TI - Factors Affecting Improved Prenatal Screening: A Narrative Review. AB - BACKGROUND: Prenatal screening deals with the detection of structural and functional abnormalities in the fetus. Health care providers can minimize unintended pregnancy outcomes by providing proper counseling and performing prenatal screening. The purpose of the present review study is to investigate factors affecting improved prenatal screening. METHODS: The present study is a narrative review searching public databases such as Google Scholar and specialized databases such as Pubmed, Magiran, Scientific Information Database, Elsevier, Ovid and Science Direct as well. Using the keywords "prenatal screening", "fetus health" and "prenatal counseling", 70 relevant articles published from 1994 to 2014 were selected. After reviewing the abstracts, the full data from 26 articles were ultimately used for writing the present review study. RESULTS: Three general themes emerged from reviewing the studies: health care providers' skills, clients' characteristics and ethical considerations, which were the main factors affecting improved prenatal screening. CONCLUSION: Prenatal screening can be successful if performed by a trained and experienced expert through techniques suitable for the mother's age. Also simultaneously providing proper counseling and giving a full description of the risks and benefits of the procedures for clients is recommended. PMID- 26652092 TI - Evaluation of Complications of Heart Surgery in Children With Congenital Heart Disease at Dena Hospital of Shiraz. AB - INTRODUCTION: Today, with progress in the field of congenital heart surgery, different complicated actions are done in children. These actions may be associated with several complications, especially open heart surgery in which the cardiopulmonary bypass (CPB) is used. Serious complications can be caused high morbidity and mortality rates. Present study has been performed to determine the incidence of morbidity and mortality in cardiac surgery in children. METHOD: In a cross-sectional retrospective, records of 203 patients undergoing surgery for congenital heart disease in Dena hospital during 2013-2015 were reviewed for incidence of complications. Data was analyzed by using descriptive and analytical statistics and using SPSS version 18. RESULTS: The mean age of samples was 3/65+/ 4/47 years. The majority of samples (73/8%) were undergoing open surgery. The overall adverse cardiovascular complications were respectively, renal complications (44/3%), lung (40/3%), anemia (35/9%), heart (34/4%), gastrointestinal (17/2%), brain (14/2%), need for re-intubation of the trachea 11/3%), infection (7/8%) required reoperation (5/9%) and vascular complications (1/4%). CONCLUSION: High incidence of complications after congenital heart surgery makes necessary attention to complications and their treatment after surgery. It is necessary to apply the measures and careful monitoring of patients to minimize these effects. PMID- 26652093 TI - Frequency of Bacterial Agents Isolated From Patients With Chronic Sinusitis in Northern Iran. AB - BACKGROUND: Sinusitis is a disease with significant health problems. Diagnosis of sinusitis is clinical. The golden standard for detection of microorganisms that cause sinusitis is the culture of sinus drainage discharge. OBJECTIVES: Due to the high prevalence of sinusitis in Iran, especially in Mazandaran province, in this study, bacteriological survey of patients with chronic sinusitis were done in order to help physicians in choosing better antibiotics for the empiric therapy of sinusitis. METHODS: This was a descriptive study. The population of the study consisted of 100 patients with chronic sinusitis caused by bacteria admitted to the Avicenna teaching hospital. Sampling for bacterial culture was performed by the endoscopy method from middle meatus (a curved anteroposterior passage in each nasal cavity that is situated below the middle nasal concha and extends along the entire superior border of the inferior nasal concha) and the opening of the maxillary sinus. Also sampling of nasal cavity was performed to determine the microbial flora. Identification of the bacteria causing chronic sinusitis was performed according to the standard microbiological procedures. Antimicrobial susceptibility testing method, the disk diffusion (Kirby-Bauer) was performed according to the CLSI (Clinical and Laboratory Standards Institute) standards. Data were analyzed using SPSS17 software. Also Fisher exact test and descriptive statistics were used to analyze the data. RESULTS: Among the 100 evaluated patients, 58% were male. The average age was 34.2+/-1.1. The most common complaint of patients were nasal congestion and post-nasal drip. The most common bacteria found in the nasopharynx were Gram-positive bacillus, coagulase negative Staphylococcus and Staphylococcus aureus with rates of 20%, 16% and 15% respectively. Bacteria isolated from opening sinus were Gram-positive bacillus 24%, Enterobacter aerogenes 10%, coagulase negative Staphylococcus 18% and Staphylococcus aureus 19%. CONCLUSIONS: Antibiotic prescription is often empiric in treatment of sinusitis. In our study resistance to some antibiotics such as penicillin subgroups that are used in treatment of chronic sinusitis was high. Due to the fact that the etiology of chronic sinusitis is not clearly understood, the frequency of all the common causative agents of this disease must be determined. PMID- 26652094 TI - Primary Health Care Physicians' Adherence and Attitude Towards Integrated Management of Childhood Illness Guidelines in Alexandria Governorate in Egypt. AB - BACKGROUND: Integrated Management of Childhood Illness (IMCI) is a cost-effective strategy that improves the quality of care provided to under - five children. Alexandria was the first governorate that applied the Integrated Management of Childhood Illness guidelines in Egypt. The aim of this study was to assess the degree of primary health care physicians' adherence and attitude towards those guidelines after 17 years of application. METHODS: This cross-sectional study was carried out on a representative sample from the primary health care facilities in Alexandria from which physicians using IMCI guidelines were included in the study. The sample units were chosen randomly from all districts of Alexandria. Observational checklists were developed to assess the degree of adherence of physicians based on the guidelines booklet. RESULTS: The highest adherence score reported was that of writing disease classification (100%). As regards infants aged up to 2 months, the highest physicians' adherence score reported was that of jaundice and possible bacterial infection assessment (100 % and 95% respectively). And in spite of its importance, only 85.7% of physicians were complied with weight assessment and its plotting in the growth curve. For children aged from 2 months up to 5 years physicians were generally well complied with the guidelines especially for assessment of dangerous signs and possible bacterial infection. CONCLUSION: Despite being applied for years, IMCI guidelines still show certain areas of poor adherence, an issue that need further investigation in order to maximize physicians' adherence and achieve the best of their performance. PMID- 26652095 TI - Change in Medication Adherence and Beliefs in Medicines Over Time in Older Adults. AB - OBJECTIVE: The temporal component of medication adherence is important while designing interventions to improve medication adherence. Thus, the objective of this study was to determine how medication adherence and beliefs in medicines change over time in older adults. METHODS: A two-year longitudinal internet-based survey among adults 65+ years was used to collect data on medication adherence (Morisky 4-item scale) and beliefs in medicines (Beliefs about Medicines Questionnaire). Paired t-test and one-way ANOVA determined if a change in beliefs in medicines and medication adherence over time was significant. A multiple linear regression was used to determine the significant predictors of change in medication adherence over time. RESULTS: 436 respondents answered both baseline and follow-up surveys. Among all respondents, there was no significant change in adherence (0.58 +/- 0.84 vs. 0.59 +/- 0.84; p > 0.05), necessity beliefs (17.13 +/- 4.31 vs. 17.10 +/- 4.29; p > 0.05), or concern beliefs (11.70 +/- 3.73 vs. 11.68 +/- 3.77; p > 0.05) over time. For older adults with lower baseline adherence, there was a statistically significant improvement in adherence (1.45 +/- 0.70 vs. 0.99 +/- 0.97; p < 0.05); but no change in beliefs in medicines over time. The significant predictors of change in medication adherence over time were baseline adherence and baseline concern beliefs in medicines. CONCLUSION: With baseline adherence and baseline concern beliefs in medicines playing a significant role in determining change in adherence behavior over time, especially in individuals with lower adherence, it is important to alleviate medication concerns at the beginning of therapy for better adherence. PMID- 26652096 TI - External Criticism by Parents and Obsessive Beliefs in Adolescents: Mediating Role of Beliefs associated with Inflated Responsibility. AB - BACKGROUND & OBJECTIVES: Obsessive-compulsive disorder (OCD) is considered as a rare disorder in children. According to cognitive theories, criticism triggers responsibility behavior and thus causes obsessive behaviors. The purpose of the present study was to investigate the mediating role of beliefs associated with responsibility in the relationship between external criticism of parents and obsessive beliefs in adolescents. MATERIALS & METHODS: In this study, 547 high school students aged from 15 to18 years were selected using multi-stage cluster random sampling from four regions of the education office in Shiraz. Obsessive Beliefs Questionnaire-child version (OBQ-CV), Pathway to Inflated Responsibility beliefs Scale (PIRBS), and perceived criticism questionnaire were used to collect data. Pearson's correlation was used to investigate the relationship between the study variables. For analysis of mediation model, multiple mediators analysis using Macro Software was used. RESULTS: External criticism only indirectly and through beliefs associated with inflated responsibility accounts for 6% of the variance of responsibility, 14% of the variance of threat estimation and 10% of the variance of perfectionism of obsessive beliefs (P<0.05). However, external criticism, both directly and indirectly and through beliefs associated with inflated responsibility accounts for 7% of the variance of the importance of obsessive beliefs. CONCLUSION: This study showed that the beliefs associated with inflated responsibility can mediate the relationship between external criticism and obsessive beliefs. According to the cognitive model of Salkovskis, criticism by parents, as a violation to and an influence on children, by affecting the subscales of inflated responsibility, can increase the symptoms of obsessive compulsive disorder. In order to identify potential affecting mechanisms of criticism on obsessive-compulsive disorder, further experimental research is required. PMID- 26652097 TI - Investigation Into Shelf Life of Fresh Dates and Pistachios in a Package Modified With Nano-Silver. AB - AIMS: The aim of this study was to apply polymer films containing silver nanoparticles as a new method for increasing the shelf life and preserving the quality of export/commercial products of Kerman Province and determine the ideal temperature for preserving these products. METHODS: After preparing nano composite films containing silver nanoparticles (3% and 5% by weight), Mazafati dates were packed in them and stored with their control samples under four temperatures. In the second series, the films were filled with fresh pistachios and stored at four temperatures. In date samples, after 2, 7, 21 and 53 days of storing the samples were examined under the certified test of Iran Institute of Industrial Standard for Dates, which includes pH, TSS, acidity and reducing sugars tests. In pistachio samples the color values and market-friendly quality were evaluated after 1, 2, 3, 6, 7 and 8 days of storage. RESULTS: In date samples, the pH value decreased with increasing acidity in 3 and 5 wt% of nano silver and their control samples. In addition, in 5 wt% samples the acidity was higher than that in 3% samples, with pH being lower in the controls at almost all the intervals. Furthermore, pH values in 5% samples were higher in comparison with 3 wt% samples and controls. The amount of reducing sugars in the control samples was lower than those in 3 and 5 wt% samples. In relation to pistachio samples, the damage over time was greater in sample stored under higher temperatures. CONCLUSION: The maximum shelf life of the dates packaged in 5 wt% of silver nano-powder was 53 days and the best temperature to store samples was determined at 4 degrees C. Packages containing nano-silver increased shelf life of fresh pistachios, with the best temperatures being 25 degrees C and 0 degrees C. PMID- 26652098 TI - The Comparison of Chlorhexidine Solution and Swab With Toothbrush and Toothpaste Effect on Preventing Oral Lesions in Hospitalized Patients in Intensive Care Unit. AB - BACKGROUND: Maintaining of oral hygiene has been known as one of the basic tasks of nurses working at intensive care unit. This study aimed to compare the effectiveness of chlorhexidine solution with toothbrush in prevention of oral lesions or ulcers in the different parts of the mouth. METHODS: In this clinical trial study, research Society included patients hospitalized with endotracheal tube since the arrival time in intensive care unit. In this study, 30 patients were selected with target-based approach and equally divided into two groups through the permutation blocking method for oral care toothbrush and toothpaste and using chlorhexidine and swab. The modified form of Beck Oral Assessment Scale (BOAS) and MPS were used to obtain needed information. Data were analyzed by means of R software (version 3.0.2) and also multiple logistic regressions in the confidence level of 95%. RESULTS: This study indicated an association between using toothbrush and the oral health level (OR: 1.52). In different parts of the mouth, there was no difference between two groups in prevention of lesions in gums, lips and tongue while, this was significant in relation to plaque, mucus and teeth with an odd ratio of 3.94 for teeth and 2.75 for mucus . In comparison, there was an association between implying chlorhexidine and saliva health level. (OR: 2.046). CONCLUSION: This survey showed that using toothbrush has a noticeable impact on declining oral lesions in varied parts of the mouth. PMID- 26652099 TI - Workspace design for crane cabins applying a combined traditional approach and the Taguchi method for design of experiments. AB - Procedures in the development process of crane cabins are arbitrary and subjective. Since approximately 42% of incidents in the construction industry are linked to them, there is a need to collect fresh anthropometric data and provide additional recommendations for design. In this paper, dimensioning of the crane cabin interior space was carried out using a sample of 64 crane operators' anthropometric measurements, in the Republic of Serbia, by measuring workspace with 10 parameters using nine measured anthropometric data from each crane operator. This paper applies experiments run via full factorial designs using a combined traditional and Taguchi approach. The experiments indicated which design parameters are influenced by which anthropometric measurements and to what degree. The results are expected to be of use for crane cabin designers and should assist them to design a cabin that may lead to less strenuous sitting postures and fatigue for operators, thus improving safety and accident prevention. PMID- 26652100 TI - From low- to high-throughput analysis. AB - The high throughput is routinely used for the first steps of drug development such as drug discovery screening and toxicity. However, for PK analysis of regulated studies, the requirements and difficulties to achieve high-throughput analysis are more demanding due to regulatory guidelines that are not needed for early steps of drug discovery. High-throughput analysis can be required for any drug type from small molecules to larger ones. Contract research organizations must be prepared to deliver the results associated to these studies in a fast turnaround. Herein, we will describe the challenges encountered by a laboratory in order to go from low- to high-throughput analysis. PMID- 26652101 TI - Structural Insights into the Competitive Binding of Diclofenac and Naproxen by Equine Serum Albumin. AB - The binding modes to equine serum albumin (ESA) of two nonsteroidal anti inflammatory drugs (NSAIDs), diclofenac (Dic) and naproxen (Nps), were studied by X-ray crystallography and isothermal titration calorimetry. On the basis of the crystal structure of ESA/Dic determined to a resolution of 1.92 A and the structure of the previously described ESA/Nps complex (2.42 A), it was found that both NSAIDs bind within drug site 2 (DS2) of ESA and both occupy secondary binding sites in separate cavities of domain II (Nps) and domain III (Dic). The two structures of the ternary complex ESA/Dic/Nps, obtained by competitive cocrystallization (2.19 A) and through a displacement experiment (2.35 A), were determined to investigate possible competition of these widely used pharmaceutical drugs in binding to ESA. In these complexes Nps occupies the DS2 pocket common for both drugs, whereas the other distinct binding sites of Dic and Nps remain unaffected. These results suggest that combined application of both drugs may result in increased concentration of free diclofenac in plasma. PMID- 26652102 TI - Novelty-Driven Cooperative Coevolution. AB - Cooperative coevolutionary algorithms (CCEAs) rely on multiple coevolving populations for the evolution of solutions composed of coadapted components. CCEAs enable, for instance, the evolution of cooperative multiagent systems composed of heterogeneous agents, where each agent is modelled as a component of the solution. Previous works have, however, shown that CCEAs are biased toward stability: the evolutionary process tends to converge prematurely to stable states instead of (near-)optimal solutions. In this study, we show how novelty search can be used to avoid the counterproductive attraction to stable states in coevolution. Novelty search is an evolutionary technique that drives evolution toward behavioural novelty and diversity rather than exclusively pursuing a static objective. We evaluate three novelty-based approaches that rely on, respectively (1) the novelty of the team as a whole, (2) the novelty of the agents' individual behaviour, and (3) the combination of the two. We compare the proposed approaches with traditional fitness-driven cooperative coevolution in three simulated multirobot tasks. Our results show that team-level novelty scoring is the most effective approach, significantly outperforming fitness driven coevolution at multiple levels. Novelty-driven cooperative coevolution can substantially increase the potential of CCEAs while maintaining a computational complexity that scales well with the number of populations. PMID- 26652110 TI - Use of quantitative pharmacology tools to improve malaria treatments. AB - The use of pharmacokinetic (PK) and pharmacodynamic (PD) data to inform antimalarial treatment regimens has accelerated in the past few decades, due in no small part to the stimulus provided by progressive development of parasite resistance to most of the currently available drugs. An understanding of the disposition, interactions, efficacy and toxicity of the mainstay of contemporary antimalarial treatment, artemisinin combination therapy (ACT), has been facilitated by PK/PD studies which have been used to refine treatment regimens across the spectrum of disease, especially in special groups including young children and pregnant women. The present review highlights recent clinically important examples of the ways in which these quantitative pharmacology tools have been applied to improve ACT, as well as 8-aminoquinoline use and the characterisation of novel antimalarial therapies such as the spiroindolones. PMID- 26652111 TI - Thalassemia and acute coronary syndromes. PMID- 26652112 TI - Serial electrophysiological studies in a Guillain-Barre subtype with bilateral facial neuropathy. AB - OBJECTIVE: Bifacial weakness with paraesthesias subtype of Guillain-Barre syndrome (GBS) is thought to be demyelinating in nature but the evolution of serial nerve conduction study (NCS) findings has not been studied. We retrospectively analyzed the changes on serial NCS of patients with bilateral facial neuropathy. METHODS: We described the clinical features, serial blink reflex, facial nerve and limb NCS of such patients. RESULTS: Five patients fulfilled our study criteria. Patients 1 and 2 were diagnosed clinically to have bilateral Bell's palsy, patients 3 and 4 as bifacial GBS subtype and patient 5 as facial palsy associated with acute HIV infection. In all, the initial neurophysiological tests showed absent blink response and normal facial NCS. Patient 1's repeat tests were normal. Patient 2's repeat blink reflex showed mildly prolonged latency. Repeat blink reflex latency of patients 3, 4 and 5 were in the demyelinating range. Patient 3 also had prolonged facial nerve latency. Patients 3 and 4 had serial limb NCS showing progressively prolonged latency. CONCLUSION: Serial NCS suggests that the bifacial GBS subtype is demyelinating in nature. SIGNIFICANCE: This study provides further evidence for a bifacial subtype of GBS with a demyelinating pathophysiology. PMID- 26652113 TI - Rhythmic and periodic EEG patterns of 'ictal-interictal uncertainty': Red flag to switch from routine to continuous EEG monitoring. PMID- 26652114 TI - Adult onset ictal aphasia with epileptic discharges in Broca's and Wernicke's areas. PMID- 26652116 TI - Scenedesmus quadricauda for Nutrient Removal and Lipid Production in Wastewater. AB - Scenedesmus quadricauda, a local freshwater microalga, was used to treat primary settled and filtrate wastewater and to produce algal lipid. For the primary settled wastewater, the maximum biomass concentrations of acclimated and unacclimated microalgae were 0.995 g/L and 0.940 g/L, respectively. Over 90% orthophosphate and 95% ammonia nitrogen in the acclimated and unacclimated cultures, respectively, were removed after five days. The lipid contents of the microalgae were higher than 13% in all cultures. The highest growth rate occurred in the 25% filtrate culture. Over 80% phosphate was removed under the 25% and 50% filtrate cultures within six days, while over 90% ammonia nitrogen was removed within five days under both conditions. The lipid content was the highest (18.1%) under the 50% filtrate condition. C16:0, C18:2n6, and C18:3n3 were dominant fatty acids. In conclusion, S. quadricauda is a viable candidate for wastewater treatment and lipid production. PMID- 26652117 TI - Improvement of the Performance of an Electrocoagulation Process System Using Fuzzy Control of pH. AB - The removal efficiencies of electrocoagulation (EC) systems are highly dependent on the initial value of pH. If an EC system has an acidic influent, the pH of the effluent increases during the treatment process; conversely, if such a system has an alkaline influent, the pH of the effluent decreases during the treatment process. Thus, changes in the pH of the wastewater affect the efficiency of the EC process. In this study, we investigated the dynamic effects of pH. To evaluate approaches for preventing increases in the pH of the system, the MATLAB/Simulink program was used to develop and evaluate an on-line computer-based system for pH control. The aim of this work was to study Proportional-Integral-Derivative (PID) control and fuzzy control of the pH of a real textile wastewater purification process using EC. The performances and dynamic behaviors of these two control systems were evaluated based on determinations of COD, colour, and turbidity removal efficiencies. PMID- 26652118 TI - Demonstrating Compliance with Stringent Nitrogen Limits Using a Biological Nutrient Removal Process in California's Central Valley. AB - The Sacramento Regional County Sanitation District (District) must be compliant with stringent nitrogen limits by 2021 that the existing treatment facilities cannot meet. An 11-month pilot study was conducted to confirm that these limits could be met with an air activated sludge biological nutrient removal (BNR) process. The pilot BNR treated an average flow of 946 m(3)/d and demonstrated that it could reliably meet the ammonia limit, but that external carbon addition may be necessary to satisfy the nitrate limit. The BNR process performed well throughout the 11 months of operation with good settleability, minimal nocardioform content, and high quality secondary effluent. The BNR process was operated at a minimum pH of 6.4 with no noticeable impact to nitrification rates. Increased secondary sludge production was observed during rainfall events and is attributed to a change in wastewater influent characteristics. PMID- 26652119 TI - Effect of Copper and Other Trace Metal Addition to Pulp and Paper Wastewater. AB - Porous pots were used to mimic, on a laboratory scale, an industrial activated sludge plant from a thermomechanical pulp and news print paper mill. Trace metal additions of Ca, Co, Cu, Fe(III), and Mg were found to improve chemical oxygen demand removal from 82% to 86 to 87%. Copper (0.1 to 1.0 mg/L) was also found to be beneficial in significantly inhibiting the growth of filamentous bacteria, contributing to a reduction of 20 to 45% in sludge volume index (SVI) with improved settle ability and decreased bulking. However, at levels of 1.0 mg/L and higher, the concentration of Cu in the porous pot effluent would potentially exceed guidelines for receiving waters. The fate and impact of Cu was affected by the presence of other trace metals, in particular Mg and Ca. The addition of Mg or Ca along with 0.5 mg/L Cu increased the amount of Cu in the aqueous phase to levels that would potentially exceed government environmental guidelines. Calcium addition was also found to inhibit the effect of Cu in reducing filamentous bacteria and SVI. PMID- 26652120 TI - Expanding DEMON Sidestream Deammonification Technology Towards Mainstream Application. AB - A cross-Atlantic R&D-cooperation involving three large utilities investigated the feasibility of mainstream deammonification-the application of partial nitritation/anammox for full-plant treatment of municipal wastewater at ambient temperatures. Two major process components have been implemented, 1) bioaugmentation of aerobic- and anaerobic ammonia oxidizers (AOB and AMX) from the DEMON-sidestream sludge liquor treatment to the mainstream and 2) implementation of hydrocyclones to select for anammox granules and retain them in the system. Different operation modes have been tested at laboratory- and pilot scale in order to promote the short-cut (more direct anammox route) in nitrogen removal metabolism. At the full-scale installation at Strass WWTP, stable repression of nitrite oxidizing biomass (NOB) has been achieved for several months. Significant anammox enrichment in the mainstream has been monitored while high efficiency in the sidestream-process has been maintained (96% annual average ammonia removal). PMID- 26652121 TI - High-Rate Anaerobic Side-Stream Reactor (ASSR) Processes to Minimize the Production of Excess Sludge. AB - High-rate anaerobic side-stream reactor (ASSR) processes were developed to minimize excess sludge production during wastewater treatment. New ASSRs were operated in 2.5-day solids retention time (SRT), much shorter than 10-day SRT used by the commercial sludge reduction process. The 2.5-day was selected based on literature review and preliminary studies, showing that maximum solublization of key floc components, such as divalent cations, extracellular polymeric substances (EPS), and protease, occur within 2 to 3 days of anaerobic digestion. The laboratory reactor study showed that 2.5-day ASSR systems produced approximately 60 and 20% less sludge than the control (no ASSR) and the 10-day ASSR, respectively. The experimental systems showed acceptable effluent quality, despite minimal sludge wastage. This was possible because sludge EPS were continuously released/degraded and regenerated as sludge underwent recirculation between ASSR and the aerobic basin. The results supported that the activated sludge process incorporating small ASSRs significantly decrease the production of excess sludge during wastewater treatment. PMID- 26652115 TI - A technical guide to tDCS, and related non-invasive brain stimulation tools. AB - Transcranial electrical stimulation (tES), including transcranial direct and alternating current stimulation (tDCS, tACS) are non-invasive brain stimulation techniques increasingly used for modulation of central nervous system excitability in humans. Here we address methodological issues required for tES application. This review covers technical aspects of tES, as well as applications like exploration of brain physiology, modelling approaches, tES in cognitive neurosciences, and interventional approaches. It aims to help the reader to appropriately design and conduct studies involving these brain stimulation techniques, understand limitations and avoid shortcomings, which might hamper the scientific rigor and potential applications in the clinical domain. PMID- 26652122 TI - Biochar from Pyrolysis of Biosolids for Nutrient Adsorption and Turfgrass Cultivation. AB - At water resource recovery facilities, nutrient removal is often required and energy recovery is an ever-increasing goal. Pyrolysis may be a sustainable process for handling wastewater biosolids because energy can be recovered in the py-gas and py-oil. Additionally, the biochar produced has value as a soil conditioner. The objective of this work was to determine if biochar could be used to adsorb ammonia from biosolids filtrate and subsequently be applied as a soil conditioner to improve grass growth. The maximum carrying capacity of base modified biochar for NH3-N was 5.3 mg/g. Biochar containing adsorbed ammonium and potassium was applied to laboratory planters simulating golf course putting greens to cultivate Kentucky bluegrass. Planters that contained nutrient-laden biochar proliferated at a statistically higher rate than planters that contained biosolids, unmodified biochar, peat, or no additive. Nutrient-laden biochar performed as well as commercial inorganic fertilizer with no statistical difference in growth rates. Biochar from digested biosolids successfully immobilized NH3-N from wastewater and served as a beneficial soil amendment. This process offers a means to recover and recycle nutrients from water resource recovery facilities. PMID- 26652123 TI - Source Separation of Urine as an Alternative Solution to Nutrient Management in Biological Nutrient Removal Treatment Plants. AB - Municipal wastewater contains a mixture of brown (feces and toilet paper), yellow (urine), and gray (kitchen, bathroom and wash) waters. Urine contributes approximately 70-80% of the nitrogen (N), 50-70% of the phosphorus (P) load and 60-70% of the pharmaceutical residues in normal domestic sewage. This study evaluated the impact of different levels of source separation of urine on an existing biological nutrient removal (BNR) process. A process model of an existing biological nutrient removal (BNR) plant was used. Increasing the amount of urine diverted from the water reclamation facilities, has little impact on effluent ammonia (NH3-N) concentration, but effluent nitrate (NO3-N) concentration decreases. If nitrification is necessary then no reduction in the sludge age can be realized. However, a point is reached where the remaining influent nitrogen load matches the nitrogen requirements for biomass growth, and no residual nitrogen needs to be nitrified. That allows a significant reduction in sludge age, implying reduced process volume requirements. In situations where nitrification is required, lower effluent nitrate (NO3-N) concentrations were realized due to both the lower influent nitrogen content in the wastewater and a more favorable nitrogen-to-carbon ratio for denitrification. The external carbon requirement for denitrification decreases as the urine separation efficiency increases due to the lower influent nitrogen content in the wastewater and a more favorable nitrogen-to-carbon ratio for denitrification. The effluent phosphorus concentration decreases when the amount of urine sent to water reclamation facilities is decreased due to lower influent phosphorus concentrations. In the case of chemical phosphate removal, urine separation reduces the amount of chemicals required. PMID- 26652125 TI - Development of a simulation evaluation tool for assessing nursing students' clinical judgment in caring for children with dehydration. AB - BACKGROUND: The lack of reliable and valid tools to evaluate learning outcomes during simulations has limited the adoption and progress of simulation-based nursing education. PURPOSES: This study had two aims: (a) to develop a simulation evaluation tool (SET(c-dehydration)) to assess students' clinical judgment in caring for children with dehydration based on the Lasater Clinical Judgment Rubric (LCJR) and (b) to examine its reliability and validity. PARTICIPANTS: Undergraduate nursing students from two nursing schools in South Korea participated in this study from March 3 through June 10, 2014. METHODS: The SET(c dehydration) was developed, and 120 nursing students' clinical judgment was evaluated. Descriptive statistics, Cronbach's alpha, Cohen's kappa coefficient, and confirmatory factor analysis (CFA) were used to analyze the data. RESULTS: A 41-item version of the SET(c-dehydration) with three subscales was developed. Cohen's kappa (measuring inter-observer reliability) of the sessions ranged from .73 to .95, and Cronbach's alpha was .87. The mean total rating of the SET(c dehydration) by the instructors was 1.92 (+/-.25), and the mean scores for the four LCJR dimensions of clinical judgment were as follows: noticing (1.74+/-.27), interpreting (1.85+/-.43), responding (2.17+/-.32), and reflecting (1.79+/-.35). CFA, which was performed to test construct validity, showed that the four dimensions of the SET(c-dehydration) was an appropriate framework. CONCLUSION: The SET(c-dehydration) provides a means to evaluate clinical judgment in simulation education. Its reliability and validity should be examined further. PMID- 26652124 TI - Novel "bi-modal" H2dedpa derivatives for radio- and fluorescence imaging. AB - A novel pyridyl functionalized analog of the promising hexadentate 68Ga3+ chelate H2dedpa (N4O2, 1,2-[[6-carboxy-pyridin-2-yl]-methylamine]ethane) was successfully synthesized and characterized. This new bifunctional chelate (BFC) was used to prepare the first proof-of-principle bi-modal H2dedpa derivative for fluorescence and nuclear imaging. Two bi-modal H2dedpa derivatives were prepared: H2dedpa propylpyr-FITC and H2dedpa-propylpyr-FITC-(N,N'-propyl-2-NI) (FITC=fluorescein, pyr=pyridyl functionalized, NI=nitroimidazole). The ligands possess the strong gallium-coordinating atoms contained within dedpa2- that are ideal for radiolabeling with 68Ga3+ for positron-emission tomography (PET) imaging, and two fluorophores for optical imaging. In addition, one analog contains two NI moieties for specific entrapment of the tracer in hypoxic cells. These new bi modal analogs were compared to the native unfunctionalized H2dedpa scaffold to determine the extent to which the addition of pyridyl functionalization would affect metal coordination, and complex stability. The non-radioactive gallium complexes were tested in a 3D tumor spheroid model. The novel pyridyl bis functionalized H2dedpa ligand, H2dedpa-propylpyr-NH2, was quantitatively radiolabeled with 67Ga (RCY>99%) under reaction conditions commensurate with unfunctionalized H2dedpa (10min at room temperature) at ligand concentrations as low as 10-5M. The resultant 67Ga-complex withstood transchelation to the in vivo metal-binding competitor apo-transferrin (2h at 37 degrees C, 93% intact), signifying that [Ga(dedpa-propylpyr-NH2)]+ is a kinetically inert complex suitable for in vivo use, but exhibited slightly reduced stability compared to the native [67Ga(dedpa)] scaffold (>99% intact). Finally, bi-model fluorescent Ga dedpa compounds were successfully imaged in a 3D tumor spheroid model. The Ga dedpa-FITC-NI derivative was specifically localized in the central hypoxic core of the spheroid. PMID- 26652126 TI - Resident Physicians Choices of Anticoagulation for Stroke Prevention in Patients With Nonvalvular Atrial Fibrillation. AB - Atrial fibrillation (AF) is a common cardiac arrhythmia and is associated with an increased risk of ischemic stroke. The aim of this study was to identify practice patterns of Canadian resident physicians pertaining to stroke prevention in nonvalvular AF according to the Canadian Cardiovascular Society guidelines. A Web based survey consisting of 16 multiple-choice questions was distributed to 11 academic centres. Questions involved identification of risks of stroke, bleeding, and selection of appropriate therapy in clinical scenarios that involve a patient with AF with a Congestive Heart Failure, Hypertension, Age, Diabetes, Stroke/Transient Ischemic Attack (CHADS2) score of 3 and no absolute contraindications to anticoagulation. There were 1014 total respondents, of whom 570 were internal, 247 family, 137 emergency medicine, and 60 adult cardiology residents. For a patient with a new diagnosis of AF, warfarin was chosen by 80.3%, novel oral anticoagulants (NOACs) by 60.3%, and acetylsalicylic acid (ASA) by 7.2% of residents. To a patient with a history of gastrointestinal bleed during ASA treatment, warfarin was recommended by 75.1%, NOACs by 36.1%, ASA by 12.1%, and 4% were unsure. For a patient with a history of an intracranial bleed, warfarin was recommended by 38.8%, NOACs by 23%, ASA by 24.8%, and 18.2% were unsure. For a patient taking warfarin who had a labile international normalized ratio, 89% would switch to a NOAC and 29.5% would continue warfarin. This study revealed that, across a wide sampling of disciplines and centres, resident physician choices of anticoagulation in nonvalvular AF differ significantly from contemporary Canadian Cardiovascular Society guidelines. PMID- 26652127 TI - A technique to measure fuel oil viscosity in a fuel power plant. AB - The viscosity measurement and control of fuel oil in power plants is very important for a proper combustion. However, the conventional viscometers are only reliable for a short period of time. This paper proposes an on-line analytic viscosity evaluation based on energy balance applied to a piece of tube entering the fuel oil main heater and a new control strategy for temperature control. This analytic evaluation utilizes a set of temperature versus viscosity graphs were defined during years of analysis of fuel oil in Mexican power plants. Also the temperature set-point for the fuel oil main heater output is obtained by interpolating in the corresponding graph. Validation tests of the proposed analytic equations were carried out in the Tuxpan power plant in Veracruz, Mexico. PMID- 26652128 TI - Optimal fractional order PID design via Tabu Search based algorithm. AB - This paper presents an optimization method based on the Tabu Search Algorithm (TSA) to design a Fractional-Order Proportional-Integral-Derivative (FOPID) controller. All parameter computations of the FOPID employ random initial conditions, using the proposed optimization method. Illustrative examples demonstrate the performance of the proposed FOPID controller design method. PMID- 26652129 TI - Possible mechanisms of Pseudomonas aeruginosa-associated lung disease. AB - Pseudomonas aeruginosa is an opportunistic bacterium causing lung injury in immunocompromised patients correlated with high morbidity and mortality. Many bacteria, including P. aeruginosa, use extracellular signals to synchronize group behaviors, a process known as quorum sensing (QS). In the P. aeruginosa complex QS system controls expression of over 300 genes, including many involved in host colonization and disease. P. aeruginosa infection elicits a complex immune response due to a large number of immunogenic factors present in the bacteria or released during infection. Here, we focused on the mechanisms by which P. aeruginosa triggers lung injury and inflammation, debating the possible ways that P. aeruginosa evades the host immune system, which leads to immune suppression and resistance. PMID- 26652130 TI - Methicillin-resistant Staphylococcus aureus carrying the new mecC gene--a meta analysis. AB - In 2011, a new mecA gene homolog, named mecC gene, was found in isolates from both humans and animals. The discovery of methicillin-resistant Staphylococcus aureus (MRSA) carrying the mecC gene has caused speculations about the origin, epidemiology, and impact of these isolates. The objective of this work is to perform a meta-analysis on the prevalence of mecC MRSA, based on previously published results. Meta-analysis showed that the overall pooled prevalence is 0.009% (95% confidence interval=0.05-0.013) and that there was evidence of heterogeneity (P<0.01, I(2)=97%). In conclusion, the very low reported prevalence provides an important baseline to monitor the epidemiology of this emerging form of MRSA. PMID- 26652131 TI - Hypovascular non-functional neuroendocrine pancreatic tumour: an unusual presentation of a rare tumour. PMID- 26652132 TI - [Short stature in children of Karapoto ethnic background, Sao Sebastiao, Alagoas, Brazil]. AB - OBJECTIVE: To describe the prevalence of short stature among children of Karapoto ethnic background. METHODS: Cross-sectional, population-based study that included children between 6 and 59 months of age from the Plak-O native village and the Terra Nova settlement, Sao Sebastiao, Alagoas, carried out between 2008 and 2009. Short stature was evaluated by the Height/Age index, using as cutoff z score <= 2. The prevalence of short stature was determined by comparing simple and relative frequencies. The population growth curves were compared to the WHO reference curves. Data analysis included the outcome variable: Height/Age and the predictor variables: place of residence, gender, age, anemia, birth weight, family income, maternal literacy. The chi-square test was used to compare the categorical variables, whereas the chi-square test with Yates correction was used for dichotomous variables, considering as statistically significant p values<=0.05. RESULTS: The prevalence of short stature was 15.6% for children from the Terra Nova settlement and 9.1% for those from Plak-O native village. The prevalence of short stature among the Karapoto ethnicity was 13.4%. The variables: maternal literacy, family income and low birth weight were statistically associated with short stature. CONCLUSIONS: The observed short stature prevalence rates are significant, being characterized as a public health problem. Among the associated factors, the following are noteworthy: unfavorable conditions of maternal literacy, family income and low birth weight. The planning of strategies to reverse the situation must take such factors into consideration. PMID- 26652133 TI - Thrombectomy in Primary Angioplasty: Do the Latest Large Studies Address the Doubts About Its Usefulness? PMID- 26652134 TI - Expression of alpha5-integrin, alpha7-integrin, Epsilon-cadherin, and N-cadherin in localized prostate cancer. AB - OBJECTIVE: To explore the correlation between the expression of alpha5-integrin, alpha7-integrin, Epsilon-cadherin, and N-cadherin in prostate cancer (PCa) and its clinicopathological data including tumor grade and clinical stage. METHODS: The expression of alpha5-integrin, alpha7-integrin, Epsilon-cadherin, and N cadherin was examined in 157 cases of PCa and adjacent normal prostatic tissue by immunohistochemical assay, and the correlation with clinicopathological features was analyzed. RESULTS: Expressions of alpha5-integrin, alpha7-integrin, and Epsilon-cadherin in PCa were lower than those in normal prostatic tissues (P<0.05). N-cadherin expression was higher in cancer prostatic tissue than in normal prostatic tissues (P<0.05). The reduced expression of alpha5-integrin, alpha7-integrin, and Epsilon-cadherin was related to Gleason score, pathological stage, lymph node metastasis, and prostate-specific antigen level, but it was not associated with positive surgical margins and patient age. The increased expression of N-cadherin was related to Gleason score, pathological stage, lymph node metastasis, and prostate-specific antigen level, but not to age and positive surgical margins. The expression of E-cadherin was highly negatively correlated with that of N-cadherin and also positively correlated with that of alpha5 integrin and alpha7-integrin. CONCLUSION: The reduced expression of alpha5 integrin, alpha7-integrin, and Epsilon-cadherin and abnormal expression of N cadherin play an important role in the occurrence and development of PCa. The results indicate that these have potential values in the diagnosis and are predictable indices in the proliferation of PCa. PMID- 26652135 TI - Watching a Procedure Evolve: Sequential Findings From the TVT Registry. PMID- 26652136 TI - Risk Factors for Sternal Wound Infection After Open Heart Operations Vary According to Type of Operation. AB - BACKGROUND: This study evaluated whether risk factors for sternal wound infections vary with the type of surgical procedure in cardiac operations. METHODS: This was a university hospital surveillance study of 3,249 consecutive patients (28% women) from 2006 to 2010 (median age, 69 years [interquartile range, 60 to 76]; median additive European System for Cardiac Operative Risk Evaluation score, 5 [interquartile range, 3 to 8]) after (1) isolated coronary artery bypass grafting (CABG), (2) isolated valve repair or replacement, or (3) combined valve procedures and CABG. All other operations were excluded. Univariate and multivariate binary logistic regression were conducted to identify independent predictors for development of sternal wound infections. RESULTS: We detected 122 sternal wound infections (3.8%) in 3,249 patients: 74 of 1,857 patients (4.0%) after CABG, 19 of 799 (2.4%) after valve operations, and 29 of 593 (4.9%) after combined procedures. In CABG patients, bilateral internal thoracic artery harvest, procedural duration exceeding 300 minutes, diabetes, obesity, chronic obstructive pulmonary disease, and female sex (model 1) were independent predictors for sternal wound infection. A second model (model 2), using the European System for Cardiac Operative Risk Evaluation, revealed bilateral internal thoracic artery harvest, diabetes, obesity, and the second and third quartiles of the European System for Cardiac Operative Risk Evaluation were independent predictors. In valve patients, model 1 showed only revision for bleeding as an independent predictor for sternal infection, and model 2 yielded both revision for bleeding and diabetes. For combined valve and CABG operations, both regression models demonstrated revision for bleeding and duration of operation exceeding 300 minutes were independent predictors for sternal infection. CONCLUSIONS: Risk factors for sternal wound infections after cardiac operations vary with the type of surgical procedure. In patients undergoing valve operations or combined operations, procedure-related risk factors (revision for bleeding, duration of operation) independently predict infection. In patients undergoing CABG, not only procedure-related risk factors but also bilateral internal thoracic artery harvest and patient characteristics (diabetes, chronic obstructive pulmonary disease, obesity, female sex) are predictive of sternal wound infection. Preventive interventions may be justified according to the type of operation. PMID- 26652137 TI - Early Impact of Fontan Operation on Enteric Protein Loss. AB - BACKGROUND: Protein-losing enteropathy (PLE) is a challenging complication after a Fontan operation. Subclinical enteric protein loss may precede development of overt PLE. We evaluated the acute effects of Fontan circulation on enteric protein loss and mesenteric vascular resistance. METHODS: A prospective cohort study was performed evaluating enteric protein loss in children undergoing Fontan operations. Stool alpha-1 antitrypsin (A1AT) concentration was measured in the preoperative, early postoperative, and intermediate postoperative (3-9 months) periods. The intestinal circulation was characterized by Doppler-derived resistance indices of the superior mesenteric artery (SMA), and serum albumin and protein levels were obtained. RESULTS: We enrolled 33 participants at a median age at operation of 3.0 years (interquartile range [IQR], 2.5-3.3 years). No clinical PLE was observed. Six of the 93 stool samples obtained had elevated A1AT levels (>54 mg/dL), with 2 abnormal samples at each of the 3 time points. Two of the 5 participants with elevated stool A1AT values had significant hemodynamic disturbances requiring intervention (junctional bradycardia or tricuspid stenosis). There was no difference in SMA resistance in the preoperative versus early postoperative periods (p = 0.9). Serum albumin levels were lower in the early postoperative period compared with the preoperative period (3.2 mg/dL [{IQR}, 2.9-3.5] versus 4.1 mg/dL; IQR, 3.4-4.5; p = 0.01) but did not correlate with abnormal stool A1AT concentration or SMA resistance indices. CONCLUSIONS: The Fontan operation does not commonly result in acute development of increased enteric protein loss. However, increased enteric protein loss may occur in children before or after a Fontan operation, particularly when hemodynamic disturbances are present. PMID- 26652138 TI - Diagnosing Neonatal Aortic Coarctation in the Setting of Patent Ductus Arteriosus. AB - BACKGROUND: In neonates, it is challenging to diagnose aortic coarctation in the setting of a patent ductus arteriosus (PDA). Frequently, serial echocardiograms are performed, and diagnosis is delayed until the PDA closes. The purpose of this study was to identify echocardiographic predictors of neonatal coarctation in the presence of a PDA in cases in which diagnosis is uncertain. METHODS: We retrospectively identified neonates diagnosed with possible but not definitive coarctation in the presence of a PDA by echocardiography (January 2004 through August 2013). The carotid-subclavian artery index (CSAi) was defined as the distal transverse arch diameter divided by the distance between the left common carotid and left subclavian arteries. Medical records were reviewed to identify patients who underwent coarctation repair within 1 year. A separate validation group was identified with the same methodology (September 2013 through April 2015). RESULTS: Thirty-three patients were identified (median age 1, range 0-8 days). Twelve patients (36%) underwent coarctation repair. The coarctation group had smaller aortic and mitral valves, distal transverse arch, and isthmus z scores, larger right innominate artery, and longer transverse arch compared with the remaining group (p < 0.05). The CSAi was lower in the coarctation group (p = 0.014), and a cutoff of less than 0.85 yielded a sensitivity of 0.83 and specificity of 0.86 for coarctation (area under the receiver operating characteristic curve, 0.91). In the validation group (n = 12; median follow-up, 316 days), none of the 8 patients with a CSAi of greater than 0.85 have required surgery. The intraclass correlation coefficient for CSAi was 0.79 (95% confidence interval, 0.18 to 0.95). CONCLUSIONS: The CSAi, a simple and reproducible measure, can identify neonates at risk for aortic coarctation even in the presence of a PDA, prevent multiple echocardiographic evaluations, and hence guide appropriate resource utilization. PMID- 26652139 TI - Esophagectomy Timing After Neoadjuvant Therapy for Distal Esophageal Adenocarcinoma. AB - BACKGROUND: The time elapsed between completion of neoadjuvant therapy and esophagectomy may influence response rate and possibly allow for avoidance of surgical intervention in selected cases ("wait and see" approach). However, a very long postradiation interval has been associated with worsened surgical outcomes in esophageal carcinoma. Therefore we analyzed outcomes of patients with invasive distal esophageal adenocarcinoma treated with neoadjuvant chemoradiation and esophagectomy based on the time elapsed between completion of neoadjuvant chemoradiation and resection. METHODS: Patients with invasive distal esophageal carcinoma diagnosed between 2003 and 2011 and treated by neoadjuvant chemoradiation followed by esophagectomy within 26 weeks were identified in the National Cancer Data Base (NCDB). Primary outcome measures were 30- and 90-day postsurgical mortality and overall survival. RESULTS: In all, 4,284 patients aged 60.3 +/- 9.4 years were analyzed (mean +/- standard deviation). The interval after radiation therapy until esophagectomy was 7.8 +/- 3.4 weeks (median, 7.1 weeks). The postradiation interval was 8 weeks or more in 35% of patients. Thirty day mortality was 2.9% (n = 127), and 90-day mortality was 7.8% (n = 336). A postradiation interval of 9 weeks or more was associated with increased perioperative mortality odds both at the 30-day (adjusted odds ratio [OR], 2.160; 95% confidence interval, 1.099-4.242; p = 0.025) and 90-day follow-up (adjusted OR, 1.912; 95% confidence interval, 1.290-2.835; p < 0.001). Similarly, a postradiation interval of 9 weeks or more was associated with an increased mortality risk (adjusted hazard ratio [HR], 1.194; 95% confidence interval, 1.032 1.380; p = 0.017). CONCLUSIONS: Perioperative mortality and overall survival are significantly associated with the time interval between neoadjuvant chemoradiation and esophagectomy. A "wait and see" approach after neoadjuvant therapy for esophageal adenocarcinoma may not be safe. Further studies based on more detailed data are needed. PMID- 26652140 TI - Outcomes With Open and Minimally Invasive Ivor Lewis Esophagectomy After Neoadjuvant Therapy. AB - BACKGROUND: Neoadjuvant therapy is integral in the treatment of locally advanced esophageal cancer. Despite increasing acceptance of minimally invasive approaches to esophagectomy, there remain concerns about the safety and oncologic soundness after neoadjuvant therapy. We examined outcomes in patients undergoing open and minimally invasive (MIE) Ivor Lewis esophagectomy after neoadjuvant therapy. METHODS: This was a retrospective series of 130 consecutive patients with esophageal cancer undergoing Ivor Lewis esophagectomy with curative intention after neoadjuvant therapy at a tertiary academic center (2008 to 2012). RESULTS: An open procedure was performed in 74 patients (56.9%), and 56 (43.1%) underwent MIE after neoadjuvant therapy. MIE patients had shorter median intensive care unit (p = 0.002) and hospital lengths of stay (p < 0.0001). The incidence of postoperative complications was similar (open: 54.8% vs MIE: 41.1%, p = 0.155). However, observed respiratory complications were significantly reduced after MIE (8.9%) compared with open (29.7%; p = 0.004). Anastomotic leak rates were similar (open: 1.4% vs. MIE: 0%, p = 1.00). Mortality at 30 and 90 days was comparable (open: 2.7% and 4.1% vs MIE: 0% and 1.8%, p = 0.506 and p = 0.634, respectively). Complete resection rates and the number of collected lymph nodes was similar. Overall survival rates at 5 years were similar (open: 61% vs MIE: 50%, p = 0.933). MIE was not a significant predictor of overall survival (hazard ratio, 1.07; 95% confidence interval, 0.61 to 1.87; p = 0.810). CONCLUSIONS: MIE proves its safety after neoadjuvant therapy because it leads to faster progression during the early postoperative period while reducing pulmonary complications. Open and MIE approaches appear equivalent with regards to perioperative oncologic outcomes after neoadjuvant therapy. Long-term outcomes need further validation. PMID- 26652142 TI - Endovascular Repair for Thoracic Aortic False Aneurysms: Single-Center Experience in 102 Patients. AB - BACKGROUND: Thoracic aortic false aneurysm is unusual and experience with endovascular repair is limited. We evaluate the efficacy of endovascular repair in patients with thoracic aortic false aneurysms. METHODS: The early and midterm outcomes of endovascular repair in 102 patients with thoracic aortic false aneurysms were analyzed. RESULTS: There were 80 men and 22 women (age 54.9 +/- 13.7 years). Emergent or urgent endovascular repair was done in 19 cases (18.6%) and elective in 83 (81.4%). Procedure was successful in 99.0%. Early death occurred in 4 patients (3.9%). No early death occurred in elective patients. Early complications occurred in 7 patients (6.9%). Follow-up was complete in 100% for 24.0 +/- 18.5 months (range, 1.5 to 67.3). Fourteen late deaths occurred (13.7%). Late events occurred in 9 patients (8.8%). Survival at 6 month, 1 year and 3 years was 90.7%, 86.7% and 84.5%, respectively. CONCLUSIONS: Satisfactory early and midterm outcomes have been achieved with endovascular repair in this series. Although emergent or urgent patients had higher rates of early mortality and morbidity, the majority of them achieved stable late survival as long as they survived at least 6 months. These results argue favorably for use of endovascular repair in the management of patients with thoracic aortic false aneurysms. PMID- 26652143 TI - Distribution and risk assessment of suspected endocrine-disrupting pesticides in creek water of Mumbai, India. AB - The present study deals with the investigation of existing pollution levels and potential ecological risk assessment of endocrine-disrupting organochlorine and organophosphorous pesticide residues in the Vasai Creek water near Mumbai. The average concentration of alpha- and beta-endosulfan (137.75 ng.L(-1)) exceeds the chronic criteria level of alpha- and beta-endosulfan (6.5 ng.L(-1)) set by US EPA for freshwater aquatic organisms. The concentration levels of aldrin (75.31 ng.L( 1)), dieldrin (71.19 ng.L(-1)) and endrin (76.60 ng.L(-1)) was found to exceed the respective criteria levels of <0.13, 65.1, and 61 ng.L(-1) as set by US EPA for protection of freshwater aquatic organisms. In addition, the level of chlorpyrifos (208.77 ng.L(-1)) exceeds the recommended concentration value of <35 ng.L(-1) set by Ministry of Environment of British Colombia. The results of our study give an indication of probable ecotoxicological risk to the marine breeding organisms of creek. PMID- 26652144 TI - Assessing the progress in depolluting the Mediterranean Sea. AB - The depollution of the Mediterranean Sea by 2020 is the overarching goal of Horizon 2020 Initiative (H2020). The first phase (2007-2013) tackled the main land-based pollution sources; municipal waste, urban wastewater and industrial emissions. As part of the H2020 roadmap implementation, the ENPI-SEIS project focused on the first H2020 review mechanism that included a) establishing a process for regular environmental reporting in the European Neighbourhood Policy South countries, and b) generating the knowledge necessary to assess the progress in depolluting the Mediterranean Sea. This paper reviews the process in line with the "Shared Environmental Information System" principles and its three pillars (content, cooperation, infrastructure). The main outcomes of the thematic assessment, based on a set of regional H2020 indicators, are also presented. This assessment highlights the major drivers and their implications on marine protection. It also identifies areas that require further attention in the next phase of H2020 (2014-2020). PMID- 26652141 TI - The Chinese Cardiac Surgery Registry: Design and Data Audit. AB - BACKGROUND: In light of the burgeoning volume and certain variation of in hospital outcomes of cardiac operations in China, a large patient-level registry was needed. We generated the Chinese Cardiac Surgery Registry (CCSR) database in 2013 to benchmark, continuously monitor, and provide feedback of the quality of adult cardiac operations. We report on the design of this database and provide an overview of participating sites and quality of data. METHODS: We established a network of participating sites with an adult cardiac surgery volume of more than 100 operations per year for continuous web-based registry of in-hospital and follow-up data of coronary artery bypass grafting (CABG) and valve operations. After a routine data quality audit, we report the performance and quality of care back to the participating sites. RESULTS: In total, 87 centers participated and submitted 46,303 surgical procedures from January 2013 to December 2014. The timeliness rates of the short-list and in-hospital data submitted were 73.6% and 70.2%, respectively. The completeness and accuracy rates of the in-hospital data were 97.6% and 95.1%, respectively. We have provided 2 reports for each site and 1 national report regarding the performance of isolated CABG and valve operations. CONCLUSIONS: The newly launched CCSR with a national representativeness network and good data quality has the potential to act as an important platform for monitoring and improving cardiac surgical care in mainland China, as well as facilitating research projects, establishing benchmarking standards, and identifying potential areas for quality improvements (ClinicalTrials.gov No. NCT02400125). PMID- 26652145 TI - Amination-Oxidation Strategy for the Copper-Catalyzed Synthesis of Monoarylamines. AB - A novel approach for the synthesis of monoarylamines from aryl halides is presented. This method employs an inexpensive, nontoxic metal source (copper) and incorporates a stable ammonia surrogate (alpha-amino acids), obviating the need for special experimental setup or handling of ammonia reagents. This process, which is proposed to proceed via an amination-oxidation sequence, selectively promotes the transformation of a range of aryl and heteroaryl iodides as well as bromides to the corresponding monoarylamines. PMID- 26652146 TI - Reverse posterior interosseous flap for defects of the dorsal ulnar wrist using previously burned and recently grafted skin. AB - BACKGROUND: In the severely burned patient, coverage of exposed bone in the dorsal ulnar wrist can be a difficult problem. This is especially challenging in patients with a high percentage total body surface area (TBSA) where donor flaps can be scarce. The use of previously burned and/or recently grafted skin as flaps is an option. It has been postulated that use of previously burned skin can result in higher rates of local or distant flap failures. The reverse posterior interosseous flap (PIF) is an axial flap, based on the retrograde posterior interosseous artery, to provide coverage of the hand. Here we describe utilization of the PIF, using previously burned and/or recently grafted skin for coverage of dorsal ulnar wrist defects. METHODS: This is a case series of three patients, with extensive burns (range 35-83%TBSA), where defects of the dorsal ulnar wrist necessitated coverage. Each patient underwent PIF(s) utilizing previously burned and/or grafted skin, all within three months after their initial burn event. RESULTS: Case 1: 28 year old male who suffered 35% TBSA via blast mechanism developed a chronic open wound over the dorsal ulnar wrist with exposed tendon. The patient successfully underwent a left PIF using previously grafted skin. Case 2: 23 year old male with 83% TBSA. Bilateral ulnar styloids were exposed. PIFs were performed bilaterally, using previously burned and recently grafted skin. Coverage was successful but received leech therapy post operatively for venous congestion. Case 3: 37 year old male with 52% TBSA, with the most severe burns isolated to his bilateral upper extremities; the ulnar head was exposed. The posterior interroseous artery was explored and PIF was attempted, but there was no retrograde flow in the distal artery due to a deeper injury than previously recognized. The patient ultimately underwent a pedicled abdominal flap for coverage. CONCLUSIONS: Defects of the distal ulnar wrist after deep and extensive burns can be problematic. Use of the reverse PIF using previously burned skin, even those that has just been recently grafted is a viable option for this difficult patient population. However, it may not be possible in all patients. Vigilance and early intervention for post-operative venous congestion are important. PMID- 26652147 TI - The Expectation Game: Patient Comprehension Is a Determinant of Outcome. AB - Patient comprehension of orthopaedic procedures is low and their expectations for successful outcomes are often unrealistic. Surgeons need to understand this and guide patients toward sensible expectations. PMID- 26652148 TI - Authors' Reply. PMID- 26652149 TI - Concerning the Article "Transhumeral Portal for Arthroscopic Glenohumeral Resurfacing Procedures: A Cadaveric Study of the Safety and Accuracy". PMID- 26652150 TI - Editorial Commentary: Arthroscopy Is Preferred Over Open Surgery for Patellar Tendonitis. AB - Jumper's knee is generally managed without surgery, but for patellar distal pole or midsubstance tendonitis (or tendinosis), if surgery is indicated, arthroscopic surgery is as effective as open, with faster return to play. PMID- 26652151 TI - Editorial Commentary: Multidirectional Shoulder Instability. AB - Multidirectional shoulder instability responds to physical therapy and rehabilitation. For patients who fail rehabilitation, arthroscopic capsular plication seems the treatment of choice. PMID- 26652152 TI - Editorial Commentary: The Importance of the Simulated Pivot-Shift Test. AB - The simulated pivot-shift test measures knee anterolateral rotatory instability in cadaveric, in vitro, anterior cruciate ligament (ACL) research. Clinically, the pivot-shift test is a primary determinant of patient satisfaction after ACL reconstructive surgery. PMID- 26652153 TI - Editorial Commentary: Lesions of the Superior Labrum From Anterior to Posterior (SLAP) Are a Slap in the Face to the Traditional Trinity of History, Examination, and Imaging. AB - Superior labrum from anterior to posterior (SLAP) lesions are a slap in the face to the revered trinity of history, physical examination, and imaging. SLAP lesions are difficult to diagnose, and arthroscopy is not only the gold standard, but the current method on which expert arthroscopic shoulder subspecialists rely. PMID- 26652154 TI - Editorial Commentary: How Do We Tell Patients Their Rotator Cuff Tear Is Massive? AB - Surgeons may tell patients that arthroscopic repair of massive rotator cuff tear results in clear improvement in patient outcomes. However, a limitation of the medical literature is that pooled findings may not be generalizable to all patients. PMID- 26652155 TI - Examining the potential clinical value of curcumin in the prevention and diagnosis of Alzheimer's disease. AB - Curcumin derived from turmeric is well documented for its anti-carcinogenic, antioxidant and anti-inflammatory properties. Recent studies show that curcumin also possesses neuroprotective and cognitive-enhancing properties that may help delay or prevent neurodegenerative diseases, including Alzheimer's disease (AD). Currently, clinical diagnosis of AD is onerous, and it is primarily based on the exclusion of other causes of dementia. In addition, phase III clinical trials of potential treatments have mostly failed, leaving disease-modifying interventions elusive. AD can be characterised neuropathologically by the deposition of extracellular beta amyloid (Abeta) plaques and intracellular accumulation of tau containing neurofibrillary tangles. Disruptions in Abeta metabolism/clearance contribute to AD pathogenesis. In vitro studies have shown that Abeta metabolism is altered by curcumin, and animal studies report that curcumin may influence brain function and the development of dementia, because of its antioxidant and anti-inflammatory properties, as well as its ability to influence Abeta metabolism. However, clinical studies of curcumin have revealed limited effects to date, most likely because of curcumin's relatively low solubility and bioavailability, and because of selection of cohorts with diagnosed AD, in whom there is already major neuropathology. However, the fresh approach of targeting early AD pathology (by treating healthy, pre-clinical and mild cognitive impairment-stage cohorts) combined with new curcumin formulations that increase bioavailability is renewing optimism concerning curcumin-based therapy. The aim of this paper is to review the current evidence supporting an association between curcumin and modulation of AD pathology, including in vitro and in vivo studies. We also review the use of curcumin in emerging retinal imaging technology, as a fluorochrome for AD diagnostics. PMID- 26652156 TI - Teaching percutaneous renal biopsy using unfixed human cadavers. AB - BACKGROUND: Percutaneous renal biopsy (PRB) is an important diagnostic procedure. Despite advances in its safety profile there remains a small but significant risk of bleeding complications. Traditionally, operators train to perform PRB through tutor instruction and directly supervised PRB attempts on real patients. We describe an approach to teaching operators to perform PRB using cadaveric simulation. METHODS: We devised a full day course hosted in the Clinical Anatomy Skills Centre, with places for nine candidates. Course faculty consisted of two Consultant Nephrologists, two Nephrology trainees experienced in PRB, and one Radiologist. Classroom instruction included discussion of PRB indications, risk minimisation, and management of complications. Two faculty members acted as models for the demonstration of kidney localisation using real-time ultrasound scanning. PRB was demonstrated using a cadaveric model, and candidates then practised PRB using each cadaver model. RESULTS: Written candidate feedback was universally positive. Faculty considered the cadaveric model a realistic representation of live patients, while the use of multiple cadavers introduced anatomical variation. CONCLUSIONS: Our model facilitates safe simulation of a high risk procedure. This might reduce serious harm associated with PRB and improve patient safety, benefiting trainee operators and patients alike. PMID- 26652157 TI - Effects Of Glycoprotein IIb/IIIa Antagonists: Anti Platelet Aggregation And Beyond. AB - BACKGROUND: The use of inhibitors of glycoprotein IIb/IIIa (GPIIb/IIIa) has provided dramatic results in terms of the prevention of acute stent thrombosis and a reduction in major adverse coronary events in patients subjected to percutaneous coronary intervention. GPIIb/IIIa or alphaIIbbeta3 is a member of the beta3 subfamily of integrins, which also includes alphaVbeta3. GPIIb/IIIa functions as a receptor for fibrinogen and several adhesion proteins sharing an arginine-glycine-aspartic acid (RGD) sequence. GPIIb/IIIa antagonists, through blockade of the receptor, prevent platelet aggregation. Among the three GPIIb/IIIa antagonists used in therapy, abciximab is an anti-beta3 monoclonal antibody, while tirofiban and eptifibatide mimic the binding sequence of the fibrinogen ligand. Although antiplatelet aggregation represents the central function of GPIIb/IIIa inhibitors, further actions have been documented for these compounds. OBJECTIVE: The aim of the present article is to review the structures and functions of GPIIb/IIIa antagonists and to highlight the clinical outcomes and results of randomized trials with these compounds. Hypotheses on the unexplored potential of GPIIb/IIIa antagonists will be put forward. CONCLUSION: GPIIb/IIIa inhibitors were developed to prevent platelet aggregation, however, these compounds can exert further biological functions, both platelet- and non platelet-related. Large-scale studies comparing the efficacy and safety of GPIIb/IIIa antagonists are lacking. More insights into the functions of these compounds may lead to generation of novel small molecules able to antagonize platelet aggregation while promoting vascular repair. PMID- 26652158 TI - Factors associated with malnutrition in hospitalized cancer patients: a croos sectional study. AB - INTRODUCTION: The incidence of cancer is increasing worldwide and with it the prevalence of malnutrition, which is responsible for the death of almost 20% of cancer patients. The objective of this study was to identify the factors associated with malnutrition in hospitalized cancer patients. METHODS: Cross sectional study conducted with 277 hospitalized patients in the Institute of Integrative Medicine Prof. Fernando Figueira from March to November 2013. The nutritional status was classified as well-nourished and moderate/severe malnutrition, according to the Patient-Generated Subjective Global Assessment. The association between moderate/severe malnutrition and demographic, behavioral, socioeconomic, clinical, therapeutic and nutritional variables was investigated through univariate regression and hierarchical Poisson models, with a 5% significance level. RESULTS: The prevalence of malnutrition was 71.1%, being classified as moderate in 35.4% and severe in 35.7%. After multivariate analysis, smokers/ex-smokers low socioeconomic status, performance status >=2 and age >=60 years were associated with increased risk of malnutrition. CONCLUSION: There was observed a high prevalence of moderate/severe malnutrition in cancer patients, with the increased risk of malnutrition associated with the presence of factors that can be assessed during hospital admission suggesting a higher alert of the medical and health care staff about the need for nutritional assessment and intervention. PMID- 26652159 TI - Combining multiple ECG features does not improve prediction of defibrillation outcome compared to single features in a large population of out-of-hospital cardiac arrests. AB - INTRODUCTION: Quantitative electrocardiographic (ECG) waveform analysis provides a noninvasive reflection of the metabolic milieu of the myocardium during resuscitation and is a potentially useful tool to optimize the defibrillation strategy. However, whether combining multiple ECG features can improve the capability of defibrillation outcome prediction in comparison to single feature analysis is still uncertain. METHODS: A total of 3828 defibrillations from 1617 patients who experienced out-of-hospital cardiac arrest were analyzed. A 2.048-s ECG trace prior to each defibrillation without chest compressions was used for the analysis. Sixteen predictive features were optimized through the training dataset that included 2447 shocks from 1050 patients. Logistic regression, neural network and support vector machine were used to combine multiple features for the prediction of defibrillation outcome. Performance between single and combined predictive features were compared by area under receiver operating characteristic curve (AUC), sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and prediction accuracy (PA) on a validation dataset that consisted of 1381 shocks from 567 patients. RESULTS: Among the single features, mean slope (MS) outperformed other methods with an AUC of 0.876. Combination of complementary features using neural network resulted in the highest AUC of 0.874 among the multifeature-based methods. Compared to MS, no statistical difference was observed in AUC, sensitivity, specificity, PPV, NPV and PA when multiple features were considered. CONCLUSIONS: In this large dataset, the amplitude related features achieved better defibrillation outcome prediction capability than other features. Combinations of multiple electrical features did not further improve prediction performance. PMID- 26652160 TI - A systematic review of the clinical and social epidemiological research among sex workers in Uganda. AB - BACKGROUND: In response to the high burden of disease among sex workers and their position as a population heavily affected by the HIV epidemic, there has been a growing body of literature investigating the prevalence and risk factors associated with HIV risk among sex workers. To contextualize and summarize the existing research evidence base, a systematic review was conducted to synthesize the epidemiological literature on sex workers in Uganda. METHODS: Database selection and search strategy development followed the Cochrane Collaboration's standards for conducting systematic review searches. All studies that included sex workers as the primary research participants were included in the review. The search was then geographically restricted to the country of Uganda. Items were identified from 18 databases (grey and peer-review) on March 10-11, 2015. RESULTS: A total of 484 articles were retrieved from the database search. After removal of duplicates, a total of 353 articles were screened for eligibility and 64 full-text articles were assessed. The final review included 24 studies with quantitative methodology conducted among sex workers in Uganda. The HIV prevalence among female sex workers ranged from 32.4-52.0 % and between 8.2-9.0 % had multiple HIV infections. Both multi-drug resistance to antiretroviral therapy (2.6 %) and antibiotics (83.1 %) were observed. Between 33.3-55.1 % reported inconsistent condom use in the past month. In the previous 6 months, over 80 % of sex workers experienced client-perpetrated violence and 18 % experienced intimate partner violence. Over 30 % had a history of extreme war-related trauma. CONCLUSIONS: There was limited information on socio-structural factors that affect sex workers' commercial working environments in Uganda, including the role of policing and criminalization, as well as the prevalence and factors associated with violence. The majority of the existing evidence is based in Kampala, highlighting a need for information on sex work in other regions of Uganda. Additionally, there is limited information on features of the non-commercial components of sex workers' lives as well as the services needed to reduce risks outside of the sex industry. PMID- 26652161 TI - Genome-wide association study reveals novel loci for litter size and its variability in a Large White pig population. AB - BACKGROUND: In many traits, not only individual trait levels are under genetic control, but also the variation around that level. In other words, genotypes do not only differ in mean, but also in (residual) variation around the genotypic mean. New statistical methods facilitate gaining knowledge on the genetic architecture of complex traits such as phenotypic variability. Here we study litter size (total number born) and its variation in a Large White pig population using a Double Hierarchical Generalized Linear model, and perform a genome-wide association study using a Bayesian method. RESULTS: In total, 10 significant single nucleotide polymorphisms (SNPs) were detected for total number born (TNB) and 9 SNPs for variability of TNB (varTNB). Those SNPs explained 0.83 % of genetic variance in TNB and 1.44 % in varTNB. The most significant SNP for TNB was detected on Sus scrofa chromosome (SSC) 11. A possible candidate gene for TNB is ENOX1, which is involved in cell growth and survival. On SSC7, two possible candidate genes for varTNB are located. The first gene is coding a swine heat shock protein 90 (HSPCB = Hsp90), which is a well-studied gene stabilizing morphological traits in Drosophila and Arabidopsis. The second gene is VEGFA, which is activated in angiogenesis and vasculogenesis in the fetus. Furthermore, the genetic correlation between additive genetic effects on TNB and on its variation was 0.49. This indicates that the current selection to increase TNB will also increase the varTNB. CONCLUSIONS: To the best of our knowledge, this is the first study reporting SNPs associated with variation of a trait in pigs. Detected genomic regions associated with varTNB can be used in genomic selection to decrease varTNB, which is highly desirable to avoid very small or very large litters in pigs. However, the percentage of variance explained by those regions was small. The SNPs detected in this study can be used as indication for regions in the Sus scrofa genome involved in maintaining low variability of litter size, but further studies are needed to identify the causative loci. PMID- 26652163 TI - Stress response genes and the severity of nicotine withdrawal. PMID- 26652164 TI - Nucleoapzymes: Hemin/G-Quadruplex DNAzyme-Aptamer Binding Site Conjugates with Superior Enzyme-like Catalytic Functions. AB - A novel concept to improve the catalytic functions of nucleic acids (DNAzymes) is introduced. The method involves the conjugation of a DNA recognition sequence (aptamer) to the catalytic DNAzyme, yielding a hybrid structure termed "nucleoapzyme". Concentrating the substrate within the "nucleoapzyme" leads to enhanced catalytic activity, displaying saturation kinetics. Different conjugation modes of the aptamer/DNAzyme units and the availability of different aptamer sequences for a substrate provide diverse means to design improved catalysts. This is exemplified with (i) The H2O2-mediated oxidation of dopamine to aminochrome using a series of hemin/G-quadruplex-dopamine aptamer nucleoapzymes. All nucleoapzymes reveal enhanced catalytic activities as compared to the separated DNAzyme/aptamer units, and the most active nucleoapzyme reveals a 20-fold enhanced activity. Molecular dynamics simulations provide rational assessment of the activity of the various nucleoapzymes. The hemin/G-quadruplex aptamer nucleoapzyme also stimulates the chiroselective oxidation of L- vs D-DOPA by H2O2. (ii) The H2O2-mediated oxidation of N-hydroxy-L-arginine to L-citrulline by a series of hemin/G-quadruplex-arginine aptamer conjugated nucleoapzymes. PMID- 26652162 TI - Frequency-selective control of cortical and subcortical networks by central thalamus. AB - Central thalamus plays a critical role in forebrain arousal and organized behavior. However, network-level mechanisms that link its activity to brain state remain enigmatic. Here, we combined optogenetics, fMRI, electrophysiology, and video-EEG monitoring to characterize the central thalamus-driven global brain networks responsible for switching brain state. 40 and 100 Hz stimulations of central thalamus caused widespread activation of forebrain, including frontal cortex, sensorimotor cortex, and striatum, and transitioned the brain to a state of arousal in asleep rats. In contrast, 10 Hz stimulation evoked significantly less activation of forebrain, inhibition of sensory cortex, and behavioral arrest. To investigate possible mechanisms underlying the frequency-dependent cortical inhibition, we performed recordings in zona incerta, where 10, but not 40, Hz stimulation evoked spindle-like oscillations. Importantly, suppressing incertal activity during 10 Hz central thalamus stimulation reduced the evoked cortical inhibition. These findings identify key brain-wide dynamics underlying central thalamus arousal regulation. PMID- 26652165 TI - African American church-based HIV testing and linkage to care: assets, challenges and needs. AB - The US National HIV AIDS strategy promotes the use of faith communities to lessen the burden of HIV in African American communities. One specific strategy presented is the use of these non-traditional venues for HIV testing and co location of services. African American churches can be at the forefront of this endeavour through the provision of HIV testing and linkage to care. However, there are few interventions to promote the churches' involvement in both HIV testing and linkage to care. We conducted 4 focus groups (n = 39 participants), 4 interviews and 116 surveys in a mixed-methods study to examine the feasibility of a church-based HIV testing and linkage to care intervention in Philadelphia, PA, USA. Our objectives were to examine: (1) available assets, (2) challenges and barriers and (3) needs associated with church-based HIV testing and linkage to care. Analyses revealed several factors of importance, including the role of the church as an access point for testing in low-income neighbourhoods, challenges in openly discussing the relationship between sexuality and HIV, and buy-in among church leadership. These findings can support intervention development and necessitate situating African American church-based HIV testing and linkage to care interventions within a multi-level framework. PMID- 26652167 TI - Unusual involvement in mycosis fungoides: Duodenal papilla. AB - BACKGROUND: Mycosis fungoides (MF) is a type of T-cell lymphoma with cutaneous involvement. It is a rare disease, of low incidence and usually affects middle aged men. In most cases only the skin is involved although in advanced stages may present with extra cutaneous involvement including the gastrointestinal tract. CASE REPORT: We report the first case of MF with compromise of duodenal papilla, emphasizing the diagnostic approach and a brief review of the subject. DISCUSSION: This case report proves the value of the endoscopic studies in patients with lymphoproliferative disorders, because of the impact in the diagnosis and prognosis. Also, this case report is relevant because there is no scientific evidence, as far as we know, of similar cases reported. PMID- 26652166 TI - Comparing co-morbidities in total joint arthroplasty patients using the RxRisk-V, Elixhauser, and Charlson Measures: a cross-sectional evaluation. AB - BACKGROUND: Joint arthroplasty patients have a high prevalence of co-morbidities and this impacts their surgical outcomes. There are different ways to ascertain co-morbidities and appropriate measurement is necessary. The purpose of this study was to: (1) describe the prevalence of co-morbidities in a cohort of total hip arthroplasty (THA) and knee arthroplasty (TKA) patients using two diagnoses based measures (Charlson and Elixhauser) and one prescription-based measure (RxRisk-V); (2) compare the agreement of co-morbidities amongst the measures. METHODS: A cross-sectional study of Australian veterans undergoing THAs (n = 11,848) and TKAs (n = 18,972) between 2001 and 2012 was conducted. Seventeen co morbidities were identified using the Charlson, 30 using the Elixhauser, and 42 using the RxRisk-V measure. Agreement between co-morbidities was calculated using Kappa (kappa) statistics. RESULTS: Combining measures, 64 conditions were identified, of these 28 were only identified using the RxRisk-V, 11 using the Elixhauser, and 2 using the Charlson. The most prevalent conditions was pain treated with anti-inflammatories (58.7% THAs, 55.9% TKAs), pain treated with narcotics (55.0% THAs, 50.9% TKAs), hypertension (56.0% THAs and TKAs), and anticoagulation disorders (53.0% THAs, 48.6% TKAs). Diabetes was the only condition with substantial agreement (all kappa > 0.6) amongst all measures. When comparing the diagnoses based algorithms, agreement was high for overlapping conditions (all kappa > 0.71). CONCLUSIONS: Different measures identified different co-morbidities, provided different estimates for the same co-morbidity, and had different levels of agreement for common co-morbidities. This highlights the importance of understanding co-morbidity measures and using them appropriately in studies and case-mix adjustments analyses. PMID- 26652169 TI - Esthetic Outcomes of Immediately Loaded Locking Taper Implants in the Anterior Maxilla: A Case Series Study. AB - The purpose of this study was to evaluate the esthetic outcome of single-tooth locking taper connection implants placed in the anterior maxilla following a postextractive nonfunctional loading protocol. This preliminary clinical study involving 16 patients evaluated the results of 21 implants placed in areas with high esthetic value. For each implant the pink esthetic score, white esthetic score, cumulative survival rate, and health status of peri-implant tissues were evaluated. The cumulative survival rate was 100% 2 years after prosthetic loading, and the mean total pink esthetic score/white esthetic score was 16.9 +/- 1.14 on a maximum value of 20. There was excellent plaque control in all patients, and inflammation indices were within the norm. Within the limits of this study, this immediate nonfunctional loading protocol seems to be a successful procedure esthetically and for the maintenance of peri-implant soft tissues. PMID- 26652168 TI - Continence Across Continents To Upend Stigma and Dependency (CACTUS-D): study protocol for a cluster randomized controlled trial. AB - BACKGROUND: Urinary incontinence occurs in 40 % of women aged 65 years and over; however, only 15 % seek care and many delay healthcare seeking for years. Incontinence is associated with depression, social isolation, reduced quality of life, falls and other comorbidities. It is accompanied by an enormous cost to the individual and society. Despite the substantial implications of urinary incontinence on social, psychological and physical well-being of older women, the impact of continence promotion on urinary symptom improvement and subsequent effects on falls, quality of life, stigma, social participation and the cost of care remains unknown. METHODS: This study is a mixed methods multi-national open label 2-arm parallel cluster randomized controlled trial aiming to recruit 1000 community-dwelling incontinent women aged 65 years and older across Quebec, Western Canada, France and United Kingdom. Participants will be recruited through community organizations. Data will be collected at 6 time points: baseline and 1 week, 3 months, 6 months, 9 months and 12 months after baseline. One of the primary objectives is to evaluate whether the continence promotion intervention improves incontinence symptoms (measured with the Patient Global Impression of Improvement questionnaire, PGI-I) at 12 months post intervention compared to the control group. Other co-primary outcomes include changes in incontinence-related stigma, fall reduction, and incremental cost-effectiveness ratio and quality adjusted life years. Data analysis will account for correlation of outcomes (clustering) within community organizations. A qualitative sub-study will explore stigma reduction. DISCUSSION: Community-based continence promotion programs may be a cost-effective strategy to reduce urinary incontinence, stigma and falls among older women with untreated incontinence, and simultaneously improve quality of life and healthy active life expectancy. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01858493 , registered 13 May 2013. PMID- 26652170 TI - Encouraging prediction during production facilitates subsequent comprehension: Evidence from interleaved object naming in sentence context and sentence reading. AB - Many studies have shown that a supportive context facilitates language comprehension. A currently influential view is that language production may support prediction in language comprehension. Experimental evidence for this, however, is relatively sparse. Here we explored whether encouraging prediction in a language production task encourages the use of predictive contexts in an interleaved comprehension task. In Experiment 1a, participants listened to the first part of a sentence and provided the final word by naming aloud a picture. The picture name was predictable or not predictable from the sentence context. Pictures were named faster when they could be predicted than when this was not the case. In Experiment 1b the same sentences, augmented by a final spill-over region, were presented in a self-paced reading task. No difference in reading times for predictive versus non-predictive sentences was found. In Experiment 2, reading and naming trials were intermixed. In the naming task, the advantage for predictable picture names was replicated. More importantly, now reading times for the spill-over region were considerable faster for predictive than for non predictive sentences. We conjecture that these findings fit best with the notion that prediction in the service of language production encourages the use of predictive contexts in comprehension. Further research is required to identify the exact mechanisms by which production exerts its influence on comprehension. PMID- 26652171 TI - Should all patients undergoing treatment with biologic agents be screened annually for latent tuberculosis infection with an interferon gamma release assay? AB - Systemic biologic therapy has become commonplace for the treatment of a variety of inflammatory dermatologic conditions, particularly psoriasis. Screening for latent tuberculosis infection (LTBI) is recommended prior to initiation of systemic biologic agents, and an interferon gamma release assays (IGRA) is often used as the screening modality. Annual screening for LTBI is also recommended for patients while on systemic biologic therapy, but the literature does not clearly support how often screening should be performed. In addition, serial testing with IGRAs, particularly among low-risk populations without any new tuberculosis (TB) exposures, has proven to be unreliable with frequent reversions and conversions. We propose that in low-incidence TB regions, repeat LTBI screening should only be considered for patients on systemic biologic therapy if any new TB exposures occurred since initial LTBI screening was performed prior to starting biologic therapy. This strategy aims to reduce false-positive LTBI testing that can expose patients to hazardous antibiotics and result in the unnecessary interruption of systemic biologic therapy. PMID- 26652173 TI - Building coherence and synergy among global health initiatives. AB - BACKGROUND: The fast growth of global health initiatives (GHIs) has raised concerns regarding achievement of coherence and synergy among distinct, complementary and sometimes competing activities. Herein, we propose an approach to compare GHIs with regard to their main purpose and operational aspects, using the Special Programme for Research and Training in Tropical Diseases (TDR/WHO) as a case study. The overall goal is to identify synergies and optimize efforts to provide solutions to reduce the burden of diseases. METHODS: Twenty-six long established GHIs were identified from among initiatives previously associated/partnered with TDR/WHO. All GHIs had working streams that would benefit from linking to the capacity building or implementation research focus of TDR. Individual profiles were created using a common template to collect information on relevant parameters. For analytical purposes, GHIs were simultaneously clustered in five and eight groups according to their 'intended outcome' and 'operational framework', respectively. A set of specific questions was defined to assess coherence/alignment against a TDR reference profile by attributing a score, which was subsequently averaged per GHI cluster. GHI alignment scores for intended outcome were plotted against scores for operational framework; based on the analysis of coherence/alignment with TDR functions and operations, a risk level (high, medium or low) of engagement was attributed to each GHI. RESULTS: The process allowed a bi-dimensional ranking of GHIs with regards to how adequately they fit with or match TDR features and perspectives. Overall, more consistence was observed with regard to the GHIs' main goals and expected outcomes than with their operational aspects, reflecting the diversity of GHI business models. Analysis of coherence indicated an increasing common trend for enhancing the engagement of developing country stakeholders, building research capacity and optimization of knowledge management platforms in support of improved access to healthcare. CONCLUSIONS: The process used offers a broader approach that could be adapted by other GHIs to build coherence and synergy with peer organizations and helps highlight the potential contribution of each GHI in the new era of sustainable development goals. Emerging opportunities and new trends suggest that engagement between GHIs should be selective and tailored to ensure efficient collaborations. PMID- 26652172 TI - Evaluating a train-the-trainer approach for improving capacity for evidence-based decision making in public health. AB - BACKGROUND: Evidence-based public health gives public health practitioners the tools they need to make choices based on the best and most current evidence. An evidence-based public health training course developed in 1997 by the Prevention Research Center in St. Louis has been taught by a transdisciplinary team multiple times with positive results. In order to scale up evidence-based practices, a train-the-trainer initiative was launched in 2010. METHODS: This study examines the outcomes achieved among participants of courses led by trained state-level faculty. Participants from trainee-led courses in four states (Indiana, Colorado, Nebraska, and Kansas) over three years were asked to complete an online survey. Attempts were made to contact 317 past participants. One-hundred forty-four (50.9 %) reachable participants were included in analysis. Outcomes measured include frequency of use of materials, resources, and other skills or tools from the course; reasons for not using the materials and resources; and benefits from attending the course. Survey responses were tabulated and compared using Chi square tests. RESULTS: Among the most commonly reported benefits, 88 % of respondents agreed that they acquired knowledge about a new subject, 85 % saw applications for the knowledge to their work, and 78 % agreed the course also improved abilities to make scientifically informed decisions at work. The most commonly reported reasons for not using course content as much as intended included not having enough time to implement evidence-based approaches (42 %); other staff/peers lack training (34 %); and not enough funding for continued training (34 %). The study findings suggest that utilization of course materials and teachings remains relatively high across practitioner groups, whether they were taught by the original trainers or by state-based trainers. CONCLUSIONS: The findings of this study suggest that train-the-trainer is an effective method for broadly disseminating evidence-based public health principles. Train-the-trainer is less costly than the traditional method and allows for courses to be tailored to local issues, thus making it a viable approach to dissemination and scale up of new public health practices. PMID- 26652174 TI - Quadratic Corrections to Harmonic Vibrational Frequencies Outperform Linear Models. AB - Simulating accurate infrared spectra is a longstanding problem in computational quantum chemistry. Linearly scaling harmonic frequencies to better match experimental data is a popular way of approximating anharmonic effects while simultaneously attempting to account for deficiencies in ab initio method and/or basis set. As this approach is empirical, it is also nonvariational and unbounded, so it is important to separate and quantify errors as robustly as possible. Eliminating the confounding factor of methodological incompleteness enables us to explore the intrinsic accuracy of the scaling approach alone. We find that single-coefficient linear scaling methods systematically overcorrect low frequencies, while generally undercorrecting higher frequencies. A two parameter polynomial model gives significantly better predictions without systematic bias in any spectral region, while a single-parameter quadratic scaling model is parameterized to minimize overcorrection errors while only slightly decreasing predictive power. PMID- 26652175 TI - Prevalence of Non-Alcoholic Fatty Pancreas Disease (NAFPD) and its risk factors among adult medical check-up patients in a private hospital: a large cross sectional study. AB - BACKGROUND: The clinical significance of non-alcoholic fatty pancreatic disease (NAFPD) or fatty pancreas is largely unknown. It is often an incidental finding on abdominal ultrasound, which is not explored further, especially its association with metabolic condition and the risk of pancreatic malignancy. The aim of this study is to evaluate the presence of NAFPD and its associated risk factors among adult medical check-up patients. METHOD: A large cross-sectional study was done among adult medical check-up patients underwent abdominal ultrasound between January and December 2013 in Medistra Hospital, Jakarta. Data was obtained from the patients' medical record and include demographic data, blood pressures, fasting blood glucose level, and lipid profile. The presence of fatty pancreas was diagnosed by ultrasound. Bivariate and multivariate analyses were done to find associated risk factors for NAFPD. Statistical analysis was done using SPSS version 17. RESULTS: A total of 1054 cases were included in this study; pancreas cannot be visualized in 153 cases and were excluded from the analysis. Fatty pancreas was present in 315 (35.0%) patients. Bivariate analyses found associations among fatty pancreas and several risk factors such as gender, age, systolic and diastolic blood pressures, body mass index (BMI), fasting plasma glucose (FPG), triglycerides (TG) and cholesterol levels. CONCLUSION: Fatty pancreas is a common finding during medical check-up with a prevalence of 35%. Fatty pancreas has significant association with metabolic factors and it might have an important role in risk of malignancy. PMID- 26652176 TI - Self-medication among medical and pharmacy students in Bangladesh. AB - BACKGROUND: This cross-sectional survey examined the pattern of self-medication and factors associated with this practice among medical and pharmacy students in context to Bangladesh. METHODS: The study used a self-administered questionnaire. A total of 500; 250 medical and 250 pharmacy, students participated in the study. As it is a comparative analysis between the medical and pharmacy students, we used independent t test and Chi square test. RESULTS: The findings indicated that the impact of self-medication is almost similar in medical and pharmacy students. It was found that medical students were more careful about getting advice from a physician or seeking professional help from some healthcare personnel. About the safety of self-medication pharmacy students were more aware than medical students were. The study also showed that female and younger medical or pharmacy students were more aware about self-medication. CONCLUSIONS: The current study presents a comprehensive picture of self-medication in medical and pharmacy students in Bangladesh. It is clear from the findings that practice of self-medication is highly prevalent in medical and pharmacy students in the country. This may potentially increase misuse or irrational use of medicines. PMID- 26652178 TI - Mongoliibacter ruber gen. nov., sp. nov., a haloalkalitolerant bacterium of the family Cyclobacteriaceae isolated from a haloalkaline lake. AB - A novel haloalkalitolerant, rod-shaped bacterium, designated strain YIM 4-4T, was isolated from the surface water of the Dugerno lake, a haloalkaline lake in Inner Mongolia. The taxonomy of strain YIM 4-4T was investigated by a polyphasic approach. Strain YIM 4-4T was Gram-stain-negative, strictly aerobic, non-motile and formed red colonies. Optimal growth conditions were 28 degrees C, pH 8.0 11.0 and 0.5-2 % NaCl. The major respiratory quinone was menaquinone-7 (MK-7). The polar lipid profile was composed predominantly of phosphatidylethanolamine, six unidentified polar lipids, one phospholipid and one aminolipid. The predominant cellular fatty acids (>5 %) were iso-C15 : 0, iso-C17 : 1I/anteiso C17 : 1B, iso-C16 : 1G, iso-C17 : 0 3-OH, C16 : 1omega7c/C16 : 1omega6c and iso C16 : 1. The genomic DNA G+C content was 43.0 mol%. 16S rRNA gene sequence analysis indicated that the members of the genera Cecembia, Fontibacter, Aquiflexum and Indibacter of the family Cyclobacteriaceae (phylum Bacteroidetes) were the most closely related, with 16S rRNA gene sequence similarities ranging from 93.6 to 94.2 %. Other members of the family Cyclobacteriaceae showed sequence similarities < 93.0 %. On the basis of phenotypic, chemotaxonomic and phylogenetic properties, strain YIM 4-4T represents a novel species of a new genus, for which the name Mongoliibacter ruber gen. nov., sp. nov. is proposed. The type strain is YIM 4-4T ( = CCTCC AB 2012966T = DSM 27929T). PMID- 26652177 TI - Transplantation of hESC-derived hepatocytes protects mice from liver injury. AB - BACKGROUND: Hepatic cell therapy has become a viable alternative to liver transplantation for life-threatening liver diseases. However, the supply of human hepatocytes is limited due to the shortage of suitable donor organs required to isolate high-quality cells. Human pluripotent stem cells reflect a potential renewable source for generating functional hepatocytes. However, most differentiation protocols use undefined matrices or factors of animal origin; as such, the resulting hepatocytes are not Good Manufacturing Practice compliant. Moreover, the preclinical studies employed to assess safety and function of human embryonic stem cell (hESC)-derived hepatocytes are generally limited to immunodeficient mice. In the present study, we evaluate the generation of hepatocytes under defined conditions using a European hESC line (VAL9) which was derived under animal-free conditions. The function capacity of VAL9-derived hepatocytes was assessed by transplantation into mice with acetaminophen-induced acute liver failure, a clinically relevant model. METHODS: We developed a protocol that successfully differentiates hESCs into bipotent hepatic progenitors under defined conditions, without the use of chromatin modifiers such as dimethyl sulphoxide. These progenitors can be cryopreserved and are able to generate both committed precursors of cholangiocytes and neonate-like hepatocytes. RESULTS: Thirty days post-differentiation, hESCs expressed hepatocyte-specific markers such as asialoglycoprotein receptor and hepatic nuclear factors including HNF4alpha. The cells exhibited properties of mature hepatocytes such as urea secretion and UGT1A1 and cytochrome P450 activities. When transplanted into mice with acetaminophen-induced acute liver failure, a model of liver damage, the VAL9 derived hepatocytes efficiently engrafted and proliferated, repopulating up to 10 % of the liver. In these transplanted livers, we observed a significant decrease of liver transaminases and found no evidence of tumourigenicity. Thus, VAL9 derived hepatocytes were able to rescue hepatic function in acetaminophen-treated animals. CONCLUSIONS: Our study reveals an efficient protocol for differentiating VAL9 hESCs to neonatal hepatocytes which are then able to repopulate livers in vivo without tumour induction. The human hepatocytes are able to rescue liver function in mice with acetaminophen-induced acute toxicity. These results provide proof-of-concept that replacement therapies using hESC-derived hepatocytes are effective for treating liver diseases. PMID- 26652179 TI - An early evaluation of bleeding-related hospital readmissions among hospitalized patients with nonvalvular atrial fibrillation treated with direct oral anticoagulants. AB - OBJECTIVE: Clinical trials have demonstrated that direct oral anticoagulants (DOACs) are efficacious in reducing stroke risk among patients with nonvalvular atrial fibrillation (NVAF) with differences in the reduction of bleeding risks vs. warfarin. The objective of this study was to assess bleeding-related hospital readmissions among hospitalized NVAF patients treated with dabigatran, rivaroxaban, and apixaban in the US. RESEARCH DESIGN AND METHODS: Patients (>=18 years) with a discharge diagnosis of NVAF who received apixaban, dabigatran, or rivaroxaban during hospitalization were identified from the Premier Hospital database (1 January 2012-31 March 2014) and the Cerner Health Facts hospital database (1 January 2012-31 August 2014). Patients identified from each database were analyzed separately and grouped into three cohorts depending on which DOAC was received. Patient characteristics, hospital resource use and costs, and frequency of readmissions within 1 month were evaluated. RESULTS: Among study populations identified from the Premier database (N = 74,730) and the Cerner database (N = 14,201), patients who received apixaban were older, had greater comorbidity, and had higher stroke and bleeding risks. After controlling for patient characteristics, including comorbidity and stroke and bleeding risks, compared with patients who received apixaban during their index hospitalizations, the odds of bleeding-related hospital readmissions were significantly greater by 1.4-fold (p < 0.01) for patients who received rivaroxaban and 1.2-fold (p = 0.16) numerically greater for patients who received dabigatran among patients identified from the Premier Hospital database. Among patients in the Cerner Health Facts hospital database, bleeding-related hospital readmissions were significantly greater by 1.6-fold (p = 0.04) for patients who received rivaroxaban and 1.3-fold (p = 0.30) numerically greater for patients who received dabigatran compared to patients who received apixaban. LIMITATIONS: No causal relationship between treatment and outcomes can be concluded. CONCLUSIONS: NVAF patients using different DOACs had different characteristics, including stroke and bleeding risks. Use of rivaroxaban, compared to apixaban was associated with significantly greater risk of bleeding-related readmissions across two database claims analyses. PMID- 26652180 TI - Understanding and Tuning the Intrinsic Hydrophobicity of Rare-Earth Oxides: A DFT+U Study. AB - Rare-earth oxides (REOs) possess a remarkable intrinsic hydrophobicity, making them candidates for a myriad of applications. Although the superhydrophobicity of REOs has been explored experimentally, the atomistic details of the structure at the oxide-water interface are still not well understood. In this work, we report a density functional theory study of the interaction between water and CeO2, Nd2O3, and alpha-Al2O3 to explain their different wettability. The wetting of the metal oxide surface is controlled by geometric and electronic factors. While the electronic term is related to the acid-base properties of the surface layer, the geometric factor depends on the matching between adsorption sites and oxygen atoms from the hexagonal water network. For all the metal oxides considered here, water dissociation is confined to the first oxide-water layer. Hydroxyl groups on alpha-Al2O3 are responsible for the strong oxide-water interaction, and thus, both Al- and hydroxyl-terminated wet. On CeO2, the intrinsic hydrophobicity of the clean surface disappears when lattice hydroxyl groups (created by the reaction of water with oxygen vacancies) are present as they dominate the interaction and drive wetting. Therefore, hydroxyls may convert a intrinsic nonwetting surface into a wetting one. Finally, we also report that surface modifications, like cation substitution, do not change the acid-base character of the surface, and thus they show the same nonwetting properties as native CeO2 or Nd2O3. PMID- 26652181 TI - Physically equivalent temperature and mental and behavioural disorders in Germany in 2009-2011. AB - BACKGROUND: We aimed to understand the relationships of the weather as biometeorological and hospital admissions due to common mental and behavioural disorders in a national setting in recent years. METHODS: This is an ecological study. Ten percent of daily hospital admissions from the included hospitals (n = 1618) across Germany that were available between 1 January 2009 and 31 December 2011 (n = 5,235,600) were extracted from Statistisches Bundesamt, Germany. We identified F01-F51 mental ad behavioural disorders by International Classification of Diseases version 10 as the study outcomes. Daily weather data from 64 weather stations covering 13 German States including air temperature, humidity, wind speed, cloud cover, radiation flux and vapour pressure were obtained and generated into physiologically equivalent temperature (PET). We then plotted two-way fractional-polynomial regression. RESULTS: For the most subtypes, the highest admissions were recorded in spring. There were small peaks in autumn or late winter for a few subtypes as well. Admissions of delirium peaked when PET was at 0 degrees C. Admissions of personality disorders peaked at the coldest - when PET was at -10 degrees C. Admissions of schizophrenia and nonorganic sleep disorder peaked when PETs were between 0 and -10 degrees C while admissions of eating disorders dropped when PETs were above 10 degrees C. Admissions of depression and anxiety disorder did not vary much across PETs. Moreover, admissions of reaction to stress and dissociate disorder peaked when PETs were between 0 and 10 degrees C as well. CONCLUSIONS: More medical resources could have been needed for mental health on days when PETs were <10 degrees C than on other days. PMID- 26652182 TI - PHLPP phosphatases as a therapeutic target in insulin resistance-related diseases. AB - INTRODUCTION: Pleckstrin homology domain leucine-rich repeat protein phosphatases (PHLPPs), originally identified as Akt kinase hydrophobic motif specific phosphatases, have subsequently been shown to regulate several molecules recurring within the insulin signaling pathway. This observation suggests that PHLPP phosphatases may have a clinically relevant role in the pathogenesis of insulin resistance-related diseases and may thus represent suitable targets for the treatment of these conditions. AREAS COVERED: The literature pertaining to PHLPPs substrates is reviewed herein, along with information on the molecular players involved in regulating the activity and expression of PHLPP phosphatases. In the present review, knowledge of genetic variants in the genes that encode for PHLPP isozymes and the surrounding regulatory regions is also summarized. In addition, data from the studies addressing the role of PHLPPs in insulin resistance-related disorders and from those investigating the possibility to manipulate these phosphatases for therapeutic purposes are presented. EXPERT OPINION: A number of issues should be resolved before PHLPPs are pursued as therapeutic targets including: the mechanisms regulating the specificity of PHLPP isozymes; the possibility of differentially regulating PHLPP family members and the possible impact of PHLPPs modulation on the risk of cancer. PMID- 26652183 TI - Coordination of DNA damage tolerance mechanisms with cell cycle progression in fission yeast. AB - DNA damage tolerance (DDT) mechanisms allow cells to synthesize a new DNA strand when the template is damaged. Many mutations resulting from DNA damage in eukaryotes are generated during DDT when cells use the mutagenic translesion polymerases, Rev1 and Polzeta, rather than mechanisms with higher fidelity. The coordination among DDT mechanisms is not well understood. We used live-cell imaging to study the function of DDT mechanisms throughout the cell cycle of the fission yeast Schizosaccharomyces pombe. We report that checkpoint-dependent mitotic delay provides a cellular mechanism to ensure the completion of high fidelity DDT, largely by homology-directed repair (HDR). DDT by mutagenic polymerases is suppressed during the checkpoint delay by a mechanism dependent on Rad51 recombinase. When cells pass the G2/M checkpoint and can no longer delay mitosis, they completely lose the capacity for HDR and simultaneously exhibit a requirement for Rev1 and Polzeta. Thus, DDT is coordinated with the checkpoint response so that the activity of mutagenic polymerases is confined to a vulnerable period of the cell cycle when checkpoint delay and HDR are not possible. PMID- 26652184 TI - Extended Tumor Control after Dendritic Cell Vaccination with Low-Dose Cyclophosphamide as Adjuvant Treatment in Patients with Malignant Pleural Mesothelioma. AB - RATIONALE: We demonstrated previously that autologous tumor lysate-pulsed dendritic cell-based immunotherapy in patients with malignant pleural mesothelioma is feasible, well-tolerated, and capable of inducing immunologic responses against tumor cells. In our murine model, we found that reduction of regulatory T cells with metronomic cyclophosphamide increased the efficacy of immunotherapy. OBJECTIVES: To assess the decrease in number of peripheral blood regulatory T cells during combination therapy of low-dose cyclophosphamide and dendritic cell immunotherapy and determine the induction of immunologic responses with this treatment in patients with mesothelioma. METHODS: Ten patients with malignant pleural mesothelioma received metronomic cyclophosphamide and dendritic cell-based immunotherapy. During the treatment, peripheral blood mononuclear cells were analyzed for regulatory T cells and immunologic responses. MEASUREMENTS AND MAIN RESULTS: Administration of dendritic cells pulsed with autologous tumor lysate combined with cyclophosphamide in patients with mesothelioma was safe, the only side effect being moderate fever. Dendritic cell vaccination combined with cyclophosphamide resulted in radiographic disease control in 8 of the 10 patients. Overall survival was promising, with 7 out of 10 patients having a survival of greater than or equal to 24 months and two patients still alive after 50 and 66 months. Low-dose cyclophosphamide reduced the percentage of regulatory T cells of total CD4 cells in peripheral blood from 9.43 (range, 4.34-26.10) to 4.51 (range, 0.27-10.30) after 7 days of cyclophosphamide treatment (P = 0.02). CONCLUSIONS: Consolidation therapy with autologous tumor lysate-pulsed dendritic cell-based therapy and simultaneously reducing the tumor induced immune suppression is well-tolerated and shows signs of clinical activity in patients with mesothelioma. Clinical trial registered with www.clinicaltrials.gov (NCT 01241682). PMID- 26652185 TI - Hydride Transfer in DHFR by Transition Path Sampling, Kinetic Isotope Effects, and Heavy Enzyme Studies. AB - Escherichia coli dihydrofolate reductase (ecDHFR) is used to study fundamental principles of enzyme catalysis. It remains controversial whether fast protein motions are coupled to the hydride transfer catalyzed by ecDHFR. Previous studies with heavy ecDHFR proteins labeled with (13)C, (15)N, and nonexchangeable (2)H reported enzyme mass-dependent hydride transfer kinetics for ecDHFR. Here, we report refined experimental and computational studies to establish that hydride transfer is independent of protein mass. Instead, we found the rate constant for substrate dissociation to be faster for heavy DHFR. Previously reported kinetic differences between light and heavy DHFRs likely arise from kinetic steps other than the chemical step. This study confirms that fast (femtosecond to picosecond) protein motions in ecDHFR are not coupled to hydride transfer and provides an integrative computational and experimental approach to resolve fast dynamics coupled to chemical steps in enzyme catalysis. PMID- 26652186 TI - Evaluation of a hybrid anaerobic biofilm reactor treating winery effluents and using grape stalks as biofilm carrier. AB - Wine production processes generate large amount of both winery wastewater and solid wastes. Furthermore, working periods, volumes and pollution loads greatly vary over the year. Therefore, it is recommended to develop a low-cost treatment technology for the treatment of winery effluents taking into account the variation of the organic loading rate (OLR). Accordingly, we have investigated the sequential operation of an anaerobic biofilm reactor treating winery effluents and using grape stalks (GSs) as biofilm carrier with an OLR ranging from 0.65 to 27 gCOD/L/d. The result showed that, during the start-up with wastewater influent, the chemical oxygen demand (COD) removal rate ranged from 83% to 93% and was about 91% at the end of the start-up period that lasted for 40 days. After 3 months of inactivity period of the reactor (no influent feeding), we have succeeded in restarting-up the reactor in only 15 days with a COD removal of 82% and a low concentration of volatile fatty acids (1 g/L), which confirms the robustness of the reactor. As a consequence, GSs can be used as an efficient carrier support, allowing a fast reactor start-up, while the biofilm conserves its activity during a non-feeding period. The proposed hybrid reactor thus permits to treat both winery effluents and GSs. PMID- 26652187 TI - Letter to the editor. AB - Santos-Concejero and Tucker argued in their letter to the editor that in our study the running economy in achieving superior performance was overlooked due to some methodological aspects. Having given the remarks of Santos-Concejero and Tucker appropriate consideration, in this letter to the editor, we argue that our paper does not downplay the influence of running economy on the determinants of the East African running phenomenon, but rather adds novel insights into the interaction between running economy, maximal oxygen uptake and performance. PMID- 26652189 TI - A call for social justice and best practices for the integrated prevention of eating disorders and obesity. PMID- 26652188 TI - Solid-State (13)C NMR Delineates the Architectural Design of Biopolymers in Native and Genetically Altered Tomato Fruit Cuticles. AB - Plant cuticles on outer fruit and leaf surfaces are natural macromolecular composites of waxes and polyesters that ensure mechanical integrity and mitigate environmental challenges. They also provide renewable raw materials for cosmetics, packaging, and coatings. To delineate the structural framework and flexibility underlying the versatile functions of cutin biopolymers associated with polysaccharide-rich cell-wall matrices, solid-state NMR spectra and spin relaxation times were measured in a tomato fruit model system, including different developmental stages and surface phenotypes. The hydrophilic hydrophobic balance of the cutin ensures compatibility with the underlying polysaccharide cell walls; the hydroxy fatty acid structures of outer epidermal cutin also support deposition of hydrophobic waxes and aromatic moieties while promoting the formation of cell-wall cross-links that rigidify and strengthen the cuticle composite during fruit development. Fruit cutin-deficient tomato mutants with compromised microbial resistance exhibit less efficient local and collective biopolymer motions, stiffening their cuticular surfaces and increasing their susceptibility to fracture. PMID- 26652190 TI - Regulatory T Cells and Influenza. PMID- 26652191 TI - Virtual Issue on Materials Genomics. PMID- 26652192 TI - A Simple, Cost-Efficient Method to Separate Microalgal Lipids from Wet Biomass Using Surface Energy-Modified Membranes. AB - For the efficient separation of lipid extracted from microalgae cells, a novel membrane was devised by introducing a functional polymer coating onto a membrane surface by means of an initiated chemical vapor deposition (iCVD) process. To this end, a steel-use-stainless (SUS) membrane was modified in a way that its surface energy was systemically modified. The surface modification by conformal coating of functional polymer film allowed for selective separation of oil-water mixture, by harnessing the tuned interfacial energy between each liquid phase and the membrane surface. The surface-modified membrane, when used with chloroform based solvent, exhibited superb permeate flux, breakthrough pressure, and also separation yield: it allowed separation of 95.5 +/- 1.2% of converted lipid (FAME) in the chloroform phase from the water/MeOH phase with microalgal debris. This result clearly supported that the membrane-based lipid separation is indeed facilitated by way of membrane being functionalized, enabling us to simplify the whole downstream process of microalgae-derived biodiesel production. PMID- 26652193 TI - Effectiveness of START psychological intervention in reducing abuse by dementia family carers: randomized controlled trial. AB - BACKGROUND: Family carers of people with dementia frequently report acting abusively toward them and carer psychological morbidity predicts this. We investigated whether START (STrAtegies for RelaTives), a psychological intervention which reduces depression and anxiety in family carers also reduces abusive behavior in carers of people living in their own homes. We also explored the longitudinal course of carer abusive behavior over two year. METHODS: We included self-identified family carers who gave support at least weekly to people with dementia referred in the previous year to three UK mental health services and a neurological dementia service. We randomly assigned these carers to START, an eight-session, manual-based coping intervention, or treatment as usual (TAU). Carer abusive behavior (Modified Conflict Tactic Scale (MCTS) score >=2 representing significant abuse) was assessed at baseline, 4, 8, 12, and 24 months. RESULTS: We recruited 260 carers, 173 to START and 87 to TAU. There was no evidence that abusive behavior levels differed between randomization groups or changed over time. A quarter of carers still reported significant abuse after two years, but those not acting abusively at baseline did not become abusive. CONCLUSION: There was no evidence that START, which reduced carer anxiety and depression, reduced carer abusive behavior. For ethical reasons, we frequently intervened to manage concerning abuse reported in both groups, which may have disguised an intervention effect. Future dementia research should include elder abuse as an outcome, and consider carefully how to manage detected abuse. PMID- 26652194 TI - Synthesis of Mycobacterium tuberculosis Sulfolipid-3 Analogues and Total Synthesis of the Tetraacylated Trehaloglycolipid of Mycobacterium paraffinicum. AB - A novel methodology for the regioselective O6 acylation of the 2,3-diacyl trehaloses to access Mycobacterium tuberculosis sulfolipid SL-3 and related 2,3,6 triester glycolipid analogues is reported for the first time. The methodology was successfully extended to achieve the first total synthesis of the tetraacylated trehalose glycolipid from Mycobacterium paraffinicum. The corresponding 2,3,6' triesters trehalose glycolipids were also synthesized starting from the common 2,3-diacyl trehalose. These synthetic glycolipids are potential candidates for serodiagnosis and vaccine development for tuberculosis. PMID- 26652195 TI - First case successful twin pregnancy by transdermal therapy for patients with 5.0 mm thick endometrium during frozen-thawed embryo transfer: a case report. AB - We reported the first case of thin endometrium patient with twin conceived via transdermal therapy during frozen-thawed embryo transfer (FET). The patient used Progynova administration to preparate endometrium in the first FET cycle. The endometrial thickness was 5.0 mm after 10 days of Progynova administration, the cycle was cancelled. In the second FET cycle, the transdermal therapy was used to support the endometrial development. The endometrial thickness reached 7.6 mm, two embryos were transferred on the day 4 of progesterone intramuscularly. The patient was carrying twins for nine months. There is a speculation that transdermal therapy may be effective for patients with thin endometrium during FET and provide a new method of clinical treatment. PMID- 26652196 TI - Defining the Pathway to Definitive Care and Surgical Decompression after Traumatic Spinal Cord Injury: Results of a Canadian Population-Based Cohort Study. AB - Early access to specialized care after acute traumatic spinal cord injury (SCI) is associated with improved outcomes. However, many SCI patients do not receive timely access to such care. To characterize and quantify patients' pathway to definitive care and surgery post SCI, and to identify factors that may delay expeditious care, a population based cohort study was performed in Ontario. Using provincial administrative health data, adult patients with acute traumatic SCI who underwent surgery between 2002 and 2011 were identified using SCI specific ICD-10 codes. The relationship between predictor variables and a) time to arrival at the site of definitive care and b) time to surgery was statistically evaluated. Of 1,111 patients meeting eligibility criteria, mean times to arrival at the site of definitive care and to surgery were 8.1 +/- 25.5 and 49.4 +/- 65.0 hours respectively, with 53.3% of patients having surgery prior to 24 hours. While most patients (88.4%) reached the site of definitive care within 6 hours, only 34.2% reached surgery within 12 hours of arrival. Older age (IRR = 1.01; 95% CI: 1.01, 1.02), increased number of stops at intermediate health care centers (IRR = 7.70; 95% CI: 7.54, 7.86), higher comorbidity index (IRR = 1.43; 95% CI: 1.14, 1.72) and fall related SCI etiology (IRR = 1.16; 95% CI: 1.02, 1.29) were associated with increased time to arrival at definitive care. For surgery, increased age (OR = 1.02; 95% CI: 1.01, 1.03) and stops at intermediate health centers (OR = 2.48; 95% CI: 1.35, 4.56) were associated with a greater odds of undergoing late surgery (>24hrs). These results can inform policy decisions and facilitate creation of a streamlined path to specialized care for patients with acute SCI. PMID- 26652197 TI - New laurane-type sesquiterpenoids from the Chinese red alga Laurencia okamurai Yamada. AB - Two new laurane-type sesquiterpenoids, debromo-3alpha-hydroperoxy-3-epiaplysin (1) and debromo-3beta-hydroperoxyaplysin (2), together with seven known related compounds (3-9), were isolated from the Chinese red alga Laurencia okamurai. Their structures were elucidated by detailed analysis of spectroscopic data and by comparison with the literature. In bioassay, compounds 2, 4, 8, and 9 exhibited significant PTP1B inhibitory activity with IC50 values ranging from 4.9 to 14.9 MUg/ml. PMID- 26652198 TI - Identification and characterization of a -1 reading frameshift in the heavy chain constant region of an IgG1 recombinant monoclonal antibody produced in CHO cells. AB - Frameshifts lead to complete alteration of the intended amino acid sequences, and therefore may affect the biological activities of protein therapeutics and pose potential immunogenicity risks. We report here the identification and characterization of a novel -1 frameshift variant in a recombinant IgG1 therapeutic monoclonal antibody (mAb) produced in Chinese hamster ovary cells during the cell line selection studies. The variant was initially observed as an atypical post-monomer fragment peak in size exclusion chromatography. Characterization of the fragment peak using intact and reduced liquid chromatography-mass spectrometry (LC-MS) analyses determined that the fragment consisted of a normal light chain disulfide-linked to an aberrant 26 kDa fragment that could not be assigned to any HC fragment even after considering common modifications. Further analysis using LC-MS/MS peptide mapping revealed that the aberrant fragment contained the expected HC amino acid sequence (1-232) followed by a 20-mer novel sequence corresponding to expression of heavy chain DNA sequence in the -1 reading frame. Examination of the DNA sequence around the frameshift initiation site revealed that a mononucleotide repeat GGGGGG located in the IgG1 HC constant region was most likely the structural root cause of the frameshift. Rapid identification of the frameshift allowed us to avoid use of a problematic cell line containing the frameshift as the production cell line. The frameshift reported here may be observed in other mAb products and the hypothesis driven analytical approaches employed here may be valuable for rapid identification and characterization of frameshift variants in other recombinant proteins. PMID- 26652199 TI - Psychological hardiness predicts cardiovascular health. AB - Many, but not all people experience diminished health, performance and well-being as a function of exposure to stress. However, the underlying neurophysiological processes which characterize hardy or resilient people are not well understood. This study examines psychological hardiness and several indicators of cardiovascular health, including body mass index (BMI) and blood cholesterol markers in a sample of 338 middle-aged adults enrolled in a national security education program. Hierarchical regression analyses reveal that after controlling for the influence of age and sex, high hardiness is related to higher HDL - high density lipoprotein and less body fat (BMI). Lower hardiness is associated with greater total cholesterol to HDL ratio, a cardiovascular disease risk factor. These results suggest that psychological hardiness confers resilience in part through an influence on cholesterol production and metabolism. PMID- 26652200 TI - Provision of Services in Perinatal Palliative Care: A Multicenter Survey in the United States. AB - BACKGROUND: Congenital anomalies account for 20% of neonatal and infant deaths in the United States. Perinatal palliative care is a recent addition to palliative care and is meant to meet the needs of families who choose to continue a pregnancy affected by a life-limiting diagnosis. OBJECTIVE: To examine characteristics of programs and services provided, assess alignment with the National Consensus Project domains of care, and identify providers and disciplines involved in programs. DESIGN: A cross-sectional survey design included 48 items addressing funding and domains of quality care. SUBJECTS: Program representatives from 30 states (n = 75). PRINCIPAL RESULTS: Perinatal palliative care programs are housed in academic medical centers, regional or community hospitals, local hospices, or community-based organizations. Significant differences by program setting were observed for type of fetal diagnoses seen, formal training in communicating bad news to parents, mechanisms to ensure continuity of care, and reimbursement mechanisms. One hundred percent of programs provided attention to spiritual needs and bereavement services; 70% of programs are less than 10 years old. Follow-up with parents to assess whether goals were met occurs at 43% of the perinatal palliative care programs. Formal measures of quality assessment were articulated in 38% of programs. CONCLUSION: This study dramatically adds to the literature available on perinatal palliative care program settings, types, and domains of care. It is clear that there are a variety of types of programs and that the field is still developing. More work is needed to determine which quality measures are needed to address perinatal care needs in this population. PMID- 26652201 TI - The expression of response gene to complement 32 on renal ischemia reperfusion injury in rat. AB - To investigate the expression of response gene to complement 32 (RGC32) in rat with acute kidney injury (AKI) and to explore the role of RGC32 in renal injury and repair induced by ischemia reperfusion. Rats were randomly divided into two groups, including sham operation group (n = 48) and acute ischemia reperfusion injury (IRI) group (n = 48). Rats were sacrificed following reperfusion 2 h, 6 h, 24 h, 48 h, 72 h, 1 week (w), 2 w, and 4 w. The distribution and expression of RGC32 in renal tissue were observed by means of immunohistochemistry. The mean density of the images detected by Image-Pro Plus 6 was designated as the representative RGC32 expression levels. Meanwhile, RGC32 mRNA expression was measured by qPCR. RGC32 mainly expressed in cytoplasm of proximal tubular epithelial cells. However, RGC32 did not express in renal interstitium and vessels. The expression levels of RGC32 measured by immunohistochemistry at different reperfusion time were 0.0168 +/- 0.0029, 0.0156 +/- 0.0021, 0.0065 +/- 0.0013, 0.0075 +/- 0.0013, 0.0096 +/- 0.0014, 0.0132 +/- 0.0016, 0.0169 +/- 0.0014, 0.0179 +/- 0.0022, respectively. Compared with the sham group, the level of RGC32 expression in IRI group was significant lower at 24 h, 48 h, 72 h after IRI (p < 0.05). The expression levels of RGC32 mRNA at different reperfusion time measured by qPCR were corroborated the immunohistochemistry finding. The in vitro experiments show the expression of alpha-SMA and extracellular matrix expression increased signification when the RGC32 was silenced. Our data showed that the RGC32 expression in AKI rat decreased significantly reduces with different reperfusion time and performs a time-dependent manner. RGC32 may play an important role in the pathogenesis of AKI following IRI and repair in rat. PMID- 26652202 TI - "Switch-On" Fluorescent Sensing of Ascorbic Acid in Food Samples Based on Carbon Quantum Dots-MnO2 Probe. AB - This work describes a "switch-on" fluorescence approach for sensing of ascorbic acid (AA) in food samples. In the present method, the fluorescence intensity (FL) of carbon quantum dots (CQDs) was first quenched by addition of MnO2 nanosheets through an inner filter effect to form a CQDs-MnO2 probe. When reductive AA was introduced into the quenched CQDs solution, the added MnO2 was destroyed due to the redox reaction between AA and MnO2 nanosheets, and the FL of the system was recovered. Under the optimal conditions, the limit of detection for AA was 42 nM, with a wide concentration linear range of 0.18-90 MUM. Furthermore, the as fabricated fluorescent sensing system was successfully applied to the analysis of AA in fresh fruits, vegetables, and commercial fruit juices samples with satisfactory results. PMID- 26652203 TI - Ni-Fe and Pd-Fe Interactions in Nickel(II) and Palladium(II) Complexes of a Ferrocene-Bridged Bis(imidazolin-2-imine) Ligand. AB - The bis(imidazolin-2-imine) ligand N,N'-bis(1,3-diisopropyl-4,5 dimethylimidazolin-2-ylidene)-1,1'-ferrocenediamine, fc(NIm)2 (1) was prepared. Its reaction with [NiCl2(dme)] (dme = 1,2-dimethoxyethane) or [PdCl2(MeCN)2] afforded the tetrahedral, paramagnetic complex [(1-kappa(2)N,N')NiCl2] (6a) or the diamagnetic, square-planar complex [(1-kappa(2)N,N')PdCl2] (6b), respectively. For the latter, slow rearrangement to the ionic complex [(1 kappaFe,kappa(2)N,N')PdCl]Cl, [7]Cl, was observed, which was followed by (1)H NMR and UV/vis spectroscopy. Treatment of [7]Cl with NaBF4 afforded [7]BF4; the palladium atoms in both cations adopt square-planar environments with short Fe-Pd bonds (ca. 2.65 A). In addition, a series of dicationic complexes of the type [(1 kappaFe,kappa(2)N,N')ML](BF4)2 (8a: M = Ni, L = MeCN; 8b: M = Pd, L = MeCN; 9a: M = Ni, L = PMe3; 9b: M = Pd, L = PMe3) was prepared from 6a (M = Ni) or [7]BF4 by chloride abstraction with NaBF4 or AgBF4 in the presence of acetonitrile or trimethylphosphine, respectively. In the presence of triphenylphosphine, the palladium(II) complex [(1-kappaFe,kappa(2)N,N')Pd(PPh3)](BF4)2 (10) was isolated. Iron-nickel and iron-palladium bonding in these complexes was studied experimentally by NMR, UV/vis, and Mossbauer spectroscopy and by cyclic voltammetry. Detailed DFT calculations were carried out for the cations [(1 kappaFe,kappa(2)N,N')M(MeCN)](2+) in the 8a/8b couple, with Bader's atoms in molecules theory revealing the presence of noncovalent, closed-shell metal-metal interactions. Potential energy surface scans with successive elongation of the Fe M bonds allow an estimation of the iron-metal bond dissociation energies (BDE) as BDE(Fe-Ni) = 11.3 kcal mol(-1) and BDE(Fe-Pd) = 24.3 kcal mol(-1). PMID- 26652204 TI - Single-Crystalline SrRuO3 Nanomembranes: A Platform for Flexible Oxide Electronics. AB - The field of oxide electronics has benefited from the wide spectrum of functionalities available to the ABO3 perovskites, and researchers are now employing defect engineering in single crystalline heterostructures to tailor properties. However, bulk oxide single crystals are not conducive to many types of applications, particularly those requiring mechanical flexibility. Here, we demonstrate the realization of an all-oxide, single-crystalline nanomembrane heterostructure. With a surface-to-volume ratio of 2 * 10(7), the nanomembranes are fully flexible and can be readily transferred to other materials for handling purposes or for new materials integration schemes. Using in situ synchrotron X ray scattering, we find that the nanomembranes can bond to other host substrates near room temperature and demonstrate coupling between surface reactivity and electromechanical properties in ferroelectric nanomembrane systems. The synthesis technique described here represents a significant advancement in materials integration and provides a new platform for the development of flexible oxide electronics. PMID- 26652205 TI - An analysis of hospital cleaning staff's attitudes and conduct regarding hand hygiene and cleaning. AB - OBJECTIVE: The aim of this study was to analyze the attitudes and conduct of hospital cleaning staff regarding cleaning and hand hygiene. METHODS: In May and June 2014, the cleaning staff of Elazig Training and Research Hospital participated in this descriptive research. Data was collected by a survey prepared by the researchers. The SPSS program was used to analyze the data. RESULTS: Of the participants, 70.3% of them were male and their mean age was 38.69 +/- 6.61. The percentage of those hand washing before starting work was 29.8% for primary school graduates or those with lower education. For those with higher levels of education, the percentage was 68.2% (p < 0.001). The percentage of participants who wash their hands after work was 54.3% for primary school graduates and those with lower levels of education. For those with a higher level of education, the percentage was 84.1% (p < 0.001). The participants' use of personal protective equipment during work was that 97.8% of them used gloves, 39.9% bonnets and 56.5% medical masks. CONCLUSIONS: The attitudes and conduct of the cleaning staff are not sufficiently hygienic. These employees need training before and throughout their employment. PMID- 26652206 TI - Magnetic Control of the Light Reflection Anisotropy in a Biogenic Guanine Microcrystal Platelet. AB - Bioinspired but static optical devices such as lenses, retarders, and reflectors have had a significant impact on the designs of many man-made optical technologies. However, while numerous adaptive and flexible optical mechanisms are found throughout the animal kingdom, highly desirable biomimetic copies of these remarkable smart systems remain, in many cases, a distant dream. Many aquatic animals have evolved highly efficient reflectors based on multilayer stacks of the crystallized nucleic acid base guanine. With exceptional levels of spectral and intensity control, these reflectors represent an interesting design pathway towards controllable micromirror structures. Here we show that individual guanine crystals, with dimensions of 5 MUm * 20 MUm * 70 nm, can be magnetically controlled to act as individual micromirrors. By applying magnetic fields of 500 mT, the reflectivity of these crystals can be switched off and on for the change in reflectivity. Overall, the use of guanine represents a novel design scheme for a highly efficient and controllable synthetic organic micromirror array. PMID- 26652208 TI - Quantifying Electron Delocalization in Electrides. AB - Electrides are ionic solids whose anions are electrons confined to crystal voids. We show that our electron delocalization range function EDR(r;d), which quantifies the extent to which an electron at point r in a calculated wave function delocalizes over distance d, provides useful insights into electrides. The EDR quantifies the characteristic delocalization length of electride electrons and provides a chemically intuitive real-space picture of the electrons' distribution. It also gives a potential diagnostic for whether a given formula unit will form a solid electride at ambient pressure, quantifies the effects of electron-electron correlation on confined electrons' interactions, and highlights analogies between covalent bonding and the interaction of interstitial quasi-atoms in high-pressure electrides. These results motivate adding the EDR to the toolbox of theoretical methods applied to electrides. PMID- 26652207 TI - Penalized weighted low-rank approximation for robust recovery of recurrent copy number variations. AB - BACKGROUND: Copy number variation (CNV) analysis has become one of the most important research areas for understanding complex disease. With increasing resolution of array-based comparative genomic hybridization (aCGH) arrays, more and more raw copy number data are collected for multiple arrays. It is natural to realize the co-existence of both recurrent and individual-specific CNVs, together with the possible data contamination during the data generation process. Therefore, there is a great need for an efficient and robust statistical model for simultaneous recovery of both recurrent and individual-specific CNVs. RESULT: We develop a penalized weighted low-rank approximation method (WPLA) for robust recovery of recurrent CNVs. In particular, we formulate multiple aCGH arrays into a realization of a hidden low-rank matrix with some random noises and let an additional weight matrix account for those individual-specific effects. Thus, we do not restrict the random noise to be normally distributed, or even homogeneous. We show its performance through three real datasets and twelve synthetic datasets from different types of recurrent CNV regions associated with either normal random errors or heavily contaminated errors. CONCLUSION: Our numerical experiments have demonstrated that the WPLA can successfully recover the recurrent CNV patterns from raw data under different scenarios. Compared with two other recent methods, it performs the best regarding its ability to simultaneously detect both recurrent and individual-specific CNVs under normal random errors. More importantly, the WPLA is the only method which can effectively recover the recurrent CNVs region when the data is heavily contaminated. PMID- 26652209 TI - Elevations in Tissue Fluid-Attenuated Inversion Recovery Signal Are Related to Good Functional Outcome after Thrombolytic Treatment. AB - BACKGROUND: Early elevations in the parenchymal signal intensity on T2-weighted images, including fluid-attenuated inversion recovery (FLAIR) sequences, within the ischemic territory are considered as a marker of successful recanalization following thrombolytic treatment. In this study, our aim was to assess whether quantitatively determined FLAIR hyperintensity increases could be predictive of improved functional outcome in patients with acute ischemic stroke. METHODS: Patients receiving intravenous thrombolysis for proximal anterior circulation strokes were included in the study. FLAIR hyperintensity ratio was determined on magnetic resonance imaging obtained within 72 hours of symptom onset. Univariate and multivariate analyses were performed to determine predictors of good functional outcome at 90 days. RESULTS: The study population was composed of 65 patients. The median (interquartile range) FLAIR hyperintensity ratio was significantly higher among patients with good functional outcome (modified Rankin Scale score <= 3 at day 90, 1.4 [1.2-1.7] versus 1.2 [1.1-1.4], P = .005). Patients with a FLAIR hyperintensity ratio of 1.3 or higher were 4.4 (95% confidence interval 1.6-12.7) times more likely to be independent functionally at the end of 3 months. Higher admission National Institutes of Health Stroke Scale score and age, together with lower FLAIR hyperintensity ratio (P = .006), were found to be significantly and independently related to unfavorable outcome at 90 day follow-up in multivariate analyses. CONCLUSIONS: Our findings suggest that a rise in FLAIR hyperintensity signal within the ischemic tissue is suggestive of favorable outcome in patients undergoing intravenous thrombolysis. This tissue marker of favorable outcome is irrespective of other parameters that are crucial in the prognosis of ischemic stroke, such as age and stroke severity. PMID- 26652210 TI - Understanding Genetics and Pediatric Cardiac Health. AB - Congenital heart defects (CHD) continue to be the most prevalent birth defect that occurs worldwide in approximately 6-8 of every 1,000 live births. High rates of morbidity and mortality in infants, children, and adults living with CHD place a growing need for health care professionals (HCPs) to better understand potentially modifiable genetic and environmental influences. This paper will present examples of research and governmental initiatives that support genetics education and research and a review of known genetic factors associated with CHD development. ORGANIZING CONSTRUCT: A review of the known genetic factors on risk for CHD formation in infants will be provided to help health care professionals gain a greater understanding of the genetic influences on pediatric cardiac health. CONCLUSIONS: There are known genetic pathways and risk factors that contribute to development of CHD. This paper is a primer for nurses and HCPs providing information of the genetics and inheritance patterns of CHD to be useful in daily clinical practice. CLINICAL RELEVANCE: Nurses work in multiple communities where they are uniquely positioned to educate and provide information about research and current models of care with families affected by CHD. Nurses and HCPs who better understand genetic risk factors associated with CHD development can more promptly refer and offer treatment for these children and families thus providing individuals of childbearing age with the necessary resources and information about risk factors. PMID- 26652211 TI - Editorial for the Genetics Issue. PMID- 26652212 TI - Alkynylation of Thiols with Ethynylbenziodoxolone (EBX) Reagents: alpha- or beta- pi-Addition? AB - The alkynylation of thiols with EthynylBenziodoXolone (EBX) reagents is a fast and chemoselective method for the synthesis of thioalkynes. Combined experimental and computational studies are reported, which led to the identification of a new mechanism for this reaction, proceeding via an initial sulfur-iodine interaction followed by beta-addition, alpha-elimination, and a 1,2-shift. Depending on the substituent on the alkyne, this mechanism can be favored over the previously disclosed concerted alpha-addition pathway. PMID- 26652213 TI - Improving cardiovascular protection: focus on a cardiovascular polypill. AB - Lack of adherence may explain, at least in part, the poor cardiovascular risk factors control observed in patients with ischemic heart disease, increasing the risk of developing new events. Polypill improves medication adherence, which may actually reduce blood pressure and LDL cholesterol compared with the drugs given separately. The fixed combination of acetylsalicylic acid 100 mg + ramipril 2.5, 5, or 10 mg + either simvastatin 40 mg or atorvastatin 20 mg is the unique cardiovascular polypill that has been registered in 22 countries worldwide. The polypill-containing simvastatin has been specifically tested in a clinical trial including only patients with ischemic heart disease. The FOCUS study showed that patients treated with the polypill showed a higher adherence compared with those receiving separate medications. PMID- 26652214 TI - Assessment of Central Corneal Thickness in Different Subtypes of Systemic Sclerosis. AB - PURPOSE: To compare central corneal thickness between patients with diffuse cutaneous systemic sclerosis and limited cutaneous systemic sclerosis. METHODS: A total of 53 consecutive patients with systemic sclerosis were enrolled in this study. All subjects were screened for age, gender, classification of disease subtype, autoantibody profile, duration of disease, organ involvement, current treatment, tear break-up time, Schirmer test, and measurement of the central corneal thickness with an ultrasonic pachymeter. RESULTS: No statistically significant differences were found in terms of age, sex, and duration of the disease, and dry eye evaluation between systemic sclerosis subsets. The mean central corneal thickness was 535.3 +/- 37.6 um (range, 471-619 um) in diffuse cutaneous systemic sclerosis patients, and 539.3 +/- 37.1 um (range, 484-651 um) in limited cutaneous systemic sclerosis (p = 0.71). CONCLUSIONS: Central corneal thickness in patients with diffuse cutaneous systemic sclerosis is not different from the one in limited cutaneous systemic sclerosis. PMID- 26652215 TI - Improved volatile fatty acids anaerobic production from waste activated sludge by pH regulation: Alkaline or neutral pH? AB - In this study, the anaerobic fermentation was carried out for volatile fatty acids (VFAs) production at different pH (between 7.0 and 10.0) conditions with untreated sludge and heat-alkaline pretreated waste activated sludge. In the fermentation with untreated sludge, the extent of hydrolysis of organic matters and extent of acidification at alkaline pH are 54.37% and 30.37%, respectively, resulting in the highest VFAs yield at 235.46mg COD/gVS of three pH conditions. In the fermentation with heat-alkaline pretreated sludge, the acidification rate and VFAs yield at neutral pH are 30.98% and 240.14mg COD/gVS, respectively, which are higher than that at other pH conditions. With the glucose or bovine serum albumin as substrate for VFAs production, the neutral pH showed a higher VFAs concentration than the alkaline pH condition. The results of terminal restriction fragment length polymorphism (T-RFLP) analysis indicated that the alkaline pH caused low microbial richness. Based on the results in this study, we demonstrated that the alkaline pH is favor of hydrolysis of organic matter in sludge while neutral pH improved the acidogenesis for the VFAs production from sludge. Our finding is obvious different to the previous research and helpful for the understanding of how heat-alkaline pretreatment and alkaline fermentation influence the VFAs production, and beneficial to the development of VFAs production process. PMID- 26652216 TI - A Framework for Assessing the Value of Investments in Nonclinical Prevention. AB - We present a high-level framework to show the process by which an investment in primary prevention produces value. We define primary prevention broadly to include investments in any of the determinants of health. Although it builds on previously developed frameworks, ours incorporates several additional features. It distinguishes direct and upstream determinants of health, a distinction that can help identify, describe, and track the impact of a policy or program on health and health care costs. It recognizes multiple dimensions of value, including the need to establish the nonhealth value of investments whose objectives are not limited to improvements in health (and whose costs should not be attributed solely to the health benefits). Finally, it emphasizes the need to describe value from the perspectives of the multiple stakeholders that can influence such investments. PMID- 26652217 TI - Descriptive Epidemiology of Objectively Measured Walking Among US Pregnant Women: National Health and Nutrition Examination Survey, 2005-2006. AB - The objective of this study was to examine population-based prevalence of walking in the United States among pregnant women. Objectively measured walking data on 197 pregnant women who participated in the National Health and Nutrition Examination Survey 2005-2006 were analyzed. In general, pregnant women showed a level of walking below the recommendation; most walking was at low-intensity levels. These findings suggest that walking, particularly at higher intensity than usual, should be promoted among pregnant women. PMID- 26652218 TI - Prevalence of Adverse Pregnancy Outcomes, by Maternal Diabetes Status at First and Second Deliveries, Massachusetts, 1998-2007. AB - INTRODUCTION: Understanding patterns of diabetes prevalence and diabetes-related complications across pregnancies could inform chronic disease prevention efforts. We examined adverse birth outcomes by diabetes status among women with sequential, live singleton deliveries. METHODS: We used data from the 1998-2007 Massachusetts Pregnancy to Early Life Longitudinal Data System, a population based cohort of deliveries. We restricted the sample to sets of parity 1 and 2 deliveries. We created 8 diabetes categories using gestational diabetes mellitus (GDM) and chronic diabetes mellitus (CDM) status for the 2 deliveries. Adverse outcomes included large for gestational age (LGA), macrosomia, preterm birth, and cesarean delivery. We computed prevalence estimates for each outcome by diabetes status. RESULTS: We identified 133,633 women with both parity 1 and 2 deliveries. Compared with women who had no diabetes in either pregnancy, women with GDM or CDM during any pregnancy had increased risk for adverse birth outcomes; the prevalence of adverse outcomes was higher in parity 1 deliveries among women with no diabetes in parity 1 and GDM in parity 2 (for LGA [8.5% vs 15.1%], macrosomia [9.7% vs. 14.9%], cesarean delivery [24.7% vs 31.3%], and preterm birth [7.7% vs 12.9%]); and higher in parity 2 deliveries among those with GDM in parity 1 and no diabetes in parity 2 (for LGA [12.3% vs 18.2%], macrosomia [12.3% vs 17.2%], and cesarean delivery [27.0% vs 37.9%]). CONCLUSIONS: Women with GDM during one of 2 sequential pregnancies had elevated risk for adverse outcomes in the unaffected pregnancy, whether the diabetes-affected pregnancy preceded or followed it. PMID- 26652220 TI - Novel use of a flowable collagen-glycosaminoglycan matrix (IntegraTM Flowable Wound Matrix) combined with percutaneous cannula scar tissue release in treatment of post-burn malfunction of the hand--A preliminary 6 month follow-up. AB - INTRODUCTION: Long-term function following severe burns to the hand may be poor secondary to scar adhesions to the underlying tendons, webspaces, and joints. In this pilot study, we report the feasibility of applying a pasty dermal matrix combined with percutaneous cannula teno- and adhesiolysis. PATIENTS AND METHODS: In this 6 month follow-up pilot study, we included eight hands in five patients with hand burns undergoing minimal-invasive, percutaneous cannula adhesiolysis and injection of INTEGRATM Flowable Wound Matrix for a pilot study of this new concept. The flowable collagen-glycosaminoglycan wound matrix (FCGWM) was applied with a buttoned 2mm cannula to induce formation of a neo-gliding plane. Post treatment follow-up was performed to assess active range of motion (AROM), grip strength, Disabilities of the Arm, Shoulder and Hand (DASH) score, Vancouver Scar Scale (VSS) and quality of life Short-Form (SF)-36 questionnaire. RESULTS: No complications were detected associated with the treatment of FCGWM injection. The mean improvement (AROM) at 6 months was 30.6 degrees for digits 2-5. The improvement in the DASH score was a mean of 9 points out of 100. The VSS improved by a mean of 2 points out of 14. DISCUSSION: The study demonstrates the feasibility and safety of percutaneous FCGWM for dermal augmentation after burn. Results from this pilot study show improvements in AROM for digits 2-5, functional scores from the patient's perspective (DASH) and scar quality (VSS). The flowable form of established INTEGRATM wound matrix offers the advantage of minimal-invasive injection after scar release in the post-burned hand with a reduction in the risk of postsurgical re-scarring. PMID- 26652219 TI - Weight Outcomes of Latino Adults and Children Participating in the Y Living Program, a Family-Focused Lifestyle Intervention, San Antonio, 2012-2013. AB - INTRODUCTION: US Latinos have disproportionately higher rates of obesity and physical inactivity than the general US population, putting them at greater risk for chronic disease. This evaluation aimed to examine the impact of the Y Living Program (Y Living), a 12-week family-focused healthy lifestyle program, on the weight status of adult and child (aged >=7 years) participants. METHODS: In this pretest-posttest evaluation, participants attended twice-weekly group education sessions and engaged in physical activity at least 3 times per week. Primary outcome measures were body mass index ([BMI], zBMI and BMI percentile for children), weight, waist circumference, and percentage body fat. Wilcoxon signed rank tests and mixed effects models were used to evaluate pretest-posttest differences (ie, absolute change and relative change) for adults and children separately. RESULTS: BMI, weight, waist circumference, and percentage body fat improved significantly (both absolutely and relatively) among adults who completed the program (n = 180; all P <= .001). Conversely, child participants that completed the program (n = 72) showed no improvements. Intervention effects varied across subgroups. Among adults, women and participants who were obese at baseline had larger improvements than did children who were obese at baseline or who were in families that had an annual household income of $15,000 or more. CONCLUSION: Significant improvements in weight were observed among adult participants but not children. This family-focused intervention has potential to prevent excess weight gain among high-risk Latino families. PMID- 26652221 TI - Assessment of the Electronic Factors Determining the Thermodynamics of "Oxidative Addition" of C-H and N-H Bonds to Ir(I) Complexes. AB - A study of electronic factors governing the thermodynamics of C-H and N-H bond addition to Ir(I) complexes was conducted. DFT calculations were performed on an extensive series of trans-(PH3)2IrXL complexes (L = NH3 and CO; X = various monodentate ligands) to parametrize the relative sigma- and pi donating/withdrawing properties of the various ligands, X. Computed energies of oxidative addition of methane to a series of three- and four-coordinate Ir(I) complexes bearing an ancillary ligand, X, were correlated with the resulting (sigma(X), pi(X)) parameter set. Regression analysis indicates that the thermodynamics of addition of methane to trans-(PH3)2IrX are generally strongly disfavored by increased sigma-donation from the ligand X, in contradiction to widely held views on oxidative addition. The trend for oxidative addition of methane to four-coordinate Ir(I) was closely related to that observed for the three-coordinate complexes, albeit slightly more complicated. The computational analysis was found to be consistent with the rates of reductive elimination of benzene from a series of isoelectronic Ir(III) phenyl hydride complexes, measured experimentally in this work and previously reported. Extending the analysis of ancillary ligand energetic effects to the oxidative addition of ammonia to three coordinate Ir(I) complexes leads to the conclusion that increasing sigma-donation by X also disfavors oxidative addition of N-H bonds to trans-(PH3)2IrX. However, coordination of NH3 to the Ir(I) center is disfavored even more strongly by increasing sigma-donation by X, which explains why the few documented examples of H-NH2 oxidative addition to transition metals involve complexes with strongly sigma-donating ligands situated trans to the site of addition. An orbital-based rationale for the observed results is presented. PMID- 26652222 TI - Application of 3-Methyl-2-vinylindoles in Catalytic Asymmetric Povarov Reaction: Diastereo- and Enantioselective Synthesis of Indole-Derived Tetrahydroquinolines. AB - The first application of 3-methyl-2-vinylindoles in catalytic asymmetric Povarov reactions has been established via the three-component reactions of 3-methyl-2 vinylindoles, aldehydes, and anilines in the presence of chiral phosphoric acid, providing easy access to chiral indole-derived tetrahydroquinolines with three contiguous stereogenic centers at high yields (up to 99%) and with excellent diastereo- and enantioselectivities (all >95:5 dr, up to 96% ee). This mode of catalytic asymmetric three-component reaction offers a step-economic and atom economic strategy for accessing enantioenriched indole-derived tetrahydroquinolines with structural diversity and complexity. PMID- 26652223 TI - Examining the asymptote in safety progress: a literature review. AB - Many industries are confronted by plateauing safety performance as measured by the absence of negative events--particularly lower-consequence incidents or injuries. At the same time, these industries are sometimes surprised by large fatal accidents that seem to have no connection with their understanding of the risks they faced; or with how they were measuring safety. This article reviews the safety literature to examine how both these surprises and the asymptote are linked to the very structures and practices organizations have in place to manage safety. The article finds that safety practices associated with compliance, control and quantification could be partly responsible. These can create a sense of invulnerability through safety performance close to zero; organizational resources can get deflected into unproductive or counterproductive initiatives; obsolete practices for keeping human performance within a pre-specified bandwidth are sustained; and accountability relationships can encourage suppression of the 'bad news' necessary to learn and improve. PMID- 26652224 TI - Knee stability after arthroscopic anterior cruciate ligament reconstruction using the middle third of the patellar ligament and quadrupled hamstring tendons grafts - A two-year follow-up. AB - Knee stability after surgical anterior cruciate ligament (ACL) reconstruction using quadrupled hamstring tendons graft (gracilis and semitendinosus) was compared with that using the middle third of the patellar ligament. All subjects participating in this study had ACL rupture diagnosed by clinical examination and MRI and underwent identical surgical procedure apart from the choice of graft. A total of 112 patients with either patellar ligament or quadrupled hamstring tendons graft were evaluated for 24 months following surgery. Patients were similar in terms of age, sex, activity level, knee instability level and rehabilitation programme. Clinical tests and a measuring instrument, the KT-1000 arthrometer, were used to evaluate knee stability after reconstruction. During the 24-month study there were no significant differences in clinical stability of the knee and the use of both grafts resulted in satisfactory knee stability. The difference between the groups according to the graft was noticed 6 months after reconstruction when the results obtained by a measuring instrument showed that knee stability was significantly higher with the patellar ligament graft (Fisher's exact test, p=0.022). PMID- 26652225 TI - Alteration of Masquelet's induced membrane characteristics by different kinds of antibiotic enriched bone cement in a critical size defect model in the rat's femur. AB - The Masquelet technique for the treatment of large bone defects consists of a 2 stage procedure. In the first stage, a polymethylmethacrylate (PMMA) cement spacer is inserted into the bony defect of a rat's femur and over a period of 2-4 weeks a membrane forms that encapsulates the defect/spacer. In a second operation the membrane is opened, the PMMA spacer is removed and the resulting cavity is filled with autologous bone. Different kinds of bone cements are available, with or without supplemental antibiotics. Both might influence the development and the characteristics of the induced membrane which might affect the bone healing response. Hence, this comparative study was performed to elucidate the effect of different bone cements with or without supplemental antibiotics on the development of an induced membrane in a critical size femur defect model in rats. A total of 72 male SD rats received a 10mm critical size defect of the femur which was stabilised by a plate osteosynthesis and filled with either Palacos+Gentamycin, Copal Gentamycin+Vancomycin, Copal+Gentamycin+Clindamycin or Copal Spacem. The induced membranes were analysed after two, four and six weeks (wks) after insertion of the cement spacers (n=6/group). Paraffin embedded histological sections of the membrane were microscopically analysed for membrane thickness, elastic fibres, vascularisation and proliferation by an independent observer blinded to the group setup. The thickness of the induced membrane increased significantly from 2 wks (553 MUm) to 6 wks (774 MUm) in group Palacos+Gentamycin whereas membrane thickness decreased significantly in groups Copal+Gentamycin+Clindamycin (682-329 MUm) and Copal Spacem (916 MUm to 371 MUm). The comparison between the groups revealed significantly increased membrane thickness in group Palacos+Gentamycin and Copal Gentamycin+Vancomycin in comparison to group Copal+Gentamycin+Clindamycin six weeks after induction. However, the fraction of elastic fibres was significantly increased in groups Copal+Gentamycin+Clindamycin (71%, 80%) and Copal Spacem (82%, 81%) after 2 and 4 weeks in comparison to the groups Palacos+Gentamycin (56%, 57%) and Copal Gentamycin+Vancomycin (63%, 69%). Those differences however were partly diminished after 6 wks. The ratio of immature (vWF+) to more mature (CD31+) blood vessels increased significantly in groups Palacos+Gentamycin and Copal Gentamycin+Vancomycin whereas no significant alterations were noted in groups Copal+Gentamycin+Clindamycin and Copal Spacem. For the first time we demonstrated that thickness and proportion of elastic fibres in induced membranes were influenced by the type of cement and the kind of supplemental antibiotics being used. Whether these alterations of the induced membrane have an effect on bone healing remains to be proven in future studies. PMID- 26652226 TI - Knee dislocation and vascular injury: 4 year experience at a UK Major Trauma Centre and vascular hub. AB - INTRODUCTION: Knee dislocation is a rare but potentially devastating injury. Quoted rates of associated vascular compromise vary dramatically between 3.3% and 64%, and the best approach to investigate and diagnose such an injury remains controversial. We aim to evaluate our own 4-year experience of knee dislocation and vascular injury as a UK Major Trauma Centre and vascular hub. METHODS: Knee dislocation was defined as disruption of at least two major stabilising ligaments of the knee and gross instability requiring an operation. Patients were identified from the Department of Trauma and Orthopaedics patient database across a 4 year period from 2010 to 2014. Electronic patient records, imaging and hard notes were retrieved and reviewed retrospectively and relevant information recorded. RESULTS: Twenty-five cases of knee dislocation were identified. Male to female ratio was 11.5:1 with a mean age of 33 years (range 17-71). One patient had a vascular injury which ultimately required a femoro-popliteal bypass graft. Twenty-four patients had documented examination findings pertaining to the vascular status of the limb. Seventeen patients had specific reference to the presence or absence of pedal pulses. The remaining seven cases were documented as either "warm well perfused" or "neurovascularly in-tact". Nine patients were discharged directly from the emergency department with outpatient follow up. All admitted cases had documented vascular examination findings the following day. Two patients had additional adjunctive non-invasive investigations. No patients were examined with duplex ultrasound, although two patients had pulses confirmed with hand-held doppler ultrasound. Three patients had an angiogram. Four cases have a documented discussion with or review from a vascular surgeon. DISCUSSION AND CONCLUSIONS: Our rates of vascular injury are in line with the most recent and largest study to date. Non-invasive investigation and selective angiography has been safe in identifying significant vascular compromise, however, there is inconsistency in management pathways, and too much reassurance attributed to the presence of pedal pulses on initial examination. Safety and consistency could be improved with the introduction of a formalised evidence-based protocol for the initial evaluation of knee dislocation and vascular injury. PMID- 26652227 TI - Dipeptidyl peptidase-4 inhibitors as add-on therapy to insulin: rationale and evidences. AB - Type 2 diabetes mellitus being a progressive disease will eventually require insulin therapy. While insulin therapy is the ultimate option, many patients still fall short of target glycemic goals. This could, perhaps be due to the fear, unwillingness and practical barriers to insulin intensification. Hypoglycemia, oedema and weight gain is another limitation. Newer therapies with dipeptidyl peptidase-4 (DPP-4) inhibitors and sodium-glucose co-transporter-2 (SGLT-2) inhibitors are exciting options as both classes do not cause hypoglycemia and are either weight neutral or cause weight loss. DPP-4 inhibitors are an appealing option as an add-on therapy to insulin especially in elderly and patients with renal impairment. Moreover, glucose-dependent insulinotropic polypeptide (GIP) mediated augmentation of glucagon by DPP-4 inhibitors could also protect against hypoglycemia. These collective properties make these class a potential add-on candidate to insulin therapy. This article will review the efficacy and safety of DPP-4 inhibitors as an add-on to insulin therapy. PMID- 26652228 TI - Corrigendum. PMID- 26652229 TI - Late-onset polyglucosan body myopathy in five patients with a homozygous mutation in GYG1. AB - Five Sardinian patients presented in their 5th or 6th decade with progressive limb girdle muscle weakness but their muscle biopsies showed vacuolar myopathy. The more or less abundant subsarcolemmal and intermyofibrillar vacuoles showed intense, partially alpha-amylase resistant, PAS-positive deposits consistent with polyglucosan. The recent description of late-onset polyglucosan myopathy has prompted us to find new genetic defects in the gene (GYG1) encoding glycogenin-1, the crucial primer enzyme of glycogen synthesis in muscle. We found a single homozygous intronic mutation harbored by five patients, who, except for two siblings, appear to be unrelated but all five live in central or south Sardinian villages. PMID- 26652230 TI - Differentiating the effects of characteristics of PM pollution on mortality from ischemic and hemorrhagic strokes. AB - Though increasing evidence supports significant association between particulate matter (PM) air pollution and stroke, it remains unclear what characteristics, such as particle size and chemical constituents, are responsible for this association. A time-series model with quasi-Poisson function was applied to assess the association of PM pollution with different particle sizes and chemical constituents with mortalities from ischemic and hemorrhagic strokes in Guangzhou, China, we controlled for potential confounding factors in the model, such as temporal trends, day of the week, public holidays, meteorological factors and influenza epidemic. We found significant association between stroke mortality and various PM fractions, such as PM10, PM2.5 and PM1, with generally larger magnitudes for smaller particles. For the PM2.5 chemical constituents, we found that organic carbon (OC), elemental carbon (EC), sulfate, nitrate and ammonium were significantly associated with stroke mortality. The analysis for specific types of stroke suggested that it was hemorrhagic stroke, rather than ischemic stroke, that was significantly associated with PM pollution. Our study shows that various PM pollution fractions are associated with stroke mortality, and constituents primarily from combustion and secondary aerosols might be the harmful components of PM2.5 in Guangzhou, and this study suggests that PM pollution is more relevant to hemorrhagic stroke in the study area, however, more studies are warranted due to the underlying limitations of this study. PMID- 26652231 TI - Watching a Procedure Evolve: Sequential Findings From the TVT Registry. PMID- 26652232 TI - Annual Outcomes With Transcatheter Valve Therapy: From the STS/ACC TVT Registry. AB - BACKGROUND: The Society of Thoracic Surgeons (STS)/American College of Cardiology (ACC) Transcatheter Valve Therapy (TVT) Registry has been a joint initiative of the STS and the ACC in concert with multiple stakeholders. The TVT Registry has important information regarding patient selection, delivery of care, science, education, and research in the field of structural valvular heart disease. OBJECTIVES: This report provides an overview on current U.S. TVT practice and trends. The emphasis is on demographics, in-hospital procedural characteristics, and outcomes of patients having transcatheter aortic valve replacement (TAVR) performed at 348 U.S. centers. METHODS: The TVT Registry captured 26,414 TAVR procedures as of December 31, 2014. Temporal trends between 2012 and 2013 versus 2014 were compared. RESULTS: Comparison of the 2 time periods reveals that TAVR patients remain elderly (mean age 82 years), with multiple comorbidities, reflected by a high mean STS predicted risk of mortality (STS PROM) for surgical valve replacement (8.34%), were highly symptomatic (New York Heart Association functional class III/IV in 82.5%), frail (slow 5-m walk test in 81.6%), and have poor self-reported health status (median baseline Kansas City Cardiomyopathy Questionnaire score of 39.1). Procedure performance is changing, with an increased use of moderate sedation (from 1.6% to 5.1%) and increase in femoral access using percutaneous techniques (66.8% in 2014). Vascular complication rates are decreasing (from 5.6% to 4.2%), whereas site-reported stroke rates remain stable at 2.2%. CONCLUSIONS: The TVT Registry provides important information on characteristics and outcomes of TAVR in contemporary U.S. clinical practice. It can be used to identify trends in practice and opportunities for quality improvement. PMID- 26652233 TI - Are we misusing fiber posts? Guest editorial. PMID- 26652236 TI - Emotional memory processing: which comes first - depression or poor sleep? PMID- 26652237 TI - Poor sleep quality influences emotional evaluations even after controlling for depression. PMID- 26652238 TI - A community-oriented framework to increase screening and treatment of obstructive sleep apnea among blacks. AB - OBJECTIVE: Obstructive sleep apnea (OSA) is a leading sleep disorder that is disproportionately more prevalent in minority populations and is a major risk factor for cardiovascular disease (CVD) morbidity and mortality. OSA is associated with many chronic conditions including hypertension, diabetes, and obesity, all of which are disproportionately more prevalent among blacks (ie, peoples of African American, Caribbean, or African descent). METHODS: This article reviews studies conducted in the United States (US) that investigated sleep screenings and adherence to treatment for OSA among blacks. In addition, guidelines are provided for implementing a practical framework to increase OSA screening and management among blacks. RESULTS: Several studies have documented racial/ethnic disparities in adherence to treatment for OSA. However, despite its public health significance, there is a paucity of studies addressing these disparities. Further, there is a lack of health programs and policies to increase screening and treatment of OSA among blacks and other minority populations. A practical framework to increase the number of blacks who are screened for OSA and treated appropriately is warranted. Such a framework is timely and major importance, as early identification of OSA in this high-risk population could potentially lead to early treatment and prevention of CVD, thereby reducing racial and ethnic disparities in sleep-related CVD morbidity and mortality. PMID- 26652239 TI - Dreaming in patients with insomnia: a fascinating topic for future research. PMID- 26652240 TI - [Continuous flow peritoneal dialysis in a paediatric intensive care unit]. PMID- 26652241 TI - [Catheter tip position and risk of mechanical complications in a neonatal unit]. AB - INTRODUCTION: The use of central catheters (CC) is associated with mechanical complications (MC). OBJECTIVE: Our objetive was to determine the relationship between CC positions and associated MC in neonates. MATERIAL: A descriptive analytical study was performed over a six year period in the NICU of the University Hospital Santa Lucia de Cartagena. Details were collected on the CC used, indication, reason for withdrawal, position in the imaging, MC, and treatment arising from them, as well as epidemiological data. RESULTS: Of the total of 604 CC studied, the majority (347) were via the umbilical vein, followed by epicutaneous (193), and femoral vein (34). There were MC in 14.2% of catheters. Incorrect position of the tip was associated with greater MC (21.1 vs 8.2%; P<.001), including withdrawal due to MC (8.4 vs 3.1%; P<.01), extravasation (4.9 vs 1.9%; P<.05), pleural and pericardial effusions (1.4 vs 0.0%; P<.05), liver haematomas (4.6 vs 0.6%; P<.01), and ascites (2.8 vs 0.0%; P<.01). The midclavicular epicutaneous position of the tip was associated with greater MC (18.5 vs 6.8%; P<.05) than the brachiocephalic (0 vs 6.8%;NS). The low and ductal position of the umbilical vein catheter was also associated with higher rates of MC (24.5 vs 6%; P<.001 and 27 vs 6%; P<.001) due to the position of the tip. The most common complication was accidentally dislodged catheter. CONCLUSIONS: The incorrect location of the tip was associated with more MC. The midclavicular epicutaneous had more risk than centrally or brachiocephalic locations. The low and ductal positions of the umbilical vein catheter were associated with higher rates of MC. PMID- 26652242 TI - Sweat as a clinical sample: what is done and what should be done. PMID- 26652243 TI - Systemic effects of oral tolerance reduce the cutaneous scarring. AB - BACKGROUND: Immunological tolerance refer to the inhibition of specific immune responsiveness and the ingestion of proteins previous to immunization is a reliable method to induce (oral) tolerance. Parenteral exposure to tolerated antigens, in adjuvant, trigger indirect and systemic effects that inhibits concomitant immune responses to other unrelated antigens and also decrease unrelated inflammatory responses. Interesting, intraperitoneal (i.p.) exposure to orally-tolerated proteins soon before an incisional linear skin wound improves the healing by primary intention in mice. An important clinical and surgical objective is to identify strategies to improve wound healing and reduce scarring. OBJECTIVE: To evaluate whether i.p. injection of an orally-tolerated protein improves wound healing by secondary intention and reduce scarring of full thickness excisional skin injury. METHODS: C57Bl/6 mice were turned tolerant to ovalbumin (OVA) by drinking a solution containing OVA; seven days later, they received an i.p. injection of OVA plus Al(OH)3 adjuvant immediately before two full-thickness excisional skin wounds, under anesthesia. The wound healing process was evaluated macro and microscopically after H&E, toluidine blue and Gomori's Trichrome staining. The presence of granulocytes, macrophages, miofibroblasts, fibronectin, collagen I and collagen III was investigated by immunofluorescence and the levels of cytokines by flow cytometry or ELISA. Mice not tolerant to OVA were included as controls. RESULTS: The i.p. injection of OVA+Al(OH)3 in mice orally tolerant to OVA reduced the subsequent inflammatory response in the wound bed and the cutaneous scarring. There was a change in the pattern of collagen deposition making it more similar to the pattern observed in intact skin. In tolerant mice, mast cells and granulocytes (Ly-6C/G+), were reduced, while lymphocytes (CD3+) were increased in the wound bed. Time course analysis of Th1/Th2/Th17 cytokines and growth factors showed slightly differences between tolerant and control groups. CONCLUSION: Parenteral injection of an orally-tolerated protein has systemic consequences that impair the inflammatory response triggered by skin injury and reduce the cutaneous scarring. PMID- 26652244 TI - Intraeye retinal nerve fiber layer and macular thickness asymmetry measurements for the discrimination of primary open-angle glaucoma and normal tension glaucoma. AB - PURPOSE: The aim of this study was to evaluate the diagnostic capability of intraeye retinal nerve fiber layer (RNFL) thickness and macular thickness (MT) asymmetry measurements for the discrimination of normal tension glaucoma (NTG) and primary open-angle glaucoma (POAG) using spectral domain optical coherence tomography (SD-OCT). METHODS: A total of 90 subjects were enrolled including 30 consecutive healthy subjects, 30 consecutive subjects with POAG, and 30 consecutive subjects with NTG. RNFL thicknesses around the optic disc as well as MT measurements were taken with circular and radial SD-OCT scans. Intraeye retinal and MT asymmetry were calculated as the absolute difference between superior and inferior hemispheres of the eye using posterior pole asymmetry analysis protocol. Analysis of variance was used for comparison and areas under the receiver operating characteristic (AROC) were obtained for different parameters among the three diagnostic groups. RESULTS: There was a significant difference in MT asymmetry for all comparison groups (normal-NTG, p<0.05; normal POAG, p<0.001; and NTG-POAG, p<0.001). Intraeye retinal nerve fiber thickness asymmetry measurements were not different between the groups (normal-NTG, p<0.187; normal-POAG, p<0.056; and NTG-POAG, p<0.837). The area under ROC curves exceeded 0.800 for all the studied parameters, including the MT asymmetry except for intraeye RNFL thickness asymmetry which had the lowest AROC as well as the least sensitivity for identifying subjects with NTG from normal (AROC=0.626, sensitivity=30%); POAG from normal (AROC=0.644, sensitivity=37%) and NTG from POAG (AROC=0.533, sensitivity=13%). CONCLUSION: The intraeye MT asymmetry holds significant potential as a distinguishing parameter for NTG and POAG. PMID- 26652245 TI - The Relationship Between Tear Ferning Patterns and Non-invasive Tear Break-up Time in Normal Asian Population. AB - PURPOSE: To investigate the relationship between tear ferning patterns (TFP) and non-invasive tear break-up time (NIBUT) in normal Asian subjects. METHODS: One hundred and forty-five adults with no ocular surface disorders were recruited. TFP and NIBUT were determined. Tears were collected using a capillary tube and allowed to air dry at room temperature for 10min. TFP was later observed using a light microscope and classified according to Rolando's classification. Measurement for NIBUT was obtained using a Tearscope with the slit lamp magnification. RESULTS: It was found that there is no significant difference between gender in TFP (Z=-1.77, P>.05) and NIBUT (Z=-1.475, P>.05). There is also no significant difference between Malay, Chinese, Indian, and other races in TFP, (H(3)=4.85, P>.05) and NIBUT (H(3)=2.18, P>.05). However, there is a significant difference between age groups of 20-29, 30-39, 40-49,and 50-60 years old in both TFP (H(3)=28.25, P<.01) and NIBUT (H(3)=36.50, P<.001). Spearman's correlation showed there was a significant relationship between TFP and NIBUT (r=-0.55, P<.001), age and NIBUT (r=-0.50, P<.001), age and TFP (r=0.41, P<.001), McMonnies score and NIBUT (r=-0.40, P<.001), McMonnies score and TFP (r=0.31, P<.001), as well as age and McMonnies score (r=0.52, P<.001). CONCLUSION: TFP and NIBUT was age dependent but not gender and race dependent. Older subjects had higher grade of TFP and McMonnies questionnaire score but lower NIBUT value. TFP and NIBUT can be used to assess the tear film quality. PMID- 26652246 TI - Reply Letter to the Editor - Nutrition therapy in critically ill patients - A review of current evidence for clinicians. PMID- 26652247 TI - 3-(Piperidin-4-ylmethoxy)pyridine Containing Compounds Are Potent Inhibitors of Lysine Specific Demethylase 1. AB - Methylation of histone lysine residues plays important roles in gene expression regulation as well as cancer initiation. Lysine specific demethylase 1 (LSD1) is responsible for maintaining balanced methylation levels at histone H3 lysine 4 (H3K4). LSD1 is a drug target for certain cancers, due to important functions of methylated H3K4 or LSD1 overexpression. We report the design, synthesis, and structure-activity relationships of 3-(piperidin-4-ylmethoxy)pyridine containing compounds as potent LSD1 inhibitors with Ki values as low as 29 nM. These compounds exhibited high selectivity (>160*) against related monoamine oxidase A and B. Enzyme kinetics and docking studies suggested they are competitive inhibitors against a dimethylated H3K4 substrate and provided a possible binding mode. The potent LSD1 inhibitors can increase cellular H3K4 methylation and strongly inhibit proliferation of several leukemia and solid tumor cells with EC50 values as low as 280 nM, while they had negligible effects on normal cells. PMID- 26652248 TI - Validation of the Chinese version of the FOUR score in the assessment of neurosurgical patients with different level of consciousness. AB - BACKGROUND: The Glasgow Coma Scale (GCS) is currently the most widely used scoring system for comatose patients. A decade ago, the Full Outline of Unresponsiveness (FOUR) score was devised to better capture four functional aspects of consciousness (eye, motor responses, brainstem reflexes, and respiration). This study aimed to validate the Chinese version of the FOUR score in patients with different levels of consciousness. METHODS: The study had two phases: (1) translation of the FOUR score, and (2) assessment of its reliability and validity. The Chinese version of the FOUR score was developed according to a standardized protocol. One hundred-twenty consecutive patients with acute brain damage, admitted to Nanfang Hospital (Southern Medical University, Guangdong, China) from November 2014 to February 2015, were enrolled. The inter-rater agreement for the FOUR score and GCS was evaluated using intraclass correlation coefficient (ICC). Receiver operating characteristic (ROC) curves were established to determine the scales' abilities to predict outcome. RESULTS: The rater agreement was excellent both for FOUR (ICC = 0.970; p < 0.001) and GCS (ICC = 0.958; p < 0.001). The FOUR score yielded an excellent test-retest reliability (ICC = 0.930; p < 0.001). Spearman's correlation coefficients between GCS and the FOUR score were high: r = 0.932, first rating; r = 0.887, second rating (all p < 0.001). Areas under the curve (AUC) for mortality were 0.834 (95 % CI, 0.740 0.928) and 0.815 (95 % CI, 0.723-0.908) for the FOUR score and GCS, respectively. CONCLUSIONS: The Chinese version of the FOUR score is a reliable scale for evaluating the level of consciousness in patients with acute brain injury. PMID- 26652249 TI - Gender analysis in the development and validation of FFQ: a systematic review. AB - FFQ comprising food items, intake frequency categories and portion sizes have been used in large-scale observational studies to assess long-term dietary exposure. Although gender is an important influence on food choice and portion size, gender differences are not often analysed during FFQ development. This study investigated whether gender differences were considered sufficiently when developing FFQ, which affects the results of validation studies. A PubMed search using combinations of 'FFQ', 'Food Frequency Questionnaire', 'Validation' and 'Validity' identified 246 validation studies available in English, published between January 1983 and May 2014, which included healthy male and female adults. The development process of the 196 FFQ used in the 246 validation studies was examined. Of these, twenty-one FFQ (10.7%) considered gender during item selection or portion size determination, and were therefore classified as gender specific (GS), but 175 (89.3%) did not consider gender, and were classified as 'not gender specific (NGS)'. When the ratios between intake levels obtained using the FFQ and a reference method for energy and seven nutrients were compared between the GS group and the NGS group, more significant differences were observed in women than in men (four v. one nutrient). Intake of three nutrients was significantly underestimated in both sexes in the GS group. In the NGS group, nutrient intakes were significantly overestimated more often in women than in men (four v. one). These results indicate that not considering gender in FFQ development causes greater inaccuracy in dietary intake assessment in women than in men. Results of nutritional epidemiological studies should be re-evaluated for their validity, especially if the studies used NGS-FFQ. PMID- 26652250 TI - Are restrictive guidelines for added sugars science based? AB - Added sugar regulations and recommendations have been proposed by policy makers around the world. With no universal definition, limited access to added sugar values in food products and no analytical difference from intrinsic sugars, added sugar recommendations present a unique challenge. Average added sugar intake by American adults is approximately 13% of total energy intake, and recommendations have been made as low 5% of total energy intake. In addition to public health recommendations, the Food and Drug Administration has proposed the inclusion of added sugar data to the Nutrition and Supplemental Facts Panel. The adoption of such regulations would have implications for both consumers as well as the food industry. There are certainly advantages to including added sugar data to the Nutrition Facts Panel; however, consumer research does not consistently show the addition of this information to improve consumer knowledge. With excess calorie consumption resulting in weight gain and increased risk of obesity and obesity related co-morbidities, added sugar consumption should be minimized. However, there is currently no evidence stating that added sugar is more harmful than excess calories from any other food source. The addition of restrictive added sugar recommendations may not be the most effective intervention in the treatment and prevention of obesity and other health concerns. PMID- 26652251 TI - Elevated soluble thrombomodulin is associated with organ failure and mortality in children with acute respiratory distress syndrome (ARDS): a prospective observational cohort study. AB - INTRODUCTION: The significance of endothelial injury in children with the acute respiratory distress syndrome (ARDS) has not been well studied. Plasma levels of soluble thrombomodulin (sTM), an endothelial surface protein involved in coagulation, have been associated with endothelial injury. We hypothesized that elevated plasma sTM would correlate with mortality and organ failure in children with ARDS. METHODS: We conducted a multicenter prospective observational study of pediatric patients with ARDS between 2008 and 2014. sTM was measured in plasma collected less than 24 hours from ARDS diagnosis. Outcomes were intensive care unit mortality and organ dysfunction by pediatric logistic organ dysfunction scores. Logistic regression was used to adjust for clinically relevant covariates. RESULTS: Plasma sTM was higher in patients with indirect lung injury compared to direct lung injury (100 ng/mL vs. 86 ng/mL, p = 0.02). Increased sTM levels were correlated with more organ dysfunction in the entire study population (Spearman's rho = 0.37, p < 0.01). Overall mortality was 16%. sTM levels were associated with increased mortality in patients with indirect lung injury (OR 2.7 per log(sTM), p = 0.02). These relationships were independent of age, oxygenation defect, or presence of acute kidney injury. CONCLUSION: Elevated plasma sTM levels are associated with organ dysfunction in children with ARDS and with higher mortality in children with indirect lung injury. These findings highlight the importance of endothelial injury in children with ARDS and may guide the development of future therapies targeted toward endothelial stabilization, repair, or functional replacement in this population. PMID- 26652253 TI - Editorial: Role of Drug Metabolism and its Mediated DDI in Drug Efficacy and Safety Part 2. PMID- 26652252 TI - Health and ageing in Nairobi's informal settlements-evidence from the International Network for the Demographic Evaluation of Populations and Their Health (INDEPTH): a cross sectional study. AB - BACKGROUND: Much of the focus on population ageing has been in high-income counties. Relatively less attention is given to the world's poorest region, Sub Saharan Africa (SSA) where children and adolescents still comprise a high proportion of the population. Yet the number of adults aged 60-plus in SSA is already twice that in northern Europe. In addition, SSA is experiencing massive rural to urban migration with consequent expansion of informal urban settlements, or slums, whose health problems are usually unrecognised and not addressed. This study aims to improve understanding of functional health and well-being in older adult slum-dwellers in Nairobi (Kenya). METHODS: The study sample comprised men and women, aged 50 years and over, living in Korogocho and Viwandani, Nairobi, Kenya (n = 1,878). Data from the International Network for the Demographic Evaluation of Populations and Their Health (INDEPTH) and the WHO Study on global AGEing and adult health (SAGE Wave 1) were analysed. The prevalence of poor self reported quality of life (QoL) and difficulties in domain-specific function is estimated by age and sex. Logistic regression investigates associations between difficulties in the domains of function and poor QoL, adjusting for age, sex and socio-demographic factors. Statistical significance is set at P<0.05. RESULTS: Women reported poorer QoL and greater functional difficulties than men in all domains except self-care. In the multivariable logistic regression the odds of poor QoL among respondents with problems or difficulties in relation to affect (OR = 7.0; 95%CI = 3.0-16.0), pain/discomfort (OR = 3.6; 95%CI = 2.3-5.8), cognition (OR = 1.8; 95 %CI = 1.2-2.9) and mobility (OR = 1.8; 95%CI = 1.1-2.8) were statistically significant. CONCLUSIONS: The findings underscore differences in the domains of functional health that encapsulate women and men's capacities to perform regular activities and the impact of poor functioning on QoL. Investing in the health and QoL of older people in SSA will be crucial in helping the region to realise key development goals and in opening opportunities for improved health outcomes and sustainable economic development. PMID- 26652254 TI - Role of Metabolic Enzymes P450 (CYP) on Activating Procarcinogen and their Polymorphisms on the Risk of Cancers. AB - Cytochrome P450 (CYP450) enzymes are the most important metabolizing enzyme family exists among all organs. Apart from their role in the deactivation of most endogenous compounds and xenobiotics, they also mediate most procarcinogens oxidation to ultimate carcinogens. There are several modes of CYP450s activation of procarcinogens. 1) Formation of epoxide and diol-epoxides intermediates, such as CYP1A1 and CYP1B1 mediates PAHs oxidation to epoxide intermediates; 2) Formation of diazonium ions, such as CYP2A6, CYP2A13 and CYP2E1 mediates activation of most nitrosamines to unstable metabolites, which can rearrange to give diazonium ions. 3) Formation of reactive semiquinones and quinines, such as CYP1A1 and CYP1B1 transformation of estradiol to catechol estrogens, subsequently formation semiquinones; 4) Formation of toxic O-esterification, such as CYP1A1 and CYP1A2 metabolizes PhIP to N(2)-acetoxy-PhIP and N(2)-sulfonyloxy-PhIP, which are carcinogenic metabolites. 5) Formation of free radical, such as CYP2E1 is involved in activation tetrachloromethane to free radicals. While for CYP2B6 and CYP2D6, only a minor role has been found in procarcinogens activation. In addition, as the gene polymorphisms reflected, the polymorphisms of CYP1A1 ( 3801T/C and -4889A/G), CYP1A2 (- 163C/A and -2467T/delT), CYP1B1 (-48G/C, -119G/T and -432G/C), CYP2E1 (-1293G/C and -1053 C/T) have been associated with an increased risk of lung cancer. The polymorphisms CYP1A1 (-3801T/C and -4889A/G), and CYP2E1 (PstI/Rsa and 9-bp insertion) have an association with higher risk colon cancers, whereas CYP1A2 (-163C/A and -3860G/A) polymorphism is found to be among the protective factors. The polymorphisms CYP1A1 (-3801T/C and -4889A/G), CYP1B1 -432G/C, CYP2B6 (-516G/T and -785A/G) may increase the risk of breast cancer. In conclusion, CYP1A1, CYP1A2, CYP1B1, CYP2A6, and CYP2E1 are responsible for most of the procarcinogens activation, and their gene polymorphisms are associated with the risk of cancers. PMID- 26652255 TI - Drug Metabolizing Enzymes in Type II Diabetes and their Pharmacogenetics During Therapy of Anti-Diabetes Drugs. AB - The type 2 diabetes or T2D mellitus has turn into an epidemic throughout the globe in recent years. Various forms of treatment modalities have been available for patients with T2D with some major classes of approved drugs that include Sulfonylureas, Meglitinides, Biguanides, Thiazolidinedione, Alpha-glucosidase inhibitors, GLP-1 analogs, DPP-4 Inhibitors, and SGLT2 inhibitors. This review focuses on the drug metabolizing enzymes (DME), gene polymorphisms, and inter individual variability in therapeutics including adverse reaction effects involving Phase-I DME and Phase-II in general. This review also covers some key anti-diabetic drugs with respect to their pharcogenomics. PMID- 26652256 TI - Interplay of Breast Cancer Resistance Protein (BCRP) and Metabolizing Enzymes. AB - The recent identification of the interplay between metabolizing enzymes and BCRP has drawn more and more attention from people. BCRP, a transporter belonging to ATP-binding cassette (ABC) family, has been hypothesized to play roles in many aspects including protecting the human body against therapeutics because it is expressed in the tissues that function as barriers in vivo. Efficient coupling of BCRP and metabolizing enzymes enables rapid elimination of foreign compounds from the body because BCRP could facilitate the excretion of metabolites catalyzed by phase I and II enzymes into bile, urine and feces. Without BCRP coupling, pass through the cell membrane may be difficult for them by passive diffusion because of the increment of the molecular weight and water solubility. Thus the metabolism-efflux alliance has extraordinary importance to drug metabolism, distribution, pharmacological effect, toxicity and elimination. In this manuscript, a brief discussion about the interplays of BCRP and metabolizing enzymes in liver, intestine, kidney, lung and other organs were presented and summarized. Many endogenous and exogenous compounds belong to different chemical groups, for instance, the dietary flavonoids and the steroidal hormones were involved. Clarifying the cooperation mechanisms of BCRP and enzymes could lead to a better prediction of drug clearance in vitro. PMID- 26652257 TI - The Targeted-liposome Delivery System of Antitumor Drugs. AB - The liposome delivery system has been intensively explored as novel drug delivery system (DDS) for antitumor drugs, due to its safety, selective cytotoxicity, long circulation and slow elimination in blood, which is favorable for cancer therapy. The liposome-based chemotherapeutics are used to treat a variety of cancers to enhance the therapeutic index of antitumor drugs. Here, the author reviewed the important targets for cancer therapy and the pharmacokinetic behavior of liposomal drugs in vivo, as well as the application of the targeting liposomal system in cancer therapy. Considering further application for clinical use, the great challenges of the liposome-based delivery system were also proposed as follows: 1) prepare stealth liposome with steric stabilization and further enhance the therapeutic effects and safety; 2) explore more safe clinical targets and complementary or different types of targeting liposome; 3) thirdly, more investment is needed on the research of pharmacokinetics of the elements such as the ligands (antibody), PEG and lipids of liposome delivery system as well as safety evaluation. Considering the complex process of the liposomal encapsulation drugs in vivo, the author inferred that there are maybe different forms of the encapsulation drug to be internalized by the tumor tissues at the same time and space, although there are little reports on it. PMID- 26652258 TI - Effects of goat milk-based formula on development in weaned rats. AB - OBJECTIVE: The aim of this article is to study the effect of goat milk-based formula (GMF) on development in weaned rats. METHODS: One hundred Sprague-Dawley rats were randomly divided into five groups: control, 20% cow milk-based formula (CMF), and 5%-GMF, 10%-GMF, and 20%-GMF groups. RESULTS: GMF did play an active role in accelerating body and femur length, but not body weight growth. Compared with the control, GMF had better cognitive, space, and locomotor activity. The level of IFN was increased in GMF groups, as well as the level of IL-2 and TNF was decreased in GMF groups. CONCLUSION: These results indicate that GMF has an effect on development and immunity improvability in weaned rats. PMID- 26652259 TI - Impact of sensory-based food education in kindergarten on willingness to eat vegetables and berries. AB - BACKGROUND: Children use all of their senses when exploring new foods, and sensory-based food education provides new possibilities for promoting healthy dietary habits. OBJECTIVE: To evaluate the effect of sensory-based food education activities on children's willingness to eat test samples of selected vegetables and berries. DESIGN: Two kindergartens in Hanko, Finland, participated in the study and the subjects were children aged 3-6 years, divided in the intervention (n=44) and control (n=24) kindergarten. In the intervention kindergarten, five sensory-based food education sessions focusing on vegetables and berries were implemented, once per week for 5 weeks. A tasting protocol was performed with the children at baseline and after the intervention. The willingness to eat (5 different vegetables and 3 Finnish berries) was categorised. Parents also filled in a questionnaire on the children's food preferences at home. RESULTS: In the intervention kindergarten, the willingness to eat the samples increased significantly (p<=0.001, Wilcoxon and Friedman), while in the control kindergarten, no significant change was observed when all of the test samples were taken into account. The parental report of their children's preferences and children's actual eating of the test samples corresponded relatively weakly. CONCLUSIONS: Sensory-based food education activities may promote a willingness to eat vegetables and berries. Child-centred test methods are important for evaluating the effects of dietary interventions among children. PMID- 26652260 TI - Nutritional intakes in children with Prader-Willi syndrome and non-congenital obesity. AB - BACKGROUND: Individuals with Prader-Willi syndrome (PWS) have extremely regulated diets to prevent the development of morbid obesity. OBJECTIVE: This study evaluated potential deficiencies in macro and micronutrients in a cohort of youth with PWS and compared them to a group of children with non-congenital obesity and to US national recommendations. DESIGN: Participants were 32 youth with PWS (age=10.8+/-2.6 years, body fat=46.7+/-10.1%) and 48 children without PWS but classified as obese (age=9.7+/-1.2 years, body fat=43.4+/-5.7%). Participants' parents completed a training session on food recording before completing a 3-day food record during a typical week including a weekend day and two weekdays, as well as a screening form indicating nutritional supplements use. RESULTS: Youth with PWS reported less calories (1,312+/-75 vs. 1,531+/-61 kcal, p=0.03), carbohydrate (175+/-10 vs. 203+/-8 g), and sugars (67+/-5 vs. 81+/-4 g; p=0.04 for both) than obese. Youth with PWS consumed more vegetables (1.1+/-0.1 vs. 0.6+/-0.1 cups) and more of them met the daily recommendation (p<0.01 for both). Likewise, youth with PWS consumed more calcium than obese (899+/-53 vs. 752+/-43 mg) and more of them met the recommended daily dose (p=0.04 for both). The majority of participants in this study did not meet the vitamin D recommendation. CONCLUSION: Despite consuming less calories, youth with PWS had a similar proportion of macronutrients in their diet as children with obesity. Micronutrient deficiencies in calcium and vitamin D in youth with PWS were noted despite a third of youth with PWS consuming multivitamin supplements. Special attention must be paid to the diets of youth with PWS and with obesity to ensure they are meeting micronutrient needs during this period of growth and development. PMID- 26652261 TI - Combined de novo and genome guided assembly and annotation of the Pinus patula juvenile shoot transcriptome. AB - BACKGROUND: Pines are the most important tree species to the international forestry industry, covering 42 % of the global industrial forest plantation area. One of the most pressing threats to cultivation of some pine species is the pitch canker fungus, Fusarium circinatum, which can have devastating effects in both the field and nursery. Investigation of the Pinus-F. circinatum host-pathogen interaction is crucial for development of effective disease management strategies. As with many non-model organisms, investigation of host-pathogen interactions in pine species is hampered by limited genomic resources. This was partially alleviated through release of the 22 Gbp Pinus taeda v1.01 genome sequence ( http://pinegenome.org/pinerefseq/ ) in 2014. Despite the fact that the fragmented state of the genome may hamper comprehensive transcriptome analysis, it is possible to leverage the inherent redundancy resulting from deep RNA sequencing with Illumina short reads to assemble transcripts in the absence of a completed reference sequence. These data can then be integrated with available genomic data to produce a comprehensive transcriptome resource. The aim of this study was to provide a foundation for gene expression analysis of disease response mechanisms in Pinus patula through transcriptome assembly. RESULTS: Eighteen de novo and two reference based assemblies were produced for P. patula shoot tissue. For this purpose three transcriptome assemblers, Trinity, Velvet/OASES and SOAPdenovo-Trans, were used to maximise diversity and completeness of assembled transcripts. Redundancy in the assembly was reduced using the EvidentialGene pipeline. The resulting 52 Mb P. patula v1.0 shoot transcriptome consists of 52 112 unigenes, 60 % of which could be functionally annotated. CONCLUSIONS: The assembled transcriptome will serve as a major genomic resource for future investigation of P. patula and represents the largest gene catalogue produced to date for this species. Furthermore, this assembly can help detect gene-based genetic markers for P. patula and the comparative assembly workflow could be applied to generate similar resources for other non-model species. PMID- 26652262 TI - The decrease in the population of Gluconacetobacter diazotrophicus in sugarcane after nitrogen fertilization is related to plant physiology in split root experiments. AB - It has been established that a decrease in the population of Gluconacetobacter diazotrophicus associated with sugarcane occurs after nitrogen fertilization. This fact could be due to a direct influence of NH(4)NO(3) on bacterial cells or to changes in plant physiology after fertilizer addition, affecting bacterial establishment. In this work, we observed that survival of G. diazotrophicus was directly influenced when 44.8mM of NH(4)NO(3) (640mgN/plant) was used for in vitro experiments. Furthermore, micropropagated sugarcane plantlets were inoculated with G. diazotrophicus and used for split root experiments, in which both ends of the system were fertilized with a basal level of NH(4)NO(3) (0.35mM; 10mgN/plant). Twenty days post inoculation (dpi) one half of the plants were fertilized with a high dose of NH(4)NO(3) (6.3mM; 180 mgN/plant) on one end of the system. This nitrogen level was lower than that directly affecting G. diazotrophicus cells; however, it caused a decrease in the bacterial population in comparison with control plants fertilized with basal nitrogen levels. The decrease in the population of G. diazotrophicus was higher in pots fertilized with a basal nitrogen level when compared with the corresponding end supplied with high levels of NH4NO3 (100dpi; 80 days post fertilization) of the same plant system. These observations suggest that the high nitrogen level added to the plants induce systemic physiological changes that affect the establishment of G. diazotrophicus. PMID- 26652263 TI - [MERS-CoV, transmission and the role of new host species]. PMID- 26652264 TI - The influence of family-supportive supervisor training on employee job performance and attitudes: An organizational work-family intervention. AB - Training supervisors to increase their family-supportive supervisor behaviors (FSSB) has demonstrated significant benefits for employee physical health, job satisfaction, and turnover intentions among employees with high levels of family to-work conflict in prior research in a grocery store context. We replicate and extend these results in a health care setting with additional important employee outcomes (i.e., employee engagement, organizational commitment, and supervisor ratings of job performance), and consider the role of the 4 dimensions underlying the FSSB. Using a quasi-experimental, pretest-posttest design, 143 health care employees completed surveys at 2 time periods approximately 10 months apart, along with their supervisors who provided ratings of employees' job performance. Between these surveys, we offered their supervisors FSSB training; 86 (71%) of these supervisors participated. Results demonstrated significant and beneficial indirect effects of FSSB training on changes in employee job performance, organizational commitment, engagement, job satisfaction, and turnover intentions through changes in employee perceptions of their supervisor's overall FSSBs. Further analyses suggest that these indirect effects are due primarily to changes in the creative work-family management dimension of FSSB. (PsycINFO Database Record PMID- 26652265 TI - Longitudinal study of the feasibility of using ecological momentary assessment to study teacher stress: Objective and self-reported measures. AB - There is a lack of comprehensive research on Ecological Momentary Assessment (EMA) feasibility to study occupational stress, especially its long-term sustainability. EMA application in education contexts has also been sparse. This study investigated the feasibility of using EMA to study teacher stress over 2 years using both objective compliance data and a self-reported feasibility survey. It also examined the influence of individual and school factors on EMA feasibility. Participants were 202 sixth through eighth grade teachers from 22 urban middle schools in the southern United States. EMA was implemented via an iPod-based Teacher Stress Diary (TSD). Teachers recorded demands, stress responses, and resources during 12 days (6 waves) over 2 years. Feasibility was assessed via compliance data generated by the TSD (e.g., entry completion) and an EMA Feasibility Survey of self-reported user-friendliness and EMA interference. The results showed high compliance regarding entry and item completion, and completion time, which was sustained over time. User-friendliness was appraised as very high and EMA interference as low. Initial difficulties regarding timing and length of assessments were addressed via EMA method refinement, resulting in improved feasibility. Teachers' ethnicity, age, marital status, grade/course taught, class size, class load, and daily workload impacted feasibility. The results supported the feasibility of using EMA to study work stress longitudinally and the value of continued feasibility monitoring. They also support EMA use to study teacher stress and inform EMA implementation in schools. Some teacher and school factors need to be taken into consideration when deciding on EMA implementation in education contexts. (PsycINFO Database Record PMID- 26652266 TI - Ethnic minorities' paranoia and self-preservative work behaviors in response to perceived ethnic discrimination, with collective self-esteem as a buffer. AB - The present research examines (a) how ethnic minorities' paranoia mediates the relations between perceived ethnic discrimination and 2 forms of self preservative work behaviors and (b) how ethnic minorities' collective self-esteem moderates the relation between perceived ethnic discrimination and paranoia. Two field studies focusing on 2 ethnic minority groups (Asian and Latino/Hispanic Americans), respectively, rendered empirical support to the focal mechanisms, which appeared robust even when perceived ethnic acceptance, psychological needs satisfaction, and neuroticism were simultaneously accounted for. Specifically, paranoia mediated the relations between perceived ethnic discrimination and voice and between perceived ethnic discrimination and workplace withdrawal. Collective self-esteem attenuated the relation between perceived ethnic discrimination and paranoia. These key findings shed light on the emotional and behavioral implications of perceived ethnic discrimination in the workplace and highlight collective self-esteem as a critical factor that attenuates the negative emotional consequence of perceived ethnic discrimination. (PsycINFO Database Record PMID- 26652267 TI - The impact of employee assistance services on workplace outcomes: Results of a prospective, quasi-experimental study. AB - Employee Assistance Programs (EAPs) are widely used to help employees experiencing personal or work-related difficulties that impact work productivity. However, rigorous research on the effectiveness of programs to improve work related outcomes is lacking. The current study represents a major advance in EAP research by using a prospective, quasi-experimental design with a large and diverse employee base. Using propensity scores calculated from demographic, social, work-related, and psychological variables collected on baseline surveys, we matched 156 employees receiving EAP to 188 non-EAP employees. Follow-up surveys were collected from 2 to 12 months post-baseline (M = 6.0). At follow-up, EAP employees had significantly greater reductions in absenteeism (b = -.596, p = .001) and presenteeism (b = -.217, p = .038), but not workplace distress (b = .079, p = .448), than did non-EAP employees. Tests of moderation of baseline alcohol use, depression, anxiety, and productivity indicate that for the most part, the program works equally well for all groups. However, EAP did more to reduce absenteeism for those who began with lower severity of depression and anxiety at baseline. Results provide the scientific rigor needed to demonstrate EAP impact on improved work outcomes. In the first study of its kind, findings confirm the value of EAPs to help employees address personal and work-related concerns that are affecting job performance. (PsycINFO Database Record PMID- 26652268 TI - Psychologically detaching despite high workloads: The role of attentional processes. AB - Although psychologically detaching from work is beneficial for employee well being and productivity, heavy workloads can interfere with detachment. Drawing from the self-regulation literature, we expand the stressor-detachment model to explore 2 attentional factors that shape the workload-detachment relationship: dispositional self-control-defined as a trait ability to regulate thoughts and behavior-and a daily planning intervention designed to direct attention away from incomplete work goals. Overall, we hypothesized that the ability to control and redirect attention is crucial for detaching from high workloads. Using an experimental daily diary design with 103 employees, we replicated previous results that daily workload is negatively associated with daily psychological detachment. However, this relationship was nonsignificant for individuals high on dispositional self-control and those that completed the planning intervention. We also observed a 3-way interaction, where the planning intervention was only effective for individuals low on dispositional self-control because employees high on self-control were naturally better at detaching from high workloads. Overall, these results illustrate the theoretical and practical utility of an attention-based perspective on detachment processes, including a simple intervention for helping individuals detach at home despite high workloads. (PsycINFO Database Record PMID- 26652269 TI - The crossover of psychological distress from leaders to subordinates in teams: The role of abusive supervision, psychological capital, and team performance. AB - This study examines the underlying mechanism of the crossover process in work teams. Drawing on conservation of resources theory, we hypothesize that a leader's psychological distress positively influences subordinates' psychological distress through abusive supervision. We further hypothesize that team performance attenuates the association between a leader's psychological distress and abusive supervision. In addition, we expect that psychological capital attenuates the positive relationship between abusive supervision and subordinates' psychological distress. Participants were drawn from 86 business teams, and multisource data were collected. The hypotheses were tested with multilevel analysis. Results supported the crossover of psychological distress from leader to subordinates, and abusive supervision serves as a mediating mechanism. The positive relationship between a leader's distress and abusive supervision is stronger when team performance is lower. In addition, the positive relationship between abusive supervision and subordinates' psychological distress is stronger when subordinates' psychological capital is lower. PMID- 26652270 TI - Bone Like Arterial Calcification in Femoral Atherosclerotic Lesions: Prevalence and Role of Osteoprotegerin and Pericytes. AB - OBJECTIVE/BACKGROUND: Arterial calcification, a process that mimics bone formation, is an independent risk factor of cardiovascular morbidity and mortality, and has a significant impact on surgical and endovascular procedures and outcomes. Research efforts have focused mainly on the coronary arteries, while data regarding the femoral territory remain scarce. METHODS: Femoral endarterectomy specimens, clinical data, and plasma from a cohort of patients were collected prospectively. Histological analysis was performed to characterize the cellular populations present in the atherosclerotic lesions, and that were potentially involved in the formation of bone like arterial calcification known as osteoid metaplasia (OM). Enzyme linked immunosorbent assays and cell culture assays were conducted in order to understand the cellular and molecular mechanisms underlying the formation of OM in the lesions. RESULTS: Twenty-eight of the 43 femoral plaques (65%) displayed OM. OM included osteoblast and osteoclast like cells, but very few of the latter exhibited the functional ability to resorb mineral tissue. As in bone, osteoprotegerin (OPG) was significantly associated with the presence of OM (p = .04). Likewise, a high plasma OPG/receptor activator for the nuclear factor kappa B ligand (RANKL) ratio was significantly associated with the presence of OM (p = .03). At the cellular level, there was a greater presence of pericytes in OM+ compared with OM- lesions (5.59 +/- 1.09 vs. 2.42 +/- 0.58, percentage of area staining [region of interest]; p = .04); in vitro, pericytes were able to inhibit the osteoblastic differentiation of human mesenchymal stem cells, suggesting that they are involved in regulating arterial calcification. CONCLUSION: These results suggest that bone like arterial calcification (OM) is highly prevalent at femoral level. Pericyte cells and the OPG/RANK/RANKL triad seem to be critical to the formation of this ectopic osteoid tissue and represent interesting potential therapeutic targets to reduce the clinical impact of arterial calcification. PMID- 26652271 TI - Rapid and reliable genotyping of HLA-B*58:01 in four Chinese populations using a single-tube duplex real-time PCR assay. AB - AIM: HLA-B*58:01 is strongly associated with allopurinol-induced severe cutaneous adverse reactions. This study aimed to develop a new and convenient method for HLA-B*58:01 genotyping and to investigate HLA-B*58:01 distribution in different Chinese populations. MATERIALS & METHODS: Combining of sequence-specific primers and TaqMan probe, a single-tube duplex real-time PCR assay for HLA-B*58:01 typing was established. RESULTS: The HLA-B*58:01 genotyping result in Buyei (n = 100) by real-time PCR showed 100% concordance with those by sequence-based typing. The prevalence of HLA-B*58:01 carrier in Buyei (17%, n = 100) was significantly higher than those in Northern Han (4%, n = 100), Tibetan (5.1%, n = 99) and Uighur (2%, n = 50) populations (p < 0.05). CONCLUSION: The newly developed reliable assay was appropriate for HLA-B*58:01 detection prior to allopurinol administration in clinical settings. PMID- 26652273 TI - Generation of contractile actomyosin bundles depends on mechanosensitive actin filament assembly and disassembly. AB - Adhesion and morphogenesis of many non-muscle cells are guided by contractile actomyosin bundles called ventral stress fibers. While it is well established that stress fibers are mechanosensitive structures, physical mechanisms by which they assemble, align, and mature have remained elusive. Here we show that arcs, which serve as precursors for ventral stress fibers, undergo lateral fusion during their centripetal flow to form thick actomyosin bundles that apply tension to focal adhesions at their ends. Importantly, this myosin II-derived force inhibits vectorial actin polymerization at focal adhesions through AMPK-mediated phosphorylation of VASP, and thereby halts stress fiber elongation and ensures their proper contractility. Stress fiber maturation additionally requires ADF/cofilin-mediated disassembly of non-contractile stress fibers, whereas contractile fibers are protected from severing. Taken together, these data reveal that myosin-derived tension precisely controls both actin filament assembly and disassembly to ensure generation and proper alignment of contractile stress fibers in migrating cells. PMID- 26652272 TI - Quantitative analyses and modelling to support achievement of the 2020 goals for nine neglected tropical diseases. AB - Quantitative analysis and mathematical models are useful tools in informing strategies to control or eliminate disease. Currently, there is an urgent need to develop these tools to inform policy to achieve the 2020 goals for neglected tropical diseases (NTDs). In this paper we give an overview of a collection of novel model-based analyses which aim to address key questions on the dynamics of transmission and control of nine NTDs: Chagas disease, visceral leishmaniasis, human African trypanosomiasis, leprosy, soil-transmitted helminths, schistosomiasis, lymphatic filariasis, onchocerciasis and trachoma. Several common themes resonate throughout these analyses, including: the importance of epidemiological setting on the success of interventions; targeting groups who are at highest risk of infection or re-infection; and reaching populations who are not accessing interventions and may act as a reservoir for infection,. The results also highlight the challenge of maintaining elimination 'as a public health problem' when true elimination is not reached. The models elucidate the factors that may be contributing most to persistence of disease and discuss the requirements for eventually achieving true elimination, if that is possible. Overall this collection presents new analyses to inform current control initiatives. These papers form a base from which further development of the models and more rigorous validation against a variety of datasets can help to give more detailed advice. At the moment, the models' predictions are being considered as the world prepares for a final push towards control or elimination of neglected tropical diseases by 2020. PMID- 26652274 TI - Impairments of the primary afferent nerves in a rat model of diabetic visceral hyposensitivity. AB - BACKGROUND: Diabetic neuropathy in visceral organs such as the gastrointestinal (GI) tract is still poorly understood, despite that GI symptoms are among the most common diabetic complications. The present study was designed to explore the changes in visceral sensitivity and the underlying functional and morphological deficits of the sensory nerves in short-term diabetic rats. Here, we compared the colorectal distension (CRD)-induced visceromotor response (VMR, an index of visceral pain) in vivo, the mechanosensitivity of colonic afferents ex vivo as well as the expression of protein gene product (PGP) 9.5 and calcitonin gene related peptide (CGRP) in colon between diabetic (3-6 weeks after streptozotocin injection) and control (age-matched vehicle injection) rats. RESULTS: VMR was markedly decreased in the diabetic compared to the control rats. There was a significant decrease in multiunit pelvic afferent nerve responses to ramp distension of the ex vivo colon and single unit analysis indicated that an impaired mechanosensitivity of low-threshold and wide dynamic range fibers may underlie the afferent hyposensitivity in the diabetic colon. Fewer PGP 9.5- or CGRP-immunoreactive fibers and lower protein level of PGP 9.5 were found in the colon of diabetic rats. CONCLUSIONS: These observations revealed the distinctive feature of colonic neuropathy in short-term diabetic rats that is characterized by a diminished sensory innervation and a blunted mechanosensitivity of the remnant sensory nerves. PMID- 26652275 TI - Female genital mutilation and cutting: a systematic literature review of health professionals' knowledge, attitudes and clinical practice. AB - BACKGROUND: The World Health Organisation (WHO) estimates that 100-140 million girls and women have undergone female genital mutilation or cutting (FGM/C). FGM/C is an ancient cultural practice prevalent in 26 countries in Africa, the Middle East and Asia. With increased immigration, health professionals in high income countries including UK, Europe, North America and Australia care for women and girls with FGM/C. FGM/C is relevant to paediatric practice as it is usually performed in children, however, health professionals' knowledge, clinical practice, and attitudes to FGM/C have not been systematically described. We aimed to conduct a systematic review of the literature to address this gap. METHODS: The review was conducted according to guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and registered with the PROSPERO International Prospective Register of Systematic Reviews (CRD42015015540, http://www.crd.york.ac.uk/PROSPERO/). Articles published in English 2000-2014 which used quantitative methods were reviewed. RESULTS: Of 159 unique articles, 18 met inclusion criteria. The methodological quality was poor - six studies met seven of the eight quality criteria. Study participants included mainly obstetricians, gynaecologists and midwives (15 studies). We found no papers that studied paediatricians specifically, but two papers reported on subgroups of paediatricians within a mixed sample of health professionals. The 18 articles covered 13 different countries: eight from Africa and 10 from high income countries. Most health professionals were aware of the practice of FGM/C, but few correctly identified the four FGM/C categories defined by WHO. Knowledge about FGM/C legislation varied: 25% of professionals in a Sudanese study, 46 % of Belgian labour ward staff and 94 % of health professionals from the UK knew that FGM/C was illegal in their country. Health professionals from high income countries had cared for women or girls with FGM/C. The need to report children with FGM/C, or at risk of FGM/C, to child protection authorities was mentioned by only two studies. CONCLUSION: Further research is needed to determine health professionals' attitudes, knowledge and practice to support the development of educational materials and policy to raise awareness and to prevent this harmful practice. PMID- 26652276 TI - High-Performance Solution-Processed Non-Fullerene Organic Solar Cells Based on Selenophene-Containing Perylene Bisimide Acceptor. AB - Non-fullerene acceptors have recently attracted tremendous interest because of their potential as alternatives to fullerene derivatives in bulk heterojunction organic solar cells. However, the power conversion efficiencies (PCEs) have lagged far behind those of the polymer/fullerene system, mainly because of the low fill factor (FF) and photocurrent. Here we report a novel perylene bisimide (PBI) acceptor, SdiPBI-Se, in which selenium atoms were introduced into the perylene core. With a well-established wide-band-gap polymer (PDBT-T1) as the donor, a high efficiency of 8.4% with an unprecedented high FF of 70.2% is achieved for solution-processed non-fullerene organic solar cells. Efficient photon absorption, high and balanced charge carrier mobility, and ultrafast charge generation processes in PDBT-T1:SdiPBI-Se films account for the high photovoltaic performance. Our results suggest that non-fullerene acceptors have enormous potential to rival or even surpass the performance of their fullerene counterparts. PMID- 26652277 TI - A process evaluation accompanying an attempted randomized controlled trial of an evidence service for health system policymakers. AB - BACKGROUND: We developed an evidence service that draws inputs from Health Systems Evidence (HSE), which is a comprehensive database of research evidence about governance, financial and delivery arrangements within health systems and about implementation strategies relevant to health systems. Our goal was to evaluate whether, how and why a 'full-serve' evidence service increases the use of synthesized research evidence by policy analysts and advisors in the Ontario Ministry of Health and Long-Term Care as compared to a 'self-serve' evidence service. METHODS: We attempted to conduct a two-arm, 10-month randomized controlled trial (RCT), along with a follow-up qualitative process evaluation, but we terminated the RCT when we failed to reach our recruitment target. For the qualitative process evaluation we modified the original interview guide to allow us to explore the (1) factors influencing participation in the trial; (2) usage of HSE, factors explaining usage patterns, and strategies to increase usage; (3) participation in training workshops and use of other supports; and (4) views about and experiences with key HSE features. RESULTS: We terminated the RCT given our 15% recruitment rate. Six factors were identified by those who had agreed to participate in the trial as encouraging their participation: relevance of the study to participants' own work; familiarity with the researchers; personal view of the importance of using research evidence in policymaking; academic background; support from supervisors; and participation of colleagues. Most reported that they never, infrequently or inconsistently used HSE and suggested strategies to increase its use, including regular email reminders and employee training. However, only two participants indicated that employee training, in the form of a workshop about finding and using research evidence, had influenced their use of HSE. Most participants found HSE features to be intuitive and helpful, although registration/sign-in and some page formats (particularly the advanced search page and detailed search results page) discouraged their use or did not optimize the user experience. CONCLUSIONS: The qualitative findings informed a re-design of HSE, which allows users to more efficiently find and use research evidence about how to strengthen or reform health systems or in how to get cost-effective programs, services and drugs to those who need them. Our experience with RCT recruitment suggests the need to consider changing the unit of allocation to divisions instead of individuals within divisions, among other lessons. TRIAL REGISTRATION: This protocol for this study is published in Implementation Science and registered with ClinicalTrials.gov ( HHS/FHS REB 10 267 ). PMID- 26652278 TI - A gateway to the brain: shuttles for brain delivery of macromolecules. PMID- 26652279 TI - Transport of digoxin-loaded polymeric nanoparticles across BeWo cells, an in vitro model of human placental trophoblast. AB - BACKGROUND: Fetal arrhythmias can lead to fetal congestive heart failure and hydrops fetalis. Digoxin (the first-line treatment) has low transplacental permeability and high risk of maternal side effects. Biodegradable digoxin-loaded PEGylated poly(lactic-co-glycolic acid) nanoparticles may increase digoxin transport across BeWo b30 cell monolayers (an in vitro model of trophoblast in human placenta) by reducing the drug's interaction with P-gp. Results/methodology: The nanoparticles showed high encapsulation efficiency and sustained release over 48 h. Transport studies revealed significantly increased permeability across BeWo cell layers of digoxin-loaded nanoparticles when compared with free digoxin. P-gp inhibition also increased the permeability of digoxin, but not digoxin-loaded nanoparticles. CONCLUSION: This represents a novel treatment strategy for fetal cardiovascular disease which may improve maternal and fetal outcomes. PMID- 26652280 TI - A discussion on adult mesenchymal stem cells for drug delivery: pros and cons. AB - Mesenchymal stem cells (MSCs) are emerging as candidates for drug delivery to treat numerous diseases. Their ease of isolation, expansion and reduced ethical concern, coupled with their 'plastic' immune functions and homing abilities make MSCs an appealing choice as cellular vehicle for drug delivery, including the delivery of RNA. However, while MSCs are currently listed for thousands of clinical trials, there are many confounding factors that have yet to be elucidated. In this review, we address many of the benefits of MSCs as therapeutic agents, and discuss confounding factors that require further scientific exploration. PMID- 26652281 TI - Cubosomes and hexosomes as versatile platforms for drug delivery. AB - Nonlamellar liquid crystalline phases are attractive platforms for drug solubilization and targeted delivery. The attractiveness of this formulation principle is linked to the nanostructural versatility, compatiblity, digestiblity and bioadhesive properties of their lipid constituents, and the capability of solubilizing and sustaining the release of amphiphilic, hydrophobic and hydrophilic drugs. Nonlamellar liquid crystalline phases offer two distinct promising strategies in the development of drug delivery systems. These comprise formation of ISAsomes (internally self-assembled 'somes' or particles) such as cubosomes and hexosomes, and in situ formation of parenteral dosage forms with tunable nanostructures at the site of administration. This review outlines the unique features of cubosomes and hexosomes and their potential utilization as promising platforms for drug delivery. PMID- 26652282 TI - Nanostructured materials for ocular delivery: nanodesign for enhanced bioadhesion, transepithelial permeability and sustained delivery. AB - Effective drug delivery to the eye is an ongoing challenge due to poor patient compliance coupled with numerous physiological barriers. Eye drops for the front of the eye and ocular injections for the back of the eye are the most prevalent delivery methods, both of which require relatively frequent administration and are burdensome to the patient. Novel drug delivery techniques stand to drastically improve safety, efficacy and patient compliance for ocular therapeutics. Remarkable advances in nanofabrication technologies make the application of nanostructured materials to ocular drug delivery possible. This article focuses on the use of nanostructured materials with nanoporosity or nanotopography for ocular delivery. Specifically, we discuss nanotopography for enhanced bioadhesion and permeation and nanoporous materials for controlled release drug delivery. As examples, application of polymeric nanostructures for greater transepithelial permeability, nanostructured microparticles for enhanced preocular retention time and nanoporous membranes for tuning drug release profile are covered. PMID- 26652283 TI - Reading span task performance, linguistic experience, and the processing of unexpected syntactic events. AB - Accounts of individual differences in online language processing ability often focus on the explanatory utility of verbal working memory, as measured by reading span tasks. Although variability in reading span task performance likely reflects individual differences in multiple underlying traits, skills, and processes, accumulating evidence suggests that reading span scores also reflect variability in the linguistic experiences of an individual. Here, through an individual differences approach, we first demonstrate that reading span scores correlate significantly with measures of the amount of experience an individual has had with written language (gauged by measures that provide "proxy estimates" of print exposure). We then explore the relationship between reading span scores and online language processing ability. Individuals with higher reading spans demonstrated greater sensitivity to violations of statistical regularities found in natural language-as evinced by higher reading times (RTs) on the disambiguating region of garden-path sentences-relative to their lower span counterparts. This result held after statistically controlling for individual differences in a non-linguistic operation span task. Taken together, these results suggest that accounts of individual differences in sentence processing can benefit from a stronger focus on experiential factors, especially when considered in relation to variability in perceptual and learning abilities that influence the amount of benefit gleaned from such experience. PMID- 26652284 TI - Keratosis lichenoides chronica: Case-based review of treatment options. AB - Keratosis lichenoides chronica (KLC) is a rare dermatological condition characterized by keratotic papules arranged in a parallel linear or reticular pattern and facial lesions resembling seborrheic dermatitis or rosacea. The clinical, histological and therapeutic information on 71 patients with KLC retrieved through a PubMed search plus one our new case were analyzed. KLC affects patients of all ages, with a modest male predominance. Pediatric cases represent about one quarter of patients. Diagnosis is usually delayed and histologically confirmed. All patients have thick, rough and scaly papules and plaques arranged in a linear or reticular pattern, on limbs (>80%) and trunk (about 60%). Face involvement is described in two-thirds of patients. Lesions are usually asymptomatic or mildly pruritic. Other manifestations, such as palmoplantar keratoderma, mucosal involvement, ocular manifestations, nail dystrophy, are reported in 20-30% of patients. Children present more frequently alopecia. No controlled trials are available. Results from small case series or single case reports show that the best treatment options are phototherapy and systemic retinoids, alone or in combination, with nearly half of patients reaching complete remission. Systemic corticosteroids as well as antibiotics and antimalarials are not effective. PMID- 26652285 TI - Physical activity and vascular disease in a prospective cohort study of older men: The Health In Men Study (HIMS). AB - BACKGROUND: The dose-response relationship between volume of physical activity and incidence of major vascular events at older age is unclear. We aimed to investigate this association in a cohort of older men. METHODS: For this prospective cohort study, 7564 men aged 65-83 years and without prior vascular disease were recruited in 1996-99 from the general population in Perth, Western Australia. Men were followed up using the Western Australian Data Linkage System to identify deaths and hospitalisations. During mean follow-up of 11 (SD 4) years, there were 1557 first major vascular events: 833 ischaemic heart disease events, 551 stroke events and 173 other vascular events. Cox regression was used to calculate hazard ratios (adjusted for age, education and smoking) for incidence of major vascular events by volume of baseline recreational physical activity (measured in metabolic equivalent [MET] hours per week). RESULTS: Hazard ratios among men who performed 0, 1-14, 15-24, 25-39, >=40 MET-hours per week of recreational physical activity were 1.00 (95% CI 0.91-1.10; referent), 0.88 (0.79 1.00), 0.81 (0.72-0.91), 0.81 (0.72-0.91) and 0.80 (0.71-0.89), respectively (P(trend) =0.006). The association was slightly attenuated with further adjustment for BMI. There was evidence of stronger associations at older ages and greater intensity of activity, but no evidence of effect modification by smoking, alcohol intake or BMI. There was also no evidence that the association varied by type of vascular event. CONCLUSIONS: Among men aged over 65 years, there was a curvilinear association between recreational physical activity and incidence of major vascular events, with an inverse association up to about 20 MET-hours per week (equivalent to 1 h of non-vigorous, or half an hour of vigorous, physical activity per day) and no evidence of further reductions in risk thereafter. PMID- 26652286 TI - Prevalence of Diverse Clones of Vancomycin-Resistant Enterococcus faecium ST78 in a Chinese Hospital. AB - BACKGROUND: Vancomycin-resistant Enterococcus (VRE) has been identified in China. However, little is known about the spread of VRE isolates. METHODS: The genetic relatedness of vancomycin-resistant Enterococcus faecium (VREfm) isolates was analyzed by pulsed-field gel electrophoresis (PFGE), their antimicrobial susceptibilities were analyzed by E-test and the VITEK 2 AST-GP67 test Kit, and their sequence types (STs) were investigated by multilocus sequence typing (MLST). S1-PFGE was used for plasmid profiling, and PCR and subsequent sequencing were performed to identify the virulence genes. RESULTS: A total of 96 nonduplicated VREfm isolates were obtained and categorized into 38 PFGE types (type 1-38). The predominant MLST type was ST78, while ST17, ST341, and ST342 were also sporadically identified. All types of clinical VREfm strains harbored the vanA gene; however, they carried plasmids of different sizes. While 92.1%, 71.1%, and 60.5% of VREfm strains carried hyl, scm, and ecbA genes, respectively, all of them were positive for esp, acm, sgrA, pilA, and pilB genes. CONCLUSIONS: Clonal VREfm spread was observed, and nonplasmid-mediated horizontal transfer of vancomycin-resistant gene might have conveyed resistance to some vancomycin susceptible E. faecium strains. E. faecium ST78 carrying vanA gene was the most prevalent clone in this study. The high prevalence of virulence genes, including esp, hyl, acm, scm, ecbA, sgrA, pilA, and pilB, confirmed their important roles in the emergence of VREfm ST78 in nosocomial infections. PMID- 26652287 TI - Vibrationally Inelastic Collision Between Li2(nu = 0) and Li: Direct and Postponed Elongation Mechanisms. AB - The mechanism for vibrational inelastic excitation during the collision between Li2(nu = 0) and Li was investigated exploiting classical trajectory simulations over a potential energy surface generated by fitting valence full configuration interaction calculations employing a large basis set. From the trajectory results, it emerges that the vibrational excitation in noncapture collisions presents uniquely a forward-scattered projectile for the highest levels of excitation (DeltaE(0 -> nu') ? Ecoll). For lower nu', a minor contribution presenting a backward-scattered projectile appears, which, however, has its major contribution coming from a "slingshot"-like (orbiting) mechanism exploiting the attractive features of the Li3 potential energy surface rather than a direct recoil. PMID- 26652288 TI - A novel screening tool (Karanth's test) for vitamin B12 deficiency: a pilot study. AB - BACKGROUND: No practical tests are currently available for screening vitamin B12 deficiency because the available techniques are invasive, expensive, and require a particular level of infrastructure and service that is not available in all places such as rural areas. Thus, we have examined the efficacy of a novel method (Karanth's test) for identifying people with vitamin B12 deficiency as part of a pilot study. METHODS: An observer-blind study was conducted on 83 consenting patients from a tertiary teaching hospital whose blood was drawn for estimation of serum vitamin B12 over a 2-month period. All of these patients completed the study. In the Karanth's test, the skin color tone is measured at the interphalangeal joint and the phalanx using the Von Luschan skin tone chart. The test result is obtained from differences in the values obtained. This test was performed on the day blood was drawn to measure the serum vitamin B12 levels in the study patients and on every day until discharge for patients tested to be deficient. RESULTS: Of the 83 patient subjects, 20 showed deficient vitamin B12 levels in the blood test. The Karanth's test readings were significantly different for patients with normal and deficient levels of vitamin B12 (95 % CI, 0.838-2.153). ROC curve analysis suggested that a difference greater than 1.5 should be considered positive. The sensitivity and specificity of the test were determined to be 80 and 84.1 %, respectively. Patients were grouped further according to the Fitzpatrick scale. There were no type I, II or III patients and insufficient IV cases to determine sensitivity and specificity. Sensitivity and specificity were determined to be 57.1 and 94.6 % in type V and 92 and 63.6 % in type VI, respectively. We found that 87 % of our patients who tested positive had normal values on discharge. CONCLUSION: The Karanth's test is a useful screen for a vitamin B12 deficiency and warrants further evaluation in a larger study population. PMID- 26652289 TI - Prevention of BRONJ Using PRGF in a Totally Edentulous Patient Restored With Postextraction Implants: A Case Report. PMID- 26652290 TI - Systematic review of reports describing potential impact of the Sunshine Act on peer-reviewed medical publications. AB - OBJECTIVE: The Physician Payments Sunshine Act, enacted in 2010, is intended to increase the transparency of relationships between US physicians and teaching hospitals and manufacturers of drugs, biologics, and medical devices. We examined current opinion regarding the impact of the Sunshine Act on peer-reviewed medical publications. RESEARCH DESIGN AND METHODS: We searched indexed databases (NLM/PubMed, EMBASE, and Scopus) and nonindexed sources (lay and medical press, medical websites, congress abstracts) for articles published between January 2010 and June 2015 that contained terms indicative of content related to the Sunshine Act (e.g., 'Sunshine Act', 'open payment program'). Nine publication professionals then systematically reviewed identified articles for publications related content. MAIN OUTCOME MEASURES: Quantification and characterization of publications that focused on the Sunshine Act and its implications for medical publishing. RESULTS: Among 1200 indexed publications, 113 had content on the Sunshine Act. Thirty-one discussed its implications for publications; nine distinguished between financial and nonfinancial transfers of value. Of the 117 nonindexed publications with content on the Sunshine Act, 16 discussed implications for publications, and seven distinguished between financial and nonfinancial transfers of value. Reporting of such transfers of value was viewed as a potential barrier to participation in publications with industry support. CONCLUSIONS: There is limited literature on the impact of the Sunshine Act on peer-reviewed publications and limited physician awareness that publication support may be reported as a transfer of value. PMID- 26652291 TI - Pt- and TCO-Free Flexible Cathode for DSSC from Highly Conducting and Flexible PEDOT Paper Prepared via in Situ Interfacial Polymerization. AB - Here, we report the preparation of a flexible, free-standing, Pt- and TCO-free counter electrode in dye-sensitized solar cell (DSSC)-derived from polyethylenedioxythiophene (PEDOT)-impregnated cellulose paper. The synthetic strategy of making the thin flexible PEDOT paper is simple and scalable, which can be achieved via in situ polymerization all through a roll coating technique. The very low sheet resistance (4 Omega/?) obtained from a film of 40 MUm thick PEDOT paper (PEDOT-p-5) is found to be superior to the conventional fluorine doped tin oxide (FTO) substrate. The high conductivity (357 S/cm) displayed by PEDOT-p-5 is observed to be stable under ambient conditions as well as flexible and bending conditions. With all of these features in place, we could develop an efficient Pt- and TCO-free flexible counter electrode from PEDOT-p-5 for DSSC applications. The catalytic activity toward the tri-iodide reduction of the flexible electrode is analyzed by adopting various electrochemical methodologies. PEDOT-p-5 is found to display higher exchange current density (7.12 mA/cm(2)) and low charge transfer resistance (4.6 Omega) compared to the benchmark Pt-coated FTO glass (2.40 mA/cm(2) and 9.4 Omega, respectively). Further, a DSSC fabricated using PEDOT-p-5 as the counter electrode displays a comparable efficiency of 6.1% relative to 6.9% delivered by a system based on Pt/FTO as the counter electrode. PMID- 26652293 TI - Salinicola rhizosphaerae sp. nov., isolated from the rhizosphere of the mangrove Avicennia marina L. AB - A Gram-stain-negative, motile, rod-shaped bacterium, designated MSSRFH1T, was isolated from the rhizosphere of the mangrove, Avicennia marina, in Pichavaram, Tamil Nadu, India. Phylogenetic analysis, based on the 16S rRNA gene sequence of MSSRFH1T, indicated that it clustered in the genus Salinicola and was most closely related to Salinicola peritrichatus JCM18795T (96.7 % similarity). The 16S rRNA gene sequence similarity was < 96.5 % with other strains of species of the genus Salinicola. The distinctiveness of strain MSSRFH1T was also shown by low similarities of its rpoD ( < 87 % similarity) and gyrB ( < 85 %) gene sequences with those of other members of the genus Salinicola. Strain MSSRFH1T could tolerate NaCl concentrations of up to 30 % (w/v). The main fatty acids of MSSRFH1T included C18 : 1omega7c, C16 : 0 and C19 : 0omega8c. The polar lipids present included diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, an unidentified amino lipid and unidentified phospholipids. Comparison of BOX-PCR fingerprints indicated that MSSRFH1T showed a unique DNA profile and its genomic G+C content was 64 mol%. On the basis of the data presented, strain MSSRFH1T represents a novel species of the genus Salinicola, for which the name Salinicola rhizosphaerae sp. nov. is proposed. The type strain is MSSRFH1T ( = KCTC 32998T = NBRC 110222T). PMID- 26652292 TI - Human adult stem cells derived from adipose tissue and bone marrow attenuate enteric neuropathy in the guinea-pig model of acute colitis. AB - INTRODUCTION: Mesenchymal stem cells (MSCs) have been identified as a viable treatment for inflammatory bowel disease (IBD). MSCs derived from bone marrow (BM MSCs) have predominated in experimental models whereas the majority of clinical trials have used MSCs derived from adipose tissue (AT-MSCs), thus there is little consensus on the optimal tissue source. The therapeutic efficacies of these MSCs are yet to be compared in context of the underlying dysfunction of the enteric nervous system innervating the gastrointestinal tract concomitant with IBD. This study aims to characterise the in vitro properties of MSCs and compare their in vivo therapeutic potential for the treatment of enteric neuropathy associated with intestinal inflammation. METHODS: BM-MSCs and AT-MSCs were validated and characterised in vitro. In in vivo experiments, guinea-pigs received either 2,4,6 trinitrobenzene-sulfonate acid (TNBS) for the induction of colitis or sham treatment by enema. MSCs were administered at a dose of 1x10(6) cells via enema 3 hours after the induction of colitis. Colon tissues were collected 24 and 72 hours after TNBS administration to assess the level of inflammation and damage to the ENS. MSC migration to the myenteric plexus in vivo was elucidated by immunohistochemistry and in vitro using a modified Boyden chamber assay. RESULTS: Cells exhibited multipotency and a typical surface immunophenotype for validation as bona fide MSCs. In vitro characterisation revealed distinct differences in growth kinetics, clonogenicity and cell morphology between MSC types. In vivo, BM MSCs were comparatively more effective than AT-MSCs in attenuating leukocyte infiltration and neuronal loss in the myenteric plexus. MSCs from both sources equally ameliorated body weight loss, gross morphological damage to the colon, changes in the neurochemical coding of neuronal subpopulations and the reduction in density of extrinsic and intrinsic nerve fibres innervating the colon. MSCs from both sources migrated to the myenteric plexus in in vivo colitis and in an in vitro assay. CONCLUSIONS: These data from in vitro experiments suggest that AT MSCs are ideal for cellular expansion. However, BM-MSCs were more therapeutic in the treatment of enteric neuropathy and plexitis. These characteristics should be considered when deciding on the MSC tissue source. PMID- 26652294 TI - Atomic Structure of Pt3Ni Nanoframe Electrocatalysts by in Situ X-ray Absorption Spectroscopy. AB - Understanding the atomic structure of a catalyst is crucial to exposing the source of its performance characteristics. It is highly unlikely that a catalyst remains the same under reaction conditions when compared to as-synthesized. Hence, the ideal experiment to study the catalyst structure should be performed in situ. Here, we use X-ray absorption spectroscopy (XAS) as an in situ technique to study Pt3Ni nanoframe particles which have been proven to be an excellent electrocatalyst for the oxygen reduction reaction (ORR). The surface characteristics of the nanoframes were probed through electrochemical hydrogen underpotential deposition and carbon monoxide electrooxidation, which showed that nanoframe surfaces with different structure exhibit varying levels of binding strength to adsorbate molecules. It is well-known that Pt-skin formation on Pt-Ni catalysts will enhance ORR activity by weakening the binding energy between the surface and adsorbates. Ex situ and in situ XAS results reveal that nanoframes which bind adsorbates more strongly have a rougher Pt surface caused by insufficient segregation of Pt to the surface and consequent Ni dissolution. In contrast, nanoframes which exhibit extremely high ORR activity simultaneously demonstrate more significant segregation of Pt over Ni-rich subsurface layers, allowing better formation of the critical Pt-skin. This work demonstrates that the high ORR activity of the Pt3Ni hollow nanoframes depends on successful formation of the Pt-skin surface structure. PMID- 26652295 TI - Pregnancy-specific distress: the role of maternal sense of coherence and antenatal mothering orientations. AB - BACKGROUND: Maternal mental health during pregnancy has been identified as a key factor in the future physiological, emotional and social development of both the mother and her baby. Yet little is known about the factors that contribute to increased levels of pregnancy-specific distress. The present study investigated the role of two psychosocial and personality-based constructs, namely women's sense of coherence (SoC) and their mothering orientations, on their pregnancy specific distress. DESIGN: During their second trimester of pregnancy, 293 Australian and New Zealand women participated in an online study. Hierarchical multiple regression analysis was used to determine the unique contribution of women's SoC (Sense of Coherence Scale, SoC 13) and their antenatal mothering orientation (Antenatal Mothering Orientation Measure-Revised, AMOM-R) to pregnancy-specific distress (Revised Prenatal Distress Questionnaire, NuPDQ). RESULTS: Low SoC was the best determinant of women's pregnancy-specific distress, accounting for over 45% of the variance (beta = -0.33, p < 0.001, 95% CI [-0.43, 0.23]). A Regulator mothering orientation was correlated with distress but did not have a unique contribution in the final model. CONCLUSIONS: This study further highlights the importance of better understanding women's perceptions of emotional health and their mothering role while taking into consideration their wider social context. PMID- 26652296 TI - Intracellular and extracellular microtubule associated protein tau as a therapeutic target in Alzheimer disease and other tauopathies. AB - INTRODUCTION: Microtubule associated protein tau, a protein mainly expressed in neurons, plays an important role in several diseases related to dementia, named tauopathies. Alzheimer disease is the most relevant tauopathy. The role of tau protein in dementia is now a topic under discussion, and is the focus of this review. AREAS COVERED: We have covered two major areas: tau pathology and tau as a therapeutic target. Tau pathology is mainly related to a gain of toxic function due to an abnormal accumulation, aberrant modifications (such as hyperphosphorylation and truncation, among others) and self-aggregation of tau into oligomers or larger structures. Also, tau can be found extracellularly in a toxic form. Tau-based therapy is mainly centered on avoiding the gain of these toxic functions of tau. EXPERT OPINION: Tau therapies are focused on lowering tau levels, mainly of modified tau species that could be toxic for neurons (phosphorylated, truncated or aggregated tau), in intracellular or extracellular form. Decreasing the levels of those toxic species is a possible therapeutic strategy. PMID- 26652297 TI - The PCL1-p53 axis promotes cellular quiescence. PMID- 26652298 TI - Protein Methyltransferases: A Distinct, Diverse, and Dynamic Family of Enzymes. AB - Methyltransferase proteins make up a superfamily of enzymes that add one or more methyl groups to substrates that include protein, DNA, RNA, and small molecules. The subset of proteins that act upon arginine and lysine side chains are characterized as epigenetic targets because of their activity on histone molecules and their ability to affect transcriptional regulation. However, it is now clear that these enzymes target other protein substrates, as well, greatly expanding their potential impact on normal and disease biology. Protein methyltransferases are well-characterized structurally. In addition to revealing the overall architecture of the subfamilies of enzymes, structures of complexes with substrates and ligands have permitted detailed analysis of biochemical mechanism, substrate recognition, and design of potent and selective inhibitors. This review focuses on how knowledge gained from structural studies has impacted the understanding of this large class of epigenetic enzymes. PMID- 26652299 TI - Cannulation of the Internal Thoracic Artery with a Central Venous Catheter. PMID- 26652300 TI - The performance of the microbial fuel cell-coupled constructed wetland system and the influence of the anode bacterial community. AB - In order to analyse the influences of substrate and electrode on the performance of microbial fuel cell-coupled constructed wetland (CW-MFC), the electrical generation efficiencies, the decolourization mechanism of reactive brilliant red X-3B, and the microbial communities in the anode were investigated. The closed circuit reactor fed with a mixture of X-3B and glucose (166.7 mg/L X-3B and 140 mg/L glucose) (the mixture CC reactor) got a decolourization rate of 92.79%, which was higher than the open circuit reactor (the mixture OC reactor) and the reactor fed with X-3B (the X-3B reactor). The mixture CC reactor got a maximum power density of 0.200 W/m(3), which was much higher than the X-3B reactor. The intermediates produced by X-3B decolourization were further degraded in CW-MCs. The PCR-denatured gradient gel electrophoresis analysis indicated the dominance of Proteobacteria-like 16S rRNA gnen sequences. The brightest band was detected to be dominant by a Lactobacillus kefiranofaciens-like sequence. The electrogenic bacteria-associated sequences, such as Geobacter metallireducens and Desulfobulbaceae, both existed in the closed circuit and the open circuit reactors, accompanied with Desulfobacterium sp., Klebsiella sp., Aminobacter sp., Flavobacterium sp., Thauera aromatic, and Sphingomonas sp. The abundances of Geobacter sulfurreducens and Betaproteobacteria in the mixture CC reactor were 32.2% and 7.2%, respectively, and were higher than those in the mixture OC reactor. In summary, substrate and electrode can promote the performance of the CW-MFC and have effects on the microbial community in the anode of the CW-MFC. PMID- 26652301 TI - Preparation and Evaluation of Contact Lenses Embedded with Polycaprolactone-Based Nanoparticles for Ocular Drug Delivery. AB - To improve the efficiency of topical ocular drug administration, we focused on development of a nanoparticles loaded contact lens to deliver the hydrophobic drug over a prolonged period of time. The cross-linked nanoparticles based on PCL (poly epsilon-caprolactone), 2-hydroxy ethyl methacrylate (HEMA), and poly ethylene glycol diacrylate (PEG-DA) were prepared by surfactant-free miniemulsion polymerization. The lens material was prepared through photopolymerization of HEMA and N-vinylpyrrolidone (NVP) using PEG-DA as the cross-linker. Effects of nanoparticles loading on critical contact lens properties such as transparency, water content, modulus and ion and oxygen permeabilities were studied. Nanoparticles and hydrogel showed high viability, indicating the absence of cytotoxicity and stimulatory effect. Drug release studies revealed that the hydrogel embedded with nanoparticles released the drug for a period of 12 days. The results of this study provide evidence that nanoparticles loaded hydrogels could be used for extended delivery of loteprednol etabonate and perhaps other drugs. PMID- 26652302 TI - Integrating exercise and mindfulness for an emerging conceptual framework: The intuitive approach to prevention and health promotion (IAPHP). PMID- 26652303 TI - Interfacial Synthesis of Gold-Polyaniline Nanocomposite and Its Electrocatalytic Application. AB - Gold-polyaniline (Au-PANI) nanocomposite was prepared using a simple interfacial polymerization method, performed in an immiscible water/toluene biphasic system using tetrachloroaurate, AuCl4(-) as an oxidant. The formation of Au nanoparticles (AuNPs) or Au-PANI nanocomposite can be controlled to a certain degree by varying the ratio of initial Au(+) and aniline concentrations. Under optimal condition (HAuCl4/aniline ratio is 1:2), green dispersion of Au-PANI nanocomposite is produced in aqueous phase, whose morphology, structure and physicochemical properties are investigated in details. The nanocomposite shows granular morphology with mostly rodlike AuNPs embedded in polymer. It was found that polyaniline in the composite is in the conducting emeraldine salt form, containing high amount of Au (28.85 wt %). Furthermore, the electrical conductivity of the nanocomposite was found to be four-fold higher than that of the polymer itself. In addition, the nanocomposite powder, isolated from the as prepared aqueous dispersion, can later be easily redispersed in water and further used for various applications. Moreover, the obtained Au-PANI nanocomposite showed excellent electrocatalytic performance toward the electrochemical oxygen reduction reaction (ORR), with high ORR onset potential and good selectivity. This makes it a promising candidate for a new class of Pt-free ORR catalyst. PMID- 26652304 TI - The impact of positive reappraisal on positive (and negative) emotion among older adults. AB - BACKGROUND: Positive reappraisal is an important cognitive strategy for older adults associated with wide-ranging improvements in psychological well-being. However, little is known about the relationship between positive reappraisal and positive and negative emotion, anxiety and depression, and whether positive reappraisal is associated with continued increases in positive emotion over time. METHODS: In the first study, 61 participants aged 62 to 88 years (M = 72, SD = 5.8) completed current measures of cognitive emotion regulation, positive emotion, negative emotion, anxiety and depression regarding their most distressing aging-related adverse life event, and rated (retrospectively) positive reappraisal use at the time of the stressor. Utilizing a longitudinal design, in a second study 60 participants aged 62 to 88 years (M = 71.2, SD = 5.7) completed the same measures for a recent adverse life event and repeated the measures 3 and 6 months later. RESULTS: In the first study, positive reappraisal reported for both time periods was significantly correlated with current positive emotion, but not negative emotion with mixed findings for anxiety and depression, and positive reappraisal use increased with time since stressor onset. In the second study, positive reappraisal was significantly correlated with positive emotion and significantly predicted positive emotion from 3-month to 6-month follow-up, and was related to anxiety and depression but not general negative emotion. CONCLUSIONS: These findings indicate that positive reappraisal is related to positive emotion but not consistently with negative emotion, and continues to be beneficial over time in older adults who have experienced a stressor. PMID- 26652305 TI - Enantioselective Synthesis of Four Stereoisomers of Sulfinyl Ferrocenyl Quinones with Central, Planar, and Helical Chirality. AB - Four stereoisomers of sulfinyl ferrocenyl-substituted helicenequinones having central, planar, and helical elements of chirality were stereoselectively formed, in one step, from reaction between enantiopure sulfinyl ferrocenyl dienes and a sulfinyl quinone. Asymmetric synthesis, kinetic resolution, or chemical resolution processes occurred in sequential cycloaddition, sulfoxide elimination, and partial aromatization steps. PMID- 26652306 TI - Predictors of recurrent hypoglycemia following a severe hypoglycemic event among hospitalized patients. AB - OBJECTIVES: Severe hypoglycemia is associated with poor hospital outcomes, but variables contributing to the adequacy of treatment have not been described. The objective of this study was to determine predictors of recurrent hypoglycemia among hospitalized patients with a severe hypoglycemic event. METHODS: Patients with severe hypoglycemia (glucose <40 mg/dl) with a concomitant insulin order were identified using the study institution's Information Warehouse. The primary outcome was the prevalence of recurrent hypoglycemia (defined as <70 mg/dl within 24 hours) and to identify independent predictors of recurrent hypoglycemia. Secondary outcomes included time to blood glucose recheck, time to blood glucose >= 70 mg/dl, and rebound hyperglycemia (defined as glucose >300 mg/dl within 24 hours). Multivariable linear and logistic regression models were performed. RESULTS: A total of 129 patients with severe hypoglycemia were identified. The median time to repeat glucose measurement was 29 (IQR 15-61) minutes, while the time to resolution of hypoglycemia was 49 (IQR 26-103) minutes. Recurrent hypoglycemia occurred in 49% of patients, while 19% of patients experienced rebound hyperglycemia. Independent predictors of recurrent hypoglycemia included lower repeat glucose (p = 0.025), low glomerular filtration rate (p = 0.033), and lack of insulin adjustment (p = 0.012). Independent predictors of maximum glucose post-event were type 1 diabetes (p = 0.0003), history of any diabetes (p = 0.013), and total bolus dose of insulin (p < 0.0001). Overnight timing of events was the only predictor of shorter time to hypoglycemia resolution (p < 0.0001). CONCLUSIONS: Recurrent hypoglycemia following severe hypoglycemia is common in the hospital, suggesting the need for enhanced monitoring in such patients. Further research is needed to identify methods to reduce the incidence of recurrent hypoglycemia. PMID- 26652307 TI - Measurements of Gene Expression at Steady State Improve the Predictability of Part Assembly. AB - Mathematical modeling of genetic circuits generally assumes that gene expression is at steady state when measurements are performed. However, conventional methods of measurement do not necessarily guarantee that this assumption is satisfied. In this study, we reveal a bi-plateau mode of gene expression at the single-cell level in bacterial batch cultures. The first plateau is dynamically active, where gene expression is at steady state; the second plateau, however, is dynamically inactive. We further demonstrate that the predictability of assembled genetic circuits in the first plateau (steady state) is much higher than that in the second plateau where conventional measurements are often performed. By taking the nature of steady state into consideration, our method of measurement promises to directly capture the intrinsic property of biological parts/circuits regardless of circuit-host or circuit-environment interactions. PMID- 26652308 TI - Assessing kinetic and epitopic diversity across orthogonal monoclonal antibody generation platforms. AB - The ability of monoclonal antibodies (mAbs) to target specific antigens with high precision has led to an increasing demand to generate them for therapeutic use in many disease areas. Historically, the discovery of therapeutic mAbs has relied upon the immunization of mammals and various in vitro display technologies. While the routine immunization of rodents yields clones that are stable in serum and have been selected against vast arrays of endogenous, non-target self-antigens, it is often difficult to obtain species cross-reactive mAbs owing to the generally high sequence similarity shared across human antigens and their mammalian orthologs. In vitro display technologies bypass this limitation, but lack an in vivo screening mechanism, and thus may potentially generate mAbs with undesirable binding specificity and stability issues. Chicken immunization is emerging as an attractive mAb discovery method because it combines the benefits of both in vivo and in vitro display methods. Since chickens are phylogenetically separated from mammals, their proteins share less sequence homology with those of humans, so human proteins are often immunogenic and can readily elicit rodent cross-reactive clones, which are necessary for in vivo proof of mechanism studies. Here, we compare the binding characteristics of mAbs isolated from chicken immunization, mouse immunization, and phage display of human antibody libraries. Our results show that chicken-derived mAbs not only recapitulate the kinetic diversity of mAbs sourced from other methods, but appear to offer an expanded repertoire of epitopes. Further, chicken-derived mAbs can bind their native serum antigen with very high affinity, highlighting their therapeutic potential. PMID- 26652309 TI - Threats to communion and agency mediate associations between stressor type and daily coping. AB - BACKGROUND AND OBJECTIVES: Basic human values have been categorized into two dimensions: those that are self or agentically focused, and those that are other or communally focused. We apply this model to cognitive appraisals of stress and argue that threat appraisals also fall into these two dimensions. The mediating roles of communal and agentic threats in linking stressors with coping responses were examined. DESIGN: A daily process methodology was used. METHODS: Three hundred and fifty undergraduate students were followed midday and evening over one week, completing structured electronic diaries regarding their experiences of the past half-day. Participants described stressors in open-ended format, which were then coded into social stress, achievement stress, and other stress categories. They also completed scales measuring stress appraisals and coping. RESULTS: Communal threat mediated links between social stressors and empathic responding, support seeking, and confrontation. Agentic threat mediated links between achievement stressors and empathic responding, support seeking, confrontation, and problem solving. CONCLUSIONS: Individuals tend to cope in ways that maintain communion when they perceive communion to be threatened; they tend to cope in ways that maintain agency when they perceive agency to be threatened. PMID- 26652310 TI - Trust in the medical profession and patient attachment style. AB - Attachment style is a person's approach to interpersonal relationships, which develops from early experiences with primary caregivers and can remain stable into adulthood. Depending on a person's attachment style, the amount of trust one has in others can vary when forming relationships, and trust is important in formation of the patient-physician relationship. The purpose of this study was to see if there is an association between attachment style and trust in physicians in general. Participants were recruited from an emergency department (ED) and an online university participant pool, and completed short questionnaires assessing attachment style and trust in the medical profession. Results revealed that individuals with a fearful attachment style reported significantly lower levels of trust in the medical profession than those with a secure attachment style. ED participants also reported higher levels of trust in the medical profession in comparison to student participants. This study provides a better understanding of trust in the medical profession, and insight into future care for patients who have low trust. PMID- 26652311 TI - Data Challenges for Planning and Evaluating Palliative Care Programs. PMID- 26652312 TI - Laughing in the Face of Fear (of Disease Detection): Using Humor to Promote Cancer Self-Examination Behavior. AB - This research examines the possible benefit of using humor to reduce anxiety associated with performing cancer self-examination behaviors. In Study 1, 187 undergraduates read a humorous public service announcement (PSA) script promoting either breast or testicular self-exams. Results suggest that perception of humor reduced anxiety about self-exams, which, in turn, related to more positive self exam attitudes. Simultaneously, humor perception associated with greater message processing motivation, which, in turn, associated with more supportive self-exam attitudes. Self-exam attitudes also positively associated with self-exam intentions. These results were largely replicated in Study 2. Further, self-exam intentions predicted self-exam behavior 1 week later. However, consistent with past research, the humorous and serious messages did not generate differences in subsequent self-exam behavior, though the intention-behavior relationship was stronger and significant for those exposed to the humorous versus the serious messages. In light of these findings, and given that humor has the advantage of attracting and holding attention in real message environments, the use of carefully constructed humor appeals may be a viable message strategy to promote health detection behaviors. PMID- 26652313 TI - Angiotensin II induces reorganization of the actin cytoskeleton and myosin light chain phosphorylation in podocytes through rho/ROCK-signaling pathway. AB - AIMS: In the present study, we have evaluated the effect of angiotensin II (Ang II) on actin cytoskeleton reorganization and myosin light-chain (MLC) phosphorylation in podocytes to demonstrate whether the Rho/Rho-associated coiled kinase (ROCK) pathway is involved podocyte injury. METHODS: Eighteen male Sprague Dawley rats were divided into three groups and treated with Ang II, saline or telmisartan. Morphological changes were studied at 28 days after treatment. Immunohistochemistry and Western blotting were used to determine the renal expression of p-MLC and ROCK2. Cultured podocytes were treated with Ang II (10(-7 )M) with or without Rho-kinase inhibitor (Y27632, 10(-6 )M) for variable time periods. F-actin was visualized with fluorescein isothiocyanate (FITC)-conjugated phalloidin or tetraethyl rhodamine isothiocyanate (TRITC)-conjugated phalloidin. p-MLC expression was evaluated by immunofluorescence and Western blot. The activation of Rho/ROCK was evaluated by Western blot. RESULTS: The expression of p-MLC in glomeruli increased significantly in rats treated with Ang II when compared to the control rats as shown by Western blot (p < 0.05). In cultured podocytes, Rho A and ROCK2 increased after incubation with Ang II. Ang II increased the expression of ROCK2, which was accompanied with altered morphology, redistribution of actin and increased phosphorylation of MLC. The distribution of actin changed to a large extent, although overall quantitative differences were not observed. Addition of Y-27632 to podocytes treated with Ang II could ameliorate F-actin cytoskeleton remodeling and the increment in p-MLC expression. CONCLUSION: Ang II-induced podocyte cytoskeleton protein expression changing through the RhoA/ROCK2 p-MLC/F-actin pathway. PMID- 26652314 TI - Nickel Oxide Nanoparticle-Deposited Silica Composite Solid-Phase Extraction for Benzimidazole Residue Analysis in Milk and Eggs by Liquid Chromatography-Mass Spectrometry. AB - A novel nickel oxide nanoparticle-deposited silica (SiO2@NiO) composite was prepared via liquid-phase deposition (LPD) and then employed as a solid-phase extraction (SPE) sorbent. When the SPE was coupled with liquid chromatography electrospray ionization mass spectrometry (LC-ESI/MS) analysis, an analytical platform for the sensitive determination of benzimidazole residues in egg and milk was established. The limits of detection of nine benzimidazoles were in the range of 0.8-2.2 ng/mL in milk and 0.3-2.1 ng/g in eggs, respectively, which was 5-10 times superior to the methods with other adsorbents for SPE. The recoveries of nine benzimidazoles spiked in milk and egg ranged from 70.8 to 118.7%, with relative standard deviations (RSDs) being less than 18.9%. This work presented the excellent extraction performance of NiO on benzimidazoles for the first time, and the applicability of the LPD technique used as sorbents for trace analysis in complex matrices was also demonstrated. PMID- 26652315 TI - Analysis of Carbohydrate-Carbohydrate Interactions Using Sugar-Functionalized Silicon Nanoparticles for Cell Imaging. AB - Protein-carbohydrate binding depends on multivalent ligand display that is even more important for low affinity carbohydrate-carbohydrate interactions. Detection and analysis of these low affinity multivalent binding events are technically challenging. We describe the synthesis of dual-fluorescent sugar-capped silicon nanoparticles that proved to be an attractive tool for the analysis of low affinity interactions. These ultrasmall NPs with sizes of around 4 nm can be used for NMR quantification of coupled sugars. The silicon nanoparticles are employed to measure the interaction between the cancer-associated glycosphingolipids GM3 and Gg3 and the associated kD value by surface plasmon resonance experiments. Cell binding studies, to investigate the biological relevance of these carbohydrate-carbohydrate interactions, also benefit from these fluorescent sugar capped nanoparticles. PMID- 26652316 TI - Stereochemistry-Dependent Proton Conduction in Proton Exchange Membrane Fuel Cells. AB - Graphene oxide (GO) is impermeable to H2 and O2 fuels while permitting H(+) shuttling, making it a potential candidate for proton exchange membrane fuel cells (PEMFC), albeit with a large anisotropy in their proton transport having a dominant in plane (sigmaIP) contribution over the through plane (sigmaTP). If GO based membranes are ever to succeed in PEMFC, it inevitably should have a dominant through-plane proton shuttling capability (sigmaTP), as it is the direction in which proton gets transported in a real fuel-cell configuration. Here we show that anisotropy in proton conduction in GO-based fuel cell membranes can be brought down by selectively tuning the geometric arrangement of functional groups around the dopant molecules. The results show that cis isomer causes a selective amplification of through-plane proton transport, sigmaTP, pointing to a very strong geometry angle in ionic conduction. Intercalation of cis isomer causes significant expansion of GO (001) planes involved in sigmaTP transport due to their mutual H-bonding interaction and efficient bridging of individual GO planes, bringing down the activation energy required for sigmaTP, suggesting the dominance of a Grotthuss-type mechanism. This isomer-governed amplification of through-plane proton shuttling resulted in the overall boosting of fuel-cell performance, and it underlines that geometrical factors should be given prime consideration while selecting dopant molecules for bringing down the anisotropy in proton conduction and enhancing the fuel-cell performance in GO-based PEMFC. PMID- 26652317 TI - Polish adaptation of three self-report measures of job stressors: the Interpersonal Conflict at Work Scale, the Quantitative Workload Inventory and the Organizational Constraints Scale. AB - AIM: The objective of the present study was to test the psychometric properties, reliability and validity of three job stressor measures, namely, the Interpersonal Conflict at Work Scale, the Organizational Constraints Scale and the Quantitative Workload Inventory. METHOD: The study was conducted on two samples (N = 382 and 3368) representing a wide range of occupations. The estimation of internal consistency with Cronbach's alpha and the test-retest method as well as both exploratory and confirmatory factor analyses were the main statistical methods. RESULTS: The internal consistency of the scales proved satisfactory, ranging from 0.80 to 0.90 for Cronbach's alpha test and from 0.72 to 0.86 for the test-retest method. The one-dimensional structure of the three measurements was confirmed. The three scales have acceptable fit to the data. The one-factor structures and other psychometric properties of the Polish version of the scales seem to be similar to those found in the US version of the scales. It was also proved that the three job stressors are positively related to all the job strain measures. CONCLUSIONS: The Polish versions of the three analysed scales can be used to measure the job stressors in Polish conditions. PMID- 26652318 TI - Stump Neuroma. AB - A 24-year-old man presented for follow-up magnetic resonance imaging to rule out tumor recurrence 1 year after he underwent an above-knee amputation for synovial cell sarcoma. PMID- 26652319 TI - Orthostetrics: Management of Orthopedic Conditions in the Pregnant Patient. PMID- 26652320 TI - Early Sports Specialization: Helpful or Harmful? PMID- 26652321 TI - Arthroscopically Assisted Surgery for Coronoid Fractures. AB - Coronoid fractures are not easily accessed surgically. Despite the majority of cases of coronoid fracture responding to conservative treatment, limited range of motion or instability can develop after such treatment. Therefore, unstable coronoid fractures should be treated surgically to improve clinical outcome. Several approaches and treatment methods have been used for coronoid fractures. The authors report the clinical characteristics, results, and outcomes of 10 cases of Regan-Morrey Type I, Type II, and Type III coronoid fractures treated using a novel arthroscopic technique. PMID- 26652323 TI - Advances in Intramedullary Nailing: Suprapatellar Nailing of Tibial Shaft Fractures in the Semiextended Position. AB - Reamed locked intramedullary nailing remains the standard treatment for displaced tibial shaft fractures. Supra-patellar tibial nailing in the semiextended position has been suggested as a safe and effective surgical technique that allows mitigating certain challenges of the standard subpatellar approach. Suprapatellar nailing seems to facilitate achieving and maintaining fracture reduction, particularly in proximal third tibia fractures. Preliminary investigations have suggested that this technique is associated with a low rate of complications, including a reduced incidence of postoperative anterior knee pain. Further clinical investigations are necessary to establish overall complication rates and long-term subjective outcomes. PMID- 26652322 TI - Preliminary Result of Percutaneous Screw Fixation for Bone Bruise of the Tibial Plateau. AB - This study reports the preliminary results of surgical treatment of bone bruise of the tibial plateau. Twelve patients underwent percutaneous screw fixation with a mean follow-up of 15 months. The mean duration of surgery was 15 minutes. Preoperatively, 1 week postoperatively, 1 month postoperatively, 6 months postoperatively, and 12 months postoperatively, the mean visual analog scale scores were 7.3, 2.6, 1.2, 0.6, and 0.5, respectively. The mean Hospital for Special Surgery scores were 56, 78, 89, 95, and 98, respectively. In selective patients with bone bruise, the percutaneous screw fixation is feasible to resolve pain and prevent compression of the articular surface. PMID- 26652324 TI - Use of a Bipolar Blood-Sealing System During Total Joint Arthroplasty. AB - The goal of the clinical use of a bipolar blood-sealing system is to reduce perioperative blood loss in total joint arthroplasty (TJA). This study was performed to determine whether a bipolar sealer is safe and effective in TJA and whether there are any advantages over monopolar sealers. The authors searched electronic databases and reference lists of relevant articles; retrieved all published randomized, controlled trials concerning the subject; and then performed a meta-analysis. Nine clinical trials involving 871 patients were included. The results of the meta-analysis indicate that using a bipolar sealer in TJA could reduce total measured blood loss, intraoperative blood loss, and operative time, which was especially observed in revision TJA for infection and primary total knee arthroplasty without tourniquet use. However, there was no significant difference between the 2 groups in terms of calculated blood loss, hemoglobin decrease, transfusion requirements, length of stay, and complications. The results of the comparison between bipolar and monopolar sealers used in TJA indicate that the routine use of a bipolar sealer for TJA may be of limited benefit except in revision TJA and primary total knee arthroplasty without tourniquet use. In the future, more high-quality randomized, controlled trials are needed to provide robust evidence and confirm the best option. PMID- 26652325 TI - Sural Versus Perforator Flaps for Distal Medial Leg Wounds. AB - Soft tissue coverage of distal medial ankle wounds is a challenging problem in orthopedic surgery because of the limited local tissues and prominent instrumentation. Traditionally, these wounds required free tissue transfer to achieve suitable coverage and subsequent bony union. To better respect the reconstructive ladder and to avoid the inherent difficulty of free flap coverage, rotational flaps have been used to cover these wounds. Both sural fasciocutaneous flaps and rotational fasciocutaneous perforator (propeller) flaps have been described for distal medial soft tissue coverage. The authors performed a retrospective chart review of patients who underwent distal medial leg coverage with the use of either sural flaps or rotational fasciocutaneous perforator flaps. The authors identified 14 patients by Current Procedural Terminology code who met the study criteria. The average age and degree of medical comorbidities were comparable in the 2 groups. The authors reviewed their medical records to evaluate fracture healing, flap size, complications, and return to normal shoe wear. All 7 sural flaps healed without incident, with underlying fracture healing. Of the 7 perforator flaps, 6 healed without incident, with underlying fracture healing. One perforator-based flap was complicated by superficial tip necrosis and went on to heal with local wound care. All patients returned to normal shoe wear. Both sural artery rotational flaps and posterior tibial artery based rotational flaps are viable options for coverage of the distal medial leg. Coverage can be achieved reliably without microsurgery, anticoagulation, or monitoring in the intensive care unit. PMID- 26652326 TI - Return to Work After Diskogenic Fusion in Workers' Compensation Subjects. AB - Lumbar fusion for degenerative disk disease (DDD) is associated with variable clinical outcomes. Patients with workers' compensation claims often have worse fusion outcomes than the general population. Few studies have evaluated the risk factors for poor outcomes within this clinically distinct population. The goal of this study was to identify preoperative predictors of return to work status after fusion for DDD in a workers' compensation setting. The authors used International Classification of Diseases, Ninth Revision (ICD-9), diagnosis and Current Procedural Terminology (CPT) procedural codes to identify 1037 subjects from the Ohio Bureau of Workers' Compensation database who underwent fusion for DDD between 1993 and 2013. Of these subjects, 23.2% (n=241) made a sustained return to work within 2 years after fusion. To identify preoperative predictors of postoperative return to work status, the authors used multivariate logistic regression analysis, adjusting for many important covariates. These included prolonged time out of work (P<.001; odds ratio [OR], 0.24), psychiatric history (P<.001; OR, 0.14), prolonged use of opioid analgesics (P<.001; OR, 0.46), male sex (P=.014; OR, 0.65), and legal representation (P=.042; OR, 0.67). The return to work rates associated with these risk factors were 10.4%, 2.0%, 11.9%, 21.1%, and 20.7%, respectively. Of the study subjects, 76.8% (n=796) did not return to work and had considerably worse postoperative outcomes, highlighted by chronic opioid dependence and high rates of failed back syndrome, additional surgery, and new psychiatric comorbidity. The low return to work rates and other generally poor outcomes reported in this study may indicate a more limited role for lumbar fusion among patients with DDD who have workers' compensation claims. More studies are needed to determine whether fusion for DDD can improve function and quality of life in these patients. PMID- 26652327 TI - Testosterone Therapy Can Interact With Thrombophilia, Leading to Osteonecrosis. AB - Although this effect is not widely recognized, testosterone therapy can interact with thrombophilia, causing osteonecrosis. In 12 men and 4 women who had idiopathic osteonecrosis a median of 6 months after the onset of testosterone therapy, the authors examined the interaction between testosterone therapy and previously undiagnosed thrombophilia. The authors hypothesized that patients who had osteonecrosis after starting testosterone therapy were more likely than 110 normal control subjects or 48 patients who had osteonecrosis and were not receiving testosterone therapy to have thrombophilia. Measures of thrombophilia included Factor V Leiden, prothrombin, PAI-1 gene mutations, Factor VIII, Factor XI, anticardiolipin antibody immunoglobulin G or immunoglobulin M, and homocysteine values. In 10 cases, osteonecrosis occurred 6 months or less after the onset of testosterone therapy, and in all 16 cases, it occurred after a median of 6 months of testosterone therapy. Of the 16 cases, 5 (31%) were Factor V Leiden heterozygotes vs 2 of 109 (2%) healthy control subjects (P=.0003) and 4 of 48 patients who had osteonecrosis and were not receiving testosterone therapy (P=.04). Of the 16 cases, 4 (25%) had high (>150%) Factor VIII levels vs 7 of 103 (7%) healthy control subjects (P=.04), and 3 (19%) had high (>150%) Factor XI levels vs 3 of 101 (3%) healthy control subjects (P=.03). Of the 16 patients with osteonecrosis, 14 (88%) had at least 1 abnormal procoagulant value (of the 8 measured) vs 47 of 110 (43%) healthy control subjects (P=.0009). Of the 5 men whose serum estradiol level was measured while they were receiving testosterone therapy, this level was high (>=42.6 pg/mL) in 4. When testosterone therapy is given to patients with thrombophilia, they are at increased risk for osteonecrosis. PMID- 26652328 TI - Platelet-Rich Plasma in the Animal Long-Bone Model: An Analysis of Basic Science Evidence. AB - Platelet-rich plasma (PRP) has been suggested as an adjunct to aid in long-bone healing. The purpose of this study was to systematically review the basic science in vivo evidence for the use of PRP in the treatment of bone pathology. The PubMed/MEDLINE and EMBASE databases were screened using the following search criteria: "(Platelet-rich plasma OR PRP OR autologous conditioned plasma OR ACP) AND (bone OR osteocytes OR osteogenesis OR nonunion OR delayed union)." Studies were included if they fulfilled the following criteria: (1) studied the effect of PRP or a similar concentrated platelet product, defined as a blood product with platelet concentration elevated to higher than baseline; (2) established a control with which to compare PRP; (3) were published in a peer-reviewed journal; and (4) looked specifically at animal long-bone models. All review articles and clinical studies, including randomized controlled trials and case series, were excluded from the review. Studies examining the effects of PRP on bones of animals with confounding pathology were excluded. In studies that contained additional treatment variables, only the portion of the experiment that compared PRP directly with the control were evaluated. Data were then extracted with a standardized table. The search yielded 29 articles for inclusion. Seventy-two percent of the studies reported platelet concentrations. Eighty-nine percent of studies reported significant improvement in earlier bone healing on histologic/histomorphometric assessment. One hundred percent showed significant increase in bone formation on radiographs in the PRP group. Eighty percent of studies reported a significant increase in bone area on microcomputed tomography. One hundred percent of studies showed a higher torsional stiffness for the PRP treated defects. In the in vivo studies evaluated, PRP confers several beneficial effects on animal long-bone models. Proof of concept for PRP as a biologic adjunct in long-bone models has been determined. PMID- 26652329 TI - Short-term Outcomes of Femoral Neck Fractures Treated With Hemiarthroplasty Using the Anterior Approach. AB - The direct anterior approach has recently gained popularity for patients undergoing elective total hip arthroplasty. It is unknown whether the reported benefits of the direct anterior approach to elective total hip arthroplasty can be extrapolated to patients undergoing hemiarthroplasty after femoral neck fracture. A retrospective review of 101 patients was performed to compare the outcomes of patients treated with hemiarthroplasty using the direct anterior approach (group 1) with those of patients undergoing the procedure with the posterior, anterolateral, or lateral approach (group 2). No differences in age, American Society of Anesthesiologists classification, and preinjury ambulatory status were identified between treatment groups. No difference in operative time was found between those undergoing the anterior approach (98.7 minutes) and those undergoing other surgical approaches (96.5 minutes) (P=.76). No difference in either the need for transfusion or the number of blood products transfused was seen (P=.21) postoperatively. Patients undergoing the direct anterior approach were more likely to be discharged by postoperative day 3 (P=.004) despite no difference in the recorded number of feet ambulated in the hospital. At a mean clinical follow-up of 16 weeks, there was no difference in the rate of return to baseline ambulatory status between groups (P=.07). The overall rates of major and minor complications for all patients were 23% and 26%, respectively, with no statistically significant differences between groups. The overall dislocation rate of all patients was found to be 3%. All dislocations were observed in group 2. Larger prospective studies are needed to further define the benefits of the direct anterior approach in this patient population. PMID- 26652330 TI - Medialized Versus Lateralized Center of Rotation in Reverse Shoulder Arthroplasty. AB - Reverse shoulder arthroplasty may be performed using components that medialize or lateralize the center of rotation. The purpose of this prospective study was to directly compare 2 reverse shoulder arthroplasty designs. Two treatment groups and 1 control group were identified. Group I comprised 9 patients using a medialized Grammont-style (GRM) prosthesis with a neck-shaft angle of 155 degrees . Group II comprised 9 patients using a lateralized (LAT) prosthesis with a neck shaft angle of 135 degrees . Pre- and postoperative assessment of range of motion, American Shoulder and Elbow Surgeons score, and visual analog scale pain score were performed. Radiographic measurements of lateral humeral offset and acromiohumeral distance were compared. The GRM prosthesis achieved greater forward flexion (143.9 degrees vs 115.6 degrees ; P=.05), whereas the LAT achieved greater external rotation (35.0 degrees vs 28.3 degrees ; P=.07). The lateral humeral offset was greater for the LAT prosthesis compared with the GRM prosthesis, but this distance was not significantly different from that found in the control group. The acromiohumeral distance was significantly greater in the GRM prosthesis group compared with both the LAT and the control groups. The results of this study confirm that different reverse shoulder arthroplasty designs produce radiographically different anatomy. Whereas the GRM prosthesis significantly alters the anatomy of the shoulder, the LAT design can preserve some anatomic relationships found in the normal shoulder. The clinical outcomes indicate that this may have an effect on range of motion, with traditional designs achieving greater forward flexion and lateralized designs achieving greater external rotation. PMID- 26652331 TI - Outcomes of Instrumented and Noninstrumented Posterolateral Lumbar Fusion. AB - The purpose of this study was to evaluate the long-term clinical and radiographic outcomes of posterolateral lumbar fusion for lumbar stenosis cases requiring bilateral facetectomy in conjunction with a laminectomy. The authors evaluated 34 consecutive patients who had undergone a lumbar laminectomy, bilateral partial facetectomy, and posterolateral fusion at a single institution between 1981 and 1996. They included 25 men and 9 women with a mean age of 42 years (range, 27-57 years). Twenty-three cases were instrumented and 11 were noninstrumented. Mean follow-up was 21 years (range, 15-29 years). Outcomes evaluated included reoperation rate, clinical outcomes evaluated by the Oswestry Disability Index (ODI) score, radiographic evaluations of adjacent segmental degeneration (ASD) and lumbar lordosis, and contributing demographic factors to disease progression. At final follow-up, 17 of the 34 patients had undergone reoperation (43% of the instrumented group and 64% of the noninstrumented group). There were no differences in the reoperation rate or ODI improvement between the instrumented and noninstrumented groups (P>.05). Female patients required more revisions, had less ODI improvement, had greater postoperative ASD, and had less maintenance of their postoperative lumbar lordosis. There was no difference in maintenance of postoperative lumbar lordosis or ASD between the instrumented and noninstrumented groups. Instrumentation did not improve revision rates, clinical outcomes, or radiographic outcomes in laminectomies requiring contemporaneous facetectomies. PMID- 26652332 TI - Medial Compartment Decompression by Fibular Osteotomy to Treat Medial Compartment Knee Osteoarthritis: A Pilot Study. AB - Compared with high tibial osteotomy and total knee arthroplasty, the authors found a simpler surgical procedure, partial fibular osteotomy, could effectively relieve knee pain and also correct the varus deformity for patients with medial compartment knee osteoarthritis (OA). From January 1996 to April 2012, a total of 156 patients with medial compartment OA were treated by proximal fibular osteotomy in the authors' hospital. A 2-cm-long section of fibula was resected 6 to 10 cm below the fibular head. A total of 110 patients with follow-up of more than 2 years were included in the study, including 34 males and 76 females with an average age of 59.2 years. Anteroposterior and lateral weight-bearing radiographs, the femorotibial angle (FTA) and lateral joint space, and the American Knee Society Score (KSS) and the visual analog scale (VAS) score of the knee joint were evaluated preoperatively and at final follow-up, respectively. At final follow-up, mean FTA and lateral joint space were 179.4 degrees +/-1.8 degrees and 6.9+/-0.7 mm, respectively, which were significantly smaller than those measured preoperatively (182.7 degrees +/-2.0 degrees and 12.2+/-1.1 mm, respectively; both P<.001). Mean KSS at final follow-up was 92.3+/-31.7, significantly higher than the mean preoperative score of 45.0+/-21.3 (P<.001). Mean VAS score and interquartile range were 2.0 and 2.0, significantly lower than the preoperative data (7 and 1.0, respectively; P<.001). The authors found that proximal fibular osteotomy can significantly improve both the radiographic appearance and function of the affected knee joint and also achieve long-term pain relief. This procedure may be an alternative treatment option for medial compartment OA. PMID- 26652333 TI - Using the Anatomical Axis as an Alternative to the Mechanical Axis to Assess Knee Alignment. AB - The treatment of knee osteoarthritis and the preparation for total knee arthroplasty require repetitive imaging to guide preoperative planning and operative technique. Full-length standing anteroposterior images are the gold standard in assessing the alignment of the limb via the measurement of the mechanical axis of the knee. The anatomical axis can be obtained from a more limited image of the knee, and as such is less expensive and exposes the patient to less ionizing radiation. The objective of this cross-sectional prospective study was to examine the extent to which the anatomical axis measured on a fixed flexed posteroanterior (Rosenberg view) radiograph correlates with the mechanical axis. The data of 209 total knee arthroplasty radiographs were analyzed to compare the preoperative correlation between the mechanical and anatomical axis. The anatomical axis correlated with the mechanical axis when it was measured from both the standing full-length anteroposterior radiograph and from a fixed-flexed posteroanterior radiograph. Using an angle of offset found from linear regression, these correlations become closer. Body mass index and Kellgren Lawrence grade were not found to have a significant effect. It is the conclusion of this study that the anatomical axis, as measured from a limited knee radiography, may serve as a plausible estimate of the mechanical axis when done with a neutral angle of offset, and that offset angle depends on gender and the imaging technique used to determine the anatomical axis. PMID- 26652334 TI - Therapists, Trainers, and Acupuncturists: Focused Review for the Orthopedic Surgeon. AB - Effective treatment of orthopedic injuries requires a multidisciplinary team, including physical and occupational therapists, athletic trainers, massage therapists, and acupuncturists. Orthopedic surgeons commonly encounter these practitioners but may not be familiar with the training, credentialing, and most importantly, the appropriate use of members of this team. There are general similarities in practice locations as well as types of symptoms addressed by the providers discussed, which include the treatment of physical pain, evaluation and treatment of physical impairment, and some facilitation of adaptation to the limitations caused by injuries. Across the 5 types of providers discussed there are widely varying training and licensing requirements, specializations, and continuing education requirements to maintain licensure. This article provides a focused review of these members of the multidisciplinary team and highlights the current American Academy of Orthopaedic Surgeons recommendations for the use of occupational and physical therapists for orthopedic conditions, including hip fractures, total hip arthroplasty, and anterior cruciate ligament reconstruction. PMID- 26652335 TI - Intermediate-Term Comparison of Posterior Cruciate-Retaining Versus Posterior Stabilized Total Knee Arthroplasty Using the New Knee Scoring System. AB - With the dramatic shift in the proportion of younger and more active patients undergoing total knee arthroplasty (TKA), the difference in patient-reported outcomes between cruciate-retaining and posterior-stabilized prostheses will become very important. The goal of this study was to clarify and compare the intermediate-term results of cruciate-retaining and posterior-stabilized TKAs with new patient-derived scores. This study included 60 patients who underwent TKA because of varus-type osteoarthritis (30 patients in the cruciate-retaining group and 30 patients in the posterior-stabilized group) an average of 8 years earlier. The authors investigated patient-reported outcomes using the Knee Society's new scoring system, which was adapted to the diverse lifestyles and activities of contemporary patients undergoing TKA. The results of 48 patients (23 patients in the cruciate-retaining group and 25 patients in the posterior stabilized group) were assessed. The questionnaire included 7 sections: symptoms, patient satisfaction, patient expectation, walking/standing, standard activities, advanced activities, and discretionary activities. For patient satisfaction, the score of the cruciate-retaining group was slightly but not significantly higher than that of the posterior-stabilized group. No significant difference in score was seen between the cruciate-retaining group and the posterior-stabilized group for any other sections. In addition, no statistically significant difference was seen in range of motion or radiographic alignment postoperatively. After intermediate-term follow-up, the authors found no statistically significant difference in clinical outcomes between patients undergoing cruciate-retaining TKA and those undergoing posterior-stabilized TKA. Additional studies are needed to corroborate and validate these results. PMID- 26652336 TI - Moral Dilemmas in Pediatric Orthopedics. AB - All orthopedic surgeons face moral dilemmas on a regular basis; however, little has been written about the moral dilemmas that are encountered when providing orthopedic care to pediatric patients and their families. This article aims to provide surgeons with a better understanding of how bioethics and professionalism apply to the care of their pediatric patients. First, several foundational concepts of both bioethics and professionalism are summarized, and definitions are offered for 16 important terms within the disciplines. Next, some of the unique aspects of pediatric orthopedics as a subspecialty are reviewed before engaging in a discussion of 5 common moral dilemmas within the field. Those dilemmas include the following: (1) obtaining informed consent and assent for either surgery or research from pediatric patients and their families; (2) performing cosmetic surgery on pediatric patients; (3) caring for pediatric patients with cognitive or physical impairments; (4) caring for injured pediatric athletes; and (5) meeting the demand for pediatric orthopedic care in the United States. Pertinent considerations are reviewed for each of these 5 moral dilemmas, thereby better preparing surgeons for principled moral decision making in their own practices. Each of these dilemmas is inherently complex with few straightforward answers; however, orthopedic surgeons have an obligation to take the lead and better define these kinds of difficult issues within their field. The lives of pediatric patients and their families will be immeasurably improved as a result. PMID- 26652337 TI - Racial Disparities in Lower Extremity Arthroplasty Outcomes and Use. AB - Race-associated disparities often occur in patients who undergo lower extremity total joint arthroplasty (TJA). Although it is imperative to elucidate and describe the disparities in race and ethnicity that may influence patient perception, satisfaction, and surgical outcomes, there is a paucity of reports detailing the nature of potential racial disparities in TJA. Therefore, the purpose of this review was to examine racial and ethnic disparities in the (1) physician-patient relationship; (2) use of TJA; (3) intraoperative and 30-day postoperative complications; and (4) patient-reported outcomes. Although there are limited studies that evaluated this topic, it has been shown that there are race-specific differences in physician-patient relationships. Specifically, African American patients report lower satisfaction rates in communication with their physician than their Caucasian counterparts and physicians were more apt to describe African Americans as less "medically cooperative." The majority of the studies the authors found regarding TJA use indicated that African Americans and Hispanics were less likely to undergo lower extremity TJA than Caucasians. Furthermore, racial minorities may have higher 30-day readmission and intra- and postoperative complication rates compared with Caucasians. Despite these compelling findings, concrete conclusions are difficult to make due to the presence of multiple confounding patient factors, and more studies examining the racial and ethnic disparities in patients with TJA are needed. PMID- 26652338 TI - Mason Type I Fractures of the Radial Head. AB - Mason type I fractures are the most common fractures of the radial head. The fractures have a benign character and often result in good, pain-free function. Nevertheless, up to 20% of patients with a Mason type I fracture report loss of extension and residual pain. Currently, there is a lack of consensus concerning diagnosis and treatment of these fractures. The goal of this study was to systematically review incidence, diagnosis, classification, treatment, and outcome of Mason type I radial head fractures in adults and establish an evidence based treatment guideline. A search of the MEDLINE, EMBASE, and Cochrane databases was conducted for English titles without restrictions on publication date. The authors included titles that addressed Mason type I radial head fractures and covered incidence, diagnostics, treatment, or functional or patient related outcome. Included were randomized controlled trials; case-control studies; comparative cohort studies; case series with more than 10 patients; and expert opinions. Reference lists were cross-checked for additional titles. The search yielded 1734 studies, of which 95 met the inclusion criteria. Seven studies showed that the elbow extension test has a high sensitivity (88.0-97.6) to rule out Mason type I radial head fractures. If radiography is required, antero-posterior and lateral radiographs suffice. For pain relief, hematoma aspiration seems safe and effective. Mason type I fractures are best treated with 48 hours of rest with a sling, followed with active mobilization. Cast immobilization should be avoided. Mobilization should be encouraged and if needed supported by physical therapy. PMID- 26652339 TI - Chronic Knee Dislocation After Total Knee Arthroplasty. AB - Knee dislocation after total knee arthroplasty (TKA), although rare, is a dangerous injury that can lead to neurovascular compromise and permanent disability. Chronic dislocation after TKA is even less common and is defined as dislocation that is present for 4 weeks or more. There are few reports of its management. Chronic dislocation may be complicated further by concomitant extensor mechanism disruption, ligamentous instability, and/or capsular contracture. This article describes 3 cases of chronically dislocated TKAs and the challenges encountered in treating this difficult problem. A higher level of constraint was required to maintain knee stability, and an extensor mechanism allograft was needed in 2 of the 3 reported patients. The preferred technique at the authors' institution is a complete allograft composite, tensioned in full extension. In the setting of a chronically dislocated TKA, the authors now recommend revision surgery with an enhanced measure of constraint (constrained condylar device or hinged knee prosthesis), reconstruction of the extensor mechanism when necessary, and restoration of the joint while compensating for concomitant bony defects. Even when surgeons follow these principles, it is important to inform the patient that long-term outcomes will likely be inferior to those of revision surgery for other causes. PMID- 26652340 TI - Pulmonary Embolism After Application of a Sterile Elastic Exsanguination Tourniquet. AB - Sterile elastic exsanguination tourniquets (HemaClear; OHK Medical Devices, Haifa, Israel) are relatively new on the market but are widely used because of the ease and speed of their application. The sterile elastic exsanguination tourniquet consists of a silicon ring wrapped in a stockinet sleeve with pull straps. The physician places the ring on the patient's fingers or toes and then pulls the straps proximally. The silicon ring rolls up the limb, and the stockinet sleeve unrolls onto the limb. During proximal rolling, the device displaces blood out of the limb (exsanguination). When the elastic ring reaches the preferred occlusion location, the pulling motion is stopped. The ring exerts suprasystolic pressure on the limb, thereby blocking arterial blood flow into the limb and thus acts as a tourniquet. HemaClear tourniquets are thin and sterile and therefore provide a large operative field. The authors report 2 cases of pulmonary embolism after HemaClear tourniquet application in patients with traumatic injuries (fractures of the patella and tibial plateau). Exsanguination applies mechanical stress that might dislodge a preexisting deep venous thrombosis, leading to the serious complication of pulmonary embolism. The authors want to increase awareness of this possible fatal complication during procedures performed on the lower limbs, when the HemaClear tourniquet is used for exsanguination of the affected limb. Careful consideration should be given to the use of HemaClear tourniquets in high-risk patients and those with traumatic injuries, especially when there has been a delay in surgery. PMID- 26652341 TI - Neurovascular Compression After the Latarjet Procedure. AB - The Latarjet procedure is an established and effective option for the treatment of recurrent anterior shoulder instability. Symptomatic compression of the vasculature around the shoulder and adjacent brachial plexus is uncommon and may be difficult to diagnose and treat. The purpose of this report is to describe a patient with neurovascular compression of the axillary artery and brachial plexus after an open Latarjet procedure. This is the first known report of documented combined vascular and neurologic thoracic outlet syndrome after a Latarjet procedure. Evaluation of this suspected problem requires a detailed clinical examination and a dynamic angiogram to verify which neurovascular structures are compressed. Treatment includes decompression of the brachial plexus and axillary vasculature by releasing tethering scar tissue or the remaining pectoralis minor that is creating a constricting sling effect. An arthroscopic approach provides for a careful and specific decompression. Additionally, the authors provide a review of the literature for neurologic complications and management for these complications. PMID- 26652342 TI - Chitosan and functionalized acrylic nanoparticles as the precursor of new generation of bio-based antibacterial films. AB - This study represents a new method for preparation of acrylic/chitosan films with antibacterial activity and non-toxic properties through an environmental friendly process containing a water-base acrylic resin and chitosan as an abundant natural polymer. Functional and positively charged acrylic particles based on butyl acrylate (BA)-methyl methacrylate (MMA)-glycidyl methacrylate (GMA) terpolymer were prepared with layered structure via semi-continuous emulsion polymerization. FTIR spectroscopy confirmed the presence of epoxy functional groups and size distribution of particles were evaluated by DLS and SEM as well. Films were prepared through mixing of chitosan solution and the prepared latex for the first time. SEM and EDX analyses revealed that chitosan has been distributed through the polymeric matrix uniformly. TGA data showed that introducing chitosan increases the maximum degradation temperature. It was found that the obtained films including positively charged chitosan reveal enhanced antibacterial activity against Staphylococcus areus and Escherichia coli. Also cytotoxicity analysis shows reasonable non-toxic behavior of the obtained composite films. PMID- 26652343 TI - Cardiomyocyte behavior on biodegradable polyurethane/gold nanocomposite scaffolds under electrical stimulation. AB - Following a myocardial infarction (MI), cardiomyocytes are replaced by scar tissue, which decreases ventricular contractile function. Tissue engineering is a promising approach to regenerate such damaged cardiomyocyte tissue. Engineered cardiac patches can be fabricated by seeding a high density of cardiac cells onto a synthetic or natural porous polymer. In this study, nanocomposite scaffolds made of gold nanotubes/nanowires incorporated into biodegradable castor oil-based polyurethane were employed to make micro-porous scaffolds. H9C2 cardiomyocyte cells were cultured on the scaffolds for one day, and electrical stimulation was applied to improve cell communication and interaction in neighboring pores. Cells on scaffolds were examined by fluorescence microscopy and scanning electron microscopy, revealing that the combination of scaffold design and electrical stimulation significantly increased cell confluency of H9C2 cells on the scaffolds. Furthermore, we showed that the gene expression levels of Nkx2.5, atrial natriuretic peptide (ANF) and natriuretic peptide precursor B (NPPB), which are functional genes of the myocardium, were up-regulated by the incorporation of gold nanotubes/nanowires into the polyurethane scaffolds, in particular after electrical stimulation. PMID- 26652344 TI - Swelling of poly(N-isopropylacrylamide) P(NIPA)-based hydrogels with bacterial synthesized prodigiosin for localized cancer drug delivery. AB - We present the results of swelling experiments on poly(N-isopropylacrylamide) P(NIPA)-based hydrogels. The swelling characteristics of P(NIPA)-based homo polymer and P(NIPA)-based co-polymers with Acrylamide (AM) and Butyl Methacrylate (BMA), were studied using weight gain experiments. The swelling due to the uptake of biosynthesized cancer drug, prodigiosin (PG), was compared to swelling in controlled environments (distilled water (DW), paclitaxelTM (PT) and bromophenol blue (BB)). PG was synthesized with Serratia marcescens (SM) subsp. marcescens bacteria. The mechanisms of drug diffusion and swelling of P(NIPA)-based hydrogels are also elucidated along with characterizing the heterogeneous porous structure of the P(NIPA)-based hydrogels. High Performance Liquefied Chromatography (HPLC) analysis revealed the purity of the biosynthesized prodigiosin to be 92.8%. PG was then absorbed by P(NIPA)-based hydrogels at temperatures between 28-48 degrees C. This is a temperature range that might be encountered during the implantation of biomedical devices for localized cancer treatment via drug delivery and hyperthermia. The results obtained are shown to provide insights for the design of implantable biomedical devices for the localized treatment of breast cancer. PMID- 26652345 TI - Differences in cytocompatibility between collagen, gelatin and keratin. AB - Keratins are cysteine-rich intermediate filament proteins found in the cytoskeleton of the epithelial cells and in the matrix of hair, feathers, wool, nails and horns. The natural abundance of cell adhesion sequences, RGD (Arg-Gly Asp) and LDV (Leu-Asp-Val), makes them suitable for tissue engineering applications. The purpose of our study is to evaluate their cytocompatibility as compared to well-known collagen and gelatin proteins. Herein, collagen, gelatin and keratin were blended with poly(hydroxybutyrate-co-hydroxyvalerate) (PHBV) and electrospun to afford nanofibrous mats, respectively. These PHBV/protein composite mats were characterized by field emission scanning electron microscopy (FE-SEM), attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR), X-ray photoelectron spectroscopy (XPS), and dynamic mechanical analysis (DMA). The cytocompatibility was evaluated with cell adhesion, cell viability and cell proliferation. The data from MTT and BrDU revealed that collagen had significantly superior cytocompatibility as compared to gelatin and keratin. Gelatin showed a better cytocompatibility than keratin without statistical significance difference. Finally, we gave the reasons to account for the above conclusions. PMID- 26652346 TI - Esterification of oleic acid with methanol by immobilized lipase on wrinkled silica nanoparticles with highly ordered, radially oriented mesochannels. AB - Mesoporous silica nanoparticles with a wrinkled structure (wrinkled silica nanoparticles, WSNs) having highly ordered, radially oriented mesochannels were synthesized by a solvothermal method. The method used a mixture of cyclohexane, ethanol, and water as solvent, tetraethoxysilane (TEOS) as source of inorganic silica, ammonium hydroxide as hydrolysis additive, cetyltrimethylammonium bromide (CTAB) as surfactant, and polyvinylpyrrolidone (PVP) as stabilizing agent of particle growth. Particle size (240nm to 540nm), specific surface areas (490m(2)g(-1) to 634m(2)g(-1)), surface morphology (radial wrinkled structures), and pore structure (radially oriented mesochannels) of WSN samples were varied using different molar ratios of CTAB to PVP. Using synthesized WSN samples with radially oriented mesochannels as support, we prepared immobilized Candida rugosa lipase (CRL) as a new biocatalyst for biodiesel production through the esterification of oleic acid with methanol. These results suggest that WSNs with highly ordered, radially oriented mesochannels have promising applications in biocatalysis, with the highest oleic acid conversion rate of about 86.4% under the optimum conditions. PMID- 26652347 TI - Impact of pore characteristics of silica materials on loading capacity and release behavior of ibuprofen. AB - Impact of pore characteristics of porous silica supports on loading capacity and release behavior of ibuprofen was investigated. The porous silica materials and ibuprofen-loaded porous silica materials were thoroughly characterized by N2 sorption, thermal gravimetric and derivative weight analyses (TG-DTW), X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), scanning electron microscope (SEM), transmission electron microscope (TEM) to determine the physical properties of materials, amount of ibuprofen adsorbed and position of ibuprofen. The detailed characterization reveals that the ibuprofen molecules adsorbed inside the mesopores. Increasing the mesopore size from 5nm to 10nm increased the ibuprofen loading from 0.74 to 0.85mmol/g, respectively. Incorporation of macropore into the structure of porous silica materials enhanced the ibuprofen loading capacity of 11.8-20.3%. The ibuprofen-loaded bimodal meso macroporous silica materials exhibited the highest dissolution of 92wt.% within an hour. The ibuprofen particles deposited on the external surface of the porous silica materials showed a lower dissolution rate than the ibuprofen adsorbed inside the mesopores due to the formation of ibuprofen crystalline. PMID- 26652348 TI - Fabrication of circular microfluidic network in enzymatically-crosslinked gelatin hydrogel. AB - It is a huge challenge to engineer vascular networks in vital organ tissue engineering. Although the incorporation of artificial microfluidic network into thick tissue-engineered constructs has shown great promise, most of the existing microfluidic strategies are limited to generate rectangle cross-sectional channels rather than circular vessels in soft hydrogels. Here we present a facile approach to fabricate branched microfluidic network with circular cross-sections in gelatin hydrogels by combining micromolding and enzymatically-crosslinking mechanism. Partially crosslinked hydrogel slides with predefined semi-circular channels were molded, assembled and in situ fully crosslinked to form a seamless and circular microfluidic network. The bonding strength of the resultant gelatin hydrogels was investigated. The morphology and the dimension of the resultant circular channels were characterized using scanning electron microscopy (SEM) and micro-computerized tomography (MUCT). Computational fluid dynamic simulation shows that the fabrication error had little effect on the distribution of flow field but affected the maximum velocity in comparison with designed models. The microfluidic gelatin hydrogel facilitates the attachment and spreading of human umbilical endothelial cells (HUVECs) to form a uniform endothelialized layer around the circular channel surface, which successfully exhibited barrier functions. The presented method might provide a simple way to fabricate circular microfluidic networks in biologically-relevant hydrogels to advance various applications of in vitro tissue models, organ-on-a-chip systems and tissue engineering. PMID- 26652349 TI - Diffusion in and around alginate and chitosan films with embedded sub-millimeter voids. AB - Hydrogel scaffolds from biopolymers have potential use in the controlled release of drugs, and as 3-D structure for the formation of tissue matrix. This article describes the solute release behavior of alginate and chitosan films with embedded voids of sub-millimeter dimensions. Nitrogen gas was bubbled in a fluidic arrangement to generate bubbles, prior to the crosslinking. The crosslinked gel was dried in a vacuum oven, and subsequently, soaked in Vitamin B 12 solution. The dimensions of the voids immediately after the cross-linking of gel, and also after complete drying were obtained using a digital microscope and scanning electron microscope respectively. The porosity of the gel was measured gravimetrically. The release of Vitamin B-12 in PBS buffer on a shaker was studied. The release experiments were repeated at an elevated temperature of 37 degrees C in the presence of lysozyme. The diffusion coefficient within the gel layer and the mass transfer coefficient at the interface with the bulk-liquid were estimated using a mathematical model. For comparison, the experiment was repeated with a film that does not have any embedded void. The enhancement in diffusion coefficient due to the presence of voids is discussed in this article. PMID- 26652350 TI - Characterization and antibacterial activity of silver exchanged regenerated NaY zeolite from surfactant-modified NaY zeolite. AB - The antibacterial activity of regenerated NaY zeolite (thermal treatment from cetyltrimethyl ammonium bromide (CTAB)-modified NaY zeolite and pretreatment with Na ions) loaded with silver ions were examined using the broth dilution minimum inhibitory concentration (MIC) method against Escherichia coli (E. coli ATCC 11229) and Staphylococcus aureus (S. aureus ATCC 6538). X-ray diffraction (XRD), attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy, field emission scanning electron microscopy (FESEM), energy dispersive X-ray (EDX) and chemical elemental analyses were used to characterize the regenerated NaY and AgY zeolites. The XRD patterns indicated that the calcination and addition of silver ions on regenerated NaY zeolite did not affect the structure of the regenerated NaY zeolite as the characteristic peaks of the NaY zeolite were retained, and no new peaks were observed. The regenerated AgY zeolite showed good antibacterial activity against both bacteria strains in distilled water, and the antibacterial activity of the samples increased with increasing Ag loaded on the regenerated AgY zeolite; the regenerated AgY zeolite was more effective against E. coli than S. aureus. However, the antibacterial activity of the regenerated AgY was not effective in saline solution for both bacteria. The study showed that CTAB-modified NaY zeolite materials could be regenerated to NaY zeolite using thermal treatment (550 degrees C, 5h) and this material has excellent performance as an antibacterial agent after silver ions loading. PMID- 26652351 TI - Synthesis, bioactivity and zeta potential investigations of chlorine and fluorine substituted hydroxyapatite. AB - Chlorine and fluorine substituted hydroxyapatites (HA-Cl-F) with different degrees of ion replacement were successfully prepared by the one step mechanochemical activation method. X-ray diffraction (XRD) and FT-IR spectra indicated that substitution of these anions in milled powders resulted in the formation of pure hydroxyapatite phase except for the small observed change in the lattice parameters and unit cell volumes of the resultant hydroxyapatite. Microscopic observations showed that the milled product had a cluster-like structure made up of polygonal and spherical particles with an average particle size of approximately ranged from 20+/-5 to 70+/-5nm. The zeta potential of milled samples was performed at three different pH (5, 7.4, and 9). The obtained zeta potential values were negative for all three pH values. Negative zeta potential was described to favor osseointegration, apatite nucleation, and bone regeneration. The bioactivity of samples was investigated on sintered pellets soaked in simulated body fluid (SBF) solution and apatite crystals formed on the surface of the pellets after being incubated for 14days. Zeta potential analysis and bioactivity experiment suggested that HA-Cl-F will lead to the formation of new apatite particles and therefore be a potential implant material. PMID- 26652352 TI - Release behavior of tetracycline hydrochloride loaded chitosan/poly(lactic acid) antimicrobial nanofibrous membranes. AB - The present work aimed to evaluate the release behavior of tetracycline hydrochloride loaded chitosan/poly(lactic acid) (Tet-CS/PLA) antimicrobial nanofibrous membranes fabricated via electrospinning technique. The electrospinning solution was a blend of Tet, CS formic acid solution and PLA chloroform/ethanol solution. The interaction between CS and PLA in CS/PLA nanofibers was confirmed to be hydrogen bond. The incorporation of Tet caused a slight decrease in the diameter of nanofibers with Tet content below 30%. Tet CS/PLA nanofibrous membrane showed a slight initial burst within the first 4h before a gradual increase in cumulative release, and the release percentage increased with increasing Tet contents. Tet release (Mt/Minfinity<0.6) from the medicated nanofibers could be described by Fickian diffusion model and the release profiles showed two sequential stages. Tet-CS/PLA nanofibrous membranes exhibited an effective and sustainable inhabitance on the growth of Staphylococcus aureus, and the antimicrobial activity increased rapidly with increasing Tet contents below 20%. Furthermore, the incorporation of Tet promoted the degradation of nanofibrous membranes. PMID- 26652353 TI - Porous calcium phosphate-poly (lactic-co-glycolic) acid composite bone cement: A viable tunable drug delivery system. AB - Calcium phosphate based cements (CPCs) are frequently used as bone void fillers for non-load bearing segmental bone defects due to their clinically relevant handling characteristics and ability to promote natural bone growth. Macroporous CPC scaffolds with interconnected pores are preferred for their ability to degrade faster and enable accelerated bone regeneration. Herein, a composite CPC scaffold is developed using newly developed resorbable calcium phosphate cement (ReCaPP) formulation containing degradable microspheres of bio-compatible poly (lactic-co-glycolic acid) (PLGA) serving as porogen. The present study is aimed at characterizing the effect of in-vitro degradation of PLGA microspheres on the physical, chemical and structural characteristics of the composite cements. The porosity measurements results reveal the formation of highly interconnected macroporous scaffolds after degradation of PLGA microspheres. The in-vitro characterizations also suggest that the degradation by products of PLGA reduces the pH of the local environment thereby increasing the dissolution rate of the cement. In addition, the in-vitro vancomycin release from the composite CPC scaffold suggests that the drug association with the composite scaffolds can be tuned to achieve control release kinetics. Further, the study demonstrates control release lasting for longer than 10weeks from the composite cements in which vancomycin is encapsulated in PLGA microspheres. PMID- 26652354 TI - Characteristics, interactions and coating adherence of heterogeneous polymer/drug coatings for biomedical devices. AB - With this rise in surgical procedures it is important to focus on the mobility and safety of the patient and reduce the infections that are associated with hip replacements. We examine the mechanical properties of gentamicin sulphate as a model antimicrobial layer for titanium-alloy based prosthetic hips to help prevent methicillin-resistant Staphylococcus aureus infection after surgery. A top layer of poly(lactic-co-glycolic acid) is added to maintain the properties of the gentamicin sulphate as well as providing a drug delivery system. Through the use of nanoindentation and micro-scratch techniques it is possible to determine the mechanical and adhesive properties of this system. Nanoindentation determined the modulus values for the poly(lactic-co-glycolic acid) and gentamicin sulphate materials to be 8.9 and 5.2GPa, respectively. Micro-scratch established that the gentamicin sulphate layer is strongly adhered to the Ti alloy and forces of 30N show no cohesive or adhesive failure. It was determined that the poly(lactic-co glycolic acid) is ductile in nature and delaminates from the gentamicin sulphate layer of at 0.5N. PMID- 26652355 TI - Assessment of PVA/silver nanocomposite hydrogel patch as antimicrobial dressing scaffold: Synthesis, characterization and biological evaluation. AB - A novel, elastic, non-adhesive and antimicrobial hydrogel PVA scaffold (loaded with AgNPs) synthesized using freeze-thaw method has been characterized in this study. The direct visualization of the as synthesized (one-pot green synthesis methodology) AgNPs using TEM shows particle size in the range of 7+/-3nm. The minimum inhibitory concentration (MIC) of AgNPs for Staphylococcus aureus and Escherichia coli was estimated to be 7.81MUg/mL, whereas for Pseudomonas aeruginosa (gram negative) it was around 3.90MUg/mL. The antimicrobial efficacy of AgNPs was further studied by protein leakage, ROS and LDH activity assay. The quantitative elemental analysis of silver was calculated before and after release in phosphate buffer (pH-7.4) by atomic absorption spectroscopy. The antimicrobial efficacy of the scaffold was retained even after 96h of release of AgNPs which suggests that the scaffold can be used as a reservoir for AgNPs to maintain a moist and sterile environment for a long period of time. PMID- 26652356 TI - Simultaneous determination of cysteine, uric acid and tyrosine using Au nanoparticles/poly(E)-4-(p-tolyldiazenyl)benzene-1,2,3-triol film modified glassy carbon electrode. AB - A novel Au nanoparticles/poly(E)-4-(p-tolyldiazenyl)benzene-1,2,3-triol (AuNPs/PTAT) film modified glassy carbon electrode (AuNPs/PTAT/GCE) was fabricated for the simultaneous determination of three antioxidants named, cysteine (Cys), uric acid (UA) and tyrosine (Tyr). The bare glassy carbon electrode (GCE) fails to separate the oxidation peak potentials of these molecules, while PTAT film modified electrode can resolve them. Electrochemical impedance spectroscopy (EIS) study indicates that the charge transfer resistance of bare electrode increased as (E)-4-(p-tolyldiazenyl)benzene-1,2,3-triol was electropolymerized at the bare electrode. Furthermore, EIS exhibits enhancement of electron transfer kinetics between analytes and electrode after electrodeposition of Au nanoparticles. Differential pulse voltammetry results show that the electrocatalytic current increases linearly in the ranges of 2 540MUmolL(-1) for Cys, 5-820MUmolL(-1) for UA and 10-560MUmolL(-1) for Tyr with detection limits (S/N=3) of 0.04MUmolL(-1), 0.1MUmolL(-1) and 2MUmolL(-1) for Cys, UA and Tyr, respectively. The proposed method was successfully applied for simultaneous determination of Cys, UA and Tyr in human urine samples. PMID- 26652357 TI - Corrosion behavior, biocompatibility and biomechanical stability of a prototype magnesium-based biodegradable intramedullary nailing system. AB - Implants made of degradable magnesium alloys are a potential alternative to conventional orthopaedic implant materials, e.g. stainless steel or titanium. Intramedullary nails made of the magnesium alloy LAE442 were subjected to cyclic fatigue tests in both distilled water and Hank's Balanced Salt Solution (HBSS) at 37.5 degrees C until implant failure or a limit of 500,000cycles was reached. In distilled water, four of the five nails were still intact after the end of the biomechanical test. In HBSS, a breakage within the first 70,000 bending cycles was observed. Additionally, the degradation rate of this alloy was determined in HBSS according to the weight loss method (0.24+/-0.12mmyear(-1)) and based on gas release (0.21+/-0.03mmyear(-1)) with a standard eudiometer. A cytotoxicity test with L929 cells was carried out in accordance with EN ISO 10993-5/12. This test demonstrated sufficient cell viability of the diluted extracts (50%, 25% and 12.5%). The relative metabolic activity of the 100% extract was reduced slightly below 70%, which is classified as a threshold value for cytotoxicity. In conclusion, this in vitro study indicates that intramedullary nails made of LAE442 may not have the required fatigue resistance for load-bearing applications and the development of a corrosion-protective coating may be necessary to prevent early failure of the implant. PMID- 26652358 TI - Enhanced amperometric detection of metronidazole in drug formulations and urine samples based on chitosan protected tetrasulfonated copper phthalocyanine thin film modified glassy carbon electrode. AB - An enhanced electrocatalytic reduction of metronidazole antibiotic drug molecule using chitosan protected tetrasulfonated copper phthalocyanine (Chit/CuTsPc) thin film modified glassy carbon electrode (GCE) has been developed. An irreversible reduction occurs at -0.47V (vs. Ag/AgCl) using Chit/CuTsPc modified GCE. A maximum peak current value is obtained at pH1 and the electrochemical reduction reaction is a diffusion controlled one. The detection limit is found to be 0.41nM from differential pulse voltammetry (DPV) method. This present investigation method is adopted for electrochemical detection of metronidazole in drug formulation and urine samples by using DPV method. PMID- 26652360 TI - Molecular mechanisms in deformation of cross-linked hydrogel nanocomposite. AB - The self-folding behavior in response to external stimuli observed in hydrogels is potentially used in biomedical applications. However, the use of hydrogels is limited because of its reduced mechanical properties. These properties are enhanced when the hydrogels are cross-linked and reinforced with nanoparticles. In this work, molecular dynamics (MD) simulation is applied to perform uniaxial tension and pull out tests to understand the mechanism contributing towards the enhanced mechanical properties. Also, nanomechanical characterization is performed using quasi static nanoindentation experiments to determine the Young's modulus of hydrogels in the presence of nanoparticles. The stress-strain responses for chitosan (CS), chitosan reinforced with hydroxyapatite (HAP) and cross-linked chitosan are obtained from uniaxial tension test. It is observed that the Young's modulus and maximum stress increase as the HAP content increases and also with cross-linking process. Load displacement plot from pullout test is compared for uncross-linked and cross-linked chitosan chains on hydroxyapatite surface. MD simulation reveals that the variation in the dihedral conformation of chitosan chains and the evolution of internal structural variables are associated with mechanical properties. Additional results reveal that the formation of hydrogen bonds and electrostatic interactions is responsible for the above variations in different systems. PMID- 26652359 TI - Fibrinolytic PLGA nanoparticles for slow clot lysis within abdominal aortic aneurysms attenuate proteolytic loss of vascular elastic matrix. AB - Abdominal aortic aneurysms (AAAs) involve chronic overexpression of proteases in the aortic wall that result in disruption of elastic fibers and consequent loss of vessel elasticity. Nearly 75% of AAAs contain flow-obstructing, fibrin-rich intraluminal thrombi (ILT), which act as a) a bioinert shield, protecting the underlying AAA wall from high hemodynamic stresses, and b) a reservoir of inflammatory cells and proteases that cause matrix breakdown. For these reasons, restoring flow through the aorta lumen and facilitating transmural diffusion of therapeutics from circulation to the AAA wall must be achieved by slow thrombolysis of the ILT to render it porous without rapid breakdown. Intravenously dosed tissue plasminogen activator (tPA) has been shown to rapidly lyse ILTs in acute stroke and myocardial infarctions. For future use in opening up AAA segments, in this study, we investigated the ability of tPA released from poly(lactic-co-glycolic acid) nanoparticles (PLGA NPs) to slowly lyse fibrin clots without inducing proteolytic injury and matrix synthesis-inhibitory effects on cultured rat aneurysmal smooth muscle cells (EaRASMCs). Fibrin clot lysis time was greatly extended over that in presence of exogenous tPA. Surface functionalization of NPs with a cationic amphiphile allowed them to bind to anionic fibrin clot, release tPA at a slower rate and to lyse the clot as a front proceeding outwards in unlike the more rapid and homogenous lysis that occurred due to anionic PLGA NPs. Elastic matrix content was decreased in EaRASMC cultures exposed to byproducts of clot lysis with exogenous tPA, but not tPA-NPs, and was likely due to increased proteolytic activity (MMPs, plasmin) in EaRASMC cultures exposed to exogenous tPA-lysed clots. Our results suggest that gradual ILT lysis via slow release of tPA from NPs will be likely beneficial over exogenous tPA delivery in preserving elastic matrix content and attenuating matrilysis in the adjoining AAA wall, in vivo, while rendering the ILT porous to facilitate transmural delivery of endoluminally delivered AAA therapeutics. PMID- 26652361 TI - Gold nanoparticle/multi-walled carbon nanotube modified glassy carbon electrode as a sensitive voltammetric sensor for the determination of diclofenac sodium. AB - A simple and highly sensitive sensor for the determination of diclofenac sodium based on gold nanoparticle/multi-walled carbon nanotube modified glassy carbon electrode is reported. Scanning electron microscopy along with energy dispersive X-ray spectroscopy, electrochemical impedance spectroscopy, cyclic voltammetry and square wave voltammetry was used to characterize the nanostructure and performance of the sensor and the results were compared with those obtained at the multi-walled carbon nanotube modified glassy carbon electrode and bare glassy carbon electrode. Under the optimized experimental conditions diclofenac sodium gave linear response over the range of 0.03-200MUmolL(-1). The lower detection limits were found to be 0.02MUmolL(-1). The effect of common interferences on the current response of DS was investigated. The practical application of the modified electrode was demonstrated by measuring the concentration of diclofenac sodium in urine and pharmaceutical samples. This revealed that the gold nanoparticle/multiwalled carbon nanotube modified glassy carbon electrode shows excellent analytical performance for the determination of diclofenac sodium in terms of a very low detection limit, high sensitivity, very good accuracy, repeatability and reproducibility. PMID- 26652362 TI - Injectability, microstructure and release properties of sodium fusidate-loaded apatitic cement as a local drug-delivery system. AB - The introduction of an antibiotic, sodium fusidate (SF), into the liquid phase of calcium carbonate-calcium phosphate (CaCO3-CaP) bone cement was evaluated, considering the effect of the liquid to powder ratio (L/P) on the composition and microstructure of the set cement and the injectability of the paste. In all cases, we obtained set cements composed mainly of biomimetic carbonated apatite analogous to bone mineral. With this study, we evi-denced a synergistic effect of the L/P ratio and SF presence on the injectability (i.e., the filter-pressing pheno-menon was suppressed) and the setting time of the SF-loaded cement paste compared to reference cement (without SF). In addition, the in vitro study of SF release, according to the European Pharmacopoeia recommendations, showed that, regardless of the L/P ratio, the cement allowed a sustained release of the antibiotic over 1month in sodium chloride isotonic solution at 37 degrees C and pH7.4; this release is discussed considering the microstructure characteristics of SF-loaded cements (i.e., porosity, pore-size distribution) before and after the release test. Finally, modelling antibiotic release kinetics with several models indicated that the SF release was controlled by a diffusion mechanism. PMID- 26652363 TI - Novel two-step method to form silk fibroin fibrous hydrogel. AB - Hydrogels prepared by silk fibroin solution have been studied. However, mimicking the nanofibrous structures of extracellular matrix for fabricating biomaterials remains a challenge. Here, a novel two-step method was applied to prepare fibrous hydrogels using regenerated silk fibroin solution containing nanofibrils in a range of tens to hundreds of nanometers. When the gelation process of silk solution occurred, it showed a top-down type gel within 30min. After gelation, silk fibroin fibrous hydrogels exhibited nanofiber network morphology with beta sheet structure. Moreover, the compressive stress and modulus of fibrous hydrogels were 31.9+/-2.6 and 2.8+/-0.8kPa, respectively, which was formed using 2.0wt.% concentration solutions. In addition, fibrous hydrogels supported BMSCs attachment and proliferation over 12days. This study provides important insight in the in vitro processing of silk fibroin into useful new materials. PMID- 26652364 TI - A combinatorial variation in surface chemistry and pore size of three-dimensional porous poly(epsilon-caprolactone) scaffolds modulates the behaviors of mesenchymal stem cells. AB - Biomaterial properties play significant roles in controlling cellular behaviors. The objective of the present study was to investigate how pore size and surface chemistry of three-dimensional (3D) porous scaffolds regulate the fate of mesenchymal stem cells (MSCs) in vitro in combination. First, on poly(epsilon caprolactone) (PCL) films, the hydrolytic treatment was found to stimulate the adhesion, spreading and proliferation of human MSCs (hMSCs) in comparison with pristine films, while the aminolysis showed mixed effects. Then, 3D porous PCL scaffolds with varying pore sizes (100-200MUm, 200-300MUm and 300-450MUm) were fabricated and subjected to either hydrolysis or aminolysis. It was found that a pore size of 200-300MUm with hydrolysis in 3D scaffolds was the most favorable condition for growth of hMSCs. Importantly, while a pore size of 200-300MUm with hydrolysis for 1h supported the best osteogenic differentiation of hMSCs, the chondrogenic differentiation was greatest in scaffolds with a pore size of 300 450MUm and treated with aminolysis for 1h. Taken together, these results suggest that surface chemistry and pore size of 3D porous scaffolds may potentially have a synergistic impact on the behaviors of MSCs. PMID- 26652365 TI - Determining the mechanical properties of electrospun poly-epsilon-caprolactone (PCL) nanofibers using AFM and a novel fiber anchoring technique. AB - Due to its low cost, biocompatibility and slow bioresorption, poly-epsilon caprolactone (PCL) continues to be a suitable material for select biomedical engineering applications. We used a combined atomic force microscopy (AFM)/optical microscopy technique to determine key mechanical properties of individual electrospun PCL nanofibers with diameters between 440-1040nm. Compared to protein nanofibers, PCL nanofibers showed much lower adhesion, as they slipped on the substrate when mechanically manipulated. We, therefore, first developed a novel technique to anchor individual PCL nanofibers to micrometer-sized ridges on a substrate, and then mechanically tested anchored nanofibers. When held at constant strain, tensile stress relaxed with fast and slow relaxation times of 1.0+/-0.3s and 8.8+/-3.1s, respectively. The total tensile modulus was 62+/ 26MPa, the elastic (non-relaxing) component of the tensile modulus was 53+/ 36MPa. Individual PCL fibers could be stretched elastically (without permanent deformation) to strains of 19-23%. PCL nanofibers are rather extensible; they could be stretched to a strain of at least 98%, and a tensile strength of at least 12MPa, before they slipped off the AFM tip. PCL nanofibers that had aged for over a month at ambient conditions became stiffer and less elastic. Our technique provides accurate nanofiber mechanical data, which are needed to guide construction of scaffolds for cells and other biomedical devices. PMID- 26652366 TI - Efficient purification of lysozyme from egg white by 2-mercapto-5 benzimidazolesulfonic acid modified Fe3O4/Au nanoparticles. AB - 2-Mercapto-5-benzimidazolesulfonic acid (MBISA) modified Fe3O4/Au nanoparticles were synthesized in aqueous solution and characterized by photo correlation spectroscopy (PCS) and vibrating sample magnetometer (VSM). The so-obtained Fe3O4/Au-MBISA nanoparticles were capable of specific adsorbing lysozyme. The maximum amount of lysozyme adsorbed on 1.0mg Fe3O4/Au-MBISA nanoparticles was 346MUg. The lysozyme desorption behavior was studied and the lysozyme recovery from Fe3O4/Au-MBISA nanoparticles approached 100% under optimal conditions, and the reusability studies showed that the nanoparticles could maintain about 91% of the initial lysozyme adsorption capacity after 7 repeated adsorption-elution cycles. The Fe3O4/Au-MBISA nanoparticles were used in the purification of lysozyme from chicken egg white, which was verified by a single SDS-PAGE band. Therefore, the obtained Fe3O4/Au-MBISA nanoparticles exhibited excellent performance in the direct purification of lysozyme from egg white. PMID- 26652367 TI - Composite scaffolds for osteochondral repair obtained by combination of additive manufacturing, leaching processes and hMSC-CM functionalization. AB - Articular repair is a relevant and challenging area for the emerging fields of tissue engineering and biofabrication. The need of significant gradients of properties, for the promotion of osteochondral repair, has led to the development of several families of composite biomaterials and scaffolds, using different effective approaches, although a perfect solution has not yet been found. In this study we present the design, modeling, rapid manufacturing and in vitro testing of a composite scaffold aimed at osteochondral repair. The presented composite scaffold stands out for having a functional gradient of density and stiffness in the bony phase, obtained in titanium by means of computer-aided design combined with additive manufacture using selective laser sintering. The chondral phase is obtained by sugar leaching, using a PDMS matrix and sugar as porogen, and is joined to the bony phase during the polymerization of PDMS, therefore avoiding the use of supporting adhesives or additional intermediate layers. The mechanical performance of the construct is biomimetic and the stiffness values of the bony and chondral phases can be tuned to the desired applications, by means of controlled modifications of different parameters. A human mesenchymal stem cell (h-MSC) conditioned medium (CM) is used for improving scaffold response. Cell culture results provide relevant information regarding the viability of the composite scaffolds used. PMID- 26652368 TI - Synthesis of flexirubin-mediated silver nanoparticles using Chryseobacterium artocarpi CECT 8497 and investigation of its anticancer activity. AB - In this work, the synthesis of silver nanoparticles from a pigment produced by a recently-discovered bacterium, Chryseobacterium artocarpi CECT 8497, was achieved, followed by an investigation of its anticancer properties. The bacterial pigment was identified as flexirubin following NMR ((1)H NMR and (13)C NMR), UV-Vis, and LC-MS analysis. An aqueous silver nitrate solution was treated with isolated flexirubin to produce silver nanoparticles. The synthesised silver nanoparticles were subsequently characterised by UV-Vis spectroscopy, Scanning Electron Microscopy (SEM), Energy Dispersive X-ray Spectroscopy (EDX), X-Ray Diffraction (XRD), and Fourier Transform Infrared (FTIR) Spectroscopy methodologies. Furthermore, the anticancer effects of synthesised silver nanoparticles in a human breast cancer cell line (MCF-7) were evaluated. The tests showed significant cytotoxicity activity of the silver nanoparticles in the cultured cells, with an IC50 value of 36MUgmL(-1). This study demonstrates that silver nanoparticles, synthesised from flexirubin from C. artocarpi CECT 8497, may have potential as a novel chemotherapeutic agent. PMID- 26652369 TI - Synthesis of doxorubicin-PLGA loaded chitosan stabilized (Mn, Zn)Fe2O4 nanoparticles: Biological activity and pH-responsive drug release. AB - We have synthesized Mn1-xZnxFe2O4 ((Mn, Zn) ferrite) magnetic nanoparticles (MNPs) having radius of 25nm to act as platforms for delivering drugs. The Mn0.9Zn0.1Fe2O4 MNPs exhibit superparamagnetic behavior with large saturation magnetization (MS). They were encapsulated in polymer so that they can be developed into PLGA-coated chitosan stabilized (Mn, Zn) MNPs, i.e., DOX PLGA@CS@Mn0.9Zn0.1Fe2O4 which can serve as an effective carrier of the anti cancer drug doxorubicin (DOX) whose release would be controlled by the pH in the environment surrounding the cancer tumor. The structure of the as-prepared particles is of a magnetic core-encapsulated by polymer shell layer of around 50nm thick. At a pH of 4.0, the DOX release within the first 5h is fast (around 57%). It becomes slower (around 46% over the next 25h) when the pH is increased to 7.4. The DOX-PLGA@CS@Mn0.9Zn0.1Fe2O4 (for concentrations lower than 125MUgmL( 1)) shows lower toxicity against HeLa cells using DOX only. When the DOX PLGA@CS@Mn0.9Zn0.1Fe2O4 is increased to 250MUgmL(-1), the DOX PLGA@CS@Mn0.9Zn0.1Fe2O4 shows greater anti-cancer activity and has satisfactory therapeutic effect. The slow sustained release of the DOX by the drug loaded particles when they are in the physiological pH environment (7.4) of normal tissues and mild toxicity of DOX against cancer cell at low concentration point to the DOX loaded PLGA@CS@Mn0.9Zn0.1Fe2O4 being safely used for treating cancer. The higher dosage of DOX needed to kill the cancer cells will be released when the synthesized carriers are subject to the pH stimuli surrounding these cells. PMID- 26652370 TI - In vitro evaluation of anti-calcification and anti-coagulation on sulfonated chitosan and carrageenan surfaces. AB - In recent years, great effort has been devoted to the development of biomaterials that come into contact with blood. The surfaces of these materials need to be of suitable mechanical strength, and present anti-thrombogenic and anti calcification properties. Chitosan is a natural polymer that has attracted attention due to its potential to act as a biomaterial. However, chitosan contains amino groups in its structure that may promote thrombogenesis and calcification. A strategy to reduce these properties constitutes the introduction of sulfonate groups (R-SO3-) in the chitosan chain. Another interesting biopolymer with similar characteristics to those of heparin is carrageenan, which has sulfate groups in its structure. As such, we evaluated "in vitro" calcification and thrombogenic processes on surfaces of pristine and sulfonated chitosan and on polyelectrolyte complexes (PEC) of chitosan and carrageenan. Results indicate that PEC demonstrate significant reductions in calcification and thrombogenic potential, probably due to the presence of sulfonate groups in both the carrageenan and treated chitosan. PMID- 26652371 TI - Localised controlled release of simvastatin from porous chitosan-gelatin scaffolds engrafted with simvastatin loaded PLGA-microparticles for bone tissue engineering application. AB - Localised controlled release of simvastatin from porous freeze-dried chitosan gelatin (CH-G) scaffolds was investigated by incorporating simvastatin loaded poly-(dl-lactide-co-glycolide) acid (PLGA) microparticles (MSIMs) into the scaffolds. MSIMs at 10% w/w simvastatin loading were prepared using a single emulsion-solvent evaporation method. The MSIM optimal amount to be incorporated into the scaffolds was selected by analysing the effect of embedding increasing amounts of blank PLGA microparticles (BL-MPs) on the scaffold physical properties and on the in vitro cell viability using a clonal human osteoblastic cell line (hFOB). Increasing the BL-MP content from 0% to 33.3% w/w showed a significant decrease in swelling degree (from 1245+/-56% to 570+/-35%). Scaffold pore size and distribution changed significantly as a function of BL-MP loading. Compressive modulus of scaffolds increased with increasing BL-MP amount up to 16.6% w/w (23.0+/-1.0kPa). No significant difference in cell viability was observed with increasing BL-MP loading. Based on these results, a content of 16.6% w/w MSIM particles was incorporated successfully in CH-G scaffolds, showing a controlled localised release of simvastatin able to influence the hFOB cell proliferation and the osteoblastic differentiation after 11 days. PMID- 26652372 TI - Mesoporous silica nanoparticles combining Au particles as glutathione and pH dual sensitive nanocarriers for doxorubicin. AB - Mesoporous silica nanoparticles (MSNs) combining gold particles (MSNs-Au) were synthesized as nanocarriers for glutathione (GSH) and pH dual-sensitive intracellular controlled release of the anti-cancer drug doxorubicin (DOX). The MSNs were used as an adsorbent for DOX, and the ultra-small gold nanospheres (Au NPs) partly operated as gatekeepers to control the release of DOX from the pores of MSNs and as the driver of drug release in the presence of GSH due to the association between GSH and Au particles. Under different pH conditions, DOX release changed due to different levels of dissociation between the -SH group on the MSNs and the Au particles. The composition, morphology, and properties of the as-prepared composites were characterized by elemental analysis, fluorescence spectroscopy, Fourier transform infrared spectroscopy, transmission electron microscopy, nitrogen adsorption-desorption, thermal gravimetric and UV-visible spectroscopy. The in vitro release experiments showed that these smart nanocarriers effectively avoided drug leakage in the neutral media. Cytotoxicity and imaging studies also indicated that DOX-loaded Au-MSNs (DOX@MSNs-Au) had a significant inhibitory effect on the growth of Tca8113 cells and sustained the release rate of DOX. PMID- 26652373 TI - Chitosan and carboxymethyl-chitosan capping ligands: Effects on the nucleation and growth of hydroxyapatite nanoparticles for producing biocomposite membranes. AB - Synthetic biomaterials based on calcium phosphates (CaP) have been widely studied for bone tissue reconstruction therapies, but no definitive solution that fulfills all of the required properties has been identified. Thus, this study reports the synthesis of composite membranes based on nanohydroxyapatite particles (nHA) embedded in chitosan (CHI) and O-carboxymethyl chitosan (CMC) matrices produced using a one-step co-precipitation method in water media. Biopolymers were used as capping ligands for simultaneously controlling the nucleation and growth of the nHA particles during the precipitation process and also to form the polymeric network of the biocomposites. The bionanocomposites were extensively characterized using light microscopy (LM), scanning and transmission electron microscopy (SEM/TEM), energy-dispersive X-ray spectroscopy (EDX), Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), atomic force microscopy (AFM), X-ray micro-CT analysis (MUCT), andMTT (3-(4,5 dimethylthiazolyl-2)-2,5-diphenyltetrazoliumbromide) cell proliferation assays for cell cytotoxicity. The results demonstrated that the ligands used during the synthesis highly affected the composites produced, primarily due the changes in the mechanisms and kinetics of nucleation and growth of the HA particles at the nanoscale level. The SEMimages revealed that the use of carboxyl-functionalized chitosan (CMC) ligands significantly reduced the average size of theHA nanoparticles and caused the formation of a narrower size distribution (90+/ 20nm) compared to theHAnanoparticles producedwith chitosan ligands (220+/-50nm). The same trend was verified by the AFM analysis,where the nHA particles were formed evenly dispersed in the polymer matrix. However, the CMC-based composites were more homogeneously distributed, which was endorsed by the images collected via X-ray micro-CT. The FTIR spectra and the XRD analysis indicated that nanosized hydroxyapatite was the predominant calcium phosphate phase produced during the co-precipitation aqueous process for both the chitosan and CMC biocomposites. These novel hybrid systems based on chitosan and chitosan derivatives with nHA composites were non-cytotoxic to a human osteoblast-like model cell line (SAOS) according to MTT in vitro assays. Moreover, the CMC-nHA biocomposites revealed a striking improvement in the cell viability response compared to the CHI-nHA biocomposite, which was attributed to the much higher surface area caused by the refinement of the nanoparticles size. Thus, the results of this study demonstrate that these novel bionanocomposite membranes offer promising perspectives as biomaterials for potential repair and replacement of cartilage and bone tissues. PMID- 26652374 TI - Biosynthesis and characterization of a non-repetitive polypeptide derived from silk fibroin heavy chain. AB - Silk fibroin heavy chain is the major protein component of Bombyx mori silk fibroin and is composed of 12 repetitive and 11 non-repetitive regions, with the non-repetitive domain consisting of a hydrophilic polypeptide chain. In order to determine the biomedical function of the non-repetitive domain or potentially use it to modify hydrophobic biomaterials, high-purity isolation is necessary. Previously, we cloned and extended a gene motif (f(1)) encoding the non repetitive domain. Here, this motif and its multimers are inserted into a glutathione S-transferase (GST)-tagged fusion-protein expression vector. Motif f(1) and multimers f(4) and f(8) were expressed in Escherichia coli BL21 cells following isopropyl beta-D-1-thiogalactopyranoside induction, purified by GST affinity chromatography, and single bands of purified fusion proteins GST-F(1), GST-F(4), and GST-F(8), were visualized by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Target polypeptides F(1), F(4), and F(8), were cleaved clearly from the GST-fusion tag following thrombin digestion. Mass spectrometry results indicate that the molecular weights associated with fusion proteins GST F(1), GST-F(4), and GST-F(8) are 31.5, 43.8, and 59.0kDa, respectively, and with the cleaved polypeptides F(1), F(4), and F(8) are 4.8, 16.8, and 32.8kDa, respectively. The F(1), F(4), and F(8) polypeptide chains are negatively charged with isoelectric points (pI) of 3.3, 3.2, and 3.0, respectively. The molecular weight and pI values of the polypeptide chains are consistent with the predicted values and the amino acid compositions similar to predicted sequences. FTIR and CD results show the molecular conformation of F(1) was mainly random coil, and more stable alpha-helix structure formed in longer molecular chain. PMID- 26652375 TI - Adhesion and internalization differences of COM nanocrystals on Vero cells before and after cell damage. AB - The adhesion and internalization between African green monkey kidney epithelial (Vero) cells (before and after oxidative damage by hydrogen peroxide) and calcium oxalate monohydrate (COM) nanocrystals (97+/-35nm) were investigated so as to discuss the molecular and cellular mechanism of kidney stone formation. Scanning electron microscope (SEM) was used to observe the Vero-COM nanocrystal adhesion; the nanocrystal-cell adhesion was evaluated by measuring the content of malonaldehyde (MDA), the activity of superoxide dismutase (SOD), the expression level of cell surface osteopontin (OPN) and the change of Zeta potential. Confocal microscopy and flow cytometry were used for the observation and quantitative analysis of crystal internalization. In the process of adhesion, the cell viability and the SOD activity declined, the MDA content, Zeta potential, and the OPN expression level increased. The adhesive capacity of injured Vero was obviously stronger than normal cells; in addition the injured cells promoted the aggregation of COM nanocrystals. The capacity of normal cells to internalize crystals was obviously stronger than that of injured cells. Cell injury increased adhesive sites on cell surface, thereby facilitating the aggregation of COM nanocrystals and their attachment, which results in enhanced risk of calcium oxalate stone formation. PMID- 26652376 TI - Biofabrication of zinc oxide nanoparticles using fruit extract of Rosa canina and their toxic potential against bacteria: A mechanistic approach. AB - The use of plant extract in the biosynthesis of nanoparticles (NPs) can be an eco friendly approach and have been suggested as a possible alternative to classic methods namely physical and chemical procedures. In this study, the biosynthesis of zinc oxide (ZnO) NPs by both "conventional heating" (CH) and "microwave irradiation" (MI) methods has been reported. Stable and spherical ZnONPs were produced using zinc nitrate and flesh extract of Rosa canina fruit (rosehip) which was used as a precursor. The flesh extract acts as a reducing and capping agent for generation of ZnONPs. The structural, morphological and colloidal properties of the as-synthesized NPs have been confirmed by X-ray Diffraction (XRD), Scanning Electron Microscopy (SEM), Energy Dispersive X-ray (EDX), Fourier transform Infrared (FT-IR) and Dynamic Light Scattering (DLS). In comparison with the CH method, the MI method has some advantages such as significantly short reaction time (within 8min) owing to the high heating rate and thus the accelerated reaction rate. Both methods led to the synthesis of nearly identical NPs with respect to shape and size according to the results of DLS, XRD and SEM techniques. The possible mechanism for synthesis pathway has been proposed based on FT IR results, XRD patterns, potentiometric data and antioxidant activity. In addition, the antibacterial activity of as-prepared ZnONPs was investigated against several bacteria such as Listeria monocytogenes, Escherichia coli, Salmonella typhimurium. Moreover, the efficacy of ZnONPs to treat cancer cell lines were measured by means of cell viability test via MTT assay in which concentrations of 0.05 and 0.1mg/mL of ZnONPs induced a very low toxicity. Thus, the present investigation reveals that ZnONPs have the potential for various medical and industrial applications. PMID- 26652377 TI - Bacterial cellulose and bacterial cellulose-vaccarin membranes for wound healing. AB - Bacterial cellulose (BC) and bacterial cellulose-vaccarin (BC-Vac) membranes were successfully produced in large scale. BC was synthesized by Gluconacetobacter xylinum. BC-Vac membranes were prepared by immersing BC in vaccarin solution. The surface morphologies of BC and BC-Vac membranes were examined by a scanning electron microscope (SEM) and an atomic force microscopy (AFM). The images showed that BC-Vac exhibited the characteristic 3D nanofibrillar network of BC matrix but there was adhesion between fibers. The mechanical properties of BC and BC-Vac membranes were evaluated and the results indicated that the adding of drug vaccarin into the BC membranes increased the malleability indicated by the increment in elongation at break compared with BC. Fourier transform infrared spectroscopy (FTIR) analysis was conducted to confirm the incorporation of vaccarin in BC-Vac and investigate the hydroxyl interactions between BC and drug vaccarin. Cell viability and cell attachment studies demonstrated that BC and BC Vac membranes had no cytotoxicity and could be a good carrier for cell growth. The wound healing performance was examined in vivo by rat skin models. Histological observations revealed that wounds treated with BC-Vac epithelialized and regenerated faster than treated with BC. Therefore, BC-Vac was considered as a potential candidate for wound dressing materials. PMID- 26652378 TI - Synthesis of gelatin nano/submicron particles by binary nonsolvent aided coacervation (BNAC) method. AB - A newly developed modified coacervation method is utilized to synthesize gelatin nano/submicron particles (GN/SPs) as a drug carrier. Binary nonsolvent aided coacervation (BNAC) method is a modified single step coacervation method, which has yielded approximately a threefold lower particle size and higher average yield in terms of weight percentage of around 94% in comparison to the conventional phase separation methods. In this study 0.5% (w/v) gelatin aqueous solution with a binary nonsolvent system of acetone and ethanol was used. Nanoparticle synthesis was optimized with respect to nonsolvent system type and pH. pH7 has resulted a minimum particle size of 55.67 (+/-43.74) nm in anhydrous medium along with a swollen particle size of 776nm (+/-38.57) in aqueous medium with a zeta potential of (-16.3+/-3.51) mV in aqueous medium. Swelling ratio of 13.95 confirms the crosslinked hydrogel nature of the particles. Furthermore, drug loading efficiency of the gelatin particles prepared at 7pH was observed with nitrofurazone as the model drug. Results of drug release study indicate the potential use of GN/SPs as drug loading matrix for wound management such as burn wound management. PMID- 26652379 TI - Fabrication of SnO2/porous silica/polyethyleneimine nanoparticles for pH responsive drug delivery. AB - To create novel nanocarriers for achieving excellent drug delivery performance, pH-responsive fluorescent porous silica (PS) nanocarriers were developed by encapsulating SnO2 nanoparticles and coating polyethyleneimine (PEI) layer. SnO2/porous silica (SnO2/PS) nanoparticles have an average diameter of 80nm and center-radial large pore channels. The large channels endow them high surface area with a Brunauer-Emmett-Teller (BET) area of 939m(2)g(-1). Aspirin was used as test drug to evaluate the releasing behavior of SnO2/porous silica/polyethyleneimine (SnO2/PS/PEI) nanoparticles. Results indicated that aspirin can be successfully incorporated into the SnO2/PS/PEI nanoparticles and the SnO2/PS/PEI nanoparticles displayed excellent pH-responsive release. The release rate in pH7.4 buffer is higher than that in pH5.5 buffer, which attributed to the PEI structure change in varied pH buffer. In addition, the SnO2/PS/PEI nanoparticles presented novel drug-dependent fluorescence, which could be used to trace the drug release. PMID- 26652380 TI - Aptamer-conjugated, fluorescent gold nanorods as potential cancer theradiagnostic agents. AB - GNRs are emerging as a new class of probes for theradiagnostic applications thanks to their unique optical properties. However, the achievement of proper nanoconstructs requires the synthesis of highly pure GNRs with well-defined aspect ratio (AR), in addition to extensive surface chemistry modification to provide them with active targeting and, possibly, multifunctionality. In this work, we refined the method of the seed mediated growth and developed a robust procedure for the fabrication of GNRs with specific AR. We also revealed and characterized unexplored aging phenomena that follow the synthesis and consistently alter GNRs' final AR. Such advances appreciably improved the feasibility of GNRs fabrication and offered useful insights on the growth mechanism. We next produced fluorescent, biocompatible, aptamer-conjugated GNRs by performing ligand exchange followed by bioconjugation to anti-cancer oligonucleotide AS1411. In vitro studies showed that our nanoconstructs selectively target cancer cells while showing negligible cytotoxicity. As a result, our aptamer-conjugated GNRs constitute ideal cancer-selective multifunctional probes and promising candidates as photothermal therapy agents. PMID- 26652381 TI - Polylactide-based microspheres prepared using solid-state copolymerized chitosan and d,l-lactide. AB - Amphiphilic chitosan-g-poly(d,l-lactide) copolymers have been manufactured via solid-state mechanochemical copolymerization and tailored to design polyester based microspheres for tissue engineering. A single-step solid-state reactive blending (SSRB) using low-temperature co-extrusion has been used to prepare these copolymers. These materials have been valorized to stabilize microspheres processed by an oil/water emulsion evaporation technique. Introduction of the copolymers either in water or in the oil phase of the emulsion allowed to replace a non-degradable emulsifier typically used for microparticle preparation. To enhance cell adhesion, these copolymers were also tailored to bring amino saccharide positively charged segments to the microbead surface. Size distribution, surface morphology, and total microparticle yield have been studied and optimized as a function of the copolymer composition. PMID- 26652382 TI - Accelerated bony defect healing by chitosan/silica hybrid membrane with localized bone morphogenetic protein-2 delivery. AB - Therapeutic agents such as growth factors have been widely applied to promote bone regeneration with implantable biomaterials. In this study, a hybrid of chitosan-xerogel membrane was combined with bone morphogenetic protein-2 (BMP-2) for enhancing bone regeneration. The characteristics of the hybrid membrane as a carrier of BMP-2 were compared with that of the pure chitosan membrane, and the effect of combining the hybrid membrane with BMP-2 on its bone healing ability was evaluated using in vitro and in vivo animal tests. The amount of BMP-2 adsorbed on the pure chitosan membrane was less than that on the hybrid membrane and, therefore, the cellular behaviors of the pure chitosan membrane were only slightly improved by the protein treatment. In contrast, the hybrid membrane showed excellent affinity toward BMP-2, and the adsorption of BMP-2 elicited a dramatic improvement in the cellular responses of the hybrid membrane. Moreover, the in vivo study demonstrated that bone regeneration was significantly enhanced when using the hybrid membrane with BMP-2 as compared to the hybrid membrane without BMP-2. These results suggest that the hybrid membrane is very efficient in carrying BMP-2 and accelerates the bone healing process through the successful delivery of BMP-2 and its osteoconductive composition. PMID- 26652383 TI - Electrochemical comparison and biological performance of a new CoCrNbMoZr alloy with commercial CoCrMo alloy. AB - A new CoCrNbMoZr alloy, with Nb and Zr content is characterized from the point of view of surface features, corrosion resistance and biological performance in order to be proposed as dental restorative material. Its properties are discussed in comparison with commercial Heraenium CE alloy based on Co, Cr and Mo as well. The microstructure of both alloys was revealed by scanning electron microscopy (SEM). The composition and thickness of the alloy native passive films were identified by X-ray photoelectron spectroscopy (XPS). The surface characteristics were analyzed by atomic force microscopy (AFM) and contact angle techniques. The quantity of ions released from alloys in artificial saliva was evaluated with inductively coupled plasma-mass spectroscopy (ICP-MS) measurements. The electrochemical stability was studied in artificial Carter-Brugirard saliva, performing open circuit potentials, polarization resistances and corrosion currents and rates. The biological performance of the new alloy was tested in vitro in terms of human adipose stem cells (hASCs) morphology, viability and proliferation status. The new alloy is very resistant to the attack of the aggressive ions from the artificial saliva. The surface properties, the roughness and wettabiliy sustain the cell behavior. The comparison of the new alloy behavior with that of existing commercial CoCrMo alloy showed the superior properties of the new metallic biomaterial. PMID- 26652384 TI - In vitro and in vivo studies of biodegradable fine grained AZ31 magnesium alloy produced by equal channel angular pressing. AB - The objective of the present work is to investigate the role of different grain sizes produced by equal channel angular pressing (ECAP) on the degradation behavior of magnesium alloy using in vitro and in vivo studies. Commercially available AZ31 magnesium alloy was selected and processed by ECAP at 300 degrees C for up to four passes using route Bc. Grain refinement from a starting size of 46MUm to a grain size distribution of 1-5MUm was successfully achieved after the 4th pass. Wettability of ECAPed samples assessed by contact angle measurements was found to increase due to the fine grain structure. In vitro degradation and bioactivity of the samples studied by immersing in super saturated simulated body fluid (SBF 5*) showed rapid mineralization within 24h due to the increased wettability in fine grained AZ31 Mg alloy. Corrosion behavior of the samples assessed by weight loss and electrochemical tests conducted in SBF 5* clearly showed the prominent role of enhanced mineral deposition on ECAPed AZ31 Mg in controlling the abnormal degradation. Cytotoxicity studies by MTT colorimetric assay showed that all the samples are viable. Additionally, cell adhesion was excellent for ECAPed samples particularly for the 3rd and 4th pass samples. In vivo experiments conducted using New Zealand White rabbits clearly showed lower degradation rate for ECAPed sample compared with annealed AZ31 Mg alloy and all the samples showed biocompatibility and no health abnormalities were noticed in the animals after 60days of in vivo studies. These results suggest that the grain size plays an important role in degradation management of magnesium alloys and ECAP technique can be adopted to achieve fine grain structures for developing degradable magnesium alloys for biomedical applications. PMID- 26652385 TI - A novel voltammetric sensor based on carbon nanotubes and nanoparticles of antimony tin oxide for the determination of ractopamine. AB - An electrochemical sensor was prepared by the modification of a glassy carbon electrode (GCE) with carbon nanotubes (CNTs) and nanoparticles of antimony tin oxide (ATO). The surface layer was characterized by scanning electronmicroscopy (SEM), energy dispersive X-ray diffraction method (EDX) and ATR FT-IR spectroscopy. The proposed electrode was assessed in respect to the electro oxidation of ractopamine. Compared with a bare GCE and a GCE electrode modified with CNTs, the ATONPs/CNTs/GCE exhibited a great catalytic activity towards the oxidation of ractopamine with a well-defined anodic peak at 600 mV. The current response was linear with the concentration of ractopamine over the range from 10 to 240 nM with a detection limit of 3.3 nM. The proposed electrode enabled the selective determination of ractopamine in the presence of high concentrations of ascorbic acid (AA), dopamine (DA) and uric acid (UA). The proposed electrode was successfully applied for the determination of ractopamine in feed and urine samples. The sensitive and selective determination of ractopamine makes the developed method of great interest for monitoring its therapeutic use and doping control purposes. PMID- 26652386 TI - Three dimensional biphasic calcium phosphate nanocomposites for load bearing bioactive bone grafts. AB - Mimicking matrix mediated bio-mineralization process, three dimensional blocks of biphasic calcium phosphate (BCP, hydroxyapatite (HA) and beta-tricalcium phosphate (TCP)) nanocomposites, having three different stoichiometries have been synthesized for possible application as load bearing synthetic bone graft or scaffolds. Biphasic blocks with three weight ratios of 20:80, 25:75 and 30:70 of HA and TCP respectively have been synthesized. Detailed structural and chemical characterization of the samples revealed a strong dependence of porosity and mechanical properties on the stoichiometry of biphasic blocks. Effect of physiological medium on the microstructure and mechanical properties of the three different blocks has also been studied. Bioactivity of the BCP block, exhibiting highest compressive strength in air as well as in physiological medium, has been evaluated through adhesion, proliferation and differentiation of mesenchymal stem cells using different markers. PMID- 26652387 TI - The synthesis of hydroxyapatite with different crystallinities by controlling the concentration of recombinant CEMP1 for biological application. AB - Cementum protein 1 (CEMP1) has been reported to be cementum specific and it plays a role in the properties and structure of cementum mineralization. This study was carried out to test the hypothesis that, CEMP1 had the capacity to guide ordered HA formation as it accumulated at targeting site. Crystals induced by protein were prepared by biomimetic method. The effects of CEMP1 concentrations (0 100MUg/ml) on the rate of calcium phosphate precipitation was monitored during 48h, while the formed mineral phases were assessed utilizing transmission electron microscope (TEM), selected area electron diffraction (SAED), X-ray diffraction (XRD), and Fourier transform infrared spectroscopy (FTIR). The results showed that recombinant cementum protein 1 (rhCEMP1) affected the crystal nucleation and growth. At lower rhCEMP1 concentrations (0-50MUg/ml), limited mineral formation occurred and only small bundles of HA crystals were found. However, with 100MUg/ml of rhCEMP1, a predominance of organized linear needle like HA crystals was observed. FTIR revealed the characteristic bands of HA appearing at 1106cm(-1), 557cm(-1), and 598cm(-1). Therefore, increasing the concentration of rhCEMP1 can lead to the formation of ordered bundles of HA crystals in vitro. PMID- 26652388 TI - Effect of PEGylated superparamagnetic iron oxide nanoparticles (SPIONs) under magnetic field on amyloid beta fibrillation process. AB - Superparamagnetic iron oxide nanoparticles (SPIONs) with specific surface coatings have been shown appropriate potential in the diagnosis and treatment of various brain diseases such as Alzheimer's. Comprehensive understanding of SPIONs interactions with amyloid beta (Abeta) and other amyloidogenic proteins is essential for their clinical application. SPIONs could be delivered to the target tissue under the magnetic field, while they might be influenced by the applied field. In this work, we exhibit the effect of different SPIONs (magnetized or non magnetized with different surface charges) on the kinetics of Abeta fibrillation in aqueous solution by the aid of ThT assay. The results showed that applying of magnetic field to the SPIONs influences on the Abeta fibrillation because of its effect on the size due to surface charge. It was found that under magnetic field and high concentrations of nanoparticles (SPIONs-PEG-NH2), the Abeta fibrillation process accelerates, while at lower concentrations the fibrillation is inhibited. Furthermore, the coating charge has a considerable role in fibrillation process and the positively charged SPIONs/magnetized, at lower particle concentrations, accelerate the fibrillation compared with the negatively charged or uncharged SPIONs. This hints that SPIONs with a positive charge have dual effects on the Abeta fibrillation process. They influence on the concentration of monomeric protein in solution and thereby the nucleation time. Also, SPIONs have an effect on binding during the protein conformation. PMID- 26652389 TI - Interaction of C60 fullerene complexed to doxorubicin with model bilipid membranes and its uptake by HeLa cells. AB - With an aim to elucidate the effects of C60 fullerene complexed with antibiotic doxorubicin (Dox) on model bilipid membranes (BLM), the investigation of the electrical properties of BLM under the action of Dox and C60 fullerene, and of their complex, C60+Dox,was performed. The complex as well as its components exert a clearly detectable influence on BLM, which is concentration-dependent and also depends on phospholipid composition. The mechanism of this effect originates either from intermolecular interaction of the drug with fatty-acid residues of phospholipids, or from membranotropic effects of the drug-induced lipid peroxidation, or from the sum of these two effects. By fluorescence microscopy the entering of C60 + Dox complex into HeLa cells was directly shown. PMID- 26652390 TI - Eggshell membrane: A natural substrate for immobilization and detection of DNA. AB - Chemically modified eggshell membranes (ESM) have been explored as potentially novel platforms for immobilization of oligonucleotides and subsequent detection of target DNA. The fibrous network of the native ESM as well those functionalized with acetic acid or n-butyl acetate has been examined by field-emission scanning electron microscopy (FESEM). The formation of surface functional moieties has been confirmed by Fourier-transform infrared spectroscopy (FTIR). DNA molecules, with an end terminal -NH2 group (at 5' end) have been immobilized on the chemically modified ESM surface. The effect of surface modification on the DNA immobilization efficiency has been investigated using fluorescence microscopy and atomic force microscopy (AFM). The above studies concurrently suggest that functionalization of ESM with n-butyl acetate causes a better homogeneity of the DNA probes on the membrane surface. On-chip hybridization of the target DNA with the surface bound capture probes has been performed on the functionalized membranes. It is observed that n-butyl acetate modification of ESM pushes the limit of detection (LOD) of the DNA sensors by at least an order of magnitude compared to the other modification method. PMID- 26652391 TI - Hyaluronic acid concentration-mediated changes in structure and function of porous carriers for corneal endothelial cell sheet delivery. AB - In this study, the effects of hyaluronic acid (HA) concentrations (0.05-1.25wt.%) on the properties of porous carriers for corneal endothelial tissue engineering were investigated. The pore size and porosity gradually increased with decreasing solid content. However, at relatively low HA concentration (i.e., 0.05wt.%), the material samples contained small interior pores and a dense surface skin layer, probably due to no gas bubble effect on the stirring processing of porous microstructures of freeze-dried polysaccharide hydrogels. The carriers prepared from 0.25wt.% HA solution had the highest freezable water content and oxygen and glucose permeability among the samples evaluated. Results of cell viability assays and quantitative real-time reverse transcription polymerase chain reaction analyses showed that the HA concentration-related alteration of porous microstructure dictates the compatibility of biopolymer carriers with corneal endothelial cell (CEC) cultures. In vivo studies demonstrated that the CEC sheet/HA carrier construct implants are therapeutically efficacious in the reconstruction of endothelial scrape-wounded corneas. It is concluded that the polysaccharide concentration is the major factor for affecting the processing of carriers and their structure and function. Porous hydrogels prepared from 0.25wt.% HA solution are capable of delivering bioengineered CEC sheets to the posterior surface of cornea. PMID- 26652392 TI - Electrospun nylon 6/zinc doped hydroxyapatite membrane for protein separation: Mechanism of fouling and blocking model. AB - Development of composite nanofibrous membrane via electrospinning a polymer with ceramic nanoparticles (NPs) for application in protein separation systems is explored during this study. Positively charged zinc doped hydroxyapatite (xZH) NPs were prepared in three different compositions via chemical precipitation method. Herein, we created a positively charged surface containing nanoparticles on electrospun Nylon-6 nanofibers (NFs) to improve the separation and selectivity properties for adsorption of negatively charged protein, namely bovine serum albumin (BSA). The decline in permeate flux was analyzed using the framework of classical blocking models and fitting, demonstrated that the transition of fouling mechanisms was dominated during the filtration process. The standard blocking model provided the best fit of the experimental results during the mid filtration period. The membrane decorated by NPs containing 4at.% zinc cations not only provided maximum BSA separation but also capable of separating higher amounts of BSA molecules (even after 1h filtration) than the pure Nylon membrane. Protein separation was achieved through this membrane with the incorporation of NPs that had high zeta potential (+5.9+/-0.2mV) and lower particle area (22,155nm(2)). The developed membrane has great potential to act as a high efficiency membrane for capturing BSA. PMID- 26652393 TI - A novel cotton fabric with anti-bacterial and drug delivery properties using SBA 15-NH2/polysiloxane hybrid containing tetracycline. AB - Here, mesoporous silica particles containing tetracycline were loaded on cotton fabric for possible application on the infected human skin. Amino functionalized mesoporous silica, SBA-15-NH2, was chosen as a safe drug carrier loaded with tetracycline via post impregnation method. Diverse content of the drug loaded silica particles were then attached on the cotton fabric surface using polysiloxane reactive softener as a soft and safe fixing agent. UV-Vis spectroscopy was used to study the drug delivery properties of the mesoporous silica on the treated cotton fabrics. The treated fabric with long drug release properties was selected as the optimized sample. Further analysis was carried out on this sample including anti-bacterial, water contact angle, bending length, mineral content and washing durability. Also, SEM images, EDX patterns, X-Ray spectra and thermal behavior of the optimum sample were studied. The optimized treated sample indicated the gradual release profile of tetracycline in PBS buffer media within 48h along with excellent anti-bacterial efficiency as a good feature for biological application. PMID- 26652394 TI - Development of ammonia sensors by using conductive polymer/hydroxyapatite composite materials. AB - In order to improve the gas sensing properties, hydroxyapatite (HAp)-based composites were prepared by mixing with different contents of conductive polymers: polypyrrole (PPy) and polyaniline (PAni). The compositions, microstructures and phase constitutions of polymer/HAp composites were characterized, and the sensing properties were studied using a chemical gas sensing (CGS-8) system. The results showed that, compared to pure HAp, the sensitivities of the composites to ammonia were improved significantly. 5%PPy/HAp and 20%PAni/HAp composites exhibited the best sensitivities to ammonia, and the sensitivities at 500ppm were 86.72% and 86.18%, respectively. Besides, the sensitivity of 5%PPy/HAp at 1000ppm was up to 90.7%. Compared to pure PPy and PAni, the response and the recovery time of 5%PPy/HAp and 20%PAni/HAp at 200ppm were shortened several times, and they were 24s/245s and 15s/54s, respectively. In addition, the composites showed a very high selectivity to ammonia. The mechanism for the enhancement of the sensitivity to ammonia was also discussed. The polymer/HAp composites are very promising in applications of ammonia sensors. PMID- 26652395 TI - Enhanced peroxidase-like activity of porphyrin functionalized ceria nanorods for sensitive and selective colorimetric detection of glucose. AB - Ceria nanorods modified with 5,10,15,20-tetrakis(4-carboxyl phenyl)-porphyrin (H2TCPP) were prepared. These nanocomposites (H2TCPP-CeO2) exhibited the intrinsic peroxidase-like activity and could catalyze the oxidation of classical peroxidase substrate 3,3',5,5'-tetramethylbiphenyl dihydrochloride (TMB.2HCl) in the presence of H2O2 to produce a typical color reaction from colorless to blue. Our results demonstrated that both the H2TCPP-CeO2 nanocomposites and CeO2 nanorods exhibited higher thermal durance than that of HRP. The affinity of The H2TCPP-CeO2 nanocomposites toward H2O2 and TMB is similar to that of HRP. Fluorescent results indicated that the catalytic mechanism of the H2TCPP-CeO2 nanocomposites were from the decomposition of H2O2 into hydroxyl radicals. Based on these studies, a simple, sensitive, and selective visual and colorimetric method using TMB as the substrate was designed to detect glucose when combined with glucose oxidase. The proposed colorimetric method can detect H2O2 at a low detection limit of 6.1*10(-6)M and a dynamic range of 10(-5)-10(-4)mol.L(-1). This method can also detect glucose at a low detection limit of 3.3*10(-5)mol.L( 1) and a dynamic range of 5.0*10(-5)-1.0*10(-4)mol.L(-1). PMID- 26652396 TI - Haversian microstructure in bovine femoral cortices: An adaptation for improved compressive strength. AB - Microstructural variations in bovine femoral cortices and its possible implications for the bone's mechanical behavior are characterized for a mature and a young bovine femur. Histological examination at several locations shows the presence of Haversian systems to be largely confined to the posterior region of any cross-section. Haversian bone is shown to have higher compressive strength than the non-Haversian primary bone present in the corresponding anterior regions. The anatomical variation in the compressive strength along diaphysis is found to correlate strongly with the Haversian density. Based on the differences in the failure surfaces observed from compressive failure, it is argued that the presence of Haversian systems plays a role in deflection of crack path, leading to non-prismatic failure surfaces. As biomaterials, such as bone cement and implants, closely interact with bone material, the structure-property relation established here can provide a basis for better design of future biomaterials. PMID- 26652397 TI - Improved performance of Bis-GMA/TEGDMA dental composites by net-like structures formed from SiO2 nanofiber fillers. AB - The major objective of this study was to explore the effects of silicon dioxide (SiO2) nanofibers on the performance of 2, 2-bis-[4-(methacryloxypropoxy)-phenyl] propane (Bis-GMA)/tri-(ethyleneglycol) dimethacrylate (TEGDMA) dental composites. At first, the mechanical properties of Bis-GMA/TEGDMA (50/50, w/w) resins containing different contents of SiO2 nanofibers were evaluated to identify the appropriate composition to achieve the significant reinforcing effect. Secondly, optimized contents (5 or 10wt.%) of SiO2 nanofibers were mixed into resins together with SiO2 microparticles, which was 60wt.% of the resin. Controls for comparison were Bis-GMA/TEGDMA resins containing only SiO2 microparticles (60wt.%) or with additional SiO2 nanoparticles (5 or 10wt.%). Properties including abrasion, polymerization shrinkage and mechanical properties were evaluated to determine the contribution of SiO2 nanofibers. In comparison with SiO2 nanoparticles, SiO2 nanofibers improved the overall performance of Bis GMA/TEGDMA composite resins, especially in improving abrasion resistance and decreasing polymerization shrinkage. The explanations were that one-dimensional SiO2 nanofibers were able to shield particular fillers from being abraded off, and able to form a kind of overlapped fibrous network to resist polymerization shrinkage. With these approaches, SiO2 nanofiber-containing Bis-GMA composite resins were envisioned a promising choice to achieve long-term durable restorations in clinical therapies. PMID- 26652398 TI - Processing and characterization of diatom nanoparticles and microparticles as potential source of silicon for bone tissue engineering. AB - Silicon plays an important role in bone formation and maintenance, improving osteoblast cell function and inducing mineralization. Often, bone deformation and long bone abnormalities have been associated with silica/silicon deficiency. Diatomite, a natural deposit of diatom skeleton, is a cheap and abundant source of biogenic silica. The aim of the present study is to validate the potential of diatom particles derived from diatom skeletons as silicon-donor materials for bone tissue engineering applications. Raw diatomite (RD) and calcined diatomite (CD) powders were purified by acid treatments, and diatom microparticles (MPs) and nanoparticles (NPs) were produced by fragmentation of purified diatoms under alkaline conditions. The influence of processing on the surface chemical composition of purified diatomites was evaluated by X-ray photoelectron spectroscopy (XPS). Diatoms NPs were also characterized in terms of morphology and size distribution by transmission electron microscopy (TEM) and Dynamic light scattering (DLS), while diatom MPs morphology was analyzed by scanning electron microscopy (SEM). Surface area and microporosity of the diatom particles were evaluated by nitrogen physisorption methods. Release of silicon ions from diatom derived particles was demonstrated using inductively coupled plasma optical emission spectrometry (ICP/OES); furthermore, silicon release kinetic was found to be influenced by diatomite purification method and particle size. Diatom derived microparticles (MPs) and nanoparticles (NPs) showed limited or no cytotoxic effect in vitro depending on the administration conditions. PMID- 26652399 TI - Supercritical fluid assisted process for the generation of cellulose acetate loaded structures, potentially useful for tissue engineering applications. AB - Supercritical CO2 phase inversion offers an alternative to obtain solvent free structures with short processing times and preservation of the morphology. We prepared cellulose acetate structures loaded with drug (ibuprofen) to perform experiments at pressures and temperatures ranging between 150 and 250 bars and 35 and 55 degrees C. The structures were properly characterized by SEM, EDX and DSC; drug controlled release experiments were also performed. Analyses showed that the operating conditions strongly influenced the structure morphology, porosity and drug release profiles. Indeed, connected microparticles, nanofibrous networks and cellular membranes were produced, which have generated different drug release profiles. PMID- 26652400 TI - A poly(ether-ester) copolymer for the preparation of nanocarriers with improved degradation and drug delivery kinetics. AB - This paper reports the synthesis and the physicochemical, functional and biological characterisations of nanocarriers made of a novel di-block biodegradable poly(ether-ester) copolymer. This material presents tunable, fast biodegradation rates, but its products are less acidic than those of other biosorbable polymers like PLGA, thus presenting a better biocompatibility profile and the possibility to carry pH-sensitive payloads. A method for the production of monodisperse and spherical nanoparticles is proposed; drug delivery kinetics and blood protein adsorption were measured to evaluate the functional properties of these nanoparticles as drug carriers. The copolymer was labelled with a fluorescent dye for internalisation tests, and rhodamine B was used as a model cargo to study transport and release inside cultured cells. Biological tests demonstrated good cytocompatibility, significant cell internalisation and the possibility to vehiculate non-cell penetrating moieties into endothelial cells. Taken together, these results support the potential use of this nanoparticulate system for systemic administration of drugs. PMID- 26652401 TI - Synthesis and characterization of Co3O4 ultra-nanosheets and Co3O4 ultra nanosheet-Ni(OH)2 as non-enzymatic electrochemical sensors for glucose detection. AB - The present study examines the synthesis of Co3O4 ultra-nanosheets (Co3O4 UNSs) and Co3O4 ultra-nanosheet-Ni(OH)2 (Co3O4 UNS-Ni(OH)2) via solvothermal process and their application as non-enzymatic electrochemical sensors for glucose detection. X-ray diffraction and transmission electron microscopy results confirmed the Co3O4 UNS deposition on Ni(OH)2 surface. The presence of Co3O4 UNSs on Ni (OH) 2 surface improved the sensitivity of glucose detection, from the increase of glucose oxidation peak current at the Co3O4 UNS-Ni(OH)2/glassy carbon electrode (current density: 2000MUA.cm(-2)), compared to the Co3O4 UNSs. These results confirmed that Ni(OH)2 on glassy carbon electrode is a sensitive material for glucose detection, moreover the Co3O4 UNSs can increase the interaction and detection of glucose due to their high surface area. The estimated limit of detection (S/N=3) and limit of quantification (S/N=10) of the linear segment (5 40MUM) are 1.08MUM and 3.60MUM respectively. The reproducibility experiments confirmed the feasibility of Co3O4 UNS-Ni(OH)2 for the quantitative detection of certain concentration ranges of glucose. PMID- 26652402 TI - Influence of polymer molecular weight on the in vitro cytotoxicity of poly (N isopropylacrylamide). AB - Poly (N-isopropylacrylamide) (PNIPAAm) is a thermosensitive polymer with various biomedical applications. We examined molecular weight (MW)-dependent cytotoxicity of PNIPAAm. Our results indicated that low-MW PNIPAAm (degree of polymerization (DP)=35) is inherently toxic to cells. Moderate-MW PNIPAAms with their DP between 100 and 200 are non-cytotoxic. When cells are seeded on top of a polymer-coated surface, PNIPAAm with a higher MW (DP=400) shows non/low cytotoxicity, while when monolayer cells are exposed to the polymer solution, cell viability drops drastically. This may be due to lack of nutrient and oxygen rather than intrinsic toxicity of the polymer. PMID- 26652403 TI - Continuous cellularization of calcium phosphate hybrid scaffolds induced by plasma polymer activation. AB - The generation of hybrid materials based on beta-tricalcium phosphate (TCP) and various biodegradable polymers like poly(l-lactide-co-d,l-lactide) (PLA) represents a common approach to overcoming the disadvantages of pure TCP devices. These disadvantages lie in TCP's mechanical properties, such as brittleness. The positive characteristic of PLA - improvement of compressive strength of calcium phosphate scaffolds - is diametrically opposed to its cell attractiveness. Therefore, the objective of this work was to optimize osteoblast migration and cellularization inside a three-dimensionally (3D) printed, PLA polymer stabilized TCP hybrid scaffold by a plasma polymer process depositing amino groups via allylamine. MG-63 osteoblastic cells inside the 10mm hybrid scaffold were dynamically cultivated for 14days in a 3D model system integrated in a perfusion reactor. The whole TCP/PLA hybrid scaffold was continuously colonized due to plasma polymerized allylamine activation inducing the migration potential of osteoblasts. PMID- 26652404 TI - Anhydride-functional silane immobilized onto titanium surfaces induces osteoblast cell differentiation and reduces bacterial adhesion and biofilm formation. AB - Bacterial infection in dental implants along with osseointegration failure usually leads to loss of the device. Bioactive molecules with antibacterial properties can be attached to titanium surfaces with anchoring molecules such as silanes, preventing biofilm formation and improving osseointegration. Properties of silanes as molecular binders have been thoroughly studied, but research on the biological effects of these coatings is scarce. The aim of the present study was to determine the in vitro cell response and antibacterial effects of triethoxysilypropyl succinic anhydride (TESPSA) silane anchored on titanium surfaces. X-ray photoelectron spectroscopy confirmed a successful silanization. The silanized surfaces showed no cytotoxic effects. Gene expression analyses of Sarcoma Osteogenic (SaOS-2) osteoblast-like cells cultured on TESPSA silanized surfaces reported a remarkable increase of biochemical markers related to induction of osteoblastic cell differentiation. A manifest decrease of bacterial adhesion and biofilm formation at early stages was observed on treated substrates, while favoring cell adhesion and spreading in bacteria-cell co cultures. Surfaces treated with TESPSA could enhance a biological sealing on implant surfaces against bacteria colonization of underlying tissues. Furthermore, it can be an effective anchoring platform of biomolecules on titanium surfaces with improved osteoblastic differentiation and antibacterial properties. PMID- 26652405 TI - Preparation of a biomimetic composite scaffold from gelatin/collagen and bioactive glass fibers for bone tissue engineering. AB - Bone tissue is a composite material made of organic and inorganic components. Bone tissue engineering requires scaffolds that mimic bone nature in chemical and mechanical properties. This study proposes a novel method for preparing composite scaffolds that uses sub-micron bioglass fibers as the organic phase and gelatin/collagen as the inorganic phase. The scaffolds were constructed by using freeze drying and electro spinning methods and their mechanical properties were enhanced by using genipin crosslinking agent. Electron microscopy micrographs showed that the structure of composite scaffolds were porous with pore diameters of approximately 70-200MUm, this was again confirmed by mercury porosimetery. These pores are suitable for osteoblast growth. The diameters of the fibers were approximately 150-450nm. Structural analysis confirmed the formation of desirable phases of sub-micron bioglass fibers. Cellular biocompatibility tests illustrated that scaffolds containing copper ion in the bioglass structure had more cell growth and osteoblast attachment in comparison to copper-free scaffolds. PMID- 26652406 TI - Partial oxidation of TiN coating by hydrothermal treatment and ozone treatment to improve its osteoconductivity. AB - Dental implants made of pure titanium suffer from abrasion and scratch during routine oral hygiene procedures. This results in an irreversible surface damage, facilitates bacteria adhesion and increases risk of peri-implantitis. To overcome these problems, titanium nitride (TiN) coating was introduced to increase surface hardness of pure titanium. However, the osteoconductivity of TiN is considered to be similar or superior to that of titanium and its alloys and therefore surface modification is necessary. In this study, TiN coating prepared through gas nitriding was partially oxidized by hydrothermal (HT) treatment and ozone (O3) treatment in pure water to improve its osteoconductivity. The effects of HT treatment and O3 treatment on surface properties of TiN were investigated and the osteoconductivity after undergoing treatment was assessed in vitro using osteoblast evaluation. The results showed that the critical temperature for HT treatment was 100 degrees C since higher temperatures would impair the hardness of TiN coating. By contrast, O3 treatment was more effective in oxidizing TiN surfaces, improving its wettability while preserving its morphology and hardness. Osteoblast attachment, proliferation, alkaline phosphatase (ALP) expression and mineralization were improved on oxidized specimens, especially on O3 treated specimens, compared with untreated ones. These effects seemed to be consequences of partial oxidation, as well as improved hydrophilicity and surface decontamination. Finally, it was concluded that, partially oxidized TiN is a promising coating to be used for dental implant. PMID- 26652407 TI - Immobilization of cationic antimicrobial peptides and natural cashew gum in nanosheet systems for the investigation of anti-leishmanial activity. AB - This report details the development of thin films containing an antimicrobial peptide, specifically, dermaseptin 01 (GLWSTIKQKGKEAAIAAA-KAAGQAALGAL-NH2, [DRS 01]), and a natural polysaccharide, for a novel application in detecting the presence of Leishmania cells and maintaining anti-leishmanial activity. The peptide DRS 01 was immobilized in conjunction with natural cashew gum (CG) onto an indium tin oxide (ITO) substrate using the Layer-by-Layer (LbL) deposition technique. The LbL film ITO/CG/DRS 01, containing DRS 01 as the outer layer, was capable of detecting the presence of Leishmania cells and acting as an anti leishmanial system. Detection was performed using cyclic voltammetry (CV) in phosphate buffer (pH7.2) in the presence of promastigote cells (0-10(7)cells/mL). The results showed a linear and inversely proportional relation between the concentration of Leishmania infantum protozoan cells and the measured current values obtained for the films, which was attributed to the effect of peptide induced lysis of the cell membrane, and resulted in freed residues that were adsorbed on the electrode surface. With this, the paper shows a method using thin films with this new material to demonstrate the anti-leishmanial activity in vitro models of carpet-like mechanisms. PMID- 26652408 TI - A facile approach toward multi-functional polyurethane/polyethersulfone composite membranes for versatile applications. AB - The complex synthesis through multistep reactions and tedious purifications based on different monomers or macromolecules limits the practical applications of functional polymers. Herein, a facile approach toward a series of functional polyurethanes (PUs) is designed for versatile biological applications within fewer step reactions under mild conditions. The tertiary amino groups in the PU are converted into zwitterions or quaternary ammonium salt via simple one-step synthesis, and then used to prepare PU/polyethersulfone composite membranes. The composite membrane with tertiary amine groups exhibits significant adsorption capability to anionic dye Congo red (CR) and toxin bilirubin. The membrane bearing zwitterionic PU displays excellent blood compatibility; while which with quaternary ammonium salts has antibacterial property. Furthermore, carboxybetaine functional composite membrane is exploited to bear Ag nanoparticles to endow with dual functions of antibacterial and antifouling properties. This work demonstrates the potential of PUs as readily available, multi-functional, and easy-to-use materials for biological applications. PMID- 26652409 TI - Characterization, corrosion behavior, cellular response and in vivo bone tissue compatibility of titanium-niobium alloy with low Young's modulus. AB - beta-Type titanium alloys with a low elastic modulus are a potential strategy to enhance bone remodeling and to mitigate the concern over the risks of osteanabrosis and bone resorption caused by stress shielding, when used to substitute irreversibly impaired hard tissue. Hence, in this study, a Ti-45Nb alloy with low Young's modulus and high strength was developed, and microstructure, mechanical properties, corrosion behaviors, cytocompatibility and in vivo osteo-compatibility of the alloy were systematically investigated for the first time. The results of mechanical tests showed that Young's modulus of the Ti Nb alloy was reduced to about 64.3GPa (close to human cortical bone) accompanied with higher tensile strength and hardness compared with those of pure Ti. Importantly, the Ti-Nb alloy exhibited superior corrosion resistance to Ti in different solutions including SBF, MAS and FAAS (MAS containing NaF) media. In addition, the Ti-Nb alloy produced no deleterious effect to L929 and MG-63 cells, and cells performed excellent cell attachment onto Ti-Nb surface, indicating a good in vitro cytocompatibility. In vivo evaluations indicated that Ti-Nb had comparable bone tissue compatibility to Ti determined from micro-CT and histological evaluations. The Ti-Nb alloy with an elasticity close to human bone, thus, could be suitable for orthopedic/dental applications. PMID- 26652410 TI - Electrochemical immunosensor for interferon-gamma based on disposable ITO detector and HRP-antibody-conjugated nano gold as signal tag. AB - Tuberculosis is the most frequent cause of infection-related death worldwide. A new disposable electrochemical immunosensor with low cost and simple fabrication was proposed to detect interferon-gamma (IFN-gamma). Diallyldimethylammonium chloride (PDDA) and Au nanoparticle (AuNP) composite were used to provide an efficient biointerface, horseradish peroxidase (HRP)-labeled antibody-conjugated AuNP (HRP-Ab2-AuNP) bioconjugates were used as a novel signal tag. The large amounts of HRP on the signal tag can catalyze the oxidation of Hydroquinone (HQ) by H2O2, which can induce an amplified reductive current. The catalytic reduction current was related to the amount of HRP immobilized on the surface, which itself was related to the concentration of IFN-gamma. Under optimized conditions, the proposed immunosensor showed a high sensitivity and a linear range of 0.1 10,000pg/mL with a detection limit of 0.048pg/mL. The assay results of clinical serum samples obtained by the immunosensor were in acceptable agreement with the reference values. Therefore, the immunosensor possessed excellent clinical value in early diagnosis and control of tuberculosis. PMID- 26652411 TI - Mesoporous silica sub-micron spheres as drug dissolution enhancers: Influence of drug and matrix chemistry on functionality and stability. AB - Mesoporous silica particles prepared through a simplified Stober method and low temperature solvent promoted surfactant removal are evaluated as dissolution enhancers for poorly soluble compounds, using a powerful anticancer agent belonging to pyrroloquinolinones as a model for anticancer oral therapy, and anti inflammatory ibuprofen as a reference compound. Mesoporous powders composed of either pure silica or silica modified with aminopropyl residues are produced. The influence of material composition and drug chemical properties on drug loading capability and dissolution enhancement are studied. The two types of particles display similar size, surface area, porosity, erodibility, drug loading capability and stability. An up to 50% w/w drug loading is reached, showing correlation between drug concentration in adsorption medium and content in the final powder. Upon immersion in simulating body fluids, immediate drug dissolution occurred, allowing acceptor solutions to reach concentrations equal to or greater than drug saturation limits. The matrix composition influenced drug solution maximal concentration, complementing the dissolution enhancement generated by a mesoporous structure. This effect was found to depend on both matrix and drug chemical properties allowing us to hypothesise general prediction behaviour rules. PMID- 26652412 TI - The fabrication of a new electrochemical sensor based on electropolymerization of nanocomposite gold nanoparticle-molecularly imprinted polymer for determination of valganciclovir. AB - A new sensitive and selective electrochemical sensor was successfully developed for the determination of valganciclovir. It is based on one-step electropolymerization of the molecularly imprinted polymer composed from 2,2' dithiodianiline, gold nanoparticles, and valganciclovir on a glassy carbon electrode modified with carboxyl-functionalized multiwalled carbon nanotubes via cyclic voltammetry. The gold nanoparticles were introduced into the polymer composite for the development of electrical response by facilitating charge transfer. The fabrication process of the sensor was characterized by cyclic voltammetry and electrochemical impedance spectroscopy. Under the optimized condition calibration curve of the imprinted sensor has two linear concentration ranges from 1.0 to 500.0nM and 500.0 to 2000.0nM, with the limit of detection of 0.3nM. The relative standard deviation (RSD) for seven parallel determination of 1.0MUM valganciclovir at optimum conditions was found to be 2.9%. The imprinted sensor has the advantages of high porous surface structure, ease of preparation, good reproducibility, good repeatability and high selectivity and sensitivity. Furthermore, the proposed method was successfully intended for the determination of valganciclovir in real samples. PMID- 26652413 TI - Boron doped diamond sensor for sensitive determination of metronidazole: Mechanistic and analytical study by cyclic voltammetry and square wave voltammetry. AB - The performance of boron-doped diamond (BDD) electrode for the detection of metronidazole (MTZ) as the most important drug of the group of 5-nitroimidazole was proven using cyclic voltammetry (CV) and square wave voltammetry (SWV) techniques. A comparison study between BDD, glassy carbon and silver electrodes on the electrochemical response was carried out. The process is pH-dependent. In neutral and alkaline media, one irreversible reduction peak related to the hydroxylamine derivative formation was registered, involving a total of four electrons. In acidic medium, a prepeak appears probably related to the adsorption affinity of hydroxylamine at the electrode surface. The BDD electrode showed higher sensitivity and reproducibility analytical response, compared with the other electrodes. The higher reduction peak current was registered at pH11. Under optimal conditions, a linear analytical curve was obtained for the MTZ concentration in the range of 0.2-4.2MUmolL(-1), with a detection limit of 0.065MUmolL(-1). PMID- 26652414 TI - Cell adhesion on NiTi thin film sputter-deposited meshes. AB - Scaffolds for tissue engineering enable the possibility to fabricate and form biomedical implants in vitro, which fulfill special functionality in vivo. In this study, free-standing Nickel-Titanium(NiTi) thin film mesheswere produced by means of magnetron sputter deposition.Meshes contained precisely defined rhombic holes in the size of 440 to 1309 MUm2 and a strut width ranging from 5.3 to 9.2 MUm. The effective mechanical properties of the microstructured superelastic NiTi thin film were examined by tensile testing. These results will be adapted for the design of the holes in the film. The influence of hole and strut dimensions on the adhesion of sheep autologous cells (CD133+) was studied after 24 h and after seven days of incubation. Optical analysis using fluorescence microscopy and scanning electron microscopy showed that cell adhesion depends on the structural parameters of the mesh. After 7 days in cell culture a large part of the mesh was covered with aligned fibrous material. Cell adhesion is particularly facilitated on meshes with small rhombic holes of 440 MUm2 and a strut width of 5.3 MUm. Our results demonstrate that free-standing NiTi thin film meshes have a promising potential for applicationsin cardiovascular tissue engineering, particularly for the fabrication of heart valves. PMID- 26652415 TI - Nanostructured Ti6Al4V alloy fabricated using modified alkali-heat treatment: Characterization and cell adhesion. AB - In order to optimize the creation of a nanostructured surface on Ti6Al4V titanium alloy, an alkali treatment was performed using a 10-M NaOH solution at various temperatures (30, 40, 50, and 60 degrees C) so as to determine the optimal temperature. This was combined with subsequent heat treatments (200, 400, 600, and 800 degrees C) in air. The effects of different temperatures for the latter treatments on the nanostructure surface and the initial cell adhesion were evaluated, and the optimal temperature of the alkali solution was found to be 30 degrees C. Further, the nanotopography, surface chemistry, and surface roughness of the nanoporous structure were retained after heat treatments performed at 200, 400, and 600 degrees C, and only the phase structure was altered. The amorphous sodium titanate phase, the content of which increased with increased heat treatment temperature, may have played a role in promoting cell adhesion on the nanoporous surface. However, heat treatment at 800 degrees C did not enhance the cell-surface attachment. Rather, the nanostructure degraded significantly with the reappearance of Al and V. PMID- 26652416 TI - Electrochemically assisted deposition of hydroxyapatite on Ti6Al4V substrates covered by CVD diamond films - Coating characterization and first cell biological results. AB - Although titanium and its alloys are widely used as implant material for orthopedic and dental applications they show only limited corrosion stability and osseointegration in different cases. The aim of the presented research was to develop and characterize a novel surface modification system from a thin diamond base layer and a hydroxyapatite (HAp) top coating deposited on the alloy Ti6Al4V widely used for implants in contact with bone. This coating system is expected to improve both the long-term corrosion behavior and the biocompatibility and bioactivity of respective surfaces. The diamond base films were obtained by Microwave Plasma Assisted Chemical Vapor Deposition (MW-PACVD); the HAp coatings were formed in aqueous solutions by electrochemically assisted deposition (ECAD) at varying polarization parameters. Scanning electron microscopy (SEM), Raman microscopy, and electrical conductivity measurements were applied to characterize the generated surface states; the calcium phosphate coatings were additionally chemically analyzed for their composition. The biological properties of the coating system were assessed using hMSC cells analyzing for cell adhesion, proliferation, and osteogenic differentiation. Varying MW-PACVD process conditions resulted in composite coatings containing microcrystalline diamond (MCD/Ti-C), nanocrystalline diamond (NCD), and boron-doped nanocrystalline diamond (B-NCD) with the NCD coatings being dense and homogeneous and the B-NCD coatings showing increased electrical conductivity. The ECAD process resulted in calcium phosphate coatings from stoichiometric and non-stoichiometric HAp. The deposition of HAp on the B-NCD films run at lower cathodic potentials and resulted both in the highest coating mass and the most homogenous appearance. Initial cell biological investigations showed an improved cell adhesion in the order B-NCD>HAp/B-NCD>uncoated substrate. Cell proliferation was improved for both investigated coatings whereas ALP expression was highest for the uncoated substrate. PMID- 26652417 TI - Computational local stiffness analysis of biological cell: High aspect ratio single wall carbon nanotube tip. AB - Carbon nanotubes (CNTs) are potentially ideal tips for atomic force microscopy (AFM) due to the robust mechanical properties, nanoscale diameter and also their ability to be functionalized by chemical and biological components at the tip ends. This contribution develops the idea of using CNTs as an AFM tip in computational analysis of the biological cells. The proposed software was ABAQUS 6.13 CAE/CEL provided by Dassault Systems, which is a powerful finite element (FE) tool to perform the numerical analysis and visualize the interactions between proposed tip and membrane of the cell. Finite element analysis employed for each section and displacement of the nodes located in the contact area was monitored by using an output database (ODB). Mooney-Rivlin hyperelastic model of the cell allows the simulation to obtain a new method for estimating the stiffness and spring constant of the cell. Stress and strain curve indicates the yield stress point which defines as a vertical stress and plan stress. Spring constant of the cell and the local stiffness was measured as well as the applied force of CNT-AFM tip on the contact area of the cell. This reliable integration of CNT-AFM tip process provides a new class of high performance nanoprobes for single biological cell analysis. PMID- 26652418 TI - Hybrid molecularly imprinted poly(methacrylic acid-TRIM)-silica chemically modified with (3-glycidyloxypropyl)trimethoxysilane for the extraction of folic acid in aqueous medium. AB - In the present study a hybrid molecularly imprinted poly(methacrylic acid trimethylolpropane trimethacrylate)-silica (MIP) was synthesized and modified with (3-glycidyloxypropyl)trimethoxysilane (GPTMS) with posterior opening of epoxy ring to provide hydrophilic properties of material in the extraction of folic acid from aqueous medium. The chemical and structural aggregates of hybrid material were characterized by means of Fourier Transform Infrared (FT-IR), Transmission Electron Microscopy (TEM), Scanning Electron Microscopy (SEM), Thermogravimetric analysis (TGA) and textural data. Selectivity data of MIP were compared to non-imprinted polymer (NIP) through competitive sorption studies in the presence of caffeine, paracetamol or 4-aminobenzamide yielding relative selectivity coefficients (k') higher than one unit, thus confirming the selective character of MIP even in the presence of structurally smaller compounds than the folic acid. The lower hydrophobic sorption by bovine serum albumin (BSA) in the MIP as compared to unmodified MIP proves the hydrophilicity of polymer surface by using GPTMS with opening ring. Under acid medium(pH 1.5) the sorption of folic acid onto MIP from batch experiments was higher than the one achieved for NIP. Equilibrium sorption of folic acid was reached at 120 min for MIP, NIP and MIP without GPTMS and kinetic sorption data were well described by pseudo-second order, Elovich and intraparticle diffusion models. Thus, these results indicate the existence of different binding energy sites in the polymers and a complex mechanism consisting of both surface sorption and intraparticle transport of folic acid within the pores of polymers. PMID- 26652419 TI - Targeted delivery and controlled release of doxorubicin into cancer cells using a multifunctional graphene oxide. AB - We have synthesized a new multifunctional graphene oxide as a drug carrier targeting to hepatocarcinoma cells. Surface modified graphene oxide with polyethyleneimine (PEI) sequentially derivatised with fluorescein isothiocyanate (FI) and polyethylene glycol (PEG)-linked lactobionic acid (LA), and acetylation of remaining terminal amines of the PEI produced a new multifunctional graphene oxide drug carrier (GO/PEI.Ac-FI-PEG-LA). Doxorubicin (DOX), an anticancer drug, was encapsulated in GO/PEI.Ac-FI-PEG-LA to give GO/PEI.Ac-FI-PEG-LA/DOX, with a drug loading percentage of 85%. We showed that both GO/PEI.Ac-FI-PEG-LA and GO/PEI.Ac-FI-PEG-LA/DOX were water soluble and stable between pH 5.0 and 9.0. In vitro release studies indicated that the release rate of DOX from GO/PEI.Ac-FI PEG-LA/DOX complexes were significantly higher at pH5.8 than that of the physiological pH. Another important feature of this carrier is its good cell viability in the tested concentration range (0-4MUM), and the GO/PEI.Ac-FI-PEG LA/DOX can specifically target cancer cells overexpressing asialoglycoprotein (ASGPR) receptors and exert growth inhibition effect to the cancer cells. The enhanced target specificity and the substantial improvement in pH responsive controlled release have made this new carrier a potential choice for non-covalent encapsulation of drugs in GO, and a delivery system for cancer therapy. PMID- 26652420 TI - The study of cellulosic fabrics impregnated with porphyrin compounds for use as photo-bactericidal polymers. AB - In the present work, we report on the preparation of cellulosic fabrics bearing two types of photo-sensitizers in order to prepare efficient polymeric materials for antimicrobial applications. The obtained porphyrin-grafted cellulosic fabrics were characterized by attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy, diffuse reflectance UV-Vis (DRUV) spectroscopy, thermo gravimetric analysis (TG) and scanning electron microscopy (SEM). Antimicrobial activity of the prepared porphyrin-cellulose was tested under visible light irradiation against Staphylococcus aureus, Pseudomunas aeroginosa and Escherichia coli. In addition, the effect of two parameters on photo-bactericidal activity of treated fibers was studied: illumination time and concentration of photosensitizers (PS). PMID- 26652421 TI - Multilayered TiAlN films on Ti6Al4V alloy for biomedical applications by closed field unbalanced magnetron sputter ion plating process. AB - Ti6Al4V alloy has been widely used as a suitable material for surgical implants such as artificial hip joints. In this study, a series of multilayered gradient TiAlN coatings were deposited on Ti6Al4V substrate using closed field unbalanced magnetron sputter ion plating (CFUBMSIP) process. Taguchi design of experiment approach was used to reveal the influence of depositing parameters to the film composition and performance of TiAlN coatings. The phase structure and chemical composition of the TiAlN films were characterized by X-ray diffractometry (XRD) and X-ray photoelectron spectroscopy (XPS). Mechanical properties, including hardness, Young's modulus, friction coefficient, wear rate and adhesion strength were systematically evaluated. Potentiodynamic tests were conducted to evaluate the corrosion resistance of the coated samples in Ringer's solution at 37 degrees C to simulate human body environment. Comprehensive performance of TiAlN films was evaluated by assigning different weight according to the application environment. S8, deposited by Ti target current of 8A, Al target current of 6A, bias voltage of -60V and nitrogen content with OEM (optical emission monitor) value of 45%, was found to achieve best performance in orthogonal experiments. Depositing parameters of S8 might be practically applied for commercialization of surgical implants. PMID- 26652422 TI - Thermally oxidized titania nanotubes enhance the corrosion resistance of Ti6Al4V. AB - The negative impact of in vivo corrosion of metallic biomedical implants remains a complex problem in the medical field. We aimed to determine the effects of electrochemical anodization (60V, 2h) and thermal oxidation (600 degrees C) on the corrosive behavior of Ti-6Al-4V, with serum proteins, at physiological temperature. Anodization produced a mixture of anatase and amorphous TiO2 nanopores and nanotubes, while the annealing process yielded an anatase/rutile mixture of TiO2 nanopores and nanotubes. The surface area was analyzed by the Brunauer-Emmett-Teller method and was estimated to be 3 orders of magnitude higher than that of polished control samples. Corrosion resistance was evaluated on the parameters of open circuit potential, corrosion potential, corrosion current density, passivation current density, polarization resistance and equivalent circuit modeling. Samples both anodized and thermally oxidized exhibited shifts of open circuit potential and corrosion potential in the noble direction, indicating a more stable nanoporous/nanotube layer, as well as lower corrosion current densities and passivation current densities than the smooth control. They also showed increased polarization resistance and diffusion limited charge transfer within the bulk oxide layer. The treatment groups studied can be ordered from greatest corrosion resistance to least as Anodized+Thermally Oxidized > Anodized > Smooth > Thermally Oxidized for the conditions investigated. This study concludes that anodized surface has a potential to prevent long term implant failure due to corrosion in a complex in-vivo environment. PMID- 26652423 TI - Effect of pore size on bone ingrowth into porous titanium implants fabricated by additive manufacturing: An in vivo experiment. AB - Selective laser melting (SLM) is an additive manufacturing technique with the ability to produce metallic scaffolds with accurately controlled pore size, porosity, and interconnectivity for orthopedic applications. However, the optimal pore structure of porous titanium manufactured by SLM remains unclear. In this study, we evaluated the effect of pore size with constant porosity on in vivo bone ingrowth in rabbits into porous titanium implants manufactured by SLM. Three porous titanium implants (with an intended porosity of 65% and pore sizes of 300, 600, and 900MUm, designated the P300, P600, and P900 implants, respectively) were manufactured by SLM. A diamond lattice was adapted as the basic structure. Their porous structures were evaluated and verified using microfocus X-ray computed tomography. Their bone-implant fixation ability was evaluated by their implantation as porous-surfaced titanium plates into the cortical bone of the rabbit tibia. Bone ingrowth was evaluated by their implantation as cylindrical porous titanium implants into the cancellous bone of the rabbit femur for 2, 4, and 8weeks. The average pore sizes of the P300, P600, and P900 implants were 309, 632, and 956MUm, respectively. The P600 implant demonstrated a significantly higher fixation ability at 2weeks than the other implants. After 4weeks, all models had sufficiently high fixation ability in a detaching test. Bone ingrowth into the P300 implant was lower than into the other implants at 4weeks. Because of its appropriate mechanical strength, high fixation ability, and rapid bone ingrowth, our results indicate that the pore structure of the P600 implant is a suitable porous structure for orthopedic implants manufactured by SLM. PMID- 26652424 TI - In vitro hyperthermia with improved colloidal stability and enhanced SAR of magnetic core/shell nanostructures. AB - Magnetic core/shell nanostructures of Fe3O4 nanoparticles coated with oleic acid and betaine-HCl were studied for their possible use in magnetic fluid hyperthermia (MFH). Their colloidal stability and heat induction ability were studied in different media viz. phosphate buffer solution (PBS), saline solution and glucose solution with different physiological conditions and in human serum. The results showed enhanced colloidal stability in these media owing to their high zeta potential values. Heat induction studies showed that specific absorption rates (SAR) of core/shells were 82-94W/g at different pH of PBS and concentrations of NaCl and glucose. Interestingly, core/shells showed 78.45+/ 3.90W/g SAR in human serum. The cytotoxicity of core/shells done on L929 and HeLa cell lines using 3-(4,5-dimethylthiazol-2-yl)2,5-diphenyl tetrazolium bromide and trypan blue dye exclusion assays showed >89% and >80% cell viability for 24 and 48h respectively. Core/shell structures were also found to be very efficient for in vitro MFH on cancer cell line. About 95% cell death was occurred in 90min after hyperthermia treatment. The mechanism of cell death was found to be elevated ROS generation in cells after exposure to core/shells in external magnetic field. This study showed that these core/shells have a great potential to be used in in vivo MFH. PMID- 26652425 TI - Comparison of bare and amino modified mesoporous silica@poly(ethyleneimine)s xerogel as indomethacin carrier: Superiority of amino modification. AB - The purpose of this study was to facilely develop amino modified mesoporous silica xerogel synthesized using biomimetic method (B-AMSX) and to investigate its potential ability to be a drug carrier for loading poorly water-soluble drug indomethacin (IMC). For comparison, mesoporous silica xerogel without amino modification (B-MSX) was also synthesized using the same method. The changes of characteristics before and after IMC loading were systemically studied using fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), small angle X-ray scattering (SAXS) and nitrogen adsorption/desorption analysis. The results showed that B-MSX and B-AMSX were spherical nanoparticles with mesoporous structure. Compared with B-MSX, IMC loading capacity of B-AMSX was higher because more drug molecules can be loaded through stronger hydrogen bonding force. DSC and SAXS analysis confirmed the amorphous state of IMC after being loaded into B-MSX and B-AMSX. The in vitro drug release study revealed that B-MSX and B-AMSX improved IMC release significantly, and B-AMSX released IMC a little faster than B-MSX because of larger pore diameter of IMC-AMSX. B-MSX and B AMSX degraded gradually in dissolution medium evidenced by color reaction and absorbance value, and B-AMSX degraded slower than B-MSX due to amino modification. In conclusion, B-AMSX with superiority of higher loading capacity and enhanced dissolution release can be considered to be a good candidate as drug carrier for IMC. PMID- 26652426 TI - Exfoliated Egyptian kaolin immobilized heteropolyoxotungstate nanocomposite as an innovative antischistosomal agent: In vivo and in vitro bioactive studies. AB - This study aims to manipulate an antischistosomal nanocomposite based on exfoliated clay immobilized heteropolyoxotungstate. The nanocomposite's physicochemical characteristics were examined using XRD, Raman spectroscopy, FTIR, DLS, SEM, HR-TEM and AFM. Nano-sized spheroidal negatively charged Keggin type heteropolyoxotungstate particles were developed along and between the exfoliated clay layers. The impact of the nanocomposite on Schistosoma mansoni infected mice was studied through parasitological, physiological and histological analyses. Infected mice were orally vaccinated by a single nanocomposite dose (15mg/kg/day) for two weeks. The schistosomicidal activities of the nanocomposite in vitro were investigated by examining its dose- and time-dependent responses in terms of % worm mortality. The time-dependent morphological alterations in schistosomes at a nanocomposite dosage of 15MUg/mL were followed by SEM. The nanocomposite exhibited potential schistosomicidal properties with a marked reduction in worm burden (~85% mortality), extensive deformities in the adult worm tegument and suckers, improvement of serum biochemical activities, and diminishment in granulomatous lesions. The in vitro release of heteropolyoxotungstate from exfoliated clay indicates the clay's ability to embrace the heteropolytungstate until its liberation at the parasitic districts. PMID- 26652427 TI - Optimization of magnetosome production by Acidithiobacillus ferrooxidans using desirability function approach. AB - Present study aimed to resolve the conflict between cell growth and magnetosome formation of Acidithiobacillus ferrooxidans (A. ferrooxidans) in batch experiments by applying response surface methodology (RSM) integrated a desirability function approach. The effects of several operating parameters on cell growth (OD600) and magnetosome production (Cmag) were evaluated. The maximum overall desirability (D) of 0.923 was achieved at iron concentration of 125.07mM, shake speed of 122.37rpm and nitrogen concentration of 2.40g/L. Correspondingly, the OD600 and Cmag were 0.522 and 1.196, respectively. The confirmation experiment confirmed that the optimum OD600 and Cmag obtained were in good agreement with the predicted values. The inductively coupled plasma atomic emission spectrometer (ICP-AES) and transmission electron microscopy (TEM) analyses revealed that the production of magnetosomes could be improved via optimization. X-ray diffraction (XRD) showed the magnetosomes are magnetite. Results indicated that RSM with a desirability function was a useful technique to get the maximum OD600 and Cmag simultaneously. PMID- 26652428 TI - Structure, apatite inducing ability, and corrosion behavior of chitosan/halloysite nanotube coatings prepared by electrophoretic deposition on titanium substrate. AB - In this study chitosan/halloysite nanotube composite (CS/HNT) coatings were deposited by electrophoretic deposition (EPD) on titanium substrate. Using HNT particles were investigated as new substituents for carbon nanotubes (CNTs) in chitosan matrix coatings. The ability of chitosan as a stabilizing, charging, and blending agent for HNT particles was exploited. Furthermore, the effects of pH, electrophoretic bath, and sonicating duration were studied on the deposition of suspensions containing HNT particles. Microstructure properties of coatings showed uniform distribution of HNT particles in chitosan matrix to form smooth nanocomposite coatings. The zeta potential results revealed that at pH around 3 there is an isoelectric point for HNT and it would have cathodic and anionic states at pH values less and more than 3, respectively. Therefore, CS/HNT composite deposits were produced in the pH range of 2.5 to 3. The apatite inducing ability of chitosan-HNT composite coating assigned that HNT particles were biocompatible because they formed carbonated hydroxyapatite particles on CS/HNT coating in corrected simulated body fluid (C-SBF). Finally, electrochemical corrosion characterizations determined that corrosion resistance in CS/HNT coating has been improved compared to bare titanium substrate. PMID- 26652430 TI - Ultrafine-grained porous titanium and porous titanium/magnesium composites fabricated by space holder-enabled severe plastic deformation. AB - Compaction of powders by equal channel angular pressing (ECAP) using a novel space holder method was employed to fabricate metallic scaffolds with tuneable porosity. Porous Ti and Ti/Mg composites with 60% and 50% percolating porosity were fabricated using powder blends with two kinds of sacrificial space holders. The high compressive strength and good ductility of porous Ti and porous Ti/Mg obtained in this way are believed to be associated with the ultrafine grain structure of the pore walls. To understand this, a detailed electron microscopy investigation was employed to analyse the interface between Ti/Ti and Ti/Mg particles, the grain structures in Ti particles and the topography of pore surfaces. It was found that using the proposed compaction method, high quality bonding between particles was obtained. Comparing with other powder metallurgy methods to fabricate Ti with an open porous structure, where thermal energy supplied by a laser beam or high temperature sintering is essential, the ECAP process conducted at a relatively low temperature of 400 degrees C was shown to produce unique properties. PMID- 26652429 TI - Development of PLGA-PEG encapsulated miltefosine based drug delivery system against visceral leishmaniasis. AB - Targeted drug delivery systems are ideal technology to increase the maximum mechanism of action with smaller dose, we have developed miltefosine encapsulated PLGA-PEG nanoparticles (PPEM) to target macrophage of infected tissues against Leishmania donovani. The structural characterization of PLGA-PEG by transmission electron microscopy (TEM) has shown a size range of 10 to 15 nm. Synthesis and drug encapsulation confirmed by dynamic light scattering (DLS) and Fourier transform infrared spectroscopy (FTIR) and confirmed NP encapsulation. The dose of nano encapsulated miltefosine decreased by fifty percent as compared to that of a conventional miltefosine and Amphoterecin B. The inhibition of amastigotes in the splenic tissue with nano encapsulated miltefosine (23.21 +/- 23) was significantly more than the conventional miltefosine (89.22 +/- 52.7) and Amphoterecin B (94.12 +/- 55.1). This study signifies that there is an increased contact surface area of the nano encapsulated drug and significant reduction in size, improved the efficacy in both in vitro and in vivo study than that of the conventional miltefosine, Amphoterecin B. PMID- 26652431 TI - Polymeric micelles with alpha-glutamyl-terminated PEG shells show low non specific protein adsorption and a prolonged in vivo circulation time. AB - Although PEG remains the gold standard for stealth functionalization in drug delivery field up to date, complete inhibition of protein corona formation on PEG coated nanoparticles remains a challenge. To improve the stealth property of PEG, herein an alpha-glutamyl group was conjugated to the end of PEG and polymeric micelles with alpha-glutamyl-terminated PEG shells were prepared. After incubation with bovine serum albumin or in fetal calf serum, the size of the micelles changed slightly, while the size of the micelles of similar diblock copolymer but without alpha-glutamyl group increased markedly. These results indicated that the micelles with alpha-glutamyl-terminated PEG shells showed low non-specific protein adsorption. In vivo blood clearance kinetics assay showed that the micelles with alpha-glutamyl-terminated PEG shells exhibited a longer in vivo blood circulation time compared with similar micelles but without alpha glutamyl groups. The better stealth property of the micelles with alpha-glutamyl terminated PEG shells was presumably attributed to the zwitterionic property of the alpha-glutamyl groups. PMID- 26652432 TI - Synergistic effect of magnetite and gold nanoparticles onto the response of a label-free impedimetric hepatitis B virus DNA biosensor. AB - A magnetite and gold nanoparticle modified carbon paste electrode (CPE) was prepared for the immobilization of a thiol modified Hepatitis B virus (HBV) probe DNA and determination trace amount of target HBV DNA. Indeed, the sensing platform integrated two nanoparticles that had previously been employed individually in the DNA biosensors. The proposed DNA biosensor could measure target HBV DNA virus concentration with a low detection limit of 3.1 (+/-0.1)*10 (13)M, which was greatly lower than the detection limit reported with gold or magnetite nanoparticles alone. The change of interfacial charge transfer resistance (RCT) was confirmed the hybrid formation between probe and target HBV DNA. The RCT difference (before and after hybridization with the target HBV DNA) was in a linear relationship with the logarithm of complementary oligonucleotide concentrations in the range of 8.3 (+/-0.1)*10(-13) to 6.4 (+/-0.2)*10(-7)M. In addition, the novel methodology for specific DNA sequence detection was highly selective, repeatable, and reproducible. Finally, this work was successfully utilized for the sensitive and label free impedimetric determination of HBV target DNA in the urine and blood plasma samples. PMID- 26652433 TI - Influence of low contents of superhydrophilic MWCNT on the properties and cell viability of electrospun poly (butylene adipate-co-terephthalate) fibers. AB - The use of poly (butylene adipate-co-terephthalate) (PBAT) in tissue engineering, more specifically in bone regeneration, has been underexplored to date due to its poor mechanical resistance. In order to overcome this drawback, this investigation presents an approach into the preparation of electrospun nanocomposite fibers from PBAT and low contents of superhydrophilic multi-walled carbon nanotubes (sMWCNT) (0.1-0.5wt.%) as reinforcing agent. We employed a wide range of characterization techniques to evaluate the properties of the resulting electrospun nanocomposites, including Field Emission Scanning Electronic Microscopy (FE-SEM), Transmission Electronic Microscopy (TEM), tensile tests, contact angle measurements (CA) and biological assays. FE-SEM micrographs showed that while the addition of sMWCNT increased the presence of beads on the electrospun fibers' surfaces, the increase of the neat charge density due to their presence reduced the fibers' average diameter. The tensile test results pointed that sMWCNT acted as reinforcement in the PBAT electrospun matrix, enhancing its tensile strength (from 1.3 to 3.6MPa with addition of 0.5wt.% of sMWCNT) and leading to stiffer materials (lower elongation at break). An evaluation using MG63 cells revealed cell attachment into the biomaterials and that all samples were viable for biomedical applications, once no cytotoxic effect was observed. MG-63 cells osteogenic differentiation, measured by ALP activity, showed that mineralized nodules formation was increased in PBAT/0.5%CNTs when compared to control group (cells). This investigation demonstrated a feasible novel approach for producing electrospun nanocomposites from PBAT and sMWCNT with enhanced mechanical properties and adequate cell viability levels, which allows for a wide range of biomedical applications for these materials. PMID- 26652434 TI - Genistein-loaded nanoparticles of star-shaped diblock copolymer mannitol-core PLGA-TPGS for the treatment of liver cancer. AB - The purpose of this research is to develop nanoparticles (NPs) of star-shaped copolymer mannitol-functionalized PLGA-TPGS for Genistein delivery for liver cancer treatment, and evaluate their therapeutic effects in liver cancer cell line and hepatoma-tumor-bearing nude mice in comparison with the linear PLGA nanoparticles and PLGA-TPGS nanoparticles. The Genistein-loaded M-PLGA-TPGS nanoparticles (MPTN), prepared by a modified nanoprecipitation method, were observed by FESEM and TEM to be near-spherical shape with narrow size distribution. The nanoparticles were further characterized in terms of their size, size distribution, surface charge, drug-loading content, encapsulation efficiency and in vitro drug release profiles. The data showed that the M-PLGA TPGS nanoparticles were found to be stable, showing almost no change in particle size and surface charge during 3-month storage of their aqueous solution. In vitro Genistein release from the nanoparticles exhibited biphasic pattern with burst release at the initial 4days and sustained release afterwards. The cellular uptake efficiency of fluorescent M-PLGA-TPGS nanoparticles was 1.25-, 1.22-, and 1.29-fold higher than that of the PLGA-TPGS nanoparticles at the nanoparticle concentrations of 100, 250, and 500MUg/mL, respectively. In the MPTN group, the ratio of apoptotic cells increased with the drug dose increased, which exhibited dose-dependent effect and a significant difference compared with Genistein solution group (p<0.05). The data also showed that the Genistein-loaded M-PLGA TPGS nanoparticles have higher antitumor efficacy than that of linear PLGA-TPGS nanoparticles and PLGA nanoparticles in vitro and in vivo. In conclusion, the star-shaped copolymer M-PLGA-TPGS could be used as a potential and promising bioactive material for nanomedicine development for liver cancer treatment. PMID- 26652435 TI - Controlled delivery of antibodies from injectable hydrogels. AB - Therapeutic antibodies are currently used for the treatment of various diseases, but large doses delivered systemically are typically required. Localized controlled delivery techniques would afford major benefits such as decreasing side effects and required doses. Injectable biopolymer systems are an attractive solution due to their minimally invasive potential for controlled release in a localized area. Here, alginate-chitosan hydrogels are demonstrated to provide controlled delivery of IgG model antibodies and also of Fab antibody fragments. Also, an alternate delivery system comprised of poly(lactic-co-glycolic acid) (PLGA) microspheres loaded with antibodies and encapsulated in alginate was shown to successfully provide another level of control over release. These biopolymer systems that offer controlled delivery for antibodies and antibody fragments will be promising for many applications in drug delivery and regenerative medicine. PMID- 26652436 TI - Bactericidal activity of titanium dioxide ultraviolet-induced films. AB - TiO2 films are used as a self-sterilization surface due to their property to form reactive oxygen species (ROS) when irradiated with ultraviolet light. These ROS attack bacteria and kill them. We present a new way to enhance the bactericidal activity of TiO2-films: formation of nanopores on the surface by four-beam high power laser irradiation. Such surfaces have significantly higher antibacterial activity as compared to conventional TiO2 surfaces after 15 and 60min of UV irradiation. Study of the bacterial cell morphology by atomic force microscopy after 60min irradiation showed that Staphylococcus aureus 956 and Escherichia coli 321-5 undergo significant morphological changes. S. aureus assume atypical elongated shapes after UV treatment alone and swollen forms with protrusions after UV treatment on TiO2 surface. E. coli exhibit oval or round forms after UV treatment alone, and round forms with small protrusions, and destroyed cells after incubation under UV on the TiO2 film. PMID- 26652437 TI - Strontium-rich injectable hybrid system for bone regeneration. AB - Current challenges in the development of scaffolds for bone regeneration include the engineering of materials that can withstand normal dynamic physiological mechanical stresses exerted on the bone and provide a matrix capable of supporting cell migration and tissue ingrowth. The objective of the present work was to develop and characterize a hybrid polymer-ceramic injectable system that consists of an alginate matrix crosslinked in situ in the presence of strontium(Sr), incorporating a ceramic reinforcement in the form of Sr-rich microspheres. The incorporation of Sr in the microspheres and in the vehicle relies on the growing evidence that Sr has beneficial effects in bone remodeling and in the treatment of osteopenic disorders and osteoporosis. Sr-rich porous hydroxyapatite microspheres with a uniform size and a mean diameter of 555 MUm were prepared, and their compression strength and friability tested. A 3.5% (w/v) ultrapure sodium alginate solution was used as the vehicle and its in situ gelation was promoted by the addition of calcium (Ca) or Sr carbonate and Glucone delta-lactone. Gelation times varied with temperature and crosslinking agent, being slower for Sr than for Ca, but adequate for injection in both cases. Injectability was evaluated using a device employed in vertebroplasty surgical procedures, coupled to a texture analyzer in compression mode. Compositions with 35%w of microspheres presented the best compromise between injectability and compression strength of the system, the force required to extrude it being lower than 100 N.Micro CT analysis revealed a homogeneous distribution of the microspheres inside the vehicle, and a mean inter-microspheres space of 220 MUm. DMA results showed that elastic behavior of the hybrid is over the viscous one and that the higher storage modulus was obtained for the 3.5%Alg-35%Sr-HAp-Sr formulation. PMID- 26652438 TI - Anisotropic mechanical behaviors and their structural dependences of crossed lamellar structure in a bivalve shell. AB - Crossed-lamellar structure is one of the most common organizations found in mollusk shells and may serve as a natural mimetic model for designing bio inspired synthetic materials. Nonetheless, the mechanical behaviors and corresponding mechanisms have rarely been investigated for individual macro-layer of such structure. The integrated effects of orientation and hydration also remain unclear. In this study, the mechanical behaviors and their structural dependences of pure crossed-lamellar structure in Saxidomus purpuratus shell were systematically examined by three-point bending and compression tests. Mechanical properties and fracture mechanisms were revealed to depend strongly on the orientation, hydration state and loading condition. Three basic cracking modes of inter-platelet, trans-platelet, and along the interfaces between first-order lamellae were identified, and the interfacial separation was enhanced by hydration. Macroscopic compressive fracture was accomplished through axial splitting during which multiple toughening mechanisms were activated. The competition among different cracking modes was quantitatively evaluated by analyzing their driving stresses and resistances from fundamental mechanics. This study helps to clarify the mechanical behaviors of naturally occurring crossed lamellar structure, and accordingly, aids in designing new bio-inspired synthetic materials by mimicking it. PMID- 26652439 TI - Multiwall carbon nanotubes chemically modified carbon paste electrodes for determination of gentamicin sulfate in pharmaceutical preparations and biological fluids. AB - This article focused on the construction and characteristics of novel and sensitive gentamicin carbon paste electrodes which are based on the incorporation of multiwall carbon nanotubes (MWCNTs) which improve the characteristics of the electrodes. The electrodes were constructed based on gentamicin-phosphotungstate (GNS-PTA) called CPE1, gentamicin-phosphomolybdate (GNS-PMA) called CPE2, GNS PTA+ MWMCNTs called MWCPE1, and GNS-PMA+ MWMCNTs called MWCPE2. The constructed electrodes, at optimum paste composition, exhibited good Nernstian response for determination of gentamicin sulfate (GNS) over a linear concentration range from 2.5*10(-6) to 1*10(-2), 3.0*10(-6) to 1*10(-2), 4.9*10(-7) to 1*10(-2) and 5.0*10(-7) to 1*10(-2)molL(-1), with lower detection limit 1*10(-6), 1*10(-6), 1.9*10(-7) and 2.2*10(-7)molL(-1), and with slope values of 29.0+/-0.4, 29.2+/ 0.7, 31.2+/-0.5 and 31.0+/-0.6mV/decade for CPE1, CPE2, MWCPE1 and MWCPE2, respectively. The response of electrodes is not affected by pH in the range 3-8 for CPE1 and CPE2 and in the range 2.5-8.5 for MWCPE1 and MWCPE2. The results showed fast dynamic response time (about 8-5s) and long lifetime (more than 2months) for all electrodes. The sensors showed high selectivity for gentamicin sulfate (GNS) with respect to a large number of interfering species. The constructed electrodes were successfully applied for determination of GNS in pure form, its pharmaceutical preparations and biological fluids using standard addition and potentiometric titration methods with high accuracy and precision. PMID- 26652440 TI - Construction of novel sensitive electrochemical sensor for electro-oxidation and determination of citalopram based on zinc oxide nanoparticles and multi-walled carbon nanotubes. AB - A new chemically modified carbon paste electrode (CMCPE) was applied to the simple, rapid, highly selective and sensitive determination of citalopram in human serum and pharmaceutical preparations using adsorptive square wave voltammetry (ASWV). The ZnO nanoparticles and multi-walled carbon nanotubes modified CPE (ZnO-MWCNT/CPE) electrode was prepared by incorporation of the ZnO nanoparticles and multi-walled carbon nanotubes (MWCNT) in carbon paste electrode. The limit of detection and the linear range were found to be 0.005 and 0.012 to 1.54MUmolL(-1) of citalopram, respectively. The effects of potentially interfering substances on the determination of this compound were investigated and found that the electrode is highly selective. The proposed CMCPE was used to the determination of citalopram in human serum, urine and pharmaceutical samples. This reveals that ZnO-MWCNT/CPE shows excellent analytical performance for the determination of citalopram in terms of very low detection limit, high sensitivity, very good repeatability and reproducibility over other methods reported in the literature. PMID- 26652441 TI - Development of new radiopaque glass fiber posts. AB - The aim of this study was to analyze the radiopacity and filler content of three experimental glass fiber posts (EGFP) in comparison with other glass/carbon fibers and metal posts from the dental market. Three EGFP were obtained by pultrusion of glass fibers in a polymer matrix based on 2,2-bis[4-(2-hydroxy-3 methacryloyloxypropoxy)-phenyl]propane (bis-GMA) and triethyleneglycol dimethacrylate (TEGDMA) monomers. Using intraoral sensor disks 27 posts, as well as mesiodistal sections of human molar and aluminum step wedges were radiographed for evaluation of radiopacity. The percentage compositions of fillers by weight and volume were investigated by combustion analysis. Two EGFP showed radiopacity higher than enamel. The commercial endodontic posts showed radiopacity as follows: higher than enamel, between enamel and dentin, and lower than dentin. The results showed statistically significant differences (p b 0.05)when evaluatedwith one-way ANOVA statistical analysis. According to combustion analyses, the filler content of the tested posts ranges between 58.84wt.% and 86.02wt.%. The filler content of the tested EGFP ranged between 68.91 wt.% and 79.04 wt.%. EGFP could be an alternative to commercial glass fiber posts. Futureglass fiber posts are recommended to present higher radiopacity than dentin and perhaps ideally similar to or higher than that of enamel, for improved clinical detection. The posts with a lower radiopacity than dentin should be considered insufficiently radiopaque. The radiopacity of some glass fiber posts is not greatly influenced by the amount of filler. PMID- 26652442 TI - Structural, compositional, mechanical characterization and biological assessment of bovine-derived hydroxyapatite coatings reinforced with MgF2 or MgO for implants functionalization. AB - Hydroxyapatite (HA) is a consecrated biomaterial for bone reconstruction. In the form of thin films deposited by pulsed laser technologies, it can be used to cover metallic implants aiming to increase biocompatibility and osseointegration rate. HA of animal origin (bovine, BHA) reinforced with MgF2 (2wt.%) or MgO (5wt.%) were used for deposition of thin coatings with improved adherence, biocompatibility and antimicrobial activity. For pulsed laser deposition experiments, a KrF* (lambda=248nm, tauFWHM<=25ns) excimer laser source was used. The deposited structures were characterized from a physical-chemical point of view by X-Ray Diffraction, Fourier Transform Infra-Red Spectroscopy, Scanning Electron Microscopy in top- and cross-view modes, Energy Dispersive X-Ray Spectroscopy and Pull-out adherence tests. The microbiological assay using the HEp-2 cell line revealed that all target materials and deposited thin films are non-cytotoxic. We conducted tests on three strains isolated from patients with dental implants failure, i.e. Microccocus sp., Enterobacter sp. and Candida albicans sp. The most significant anti-biofilm effect against Microcococcus sp. strain, at 72h, was obtained in the presence of BHA:MgO thin films. For Enterobacter sp. strain a superior antimicrobial activity at 72h was noticed, in respect with simple BHA or Ti control. The enhanced antimicrobial performances, correlated with good cytocompatibility and mechanical properties recommend these biomaterials as an alternative to synthetic HA for the fabrication of reliable implant coatings for dentistry and other applications. PMID- 26652443 TI - Spray-dried powders improve the controlled release of antifungal tioconazole loaded polymeric nanocapsules compared to with lyophilized products. AB - This work aimed to obtain solid formulations from polymeric nanocapsules and nanoemulsions containing tioconazole, a broad spectrum antifungal drug. Two dehydration methods were used: spray-drying and freeze drying, using lactose as adjuvant (10%, w/v). The liquid formulations had a mean particle size around 206 nm and 182 nm for nanocapsules and nanoemulsions, respectively, and an adequate polydispersity index. Tioconazole content was close to the theoretical amount (1.0 mg/mL). After drying, the content ranged between 98 and 102%with a mean nanometric size of the dried products after redispersion. Scanning electron microscopy showed that the particles are rounded, sphere-shaped for the dried products obtained by spray-drying, and shapeless and irregular shapes for those obtained by freeze-drying. In the microbiological evaluation, all dried products remained active against the yeast Candida albicans when compared to the original systems. The dried products obtained by spray-drying from nanocapsules presented better control of the tioconazole release when compared to the freeze-drying products. PMID- 26652444 TI - Reducing the content of carrier polymer in pectin nanofibers by electrospinning at low loading followed with selective washing. AB - Nanofibers of natural polymers represent an essential class of materials in biomedicine. Pectin is a plant-sourced anionic polysaccharide widely used in food products and biomedicine owning to its abundance, biocompatibility and inherent bioactivity. However, current electrospun pectin nanofibers are suffered from high content of carrier polymer, which may lead to low integrity and mechanical strength as well as in vivo toxicity. We report here a strategy to reduce the content of carrier polymer, polyethylene oxide (PEO) in our study, in pectin nanofibers, via electrospinning at low loading followed with selective washing. With improved electrospinning condition, we first enabled electrospinning of pectin nanofibers at low PEO loading. Then the PEO was removed by washing with a selective solvent to give pectin nanofibers containing only 1.5% PEO. The strategy was versatile to pectins from various sources and of various degree of esterification. The pectin nanofibers exhibited Young's modulus as high as 358.5MPa. In view of their rich bioactivity, the pectin nanofibers of low content of carrier polymer are promising materials for a wide range of biomedical applications. PMID- 26652445 TI - An evaluation of the biocompatibility properties of a salt-modified polyvinyl alcohol hydrogel for a knee meniscus application. AB - The treatment of irreparable knee meniscus tears remains a major challenge for the orthopaedic community. The main purpose of this research was to analyse the biocompatibility properties of a salt-modified polyvinyl alcohol hydrogel, in order to assess its potential for use as an artificial meniscal implant. Aqueous polyvinyl alcohol was treated with a sodium sulphate solution to precipitate out the polyvinyl alcohol resulting in a pliable hydrogel. Cytotoxicological analysis indicates that PVA/sodium sulphate hydrogels display a non-toxic disposition and were found to be compatible with the L929 fibroblast cell line. PMID- 26652446 TI - Improving bone cement toughness and contrast agent confinement by using acrylic branched polymers. AB - A new biomedical material to be used as part of acrylic bone cement formulations is described. This new material is tough, its Young's Modulus is similar to the one of poly (methylmethacrylate) and the contrast agent, usually employed in acrylic bone cements, is homogeneously distributed among the polymeric matrix. Additionally, its wear coefficient is 66% lower than the one measured in poly(methyl methacrylate). The developed material is a branched polymer with polyisoprene backbone and poly(methyl methacrylate) side chains, which are capable of retaining barium sulphate nanoparticles thus avoiding their aggregation. The grafting reaction was carried out in presence of the nanoparticles, using methyl methacrylate as solvent. From the (1)H-NMR spectra it was possible to determine the average number of MMA units per unit of isoprene (3.75:1). The ability to retain nanoparticles (about 8wt.%), attributed to their interaction with the polymer branches, was determined by thermogravimetric analysis and confirmed by FTIR and microscopy techniques. By SEM microscopy it was also possible to determine the homogeneous spatial distribution of the barium sulphate nanoparticles along the polymer matrix. PMID- 26652447 TI - Fabrication and formation studies on single-walled CA/NaCS-WSC microcapsules. AB - The micron-sized calcium alginate/sodium cellulose sulfate-water soluble chitosan (CA/NaCS-WSC) microcapsules were prepared by membrane emulsification method using sodium alginate (NaAlg), NaCS and WSC as raw materials. The CA/NaCS microspheres prepared dispersed well and held spherical shape with an emulsifier volume ratio of 7:3 (Span 80:Tween 80) and a concentration of cross-linking agent of 1.5% (w/v) calcium chloride and 5% (w/v) sodium chloride. The CA/NaCS-WSC microcapsules had a spherical shape with average diameter of 62.36+/-13.87MUm. A fluorescent ring could be seen obviously on the surface of CA/NaCS-WSC microcapsules under confocal microscope, when WSC was labeled by fluorescein isothiocyanate. The discussion on the formation studies implied that Ca(2+) could diffuse into the droplets of NaAlg/NaCS forming CA/NaCS microspheres, while NaCS could react with WSC forming a polyelectrolyte complexes film. The microcapsules prepared with typical wall-capsule/core structure could be used to develop micron sized drug delivery carriers. PMID- 26652448 TI - Fluorescent detection and imaging of Hg(2+) using a novel phenanthroline derivative based single- and two-photon excitation. AB - A novel phenanthroline derivative, 4-[4-(N-methyl)styrene]-imidazo[4,5 f][1,10]phenanthroline-benzene iodated salt (MSIPBI), was synthesized, and the linear absorption and fluorescent spectra of MSIPBI in different solvents were investigated. The photophysical properties in unbound and in ligand-metal complexes were evaluated by UV absorption and one- and two-photon fluorescent spectra, and the quantum yields, two-photon active cross-sections and the binding constant of dye-metal were calculated. The results indicated that MSIPBI has a large Stokes shift (more than 167nm), and the dye was selective and sensitive for the detection of Hg(2+) with a two-photon active cross-section of 55.5GM in tris HCl buffer solution at 800nm. Furthermore, the results of the fluorescence microscopy imaging indicated that MSIPBI is an efficient fluorescent probe for the detection of Hg(2+) in living cells by one- and two-photon excitation. Moreover, the experiments of determination Hg(2+) in river water and tap water were finished. PMID- 26652449 TI - Kinetic study of antibiotic ciprofloxacin ozonation by MWCNT/MnO2 using Monte Carlo simulation. AB - Kinetic Monte Carlo simulation was used to investigate kinetics of antibiotic ciprofloxacin degradation by direct and heterogeneous catalytic (MnO2 and carbon nano-tube loaded with MnO2) ozonation. The reaction kinetic mechanisms of each system have been obtained. The rate constant values for the each step of the reaction mechanisms were attained as adjustable parameters by kinetic Monte Carlo simulation. The carbon nano-tube loaded with MnO2 plays important role as catalyst in the ciprofloxacin ozonation by increasing reactivity of ozone and ciprofloxacin drug on the surface of carbon nano-tube. Optimized amount of ozone and catalysts were obtained via studying the effect of inlet ozone concentration and initial amount of catalyst on the rate of ciprofloxacin degradation using Monte Carlo simulation. The simulation results of this study have reasonably agreement with the present experimental data for the ozonation of ciprofloxacin drug. PMID- 26652450 TI - Trypsin as enhancement in cyclical tracheal decellularization: Morphological and biophysical characterization. AB - There are different types of tracheal disorders (e.g. cancer, stenosis and fractures). These can cause respiratory failure and lead to death of patients. Several attempts have been made for trachea replacement in order to restore the airway, including anastomosis and implants made from synthetic or natural materials. Tracheal allotransplantation has shown high rejection rates, and decellularization has emerged as a possible solution. Decellularization involves the removal of antigens from cells in the organ or tissue, leaving a matrix that can be used as 3D cell-scaffold. Although this process has been used for tracheal replacement, it usually takes at least two months and time is critical for patients with tracheal disorders. Therefore, there is necessary to develop a tracheal replacement process, which is not only effective, but also quick to prepare. The aim of this research was to develop a faster trachea decellularization protocol using Trypsin enzyme and Ethylenediaminetetraacetic acid (EDTA) as decellularization agents. Three protocols of cyclic trachea decellularization (Protocols A, B, and C) were compared. Following Protocol A (previously described in the literature), 15 consecutive cycles were performed over 32 days. Protocol B (a variation of Protocol A) - EDTA being added - with 15 consecutive cycles performed over 60 days. Finally, Protocol C, with the addition of Trypsin as a decellularization agent, 5 consecutive cycles being performed over 10 days. For the three protocols, hematoxylin-eosin (H&E) staining and DNA residual content quantification were performed to establish the effectiveness of the decellularization process. Scanning Electron Microscopy (SEM) was used to observe the changes in porosity and microarrays. To evaluate the structural matrices integrity, Thermogravimetric Analysis (TGA) and biomechanical test were used. None of the protocols showed significant alteration or degradation in the components of the extracellular matrix (ECM). However, in Protocol C, more cellular components were removed in less time, making it the most efficient process. In addition, the cell tracking and viability was evaluated with chondrocytes seeding on the scaffold obtained by Protocol C, which showed an adequate cell scaffolding ability of this matrix. PMID- 26652451 TI - Copper/zinc bimetal nanoparticles-dispersed carbon nanofibers: A novel potential antibiotic material. AB - Copper (Cu) and zinc (Zn) nanoparticles (NPs) were asymmetrically distributed in carbon nanofibers (CNFs) grown on an activated carbon fiber (ACF) substrate by chemical vapor deposition (CVD). The CVD conditions were chosen such that the Cu NPs moved along with the CNFs during tip-growth, while the Zn NPs remained adhered at the ACF. The bimetal-ACF/CNF composite material was characterized by the metal NP release profiles, in-vitro hemolytic and antibacterial activities, and bacterial cellular disruption and adhesion assay. The synergetic effects of the bimetal NPs distributed in the ACFs/CNFs resulted from the relatively slower release of the Cu NPs located at the tip of the CNFs and faster release of the Zn NPs dispersed in the ACF. The Cu/Zn-grown ACFs/CNFs inhibited the growth of the Gram negative Escherichia coli, Gram positive Staphylococcus aureus, and Methicillin resistance Staphylococcus aureus bacterial strains, with superior efficiency (instant and prolonged inhibition) than the Cu or Zn single metal grown ACFs/CNFs. The prepared bimetal-carbon composite material in this study has potential to be used in different biomedical applications such as wound healing and antibiotic wound dressing. PMID- 26652452 TI - The physical and chemical properties of the polyvinylalcohol/polyvinylpyrrolidone/hydroxyapatite composite hydrogel. AB - A hydrogel of polyvinylalcohol (PVA)/polyvinylpyrrolidone (PVP)/hydroxyapatite (HA) was prepared by a repeated freezing and thawing technique. The effect of HA on the hydrogel was evaluated by comparing the physical and chemical properties of PVA/PVP/HA and PVA/PVP hydrogels. By using theoretical models, the information about the swelling kinetics and the dehydration kinetics have been obtained. From the analysis of structure, mechanical properties, and molecular interaction, the application of PVA/PVP/HA hydrogel as a biomaterial has been evaluated. Relative to PVA/PVP, the PVA/PVP/HA hydrogel is of denser network structure, lower water content, larger storage modulus, and higher dehydration activation energy. These results reveal that, as HA fills in the hydrogel, the molecular interaction is enhanced, the free space of network is compressed, and the diffusion activation energy of water is increased. In spite of its water content being decreased, it is still in the range of meeting the requirement of bio-application. When the hydrogel is subjected to external forces, the matrix will transfer the load to the HA powder, thus enhance the strength of the hydrogel. For application in bio materials, HA will still have osteoinductivity because its crystalline structure is not interrupted in PVA/PVP/HA hydrogel environment. PMID- 26652453 TI - VEGF-conjugated alginate hydrogel prompt angiogenesis and improve pancreatic islet engraftment and function in type 1 diabetes. AB - Type 1 diabetes was a life-long disease that affected numerous people around the world. Insulin therapy has its limitations that may involve hyperglycemia and heavy burden of patient by repeated dose. Islet transplantation emerged as a promising approach to reach periodical reverse of diabetes, however, transplanted islets suffer from foreign body reaction and lack of nutrition and oxygen supply, especially in the blood-vessel-shortage subcutaneous site which was preferred by patient and surgeon. In this study, we designed and synthesized a vascular endothelial growth factor (VEGF) conjugated alginate material to encapsulate the transplanted islets via 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide/N hydroxysuccinimide (EDC/NHS) reaction, and successful conjugation was confirmed by Nuclear Magnetic Resonance H1 spectrum. The best VEGF concentration (100ng/ml) was determined by the combined studies of the mechanical property and endothelial cell growth assay. In vivo study, conjugated VEGF on alginate exhibited sustained promoting angiogenesis property after subcutaneous transplantation by histology study and islets encapsulated in this material achieved long term therapeutic effect (up to 50days) in the diabetic mice model. In conclusion, this study establishes a simple biomaterial strategy for islet transplantation to enhance islet survival and function, which could be a feasible therapeutic alternative for type 1 diabetes. PMID- 26652454 TI - A high sensitive label-free immunosensor for the determination of human serum IgG using overoxidized polypyrrole decorated with gold nanoparticle modified electrode. AB - Herein, an electrochemical human immunoglobulin G (HIgG) immunosensor was fabricated using overoxidized polypyrrole decorated with gold nanoparticle (OPPy Aunano) modified screen printed electrode (OPPy-Aunano/SPE). The results clearly demonstrate that OPPy-Aunano film is very permeable to [Fe(CN)6](3-/4-). Therefore, the fabrication of immunosensor based on permeability of OPPy-Aunano film to [Fe(CN)6](3-/4-) probe is a novel strategy for the fabrication of label free electrochemical immunosensor. The electrochemical impedance spectroscopy (EIS) techniques are used for the determination of HIgG in the concentration range 0.5 to 125.0ngmL(-1) and with a limit of detection of 0.02ngmL(-1), respectively. PMID- 26652455 TI - Preparation and characterization of glycidyl methacrylate organo bridges grafted mesoporous silica SBA-15 as ibuprofen and mesalamine carrier for controlled release. AB - Mesoporous silica SBA-15 was synthesized and functionalized with bridged polysilsesquioxane monomers obtained by the reaction of 3-aminopropyltriethoxy silane with glycidyl methacrylate in 2:1 ratio. The synthesized mesoporous silica materials were characterized by elemental analysis, infrared spectroscopy, nuclear magnetic resonance spectroscopy, nitrogen adsorption, X-ray diffraction, thermogravimetry and scanning electron microscopy. The nuclear magnetic resonance in the solid state is in agreement with the sequence of carbon distributed in the attached organic chains, as expected for organically functionalized mesoporous silica. After functionalization with organic bridges the BET surface area was reduced from 1311.80 to 494.2m(2)g(-1) and pore volume was reduced from 1.98 to 0.89cm(3)g(-1), when compared to original precursor silica. Modification of the silica surface with organic bridges resulted in high loading capacity and controlled release of ibuprofen and mesalamine in biological fluids. The Korsmeyer-Peppas model better fits the release data indicating Fickian diffusion and zero order kinetics for synthesized mesoporous silica. The drug release rate from the modified silica was slow in simulated gastric fluid, (pH1.2) where less than 10% of mesalamine and ibuprofen were released in initial 8h, while comparatively high release rates were observed in simulated intestinal (pH6.8) and simulated body fluids (pH7.2). The preferential release of mesalamine at intestinal pH suggests that the modified silica could be a simple, efficient, inexpensive and convenient carrier for colon targeted drugs, such a mesalamine and also as a controlled drug release system. PMID- 26652456 TI - Effect of hydroxyapatite nano-particles on morphology, rheology and thermal behavior of poly(caprolactone)/chitosan blends. AB - The effect of hydroxyapatite nano-particles (nHA) on morphology, and rheological and thermal properties of PCL/chitosan blends was investigated. The tendency of nHA to reside in the submicron-dispersed chitosan phase is determined using SEM and AFM images. The presence of electrostatic interaction between amide sites of chitosan and ionic groups on the nHA surface was proved by FTIR. It is shown that the chitosan phase is thermodynamically more favorable for the nano-particles to reside than the PCL phase. Lack of implementation of Cox-Merz theory for this system shows that the polymer-nano-particle network is destructed by the flow. Results from dynamic rheological measurements and Zener fractional model show that the presence of nHA increases the shear moduli and relaxation time of the PCL/chitosan blends. DSC measurements showed that nHA nano-particles are responsible for the increase in melting and crystallization characteristics of the PCL/chitosan blends. Based on thermogravimetric analysis, the PCL/chitosan/nHA nano-composites exhibited a greater thermal stability compared to the nHA-free blends. PMID- 26652457 TI - Biosynthesis of bifunctional iron oxyhydrosulfate by Acidithiobacillus ferroxidans and their application to coagulation and adsorption. AB - Coagulation and adsorption are important environmental technologies, which were widely applied in water treatment. In this study, a type of villous iron oxyhydrosulfate with low crystallinity, high content iron, sulfate and hydroxyl was synthesized by Acidithiobacillus ferrooxidans, which possessed coagulation and heavy metal adsorption ability simultaneously. The results showed that the Cu(II) adsorption capacity increased within a small range over the pH range of 3.0-5.0 but increased evidently over the range of 6.0-8.0. The maximal Cu(II) adsorption capacity of sample Af and Gf reached 50.97 and 46.08mg/g respectively. The optimum pH for Cr(VI) adsorption was 6.0, and the maximal adsorption capacity reached 51.32 and 59.57mg/g. The Langmuir isotherm can better describe the adsorption behavior of Cr(VI). Coagulation performance of the iron oxyhydrosulfate (Sh) has been significantly enhanced by polysilicic acid (PSA), which was mainly determined by PSA/Sh ratio, pH and coagulant dosage. Coagulation efficiency maintained approximately at 98% when the PSA/Sh ratio ranged from 0.4/0.1 to 1.0/0.1. Polysilicic acid worked efficiently in wide pH range extending, from 2 to 3.5. Coagulation performance improved significantly with the increasing of the coagulant dosage at lower dosage range, while, at higher dosage range, the improvement was not evident even with more coagulant addition. PMID- 26652458 TI - Effect of chemical heterogeneity of biodegradable polymers on surface energy: A static contact angle analysis of polyester model films. AB - Biodegradable and bioassimilable poly((R,S)-3,3 dimethylmalic acid) (PDMMLA) derivatives were synthesized and characterized in order to develop a new coating for coronary endoprosthesis enabling the reduction of restenosis. The PDMMLA was chemically modified to form different custom groups in its side chain. Three side groups were chosen: the hexyl group for its hydrophobic nature, the carboxylic acid and alcohol groups for their acid and neutral hydrophilic character, respectively. The sessile drop method was applied to characterize the wettability of biodegradable polymer film coatings. Surface energy and components were calculated. The van Oss approach helped reach not only the dispersive and polar acid-base components of surface energy but also acid and basic components. Surface topography was quantified by atomic force microscopy (AFM) and subnanometer average values of roughness (Ra) were obtained for all the analyzed surfaces. Thus, roughness was considered to have a negligible effect on wettability measurements. In contrast, heterogeneous surfaces had to be corrected by the Cassie-Baxter equation for copolymers (10/90, 20/80 and 30/70). The impact of this correction was quantified for all the wettability parameters. Very high relative corrections (%) were found, reaching 100% for energies and 30% for contact angles. PMID- 26652459 TI - Preparation, characterization and in vitro dissolution behavior of porous biphasic alpha/beta-tricalcium phosphate bioceramics. AB - The ideal bone tissue engineering scaffolds are long-cherished with the properties of interconnected macroporous structures, adjustable degradation and excellent biocompatibility. Here, a series of porous alpha/beta-tricalcium phosphate (alpha/beta-TCP) biphasic bioceramics with different phase ratios of alpha-TCP and beta-TCP were successfully synthesized by heating an amorphous calcium phosphate precursor. The chemical and morphological characterization showed that alpha- and beta-TCP phases co-existed in the alpha/beta-TCP bioceramics and they had interconnected pore structures with size between 200 and 500MUm. The in vitro dissolution behavior and bioactivity of the dual alpha/beta TCP were also probed in static and dynamic SBF for the first time. The results revealed that alpha/beta-TCP scaffolds had good in vitro bioactivity, as the formation of bone-like apatite layers was induced on the scaffolds after mineralization in SBF. Moreover, dissolution rate of alpha/beta-TCP bioceramics in dynamic environment was higher than that under static condition. Compared with monophasic TCP ceramics, these porous alpha/beta-TCP bioceramics displayed a tailored dissolution rate proportionate to the TCP content (alpha and beta) in the materials. Further, the degradation profile of porous alpha/beta-TCP was well described by Avrami equation. The porous dual alpha/beta-TCP bioceramics with controllable degradation behavior hold great potential to be applied in bone tissue engineering as bone substitutes. PMID- 26652460 TI - Host-guest system of hesperetin and beta-cyclodextrin or its derivatives: Preparation, characterization, inclusion mode, solubilization and stability. AB - The inclusion complexation behavior, characterization and binding ability of hesperetin with beta-cyclodextrin and its derivatives were investigated in both the solution and solid state by means of XRD, DSC, SEM, (1)H and 2D NMR and UV vis spectroscopy. The results showed that the water solubility and stability of hesperetin were obviously increased in the inclusion complex with cyclodextrins. This satisfactory water solubility and high stability of the hesperetin/CD complexes will be potentially useful for their application as herbal medicines or healthcare products. PMID- 26652461 TI - Guanidine hydrochloride embedded polyurethanes as antimicrobial and absorptive wound dressing membranes with promising cytocompatibility. AB - Preparation and assessments of novel absorptive wound dressing materials with efficient antimicrobial activity as well as very good cytocompatibility were described in this work. An amine terminated poly(hexamethylene guanidine hydrochloride) was prepared and used as curing agent of different epoxy terminated polyurethane prepolymers. The structures of prepared materials were elucidated by evaluation of their (1)H NMR and FTIR spectra. The recorded tensile strength of membranes confirmed the excellent dimensional stability of the film type dressings even at fully hydrated conditions. Therefore, these dressings could protect the wound bed from external forces during the healing period. The structurally optimized dressing membranes could preserve the desired moist environment over the wounded area, as a result of their balanced equilibrium, water absorption and water vapor transmission rate. Therefore, a very good condition for stimulation of self-healing of wound bed was attained. Also, owing to the presence of guanidine hydrochloride moieties embedded into the structure of dressings, efficient antimicrobial activity against Staphylococcus aureus, Pseudomonas aeruginosa and Candida albicans were detected. In vitro cytotoxicity assay of the prepared dressings revealed cytocompatibility of these materials against fibroblast cells. Therefore, they could support cell growth and proliferation at the wounded area. PMID- 26652462 TI - Effect of ultrasonication on the fibril-formation and gel properties of collagen from grass carp skin. AB - Controlling the fibril-formation process of collagen in vitro to fabricate novel biomaterials is a new area in the field of collagen research. This study aimed to determine the effect of ultrasonication on collagen fibril formation and the properties of the resulting collagen gels. Native collagen, extracted from the skin of grass carp, self-assembled under ultrasonic conditions (at different ultrasonic power and duration). The self-assembly kinetics, fibrillar morphology, and physical and cell growth-promoting properties of the collagen gels were analyzed and compared. The results showed that the self-assembly rate of collagen was increased by ultrasonication at the nucleation stage. The resulting fibrils exhibited smaller diameters and D-periodicity lengths than that of the untreated collagen samples (p<0.05). The viscoelasticity and textural properties of collagen gels also changed after ultrasonication at the nucleation stage. Texture profile analysis and cell proliferation assays showed that ultrasonication produced softer collagen gel colloids, which were more suitable for cell proliferation than the untreated collagen gels. PMID- 26652463 TI - Bone bonding strength of diamond-structured porous titanium-alloy implants manufactured using the electron beam-melting technique. AB - The present study examined the bone bonding strength of diamond-structured porous titanium-alloy (Porous-Ti-alloy) manufactured using the electron beam-melting technique in comparison with fiber mesh-coated or rough-surfaced implants. Cylindrical implants with four different pore sizes (500, 640, 800, and 1000MUm) of Porous-Ti-alloy, titanium fiber mesh (FM), and surfaces roughened by titanium arc spray (Ti-spray) were implanted into the distal femur of rabbits. Bone bonding strength and histological bone ingrowth were evaluated at 4 and 12weeks after implantation. The bone bonding strength of Porous-Ti-alloy implants (640MUm pore size) increased over time from 541.4N at 4weeks to 704.6N at 12weeks and was comparable to that of FM and Ti-spray implants at both weeks. No breakage of the porous structure after mechanical testing was found with Porous-Ti-alloy implants. Histological bone ingrowth that increased with implantation time occurred along the inner structure of Porous-Ti-alloy implants. There was no difference in bone ingrowth in Porous-Ti-alloy implants with pore sizes among 500, 640, and 800MUm; however, less bone ingrowth was observed with the 1000MUm pore size. These results indicated Porous-Ti-alloy implants with pore size under 800MUm provided biologically active and mechanically stable surface for implant fixation to bone, and had potential advantages for weight bearing orthopedic implants such as acetabular cups. PMID- 26652464 TI - PLGA/DPPC/trimethylchitosan spray-dried microparticles for the nasal delivery of ropinirole hydrochloride: in vitro, ex vivo and cytocompatibility assessment. AB - In the present study we investigated polymer-lipid microparticles loaded with ropinirole hydrochloride (RH) for nasal delivery. RH microparticles were further evaluated by means of scanning electron microscopy (SEM), zeta-potential measurements, Fourier-transform infrared spectroscopy (FT-IR), X-ray photoelectron spectroscopy (XPS) and x-ray diffraction (XRD). In vitro release studies were performed in simulated nasal electrolyte solution (SNES) pH5.5 at 35 degrees C. Ex vivo permeation studies were conducted across sheep nasal mucosa. Cytocompatibility was tested in cultured human airway epithelial cells (Calu-3). SEM studies revealed spheroid microparticles in the range of 2.09MUm to 2.41MUm. The presence of trimethylchitosan (TMC) induced a slight shift towards less negative zeta-potential values. Surface chemistry (XPS) revealed the presence of dipalmitoylphospatidylcholine (DPPC) and poly(lactic-co-glycolic acid) (PLGA) onto microparticles' surface, further corroborating the FT-IR and XRD findings. In vitro release studies showed that the microparticle composition can partly modulate the release of RH. Ex vivo studies demonstrated a 2.35-folded enhancement of RH permeation when RH was co-formulated with TMC of low molecular weight, compared to the control. All formulations tested were found to be non toxic to cells. The results suggest that polymer-lipid microparticles may be a promising carrier for the nasal delivery of RH. PMID- 26652465 TI - DNA intercalation studies and antimicrobial activity of Ag@ZrO2 core-shell nanoparticles in vitro. AB - Ag@ZrO2 core-shell nanoparticles were prepared by one pot simultaneous reduction of AgNO3 and hydrolysis of zirconium (IV) isopropoxide. The formation of core shell nanoparticles was confirmed by absorption, XRD, and HR-TEM techniques. The antibacterial activity of Ag@ZrO2 core-shell nanoparticles against Escherichia coli and Staphylococcus aureus and the antifungal properties against Candida albicans, Candida glabrata, Aspergillus niger and Aspergillus flavus were examined by the agar diffusion method. DNA intercalation studies were carried out in CT-DNA. As a result ZrO2 supported on the surface of AgNPs not only prevented aggregation, but also proved to have enhanced antimicrobial activity and DNA intercalation than the Ag nanoparticles. PMID- 26652466 TI - Testing the variability of PSA expression by different human prostate cancer cell lines by means of a new potentiometric device employing molecularly antibody assembled on graphene surface. AB - Prostate Specific Antigen (PSA) is widely used as a biomarker for prostate cancer. Recently, an electrochemical biosensor for PSA detection by means of molecularly imprinted polymers (MIPs) was developed. This work evaluated the performance and the effectiveness of that PSA biosensor in screening the biomarker PSA in biological media with complex composition, collected from different human prostate cell line cultures. For that, the prostate cancer LNCaP and PC3 cells, and the non-cancerous prostate cell line PNT2 were cultured for 2, 7 and 14days in either alpha-MEM or RPMI in the presence of 10% or 30% fetal bovine serum. Human gingival fibroblasts were used as a non-cancerous non prostatic control. The different culture conditions modulated cellular proliferation and the expression of several prostate markers, including PSA. The electrochemical biosensor was able to specifically detect PSA in the culture media and values obtained were similar to those achieved by a commercial Enzyme Linked Immunosorbent Assay (ELISA) kit, the most commonly used method for PSA quantification in prostate cancer diagnosis. Thus, the tested biosensor may represent a useful alternative as a diagnostic tool for PSA determination in biological samples. PMID- 26652467 TI - Surface treatment influences electrochemical stability of cpTi exposed to mouthwashes. AB - The role of surface treatment on the electrochemical behavior of commercially pure titanium (cpTi) exposed to mouthwashes was tested. Seventy-five disks were divided into 15 groups according to surface treatment (machined, sand blasted with Al2O3, and acid etched) and electrolyte solution (artificial saliva - control, 0.12% chlorhexidine digluconate, 0.05% cetylpyridinium chloride, 0.2% sodium fluoride, and 1.5% hydrogen peroxide) (n = 5). Open-circuit-potential and electrochemical impedance spectroscopy were conducted at baseline and after 7 and 14 days of immersion in each solution. Potentiodynamic test and total weight loss of disks were performed after 14 days of immersion. Scanning electron microscopy, energy dispersive spectroscopy, white light interferometry and profilometry were conducted for surface characterization before and after the electrochemical tests. Sandblasting promoted the lowest polarization resistance (Rp) (P b .0001) and the highest capacitance (CPE) (P b .006), corrosion current density (Icorr) and corrosion rate (P b .0001). In contrast, acid etching increased Rp and reduced CPE, independent to the mouthwash; while hydrogen peroxide reduced Rp (P b .008) and increased Icorr and corrosion rate (P b .0001). The highest CPE values were found for hydrogen peroxide and 0.2% sodium fluoride. Immersion for longer period improved the electrochemical stability of cpTi (P b .05). In conclusion, acid etching enhanced the electrochemical stability of cpTi. Hydrogen peroxide and sodium fluoride reduced the resistance to corrosion of cpTi, independent to the surface treatment. Chlorhexidine gluconate and cetylpyridinium chloride did not alter the corrosive behavior of cpTi. PMID- 26652468 TI - Interactions among biotic and abiotic factors affect the reliability of tungsten microneedles puncturing in vitro and in vivo peripheral nerves: A hybrid computational approach. AB - Tungsten is an elective material to produce slender and stiff microneedles able to enter soft tissues and minimize puncture wounds. In particular, tungsten microneedles are used to puncture peripheral nerves and insert neural interfaces, bridging the gap between the nervous system and robotic devices (e.g., hand prostheses). Unfortunately, microneedles fail during the puncture process and this failure is not dependent on stiffness or fracture toughness of the constituent material. In addition, the microneedles' performances decrease during in vivo trials with respect to the in vitro ones. This further effect is independent on internal biotic effects, while it seems to be related to external biotic causes. Since the exact synergy of phenomena decreasing the in vivo reliability is still not known, this work explored the connection between in vitro and in vivo behavior of tungsten microneedles through the study of interactions between biotic and abiotic factors. A hybrid computational approach, simultaneously using theoretical relationships and in silico models of nerves, was implemented to model the change of reliability varying the microneedle diameter, and to predict in vivo performances by using in vitro reliability and local differences between in vivo and in vitro mechanical response of nerves. PMID- 26652469 TI - Examination of a biodegradable magnesium screw for the reconstruction of the anterior cruciate ligament: A pilot in vivo study in rabbits. AB - The reconstruction of the anterior cruciate ligament is, for the most part, currently performed with interference screws made of titanium or degradable polymers. The aim of this study was to investigate the use of biodegradable magnesium interference screws for such a procedure because of their known biocompatibility and reported osteoconductive effects. The left tibiae of each of 18 rabbits were implanted with a magnesium-based (MgYREZr-alloy) screw, and another 18 with a titanium-based control. Each group was divided into observation periods of 4, 12 and 24weeks. After sacrifice, MUCT scans were acquired to assess the amount of the gas liberated and the degradation rate of the implant. Histological evaluations were performed to investigate the local tissue response adjacent to the implant and to assess the status of the attachment between the tendon and the bone tissue. The MUCT scans showed that liberation of gas was most prominent 4weeks after implantation and was significantly decreased by 24weeks. All screws remained in situ and formed a sufficient connection with the tendon and sufficient osseous integration at 24weeks. Histological evaluations showed neither inflammatory reactions nor necrosis of the tendon. The results of this pilot study in rabbits indicate that this magnesium-based interference screw should be considered as an alternative to conventional implant materials. PMID- 26652470 TI - A novel silica nanotube reinforced ionic incorporated hydroxyapatite composite coating on polypyrrole coated 316L SS for implant application. AB - An attempt has been made to deposit a novel smart ion (Sr, Zn, Mg) substituted hydroxyapatite (I-HAp) and silica nanotube (SiNTs) composite coatings on polypyrrole (PPy) coated surgical grade 316L stainless steel (316L SS) to improve its biocompatibility and corrosion resistance. The I-HAp/SiNTS/PPy bilayer coating on 316L SS was prepared by electrophoretic deposition technique. Potentiodynamic polarization and electrochemical impedance spectroscopy (EIS) studies were carried out. These results confirmed the significant improvement of the corrosion resistance of the 316L SS alloy by the I-HAp/SiNTs/PPy bilayer composite coating. The adhesion strength and hardness test confirmed the anticipated mechanical properties of the composite. A low contact angle value revealed the hydrophilic nature. Inductively coupled plasma-atomic emission spectroscopy (ICP-AES) was used for the leach out analysis of the samples. Added to this, the bioactivity of the composite was analyzed by observing the apatite formation in the SBF solution for 7, 14, 21 and 28days of incubation. An enhancement of in vitro osteoblast attachment and cell viability was observed, which could lead to the optimistic orthopedic and dental applications. PMID- 26652471 TI - Anodization parameters influencing the morphology and electrical properties of TiO2 nanotubes for living cell interfacing and investigations. AB - Nanotube structures have attracted tremendous attention in recent years in many applications. Among such nanotube structures, titania nanotubes (TiO2) have received paramount attention in the medical domain due to their unique properties, represented by high corrosion resistance, good mechanical properties, high specific surface area, as well as great cell proliferation, adhesion and mineralization. Although lot of research has been reported in developing optimized titanium nanotube structures for different medical applications, however there is a lack of unified literature source that could provide information about the key parameters and experimental conditions required to develop such optimized structure. This paper addresses this gap, by focussing on the fabrication of TiO2 nanotubes through anodization process on both pure titanium and titanium alloys substrates to exploit the biocompatibility and electrical conductivity aspects, critical factors for many medical applications from implants to in-vivo and in-vitro living cell studies. It is shown that the morphology of TiO2 directly impacts the biocompatibility aspects of the titanium in terms of cell proliferation, adhesion and mineralization. Similarly, TiO2 nanotube wall thickness of 30-40nm has shown to exhibit improved electrical behaviour, a critical factor in brain mapping and behaviour investigations if such nanotubes are employed as micro-nano-electrodes. PMID- 26652472 TI - Structure and mechanical properties of selected protective systems in marine organisms. AB - Marine organisms have developed a wide variety of protective strategies to thrive in their native environments. These biological materials, although formed from simple biopolymer and biomineral constituents, take on many intricate and effective designs. The specific environmental conditions that shape all marine organisms have helped modify these materials into their current forms: complete hydration, and variation in hydrostatic pressure, temperature, salinity, as well as motion from currents and swells. These conditions vary throughout the ocean, being more consistent in the pelagic and deep benthic zones while experiencing more variability in the nearshore and shallows (e.g. intertidal zones, shallow bays and lagoons, salt marshes and mangrove forests). Of note, many marine organisms are capable of migrating between these zones. In this review, the basic building blocks of these structural biological materials and a variety of protective strategies in marine organisms are discussed with a focus on their structure and mechanical properties. Finally, the bioinspired potential of these biological materials is discussed. PMID- 26652473 TI - Bioengineered silk scaffolds in 3D tissue modeling with focus on mammary tissues. AB - In vitro generation of three-dimensional (3D) biological tissues and organ-like structures is a promising strategy to study and closely model complex aspects of the molecular, cellular, and physiological interactions of tissue. In particular, in vitro 3D tissue modeling holds promises to further our understanding of breast development. Indeed, biologically relevant 3D structures that combine mammary cells and engineered matrices have improved our knowledge of mammary tissue growth, organization, and differentiation. Several polymeric biomaterials have been used as scaffolds to engineer 3D mammary tissues. Among those, silk fibroin based biomaterials have many biologically relevant properties and have been successfully used in multiple medical applications. Here, we review the recent advances in engineered scaffolds with an emphasis on breast-like tissue generation and the benefits of modified silk-based scaffolds. PMID- 26652474 TI - Fabrication of functional PLGA-based electrospun scaffolds and their applications in biomedical engineering. AB - Electrospun PLGA-based scaffolds have been applied extensively in biomedical engineering, such as tissue engineering and drug delivery system. Due to lack of the recognition sites on cells, hydropholicity and single-function, the applications of PLGA fibrous scaffolds are limited. In order to tackle these issues, many works have been done to obtain functional PLGA-based scaffolds, including surface modifications, the fabrication of PLGA-based composite scaffolds and drug-loaded scaffolds. The functional PLGA-based scaffolds have significantly improved cell adhesion, attachment and proliferation. Moreover, the current study has summarized the applications of functional PLGA-based scaffolds in wound dressing, vascular and bone tissue engineering area as well as drug delivery system. PMID- 26652475 TI - Volume Increases of the Gluteus Maximus, Gluteus Medius, and Thigh Muscles After Hip Arthroplasty. AB - BACKGROUND: Muscle atrophy in osteoarthritis (OA) patients is expected to recover after total hip arthroplasty (THA) because of the increase in activity levels. Although some reports have shown an increase in the thigh muscles (Th) after THA, no reports of increases in the gluteal muscles and of analyses of the factors related to muscle recovery have been published. In this study, the changes in the gluteal and Th volumes after THA were quantitatively evaluated using computed tomography (CT) images, and the factors related to muscle recovery were analyzed. METHODS: The subjects were 40 OA hips with CT images taken 3 weeks after THA (first postoperative [postop] CT) and more than 2 years after THA (second postop CT). The cross-sectional areas of gluteus maximus (G-max), gluteus medius (G med), and Th were measured in both CT images. The factors related to muscle recovery that were measured and evaluated were age, gender, days from operation, surgical approach, Kellgren-Lawrence grades, and hip functional score (Japanese Orthopaedics Association hip score). RESULTS: All measured cross-sectional areas of the operated side increased significantly from the first postop CT to the second postop CT (G-max, 40%; G-med, 11%; and Th, 20%). In the analysis of the factors related to muscle recovery, the increase rate of G-max correlated significantly with patient age, and the increase rate of G-med correlated significantly with the increase in Japanese Orthopaedics Association hip score. CONCLUSIONS: Hip OA can lead to atrophy of the gluteal and Th, but the muscle volume can recover more than 2 years after THA. PMID- 26652476 TI - Correlations Between Functional Knee Outcomes and Health-Related Quality of Life After Total Knee Arthroplasty in an Asian Population. AB - BACKGROUND: Current literature evaluating postoperative outcomes after total knee arthroplasty for osteoarthritis in the Asian population is sparse. We aimed to evaluate correlations between improvements in knee outcomes vs changes in generic health-related quality of life. METHODS: Postoperative outcomes were collected prospectively for 369 patients and compared at a 2-year follow-up using Short Form 36 (SF-36), Knee Society Score (KSS), and Oxford Knee Score (OKS). The Spearman correlation coefficient was used to evaluate the strength of correlation between changes in knee scores (KSS and OKS) vs changes in each domain of the SF 36 scores. RESULTS: All parameters achieved statistically significant improvements (P < .05) in postoperative scores at 2-year follow-up with the exception of general health (P = .221) component of SF-36. For KSS knee score, there was low correlation with bodily pain (0.32). For KSS function score, there was moderate correlation with physical functioning (0.57) and low correlation with role physical (0.31) and social functioning (0.36). For OKS, there was moderate correlation with physical functioning (0.61) and social functioning (0.54) and low correlation with role physical (0.38) and bodily pain (0.50). All other parameters of SF-36 showed little correlation (<0.3). CONCLUSION: Improvements in knee-specific outcomes (KSS and OKS) after total knee arthroplasty correlate well with improvements in physical domains of health related quality of life (SF-36) but poorly with the mental and social health domains. PMID- 26652478 TI - Asymmetric Synthesis of 1,2-Diamines bearing Tetrasubstituted Centers from Nonstabilized Azomethine Ylides and N-Sulfinylketimines under Bronsted Acid Catalysis. AB - The first asymmetric cycloaddition of nonstabilized azomethine ylide and N sulfinylimines is presented. In reactions with aryl-alkyl and heteroaryl-alkyl ketimines, excellent diastereoselectivities and good yields are obtained in all cases, regardless of the electronic character of the substituents at the aromatic rings. Moreover, the cycloadducts obtained can easily be deprotected in acid media, giving access to free 1,2-diamines which are prevalent in many natural and pharmaceutical products. PMID- 26652477 TI - Body Mass Index More Than 45 kg/m(2) as a Cutoff Point Is Associated With Dramatically Increased Postoperative Complications in Total Knee Arthroplasty and Total Hip Arthroplasty. AB - BACKGROUND: Higher body mass index (BMI) has been associated with postoperative complications in total knee arthroplasty (TKA) and total hip arthroplasty (THA). However, the association of incremental increases of BMI and its effects on postoperative complications has not been well studied. We hypothesize that there is a BMI cutoff at which there is a significant increase of the risk of postoperative complications. METHODS: We studied the American College of Surgeons National Surgical Quality Improvement Program from 2006 to 2013. The final cohort included 77,785 primary TKA and 49,475 primary THA subjects, respectively. Patients were separated into 7 groups based on BMI (18.5-24.9 kg/m(2), 25.0-29.9 kg/m(2), 30.0-34.9 kg/m(2), 35.0-39.9 kg/m(2), 40.0-44.9 kg/m(2), 45.0-49.9 kg/m(2), and >50.0 kg/m(2)). We analyzed data on five 30-day composite complication variables, including any complication, major complication, wound infection, systemic infection, and cardiac and/or pulmonary complication. RESULTS: The odds ratio for 4 (any complication, major complication, wound infection, and systemic infection) of 5 composite complications started to increase exponentially once BMI reached 45.0 kg/m(2) or higher in TKA. Similarly, the odds ratio in 3 (any complication, systemic infection, and wound infection) of 5 composite complications showed similar trends in THA patients. These findings were further confirmed with propensity score matching and entropy balancing. CONCLUSIONS: Our study suggested that there was a positive correlation between BMI and incidences of 30-day postoperative complications in both TKA and THA. The odds of complications increased dramatically once BMI reached 45.0 kg/m(2). PMID- 26652480 TI - Bioinformatics approach to predict target genes for dysregulated microRNAs in hepatocellular carcinoma: study on a chemically-induced HCC mouse model. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is an aggressive epithelial tumor which shows very poor prognosis and high rate of recurrence, representing an urgent problem for public healthcare. MicroRNAs (miRNAs/miRs) are a class of small, non-coding RNAs that attract great attention because of their role in regulation of processes such as cellular growth, proliferation, apoptosis. Because of the thousands of potential interactions between a single miR and target mRNAs, bioinformatics prediction tools are very useful to facilitate the task for individuating and selecting putative target genes. In this study, we present a chemically-induced HCC mouse model to identify differential expression of miRNAs during the progression of the hepatic injury up to HCC onset. In addition, we describe an established bioinformatics approach to highlight putative target genes and protein interaction networks where they are involved. RESULTS: We describe four miRs (miR-125a-5p, miR-27a, miR-182, miR-193b) which showed to be differentially expressed in the chemically-induced HCC mouse model. The miRs were subjected to four of the most used predictions tools and 15 predicted target genes were identified. The expression of one (ANK3) among the 15 predicted targets was further validated by immunoblotting. Then, enrichment annotation analysis was performed revealing significant clusters, including some playing a role in ion transporter activity, regulation of receptor protein serine/threonine kinase signaling pathway, protein import into nucleus, regulation of intracellular protein transport, regulation of cell adhesion, growth factor binding, and regulation of TGF-beta/SMAD signaling pathway. A network construction was created and links between the selected miRs, the predicted targets as well as the possible interactions among them and other proteins were built up. CONCLUSIONS: In this study, we combined miRNA expression analysis, obtained by an in vivo HCC mouse model, with a bioinformatics-based workflow. New genes, pathways and protein interactions, putatively involved in HCC initiation and progression, were identified and explored. PMID- 26652481 TI - Utility of Leflunomide in the Treatment of Drug Resistant Cytomegalovirus Retinitis. AB - PURPOSE: To describe leflunomide use in the treatment of drug resistant cytomegalovirus retinitis. Leflunomide has been shown to be effective in the treatment of systemic CMV viremia. METHODS: Retrospective chart review of patients with CMV retinitis treated with leflunomide. RESULTS: Two HIV-negative organ transplant recipients with UL 97 mutation resistant-genotype CMV were identified. Patient 1 developed CMV viremia post-kidney transplant and subsequently bilateral CMV retinitis. Retinitis progressed, despite intravitreal injection of ganciclovir and foscarnet, and IV foscarnet and oral valganciclovir. Retinitis control was achieved with the addition of oral leflunomide. Disease remained inactive for 22 months. Patient 2 developed CMV retinitis after lung transplant. Disease progressed despite intravitreal foscarnet injections and oral valganciclovir. Control of retinitis was achieved with addition of oral leflunomide, allowing cessation of intravitreal therapy. Disease remained inactive until his death. CONCLUSIONS: Leflunomide may be considered as a treatment option for resistant CMV retinitis. PMID- 26652482 TI - Design, synthesis and biological evaluation of pyrazolyl-nitroimidazole derivatives as potential EGFR/HER-2 kinase inhibitors. AB - A series of novel pyrazole-nitroimidazole derivatives had been arranged and evaluated for their EGFR/HER-2 tyrosine kinase inhibitory activity as well as their antiproliferative properties on four kinds of cancer cell lines (MCF-7, Hela, HepG2, B16-F10). The bioassay results showed most of the designed compounds exhibited potential antiproliferation activity, with the IC50 values ranging from 0.13MUM to 128.06MUM in four tumor cell lines. Among them, compound 5c exhibited remarkable inhibitory activity against EGFR/HER-2 tyrosine kinase with IC50 value of 0.26MUM/0.51MUM, respectively, comparable to the positive control erlotinib (IC50=0.41MUM for HER-2 and IC50=0.20MUM for EGFR) and lapatinib (IC50=0.54MUM for HER-2 and IC50=0.28MUM for EGFR). Molecular modeling simulation studies were performed in order to predict the biological activity of the proposed compounds and activity relationship (SAR) of these pyrazole-nitroimidazole derivatives. PMID- 26652483 TI - Discovery of 2-(4-sulfonamidophenyl)-indole 3-carboxamides as potent and selective inhibitors with broad hepatitis C virus genotype activity targeting HCV NS4B. AB - A novel series of 2-(4-sulfonamidophenyl)-indole 3-carboxamides was identified and optimized for activity against the HCV genotype 1b replicon resulting in compounds with potent and selective activity. Further evaluation of this series demonstrated potent activity across HCV genotypes 1a, 2a and 3a. Compound 4z had reduced activity against HCV genotype 1b replicons containing single mutations in the NS4B coding sequence (F98C and V105M) indicating that NS4B is the target. This novel series of 2-(4-sulfonamidophenyl)-indole 3-carboxamides serves as a promising starting point for a pan-genotype HCV discovery program. PMID- 26652484 TI - SILVER COATED PROSTHESIS IN ONCOLOGICAL LIMB SALVAGE SURGERY REDUCE THE INFECTION RATE. AB - Silver coatings, used in many surgical devices, have demonstrated good antimicrobial activity and low toxicity. Oncological musculoskeletal surgery have a high risk of infection, so in the last decades, silver-coated mega-prostheses have been introduced and are becoming increasingly widespread. In this study, a retrospective analysis of 158 cases of bone tumors, primary or metastatic, treated between 2005- 2015 with wide margins resection and tumor implants reconstruction, was performed. The average age was 59 years (range 11-78 years), the same surgeon with antibiotic prophylaxis according to a standard protocol treated all patients. Silver-coated prostheses were implanted in 58.5% of patients and uncoated tumor prostheses in the remaining 41.5%. Patients were re evaluated annually and complications were recorded, focusing analysis on infective complications. The average follow-up was 39.7 months: 23.4% of patients died at a median time of 35.3 months after surgery; 18.4% developed complications that required new surgery, of which 12.6% of these were due to infection. Patients treated with silver-coated implants developed early infection in 2.2% of cases against the 10.7% of the patients treated with standard tumor prosthesis. This difference between the two groups was statistically significant. The percentage of late infections occurring from 6 months after surgery was similar in both groups. Silver blood level taken in a sample of patients at different times after surgery, always showed values well below the threshold of toxicity and no patient showed any sign of local or general toxicity secondary to silver. Our study demonstrates that tumor silver-coated implants have a rate of early infection significantly lower than traditional implants, while there were no differences in the rate of late infections as described also in the literature. We recommend the use of silver?coated prosthesis as primary implants for limb salvage surgery in primary or metastatic bone tumors, considering the absence of toxicity and the lower rate of early infection. PMID- 26652486 TI - PTEN ELEVATION, AUTOPHAGY AND METABOLIC REPROGRAMMING MAY BE INDUCED IN HUMAN CHONDROCYTES DURING STEROIDS OR NUTRIENT DEPLETION AND OSTEOARTHRITIS. AB - The exact mechanisms controlling the development and progression of osteoarthritis have not yet been clarified. Our aim was to investigate new pathomechanisms, with an emphasis on novel molecular targets that might regulate human chondrocytes in osteoarthritis. As a model for studying cell survival and metabolism, C-28/I2 and T/C-28a4 human chondrocytes were grown in complete medium, in dex-tran-coated charcoal treated medium and in serum-free medium. Healthy and osteoarthritic human cartilage samples were obtained from discarded surgical material. Cell survival, PTEN, AKT, Beclin1, AMBRA, AMPK and glucose/triglyceride metabolism were evaluated by immunoblotting and spectro photometric assays. Starvation and steroids depletion decreased cell survival concomitantly with PTEN elevation, repression of the PI3K/AKT signaling axis and autophagy activation. These experimental conditions promoted the accumulation of glucose, decreased levels of G6PDH and resulted in differen-tial expression of OXPHOS complexes. Furthermore, they induced the expression of AMPK, reduced triglyceride levels and increased lipase activity, which was accompanied by a change in chondrocytes toward a fibroblast-like morphology. In osteoarthritic human cartilage, increased PTEN, AMPK and autophagy reflected the chondrocyte responses observed during starvation and steroids depletion. In conclusion, we defined the metabolic phenotype of human chondrocytes, in which both starvation and steroids depletion induce the activation of PTEN, AMPK and autophagy signaling, concomitant with metabolic reprogramming. Our data may aid in the development of novel in vitro models for the discovery and design of drugs or nutraceuticals capable of ameliorating the course of osteoarthritis. PMID- 26652487 TI - ENDOTHELIAL PROGENITOR CELL ADHESION, GROWTH AND CHARACTERIZATION ON TRABECULAR TITANIUM AND TRABECULAR TITANIUM COATED WITH COLLAGEN OR DECELLULARIZED ECM. AB - Adequate blood supply is essential for prosthesis osteointegration and bone healing as it supplies oxygen, nutrition and progenitor cells. The bone healing process and vascularization depend upon the endothelial cells, which speed up implant osteointegration. Endothelial Progenitor Cells (EPC) are a population of stem cells that can reproduce, migrate and acquire mature endothelial phenotype. Their recruitment occurs in the tissue lesion to enhance neovascularization. Trabecular TitaniumTM (TTTM) is a new biomaterial with very interesting biomechanical characteristics and fast osteointegration. This study has investigated adhesion, proliferation and characteristics of EPC on three types of biomaterial: unmodified trabecular titanium, trabecular titanium coated with the ECM deposited by human mesenchymal stem cells isolated from subcutaneous adipose tissue and decellularized and trabecular titanium coated with type I collagen (control scaffold). MTT assay showed similar percentages of EPCs seeded on the different kinds of scaffold: 67% on TT, 70% on decellularized scaffolds and 82% on collagen-coated scaffolds. There were no statistically significant differences between the three groups. We therefore conclude that TTTM allows EPC adhesion and proliferation and, consequently, by permitting vascularization, it favours prosthesis osteointegration. PMID- 26652488 TI - BIOPHYSICAL STIMULATION FOR NONUNIONS. AB - Nonunions account for 5-10% on the total number of fractures. Biophysical stimulation is a non-surgical, conservative, frequently used therapy in nonunions and a greater efficacy has been demonstrated for pulsed electromagnetic fields (PEMF). The mechanisms of action of PEMF at cellular and molecular levels are still under debate and no dose-response study is available. Moreover, the vast majority of in vitro studies were conducted on healthy cells. The primary aim of the research was to investigate the capacity of PEMF with different exposure times to stimulate the osteogenic process in cells from the callus of a nonunion patient. Another important objective was the characterization of nonunion cells in terms of clonogenicity, cluster of differentiation expression and the tri lineage differentiation capacity. Overall, the results indicated the presence of osteochondroprogenitor cells in the callus of a nonunion, with an impairment in the osteogenic differentiation process. PEMF may enhance cell viability, the formation of osteoid matrix and accelerate the process of osteogenic differentiation. BMP-4 production, TIMP1 and TIMP2 expression were influenced, as well as VEGFA, whose early upregulation may account for a possible improvement in both the osteogenic and vasculogenic processes. In conclusion, even with some discussed limitations, these preliminary data showed the presence of a multipotent progenitor population and suggested some hints of the effect of PEMF on nonunion cells. PMID- 26652489 TI - CELLULAR MECHANISMS OF BONE REGENERATION: ROLE OF WNT-1 IN BONE-MUSCLE INTERACTION DURING PHYSICAL ACTIVITY39. AB - Wnt1 is one of the several glycoproteins activating Wnt signaling, critical for normal skeletal development and bone homeostasis. Wnt1 was previously believed to solely regulate central nervous system development, in particular in midbrain and cerebellum. However, remarkable findings have recently shown that several patients affected by severe form of Osteogenesis Imperfecta (OI) display a Wnt1 mutation thereby revealing a possible role of Wnt1 in bone metabolism. Here, we show that recombinant Wnt1 (r-Wnt1) strongly increases differentiation of bone marrow stromal cells into mature osteoblasts, as demonstrated by the enhanced number of cells positively stained for alkaline phosphatase, one of the osteoblastic marker genes, whose mRNA levels are also significantly up-regulated. Furthermore, other osteogenic master genes such as Collagen I and Osteopontin are also enhanced when bone marrow precursors were differentiated toward osteoblastic phenotype in the presence of r-Wnt1. Intriguingly, by in vivo and in vitro findings, we report that in the bone marrow of mice subjected to physical activity there is a high endogenous Wnt1 synthesis compared to mice kept in resting conditions. Moreover, conditioned medium collected from ex vivo myoblasts, harvested from exercised mice, up-regulates Wnt1 expression in osteoblast cell cultures obtained from control mice. Overall our findings support the role of Wnt1 in regulating bone metabolism and suggest that this molecule could be one of the mediators through which physical activity may exert beneficial effect on bone. PMID- 26652490 TI - EFFECT OF PLATELET RICH PLASMA CONCENTRATION ON SKELETAL MUSCLE REGENERATION: AN EXPERIMENTAL STUDY. AB - Skeletal muscle injuries are common causes of severe long-term pain and physical disability, accounting for up to 55% of all sports injuries. The phases of the healing processes after direct or indirect muscle injury are complex but clearly defined and include well-coordinated steps: degeneration, inflammation, regeneration, and fibrosis. Despite this frequent occurrence and the presence of a body of data on the pathophysiology of muscle injuries, none of the current treatment strategies have shown to be really effective in strictly controlled trials. Platelet-rich plasma (PRP) is a promising alternative approach based on the ability of autologous growth factors (GFs) to accelerate tissue healing, improve muscular regeneration, increase neovascularization and reduce fibrosis. The present study is focused on the use of different concentrations of PRP as a source of GFs. Unilateral muscle lesions were created on the longissimus dorsi muscle of Wistar rats. Twenty-four h after surgical trauma, the lesion was filled with an intramuscular injection of PRP at 2 different concentrations. A group of rats were left untreated (controls). Animals were sacrificed at 3, 15 and 60 days from surgery. Histological, immunohistochemical and histomorphometric analyses were performed to evaluate muscle regeneration, neovascularization, fibrosis and inflammation. The PRP-treated muscles showed better muscle regeneration, more neovascularization and a slight reduction of fibrosis compared with the control muscles in a dose dependent manner. However, further studies also assessing pain and functional recovery are scheduled. PMID- 26652491 TI - HISTOLOGICAL FEATURES OF PSEUDOTUMOR AFTER SMALL HEAD DIAMETER METAL-ON-METAL TOTAL HIP ARTHROPLASTY. AB - The pathologic aspects of periprosthetic tissues in failed second-generation metal-on-metal (MoM) resurfacing hip arthroplasties have been widely described in terms of necrosis and inflammation. To our knowledge little data are reported on the association of this lesion with the use of small head diameter (less than 32 mm). In this study we present a small series of pseudo-tumor in small head metal on-metal total hip arthroplasty focusing our attention on the histologic aspects of the harvested pathologic tissue. The histological examination of our cases showed a presence of lymphocytic infiltrate suggesting a delayed hypersensitivity reaction to metal of type IV (ALVAL) but different to each other in terms of the prevalence of the cellular component. If macrophages are predominant, the pathogenetic mechanism seems to be the reaction against metallic particle. On the other hand, if granulocytes are predominant, it is possible to consider a hypersensitivity reaction. Our observation suggests that the evidence of Pseudotumor in case of small-head metal-on-metal arthroplasty should be considered with the same properties of big-head and therefore these patients should be followed scrupulously. PMID- 26652492 TI - PATHOLOGIC AND IMPENDING FRACTURES: BIOLOGICAL AND CLINICAL ASPECTS. AB - Bone metastases from carcinomas are epidemiologically rising because of the increased survival rate of oncologic patients, related to several factors such as improvement of primary and secondary screening, advancement of medical research and technology and the better understanding of mechanisms underlying bone metastases origination from primary tumor. Skeletal Related Events (SREs) can seriously affect quality of life in patients with metastatic disease. These events include the necessity of radiotherapy or bone surgery, malignant hypercalcemia, pathologic fractures and spinal cord compression. Among the SREs, pathologic fractures are the most disabling events and represent an emergency in these delicate patients. A pathologic fracture is defined as a fracture that occurs at the level of a pre-existing bone lesion (that is often a tumor), spontaneously or as the result of low-energy trauma (1). The pre-existence of the metastatic lesion in the bone, its evaluation and the assessment of progression can make these complications predictable and preventable. Pathologic fractures imply several severe consequences, including patient immobilization (in the case of fractures involving the lower limbs), loss of autonomy, anaemia, need of blood transfusion, discontinuation of medical therapies or radiotherapy and protracted hospitalization. Secondary effects of prolonged immobilization and loss of autonomy further lengthen this list of complications in patients who are already significantly limited in their activities. In the present paper, the authors present a review on the main aspects involved in bone metastastic disease: biology, quality of life, economic impact and survival. PMID- 26652493 TI - ASSESSING BONE MINERAL DENSITY IN ITALIAN ADULT CYSTIC FIBROSIS PATIENTS: A CROSS SECTIONAL STUDY. AB - The purpose of this study was to assess bone mineral density in a cystic fibrosis (CF) outpatient clinic population and to investigate the relationship between BMD and forced expiratory volume in one second (FEV1), DEXA T-scores and 25 hidroxivitamin D (25-OHD) serum levels. We examined a consecutive series of 44 CF patients. Bone mass density was measured by dual-photon X-ray absorptiometry of lumbar spine and femur (total and neck) and lung function was performed in all patients. Medication data were obtained from medical records. A correlation analysis was performed to determine the relationship between BMD and forced expiratory volume in one second (FEV1), DEXA T-scores and 25-hidroxivitamin D (25 OHD) serum levels. In the results, age showed a significant inverse correlation indicating that as the age increases, bone density decreases and we concluded that most CF patients have low BMD and that there is a positive correlation with lung function and an inverse correlation with age. PMID- 26652494 TI - VITAMIN D DEFICIENCY IN ADULTS: SEARCHING FOR THE PROPER LOADING DOSE. AB - Vitamin D is the main hormone regulating calcium phosphate homeostasis and mineral bone metabolism. Vitamin D deficiency is indeed extremely frequent in musculoskeletal diseases. Recent studies have shown that the treatment of osteoporosis needs to have an optimal vitamin D and calcium supplementation for its efficacy. Actually no agreement exists on the estabilished dose of vitamin D to administer in deficency states. We conducted a prospective study to develop a practical cholecalciferol loading dose regimen that would enable rapid correction of vitamin D deficiency. Sixty post-menopausal age woman were enrolled secondary to a fragility fracture (hip, vertebral, wrist) and screened for 25 hydroxyvitamin D (25(OH)D), calcium, and PTH at baseline (T0), after one month (T1), two months (T2), three months (T3) and six months (T4). Secondary to initial blood values of vitamin D patients were divided into 2 groups; the first group (group A, n=30) included patients with 25(OH)D values between 10-30 ng/ml and the second group (group B, n=30) with values under 10 ng/ml. Each group was then divided in 3 subgroups secondary to the randomized administered dose of 25(OH)D. By this, patients can alternatively receive 25000 UI two times monthly, 100000 UI monthly, 10000 UI (25 drops) weekly. The highest values of mean increase of 25(OH)D were observed in patients treated with 100000 UI. Patients treated with 10000 UI weekly did never achieve the target value. Additionally, as vitamin levels increased, pain intensity decreased. Vitamin D supplementation of 100000 UI monthly seems to be adequate to ensure that serum 25(OH)D values reach the threshold level; by this, it will confer the expected effects without risks of toxicity. PMID- 26652495 TI - OPTIMAL IMPROVEMENT IN FUNCTION AFTER TOTAL HIP AND KNEE REPLACEMENT: HOW DEEP DO YOU KNOW YOUR PATIENT?S MIND? AB - Osteoarthritis (OA) of the hip and knee causes pain and loss of joint mobility, leading to limitations in physical function. When conservative treatment fails total hip and knee replacement is a cost-effective surgical option. Patients have high expectations regarding functional outcome after these procedures. If such expectations are not met, they may still be dissatisfied with the outcome of a technically successful procedure. Recently, numerous studies reported that psychological factors can influence the outcome of total knee replacement (tkr) and total hip artrhoplasty with total hip replacement (thr). We conducted a prospective study on a consecutive sample of 280 patients affected by hip or knee OA who underwent total joint replacement. At patients? admission, Harris Hip Score (HHS) and Knee Society Score (KSS) were used to assess pain and function. Furthermore, SF-36, Mini-Mental Status Examination (MMSE), Symptom Checklist-90-R (SCL-90-R), Coping Orientation to Problems Experienced (BRIEF-COPE) and the Amsterdam Preoperative Anxiety and Information Scale (APAIS) were administered. Patients had clinical and radio graphical follow up at 1, 3 and 6 months post operatively. The HHS and KSS values before surgery showed a linear correlation with both SCL-90-R and MMSE. None of the investigated variables influenced post operative HHS and KSS scores; however, the improvement of functional scores resulted conditioned by SCL-90-R values, VAS score, schooling and MMSE. Psychological factors and mental status in primary total hip and knee replacement can affect outcome and patient satisfaction. Strategies focused on identification and facing of these conditions must be considered to improve outcome of total replacement. PMID- 26652496 TI - ANTIBIOTIC-LOADED REGENOSS FOR THE TREATMENT OF SEPTIC BONE DEFECTS: IN VITRO STUDY AND PRELIMINARY CLINICAL EXPERIENCE. AB - Bone and joint infections are a difficult to treat condition, often associated with bone loss. Although the management of septic bone defects may currently be achieved through various treatment modalities, there is a continuous need for bone substitutes able at the same time to favour bone repair and to provide local antibacterial protection. RegenOss, a biomimetic and resorbable bone substitute, has been previously shown to be highly biocompatible and osteoconductive. Aims of the present study were to test the in vitro ability of RegenOss to act as a local carrier of antibiotics and to investigate its clinical safety and efficacy in a continuous series of patients, affected by bone loss in active or previous infection. In vitro study was performed by adding vancomycin, levofloxacin or meropenem and assessing elution properties of RegenOss at fixed time intervals by means of a microbiological assay. At 48 hours, 98.5% of meropenem, 94.1% of levofloxacin and 76.3% of vancomycin were recovered in the medium, while all antibiotics were completely eluted at seven days. Clinical safety and efficacy of vancomicyn- or vancomicyn and meropenem-loaded RegenOss had been tested in 13 consecutive patients. After the surgical procedure, each patient underwent clinical, laboratory and radiographic evaluation at 3, 6, 12, 18 and 24 months. No adverse events associated with the use of RegenOss were observed. Twelve patients showed no infection recurrence and ten satisfactory bone healing at follow-up. In conclusion, this study shows the ability of RegenOss to act as local carrier when loaded with three different antibiotics with a complete elution in one week. The clinical use of antibiotic-loaded RegenOss appears safe in this preliminary clinical series, while larger studies are needed to confirm the efficacy of the intra-operative combination of this biomimetic bone substitute with various antibacterials in the treatment of septic bone defects. PMID- 26652497 TI - OSTEOARTICULAR ALLOGRAFTS IN PAEDIATRIC BONE TUMOR RECONSTRUCTION OF THE KNEE. AB - Osteoarticular allografts represent a reconstructive option after bone tumor resection around the knee in growing children. The major advantage is the chance to preserve the growth plate of the remaining bone, but the disadvantage is the high failure rate eventually requiring definitive prosthetic replacement at skeletal maturity. We retrospectively reviewed 22 patients who underwent osteoarticular allograft reconstructions of the distal femur (16) or proximal tibia (6). There were 12 females and 10 males with an average age at surgery of 11 years (7-15). The diagnosis was osteosarcoma in 19 cases and Ewing sarcoma in 3. All patients underwent pre- and post-operative chemotherapy. At an average follow-up of 103 months (12-167), 18 patients (82%) were alive and 4 had died (18%). We observed 10 allograft failures requiring prosthetic replacement, 6 in distal femur and 4 in proximal tibia reconstructions. At last follow-up 8 allografts (36%) were still in place. Overall allograft survival was 79.6% at five and 45.8% at ten years. In distal femur, allograft survival was 86.2% at five and 59.1% at ten years. In proximal tibia, allograft survival was 62.5% at 5 years and 31.2% at 67 months. Average limb shortening was 3 cm (0- 5) in 8 patients with the allograft still in situ and 2 cm (0-4) in 10 patients after prosthetic replacement. Average MSTS functional score of the whole series was 25 (83.7%). The MSTS score of patients after revision with prosthetic replacement was 24 (80%) while patients who still had the allograft retained had an average MSTS scores of 26.8 (89.3%). In conclusion, osteoarticular allograft reconstruction of the knee after bone tumor resection in pediatric age can be considered a temporary solution with the aim to limit limb length discrepancy before definitive prosthetic replacement after skeletal maturity. PMID- 26652498 TI - DOES TOTAL KNEE REPLACEMENT MODIFY FLEXION AXIS OF THE KNEE ON FRONTAL AND AXIAL PLANE REGARDLESS FROM LIMB ALIGNMENT? AB - The optimal reference for rotational positioning of femoral component in total knee replacement (TKR) is debated. Navigation has been suggested for intra-op acquisition of patient?s specific kinematics and functional flexion axis (FFA). The main purpose of the present study is to prospectively investigate whether pre operative FFA in patients with osteoarthritis (OA) and varus alignment changes after TKR and whether a correlation exists between post-op FFA and pre-op alignment. A navigated TKR was performed in 108 patients using a specific software to acquire passive joint kinematics before and after TKR. The knee was cycled through three passive range of motions (PROM), from 0 degrees to 120 degrees . FFA was computed using the mean helical axis algorithm. The angle between FFA and surgical TEA was determined on frontal (alphaf) and axial (alphaa) plane. The pre- and post-op hip-knee-ankle angle (HKA) was determined. Post-op FFA was different from pre-op FFA only on frontal plane. No significant difference was found on axial plane. No correlation was found between HKA-pre and alphaA-pre. A significant correlation was found between HKA-pre and alphaF?pre. The study concluded that TKR modifies FFA only on frontal plane. No difference was found on axial plane. Pre-op FFA is in a more varus position respect to TEA. The position of FFA on frontal plane is dependent on limb alignment. The present study has demonstrated TKR modifies the position of FFA only on frontal plane. The position of FFA on axial plane is not dependent on the amount of varus deformity and is not influenced by TKR. Level of evidence, IV, case series. PMID- 26652499 TI - PAIN MANAGEMENT AFTER TOTAL KNEE ARTHROPLASTY: THE GOOD, THE BAD AND THE UGLY. AB - Improvement in pain management after knee replacement surgery has made progress in the last years, improving the results of this type of operation. Among these techniques, multimodal have shown the best results. In this study we try to compare the results of a combination of intravenous analgesia (IA), oral controlled analgesia (OCA) and periarticular injection (PAI) with our traditional protocol consisting in intravenous analgesia and femoral nerve block (IA/FNB). ne hundred patients, undergoing primary unilateral total knee arthroplasty between June 2014 and June 2015 were randomized into 2 groups. Mean patient age was 69.4. The first group received the intravenous analgesia combined with continuous femoral nerve block, while the second group received the new combined protocol. We used the same technique with standard medial parapatellar approach for all patients and they all received pre-emptive analgesia and postoperative pain protocols. All patients were interviewed daily postoperatively at 3 days, at discharge and at 3 months. The 2 groups had a similar discharge period (traditional group 7.3 days, combined group 6.9 days). In both groups, the results indicated no statistical difference in regards to rest and continuous passive movement. Pain on ambulation was the only category that was statistically lower in the PAI/IA/OCA group compared to traditional group. PMID- 26652500 TI - BIOTECHNOLOGIES AND BIOMATERIALS IN SPINE SURGERY. AB - Over the past few decades, spine disorders have become a major health concern and the number of spinal surgical procedures has been rising significantly. Several biotechnologies and biomaterials are often used in spine surgery to increase the effectiveness of the treatment. In the degenerative spine, when conservative treatment is ineffective the most recommended surgical procedure is decompression followed by spinal fusion. Success rates of spine fusion extensively rely on bone grafts peculiar properties. Autograft has been considered the gold standard to achieve a solid fusion but current research is focused on the development of new biomaterials. Osteoporosis is the main cause of vertebral compression fractures that are significantly associated with pain and disability, especially in the aging population. Vertebral augmentation is a minimally invasive approach in which cement is injected into the vertebral body to stabilize the fracture. New cements are being developed in the clinical scenario with reabsorbable properties and biomechanical features more similar to the native bone. The development of disc regeneration strategies such as nucleus pulposus restoration and annulus fibrosus repair may represent a minimally invasive procedure towards regeneration rather than fusion. Therefore, biomaterials and tissue engineering are fields of growing interest among both surgeons and manufacturing companies, with a major involvement in spine surgery. This review discusses current and novel biotechnologies and biomaterial used in spine surgery employing fusion, augmentation and regeneration. PMID- 26652501 TI - Bioinspired Interfaces with Superwettability: From Materials to Chemistry. AB - Superwettability is a special case of the wetting phenomenon among liquids, gases, and solids. The superhydrophobic/superhydrophilic effect discovered initially has undergone a century of development based on materials science and biomimetics. With the rapid development of research on anti-wetting materials, superoleophobic/superoleophilic surfaces have been fabricated to repel organic liquids besides water. Further studies of underwater superoleophobic/superoleophilic/superaerophobic/superaerophilic materials provide an alternative way to fabricate anti-wetting surfaces rather than lowering the surface energy. Owing to a series of efforts on the studying of extreme wettabilities, a mature superwettability system gradually evolved and has since become a vibrant area of active research, covering topics of superhydrophobicity/superhydrophilicity, superoleophobicity/superoleophilicity in gas or under liquid, superaerophobicity/superaerophilicity under liquid, and combinations of these states. The kinetic study of the superwettability system includes statics and dynamics, while the studied material structures range from traditional two-dimensional materials to three-dimensional, one-dimensional, and zero-dimensional materials. Furthermore, the wetting liquids range from water to oil, aqueous solutions, and ionic liquids, as well as liquid crystals and other types of liquids. The wetting conditions extend over a wide range of temperatures, pressures, and other external fields. With the development of this series of research, many new theories and functional interfacial materials have been fabricated, including self-cleaning textiles, oil/water separation systems, and water collection systems, and some of these have already been applied in industry. Moreover, the study of superwettability has also introduced many new phenomena and principles to the field of interfacial chemistry that display its vast potential in both materials and chemistry. The present Perspective aims to summarize the most recent research on these materials and their interfacial chemistry. An overview of novel materials in superwettability systems and interfacial materials is presented. Specifically, the evolution of superwettable materials will be introduced, and the fundamental rules for building these superwetting materials will be discussed, followed by a summary of recent progress in the application of superwettable materials to alter the behaviors of chemical reactants and products. Specific emphasis is placed on recent strategies that exploit superwettable materials to influence the performance of traditional chemical reactions and their unique contributions to chemistry, including the effective collection of reaction products, unique growth models of precipitates, and a simple strategy for the alignment/assembly of nanoscale building blocks. Finally, a short perspective is provided on the potential for future developments in the field. PMID- 26652502 TI - Phthalimide Compounds Containing a Trifluoromethylphenyl Group and Electron Donating Aryl Groups: Color-Tuning and Enhancement of Triboluminescence. AB - Trifluoromethylphenyl-substituted phthalimide derivatives favorably form triboluminescence (TL) active noncentrosymmetric crystals. Oligothienyl-, oligophenyl-, and naphthyl-substituted phthalimide derivatives were successfully developed as a series of metal free TL compounds. X-ray crystal structure analyses of bithienyl and naphthyl derivatives revealed noncentrosymmetric layer structures in the same direction. Introduction of suitable electron rich pi-units such as thienyl groups enhances their photoluminescence and TL characteristics, and the colors can be also controlled in the visible region. A rigid naphthyl substituted imide derivative exhibits extremely high TL performance. PMID- 26652503 TI - Analysis of noise pollution in an andesite quarry with the use of simulation studies and evaluation indices. AB - This paper presents the verification of two partial indices proposed for the evaluation of continuous and impulse noise pollution in quarries. These indices, together with the sound power of machines index and the noise hazard index at the workstation, are components of the global index of assessment of noise hazard in the working environment of a quarry. This paper shows the results of acoustic tests carried out in an andesite quarry. Noise generated by machines and from performed blasting works was investigated. On the basis of acoustic measurements carried out in real conditions, the sound power levels of machines and the phenomenon of explosion were determined and, based on the results, three dimensional models of acoustic noise propagation in the quarry were developed. To assess the degree of noise pollution in the area of the quarry, the continuous and impulse noise indices were used. PMID- 26652504 TI - Phase-dependent changes in local dynamic stability during walking in elderly with and without knee osteoarthritis. AB - Previously, we reported reduced time-averaged knee local stability, in the unaffected, but not the affected leg of elderly with knee osteoarthritis OA compared to controls. Since stability may show phase-related changes, we reanalyzed the dataset reported previously using time-dependent local stability, lambda(t), and also calculated time-averaged local stability, lambdas, for comparison. We studied treadmill walking at increasing speeds, focusing on sagittal plane knee movements. 16 patients, 12 healthy peers and 15 young subjects were measured. We found a clear maximum in lambda(t) (i.e. minimum in stability) at around 60% of the stride cycle (StanceMax lambda(t)), a second clear maximum (SwingMax lambda(t)) at around 95% followed by a minimum between 70% and 100% (SwingMin lambda(t)). StanceMax lambda(t) of both legs was significantly higher in the OA than the young control group. Values for healthy elderly fell between those of the other groups, were significantly higher than in young adults, but there was only a trend towards a significant difference with the StanceMax lambda(t) of the OA group's affected side. Time-averaged and time dependent stability measures within one leg were uncorrelated, while time dependent stability measures at the affected side were inversely correlated with lambdas at the unaffected side. The results indicate that time-dependent local dynamic stability might provide a more detailed insight into the problems of gait stability in OA than conventional averaged local dynamic stability measures and support the notion that the paradoxical decline in unaffected side time-averaged local stability may be caused by a trade-off between affected and unaffected side stability. PMID- 26652505 TI - Accuracy evaluation of a lower-cost and four higher-cost laser scanners. AB - Knowing the accuracy of laser scanners is imperative to select the best scanner to generate bone models. However, errors stated by manufacturers may not apply to bones. The three objectives of this study were to determine: 1) whether the overall error stated by the manufacturers of five laser scanners was different from the root mean squared error (RMSE) computed by scanning a gage block; 2) the repeatability of 3D models generated by the laser scanners when scanning a complex freeform surface such as a distal femur and whether this differed from the repeatability when scanning a gage block; 3) whether the errors for one lower cost laser scanner are comparable to those of four higher-cost laser scanners. The RMSEs in scanning the gage block were 2 to 52um lower than the overall errors stated by the manufacturers. The repeatability in scanning the bovine femur 10 times was significantly worse than that in scanning the gage block 10 times. The precision of the lower-cost laser scanner was comparable to that of the higher cost laser scanners, but the bias was an order of magnitude greater. The contributions of this study are that 1) the overall errors stated by the manufacturers are an upper bound when simple geometric objects like a gage block are scanned, 2) the repeatability is worse on average three times when scanning a complex freeform surface compared to scanning the gage block, and 3) the main difference between the lower-cost and the higher-cost laser scanners is the bias. PMID- 26652506 TI - Fatty liver in adults receiving antiepileptic medications: relationship to the metabolic risks. AB - This study aimed to determine the frequency of fatty liver disease (FLD) induced by antiepileptic drugs (AEDs) and its relationship to the metabolic profile. This study included 130 patients (valproate or VPA = 75; carbamazepine or CBZ = 40; lamotrigine or LTG = 15). Liver ultrasonography (US) was done. Serum lipids, uric acid, free fatty acids (FFAs), glucose, insulin and leptin were measured. Compared to controls and patients on CBZ or LTG, higher BMI; TC, TG, LDL-c, uric acid, FFAs, glucose, insulin and leptin concentrations and enlarged liver lobes volume and span and insulin resistance (45%) were reported with VPA. With FLD, significant correlations were reported between BMI with leptin (r = 0.390;p < 0.01), insulin (r = 0.655;p < 0.001) and FFAs (r = 0.570;p < 0.001) and insulin with leptin (r = 0.355;p < 0.01). In multivariate analysis, with FLD, liver span was correlated with BMI (OR:4.50;95%CI:1.54-13.3,p = 0.01) and leptin concentrations (OR:2.55;95%CI:1.04-6.27,p = 0.045). We conclude that VPA therapy is a risk for FLD and is correlated with the associated adverse metabolic profile. PMID- 26652507 TI - 50th Anniversary Perspective on Volume 1: Effler DB, Favaloro R, Groves LK. Heart Valve Replacement: Clinical Experience. Ann Thorac Surg 1965;1:4-24. PMID- 26652508 TI - 50th Anniversary Landmark Commentary on Tribble CG, Killinger WA Jr, Harman PK, Crosby IK, Nolan SP, Kron IL. Anterolateral thoracotomy as an alternative to repeat median sternotomy for replacement of the mitral valve. Ann Thorac Surg 1987;43:380-2. PMID- 26652509 TI - 50th Anniversary Landmark Commentary on Reed CE, Parker EF, Crawford FA Jr. Surgical resection for complications of pulmonary tuberculosis. Ann Thorac Surg 1989;48:165-7. PMID- 26652510 TI - 50th Anniversary Landmark Commentary on Edwards FH, Clark RE, Schwartz M. Coronary artery bypass grafting: The Society of Thoracic Surgeons National Database experience. Ann Thorac Surg 1994;57:12-9. PMID- 26652511 TI - Scholarship in Education: The Clarion Call. PMID- 26652512 TI - From Open Operations to Nonintubated Uniportal Video-Assisted Thoracoscopic Lobectomy: Minimizing the Trauma to the Patient. PMID- 26652513 TI - Invited Commentary. PMID- 26652514 TI - Invited Commentary. PMID- 26652515 TI - Invited Commentary. PMID- 26652516 TI - Invited Commentary. PMID- 26652517 TI - Invited Commentary. PMID- 26652518 TI - Invited Commentary. PMID- 26652519 TI - Invited Commentary. PMID- 26652520 TI - Invited Commentary. PMID- 26652521 TI - Invited Commentary. PMID- 26652522 TI - Expandable Valve for Pediatric Application Constructed From Human Venous Valved Conduit Within a Stent. AB - PURPOSE: Options for pediatric valve replacement are limited by inability to adapt to child growth. An expandable valve design is presented in which human cryopreserved venous valved conduits are constructed within a bare-metal stent scaffold. We demonstrate functionality in vitro and acute competence in vivo. DESCRIPTION: A cryopreserved femoral venous valved conduit was compressed within a bare-metal stent scaffold and sutured at the proximal and distal ends. In vitro testing was performed at low and high pressure after sequential balloon expansion. Valve morphology was measured in the nondistended state. The construct was tested in 2 patients. EVALUATION: In vitro testing confirmed competence of the 14-mm femoral valve construct at 10-mm to 14-mm diameters. The median leaflet commissural height-to-diameter ratio was 2.2 (range, 1.6 to 4.1) for femoral. The construct was implanted in 2 patients at internal diameters of 6 mm and 8 mm. Echocardiograms demonstrated competence at short-term follow-up. In 1 patient, competence was demonstrated after balloon expansion. CONCLUSIONS: This study demonstrates the feasibility of this expandable valve design using an allograft venous valved conduit compressed within a stent. PMID- 26652523 TI - Expanded Polytetrafluoroethylene for Chordal Replacement: Preventing Knot Failure. AB - PURPOSE: Expanded polytetrafluoroethylene suture is commonly used for chordal replacement in mitral valve repair, but due to material characteristics, knots can unravel. Our aim was to determine the knot security, including how many throws are necessary to prevent knot failure, with Gore-Tex (W.L. Gore and Associates, Elkton, MD) and the newly available Chord-X (On-X Life Technologies Inc, Austin, TX). DESCRIPTION: Knots were evaluated for maximal load based on: number of throws (6, 8, 10, and 12), tension to secure each throw (10%, 50%, and 85%) and suture type (Gore-Tex CV-5 and Chord-X 3-0). A physiologic force of 2 N was used for comparison. EVALUATION: We evaluated 240 knots. For all knots, the mean load to failure was 11.1 +/- 5.8 N. Failure occurred due to unraveling in 141 knots (59%) at 7.1 +/- 4.1 N and to breaking in 99 (41%) at 16.7 +/- 2.0 N (p < 0.01). Gore-Tex failed at higher loads (12.6 +/- 6.0 N vs 9.5 +/- 5.2 N, p < 0.01); however, an equivalent number, 6 Gore-Tex and 6 Chord-X, unraveled at 2 N, all with fewer than 10 throws. CONCLUSIONS: Expanded polytetrafluoroethylene has adequate strength to prevent breakage; however, a risk of knot unraveling at physiologic conditions exists when fewer than 10 throws are performed. PMID- 26652524 TI - Prolonged Use of the Hemolung Respiratory Assist System as a Bridge to Redo Lung Transplantation. AB - Although extracorporeal membrane oxygenation (ECMO) has been used frequently as a bridge to primary lung transplantation, active centers are conservative with this approach in patients requiring redo lung transplantation. We report the use of extracorporeal carbon dioxide removal, using the Hemolung respiratory assist system, as a prolonged bridge to lung transplantation, and the first use of the Hemolung as a bridge to redo lung transplantation. Hemolung support improved the patient's clinical status and allowed redo lung transplantation. PMID- 26652525 TI - Primary Ectopic Mediastinal Goiter in a Patient With Crohn's Disease Presenting as Myasthenia Gravis. AB - Mediastinum is an uncommon location for ectopic goiter. Primary ectopic mediastinal goiter has been reported to present mostly with compressive symptoms. We report a case of a 62-year-old man with history of Crohn's disease, who presented with symptoms of myasthenia gravis and was found to have an anterior mediastinal mass. The mass was resected completely with successful outcome. On histopathologic examination this mass turned out to be colloid goiter. This is an extremely rare presentation of a primary ectopic mediastinal goiter. PMID- 26652526 TI - Minimally Invasive Tracheal Resection: Cervical Approach Plus Video-Assisted Thoracoscopic Surgery. AB - Tracheal resection for adenoid cystic carcinoma (ACC) is a well-documented procedure. Surgical resection of these lesions offers patients the greatest potential chance of survival. Midtracheal tumors are usually resected through a maximally invasive sternotomy or thoracotomy. We report a midtracheal resection of a symptomatic ACC in a 25-year-old man by video-assisted thoracoscopic hilar release and suprasternal anastomotic approaches. The patient's recovery was complicated by chylothorax and pneumonia. PMID- 26652527 TI - Disseminated Pleural Siliconoma Mimicking Malignant Pleural Mesothelioma. AB - A 48-year-old woman with a 3-month history of back pain was admitted for further examination of multiple left pleural nodules. She had undergone bilateral breast augmentation with silicone implants 10 years previously. Nine years after the operation, both ruptured implants were removed, and autologous fat was injected. Computed tomography revealed multiple pleural nodules suggestive of malignant pleural mesothelioma. Thoracoscopic exploration revealed multiple pleural nodules with massive pleural adhesions. The nodules were filled with viscous liquid and were histologically determined to be siliconomas. Disseminated pleural siliconoma should be recognized as a late adverse event of silicone breast implantation. PMID- 26652528 TI - Giant Solitary Fibrous Tumor of Esophagus Resected by Endoscopic Submucosal Dissection. AB - Solitary fibrous tumor is one of the most common soft tissue benign tumors that occur in adults, but it rarely occurs in the gastrointestinal tract and even more infrequently occurs in the esophagus. Only 4 cases of esophageal solitary fibrous tumors have been reported in PubMed using the search terms "solitary fibrous tumor" and "esophagus". These cases were all treated using surgical methods. Thus, we report a case of primary solitary fibrous tumor of the esophagus treated by endoscopic submucosal dissection. Endoscopic submucosal dissection was well tolerated in this patient, suggesting that it may be a therapeutic option for primary giant esophageal neoplasms. PMID- 26652529 TI - Splenic Rupture Caused by Giant Paraesophageal Hernia. AB - Splenic hemorrhage secondary to retching and vomiting from incarceration of paraesophageal hernia is a rare but life-threatening complication. Clinicians need to be aware of this complication in the event of sudden unexplained hemodynamic instability. Surgical intervention for the hernia is best performed as soon as possible once the patient is stabilized, before complications such as perforation or further bleeding occur. We report two cases of splenic rupture and intraperitoneal bleeding resulting from traction of the gastrosplenic pedicle associated with retching and vomiting from a giant paraesophageal hernia. PMID- 26652530 TI - Anomalous Origin of Coronary Artery From Main Pulmonary Artery in Hypoplastic Left Heart Syndrome. AB - We report a case of anomalous origin of the left anterior descending coronary artery (LAD) from the main pulmonary artery in a child with hypoplastic left heart syndrome (mitral atresia/aortic atresia). Mechanical circulatory support was necessary because of the inability to wean from cardiopulmonary bypass after the Norwood procedure. The patient died at 4 months of age having continued depressed right ventricular function. The diagnosis was made during a catheterization performed 6 weeks after surgery because of concern for stenosis of Blalock-Taussig shunt. We believe his prolonged postoperative recovery and eventual demise can partially be attributed to lack of cardioplegia to the anomalous LAD territory during surgery. PMID- 26652531 TI - Resection of Carcinoid Tumor Metastatic to the Right Ventricle and Tricuspid Valve. AB - Carcinoid tumors rarely metastasize to the heart, and previous reports involved the myocardium only. We present a case of carcinoid tumor metastatic to the right ventricle (RV) and tricuspid valve. Preoperative cardiac magnetic resonance imaging (CMR) showed the tumor arising from the right ventricular free wall and involving the tricuspid valve apparatus. The tumor was resected through a right atriotomy and required tricuspid valve replacement. PMID- 26652532 TI - Neo-Left Atrium Construction on the Beating Heart After Extirpation of a Huge Mediastinal Tumor Invading Heart and Lung. AB - We report on construction of a neo-left atrium (LA) with 2 bovine pericardial patches after in toto removal of a huge mediastinal tumor invading the heart and lung. The procedure was performed on the beating heart using normothermic cardiopulmonary bypass (CPB) without cardioplegic arrest. Treatment consisted of tumor removal necessitating left pneumonectomy, excision of the LA, resection of the mitral annulus, excision of the tumor from the left ventricle, and construction of a new LA using 2 bovine pericardial patches and a new mitral bioprosthesis. Histologic examination revealed myofibrosarcoma. The patient died 22 months after the operation. PMID- 26652534 TI - Sequential Management of Coexisting Aorta-to-Pulmonary and Coronary-to-Pulmonary Vein Fistulae. AB - In a 42-year-old man who presented with exertional dyspnea, a large fistula between the pulmonary vein and the left circumflex artery, and multiple aorta-to pulmonary vein fistulae, were observed on coronary computed tomographic and magnetic resonance angiograms. Surgical ligation of the coronary artery-to pulmonary vein fistula and coil embolization for two aorta-to-pulmonary vein fistulae were performed sequentially. The patient's symptoms were relieved after fistula occlusion and recovery of hemodynamic values. PMID- 26652533 TI - Single-Stage Minimally Invasive Surgery for Synchronous Primary Pulmonary Adenocarcinoma and Left Atrial Myxoma. AB - We report the first successful short-term outcome of single-stage combined video assisted thoracoscopic surgery lobectomy and port access surgery in a patient with operable primary right lower lobe adenocarcinoma and a synchronous cardiac myxoma. The video-assisted thoracic surgery right lower lobectomy with systematic lymph node dissection was performed first, followed by myxoma excision by port access surgery through the same working port incision. The histopathologic analysis confirmed a pT2a N0 M0 R0 (TNM 7th edition) primary poorly differentiated pulmonary adenocarcinoma and a completely excised cardiac myxoma. Postoperative recovery was uneventful, and follow-up at 6 weeks confirmed an excellent surgical and oncologic outcome. PMID- 26652535 TI - Anomalous Aortic Origin of the Left Coronary Artery From the Right Coronary Sinus: Diagnosis and Surgical Repair of Intramural Retrovalvular Coronary Artery. AB - Anomalous aortic origin of the left coronary artery from the right coronary sinus is a rare congenital anomaly that may cause sudden death. Direct translocation of the left coronary artery could be difficult due to its intramural course and proximity to the aortic valve. We described the surgical management of a child after sudden hemodynamic collapse and the coronary translocation technique that prevented distortion of the aortic root and allowed successful translocation of the abnormal coronary artery despite its intramural course immediately behind the aortic valve commissure. PMID- 26652536 TI - Neonatal Repair in a Patient With Heterotaxy, Truncus Arteriosus, Pulmonary Artery Sling, and Tracheal Stenosis. AB - We present a newborn with heterotaxy features, multiple congenital anomalies, truncus arteriosus with long segment tracheal stenosis, and a left pulmonary artery sling. The patient had complete neonatal repair with slide tracheoplasty and repair of the left pulmonary artery sling with anterior translocation of the pulmonary artery. The truncus was repaired with a transventricular ventricular septal defect closure with a patch and right ventricle to pulmonary artery conduit. Complete repair of complex cardiac neonatal lesions with critical tracheal stenosis is feasible and should be the strategy of choice in these complex patients. PMID- 26652537 TI - Aortic Surgical Emergencies in Young Children With Loeys-Dietz Syndrome. AB - Loeys-Dietz syndrome presents early in life with rapidly progressive aortic aneurysmal disease. Aortic emergency in young children with Loeys-Dietz syndrome is an extremely rare occurrence. In this communication we report on 2 young children whose diagnoses were missed and consequently underwent urgent aortic repair due to aortic emergencies. For personalized management of aortic disease in Loeys-Dietz syndrome patients, when and how do we intervene? PMID- 26652538 TI - One-Stage Hybrid Procedure to Treat Aortic Coarctation Complicated by Intracardiac Anomalies in Two Adults. AB - The traditional approach for treating aortic coarctation with intracardiac anomalies in adults is surgery using 2 surgical incisions or a two-stage hybrid method with a peripheral artery pathway that requires intervention. This paper reports a one-stage hybrid procedure to treat this type of congenital heart disease using 1 surgical incision combined with an ascending aorta puncture intervention approach as transaortic intervention approach. Here, we present 2 aortic coarctation cases; 1 complicated by ventricular septal defect and patent ductus arteriosus, and another complicated by an incomplete atrioventricular septal defect and mitral valve cleft. Both were successfully treated by our one stage hybrid approach. PMID- 26652539 TI - Ectopic Pancreas in Mediastinum Presenting as Hemoptysis. PMID- 26652540 TI - External Compression of Right Coronary Cleft Resulting From ECMO Cannula Causing Refractory Ventricular Fibrillation: An Unusual Adverse Event. PMID- 26652541 TI - Nonanastomotic Rupture of a Woven Polyester Graft Caused by a Tacking Stitch After Aortic Arch Replacement. PMID- 26652542 TI - The Ring of the Aortas: The Silent Variation. PMID- 26652543 TI - Reverse-Puncture Anastomotic Technique for Minimally Invasive Ivor-Lewis Esophagectomy. AB - We used a reverse-puncture anastomotic technique in a total minimally invasive Ivor-Lewis esophagectomy. In the operation, a needle with a wire passed through the puncture head of the anvil of a circular stapler was used to make a fixed knot. In the proximal esophagus, the tissue was hemitransected, and the anvil was then inserted into the esophagus. The needle was then pulled from the inner to the anterior wall of the esophagus. After the wire was tightened, the center rod of the anvil was removed. After closure of the esophageal stump, the intrathoracic esophagogastrostomy was completed. PMID- 26652544 TI - Modified Transverse Thoracosternotomy and Cost-Effective Reinforced Sternal Closure. AB - The bilateral transverse thoracosternotomy clamshell incision provides excellent exposure to the mediastinal structures in double lung transplantation. The use of a modified transverse sternotomy and a figure of 8 configuration with one monofilament metal wire, along with two longitudinal wires across the sternal division, results in greater stability and equally distributed oblique tension. Our described technique was more cost effective and resulted in no incidence of dehiscence. We present our experience using a modified transverse sternotomy and reinforced sternal closure method. PMID- 26652545 TI - Removal of Retained Pacing Leads With Vena Caval Inflow Occlusion When Cardiopulmonary Bypass Is Contraindicated. AB - Treatment of infected pacing leads ranges from percutaneous extraction to surgical removal with the use of cardiopulmonary bypass (CPB). Vena caval inflow occlusion (VCIO) is an old technique that has been used with success in the pediatric population. We report on the use of inflow occlusion (IO) in removing infected pacing leads from the right side of the heart in patients in whom endovascular lead extraction failed. VCIO is a safe and simple technique in patients with infected leads who have contraindications for CPB. PMID- 26652546 TI - Distal Dunk for Right Ventricle to Pulmonary Artery Shunt in Stage 1 Palliation. AB - The use of a right ventricle-to-pulmonary artery (RV-PA) conduit for stage 1 palliation of hypoplastic left heart syndrome is common. A prospective randomized multiinstitutional study revealed that approximately 40% of those receiving this shunt required intervention on the shunt or pulmonary arteries, or both. A technique has been developed to help ameliorate proximal conduit stenosis. We present a new technique to improve distal conduit stenosis and decrease anastomotic bleeding from this site. The technique involves dunking a segment of the shunt into the pulmonary arteries and suture placement in the shunt rings and not in the polytetrafluoroethylene (PTFE). PMID- 26652547 TI - Dr Anthony Dobell, Legendary McGill Trailblazer: May 7, 1927, to June 17, 2015. AB - Anthony R. C. Dobell died on June 17, 2015, at the age of 88. Dobell was the first Canadian president of the Society of Thoracic Surgeons. He was a pioneer in the development of pediatric and adult cardiac surgery at McGill University. He was inspired by Dr John Gibbon during his residency training at Jefferson Medical College in Philadelphia. He developed a McGill-based residency in Cardiothoracic Surgery and always took pride in the legacy of more than 40 residents scattered throughout North America. PMID- 26652548 TI - Experience From the Inaugural TSRA Traveling Fellowship Award. PMID- 26652549 TI - Meta-Analysis of Survival in Mesothelioma: Can We Mix Apples and Oranges? PMID- 26652550 TI - Reply: To PMID 7436618. PMID- 26652551 TI - When and How Should Subcentimetric Lung Nodules Be Referred for Operation? PMID- 26652552 TI - Reply: To PMID 25825199. PMID- 26652553 TI - Postresectional Airway Fistula Occlusion via Stem-Cell Transplantation: Is It Oncologically Safe? PMID- 26652554 TI - Pain Control With Liposomal Bupivacaine After Thoracoscopies/Thoracotomies. PMID- 26652555 TI - Reply: To PMID 24370201. PMID- 26652556 TI - The Potential of Personalized External Aortic Root Support (PEARS) to Restore and Maintain Aortic Valve Competence. PMID- 26652557 TI - Reply: To PMID 25841843. PMID- 26652558 TI - Is a Robotic Operation Safe for Mitral Valve Repair? PMID- 26652559 TI - Simultaneous Carotid Artery Stenting and Heart Surgery: The Risk of Bleeding. PMID- 26652560 TI - Tricuspid Regurgitation Secondary to Severe Pulmonary Regurgitation: When to Operate on Which Valves? PMID- 26652561 TI - Reply: To PMID 25886809. PMID- 26652562 TI - Pulmonary Valve Replacement: What Did We Learn? PMID- 26652563 TI - Reply: To PMID 25483002. PMID- 26652564 TI - Role of Pericardiectomy in Postcardiac Transplant Constrictive Pericarditis. PMID- 26652566 TI - Right Lower Lobe Superior Segmentectomy in a Patient With a Displaced Bronchus. AB - An 81-year-old woman with adenocarcinoma in the lower superior segment of the right lung underwent superior segmentectomy of the right lower lobe through a thoracotomy. Preoperatively, we detected an anomalous B10c bronchus branching from the right lower superior segment bronchus with multiplanar reconstruction computed tomography and virtual bronchoscopy. Intraoperatively, we stapled and cut the right lower superior segment bronchus at the level of the peripheral anomalous B10c bronchus under bronchoscopic visualization. Precise anatomic understanding is very important for segmentectomy, especially in patients with anomalous bronchi. Multiplanar reconstruction computed tomography and virtual bronchoscopy are useful for preoperative planning. PMID- 26652565 TI - Reply: To PMID 25979240. PMID- 26652567 TI - Inflammatory Myofibroblastic Tumor of the Lung: Two Progressing Pulmonary Nodules in a 25-Year-Old Adult With a Moraxella catharalis Infection. AB - Inflammatory myofibroblastic tumor of the lung is a rare pulmonary lesion of intermediate biologic potential. Approximately half of all inflammatory myofibroblastic tumors show a rearrangement of the anaplastic lymphoma kinase (ALK) gene locus with potentially aberrant kinase expression. We present a 25 year-old man with recurrent exertional hemoptysis and two progressing pulmonary nodules in the right lung shown by computed tomography. After an anterolateral thoracotomy, pathologic studies revealed an inflammatory myofibroblastic tumor with rearrangement in the ALK gene, although aberrant expression of the anaplastic lymphoma kinase was not detected. In preoperative bronchial washings Moraxella catharalis was found. PMID- 26652568 TI - A Bronchopleurocutaneous Fistula Caused by Unexpected Foreign Body Aspiration: False Barley (Hordeum murinum). AB - A 13-year-old boy with no previous history of foreign body aspiration, presenting with side pain, was referred to our clinic with a pneumonia diagnosis by an external medical facility where he had been started on antibiotic treatment. Consolidation in the right inferior lobe and minimal pleural effusion were found on the lung radiograph and computed tomography scan. Skin hyperemia and abscess formation in the right chest were observed subsequently. A drain was placed; bronchoscopy, sampling for cultures, and a biopsy were performed. Four months after this first episode ended with inconclusive results, the patient returned, reporting that a spike of grass was protruding from the continued abscess drainage. The skin lesion closed after emptying of the abscess cavity; a check-up bronchoscopy was unremarkable. The extrusion from the skin of the foreign body, a rare event in the published literature, was our first such case. PMID- 26652569 TI - Robotic Assisted Extended Sleeve Lobectomy After Neoadjuvant Chemotherapy. AB - A 61-year-old man had experienced an irritating cough for 1 month. He received a diagnosis of lung adenocarcinoma by bronchoscopy. Computed tomography showed a mass in the left hilum and mediastinal lymph node enlargement. After two cycles of neoadjuvant chemotherapy, the patient underwent a robotic assisted atypical sleeve lobectomy (left lower lobe + S4+5). The patient's postoperative course was uneventful, and he was discharged on the tenth postoperative day. This is the first description of the feasibility of robotic extended sleeve lobectomy for a lung cancer patient receiving neoadjuvant chemotherapy. PMID- 26652570 TI - Lung Transplant for Pulmonary Arterial Hypertension After Arterial Switch Operation. AB - Pulmonary arterial hypertension after arterial switch operation for transposition of the great arteries is an infrequent but life-threatening complication. We report successful lung transplantation in a case of pulmonary hypertension after arterial switch operation. Cardiopulmonary bypass outflow was established through the right subclavian and femoral arteries because of the previous arterial switch operation. Abnormal anatomy and severe pleural and pericardial adhesions as a result of previous operations resulted in prolonged graft ischemic and operation times. Despite delayed left heart adaptation and primary graft dysfunction requiring prolonged extracorporeal membrane oxygenation, the recipient was eventually discharged without activity limitations. PMID- 26652571 TI - Surgery for Semilunar Valve Regurgitation During Ventricular Assist Device Support in Children. AB - Semilunar valve regurgitation (SVR) in children on ventricular assist device (VAD) support is a difficult task. Three children with SVR prior or during VAD support, underwent uneventful semilunar valve surgery, and 2 patients were successfully bridged to heart transplantation. We conclude that surgical management of SVR during VAD support in children is feasible with low operative risk, and is mandatory to optimize VAD support while on waiting list. PMID- 26652572 TI - Surgical Repair of Interrupted Aortic Arch and Interrupted Pulmonary Artery. AB - Interrupted aortic arch (IAA) is usually associated with ventricular septal defect and patent ductus arteriosus. We report surgical repair in a case of IAA, ventricular septal defect, and interruption of the pulmonary artery with the right pulmonary artery arising from the innominate artery through a separate ductus arteriosus. PMID- 26652573 TI - The effect of percutaneous release of the medial collateral ligament in arthroscopic medial meniscectomy on functional outcome. AB - BACKGROUND: Pie crusting (PC) of the medial collateral ligament (MCL) in the knee has been used empirically to achieve more space in the medial compartment during knee arthroscopy. However, there are no reported studies analyzing the functional results of the application of the PC technique to the MCL in patients undergoing arthroscopic meniscectomy of the medial meniscus, and to determine the rate of iatrogenic injury and associated morbidity. DESCRIPTION OF TECHNIQUE: The patient was in a supine position with a tourniquet and a side post. Percutaneous controlled release of the posterior part of the MCL was performed using an intramuscular needle, and a mild valgus force was applied while viewing with the arthroscope of the controlled progressive gain in medial compartment space. PATIENTS AND METHODS: A retrospective clinical study of 140 patients undergoing arthroscopic meniscectomy with or without MCL PC was conducted. Tegner and Lysholm tests and visual analogue scales were used to assess pain and functional results. RESULTS: The patients in the group with meniscectomy and PC had higher scores on the Lysholm scale, less pain at rest after two months, and achieved significantly better pain control during physical activity at six months. No complication, residual instability, or iatrogenic injury to the cartilage were observed in the meniscectomy plus PC group. CONCLUSION: The MCL PC technique for medial meniscectomy is a safe and effective way to reduce iatrogenic injury to the cartilage and does not affect knee stability. Decompression of the medial compartment results in better functional outcomes at two months and lesser pain during physical activity at six months. PMID- 26652574 TI - Defining priorities for dog population management through mathematical modeling. AB - We simulated dog population dynamics for a thirty-years period using a logistic growth model. Through sensitivity analyses, we determined the influence of the parameters used in the model. Carrying capacity was the most influential parameter in all simulations. In the owned-dog population, the influence of immigration, abandonment and births was 19%, 16% and 6% of the influence of the carrying capacity, respectively. In the sterilized owned-dog population, the influence of abandonment, female and male sterilization was 37%, 30% and 27% of the influence of the carrying capacity. In the stray population, the influence of abandonment, carrying capacity of the owned-dog population and adoption was 10%, 9% and 6% of the influence of the carrying capacity. In the sterilized stray population, the influence of births, female sterilization and male sterilization was 45%, 15% and 13% of the influence of the carrying capacity. Other parameters had lower influence values. Modification of the carrying capacity requires different interventions for the owned- and stray-dog populations. Dog trade control is a way to reduce immigration. The evaluation of sterilization effects must focus on the variations in the infertile population fraction. Adoption may improve the effects of the reduction in carrying capacity on the stray-dog population. PMID- 26652575 TI - Urban health & wellbeing. PMID- 26652576 TI - Jacqui Matthews: The Horse (Worm) Whisperer. PMID- 26652577 TI - Emergent pediatric anticoagulation reversal using a 4-factor prothrombin complex concentrate. PMID- 26652578 TI - Blockade of thymic stromal lymphopoietin (TSLP) receptor inhibits TSLP-driven proliferation and signalling in lymphoblasts from a subset of B-precursor ALL patients. AB - PURPOSE: The cytokine thymic stromal lymphopoietin (TSLP) and its receptor TSLPR are involved in intercellular communication in the course of allergic inflammation and have recently been implicated in the development of various malignancies including B cell precursor acute lymphoblastic leukemia (BCP-ALL). We studied TSLPR expression, TSLP-induced signal transduction and its antibody mediated inhibition in long-term cultures of primary cells derived from B precursor ALL patients. METHODS: TSLPR expression was determined by flow cytometry and Western blot analysis, cell proliferation, signal transduction via the JAK/STAT pathway was analysed by Western blot detection of STAT tyrosine phosphorylation and by measuring TSLP-dependent activation of a STAT-specific reporter gene construct. For inhibition studies a recently introduced antagonistic antibody to the TSLPRalpha-subunit was used. RESULTS: TSLPR surface expression was observed in leukemic lymphoblasts from two out of ten patients with BCP-ALL. Upon TSLP stimulation, the cells with the highest TSLPR expression level showed enhanced proliferation and JAK/STAT-mediated gene regulation in a dose-dependent manner. By employment of an inhibitory antibody to the TSLPR, both TSLP-triggered cell proliferation and STAT transcription factor activation were specifically inhibited. CONCLUSIONS: These results suggest that blockade of the TSLPR might be a therapeutic option for a subset of BCP-ALL patients. PMID- 26652584 TI - Immunoglobulin A nephropathy in rheumatic diseases. PMID- 26652585 TI - Peu d'orange and groove sign. PMID- 26652586 TI - Bioanalytical method validation for the simultaneous determination of ceftazidime and avibactam in rat plasma. AB - BACKGROUND: Combination therapies have gained momentum in the disease management strategies of various indications. While it is challenging and more time consuming to develop a combined analytical method, the strategy of simultaneous analysis offers significant advantages in terms of efficiency and cost effectiveness. RESULTS: Due to a significant difference in efficacious dose for ceftazidime and avibactam, the calibration ranges validated in this paper were set to 0.05-50 MUg/ml for ceftazidime and 0.005-5.0 MUg/ml for avibactam. Interday results of ceftazidime were within 8% for accuracy and 9% for precision and within 9% for both accuracy and precision of avibactam. CONCLUSION: A sensitive and selective LC-MS/MS method was developed for the simultaneous quantification of ceftazidime and avibactam in rat plasma. PMID- 26652587 TI - Investing in nursing and midwifery enterprise: Empowering women and strengthening health systems--A landscaping study of innovations in low- and middle-income countries. AB - Women's empowerment and global health promotion are both central aims in the development agenda, with positive associations and feedback loops between empowerment and health outcomes. To date, most of the work exploring connections between health and empowerment has focused on women as health consumers. This article summarizes a much longer landscape review that examines ways in which various health programs can empower women as providers, specifically nurses and midwives. We conducted a scan of the Center for Health Market Innovations database to identify how innovative health programs can create empowerment opportunities for nurses and midwives. We reviewed 94 programs, exploring nurses' and midwives' roles and inputs that contribute to their empowerment. There were four salient models: provider training, information and communications technologies, cooperatives, and clinical franchises. By documenting these approaches and their hallmarks for empowering female health workers, we hope to stimulate greater uptake of health innovations coupled with gender-empowerment opportunities globally. The full report with expanded methodology and findings is available online. PMID- 26652588 TI - Discovery, Optimization, and in Vivo Evaluation of Benzimidazole Derivatives AM 8508 and AM-9635 as Potent and Selective PI3Kdelta Inhibitors. AB - Lead optimization efforts resulted in the discovery of two potent, selective, and orally bioavailable PI3Kdelta inhibitors, 1 (AM-8508) and 2 (AM-9635), with good pharmacokinetic properties. The compounds inhibit B cell receptor (BCR)-mediated AKT phosphorylation (pAKT) in PI3Kdelta-dependent in vitro cell based assays. These compounds which share a benzimidazole bicycle are effective when administered in vivo at unbound concentrations consistent with their in vitro cell potency as a consequence of improved unbound drug concentration with lower unbound clearance. Furthermore, the compounds demonstrated efficacy in a Keyhole Limpet Hemocyanin (KLH) study in rats, where the blockade of PI3Kdelta activity by inhibitors 1 and 2 led to effective inhibition of antigen-specific IgG and IgM formation after immunization with KLH. PMID- 26652589 TI - Cost-effectiveness of integrated collaborative care for comorbid major depression in patients with cancer. AB - OBJECTIVES: Comorbid major depression is associated with reduced quality of life and greater use of healthcare resources. A recent randomised trial (SMaRT, Symptom Management Research Trials, Oncology-2) found that a collaborative care treatment programme (Depression Care for People with Cancer, DCPC) was highly effective in treating depression in patients with cancer. This study aims to estimate the cost-effectiveness of DCPC compared with usual care from a health service perspective. METHODS: Costs were estimated using UK national unit cost estimates and health outcomes measured using quality-adjusted life-years (QALYs). Incremental cost-effectiveness of DCPC compared with usual care was calculated and scenario analyses performed to test alternative assumptions on costs and missing data. Uncertainty was characterised using cost-effectiveness acceptability curves. The probability of DCPC being cost-effective was determined using the UK National Institute for Health and Care Excellence's (NICE) cost effectiveness threshold range of L 20,000 to L 30,000 per QALY gained. RESULTS: DCPC cost on average L 631 more than usual care per patient, and resulted in a mean gain of 0.066 QALYs, yielding an incremental cost-effectiveness ratio of L 9549 per QALY. The probability of DCPC being cost-effective was 0.9 or greater at cost-effectiveness thresholds above L 20,000 per QALY for the base case and scenario analyses. CONCLUSIONS: Compared with usual care, DCPC is likely to be cost-effective at the current thresholds used by NICE. This study adds to the weight of evidence that collaborative care treatment models are cost-effective for depression, and provides new evidence regarding their use in specialist medical settings. PMID- 26652590 TI - Attachment security and pain--The disrupting effect of captivity and PTSS. AB - The present study assesses the possible disruption effect of posttraumatic stress symptoms (PTSS) with regard to the protective role of attachment on pain, among ex-POWs. While secure attachment seems to serve as a buffer, decreasing the perception of pain, this function may be disrupted by PTSS. The study sample included 104 subjects who were combat veterans of the 1973 Yom Kippur War comprising of 60 male ex-prisoners of war (ex-POWs) and 44 comparable male combat veterans. Both attachment and pain were investigated experimentally in the laboratory and via questionnaires. We found that ex-POWs showed higher levels of clinical pain and attachment insecurities compared to controls. Moreover, attachment avoidance and soothing effect of attachment (SEA) were both associated with lower levels of clinical pain. Most importantly, PTSS moderated the associations between attachment and pain, as well as the mediation role of attachment between captivity and pain. The results imply that although attachment can be an important resource for coping with pain, it can be severely disrupted by PTSS among trauma survivors. PMID- 26652591 TI - Emotion regulation and functional neurological symptoms: Does emotion processing convert into sensorimotor activity? AB - OBJECTIVE: Functional neurological symptoms (FNS) are hypothetically explained as a shift of emotion processing to sensorimotor deficits, but psychophysiological evidence supporting this hypothesis is scarce. The present study measured neuromagnetic and somatic sensation during emotion regulation to examine frontocortical and sensorimotor activity as signals of altered emotion processing. METHODS: Magnetoencephalographic (MEG) activity was mapped during an emotion regulation task in 20 patients with FNS and 20 healthy comparison participants (HC). Participants were instructed to (A) passively watch unpleasant or neutral pictures or (B) down-regulate their emotional response to unpleasant pictures utilizing cognitive reappraisal strategies. Group- and task-specific cortical activity was evaluated via 8-12 Hz (alpha) power modulation, while modulation of somatic sensation was measured via perception and discomfort thresholds of transcutaneous electrical nerve stimulation. RESULTS: Implementing emotion regulation strategies induced frontocortical alpha power modulation in HC but not in patients, who showed prominent activity modulation in sensorimotor regions. Compared to HC, discomfort threshold for transcutaneous stimulation decreased after the task in patients, who also expressed increased symptom intensity. CONCLUSIONS: Reduced frontocortical, but enhanced sensorimotor involvement in emotion regulation efforts offers a trace to modeling a conversion of (aversive) feelings into (aversive) somatic sensations in FNS. PMID- 26652592 TI - Common and unique associated factors for medically unexplained chronic widespread pain and chronic fatigue. AB - OBJECTIVE: Chronic widespread pain and chronic fatigue share common associated factors but these associations may be explained by the presence of concurrent depression and anxiety. METHODS: We mailed questionnaires to a randomly selected sample of people in the UK to identify participants with chronic widespread pain (ACR 1990 definition) and those with chronic fatigue. The questionnaire assessed sociodemographic factors, health status, healthcare use, childhood factors, adult attachment, and psychological stress including anxiety and depression. To identify persons with unexplained chronic widespread pain or unexplained chronic fatigue; we examined participant's medical records to exclude medical illness that might cause these symptoms. RESULTS: Of 1443 participants (58.0% response rate) medical records of 990 were examined. 9.4% (N=93) had unexplained chronic widespread pain and 12.6% (N=125) had unexplained chronic fatigue. Marital status, childhood psychological abuse, recent threatening experiences and other somatic symptoms were commonly associated with both widespread pain and fatigue. No common effect was found for few years of education and current medical illnesses (more strongly associated with chronic widespread pain) or recent illness in a close relative, neuroticism, depression and anxiety scores (more strongly associated with chronic fatigue). Putative associated factors with a common effect were associated with unexplained chronic widespread pain or unexplained chronic fatigue only when there was concurrent anxiety and/or depression. DISCUSSION: This study suggests that the associated factors for chronic widespread pain and chronic fatigue need to be studied in conjunction with concurrent depression/anxiety. Clinicians should be aware of the importance of concurrent anxiety or depression. PMID- 26652593 TI - The acceptability of repeat Internet-based hybrid diet assessment of previous 24 h dietary intake: administration of the Oxford WebQ in UK Biobank. AB - Although dietary intake over a single 24-h period may be atypical of an individual's habitual pattern, multiple 24-h dietary assessments can be representative of habitual intake and help in assessing seasonal variation. Web based questionnaires are convenient for the participant and result in automatic data capture for study investigators. This study reports on the acceptability of repeated web-based administration of the Oxford WebQ--a 24-h recall of frequency from a set food list suitable for self-completion from which energy and nutrient values can be automatically generated. As part of the UK Biobank study, four invitations to complete the Oxford WebQ were sent by email over a 16-month period. Overall, 176 012 (53% of those invited) participants completed the online version of the Oxford WebQ at least once and 66% completed it more than once, although only 16% completed it on all four occasions. The response rate for any one round of invitations varied between 34 and 26%. On most occasions, the Oxford WebQ was completed on the same day that they received the invitation, although this was less likely if sent on a weekend. Participants who completed the Oxford WebQ tended to be white, female, slightly older, less deprived and more educated, which is typical of health-conscious volunteer-based studies. These findings provide preliminary evidence to suggest that repeated 24-h dietary assessment via the Internet is acceptable to the public and a feasible strategy for large population-based studies. PMID- 26652594 TI - Stressing the Limits of Strain Echocardiography. PMID- 26652595 TI - Pressure Recovery in Congenital Aortic Stenosis. PMID- 26652597 TI - Focus on sonography credentialing: The adult congenital sonographer: Part one in a two-part series on sonographer registry. PMID- 26652598 TI - Focus on Education for the ASE Community. PMID- 26652599 TI - Introduction to glyco-neuroscience. PMID- 26652600 TI - Exploratory screening for Fabry's disease in young adults with cerebrovascular disorders in northern Sardinia. AB - BACKGROUND: The etiologic determinants of stroke in young adults remain a diagnostic challenge in up to one-fourth of cases. Increasing evidences led to consider Fabry's disease (FD) as a possible cause to check up. We aimed at evaluating the prevalence of unrecognized FD in a cohort of patients with juvenile stroke in northern Sardinia. METHODS: For this study, we enrolled 178 patients consecutively admitted to our Neurological Ward for ischemic stroke, transient ischemic attack, intracerebral haemorrhage, neuroradiological evidence of silent infarcts, or white matter lesions possibly related to cerebral vasculopathy at brain MRI, and cerebral venous thrombosis. The qualifying events have to occur between 18 and 55 years of age. RESULTS: We identified two patients with an alpha-galactosidase A gene variant, with a prevalence of 0.9 %. According to recent diagnostic criteria, one patient, included for the occurrence of multiple white matter lesions at brain MRI, had a diagnosis of definite FD, the other, included for ischemic stroke, had a diagnosis of uncertain FD. CONCLUSIONS: Our study places in a middle position among studies that found a prevalence of FD up to 4 % and others that did not find any FD patients. Our findings confirm that FD should be considered in the differential diagnosis of patients with juvenile stroke, particularly those with a personal or familial history positive for cerebrovascular events, or evidence of combined cardiologic and/or renal impairment. All types of cerebrovascular disorders should be screened for FD, including patients with white matter lesions possibly related to cerebral vasculopathy at brain MRI. PMID- 26652601 TI - Cell adhesion manipulation through single cell assembly for characterization of initial cell-to-cell interaction. AB - BACKGROUND: Cell-to-cell interactions are complex processes that involve physical interactions, chemical binding, and biological signaling pathways. Identification of the functions of special signaling pathway in cell-to-cell interaction from the very first contact will help characterize the mechanism underlying the interaction and advance new drug discovery. METHODS: This paper reported a case study of characterizing initial interaction between leukemia cancer cells and bone marrow stromal cells, through the use of an optical tweezers-based cell manipulation tool. Optical traps were used to assemble leukemia cells at different positions of the stromal cell layer and enable their interactions by applying a small trapping force to maintain the cell contact for a few minutes. Specific drug was used to inhibit the binding of molecules during receptor-ligand mediated adhesion. RESULTS AND CONCLUSIONS: Our results showed that the amount of adhesion molecule could affect cell adhesion during the first few minutes contact. We also found that leukemia cancer cells could migrate on the stromal cell layer, which was dependent on the adhesion state and activation triggered by specific chemokine. The reported approaches provided a new opportunity to investigate cell-to-cell interaction through single cell adhesion manipulation. PMID- 26652602 TI - Metabolic and coagulation effects of citrate: down to the last detail! PMID- 26652603 TI - Comparison of growth and nutritional status in infants receiving goat milk-based formula and cow milk-based formula: a randomized, double-blind study. AB - OBJECTIVE: To compare the growth and nutritional status of infants fed goat milk based formula (GMF) and cow milk-based formula (CMF). METHODS: The study was conducted in Beijing, China. It was a double-blind randomized controlled trial. A total of 79 infants aged 0-3 months old were recruited and randomized in GMF or CMF group. The infants were fed the allocated formula to 6 months. The weight, length, and head circumference were measured at the enrolment, 3 and 6 months. The start time and types of solid food were recorded. Blood elements, urinal, and fecal parameters were also tested. RESULTS: The average weight of infants in the GMF group (mean+/-SD) was 4.67+/-0.99 kg and in the CMF group 4.73+/-1.10 kg at enrolment, and 8.75+/-0.98 kg (GMF) and 8.92+/-0.88 kg (CMF) at 6 months. There were no differences in the adjusted intention-to-treat analyses of weight, length, head circumference, and BMI z-scores between the two formula-fed groups over the 6-month study. Similarly, there were no remarkable differences in the timing and types of solid food, blood elements, urinal, and feces parameters, between the GMF and CMF group. No group differences have been shown in bowel motion consistency, duration of crying, ease of settling, or frequency of adverse events. CONCLUSIONS: GMF-provided growth and nutritional outcomes did not differ from those provided by CMF. PMID- 26652604 TI - Protective effects of L-arabinose in high-carbohydrate, high-fat diet-induced metabolic syndrome in rats. AB - BACKGROUND: L-Arabinose is a non-caloric sugar, which could affect glucose and lipid metabolism and suppress obesity. However, few reports have described the effect of L-arabinose in metabolic syndrome, a combination of medical disorders that increase the risk of diabetes and cardiovascular disease. OBJECTIVE: This study was conducted to explore the effects of L-arabinose in rats with metabolic syndrome induced by a high-carbohydrate, high-fat (HCHF) diet. METHODS: After the rat model for metabolic syndrome was successfully established, L-arabinose was administrated by oral gavage for 6 weeks. The biochemical index and histological analysis were measured, and the expression levels of genes related to fatty acid metabolism were analyzed using real-time PCR. RESULTS: Following treatment with L arabinose, metabolic syndrome rats had an obvious reduction in body weight, systolic blood pressure, diastolic blood pressure, fasting blood glucose, triglycerides, total cholesterol, serum insulin, TNF-alpha, and leptin. Further study showed that treatment with L-arabinose significantly increased the expression of mRNA for hepatic CPT-1alpha and PDK4, but the expression of mRNA for hepatic ACCalpha was reduced. CONCLUSIONS: This work suggests that L arabinose could lower body weight, Lee's index, and visceral index and improve dyslipidemia, insulin resistance, inflammation, and viscera function, which indicate that it might be a promising candidate for therapies combating metabolic syndrome. PMID- 26652605 TI - Prognostic role of sex steroid receptors in pancreatic adenocarcinoma. AB - From the available literature, it is unclear what proportion of pancreatic adenocarcinomas express estrogen receptors (ERalpha, ERbeta), progesterone receptors (PR), and androgen receptors (AR), and if any of these markers have prognostic significance. We aimed to assess (1) the expression and (2) the correlation of the aforementioned markers with clinicopathological parameters and prognosis in patients with pancreatic adenocarcinoma. During a five-year period, 60 patients with pancreatic ductal adenocarcinoma underwent surgical resection at a single institution. Immunohistochemical stains of the studied markers were quantified by Image analysis system. ERalpha expression was positively associated with PR expression. Moreover, ERbeta was inversely associated with the presence of metastases, whereas no significant associations implicated AR. As far as the prognostic significance of the studied receptors is concerned, higher ERalpha expression correlated with poorer survival at the univariate analysis, but the finding dissipated at the multivariate approach. No significant associations with overall survival were noted regarding the other receptors. The role of sex hormone receptors in the survival from pancreatic adenocarcinoma seems rather limited. Further prospective studies assessing those receptors should ideally be designed in order to confirm our results and possibly outline additional correlations between other steroid receptors and features of pancreatic adenocarcinoma. PMID- 26652606 TI - 'Live more': Study protocol for a community-based lifestyle education program addressing non-communicable diseases in low-literacy areas of the South Pacific. AB - BACKGROUND: Non-communicable diseases (NCDs) have reached epidemic proportions in Pacific Island countries. Unhealthy lifestyle is one of the major risk factors and lifestyle interventions have been shown to be efficacious for primary, secondary and early tertiary prevention. However, there is a paucity of evidence regarding effective community-based lifestyle interventions in the Pacific Islands. The Complete Health Improvement Program for high-income countries was contextualised for rural communities with relatively low-literacy rates in low income countries using the REFLECT delivery approach. This study will assess the effect of this 'Live More' program to reduce participant's NCD risk factors and improve lifestyle behaviours associated with health and wellbeing, in low literacy communities in countries of the South Pacific. METHODS/DESIGN: This study is a 6-month cluster-randomised controlled trial of 288 adults (equal proportions of men and women aged 18 years and over) with waist circumference of >=92 cm for men and >=80 cm for women in four rural villages in each of Fiji, Vanuatu and Solomon Islands. Participants will permanently reside in their village and be able to prepare their own meals. Two villages will be randomised to the 'Live More' intervention (n = 24) or to control receiving only country specific Ministry of Health literature (n = 24). Intervention participants will meet three times a week in the first month, then once a week for the next two months and once a month for the last three months. Themes covered include: NCDs and their causes; and the benefits of positive lifestyle choices, positive psychology, stress management, forgiveness and self-worth, and how these influence long-term health habits. Outcome assessments at baseline, 30-days, 3 months and 6-months include body mass index, waist circumference, blood lipids, blood pressure and blood glucose. Secondary outcomes include changes in medication and substance use, diet, physical activity, emotional health and supportive relationships, collected by lifestyle questionnaire at the same time points. DISCUSSION: This is the first lifestyle intervention using the Reflect approach to target NCDs. The findings from the study will be used to guide broader delivery of a lifestyle intervention to improve health and wellbeing across the South Pacific. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12614001206617 . PMID- 26652607 TI - Guardianship law versus supported decision-making policies: Perceptions of persons with intellectual or psychiatric disabilities and parents. AB - Article 12 of the Convention for the Rights of Persons with Disabilities recognizes all persons with disabilities as having legal capacity in all areas of life. However, in adherence to the Israeli Legal Capacity and Guardianship Law (1962), many persons with intellectual disability (ID) or mental illness (MI) have these rights revoked because of the appointment of a guardian. Little is known about these persons' perceptions about guardianship and supported decision making (SDM). Using focus groups, we examined the perceptions of persons with ID, persons with MI, and parents regarding guardianship and SDM. Most participants expressed their desire to adopt a model of SDM in their daily decision making, though differences were found among the groups. Persons with MI emphasized their right to be independent in decisions regarding their lives, and parents of these persons aspired to support their children to reach independence, except in times of crisis. Persons with ID also desired more independence, but they were uncertain if this would be possible for them. Some individuals with ID preferred that decisions regarding their lives be made on their behalf. Parents of persons with ID felt that it was critical for them to serve as guardians of their children. Recommendations are provided on how to promote the legal capacity of individuals with disabilities. (PsycINFO Database Record PMID- 26652608 TI - Weighing the evidence for harm from long-term treatment with antipsychotic medications: A systematic review. AB - Research findings supporting the use of antipsychotic medication for acute treatment of schizophrenia are relatively consistent and undisputed. However, the rationale for recommending long-term antipsychotic medication treatment-the current standard of care treatment strategy-is unclear. A controversial hypothesis proposed recently suggests people with schizophrenia who are exposed to long-term treatment with antipsychotic medications have worse outcomes than people with schizophrenia who are not exposed to these medications. We tested whether a systematic appraisal of published literature would produce data consistent with this hypothesis. We reviewed the published literature to identify studies of patients with psychotic disorders who were followed for at least 2 years that compared outcomes in patients who received antipsychotic medication during the follow-up with patients who did not receive antipsychotic medication during the follow-up. We included all English language articles published through 2013 in this review. Our process for selecting studies and documenting study findings included a consensus decision of 2 members of the research team. We found the published data to be inadequate to test this hypothesis. By extension, these data were also inadequate to conclusively evaluate whether long-term antipsychotic medication treatment results in better outcomes on average. We conclude that careful reappraisal of existing data is useful to ensure standard of care treatment strategies are indeed evidence-based. In the case of long-term use of antipsychotic medications, new data may be needed to establish a sufficient evidence base to understand its benefit/risk balance for patients with schizophrenia. (PsycINFO Database Record PMID- 26652609 TI - Artefacts at a glance: differentiating features of artefactual stenosis from true stenosis at the genu of the petrous internal carotid artery on TOF MRA. AB - AIM: To investigate the distinguishing features of artefactual stenosis from true stenosis at the genu of the petrous internal carotid artery (ICA) on time of flight (TOF) magnetic resonance angiography (MRA). MATERIALS AND METHODS: Both TOF MRA and digital subtraction angiography (DSA) were performed in 65 patients with 74 vessels who demonstrated artefactual stenosis in 43 patients with 50 vessels and true stenosis in 22 patients with 24 vessels. The following findings of the signal loss were compared between the two groups: (1) margin, (2) darkness, (3) the presence of bilaterality, (4) the presence of tandem arterial stenosis, (5) the location of the epicentre, and (6) length. RESULTS: In five out of the six evaluated items, statistically significant differences were present between the two groups (p<0.00 in all five items). Artefactual stenosis more frequently showed signal loss with ill-defined margins (47/50), less darkness compared to the background darkness (46/50), the absence of tandem arterial stenosis (35/50), epicentre at the genu (34/50), and shorter length (2.57 +/- 0.68 mm). No significant difference was noted in the presence of bilaterality of signal loss between the two groups (p=0.706). CONCLUSION: Several MRA features can be useful for suggesting artefactual stenosis rather than true stenosis at the genu of the petrous ICA on TOF MRA. PMID- 26652610 TI - The radiological diagnosis of frontotemporal dementia in everyday practice: an audit of reports, review of diagnostic criteria, and proposal for service improvement. AB - AIM: To investigate how commonly valuable diagnostic information regarding the frontotemporal dementias (FTDs) may be missed on routine radiological reporting. MATERIALS AND METHODS: The magnetic resonance imaging (MRI) examination results of a series of 39 consecutive patients in whom the diagnosis was initially thought to be a form of FTD were audited. Twenty-two patients satisfied formal diagnostic criteria for subtypes of FTD. The initial non-specialist radiological reports of the MRI examinations were compared with those of a radiologist who specifically examined the images for the possibility of atypical dementia. RESULTS: Six of the 22 original reports provided a full and accurate description of the radiological findings, while two provided a fully accurate interpretation. CONCLUSION: Valuable diagnostic information may be missed unless clinicians and radiologists jointly review and discuss brain imaging in cases of dementia. The use of standardised scales may enhance the reporting of MRI examinations for dementia. PMID- 26652611 TI - Methotrexate pharmacokinetic genetic variants are associated with outcome in rheumatoid arthritis patients. AB - BACKGROUND: Methotrexate (MTX) is the most used drug for the treatment of rheumatoid arthritis (RA) although outcome differs among patients. AIM: To evaluate whether polymorphisms in pharmacokinetic genes are associated with outcome in RA patients receiving MTX. PATIENTS & METHODS: We analyzed 28 SNPs in SLC19A1/RFC1, ABCB1, FPGS and GGH genes. RESULTS: We studied 194 RA patients receiving MTX monotherapy. Two FPGS SNPs, rs10987742 and rs10106, were associated with response (p = 0.033 and p = 0.041, respectively). The FPGS rs10106 variant was also associated with MTX survival (p = 0.005) and toxicity (p = 0.021). Three ABCB1 SNPs, rs868755, rs10280623 and rs1858923, were associated with toxicity (p = 0.025, p = 0.048 and p = 0.031, respectively). CONCLUSION: FPGS and ABCB1 genetic variants can influence the outcome in RA patients receiving MTX monotherapy. PMID- 26652612 TI - Prevalence of Foot Ulcers, Foot at Risk and Associated Risk Factors Among Jordanian Diabetics. AB - OBJECTIVE: To examine the prevalence of foot ulcers, foot at risk, and the associated risk factors among Jordanian diabetics. METHODS: A cross-sectional design was applied on 1000 diabetes patients (both type-1 and type-2) aged >20 years. The participants were selected systematically from among every second patient visiting the diabetes clinics at National Center for Diabetes, Endocrinology, and Genetics (NCDEG) in Amman, Jordan. The participants were interviewed, examined, and then their medical records were reviewed. The factors including sensory neuropathy, vibratory neuropathy, painful neuropathy, vascular insufficiency, retinopathy, and dermatological changes were recorded for all patients. Foot at risk was identified based on the risk category classification and foot ulcers were evaluated based on the Wagner's classification system. RESULTS: A total of 53 (5.3%) patients had foot ulcers, 17 (1.7%) had undergone amputations, and 172 (17.2%) had foot at risk. A total of 62 patients were identified in the risk category-1, 82 in the risk category-2, and 28 in the risk category-3. Loss of protective sensation was detected in 174 (17.4%) patients, loss of vibratory sensation in 162 (16.2%) patients, absence of posterior tibial pulse in 115 (11.5%) patients, absence of dorsalis pedis pulse in 97 (9.7%) patients, and claudication in 72 (7.2%) patients. Loss of protective sensation (p < 0.000), loss of vibratory sensation (p < 0.039), and vascular insufficiency (p = 0.02) were found to be significantly higher in diabetic patients with foot ulcers than in those without foot ulcers. CONCLUSION: The prevalence of foot ulcer in Jordan was 5.3%, while foot at risk was prevalent in 17.2% patients. Patients with loss of protective sensation, loss of vibratory sensation, and vascular insufficiency of the lower limbs were found to be at a higher risk for the development of foot ulceration. PMID- 26652613 TI - Safety of bioabsorbable implants in vitro. AB - BACKGROUND: The aim of the present study was to investigate the safety of bioabsorbable plates and screws in humans. METHODS: For this purpose, an implant system based on [poly(lactic-co-glycolic acids)(85:15)] was designed. The system was tested for pH, temperature, and swelling and then its surface morphology was analyzed for surface porosity using environmental electron microscopy. Then, the effects of this bioabsorbable system on the viability and profileration of osteocytes were examined on a molecular level via in vitro experiments. A [poly(lactic-co-glycolic acids)(90:10)] bioabsorbable implant, which is commercially available and used in orthopedic surgery, was used as control group. For the statistical evaluation of the data obtained in the present study, the groups were compared by Tukey HSD test following ANOVA. The significance level was set as p < 0.05. RESULTS: It was observed that the osteocytes cultivated on the PLGA system designed in the present study included more live cells and allowed more proliferation compared to the control. CONCLUSION: One of the criteria in the selection of implants for orthopedic surgery is that a good implant should not need removal and thus a second surgery. In the present study, a bioabsorbable implant was designed considering this criterion. The present study is the first step to prove the safety of this new design by in vitro toxicity and viability experiments. PMID- 26652614 TI - Diversity of Haemaphysalis-associated piroplasms of ruminants in Central-Eastern Europe, Hungary. AB - BACKGROUND: Increasing numbers of genetic variants are being recognized among piroplasms, but the precise taxonomical status, the tick vector and the geographical range of several species or genotypes are still unknown. Bovine piroplasmosis was reported to re-emerge in north-east Hungary. Because Theileria infection was newly diagnosed in one cattle herd in the same region of the country, the aim of this study was to molecularly identify the relevant agent, to find its local vector tick species, and to examine the range of Babesia/Theileria spp. of ruminants in Haemaphysalis sp. ticks collected previously in Hungary. FINDINGS: Blood samples were drawn on two occasions from 90 dairy cattle in northern Hungary, and ticks were collected on their pastures. In addition, questing ticks (315 Haemaphysalis inermis, 259 H. concinna and 22 H. punctata), which originated mainly in the same region of the country from 2007, were included in the study. DNA was extracted from these samples, followed by molecular analysis for piroplasms. In the cattle Theileria orientalis was identified, with 100 % sequence homology to isolates from Japan, China, South Africa and Australia. Based on GenBank data this genotype has not been previously reported in Europe. The prevalence of infection in the herd remained almost constant in the main tick season, suggesting exposure in previous years. Retrospective analysis of ticks revealed the presence of Babesia crassa in H. inermis, for the first time in Europe and in this tick species. On the other hand, H. concinna carried five different piroplasms, including B. motasi that was also newly detected in Central-Eastern Europe and in this tick species; whereas H. punctata harboured Theileria sp. OT3, hitherto known to occur in the Mediterranean region. CONCLUSIONS: Results of this study broaden the range of piroplasms that are infective for ruminants in Central-Eastern Europe. Although bovine babesiosis and theileriosis was known to occur in Hungary, molecular evidence is provided here for the first time on the presence of Babesia and/or Theileria spp. of sheep, goats and cervids in Hungary. PMID- 26652615 TI - Olanzapine-induced ischemic colitis. AB - Ischemic colitis (IC) is an uncommon adverse event associated with antipsychotic agents, more commonly found with phenothiazine drugs and atypical neuroleptics such as clozapine. The risk of developing ischemic colitis increases when anticholinergic drugs are associated. We report the case of a 38-year-old woman with a history of schizoaffective disorder who had been on chronic quetiapine for 3 years, and presented to the ER because of diarrhea for 5 days. Four months previously, olanzapine had been added to her psychiatric drug regimen. Physical examination revealed abdominal distension with abdominal tympanic sounds and tenderness. Emergency laboratory tests were notable for increased acute phase reagents. Tomography revealed a concentric thickening of the colonic wall in the transverse, descending and sigmoid segments, with no signs of intestinal perforation. Colonoscopy demonstrated severe mucosal involvement from the sigmoid to the hepatic flexure, with ulcerations and fibrinoid exudate. Biopsies confirmed the diagnosis of ischemic colitis. The only relevant finding in her history was the newly added drug to her baseline regimen. An adverse effect was suspected because of its anticholinergic action at the intestinal level, and the drug was withdrawn. After 6 months of follow-up clinical, laboratory and endoscopic recovery was achieved. Therefore, antipsychotic medication should be considered as a potential cause of ischemic colitis, particularly atypical antipsychotics such as clozapine and olanzapine; despite being uncommon, this adverse event may result in high morbidity and mortality. PMID- 26652616 TI - Prioritization of self-relevant perspectives in ageing. AB - This study investigated whether age-related sensitivity to self-relevance may benefit perspective taking, despite generally poorer perspective-taking capacity in older adults. In one perceptual matching task and two visual perspective taking paradigms, we examined age differences in sensitivity to avatars representing self and other. In the matching task, older (60-83 years) and younger (18-20 years) adults were similarly biased toward the self- versus other associated avatar. In the perspective-taking tasks, participants viewed these avatars within a virtual room. Task-relevant perspectives were either the same (i.e., congruent) or different (i.e., incongruent). In the 3PP-3PP task, both avatars were present, and participants adopted the perspective of one or the other. As in the matching task, young and old were similarly biased toward the self-associated avatar. However, age differences emerged in the 1PP-3PP task, which presented only one avatar per trial (varying between self and other), and participants responded based on their own first-person perspective or the avatar's. In summary, age modulated the ability to take perspectives primarily when participants' own first-person perspective was task relevant. Relative to younger adults, older adults prioritized the self (vs. other) avatar more during initial perspective computation and the first-person (vs. third-person) perspective more when selecting between incongruent perspectives. PMID- 26652617 TI - Oleogels: a promising tool for delivery of hydrophobic bioactive molecules. PMID- 26652618 TI - Subcutaneous administration of monoclonal antibodies: a small space to inject, a big challenge to conquer. PMID- 26652619 TI - Design, characterization and in vitro evaluation of a novel thiolated polymer: preactivated carboxymethyl cellulose. AB - AIM: To design a novel preactived carboxymethyl cellulose derivative. METHODS: First, carboxymethyl cellulose (CMC) was chemically modified by amide bond formation between primary amino group of cysteine (CYS) and carboxylic moiety of CMC mediated by carbodiimide. Second, obtained CMCCYS was preactivated with 2,2' dithiodinicotinic acid. Designed CMC-S-S-MNA was characterized by FT-IR. Furthermore, cytotoxicity was conducted on Caco-2 cell line. Swelling behavior, erosion and release of novel CMC-S-S-MNA were performed compared with thiolated and unmodified cellulose, respectively. RESULTS: CMC-S-S-MNA showed no harmful effect on cells. CMC-S-S-MNA exhibited 2.13-fold higher stability in comparison to unmodified cellulose. Furthermore, preactivated carboxymethyl cellulose cysteine revealed 1.9-fold controlled released compared with respective unmodified carboxymethyl cellulose. CONCLUSION: Novel preactivated carboxymethyl cellulose represents a versatile excipient for drug delivery. PMID- 26652620 TI - Recent advances in amphiphilic polymers for simultaneous delivery of hydrophobic and hydrophilic drugs. AB - Nanomedicine has evolved with the use of biological compounds such as proteins, peptides and DNA. These hydrophilic and often highly charged compounds require a delivery system to allow effective transport and release at the site of action. These new biological therapeutics have not replaced the more traditional smaller molecule, but instead are working synergistically to the benefit of the end user. To that end, drug delivery systems are now required to encapsulate both larger hydrophilic compounds as well as the smaller and generally more hydrophobic compound. This review highlights the emerging role in drug delivery of amphiphilic polymers that by their very nature can associate with compounds of differing physicochemical properties, in particular the role of micelles, polymersomes and nanocapsules. PMID- 26652621 TI - Role of pressure-sensitive adhesives in transdermal drug delivery systems. AB - Transdermal drug delivery systems (TDDS) are employed for the delivery of drugs across skin into the systemic circulation. Pressure-sensitive adhesive (PSA) is one of the most critical components used in a TDDS. The primary function of PSA is to help in adhesion of patch to skin, but more importantly it acts as a matrix for the drug and other excipients. Hence, apart from adhesion of the patch, PSA also affects other critical quality attributes of the TDDS such as drug delivery, flux through skin and physical and chemical stability of the finished product. This review article provides a summary of the adhesives used in various types of TDDS. In particular, this review will cover the design types of TDDS, categories of PSAs and their evaluation and regulatory aspects. PMID- 26652622 TI - The co-expression of MMP-9 and Tenascin-C is significantly associated with the progression and prognosis of pancreatic cancer. AB - BACKGROUND: Matrix metalloproteinase-9 (MMP-9) and Tenascin-C (TN-C) have been shown to be involved in the metastasis of many tumors. The purpose of this study was to determine the relationship between the co-expression of these two molecules and the clinical prognosis of pancreatic cancer. METHODS: We investigated the expression of TN-C and MMP-9 in 103 pancreatic cancer tissues by immunohistochemistry and used statistical analyses to investigate the correlations of individual expression or co-expression of these two molecules with clinicopathological parameters and survival of pancreatic cancer. RESULTS: The expression of MMP-9 and TN-C were increased in pancreatic cancer. The co expression of MMP-9 and TN-C was also detected. The expression of MMP-9 and TN-C were correlated with vascular invasion, lymph node invasion, liver metastases and TNM stage. The co-expression of MMP-9 and TN-C was significantly related to the pancreatic cancer metastases. The individual overexpression of MMP-9 or TN-C significantly decreased the overall survival rates. The co-expression of MMP-9 and TN-C had the lowest overall survival rates. The co-expression of MMP-9 and TN C was an independent predictor of survival for pancreatic cancer patients. CONCLUSIONS: Co-expression of MMP-9 and TN-C was associated with poorer prognosis and was found to be an independent predictor of survival. PMID- 26652623 TI - Metazoans of redoxcline sediments in Mediterranean deep-sea hypersaline anoxic basins. AB - BACKGROUND: The deep-sea hypersaline anoxic basins (DHABs) of the Mediterranean (water depth ~3500 m) are some of the most extreme oceanic habitats known. Brines of DHABs are nearly saturated with salt, leading many to suspect they are uninhabitable for eukaryotes. While diverse bacterial and protistan communities are reported from some DHAB haloclines and brines, loriciferans are the only metazoan reported to inhabit the anoxic DHAB brines. Our goal was to further investigate metazoan communities in DHAB haloclines and brines. RESULTS: We report observations from sediments of three DHAB (Urania, Discovery, L'Atalante) haloclines, comparing these to observations from sediments underlying normoxic waters of typical Mediterranean salinity. Due to technical difficulties, sampling of the brines was not possible. Morphotype analysis indicates nematodes are the most abundant taxon; crustaceans, loriciferans and bryozoans were also noted. Among nematodes, Daptonema was the most abundant genus; three morphotypes were noted with a degree of endemicity. The majority of rRNA sequences were from planktonic taxa, suggesting that at least some individual metazoans were preserved and inactive. Nematode abundance data, in some cases determined from direct counts of sediments incubated in situ with CellTracker(TM) Green, was patchy but generally indicates the highest abundances in either normoxic control samples or in upper halocline samples; nematodes were absent or very rare in lower halocline samples. Ultrastructural analysis indicates the nematodes in L'Atalante normoxic control sediments were fit, while specimens from L'Atalante upper halocline were healthy or had only recently died and those from the lower halocline had no identifiable organelles. Loriciferans, which were only rarely encountered, were found in both normoxic control samples as well as in Discovery and L'Atalante haloclines. It is not clear how a metazoan taxon could remain viable under this wide range of conditions. CONCLUSIONS: We document a community of living nematodes in normoxic, normal saline deep-sea Mediterranean sediments and in the upper halocline portions of the DHABs. Occurrences of nematodes in mid halocline and lower halocline samples did not provide compelling evidence of a living community in those zones. The possibility of a viable metazoan community in brines of DHABs is not supported by our data at this time. PMID- 26652624 TI - Sensitive Detection of Single-Nucleotide Mutation in the BRAF Mutation Site (V600E) of Human Melanoma Using Phosphate-Pyrene-Labeled DNA Probes. AB - A series of novel nucleotide phosphoramidites were rationally designed and synthesized and were then site-specifically incorporated in DNA oligonucleotide probes with pyrene-modified phosphate. These oligodeoxynucleotide (ODN) probes almost have no inherent fluorescence emission with pyrene modification at 3' phosphate of corresponding nucleotides as a result of the photoinduced electron transfer quenching effect of nucleobases (thymidine ~ cytidine > guanosine ? adenosine). However, strong fluorescence emission was observed only with the perfectly matched duplex for the probes with pyrene modified at 3' phosphate of thymidine and cytidine. These rationally designed ODN probes successfully worked as "turn on" fluorescence oligonucleotide sensors for single-nucleotide polymorphism (SNP) and were used for detecting a single BRAF mutation site (V600E) of human melanoma. PMID- 26652625 TI - Single-Site Organozirconium Catalyst Embedded in a Metal-Organic Framework. AB - A structurally well-defined mesoporous Hf-based metal-organic framework (Hf-NU 1000) is employed as a well-defined scaffold for a highly electrophilic single site d(0) Zr-benzyl catalytic center. This new material Hf-NU-1000-ZrBn is fully characterized by a variety of spectroscopic techniques and DFT computation. Hf-NU 1000-ZrBn is found to be a promising single-component catalyst (i.e., not requiring a catalyst/activator) for ethylene and stereoregular 1-hexene polymerization. PMID- 26652626 TI - The Readiness for Interprofessional Learning Scale: To RIPLS or not to RIPLS? That is only part of the question. PMID- 26652627 TI - Integrating informatics and interprofessional education and practice to drive healthcare transformation. PMID- 26652628 TI - Integrating the Electronic Health Record into high-fidelity interprofessional intensive care unit simulations. AB - With the rapid adoption of electronic health records (EHR), there is a growing appreciation for the central role they play in clinical decision making and team communication, with many studies documenting new safety issues with integration of the EHR into the clinical enterprise. To study these issues, we created a high fidelity simulation instance of our clinical EHR. In this paper, we describe the impact of integrating the EHR into high-fidelity, interprofessional intensive care unit (ICU) simulations, and the errors induced. We found a number of safety issues directly related to the EHR including alert fatigue, negative impacts on interprofessional communication, and problems with selective data gathering, and these issues were present for all members of the interprofessional team. Through successful integration of the EHR into high-fidelity team-based simulations, we now have an infrastructure to focus educational initiative and deploy informatics solutions to mitigate these safety issues. PMID- 26652629 TI - Leveraging mobile smart devices to improve interprofessional communications in inpatient practice setting: A literature review. AB - As mobile smart device use has increased in society, the healthcare community has begun using these devices for communication among professionals in practice settings. The purpose of this review is to describe primary literature which reports on the experiences with interprofessional healthcare communication via mobile smart devices. Based on these findings, this review also addresses how these devices may be utilized to facilitate interprofessional education (IPE) in health professions education programs. The literature search revealed limited assessments of mobile smart device use in clinical practice settings. In available reports, communication with mobile smart devices was perceived as more effective and faster among interdisciplinary members. Notable drawbacks included discrepancies in the urgency labeling of messages, increased interruptions associated with constant accessibility to team members, and professionalism breakdowns. Recently developed interprofessional competencies include an emphasis on ensuring that health profession students can effectively communicate on interprofessional teams. With the increasing reliance on mobile smart devices in the absence of robust benefit and risk assessments on their use in clinical practice settings, use of these devices may be leveraged to facilitate IPE activities in health education professions programs while simultaneously educating students on their proper use in patient care settings. PMID- 26652630 TI - Refining a self-assessment of informatics competency scale using Mokken scaling analysis. AB - Healthcare environments are increasingly implementing health information technology (HIT) and those from various professions must be competent to use HIT in meaningful ways. In addition, HIT has been shown to enable interprofessional approaches to health care. The purpose of this article is to describe the refinement of the Self-Assessment of Nursing Informatics Competencies Scale (SANICS) using analytic techniques based upon item response theory (IRT) and discuss its relevance to interprofessional education and practice. In a sample of 604 nursing students, the 93-item version of SANICS was examined using non parametric IRT. The iterative modeling procedure included 31 steps comprising: (1) assessing scalability, (2) assessing monotonicity, (3) assessing invariant item ordering, and (4) expert input. SANICS was reduced to an 18-item hierarchical scale with excellent reliability. Fundamental skills for team functioning and shared decision making among team members (e.g. "using monitoring systems appropriately," "describing general systems to support clinical care") had the highest level of difficulty, and "demonstrating basic technology skills" had the lowest difficulty level. Most items reflect informatics competencies relevant to all health professionals. Further, the approaches can be applied to construct a new hierarchical scale or refine an existing scale related to informatics attitudes or competencies for various health professions. PMID- 26652631 TI - The National United States Center Data Repository: Core essential interprofessional practice & education data enabling triple aim analytics. AB - Understanding the impact that interprofessional education and collaborative practice (IPECP) might have on triple aim patient outcomes is of high interest to health care providers, educators, administrators, and policy makers. Before the work undertaken by the National Center for Interprofessional Practice and Education at the University of Minnesota, no standard mechanism to acquire and report outcome data related to interprofessional education and collaborative practice and its effect on triple aim outcomes existed. This article describes the development and adoption of the National Center Data Repository (NCDR) designed to capture data related to IPECP processes and outcomes to support analyses of the relationship of IPECP on the Triple Aim. The data collection methods, web-based survey design and implementation process are discussed. The implications of this informatics work to the field of IPECP and health care quality and safety include creating standardized capacity to describe interprofessional practice and measure outcomes connecting interprofessional education and collaborative practice to the triple aim within and across sites/settings, leveraging an accessible data collection process using user friendly web-based survey design to support large data scholarship and instrument testing, and establishing standardized data elements and variables that can potentially lead to enhancements to national/international information system and academic accreditation standards to further team-based, interprofessional, collaborative research in the field. PMID- 26652632 TI - The United States National Center for Interprofessional Practice and Education: Integrating an informatics approach to interprofessional work. AB - The National Center for Interprofessional Practice and Education, a United States public-private partnership, was formed to provide national leadership, scholarship, evidence, and coordination to advance interprofessional education (IPE) and practice. Many external drivers led to the creation of the partnership that culminated in the National Center: patient safety initiatives, the need for care coordination and transitions efforts, quality improvement imperatives, calls for teamwork and workforce optimization, newly defined national core competencies for interprofessional collaborative practice, practice redesign, escalating health care costs, and state and federal policies. The National Center principals who have served in a variety of senior leadership roles--a clinician, educationalist, and informaticist--recognized the opportunity to leverage the potential that informatics could bring not only to the center but also to the field of IPECP. An informatics approach focuses on collaborative processes and works to address information processing, communications, and data collection. To do so, the National Center created multiple platforms: informatics education, a resource exchange, communication strategy, incubator network, national data repository, and learning system. PMID- 26652633 TI - Professional equipoise: Getting beyond dominant discourses in an interprofessional team. AB - In 2011, the US Department of Veterans Affairs established five Centers of Excellence to study training in the patient-centered medical home clinical microsystem. Early on, our center began a discourse analysis in order to better understand each profession's assumptions about roles, responsibilities, and the basis for "truth" in clinical care. We discovered that these different discourses were pervasive and led to unhelpful stereotypes of each other. This article describes the evidence we identified that led us to hypothesize these conflicting discourses and stereotypes. Specifically, we report on our attempts to identify the traditional discourses of four post-graduate professions--medicine, nurse practitioner, psychology, and pharmacy. We also share lessons from our efforts to defuse participants from their identified discursive assumptions, and develop appreciation and value for the discursive contributions of other professions--a process we call professional equipoise. We conclude that we can change these discourses and the professional identity formation of novices if we provide sustained, integrated interprofessional education curriculum. This implies that we need: embedded, longitudinal training; faculty role modeling of inquisitiveness, respectful relationships, and risk taking; and safe and honest discussion about our differences. PMID- 26652634 TI - Does gender matter? Differences between students at an interprofessional training ward. AB - Studies on graduates' transitions from education into clinical work highlight inequalities concerning how women and men experience their professional learning and development. This study explores how female and male students from different programs within the health care education system (i.e. medicine, nursing, occupational therapy, and physiotherapy programmes) experience an interprofessional training ward (IPTW) as a part of their professional identity formation. Students from the medicine, nursing, physiotherapy, and occupational therapy programmes collaborate in teams during two weeks at one of three IPTWs at the medical school, Linkoping University. They together take the responsibility for diagnosis, treatment, and rehabilitation of the patients, albeit with professional supervisors as support. During 2010 to 2011, 454 (93%) of the 488 students who practiced at the IPTWs answered a questionnaire on their experiences of the IPTW. The students stated that the IPTW had positively influenced their professional development. The female and male medical students were significantly less positive than other female and male students, respectively, concerning the value of IPTW. The male students from all programmes were slightly, but significantly, less positive than all the female students. These findings show that students "do gender" as an integral part of the educational practice. It is important to scrutinise the IPTW as an educational practice, influencing students' preparation for future work. Gender should be discussed not only during the IPTW rotation but also in general during the curriculum for all healthcare programmes. PMID- 26652635 TI - Design and evaluation of interprofessional cross-cultural communication sessions. AB - The 2013 National Standards for Culturally and Linguistically Appropriate Services (CLAS) call for healthcare professionals to provide quality care and services that are responsive to diverse cultural health beliefs and practices. Accreditation organizations for health professional programs require their curriculum to adequately prepare future practitioners for serving culturally and linguistically diverse populations. Another common curricular need of health professional programs is interprofessional education (IPE). This study presents data that evaluates two IPE culturally competent communication sessions designed for pharmacy and nursing students. Teams of nursing and pharmacy students (n = 160) engaged in case studies focused on developing cross-cultural communication skills, using the LEARN model. Quantitative survey data collected pre-test and post-test measured cultural competency (including subscales of perceived skills, perceived knowledge, confidence in encounter, and attitude) and knowledge related to culturally competent communication. Univariate ANOVA results indicate that actual knowledge as measured by the test and all four Clinical Cultural Competency Questionnaire (CCCQ) subscales significantly increased after the IPE sessions. Pharmacy students scored higher than nursing students on the knowledge pre-test, and nursing students had a more positive attitude at pre-test. The IPE sessions effectively addressed all learning outcomes and will continue in future course offerings. Using cross-cultural communication as a thematic area for IPE program development resulted in educational benefits for the students. To further strengthen nursing and pharmacy students' interprofessional practice, additional IPE opportunities are to be explored. PMID- 26652636 TI - A comparative study of professional and interprofessional values between health professional associations. AB - The need for effective interprofessional collaboration to ensure safe patient care is crucial. However, health professions are guided by separate professional codes of conduct. To examine whether professional codes are consistent across professions, this review examines 13 key health professional associations in the United States and compares their values to the guiding principles of interprofessional practice defined by the Interprofessional Professionalism Collaborative (IPC). Findings indicate that all six of the IPC's principles (altruism/caring, excellence, ethics, respect, communication, and accountability) were shared by the majority of professions, with many emphasizing two additional attributes, integrity and justice, suggesting there is room to expand the IPC's core principles. Few associations included interprofessional communication and collaboration in their professional codes. There is potential for associations to promote greater interprofessional collaboration by reshaping their professional frameworks. With many shared values across professions, establishing a common framework of interprofessional professionalism is feasible. PMID- 26652637 TI - One Health: An opportunity for an interprofessional approach to healthcare. AB - One Health has been viewed as the collaborative effort between professions and disciplines working locally, nationally, and globally to attain optimal health for people, animals, and the environment. For One Health principles to be operationalised, interprofessional education and interprofessional collaborative practice are essential. However, interprofessional initiatives between the human health professions and veterinary medicine focus primarily on patient care in the human health setting. The purpose of this report is to describe two models of collaboration between human and veterinary medicine that have been designed to address human and animal health challenges in practice. Initiatives that involve this cooperation are providing access to affordable and clean drinking water. Implications linked to these initiatives are explored in relation to the need for an interprofessional approach to attain optimal health for people, animals, and the environment. PMID- 26652638 TI - A novel interprofessional approach to end-of-life care education: A pilot study. AB - Navigating the biomedical, emotional, and logistical complexity of end-of-life (EOL) care requires seamless interprofessional teamwork. Unfortunately, EOL care, interprofessional collaboration, and the role of support services such as hospice are not adequately emphasized in nursing and medical curricula. This article describes a student-run program, entitled the "HeArt of Medicine", which was designed to foster a reflective and collaborative approach to EOL care. The program consists of three workshops with a novel blend of art, science, and practical information, highlighting the need for interprofessional teamwork. Participants were surveyed before and after the workshops on their attitudes toward EOL care. Composite participant scores after workshops demonstrated increased comfort with and knowledge of EOL care topics (p = 0.001). The results show that this program has had a positive impact on participants' knowledge, comfort, and collaboration in EOL settings. PMID- 26652639 TI - Developing a culture of safety: Exploring students' perceptions of errors in an interprofessional setting. AB - Healthcare has a long tradition of silence around mistakes that cause or have the potential to cause harm to a patient, and there is evidence that this culture may be present from the beginning of a health professional's training. The purpose of this pilot study was to examine a team of interprofessional students' interactions with a preceptor in a simulation environment. The debriefing explored the students' reactions and assisted them with how to manage similar situations in the future to improve patient safety. The results showed that the students felt powerless to stop the simulated preceptor from doing harm to the patient, or to even question the preceptor's unsafe actions. Recommendations for educators include incorporating discussions and interprofessional training about handling mistakes into the curriculum, in the context of patient safety. PMID- 26652640 TI - Determining the need for team-based training in delirium management: A needs assessment of surgical healthcare professionals. AB - The high incidence of delirium in surgical units is a serious quality concern, given its impact on morbidity and mortality. While successful delirium management depends upon interdisciplinary care, training needs for surgical teams have not been studied. A needs assessment of surgical units was conducted to determine perceived comfort in managing delirium, and interprofessional training needs for team-based care. We administered a survey to 106 General Surgery healthcare professionals (69% response rate) with a focus on attitudes towards delirium and team management. Although most respondents identified delirium as important to patient outcomes, only 61% of healthcare professionals indicated that a team based approach was always observed in practice. Less than half had a clear understanding of their role in delirium care, while just over half observed team communication of delirium care plans during handover. This is the first observation of clear gaps in perceived team performance in a General Surgery setting. PMID- 26652642 TI - Efficient Formation of Ultracold Molecules with Chirped Nanosecond Pulses. AB - We describe experiments and associated quantum simulations involving the production of ultracold (87)Rb2 molecules with nanosecond pulses of frequency chirped light. With appropriate chirp parameters, the formation is dominated by coherent processes. For a positive chirp, excited molecules are produced by photoassociation early in the chirp, and then transferred into high vibrational levels of the lowest triplet state by stimulated emission later in the chirp. Generally good agreement is seen between the data and the simulations. Shaping of the chirp can lead to a significant enhancement of the formation rate. Further improvements using higher intensities and different intermediate states are predicted. PMID- 26652643 TI - Collaborative research networks in health: a pragmatic scoping study for the development of an imaging network. AB - BACKGROUND: Collaborative research networks are often touted as a solution for enhancing the translation of knowledge, but questions remain about how to evaluate their impact on health service delivery. This pragmatic scoping study explored the enabling factors for developing and supporting a collaborative imaging network in a metropolitan university in Australia. METHODS: An advisory group was established to provide governance and to identify key informants and participants. Focus group discussions (n = 2) and semi-structured interviews (n = 22) were facilitated with representatives from a broad range of disciplines. In addition, a survey, a review of relevant websites (n = 15) and a broad review of the literature were undertaken to elicit information on collaborative research networks and perceived needs and factors that would support their involvement in a multi-disciplinary collaborative research network. Findings were de-identified and broad themes were identified. RESULTS: Participants identified human factors as having priority for developing and sustaining a collaborative research network. In particular, leadership, a shared vision and a communication plan that includes social media were identified as crucial for sustaining an imaging network in health research. It is important to develop metrics that map relationships between network members and the role that communication tools can contribute to this process. CONCLUSIONS: This study confirms that human factors remain significant across a range of collaborative endeavours. The use of focus group discussions, interviews, and literature and website reviews means we can now strongly recommend the primacy of human factors. More work is needed to identify how the network operates and what specific indicators or metrics help build the capacity of clinicians and scientists to participate in translational research. PMID- 26652644 TI - Exploring Effectiveness of Computer-Aided Planning in Implant Positioning for a Single Immediate Implant Placement. AB - The value of computer-aided implant planning using cone-beam computerized tomography (CBCT) for single immediate implants was explored. Eighteen patients requiring extraction of a tooth followed by a single immediate implant were enrolled. Small volume preoperative CBCT scans were used to plan the position of the implant. A taper screwed-type implant was immediately placed into a fresh socket using only the final 1 or 2 drills for osteotomy. Postoperative CBCTs were used for the analysis of actual implant placement positioning. Measurements of the planned and the actual implant position were made with respect to their position relative to the adjacent teeth. Mesio-distal displacements and the facial-lingual deviation of the implant from the planned position were determined. Changes in the angulation of the planned and actual implant position in relation to the clinical crown were also measured. To statistically summarize the results, box plots and 95% CIs for means of paired differences were used. The analysis showed no statistical difference between the planned position and final implant placement position in any measurement. The CBCT scans coupled with the computer-aided implant planning program along with a final 1-to-2 drill protocol may improve the accuracy of single immediate implant placement for taper screwed type implants. PMID- 26652645 TI - Angiogenesis inhibitors for patients with ovarian cancer: a meta-analysis of 12 randomized controlled trials. AB - OBJECTIVES: To investigate the effects of angiogenesis inhibitors in the treatment of patients with advanced or recurrent ovarian cancer, a meta-analysis was performed and overall survival (OS), progression-free survival (PFS), and toxicity were assessed. PATIENTS AND METHODS: The PubMed and Embase databases, and the Cochrane Central Register of Controlled Trials were searched for publications between January 2000 and June 2015. Hazard ratios (HRs) with their 95% confidence intervals (CIs), or data for calculating HRs with 95% CIs were derived. RESULTS: The 12 trials in this meta-analysis were divided into three groups: four trials with a VEGF inhibitor (the bevacizumab group), six trials with VEGFR inhibitors (the VEGFRIs group), and two trials with an angiopoietin inhibitor (the trebananib group). PFS improvement was seen in all groups (HR = 0.61, 95% CI 0.48 to 0.79, P < 0.001 for bevacizumab; HR = 0.71, 95% CI 0.59 to 0.87, P = 0.001 for VEGFRIs; and HR = 0.67, 95% CI 0.62 to 0.72, P < 0.001 for trebananib). Regarding OS, bevacizumab showed a trend of improvement (HR = 0.90, 95% CI 0.80 to 1.01, P = 0.079), VEGFRIs showed no improvement (HR = 0.92, 95% CI 0.75 to 1.11, P = 0.368), and trebananib demonstrated a significant prolongation (HR = 0.81, 95% CI 0.67 to 0.99, P = 0.036). Bevacizumab was associated with more class-specific adverse events (RR = 4.05, 95% CI 1.99 to 8.27, P < 0.001). Although the toxicity profiles differed, VEGFRIs developed common higher incidences of hypertension, diarrhea, and fatigue. A higher incidence of edema was reported in the trebananib group (RR = 2.60, 95% CI 0.84 to 8.00, P = 0.097). CONCLUSIONS: Anti-angiogenic therapy showed clear PFS benefit with increased toxicity, but its role in OS was undefined for ovarian cancer which emphasized the need for patient selection. PMID- 26652646 TI - Solution-Processed Gas Sensors Employing SnO2 Quantum Dot/MWCNT Nanocomposites. AB - Solution-processed SnO2 colloidal quantum dots (CQDs) have emerged as an important new class of gas-sensing materials due to their potential for low-cost and high-throughput fabrication. Here we employed the design strategy based on the synergetic effect from highly sensitive SnO2 CQDs and excellent conductive properties of multiwalled carbon nanotubes (MWCNTs) to overcome the transport barrier in CQD gas sensors. The attachment and coverage of SnO2 CQDs on the MWCNT surfaces were achieved by simply mixing the presynthesized SnO2 CQDs and MWCNTs at room temperature. Compared to the pristine SnO2 CQDs, the sensor based on SnO2 quantum dot/MWCNT nanocomposites exhibited a higher response upon exposure to H2S, and the response toward 50 ppm of H2S at 70 degrees C was 108 with the response and recovery time being 23 and 44 s. Because of the favorable energy band alignment, the MWCNTs can serve as the acceptor of the electrons that are injected from H2S into SnO2 quantum dots in addition to the charge transport highway to direct the electron flow to the electrode, thereby enhancing the sensor response. Our research results open an easy pathway for developing highly sensitive and low-cost gas sensors. PMID- 26652647 TI - Prevalence of frailty and contributory factors in three Chinese populations with different socioeconomic and healthcare characteristics. AB - BACKGROUND: Frailty predicts dependence and mortality, and is an important health indicator for aging populations. Comparing frailty prevalence between populations of the same ethnicity but different socioeconomic, lifestyle, health and social care systems, and environmental characteristics would address the role of these factors in contributing to frailty. METHODS: We compare frailty prevalence and contributory factors across three Chinese populations: Beijing rural, Beijing urban, and Hong Kong (urban). Older people aged 65 years and above living in the community were invited to respond to a general health questionnaire covering demographic, socioeconomic, medical and drug histories, geriatric syndromes, assessment of physical and cognitive functioning, psychological wellbeing and nutritional status. Frailty is defined as an index calculated from multiple deficits > = 0.25 (FI). The ratio of FI/life expectancy at birth was used as an indicator of compression of morbidity. Risk factors and attributable fraction for frailty were compared across the three cohorts. RESULTS: The prevalence of frailty increases with age in all three cohorts, and was lower among rural compared with urban (Beijing and Hong Kong) populations. The highest FI/LE ratio was observed in the Beijing urban population, followed by Hong Kong, with the Beijing rural population having the lowest ratio. Risk factors for frailty were similar in all three populations. Those having the highest ORs were multi morbidity (number of diseases > = 3), polypharmacy (number of drugs > = 4), age 85+, female gender, followed by low education level, and physical inactivity. For all three cohorts, age and multi-morbidity constitute the highest attributable fraction, and were highest in the Beijing rural cohort. A major difference between the Beijing and Hong Kong cohorts is the high AF from polypharmacy in Beijing and the 'protective' contribution of being married; and the effect of being a teetotaler in the Hong Kong cohort. CONCLUSIONS: This comparison draws attention to the importance of frailty prevention for ageing populations. PMID- 26652648 TI - Behind the wheel: community consultation informs adaptation of safe-transport program for older drivers. AB - BACKGROUND: Safe-transport is important to well-being in later life but balancing safety and independence for older drivers can be challenging. While self regulation is a promising tool to promote road safety, more research is required to optimise programs. METHODS: Qualitative research was used to inform the choice and adaptation of a safe-transport education program for older drivers. Three focus groups were conducted with older drivers living in northwest Sydney to explore four key areas related to driving in later life including aged-based licensing, stopping or limiting driving, barriers to driving cessation and alternative modes of transportation. Data were analysed using content analysis. RESULTS: Four categories emerged from the data; bad press for older drivers, COMPETENCE not age, call for fairness in licensing regulations, and hanging up the keys: It's complicated! Two key issues being (1) older drivers wanted to drive for as long as possible but (2) were not prepared for driving cessation; guided the choice and adaption of the Knowledge Enhances Your Safety (KEYS) program. This program was adapted for the Australian context and focus group findings raised the need for practical solutions, including transport alternatives, to be added. Targeted messages were developed from the data using the Precaution Adoption Process Model (PAPM), allowing the education to be tailored to the individual's stage of behaviour change. CONCLUSION: Adapting our program based on insights gained from community consultation should ensure the program is sensitive to the needs, skills and preferences of older drivers. PMID- 26652649 TI - Platelet-derived growth factor (PDGF)-AA/AB in human serum are potential indicators of the proliferative capacity of human synovial mesenchymal stem cells. AB - INTRODUCTION: For expansion of human mesenchymal stem cells (MSCs), autologous human serum is safer than fetal bovine serum in clinical situations. One of the problems with the use of autologous human serum is that its proliferative effect on MSCs varies widely between donors. The threefold goals of this study were: (1) to demonstrate an improved method for preparing human serum; (2) to identify growth factors predictive of proliferative potential; and (3) to identify a cytokine to promote MSC proliferation in human serum. METHODS: Fresh blood was collected using a closed bag system containing glass beads. The bag was shaken at 20 degrees C for 30 minutes for rapid preparation, or kept stationary at 4 degrees C for 24 hours for slow preparation. Passage 0 synovial MSCs derived from four donors were cultured with 10 % conventional rapid preparation serum or modified slow preparation serum from four different donors. To perform the colony forming unit assay, synovial MSCs were cultured in these serums. The protein expression profile in serum was analyzed using cytokine array. The candidate proteins were speculated from the correlation between the colony-forming ability and protein expression. As an evaluation of the candidate proteins, proliferation ability, surface marker phenotype and differentiation capability of synovial MSCs were examined. RESULTS: Compared with rapid preparation serum, slow preparation serum resulted in a significantly higher total colony number and twofold higher expression levels of nine proteins (angiopoietin-1, BDNF, EGF, ENA-78, IGFBP-2, platelet-derived growth factor (PDGF)-AA, PDGF-AB/BB, RANTES and TfR). Colony number was positively correlated with PDGF-AA/AB concentrations. Exogenous PDGF AA significantly promoted proliferation of synovial MSCs, whereas PDGF receptor (PDGFR) inhibitor decreased it. Addition of PDGFs or PDGFR inhibitor did not affect surface epitopes of synovial MSCs. Pretreatment with PDGFs or PDGFR inhibitor did not affect chondrogenic, adipogenic, or calcification potentials of synovial MSCs. CONCLUSION: Slow preparation serum contained higher concentrations of PDGF-AA/AB and increased the colony formation number of synovial MSCs. PDGF AA/AB were indicators of the proliferative potential of human serum. Exogenous PDGF-AA increased proliferation of synovial MSCs without alteration of surface epitopes and differentiation potentials. PMID- 26652650 TI - Mucilaginibacter roseus sp. nov., isolated from a freshwater river. AB - A bacterial strain, designated TTM-1T, was isolated from a water sample taken from the Caohu River in Taiwan and characterized in a taxonomic study using a polyphasic approach. Cells of strain TTM-1T were Gram-stain-negative, aerobic, non-motile, rod-shaped and covered by large capsules, and formed pink-coloured colonies. Growth occurred at 10-37 degrees C (optimum 30-37 degrees C), at pH 6 8 (optimum pH 6-7) and with 0-2 % NaCl (optimum 0.5 %). Phylogenetic analyses based on 16S rRNA gene sequences showed that strain TTM-1T belonged to the genus Mucilaginibacter and was most closely related to Mucilaginibacter defluvii A5T with a 16S rRNA gene sequence similarity of 97.3 %. The predominant fatty acids of strain TTM-1T were summed feature 3 (C16 : 1omega7c and/or C16 : 1omega6c; 37.1 %) and iso-C15 : 0 (30.7 %). The polar lipid profile consisted of phosphatidylethanolamine and several uncharacterized aminophospholipids and phospholipids. The major isoprenoid quinone was MK-7. The DNA G+C content of the genomic DNA was 45.1 mol%. The DNA-DNA relatedness of strain TTM-1T with respect to recognized species of the genus Mucilaginibacter was less than 70 %. On the basis of the phylogenetic inference and phenotypic data, strain TTM-1T represents a novel species of the genus Mucilaginibacter, for which the name Mucilaginibacter roseus sp. nov. is proposed. The type strain is TTM-1T ( = LMG 28454T = KCTC 42273T). PMID- 26652651 TI - Pathobiology of pancreatic cancer: implications on therapy. AB - Although the concept of tumor heterogeneity was established several decades ago, the interest in this topic is still unbroken. With the identification of inter- and intratumoral genomic rearrangements and the detection of cancer stem cells (CSCs) through phenotypic variations of cancer cells there are increasing options for pancreatic cancer therapy. Indeed, some pre-clinical studies have shown promising results in the treatment of drug-resistant CSCs, whereby a few strategies were already tested in clinical trials. Basically, CSCs are influenced by the tumor microenvironment and an epigenetic reprogramming to gain stem cell like characteristics. Targeting options inhibiting the epithelial-mesenchymal crosstalk or promoting epigenetic-driven differentiation of CSCs to a less aggressive phenotype raised the possibilities of further therapeutic applications, which will be discussed in this review. PMID- 26652652 TI - Transient generation of hydrogen peroxide is responsible for carcinostatic effects of hydrogen combined with platinum nanocolloid, together with increases intracellular ROS, DNA cleavages, and proportion of G2/M-phase. AB - In our previous study, we demonstrated that combined treatment with hydrogen (H2) and platinum nanocolloid (Pt-nc) exerted markedly antiproliferative effects on cancer cells compared with each treatment alone. However, because the related mechanisms remain unclear, we investigated carcinostatic mechanisms of the combined treatment with H2 + Pt-nc. Significant suppression of cell proliferation was confirmed at 52 h following combined treatment, and the similar effect was also observed by the 30- or 40-min transient treatment with H2 + Pt-nc. The transient treatments led to changes in cell size and morphology, loss of microvilli, and apoptosis-like cell death at 120 h after treatment. Moreover, transient combined treatment with H2 + Pt-nc induced cell-cycle arrest, as reflected by decreased proportions of G1-phase cells and accumulation of G2/M phase cells. In contrast, intracellular peroxide levels were temporarily and significantly increased immediately after H2 + Pt-nc treatment but not after treatment with H2 or Pt-nc alone. Additionally, combined treatment-induced carcinostatic effects were significantly diminished in the presence of catalase, and marked hydrogen peroxide (H2O2) generation was confirmed after mixing Pt-nc into cell culture media containing a high concentration of H2. These changes are in agreement with the results that carcinostatic effects were induced after only 40 min of treatment with H2 + Pt-nc. Thus, transient and marked generation of H2O2 is responsible for the carcinostatic effects of combined treatment with H2 + Pt-nc. PMID- 26652653 TI - On the influence of protein-DNA register during homologous recombination. AB - Homologous recombination enables the exchange of genetic information between related DNA molecules and is a driving force in evolution. Using single-molecule optical microscopy we have recently shown that members of the Rad51/RecA family of recombinases stabilize paired homologous strand of DNA in precise 3-nt increments. Here we discuss an interesting conceptual implication of these results, which is that the recombinases may actively sense and reorganize their alignment register relative to the bound DNA sequences to ensure optimal base triplet pairing interactions during the early stages of recombination. PMID- 26652654 TI - The Anchored Flexibility Model in LC8 Motif Recognition: Insights from the Chica Complex. AB - LC8 is a dimeric hub protein involved in a large number of interactions central to cell function. It binds short linear motifs--usually containing a Thr-Gln-Thr (TQT) triplet--in intrinsically disordered regions of its binding partners, some of which have several LC8 recognition motifs in tandem. Hallmarks of the 7-10 amino acid motif are a high variability of LC8 binding affinity and extensive sequence permutation outside the TQT triplet. To elucidate the molecular basis of motif recognition, we use a 69-residue segment of the human Chica spindle adaptor protein that contains four putative TQT recognition motifs in tandem. NMR-derived secondary chemical shifts and relaxation properties show that the Chica LC8 binding domain is essentially disordered with a dynamically restricted segment in one linker between motifs. Calorimetry of LC8 binding to synthetic motif mimicking peptides shows that the first motif dominates LC8 recruitment. Crystal structures of the complexes of LC8 bound to each of two motif peptides show highly ordered and invariant TQT-LC8 interactions and more flexible and conformationally variable non-TQT-LC8 interactions. These data highlight rigidity in both LC8 residues that bind TQT and in the TQT portion of the motif as an important new characteristic of LC8 recognition. On the basis of these data and others in the literature, we propose that LC8 recognition is based on rigidly fixed interactions between LC8 and TQT residues that act as an anchor, coupled with inherently flexible interactions between LC8 and non-TQT residues. The "anchored flexibility" model explains the requirement for the TQT triplet and the ability of LC8 to accommodate a large variety of motif sequences and affinities. PMID- 26652655 TI - The complete mitochondrial genome of the palette surgeonfish, Paracanthurus hepatus (Perciformes: Acanthuridae). AB - In this study, the complete mitogenome sequence of the palette surgeonfish, Paracanthurus hepatus (Perciformes: Acanthuridae), has been sequenced by next generation sequencing method. The assembled mitogenome was 16 498 bp in length, consisted of 13 protein-coding genes, 22 transfer RNAs, 2 ribosomal RNAs genes. The overall base composition of palette surgeonfish was 28.6% for A, 28.6% for C, 16.3% for G, 26.4% for T and showed 87% identities to somber surgeonfish Zebrasoma flavescens. The complete mitogenome of the palette surgeonfish provides essential and important DNA molecular data for further phylogeography and evolutionary analysis for surgeonfish's phylogeny. PMID- 26652656 TI - Albumin Incorporation in Polyethylenimine-DNA Polyplexes Influences Transfection Efficiency. AB - Polyplexes of plasmid with synthetic polycationic vectors, such as linear polyethylenimine (LPEI), have been widely investigated. While much is known about the role of physicochemical characterization of the polycation in transfection, the role of serum components in the transfection using LPEI-polyplexes needs further investigation. In this study, bovine serum albumin was incorporated into the polyplex, either through precomplexation with circular DNA coding for green fluorescent protein prior to polyplex formation with LPEI or after formation of the polyplex. The transfection efficiency of these ternary polyplexes was then studied in HeLa cells. It was observed that the order of incorporation of albumin into polyplexes has a distinct effect on its uptake and transfection efficiency. Through colocalization and albumin depletion studies, we conclude that albumin plays a role in both the translocation of the complex into the cell and its unpackaging. PMID- 26652657 TI - Embodied self-regulation and mindful self-care in the prevention of eating disorders. PMID- 26652658 TI - Influence of methanethiol on biological sulphide oxidation in gas treatment system. AB - Inorganic and organic sulphur compounds such as hydrogen sulphide (H2S) and thiols (RSH) are unwanted components in sour gas streams (e.g. biogas and refinery gases) because of their toxicity, corrosivity and bad smell. Biological treatment processes are often used to remove H2S at small and medium scales (<50 tons per day of H2S). Preliminarily research by our group focused on achieving maximum sulphur production from biological H2S oxidation in the presence of methanethiol. In this paper the underlying principles have been further studied by assessing the effect of methanethiol on the biological conversion of H2S under a wide range of redox conditions covering not only sulphur but also sulphate producing conditions. Furthermore, our experiments were performed in an integrated system consisting of a gas absorber and a bioreactor in order to assess the effect of methanethiol on the overall gas treatment efficiency. This study shows that methanethiol inhibits the biological oxidation of H2S to sulphate by way of direct suppression of the cytochrome c oxidase activity in biomass, whereas the oxidation of H2S to sulphur was hardly affected. We estimated the kinetic parameters of biological H2S oxidation that can be used to develop a mathematical model to quantitatively describe the biodesulphurization process. Finally, it was found that methanethiol acts as a competitive inhibitor; therefore, its negative effect can be minimized by increasing the enzyme (biomass) concentration and the substrate (sulphide) concentration, which in practice means operating the biodesulphurization systems under low redox conditions. PMID- 26652659 TI - Long-Term Anticoagulation for Unprovoked Pulmonary Embolism, Monitoring Sleep with an App, and Interventional Bronchoscopy for Airway Obstruction. PMID- 26652660 TI - Mechanisms of the Effect of Involuntary Retirement on Older Adults' Self-Rated Health and Mental Health. AB - This study examined mechanisms of the effect of involuntary retirement on self rated health and mental health among adults aged 50 or older. Using two waves of the Health and Retirement Study (2006 and 2010), we selected a sample of 1,195 individuals working for pay at baseline who responded to a lifestyle questionnaire in both waves. Regression-based path analyses were conducted to test the mediating effects of financial control, positive and negative family relationships, and social integration on the relationship between involuntary retirement and self-rated health and mental health. Results of mediation analyses indicated that transition to involuntary retirement was directly negatively associated with subsequent self-rated health and indirectly negatively associated with mental health via perception of less financial control. Voluntary retirement was indirectly positively associated with both self-rated and mental health via perception of more financial control. No significant direct or indirect effects of retirement were found when retirement was measured with an aggregate measure without specifying its voluntariness. Findings emphasize the importance of specifying the voluntariness of retirement and recognizing the heterogeneity in the mechanisms of involuntary and voluntary retirement. PMID- 26652661 TI - Emulsion Synthesis of Size-Tunable CH3NH3PbBr3 Quantum Dots: An Alternative Route toward Efficient Light-Emitting Diodes. AB - We report a facile nonaqueous emulsion synthesis of colloidal halide perovskite quantum dots by controlled addition of a demulsifier into an emulsion of precursors. The size of resulting CH3NH3PbBr3 quantum dots can be tuned from 2 to 8 nm by varying the amount of demulsifier. Moreover, this emulsion synthesis also allows the purification of these quantum dots by precipitation from the colloidal solution and obtains solid-state powder which can be redissolved for thin film coating and device fabrication. The photoluminescence quantum yields of the quantum dots is generally in the range of 80-92%, and can be well-preserved after purification (~80%). Green light-emitting diodes fabricated comprising a spin cast layer of the colloidal CH3NH3PbBr3 quantum dots exhibited maximum current efficiency of 4.5 cd/A, power efficiency of 3.5 lm/W, and external quantum efficiency of 1.1%. This provides an alternative route toward high efficient solution-processed perovskite-based light-emitting diodes. In addition, the emulsion synthesis is versatile and can be extended for the fabrication of inorganic halide perovskite colloidal CsPbBr3 nanocrystals. PMID- 26652662 TI - Depressive symptomatology and associated factors in dementia in Europe: home care versus long-term care. AB - BACKGROUND: This study forms part of a larger European programme investigating the transition from home care to long-term care (LTC) facility in people with dementia (PwD) at the margins of LTC. The aim of this study was to explore the factors associated with depressive symptomatology in PwD in different settings. METHODS: A total of 1,538 PwD, of which 957 received home care and 581 lived in a LTC facility, and their carers were interviewed. The Cornell Scale for Depression in Dementia (CSDD) measured depressive symptomatology. PwD completed measures of cognition and quality of life (QoL), and informal or formal carers completed measures on the PwD' QoL, neuropsychiatric behavior, activities of daily living, comorbidities, pain, and falls. Logistic regression was used to assess which factors contributed to depressive symptomatology in the two settings. RESULTS: Those receiving home care, living in Germany, and with severe dementia, showed the highest prevalence of depressive symptomatology. In the home care group, high levels of pain, neuropsychiatric behavior, and comorbidity, as well as low self- and proxy-rated QoL were factors associated with depressive symptomatology. In the LTC group, low proxy-rated QoL, more severe neuropsychiatric behavior, being a male informal carer and living in Germany were associated with depressive symptomatology. CONCLUSIONS: Evidence highlights the need for targeting different aspects in the management of depression in dementia, including offering improved pain management for those living in the community. Further research needs to explore cultural variations and carer gender factors associated with higher levels of depressive symptomatology. PMID- 26652663 TI - Metal-Free Microwave-Assisted Decarboxylative Elimination for the Synthesis of Olefins. AB - A metal-free efficient synthesis of olefins via microwave-assisted direct decarboxylative elimination of arylacetic acids is described. This reaction, using commercially available reagent PIFA as oxidant, readily provides a variety of desired products in moderate to good yields. PMID- 26652664 TI - CT fluoroscopy-guided closed-tip catheter placement before regional hyperthermia treatment of soft tissue sarcomas: 5-Year experience in 35 consecutive patients. AB - PURPOSE: This study was designed to assess technical success and complications in patients with high-risk soft tissue sarcomas undergoing CT fluoroscopy-guided closed-tip catheter placement before treatment with combined chemotherapy and regional hyperthermia. MATERIALS AND METHODS: This retrospective study comprised all patients referred for insertion of closed-tip catheters for the introduction of thermometry probes before regional hyperthermia treatment at a single university centre from 2010 to 2015. Catheter placements were performed under local anaesthesia and intermittent CT fluoroscopy guidance. Technical success, complication rate, duration of catheter insertion and dose-length product (DLP) were analysed. Technical success was defined as intratumoural catheter placement suitable for subsequent thermometry. RESULTS: A total of 35 procedures were performed on 35 patients (22 men, 13 women). In 34 out of 35 interventions catheters were inserted successfully; in one patient catheter placement was not feasible. No intra-interventional complications occurred. In six patients post interventional complications were observed - two major (one abscess formation and one severe catheter dislocation) and four minor complications. Technical failure was observed in 11.4% of patients, especially catheter kinking. A total of 55 catheters were placed, with a mean number of 1.7 +/- 0.7 per patient. Mean total DLP was 723.2 +/- 355.9 mGy*cm. CONCLUSION: CT fluoroscopy-guided closed-tip catheter placement into high-risk soft tissue sarcomas was characterised by high technical success and relatively low complication rate. While major complications were rarely observed, catheter-kinking preventing successful thermometry represented the most frequent technical failure. PMID- 26652665 TI - Biofilm formation in an experimental water distribution system: the contamination of non-touch sensor taps and the implication for healthcare. AB - Hospital tap water is a recognised source of Pseudomonas aeruginosa. U.K. guidance documents recommend measures to control/minimise the risk of P. aeruginosa in augmented care units but these are based on limited scientific evidence. An experimental water distribution system was designed to investigate colonisation of hospital tap components. P. aeruginosa was injected into 27 individual tap 'assemblies'. Taps were subsequently flushed twice daily and contamination levels monitored over two years. Tap assemblies were systematically dismantled and assessed microbiologically and the effect of removing potentially contaminated components was determined. P. aeruginosa was repeatedly recovered from the tap water at levels above the augmented care alert level. The organism was recovered from all dismantled solenoid valves with colonisation of the ethylene propylene diene monomer (EPDM) diaphragm confirmed by microscopy. Removing the solenoid valves reduced P. aeruginosa counts in the water to below detectable levels. This effect was immediate and sustained, implicating the solenoid diaphragm as the primary contamination source. PMID- 26652666 TI - Colonisation and succession of marine biofilm-dwelling ciliate assemblages on biocidal antifouling and fouling-release coatings in temperate Australia. AB - Ciliate assemblages are often overlooked, but ubiquitous components of microbial biofilms which require a better understanding. Ciliate, diatom and bacterial colonisation were evaluated on two fouling-release (FR) coatings, viz. Intersleek 970 and Hempasil X3, and two biocidal antifouling (AF) coatings, viz. Intersmooth 360 and Interspeed 5640, in Port Phillip Bay, Australia. A total of 15 genera were identified during the 10 week deployment. Intersleek 970 displayed the most rapid fouling by ciliates, reaching 63.3(+/- 5.9) cells cm(-2). After 10 weeks, all four coatings were extensively fouled. However, the toxicity of the AF coatings still significantly inhibited microbial fouling compared to the FR coatings. On all treatments, colonies of sessile peritrichs dominated the ciliate assemblage in the early stage of succession, but as the biofilm matured, vagile ciliates exerted more influence on the assemblage structure. The AF coatings showed selective toxic effects, causing significant differences in the ciliate species assemblages among the treatments. PMID- 26652667 TI - Impact of diatomaceous biofilms on the frictional drag of fouling-release coatings. AB - Skin-friction results are presented for fouling-release (FR) hull coatings in the unexposed, clean condition and after dynamic exposure to diatomaceous biofilms for 3 and 6 months. The experiments were conducted in a fully developed turbulent channel flow facility spanning a wide Reynolds number range. The results show that the clean FR coatings tested were hydraulically smooth over much of the Reynolds number range. Biofilms, however, resulted in an increase in skin friction of up to 70%. The roughness functions for the biofilm-covered surfaces did not display universal behavior, but instead varied with the percentage coverage by the biofilm. The effect of the biofilm was observed to scale with its mean thickness and the square root of the percentage coverage. A new effective roughness length scale (keff) for biofilms based on these parameters is proposed. Boundary layer similarity-law scaling is used to predict the impact of these biofilms on the required shaft power for a mid-sized naval surface combatant at cruising speed. The increase in power is estimated to be between 1.5% and 10.1% depending on the biofilm thickness and percentage coverage. PMID- 26652671 TI - Twenty Years of Online Dating: Current Psychology and Future Prospects. PMID- 26652669 TI - Rapamycin reduces fibroblast proliferation without causing quiescence and induces STAT5A/B-mediated cytokine production. AB - Rapamycin is a well-known inhibitor of the Target of Rapamycin (TOR) signaling cascade; however, the impact of this drug on global genome function and organization in normal primary cells is poorly understood. To explore this impact, we treated primary human foreskin fibroblasts with rapamycin and observed a decrease in cell proliferation without causing cell death. Upon rapamycin treatment chromosomes 18 and 10 were repositioned to a location similar to that of fibroblasts induced into quiescence by serum reduction. Although similar changes in positioning occurred, comparative transcriptome analyses demonstrated significant divergence in gene expression patterns between rapamycin-treated and quiescence-induced fibroblasts. Rapamycin treatment induced the upregulation of cytokine genes, including those from the Interleukin (IL)-6 signaling network, such as IL-8 and the Leukemia Inhibitory Factor (LIF), while quiescent fibroblasts demonstrated up-regulation of genes involved in the complement and coagulation cascade. In addition, genes significantly up-regulated by rapamycin treatment demonstrated increased promoter occupancy of the transcription factor Signal Transducer and Activator of Transcription 5A/B (STAT5A/B). In summary, we demonstrated that the treatment of fibroblasts with rapamycin decreased proliferation, caused chromosome territory repositioning and induced STAT5A/B mediated changes in gene expression enriched for cytokines. PMID- 26652670 TI - Progression of neuropsychiatric and cognitive features due to exons 2 to 5 deletion in the epsilon-sarcoglycan gene: a case report. AB - Physical symptoms of myoclonus dystonia due to epsilon-sarcoglycan mutations are well documented; however, the progression of neuropsychiatric and cognitive symptoms remains unclear. We present a case of a 34-year-old woman with early childhood onset of myoclonic jerks, dystonic posture and developmental delay due to exons 2 to 5 deletion in the epsilon-sarcoglycan gene. Over time, she developed neuropsychiatric symptoms. She underwent bilateral deep brain stimulation of the ventral intermediate nucleus of the thalamus for her motor symptoms, which greatly improved but she exhibited slow deterioration of her neuropsychiatric and cognitive symptoms, particularly apathy, aggression and severe executive dysfunction. PMID- 26652672 TI - Predictors and Social Consequences of Online Interactive Self-Disclosure: A Literature Review from 2002 to 2014. AB - Computer-mediated communication has become ubiquitous in the lives of today's youth. The current review synthesizes recent findings regarding adolescents' and young adults' online interactive self-disclosure, with a particular emphasis on the direct antecedents and effects. Three broad categories of predictors are discussed, including demographic information and internal states, dispositional factors, as well as contextual factors. In addition, the synthesis of studies exploring consequences of online interactive self-disclosure indicates positive outcomes for social-related constructs. The article concludes with recommendations for future research, including the analysis of actual computer mediated exchanges and longitudinal research that takes into account the dynamic process of self-disclosure over time and across media. PMID- 26652673 TI - On Predicting Sociodemographic Traits and Emotions from Communications in Social Networks and Their Implications to Online Self-Disclosure. AB - Social media services such as Twitter and Facebook are virtual environments where people express their thoughts, emotions, and opinions and where they reveal themselves to their peers. We analyze a sample of 123,000 Twitter users and 25 million of their tweets to investigate the relation between the opinions and emotions that users express and their predicted psychodemographic traits. We show that the emotions that we express on online social networks reveal deep insights about ourselves. Our methodology is based on building machine learning models for inferring coarse-grained emotions and psychodemographic profiles from user generated content. We examine several user attributes, including gender, income, political views, age, education, optimism, and life satisfaction. We correlate these predicted demographics with the emotional profiles emanating from user tweets, as captured by Ekman's emotion classification. We find that some users tend to express significantly more joy and significantly less sadness in their tweets, such as those predicted to be in a relationship, with children, or with a higher than average annual income or educational level. Users predicted to be women tend to be more opinionated, whereas those predicted to be men tend to be more neutral. Finally, users predicted to be younger and liberal tend to project more negative opinions and emotions. We discuss the implications of our findings to online privacy concerns and self-disclosure behavior. PMID- 26652674 TI - Assessment of Personality and Absorption for Mediated Environments in a College Sample. AB - While technological advancement enhances the effectiveness and versatility of mediated environments, researchers have sought to better understand how endogenous characteristics of individuals relate to the ways in which mediated environments are experienced. Although the Big Five personality traits and absorption have shown marked relations with reports of immersion, further investigation of these traits is needed. In particular, there is need for a psychometrically sound model that integrates these concepts. The aim of this study was to build upon previous research looking at the Big Five personality traits, absorption, and immersion in a large sample of college-aged individuals. Results indicate that the Big Five traits of neuroticism, openness to experience, and extraversion are positively related to immersion and that openness to experience possesses the strongest relationship with immersive tendency overall. By integrating an established measure of absorption, a more psychometrically sound model was achieved. PMID- 26652675 TI - The Relationship Between Video Game Play and the Acquired Capability for Suicide: An Examination of Differences by Category of Video Game and Gender. AB - This study examined the relationship between video game (VG) play and the acquired capability for suicide (ACS), as well as the moderating effects of VG category and gender on this relationship. Participants were 228 college students who played VGs on a weekly basis and who completed self-report assessments of VG play, painful and provocative events, and the ACS. Results indicated that there was a significant positive association between hours of VG play and the ACS. The action category of VGs was a significant moderator of the relationship between hours of VG play and the ACS after adjusting for previous painful and provocative events. Gender did not significantly moderate the relationship between hours of VG play and the ACS, and there was no significant three-way interaction between hours of VG play, playing action category VGs, and gender. This suggests that individuals who play many hours of action VGs may be more capable of lethal self harm if they experience suicide ideation, although this association does not exist for individuals who play other categories of VGs. PMID- 26652678 TI - Human plasma concentrations of five cytochrome P450 probes extrapolated from pharmacokinetics in dogs and minipigs using physiologically based pharmacokinetic modeling. AB - The pharmacokinetics of cytochrome P450 probes in humans can be extrapolated from corresponding data in cynomolgus monkeys using simplified physiologically based pharmacokinetic (PBPK) modeling. In the current study, despite some species difference in drug clearances, this modeling methodology was adapted to estimate human plasma concentrations of P450 probes based on data from commonly used medium-sized experimental animals, namely dogs and minipigs. Using known species allometric scaling factors and in vitro metabolic clearance data, the observed plasma concentrations of slowly eliminated caffeine and warfarin and rapidly eliminated omeprazole, metoprolol and midazolam in two young dogs were scaled to human oral monitoring equivalents. Using the same approach, the previously reported pharmacokinetics of the five P450 probes in minipigs was also scaled to human monitoring equivalents. The human plasma concentration profiles of the five P450 probes estimated by the simplified human PBPK models based on observed/reported pharmacokinetics in dogs/minipigs were consistent with previously published pharmacokinetic data in humans. These results suggest that dogs and minipigs, in addition to monkeys, could be suitable models for humans during research into new drugs, especially when used in combination with simple PBPK models. PMID- 26652679 TI - How Are Children of Older Mothers Doing? Evidence from the United Kingdom. AB - Childbearing has been increasingly delayed in Western countries. As older mothers are likely to be advantaged over their younger counterparts, the demographic literature has tended to view this demographic trend as potentially beneficial for child well-being. Conversely, less attention has been given to medical studies showing that giving birth at advanced ages is associated with health risks for children. This article uses data from the Millennium Cohort Study (UK) and ordinary least squares and logistic regression models to compare cognitive and behavioral outcomes, and obesity at age 5 for first-born children by maternal age at first birth. On one hand, the findings suggest that giving birth to the first child at ages 30-39 compared to ages 23-29 is positively associated with children's cognitive and behavioral outcomes and not associated with obesity. On the other hand, delaying the first birth to ages 40 and above is not associated with children's cognitive and behavioral outcomes and is associated with increased risk of obesity. Although the results are unable to support the argument that this occurs because of the health risks associated with giving birth at advanced maternal ages, they suggest that there is a need to more closely investigate the potential trade-offs involved when births are delayed toward older maternal ages. PMID- 26652680 TI - Are Improvements in Child Health Due to Increasing Status of Women in Developing Nations? AB - This research tests the hypothesis that change over time in women's status leads to improvements in their children's health. Specifically, we examine whether change in resources and empowerment in mother's roles as biological mothers, caregivers, and providers and social contexts that promote the rights and representation of and investment in women are associated with better nutritional status and survival of young children. Analysis is based on a broad sample of countries (n = 28), with data at two or more points in time to enable examination of change. Key indicators of child health show improvement in the last 13 years in developing nations. Much of this improvement--90 percent of the increase in nutritional status and 47 percent of the reduction in mortality--is associated with improving status of women. Increased maternal education, control over reproduction, freedom from violence, access to health care, legislation and enforcement of women's rights, greater political representation, equality in the education system, and lower maternal mortality are improving children's health. These results imply that further advancement of women's position in society would be beneficial. PMID- 26652681 TI - Fertility Decline and the 1918 Influenza Pandemic in Taiwan. AB - The impact of the 1918 influenza pandemic on human fertility has been subject to significant scholarly debate. The current study characterizes the inter-temporal association between excess deaths during the pandemic and the subsequent birth deficit by identifying the length of time between these two phenomena using cross correlations of monthly death and birth data from Taiwan from 1906 to 1943. The analysis demonstrates a strong and negative correlation between deaths (d) at time t and births (b) at time t + 9 (r(db)(9) = -0.68, p < .0001). In other words, a significant drop in births was observed nine months after pandemic mortality peaked. The findings suggest that the 1918 influenza pandemic impacted subsequent births primarily through the mechanism of reduced conceptions and embryonic loss during the first month of pregnancy rather than through late-first trimester embryonic loss. PMID- 26652682 TI - Blood Substrate Collection and Handling Procedures under Pseudo-Field Conditions: Evaluation of Suitability for Inflammatory Biomarker Measurement. AB - Routine incorporation of blood-based biomarker measurements in population studies has been hampered by challenges in obtaining samples suitable for biomarker assessment outside of laboratory settings. Here, we assessed the suitability of venous blood left unprocessed for 4, 24, or 48 hours post-collection at either room temperature or 4 degrees C for quantification of two biomarkers, Interleukin 6 (IL-6) and C-reactive protein (CRP). Blood samples were collected in both K2EDTA tubes and a dedicated plasma-preservation tube, P100. Dried blood spot (DBS) samples from the same subjects were also collected in order to compare delayed-processing plasma performance against a popular alternative collection method. We found that K2EDTA mean plasma concentrations of both IL-6 and CRP were not significantly different from concentrations in plasma processed immediately; this was observed for tubes stored up to 48 hours pre-processing at either temperature. Concentrations of IL-6 measured in P100 tubes showed significant time-dependent increases when stored at room temperature; otherwise, levels of IL 6 and CRP were similar to those found in samples processed immediately. Levels of CRP in DBS were correlated with plasma CRP levels, even when pre-processed blood was stored for up to 48 hours. These data indicate that plasma is suitable for IL 6 and CRP estimation under data collection conditions that involve processing delays. PMID- 26652684 TI - Sick But Unaware: Hypertension in Indonesia. AB - Discrepancies between self-reported and measured hypertension pose a great risk to health because they prevent timely treatment. Analyzing the Indonesian Family Life Survey, we compared self-reported and measured hypertension to assess the extent of the misclassification of hypertension. Building on this, we estimated factors related to self-reported and measured hypertension. Our results show that different factors were involved in each case, suggesting that they are two different phenomena. More importantly, we estimated factors that increased awareness of hypertension and found that visiting a health facility was a very effective way of increasing awareness of hypertension among hypertensive patients. PMID- 26652683 TI - Validation of Biomarkers of CVD Risk from Dried Blood Spots in Community-Based Research: Methodologies and Study-Specific Serum Equivalencies. AB - Dried blood spot (DBS) methodology offers significant advantages over venipuncture in studies of vulnerable populations or large-scale studies, including reduced participant burden and higher response rates. Uncertainty about the validity of cardiovascular disease (CVD) risk biomarkers remains a barrier to wide-scale use. We determined the validity of DBS-derived biomarkers of CVD risk versus gold-standard assessments, and study-specific, serum-equivalency values for clinical relevance of DBS-derived values. Concurrent venipuncture serum and DBS samples (n = 150 adults) were assayed in Clinical Laboratory Improvement Amendments-certified and DBS laboratories, respectively. Time controls of DBS standard samples were assayed single-blind along with test samples. Linear regression analyses evaluated DBS-to-serum equivalency values; agreement and bias were assessed via Bland-Altman plots. Linear regressions of venipuncture values on DBS-to-serum equivalencies provided R(2) values for total cholesterol, high density lipoprotein cholesterol (HDL-C), and C-reactive protein (CRP) of 0.484, 0.118, and 0.666, respectively. Bland-Altman plots revealed minimal systematic bias between DBS-to-serum and venipuncture values; precision worsened at higher mean values of CRP. Time controls revealed little degradation or change in analyte values for HDL-C and CRP over 30 weeks. We concluded that DBS-assessed biomarkers represent a valid alternative to venipuncture assessments. Large studies using DBS should include study-specific serum-equivalency determinations to optimize individual-level sensitivity, the viability of detecting intervention effects, and generalizability in community-level primary prevention interventions. PMID- 26652685 TI - Corrigendum. PMID- 26652687 TI - The Moonlighter's List. PMID- 26652688 TI - Effects of Long-Term Exposure to Free Nepsilon-(Carboxymethyl)lysine on Rats Fed a High-Fat Diet. AB - Recently correlation studies between dietary advanced glycation end products (AGEs) and the progression of chronic diseases have attracted much attention. To explore the impact of dietary AGEs on the health risk of people consuming a high fat diet (HFD), male Sprague-Dawley rats were used as the research subject. Under HFD, free N(epsilon)-(carboxymethyl)lysine (CML, a major AGE, 60 mg/kg body weight/day) was administered by gavage for 12 consecutive weeks. The results indicated that protein-bound CML accumulation in the kidney, heart, lung, pancreas, and muscle significantly increased to 178 +/- 36, 161 +/- 2, 106 +/- 11, 39 +/- 8, and 141 +/- 20 MUg/g dry matter, respectively, compared to HFD control levels of 86 +/- 9, 127 +/- 10, 89 +/- 6, 23 +/- 2, and 95 +/- 3 MUg/g dry matter, whereas no statistical increase was found in the liver and spleen. An increase of the protein-bound CML might be due to free CML binding to proteins in tissues by covalent bonds. Moreover, the rats' serum low-density lipoprotein cholesterol concentration, fasting blood glucose levels, and energy expenditure also increased obviously. These findings indicated that long-term intake of high dose free CML might be a health risk factor for rats with HFD. This could provide valuable information for further study on the possible effects of long-term consumption of CML-rich fatty foods on human health, involving the progression of chronic disease. PMID- 26652689 TI - Analysis of occupational accidents: prevention through the use of additional technical safety measures for machinery. AB - This article presents an analysis of results of 1035 serious and 341 minor accidents recorded by Poland's National Labour Inspectorate (PIP) in 2005-2011, in view of their prevention by means of additional safety measures applied by machinery users. Since the analysis aimed at formulating principles for the application of technical safety measures, the analysed accidents should bear additional attributes: the type of machine operation, technical safety measures and the type of events causing injuries. The analysis proved that the executed tasks and injury-causing events were closely connected and there was a relation between casualty events and technical safety measures. In the case of tasks consisting of manual feeding and collecting materials, the injuries usually occur because of the rotating motion of tools or crushing due to a closing motion. Numerous accidents also happened in the course of supporting actions, like removing pollutants, correcting material position, cleaning, etc. PMID- 26652690 TI - Photodependent Melting of Unmodified DNA Using a Photosensitive Intercalator: A New and Generic Tool for Photoreversible Assembly of DNA Nanostructures at Constant Temperature. AB - External control of DNA melting and hybridization, a key step in bio- and DNA nanotechnology, is commonly achieved with temperature. The use of light to direct this process is a challenging alternative, which has been only possible with a DNA modification, such as covalent grafting or mismatch introduction, so far. Here we describe the first photocontrol of DNA melting that relies on the addition of a molecule that noncovalently interacts with unmodified DNA and affects its melting properties in a photoreversible and highly robust manner, without any prerequisite in the length or sequence of the target DNA molecule. We synthesize azobenzene-containing guanidinium derivatives and show that a bivalent molecule with a conformation-dependent binding mode, AzoDiGua, strongly increases the melting temperature (Tm) of DNA under dark conditions because its trans isomer intercalates in the DNA double helix. Upon UV irradiation at 365 nm, the trans-cis isomerization induced the ejection of AzoDiGua from the intercalation binding sites, resulting in a decrease in Tm up to 18 degrees C. This illumination-dependent Tm shift is observed on many types of DNA, from self complementary single-stranded or double-stranded oligonucleotides to long genomic duplex DNA molecules. Finally, we show that simply adding AzoDiGua allows us to photoreversibly control the assembly/disassembly of a DNA nanostructure at constant temperature, as demonstrated here with a self-hybridized DNA hairpin. We anticipate that this strategy will be the key ingredient in a new and generic way of placing DNA-based bio- and nanotechnologies under dynamic control by light. PMID- 26652691 TI - Mechanism for Asymmetric Nanoscale Electrowetting of an Ionic Liquid on Graphene. AB - The electrowetting behavior of 1-butyl-3-methylimidazolium tetrafluoroborate ([bmim][BF4]) confined between two oppositely charged graphene layers is investigated using molecular dynamics simulations. By introducing charges on the surface, counterions are attracted to the surface and co-ions are repelled from it, leading to the reduction of the solid-liquid interfacial free energy and consequently the contact angle. Recently, we have shown that changes in the contact angle upon charging the surface are asymmetric with respect to surface polarity and opposite to the changes in the solid-liquid interfacial free energy. In this work, the asymmetry of the solid-liquid interfacial free energy is shown to originate from differences in structural organization of the ions at the interface, with positively polarized surfaces inducing a more favorable electrostatic arrangement of the ions. Analysis of the liquid structure in the vicinity of the three phase contact line, however, shows that the ion size asymmetry, together with differences in orientational ordering of the cations on oppositely polarized surfaces, instead leads to enhanced spreading on the negatively polarized surfaces, resulting in a corresponding contact angle asymmetry. PMID- 26652692 TI - A review of supportive care and recommended preventive approaches for patients with chronic lymphocytic leukemia. AB - Chronic lymphocytic leukemia (CLL) is the most prevalent type of adult leukemia encountered in the western world. Patients with CLL are typically older, with a median age in the 70s, and are at risk for certain complications due to the disease itself and due to the therapies imparted for this. Patients with CLL are at a higher risk of infections, partly due to disease and partly due to the immune dysfunction induced by treatment, such as purine analogous-based chemoimmunotherapy, which leads to lymphocyte depletion. Infections are a leading cause of complications and death in CLL patients. Also, CLL patients have been shown to have a higher incidence of other malignancies. Despite this knowledge, there are no definite guidelines as to what is the best approach to manage or prevent these associated complications of CLL. In this review, the authors discuss the data available and outline recommendations as to the best way to approach this issue in daily practice. PMID- 26652693 TI - SPECT/CT demonstrates the osseointegrative response of a stemless shoulder prosthesis. AB - BACKGROUND: This study evaluates bone remodeling processes in the proximal humerus induced by the implantation of a stemless shoulder prosthesis with regard to time of response and type and extent of bone turnover. METHODS: Twenty-eight patients with primary osteoarthritis of the shoulder undergoing a stemless shoulder arthroplasty were prospectively evaluated. The local metabolic bone activity in 5 regions of interest (ROIs 1-5) around the implant and in 1 reference region (ROI ref.) in the humeral diaphysis was analyzed after the application of technetium Tc 99m DPD using single-photon emission computed tomography integrated with multidetector computed tomography (SPECT/CT). The study cohort was divided into 4 groups according to the timing of the most recent follow-up appointment to evaluate the primary osseointegrative response after surgery. The bone uptake values were expressed in target (ROIs 1-5) to nontarget (ROI ref.) ratios. RESULTS: No difference within the 4 subgroups with respect to the time of local metabolic bone activity in the ROIs was found at 90 days after surgery. The highest initial metabolic activity and most temporal modifications were found in ROI 1, which was localized in the superior segment of the stem. CONCLUSIONS: SPECT/CT data suggest that the primary osseointegration of a stemless shoulder prosthesis is almost completed 3 months after implantation. Variations in metabolic activity pattern in the ROIs during follow-up may be caused by different loading conditions of the bone. PMID- 26652694 TI - Outcomes using the extensor digitorum communis splitting approach for the treatment of radial head fractures. AB - BACKGROUND: Surgery on the radial head is usually performed via the Kocher interval. Iatrogenic injury to the posterior interosseous nerve (PIN) and lateral ligamentous complex are known complications of lateral elbow approaches. The extensor digitorum communis (EDC) splitting approach for lateral elbow exposure is known to provide better access to the anterior half of the radial head while reducing the risk of injury to the lateral ligaments. The aim of this study was to provide clinical outcome data for the EDC splitting approach. METHODS: Thirteen patients with closed radial head fractures underwent internal fixation or replacement via the EDC splitting approach. Patients were evaluated using the Mayo Elbow Performance, American Shoulder and Elbow Surgeons (ASES), and Disabilities of Arm, Shoulder and Hand scores. Clinical assessments of the elbows were also performed. RESULTS: Ten patients underwent open reduction and internal fixation of their radial heads, and 3 underwent radial head replacements. At final follow-up, all patients achieved good to excellent Mayo Elbow Performance scores, with a mean score of 90 (range 80-100). They had a mean ASES elbow score of 89.6 (range 77-97) and a mean Disabilities of Arm, Shoulder and Hand score of 12.8 (range 6.67-25.8). Patients reported a mean overall ASES satisfaction score of 8.5 (range 6-10). There were no significant surgical complications, including iatrogenic damage to the PIN or the lateral ligaments. CONCLUSION: The EDC splitting approach is a feasible method of exposing the lateral elbow, providing safe and reliable access to the radial head. PMID- 26652695 TI - Is a generic targeting guide useful for glenoid component placement in shoulder arthroplasty? AB - BACKGROUND: This study compared postoperative glenoid component version using traditional instrumentation to a generic glenoid targeting guide during total or reverse total shoulder arthroplasty. METHODS: Glenoid component version was measured on postoperative radiographs of 184 shoulders (traditional, 109; targeting guide, 75). Demographics, preoperative imaging, and operative technique were identified from medical records. Absolute deviation from neutral version and standard deviations (SDs) were calculated. RESULTS: Average mean +/- SD deviation in component version for the traditional technique group was 10 degrees +/- 7 degrees compared with 9 degrees +/- 6 degrees for the targeting guide group (P = .37; SD P = .12). No significant difference was noted based on operation, body mass index, preoperative version, or operative indication. For the last 30 shoulders in the targeting group, the absolute mean deviation was 6 degrees compared with 11 degrees in the first 30 of that group (P < .01) and 10 degrees in the entire traditional group (P = .01). The SD in the last 30 shoulders in the targeting group was 5 degrees compared with 7 degrees in the first 30 in that group (P = .04) and 7 degrees in the traditional group (P < .01). CONCLUSIONS: No significant difference in component accuracy was noted between the 2 techniques. The narrower SD in the targeting group, although not statistically significant, suggests less glenoid placement in the extremes of version. A learning curve was noted with the targeting guide, with significantly improved accuracy in later patients. PMID- 26652696 TI - Does scapular morphology affect the integrity of the rotator cuff? AB - BACKGROUND: Current evidence suggests that distinct scapular morphologies may predispose patients to a rotator cuff tear. The objective of this longitudinal study was to evaluate the relationship between symptomatic degenerative cuff tears and different radiographic acromial characteristics, including acromion shape, indices (acromial index [AI], critical shoulder angle [CSA]), and acromial spur. METHODS: We divided 166 patients into 3 groups matched for age and sex: group 1, degenerative full-thickness tear; group 2, partial thickness bursal tear; and group 3, normal cuff. Patients were evaluated with standard radiographs and ultrasonography. RESULTS: The presence of an acromial spur was strongly associated with a full-thickness cuff tear (odds ratio, 3.5; P = .001). AI and CSA revealed a statistically significant difference between means of group 1 (P = .006) and group 3 (P < .001). There was no statistically significant difference in means of AI between groups 1 and 2 (P = .695) and between groups 2 and 3, with respect to AI (P = .071) and CSA (P = .125). Receiver operating characteristic curve revealed a higher area for CSA (0.70) than for AI (0.61). Stepwise logistic regression rejected AI as a cuff tear predictor but confirmed CSA and a spur to be stronger predictors of a full-thickness cuff tear. There was no association between the Bigliani acromial type and rotator cuff tear (P = .06). CONCLUSIONS: The presence of an acromion spur is strongly associated with full-thickness cuff tear. Higher AI and CSA are associated with a full-thickness tear but not with partial tears. The type of acromion is not related to cuff tear. PMID- 26652697 TI - Tranexamic acid decreases blood loss after total shoulder arthroplasty. AB - BACKGROUND: Tranexamic acid (TXA) significantly decreases blood loss and transfusion rates after total hip and total knee arthroplasty. The purpose of this study was to determine the effects of intravenous TXA on blood loss and patient outcomes after total shoulder arthroplasty (TSA). METHODS: TXA was used in 106 consecutive patients undergoing primary anatomic and reverse TSA with a dose of 20 mg/kg intravenously (TXA group) and compared with the previous consecutive 88 patients without TXA (non-TXA group). All patients had a blood sample drawn for a hemoglobin and hematocrit determination the morning after surgery. Analysis of variance and chi(2) techniques were used to analyze study hypotheses. RESULTS: Statistically significant differences in both hemoglobin loss (TXA group Delta = 2.13 vs. non-TXA group Delta = 2.63; P = .01) and hematocrit loss (TXA group Delta = 6.4 vs. non-TXA group Delta = 8.14; P < .01) were seen in the TXA group compared with the non-TXA group. In patients receiving TXA, there were statistically significant decreases in the time spent in the recovery room (mean, TXA group 69 minutes vs. non-TXA group 87 minutes; P < .02) and total length of hospitalization (mean, TXA group 1.18 days vs. non-TXA group 1.4 days; P = .01). Two patients in the TXA group received a blood transfusion, whereas 6 patients in the non-TXA group did. CONCLUSIONS: TXA 20 mg/kg intravenously given just before primary anatomic and reverse TSA results in statistically significant reductions in blood loss. Patients spent 21% less time in the recovery room and had a 16% shorter hospitalization, resulting in financial savings for the hospital. PMID- 26652698 TI - Preoperative opioid use associated with worse outcomes after anatomic shoulder arthroplasty. AB - BACKGROUND: Preoperative opioid use has been associated with worse clinical outcomes after orthopedic surgery. The purpose of this study was to evaluate the impact of preoperative opioid use on outcomes and patient satisfaction after anatomic total shoulder arthroplasty (TSA). METHODS: We identified 224 TSAs performed for primary glenohumeral joint osteoarthritis with 2- to 5-year follow up in a prospective shoulder arthroplasty registry. Sixty patients with a history of preoperative opioid use for shoulder pain were compared with a control group of 164 patients. Patient-reported outcome measurements, range of motion measurements, and patient satisfaction were assessed preoperatively and at most recent follow-up. RESULTS: Preoperative opioid use was associated with significantly worse preoperative patient-reported outcome scores for nearly all outcome measures. Both groups significantly improved on all outcome scores and range of motion measurements from preoperative to most recent follow-up; however, the nonopioid group had significantly better postoperative outcome scores. There was a statistical difference between the 2 groups regarding the number of satisfied patients, with 80% satisfied in the opioid group (48 of 60 patients) compared with 91% satisfied in the nonopioid group (149 of 164 patients) (P = .03). CONCLUSION: Patients with a history of preoperative opioid use can achieve significant improvements in patient-reported outcome measurements and patient satisfaction after anatomic TSA for primary glenohumeral joint arthritis. However, patients with preoperative opioid use have a significantly lower preoperative baseline and achieve significantly lower final outcome scores after TSA compared with patients without a history of preoperative opioid use. PMID- 26652699 TI - Arthroscopic reduction and fixation of large solitary and multifragmented anterior glenoid rim fractures. AB - BACKGROUND: The optimal treatment of large anterior glenoid rim fractures is still a matter of debate. The purpose of this study was to evaluate the clinical and radiologic results of an arthroscopic reduction and fixation of acute displaced large solitary or multifragmented anterior glenoid rim fractures using anchors or bioabsorbable compression screws. METHODS: Twenty-three consecutive patients (7 women, 16 men; mean age, 47.9 [15-74] years) were treated. The patients were followed up clinically (range of motion, instability testing, and shoulder outcome scores) and with conventional radiographs (true anterior posterior, axillary, and Bernageau views). RESULTS: With a minimum follow-up of 24 months, 21 patients could be evaluated. The average Constant score was 84.5 points, the Rowe score was 90.8 points, the Melbourne Instability Shoulder Score was 96.2 points, the Western Ontario Shoulder Instability Index was 89.2%, and the subjective shoulder value averaged 92.1%. No patient had suffered recurrent instability. The radiologic evaluation revealed signs of osteoarthritis in 7 cases, which was pre-existing in 1 patient. Patients with osteoarthritis were on average 10 years older at the time of surgery compared with patients without osteoarthritis. A postoperative step-off of the glenoid was detected in 7 cases and averaged 2 (1-3) mm. We could not find a correlation between the step-off and the presence of osteoarthritis. CONCLUSION: Arthroscopic reconstruction of acute large solitary and multifragmented fractures of the glenoid rim shows good and excellent clinical results. In the majority of cases, an anatomic reduction and healing of the glenoid fracture can be achieved. The rate of osteoarthritis needs further investigation. PMID- 26652700 TI - How do deltoid muscle moment arms change after reverse total shoulder arthroplasty? AB - BACKGROUND: Although many advantages of reverse total shoulder arthroplasty (RTSA) have been demonstrated, a variety of complications indicate there is much to learn about how RTSA modifies normal shoulder function. This study used a subject-specific computational model driven by in vivo kinematic data to assess how RTSA affects deltoid muscle moment arms after surgery. METHODS: A subject specific 12 degree-of-freedom musculoskeletal model was used to analyze the shoulders of 26 individuals (14 RTSA and 12 normal). The model was modified from the work of Holzbaur to directly input 6 degree-of-freedom humeral and scapular kinematics obtained using fluoroscopy. RESULTS: The moment arms of the anterior, lateral, and posterior aspects of the deltoid were significantly different when RTSA and normal cohorts were compared at different abduction angles. Anterior and lateral deltoid moment arms were significantly larger in the RTSA group at the initial elevation of the arm. The posterior deltoid was significantly larger at maximum elevation. There was large intersubject variability within the RTSA group. CONCLUSIONS: Placement of implant components during RTSA can directly affect the geometric relationship between the humerus and scapula and the muscle moment arms in the RTSA shoulder. RTSA shoulders maintain the same anterior and posterior deltoid muscle moment-arm patterns as healthy shoulders but show much greater intersubject variation and larger moment-arm magnitudes. These observations provide a basis for determining optimal implant configuration and surgical placement to maximize RTSA function in a patient-specific manner. PMID- 26652701 TI - Reliability analysis of glenoid component inclination measurements on postoperative radiographs and computed tomography-based 3D models in total and reversed shoulder arthroplasty patients. AB - BACKGROUND: Only a few articles describe the reproducibility and clinical feasibility of glenoid inclination measurements on conventional radiographs, and none of them validated their method in shoulder arthroplasty cases. From a clinical point of view, the angle measured between the supraspinatus fossa and the glenoid fossa line (angle beta) appears to be the most interesting angle to assess glenoid inclination. This study aimed to validate the angle beta in shoulder arthroplasty patients to facilitate the assessment of glenoid component inclination. MATERIALS AND METHODS: Seventeen patients who underwent total or reverse shoulder arthroplasty were evaluated. The angle beta was measured by 2 independent observers on postoperative radiographs and 3-dimensional (3D) models. The interobserver variability and accuracy of angle beta were analyzed by calculating the intraclass correlation coefficient (ICC) and by generating Bland Altman plots. RESULTS: The angle beta showed a good interobserver variability (ICC = 0.971 for radiographs, ICC = 0.980 for 3D models) and a good agreement between the radiographic and 3D measurements (ICC = 0.904 for observer 1 and ICC = 0.908 for observer 2). Bland-Altman plots demonstrated that in 95% of the measurements on radiographs, the error will be <10. In the investigated population, 85% showed an error <6. CONCLUSION: This study demonstrates that angle beta can be measured on radiographs to assess glenoid component inclination in total and reverse shoulder arthroplasty, but clinicians and researchers should keep in mind that measurement errors of 10 degrees may occur in a minority of cases. PMID- 26652702 TI - A 3D finite element model for geometrical and mechanical comparison of different supraspinatus repair techniques. AB - BACKGROUND: Contact pressure and contact area are among the most important mechanical factors studied to predict the effectiveness of a rotator cuff repair. The suture configurations can strongly affect these factors but are rarely correlated with each other. For example, there is a significant difference between the single-row technique and the transosseous or transosseous-like approaches in terms of footprint contact area coverage. A finite element model based approach is presented and applied to account for various parameters (eg, suture pretension, geometry of the repair, effect of the sutures, geometry of the lesion) and to compare the efficacy of different repair techniques in covering the original footprint. METHODS: The model allows us to evaluate the effect of parameters such as suture configuration and position and suture pretension. The validity of such an approach was assessed in comparing 3 different repair techniques: single row, transosseous equivalent, and double row. RESULTS: Results from the application of the models show that the double-row and transosseous equivalent techniques lead to progressive increase of the contact area compared with the single-row approach, supporting the conclusion that transosseous equivalent fixation leads to an increase of the contact area and a better distribution of the pressure coverage. CONCLUSION: The 3-dimensional finite element model approach allows multiple variables to be assessed singularly, weighing the specific influence. Moreover, the approach presented in this study could be a valid tool to predict and to reproduce different configurations, identifying how to reduce the stress over the tendon and when a repair could be effective or not. PMID- 26652703 TI - Indications and outcomes of shoulder arthroscopy after shoulder arthroplasty. AB - BACKGROUND: Arthroscopy is a widely used intervention in the treatment of a variety of shoulder conditions. Arthroscopy has also been selectively used in symptomatic patients after shoulder arthroplasty. The purpose of this systematic review was to determine indications for shoulder arthroscopy in patients after shoulder arthroplasty and to report patient outcomes after these procedures. MATERIALS AND METHODS: The electronic databases MEDLINE, EMBASE, and PubMed were searched and screened in duplicate for studies involving shoulder arthroscopy in shoulder arthroplasty patients. A full-text review of eligible studies was conducted in duplicate, and references were searched using predetermined inclusion and exclusion criteria. RESULTS: The review included 11 studies containing 84 patients. All were Level IV evidence. The most common indications for shoulder arthroscopy in the setting of shoulder arthroplasty were pain or loss of range of motion without a clear diagnosis, suspected periprosthetic infection, and rotator cuff assessment. Although 92% of patients were satisfied with the procedure and standardized shoulder scores increased in all studies that reported them, 44% of patients still went on to additional revision surgery after arthroscopy. CONCLUSIONS: Shoulder arthroscopy in patients after arthroplasty is most frequently used as a diagnostic tool; however, it has utility in treating a number of predetermined pathologies. Despite the low sample size and quality of evidence in our review, patient satisfaction after arthroscopy is high because standardized outcome scores improve, and the risk of complications is low. However, a high percentage of patients who receive arthroscopy later require further surgery. PMID- 26652704 TI - Functional and radiologic outcomes of uncemented reverse shoulder arthroplasty in proximal humeral fractures: cementing the humeral component is not necessary. AB - BACKGROUND: Our aim was to determine the radiologic and functional outcomes of patients who underwent reverse shoulder arthroplasty (RSA) for proximal humeral fractures and to assess whether the uncemented humeral components put them at risk for early loosening and failure. METHODS: Thirty-three patients were identified in our hospital database (January 2004-December 2012). Twenty patients were assessed using American Shoulder Elbow Surgeons (ASES) score, Constant Shoulder Score (CSS), and the Oxford Shoulder Score (OSS). Up-to-date shoulder radiographs were evaluated for evidence of radiologic loosening. RESULTS: The mean follow-up period was 3.0 years (range, 2.5-7.8 years), and the mean age at the time of surgery was 76.5 years (range, 62-87 years). The mean ASES was 75.9 of 100 (range, 55-98.3), with a mean visual analog scale pain score of 2 of 10. The mean OSS was 42.5 of 48 (range, 35-48), and the mean CSS was 54.1 of 100 (range, 32-72). Upon radiographic assessment of the humeral component, 6 patients (30%) had 3 or more lucent zones, and 12 patients (60%) had a lucent zone measuring more than 2 mm in width; however, only 2 patients (10%) had 3 or more lucent zones measuring 2 mm or more in width and were identified as "at risk of loosening." No patients had tilt or subsidence of the humeral prosthesis. CONCLUSIONS: Our study demonstrated satisfactory functional and radiologic outcomes of patients compared with other studies, suggesting that RSA is a good management option for elderly patients with these fractures. The uncemented nature of the humeral component did not result in early loosening or failure. PMID- 26652706 TI - High aspect ratio nanoimprinted grooves of poly(lactic-co-glycolic acid) control the length and direction of retraction fibers during fibroblast cell division. AB - Retraction fibers (RFs) determine orientation of the cell division axis and guide the spreading of daughter cells. Long and unidirectional RFs, which are especially apparent during mitosis of cells in three-dimensional (3D) environments, enable improved control over cell fate, following division. However, 3D gel environments lack the cues necessary for predetermining the orientation of RFs to direct tissue architecture. While patterning of focal adhesion regions by microcontact printing can determine orientation of the RFs through enhancing focal adhesion numbers along particular directions, the RFs remain short due to the two-dimensional culture environment. Herein, the authors demonstrate that nanoimprinted grooves of polylactic acid glycolic acid (PLGA) with a high aspect ratio (A.R. of 2.0) can provide the cues necessary to control the direction of RFs, as well as enable the maintenance of long and unidirectional RFs as observed within 3D cultures, while the same is not possible with PLGA grooves of lower A.R. (1.0 or lower). Based on enhanced levels of contact guidance of premitotic fibroblast protrusions at high A.R. grooves and deeper levels of focal adhesion due to filopodia extensions into these grooves, it is suggested that submicron (800 nm width) PLGA grooves with A.R. of 2 are capable of supporting mechanical forces from cell protrusions to a greater depth, thereby enabling the maintenance of the protrusions as long and unidirectional RFs during cell division. Given the scalability and versatility of nanoimprint techniques, the authors envision a platform for designing nanostructures to direct tissue regeneration and developmental biology. PMID- 26652707 TI - MIA: Mutual Information Analyzer, a graphic user interface program that calculates entropy, vertical and horizontal mutual information of molecular sequence sets. AB - BACKGROUND: Short and long range correlations in biological sequences are central in genomic studies of covariation. These correlations can be studied using mutual information because it measures the amount of information one random variable contains about the other. Here we present MIA (Mutual Information Analyzer) a user friendly graphic interface pipeline that calculates spectra of vertical entropy (VH), vertical mutual information (VMI) and horizontal mutual information (HMI), since currently there is no user friendly integrated platform that in a single package perform all these calculations. MIA also calculates Jensen-Shannon Divergence (JSD) between pair of different species spectra, herein called informational distances. Thus, the resulting distance matrices can be presented by distance histograms and informational dendrograms, giving support to discrimination of closely related species. RESULTS: In order to test MIA we analyzed sequences from Drosophila Adh locus, because the taxonomy and evolutionary patterns of different Drosophila species are well established and the gene Adh is extensively studied. The search retrieved 959 sequences of 291 species. From the total, 450 sequences of 17 species were selected. With this dataset MIA performed all tasks in less than three hours: gathering, storing and aligning fasta files; calculating VH, VMI and HMI spectra; and calculating JSD between pair of different species spectra. For each task MIA saved tables and graphics in the local disk, easily accessible for future analysis. CONCLUSIONS: Our tests revealed that the "informational model free" spectra may represent species signatures. Since JSD applied to Horizontal Mutual Information spectra resulted in statistically significant distances between species, we could calculate respective hierarchical clusters, herein called Informational Dendrograms (ID). When compared to phylogenetic trees all Informational Dendrograms presented similar taxonomy and species clusterization. PMID- 26652708 TI - Efficacy, persistence and vector susceptibility to pirimiphos-methyl (Actellic 300CS) insecticide for indoor residual spraying in Zanzibar. AB - BACKGROUND: Indoor residual spraying (IRS) of households with insecticide is a principal malaria vector control intervention in Zanzibar. In 2006, IRS using the pyrethroid lambda-cyhalothrine was introduced in Zanzibar. Following detection of pyrethroid resistance in 2010, an insecticide resistance management plan was proposed, and IRS using bendiocarb was started in 2011. In 2014, bendiocarb was replaced by pirimiphos methyl. This study investigated the residual efficacy of pirimiphos methyl (Actellic 300CS) sprayed on common surfaces of human dwellings in Zanzibar. METHODS: The residual activity of Actellic 300CS was determined over 9 months through bioassay tests that measured the mortality of female Anopheles mosquitoes, exposed to sprayed surfaces under a WHO cone. The wall surfaces included; mud wall, oil or water painted walls, lime washed wall, un-plastered cement block wall and stone blocks. Insecticide susceptibility testing was done to investigate the resistance status of local malaria vectors against Actellic 300CS using WHO protocols; Anopheline species were identified using PCR methods. RESULTS: Baseline tests conducted one-day post-IRS revealed 100% mortality on all sprayed surfaces. The residual efficacy of Actellic 300CS was maintained on all sprayed surfaces up to 8 months post-IRS. However, the bioassay test conducted 9 months post-IRS showed the 24 h mortality rate to be <=80% for lime wash, mud wall, water paint and stone block surfaces. Only oil paint surface retained the recommended residual efficacy beyond 9 months post-IRS, with mortality maintained at >=97 %. Results of susceptibility tests showed that malaria vectors in Zanzibar were fully (100%) susceptible to Actellic 300CS. The predominant mosquito vector species was An. arabiensis (76.0%) in Pemba and An. gambiae (83.5%) in Unguja. CONCLUSION: The microencapsulated formulation of pirimiphos methyl (Actellic 300CS) is a highly effective and appropriate insecticide for IRS use in Zanzibar as it showed a relatively prolonged residual activity compared to other products used for the same purpose. The insecticide extends the residual effect of IRS thereby making it possible to effectively protect communities with a single annual spray round reducing overall costs. The insecticide proved to be a useful alternative in insecticide resistance management plans. PMID- 26652709 TI - The pharmacogenetics of opioid therapy in the management of postpartum pain: a systematic review. AB - AIMS: Opioids are commonly prescribed for postpartum pain. Yet, providing adequate pain relief, while ensuring that the mother and her breastfeeding infant are protected from adverse events can be challenging. The objective of this systematic review was to identify the role of opioid pharmacogenetics in analgesia and adverse events among patients being treated for postpartum pain, along with their breastfeeding infants. METHODS: A comprehensive search of the literature was conducted in seven databases on June 3-4, 2015. Two reviewers independently screened studies for eligibility, extracted data and evaluated study quality using the Newcastle-Ottawa Scale. RESULTS: Among the 2082 papers retrieved from the search, 17 were included in the review. These 17 papers consisted of various study designs, opioids, polymorphisms and patient outcomes. This systematic review reveals that CYP2D6, OPRM1 A118G, UGT2B7 C802T and ABCB1 G2677AT may contribute to postpartum analgesia or adverse events. CONCLUSION: These findings may assist in personalizing care for patients receiving opioids during the postpartum period. PMID- 26652710 TI - Trends in human immunodeficiency virus seroprevalence in blood donors in northern Pakistan. AB - OBJECTIVE: To study trends in human immunodeficiency virus (HIV) seroprevalence in blood donors in northern Pakistan. STUDY DESIGN: Analysis of annual data from blood transfusion centre. PLACE AND DURATION OF STUDY: Data records from people who had donated blood at the Armed Forces Institute of Transfusion (AFIT) between 1998 and 2013 were retrieved and analysed. METHODS: All blood donations were tested for the presence of HIV antibodies using Abbott Inc's AxSYM from 1998 to 2006, and Abbott Inc's Architect 2000i with chemiluminescence microplate immunoassay from 2007 to 2013. RESULTS: Over the 16-year study period, 66 donors tested positive for HIV antibodies out of 626,413 donations (0.01%, i.e. 10 per 100,000 donations). From 1998 to 2006, 16 HIV-positive cases were detected out of 280,245 donations (0.0057%, i.e. 5.7 per 100,000 donations). However, from 2007 to 2013, 50 HIV-positive cases were detected out of 346,168 donations (0.0144%, i.e. 14 per 100,000 donations). The difference in HIV positivity between the two groups was found to be significant (0.0057% vs 0.0144%, chi(2) = 10.4, P = 0.008). CONCLUSION: A gradual and persistent increase in the number of HIV positive cases among blood donors in northern Pakistan was seen over the study period. The HIV-positive cases reported one or more high-risk activities in the past which predisposed them to HIV infection. PMID- 26652711 TI - Responses in whole-body amino acid kinetics to an acute, sub-clinical endotoxin challenge in lambs. AB - Some effects of parasitism, endotoxaemia or sepsis can be mitigated by provision of extra protein. Supplemented protein may encompass a metabolic requirement for specific amino acids (AA). The current study investigates a method to identify and quantify the amounts of AA required during inflammation induced by an endotoxin challenge. One of each pair of six twin sheep was infused in the jugular vein for 20 h with either saline (control) or lipopolysaccharide (LPS, 2 ng/kg body weight per min) from Escherichia coli. Between 12 and 20 h a mixture of stable isotope-labelled AA was infused to measure irreversible loss rates. From 16 to 20 h all sheep were supplemented with a mixture of unlabelled AA infused intravenously. Blood samples were taken before the start of infusions, and then continuously over intervals between 14 and 20 h. At 20 h the sheep were euthanised, and liver and kidney samples were taken for measurement of serine threonine dehydratase (SDH) activity. LPS infusion decreased plasma concentrations of most AA (P<0.05; P<0.10 for leucine and tryptophan), except for phenylalanine (which increased P=0.022) and tyrosine. On the basis of the incremental response to the supplemental AA, arginine, aspartate, cysteine, glutamate, lysine (tendency only), glycine, methionine, proline, serine and threonine were important in the metabolic response to the endotoxaemia. The AA infusion between 16 and 20 h restored the plasma concentrations in the LPS treated sheep for the majority of AA, except for glutamine, isoleucine, methionine, serine and valine. LPS treatment increased (P<0.02) SDH activity in both liver and kidney. The approach allows quantification of key AA required during challenge situations. PMID- 26652712 TI - Status of Dyslipidemia in Vitamin D Supplemented Argentinean Indigenous Children Versus A Non-supplemented Mixed Population Group. AB - BACKGROUND: Epidemiological studies have suggested an inverse association between circulating levels of vitamin D and cardiovascular disease risk biomarkers, including an atherogenic lipid profile. OBJECTIVE: To compare the prevalence and the distribution of lipid levels among vitamin D supplemented Argentinean indigenous San Antonio de los Cobres (SAC) children with a nonsupplemented Buenos Aires (BA) mixed population group. METHODS: A group of indigenous children from SAC with hypovitaminosis D supplemented with vitamin D; and a nonsupplemented group from a BA mixed population were compared via a cross sectional study. Anthropometric measures, glucose, lipids, vitamin D, and insulin were measured. RESULTS: The mean ages were 10.3 + 2.3 in SAC and 8.7 +/- 1.8 years in BA children. There was a lower prevalence of overweight 7.9%(15/192) vs 17.8% (23/129); and of obesity 1.6% (3/192) vs 30.2% (39/129) in SAC vs. BA respectively. Approximately half of the SAC children versus 30% from BA had optimal vitamin D levels (>=30ng/mL). There was a significantly higher prevalence of high triglycerides (TG) (27.6%vs 4.6%) and low HDL-C (21.3% vs 5.4%) in SAC vs BA children, respectively. In separate linear regression models, we found that despite effective vitamin D repletion, SAC children had higher TG and TG/HDL-C values, whereas HDL-C levels were lower than those of BA children adjusted for age, gender, BMI, and insulin levels. CONCLUSION: Indigenous Argentinean children have a higher risk for dyslipidemia in comparison with BA children, even after vitamin D treatment, suggesting that dyslipidemia could be related to diet or ethnic backgrounds. PMID- 26652713 TI - Advances in quantitative bioanalysis of oligonucleotide biomarkers and therapeutics. AB - Technical advances and demands for high-throughput accurate quantification of oligonucleotide therapeutics and biomarkers in pharmaceutical research and clinical diagnosis have aided evolution in quantitative bioanalysis of oligonucleotides. Many bioanalytical methods are available for absolute quantification of oligonucleotides in biological matrices. They can be broadly classified into two categories: hybridization-based assays commonly used by molecular biologists and chromatographic assays routinely used by chemists. Each category has its own advantages and disadvantages for specific applications. This review summarizes the mechanisms and applications of some of the current most commonly used techniques in each category. PMID- 26652714 TI - Is graduate entry education a solution to increasing numbers of men in nursing? AB - Males have traditionally constituted a very small proportion of the nursing workforce in many countries, including Australia. Together with a need to address the gender imbalance, nursing workforce shortages require strategies for recruiting new nurses, including males. This study examined characteristics of males entering one accelerated graduate entry masters pre-registration nursing program in Victoria, Australia. A quantitative survey gathered a variety of demographic data and factors relating to participants' decisions to undertake nursing. Data were analysed using descriptive statistics including frequencies and distributions. Forty-three male nursing students from four cohorts of the Master of Nursing Practice (MNP) course from 2009 to 2011 completed the survey. The proportion of males (30%) was considerably greater than traditional nursing courses and the profession generally. Participants demonstrated wide distributions in age ranges, professional backgrounds and previous years in the workforce. Graduate entry appears attractive to males of varying ages, personal and professional backgrounds. More research is needed to examine this phenomenon on a larger scale. PMID- 26652715 TI - Regulation of corticotropin-releasing hormone. PMID- 26652716 TI - MMP2 and MMP7 at the invasive front of gastric cancer are not associated with mTOR expression. AB - BACKGROUND: Regulation of MMP expression by activation of mTOR signalling has been demonstrated for several tumor types, but has thus far not been confirmed in gastric cancer. FINDINGS: The study compromised 128 patients who underwent gastric resection for cancer (66.4 % male; 86 intestinal, 42 diffuse type). Immunohistochemical staining of MMPs was performed to analyse the topographical pattern of MMP expression at the tumor center and the invasive front, respectively. MMP2 showed higher expression at the invasive front compared to the tumor center, whereas MMP7 staining scores were higher in the tumor center, and there was no difference for MMP9. The expression of p-mTOR was higher in the tumor center than at the invasive front, with a similar trend for mTOR. For intestinal type gastric cancer there was a weak correlation of MMP9 with expression of mTOR in the tumor center. Otherwise, there was no correlation of the MMPs with mTOR. By treatment of MKN45 gastric cancer cells with rapamycin, a reduction of p-mTOR in the Western blot was achieved; however, expression of MMPs remained unaffected. CONCLUSIONS: Expression of MMP2 and MMP7 in gastric cancer is not associated with mTOR, MMP9 expression might be related to mTOR signalling in a subset of tumors. PMID- 26652717 TI - Discovery and Characterization of (8S,9R)-5-Fluoro-8-(4-fluorophenyl)-9-(1-methyl 1H-1,2,4-triazol-5-yl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one (BMN 673, Talazoparib), a Novel, Highly Potent, and Orally Efficacious Poly(ADP ribose) Polymerase-1/2 Inhibitor, as an Anticancer Agent. AB - We discovered and developed a novel series of tetrahydropyridophthlazinones as poly(ADP-ribose) polymerase (PARP) 1 and 2 inhibitors. Lead optimization led to the identification of (8S,9R)-47 (talazoparib; BMN 673; (8S,9R)-5-fluoro-8-(4 fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-2,7,8,9-tetrahydro-3H pyrido[4,3,2-de]phthalazin-3-one). The novel stereospecific dual chiral-center embedded structure of this compound has enabled extensive and unique binding interactions with PARP1/2 proteins. (8S,9R)-47 demonstrates excellent potency, inhibiting PARP1 and PARP2 enzyme activity with Ki = 1.2 and 0.87 nM, respectively. It inhibits PARP-mediated PARylation in a whole-cell assay with an EC50 of 2.51 nM and prevents proliferation of cancer cells carrying mutant BRCA1/2, with EC50 = 0.3 nM (MX-1) and 5 nM (Capan-1), respectively. (8S,9R)-47 is orally available, displaying favorable pharmacokinetic (PK) properties and remarkable antitumor efficacy in the BRCA1 mutant MX-1 breast cancer xenograft model following oral administration as a single-agent or in combination with chemotherapy agents such as temozolomide and cisplatin. (8S,9R)-47 has completed phase 1 clinical trial and is currently being studied in phase 2 and 3 clinical trials for the treatment of locally advanced and/or metastatic breast cancer with germline BRCA1/2 deleterious mutations. PMID- 26652718 TI - [Perception of pT1a,b pN0 breast tumor prognosis by the French oncology community: Results of the EURISTIC national survey]. AB - The prognosis of infracentimetric breast cancers (BC) is heterogeneous. The EURISTIC survey describes how French oncology specialists perceive the prognosis of pT1a,b pN0 BCs. A self-administered questionnaire has been sent to over 2000 French BC specialists. Six hundred and sixty-three physicians responded. Fifty eight percent do not consider tumor size as a key prognostic criterion. They consider that the cutoff for poor prognosis is 22mm, 10mm and 7mm for hormone receptors (HRs)+, HER2+ and triple-negative (TN) tumors respectively. Eighty three percent of respondents consider that a HR+ pT1a,b tumor has a good prognosis (21% and 8% for HER2+ and TN respectively). Factors perceived as most detrimental are: HER2 overexpression (29% of respondents); HR- (20%); high grade (20%); TN status (14%); high KI67 (5%); presence of lymphovascular invasion (3%); young age (2%) and high mitotic index (1%). For French specialists, immunohistochemical characteristics, in particular hormone and HER2 status, are strong prognostic factors in BCs below 1cm. PMID- 26652719 TI - Lack of sex chromosome specific meiotic silencing in platypus reveals origin of MSCI in therian mammals. AB - BACKGROUND: In therian mammals heteromorphic sex chromosomes are subject to meiotic sex chromosome inactivation (MSCI) during meiotic prophase I while the autosomes maintain transcriptional activity. The evolution of this sex chromosome silencing is thought to result in retroposition of genes required in spermatogenesis from the sex chromosomes to autosomes. In birds sex chromosome specific silencing appears to be absent and global transcriptional reductions occur through pachytene and sex chromosome-derived autosomal retrogenes are lacking. Egg laying monotremes are the most basal mammalian lineage, feature a complex and highly differentiated XY sex chromosome system with homology to the avian sex chromosomes, and also lack autosomal retrogenes. In order to delineate the point of origin of sex chromosome specific silencing in mammals we investigated whether MSCI exists in platypus. RESULTS: Our results show that platypus sex chromosomes display only partial or transient colocalisation with a repressive histone variant linked to therian sex chromosome silencing and surprisingly lack a hallmark MSCI epigenetic signature present in other mammals. Remarkably, platypus instead feature an avian like period of general low level transcription through prophase I with the sex chromosomes and the future mammalian X maintaining association with a nucleolus-like structure. CONCLUSIONS: Our work demonstrates for the first time that in mammals meiotic silencing of sex chromosomes evolved after the divergence of monotremes presumably as a result of the differentiation of the therian XY sex chromosomes. We provide a novel evolutionary scenario on how the future therian X chromosome commenced the trajectory toward MSCI. PMID- 26652721 TI - Correction to Mayr, Spieler, and Hutcheon (2015). PMID- 26652720 TI - Dissociative global and local task-switching costs across younger adults, middle aged adults, older adults, and very mild Alzheimer's disease individuals. AB - A task-switching paradigm was used to examine differences in attentional control across younger adults, middle-aged adults, healthy older adults, and individuals classified in the earliest detectable stage of Alzheimer's disease (AD). A large sample of participants (570) completed a switching task in which participants were cued to classify the letter (consonant/vowel) or number (odd/even) task-set dimension of a bivalent stimulus (e.g., A 14), respectively. A pure block consisting of single-task trials and a switch block consisting of nonswitch and switch trials were completed. Local (switch vs. nonswitch trials) and global (nonswitch vs. pure trials) costs in mean error rates, mean response latencies, underlying reaction time (RT) distributions, along with stimulus-response congruency effects were computed. Local costs in errors were group invariant, but global costs in errors systematically increased as a function of age and AD. Response latencies yielded a strong dissociation: Local costs decreased across groups whereas global costs increased across groups. Vincentile distribution analyses revealed that the dissociation of local and global costs primarily occurred in the slowest response latencies. Stimulus-response congruency effects within the switch block were particularly robust in accuracy in participants in the very mild AD group. We argue that the results are consistent with the notion that the impaired groups show a reduced local cost because the task sets are not as well tuned, and hence produce minimal cost on switch trials. In contrast, global costs increase because of the additional burden on working memory of maintaining 2 task sets. PMID- 26652723 TI - The two faces of selective memory retrieval: Earlier decline of the beneficial than the detrimental effect with older age. AB - Recent work with young adults has shown that, depending on study context access, selective memory retrieval can both impair and improve recall of other memories (Bauml & Samenieh, 2010). Here, we investigated the 2 opposing effects of selective retrieval in older age. In Experiment 1, we examined 64 younger (20-35 years) and 64 older participants (above 60 years), and manipulated study context access using list-method directed forgetting. Whereas both age groups showed a detrimental effect of selective retrieval on to-be-remembered items, only younger but not older adults showed a beneficial effect on to-be-forgotten items. In Experiment 2, we examined 112 participants from a relatively wide age range (40 85 years), and manipulated study context access by varying the retention interval between study and test. Overall, a detrimental effect of selective retrieval arose when the retention interval was relatively short, but a beneficial effect when the retention interval was prolonged. Critically, the size of the beneficial but not the detrimental effect of retrieval decreased with age and this age related decline was mediated by individuals' working memory capacity, as measured by the complex operation span task. Together, the results suggest an age-related dissociation in retrieval dynamics, indicating an earlier decline of the beneficial than the detrimental effect of selective retrieval with older age. PMID- 26652722 TI - They can take a hint: Older adults effectively integrate memory cues during recognition. AB - Adaptively biasing recognition judgments in light of environmental cues improves net accuracy. Based on previous work suggesting that strategically shifting biases on a trial-wise basis should be cognitively demanding, the authors predicted that older adults would not achieve the same accuracy benefits from environmental cues as the young. However, despite showing clear declines in cognitive control as indexed by complex span, older adults demonstrated similar accuracy gains and similar alterations of response probabilities with cues of 75% reliability (Experiment 1) and more complex cues spanning 3 levels of reliability (Experiment 2). Despite preserved gains in accuracy, older adults clearly demonstrated disproportionate slowing that was specific to trials in which cues were invalid. This slowing may reflect impairments in behavioral inhibition that could impinge upon accuracy were responding increasingly sped and future work manipulating response speed and measures of inhibition may yield further insights. PMID- 26652724 TI - Exercise and fitness modulate cognitive function in older adults. AB - This study investigated the effects of acute exercise on cognitive function and the modulatory role of fitness in the relationship between exercise and cognition. Forty-six healthy older adults, categorized into higher or lower fitness groups, completed the Stroop test after both 30 min of aerobic exercise and a reading control with a counterbalanced order. Our findings demonstrated that acute exercise leads to general improvements in 2 types of cognitive functions and to specific improvements in executive function. Additionally, older adults with initially higher fitness levels experienced greater beneficial effects from acute exercise. PMID- 26652725 TI - "Older is always better": Age-related differences in vocabulary scores across 16 years. AB - Cross-sectional studies of cognitive aging compare age groups at 1 time point. It is unclear from such studies whether age-related cognitive differences remain stable across time. We present a cross-sectional investigation of vocabulary scores of 2,000 younger and older adults collected across 16 years, using the same laboratory and protocol. We found a steady decrease with year of testing and an advantage for older adults. An additive relation between age group and year of testing implied that age-related differences in vocabulary are independent of changes over time, suggesting that younger and older adults are similarly affected by changes in word usage. PMID- 26652726 TI - Doppler ultrasonography helps discriminate between cirrhotic and non-cirrhotic patients with viral B and C hepatitis. AB - OBJECTIVE: The aim of this study was to define the cutoff values between compensated cirrhosis and non-cirrhotic patients with viral hepatitis B and C, using the criteria of the Doppler parameters of liver vascularity. MATERIALS AND METHODS: Seventy non-cirrhotic patients with viral hepatitis B and C and 30 cirrhotic patients were included in this prospective study. The diagnostic decisiveness properties of the Doppler values in the pre-determination of liver cirrhosis were evaluated using receiver operating characteristics curve analysis. RESULTS: Taking the cutoff value for hepatic vein waveform index as 0.605, a sensitivity of 80% and a specificity of 77.1% were obtained. The sensitivity was 80%, and the specificity was 68.6% for a mean max portal velocity cutoff value of 18.25cm/s. When the hepatic artery resistivity index cutoff value was taken as 0.705 for the diagnosis of cirrhosis, the sensitivity was 82.5% and the specificity 72.1%. For a hepatic artery pulsatility index cutoff value of 1.295, a sensitivity of 82.5% and a specificity of 72.1% were found. CONCLUSION: It is not possible to diagnose cirrhosis with only hemodynamic changes. However, the cutoff values may be helpful in the selection of patients to undergo the procedure of liver biopsy. PMID- 26652727 TI - Obsessive compulsive features predict cautious decision strategies. AB - INTRODUCTION: Obsessive compulsive disorder (OCD) is occasionally characterized by decision-making deficits. Compared to the isolated analysis of the choice and response times, characterizing decision outputs at the level of latent processes can be a more powerful approach in revealing differences, even in subclinical cases. We hypothesized that participants with higher obsessive compulsive (OC) features would set their decision thresholds higher and thus make more cautious decisions. METHOD: We used a perceptual two-alternative forced-choice (2AFC) task (dot motion discrimination) to test this hypothesis in a non-clinical sample (N = 74). We fitted the data with the diffusion model and evaluated the optimality of decision outputs. We also conducted exploratory analyses to reveal which subscales best predicted the differences at the level of latent decision processes. RESULTS: Higher OC total scores in Maudsley and Padua scales significantly predicted higher threshold settings (cautiousness). The follow-up exploratory analyses with subscale scores showed that checking and rumination tendencies predicted higher threshold settings whereas washing tendency predicted faster non-decision times. CONCLUSIONS: Our primary results showed that participants with higher degrees of OC features exhibit more cautious decision making. Our exploratory analyses also revealed distinctions based on different types of OC features in both controlled (cautiousness in decision making) and automatic (faster non-decision times) elements of the decision process. PMID- 26652728 TI - A retrospective study of direct cost to patients associated with the use of oral oncology medications for the treatment of multiple myeloma. AB - OBJECTIVE: To examine direct cost to patients associated with oral oncolytics for the management of multiple myeloma (MM) both before and after financial assistance, and assess the effect on adherence. METHODS: In this retrospective study, pharmacy claims were analyzed for those patients with a diagnosis of MM who received thalidomide, lenalidomide, or pomalidomide from a large specialty pharmacy in the US between January 1, 2011, and December 31, 2013. Average direct cost to patients, per prescription, was analyzed both before and after financial assistance. Adherence was assessed through an analysis of medication possession ratio (MPR) for those patients who filled a prescription >=2 times throughout the 3-year time period. RESULTS: A total of 77,821 prescriptions for thalidomide, lenalidomide, and pomalidomide were filled by 6731 unique patients between January 1, 2011, and, December 31, 2013. The average direct cost to patients, per prescription, for any of these three agents was $227.23 prior to financial assistance and $80.11 after financial assistance, representing an average patient savings of $147.14 per prescription. Prior to financial assistance, the average direct cost to patients was <=$50 for 57.6% of all prescriptions. After financial assistance, 86.2% of patients had a direct cost of <=$50 per prescription. Adherence, as assessed by MPR, did not vary significantly based on direct cost to the patient. LIMITATIONS: This study included patients receiving therapy from a single specialty pharmacy for a single indication. There may be patients included in the analysis who received prescriptions from other pharmacies prior to or after the prescriptions available for analysis. Most of the prescriptions included in the analysis were for lenalidomide. CONCLUSIONS: This retrospective study demonstrated that the specialty pharmacy helped patients significantly reduce their direct cost expenditures by securing funding and co-pay assistance. PMID- 26652729 TI - Health, pathology, and rehabilitation of the sensory-motor loop. PMID- 26652730 TI - Intravitreal memantine retinal toxicity in rabbits. AB - OBJECTIVE: To histologically evaluate whether the intravitreal application of memantine produces retinal toxicity in rabbits. METHODS: A cross-sectional design, experimental, descriptive study was performed on 16 eyes of 16 New Zealand rabbits of 3 kg, divided in 4 groups of 4 rabbits. A dose of 70 ng/ml of intravitreal memantine was administered in Group A, a dose of 150 ng/ml in Group B, a dose of 400 ng/ml in Group C, and Group D received 1 ml of balanced salt solution. The injected eye of half of each group was enucleated 15 days after the injection, and the rest within 30 days after injection. Following enucleation, each eye was placed in 10% formaldehyde. Histopathological analysis was performed on all enucleated eyes. The animals were treated according to the guidelines of the Association for Research on Vision and Ophthalmology (ARVO). RESULTS: Groups A, B and D did not show any histopathological changes after their enucleation at 15 and 30 days. Group C showed changes in the photoreceptor layer after enucleation at 15 and 30 days. CONCLUSIONS: In our study, it was observed that memantine concentrations at 70 ng/ml and 150 ng/ml are safe when administered intravitreally; however, doses of 400 ng/ml produced retinal structural changes. This research should continue to assess its clinical usefulness. PMID- 26652731 TI - Focal choroidal excavation: Clinical findings and complications. AB - OBJECTIVE: To describe the clinical findings and its complications in 2 patients with focal choroidal excavation (FCE). METHODS: A retrospective case-series including 4 eyes of 2 patients with FCE that underwent a comprehensive ophthalmological examination including slit-lamp examination, colour fundus photography, spectral-domain optical coherence tomography (SD-OCT), fluorescein angiography (FA), and indocyanine green angiography. RESULTS: In the 2 patients, both the anterior and posterior segment evaluations were mostly normal despite the of presence yellowish spots in the macular area of the right eye of patient 1, and of a small yellowish elevated lesion with serous macular detachment in the macular area of the left eye in patient 2. At diagnosis, SD-OCT revealed a conforming FCE in patient 1, and in patient 2, an FCE with perilesional subretinal fluid and a neuroepithelium detachment, suspicious of FCE complicated with central serous retinopathy (CSCR). At one year of follow-up, patient 1 developed choroidal neovascularisation (CNV) over the focal choroidal excavation. FA and indocyanine green angiography examinations revealed areas with hypofluorescence in earlier frames, and a diffuse leakage in late frames. After ranibizumab injections, the SD-OCT of patient 1 revealed no active exudation, while patient 2 showed partial resolution of subretinal fluid. CONCLUSIONS: FCE is a newly described entity of unclear aetiology. It is characterised by a choroidal excavation in eyes, with absence of posterior staphyloma, scleral ectasia, trauma, or retinal disease. Although most lesions remain stable, there could be an association with CRSC or CNV. PMID- 26652732 TI - A20 Inhibits beta-Cell Apoptosis by Multiple Mechanisms and Predicts Residual beta-Cell Function in Type 1 Diabetes. AB - Activation of the transcription factor nuclear factor kappa B (NFkB) contributes to beta-cell death in type 1 diabetes (T1D). Genome-wide association studies have identified the gene TNF-induced protein 3 (TNFAIP3), encoding for the zinc finger protein A20, as a susceptibility locus for T1D. A20 restricts NF-kappaB signaling and has strong antiapoptotic activities in beta-cells. Although the role of A20 on NF-kappaB inhibition is well characterized, its other antiapoptotic functions are largely unknown. By studying INS-1E cells and rat dispersed islet cells knocked down or overexpressing A20 and islets isolated from the beta-cell specific A20 knockout mice, we presently demonstrate that A20 has broader effects in beta-cells that are not restricted to inhibition of NF-kappaB. These involves, suppression of the proapoptotic mitogen-activated protein kinase c-Jun N-terminal kinase (JNK), activation of survival signaling via v-akt murine thymoma viral oncogene homolog (Akt) and consequently inhibition of the intrinsic apoptotic pathway. Finally, in a cohort of T1D children, we observed that the risk allele of the rs2327832 single nucleotide polymorphism of TNFAIP3 predicted lower C peptide and higher hemoglobin A1c (HbA1c) levels 12 months after disease onset, indicating reduced residual beta-cell function and impaired glycemic control. In conclusion, our results indicate a critical role for A20 in the regulation of beta-cell survival and unveil novel mechanisms by which A20 controls beta-cell fate. Moreover, we identify the single nucleotide polymorphism rs2327832 of TNFAIP3 as a possible prognostic marker for diabetes outcome in children with T1D. PMID- 26652733 TI - CRTC2 Is a Coactivator of GR and Couples GR and CREB in the Regulation of Hepatic Gluconeogenesis. AB - Glucocorticoid hormones play essential roles in the regulation of gluconeogenesis in the liver, an adaptive response that is required for the maintenance of circulating glucose levels during fasting. Glucocorticoids do this by cooperating with glucagon, which is secreted from pancreatic islets to activate the cAMP signaling pathway in hepatocytes. The cAMP-response element-binding protein (CREB)-regulated transcription coactivator 2 (CRTC2) is a coactivator known to be specific to CREB and plays a central role in the glucagon-mediated activation of gluconeogenesis in the early phase of fasting. We show here that CRTC2 also functions as a coactivator for the glucocorticoid receptor (GR). CRTC2 strongly enhances GR-induced transcriptional activity of glucocorticoid-responsive genes. CRTC2 physically interacts with the ligand-binding domain of the GR through a region spanning amino acids 561-693. Further, CRTC2 is required for the glucocorticoid-associated cooperative mRNA expression of the glucose-6 phosphatase, a rate-limiting enzyme for hepatic gluconeogenesis, by facilitating the attraction of GR and itself to its promoter region already occupied by CREB. CRTC2 is required for the maintenance of blood glucose levels during fasting in mice by enhancing the GR transcriptional activity on both the G6p and phosphoenolpyruvate carboxykinase (Pepck) genes. Finally, CRTC2 modulates the transcriptional activity of the progesterone receptor, indicating that it may influence the transcriptional activity of other steroid/nuclear receptors. Taken together, these results reveal that CRTC2 plays an essential role in the regulation of hepatic gluconeogenesis through coordinated regulation of the glucocorticoid/GR- and glucagon/CREB-signaling pathways on the key genes G6P and PEPCK. PMID- 26652734 TI - Single molecule compression reveals intra-protein forces drive cytotoxin pore formation. AB - Perfringolysin O (PFO) is a prototypical member of a large family of pore-forming proteins that undergo a significant reduction in height during the transition from the membrane-assembled prepore to the membrane-inserted pore. Here, we show that targeted application of compressive forces can catalyze this conformational change in individual PFO complexes trapped at the prepore stage, recapitulating this critical step of the spontaneous process. The free energy landscape determined from these measurements is in good agreement with that obtained from molecular dynamics simulations showing that an equivalent internal force is generated by the interaction of the exposed hydrophobic residues with the membrane. This hydrophobic force is transmitted across the entire structure to produce a compressive stress across a distant, otherwise stable domain, catalyzing its transition from an extended to compact conformation. Single molecule compression is likely to become an important tool to investigate conformational transitions in membrane proteins. PMID- 26652735 TI - Effects of a Low-Intensity Laser on Dental Implant Osseointegration: Removal Torque and Resonance Frequency Analysis in Rabbits. AB - The objective of this study was to investigate how a low-intensity laser affects the stability and reverse torque resistance of dental implants installed in the tibia of rabbits. Thirty rabbits received 60 dental implants with the same design and surface treatment, one in each proximal metaphysis of the tibia. Three groups were prepared (n = 10 animals each): conventional osseointegration without treatment (control group), surgical sites irradiated with a laser beam emitted in the visible range of 680 nm (Lg1 group), surgical sites irradiated with a laser beam with a wavelength in the infrared range of 830 nm (Lg2 group). Ten irradiation sessions were performed 48 hours apart; the first session was during the immediate postoperative period. Irradiation energy density was 4 J/cm(2) per point in 2 points on each side of the tibias. The resonance frequency and removal torque values were measured at 2 time points after the implantations (3 and 6 weeks). Both laser groups (Lg1 and Lg2) presented a significant difference between resonance frequency analysis values at the baseline and the values obtained after 3 and 6 weeks (P > .05). Although the removal torque values of all groups increased after 6 weeks (P < .05), both laser groups presented greater mean values than those of the control group (P < .01). Photobiomodulation using laser irradiation with wavelengths of 680 and 830 nm had a better degree of bone integration than the control group after 6 weeks of observation time. PMID- 26652736 TI - Pneumococcal pneumonia prevention among adults: is the herd effect of pneumococcal conjugate vaccination in children as good a way as the active immunization of the elderly? AB - The indirect protection of adults as a result of pneumococcal conjugate vaccination of infants has been discussed from different epidemiological points of view. In some countries, including Italy, even after pediatric vaccination, vaccine serotypes are still responsible for most pneumonia and invasive diseases in the elderly. Although the Community-Acquired Pneumonia Immunization Trial in Adults (CAPITA) produced encouraging results, it has not showed the efficacy of the 13-valent conjugate vaccine in preventing pneumococcal community-acquired pneumonia regardless of the number of episodes and serotype. Addressing these points by monitoring the direct impact of adult vaccination in real life distinguished from the effects of herd immunity will assist public health decision-making on the most effective adult pneumococcal vaccination strategies. PMID- 26652737 TI - Spectroscopic and Theoretical Study of the Intramolecular pi-Type Hydrogen Bonding and Conformations of 2-Cyclohexen-1-ol. AB - The infrared and Raman spectra of 2-cyclohexen-1-ol have been recorded and analyzed. The experimental work has been complemented by ab initio and density functional theory computations. The calculations show that in the vapor phase the conformations with the pi-type hydrogen bonding are the lowest in energy, and these findings are supported by the experimental spectra, which agree well with the theoretical predictions. The six conformers predicted result from differences between the direction on the ring-twisting angle and the -OH internal rotation angle. The lowest-energy conformer has the hydrogen of the OH group pointing to the middle of the C?C double bond. The other conformers are calculated to be 72 cm(-1) (0.21 kcal/mol) to 401 cm(-1) (1.15 kcal/mol) higher in energy. In the liquid phase, only two conformers can be identified in the spectra, and these correspond to different directions of the ring-twisting. PMID- 26652738 TI - Bilberry and bilberry press cake as sources of dietary fibre. AB - BACKGROUND: Dietary recommendations for Nordic countries urge the use of plant foods as a basis for healthy nutrition. Currently, the level of dietary fibre (DF) intake is not adequate. Berries are an elementary part of the recommended Nordic healthy diet and could be consumed in higher amounts. MATERIALS AND METHODS: Finnish bilberries and a bilberry press cake from juice processing were studied for DF content, carbohydrate composition, and non-carbohydrate fibre content, which was analysed as sulphuric acid insoluble and soluble material. The microstructure of all samples was also studied using light microscopy and toluidine blue O, calcofluor, and acid fuchsin staining. RESULTS: The total DF contents of fresh and freeze-dried bilberries and the press cake were 3.0, 24.1, and 58.9%, respectively. Most of the DF was insoluble. Only about half of it was carbohydrate, the rest being mostly sulphuric acid-insoluble material, waxy cutin from skins, and resilient seeds. Bilberry seeds represented over half of the press cake fraction, and in addition to skin, they were the major DF sources. Microscopy revealed that skins in the press cake were intact and the surface of the seeds had thick-walled cells. CONCLUSIONS: Bilberry press cake is thus a good source of insoluble non-carbohydrate DF, and could be used to provide DF-rich foods to contribute to versatile intake of DF. PMID- 26652739 TI - Dietary fibre intakes and reduction in functional constipation rates among Canadian adults: a cost-of-illness analysis. AB - BACKGROUND: Evidence-based research highlights beneficial impacts of dietary fibre on several aspects of the gut pathophysiology that are accompanied by a considerable financial burden in healthcare services. Recommended intakes of dietary fibre may thus associate with financial benefits at a population level. OBJECTIVE: We sought to systematically assess the potential annual savings in healthcare costs that would follow the reduction in rates of functional constipation and irregularity with increased dietary fibre intakes among Canadian adults. DESIGN: A cost-of-illness analysis was developed on the basis of current and recommended levels of fibre intake in Canada, constipation reduction per 1 g fibre intake, proportion of adults who are likely to consume fibre-rich diets, and population expected to respond to fibre intake. Sensitivity analyses covering a range of assumptions were further implemented within the economic simulation. RESULTS: Our literature searches assumed a 1.8% reduction in constipation rates with each 1 g/day increase in fibre intake. With intakes corresponding to the Institute of Medicine's adequate levels of 38 g/day for men and 25 g/day for women, among 5 and 100% of the adult populations, anywhere between CAD$1.5 and CAD$31.9 million could be saved on constipation-related healthcare costs annually. Each 1 g/day increase in dietary fibre was estimated to result in total annual healthcare cost savings that ranged between CAD$0.1 and CAD$2.5 million. CONCLUSIONS: The present research suggests an economic value of increasing dietary fibre intake beyond its well-known health benefits. Healthy-eating behaviours consistent with the recommended intakes of dietary fibre by the general public should hence be advocated as a practical approach for reducing costs associated with the management of constipation in Canada. PMID- 26652740 TI - Flavonoid intake and the risk of age-related cataract in China's Heilongjiang Province. AB - BACKGROUND/OBJECTIVES: Epidemiological evidence suggests that diets rich in flavonoids may reduce the risk of developing age-related cataract (ARC). Flavonoids are widely distributed in foods of plant origin, and the objective of this study was to evaluate retrospectively the association between the intakes of the five flavonoid subclasses and the risk of ARC. SUBJECTS/METHODS: A population based case-control study (249 cases and 66 controls) was carried out in Heilongjiang province, which is located in the northeast of China, and where intakes and availability of fresh vegetables and fruits can be limited. Dietary data gathered by food-frequency questionnaire (FFQ) were used to calculate flavonoid intake. Adjusted odds ratio (OR) and 95% confidence interval (CI) were estimated by logistic regression. RESULTS: No linear associations between risk of developing ARC and intakes of total dietary flavonoids, anthocyanidins, flavon-3 ol, flavanone, total flavones or total flavonols were found, but quercetin and isorhamnetin intake was inversely associated with ARC risk (OR 11.78, 95% CI: 1.62-85.84, p<0.05, and OR 6.99, 95% CI: 1.12-43.44, p<0.05, quartile 4 vs. quartile 1, respectively). CONCLUSION: As quercetin is contained in many plant foods and isorhamnetin in very few foods, we concluded that higher quercetin intake may be an important dietary factor in the reduction of the risk of ARC. PMID- 26652741 TI - The state of regional therapy in the management of metastatic colorectal cancer to the liver. AB - Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality in the United States. Most colorectal cancer patients die from advanced disease, and two-thirds of CRC deaths are due to liver metastases. Liver resection provides the best curative option for patients with colorectal liver metastases (CRLM), yet only 20% of those patients are eligible for liver metastases resection for curative intent. Loco-regional treatment of CRLM may provide additional benefits in terms of down-staging for resection and prolonged hepatic disease control. This review focusses on hepatic arterial infusion, radioembolization and chemoembolization. PMID- 26652742 TI - m(6)A: A novel hallmark of translation. PMID- 26652743 TI - The NIHR Public Health Research Programme: responding to local authority research needs in the United Kingdom. AB - The remit of the National Institute for Health Research Public Health Research (PHR) Programme is to evaluate public health interventions, providing new knowledge on the benefits, costs, acceptability and wider impacts of interventions, set outside of the National Health Service, intended to improve the health of the public and reduce inequalities. This paper illustrates how the PHR Programme is providing new knowledge for public health decision makers, based on the nine key areas for local authority public health action, described by the King's Fund. Many funded PHR projects are evaluating interventions, applied in a range of settings, across the identified key areas for local authority influence. For example, research has been funded on children and young people, and for some of the wider determinants of health, such as housing and travel. Other factors, such as spatial planning, or open and green spaces and leisure, are less represented in the PHR Programme. Further opportunities in research include interventions to improve the health of adolescents, adults in workplaces, and communities. Building evidence for public health interventions at local authority level is important to prioritise and implement effective changes to improve population health. PMID- 26652745 TI - What do tomorrow's doctors need to learn about ecosystems? - A BEME Systematic Review: BEME Guide No. 36. AB - BACKGROUND: Human health is fundamentally determined by the health of ecosystems. Guidance is lacking about how to address the topic of ecosystems within medical education. AIMS: To determine the nature of discussions around ecosystems in the educational, medical and medical education literature. To identify learning needs of tomorrow's doctors. METHODS: A narrative synthesis approach was used. Systematic searches were completed in 14 databases. Two independent reviewers screened results. Preliminary synthesis included textual descriptions and quality appraisal. Data were analysed using the Education for Sustainable Healthcare framework and thematic analysis. Relationships between studies were explored. Best evidence synthesis, contacting authors of primary studies and critical reflection reinforced robustness. RESULTS: Six thousand seven hundred and fifty three abstracts and 123 full texts were screened. Twenty-seven studies were included. Many studies lacked clear reporting. Medical students and doctors displayed knowledge about ecosystems, but lacked confidence to enact sustainable practices. Education about causes and consequences of environmental change is required. Few studies proposed specific learning objectives. CONCLUSIONS: To prepare for roles as health care workers and leaders, medical students must learn about relationships between ecosystems, health and health care. The Education for Sustainable Healthcare framework outlines essential knowledge and attitudes but requires addition of practical competencies. Further research should explore the framework's relevance in different contexts, in order to structure training accordingly. PMID- 26652744 TI - Cholesterol Modifies Huntingtin Binding to, Disruption of, and Aggregation on Lipid Membranes. AB - Huntington's disease (HD) is an inherited neurodegenerative disease caused by abnormally long CAG-repeats in the huntingtin gene that encode an expanded polyglutamine (polyQ) domain near the N-terminus of the huntingtin (htt) protein. Expanded polyQ domains are directly correlated to disease-related htt aggregation. Htt is found highly associated with a variety of cellular and subcellular membranes that are predominantly comprised of lipids. Since cholesterol homeostasis is altered in HD, we investigated how varying cholesterol content modifies the interactions between htt and lipid membranes. A combination of Langmuir trough monolayer techniques, vesicle permeability and binding assays, and in situ atomic force microscopy were used to directly monitor the interaction of a model, synthetic htt peptide and a full-length htt-exon1 recombinant protein with model membranes comprised of total brain lipid extract (TBLE) and varying amounts of exogenously added cholesterol. As the cholesterol content of the membrane increased, the extent of htt insertion decreased. Vesicles containing extra cholesterol were resistant to htt-induced permeabilization. Morphological and mechanical changes in the bilayer associated with exposure to htt were also drastically altered by the presence of cholesterol. Disrupted regions of pure TBLE bilayers were grainy in appearance and associated with a large number of globular aggregates. In contrast, morphological changes induced by htt in bilayers enriched in cholesterol were plateau-like with a smooth appearance. Collectively, these observations suggest that the presence and amount of cholesterol in lipid membranes play a critical role in htt binding and aggregation on lipid membranes. PMID- 26652746 TI - Home support workers perceptions of family members of their older clients: a qualitative study. AB - BACKGROUND: Health care discourse is replete with references to building partnerships between formal and informal care systems of support, particularly in community and home based health care. Little work has been done to examine the relationship between home health care workers and family caregivers of older clients. The purpose of this study is to examine home support workers' (HSWs) perceptions of their interactions with their clients' family members. The goal of this research is to improve client care and better connect formal and informal care systems. METHODS: A qualitative study, using in-depth interviews was conducted with 118 home support workers in British Columbia, Canada. Framework analysis was used and a number of strategies were employed to ensure rigor including: memo writing and analysis meetings. Interviews were transcribed verbatim and sent to a professional transcription agency. Nvivo 10 software was used to manage the data. RESULTS: Interactions between HSWs and family members are characterized in terms both of complementary labour (family members providing informational and instrumental support to HSWs), and disrupted labour (family members creating emotion work and additional instrumental work for HSWs). Two factors, the care plan and empathic awareness, further impact the relationship between HSWs and family caregivers. CONCLUSIONS: HSWs and family members work to support one another instrumentally and emotionally through interdependent interactions and empathic awareness. Organizational Care Plans that are too rigid or limited in their scope are key factors constraining interactions. PMID- 26652747 TI - Problems associated with reconstitution, administration, and storage of antibiotic suspensions for pediatrics: a cross-sectional study in Nablus city, Palestine. AB - BACKGROUND: The objective of this study was to evaluate the appropriateness of antibiotic suspensions use for pediatrics among Palestinian mothers' including their reconstitution, dose administration, duration, and storage conditions. METHODS: This study was a questionnaire based cross sectional descriptive study. It was conducted at a governmental primary healthcare center and a pediatric private clinic in Nablus city between January and March 2013. A sample of 400 mothers were met and asked to answer a face to face questionnaire. RESULTS: The results showed that 347 (86.8 %) of mothers told that they read instructions, 311 (77.8 %) could understand manufacturers' instructions, and 176 (44.0 %) of mothers asked pharmacists for advice when instructions were not well understood. In order to prepare antibiotic suspension, 302 (75.5 %) used boiled then cooled water, 192 (48.4 %) of mothers used a syringe to measure the needed amount of water, and 304 (76.6 %) added water in two steps, 392 (98.0 %) of mothers claimed that they shook the suspension bottle before use. Regarding dose administration, 313 (78.2 %) considered syringe as the most accurate tool for dose administration, most of mothers told that they gave drug dose with major meals when direction were to give three times daily, about use duration only 6 (1.5 %) mothers said that they used antibiotic suspension after 2 weeks, and 53 (6.5 %) gave left over antibiotic suspension to another child. One hundred seventy seven (44.2 %) mothers told they stored dry powder antibiotic in medicinal cabinet, while 226 (56.5 %) of them stored suspension in refrigerator. CONCLUSION: The results reflect a good level of correct practice. However, there is a room for improvement. The pharmacists are recommended to explain the correct directions, to supply a syringe with suitable calibration for dose administration, and to counsel parents about suitable storage condition, frequency of dosing and duration of use. PMID- 26652748 TI - Cognitive Flexibility: A Default Network and Basal Ganglia Connectivity Perspective. AB - The intra/extradimensional set-shifting task (IED) provides a reliable assessment of cognitive flexibility, the shifting of attention to select behaviorally relevant stimuli in a given context. Impairments in this domain were previously reported in patients with altered neurotransmitter systems such as schizophrenia and Parkinson's disease. Consequently, corticostriatal connections were implicated in the mediation of this function. In addition, parts of the default mode network (DMN), namely the medial prefrontal and posterior cingulate/precuneus cortices, are also being progressively described in association with set-shifting paradigms. Nevertheless, a definitive link between cognitive flexibility and DMN connectivity remains to be established. To this end, we related resting state functional magnetic resonance imaging (fMRI)-based functional connectivity of DMN with IED task performance in a healthy population, measured outside the scanner. The results demonstrated that greater posterior cingulate cortex/precuneus (DMN) connectivity with the ventromedial striatopallidum at rest correlated with fewer total adjusted errors on the IED task. This finding points to a relationship between DMN and basal ganglia connectivity for cognitive flexibility, further highlighting this network's potential role in adaptive human cognition. PMID- 26652749 TI - Descending pain modulation in irritable bowel syndrome (IBS): a systematic review and meta-analysis. AB - BACKGROUND: Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder. While abdominal pain is a dominant symptom of IBS, many sufferers also report widespread hypersensitivity and present with other chronic pain conditions. The presence of widespread hypersensitivity and extra intestinal pain conditions suggests central nervous dysfunction. While central nervous system dysfunction may involve the spinal cord (central sensitisation) and brain, this review will focus on one brain mechanism, descending pain modulation. METHOD/DESIGN: We will conduct a comprehensive search for the articles indexed in the databases Ovid MEDLINE, Ovid Embase, Ovid PsycINFO and Cochrane Central Register of Controlled Trial (CENTRAL) from their inception to August 2015, that report on any aspect of descending pain modulation in irritable bowel syndrome. Two independent reviewers will screen studies for eligibility, assess risk of bias and extract relevant data. Results will be tabulated and, if possible, a meta-analysis will be carried out. DISCUSSION: The systematic review outlined in this protocol aims to summarise current knowledge regarding descending pain modulation in IBS. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015024284. PMID- 26652750 TI - Fabivirga thermotolerans gen. nov., sp. nov., a novel marine bacterium isolated from culture broth of a marine cyanobacterium. AB - A Gram-stain-negative, red, non-spore-forming, strictly aerobic bacterium, designated strain A4T, was isolated from culture broth of a marine cyanobacterium. Cells were flexible rods with gliding motility. Phylogenetic analysis, based on 16S rRNA gene sequences, revealed that strain A4T formed a coherent cluster with members of the genera Roseivirga and Fabibacter, and represents a distinct lineage in the family Flammeovirgaceae. Thermotolerance and a distinctive cellular fatty acid profile could readily distinguish this isolate from any bacteria of the genera Roseivirga and Fabibacter with a validly published name. On the basis of the phenotypic, chemotaxonomic and phylogenetic characteristics, strain A4T is suggested to represent a novel species in a novel genus, for which the name Fabivirga thermotolerans gen. nov., sp. nov. is proposed. The type strain is A4T ( = KCTC 42507T = CGMCC 1.15111T). PMID- 26652751 TI - pH-Reversible Cationic RNase A Conjugates for Enhanced Cellular Delivery and Tumor Cell Killing. AB - Intracellularly-acting therapeutic proteins are considered promising alternatives for the treatment of various diseases. Major limitations of their application are low efficiency of intracellular delivery and possible reduction of protein activity during derivatization. Herein, we report pH-sensitive covalent modification of proteins with a histidine-rich cationic oligomer (689) for efficient intracellular transduction and traceless release of functional proteins. Enhanced Green fluorescent protein (EGFP), as model for the visualization of protein transduction, and RNase A, as therapeutic protein with antitumoral effect, were modified with the pH-sensitive bifunctional AzMMMan linker and varying amounts of cationic oligomer. The modification degree showed impact on the internalization and cellular distribution of EGFP as well as the biological effect of RNase A conjugates, which mediated considerable toxicity against cancer cells at optimal ratio. The presented conjugates demonstrate their qualification to achieve efficient intracellular delivery and controlled release without protein inactivation and potential prospective applications in protein based therapies. PMID- 26652752 TI - Eating disorders prevention: Looking backward, moving forward; looking inward, moving outward. PMID- 26652753 TI - Removal of bisphenol A and its derivatives from aqueous medium through laccase catalyzed treatment enhanced by addition of polyethylene glycol. AB - In this study, enzymatic removal of bisphenol A (BPA) from the aqueous medium was investigated through the generation of water-insoluble oligomers, and this procedure was applied to removal of bisphenol derivatives. The experimental parameters, such as the temperature, pH value, enzyme concentration, and concentration and molecular weight of polyethylene glycol (PEG), were determined for the laccase-catalyzed treatment of BPA. The optimum conditions were determined to be pH 7.0 and 40 degrees C in the absence of PEG. Water-insoluble oligomers generated under these conditions were readily removed by filtration or centrifugation. The optimum pH value was decreased to 5.0 in the presence of PEG and the laccase dose was reduced to one-fiftieth of that in the absence of PEG. This indicates that the addition of PEG protects the enzymatic activity and prevents capture of laccase molecules in the oligomers. The oligomers generated in the presence of PEG were removed from the aqueous medium by filtration with a membrane filter or by centrifugation. The oligomers were completely filtrated out with a filter paper by decreasing the pH value to 3.0. In addition, several bisphenol derivatives were also treated and subsequently removed by adjusting the laccase dose in the presence of PEG using the above procedure. PMID- 26652754 TI - Nogo-B Receptor Modulates Pulmonary Artery Smooth Muscle Cell Function in Developing Lungs. AB - Nogo-B and its receptor (NgBR) are involved in blood vessel growth in developing lungs, but their role in pulmonary artery smooth muscle cell (PASMC) growth is unknown. We hypothesized that NgBR regulates growth of PASMCs by modulating the function of endoplasmic reticulum (ER) and formation of reactive oxygen species (ROS). In utero constriction of the ductus arteriosus created pulmonary hypertension in fetal lambs (hypertensive fetal lamb [HTFL]). PASMCs isolated 8 days after surgery were assessed for the alteration of protein levels by immunoblots and ROS formation by dihydroethidium and Cell ROX deep red fluorescence. NgBR small interfering RNA and plasmid DNA were used to manipulate NgBR levels. Proliferation and wound healing were assessed by cell counts and scratch recovery assay, respectively. Acute ER stress was induced by tunicamycin. Differences of mitogen-activated protein kinase and Akt pathway activation in HTFL versus control PASMCs were evaluated. Results showed that HTFL PASMCs had decreased NgBR levels and increased proliferation, wound healing, ER stress, and ROS formation compared with controls. Knockdown of NgBR in control PASMCs generated a phenotype similar to HTFL, and overexpression in HTFL restored the defective phenotype to control. Decreased NgBR levels were associated with increased ROS formation in HTFL PASMCs. Subsequently, scavenging ROS decreased proliferation and wound healing. Mechanistically, ROS formation decreases NgBR expression, which induces ER stress. This leads to extracellular signal-regulated kinase pathway activation and PASMC phenotype alteration. Our data suggest that decreased NgBR expression in pulmonary hypertension of the newborn contributes to increased PASMC proliferation and oxidative stress, which lead to the pathogenesis of lung injury. PMID- 26652756 TI - Training for Research and Teaching in Geropsychology: Preparing the Next Generation of Scholars and Educators. AB - For geropsychology to flourish in the years ahead, we need scientists to advance knowledge and teachers to draw new professionals into the field. In this project the authors surveyed 100 geropsychologists who completed a doctoral degree in clinical or counseling psychology about their experience with training for research and teaching. The majority were currently conducting some degree of research (38%) and some form of teaching (45%). The majority of ratings for components of research training were in the "very good to excellent" range, whereas elements of teacher training were rated in the "poor to good" range, though there was variability among persons and components. Qualitative comments revealed enthusiasm for research and teaching roles and a need to enhance our training of geropsychologists as educators. The authors provide several suggestions that could enhance research and teacher training for current and future students of professional geropsychology. PMID- 26652757 TI - Influence of Substrate Microstructure on the Transport Properties of CVD Graphene. AB - We report the study of electrical transport in few-layered CVD-graphene located on nanostructured surfaces in view of its potential application as a transparent contact to optoelectronic devices. Two specific surfaces with a different characteristic feature scale are analyzed: semiconductor micropyramids covered with SiO2 layer and opal structures composed of SiO2 nanospheres. Scanning tunneling microscopy (STM) and scanning electron microscopy (SEM), as well as Raman spectroscopy, have been used to determine graphene/substrate surface profile. The graphene transfer on the opal face centered cubic arrangement of spheres with a diameter of 230 nm leads to graphene corrugation (graphene partially reproduces the opal surface profile). This structure results in a reduction by more than 3 times of the graphene sheet conductivity compared to the conductivity of reference graphene located on a planar SiO2 surface but does not affect the contact resistance to graphene. The graphene transfer onto an organized array of micropyramids results in a graphene suspension. Unlike opal, the graphene suspension on pyramids leads to a reduction of both the contact resistance and the sheet resistance of graphene compared to resistance of the reference graphene/flat SiO2 sample. The sample annealing is favorable to improve the contact resistance to CVD-graphene; however, it leads to the increase of its sheet resistance. PMID- 26652758 TI - Developing a Performance Assessment Framework and Indicators for Communicable Disease Management in Natural Disasters. AB - INTRODUCTION: Communicable disease management (CDM) is an important component of disaster public health response operations. However, there is a lack of any performance assessment (PA) framework and related indicators for the PA. This study aimed to develop a PA framework and indicators in CDM in disasters. METHODS: In this study, a series of methods were used. First, a systematic literature review (SLR) was performed in order to extract the existing PA frameworks and indicators. Then, using a qualitative approach, some interviews with purposively selected experts were conducted and used in developing the PA framework and indicators. Finally, the analytical hierarchy process (AHP) was used for weighting of the developed indicators. RESULTS: The input, process, products, and outcomes (IPPO) framework was found to be an appropriate framework for CDM PA. Seven main functions were revealed to CDM during disasters. Forty PA indicators were developed for the four categories. CONCLUSION: There is a lack of any existing PA framework in CDM in disasters. Thus, in this study, a PA framework (IPPO framework) was developed for the PA of CDM in disasters through a series of methods. It can be an appropriate framework and its indicators could measure the performance of CDM in disasters. PMID- 26652759 TI - Synthesis of Chiral beta-Amino Nitroalkanes via Rhodium-Catalyzed Asymmetric Hydrogenation. AB - The asymmetric hydrogenation of beta-amino nitroolefins has been successfully achieved by rhodium/bis(phosphine)-thiourea L1 with excellent enantioselectivities and yields (up to 96% ee, 96% yield, >99% conversion, TON up to 1000) under mild conditions. Chiral beta-amino nitroalkane products and their derivatives are versatile intermediates in organic synthesis. PMID- 26652761 TI - Fully non-linear hyper-viscoelastic modeling of skeletal muscle in compression. AB - Understanding the behavior of skeletal muscle is critical to implementing computational methods to study how the body responds to compressive loading. This work presents a novel approach to studying the fully nonlinear response of skeletal muscle in compression. Porcine muscle was compressed in both the longitudinal and transverse directions under five stress relaxation steps. Each step consisted of 5% engineering strain over 1 s followed by a relaxation period until equilibrium was reached at an observed change of 1 g/min. The resulting data were analyzed to identify the peak and equilibrium stresses as well as relaxation time for all samples. Additionally, a fully nonlinear strain energy density-based Prony series constitutive model was implemented and validated with independent constant rate compressive data. A nonlinear least squares optimization approach utilizing the Levenberg-Marquardt algorithm was implemented to fit model behavior to experimental data. The results suggested the time dependent material response plays a key role in the anisotropy of skeletal muscle as increasing strain showed differences in peak stress and relaxation time (p < 0.05), but changes in equilibrium stress disappeared (p > 0.05). The optimizing procedure produced a single set of hyper-viscoelastic parameters which characterized compressive muscle behavior under stress relaxation conditions. The utilized constitutive model was the first orthotropic, fully nonlinear hyper viscoelastic model of skeletal muscle in compression while maintaining agreement with constitutive physical boundaries. The model provided an excellent fit to experimental data and agreed well with the independent validation in the transverse direction. PMID- 26652762 TI - Marker gene tethering by nucleoporins affects gene expression in plants. AB - In non-plant systems, chromatin association with the nuclear periphery affects gene expression, where interactions with nuclear envelope proteins can repress and interactions with nucleoporins can enhance transcription. In plants, both hetero- and euchromatin can localize at the nuclear periphery, but the effect of proximity to the nuclear periphery on gene expression remains largely unknown. This study explores the putative function of Seh1 and Nup50a nucleoporins on gene expression by using the Lac Operator / Lac Repressor (LacI-LacO) system adapted to Arabidopsis thaliana. We used LacO fused to the luciferase reporter gene (LacO:Luc) to investigate whether binding of the LacO:Luc transgene to nucleoporin:LacI protein fusions alters luciferase expression. Two separate nucleoporin-LacI-YFP fusions were introduced into single insert, homozygous LacO:Luc Arabidopsis plants. Homozygous plants carrying LacO:Luc and a single insert of either Seh1-LacI-YFP or Nup50a-LacI-YFP were tested for luciferase activity and compared to plants containing LacO:Luc only. Seh1-LacI-YFP increased, while Nup50a-LacI-YFP decreased luciferase activity. Seh1-LacI-YFP accumulated at the nuclear periphery as expected, while Nup50a-LacI-YFP was nucleoplasmic and was not selected for further study. Protein and RNA levels of luciferase were quantified by western blotting and RT-qPCR, respectively. Increased luciferase activity in LacO:Luc+Seh1-LacI-YFP plants was correlated with increased luciferase protein and RNA levels. This change of luciferase expression was abolished by disruption of LacI-LacO binding by treating with IPTG in young seedlings, rosette leaves and inflorescences. This study suggests that association with the nuclear periphery is involved in the regulation of gene expression in plants. PMID- 26652764 TI - Weight Gain and Dyslipidemia in Early Adulthood Associate With Polycystic Ovary Syndrome: Prospective Cohort Study. AB - CONTEXT: Obesity affects the majority of women with polycystic ovary syndrome (PCOS), but previous studies are inconsistent about the prevalence of obesity and the importance of weight gain in the development of the syndrome. OBJECTIVE: Our objective was to explore the association between weight, weight gain, hyperandrogenism, and PCOS from adolescence to late adulthood. DESIGN: The study includes a prospective Northern Finland Birth Cohort 1966 study including 5889 females born in 1966 and followed at the ages of 14, 31, and 46 years. SETTING: The setting was the general community. PARTICIPANTS: Women presenting both oligo/amenorrhea (OA) and hirsutism (H) at age 31 (N = 125) or with formally diagnosed PCOS by age 46 (N = 181) were compared with women without PCOS symptoms or diagnosis (n = 1577). INTERVENTIONS: None. MAIN OUTCOME MEASURES: Body mass index (BMI), weight change through life, waist circumference, Free Androgen Index, lipids, glucose, insulin, high-sensitivity C-reactive protein, homeostatic model assessment for insulin resistance, and PCOS. RESULTS: Women with OA+H at age 31 or diagnosis of PCOS by age 46 had the highest BMI at all ages compared with the controls. Increase of BMI between ages 14 and 31, but not between 31 and 46, was greater in women with isolated OA (P = .006), OA+H (P = .001), and diagnosis of PCOS (P = .001) compared with controls. In the multivariate analysis, PCOS was significantly associated with BMI at all ages (BMI at age 31: odds ratio [OR] = 1.05 [95% confidence interval (CI), 1.00-1.10], Free Androgen Index (OR = 1.08 [95% CI, 1.03-1.14]), serum levels of insulin (OR = 1.05 [95% CI, 1.00-1.09]), and triglycerides (OR = 1.48 [95% CI, 1.08-2.03]). CONCLUSIONS: Symptoms or diagnosis of PCOS are associated with dyslipidemia, hyperandrogenemia, and significantly increased weight gain, especially in early adulthood. This observation is important because it may identify a sensitive time period when weight gain plays a crucial role in the emergence of PCOS and when preventive actions against metabolic and cardiovascular diseases should be implemented. PMID- 26652763 TI - A Diet Rich in Medium-Chain Fatty Acids Improves Systolic Function and Alters the Lipidomic Profile in Patients With Type 2 Diabetes: A Pilot Study. AB - CONTEXT: Excessive cardiac long-chain fatty acid (LCFA) metabolism/storage causes cardiomyopathy in animal models of type 2 diabetes. Medium-chain fatty acids (MCFAs) are absorbed and oxidized efficiently. Data in animal models of diabetes suggest MCFAs may benefit the heart. OBJECTIVE: Our objective was to test the effects of an MCFA-rich diet vs an LCFA-rich diet on plasma lipids, cardiac steatosis, and function in patients with type 2 diabetes. DESIGN: This was a double-blind, randomized, 2-week matched-feeding study. SETTING: The study included ambulatory patients in the general community. PATIENTS: Sixteen patients, ages 37-65 years, with type 2 diabetes, an ejection fraction greater than 45%, and no other systemic disease were included. INTERVENTION: Fourteen days of a diet rich in MCFAs or LCFAs, containing 38% as fat in total, was undertaken. MAIN OUTCOME MEASURES: Cardiac steatosis and function were the main outcome measures, with lipidomic changes considered a secondary outcome. RESULTS: The relatively load-independent measure of cardiac contractility, S', improved in the MCFA group (P < .05). Weight-adjusted stroke volume and cardiac output decreased in the LCFA group (both P < .05). The MCFA, but not the LCFA, diet decreased several plasma sphingolipids, ceramide, and acylcarnitines implicated in diabetic cardiomyopathy, and changes in several sphingolipids correlated with improved fasting insulins. CONCLUSIONS: Although a diet high in MCFAs does not change cardiac steatosis, our findings suggest that the MCFA-rich diet alters the plasma lipidome and may benefit or at least not harm cardiac function and fasting insulin levels in humans with type 2 diabetes. Larger, long-term studies are needed to further evaluate these effects in less-controlled settings. PMID- 26652765 TI - Periodic Paralysis as a New Phenotype of Resistance to Thyroid Hormone Syndrome in a Chinese Male Adult. AB - CONTEXT: A majority of patients with resistance to thyroid hormone (RTH) are asymptomatic, whereas some patients show signs of hyperthyroidism, or hypothyroidism, or both. Thyrotoxic periodic paralysis is the most common form of acquired periodic paralysis. However, it has not been reported in a patient with RTH up to now. OBJECTIVE: We evaluated a 36-year-old male patient from China with elevated serum free T4 and free T3 and inappropriately high TSH who presented with periodic paralysis. STUDY DESIGN: Clinical, biochemical, and radiological assessments, as well as DNA sequencing, were performed. RESULTS: The patient's laboratory tests revealed the following: TSH, 6.14 mIU/L (0.27-4.2 mIU/L); free T3, 12.85 pmol/L (2.8-7.1 pmol/L); free T4, 33.62 pmol/L (9.05-25.5 pmol/L); and serum SHBG, 19.4 nmol/L (18.3-54.1 nmol/L). No significant suppression of TSH was observed in the rapid TSH suppression test with somatostatin analogs. Compound muscle action potential after exercise of the patient was reduced by 58%. Sequencing of thyroid hormone receptor genes confirmed a C446S mutation in the THRbeta gene. CONCLUSIONS: This is the first report of periodic paralysis as a new phenotype of RTH syndrome. PMID- 26652766 TI - Circulating Follistatin Is Liver-Derived and Regulated by the Glucagon-to-Insulin Ratio. AB - CONTEXT: Follistatin is a plasma protein recently reported to increase under conditions with negative energy balance, such as exercise and fasting in humans. Currently, the perception is that circulating follistatin is a result of para/autocrine actions from various tissues. The large and acute increase in circulating follistatin in response to exercise suggests that it may function as an endocrine signal. OBJECTIVE: We assessed origin and regulation of circulating follistatin in humans. DESIGN/INTERVENTIONS: First, we assessed arterial-to venous difference of follistatin over the splanchnic bed at rest and during exercise in healthy humans. To evaluate the regulation of plasma follistatin we manipulated glucagon-to-insulin ratio in humans at rest as well as in cultured hepatocytes. Finally, the impact of follistatin on human islets of Langerhans was assessed. RESULTS: We demonstrate that in humans the liver is a major contributor to circulating follistatin both at rest and during exercise. Glucagon increases and insulin inhibits follistatin secretion both in vivo and in vitro, mediated via the secondary messenger cAMP in the hepatocyte. Short-term follistatin treatment reduced glucagon secretion from islets of Langerhans, whereas long-term follistatin treatment prevented apoptosis and induced proliferation of rat beta cells. CONCLUSIONS: In conclusion, in humans, the liver secretes follistatin at rest and during exercise, and the glucagon-to-insulin ratio is a key determinant of circulating follistatin levels. Circulating follistatin may be a marker of the glucagon-to-insulin tone on the liver. PMID- 26652767 TI - Effect of Extraction Conditions on the Saccharide (Neutral and Acidic) Composition of the Crude Pectic Extract from Various Agro-Industrial Residues. AB - The influence of different extraction methodologies was assessed on the composition of both neutral (arabinose, rhamnose, galactose) and acidic (galacturonic acid) pectic polysaccharides obtained from four agro-industrial residues, namely, berry pomace (BP), onion hulls (OH), pressed pumpkin (PP), and sugar beet pulp (SBP). For acidic pectic polysaccharides, the extraction efficiency was obtained as BP (nitric acid-assisted extraction, 2 h, 62.9%), PP (enzymatic-assisted extraction, 12 h, 75.0%), SBP (enzymatic-assisted extraction, 48 h, 89.8%; and nitric acid-assisted extraction, 4 h, 76.5%), and OH (sodium hexametaphosphate-assisted extraction, 0.5 h, 100%; and ammonium oxalate-assisted extraction, 0.5 h, 100%). For neutral pectic polysaccharides, the following results were achieved: BP (enzymatic-assisted extraction, 24 h, 85.9%), PP (nitric acid-assisted extraction, 6 h, 82.2%), and SBP (enzymatic assisted extraction, 48 h, 97.5%; and nitric acid-assisted extraction, 4 h, 83.2%). On the basis of the high recovery of pectic sugars, SBP and OH are interesting candidates for the further purification of pectin and production of pectin derived products. PMID- 26652768 TI - Could specific cell targeting overcome resistance associated with current treatments for African trypanosomiasis? PMID- 26652769 TI - A Patient Just Died. PMID- 26652770 TI - Cellular Therapies for Muscular Dystrophies: Frustrations and Clinical Successes. AB - Cell-based therapy for muscular dystrophies was initiated in humans after promising results obtained in murine models. Early trials failed to show substantial clinical benefit, sending researchers back to the bench, which led to the discovery of many hurdles as well as many new venues to optimize this therapeutic strategy. In this review we summarize progress in preclinical cell therapy approaches, with a special emphasis on human cells potentially attractive for human clinical trials. Future perspectives for cell therapy in skeletal muscle are discussed, including the perspective of combined therapeutic approaches. PMID- 26652771 TI - Induction of Cytotoxicity in Pyridine Analogues of the Anti-metastatic Ru(III) Complex NAMI-A by Ferrocene Functionalization. AB - A series of novel ferrocene (Fc) functionalized Ru(III) complexes was synthesized and characterized. These compounds are derivatives of the anti-metastatic Ru(III) complex imidazolium [trans-RuCl4(1H-imidazole) (DMSO-S)] (NAMI-A) and are derived from its pyridine analogue (NAMI-Pyr), with direct coupling of Fc to pyridine at the 4 or 3 positions, or at the 4 position via a two-carbon linker, which is either unsaturated (vinyl) or saturated (ethyl). Electron paramagnetic resonance (EPR) and UV-vis spectroscopic studies of the ligand exchange processes of the compounds in phosphate buffered saline (PBS) report similar solution behavior to NAMI-Pyr. However, the complex with Fc substitution at the 3 position of the coordinated pyridine shows greater solution stability, through resistance to the formation of oligomeric species. Further EPR studies of the complexes with human serum albumin (hsA) indicate that the Fc groups enhance noncoordinate interactions with the protein and help to inhibit the formation of protein coordinated species, suggesting the potential for enhanced bioavailability. Cyclic voltammetry measurements demonstrate that the Fc groups modestly reduce the reduction potential of the Ru(III) center as compared to NAMI-Pyr, while the reduction potentials of the Fc moieties of the four compounds vary by 217 mV, with the longer linkers giving significantly lower values of E1/2. EPR spectra of the compounds with 2-carbon linkers show the formation of a high-spin Fe(III) species (S = 5/2) in PBS with a distinctive signal at g = 4.3, demonstrating oxidation of the Fe(II) ferrocene center and likely reflecting degradation products. Density functional theory calculations and paramagnetic (1)H NMR describe delocalization of spin density onto the ligands and indicate that the vinyl linker could be a potential pathway for electron transfer between the Ru and Fe centers. In the case of the ethyl linker, electron transfer is suggested to occur via an indirect mechanism enabled by the greater flexibility of the ligand. In vitro assays with the SW480 cell line reveal cytotoxicity induced by the ruthenium ferrocenylpyridine complexes that is at least an order of magnitude higher than the unfunctionalized complex, NAMI-Pyr. Furthermore, migration studies with LNCaP cells reveal that Fc functionalization does not reduce the ability of the compounds to inhibit cell motility. Overall, these studies demonstrate that NAMI-A-type compounds can be functionalized with redox-active ligands to produce both cytotoxic and anti-metastatic activity. PMID- 26652772 TI - Equipment failures and their contribution to industrial incidents and accidents in the manufacturing industry. AB - Accidental events in manufacturing industries can be caused by many factors, including work methods, lack of training, equipment design, maintenance and reliability. This study is aimed at determining the contribution of failures of commonly used industrial equipment, such as machines, tools and material handling equipment, to the chain of causality of industrial accidents and incidents. Based on a case study which aimed at the analysis of an existing pulp and paper company's accident database, this paper examines the number, type and gravity of the failures involved in these events and their causes. Results from this study show that equipment failures had a major effect on the number and severity of accidents accounted for in the database: 272 out of 773 accidental events were related to equipment failure, where 13 of them had direct human consequences. Failures that contributed directly or indirectly to these events are analyzed. PMID- 26652774 TI - Cellulose Nanofibrils and Mechanism of their Mineralization in Biomimetic Synthesis of Hydroxyapatite/Native Bacterial Cellulose Nanocomposites: Molecular Dynamics Simulations. AB - Molecular dynamics (MD) simulation of a nanofibril of native bacterial cellulose (BC) in solutions of mineral ions is presented. The supersaturated calcium phosphate (CP) solution with the ionic composition of hydroxyapatite and CaCl2 solutions with the concentrations below, equal to, and above the solubility limits are simulated. The influence of solvation models (TIP3P and TIP4P-ew water models) on structural characteristics of the simulated nanofibril and on the crystal nucleation process is assessed. The structural characteristics of cellulose nanofibrils (in particular, of the surface layer) are found to be nearly independent of the solvation models used in the simulation and on the presence of ions in the solutions. It is shown that ionic clusters are formed in the solution rather than on the fibril surface. The cluster sizes are slightly different for the two water models. The effect of the ion-ion interaction parameters on the results is discussed. The main conclusion is that the activity of hydroxyl groups on the BC fibril surface is not high enough to cause adsorption of Ca(2+) ions from the solution. Therefore, the nucleation of CP crystals takes place initially in solution, and then the crystallites formed can be adsorbed on BC nanofibril surfaces. PMID- 26652773 TI - Nonlinear Absorption and Low-Threshold Multiphoton Pumped Stimulated Emission from All-Inorganic Perovskite Nanocrystals. AB - Halide perovskite materials have attracted intense research interest due to the striking performance in photoharvesting photovoltaics as well as photoemitting applications. Very recently, the emerging CsPbX3 (X = Cl, Br, I) perovskite nanocrystals have been demonstrated to be efficient emitters with photoluminescence quantum yield as high as ~90%, room temperature single photon sources, and favorable lasing materials. Herein, the nonlinear optical properties, in particular, the multiphoton absorption and resultant photoluminescence of the CsPbBr3 nanocrystals, were investigated. Notably, a large two-photon absorption cross-section of up to ~1.2 * 10(5) GM is determined for 9 nm sized CsPbBr3 nanocrystals. Moreover, low-threshold frequency upconverted stimulated emission by two-photon absorption was observed from the thin film of close-packed CsPbBr3 nanocrystals. The stimulated emission is found to be photostable and wavelength-tunable. We further realize the three-photon pumped stimulated emission in green spectra range from colloidal nanocrystals for the first time. Our results reveal the strong nonlinear absorption in the emerging CsPbX3 perovskite nanocrystals and suggest these nanocrystals as attractive multiphoton pumped optical gain media, which would offer new opportunities in nonlinear photonics and revive the nonlinear optical devices. PMID- 26652776 TI - Corrigendum. PMID- 26652775 TI - The role of next-generation sequencing in understanding the genomic basis of diffuse large B cell lymphoma and advancing targeted therapies. AB - Next Generation Sequencing (NGS) has redefined the genetic landscape of Diffuse Large B-Cell Lymphoma (DLBCL) by identifying recurrent somatic mutations. Importantly, in some cases these mutations impact potentially actionable targets, thus affording novel personalized therapy opportunities. At the forefront of today's precision therapy era, how to best incorporate NGS into daily clinical practice is of primordial concern, in order to tailor patient's treatment regimens according to their individual mutational profiles. With the advent of cell-free DNA sequencing, which provides a sensitive and less invasive means of monitoring DLBCL patients, the clinical feasibility of NGS has been greatly improved. This article reviews the current landscape of DLBCL mutations, as well as the targeted therapies developed to counter their effects, and discusses how best to utilize NGS data for treatment decision-making. PMID- 26652777 TI - Quantitative Analysis of Vocal Fold Vibration in Vocal Fold Paralysis With the Use of High-speed Digital Imaging. AB - INTRODUCTION: The goal of this work was to objectively elucidate the vibratory characteristics of vocal fold paralysis (VFP) using high-speed digital imaging (HSDI). METHODS: HSDI was performed in 29 vocally healthy subjects (12 women and 17 men) and in 107 patients with VFP (40 women and 67 men). Then, the HSDI data were evaluated by visual-perceptual rating, single-line kymography, multiline kymography, laryngotopography, and glottal area waveform analysis. RESULTS: Patients with VFP compared with vocally healthy subjects revealed more frequent incomplete glottal closure, greater asymmetry in amplitude, mucosal wave, frequency, and phase, as well as larger open quotient, smaller speed index, larger maximal and minimal glottal area, and smaller glottal area difference. Paralyzed vocal folds in VFP revealed reduced mucosal wave than nonparalyzed vocal folds in VFP or in intact vocal folds in vocally healthy subjects. CONCLUSIONS: HSDI was effective in documenting the characteristics of vocal fold vibrations in patients with VFP and in exploring the vibratory disturbance for estimating the severity of dysphonia. PMID- 26652778 TI - Quantification of Respiratory Laryngeal Morphometry: Comparison of Laryngeal Lumen Angle Estimate Methods. AB - OBJECTIVES: Evaluate the effects of (1) laryngeal configuration, (2) image barrel distortion, and (3) lens perspective on the accuracy of anterior and posterolateral laryngeal lumen angle morphometric estimates. STUDY DESIGN: Prospective, repeated-measures. METHODS: Twenty-four (24) excised canine larynges were manipulated across four different length-by-width configurations to evaluate the influence of laryngeal configuration on relative precision of three laryngeal morphometric angle estimate methods. Physical measurements of the laryngeal specimens were compared (statistically and descriptively) with corresponding unadjusted and barrel-distortion corrected laryngoscopic laryngeal images. Additional post hoc analysis involved systematic manipulation of camera lens-to object perspective (shift, tilt, and distance) using a synthetic object representing the physical laryngeal specimen and simulated image of the laryngoscopic laryngeal images. Morphometric angle estimates between the synthetic object and the simulated images were compared across simulated lens-to object perspective manipulations to evaluate influences of lens perspective artifacts on laryngeal morphometric estimate precision. RESULTS: Statistical analysis showed that laryngeal morphometric angle estimates were impervious to laryngeal configuration manipulations, but were influenced by image barrel correction methods. Statistically significant differences were found between the unadjusted and barrel-corrected images within the anterior angle method. Simulated camera lens-to-object perspective manipulations showed that tilt and distance have substantial negative influence on laryngeal morphometric estimate precision. CONCLUSIONS: Laryngeal lumen angles can be used to measure respiratory laryngeal morphometry. However, image-correction algorithms are necessary to correct images and quantify morphometric estimate error caused by camera lens distortion and lens-to-object perspective. Findings provide a platform for future research on quantifying laryngeal morphometry, especially for individuals with laryngeal breathing disorders. PMID- 26652779 TI - [Atherosclerosis: from etiology to its possible influencing]. AB - Atherosclerosis as an inflammatory process affecting vessel wall has more forms usually occurring together. Classical atherosclerotic vascular lesion characterised by lipid accumulation in the subendothelial space is frequently accompanied by changes in deeper layers of arterial wall, in which increased extracellular tissue mass and smooth muscle cells activation represent the most prominent feature. Due to a specific constellation of risk factors the first or second pathology may be more expressed. While initiation and progression of classical atherosclerosis are mostly driven by lipoproteins (especially of LDL class) the most important factor of arterial media changes seem to be different risk factors e.g. hyperactivity of renin-angiotensin-aldosterone system (RAS). Influencing these two basic pathogenic mechanisms undoubtedly slows down the course of vascular changes and impacts positively on the prognosis of the patients. It is noteworthy, that simultaneous targeting of both of these mechanisms yields synergistic effects as evidenced both by experimental and clinical works. Using the opportunities offered by intensive lowering of atherogenic plasma lipids and over activation of the RAS system reduce not only the incidence of typical atherotromobotic complications (e.g. acute coronary syndrome) but also the events caused by changes of medial part of arterial wall or left myocardial ventricle (malignant arrhythmia, heart failure). These two strategies represent necessary conditions for successful cardiovascular prevention. PMID- 26652780 TI - [Practical approach to statin intolerance]. AB - Statins significantly decrease the cardiovascular risk and the reduction of cholesterol by statins has become a milestone in the prevention of cardiovascular diseases for a large group of patients. In spite of that an adequate use of statins in many patients is limited by adverse symptoms which lead to interruption of the therapy in some patients and low adherence to the therapy in others. Therefore the subject of statin intolerance is of great clinical importance. Statin intolerance can be defined as an incidence of myalgia or other adverse symptoms associated with a statin therapy, which lead to its interruption. Nonetheless, even if such symptoms develop during the statin therapy, these adverse effects are frequently not associated with the treatment and most patients with an anamnesis suggesting episodes of such symptoms are able to tolerate an adequate statin therapy. It is therefore of great clinical importance to identify the actual cases of statin intolerance in order to avoid the unnecessary interruption of the statin therapy in the patients who would benefit from it. Regarding patients with a proven statin intolerance, statins should be administered according to an altered scheme and if tolerated, the dose should be gradually increased until the highest tolerated level is reached. When this careful approach is followed, most patients are able to tolerate some level of statin therapy at least. Besides that, there may be also other lipid-reducing drugs needed to reach the required goals. If the achievement of the lipid target values is difficult, a rigorous control of the risk factors may help in reducing the cardiovascular risk. PMID- 26652781 TI - [Early diagnosis of familial hypercholesterolemia in Czech Republic in pursuance of MedPed Project]. AB - Recent studies have revealed the prevalence of familial hypercholesterolemia (FH) is approximately twice higher than previously estimated and, thus, the disease affects one in 250 persons from the general population. Therefore FH remains the most frequent inherited metabolic disorder. Due to the genetic defect LDL cholesterol accumulates both in the plasma and tissues leading to premature and accelerated atherosclerosis. Untreated patients with FH might suffer from myocardial infarction in the third or fourth decade, one third of these events being fatal. The disease is under-diagnosed and undertreated worldwide. In the Czech Republic the MedPed project focused on early diagnosis and initiation of proper treatment of FH aiming at lowering of the above mentioned risks was initiated in 1998. A crucial part of the project is so called cascade screening among the relatives of identified FH probands. There are 6,350 registered FH subjects in the nationwide registry, which represents 16% of the expected number of FH patients in the Czech Republic. This result of screening efforts ranks among the top countries in the world, however, also in spite of the recent expansion of FH treatment options early detection and initiation of treatment of FH remains in the centre of our attention. PMID- 26652782 TI - [PCSK9 inhibition as the new hope for patients with familial hypercholesterolemia, statin intolerance and eventually for those at the highest cardiovascular risk? Focused on alirocumab, Praluent(r)]. AB - At the present time there are novel hypolipidemics registered globally (alirocumab was the first drug of this group in the world registered by an American drug agency FDA) and in Europe, which in many ways differ from the medicines administered until now. They are bringing another advancement in the treatment of disorders of lipid metabolism and in preventive cardiology. Alirocumab is a fully human monoclonal antibody to PCSK-9 enzyme (proprotein convertase subtilisin kexin-9). PCSK-9 enzyme plays an important role in the metabolism of LDL-cholesterol through affecting the breakdown and eventually the amount and activity of LDL-receptors. From the clinical point of view it is essential that drugs from this group are administered parenterally, as a subcutaneous injection. In the case of Praluent(r) the interval between administration is two weeks. The dose is then 75 or 150 mg in a 1 ml injection. From the clinical point of view it is particularly important that alirocumab decreases LDL-C concentrations by 50-60%, it decreases Lp/a/ levels by 25-30%, and it also positively influences other components of lipid metabolism and, above all, is very likely to have a potential to decrease a cardiovascular risk. Although the resuIts of morbidity and mortality studies are expected in the coming years, initial analyses strongly indicate a clinically significant reduction of CV events. Alirocumab, Praluent can be administered as monotherapy (mainly to statin-intolerant patients), however it will be primarily administered in combination with the other hypolipidemic drugs (in particular statins) where the effort to reach target values has not succeeded. PMID- 26652783 TI - [Evolocumab and PROFICIO Project: Initial Results]. AB - The PROFICIO project includes 20 clinical studies evaluating the effect of evolocumab on the incidence of cardio-vascular disease including its safety profile and tolerance. Most of the included studies follow the average proportional decrease of LDL-cholesterol concentrations over 10 and 12 weeks of administering evolocumab as compared to the input values. The first results were announced at the congress of the European Society of Cardiology (ESC) in London at the end of August and beginning of September 2015. This subanalysis comprised 3146 patients, who underwent one of the selected studies of phase 3 clinical testing and who were administered a dose of 140 mg s.c. evolocumab once in 2 weeks, or 420 mg s.c. once in 4 weeks. LDL-cholesterol levels decreased after evolocumab by 56.5-74.9% in the individual studies as compared to placebo and by 36.9-44.9% compared to ezetimib. The incidence of adverse effects did not differ from the group which used placebo. PMID- 26652784 TI - [Position of lipoprotein apheresis in present]. AB - Lipoprotein apheresis (LA) is an effective treatment method the patients with severe hypercholesterolemia, resistant to the standard therapy. LA is an extracorporeal elimination technique, which specifically removes low density lipoprotein (LDL) cholesterol from the circulation. At present, lipoprotein apheresis, combined with high-dose statin and ezetimibe therapy, is the best available means of treating patients with homozygous and statin refractory heterozygous familial hypercholesterolaemia (FH). However, the extent of cholesterol-lowering achieved is often insufficient to meet the targets set by current guidelines. The recent advent of new classes of lipid-lowering agents provides new hope that the latter objective may now be achievable. These compounds act either by reducing low density lipoprotein (LDL) cholesterol production by inhibiting apolipoprotein B synthesis with an antisense oligonucleotide (mipomersen), or by inhibiting microsomal triglyceride transfer protein (lomitapid), or by enhancing LDL catabolism via monoclonal antibody mediated inhibition of the activity of proprotein convertase subtilisin/kexin 9 (PCSK9-alirocumab, evolocumab etc). The promising is the combination of LDL apheresis with new drugs, namely for its potential to further decrease of LDL cholesterol between apheresis. Depending on the outcome of current trials, it seems likely that these compounds, used alone or combined with lipoprotein apheresis, will markedly improve the management of refractory FH. PMID- 26652785 TI - [The effect of a simvastatin and ezetimib combination on blood lipids and cardiovascular events in diabetic patients (comments on the subanalysis results within the IMPROVE-IT study)]. AB - IMPROVE-IT study demonstrated that the addition 10 mg of ezetimibe to 40 mg of simvastatin in patients after acute coronary syndrome reduces significantly not only their LDL-cholesterol, but also the number of cardiovascular events. Recently published subanalysis of this study was focused on whether these combinations of drugs is more preferable for patients with diabetes mellitus or for patients without diabetes. The addition of ezetimibe to a simvastatin resulted in a greater decline of LDL-cholesterol level in diabetic group than in patients without diabetes. In patients with diabetes mellitus their cardiovascular morbidity and mortality were decreased significantly; reduction of these clinical end-points in the group of patients without diabetes were not statistically significant. PMID- 26652786 TI - [What is the contribution of the review of the evidence on reducing macrovascular risk in patients with atherogenic dyslipidemia? Report on consensus of experts in the importance of the combined therapy by fenofibrate with statin]. AB - A meeting of European experts in cardiovascular (CV) disease and lipids was convened in Paris, November 2014, where an important problem of preventive cardiology--residual vascular risk done by atherogenic dyslipidemia (AD)--was discussed. On the basis of discussion have the experts summarised a consensus concerning AD, its CV risk and up to date evidence of combined therapy with statin and fenofibrate on CV risk. Atherogenic dyslipidemia should be the secondary aim of dyslipidemia treatment, because it is a reason of residual vascular risk. Non-HDL-cholesterol should be the secondary target of AD treatment, which is a most unexpensive and easiest marker of residual vascular risk. Combined therapy with statin and fenofibrate is safe, well tolerated and reduces plasma atherogenity and CV events in patients with AD and high CV risk, type 2 diabetes or metabolic syndrome. PMID- 26652787 TI - [The TECOS, EXAMINE and SAVOR studies--how do they differ and what are their outcomes?]. AB - The treatment of diabetes mellitus type 2 is effective, but still is not optimal. DPP4 inhibitors (gliptins) are a new group of peroral antidiabetic drugs. The third clinical mortality study with gliptins in patients with diabetes mellitus type 2 was finished in 2015. The studies are known under acronym TECOS, SAVOR and EXAMINE and the tested drugs are sitagliptin, saxagliptin and alogliptin. The studies included about 37,000 patients. The studies confirmed the cardiovascular safety of the DPP4 inhibitors, but the question about increased heart failure remains open. The effectiveness of lowering glycaemia (glycated haemoglobin) was confirmed and also the pancreatic safety is confirmed. PMID- 26652788 TI - [Clinical importance of basal insulin analogues and insulin Toujeo(r) 300 units/ml]. AB - Type 2 diabetes mellitus is a heterogeneous disease that requires a personalized approach to treatment with goals tailored to capabilities and abilities of the patient, his other diseases so as to ensure good diabetes control without the risk of hypoglycemic events and the development or progression of late diabetic complications. Recommendations for treatment of diabetes is classified in second line as a one of the possibilities of treatment of basal insulin immediately after the failure of therapy with metformin and diet. The new generation of basal insulin analogues provides its effect profile and features a completely new quality to the treatment of diabetes. Toujeo(r) 300 units/ml is a new long-acting basal insulin glargine concentration of 300 units/ ml with a low glycemic variability, which in studies has demonstrated consistent control of diabetes in a significant reduction in the risk of hypoglycemia especially at night compared with insulin glargin of concentration 100 units/ml. PMID- 26652789 TI - Development of a Quantitative SRM-Based Proteomics Method to Study Iron Metabolism of Synechocystis sp. PCC 6803. AB - The cyanobacterium Synechocystis sp. PCC 6803 (S. 6803) is a well-established model species in oxygenic photosynthesis research and a potential host for biotechnological applications. Despite recent advances in genome sequencing and microarray techniques applied in systems biology, quantitative proteomics approaches with corresponding accuracy and depth are scarce for S. 6803. In this study, we developed a protocol to screen changes in the expression of 106 proteins representing central metabolic pathways in S. 6803 with a targeted mass spectrometry method, selected reaction monitoring (SRM). We evaluated the response to the exposure of both short- and long-term iron deprivation. The experimental setup enabled the relative quantification of 96 proteins, with 87 and 92 proteins showing adjusted p-values <0.01 under short- and long-term iron deficiency, respectively. The high sensitivity of the SRM method for S. 6803 was demonstrated by providing quantitative data for altogether 64 proteins that previously could not be detected with the classical data-dependent MS approach under similar conditions. This highlights the effectiveness of SRM for quantification and extends the analytical capability to low-abundance proteins in unfractionated samples of S. 6803. The SRM assays and other generated information are now publicly available via PASSEL and Panorama. PMID- 26652790 TI - A non-pharmacologic approach to decrease restraint use. AB - AIMS: To evaluate an education intervention to decrease restraint use in patients in a Trauma Intensive Care Unit (TICU) and to evaluate nurses' perceptions regarding restraints. OBJECTIVES: To measure restraint use pre/post-intervention and to measure nurses' perceptions of restraint use. METHODS: Pre/post intervention design to collate incidences of delirium and restraints pre/post intervention. Data reporting nurses' views and preferences were collected pre intervention. MEASURES: Patients were assessed by nursing on admission and every shift with the Confusion Assessment Method for TICU. Restraint use was measured in a 24-hour period. Nurses' perception of restraints was measured using Perceptions of Restraint Use Questionnaire (PRUQ). RESULTS: A statistically significant difference was demonstrated in restraint use before and after the educational intervention. Mean and standard deviation for restraints per 1000 patient days pre-intervention was 314.1 (35.4), post-intervention 237.8 (56.4) (p=0.008). Mean PRUQ overall, 3.57 (range 1-5) indicated that nurses had positive attitudes towards restraints in certain circumstances. The primary reasons for using restraints were: "protecting patients from falling out of bed", 37 (72.5%), and "protecting patients from falling out of chair", 34 (66.7%). CONCLUSION: This study demonstrates that a low risk educational intervention aimed at use of an alternative device use can reduce restraint use. PMID- 26652791 TI - Optical Head-Mounted Computer Display for Education, Research, and Documentation in Hand Surgery. AB - Intraoperative photography and capturing videos is important for the hand surgeon. Recently, optical head-mounted computer display has been introduced as a means of capturing photographs and videos. In this article, we discuss this new technology and review its potential use in hand surgery. PMID- 26652792 TI - Biological Augmentation of Flexor Tendon Repair: A Challenging Cellular Landscape. AB - Advances in surgical technique and rehabilitation have transformed zone II flexor tendon injuries from an inoperable no-man's land to a standard surgical procedure. Despite these advances, many patients develop substantial range of motion-limiting adhesions after primary flexor tendon repair. These suboptimal outcomes may benefit from biologic augmentation or intervention during the flexor tendon healing process. However, there is no consensus biological approach to promote satisfactory flexor tendon healing; we propose that insufficient understanding of the complex cellular milieu in the healing tendon has hindered the development of successful therapies. This article reviews recent advances in our understanding of the cellular components of flexor tendon healing and adhesion formation, including resident tendon cells, synovial sheath, macrophages, and bone marrow-derived cells. In addition, it examines molecular approaches that have been used in translational animal models to improve flexor tendon healing and gliding function, with a specific focus on progress made using murine models of healing. This information highlights the importance of understanding and potentially exploiting the heterogeneity of the cellular environment during flexor tendon healing, to define rational therapeutic approaches to improve healing outcomes. PMID- 26652793 TI - Quantitative Reactivity Scales for Dynamic Covalent and Systems Chemistry. AB - Dynamic covalent chemistry (DCC) has become a powerful tool for the creation of molecular assemblies and complex systems in chemistry and materials science. Herein we developed for the first time quantitative reactivity scales capable of correlation and prediction of the equilibrium of dynamic covalent reactions (DCRs). The reference reactions are based upon universal DCRs between imines, one of the most utilized structural motifs in DCC, and a series of O-, N-, and S- mononucleophiles. Aromatic imines derived from pyridine-2-carboxyaldehyde exhibit capability for controlling the equilibrium through distinct substituent effects. Electron-donating groups (EDGs) stabilize the imine through quinoidal resonance, while electron-withdrawing groups (EWGs) stabilize the adduct by enhancing intramolecular hydrogen bonding, resulting in curvature in Hammett analysis. Notably, unique nonlinearity induced by both EDGs and EWGs emerged in Hammett plot when cyclic secondary amines were used. This is the first time such a behavior is observed in a thermodynamically controlled system, to the best of our knowledge. Unified quantitative reactivity scales were proposed for DCC and defined by the correlation log K = S(N) (R(N) + R(E)). Nucleophilicity parameters (R(N) and S(N)) and electrophilicity parameters (R(E)) were then developed from DCRs discovered. Furthermore, the predictive power of those parameters was verified by successful correlation of other DCRs, validating our reactivity scales as a general and useful tool for the evaluation and modeling of DCRs. The reactivity parameters proposed here should be complementary to well-established kinetics based parameters and find applications in many aspects, such as DCR discovery, bioconjugation, and catalysis. PMID- 26652794 TI - MRMPlus: an open source quality control and assessment tool for SRM/MRM assay development. AB - BACKGROUND: Selected and multiple reaction monitoring involves monitoring a multiplexed assay of proteotypic peptides and associated transitions in mass spectrometry runs. To describe peptide and associated transitions as stable, quantifiable, and reproducible representatives of proteins of interest, experimental and analytical validation is required. However, inadequate and disparate analytical tools and validation methods predispose assay performance measures to errors and inconsistencies. RESULTS: Implemented as a freely available, open-source tool in the platform independent Java programing language, MRMPlus computes analytical measures as recommended recently by the Clinical Proteomics Tumor Analysis Consortium Assay Development Working Group for "Tier 2" assays - that is, non-clinical assays sufficient enough to measure changes due to both biological and experimental perturbations. Computed measures include; limit of detection, lower limit of quantification, linearity, carry-over, partial validation of specificity, and upper limit of quantification. CONCLUSIONS: MRMPlus streamlines assay development analytical workflow and therefore minimizes error predisposition. MRMPlus may also be used for performance estimation for targeted assays not described by the Assay Development Working Group. MRMPlus' source codes and compiled binaries can be freely downloaded from https://bitbucket.org/paiyetan/mrmplusgui and https://bitbucket.org/paiyetan/mrmplusgui/downloads respectively. PMID- 26652795 TI - Nonsecular Medical Anthropology. AB - A nonsecular medical anthropology insists on the ways medicine and science have constituted 'the secular' itself through the 'secular self'-how medical knowing has been used to craft the secular political subject. As James Boon noted, too often in social theory, "religion gets safely tucked away-restricted theoretically to 'meaning' rather than power" (1998:245). The authors of the six articles in this special issue 'untuck' religiosity from within the norms and numbers of medicine itself, and examine how 'secular' medicine has relied on religious traditions to produce political secularity. These articles demonstrate that 'secular' medicine relies on religious others whose exclusion bespeaks latent religious commitments of citizenship in the modern political realm of health. PMID- 26652796 TI - HPV vaccines: so much learnt, so many more lessons to come. PMID- 26652798 TI - Breakdown of Shape Memory Effect in Bent Cu-Al-Ni Nanopillars: When Twin Boundaries Become Stacking Faults. AB - Bent Cu-Al-Ni nanopillars (diameters 90-750 nm) show a shape memory effect, SME, for diameters D > 300 nm. The SME and the associated twinning are located in a small deformed section of the nanopillar. Thick nanopillars (D > 300 nm) transform to austenite under heating, including the deformed region. Thin nanopillars (D < 130 nm) do not twin but generate highly disordered sequences of stacking faults in the deformed region. No SME occurs and heating converts only the undeformed regions into austenite. The defect-rich, deformed region remains in the martensite phase even after prolonged heating in the stability field of austenite. A complex mixture of twins and stacking faults was found for diameters 130 nm < D < 300 nm. The size effect of the SME in Cu-Al-Ni nanopillars consists of an approximately linear reduction of the SME between 300 and 130 nm when the SME completely vanishes for smaller diameters. PMID- 26652799 TI - Allergen extracts for immunotherapy: to mix or not to mix? AB - Allergen immunotherapy (AIT) is established as a curative treatment for allergic rhinitis, asthma, as well as insect venom allergy. AIT is based on the administration of natural allergen extracts via the subcutaneous or sublingual routes to reorient the immune system towards tolerogenic mechanisms. In this regard, since many patients are poly-allergic, mixtures of allergen extracts are often used with a potential risk to cause allergen degradation, thereby affecting treatment efficacy. Herein, we discuss the advantages and drawbacks of mixing homologous (i.e., related) or heterogeneous (i.e., unrelated) allergen extracts. We provide evidence for incompatibilities between mixes of grass pollen and house dust mite extracts containing bodies and feces, and summarize critical points to consider when mixing allergen extracts for AIT. PMID- 26652800 TI - The Code of Ethics for Nurses-More Relevant Than Ever. PMID- 26652797 TI - Immunogenicity and HPV infection after one, two, and three doses of quadrivalent HPV vaccine in girls in India: a multicentre prospective cohort study. AB - BACKGROUND: An increase in worldwide HPV vaccination could be facilitated if fewer than three doses of vaccine are as effective as three doses. We originally aimed to compare the immunogenicity and frequency of persistent infection and cervical precancerous lesions caused by vaccine-targeted HPV after vaccination with two doses of quadrivalent vaccine on days 1 and 180 or later, with three doses on days 1, 60, and 180 or later, in a cluster-randomised trial. Suspension of the recruitment and vaccination due to events unrelated to our study meant that some enrolled girls could not be vaccinated and some vaccinated girls received fewer than the planned number of vaccinations by default. As a result, we re-analysed our data as an observational cohort study. METHODS: Our study was designed to be done in nine locations (188 clusters) in India. Participants were unmarried girls aged 10-18 years vaccinated in four cohorts: girls who received three doses of vaccine on days 1, 60, and 180 or later, two doses on days 1 and 180 or later, two doses on days 1 and 60 by default, and one dose by default. The primary outcomes were immunogenicity in terms of L1 genotype-specific binding antibody titres, neutralising antibody titres, and antibody avidity after vaccination for the vaccine-targeted HPV types 16, 18, 6, and 11 and incident and persistent infections with these HPVs. Analysis was per actual number of vaccine doses received. This study is registered with ISRCTN, number ISRCTN98283094; and with ClinicalTrials.gov, number NCT00923702. FINDINGS: Vaccination of eligible girls was initiated on Sept 1, 2009, and continued until April 8, 2010. Of 21 258 eligible girls identified at 188 clusters, 17 729 girls were recruited from 178 clusters before suspension. 4348 (25%) girls received three doses, 4979 (28%) received two doses on days 1 and 180 or later, 3452 (19%) received two doses at days 1 and 60, and 4950 (28%) received one dose. Immune response in the two-dose HPV vaccine group was non-inferior to the three-dose group (median fluorescence intensity ratio for HPV 16 1.12 [95% CI 1.02-1.23] and for HPV 18 1.04 [0.92 1.19]) at 7 months, but was inferior in the two-dose default (0.33 [0.29-0.38] for HPV 16 and 0.51 [0.43-0.59] for HPV 18) and one-dose default (0.09 [0.08 0.11] for HPV 16 and 0.12 [0.10-0.14] for HPV 18) groups at 18 months. The geometric mean avidity indices after fewer than three doses by design or default were non-inferior to those after three doses of vaccine. Fewer than three doses by design and default induced detectable concentrations of neutralising antibodies to all four vaccine-targeted HPV types, but at much lower concentration after one dose. Cervical samples from 2649 participants were tested and the frequency of incident HPV 16, 18, 6, and 11 infections was similar irrespective of the number of vaccine doses received. The testing of at least two samples from 838 participants showed that there was no persistent HPV 16 or 18 infections in any study group at a median follow-up of 4.7 years (IQR 4.2-5.1). INTERPRETATION: Despite the limitations imposed by the suspension of the HPV vaccination, our findings lend support to the WHO recommendation of two doses, at least 6 months apart, for routine vaccination of young girls. The short-term protection afforded by one dose of HPV vaccine against persistent infection with HPV 16, 18, 6, and 11 is similar to that afforded by two or three doses of vaccine and merits further assessment. FUNDING: Bill & Melinda Gates Foundation. PMID- 26652801 TI - Health Literacy Education in Health Professions Schools: An Integrative Review. AB - BACKGROUND: Most Americans lack the health literacy skills to function in today's health care environment. The Institute of Medicine's Health Literacy: A Prescription to End Confusion report recommended that health professionals be trained to effectively communicate with patients with low health literacy. METHOD: An integrative review was conducted, using six electronic databases: CINAHL, ERIC, MEDLINE, PsycINFO, SocINDEX, and Web of Science. RESULTS: Nine articles met the inclusion criteria. Educational interventions include multimodal approaches using didactic content, followed by active learning strategies. Evaluative methods in the classroom were used in all studies; however, only one study assessed students' health literacy skills. CONCLUSION: Findings support research efforts that (a) clarify where health literacy should be taught, (b) target the assessment of students' health literacy skills, (c) perform rigorous psychometric testing of evaluative instruments used, and (d) create interprofessional learning opportunities. PMID- 26652802 TI - Shared Curriculum Model: A Promising Practice for Education Transformation. AB - BACKGROUND: The shared curriculum model is one of four successful models of academic progression identified through a consensus-building process facilitated by The Future of Nursing: Campaign for Action, with support from the Robert Wood Johnson Foundation, AARP, and the AARP Foundation. METHOD: Seamless academic progression from the associate degree in nursing (ADN) to the baccalaureate degree in nursing (BSN) is achieved either by simultaneously revising both ADN and BSN curricula or by making targeted adjustments in ADN or BSN curricula to create a unified academic progression. Systematic vetting and definitive agreement on nursing prerequisites and corequisites, general education courses, nursing major content, and general degree requirements are necessary to ensure coordinated degree progression. A standardized set of expectations for beginning professional practice and for unique baccalaureate nursing knowledge ensures vital nursing content across the ADN-to-BSN continuum. RESULTS: Examples of state and regional ADN-to-BSN progression programs using the shared curriculum model are highlighted. CONCLUSION: The shared curriculum model is a promising practical and sustainable approach to seamless ADN-to-BSN academic progression. PMID- 26652803 TI - Advancing Associate Degree in Nursing-to-Baccalaureate Degree in Nursing Academic Progression: The California Collaborative Model for Nursing Education. AB - BACKGROUND: In 2004, nurse leaders in California recognized the imminent need to increase the number and educational preparation of the state's nursing workforce. The California Collaborative Model for Nursing Education (CCMNE), a key strategy to meet this goal, was introduced in 2008. METHOD: The CCMNE set a new statewide standard for associate degree in nursing (ADN)-to-baccalaureate degree in nursing (BSN) progression by defining seamless academic progression parameters. The CCMNE's five core components are dual enrollment, integrated curriculum, shared faculty, BSN within 1 year of ADN conferral, and permanence and sustainability. Flexibility in operationalizing the core components accelerated the development of effective approaches systematically shared across the state to support CCMNE development and implementation. RESULTS: Nearly 7% of the current California ADN student population is dually enrolled in a BSN program through 19 university based CCMNE partnerships with 59 community colleges. CONCLUSION: The CCMNE provides ADN students early access to BSN education, which is promising for increasing the percentage of baccalaureate-educated nurses in the workforce. PMID- 26652804 TI - Group Empowerment in Nursing Education. AB - BACKGROUND: Nursing education is experiencing rapid changes, as nurses are expected to transform and lead health care delivery within the United States. The ability to produce exceptional graduates requires faculty who are empowered to achieve goals. METHOD: The Sieloff-King Assessment of Group Empowerment Within Organizations (SKAGEO) was adapted and administered online to a stratified sample of administrators and faculty in American Association of Colleges of Nursing member schools. RESULTS: Participants' scores were within high ranges in both empowerment capacity and capability; however, administrator group scores were higher. Data analyses indicated that administrator leadership competencies were associated with group empowerment. CONCLUSION: This study suggests that empowered faculty and administrator groups anticipate changing health care trends and effect student outcomes and competencies by their interventions. Also, it can be inferred that as a result of administrators' competencies, participants teach in empowered work environments where they can model ideal behaviors. PMID- 26652805 TI - Evaluation of Patients' Satisfaction With Nursing Students' Care on a Perinatology Ward. AB - BACKGROUND: The aim of this study was to evaluate patient satisfaction with the care provided by nursing students on a perinatology ward. METHOD: The sample for this descriptive study included 210 patients. Data were collected using an interview form and the Turkish version of the Oncology Patients' Perceptions of the Quality of Nursing Care Scale-Short Form. RESULTS: According to the mean scores for all subscales in the instrument, patients were highly satisfied with the care they received from the nursing students. Multivariate analysis revealed that the reason for hospitalization was found to be the most statistically significant factor affecting patient perceptions of quality of care. CONCLUSION: A high level of satisfaction with the care provided by nursing students indicates that the students were able to meet the patients' needs, which may serve as an indicator of the quality of nursing education and quality of care provided by future nurses. PMID- 26652806 TI - Culture and Climate: Factors That Influence the Academic Success of African American Students in Prelicensure Nursing Education. AB - BACKGROUND: Despite numerous calls to diversify the nursing workforce, little progress has been made in increasing the numbers of African American graduates from prelicensure nursing programs, thus widening the diversity gap in the number of African Americans who enter the RN workforce. METHOD: An integrative literature review was conducted to determine whether, from the students' perspective, the institutional climate and culture influenced their academic success. RESULTS: Themes of Alienation and Isolation, Persistent Determination, and Difficulty Seeking Help emerged as having an influence on students' academic success. CONCLUSION: On the basis of this review, professional development programs on topics such as implicit bias, microaggressions, and other unintentional and unconscious behaviors are recommended. PMID- 26652807 TI - Professional Presentation Skills Development in a Graduate Nursing Program. AB - BACKGROUND: Expert communication skills are essential for nurse leaders to effectively influence health care. Because effective communication is a learned process, the curriculum should promote the development of presentation skills. An educational strategy was designed to promote the development of effective presentation skills for learners in the Nursing Leadership and Administration (NLA) track of the master's in nursing curriculum. METHOD: Sixteen learners in the NLA cohort were participants in a three-session presentation skills workshop. Following a baseline presentation, participants were taught presentation strategies and skills. Expert evaluators and learner self-assessments rated their presentation skills. RESULTS: Analysis of evaluators' ratings showed statistically significant (p < .001) increases in learners' presentation effectiveness. Analysis of learner self-ratings showed a statistically significant (p = .008) increase in perceived effectiveness of overall presentation skills. CONCLUSION: This unique educational intervention improved nurse leaders' presentation skills. Faculty found that the professional presentation skill workshop was important to learners' success. PMID- 26652808 TI - Engagement and Creation of Professional Identity in Undergraduate Nursing Students: A Convention-Style Orientation Event. AB - BACKGROUND: In an innovative event that challenged traditional orientation programs, the Curtin University School of Nursing and Midwifery brought together nursing students, academic and student support staff, and health industry representatives. This unique whole-of-school convention consisted of sessions tailored to each student year group and aimed to promote nursing identity, highlight leadership opportunities, and showcase employer pathways. METHOD: To evaluate the event, a survey approach was used to collect quantitative data via questionnaire and qualitative data via open-ended questions from first-year students (n = 113), staff (n = 24), and industry representatives (n = 14). RESULTS: Students, staff, and industry evaluations indicated a successful event that achieved its goals, including student engagement and motivation and community building. CONCLUSION: This orientation model could be used as a basis for institution-wide engagement activities. PMID- 26652809 TI - Sharing a Piece of the PIIE: Program of International Interprofessional Education/Programa Internacional Interprofesional Educativo. AB - BACKGROUND: Interprofessional education and global health are priorities in health professions education. Health organizations such as the Institute of Medicine and the World Health Organization recommend that education of health care providers be interdisciplinary and use technology. METHOD: A webinar took place between adult gerontology nurse practitioner (AGNP) students in the United States and the providers of a clinic in the Dominican Republic. The providers from the Dominican Republic presented a case typical of their practices but one with which AGNP students were not familiar. Similarly, the AGNP students presented a case representing new information for the Dominican providers. RESULTS: All participants responded positively to the webinar, primarily because of the technological and case-based approach to learning; they benefitted from disease review and interprofessional collaboration. CONCLUSION: A webinar format across clinical settings and countries is a novel interprofessional way to disseminate information in a mutually beneficial way. PMID- 26652810 TI - Clinical Policy Evaluation Activity: Reinforcing Evidence-Based Practice. PMID- 26652811 TI - Effect of two different feeding methods on preventing ventilator associated pneumonia in the paediatric intensive care unit (PICU): A randomised controlled study. AB - BACKGROUND: For infants and children who require intubation in the paediatric intensive care unit (PICU), ventilator-associated pneumonia (VAP) is a significant cause of secondary morbidity and mortality linked with extended use of intubation. Nurses are primarily responsible for the prevention of VAP and there are a number of procedures that contribute towards this end. Although enteral nutrition has been reported to be effective in the prevention of VAP, this remains controversial. OBJECTIVE: To compare and evaluate the effects of intermittent feeding through a nasogastric catheter with those of continuous feeding through a nasoduodenal catheter in preventing VAP in the PICU. DESIGN: The research design was a randomised, controlled experimental study. METHODS: Forty paediatric patients were randomised and divided into two groups of 20: one group for nasoduodenal (ND) feeding and the other for nasogastric (NG) feeding. Patients were assessed for the development of VAP using the clinical pulmonary infection score and Centers for Disease Control and Prevention criteria while working in accordance with the VAP prevention bundles introduced within the unit. RESULTS: The incidence of paediatric VAP was 15%. The rate of VAP in patients who were ND fed was 10%, whereas the rate of VAP in patients who had NG feeding was 20%. No statistically significant difference was observed between the ND- and NG fed patients (p=0.661). CONCLUSION: Although the results of our study were not statistically significant, nasoduodenal feeding helped to reduce the incidence of VAP. PMID- 26652812 TI - [Progress of pulmonary vascular disease 2014]. PMID- 26652813 TI - [Management of genetic testing in patients with sudden cardiac death risk]. PMID- 26652814 TI - [Efficacy of inhaled iloprost on top of other targeted therapies for patients with pulmonary hypertension and severe right heart failure]. AB - OBJECTIVE: To investigate the efficacy and safety of inhaled iloprost on top of other pulmonary hypertension (PH) specific therapies for patients with PH and severe right heart failure. METHODS: We consecutively enrolled WHO functional class IV patients with PH and chronic thromboembolic pulmonary hypertension (CTEPH) in Shanghai Pulmonary Hospital from January 2011 to January 2013. Inhaled iloprost was administrated to all enrolled patients, oral endothelin antagonist receptors (ERAs) and/or type 5 phosphodiasterase inhibitors (PDE5-I) were also used as basis therapies. The in-hospital outcomes and the changes of right heart functional parameters were observed. RESULTS: Twenty-four patients with PH and 5 patients with CTEPH were enrolled. After a mean treatment duration of (23 +/- 13) days, 3 patients dead and significant improvement was observed in the remaining 26 patients. Compared with the baseline, heart rate decreased from (99 +/- 14) to (91 +/- 12) bpm (P = 0.001), plasma NT-proBNP level decreased from 5 823 (3 029 13 248) to 3 220 (1 678-6 720) ng/L (P < 0.001), tricuspid annular plane systolic excursion (TAPSE) increased from (1.3 +/- 0.4) to (1.4 +/- 0.3) cm (P = 0.018), right ventricular diameter decreased (left-to-right diameter from (57 +/- 11) to (53 +/- 10) mm, P = 0.040, and superoinferior diameter from (69 +/- 11) to (64 +/ 16) mm, P = 0.027), Tbil also decreased from (41 +/- 34) to (26 +/- 17) umol/L (P < 0.001). No severe side effects were observed. CONCLUSION: The strategy of inhaled iloprost on top of other PAH-specific target therapy medications is effective and safe for PH patients with severe right heart failure. PMID- 26652815 TI - [Comparison of the classification of pulmonary hypertension due to left heart disease according to transpulmonary pressure gradient or diastolic pressure difference methods]. AB - OBJECTIVE: To compare the features of patients with pulmonary hypertension due to left heart disease classified according to transpulmonary gradient (TGP) or diastolic pressure difference (DPD). METHODS: Thirty-three patients with pulmonary hypertension due to left heart disease diagnosed by right heart catheterization were enrolled. Patients were divided into two groups according to TPG: 17 patients with TPG <= 12 mmHg (1 mmHg = 0.133 kPa) and 16 patients with TPG > 12 mmHg; or divided into two groups according to DPD: 23 patients with DPD < 7 mmHg and 10 patients with DPD >= 7 mmHg. McNemar's method was used to test the agreement of the two classification methods. RESULTS: Below are the patients features according to the classification by TPG: central venous pressure ((9.0 +/ 2.5) vs. (12.7 +/- 5.4) mmHg), mean right atria pressure ((9.1 +/- 2.4) vs. (12.8 +/- 5.2) mmHg), right heart systolic pressure ((45.5 +/- 9.8) vs. (66.8 +/- 15.4) mmHg), right heart mean pressure ((22.6 +/- 5.2) vs. (33.1 +/- 7.5) mmHg), pulmonary systolic pressure ((44.2 +/- 10.3) vs. (64.8 +/- 14.2) mmHg), pulmonary diastolic pressure ((24.2 +/- 4.5) vs. (33.1 +/- 8.3) mmHg), pulmonary mean pressure ((32.3 +/- 5.7) vs. (45.8 +/- 8.6) mmHg), cardiac index ((2.6 +/- 1.0) vs. (1.9 +/- 0.9) L . min(-1) . m(-2)), right heart EF ((31.2 +/- 12.6)% vs. (22.6 +/- 7.1) %) and pulmonary vascular resistance ((2.3 +/- 0.8) vs. (6.3 +/- 2.6) Wood) were significantly different between the two groups (all P < 0.05). According to the classification of DPD, only right heart diastolic pressure ((7.4 +/- 3.7) vs. (11.5 +/- 5.7) mmHg), pulmonary diastolic pressure ((25.9 +/- 6.4) vs. (34.7 +/- 8.0) mmHg) and pulmonary vascular resistance ((3.3 +/- 2.0) vs. (6.2 +/- 3.4) Wood) were significantly different between the two groups (all P < 0.05). These was a weak agreement (kappa = 0.386 6, 95% CI: 0.092 2-0.681 0) between the two classification methods. CONCLUSION: TPG classification is superior to DPD classification for pulmonary hypertension patients due to left heart disease on identifying the hemodynamic differences. PMID- 26652816 TI - [Comparison of echocardiographic parameters in healthy Chinese children born and living at high altitude or at sea-level]. AB - OBJECTIVE: Chronic hypoxia at high altitude might result in cardiopulmonary adaptations including pulmonary arterial hypertension and cardiac remodeling. But little is known about the adaptive changes in healthy children born and living at high altitude. We compared the echocardiographic measurements between the healthy children living at 16 m (Shanghai, n = 220) and 3 700 m (Qinghai, total 257, Han children 117, Tibetan children 140). METHODS: Children's age ranged from 15 d to 14 years. Echocardiography measurements were performed, values of the left and right ventricular dimensions and wall thickness, systolic and diastolic function including cardiac output index (CI), as well as mean pulmonary arterial pressure (mPAP) were obtained. RESULTS: mPAP and right heart dimension, CI, right ventricular anterior wall thickness were significantly higher while ventricular systolic and diastolic function were significantly lower in 3 700 m group than in 16 m group (all P < 0.05). Left ventricular dimension was similar between the two groups. There were no differences on above measured parameters between the Han and Tibetan children from 3 700 m group (all P > 0.05). CONCLUSIONS: Children born and living at high altitude in China have significantly higher mPAP, dilated right heart and lower systolic and diastolic function of both ventricles and higher CI compared to children born and living at see-level. Above parameters were similar between the Han and the Tibetan childen born and living at high altitude. Present study provides reference values for the healthy children living at high altitude. PMID- 26652817 TI - [Efficacy comparison of 3 rivaroxaban regimen in patients with venous thromboembolism]. AB - OBJECTIVE: To compare the efficacy and safety of 3 rivaroxaban regimen in patients with venous thromboembolism (VTE). METHODS: This is a retrospective study. Thirty three inpatients with VTE received rivaroxaban were divided into 3 groups, in which 16 patients were treated with 15 mg rivaroxaban twice daily for 21 days then followed by 20 mg once per day till 3 months (group 1), 9 patients were treated with 20 mg rivaroxaban once daily for 3 months (group 2), 8 patients were treated with 10 mg rivaroxaban once daily for 3 months. The reduction rate of D-Dimer on the third therapy day, the duration of D-Dimer normalization and hospital stay as well as symptom remission, the imaging assessment results after three months treatment, rate of recurrent VTE, bleeding, liver and kidney function were compared among the 3 groups. RESULTS: The reduction rates of D Dimer on the third therapy day were significantly higher ((46.12 +/- 15.42) % vs. (26.59 +/- 8.11) % and (25.55 +/- 14.00) %, P = 0.02, P = 0.01), and the duration of D-Dimer normalization was significantly shorter ((17.9 +/- 7.7) days vs. (24.1 +/- 5.1) days and (26.3 +/- 6.2) d, P = 0.03, P < 0.01) in group 1 than in group 2 and 3. There was one recurrent deep-vein thrombosis in group 3, one non-major bleeding in group 1 and group 3. Major bleeding or liver and kidney dysfunction were not observed in these patients. CONCLUSIONS: Venous thromboembolism can be safely and effectively treated by rivaroxaban, and does of 15 mg twice daily for 21 days followed by 20 mg once daily for 3 months are superior to the other 2 tested therapy regimen in this patient cohort. PMID- 26652818 TI - [Association between ABO blood group and acute myocardial infarction]. AB - OBJECTIVE: To explore the association between the ABO blood group and the risk of myocardial infarction in Chinese people. METHODS: We retrospectively recruited 1 988 consecutive patients with acute myocardial infarction (AMI) and 1 856 non coronary artery disease (non-CAD) subjects who hospitalized in our hospital between January 2013 and December 2013. The clinical features and ABO blood group were analyzed. RESULTS: Blood group distribution was A (27.1%, 539/1 988), B (34.4%, 684/1 988), AB (10.8%, 215/1 988), O (27.7%, 551/1 988) in patients with AMI and A (26.7%, 496/1 856), B(32.2%, 598/1 856), AB(10.8%, 200/1 856), O (30.4%, 564/1 856) in non-CAD group. The single factor analysis showed that blood group O tended to be more common in the non-CAD group than in AMI group (P = 0.06). After adjustment for common cardiovascular risk factors such as age, gender, hypertension, diabetes, smoking and serum cholesterol level, the A, B, and AB blood groups were associated with increased risk of AMI compared with O blood group, and the difference was significant with A blood group (OR = 1.229, 95% CI 1.019-1.482, P = 0.031) and B blood groups (OR = 1.214, 95% CI 1.017 1.449, P = 0.032). In addition, non-O blood group remained significantly associated with the increased risk of AMI than O blood group after logistic regression analysis (OR = 1.223, 95% CI 1.048-1.426, P = 0.01). CONCLUSION: Our results suggest that non-O blood group is associated with the increased risk of AMI. PMID- 26652819 TI - [Association between ABO blood groups and coronary heart disease in Chinese Guangxi Zhuang population]. AB - OBJECTIVE: To investigate this association between ABO blood groups and coronary heart disease (CHD) in the Chinese Guangxi Zhuang population. METHODS: From August 2010 to April 2013, we performed a case-control study in a Chinese Zhuang population, which included 1 024 CHD cases and 1 024 age and gender-matched non CHD controls. The ABO blood groups and biological variables were measured by standard laboratory procedures. The Gensini score was used to evaluate the severity of coronary artery stenosis. RESULTS: Compared to non-CHD control group, CHD group had higher levels of fasting blood glucose ((6.71 +/- 6.72) mmol/L vs. (4.98 +/- 1.55) mmol/L, P < 0.001), LDL-C ((2.89 +/- 1.18) mmol/L vs. (2.60 +/- 1.05) mmol/L, P = 0.002) and CRP ((7.74 +/- 7.32) mg/L vs. (2.93 +/- 2.19)mg/L, P < 0.001) as well as higher proportion of history of hypertension (57.0% vs. 27.5%, P < 0.001), history of diabetes (29.6% vs. 9.6%, P < 0.001), family history of CHD (35.3% vs. 10.6%, P < 0.001) and smoking (51.0% vs. 38.2%, P < 0.001). Logistic analysis indicated that ABO blood groups were associated with CHD risk in the Chinese Zhuang population. Compared with group O, the group B individuals had a higher risk of CHD (OR = 2.33, 95% CI 1.88-2.90, P < 0.001), this result remained after adjustment for the conventional CHD risk factors (OR = 1.55, 95% CI 1.05-2.52, P = 0.047). In addition, there were significant differences of Gensini score between non-O subjects and group O subjects in the CHD group, and MACE at 1-year follow-up was similar between ABO blood groups of CHD individuals. CONCLUSION: ABO blood groups are associated with CHD risk in the Chinese Zhuang population. PMID- 26652820 TI - [The value of area strain imaging diastolic index for predicting left anterior descending severe stenosis]. AB - OBJECTIVE: To evaluate the value of locating and defining severe stenosis of left anterior descending (LAD) with area strain imaging diastolic indexes (ASI-DI) derived from three dimensional speckle tracking imaging (3D-STI). METHODS: A total of 92 suspected coronary heart disease patients with left ventricular ejection fraction (LVEF) >= 50% and without regional wall motion abnormality, who underwent echocardiography before coronary angiography in our department from July 2012 to April 2014, were included in this retrospective study. Patients were divided into three groups by the level of LAD stenosis: severe stenosis group (>= 75%, n = 36), mild to moderate stenosis group (1%-74%, n = 22) and control group (without coronary artery stenosis, n = 34). Global peak systolic area strain (GPSAS), global ASI-DI (GASI-DI), and ASI-DI of the regional myocardial segments with blood supplied by LAD were measured. Receiver operating curves (ROC) were obtained between ASI-DI and stenosis level of LAD to locate and to find out the optimal segment and cutoff values. RESULTS: There was no significant difference of GPSAS among serious stenosis group, mild and moderate stenosis group and control group ((-25.2 +/- 6.2) % vs. (-20.3 +/- 6.6) % vs. (-21.3 +/- 8.6) %, P = 0.159). GASI-DI was significantly lower in severe stenosis group than in mild to moderate stenosis group and control group ((-34.3 +/- 14.7) vs. (-48.1 +/- 13.3) % vs. (-59.4 +/- 12.2) %, both P < 0.01). GASI-DI was similar between mild to moderate stenosis group and control group (P = 0.217). The optimal cutoff values of ASI-DI were 40.3% and area under the curve (AUC) were 0.829 in the base anterior segment for detecting proximal severe stenosis of LAD (sensitivity 0.967, specificity 0.651), 38.3% and 0.843 in the middle anteroseptum for detecting mid-distal sever stenosis of LAD (sensitivity 0.967, specificity 0.651). CONCLUSIONS: Patients with severe LAD stenosis can be screened by ASI-DI among patients with LVEF >= 50% and without regional wall motion abnormality. The ASI-DI of base anterior segment and middle anteroseptum can be used to locate the proximal and mid-distal sever stenosis of LAD. PMID- 26652821 TI - [Clinical values of ST-segment changes in ST-segment elevated myocardial infarction patients within 24 hours post primary percutaneous coronary interventions]. AB - OBJECTIVE: To explore the clinical values of ST-segment changes in ST-segment elevated myocardial infarction (STEMI) patients within 24 hours after primary percutaneous coronary intervention (PCI). METHODS: A total of 225 patients with STEMI underwent primary PCI were enrolled, the ST segment resolution 1 hour after PCI was calculated and the patients were divided into group A (n = 135, Sgr;STE resolved >= 50%) and group B (n = 90, Sgr;STE resolved < 50%). The patients in group B were further divided into group C (n = 56, Sgr;STE resolved >= 50%) and group D (n = 34, Sgr;STE resolved < 50%) according to the ST segment resolution at 24 hours after PCI. TIMI flow after PCI, in-hospital major adverse cardiac events (MACE) and cardiac function about 7 days post PCI were analyzed. RESULTS: Data between group A and group B were similar except the incidence of pre-PCI Killip >= II was significantly higher in group B than in group A (37.8% (34/90) vs. 17.0% (23/135), P < 0.05). Incidence of complicated diabetes (P < 0.05), pre PCI Killip >= II (55.9% (19/34) vs. 26.8% (15/56), P < 0.05) and multivessel disease (70.6% (24/34) vs. 35.7% (20/56), P < 0.05) were significantly higher in group D than in group C. TIMI 3 and the opening time of IRA was similar between group A and group B and between group C and group D. The incidence of in-hospital MACE was significantly higher in group B than in group A (14.4% (13/90) vs. 3.0% (4/135), P < 0.05) which was similar between group C and group D. CONCLUSION: Early (1 hour) but not late (24 hours) ST resolution post PCI is related to a favorable clinical outcome in STEMI patients. PMID- 26652822 TI - [Change on burden of diseases from hypercholesterolemia among the Chinese population from 1990 to 2010]. AB - OBJECTIVE: To quantify the change on burden of disease from hypercholesterolemia in China from 1990 to 2010. METHODS: Related data were obtained from the Global Burden of Diseases, Injuries, and Risk Factors Study 2010 (GBD 2010). Population attributable risk was adopted to estimate the burden of disease from hypercholesterolemia. RESULTS: The death and burden of disease from hypercholesterolemia for Chinese residents increased from 98 000 and 2.237 million disability-adjusted of life years (DALY) in 1990 to 281 000 and 5.912 million DALY respectively. In 2010, 251 000 ischemic heart disease and 30 000 ischemic stroke deaths were caused by hypercholesterolemia, accounted for 3.4% (28.1/830.2) of the total deaths. In 2010, the DALY of ischemic heart disease and ischemic stroke attributed to hypercholesterolemia was 5.169 million and 0.743 million respectively. DALY was 3.356 million in male and 2.555 million in female. Years of life lost due to premature mortality (YLL) was 5.268 million, and years lived with disability (YLD) was 0.644 million. CONCLUSION: Hypercholesterolemia is a major risk factor for deaths and life loss in 2010, and the burden of disease and death from hypercholesterolemia increased obviously from 1990 to 2010 in China. PMID- 26652823 TI - [Predict value of time to peak of systolic velocity derived from velocity vector imaging on cardiac resynchronization therapy response in refractory heart failure patients]. AB - OBJECTIVE: To investigate the impact of cardiac resynchronization therapy (CRT) on left ventricular systolic function evaluated by velocity vector imaging (VVI) in refractory heart failure patients and the predictive value of VVI on CRT responses. METHODS: This study included 38 patients with medically refractory heart failure (HF) patients underwent CRT in our department from May 2007 to April 2011. Left ventricular long axis dyssynchrony indexes including time to peak of systolic velocity (Ts max-min), standard deviation of the time to peak of systolic velocity (Ts-SD) before and at 3-6 months post CRT. CRT response was defined as 15% decrease in left ventricular end-systolic volume. ROC curve and the area under the curve (AUC) were calculated. RESULTS: Twenty-four patients were defined as responder. No significant difference was observed between responders and non-responders in medical therapy. When using Ts max-min to predict response, the AUC of ROC curves was 0.76 +/- 0.07. The sensitivity and specifity was 70.8% and 77.8% respectively with Ts max-min >= 124.0 ms. When using Ts-SD to predict response, the AUC of ROC curves was 0.82 +/- 0.07. The sensitivity and specifity was 79.2% and 71.2% respectively with Ts-SD >= 40.5. CONCLUSION: Ts-SD is a useful index to predict CRT response in refractory HF patients. PMID- 26652824 TI - [Establishment and characterization of a minipig model of microvascular coronary artery spasm]. AB - OBJECTIVE: To observe the feasibility of establishing a porcine model of microvascular coronary artery spasm by intracoronary neuropeptide Y (NPY) infusion, and to analyze the characterization of this model. METHODS: Minipigs were divided into four groups (n = 4 each): normal saline (NS) group, 1 nmol NPY group, 3 nmol NPY group, and 6 nmol NPY group. Arterial sheaths were planted into bilateral femoral arteries of minipigs. A pigtail catheter was placed at the left sheath to determine the hemodynamic parameters. NS and different doses of NPY were injected into the left anterior descending branch through the right sheath. Intravenous myocardial contrast echocardiography (MCE) was applied to measure the microvessel volume (alpha), filling velocity (beta), and microcirculation blood flow (MBF) before and at 10 and 30 minutes after NS and NPY injection. RESULTS: Before and after injection, there were no difference in alpha, beta and MBF between NS and 1 nmol NPY group (all P > 0.05). In 3 nmol NPY group, alpha and MBF decreased at 10 min (P < 0.01 and 0.05, respectively), which were recovered at 30 min except alpha. Reductions of beta (P < 0.05) and MBF (P < 0.01) were observed at 10 min in 6 nmol NPY group, which were recovered at 30 min, but MBF still remained lower than at baseline (P < 0.01) and compared to 3 nmol NPY group (P < 0.05). CONCLUSION: Intracoronary injection of NPY into the anterior descending coronary artery can establish the porcine model of microvascular coronary artery spasm, which might serve as a useful animal model for coronary microvascular studies. PMID- 26652825 TI - [Impact of ideal health behaviors and factors on the newly developed carotid plaques]. AB - OBJECTIVE: To explore the impact of ideal health behaviors on the newly developed carotid plaques. METHODS: A total of 5 852 employees (including retired employees from Tangshan Kailuan company) aged over 40 years were included in this study through stratified random sampling. Subjects with previous stroke, transient ischemic attack, myocardial infarction were excluded. Results from the unified questionnaire, blood biochemistry measurements and ultrasonography carotid artery measurements were analyzed. Present study analyzed the data from 2 372 participants without carotid plaques in 2010-2011 examinations. The newly developed carotid plaques in 2012-2013 health examinations were observed and multiple logistic regression analysis was used to explore the impact of ideal health behaviors and factors on the newly developed carotid plaques. RESULTS: (1) There were 359 subjects with newly developed carotid artery plaques among the 2 372 subjects (15.1%), prevalence rate was 23.1% (43/186), 17.5% (186/1 065), 12.4% (122/986), 5.9% (8/135) in the groups with 0-1, 2-3, 4-5 and 6-7 components of ideal cardiovascular health behaviors and factors, respectively (P < 0.001). (2) Multiple logistic regression analysis showed that after adjusting for age, gender, high density lipoprotein cholesterol, heart rate, and high sensitive c reactive protein, compared to with 0-1 components of ideal cardiovascular health behaviors and factors, participants with 4-5 and 6-7 components of ideal cardiovascular health behaviors and factors were associated with reduced risk of the newly developed carotid plaques, the OR (95% CI) values were 0.52(0.34-0.80) and 0.28(0.12-0.64), respectively. CONCLUSION: Higher number of ideal cardiovascular health behaviors and factors is associated with lower incidence of newly developed carotid plaques. PMID- 26652826 TI - [Cut-off values of waist circumference for central obesity in Chinese adults]. AB - OBJECTIVE: To investigate the appropriate cut-off values of waist circumference(WC)for central obesity and severe central obesity in Chinese adults. METHODS: A total of 10 265 participants aged 35-69 years from the cross sectional survey of the PRC-USA Collaborative Study of Cardiovascular and Cardiopulmonary Epidemiology between 1993 and 1994 with integral data were included. Each integer unit in centimeters of WC in a given range was used as the cut-off point to detect clustering of risk factors, which was defined as an individual with 2 or more risk factors including hypertension, diabetes, hypercholesterolemia, hypertriglyceridemia and low levels of high-density lipoprotein cholesterol. Sensitivity, specificity and distance from the receiver operating characteristic (ROC) curves to the upper left corner of the ROC graph were calculated. The WC value corresponding to the point on the ROC curve nearest to the upper left corner was considered as the optimal cut-off value for central obesity and the value corresponding to the point with specificity of 90% or more was considered as the optimal cut-off for severe central obesity. RESULTS: The mean WC was (80.5 +/- 9.9) cm in men and (77.8 +/- 10.0) cm in women; 18.1% (890/4 921) of men and 14.5% (776/5 344) of women were identified with two or more major risk factors. Based on the ROC curve analysis, the optimal value of WC to detect clustering of risk factors was >= 84 cm for men and >= 80 cm for women, and the shortest distance to the upper left corner was 0.430 and 0.450, respectively. The cut-off values of WC to detect clustering of risk factors with specificity of 90% or more were >= 93 cm and >= 91 cm for men and women, respectively. CONCLUSION: The cut-off points of WC for central obesity and severe central obesity in Chinese adults obtained from this study are equal or similar to the WC cut-off values proposed by the Guidelines for Prevention and Control of Overweight and Obesity in Chinese Adults. PMID- 26652827 TI - [Emergent percutaneous coronary intervention in a patient with acute myocardial infarction at 9 years after heart transplantation]. PMID- 26652828 TI - [Acute pulmonary edema as first clinical presentation in a patient with hypertrophic cardiomyopathy]. PMID- 26652829 TI - [Research progress on the impacts and mechanisms of exercise intervention on blood pressure in hypertensive patients]. PMID- 26652830 TI - [Research progress and clinical prospect of microRNAs in heart failure]. PMID- 26652831 TI - [Progress on the role of microRNAs on vascular smooth muscle cells proliferation and the involvement of microRNAs on the pathogenesis of cardiovascular diseases]. PMID- 26652832 TI - Pharmacokinetics and pharmacodynamics in antibiotic dose optimization. AB - INTRODUCTION: Identifying the optimized dosing regimen and algorithm is critical in the development of antibiotics. Suboptimal regimens and inappropriate choice of drug give rise to drug-resistant bacteria which have limited the therapeutic utility of many commercially available antimicrobial agents. Strategies to optimize therapy of antimicrobial candidates to speed up the development process are urgently needed. AREAS COVERED: We examined pharmacokinetics and pharmacodynamics of antimicrobial agents with modeling and simulation approaches. The approach that is based on minimum inhibitory concentration to evaluate antimicrobial dosing strategy is widely utilized in drug development. The modeling approach utilizing information from time-kill kinetic studies is a tool that can provide more information on the time-course of bacterial response to a particular dosing regimen. Animal studies of dosing regimens that mimic human pharmacokinetics are another option to evaluate antimicrobial efficacy. Empirical, semi-mechanistic and mechanistic models of bacterial dynamics and development of drug resistance in response to drug therapy are discussed. EXPERT OPINION: Both theories and applications of these approaches provide an overall understanding of how the tools can streamline drug development process and help make crucial decisions. Many opportunities and potentials are presented to incorporate more rigorous integration of PK-PD modeling approaches even at preclinical stage to extrapolate to clinical settings, thus enabling successful trials and optimizing dosing strategies in relevant populations where the drug is mostly used. PMID- 26652833 TI - Contribution of individual components of a job cycle on overall severity of whole body vibration exposure: a study in Indian mines. AB - Drivers of earth-moving machines are exposed to whole-body vibration (WBV). In mining operations there can be a combination of relatively high magnitudes of vibration and long exposure times. Effective risk mitigation requires understanding of the main aspects of a task that pose a hazard to health. There are very few published studies of WBV exposure from India. This paper reports on a study that considered the contribution of the component phases of dumper operations, on the overall vibration exposure of the drivers. It shows that vibration magnitudes are relatively high, and that haulage tasks are the main contributor to the exposure. It is recommended that driver speed, haul road surfaces and vehicle maintenance/selection are optimized to ensure minimization of vibration. If this is not sufficient, operation times might need to be reduced in order to ensure that the health guidance caution zone from Standard No. ISO 2631-1:1997 is not exceeded. PMID- 26652834 TI - The role of an ARM procedure in the prevention of breast cancer related lymphedema. PMID- 26652835 TI - Graphene-Assisted Label-Free Homogeneous Electrochemical Biosensing Strategy based on Aptamer-Switched Bidirectional DNA Polymerization. AB - In this contribution, taking the discrimination ability of graphene over single stranded (ss) DNA/double-stranded (ds) DNA in combination with the electrochemical impedance transducer, we developed a novel label-free homogeneous electrochemical biosensor using graphene-modified glassy carbon electrode (GCE) as the sensing platform. To convert the specific aptamer-target recognition into ultrasensitive electrochemical signal output, a novel aptamer-switched bidirectional DNA polymerization (BDP) strategy, capable of both target recycling and exponential signal amplification, was compatibly developed in this study. In this strategy, all the designed DNA structures could be adsorbed on the graphene/GCE and, thus, serve as the electrochemical impedance signal reporter, while the target acts as a trigger of this BDP reaction, in which these designed DNA structures are bound together and, then, converted to long dsDNA duplex. The distinct difference in electrochemical impedance spectroscopy between the designed structures and generated long dsDNA duplex on the graphene/GCE allows label-free and homogeneous detection of target down to femto-gram level. The target can be displaced from aptamer through the polymerization to initiate the next recognition-polymerization cycle. Herein, the design and signaling principle of aptamer-switched BDP amplification system were elucidated, and the working conditions were optimized. This method not only provides a universal platform for electrochemical biosensing but also shows great potential in biological process researches and clinic diagnostics. PMID- 26652836 TI - "You should go so that others can come"; the role of facilities in determining an early departure after childbirth in Morogoro Region, Tanzania. AB - BACKGROUND: Tanzania is among ten countries that account for a majority of the world's newborn deaths. However, data on time-to-discharge after facility delivery, receipt of postpartum messaging by time to discharge and women's experiences in the time preceding discharge from a facility after childbirth are limited. METHODS: Household survey of 1267 women who delivered in the preceding 2 14 months; in-depth interviews with 24 women, 12 husbands, and 5 community elders. RESULTS: Two-thirds of women with vaginal, uncomplicated births departed within 12 h; 90 % within 24 h, and 95 % within 48 h. Median departure times varied significantly across facilities (hospital: 23 h, health center: 10 h, dispensary: 7 h, p < 0.001). Quantitative and qualitative data highlight the importance of type of facility and facility amenities in determining time-to discharge. In multiple logistic regression, level of facility (hospital, health center, dispensary) was the only significant predictor of early discharge (p = 0.001). However across all types of facilities a majority of women depart before 24 h ranging from hospitals (54 %) to health centers (64 %) to dispensaries (74 %). Most women who experienced a delivery complication (56 %), gave birth by caesarean section (90 %), or gave birth to a pre-term baby (70 %) stayed longer than 24 h. Reasons for early discharge include: facility practices including discharge routines and working hours and facility-based discomforts for women and those who accompany them to facilities. Provision of postpartum counseling was inadequate regardless of time to discharge and regardless of type of facility where delivery occurred. CONCLUSION: Our quantitative and qualitative findings indicate that the level of facility care and comforts existing or lacking in a facility have the greatest effect on time to discharge. This suggests that individual or interpersonal characteristics play a limited role in deciding whether a woman would stay for shorter or longer periods. Implementation of a policy of longer stay must incorporate enhanced postpartum counseling and should be sensitive to women's perceptions that it is safe and beneficial to leave hospitals soon after birth. PMID- 26652837 TI - Sustained-release Corticosteroids for Uveitis. PMID- 26652838 TI - Corrigendum. PMID- 26652840 TI - Serum folate levels in schizophrenia: A meta-analysis. AB - To clarify the relationship between serum folate and schizophrenia (SZ) risk, the meta-analysis was conducted. PubMed, Embase, and Web of Science were searched without language restrictions. Weighted mean difference (WMD) as a summary statistic was used in this meta-analysis. Subgroup analyses by publication language (English and non-English), ethnicity (Caucasian, Asian, African, Latino, and mixed population), duration (acute, chronic, patients including both acute and chronic SZ, and not mentioned about either chronic or acute), measurement time (before drugs using and after drugs using), gender (male and female) and age (<50 years old and >50 years old) were performed. Power analysis was also conducted to detect the reliability of the meta-analyses' results. In summary, the subgroups which failed to detect significant decreased associations were always with lower statistic power and could not be confirmed. The results supported that decreased serum folate was associated with SZ risk in total studies and subgroups of English publications, Caucasians, Asians, acute SZ patients, measurement after drugs using in SZ patients, and age<50 with the great enough powers, respectively. In conclusion, the present meta-analysis found that folate deficiency is associated to SZ, and subgroups which did not reach enough statistical power need further investigation in the future. PMID- 26652841 TI - Use of psychiatric medications in schizophrenia and other psychoses in a general population sample. AB - The information on the use of psychiatric medications in general population-based samples is limited. Our aim was to analyse the use of psychiatric medications and factors associated with antipsychotic use in psychoses in a general population sample. Fifty-five persons with schizophrenia, 21 with bipolar psychosis or psychotic depression and 20 with other psychoses from the Northern Finland Birth Cohort 1966 were examined at about 43 years of age. The frequency of use and dosage of psychiatric medication and the factors associated with the use of antipsychotics were analysed. Antipsychotics were used by 85% of schizophrenia, 65% of bipolar psychosis or psychotic depression and 62% of other psychoses cases; antidepressants were used by 22%, 60% and 33%; and benzodiazepines by 42%, 35% and 10%, respectively. In all the diagnostic groups, higher symptom scores and a higher number of hospital days were associated with the use of antipsychotics. In schizophrenia and other psychoses, poorer social and occupational functioning, and in other psychoses, female gender and lower education were also associated with the use of antipsychotics. Our results may partly indicate that, especially in schizophrenia, the effectiveness of antipsychotics is not as good as expected. PMID- 26652842 TI - Automatic and controlled processing and the Broad Autism Phenotype. AB - Research related to verbal fluency in the Broad Autism Phenotype (BAP) is limited and dated, but generally suggests intact abilities in the context of weaknesses in other areas of executive function (Hughes et al., 1999; Wong et al., 2006; Delorme et al., 2007). Controlled processing, the generation of search strategies after initial, automated responses are exhausted (Spat, 2013), has yet to be investigated in the BAP, and may be evidenced in verbal fluency tasks. One hundred twenty-nine participants completed the Delis-Kaplan Executive Function System Verbal Fluency test (D-KEFS; Delis et al., 2001) and the Broad Autism Phenotype Questionnaire (BAPQ; Hurley et al., 2007). The BAP group (n=53) produced significantly fewer total words during the 2nd 15" interval compared to the Non-BAP (n=76) group. Partial correlations indicated similar relations between verbal fluency variables for each group. Regression analyses predicting 2nd 15" interval scores suggested differentiation between controlled and automatic processing skills in both groups. Results suggest adequate automatic processing, but slowed development of controlled processing strategies in the BAP, and provide evidence for similar underlying cognitive constructs for both groups. Controlled processing was predictive of Block Design score for Non-BAP participants, and was predictive of Pragmatic Language score on the BAPQ for BAP participants. These results are similar to past research related to strengths and weaknesses in the BAP, respectively, and suggest that controlled processing strategy use may be required in instances of weak lower-level skills. PMID- 26652844 TI - Optoelectronic system for the determination of blood volume in pneumatic heart assist devices. AB - BACKGROUND: The following article describes the concept of optical measurement of blood volume in ventricular assist devices (VAD's) of the pulsatile type. The paper presents the current state of art in blood volume measurements of such devices and introduces a newly developed solution in the optic domain. The objective of the research is to overcome the disadvantages of the previously developed acoustic method-the requirement of additional sensor chamber. METHODS: The idea of a compact measurement system has been introduced, followed by laboratory measurements. Static tests of the system have been presented, followed by dynamic measurements on a physical model of the human ventricular system. The results involving the measurements of blood chamber volume acquired by means of an optical system have been compared with the results acquired by means of the Transonic T410 ultrasound flow rate sensor (11PLX transducer, uncertainty +/-5 %). RESULTS: Preliminary dynamic measurements conducted on the physical model of the human cardiovascular system show that the proposed optical measurement system may be used to measure the transient blood chamber volumes of pulsatile VAD's with the uncertainties (standard mean deviation) lower than 10 %. CONCLUSIONS: The results show that the noninvasive measurements of the temporary blood chamber volume in the POLVAD prosthesis with the use of the developed optical system allows us to carry out accurate static and dynamic measurements. PMID- 26652843 TI - Missense mutations in progranulin gene associated with frontotemporal lobar degeneration: study of pathogenetic features. AB - GRN, the gene coding for the progranulin (PGRN) protein, was recognized as a gene linked to frontotemporal lobar degeneration (FTLD). The first mutations identified were null mutations giving rise to haploinsufficiency. Missense mutations were subsequently detected, but only a small subset has been functionally investigated. We identified missense mutations (C105Y, A199V, and R298H) in FTLD cases with family history and/or with low plasma PGRN levels. The aim of this study was to determine their pathogenicity. We performed functional studies, analyzing PGRN expression, secretion, and cleavage by elastase. GRN C105Y affected both secretion and elastase cleavage, likely representing a pathogenic mutation. GRN A199V did not alter the physiological properties of PGRN and GRN R298H produced only moderate effects on PGRN secretion, indicating that their pathogenicity is uncertain. In the absence of strong segregation data and neuropathological examinations, genetic, biomarker, and functional studies can be applied to an algorithm to assess the likelihood of pathogenicity for a mutation. This information can improve our understanding of the complex mechanisms by which GRN mutations lead to FTLD. PMID- 26652845 TI - A case report of primary neuroendocrine carcinoma of the perihilar bile duct. AB - BACKGROUND: Although neuroendocrine tumors are most commonly found in the digestive system, neuroendocrine tumors originating from the bile duct are rare, and neuroendocrine carcinomas derived from the perihilar bile duct are extremely rare. This report presents the clinical course and clinicopathological features of neuroendocrine carcinomas arising from the extrahepatic bile duct. CASE PRESENTATION: A 70-year-old Japanese woman was preoperatively diagnosed with perihilar cholangiocarcinoma, and a radical resection with an extended left hepatic lobectomy and a choledochojejunostomy was performed. From the histopathological findings, we diagnosed the tumor as a neuroendocrine carcinoma of the bile duct (small cell type) with lymph node metastasis. The patient was treated with the same adjuvant chemotherapy as that used for small cell carcinoma of the lung. At 10 months after surgery, there was no recurrence of the disease. CONCLUSION: Neuroendocrine carcinoma of the extrahepatic biliary tracts is a very rare and highly malignant disease with a poor prognosis. A multidisciplinary approach could improve the prognosis for this neoplasm. PMID- 26652846 TI - Perceptions of environmental health risks among residents in the "Toxic Doughnut": opportunities for risk screening and community mobilization. AB - BACKGROUND: Surrounded by landfills, and toxic and hazardous facilities, Altgeld Gardens is located in a "toxic doughnut". With high rates of environmentally related conditions, residents have called for a community-based environmental health assessment to improve overall health in their community. The purpose of this study was to investigate the attitudes and beliefs of environmental health risks of Altgeld's residents which would assist community organizing efforts and provide the groundwork for a community-based environmental health assessment. METHODS: A questionnaire was designed and administered to 42 Altgeld residents who also participated in focus groups to assess their perceptions of environmental health risks. RESULTS: All participants were Altgeld residents for at least two years and were fairly representative of the broader community. Physical and social hazards were primarily identified as posing risks to participants' family and the broader community. Physical hazards included the dumping of hazardous waste and landfills; social hazards were crime and drugs. CONCLUSIONS: These findings have been useful in community organizing efforts and in program planning for local community-based organizations and public health agencies. The results have also been used to prioritize health and environmental risk issues impacting the community. PMID- 26652853 TI - Prevalence and clinical implications of renal artery stenosis in pediatric moyamoya disease. AB - PURPOSE: Until recently, extracranial involvement of moyamoya disease (MMD) had not been fully elucidated. The purpose of this study was to determine the prevalence and clinical implications of renal artery stenosis in pediatric MMD patients. MATERIALS & METHODS: This retrospective study included 101 pediatric (<18 years old) MMD patients who visited our hospital from July 2008 to May 2013. All patients had legible abdominal or renal angiography. Baseline characteristics, including hypertension (HT) and angiographic findings, were retrospectively evaluated. RESULT: The median age was 8 (range 2-16) years. Six patients (5.9%) had HT. Renal artery stenosis was identified in 8 patients (7.9%). Five of 8 renal artery stenosis patients had HT. Statistical analysis showed that advanced stages of MMD and HT were associated with renal artery stenosis (p < 0.05). CONCLUSION: Renal artery stenosis was not uncommon in pediatric MMD. Renal artery evaluation could help determine the cause of HT in advanced pediatric MMD cases. Further prospective and large-scale studies may be helpful in elucidating the extracranial manifestation of MMD. PMID- 26652854 TI - Women's intention to exclusively breast feed: The Israeli perspective. AB - BACKGROUND: research reveals that there are numerous factors related to women's intention to exclusively breast feed (EBF). Moreover, several studies do not differentiate between exclusive and partial breast feeding. OBJECTIVE: the aim of the present study was to identify factors associated with Israeli women's intention to EBF their next baby based on the Theory of Planned Behavior (TPB), within the context of Israeli ethnic and cultural diversity. DESIGN: the study is a correlational quantitative study. SETTING: women were recruited at lectures on women's health at an urban setting in central Israel during September-December 2013. The lectures were organised by a local nursing school and were open for the general public. PARTICIPANTS: a convenience sample of 200 Hebrew-speaking women of childbearing age, who had at least one child over six months old which had been EBF for at least one month. METHODS: the women completed a closed questionnaire based on the TPB. FINDINGS: in the multivariate analysis, behavioural beliefs, behavioural attitudes, knowledge of EBF, and EBF duration of the previous child predicted 35.3% of Israeli women's intentions to EBF in the future. In addition, study findings revealed the importance that women attributed to their spouses' opinion concerning EBF. Muslim Arab women expressed higher intention to EBF than Jewish women. CONCLUSIONS: the findings of this study will constitute the basis of a nurse-administered intervention programme for promoting EBF in Israeli society. In the context of this programme, nurses' interventions will emphasise the benefits of EBF for mothers and infants, and provide women and their spouses with tools and information to support EBF. Nurses' interventions will also take into account the influence of ethnicity and culture, as well as the duration of women's previous EBF experiences. PMID- 26652855 TI - Lactobacillus crispatus inhibits growth of Gardnerella vaginalis and Neisseria gonorrhoeae on a porcine vaginal mucosa model. AB - BACKGROUND: The vaginal microbiota can impact the susceptibility of women to bacterial vaginosis (BV) and sexually transmitted infections (STIs). BV is characterized by depletion of Lactobacillus spp., an overgrowth of anaerobes (often dominated by Gardnerella vaginalis) and a pH > 4.5. BV is associated with an increased risk of acquiring STIs such as chlamydia and gonorrhea. While these associations have been identified, the molecular mechanism(s) driving the risk of infections are unknown. An ex vivo porcine vaginal mucosal model (PVM) was developed to explore the mechanistic role of Lactobacillus spp. in affecting colonization by G. vaginalis and Neisseria gonorrhoeae. RESULTS: The data presented here demonstrate that all organisms tested can colonize and grow on PVM to clinically relevant densities. Additionally, G. vaginalis and N. gonorrhoeae form biofilms on PVM. It was observed that lactic acid, acetic acid, and hydrochloric acid inhibit the growth of G. vaginalis on PVM in a pH-dependent manner. N. gonorrhoeae grows best in the presence of lactic acid at pH 5.5, but did not grow well at this pH in the presence of acetic acid. Finally, a clinical Lactobacillus crispatus isolate (24-9-7) produces lactic acid and inhibits growth of both G. vaginalis and N. gonorrhoeae on PVM. CONCLUSIONS: These data reveal differences in the effects of pH, various acids and L. crispatus on the growth of G. vaginalis and N. gonorrhoeae on a live vaginal mucosal surface. The PVM is a useful model for studying the interactions of commensal vaginal microbes with pathogens and the mechanisms of biofilm formation on the vaginal mucosa. PMID- 26652856 TI - The Graz Malnutrition Screening (GMS): a new hospital screening tool for malnutrition. AB - Despite the significant impact of malnutrition in hospitalised patients, it is often not identified by clinical staff in daily practice. To improve nutritional support in hospitals, standardised routine nutritional screening is essential. The Graz Malnutrition Screening (GMS) tool was developed for the purpose of malnutrition risk screening in a large hospital setting involving different departments. It was the aim of the present study to validate the GMS against Nutritional Risk Screening (NRS) and Mini Nutritional Assessment-short form (MNA sf) in a randomised blinded manner. A total of 404 randomly selected patients admitted to the internal, surgical and orthopaedic wards of the University Hospital Graz were screened in a blinded manner by different raters. Concurrent validity was determined by comparing the GMS with the NRS and in older patients (70+ years) with the MNA-sf additionally. According to GMS, 31.9 or 28.5% of the admitted patients were categorised as at 'risk of malnutrition' (depending on the rater). According to the reference standard of NRS, 24.5% of the patients suffered from malnutrition. Pearson's r values of 0.78 compared with the NRS and 0.84 compared with the MNA showed strong positive correlations. Results of accuracy (0.85), sensitivity (0.94), specificity (0.77), positive predictive value (0.76) and negative predictive value (0.95) of GMS were also very high. Cohen's kappa for internal consistency of the GMS was 0.82. GMS proves to be a valid and reliable instrument for the detection of malnutrition in adult patients in acute-care hospitals. PMID- 26652857 TI - The first detection of Rickettsia aeschlimannii and Rickettsia massiliae in Rhipicephalus turanicus ticks, in northwest China. AB - BACKGROUND: Rickettsia spp. belonging to the spotted fever group (SFG) cause infections in humans, domestic animals and wildlife. At least five SFG rickettsial species have been reported in China, but the occurrence of Rickettsia aeschlimannii and R. massiliae in ticks has not been characterized to date. FINDINGS: A total of 114 adult ticks were collected from sheep in Yining County, Xinjiang Uygur Autonomous Region, in northwest China. The ticks were identified from morphological and molecular characteristics. All samples were examined by polymerase chain reaction (PCR), and six genetic markers were used to determine the Rickettsia spp. in the ticks. The ticks collected were identified as Rhipicephalus turanicus. Three different lineages of Rh. turanicus from Yining County were discovered on phylogenetic analysis of 16S rDNA and cox1. Twenty-one of the 114 samples (18.42%) were positive for rickettsial agents. Phylogenetic analysis based on six genetic sequences showed that three rickettsial species were present, namely: R. aeschlimannii (19.05%, 4/21), R. massiliae (19.05%, 4/21) and R. sibirica variant (61.90%, 13/21), which is clustered in the clade of R. sibirica subsp. sibirica. CONCLUSIONS: This is the first description of R. aeschlimannii and R. massiliae in China. R. massiliae, R. aeschlimannii and R. sibirica variant co-circulate in the region of the China-Kazakhstan border, in northwest China. Rickettsial agents in ticks of the genus Rhipicephalus from migrant birds, transported livestock, wildlife and human beings should be investigated further in the region of the China-Central Asian border. PMID- 26652858 TI - Ultrasound validation of mathematically modeled irreversible electroporation ablation areas. AB - OBJECTIVE: Currently, the prediction of the dimensions of irreversible electroporation (IRE) ablation is modeled using algorithms derived from mathematical and ex vivo models. These algorithms have not been validated using in vivo studies. The aim of this study was to assess the correlation between the mathematical prediction model to and ultrasonographic and histopathologic findings for in vivo ablations in a porcine model. METHODS: IRE ablations were performed on porcine liver and spleen with probe spacings ranging from 0.6 to 2.6 cm. Pre and 2-hour postablation ultrasound (US) images were recorded and validated with confirmation by histopathology. Three dimensions of the regions of ablation were recorded, and ablation volumes were calculated and correlated with theoretic mathematical models for each given probe spacing. RESULTS: In vivo axial and anterior-posterior (AP) distances of ablation were greater than predicted for nearly all probe spacings (P < .05). Ablation volumes were significantly less than predicted for the all probe spacings when modeled using both a cylinder and an ellipsoid. Geometrically, mathematically derived regions of ablation demonstrated more central tapering ("necking") and diminished volumes compared to their in vivo counterparts. The relationships between probe spacing and AP dimensions of ablation were less linear (r(2) = 0.57) than the relationships observed via ultrasonography. CONCLUSION: The current mathematical models predict regions of ablation observed in vivo poorly. They underestimate dimensions of ablation and, by extension, the volumes of ablation. Further work should be done to improve models for ablative planning, and physicians should recognize the limitations of existing models when planning ablative treatments. PMID- 26652859 TI - The relative effect of hospital and surgeon volume on failure to rescue among patients undergoing liver resection for cancer. AB - BACKGROUND: Although previous reports have focused on factors at the hospital level to explain variations in postoperative outcomes, less is known regarding the effect of provider-specific factors on postoperative outcomes such as failure to-rescue (FTR) and postoperative mortality. The current study aimed to quantify the relative contributions of surgeon and hospital volume on the volume-outcomes relationship among a cohort of patients undergoing liver resection. METHODS: Patients undergoing liver surgery for cancer were identified using the Nationwide Inpatient Sample from 2001 and 2009. Multivariable logistic regression analysis was performed to identify factors associated with mortality and FTR. Point estimates were used to calculate the relative effects of hospital and surgeon volume on mortality and FTR. RESULTS: A total of 5,075 patients underwent liver surgery and met inclusion criteria. Median patient age was 62 years (interquartile range, 52-70) and 55.2% of patients were male. Mortality was lowest among patients treated at high-volume hospitals and among patients treated by high-volume surgeons (both P < .001). Similar patterns in FTR were noted relative to hospital and surgeon volume (hospital volume: low vs intermediate vs high; 10.3 vs 9.0 vs 5.2%; surgeon volume: low vs intermediate vs high, 11.1 vs 9.1 vs 4.1%; both P < .05). On multivariable analysis, compared with high-volume surgeons, lower volume surgeons demonstrated greater odds for mortality (intermediate: odds ratio [OR], 2.27 [95% CI, 1.27-4.06; P = .006]; low, OR, 2.83 [95% CI, 1.52-5.27; P = .001]), and FTR (intermediate: OR, 2.86 [95% CI, 1.53 5.34, P = .001]; low, OR, 3.40 [95% CI, 1.75-6.63; P < .001]). While hospital volume accounted for 0.5% of the surgeon volume effect on increased FTR for low volume surgeons, surgeon volume accounted for nearly all of the hospital volume effect on increased FTR in low-volume hospitals. CONCLUSION: The risk of complications, mortality, and FTR were less among both high-volume hospitals and high-volume surgeons, but the beneficial effect of volume on outcomes was attributable largely to surgeon volume. PMID- 26652860 TI - A Pyrazolo[3,4-d]pyrimidin-4-amine Derivative Containing an Isoxazole Moiety Is a Selective and Potent Inhibitor of RET Gatekeeper Mutants. AB - Aberrant RET kinase signaling plays critical roles in several human cancers such as thyroid carcinoma. The gatekeeper mutants (V804L or V804M) of RET are resistant to currently approved RET inhibitors such as cabozantinib and vandetanib. We, for the first time, report a highly selective and extremely potent RET inhibitor, 6i rationally designed. Compound 6i inhibits strongly RET gatekeeper mutants and other clinically relevant RET mutants as well as wt-RET. This substance also significantly suppresses growth of thyroid cancer-derived TT cell lines and Ba/F3 cells transformed with various RET mutants. Docking studies reveal that the isoxazole moiety in 6i is responsible for binding affinity improvement by providing additional site for H-bonding with Lys758. Also, 6i not only substantially blocks cellular RET autophosphorylation and its downstream pathway, it markedly induces apoptosis and anchorage-independent growth inhibition in TT cell lines while having no effect on normal thyroid Nthy ori-3-1 cells. PMID- 26652861 TI - The potential anticancer effect of beta-blockers and the genetic variations involved in the interindividual difference. AB - beta-ARs are extensively spread in different tissues of our body, which could be activated by neurotransmitters norepinephrine and epinephrine to mediate physiological function and abnormal states including cancer. Recently, beta-AR blockers could have significant implications in cancer therapy. But the precise molecular mechanisms are far from being fully understood. Through identifying the beta-AR system signal pathways relevant to cancer, we can understand the mechanisms of beta-blockers used for cancer treatment. What's more, retrospective clinical data made beta-blockers jump out of the traditional field of cardiovascular disease and strengthened our confidence in cancer therapy. At last, genetic studies of beta-adrenergic system offered crucial genes to analyze the effects of polymorphisms on cancer susceptibility, therapy response and prognosis of cancer patients. PMID- 26652862 TI - Community-acquired bacterial meningitis in adults in the Netherlands, 2006-14: a prospective cohort study. AB - BACKGROUND: We studied causative pathogens, clinical characteristics, and outcome of adult community-acquired bacterial meningitis after the introduction of adjunctive dexamethasone treatment and nationwide implementation of paediatric conjugate vaccines. METHODS: In this cohort study, we prospectively assessed adults (age >16 years) with community-acquired bacterial meningitis in the Netherlands, identified through the National Reference Laboratory for Bacterial Meningitis or individual physicians between Jan 1, 2006, and July 1, 2014. We identified independent predictors of an unfavourable outcome (Glasgow Outcome Scale score 1-4) by logistic regression. FINDINGS: We assessed 1412 episodes of community-acquired bacterial meningitis. Incidence declined from 1.72 cases per 100,000 adults per year in 2007-08, to 0.94 per 100,000 per year in 2013-14. Streptococcus pneumoniae caused 1017 (72%) of 1412 episodes. Rates of adult bacterial meningitis decreased most sharply among pneumococcal serotypes included in paediatric conjugate vaccine, and in meningococcal meningitis. We found no evidence of serotype or serogroup replacement. The overall case fatality rate was 244 (17%) of 1412 episodes and unfavourable outcome occurred in 531 (38%) of 1412 episodes. Predictors of unfavourable outcome were advanced age, absence of otitis or sinusitis, alcoholism, tachycardia, lower score on the Glasgow Coma Scale, cranial nerve palsy, a cerebrospinal fluid white-cell count lower than 1000 cells per MUL, a positive blood culture, and a high serum C-reactive protein concentration. Adjunctive dexamethasone was administered for 1234 (89%) of 1384 assessed episodes. The multivariable adjusted odds ratio of dexamethasone treatment for unfavourable outcome was 0.54 (95% CI 0.39-0.73). INTERPRETATION: The incidence of adult bacterial meningitis has decreased substantially, which is partly explained by herd protection by paediatric conjugate vaccines. Adjunctive dexamethasone treatment was associated with substantially improved outcome. FUNDING: European Research Council, National Institute of Public Health and the Environment, European Union, Academic Medical Center, and Netherlands Organization for Health Research and Development. PMID- 26652863 TI - Bacterial meningitis: the end of the beginning? PMID- 26652864 TI - Development and clinical validation of an LC-MS/MS method for the quantification of pazopanib in DBS. AB - BACKGROUND: Pazopanib is approved for the treatment of renal cell carcinoma and soft tissue sarcoma. Analyses show increased benefit in patients with plasma trough concentrations >=20.5 MUg/ml compared with patients with lower concentrations. METHODS & RESULTS: We developed a DBS assay as a patient friendly approach to guide treatment. The method was validated according to US FDA and EMA guidelines and European Bioanalysis Forum recommendations. Influence of spot homogeneity, spot volume and hematocrit were shown to be within acceptable limits. Analysis of paired clinical samples showed a good correlation between the measured plasma and DBS concentrations (R(2) of 0.872). CONCLUSION: The method was successfully validated, applied to paired clinical samples and is suitable for application to therapeutic drug monitoring of pazopanib. PMID- 26652865 TI - The Effects of IGF-1 on Trk Expressing DRG Neurons with HIV-gp120- Induced Neurotoxicity. AB - BACKGROUND: HIV envelope glycoprotein gp120 is the main protein that causes HIVassociated sensory neuropathy. However, the underlying mechanisms of gp120 induced neurotoxicity are still unclear. There are lack effective treatments for relieving HIV-related neuropathic symptoms caused by gp120-induced neurotoxicity. METHODS: In the present study, tyrosine kinase receptor (Trk)A, TrkB, and TrkC expression in primary cultured dorsal root ganglion (DRG) neurons with gp120 induced neurotoxicity was investigated. The effects of IGF-1 on distinct Trk positive DRG neurons with gp120-induced neurotoxicity were also determined. RESULTS: The results showed that gp120 not only dose-dependently induced DRG neuronal apoptosis and inhibited neuronal survival and neurite outgrowth, but also decreased distinct Trk expression levels. IGF-1 rescued DRG neurons from apoptosis and improved neuronal survival of gp120 neurotoxic DRG neurons in vitro. IGF-1 also improved TrkA and TrkB, but not TrkC, expression in gp120 neurotoxic conditions. The effects of IGF-1 could be blocked by preincubation with the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002. CONCLUSION: These results suggested that gp120 may have a wide range of neurotoxicity on different subpopulations of DRG neurons, while IGF-1 might only relieve some subpopulations of DRG neurons with gp120-induced neurotoxicity. These data provide novel information of mechanisms of gp120 neurotoxicity on primary sensory neurons and the potential therapeutic effects of IGF-1 on gp120-induced neurotoxicity. PMID- 26652867 TI - Predicting the conversion of mild cognitive impairment to Alzheimer's disease based on the volumetric measurements of the selected brain structures in magnetic resonance imaging. AB - INTRODUCTION: Mild cognitive impairment (MCI) is defined as abnormal cognitive state, but does not meet the criteria for the diagnosis of dementia. According to the new guidelines Alzheimer's disease (AD) involves not only dementia's phase but also predementia phase which is asymptomatic and pathological process in the brain is already present. For this reason it is very important to determine the suitability of markers which should be positive before onset of the first symptoms. One of these biomarkers is a structural magnetic resonance imaging with hippocampal volumetric assessment. The aim of this study was to investigate the usefulness of structural brain magnetic resonance imaging with volumetric assessment of the hippocampus and entorhinal cortex, posterior cingulate gyrus, parahippocampal gyrus, temporal gyri: superior, medial and inferior, to predict the conversion of MCI to AD. MATERIAL AND METHODS: Magnetic resonance imaging of brain was performed at the baseline visit in 101 patients diagnosed with MCI. Clinic follow-ups were scheduled after 6.12 and 24 months. RESULTS: Amongst 101 patients with MCI, 17 (16.8%) converted into AD within two years of observation. All measured volumes were lower in converters than non-converters. Discriminant analysis was conducted and sensitivity for MCI conversion to AD was 64.7%, specificity 96.4%. 91% of patients were correctly classified (converter or non converter). CONCLUSIONS: Volumetric measurements may help clinicians to predict MCI conversion to AD but due to low sensitivity it cannot be use separately. The study group requires further observation. PMID- 26652866 TI - Testing health information technology tools to facilitate health insurance support: a protocol for an effectiveness-implementation hybrid randomized trial. AB - BACKGROUND: Patients with gaps in health insurance coverage often defer or forgo cancer prevention services. These delays in cancer detection and diagnoses lead to higher rates of morbidity and mortality and increased costs. Recent advances in health information technology (HIT) create new opportunities to enhance insurance support services that reduce coverage gaps through automated processes applied in healthcare settings. This study will assess the implementation of insurance support HIT tools and their effectiveness at improving patients' insurance coverage continuity and cancer screening rates. METHODS/DESIGN: This study uses a hybrid cluster-randomized design-a combined effectiveness and implementation trial-in community health centers (CHCs) in the USA. Eligible CHC clinic sites will be randomly assigned to one of two groups in the trial's implementation component: tools + basic training (Arm I) and tools + enhanced training + facilitation (Arm II). A propensity score-matched control group of clinics will be selected to assess the tools' effectiveness. Quantitative analyses of the tools' impact will use electronic health record and Medicaid data to assess effectiveness. Qualitative data will be collected to evaluate the implementation process, understand how the HIT tools are being used, and identify facilitators and barriers to their implementation and use. DISCUSSION: This study will test the effectiveness of HIT tools to enhance insurance support in CHCs and will compare strategies for facilitating their implementation in "real-world" practice settings. Findings will inform further development and, if indicated, more widespread implementation of insurance support HIT tools. TRIAL REGISTRATION: Clinical trial NTC02355262. PMID- 26652868 TI - The effects of physiotherapy with PNF concept on gait and balance of patients with Huntington's disease - pilot study. AB - BACKGROUND AND PURPOSE: Huntington's disease (HD) is a neurodegenerative, progressive disorder of the central nervous system which causes significant gait and balance disturbances. This is a pilot study which aims to determine the effects of a physiotherapy programme with use of Proprioceptive Neuromuscular Facilitation (PNF) on gait and balance in HD patients. MATERIAL AND METHODS: 30 HD patients aged 21-60 with genetically confirmed diagnosis participated in the study. Participants followed a 3-week-long PNF-based physiotherapy programme. Gait and balance were evaluated twice in each participant: first at baseline and then after the course of physiotherapy. The following methods were used for gait disturbances: Tinetti Gait Assessment Tool, Up and Go Test, Timed Walking Tests for 10m and 20m (TWT10m, TWT20m). Balance was assessed with use of Berg Balance Scale, Pastor Test and Functional Reach Test. RESULTS: There was a significant improvement in all measures of balance and gait. CONCLUSION: PNF-based physiotherapy is effective and safe in HD patients. PMID- 26652869 TI - Thoracolumbar burst fractures requiring instrumented fusion: Should reducted bone fragments be removed? A retrospective study. AB - BACKGROUND: Thoracolumbar burst fractures are common clinical entity encountered in neurosurgical practice, accounting for 10-20% of all spinal fractures. Clinical picture could be devastating due to severe neurological deficits which lead the patients dependent both socially and emotionally. MATERIALS AND METHODS: This study compared two groups of patients who were operated because of thoracolumbar burst fracture secondary to spinal trauma in terms of neurologic deficits, degree of improvement, and radiologic measurements at one-year follow up. The first group (group I) included the patients who underwent posterior total laminectomy, peroperative reduction of intracanal bone fragments, and posterior spinal instrumentation and the second group (group II) included the patients who underwent total laminectomy, and spinal instrumentation without reduction of free bone fragments. RESULTS: Neither group showed significant correlation with any measurement parameter. Radiological assessments and clinical improvements did not disclosed significant difference between the two groups at one-year follow-up. CONCLUSION: Retropulsion of free bone fragments extend the time of surgery and causes complications. This study found that there is no need to retropulse the bone fragments in the spinal canal in patients with unstable burst fractures who underwent total laminectomy and posterior long segment stabilization. PMID- 26652870 TI - Clinical course and management of intracranial meningiomas in neurofibromatosis type 2 patients. AB - OBJECTIVE: The aim of this study is to evaluate our surgical experience with intracranial meningiomas in NF2 patients and provide knowledge of the natural history of these lesions. METHODS: We included in the natural growth study patients with the diagnosis of NF2 who harbored intracranial meningiomas and were observed for at least 1 year. Tumors that were resected before achieving long term follow-up were excluded from this analysis. RESULTS: We found 118 intracranial meningiomas in 34 patients in our series. 8 meningiomas in 7 patients were symptomatic. It was found that with an increase in tumor volume, brain edema and with the tumor location at the skull base, meningiomas are more likely to be symptomatic. Univariate analysis revealed that tumor growth was associated with a younger age at the onset of NF2-related symptoms, greater initial tumor volume, brain edema and with the presence of intracranial non vestibular schwannoma. Multivariate analysis showed that the probability of tumor growth is associated with prolonged follow-up time. De novo meningiomas exhibited a significantly higher growth rate than other meningiomas. These tumors were more frequent in patients with intracranial non-vestibular schwannoma and with increasing length of meningioma observation. CONCLUSION: Meningiomas occur in about half NF2 patients. Many of them exhibit slow growth and long remain asymptomatic, however, those associated with early onset of NF2 symptoms and other features of the disease severity should be monitored in case of clinical and radiological progression that may require surgical treatment. PMID- 26652871 TI - Surgery for sporadic vestibular schwannoma. Part III: Facial and auditory nerve function. AB - OBJECTIVE: The aim of this analysis was to assess short-term and long-term outcomes with respect to the preservation of facial and auditory nerve function following surgery for sporadic vestibular schwannomas. MATERIAL AND METHODS: The study included 220 consecutive patients operated on with the retrosigmoid (217) or translabyrinthine (3) approach. The mean extrameatal diameter of the tumor was 30mm. In 217 patients, gross total resection was performed and near-total in 3. Before surgery, the facial nerve (CNVII) weakness was found in 18% of patients and only 20% had serviceable hearing. Intraoperative neurophysiological CNVII monitoring was routinely used (the last 211 procedures). Intraoperative monitoring of the cochlear nerve function was used when the preservation of hearing was attempted (45 procedures). RESULTS: The rate of CNVII continuity loss during surgery was 11%, however, this decreased to 6% in the second half of the series. Facial nerve function deteriorated, in 88% of the patients shortly after surgery. However, it improved in 87% in follow-up. Delayed CNVII palsy was found in 5% of the patients and had a good prognosis in 88%. Final satisfactory CNVII function (CNVII-SF, HB grades I-III) was achieved in 76% of the patients when excluding the anastomosis results, and 87% when including them. In recent years, the rate of CNVII-SF has risen to 94%. Non-serviceable hearing was preserved in 49% of the patients, on whom it was attempted. CONCLUSION: Considering the size of the tumors and extent of the resections, the preservation of CNVII function is currently very high. A close surveillance of CNVII function evolution following surgery is mandatory, as 2/3 of the patients discharged with deep paresis will need different face reanimation procedures. The preservation of useful hearing is still problematic, especially in patients with large tumors. PMID- 26652872 TI - Relationship between the spino-pelvic parameters and the slip grade in isthmic spondylolisthesis. AB - PURPOSE OF THE STUDY: Analysis of changes in the spino-pelvic alignment, depending on the slip grade in patients with low and high-grade isthmic slip. MATERIALS AND METHODS: A group of 60 patients who had lumbar spine radiograms adequate to measure the spino-pelvic parameters selected from a series of 195 cases of isthmic spondylolisthesis. We analyzed the following spino-pelvic parameters: pelvic incidence (PI), sacral slope (SS), pelvic tilt (PT), lumbosacral angle by Dubousset (LSA) and lumbar lordosis (LL). The ANOVA statistical test was used to examine whether there is a significant correlation between (1) the slip grade and the value of PI, PT, and LL, and the Pearson correlation was used to examine a correlation between (2) the size of PI and the value of other spino-pelvic parameters, (3) the value of LL and SS, (4) value of the LSA and LL, PI and PT. RESULTS: The greater the slip grade, the greater the value of PI, PT, and LL and lower LSA. Positive correlations have been found between PI and SS, PT and LL. There was also a positive correlation between LL and SS. Negative correlations were noted between LSA and LL, PI and PT. CONCLUSION: The spino-pelvic alignment changes with the grade of isthmic spondylolisthesis, and the individual spino-pelvic parameters correlate together to form a causal chain in the development of isthmic spondylolisthesis. PMID- 26652873 TI - The effectiveness of neurolytic block of sphenopalatine ganglion using zygomatic approach for the management of trigeminal neuropathy. AB - This study was performed to present the outcomes of trigeminal neuropathy management with the application of neurolytic block of sphenopalatine ganglion. This type of procedure is used in cases where pain is not well controlled with medical treatment. Twenty patients were treated with sphenopalatine ganglion neurolysis after their response to pharmacological management was not satisfactory. Significant pain relief was experienced by all but one patient and they were able to reduce or stop their pain medication. The time of pain relief was between a few months and 9 years during the study period. Number of procedures implemented varied as some of the patients have been under the care of our Pain Clinic for as long as 18 years, satisfied with this type of management and willing to have the procedure repeated if necessary. It appears that neurolytic block of sphenopalatine ganglion is effective enough and may be an option worth further consideration in battling the pain associated with trigeminal neuropathy. PMID- 26652874 TI - Predictors of intracranial cerebral artery stenosis in patients before cardiac surgery and its impact on perioperative and long-term stroke risk. AB - BACKGROUND: The aim of this prospective study was to determine the prevalence of stenosis within intracranial and extracranial arteries in patients before coronary artery bypass surgery (CABG), to evaluate the influence of intracranial artery stenosis on neurological outcome and to identify preoperative risk factors for these patients. METHODS: One hundred and seventy-five patients (71% males, mean age=66.1) scheduled for CABG were enrolled for extracranial Doppler duplex sonography, transcranial color-coded duplex sonography (TCCS) and transcranial Doppler (TCD) examination. RESULTS: Twenty-six patients (14.7%) had extracranial stenosis or occlusion and 13 patients (7.3%) intracranial vascular disease. Six patients (3.5%) had both extra- and intracranial artery disease. The presence of peripheral artery disease and diabetes mellitus was a strong risk factor for extracranial artery stenosis but not for intracranial artery stenosis, which occurred independently also of typical atherosclerotic risk factors like age >70, male sex, hypertension, hyperlipidemia, hyperhomocysteinemia, smoking habit, obesity (BMI>30) and waist to hip ratio >1. Functional neurological outcome of the patients with intracranial arterial disease evaluated 7 days after CABG was the same as the patients without extra- and intracranial stenosis. However, 12 months neurological follow-up revealed significantly more ischemic strokes in patients with intracranial artery stenosis compared to patients without intracranial stenosis (p=0.015). CONCLUSION: The occurrence of intracranial artery stenosis in CABG patients cannot be predicted by well-known atherosclerotic risk factors and seems not to be associated with perioperative stroke. PMID- 26652875 TI - Auditory spatial deficits in brainstem disorders. AB - PURPOSE: Brainstem disorders seem to negatively influence the central auditory system, causing spatial hearing deficits. MATERIAL AND METHODS: We tested 11 patients with brainstem lesions due to ischemic stroke (IS), multiple sclerosis (MS), or cerebellopontine angle tumor (CPAT) together with 50 age- and sex matched healthy volunteers. We used pure tone audiometry (PTAud), brainstem auditory evoked potentials (BAEPs) and the horizontal minimum audible angle test (HMAAT) for 8 azimuths with binaural stimulation. RESULTS: The chosen patients and the controls had normal or near normal hearing in PTAud. BAEPs interaural wave I-V latency difference was over 7 times longer in the patients group compared to the controls. Additionally, 9 of the 11 patients (81.1%) had abnormal HMAAT results. The biggest quantitative disturbances in HMAAT were present in the CPAT and the MS patients. The sound localization ability in HMAAT was significantly worse in the patients in 0 degrees azimuth in comparison with the controls, and in 45 degrees and 90 degrees azimuth in patients with auditory pathway involvement compared with the ones without the involvement. CONCLUSIONS: Our study confirms the strong relationship between various brainstem pathologies and sound localization disability and sheds some light on the complexity of the relationship. PMID- 26652876 TI - Brain perfusion evaluated by perfusion-weighted magnetic resonance imaging before and after stenting internal carotid artery stenosis in asymptomatic and symptomatic patients. AB - PURPOSE: To evaluate the brain perfusion with MRI perfusion weighted imaging (PWI) before and after ICA stenting in asymptomatic and symptomatic patients. MATERIALS AND METHODS: PWI was performed 3-21 days before and 3 days after ICA stenting in 31 asymptomatic patients with ICA >70% stenosis - Group I, and in 14 symptomatic patients with ICA >50% stenosis - Group II. PWI was evaluated qualitatively and quantitatively in 5 cerebral territories with: mean transit time (MTT), cerebral blood volume (CBV) and cerebral blood flow (CBF). Mean values of perfusion parameters were measured before and after stenting DeltaMTT, DeltaCBV, DeltaCBF were calculated as subtraction of after-treatment values from those before treatment. RESULTS: In qualitative evaluation after ICA stenting perfusion was normalized in 21 patients (80.8%) in Group I and in 8 patients (80%) in Group II. In quantitative estimation MTT decreased significantly after CAS on stented side vs. non-stented side in all examined patients regardless of the group, p<0.05. MTT decreased more in Group II than in Group I in all territories (p<0.05) with the exception of temporal lobe. CBV and CBF have shown insignificant differences. PMID- 26652877 TI - The role of neuroimaging in the diagnosis of the atypical parkinsonian syndromes in clinical practice. AB - Atypical parkinsonian disorders (APD) are a heterogenous group of neurodegenerative diseases such as: progressive supranuclear palsy (PSP), multiple system atrophy (MSA), cortico-basal degeneration (CBD) and dementia with Lewy bodies (DLB). In all of them core symptoms of parkinsonian syndrome are accompanied by many additional clinical features not typical for idiopathic Parkinson's disease (PD) like rapid progression, gaze palsy, apraxia, ataxia, early cognitive decline, dysautonomia and usually poor response to levodopa therapy. In the absence of reliably validated biomarkers the diagnosis is still challenging and mainly based on clinical criteria. However, robust data emerging from routine magnetic resonance imaging (MRI) as well as from many advanced MRI techniques such as: diffusion weighted imaging (DWI) and diffusion tensor imaging (DTI), magnetic resonance spectroscopy (MRS), voxel-based morphometry (VBM), susceptibility-weighted imaging (SWI) may help in differential diagnosis. The main aim of this review is to summarize briefly the most important and acknowledged radiological findings of conventional MRI due to its availability in standard clinical settings. Nevertheless, we present shortly other methods of structural (like TCS - transcranial sonography) and functional imaging (like SPECT - single photon emission computed tomography or PET - positron emission tomography) as well as some selected advanced MRI techniques and their potential future applications in supportive role in distinguishing APD. PMID- 26652878 TI - Emergency microsurgical embolectomy in acute ischemic stroke with diffusion negative MRI. AB - Although diffusion-weighted imaging (DWI) is highly sensitive and specific for the detection of acute ischemic injury, there are increasing reports that it may fail to demonstrate an acute stroke. Here, we present a case involving an acute ischemic stroke with a false-negative DWI in a 64-year-old woman who had undergone an emergency microsurgical embolectomy for an occluded middle cerebral artery (MCA). Although the endovascular mechanical embolectomy failed in treating the occluded MCA, we were able to successfully treat our patient with the second treatment option of a microsurgical embolectomy. Microsurgical embolectomy might be the treatment of choice, especially if the mechanical catheter is expected to not be able to access the target artery due to tortuous vascular structures. PMID- 26652879 TI - A ganglion cyst derived from a synovial cyst: A case report. AB - The synovial and ganglion cysts originating from the facet joint have been named under the name of the Juxtafacet cyst by the several researchers. They put forward that the synovial cyst originated from the synovial joint. But, they failed to clarify the pathophysiology of the formation of the ganglion cyst. In this case report, we reported a 67-year-old male patient was referred to the emergency from another center with the complaint of a left leg pain and weakness in the left foot and patient was treated with microchirurgical technique. His patological examination was evaluated a ganglion cyst. We have discussed and explained the pathophysiology of the formation of a ganglion cyst derivered from a synovial cyst. And separately, we have presented the spinal cysts by grouping them under a new classification called a cystic formation of the soft tissue attachments of the mobile spine as well as dividing them into sub-groups. PMID- 26652880 TI - Malignant transformation of diffuse infiltrating glial neoplasm after prolonged stable period initially discovered with hypothalamic hamartoma. AB - We present a case of malignant transformation of diffuse infiltrating glial neoplasm after a prolonged stable period on magnetic resonance imaging (MRI) and spectroscopy (MRS) initially discovered with a hypothalamic hamartoma. Although MRI and MRS suggest the possibility of malignant transformation in future, they cannot precisely predict the timing of rapid growth. PMID- 26652881 TI - A large cavernous malformation of the third ventricle floor: A case report. AB - Suprasellar and third ventricular region cavernous malformations originating from the floor of the third ventricle are extremely rare. We report a case of third ventricular cavernous malformation arising from the ventricle floor in a 24-year old woman who presented with short-term memory loss and disorientation. Computed tomography revealed a suprasellar mass with calcification in the posterior chiasmatic region. T2-weighted magnetic resonance imaging revealed a mass with heterogeneous intensity and without hydrocephalus. The mass was slightly enhanced subsequent to gadolinium infusion. Using a basal interhemispheric translamina terminalis approach and a neuroendoscope, we confirmed that the tumor was located at the floor of the third ventricle and removed it. Histopathological examination confirmed the diagnosis of cavernous malformation. The postoperative course was uneventful, but the patient's short-term memory loss persisted. Despite its rarity, cavernous malformation should be suspected when a tumor is detected in the vicinity of the third ventricle floor. It is treatable through surgical resection. PMID- 26652883 TI - Traumatic brain injury presenting with bilateral basal ganglia hemorrhage. AB - CONTEXT: Traumatic basal ganglia hemorrhage (TBGH) is a rare presentation of traumatic brain injury. Bilateral lesions are even rarer. Only twelve similar cases were previously published. CASE REPORT: We report the case of a patient with bilateral TBGH. He was managed conservatively. Long-term follow-up disclosed a cognitive dysfunctions attributed to associated diffuse axonal injury. Acceleration and deceleration forces may have torn pallidum arterial branches determining hemorrhage. CONCLUSION: Bilateral TBGH is an uncommon presentation of traumatic brain injury. Associated diffuse axonal injury worsens the outcome. PMID- 26652882 TI - Acute liver failure and liver transplantation in a patient with multiple sclerosis treated with interferon beta. AB - In the treatment of multiple sclerosis (MS), interferon beta (IFNbeta) applies. It rarely can lead to acute liver failure (ALF). A 42-year-old female with MS was admitted to the Department because of jaundice, general weakness, drowsiness and nausea. Four weeks earlier, she had started therapy with IFNbeta-1a. Liver tests made prior to initiation of IFNbeta-1a were normal but on admission to the Department exceed several times the upper limit. ALF was recognized and IFNbeta 1a was immediately stopped. In the fourth day of hospitalization, symptoms of hepatic encephalopathy have progressed. The patient was transferred to the Department of Transplantation, where hepatic coma developed and three days later the orthotopic liver transplantation was performed. In histopathological picture of the removed liver extensive necrosis and fibrosis dominated. Immunosuppressive therapy consisted of tacrolimus, mycophenolate mofetil and tapering prednisone. Within five years after surgery, there was no recurrence of symptoms of MS and the transplanted organ is functioning properly. ALF is a rare complication of IFNbeta therapy but it can occur. The appearance of symptoms suggestive of liver injury should prompt extension of diagnosis and, if necessary, discontinuation of therapy. PMID- 26652884 TI - A thoracic tuberculous spondylodisctis after intravesical BCG immunotherapy of bladder cancer - Case report and literature review. AB - We report a rare case of tuberculosis of the thoracic spine caused by Mycobacterium bovis infection as a complication of BCG (Bacillus Calmette-Guerin) intravesical immunotherapy, which is a well known and acknowledged treatment of superficial bladder cancers applied since 1976. Although this therapy is broadly used in urology and considered to be safe and well tolerated, one should be aware of the potential local and systemic side effects as in the case of our patient, who developed tuberculous spondylodiscitis after intravesical BCG therapy. PMID- 26652885 TI - Twiddler syndrome in a patient with tremor dominant Parkinson's disease. A case report and literature review. AB - Twiddler syndrome is described as a spontaneous rotation or intentional external manipulation of implanted cardiac or occasionally deep brain stimulation (DBS) devices. We report this hardware related complication in a patient with tremor dominant Parkinson's disease (PD), who underwent unilateral subthalamic nucleus (STN) DBS and subsequently developed twiddler syndrome. The clinical course of twiddler syndrome in this patient is described. Some surgical nuances which may prevent its occurrence are suggested. Our case report indicates that twiddler syndrome occurs in DBS patients. Impedance check of DBS hardware, plain chest X ray, or palpation for a knobbly extension lead through the skin above the IPG allows the correct diagnosis and subsequently a prompt surgical revision. Our subsequent literature review revealed only 10 patients with twiddler syndrome in DBS patient population worldwide. This number may suggest that this syndrome may be unrecognized or underreported, given the number of patients with movement disorders implanted with DBS hardware worldwide. PMID- 26652886 TI - Artistic activity from health through disease, then death in a patient with frontotemporal dementia. PMID- 26652887 TI - Point-of-care G6PD diagnostics for Plasmodium vivax malaria is a clinical and public health urgency. AB - Malaria caused by Plasmodium vivax threatens over 2 billion people globally and sickens tens of millions annually. Recent clinical evidence discredits the long held notion of this infection as intrinsically benign revealing an often threatening course associated with mortality. Most acute attacks by this species derive from latent forms in the human liver called hypnozoites. Radical cure for P. vivax malaria includes therapy aimed both at the acute attack (blood schizontocidal) and against future attacks (hypnozoitocidal). The only hypnozoitocide available is primaquine, a drug causing life-threatening acute hemolytic anemia in patients with the inherited blood disorder glucose-6 phosphate dehydrogenase (G6PD) deficiency. This disorder affects 400 million people worldwide, at an average prevalence of 8 % in malaria-endemic nations. In the absence of certain knowledge regarding the G6PD status of patients infected by P. vivax, providers must choose between the risk of harm caused by primaquine and that caused by the parasite by withholding therapy. Resolving this dilemma requires the availability of point-of-care G6PD diagnostics practical for use in the impoverished rural tropics where the vast majority of malaria patients seek care. PMID- 26652888 TI - THE RELATIONSHIP BETWEEN MENTAL TOUGHNESS, STRESS, AND BURNOUT AMONG ADOLESCENTS: A LONGITUDINAL STUDY WITH SWISS VOCATIONAL STUDENTS (.). AB - Past research has shown that higher stress is associated with increased burnout symptoms. The purpose of this study was to test whether mental toughness protects against symptoms of burnout and whether mental toughness moderates the relationship between perceived stress and burnout over time. Fifty-four vocational students (M age = 18.1 yr., SD = 1.2; 27 males, 27 females) completed self-report questionnaires twice, 10 mo. apart. Perceived stress, mental toughness, and burnout were measured using the Adolescent Stress Questionnaire (ASQ), the Mental Toughness Questionnaire (MTQ), and the Shirom-Melamed Burnout Measure (SMBM). Students who perceived higher stress and lower mental toughness scores reported higher burnout symptoms. Although no significant interaction effects were found between stress and mental toughness in the prediction of burnout, the graphical inspection of the interactions indicated that among students with high stress, those with high mental toughness remained below the cutoff for mild burnout, whereas an increase in burnout symptoms was observable among peers with low mental toughness. PMID- 26652889 TI - SUPERVISORS' TRANSFORMATIONAL LEADERSHIP AND BULLYING IN THE WORKPLACE. AB - The study tests the relationship between supervisors' transformational, transactional, and laissez-faire leadership and perceived bullying in the workplace. Transformational and transactional leaders can create conditions that make bullying at work less frequent but laissez-faire leadership may cause conflict that can result in bullying. The participants were 288 adults (122 women, 164 men; M age = 38.9 yr., SD = 11.7; M tenure = 7.2 yr.) employed across several organizations. Of the participants, 53.2% were contacted during an evening class in organizational behavior, and the others were workers from a waterproofing company. Scales measuring perceived leadership of a supervisor and perceived bullying at work were administered. Supervisor's transformational and transactional leadership were negatively related to work-related bullying, person related bullying, and physically intimidating bullying. Transactional leadership was also negatively related to Work-related bullying, perceived Person-related bullying, and perceived Physically intimidating bullying. Supervisor's laissez faire leadership was positively related to Work-related bullying, perceived Person-related bullying, and perceived Physically intimidating bullying. The use of Bass's model of transformational leadership in relation with the three-factor structure of the Negative Acts Questionnaire-Revised is unique in research on leadership and bullying. The relationship between laissez-faire leadership and leadership support results from previous studies: transactional or transformational leadership is likely to provide an environment that makes bullying more rare than under a negative or passive leadership. PMID- 26652891 TI - Asymptomatic, blue, dome-shaped lesion on buccal mucosa. AB - An asymptomatic, blue, dome-shaped lesion on the buccal mucosa can include a plethora of entities clinically as well as histopathologically. Its clinical presentation may mimic reactive, developmental, benign or malignant conditions. This emphasizes the need on histopathological assessment of every docile looking lesion to explore its exact biological behavior. PMID- 26652892 TI - Osteolipoma: a rare tumor in the oral cavity. AB - Osteolipoma is a rarely reported histologic variant of lipoma that exhibits bone formation. To the best of our knowledge, only 13 well-documented case reports of osteolipoma in the oral cavity have been published in the English literature. This study presents the clinical, radiographic, and histologic features of an osteolipoma in the oral cavity and reviews the pertinent literature. The patient was a 29-year-old female, who presented with an 8-month history of a painless, progressively enlarging, well-defined, movable submucosal mass in the left posterior buccal mucosa. The lesion had a hard consistency. Imaging findings revealed a spherical radiopacity with an irregular trabecular pattern. The lesion was excised and the diagnosis of osteolipoma was established. No recurrence was observed after a 5-year follow-up. PMID- 26652893 TI - Real-world dosing and drug costs with everolimus or axitinib as second targeted therapies for advanced renal cell carcinoma: a retrospective chart review in the US. AB - OBJECTIVE: To describe dosing patterns and to compare the drug costs per month spent in progression-free survival (PFS) among patients with advanced renal cell carcinoma (aRCC) treated with everolimus or axitinib following a first tyrosine kinase inhibitor (TKI). METHODS: A medical record retrospective review was conducted among medical oncologists and hematologists/oncologists in the US. Patient eligibility criteria included: (1) age >=18 years; (2) discontinuation of first TKI (sunitinib, sorafenib, or pazopanib) for medical reasons; (3) initiation of axitinib or everolimus as a second targeted therapy during February 2012-January 2013. Real-world dosing patterns were summarized. Dose-specific drug costs (as of October 2014) were based on wholesale acquisition costs from RED BOOK Online. PFS was compared between everolimus and axitinib using a multivariable Cox proportion hazards model. Everolimus and axitinib drug costs per month of PFS were compared using multivariable gamma regression models. RESULTS: A total of 325 patients received everolimus and 127 patients received axitinib as second targeted therapy. Higher proportions of patients treated with axitinib vs everolimus started on a higher than label-recommended starting dose (14% vs 2%) or experienced dose escalation (11% vs 1%) on second targeted therapy. The PFS did not differ significantly between patients receiving everolimus or axitinib (adjusted hazard ratio (HR) = 1.16; 95% confidence interval [CI] = 0.73-1.82). After baseline characteristics adjustment, axitinib was associated with 17% ($1830) higher drug costs per month of PFS compared to everolimus ($12,467 vs $10,637; p < 0.001). LIMITATIONS: Retrospective observational study design and only drug acquisition costs considered in drug costs estimates. CONCLUSIONS: Patients with aRCC receiving axitinib as second targeted therapy were more likely to initiate at a higher than label-recommended dose and were more likely to dose escalate than patients receiving everolimus. With similar observed durations of PFS, drug costs were significantly higher-by 17% per month of PFS-with axitinib than with everolimus. PMID- 26652894 TI - From initiating injecting drug use to regular injecting: Retrospective survival analysis of injecting progression within a sample of people who inject drugs regularly. AB - BACKGROUND: The initiation of injecting drug use and the commencement of a pattern of regular injecting are key milestones in injecting careers. The progression from initiation to regular injecting is a poorly understood period in these careers. METHODS: Cross-sectional baseline data from a sample of people who inject drugs regularly (N=691), recorded the age at which participants initiated injecting drug use and the age they became regular (at least once per month) injectors. Survival analysis compared the rapidity of progression to regular injecting across sub-groups within the sample using bivariate log-rank testing and multivariable Cox regression. RESULTS: Half of all participants progressed to regular injecting within 1 year of initiation and by the fourth year post initiation, 91% had progressed. In bivariate analysis, there were significant differences in equality of hazards by sex (X(2)=7.75, p<0.01), from whom participants learnt to inject (X(2)=22.32, p<0.01) and the drug of injection initiation (X(2)=18.36; p<0.01). In the multivariable Cox model, only initiating injecting with heroin (HR=1.28; 95% CI: 1.09-1.50) compared with other drugs (predominantly methamphetamine) showed a significantly greater hazard, suggesting a faster progression to regular injecting. CONCLUSION: This study showed that among our sample of eventual regular injectors, progression from initiation to regular injecting was rapid. By gaining a greater understanding of the dynamics of this progression, the ability to appropriately target interventions and future research is subsequently informed. PMID- 26652895 TI - Opioid antagonists block acetaldehyde-induced increments in dopamine neurons activity. AB - BACKGROUND: Acetaldehyde is the main metabolite of ethanol ingested through alcoholic beverages. Traditionally considered aversive is presently being viewed as an activating agent of the mesolimbic dopamine system but underlying mechanisms are only partially known. METHODS: Through in vivo electrophysiology experiments in rats we have studied the role of endogenous opioids in acetaldehyde-induced increments in dopamine activity. RESULTS: Here we show that acetaldehyde-induced increase in firing rate, burst firing and spikes/burst of antidromically-identified ventro-tegmental area nucleus accumbens-projecting neurons are abolished by pretreatment with the opiate unselective antagonist naltrexone (0.4 mg/kg/ip). Similar effects are obtained after administration of naloxone (0.1 mg/kg/iv). These results indicate that endogenous opiate system(s) participate in acetaldehyde-induced increments in dopaminergic neuronal activity. CONCLUSION: These data may explain the reduction in acetaldehyde-induced dopamine release in the nucleus accumbens after blockade of opiate receptors. Considering the paucity of efficacious therapies in alcoholism, and recent developments in ethanol-derived acetaldehyde effects, further experiments are warranted to further elucidate its role as a biomarker potentially useful to develop new strategies in the search for effective compounds aimed at reducing excessive alcohol intake, abuse and ultimately alcoholism. PMID- 26652896 TI - Prevalence, prescribed quantities, and trajectory of multiple prescriber episodes for benzodiazepines: A 2-year cohort study. AB - BACKGROUND: Little is known about the use of multiple prescribers for benzodiazepines, which might reflect fragmented patient care and increases the risk of hospital admission for drug dependence or poisoning. Therefore, we aimed to identify the prevalence, prescribed quantities, and trajectory of multiple prescriber episodes for benzodiazepines. METHODS: We conducted a 2-year cohort study of 1178,361 recipients aged 0-74 years using a large health insurance claims database in Japan. We quantified multiple prescriber episodes for benzodiazepines occurring in ambulatory care settings in a baseline and subsequent year by (1) counting the number of unique providers within a 12-month period, (2) calculating the maximum number of unique providers within a single month, and (3) identifying consecutive overlapping prescriptions of over 30 days duration. RESULTS: Among 58,314 patients with a benzodiazepine prescription during the baseline year, 282 (0.5%) filled prescriptions from four or more providers within a 12-month period, 439 (0.8%) filled prescriptions from three or more providers within a single month, and 757 (1.3%) filled consecutive overlapping prescriptions. The odds for multiple prescriber episodes were significantly higher among patients with multiple chronic conditions. Consecutive overlapping prescriptions had the best accuracy to detect patients with potentially questionable prescribed quantities as well as to predict those with multiple prescriber episodes in the subsequent year. CONCLUSIONS: These results highlight the need for pharmacists to increase their involvement in prescription oversight and for health insurance agencies to implement a prescription monitoring program to screen for patients with multiple prescriber episodes for benzodiazepines. PMID- 26652897 TI - Veni, vidi, vici: The appearance and dominance of new psychoactive substances among new participants at the largest needle exchange program in Hungary between 2006 and 2014. AB - BACKGROUND: There has been an almost exponential growth in the number of new psychoactive substances (NPS) on the drug markets in Europe during the past decade. While most users of NPS use them by routes other than injecting, percutaneous use of NPS is associated with very frequent injecting episodes and paraphernalia sharing. METHODS: We assessed to what extent new clients between 2006 and 2014 (N=3680) at Blue Point, Hungary's largest needle exchange program, exhibited a shift during these years in the drugs they primarily injected. RESULTS: Until 2010, 99% of clients injected either heroin or amphetamines. After 2010, however, there was a "replacement chain" of new substances, with one appearing and disappearing after the other: between 2010 and 2014, NPS under five names appeared and gained dominant prevalence (from 0% to 80%), and gradually replaced first the two "traditional" drugs amphetamine and heroin (which diminished to 17% together in 2014) and later each other. We also saw an increase in the proportion of female and older clients. CONCLUSIONS: While our findings are restricted to injected NPS, they suggest that NPS affect the vast majority of the population of people who inject drugs not only in terms of drug use patterns, but maybe also in terms of demographics. Given that over 80% of people who inject drugs use NPS and injecting NPS is associated with increased injecting risks, harm reduction services should be made more available to avoid an epidemic of blood-borne infections. PMID- 26652898 TI - Effect of traumatic event reexposure and PTSD on substance use disorder treatment response. AB - BACKGROUND: A remarkably high rate of traumatic event reexposure has been demonstrated in community-based substance users which negatively impacts their substance use disorder (SUD). The rate and effect of such reexposure in treatment is unknown. Despite increasing evidence that a diagnosis of posttraumatic stress disorder (PTSD) has little influence on long-term SUD treatment outcomes, it is possible that PTSD symptom fluctuations could have effects. METHODS: This prospective longitudinal study examined the rate and effect of traumatic event reexposure and PTSD symptoms in 169 male and female methadone maintenance patients with a comorbid psychiatric disorder who were participating in a parent study. Traumatic events and PTSD symptoms were tested for association with drug use, treatment interruption, and counseling adherence in the same month, one month later, and two months later. RESULTS: Approximately 18% of patients were reexposed to a traumatic event each month during the 12-month study. Reexposure was associated with about twice the risk of treatment interruption in the same month and one month later. Every 10% increase in PTSD symptom severity was associated with a 36% increased risk of treatment interruption two months later. No effects were seen on drug use or counseling adherence. CONCLUSIONS: SUD patients have a relatively high rate of traumatic event reexposure. Both traumatic events and PTSD symptoms are associated with increased risk of treatment interruption, resulting in SUD patients leaving treatment at precisely the time they could benefit from treatment support. PMID- 26652899 TI - Measures of outcome for stimulant trials: ACTTION recommendations and research agenda. AB - BACKGROUND: The development and approval of an efficacious pharmacotherapy for stimulant use disorders has been limited by the lack of a meaningful indicator of treatment success, other than sustained abstinence. METHODS: In March, 2015, a meeting sponsored by Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) was convened to discuss the current state of the evidence regarding meaningful outcome measures in clinical trials for stimulant use disorders. Attendees included members of academia, funding and regulatory agencies, pharmaceutical companies, and healthcare organizations. The goal was to establish a research agenda for the development of a meaningful outcome measure that may be used as an endpoint in clinical trials for stimulant use disorders. RESULTS AND CONCLUSIONS: Based on guidelines for the selection of clinical trial endpoints, the lessons learned from prior addiction clinical trials, and the process that led to identification of a meaningful indicator of treatment success for alcohol use disorders, several recommendations for future research were generated. These include a focus on the validation of patient reported outcome measures of functioning, the exploration of patterns of stimulant abstinence that may be associated with physical and/or psychosocial benefits, the role of urine testing for validating self-reported measures of stimulant abstinence, and the operational definitions for reduction based measures in terms of frequency rather than quantity of stimulant use. These recommendations may be useful for secondary analyses of clinical trial data, and in the design of future clinical trials that may help establish a meaningful indicator of treatment success. PMID- 26652901 TI - An up to 7-Year Retrospective Analysis of Biologic and Technical Complication With the All-on-4 Concept. AB - The aim of this study was to evaluate retrospectively biologic and technical complications as well as clinical and radiographic outcomes of patients treated with 4 implants according to the All-on-4 protocol and followed up to 7 years of function. Data from 56 consecutive patients presenting complete edentulous jaw, aged 18 years or older, treated between January 2008 and December 2013, were evaluated. The outcomes were implant and prosthetic survival and success rates, any complications, and marginal bone loss (MBL). Two-hundred twenty-four implants were placed in 56 patients. During the entire follow-up, 1 maxillary implant but no prosthesis failed during the healing process. Fourteen patients experienced 1 complication each (10 technical, 4 biologic). The overall implant and prosthetic success rate was 98.2% and 82.1%, respectively. All complications were considered as minor and successfully resolved chairside. A mean MBL of 1.30 +/- 0.63 mm was observed at the last follow-up. Statistically significant difference was found for postextractive implants (0.79 +/- 0.26) vs implants placed in healed sites (1.03 +/- 0.46; P = 0.024). Within the limits of the present study, the All-on-4 concept may be a valuable surgical and prosthetic option for the treatment of complete edentulous jaws. However, minor technical and biologic complications can occur. Further long-term prospective data with primary outcomes focused on success rates are needed. PMID- 26652900 TI - Exercise training - A beneficial intervention in the treatment of alcohol use disorders? AB - BACKGROUND: A growing body of evidence suggests that exercise training may have multiple beneficial effects in individuals with mental health or substance use disorders. Yet, relatively little knowledge exists regarding the benefits of exercise training to augment treatment for alcohol use disorders (AUDs). PURPOSE: The purpose of this narrative review is to present a summary of the growing body of published literature supporting exercise training as a treatment strategy for individuals with AUDs. We will provide evidence on the myriad of ways in which exercise may exert a positive effect on AUD outcomes including stress, anxiety, impulsivity, and depression. Further, we will explore how these mechanisms share common neurobiological pathways. The role of exercise in enhancing the social environment and increasing individual self-efficacy to reduce excess and/or inappropriate alcohol consumption will also be discussed. DISCUSSION: We will conclude with a description of completed investigations involving exercise training and provide suggestions for next steps in this innovative field of study. PMID- 26652902 TI - Differential Regulation of Progesterone Receptor-Mediated Transcription by CDK2 and DNA-PK. AB - Progesterone receptor (PR) function is altered by cell signaling, but the mechanisms of kinase-specific regulation are not well defined. To examine the role of cell signaling in the regulation of PR transcriptional activity, we have utilized a previously developed mammalian-based estrogen-response element promoter array cell model and automated cell imaging and analysis platform to visualize and quantify effects of specific kinases on different mechanistic steps of PR-mediated target gene activation. For these studies, we generated stable estrogen-response element array cell lines expressing inducible chimeric PR that contains a swap of the estrogen receptor-alpha DNA-binding domain for the DNA binding domain of PR. We have focused on 2 kinases important for steroid receptor activity: cyclin-dependent kinase 2 and DNA-dependent protein kinase. Treatment with either a Cdk1/2 inhibitor (NU6102) or a DNA-dependent protein kinase inhibitor (NU7441) decreased hormone-mediated chromatin decondensation and transcriptional activity. Further, we observed a quantitative reduction in the hormone-mediated recruitment of select coregulator proteins with NU6102 that is not observed with NU7441. In parallel, we determined the effect of kinase inhibition on hormone-mediated induction of primary and mature transcripts of endogenous genes in T47D breast cancer cells. Treatment with NU6102 was much more effective than NU7441, in inhibiting induction of PR target genes that exhibit a rapid increase in primary transcript expression in response to hormone. Taken together, these results indicate that the 2 kinases regulate PR transcriptional activity by distinct mechanisms. PMID- 26652903 TI - Sustained betaAR Stimulation Mediates Cardiac Insulin Resistance in a PKA Dependent Manner. AB - Insulin resistance is a condition in which cells are defective in response to the actions of insulin in tissue glucose uptake. Overstimulation of beta-adrenergic receptors (betaARs) leads to the development of heart failure and is associated with the pathogenesis of insulin resistance in the heart. However, the mechanisms by which sustained betaAR stimulation affects insulin resistance in the heart are incompletely understood. In this study, we demonstrate that sustained betaAR stimulation resulted in the inhibition of insulin-induced glucose uptake, and a reduction of insulin induced glucose transporter (GLUT)4 expression that were mediated by the beta2AR subtype in cardiomyocytes and heart tissue. Overstimulation of beta2AR inhibited the insulin-induced translocation of GLUT4 to the plasma membrane of cardiomyocytes. Additionally, betaAR mediated cardiac insulin resistance by reducing glucose uptake and GLUT4 expression via the cAMP dependent and protein kinase A-dependent pathways. Treatment with beta-blockers, including propranolol and metoprolol antagonized isoproterenol-mediated insulin resistance in the heart. The data in this present study confirm a critical role for protein kinase A in betaAR-mediated insulin resistance. PMID- 26652905 TI - Sensitive and Selective Ratiometric Fluorescence Probes for Detection of Intracellular Endogenous Monoamine Oxidase A. AB - Monoamine oxidase A (MAO-A) is known to widely exist in most cell lines in the body, and its dysfunction (unusually high or low levels of MAO-A) is thought to be responsible for several psychiatric and neurological disorders. Thus, a sensitive and selective method for evaluating the relative MAO-A levels in different live cells is urgently needed to better understand the function of MAO A, but to our knowledge such a method is still lacking. Herein, we rationally design two new ratiometric fluorescence probes (1 and 2) that can sensitively and selectively detect MAO-A. The probes are constructed by incorporating a recognition group of propylamine into the fluorescent skeleton of 1,8 naphthalimide, and the detection mechanism is based on amine oxidation and beta elimination to release the fluorophore (4-hydroxy-N-butyl-1,8-naphthalimide), which is verified by HPLC analysis. Reaction of the probes with MAO-A produces a remarkable fluorescence change from blue to green, and the ratio of fluorescence intensity at 550 and 454 nm is directly proportional to the concentration of MAO A in the ranges of 0.5-1.5 and 0.5-2.5 MUg/mL with detection limits of 1.1 and 10 ng/mL (k = 3) for probes 1 and 2, respectively. Surprisingly, these probes show strong fluorescence responses to MAO-A but almost none to MAO-B (one of two isoforms of MAO), indicating superior ability to distinguish MAO-A from MAO-B. The high specificity of the probes for MAO-A over MAO-B is further supported by different inhibitor experiments. Moreover, probe 1 displays higher sensitivity than probe 2 and is thus investigated to image the relative MAO-A levels in different live cells, such as HeLa and NIH-3T3 cells. It is found that the concentration of endogenous MAO-A in HeLa cells is approximately 1.8 times higher than that in NIH-3T3 cells, which is validated by the result from an ELISA kit. Additionally, the proposed probes may find more uses in the specific detection of MAO-A between the two isoforms of MAO, thereby promoting our understanding of the behavior and function of MAO-A in living biosystems. PMID- 26652904 TI - Differential effects of hormone therapy on serotonin, vascular function and mood in the KEEPS. AB - BACKGROUND: Serotonin (5-hydroxytryptamine, 5-HT) is modulated by sex steroid hormones and affects vascular function and mood. In the Kronos Early Estrogen Prevention Cognitive and Affective Ancillary Study (KEEPS-Cog), women randomized to oral conjugated equine estrogens (oCEE) showed greater benefit on affective mood states than women randomized to transdermal 17beta-estradiol (tE2) or placebo (PL). This study examined the effect of these treatments on the platelet content of 5-HT as a surrogate measure of 5-HT synthesis and uptake in the brain. METHODS: The following were measured in a subset (n = 79) of women enrolled in KEEPS-Cog: 5-HT by ELISA, carotid intima-medial thickness (CIMT) by ultrasound, endothelial function by reactive hyperemic index (RHI), and self-reported symptoms of affective mood states by the Profile of Mood States (POMS) questionnaire. RESULTS: Mean platelet content of 5-HT increased by 107.0%, 84.5% and 39.8%, in tE2, oCEE and PL groups, respectively. Platelet 5-HT positively correlated with estrone in the oCEE group and with 17beta- estradiol in the tE2 group. Platelet 5-HT showed a positive association with RHI, but not CIMT, in the PL and oCEE groups. Reduction in mood scores for depression-dejection and anger hostility was associated with elevations in platelet 5-HT only in the oCEE group (r = -0.5, p = 0.02). CONCLUSIONS: Effects of oCEE compared to tE2 on RHI and mood may be related to mechanisms involving platelet, and perhaps neuronal, uptake and release of 5-HT and reflect conversion of estrone to bioavailable 17beta-estradiol in platelets and the brain. PMID- 26652906 TI - Covalency-Dependent Vibrational Dynamics in Two-Dimensional Titanium Carbides. AB - Structure and vibrational dynamics of T-terminated titanium carbide monosheets Ti2CT2 (T = O, F, OH) are studied by means of first-principles calculations to understand their inherent relation. Terminations modulate the crystal structures through the redistribution of valence electron density among the atoms in the monosheets, particularly Ti atoms. Phonon partial density of states analysis shows a clear feature of collaborative vibration, which reflects the covalent nature of bonds in the monosheets. Two metrics of covalency and cophonicity proposed very recently are adopted to quantitatively correlate the vibrational properties with the electrostructural characteristics of the system. A remarkable positive correlation between the covalency and vibrational dynamics specified as Raman shifts and IR wavenumbers is found. The bond-specific covalency metrics depend on not only the identity of terminations but also the thickness of the two dimensional titanium carbides. For example, in the case of Ti3C2T2 with increased thickness, red shift in Raman shifts and IR wavenumbers occurs as a result of the decrease in covalency. PMID- 26652907 TI - Optimal therapy for resectable rectal cancer. AB - A lot can be gained by improving our understanding of the optimal sequence of existing therapies in rectal cancer, with the more difficult task of balancing the morbidity of recurrence with the morbidity of prescribed therapies that are particularly toxic owing to tumour location. This review aims to highlight a recent shift in treatment strategies in the opposite direction, with a focus on earlier, more intense systemic treatments with reduced local therapies. Understanding the rationale for and evidence to support this shift will help identify gaps, shape future trials, and ultimately answer the question of whether this is indeed the right path to follow with regards to maintaining local control rates and long-term outcomes for patients, and improving distal disease control and local treatment-related morbidities without compromising quality of life. PMID- 26652908 TI - Risk of lymphoid neoplasms in a Swedish population-based cohort of 337,437 patients undergoing appendectomy. AB - OBJECTIVE: Appendectomy remains one of the most common surgical procedures, but possible long-term consequences for health and disease are incompletely investigated. The appendix forms part of the secondary lymphoid system and appendectomy has been associated with increased risks of hematolymphoproliferative malignancies in some studies. MATERIALS AND METHODS: We examined the risk of lymphoid neoplasms in a large cohort of 337,437 appendectomised patients <60 years of age in Sweden 1975-2009. We estimated relative risks of non-Hodgkin lymphoma (NHL) and major subtypes, Hodgkin lymphoma (HL), chronic lymphocytic leukaemia (CLL), myeloma, and acute lymphoblastic leukaemia (ALL) versus the general population using standardised incidence ratios (SIRs) with 95% confidence intervals (CIs). RESULTS: There was no increased risk of NHL (SIR = 0.97, 95%CI 0.88-1.06), major NHL subtypes, CLL (SIR = 0.87, 95%CI 0.70-1.06), myeloma (SIR = 1.14, 95%CI 0.96-1.33) or ALL (SIR = 1.10, 95%CI 0.80 1.47) following appendectomy. An increased risk of HL was observed among patients diagnosed with appendicitis (SIR = 1.29, 95%CI 1.07-1.54, p=0.007), especially individuals aged <20 years at surgery (SIR = 1.43, 95%CI 1.11-1.82), and for the nodular sclerosis subtype of HL (SIR = 1.55, 95%CI 1.01-2.27). A marginally increased risk of myeloma was noted among men, but the association was limited to the first few years of follow-up. CONCLUSION: Appendectomy is not associated with any notable increase in risk of lymphoid neoplasms. A small increased risk of HL following appendicitis (rather than appendectomy per se) could reflect a true association, or shared susceptibility to infection/inflammation among individuals prone to develop HL. The association observed for myeloma may be explained by chance or surveillance bias. PMID- 26652909 TI - Mitotic phosphatase activity is required for MCC maintenance during the spindle checkpoint. AB - The spindle checkpoint prevents activation of the anaphase-promoting complex (APC/C) until all chromosomes are correctly attached to the mitotic spindle. Early in mitosis, the mitotic checkpoint complex (MCC) inactivates the APC/C by binding the APC/C activating protein CDC20 until the chromosomes are properly aligned and attached to the mitotic spindle, at which point MCC disassembly releases CDC20 to activate the APC/C. Once the APC/C is activated, it targets cyclin B and securin for degradation, and the cell progresses into anaphase. While phosphorylation is known to drive many of the events during the checkpoint, the precise molecular mechanisms regulating spindle checkpoint maintenance and inactivation are still poorly understood. We sought to determine the role of mitotic phosphatases during the spindle checkpoint. To address this question, we treated spindle checkpoint-arrested cells with various phosphatase inhibitors and examined the effect on the MCC and APC/C activation. Using this approach we found that 2 phosphatase inhibitors, calyculin A and okadaic acid (1 MUM), caused MCC dissociation and APC/C activation leading to cyclin A and B degradation in spindle checkpoint-arrested cells. Although the cells were able to degrade cyclin B, they did not exit mitosis as evidenced by high levels of Cdk1 substrate phosphorylation and chromosome condensation. Our results provide the first evidence that phosphatases are essential for maintenance of the MCC during operation of the spindle checkpoint. PMID- 26652910 TI - Diaspora engagement of African migrant health workers - examples from five destination countries. AB - BACKGROUND: Migrant health workers fill care gaps in their destination countries, but they also actively engage in improving living conditions for people of their countries of origin through expatriate professional networks. This paper aims to explore the professional links that migrant health workers from sub-Saharan African countries living in five African and European destinations (Botswana, South Africa, Belgium, Austria, and the United Kingdom) have to their countries of origin. DESIGN: Qualitative interviews were conducted with migrant doctors, nurses, and midwives from sub-Saharan Africa (N=66). A qualitative content analysis of the material was performed using the software ATLAS.ti. RESULTS: Almost all migrant health workers have professional ties with their countries of origin supporting health, education, and social structures. They work with non governmental organizations, universities, or hospitals and travel back and forth between their destination country and country of origin. For a few respondents, professional engagement or even maintaining private contacts in their country of origin is difficult due to the political situation at home. CONCLUSIONS: The results show that African migrant health workers are actively engaged in improving living conditions not only for their family members but also for the population in general in their countries of origin. Our respondents are mediators and active networkers in a globalized and transnationally connected world. The research suggests that the governments of these countries of origin could strategically use their migrant health workforce for improving education and population health in sub-Saharan Africa. Destination countries should be reminded of their need to comply with the WHO Global Code of Practice for the international recruitment of health professionals. PMID- 26652911 TI - Direct Catalytic Asymmetric Mannich-Type Reaction of alpha- and beta-Fluorinated Amides. AB - The last two decades have witnessed the emergence of direct enolization protocols providing atom-economical and operationally simple methods to use enolates for stereoselective C-C bond-forming reactions, eliminating the inherent drawback of the preformation of enolates using stoichiometric amounts of reagents. In its infancy, direct enolization relied heavily on the intrinsic acidity of the latent enolates, and the reaction scope was limited to readily enolizable ketones and aldehydes. Recent advances in this field enabled the exploitation of carboxylic acid derivatives for direct enolization, offering expeditious access to synthetically versatile chiral building blocks. Despite the growing demand for enantioenriched fluorine-containing small molecules, alpha- and beta-fluorinated carbonyl compounds have been neglected in direct enolization chemistry because of the competing and dominating defluorination pathway. Herein we present a comprehensive study on direct and highly stereoselective Mannich-type reactions of alpha- and beta-fluorine-functionalized 7-azaindoline amides that rely on a soft Lewis acid/hard Bronsted base cooperative catalytic system to guarantee an efficient enolization while suppressing undesired defluorination. This protocol contributes to provide a series of fluorinated analogs of enantioenriched beta amino acids for medicinal chemistry. PMID- 26652912 TI - Tryptophan 415 Is Critical for the Cholesterol Transport Functions of Scavenger Receptor BI. AB - High density lipoproteins (HDL) are anti-atherogenic particles, primarily due to their role in the reverse cholesterol transport pathway whereby HDL delivers cholesteryl esters (CE) to the liver for excretion upon interaction with its receptor, scavenger receptor BI (SR-BI). We designed experiments to test the hypothesis that one or more of the eight highly conserved tryptophan (Trp; W) residues in SR-BI are critical for mediating function. We created a series of Trp to-phenylalanine (Phe, F) mutant receptors, as well as Trp-less SR-BI (DeltaW-SR BI), and assessed their ability to mediate cholesterol transport. Wild-type (WT) or mutant SR-BI receptors were transiently expressed in COS-7 cells, and cell surface expression was confirmed. Next, we showed that Trp-less- and W415F-SR-BI had significantly decreased abilities to bind HDL and promote selective uptake of HDL-CE, albeit with higher selective uptake efficiency as compared to WT-SR-BI. Interestingly, only Trp-less-, but not W415F-SR-BI, showed an impaired ability to mediate efflux of free cholesterol (FC). Furthermore, both W415F- and Trp-less-SR BI were unable to reorganize plasma membrane pools of FC based on lack of sensitivity to exogenous cholesterol oxidase. Restoration of Trp 415 into the Trp less-SR-BI background was unable to rescue Trp-less-SR-BI's impaired functions, suggesting that Trp 415 is critical, but not sufficient for full receptor function. Furthermore, with the exception of Trp 262, restoration of individual extracellular Trp residues, in combination with Trp 415, into the Trp-less-SR-BI background partially rescued SR-BI function, indicating that Trp 415 must be present in combination with other Trp residues for proper cholesterol transport functions. PMID- 26652913 TI - Status of portfolios in undergraduate medical education in the LCME accredited US medical school. AB - AIM: We sought to investigate the number of US medical schools utilizing portfolios, the format of portfolios, information technology (IT) innovations, purpose of portfolios and their ability to engage faculty and students. METHODS: A 21-question survey regarding portfolios was sent to the 141 LCME-accredited, US medical schools. The response rate was 50% (71/141); 47% of respondents (33/71) reported that their medical school used portfolios in some form. Of those, 7% reported the use of paper-based portfolios and 76% use electronic portfolios. Forty-five percent reported portfolio use for formative evaluation only; 48% for both formative and summative evaluation, and 3% for summative evaluation alone. RESULTS: Seventy-two percent developed a longitudinal, competency-based portfolio. The most common feature of portfolios was reflective writing (79%). Seventy-three percent allow access to the portfolio off-campus, 58% allow usage of tablets and mobile devices, and 9% involve social media within the portfolio. Eighty percent and 69% agreed that the portfolio engaged students and faculty, respectively. Ninety-seven percent reported that the portfolios used at their institution have room for improvement. CONCLUSION: While there is significant variation in the purpose and structure of portfolios in the medical schools surveyed, most schools using portfolios reported a high level of engagement with students and faculty. PMID- 26652914 TI - A Comprehensive Analysis of Connectivity and Aging Over the Adult Life Span. AB - Aging has been associated with decreased intra- and internetwork connectivity during rest and task. Recent work has shown the influential role of the salience network over the default mode network (DMN) and executive control network (ECN). This study comprehensively investigates age-related changes in intra- and internetwork connectivity and effective connectivity between the DMN, ECN, and salience network across the adult life span. Two hundred ten participants completed a working memory task, an inhibition task, and a resting-state functional magnetic resonance imaging scan. Networks were extracted using independent component analysis; then, regression analyses and t-tests between three age groups, 21-40 (younger), 41-60 (middle), and 61-80 (older), were conducted. Older age was associated with decreased intranetwork connectivity. Functional network connectivity analyses revealed older age was associated with increased internetwork connectivity between the salience network and the ECNs and DMNs. In both cases, the effects were more pronounced in the tasks compared to resting state. Granger causality analyses indicated the salience network was influenced by the DMN and ECN in all age groups during both tasks, but not rest. However, middle adults showed increased influence from the salience network to the right ECN compared to younger adults during the flanker task. Taking everything into account, these findings indicate the role of the salience network changes over the life span, which may have implications for the early detection of pathophysiology in older adults. PMID- 26652915 TI - Molecular Design of Squalene/Squalane Countertypes via the Controlled Oligomerization of Isoprene and Evaluation of Vaccine Adjuvant Applications. AB - The potential to replace shark-derived squalene in vaccine adjuvant applications with synthetic squalene/poly(isoprene) oligomers, synthesized by the controlled oligomerization of isoprene is demonstrated. Following on from our previous work regarding the synthesis of poly(isoprene) oligomers, we demonstrate the ability to tune the molecular weight of the synthetic poly(isoprene) material beyond that of natural squalene, while retaining a final backbone structure that contained a minimum of 75% of 1,4 addition product and an acceptable polydispersity. The synthesis was successfully scaled from the 2 g to the 40 g scale both in the bulk (i.e., solvent free) and with the aid of additional solvent by utilizing catalytic chain transfer polymerization (CCTP) as the control method, such that the target molecular weight, acceptable dispersity levels, and the desired level of 1,4 addition in the backbone structure and an acceptable yield (~60%) are achieved. Moreover, the stability and in vitro bioactivity of nanoemulsion adjuvant formulations manufactured with the synthetic poly(isoprene) material are evaluated in comparison to emulsions made with shark-derived squalene. Emulsions containing the synthetic poly(isoprene) achieved smaller particle size and equivalent or enhanced bioactivity (stimulation of cytokine production in human whole blood) compared to corresponding shark squalene emulsions. However, as opposed to the shark squalene-based emulsions, the poly(isoprene) emulsions demonstrated reduced long-term size stability and induced hemolysis at high concentrations. Finally, we demonstrate that the synthetic oligomeric poly(isoprene) material could successfully be hydrogenated such that >95% of the double bonds were successfully removed to give a representative poly(isoprene) derived squalane mimic. PMID- 26652916 TI - Reds are more important than greens: how UK supermarket shoppers use the different information on a traffic light nutrition label in a choice experiment. AB - BACKGROUND: Colour coded front-of-pack nutrition labelling ('traffic light labelling') has been recommended for use in the UK since 2006. The voluntary scheme is used by all the major retailers and some manufacturers. It is not clear how consumers use these labels to make a single decision about the relative healthiness of foods. Our research questions were: Which of the four nutrients on UK traffic light labels (total fat, saturated fat, sugar and salt) has the most influence on decisions? Do green lights or red lights have a greater influence? Are there age and gender differences in how people use the colour and nutrient information? METHODS: We recruited participants from a UK supermarket chain membership list to conduct an online choice experiment in May 2014. We analysed data using multilevel logisitic models with food choices (n = 3321) nested in individuals (n = 187) as the unit of analysis. RESULTS: A food with more reds was 11.4 (95% confidence intervals: 10.3, 12.5) times less likely to be chosen as healthy, whereas a food with more greens was 6.1 (5.6, 6.6) times more likely to be chosen as healthy. Foods with better colours on saturated fat and salt were 7.3 (6.7, 8.0) and 7.1 (6.5, 7.8) times more likely to be chosen as healthy - significantly greater than for total fat (odds ratio 4.8 (4.4, 5.3)) and sugar (5.2 (4.7, 5.6)). Results were broadly similar for different genders and age groups. CONCLUSIONS: We found that participants were more concerned with avoiding reds than choosing greens, and that saturated fat and salt had a greater influence on decisions regarding healthiness than total fat and sugar. This could influence decisions about food reformulation and guidance on using nutrition labelling. PMID- 26652917 TI - Cardiovascular risk factors awareness and prevalence among primary care physicians: an insight from the West region Awareness Initiative Survey to fight cardiovascular disease (WAIT-CVD) in Cameroon. AB - BACKGROUND: Data on the frequency and awareness of cardiovascular risk factors in practicing doctors are lacking in Cameroon. This study reports on the prevalence of cardiovascular risk factors in primary care physicians (PCPs) at the forefront for the fight against chronic diseases, and the implications for cardiovascular disease prevention and management. METHODS: We carried out a cross-sectional study in the west region of Cameroon. Participants were recruited from 111 PCPs who lived and worked in the region at the time of the study. Data were collected on designed questionnaires adapted from the WHO STEPS approach in two steps, and a nurse-led examination was performed. RESULTS: Sixty five (65) consenting doctors, aged 39.1 (SD 8.9) years, with 45 (69.2 %) males, were included. Self reported hypertension rate was 4.6 % (n = 3). The frequency of pre-hypertension was 21.5 % (n = 14) and of hypertension was 26.2 % (n = 17). Self-reported diabetes rate was 3.1 % (n = 2). The frequency of overweight was 46.2 % (n = 30), and obesity was 23.1 % (n = 15). Eight (12.3 %) participants were smokers, 25 (38.5 %) had excessive alcohol consumption (more than two drinks per day for men and one drink per day for women) and 54 (83.1 %) practiced physical exercise, although below the recommendations. Positive family history any CVD was reported in 52.4 % (39.4-65.1). Up to 35.4 % (23.9-48.2) have never done their lipid profile test. There was no difference in cardiovascular risk factors between males and females, except for systolic blood pressure (p < 0.001) and diastolic blood pressure (p = 0.002) that were higher in males. No significant difference was noted in the other risk profiles and the rate of awareness between sexes. CONCLUSION: There are high prevalence of cardiovascular risk factors with low awareness among PCPs in the West region of Cameroon. This is alarming as doctors at the fore front for the fight against cardiovascular diseases are not aware of their own risk profile. There is need for more awareness programs targeting doctors so as to prevent a sick population with sick doctors. PMID- 26652920 TI - Quantitative fetal fibronectin to predict spontaneous preterm birth: a review. AB - Spontaneous preterm birth (sPTB) is the leading cause of neonatal morbidity and mortality globally. Accurate prediction of sPTB would enable targeting of interventions such as admission to hospital, antenatal corticosteroids, magnesium sulphate and in utero transfer as well as guiding prophylactic treatment (e.g., cerclage or progesterone). Measurement of fetal fibronectin concentration in the cervicovaginal fluid is a known predictor of sPTB. Traditionally a positive/negative test (defined by a threshold of 50 ng/ml), recent work has demonstrated improved prediction when used as a quantitative test, whereby the concentration of fetal fibronectin is measured by an automated bedside reader. This review examines the evidence surrounding the use of quantitative fetal fibronectin in asymptomatic women at high risk of sPTB, as well as those with symptoms of threatened sPTB. PMID- 26652921 TI - Can posterior teeth of patients be translated buccally, and does bone form on the buccal surface in response? AB - OBJECTIVE: To produce buccal translation and determine whether buccal bone forms on the cortical surfaces. MATERIALS AND METHODS: Eleven patients requiring maxillary first premolar extractions participated in this prospective, randomized, split-mouth study. Pre- and posttreatment records included models, photographs, and small field of view CBCT images. One randomly chosen maxillary first premolar was moved buccally with 50 g of force applied approximately at the tooth's center of resistance. The other premolar served as the control. Forces were re-activated every 3 weeks for approximately 9 weeks, after which the teeth were held in place for 3 weeks. Pre- and posttreatment records were analyzed and superimposed to evaluate changes in the dental-alveolar complex. RESULTS: There was significant (P < .05) movement of the experimental premolar with minimal buccal tipping (2.2 degrees ). Changes in maximum bone height were bimodal, with 6 patients showing 0.42 mm and 5 patients showing 8.3 mm of vertical bone loss. Buccal bone thickness 3 mm apical to the CEJ decreased 0.63 mm. Direct measurements and CBCT superimpositions showed that buccal bone over the roots grew 0.46 mm and 0.51 mm, respectively. CONCLUSIONS: It is possible to produce buccal bodily tooth movement with only limited amounts of tipping. Such movements are capable of producing buccal bone apposition, but there are potential limitations. PMID- 26652918 TI - Cost-effectiveness analysis of human papillomavirus vaccination in South Africa accounting for human immunodeficiency virus prevalence. AB - BACKGROUND: This study aims at evaluating the cost-effectiveness of a 2-dose schedule human papillomavirus (HPV) vaccination programme of HPV and human immunodeficiency virus (HIV) naive 12-year-old girls, in addition to cervical cancer (CC) screening alone, in South Africa. The study aims to account for both the impact of the vaccine among girls who are HIV-positive (HIV+) as well as HIV negative (HIV-) population. METHODS: A previously published Markov cohort model was adapted to assess the impact and cost-effectiveness of a HPV vaccination programme in girls aged 12 years (N = 527 900) using the AS04-adjuvanted HPV 16/18 vaccine from a public payer perspective. Two subpopulations were considered: HIV- and HIV+ women. Each population followed the HPV natural history with different transition probabilities. Model input data were obtained from the literature, local databases and Delphi panel. Costs and outcomes were discounted at 5 %. Extensive sensitivity analyses were conducted to assess the robustness of the evaluation. RESULTS: Implementation of the AS04-adjuvanted HPV-16/18 vaccine in combination with current cytological screening in South African girls could prevent up to 8 869 CC cases and 5 436 CC deaths over the lifetime of a single cohort. Without discounting, this HPV vaccine is dominant over screening alone; with discounting, the incremental cost-effectiveness ratio is ZAR 81 978 (South African Rand) per quality-adjusted life years (QALY) gained. HPV vaccination can be considered cost-effective based on World Health Organization (WHO) recommended threshold (3 x gross domestic product/capita = ZAR 200 293). In a scenario with a hypothetical targeted vaccination in a HIV+ subpopulation alone, the modelled outcomes suggest that HPV vaccination is still cost-effective, although the incremental cost-effectiveness ratio increases to ZAR 102 479. Results were sensitive to discount rate, vaccine efficacy, HIV incidence and mortality rates, and HPV-related disease transition probabilities. CONCLUSIONS: The AS04 adjuvanted HPV-16/18 vaccine can be considered cost-effective in a South African context although the cost-effectiveness is expected to be lower in the HIV+ subpopulation than in the overall female population. With improved access to HIV treatment, the HIV mortality and incidence rates are likely to be reduced, which could improve cost-effectiveness of the vaccination programme in South Africa. PMID- 26652922 TI - Resting blood pressure reductions following isometric handgrip exercise training and the impact of age and sex: protocol for a systematic review. AB - BACKGROUND: The risk of developing cardiovascular disease is directly correlated to one's resting blood pressure (BP), age, and biological sex. Resting BP can be reduced using handgrip exercise training, but the impact of age and sex on the effectiveness of training is not well documented. METHODS/DESIGN: A systematic search of the literature will be conducted for all experimental studies (including randomized controlled trials and prospective experiments) that report the influence of isometric handgrip exercise training on resting systolic blood pressure. The databases Medline, Embase, Cochrane Reviews, Cumulative Index to Nursing and Allied Health Literature (CINAHL), SPORTDiscus, Web of Science, Allied and Complementary Medicine (AMED), PubMed, and Scopus will be searched until 1 December 2015. Screening of potential articles, data abstraction, and quality appraisal will be completed in duplicate independently. When necessary, corresponding authors will be contacted in order to facilitate the separation of pooled data into age and sex categories. Methodological quality will be determined using the Quality Assessment Framework developed by the Cochrane Collaboration and the Newcastle-Ottawa Quality Assessment Scale as appropriate. Any discrepancies will be resolved by a third author. Findings will be presented in accordance with the preferred reporting items for systematic reviews and meta analysis (PRISMA) guidelines. DISCUSSION: This systematic review will determine the overall effectiveness of handgrip exercise training in improving resting blood pressure. A novel, focused assessment will contrast effectiveness of handgrip training based on the age (younger 18-54 years, older >55 years) and the sex (men, women) of study participants. This information is essential to consolidate before moving forward with the development and implementation of handgrip exercise training programmes which are designed to best meet the needs of particular cohorts. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015019792. PMID- 26652923 TI - Pontibacter ummariensis sp. nov., isolated from a hexachlorocyclohexane contaminated soil. AB - A Gram-stain-negative, pinkish-red, rod-shaped bacterium designated strain NKM1T was isolated from soil samples contaminated with hexachlorocyclohexane isomers, collected from Ummari village, Lucknow, Uttar Pradesh, India. The strain was characterized by a polyphasic taxonomic approach. 16S rRNA gene sequence analysis showed that strain NKM1T clustered exclusively with members of the genus Pontibacter of the family Cytophagaceae, phylum Bacteroidetes. The 16S rRNA gene sequence similarity to type strains of the genus Pontibacter ranged from 96.7 to 93.8 %, with the highest sequence similarity found with Pontibacter odishensis JC130T (96.7 %). Cells of strain NKM1T were aerobic, non-flagellated and non motile. Strain NKM1T was catalase- and oxidase-positive but negative for nitrate reduction and hydrolysis of gelatin. The major fatty acids in strain NKM1T were anteiso-C15 : 0, iso-C15 : 0, C16 : 0, C18 : 1omega9c and summed feature 3 (C16 : 1omega7c and/or C16 : 1omega6c). The polar lipid profile of strain NKM1T showed the presence of phosphatidylethanolamine and unknown glycolipids as well as aminolipids. sym-Homospermidine was found to be the major polyamine and menaquinone 7 (MK-7) was the major respiratory quinone. The DNA G+C content of strain NKM1T was determined to be 58.6 mol%. Based on phenotypic, chemotaxonomic, physiological and biochemical evidence, it is proposed that isolate NKM1T represents a novel species that belongs to the genus Pontibacter, for which the name Pontibacter ummariensis sp. nov. is proposed. The type strain is NKM1T ( = DSM 100161T = KCTC 42944T = MCC 2777T). PMID- 26652924 TI - Biomimetic Water-Collecting Fabric with Light-Induced Superhydrophilic Bumps. AB - To develop an efficient water-collecting surface that integrates both fast water capturing and easy drainage properties is of high current interest for addressing global water issues. In this work, a superhydrophobic surface was fabricated on cotton fabric via manipulation of both the surface roughness and surface energy. This was followed by a subsequent spray coating of TiO2 nanosol that created light-induced superhydrophilic bumps with a unique raised structure as a result of the interfacial tension of the TiO2 nanosol sprayed on the superhydrophobic fiber surface. These raised TiO2 bumps induce both a wettability gradient and a shape gradient, synergistically accelerating water coalescence and water collection. The in-depth study revealed that the quantity and the distribution of the TiO2 had a significant impact on the final water collection efficiency. This inexpensive and facilely fabricated fabric biomimicks the desert beetle's back and spider silk, which are capable of fog harvesting without additional energy consumption. PMID- 26652925 TI - An Historical Examination of the Development of Emergency Medical Services Education in the US through Key Reports (1966-2014). AB - INTRODUCTION: The Emergency Medical Services (EMS) approach to emergency prehospital care in the United States (US) has global influence. As the 50-year anniversary of modern US EMS approaches, there is value in examining US EMS education development over this period. This report describes US EMS education milestones and identifies themes that provide context to readers outside the US. METHOD: As US EMS education is described mainly in publications of federal US EMS agencies and associations, a Google search and hand searching of documents identified publications in the public domain. MEDLINE and CINAHL Plus were searched for peer reviewed publications. Documents were reviewed using both a chronological and thematic approach. RESULTS: Seventy-eight documents and 685 articles were screened, the full texts of 175 were reviewed, and 41 were selected for full review. Four historical periods in US EMS education became apparent: EMS education development (1966-1980); EMS education consolidation and review (1981 1989); EMS education reflection and change (1990-1999); and EMS education for the future (2000-2014). Four major themes emerged: legislative authority, physician direction, quality, and development of the profession. CONCLUSION: Documents produced through broad interprofessional consultations, with support from federal and US EMS authorities, reflect the catalysts for US EMS education development. The current model of US EMS education provides a structure to enhance educational quality into the future. Implementation evaluation of this model would be a valuable addition to the US EMS literature. The themes emerging from this review assist the understanding of the characteristics of US EMS education. PMID- 26652926 TI - Lewis Acid Mediated Vinylogous Additions of Enol Nucleophiles into an alpha,beta Unsaturated Platinum Carbene. AB - A variety of substituted indoles and benzofurans are accessed via a platinum catalyzed annulation and vinylogous addition of enol nucleophiles. Several beta dicarbonyl compounds participate in the reaction, as do alpha-nitro and alpha cyano carbonyl species. Subjecting the indole products to acidic conditions results in the formation of fused heterocycles. PMID- 26652929 TI - Accuracy of software designed for automated localization of the inferior alveolar nerve canal on cone beam CT images. AB - OBJECTIVES: The aim of this study was to design and evaluate a new method for automated localization of the inferior alveolar nerve canal on CBCT images. METHODS: The proposed method is based on traversing both panoramic and cross sectional slices. For the panoramic slices, morphological skeletonization is imposed, and a modified Hough transform is used while traversing the cross sectional slices. A total of 40 CBCT images were randomly selected. Two experts twice located the inferior alveolar nerve canal during two examinations set 6 weeks apart. Agreement between experts was achieved, and the result of this manual technique was considered the gold standard for our study. The distances for the automated method and those determined using the gold standard method were calculated and recorded. The mean time required for the automated detection was also recorded. RESULTS: The average mean distance error from the baseline was 0.75 +/- 0.34 mm. In all, 86% of the detected points had a mean error of <1 mm compared with those determined by the manual gold standard method. CONCLUSIONS: The proposed method is far more accurate and faster than previous methods. It also provides more accuracy than human annotation within a shorter time. PMID- 26652930 TI - Characterization of the Amaranthus palmeri Physiological Response to Glyphosate in Susceptible and Resistant Populations. AB - The herbicide glyphosate inhibits the plant enzyme 5-enolpyruvylshikimate3 phosphate synthase (EPSPS) in the aromatic amino acid (AAA) biosynthetic pathway. The physiologies of an Amaranthus palmeri population exhibiting resistance to glyphosate by EPSPS gene amplification (NC-R) and a susceptible population (NC-S) were compared. The EPSPS copy number of NC-R plants was 47.5-fold the copy number of NC-S plants. Although the amounts of EPSPS protein and activity were higher in NC-R plants than in NC-S plants, the AAA concentrations were similar. The increases in total free amino acid and in AAA contents induced by glyphosate were more evident in NC-S plants. In both populations, the EPSPS protein increased after glyphosate exposure, suggesting regulation of gene expression. EPSPS activity seems tightly controlled in vivo. Carbohydrate accumulation and a slight induction of ethanol fermentation were detected in both populations. PMID- 26652931 TI - Personalized medicine: the enabling role of nanotechnology. PMID- 26652928 TI - Mesenchymal stem cells: potential for therapy and treatment of chronic non healing skin wounds. AB - Wound healing is a complex physiological process including overlapping phases (hemostatic/inflammatory, proliferating and remodeling phases). Every alteration in this mechanism might lead to pathological conditions of different medical relevance. Treatments for chronic non-healing wounds are expensive because reiterative treatments are needed. Regenerative medicine and in particular mesenchymal stem cells approach is emerging as new potential clinical application in wound healing. In the past decades, advance in the understanding of molecular mechanisms underlying wound healing process has led to extensive topical administration of growth factors as part of wound care. Currently, no definitive treatment is available and the research on optimal wound care depends upon the efficacy and cost-benefit of emerging therapies. Here we provide an overview on the novel approaches through stem cell therapy to improve cutaneous wound healing, with a focus on diabetic wounds and Systemic Sclerosis-associated ulcers, which are particularly challenging. Current and future treatment approaches are discussed with an emphasis on recent advances. PMID- 26652932 TI - Diabetic Retinopathy in Newly Diagnosed Subjects With Type 2 Diabetes Mellitus: Contribution of beta-Cell Function. AB - PURPOSE: The association of hyperglycemia and diabetic retinopathy (DR) in established type 2 diabetes mellitus (T2DM) subjects is well accepted. However, the association between beta-cell responsiveness and insulin sensitivity leading to fasting and postprandial hyperglycemia with DR in newly diagnosed treatment naive T2DM subjects remain unreported. METHODS: A total of 544 newly diagnosed treatment-naive T2DM subjects were screened for DR (digital photography) and underwent a standardized meal tolerance test. Serial plasma glucose and insulin levels were measured, and fasting (M0) and postprandial beta-cell responsiveness calculated Calculating Pancreatic Response Program along with homeostasis model assessment-beta cell function (HOMA-B) and HOMA-Insulin Sensitivity. A subgroup of 201 subjects also underwent a frequently sampled IV glucose tolerance test and the acute insulin response to glucose, insulin sensitivity, and glucose effectiveness (SG) estimated (MINMOD model). RESULTS: A total of 16.5% (90) subjects had DR at diagnosis. Subjects with DR had significantly reduced M0, HOMA B and SG leading to higher fasting and postprandial (2 hour) glucose and significantly lower fasting and postprandial (2 hour) insulin. Factors independently associated with DR in multivariate logistic regression analysis were M0, HOMA-B, and SG with fasting and postprandial (2 hour) glucose and insulin. There was no statistical difference in glycated hemoglobin, systolic blood pressure, acute insulin response to glucose, and insulin sensitivity between those with or without DR. PRINCIPAL CONCLUSIONS: In this cohort of newly diagnosed T2DM subjects, DR is associated with reduced beta-cell responsiveness, resulting from beta-cell failure rather than insulin resistance, leading to fasting and postprandial hyperglycemia and hypoinsulinemia. PMID- 26652933 TI - Epigenetic Mutation of the Succinate Dehydrogenase C Promoter in a Patient With Two Paragangliomas. AB - CONTEXT: Mutational inactivation of the succinate dehydrogenase (SDH) complex is a well-described cause of tumor development in pheochromocytomas/paragangliomas (PPGLs) and gastrointestinal stromal tumors (GISTs). Epigenetic inactivation of the SDHC gene is a more recently discovered phenomenon, which so far has only been described in GISTs and PPGLs from patients with Carney triad syndrome. CASE DESCRIPTION: A 33-year-old patient presented with two abdominal paragangliomas (PGLs) and an adrenocortical adenoma. Both PGLs showed high succinate:fumarate ratios indicative of SDHx mutations; however, no mutations in any of the known PPGL susceptibility genes were found in leucocyte or tumor DNA. We identified methylation of the SDHC promoter region in both PGLs, which coincided with decreased SDHC expression at mRNA and protein levels and a hypermethylated epigenomic signature (CpG island methylator phenotype). Low-level SDHC promoter methylation was also observed in the adenoma but not in normal adrenal tissue or blood, suggesting postzygotic somatic mosaicism for SDHC promoter methylation in the patient. CONCLUSIONS: This report provides evidence that SDHC promoter methylation can cause PGLs due to SDHC inactivation, emphasizing the importance of considering epigenetic changes and functional readouts in the genetic evaluation of patients not only with GISTs and Carney triad but also with PPGL. PMID- 26652934 TI - Salvage treatment for relapsed/refractory Hodgkin lymphoma: role of allografting, brentuximab vedotin and newer agents. AB - INTRODUCTION: Second-line, salvage chemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation (AUTO-SCT) is the standard of care for patients with relapsed/refractory (R/R) Hodgkin lymphoma (HL). Approximately 50% of patients relapse after AUTO-SCT and their prognosis is generally poor. Brentuximab Vedotin (BV) has demonstrated efficacy in this setting and allogeneic (ALLO)-SCT represents an option with curative potential in this subgroup of patients. AREAS COVERED: A systematic review has been conducted to explore the actual knowledge on ALLO-SCT, BV and newer agents in R/R HL. EXPERT OPINION: The introduction of BV in clinical practice has significantly improved the management of post-AUTO-SCT relapses and the drug can induce durable remissions in a subset of R/R HL. Allografting select patients has been used to improve clinical outcomes and recent case series have begun to explore BV as a potential 'bridge' to allo-SCT, even though the optimal timing of ALLO-SCT after BV response remains undetermined. However, reduced tumor burden at the time of ALLO-SCT is a key factor to decrease relapse risk. Based on the unique composition of the tumor, more recently new agents such as PD-1 inhibitors have been developed. The potential role of PD-1 inhibitors with ALLO-SCT remains to be explored. PMID- 26652935 TI - To Cry or Not to Cry? PMID- 26652936 TI - Letter to the Editor. PMID- 26652937 TI - Effect of Ligand Field Tuning on the SMM Behavior for Three Related Alkoxide Bridged Dysprosium Dimers. AB - The synthesis and characterization of three Dy2 compounds, [Dy2(HL1)2(NO3)4] (1), [Dy2(L2)2(NO3)4] (2), and [Dy2(HL3)2(NO3)4] (3), formed using related tripodal ligands with a central tertiary amine bearing picolyl and alkoxy arms, 2-[(2 hydroxy-ethyl)-pyridin-2-ylmethylamino]-ethanol (H2L1), 2-(bis-pyridin-2 ylmethylamino)-ethanol (HL2), and 2-(bis-pyridin-2-ylmethylamino)-propane-1,3 diol (H2L3), are reported. The compounds are rare examples of alkoxide-bridged {Dy2} complexes and display capped square antiprism coordination geometry around each Dy(III) ion. Changes in the ligand field environment around the Dy(III) ions brought about through variations in the ligand donors can be gauged from the magnetic properties, with compounds 1 and 2 showing antiparallel coupling between the Dy(III) ions and 3 showing parallel coupling. Furthermore, slow relaxation of the magnetization typical of SMM behavior could be observed for compounds 2 and 3, suggesting that small variations in the ligand field can have a significant influence on the slow relaxation processes responsible for SMM behavior of Dy(III)-based systems. PMID- 26652938 TI - The concept of resilience in OSH management: a review of approaches. AB - The concept of resilience has become very popular, especially in the 21st century. This concept is applicable to many fields, from mechanics to a broad range of social sciences. Resilience has even become part of the national and global policies of the USA, the United Nations and the European Commission. The concept of resilience has also been implemented in the area of safety and health based on the criticism of the traditional approach to occupational safety and health, which does not result in a satisfactory level of occupational safety. The concept of resilience was adopted to research occupational safety and health in different fields and thus with different approaches, such as via socio-technical studies, the psychological and behavioral aspects of organizational resilience and the link with research on individual or family resilience and its influence on work. PMID- 26652939 TI - Temperature-Dependent Adhesion of Graphene Suspended on a Trench. AB - Graphene deposited over a trench has been studied in the context of nanomechanical resonators, where experiments indicate adhesion of the graphene sheet to the trench boundary and sidewalls leads to self-tensioning; however, this adhesion is not well understood. We use molecular dynamics to simulate graphene deposited on a trench and study how adhesion to the sidewalls depends on substrate interaction, temperature, and curvature of the edge of the trench. Over the range of parameters we study, the depth at the center of the sheet is approximately linear in substrate interaction strength and temperature but not trench width, and we explain this using a one-dimensional model for the sheet configuration. PMID- 26652940 TI - Thermotriggered Catalyst-Free Modification of a Glass Surface with an Orthogonal Agent Possessing Nitrile N-Oxide and Masked Ketene Functions. AB - The thermotriggered modification of surfaces was performed under catalyst-free conditions using an orthogonal agent possessing both nitrile N-oxide and Meldrum's acid moieties. The nitrile N-oxide moiety of the orthogonal agent successfully underwent catalyst-free 1,3-dipolar cycloaddition to unsaturated bonds of glass surfaces to produce Meldrum's acid-functionalized surfaces. The subsequent thermal decomposition of Meldrum's acid moiety in the presence of nucleophiles afforded versatile nucleophile-modified surfaces (e.g., wet, waterproof, and photoactive surfaces). Surface characteristics were investigated with the water contact angle, time-of-flight secondary ion mass spectrometry (TOF SIMS), and X-ray photoelectron spectroscopy (XPS). In addition, the surface modification of silica nanoparticles using the orthogonal agent was also achieved to evaluate the density of the functional group concentration on the surface. PMID- 26652941 TI - Clinical management of HIV-associated hematologic malignancies. AB - HIV is associated with an excess risk for lymphoid malignancies. Although the risk of lymphoma has decreased in HIV-infected individuals in the era of effective combination antiretroviral therapy, it remains high. Treatment outcomes have improved due to improvements in HIV and cancer therapeutics for the common HIV-associated lymphomas. R-CHOP/R-EPOCH are the standard of care for HIV associated diffuse large B-cell lymphoma. HIV-infected patients with Burkitt lymphoma and good performance status should receive dose-intensive regimens. HIV infected patients with primary central nervous system lymphoma can respond favorably to high-dose methotrexate-based therapy. In many cases, treatment and expected outcomes for HIV-infected patients with either Hodgkin or non-Hodgkin's lymphomas are very similar to HIV-negative patients. There is currently no standard treatment for HIV-associated multicentric Castleman disease or primary effusion lymphoma. For those hematologic cancers in which transplantation is part of standard care, this modality should be considered an option in those with well controlled HIV infection. PMID- 26652942 TI - The design of multitarget ligands for chronic and neuropathic pain. AB - BACKGROUND: Monodrug therapy has been used with success to fight various pathologies. When one medicine fails, co-administration of two or more drugs at the same time may be successfully applied in the treatment of infections, hypertension, HIV and in many other fields. DISCUSSION: This approach has some weakness related to the pharmacokinetic of the two different substances administered, side effects, possible drug-drug interaction. Bivalent ligand approach would maintain the strength of the multidrug therapy (synergistic effect, lower doses, and little side effects) and overcome the weakness of a co administration. CONCLUSION: In this review we have described the state-of-the-art of the multitarget approach for the control of pain. Several approaches adopted by different research groups and future perspectives have been discussed. PMID- 26652956 TI - Temporary Abdominal Closure After Abdominal Aortic Aneurysm Repair: A Systematic Review of Contemporary Observational Studies. AB - OBJECTIVES: The aim of this paper was to review the literature on temporary abdominal closure (TAC) after abdominal aortic aneurysm (AAA) repair. METHODS: This was a systematic review of observational studies. A PubMed, EMBASE and Cochrane search from 2007 to July 2015 was performed combining the Medical Subject Headings "aortic aneurysm" and "temporary abdominal closure", "delayed abdominal closure", "open abdomen", "abdominal compartment syndrome", "negative pressure wound therapy", or "vacuum assisted wound closure". RESULTS: Seven original studies were found. The methods used for TAC were the vacuum pack system with (n = 1) or without (n = 2) mesh bridge, vacuum assisted wound closure (VAWC; n = 1) and the VAWC with mesh mediated fascial traction (VACM; n = 3). The number of patients included varied from four to 30. Three studies were exclusively after open repair, one after endovascular aneurysm repair, and three were mixed series. The frequency of ruptured AAA varied from 60% to 100%. The primary fascial closure rate varied from 79% to 100%. The median time to closure of the open abdomen was 10.5 and 17 days in two prospective studies with a fascial closure rate of 100% and 96%, respectively; the inclusion criterion was an anticipated open abdomen therapy time >=5 days using the VACM method. The graft infection rate was 0% in three studies. No patient with long-term open abdomen therapy with the VACM in the three studies was left with a planned ventral hernia. The in hospital survival rate varied from 46% to 80%. CONCLUSIONS: A high fascial closure rate without planned ventral hernia is possible to achieve with VACM, even after long-term open abdomen therapy. There are, however, few publications reporting specific results of open abdomen treatment after AAA repair, and there is a need for randomized controlled trials to determine the most efficient and safe TAC method during open abdomen treatment after AAA repair. PMID- 26652957 TI - Re: 'The Impact of Early Pelvic and Lower Limb Reperfusion and Attentive Peri operative Management on the Incidence of Spinal Cord Ischemia During Thoraco abdominal Aortic Aneurysm Endovascular Repair'. PMID- 26652959 TI - [Realistic possibilities of using data sources in quality assessment of care of patients with diabetes in the Czech Republic: National Diabetes Information System]. AB - Diabetes mellitus is a serious health and economic problem of our time. Therapy is primarily perceived as prevention of the late complications of diabetes. Most pharmacoeconomic analyses state that the cost associated with the therapy of diabetes mellitus is largely spent on the therapy of its complications. The project of the National Diabetes Information System is based on the essential principle of automated collection of data which is available in digital form in the Czech Republic and which describes the quality and quantity of the care provided for patients with diabetes mellitus and its results. Benefits of the posited National Diabetes Information System embrace minimizing of selective loss of data, a comprehensive view of epidemiology, therapy and its results, possibility of following trends, inclusion of costs related to hospitalization and social benefits. Risks involve correct interpretation and a possible system error. If we succeeded in implementing such system in the Czech Republic, it would be the first fully automatic information system on such a comprehensive scale worldwide. CONCLUSION: The data describing the incidence and prevalence of diabetes mellitus, therapy structure, direct healthcare costs and induced costs of social payments is in the largest part available in digital form. This creates a basis for the foundation of the National Diabetes Information System which will allow for continuous quality assessment of care for patients with diabetes mellitus, including the related pharmacoeconomic and social impacts. PMID- 26652958 TI - Measuring Biological Age via Metabonomics: The Metabolic Age Score. AB - Chronological age is one of the most important risk factors for adverse clinical outcome. Still, two individuals at the same chronological age could have different biological aging states, leading to different individual risk profiles. Capturing this individual variance could constitute an even more powerful predictor enhancing prediction in age-related morbidity. Applying a nonlinear regression technique, we constructed a metabonomic measurement for biological age, the metabolic age score, based on urine data measured via (1)H NMR spectroscopy. We validated the score in two large independent population-based samples by revealing its significant associations with chronological age and age related clinical phenotypes as well as its independent predictive value for survival over approximately 13 years of follow-up. Furthermore, the metabolic age score was prognostic for weight loss in a sample of individuals who underwent bariatric surgery. We conclude that the metabolic age score is an informative measurement of biological age with possible applications in personalized medicine. PMID- 26652960 TI - [The mortality of patients with diabetes mellitus using oral antidiabetic drugs in the Czech Republic decreased over the decade of 2003-2013 and came closer to the population average]. AB - INTRODUCTION: Every year official data is published which describes the care of patients with diabetes mellitus in the Czech Republic. An overall number of individuals with diabetes, the number of newly reported cases and the number of patient deaths is always specified. However this data does not allow us to identify the differences in mortality between the individual cohorts of diabetic patients in relation to therapy. GOAL: Comparison of the mortality development in the periods of 2002-2006 and 2010-2013 in a representative sample of the patient population with type 2 diabetes mellitus using oral antidiabetic drugs, kept in the database of the General Health Insurance Company of the Czech Republic (VZP) which provided health care coverage for 63% of Czech population in 2013. METHODOLOGY: A retrospective epidemiologic analysis. We identified all individuals in the VZP database who had a record of DM diagnosis (E10-E16 based on ICD 10) or who had any antidiabetic therapy prescribed (ATC group A10) in the periods of 2002-2008 and 2009-2013. We only selected those patients for the analysis who were treated with oral antidiabetic medicines (in the given year or the preceding years they had a record of treatment with at least one medicine from A10B group, while having no record of treatment with medicines from A10A group within both years). 237,665 individuals met the selected criteria in 2003 and 315,418 individuals in 2013. RESULTS: Mortality rates dropped for all age groups (from 2003-2013): for 50-59 year olds by 1.2%-0.7%; in 60-69 year olds by 2.6%-1.6%; for 70-79 year olds by 5.8%-3.5%. In 2013 mortality rates came close to the general population where for the same age groups they reached 0.6%, 1.5% and 3.4% respectively. When expressed in relative terms, the mortality among 50 59 year olds declined by 42% (Czechia by 25%), among 60-69 year olds by 39% (Czechia by 17%) and among 70-79 year olds by 40% (Czechia by 28%) from the year 2003. The decline in mortality among the patients with DM treated with oral antidiabetic medicines was greater in both absolute and relative terms in the period of 2003-2013 than among the general population in the Czech Republic. CONCLUSION: The analysis of mortality among the patients treated with oral antidiabetic medicines, registered in the VZP database, has shown a clearly favourable trend of mortality decline which is faster than among the general population. The fact that mortality among this cohort is getting closer to that among the general population of the corresponding age is a finding of critical importance. There is a justified expectation that mortality, with increasingly extensive utilization of the present therapeutic procedures, will continue to decrease. PMID- 26652961 TI - [Incidence of amputations among patients with diabetes mellitus in the Czech Republic from 2010 to 2014]. AB - INTRODUCTION: Information about the incidence of organ-affecting complications of diabetes, including the diabetic foot syndrome, can be obtained from the documents of the Institute of Health Information in the Czech Republic. GOAL: Assessment of the development of high amputations and minor surgical procedures on the lower limb from 2010 to 2014 in a representative sample of the population of patients with DM kept in the General Health Insurance Company of the Czech Republic database. METHODOLOGY: We identified all individuals in the VZP database who had a record of DM diagnosis (E10-E16 based on ICD 10) or any antidiabetic therapy prescribed (ATC group A10) in the period of 2010-2014. A set of patients who had an agent from A10 group prescribed at least once in the given year was extracted for analysis. In the next step we identified individuals, who in the period of 2010-2014 also underwent a surgical procedure on the lower limb due to diabetic foot. RESULTS: An absolute number of lower limb amputations remains at a stationary level. CONCLUSION: The submitted analysis presents the first assessment of the development of surgical treatment of diabetic foot in the Czech Republic. The amount of surgical procedures on the diabetic foot remains stable, regarding both high amputations and lower limb minor surgical procedures. In the context of an absolute increase of patients treated for diabetes mellitus, the stationary state is an indication of a relative decrease, which is favourable in particular with regard to the amputation of long bones. PMID- 26652962 TI - [Analysis of the development of metformin and sulfonylurea prescriptions in the Czech Republic]. AB - INTRODUCTION: In the Czech Republic, patients with diabetes mellitus (DM) are followed and treated predominantly by specialists (approx. 80% at a specialist diabetology clinic), a minor part by general practitioners (up to 20%). Long-term development of the changes in prescribing metformin and sulfonylurea in the Czech Republic and its concordance with recommended procedures has not been evaluated until now. GOAL: Comparison of the development of metformin (MET) and sulfonylurea (SU) prescriptions in the period of 2002-2006 with that of 2010-2014 in a representative sample of the patient population with DM kept in the database of the General Health Insurance Company of the Czech Republic (VZP) which provided health care coverage for 63% of Czech Republic population in 2014. METHODOLOGY: We identified all individuals in the VZP database who had a record of DM diagnosis (E10-E16 based on ICD 10) or who had any antidiabetic therapy prescribed (ATC group A10) in the periods of 2002-2006 and 2010-2014. A cohort of patients was extracted for analysis, who had an agent from A10 group prescribed at least once in a relevant year (n=308,962 in 2002; n=426,695 in 2014). A number of patients was evaluated for each year, who had at least once MET or SU prescribed. The number of patients treated with MET or SU was then expressed as a percentage of all who had any therapy from A10 group prescribed in the year in question. RESULTS: Metformin prescriptions have linearly risen from 43% to 77%, while sulfonylurea prescriptions have linearly decreased from 65% to 37%. CONCLUSION: The analysis presents the first evaluation of the development of metformin prescriptions conducted in the Czech Republic and evaluation of its concordance with the recommended procedures for the treatment of DM. The amount of metformin prescribed in the Czech Republic increased from 43% to 77% while the amount of SU prescribed decreased from 65% to 37% between 2002 and 2014. This development and the current ratio between the prescribed amounts of MET and SU demonstrate the implementation of the recommended procedures into practice and prove the high quality of care for patients with DM2T in specialists- diabetologists surgeries. PMID- 26652963 TI - [Hypolipidemic and antihypertensive therapy in diabetic patients in the Czech Republic: notes on the VZP (General Health Insurance Company) Data]. AB - Diabetes mellitus and in particular type 2 diabetes mellitus is one of the most important risk factors of cardiovascular disease. To influence cardiovascular risk there is enormous important not only positive influence of glycemia, but also the treatment of diabetic dyslipidemia and hypertension. The present work provides an analysis of lipid-lowering and antihypertensive therapy for all diabetics registered with General Health Insurance Company in the period 2010 2013. In this time 866,570 patients with diabetes mellitus registered with General Health Insurance Company were treated, the majority of them were diabetics independent on insulin. Approximately half of the patients were observed by dialectologists and half of them by the doctors of other specialization. Out of antihypertensive medi-cation, patients were most often treated by drugs that affect the renin-angiotensin system, as well as beta blockers and diuretics. Prescription of the lipid-lowering therapy, especially prescription of statins, in accordance with the guidelines, is increasing, but remains insufficient (at 2013 43.6% diabetics treated by dialectologists and 51.3% diabetics treated by GP's didn't have lipid lowering therapy). Inadequate use of combination lipid-lowering therapy was recorded too, still represented mainly by combination of statin and fibrate, but in coming years we expect (based on the positive results of the subanalysis IMPROVE-IT study), an increase of combination therapy statin and ezetimibe. PMID- 26652964 TI - [Monitoring of diabetes compensation in patients treated with an insulin pump in the Czech Republic]. AB - INTRODUCTION: Insulin pump treatment (IP) is one of the ways of intensive insulin therapy, designed preferentially for patients with type 1 diabetes. The price of the treatment is higher than that of the conventional basalbolus and insulin regimens using repeated insulin application with a dose selector. GOAL: Quality assessment of IP therapy monitoring in patients with DM in a representative sample of the patient population with DM kept in the database of the General Health Insurance Company of the Czech Republic (VZP) which provided health care coverage for 63% of Czech population in 2014. METHODOLOGY: We identified all individuals in the VZP database who had a record of DM diagnosis (E10-E16 based on ICD 10) or who had any antidiabetic therapy prescribed (ATC group A10) in the period of 2009-2013. Over the whole period of 2009-2014 there were overall n=4,002 unique patients with DM identified in the VZP data, who were treated with IP within the assessment period. Incidence for the year 2014 (the newly treated with an insulin pump): all patients who had IP recorded in 2014 while in the preceding period of 2009-2013 they had no record of IP use. Prevalence for the year 2014 (all treated with an insulin pump): all the patients who for the period of 2010-2014 had at least once insulin pump use recorded and who did not die before 2014. Quality control parameters (HbA1c examination and consumption of glucose level test strips) for patients treated with IP were only assessed in detail for the year 2014, namely for all patients undergoing insulin pump treatment in 2014 throughout the year (i.e. from 1 January 2014 to 31 December 2014), i.e. in n=3,189 patients in all. RESULTS: In 2014 there were 247 incident patients and 3 794 prevalent patients. IP was newly introduced for almost 50% of the patients aged 20-39 years. In 2014 an average frequency of HbA1c examination equaled 3.38 per patient and 98.5% patients were examined for HbA1c at least once. An average consumption of glucose level testing strips per patient was 879 pieces. CONCLUSION: The pilot project of assessment of quality parameters for IP therapy monitoring shows that the patients treated with IP have glycated hemoglobin checked quite frequently (3.38 checkups per patient in 2014) and they measure their blood glucose 2-3 times a day on average. PMID- 26652965 TI - [The PROROK project results after 6 months of intervention (Prospective observation project focusing on the relevance of the difference between fasting blood glucose levels and postprandial blood glucose for estimation of success of type 2 diabetes therapy)]. AB - INTRODUCTION: The PROROK project (Prospective observation project focusing on the relevance of the difference between fasting and postprandial blood glucose levels for the estimation of success of type 2 diabetes therapy) had a character of non interventional, prospective, multicentric observation study lasting 6 months, whose goal was to quantify the relevance of the difference between fasting and postprandial blood glucose levels to the success of the treatment with GLP1 receptor agonists, resp. the treatment with basal, premixed insulin, or a combination of basal-bolus insulin. Physicians chose a therapy for patients with insufficiently compensated problems as they considered appropriate; 4,972 patients were included. GOAL: Evaluation of the intervention results for the patients included in the PROROK observation project with a focus on the choice of therapy by the treating diabetologist after 6 months of observation. RESULTS: An average improvement of the glycated hemoglobin values in the whole cohort reached 1.6%, the median of the resulting glycated hemoglobin reached 5.9% and 5.8% resp. (basal insulin). Statistically significant was the change in the median weight in the cohort treated with GLP-1 receptor agonists, from 105 kg to 100 kg; this did not significantly change in the other cohorts. The change of waist circumference over time in all patients and in the individual cohorts was consistent with the change of weight. The median change of fasting blood glucose levels in the whole cohort was -1.7 mmol/l after 3 months and -2.4 mmol/l (p<0.001) after 6 months. The greatest absolute decrease was recorded in the cohort treated with basal insulin (-2.8 mmol/l). The median change of postprandial blood glucose levels was -2.4 mmol/l after 3 months and -3.3 mmol/l (p<0.001) after 6 months. The greatest absolute decrease was recorded in the branch treated with a combination of prandial and basal insulin (-3.9 mmol/l). All differences p<0.001. CONCLUSION: The choice of therapy in the PROROK project is in agreement with the basic findings in pathophysiology of type 2 diabetes and with the options of an individually chosen targeted intervention involving antidiabetic therapy. The results of the six-month observation have proven the individual choice of therapy correct. In the cohort of diabetic patients differing at the beginning in weight, waist circumference, fasting blood glucose and the difference between fasting and postprandial glucose levels, an individually chosen therapy led to the same final result, while an absolute change in the followed parameters differed in the individual groups. PMID- 26652966 TI - [Clinical and economic benefits of the new antidiabetic drugs in the Czech Republic]. AB - GOAL: Description of efficiency, safety and cost-effectiveness of the therapy with new antidiabetics from the incretins group for the patients whose treatment with DPP4 inhibitors and GLP1 receptor agonists respectively, commenced based on the real data from the routine clinical practice in the Czech Republic. METHODOLOGY: Collection of clinical data before the commencement of treatment and in the following 12 months. The following data was collected for all patients: demographic data, time elapsed from diagnosis, body weight, BMI, HbA1c, systolic and diastolic blood pressure, total cholesterol, LDL-cholesterol, HDL-cholesterol and triglycerides. After that a pharmaco-economic model was analyzed which can predict long-term incidence of microvascular and macrovascular complications, life span and a quality-adjusted life-year (QALY) span of life. RESULTS: The data of 320 patients followed for 12 months was analyzed (255 treated with DPP4 inhibitors and 65 treated with GLP1 receptor agonists). The patients average age was 60.4/57.9 years and this innovative therapy was commenced for them after 9.1 years on average from their being diagnosed with diabetes. The initial glycated hemoglobin was higher (7.0%, or 7.6% HbA1c/IFCC). The previous therapy had been mainly based on metformin and on sulfonylurea derivatives. After 12 months of treatment statistically significant decreases were recorded in glycated hemoglobin (by 1.4% and 1.8% resp.), systolic blood pressure (by 4.7 mm Hg and 4.6 mm Hg resp.), diastolic blood pressure (by 1.8 mm Hg and 3.0 mm Hg resp.), LDL-cholesterol (by 0.3 mmol/l), triglycerides (by 0.4 mmol/l and 0.2 mmol/l resp.), body weight (by 1.6 kg and 4.5 kg resp.) and BMI (by 0.5 and 1.6 resp.). The pharmacoeconomic model predicted that the improvement of diabetes compensation in the group of DPP4 inhibitors would lead in one diabetic patient to life extension by 0.36 year and by 0.31 QALY, and in the group of GLP1 agonists by 0.45 year and by 0.39 QALY. CONCLUSION: The analysis has shown that the treatment based on modern antidiabetic medications in the conditions of the Czech Republic reduces the incidence of microvascular and macrovascular complications, extends the life span and the standard quality (QALY) life span and, due to the prevented complications, also reduces health insurance spending. PMID- 26652967 TI - [Towards a new challenge]. PMID- 26652968 TI - Small molecules enhance functional O-mannosylation of Alpha-dystroglycan. AB - Alpha-dystroglycan (alpha-DG), a highly glycosylated receptor for extracellular matrix proteins, plays a critical role in many biological processes. Hypoglycosylation of alpha-DG results in various types of muscular dystrophies and is also highly associated with progression of majority of cancers. Currently, there are no effective treatments for those devastating diseases. Enhancing functional O-mannosyl glycans (FOG) of alpha-DG on the cell surfaces is a potential approach to address this unmet challenge. Based on the hypothesis that the cells can up-regulate FOG of alpha-DG in response to certain chemical stimuli, we developed a cell-based high-throughput screening (HTS) platform for searching chemical enhancers of FOG of alpha-DG from a large chemical library with 364,168 compounds. Sequential validation of the hits from a primary screening campaign and chemical works led to identification of a cluster of compounds that positively modulate FOG of alpha-DG on various cell surfaces including patient-derived myoblasts. These compounds enhance FOG of alpha-DG by almost ten folds, which provide us powerful tools for O-mannosylation studies and potential starting points for the development of drug to treat dystroglycanopathy. PMID- 26652969 TI - Synthesis and antitumor activity evaluation of PI3K inhibitors containing 3 substituted quinazolin-4(3H)-one moiety. AB - In present study, a series of N-(2-methoxy-5-(3-substituted quinazolin-4(3H)-one 6-yl)-pyridin-3-yl)phenylsulfonamide were synthesized. Their antiproliferative activities in vitro were evaluated via MTT assay against HCT116 and MCF-7 cancer cell lines. The SAR of title compounds was discussed. The compounds (S)-C5 and (S)-C8 displayed potent inhibitory activity against PI3Ks and mTOR, especially against PI3Kalpha. In addition, compound (S)-C5 can efficaciously inhibit tumor growth in a mice S-180 model. These findings suggest that our designed compounds can serve as potent PI3K inhibitors and effective anticancer agents. PMID- 26652970 TI - Central retinal artery occlusion after phacoemulsification under peribulbar anaesthesia: Pathogenic hypothesis. AB - CLINICAL CASE: A 77-year-old patient had uneventful cataract surgery in the right eye under peribulbar anaesthesia. The next day, a severe and progressive eyelid swelling was noted, caused by an unknown allergic reaction to povidone-iodine. The allergic signs dissapeared by the fifth day, but amaurosis and a cherry-red spot were detected. Doppler ultrasound and CT angiography confirmed an 80% ipsilateral internal carotid artery stenosis. DISCUSSION: Retinal vascular occlusion after orbital loco-regional anaesthesia is rare. When this complication occurs, carotid disease, and local or systemic factors, should be evaluated. PMID- 26652971 TI - Identification of iridocorneal angle structures assessed by Fourier domain optical coherence tomography. AB - OBJECTIVE: To study the structures of the iridocorneal angle using anterior segment optical coherence tomography (OCT) defining their tomographic characteristics and quantifying their identification frequency. MATERIAL AND METHODS: A cross-sectional study was performed on 267 right eyes of 267 consecutive healthy patients. Fourier domain OCT RTVue (Optovue Inc, CA, EE. UU.) was used to examine the iridocorneal angle in the nasal and temporal sectors. The structures evaluated were: Sclerocorneal limbus, sclerocorneal transition, Schwalbe's line, trabecular meshwork, Schlemm's canal, scleral spur, and angular recess. Within and between agreements to identify structures were calculated using Cohen's kappa coefficient. RESULTS: The mean age was 41.3 +/- 14.3 years (range 20-80), with 57% being women. The sclerocorneal limbus, sclerocorneal transition, and Schwalbe's line were identified by 98.7, 97 and 93.4% of the images, respectively, with the trabecular meshwork and Schlemm's canal being identified in 91% of cases. The scleral spur could be identified in 85.4%, and the angular recess in 74.5%. There was no difference in the identification between the temporal and nasal sectors. Within and between agreement was k=0.92 and k=0.88, respectively, in the identification of the structures of the total images studied. CONCLUSIONS: Fourier domain OCT is a reliable technique for the identification of the structures of the iridocorneal angle, among which can be highlighted are, the trabecular meshwork, Schlemm's canal, scleral spur, and Schwalbe's line. PMID- 26652972 TI - A Panel of Protease-Responsive RNA Polymerases Respond to Biochemical Signals by Production of Defined RNA Outputs in Live Cells. AB - RNA is an attractive biomolecule for biosensing and engineering applications due to its information storage capacity and ability to drive gene expression or knockdown. However, methods to link chemical signals to the production of specific RNAs are lacking. Here, we develop protease-responsive RNA polymerases (PRs) as a strategy to encode multiple specific proteolytic events in defined sequences of RNA in live mammalian cells. This work demonstrates that RNAP-based molecular recording devices can be deployed for multimodal analyses of biochemical activities or to trigger gene circuits using measured signaling events. PMID- 26652973 TI - Comparative analysis of essential oil composition from flower and leaf of Magnolia kwangsiensis Figlar & Noot. AB - The essential oils from Magnolia kwangsiensis Figlar & Noot. were obtained using hydrodistillation, and analysed by GC and GC-MS. A total of 31, 27 and 26 constituents were identified in the oils from male flower, female flower and leaf of M. kwangsiensis, and they comprised 99.2, 98.5 and 96.2% of the oils, respectively. Monoterpene hydrocarbons predominated in the oils and accounted for 48.3% of male flower oil, 54.0% of female flower oil and 44.6% of leaf oil. The compositions of flower oils were quite similar but with different content, and were different from those of leaf oil. PMID- 26652974 TI - Red Blood Cell Spectrin Skeleton in the Spotlight. AB - Das et al. recently reported a role for the major merozoite surface protein MSP1 in malarial parasite egress from the red blood cell (RBC). On the basis of these new data and physical considerations, we propose an updated model for the main steps of this essential process for parasite proliferation. PMID- 26652975 TI - The challenges and limitations of widespread direct oral anticoagulant treatment: practical suggestions for their best use. AB - For many decades vitamin K antagonists (VKA), whilst extremely effective but associated with significant drawbacks, were the only drugs available for chronic anticoagulation. However, recently, novel direct oral anticoagulant drugs, completely different to VKA and at least as effective and safe as VKA, have been introduced in clinical practice and their use is becoming increasingly more widespread. Their availability can extend effective anticoagulant treatment to a larger number of subjects requiring anticoagulation and substantially improve the quality of life of many patients. However, these drugs and their use also have limitations. The aim of this article is to analyze these limitations and the challenges potentially associated with their use, a move crucial to promote proper, effective and safe use of the drugs in everyday practice. PMID- 26652976 TI - Analysis of survival adjusted for quality of life using the Q-TWiST function: Interface in R. AB - OBJECTIVE: The analysis of treatment effects in clinical trials usually focus on efficacy and safety in separate descriptive statistical analyses. The Q-TWiST (Quality adjusted Time Without Symptoms and Toxicity) method has been proposed by Gelber in the 90s to enable a statistical comparison between two groups with a graphical representation by incorporating benefit and risk into a single analysis. Although the method has been programmed in SAS, it is rarely used. The availability of the method in the freely software environment system like R would greatly enhanced the accessibility by researchers. The objective of this paper is to present a program for Q-TWiST analyses within R software environment. METHODS: The qtwist function was developed in order to estimate and compare Q-TWiST for two groups. Two individual patient data files are required used for input: one for visits and one for follow-up. Q-TWiST is obtained as a sum of time spent in three health states: period in toxicity (TOX), period without relapse and toxicity (TWiST) and period in relapse (REL), weighted by associated utility scores restricted to median overall survival for example. The bootstrap method is used for testing statistical significance. Threshold analysis and gain functions allow a group comparison for different utility values. RESULTS: Input data is checked for consistency. Descriptive statistics and mean durations for each health state are provided, allowing statistical comparisons. Graphical results are presented in a PDF file. The use of the function is illustrated with data from a simulated data set and a randomized clinical trial. CONCLUSIONS: qtwist is an easy to use R function, allowing a quality adjusted survival analysis with the Q-TWiST method. PMID- 26652977 TI - dfcomb: An R-package for phase I/II trials of drug combinations. AB - In this paper, we present the dfcomb R package for the implementation of a single prospective clinical trial or simulation studies of phase I combination trials in oncology. The aim is to present the features of the package and to illustrate how to use it in practice though different examples. The use of combination clinical trials is growing, but the implementation of existing model-based methods is complex, so this package should promote the use of innovative adaptive designs for early phases combination trials. PMID- 26652978 TI - Image-guided installation of 3D-printed patient-specific implant and its application in pelvic tumor resection and reconstruction surgery. AB - Nowadays, the diagnosis and treatment of pelvic sarcoma pose a major surgical challenge for reconstruction in orthopedics. With the development of manufacturing technology, the metal 3D-printed customized implants have brought revolution for the limb-salvage resection and reconstruction surgery. However, the tumor resection is not without risk and the precise implant placement is very difficult due to the anatomic intricacies of the pelvis. In this study, a surgical navigation system including the implant calibration algorithm has been developed, so that the surgical instruments and the 3D-printed customized implant can be tracked and rendered on the computer screen in real time, minimizing the risks and improving the precision of the surgery. Both the phantom experiment and the pilot clinical case study presented the feasibility of our computer-aided surgical navigation system. According to the accuracy evaluation experiment, the precision of customized implant installation can be improved three to five times (TRE: 0.75+/-0.18 mm) compared with the non-navigated implant installation after the guided osteotomy (TRE: 3.13+/-1.28 mm), which means it is sufficient to meet the clinical requirements of the pelvic reconstruction. However, more clinical trials will be conducted in the future work for the validation of the reliability and efficiency of our navigation system. PMID- 26652979 TI - Automatic 3D pulmonary nodule detection in CT images: A survey. AB - This work presents a systematic review of techniques for the 3D automatic detection of pulmonary nodules in computerized-tomography (CT) images. Its main goals are to analyze the latest technology being used for the development of computational diagnostic tools to assist in the acquisition, storage and, mainly, processing and analysis of the biomedical data. Also, this work identifies the progress made, so far, evaluates the challenges to be overcome and provides an analysis of future prospects. As far as the authors know, this is the first time that a review is devoted exclusively to automated 3D techniques for the detection of pulmonary nodules from lung CT images, which makes this work of noteworthy value. The research covered the published works in the Web of Science, PubMed, Science Direct and IEEEXplore up to December 2014. Each work found that referred to automated 3D segmentation of the lungs was individually analyzed to identify its objective, methodology and results. Based on the analysis of the selected works, several studies were seen to be useful for the construction of medical diagnostic aid tools. However, there are certain aspects that still require attention such as increasing algorithm sensitivity, reducing the number of false positives, improving and optimizing the algorithm detection of different kinds of nodules with different sizes and shapes and, finally, the ability to integrate with the Electronic Medical Record Systems and Picture Archiving and Communication Systems. Based on this analysis, we can say that further research is needed to develop current techniques and that new algorithms are needed to overcome the identified drawbacks. PMID- 26652980 TI - Resolving complex research data management issues in biomedical laboratories: Qualitative study of an industry-academia collaboration. AB - This paper describes a distributed collaborative effort between industry and academia to systematize data management in an academic biomedical laboratory. Heterogeneous and voluminous nature of research data created in biomedical laboratories make information management difficult and research unproductive. One such collaborative effort was evaluated over a period of four years using data collection methods including ethnographic observations, semi-structured interviews, web-based surveys, progress reports, conference call summaries, and face-to-face group discussions. Data were analyzed using qualitative methods of data analysis to (1) characterize specific problems faced by biomedical researchers with traditional information management practices, (2) identify intervention areas to introduce a new research information management system called Labmatrix, and finally to (3) evaluate and delineate important general collaboration (intervention) characteristics that can optimize outcomes of an implementation process in biomedical laboratories. Results emphasize the importance of end user perseverance, human-centric interoperability evaluation, and demonstration of return on investment of effort and time of laboratory members and industry personnel for success of implementation process. In addition, there is an intrinsic learning component associated with the implementation process of an information management system. Technology transfer experience in a complex environment such as the biomedical laboratory can be eased with use of information systems that support human and cognitive interoperability. Such informatics features can also contribute to successful collaboration and hopefully to scientific productivity. PMID- 26652981 TI - Erratum to: Efficient experimental design for uncertainty reduction in gene regulatory networks. PMID- 26652983 TI - [Expert recommendations on the clinical use of Lipoprotein-associated phospholipase A2]. PMID- 26652982 TI - Natural products and complementary therapies for chemotherapy-induced peripheral neuropathy: A systematic review. AB - Chemotherapy-induced peripheral neuropathy (CIPN) is a serious dose-limiting side effect without any FDA-approved treatment option. Prior reviews focus mostly on pharmacological interventions, but nonpharmaceutical interventions have also been evaluated. A Web of Science and PubMed database search to identify relevant RCTs from January 2005 to May 2015 included the terms: CIPN, cancer; and supplements, vitamin E, goshajinkigan, kampo, acetyl-L-carnitine, carnitine, alpha-lipoic acid, omega-3, glutamine, or glutamate; or massage, acupuncture, mind-body practice, yoga, meditation, Tai-Chi, physical activity, or exercise. Of 1465 publications screened, 12 RCTs evaluated natural products and one evaluated electroacupuncture. Vitamin E may help prevent CIPN. L-Glutamine, goshajinkigan, and omega-3 are also promising. Acetyl-L-carnitine may worsen CIPN and alpha lipoic acid activity is unknown. Electroacupuncture was not superior to placebo. No RCTs were published regarding other complementary therapies, although some studies mention positive incidental findings. Natural products and complementary therapies deserve further investigation, given the lack of effective CIPN interventions. PMID- 26652984 TI - [Safety of percutaneous coronary intervention in patients with acute coronary syndromes complicating chronic kidney disease]. AB - OBJECTIVE: To evaluate the safety of percutaneous coronary intervention (PCI) in patients with acute coronary syndromes (ACS) complicating chronic kidney disease (CKD). METHODS: We retrospectively evaluated the medical data of 335 patients hospitalized in our hospital with a diagnosis of ACS and CKD between 1 January 2011 and 30 May 2014. Patients were divided into two groups: PCI group who received PCI treatment during hospitalization (n = 135) and non-PCI group who did not receive PCI treatment (n = 200). Multivariable logistic regression analysis was performed to evaluate the connection between PCI and in-hospital death and acute renal insufficiency. RESULTS: The median GFR level of 335 patients was 36.26 (25.09-47.65) ml . min-1 . 1.73 m-2. GFR level was similar between the two groups (P = 0.205). Multivariable logistic regression analysis showed that PCI did not increase the risk of in-hospital death (OR = 0.465, 95% CI: 0.190-1.136, P = 0.093) and in-hospital acute renal insufficiency (OR = 0.830, 95% CI: 0.375 1.836, P = 0.669). In patients of 45 ml . min-1 . 1.73 m-2 <= GFR < 60 ml . min-1 . 1.73 m-2, 30 ml . min-1 . 1.73 m-2 <= GFR < 45 ml . min-1 . 1.73 m-2 and GFR < 30 ml . min-1 . 1.73 m-2, the OR of in-hospital death in PCI group were 0.235 (95% CI: 0.024-2.301, P = 0.213), 0.640 (95% CI: 0.112-3.649, P = 0.616) and 0.919 (95% CI: 0.159-5.307, P = 0.925), and the OR of in-hospital acute renal insufficiency were 0.436 (95% CI: 0.120-1.587, P = 0.208), 2.209 (95% CI: 0.394 12.391, P = 0.368) and 0.724 (95% CI: 0.127-4.117, P = 0.716) indicating that PCI did not increase above events in ACS patients complicating CKD. CONCLUSION: PCI does not increase the risk of in-hospital death and in-hospital acute renal insufficiency in ACS patients complicating CKD. PMID- 26652985 TI - [Value of fractional flow reserve measurement in endovascular therapy for patients with Stanford B type aortic dissection complicated with renal blood flow injury]. AB - OBJECTIVE: To analyze the value of fractional flow reserve (FFR) measurement on endovascular therapy for patients with renal artery stenosis. METHODS: Clinical data of 12 patients with Stanford B type aortic dissection complicated with renal blood flow injury in Anzhen hospital hospitalized from May 2013 to February 2014 were retrospectively analyzed. Renal artery angiography was performed and fractional flow reserve (FFR) was measured before Thoracic endovascular aortic repair. After operation, renal artery FFR was measured again, and renal artery stenting was performed in patients with FFR <= 0.90 or average pressure difference between proximal and distal of renal artery > 20 mmHg (1 mmHg = 0.133 kPa) and not applied for patients with FFR > 0.90.The patients were then subsequently followed up clinically. Kidney function were measured after 1 month, and contrast-enhanced ultrasonography data were obtained at 1 and 3 months later, respectively. RESULTS: The FFR of 1 patient was 0.90, while the FFR of other patients were less than 0.90 before thoracic endovascular aortic repair. After the procedure,the angiography showed that the blood flow of renal artery in 8 patients were fluency, and the FFR index was over 0.90. There were 4 patients with FFR less than 0.90. After renal artery stenting, the FFR of these 4 patients were all above 0.90. Compared with pre-procedure, blood urea nitrogen ((8.84 +/- 3.99) mmol/L vs. (5.18 +/- 1.69) mmol/L, P = 0.011) and uric acid ((359.3 +/- 77.3) umol/L vs. (276.9 +/- 108.3) umol/L, P = 0.008) decreased significantly after 1 month, and there was no significant difference in serum creatinine (P = 0.760). Contrast-enhanced ultrasonography results showed that blood flow of renal artery were fluency after 1 month and 3 months. CONCLUSION: In patients with aortic dissection complicating renal blood flow injury, the FFR measurement is meaningful in evaluating the blood flow status of target organs and guide the endovascular revascularization. PMID- 26652986 TI - [Survey on the early reperfusion therapy status in patients with ST-segment elevation myocardial infarction hospitalized in tertiary and secondary hospitals in Henan province]. AB - OBJECTIVE: To observe the early reperfusion therapy status for patients with ST elevation acute myocardial infarction (STEMI) hospitalized in tertiary and secondary hospitals in Henan province. METHODS: Baseline data, early reperfusion treatment and in-hospital mortality of STEMI patients hospitalized in 17 hospitals in Henan province (8 tertiary hospitals, 9 secondary hospitals) from June 2011 to June 2012 were obtained using a uniformed questionnaire. RESULTS: One thousand six hundred and eighty six patients were enrolled, of which 886 patients were hospitalized in tertiary hospitals and 880 patients were early hospitalized in secondary hospitals. Six hundred and fifty four patients (38.8%, 654/1 686) underwent early reperfusion therapy (543 with thrombolysis and 111 with primary percutaneous coronary intervention (PCI)). There was no difference in the proportion of early reperfusion therapy between tertiary and secondary hospitals (40.1% (355/886) vs. 37.4% (299/800), P = 0.257). The median time from symptom onset to first medical contact, door-to-needle and door-to-balloon was 132 min, 18 min and 60 min, respectively. The median time from symptom onset to first medical contact (150 min vs. 120 min, P = 0.001), door-to-needle (30 min vs. 18 min, P = 0.003) and symptom onset-to-thrombolysis (3.5 h vs. 2.7 h, P = 0.001) were significantly longer in tertiary hospitals than in secondary hospitals. No difference was found in median time of door-to-balloon, symptom onset-to-primary PCI or symptom onset-to-elected PCI between tertiary and secondary hospitals (all P > 0.05). The proportion of door-to-needle <= 30 min was lower in tertiary hospitals than in secondary hospitals (46.4% (84/181) vs. 62.2% (153/246), P = 0.001). However, there was no difference in the proportion of door-to-balloon <= 90 min between tertiary and secondary hospitals (58.8% (60/102) vs. 57.1% (4/7), P = 1.000). In-hospital mortality was also similar between tertiary and secondary hospitals (5.8% (51/886) vs. 5.5% (44/800), P = 0.820). CONCLUSIONS: Early reperfusion rate is low, and thrombolysis is the main early reperfusion therapy in both tertiary and secondary hospitals in Henan province. Tertiary hospitals did not take advantage of their primary PCI capability. There is great room for improvement in early reperfusion therapy in tertiary and secondary hospitals. PMID- 26652987 TI - [Efficacy comparison between 5 mg perindopril arginine salt and 4 mg perindopril tert-butylamine salt for patients with mild to moderate essential hypertension]. AB - OBJECTIVE: To compare the efficacy and safety of 5 mg perindopril arginine salt and 4 mg perindopril tert-butylamine salt for patients with mild to moderate essential hypertension. METHODS: The study was designed as multicenter, randomized, double-blind, active controlled trial with two parallel groups enrolling 524 participants with mild to moderate essential hypertension. After 2 week run-in period, 186 patients were enrolled and randomly treated with 5 mg perindopril arginine salt and 183 patients were enrolled and randomly treated with 4 mg perindopril tert-butylamine salt. The random sequence was generated by the I.R.I.S., and a balance was made in each center. After double-blind treatment for 8 weeks, the dose could be doubled for patients with uncontrolled BP ((SBP) >= 140 mmHg (1 mmHg = 0.133 kPa) or diastolic blood pressure (DBP) >= 90 mmHg) and patients were treated for another 4 weeks. RESULTS: The sitting SBP was similarly decreased by (19.9 +/- 17.2) mmHg in perindopril arginine group and (18.5 +/- 14.7) mmHg (P = 0.000 5) in perindopril tert-butylamine group post 8 weeks treatment. Dose was doubled in 109 patients (59.9%) in perindopril arginine group and 116 patients (63.7%) in perindopril tert-butylamine group. At 12 weeks post therapy, the sitting SBP decreased by (19.8 +/- 16.2) and (19.6 +/- 16.3) mmHg respectively in the 2 groups. The decrease of sitting DBP was also similar in both groups (-12.0 +/- 10.0) mmHg and (-11.0 +/- 8.9) mmHg (P < 0.000 1), respectively. The control rate or response rate was also similar between the two groups (control rate over 8 weeks was 38.5% vs. 31.3%, 95% CI (-2.6-16.9), control rate over 12 weeks was 36.3% vs. 35.7%, 95% CI (-9.3-10.4), response rate over 8 weeks was 64.3% vs. 63.2%, 95% CI (-8.8-11.0), response rate over 12 weeks was 65.9% vs. 64.8%, 95% CI (-8.7-10.9)). Incidence of adverse events was low and similar in both therapy groups. CONCLUSIONS: The results show that perindopril arginine salt 5 mg is as efficient as perindopril tert-butylamine 4 mg on lowering BP for patients with mild to moderate essential hypertension. Both drugs have good safety profile and are well tolerated by patients in this cohort. PMID- 26652988 TI - [Prevalence and prognostic value of hyponatremia on admission in hospitalized patients with heart failure]. AB - OBJECTIVE: To investigate the prevalence and prognostic value of hyponatremia on admission in hospitalized patients for heart failure (HF) from the first HF management center in China. METHODS: Consecutive adult (age of 18 years or older) symptomatic HF patients (NYHA functional class II-IV) admitted between March 2009 and March 2012 in our center were included in the present analysis. Hyponatremia was defined as a serum sodium level < 135 mmol/L. Association between hyponatremia on admission and in-hospital mortality as well as all-cause death and heart failure death during 1-year follow-up after discharge was analyzed. RESULTS: A total of 1 048 hospitalized patients for HF with complete baseline data were enrolled and the prevalence of hyponatremia on admission was 9.2% (96/1 048). Blood pressure was significantly lower while NYHA functional class and N terminal pro-B type natriuretic peptide levels were significantly higher in hyponatremic patients than non-hyponatremic patients (all P < 0.05). Kaplan-Meier survival analysis showed that patients with hyponatremia on admission had significant higher in-hospital mortality (P < 0.01), all-cause death rate (P < 0.01) and HF death rate (P < 0.01) during 1-year follow-up post discharge compared with non-hyponatremic patients with. Multiple Cox proportional hazard analysis showed that hyponatremia on admission remained as independent predictor for all-cause death (hazard risk (HR) = 2.105, 95% confidence interval (CI) 1.460 3.036, P < 0.01) and HF death (HR = 2.458, 95% CI: 1.704-3.545, P < 0.01) after adjustment for other covariates. CONCLUSION: Hyponatremia is relatively common in patients hospitalized with HF in China and hyponatremia on admission is associated with higher in-hospital mortality and all-cause death and HF death one year after discharge. PMID- 26652989 TI - [Clinical features and long-term outcome comparison of patients with midventricular obstructive hypertrophic cardiomyopathy and apical hypertrophic cardiomyopathy]. AB - OBJECTIVE: To compare the clinical features and long-term outcome of patients with midventricular obstructive hypertrophic cardiomyopathy (MVOHCM) and patients with apical hypertrophic cardiomyopathy (AHCM) in China. METHODS: This retrospective study analyzed clinical data of 66 patients with MVOHCM and 263 patients with AHCM from a consecutive single-center cohort consisting of 2 413 patients with HCM. The clinical features, cardiovascular mortality and morbidity were compared between the two groups. RESULTS: Compared with the AHCM, patients in the MVOHCM group was younger and more likely to be symptomatic over a mean follow-up of 7 years. The proportion of MVOHCM and AHCM were 2.7% (66/2 413) and 10.9% (263/2 413) (P < 0.001), respectively, in this cohort. Cardiovascular mortality of the two groups were 13.6% (9/66) and 0.8% (2/263) (P < 0.001), and cardiovascular morbidity of the two groups were 53.0% (35/66) and 14.4% (38/263) (P < 0.001). CONCLUSION: MVOHCM is rarer, but the clinical manifestations and long-term outcomes are worse compared with AHCM in this patient cohort. PMID- 26652990 TI - [Effects and mechanism of fibroblast growth factor 21 on rat vascular smooth muscle cells calcification]. AB - OBJECTIVE: To observe the effect and mechanism of fibroblast growth factor 21 (FGF21) on rat vascular smooth muscle cells (VSMCs) calcification in vitro. METHODS: VSMCs was treated with calcification medium containing calcium chloride and beta-glycerophosphate to induce rat VSMCs calcification in vitro. VSMCs were divided into 5 groups: the control group (cultured in normal medium), the calcification group (incubated in calcified medium), the FGF21 group (cultured in calcified medium and FGF21), the PD166866 group (cultured in calcified medium and FGF21 and PD166866, inhibitor of fibroblast growth factor receptor-1 (FGFR1)), the GW9662 group (cultured in calcified medium and FGF21 and GW9662, inhibitor of peroxisome proliferators activated receptor-gamma (PPAR-gamma)). The calcification of VSMCs was detected by calcium content, alkaline phosphatase activity and alizarin red staining. The protein and mRNA expression of FGFR1, beta-Klotho, osteocalcin and smooth muscle 22alpha (SM22alpha) were determined by western blot analysis and realtime-PCR, respectively. RESULTS: (1) The mRNA (P < 0.01) and protein expressions of beta-Klotho and FGFR1 were significantly downregulated in calcification group compared with control group (P < 0.05 or 0.01). (2) The protein levels and mRNA expression of calcium content, alkaline phosphatase activity and osteocalcin were significantly downregulated, while the protein levels and mRNA of SM22alpha were significantly increased in FGF21 group compared with calcification group (all P < 0.05). Moreover, alizarin red staining verified positive red nodules on calcified VSMCs was significantly reduced in FGF21 group than in calcification group. (3) Calcium content, alkaline phosphatase activity and alizarin red staining were similar between PD166866 group and calcification group (all P > 0.05). (4) Calcium content, alkaline phosphatase activity and alizarin red staining were similar between GW9662 group and calcification group (all P > 0.05). CONCLUSION: The inhibition of VSMCs calcification by FGF21 is mediated by further downregulating FGFR1 and beta Klotho while activating PPAR-gamma pathways. PMID- 26652991 TI - [CD137 signaling regulates the expression of nuclear factor of activated T cells c1 through miR-145a-5p in ApoE(-)/(-) mice]. AB - OBJECTIVE: To investigate if miR-145a-5p participates the modulation process of CD137 signaling on the expression of nuclear factor of activated T cells c1 (NFATc1) in ApoE(-)/(-) mice. METHODS: Atherosclerotic plaque model was produced by perivascular carotid collar placement in ApoE(-)/(-) mice. After surgery, the mice were randomly divided into the following groups: CD137 activated group (CD137 group, n = 6), CD137 inhibited group (anti-CD137 group, n = 6) and control group (n = 6). The mRNA expression of miR-145a-5p in plaque and cells was measured by real-time quantitative PCR (RT-PCR). Immunofluorescence was used to observe the distribution of NFATc1 in plaque and the expression of NFATc1 at mRNA and protein levels were detected by qRT-PCR, Western blot, respectively. The mouse vascular smooth muscle cells (VSMCs) were isolated and transfected with miR 145a-5p mimics or inhibitors by Lipofectamine. The eukaryotic expression vector and luciferase vector including p3xFLAG-NFATc1, p3xFLAG-NFATc1-3'UTR, psicheck2 NFATc1, psicheck2-NFATc1-Mut were constructed through molecular cloning and homologous recombination techniques, 293T cells were transfected with the miR 145a-5p mimics or inhibitors and the protein level and fluorescence intensity were then measured, respectively. RESULTS: In vivo or in vitro, the level of miR 145a-5p was significantly decreased (0.21 +/- 0.06 vs. 1.00 +/- 0.00, P < 0.05, 0.22 +/- 0.07 vs. 0.50 +/- 0.12, P < 0.05) while the opposite effects were observed in anti-CD137 group. NFATc1 expression was decreased or increased in VSMCs transfected with miR-145a-5p mimics or inhibitors, respectively (all P < 0.05). miR-145a-5p mimics decreased the expression of p3xFLAG-NFATc1-3'UTR and the fluorescence intensity (0.56 +/- 0.08 vs. 1.00 +/- 0.00, P < 0.05). CONCLUSION: CD137 signaling participates the regulation process on the expression of NFATc1 through miR-145a-5p in ApoE(-)/(-) mice. PMID- 26652992 TI - [Exercise preconditioning attenuates pressure overload-induced pathological cardiac hypertrophy: potential role of HSF1 and NF-kappaB p65 signaling]. AB - OBJECTIVE: To observe the effect of exercise preconditioning (EP) on pressure overload-induced pathological cardiac hypertrophy and explore related mechanisms. METHODS: Ten-week-old male Sprague-Dawley rats (n = 80) were randomly divided into four groups via random number table method: sham, TAC, EP + sham and EP + TAC. Two EP groups were subjected to 4 weeks of treadmill training, and followed by sham and TAC operations. Eight weeks after the surgery, mean arterial pressure (MAP), cardiac morphology, mRNA expressions of the B-type natriuretic peptide (BNP) and heat shock protein (HSP) 70 and protein expression of the BNP, heat shock transcription factor 1 (HSF1), HSP70, nuclear factor kappaB (NF-kappaB) p65, and interleukin-2 (IL-2) were examined. RESULTS: (1) Pathological cardiac hypertrophy index: eight weeks after TAC, MAP, heart size, HW/BW, cross-sectional area of the cardiomyocytes (CSA) and mRNA and protein expressions of BNP in the LV were all significantly higher in the TAC and EP + TAC groups than respective sham groups (all P < 0.05). HW/BW, CSA, and mRNA and protein expressions of BNP in the LV were significantly lower in EP + TAC group than in TAC group (all P < 0.05). (2) mRNA and protein expressions of HSF1 and HSP70 and nuclear HSF1 levels were significantly downregulated post TAC, however, EP treatment significantly increased the expression of HSF1 and nuclear HSF1 levels in TAC rats (all P < 0.05). (3) mRNA and protein expressions of NF-kappaB p65 and IL-2 were significantly increased in the TAC and EP + TAC groups compared with the respective sham groups (all P < 0.05), which were significantly downregulated in EP + TAC group compared to TAC group (all P < 0.05). CONCLUSIONS: EP could effectively reduce the cardiac hypertrophic responses induced by TAC possibly through upregulating the expressions of HSF1 and HSP70 and inhibiting the expression of NF-kappaB p65 and its nuclear translocation. PMID- 26652993 TI - [Reference value and clinical correlates of soluble ST2 in healthy community based Chinese population]. AB - OBJECTIVE: This study was designed to investigate the plasma level of soluble ST2 (sST2) and related influencing factors, and establish its reference value in the healthy community-based population in Beijing area of China. METHODS: We measured plasma sST2 level by enzyme-linked immunosorbent assay between March 2012 and August 2012 in 1 334 healthy subjects in communities, including 597 males and 737 females. Empiric and quantile regression methods were used to determine the reference range of plasma sST2. A multiple linear regression model was established to analyze the factors that might affect the level of plasma sST2. RESULTS: Gender is the most important factor affecting the plasma level of sST2 in healthy people. Plasma level of sST2 is significantly higher in men than in women (P < 0.01). Within each age strata, i.e. < 45, 45-54, 55-64, >= 65 years old, the plasma levels of sST2 were significantly higher in men than age-matched female (all P < 0.01). Age, body mass index (BMI), systolic blood pressure, diastolic blood pressure, and smoking did not affect plasma sST2 level. Reference range of sST2 was 5.7-53.5 ug/L for men and 4.4-42.4 ug/L for women (95% nonparametric reference interval). The one-side upper 95th percentile value of sST2 to discriminate the cardiovascular disease from healthy state was 47.2 ug/L for men and 37.2 ug/L for women. CONCLUSIONS: This study established the normal reference range of plasma sST2 in healthy community-based population. The major influencing factor of sST2 level in healthy population is gender. PMID- 26652994 TI - [One case of left atrial myxoma complicating retroperitoneal Castleman diseae]. PMID- 26652995 TI - [Cardiac and pulmonary function improvement post exercise in one heart transplant patient]. PMID- 26652996 TI - [One case of right atrium vascular endothelial sarcoma with lungs and skull]. PMID- 26652997 TI - [A case of cardiac amyloidosis misdiagnosed as hypertrophic cardiomyopathy]. PMID- 26652998 TI - [Surgical treatment of giant coronary artery aneurysm complicated by acute myocardial infarction: a case report]. PMID- 26652999 TI - [A case report on ultrasonic diagnosis of fetal hypertrophic cardiomyopathy complicating liver congestion]. PMID- 26653000 TI - [Rhabdomyolysis post Angong Niuhuang use: a case report]. PMID- 26653001 TI - [Experimental study progress in the pharmacotherapy of vascular restenosis]. PMID- 26653002 TI - [Dabigatran induced drug eruption: a case report]. PMID- 26653003 TI - [Research progress on the role of nuclear imaging technique in cardiac amyloidosis]. PMID- 26653004 TI - [Efficacy and safety of apixaban in the prevention and treatment of deep vein thrombosis and pulmonary embolism]. PMID- 26653005 TI - Novel inhibitors of the methicillin-resistant Staphylococcus aureus (MRSA) pyruvate kinase. AB - Novel bisindolyl-cycloalkane indoles resulted from the reaction of aliphatic dialdehydes and indole. As bisindolyl-natural alkaloid compounds have recently been reported as inhibitors of the methicillin-resistant Staphylococcus aureus (MRSA)-pyruvate kinase (PK), we tested our novel compounds as MRSA PK inhibitors and now report first inhibiting activities. We discuss structure-activity relationships of structurally varied compounds. Activity influencing substituents have been characterized and relations to antibacterial activities of the most active compounds have been proved. PMID- 26653007 TI - Gradual development of psoriatic skin lesions by constitutive low-level expression of IL-17A. AB - Psoriasis is a common chronic inflammatory skin disease restricted to humans. The understanding of its pathogenesis has long been hampered by the lack of suitable chronic mouse models. The cytokine IL-17A has emerged as a key player in epithelial immune responses and the defense against extracellular pathogens. Moreover, enhanced expression of IL-17A can turn pathologic and is closely associated with psoriasis. In this study, we generated a novel transgenic mouse model that recapitulates many characteristics of psoriasis. DC-IL-17Aind mice with constitutive low-level expression of IL-17A by CD11c+ cells gradually develop skin lesions during adult life. The lesions preferentially occur at sites of mechanical stress and exhibit macroscopic, histologic and genetic hallmarks of psoriatic plaques. Intriguingly, the age of disease onset depends on the levels of IL-17A and disruption of the epidermal barrier by tape-stripping triggers psoriatic plaque formation in the DC-IL-17Aind model. In summary, our results suggest that deregulated IL-17A together with epidermal trauma initiates skin inflammation and lesion formation in mice closely resembling plaque-type psoriasis. Due to the gradual development and chronic nature of disease, DC-IL 17Aind mice provide a unique tool to dissect the pathogenesis of human psoriasis and potentially could serve as a model to validate novel therapeutic strategies. PMID- 26653006 TI - Avidity of human T cell receptor engineered CD4(+) T cells drives T-helper differentiation fate. AB - The role of the T cell receptor (TCR) in antigen recognition and activation of T lymphocytes is well established. However, how the TCR affects T-helper differentiation/skewing is less well understood, particularly for human CD4(+) (CD4) T cell subsets. Here we investigate the role of TCR specific antigen avidity in differentiation and maintenance of human Th1, Th2 and Th17 subsets. Two human TCRs, both specific for the same peptide antigen but with different avidities, were cloned and expressed in human CD4 T cells. These TCR engineered cells were then stimulated with specific antigen in unskewed and T-helper skewed conditions. We show that TCR avidity can control the percentage of IL-4 and IFN gamma co-expression in unskewed TCR engineered cells, that effector function can be maintained in a TCR avidity-dependent manner in skewed TCR engineered cells, and that increased TCR avidity can accelerate Th1 skewing of TCR engineered cells. PMID- 26653008 TI - Manganese Oxide-Coated Carbon Nanotubes As Dual-Modality Lymph Mapping Agents for Photothermal Therapy of Tumor Metastasis. AB - Lymph node (LN) status is a major indicator of stage and survival of lung cancer patients. LN dissection is a primary option for lung cancer LN metastasis; however, this strategy elicits adverse effects and great trauma. Therefore, developing a minimally invasive technique to cure LN metastasis of lung cancer is desired. In this study, multiwalled carbon nanotubes (MWNTs) coated with manganese oxide (MnO) and polyethylene glycol (PEG) (namely MWNTs-MnO-PEG) was employed as a lymphatic theranostic agent to diagnose and treat metastatic LNs. After single local injection and lymph drainage were performed, regional LNs were clearly mapped by T1-weighted magnetic resonance (MR) of MnO and dark dye imaging of MWNTs. Meanwhile, metastatic LNs could be simultaneously ablated by near infrared (NIR) irradiation under the guidance of dual-modality mapping. The excellent result was obtained in mice bearing LNs metastasis models, showing that MWNTs-MnO-PEG as a multifunctional theranostic agent was competent for dual modality mapping guided photothermal therapy of metastatic LNs. PMID- 26653009 TI - The Predict-IV project: Towards predictive toxicology using in vitro techniques. PMID- 26653011 TI - Carbendazim exposure induces developmental, biochemical and behavioural disturbance in zebrafish embryos. AB - Carbendazim is a widely used broad spectrum benzimidazole fungicide; however, its effects to non-target aquatic organisms are poorly studied. The aim of this study was to investigate the toxic effects of carbendazim to zebrafish early life stages at several levels of biological organization, including developmental, biochemical and behavioural levels. The embryo assay was done following the OECD guideline 236 and using a concentration range between 1.1 and 1.8mg/L. Lethal and developmental endpoints such as hatching, edemas, malformations, heart beat rate, body growth and delays were assessed in a 96h exposure. A sub-teratogenic range (from 0.16 to 500MUg/L) was then used to assess effects at biochemical and behavioural levels. Biochemical markers included cholinesterase (ChE), glutathione-S-transferase (GST), lactate dehydrogenase (LDH) and catalase (CAT) and were assessed at 96h. The locomotor behaviour was assessed using an automated video tracking system at 120h. Carbendazim (96h-LC50 of 1.75mg/L) elicited several developmental anomalies in zebrafish embryos with EC50 values ranging from 0.85 to 1.6mg/L. ChE, GST and LDH activities were increased at concentrations equal or above 4MUg/L. The locomotor assay showed to be extremely sensitive, detecting effects in time that larvae spent swimming at concentrations of 0.16MUg/L and thus, being several orders of magnitude more sensitive that developmental parameters or lethality. These are ecological relevant concentrations and highlight the potential of behavioural endpoints as early warning signs for environmental stress. Further studies should focus on understanding how the behavioural disturbances measured in these types of studies translate into fitness impairment at the adult stage. PMID- 26653012 TI - [Sleepiness repercussion on gait and balance]. PMID- 26653013 TI - Understanding home delivery in a context of user fee reduction: a cross-sectional mixed methods study in rural Burkina Faso. AB - BACKGROUND: Several African countries have recently reduced/removed user fees for maternal care, producing considerable increases in the utilization of delivery services. Still, across settings, a conspicuous number of women continue to deliver at home. This study explores reasons for home delivery in rural Burkina Faso, where a successful user fee reduction policy is in place since 2007. METHODS: The study took place in the Nouna Health District and adopted a triangulation mixed methods design, combining quantitative and qualitative data collection and analysis methods. The quantitative component relied on use of data from the 2011 round of a panel household survey conducted on 1130 households. We collected data on utilization of delivery services from all women who had experienced a delivery in the previous twelve months and investigated factors associated with home delivery using multivariate logistic regression. The qualitative component relied on a series of open-ended interviews with 55 purposely selected households and 13 village leaders. We analyzed data using a mixture of inductive and deductive coding. RESULTS: Of the 420 women who reported a delivery, 47 (11 %) had delivered at home. Random effect multivariate logistic regression revealed a clear, albeit not significant trend for women from a lower socio-economic status and living outside an area to deliver at home. Distance to the health facility was found to be positively significantly associated with home delivery. Qualitative findings indicated that women and their households valued facility-based delivery above home delivery, suggesting that cultural factors do not shape the decision where to deliver. Qualitative findings confirmed that geographical access, defined in relation to the condition of the roads and the high transaction costs associated with travel, and the cost-sharing fees still applied at point of use represent two major barriers to access facility-based delivery. CONCLUSIONS: Findings suggest that the current policy in Burkina Faso, as similar policies in the region, should be expanded to remove fees at point of use completely and to incorporate benefits/solutions to support the transport of women in labor to the health facility in due time. PMID- 26653014 TI - Effectiveness of short message service-based intervention (SMS) on self-care in type 2 diabetes: A feasibility study. AB - AIM: The objective of the current study is to assess the effectiveness of Mobile Short Message Service (SMS) intervention on education of basic self-care skills in patients with type 2 diabetes. Moreover, we aimed to determine whether delivering individually-tailored educational messages can be more effective than general educational messages. METHODS: A total of 150 patients with diabetes type 2 were randomized into three groups: tailored SMS group, non-tailored SMS group, and the control group. Biochemical parameters including HbA1c, FBS, lipid profile were evaluated for the three groups at baseline and after 12 weeks. Moreover, self-care Inventory (SCI), Diabetes Management Self-Efficacy Scale (DMSES) and Diabetes Self-Care Barriers assessment scale for Older Adults (DSCB-OA) were completed. In the tailored SMS group, each person received 75% of their messages based on the top two barriers to adherence that they had experienced and reported in their scale. In the non-tailored SMS group, random messages were sent to every patient. RESULTS: After 12 weeks, although HgA1c levels did not significantly change, significant decline was observed in FBS and mean BMI in both intervention groups. Mean SCI-R scores significantly increased and mean DSCB and DMSES scores significantly decreased in both tailored and non-tailored SMS groups. In the control group, mean SCI-R scores decreased and mean DSCB and DMSES scores significantly increased (P<0.001). CONCLUSION: Sending short text messages as a method of education in conjunction with conventional diabetes treatment can improve glycemic control and positively influence other aspects of diabetes self care. According to our findings, sending SMS regularly in particular times appears to be as effective as sending individually tailored messages. PMID- 26653024 TI - Carcinoembryonic antigen-related cell adhesion molecule 1 is expressed and as a function histotype in ovarian tumors. AB - Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is a cell cell adhesion receptor and is implicated in several cellular functions. It is rarely reported in ovarian tumors. The aim of this study is to determine the expression of CEACAM1 in ovarian tumors, trying to see whether CEACAM1 has different expression patterns as a function of histotype. Antigen expression was examined by immunohistochemistry with mouse anti-human antibody for CEACAM1. Immunohistochemistry was performed using avidin-biotin-diaminobenzide staining. The results were expressed as average score +/- SD (0, negative; 8, highest) for each histotype. In ovarian tumors, the benign serous and mucinous cystadenoma negatively or weakly expressed CEACAM1, the malignant epithelial tumors strongly expressed CEACAM1, and there was significant difference between benign epithelial tumor and adenocarcinoma (P < .05). The well-differentiated serous adenocarcinoma expressed CEACAM1 mainly with membrane pattern, and the intermediately and poorly differentiated serous adenocarcinomas expressed CEACAM1 mainly with cytoplasmic pattern (P < .05). In addition, CEACAM1 expression is elevated in solid tumors of ovary but variable as a function of histotype. Compared with membranous expression, the cytoplasmic expression was observed almost in metastatic carcinoma that might decrease the adhesive interactions of the carcinoma cells with the surrounding cells, especially with tumor cells, and this could facilitate the tumor cells to metastasize to distant regions. So, we thought that cytoplasmic CEACAM1 might play an important role in tumor progression, especially in tumor metastasis. PMID- 26653025 TI - Understanding Brassicaceae evolution through ancestral genome reconstruction. AB - BACKGROUND: Brassicaceae is a family of green plants of high scientific and economic interest, including thale cress (Arabidopsis thaliana), cruciferous vegetables (cabbages) and rapeseed. RESULTS: We reconstruct an evolutionary framework of Brassicaceae composed of high-resolution ancestral karyotypes using the genomes of modern A. thaliana, Arabidopsis lyrata, Capsella rubella, Brassica rapa and Thellungiella parvula. The ancestral Brassicaceae karyotype (Brassicaceae lineages I and II) is composed of eight protochromosomes and 20,037 ordered and oriented protogenes. After speciation, it evolved into the ancestral Camelineae karyotype (eight protochromosomes and 22,085 ordered protogenes) and the proto-Calepineae karyotype (seven protochromosomes and 21,035 ordered protogenes) genomes. CONCLUSIONS: The three inferred ancestral karyotype genomes are shown here to be powerful tools to unravel the reticulated evolutionary history of extant Brassicaceae genomes regarding the fate of ancestral genes and genomic compartments, particularly centromeres and evolutionary breakpoints. This new resource should accelerate research in comparative genomics and translational research by facilitating the transfer of genomic information from model systems to species of agronomic interest. PMID- 26653026 TI - Unnatural natural history of Duchenne muscular dystrophy. PMID- 26653027 TI - Rethinking of ureteral stent removal using an extraction string; what patients feel and what is patients' preference? : a randomized controlled study. AB - BACKGROUND: Ureteral stent removal using an extraction string is advantageous because it can obviate an invasive cystoscopy, but there is a paucity of data on how patients feel about it, and how bothersome or beneficial it is. We performed this study to evaluate patients' preference for stent removal using an extraction string and which parameters could affect it. METHODS: In total, 114 consecutive patients undergoing ureteral stent insertion after ureteroscopic stone removal (URS) for unilateral recurrent ureter stones were enrolled. Patients were randomized to a string group or a no string group. Stent removal was performed on the first visit within 7 days postoperatively. All patients were asked to complete the ureteral stent symptom questionnaire, to rate the degree of pain during stent removal using a visual analog scale (VAS) and to answer to questions regarding their preference. RESULTS: No significant differences were found in domain total scores including urinary symptoms (p = 0.17), pain (p = 0.62), general health (p = 0.37), work performance (p = 0.41). However, regarding separate questions for 'dysuria' and 'difficulties with heavy physical activity', there were significant intergroup differences (p = 0.03 and p = 0.04, respectively). Particular, a significantly higher proportion of patients in the string group checked 'stoppage of sexual intercourse due to stent-related problems' than in the no string group (p = 0.03). VAS score on stent removal was significantly higher in the no string group than the string group (p = 0.005). Among the patients who remember the experience of an indwelling ureteral stent in the past, 85% (17/20) of the no string group answered 'No' to the question of 'difference between the methods used in this time and in the past'. On the contrary, 84.2% (16/19) answered 'Yes' to the same question in the string group. And, all 16 patients of the string group who noted differences between the methods preferred ureteral stent removal using an extraction string to the past method. CONCLUSIONS: Despite of minor increased morbidity related to the extraction string, patients preferred ureteral stent removal using the extraction string after URS. The patients with the extraction string felt less pain on stent removal than flexible cystoscopic stent removal. TRIAL REGISTRATION: KCT0001700 . The trial was registered in the Clinical Research Information Service (CRiS), Republic of Korea; registration date: 18/11/2015. PMID- 26653028 TI - Excess maternal salt or fructose intake programmes sex-specific, stress- and fructose-sensitive hypertension in the offspring. AB - The Western diet is typically high in salt and fructose, which have pressor activity. Maternal diet can affect offspring blood pressure, but the extent to which maternal intake of excess salt and fructose may influence cardiovascular function of the offspring is unknown. We sought to determine the effect of moderate maternal dietary intake of salt and/or fructose on resting and stimulated cardiovascular function of the adult male and female offspring. Pregnant rats were fed purified diets (+/- 4% salt) and water (+/- 10% fructose) before and during gestation and through lactation. Male and female offspring were weaned onto standard laboratory chow. From 9 to 14 weeks of age, cardiovascular parameters (basal, circadian and stimulated) were assessed continuously by radiotelemetry. Maternal salt intake rendered opposite-sex siblings with a 25 mmHg difference in blood pressure as adults; male offspring were hypertensive (15 mmHg mean arterial pressure (MAP)) and female offspring were hypotensive (10 mmHg MAP) above and below controls, respectively. Sex differences were unrelated to endothelial nitric oxide activity in vivo, but isolation-induced anxiety revealed a significantly steeper coupling between blood pressure and heart rate in salt exposed male offspring but not in female offspring. MAP of all offspring was refractory to salt loading but sensitive to subsequent dietary fructose, an effect exacerbated in female offspring from fructose-fed dams. Circadian analyses of pressure in all offspring revealed higher mean set-point for heart rate and relative non-dipping of nocturnal pressure. In conclusion, increased salt and fructose in the maternal diet has lasting effects on offspring cardiovascular function that is sex-dependent and related to the offspring's stress-response axis. PMID- 26653029 TI - Relationship between risk factors for infertility in women and lead, cadmium, and arsenic blood levels: a cross-sectional study from Taiwan. AB - BACKGROUND: The World Health Organization reported that more than 10 % of women are severely affected by infertility, making the condition a major worldwide public health problem. Lead (Pb), cadmium (Cd), and arsenic (As) are environmental pollutants that may contribute to reproductive disorders. This cross-sectional study investigated the association between blood concentrations of Pb, Cd, and As and risk factors for infertility in women. METHODS: Women who were infertile (N = 310) or pregnant (N = 57) were recruited from the gynecology and obstetrics department of a hospital. The participants were interviewed to obtain their sociodemographic, reproductive, and lifestyle information. The concentrations of Pb, Cd, and As in their blood samples were measured using inductively coupled plasma mass spectrometry. RESULTS: Our findings suggested that the concentrations of Pb and As, but not Cd, were significantly higher in the blood of infertile women than in that of pregnant women. A higher percentage of the infertile women consumed more alcohol, used Chinese herbal medicine more frequently, and lacked physical activity compared with the pregnant women. After accounting for potentially relevant predictors, we observed that blood Pb levels might be elevated by using Chinese herbal medicine 1-6 times per week (aOR = 2.82, p = 0.05). In addition, engaging in physical activity 1-2 times per week (aOR = 0.37, p = 0.05) might assist in reducing Pb accumulation in infertile women, though the p value was borderline. CONCLUSIONS: Lack of physical activity and frequent use of Chinese herbal medicine may be associated with elevated blood Pb levels in infertile women. Chinese herbal medicine use was observed to increase the Pb body burden of both infertile and pregnant women in this study. The risk-benefit for Chinese herbal medicine intake should be evaluated by women of childbearing age. PMID- 26653031 TI - Reductive dehalogenation of endosulfan by cast iron: Kinetics, pathways and modeling. AB - Cast iron has been a material of choice for in-situ remediation of groundwater. In this study interaction of endosulfan with High Carbon Iron Filings (HCIF) was studied in batch reactors. Decline in total concentration (Ct) could be related to aqueous concentration (Ca) by equation dCt/dt = k1.M.Ca(n), where reaction rate constant (k1) and order (n) were found to be 1.246 * 10(-4) L g(-1) iron h( 1) and 1.47, respectively. Partitioning of endosulfan to HCIF could be explained by Freundlich isotherm. The process of simultaneous reductive dehalogenation and adsorption/desorption was successfully modelled. The reductive dehalogenation of endosulfan resulted in by-products identified as [(3a, alpha,7beta,7a alpha,8s) 4,5,6,7,8 Pentachloro 3a,4,7,7a-tetrahydro] (C9H3Cl5O3) and Benzofuran,4,5,7 trichloro-2,3-dihydro-2-methyl (C9H7Cl3O). PMID- 26653032 TI - Microbiological testing of pharmaceuticals and cosmetics in Egypt. AB - BACKGROUND: Microbial contamination of pharmaceuticals poses a great problem to the pharmaceutical manufacturing process, especially from a medical as well as an economic point of view. Depending upon the product and its intended use, the identification of isolates should not merely be limited to the United States Pharmacopeia (USP) indicator organisms. RESULTS: Eighty-five pre-used non-sterile pharmaceuticals collected from random consumers in Egypt were examined for the eventual presence of bacterial contaminants. Forty-one bacterial contaminants were isolated from 31 of the tested preparations. These isolates were subjected to biochemical identification by both conventional tests as well as API kits, which were sufficient for the accurate identification of only 11 out of the 41 bacterial contaminants (26.8%) to the species level. The remaining isolates were inconclusively identified or showed contradictory results after using both biochemical methods. Using molecular methods, 24 isolates (58.5%) were successfully identified to the species level. Moreover, polymerase chain reaction (PCR) assays were compared to standard biochemical methods in the detection of pharmacopoeial bacterial indicators in artificially-contaminated pharmaceutical samples. CONCLUSION: PCR-based methods proved to be superior regarding speed, cost-effectiveness and sensitivity. Therefore, pharmaceutical manufacturers would be advised to adopt PCR-based methods in the microbiological quality testing of pharmaceuticals in the future. PMID- 26653033 TI - Phenyl Benzenesulfonylhydrazides Exhibit Selective Indoleamine 2,3-Dioxygenase Inhibition with Potent in Vivo Pharmacodynamic Activity and Antitumor Efficacy. AB - Tryptophan metabolism has been recognized as an important mechanism in immune tolerance. Indoleamine 2,3-dioxygenase plays a key role in local tryptophan metabolism via the kynurenine pathway and has emerged as a therapeutic target for cancer immunotherapy. Our prior study identified phenyl benzenesulfonyl hydrazide 2 as a potent in vitro (though not in vivo) inhibitor of indoleamine 2,3 dioxygenase. Further lead optimization to improve in vitro potencies and pharmacokinetic profiles resulted in N'-(4-bromophenyl)-2-oxo-2,3-dihydro-1H indole-5-sulfonyl hydrazide 40, which demonstrated 59% oral bioavailability and 73% of tumor growth delay without apparent body weight loss in the murine CT26 syngeneic model, after oral administration of 400 mg/kg. Accordingly, 40, is proposed as a potential drug lead worthy of advanced preclinical evaluation. PMID- 26653034 TI - IL-8 and VEGFR-2 polymorphisms modulate long-term functional response to intravitreal ranibizumab in exudative age-related macular degeneration. AB - AIM: To investigate possible associations between VEGFR-2 and IL-8 gene SNPs and 1-year response to intravitreal ranibizumab for exudative age-related macular degeneration. MATERIALS & METHODS: Sixty-four eyes underwent a loading phase of three monthly intravitreal injections of ranibizumab 0.5 mg/0.05 ml followed by Pro Re Nata retreatment. VEGFR-2 rs2071559 (-604 A/G) and IL-8 rs4073 (-251 A/T) were analyzed. RESULTS: Ranibizumab was significantly more effective as measured by visual acuity in patients harboring the IL-8 rs4073 TT genotype (p = 0.045), whereas patients carrying the VEGFR-2 rs2071559 CC genotype revealed better functional response as measured by mean retinal sensitivity (p = 0.034). CONCLUSION: IL-8 rs4073 and VEGFR-2 rs2071559 genotypes may represent important molecular determinants to modulate final outcomes in neovascular age-related macular degeneration patients. PMID- 26653036 TI - Survey on the tiered approach for Japanese bioanalysts operated by Japan bioanalysis forum DG2014-09. PMID- 26653035 TI - The characterization and manipulation of the bacterial microbiome of the Rocky Mountain wood tick, Dermacentor andersoni. AB - BACKGROUND: In North America, ticks are the most economically impactful vectors of human and animal pathogens. The Rocky Mountain wood tick, Dermacentor andersoni (Acari: Ixodidae), transmits Rickettsia rickettsii and Anaplasma marginale to humans and cattle, respectively. In recent years, studies have shown that symbiotic organisms are involved in a number of biochemical and physiological functions. Characterizing the bacterial microbiome of D. andersoni is a pivotal step towards understanding symbiont-host interactions. FINDINGS: In this study, we have shown by high-throughput sequence analysis that the composition of endosymbionts in the midgut and salivary glands in adult ticks is dynamic over three generations. Four Proteobacteria genera, Rickettsia, Francisella, Arsenophonus, and Acinetobacter, were identified as predominant symbionts in these two tissues. Exposure to therapeutic doses of the broad spectrum antibiotic, oxytetracycline, affected both proportions of predominant genera and significantly reduced reproductive fitness. Additionally, Acinetobacter, a free-living ubiquitous microbe, invaded the bacterial microbiome at different proportions based on antibiotic treatment status suggesting that microbiome composition may have a role in susceptibility to environmental contaminants. CONCLUSIONS: This study characterized the bacterial microbiome in D. andersoni and determined the generational variability within this tick. Furthermore, this study confirmed that microbiome manipulation is associated with tick fitness and may be a potential method for biocontrol. PMID- 26653037 TI - The Evolving Health Care System: The Need for Nursing Education Reform. PMID- 26653038 TI - Answering the Call for a Bachelors-Prepared Nursing Workforce: An Innovative Model for Academic Progression. AB - Forces that have produced national reform of a fragmented, inefficient, and expensive health care services sector have also set the stage for reform of a fragmented, inefficient, and expensive system for nursing education. Changes in health care, health policy, education policy, and funding for public higher education have led to the development of new nursing education models designed to increase the number of baccalaureate-prepared nurses entering the workforce. This article describes the development and implementation of one such model that features a common concept-based curriculum and university-community college partnerships at its core. This plan increases access for nursing students across the state to earn a prelicensure bachelor of science in nursing degree and preserves the integrity and accessibility of associate degree nursing education. PMID- 26653039 TI - The Initiative to Move Toward a More Highly Educated Nursing Workforce: Findings from the Kansas Registered Nurse Workforce Survey. AB - The Institute of Medicine report, The Future of Nursing: Leading Change, Advancing Health, recommends increasing the proportion of registered nurses (RNs) with a baccalaureate in nursing (BSN) to 80% by 2020. Kansas lacks a central mechanism to collect current data on the RN workforce; therefore, detailed information about the RN workforce, including current educational level, is unknown. The purposes of the survey were to (a) describe the Kansas RN workforce, (b) examine the relationship between nursing education and employment, (c) compare and contrast the workforce to other states and national data and (d) discuss implications of strategic planning and policy making for nursing education. The on-line Kansas RN Workforce Survey link was sent to 44,568 RNs by e-mail, and the response rate was 15.6% (n = 6,948). The survey consisted of 34 questions on demographics, education, licensing, and employment. Kansas RNs were predominately women (92%) and Caucasian with an average age of 47.7 years. Approximately 46.3% of RNs obtained a BSN as their initial education. Analysis of highest level of nursing education showed that 60.5% of Kansas RNs were at least baccalaureate prepared, with 14.9% obtaining a master's degree or higher. More than 50% of RNs worked in hospitals as staff nurses. RNs with advanced education were more likely to be employed, tended to work in academic settings or ambulatory clinics, and were more likely to be faculty or in management/leadership positions. Overall, the Kansas RN workforce is closer to reaching the 80% baccalaureate-prepared goal recommended by the Future of Nursing report than has been reported. Educational level was closely related to RNs' choices of work settings and positions. Additional work such as promoting academic progression needs to continue to build a more highly educated RN workforce. PMID- 26653040 TI - Transitioning from Departments to Schools of Nursing: A Qualitative Analysis of Journeys by Ten Deans. AB - Transitioning from a department to a school of nursing creates an environment that is more conducive to attracting qualified faculty and enhancing program growth to meet the projected nursing workforce needs. A comprehensive review of the literature revealed limited research to guide nursing programs considering this transition. This qualitative study explored the conditions and outcomes associated with successful or unsuccessful attempts to transition from a department to school of nursing from the perspective of 10 deans affiliated with the American Association of Colleges of Nursing (AACN). Meleis' transitions theory (2010) guided this study in its exploration of facilitating and inhibiting conditions. With institutional review board approval and participant permission, interviews were conducted in-person or by telephone, audio-recorded, and transcribed verbatim. Transcripts were independently reviewed and coded for emerging themes. Content analysis revealed the following themes: titles matter, support is essential, voice at the table, buy-in or dissension, it just brings nursing to totally different level, think differently, and legitimizing your position. For these deans, consideration of the facilitating and inhibiting conditions is critical in determining whether decisions are favorable and in support of the transition. Developing an understanding from the experiences of these 10 deans offers guidance to nursing academic administrators who are contemplating transitioning from a department to a school of nursing. Future research is needed to explore conditions relative to faculty governance and infrastructure, examine the experiences of those undergoing transitions, and expand study findings to develop a self-study guide for programs in assessing their readiness for such a transition. PMID- 26653041 TI - Planning and Selecting Evaluation Designs for Leadership Training: A Toolkit for Nurse Managers and Educators. AB - Leadership development training and education for nurses is a priority in modern health care systems. Consequently, effective evaluation of nurse leadership development programs is essential for managers and educators in health care organizations to determine the impact of such programs on staff behaviors and patient outcomes. Our team has identified a framework for the evaluation of the design and implementation of such programs. Following this, we provide practical tools for the selection of evaluation methodologies for leadership development programs for use by health care educators and program commissioners. PMID- 26653042 TI - Exploring Job Satisfaction of Nursing Faculty: Theoretical Approaches. AB - The Future of Nursing report identified the shortage of nursing faculty as 1 of the barriers to nursing education. In light of this, it is becoming increasingly important to understand the work-life of nursing faculty. The current research focused on job satisfaction of nursing faculty from 4 theoretical perspectives: human capital theory, which emphasizes the expected monetary and nonmonetary returns for any career choices; structural theory, which emphasizes the impact of institutional features on job satisfaction; positive extrinsic environment by self-determination theory, which asserts that a positive extrinsic environment promotes competency and effective outcomes at work; and psychological theory, which emphasizes the proposed relationship between job performance and satisfaction. In addition to the measures for human capital theory, institutional variables (from structural theory and self-determination theory), and productivity measures (from psychological theory), the authors also selected sets of variables for personal characteristics to investigate their effects on job satisfaction. The results indicated that variables related to human capital theory, especially salary, contributed the most to job satisfaction, followed by those related to institutional variables. Personal variables and productivity variables as a whole contributed as well. The only other variable with marginal significance was faculty's perception of institutional support for teaching. PMID- 26653043 TI - Selecting Standardized Tests in Nursing Education. AB - Nursing faculty frequently utilize or consider the use of nationally standardized tests to evaluate nursing student performance and their potential to pass the National Council Licensure Examination (NCLEX)((c)) after graduation. There is little literature available to advise and guide nursing faculty in criteria to consider when selecting a standardized testing company to assess student readiness for NCLEX. The intent of this article is to share criteria to consider when evaluating a standardized test or testing program that has been gathered through an informal survey of faculty who are currently using standardized tests. PMID- 26653044 TI - Integrating Sexual Minority Health Issues into a Health Assessment Class. AB - The health needs of the lesbian, gay, bisexual, and transgender (LGBT) population are traditionally overlooked by the health care community and are rendered invisible by most nursing school curricula. Initial contact with a nurse during a health history and assessment can have an impact on whether the person will feel comfortable disclosing his or her identity, returning for services, or following plans of care. Because the first interaction with a nurse can be critical, the health assessment course is an appropriate place in the curriculum to discuss the needs of the LGBT community. This article includes a discussion of unique health risks to the LGBT population, benefits, and challenges of incorporating these issues into the classroom and recommendations for including the care of this population into a health assessment nursing course. Specific communication techniques are provided that may be helpful during history taking and physical examination with a patient who is LGBT. Guidance regarding physical examination of the transgender patient is also included. These suggestions will be helpful to nurse faculty who teach health assessment, nursing students, educators who design and implement professional development and continuing education for established nurses, preceptors in the clinical setting, and any nurse who is unfamiliar with the needs and concerns specific to the LGBT population. PMID- 26653046 TI - Oral radiological contrast in the pleural cavity. PMID- 26653045 TI - Meta-Evaluation: Experiences in an Accelerated Graduate Nurse Education Program. AB - Most schools of nursing are engaged in some form of program evaluation and recognize the potential benefits in using program evaluation outcomes to influence continuous improvement in program quality. A number of factors exist that may negatively influence program evaluation quality and adversely affect the ability to make sound decisions based on program evaluation outcomes. The potential limitations that threaten program evaluation quality underscore the importance of evaluating the evaluation process itself, also known as meta evaluation. However, there is an absence of discussion in the nursing literature of the importance of program meta-evaluation. This article seeks to address this gap in the nursing literature and illuminate the need for more schools of nursing to engage in the meta-evaluation process. By introducing 1 model of program meta evaluation and describing our own endeavors in the program meta-evaluation process, we hope to inspire other schools of nursing to consider using a systematic and formalized process to evaluate their own program evaluation processes to ensure that data obtained from program evaluation are of optimal quality to influence sound, data-driven decisions to promote continued quality and excellence in nursing education programs. PMID- 26653047 TI - New care models in internal medicine: responding to the need for comprehensive care for patients. PMID- 26653048 TI - Incidence of leptospirosis in Spain, 2009-2012. PMID- 26653049 TI - Editorial: Immunophilins, Protein Chemistry and Cell Biology of a Promising New Class of Drug Targets - Part I. PMID- 26653050 TI - "Assessment of identity during adolescence using daily diary methods: Measurement invariance across time and sex": Correction to Becht et al. (2015). AB - Reports an error in "Assessment of Identity During Adolescence Using Daily Diary Methods: Measurement Invariance Across Time and Sex" by Andrik I. Becht, Susan J. T. Branje, Wilma A. M. Vollebergh, Dominique F. Maciejewski, Pol A. C. van Lier, Hans M. Koot, Jaap J. A. Denissen and Wim H. J. Meeus (Psychological Assessment, Advanced Online Publication, Aug 10, 2015, np). In the article the participants should have been reported as N = 494. No differences were found in the results upon reanalyzing the data with the correct number of participants. Additionally, the last sentence of the first full paragraph in the Invariance Across Boys and Girls subsection of the Method section should read "In the fourth model, strict invariance was examined, in which the residual variances were constrained to be equal for boys and girls." (The following abstract of the original article appeared in record 2015-36246-001.) The aim of this study was to assess measurement invariance of adolescents' daily reports on identity across time and sex. Adolescents (N = 497; mean age = 13.32 years at Time 1, 56.7% boys) from the general population reported on their identity commitments, exploration in depth and reconsideration on a daily basis for 3 weeks within 1 year across 5 years. We used the single-item version of the Utrecht Management of Identity Commitments Scale (UMICS; Klimstra et al., 2010), a broad measure of identity-formation processes covering both interpersonal and educational identity domains. This study tested configural, metric, scalar, and strict measurement invariance across days within weeks, across sex, across weeks within years, and across years. Results indicated that daily diary reports show strict measurement invariance across days, across weeks within years, across years, and across boys and girls. These results support the use of daily diary methods to assess identity at various time intervals ranging from days to years and across sex. Results are discussed with regard to future implications to study identity processes, both on smaller and larger time intervals. (PsycINFO Database Record PMID- 26653051 TI - Assessment of the psychometric properties of the Revised Academic Hardiness Scale in college student samples. AB - Academic hardiness, a construct representing how students tend to respond to academic stressors, has seen increased attention in the recent literature. However, as yet, no measure exists that has been validated for use with college students. The current study addresses this gap in the literature by examining the psychometric properties of the Revised Academic Hardiness Scale (RAHS; Benishek, Feldman, Shipon, Mecham, & Lopez, 2005) in several samples of college students from 2 institutions of higher education. Study 1 showed a 4-factor model (Commitment, Control of Affect, Challenge, and Control of Effort) to be the best fitting solution. Studies 2 and 3 found support for the test-retest reliability, convergent validity, and discriminant validity of the 4 factors' scores. Finally, Study 4 showed evidence of the predictive validity of the RAHS scores, which accounted for significant variance in first- and second-semester college grade point average and persistence to a 2nd year at the university beyond the variance accounted for by high school academic variables. Overall, the RAHS appears to be a psychometrically sound measure for use with college students. (PsycINFO Database Record PMID- 26653052 TI - Psychometric properties of the PTSD Checklist for Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition (PCL-5) in veterans. AB - This study examined the psychometric properties of the posttraumatic stress disorder (PTSD) Checklist for Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition (PCL-5; Weathers, Litz, et al., 2013b) in 2 independent samples of veterans receiving care at a Veterans Affairs Medical Center (N = 468). A subsample of these participants (n = 140) was used to define a valid diagnostic cutoff score for the instrument using the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5; Weathers, Blake, et al., 2013) as the reference standard. The PCL-5 test scores demonstrated good internal consistency (alpha = .96), test-retest reliability (r = .84), and convergent and discriminant validity. Consistent with previous studies (Armour et al., 2015; Liu et al., 2014), confirmatory factor analysis revealed that the data were best explained by a 6-factor anhedonia model and a 7-factor hybrid model. Signal detection analyses using the CAPS-5 revealed that PCL-5 scores of 31 to 33 were optimally efficient for diagnosing PTSD (kappa(.5) = .58). Overall, the findings suggest that the PCL 5 is a psychometrically sound instrument that can be used effectively with veterans. Further, by determining a valid cutoff score using the CAPS-5, the PCL 5 can now be used to identify veterans with probable PTSD. However, findings also suggest the need for research to evaluate cluster structure of DSM-5. (PsycINFO Database Record PMID- 26653053 TI - Reassessing the "traditional background hypothesis" for elevated MMPI and MMPI-2 Lie-scale scores. AB - The Lie (L) scale of the Minnesota Multiphasic Personality Inventory (MMPI) is widely regarded as a measure of conscious attempts to deny common human foibles and to present oneself in an unrealistically positive light. At the same time, the current MMPI-2 manual states that "traditional" and religious backgrounds can account for elevated L scale scores as high as 65T-79T, thereby tempering impression management interpretations for faith-based individuals. To assess the validity of the traditional background hypothesis, we reviewed 11 published studies that employed the original MMPI with religious samples and found that only 1 obtained an elevated mean L score. We then conducted a meta-analysis of 12 published MMPI-2 studies in which we compared L scores of religious samples to the test normative group. The meta-analysis revealed large between-study heterogeneity (I2 = 87.1), L scale scores for religious samples that were somewhat higher but did not approach the upper limits specified in the MMPI-2 manual, and an overall moderate effect size (d- = 0.54, p < .001; 95% confidence interval [0.37, 0.70]). Our analyses indicated that religious-group membership accounts, on average, for elevations on L of about 5 t-score points. Whether these scores reflect conscious "fake good" impression management or religious based virtuousness remains unanswered. (PsycINFO Database Record PMID- 26653054 TI - Clinical utility of the MMPI-2-RF SUI items and scale in a forensic inpatient setting: Association with interview self-report and future suicidal behaviors. AB - In this study, we examined whether the 5 Minnesota Multiphasic Personality Inventory-2-Restructured Form (MMPI-2-RF; Ben-Porath & Tellegen, 2008/2011) Suicidal/Death Ideation (SUI) items (93, 120, 164, 251, and 334) would provide incremental suicide-risk assessment information after accounting for information garnered from clinical interview questions. Among 229 forensic inpatients (146 men, 83 women) who were administered the MMPI-2-RF, 34.9% endorsed at least 1 SUI item. We found that patients who endorsed SUI items on the MMPI-2-RF concurrently denied conceptually related suicide-risk information during the clinical interview. For instance, 8% of the sample endorsed Item 93 (indicating recent suicidal ideation), yet denied current suicidal ideation upon interview. Conversely, only 2.2% of the sample endorsed current suicidal ideation during the interview, yet denied recent suicidal ideation on Item 93. The SUI scale, as well as the MMPI-2-RF Demoralization (RCd) and Low Positive Emotions (RC2) scales, correlated significantly and meaningfully with conceptually related suicide-risk information from the interview, including history of suicide attempts, history of suicidal ideation, current suicidal ideation, and months since last suicide attempt. We also found that the SUI scale added incremental variance (after accounting for information garnered from the interview and after accounting for scores on RCd and RC2) to predictions of future suicidal behavior within 1 year of testing. Relative risk ratios indicated that both SUI-item endorsement and the presence of interview-reported risk information significantly and meaningfully increased the risk of suicidal behavior in the year following testing, particularly when endorsement of suicidal ideation occurred for both methods of self-report. (PsycINFO Database Record PMID- 26653055 TI - The Pittsburgh Sleep Quality Index: Validity and factor structure in young people. AB - The Pittsburgh Sleep Quality Index (PSQI) is a widely used measure of sleep quality in adolescents, but information regarding its psychometric strengths and weaknesses in this population is limited. In particular, questions remain regarding whether it measures one or two sleep quality domains. The aims of the present study were to (a) adapt the PSQI for use in adolescents and young adults, and (b) evaluate the psychometric properties of the adapted measure in this population. The PSQI was slightly modified to make it more appropriate for use in youth populations and was translated into Spanish for administration to the sample population available to the study investigators. It was then administered with validity criterion measures to a community-based sample of Spanish adolescents and young adults (AYA) between 14 and 24 years old (N = 216). The results indicated that the questionnaire (AYA-PSQI-S) assesses a single factor. The total score evidenced good convergent and divergent validity and moderate reliability (Cronbach's alpha = .72). The AYA-PSQI-S demonstrates adequate psychometric properties for use in clinical trials involving adolescents and young adults. Additional research to further evaluate the reliability and validity of the measure for use in clinical settings is warranted. PMID- 26653057 TI - Guest Editorial: Psychoanalysis and Indian Ethos. PMID- 26653056 TI - Can the disease course in Parkinson's disease be slowed? AB - BACKGROUND: The diagnosis of Parkinson's disease (PD), which is needed for useful symptomatic therapy, is based on clinical criteria. However, it became quite clear in recent years that the same features can occur through different etiopathogenic mechanisms. Even a pathological diagnosis of PD, based on the demonstration of alpha-synuclein deposits in a typical distribution, can result from different causes and, vice versa, nigral cell loss can occur without alpha synuclein deposition. DISCUSSION: Thus far, attempts to influence the progression of PD have failed. However, since the clinical manifestations of PD can be the result of diverse mechanisms, a single intervention may not be able to slow the course of the disease in all patients. Indeed, targeting the underlying pathogenic processes, which differ among cases, may be more effective. PD may develop as a consequence of mitochondrial damage, which itself may result from a variety of genetic or environmental factors. Correction of the ensuing oxidative stress may theoretically be useful in these PD patients, but will not affect the progression of the disease among other PD patients in whom an identical clinical syndrome derives from defects in other pathways such as the ubiquitin-proteasome system and lysosomal dysfunction, among others. Precision medicine can now be used to identify the underlying pathogenic mechanisms in individual patients, paving the way to the development of real disease modification through a pathway oriented approach, aimed at the underlying biologic processes of disease occurrence and evolution. PMID- 26653058 TI - Encounters With Erik Erikson. AB - This article recollects events from the author's association with Erik Erikson that lasted for a quarter of a century, from a first meeting in India when Erikson was working on his book Gandhi's Truth, to a few months before his death, to sketch a portrait of the man and his influence on Kakar's own career. PMID- 26653059 TI - Inaccessible Masturbation, Impossible Mourning: Collective Melancholia, the Prohibition on Female Sexual Subjects in India, and Masturbation Fantasy as a Zone of the Strange. AB - This paper explores a subjective experience-and identification-that a cohort of Indian women identifies as "home." This experience of "home" provides an attachment to a collective melancholia that keeps in place a prohibited female sexual subjectivity. The paper provides a brief historical overview of the prohibition of female sexual subjectivity and erotic agency in India. Following this, it discusses women's masturbation fantasies that illustrate the toggle between women's permitted and prohibited identifications. A clinical case example is presented to illustrate the hopelessness and mourning inherent in the psychoanalytic journey into subjectivity, a journey involving a departure from a shared cultural history. PMID- 26653060 TI - Morphology of the Closet: Some Secrets From Indian Life. AB - This paper looks at the morphology, the structures of closets that emerge from mythological, clinical, and literary instances in Indian life. Through the variety of shapes that emerge, the word closet itself is seen as hiding many things from view, for instance, the angle, texture, and location, but most of all a communication to the internal objects. Can we then dismantle the word and try to open the contents out in order to reflect on the nature of the internal objects? PMID- 26653061 TI - Indian Culture and the Experience of Psychoanalytic Treatment. AB - While there is a long history to the acquaintance between psychoanalysis and India, psychoanalytic thought has never quite taken hold in Indian culture. However, due to economic globalization, the boom in digital technologies, and the consequent increase in interactions between the East and West, it is becoming increasingly necessary to take notice of the cultural dimensions of psychological experience and its place in psychoanalytic theory and practice. This article explores how the experience of participating in a psychoanalytically oriented treatment structure may be shaped by Indian culture. Developmental, social, clinical, and technical perspectives are considered in each instance. PMID- 26653062 TI - Where Is India in My Psychoanalytic Work? AB - Taking for granted that an analyst's ethnic and national origin can influence his or her theoretical and technical preferences, I have attempted to highlight the role of India in my psychoanalytic life. I have expanded the death instinct concept and sought to soften the impasse between psychoanalysis and religion from an Indian perspective. I have also demonstrated how aspects of Indian culture affect my clinical practice, including my office decor, my therapeutic attitude, my language, and my interventions with patients. By providing such details, I am hoping to establish my veracity for non-Indian psychoanalysts and to inspire Indian psychoanalysts towards greater authenticity. More importantly, my hope is to enhance dialogue between psychoanalysis and Indian thought since such discourse has the potential to enrich both disciplines. PMID- 26653065 TI - HRT for menopause: a delicate balance. PMID- 26653066 TI - mHealth: only as good as the company it keeps. PMID- 26653068 TI - Predictors of glycemic control and diabetes-related costs among type 2 diabetes patients initiating therapy with liraglutide in the United States. AB - OBJECTIVE: Liraglutide has been shown to significantly improve glycemic control and reduce body weight while minimizing the risk of hypoglycemia in adult patients with type 2 diabetes (T2D). This study aimed to identify characteristics that predict clinical and economic outcomes associated with liraglutide therapy in clinical practice in the US. METHODS: Using the Truven Health MarketScan Laboratory Database, glycemic control (A1C <7%) and diabetes-related costs were evaluated in T2D patients initiating liraglutide between January 1, 2010 and June 30, 2012. Patients were required to have >=1 post-index claim for liraglutide and A1C values at baseline and 6 months follow-up. All valid values of baseline A1C were included. Patients previously treated with GLP-1 receptor agonist(s) or insulin, or with evidence of type 1 diabetes, pregnancy, or gestational diabetes during the study period were excluded. Multivariable regression models were used to identify predictors of glycemic control and diabetes-related costs. RESULTS: Of 417 patients newly treated with liraglutide, 54.0% achieved glycemic control (A1C <7%) during follow-up. Factors associated with increased odds of glycemic control during follow-up were: being female, POS/EPO health plan type, baseline A1C, early liraglutide initiation (0-1 prior oral anti diabetics [OADs] vs >=2), adherence to liraglutide (defined as the proportion of days covered [PDC]), and diabetic retinopathy. Being female, earlier liraglutide initiation (0-1 prior OADs), and higher patient share of liraglutide costs were associated with significantly lower diabetes-related costs during follow-up. Factors associated with significantly higher post-index diabetes-related costs were: higher baseline A1C, baseline use of sulfonylureas, and diabetic retinopathy. CONCLUSIONS: Within this commercially-insured population of T2D patients treated with liraglutide, gender, baseline A1C, early liraglutide initiation (0-1 prior OADs), diabetic retinopathy, better adherence, and patient share of liraglutide costs were associated with increased odds of achieving glycemic control and the odds of having higher or lower diabetes-related costs. PMID- 26653067 TI - Effectiveness of an mHealth intervention to improve the cardiometabolic profile of people with prehypertension in low-resource urban settings in Latin America: a randomised controlled trial. AB - BACKGROUND: Poor diet and physical inactivity strongly affect the growing epidemic of cardiovascular disease worldwide. Mobile phone-based health interventions (mHealth) have been shown to help promote weight loss and increase physical activity and are an attractive approach for health-care systems with limited resources. We aimed to assess whether mHealth with advice for lifestyle improvements would reduce blood pressure, promote weight loss, and improve diet quality and physical activity in individuals with prehypertension living in low resource urban settings in Latin America. METHODS: In this parallel-group, randomised controlled trial, we recruited individuals (aged 30-60 years) with systolic blood pressure between 120 and 139 mm Hg, diastolic blood pressure between 80 and 89 mm Hg, or both from health-care centres, workplaces, and community centres in low-resource urban settings in Argentina, Guatemala, and Peru. Participants were randomly assigned to receive either monthly motivational counselling calls and weekly personalised text messages to their mobile phones about diet quality and physical activity for 12 months, or usual care. Randomisation was stratified by country, and we applied minimisation by sex and age groups. Study personnel collecting and analysing data were masked to group assignment. The primary outcomes were mean between-group differences in the changes in systolic and diastolic blood pressure from baseline to 12 months in an intention-to-treat analysis of all participants who completed assessments at 12 months. Secondary outcome measures were changes in bodyweight, waist circumference, and self-reported target behaviours from baseline to 12 months. The trial is registered with ClinicalTrials.gov, number NCT01295216. FINDINGS: Between March 1, 2012, and Nov 30, 2012, we randomly assigned 637 participants to receive intervention (n=316) or usual care (n=321). 266 (84%) participants in the intervention group and 287 (89%) in the control group were assessed at 12 months. The intervention did not affect change in systolic blood pressure (mean net change -0.37 mm Hg [95% CI -2.15 to 1.40]; p=0.43) or diastolic blood pressure (0.01 mm Hg [-1.29 to 1.32]; p=0.99) compared with usual care. However, we noted a significant net reduction in bodyweight (-0.66 kg [-1.24 to -0.07]; p=0.04) and intake of high-fat and high-sugar foods (-0.75 [-1.30 to -0.20]; p=0.008) in the intervention group compared with the control group. In a prespecified subanalysis, we found that participants in the intervention group who received more than 75% of the calls (nine or more, from a maximum of 12) had a greater reduction of bodyweight (-4.85 [-8.21 to -1.48]) and waist circumference (-3.31 [ 5.95 to -0.67]) than participants in the control group. Additionally, participants in the intervention group had an increase in the intake of fruits and vegetables and a decrease in diets high in sodium, fat, and simple sugars relative to participants in the control group. However, we found no changes in systolic blood pressure, diasatolic blood pressure, or physical activity in the group of participants who received more than 75% of the calls compared with the group who received less than 50% of the calls. INTERPRETATION: Our mHealth-based intervention did not result in a change in blood pressure that differed from usual care, but was associated with a small reduction in bodyweight and an improvement in some dietary habits. We noted a dose-response effect, which signals potential opportunities for larger effects from similar interventions in low-resource settings. More research is needed on mHealth, particularly among people who are poor and disproportionally affected by the cardiovascular disease epidemic and who need effective and affordable interventions to help bridge the equity gap in the management of cardiometabolic risk factors. FUNDING: National Heart, Lung, and Blood Institute (US National Institutes of Health) and the Medtronic Foundation. PMID- 26653069 TI - Portuguese Journal of Pulmonology as a journal open to a variety of respiratory research (II). PMID- 26653070 TI - Greek Gods and Portuguese Pneumology: implementing HERMES. PMID- 26653071 TI - A silent revolution: phenotyping asthma for personalised medicine. PMID- 26653072 TI - Discriminative Ability of Plasma Branched-Chain Amino Acid Levels for Glucose Intolerance in Families At Risk for Type 2 Diabetes. AB - BACKGROUND: Insulin resistance and glucose intolerance have been associated with increased plasma levels of branched-chain amino acids (BCAA). BCAA levels do not predict T2DM in the population. We determined the discriminative ability of fasting BCAA levels for glucose intolerance in nondiabetic relatives of patients with T2DM of two different ethnicities. METHODS: Based on oral glucose tolerance test (OGTT), first-degree relatives of patients with T2DM were categorized as normal glucose tolerance, prediabetes, or T2DM. Included were 34, 12, and 18 Caucasian and 22, 12, and 23 Asian Indian participants, respectively. BCAA levels were measured in fasting plasma together with alanine, phenylalanine, and tyrosine. Insulin sensitivity and beta-cell function were assessed by indices derived from an extended OGTT and their relationship with plasma BCAA levels was assessed in multivariate regression analysis. The value of the amino acids for discriminating prediabetes among nondiabetic family members was determined with the area under the curve of receiver-operated characteristics (c-index). RESULTS: BCAA levels were higher in diabetic than in normoglycemic family members in the Caucasians (P = 0.001) but not in the Asian Indians. In both groups, BCAA levels were associated with waist-hip ratio (beta = 0.31; P = 0.03 and beta = 0.42; P = 0.001, respectively) but not with indices of insulin sensitivity or beta-cell function. The c-index of BCAA for discriminating prediabetes among nondiabetic participants was 0.83 and 0.74 in Caucasians and Asian Indians, respectively, which increased to 0.84 and 0.79 by also including the other amino acids. The c index of fasting glucose for discriminating prediabetes increased from 0.91 to 0.92 in Caucasians and 0.85 to 0.97 (P = 0.04) in Asian Indians by inclusion of BCAA+alanine, phenylalanine, and tyrosine. CONCLUSIONS: Adding fasting plasma BCAA levels, combined with phenylalanine, tyrosine and alanine to fasting glucose improved discriminative ability for the prediabetic state within Asian Indian families at risk for T2DM. BCAA levels may serve as biomarkers for early development of glucose intolerance in these families. PMID- 26653073 TI - Experience of menopause in aboriginal women: a systematic review. AB - Every woman experiences the menopause transition period in a very individual way. Menopause symptoms and management are greatly influenced by socioeconomic status in addition to genetic background and medical history. Because of their very unique cultural heritage and often holistic view of health and well-being, menopause symptoms and management might differ greatly in aboriginals compared to non-aboriginals. Our aim was to investigate the extent and scope of the current literature in describing the menopause experience of aboriginal women. Our systematic literature review included nine health-related databases using the keywords 'menopause' and 'climacteric symptoms' in combination with various keywords describing aboriginal populations. Data were collected from selected articles and descriptive analysis was applied. Twenty-eight relevant articles were included in our analysis. These articles represent data from 12 countries and aboriginal groups from at least eight distinctive geographical regions. Knowledge of menopause and symptom experience vary greatly among study groups. The average age of menopause onset appears earlier in most aboriginal groups, often attributed to malnutrition and a harsher lifestyle. This literature review highlights a need for further research of the menopause transition period among aboriginal women to fully explore understanding and treatment of menopause symptoms and ultimately advance an important dialogue about women's health care. PMID- 26653074 TI - Role of routine cystoscopy and cystography in exstrophy-epispadias complex. AB - OBJECTIVE: Our institutional protocol for the treatment of exstrophy-epispadias complex includes routine endoscopic and cystographic evaluation of the bladder with the child under general anesthesia. The protocols briefly described in the literature include a cystographic evaluation and the measurement of bladder capacity, but there are no reports on concurrent endoscopic findings and the value of examinations in this setting. Our objective is to evaluate the role and necessity of our management protocol by reviewing the findings in our patients' medical charts. STUDY DESIGN: Cystoscopies are performed in children with exstrophy-epispadias complex during the second year of life and then every 18 months until a capacity of 90 mL has been reached and bladder neck reconstruction, the last stage of modern staged repair, is performed. Patients referred from other institutions are evaluated on presentation. The examinations are performed by means of a pediatric cystoscope with the child under general anesthesia. Cystography is performed under a pressure of 30 cm/H2O. The contribution of the findings of these periodic evaluations vis-a-vis the surgical findings were studied. RESULTS: The medical charts of 49 patients who had been surgically treated for exstrophy-epispadias complex in our institution between 2000 and 2014 were reviewed. Thirty patients underwent at least one evaluation. Eighteen underwent serial examinations: four underwent two procedures, eleven underwent three procedures, and three underwent four procedures. The findings in eight cases were significant and they were treated on detection: bladder neck stricture (n = 5), bladder scar bridge (n = 2), and bladder stone (n = 1). Vesicoureteral reflux was present in all 30 patients, and high-grade reflux was present in 10 patients, of whom four had a bladder neck stricture. Fourteen of the 30 patients had a bladder capacity of 90 mL on the first evaluation, as did an additional eight children during later evaluations. Bladder capacity decreased below 90 mL in one child. Seven children did not reach the target capacity (Figure). CONCLUSION: Cystoscopic and cystometrographic evaluation of an exstrophic bladder allows early diagnosis of treatable bladder pathologies and monitoring of bladder capacity. It is a valuable tool in the follow-up period preceding bladder neck reconstruction. PMID- 26653075 TI - Retrospective diagnosis of Birt-Hogg-Dube syndrome in a 74-year-old male: The importance of imaging. PMID- 26653076 TI - Nitrogen-Doped Carbon Nanotubes Supported by Macroporous Carbon as an Efficient Enzymatic Biosensing Platform for Glucose. AB - Effective immobilization of enzymes/proteins on an electrode surface is very essential for biosensor development, but it still remains challenging because enzymes/proteins tend to form close-packed structures on the electrode surface. In this work, nitrogen-doped carbon nanotubes (NCNTs) supported by three dimensional Kenaf Stem-derived porous carbon (3D-KSC) (denoted as 3D-KSC/NCNTs) nanocomposites were constructed as the supporting matrix to load glucose oxidase (GOD) for preparing integrated glucose biosensors. These NCNTs are vertically arrayed on the channel walls of the 3D-KSC via the chemical vapor deposition method, which could noticeably increase the effective surface area, mechanical stability, and active sites (originating from the doped nitrogen) of the nanocomposites. The integrated glucose biosensor exhibits some advantages over the traditional GOD electrodes in terms of the capability to promote the direct electron transfer of GOD, enhance the mechanical stability of the biosensor attributed to the strong interaction between NCNTs and GOD, and enlarge the specific surface area to efficiently load a large number of GODs. The as-prepared biosensor shows a good performance toward both oxygen reduction and glucose biosensing. This study essentially offers a novel approach for the development of biosensors with excellent analytical properties. PMID- 26653077 TI - Extension of Structure-Reactivity Correlations for the Hydrogen Abstraction Reaction by Bromine Atom and Comparison to Chlorine Atom and Hydroxyl Radical. AB - Recently we presented structure-reactivity correlations for the gas-phase ambient temperature rate constants for hydrogen abstraction from sp(3)-hybridized carbon by chlorine atom and hydroxyl radical (Cl*/HO* + HCR3 -> HCl/HOH + *CR3); the reaction enthalpy effect was represented by the independent variable DeltarH and the "polar effect" by the independent variables F and R, the Hammett constants for field/inductive and resonance effects. Both these reactions are predominantly exothermic and have early transition states. Here, we present a parallel treatment for Br* whose reaction is significantly endothermic with a correspondingly late transition state. Despite lower expectations because the available database is less extensive and much more scattered and because long temperature extrapolations are often required, the resulting least-squares fit (log k298,Br = -0.147 DeltarH - 4.32 SigmaF - 4.28 SigmaR - 12.38 with r(2) = 0.92) was modestly successful and useful for initial predictions. The coefficient of DeltarH was ~4-fold greater, indicative of the change from an early to a late transition state; meanwhile the sizable coefficients of SigmaF and SigmaR indicate the persistence of the "polar effect". Although the mean unsigned deviation of 0.79 log k298 units is rather large, it must be considered in the context of a total span of over 15 log units in the data set. The major outliers are briefly discussed. PMID- 26653078 TI - Mitochondria-Targeted Approach: Remarkably Enhanced Cellular Bioactivities of TPP2a as Selective Inhibitor and Probe toward TrxR. AB - A mitochondria-targeted approach was developed to increase the cellular bioactivities of thioredoxin reductase (TrxR) inhibitors. By being conjugated with a triphenylphosphine (TPP) motif to a previously found TrxR inhibitor 2a, the resulted compound TPP2a can target subcellular mitochondria and efficiently inhibit cellular TrxR, leading to remarkably increased cellular ROS level and mitochondrial apoptosis of HeLa cancer cells. The cellular bioactivities of TPP2a, including its cytotoxicity against a panel of cancer cell lines, dramatically elevated compared with its parental compound 2a. The selectively and covalently interaction of TPP2a with subcellular mitochondrial TrxR was validated by fluorescent microscopy. Moreover, a nonspecific signal quenching coupled strategy was proposed based on the environmentally sensitive fluorescence of TPP2a, which makes it possible to label TrxR by removing the nonspecific backgrounds caused by TPP2a under complex biosettings such as cellular lysates and living cells, implicating a potential of TPP2a for TrxR-specific labeling. PMID- 26653079 TI - Navigating MRI-TRUS fusion biopsy: optimizing the process and avoiding technical pitfalls. AB - Multi-parametric MRI (mpMRI) is widely used in the detection and characterization of clinically- significant prostate cancer. MRI-TRUS (trans-rectal ultrasound) fusion biopsy is an in-office procedure that promises to empower urologists to successfully target these MRI-visible lesions for histological confirmation. We describe the moving parts in the process and discuss methods to optimize biopsy outcomes. mpMRI is highly technical and reader-dependent. The acquisition of US images to generate a valid 3D US model and subsequent registration and fusion requires the urologist to attain equilibrium of probe position and pressure to achieve maximum registration accuracy. Environmental, medical and engineering measures can be undertaken to improve targeting accuracy. The art and skill of 'hitting' a visual target involves real-time recognition and adjustment for potential errors/ mis-registration in the fusion guide. A multi-disciplinary team effort is critical to improve all steps of the procedure. PMID- 26653080 TI - A prospective study on the causes of notably raised alanine aminotransferase (ALT). AB - OBJECTIVE: High levels of alanine aminotransferase (ALT) can be a marker of severe liver disease with variable aetiologies and prognosis. Very few prospective studies have been undertaken on the aetiology and prognosis of patients with high ALT levels. No population-based prospective study has systematically evaluated drug-induced liver injury (DILI) among these patients. The objective was to determine the aetiology and prognosis of patients with high ALT. MATERIALS AND METHODS: In a catchment area of 160,000 inhabitants, a population-based prospective study identified all adult patients with serum level of ALT >500 U/L during a 12-month period. All underwent thorough diagnostic work up and follow-up. In suspected DILI, causality was assessed with Roussel Uclaf Causality Assessment Method. RESULTS: A total of 155 patients were identified with ALT >500 U/L, 12 children and one with ALT of non-liver-related origin, leaving 142 patients for the analysis: 73 (51%) males, median age 52 (IQR 36-68, range 19-89 years). The most common causes were choledocholithiasis 48/142 (34%), ischaemic hepatitis 26 (18%), viral hepatitis 16 (11%) and DILI 15 (11%), hepatobiliary malignancy (n = 6), surgery/interventions (n = 8) and other aetiologies (n = 23). No specific aetiology was found in 6% of cases. In the total study cohort 99 (70%) required hospitalisation, 78 (55%) had jaundice and 22 (16%) died, liver-related death in 10%, 35% in IH and 7% in DILI. CONCLUSIONS: The most common cause of notably high ALT was choledocholithiasis. Ischaemic hepatitis was a common aetiology with approximately 35% liver-related mortality. Viral hepatitis and DILI were important aetiologies among these patients. PMID- 26653081 TI - Telomere maintenance is pivotal for high-risk neuroblastoma. PMID- 26653082 TI - Implications of Human Transient Receptor Potential Melastatin 8 (TRPM8) Channel Gating from Menthol Binding Studies of the Sensing Domain. AB - The transient receptor potential melastatin 8 (TRPM8) ion channel is the primary cold sensor in humans. TRPM8 is gated by physiologically relevant cold temperatures and chemical ligands that induce cold sensations, such as the analgesic compound menthol. Characterization of TRPM8 ligand-gated channel activation will lead to a better understanding of the fundamental mechanisms that underlie TRPM8 function. Here, the direct binding of menthol to the isolated hTRPM8 sensing domain (transmembrane helices S1-S4) is investigated. These data are compared with two mutant sensing domain proteins, Y745H (S2 helix) and R842H (S4 helix), which have been previously identified in full length TRPM8 to be menthol insensitive. The data presented herein show that menthol specifically binds to the wild type, Y745H, and R842H TRPM8 sensing domain proteins. These results are the first to show that menthol directly binds to the TRPM8 sensing domain and indicates that Y745 and R842 residues, previously identified in functional studies as crucial to menthol sensitivity, do not affect menthol binding but instead alter coupling between the sensing domain and the pore domain. PMID- 26653083 TI - Mepolizumab in the treatment of severe eosinophilic asthma. AB - IL-5 is crucial in the pathogenesis and evolution of eosinophilic asthma. Mepolizumab is a high-affinity humanized monoclonal antibody of the IgG1/k subtype that inhibits the binding of IL-5 to its receptor expressed on eosinophils, thereby inducing significant reduction in eosinophil circulation, as well as asthma exacerbations and corticosteroid treatment. This review deals with the currently available studies of mepolizumab in the treatment of patients with severe eosinophilic asthma. PMID- 26653085 TI - Is Ongoing Sulfluramid Use in South America a Significant Source of Perfluorooctanesulfonate (PFOS)? Production Inventories, Environmental Fate, and Local Occurrence. AB - Despite international phase-out initiatives, production and use of perfluorooctanesulfonate (PFOS) and related substances continues in some countries. In Brazil, the PFOS-precursor N-ethyl perfluorooctane sulfonamide (EtFOSA) is used in Sulfluramid, a pesticide for controlling leaf-cutting ants. New data on production, environmental fate, and occurrence of Brazilian Sulfluramid are reported herein. From 2003 to 2013, Brazilian Sulfluramid manufacturing increased from 30 to 60 tonnes yr(-1) EtFOSA. During this time <1.3 tonnes yr(-1) were imported, while exports increased from ~0.3 to 2 tonnes yr( 1). From 2004 to 2015, most EtFOSA was exported to Argentina (7.2 tonnes), Colombia (2.07 tonnes), Costa Rica (1.13 tonnes), Equador (2.16 tonnes), and Venezuela (2.4 tonnes). Within Brazil, sales occurred primarily in the states of Minas Gerais, Sao Paulo, Mato Grosso do Sul, Espirito Santo, and Bahia. Model simulations predict EtFOSA will partition to soils, while transformation products perfluorooctane sulfonamide (FOSA) and PFOS are sufficiently mobile to leach into surface waters. In support of these predictions, up to 3400 pg L(-1) of FOSA and up to 1100 pg L(-1) of PFOS were measured in Brazilian surface water, while EtFOSA was not detected. The high FOSA/PFOS ratio observed here (up to 14:1) is unprecedented in the scientific literature to our knowledge. Depending on the extent of conversion of EtFOSA, cumulative Brazilian Sulfluramid production and import from 2004 to 2015 may contribute between 167 and 487 tonnes of PFOS/FOSA to the environment. These levels are clearly nontrivial and of concern since production is continuing unabated. PMID- 26653084 TI - Human papillomavirus variants among Inuit women in northern Quebec, Canada. AB - BACKGROUND: Inuit communities in northern Quebec have high rates of human papillomavirus (HPV) infection, cervical cancer and cervical cancer-related mortality as compared to the Canadian population. HPV types can be further classified as intratypic variants based on the extent of homology in their nucleotide sequences. There is limited information on the distribution of intratypic variants in circumpolar areas. OBJECTIVE: Our goal was to describe the HPV intratypic variants and associated baseline characteristics. DESIGN: We collected cervical cell samples in 2002-2006 from 676 Inuit women between the ages of 15 and 69 years in Nunavik. DNA isolates from high-risk HPVs were sequenced to determine the intratypic variant. RESULTS: There were 149 women that were positive for HPVs 16, 18, 31, 33, 35, 45, 52, 56 or 58 during follow-up. There were 5 different HPV16 variants, all of European lineage, among the 57 women positive for this type. There were 8 different variants of HPV18 present and all were of European lineage (n=21). The majority of samples of HPV31 (n=52) were of lineage B. The number of isolates and diversity of the other HPV types was low. Age was the only covariate associated with HPV16 variant category. CONCLUSIONS: These frequencies are similar to what was seen in another circumpolar region of Canada, although there appears to be less diversity as only European variants were detected. This study shows that most variants were clustered in one lineage for each HPV type. PMID- 26653086 TI - Macromolecular Hydrogen Sulfide Donors Trigger Spatiotemporally Confined Changes in Cell Signaling. AB - Hydrogen sulfide (H2S) is involved in a myriad of cell signaling processes that trigger physiological events ranging from vasodilation to cell proliferation. Moreover, disturbances to H2S signaling have been associated with numerous pathologies. As such, the ability to release H2S in a cellular environment and stimulate signaling events is of considerable interest. Herein we report the synthesis of macromolecular H2S donors capable of stimulating cell signaling pathways in both the cytosol and at the cell membrane. Specifically, copolymers having pendent oligo(ethylene glycol) and benzonitrile groups were synthesized, and the benzonitrile groups were subsequently transformed into primary aryl thioamide groups via thionation using sodium hydrosulfide. These thioamide moieties could be incorporated into a hydrophilic copolymer or a block copolymer (i.e., into either the hydrophilic or hydrophobic domain). An electrochemical sensor was used to demonstrate release of H2S under simulated physiological conditions. Subsequent treatment of HEK293 cells with a macromolecular H2S donor elicited a slow and sustained increase in cytosolic ERK signaling, as monitored using a FRET-based biosensor. The macromolecular donor was also shown to induce a small, fast and sustained increase in plasma membrane-localized PKC activity immediately following addition to cells. Studies using an H2S-selective fluorescent probe in live cells confirmed release of H2S from the macromolecular donor over physiologically relevant time scales consistent with the signaling observations. Taken together, these results demonstrate that by using macromolecular H2S donors it is possible to trigger spatiotemporally confined cell signaling events. Moreover, the localized nature of the observed signaling suggests that macromolecular donor design may provide an approach for selectively stimulating certain cellular biochemical pathways. PMID- 26653087 TI - Decreasing Risk for Mass Shootings in the United States. PMID- 26653090 TI - A Question About the Safety of Buprenorphine/Naloxone and Benzodiazepine Drugs. AB - Drug overdose is the leading cause of injury death in the United States, and most deaths are related to prescription drugs. A substantial proportion of these deaths involve opioid or benzodiazepine drugs, and many overdoses include a combination of both drug classes. Buprenorphine/naloxone has an unusual pharmacology that distinguishes it from other opioid drugs. Animal and human studies have found that buprenorphine is associated with a ceiling to its cardio respiratory depressant effect at higher doses, such that it may have a wider safety margin compared to other opioid drugs. Compared to buprenorphine alone, buprenorphine/naloxone is associated with less cardiorespiratory depression. Drug safety data from the National Poison Data System, Drug Abuse Warning Network, and other sources suggest that the safety of buprenorphine/naloxone is favorable compared to the morbidity and mortality associated with other opioid drugs and other classes of psychotropic drugs. PMID- 26653091 TI - Mental Health of Young Refugees. AB - Children and adolescents exposed to violence and upheaval of war and relocation are at high risk of developing posttraumatic stress disorder (PTSD) and depression. Rates of PTSD among refugee children may exceed 50%. Additional stressors encountered while adjusting to host cultures add another layer of difficulty. Most refugee children struggling with symptoms of PTSD or depression are never linked with appropriate mental health care resources. Psychiatric nurses can serve a critical function in the identification and treatment of refugee children experiencing PTSD and depression. PMID- 26653093 TI - A recommended epidemiological study design for examining the adverse health effects among emergency workers who experienced the TEPCO fukushima daiichi NPP accident in 2011. AB - Results from medical examinations conducted in 2012 of workers who were engaged in radiation work in 2012 as a result of the 2011 Fukushima Daiichi Nuclear Power Plant (NPP) accident showed that the prevalence of abnormal findings was 4.21%, 3.23 points higher than the 0.98% that was found prior to the accident in the jurisdiction area of the labor inspection office which holds jurisdiction over the NPP. The Ministry of Health, Labour and Welfare (MHLW) concluded that the 2010 and 2012 data cannot be easily compared because 70% of the enterprises within the jurisdiction of the office that reported the 2012 results were different from those that did so in 2010. In addition, although the radiation workers' estimated average dose weighted by number of workers was 3.66 times higher than decontamination workers' dose, the prevalence among radiation workers was only 1.14 times higher than that among decontamination workers. Based on the results of the medical examinations, however, the MHLW decided to implement an epidemiological study on the health effects of radiation exposure on all emergency workers. This article explains key issues of the basic design of the study recommended by the expert meeting established in the MHLW and also identifies challenges that could not be resolved and thus required further consideration by the study researchers. The major issues included: (a) study methods and target group; (b) evaluation of cumulative doses; (c) health effects (end points); (d) control of confounding factors; and (e) study implementation framework. Identified key challenges that required further deliberation were: (a) preventing arbitrary partisan analysis; (b) ensuring a high participation rate; (c) inquiry about the medical radiation doses; and (d) the preparedness of new analytical technology. The study team formulated and implemented the pilot study in 2014 and started the full-scale study in April 2015 with funding from a research grant from the MHLW. PMID- 26653094 TI - A comparative study on the effects of air gap wind and walking motion on the thermal properties of Arabian Thawbs and Chinese Cheongsams. AB - This paper reports on an experimental investigation on the effects of air gap, wind and walking motion on the thermal properties of traditional Arabian thawbs and Chinese cheongsams. Total thermal resistance (It) and vapour resistance (Re) were measured using the sweating fabric manikin - 'Walter', and the air gap volumes of the garments were determined by a 3D body scanner. The results showed the relative changes of It and Re of thawbs due to wind and walking motion are greater than those of cheongsams, which provided an explanation of why thawbs are preferred in extremely hot climate. It is further shown that thermal insulation and vapour resistance of thawbs increase with the air gap volume up to about 71,000 cm(3) and then decrease gradually. Thawbs with higher air permeability have significantly lower evaporative resistance particularly under windy conditions demonstrating the advantage of air permeable fabrics in body cooling in hot environments. Practitioner Summary: This paper aims to better understand the thermal insulation and vapour resistance of traditional Arabian thawbs and Chinese cheongsams, and the relationship between the thermal properties and their fit and design. The results of this study provide a scientific basis for designing ethnic clothing used in hot environments. PMID- 26653095 TI - Queen of Fights: Lesbians in Tunisian Sports. AB - Sport within the Muslim context, including in the location of this study, Tunisia, remains an institution designed for the promotion of a heterosexual form of masculinity and the degradation of both femininity and women's athleticism. Unlike recent advancements in the West, homosexuality remains viewed almost entirely negatively by the political, religious, and social debates in Muslim cultures. This overt hostility has almost entirely erased any visible gay culture within Muslim sports. It is within this context that this study finds importance. It represents the first-ever examination into the lives of lesbian Muslim athletes, in either a Muslim majority or non-majority state. Conducted on three lesbian athletes living in the Islamic country of Tunisia, we show that each is out of the closet to varying degrees but that homophobia within their sports-even on majority lesbian teams-remains rife. We discuss the coping strategies these athletes invoke to negotiate their sexual orientation in this highly homophobic nation and homohysteric sporting culture. PMID- 26653096 TI - Video Laryngoscopy Improves Odds of First-Attempt Success at Intubation in the Intensive Care Unit. A Propensity-matched Analysis. AB - RATIONALE: Urgent tracheal intubation is performed frequently in intensive care units and incurs higher risk than when intubation is performed under more controlled circumstances. Video laryngoscopy may improve the chances of successful tracheal intubation on the first attempt; however, existing comparative data on outcomes are limited. OBJECTIVES: To compare first-attempt success and complication rates during intubation when using video laryngoscopy compared with traditional direct laryngoscopy in a tertiary academic medical intensive care unit. METHODS: We prospectively collected and analyzed data from a continuous quality improvement database of all intubations in one medical intensive care unit between January 1, 2012, and December 31, 2014. Propensity matching and multivariable logistic regression were used to reduce the risk of bias and control for confounding. MEASUREMENTS AND MAIN RESULTS: A total of 809 intubations took place over the study period. Of these, 673 (83.2%) were performed using video laryngoscopy and 136 (16.8%) using direct laryngoscopy. First-attempt success with video laryngoscopy was 80.4% (95% confidence interval [CI], 77.2-83.3%) compared with 65.4% (95% CI, 56.8-73.4%) for intubations performed with direct laryngoscopy (P < 0.001). In a propensity-matched analysis, the odds ratio for first-attempt success with video laryngoscopy versus direct laryngoscopy was 2.81 (95% CI, 2.27-3.59). The rate of arterial oxygen desaturation events during the first intubation attempt was significantly lower for video laryngoscopy than for direct laryngoscopy (18.3% vs. 25.9%; P = 0.04). The rate of esophageal intubation during any attempt was also significantly lower for video laryngoscopy (2.1% vs. 6.6%; P = 0.008). CONCLUSIONS: Video laryngoscopy was associated with significantly improved odds of first-attempt success at tracheal intubation by nonanesthesiologists in a medical intensive care unit. Esophageal intubation and oxygen desaturation occurred less frequently with the use of video laryngoscopy. Randomized clinical trials are needed to confirm these findings. PMID- 26653097 TI - Differential associations of urbanicity and income with physical activity in adults in urbanizing China: findings from the population-based China Health and Nutrition Survey 1991-2009. AB - BACKGROUND: High urbanicity and income are risk factors for cardiovascular related chronic diseases in low- and middle-income countries, perhaps due to low physical activity (PA) in urban, high income areas. Few studies have examined differences in PA over time according to income and urbanicity in a country experiencing rapid urbanization. METHODS: We used data from the China Health and Nutrition Survey, a population-based cohort of Chinese adults (n = 20,083; ages 18-75y) seen a maximum of 7 times from 1991-2009. We used sex-stratified, zero inflated negative binomial regression models to examine occupational, domestic, leisure, travel, and total PA in Chinese adults according to year, urbanicity, income, and the interactions among urbanicity, income, and year, controlling for age and region of China. RESULTS: We showed larger mean temporal PA declines for individuals living in relatively low urbanicity areas (1991: 500 MET-hours/week; 2009: 300 MET-hours/week) compared to high urbanicity areas (1991: 200 MET hours/week; 2009: 125 MET-hours/week). In low urbanicity areas, the association between income and total PA went from negative in 1991 (p < 0.05) to positive by 2000 (p < 0.05). In relatively high urbanicity areas, the income-PA relationship was positive at all time points and was statistically significant at most time points after 1997 (p < 0.05). Leisure PA was the only domain of PA that increased over time, but >95% of individuals in low urbanicity areas reported zero leisure PA at each time point. CONCLUSIONS: Our findings show changing associations for income and urbanicity with PA over 18 years of urbanization. Total PA was lower for individuals living in more versus less urban areas at all time points. However, these differences narrowed over time, which may relate to increases in individual-level income in less urban areas of China with urbanization. Low income individuals in higher urbanicity areas are a particularly critical group to target to increase PA in China. PMID- 26653098 TI - Implantable Graphene-based Neural Electrode Interfaces for Electrophysiology and Neurochemistry in In Vivo Hyperacute Stroke Model. AB - Implantable microelectrode arrays have attracted considerable interest due to their high temporal and spatial resolution recording of neuronal activity in tissues. We herein presented an implantable multichannel neural probe with multiple real-time monitoring of neural-chemical and neural-electrical signals by a nonenzymatic neural-chemical interface, which was designed by creating the newly developed reduced graphene oxide-gold oxide (rGO/Au2O3) nanocomposite electrode. The modified electrode on the neural probe was prepared by a facile one-step cyclic voltammetry (CV) electrochemical method with simultaneous occurrence of gold oxidation and GOs reduction to induce the intimate attachment by electrostatic interaction using chloride ions (Cl(-)). The rGO/Au2O3-modified electrode at a low deposition scan rate of 10 mVs(-1) displayed significantly improved electrocatalytic activity due to large active areas and well-dispersive attached rGO sheets. The in vitro amperometric response to H2O2 demonstrated a fast response of less than 5 s and a very low detection limit of 0.63 MUM. In in vivo hyperacute stroke model, the concentration of H2O2 was measured as 100.48 +/ 4.52 MUM for rGO/Au2O3 electrode within 1 h photothrombotic stroke, which was much higher than that (71.92 MUM +/- 2.52 MUM) for noncoated electrode via in vitro calibration. Simultaneously, the somatosensory-evoked potentials (SSEPs) test provided reliable and precise validation for detecting functional changes of neuronal activities. This newly developed implantable probe with localized rGO/Au2O3 nanocomposite electrode can serve as a rapid and reliable sensing platform for practical H2O2 detection in the brain or for other neural-chemical molecules in vivo. PMID- 26653099 TI - Rapid dissemination of colistin and carbapenem resistant Acinetobacter baumannii in Central Greece: mechanisms of resistance, molecular identification and epidemiological data. AB - BACKGROUND: Colistin-resistant/carbapenem-resistant Acinetobacter baumannii is a significant challenge for antibiotic treatment and infection control policies. Since 2012, in Central Greece an increase of colistin/pan- resistant A. baumannii has occurred, indicating the need for further analysis. METHODS: A total of 86 colistin-resistant/carbapenem-resistant out of 1228 A. baumannii clinical isolates, consecutively collected between 2012 and 2014 in a tertiary Greek hospital of Central Greece, as well as one environmental isolate from surveillance cultures were studied. Molecular typing and mechanisms of resistance to colistin and to carbapenems were assessed, whereas, epidemiological and clinical data of the patients were reviewed. RESULTS: During the study period, the rate of colistin resistance gradually increased and reached 21.1 % in 2014. All colistin-resistant/carbapenem-resistant A. baumannii belonged to 3LST ST101 clone that corresponds to the international clonal lineage II. Carbapenem resistance was associated with the presence of bla oxa-23-like, while resistance to colistin probably correlated with G54E and R109H amino acid substitutions in PmrA and PmrC, respectively. CONCLUSIONS: Epidemiological data of the patients indicated that the first detection of colistin-resistant/carbapenem-resistant ST101 clone in the University Hospital of Larissa (UHL) was associated with a patient who previously had received colistin, while, the movement of the infected patients into the hospital probably resulted to its spread. PMID- 26653101 TI - Acceptability and feasibility of the 'DASH for Asthma' intervention in a randomized controlled trial pilot study. AB - OBJECTIVE: 'DASH for Asthma' (n 90) was a 6-month randomized controlled trial that demonstrated potential benefits of a DASH (Dietary Approaches to Stop Hypertension) behavioural intervention for improving diet quality and asthma control by comparing intervention to usual care in adults with uncontrolled asthma. The present study examined acceptability and feasibility of the intervention from the perspective of intervention participants and lifestyle coaches. DESIGN: Grounded in Social Cognitive Theory, the 3-month intensive stage, including three individual and eight group sessions, focused on diet modifications and behavioural self-regulation. The 3-month maintenance stage contained telephone consultations. Participants and lifestyle coaches completed surveys including 5-point Likert scales and open-ended questions. We analysed data using descriptive and inductive content analyses. SUBJECTS: Forty-six intervention participants (survey response rate was 65-72 %) and two lifestyle coaches. RESULTS: Participants and lifestyle coaches were highly satisfied (all mean ratings >4) with individual and group sessions. Participants identified mastery of knowledge and skills (awareness, goal setting, self-monitoring, problem solving), social learning (class members sharing experiences and ideas) and good coaching skills (reflective listening, empathy, motivational counselling) as important contributors to self-efficacy and programme satisfaction. Participants also valued personalized feedback received in individual sessions. Lifestyle coaches viewed participant engagement as a facilitator to effective sessions. Finally, participants and lifestyle coaches identified food tasting as beneficial for observational learning and facilitation of participant engagement. High class attendance and self-monitoring rate also reflected the high engagement among participants. CONCLUSIONS: The DASH behavioural intervention was feasible and highly acceptable to participants with uncontrolled asthma and lifestyle coaches. PMID- 26653100 TI - Informed consent in clinical practice: patients' experiences and perspectives following surgery. AB - BACKGROUND: Informed consent during medical practice is an essential component of comprehensive medical care and is a requirement that should be sought all the time the doctor interacts with the patients, though very challenging when it comes to implementation. Since the magnitude and frequency of surgery related risk are higher in a resource limited setting, informed consent for surgery in such settings should be more comprehensive. This study set out to evaluate patients' experiences and perspectives of informed consent for surgery. METHODS: This was a survey of post-operative patients at three university teaching hospitals in Uganda. The participants were interviewed using guided, semi structured questionnaires. Patients from different surgical disciplines participated in the study. RESULTS: A total of 371 patients participated in the study. Eighty percent of the participants reported having been given explanations on the indication for their surgery, 56.1 % had all their questions answered before the operation, 17 % did not know the type of operation they had undergone and another 17 % did not give their consent for the operation. Additionally, more than 81 % of the participants reported giving their own permission for surgery, although only 23.7 % were able to identify the person who obtained consent from them and 22.4 % knew the names of the surgeons who conducted the surgical procedure on them. About 20 % of the participants were not satisfied with the information provided by both the doctor before and after the operation. However, there were varying responses on when doctors should explain to patients with the majority saying it should be done before treatment or surgery, while others thought it should be done on admission, others proposed that it be made immediately after the examination among other responses. On what should be done to improve communication between doctors and patients, a number of suggestions, including the need for a detailed explanation for the patient by the doctor about their disease conditions and treatment options were suggested. CONCLUSIONS: Patients' perceptions of what constitutes informed consent are diverse and many patients undergo surgery without knowledge of the identity of the surgeon or the reason for the surgery. There is a need to improve on patients' participation in informed decision making, and this can be achieved through continuing medical education for doctors. PMID- 26653102 TI - Cobalt-Catalyzed Carbonylative Cyclization of Pyridinyl Diazoacetates for the Synthesis of Pyridoisoquinolinones. AB - Dicobalt octacarbonyl-catalyzed carbonylative cyclization of pyridinyl diazoacetates is developed for the synthesis of pyridoisoquinolinones under mild conditions (room temperature) in a carbon monoxide atmosphere. Moreover, a synthetic method for various pyridoisoquinolinones from ethylpyridinyl aryl acetates is demonstrated through diazotization using TsN3 and DBU followed by Co catalyzed carbonylation to generate ketene intermediates, which can subsequently undergo intramolecular cyclization under mild conditions in a carbon monoxide atmosphere in a semi-one-pot fashion. PMID- 26653103 TI - Adhesive Bioactive Coatings Inspired by Sea Life. AB - Inspired by nature, in particular by the marine mussels adhesive proteins (MAPs) and by the tough brick-and-mortar nacre-like structure, novel multilayered films are prepared in the present work. Organic-inorganic multilayered films, with an architecture similar to nacre based on bioactive glass nanoparticles (BG), chitosan, and hyaluronic acid modified with catechol groups, which are the main components responsible for the outstanding adhesion in MAPs, are developed for the first time. The biomimetic conjugate is prepared by carbodiimide chemistry and analyzed by ultraviolet-visible spectrophotometry. The buildup of the multilayered films is monitored with a quartz crystal microbalance with dissipation monitoring, and their topography is characterized by atomic force microscopy. The mechanical properties reveal that the films containing catechol groups and BG present an enhanced adhesion. Moreover, the bioactivity of the films upon immersion in a simulated body fluid solution is evaluated by scanning electron microscopy coupled with energy dispersive X-ray spectroscopy, Fourier transform infrared spectroscopy, and X-ray diffraction. It was found that the constructed films promote the formation of bonelike apatite in vitro. Such multifunctional mussel inspired LbL films, which combine enhanced adhesion and bioactivity, could be potentially used as coatings of a variety of implants for orthopedic applications. PMID- 26653104 TI - Full predicted energy from nutrition and the effect on mortality and infectious complications in critically ill adults: a protocol for a systematic review and meta-analysis of parallel randomised controlled trials. AB - BACKGROUND: Whilst nutrition is vital to survival in health, the precise role of nutrition during critical illness is controversial. More specifically, the exact amount of energy that is required during critical illness to optimally influence clinical outcomes remains unknown. The aim of this systematic literature review and meta-analysis is to evaluate the clinical effects of optimising nutrition to critically ill adult patients, such that the entire predicted amount of energy that the patient requires is delivered, on mortality and other important outcomes. METHODS: A systematic literature review and meta-analysis will be conducted by searching for studies indexed in Medical Literature Analysis and Retrieval System Online (MEDLINE), Excerpta Medica Database (EMBASE), Cumulative Index to Nursing and Allied Health Literature (CINAHL) and the Cochrane Library. Searches will be restricted to English. Studies will be considered for inclusion if they are a parallel randomised controlled trial investigating a nutrition intervention in an adult critical care population, where one arm delivers 'full predicted energy from nutrition' (defined as provision of >=80% of the predicted energy required) and the other arm delivers energy less than 80% of the predicted requirement. Two authors will independently perform title screening, full-text screening, data extraction and quality assessment for this review. The quality of individual studies will be assessed using the 'Risk of Bias' tool, and to assess the overall body of evidence, a 'Summary of Findings' table and the Grades of Recommendation, Assessment, Development and Evaluation system will be used, all recommended by the Cochrane Library. Pending the study heterogeneity that is determined, a fixed-effect meta-analysis with pre-defined subgroup analyses will be performed. DISCUSSION: Currently, it is controversial whether optimal energy delivery is beneficial for outcomes in critically ill patients. This systematic review and meta-analysis will evaluate whether delivering optimal energy to critically ill adult patients improves outcomes when compared to delivery of lesser amounts. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015027512. PMID- 26653106 TI - Pseudorhodobacter psychrotolerans sp. nov., a psychrotolerant bacterium isolated from terrestrial soil, and emended description of the genus Pseudorhodobacter. AB - A Gram-stain-negative, facultatively aerobic, cream-coloured, ovoid-shaped, non motile and psychrotolerant bacterial strain, PAMC 27389T, was isolated from terrestrial soil collected on King George Island, Antarctica. Phylogenetic analysis based on the 16S rRNA gene sequence revealed that strain PAMC 27389T belongs to the genus Pseudorhodobacter, sharing highest similarities with the type strains of Pseudorhodobacter wandonensis (96.9 %), Pseudorhodobacter antarcticus (96.8 %), Pseudorhodobacter ferrugineus (96.5 %) and Pseudorhodobacter aquimaris (95.4 %). Average nucleotide identity values between strain PAMC 27389T and the type strains of P. wandonensis, P. antarcticus, P. ferrugineus and P. aquimaris were 70.8, 70.9, 71.0 and 70.5 %, respectively and the genome-to-genome distances were 18.4-19.1 %, indicating PAMC 27389T is clearly distinguished from the most closely related Pseudorhodobacter species. The genomic DNA G+C content was 60.1 mol%. Strain PAMC 27389T grew at 0-37 degrees C (optimally at 15-20 degrees C), at pH 5.5-9.0 (optimally at pH 6.5 7.0) and in the presence of 0.5-3.0 % (w/v) sea salt (optimally with 0.5 %). It lacked bacteriochlorophyll a. The major fatty acids (>5 %) were summed feature 8 (C18 : 1omega7c and/or C18 : 1omega6c) and C18 : 1omega7c 11-methyl. The major polar lipids were phosphatidylcholine, phosphatidylglycerol, an unidentified phospholipid, an unidentified aminolipid, an unidentified lipid and three unidentified aminophospholipids. The major respiratory quinone was Q-10. Based on the phenotypic, chemotaxonomic and genomic data presented, we propose the name Pseudorhodobacter psychrotolerans sp. nov. with the type strain PAMC 27389T ( = KCTC 42640T = JCM 30764T). PMID- 26653107 TI - Phototropins do not alter accumulation of evening-phased circadian transcripts under blue light. AB - The circadian system induces rhythmic variation in a suite of biochemical and physiological processes that serve to optimise plant growth in diel cycles. To be of greatest utility, these rhythmic behaviors are coordinated with regular environmental changes such as the rising and setting of the sun. Photoreceptors, along with metabolites produced during photosynthesis, act to synchronise the internal timing mechanism with lighting cues. We have recently shown that phototropins help maintain robust rhythms of photosynthetic operating efficiency (phiPSII or Fq'/Fm') under blue light, although rhythmic accumulation of morning phased circadian transcripts in the nucleus was unaffected. Here we report that evening-phased nuclear clock transcripts were also unaffected. We also observe that rhythms of nuclear clock transcript accumulation are maintained in phototropin mutant plants under a fluctuating lighting regime that induced a loss of Fq'/Fm' rhythms. PMID- 26653108 TI - Development of a Polyclonal Antibody-Based Sandwich Enzyme-Linked Immunosorbent Assay for the Detection of Spores of Alicyclobacillus acidoterrestris in Various Fruit Juices. AB - A polyclonal rabbit antibody-based sandwich ELISA for the rapid and specific detection of spores of Alicyclobacillus acidoterrestris was established. The reactivity of the antisera with spores was confirmed by immunofluorescence. For a thorough evaluation of the ELISA, 61 strains and isolates of Alicyclobacillus spp. were characterized regarding their guaiacol production ability and genetic variability. The ELISA was highly sensitive, the detection limits were isolate dependent and ranged from 2.1 * 10(3) - 3.8 * 10(4) spores/mL, except for one isolate, for which a slightly lower sensitivity (5 * 10(5) spores/mL) was observed. Inclusivity tests revealed that the ELISA reacts with all tested A. acidoterrestris, while no cross-reactions with spores of 30 strains of Bacillus spp. and Clostridium spp. were observed. Further on, the assay applicability was tested with orange, apple (clear and unfiltered), tomato, pink grapefruit, pear, and white grape juices. Juices were inoculated with 1 or 10 spores/mL of A. acidoterrestris. After enrichment for 48 h, the established ELISA enabled the reliable and reproducible detection of contaminated samples. The enriched samples could be applied directly to the assay, underlining the robustness of the developed ELISA method. PMID- 26653109 TI - Recent nanomedicine articles of outstanding interest: functional nanomaterials for Brain Research through Advancing Innovative Neurotechnologies initiative. PMID- 26653110 TI - Targeting the IL-23/IL-17 axis for the treatment of psoriasis and psoriatic arthritis. AB - INTRODUCTION: A growing amount of data supporting the pathogenic role of the IL 23/IL-17 axis in inflammatory/autoimmune disorders has provided the rationale to target the system for therapeutic purpose. Several compounds have been and are currently under intense investigation in psoriasis and psoriatic arthritis (PsA) yielding impressive results. AREAS COVERED: In this review article, we provide an overview of currently available data on the IL-23/IL-17 system as a target for treatment for psoriasis and PsA. We searched MEDLINE for articles on drug therapy for psoriasis and PsA published between 1 January 2010 and 31 May 2015. One of these agents, ustekinumab, has been recently approved for the treatment of psoriasis and PsA, and a number of IL-23/IL-17-targeted compounds under investigation in these diseases. EXPERT OPINION: As our knowledge of the role of the IL-23/IL-17 axis in the pathogenesis of psoriasis and PsA deepens, it enables the development of more targeted therapies in the management of these conditions. Early data on IL-23/IL-17 targeting drugs appear promising, although incomplete. Given the key role IL-23/IL-17 in host defence, the safety profile of targeted drugs should be thoroughly assessed in future studies. PMID- 26653111 TI - Insulin Sensitivity and beta-Cell Function in SGA Children Treated With GH and GnRHa: Results of a Long-Term Trial. AB - CONTEXT: Pubertal children born small for gestational age with a poor adult height (AH) expectation can benefit from treatment with GH 1 mg/m(2)/d (~0.033 mg/kg/d) in combination with 2 years of GnRH analog (GnRHa) and even more so with GH 2 mg/m(2)/d. Because both GH and GnRHa can negatively influence insulin sensitivity, combining these treatments has raised concerns. The long-term GH dose effects on insulin sensitivity in children treated with combined GH/GnRHa are unknown. OBJECTIVE: The purpose of this study was to investigate insulin sensitivity and beta-cell function by a very precise method during long-term GH treatment, either with or without 2 years of additional GnRHa and to study differences in insulin sensitivity during treatment until AH between GH at 1 or 2 mg/m(2)/d. METHODS: This was a randomized, dose-response GH trial involving 110 short small for gestational age children (59 girls) treated with GH until AH (GH randomized to 1 or 2 mg/m(2)/d). Sixty-seven children received additional GnRHa treatment. Frequently sampled intravenous glucose tolerance tests were performed and insulin sensitivity (Si), acute insulin response (AIR), and disposition index (DI) were calculated using Bergman's MINMOD. The GH dose effect was evaluated in a subgroup of 48 children who started GH treatment in early puberty (randomized to 1 or 2 mg/m(2)/d) combined with 2 years of GnRHa. RESULTS: At AH, after 5.9 years of GH treatment, Si, AIR, and DI were similar between children treated with combined GH/GnRHa and those treated with GH only. In the subgroup of children who started GH treatment in early puberty (randomized to 1 or 2 mg/m(2)/d) together with 2 years of GnRHa treatment, there were no significant differences in Si, AIR, or DI between the GH dose groups during the treatment. CONCLUSIONS: Combined GH/GnRHa treatment has no long-term negative effects on insulin sensitivity and beta-cell function compared with GH only. Started in early puberty, a GH dose of 2 mg/m(2)/d results in a similar insulin sensitivity at AH as a GH dose of 1 mg/m(2)/d. PMID- 26653112 TI - Vitamin D Supplementation Modulates T Cell-Mediated Immunity in Humans: Results from a Randomized Control Trial. AB - CONTEXT: Although studies have linked vitamin D deficiency with immune-mediated diseases, data demonstrating a direct effect on T-cell function are sparse. OBJECTIVE: Our objective was to determine whether oral vitamin D3 influences T cell activation in humans with vitamin D deficiency. DESIGN: This was a single center ancillary study within Vitamin D Therapy in Individuals at High Risk of Hypertension, a double-blind, multicenter, randomized controlled trial. SETTING: This study was undertaken in a single academic medical center. PARTICIPANTS: Adults with vitamin D deficiency and untreated pre- or early stage I hypertension were included. INTERVENTION: In Vitamin D Therapy in Individuals at High Risk of Hypertension, participants were randomized to either low- (400 IU daily) or high- (4000 IU daily) dose oral vitamin D3 for 6 months. In this ancillary study of 38 patients, we measured CD4+ T-cell activation estimated by intracellular ATP release after stimulation of whole blood with plant lectin phytohemagglutinin collected at baseline (pretreatment) and 2-month follow-up. MAIN OUTCOME MEASURE: Determining whether ATP level changes were significantly different between treatment groups was the main outcome measure. RESULTS: Treatment with 4000 IU of vitamin D3 decreased intracellular CD4+ ATP release by 95.5 ng/ml (interquartile range, -219.5 to 105.8). In contrast, 400 IU of vitamin D3 decreased intracellular CD4+ ATP release by 0.5 ng/ml (interquartile range, -69.2 to 148.5). In a proportional odds model, high-dose vitamin D3 was more likely than low-dose vitamin D3 to decrease CD4+ ATP release (odds ratio, 3.43; 95% confidence interval, 1.06-1.11). CONCLUSIONS: In this ancillary study of a randomized controlled trial, we found that high-dose vitamin D3 significantly reduced CD4+ T-cell activation compared to low-dose vitamin D3, providing human evidence that vitamin D can influence cell-mediated immunity. PMID- 26653113 TI - The NK3 Receptor Antagonist ESN364 Suppresses Sex Hormones in Men and Women. AB - CONTEXT: Women's health disorders are commonly treated by agents that suppress the hypothalamic-pituitary-gonadal axis. NK3 receptor antagonism modulates this axis with distinct pharmacology compared to existing therapies. OBJECTIVE: The study aim was to evaluate safety, pharmacokinetics, and pharmacodynamics on gonadotropins and sex hormones after single- and multiple-dose administration of an NK3R antagonist to healthy men and women. DESIGN AND SETTING: This was a first in-human, double-blind, placebo-controlled, combined single and multiple ascending dose trial. PARTICIPANTS: Forty-one men and 24 regularly cycling women participated in the study. INTERVENTION(S): In part 1 of the study, men received single oral doses of 3-180 mg or placebo. In part 2, men received placebo or 20, 60, or 180 mg each day for 10 days. In part 3, women received placebo or 20, 60, or 180 mg each day for 21 days, where dosing was initiated on day 3 +/- 2 after menses. MAIN OUTCOME MEASURE(S): Safety, tolerability, pharmacokinetics, and pharmacodynamics on circulating levels of LH, FSH, testosterone, estradiol, and progesterone, in addition to physiological biomarkers of endometrial thickening, follicle growth, and the duration of the menstrual cycle were evaluated. RESULTS: ESN364 was well-tolerated and rapidly bioavailable with linear pharmacokinetics and no drug accumulation with repeated, daily oral administration. Drug treatment dose-dependently decreased basal LH, but not FSH, and consequently decreased estradiol and progesterone (in women) as well as testosterone (in men). The hormonal changes in women corresponded to delayed ovulation, decreased endometrial thickening, impeded follicular maturation, and prolongation of the menstrual cycle. Drug effects were rapidly reversible. CONCLUSIONS: Oral administration of the NK3R antagonist, ESN364, suppressed the hypothalamic pituitary-gonadal axis in healthy volunteers by selective modulation of gonadotropin secretion, leading to a restrained decrease in ovarian hormone levels in women. These results suggest that ESN364 may offer therapeutic benefit in the treatment of women's health disorders with a mitigated risk of menopausal like adverse events. PMID- 26653114 TI - Experimental and Computational Mechanistic Studies Guiding the Rational Design of Molecular Electrocatalysts for Production and Oxidation of Hydrogen. AB - Understanding how to control the movement of protons and electrons is crucial to the design of fast, efficient electrocatalysts for H2 production and oxidation based on earth-abundant metals. Our work seeks to address fundamental questions about proton movement. We have demonstrated that incorporating a pendant amine functioning as a proton relay in the second coordination sphere of a metal complex helps proton mobility, resulting in faster and more energy-efficient catalysts. Proton-transfer reactions can be rate-limiting and are influenced by several factors, such as pKa values, steric effects, hydrogen bonding, and solvation/desolvation of the exogenous base and acid employed. The presence of multiple protonation sites introduces branching points along the catalytic cycle, making less productive pathways accessible or leading to the formation of stable off-cycle species. Using ligands with only one pendant amine mitigates this problem and results in catalysts with high rates for production of H2, although generally at higher overpotentials. For H2 oxidation catalysts, iron complexes with a high H2 binding affinity were developed. However, these iron complexes had a pKa mismatch between the protonated metal center and the protonated pendant amine, and consequently intramolecular proton movement was slow. Taken altogether, our results demonstrate the necessity of optimizing the entire catalytic cycle because optimization of a specific catalytic step can negatively influence another step and not necessarily lead to a better catalytic performance. We discuss a general procedure, based on thermodynamic arguments, which allows the simultaneous minimization of the free-energy change of each catalytic step, yielding a nearly flat free-energy surface, with no large barriers due to energy mismatches from either high- or low-energy intermediates. PMID- 26653115 TI - All-Electrical Measurement of Interfacial Dzyaloshinskii-Moriya Interaction Using Collective Spin-Wave Dynamics. AB - Dzyaloshinskii-Moriya interaction (DMI), which arises from the broken inversion symmetry and spin-orbit coupling, is of prime interest as it leads to a stabilization of chiral magnetic order and provides an efficient manipulation of magnetic nanostructures. Here, we report all-electrical measurement of DMI using propagating spin wave spectroscopy based on the collective spin wave with a well defined wave vector. We observe a substantial frequency shift of spin waves depending on the spin chirality in Pt/Co/MgO structures. After subtracting the contribution from other sources to the frequency shift, it is possible to quantify the DMI energy in Pt/Co/MgO systems. The result reveals that the DMI in Pt/Co/MgO originates from the interfaces, and the sign of DMI corresponds to the inversion asymmetry of the film structures. The electrical excitation and detection of spin waves and the influence of interfacial DMI on the collective spin-wave dynamics will pave the way to the emerging field of spin-wave logic devices. PMID- 26653116 TI - Factors affecting the musculoskeletal disorders of workers in the frozen food manufacturing factories in Thailand. AB - The purpose of this research was to study factors affecting musculoskeletal disorders. The sample population of the study was 528 factory workers from the frozen food industry, as well as a controlled group of 255 office workers. The samples were collected during interviews using the Nordic questionnaire to assess musculoskeletal disorders, and to assess the risk by the rapid upper limb assessment and rapid entire body assessment techniques. The findings of the study were that most symptoms were found in the dissecting department, higher than in the controlled group. The details of the symptoms were, accordingly: elbow pain (adjusted odds ratio, 35.1; 95% CI [17.4, 70.9]). Regarding the risk of alcohol drinking, workers were exposed to more risks when alcohol was consumed. It is suggested that workers' health should be monitored regularly. People who work in a cold environment should be encouraged to wear body protection and to avoid drinking. PMID- 26653117 TI - Diagnosis and management of congenital dyserythropoietic anemias. AB - Congenital dyserythropoietic anemias (CDAs) are inherited disorders hallmarked by chronic hyporegenerative anemia, relative reticulocytopenia, hemolytic component and iron overload. They represent a subtype of the inherited bone marrow failure syndromes, characterized by impaired differentiation and proliferation of the erythroid lineage. Three classical types were defined by marrow morphology, even if the most recent classification recognized six different genetic types. The pathomechanisms of CDAs are different, but all seem to involve the regulation of DNA replication and cell division. CDAs are often misdiagnosed, since either morphological abnormalities or clinical features can be commonly identified in other clinically-related anemias. However, differential diagnosis is essential for guiding both follow up and management of the patients. PMID- 26653118 TI - Pushing the boundaries of computational approaches: special focus issue on computational chemistry and computer-aided drug discovery. PMID- 26653128 TI - Behavioral and neurochemical characterization of TrkB-dependent mechanisms of agomelatine in glucocorticoid receptor-impaired mice. AB - Growing evidence indicates that impairment of the stress response, in particular the negative feedback regulation mechanism exerted by the hypothalamo-pituitary adrenal (HPA) axis, might be responsible for the hippocampal atrophy observed in depressed patients. Antidepressants, possibly through the activation of BDNF signaling, may enhance neuroplasticity and restore normal hippocampal functions. In this context, glucocorticoid receptor-impaired (GR-i) mice-a transgenic mouse model of reduced GR-induced negative feedback regulation of the HPA axis-were used to investigate the role of BDNF/TrkB signaling in the behavioral and neurochemical effects of the new generation antidepressant drug, agomelatine. GR i mice exhibited marked alterations in depressive-like and anxiety-like behaviors, together with a decreased cell proliferation and altered levels of neuroplastic and epigenetic markers in the hippocampus. GR-i mice and their wild type littermates were treated for 21 days with vehicle, agomelatine (50mg/kg/day; i.p) or the TrkB inhibitor Ana-12 (0.5mg/kg/day, i.p) alone, or in combination with agomelatine. Chronic treatment with agomelatine resulted in antidepressant like effects in GR-i mice and reversed the deficit in hippocampal cell proliferation and some of the alterations of mRNA plasticity markers in GR-i mice. Ana-12 blocked the effect of agomelatine on motor activity as well as its ability to restore a normal hippocampal cell proliferation and expression of neurotrophic factors. Altogether, our findings indicate that agomelatine requires TrkB signaling to reverse some of the molecular and behavioral alterations caused by HPA axis impairment. PMID- 26653129 TI - Diagnostic and Prognostic Metabolites Identified for Joint Symptoms in the KORA Population. AB - This study aims at identifying metabolites that significantly associate with self reported joint symptoms (diagnostic) and metabolites that can predict the change from a symptom-free status to the development of self-reported joint symptoms after a 7 years period (prognostic). More than 300 metabolites were analyzed for 2246 subjects from the longitudinal study of the KORA (Cooperative Health Research in the Region of Augsburg, Germany), specifically the fourth survey S4 and its 7-year follow-up study F4. Two types of self-reported symptoms, chronic joint inflammation and worn out joints, were used for the analyses. Diagnostic analysis identified dysregulated metabolites in cases with symptoms compared with controls. Prognostic analysis identified metabolites that differentiate subjects in S4 who remained symptom-free after 7 years (F4) from those who developed any combination of symptoms. 48 metabolites were identified as nominally significantly (p < 0.05) associated with the self-reported symptoms in the diagnostic analysis, among which steroids show Bonferroni significance. 45 metabolites were identified as nominally significantly associated with developing symptoms after 7 years, among which hippurate showed Bonferroni significance. We show that metabolic profiles of self-reported joint symptoms are in line with metabolites known to associate with various forms of arthritis and suggest that future studies may benefit from that by investigating the possible use of self reporting/questionnaire along with metabolic markers for the early referral of patients for further diagnostic workup and treatment of arthritis. PMID- 26653130 TI - Multifunctional Microspheres Encoded with Upconverting Nanocrystals and Magnetic Nanoparticles for Rapid Separation and Immunoassays. AB - Immunoassays based on the downconversion target materials (organic dyes or quantum dots) lead to fairly strong spectral interference between the coded signal and reporter signal, which seriously affects the detection accuracy and hampers their applications. In this work, a new kind of upconverting nanocrystals encoded magnetic microspheres (UCNMMs) were designed and prepared successfully to solve the problem mentioned above. The UCNMMs were obtained by incorporating magnetic Fe3O4 nanoparticles and upconverting nanocrystals with polystyrene microspheres. Due to that upconverting nanocrystals (UCNs) and reporter signals are excitated by near-infrared and UV/visible light separately, immunoassays based on UCNMMs do not occur optical spectral interferences. Furthermore, these new functionalized UCNMMs have excellent properties in binding biomolecules and fast separating, which would have large potential applications in multiplexed assays. PMID- 26653131 TI - Carl E. Misch, DDS, PhD: More Than One Lifetime of Accomplishment. PMID- 26653132 TI - The Effects of Defect Type and Depth, and Measurement Direction on the Implant Stability Quotient Value. AB - The purpose of this study was to evaluate the effect of defect type and depth as well as measurement direction on implant stability in an ex vivo peri-implant bovine rib bone model. Six kinds of defects (3-wall 2.5 mm, 3-wall 5 mm, 1-wall 2.5 mm, 1-wall 5 mm, circumferential 2.5 mm, circumferential 5 mm), and control (no defect) were prepared in 14 bovine rib bones. A total of 84 defects and 14 controls were created. The same type and size of implants (4 * 10 mm) were placed in each group. The thickness of cortical bone and the insertion torque were measured for each defect, and the implant stability quotient (ISQ) value was measured 3 times from 4 different directions. The thickness of cortical bone ranged from 2.71-3.18 mm. Insertion torque decreased as the defect size increased. As the defect size for the same defect depth increased, the ISQ value decreased (P < .001). There were significant differences between the ISQ values obtained with different measurement directions only between the control and 3 wall 5 mm defect (P < .0001). The ISQ value opposite to the defect direction was higher than that in the defect direction in all 3 directions of the 3-wall and 1 wall 5 mm defects. ISQ values were influenced by defect type and depth. Loss of cortical bone reduced the stability of implants and reduced the ISQ value. Measurement direction also influenced ISQ values. PMID- 26653134 TI - Magnetically Hard Fe3Se4 Embedded in Bi2Se3 Topological Insulator Thin Films Grown by Molecular Beam Epitaxy. AB - We investigated the structural, magnetic, and electronic properties of Bi2Se3 epilayers containing Fe grown on GaAs(111) by molecular beam epitaxy. It is shown that, in the window of growth parameters leading to Bi2Se3 epilayers with optimized quality, Fe atom clustering leads to the formation of FexSey inclusions. These objects have platelet shape and are embedded within Bi2Se3. Monoclinic Fe3Se4 is identified as the main secondary phase through detailed structural measurements. Due to the presence of the hard ferrimagnetic Fe3Se4 inclusions, the system exhibits a very large coercive field at low temperature and room temperature magnetic ordering. Despite this composite structure and the proximity of a magnetic phase, the surface electronic structure of Bi2Se3 is preserved, as shown by the persistence of a gapless Dirac cone at Gamma. PMID- 26653135 TI - An examination of the developmental propensity model of conduct problems. AB - The present study tested specific hypotheses advanced by the developmental propensity model of the etiology of conduct problems in the Colorado Longitudinal Twin Study, a prospective, longitudinal, genetically informative sample. High negative emotionality, low behavioral inhibition, low concern and high disregard for others, and low cognitive ability assessed during toddlerhood (age 14 to 36 months) were examined as predictors of conduct problems in later childhood and adolescence (age 4 to 17 years). Each hypothesized antisocial propensity dimension predicted conduct problems, but some predictions may be context specific or due to method covariance. The most robust predictors were observed disregard for others (i.e., responding to others' distress with active, negative responses such as anger and hostility), general cognitive ability, and language ability, which were associated with conduct problems reported by parents, teachers, and adolescents, and change in observed negative emotionality (i.e., frustration tolerance), which was associated with conduct problems reported by teachers and adolescents. Furthermore, associations between the most robust early predictors and later conduct problems were influenced by the shared environment rather than genes. We conclude that shared environmental influences that promote disregard for others and detract from cognitive and language development during toddlerhood also predispose individuals to conduct problems in later childhood and adolescence. The identification of those shared environmental influences common to early antisocial propensity and later conduct problems is an important future direction, and additional developmental behavior genetic studies examining the interaction between children's characteristics and socializing influences on conduct problems are needed. (PsycINFO Database Record PMID- 26653136 TI - Inhibition of vicariously learned fear in children using positive modeling and prior exposure. AB - One of the challenges to conditioning models of fear acquisition is to explain how different individuals can experience similar learning events and only some of them subsequently develop fear. Understanding factors moderating the impact of learning events on fear acquisition is key to understanding the etiology and prevention of fear in childhood. This study investigates these moderators in the context of vicarious (observational) learning. Two experiments tested predictions that the acquisition or inhibition of fear via vicarious learning is driven by associative learning mechanisms similar to direct conditioning. In Experiment 1, 3 groups of children aged 7 to 9 years received 1 of 3 inhibitive information interventions-psychoeducation, factual information, or no information (control) prior to taking part in a vicarious fear learning procedure. In Experiment 2, 3 groups of children aged 7 to 10 years received 1 of 3 observational learning interventions-positive modeling (immunization), observational familiarity (latent inhibition), or no prevention (control)-before vicarious fear learning. Results indicated that observationally delivered manipulations inhibited vicarious fear learning, while preventions presented via written information did not. These findings confirm that vicarious learning shares some of the characteristics of direct conditioning and can explain why not all individuals will develop fear following a vicarious learning event. They also suggest that the modality of inhibitive learning is important and should match the fear learning pathway for increased chances of inhibition. Finally, the results demonstrate that positive modeling is likely to be a particularly effective method for preventing fear related observational learning in children. PMID- 26653137 TI - Taking the bull by the horns: Ethical considerations in the design and implementation of an Ebola virus therapy trial. AB - Ebola virus is categorized as one of the most dangerous pathogens in the world. Although there is no known cure for Ebola virus, there is some evidence that the severity of the disease can be curtailed using plasma from survivors. Although there is a general consensus on the importance of research, methodological and ethical challenges for conducting research in an emergency situation have been identified. Performing clinical trials is important, especially for health conditions that are of public health significance (including rare epidemics) to develop new therapies as well as to test the efficacy and effectiveness of new interventions. However, routine clinical trial procedures can be difficult to apply in emergency public health crises hence require a consideration of alternative approaches on how therapies in these situations are tested and brought to the market. This paper examines some of the ethical issues that arise when conducting clinical trials during a highly dangerous pathogen outbreak, with a special focus on the Ebola virus outbreak in West Africa. The issues presented here come from a review of a protocol that was submitted to the Global Emerging Pathogens Treatment Consortium (GET). In reviewing the proposal, which was about conducting a clinical trial to evaluate the safety and efficacy of using convalescent plasma in the management of Ebola virus disease, the authors deliberated on various issues, which were documented as minutes and later used as a basis for this paper. The experiences and reflections shared by the authors, who came from different regions and disciplines across Africa, present wide ranging perspectives on the conduct of clinical trials during a dangerous disease outbreak in a resource-poor setting. PMID- 26653138 TI - The piglet as a model for studying dietary components in infant diets: effects of galacto-oligosaccharides on intestinal functions. AB - Prebiotic oligosaccharides, including galacto-oligosaccharides (GOS), are used in infant formula to mimic human milk oligosaccharides, which are known to have an important role in the development of the intestinal microbiota and the immune system in neonates. The maturation of the intestines in piglets closely resembles that of human neonates and infants. Hence, a neonatal piglet model was used to study the multi-faceted effect of dietary GOS in early life. Naturally farrowed piglets were separated from the mother sow 24-48 h postpartum and received a milk replacer with or without the addition of GOS for 3 or 26 d, whereafter several indicators of intestinal colonisation and maturation were measured. Dietary GOS was readily fermented in the colon, leading to a decreased pH, an increase in butyric acid in caecum digesta and an increase in lactobacilli and bifidobacteria numbers at day 26. Histomorphological changes were observed in the intestines of piglets fed a GOS diet for 3 or 26 d. In turn, differences in the intestinal disaccharidase activity were observed between control and GOS-fed piglets. The mRNA expression of various tight junction proteins was up-regulated in the intestines of piglet fed a GOS diet and was not accompanied by an increase in protein expression. GOS also increased defensin porcine beta-defensin-2 in the colon and secretory IgA levels in saliva. In conclusion, by applying a neonatal piglet model, it could be demonstrated that a GOS-supplemented milk replacer promotes the balance of the developing intestinal microbiota, improves the intestinal architecture and seems to stimulate the intestinal defence mechanism. PMID- 26653139 TI - Capturing the temporal evolution of choice across prefrontal cortex. AB - Activity in prefrontal cortex (PFC) has been richly described using economic models of choice. Yet such descriptions fail to capture the dynamics of decision formation. Describing dynamic neural processes has proven challenging due to the problem of indexing the internal state of PFC and its trial-by-trial variation. Using primate neurophysiology and human magnetoencephalography, we here recover a single-trial index of PFC internal states from multiple simultaneously recorded PFC subregions. This index can explain the origins of neural representations of economic variables in PFC. It describes the relationship between neural dynamics and behaviour in both human and monkey PFC, directly bridging between human neuroimaging data and underlying neuronal activity. Moreover, it reveals a functionally dissociable interaction between orbitofrontal cortex, anterior cingulate cortex and dorsolateral PFC in guiding cost-benefit decisions. We cast our observations in terms of a recurrent neural network model of choice, providing formal links to mechanistic dynamical accounts of decision-making. PMID- 26653141 TI - DSP-based adaptive backstepping using the tracking errors for high-performance sensorless speed control of induction motor drive. AB - This paper presents a modified structure of the backstepping nonlinear control of the induction motor (IM) fitted with an adaptive backstepping speed observer. The control design is based on the backstepping technique complemented by the introduction of integral tracking errors action to improve its robustness. Unlike other research performed on backstepping control with integral action, the control law developed in this paper does not propose the increase of the number of system state so as not increase the complexity of differential equations resolution. The digital simulation and experimental results show the effectiveness of the proposed control compared to the conventional PI control. The results analysis shows the characteristic robustness of the adaptive control to disturbances of the load, the speed variation and low speed. PMID- 26653140 TI - A gene-expression screen identifies a non-toxic sumoylation inhibitor that mimics SUMO-less human LRH-1 in liver. AB - SUMO-modification of nuclear proteins has profound effects on gene expression. However, non-toxic chemical tools that modulate sumoylation in cells are lacking. Here, to identify small molecule sumoylation inhibitors we developed a cell-based screen that focused on the well-sumoylated substrate, human Liver Receptor Homolog-1 (hLRH-1, NR5A2). Our primary gene-expression screen assayed two SUMO sensitive transcripts, APOC3 and MUC1, that are upregulated by SUMO-less hLRH-1 or by siUBC9 knockdown, respectively. A polyphenol, tannic acid (TA) emerged as a potent sumoylation inhibitor in vitro (IC50 = 12.8 uM) and in cells. TA also increased hLRH-1 occupancy on SUMO-sensitive transcripts. Most significantly, when tested in humanized mouse primary hepatocytes, TA inhibits hLRH-1 sumoylation and induces SUMO-sensitive genes, thereby recapitulating the effects of expressing SUMO-less hLRH-1 in mouse liver. Our findings underscore the benefits of phenotypic screening for targeting post-translational modifications, and illustrate the potential utility of TA for probing the cellular consequences of sumoylation. PMID- 26653142 TI - New Insights into Nisin's Antibacterial Mechanism Revealed by Binding Studies with Synthetic Lipid II Analogues. AB - Nisin is the preeminent lantibiotic, and to date its antibacterial mechanism has been investigated using a variety of techniques. While nisin's lipid II-mediated mode of action is well-established, a detailed analysis of the thermodynamic parameters governing this interaction has not been previously reported. We here describe an approach employing isothermal titration calorimetry to directly measure the affinity of nisin for lipid II and a number of synthetic lipid II precursors and analogues. Our measurements confirm the pyrophosphate unit of lipid II as the primary site of nisin binding and also indicate that the complete MurNAc moiety is required for a high-affinity interaction. Additionally, we find that while the pentapeptide unit of the lipid II molecule is not required for strong binding by nisin, it does play an important role in stabilizing the subsequently formed nisin-lipid II pore complex, albeit at an entropic cost. The anchoring of lipid II in a membrane environment was also found to play a significant role in enhancing nisin binding and is required in order to achieve a high-affinity interaction. PMID- 26653143 TI - Phycicoccus endophyticus sp. nov., an endophytic actinobacterium isolated from Bruguiera gymnorhiza. AB - A novel endophytic actinobacterium, designated strain IP6SC6T, was isolated from surface-sterilized bark of Bruguiera gymnorhiza collected from Zhanjiang Mangrove Forest National Nature Reserve in Guangdong, China. Cells of strain IP6SC6T were Gram-stain-positive, aerobic, non-spore-forming, non-motile rods. Strain IP6SC6T grew at 20-42 degrees C (optimum, 37 degrees C), at pH 6.0-9.0 (optimum, pH 7.0) and in the presence of 0-8 % (w/v) NaCl (optimum, 0-2 %). Chemotaxonomic analyses showed that the isolate possessed meso-diaminopimelic acid as the diamino acid of the peptidoglycan, galactose and glucose as whole-cell sugars, and MK-8(H4) as the predominant menaquinone. The major polar lipids were diphosphatidylglycerol, phosphatidylinositol and an unknown lipid. The major fatty acids were iso-C15 : 0, anteiso-C15 : 0, anteiso-C17 : 0 and iso-C16 : 0. The G+C content of the genomic DNA was 72.5 mol%. Phylogenetic analyses based on 16S rRNA gene sequences revealed that strain IP6SC6T belonged to the genus Phycicoccus and shared the highest sequence similarity with Phycicoccus jejuensis NRRL B-24460T (96.97 %). On the basis of phylogenetic analysis and phenotypic and chemotaxonomic characteristics, strain IP6SC6T represents a novel species of the genus Phycicoccus, for which the name Phycicoccus endophyticus sp. nov. is proposed. The type strain is IP6SC6T ( = DSM 100020T = CGMCC 4.7300T). PMID- 26653144 TI - Two new diacetylene glycosides: bhutkesoside A and B from the roots of Ligusticopsis wallichiana. AB - Two new diacetylene glycosides: bhutkesoside A (1) and B (2), along with 10 known compounds, i.e. falcarindiol (3), chlorogenic acid (4), 5-O-p-coumaroyl-quinic acid (5), 3,5-di-O-caffeoyl-quinic acid (6), 4-hydroxy-7-methoxy-phenylethanol (7), ferulic acid (8), dehydrodiconiferyl alcohol-4-O-beta-d-glucopyranoside (9), 5,7-dihydroxy-2-methylchromone-7-O-rutinoside (10), schumanniofioside B (11) and marmesinin (12) were isolated from the roots of Ligusticopsis wallichiana (DC) Pimenov & Kljuykov (Apiaceae), commonly known as 'Bhutkesh' in Nepal. The structures were determined on the basis of spectroscopic data. Compounds 4 and 6 showed potent antioxidant activity on DPPH free radical scavenging assay. PMID- 26653145 TI - Identifying Vasopressor and Inotrope Use for Health Services Research. AB - RATIONALE: Identifying vasopressor and inotrope (vasopressor) use from administrative claims data may provide an important resource to study the epidemiology of shock. OBJECTIVES: Determine accuracy of identifying vasopressor use using International Classification of Disease, Ninth Revision, Clinical Modification (ICD-9-CM) coding. METHODS: Using administrative data enriched with pharmacy billing files (Premier, Inc., Charlotte, NC), we identified two cohorts: adult patients admitted with a diagnosis of sepsis from 2010 to 2013 or pulmonary embolism (PE) from 2008 to 2011. Vasopressor administration was obtained using pharmacy billing files (dopamine, dobutamine, epinephrine, milrinone, norepinephrine, phenylephrine, vasopressin) and compared with ICD-9-CM procedure code for vasopressor administration (00.17). We estimated performance characteristics of the ICD-9-CM code and compared patients' characteristics and mortality rates according to vasopressor identification method. MEASUREMENTS AND MAIN RESULTS: Using either pharmacy data or the ICD-9-CM procedure code, 29% of 541,144 patients in the sepsis cohort and 5% of 81,588 patients in the PE cohort were identified as receiving a vasopressor. In the sepsis cohort, the ICD-9-CM procedure code had low sensitivity (9.4%; 95% confidence interval, 9.2-9.5), which increased over time. Results were similar in the PE cohort (sensitivity, 5.8%; 95% confidence interval, 5.1-6.6). The ICD-9-CM code exhibited high specificity in the sepsis (99.8%) and PE (100%) cohorts. However, patients identified as receiving vasopressors by ICD-9-CM code had significantly higher unadjusted in-hospital mortality, had more acute organ failures, and were more likely hospitalized in the Northeast and West. CONCLUSIONS: The ICD-9-CM procedure code for vasopressor administration has low sensitivity and selects for higher severity of illness in studies of shock. Temporal changes in sensitivity would likely make longitudinal shock surveillance using ICD-9-CM inaccurate. PMID- 26653146 TI - The effectiveness of workplace interventions to increase physical activity and decrease sedentary behaviour in adults: protocol for a systematic review. AB - BACKGROUND: A physically active lifestyle plays a preventative role in the development of various chronic diseases and mental health conditions. Unfortunately, few adults achieve the minimum amount of physical activity and spend excessive time sitting. Developing targeted interventions to increase active living among adults is an important endeavour for public health. One plausible context to reach adults is the workplace. This systematic review aims to review the effectiveness of workplace interventions on increasing physical activity and decreasing sedentary behaviour in the workplace. METHODS: An advisory group of practitioners will work in collaboration with the research team to inform the systematic review and knowledge mobilization. Fifteen electronic databases will be searched to identify studies examining the effectiveness of workplace interventions on physical activity and sedentary behaviour. All experimental designs and observational studies (non-experimental intervention studies) meeting the study criteria will be included. Studies examining generally healthy, employed, adult participants will be included for the review. Interventions will focus on increasing physical activity and/or decreasing sedentary behaviour from the individual to policy level. The primary outcome variables will be reported or observed physical activity and/or sedentary behaviour in the workplace. Secondary outcomes will include variables ranging from return on investment to quality of life. Study quality will be assessed for risk of bias following the protocol identified in the Cochrane Handbook for Systematic Reviews of Interventions and supplemented by the guidelines developed by the Cochrane Effective Practice and Organisation of Care group, using RevMan. The quality of the evidence will be assessed using the Grading of Recommendations, Assessment, Development and Evaluation approach. Meta-analyses, forest plots, and harvest plots will be used where appropriate to assess the direction, size, and consistency of the intervention effect across the studies using similar intervention strategies. Follow-up knowledge mobilization activities and products will be developed to support the use of this knowledge in practice. DISCUSSION: This protocol paper describes a systematic review assessing the effectiveness of various types of workplace interventions on increasing physical activity and decreasing sedentary behaviour at work. Collaborating with an advisory group of potential knowledge users throughout the process postulates a greater use and reach of the information gained from this systematic review by knowledge users. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015019398. PMID- 26653149 TI - Alcohol-related visual cues impede the ability to process auditory information: Seeing but not hearing. AB - Studies of visual attention find that drinkers spend more time attending to images of alcohol-related stimuli compared to neutral images. It is believed that this attentional bias contributes to the maintenance of alcohol use. However, no research has examined the possibility that this bias of visual attention might actually impede the functioning of other modalities, such as the processing of accompanying auditory stimuli. This study aimed to determine if alcohol-related images engender greater sensory dominance than neutral images, such that processing accompanying information from another modality (audition) would be impeded. Drinkers who had an attentional bias to alcohol-related images performed a multisensory perception task that measured how alcohol-related versus neutral visual images affected their ability to detect and respond to simultaneously presented auditory signals. In accord with the hypothesis, compared with neutral images, the presentation of alcohol-related images impaired the ability to detect and respond to auditory signals. Increased dominance of the visual modality was demonstrated by more bimodal targets being misclassified as visual-only targets in the alcohol target condition compared with that of the neutral. Findings suggest that increased processing of alcohol-related stimuli may impede an individual's ability to encode and interpret information obtained from other sensory modalities. PMID- 26653148 TI - Detailed reconstruction of the nervous and muscular system of Lobatocerebridae with an evaluation of its annelid affinity. AB - BACKGROUND: The microscopic worm group Lobatocerebridae has been regarded a 'problematicum', with the systematic relationship being highly debated until a recent phylogenomic study placed them within annelids (Curr Biol 25: 2000-2006, 2015). To date, a morphological comparison with other spiralian taxa lacks detailed information on the nervous and muscular system, which is here presented for Lobatocerebrum riegeri n. sp. based on immunohistochemistry and confocal laser scanning microscopy, supported by TEM and live observations. RESULTS: The musculature is organized as a grid of longitudinal muscles and transverse muscular ring complexes in the trunk. The rostrum is supplied by longitudinal muscles and only a few transverse muscles. The intraepidermal central nervous system consists of a big, multi-lobed brain, nine major nerve bundles extending anteriorly into the rostrum and two lateral and one median cord extending posteriorly to the anus, connected by five commissures. The glandular epidermis has at least three types of mucus secreting glands and one type of adhesive unicellular glands. CONCLUSIONS: No exclusive "annelid characters" could be found in the neuromuscular system of Lobatocerebridae, except for perhaps the mid ventral nerve. However, none of the observed structures disputes its position within this group. The neuromuscular and glandular system of L. riegeri n. sp. shows similarities to those of meiofaunal annelids such as Dinophilidae and Protodrilidae, yet likewise to Gnathostomulida and catenulid Platyhelminthes, all living in the restrictive interstitial environment among sand grains. It therefore suggests an extreme evolutionary plasticity of annelid nervous and muscular architecture, previously regarded as highly conservative organ systems throughout metazoan evolution. PMID- 26653150 TI - Throat hit in users of the electronic cigarette: An exploratory study. AB - A cross-sectional survey on the Internet in 2012-2014 was used to study the "throat hit," the specific sensation in the throat felt by users of e-cigarettes. Participants were 1672 current users of e-cigarettes, visitors of Websites dedicated to e-cigarettes and to smoking cessation. It was assessed whether the strength of the throat hit was associated with the characteristics of e cigarettes and e-liquids, modifications of the devices, patterns of use, reasons for use, satisfaction with e-cigarettes, dependence on e-cigarettes, smoking behavior, and perceived effects on smoking. The strongest throat hit was obtained by using better-quality models and liquids with high nicotine content. Those who reported a "very strong" throat hit used liquids with 17.3 mg/mL nicotine, versus 7.1 mg/mL for those reporting a "very weak" hit (p < .001). The strength of the throat hit was also associated with ratings of dependence on e-cigarettes, and with the perceived efficacy of e-cigarettes to relieve craving for tobacco and to facilitate smoking cessation. All the variables assessing satisfaction with e cigarettes were associated with a stronger throat hit. From a public health perspective, there is a trade-off between e-cigarette models that provide high levels of nicotine, a strong throat hit, high satisfaction, and more effects on smoking, but may also be addictive, and models than contain less nicotine and are less addictive, but produce a weaker throat hit, are less satisfactory, and are possibly less efficient at helping people quit smoking. This trade-off must be kept in mind when regulating e-cigarettes. PMID- 26653152 TI - Turn-On Sulfide pi Donors: An Ultrafast Push for Twisted Mechanophores. AB - Attached to electron-rich aromatic systems, sulfides are very weak acceptors; however, attached to electron-poor aromatics, they turn into quite strong donors. Here, we show that this underappreciated dual nature of sulfides deserves full consideration for the design of functional systems. Tested with newly designed and synthesized planarizable push-pull mechanophores, sulfide acceptors in the twisted ground state are shown to prevent oxidative degradation and promote blue shifting deplanarization. Turned on in the planar excited state, sulfide donors promote red-shifting polarization. Impressive Stokes shifts are the result. Demonstrating the usefulness of time-resolved broadband emission spectra to address significant questions, direct experimental evidence for the ultrafast (3.5 ps), polarity-independent and viscosity-dependent planarization from the twisted Franck-Condon S1 state to the relaxed S1 state could be secured. PMID- 26653151 TI - Synthesis and anticancer evaluation of complex unsaturated isosteviol-derived triazole conjugates. AB - BACKGROUND: For the last two decades, diterpenoid isosteviol and its derivatives have gained significant attention for novel chemical transformation in the drug discovery field. RESULTS: An efficient way towards the synthesis of structurally diverse isosteviol derivatives was described here employing unsaturated functionalities as attractive templates for further transformation such as epoxidation. These structurally diverse compounds exhibited promising cytotoxic activities on different types of cancer cell lines, leading to drug discovery derived from natural products for the treatment of cancer. CONCLUSION: In this work, novel isosteviol derivatives with Michael acceptors were synthesized to expand the diversity and complexity of a class of isosteviol-derived triazole conjugates to facilitate the development of potential antitumor agents. PMID- 26653153 TI - DFT Study on Nitrite Reduction Mechanism in Copper-Containing Nitrite Reductase. AB - Dissimilatory reduction of nitrite by copper-containing nitrite reductase (CuNiR) is an important step in the geobiochemical nitrogen cycle. The proposed mechanisms for the reduction of nitrite by CuNiRs include intramolecular electron and proton transfers, and these two events are understood to couple. Proton coupled electron transfer is one of the key processes in enzyme reactions. We investigated the geometric structure of bound nitrite and the mechanism of nitrite reduction on CuNiR using density functional theory calculations. Also, the proton transfer pathway, the key residues, and their roles in the reaction mechanism were clarified in this study. In our results, the reduction of T2 Cu site promotes the proton transfer, and the hydrogen bond network around the binding site has an important role not only to stabilize the nitrite binding but also to promote the proton transfer to nitrite. PMID- 26653154 TI - Investigation of the flow-field in the upper respiratory system when wearing N95 filtering facepiece respirator. AB - This article presents a reverse modeling of the headform when wearing a filtering facepiece respirator (FFR) and a computational fluid dynamics (CFD) simulation based on the modeling. The whole model containing the upper respiratory airway, headform, and FFR was directly recorded by computed tomography (CT) scanning, and a medical contrast medium was used to make the FFR "visible." The FFR was normally worn by the subject during CT scanning so that the actual deformation of both the FFR and the face muscles during contact can be objectively conserved. The reverse modeling approach was introduced to rebuild the geometric model and convert it into a CFD solvable model. In this model, we conducted a transient numerical simulation of air flow containing carbon dioxide, thermal dynamics, and pressure and wall shear stress distribution in the respiratory system taking into consideration an individual wearing a FFR. The breathing cycle was described as a time-dependent profile of the air velocity through the respiratory airway. The result shows that wearing the N95 FFR results in CO2 accumulation, an increase in temperature and pressure elevation inside the FFR cavity. The volume fraction of CO2 reaches 1.2% after 7 breathing cycles and then is maintained at 3.04% on average. The wearers re-inhale excessive CO2 in every breathing cycle from the FFR cavity. The air temperature in the FFR cavity increases rapidly at first and then stays close to the exhaled temperature. Compared to not wearing an FFR, wearers have to increase approximately 90 Pa more pressure to keep the same breathing flow rate of 30.54 L/min after wearing an FFR. The nasal vestibule bears more wall shear stress than any other area in the airway. PMID- 26653155 TI - Beclomethasone HFA for the treatment of allergic rhinitis. AB - INTRODUCTION: Allergic rhinitis (AR) is a common chronic disorder, affecting 10 30% of populations. AR has significant morbidity and expense. AR patients treat themselves with over-the-counter medications. However the usual H1 antihistamines are often inadequate. Intranasal corticosteroids effectively diminish AR symptoms. Beclomethasonedipropionate (BDP) was reported to effectively treat adults and children with AR. BDP was a chlorofluorocarbon (CFC) propellant pressurized metered dose inhaler (pMDI). Subsequently BDP appeared in an aqueous format. Some patients preferred the dryer sensation of pMDI to aqueous formulations. The protocol of Montreal, removed CFC devices from medical practice. The remaining intranasal steroids were in aqueous format. Many patients did not like the sensory perceptions using liquids intranasal. They were unlikely to be compliant. BDP hydrofluoroalkanepMDI (BDP HFA) was developed. AREAS COVERED: The need of active treatment of AR will be reviewed. Chemistry, pharmacokinetics and pharmacodynamics of BDP HFA will be presented. Clinical efficacy studies and safety data which led to the approval of BDP for use in adults and children will be reviewed. EXPERT OPINION: BDP HFA is an option to treat AR, demonstrating a favorable therapeutic index in large double-blind placebo-controlled studies. BDP HFA appeals to select AR patients. PMID- 26653156 TI - AIDS and universal health coverage--stronger together. PMID- 26653157 TI - Preface. PMID- 26653158 TI - Quality improvement 101 for surgeons: Navigating the alphabet soup. AB - It is a fundamental value of the surgical profession to improve care for its patients. In the last 100 years, the principles of prospective quality improvement have started to work their way into the traditional method of retrospective case review in morbidity and mortality conference. This article summarizes the history of "improvement science" and its intersection with the field of surgery. It attempts to clarify the principles and jargon that may be new or confusing to surgeons with a different vocabulary and experience. This is done to bring the significant power and resources of improvement science to the traditional efforts to improve surgical care. PMID- 26653159 TI - Essentials of navigating and teaching surgical quality improvement. AB - Quality improvement (QI) has become a focus of contemporary surgical practice. The purpose of this review is to provide a framework of working knowledge regarding QI for the practicing surgeon. QI design, implementation methods, measurement tactics, statistical analysis, and presentation tools based on the Institute of Healthcare Improvement model are reviewed. Additional principles to optimize QI success such as fostering communication, building a culture of QI, leadership involvement, and financial planning are also explored. Lastly, resources for QI education and teaching are provided for those interested in learning more about this expanding field. PMID- 26653160 TI - The Swiss cheese model of adverse event occurrence--Closing the holes. AB - Traditional surgical attitude regarding error and complications has focused on individual failings. Human factors research has brought new and significant insights into the occurrence of error in healthcare, helping us identify systemic problems that injure patients while enhancing individual accountability and teamwork. This article introduces human factors science and its applicability to teamwork, surgical culture, medical error, and individual accountability. PMID- 26653161 TI - Culture of safety: A foundation for patient care. AB - The 1999 IOM report on patient safety identified the house of medicine as a culture that tolerated injury at a frightening level. Identifying other industries that had cultures that would not tolerate such levels of error has begun to change the culture of healthcare to a more "high-reliability" culture. Various organizational and standardized communication tools have been imported from the military, airline, and energy industries to flatten the hierarchy and improve the reliability of communication and handoffs in healthcare. Reporting structures that focus on the effectiveness of the team and the system, more than blaming the individual, have demonstrated noticeable improvements in safety and changed culture. Further sustained efforts in developing a culture focused on safety as a priority is needed for sustainable reduction of harm, and improve the reliability of care. PMID- 26653162 TI - Quality, patient safety, and professional values. AB - From the time of Earnest Codman until recently, measuring and improving quality has variably been viewed as a supportive group in the hospital, or an irritating "fringe" movement in health care. A more thoughtful view of quality improvement (QI) is that it is a central tenet of surgical professionalism, and really what we signed up for when we accepted the responsibility of healing patients using surgery as our methodology. The following article uses a patient safety event to highlight the successful use of a well-known method of improving care, while engaging trainees in the principles of physician engagement, accountability, and professionalism. PMID- 26653163 TI - Variation in pediatric surgical care. AB - Variation in care and outcomes are common in the management of children with surgical diseases. Differences in the availability of resources, patient and family preferences, ever-increasing fiscal pressure, and lack of high-quality data to guide clinical decision making are just a few factors that contribute to both the over and under-utilization of healthcare resources. Identification of data-driven, value-based "best practices" that are sensitive to differences in resource availability and patient preferences may be an important first step in establishing a practical framework for reducing unwarranted practice variation. The goal of this article is to explore the causes and influence of practice variation using appendicitis as a common condition to illustrate key concepts, and to propose solutions to mitigate unwarranted practice variation while preserving the spirit of innovation necessary to advance the field. PMID- 26653164 TI - Improving surgical care for children through multicenter registries and QI collaboratives. AB - The role of the healthcare organization is shifting and must overcome the challenges of fragmented, costly care, and lack of evidence in practice, to reduce cost, ensure quality, and deliver high-value care. Notable gaps exist within the expected quality and delivery of pediatric healthcare, necessitating a change in the role of the healthcare organization. To realize these goals, the use of collaborative networks that leverage massive datasets to provide information for the development of learning healthcare systems will become increasingly necessary as efforts are made to narrow the gap in healthcare quality for children. By building upon the lessons learned from early collaborative efforts and other industries, operationalizing new technologies, encouraging clinical-community partnerships, and improving performance through transparent pursuit of meaningful goals, pediatric surgery can increase the adoption of best practices by developing collaborative networks that provide evidence-based clinical decision support and accelerate progress toward a new culture of delivering high-quality, high-value, and evidenced-based pediatric surgical care. PMID- 26653165 TI - Improving quality on the pediatric surgery service: Missed opportunities and making it happen. AB - In surgery, quality improvement efforts have evolved from the traditional case-by case review typical for morbidity and mortality conferences to more accurate and comprehensive data collection accomplished through participation in national registries such as the National Surgical Quality Improvement Program. Gaining administrative support to participate in these kinds of initiatives and commitment of the faculty and staff to make change in a data-driven manner rather than as a reaction to individual events can be a challenge. This article guides the reader through the process of interacting with administrative leadership to gain support for evidence-based quality improvement endeavors. General principles that are discussed include stakeholder engagement, taking advantage of preexisting resources, and the sharing of data in order to shape QI efforts and demonstrate their effectiveness. PMID- 26653166 TI - Optimization of care for the pediatric surgical patient: Why now? AB - In 2015, the American College of Surgeons (ACS) has begun to verify hospitals and ambulatory centers which meet consensus based optimal resource standards as "Children's Surgical Centers." The intent is to identify children-specific resources available within an institution and using a stratification system similar to the ACS Trauma Program match these to the needs of infants and children with surgical problems. This review briefly summarizes the history, supporting data and processes which drove this initiative. PMID- 26653167 TI - Improving surgeon wellness: The second victim syndrome and quality of care. AB - Improving quality of care logically involves optimizing the duty-readiness and well-being of the healthcare provider. Medical errors and poor outcomes adversely impact the involved providers, especially surgeons, as well as the patients and their families. Unfortunately our current system does little to support these "second victims" who experience various degrees of emotional and psychological stresses including confusion, loss of confidence, and debilitating anxiety. These factors contribute to the alarmingly high rates of professional "burnout," substance abuse, and suicide of healthcare providers as well as increase the likelihood of subsequent medical errors. Mindful efforts to improve the healthcare culture and develop personal support systems can help surgeons become more resilient, provide higher quality patient care, and have longer productive professional lives. Institutional support systems are also necessary to assist "second victims" to recover from the impact of an adverse patient event. PMID- 26653168 TI - Patient-centered care and quality: Activating the system and the patient. AB - Patient-centered care is an expectation in our current environment, yet it is only one of the six domains that the Institute of Medicine has described as critical in redesigning the architecture of a medical system. Patients requiring long-term feeding tube access represent a particularly complex group of patients who stress the mechanisms placed within a healthcare system to optimize quality and safety. We describe the implementation of a new approach to this patient population that serves as an example of redesigning a system of care to optimize safety using the principles of patient-centered care while delivering safe, effective, timely, efficient, and equitable care. PMID- 26653169 TI - Surgical innovation-enhanced quality and the processes that assure patient/provider safety: A surgical conundrum. AB - Innovation is a crucial part of surgical history that has led to enhancements in the quality of surgical care. This comprises both changes which are incremental and those which are frankly disruptive in nature. There are situations where innovation is absolutely required in order to achieve quality improvement or process improvement. Alternatively, there are innovations that do not necessarily arise from some need, but simply are a new idea that might be better. All change must assure a significant commitment to patient safety and beneficence. Innovation would ideally enhance patient care quality and disease outcomes, as well stimulate and facilitate further innovation. The tensions between innovative advancement and patient safety, risk and reward, and demonstrated effectiveness versus speculative added value have created a contemporary "surgical conundrum" that must be resolved by a delicate balance assuring optimal patient/provider outcomes. This article will explore this delicate balance and the rules that govern it. Recommendations are made to facilitate surgical innovation through clinical research. In addition, we propose options that investigators and institutions may use to address competing priorities. PMID- 26653171 TI - Stenotrophomonas tumulicola sp. nov., a major contaminant of the stone chamber interior in the Takamatsuzuka Tumulus. AB - During investigation of the biological contamination of the 1300-year-old mural paintings and plaster walls inside the stone chambers of the Takamatsuzuka and Kitora Tumuli (TT and KT) in Asuka-mura, Nara Prefecture, Japan, the identity of 17 bacterial isolates from blackish mouldy spots and viscous gels (biofilms) collected from both tumuli (16 isolates from TT and one from KT) during our 2005 2007 microbiological survey was systematically elucidated. One cluster of the major bacterial isolates was assigned to the genus Stenotrophomonas (class Gammaproteobacteria) by phylogenetic analysis of the 16S rRNA gene sequences. These isolates were divided into two groups A and B. Group A comprised 15 TT isolates that took a phylogenetic position near Stenotrophomonas chelatiphaga LPM 5T. Based on our analysis of the phenotypic (cultural, morphological, physiological and chemotaxonomic) characteristics and genotypic/molecular characteristics (DNA base composition, DNA-DNA relatedness, and 16S rRNA and gyrB gene sequences), the novel species name Stenotrophomonas tumulicola sp. nov. is proposed for the group A isolates with the type strain T5916-2-1bT ( = JCM 30961T = NCIMB 15009T). Group B, which contained only one TT and one KT isolate, was closely related to [Pseudomonas] geniculata, [P.] hibiscicola, [P.] beteli, Stenotrophomonas maltophilia and Stenotrophomonas pavanii. The two isolates were genotypically and phenotypically assignable to S. maltophilia. PMID- 26653172 TI - Development of an Excel-based laboratory information management system for improving workflow efficiencies in early ADME screening. AB - BACKGROUND: There is a clear requirement for enhancing laboratory information management during early absorption, distribution, metabolism and excretion (ADME) screening. The application of a commercial laboratory information management system (LIMS) is limited by complexity, insufficient flexibility, high costs and extended timelines. RESULTS: An improved custom in-house LIMS for ADME screening was developed using Excel. All Excel templates were generated through macros and formulae, and information flow was streamlined as much as possible. This system has been successfully applied in task generation, process control and data management, with a reduction in both labor time and human error rates. CONCLUSION: An Excel-based LIMS can provide a simple, flexible and cost/time saving solution for improving workflow efficiencies in early ADME screening. PMID- 26653170 TI - HisAK70: progress towards a vaccine against different forms of leishmaniosis. AB - BACKGROUND: Leishmania major and Leishmania infantum are among the main species that are responsible for cutaneous leishmaniosis (CL) and visceral leishmaniosis (VL), respectively. The leishmanioses represent the second-largest parasitic killer in the world after malaria. Recently, we succeeded in generating a plasmid DNA (pCMV-HISA70m2A) and demonstrated that immunized mice were protected against L. major challenge. The efficacy of the DNA-vaccine was further enhanced by the inclusion of KMP-11 antigen into the antibiotic-free plasmid pVAX1-asd. METHODS: Here, we describe the use of a HisAK70 DNA-vaccine encoding seven Leishmania genes (H2A, H2B, H3, H4, A2, KMP11 and HSP70) for vaccination of mice to assess the induction of a resistant phenotype against VL and CL. RESULTS: HisAK70 was successful in vaccinated mice, resulting in a high amount of efficient sterile hepatic granulomas associated with a hepatic parasite burden fully resolved in the VL model; and resulting in 100% inhibition of parasite visceralization in the CL model. CONCLUSIONS: The results suggest that immunization with the HisAK70 DNA vaccine may provide a rapid, suitable, and efficient vaccination strategy to confer cross-protective immunity against VL and CL. PMID- 26653173 TI - Variation at the DRD4 locus is associated with wariness and local site selection in urban black swans. AB - BACKGROUND: Interactions between wildlife and humans are increasing. Urban animals are often less wary of humans than their non-urban counterparts, which could be explained by habituation, adaptation or local site selection. Under local site selection, individuals that are less tolerant of humans are less likely to settle in urban areas. However, there is little evidence for such temperament-based site selection, and even less is known about its underlying genetic basis. We tested whether site selection in urban and non-urban habitats by black swans (Cygnus atratus) was associated with polymorphisms in two genes linked to fear in animals, the dopamine receptor D4 (DRD4) and serotonin transporter (SERT) genes. RESULTS: Wariness in swans was highly repeatable between disturbance events (repeatability = 0.61) and non-urban swans initiated escape from humans earlier than urban swans. We found no inter-individual variation in the SERT gene, but identified five DRD4 genotypes and an association between DRD4 genotype and wariness. Individuals possessing the most common DRD4 genotype were less wary than individuals possessing rarer genotypes. As predicted by the local site selection hypothesis, genotypes associated with wary behaviour were over three times more frequent at the non-urban site. This resulted in moderate population differentiation at DRD4 (FST = 0.080), despite the sites being separated by only 30 km, a short distance for this highly-mobile species. Low population differentiation at neutrally-selected microsatellite loci and the likely occasional migration of swans between the populations reduces the likelihood of local site adaptations. CONCLUSION: Our results suggest that wariness in swans is partly genetically-determined and that wary swans settle in less-disturbed areas. More generally, our findings suggest that site-specific management strategies may be necessary that consider the temperament of local animals. PMID- 26653174 TI - Intrapartum translabial ultrasound with pushing used to predict the difficulty in vacuum-assisted delivery of fetuses in non-occiput posterior position. AB - OBJECTIVE: Our aim is to evaluate the capacity of intrapartum translabial ultrasound (ITU) with pushing in the prediction of difficulty of fetal extraction in vacuum assisted deliveries. Prospective, observational study performed (2/2015 8/2015) on 75 nulliparous women, >=37 weeks with singleton pregnancies at full dilatation who had ITU-with-pushing performed, previous to vacuum-placement for fetal extraction. Working on the translabial sagittal-plane, we assessed: Angle Progression (AoP), Progression-Distance (PD) and Head-Direction (HD); in the axial plane we evaluated: Midline-Angle (MLA) and Head-Perineum-Distance (HPD). Vacuum extractions were classified as easy-difficulty (ED) (<=3 vacuum-pulls), difficult-unsuccessful (DD) (>3 vacuum-pulls). We did not assess occipito posterior-presentations. RESULTS: Seventy nulliparous were studied (44-ED,26-DD). We observed no differences in obstetric, neonatal or intrapartum characteristics between the two study groups, with the following exceptions: newborn weight (3272 +/- 438 g versus 3540 +/- 372 g; p = 0.011) and number of vacuum-pulls (1.4-ED-vs 4.4-DD; p < 0.0005). AoP-pushing was 143.9 degrees +/- 14.6 degrees in ED and 115.1 degrees +/- 12.9 degrees in DD (p < 0.0005); Head-Up was 79.5% versus 38.4% (p < 0.0005); PD-Pushing was 42.7 +/- 11.3 mm versus 30.4 +/- 9.8 mm (p < 0.0005); MLA-Pushing was 27.6 degrees +/- 26.6 degrees versus 57.5 degrees +/ 26.5 degrees (p=0.025); HPD-Pushing was 40.8 +/- 10.0 mm versus 47.4 +/- 10.9 mm (p = 0.039). CONCLUSION: We identified that the presence of an AoP-Pushing > 128 degrees predicts an Easy-Vacuum-Delivery (<=3 Vacuum-Pulls) in >85% of cases (Sen 80%-FPR 9.3%). PMID- 26653175 TI - Effects of strigolactone signaling on Arabidopsis growth under nitrogen deficient stress condition. AB - Strigolactones (SLs) are a group of terpenoid lactones found in plants that regulate diverse developmental phenomena. SLs are thought to be involved in the maintenance of phosphate homeostasis. In addition, SL signaling is required for the regulation of shoot branching by nitrogen supply in Arabidopsis. In this study, we evaluated the effects of SLs on nitrogen deficient-inducing phenomena (leaf senescence and reduction of plant weight) in Arabidopsis. SL-biosynthesis (max1-1) and SL-insensitive (atd14-1) mutants showed altered responses to nitrogen deficient in comparison with wild-type (WT) plants. Nitrogen deficient conditions led to alterations in the expression levels of SL biosynthesis genes (MAX3 and MAX4). These results indicate that SLs could be key mediators of plant growth response to nitrogen supply. PMID- 26653176 TI - Molybdenum cofactor deficiency. AB - Molybdenum cofactor deficiency (MoCD) is a severe autosomal recessive inborn error of metabolism first described in 1978. It is characterized by a neonatal presentation of intractable seizures, feeding difficulties, severe developmental delay, microcephaly with brain atrophy and coarse facial features. MoCD results in deficiency of the molybdenum cofactor dependent enzymes sulfite oxidase, xanthine dehydrogenase, aldehyde oxidase and mitochondrial amidoxime reducing component. The resultant accumulation of sulfite, taurine, S-sulfocysteine and thiosulfate contributes to the severe neurological impairment. Recently, initial evidence has demonstrated early treatment with cyclic PMP can turn MoCD type A from a previously neonatal lethal condition with only palliative options, to near normal neurological outcomes in affected patients. We review MoCD and focus on describing the currently published evidence of this exciting new therapeutic option for MoCD type A caused by pathogenic variants in MOCD1. PMID- 26653177 TI - Nanoparticle systems reduce systemic toxicity in cancer treatment. PMID- 26653178 TI - [Meropenem and valproic acid: A clinically relevant drug-drug interaction]. PMID- 26653179 TI - Renewable and Ultralong Nanoelectrochemical Sensor: Nanoskiving Fabrication and Application for Monitoring Cell Release. AB - Nanoscaled electrode has been attracting increasing attention because of striking fundamentals and practical applications. Usually, the nanoscaled electrode is fabricated by manual or photo or electron-beam lithography, which is not easy to reproducibly fabricate with simple equipment. In this paper, a cost-effective method, nanoskiving, is developed to fabricate an ultralong nanowire electrode (ULNE). The ULNE is reproducibly obtained by simply sectioning a sandwich epoxy block with a Au film. The width of ULNE could be down to nanometer dependence on the thickness of the Au film, while the length could reach to the millimeter. Thus, the created Au ULNE shows steady-state microamperometric current, characteristic of the nanoelectrode array attributed to its macroscopic length and nanoscaled width without considering the overlap of the diffusion layer of the neighboring nanoelectrode. The electrodeposited Pt/Au ULNE displays unusual electrocatalytic performance toward both the oxidation and reduction of hydrogen peroxide and, as a nanosensor, gives rise to high sensitivity and selectivity of monitoring hydrogen peroxide released from cells stimulated by ascorbic acid. PMID- 26653181 TI - Disc large 1 expression is altered by human papillomavirus E6/E7 proteins in organotypic cultures of human keratinocytes. AB - Loss of cell polarity is a fundamental process in cell transformation. Among polarity proteins, we focused on human disc large (DLG1), which is localized mainly at adherens junctions and contributes to the control of cell proliferation. We previously demonstrated that its expression is altered in HPV associated cervical neoplastic lesions, but the mechanisms beyond this remain unknown. In this study, we analysed the contribution of HPV proteins to the changes in DLG1 expression in the squamous epithelium. We observed tissue and intracellular misdistribution of DLG1 when high-risk HPV-18 E7 or E6/E7 proteins were expressed in organotypic raft cultures. The viral oncoproteins induce the loss of DLG1 from the cell borders and an increase in the level of DLG1 protein, reflecting the pattern observed in cervical lesions. These findings were corroborated in cultures bearing the entire HPV-18 genome. Interestingly, changes in tissue distribution and abundance of DLG1 were also detected in organotypic cultures expressing the low-risk HPV-11 E7 or E6/E7 proteins, suggesting a conserved function among different HPV types. However, for low-risk HPVs, the subcellular localization of DLG1 at cell-to-cell contacts was predominantly maintained. This report offers new evidence, we believe, of the involvement of HPV proteins in DLG1 expression pattern and our data support previous observations regarding DLG1 expression in cervical lesions. PMID- 26653180 TI - Discovery and Characterization of 2-Acylaminoimidazole Microsomal Prostaglandin E Synthase-1 Inhibitors. AB - As part of a program aimed at the discovery of antinociceptive therapy for inflammatory conditions, a screening hit was found to inhibit microsomal prostaglandin E synthase-1 (mPGES-1) with an IC50 of 17.4 MUM. Structural information was used to improve enzyme potency by over 1000-fold. Addition of an appropriate substituent alleviated time-dependent cytochrome P450 3A4 (CYP3A4) inhibition. Further structure-activity relationship (SAR) studies led to 8, which had desirable potency (IC50 = 12 nM in an ex vivo human whole blood (HWB) assay) and absorption, distribution, metabolism, and excretion (ADME) properties. Studies on the formulation of 8 identified 8.H3PO4 as suitable for clinical development. Omission of a lipophilic portion of the compound led to 26, a readily orally bioavailable inhibitor with potency in HWB comparable to celecoxib. Furthermore, 26 was selective for mPGES-1 inhibition versus other mechanisms in the prostanoid pathway. These factors led to the selection of 26 as a second clinical candidate. PMID- 26653182 TI - Time trends and risk factor associated with premature birth and infants deaths due to prematurity in Hubei Province, China from 2001 to 2012. AB - BACKGROUND: The nutrition and epidemiologic transition has been associated with an increasing incidence of preterm birth in developing countries, but data from large observational studies in China have been limited. Our study was to describe the trends and factors associated with the incidence of preterm birth and infant mortality due to prematurity in Hubei Province, China. METHODS: We conducted a population-based survey through the Maternal and Child Health Care Network in Hubei Province from January 2001 to December 2012. We used data from 16 monitoring sites to examine the trend and risk factors for premature birth as well as infant mortality associated with prematurity. RESULTS: A total of 818,481 live births were documented, including 76,923 preterm infants (94 preterm infants per 1,000 live births) and 2,248 deaths due to prematurity (2.75 preterm deaths per 1,000 live births). From 2001 to 2012, the incidence of preterm birth increased from 56.7 to 105.2 per 1,000 live births (P for trend < 0.05), while the infant mortality rate due to prematurity declined from 95.0 to 13.4 per 1,000 live births (P for trend < 0.05). Older maternal age, lower maternal education, use of assisted reproductive technology (ART), higher income, residence in urban areas, and infant male sex were independently associated with a higher incidence of preterm birth (all p values < 0.05). Shorter gestation, lower birth weight, and lower income were associated with a higher mortality rate, while use of newborn emergency transport services (NETS) was associated with a lower preterm mortality rate (all p values < 0.05). CONCLUSION: An increasing incidence of preterm birth and a parallel reduction in infant mortality due to prematurity were observed in Hubei Province from 2001 to 2012. Our results provide important information for areas of improvements in reducing incidence and mortality of premature birth. PMID- 26653184 TI - Chronic Obstructive Pulmonary Disease Rehospitalization. A Big Problem that Now Needs Solutions. PMID- 26653185 TI - Understanding Costs When Seeking Value in Critical Care. PMID- 26653186 TI - Walking on Water: Volume Overload and Ambulation in Survivors of Septic Shock. PMID- 26653187 TI - The Evolution of the ProVent Score from Medical to Surgical Applications. PMID- 26653188 TI - Treatment of Tuberculosis. A Historical Perspective. AB - Of all achievements in medicine, the successful treatment of tuberculosis has had one of the greatest impacts on society. Tuberculosis was a leading cause of disease and a mortal enemy of humanity for millennia. The first step in finding a cure was the discovery of the cause of tuberculosis by Robert Koch in 1882. The sanatorium movement that began shortly afterward in Europe, and soon spread to the United States, brought attention to the plight of afflicted persons, and catalyzed public health action. The antituberculosis benefit of streptomycin was announced in 1945, although application was limited by the rapid development of resistance. para-Aminosalicylic acid, also discovered in 1945, when combined with streptomycin was found to greatly reduce the occurrence of drug resistance. In 1952, isoniazid opened the modern era of treatment; it was inexpensive, well tolerated, and safe. In the early 1960s, ethambutol was shown to be effective and better tolerated than para-aminosalicylic acid, which it replaced. In the 1970s, rifampin found its place as a keystone in the therapy of tuberculosis. The use of rifampin enabled the course of treatment to be reduced to nine months. Incorporation of pyrazinamide into the first-line regimen led to a further reduction of treatment duration to six months. Treatment of multiple drug resistant tuberculosis remains a difficult problem requiring lengthy treatment with toxic drugs. However, shortened regimens show promise, and two new drugs, bedaquiline and delamanid, have demonstrated effectiveness in preliminary studies and are being used for extensively drug-resistant tuberculosis. PMID- 26653190 TI - Nationwide Study of Humidifier Disinfectant Lung Injury in South Korea, 1994 2011. Incidence and Dose-Response Relationships. AB - RATIONALE: Humidifier disinfectant lung injury is an acute lung disease attributed to recurrent inhalation of certain disinfectant aerosols emitted from room humidifiers. An outbreak of this toxic lung injury occurred in South Korea from 1995 until all humidifier disinfectant products were recalled from the consumer market by the government in 2011. OBJECTIVES: A nationwide study was conducted to ascertain and classify all potential cases of humidifier disinfectant lung injury in Korea and to assess dose-response relationships. METHODS: By several mechanisms, clinicians and the general public were invited to report all suspected cases of humidifier disinfectant lung injury to public health officials in South Korea. A committee was convened to define diagnostic criteria based on pathologic, radiologic, and clinical findings for index cases, combined with assessment of environmental exposure to humidifier disinfectants. Clinical review and environmental assessments were performed and later combined to determine overall likelihood of disease for each study participant, classified as definite, probable, possible, or unlikely. Survival time from exposure to onset of symptoms was analyzed to assess dose-response relationships. Three broad categories of risk factors were examined: (1) biological susceptibility, (2) temporal cycle of exposure and recovery, and (3) spatial conditions and density of disinfectant. MEASUREMENTS AND MAIN RESULTS: Of 374 possible cases identified and reviewed, 329 were unanimously classified by the diagnostic committee, as follows: 117 definite, 34 probable, 38 possible and 140 unlikely cases. A total of 62 individuals with definite or probable disease died. Risk factors examined for polyhexamethyleneguanidine phosphate exposure that were found to be significant in shortening survival included age 4 years or younger at onset, use of disinfectant for 7 days per week, airborne density of 800 MUg/m(3) or more of disinfectant, and daily exposure 11 or more hours in duration. CONCLUSIONS: Dose response analysis indicated that development of humidifier disinfectant lung injury and death were associated strongly with recurrent, intense, acute exposure without sufficient recovery time between exposures, more so than long-term cumulative exposure. These findings may explain some reversible or clinically unapparent cases among coexposed family members. PMID- 26653191 TI - ATS Core Curriculum 2015: Part IV. Adult Critical Care Medicine. PMID- 26653192 TI - Flexible Airway Endoscopy in Children. PMID- 26653193 TI - More than Meets the Eye. A 23-Year-Old Woman with Rapidly Progressive Respiratory Failure, Mucositis, and Rash. PMID- 26653189 TI - Characteristics of Alpha-1 Antitrypsin-Deficient Individuals in the Long-term Oxygen Treatment Trial and Comparison with Other Subjects with Chronic Obstructive Pulmonary Disease. AB - RATIONALE: Alpha-1 antitrypsin deficiency (AATD) predisposes to chronic obstructive pulmonary disease, but is underrecognized. Oxygenation and exercise desaturation in individuals with AATD-associated chronic obstructive pulmonary disease has been sparsely studied. The Long-term Oxygen Treatment Trial (LOTT) permits comparing these features of individuals with AATD with alpha-1 antitrypsin-replete (called "usual chronic obstructive pulmonary disease") LOTT participants. OBJECTIVES: Compare demographic, clinical, baseline oxygenation, and exercise desaturation features in participating AATD subjects with those of other LOTT subjects. METHODS: LOTT is a multicenter randomized controlled trial comparing use of supplemental oxygen versus not in subjects with chronic obstructive pulmonary disease and moderate hypoxemia (resting oxygen saturation as measured by pulse oximetry, 89-93%) or normal oxygen saturation at rest and significant exercise desaturation. MEASUREMENT AND MAIN RESULTS: Among the 597 LOTT participants with nonmissing alpha-1 antitrypsin levels, 11 (1.8%) had severe AATD and 44 (7.4%) had mild/moderate AATD. Comparison of the 11 severely AAT-deficient individuals with the 542 LOTT participants with usual chronic obstructive pulmonary disease showed that the AATD subjects were younger and despite less smoking, had lower FEV1/FVC (mean post-bronchodilator FEV1/FVC, 0.38 +/- 0.06 vs. 0.46 +/- 0.13; P = 0.002). Comparison with 27 age-, sex-, and FEV1 matched alpha-1 antitrypsin-normal LOTT participants showed no baseline difference in resting room air pulse oximetry saturation (AATD, 93.6% +/- 2.3% vs. 92.7% +/- 2.2%; P = 0.64). Exercise-related desaturation was more severe in the individuals with AATD based on desaturation to 88% or less sooner during a 6 minute-walk test, having a higher percentage of desaturation points (e.g., <90%) during exercise, and having a higher distance-saturation product (defined as the distance walked in 6 min multiplied by the nadir saturation achieved during the 6 minute-walk test). CONCLUSIONS: These data suggest that individuals with AATD experience more profound desaturation with exercise than age-, sex-, race-, and FEV1-matched control subjects with usual chronic obstructive pulmonary disease. Clinical trial registered with www.clinicaltrials.gov (NCT 00692198). PMID- 26653183 TI - Climate oscillations, glacial refugia, and dispersal ability: factors influencing the genetic structure of the least salmonfly, Pteronarcella badia (Plecoptera), in Western North America. AB - BACKGROUND: Phylogeographic studies of aquatic insects provide valuable insights into mechanisms that shape the genetic structure of communities, yet studies that include broad geographic areas are uncommon for this group. We conducted a broad scale phylogeographic analysis of the least salmonfly Pteronarcella badia (Plecoptera) across western North America. We tested hypotheses related to mode of dispersal and the influence of historic climate oscillations on population genetic structure. In order to generate a larger mitochondrial data set, we used 454 sequencing to reconstruct the complete mitochondrial genome in the early stages of the project. RESULTS: Our analysis revealed high levels of population structure with several deeply divergent clades present across the sample area. Evidence from five mitochondrial genes and one nuclear locus identified a potentially cryptic lineage in the Pacific Northwest. Gene flow estimates and geographic clade distributions suggest that overland flight during the winged adult stage is an important dispersal mechanism for this taxon. We found evidence of multiple glacial refugia across the species distribution and signs of secondary contact within and among major clades. CONCLUSIONS: This study provides a basis for future studies of aquatic insect phylogeography at the inter-basin scale in western North America. Our findings add to an understanding of the role of historical climate isolations in shaping assemblages of aquatic insects in this region. We identified several geographic areas that may have historical importance for other aquatic organisms with similar distributions and dispersal strategies as P. badia. This work adds to the ever-growing list of studies that highlight the potential of next-generation DNA sequencing in a phylogenetic context to improve molecular data sets from understudied groups. PMID- 26653194 TI - Endobronchial Excision of a Large Near-Occlusive Tracheal Tumor. Operative and Anesthetic Considerations. PMID- 26653195 TI - Endobronchial Instillation of DNase to Facilitate Bronchoscopic Drainage of a Lung Abscess. PMID- 26653196 TI - Cough Augmentation in a Patient with Neuromuscular Disease. PMID- 26653197 TI - A Sleep-Disordered Breathing Pattern Related to Positive Airway Pressure Therapy. PMID- 26653198 TI - Reproducibility of a Single Blood Eosinophil Measurement as a Biomarker in Severe Eosinophilic Asthma. PMID- 26653199 TI - Missing Stowaways and Lack of Expected Concurrent Infections. PMID- 26653200 TI - Reply: Missing Stowaways and Lack of Expected Concurrent Infections. PMID- 26653201 TI - American Thoracic Society and National Heart, Lung, and Blood Institute Implementation Research Workshop Report. AB - To advance implementation research (IR) in respiratory, sleep, and critical care medicine, the American Thoracic Society and the Division of Lung Diseases from the NHLBI cosponsored an Implementation Research Workshop on May 17, 2014. The goals of IR are to understand the barriers and facilitators of integrating new evidence into healthcare practices and to develop and test strategies that systematically target these factors to accelerate the adoption of evidence-based care. Throughout the workshop, presenters provided examples of IR that focused on the rate of adoption of evidence-based practices, the feasibility and acceptability of interventions to patients and other stakeholders who make healthcare decisions, the fidelity with which practitioners use specific interventions, the effects of specific barriers on the sustainability of an intervention, and the implications of their research to inform policies to improve patients' access to high-quality care. During the discussions that ensued, investigators' experience led to recommendations underscoring the importance of identifying and involving key stakeholders throughout the research process, ensuring that those who serve as reviewers understand the tenets of IR, managing staff motivation and turnover, and tackling the challenges of scaling up interventions across multiple settings. PMID- 26653202 TI - Aging and Lung Disease. Clinical Impact and Cellular and Molecular Pathways. AB - With the expected rapid growth of the aging population worldwide, there is a clear need to understand the complex process of aging to develop interventions that might extend the health span in this group of patients. Aging is associated with increased susceptibility to a variety of chronic diseases, and lung pathologies are no exception. The prevalence of lung diseases such as idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease has been found to increase considerably with age. In October 2014, the Division of Pulmonary, Allergy, and Critical Care of the University of Pittsburgh cohosted the Pittsburgh-Munich Lung Conference focused in aging and lung disease with the Comprehensive Pneumology Center, Institute of Lung Biology and Disease, Ludwig Maximilians University and Helmholtz Zentrum Munich Germany. The purpose of the conference was to disseminate novel concepts in aging mechanisms that have an impact in lung physiology and pathogenesis of pulmonary diseases that commonly occur in older populations. The conference included 28 presentations on diverse topics, which are summarized in this report. The participants identified priorities for future basic and translational investigations that will assist in the identification of molecular insights involved in the pathogenesis of age related pulmonary diseases and the design of therapeutic interventions for these lung conditions. PMID- 26653204 TI - Endoscopic approach to the resection of adenoid cystic carcinoma of paranasal sinuses and nasal cavity: case report and own experience. AB - Adenoid cystic carcinoma (ACC) is a rare malignant tumor that might occur in nasal cavity and paranasal sinuses. It is characteristic for poor prognosis, especially the solid histopathological subtype of the tumor. ACC might spread along nerves and fascias and it is usually diagnosed at advanced stage. Computed tomography and magnetic resonance imaging together with fine-needle biopsy are the gold standards in the diagnostic procedure of the cancer. Surgery with adjuvant therapy are the most common methods of treatment. Among the surgical approaches, the functional endonasal sinus surgery seems to be the most appropriate and favorable way of treatment. In the study, the authors present a case of a 62-year-old patient with T4aN0M0 ACC tumor treated endoscopically at the Department of Laryngology and ENT Oncology, WSS No. 5 in Sosnowiec. The authors indicate the usefulness of FESS procedure in the treatment of malignancies of nasal cavity and paranasal sinuses. They also review the recent publications on endonasal versus open approach in similar cases. In conclusions, the authors favor endonasal approach as a mini-invasive method of surgical treatment of ACC of paranasal sinuses that results in satisfactory oncological outcome and high quality of patient's life. PMID- 26653205 TI - moCluster: Identifying Joint Patterns Across Multiple Omics Data Sets. AB - Increasingly, multiple omics approaches are being applied to understand the complexity of biological systems. Yet, computational approaches that enable the efficient integration of such data are not well developed. Here, we describe a novel algorithm, termed moCluster, which discovers joint patterns among multiple omics data. The method first employs a multiblock multivariate analysis to define a set of latent variables representing joint patterns across input data sets, which is further passed to an ordinary clustering algorithm in order to discover joint clusters. Using simulated data, we show that moCluster's performance is not compromised by issues present in iCluster/iCluster+ (notably, the nondeterministic solution) and that it operates 100* to 1000* faster than iCluster/iCluster+. We used moCluster to cluster proteomic and transcriptomic data from the NCI-60 cell line panel. The resulting cluster model revealed different phenotypes across cellular subtypes, such as doubling time and drug response. Applying moCluster to methylation, mRNA, and protein data from a large study on colorectal cancer patients identified four molecular subtypes, including one characterized by microsatellite instability and high expression of genes/proteins involved in immunity, such as PDL1, a target of multiple drugs currently in development. The other three subtypes have not been discovered before using single data sets, which clearly illustrates the molecular complexity of oncogenesis and the need for holistic, multidata analysis strategies. PMID- 26653203 TI - Rationale and design of FORTH: a randomised controlled trial assessing the effectiveness of HIV self-testing in increasing HIV testing frequency among gay and bisexual men. AB - BACKGROUND: Gay and bisexual men (GBM) are a major risk group for HIV acquisition, yet the majority of higher-risk GBM test for HIV less often than recommended (3-6 monthly). HIV self-testing has the potential to increase testing frequency and improve awareness of personal HIV status. HIV self-tests have been approved in some countries, however there are concerns whether self-testing would increase HIV testing frequency enough to compensate for the reduced sensitivity of self-tests in early infection. We describe here a randomised controlled trial to assess the effectiveness of self-testing in increasing HIV testing frequency among higher-risk GBM, and its acceptability. METHODS/DESIGN: Participants are higher-risk HIV negative GBM (>5 partners or condomless anal intercourse in previous 3 months; n = 350), including 50 GBM who tested for HIV over two years ago or never tested before ('infrequent-testers'). Participants are recruited from sexual health clinics and community-based organisations, and randomised 1:1 to either self-testing or standard-care (routine clinic-based testing) arms. The trial employs a wait-list control design: participants in the standard-care arm switch to self-testing arm in the second year, and gain access to self-test kits. Participants in the self-testing arm receive four oral-fluid self-test kits at enrolment, with additional kits provided on request. Demographics, sexual behaviour and HIV testing preferences are collected at baseline, and the frequency and pattern of HIV and sexually transmissible infection (STI) testing is collected via online 3-monthly questionnaires. The acceptability of self testing is assessed at 12 months via an online questionnaire and in-depth interviews. A 24-h telephone support is provided, with expedited follow-up of those with reactive self-test results. The primary outcome is HIV testing frequency (mean number of HIV tests per person) over 12 months, and the secondary outcomes are: mean number of STI tests (chlamydia, gonorrhoea, syphilis) per person; reasons for HIV testing; and acceptability of HIV self-testing. DISCUSSION: This is the first trial to evaluate the use of self-testing among GBM in Australia, and the first internationally among infrequent testers. The study will provide evidence on whether self-testing increases HIV testing frequency, and its acceptability among GBM. The findings will improve our understanding of self-testing patterns, and whether GBM supplement or replace their existing testing routine. TRIAL REGISTRATION: Australian and New Zealand Clinical Trial Registration number: ACTRN12613001236785 , registered on November 12, 2013. PMID- 26653206 TI - The politics of drug control in Nigeria: Exclusion, repression and obstacles to policy change. AB - BACKGROUND: International agencies have viewed West Africa as a major player in the global trade in cocaine and heroin and in efforts to control that trade, as there have been reports of escalating arrests of drug smugglers, large-scale drug seizures and 'narco-states' in the subregion. It is claimed that a substantial share of the drugs available in Western markets transit through West Africa today and are increasingly used there as well. Notwithstanding this growing alarm, there is little serious scholarship addressing the issue of drugs and drug policy in West Africa. METHODS: The article assesses and challenges some of the existing depictions of drugs and drug policy in West Africa through an empirical case study of drug control in Nigeria - one of West Africa's most notorious 'drug hubs' and recently hailed as a policy model by international experts. Based on previously inaccessible government documents, interviews with key officials in Nigeria, as well as ethnographic work at Nigeria's key drug agency, the article provides a unique insight into the politics of drug policy-making and implementation in West Africa. RESULTS: After describing the dominant official narratives of Nigeria's drug control, the article shows how the key political dynamics underlying drug policy remain obscured by these narratives. Nigerian drug policy has been characterised by a highly exclusive policy-making process, repression as the sole means of implementation and a strong bond with international drug agencies. This policy emerged in the 1980s and 1990s and has remained the unchallenged norm until today. The political processes underlying Nigerian drug policy also explain why policy reform has been and will be difficult to accomplish. CONCLUSION: These domestic political processes have largely been ignored in the existing depictions of drugs in West Africa, as they have mainly focused on externally driven drug threats and foreign policy responses. Most importantly, they have ignored the role played by the state. Rather than being too weak, the Nigerian state has shown a clear tendency towards repressive and coercive drug policy, which has received little popular support. PMID- 26653207 TI - Excavations at Schoningen and paradigm shifts in human evolution. AB - The exceptional preservation at Schoningen together with a mixture of perseverance, hard work, and sheer luck led to the recovery of unique finds in an exceptional context. The 1995 discovery of numerous wooden artifacts, most notably at least 10 carefully made spears together with the skeletons of at least 20 to 25 butchered horses, brought the debate about hunting versus scavenging among late archaic hominins and analogous arguments about the purportedly primitive behavior of Homo heidelbergensis and Neanderthals to an end. Work under H. Thieme's lead from 1992 to 2008 and results from the current team since 2008 demonstrate that late H. heidelbergensis or early Neanderthals used sophisticated artifacts made from floral and faunal materials, in addition to lithic artifacts more typically recovered at Lower Paleolithic sites. The finds from the famous Horse Butchery Site and two dozen other archaeological horizons from the edges of the open-cast mine at Schoningen provide many new insights into the technology and behavioral patterns of hominins about 300 ka BP during MIS 9 on the Northern European Plain. An analysis of the finds from Schoningen and their contexts shows that the inhabitants of the site were skilled hunters at the top of the food chain and exhibited a high level of planning depth. These hominins had command of effective means of communication about the here and now, and the past and the future, that allowed them to repeatedly execute well-coordinated and successful group activities that likely culminated in a division of labor and social and economic patterns radically different from those of all non-human primates. The unique preservation and high quality excavations have led to a major paradigm shift or "Schoningen Effect" that changed our views of human evolution during the late Lower Paleolithic. In this respect, we can view the behaviors documented at Schoningen as a plausible baseline for the behavioral sophistication of archaic hominins of the late Middle Pleistocene and subsequent periods. PMID- 26653208 TI - Lower Paleolithic bone tools from the 'Spear Horizon' at Schoningen (Germany). AB - The Lower Paleolithic locality of Schoningen 13 II-4 is famous for the discovery of wooden spears found amongst the butchered remains of numerous horses and other large herbivores. Although the spears have attracted the most interest, other aspects of the associated artifact assemblage have received less attention. Here we describe an extraordinary assemblage of 88 bone tools from the 'Spear Horizon.' This sample includes numerous long-bone shaft fragments (mostly of horse), three ribs used as 'retouchers' to resharpen flint tools, and a complete horse innominate that was used as an anvil in bipolar knapping. Most of the retouchers were prepared by scraping the diaphysis of fresh and dry long-bones. Technological analysis of the associated lithic assemblage demonstrates exhaustive resharpening to maintain functional cutting edges. Whereas the flint tools were brought to the site, curated, and maintained, the retouchers had a shorter use-history and were either discarded after a limited period or broken to extract marrow. Horse and bison metapodials with flaked and rounded epiphyses are interpreted as hammers used to break marrow bones. Several of the 'metapodial hammers' were additionally used as knapping percussors. These constitute the earliest evidence of multi-purpose bone tools in the archeological record. Our results highlight the advanced knowledge in the use of bones as tools during the Lower Paleolithic, with major implications for understanding aspects of non lithic technology and planning depth in early hominins. PMID- 26653209 TI - Clarification of the calculation of minimum detectable activity in low-level radioactivity measurements. AB - We discuss a new method to determine the value of minimum detectable activity (MDA) in low-level measurements. The method is based on the Feldman-Cousins unified approach which effectively combines the construction of confidence intervals with the determination of the decision threshold and MDA. The new method requires a single probability to be pre-specified for the determination of MDA as well as decision threshold and confidence interval, in contrast with the ISO 11929 method requiring three probabilities. PMID- 26653210 TI - Uncertainty assessment in the free release measurement by gamma spectrometry of rotating waste drums. AB - The assessment of uncertainty in free release measurements by integral gamma scanning method is described and applied to the measurement of homogeneous and heterogeneous waste drums. It is based on the propagation of distributions using the Monte Carlo method. In addition, two techniques for the uncertainty reduction are also described. The first technique makes use of containers constructed from two concentric cylinders and the second technique is based on the measurement of a group of waste drums. It is proved that the uncertainty of clearance measurements can be reduced using both techniques. PMID- 26653211 TI - Determination of impurities in (124)I samples by high resolution gamma spectrometry. AB - (124)I is a radionuclide used in the diagnosis of tumors. The National Health Agency requires identification and activity measurement of impurities. Using gamma spectrometry with an efficiency calibrated high-purity germanium detector, impurities (125)I and (126)I in an (1)(24)I production sample were identified. Activity ratios of (125)I and (126)I to (124)I were approximately 0.5% and 98%, respectively. PMID- 26653212 TI - Assessment of measurement result uncertainty in determination of (210)Pb with the focus on matrix composition effect in gamma-ray spectrometry. AB - Reference materials were used to assess measurement result uncertainty in determination of (210)Pb by gamma-ray spectrometry, liquid scintillation counting, or indirectly by alpha-particle spectrometry, using its daughter (210)Po in radioactive equilibrium. Combined standard uncertainties of (210)Pb massic activities obtained by liquid scintillation counting are in the range 2 12%, depending on matrices and massic activity values. They are in the range 1-3% for the measurement of its daughter (210)Po using alpha-particle spectrometry. Three approaches (direct computation of counting efficiency and efficiency transfer approaches based on the computation and, respectively, experimental determination of the efficiency transfer factors) were applied for the evaluation of (210)Pb using gamma-ray spectrometry. Combined standard uncertainties of gamma ray spectrometry results were found in the range 2-17%. The effect of matrix composition on self-attenuation was investigated and a detailed assessment of uncertainty components was performed. PMID- 26653213 TI - (Mis)use of (133)Ba as a calibration surrogate for (131)I in clinical activity calibrators. AB - Using NIST-calibrated solutions of (131)Ba and (131)I in the 5mL NIST ampoule geometry, measurements were made in three NIST-maintained Capintec activity calibrators and the NIST Vinten 671 ionization chamber to evaluate the suitability of using (133)Ba as a calibration surrogate for (131)I. For the Capintec calibrators, the (133)Ba response was a factor of about 300% higher than that of the same amount of (131)I. For the Vinten 671, the Ba-133 response was about 7% higher than that of (131)I. These results demonstrate that (133)Ba is a poor surrogate for (131)I. New calibration factors for these radionuclides in the ampoule geometry for the Vinten 671 and Capintec activity calibrators were also determined. PMID- 26653214 TI - Renewing the radiopharmaceutical accuracy check service for Canadian radionuclide calibrators. AB - From 1986 to 2000, a fraction of the Canadian nuclear medicine community participated in a service offered by the National Research Council (NRC) of Canada to check the accuracy of administered doses of radiopharmaceuticals. The NRC renewed this service in recent years with a revalidation and reviving of the Secondary Standard Ionizing Radiation Chamber System (SSIRCS). The NRC conducted mock services for (99m)Tc, in varying geometries (syringes and serum vials), on two NRC commercial radionuclide calibrators, and at a nuclear medicine department in Canada. These tests showed the measured doses to be within 10% of the prepared standard but in some cases were sufficiently different from unity to warrant specific geometry factors to be derived. PMID- 26653215 TI - Activity standardization, photon emission probabilities and half-life measurements of (177)Lu. AB - Activity standardization of (177)Lu and measurement of two nuclear parameters were done. Activity standardization of (177)Lu was done utilizing the 4pibeta gamma coincidence method with a combined standard uncertainty of 0.28%. Emission probability of 112.95keV and 208.37keV was measured by calibrated spectrometer with HPGe detector. The efficiency was computed with MCNP code and validated using experimental points. Half-life was derived from prolonged measurement of peak area by three different spectrometer systems and also from measurement with ionization chamber. PMID- 26653216 TI - Photochemistry of CH3Cl: Dissociation and CH...Cl Hydrogen Bond Formation. AB - State-of-the-art electronic structure calculations (MR-CISD) are used to map five different dissociation channels of CH3Cl along the C-Cl coordinate: (i) CH3(X(2)A2") + Cl((2)P), (ii) CH3(3s(2)A1') + Cl((2)P), (iii) CH3(+)((1)A1') + Cl(-)((1)S), (iv) CH3(3p(2)E') + Cl((2)P), and (v) CH3(3p(2)A2") + Cl((2)P). By the first time these latter four dissociation channels, accessible upon VUV absorption, are described. The corresponding dissociation limits, obtained at the MR-CISD+Q level, are 3.70, 9.50, 10.08, 10.76, and 11.01 eV. The first channel can be accessed through nsigma* and n3s states, while the second channel can be accessed through n(e)3s, n(e)3p(sigma), and sigma3s states. The third channel, corresponding to the CH3(+) + Cl(-) ion-pair, is accessed through n(e)3p(e) states. The fourth is accessed through n(e)3p(e), n(e)3p(sigma), and sigma3p(sigma), while the fifth through sigma3p(e) and sigma(CH)sigma* states. The population of the diverse channels is controlled by two geometrical spots, where intersections between multiple states allow a cascade of nonadiabatic events. The ion-pair dissociation occurs through formation of CH3(+)...Cl(-)and H2CH(+)...Cl(-) intermediate complexes bound by 3.69 and 4.65 eV. The enhanced stability of the H2CH(+)...Cl(-) complex is due to a CH...Cl hydrogen bond. A time-resolved spectroscopic setup is proposed to detect those complexes. PMID- 26653217 TI - Putative suppressing effect of IgG Fc-conjugated haemagglutinin (HA) stalk of influenza virus H7N9 on the neutralizing immunogenicity of Fc-conjugated HA head: implication for rational design of HA-based influenza vaccines. AB - The emergence of influenza A H7N9 in infection has posed a great threat to public health globally. Poor immunogenicity of H7N9 haemagglutinin (HA) is a major obstacle to the development of an effective H7N9 vaccine. Here, we found that the vaccine containing the H7HA head conjugated with IgG Fc (Hd-Fc) induced strong neutralizing antibody responses and protection against H7N9 infection, whilst the Fc-conjugated H7HA stalk (St-Fc)-based vaccine could not induce neutralizing antibodies, although the St-Fc-immunized mice were partially protected. The vaccines containing the full-length extracellular domain of HA conjugated with Fc and the mixture of Hd-Fc plus St-Fc induced significantly lower neutralizing antibody and haemagglutination inhibition titres than the Hd-Fc-based vaccine. These results suggest that the St-Fc may have inhibitory effects on the neutralizing immunogenicity of Hd-Fc. Therefore, the neutralizing domain(s), such as the receptor-binding domain, in the HA head should be kept and the non neutralizing domain(s) in the HA stalk with the ability to potentially suppress the neutralizing immunogenicity of HA head should be removed from Fc-conjugated HA-based influenza vaccines to increase the neutralizing antibody response. PMID- 26653218 TI - Mitochondrial group I and group II introns in the sponge orders Agelasida and Axinellida. AB - BACKGROUND: Self-splicing introns are present in the mitochondria of members of most eukaryotic lineages. They are divided into Group I and Group II introns, according to their secondary structure and splicing mechanism. Being rare in animals, self-splicing introns were only described in a few sponges, cnidarians, placozoans and one annelid species. In sponges, three types of mitochondrial Group I introns were previously described in two demosponge families (Tetillidae, and Aplysinellidae) and in the homoscleromorph family Plakinidae. These three introns differ in their insertion site, secondary structure and in the sequence of the LAGLIDADG gene they encode. Notably, no group II introns have been previously described in sponges. RESULTS: We report here the presence of mitochondrial introns in the cytochrome oxidase subunit 1 (COI) gene of three additional sponge species from three different families: Agelas oroides (Agelasidae, Agelasida), Cymbaxinella (p) verrucosa (Hymerhabdiidae, Agelasida) and Axinella polypoides (Axinellidae, Axinellida). We show, for the first time, that sponges can also harbour Group II introns in their COI gene, whose presence in animals' mitochondria has so far been described in only two phyla, Placozoa and Annelida. Surprisingly, two different Group II introns were discovered in the COI gene of C. verrucosa. Phylogenetic analysis indicates that the Group II introns present in C. verrucosa are related to red algae (Rhodophyta) introns. CONCLUSIONS: The differences found among intron secondary structures and the phylogenetic inferences support the hypothesis that the introns originated from independent horizontal gene transfer events. Our results thus suggest that self splicing introns are more diverse in the mitochondrial genome of sponges than previously anticipated. PMID- 26653219 TI - HERC5 is a prognostic biomarker for post-liver transplant recurrent human hepatocellular carcinoma. AB - BACKGROUND AND AIMS: Orthotopic liver transplantation (OLT) can be an effective treatment option for certain patients with early stage hepatocellular carcinoma (HCC) meeting Milan, UCSF, or Hangzhou criteria. However, HCC recurrence rates post-OLT range from 20 to 40 %, with limited follow-up options. Elucidating genetic drivers common to primary and post-OLT recurrent tumors may further our understanding and help identify predictive biomarkers of recurrence-both to ultimately help manage clinical decisions for patients undergoing OLT. METHODS: Whole exome and RNA sequencing in matched primary and recurrent tumors, normal adjacent tissues, and blood from four Chinese HCC patients was conducted. SiRNA knockdown and both qRT-PCR and Western assays were performed on PLCPRF5, SNU449 and HEPG2 cell lines; immunohistochemistry and RNA Sequencing were conducted on the primary tumors of Chinese HCC patients who experienced tumor recurrence post OLT (n = 9) or did not experience tumor recurrence (n = 12). RESULTS: In three independent HCC studies of patients undergoing transplantation (n = 21) or surgical resection (n = 242, n = 44) of primary tumors (total n = 307), HERC5 mRNA under-expression correlated with shorter: time to tumor recurrence (p = 0.007 and 0.02) and overall survival (p = 0.0063 and 0.023), even after adjustment for relevant clinical variables. HERC5 loss drives CCL20 mRNA and protein over-expression and associates with regulatory T cell infiltration as measured by FOXP3 expression. Further, matched primary and recurrent tumors from the 4 HCC patients indicated clonal selection advantage of Wnt signaling activation and CDKN2A inactivation. CONCLUSIONS: HERC5 plays a crucial role in HCC immune evasion and has clinical relevance as a reproducible prognostic marker for risk of tumor recurrence and survival in patients. PMID- 26653221 TI - [Effects of chronic manganese sulfate toxicity test on myocardial ultrastructure and heart organ index of rats]. AB - OBJECTIVE: To observe the effects of manganese sulfate on blood pressure, myocardial ultrastructure and heart organ index of rats. METHODS: Forty male SPF SD rats were randomly divided into 4 groups: control group (0 mg/kg), 5 mg/kg dose group, 15 mg/kg dose group and 25 mg/kg dose group, 10 rats each group. Intraperitoneal injection was performed for six months, by five times each week, the rat blood pressure was measured by tail cuff method, and the heart organ index of the rats was computed. Three rats were selected from each group randomly, and the myocardial ultrastructure of the rats was observed by using transmission electron microscopy (TEM). The BMD and BMDL between manganese sulfate injected dose and the rats heart organ index were evaluated by BMD (Benchmark Dose). RESULTS: There was no significant of blood pressure between the experimental group and the control group (P > 0.05).The heart organ indexes of the four groups were 0.24% +/- 0.10%, 0.25% +/- 0.02%, 0.26% +/- 0.02%, and 0.24% +/- 0.02%. Statistical significance of heart organ indexes was found between the 15 mg/kg dose group and the control group (P < 0.05). Observed by TEM, we found that-different degrees of mitochondrial crest fracture or disappear, mitochondria swelling, hydropic change and myocardial fibers degeneration happened in the rats of the three exposed groups, but not the control group. The BMD and BMDL were calculated as 9.33 mg/kg and 4.28 mg/kg in the study of manganese sulfate injected dose and the rats heart organ index. CONCLUSION: Chronic manganese poisoning can lead to myocardial mitochondria superfine lesions, myocardial fiber damage and heart organ index change in rats. PMID- 26653220 TI - [Nickel exposure to A549 cell damage and L-ascorbic acid interference effect]. AB - OBJECTIVE: Studying different concentrations of nickel smelting smoke subjects of human lung adenocarcinoma cells (A549) carcinogenic effects, discusses the influence of L-ascorbic acid protection. METHODS: The A549 cells were divided into experimental and L-ascorbic acid in the intervention group. Plus exposure group concentration of nickel refining dusts were formulated 0.00, 6.25, 12.50, 25.00, 50.00, 100.00 ug/ml suspension, the intervention group on the basis of the added exposure group containing L-ascorbic acid (100 mmol/L), contact 24 h. Detection of cell viability by MTT assay. When the test substance concentration select 0.00, 25.00, 50.00, 100.00 ug/ml experiment for internal Flou-3 fluorescent probe to detect cell Ca2+ concentration, within DCFH-DA detect intracellular reactive oxygen (ROS) content, real-time quantitative PCR (real time, in the RT-PCR) was used to detect cell HIF-1alpha gene expression. RESULTS: With the increase of concentration, subjects increased cell growth inhibition rate, intracellular Ca2+ concentration increases, ROS content increased, HIF 1alpha gene expression increased, differences were statistically significant (P < 0.05). After L-ascorbic acid intervention treatment, the results of the intervention group were lower than that of the experimental group, and the difference was statistically significant (P < 0.05), so L-ascorbic acid can effectively protect the nickel exposure damage to cells. CONCLUSION: With subjects following exposure to nickel concentration increased, its effect on A549 cell damage increases, L-ascorbic acid cell damage caused by nickel has certain protective effect. PMID- 26653222 TI - [The discriminant analysis of the silicosis's induction on cytokines in phlegm and combined multi-markers]. AB - OBJECTIVE: To investigate the changes of cytokines in induced sputum at different stages of silicosis patients. METHODS: A total of 200 workers from one of the Shandong Province gold mine were chosen as object of observation. Among which 40 patients at silicosis stage I and 40 patients at silicosis stage II were divided into silicosis observed object group, silicosis stage I group, silicosis stage II group, and another 80 workers exposed to silica dust without suffering from silicotic Clinical symptoms, however, were chosen as group of dust exposed, and 40 logistical workers without being exposed and history of silicosis's illness were chosen as control group. And ask their basic information by questionnaire. Then, spray-inhalation the induced sputum and apply the ELISA to assess the level of tumor necrosis factor (TNF), interleukin (IL), macrophage inflammatory protein 1 (MIP-1alpha), monocyte chemotactic factor-1 (MCP-1), metalloproteinases (MMP), transforming growth factor-beta (TGF-beta), platelet derived growth factor (PDGF) in induced sputum from subjects. RESULTS: The level of TGF-beta [(901.60 +/- 30.09) ng/L] in the induced sputumof patients in silicosis stage I group is lower than that in the observed object group [(913.02 +/- 20.51) ng/L], and the level of MMP-9 [(212.49 +/- 5.97) ng/L], MCP-1 [(129.91 +/- 4.30) ng/L] has various degrees of increase than that in control group, observed object group and dust exposed group. All the differences have statistical significances (P < 0.05). The level of TNF-alpha [(85.76 +/- 3.78) ng/L] in the induced sputum of patients in silicosis stage I group reaches the maximum, there are significant differences comparing with that level in the silica dust exposure group and the control group, whose differences are statistically significant (P < 0.05). Compared with the control group, the level of MMP-2 (427.95 +/- 23.64) in the induced sputum of patients in silicosis stage I group has increased, whose differences also have statically significant (P < 0.05). Compared with the control group, silica dust exposed group, the observation group of objects, the pneumosilicosis patients of IL-16 in induced sputum IL-16 (21.40 +/- 9.24) decreased, the content of PDGF [(5.96 +/- 0.51) ng/L], MMP-2 [(447.86 +/- 27.10) ng/L], MMP-9 [(223.91 +/- 12.28) ng/L], MCP-1 [(122.87 +/- 6.08) ng/L] increased, the differences are statistically significant (P < 0.05). CONCLUSION: As silicosis biomarkers, TNF alpha, TGF-beta, IL-16, PDGF, MMP-2, MMP-9 and MCP-1 have certain significance, further suggesting that early detection rate of patients with silicosis can be improved by employing the multiple indexes discriminate equation. PMID- 26653223 TI - [Effect of hydrogen-saline on lung injury and heme oxygenase-1 expression in the lung tissue of acute paraquat-intoxicated mice]. AB - OBJECTIVE: To investigate the effect of Hydrogen-saline on Lung Injury and HO-1 Expression in The Lung Tissue of Acute Paraquat-intoxicated mice. METHODS: 108 male clean-grade mice were divided randomly into 3 groups: normal control group (n = 8), PQ group (n = 50) and PQ HN group (n = 50), PQ group were lavaged with 20% PQ (50 mg/kg). PQ+Hyclrogen saline group were intxaperitoneal injected with 5 ml/kg saturated hydragen saline after lavaged, 2 times/d. We observe its performance after the poisoning, The lung tissue were taken to HE stained, MDA and SOD activity of lung tissue homogenate were detected, HO-1 activity were observed by immunohistochemistry and western method at 6 h, 1 d, 3 d, 7 d and 14 d. RESULTS: mice came to shortness of breath, exhaustion and death after poisoned. PQ+hydrogen saline group was more alleviative than PQ group. The lung MDA of PQ group was markedly increased at 6 h and 24 h and SOD was decreased at 6 h, 24 h, 3 d, 7 d, 14 d than normal control group. In Comparison with PQ group, the lung MDA was decreased at 24 h and SOD was increased at 24 h and 3 d (P < 0.05). HO-1 expression trend and distribution in PQ+hydrogen saline group are similar with PQ group, but were significantly higher than that of PQ group and the control group each time point (P < 0.05). CONCLUSION: Oxidative stress plays important roles in lung injury caused by paraquat. Hydrogen-saline may increase expression of HO-1 and alleviate oxidative stress damage in lung. PMID- 26653224 TI - [Analyses on the characteristics and the trends of pneumoconiosis notified between 2001 and 2012 in Hebei Province]. AB - OBJECTIVE: To describe the incidence, development and death of pneumoconiosis reported in Hebei from 2001 to 2012 and investigate the epidemiological trends and characteristics of pneumoconiosis to provide basic data for formulating the guidelines and policies for control of pneumoconiosis. METHODS: The Hebei database of new cases of pneumoconiosis reposed from 2001 to 2012 were subjected to systematic arrangement. Clean data and descriptive analysis using SPSS 17.0. The statistical indices included number of new and death pneumoconiosis cases in each year. RESULTS: From 2001 to 2012 a total of 4558 new cases of pneumoconiosis were reported. The situation was same to coal-workers' pneumoconiosis and silicosis. (2) The pneumoconiosis cases were distributed mainly in the city of Tang Shan, Cheng De, Zhang Jia Kou and Han Dan (88.24%). (3) Most cases were centerred in coal industry, metallurgical industry, nonferrous metals industry, architectural material industry and light industry. (4) The mean age of onset in new cases was shorted each year for silicosis, coal-workers' pneumoconiosis, potter pneumoconiosis and electric welder pneumoconiosis, especially for 2010 to 2012 (9 years). (5) The work types of these cases mainly included drilling (26.72%), mining as the main work (6.67%), hybrid coal mine work (6.95%), molding worker (5.24%) and berterring worker (4.82%). (6) The new cases of pneumoconiosis reposed from 2001 to 2012 were diagnosissed I (3415, 74.92%), II (782, 17.16%), III (361, 7.92%). (7) The death cases of pneumoconiosis reposed from 2001 to 2012 were 1182, most of them were distributed mainly in the city of Tang Shan, Cheng De, Zhang Jia Kou and Han Dan (88.24%). CONCLUSION: The incidence of pneumoconiosis is still high: the new cases of pneumoconiosis is still rising. The mean age of onset in new cases was shorted each year. The new cases of pneumoconiosis reposed from 2001 to 2012 were diagnosed II was above 25%. The prevention and control of pneumoconiosis should be enhanced in key industries and for people engaging in key regions, industries, types of work according to the epidemiological characteristics of pneumoconiosis. Most cases were centerred in coal-workers' pneumoconiosis and silicosis. PMID- 26653225 TI - [The analysis of the stage progerssion of pneumoconiosis cases in Zi Bo from 2005 to 2014]. PMID- 26653226 TI - [Effects of 1-bromopropane on hematological changes of exposed workers]. PMID- 26653227 TI - [Cardiac effects of 1-bromopropane on exposed workers]. PMID- 26653228 TI - [Effects of 1-bromopropane on blood glucose of exposed workers]. PMID- 26653229 TI - [Electrophysiological effects of 1-bromopropane on exposed workers]. PMID- 26653230 TI - [Effects of 1-bromopropane on liver and kidney functions of exposed workers]. AB - OBJECTIVE: To study the effects of 1-bromopropane (1-BP) on liver and kidney functions of exposed workers. METHODS: Occupational health situation in three 1 BP plants was investigated. Fifty-four workers from the 1-BP manufacturing line were chose to be contact group, while 42 workers from non-1-BP manufacturing line as control group. All workers underwent questionnaire survey, liver function test as well as kidney function test. RESULT: Working years has no impact on liver and kidney functions of workers from contact group. Compared with the control, liver and kidney functions test of the two groups showed no statistical difference either. CONCLUSION: The present investigation doesn't prove any impact of occupational 1-BP exposure on worker's liver and kidney functions. PMID- 26653231 TI - [Effects of shRNA interference the expression of connective tissue growth factor mediated by lentivirus in lung fibrosis of paraquat poisoning rats]. PMID- 26653232 TI - [The effect of paraquat on voltage-dependent anion channel and caspase-3, 8, 9 in the mitochondria of rat lung]. AB - OBJECTIVE: To investigate the effects of different concentrations of paraquat (PQ) poisoning on the expression of voltage-dependent anion channel (VDAC) and caspase family in the mitochondria of rat lung tissue, and to explore possible mechanisms of acute lung injury induced by acute PQ poisoning. METHODS: Two hundred healthy adult Wister rats with equal numbers of male and female ones were randomly and equally divided into control group and poisoned group. The control group received one-time gastric lavage with 1 ml of normal saline, and the poisoned group with PQ (50 mg/kg) diluted in 1 ml of normal saline. Twenty rats were collected at 1, 24, 72, 120, and 168 h after lavage with normal saline or PQ and dissected after anesthesia. Mitochondria were separated from rat lung tissue, and the content of VDAC and caspase-3, -8, and -9 were determined. RESULTS: The expression of VDAC and caspase-3, -8, and -9 in the poisoned rats were significantly higher than that in the control group (P < 0.001). At 1, 24, 72, 120, and 168 h after exposure, acute diffuse damages were found in alveolar capillary endothelial cells, alveolar epithelial cells, and pulmonary interstitial cells. Inflammatory cell infiltration in the pulmonary interstitium, alveolar structural disorder, and substantially increased fibroblasts were also found in rat lung tissue. CONCLUSION: PQ poisoning can up-regulate the expression of VDAC and caspase-3, -8, and -9 in mitochondria of rat lung tissue to induce acute lung injury. PMID- 26653233 TI - [The expressions of P38 mitogen-activated protein kinases and JNK mitogen activated protein kinases in the renal tissue of rats with acute paraquat poisoning and the therapeutical effects of melatonin]. AB - OBJECTIVE: To investigate the expressions of P38 mitogen-activated protein kinases (P38 MAPK), JNK mitogen-activated protein kinases (JNK MAPK) and the therapeutical effects of melatonin in the renal tissue of acute acuteparaquat induced rats. METHODS: Seventy-eight healthy adult Sprague-Dawley (SD) rats (39 male, 39 female) were randomly divided into three groups: (1) Control group (group A): 6 rats, (2) Poisoned group (group B): 36 rats, (3) Therapeutical group (group C): 36 rats. At 1, 3, 5, 7, 10 and 14 days after poisoning, six rats in Group B and group C were used to assess renal pathological changes and the expression of P38 MAPK, JNK MAPK in kidney were evaluated by immunohistochemistry. RESULTS: Compared with control group, the expression of P38MAPK in renal tissue of poisoned group significantly rose at the first day, reached the peak at the 10th day and afterwards decreased slowly. Expression of JNK MAPK reached the peak at the first day, and kept at relatively high levels up to the 14th day. Melatonin weakened markedly the expressions of P38 MAPK and JNK MAPK in renal tissue of acute acuteparaquat-induced rats. CONCLUSION: P38 MAPK and JNK MAPK play an important role in renal injury of acute paraquat -poisoning rats. Melatonin takes a significant effect on the activation of them. PMID- 26653234 TI - [The study of kidney injury in rats with acute paraquat poisoning]. AB - OBJECTIVE: To explore the dynamic variation rule of kidney injury makers of molecule 1 (KIM-1), Cystatinc (Cys-C), Blood urea nitrogen (BUN) and Creatinine (Cr) in kidney injury in rats with acute paraquat poisoning. METHODS: Healthy adult rats were randomly divided into control group (normal saline solution) and exposure group (2% paraquat solution 40 mg/kg), and 90 in each group. Six rats in each group were randomly sacrificed at one, one point five, two, three, six, twelve, twenty four, seventy two or one hundred and sixty eight hours after different administration, abdominal aortic blood and the kidney tissue were collected. The concenstrations of kidney injury makers of molecule 1 (KIM-1), cystatinc (Cys-C), blood urea nitrogen (BUN) and creatinine (Cr) were determined by ELASA. The concenstrations of paraquat were determined by HPLC. Pathological changes of kidney tissue that stained by HE were axamined by optical microscopy. The cell apoptosis in kidney tissue were analyzed by TUNEL assay. The ptotein expression of KIM-1 was determined by immunohistochemistry. RESULTS: Serum levels of KIM-1 were significantly increased in exposure group as compared with control group at two, three, six, twelve, twenty four, seventy two or one hundred and sixty eight hours, and the peak level was at twenty four hours, and there was a statistical significance between control group and exposure group (P < 0.01). Serum levels of Cys-C were significantly increased in exposure group as compared with control group at six, twelve, twenty four, seventy two or one hundred and sixty eight hours, the peak level was at twenty four hours, and there was a statistical significance between control group and exposure group (P < 0.01). Serum levels of BUN were significantly increased in exposure group as compared with control group at twelve, twenty four, seventy two or one hundred and sixty eight hours, and the peak level was at seventy two hours, and there was a statistical significance between control group and exposure group (P < 0.01). Compared with control group, there was mild tubular epithelial cells edema in exposure group of three hours, serious epithelial cells edema and few slightly increased glomeruli in exposure group of six hours, severe epithelial cells swelling, tube formation, and interstitial lesions including edema, congestionin and increased inflammatory cell infiltration in exposure group of twelve hours, these pathologic changes gradually reached the peak at twenty four hours, the pathologic injury score was 5.56 +/- 0.0349 (P < 0.01), and then the pathological lesion was more palliative. Apoptosis rate of kidney tissue were significantly increased in exposure group as compared with control group at three, six, twelve, twenty four, seventy two or one hundred and sixty eight hours, and the peak level was at twenty four hours, and there was a statistical significance between control group and exposure group (P < 0.01). The immunohistochemical assay indicated that KIM-1 of control group were weakly positive expressed in tubular epithelial cell membrane, but the positive expression of KIM-1 were slightly increased in exposure group of two hours, the.immunohistochemistry score was 5.47 +/- 0.1033 (P < 0.05), the positive expression of KIM-1 were gradually increased in exposure group of three, six and twelve hours, it reached peak at twenty four hours, the.immunohistochemistry score was 11.73 +/- 0.4676 (P < 0.01), then the positive expression of KIM-1 decreased, but there was still positive expression at one hundred and sixty eight hours. CONCLUSION: Serum levels of KIM-1 and Cys-C were significantly increased in the kidney injury in rats with acute paraquat poisoning in early stage, earlier than the changes of BUN and Cr. KIM-1 had relation with apoptosis rate. Cys-C had relation with pathological lesion changes. PMID- 26653235 TI - [Xuebijing combined ulinastatin in treating acute paraquat poisoning]. PMID- 26653236 TI - [Exploring the effect of embolization of bronchial artery in patients with pneumoconiosis massive hemoptysis]. AB - OBJECTIVE: To explore the effect of embolization of bronchial artery (BAE) in patients with pneumoconiosis massive hemoptysis. METHODS: 49 patients with pneumoconiosis massive hemoptysis in observation group were underwent BAE, and 66 patients with pneumoconiosis hemoptysis in control group were cured with internal medicine. The rate of hemoptysis recurrence and controlling were counted during a year follow up. RESULTS: The rate of hemoptysis recurrence in observation group was 18.8% (9/48), and in control group was 35.9% (23/64) during a year follow up, there was a significant difference (P < 0.05). The rate of massive hemoptysis recurrence in the both group were 4.2% (2/48) and 9.3% (6/64) respectively, there was not a significant difference (P > 0.05). CONCLUSION: BAE is an effective technique in patients with pneumoconiosis massive hemoptysis. PMID- 26653237 TI - [Analysis of the clinical diagnosis of asbestosis complicated with malignant mesothelioma]. AB - OBJECTIVE: To discuss the clinical characteristics, diagnosis and treatment of the clinical characteristics and prognosis of asbestosis complicated with malignant mesothelioma patients. METHODS: In 3 cases of asbestosis complicated with malignant mesothelioma were retrospectively analyzed. RESULTS: In the 3 patients, 2 cases of pleural mesothelioma, with chest tightness, chest and back pain as initial symptom; 1 case of peritoneal mesothelioma, with abdominal distention, abdominal pain, dysuria as initial symptom. One case of the pleural mesothelioma misdiagnosed as tuberculous pleurisy. 3 patients were in CT or B ultrasound guided biopsy pathology confirmed to be malignant mesothelioma. 2 patients received systemic chemotherapy, another received symptomatic and supportive treatment. Up till now, 3 patients have died. CONCLUSION: The disease is a high degree of malignant, the early clinical manifestations are not specific, easily missed diagnosis and misdiagnosis. The treatment effect is not ideal, the prognosis is poor. Biopsy is a reliable method for diagnosis of MM. PMID- 26653238 TI - [Right ventricular systolic function of patients with pneumoconiosis based on the evaluation of systolic displacement of tricuspid annulus]. AB - OBJECTIVE: To determine the tricuspid annular plane systolic excursion (TAPSE) using M-mode echocardiography, and to evaluate the right ventricular systolic function in patients with pneumoconiosis. METHODS: One hundred and eighty-three patients with pneumoconiosis were enrolled as subjects, and one hundred and ninety-nine healthy volunteers were used as controls. According to the types of ventilation dysfunction, patients were divided into four groups: normal type, obstructive type, restrictive type, and mixed type. In the apex four-chamber sections, the displacement of tricuspid annular plane on the right ventricular free wall side was measured from end-diastole to end-systole using M-mode echocardiography. RESULTS: The average TAPSE in the pneumoconiosis group was significantly lower than that in the control group (18.61 +/- 3.08 vs 22.38 +/- 3.03 mm, P < 0.01). Along with the progression of pneumoconiosis, the TAPSE values in patients with stage I, II, and III pneumoconiosis were significantly decreased compared with those in the control group (P < 0.01). The TAPSE values in patients diagnosed with normal, obstructive, restrictive, and mixed types of pneumoconiosis in pulmonary function tests were all significantly lower than those in the control group (P < 0.01). Among all patients, patients with mixed type of pneumoconiosis had the most significant reduction in the TAPSE. CONCLUSION: The TAPSE is substantially decreased in patients with pneumoconiosis and further decreased along with the progression of pneumoconiosis. Measurement of the TAPSE is an easy way to evaluate the right ventricular systolic function in patients with pneumoconiosis. PMID- 26653239 TI - [Analysis on eleven cases of severe occupational heatstroke]. PMID- 26653240 TI - [Reports on one case of pneumonoconiosis patient experiencing recurring benign paroxysmal vertigo after lung lavage]. PMID- 26653241 TI - [Clinical analysis of hard metal lung disease]. AB - OBJECTIVE: To analyze the clinical features and investigate the clinical diagnostic methods of hard metal lung disease (HMLD), then provide reference for the diagnostic criteria of occupational HMLD. METHODS: Retrieved the open published case reports associated with HMLD from January, 2000 to June, 2014. Regarding the ages, sex, types and years of work, clinical features and laboratory results for analyzing. RESULTS: Collected 21 clinical cases of HMLD belonged to 6 internal reports and 15 oversea reports. Among them 15 male and 6 female, ages were from 22 to 58, length of service between 1 year and 43 years. Clinical presentations included cough (20 cases), dyspnea on progressive (10 cases), and pulmonary function testing showed a restrictive abnormality. The imaging features presented as bilateral areas of ground-glass attenuation, diffuse small nodules, extensive reticular opacities and traction bronchiectasis. The finding of giant cell interstitial pneumonia (GIP) was almost pathognomonic for hard metal pneumoconiosis. The main pathological findings contained a different levels of lymphocyte, acidophilic cell infiltration, hyperplasia of fibrous tissue and numerous large multinucleated histiocytes which ingested inflammatory cells were admixed with macrophages. 16 cases of the 21 reports showed GIP. CONCLUSIONS: Clinical presentations include cough and dyspnea on progressive, and pulmonary function testing show a restrictive abnormality. The imaging features present as bilateral areas of ground-glass attenuation, areas of consolidation, diffuse small nodules, extensive reticular opacities and traction bronchiectasis. The prime pathological findings contain interstitial pneumonia with intra-alveolar macrophages and a large amount of multinucleated histiocytes. PMID- 26653242 TI - [One case of chronic benzene poisoning diagnosis analysis of controversial]. PMID- 26653243 TI - [Determination of urinary 1-bromopropane by headspace-gas chromatography]. PMID- 26653244 TI - [Determination of N-acetyl-S-(n-propyl)-L-cysteine: the major metabolite of 1 bromopropane in human urine]. PMID- 26653245 TI - [Determination of total Bromine in urine by inductively coupled plasma mass spectrometry (ICP-MS)]. AB - OBJECTIVE: To establish a method to determine total bromine in urine. METHOD: Diluted urine samples were directly introduced into ICP-MS then quantized by standard curve. RESULT: Total bromine in urine was linear within 1.0~50 mg/L with r > 0.999, When spiked at a concentration of 0.020 mg/L, 0.050 mg/L, 0.150 mg/L, the recovery was 95%~98%, intra-assay precision was 1.4% 3.2%, inter-assay precision was 3.4% to 5.0%. Urine could store in -20 degrees C refrigerator 3 months without any bromine loss. CONCLUSION: Using ICP-MS to determine the urinary total bromine, the method is fast, accurate, wide linear range of features, could meet with the requirement of Part 5 of occupational health standards guide: Method determination of chemical substances in biological materials (GBZ/T 210.5-2008), a strong competitive advantage in a wide range of survey, suitable for promotion. PMID- 26653246 TI - [Latest research progress in biological exposure limits of 1-bromopropane]. PMID- 26653248 TI - Eye movements and brain oscillations to symbolic safety signs with different comprehensibility. AB - BACKGROUND: The aim of this study was to investigate eye movements and brain oscillations to symbolic safety signs with different comprehensibility. METHODS: Forty-two young adults participated in this study, and ten traffic symbols consisting of easy-to-comprehend and hard-to-comprehend signs were used as stimuli. During the sign comprehension test, real-time eye movements and spontaneous brain activity [electroencephalogram (EEG) data] were simultaneously recorded. RESULTS: The comprehensibility level of symbolic traffic signs significantly affects eye movements and EEG spectral power. The harder to comprehend the sign is, the slower the blink rate, the larger the pupil diameter, and the longer the time to first fixation. Noticeable differences on EEG spectral power between easy-to-comprehend and hard-to-comprehend signs are observed in the prefrontal and visual cortex of the human brain. CONCLUSIONS: Sign comprehensibility has significant effects on real-time nonintrusive eye movements and brain oscillations. These findings demonstrate the potential to integrate physiological measures from eye movements and brain oscillations with existing evaluation methods in assessing the comprehensibility of symbolic safety signs. PMID- 26653247 TI - HIV treatment and care among Italian inmates: a one-month point survey. AB - BACKGROUND: HIV infection, with an estimated prevalence be between 2 and 50 times those of the general adult population is a major health challenge for prison authorities worldwide. Since no nationwide surveillance system is present in Italy, data on HIV prevalence and treatment in prisons are limited to only a few and small observational studies. We aimed to estimate HIV prevalence and obtain an overview on diagnostic and therapeutic activities concerning HIV infection in the Italian penitentiary system. METHODS: We piloted a multi-centre cross sectional study investigating the prevalence of HIV infection and assessing HIV related medical activities in Italian correctional institutions. RESULTS: A total of 15,675 prisoners from 25 institutions, accounting for approximately one-fourth of the prison inmates in Italy, were included in the study, of whom, 97.7 % were males, 37.1 % foreigners and 27 % had a history of intravenous drug addiction. HIV-tests were available in 42.3 % of the total population, with a known HIV Infection proportion of 5.1 %. In the month prior to the study, 604 of the 1,764 subjects who entered prison were tested for HIV, with a HIV-positive prevalence of 3.3 %. Among the 338 HIV-positive prisoners, 81.4 % were under antiretroviral treatment and 73.5 % showed undetectable HIV-RNA. In 23/338 (6.8 %) a coinfection with HBV and in 189/338 (55.9 %) with HCV was also present. Among the 67 (19.8 %) inmates with HIV who did not receive HIV treatment, 13 (19.5 %) had T-CD4+ count <350 cells/mm(3) and 9 (69.2 %) of these had refused the treatment. The majority of the inmates with HIV-infection were on a PI-based (62.5 %) or on NNRTIs-based (24.4 %) regimen. Only a minority of patients received once daily regimens (17.2 %). CONCLUSIONS: Although clinical and therapeutic management of HIV infection remains difficult in Italian prisons, diagnostics, treatment and care were offered to the majority of HIV-infected inmates. Specific programs should be directed towards the prison population and strict cooperation between prison and health institutions is needed to increase HIV treatment. PMID- 26653249 TI - Acute unilateral sensorineural hearing loss associated with anabolic steroids and polycythaemia: case report. AB - BACKGROUND: Unilateral sudden sensorineural hearing loss due to an infarct in the vertebrobasilar system has been widely reported. Most patients have a background of traditional coronary risk factors related to these cerebrovascular episodes. CASE REPORT: A 32-year-old male, a regular user of anabolic steroids, presented to the emergency department with unilateral sensorineural hearing loss and symptoms suggestive of an infarct of the anterior inferior cerebellar artery but in the absence of risk factors for ischaemic stroke. RESULTS: Magnetic resonance imaging confirmed the presence of infarction in the region supplied by the anterior inferior cerebellar artery. Polycythaemia was found on haematological analysis, which we believe was secondary to the use of anabolic steroids. The patient was commenced on aspirin as per the stroke management protocol. There was resolution of neurological symptomatology six weeks after the episode, but no improvement in hearing. CONCLUSION: To our knowledge, this is the first case report of unilateral sensorineural hearing loss secondary to the use of anabolic steroids causing polycythaemia. This cause should be considered in the differential diagnosis of patients presenting with sensorineural hearing loss, especially in young males, when no other risk factors can be identified. PMID- 26653250 TI - An exploration of the prevalence and predictors of work-related well-being among psychosocial oncology professionals: An application of the job demands-resources model. AB - OBJECTIVE: Burnout is reportedly high among oncology healthcare workers. Psychosocial oncologists may be particularly vulnerable to burnout. However, their work engagement may also be high, counteracting stress in the workplace. This study aimed to document the prevalence of both burnout and work engagement, and the predictors of both, utilizing the job demands-resources (JD-R) model, within a sample of psychosocial oncologists. METHOD: Psychosocial-oncologist (N = 417) clinicians, recruited through 10 international and national psychosocial oncology societies, completed an online questionnaire. Measures included demographic and work characteristics, burnout (the MBI-HSS Emotional Exhaustion (EE) and Depersonalization (DP) subscales), the Utrecht Work Engagement Scale, and measures of job demands and resources. RESULTS: High EE and DP was reported by 20.2 and 6.6% of participants, respectively, while 95.3% reported average to high work engagement. Lower levels of job resources and higher levels of job demands predicted greater burnout, as predicted by the JD-R model, but the predicted interaction between these characteristics and burnout was not significant. Higher levels of job resources predicted higher levels of work engagement. SIGNIFICANCE OF RESULTS: Burnout was surprisingly low and work engagement high in this sample. Nonetheless, one in five psychosocial oncologists have high EE. Our results suggest that both the positive (resources) and negative (demands) aspects of this work environment have an on impact burnout and engagement, offering opportunities for intervention. Theories such as the JD-R model can be useful in guiding research in this area. PMID- 26653251 TI - Track structure modeling in liquid water: A review of the Geant4-DNA very low energy extension of the Geant4 Monte Carlo simulation toolkit. AB - Understanding the fundamental mechanisms involved in the induction of biological damage by ionizing radiation remains a major challenge of today's radiobiology research. The Monte Carlo simulation of physical, physicochemical and chemical processes involved may provide a powerful tool for the simulation of early damage induction. The Geant4-DNA extension of the general purpose Monte Carlo Geant4 simulation toolkit aims to provide the scientific community with an open source access platform for the mechanistic simulation of such early damage. This paper presents the most recent review of the Geant4-DNA extension, as available to Geant4 users since June 2015 (release 10.2 Beta). In particular, the review includes the description of new physical models for the description of electron elastic and inelastic interactions in liquid water, as well as new examples dedicated to the simulation of physicochemical and chemical stages of water radiolysis. Several implementations of geometrical models of biological targets are presented as well, and the list of Geant4-DNA examples is described. PMID- 26653252 TI - Current and Emerging Pharmacotherapies for Type 2 Diabetes. PMID- 26653253 TI - Exercise as Medicine: Key Concepts in Discussing Physical Activity with Patients who have Type 2 Diabetes. AB - People with type 2 diabetes stand to benefit substantially from being physically active. Practice guidelines consistently recommend that people with diabetes obtain at least 150 minutes of moderate to vigorous aerobic exercise per week. Although the message of 150 minutes per week is important, there are several other key messages regarding physical activity that may not be communicated as often or as clearly. This article gives an overview of the importance of resistance training, the dose-response relationship between physical activity and health outcomes, and the emerging evidence concerning the role of sedentary behavior in people with type 2 diabetes. This article provides valuable content for healthcare providers that will help to inform their discussions about physical activity with patients who have type 2 diabetes. PMID- 26653254 TI - Novel Strategies for Inducing Glycemic Remission during the Honeymoon Phase of Type 2 Diabetes. AB - A lofty goal in the management of type 2 diabetes is the achievement of glycemic remission. Glycemic remission can be defined as the sustained maintenance of normoglycemia without antidiabetic therapy for variable periods of time after stopping an initial disease-modifying intervention. Although this goal remains largely elusive at this time, growing recognition of the potential reversibility of pancreatic beta-cell dysfunction early in the course of type 2 diabetes has yielded a target for such disease modification. Furthermore, short-term intensive insulin therapy for 2 to 5 weeks has emerged as an intervention that could be applied as a biologic agent for this purpose during a window of opportunity that we have called the honeymoon phase of type 2 diabetes. This recognition has led to a novel therapeutic paradigm consisting of initial induction therapy to improve reversible beta-cell dysfunction during the honeymoon phase, followed by maintenance therapy aimed at preserving this beneficial beta-cell effect. This concept of induction and maintenance therapy is being applied in a series of recent and ongoing clinical trials, toward the goal of ultimately preserving beta cell function and thereby modifying the natural history of type 2 diabetes. PMID- 26653255 TI - Novel and Emerging Insulin Preparations for Type 2 Diabetes. PMID- 26653257 TI - Retraction Note: Mast cells are the main interleukin 17-positive cells in anticitrullinated protein antibody-positive and -negative rheumatoid arthritis and osteoarthritis synovium. PMID- 26653256 TI - Lipid Management in Diabetes with a Focus on Emerging Therapies. AB - We reviewed the current and potential future management of dyslipidemia in patients with diabetes, with a focus on reduction of risk for macrovascular disease. We considered novel dyslipidemia therapies, in particular, inhibitors of proprotein convertase subtilisin kexin 9 (PCSK9), which have been approved in Canada for reducing low-density lipoprotein (LDL) cholesterol in certain patient groups. We searched for English-language randomized clinical trials (RCTs) of lipid-lowering modalities, mainly since 2012, that included patients with diabetes. The results from some RCTs may have future impacts on the approach to patients with diabetes. In particular, ezetimibe added to statins in the context of acute coronary syndromes seems to have particular benefits in patients with diabetes. Also, patients with diabetes show no differences, so far, from patients without diabetes with respect to efficacy of PCSK9 inhibitors in LDL cholesterol reduction and also in the frequency of adverse effects. RCTs of clinical outcomes with PCSK9 inhibitors performed exclusively in patients with diabetes are desirable, but approval of these agents for use in Canada has occurred before the availability of such results. Clinicians will have to gauge whether certain subjects with diabetes might benefit from this therapy, such as those with superimposed familial dyslipidemia, those with recurrent cardiovascular events and recalcitrant LDL cholesterol levels despite maximally tolerated statin therapy and those with high cardiovascular risk who cannot tolerate any dose of statins. PMID- 26653258 TI - The Sustainable Development Goals and Implications for Eye Health Research. PMID- 26653259 TI - Perceptions of Eye Health and Eye Health Services among Adults Attending Outreach Eye Care Clinics in Papua New Guinea. AB - PURPOSE: To determine how people attending outreach eye care clinics in Papua New Guinea (PNG) perceive eye health and eye health services. METHODS: An interview based questionnaire was administrated to a convenience sample of 614 adult participants across four provinces and perceptions of eye health and eye health services were recorded. Presenting and near visual acuity were measured and cause of visual impairment (VI) determined. RESULTS: In this sample, 113/614 participants (18.4%) presented with distance VI, 16 (2.6%) with distance blindness, and 221 (47.6%) with near VI. Older participants and those with near VI were more likely to indicate that it is hard to have an eye examination due to travel time, lack of transport and transport costs. Female participants and those from underserved areas were more likely to report shame and fear of jealousy from others when asked about their attitudes towards spectacles. Participants reporting that they were willing to pay higher amounts for testing and spectacles/treatment also reported higher education levels, higher household incomes and were more likely to be male. A quarter of participants (25.9%) indicated that they did not like having an eye examination because their reading and writing was poor. CONCLUSIONS: People attending outreach eye care clinics in PNG reported finding it difficult to attend eye health services due to transport difficulties and anticipated high costs. Negative attitudes towards spectacles were also prevalent, and negative perceptions appeared more frequently among older participants and those with less education. PMID- 26653260 TI - Impact of a Brief Educational Intervention on Glaucoma Persistence: A Randomized Controlled Clinical Trial. AB - PURPOSE: To determine whether two sessions of a glaucoma educational intervention resulted in better persistence to glaucoma eye drop therapy compared to normal care. METHODS: A total of 165 patients newly diagnosed with glaucoma who required eye drop therapy were recruited into a randomized clinical trial from the glaucoma clinic at Maisonneuve-Rosemont Hospital in Montreal, Canada. Patients were randomized to either an immediate intervention or normal care. The intervention consisted of two 60-90 minute sessions of education on glaucoma and its management, given in a small group format by a non-practicing ophthalmologist. Persistence to glaucoma medication was examined for 1 year by the use of Hospital medical records and by pharmacy claims records from the Regie de l'assurance maladie du Quebec (Quebec Health Insurance Program). A questionnaire was administered, and medication possession ratio calculated. The primary outcome was persistence, defined as having medication available at least 75% of the time. Secondary outcomes included eye drop instillation technique and perception of the importance of eye drop therapy. RESULTS: The intervention group achieved better persistence to eye drop therapy, as 77% of controls and 89% of people receiving the intervention were persistent (p = 0.049). The intervention also resulted in better eye drop instillation technique (p < 0.001) and greater perception of the importance of eye drop therapy (p < 0.001). CONCLUSIONS: Brief instructional sessions offered to newly diagnosed glaucoma patients can result in better persistence rates over 1-year follow-up. Strategies to permanently offer these types of initiatives should be considered. PMID- 26653261 TI - The Effect of Counseling on Cataract Patient Knowledge, Decisional Conflict, and Satisfaction. AB - PURPOSE: Cataract is the leading cause of non-refractive preventable blindness, and comprehensive strategies to increase cataract surgery rates are imperative, including high-quality supportive patient education. We evaluated the effectiveness of non-physician pre-surgical counselors teaching patients about cataract and cataract surgery in improving patient knowledge, decisional conflict, and satisfaction. METHODS: A survey was given before and after 61 newly diagnosed cataract patients underwent pre-surgical counseling at the Aravind Eye Hospital, Madurai, India. The survey measured change in cataract knowledge and decisional conflict, a measure of anxiety surrounding the decision to undergo surgery, along with patient satisfaction. Multiple regression was used to identify factors that influenced change in knowledge. RESULTS: Both patient knowledge scores and decisional conflict scores improved following counseling (mean difference +2.0, p = 0.004 and +8.4, p < 0.0001, respectively). Multiple regression analysis identified female sex (beta = 2.5, p < 0.001) and being illiterate (beta = 1.7, p = 0.04) as important predictors of increased knowledge post-counseling. CONCLUSION: Counseling both improved knowledge and reduced decisional conflict about cataract surgery, particularly among patients who had traditionally had more limited access to healthcare such as women and illiterate patients. Increased use of high quality counseling might help to further reduce the global burden of cataract and other forms of blindness. PMID- 26653263 TI - Clinical Competency of 1-Year Trained Vision Technicians in Andhra Pradesh, India. AB - PURPOSE: To assess clinical competency of 1-year trained vision technicians (VTs) in detecting and referring causes of visual impairment in India. METHODS: Eye examination results and management plans for 328 patients examined by 24 VTs in 24 vision centers of LV Prasad Eye Institute in Andhra Pradesh were compared with those of a standard optometrist who examined the same patients. Eye examinations included retinoscopy and subjective refraction, slit lamp examination, applanation tonometry and undilated direct ophthalmoscopy. Data were analyzed for level of concordance in retinoscopy, spectacle prescription, disease detection and referral. RESULTS: VTs demonstrated moderate to good levels of agreement in refraction, disease detection and referral. Sensitivity and specificity for ocular pathology identification were 77.4% (95% confidence interval, CI, 69.4 84.2%) and 86.6% (95% CI 81.1-91.1%), respectively. The highest sensitivity was demonstrated in detecting significant cataract (91.5%) and refractive error (83.0%). VT spectacle prescriptions were accurate 76% of the time for mean spherical equivalent and 65% of the time for astigmatism. VT sensitivity in detecting posterior segment abnormalities was low (18.5%) resulting in failure to detect retinal conditions such as diabetic retinopathy and maculopathy. Despite lack of recognition of the specific pathology, referral decisions were correct in 78.4% of cases. CONCLUSION: VTs in India competently detect and manage or refer the two most common causes of visual impairment; uncorrected refractive error and cataract. Over two-thirds of patients received accurate and appropriate services from VTs, suggesting that they are a useful and competent cadre for rural and remote eye care. PMID- 26653262 TI - Estimating the Future Impact of a Multi-Pronged Intervention Strategy on Ocular Disease Sequelae Caused by Trachoma: A Modeling Study. AB - PURPOSE: Trachoma control programs are underway in endemic regions worldwide. They are based on the SAFE strategy (Surgery for trichiasis, Antibiotic distribution, Facial cleanliness, and Environmental improvement). Although much is known about the effect of community-wide treatment with antibiotics on the prevalence of Chlamydia trachomatis, the impact of the SAFE strategy on severe ocular disease sequelae (the main focus of the Global Elimination of blinding Trachoma by 2020 program) remains largely unknown. METHODS: We use a mathematical model to explore the impact of each of the components of the SAFE strategy, individually and together, on disease sequelae, arising from repeat infection and subsequent conjunctival scarring. We ask whether two elimination goals, to reduce the prevalence of trachomatous trichiasis to 1 per 1000 persons, and the incidence of corneal opacity to 1 per 10,000 persons per annum, are achievable, and which combinations of interventions have the greatest impact on these indicators. RESULTS: In high prevalence communities (here, >20% infection of children aged 1-9 years), a combination of efforts is needed to bring down sustainably the prevalence and incidence of ocular disease sequelae. CONCLUSION: The mass delivery of antibiotics is highly beneficial for the clearance of infection, inflammation and prevention of subsequent scarring, but needs to be supplemented with sustained reductions in transmission and surgery to consider realistically the elimination of blindness by the year 2020. PMID- 26653265 TI - Impaired quality of life after bicycle trauma. AB - INTRODUCTION: Bicycle crashes often affect individuals in working age, and can impair quality of life (QoL) as a consequence. The aim of this study was to investigate QoL in bicycle trauma patients and to identify those at risk of impaired QoL. PATIENTS AND METHODS: 173 bicycle trauma patients who attended a level I trauma centre from 2010 to 2012 received Hadorn's QoL questionnaire six months after their crash. Medical data was collected from the patient's records. Univariate ordinal logistic regression was used to investigate the association between QoL and other factors. RESULTS: 148 patients returned the questionnaire (85.5%). The majority had only mild or minor injuries (85.1%; n=126). However, 72.1% (n=106) still suffered from pain or other physical symptoms more than six months after their bicycle crash. Patients with a Glasgow Coma Scale (GCS) <=13 or an Injury Severity Score (ISS) >15 experienced impaired emotions/outlook on life (p-values 0.003 and 0.045, respectively). Physical suffering was reported by patients with a GCS <=13 and in those with injuries to the cervical spine (p values 0.02 and 0.025, respectively). Patients with an ISS >15 or facial fractures experienced limitations in daily activities (p-values 0.031 and 0.025, respectively). CONCLUSIONS: More than 70% of bicycle trauma patients suffered physically more than six months after their crash, even though only 15% were severely injured. Risk factors for an impaired QoL were cervical spine injuries or facial fractures, a GCS <=13 and an ISS >15. PMID- 26653266 TI - The effect of delay to surgery on morbidity, mortality and length of stay following periprosthetic fracture around the hip. AB - With the increasing prevalence of total hip arthroplasty and the increasing longevity of patients with implants in situ, periprosthetic fractures of the proximal femur are seen with greater frequency. They represent a challenging surgical problem, requiring combined arthroplasty and trauma skills in a potentially compromised surgical bed. We present data from the 82 consecutive patients with periprosthetic fractures around the hip presenting to two NHS Foundation Trusts in the period January 2009 to February 2014. Inpatient mortality across all sites was 11.0%. This increased to 17.1% at 1 year. There was no association between delay to surgery and either inpatient or 1 year mortality. Mean delay to surgery was 4.1 days in those without inpatient mortality, 5.2 days in those with (p=0.3075). Mean delay to surgery was 4.5 days in those with 1 year mortality, 4.16 days in those without (p=0.6203). The number of post-operative complications was not significantly positively correlated with increasing delay to surgery (Pearson correlation coefficient -0.04437). It would appear that a delay to order necessary equipment and obtain relevant surgical expertise for the treatment of these complex fractures is safe and not associated with increased mortality or post-operative complications. PMID- 26653267 TI - Effect of administration of antibodies against nerve growth factor in a rat model of muscle injury. AB - INTRODUCTION: Although muscle injury is a common source of pain, the mechanism causing such pain is not completely known. We have previously reported nerve growth factor (NGF) as a proinflammatory mediator involved in acute pain, and clinical trials have shown the effectiveness of anti-NGF antibodies for management of low back pain. Here, we aim to examine the effects of anti-NGF antibodies on muscle-derived pain by studying their effects on sensory innervation in a rat muscle injury model. METHODS: A nervous system tracer, Fluoro-Gold, was applied to both gastrocnemius muscles of 24 male Sprague Dawley rats to stain the sensory nerves. Then, the drop-mass method was used to damage the right gastrocnemius muscle of the posterior limb. Anti-NGF antibodies (50MUL) were injected into the injured muscles in 12 rats. Tissues were evaluated 1, 3, and 7 days post-injury by performing haematoxylin-and-eosin (HE) staining. The percentage of the total number of FG-positive cells that were also positive for a pain-related neuropeptide, calcitonin gene-related peptide (CGRP), was determined for the bilateral dorsal root ganglia from L1 to L6 7 days post-injury. RESULTS: HE staining showed active inflammation, indicated by increased basophil and eosinophil accumulation, at the injury site 1 and 3 days post-injury, as well as scar tissue formation 7 days post-injury. Injection of anti-NGF reduced muscle necrosis 1 and 3 days post-injury, and resulted in replacement of granulation tissue and muscle fibre regeneration 7 days post-injury. Anti-NGF also significantly inhibited CGRP among FG-positive cells (treatment group 38.2%, control group 49.6%; P<0.05). DISCUSSION: This study found active inflammation induced by NGF, which may contribute to pain after muscle injury. Anti-NGF antibodies successfully suppressed the pain mediator NGF and inhibited inflammation, suggesting NGF as a target for control in pain management. PMID- 26653268 TI - Performance characteristics of five triage tools for major incidents involving traumatic injuries to children. AB - Context Triage tools are an essential component of the emergency response to a major incident. Although fortunately rare, mass casualty incidents involving children are possible which mandate reliable triage tools to determine the priority of treatment. OBJECTIVE: To determine the performance characteristics of five major incident triage tools amongst paediatric casualties who have sustained traumatic injuries. DESIGN, SETTING, PARTICIPANTS: Retrospective observational cohort study using data from 31,292 patients aged less than 16 years who sustained a traumatic injury. Data were obtained from the UK Trauma Audit and Research Network (TARN) database. Interventions Statistical evaluation of five triage tools (JumpSTART, START, CareFlight, Paediatric Triage Tape/Sieve and Triage Sort) to predict death or severe traumatic injury (injury severity score >15). Main outcome measures Performance characteristics of triage tools (sensitivity, specificity and level of agreement between triage tools) to identify patients at high risk of death or severe injury. RESULTS: Of the 31,292 cases, 1029 died (3.3%), 6842 (21.9%) had major trauma (defined by an injury severity score >15) and 14,711 (47%) were aged 8 years or younger. There was variation in the performance accuracy of the tools to predict major trauma or death (sensitivities ranging between 36.4 and 96.2%; specificities 66.0-89.8%). Performance characteristics varied with the age of the child. CareFlight had the best overall performance at predicting death, with the following sensitivity and specificity (95% CI) respectively: 95.3% (93.8-96.8) and 80.4% (80.0-80.9). JumpSTART was superior for the triaging of children under 8 years; sensitivity and specificity (95% CI) respectively: 86.3% (83.1-89.5) and 84.8% (84.2-85.5). The triage tools were generally better at identifying patients who would die than those with non-fatal severe injury. CONCLUSION: This statistical evaluation has demonstrated variability in the accuracy of triage tools at predicting outcomes for children who sustain traumatic injuries. No single tool performed consistently well across all evaluated scenarios. PMID- 26653269 TI - Do thoraco-lumbar spinal injuries classification systems exhibit lower inter- and intra-observer agreement than other fractures classifications?: A comparison using fractures of the trochanteric area of the proximal femur as contrast model. AB - INTRODUCTION: It has been postulated that the complex patterns of spinal injuries have prevented adequate agreement using thoraco-lumbar spinal injuries (TLSI) classifications; however, limb fracture classifications have also shown variable agreements. This study compared agreement using two TLSI classifications with agreement using two classifications of fractures of the trochanteric area of the proximal femur (FTAPF). MATERIAL AND METHODS: Six evaluators classified the radiographs and computed tomography scans of 70 patients with acute TLSI using the Denis and the new AO Spine thoraco-lumbar injury classifications. Additionally, six evaluators classified the radiographs of 70 patients with FTAPF using the Tronzo and the AO schemes. Six weeks later, all cases were presented in a random sequence for repeat assessment. The Kappa coefficient (kappa) was used to determine agreement. RESULTS: Inter-observer agreement: For TLSI, using the AOSpine classification, the mean kappa was 0.62 (0.57-0.66) considering fracture types, and 0.55 (0.52-0.57) considering sub-types; using the Denis classification, kappa was 0.62 (0.59-0.65). For FTAPF, with the AO scheme, the mean kappa was 0.58 (0.54-0.63) considering fracture types and 0.31 (0.28-0.33) considering sub-types; for the Tronzo classification, kappa was 0.54 (0.50-0.57). Intra-observer agreement: For TLSI, using the AOSpine scheme, the mean kappa was 0.77 (0.72-0.83) considering fracture types, and 0.71 (0.67-0.76) considering sub types; for the Denis classification, kappa was 0.76 (0.71-0.81). For FTAPF, with the AO scheme, the mean kappa was 0.75 (0.69-0.81) considering fracture types and 0.45 (0.39-0.51) considering sub-types; for the Tronzo classification, kappa was 0.64 (0.58-0.70). CONCLUSION: Using the main types of AO classifications, inter- and intra-observer agreement of TLSI were comparable to agreement evaluating FTAPF; including sub-types, inter- and intra-observer agreement evaluating TLSI were significantly better than assessing FTAPF. Inter- and intra-observer agreements using the Denis classification were also significantly better than agreement using the Tronzo scheme. PMID- 26653270 TI - Missed subtle fractures on the trauma-meeting digital projector. AB - INTRODUCTION: Since the introduction of digital X-rays, many orthopaedic departments have used digital projection systems to display diagnostic images during discussion, there has been no published work directly comparing the sensitivity high resolution diagnostic monitors with standard digital projection systems in the context of orthopaedic injuries. MATERIALS AND METHODS: Participants were asked to review AP pelvic radiographs of non-displaced hip fractures on the department's digital projector and again on a diagnostic monitor, results were compared to determine if a true difference in sensitivity between the imaging modalities existed. RESULTS: A significant difference in the sensitivity of the diagnostic monitor and meeting room projector was found, 0.85 vs 0.55, respectively (95% CI 0.78-0.89 vs 0.47-0.63); absolute difference 0.3 (95% CI 0.28-0.32, p<=0.001). Inter-observer agreement was moderate. DISCUSSION: A difference in sensitivity was demonstrated to a high level of statistical power, and a positive result on either modality was highly likely to represent a true fracture, however a fracture cannot be confidently excluded examining a single image using the digital projector alone. The study was limited to a single view of one particular fracture type and may not be generalisable to all types of subtle fracture; in addition, the retrospective nature of the image review means that the sensitivity figures cannot be applied to a presenting patient population. CONCLUSIONS: This study demonstrates a significant difference in sensitivity between the two display types which may have implications with regard to reducing delays and unnecessary further imaging if clinicians are not aware of this potential limitation. Clinicians, if clinically suspicious of a fracture should always seek to review the images on a validated PACS display device if a fracture is not seen on a non-validated device. Departments should evaluate their current equipment, consider what equipment is available, what is the most suitable equipment for the environment in which it is being used and what the potential implications for patient care may be as a result. PMID- 26653273 TI - Situation awareness acquired from monitoring process plants - the Process Overview concept and measure. AB - We introduce Process Overview, a situation awareness characterisation of the knowledge derived from monitoring process plants. Process Overview is based on observational studies of process control work in the literature. The characterisation is applied to develop a query-based measure called the Process Overview Measure. The goal of the measure is to improve coupling between situation and awareness according to process plant properties and operator cognitive work. A companion article presents the empirical evaluation of the Process Overview Measure in a realistic process control setting. The Process Overview Measure demonstrated sensitivity and validity by revealing significant effects of experimental manipulations that corroborated with other empirical results. The measure also demonstrated adequate inter-rater reliability and practicality for measuring SA based on data collected by process experts. Practitioner Summary: The Process Overview Measure is a query-based measure for assessing operator situation awareness from monitoring process plants in representative settings. PMID- 26653274 TI - Hollow Silica as an Optically Transparent and Thermally Insulating Polymer Additive. AB - We present an improved synthesis route to hollow silica particles starting from tetramethyl orthosilicate (TMOS) instead of the traditionally used ethyl ester. The silica was first deposited onto polystyrene (PS) particles that were later removed. The here introduced, apparently minor modification in synthesis, however, allowed for a very high purity material. The improved, low density hollow silica particles were successfully implemented into polymer films and permitted maintaining optical transparency while significantly improving the heat barrier properties of the composite. Mechanistic investigations revealed the dominant role of here used methanol as a cosolvent and its role in controlling the hydrolysis rate of the silicic ester, and subsequent formation of hollow silica particles. Systematic experiments using various reaction parameters revealed a transition between regions of inhomogeneous material production at fast hydrolysis rate and reliable silica deposition on the surface of PS as a core-shell structured particle. The shell-thickness was controlled from 6.2 to 17.4 nm by increasing TMOS concentration and the diameter from 95 to 430 nm through use of the different sizes of PS particles. Hollow silica particle with the shell-thickness about 6.2 nm displayed a high light transmittance intensity up to 95% at 680 nm (length of light path ~ 1 cm). Polyethersulfone (PES)/hollow silica composite films (35 +/- 5 MUm thick) exhibited a much lower thermal conductivity (0.03 +/- 0.005 W m.K(-1)) than pure polymer films. This indicates that the prepared hollow silica is able to be used for cost and energy effective optical devices requiring thermal insulation. PMID- 26653275 TI - Asymmetric Synthesis of alpha-Aminoboronic Acid Derivatives by Copper-Catalyzed Enantioselective Hydroamination. AB - A copper-catalyzed regio- and enantioselective hydroamination of alkenyl dan boronates (dan =1,8-diaminonaphthyl) with hydrosilanes and hydroxylamines proceeds to deliver the chiral alpha-aminoboronic acids in good yields with high enantiomeric ratios. The key to success is the introduction of an umpolung, electrophilic amination strategy. The copper catalysis can provide an unprecedented catalytic asymmetric approach to alkyl-substituted chiral alpha aminoboronic acid derivatives of great potential in the fields of organic synthesis and medicinal chemistry. PMID- 26653276 TI - Assessment of nitrite oxide and maternal-fetal Doppler parameters during pregnancy. AB - OBJECTIVE: The objective was to evaluate and compare the whole blood nitrite concentration in the three trimesters of pregnancy. Additionally, we investigate whether there is any relation between nitrite concentrations and Doppler ultrasound analysis of some maternal and fetal vessels. METHODS: Thirty-three healthy pregnant women were examined at the first (11-14 weeks), second (20-24 weeks) and third trimester (34-36 weeks) of pregnancy. In the three exams, we determined the maternal whole blood nitrite concentration and uterine arteries Doppler analysis to determine pulsatility index (PI), and resistance index (RI). In the second and third trimester we also performed fetal umbilical and middle cerebral arteries PI and RI. We compared the concentrations of nitrite in three trimesters and correlated with Doppler parameters. RESULTS: No difference was observed in the whole blood nitrite concentrations across trimesters: 151.70 +/- 77.90 nmol/ml, 142.10 +/- 73.50 nmol/ml and 147.10 +/- 87.30 nmol/ml; first, second and third trimesters, respectively. We found no difference in correlation between whole blood nitrite concentration and Doppler parameters from the evaluated vessels. CONCLUSIONS: In healthy pregnant women, the nitrite concentrations did not change across gestational trimesters and there was also no strong correlation with Doppler impedance indices from maternal uterine arteries and fetal umbilical and middle cerebral arteries. PMID- 26653278 TI - The recurrently wheezing preschool child-benign or asthma in the making? PMID- 26653277 TI - Interplay between miRNA regulation and mechanical stress for CUC gene expression at the shoot apical meristem. AB - The shoot apical meristem is the central organizer of plant aerial organogenesis. The molecular bases of its functions involve several cross-talks between transcription factors, hormones and microRNAs. We recently showed that the expression of the homeobox transcription factor STM is induced by mechanical perturbations, adding another layer of complexity to this regulation. Here we provide additional evidence that mechanical perturbations impact the promoter activity of CUC3, an important regulator of boundary formation at the shoot meristem. Interestingly, we did not detect such an effect for CUC1. This suggests that the robustness of expression patterns and developmental programs is controlled via a combined action of molecular factors as well as mechanical cues in the shoot apical meristem. PMID- 26653279 TI - Long-term omalizumab therapy for refractory chronic spontaneous urticaria: a real life experience. PMID- 26653280 TI - Allergen of the Month-Japanese Maple. PMID- 26653281 TI - Large-scale screening and characterization of enteroviruses and kobuviruses infecting pigs in Vietnam. AB - A recent survey of pigs in Dong Thap province, Vietnam identified a high frequency of enterovirus species G (EV-G) infection (144/198; 72.7%). Amongst these was a plethora of EV-G types (EV-G1, EV-G6 and four new types EV-G8-EV G11). To better characterize the genetic diversity of EV-G and investigate the possible existence of further circulating types, we performed a larger-scale study on 484 pig and 45 farm-bred boar faecal samples collected in 2012 and 2014, respectively. All samples from the previous and current studies were also screened for kobuviruses. The overall EV infection frequency remained extremely high (395/484; 81.6%), but with comparable detection rates and viral loads between healthy and diarrhoeic pigs; this contrasted with less frequent detection of EV-G in boars (4/45; 8.9%). EV was most frequently detected in pigs <= 14 weeks old (~ 95%) and declined in older pigs. Infections with EV-G1 and EV-G6 were most frequent, whilst less commonly detected types included EV-G3, EV-G4 and EV-G8-EV-G11, and five new types (EV-G12-EV-G16). In contrast, kobuvirus infection frequency was significantly higher in diarrhoeic pigs (40.9 versus 27.6%; P = 0.01). Kobuviruses also showed contrasting epizootiologies and age associations; a higher prevalence was found in boars (42%) compared with domestic pigs (29%), with the highest infection frequency amongst pigs >52 weeks old. Although genetically diverse, all kobuviruses identified belonged to the species Aichivirus C. In summary, this study confirms infection with EV-G was endemic in Vietnamese domestic pigs and exhibits high genetic diversity and extensive inter type recombination. PMID- 26653282 TI - (18)F-FDG PET/CT versus bone scintigraphy in the follow-up of gastric cancer. AB - A 53-year-old patient underwent a positron emission tomography/computed tomography with 2-fluoro-2-deoxy-d-glucose ((18)F-FDG PET/CT) in the suspicious of gastric tumor recurrence (mediastinal and abdominal lymph nodes). PET/CT identified only an area of (18)F-FDGuptake in the twelfth thoracic vertebrae. Unexpectedly, a bone scintigraphy revealed many "hot" spots changing the diagnosis (single metastasis versus plurimetastatic disease) and impacting on patient's management. PMID- 26653283 TI - [A fascinating job]. PMID- 26653284 TI - Nanomedicine and nanotoxicology: the pros and cons for neurodegeneration and brain cancer. AB - Current strategies for brain diseases are mostly symptomatic and noncurative. Nanotechnology has the potential to facilitate the transport of drugs across the blood-brain barrier and to enhance their pharmacokinetic profile. However, to reach clinical application, an understanding of nanoneurotoxicity in terms of oxidative stress and inflammation is required. Emerging evidence has also shown that nanoparticles have the ability to alter autophagy, which can induce inflammation and oxidative stress, or vice versa. These effects may increase neurodegenerative processes damage, but on the other hand, they may have benefits for brain cancer therapies. In this review, we emphasize how nanomaterials may induce neurotoxic effects focusing on neurodegeneration, and how these effects could be exploited toward brain cancer treatment. PMID- 26653285 TI - Unified quantitative characterization of epithelial tissue development. AB - Understanding the mechanisms regulating development requires a quantitative characterization of cell divisions, rearrangements, cell size and shape changes, and apoptoses. We developed a multiscale formalism that relates the characterizations of each cell process to tissue growth and morphogenesis. Having validated the formalism on computer simulations, we quantified separately all morphogenetic events in the Drosophila dorsal thorax and wing pupal epithelia to obtain comprehensive statistical maps linking cell and tissue scale dynamics. While globally cell shape changes, rearrangements and divisions all significantly participate in tissue morphogenesis, locally, their relative participations display major variations in space and time. By blocking division we analyzed the impact of division on rearrangements, cell shape changes and tissue morphogenesis. Finally, by combining the formalism with mechanical stress measurement, we evidenced unexpected interplays between patterns of tissue elongation, cell division and stress. Our formalism provides a novel and rigorous approach to uncover mechanisms governing tissue development. PMID- 26653287 TI - Incorporation of subject-level covariates in quantile normalization of miRNA data. AB - BACKGROUND: Most currently-used normalization methods for miRNA array data are based on methods developed for mRNA arrays despite fundamental differences between the data characteristics. The application of conventional quantile normalization can mask important expression differences by ignoring demographic and environmental factors. We present a generalization of the conventional quantile normalization method, making use of available subject-level covariates in a colorectal cancer study. RESULTS: In simulation, our weighted quantile normalization method is shown to increase statistical power by as much as 10 % when relevant subject-level covariates are available. In application to the colorectal cancer study, this increase in power is also observed, and previously reported dysregulated miRNAs are rediscovered. CONCLUSIONS: When any subject level covariates are available, the weighted quantile normalization method should be used over the conventional quantile normalization method. PMID- 26653288 TI - Assessment of Laparoscopic Skills in Veterinarians Using a Canine Laparoscopic Simulator. AB - The aim of the present study was to assess the content and construct validity of the Canine Laparoscopic Simulator (CLS). Forty-two veterinarians were assigned to experienced (n=12), control (n=15), and training (n=15) groups, which were assessed while performing four laparoscopic tasks on the CLS. The initial and final assessments of all tasks were performed blindly by two experienced surgeons using the Global Operative Assessment of Laparoscopic Skills (GOALS) and a task specific checklist. At the end of the study, the subjects completed an anonymous survey. The experienced group performed all of the tasks faster, with higher GOALS and checklist scores than the training and control groups (p<=.001). In the second assessment, the training group reduced the time needed to complete all of the tasks and obtained significantly higher GOALS and checklist scores than the control group. The participants perceived the CLS and its training program to be positive or very positive. The CLS and its training program demonstrated content and construct validity, supporting the suitability of the simulator for training and teaching and its ability to distinguish the degree of experience in laparoscopic surgery among veterinarians. In addition, face validity showed that the veterinarians fully accepted the CLS's usefulness for learning basic laparoscopic skills. PMID- 26653290 TI - Performance of the TPSS Functional on Predicting Core Level Binding Energies of Main Group Elements Containing Molecules: A Good Choice for Molecules Adsorbed on Metal Surfaces. AB - Here we explored the performance of Hartree-Fock (HF), Perdew-Burke-Ernzerhof (PBE), and Tao-Perdew-Staroverov-Scuseria (TPSS) functionals in predicting core level 1s binding energies (BEs) and BE shifts (DeltaBEs) for a large set of 68 molecules containing a wide variety of functional groups for main group elements B -> F and considering up to 185 core levels. A statistical analysis comparing with X-ray photoelectron spectroscopy (XPS) experiments shows that BEs estimations are very accurate, TPSS exhibiting the best performance. Considering DeltaBEs, the three methods yield very similar and excellent results, with mean absolute deviations of ~0.25 eV. When considering relativistic effects, BEs deviations drop approaching experimental values. So, the largest mean percentage deviation is of 0.25% only. Linear trends among experimental and estimated values have been found, gaining offsets with respect to ideality. By adding relativistic effects to offsets, HF and TPSS methods underestimate experimental values by solely 0.11 and 0.05 eV, respectively, well within XPS chemical precision. TPSS is posed as an excellent choice for the characterization, by XPS, of molecules on metal solid substrates, given its suitability in describing metal substrates bonds and atomic and/or molecular orbitals. PMID- 26653291 TI - Chances and challenges of retinoid X receptor gamma targeting for regenerative multiple sclerosis treatment. PMID- 26653289 TI - Non-invasive measurement using cardiovascular magnetic resonance of changes in pulmonary artery stiffness with exercise. AB - BACKGROUND: Exercise stress tests are commonly used in clinical settings to monitor the functional state of the heart and vasculature. Large artery stiffness is one measure of arterial function that can be quantified noninvasively during exercise stress. Changes in proximal pulmonary artery stiffness are especially relevant to the progression of pulmonary hypertension (PH), since pulmonary artery (PA) stiffness is the best current predictor of mortality from right ventricular failure. METHODS: Cardiovascular magnetic resonance (CMR) was used to investigate the effect of exercise stress on PA pulse wave velocity (PWV) and relative area change (RAC), which are both non-invasive measures of PA stiffness, in healthy subjects. All 21 subjects (average age 26 +/- 4 years; 13 female and 8 male) used a custom-made MR-compatible stepping device to exercise (two stages of mild-to-moderate exercise of 3-4 min duration each) in a supine position within the confines of the scanner. To measure the cross-sectional area and blood flow velocity in the main PA (MPA), two-dimensional phase-contrast (2D-PC) CMR images were acquired. To measure the reproducibility of metrics, CMR images were analyzed by two independent observers. Inter-observer agreements were calculated using the intraclass correlation and Bland-Altman analysis. RESULTS: From rest to the highest level of exercise, cardiac output increased from 5.9 +/- 1.4 L/min to 8.2 +/- 1.9 L/min (p < 0.05), MPA PWV increased from 1.6 +/- 0.5 m/s to 3.6 +/- 1.4 m/s (p < 0.05), and MPA RAC decreased from 0.34 +/- 0.11 to 0.24 +/- 0.1 (p < 0.05). While PWV also increased from the first to second exercise stage (from 2.7 +/- 1.0 m/s to 3.6 +/- 1.4 m/s, p < 0.05), there was no significant change in RAC between the two exercise stages. We found good inter-observer agreement for quantification of MPA flow, RAC and PWV. CONCLUSION: These results demonstrate that metrics of MPA stiffness increase in response to acute moderate exercise in healthy subjects and that CMR exercise stress offers great potential in clinical practice to noninvasively assess vascular function. PMID- 26653292 TI - Aging, source memory, and the experience of "remembering". AB - In a previous study, we found source memory for perceptual features to differentiate between younger but not older adults' reports of recollective ("remember"; R) and "know" (K) experiences. In two experiments with younger (17 30 years) and older (64-81 years) participants, we examined whether memory for meaningful speaker sources would accompany older adults' recollective experience. Indeed, memory for male and female speakers (but not partial memory for gender; Experiment 1) as well as bound memory for speakers and their facial expressions (Experiment 2) distinguished between both younger and older adults' RK reports. Thus, memory for some sources forms a common basis for younger and older adults' retrieval experience. Nonetheless, older adults still showed lower objective source memory and lower subjective source-attribution confidence than younger adults when reporting recollective experiences, suggesting that source memory is less relevant to their retrieval experience than for younger adults. PMID- 26653293 TI - The face of Ebola: changing frequency of haemorrhage in the West African compared with Eastern-Central African outbreaks. AB - BACKGROUND: The West-African (WA) Zaire Ebolavirus disease (EVD) outbreak was characterized by an exceptionally high number of cases and deaths as compared with the Eastern-Central African (ECA) outbreaks. Despite the Zaire Ebolavirus being the most lethal for humans, case-fatality rate, close to 80 % in ECA outbreaks, almost halved to 47 % in Guinea-Liberia-Sierra Leone (WA). Such an improvement was due to the remarkable implementation of international humanitarian aids. Some studies also suggested that the long human-to-human transmission cycle occurred in WA, gave rise to human adaptation and consequent immune escape. Haemorrhage, the main feature in seriously infected EVD patients, is due to the immune system that triggers the infected endothelial cells which expose the spike-like glycoprotein (GP) of the virion on their surface. If the human adaptation hypothesis holds true, the proportion of EVD patients with haemorrhage in the WA outbreak should be lower than in the ECA outbreaks due to immune escape. Therefore, the aim of this meta-analysis was to compare the relative frequencies of three typical haemorrhagic symptoms (conjunctival -CB, nasal -NB, gingival -GB- bleedings) in the ECA and WA outbreaks. METHODS: Literature searches were performed through PubMed and Scopus using generic keywords; surveys including at least ten patients reporting CB, NB, GB relative frequencies were extracted and split into ECA and WA. The meta-analytical methods chosen were based on the levels of between-study heterogeneity and publication bias. Pooled CB, NB, GB relative frequencies in ECA and WA were estimated and compared. Subgroup analysis including only studies on Zaire Ebolavirus also was performed. RESULTS: Fifteen studies (10 ECA, 5 WA) were located with 4,867 (CB), 3,859 (NB), 4,278 (GB) EVD patients overall. GB pooled relative frequency was 45.3 % (95 % confidence interval -95 CI, 34.7-56.1 %) and 18.0 % (95 CI, 6.0-34.5 %), in ECA and WA; NB was 10.6 % (95 CI, 5.7-16.8 %) and 1.3 % (1.0-1.8 %); GB was 24.2 % (95 CI, 11.9-39.2 %) and 1.9 % (95 CI, 1.4-2.4 %). Subgroup analysis confirmed these results. CONCLUSIONS: During the WA outbreak the relative frequency of GB decreased by two thirds, while NB and GB almost disappeared, suggesting that the Zaire Ebolavirus human adaptation hypothesis is plausible. PMID- 26653295 TI - Disturbing Trends in Physician Burnout and Satisfaction With Work-Life Balance: Dealing With Malady Among the Nation's Healers. PMID- 26653294 TI - Genomic legacy of the African cheetah, Acinonyx jubatus. AB - BACKGROUND: Patterns of genetic and genomic variance are informative in inferring population history for human, model species and endangered populations. RESULTS: Here the genome sequence of wild-born African cheetahs reveals extreme genomic depletion in SNV incidence, SNV density, SNVs of coding genes, MHC class I and II genes, and mitochondrial DNA SNVs. Cheetah genomes are on average 95 % homozygous compared to the genomes of the outbred domestic cat (24.08 % homozygous), Virunga Mountain Gorilla (78.12 %), inbred Abyssinian cat (62.63 %), Tasmanian devil, domestic dog and other mammalian species. Demographic estimators impute two ancestral population bottlenecks: one >100,000 years ago coincident with cheetah migrations out of the Americas and into Eurasia and Africa, and a second 11,084 12,589 years ago in Africa coincident with late Pleistocene large mammal extinctions. MHC class I gene loss and dramatic reduction in functional diversity of MHC genes would explain why cheetahs ablate skin graft rejection among unrelated individuals. Significant excess of non-synonymous mutations in AKAP4 (p<0.02), a gene mediating spermatozoon development, indicates cheetah fixation of five function-damaging amino acid variants distinct from AKAP4 homologues of other Felidae or mammals; AKAP4 dysfunction may cause the cheetah's extremely high (>80 %) pleiomorphic sperm. CONCLUSIONS: The study provides an unprecedented genomic perspective for the rare cheetah, with potential relevance to the species' natural history, physiological adaptations and unique reproductive disposition. PMID- 26653296 TI - Residents' Clinic Articles in the Age of Competency-Based Medical Education. PMID- 26653297 TI - Changes in Burnout and Satisfaction With Work-Life Balance in Physicians and the General US Working Population Between 2011 and 2014. AB - OBJECTIVE: To evaluate the prevalence of burnout and satisfaction with work-life balance in physicians and US workers in 2014 relative to 2011. PATIENTS AND METHODS: From August 28, 2014, to October 6, 2014, we surveyed both US physicians and a probability-based sample of the general US population using the methods and measures used in our 2011 study. Burnout was measured using validated metrics, and satisfaction with work-life balance was assessed using standard tools. RESULTS: Of the 35,922 physicians who received an invitation to participate, 6880 (19.2%) completed surveys. When assessed using the Maslach Burnout Inventory, 54.4% (n=3680) of the physicians reported at least 1 symptom of burnout in 2014 compared with 45.5% (n=3310) in 2011 (P<.001). Satisfaction with work-life balance also declined in physicians between 2011 and 2014 (48.5% vs 40.9%; P<.001). Substantial differences in rates of burnout and satisfaction with work life balance were observed by specialty. In contrast to the trends in physicians, minimal changes in burnout or satisfaction with work-life balance were observed between 2011 and 2014 in probability-based samples of working US adults, resulting in an increasing disparity in burnout and satisfaction with work-life balance in physicians relative to the general US working population. After pooled multivariate analysis adjusting for age, sex, relationship status, and hours worked per week, physicians remained at an increased risk of burnout (odds ratio, 1.97; 95% CI, 1.80-2.16; P<.001) and were less likely to be satisfied with work life balance (odds ratio, 0.68; 95% CI, 0.62-0.75; P<.001). CONCLUSION: Burnout and satisfaction with work-life balance in US physicians worsened from 2011 to 2014. More than half of US physicians are now experiencing professional burnout. PMID- 26653298 TI - Hidradenitis Suppurativa: A Guide for the Practicing Physician. AB - Hidradenitis suppurativa is a chronic inflammatory disease of apocrine gland bearing skin. Although immunologic derangements, genetic predisposition, obesity, and smoking are likely important factors, the pathogenesis of the disease and the effect of available treatments on disease course have not been fully elucidated. In the absence of proper treatment, chronic inflammation results in diffuse scarring and a wide array of complications, including the development of cutaneous squamous cell carcinoma. This severe and chronic disease can have detrimental effects on self-esteem and quality of life. No ideal treatment regimen has been defined, but several therapies have been found to reduce lesion severity and improve symptoms. We reviewed the literature through July 2014 for existing treatments. Published articles were obtained via systematic review of medical databases (PubMed, Embase, Google Scholar) and scrutiny of citation lists using the search terms "hidradenitis suppurativa" and "acne inversa". Given the scarce literature on treatment strategies, we also reviewed data from any case reports or prospective and retrospective studies that were located. On the basis of the existing literature, we provide an evidence-based algorithm for the management of this disease in the primary care setting. More research is needed to evaluate the comparative effectiveness of topical and systemic treatments and to better understand the pathogenesis, natural history, and subtypes of hidradenitis suppurativa. PMID- 26653299 TI - 75-Year-Old Man With Fever, Cough, Myalgias, and Pruritus. PMID- 26653300 TI - Evaluation and Treatment of Low Back Pain: A Clinically Focused Review for Primary Care Specialists. AB - Low back pain (LBP) is a leading cause of disability worldwide. In the absence of a classification system for pain syndromes, classification of LBP on the basis of the distribution of pain as axial (pain generally localized to the low back) or radicular neuropathic (pain radiating to the lower extremities) is relevant to clinical practice because the distribution of pain is often a corollary of frequently occurring disease processes involving the lumbar spine. Common sources of axial LBP include the intervertebral disc, facet joint, sacroiliac joint, and paraspinal musculature, whereas common sources of radicular pain include a herniated intervertebral disc and spinal stenosis. The accuracy of historical and physical examination findings has been established for sacroiliac joint pain, radiculopathy, and lumbar spinal stenosis. However, the accuracy of similar data, so-called red flags, for identifying the underlying medical sources of LBP has been overstated. Diagnostic imaging studies can be useful, and adherence to established guidelines can protect against overuse. Multiple pharmacological trials exist for the management of LBP; however, the long-term outcomes of commonly used drugs are mixed. For carefully selected patients with axial LBP, radiofrequency denervation techniques can provide sustained pain relief. In patients with radicular pain, transforaminal epidural steroid injections may provide short-term pain relief, but neurostimulation may confer more enduring benefits of refractory symptoms. Pain-related indications for commonly performed operations include spinal decompression for radicular symptoms as well as spinal fusion or disc prosthesis for discogenic LBP. Physical modalities and psychological treatments can improve pain and functioning, but patient preferences may influence treatment adherence. PMID- 26653301 TI - Advances in the Treatment of Metastatic Prostate Cancer. AB - During the past several years, there has been substantial progress in the development of treatments for advanced prostate cancer with the approval of multiple new life-prolonging agents using different mechanisms of action. Such progress was attainable because of advances in our understanding of the biology behind mechanisms of androgen receptor pathway activation, complex tumor microenvironment interaction of bone metastasis, antitumor immunology, and new oncogenic pathways. Continuous efforts are being made to develop new therapeutics with novel mechanisms of action, define the optimal sequences and/or combinations of current agents, and identify reliable surrogate end points to facilitate new drug development. PMID- 26653302 TI - Interpreting Urine Drug Screen Results in the Context of Poppy Seed Use. PMID- 26653303 TI - Examining the Burden of Licensure, Certification, and Related Credentialing Costs in Young Physicians. PMID- 26653304 TI - A Discussion of the Refutation of Memory-Based Dietary Assessment Methods (M BMs): The Rhetorical Defense of Pseudoscientific and Inadmissible Evidence. PMID- 26653306 TI - Mycosis Fungoides: The Multicentric Tumor D'emblee. PMID- 26653307 TI - 50-Year-Old Woman With Fatigue. PMID- 26653308 TI - Friedrich August Johannes Loffler (Loeffler), German Bacteriologist. PMID- 26653310 TI - Relative and contextual contribution of different sources to the composition and abundance of indoor air bacteria in residences. AB - BACKGROUND: The study of the microbial communities in the built environment is of critical importance as humans spend the majority of their time indoors. While the microorganisms in living spaces, especially those in the air, can impact health and well-being, little is known of their identity and the processes that determine their assembly. We investigated the source-sink relationships of airborne bacteria in 29 homes in the San Francisco Bay Area. Samples taken in the sites expected to be source habitats for indoor air microbes were analyzed by 16S rRNA-based pyrosequencing and quantitative PCR. The community composition was related to the characteristics of the household collected at the time of sampling, including the number of residents and pets, activity levels, frequency of cooking and vacuum cleaning, extent of natural ventilation, and abundance and type of vegetation surrounding the building. RESULTS: Indoor air harbored a diverse bacterial community dominated by Diaphorobacter sp., Propionibacterium sp., Sphingomonas sp., and Alicyclobacillus sp. Source-sink analysis suggested that outdoor air was the primary source of indoor air microbes in most homes. Bacterial phylogenetic diversity and relative abundance in indoor air did not differ statistically from that in outdoor air. Moreover, the abundance of bacteria in outdoor air was positively correlated with that in indoor air, as would be expected if outdoor air was the main contributor to the bacterial community in indoor bioaerosols. The number of residents, presence of pets, and local tap water also influenced the diversity and size of indoor air microbes. The bacterial load in air increased with the number of residents, activity, and frequency of natural ventilation, and the proportion of bacteria putatively derived from skin increased with the number of residents. Vacuum cleaning increased the signature of pet- and floor-derived bacteria in indoor air, while the frequency of natural ventilation decreased the relative abundance of tap water-derived microorganisms in air. CONCLUSIONS: Indoor air in residences harbors a diverse bacterial community originating from both outdoor and indoor sources and is strongly influenced by household characteristics. PMID- 26653311 TI - Professional practice guidelines: Guidance for developers and users. AB - This document is a guide for the development, evaluation, and review of proposed and existing professional practice guidelines. It is designed to promote quality and consistency in professional practice guideline development and to describe the criteria by which these guidelines are evaluated and reviewed. These criteria are designed to assist in the development of guidelines that are broadly applicable to a range of practice areas yet provide sufficient specificity to assist the practitioner in providing high quality psychological services. The intent behind these criteria is to ensure deliberation and care in the development of professional practice guidelines. This document is intended for professional practice guideline development committees composed entirely of psychologists and for other efforts in which psychologists are involved. PMID- 26653312 TI - Guidelines for psychological practice with transgender and gender nonconforming people. AB - In 2015, the American Psychological Association adopted Guidelines for Psychological Practice with Transgender and Gender Nonconforming Clients in order to describe affirmative psychological practice with transgender and gender nonconforming (TGNC) clients. There are 16 guidelines in this document that guide TGNC-affirmative psychological practice across the lifespan, from TGNC children to older adults. The Guidelines are organized into five clusters: (a) foundational knowledge and awareness; (b) stigma, discrimination, and barriers to care; (c) lifespan development; (d) assessment, therapy, and intervention; and (e) research, education, and training. In addition, the guidelines provide attention to TGNC people across a range of gender and racial/ethnic identities. The psychological practice guidelines also attend to issues of research and how psychologists may address the many social inequities TGNC people experience. PMID- 26653318 TI - Raymond D. Fowler Jr. (1930-2015). PMID- 26653319 TI - Paul W. Clement (1939-2014). PMID- 26653320 TI - Carolyn Kent Rovee-Collier (1942-2014). PMID- 26653321 TI - Roger Ellis Millsap (1954-2014). PMID- 26653322 TI - Brian Sutton-Smith (1924-2015). PMID- 26653323 TI - iTAP: integrated transcriptomics and phenotype database for stress response of Escherichia coli and Saccharomyces cerevisiae. AB - BACKGROUND: Organisms are subject to various stress conditions, which affect both the organism's gene expression and phenotype. It is critical to understand microbial responses to stress conditions and uncover the underlying molecular mechanisms. To this end, it is necessary to build a database that collects transcriptomics and phenotypic data of microbes growing under various stress factors for in-depth systems biology analysis. Despite of numerous databases that collect gene expression profiles, to our best knowledge, there are few, if any, databases that collect both transcriptomics and phenotype data simultaneously. In light of this, we have developed an open source, web-based database, namely integrated transcriptomics and phenotype (iTAP) database, that records and links the transcriptomics and phenotype data for two model microorganisms, Escherichia coli and Saccharomyces cerevisiae in response to exposure of various stress conditions. RESULTS: To collect the data, we chose relevant research papers from the PubMed database containing all the necessary information for data curation including experimental conditions, transcriptomics data, and phenotype data. The transcriptomics data, including the p value and fold change, were obtained through the comparison of test strains against control strains using Gene Expression Omnibus's GEO2R analyzer. The phenotype data, including the cell growth rate and the productivity, volumetric rate, and mass-based yield of byproducts, were calculated independently from charts or graphs within the reference papers. Since the phenotype data was never reported in a standardized format, the curation of correlated transcriptomics-phenotype datasets became extremely tedious and time-consuming. Despite the challenges, till now, we successfully correlated 57 and 143 datasets of transcriptomics and phenotype for E. coli and S. cerevisiae, respectively, and applied a regression model within the iTAP database to accurately predict over 93 and 73 % of the growth rates of E. coli and S. cerevisiae, respectively, directly from the transcriptomics data. CONCLUSION: This is the first time that transcriptomics and phenotype data are categorized and correlated in an open-source database. This allows biologists to access the database and utilize it to predict the phenotype of microorganisms from their transcriptomics data. The iTAP database is freely available at https://sites.google.com/a/vt.edu/biomolecular-engineering-lab/software . PMID- 26653324 TI - Assessment of Learning, Memory, and Attention in Developmental Neurotoxicity: Regulatory Studies: Special Issue and Request for Comments. PMID- 26653325 TI - Aggregation-Induced Emission Luminogen-Embedded Silica Nanoparticles Containing DNA Aptamers for Targeted Cell Imaging. AB - Conventional fluorophores usually undergo aggregation-caused quenching (ACQ), which limits the loading amount of these fluorophores in nanoparticles for bright fluorescence imaging. On the contrary, fluorophores with aggregation-induced emission (AIE) characteristics are strongly fluorescent in their aggregate states and have been an ideal platform for developing highly fluorescent nanomaterials, such as fluorescent silica nanoparticles (FSNPs). In this work, AIE luminogens based on salicylaldehyde hydrazones were embedded in silica nanoparticles through a facile noncovalent approach, which afforded AIE-FSNPs emitting much brighter fluorescence than that of some commercial fluorescein-doped silica and polystyrene nanoparticles. These AIE-FSNPs displaying multiple fluorescence colors were fabricated by a general method, and they underwent much less fluorescence variation due to environmental pH changes compared with fluorescein hybridized FSNPs. In addition, a DNA aptamer specific to nucleolin was functionalized on the surface of AIE-FSNPs for targeted cell imaging. Fluorescent microscopy and flow cytometry studies both revealed highly selective fluorescence staining of MCF-7 (a cancer cell line with nucleolin overexpression) over MCF-10A (normal) cells by the aptamer-functionalized AIE-FSNPs. The fluorescence imaging in different color channels was achieved using AIE-FSNPs containing each of the AIE luminogens, as well as photoactivatable fluorescent imaging of target cells by the caged AIE fluorophore. PMID- 26653327 TI - Proteomics Quality Control: Quality Control Software for MaxQuant Results. AB - Mass spectrometry-based proteomics coupled to liquid chromatography has matured into an automatized, high-throughput technology, producing data on the scale of multiple gigabytes per instrument per day. Consequently, an automated quality control (QC) and quality analysis (QA) capable of detecting measurement bias, verifying consistency, and avoiding propagation of error is paramount for instrument operators and scientists in charge of downstream analysis. We have developed an R-based QC pipeline called Proteomics Quality Control (PTXQC) for bottom-up LC-MS data generated by the MaxQuant software pipeline. PTXQC creates a QC report containing a comprehensive and powerful set of QC metrics, augmented with automated scoring functions. The automated scores are collated to create an overview heatmap at the beginning of the report, giving valuable guidance also to nonspecialists. Our software supports a wide range of experimental designs, including stable isotope labeling by amino acids in cell culture (SILAC), tandem mass tags (TMT), and label-free data. Furthermore, we introduce new metrics to score MaxQuant's Match-between-runs (MBR) functionality by which peptide identifications can be transferred across Raw files based on accurate retention time and m/z. Last but not least, PTXQC is easy to install and use and represents the first QC software capable of processing MaxQuant result tables. PTXQC is freely available at https://github.com/cbielow/PTXQC . PMID- 26653326 TI - A Population-based survey of the prevalence and types of glaucoma in Nigeria: results from the Nigeria National Blindness and Visual Impairment Survey. AB - BACKGROUND: Glaucoma is the leading cause of irreversible blindness worldwide. There tends to be a lower reporting of glaucoma in Africa compared to other blinding conditions in global burden data. Research findings of glaucoma in Nigeria will significantly increase our understanding of glaucoma in Nigeria, in people of the West African diaspora and similar population groups. We determined the prevalence and types of glaucoma in Nigeria from the Nigeria National Blindness and Visual Impairment cross-sectional Survey of adults aged >=40 years. METHODS: Multistage stratified cluster random sampling with probability proportional-to-size procedures were used to select a nationally representative sample of 15,027 persons aged >=40 years. Participants had logMAR visual acuity measurement, FDT visual function testing, autorefraction, A-scan biometry and optic disc assessment. Participants with visual acuity of worse than 6/12 or suspicious optic discs had detailed examination including Goldmann applanation tonometry, gonioscopy and fundus photography. Disc images were graded by Moorfields Eye Hospital Reading Centre. Glaucoma was defined using International Society of Geographical and Epidemiological Ophthalmology criteria; and classified into primary open-angle or primary angle-closure or secondary glaucoma. Diagnosis of glaucoma was based on ISGEO classification. The type of glaucoma was determined by gonioscopy. RESULTS: A total of 13,591 participants in 305 clusters were examined (response rate 90.4 %). Optic disc grading was available for 25,289 (93 %) eyes of 13,081 (96 %) participants. There were 682 participants with glaucoma; a prevalence of 5.02 % (95 % CI 4.60-5.47). Among those with definite primary glaucoma that had gonioscopy (n = 243), open-angle glaucoma was more common (86 %) than angle-closure glaucoma (14 %). 8 % of glaucoma was secondary with the commonest causes being couching (38 %), trauma (21 %) and uveitis (19 %). Only 5.6 % (38/682) of participants with glaucoma knew they had the condition. One in every 5 persons with glaucoma (136;20 %) was blind i.e., visual acuity worse than 3/60. CONCLUSION: Nigeria has a high prevalence of glaucoma which is largely open-angle glaucoma. A high proportion of those affected are blind. Secondary glaucoma was mostly as a consequence of procedures for cataract. Public health control strategies and high quality glaucoma care service will be required to reduce morbidity and blindness from glaucoma. PMID- 26653328 TI - Synthesis and Biological Investigation of Oxazole Hydroxamates as Highly Selective Histone Deacetylase 6 (HDAC6) Inhibitors. AB - Histone deacetylase 6 (HDAC6) catalyzes the removal of an acetyl group from lysine residues of several non-histone proteins. Here we report the preparation of thiazole-, oxazole-, and oxadiazole-containing biarylhydroxamic acids by a short synthetic procedure. We identified them as selective HDAC6 inhibitors by investigating the inhibition of recombinant HDAC enzymes and the protein acetylation in cells by Western blotting (tubulin vs histone acetylation). The most active compounds exhibited nanomolar potency and high selectivity for HDAC6. For example, an oxazole hydroxamate inhibits HDAC6 with an IC50 of 59 nM and has a selectivity index of >200 against HDAC1 and HDAC8. This is the first report showing that the nature of a heterocycle directly connected to a zinc binding group (ZBG) can be used to modulate subtype selectivity and potency for HDAC6 inhibitors to such an extent. We rationalize the high potency and selectivity of the oxazoles by molecular modeling and docking. PMID- 26653329 TI - Good appearance of food gives an appetizing impression and increases cerebral blood flow of frontal pole in healthy subjects. AB - We investigated the effect of food appearance on appetite and on left-frontal pole blood flow in healthy young subjects. The iEat, a new form of foods with good appearance and greater softness was hypothesized to have the better effects to the subjects than blender-processed foods. The effect on appetite and left frontal pole blood flow using hemoencephalography was assessed while participants were viewing the slideshows of two kinds of foods respectively. The slideshows were used to control the showing time and other variables. The pictures of iEat foods stimulated both of them more than the blender-processed ones. The measurement of cerebral blood flow could be a useful method to monitor the cognitive and emotional aspects of feeding behavior that are important for humans. Like iEat, the foods that look as good as ordinary food yet are softer can be used for people with poor appetite and eating difficulties to ordinary food. PMID- 26653330 TI - Simultaneous Raising of Rabbit Monoclonal Antibodies to Fluoroquinolones with Diverse Recognition Functionalities via Single Mixture Immunization. AB - Highly specific monoclonal and polyclonal antibodies are the key components in a diverse set of immunoassay applications, from research work to routine monitoring and analysis. In the current manuscript, combinatorial strategies for a single mixture immunization, screening and rabbit hybridoma cell technology were described. Fluoroquinolones (FQs) drugs were chosen as representative analytes. Six FQs were conjugated with bovine serum albumin and used as immunogens for subsequent immunization, while a mixture of all was injected for coimmunization. The hybridomas obtained against the individual and multiple FQs were used for the production of diverse varieties of rabbit monoclonal antibodies (RabMAbs) against the target analytes. As was proven by indirect competitive ELISA and quantitative lateral flow immunoassay, this approach opens a new way for simultaneously obtaining functional monoclonal antibodies which are capable of recognizing both individual and multiple analytes in a single preparation circle. This addresses various needs of different monitoring regulations as analytical methodology advances. PMID- 26653331 TI - [Use of Twitter((r)) in a congress: First experience for French internal medicine]. AB - INTRODUCTION: Twitter((r)) is a social "microblogging" network in which users can send and receive updates of up to 140 characters. Nowadays its use in medicine has become common in the United Kingdom and in the USA, particularly in scientific meetings where attendees tweet relevant information from the various lectures. Then, the tweeted information is relayed by followers who may be present or not at the lectures. RESULTS: Using Twitter((r)) on the 70th Congress of French Society of Internal Medicine with @MielLorraine and @secretaireMIEL accounts was the first time in internal medicine in France. In total, 825 tweets were posted by both accounts and 59% were original. The two accounts were followed by respectively 12 and 10 followers. People outside the congress were able to get information and to start discussion on many topics. CONCLUSION: This experience emphasizes the fact that Twitter((r)) improves interactions during congresses. Therefore, we should continue on a going forward basis to develop this tool. PMID- 26653332 TI - Insight into the Nanoscale Mechanism of Rapid H2O Transport within a Graphene Oxide Membrane: Impact of Oxygen Functional Group Clustering. AB - Realistic models of graphene oxide membranes were developed and validated to interpret the exceptional water permeation in association with X-ray photoelectron spectroscopy, thermogravimetric and differential scanning calorimetry analysis, and dynamic vapor sorption measurements. With respect to the GO oxidization level, surface distributions of functionalized domains were analyzed in line with TEM observations, and 3 types of interlayer domains in slit pores of GO membranes were identified. The hydrophilicity degrees of as-defined domains strongly influence their H2O uptake capacities. Calculated sorption enthalpies and isotherms are in good agreement with experimental data, and the results indicate the dominant role of dipole interactions. GO expansion shows a transition from the interstratification of an H2O monolayer to the accumulation of H2O multilayers at an interlayer distance of 0.8 nm. The evolution of both hydrogen bonds and H2O diffusivities suggests the existence of three types of H2O species with different binding states and molecular mobilities. The computed H2O permeability on the basis of sorption-diffusion theory supports the exceptional H2O transport capacity in GO membranes. PMID- 26653333 TI - Daily Fasting Blood Glucose Rhythm in Male Mice: A Role of the Circadian Clock in the Liver. AB - Fasting blood glucose (FBG) and hepatic glucose production are regulated according to a circadian rhythm. An early morning increase in FBG levels, which is pronounced among diabetic patients, is known as the dawn phenomenon. Although the intracellular circadian clock generates various molecular rhythms, whether the hepatic clock is involved in FBG rhythm remains unclear. To address this issue, we investigated the effects of phase shift and disruption of the hepatic clock on the FBG rhythm. In both C57BL/6J and diabetic ob/ob mice, FBG exhibited significant daily rhythms with a peak at the beginning of the dark phase. Light phase restricted feeding altered the phase of FBG rhythm mildly in C57BL/6J mice and greatly in ob/ob mice, in concert with the phase shifts of mRNA expression rhythms of the clock and glucose production-related genes in the liver. Moreover, the rhythmicity of FBG and Glut2 expression was not detected in liver-specific Bmal1-deficient mice. Furthermore, treatment with octreotide suppressed the plasma growth hormone concentration but did not affect the hepatic mRNA expression of the clock genes or the rise in FBG during the latter half of the resting phase in C57BL/6J mice. These results suggest that the hepatic circadian clock plays a critical role in regulating the daily FBG rhythm, including the dawn phenomenon. PMID- 26653334 TI - FSH Regulates mRNA Translation in Mouse Oocytes and Promotes Developmental Competence. AB - A major challenge in assisted reproductive technology is to develop conditions for in vitro oocyte maturation yielding high-quality eggs. Efforts are underway to assess whether known hormonal and local factors play a role in oocyte developmental competence and to identify the molecular mechanism involved. Here we have tested the hypothesis that FSH improves oocyte developmental competence by regulating the translational program in the oocyte. Accumulation of oocyte proteins (targeting protein for the Xenopus kinesin xklp2 and IL-7) associated with improved oocyte quality is increased when cumulus-oocyte complexes are incubated with FSH. This increase is due to enhanced translation of the corresponding mRNAs, as indicated by microinjection of constructs in which the 3' untranslated region of the Tpx2 or Il7 transcripts is fused to the luciferase reporter. A transient activation of the phosphatidyl-inositol 3-phosphate/AKT cascade in the oocyte preceded the increase in translation. When the epidermal growth factor (EGF) receptor is down-regulated in follicular cells, the FSH induced rate of maternal mRNA translation and AKT activation were lost, demonstrating that the effects of FSH are indirect and require EGF receptor signaling in the somatic compartment. Using Pten(fl/fl):Zp3cre oocytes in which the AKT is constitutively activated, translation of reporters was increased and was no longer sensitive to FSH stimulation. More importantly, the oocytes lacking the phosphate and tensin homolog gene showed increased developmental competence, even when cultured in the absence of FSH or growth factors. Thus, we demonstrate that FSH intersects with the follicular EGF network to activate the phosphatidyl inositol 3-phosphate/AKT cascade in the oocyte to control translation and developmental competence. These findings provide a molecular rationale for the use of FSH to improve egg quality. PMID- 26653335 TI - Actions of Bisphenol A and Bisphenol S on the Reproductive Neuroendocrine System During Early Development in Zebrafish. AB - Bisphenol A (BPA) is a well-known environmental, endocrine-disrupting chemical, and bisphenol S (BPS) has been considered a safer alternative for BPA-free products. The present study aims to evaluate the impact of BPA and BPS on the reproductive neuroendocrine system during zebrafish embryonic and larval development and to explore potential mechanisms of action associated with estrogen receptor (ER), thyroid hormone receptor (THR), and enzyme aromatase (AROM) pathways. Environmentally relevant, low levels of BPA exposure during development led to advanced hatching time, increased numbers of GnRH3 neurons in both terminal nerve and hypothalamus, increased expression of reproduction related genes (kiss1, kiss1r, gnrh3, lhbeta, fshbeta, and eralpha), and a marker for synaptic transmission (sv2). Low levels of BPS exposure led to similar effects: increased numbers of hypothalamic GnRH3 neurons and increased expression of kiss1, gnrh3, and eralpha. Antagonists of ER, THRs, and AROM blocked many of the effects of BPA and BPS on reproduction-related gene expression, providing evidence that those three pathways mediate the actions of BPA and BPS on the reproductive neuroendocrine system. This study demonstrates that alternatives to BPA used in the manufacture of BPA-free products are not necessarily safer. Furthermore, this is the first study to describe the impact of low-level BPA and BPS exposure on the Kiss/Kiss receptor system during development. It is also the first report of multiple cellular pathways (ERalpha, THRs, and AROM) mediating the effects of BPA and BPS during embryonic development in any species. PMID- 26653336 TI - Azacyclic FTY720 Analogues That Limit Nutrient Transporter Expression but Lack S1P Receptor Activity and Negative Chronotropic Effects Offer a Novel and Effective Strategy to Kill Cancer Cells in Vivo. AB - FTY720 sequesters lymphocytes in secondary lymphoid organs through effects on sphingosine-1-phosphate (S1P) receptors. However, at higher doses than are required for immunosuppression, FTY720 also functions as an anticancer agent in multiple animal models. Our published work indicates that the anticancer effects of FTY720 do not depend on actions at S1P receptors but instead stem from FTY720s ability to restrict access to extracellular nutrients by down-regulating nutrient transporter proteins. This result was significant because S1P receptor activation is responsible for FTY720s dose-limiting toxicity, bradycardia, that prevents its use in cancer patients. Here, we describe diastereomeric and enantiomeric 3- and 4-C-aryl 2-hydroxymethyl pyrrolidines that are more active than the previously known analogues. Of importance is that these compounds fail to activate S1P1 or S1P3 receptors in vivo but retain inhibitory effects on nutrient transporter proteins and anticancer activity in solid tumor xenograft models. Our studies reaffirm that the anticancer activity of FTY720 does not depend upon S1P receptor activation and uphold the promise of using S1P receptor-inactive azacyclic FTY720 analogues in human cancer patients. PMID- 26653337 TI - A new primary cleft lip repair technique tailored for Asian patients that combines three surgical concepts: Comparison with rotation--advancement and straight-line methods. AB - Various techniques have been described for unilateral cleft lip repair. These may be broadly classified into three types of procedure/concept: the straight-line method (SL; Rose-Thompson effect); rotation-advancement (RA; upper-lip Z-plasty); and the triangular flap method (TA; lower-lip Z-plasty). Based on these procedures, cleft lip repair has evolved in recent decades. The cleft lip repair method in our institution has also undergone several changes. However, we have found that further modifications are needed for Asian patients who have wider philtral dimples and columns than Caucasians, while following the principles of the original techniques mentioned above. Here, we have incorporated the advantages of each procedure and propose a refined hybrid operating technique, seeking a more appropriate procedure for Asian patients. To evaluate our new technique, a comparison study was performed to evaluate RA, SL, and our technique. We have used our new technique to treat 137 consecutive cleft lip cases of all types and degrees of severity, with or without a cleft palate, since 2009. In the time since we adopted the hybrid technique, we have observed improved esthetics of the repaired lip. Our technique demonstrated higher glance impression average scores than RA/SL. PMID- 26653338 TI - [Inhaled in chronic obstructive pulmonary disease therapy update]. AB - Knowledge of chronic obstructive pulmonary disease has increased significantly in recent years, and today we have a more comprehensive concept of the disease. Additionally, drug development allows having a wide range of therapeutic options. The inhaled route is the choice, as it allows drugs to act directly on the bronchial tree. In the past few months, new molecules and devices have been developed that increases our options when treating, but also our doubts when choosing one or the other, so an update of inhaled medications for chronic obstructive pulmonary disease is necessary. The different types of inhalers currently available are reviewed in this article, as well as the advantages and disadvantages of each of them, in order to determine how to choose the right device. PMID- 26653339 TI - [Digoxin use in patients with atrial fibrillation and adverse cardiovascular outcomes: A retrospective analysis of the rivaroxaban once daily oral direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation (ROCKET AF)]. PMID- 26653340 TI - Reductions in physical pain predict lower risk of relapse following alcohol treatment. AB - OBJECTIVE: Physical pain is considered a potential predictor of relapse in alcohol-dependent individuals after treatment. The aim of this study was to evaluate whether reductions in pain level during the follow-up period after treatment were associated with lower relapse risk. METHOD: A sample of 366 participants was recruited from alcohol treatment centers in Warsaw, Poland. At baseline, information was obtained about pain level, demographics, childhood abuse, impulsivity, depressive symptoms, severity of alcohol and sleep problems. After finishing the alcohol treatment program, patients were followed for 12 months and alcohol drinking (relapse) as well as pain severity were evaluated. RESULTS: In the followed-up group, 29.5% of patients confirmed that they drank any alcohol during past 4 weeks. Comparing follow-up to baseline pain, 48.6% of subjects reported an increased severity of pain, 28.8% reported the same level of pain, 22.6% reported decreased level of pain. There was a significant association between the decrease in level of pain and the lower risk of relapse. Other factors associated with relapse during 4 weeks prior to the follow-up were baseline severity of depressive symptoms, low baseline social support and number of drinking days during 4 weeks prior to entering treatment. In multivariate analysis, a decrease in pain level was associated with a lower likelihood of relapse (OR=0.159; 95%CI:0.04-0.62; p=0.008) even when controlled for other factors associated with relapse. CONCLUSIONS: Decreases in pain level following treatment for alcohol dependence are associated with, and may contribute to, a lower risk of alcohol relapse. PMID- 26653341 TI - Nonmedical opioid use and heroin use in a nationally representative sample of us high school seniors. AB - BACKGROUND: Nonmedical use of opioids has become increasingly problematic in recent years with increases in overdoses, treatment admissions, and deaths. Use also appears to be contributing to heroin initiation, which has increased in recent years. Further research is needed to examine which adolescents are at highest risk for nonmedical use of opioids and heroin and to explore potential links between nonmedical opioid use and heroin use. METHODS: Data were analyzed from a nationally representative sample of American high school seniors in the Monitoring the Future study (2009-2013, Weighted N=67,822). We examined associations between frequency and recency of nonmedical use of opioids and heroin. Sociodemographic correlates of use of each drug were also examined. RESULTS: 12.4% of students reported lifetime nonmedical opioid use and 1.2% reported lifetime heroin use. As frequency of lifetime nonmedical opioid use increased, so too did the odds for reporting heroin use, with over three-quarters (77.3%) of heroin users reporting lifetime nonmedical opioid use. Recent (30-day) nonmedical opioid use was a robust risk factor for heroin use and almost a quarter (23.2%) of students who reported using opioids >=40 times reported lifetime heroin use. Black and Hispanic students were less likely to report nonmedical opioid or heroin use than white students, but they were more likely to report heroin use in absence of nonmedical opioid use. DISCUSSION: Recent and frequent nonmedical opioid use are risk factors for heroin use among adolescents. Prevention needs to be targeted to those at highest risk. PMID- 26653342 TI - Chiral 2 + 3 Keto-Enamine Pseudocyclophanes Derived from 1,3,5 Triformylphloroglucinol. AB - The reactions of 1,3,5-triformylphloroglucinol with (1R,2R)-1,2 diaminocyclohexane, (1R,2R)-1,2-diphenylethylenediamine, or (R)-2,2'-diamino-1,1' binaphthyl result in the formation of enantiopure [2 + 3] keto-enamine condensation products, in contrast to analogous reactions of 1,3,5 triformylbenzene, where [4 + 6] Schiff base cages are formed. The X-ray crystal structure of the diaminocyclohexane 2 + 3 derivative as well as modeled structures of other compounds of this type show cyclophane-like molecules with close contact between the phloroglucinol rings. Density Functional Theory (DFT) calculations confirm that there is a sizable pi-pi interaction between these rings influencing the conformation of these molecules. PMID- 26653343 TI - Early detection and successful treatment of Wernicke encephalopathy in a patient with advanced carcinoma of the external genitalia during chemotherapy. AB - OBJECTIVE: Few reports of Wernicke encephalopathy in oncological settings have been published. Some cases of Wernicke encephalopathy are related to appetite loss; however, the degree to which loss of appetite leads to thiamine deficiency is not known. METHOD: A 63-year-old female with advanced cancer of the external genitalia was referred for psychiatric consultation because of disorientation, insomnia, and bizarre behaviors. Her symptoms fulfilled the diagnostic criteria for delirium. Routine laboratory examinations did not reveal the cause of the delirium. Thiamine deficiency was suspected because appetite loss had continued for 19 days since she had been admitted to hospital. RESULTS: Intravenous administration of thiamine resulted in recovery from the delirium within three days. Serum thiamine level was found to be 16 ng/ml (normal range: 24-66 ng/ml). The clinical findings, the low level of thiamine in the serum, and the effective alleviation of delirious symptoms after thiamine administration fulfilled Francis's criteria for delirium induced by thiamine deficiency. SIGNIFICANCE OF RESULTS: Clinicians must be aware of the possibility of Wernicke encephalopathy in cancer patients, especially in those with loss of appetite for longer than 18 days. The degree of appetite loss in such patients might serve as a reference. Early detection and intervention may alleviate the symptoms of delirium and prevent irreversible brain damage. PMID- 26653344 TI - Crucial considerations for pipelines to validate circulating biomarkers for breast cancer. AB - Despite decades of progress in breast imaging, breast cancer remains the second most common cause of cancer mortality in women. The rapidly proliferative breast cancers that are associated with high relapse rates and mortality frequently present in younger women, in unscreened individuals, or in the intervals between screening mammography. Biomarkers exist for monitoring metastatic disease, such as CEA, CA27.29 and CA15-3, but there are no circulating biomarkers clinically available for early detection, prognosis, or monitoring for clinical relapse. There has been significant progress in the discovery of potential circulating biomarkers, including proteins, autoantibodies, nucleic acids, exosomes, and circulating tumor cells, but the vast majority of these biomarkers have not progressed beyond initial research discovery, and none have yet been approved for clinical use in early stage disease. Here, the authors review the crucial considerations of developing pipelines for the rapid evaluation of circulating biomarkers for breast cancer. PMID- 26653356 TI - Prognostic value of nutritional and hematologic markers in head and neck squamous cell carcinoma treated by chemoradiotherapy. AB - PURPOSE: Malnutrition and systemic lymphopenia are common in many cancers and are associated with tumor progression. The purpose of this study was to investigate the prognostic values of nutritional and hematologic markers in patients with head and neck squamous cell carcinoma (HNSCC). METHODS: This prospective study included 153 patients with treatment-naive HNSCC who underwent definitive chemoradiotherapy. Body weight, serologic and hematologic parameters were measured at baseline and after 2 months of treatment. Univariate and multivariate analyses using Cox proportional hazards model were used to identify predictors of progression-free survival (PFS), cancer-specific survival (CSS), and overall survival (OS). RESULTS: Body weight, body mass index (BMI), serum albumin, total serum proteins, hemoglobin, and circulating neutrophil, lymphocyte, monocyte, and platelet counts significantly decreased, but neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) significantly increased after 2 months of treatment (P<0.05 each). Multivariate analyses showed that pretreatment hypoalbuminemia and high NLR were independent predictors of PFS (P<0.01 each). ECOG performance status, BMI<18.5 kg/m(2) and NLR were independent predictors of CSS and OS (P<0.01 each). CONCLUSIONS: Our data support the evidence that several nutritional and hematologic markers are associated with the prognosis of HNSCC. PMID- 26653357 TI - Marrow damage and hematopoietic recovery following allogeneic bone marrow transplantation for acute leukemias: Effect of radiation dose and conditioning regimen. AB - BACKGROUND AND PURPOSE: Total body irradiation (TBI) is a common component of hematopoietic cell transplantation (HCT) conditioning regimens. Preclinical studies suggest prolonged bone marrow (BM) injury after TBI could contribute to impaired engraftment and poor hematopoietic function. MATERIALS AND METHODS: We studied the longitudinal changes in the marrow environment in patients receiving allogeneic HCT with myeloablative (MA, n=42) and reduced intensity (RIC, n=56) doses of TBI from 2003-2013, including BM cellularity, histologic features of injury and repair, hematologic and immunologic recovery. RESULTS: Following MA conditioning, a 30% decrease in the marrow cellularity persisted at 1 year post transplant (p=0.03). RIC HCT marrow cellularity transiently decreased but returned to baseline by 6 months even though the RIC group received mostly umbilical cord blood (UCB) grafts (82%, vs. 17% in the MA cohort, p<0.01). There was no evidence of persistent marrow vascular damage or inflammation. Recipients of more intensive conditioning did not show more persistent cytopenias with the exception of a tendency for minimal thrombocytopenia. Immune recovery was similar between MA and RIC. CONCLUSIONS: These findings suggest that TBI associated with MA conditioning leads to prolonged reductions in marrow cellularity, but does not show additional histological evidence of long-term injury, which is further supported by similar peripheral counts and immunologic recovery. PMID- 26653358 TI - The PSA-response to salvage radiotherapy after radical prostatectomy correlates with freedom from progression and overall survival. AB - BACKGROUND AND PURPOSE: In a retrospective analysis, we examined factors influencing the outcome of prostate cancer (PCa) patients receiving salvage radiotherapy (SRT) for PSA recurrence after radical prostatectomy (RP). MATERIAL AND METHODS: 306 patients received 3D-conformal SRT at a median pre-SRT PSA of 0.298 ng/ml. Post-SRT progression was defined as PSA ?0.2 ng/ml above nadir and rising further, or hormone treatment, or clinical recurrence. Data were analyzed with the Kaplan-Meier method and multivariable Cox regression. RESULTS: Application of SRT at a PSA <0.2 ng/ml correlated significantly with achieving a post-SRT PSA nadir <0.1 ng/ml and with improved freedom from progression (median follow-up 7.2 years). The post-SRT nadir <0.1 ng/ml correlated significantly with less recurrences and with better overall survival. In multivariable Cox analysis restricted to pre-SRT parameters, a pre-SRT PSA ?0.2 ng/ml had the strongest impact (hazard ratio 2.4) on progression. If the post-SRT PSA nadir was included in the model, then failing the nadir was the most important risk factor (hazard ratio 8.1). CONCLUSIONS: Early SRT at a PSA <0.2 ng/ml is a favorable treatment option for post-RP biochemical recurrence. It correlated with a post-SRT PSA nadir <0.1 ng/ml which was associated with improved freedom from progression and overall survival. PMID- 26653359 TI - Use of bottom ash from olive pomace combustion in the production of eco-friendly fired clay bricks. AB - Olive pomace bottom ash was used to replace different amounts (10-50wt%) of clay in brick manufacturing. The aim of this study is both studying bricks properties and showing a new way of olive pomace bottom ash recycling. Properties of waste bricks were compared to conventional products following standard procedures in order to determine the maximum waste percentage. The amount of olive pomace bottom ash is limited to 20wt%, obtaining bricks with superior engineering properties when 10wt% of waste is added. Adding higher amount of waste (30-50wt%) resulted in bricks with water absorption and compressive strength values on the edge of meeting those established by standards. Therefore, the addition of 10 and 20wt% of olive pomace bottom ash produced bricks with a bulk density of 1635 and 1527kg/m(3) and a compressive strength of 33.9MPa and 14.2MPa, respectively. Fired bricks fulfil standards requirements for clay masonry units, offering, at the same time, better thermal insulation of buildings due to a reduction in thermal conductivity of 14.4% and 16.8% respectively, compared to control bricks (only clay). PMID- 26653360 TI - Assessing the role of informal sector in WEEE management systems: A System Dynamics approach. AB - Generally being ignored by academia and regulators, the informal sector plays important roles in Waste Electrical and Electronic Equipment (WEEE) management systems, especially in developing countries. This study aims: (1) to capture and model the variety of informal operations in WEEE management systems, (2) to capture the dynamics existing within the informal sector, and (3) to assess the role of the informal sector as the key player in the WEEE management systems, influencing both its future operations and its counterpart, the formal sector. By using System Dynamics as the methodology and India as the reference system, this study is able to explain the reasons behind, on the one hand, the superiority of the informal sector in WEEE management systems and, on the other hand, the failure of the formal systems. Additionally, this study reveals the important role of the second-hand market as the determinant of the rise and fall of the informal sector in the future. PMID- 26653361 TI - Combined VIth and VIIth nerve palsy: Consider idiopathic intracranial hypertension! AB - BACKGROUND: Idiopathic intracranial hypertension (IIH) is a rare condition in children. VIth nerve palsy is the most common cranial nerve deficit related to that condition. Other cranial nerve dysfunctions have also been described but remain rare in paediatric daily practice. CASE PRESENTATION: We here report the case of a 13-year-old girl who presented with VIth and contralateral VIIth nerve palsy due to IIH. CONCLUSION: Although rarely encountered, paediatricians should be familiar with the possible association of VIth and contralateral VIIth nerve palsy in children suffering from IIH. Moreover, other cranial nerve deficits may also be affected. PMID- 26653363 TI - Template for Reporting Results of Monitoring Tests for Patients With Chronic Myelogenous Leukemia (BCR-ABL1(+)). PMID- 26653362 TI - Peripheral neuropathy in patients with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency - A follow-up EMG study of 12 patients. AB - BACKGROUND: The neonatal screening and early start of the dietary therapy have improved the outcome of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD). The acute symptoms of LCHADD are hypoketotic hypoglycemia, failure to thrive, hepatopathy and rhabdomyolysis. Long term complications are retinopathy and neuropathy. Speculated etiology of these long term complications are the accumulation and toxicity of hydroxylacylcarnitines and long-chain fatty acid metabolites or deficiency of essential fatty acids. AIMS: To study the possible development of polyneuropathy in LCHADD patients with current dietary regimen. METHODS: Development of polyneuropathy in 12 LCHADD patients with the homozygous common mutation c.G1528C was evaluated with electroneurography (ENG) studies. The ENG was done 1-12 times to each patient, between the ages of 3 and 40 years. Clinical data of the patients were collected from the patient records. RESULTS: The first sign of polyneuropathy was detected between the ages of 6-12 years, the first abnormality being reduction of the sensory amplitudes of the sural nerves. With time, progression was detected by abnormalities in sensory responses extending to upper limbs, as well as abnormalities in motor responses in lower limbs. Altogether, eight of the patients had polyneuropathy, despite good compliancy of the diet. CONCLUSIONS: This study is the first to report the evolution of polyneuropathy with clinical neurophysiological methods in a relative large LCHADD patient group. Despite early start, and good compliance of the therapy, 6/10 of the younger patients developed neuropathy. However, in most patients the polyneuropathy was less severe than previously described. PMID- 26653364 TI - Template for Reporting Results of Biomarker Testing of Specimens From Patients With Myeloproliferative Neoplasms. PMID- 26653365 TI - Quantification and bio-assay of alpha-glucosidase inhibitors from the roots of Glycyrrhiza uralensis Fisch. AB - This work aimed to investigate the alpha-glucosidase inhibitor from the roots of Glycyrrhiza uralensis Fisch. Seven flavonoids were isolated, and the total content of compounds 1-7 were more than 50% in Glycyrrhiza total flavones (GTF), and the content of compound 1 and 2 was abundant in GTF. The results of the alpha glucosidase inhibitory activities indicated that compounds 1-6 and GTF respectively with the IC50 values of 31.303, 30.263, 23.363, 19.528, 10.854, 26.454 and 21.641 MUg/mL exhibited the more potent activity than acarbose with the IC50 values of 38.995 MUg/mL. These result suggested that Glycyrrhiza flavonoids may become a valid alternative of potential basis for new hypoglycaemic and antidiabetic agents. PMID- 26653366 TI - Head trauma is the major risk factor for cerebral sinus-vein thrombosis. AB - BACKGROUND: Cerebral sinus vein thrombosis (CSVT) is a rare disease with significant neurological sequelae and high mortality rate. Incidence of CSVT diagnosis in the western world has increased despite the reduced occurrence of infections. AIM: To identify risk factors that may explain the predisposition to site specific thrombosis. METHODS: Ninety consecutive patients diagnosed with acute CSVT in tertiary hospital. As a control group we used the data extracted from the National Trauma Registry and Healthcare Services. RESULTS: Trauma history up to one month prior to diagnosis of CVST was found in 13 (14%) patients. Six patients had skull fractures, the others had blunt trauma. The overall SMR was 941 (p<0.0001); the separate results for men and women were 1206 and 543, respectively. Infections confined to the head and neck in 7% of the cases and brain tumor were observed in 8%. At the time of CVST, 23 of 50 (46%) women had a hormonal risk factor. The SMR for OC use was 1.63 (p=0.0298). Prothrombotic polymorphisms were detected in 16 of 63 (25.4%) patients who were tested for factor V Leiden and prothrombin G20210A mutation (OR=3.47, p=0.002) in comparison to 49% in DVT patients (OR=9.95, p<0.0001). CONCLUSIONS: Assessment for CVST in patients with recent trauma and headache even after intact head CT is required. The other risk factors, such as hormone related and prothrombotic polymorphisms, were not specific just for CVST and the latter play a lesser role in CVST than in DVT. PMID- 26653367 TI - Venous thromboembolism at time of diagnosis of ovarian cancer: Survival differs in symptomatic and asymptomatic cases. AB - OBJECTIVES: To determine the impact on survival of symptomatic and asymptomatic venous thromboembolism (VTE) at time of diagnosis of primary ovarian malignancy. MATERIALS AND METHODS: The clinical records of 397 consecutive cases of primary ovarian malignancy were studied. Clinical, pathological and survival data were obtained. RESULTS AND CONCLUSIONS: Of 397 cases, 19 (4.8%) were found to have VTE at diagnosis, of which 63.2% (n=12) were asymptomatic. VTE was significantly associated with reduced overall median survival (28 vs. 45 months, p=0.004). Decreased survival was associated with symptomatic VTE compared to patients with asymptomatic VTE (21 vs. 36 months, p=0.02) whose survival was similar to that of patients without VTE. Decreased survival remained significant in symptomatic patients after controlling for stage of disease at diagnosis, cytoreductive status and adjuvant chemotherapy use. Overall these data suggest for the first time that symptomatic but not asymptomatic VTE prior to primary treatment of ovarian cancer is an independent adverse prognostic factor. PMID- 26653368 TI - Five int22h homologous copies at the Xq28 locus identified in intron22 inversion type 3 of the Factor VIII gene. PMID- 26653369 TI - The acute respiratory exposure by intratracheal instillation of Sprague-Dawley rats with diesel particulate matter induces retinal thickening. AB - CONTEXT: Adverse health effects of ambient particulate matter (PM) have been demonstrated in humans, mostly in terms of respiratory and cardiovascular events. However, whether ambient particle could affect the eyes had not been fully revealed. OBJECTIVE: This study investigated the effect of acute respiratory exposure to PM on eyes. METHODS: Diesel exhaust product (DEP) of 200 mg/l was given endotracheally in Sprague-Dawley rats for 1 h (n = 12) and compared to normal control (n = 4). We enucleated eyes and histologically evaluated. Immunohistochemical stains for CD34 (Dako, Glostrup, Denmark, 1:50) and Ki-67 (DakoCytomation, Glostrup, Denmark, 1:150) were performed to evaluate new vessel formation and proliferation activity. RESULTS: After endotracheal DEP exposure, the thickness of retina was significantly increased to 258 +/- 96 MUm in DEP group, while that of control was 113 +/- 9 MUm (p = 0.025). Among the retinal structure, inner plexiform, inner and outer nuclear and rod/cone cell layers were significantly thickened (p = 0.00, 0.017, 0.004, 0.001, respectively). The outer plexiform layer of DEP group showed a tendency of thickening, but statistically insignificant. The afferent fiber and ganglion cell layer showed no thickness difference between two groups, but prominent capillaries with congestion were noted in DEP group. Neither neovascularization nor increased proliferation was demonstrated on CD34 and Ki-67 immunohistochemical staining in DEP group. CONCLUSION: This study shows that the acute respiratory exposure of ambient PM increased retinal thickness, especially inner plexiform, inner and outer nuclear and rod/cone cell layers. We thought that increase of retinal thickness in DEP group resulted in hypoxia-induced edema. PMID- 26653370 TI - [Study on relationships between biomarkers in workers with low-level occupational lead exposure]. AB - OBJECTIVE: To investigate the lead exposure, its effects, and the relationships between biomarkers of susceptibility in the workers with low-level occupational lead exposure, and to explore its sensitivity and practical value to evaluate the health hazard. METHODS: The concentrations of lead fume and lead dust in workplaces of a lead acid storage battery enterprise in Jiangsu Province, China, were measured by occupational health monitoring method. The blood samples of 233 workers with occupational lead exposure and 76 non-occupational lead exposure were collected to measure the blood lead (Pb-B) level using graphite furnace atomic absorption spectrometry (GFAAS), the zinc Protoporphyrin (ZPP) level with blood fluorescence assay, and the delta-aminolevulinic acid dehydratase (ALAD) concentration by a spectrophotometer, and to determine the gene polymorphism of ALAD with TaqMan real-time polymerase chain reaction. At the same time, their urine samples were collected to measure urine lead (Pb-U) concentration with GFAAS and delta-aminolevulinic acid (ALA-U) concentration with a spectrophotometer. The correlations between the above indices were analyzed by multiple linear regression method. RESULTS: The concentration of lead fume in 18 testing sites and the concentration of lead dust in 30 testing sites were 0.002 0.019 mg/m3 and 0.004-0.013 mg/m3, respectively. Pb-B level was positively correlated with Pb-U concentration (r=0.62, P<0.01) and ZPP level (r=0.47, P<0.01) and was negatively correlated with ALAD concentration (r=-0.77, P<0.01) in 233 workers with occupational lead exposure. Among 233 workers, 218 (93.6%) had <=70 ug/L Pb-U, and 15 (6.9%) had >=400>=g/L Pb-B. Pb-B level was not correlated with ZPP level as Pb-B level was <190 ug/L (r=0.18, P=0.068 ), while Pb-B level was positively correlated with ZPP level as Pb-B level was >=190 ug/L (r=0.36, P<0.01). Pb-U concentration was positively correlated with ALA-U concentration (r=0.49, P<0.01) and ZPP level (r=0.47, P<0.01). ZPP level was negatively correlated with ALAD concentration (r=-0. 19, P<0.01), and was positively correlated with ALA-U concentration (r=0.27, P<0.01). ALAD concentration was not correlated with ALA-U concentration (r =-0. 11, P>0.05). And in 233 workers with occupational lead exposure, there were no significant differences in Pb-B level, ZPP level, and ALAD activity between the workers with ALAD1-2 genotype and the workers with ALAD1-1 genotype (P>0.05). In 76 workers with non-occupational lead exposure, there was no significant difference in Pb-B level between the workers with ALAD1-2 genotype and the workers with ALAD1-1 genotype (P >0.05). The workers with ALAD1-2 genotype had a significantly lower ALAD activity, and a significantly higher ZPP level compared with those ALAD1-1 genotype (P<0.01). CONCLUSION: In the workers with low-level occupational lead exposure, ZPP level is positively correlated with Pb-B level when Pb-B level was >=190 u/L. ALAD could be used as an effect biomarker of low Pb-B level. ALAD gene polymorphism shows different effects on the Pb-B level and the toxic effects between the workers with occupational lead exposure and the workers with non occupational lead exposure. PMID- 26653371 TI - [Effects of nano-lead exposure on learning and memory as well as iron homeostasis in brain of offspring rats]. AB - OBJECTIVE: To investigate the effects of nano-lead exposure on learning and memory and iron homeostasis in the brain of the offspring rats on postnatal day 21 (PND21) and postnatal day 42 (PND42). METHODS: Twenty adult pregnant female Sprague-Dawley rats were randomly divided into control group and nano-lead group. Rats in the nano-lead group were orally administrated 10 mg/kg nano-lead, while rats in the control group were administrated an equal volume of normal saline until PND21. On PND21, the offspring rats were weaned and given the same treatment as the pregnant rats until 42 days after birth. The learning and memory ability of offspring rats on PND21 and PND42 was evaluated by Morris water maze test. The hippocampus and cortex s amples of offspring rats on PND21 and PND42 were collected to determine iron and lead levels in the hippocampus and cortex by inductively coupled plasma-mass spectrometry. The distributions of iron in the hippocampus and cortex were observed by Perl's iron staining. The expression levels of ferritin, ferroportin 1 (FPN1), hephaestin (HP), and ceruloplasmin (CP) were measured by enzyme-linked immunosorbent assay. RESULTS: After nano-lead exposure, the iron content in the cortex of offspring rats on PND21 and PND42 in the nano-lead group was significantly higher than those in the control group (32.63 +/- 6.03 ug/g vs 27.04 +/- 5.82 ug/g, P<0.05; 46.20 +/-10.60 ug/g vs 36.61 +/- 10.2ug/g, P<0.05). The iron content in the hippocampus of offspring rats on PND42 in the nano-lead group was significantly higher than that in the control group (56.9 +/- 4.37ug/g vs 37.71 +/- 6.92ug/g, P<0.05). The Perl's staining showed massive iron deposition in the cortex and hippocampus in the nano-lead group. FPNl level in the cotfex of offspring rats on PND21 in the nano-lead group was significantly lower than that in the control group (3.64 +/- 0.23 ng/g vs 4.99 +/- 0.95 ng/g, P<0.05). FPN1 level in the hippocampus of offspring rats on PND42 in the nano-lead group was significantly lower than that in the control group (2.28 +/- 0.51 ng/g vs 3.69 +/- 0.69 ng/g, P<0.05). The escape latencies of offspring rats on PND21 and PND42 in the nano-lead group were longer than those in the control group (15.54 +/- 2.89 s vs 9.01 +/- 4.66 s; 6.16 +/- 1.42 s vs 4.26 +/- 1.51 s). The numbers of platform crossings of offspring rats on PND21 and PND42 in the nano- lead group were significantly lower than those in the control group (7.77 +/- 2.16 times vs 11.2 +/- 1.61 times, P<0.05; 8.12 +/- 1.51 times vs 13.0 +/- 2.21 times, P<0.05). ONCLUSION: n Nano-lead exposure can result in iron homeostasis disorders in the hippocampus and cortex of offspring rats and affect their learning and memory ability. PMID- 26653372 TI - [Changes in lung injury and oxidative stress of Sprague-Dawley rats after single intratracheal instillation of potassium dichromate]. AB - OBJECTIVE: To investigate the changes in lung injury and oxidative stress of sprague-Dawleyy (SD) rats at different times after single intratracheal instillation of potassium dichromate. METHODS: A total of 50 healthy male SD rats were randomly divided into control group and potassium dichromate group. The potassium dichromate group and the control group received 3 ml/kg intratracheal instillation of K2Cr2O7 (1.5 mg/kg) and normal saline, respectively. Rats in these two groups were sacrificed in batches at 1, 3, 7, 14, and 28 days after exposure. The changes in the following indices were observed and analyzed: body weight, lung coefficient, alkaline phosphatase (AKP) in bronchoalveolar lavage fluid, glutathione peroxidase (GSH-Px) in lung homogenate, and reduced glutathione (GSH) in serum. RESULTS: The rats in the potassium dichromate group had significantly decreased body weight on day 1 and day 3 after exposure than the control group (P<0.05). Lung coefficient increased significantly on day 7 (P<0.05) and kept increasing until the end of the experiment. The potassium dichromate group had a significantly higher activity of AKP than the control group on day 1 and day 7 after exposure (P<0.05). However, the potassium dichromate group had a significantly lower activity of GSH-Px than the control group on day 1 and day 3 after exposure (P<0.05). And the potassium dichromate group had a lower activity of reduced GSH than the control group on day 3 and day 7 after exposure. CONCLUSION: Single intratracheal instillation of 1.5 mg/kg potassium dichromate could result in lung inflammatory injury. of SD rats, and the injury is more severe on day 7 after exposure. Body injury is related to antioxidant activity, and the antioxidant.activity cannot recover completely on day 28 after exposure. PMID- 26653373 TI - [Effects of methomyl on acetylcholinesterase in erythrocyte membrane and various brain areas]. AB - OBJECTIVE: To study the toxicity of methomyl to acetylcholinesterase (AChE) in different regions. METHODS: The optimal temperature and time for measurement of AChE activity were determined in vitro. The dose- and time-response relationships of methomyl with AChE activity in human erythrocyte membrane, rat erythrocyte membrane, cortical synapses, cerebellar synapses, hippocampal synapses, and striatal synapses were evaluated. The half maximal inhibitory concentration (IC50) and bimolecular rate constant (K) of methomyl for AChE activity in different regions were calculated, and the type of inhibition of AChE activity by methomyl was determined. RESULTS: AChE achieved the maximum activity at 370 degrees C, and the optimal time to determine initial reaction velocity was 0-17 min. There were dose- and time-response relationships between methomyl and AChE activity in the erythrocyte membrane and various brain areas. The IC50 value of methomyl for AChE activity in human erythrocyte membrane was higher than that in rat erythrocyte membrane, while the Ki value of methomyl for AChE activity in rat erythrocyte membrane was higher than that in human erythrocyte membrane. Among synapses in various brain areas, the striatum had the highest IC50 value, followed by the cerebellum, cerebral cortex, and hippocampus, while the cerebral cortex had the highest Ki value, followed by the hippocampus, striatum, and cerebellum. Lineweaver-Burk diagram demonstrated that with increasing concentration of methomyl, the maximum reaction velocity (Vmax) of AChE decreased, and the Michaelis constant (Km) remained the same. CONCLUSION: Methomyl is a reversible non-competitive inhibitor of AChE. AChE of rat erythrocyte membrane is more sensitive to methomyl than that of human erythrocyte membrane; the cerebral cortical synapses have the most sensitive AChE to methomyl among synapses in various brain areas. PMID- 26653374 TI - [Evaluation and analysis of monitoring and early warning functions of the occupational disease reporting system in China]. AB - OBJECTIVE: To evaluate the monitoring and early warning functions of the occupational disease reporting system right now in China, and to analyze their influencing factors. METHODS: An improved audit tool (ODIT) was used to score the monitoring and early warning functions with a total score of 10. The nine indices were completeness of information on the reporting form, coverage of the reporting system, accessibility of criteria or guidelines for diagnosis, education and training for physicians, completeness of the reporting system, statistical methods, investigation of special cases, release of monitoring information, and release of early warning information. RESULTS: According to the evaluation, the occupational disease reporting system in China had a score of 5.5 in monitoring existing occupational diseases with a low score for release of monitoring information; the reporting system had a score of 6.5 in early warning of newly occurring occupational diseases with low scores for education and training for physicians as well as completeness of the reporting system. CONCLUSION: The occupational disease reporting system in China still does not have full function in monitoring and early warning. It is the education and participation of physicians from general hospitals in the diagnosis and treatment of occupational diseases and suspected occupational diseases that need to be enhanced. In addition, the problem of monitoring the incidence of occupational diseases needs to be solved as soon as possible. PMID- 26653375 TI - [An analysis of characteristics of exposure to nanoparticles in a workplace manufacturing iron oxide nanoparticles]. AB - OBJECTIVE: To investigate the characteristics of exposure to iron oxide nanoparticles in workplace. METHODS: The real-time particle number (NC), surface area (SAC), and mass (MC) concentrations of nanoparticles were measured in various locations of a selected workplace manufacturing iron oxide nanoparticles. The collected particles were analyzed for morphology and elemental composition. RESULTS: The average NCs and SACs in milling site (16,566 pt/cm3, 106.082 um2/cm3), packaging site (12,386 pt/cm3, 89.861 um2/cm3), shipping site (13,808 pt/cm3, 102.071 um2/cm3), and product storage room (17,192 pt/cm, 115.044 um2/cm3) of the yellow powder (alpha-Fe2O3 . nH2O) were all significantly higher than the workplace background concentrations (11,420 pt/cm3, 85.026 um2/cm3) (all P<0.05). The NC was highly correlated with the SAC (r= 0.784), while both NC and SAC were loosely correlated with the MC (r1=0.323, r2=0.331). Scanning electron microscopy revealed a spindle-like shape of the iron oxide nanoparticle; the chemical composition of the collected particles contained 19.33 weight percent iron (Fe). CONCLUSION: The milling site and product storage room of the yellow powder are exposed to a higher concentration of nanoparticles, which are mainly composed of iron oxide nanoparticles. The NC is highly correlated with the SAC. PMID- 26653376 TI - [An analysis of eligibility for occupational health inspection agencies in eight provinces of China]. AB - OBJECTIVE: To investigate the eligibility and main problems for occupational health inspection agencies in China, and to provide technical references for improvement of occupational health inspection. METHODS: A survey was performed in occupational health inspection agencies that obtained eligibility before June 2011 in eight provinces: Zhejiang, Jiangsu, Shandong, Hubei, Guangxi, Shanghai, Chongqing, and Shenzhen. The survey used the General Information Questionnaire for Occupational Health Inspection Agency made by the project of Occupational Health Surveillance and Diagnosis and Identification of Occupational Diseases in China and Australia. RESULTS: A total of 650 agencies obtained eligibility for occupational health inspection in the eight provinces. These agencies contained 343 centers of disease control and prevention (CDC) or health and epidemic prevention stations (52.8%), 219 hospitals (33.7%), 25 institutes or centers for occupational disease prevention and control (3.8%), 29 community health service centers (4.5%), and 34 other agencies (5.2%) including departments of preventive and health care and preventive medicine outpatient departments. Four hundred and fifty-three agencies completed the questionnaire survey with a response rate of 69.7%. The main types of eligible agencies were different among various regions. A majority of occupational health inspection agencies were hospitals in Shanghai and Zhejiang (67.1%, 62.3%), departments of preventive and health care in Shenzhen (70.0%), and CDCs in Chongqing, Jiangsu, Hubei, and Guangxi. Each agency obtained 3.5 occupational health inspection eligibilities on average. Most of agencies could perform eligible health inspection for dust, harmful physical factors, or harmful chemical factors (84.8%, 87.9%, 87.2%). Moreover, 72.8% of agencies were eligible for all the three types of inspections. A few agencies were able to perform eligible health inspection for harmful biological factors or radiation work (22.5%, 23.0%). CONCLUSION: An occupational health inspection network has been established in these surveyed regions. CDCs, institutes for occupational disease prevention and control, and hospitals are the main agencies for occupational health inspection. In order to build up a network of occupational disease prevention and control, various agencies should make full use of their own advantages and enhance abilities and technical cooperation. PMID- 26653377 TI - [Determination of normal reference value of pyrrole adducts in urine in young people in a university in Shandong, China]. AB - OBJECTIVE: To determine the normal reference value of pyrrole adducts in urine in young people in a university in Shandong, China, and to provide a reliable basis for the clinical diagnosis of n-hexane poisoning. METHODS: A total of 240 college students were randomly selected. After excluding 32 ineligible students, 208 subjects were included in this study, consisting of 104 males and 104 females, with a mean age of 21?3 years (range: 18 to 24 years). Morning urine was collected from each subject. The content of pyrrole adducts was determined by chromatometry. RESULTS: The content of pyrrole adducts in both male and female obeyed a positively skewed distribution. The median level of pyrrole adducts in male subjects was 0.88 nmol/ml, and the reference value was 0.14-3.92 nmol/ml. The median level of pyrrole adducts in female subjects was 0.93 nmol/ ml, and the reference value was 0.09-3.27 nmol/ml. Student's t test identified no statistical difference in pyrrole adduct level between male and female subjects (t=0.15, P>0.05). CONCLUSION: The median level of pyrrole adducts in normal young people is 0.91 nmol/ml, and the reference value is 0.11-3.95 nmol/ml. PMID- 26653378 TI - [Analysis of urinary N-acetyl-S-(n-propyl)-L-cysteine as biomarker for occupational 1-bromopropane exposure]. PMID- 26653379 TI - [Reliability and validity of Professional Quality of Life Scale among government staff in earthquake - stricken areas in China]. AB - OBJECTIVE: To evaluate the reliability and validity of Professional Quality of Life Scale (ProQOL-30, 4th version, 30 items) among government staff in the Wenchuan earthquake-stricken areas METHODS: A total of 1,175 members of government staff in the Wenchuan earthquake-stricken areas were selected by convenience sampling and required to complete the ProQOL and Self-Reporting Questionnair (SRQ). The reliability and validity of the scale was evaluated by correlation analysis, t-test, and confirmatory factor analysis. RESULTS: Item total correlation coefficients of the three subscales were 0.590 - 0.752, 0.389 - 0.603, and 0.340 - 0.647, respectively (P<0.05), and the average coefficients were 0.672, 0.482, and 0.555 respectively (P<0.05). The Cronbach's alpha coefficients of the three subscales were 0.864, 0.569, and 0.742 respectively, and the split-half reliabilities were 0.829, 0.490, and 0.677, respectively. P value was 0.88 in thE chi-square test of confirmatory factor analysis model. Goodness-of-fit indices of ProQOL-30 included GFI=0.895 NFI=0.856, CFI=0.895, RMSEA=0.063, and AGFI=0.912. For the ProQOL-28 as an optimized version o ProQOL 30, the Cronbach's a coefficients for burnout and trauma/compassion fatigue increased to 0.616 and 0.757, respectively. P value was 0.91 in the chi-square test of confirmatory factor analysis model test. Goodness-of-fit indices of ProQOL-28 were GFI =0.913, AGFI =0.924, NFI =0.900, CFI =0.913, and RMSEA =0.031 CONCLUSION: ProQOL-28 has good reliability and validity among government staff in the earthquake-stricker areas in China. PMID- 26653380 TI - [Study on perceived fatigue evaluating model during simulated load carriage]. AB - OBJECTIVE: To establish a perceived fatigue evaluating model during simulated load carriage that is based on objective variables through analyzing the characteristics and trends of shoulder force, shoulder pressure, waist pressure, back pressure, and perceived fatigue, and to provide an analytical technique for research on load carriage. METHODS: A 50-min simulated walking (at a speed of 5 km/h and a slope of 0%) experiment including 14 healthy male adults was conducted under four levels of backpack payloads (25, 29, 34, 37 kg). Shoulder force and trunk pressure were sampled simultaneously and analyzed with time- and frequency- domain methods. Multivariable linear regression was used to build a perceived fatigue evaluating model during load carriage. RESULTS: The perceived fatigue evaluating model based on shoulder force, trunk pressure distribution ratio, load, and body mass index (BMI) was established. Its adjusted determination coefficient (aR2) was 0.709 and the absolute percentage error (APE) at the end of the experiment was less than 20%. The goodness of fit of the model based on frequency-domain independent variables was much higher compared with the model based on time-domain independent variables. The addition of BMI that represents the individual differences to the model obviously improved the goodness of fit. CONCLUSION: The perceived fatigue evaluating model established in this study does not rely on the physiological changes of individuals, and thus can be used to establish an evaluation system for human load carriage with dummy as a substitution for human in experiments and to provide a scientific basis for efficient human load carriage. PMID- 26653381 TI - [Analysis of posttraumatic stress disorder in rescuers and firefighters]. AB - OBJECTIVE: To investigate the occurrence and associated factors for posttraumatic stress disorder (PTSD) in rescuers and firefighters. METHODS: The PTSD of 264 rescuers and firefighters who had participated in rescue was evaluated using the self-designed fireman general situation questionnaire and PTSD Checklist-Civilian Version (PCL-C). The factors associated with the occurrence of PTSD were also analyzed. RESULTS: The incidence rate of PTSD in the subjects was 8.3%. The PTSD rate of special service corps (12%) was significantly higher than that of other subjects (P<0.05). The incidence of PTSD was highest in the rescuers and firefighters above the third rank, but without significant differences (P>0.05). The PTSD rate of married rescuers and firefighters was significantly higher than that of unmarried subjects (P<0.05). The PTSD rate of subjects addicted to drinking was significantly higher than that of non-drinking subjects (P<0.05). Subjects with more frequent attendance were more susceptible to PTSD compared with those with less attendance. CONCLUSION: The incidence rate of PTSD is high in rescuers and firefighters who have attended rescues. It is necessary to implement both short-term and long-term counseling programs for stress management and intervention in order to reduce the psychological trauma after rescue and improve the mental health of rescuers and firefighters. PMID- 26653382 TI - [Research on express employees' turnover intention and prevention mechanisms]. PMID- 26653383 TI - [Investigation of pathogenic microorganisms resistant tubercalosilicosis complicated with lower respiratory tract infection]. PMID- 26653384 TI - [Current situation of prevention and treatment of silicosis in Jinshan District of Shanghai, China]. AB - OBJECTIVE: To study the current situation of the prevention and treatment of silicosis in Jinshan District of Shanghai, China, and to provide a scientific basis for the introduction of preventive and control measures for the disease. METHODS: An occupational hygienic investigation was carried out among enterprises exposed to silica dust hazard in Jinshan District using cross-sectional epidemiological study. Based on GBZ 159-2004 Specifications of air sampling for hazardous substances monitoring in the workplace and GBZ/T 192.1-2007 Method for determination of dust in the air of workplace Part 1: Total dust concentration, individual sampling and evaluation of test results were conducted among workers exposed to silica dust. RESULTS: A total of 302 workers in 30 enterprises were exposed to silica dust, and the coverage of employment injury insurance and occupational health inspection rate were 98.3% and 92.4%, respectively. The equipment rate of anti-dust respirators of the enterprises was 56.7%, and the qualification rate of silica dust monitoring in work place was 40.4%. The enterprises exposed to silica dust were mainly those who were operated in dry condition and engaged in manual work using opening-type equipment without negative pressure. CONCLUSION: Enterprises exposed to silica dust in Jinshan District of Shanghai have safety hazards like poor production and protective equipment, incomplete protective articles, and low qualification rate of silica dust test in workplace, so occupational health protection measures need to be strengthened. PMID- 26653385 TI - [A literature analysis of power frequency electric field testing data]. AB - OBJECTIVE: To analyze the literature on power frequency electric field testing data and to propose views and suggestions for current testing. METHODS: The literature on power frequency electric field testing data published in the previous years was searched to identify 306 articles involving 193 valid testing data. Mann-Whitney test and Wilcoxon W test were used for analyzing the testing data. RESULTS: The classification of data was carried out according to one quarter of occupational exposure limit (1.25 kV/m), one half of the exposure limit (2.5 kV/m), and the exposure limit (5 kV/m). The structure of testing data showed a significant difference between the non-power facility group and the power facility group (P<0.05). CONCLUSION: As occupational hazard factors, the radiation exposure from power frequency electric field is extensive. However, the power frequency electric field testing data in actual workplaces except high voltage power facilities are far less than the occupational exposure limit with little harmfulness. There is a phenomenon of excessive testing at present. PMID- 26653386 TI - [Clinical characterization and treatment of acute spinal cord decompression sickness after repeated dives]. AB - OBJECTIVE: To analyze and summarize the characteristics and treatment of acute spinal cord decompression sickness. To explore the factors that influence the treatment effect. METHODS: 77 cases of acute spinal cord decompression sickness patients should be divided into 4 groups according to the pressurized treatment and drug treatment options. They were group I, group II, group III and group IV. At the same time they were get hyperbaric oxygen therapy and other treatment. The evaluation index, were Frankel function classification and paraplegia index. There were 17 factors that affected the treatment effect. RESULTS: The rate of early cure was 57.14% (44/77). The rate of late cure was 74.03% (57/77). Their difference was statistically significant (P<0.05). In 3 months and 1 year the cure rate of group IV and group B were the highest. But there was no difference between them(P>0.05). They were higher than group ii and group I (P<0.05). The Frankel function classification in 3months and 1 year in each group was higher than before treatment (P<0.05). The paraplegia index in 3 months and 1 year in each group was lower than before treatment (P<0.05). In 3 months and 1 year the Frankel function classification was increased gradually and the paraplegia index was decreased gradually in group I , group II, group III (P<0.05). In group IV and group III the Frankel function and the paraplegia index had not significant difference (P>0.05). Among the 17 factors that affect the treatment effect there are 9 factors that affect the proportion of the large. CONCLUSIONS: The first choice of treatment method for the patients with acute spinal cord decompression sickness would be group III. Drug therapy was also imporpant. At the same time the hyperbaric oxygen therapy and other treatments were taken. Although the cure rate was not high in this article. But most of the cure is within 3 months. Within 1 year.the cure rate still could be improved. 9 factors that affect the efficacy of acute spinal cord decompression sickness was more noteworthy. PMID- 26653387 TI - [Diagnosis and treatment discussion of mine workers with noise induced deafness]. PMID- 26653388 TI - [Clinical significance of serum amylase and lipase in patients with acute paraquat poisoning]. AB - OBJECTIVE: To investigate the changes in serum amylase (AMY) and lipase (LPS) and their clinical significance in patients with acute paraquat poisoning (APP). METHODS: The clinical data of 62 APP. patients who were admitted to Guangzhou 12th People's Hospital in 2014 were retrospectively analyzed. With clinical death being regarded as the end point of observation, the 62 patients were divided into survival group (n=32) and death group (n=30). The fasting venous blood of the patients on the 1st, 3rd, and 7th day after admission were collected, and the AMY and LPS levels were determined; the obtained data were compared between the two groups and analyzed statistically. RESULTS: The AMY and LPS levels of the survival group on the 1st, 3rd, and 7th day after admission were significantly lower than those of the death group (P<0.05); the AMY and LPS levels of the death group on the 3rd day were significantly higher than those on the 1st day after admission (P<0.05); the survival group demonstrated no significant changes in AMY and LPS levels (P>0.05). CONCLUSION: Changes in AMY and LPS levels in APP patients are reliable indicators for the determination of poisoning severity and prognosis. PMID- 26653389 TI - [Clinical analysis of secondary epilepsy induced by xylene poisoning]. PMID- 26653390 TI - [Determination of thiodiglycolic acid in urine with gas chromatography-mass spectrometer]. AB - OBJECTIVE: To establish a rapid determination method with gas chromatography-mass spectrometer (GC-MS) for thiodiglycolic acid (TDGA), a vinyl chloride (VCM) biomarker. METHODS: A high- sensitivity determination method was established using a moderate methyl esterification instead of methyl esterification of highly toxic diazo reaction. RESULTS: The standard curve regression linear equation of the method was: y=8460.5x-4758.2, the linear coefficient was 0.999 7, the minimum quantity concentration was 2.0 ug/L, the range of precision value was 0.81% 2.38%, and the average recovery of standard addition was 99.0%-102.9%. CONCLUSION: This method reduces the risk of traditional methyl esterification, improves the determination sensitivity compared with the GC-FPD method, and meets the determination requirement of TDGA. PMID- 26653391 TI - [Simultaneous determination of three organic fluorides in workplace air by portable gas chromatography-mass spectrometer]. AB - OBJECTIVE: To establish a method for rapid determination of organic fluorides in the air of a fluorine chemical plant using portable gas chromatography-mass spectrometer (GC-MS). METHODS: Standard samples of monochlorodifluoromethane, tetrafluoroethylene, and hexafluoropropylene of different concentrations were prepared by static volumetric method with high-purity nitrogen as the diluent gas. The samples were injected into the GC-MS by a hand-held probe. Retention time and characteristic ion were used for qualitative analysis, and the area of selected ion peak was used for quantitative analysis. The standard curves were then created for quantitative determination of the three organic fluorides. RESULTS: The linear ranges for monochlorodifluoromethane, tetrafluoroethylene, and hexafluoropropylene by the method were 0.39-7.72, 0.45-8.84, and 0.61-12.20 mg/m3, respectively, the average recovery rates for the three concentrations were 102.8%, 96.0%, and 106.5%, respectively, and the average deviations were 2.1%, 5.1%, and 2.4%, respectively. CONCLUSION: The portable GC-MS can be used for the simultaneous qualitative and quantitative analysis of monochlorodifluoromethane, tetrafluoroethylene, and hexafluoropropylene in the workplace air, and the method is simple, fast, and accurate. PMID- 26653392 TI - [Determination of dichloromethane in urine by gas chromatography]. PMID- 26653393 TI - In-car usage-based insurance feedback strategies. A comparative driving simulator study. AB - Usage-Based Insurances (UBI) enable policyholders to actively reduce the impact of vehicle insurance costs by adopting a safer and more eco-friendly driving style. UBI is especially relevant for younger drivers, who are a high-risk population. The effectiveness of UBI should be enhanced by providing in-car feedback optimised for individual drivers. Thirty young novice drivers were therefore invited to complete six experimental drives with an in-car interface that provided real-time information on rewards gained, their driving behaviour and the speed limit. Reward size was either displayed directly in euro, indirectly as a relatively large amount of credits, or as a percentage of the maximum available bonus. Also, interfaces were investigated that provided partial information to reduce the potential for driver distraction. Compared to a control no-UBI condition, behaviour improved similarly across interfaces, suggesting that interface personalisation after an initial familiarisation period could be feasible without compromising feedback effectiveness. Practitioner Summary: User experiences and effects on driving behaviour of six in-car interfaces were compared. The interface provided information on driving behaviour and rewards in a UBI setting. Results suggest that some personalisation of interfaces may be an option after an initial familiarisation period as driving behaviour improved similarly across interfaces. PMID- 26653394 TI - Incidence and risk factors of delayed postpolypectomy bleeding in patients with chronic liver disease. AB - OBJECTIVE: Hepatologists and colonoscopists often hesitate to perform a colonoscopic polypectomy in patients with chronic liver disease (CLD), especially those with cirrhosis, because of the risk of postpolypectomy bleeding (PPB). We aimed to investigate the incidence and risk factors of delayed PPB after a colonoscopic polypectomy in patients with CLD. MATERIALS AND METHODS: In total, 152 patients with CLD who underwent colonoscopic polypectomy from December 2005 to December 2012 were retrospectively reviewed. RESULTS: Cirrhosis was identified in 80 (52.6%) patients. During the study period, 442 polyps were removed and delayed PPB developed in 14 (9.2%) patients. The incidence of delayed PPB was significantly higher in patients with cirrhosis than in those without the disease (13.8% [n = 11] vs. 4.2% [n = 3], p = 0.041). The polyp size (odds ratio, 1.087; 95% confidence interval, 1.009-1.172) and cirrhosis (odds ratio, 8.535; 95% confidence interval, 2.417-30.140) were independent risk factors for delayed PPB. In patients with cirrhosis, the optimal cut-off size to identify high-risk polyps for delayed PPB was 10 mm (area under the receiver operating characteristics curve, 0.737; sensitivity, 52%; specificity, 88%). CONCLUSION: Caution is needed when colonoscopic polypectomy is planned in patients with CLD who have larger polyps and cirrhosis. PMID- 26653395 TI - Meet our new editor. PMID- 26653396 TI - Prognostic value of mean platelet volume on tinnitus. AB - OBJECTIVE: This study aimed to determine whether there was any relationship between tinnitus and mean platelet volume. METHODS: This retrospective study was conducted between January 2013 and January 2014 in Ankara Ataturk Hospital and Ondokuz Mayis University Hospital, Turkey, on a study group of 86 patients with tinnitus and a control group of 84 healthy subjects. Mean platelet volume was recorded and comparisons were made between the two groups. RESULTS: Mean (+/- standard deviation) platelet volume was 7.67 +/- 0.83 MUm(3) in the study group and 7.28 +/- 0.56 MUm(3) in the control group. There was a statistically significant difference in mean platelet volume between the tinnitus patients and the healthy subjects (p < 0.05). CONCLUSION: The clinical findings indicated that tinnitus patients had a higher mean platelet volume than the healthy control subjects; however, the pathophysiological mechanism remains unclear. PMID- 26653397 TI - A systematic review of supportive supervision as a strategy to improve primary healthcare services in Sub-Saharan Africa. AB - BACKGROUND: It may be assumed that supportive supervision effectively builds capacity, improves the quality of care provided by frontline health workers, and positively impacts clinical outcomes. Evidence on the role of supervision in Sub Saharan Africa has been inconclusive, despite the critical need to maximize the workforce in low-resource settings. OBJECTIVES: To review the published literature from Sub-Saharan Africa on the effects of supportive supervision on quality of care, and health worker motivation and performance. SEARCH STRATEGY: A systematic review of seven databases of both qualitative and quantitative studies published in peer-reviewed journals. SELECTION CRITERIA: Selected studies were based in primary healthcare settings in Sub-Saharan Africa and present primary data concerning supportive supervision. DATA COLLECTION AND ANALYSIS: Thematic synthesis where data from the identified studies were grouped and interpreted according to prominent themes. MAIN RESULTS: Supportive supervision can increase job satisfaction and health worker motivation. Evidence is mixed on whether this translates to increased clinical competence and there is little evidence of the effect on clinical outcomes. CONCLUSIONS: Results highlight the lack of sound evidence on the effects of supportive supervision owing to limitations in research design and the complexity of evaluating such interventions. The approaches required a high level of external inputs, which challenge the sustainability of such models. PMID- 26653398 TI - Surface Modification of Polymers by Reaction of Alkyl Radicals. AB - The surfaces of poly(methyl methacrylate) and polyethylene are modified either (i) by a two-step process including the thermal reaction of alkyl radicals derived from bromohexanoic acid in a mixture of 2,6-dimethylbenzene diazonium salt and neat isopentyl nitrite at 60 degrees C, followed by reaction with p nitroaniline, anthraquinone, neutral red, and polyethylene glycol moieties, or (ii) by reaction of a previously anthraquinone-modified bromohexanoic acid. The modified surfaces are characterized by IR, XPS, UV, and water contact angles. A mechanism is proposed to rationalize the results. This approach is an efficient way to modify and pattern polymer surfaces with different organic groups and chemical functionalities under mild conditions. PMID- 26653399 TI - [Chronic renal failure in sickle cell disease: A retrospective analysis of 100 adults sickle cell patients from black Africa]. AB - The prevalence of chronic renal failure (CRF) in sickle cell disease (SCD) patients could vary from one country to another depending on the modalities of management. The aim of the present study was to appreciate the epidemiology of CRF in SCD patients from black Africa in order to search for promoting factors. One hundred SCD adult patients have been considered for the study. The glomerular filtration rate (GFR) has been estimated according to the CKD-EPI formula. Three groups of patients have been identified according to the value of their GFR. The mean age of the patients was 30.84+/-8.26 years. Male gender has represented 51% of the study population. The mean GFR value was 175.4+/-86.2 mL/min/1.73 m(2). The prevalence of CRF was 11%. About 3% of them had severe CRF. Subjects with normal GFR were 20%. Subjects with glomerular hyperfiltration (HF) were 69%. By univariate analysis, when subjects with HF were compared with those presenting normal GFR, the following factors have appeared to be significantly associated: female gender (female 60.9% versus male 39.1%; P<0.01), weight <60 kg (weight <60 kg; 53.67+/-9.45 kg versus weight >60 kg; 59.9+/-9.41 kg; P<0.008), age <30 years (younger age 29.36+/-7.9 years versus older age 35.14+/-8.02 years; P<0.001), lower hemoglobin value (9.38+/-2,3 g/dL versus 10.33+/-2.61 g/dL; P<0.04). By logistic regression analysis, age <30 years (age >30 years; OR=0.12 [CI95% 0.03 04]; P<0.001), female gender (male gender; OR=0.17 [0.04-0.64]; P<0.01), weight <60 kg (weight >60 kg; OR=0.19 [CI95% 0.05-0.72]; P<0.01) were associated with HF. By univariate analysis, when subjects with CRF were compared with those presenting normal GFR, a lower hemoglobin value was significantly associated with CRF (7.92+/-2.7 g/dL versus 10.43+/-2.5 g/dL; P<0.009). There was a trend for subjects not being under maintenance therapy to more experience CRF (36.4% versus 70%; P<0.07). By logistic regression analysis, only a low hemoglobin value was associated to CRF (higher hemoglobin level; OR=0.55 [0.20-6.3]; P<0.01). In total, CRF and HF are frequent complications in SCD adult patients from black Africa. PMID- 26653400 TI - Black Rice with Giant Embryo Attenuates Obesity-Associated Metabolic Disorders in ob/ob Mice. AB - Obesity is closely associated with metabolic disorders such as hyperglycemia and dyslipidemia. Leptin-deficient ob/ob mice (C57BL/6J-ob/ob) and C57BL/6J mice were randomly assigned to a diet of black rice with giant embryo (BR), white rice (WR), or AIN-93G (control) and pair-fed for 14 weeks. Although there was no significant difference in body weight, BR-fed ob/ob mice had (1) significantly lower body fat mass than WR- and control-fed ob/ob mice determined by dual-energy X-ray absorptiometry; (2) significantly lower blood glucose, serum insulin, and triacylglycerol levels than control-fed ob/ob mice; and (3) significantly lower liver weight, hepatic triacylglycerol, and hepatic lipid droplets than both WR- and control-fed ob/ob mice. Furthermore, DNA damage in the liver, determined by phosphorylated H2AX protein, and in the kidney, determined by single-cell gel electrophoresis, was significantly lower in BR-fed than WR- and control-fed ob/ob mice. This study indicates that BR ameliorates obesity and its related metabolic disorders. PMID- 26653401 TI - Direction-selective units in the frog's basal optic root nucleus. AB - Electrophysiological responses from 91 direction-selective (DS) units located in the basal optic root (nBOR) and the adjacent dorsomedial area have been recorded extracellularly in the frog (Rana temporaria L.). Based on characteristics of the recorded responses, 23 of the units are considered to be retinal ganglion cells' (RGC; axon terminals). The majority of the remaining 68 units were considered to be DS neurons of the nBOR. The results of our study suggest that in the nBOR area there might be four subtypes of the tegmental and retinal DS units that respond selectively to stimuli moving in the dorso-ventral, ventro-dorsal, caudo-rostral and rostro-caudal directions. The receptive field (RF) sizes of the nBOR DS neurons were estimated to be about 30-[Formula: see text], while those for the retinal units were significantly smaller - just 6-[Formula: see text]. In response to abrupt darkening within the units' RFs, both the nBOR DS neurons and the RGC DS units respond by a weak discharge. Our results indicate that the frog nBOR DS neurons integrate the inputs from the retinal OFF-type DS units over relatively large segments of the visual field. PMID- 26653402 TI - The plasma membrane repair shop: Fixing the damage. PMID- 26653403 TI - Development and pathology of the gonad. PMID- 26653404 TI - Reference values of focused assessment with sonography for obstetrics (FASO) in low-risk population. AB - OBJECTIVE: Hemorrhagic shock is a relatively common occurrence in the postpartum period. In our hospital, we performed abdominal ultrasonography using the focused assessment with sonography for obstetrics (FASO) technique (a modified version of FAST). The aim of the present study was to determine the reference values for the ultrasonographic findings to establish the criteria for the diagnosis of a postpartum hemorrhage and severe shock using the FASO. METHODS: The present prospective cohort study included all postpartum women who vaginally delivered singleton infants. Abdominal ultrasonography was performed after delivery. The observation points of ultrasonography were as follows: (1) the diameter of the intrauterine cavity, (2) the pouch of Douglas, (3) Morison's pouch, (4) between the spleen and kidney, and (5) the diameter of the inferior vena cava. RESULTS: One hundred and eighty-two postpartum women were included in this study. The mean uterine cavity was 9.8 +/- 7.3 mm. An echo-free space in the pouch of Douglas was observed in three cases, in one case in Morison's pouch, and not observed between the spleen and kidney. A negative correlation was found between the volume of bleeding and IVCi (p = 0.0008, r(2)= -0.061) and IVCe (p < 0.0001, r(2)= -0.106). CONCLUSIONS: The present study establishes criteria that can be used to diagnose a postpartum hemorrhage or severe shock using the FASO. PMID- 26653405 TI - Mediation Analysis: A Practitioner's Guide. AB - This article provides an overview of recent developments in mediation analysis, that is, analyses used to assess the relative magnitude of different pathways and mechanisms by which an exposure may affect an outcome. Traditional approaches to mediation in the biomedical and social sciences are described. Attention is given to the confounding assumptions required for a causal interpretation of direct and indirect effect estimates. Methods from the causal inference literature to conduct mediation in the presence of exposure-mediator interactions, binary outcomes, binary mediators, and case-control study designs are presented. Sensitivity analysis techniques for unmeasured confounding and measurement error are introduced. Discussion is given to extensions to time-to-event outcomes and multiple mediators. Further flexible modeling strategies arising from the precise counterfactual definitions of direct and indirect effects are also described. The focus throughout is on methodology that is easily implementable in practice across a broad range of potential applications. PMID- 26653406 TI - Cervical zygapophysial (facet) joint pain: effectiveness of interventional management strategies. AB - Diagnostic facet joint nerve blocks have been utilized in the diagnosis of cervical facet joint pain in patients without disk herniation or radicular pain due to a lack of reliable noninvasive diagnostic measures. Therapeutic interventions include intra-articular injections, facet joint nerve blocks and radiofrequency neurotomy. The diagnostic accuracy and effectiveness of facet joint interventions have been assessed in multiple diagnostic accuracy studies, randomized controlled trials (RCTs), and systematic reviews in managing chronic neck pain. This assessment shows there is Level II evidence based on a total of 11 controlled diagnostic accuracy studies for diagnosing cervical facet joint pain in patients without disk herniation or radicular pain utilizing controlled diagnostic blocks. Due to significant variability and internal inconsistency regarding prevalence in a heterogenous population; despite 11 studies, evidence is determined as Level II. Prevalence ranged from 36% to 67% with at least 80% pain relief as the criterion standard with a false-positive rate ranging from 27% to 63%. The evidence is Level II for the long-term effectiveness of radiofrequency neurotomy and facet joint nerve blocks in managing cervical facet joint pain. There is Level III evidence for cervical intra-articular injections. PMID- 26653407 TI - Systematic evaluation of self-adjuvanting lipopeptide nano-vaccine platforms for the induction of potent CD8(+) T-cell responses. AB - AIM: Systematically evaluate lipid core peptide vaccine delivery platforms to identify core features promoting strong CD8(+) T-cell responses. MATERIALS & METHODS: Three different self-adjuvanting lipid core peptide nanovaccines each comprising four copies of the dominant ovalbumin CD8(+) T-cell epitope and varying in the utilization of a polylysine or glucose core with 2-amino hexadecanoic acid (C16) or 2-amino-dodecanoic acid (C12) lipids were synthesized. Vaccines were tested for ability to induce CD8(+) T-cell responses and inhibit tumor growth in vivo. RESULTS: The construct utilizing C12 lipids and polylysine core induced very robust effector T cells shown to have in vivo effector capability as demonstrated by in vivo cytotoxicity and ability to inhibit tumor growth as well as modulation of dendritic cell activation. CONCLUSION: The C12 polylysine platform was an effective configuration for induction of potent CD8(+) T-cell responses. PMID- 26653408 TI - Perimenopause: From Research to Practice. AB - The menopausal transition, or perimenopause, is associated with profound reproductive and hormonal changes. These changes have been well chronicled and matched with concomitant symptoms. The pattern of appearance of menopausal symptoms and their natural history have become increasingly clear thanks to the conduct of several long-term, longitudinal cohort studies that have examined many aspects of women's biology and psychology through this time of life. Menopausal symptoms are highly prevalent; they are sufficiently bothersome to drive almost 90% of women to seek out their healthcare provider for advice on how to cope. (1) The classic symptom of menopause is the hot flash, which is experienced by most women, and is moderately to severely problematic for about 1/3 of women. While most women will have an experience of hot flashes limited to just a year or two, others will experience them for a decade or more, and a small proportion of women will never be free of them. Poor sleep becomes more common in perimenopausal women not only in association with the menopausal transition but also in relation to aging. Depressed mood and increased anxiety also increase during the transition, with an abrupt rise in prevalence as women approach the later stages of the menopausal transition and have longer bouts of amenorrhea. These common symptoms often interact with one another such that depressed women tend to experience worse hot flashes along with worse sleep. As women enter the latter stages of the transition, vaginal dryness and dyspareunia also become more likely, affecting about 1/3 of the population. Unlike hot flashes, mood issues, and sleep, vaginal symptoms will not go away without treatment. Clinical approaches to these problems often involve hormone therapy, which can be safely given to most perimenopausal women on a short-term basis. Therapeutic strategies that are nonhormonal and behavioral can also be deployed. PMID- 26653409 TI - Development of the Multicomponent Coupled-Cluster Theory for Investigation of Multiexcitonic Interactions. AB - Multicomponent systems are defined as chemical systems that require a quantum mechanical description of two or more different types of particles. Non-Born Oppenheimer electron-nuclear interactions in molecules, electron-hole interactions in electronically excited nanoparticles, and electron-positron interactions are examples of physical systems that require a multicomponent quantum mechanical formalism. The central challenge in the theoretical treatment of multicomponent systems is capturing the many-body correlation effects that exist not only between particles of identical types (electron-electron) but also between particles of different types (electron-nuclear and electron-hole). In this work, the development and implementation of multicomponent coupled-cluster (mcCC) theory for treating particle-particle correlation in multicomponent systems are presented. This method provides a balanced treatment of many-particle correlation effects in a general multicomponent system while maintaining a size consistent and size-extensive formalism. The coupled-cluster ansatz presented here is an extension of the electronic structure CCSD formulation for multicomponent systems and is defined as |PsimcCC? = eT1I+T2I+T1II+T2II+T11I,II+T12I,II+T21I,II+T22I,II|0I0II?. The cluster amplitudes in the mcCC wave function were obtained by projecting the mcCC Schrodinger equation onto a direct product space of singly and doubly excited states of type I and II particles and then solving the resulting mcCC equations iteratively. These equations were derived using an automated application of the generalized Wick's theorem and were implemented using a computer-assisted source code generation approach. The applicability of the mcCC method was demonstrated by calculating ground state energies of multicomponent Hooke's atom and positronium hydride systems as well as by calculating exciton and biexciton binding energies in multiexcitonic systems. For each case, the mcCC results were benchmarked against full configuration interaction (FCI) calculations and were found to be in excellent agreement with the FCI results. The effect of neglecting certain classes of multicomponent connected excitation terms from the mcCC wave function was also investigated. The results from this study demonstrate that connected cluster operators that generate simultaneous excitation in type I and type II space are critical for capturing electron-hole correlation in multiexcitonic systems. PMID- 26653410 TI - Sensitive and specific detection of classical scrapie prions in the brains of goats by real-time quaking-induced conversion. AB - Real-time quaking-induced conversion (RT-QuIC) is a rapid, specific and highly sensitive prion seeding activity detection assay that uses recombinant prion protein (rPrPSen) to detect subinfectious levels of the abnormal isoforms of the prion protein (PrPSc). Although RT-QuIC has been successfully used to detect PrPSc in various tissues from humans and animals, including sheep, tissues from goats infected with classical scrapie have not yet been tested. Therefore, the aims of the present study were to (1) evaluate whether prion seeding activity could be detected in the brain tissues of goats with scrapie using RT-QuIC, (2) optimize reaction conditions to improve scrapie detection in goats, and (3) compare the performance of RT-QuIC for the detection of PrPSc with the more commonly used ELISA and Western blot assays. We further optimized RT-QuIC conditions for sensitive and specific detection of goat scrapie seeding activity in brain tissue from clinical animals. When used with 200 mM sodium chloride, both full-length sheep rPrPSen substrates (PrP genotypes A136R154Q171 and V136R154Q171) provided good discrimination between scrapie-infected and normal goat brain samples at 10(- )3 dilution within 15 h. Our findings indicate that RT-QuIC was at least 10,000-fold more sensitive than ELISA and Western blot assays for the detection of scrapie seeding activity in goat brain samples. In addition to PRNP WT samples, positive RT-QuIC reactions were also observed with three PRNP polymorphic goat brain samples (G/S127, I/M142 and H/R143) tested. Taken together, these findings demonstrate that RT-QuIC sensitively detects prion seeding activity in classical scrapie-infected goat brain samples. PMID- 26653411 TI - Advances in implantable cardioverter defibrillator therapy. AB - Since the first implant in 1980, implantable cardioverter defibrillator (ICD) technology has progressed rapidly. Modern ICD's have hundreds of programmable options with the general goal of preventing inappropriate shocks and providing shocks for truly life threatening symptomatic ventricular arrhythmias. New studies on ICD programming have shown the benefits of prolonged detection intervals in reaching this goal. Anti-tachycardia pacing (ATP) therapy has become an important adjunct to defibrillator shocks. Remote monitoring technologies have surfaced which have been shown to identify arrhythmias and problems with the device in an expedient fashion. The subcutaneous ICD offers the advantage of avoiding intravascular leads and their inherent risks. Lastly, the current understanding of the effects of MRI in ICD patients has advanced creating new opportunities to provide MRI safely to such patients. PMID- 26653412 TI - Discovery of novel FFA4 (GPR120) receptor agonists with beta-arrestin2-biased characteristics. AB - BACKGROUND: Free fatty acid 4 (FFA4) (GPR120) receptor functions as a receptor for unsaturated long-chain free fatty acids by regulating the secretion of glucagon-like peptide-1 and suppressing the inflammatory process, in which these two distinct biological functions are modulated by two signaling pathways, Gq and beta-arrestin2, respectively. RESULTS: By using pharmacophore modeling and virtual screening methods, several compounds are found with excellent activities for agonizing FFA4 receptor. It needs to be noted that among them, some molecules demonstrate appealing beta-arrestin2-biased properties for the FFA4 receptor. CONCLUSION: These compounds may serve as the useful toolkits for detecting differential biased mechanism and developing new candidate therapeutic agents of the FFA4 receptor. PMID- 26653413 TI - Microlinguistic processes that contribute to the ability to relay main events: influence of age. AB - The purpose of the current study was to determine the microlinguistic processes that contribute to picture description in healthy adults across the life span. Two-hundred forty healthy adults were separated into three groups, young (n = 80; 20-39), middle (n = 80; 40-69), and older (n = 80; 70-89). Participants provided language samples in response to two single and two sequential pictures analyzed for total number of words, informativeness, lexical diversity, syntactic complexity, and main events. The older group produced a significantly lower proportion of main events for the single and sequential pictures compared to the other groups. Group differences on the microlinguistic measures varied depending on the measure and the stimulus type. Further, regardless of task, total number of words significantly related to main event production for the young and middle aged groups, but not the older group. Results of the current study extend previous findings by researchers who have investigated discourse production in cognitively healthy, older adults. Using a multi-level approach, we found that linguistic processes across different levels interact; however, the relationship is age-dependent. By including a middle-aged group we identify the potential course of documented change and our results indicate that the changes in language processes with age may not be linear. PMID- 26653414 TI - Erratum to: 'Integrated analysis of the local and systemic changes preceding the development of post-partum cytological endometritis'. PMID- 26653415 TI - The experience of taking methotrexate for juvenile idiopathic arthritis: results of a cross-sectional survey with children and young people. AB - BACKGROUND: Children and young people (CYP) with juvenile idiopathic arthritis (JIA) are known to have impaired health-related quality of life (HRQoL), which is improved significantly for many by treatment with methotrexate (MTX). However, a significant proportion of CYP experience difficulties in taking MTX, which may reduce its potential benefits for HRQoL. The aim of this research was to examine how CYP with JIA perceive MTX treatment and how this relates to HRQoL. METHODS: CYP aged 8-16 years taking MTX for JIA completed an adapted Parent Adherence Report Questionnaire, which contains 100 mm visual analogue scales, to assess difficulty taking MTX, adherence, frequency of negative reactions and helpfulness of MTX. They also completed the Pediatric Quality of Life Inventory (PedsQL) Generic and Rheumatology scales. We collected data on age, gender, JIA course, disease duration, MTX duration of use, route and dose. Number of inflamed and limited joints were indicators of disease severity. RESULTS: One hundred sixteen CYP participated. Most considered MTX helpful (median 87; interquartile range (IQR) 50.75-98) and reported adherence was high (median 98; IQR 90-100). There was greater variability on scores for difficulty (median 22; IQR 2-69) and frequency of negative reactions (median 14.5; IQR 1.25-80). Mean (S.D.) scores on the PedsQL Physical and Psychosocial subscales were 71.63 (24.02) and 71.78 (19.59) respectively, indicating poorer HRQoL than that reported by healthy children. After controlling for demographic and disease variables, poorer physical HRQoL was significantly accounted for by greater difficulty in taking MTX. Poorer psychosocial HRQoL was significantly accounted for by subcutaneous MTX administration, a lower rating of MTX helpfulness and a greater reported difficulty in taking MTX. CONCLUSIONS: Taking MTX for JIA was viewed as helpful by most CYP but HRQoL was poorer in those who reported greater difficulty in taking MTX. PMID- 26653416 TI - Determination of selected environmental contaminants in foraging honeybees. AB - Colony losses of honeybees have been of great concern in the last years. To explain these losses, several studies have been reported, and various factors, such as pathogens and pesticides, have been considered as possible causes. Nevertheless, organic contaminants, rather than pesticides, are continuously released to the environment, and can be intercepted by honeybees during foraging with the possible consequent damage. Azoles and organophosphorus esters have been selected in this work as environmental contaminants to be monitored in honeybees. A fast and robust method has been developed to determine these organic pollutants in honeybees. It is based on matrix solid phase dispersion (MSPD), which performs sample dispersion with extraction and clean up in the same step, followed by LC ESI-MS/MS determination. Recoveries of the method varied between 73% and 119% and MQLs ranged from 0.8 to 4 ng g(-1). Honeybee samples from ten apiaries located in different regions were analyzed applying the developed method. Azole compounds were found at low levels, but not in all samples, while organophosphorus esters were found in most samples whatever location. Tris-(2-chloroisopropyl) phosphate, TCPP, and tributyl phosphate, TBP, were detected in all honeybees samples at levels higher than the rest of organophosphates analyzed. PMID- 26653417 TI - Inferential monitoring of chlorinated solvents through Raman spectroscopic observation of the vibrational modes of water. AB - Recent improvements in diode laser, fiber optic, and data acquisition technology have rejuvenated interest in field applications of Raman spectroscopy in a wide range of settings. One such application involves the observation of chlorinated solvents to facilitate the practice of "monitored natural attenuation." In this context, this manuscript focuses on means to improve the sensitivity of in-situ Raman analysis of chlorinated solvents. In particular, the work explores the performance limits of a Time-Resolved Raman Spectroscopy (TRRS) system employed to observe chlorinated solvents in aqueous samples via laboratory tests conducted on both liquid standards of trichloroethylene (TCE) and simulated biodegraded field samples. Quantitative assessment of TCE in solution is carried out through both direct observation of TCE Raman functional groups (381 cm(-1) (delta skeletal), 840 cm(-1) (nuCCl) and 1242 cm(-1) (deltaCH)) and indirect observation of the broad OH stretching (2700-3800 cm(-1)) Raman modes of water. Results from tests on simple solutions show that the TRRS system can detect TCE at aqueous concentrations as low as 70 ppm by directly monitoring the 381 cm(-1) TCE line, whereas observation of the OH stretching line of water (3393 cm(-1)) provides an indirect indication of TCE presence with nearly a 9* improvement in detection level. This unique and counterintuitive mechanism to detect the presence of chlorinated compounds in solution takes advantage of the influence of chlorine on the vibrational modes of water. This influence, which is believed to be attributed to the formation of hydrogen bonds and their resultant interactions with the solvation shell, may serve as a more sensitive and robust indication of the presence of aggregate chlorinated solvent contamination in aqueous systems. Tests performed on simulated biodegraded field samples demonstrate that the indirect detection mechanism is apparent even in complex samples representative of typical field conditions. PMID- 26653418 TI - Simultaneous determination of Co, Al and Fe by HR CS-GFAAS. AB - In this study, simultaneous determination of Al, Co and Fe by high resolution continuum source graphite furnace atomic absorption spectrometer (HR-CS GFAAS) was performed satisfactorily. For this purpose, the spectral area between 237.148 and 237.403 was monitored and Al, Co and Fe absorbances were detected at absorption lines, 237.312 nm, 237.185+237.283+237.386 nm and 237.362 nm, respectively. The characteristic concentrations and LOD values for the working wavelengths of Co, Al, and Fe were 48.0, 6.00, 54.0 ug L(-1), and 12.0, 14.0, 16.0 ug L(-1), respectively. The linear working ranges were spread over 0.01-10, 0.05-2.5 and 0.05-10 mg L(-1) for Co, Al, and Fe, respectively. In the end, Al, Co and Fe in several certificated reference materials and waste water samples were determined satisfactorily by HR-CS GFAAS. With this proposed method a fast and straightforward simultaneous determination by HR CS AAS shown as possible. PMID- 26653419 TI - Copper-incorporated SBA-15 with peroxidase-like activity and its application for colorimetric detection of glucose in human serum. AB - The copper incorporated SBA-15 (Cu-SBA-15) materials with different amount of Cu in framework were synthesized, and the products were characterized by X-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FT-IR), scanning electron microscope (SEM), transmission electron microscope (TEM) and N2 adsorption/desorption. The Cu contents incorporated into the framework of SBA-15 were measured by inductively coupling plasma atomic emission spectrometer (ICP AES). Cu-SBA-15 samples were found to exhibit the peroxidase-like activity, similar to the natural peroxidase. The effect of various parameters such as the content of Cu incorporated, pH and temperature on the peroxidase-like activity was studied. Based on the peroxidase-like activity, the Cu-SBA-15 was applied to the determination of H2O2. The linear range for detecting H2O2 was from 0.8 to 60mM with a detection limit of 3.7 uM. Coupled with glucose oxidase, the Cu-SBA 15 was successfully used for the determination of glucose with the linear range of 2-80 mM and a detection limit of 5.4 uM. The determination of glucose in human serum showed high accuracy, good reproducibility, as well as high selectivity against uric acid, ascorbic acid, dopamine and glucose analogs including fructose, maltose and lactose. PMID- 26653420 TI - Novel surface dummy molecularly imprinted silica as sorbent for solid-phase extraction of bisphenol A from water samples. AB - A novel surface molecularly imprinted silica composite was prepared by a dummy template imprinting strategy for the solid-phase extraction (SPE) of bisphenol A (BPA). 2,2-Bis(4-hydroxyphenyl) hexafluoropropane (BPAF) was chosen as the template molecule, and a hybrid technique was used for imprinting procedure. The imprinted silica was characterized by FT-IR spectroscopy, scanning electron microscope, thermo-gravimetric analysis, and nitrogen adsorption-desorption isotherms. The static binding test verified that the imprinted silica had much higher recognition ability for BPA than the non-imprinted silica, and the kinetic adsorption test presented the fast binding kinetics of the surface imprinted silica for BPA. When used as a SPE sorbent, the imprinted silica showed high extraction efficiencies and high enrichment factor for BPA. Based on the imprinted silica, a SPE-HPLC-UV method was developed and successfully applied to the detection of BPA in BPA-spiked lake water, tap water and drinking water samples with a high recovery of 97.3-106.0%, a RSD of 1.2-3.8% (n=3) and a limit of detection (S/N=3) of 0.3 ng/mL. The analysis results of a certified BPA sample also demonstrated the reliability of present method. The new surface dummy molecularly imprinted silica completely avoided the interference of the residual template molecules and greatly improved the binding kinetic of the target molecules. Therefore, it can be used as a good sorbent for SPE of BPA in environmental water samples. PMID- 26653421 TI - An innovative approach to prepare hypericin molecularly imprinted pearls using a "phyto-template". AB - In this paper, an innovative method that uses hypericin "phyto-template" molecules is being applied herein for the first time to produce molecularly imprinted polymer (MIP) pearls able to selectively retain hypericin from Hypericum Perforatum L primary extracts. For this purpose, the wet phase inversion method was preferred for preparing the hypericin-MIP pearls for several reasons referring to economical benefits but also due to the fact that hypericin "phyto-template" molecules can be generated along with the phase inversion of the copolymer. Practically, the precursor poly(acrylonitrile-co-methacrylic acid) solution was mixed with a purified and concentrated naphtodianthrone phyto extract (consisting only of hypericin and pseudo-hypericin). In the subsequent phase inversion step hypericin was trapped in the copolymer droplets, as a result to its poor solubility in the inversion water bath, and further served as "phyto template" in the imprinting step. This in situ repartition of hypericin and pseudo-hypericin was sustained by HPLC-DAD chromatograms which recorded only the presence of hypericin during the extraction stage of imprinted pearls. Batch rebinding measurements, all together, validated the efficiency of this innovative imprinting procedure. The hypericin rebinding of imprinted pearls was quantitative (up to 318 ug/L) and approximately 5 times more specific relative to the blank pearls. Competitive re-binding revealed a more selective behaviour of imprinted pearls for hypericin when the up-take was measured against pseudohypericin (selectivity coefficient above 4.50). PMID- 26653422 TI - Facile synthesis of magnetic carbon nitride nanosheets and its application in magnetic solid phase extraction for polycyclic aromatic hydrocarbons in edible oil samples. AB - In this study, we proposed a method to fabricate magnetic carbon nitride (CN) nanosheets by simple physical blending. Low-cost CN nanosheets prepared by urea possessed a highly pi-conjugated structure; therefore the obtained composites were employed as magnetic solid-phase extraction (MSPE) sorbent for extraction of polycyclic aromatic hydrocarbons (PAHs) in edible oil samples. Moreover, sample pre-treatment time could be carried out within 10 min. Thus, a simple and cheap method for the analysis of PAHs in edible oil samples was established by coupling magnetic CN nanosheets-based MSPE with gas chromatography-mass spectrometry (GC/MS) analysis. Limits of quantitation (LOQs) for eight PAHs ranged from 0.4 to 0.9 ng/g. The intra- and inter-day relative standard deviations (RSDs) were less than 15.0%. The recoveries of PAHs for spiked soybean oil samples ranged from 91.0% to 124.1%, with RSDs of less than 10.2%. Taken together, the proposed method offers a simple and cost-effective option for the convenient analysis of PAHs in oil samples. PMID- 26653423 TI - Prediction of banana quality indices from color features using support vector regression. AB - Banana undergoes significant quality indices and color transformations during shelf-life process, which in turn affect important chemical and physical characteristics for the organoleptic quality of banana. A computer vision system was implemented in order to evaluate color of banana in RGB, L*a*b* and HSV color spaces, and changes in color features of banana during shelf-life were employed for the quantitative prediction of quality indices. The radial basis function (RBF) was applied as the kernel function of support vector regression (SVR) and the color features, in different color spaces, were selected as the inputs of the model, being determined total soluble solids, pH, titratable acidity and firmness as the output. Experimental results provided an improvement in predictive accuracy as compared with those obtained by using artificial neural network (ANN). PMID- 26653424 TI - Visual and colorimetric detection of p-aminophenol in environmental water and human urine samples based on anisotropic growth of Ag nanoshells on Au nanorods. AB - A simple, sensitive, selective and high-resolution colorimetric method has been developed for the detection of p-aminophenol in environmental water and human urine samples. In the presence of p-aminophenol, silver ions are reduced to silver atoms and subsequently Ag nanoshells anisotropically grow on the surface of Au nanorods to generate orange slice-like Au@Ag core-shell nanocrystals, thereby resulting in the blue-shift of longitudinal surface plasmon resonance band of Au nanorods accompanying a sharp-contrast multicolor change. Using Au@Ag core-shell nanocrystals as the transducer, sub-micromolar p-aminophenol can be detected by the colorimetric method and 10 MUmol L(-1) p-aminophenol can be visual readout by the naked eyes. Furthermore, a simple, cheap, portable test kit is constructed for the visual assay of urinary p-aminophenol without complicated sample pretreatment and sophisticated instruments. The proposed colorimetric method has the potential for the rapid and on-site analyses of p-aminophenol in environmental water and human urine samples. PMID- 26653425 TI - Identification and quantification of seven volatile n-nitrosamines in cosmetics using gas chromatography/chemical ionization-mass spectrometry coupled with head space-solid phase microextraction. AB - An analytical method was developed for the identification and quantification of seven volatile n-nitrosamines (n-nitrosodimethylamine [NDMA], n nitrosoethylmethylamine [NMEA], n-nitrosodiethylamine [NDEA], n nitrosodipropylamine [NDPA], n-nitrosodibutylamine [NDBA], n-nitrosopiperidine [NPIP], and n-nitrosopyrrolidine [NPYR]) in water insoluble cream type cosmetics. It was found that the head space-solid phase microextraction (HS-SPME) was suitable for extraction, clean up, and pre-concentration of n-nitrosamines in the cream type samples so its optimal conditions were investigated. Identification and quantification of n-nitrosamines using single quadrupole gas chromatography/mass spectrometry (GC/MS) in chemical ionization (CI) mode were carried out with accurate mass measurements. Their accurate masses of protonated molecular ions were obtained within 10 mDa of the theoretical masses when sufficiently high signal was acquired from the unique calibration method using mass and isotope accuracy. For the method validation of quantification, spiking experiments were carried out to determine the linearity, recovery, and method detection limit (MDL) using three deuterated internal standards. The average recovery was 79% within 20% relative standard deviation (RSD) at the concentration of 50 ng/g. MDLs ranged from 0.46 ng/g to 36.54 ng/g, which was satisfactory for the directive limit of 50 ng/g proposed by the European Commission (EC). As a result, it was concluded that the method could be provided for the accurate mass screening, confirmation, and quantification of n nitrosamines when applied to cosmetic inspection. PMID- 26653426 TI - ColiSense, today's sample today: A rapid on-site detection of beta-D Glucuronidase activity in surface water as a surrogate for E. coli. AB - A sensitive field-portable fluorimeter with incubating capability and triplicate sample chambers was designed and built. The system was optimised for the on-site analysis of E. coli in recreational waters using fluorescent based enzyme assays. The target analyte was beta-D-Glucuronidase (GUS) which hydrolyses a synthetic substrate 6-Chloro-4-Methyl-Umbelliferyl-beta-D-Glucuronide (6-CMUG) to release the fluorescent molecule 6-Chloro-4-Methyl-Umbelliferyl (6-CMU). The system was calibrated with 6-CMU standards. A LOD of 5 nM and a resolution of less than 1 nM was determined while enzyme kinetic tests showed detection of activities below 1 pmol min(-1) mL(-1) of sample. A field portable sample preparation, enzyme extraction protocol and continuous assay were applied with the system to analyse freshwater and marine samples. Results from a one day field trial are shown which demonstrated the ability of the system to deliver results on-site within a 75 min period. PMID- 26653427 TI - Ultrasound-assisted dispersive liquid-liquid microextraction for the determination of synthetic musk fragrances in aqueous matrices by gas chromatography-mass spectrometry. AB - A rapid and simple method for the simultaneous determination of twelve synthetic musks in water samples, using ultrasound-assisted dispersive liquid-liquid microextraction (UA-DLLME) coupled with gas chromatography-mass spectrometry (GC MS) was successfully developed. The influence of seven factors (volume of the extraction solvent and disperser solvent, sample volume, extraction time, ionic strength, type of extraction and disperser solvent) affecting the UA-DLLME extraction efficiency was investigated using a screening design. The significant factors were selected and optimised employing a central composite design: 80 MUL of chloroform, 880 MUL of acetonitrile, 6 mL of sample volume, 3.5% (wt) of NaCl and 2 min of extraction time. Under the optimised conditions, this methodology was successfully validated for the analysis of 12 synthetic musk compounds in different aqueous samples (tap, sea and river water, effluent and influent wastewater). The proposed method showed enrichment factors between 101 and 115 depending on the analyte, limits of detection in the range of 0.004-54 ng L(-1) and good repeatability (most relative standard deviation values below 10%). No significant matrix effects were found, since recoveries ranged between 71% and 118%. Finally, the method was satisfactorily applied to the analysis of five different aqueous samples. Results demonstrated the existence of a larger amount of synthetic musks in wastewaters than in other water samples (average concentrations of 2800 ng L(-1) in influent and 850 ng L(-1) in effluent). Galaxolide, tonalide and exaltolide were the compounds most detected. PMID- 26653428 TI - An evaluation of microwave-assisted fusion and microwave-assisted acid digestion methods for determining elemental impurities in carbon nanostructures using inductively coupled plasma optical emission spectrometry. AB - It is common for as-prepared carbon nanotube (CNT) and graphene samples to contain remnants of the transition metals used to catalyze their growth; contamination may also leave other trace elemental impurities in the samples. Although a full quantification of impurities in as-prepared samples of carbon nanostructures is difficult, particularly when trace elements are intercalated or encapsulated within a protective layer of graphitic carbon, reliable information is essential for reasons such as quantifying the adulteration of physico-chemical properties of the materials and for evaluating environmental issues. Here, we introduce a microwave-based fusion method to degrade single- and double-walled CNTs and graphene nanoplatelets into a fusion flux thereby thoroughly leaching all metallic impurities. Subsequent dissolution of the fusion product in diluted hydrochloric and nitric acid allowed us to identify their trace elemental impurities using inductively coupled plasma optical emission spectrometry. Comparisons of the results from the proposed microwave-assisted fusion method against those of a more classical microwave-assisted acid digestion approach suggest complementarity between the two that ultimately could lead to a more reliable and less costly determination of trace elemental impurities in carbon nanostructured materials. PMID- 26653429 TI - PVDF-ErGO-GRC electrode: A single setup electrochemical system for separation, pre-concentration and detection of lead ions in complex aqueous samples. AB - An effective electrode was developed based on electromembrane extraction (EME) and square wave voltammetry (SWV) for simultaneous separation, pre-concentration and determination of lead (II) (Pb(II)) ions in complex aqueous samples. Electrochemically reduced graphene oxide-graphite reinforced carbon (ErGO-GRC) was utilized in conjunction with the SWV. Pb(II) ions were extracted from an aqueous sample solution into an acidic acceptor phase (1M HCl) in the lumen of the polyvinylidene fluoride (PVDF) membrane bag by the application of voltage of maximum 6 V across the supported liquid membrane (SLM), consisting of organic solvent and di-(2-ethylhexyl)phosphoric acid (D2EHPA). The parameters affecting the EME were optimized for Pb(II) ions. The optimum EME conditions were found to be 20% D2EHPA in 1-octanol impregnated in the wall of PVDF membrane (PVDF17) as the SLM, extraction time of 20 min, pH of sample solution of 8 and a voltage of 5 V. The PVDF-ErGO-GRC electrode system attained enrichment factors of 40 times and 80% of extraction with relative standard deviations (n=5) of 8.3%. Good linearity ranging from 0.25 to 2 nM with coefficients correlation of 0.999 was obtained. The Pb(II) ions detection limit of PVDF-ErGO-GRC electrode was found to be 0.09 nM. The newly developed single setup electrochemical system was applied to complex aqueous samples such as tap, river and sea water to evaluate the feasibility of the method for applications. PMID- 26653430 TI - Facile synthesis of CdTe@GdS fluorescent-magnetic nanoparticles for tumor targeted dual-modal imaging. AB - Multimodal imaging has made great contribution for diagnosis and therapy of disease since it can provide more effective and complementary information in comparison to any single imaging modality. The design and fabrication of fluorescent-magnetic nanoparticles for multimodal imaging has rapidly developed over the years. Herein, we demonstrate the facile synthesis of GdS coated CdTe nanoparticles (CdTe@GdS NPs) as multimodal agents for fluorescence (FL) and T1 weighted magnetic resonance (MR) imaging. These nanoparticles obtain both prominent fluorescent and paramagnetic properties by coating the GdS shell on the surface of CdTe core via a simple room-temperature route in aqueous solution directly. It is shown that the as-prepared CdTe@GdS NPs have high quantum yield (QY) value of 12% and outstanding longitudinal relaxation rate (r1) of 11.25 mM s(-1), which allow them to be employed as FL/MR dual-modal imaging contrast agents. They also exhibit small particle size of 5 nm, excellent colloidal stability and low cellular toxicity for concentrations up to 750 MUg mL(-1). In addition, with the conjugation of folic acid, the nanoparticles were successfully used for tumor-targeted FL/MR dual-modal imaging in vitro and in vivo. PMID- 26653431 TI - Label-free fluorescence strategy for sensitive microRNA detection based on isothermal exponential amplification and graphene oxide. AB - MicroRNAs (miRNAs) play an important role in many biological processes, and have been regarded as potential targets and biomarkers in cancer diagnosis and therapy. Also, to meet the big challenge imposed by the characteristics of miRNAs, such as small size and vulnerability to enzymatic digestion, it is of great importance to develop accurate, sensitive and simple miRNA assays. Herein, we developed a label-free fluorescence strategy for sensitive miRNA detection by combining isothermal exponential amplification and the unique features of SYBR Green I (SG) and graphene oxide (GO), in which SG gives significantly enhanced fluorescence upon intercalation into double-stranded DNAs (dsDNAs), and GO selectively adsorbs miRNA, single-stranded DNA and SG, to protect miRNA from enzymatic digestion, and to quench the fluorescence of the adsorbed SG. In the presence of the target miRNA, the ingeniously designed hairpin probe (HP) is unfolded and the subsequent polymerization and strand displacement reaction takes place to initiate the target recycling process. The newly formed dsDNAs are then recognized and cleaved by the nicking enzyme, generating new DNA triggers with the same sequence as the target miRNA, which hybridize with intact HPs to initiate new extension reactions. As a result, the circular exponential amplification for target miRNA is achieved and large amount of dsDNAs are formed to generate significantly enhanced fluorescence upon the intercalation of SG. Thus sensitive and selective fluorescence miRNA detection is realized, and the detection limit of 3 fM is obtained. Besides, this method exhibits additional advantages of simplicity and low cost, since expensive and tedious labeling process is avoided. Therefore, the as-proposed label-free fluorescence strategy has great potential in the applications in miRNA-related clinical practices and biochemical researches. PMID- 26653432 TI - Solid phase extraction of amoxicillin using dibenzo-18-crown-6 modified magnetic multiwalled carbon nanotubes prior to its spectrophotometric determination. AB - This work reports on a method for selective extraction and sensitive determination of amoxicillin drug (AMX). The method is based on solid phase extraction of AMX by a novel modified magnetic nanoadsorbent prior to spectrophotometric determination of AMX using a procedure based on formation a colored azo-derivative of the investigated drug. The nanoadsorbent has been synthesized by modification of magnetic-multiwalled carbon nanotube with dibenzo 18-crown-6 moieties. The synthesized nanoparticles were characterized using TEM, XRD and FT-IR measurements. At the next step, various factors that could potentially affect adsorption and desorption efficiencies of AMX, have been optimized. The results showed that under the optimized conditions, sensitive and selective determination of the investigated drug in concentration range of 5.0 1000.0 ng mL(-1) with the limit of detection of 3.0 ng mL(-1) was achievable. Furthermore, the real sample analysis (i.e. amoxicillin capsules and human urine samples) results indicated that a reliable promising candidate method has been developed for the determination of AMX in the investigated real samples. PMID- 26653433 TI - Upconversion nanosensor for sensitive fluorescence detection of Sudan I-IV based on inner filter effect. AB - Sudan dyes are banned as food additives due to the carcinogenicity of their metabolites in the human body. Therefore, it is of great significance for sensitive detection of Sudan dyes. This paper reports a novel nanosensor for Sudan dyes detection based on fluorescence (FL) quenching of hexadecyl trimethyl ammonium bromide (CTAB) stabilized upconversion nanoparticles (UCNPs) through the inner filter effect (IFE). In the presence of Sudan I-IV, the fluorescence emission of UCNPs was effectively quenched due to the absorption bands of Sudan I IV largely covered the emission bands of UCNPs. Under the optimized conditions, the FL was quenched with Sudan concentration over the range of 0.05-40, 0.01-20, 0.01-40 and 0.05-40 MUg/mL for Sudan I-IV, respectively. The corresponding limit of detection is 15.1, 2.83, 3.52 and 16.7 ng/mL (at 3sigma/slope) respectively. Meanwhile, the nanosensor shows good selectivity, sensitivity and can be successfully applied to detection of Sudan in chili powder samples. PMID- 26653434 TI - Metabolomic profile related to cardiovascular disease in patients with type 2 diabetes mellitus: A pilot study. AB - Type 2 diabetes mellitus (T2DM) patients have an increased risk of cardiovascular disease (CVD) that represents one of the main causes of mortality in this population. The knowledge of the underlie factors involved in the development of CVD and the discovery of new biomarkers of the disease could help to early identification of high-risk patients. Using liquid chromatography coupled to high resolution mass spectrometry (LC-HRMS) we analyzed the serum metabolomic profile of 30 subject distributed according three groups: (i) T2DM patients with CVD; (ii) T2DM patients without CVD; (iii) non-diabetic subjects as controls (C) in order to identify potential biomarkers of the CVD related to T2DM. A partial least squares discriminant analysis (PLS-DA) and one-way analysis of variance (ANOVA) were applied to identify differential metabolites between different groups. Four glycerophospholipids were further identified as potential biomarkers of CVD in T2DM patients. Specifically, a reduction in phosphatidylcholine, lysophosphatidylcholine and lysophosphatidylethanolamine (LPE) serum levels were found in T2DM patients compared to controls, presenting the patients with CVD the lowest serum levels of these metabolites. These results show a generalized reduction of circulating phospholipids species in T2DM patients which is more pronounced in those with CVD providing information of the pathways involved in the pathogenesis and progression of CVD associated to T2DM. PMID- 26653435 TI - Three-way analysis of the UPLC-PDA dataset for the multicomponent quantitation of hydrochlorothiazide and olmesartan medoxomil in tablets by parallel factor analysis and three-way partial least squares. AB - An application of parallel factor analysis (PARAFAC) and three-way partial least squares (3W-PLS1) regression models to ultra-performance liquid chromatography photodiode array detection (UPLC-PDA) data with co-eluted peaks in the same wavelength and time regions was described for the multicomponent quantitation of hydrochlorothiazide (HCT) and olmesartan medoxomil (OLM) in tablets. Three-way dataset of HCT and OLM in their binary mixtures containing telmisartan (IS) as an internal standard was recorded with a UPLC-PDA instrument. Firstly, the PARAFAC algorithm was applied for the decomposition of three-way UPLC-PDA data into the chromatographic, spectral and concentration profiles to quantify the concerned compounds. Secondly, 3W-PLS1 approach was subjected to the decomposition of a tensor consisting of three-way UPLC-PDA data into a set of triads to build 3W PLS1 regression for the analysis of the same compounds in samples. For the proposed three-way analysis methods in the regression and prediction steps, the applicability and validity of PARAFAC and 3W-PLS1 models were checked by analyzing the synthetic mixture samples, inter-day and intra-day samples, and standard addition samples containing HCT and OLM. Two different three-way analysis methods, PARAFAC and 3W-PLS1, were successfully applied to the quantitative estimation of the solid dosage form containing HCT and OLM. Regression and prediction results provided from three-way analysis were compared with those obtained by traditional UPLC method. PMID- 26653436 TI - Magnetic solid-phase extraction of protein with deep eutectic solvent immobilized magnetic graphene oxide nanoparticles. AB - As a new type of green solvent, four kinds of choline chloride (ChCl)-based deep eutectic solvents (DESs) have been synthesized, and then a core-shell structure magnetic graphene oxide (Fe3O4-NH2@GO) nanoparticles have been prepared and coated with the ChCl-based DESs. Magnetic solid-phase extraction (MSPE) based Fe3O4-NH2@GO@DES was studied for the first time for the extraction of proteins. The characteristic results of vibrating sample magnetometer (VSM), X-ray diffraction (XRD), Fourier transform infrared spectrometry (FT-IR), thermal gravimetric analysis (TGA) and field emission scanning electron microscopy (FESEM) indicated the successful preparation of Fe3O4-NH2@GO@DES. The concentrations of proteins in studies were determined by a UV-vis spectrophotometer. The advantages of Fe3O4-NH2@GO@DES in protein extraction were compared with Fe3O4-NH2@GO and Fe3O4-NH2, and Fe3O4-NH2@GO@ChCl-glycerol was selected as the suitable extraction solvent. The influence factors of the extraction process such as the pH value, the temperature, the extraction time, the concentration of protein and the amount of Fe3O4-NH2@GO@ChCl-glycerol were evaluated. Desorption experimental result showed 98.73% of BSA could be eluted from the solid extractant with 0.1 mol/L Na2HPO4 solution contained 1 mol/L NaCl. Besides, the conformation of BSA was not changed during the elution by the investigation of circular dichromism (CD) spectra. Furthermore, the analysis of real sample demonstrated that the prepared magnetic nanoparticles did have extraction ability on proteins in bovine whole blood. PMID- 26653437 TI - The estimation of total petroleum hydrocarbons content in waste water by IR spectrometry with multivariate calibrations. AB - Alkanes, cycloalkanes and arenes have rather different sensitivities to IR spectrometric determination, leading to high relative uncertainty (deltac) for the total petroleum hydrocarbon index (TPH) in natural and waste waters. Another source of TPH uncertainty is the mismatch of group composition of the hydrocarbon mixture in the sample and in the standard substance used for one-dimensional calibration. Increasing the number of wavelengths and using of multivariate calibrations permit the reduction of deltac to <10% rel. These calibrations may be constructed from IR-spectra and findings of extracts from aqueous solutions with known content of hydrocarbons. The method takes into account the losses of hydrocarbons during sample preparation. The accuracy of TPH estimations for this method is much better than for standard methods based on one-dimensional calibration with Simard mixture. This new method is useful in produced waste water analysis. PMID- 26653438 TI - Optical sensor based on hybrid FBG/titanium dioxide coated LPFG for monitoring organic solvents in edible oils. AB - A hybrid optical sensing scheme based on a fiber Bragg grating (FBG) combined with a titanium dioxide coated long period fiber grating (LPFG) for monitoring organic solvents in high refractive index edible oils is reported. In order to investigate and optimize the sensor performance, two different FBG/LPFG interrogation systems were investigated. The readout of the sensor was implemented using either the wavelength shift of the LPFG resonance dip or the variation in the optical power level of the reflected/transmitted light at the FBG wavelength peak, which in turn depends on the wavelength position of the LPFG resonance. Hexane concentrations up to 20%V/V, corresponding to the refractive index range from 1.451 to 1.467, were considered. For the transmission mode of operation, sensitivities of 1.41 nm/%V/V and 0.11 dB/%V/V, with resolutions of 0.58%V/V and 0.29%V/V, were achieved when using the LPFG wavelength shift and the FBG transmitted optical power, respectively. For the FBG reflection mode of operation, a sensitivity of 0.07 dB/%V/V and a resolution better than 0.16%V/V were estimated. PMID- 26653439 TI - Spreadsheet for designing valid least-squares calibrations: A tutorial. AB - Instrumental methods of analysis are used to define the price of goods, the compliance of products with a regulation, or the outcome of fundamental or applied research. These methods can only play their role properly if reported information is objective and their quality is fit for the intended use. If measurement results are reported with an adequately small measurement uncertainty both of these goals are achieved. The evaluation of the measurement uncertainty can be performed by the bottom-up approach, that involves a detailed description of the measurement process, or using a pragmatic top-down approach that quantify major uncertainty components from global performance data. The bottom-up approach is not so frequently used due to the need to master the quantification of individual components responsible for random and systematic effects that affect measurement results. This work presents a tutorial that can be easily used by non experts in the accurate evaluation of the measurement uncertainty of instrumental methods of analysis calibrated using least-squares regressions. The tutorial includes the definition of the calibration interval, the assessments of instrumental response homoscedasticity, the definition of calibrators preparation procedure required for least-squares regression model application, the assessment of instrumental response linearity and the evaluation of measurement uncertainty. The developed measurement model is only applicable in calibration ranges where signal precision is constant. A MS-Excel file is made available to allow the easy application of the tutorial. This tool can be useful for cases where top-down approaches cannot produce results with adequately low measurement uncertainty. An example of the application of this tool to the determination of nitrate in water by ion chromatography is presented. PMID- 26653440 TI - New chrysin-functionalized silica-core shell magnetic nanoparticles for the magnetic solid phase extraction of copper ions from water samples. AB - This study describes the synthesis, characterization and application of a new chrysin-based silica core-shell magnetic nanoparticles (Fe3O4@SiO2-N-chrysin) as an adsorbent for the preconcentration of Cu(II) from aqueous environment. The morphology, thermal stability and magnetic property of Fe3O4@SiO2-N-chrysin were analyzed using FTIR, FESEM, TEM, XRD, thermal analysis and VSM. The extraction efficiency of Fe3O4@SiO2-N-chrysin was analyzed using the batch wise method with flame atomic absorption spectrometry. Parameters such as the pH, the sample volume, the adsorption-desorption time, the concentration of the desorption solvent, the desorption volume, the interference effects and the regeneration of the adsorbent were optimized. It was determined that Cu(II) adsorption is highly pH-dependent, and a high recovery (98%) was achieved at a pH 6. The limit of detection (S/N=3), the limit of quantification (S/N=10), the preconcentration factor and the relative standard deviation for Cu(II) extraction were 0.3 ng mL( 1), 1 ng mL(-1), 100 and 1.9% (concentration=30 ng mL(-1), n=7), respectively. Excellent relative recoveries of 97-104% (%RSD<3.12) were achieved from samples from a spiked river, a lake and tap water. The MSPE method was also validated using certified reference materials SLRS-5 with good recovery (92.53%). PMID- 26653441 TI - Rapid detection of Escherichia coli O157:H7 and Salmonella Typhimurium in foods using an electrochemical immunosensor based on screen-printed interdigitated microelectrode and immunomagnetic separation. AB - Foodborne pathogens have continuously been a serious food safety issue and there is a growing demand for a rapid and sensitive method to screen the pathogens for on-line or in-field applications. Therefore, an impedimetric immunosensor based on the use of magnetic beads (MBs) for separation and a screen-printed interdigitated microelectrode (SP-IDME) for measurement was studied for the rapid detection of Escherichia coli O157:H7 and Salmonella Typhimurium in foods. Streptavidin coated MBs were functionalized with corresponding biotinylated antibodies (Ab) to capture the target bacteria. The glucose oxidase (GOx)-Ab conjugates were employed to label the MBs-Ab-cell complexes. The yielded MBs-Ab cell-Ab-GOx biomass was mixed with the glucose solution to trigger an enzymatic reaction which produced gluconic acid. This increased the ion strength of the solution, thus decreasing the impedance of the solution measured on the SP-IDME. Our results showed that the immunosensor was capable of specifically detecting E. coli O157:H7 and S. Typhimurium within the range of 10(2)-10(6) cfu ml(-1) in the pure culture samples. E. coli O157:H7 in ground beef and S. Typhimurium in chicken rinse water were also examined. The limits of detection (LODs) for the two bacteria in foods were 2.05*10(3) cfu g(-1) and 1.04*10(3) cfu ml(-1), respectively. This immunosensor required only a bare electrode to measure the impedance changes, and no surficial modification on the electrode was needed. It was low-cost, reproducible, easy-to-operate, and easy-to-preserve. All these merits demonstrated this immunosensor has great potential for the rapid and on site detection of pathogenic bacteria in foods. PMID- 26653442 TI - A label-free electrochemical immunosensor for hepatitis B based on hyaluronic acid-carbon nanotube hybrid film. AB - An electrochemical immunosensor developed for detection of antibodies to hepatitis B core protein (anti-HBc) is described. Anti-HBc is the earliest serological marker from hepatitis B virus (HBV) infection, remaining all life after contact with virus, being considered the most important marker for uses in screening of blood bank. A nanohybrid surface assembled onto a glassy carbon electrode consisting of amino carbon nanotubes recovered by hyaluronic acid was used as sensing platform to detect the anti-HBc. All the steps of electrode surface modification were characterized by Scanning Electronic Microscopy and extensively evaluated by electrochemical techniques. The electrode response was measured by direct anti-HBc antigen interactions by square wave voltammetry, dispensing uses of label or chemical mediators. Under optimal conditions, the anodic peak current which was proportional to the anti-HBs concentration. The immunosensor response was linear toward anti-HBc in concentrations up to 6 ng mL( 1), with a detection limit of 0.03 ng mL(-1). The linear range achieved was according to clinical level, indicating the immunosensor as promising tool for use as a criterion for blood bag disposal. The enhancement of the hyaluronic acid by carbon nanotube promoted an increase of charge electron transfer, besides a stable platform for HBc. PMID- 26653443 TI - Combining PLS regression with portable NIR spectroscopy to on-line monitor quality parameters in intact olives for determining optimal harvesting time. AB - This study presents a systematized method for predicting water content, fat content and free acidity in olive fruits by on-line NIR Spectroscopy combined with chemometric techniques (PCA, LDA and PLSR). Three cultivar varieties of Olea europaea - Hojiblanca cv., Picual cv. and Arbequina cv. - were monitored. Five olive cultivation areas of Southern Spain (Andalucia) and Southern Portugal (Alentejo) were studied in 2011 and 2012. 465 olive samples were collected during the ripening process (non-mature olives) and compared with other 203 samples of mature olives collected at the final ripening stage. NIR spectra were measured directly in the olive fruits in the wavelength region from 1000 to 2300 nm in reflectance mode. The reference analyses were performed on the olive paste by oven drying for the moisture, by mini-Soxhlet extraction for the fat content and by acid titration of the oil extracted from the olive paste. Calibrations and predictive models were developed by Partial Least Square Regression (PLSR) previous Principal Component and Linear Discriminant analyses (PCA and LDA) were employed as exploratory and clean-up tools of data sets. The final models obtained for the total samples showed acceptable statistics of prediction with R(2)=0.88, RMSEV%=4.88 and RMSEP%=4.98 for water content, R(2)=0.76, RMSECV%=19.5 and RMSEP%=20.0 for fat content and R(2)=0.83, RMSECV%=36.8 and RMSEP%=38.8 for free acidity. Regression coefficients were better for only one maturity state (ripe period) than for olive fruit with different composition (ripening period). All models obtained were applied to predict LQPs on a new set of samples with satisfactory results, a good prediction potential of the models. PMID- 26653444 TI - A novel reaction-based colorimetric and ratiometric fluorescent sensor for cyanide anion with a large emission shift and high selectivity. AB - A hybrid carbazole-hemicyanine dye (Cac) has been developed as a novel colorimetric and ratiometric fluorescent sensor for cyanide detection. Upon treatment with cyanide, Cac displayed a remarkable fluorescence ratiometric response, with the emission wavelength displaying a very large emission shift (214 nm). The detection of cyanide was performed via the nucleophilic addition of cyanide anion to the indolium group of the sensor, which resulted in the blocking of the intramolecular charge transfer (ICT) process in the sensor, inducing a ratiometric fluorescence change and simultaneously an obvious color change. Furthermore, competitive anions did not showed any significant changes both in color and emission intensity ratio (I381/I595), indicating the high selectivity of the sensor to CN(-). PMID- 26653445 TI - Simultaneous spectrophotometric determination of synthetic dyes in food samples after cloud point extraction using multiple response optimizations. AB - A sensitive cloud point extraction method for simultaneous determination of trace amounts of sunset yellow (SY), allura red (AR) and brilliant blue (BB) by spectrophotometry was developed. Experimental parameters such as Triton X-100 concentration, KCl concentration and initial pH on extraction efficiency of dyes were optimized using response surface methodology (RSM) with a Doehlert design. Experimental data were evaluated by applying RSM integrating a desirability function approach. The optimum condition for extraction efficiency of SY, AR and BB simultaneously were: Triton X-100 concentration 0.0635 mol L(-1), KCl concentration 0.11 mol L(-1) and pH 4 with maximum overall desirability D of 0.95. Correspondingly, the maximum extraction efficiency of SY, AR and BB were 100%, 92.23% and 95.69%, respectively. At optimal conditions, extraction efficiencies were 99.8%, 92.48% and 95.96% for SY, AR and BB, respectively. These values were only 0.2%, 0.25% and 0.27% different from the predicted values, suggesting that the desirability function approach with RSM was a useful technique for simultaneously dye extraction. Linear calibration curves were obtained in the range of 0.02-4 for SY, 0.025-2.5 for AR and 0.02-4 MUg mL(-1) for BB under optimum condition. Detection limit based on three times the standard deviation of the blank (3Sb) was 0.009, 0.01 and 0.007 MUg mL(-1) (n=10) for SY, AR and BB, respectively. The method was successfully used for the simultaneous determination of the dyes in different food samples. PMID- 26653446 TI - Study of nucleic acid-ligand interactions by capillary electrophoretic techniques: A review. AB - The understanding of nucleic acids-ligand (proteins, nucleic acids or various xenobiotics) interactions is of fundamental value, representing the basis of complex mechanisms that govern life. The development of improved therapeutic strategies, as well as the much expected breakthroughs in case of currently untreatable diseases often relies on the elucidation of such biomolecular interactions. Capillary electrophoresis (CE) is becoming an indispensable analytical tool in this field of study due to its high versatility, ease of method development, high separation efficiency, but most importantly due to its low sample and buffer volume requirements. Most often the availability of the compounds of interest is severely limited either by the complexity of the purification procedures or by the cost of their synthesis. Several reviews covering the investigation of protein-protein and protein-xenobiotics interactions by CE have been published in the recent literature; however none of them promotes the use of these techniques in the study of nucleic acid interactions. Therefore, various CE techniques applicable for such interaction studies are discussed in detail in the present review. The paper points out the particular features of these techniques with respect the estimation of the binding parameters, in analytical signal acquisition and data processing, as well as their current shortcomings and limitations. PMID- 26653447 TI - Highly selective colorimetric and fluorometric chemosensor for cyanide on silica gel and DMSO/H2O (7:3 v/v) mixed solvent and its imaging in living cells. AB - The chemosensor 2,3-bis((E)-((2-hydroxynaphthalen-1 yl)methylene)amino)maleonitrile (1) has been synthesized using 2-hydroxy-1 napthaldehyde and 2,3-diaminomaleonitrile and characterized. Sensor 1 exhibits selective binding with CN(-) in dimethyl sulfoxide (DMSO)/H2O (7:3 v/v) and DMSO/aqueous Tris (Tris(hydroxymethyl)aminomethane) buffer (7:3 v/v, 10 mM, pH 7.2) media with significant changes in its UV-visible and fluorescence spectra. Titration of 1-Zn(II) complex with CN(-) ion in DMSO/aqueous Tris buffer (7:3 v/v, 10 mM, pH 7.2) regenerates the free sensor 1, as supported by UV-visible spectra. (1)H NMR titration of 1 with CN(-) in (CD3)2SO confirms the hydrogen bonding interaction between the two OH groups of the former and the latter in bidentate manner. Sensor 1 impregnated on silica gel thin layer chromatography (TLC) strip followed by dipping in anion solutions in DMSO/H2O (7:3 v/v) generates yellow to red spectacular colour change with CN(-) ion selectively which can be exploited as potential tool for ready-made detection of toxic CN(-) ion in environmental and analytical chemistry. Similar visual change in colour for 1 is observed selectively with CN(-) also when both of them are taken in DMSO/H2O (7:3 v/v) solution. Sensor 1 is used as an imaging reagent for detection of the cellular uptake of CN(-) ion in Baby Hamster Kidney (BHK-21) cells. PMID- 26653448 TI - Employment of bromophenol red and bovine serum albumin as luminol signal co enhancer in chemiluminescent detection of sequence-specific DNA. AB - Bromophenol red, known as chemical indicator, was found to act as a novel potent signal enhancer of the peroxidase-catalyzed luminol-H2O2 chemiluminescent (CL) reaction. It was found interestingly that bovine serum albumin (BSA) played a role in the enhanced chemiluminescent reaction (ECR). The addition of 2.5 mg mL( 1) BSA into bromophenol red-enhance CL system showed 36 times stronger CL signal than that without addition of BSA. Mechanism study showed that the luminophors in the ECR were still 3-aminophthalate ion in an excited state (3-APA*). In addition, singlet oxygen ((1)O2) and hydroxyl radical ((?)OH) played a role in the ECR. The possible mechanism was discussed in the present study. The effect of pH, reaction time, and concentration of bromophenol red, BSA, luminol, and H2O2 on CL intensity of the peroxidase-catalyzed CL reaction was studied. The detection limit value (LOD) of HRP and streptavidin-modified HRP in the proposed ECR with bromophenol red and BSA was 0.20 ng mL(-1) and 0.05 ng mL(-1), respectively. This novel luminol-H2O2-HRP-bromophenol red-BSA CL system was applied to the CL detection of sequence-specific DNA based on a magnetic separation process. As low as 0.4 fmol of target DNA could be sensitively detected using the proposed CL system without any amplification process. The obtained results demonstrate very promising perspectives for using bromophenol red and BSA to improve the sensitivity of CL detection of sequence-specific DNA. In addition, this novel ECR system can also be generalized for CL immunoassay, CL western blotting, and so on. PMID- 26653449 TI - Silver and gold enhancement methods for lateral flow immunoassays. AB - Sensitivity is the main concern at the development of rapid test by lateral flow immunoassays. On the other hand, low limits of detection are often required at medical diagnostics and other field of analysis. To overcome this drawback, several enhancement protocols have been described. In this paper, we have selected different silver enhancement methods and one dual gold conjugation, and we critically compared the amplification produced when applied to a gold nanoparticle based lateral flow immunoassay for the detection of prostate specific antigen (PSA). The highest amplification was obtained by using an immersion method based on a solution of silver nitrate and hydroquinone/citrate buffer in proportion 1:1. Under these conditions, the system is capable of detecting PSA within 20 min at levels as low as 0.1 ng/mL, with a 3-fold sensitivity improvement. PMID- 26653450 TI - A graphitic carbon nitride based fluorescence resonance energy transfer detection of riboflavin. AB - Fluorescence resonance energy transfer (FRET), which occurs between two luminescent chromophores, can greatly improve the selectivity and sensitivity of a fluorescent assay when a ratiometric signaling with the fluorescence enhancement of the acceptor at the expense of the donor is adopted. In this study, a fluorescence ratiometric detection (FRD) of riboflavin (RF) has been made based on FRET, as the strong overlap occurred between the emission spectrum of graphitic carbon nitride (g-C3N4) and absorption spectrum of RF, in which g C3N4 acts as the energy donor and RF as the energy acceptor. With increasing concentration of RF, the fluorescence intensity of g-C3N4 emission at 444 nm decreased and the fluorescence peak at 523 nm for RF increased regularly, making the fluorescence intensity ratio of 523 nm to 444 nm linearly dependent on the concentration of RF in the range from 0.4 MUM to 10 MUM, giving a limit of the detection of 170 nM. This method can be used to quantify RF in complex systems such as milk and drink, showing that the novel FRET-based fluorescence ratiometric detection can enable an attractive assay platform for analytes of interest. PMID- 26653451 TI - Ion-imprinted silica adsorbent modified diffusive gradients in thin films technique: Tool for speciation analysis of free lead species. AB - A new diffusive gradients in thin films (DGT) device, using Pb(II) ion-imprinted silica (IIS) as the binding agents and commercial cellulose acetate dialysis (CAD) membrane as the diffusion layer (CAD/IIS-DGT), has been developed and evaluated for sampling and measurement of free Pb(II) species. The CAD/IIS-DGT devices were successfully applied to the measurement of free Pb(II) species in synthetic solutions, in natural freshwaters and in industrial wastewaters. The CAD/IIS-DGT provides reliable results over pH range of 4.5-6.5 and a wide range of ionic strength from 1.0*10(-3) to 0.7 mol L(-1). The concentrations of the free Pb(II) species in synthetic solution containing different concentrations of ligands measured by CAD/IIS-DGT showed a good agreement with the value measured by Pb-ion selective electrode. Field deployments of the CAD/IIS-DGT devices allowed accurate measurements of the concentrations of free Pb(II) species. PMID- 26653452 TI - Preconcentration of polar phenolic compounds from water samples and soil extract by liquid-phase microextraction and determination via liquid chromatography with ultraviolet detection. AB - This work proposes a liquid-phase microextraction (LPME) method to extract the highly polar compounds phenol (Ph), o-cresol (o-Cr), m-cresol (m-Cr), p-cresol (p Cr), and 2,4-dimethylphenol (2,4-DMP) from aqueous matrices. The first extraction step of the LPME method employed a common volumetric flask and n-octanol, and the second extraction step used NaOH as the acceptor phase. The optimized extraction conditions were 900 MUL of n-octanol as the extraction solvent, NaOH at 0.60 mol L(-1) as the acceptor phase, an extraction time of 5.0 min, HCl at 0.01 mol L(-1) and NaCl at 20.0% as the donor phase, and an extraction temperature of 20.0 degrees C. The analysis of 50.0 mL of aqueous sample, pretreated under the optimized LPME conditions, afforded a limit of detection (LOD) between 0.3 and 3.5 MUg L(-1), a limit of quantification (LOQ) between 1.2 and 11.6 MUg L(-1), and a linear range from 2.50 to 50.0 MUg L(-1) for Ph, o-Cr, m-Cr and p-Cr and from 12.5 to 250 MUg L(-1) for 2,4-DMP. The proposed LPME method was a successful sample preparation strategy, and allowed for precise and accurate quantification of polar phenolic compounds in aqueous matrices such as tap water, river water, groundwater, and seawater, and also in a soil extract. The recovery values ranged from 72.5% to 126.0%, and the relative standard deviation was between 0.3 and 11.5%. PMID- 26653453 TI - Anion-intercalated layered double hydroxides modified test strips for detection of heavy metal ions. AB - In this work, a novel approach for facile and rapid detection of heavy metal ions using anion-intercalated layered double hydroxides (LDHs) modified test strips is demonstrated. By intercalating Fe(CN)6(4-) or S(2-) anions into the interlayers of LDHs on the filter paper, various heavy metal ions can be easily detected based on the color change before and after reaction between the anions and the heavy metal ions. Upon the dropping of heavy metal ions solutions to the test strips, the colors of the test strips changed instantly, which can be easily observed by naked eyes. With the decrease of the concentration, the color depth changed obviously. The lowest detection concentration can be up to 1*10(-6) mol L(-1). Due to the easily intercalation of anions into the interlayer of the LDHs on test trips, this procedure provides a general method for the construction of LDHs modified test strips for detection of heavy metal ions. The stability of the prepared test strips is investigated. Furthermore, all the results were highly reproducible. The test strips may have potential applications in environmental monitoring fields. PMID- 26653454 TI - A sensitive surface-enhanced Raman scattering enzyme-catalyzed immunoassay of respiratory syncytial virus. AB - Respiratory viruses have become a major global health challenge which would benefit from advances in screening methods for early diagnosis. Respiratory syncytial virus (RSV) is one of the most important pathogen causing severe lower respiratory tract infections. Here we present a novel surface-enhanced Raman scattering (SERS) enzyme-catalyzed immunoassay of RSV by employing peroxidase substrate 3, 3'-5, 5'-tetramethylbenzidine (TMB) as Raman molecule. Horseradish peroxidase (HRP) attached to the detection antibody in a novel sandwich immunoassay catalyzes the oxidation of TMB by H2O2 to give a radical cation (TMB(+)), which could be easily adsorbed on the negatively charged surface of silver nanoparticles (AgNPs) through electrostatic interaction, inducing the aggregation of AgNPs and thus giving a strong SERS signal. A linear relationship was obtained between the Raman intensity and the amount of RSV in the range from 0.5 to 20 pg/mL, and the minimum detectable concentration of this SERS-based enzyme immunoassay was 0.05 pg/mL, which was 20 times lower than that found in the colorimetric method. PMID- 26653455 TI - Development of a cheap and accessible carbon fibers-in-poly(ether ether ketone) tube with high stability for online in-tube solid-phase microextraction. AB - Carbon fibers (CFs) are one kind of important industrial materials that can be obtained commercially at low price. Based on the high extraction efficiency of carbon sorbents, a cheap and accessible carbon fibers-in-poly(ether ether ketone) (PEEK) tube was developed for online in-tube solid-phase microextraction (SPME) method. Coupled to high performance liquid chromatography (HPLC), the CFs-in-tube SPME was applied to analyze eight polycyclic aromatic hydrocarbons (PAHs) in environmental aqueous samples. Extraction conditions (sampling rate, extraction time, methanol content) and desorption time were investigated for optimization of conditions. Under the optimum conditions, the CFs-in-tube SPME-HPLC method provided high extraction efficiency with enrichment factors up to 1748. Good linearity (0.05-50 MUg L(-1), 0.5-50 MUg L(-1)) and low detection limits (0.01 0.1 MUg L(-1)) were also obtained. The online analysis method was finally applied to determine several model PAHs analytes in real environmental aqueous samples. Some target analytes were detected and relative recoveries were in the range of 92.3-111%. Due to natural chemical stability of carbon fibers and PEEK tube, the CFs-in-tube device exhibited high resistance to organic solvent, acid and alkaline conditions. PMID- 26653456 TI - Development and application of a dispersive liquid-liquid microextraction method for the determination of tetracyclines in beef by liquid chromatography mass spectrometry. AB - A rapid, cost effective and environmentally friendly extraction method, based on dispersive liquid-liquid microextraction (DLLME) was developed for the determination of six tetracyclines in meat destined for human consumption. Meat extracts were analysed for tetracyclines using liquid chromatography tandem mass spectrometry (LC-MS/MS), a sensitive and selective analytical technique. Various factors influencing the pre-concentration of tetracyclines such as sample pH, type and volume of both disperser solvent and extraction solvent were optimized. Validation parameters such as calibration function, limit of detection (LOD), limit of quantification (LOQ), detection capability (CCalpha), decision limit (CCbeta), accuracy and precision were established according to Commission Decision 2002/657/EC. Linearity in the range of 25-200 ug kg(-1) was obtained with regression coefficients ranging from 0.9991 to 0.9998. Recoveries of spiked blank muscle samples at three levels (50, 100 and 150 ug kg(-1)) ranged from 80% to 105% and reproducibility was between 2% and 7%. LODs and LOQs ranged from 2.2 to 3.6 ug kg(-1) and from 7.4 to 11.5 ug kg(-1) respectively while CCalpha ranged from 105 to 111 ug kg(-1) and CCbeta ranged from 107 to 122 ug kg(-1). The proposed method compared well with the existing accepted dispersive solid phase extraction method and was successfully applied to the pre-concentration and determination of tetracyclines in meat samples. Eleven of the thirty bovine muscle samples obtained from local abattoirs and butcheries were found to contain residues of two tetracycline antibiotics (chlortetracycline and oxytetracycline), with oxytetracycline being the most detected. Concentration levels of the tetracycline residues detected in bovine muscle samples were lower (12.4 and 68.9 ug kg(-1)) than the stipulated European Union maximum residue level (MRL) of 100 ug kg(-1), hence the meat was fit for human consumption. From this work it can be concluded that the DLLME is indeed a greener sample preparation method and could be used as an alternative to dispersive solid phase microextraction (dSPE). PMID- 26653457 TI - Vibrational spectroscopic methods for the overall quality analysis of washing powders. AB - The aim of this study was to compare and evaluate the ability of near infrared- (NIR), Raman- and attenuated-total-reflection infrared (ATR-IR) spectroscopy as tools for the identification of washing powder brands as well as for an overall quantitative analysis of all ingredients of the analyzed laundry detergents. The laundry detergents used in this work were composed of 22 different ingredients. For this purpose, principal component analysis (PCA) cluster models and partial least-squares (PLS) regression models were developed and different data pre processing algorithms such as standard-normal-variate (SNV), multiplicative scatter correction (MSC), first derivative BCAP (db1), second derivative smoothing (ds2), smoothing Savitzky Golay 9 points (sg9) as well as different normalization procedures such as normalization between 0 and 1 (n01), normalization unit length (nle) or normalization by closure (ncl) were applied to reduce the influence of systematic disturbances. The performance of the methods was evaluated by comparison of the number of principal components (PCs), regression coefficient (r), Bias, Standard error of prediction (SEP), ratio performance deviation (RPD) and range error ratio (RER) for each calibration model. For each of the 22 ingredients separate calibration models were developed. Raman spectroscopy was suitable for the analysis of only two ingredients (dye transfer inhibitor 1 and surfactant 6) and it was not possible to record all Raman spectra due to high fluorescence. NIR and ATR-IR are powerful methods to analyze washing detergents with low numbers of PCs being necessary, regression coefficients of only little below 1, small Biases and SEPs compared to the range and high RPDs and RERs. PMID- 26653458 TI - A comparison of sorptive extraction techniques coupled to a new quantitative, sensitive, high throughput GC-MS/MS method for methoxypyrazine analysis in wine. AB - Methoxypyrazines are volatile compounds found in plants, microbes, and insects that have potent vegetal and earthy aromas. With sensory detection thresholds in the low ng L(-1) range, modest concentrations of these compounds can profoundly impact the aroma quality of foods and beverages, and high levels can lead to consumer rejection. The wine industry routinely analyzes the most prevalent methoxypyrazine, 2-isobutyl-3-methoxypyrazine (IBMP), to aid in harvest decisions, since concentrations decrease during berry ripening. In addition to IBMP, three other methoxypyrazines IPMP (2-isopropyl-3-methoxypyrazine), SBMP (2 sec-butyl-3-methoxypyrazine), and EMP (2-ethyl-3-methoxypyrazine) have been identified in grapes and/or wine and can impact aroma quality. Despite their routine analysis in the wine industry (mostly IBMP), accurate methoxypyrazine quantitation is hindered by two major challenges: sensitivity and resolution. With extremely low sensory detection thresholds (~8-15 ng L(-1) in wine for IBMP), highly sensitive analytical methods to quantify methoxypyrazines at trace levels are necessary. Here we were able to achieve resolution of IBMP as well as IPMP, EMP, and SBMP from co-eluting compounds using one-dimensional chromatography coupled to positive chemical ionization tandem mass spectrometry. Three extraction techniques HS-SPME (headspace-solid phase microextraction), SBSE (stirbar sorptive extraction), and HSSE (headspace sorptive extraction) were validated and compared. A 30 min extraction time was used for HS-SPME and SBSE extraction techniques, while 120 min was necessary to achieve sufficient sensitivity for HSSE extractions. All extraction methods have limits of quantitation (LOQ) at or below 1 ng L(-1) for all four methoxypyrazines analyzed, i.e., LOQ's at or below reported sensory detection limits in wine. The method is high throughput, with resolution of all compounds possible with a relatively rapid 27 min GC oven program. PMID- 26653459 TI - Comparison of three development approaches for Stationary Phase Optimised Selectivity Liquid Chromatography based screening methods Part II: A group of structural analogues (PDE-5 inhibitors in food supplements). AB - Three approaches for the development of a screening method to detect adulterated dietary supplements, based on Stationary Phase Optimised Selectivity Liquid Chromatography were compared for their easiness/speed of development and the performance of the optimal method obtained. This comparison was performed for a heterogeneous group of molecules, i.e. slimming agents (Part I) and a group of structural analogues, i.e. PDE-5 inhibitors (Part II). The first approach makes use of primary runs at one isocratic level, the second of primary runs in gradient mode and the third of primary runs at three isocratic levels to calculate the optimal combination of segments of stationary phases. In each approach the selection of the stationary phase was followed by a gradient optimisation. For the PDE-5 inhibitors, the group of structural analogues, only the method obtained with the third approach was able to differentiate between all the molecules in the development set. Although not all molecules are baseline separated, the method allows the identification of the selected adulterants in dietary supplements using only diode array detection. Though, due to the mobile phases used, the method could also be coupled to mass spectrometry. The method was validated for its selectivity following the guidelines as described for the screening of pesticide residues and residues of veterinary medicines in food. PMID- 26653460 TI - Facile fabrication of ionic liquid doped polycarbazole coating for the headspace solid-phase microextraction of some environmental pollutants. AB - A novel polycarbazole (PCz)-ionic liquid (IL, i.e. 1-hydroxyethyl-3 methylimidazolium bis[(trifluoromethyl)sulfonyl]imide, [HOEMIm][NTf2]) composite coating (PCz-IL) was fabricated by electrodeposition. The IL could facilitate the electrodeposition of poor-conductive PCz and a more porous coating was obtained. The composite coating exhibited enhanced extraction capacity for some environmental pollutants (i.e. o-chlorotoluene, p-bromotoluene, o-nitrotoluene, m nitrotoluene, p-nitrotoluene), as they could interact through pi-pi and hydrophobic interactions. Compared with [HOEMIm][NTf2] coated fiber, some other PCz-IL fibers (here IL=1-hydroxyethyl-3-methylimidazolium hexafluorophosphate and 1-methyl-3-octylimidazolium hexafluorophosphate) and commercial fibers (i.e. polydimethylsiloxane and polyacrylate), the PCz-IL fiber showed better performance. It was used for the determination of the environmental pollutants by coupling with gas chromatography, the limits of detection were 47.8-65.9 ng L(-1) under the optimized conditions and the linear ranges were 0.1-500 MUg L(-1) with correlation coefficients above 0.9947 for different compounds. The relative standard deviations (RSDs) were 3.4-4.6% for five successive extractions with single fiber, and the RSDs for inter-fiber were 6.5-10.4% (n=5). The fiber was successfully applied to the detection of real samples and the recoveries for standards added were 88.6-108.8% with RSDs below 9.7%. PMID- 26653461 TI - Electrochemical determination of bisphenol A at ordered mesoporous carbon modified nano-carbon ionic liquid paste electrode. AB - A simple bisphenol A (BPA) sensor was successfully fabricated based on ordered mesoporous carbon CMK-3 modified nano-carbon ionic liquid paste electrode (CMK 3/nano-CILPE). The nanostructure of CMK-3 and the surface morphologies of modified electrodes were characterized by transmission electron microscopy (TEM) and scanning electron microscopy (SEM). Electrochemical properties of the fabricated electrodes were investigated by cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS). The fabricated sensor displayed excellent electroactivity towards bisphenol A using linear sweep voltammetry (LSV). Experimental conditions influencing the analytical performance of the modified electrode were optimized. Under optimal conditions, the oxidation peak current was proportional to BPA concentration in the range from 0.2 MUM to 150 MUM with a detection limit of 0.05 MUM (S/N=3). This method was successfully used for determination of BPA leached from drinking bottle and plastic bag with good recoveries. PMID- 26653462 TI - Restricted access supramolecular solvents for removal of matrix-induced ionization effects in mass spectrometry: Application to the determination of Fusarium toxins in cereals. AB - Ion suppression/enhancement caused by matrix effects continues being a major concern in liquid chromatography-mass spectrometry (LC-MS). This research explores the ability of a supramolecular solvent (SUPRAS) made up of inverted hexagonal aggregates of oleic acid to behave as a liquid with restricted access properties (SUPRAS-RAM). Fusarium toxins in cereals were extracted with the oleic acid-based SUPRAS-RAM prior to their quantification by LC-electrospray ionization (ESI)-ion trap-MS (LC-ESI-IT-MS) in order to investigate the capability of this solvent to remove or reduce ionization suppression and/or enhancement in the analysis of complex samples by MS. The method involved the vortex-shaking of 300 mg of cereal with 600 MUL of the SUPRAS-RAM for 15 min, centrifugation for separation of the supernatant and quantitation by LC-ESI-IT-MS. Macromolecules such as proteins and carbohydrates were excluded from extraction by chemical and physical mechanisms. Extraction of analytes and sample clean-up were thus carried out in a single step. No evaporation of the extracts was needed. Method detection limits for the legislated Fusarium toxins [i.e. deoxynivalenol (DON), zearalenone (ZEA) and fumonisins B1 (FB1) and B2 (FB2)] were 15 MUg kg(-1) for DON and ZEA and 8 MUg kg(-1) for fumonisins. These values were far below the maximum levels set by the European Commission for these toxins in foodstuffs. The method was successfully applied to the determination of these toxins in wheat and maize harvested in the South of Spain. No contamination of Fusarium toxins was found in samples at detectable levels. Recoveries in spiked samples were in the range 87 105%, with relative standard deviations between 1 and 7%. The use of the oleic acid-based SUPRAS-RAM effectively removed matrix interferences and allowed reliable quantitation of Fusarium toxins in cereals using solvent-based calibration. PMID- 26653463 TI - New insights into side effect of solvents on the aggregation of human islet amyloid polypeptide 11-20. AB - The formation of highly ordered fibrils for the human islet amyloid polypeptide (hIAPP) is considered as one of the precipitating factors of type 2 diabetes mellitus. In this study, an emerging new approach microscale thermophoresis and conventional ThT fluorescence assay were utilized to investigate the aggregation behavior of hIAPP(11-20), giving a new insight of the solvent effect on the aggregation of hIAPP(11-20). hIAPP(11-20) displayed different aggregation behaviors in various buffers, revealing that hIAPP(11-20) not only self aggregates but also binds to solvent components. hIAPP(11-20) had a higher binding affinity for Tris than other selected buffers because multiple hydrogen bonds form, resulting in weaker self-aggregation of hIAPP(11-20) at the early stage of aggregation and prolonging the fibril formation process. hIAPP(11-20) displayed similar self-aggregation in both HEPES and pure water. Negatively charged phosphate ions in the PBS solution 'neutralize' the charges carried by hIAPP(11-20) itself to some extent, causing rapid aggregation of hIAPP(11-20), and leading to a shorter fibrillation process of hIAPP(11-20). These results revealed that solvents contribute to the aggregation of hIAPP(11-20) and demonstrated the affect of solvents on the activity of biomolecules. Additionally, as a new technique, microscale thermophoresis offers a powerful and promising approach to study the early stages of aggregation of peptides or proteins. PMID- 26653464 TI - Preparation of C18-functionalized magnetic polydopamine microspheres for the enrichment and analysis of alkylphenols in water samples. AB - In this work, C18-functionalized magnetic polydopamine microspheres (Fe3O4@PDA@C18) were successfully synthesized and applied to the analysis of alkylphenols in water samples. The magnetic Fe3O4 particles coated with hydrophilic surface were synthesized via a solvothermal reaction and the self polymerization of dopamine. And then the C18 groups were fabricated by a silylanization method. Benefit from the merits of Fe3O4 particles, polydopamine coating and C18 groups, the Fe3O4@PDA@C18 material possessed several properties of super magnetic responsiviness, good water dispersibility, pi-electron system and hydrophobic C18 groups. Thus, the materials had great potential to be developed as the adsorbent for the magnetic solid-phase extraction (MSPE) technique. Here, we selected three kinds of alkylphenols (4-tert-octylphenol, 4-n nonylphenol, 4-n-octylphenol) to be the target analyst for evaluating the performance of the prepared material. In this study, various extraction parameters were investigated and optimized, such as pH values of water sample solution, amount of adsorbents, adsorption and desorption time, the species of desorption solution. Meanwhile, the method validations were studied, including linearity, limit of detection and method precision. From the results, Fe3O4@PDA@C18 composites were successfully applied as the adsorbents for the extraction of alkylphenols in water samples. The proposed material provided an approach for a simple, rapid magnetic solid-phase extraction for hydrophobic compounds in environmental samples. PMID- 26653465 TI - Graphene oxide as sensitive layer in Love-wave surface acoustic wave sensors for the detection of chemical warfare agent simulants. AB - A Love-wave device with graphene oxide (GO) as sensitive layer has been developed for the detection of chemical warfare agent (CWA) simulants. Sensitive films were fabricated by airbrushing GO dispersions onto Love-wave devices. The resulting Love-wave sensors detected very low CWA simulant concentrations in synthetic air at room temperature (as low as 0.2 ppm for dimethyl-methylphosphonate, DMMP, a simulant of sarin nerve gas, and 0.75 ppm for dipropylene glycol monomethyl ether, DPGME, a simulant of nitrogen mustard). High responses to DMMP and DPGME were obtained with sensitivities of 3087 and 760 Hz/ppm respectively. Very low limit of detection (LOD) values (9 and 40 ppb for DMMP and DPGME, respectively) were calculated from the achieved experimental data. The sensor exhibited outstanding sensitivity, good linearity and repeatability to all simulants tested. The detection mechanism is here explained in terms of hydrogen bonding formation between the tested CWA simulants and GO. PMID- 26653466 TI - Rapid determination of 88 veterinary drug residues in milk using automated TurborFlow online clean-up mode coupled to liquid chromatography-tandem mass spectrometry. AB - A novel method based on TurborFlow online solid phase extraction (SPE) combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS) has been established for simultaneous screening and confirmation of 88 wide-range veterinary drugs belonging to eight families (20 sulfonamides, 7 macrolides, 15 quinolones, 8 penicillins, 13 benzimidazoles, 4 tetracyclines, 2 sedatives, and 19 hormones) in milk. The preparation method consists of sample dilution and ultrasonic extraction, followed by an automated turbulent flow cyclone chromatography sample clean-up system. The detection was achieved in selected reaction monitoring mode (SRM). The total run time was within 39 min, including automated extraction, analytical chromatography and re-equilibration of the turboflow system. The optimization of different experimental parameters including extraction, purification, separation, and detection were evaluated separately in this study. The developed method was validated and good performing characteristics were obtained. The linear regression coefficients (R(2)) of matrix-match calibration standard curves established for quantification were higher than 0.9930. The limits of detection (LOD) were in the range of 0.2-2.0 MUg/kg given by signal-noise ratio >=3 (S/N) and the limits of quantification (LOQ, S/N>=10) ranged between 0.5 MUg/kg and 10 MUg/kg. Average recoveries of spiked target compounds with different levels were between 63.1% and 117.4%, with percentage relative standard deviations (RSD) in the range of 3.3-17.6%. The results indicated that the developed method has great potential for the routine laboratory analysis of large numbers of samples on measuring different classes of compounds. In comparison to traditional procedures, the automated sample clean-up ensures rapid, effective, sensitive analyses of veterinary drugs in milk. PMID- 26653467 TI - Facile electrochemical method and corresponding automated instrument for the detection of furfural in insulation oil. AB - Determining the concentration of furfural contained in the insulation oil of a transformer has been established as a method to evaluate the health status of the transformer. However, the detection of furfural involves the employment of expensive instruments and/or time-consuming laboratorial operations. In this paper, we proposed a convenient electrochemical method to make the detection. The quantification of furfural was realized by extraction of furfural from oil phase to aqueous phase followed by reductive detection of furfural with differential pulse voltammetry (DPV) at a mercury electrode. This method is very sensitive and the limit of detection, corresponding to furfural contained in oil, is estimated to be 0.03 MUg g(-1). Furthermore, excellent linearity can be obtained in the range of 0-10 MUg g(-1). These features make the method very suitable for the determination of furfural in real situation. A fully automated instrument that can perform the operations of extraction and detection was developed, and this instrument enables the whole measurement to be finished within eight minutes. The methodology and the instrument were tested with real samples, and very favorable agreement between results obtained with this instrument and HPLC indicates that the proposed method along with instrument can be employed as a facile tool to diagnose the health status of aged transformers. PMID- 26653468 TI - Determination of gold and silver in geological samples by focused infrared digestion: A re-investigation of aqua regia digestion. AB - Focused infrared radiation-based digestions, for the determination of gold and silver, can be achieved in a timeframe as short as 10-15 min, making it an attractive candidate technology for the mining industry, where very large numbers of samples are analyzed on a daily basis. An investigation was carried out into gold and silver dissolution chemistry from geological samples using this novel digestion technique. This study investigated in-depth the issue of low recoveries of gold from aqua regia (AR) digestions, reported by a number of researchers. Conventional AR digestions consistently delivered gold recoveries in a range of 69-80% of the certified values for the four certified reference materials (CRM) employed (CCU-1d, SN26, OREAS 62c, and AMiS 0274), while silver recoveries were satisfactory. By gradually shifting the HCl:HNO3 ratio (v/v) from 3:1 to a reversed 1:3 ratio, recoveries of gold and silver exhibited inverse trends. At a HCl:HNO3 ratio of 1:3, complete recovery of gold was achieved with excellent reproducibility in all CRMs. Meanwhile, silver recoveries plunged significantly at this ratio in samples with higher silver concentrations. Silver values were recovered, however, when the silver was re-solubilized by adding a small volume of concentrated HCl to the cooled reverse aqua regia digests. Recoveries of base metals, such as Fe and Cu, were satisfactory throughout and were much less sensitive to changes in the digestion medium. Using four CRMs and five real-world gold/silver containing samples, the utility of the proposed reverse aqua regia was systematically studied. The uncomplicated nature of the digestion methods reported here, that are fast, effective and inexpensive, may be useful to analysts developing/optimizing their methods for the rapid determination of Au and Ag in a variety of mineral phases, particularly where rapid results are desirable, such as in prospecting and mine development. PMID- 26653469 TI - Poly(amidoamine) (PAMAM): An emerging material for electrochemical bio(sensing) applications. AB - Poly(amidoamine) (PAMAM) dendrimers have received attention due to their large surface areas with high concentration of functional end groups to bind biological material. They are monodisperse and hyper-branched polymers which include active functional groups outside its surface. These functional groups have been used for immobilizing the biorecognition molecules. They act as bioconjugating reagents and they have various applications in the fields of chemical and biochemical biosensors. Electrochemical techniques (amperometric, impedimetric, potentiometric, electrochemiluminescence) are useful for the determination of target molecules, with high sensitivity and selectivity. Dendrimer-modified enzyme biosensors, DNA biosensors, immunosensors and chemical sensors have been fabricated by using PAMAM dendrimer. This review provides a brief description of PAMAM dendrimers and its applications in biosensors and sensors. These sensors' limit of detection values are also compared in detail. Also this is the first review that assesses PAMAM dendrimers from the point of its usability in biosensor and sensor technologies. PMID- 26653470 TI - Designed synthesis of carbon-functional magnetic graphene mesoporous silica materials using polydopamine as carbon precursor for the selective enrichment of N-linked glycan. AB - Glycosylation, which has been confirmed to be associated with many diseases, is an important protein post-translation modification. Taking into account the low abundant of glycan, the purification of complex biological samples is considered to be very significant before mass spectrometry detection. In this work, carbon functionalized magnetic graphene /mesoporous silica materials (C-Mag G@mSiO2 materials) with high content of carbon were designed and synthesized by using polydopamine as carbon precursor. Taking advantage of the special interaction between carbon and glycan, C-Mag G@mSiO2 materials were successfully applied to enrich N-linked glycans in different complex samples, such as standard glycoprotein digestion, the mixture of standard glycoprotein digestion, glycoprotein and non-glycoprotein, and human serum. PMID- 26653472 TI - Matrix-free analysis of selected benzodiazepines in human serum samples using alternating trilinear decomposition modeling of fast liquid chromatography diode array detection data. AB - This paper describes the development and validation of a simple and efficient bioanalytical procedure for simultaneous determination of alprazolam, clonazepam, diazepam in human serum samples using high performance liquid chromatography with photodiode-array detection, regarding a fast elution methodology in 4 min. Briefly, this method consists of a simple liquid extraction step of serum samples followed by HPLC analysis on a C18 column. After confirming the absence of matrix effect, an external standard methodology has been applied for quantification purposes. Due to the presence of serum endogenous components as uncalibrated components in the sample, the second-order calibration based on alternating trilinear decomposition has been applied on a set of absorbance matrices collected as a function of retention time and wavelengths. Acceptable resolution and quantification results were achieved in the presence of matrix interferences and the second-order advantage was fully exploited. The average recoveries for alprazolam, clonazepam and diazepam were 89.1%, 96.3% and 94.7% and relative standard deviation values for intra- and inter-day precision were equal or lower than 8.1% and 9.4%, respectively. The developed method enabled us to determine the analytes in the various serum samples in the presence of overlapped profiles, while keeping experimental time and extraction step at the minimum. PMID- 26653471 TI - Determination of high-molecular weight polycyclic aromatic hydrocarbons in high performance liquid chromatography fractions of coal tar standard reference material 1597a via solid-phase nanoextraction and laser-excited time-resolved Shpol'skii spectroscopy. AB - This article presents an alternative approach for the analysis of high molecular weight - polycyclic aromatic hydrocarbons (HMW-PAHs) with molecular mass 302 Da in complex environmental samples. This is not a trivial task due to the large number of molecular mass 302 Da isomers with very similar chromatographic elution times and similar, possibly even virtually identical, mass fragmentation patterns. The method presented here is based on 4.2K laser-excited time-resolved Shpol'skii spectroscopy, a high resolution spectroscopic technique with the appropriate selectivity for the unambiguous determination of PAHs with the same molecular mass. The potential of this approach is demonstrated here with the analysis of a coal tar standard reference material (SRM) 1597a. Liquid chromatography fractions were submitted to the spectroscopic analysis of five targeted isomers, namely dibenzo[a,l]pyrene, dibenzo[a,e]pyrene, dibenzo[a,i]pyrene, naphtho[2,3-a]pyrene and dibenzo[a,h]pyrene. Prior to analyte determination, the liquid chromatographic fractions were pre-concentrated with gold nanoparticles. Complete analysis was possible with microliters of chromatographic fractions and organic solvents. The limits of detection varied from 0.05 (dibenzo[a,l]pyrene) to 0.24 ug L(-1) (dibenzo[a,e]pyrene). The excellent analytical figures of merit associated to its non-destructive nature, which provides ample opportunity for further analysis with other instrumental methods, makes this approach an attractive alternative for the determination of PAH isomers in complex environmental samples. PMID- 26653473 TI - A simple liquid extraction protocol for overcoming the ion suppression of triacylglycerols by phospholipids in liquid chromatography mass spectrometry studies. AB - It is well-known that triacylglycerol (TAG) ions are suppressed by phospholipid (PL) ions in regiospecific analysis of TAG by mass spectrometry (MS). Hence, it is essential to remove the PL during sample preparation prior to MS analysis. The present article proposes a cost-effective liquid-liquid extraction (LLE) method to remove PL from TAG in different kinds of biological samples by using methanol, hexane and water. High performance thin layer chromatography confirmed the lack of PL in krill oil and salmon liver samples, submitted to the proposed LLE protocol, and liquid chromatography tandem MS confirmed that the identified TAG ions were highly enhanced after implementing the LLE procedure. PMID- 26653474 TI - Determination of reduced sulfur compounds in air samples for the monitoring of malodor caused by landfills. AB - A reliable method for determining malodorous reduced sulfur compounds (RSC) in atmospheric samples has been developed. The method uses an activated coconut solid-phase sorbent for active sampling, hexane as desorption solvent, and gas chromatography-mass spectrometry (GC-MS) technique for specific and sensitive separation-detection. The compounds analyzed were hydrogen sulfide, ethyl mercaptan, dimethyl sulfide, carbon disulfide, butyl mercaptan and dimethyl disulfide. Recovery efficiency varied between 75% and 97% and no detectable losses were observed during storage at -20 degrees C. Satisfactory analytical parameters were reported, such as good linearity (r(2)>0.98), low detection limits (0.6-59 pg m(-3)), adequate repeatability (9%) and reproducibility (17%), and fast GC-MS analysis (<6.5 min). The accurate determination of RSCs, free of interferences from atmospheric components, such as ozone or water was demonstrated. The method has been applied to analyze the composition of environmental air close to three landfills processing urban and industrial solid wastes. The results indicated that hydrogen sulfide and ethyl mercaptan were the main molecules responsible of malodor phenomenon in the study areas. PMID- 26653475 TI - Calibration free concentration analysis by surface plasmon resonance in a capture mode. AB - Surface plasmon resonance (SPR) is the gold standard for determining rate and equilibrium constants of bimolecular complexes. Accuracy of these parameters depends on the correct determination of the concentration of the injected analyte. Calibration free concentration analysis (CFCA) has been developed to overcome the limitation of measuring protein concentrations spectroscopically, which may overestimate the fraction of the protein that really binds to the immobilized ligand, i.e. the active concentration. In this work, we demonstrate that CFCA can also be implemented in a capture format for measuring active concentrations. Capture CFCA (CCFCA) was first validated by measuring the concentration of a HLA-B*44:02 antigen solution. The active concentration of this molecule determined by CCFCA was similar to that obtained by covalent CFCA. CCFCA was then used to determine the concentration of the W6/32 pan class I HLA monoclonal antibody over three different HLA molecules captured by another specific antibody. This could not have been performed by covalent CFCA because immobilized HLA molecules cannot withstand regeneration. By exploring different capture levels we also show that CCFCA gives consistent results even at low capture levels. Knowing the active concentration of W6/32, we then determined the rate and equilibrium constants of W6/32-HLA complexes on the same flow cell. CCFCA is of general use for measuring active concentrations and of great interest for analytes recognizing ligands that cannot be covalently immobilized on sensor chips. The capture mode also allows determining the kinetic constants of multiple analyte-ligand complexes on the same flow cell. This increases experiments throughput and reduces sensor chip consumption. PMID- 26653476 TI - Optimisation and validation of a HS-SPME-GC-IT/MS method for analysis of carbonyl volatile compounds as biomarkers in human urine: Application in a pilot study to discriminate individuals with smoking habits. AB - A new and simple analytical approach consisting of an automated headspace solid phase microextraction (HS-SPME) sampler coupled to gas chromatography-ion trap/mass spectrometry detection (GC-IT/MS) with a prior derivatization step with O-(2,3,4,5,6-pentafluorobenzyl)hydroxylamine hydrochloride (PFBHA) was developed to detect volatile carbonyl metabolites with low molecular weights in human urine. A central composite design (CCD) was used to optimise the PFBHA concentration and extraction conditions that affect the efficiency of the SPME procedure. With a sample volume of 1 mL, optimal conditions were achieved by adding 300 mg/L of PFBHA and allowing the sample to equilibrate for 6 min at 62 degrees C and then extracting the samples for 51 min at the same temperature, using a divinylbenzene/polydimethylsiloxane (DVB/PDMS) fibre. The method allowed the simultaneous identification and quantification of 44 carbonyl compounds consisting of aldehydes, dialdehydes, heterocyclic aldehydes and ketones. The method was validated with regards to the linearity, inter- and intra-day precision and accuracy. The detection limits ranged from 0.009 to 0.942 ng/mL, except for 4-hydroxy-2-nonenal (15 ng/mL), and the quantification limits varied from 0.029 to 1.66 ng/mL, except for butanal (2.78 ng/mL), 2-butanone (2.67 ng/mL), 4-heptanone (3.14 ng/mL) and 4-hydroxy-2-nonenal (50.0 ng/mL). The method accuracy was satisfactory, with recoveries ranging from 90 to 107%. The proof of applicability of the methodology was performed in a pilot target analysis of urine samples obtained from 18 healthy smokers and 18 healthy non-smokers (control group). Chemometric supervised analysis was performed using the volatile patterns acquired for these samples and clearly showed the potential of the volatile carbonyl profiles to discriminate urine from smoker and non-smoker subjects. 5-Methyl-2-furfural (p<0.0001), 2-methylpropanal, nonanal and 2 methylbutanal (p<0.05) were identified as potentially useful biomarkers to identify smoking habits. PMID- 26653477 TI - Determination of the isomeric forms proportion of fluorogenic naphthalene-2,3 dicarboxaldehyde in a binary mixture of water:methanol using electrochemical methods. AB - The electrochemical response of the fluorogenic label naphthalene-2,3 dicarboxyaldehyde (NDA) in a binary mixture of water/methanol was characterized with cyclic voltammetry (CV) and differential pulse voltammetry (DPV) electrochemical techniques. Naphthalene-2,3-dicarboxyaldehyde does exist in three isomeric forms in aqueous solution: the unhydrated dialdehyde (DA), the acyclic monohydrated (MA) and the cyclic hemiacetal (HAC). The study underlines that the proportion of each of them varies according to the working pH. At low and high pH, the dialdehyde form is in larger proportion than the acyclic monohydrated form. Conversely at intermediate pH, the concentration of the acyclic form is in greater proportion than the dialdehyde form. These results allowed us to determine the optimal pH of 9 for which the labeling of biomolecules could be more efficient due to the base catalyzed regeneration of the unhydrated form. At this pH, the data processing from the analysis of measured currents and estimation of diffusion coefficients of each form according to the semi-empirical models of Wilke-Chang, Scheibel, Reddy-Doraiswamy and Lusis-Ratcliff allowed us to obtain the concentration of dialdehyde (0.28 mM), acyclic monohydrated (0.57 mM) and cyclic hemiacetal monohydrated (0.15 mM) forms starting from 1mM naphthalene-2,3-dicarboxyaldehyde. PMID- 26653478 TI - Rapid amperometric detection of trace metals by inhibition of an ultrathin polypyrrole-based glucose biosensor. AB - A sensitive and reliable inhibitive amperometric glucose biosensor is described for rapid trace metal determination. The biosensor utilises a conductive ultrathin (55 nm thick) polypyrrole (PPy) film for entrapment of glucose oxidase (GOx) to permit rapid inhibition of GOx activity in the ultrathin film upon exposure to trace metals, resulting in reduced glucose amperometric response. The biosensor demonstrates a relatively fast response time of 20s and does not require incubation. Furthermore, a complete recovery of GOx activity in the ultrathin PPy-GOx biosensor is quickly achieved by washing in 2mM EDTA for only 10s. The minimum detectable concentrations achieved with the biosensor for Hg(2+), Cu(2+), Pb(2+) and Cd(2+) by inhibitive amperometric detection are 0.48, 1.5, 1.6 and 4.0 uM, respectively. Also, suitable linear concentration ranges were achieved from 0.48-3.3 uM for Hg(2+), 1.5-10 uM for Cu(2+), 1.6-7.7 uM for Pb(2+) and 4-26 uM for Cd(2+). The use of Dixon and Cornish-Bowden plots revealed that the suppressive effects observed with Hg(2+) and Cu(2+) were via non competitive inhibition, while those of Pb(2+) and Cd(2+) were due to mixed and competitive inhibition. The stronger inhibition exhibited by the trace metals on GOx activity in the ultrathin PPy-GOx film was also confirmed by the low inhibition constant obtained from this analysis. The biosensor was successfully applied to the determination of trace metals in tap water samples. PMID- 26653479 TI - Graphene oxide vs. reduced graphene oxide as carbon support in porphyrin peroxidase biomimetic nanomaterials. AB - The paper describes the preparation of supramolecular assemblies of tetrapyridylporphyrin (TPyP) and its metallic complexes with graphene oxide (GO) and thermally reduced graphene oxide (TRGO). The two carbon supports are introducing different characteristics in the absorption spectra of the investigated nanocomposites. Raman spectroscopy shows that the absorption of iron tetrapyridylporphyrin is more efficient on GO than TRGO, suggesting that oxygen functionalities are involved in the non-covalent interaction between the iron porphyrin and graphene. The biomimetic peroxidase activity is investigated and the two iron-containing composites exhibit a better catalytic activity than each component of the assembly, and their cobalt and manganese homologues, respectively. The main advantages of this work include the demonstration of graphene oxide as a very good support for graphene-based nanomaterials with peroxidase-like activity (K(M)=0.292 mM), the catalytic activity being observed even with very small amounts of porphyrins (the TPyP:graphene ratio=1:50). Its potential application in the detection of lipophilic antioxidants (vitamin E can be measured in the 10(-5)-10(-4) M range) is also shown. PMID- 26653480 TI - Comparison of three development approaches for Stationary Phase Optimised Selectivity Liquid Chromatography based screening methods Part I: A heterogeneous group of molecules (slimming agents in food supplements). AB - Three approaches for the development of a screening method to detect adulterated dietary supplement, based on Stationary Phase Optimised Selectivity Liquid Chromatography were compared for their easiness/speed of development and the performance of the optimal method obtained. This comparison was performed for a heterogeneous group of molecules, i.e. slimming agents (Part I) and a group of structural analogues, i.e. PDE-5 inhibitors (Part II). The first approach makes use of primary runs at one isocratic level, the second of primary runs in gradient mode and the third of primary runs at three isocratic levels to calculate the optimal combination of segments of stationary phases. In each approach the selection of the stationary phase was followed by a gradient optimisation. For the slimming agents, the heterogeneous group of molecules, the method obtained with the first approach was selected as optimal, based on the speed of development and the performance of the method. The method shows a good separation of the compounds, allowing the screening to be performed with diode array detection, and is fully compatible with mass spectrometry. The method was validated for its selectivity following the guidelines as described for the screening of pesticide residues and residues of veterinary medicines in food. PMID- 26653481 TI - Fast separation and analysis of reduced monoclonal antibodies with capillary zone electrophoresis coupled to mass spectrometry. AB - Capillary zone electrophoresis-electrospray ionization-mass spectrometry (CZE-ESI MS) was used for analysis of reduced antibodies. We first developed a simple protocol to condition commercial linear-polyacrylamide coated capillaries for use in top-down proteomics. We then suspended reduced antibodies in a solution of 35% acetic acid, 50% acetonitrile in water. Heavy and light chains were baseline resolved within 10 min and with 3-30 ug/mL detection limits using a 0.1% aqueous formic acid background electrolyte. Quintuplicate runs of a two-antibody mixture produced relative standard deviations of ~1% in migration time and 10% in peak amplitudes. Resolution was further improved for the two-antibody mixture by using 5% acetic acid as the background electrolyte, highlighting the potential of capillary electrophoresis-mass spectrometry for analysis of antibody mixtures. PMID- 26653482 TI - Method for determination of levoglucosan in snow and ice at trace concentration levels using ultra-performance liquid chromatography coupled with triple quadrupole mass spectrometry. AB - A method is developed for determination of levoglucosan at trace concentration levels in complex matrices of snow and ice samples. This method uses an injection mixture comprising acetonitrile and melt sample at a ratio of 50/50 (v/v). Samples are analyzed using ultra-performance liquid chromatography system combined with triple tandem quadrupole mass spectrometry (UPLC-MS/MS). Levoglucosan is analyzed on BEH Amide column (2.1 mm * 100 mm, 1.7 um), and a Z spray electrospray ionization source is used for levoglucosan ionization. The polyether sulfone filter is selected for filtrating insoluble particles due to less impact on levoglucosan. The matrix effect is evaluated by using a standard addition method. During the method validation, limit of detection (LOD), linearity, recovery, repeatability and reproducibility were evaluated using standard addition method. The LOD of this method is 0.11 ng mL(-1). Recoveries vary from 91.2% at 0.82 ng mL(-1) to 99.3% at 4.14 ng mL(-1). Repeatability ranges from 17.9% at a concentration of 0.82 ng mL(-1) to 2.8% at 4.14 ng mL(-1). Reproducibility ranges from 15.1% at a concentration of 0.82 ng mL(-1) to 1.9% at 4.14 ng mL(-1). This method can be implemented using less than 0.50 mL sample volume in low and middle latitude regions like the Tibetan Plateau. PMID- 26653483 TI - Molecularly imprinted solid phase extraction in a syringe filter for determination of triazine herbicides in Radix Paeoniae Alba by ultra-fast liquid chromatography. AB - A novel, cost-effective and simple solid phase extraction (SPE) method, by using a syringe connected with a nylon membrane filter as the adsorbent container, was developed for the extraction of triazine herbicides from Radix Paeoniae Alba (RPA) samples. The selective molecularly imprinted polymers (MIPs) synthesized with the template of atrazine were employed as the adsorbents for the enrichment and purification of analytes. The extraction parameters, including the volume and type of loading solvent, the type of washing solvent and eluting solvent, were investigated. Under the optimized conditions, the final extracts were analyzed by ultra-fast liquid chromatography (UFLC). Recoveries of the developed method range from 92.4% to 107.3% with intra- and inter-day relative standard deviations (RSDs) lower than 8.2%. The calibration curve is linear in the concentration range of 0.005-2.4 ug g(-1) for desmetryn, atrazine and terbumeton, and 0.005-1.5 ug g(-1) for dimethametryn and dipropetryn, with the correlation coefficient (R(2)) higher than 0.9995. The limits of detection (LODs) of five triazine herbicides are in the range of 0.09-0.39 ng g(-1), which are lower than the maximum residue levels (MRLs) established by various official organizations. Analytical results of three real Radix Paeoniae Alba samples indicate that the proposed method is cost-effective and easy-to-use than other routine pretreatment methods. PMID- 26653484 TI - Simultaneous achiral-chiral analysis of pharmaceutical compounds using two dimensional reversed phase liquid chromatography-supercritical fluid chromatography. AB - A new interface was designed to enable the coupling of reversed phase liquid chromatography (RPLC) and supercritical fluid chromatography (SFC). This online two-dimensional chromatographic system utilizing RPLC in the first dimension and SFC in the second was developed to achieve simultaneous achiral and chiral analysis of pharmaceutical compounds. The interface consists of an eight-port, dual-position switching valve with small volume C-18 trapping columns. The peaks of interest eluting from the first RPLC dimension column were effectively focused as sharp concentration pulses on small volume C-18 trapping column/s and then injected onto the second dimension SFC column. The first dimension RPLC separation provides the achiral purity result, and the second dimension SFC separation provides the chiral purity result (enantiomeric excess). The results are quantitative enabling simultaneous achiral, chiral analysis of compounds. The interface design and proof of concept demonstration are presented. Additionally, comparative studies to conventional SFC and case studies of the applications of 2D LC-SFC in pharmaceutical analysis is presented. PMID- 26653485 TI - Overview of the Chemcatcher(r) for the passive sampling of various pollutants in aquatic environments Part A: Principles, calibration, preparation and analysis of the sampler. AB - The passive sampler Chemcatcher((r)), which was developed in 2000, can be adapted for various types of water contaminants (e.g., trace metals, polycyclic aromatic hydrocarbons, pesticides and pharmaceutical residues) depending on the materials chosen for the receiving phase and the membrane. The Chemcatcher((r)) has been used in numerous research articles in both laboratory experiments and field exposures, and here we review the state-of-the-art in applying this passive sampler. Part A of this review covers (1) the theory upon which the sampler is based (i.e., brief theory, calculation of water concentration, Performance and Reference Compounds), (2) the preparation of the device (i.e., sampler design, choice of the membrane and disk, mounting of the tool), and (3) calibration procedures (i.e., design of the calibration tank, tested parameters, sampling rates). PMID- 26653486 TI - Overview of the Chemcatcher(r) for the passive sampling of various pollutants in aquatic environments Part B: Field handling and environmental applications for the monitoring of pollutants and their biological effects. AB - The Chemcatcher((r)) has been used for a wide range of environmental applications in various media (river water, seawater, sewage water, and treated wastewater). The aim of part B of this review is to compile and discuss the results obtained during these applications, from a screening or quantitative monitoring of water contamination, to a comparison with biomonitoring and bioassays. Special attention will also be paid to, firstly, the influence of environmental factors on analyte uptake and, secondly, the use of Performance and Reference Compounds for the in situ correction of sampling rates. PMID- 26653487 TI - Automatic flow analysis method to determine traces of Mn2+ in sea and drinking waters by a kinetic catalytic process using LWCC-spectrophotometric detection. AB - A new automatic kinetic catalytic method has been developed for the measurement of Mn(2+) in drinking and seawater samples. The method is based on the catalytic effect of Mn(2+) on the oxidation of tiron by hydrogen peroxide in presence of Pb(2+) as an activator. The optimum conditions were obtained at pH 10 with 0.019 mol L(-1) 2'2 bipyridyl, 0.005 mol L(-1) tiron and 0.38 mol L(-1) hydrogen peroxide. Flow system is based on multisyringe flow injection analysis (MSFIA) coupled with a lab-on-valve (LOV) device exploiting on line spectrophotometric detection by a Liquid Waveguide Capillary Cell (LWCC), 1m optical length and performed at 445 nm. Under the optimized conditions by a multivariate approach, the method allowed the measurement of Mn(2+) in a range of 0.03-35 ug L(-1) with a detection limit of 0.010 ug L(-1), attaining a repeatability of 1.4% RSD. The method was satisfactorily applied to the determination of Mn(2+) in environmental water samples. The reliability of method was also verified by determining the manganese content of the certified standard reference seawater sample, CASS-4. PMID- 26653488 TI - On-line in-syringe magnetic stirring assisted dispersive liquid-liquid microextraction HPLC--UV method for UV filters determination using 1-hexyl-3 methylimidazolium hexafluorophosphate as extractant. AB - An environmental friendly and fully automated method using in-syringe magnetic stirring assisted dispersive liquid-liquid microextraction coupled with high performance liquid chromatography has been developed for the determination of UV filters in environmental water samples. The main "green" features on this method are the use of an ionic liquid as extracting solvent, avoiding the use of chlorinated solvents, and the on-line microextraction, preconcentration, separation and detection minimizing the use of reagents and so the waste generation. After sample treatment, 20 uL of the organic droplet was injected onto the HPLC-UV system. Various parameters affecting the extraction efficiency were studied using multivariate optimization approach, including the quantity of extraction and dispersive solvents, extraction and sedimentation time, ionic strength and pH. Under optimized conditions, limits of detection were within the range of 0.08-12 ug/L, for 3.5 mL sample volume. Linearity ranges were up to 500 ug/L for the UV-filters studied. Furthermore, enrichment factors ranging from 11 to 23 folds were obtained. Intra- and inter-assay precisions were 6% and 8%, respectively. Finally, the proposed method was successfully applied to determine UV filters in surface seawater and swimming pool samples attaining satisfactory recoveries over the range of 89-114% and 86-107%, respectively. PMID- 26653489 TI - A critical comparison of constant and pulsed flow systems exploiting gas diffusion. AB - Considering the beneficial aspects arising from the implementation of pulsed flows in flow analysis, and the relevance of in-line gas diffusion as an analyte separation/concentration step, influence of flow pattern in flow systems with in line gas diffusion was critically investigated. To this end, constant or pulsed flows delivered by syringe or solenoid pumps were exploited. For each flow pattern, two variants involving different interaction times of the donor with the acceptor streams were studied. In the first one, both the acceptor and donor streams were continuously flowing, whereas in the second one, the acceptor was stopped during the gas diffusion step. Four different volatile species (ammonia, ethanol, carbon dioxide and hydrogen sulfide) were selected as models. For the flow patterns and variants studied, the efficiencies of mass transport in the gas diffusion process were compared, and sensitivity, repeatability, sampling frequency and recorded peak shape were evaluated. Analysis of the results revealed that sensitivity is strongly dependent on the implemented variant, and that flow pattern is an important feature in flow systems with in-line gas diffusion. PMID- 26653490 TI - Tungsten coil atomic emission spectrometry combined with dispersive liquid-liquid microextraction: A synergistic association for chromium determination in water samples. AB - A novel and environment friendly analytical method is reported for total chromium determination and chromium speciation in water samples, whereby tungsten coil atomic emission spectrometry (WCAES) is combined with in situ ionic liquid formation dispersive liquid-liquid microextraction (in situ IL-DLLME). A two stage multivariate optimization approach has been developed employing a Plackett Burman design for screening and selection of the significant factor involved in the in situ IL-DLLME procedure, which was later optimized by means of a circumscribed central composite design. The optimum conditions were complexant concentration: 0.5% (or 0.1%); complexant type: DDTC; IL anion: PF6(-); [Hmim][Cl] IL amount: 60 mg; ionic strength: 0% NaCl; pH: 5 (or 2); centrifugation time: 10 min; and centrifugation speed: 1000 rpm. Under the optimized experimental conditions the method was evaluated and proper linearity was obtained with a correlation coefficient of 0.991 (5 calibration standards). Limits of detection and quantification for both chromium species were 3 and 10 ug L(-1), respectively. This is a 233-fold improvement when compared with chromium determination by WCAES without using preconcentration. The repeatability of the proposed method was evaluated at two different spiking levels (10 and 50 ug L( 1)) obtaining coefficients of variation of 11.4% and 3.6% (n=3), respectively. A certified reference material (SRM-1643e NIST) was analyzed in order to determine the accuracy of the method for total chromium determination and 112.3% and 2.5 ug L(-1) were the recovery (trueness) and standard deviation values, respectively. Tap, bottled mineral and natural mineral water samples were analyzed at 60 ug L( 1) spiking level of total Cr content at two Cr(VI)/Cr(III) ratios, and relative recovery values ranged between 88% and 112% showing that the matrix has a negligible effect. To our knowledge, this is the first time that combines in situ IL-DLLME and WCAES. PMID- 26653491 TI - Automated determinations of selenium in thermal power plant wastewater by sequential hydride generation and chemiluminescence detection. AB - After the Fukushima disaster, power generation from nuclear power plants in Japan was completely stopped and old coal-based power plants were re-commissioned to compensate for the decrease in power generation capacity. Although coal is a relatively inexpensive fuel for power generation, it contains high levels (mgkg( 1)) of selenium, which could contaminate the wastewater from thermal power plants. In this work, an automated selenium monitoring system was developed based on sequential hydride generation and chemiluminescence detection. This method could be applied to control of wastewater contamination. In this method, selenium is vaporized as H2Se, which reacts with ozone to produce chemiluminescence. However, interference from arsenic is of concern because the ozone-induced chemiluminescence intensity of H2Se is much lower than that of AsH3. This problem was successfully addressed by vaporizing arsenic and selenium individually in a sequential procedure using a syringe pump equipped with an eight-port selection valve and hot and cold reactors. Oxidative decomposition of organoselenium compounds and pre-reduction of the selenium were performed in the hot reactor, and vapor generation of arsenic and selenium were performed separately in the cold reactor. Sample transfers between the reactors were carried out by a pneumatic air operation by switching with three-way solenoid valves. The detection limit for selenium was 0.008 mg L(-1) and calibration curve was linear up to 1.0 mg L(-1), which provided suitable performance for controlling selenium in wastewater to around the allowable limit (0.1 mg L(-1)). This system consumes few chemicals and is stable for more than a month without any maintenance. Wastewater samples from thermal power plants were collected, and data obtained by the proposed method were compared with those from batchwise water treatment followed by hydride generation-atomic fluorescence spectrometry. PMID- 26653493 TI - Single peak parameters technique for simultaneous measurements: Spectrophotometric sequential injection determination of Fe(II) and Fe(III). AB - Spectrophotometric sequential injection system (SI) is proposed to automate the method of simultaneous determination of Fe(II) and Fe(III) on the basis of parameters of a single peak. In the developed SI system, sample and mixture of reagents (1,10-phenanthroline and sulfosalicylic acid) are introduced into a vessel, where in an acid environment (pH?3) appropriate compounds of Fe(II) and Fe(III) with 1,10-phenanthroline and sulfosalicylic acid are formed, respectively. Then, in turn, air, sample, EDTA and sample again, are introduced into a holding coil. After the flow reversal, a segment of air is removed from the system by an additional valve and as EDTA replaces sulfosalicylic acid forming a more stable colorless compound with Fe(III), a complex signal is registered. Measurements are performed at wavelength 530 nm. The absorbance measured at minimum of the negative peak and the area or the absorbance measured at maximum of the signal can be used as measures corresponding to Fe(II) and Fe(III) concentrations, respectively. The time of the peak registration is about 2 min. Two-component calibration has been applied to analysis. Fe(II) and Fe(III) can be determined within the concentration ranges of 0.04-4.00 and 0.1-5.00 mg L( 1), with precision less than 2.8% and 1.7% (RSD), respectively and accuracy better than 7% (RE). The detection limit is 0.04 and 0.09 mg L(-1) for Fe(II) and Fe(III), respectively. The method was applied to analysis of artesian water samples. PMID- 26653492 TI - Dynamic leaching and fractionation of trace elements from environmental solids exploiting a novel circulating-flow platform. AB - A dynamic flow-through microcolumn extraction system based on extractant re circulation is herein proposed as a novel analytical approach for simplification of bioaccessibility tests of trace elements in sediments. On-line metal leaching is undertaken in the format of all injection (AI) analysis, which is a sequel of flow injection analysis, but involving extraction under steady-state conditions. The minimum circulation times and flow rates required to determine the maximum bioaccessible pools of target metals (viz., Cu, Zn, Cd, and Pb) from lake and river sediment samples were estimated using Tessier's sequential extraction scheme and an acid single extraction test. The on-line AIA method was successfully validated by mass balance studies of CRM and real sediment samples. Tessier's test in on-line AI format demonstrated to be carried out by one third of extraction time (6h against more than 17 h by the conventional method), with better analytical precision (<9.2% against >15% by the conventional method) and significant decrease in blank readouts as compared with the manual batch counterpart. PMID- 26653494 TI - Iron speciation in natural waters by sequential injection analysis with a hexadentate 3-hydroxy-4-pyridinone chelator as chromogenic agent. AB - A sequential injection method for iron speciation in various types of natural waters was developed using a synthesised hexadentate 3-hydroxy-4-pyridinone chelator (CP256). The denticity of the ligand that allow formation of the corresponding iron(III) complex in a 1:1 stoichiometry proved to be highly advantageous, in comparison with parent bidentate, hydroxy-4-piridinone chelators, with a two fold increase of reaction sensitivity and over 65% decrease of the LOD. A solid phase extraction approach was employed to attain matrix elimination, facilitating iron(III) determination and application to high salinity waters. The combination with the total iron determination obtained by the direct reaction of the ligand resulted in iron speciation. Two detection spectrophotometric cells were tested, a conventional flow cell (CFC) and a liquid waveguide capillary cell (LWCC). The dynamic concentration ranges were 0.1-2 mg/L with the CFC detection and 0.005-0.1 mg/L with the LWCC, with limit of detection of 30 ug/L and 6 ug/L, respectively. The developed method was successfully applied to a variety of natural waters. PMID- 26653495 TI - Optimization using the gradient and simplex methods. AB - Traditionally optimization of analytical methods has been conducted using a univariate method, varying each parameter one-by-one holding fixed the remaining. This means in many cases to reach only local minima and not get the real optimum. Among the various options for multivariate optimization, this paper highlights the gradient method, which involves the ability to perform the partial derivatives of a mathematical model, as well as the simplex method that does not require that condition. The advantages and disadvantages of those two multivariate optimization methods are discussed, indicating when they can be applied and the different forms that have been introduced. Different cases are described on the applications of these methods in analytical chemistry. PMID- 26653496 TI - Formaldehyde vapor produced from hexamethylenetetramine and pesticide: Simultaneous monitoring of formaldehyde and ozone in chamber experiments by flow based hybrid micro-gas analyzer. AB - Simultaneous analysis of HCHO and O3 was performed by the developed flow analysis system to prove that HCHO vapor is produced from solid pesticide in the presence of O3. HCHO is produced in many ways, including as primary emissions from fuel combustion and in secondary production from anthropogenic and biogenic volatile organic compounds by photochemical reactions. In this work, HCHO production from pesticides was investigated for the first time. Commonly pesticide contains surfactant such as hexamethylenetetramine (HMT), which is a heterocyclic compound formed from six molecules of HCHO and four molecules of NH3. HMT can react with gaseous oxidants such as ozone (O3) to produce HCHO. In the present study, a flow analysis system was developed for simultaneous analysis of HCHO and O3, and this system was used to determine if solid pesticides produced HCHO vapor in the presence of O3. HMT or the pesticide jimandaisen, which contains mancozeb as the active ingradient and HMT as a stabilizer was placed at the bottom of a 20-L stainless steel chamber. Air in the chamber was monitored using the developed flow system. Analyte gases were collected into an absorbing solution by a honeycomb-patterned microchannel scrubber that was previously developed for a micro gas analysis system (MUGAS). Subsequently, indigotrisulfonate, a blue dye, was added to the absorbing solution to detect O3, which discolored the solution. HCHO was detected after mixing with the Hantzsch reaction reagent. Both gases could be detected at concentrations ranging from parts per billion by volume (ppbv) to 1000 ppbv with good linearity. Both HMT and jimandaisen emitted large amount of HCHO in the presence of O3. PMID- 26653497 TI - Graphene/polyvinylpyrrolidone/polyaniline nanocomposite-modified electrode for simultaneous determination of parabens by high performance liquid chromatography. AB - A nanocomposite of graphene (G), polyvinylpyrrolidone (PVP) and polyaniline (PANI) modified onto screen-printed carbon electrode (SPCE) using an electrospraying technique was developed for simultaneous determination of five parabens in beverages and cosmetic products by high performance liquid chromatography. PVP and PANI were used as the dispersing agents of graphene, and also for the enhancement of electrochemical conductivity of the electrode. The electrochemical behavior of each paraben was investigated using the G/PVP/PANI nanocomposite-modified SPCE, compared to the unmodified SPCE. Using HPLC along with amperometric detection at a controlled potential of +1.2V vs Ag/AgCl, the chromatogram of five parabens obtained from the modified SPCE exhibits well defined peaks and higher current response than those of its unmodified counterpart. Under the optimal conditions, the calibration curves of five parabens similarly provide a linear range between 0.1 and 30 ug mL(-1) with the detection limits of 0.01 ug mL(-1) for methyl paraben (MP), ethyl paraben (EP) and propyl paraben (PP), 0.02 and 0.03 ug mL(-1) for isobutyl paraben (IBP) and butyl paraben (BP), respectively. Furthermore, this proposed method was applied for the simultaneous determination of five parabens in real samples including a soft drink and a cosmetic product with satisfactory results, yielding the recovery in the range of 90.4-105.0%. PMID- 26653498 TI - Automated IR determination of petroleum products in water based on sequential injection analysis. AB - The simple and easy performed automated method for the IR determination of petroleum products (PP) in water using extraction-chromatographic cartridges has been developed. The method assumes two stages: on-site extraction of PP during a sampling by using extraction-chromatographic cartridges and subsequent determination of the extracted PP using sequential injection analysis (SIA) with IR detection. The appropriate experimental conditions for extraction of the dissolved in water PP and for automated SIA procedure were investigated. The calibration plot constructed using the developed procedure was linear in the range of 3-200 MUg L(-1). The limit of detection (LOD), calculated from a blank test based on 3sigma was 1 ug L(-1). The sample volume was 1L. The system throughput was found to be 12 h(-1). PMID- 26653499 TI - Vapor permeation-stepwise injection simultaneous determination of methanol and ethanol in biodiesel with voltammetric detection. AB - A novel vapor permeation-stepwise injection (VP-SWI) method for the determination of methanol and ethanol in biodiesel samples is discussed. In the current study, stepwise injection analysis was successfully combined with voltammetric detection and vapor permeation. This method is based on the separation of methanol and ethanol from a sample using a vapor permeation module (VPM) with a selective polymer membrane based on poly(phenylene isophtalamide) (PA) containing high amounts of a residual solvent. After the evaporation into the headspace of the VPM, methanol and ethanol were transported, by gas bubbling, through a PA membrane to a mixing chamber equipped with a voltammetric detector. Ethanol was selectively detected at +0.19 V, and both compounds were detected at +1.20 V. Current subtractions (using a correction factor) were used for the selective determination of methanol. A linear range between 0.05 and 0.5% (m/m) was established for each analyte. The limits of detection were estimated at 0.02% (m/m) for ethanol and methanol. The sample throughput was 5 samples h(-1). The method was successfully applied to the analysis of biodiesel samples. PMID- 26653500 TI - Ultra-high performance liquid chromatographic determination of antioxidants in teas using inkjet-printed graphene-polyaniline electrode. AB - A development of ultra-high performance liquid chromatographic coupled with a novel inkjet-printed conductive ink-modified electrode for a fast and simultaneous determination of polyphenolic antioxidants was achieved. Two printing techniques were selected for fabrication and modification including (i) an in-house screen-printing method and (ii) an inkjet-printing method, respectively. A conductive ink containing graphene and polyaniline nanocomposite (G-PANI) was precisely casted onto the surface of screen-printed carbon electrode (SPCE) using a dimatix inkjet material printer. Compared to a bare SPCE, the G PANI-modified screen-printed carbon electrode (G-PANI/SPCE) exhibited higher electrochemical sensitivity with increase (2-4 times) of peak current of each antioxidant. Moreover, four antioxidants were successfully separated and determined within 3 min using a reverse phase ultra-high performance liquid chromatography (UHPLC) with a mobile phase containing phosphate buffer and acetonitrile (90:10 v/v). Under an optimal detection potential at +1.2V vs. Ag/AgCl, linear calibrations and limits of detection (S/N=3) for antioxidants were found to be 0.01-10 ug mL(-1) and 1.38-1.94 ng mL(-1), respectively. Finally, this proposed method has been successfully used for the determination of antioxidants in tea samples, the results obtained from our presented method were within a highly good agreement those obtained from a standard UHPLC-UV method. PMID- 26653501 TI - Electro-enhanced hollow fiber membrane liquid phase microextraction of Cr(VI) oxoanions in drinking water samples. AB - Hollow fiber membrane liquid phase microextraction (HF-LPME) of metal oxoanions was studied using an ionic carrier enhanced by the application of an electric field (electro-enhanced HF-LPME). The Cr(VI) oxoanion was used as the model. The transportation of Cr(VI) oxoanions across the supported liquid membrane (SLM) was explored via the ion-exchange process and electrokinetic migration. The type of SLM, type of acceptor solution, extraction time, electric potential, and stirring rate were investigated and optimized using MilliQ water. Electro-enhanced HF-LPME provided a much higher enrichment factor compared to conventional HF-LPME (no electric potential) for the same extraction time. A mixture of an anion exchange carrier (methyltrialkyl-ammonium chloride, Aliquat 336) in the SLM facilitated the transportation of Cr(VI) oxoanions. The SLM that gave the best performance was 1-heptanol mixed with 5% Aliquat 336 with 1M NaOH as the acceptor. Linearity was obtained in the working range of 3-15 ug L(-1) Cr(VI) (R(2)>0.99) at 30 V with a 5 min extraction time. The limit of detection was below 5 ug L(-1). The relative standard deviation was less than 12%. The method was applied to drinking water samples. The recoveries of spiked Cr(VI) in drinking water samples were in the range of 96-101% based on the matrix-matched calibration curves. The method was limited to samples containing low levels of ions due to the occurrence of electrolysis. The type of SLM, particularly regarding its resistance, should be tuned to control this problematic phenomenon. PMID- 26653502 TI - Automatic flow-through dynamic extraction: A fast tool to evaluate char-based remediation of multi-element contaminated mine soils. AB - An automatic in-vitro bioaccessibility test based upon dynamic microcolumn extraction in a programmable flow setup is herein proposed as a screening tool to evaluate bio-char based remediation of mine soils contaminated with trace elements as a compelling alternative to conventional phyto-availability tests. The feasibility of the proposed system was evaluated by extracting the readily bioaccessible pools of As, Pb and Zn in two contaminated mine soils before and after the addition of two biochars (9% (w:w)) of diverse source origin (pine and olive). Bioaccessible fractions under worst-case scenarios were measured using 0.001 mol L(-1) CaCl2 as extractant for mimicking plant uptake, and analysis of the extracts by inductively coupled optical emission spectrometry. The t-test of comparison of means revealed an efficient metal (mostly Pb and Zn) immobilization by the action of olive pruning-based biochar against the bare (control) soil at the 0.05 significance level. In-vitro flow-through bioaccessibility tests are compared for the first time with in-vivo phyto-toxicity assays in a microcosm soil study. By assessing seed germination and shoot elongation of Lolium perenne in contaminated soils with and without biochar amendments the dynamic flow-based bioaccessibility data proved to be in good agreement with the phyto-availability tests. Experimental results indicate that the dynamic extraction method is a viable and economical in-vitro tool in risk assessment explorations to evaluate the feasibility of a given biochar amendment for revegetation and remediation of metal contaminated soils in a mere 10 min against 4 days in case of phyto toxicity assays. PMID- 26653503 TI - On-line lab-in-syringe cloud point extraction for the spectrophotometric determination of antimony. AB - Most of the procedures for antimony determination require time-consuming sample preparation (e.g. liquid-liquid extraction with organic solvents), which are harmful to the environment. Because of the high antimony toxicity, a rapid, sensitive and greener procedure for its determination becomes necessary. The goal of this work was to develop an analytical procedure exploiting for the first time the cloud point extraction on a lab-in-syringe flow system aiming at the spectrophotometric determination of antimony. The procedure was based on formation of an ion-pair between the antimony-iodide complex and H(+) followed by extraction with Triton X-114. The factorial design showed that the concentrations of ascorbic acid, H2SO4 and Triton X-114, as well as second and third order interactions were significant at the 95% confidence level. A Box-Behnken design was applied to obtain the response surfaces and to identify the critical values. System is robust at the 95% confidence level. A linear response was observed from 5 to 50 ug L(-1), described by the equation A=0.137+0.050C(Sb) (r=0.998). The detection limit (99.7% confidence level), the coefficient of variation (n=5; 15 ug L(-1)) and the sampling rate was estimated at 1.8 ug L(-1), 1.6% and 16 h(-1), respectively. The procedure allows quantification of antimony in the concentrations established by environmental legislation (6 ug L(-1)) and it was successfully applied to the determination of antimony in freshwater samples and antileishmanial drugs, yielding results in agreement with those obtained by HGFAAS at the 95% confidence level. PMID- 26653504 TI - A flow method based on solvent extraction coupled on-line to a reversed micellar mediated chemiluminescence detection for selective determination of gold(III) and gallium(III) in water and industrial samples. AB - A rapid and sensitive flow method, based on the combination of on-line solvent extraction with reversed micellar mediated chemiluminescence (CL) detection using rhodamine B (RB), was investigated for the selective determination of Au(III) and Ga(III) in aqueous solutions. 2.0 M HCl was the optimum for extracting Au(III) while a 5.0M HCl solution containing 2.5M LiCl was selected as an optimum acidic medium for extraction of Ga(III). The Au(III) and Ga(III) chloro-complex anions were extracted from the above aqueous acidic solutions into toluene as their ion pair complexes with the protonated RBH(+) ion followed by membrane phase separation in a flow system. In a flow cell of a detector, the extract was mixed with the reversed micellar solution of cetyltrimethylammonium chloride (CTAC) in 1-hexanol-cyclohexane/water (1.0M HCl) containing 0.10 M cerium(IV) and 0.05 M lithium sulfate. Then uptake of the ion-pair by the CTAC reversed micelles and the subsequent CL oxidation of RB with Ce(IV) occurred easily and the CL signals produced were recorded. Using a flow injection system, a detection limit (DL) of 0.4 MUM Au(III) and 0.6 MUM Ga(III), and linear calibration graphs with dynamic ranges from the respective DLs to 10 MUM for Au(III) and Ga(III) were obtained under the optimized experimental conditions. The relative standard deviations (n=6) obtained at 2.0 uM Au(III) and 4.0 uM Ga(III) were 3.0% and 2.4%, respectively. The presented CL methodology has been applied for the determination of Au(III) and Ga(III) in water and industrial samples with satisfactory results. PMID- 26653505 TI - Bianalyte multicommutated flow analysis system for microproteinuria diagnostics. AB - In this work a bianalyte multicommutated flow analysis (MCFA) system for determination of microproteinuria is presented. The developed MCFA system is based on two dedicated optoelectronic flow-through detectors which allow estimation of urinary protein creatinine ratio. For total protein determination, turbidimetric Exton's method was used, whereas creatinine was determined by the photometric Jaffe reaction. The developed analytical system is fully-mechanized, easy to operate, economic in reagent consumption and characterized by satisfactory analytical parameters. It allows protein determination in the range 36-300 mg L(-1) with 33 mg L(-1) detection limit and simultaneous determination of creatinine in the range 0.045-2.50 mmol L(-1) with 0.025 mmol L(-1) detection limit. The measurement procedure for the presented MCFA system offers performing 30 peaks per hour for both analytes. To prove the analytical usefulness of the system, real human urine samples have been analyzed. The correlation and agreement between results offered by the developed system and clinical analyzers are fully acceptable. PMID- 26653506 TI - Talanta, JFIA, and ICFIA/JAFIA--A history. AB - The Winter Conference on Flow Injection Analysis (WCFIA) began in 1989, and became the International Conference on Flow Injection Analysis, when merging with the Japanese Association for Flow Injection Analysis (JAFIA) in 1995. Talanta has published special issues on the conference since 1995. Beginning in 2013, accepted manuscripts are published in regular issues of Talanta, and a virtual special issue of all manuscripts is compiled for access online. Reports of the conferences have been published in the Journal of Flow Injection Analysis (JFIA) beginning in 1992, in English and in Japanese. Some reports in English have been published in TrAC, from 1993 to 2008. This report provides, for the record, all Special Issues and all reports, listing the venues, conference organizers, and guest editors for special issues, along with the titles of the reports for the cited issues. PMID- 26653507 TI - The effect of environmental degradation on the characterisation of automotive clear coats by infrared spectroscopy. AB - This paper presents a study into the chemical changes occurring within automotive clear coats as a result of environmental weathering, and their potential effect upon the characterisation of samples using infrared spectroscopy combined with chemometric modelling. Testing of three samples, collected from separate vehicles, exposed to the outside environment revealed no changes in model predictions over a 175 day period; however, incorrect predictions were observed following 435 days of exposure. Inspection of the corresponding infrared spectra revealed that these changes were likely due to the hydrolysis and photodegradation of polymer chains present in the clear coat, which were not observed in samples stored away from the outside environment over a one-year period. Analysis of previously weathered samples using synchrotron infrared microscopy found these changes occurred in a top-down fashion rather than within the bulk of the clear coat. This indicates that although weathering may affect the surface characterisation of clear coats over time, the targeting of deeper portions of the clear coat layer may still provide useful information as to the identity of the vehicle. PMID- 26653508 TI - Assessing a novel contact heater as a new method of recovering explosives traces from porous surfaces. AB - It can be very challenging to recover explosives traces from porous surfaces, such as clothing and car seats, compared to non-porous surfaces. The contact heater has been developed as a novel instrument designed to recover explosives traces from porous surfaces. Samples are taken by heating and drawing air across a surface, with the air flowing through a sampling cartridge containing adsorbent polymer beads, which act to trap any recovered explosive material. Any collected explosive can then be eluted from this cartridge using a solvent, prior to analysis. This paper outlines work performed to evaluate the usefulness of the contact heater with regards to the recovery of explosives traces from porous materials. Ethylene glycol dinitrate (EGDN) and triacetone triperoxide (TATP) were chosen as two representative explosives for this study. Quantification was performed using GC-MS for EGDN and LC-MS/MS for TATP. Different sampling temperatures, sampling times and elution solvents were investigated. Recovery was trialled from leather, carpet and denim. Recoveries of up to 71% were obtained following optimisation. It was also possible to recover TATP from fabrics exposed to TATP vapour in a vapour-laden jar up to two hours after exposure. The contact heater therefore appears to be a very useful tool for the recovery of explosives traces from porous materials. PMID- 26653509 TI - Headspace in-tube microextraction coupled with micellar electrokinetic chromatography of neutral aromatic compounds. AB - Headspace (HS) extraction can be carried out easily and aptly via single drop microextraction coupled with capillary electrophoresis (CE). However, one drawback is the difficulty of keeping the single drop stably at the capillary tip. To solve this problem, we have recently demonstrated HS in-tube microextraction (ITME) of acidic compounds such as chlrophenols in an acidic sample using a basic run buffer plug in the separation capillary for CE as an acceptor phase. In this report, an organic acceptor plug in a capillary was used to extract neutral organic volatile pollutants such as BTEX (benzene, toluene, ethylbenzene, and m-xylene). After extraction, the analytes enriched in the organic acceptor plug were analyzed with micellar electrokinetic chromatography (MEKC). The enrichment factors for BTEX in a standard solution were up to 350 under an optimal condition of 25 degrees C for 20 min. As an application, BTEX spiked into bottled water were analyzed with HS-ITME-MEKC, and the enrichment factors for BTEX were up to 320. The limits of detections were 1-4 ppb, which are at least 200 times lower than the US Environmental Protection Agency guidelines for drinking water, except benzene. The entire procedure of HS-ITME-MEKC was carried out automatically using a commercial CE instrument. PMID- 26653510 TI - Second-level nurse returns? PMID- 26653511 TI - Tough choices: patient care versus cost savings. PMID- 26653512 TI - Smoking cessation support: Indian nursing students' practices, attitudes and perceived barriers. AB - BACKGROUND: Tobacco use is a significant global health issue. Studies that examined nursing students' attitudes towards smoking cessation support were limited from India. AIM: To assess undergraduate nursing students' practices, beliefs, attitudes and perceived barriers towards smoking cessation support. METHODS: A cross-sectional descriptive design was adopted among undergraduate nursing students (n=178) using self-reported questionnaires. RESULTS: Findings revealed that a majority (68.5%) of the students inquire about their clients' smoking habits and 78.1% of them advise patients who are smokers about the health effects of smoking. Although student nurses hold positive attitudes in the enthusiasm domain (28.8 +/- 7.29), the majority of them lack self-efficacy towards smoking cessation support (14.2 +/- 4.70). 'Patient's lack of motivation' (89.3%), 'lack of training/knowledge' (88.2%) and 'lack of communication skills' (77.5%) were the major barriers encountered by the participants during tobacco counselling. CONCLUSION: The findings suggest that there is an urgent need to include a tobacco-control curriculum at undergraduate level to improve their competency in giving smoking cessation support. PMID- 26653513 TI - Managing opioid-induced constipation. PMID- 26653514 TI - The dorso-ventro debate: in search of empirical evidence. AB - Identification of safe injections sites is a skill practised routinely by nurses, which, as with all nursing practice, is informed by empirical evidence. Despite this, discussion as to whether the dorsogluteal site should be eradicated from nursing practice in favour of the ventrogluteal site shows no sign of abating. Review of commonly cited evidence in this debate aimed to identify the validity of excluding the dorsogluteal site in favour of the ventrogluteal site by investigating the empirical evidence, which routinely informs this decision. Empirical evidence suggests a case to exclude the dorsogluteal site for children under age 10 for fear of damaging the sciatic nerve, but not so for adults. Recommendations are made for conclusive research into the viability of the dorsogluteal site and an authoritative decision based on empirical evidence, not hearsay, with regard to its continuance or eradication from nursing practice. PMID- 26653515 TI - Caring for gay men and lesbians in nursing homes in Ireland. AB - This article examines the literature relating to the attitudes of nurses currently practicing in nursing homes towards caring for gay men and lesbians in Ireland. Nurses' knowledge of and attitudes towards the sexuality of those in their care can potentially have an impact on the quality of care they deliver and the patient experience. There is a consensus in the literature regarding the expression of sexuality as a lifelong need and integral element of quality of life. Research to date focusing on the needs of older gay or lesbian individuals has been virtually non-existent, despite increases in life expectancy and increasing numbers of older people, and therefore older gay and lesbian people requiring nursing home care. PMID- 26653516 TI - NHS generic project: response from the wound care community. AB - This series of letters outlines the response from MA Healthcare, key opinion leaders and industry to the news that the Government is planning to introduce a generic project for wound dressings. PMID- 26653517 TI - Improving and protecting standards of care in England. AB - Emeritus professor Alan Glasper, from the University of Southampton, discusses the launch of the latest Care Quality Commission report, which describes the state of health care and adult social care in England during the period 2014/15. PMID- 26653518 TI - Nursing in police custody: creating a professional identity. PMID- 26653519 TI - Service-user involvement in nurse education. PMID- 26653520 TI - Teamwork and solidarity: improving health care for all. AB - Emma Blakey considers one of most important lessons she learnt as a student nurse on placement, and explores how team work can influence patient care and how solidarity can change society. PMID- 26653521 TI - A nurse's role in nurturing a patient's intimacy and sexuality. AB - In this monthly column, Aysha Mendes discusses the importance of the role of the nurse in being comfortable discussing intimacy and sexuality with their patients in order to ensure that people can express themselves and that needs are not being neglected on account of their medical conditions. PMID- 26653522 TI - Deprivation of liberty safeguard deaths to be reported to the coroner. AB - The Chief Coroner has issued guidance that all deaths where a person is subject to a deprivation of liberty safeguard or Court of Protection welfare order allowing a deprivation of liberty must be reported to the coroner and an inquest held. In this article the author considers the impact of the guidance. PMID- 26653523 TI - Calling into question the NHS approach to patient safety. AB - In a two-part column John Tingle discusses the Health Foundation's recent report on changing the NHS approach to patient safety. Part one looks at the first part of the report: the case for change. PMID- 26653524 TI - Written communication: from staff nurse to nurse consultant. PMID- 26653525 TI - Open visiting hours benefit everyone. PMID- 26653526 TI - Why women perform better in college than admission scores would predict: Exploring the roles of conscientiousness and course-taking patterns. AB - Women typically obtain higher subsequent college GPAs than men with the same admissions test score. A common reaction is to attribute this to a flaw in the admissions test. We explore the possibility that this underprediction of women's performance reflects gender differences in conscientiousness and college course taking patterns. In Study 1, we focus on using the ACT to predict performance in a single, large course where performance is decomposed into cognitive (exam and quiz scores) and less cognitive, discretionary components (discussion and extra credit points). The ACT does not underpredict female's cognitive performance, but it does underpredict female performance on the less cognitive, discretionary components of academic performance, because it fails to measure and account for the personality trait of conscientiousness. In Study 2, we create 2 course difficulty indices (Course Challenge and Mean Aptitude in Course) and add them to an HLM regression model to see if they reduce the degree to which SAT scores underpredict female performance. Including Course Challenge does result in a modest reduction of the gender coefficient; however, including Mean Aptitude in Course does not. Thus, differences in course-taking patterns is a partial (albeit small) explanation for the common finding of differential prediction by gender. PMID- 26653527 TI - Ups and downs of the expatriate experience? Understanding work adjustment trajectories and career outcomes. AB - We examine changes in work adjustment among 179 expatriates from 3 multinational organizations from predeparture through the first 9 months of a new international assignment. Our 10-wave results challenge classic U-shaped theories of expatriate adjustment (e.g., Torbiorn, 1982). Consistent with uncertainty reduction theory, our results instead suggest that expatriates typically experience a gradual increase in work adjustment over time. Two resources that expatriates bring to their assignments (previous culture-specific work experience and core self evaluations) moderate the trajectory of work adjustment. Trajectory of adjustment predicts Month 9 career instrumentality and turnover intention, as well as career advancement (job promotion) 1.5 years further. Implications for theory, as well as for changes in expatriate management practices, are discussed. PMID- 26653528 TI - What it takes to get proactive: An integrative multilevel model of the antecedents of personal initiative. AB - Building upon and extending Parker, Bindl, and Strauss's (2010) theory of proactive motivation, we develop an integrated, multilevel model to examine how contextual factors shape employees' proactive motivational states and, through these proactive motivational states, influence their personal initiative behavior. Using data from a sample of hotels collected from 3 sources and over 2 time periods, we show that establishment-level initiative-enhancing human resource management (HRM) systems were positively related to departmental initiative climate, which was positively related to employee personal initiative through employee role-breadth self-efficacy. Further, department-level empowering leadership was positively related to initiative climate only when initiative enhancing HRM systems were low. These findings offer interesting implications for research on personal initiative and for the management of employee proactivity in organizations. (PsycINFO Database Record PMID- 26653529 TI - Seeing you seeing me: Stereotypes and the stigma magnification effect. AB - [Correction Notice: An Erratum for this article was reported in Vol 101(5) of Journal of Applied Psychology (see record 2016-21000-001). In the article, Table 2 contained a production-related formatting error. Values from column 11 onward were shifted upwards in the table. All versions of this article have been corrected.] Despite an increased interest in the phenomenon of stigma in organizations, we know very little about the interactions between those who are stigmatized and those who stigmatize them. Integrating both the perceptions of the stigmatized worker and the stigmatizing customer into one model, the present study addresses this gap. It examines the role of stereotypes held by customers of stigmatized organizations and metastereotypes held by the stigmatized workers themselves (i.e., their shared beliefs of the stereotypes customers associate with them) in frontline exchanges. To do so, data regarding frontline workers (vendors) of homeless-advocate newspapers from 3 different sources (vendors, customers, trained observers) were gathered. Multilevel path-analytic hypotheses tests reveal (a) how frontline workers' prototypicality for a stigmatized organization renders salient a stigma within frontline interactions and (b) how stereotypes by customers and metastereotypes by frontline workers interact with each other in such contacts. The results support a hypothesized interaction between frontline workers' metastereotypes and customers' stereotypes-what we call the "stigma magnification effect". The study also derives important practical implications by linking stigma to frontline workers' discretionary financial gains. (PsycINFO Database Record PMID- 26653530 TI - Tethered to work: A family systems approach linking mobile device use to turnover intentions. AB - We examined the use of a mobile device for work during family time (mWork) to determine the role that it plays in employee turnover intentions. Using a sample of 344 job incumbents and their spouses, we propose a family systems model of turnover and examine 2 paths through which we expect mWork to relate to turnover intentions: the job incumbent and the spouse. From the job incumbent, we found that the job incumbent's mWork associated with greater work-to-family conflict and burnout, and lower organizational commitment. From the spouse, we found that incumbent mWork and greater work-to-family conflict associated with increased resentment by the spouse and lower spousal commitment to the job incumbent's organization. Both of these paths played a role in predicting job incumbent turnover intentions. We discuss implications and opportunities for future research on mWork for integrating work and family into employee turnover intentions. PMID- 26653531 TI - Strategic consequences of emotional misrepresentation in negotiation: The blowback effect. AB - Recent research indicates that expressing anger elicits concession making from negotiating counterparts. When emotions are conveyed either by a computer program or by a confederate, results appear to affirm a long-standing notion that feigning anger is an effective bargaining tactic. We hypothesize this tactic actually jeopardizes postnegotiation deal implementation and subsequent exchange. Four studies directly test both tactical and strategic consequences of emotional misrepresentation. False representations of anger generated little tactical benefit but produced considerable and persistent strategic disadvantage. This disadvantage is because of an effect we call "blowback." A negotiator's misrepresented anger creates an action-reaction cycle that results in genuine anger and diminishes trust in both the negotiator and counterpart. Our findings highlight the importance of considering the strategic implications of emotional misrepresentation for negotiators interested in claiming value. We discuss the benefits of researching reciprocal interdependence between 2 or more negotiating parties and of modeling value creation beyond deal construction to include implementation of terms. (PsycINFO Database Record PMID- 26653532 TI - Toward a periodic table of personality: Mapping personality scales between the five-factor model and the circumplex model. AB - In this study, we examine the structures of 10 personality inventories (PIs) widely used for personnel assessment by mapping the scales of PIs to the lexical Big Five circumplex model resulting in a Periodic Table of Personality. Correlations between 273 scales from 10 internationally popular PIs with independent markers of the lexical Big Five are reported, based on data from samples in 2 countries (United Kingdom, N = 286; United States, N = 1,046), permitting us to map these scales onto the Abridged Big Five Dimensional Circumplex model (Hofstee, de Raad, & Goldberg, 1992). Emerging from our findings we propose a common facet framework derived from the scales of the PIs in our study. These results provide important insights into the literature on criterion related validity of personality traits, and enable researchers and practitioners to understand how different PI scales converge and diverge and how compound PI scales may be constructed or replicated. Implications for research and practice are considered. PMID- 26653534 TI - Non-stoichiometric inhibition in integrated lead finding - a literature review. AB - INTRODUCTION: Non-stoichiometric inhibition summarizes different mechanisms by which low-molecular weight compounds can reproducibly inhibit high-throughput screening (HTS) and other lead finding assays without binding to a structurally defined site on their molecular target. This disqualifies such molecules from optimization by medicinal chemistry, and therefore their rapid elimination from screening hit lists is essential for productive and effective drug discovery. AREAS COVERED: This review covers recent literature that either investigates the various mechanisms behind non-stoichiometric inhibition or suggests assays and readouts to identify them. In addition, combination of the various methods to distill promising molecules out of raw primary hit lists step-by-step is considered. Emerging technologies to demonstrate target engagement in cells are also discussed. EXPERT OPINION: Over the last few years, awareness of non stoichiometric inhibitors within screening libraries and HTS hit lists has considerably increased, not only in the pharmaceutical industry but also in the academic drug discovery community. This has resulted in a variety of methods to detect and handle such compounds. These range from in silico approaches to flag suspicious compounds, and counterassays to measure non-stoichiometric inhibition, to biophysical methods that positively demonstrate stoichiometric binding. In addition, novel technologies to verify target engagement within cells are becoming available. While still a time- and resource-consuming nuisance, non stoichiometric inhibitors therefore do not fundamentally jeopardize the discovery of low molecular weight lead and drug candidates. Rather, they should be viewed as a manageable issue that with appropriate expertise can be overcome through integration of the above-mentioned approaches. PMID- 26653533 TI - Microbiology of healthcare-associated infections and the definition accuracy to predict infection by potentially drug resistant pathogens: a systematic review. AB - BACKGROUND: Healthcare-associated infections (HCAI) represent up to 50 % of all infections among patients admitted from the community. The current review intends to provide a systematic review on the microbiological profile involved in HCAI, to compare it with community-acquired (CAI) and hospital-acquired infections (HAI) and to evaluate the definition accuracy to predict infection by potentially drug resistant pathogens. METHODS: We search for HCAI in MEDLINE, SCOPUS and ISI Web of Knowledge with no limitations in regards to publication language, date of publication, study design or study quality. Only studies using the definition by Friedman et al. were included. This review was registered at PROSPERO Systematic Review Registration with the Number CRD42014013648. RESULTS: A total of 21 eligible studies with 12,096 infected patients were reviewed; of these 3497 had HCAI, 2723 were microbiologically documented. Twelve studies were on pneumonia involving 1051 patients with microbiological documented HCAI, the application of the current guidelines for this group of patients would result in an appropriate antibiotic therapy in 95 % of cases at the expense of overtreatment in 73 %; the application of community-acquired pneumonia guidelines would be adequate in only 73-76 % of the cases; an alternative regimen with piperacillin-tazobactam or aztreonam plus azithromycin would increase antibiotic adequacy rate to 90 %. Few studies were found on additional focus of infection: endocarditis, urinary, intra abdominal and bloodstream infections. All studies included in this review showed an association of the HCAI definition with infection by PDR pathogens when compared to CAI [odds ratio (OR) 4.05, 95 % confidence interval (95 % CI) 2.60 6.31)]. The sensitivity of HCAI to predict infection by a PDR pathogen was 0.69 (0.65-0.72), specificity was 0.67 (0.66-0.68), positive likelihood ratio was 1.9 and the area under the summary ROC curve was 0.71. CONCLUSIONS: This systematic review provides evidence that HCAI represents a separate group of infections in terms of the microbiology profile, including a significant association with infection by PDR pathogens, for the main focus of infection. The results provided can help clinician in the selection of empiric antibiotic therapy and international societies in the development of specific treatment recommendations. PMID- 26653535 TI - A genome-wide survey of DNA methylation in hexaploid wheat. AB - BACKGROUND: DNA methylation is an important mechanism of epigenetic gene expression control that can be passed between generations. Here, we use sodium bisulfite treatment and targeted gene enrichment to study genome-wide methylation across the three sub-genomes of allohexaploid wheat. RESULTS: While the majority of methylation is conserved across all three genomes we demonstrate that differential methylation exists between the sub-genomes in approximately equal proportions. We correlate sub-genome-specific promoter methylation with decreased expression levels and show that altered growing temperature has a small effect on methylation state, identifying a small but functionally relevant set of methylated genes. Finally, we demonstrate long-term methylation maintenance using a comparison between the D sub-genome of hexaploid wheat and its progenitor Aegilops tauschii. CONCLUSIONS: We show that tri-genome methylation is highly conserved with the diploid wheat progenitor while sub-genome-specific methylation shows more variation. PMID- 26653536 TI - Self-tracking the microbiome: where do we go from here? AB - The quantified self community brings together enthusiasts who are using technological devices to monitor their health and social media to share their personal data with others online. In light of the growing popularity of this movement, self-trackers are challenging the health-care system by raising important questions about data ownership and risk-taking. As we enter a new era of consumer genomics, a significant number of quantified self (QS) individuals are now interested in the monitoring of their microbiome and performing personal interventions. In this paper, we discuss the scientific validity of experiments involving serial observations of a single individual as opposed to randomized clinical trials. We look at self-tracking from an ethical standpoint by questioning the risks and assessing the potential benefits for personalized medicine in general and for microbiome research in particular. PMID- 26653537 TI - Hollow-Cuboid Li3VO4/C as High-Performance Anodes for Lithium-Ion Batteries. AB - Li3VO4 has been demonstrated to be a promising anode material for lithium-ion batteries with a low, safe voltage and large capacity. However, its poor electronic conductivity hinders its practical application particularly at a high rate. This work reports that Li3VO4 coated with carbon was synthesized by a one pot, two-step method with F127 ((PEO)100-(PPO)65-(PEO)100) as both template and carbon source, yielding a microcuboid structure. The resulting Li3VO4/C cuboid shows a stable capacity of 415 mAh g(-1) at 0.5 C and excellent capacity stability at high rates (e.g., 92% capacity retention after 1000 cycles at 10 C = 4 A g(-1)). The lithiation/delithiation process of Li3VO4/C was studied by ex situ X-ray diffraction and Raman spectroscopy, which confirmed that Li3VO4/C underwent a reversible intercalation reaction during discharge/charge processes. The excellent electrochemical performance is attributed largely to the unique microhollow structure. The voids inside hollow structure can not only provide more space to accommodate volume change during discharge/charge processes but also allow the lithium ions insertion and extraction from both outside and inside the hollow structure with a much larger surface area or more reaction sites and shorten the lithium ions diffusion distance, which leads to smaller overpotential and faster reaction kinetics. Carbon derived from F127 through pyrolysis coats Li3VO4 conformably and thus offers good electrical conduction. The results in this work provide convincing evidence that the significant potential of hollow cuboid Li3VO4/C for high-power batteries. PMID- 26653538 TI - Reproducibility of Differential Proteomic Technologies in CPTAC Fractionated Xenografts. AB - The NCI Clinical Proteomic Tumor Analysis Consortium (CPTAC) employed a pair of reference xenograft proteomes for initial platform validation and ongoing quality control of its data collection for The Cancer Genome Atlas (TCGA) tumors. These two xenografts, representing basal and luminal-B human breast cancer, were fractionated and analyzed on six mass spectrometers in a total of 46 replicates divided between iTRAQ and label-free technologies, spanning a total of 1095 LC MS/MS experiments. These data represent a unique opportunity to evaluate the stability of proteomic differentiation by mass spectrometry over many months of time for individual instruments or across instruments running dissimilar workflows. We evaluated iTRAQ reporter ions, label-free spectral counts, and label-free extracted ion chromatograms as strategies for data interpretation (source code is available from http://homepages.uc.edu/~wang2x7/Research.htm ). From these assessments, we found that differential genes from a single replicate were confirmed by other replicates on the same instrument from 61 to 93% of the time. When comparing across different instruments and quantitative technologies, using multiple replicates, differential genes were reproduced by other data sets from 67 to 99% of the time. Projecting gene differences to biological pathways and networks increased the degree of similarity. These overlaps send an encouraging message about the maturity of technologies for proteomic differentiation. PMID- 26653539 TI - Design, Synthesis, and Biological Characterization of Novel Mitochondria Targeted Dichloroacetate-Loaded Compounds with Antileukemic Activity. AB - The mitochondrial kinase inhibitor dichloroacetate (DCA) has recently received attention in oncology due to its ability to target glycolysis. However, DCA molecule exhibits poor bioavailability and cellular uptake with limited ability to reach its target mitochondria. To overcome these biases, we have synthesized novel DCA-loaded compounds. The selection of the most promising therapeutic molecule was evaluated by combining in vitro assays, to test the antitumoral potential on leukemic cells, and a preliminary characterization of the molecule stability in vivo, in mice. Among the newly synthesized compounds, we have selected the multiple DCA-loaded compound 10, characterized by a tertiary amine scaffold, because it exhibited enhanced (>30-fold) in vitro antitumor activity with respect to DCA and increased in vivo stability. On the basis of these results, we believe that compound 10 should be considered for further preclinical evaluations for the treatment of cancers and/or other diseases characterized by altered metabolic origin. PMID- 26653540 TI - Comparison of total ankle replacement and ankle arthrodesis in patients with haemophilia using gait analysis: two case reports. AB - BACKGROUND: Severe hemophilia is an inherited, lifelong bleeding disorder characterized by spontaneous bleeding, which results in painful joint deformities. Currently two surgical treatments are available to treat haemophilia related ankle joint destruction: ankle arthrodesis and total ankle replacement. The aim of the present study was to compare these two surgical procedures in haemophiliac subjects. CASE PRESENTATION: Kinematic and dynamic parameters were quantified using a three-dimensional gait-analysis system in two similar clinical cases. In Caucasian case 1, ankle arthrodesis was chosen because of a kinematic ankle flexion defect and lack of dynamic power regeneration. The defect in energy absorption was compensated for by the contralateral side. Total ankle replacement in Caucasian case 2 allowed sparing the ipsilateral knee (maximum 0.27 preoperatively vs. 0.71 W/kg postoperatively) and hip joints powers (maximum 0.43 preoperatively vs. 1.25 W/kg postoperatively) because of the small ankle dorsiflexion motion. CONCLUSIONS: Total ankle replacement is recommended for haemophiliac patients who present with a preserved ankle range of motion. PMID- 26653541 TI - Beetroot juice increase nitric oxide metabolites in both men and women regardless of body mass. AB - The nitrate (NO3(-)) present in beetroot juice (BJ) has been studied for its effect on the cardiovascular system by converting to nitric oxide (NO). In the present study, we evaluated the effect of BJ on the excretion of NO metabolites and its relationship with body mass in both men and women. NO metabolites - urinary NO3(-), nitrite (NO2(-)) and NOx were analyzed by using a high performance liquid chromatography system. There were significant increases in urinary NO3(-), NO2(-) and NOx in BJ as compared to PLA (BJ without NO3(-)). No significant difference between men and women was observed in NO metabolites after BJ at any time point. There were no significant relationships between urinary NO3(-), NO2(-) and NOx and body mass in BJ intervention for both men and women. In conclusion, urinary NO metabolites after BJ consumption increases in similar manner between sexes regardless of body mass. PMID- 26653542 TI - Pretreatment of LPS inhibits IFN-beta-induced STAT1 phosphorylation through SOCS3 induced by LPS. AB - It has been known that LPS activates macrophages and induces IFN-beta production from macrophages. The endogenous IFN-beta produced by LPS stimulates the cells, which plays a role in innate immune. However, it was not elucidated yet if the signaling by exogenous IFN-beta was influenced by LPS stimulation. In this study, it was found pretreatment of LPS interrupted IFN-beta-induced JAK1/STAT1 phosphorylation. LPS pretreatment also reduced IFN-beta-induced ISG54, one of IFN beta-inducible genes. Pretreatment with LPS for more than 2h shows inhibitory effect on IFN-beta-induced STAT1 phosphorylation but simultaneous treatment or post-treatment of LPS with IFN-beta did not show the inhibitory effect. The study using a neutralizing antibody to IFN-beta indicated that IFN-beta produced by LPS does not take part in the inhibitory effect of LPS. Furthermore, LPS did not affect the expression of IFN alphabeta receptor. A previous report has shown that LPS-induced SOCS3 inhibited IFN-gamma-induced STAT1 phosphorylation, likewise, it was also shown in this study that LPS induced SOCS3 expression and its expression inhibited IFN-beta-induced STAT1 phosphorylation which was confirmed by the knockdown study by the siRNA of SOCS3. The real-time PCR and immune-blot studies of SOCS3 indicated that LPS induced SOCS3 is independent of IL-6, IL-10, TNF alpha and STAT3, and might depend on p38 activation by LPS. It was suggested that bacterial LPS rather interfere with IFN-beta actions, dependent on the timing of LPS stimulation. PMID- 26653543 TI - Activities of apocynin in cytotoxicity assays of potential pathological relevance. AB - Low levels of some reactive oxygen and nitrogen species (ROS, RNS) are of physiological importance; but high levels result in oxidative stress and can perturb many cell functions including signal transduction and transport, and contribute to aging and chronic diseases. Apocynin (1-(4-hydroxy-3 methoxyphenyl)ethanone) is a phytochemical with reported antioxidant activities in some experimental models of human disease. The major objectives of the current study were to test the antioxidant capacity of apocynin in a hemin-peroxide assay, and test its capacity to moderate pro-oxidant-dependent inhibition of a cell function-endocytic transport. Apocynin, tested at concentrations up to 20MUM, did not exhibit statistically significant antioxidant activity (94.3+/ 7.8% relative to controls, p>0.05) in the oxidation assay. When tested against the inhibition of endocytic transport by hydrogen peroxide, apocynin treatment did not significantly rescue such inhibition in the cell types tested (p>0.05, relative to peroxide alone). When cells were treated with a cytotoxic protein aggregate that increased both ROS and RNS, apocynin treatment only inhibited production of the latter (30.0+/-3.6% inhibition relative to controls without apocynin, p<0.05). The results provide evidence that apocynin, unlike other phytochemicals such as curcumin, does not exhibit antioxidant activity in the heme-peroxide assay. The results also provide the first evidence that apocynin does not rescue hydrogen peroxide-mediated inhibition of endocytic transport, nor prevent hydrogen peroxide production by a cytotoxic protein aggregate. In the latter toxicity assay, however, apocynin could moderate oxidative stress by decreasing cellular levels of RNS. PMID- 26653544 TI - Peritumoral ductular reaction is related to nuclear translocation of beta-catenin in hepatocellular carcinoma. AB - Increased peritumoral ductular reaction (DR) is related to poor prognosis in hepatocellular carcinoma (HCC) but the mechanism is unclear. Nuclear translocation of beta-catenin is correlated with HCC metastasis and recurrence. Thus, we aim to explore whether there is a relationship between peritumoral DR and tumoral nuclear translocation of beta-catenin in HCC. Hepatitis B virus (HBV) related HCC patients (n=120) were enrolled into this study from January 2003 to December 2007. Clinicopathological variables were collected and immunohistochemistry staining for cytokeratin 19 (CK19), proliferating cell nuclear antigen (PCNA), beta-catenin, phosphorylated-Smad2 (PSmad2) and transforming growth factor-beta1 (TGF-beta1) were performed in tumor and/or peritumor liver tissues. Peritumoral DR is significantly correlated with local inflammation (P<0.001), fibrosis (P<0.001), tumor size (P=0.006) and CK19 expression in the tumor (P=0.005). More patients with peritumoral DR had nuclear accumulation of beta-catenin than patients with mild peritumoral DR (37.50% vs. 14. 58%, P=0.011). HCCs in the obvious DR group had stronger expression of PSmad2 than that in the mild DR group, and patients with nuclear translocation of beta catenin also had higher PSmad2 expression. In conclusion, increased peritumoral DR is related to tumoral nuclear translocation of beta-catenin in HCC and enhanced action of TGF-beta1 signaling may be involved in this relationship. PMID- 26653545 TI - Update on the role of p75NTR in neurological disorders: A novel therapeutic target. AB - As a low-affinity neurotrophins receptor, p75 neurotrophin receptor (p75NTR) is a transmembrane receptor involved in a diverse array of cellular responses, including apoptosis, survival, neurite outgrowth, migration, and cell cycle arrest, which may be related to some neurological disorders, such as Alzheimer's disease (AD), schizophrenia, major depressive disorder (MDD), posttraumatic stress disorder (PTSD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). Indeed, a series of studies during the last decade has demonstrated that the p75NTR signaling plays key roles in most aspects of the neurological disorder diseases. In spite of the limited information available, this review still tried to summary the relationship between p75NTR and diverse neurological disorder diseases, and tried to further clarify the possible mechanism, which may provide a novel therapeutic target for the treatment of neurological disorders. PMID- 26653546 TI - Multiple-purpose immunotherapy for cancer. AB - Anti-cancer vaccination is a useful strategy to elicit antitumor immune responses, while overcoming immunosuppressive mechanisms. Whole tumor cells or lysates derived thereof hold more promise as cancer vaccines than individual tumor-associated antigens (TAAs), because vaccinal cells can elicit immune responses to multiple TAAs. Cancer cell-based vaccines can be autologous, allogeneic or xenogeneic. Clinical use of xenogeneic vaccines is advantageous in that they can be most effective in breaking the preexisting immune tolerance to TAAs. An attractive protocol would be to combine vaccinations with immunostimulating and/or immunosuppression-blocking modalities. It is reasonable to anticipate that combined immunotherapeutic strategies will allow for substantial improvements in clinical outcomes in the near future. PMID- 26653547 TI - Bioactivity of genistein: A review of in vitro and in vivo studies. AB - Genistein is a soy derived isoflavanoid compound with multitude of health benefits. This compound is found to be a potent agent in both prophylaxis and treatment of cancer and various other chronic diseases. Ranging from its antioxidant activity to its effect on various cancer types, genistein has been a compound of interest in a number of studies carried out so far. The great interest that has focused on genistein led to the identification of numerous intracellular targets of its action in the live cells. Retardation of atherogenic activity and increasing the antioxidant defense of a cell has been attributed to genistein while as it has also been reported that genistein possesses suppressive effects on both the cell-mediated and humoral components of the adaptive immune system. At the molecular level, genistein reduces the number of developing CD4(+) and CD8(+) thymocytes suggesting a possible mechanism for genistein effects on cell-mediated immunity. Genistein may inhibit cancer progression by inducing apoptosis or inhibiting proliferation. In addition, genistein has its prominent role in preventing the DNA damage. Apolipoprotein B secretion gets reduced when the subjects are administered with genistein. Genistein confers a better protection to ischemic conditions thereby giving a significant cardioprotection. At cellular level adipocyte differentiation is another property of genistein which makes it a better neutraceutical which can reduce the atherogenic condition and hypercholesterolemia. Expression of human endothelial nitric oxide synthase is associated with genistein supplementation. The advantage of using genistein is its multidirectional action and its lesser toxicity. PMID- 26653548 TI - Altered sensitivity to ellagic acid in neuroblastoma cells undergoing differentiation with 12-O-tetradecanoylphorbol-13-acetate and all-trans retinoic acid. AB - Ellagic acid has previously been reported to induce reduced proliferation and activation of apoptosis in several tumor cell lines including our own previous data from non-differentiated human neuroblastoma SH-SY5Y cells. The aim of this study was now to investigate if in vitro differentiation with the phorbol ester 12-O- tetradecanoylphorbol-13-acetate or the vitamin A derivative all-trans retinoic acid altered the sensitivity to ellagic acid in SH-SY5Y cells. The methods used were cell counting and LDH-assay for evaluation of cell number and cell death, flow cytometric analysis of SubG1- and TUNEL-analysis for apoptosis and western blot for expression of apoptosis-associated proteins. In vitro differentiation was shown to reduce the sensitivity to ellagic acid with respect to cell detachment, loss of viability and activation of apoptosis. The protective effect was phenotype-specific and most prominent in all-trans retinoic acid differentiated cultures. Differentiation-dependent up-regulation of Bcl-2 and integrin expression is introduced as possible protective mechanisms. The presented data also point to a positive correlation between proliferative activity and sensitivity to ellagic-acid-induced cell detachment. In conclusion, the presented data emphasize the need to consider degree of neuronal differentiation and phenotype of neuroblastoma cells when discussing a potential pharmaceutical application of ellagic acid in tumor treatment. PMID- 26653549 TI - NDRG1 promotes the multidrug resistance of neuroblastoma cells with upregulated expression of drug resistant proteins. AB - BACKGROUND: Resistance to chemotherapeutic drugs and recurrence are two major causes of poor prognosis in many tumors including neuroblastoma. This study aimed to investigate the effect of the elevated intracellular NDRG1 expression on drug resistance of human neuroblastoma cells to chemotherapy, for exploring novel approaches for biotherapy of neuroblastoma. METHODS: Human neuroblastoma KP-N-Ns cell lines were transfected with the lentivirus vector containing human NDRG1 cDNA, with empty vector-transfected or blank cells as controls. Transfection status was confirmed under fluorescence microscope, while PCR assay and western blot analysis were performed to determine the expression changes. MTT and TUNEL assays were used to detect the resistance of the cells to anticancer drugs, including vincristine, cyclophosphamide and so on. Additionally, the expression of drug resistant proteins was detected. RESULTS: Stable lentiviral transfection cell line was successfully established with significantly upregulated NDRG1 expression. MTT assay revealed greater cell growth under NDRG1 overexpression with drugs stimulation, as compared to controls. TUNEL assay also showed less apoptosis of NDRG1 overexpressing cells than those of controls when exposed to these drugs, suggesting the increasing drug resistance through NDRG1 overexpression. Besides, the expression of MDR, LRP-1 and MRP-1 was also increased in NDRG1 overexpressing cells, implying NDRG1-mediated pathways in multidrug resistance of neuroblastoma. CONCLUSION: NDRG1 could increase the resistance of neuroblastoma cells to chemotherapeutic drugs, with its positive regulation on drug resistant proteins. This study provided new insights for exploring the mechanism of the resistance to chemotherapeutic drugs and also novel approach for biotherapy in neuroblastoma. PMID- 26653550 TI - Diagnostic importance of S100A9 and S100A12 in breast cancer. AB - BACKGROUND: The most frequent cause of cancer deaths throughout the world is breast cancer (BC). Therefore, preventing, diagnosing and treating BC has gained importance. S100 protein probably plays an important role in carcinogenesis, cancer development, and metastasis. In this study, we aimed at diagnostic and clinic-pathological importance of serum levels of S100A9 and S100A12 with known cytokine-like pro-inflammatory effects in BC. MATERIAL AND METHOD: Serum samples were collected with BC and the control group consisting of healthy individuals. All the samples were analyzed with enzyme-linked immunosorbent assay for serum S100A9 and S100A12 levels before starting the systemic chemotherapy. Clinicopathological characteristics of BC and other blood parameters were compared in relation with serum S100A9 and S100A12 levels. RESULTS: While the serum S100A9 levels were found significantly higher as compared to healthy individuals (190.85+/-32.29 and 92.72+/-54, respectively) (p=0.001), it was observed that there were no differences in S100A12 (120.50+/-15.78 and 112.21+/ 10.46, respectively) (p=0.056) levels. As regards the subgroup analysis in BC patients, no statistically significant results were found in body mass index (BMI), smoking, menopause status, histopathologic type, grade, and biological subtype of BC, tumor size, presence of lymph node metastases, lymphovascular invasion (LVI), perineural invasion (PNI) and stage. As regards the blood parameters and serum S100 A9, while only statistically significant results were found with anemia (209.05+/-33.12 and 181.75+/-28.21, respectively) (p=0.005), no statistically significant results were found with leukocytosis, thrombocytosis and tumor markers. CONCLUSION: In this study, while we found the level of S100A9, which has a potential cytokine-like function in inflammation, significantly higher, we could not find any increase in S100A12 level. Therefore, it is possible that S100A9 can play a key role in inflammation-related BC. Despite of there are no significance relationship between S100A9 and S100A12 clinicopathological features of BC, the determination of S100A9 levels contributes to diagnosis the of BC patients. In future, we suggest that serum S100A9 is investigated as a diagnostic tool even the target marker in BC to suppress inflammation in treatment. PMID- 26653551 TI - Modification of sPD1 with CRT induces potent anti-tumor immune responses in vitro and in vivo. AB - As a key factor for tumor occurrence and development, tumor cells escape immune surveillance and inhibit the body immune killer effect through negative signaling pathways. In this research, we designed and expressed the fusion protein CRT-sPD1 to block PD1/PDL1 negative signal pathway, indirectly bind CRT to the tumor cell surface and to increase the cell immunogenicity activity. Results from western blotting, flow cytometry (FCM) and ELISA showed that the cell lines that stably express CRT, PD1 and CRT-sPD1 protein were obtained and the transfected cellular supernatant contained PD1 and CRT-sPD1 could bind to PDL1 on the surface of EL4 cells. Vitro experiments indicated the secreted mCRT-sPD1 protein could bind to PDL1 and enhance lymphocyte proliferation and CTL activity. We also found that fusion protein CRT-sPD1 could activate and induce the immune system to kill the tumor cells, specifically inhibit the tumor growth and prolong the survival period in mouse tumor model. And all these suggested that CRT-sPD1 could be used as drug development and utilization of cancer immunotherapy. PMID- 26653552 TI - Aminopeptidase N inhibitor 4cc synergizes antitumor effects of 5-fluorouracil on human liver cancer cells through ROS-dependent CD13 inhibition. AB - Aminopeptidase N (APN, also known as CD13) is involved in cellular processes of various types of tumors and a potential anti-cancer therapeutic target. Here, we report the effect of an APN inhibitor 4cc in enhancing sensitivity of hepatocellular carcinoma (HCC) cell lines and xenograft model in response to 5 fluorouracil (5-FU) in vivo and in vitro. The treatment of the combination of 4cc with 5-FU, compared to the combination of bestain with 5-FU, markedly suppressed cell growth and induced apoptosis of HCC cells, accompanying the increase in the level of reactive oxygen species (ROS) and followed by a decrease in the mitochondrial membrane potential (DeltaPsiM). Furthermore, the combination of 4cc and 5-FU showed a significant inhibitory effect on the growth of HCC xenograft tumors. In addition, following the treatment of 4cc, APN activity and clonogenic formation and the number of CD13-positive cells in PLC/PRF/5 cells were significantly decreased, suggesting that 4cc may also inhibit liver cancer stem cells by CD13 inhibition. These results showed that the APN inhibitor 4cc synergizes antitumor effects of 5-FU on human liver cancer cells via ROS-mediated drug resistance inhibition and concurrent activation of the mitochondrial pathways of apoptosis. PMID- 26653553 TI - Expression of c-erb-B2 gene in bladder cancer of Egyptian patients and its correlation with p53 and bcl-2. AB - Urinary bladder cancer is the 9th most common type of cancer and the 13th most common cause of death worldwide. C-erbB-4 is a class of oncogenes plays a role in cancer development. The present work was performed to assess C-erbB-4 oncogene amplification by PCR technology and its correlation with p53 and bcl-2. This study included 50 male patients (10 controls and 40 urinary bladder cancer patients). The bladder cancer patients include 20 specimens diagnosed as transitional cell carcinoma (TCC) and 20 specimens diagnosed as squamous cell carcinoma (SCC). The results revealed that 7 (35%) of both TCC and SCC showed c erb-B2 gene amplification. 12 (60%) of TCC and 6 (30%) of SCC showed positive expression of p53. 11 (55%) of TCC and 6 (30%) of SCC showed positive Bcl-2 expression. A direct statistically significant association was detected between c erb-B2 expression and Bcl-2 and p53 expression in TCC and SCC specimens. Seven (35%) of TCC showed c-erb-B2 gene amplification and expression of both p53 and Bcl-2. Five (25%) of the examined SCC specimens showed c-erb-B2 gene amplification and positive expression for both p53 and Bcl-2. The results indicated that a direct statistically significant association was detected in TCC group between amplification of c-erb-B2 gene by PCR and expressionof p53 and Bcl 2 by immunohistochemistry. PMID- 26653554 TI - MiR-1290 promotes cancer progression by targeting nuclear factor I/X(NFIX) in esophageal squamous cell carcinoma (ESCC). AB - The nuclear factor I/X (NFIX) plays important roles in cell differentiation, but its function in cancer is still unclear. Besides, accumulating studies reported the important role of microRNAs (miRNAs) in the regulation of gene expression, among of which, the miR-1290 has been widely reported in various cancers. In this study, we investigated the mechanism through which NFIX was regulated by miRNAs. Firstly, we found that the NFIX protein and mRNA levels were consistently down regulated in ESCC tissues suggesting that a post-transcriptional mechanism maybe involved in the regulation of NFIX. Since microRNAs (miRNAs) are powerful post transcriptional regulators of gene expression, we performed bioinformatic analyses to search for miRNAs that potentially target NFIX. We identified the specific targeting site of miR-1290 in the 3'-UTR of NFIX and the inverse correlation between the levels of miR-1290 and NFIX protein and mRNA in ESCC tissue samples was then confirmed. By overexpressing or silencing miR-1290 in ESCC cells, we experimentally validated that miR-1290 directly binds to the 3' UTR of the NFIX transcript and degrade the NFIX mRNA to regulate NFIX expression. Furthermore, the biological consequences that miR-1290 mediated by targeting NFIX were examined in vitro. We demonstrated that miR-1290 could promote proliferation, migration and invasion via the negative regulation of NFIX expression. Taken together, our findings suggested that miR-1290 functions as a tumor oncogene in the progression of ESCC by targeting NFIX. PMID- 26653555 TI - Elevated expression of microRNA-30b in osteoarthritis and its role in ERG regulation of chondrocyte. AB - ERG (ETS-related gene) belongs to the ETS family of transcription factors, and has been recently reported to contribute to homeostatic balance in skeleton cell plasticity. MicroRNA-30 (miR-30) family is also demonstrated to play a role in controlling chondrocyte differentiation. The current study investigated the miR 30b and ERG expression in articular cartilage of osteoarthritis (OA) patients. A total of 20 subjects, with 10 OA patients and 10 healthy participants, were included in this study. Human chondrosarcoma cell line SW1353 was used to explore the relationship of miR-30b and ERG in vitro. In OA patients, a significant increase of miR-30b and a decrease of ERG were observed in articular cartilage compared with Normal ones. MiR-30b mimic down-regulated the ERG mRNA and protein expression levels, while miR-30b inhibitor up-regulated ERG expression. In addition, miR-30b mimic also decreased the mRNA expression of COL2a and aggrecan, while miR-30b inhibitor had the opposite effect. Luciferase reporter assay confirmed that miR-30b targeted ERG. In conclusion, miR-30b was involved in the process of OA, and it probably functioned through its target gene ERG. PMID- 26653556 TI - L-Arginine and vitamin C attenuate pro-atherogenic effects of high-fat diet on biomarkers of endothelial dysfunction in rats. AB - High-fat diet (HFD) is known to cause endothelial dysfunction and contribute to atherosclerosis progression. The objective of this study was to evaluate the efficacy of L-arginine (L-Arg) and vitamin C supplementation as a potentially useful strategy for modulation of serum homocysteine (Hcy) levels, tumor necrosis factor alpha (TNF-alpha), oxidative stress, and insulin resistance induced by HFD in rats. Six weeks-old female and male Wistar rats were divided into five groups of twelve rats each and treated for six weeks with: group 1, standard diet; group 2, HFD; group 3, HFD supplemented with L-Arg (20g/kg diet); group 4, HFD supplemented with L-Arg (20g/kg diet) plus vitamin C (100mg/kg diet); group 5, HFD supplemented with vitamin C (100mg/kg diet). HFD significantly elevated TNF alpha, reduced total antioxidant status (TAS), and increased insulin resistance (HOMA-IR). Significant increases of total cholesterol (TCH), LDL cholesterol (LDL), triglyceride (TG) and a decrease of HDL cholesterol (HDL) were observed in HFD rats. Supplementation with l-Arg prevented the decrease of TAS and the increases in HOMA-IR, LDL, and TG levels. Moreover, Hcy and TNF-alpha levels were reduced in L-Arg supplemented group. Supplementation with vitamin C significantly atenuated TAS decrease and lowered LDL levels. L-Arg plus vitamin C enhanced L Arg effect on TAS and protected against TNF-alpha increase. Western blot analysis showed that l-Arg supplementation of HFD rats reduced the level of protein carbonyls. Taken together, these findings indicate that supplemental l-arginine and/or vitamin C, by their abilities to modulate biomarkers of HFD-induced endothelial dysfunction, are anti-atherogenic. PMID- 26653557 TI - Advances and perspectives of colorectal cancer stem cell vaccine. AB - Colorectal cancer is essentially an environmental and genetic disease featured by uncontrolled cell growth and the capability to invade other parts of the body by forming metastases, which inconvertibly cause great damage to tissues and organs. It has become one of the leading causes of cancer-related mortality in the developed countries such as United States, and approximately 1.2 million new cases are yearly diagnosed worldwide, with the death rate of more than 600,000 annually and incidence rates are increasing in most developing countries. Apart from the generally accepted theory that pathogenesis of colorectal cancer consists of genetic mutation of a certain target cell and diversifications in tumor microenvironment, the colorectal cancer stem cells (CCSCs) theory makes a different explanation, stating that among millions of colon cancer cells there is a specific and scanty cellular population which possess the capability of self renewal, differentiation and strong oncogenicity, and is tightly responsible for drug resistance and tumor metastasis. Based on these characteristics, CCSCs are becoming a novel target cells both in the clinical and the basic studies, especially the study of CCSCs vaccines due to induced efficient immune response against CCSCs. This review provides an overview of CCSCs and preparation technics and targeting factors related to CCSCs vaccines in detail. PMID- 26653558 TI - MicroRNA-130b promotes cell migration and invasion by targeting peroxisome proliferator-activated receptor gamma in human glioma. AB - MircroRNA-130b (miR-130b) has been recognized as an oncogenic miRNA and is implicated in the initiation and development of human cancers. Deregulation of miR-130b has been reported in several tumors. However, the clinical significance and its underlying role in human glioma are poorly explored. Herein, we found that the expression of miR-130b was significantly up-regulated in glioma tissues as compared with that in normal brain (NB) tissues. Clinical association analysis disclosed that high-expression of miR-130b was evidently associated with advanced tumor stage (grade III+IV) in glioma. Moreover, we disclosed that the high expression of miR-130b conferred an obviously reduced survival of glioma patients. Multivariate Cox regression analysis showed that miR-130b expression was an independent prognostic indicator for glioma patients. Our gain- or loss-of function studies showed that miR-130b promoted invasion and migration of glioma cells. Notably, miR-130b regulated peroxisome proliferator-activated receptor gamma (PPARgamma) abundance and epithelial-mesenchymal transition (EMT) in glioma cells. Hereby, PPARgamma was identified as a functional target of miR-130b in glioma. Furthermore, an inverse correlation between miR-130b and PPARgamma expression was observed in glioma tissues. In conclusion, miR-130b is an independent prognostic biomarker for indicating survival of glioma patients and promotes glioma cell migration and invasion by targeting PPARgamma. PMID- 26653559 TI - In vitro and in vivo antileishmanial properties of a 2-n-propylquinoline hydroxypropyl beta-cyclodextrin formulation and pharmacokinetics via intravenous route. AB - 2-n-propylquinoline (2-n-PQ) had shown interesting in vivo antileishmanial activities after administration by oral route on leishmaniasis animal models. However, the lipophilic properties of this compound avoid its use by intravenous route, this route being indicated in cases of severe visceral leishmaniasis with vomiting. Thus, a 2-n-propylquinoline hydroxypropyl beta-cyclodextrin (2-n-PQ HPC) formulation was set up in this aim. The formulation was active in vitro both on Leishmania donovani axenic and intramacrophage amastigotes with IC50 values at 6.22+/-0.82MUM and 20.01+/-0.52MUM, respectively, without any toxicity on macrophages. 2-n-PQ-HPC exhibited similar activity on WT and drug-resistant parasites. Its in vitro interactions with antimonials, amphotericin B and miltefosine were found as additive both in axenic amastigotes and intramacrophage amastigotes. 2-n-PQ-HPC was not able to generate drug resistance after in vitro drug pressure since the resistance index was less than 4. 2-n-PQ-HPC was also active on the L. donovani/Balb/c mice model with an intravenous treatment regimen at 10mgkg(-1)day(-1) on 10 consecutive days without hepatic, renal and blood toxicity. The pharmacokinetics of 2-n-PQ in rats showed that after an intravenous treatment of the formulation at 10mgkg(-1), the plasma drug concentrations rapidly declined bi-exponentially with a half-life of 58.7min and a total clearance of 18.63lh(-1)kg(-1). The apparent volume of distribution was higher than the blood volume in rats, indicating that 2-n-PQ was well distributed in tissues, allowing parasite elimination. Such a formulation is worth of further antiparasitic and toxicological evaluations. PMID- 26653560 TI - Clinical analysis of 95 cases of pulmonary sarcomatoid carcinoma. AB - OBJECTIVES: To collect data on the clinical characteristics, pathologic presentation, and prognosis of patients with pulmonary sarcomatoid carcinoma. METHODS: From September 24, 2008 to June 3, 2014, 95 patients were hospitalized at the Shanghai Chest Hospital for the treatment of pulmonary sarcomatoid carcinoma. We retrospectively collected patient gender, age, smoking history, time of initial diagnosis, diagnostic methods, tumor location, pathohistological subtype, tumor size, TNM stage, immunohistochemical results, subsequent treatments, and patient survival. RESULTS: Of the 95 patients included in this study, 80 were male and 15 were female. Median patient age was 64 years (range: 43-80 years). There were 29 cases of pleomorphic carcinoma, one case of giant cell carcinoma, six cases of spindle cell carcinoma, and six cases of carcinosarcoma. The other 53 cases were not subtyped. The median survival was 11.54 months (range: 0.9-100.9 months). 1-, 2-, 3-, and 5-year survival was 32%, 30%, 25%, and 21%, respectively. Univariate analysis showed that tumor size, stage, T1+T2 vs T3+T4 stage, N stage, and M stage were prognostic factors for survival. Multivariate regression analysis showed that T stage and lymph node metastases were independent prognostic factors. CONCLUSION: Pulmonary sarcomatoid carcinoma is an uncommon, aggressive cancer. T1+T2 vs T3+T4 stage and lymph node metastases were independent prognostic factors. Our results underscore the importance of early detection and early diagnosis. Effective treatments for this disease are lacking. PMID- 26653561 TI - The tumor-suppressor gene LZTS1 suppresses hepatocellular carcinoma proliferation by impairing PI3K/Akt pathway. AB - BACKGROUND: To study the role of LZTS1 in hepatocellular carcinoma (HCC) proliferation and the molecular mechanism involved. METHODS: LZTS1 expression was studied in 10 HCC cell lines and 1 normal hepatocyte cell line by western blot analysis and qRT-PCR. One HCC cell line was selected and transfected with LZTS1 lentivirus. Cell proliferation and cell cycle were then determined by CCK-8 assay and flow cytometry, respectively. LZTS1, cyclin D1, CDK1, Cdc25C, pS473 Akt, and pT308 Akt mRNA and protein expressions were measured. PS473 Akt and pT308 Akt expression level was also compared with the HCC cells treated with LY294002. RESULTS: Compared with the normal hepatocyte cells, LZTS1 expression in HCC cells was significantly lower. After the transfection with LZTS1 lentivirus, HCC cell proliferation ability decreased markedly and HCC cells were blocked at G2/M phase. Cyclin D1 and CDK1 expression were both decreased but not significantly. Cdc25C expression was increased significantly. PS473 Akt and pT308 Akt expression level was increased significantly as well, which were almost the same with those transfected with LY294002. CONCLUSION: LZTS1 could inhibit HCC cell proliferation by impairing PI3K/Akt pathway. PMID- 26653562 TI - Prognostic value of regulator of G-protein signaling 6 in colorectal cancer. AB - Reprogrammed metabolism is a hallmark of cancer cells. Regulator of G-protein signaling 6 (RGS6), which is frequently down-regulated in multiple human malignancies, has been demonstrated to play a critical function in energy metabolism, cell apoptosis and tumorigenesis. However, limited knowledge is known about the expression pattern and prognostic value of RGS6 in colorectal cancer (CRC). In this study, we first observed that RGS6 mRNA and protein is commonly downregulated in 32 paired CRC tissues compared with their normal counterparts. Furthermore, by a large scale of immunohistochemical analysis in a tissue microarray containing 310 cases of CRC specimens, we demonstrated that the protein expression of RGS6 expression is downregulated in 40.97% (127/310) samples and detected that decreasing RGS6 expression is closely correlated with enhanced tumor size, CEA level, T classification, TNM stage, and easier lymphatic and distant metastasis. Meanwhile, Kaplan-Meier survival analysis showed that CRC patients with a lower RGS6 expression have a poorer clinical outcome than those with a higher RGS6 expression. Multivariate Cox regression analysis revealed that RGS6, lymphatic metastasis and distant metastasis are the independent prognostic factors for overall survival rate of CRC patients. Taken together, our studies reveal the prognostic value of RGS6 in CRC and support that RGS6 may act as a molecular target for CRC treatment. PMID- 26653563 TI - Safflower yellow reduces lipid peroxidation, neuropathology, tau phosphorylation and ameliorates amyloid beta-induced impairment of learning and memory in rats. AB - Insoluble plaques of amyloid beta proteins (Abeta) and neurofibrillary tangles of hyperphosphorylated tau are key markers for Alzheimer's disease (AD). Safflower yellow (SY) is one of traditional Chinese medicine extracted from safflower, which is suggested to have therapeutic potential for neurodegenerative disorders. However, whether SY can ameliorate impairment of learning and memory in AD model, and its causal mechanism are still unclear. Here, we applied different doses of SY intragastrically to Wistar rats injected with amyloid beta (1-42) for 1 month. By the Morris water maze test, we found that treatment of SY significantly attenuated amyloid beta (1-42)-induced impairment of memory in rats. Mechanistically, SY treatment increased the level of superoxidedismutase (SOD) and Glutathione peroxidase (GSH-Px), and decreased the level of malondialdehyde (MDA) and acetylcholinesterase (T-CHE) in brain tissues of AD rats. Pathological analysis also showed that SY treatment inhibited the morphological alteration of neurons and tau hyperphosphorylation induced by amyloid beta (1-42)-injection in the cortex and hippocampus. Moreover, SY treatment inhibited CDK-5 and GSK-3 signaling pathways, which are upregulated in AD rats. Our data indicate that safflower yellow can serve as a therapeutic candidate for Alzheimer's disease. PMID- 26653564 TI - Selective Identification of Organic Iodine Compounds Using Liquid Chromatography High Resolution Mass Spectrometry. AB - A method to selectively and sensitively detect organic iodine compounds and identify their structures has been developed using liquid chromatography-high resolution mass spectrometry (LC-HRMS). Using extracted ion chromatograms of product ions (iodine ion) collected on a rapid scanning quadrupole orbitrap mass spectrometer, the retention times of the unknown organic iodine compounds were determined, and the structural information were acquired according to the MS/MS experiments and the matching with reference standards. We have demonstrated the application of this method by identifying unknown organic iodine compounds in seaweed. A total of 28 possible organic iodine peaks were discovered, among them, the accurate mass and element composition of the corresponding precursor ions were identified for 12 peaks, and molecular structures were confirmed for 4 peaks, which were 3-iodo-L-tyrosine, 3,5-diiodo-L-tyrosine, 4-iodophenol, and 2 iodobenzoic acid. This method is expected to lead to the future discovery of new organic iodine compounds via LC-HRMS in different environmental samples, which is crucial for understanding the iodine biogeochemical cycling. PMID- 26653566 TI - Energy expenditure in mechanically ventilated patients: The weight of body weight! AB - BACKGROUND & AIMS: Optimal nutritional care for intensive care unit (ICU) patients requires precise determination of energy expenditure (EE) to avoid deleterious under- or overfeeding. The reference method, indirect calorimetry (IC), is rarely accessible and inconstantly feasible. Various equations for predicting EE based on body weight (BW) are available. This study aims at determining the best prediction strategy unless IC is available. METHODS: Mechanically ventilated patients staying >=72 h in the ICU were included, except those with contraindications for IC measurements. IC and BW measurements were routinely performed. EE was predicted by the ESPEN formula and other predictive equations using BW (i.e. anamnestic (AN), measured (MES), adjusted for cumulated water balance (ADJ), calculated for a body mass index (BMI) of 22.5). Comparisons were made using Pearson correlation and Bland & Altman plots. RESULTS: 85 patients (57 +/- 19 y, 61 men, SAPS II 43 +/- 16) were included. Correlations between IC and predicted EE using the ESPEN formula with different BW (BWAN, BWMES, BWADJ, and BWBMI22.5) were 0.44, 0.40, 0.36, and 0.47, respectively. Bland & Altman plots showed wide and inconsistent variations. Predictive equations including body temperature and minute ventilation showed the best correlations, but when using various BWs, differences in predicted EE were observed. CONCLUSION: No EE predictive equation, regardless of the BW used, gives statistically identical results to IC. If IC cannot be performed, predictive equations including minute ventilation and body temperature should be preferred. BW has a significant impact on estimated EE and the use of measured BWMES or BW BMI 22.5 is associated with the best EE prediction. Clinical trial registration number on ClinicalTrial.gov: NCT02552446. Ethical committee number: CE-14-070. PMID- 26653567 TI - Highly Reversible and Ultrafast Sodium Storage in NaTi2(PO4)3 Nanoparticles Embedded in Nanocarbon Networks. AB - Sodium ion batteries (NIBs) have been considered as an alternative for Li ion batteries (LIBs). NaTi2(PO4)3 (denoted as NTP) is a superior anode material for NIBs. However, the poor electrochemical performance of NTP resulting from the low electronic conductivity prevents its application. Here, NTP nanoparticles embedded in carbon network (denoted as NTP/C) were fabricated using a simple soft template method. This anode material exhibits superior electrochemical performance when used as anode electrodes for NIBs, including highly reversible capacity (108 mAh g(-1) at 100 C) for excellent rate performance and long cycle life (83 mAh g(-1) at 50 C after 6000 cycles). The excellent sodium storage property can be resulted from the synergistic effects of nanosized NTP, thinner carbon shell and the interconnected carbon network, leading to the low charge transfer resistance, the large surface area for electrolyte to soak in and enough void to buffer the volume variation during the repeated cycle. PMID- 26653568 TI - Nodal Promotes Functional Luteolysis via Down-Regulation of Progesterone and Prostaglandins E2 and Promotion of PGF2alpha Synthetic Pathways in Mare Corpus Luteum. AB - In the present work, we investigated the role of Nodal, an embryonic morphogen from the TGFbeta superfamily in corpus luteum (CL) secretory activity using cells isolated from equine CL as a model. Expression pattern of Nodal and its receptors activin receptor A type IIB (ACVR2B), activin receptor-like kinase (Alk)-7, and Alk4, as well as the Nodal physiological role, demonstrate the involvement of this pathway in functional luteolysis. Nodal and its receptors were immune localized in small and large luteal cells and endothelial cells, except ACVR2B, which was not detected in the endothelium. Nodal mRNA in situ hybridization confirmed its transcription in steroidogenic and endothelial cells. Expression analysis of the aforementioned factors evidenced that Nodal and Alk7 proteins peaked at the mid-CL (P < .01), the time of luteolysis initiation, whereas Alk4 and ACVR2B proteins increased from mid- to late CL (P < .05). The Nodal treatment of luteal cells decreased progesterone and prostaglandin (PG) E2 concentrations in culture media (P < .05) as well as mRNA and protein of secretory enzymes steroidogenic acute regulatory protein, cholesterol side-chain cleavage enzyme, cytosolic PGE2 synthase, and microsomal PGE2 synthase-1 (P < .05). Conversely, PGF2alpha secretion and gene expression of PG-endoperoxidase synthase 2 and PGF2alpha synthase were increased after Nodal treatment (P < .05). Mid-CL cells cultured with PGF2alpha had increased Nodal protein expression (P < .05) and phosphorylated mothers against decapentaplegic-3 phosphorylation (P < .05). Finally, the supportive interaction between Nodal and PGF2alpha on luteolysis was shown to its greatest extent because both factors together more significantly inhibited progesterone (P < .05) and promoted PGF2alpha (P < .05) synthesis than Nodal or PGF2alpha alone. Our results neatly pinpoint the sites of action of the Nodal signaling pathway toward functional luteolysis in the mare. PMID- 26653569 TI - Research-Focused Isolation of Human Islets From Donors With and Without Diabetes at the Alberta Diabetes Institute IsletCore. AB - Recent years have seen an increased focus on human islet biology, and exciting findings in the stem cell and genomic arenas highlight the need to define the key features of mature human islets and beta-cells. Donor and organ procurement parameters impact human islet yield, although for research purposes islet yield may be secondary in importance to islet function. We examined the feasibility of a research-only human islet isolation, distribution, and biobanking program and whether key criteria such as cold ischemia time (CIT) and metabolic status may be relaxed and still allow successful research-focused isolations, including from donors with type 1 diabetes and type 2 diabetes. Through 142 isolations over approximately 5 years, we confirm that CIT and glycated hemoglobin each have a weak negative impacts on isolation purity and yield, and extending CIT beyond the typical clinical isolation cutoff of 12 hours (to >= 18 h) had only a modest impact on islet function. Age and glycated hemoglobin/type 2 diabetes status negatively impacted secretory function; however, these and other biological (sex, body mass index) and procurement/isolation variables (CIT, time in culture) appear to make only a small contribution to the heterogeneity of human islet function. This work demonstrates the feasibility of extending acceptable CIT for research-focused human islet isolation and highlights the biological variation in function of human islets from donors with and without diabetes. PMID- 26653570 TI - EP24.15 as a Potential Regulator of Kisspeptin Within the Neuroendocrine Hypothalamus. AB - The neuropeptide kisspeptin (Kiss1) is integral to the advent of puberty and the generation of cyclical LH surges. Although many complex actions of Kiss1 are known, the mechanisms governing the processing/regulation of this peptide have not been unveiled. The metallo enzyme, endopeptidase 24.15 (thimet oligopeptidase), has been demonstrated to play a key role in the processing and thus the duration of action of the reproductive neuropeptide, GnRH, which signals downstream of Kiss1. Initial in silico modeling implied that Kiss1 could also be a putative substrate for EP24.15. Coincubation of Kiss1 and EP24.15 demonstrated multiple cleavages of the peptide predominantly between Arg29-Gly30 and Ser47 Phe48 (corresponding to Ser5-Phe6 in Kiss-10; Kiss-10 as a substrate had an additional cleavage between Phe6-Gly7) as determined by mass spectrometry. Vmax for the reaction was 2.37+/-0.09 pmol/min . ng with a Km of 19.68 +/- 2.53MUM, which is comparable with other known substrates of EP24.15. EP24.15 immunoreactivity, as previously demonstrated, is distributed in cell bodies, nuclei, and processes throughout the hypothalamus. Kiss1 immunoreactivity is localized primarily to cell bodies and fibers within the mediobasal and anteroventral-periventricular hypothalamus. Double-label immunohistochemistry indicated coexpression of EP24.15 and Kiss1, implicating that the regulation of Kiss1 by EP24.15 could occur in vivo. Further studies will be directed at determining the precise temporal sequence of EP24.15 effects on Kiss1 as it relates to the control of reproductive hormone secretion and treatment of fertility issues. PMID- 26653571 TI - Activation of Medulla-Projecting Perifornical Neurons Modulates the Adrenal Sympathetic Response to Hypoglycemia: Involvement of Orexin Type 2 (OX2-R) Receptors. AB - Iatrogenic hypoglycemia in response to insulin treatment is commonly experienced by patients with type 1 diabetes and can be life threatening. The body releases epinephrine in an attempt to counterregulate hypoglycemia, but the neural mechanisms underlying this phenomenon remain to be elucidated. Orexin neurons in the perifornical hypothalamus (PeH) project to the rostral ventrolateral medulla (RVLM) and are likely to be involved in epinephrine secretion during hypoglycemia. In anesthetized rats, we report that hypoglycemia increases the sympathetic preganglionic discharge to the adrenal gland by activating PeH orexin neurons that project to the RVLM (PeH-RVLM). Electrophysiological characterization shows that the majority of identified PeH-RVLM neurons, including a subpopulation of orexin neurons, are activated in response to hypoglycemia or glucoprivation. Furthermore, the excitatory input from the PeH is mediated by orexin type 2 receptors in the RVLM. These results suggest that activation of orexin PeH-RVLM neurons and orexin type 2 receptors in the RVLM facilitates epinephrine release by increasing sympathetic drive to adrenal chromaffin cells during hypoglycemia. PMID- 26653572 TI - Hybrid Perovskites for Photovoltaics: Charge-Carrier Recombination, Diffusion, and Radiative Efficiencies. AB - Photovoltaic (PV) devices that harvest the energy provided by the sun have great potential as renewable energy sources, yet uptake has been hampered by the increased cost of solar electricity compared with fossil fuels. Hybrid metal halide perovskites have recently emerged as low-cost active materials in PV cells with power conversion efficiencies now exceeding 20%. Rapid progress has been achieved over only a few years through improvements in materials processing and device design. In addition, hybrid perovskites appear to be good light emitters under certain conditions, raising the prospect of applications in low-cost light emitting diodes and lasers. Further optimization of such hybrid perovskite devices now needs to be supported by a better understanding of how light is converted into electrical currents and vice versa. This Account provides an overview of charge-carrier recombination and mobility mechanisms encountered in such materials. Optical-pump-terahertz-probe (OPTP) photoconductivity spectroscopy is an ideal tool here, because it allows the dynamics of mobile charge carriers inside the perovskite to be monitored following excitation with a short laser pulse whose photon energy falls into the range of the solar spectrum. We first review our insights gained from transient OPTP and photoluminescence spectroscopy on the mechanisms dominating charge-carrier recombination in these materials. We discuss that mono-molecular charge-recombination predominantly originates from trapping of charges, with trap depths being relatively shallow (tens of millielectronvolts) for hybrid lead iodide perovskites. Bimolecular recombination arises from direct band-to-band electron-hole recombination and is found to be in significant violation of the simple Langevin model. Auger recombination exhibits links with electronic band structure, in accordance with its requirement for energy and momentum conservation for all charges involved. We further discuss charge-carrier mobility values extracted from OPTP measurements and their dependence on perovskite composition and morphology. The significance of the reviewed charge-carrier recombination and mobility parameters is subsequently evaluated in terms of the charge-carrier diffusion lengths and radiative efficiencies that may be obtained for such hybrid perovskites. We particularly focus on calculating such quantities in the limit of ultra-low trap related recombination, which has not yet been demonstrated but could be reached through further advances in material processing. We find that for thin films of hybrid lead iodide perovskites with typical charge-carrier mobilities of ~30cm(2)/(V s), charge-carrier diffusion lengths at solar (AM1.5) irradiation are unlikely to exceed ~10 MUm even if all trap-related recombination is eliminated. We further examine the radiative efficiency for hybrid lead halide perovskite films and show that if high efficiencies are to be obtained for intermediate charge-carrier densities (n ~ 10(14) cm(-3)) trap-related recombination lifetimes will have to be enhanced well into the microsecond range. PMID- 26653573 TI - Neoadjuvant multimodal treatment of pancreatic ductal adenocarcinoma. AB - Treatment of pancreatic ductal adenocarcinoma (PDAC) is increasingly multidisciplinary, with neoadjuvant strategies (chemotherapy, radiation, and surgery) administered in patients with resectable, borderline resectable, or locally advanced disease. The rational supporting this management is the achievement of both higher margin-negative resections and conversion rates into potentially resectable disease and in vivo assessment of novel therapeutics. International guidelines suggest an initial staging of the disease followed by a multidisciplinary approach, even considering the lack of a treatment approach to be considered as standard in this setting. This review will focus on both literature data supporting these guidelines and on new opportunities related to current more active chemotherapy regimens. An analysis of the pathological assessment of response to therapy and the potential role of target therapies and translational biomarkers and ongoing clinical trials of significance will be discussed. PMID- 26653574 TI - Chemical shift and diffusion-weighted magnetic resonance imaging of the anterior mediastinum in oncology: Current clinical applications in qualitative and quantitative assessment. AB - Recently, the use of magnetic resonance (MR) in clinical practice for the evaluation of the anterior mediastinum has considerably increased due to technological improvements and standardization of thoracic protocols. Currently, MR imaging is increasingly seen as a useful problem-solving modality, especially in equivocal cases at computed tomography, with the advantage of a higher contrast resolution and no radiation exposure. Chemical shift and diffusion weighted MR are helpful in tissue characterization and present advantages over conventional MR imaging, first in providing quantitative data, without the need for the administration of contrast medium. By detecting microscopic fat in tissue, chemical shift imaging is useful for differentiating normal thymus and rebound hyperplasia from cancer tissue at diagnosis and after chemotherapy in oncologic patients, and for distinguishing lymphoid hyperplasia from thymoma in autoimmune diseases such as myasthenia gravis. Diffusion-weighted MR reflects diffusivity of water molecules within tissue and is increasingly used as a cancer biomarker, even in the thorax, for the detection and characterization of tumors, for their differentiation from benign conditions, and for monitoring treatment response. In this review, based on the current literature, technical considerations about image acquisition and data analysis of chemical shift and diffusion-weighted MR are discussed along with clinical applications in the field of benign and malignant disease of the anterior mediastinum. PMID- 26653575 TI - Reconstitution of disrupted photoreceptor layer in uveitis associated with Behcet's disease by infliximab treatment. AB - BACKGROUND: Behcet's disease (BD)-associated uveitis causes retinal damage leading to severe visual disturbance. The early morphological changes in the retina are revealed by disappearance or disruption of the external limiting membrane (ELM), inner segment ellipsoid zone (EZ) and cone interdigitation zone (CIZ) in the outer retina shown on spectral domain-optical coherence tomography (SD-OCT). However, it is unknown whether these changes in the retina are reversible in BD-associated uveitis. CASE PRESENTATION: A 38-year-old man was referred to our hospital with 5 years history of panuveitis in both eyes. Recurrent oral ulcer, folliculitis, and genital ulcer were noted as systemic complications. Moderate cell infiltration into the anterior chamber, and diffuse vitritis were observed in both eyes, and best corrective visual acuity (BCVA) was 20/60 in the right and 20/200 in the left eye. Fluorescein angiography (FA) showed severe dye leakage from extensive retinal vessels in both eyes. Spectral domain-optical coherence tomography (SD-OCT) revealed retinal cysts and disruption of the external limiting membrane (ELM), inner segment ellipsoid zone (EZ) and cone interdigitation zone (CIZ) in the macular region of both eyes. BD was diagnosed based on the ocular features and systemic lesions, and infliximab therapy was initiated for the severe visual disturbance. After treatment with infliximab, foveal excavation was first recovered with disappearance of retinal cysts, and then ELM and EZ were gradually reconstituted on SD-OCT. Finally, CIZ became distinguishable after 24 months of infliximab therapy. BCVA was recovered to 20/25 in both eyes, and ocular inflammatory attack did not recur after the initiation of infliximab therapy. CONCLUSION: Disruption of ELM, EZ, and CIZ shown on SD-OCT in BD-associated uveitis could be reconstituted by continuous infliximab treatment, which leaded to the improvement of visual acuity. PMID- 26653576 TI - [Male sexuality after external continent urinary diversion type Mitrofanoff]. AB - OBJECTIVE: To evaluate the influence of continent external urinary diversion type Mitrofanoff on male sexuality. MATERIAL AND METHODS: Between 1992 and 2011, 140 patients underwent continent urinary diversion type Mitrofanoff at an academic hospital. Among 76 men, 46 were interviewed about their sexuality after this operation. This study was performed using a set of validated questionnaires (IIEF, DAN PSS and Urolife), grouped by the model of the CTMH. Patients were divided according to their marital status: group 1: patients married before surgery (15 cases), group 2: patients married after surgery (7 cases) and group 3: singles (24 cases). RESULTS: In the first group, the functional dimension of sexuality was positive with an overall score of 81%, the sexual discomfort score was assessed at 26 % and the sexual satisfaction score was 77%. In the second group, sexual function was considered conserved in all cases with a satisfaction score estimated at 98%. These patients reported a feeling of well-being following the disappearance of urinary incontinence with integrity of their body images. In contrast, in the last group, relatively impaired sexual function was noted (65%) with a satisfaction score estimated at 59%. These disorders were multifactorial, mainly related to neurological causal pathology. CONCLUSION: To our knowledge, this is the first study about male sexuality in patients with a continent urinary diversion type Mitrofanoff. Marital status has a major role in the sexuality of these patients. A prospective study with pre- and postoperative evaluation will better clarify the factors affecting sexuality in these patients. PMID- 26653577 TI - [Assessment of the optimization of the conditions of mitomycin C intravesical instillation completion in the setting of non-muscle invasive bladder cancer treatment]. AB - OBJECTIVE: The efficacy of intravesical instillation of mitomycin C (MMC) requires alkalinisation and concentration of urine before each instillation. The objective of the study was to assess compliance and effectiveness of urine alkalinazation and fluid restriction protocols in patients treated with intravesical instillations of MMC for TVNIM. MATERIAL ET METHOD: Descriptive prospective epidemiological study in all patients consecutively treated with intravesical instillations of MMC for non-muscle invasive bladder cancer (NMIBC). Patients should be advised to drink 2 liters of water from Vichy and to perform fluid restriction the day before the instillations. Before each instillation, a questionnaire on the implementation of these measures was filled, density and pH were determined by urinalysis strips. RESULTS: On 126 questionnaires fulfilled, 117 patients (93%) and 106 patients (84%) reported having made alkalinization and fluid restriction, respectively. Ninety-one of patients (78%) reported having performed alkalinization had a pH greater than or equal to 6.5 and the mean urinary pH was 6.94 vs. 5.94 in patients stating not to have made alkalizing (P=0.0001). No significant differences in urine density according to fluid restriction was found. CONCLUSION: The observance of the instructions regarding urine alkalinization before MMC instillations was satisfactory and has achieved a sufficiently high urinary pH to prevent degradation of the product in 91% of cases. Conversely, the fluid restriction was not followed closely and has not shown its effectiveness on the concentration of urine. PMID- 26653578 TI - Erratum to: 'Exploring the function and effectiveness of knowledge brokers as facilitators of knowledge translation in health related settings: a systematic review and thematic analysis'. PMID- 26653579 TI - Full-order Luenberger observer based on fuzzy-logic control for sensorless field oriented control of a single-sided linear induction motor. AB - This paper investigates sensorless indirect field oriented control (IFOC) of SLIM with full-order Luenberger observer. The dynamic equations of SLIM are first elaborated to draw full-order Luenberger observer with some simplifying assumption. The observer gain matrix is derived from conventional procedure so that observer poles are proportional to SLIM poles to ensure the stability of system for wide range of linear speed. The operation of observer is significantly impressed by adaptive scheme. A fuzzy logic control (FLC) is proposed as adaptive scheme to estimate linear speed using speed tuning signal. The parameters of FLC are tuned using an off-line method through chaotic optimization algorithm (COA). The performance of the proposed observer is verified by both numerical simulation and real-time hardware-in-the-loop (HIL) implementation. Moreover, a detailed comparative study among proposed and other speed observers is obtained under different operation conditions. PMID- 26653580 TI - Molecular Iodine-Mediated Chemoselective Synthesis of Multisubstituted Pyridines through Catabolism and Reconstruction Behavior of Natural Amino Acids. AB - A new process has been developed for the selective construction of 2,6 disubstituted, 2,4,6-trisubstituted, and 3,5-disubstituted pyridines based on the catabolism and reconstruction behaviors of amino acids. Molecular iodine was used as a tandem catalyst to trigger the decarboxylation-deamination of amino acids and to promote the subsequent formation of the pyridine products. PMID- 26653581 TI - Gender-related differential item functioning in DSM-IV/DSM-5-III (alternative model) diagnostic criteria for borderline personality disorder. AB - A number of studies have evaluated the possibility of bias in the diagnostic criteria in borderline personality disorder as an explanation of gender differences in prevalence. Previous studies have used both regression and latent trait approaches but the results have been inconsistent. The current study extended prior investigations in testing differential function of Borderline diagnostic criteria using both regression and latent-trait methods in the same sample, examining both Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV) and DSM-5 alternative model criteria for borderline personality. Data were obtained from a national sample of 337 clinicians providing diagnostic information on 1 of their target patients. Chronic feelings of emptiness was the only criterion that demonstrated consistent evidence of potential differential functioning across methods and diagnostic models. Implications of these results for the conceptualization of borderline personality are discussed. (PsycINFO Database Record PMID- 26653582 TI - "Impulsive" suicide attempts: What do we really mean? AB - Suicide attempts are often regarded as impulsive acts. However, there is little consensus regarding the definition or clinical characteristics of an "impulsive" attempt. To clarify this issue, we examined 3 indicators of the impulsivity of an attempt: (a) preparation, (b) time contemplating the attempt, and (c) self-report that impulsivity motivated the attempt. We examined relationships among the indicators and their relationship to trait impulsivity and characteristics of the suicide attempt. Adult participants (N = 205) with a history of suicide attempts were administered validated interviews and questionnaires. In general, the 3 attempt impulsivity indicators correlated only moderately with each other and not at all with trait impulsivity or with important characteristics of the attempt (e.g., lethality, preattempt communication, motivations). However, there were 2 exceptions. First, intent to die was inversely related to the 3 attempt impulsivity indicators (rs ranged from -.17 to .45) such that more impulsive attempts were associated with lower intent. Second, self-report that the attempt was motivated by impulsivity was related to 3 facets of trait impulsivity (rs ranged from .16 to .41). These findings suggest that individuals endorsing trait impulsivity are likely to describe their attempts as motivated by impulsivity, regardless of the presence of preparation or prolonged contemplation. Overall, study results suggest that the common conception of a unidimensional impulsive attempt may be inaccurate and that the emphasis on general impulsivity in prevention guidelines should be tempered. Implications for suicide risk assessment and prevention are discussed. (PsycINFO Database Record PMID- 26653583 TI - Patients' perspectives on information from physicians during palliative chemotherapy: A qualitative study. AB - OBJECTIVE: During the course of their disease, patients with cancer receiving palliative chemotherapy receive extensive amounts of information from physicians. The objective of our study was to describe patients' perspectives on the information they received from physicians during palliative chemotherapy with regard to their cancer diagnosis, treatments, prognosis, and future planning. METHOD: A total of 15 semistructured face-to-face interviews with patients who had incurable cancer were conducted, transcribed verbatim, and analyzed with qualitative content analysis. RESULTS: Three categories were defined during the analytical process: "having a chronic disease," "depending on chemotherapy," and "living with an unpredictable future." SIGNIFICANCE OF RESULTS: Our study demonstrated that patients undergoing palliative chemotherapy perceived that their disease was incurable and chronic, that they were dependent on chemotherapy, and that their future was uncertain. Compared with other studies, the patients in our study seemed to be more aware of their prognosis and the goals of care. PMID- 26653594 TI - Current status of publicly available sarcoma cell lines for use in proteomic studies. AB - Cell lines are valuable resources for proteomic studies and can be used as tools to verify the significance of proteomic findings. Here, the authors overview the current status of the publicly available sarcoma cell lines. The authors surveyed seven major cell banks and found that the diversity observed in the sarcoma cell banks was largely insufficient; sarcoma cell lines are available for only a limited histological subtype. They also observed a number of issues with the pathological diagnosis of the cell lines, limitations in their behavioral diversity, and various unmet needs. Well characterized cell lines with accurate diagnosis based on modern diagnosis criteria should be available from public cell banks. The authors conclude that additional cell lines, along with detailed genetic and pathological analyses, should be prepared and deposited in order to promote sarcoma-specific proteomic research. The authors focused on sarcoma cell lines, but their discussion can be applied to the other cancers. PMID- 26653612 TI - Implementing an optimized glucose-lowering strategy with a novel once daily modified release gliclazide formulation. AB - AIM: The 6-months titration profile of a new scored gliclazide modified release (MR) formulation (MR 60 mg) was explored in individuals with type 2 diabetes. METHODS: This international study enrolled 7170 individuals, age >= 35 years with HbA1c >= 7.5% (59 mmol/mol) and not on insulin. Participants were started on 30 120 mg gliclazide MR 60 mg once daily as a first line (FIRST), add-on (ADD) or switch from a previous oral antihyperglycemic treatment strategy (SWITCH). Uptitration was capped at 120 mg. RESULTS: Women comprised 58.5% of the cohort. Mean baseline age was 58.9 years, body mass index 30.1 kg/m(2) and diabetes duration 5.1 years. Mean baseline HbA1c for the FIRST (n=2023), ADD (n=3136) and SWITCH (n=1834) groups was 8.9% (74 mmol/mol), 8.8% (73 mmol/mol) and 8.8% (73 mmol/mol), respectively. Probability of reaching optimal dose at months 1, 2, 3 and 6 was 15%, 39%, 59% and 92%, respectively. Mean HbA1c changes from baseline to month 6 were FIRST: -1.98%, ADD: -1.74% and SWITCH: -1.61% (all p<0.01). Overall, 65.3% achieved HbA1c <= 7.0% (53 mmol/mol); average duration for achieving glucose control was 80.1 days. Mean weight loss ranged from -1.45 to 1.27 kg. Severe hypoglycemia was experienced by 0.06% of participants. Most (95.5%) indicated a greater likelihood of adherence with the gliclazide MR 60 mg regime relative to their previous therapy. CONCLUSIONS: In this large, real world study, progressive uptitration with gliclazide MR 60 mg once daily appears to be efficacious and safe in individuals with suboptimal glycemic control at various stages of the diabetes continuum. PMID- 26653613 TI - Thermodynamic profiling of inhibitors of Nrf2:Keap1 interactions. AB - Keap1 binds to the transcription factor Nrf2 and negatively modulates the expression of genes involved in cellular protection against oxidative stress. Small molecules have been discovered to inhibit the Nrf2:Keap1 interactions and act as antagonists of Keap1. The affinities of these small molecules are not very high and need further improvement in follow up hit-to-lead programs. In addition to the affinity parameters Ki, Kd, and IC50 thermodynamic parameters provide useful information for the selection and optimization of these hit molecules at the early stage of the lead discovery process. In this letter a tracer displacement assay was used to determine the thermodynamic signature of some of the known inhibitors of the Nrf2:Keap1 interaction. An optimized assay protocol is presented, which can be applied to other small molecules in hit-to-lead programs in a medium throughput manner. PMID- 26653614 TI - Flat SAR of P3-methylsulphonamide based small molecule legumain inhibitors. AB - This letter describes the design, development and SAR exploration of a novel series of small legumain inhibitors. The SAR of a new small molecule legumain inhibitor chemotype was explored and found to have improved physiochemical properties compared to previously developed inhibitors within our group. However, further development of this series was found to be limited as the SAR was observed to be relatively flat. PMID- 26653615 TI - The Radiology of Vertebral Fractures in Childhood Osteoporosis Related to Glucocorticoid Administration. AB - A number of unusual conditions cause decreased bone mass and density in children and these may be associated with low-trauma fractures. However, a series of reports have more recently identified that children with chronic disease sustain vertebral fractures (VFs) much more often than had been suspected. The common denominator involved is glucocorticoid (GC) administration, although other factors such as disease activity come into play. This review will focus on the imaging findings in this form of secondary osteoporosis. Spinal fractures in children have been found to correlate with back pain. At the same time, up to 2/3 of children with VFs in the GC-treated setting are asymptomatic, underscoring the importance of routine surveillance in at-risk children. Other predictors of prevalent and incident VFs include GC exposure (average daily and cumulative dose), declines in lumbar spine bone mineral density Z-scores and increases in body mass index Z-scores, as well as increases in disease activity scores. The imaging diagnosis of osteoporotic VFs in children is made differently from that in adults because immature vertebral bodies continue to ossify during growth. Thus, it is not possible to assess the vertebral end plates or periphery until late, as enchondral ossification extends centripetally within the centrum. Diagnosis, therefore, is much more dependent upon changes in shape than on loss of structural integrity, which may have a more prominent diagnostic role in adults. However, children have a unique ability to model (a growth-dependent process) and thereby reshape previously fractured vertebral bodies. If the underlying disease is successfully treated and the child has sufficient residual growth potential, this means that, on one hand, treatment of the bone disease may be of more limited duration, and, as a last recourse, the diagnosis may be apparent retrospectively. PMID- 26653616 TI - Mechanisms Used by Plants to Cope with DNA Damage. AB - Because the genome stores all genetic information required for growth and development, it is of pivotal importance to maintain DNA integrity, especially during cell division, when the genome is prone to replication errors and damage. Although over the last two decades it has become evident that the basic cell cycle toolbox of plants shares several similarities with those of fungi and mammals, plants appear to have evolved a set of distinct checkpoint regulators in response to different types of DNA stress. This might be a consequence of plants' sessile lifestyle, which exposes them to a set of unique DNA damage-inducing conditions. In this review, we highlight the types of DNA stress that plants typically experience and describe the plant-specific molecular mechanisms that control cell division in response to these stresses. PMID- 26653617 TI - In vitro antioxidant, antifungal and antibacterial activities of five international Calibrachoa cultivars. AB - The total phenolic, flavonoid and tannin contents in leaf extracts of Calibrachoa x hybrida (C.h.) (Solanaceae) international cultivars, as well as their overall antioxidant activities using DPPH and linoleic acid assays, were investigated. Furthermore, the antifungal and the antibacterial activities were examined against a wide spectrum of micro-organisms. DPPH and linoleic acid assays ranged from 62.1 to 80.1% and of 74.1-93.4%, respectively. C.h. Superbells(r) Trailing Rose (CHST), C.h. Superbells(r) Frost Fire, C.h. Superbells(r) Strawberry Punch, C.h. Superbells(r) Dreamsicle and C.h. Superbells(r) Plum (CHSP) varied in their antifungal and the antibacterial activities against a wide spectrum of micro organisms. CHSP exhibited the highest antioxidant, antifungal and antibacterial activities followed by CHST. These activities might be attributed to the presence of phenolic, flavonoid and tannin compounds, indicating that these cultivars might be potential sources of therapeutic substances. PMID- 26653618 TI - Pro -con debate: "That antibiotic prophylaxis should be used in children with repaired oesophageal atresia and tracheo-oesophageal fistula". PMID- 26653619 TI - Ultrastrong Alkali-Resisting Lanthanide-Zeolites Assembled by [Ln60] Nanocages. AB - Zeolites, as one of the most important porous materials, are most widely utilized in sorbents, catalysis, and ion-exchange fields. However, the multi-functional lanthanide-zeolites constructed exclusively by lanthanide ions and oxygen linkers are to our knowledge unknown hitherto. Herein, we, for the first time, report the unique structure and multifunctions of lanthanide zeolites (1.Gd, 1.Tb, 1.Dy), featuring 60 nuclear [Ln60] nanocages as building blocks and ultrastrong alkali resisting. These compounds possess extremely high stability and still retain single crystallinity after treatment in boiling water, 0.1 M HCl, and 20 M NaOH aqueous solutions. Magnetic studies revealed 1.Gd has large magnetocaloric effect with -DeltaSm(max) = 66.5 J kg(-1) K(-1), falling among the largest values known to date. Importantly, these lanthanide-zeolites themselves can efficiently catalyze the cycloaddition of CO2 with epoxides under mild conditions. Our finding extends the conventional zeolites to lanthanide counterparts, opening a new space for seeking novel and/or multifunctional zeolites. PMID- 26653620 TI - First-in-Man Experience of a Novel Transcatheter Repair System for Treating Severe Tricuspid Regurgitation. AB - BACKGROUND: Isolated tricuspid valve surgery is associated with high morbidity and mortality, especially in patients with prior cardiac surgery. The transcatheter Forma Repair System (Edwards Lifesciences, Irvine, California) is designed to provide a surface for native leaflet coaptation to reduce tricuspid regurgitation (TR) by occupying the regurgitant orifice area. OBJECTIVES: This study sought to evaluate the feasibility and exploratory efficacy with this transcatheter repair system for the treatment of severe TR. METHODS: Seven high risk patients with severe TR and clinical signs of heart failure were declined for surgery and offered transcatheter treatment with this device. All procedures were performed within a cardiac catheterization laboratory or hybrid operating room under general anesthesia with transesophageal echocardiographic guidance. Vascular access was via the left axillary vein. Baseline characteristics, procedural and in-hospital outcomes, as well as 30-day follow-up were prospectively collected. RESULTS: All patients had severe TR and New York Heart Association (NYHA) functional class II to IV (mean age 76 +/- 13 years; mean logistic EuroSCORE 25.7 +/- 17.4%), and underwent device implantation to improve tricuspid leaflet coaptation, thereby reducing TR. Device implantation was successful without procedural complications in all patients, with significant reductions in TR severity (moderate in 3 patients and mild in 4 patients). Median hospital length of stay was 4 days. At 30-day follow-up, all patients but 1 demonstrated improvements in NYHA functional status (to class II) with pronounced reductions in the presence and severity of peripheral edema. TR severity was assessed as being moderate at 30-day transthoracic echocardiography follow-up in all patients. No complications related to the device or vascular access were observed during follow-up. CONCLUSIONS: A transcatheter-based treatment option for severe TR appears safe and feasible with this repair system. Improvements in TR severity were documented in all patients, which were accompanied by improvements in peripheral edema and functional status. PMID- 26653621 TI - Renal Artery Stent Outcomes: Effect of Baseline Blood Pressure, Stenosis Severity, and Translesion Pressure Gradient. AB - BACKGROUND: Multiple randomized clinical trials comparing renal artery stent placement plus medical therapy with medical therapy alone have not shown any benefit of stent placement. However, debate continues whether patients with extreme pressure gradients, stenosis severity, or baseline blood pressure benefit from stent revascularization. OBJECTIVES: The study sought to test the hypothesis that pressure gradients, stenosis severity, and/or baseline blood pressure affects outcomes after renal artery stent placement. METHODS: Using data from 947 patients with a history of hypertension or chronic kidney disease from the largest randomized trial of renal artery stent placement, the CORAL (Cardiovascular Outcomes in Renal Atherosclerotic Lesions) study, we performed exploratory analyses to determine if subsets of patients experienced better outcomes after stent placement than the overall cohort. We examined baseline stenosis severity, systolic blood pressure, and translesion pressure gradient (peak systolic and mean) and performed interaction tests and Cox proportional hazards analyses for the occurrence of the primary endpoint through all follow up, to examine the effect of these variables on outcomes by treatment group. RESULTS: There were no statistically significant differences in outcomes based on the examined variables nor were there any consistent nonsignificant trends. CONCLUSIONS: Based on data from the CORAL randomized trial, there is no evidence of a significant treatment effect of the renal artery stent procedure compared with medical therapy alone based on stenosis severity, level of systolic blood pressure elevation, or according to the magnitude of the trans-stenotic pressure gradient. (Benefits of Medical Therapy Plus Stenting for Renal Atherosclerotic Lesions [CORAL]; NCT00081731). PMID- 26653622 TI - The CORAL Trial, Round 2. PMID- 26653623 TI - Mechanical Thrombectomy for Acute Ischemic Stroke: A Meta-Analysis of Randomized Trials. AB - BACKGROUND: Acute ischemic stroke is a leading cause of serious disability and death worldwide. Individual randomized trials have shown possible benefits of mechanical thrombectomy after usual care compared with usual care alone (i.e., intravenous thrombolysis) in the management of acute ischemic stroke patients. OBJECTIVES: This study systematically determined if mechanical thrombectomy after usual care would be associated with better outcomes in patients with acute ischemic stroke caused by large artery occlusion. METHODS: The authors included randomized trials that compared mechanical thrombectomy after usual care versus usual care alone for acute ischemic stroke. Random effects summary risk ratios (RR) were constructed using a DerSimonian and Laird model. RESULTS: Nine trials with 2,410 patients were available for analysis. Compared with usual care alone, mechanical thrombectomy was associated with a higher incidence of achieving good functional outcome, defined as a modified Rankin scale (mRS) of 0 to 2 (RR: 1.45; 95% confidence interval [CI]: 1.22 to 1.72; p < 0.0001) and excellent functional outcome defined as mRS 0 to 1 (RR: 1.67; 95% CI: 1.27 to 2.19; p < 0.0001) at 90 days. There was a trend toward reduced all-cause mortality with mechanical thrombectomy (RR: 0.86; 95% CI: 0.72 to 1.02; p = 0.09). The risk of symptomatic intracranial hemorrhage was similar with either treatment modality (RR 1.06: 95% CI: 0.73 to 1.55; p = 0.76). CONCLUSIONS: In acute ischemic stroke due to large artery occlusion, mechanical thrombectomy after usual care was associated with improved functional outcomes compared with usual care alone, and was found to be relatively safe, with no excess in intracranial hemorrhage. There was a trend for reduction in all-cause mortality with mechanical thrombectomy. PMID- 26653624 TI - Standards and Barriers in Acute Stroke Therapy: A Leap Forward in the Evolution of Endovascular Interventions for Stroke. PMID- 26653625 TI - Hemoglobin Level and Hospital Mortality Among ICU Patients With Cardiac Disease Who Received Transfusions. AB - BACKGROUND: There is a paucity of randomized clinical trial data on the use of red blood cell (RBC) transfusion in critically ill patients, specifically in the setting of cardiac disease. OBJECTIVES: This study examined how hemoglobin (Hgb) level and cardiac disease modify the relationship of RBC transfusion with hospital mortality. The aim was to estimate the Hgb level threshold below which transfusion would be associated with reduced hospital mortality. METHODS: We performed secondary data analyses of Veterans Affairs intensive care unit (ICU) episodes across 5 years. Logistic regression quantified the effect of transfusion on hospital mortality while adjusting for nadir Hgb level, demographic characteristics, admission information, comorbid conditions, and ICU admission diagnoses. RESULTS: Among 258,826 ICU episodes, 12.4% involved transfusions. Hospital death occurred in 11.6%. Without comorbid heart disease, transfusion was associated with decreased adjusted hospital mortality when Hgb was approximately <7.7 g/dl, but transfusion increased mortality above this Hgb level. Corresponding Hgb level thresholds were approximately 8.7 g/dl when comorbid heart disease was present and approximately 10 g/dl when the ICU admission diagnosis was acute myocardial infarction (AMI). Sensitivity analysis using additional adjustment for selected blood tests in a subgroup of 182,792 ICU episodes lowered these thresholds by approximately 1 g/dl. CONCLUSIONS: Transfusion of critically ill patients was associated with reduced hospital mortality when Hgb level was <8 to 9 g/dl in the presence of comorbid heart disease. This Hgb level threshold for transfusion was 9 to 10 g/dl when AMI was the ICU admission diagnosis. PMID- 26653626 TI - Transfusion in Ischemic Heart Disease: Correlation, Confounding, and Confusion. PMID- 26653628 TI - Eating Away at Heart Failure. PMID- 26653627 TI - Systems Genomics Identifies a Key Role for Hypocretin/Orexin Receptor-2 in Human Heart Failure. AB - BACKGROUND: The genetic determinants of heart failure (HF) and response to medical therapy remain unknown. We hypothesized that identifying genetic variants of HF that associate with response to medical therapy would elucidate the genetic basis of cardiac function. OBJECTIVES: This study sought to identify genetic variations associated with response to HF therapy. METHODS: This study compared extremes of response to medical therapy in 866 HF patients using a genome-wide approach that informed the systems-based design of a customized single nucleotide variant array. The effect of genotype on gene expression was measured using allele-specific luciferase reporter assays. Candidate gene transcription deficient mice underwent echocardiography and treadmill exercise. The ability of the target gene agonist to rescue mice from chemically-induced HF was assessed with echocardiography. RESULTS: Of 866 HF patients, 136 had an ejection fraction improvement of 20% attributed to resynchronization (n = 83), revascularization (n = 7), tachycardia resolution (n = 2), alcohol cessation (n = 1), or medications (n = 43). Those with the minor allele for rs7767652, upstream of hypocretin (orexin) receptor-2 (HCRTR2), were less likely to have improved left ventricular function (odds ratio: 0.40 per minor allele; p = 3.29 * 10(-5)). In a replication cohort of 798 patients, those with a minor allele for rs7767652 had a lower prevalence of ejection fraction >35% (odds ratio: 0.769 per minor allele; p = 0.021). In an HF model, HCRTR2-deficient mice exhibited poorer cardiac function, worse treadmill exercise capacity, and greater myocardial scarring. Orexin, an HCRTR2 agonist, rescued function in this HF mouse model. CONCLUSIONS: A systems approach identified a novel genetic contribution to human HF and a promising therapeutic agent efficacious in an HF model. PMID- 26653629 TI - Making Sense of Statistics in Clinical Trial Reports: Part 1 of a 4-Part Series on Statistics for Clinical Trials. AB - This paper is a practical guide to the essentials of statistical analysis and reporting of randomized clinical trials (RCTs). It is the first in a series of 4 educational papers on statistical issues for RCTs, which will also include statistical controversies in RCT reporting and interpretation, the fundamentals of design for RCTs, and statistical challenges in the design and monitoring of RCTs. Here, we concentrate on displaying results in tables and figures, estimating treatment effects, expressing uncertainty using confidence intervals, and using p values wisely to assess the strength of evidence for a treatment difference. The various methods and their interpretation are illustrated by recent, topical cardiology trial results. PMID- 26653631 TI - The Hazards of Physician Advertising. PMID- 26653632 TI - The Cardiac Imaging Specialist: Pursuing Further Training. PMID- 26653630 TI - Building Sustainable Capacity for Cardiovascular Care at a Public Hospital in Western Kenya. AB - Cardiovascular disease deaths are increasing in low- and middle-income countries and are exacerbated by health care systems that are ill-equipped to manage chronic diseases. Global health partnerships, which have stemmed the tide of infectious diseases in low- and middle-income countries, can be similarly applied to address cardiovascular diseases. In this review, we present the experiences of an academic partnership between North American and Kenyan medical centers to improve cardiovascular health in a national public referral hospital. We highlight our stepwise approach to developing sustainable cardiovascular services using the health system strengthening World Health Organization Framework for Action. The building blocks of this framework (leadership and governance, health workforce, health service delivery, health financing, access to essential medicines, and health information system) guided our comprehensive and sustainable approach to delivering subspecialty care in a resource-limited setting. Our experiences may guide the development of similar collaborations in other settings. PMID- 26653633 TI - Normalization of Visceral Fat and Complete Reversal of Cardiovascular Remodeling Accompany Gastric Bypass, not Banding. PMID- 26653634 TI - Acute Increase of Cardiac Output Reduces Central Sleep Apneas in Heart Failure Patients. PMID- 26653635 TI - Gaps in Cardiac Rehabilitation Referral: A Universal Problem. PMID- 26653636 TI - Reply: The Gaps in Cardiac Rehabilitation Referral: The Elephant in the Room. PMID- 26653637 TI - The Gaps in Cardiac Rehabilitation Referral: The Elephant in the Room. PMID- 26653638 TI - Reply: Elimination of All Inducible Ventricular Tachycardias as the Endpoint for Ablation. PMID- 26653639 TI - Elimination of All Inducible Ventricular Tachycardias as the Endpoint for Ablation. PMID- 26653640 TI - The effect of systemic isotretinoin on male fertility. AB - BACKGROUND/OBJECTIVE: Acne vulgaris is one of the most common diseases of the youth. Systemic isotretinoin is the only drug which acts on all of the etiopathogenic mechanisms of acne. Isotretinoin has some well-known side effects. Besides these, there is a suspicion whether it causes infertility or not. In this study, we aimed to evaluate the effects of systemic isotretinoin on male fertility. METHODS: Eighty one male patients, who were older than 18 years of age, and had severe or refractory acne vulgaris were included in the study. They were given a total dose of 120 mg/kg of systemic isotretinoin over a period of six months. Before and after the study, the spermiogram parameters of the patients were evaluated to show any possible effect on male fertility. The patients' total testosterone, follicle stimulating hormone and luteinizing hormone levels were also evaluated. RESULTS: All of the spermiogram parameters changed positively (p < 0.05). There was no significant change in the hormone levels. CONCLUSION: Systemic isotretinoin has a positive effect on male fertility. Since the hormone levels did not change significantly, this positive effect of isotretinoin is not via the hypothalamic-pituitary-gonadal axis but can be due to its regenerative and proliferative effects on the testes. PMID- 26653641 TI - [Cohort study of effects on lung function of coke oven workers exposured to coke oven emissions]. AB - OBJECTIVE: Through comparative study on pulmonary function damage of coke oven workers exposed to coke oven emissions with the same group before and after five years, and further explore the relationship between the coke oven emissions and injury in pulmonary function of coke oven worker. METHODS: Select a coking plant in Shanxi 165 coke oven workers (exposed group) and 52 auxiliary workers (control group) for the study, using a uniform questionnaire to collect workers' personal information. Fixed workplace air samples collected periodically. Air samples of benzo (a) pyrene concentrations was measured by high pressure liquid chromatograph. Pulmonary function of research object was measured by portable spirometer respectively in 2009 and 2013, and comparative analysis on it. RESULTS: The concentration of B(a)P was no significant difference in the same area between 5 years in 2009-2013. Compared with 2009, 2013 control workers lung function index and the abnormal rate had no significant difference (P > 0.05). But FVC%, FEV1.0%, MVV%, VC% and FEF25% of exposed workers in 2013 was significantly lower than in 2009, FVC%, FEV1.0%, VC% and FEF25% pulmonary dysfunction rate in 2013 was also significantly higher than in 2009, difference was statistically significant (P < 0.05). Workers emerging pulmonary function abnormalities mainly distributed in furnace roof and side. furnace roof group FVC%, FEV1.0%, VC% additional abnormal number (rate) was significantly higher than furnace floor and the control group (P < 0.05), and furnace side groop was significantly higher than the control group, the difference was statistically significant (P < 0.05). Multivariate Logistic regression analysis showed that after 5 years FVC%, FEV1% and VC% of abnormal lung function emerging adjusted OR of furnace roof workers were 7.939, 5.966 and 4.956. For abnormal of FVC%, FEV1%, VC% and MVV%, the contacting coke seniority is a risk factor. There is a positive interaction between contacting coke seniority and furnace roof (P < 0.05). CONCLUSION: Coke oven workers lung function damage associated with exposureing to coke oven emissions, coke oven emissions exposure level and exposure time are the main factors of coke oven workers in lung function damage, there is a positive interaction between the two factors. PMID- 26653642 TI - [Study on the expression of bradykinin and its receptors B1R and B2R in the kidney immune injury in trichloroethylene-sensitized mouse]. AB - OBJECTIVE: To study the expression of bradykinin and its receptors B1R and B2R in the kidney immune injury in trichloroethylene-sensitized mouse and discuss the pathogenesis of Dermatitis Medicamentosa-like of TCE (ODMLT). METHODS: On the first days, intradermal injection by 50% TCE and the amount of FCA mixture 100 ul for initial sensitization; on 4, 7, 10 days, painted abdominal skin by 100 ul 50% TCE for three sensitization, on 17, 19 days, painted on the back skin by 100 ul 30% TCE for initial excitation and the last challenge; 24 h before each challenge, PKSI-527+TCE group received intraperitoneal injection by inhibitor PKSI-527 (50 mg/kg); solvent control group treat without TCE and sensitization and excitation reagent the same proportion of olive oil and acetone mixture, blank control group without any treatment. Before killing the mouse, renal weight and body weight were recorded. The renals and plasma were separated at 24 h, 48 h, 72 h and 7 d after the last challenge and observed pathological of the renals. Expression of B1R and B2R in renal were examined by immunofluorescence technique. Plasma were examined by ELISA for BK. RESULTS: The renal pathological examination revealed the apparent damage of TCE sensitized mice which compared to solvent control group showed obvious cellular infiltration, vacuolar degeneration of renal tubular epithelial cells. The renal damage of PKSI-527+TCE-sensitized groups which compared to the corresponding point of TCE-sensitized groups showed significantly reduced. The expression of BK in 24 h, 48 h and 72 h TCE-sensitized groups were significant higher than solvent control group and related TCE non sensitized groups (P < 0.05) and 72 h point compared to the corresponding point of PKSI-527+TCE group was also increased, the difference was statistically significant (P < 0.05). The expression levels of B1R and B2R in the kidney in 24 h, 48 h, 72 h and 7 d TCE-sensitized groups were obviously higher than solvent control group and related TCE non-sensitized groups. The expression levels of B1R and B2R in the kidney in the four point of PKSI-527+TCE sensitized group were relatively lower than the corresponding point of TCE sensitized group. CONCLUSION: KKS activation may involved in the renal immune injury of trichloroethylene-sensitized mouse and the expression change of bradykinin and its receptors B1R and B2R which may play an important role in the process. PMID- 26653643 TI - [Gene variance in microsomal epoxide hydrolase and the susceptibility of coal workers' pneumoconiosis]. AB - OBJECTIVE: To explore whether the tagging single nucleotide polymorphisms (SNPs) within EPHX1 gene were involved in the genetic susceptibility to coal worker's pneumoconiosis (CWP) by case-control study. METHODS: This study consisted of 697 CWP patients and 694 controls. All the subjects were Han Chinese, underground coal miners and recruited from coal mines of Xuzhou Mining Business Group Co Ltd.. The venous blood samples were obtained from all subjects and extracted genome DNA from the isolated leucocytes. Three SNPs were selected from the HapMap and the genotyping was done by the TaqMan method with the ABI 7900HT Real Time PCR system. RESULTS: The Single SNP analyses showed that the genotype frequencies of EPHX1 (rs2234922) was significantly associated with decreased risk of CWP under co-dominant model (OR = 0.22, 95% CI = 0.06~0.79, P = 0.020), recessive model (OR = 0.23, 95% CI = 0.06~0.82, P = 0.023), and addictive model (OR = 0.75, 95% CI = 0.58~0.96, P = 0.022). The further stratification analysis showed that the risk of CWP will significantly decreased in non-smoking groups (OR = 0.10, 95% CI = 0.01~0.83, P = 0.033). CONCLUSIONS: Our results suggest that individuals with the EPHX1 (rs223492) GG genotype was associated with a dereased risk of CWP, and it has a protective effect on the developing CWP. PMID- 26653644 TI - [Effect of silicon dioxide nanoparticles on expression and DNA methylation of PARP-1 gene in HaCaT cells]. AB - OBJECTIVE: To study the effect of silicon dioxide nanoparticles on the expression and promoter region CpG islands methylation of (Poly [ADP-ribose] polymerase 1, PARP-1) gene in human HaCaT Cell. METHODS: HaCaT Cells were treated with nm SiO2at 0, 2.5, 5 and 10 ug/mL and micro-SiO2at 10 ug/ml for 24 h and DAC treatment was given at 10 ug/ml group for 48 h. Real-time PCR and western blot assay was used to detect the expression of PARP-1 mRNA and protein. BSP (Bisulfite Pyrosequence, BSP) assay was used to detect the promoter region CpG islands methylation status of PARP-1 gene. RESULTS: After exposure to nano SiO2particles, compared to CTRL group, the mRNA and protein expression of PARP-1 in micro-SiO2and 2.5 ug/ml group unchanged, but he mRNA and protein expression of PARP-1 in 5, 10 ug/ml as well as DAC group was down-regulated and there are statistical significance between CTRL group and 5, 10 ug/ml as well as DAC group and the PARP-1 promoter region CpG islands showed methylation. CONCLUSION: nano SiO2can down-regulate PARP-1 expression in HaCaT Cell and this is associated with the change in the methylation of PARP-1 gene promoter region CpG islands induced by nano-SiO2particles. PMID- 26653645 TI - [The protective effect of ulinastatin on paraquat-induced injury in HK-2 cells and the underlying mechanisms]. AB - OBJECTIVE: To investigate the protective effect of ulinastatin (UTI) on HK-2 cells during paraquat (PQ)-induced injury and its underlying mechanisms. METHODS: Routinely cultured HK-2 cells were divided into blank control group, PQ group, UTI+PQ group and UTI group. Cell viability was determined by CCK-8 assay. The concentration of PQ in HK-2 cells were measured by high performance liquid chromatography (HPLC). The production of total reactive oxygen species (ROS) were detected by fluorescence microscopy. The activities of superoxide dismutase activity (SOD) and the content of malondialdehyde (MDA) in HK-2 cells were observed by chemical colorimetry. The levels of tumor necrosis factor alpha (TNF alpha) and interleukin 6 (IL-6) were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: PQ, even at a dose of 200 uM, could significant suppress the viability of HK-2 cells in a dose-dependent and time-dependent. UTI showed no significant inhibitory effect on the viability of HK-2 cells when given at a dose below 8 000 U/ml (P > 0.05). Compared with the PQ group, the UTI+PQ group had significantly increased the viability of HK-2 cells in a dose-dependent of UTI (P < 0.05). Compared with the PQ group on the same hour, the UTI+PQ group showed decreased in PQ concentration in HK-2 cells (P < 0.05 for all except 6 h). Compared with the blank control group, the PQ group had significantly decreased SOD activity and significantly increased ROS level and MDA content (P < 0.05). Compared with the PQ group, the UTI+PQ group had significantly increased SOD activity and significantly decreased ROS level and MDA content (P < 0.05). Compared with the blank control group, the PQ group had significantly increased IL-6 and TNF-alpha level (P < 0.05); Compared with the PQ group, the UTI+PQ group had significantly decreased IL-6 and TNF-alpha level (P < 0.05). CONCLUSION: UTI significantly reduces the PQ-induced oxidative damage and inflammatory injury and its mechanism may be by reducing the accumulation of PQ in HK-2 cells. PMID- 26653646 TI - [DNA methylation and telomere damage in occupational people exposed to coal tar pitch]. AB - OBJECTIVE: To investigate the promoter methylation of p16, FHIT and RASSF1A gene and telomere damage in the workers exposed to coal tar pitch, and to explore the effective biomarker of occupational exposure to coal tar pitch. METHODS: 180 cases of workers exposed to coal tar pitch in a certain carbon plant named as exposure group, and 145 healthy cases with a medical examination in the first affiliated hospital of Zhengzhou University were selected as control group. Relative telomere length in peripheral blood DNA was detected using real-time quantitative PCR, and the promoter methylation rate of p16, RASSF1A and FHIT gene in peripheral blood DNA were determined by real-time quantitative methylation specific PCR. The relative telomere length and gene promoter methylation in two groups were compared, and influencing factors were analyzed. RESULTS: Relative telomere length in exposed group was lower than that in the control group, and the difference was statistically significant (Z = -5.395, P < 0.001). There was no significant difference in the promoter methylation rate of p16, FHIT and RASSF1A gene between the two groups (P > 0.05). Stratification analysis by gender, age, and smoking, we found that when the age was less than or equal to 40, the promoter methylation rate of p16 in exposed group was more than that in control group, and the difference was statistically significant (Z = -1.914, P = 0.011). CONCLUSION: Occupational exposure to coal tar pitch may induce leukocyte DNA telomere length of human peripheral blood shortened, and may not change the promoter methylation rates of p16, FHIT and RASSF1A gene. PMID- 26653647 TI - [A experiment research of beryllium oxide induced oxidative lung injury and the protective effects of LBP in rats]. AB - OBJECTIVE: To explore beryllium oxide induced oxidative lung injury and the protective effects of LBP. METHODS: Intoxication of animals were induced by once intratracheal injection and LBP intervention by intragastric administration. The content of HIF-1, VEGF and HO-1 of lung tissues were measured by kits. The pathological changes of lung tissue were showed by pathological section. The changes of lung ultrastructure were observed by electron microscope. RESULTS: Pathological changes of the lung tissue in beryllium oxide exposure group rats were in line with the characteristics of beryllium disease in human. Compared with the control group, HO-1 was increased in beryllium oxide exposure 40 d group and low doses of LBP group, compared with the control group, HO-1 was increased in beryllium oxide exposure 80d group and LBP treatment groups (P < 0.05 or P < 0.01). Compared with the control group, HIF-1 was increased in beryllium oxide exposure 40 d group, LBP treatment groups, beryllium oxide exposure 60 d and 80 d groups (P < 0.05 or P < 0.01). Compared with the control group, VEGF was increased of all phases, especially in beryllium oxide exposure 40d and 80 groups, LBP treatment groups and beryllium oxide exposure 60 d (P < 0.05 or P < 0.01). The content of HO-1 of beryllium oxide exposure group was higher than the LBP treatment for 40d group but below LBP treatment for 80 d group (P < 0.05). The content of HIF1 of beryllium oxide exposure group was higher than high dose of LBP treatment for 60d group and LBP treatment for 80 d group (P < 0.01). The content of VEGF of beryllium oxide exposure group was higher than LBP treatment for 40 d group and high dose of LBP treatment for 60 d (P < 0.05 or P < 0.01). CONCLUSIONS: BeO can cause abnormal expression of related genes of lung tissue in rats, LBP has protective effects on BeO caused lung injury. PMID- 26653648 TI - [An analysis of manganese level and results of occupational health inspection among workers in a workplace]. AB - OBJECTIVE: To understand the toxic effects of manganese exposure on health by measurement of manganese concentration and occupational health inspection among workers in an enterprise exposed to manganese, and to provide a basis for occupational disease control. METHODS: The air concentrations of manganese in 12 workplaces where workers often stayed were measured by typical sampling; occupational health inspection was performed among a total of 538 workers in the enterprise by cluster sampling. RESULTS: The average concentrations of manganese in the workplace from 2011 to 2013 were 0.179 mg/m(3), 0.122 mg/m(3), and 0.082 5 mg/m(3), respectively, indicating a significant decrease in manganese level within the three years by rank-sum test (P < 0.05). The results of health inspection showed that 165 (30.7%) out of 538 workers had abnormal indices, and the incidence of autonomic nervous system abnormalities reached 32.7% (176/538). There was no correlation between manganese concentration in the workplace and the incidence of abnormal indices in health inspection, while the manganese concentration in the workplace was positively correlated with the incidence of autonomic nervous system symptoms (r = 0.718, P < 0.05). CONCLUSION: The manganese concentration in the workplace is positively correlated with the incidence of autonomic nervous system symptoms. Early exposure to a low level of manganese can induce functional changes and potential damages in the nervous system. PMID- 26653650 TI - [Analysis of pneumoconiosis disease diagnosis and identification of the conclusions of the reasons of the differences]. PMID- 26653649 TI - [Study on the therapeutic effects of tetrandrine combined with N-acetylcysteine on experimental silicosis of rats]. AB - OBJECTIVE: To compare the effects of oral treatment with tetrandrine (TD) and N acetylcys-teine (NAC) separately or jointly on silica-exposed rats. METHODS: 40 sprague-Dawly (SD) rats were randomly divided into normal saline group, quartz group, TD treatment group (50 mg/kg), NAC treatment group (500 mg/kg) and combined treatment group (TD: 50 mg/kg + NAC: 500 mg/kg). Rats in normal saline group and other groups received intratracheal instillation of normal saline and quartz dust suspension respectively. Treatment groups were given TD, NAC separately or jointly via esophagus the next day after instillation, once a day and six times a week for 30 consecutive days. At the end of experiment, the pathological changes of lung tissues were evaluated by the methods of Foot, HE and Masson staining, the level of hydroxyproline (HYP), malondjalde-hyde (MDA), tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in lung tissues were measured by alkaline hydrolysis method, the barbituric acid method and enzyme-linked immunosorbent assay (ELISA) respectively. RESULTS: Compared with the quartz group, lymph nodes/body coefficients in all treatment groups and lung/body coefficient in combined treatment group were significantly decreased (P < 0.05). Pathology results showed that the normal saline group demonstrated no obvious evidence of lung damage. The quartz group lungs silicotic lesions focused on II~III level, the TD treatment group was mainly with I level, the NAC treatment group was mainly with I~II level, and the combined treatment group only showed little silicotic nodule, no obvious fibrosis. HYP content in TD treatment group and combined treatment group were significantly lower than that in the quartz group (P < 0.05), while it showed no obvious change in NAC treatment group. MDA content in lung tissues of each treatment group (TD treatment group, NAC treatment group and combined treatment group) were 18.80 +/- 2.94, 20.13 +/- 4.01 and 17.05 +/- 3.52 nmol/ml respectively, which lower than in the quartz group (23.99 +/- 3.26 nmol/ml). The level of IL-6 in lung tissues of the quartz group were 89.57 +/- 8.78 pg/ml. After TD and NAC monotherapy, the IL-6 content decreased to 79.22 +/- 9.65 pg/ml and 81.63 +/- 5.72 pg/ml, and it decreased more significantly after combined medication (74.37 +/- 3.17 pg/ml). The level of TNF alpha in the quartz group were 59.05 +/- 4.48 pg/ml. After TD and NAC monotherapy, the TNF-alpha content decreased to 50.48 +/- 2.76 pg/ml and 54.28 +/ 4.30 pg/ml, and it decreased more significantly after combined medication (49.10 +/- 4.98 pg/ml). CONCLUSION: NAC and TD could reduce MDA, TNF-alpha and IL-6 levels in lung tissue, and alleviate SiO2-induced pulmonary fibrosis in rats. Combined treatment with TD and NAC was more effective than TD or NAC treatment separately. PMID- 26653651 TI - [Application of color doppler ultrasound examination of thyroid in occupational health care of radiation-exposed physicians]. AB - OBJECTIVE: To explore the value of color doppler ultrasound examination of thyroid in occupational health care of radiation-exposed physicians. METHODS: One hundred and thirty-four radiation-exposed physicians (observation group) and sixty-eight non-radiation-exposed physicians (control group) received color doppler ultrasound examination of thyroid using ALOKA SSD-4000 color doppler ultrasonic diagnostic apparatus, and the results were compared between the two groups. RESULTS: The anteroposterior diameters of the left lobe, right lobe, and isthmus of the thyroid in the observation group were significantly larger than those in the control group (P < 0.01). Compared with the control group, the observation group had significantly larger internal diameters and peak blood flow velocities during systole of the right superior thyroid artery (P < 0.05, P < 0.05). There were no significant differences in detection rates of thyroid nodules and lymph nodes between the observation group and the control group (18.7% vs 13.2%, P > 0.05; 6.7% vs 1.5%, P > 0.05). The radiation-exposed physicians were exposed to low-dose ionizing radiation with a dose between 0.14 and 1.67 mSv/a. CONCLUSION: The color doppler ultrasound examination of the thyroid can detect early changes in the thyroid of radiation-exposed physicians exposed to long-term and low-dose ionizing radiation. PMID- 26653652 TI - [Use of digital X-ray machine in occupational disease prevention and treatment organizations]. PMID- 26653653 TI - [Influencing factors for needlestick injuries in student nurses]. AB - OBJECTIVE: To investigate the needlestick injuries in student nurses during nine months of in-ternship in our hospital, and reveal the high-risk periods, risk procedures, and influencing factors for needlestick injuries, and explore the prevention approaches. METHODS: Three hundred and fifty student nurses who interned at our hospital from April to December 2014 and from July 2014 to March 2015 were surveyed using self-de-signed questionnaires. Three hundred and forty questionnaires were recovered and 334 out of them were valid. Data were collected and questionnaires were analyzed. RESULTS: The incidence of needlestick injuries was 60.8%; the incidence of needlestick injuries was substantially higher at the early stage than at the late stage of the internship, and higher in the day shift than in the night shift. Moreover, the incidence of needlestick injuries was the highest during the removal of a syringe or infusion needle, accounting for 24.3% of the total incidence. Some other significant factors for needlestick injuries in student nurses included education level, reports on oc-cupational exposure, constant update of nursing knowledge, regular hematological examination, and relevant training experiences. According to 61.7% of student nurses, clinical operations were affected due to underlying concern about needlestick injuries. CONCLUSION: More attention should be paid to high incidence of needlestick injuries in student nurses, especially at the early stage of their internship. To reduce the incidence of needlestick injuries, education on occupational protection should be given to student nurses in advance, and the pre-job training should be enhanced. PMID- 26653654 TI - [Effect of chronic aluminum exposure on neuron apoptosis and expression of P53 phosphorylation in rats]. AB - OBJECTIVE: To explore the role of P53 phosphorylation in neuron apoptosis of rats by chronic aluminum exposure. METHODS: A total of male 40 SD rats were divided randomly into 4 groups (n = 10/dose), the exposed groups were fed with normal diet with different concentration of AlCl3 . 6H2O for 6 months respectively. The dosage of low, middle and high groups were 10.73, 107.33, 1073.33 mg/kg in sequence. The control group received normal diet. The neuron apoptosis was measured by method of Tunel. The expressions of P53 and pP53-ser15 protein in the cortex were detected by Western-blot. RESULTS: Tunel staining showed that the low, middle and high group rats had increased apoptosis rate than control group (P < 0.01). Western-blot test demonstrated that the expression of P53 protein in the cortex of high group rats were significantly higher than the control and low groups (P < 0.05). The expression of pP53-ser15 protein in the cortex of middle and high group rats were also higher than the control and low groups (P < 0.05). CONCLUSION: Chronic aluminum exposure can lead to over expression of P53 and pP53 ser15 protein in cerebral cortex, which maybe one of the most important mechanisms of neuron apoptosis induced by AlCl3. PMID- 26653655 TI - [The study on the relationship between hippocampus neuronal apoptosis and hippocampus synaptic plasticity in rats exposed to aluminum]. AB - OBJECTIVE: To investigate the effect of aluminum exposure on neuronal apoptosis of rats hippocampus and the correlation of and synaptic plasticity. METHODS: There were 40 SPF grade SD rats which were randomly divided into four groups: the control group, the low dose group, the medium dose group and the high dose group, 10 rats in each group. The rats were daily gavaged with aluminum lactate for 30 days. The hippocampal fEPSPs in rat was measured by electrophysiological grapher and the neuronal apoptosis in hippocampus was detected by Flow cytometer. In addition, the relative expression of gene which includes caspase-3, 8, 9 was measured by Real-time PCR. RESULTS: Compared to the control group, the average of fEPSPs which after HFS 10, 20, 30, 40, 50, 60 min was decreased at different time point in the low dose group, the medium dose group and the high dose group (P < 0.05). Compared with the control group, the rate of apoptosis was significantly increased in the medium dose group and the high dose group (P < 0.05). Compared to the control group, the relative expression of caspase-3 in the medium dose group and the high dose group was significantly increased in Real-time PCR (P < 0.05), and the relative expression of caspase-8 in the high dose group was significantly increased (P < 0.05). CONCLUSION: Aluminum exposure may induced neuronal apoptosis in rats, and then affect hippocampal synaptic plasticity. PMID- 26653656 TI - [Effect of carbon disulfide exposure on fatty acid metabolism in ApoE knockout and C57BL/6J mice]. AB - OBJECTIVE: To study the influences of carbon disulfide (CS2) exposure on fatty acid metabolism in apolipoprotein E (ApoE) knockout mice and C57BL/6J mice. METHODS: Twenty-four male ApoE knockout mice were randomly and equally divided into four groups: a CS2-exposed normal diet group, a CS2-unexposed normal diet group, a CS2-exposed high-fat diet group, and a CS2-unexposed high-fat diet group. Twenty-four C57BL/6J male mice were divided into four groups in the same way. The CS2-exposed groups were exposed to CS2 (1 g/m(3)) by static inhalation for 5 hours a day, 5 days a week. After two weeks, the whole blood of mice was collected. Methyl ester derivatization of fatty acids was performed using an acid catalyzed method. Fatty acid contents before and after exposure were compared by gas chromatography-mass spectroscopy. RESULTS: There were significant differences in fatty acid contents of mice between the four groups. For the C57BL/6J mice, the arachidic acid contents in the CS2-exposed high-fat diet group were significantly lower than those in the CS2-unexposed high-fat diet group (P = 0.045 0). For the ApoE knockout mice, the arachidonic acid contents in the CS2 exposed normal diet group were significantly lower than those in the CS2 unexposed control diet group (P = 0.045 2). For the ApoE knockout mice, the gamma linolenic acid contents in the CS2-exposed high-fat diet group were significantly higher than those in the unexposed high-fat diet group (P = 0.044 7). CONCLUSION: Exposure to CS2 can induce fatty acid metabolism disorder in mice, indicating that CS2 may increase the risk of atherosclerosis and other cardiovascular diseases. PMID- 26653657 TI - [Clinical analysis of thoracoscopy of 30 coalworker's pneumoconiosiswith pleural effusion cases]. AB - OBJECTIVE: To investigate the diagnostic value of thoracoscopy on idiopathic coalworker's pneumoconiosis with pleural effusion in general medicine. METHOD: Routine (general medicine) thoracoscopyof patients suffering from iIdiopathiccoalworker's pneumoconiosis with pleural effusion, pathological examination of lesions obtained (direct vision). RESULT: Pathological examination revealed grayish-white miliary nodules with multiple protruding nodules, irregular focal pleura thickening, pulmonary congestion, edema, fibrous adhesion. Thorascopy produced a diagnostic rate of 93.3%. Confirmed cases includes 13 cases of tuberculous pleurisy, 11 cases of malignant pleural effusion, 4 cases of cardiac insufficiency with pleural effusion and 2 cases of idiopathic pleural effusion, with no serious complications. CONCLUSION: Thoracoscopy of idiopathic coalworker's pneumoconiosis with pleural effusion is a safe, accurate diagnostic methodin general medicine, and could benefit the establishment of a treatment method quickly, visual observation of the lesions of patients suffering from coalworker's pneumoconiosis with pleural effusion using thoracoscopy, and at the same time offer preliminary investigationof the correlation between the intensity and compactibilityof coal macule distribution and clinical stages of coalworker's Pneumoconiosis. PMID- 26653658 TI - [A case report of acute paraquat poisoning with high amylase and lipaselevel]. PMID- 26653659 TI - [One case complicated with disseminated intravascular coagulation in acute dichlorvos poisoning]. PMID- 26653660 TI - [Three cases of acute trichloroethylene poisoning associated with skin damage]. PMID- 26653661 TI - [Intratympanic methylprednisolone hemisuccinate injection in treating the refractory noise induced deafness]. AB - OBJECTIVE: To analyze the efficacy of Methylprednisolone hemisuccinate intratympanic injection for refractory noise induced deafness. METHODS: One hundred and twenty cases (215 ears) of noise induced deafness were treated with either hormone group (107 ears) or with non hormone group (108 ears). Following prior interventions, 145 ears went on to receive intratympanic Methylprednisolone hemisuccinate injection twice a week. RESULTS: After Intratympanic therapy, the total effective rate was 46.2%. 32 of 71 ears (45.1%) demonstrated hearing improvement in hormone group and 35 of 74 ears (47.3%) in non hormone group. The difference was statistically insignificant (P = 0.788). CONCLUSION: Intratympanic therapy appears to provide additional treatment benefits for patients with refractory noise induced deafness who have been treated with prior interventions. The outcome is not affected by pretreatment with hormone. PMID- 26653662 TI - [A review of developments in paraquat neurotoxicity research]. PMID- 26653663 TI - [Role and significance of paraoxonase in acute organophosphate poisoning]. PMID- 26653664 TI - [Research status of trichloropropane poisoning]. PMID- 26653665 TI - [Hard metal lung disease]. PMID- 26653666 TI - Aflatoxins and ochratoxin A in export quality raisins collected from different areas of Pakistan. AB - During 2012-2014, 170 samples of export quality raisins were collected from different vendors in Pakistan. The collected samples were analysed for the presence of aflatoxins (AFs) and Ochratoxin A (OTA) contamination using high performance liquid chromatography technique. The limit of detection and limit of quantification of AFs/OTA were 0.12/0.10 and 0.36/0.30 ug kg(-1), respectively. Only 5% of the samples were contaminated with AFs, ranging 0.15-2.58 ug kg(-1) with a mean of 0.05 +/- 0.26 ug kg(-1). None of the raisin samples exhibited AFs contamination above the maximum limit (ML = 4 ug kg(-1)) as set by the European Union (EU). About 72% of the samples were contaminated with OTA, ranging 0.14 12.75 ug kg(-1) with a mean of 2.10 +/- 1.9 ug kg(-1). However, in 95.3% of the tested samples, OTA level was lower than the ML of 10 ug kg(-1) as regulated by the EU. Apparently, a strict and continuous monitoring plan, including regulatory limits, improves food safety and quality for all types of commodities. PMID- 26653667 TI - Six-year course and prognosis of traumatic knee symptoms in general practice: Cohort study. AB - BACKGROUND: Traumatic knee symptoms are frequently seen, however, evidence about the course and prognostic factors are scarce. OBJECTIVES: To describe the one and six-year course of traumatic knee symptoms presenting in general practice, and to identify prognostic factors for persistent knee symptoms. METHODS: Adolescents (>=12 years) and adults with traumatic knee symptoms (n = 328) from general practice were followed for six years with self-report questionnaires and physical examination. RESULTS: Persistent knee symptoms were reported by 27% of the patients at one year and by 33% at six years. There was a strong relationship (OR: 11.0, 95% CI: 5.0-24.2) between having persistent knee symptoms at one year and at six-year follow-up. Prognostic factors associated with persistent knee symptoms at one year were age, poor general health, history of non-traumatic knee symptoms, absence floating patella and laxity on the anterior drawer test (AUC: 0.72). At six-year follow-up, age, body mass index > 27, non-skeletal co morbidity, self-reported crepitus of the knee, history of non-traumatic knee symptoms, and laxity on the anterior drawer test were associated with persistent knee symptoms (AUC: 0.82). CONCLUSION: Traumatic knee symptoms in general practice seem to become a chronic disorder in one out of three patients. Several prognostic factors assessed at baseline were associated with persistent knee symptoms at one and six-year follow-up. PMID- 26653668 TI - Effect of abatacept on the immunogenicity of 23-valent pneumococcal polysaccharide vaccination (PPSV23) in rheumatoid arthritis patients. AB - INTRODUCTION: Patients with rheumatoid arthritis (RA) treated with abatacept (ABT) are at increased risk for vaccine-preventable infections. The aim of the present study is to evaluate the humoral response to 23-valent pneumococcal polysaccharide (PPSV23) vaccination in RA patients receiving ABT. METHODS: The immunogenicity study was nested within a randomized, double-blind placebo controlled study, designed to evaluate the efficacy of the PPSV23. PPSV23 was given to 111 RA patients, who were classified into three groups: RA control (n = 35), methotrexate (MTX) alone (n = 55), and ABT (n = 21). Before and 4-6 weeks after vaccination, we measured the patients' concentrations of antibodies against pneumococcal serotypes 6B and 23F using an enzyme-linked immunosorbent assay and determined their antibody functionality using a multiplexed opsonophagocytic killing assay, reported as the opsonization index (OI). RESULTS: The pneumococcal serotype-specific IgG concentrations and OIs were both significantly increased in all treatment groups in response to PPSV23 vaccination. In the ABT group, the IgG responses for the 6B serotype were lower compared with those in the MTX alone or control groups, whereas the OI responses were similar to those in the other two groups. In a subgroup analysis, the pneumococcal serotype-specific IgG responses were significantly lower in both serotypes (6B and 23F) in the ABT/MTX group; however, the OI responses in the ABT group were not different from the control group. There was no association between the pneumococcal serotype-specific IgG and OI responses for the 6B serotype in patients receiving ABT in contrast to the control or MTX alone patients. No severe adverse effects were observed in any of the treatment groups. CONCLUSIONS: OI responses indicate antibody functionality rather than simply their amount, so the similarity of these measurements between all three groups suggests that RA patients receiving ABT still benefit from receiving the PPSV23 vaccination, even though they produce less IgG in response to it. The results suggest an influence of ABT on the humoral response to PPSV23 vaccination under MTX treatment; however, preserved opsonin responses are expected in RA patients treated with ABT plus MTX. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry: UMIN000009566. Registered 12 December 2012. PMID- 26653670 TI - Correction to Glycans of Antibodies as a Specific Site for Drug Conjugation Using Glycosyltransferases. PMID- 26653669 TI - Characterization of Oat (Avena nuda L.) beta-Glucan Cryogelation Process by Low Field NMR. AB - Low-field nuclear magnetic resonance (LF-NMR) is a useful method in studying the water distribution and mobility in heterogeneous systems. This technique was used to characterize water in an oat beta-glucan aqueous system during cryogelation by repeated freeze-thaw treatments. The results indicated that microphase separation occurred during cryogelation, and three water components were determined in the cryostructure. The spin-spin relaxation time was analyzed on the basis of chemical exchange and diffusion exchange theory. The location of each water component was identified in the porous microstructure of the cryogel. The pore size measured from the SEM image is in accordance with that estimated from relaxation time. The formation of cryogel is confirmed by rheological method. The results suggested that the cryogelation process of the polysaccharide could be monitored by LF-NMR through the evolution of spin-spin relaxation characteristics. PMID- 26653671 TI - Modified approach to powered endoscopic dacryocystorhinostomy. AB - OBJECTIVE: This paper presents modifications to powered endoscopic dacryocystorhinostomy without stenting for the management of acquired nasolacrimal duct obstruction. STUDY DESIGN: A retrospective, non-randomised review. METHOD: A total of 105 patients with epiphora secondary to acquired nasolacrimal duct obstruction were operated on by our modified powered endoscopic dacryocystorhinostomy approach. RESULTS: Of 105 patients, 100 (95.2 per cent) have remained asymptomatic. One patient with a narrow ostium had improved symptoms, while four patients continued to experience persistent symptoms (treatment failures). CONCLUSION: The modified powered endoscopic dacryocystorhinostomy approach led to excellent results, without bone exposure and granulations, and with early mucosalisation. PMID- 26653672 TI - Encapsulation of MEH-PPV:PCBM Hybrids in the Cores of Block Copolymer Micellar Assemblies: Photoinduced Electron Transfer in a Nanoscale Donor-Acceptor System. AB - The objective of this work is to demonstrate that conjugated polymer:fullerene hybrid nanoparticles encapsulated in the hydrophobic cores of triblock copolymer micelles may successfully act as spatially confined donor-acceptor systems capable of facilitating photoinduced charge carrier separation. To this end, aqueous dispersions of poly[2-methoxy-5-(2-ethylhexyloxy)-1,4-phenylenevinylene] (MEH-PPV) nanoparticles were first prepared by solubilization of the polymer in the cores of poly(oxyethylene)-poly(oxypropylene)-poly(oxyethylene) triblock copolymer, Pluronic F-127 micelles. A number of significant optical spectroscopic changes were observed on transfer of the conjugated polymer from a nonaqueous solvent to the aqueous micellar environment. These were primarily attributed to increased interchain interactions due to conjugated polymer chain collapse during encapsulation in the micellar cores. When prepared in buffer solution, the micelles exhibited good long-term collodial stability. When MEH-PPV micelles were blended by the addition of controlled amounts of [6,6]-phenyl-C61-butyric acid methyl ester (PCBM), the observed correspondence of photoluminescence emission quenching, quantum yield decreases, and emission lifetime shortening with increasing PCBM concentration indicated efficient photoinduced donor-to-acceptor charge transfer between MEH-PPV and the fullerenes in the cores of the micelles, an assignment that was confirmed by transient absorption spectroscopic monitoring of carrier photogeneration and recombination. PMID- 26653673 TI - Use of the alpha shape to quantify finite helical axis dispersion during simulated spine movements. AB - In biomechanical studies examining joint kinematics the most common measurement is range of motion (ROM), yet other techniques, such as the finite helical axis (FHA), may elucidate the changes in the 3D motion pathology more effectively. One of the deficiencies with the FHA technique is in quantifying the axes generated throughout a motion sequence. This study attempted to solve this issue via a computational geometric technique known as the alpha shape, which bounds a set of point data within a closed boundary similar to a convex hull. The purpose of this study was to use the alpha shape as an additional tool to visualize and quantify FHA dispersion between intact and injured cadaveric spine movements and compare these changes to the gold-standard ROM measurements. Flexion-extension, axial rotation, and lateral bending were simulated with five C5-C6 motion segments using a spinal loading simulator and Optotrak motion tracking system. Specimens were first tested intact followed by a simulated injury model. ROM and the FHAs were calculated post-hoc, with alpha shapes and convex hulls generated from the anatomic planar intercept points of the FHAs. While both ROM and the boundary shape areas increased with injury (p<0.05), no consistent geometric trends in the alpha shape growth were identified. The alpha shape area was sensitive to the alpha value chosen and values examined below 2.5 created more than one closed boundary. Ultimately, the alpha shape presents as a useful technique to quantify sequences of joint kinematics described by scatter plots such as FHA intercept data. PMID- 26653674 TI - Generalization of treadmill perturbation to overground slip during gait: Effect of different perturbation distances on slip recovery. AB - Treadmill-perturbation training (TM-training) may improve a person's fall resistance, whereby adjusting slip distance can be a simple way to manipulate training intensity. The purpose of this study was to determine the effects of different slip distances in TM-training (12-cm vs. 18-cm) on its generalization to the recovery from a novel "free" slip during overground walking. Generalization here means the ability to apply learned skill from TM-training to slip recovery during overground walking. Thirty-six young adults in the TM_12 or the TM_18 group underwent either a 12-cm or an 18-cm slip during the treadmill walking for seven times, or in the control group were not exposed to any perturbation. Their responses were also contrasted with previously reported results from overground-perturbation training (OG-training) in which participants received either a 12-cm or an 18-cm slip during level walking with the same number of repetitions. Everyone was then exposed to the same generalization test during a novel "free" slip in overground walking. Their proactive and reactive control of stability was measured and compared. TM-training displayed a significant training effect in comparison to the control group (p<0.05), while most of the improvements were found in the reactive control of stability and were much-limited in comparison to that of OG-training. Also unlike OG-training, no significant differences were found between the results obtained from the TM_12 and the TM_18 groups (p>0.05). These results underscore the further needs to investigate the potential of the treadmill as a convenient instrument that can effectively deliver perturbation training. PMID- 26653675 TI - Role of Cytochrome P450 Hydroxylase in the Decreased Accumulation of Vitamin E in Muscle from Turkeys Compared to that from Chickens. AB - Turkeys and chickens reared to 5 weeks of age and fed diets with feedstuffs low in endogenous tocopherols were examined. Treatments included feed supplemented with RRR (natural source vitamin E) alpha tocopheryl acetate (AcT, 35 mg/kg feed) and all-racemic (synthetic vitamin E) AcT (10 and 58 mg/kg feed). Alpha tocopherol hydroxylase activity was greater in liver microsomes prepared from turkeys compared to that from chickens (p < 0.01). Alpha and gamma tocopherol metabolites were higher in turkey bile than in chicken when assessing the RRR AcT diet and the all-racemic AcT diet at 58 mg/kg feed (p < 0.01). Turkey cytochrome P450 2C29 was increased relative to its chicken ortholog on the basis of RNA-Seq transcript abundance (p < 0.001) and activity-based protein profiling (p < 0.01) of liver tissue. Alpha tocopherol concentrations in plasma, liver, and muscle from turkey were lower than the respective tissues from chicken (p < 0.05). Lipid oxidation was greater in turkey thigh than in chicken (p < 0.05). These results suggest that elevated tocopherol metabolism by cytochrome P450 hydroxylase(s) in turkeys contributes to the decreased accumulation of alpha tocopherol in turkey tissues compared to that of chickens. PMID- 26653676 TI - A conservative oxygenation strategy is feasible and appears to be safe compared with liberal oxygenation in mechanically ventilated patients [synopsis]. PMID- 26653677 TI - A conservative oxygenation strategy is feasible and appears to be safe compared with liberal oxygenation in mechanically ventilated patients [commentary]. PMID- 26653679 TI - Uterine fibroids at routine second-trimester ultrasound survey and risk of sonographic short cervix. AB - OBJECTIVE: To determine whether women with sonographically identified uterine fibroids are at higher risk for a short cervix. METHODS: This retrospective cohort study evaluated all women with singleton gestations who had a routine second-trimester ultrasound at 17-23 weeks gestational age from 2010 to 2013. When fibroids were noted, their presence, number, location and size were recorded. Exclusion criteria included a history of cervical conization or loop electrosurgical excision procedure (LEEP), uterine anomalies, maternal age greater than 40 years, and a previously placed cerclage. The primary variable of interest was short cervix (<25 mm). Secondary variables of interest included gestational age at delivery, mode of delivery, indication for cesarean, malpresentation, birth weight, and Apgar scores. A multivariable logistic regression analysis was performed. RESULTS: Fibroids were identified in 522/10 314 patients (5.1%). In the final multivariable logistic regression model, short cervix was increased in women with fibroids (OR 2.29, 95% CI: 1.40, 3.74). The number of fibroids did not affect the frequency of short cervix. Fibroids were significantly associated with preterm delivery (<37 weeks), primary cesarean, breech presentation, lower birth weight infants, and lower Apgar scores. CONCLUSIONS: Women with uterine fibroids may be at higher risk for a short cervix. Fibroids are also associated with several adverse obstetric and neonatal outcomes. PMID- 26653678 TI - Immunostimulatory Activity of the Cytokine-Based Biologic, IRX-2, on Human Papillomavirus-Exposed Langerhans Cells. AB - Langerhans cells (LCs) are the antigen-presenting cells of the epithelial layer and are responsible for initiating immune responses against skin and mucosa invading viruses. Human papillomavirus (HPV)-mediated suppression of LC function is a crucial mechanism of HPV immune evasion, which can lead to persistent infection and development of several human cancers, including cervical, anal, and head and neck cancers. The cell-derived cytokine-based biologic, IRX-2, consists of multiple well-defined cytokines and is broadly active on various immune cell subsets. In this study, we investigated primary human LC activation after exposure to HPV16, followed by treatment with IRX-2 in vitro, and evaluated their subsequent ability to induce HPV16-specific T cells. In contrast to its activity on dendritic cells, HPV16 alone is not sufficient to induce phenotypic and functional activation of LCs. However, IRX-2 induces a significant upregulation of antigen presentation and costimulatory molecules, T helper 1 (Th1)-associated cytokine release, and chemokine-directed migration of LCs pre-exposed to HPV16. Furthermore, LCs treated with IRX-2 after HPV16 exposure induced CD8(+) T-cell responses against specific HLA-A*0201-binding HPV16 T-cell epitopes. The present study suggests that IRX-2 is an attractive immunomodulator for assisting the immune response in eradication of HPV-infected cells, thereby potentially preventing HPV-induced cancers. PMID- 26653680 TI - Quantification of Myocardial Extracellular Volume Fraction with Cardiac MR Imaging in Thalassemia Major. AB - Purpose To quantify myocardial extracellular volume (ECV) by using cardiac magnetic resonance (MR) imaging in thalassemia major and to investigate the relationship between ECV and myocardial iron overload. Materials and Methods With institutional review board approval and informed consent, 30 patients with thalassemia major (mean age +/- standard deviation, 34.6 years +/- 9.5) and 10 healthy control subjects (mean age, 31.5 years +/- 4.4) were prospectively recruited (clinicaltrials.gov identification number NCT02090699). Nineteen patients (63.3%) had prior myocardial iron overload (defined as midseptal T2* < 20 msec on any prior cardiac MR images). Cardiac MR imaging at 1.5 T included cine steady-state free precession for ventricular function, T2* for myocardial iron quantification, and unenhanced and contrast material-enhanced T1 mapping. ECV was calculated with input of the patient's hematocrit level. Peak systolic global longitudinal strain by means of speckle tracking was assessed with same day transthoracic echocardiography. Statistical analysis included use of the two sample t test, Fisher exact test, and Spearman correlation. Results Unenhanced T1 values were significantly lower in patients with prior myocardial iron overload than in control subjects (850.3 +/- 115.1 vs 1006.3 +/- 35.4, P < .001) and correlated strongly with T2* values (r = 0.874, P < .001). Patients with prior myocardial iron overload had higher ECV than did patients without iron overload (31.3% +/- 2.8 vs 28.2% +/- 3.4, P = .030) and healthy control subjects (27.0% +/ 3.1, P = .003). There was no difference in ECV between patients without iron overload and control subjects (P = .647). ECV correlated with lowest historical T2* (r = -0.469, P = .010) but did not correlate significantly with left ventricular ejection fraction (r = -0.216, P = .252) or global longitudinal strain (r = -0.164, P = .423). Conclusion ECV is significantly increased in thalassemia major and is associated with myocardial iron overload. These abnormalities may potentially reflect diffuse interstitial myocardial fibrosis. ((c)) RSNA, 2015 Online supplemental material is available for this article. PMID- 26653681 TI - Is Post-TIPS Anticoagulation Therapy Necessary in Patients with Cirrhosis and Portal Vein Thrombosis? A Randomized Controlled Trial. AB - Purpose To determine whether posttransjugular intrahepatic portosystemic shunt (TIPS) placement anticoagulation therapy could benefit patients with cirrhosis and portal vein thrombosis (PVT) from the perspective of a change in portal vein patency status and clinical outcomes. Materials and Methods The study was approved by the institutional review board, and informed consent was obtained from each patient. From October 2012 to February 2014, patients with cirrhosis and PVT who underwent TIPS placement were randomly assigned to the anticoagulation therapy or control group. All patients were followed at 1, 3, 6, and 12 months after the TIPS procedure. Outcome measures were a change of portal vein patency status and clinical measures including gastrointestinal rebleeding, shunt dysfunction, hepatic encephalopathy, and survival. Student t test, chi(2) test, Fisher exact test, Mann-Whitney U test, and logistical regression were applied where appropriate. Results A total of 64 patients were enrolled in the study, with 31 allocated to the anticoagulation group and 33 allocated to the control group. Overall, thrombi were improved in 61 patients (96.8%) after the procedure. PVT recanalization (ie, complete disappearance; reconstruction of cavernous transformation) was achieved in 26 patients (83.9%) in the anticoagulation therapy group and in 23 (71.8%) patients in tthe control group (P = .252). The presence of a superior mesenteric vein thrombus may help predict recanalization failure (unadjusted relative risk = 0.243; 95% confidence interval: 0.070, 0.843; P = .026). Clinical outcomes were also similar between the two groups. Conclusion Anticoagulation therapy may not be necessary in certain patients with PVT because TIPS placement alone can achieve a high persistent recanalization rate. ((c)) RSNA, 2015. PMID- 26653682 TI - (18)F FDG PET/CT versus CT/MR Imaging and the Prognostic Value of Contralateral Neck Metastases in Patients with Head and Neck Squamous Cell Carcinoma. AB - PURPOSE: To evaluate whether contralateral neck metastasis (CNM) from previously untreated head and neck squamous cell carcinoma (HNSCC) can be accurately detected at combined computed tomography (CT)/magnetic resonance (MR) imaging and fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT and assess the prognostic value of CNM. MATERIALS AND METHODS: This prospective study was approved by the institutional review board, and written informed consent was obtained from all enrolled patients. In total, 160 patients with HNSCC were preoperatively evaluated with FDG PET/CT and CT/MR imaging. Histopathologic results of neck dissection samples served as the reference standard for all cases. McNemar test and logistic regression with generalized estimating equations were used to compare the diagnostic value of FDG PET/CT and CT/MR imaging, and Cox proportional hazard modeling was used to assess the prognostic value of CNM. RESULTS: Of the 160 enrolled patients, 94 (58.8%) had a neck metastasis on 231 sides and with 974 levels, and 20 patients (21.3%) had a contralateral neck metastasis. FDG PET/CT was significantly more sensitive than CT/MR imaging according to per-patient (91.5% vs 73.4%; P < .001), per-side (91.1% vs 69.6%; P < .001), and per-level analyses (78.9% vs 53.0%; P < .001). On the per-side basis, FDG PET/CT was also significantly more sensitive and accurate than CT/MR imaging when evaluating the contralateral neck (85.0% vs 45.0%, P = .008, and 91.6% vs 80.3%, P = .008, respectively). However, at univariate analysis, CNM was significantly associated only with cancer-specific death (P = .001) and overall survival (P = .015). CONCLUSION: CNM from HNSCC can be detected at FDG PET/CT with higher sensitivity and accuracy than at CT/MR imaging. PMID- 26653683 TI - Can Current Preoperative Imaging Be Used to Detect Microvascular Invasion of Hepatocellular Carcinoma? AB - PURPOSE: To determine the accuracy of imaging features, such as tumor dimension, multinodularity, nonsmooth tumor margins, peritumoral enhancement, and radiogenomic algorithm based on the association between imaging features (internal arteries and hypoattenuating halos) and gene expression that the authors called two-trait predictor of venous invasion (TTPVI), in the prediction of microvascular invasion (MVI) in hepatocellular carcinoma (HCC). MATERIALS AND METHODS: This single-center retrospective study was approved by the institutional review board, and the requirement for informed consent was waived. One hundred twenty-five patients (median age, 63 years; interquartile range, 53-71 years) with a diagnosis of HCC and indications for hepatic resection were included. Two observers independently reviewed radiologic images to evaluate the following features for MVI: maximum diameter, number of lesions, tumor margins, TTPVI, and peritumoral enhancement. Interobserver agreement was checked, and diagnostic accuracy of radiologic features was investigated. RESULTS: The total number of HCC nodules was 140. Large tumor size, nonsmooth tumor margins, TTPVI, and peritumoral enhancement were significantly related to the presence of MVI (P < .05 in all cases and for both observers). Multinodularity was not significantly related (P = .158). Moreover, the diagnostic accuracy of the three "worrisome" radiologic features (nonsmooth tumor margins, peritumoral enhancement, and TTPVI) was associated with tumor size: The negative predictive value of the absence of worrisome features decreased from 0.84 for observer 1 and 0.91 for observer 2 for tumors smaller than 2 cm to 0.56 and 0.71, respectively, for tumors larger than 5 cm, whereas the presence of all three worrisome features returned to a positive predictive value of 0.95 for observer 1 and 0.96 for observer 2 independent of tumor size, with no significant interobserver differences (P > .10). CONCLUSION: "Worrisome" imaging features, such as tumor dimension, nonsmooth tumor margins, peritumoral enhancement, and TTPVI, have high accuracy in the prediction of MVI in HCC. PMID- 26653684 TI - Pleural Tags on CT Scans to Predict Visceral Pleural Invasion of Non-Small Cell Lung Cancer That Does Not Abut the Pleura. AB - PURPOSE: To evaluate the association of pleural tags with visceral pleural invasion of non-small cell lung cancer (NSCLC) that does not abut the pleural surface. MATERIALS AND METHODS: This retrospective study was approved by the institutional review board. Informed consent was waived. The study of NSCLC that does not abut the pleura in 141 patients (44 patients [31.2%] with visceral pleural invasion proved by pathologic analysis and 97 patients [68.8%] without pleural invasion) was conducted at a single tertiary center. The pleural tags were classified into three types (type 1, one or more linear pleural tag; type 2, one or more linear pleural tag with soft tissue component at the pleural end; and type 3, one or more soft tissue cord-like pleural tag) and prioritized into types 3, 2, and 1 when more than one type was present. Diagnostic accuracy, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and positive likelihood ratio (LR) were calculated. RESULTS: In the absence of pleural tags, no pleural invasion was found. The presence of type 2 pleural tags was moderately associated with visceral pleural invasion with the following results: positive LR, 5.06; accuracy, 71%; sensitivity, 36.4%; specificity, 92.8%; PPV, 76.2%; and NPV, 69.6%. Type 1 pleural tags provided weak evidence to rule out visceral pleural invasion (positive LR, 0.38). Type 3 pleural tags indicated minimal increase in the likelihood of visceral pleural invasion (positive LR, 1.68). CONCLUSION: Type 2 pleural tags on conventional CT images can increase the accuracy of early diagnosis of visceral pleural invasion by NSCLC that does not abut the pleura. PMID- 26653685 TI - Predictors of tumor-infiltrating lymphocyte efficacy in melanoma. AB - In the past decades, the increasing knowledge in cellular immunology and tumor host immune interactions, led to the development of immunotherapy approaches. Immunotherapy, based on adoptive cell transfer of ex vivo activated and expanded tumor-infiltrating T lymphocytes (TILs), has shown promising clinical results in patients with metastatic melanoma. TIL therapy yields response rates of around 50% and significant survival benefit in refractory melanoma patients, even after failing other immunotherapies, such as checkpoint inhibitors or cytokine-based therapy. Identifying predictors of TIL efficacy and detection of TIL subsets with specific reactivity against the patient's tumor might be an important milestone toward further improvement of clinical responses and prolonged survival. PMID- 26653686 TI - Partially reversible bortezomib-induced cardiotoxicity: an unusual cause of acute cardiomyopathy. AB - Chemotherapy-associated cardiotoxicity can present as a spectrum from arrhythmia to acute congestive heart failure. Unlike anthracyclines, proteasome inhibitors - for example, bortezomib - are not notorious for causing cardiotoxicity in absence of pre-existing cardiac dysfunction or without concomitant use of other cardiotoxic agents. We describe a 66-year-old woman with end-stage renal disease who developed acute dyspnea hours after a third treatment with bortezomib for IgG kappa myeloma. The Naranjo adverse drug reaction probability scale indicated a probable relationship (score of 5) between bortezomib and acute left ventricular dysfunction. Patients receiving proteasome inhibitors should be closely monitored for evidence of cardiac dysfunction during treatment. PMID- 26653687 TI - A rare case of bilateral aspergillus endophthalmitis. AB - Aspergillus endophthalmitis is a devastating inflammatory condition of the intraocular cavities that may result in irreparable loss of vision and rapid destruction of the eye. Almost all cases in the literature have shown an identified source causing aspergillus endophthalmitis as a result of direct extension of disease. We present a rare case of bilateral aspergillus endophthalmitis. A 72-year-old woman with a history of diabetes mellitus, congenital Hirschsprung disease, and recent culture-positive candida pyelonephritis with hydronephrosis status post-surgical stent placement presented with difficulty opening her eyes. She complained of decreased vision (20/200) with pain and redness in both eyes - right worse then left. Examination demonstrated multiple white fungal balls in both retinas consistent with bilateral fungal endophthalmitis. Bilateral vitreous taps for cultures and staining were performed. Patient was given intravitreal injections of amphotericin B, vancomycin, ceftazidime, and started on oral fluconazole. Patient was scheduled for vitrectomy to decrease organism burden and to remove loculated areas of infection that would not respond to systemic antifungal agents. Four weeks after initial presentation, the fungal cultures revealed mold growth consistent with aspergillus. Patient was subsequently started on voriconazole and fluconazole was discontinued due to poor efficacy against aspergillus. Further workup was conducted to evaluate for the source of infection and seeding. Transthoracic cardiogram was unremarkable for any vegetation or valvular abnormalities. MRI of the orbits and sinuses did not reveal any mass lesions or bony destruction. CT of the chest was unremarkable for infection. Aspergillus endophthalmitis may occur because of one of these several mechanisms: hematogenous dissemination, direct inoculation by trauma, and contamination during surgery. Our patient's cause of bilateral endophthalmitis was through an unknown iatrogenic seed. PMID- 26653688 TI - Kaposi sarcoma can also involve the heart. AB - Kaposi sarcoma (KS) is a low-grade angioproliferative tumor associated with infection with human herpes virus 8 (HHV-8). The disease was named after Moritz Kaposi, a Hungarian dermatologist who first described it in 1872 as 'idiopathic multiple pigmented sarcoma of the skin.' HHV-8 infection is required for the development of KS, but not all infected persons develop the disease. KS is also considered an acquired immune deficiency syndrome (AIDS)-defining illness by the Centers for Disease Control and Prevention guidelines. According to data from the United States AIDS and cancer registries, both KS and non-Hodgkin lymphoma are the most common malignancies associated with human immunodeficiency virus (HIV) infection. However, the incidence of both malignancies has decreased dramatically since 1996 following the widespread utilization of highly active antiretroviral therapies. HIV-associated KS can involve virtually any site in the body including lymph nodes, gastrointestinal tract, respiratory system, heart, pericardium, bone marrow, and other visceral organs. However, cutaneous disease is the most common and is the usual initial presentation for KS. KS-related pericardial effusion can be a life-threatening emergency and should be considered in HIV/AIDS patients who present with signs and symptoms of pericardial effusion. The importance of diagnosing and differentiating KS-related pericardial effusion from other causes of pericardial effusion lies in the differences in the treatment and management in comparison to other etiologies of pericardial effusion. We report a case of a 54-year old man who presented to our hospital with a large pericardial effusion and was subsequently diagnosed to have HIV-related KS pericardial effusion. A brief review of the literature on the diagnosis and management is also presented. PMID- 26653689 TI - Effectiveness of iterative interventions to increase research productivity in one residency program. AB - BACKGROUND: The Accreditation Council for Graduate Medical Education requires residency programs to expose residents to research opportunities. OBJECTIVE: The purpose of this study was to assess the impact of a series of iterative interventions to increase scholarly activity in one internal medicine residency. METHODS: Retrospective analysis of the effectiveness of a series of interventions to increase resident and faculty scholarly productivity over a 14-year period was performed using quality improvement methodology. Outcomes measured were accepted regional and national abstracts and PubMed indexed manuscripts of residents and faculty. RESULTS: Initially, regional meeting abstracts increased and then were supplanted by national meeting abstracts. Sustained gains in manuscript productivity occurred in the eighth year of interventions, increasing from a baseline of 0.01 publications/FTE/year to 1.57 publications/FTE/year in the final year measured. Run chart analysis indicated special cause variation associated with the interventions performed. CONCLUSIONS: Programs attempting to stimulate research production among faculty and residents can choose among many interventions cited in the literature. Since success of any group of interventions is likely additive and may take years to show benefit, measuring outcomes using quality improvement methodology may be an effective way to determine success. PMID- 26653690 TI - Not the usual suspect: a case of erythema induration of Bazin in an urban primary care clinic. AB - Frontline clinicians in the United States, especially those working in safety net hospitals or with immigrant populations, will likely see cutaneous tuberculosis given the tremendous burden of tuberculosis infection worldwide. The tuberculid is a subtype of cutaneous tuberculosis that poses a diagnostic challenge because organisms are not found in smears or cultures taken from the lesions. Tuberculid lesions can mimic erythema nodosum, thrombophlebitis, and cellulitis. We describe the case of a 57-year-old woman immigrant from China who presented with tender, subcutaneous nodules on her ankle and thigh in the setting of prior exposure to tuberculosis. We describe the clinical, pathophysiologic, and histopathologic features of tuberculids in order to raise awareness among primary care clinicians about this difficult to diagnose but readily treatable manifestation of tuberculosis. PMID- 26653691 TI - Left ventricular outflow track obstruction and mitral valve regurgitation in a patient with takotsubo cardiomyopathy. AB - INTRODUCTION: Takotsubo cardiomyopathy (TCM) can be complicated by left ventricular outflow tract (LVOT) obstruction and severe acute mitral regurgitation (MR), leading to hemodynamic instability in an otherwise benign disorder. Despite the severity of these complications, there is a paucity of literature on the matter. Because up to 20-25% of TCM patients develop LVOT obstruction and/or MR, it is important to recognize the clinical manifestations of these complications and to adhere to specific management in order to reduce patient morbidity and mortality. We report the clinical history, imaging, treatment strategy, and clinical outcome of a patient with TCM that was complicated with severe MR and LVOT obstruction. We then discuss the pathophysiology, characteristic imaging, key clinical features, and current treatment strategy for this unique patient population. CASE REPORT: A postmenopausal woman with no clear risk factor for coronary artery disease (CAD) presented to the emergency department with chest pain after an episode of mental/physical stress. Physical examination revealed MR, mild hypotension, and pulmonary vascular congestion. Her troponins were mildly elevated. Cardiac catheterization excluded obstructive CAD, but revealed severe apical hypokinesia and ballooning. Notably, multiple diagnostic tests revealed the presence of severe acute MR and LVOT obstruction. The patient was diagnosed with TCM complicated by underlying MR and LVOT obstruction, and mild hemodynamic instability. The mechanism of her LVOT and MR was attributed to systolic anterior motion of the mitral valve (SAM), which the transesophageal echocardiogram clearly showed during workup. She was treated with beta-blocker, aspirin, and ACE I with good outcome. Nitroglycerin and inotropes were discontinued and further avoided. CONCLUSIONS: Our case illustrated LVOT obstruction and MR associated with underlying SAM in a patient with TCM. LVOT obstruction and MR are severe complications of TCM and may result in heart failure and/or pulmonary edema. Timely and accurate identification of these complications is critical to achieve optimal clinical outcomes in patients with TCM. PMID- 26653692 TI - A widened pulse pressure: a potential valuable prognostic indicator of mortality in patients with sepsis. AB - BACKGROUND: Sepsis is one of the leading causes of death in the United States and the most common cause of death among critically ill patients in non-coronary intensive care units. Previous studies have showed pulse pressure (PP) to be a predictor of fluid responsiveness in patients with sepsis. Additionally, previous studies have correlated PP to cardiovascular risk factors and increase in mortality in end-stage renal disease patients. OBJECTIVES: To determine the correlation between PP and mortality in patients with sepsis. METHODS: A retrospective review was conducted on 5,003 patients admitted with the diagnosis of sepsis using ICD-9 codes during the time period from January 2010 to December 2014 at two community-based hospitals in central Pennsylvania. RESULTS: Our study findings showed significant decrease in the mortality when the PP was greater than 70 mmHg of patients with sepsis (p-value: 0.0003, odds ratio: 0.67, 95% confidence limit: 0.54-0.83). CONCLUSION: Based on our findings, we suggest that PP could be a valuable clinical tool in the early assessment of patients admitted with sepsis and could be used as a prognostic factor to assess and implement management therapy for the patients with sepsis. PMID- 26653693 TI - Graying of the HIV epidemic: a challenge for inpatient medicine providers. AB - Since the advent of anti-retroviral therapy, patients with HIV are living longer, and in the year 2015, over half of those infected with the virus will be older than age 50. Moreover, as the general aging population continues to grow, more elderly individuals will become newly infected with HIV. Older patients with HIV contribute to high numbers of initial and rehospitalizations, have longer lengths of hospital day stays, and are at increased risk of death compared to younger patients with HIV and those without HIV. Age-related comorbidities can be exaggerated in HIV-positive patients on and off therapy. Furthermore, signs and symptoms of HIV and AIDS may mimic features seen in the normal aging process of older adults. Internists caring for patients in inpatient settings will be expected to care for and diagnose increasing numbers of older patients with HIV. This will be critical for improving quality of patient care, reducing morbidity and mortality, and managing newly diagnosed patients earlier in the disease course while reducing spread of the virus. Internists should be central leaders in the development of targeted and non-targeted HIV screening efforts in inpatient general medicine wards. PMID- 26653694 TI - Aortocavitary fistula as a complication of infective endocarditis and subsequent complete heart block in a patient with severe anemia. AB - Infective endocarditis has different presentations depending on the involvement of valvular and perivalvular structures, and it is associated with high morbidity and mortality. Aortocavitary fistula is a rare complication. We introduce the case of a 48-year-old female with native valve endocarditis, complicated by aortocavitary fistula to the right atrium, and consequently presented with syncope. PMID- 26653695 TI - Acetaminophen overdose associated with double serum concentration peaks. AB - Acetaminophen is the most commonly used analgesic-antipyretic medication in the United States. Acetaminophen overdose, a frequent cause of drug toxicity, has been recognized as the leading cause of fatal and non-fatal hepatic necrosis. N Acetylcysteine is the recommended antidote for acetaminophen poisoning. Despite evidence on the efficacy of N-acetylcysteine for prevention of hepatic injury, controversy persists about the optimal duration of the therapy. Here, we describe the case of a 65-year-old male with acetaminophen overdose and opioid co ingestion who developed a second peak in acetaminophen serum levels after completing the recommended 21-hour intravenous N-acetylcysteine protocol and when the standard criteria for monitoring drug levels was achieved. Prolongation of N acetylcysteine infusion beyond the standard protocol, despite a significant gap in treatment, was critical for successful avoidance of hepatotoxicity. Delay in acetaminophen absorption may be associated with a second peak in serum concentration following an initial declining trend, especially in cases of concomitant ingestion of opioids. In patients with acetaminophen toxicity who co ingest other medications that may potentially delay gastric emptying or in those with risk factors for delayed absorption of acetaminophen, we recommend close monitoring of aminotransferase enzyme levels, as well as trending acetaminophen concentrations until undetectable before discontinuing the antidote therapy. PMID- 26653696 TI - When a pulmonary embolism is not a pulmonary embolism: a rare case of primary pulmonary leiomyosarcoma. AB - Arterial leiomyosarcomas account for up to 21% of vascular leiomyosarcomas, with 56% of arterial leiomyosarcomas occurring in the pulmonary artery. While isolated cases of primary pulmonary artery leiomyosarcoma document survival up to 36 months after treatment, these uncommon, aggressive tumors are highly lethal, with 1-year survival estimated at 20% from the onset of symptoms. We discuss a rare case of a pulmonary artery leiomyosarcoma that was originally diagnosed as a pulmonary embolism (PE). A 72-year-old Caucasian female was initially diagnosed with 'saddle pulmonary embolism' based on computerized tomographic angiography of the chest 2 months prior to admission and placed on anticoagulation. Dyspnea escalated, and serial computed tomography scans showed cardiomegaly with pulmonary emboli involving the right and left main pulmonary arteries with extension into the right and left upper and lower lobe branches. An echocardiogram on admission showed severe pulmonary hypertension with a pulmonary artery pressure of 82.9 mm Hg, and a severely enlarged right ventricle. Respiratory distress and multiorgan failure developed and, unfortunately, the patient expired. Autopsy showed a lobulated, yellow mass throughout the main pulmonary arteries measuring 13 cm in diameter. The mass extended into the parenchyma of the right upper lobe. On microscopy, the mass was consistent with a high-grade primary pulmonary artery leiomyosarcoma. Median survival of patients with primary pulmonary artery leiomyosarcoma without surgery is one and a half months, and mortality is usually due to right-sided heart failure. Pulmonary artery leiomyosarcoma is a rare but highly lethal disease commonly mistaken for PE. Thus, we recommend clinicians to suspect this malignancy when anticoagulation fails to relieve initial symptoms. In conclusion, early detection and suspicion of pulmonary artery leiomyosarcoma should be considered in patients refractory to anticoagulation, prompting initiation of early intervention. PMID- 26653697 TI - Isolated pulmonic valve endocarditis presenting as neck pain. AB - We discuss a unique case of a 52-year-old man with no history of intravenous drug use or dental procedures who presented with neck pain, 2 weeks of fevers, chills, night sweats, cough, and dyspnea found to have isolated pulmonic valve (PV) endocarditis. The patient did not have an associated murmur, which is commonly seen in right-sided infectious endocarditis. A transthoracic echocardiogram showed a thickened PV leaflet, with subsequent transesophageal echocardiogram showing a PV mass. Speciation of blood cultures revealed Streptococcus oralis. In right-sided infective endocarditis, usually the tricuspid valve is involved; however, in our case the tricuspid valve was free of any mass or vegetation. The patient did meet Duke criteria and was thus started on long-term intravenous antibiotics for infectious endocarditis. The patient's symptoms quickly improved with antibiotics. A careful history and evaluating the patient's risk factors are key in earlier detection of infective endocarditis (IE). Because of early detection and a high index of suspicion, the patient had no further complications and did not require any surgery. In conclusion, clinical suspicion of right-sided IE should be high in patients who present with persistent fevers and pulmonary symptoms in order to reduce the risk of complications, and to improve outcomes. PMID- 26653698 TI - Critical gastrointestinal bleed due to secondary aortoenteric fistula. AB - Secondary aortoenteric fistula (SAEF) is a rare yet lethal cause of gastrointestinal bleeding and occurs as a complication of an abdominal aortic aneurysm repair. Clinical presentation may vary from herald bleeding to overt sepsis and requires high index of suspicion and clinical judgment to establish diagnosis. Initial diagnostic tests may include computerized tomography scan and esophagogastroduodenoscopy. Each test has variable sensitivity and specificity. Maintaining the hemodynamic status, control of bleeding, removal of the infected graft, and infection control may improve clinical outcomes. This review entails the updated literature on diagnosis and management of SAEF. A literature search was conducted for articles published in English, on PubMed and Scopus using the following search terms: secondary, aortoenteric, aorto-enteric, aortoduodenal, aorto-duodenal, aortoesophageal, and aorto-esophageal. A combination of MeSH terms and Boolean operators were used to device search strategy. In addition, a bibliography of clinically relevant articles was searched to find additional articles (Appendix A). The aim of this review is to provide a comprehensive update on the diagnosis, management, and prognosis of SAEF. PMID- 26653699 TI - Tricuspid valve endocarditis complicated by Mobitz type II heart block - a case report and literature review. AB - We present a case of a middle-aged male who manifested with low-grade fever and lower back pain. MRI and bone scan of the spine were suggestive of vertebral osteomyelitis. Blood cultures were persistently positive for Enterococcus faecalis and echocardiogram revealed tricuspid valve endocarditis. There was no history of IV drug use and urine toxicology was negative. EKG showed Mobitz type II AV block and a transesophageal echocardiogram revealed no valve ring or septal abscesses. The heart block persisted despite antibiotic therapy and an epicardial pacemaker was placed. This is a rare presentation of high-grade AV block with tricuspid endocarditis in the absence of echocardiographic evidence of perivalvular extension of infection. Also, unique in this case is the finding of E. faecalis hematogenous vertebral osteomyelitis. PMID- 26653700 TI - Takotsubo cardiomyopathy precipitated by delirium tremens. AB - A 57-year-old woman presented with alcohol withdrawal symptoms, which later progressed to delirium tremens. During hospitalization, she developed respiratory distress with acute pulmonary edema. Electrocardiogram (ECG) showed diffuse ST elevation with elevated cardiac enzymes. Echocardiogram showed estimated ejection fraction of 20-25% with characteristic apical ballooning. After several days of supportive care, the patient showed significant clinical improvement with normalization of ECG, cardiac enzymes, and echocardiographic findings. Coronary angiogram revealed no coronary abnormalities. Although Takotsubo cardiomyopathy has been associated with diverse forms of physical or emotional stress, only a few cases have been described with delirium tremens in the medical literature. PMID- 26653701 TI - Competency-based residency training and the web log: modeling practice-based learning and enhancing medical knowledge. AB - BACKGROUND: By using web-based tools in medical education, there are opportunities to innovatively teach important principles from the general competencies of graduate medical education. OBJECTIVES: Postulating that faculty transparency in learning from uncertainties in clinical work could help residents to incorporate the principles of practice-based learning and improvement (PBLI) in their professional development, faculty in this community-based residency program modeled the steps of PBLI on a weekly basis through the use of a web log. METHOD: The program confidentially surveyed residents before and after this project about actions consistent with PBLI and knowledge acquired through reading the web log. RESULTS: The frequency that residents encountered clinical situations where they felt uncertain declined over the course of the 24 weeks of the project from a mean frequency of uncertainty of 36% to 28% (Wilcoxon signed rank test, p=0.008); however, the frequency with which residents sought answers when faced with uncertainty did not change (Wilcoxon signed rank test, p=0.39), remaining high at approximately 80%. Residents answered a mean of 52% of knowledge questions correct when tested prior to faculty posts to the blog, rising to a mean of 65% of questions correct when tested at the end of the project (paired t-test, p=0.001). CONCLUSIONS: Faculty role modeling of PBLI behaviors and posting clinical questions and answers to a web log led to modest improvements in medical knowledge but did not alter behavior that was already taking place frequently among residents. PMID- 26653702 TI - JCHIMP at 5 years: growth and development. PMID- 26653703 TI - Dynamic Bioreactor Culture of High Volume Engineered Bone Tissue. AB - Within the field of tissue engineering and regenerative medicine, the fabrication of tissue grafts of any significant size--much less a whole organ or tissue- remains a major challenge. Currently, tissue-engineered constructs cultured in vitro have been restrained in size primarily due to the diffusion limit of oxygen and nutrients to the center of these grafts. Previously, we developed a novel tubular perfusion system (TPS) bioreactor, which allows the dynamic culture of bead-encapsulated cells and increases the supply of nutrients to the entire cell population. More interestingly, the versatility of TPS bioreactor allows a large range of engineered tissue volumes to be cultured, including large bone grafts. In this study, we utilized alginate-encapsulated human mesenchymal stem cells for the culture of a tissue-engineered bone construct in the size and shape of the superior half of an adult human femur (~ 200 cm(3)), a 20-fold increase over previously reported volumes of in vitro engineered bone grafts. Dynamic culture in TPS bioreactor not only resulted in high cell viability throughout the femur graft, but also showed early signs of stem cell differentiation through increased expression of osteogenic genes and proteins, consistent with our previous models of smaller bone constructs. This first foray into full-scale bone engineering provides the foundation for future clinical applications of bioengineered bone grafts. PMID- 26653704 TI - Is the economic crisis affecting birth outcome in Spain? Evaluation of temporal trend in underweight at birth (2003-2012). AB - BACKGROUND: There is growing evidence of the impact of the current European economic crisis on health. In Spain, since 2008, there have been increasing levels of impoverishment and inequality, and important cuts in social services. AIM: The objective is to evaluate the impact of the economic crisis on underweight at birth in Spain. METHOD: Trends in underweight at birth were examined between 2003 and 2012. Underweight at birth is defined as a singleton, term neonatal weight lesser than -2 SD from the median weight at birth for each sex estimated by the WHO Standard Growth Reference. Using data from the Statistical Bulletin of Childbirth, 2 933 485 live births born to Spanish mothers have been analysed. Descriptive analysis, seasonal decomposition analysis and crude and adjusted logistic regression including individual maternal and foetal variables as well as exogenous economic indicators have been performed. RESULTS AND CONCLUSIONS: Results demonstrate a significant increase in the prevalence of underweight at birth from 2008. All maternal-foetal categories were affected, including those showing the lowest prevalence before the crisis. In the full adjusted logistic regression, year-on-year GDP per capita remains predictive on underweight at birth risk. Previous trends in maternal socio-demographic profiles and a direct impact of the crisis are discussed to explain the trends described. PMID- 26653705 TI - Benchmark ab Initio Conformational Energies for the Proteinogenic Amino Acids through Explicitly Correlated Methods. Assessment of Density Functional Methods. AB - The relative energies of the YMPJ conformer database of the 20 proteinogenic amino acids, with N- and C-termination, have been re-evaluated using explicitly correlated coupled cluster methods. Lower-cost ab initio methods such as MP2-F12 and CCSD-F12b actually are outperformed by double-hybrid DFT functionals; in particular, the DSD-PBEP86-NL double hybrid performs well enough to serve as a secondary standard. Among range-separated hybrids, omegaB97X-V performs well, while B3LYP-D3BJ does surprisingly well among traditional DFT functionals. Treatment of dispersion is important for the DFT functionals; for the YMPJ set, D3BJ generally works as well as the NL nonlocal dispersion functional. Basis set sensitivity for DFT calculations on these conformers is weak enough that def2 TZVP is generally adequate. For conformer corrections to heats of formation, B3LYP-D3BJ and especially DSD-PBEP86-D3BJ or DSD-PBEP86-NL are adequate for all but the most exacting applications. The revised geometries and energetics for the YMPJ database have been made available as Supporting Information and should be useful in the parametrization and validation of molecular mechanics force fields and other low-cost methods. The very recent dRPA75 method yields good performance, without resorting to an empirical dispersion correction, but is still outperformed by DSD-PBEP86-D3BJ and particularly DSD-PBEP86-NL. Core valence corrections are comparable in importance to improvements beyond CCSD(T*)/cc-pVDZ-F12 in the valence treatment. PMID- 26653706 TI - Meta-analysis of downregulated E-cadherin as a poor prognostic biomarker for cervical cancer. AB - AIM: This meta-analysis was conducted to evaluate the diagnostic and prognostic functions of E-cadherin expression in cervical cancer. METHODS: PubMed and other databases were searched for articles associated with E-cadherin and cervical cancer. These articles were published before June 2015 and written in English or Chinese. Random-effects model was used to pool odds ratios on the heterogeneity test in the meta-analysis. RESULTS: All of 20 studies were analyzed, in which 522 (42.6%) subjects exhibited reduced E-cadherin expression. Evaluation of clinicopathologic features showed that the downregulation of E-cadherin was related to the overall survival, clinicopathological parameters and age. CONCLUSION: Downregulation of E-cadherin in cervical cancer patients showed poor overall survival. Therefore, E-cadherinmay be a metastasis-suppressor gene in cervical cancer. PMID- 26653707 TI - Driver sleepiness on YouTube: A content analysis. AB - Driver sleepiness is a major contributor to severe crashes and fatalities on our roads. Many people continue to drive despite being aware of feeling tired. Prevention relies heavily on education campaigns as it is difficult to police driver sleepiness. The video sharing social media site YouTube is extremely popular, particularly with at risk driver demographics. Content and popularity of uploaded videos can provide insight into the quality of publicly accessible driver sleepiness information. The purpose of this research was to answer two questions; firstly, how prevalent are driver sleepiness videos on YouTube? And secondly, what are the general characteristics of driver sleepiness videos in terms of (a) outlook on driver sleepiness, (b) tone, (c) countermeasures to driver sleepiness, and, (d) driver demographics. Using a keywords search, 442 relevant videos were found from a five year period (2nd December 2009-2nd December 2014). Tone, outlook, and countermeasure use were thematically coded. Driver demographic and video popularity data also were recorded. The majority of videos portrayed driver sleepiness as dangerous. However, videos that had an outlook towards driver sleepiness being amusing were viewed more often and had more mean per video comments and likes. Humorous videos regardless of outlook, were most popular. Most information regarding countermeasures to deal with driver sleepiness was accurate. Worryingly, 39.8% of videos with countermeasure information contained some kind of ineffective countermeasure. The use of humour to convey messages about the dangers of driver sleepiness may be a useful approach in educational interventions. PMID- 26653708 TI - Reproductive Factors Predicting Angiographic Obstructive Coronary Artery Disease: The KoRean wOmen'S Chest Pain rEgistry (KoROSE). AB - BACKGROUND: Whether reproductive factors are associated with coronary artery disease (CAD) has been debated. The aim of this study was to investigate etiologic associations of a wide range of reproductive factors of women with the presence of angiographic obstructive CAD. MATERIALS AND METHODS: Study data were obtained from a nationwide registry that enrolled 687 Korean women (59.9 +/- 11.4 years) with chest pain undergoing invasive coronary angiography (ICA). Obstructive CAD was defined as >=50% luminal stenosis of one or more epicardial coronary arteries in ICA. Information on reproductive history, including ages at menarche and menopause, duration of reproductive capacity, number of pregnancies, hormonal replacement therapy, and history of twin pregnancy, was obtained using a standardized questionnaire. RESULTS: A total of 178 women (25.9%) had obstructive CAD. Multivariable logistic regression analysis identified that later age at menarche (odds ratio [OR] = 1.265, 95% confidence interval [CI] = 1.064-1.504, p = 0.008, per year) and increased number of pregnancies (OR = 1.223, 95% CI = 1.026-1.457, p = 0.025, per pregnancy) were the independent predictors of obstructive CAD even after controlling for potential confounders, including age, diabetes mellitus, hypertension, dyslipidemia, renal function, high-density lipoprotein level, white blood cell count, hemoglobin, and E/e'. CONCLUSIONS: Later age at menarche and increased number of pregnancies may be reproductive risk factors for angiographic obstructive CAD, suggesting the important role of hormonal status in the development of CAD. PMID- 26653709 TI - Interference control commonalities in patients with schizophrenia, bipolar disorder, and borderline personality disorder. AB - BACKGROUND: Whereas deficits in executive functioning have been widely reported in schizophrenia and, somewhat less, in bipolar disorder, few studies have addressed this issue in people diagnosed with borderline personality disorder. Importantly, no studies to date have compared the ability to cope with interfering information in all three groups of patients. Impairment in executive control has been associated with reduced daily functioning. METHOD: The sample included 20 patients diagnosed with schizophrenia, 19 with bipolar disorder, 20 with borderline personality disorder, and 19 demographically matched healthy volunteers. Participants were administered two different experimental tasks to assess the ability to exert control over interference arisen from semantic memory or from distracting perceptual information. RESULTS: The three groups of patients showed similar impairment in solving interference from semantic memory compared to controls. However, no psychiatric group showed impairment in controlling interference from distracting perceptual information relative to controls. CONCLUSIONS: Our study shows, for the first time, that schizophrenia, bipolar disorder, and borderline personality disorder entail a common impairment in exerting control over interference arisen from memory but intact control over perceptual interference. These findings reinforce the idea that similar cognitive functioning may underlie severe mental disorders sharing poor global functioning but with different patterns of symptomatology. PMID- 26653710 TI - Appropriate use criteria: a review of need, development and applications. AB - The costs of healthcare in developed countries have seen a dramatic increase in tandem with the increasing utilization of diagnostic testing. As a result, Appropriate Use Criteria (AUC)-based practices have become more commonplace as a provider-driven solution to reducing unnecessary tests and procedures across various specialty societies. The AUC are meant to serve as a distinct entity from clinical guidelines to help inform clinicians of the 'appropriateness' of a diagnostic test or procedure. In this article, we discuss the development, implementation, impact, and practical applications of AUC to improve appropriate utilization by providers, healthcare institutions, payers, and policy makers. We also focus on the role of education and feedback as a potentially efficacious future method of implementation of global quality improvement and cost-mitigating strategies. AUC represent a growing quality improvement tool in cardiovascular medicine that can play an important role in reducing inappropriate testing while preserving physician autonomy. PMID- 26653711 TI - Elevated plasma-soluble CD16 levels in porcine reproductive and respiratory syndrome virus-infected pigs: correlation with ADAM17-mediated shedding. AB - Soluble CD16 (sCD16) is closely correlated with chronic diseases in humans. Here, plasma sCD16 levels in pigs were increased by infection with porcine reproductive and respiratory syndrome virus (PRRSV) but not with porcine epidemic diarrhea virus, porcine circovirus type 2 and pseudorabies virus. Of interest, PRRSV attached to blood neutrophils and reduced surface CD16 expression on neutrophils. In vitro data confirmed that PRRSV caused CD16 shedding in neutrophils. Further analyses revealed that ADAM17 was involved in porcine CD16 shedding. Thus, our findings suggest that increase in sCD16 levels may be an indicator of PRRSV infection. PMID- 26653712 TI - Differential expression of small RNAs under chemical stress and fed-batch fermentation in E. coli. AB - BACKGROUND: Bacterial small RNAs (sRNAs) are recognized as posttranscriptional regulators involved in the control of bacterial lifestyle and adaptation to stressful conditions. Although chemical stress due to the toxicity of precursor and product compounds is frequently encountered in microbial bioprocessing applications, the involvement of sRNAs in this process is not well understood. We have used RNA sequencing to map sRNA expression in E. coli under chemical stress and high cell density fermentation conditions with the aim of identifying sRNAs involved in the transcriptional response and those with potential roles in stress tolerance. RESULTS: RNA sequencing libraries were prepared from RNA isolated from E. coli K-12 MG1655 cells grown under high cell density fermentation conditions or subjected to chemical stress with twelve compounds including four organic solvent-like compounds, four organic acids, two amino acids, geraniol and decanoic acid. We have discovered 253 novel intergenic transcripts with this approach, adding to the roughly 200 intergenic sRNAs previously reported in E. coli. There are eighty-four differentially expressed sRNAs during fermentation, of which the majority are novel, supporting possible regulatory roles for these transcripts in adaptation during different fermentation stages. There are a total of 139 differentially expressed sRNAs under chemical stress conditions, where twenty-nine exhibit significant expression changes in multiple tested conditions, suggesting that they may be involved in a more general chemical stress response. Among those with known functions are sRNAs involved in regulation of outer membrane proteins, iron availability, maintaining envelope homeostasis, as well as sRNAs incorporated into complex networks controlling motility and biofilm formation. CONCLUSIONS: This study has used deep sequencing to reveal a wealth of hitherto undescribed sRNAs in E. coli and provides an atlas of sRNA expression during seventeen different growth and stress conditions. Although the number of novel sRNAs with regulatory functions is unknown, several exhibit specific expression patterns during high cell density fermentation and are differentially expressed in the presence of multiple chemicals, suggesting they may play regulatory roles during these stress conditions. These novel sRNAs, together with specific known sRNAs, are candidates for improving stress tolerance and our understanding of the E. coli regulatory network during fed-batch fermentation. PMID- 26653713 TI - Sex differences in a rat model of risky decision making. AB - Many debilitating psychiatric conditions, including drug addiction, are characterized by poor decision making and maladaptive risk-taking. Recent research has begun to probe this relationship to determine how brain mechanisms mediating risk-taking become compromised after chronic drug use. Currently, however, the majority of work in this field has used male subjects. Given the well-established sex differences in drug addiction, it is conceivable that such differences are also evident in risk-based decision making. To test this possibility, male and female adult rats were trained in a risky decision making task (RDT), in which they chose between a small, "safe" food reward and a large, "risky" food reward accompanied by an increasing probability of mild footshock punishment. Consistent with findings in human subjects, females were more risk averse, choosing the large, risky reward significantly less than males. This effect was not due to differences in shock reactivity or body weight, and risk taking in females was not modulated by estrous phase. Systemic amphetamine administration decreased risk-taking in both males and females; however, females exhibited greater sensitivity to amphetamine, suggesting that dopaminergic signaling may partially account for sex differences in risk-taking. Finally, although males displayed greater instrumental responding for food reward, reward choice in the RDT was not affected by satiation, indicating that differences in motivation to obtain food reward cannot fully account for sex differences in risk taking. These results should prove useful for developing targeted treatments for psychiatric conditions in which risk-taking is altered and that are known to differentially affect males and females. PMID- 26653714 TI - Drug-motivated behavior in rats with lesions of the thalamic orosensory area. AB - Rats suppress intake of a palatable taste cue when paired with a rewarding or an aversive stimulus in appetitive or aversive conditioning, respectively. A similar phenomenon occurs with drugs of abuse, but the nature of this conditioning has been subject for debate. While relatively little is known about the underlying neural circuitry, we recently reported bilateral lesions of the thalamic trigeminal orosensory area isolate drug-induced suppression of intake of a taste cue. The lesion blocks avoidance of the taste cue when paired with experimenter delivered drugs of abuse, yet has no effect on avoidance of the same cue when paired with an aversive agent or when it predicts access to a highly palatable sucrose solution. We hypothesize the lesion may blunt the rewarding properties of the drug. To test this, we used a runway apparatus, as running speed has been shown to increase with increasing reward value. Our hypothesis was supported by failure of the lesioned rats to increase running speed for morphine. Interestingly, lesioned rats did avoid intake of the drug-paired cue when presented in the runway apparatus and displayed naloxone-precipitated withdrawal. Using a partial crossover design, the lesion prevented avoidance of a cocaine paired cue when presented in the home cage. We conclude that the lesion disrupts avoidance of a taste cue in anticipation of the rewarding properties of a drug but, at least in the presence of contextual cues, allows for avoidance of a taste cue as it elicits the onset of an aversive conditioned state of withdrawal. PMID- 26653715 TI - A computational framework for interspecies pharmacokinetics, exposure and toxicity assessment of gold nanoparticles. AB - AIM: To develop a comprehensive computational framework to simulate tissue distribution of gold nanoparticles (AuNP) across several species. MATERIALS & METHODS: This framework was built on physiologically based pharmacokinetic modeling, calibrated and evaluated with multiple independent datasets. RESULTS: Rats and pigs seem to be more appropriate models than mice in animal-to-human extrapolation of AuNP pharmacokinetics and that the dose and age should be considered. Incorporation of in vitro and/or in vivo cellular uptake and toxicity data into the model improved toxicity assessment of AuNP. CONCLUSION: These results partially explain the current low translation rate of nanotechnology based drug delivery systems from mice to humans. This simulation approach may be applied to other nanomaterials and provides guidance to design future translational studies. PMID- 26653716 TI - Reduced physical activity in children and adolescents with Juvenile Idiopathic Arthritis despite satisfactory control of inflammation. AB - BACKGROUND: Vascular health is of concern in patients with Juvenile Idiopathic Arthritis (JIA) since Rheumatoid Arthritis (RA) epidemiologically has a well described association with premature development of atherosclerosis. Chronic inflammation with persisting systemic circulating inflammatory proteins may be a cause of vascular damage, but general physical inactivity could be an important contributor. Pain and fatigue are common complaints in patients with JIA and may well lead to an inactive sedentary lifestyle. For this reason we assessed the physical activity (PA) objectively in patients with moderate to severe Juvenile Idiopathic Arthritis (JIA) in comparison with gender and age matched healthy schoolchildren, and looked for associations between PA and features of JIA. METHODS: One hundred thirty-three patients, 7-20 years of age, participated. Disease activity, disability, functional ability, and pain were assessed and PA was measured by accelerometry through 7 days and compared to PA in age- and gender-matched healthy schoolchildren. RESULTS: We found a significantly lower level of PA in patients compared to gender- and age-matched healthy schoolchildren both in average activity (counts per minute, cpm) (475.6 vs. 522.7, p = 0.0000018) and in minutes per day spent with cpm >1500 (67.9 vs. 76.4, p = 0.0000014), with cpm >2000 (moderate physical activity) (48.4 vs. 52.8, p = 0.0001, and with cpm >3000 (high physical activity) (24.7 vs. 26.5, p = 0.00015). A negative association (beta = -0.213, p = 0.014) between active disease in weight bearing joints and high physical activity remained the only significant association between disease related factors and PA. Of the girls 19% and of the boys 45% (vs. 39% and 61% in the reference group) met standards set by Danish Health Authorities for daily PA in childhood. CONCLUSION: Children and adolescents with JIA are less physically active than their healthy peers and less active than recommended for general health by the Danish Health Authorities. This is not explained by pain or objective signs of inflammation. When inflammation has been curbed, restoration of an active healthy lifestyle should be highly prioritized. PMID- 26653717 TI - Considering the benefits of a new stoma appliance: a clinical trial. AB - For people living with a stoma, leakage is one of the main problems compromising quality of life. The right choice of stoma appliance is therefore of utmost importance. This randomised, controlled clinical trial investigated the benefits of a new stoma appliance, SenSura Mio Convex Soft, specifically for people who experience leakage using a flat stoma appliance. The degree of leakage under the baseplate was measured using a new objective method. The study included 38 participants with an ileostomy or colostomy. Results showed that while being flexible and comfortable, the new appliance reduced leakage significantly and provided a better feeling of security when compared with the participants' own flat stoma appliance. The product was the preferred of the convex stoma appliances in the study. This study demonstrated that it may be a solution for people with a stoma challenged by leakage using flat stoma appliances. PMID- 26653718 TI - Ureteric stent removal post cystectomy. AB - AIM: The aim of this study was to develop a step-by-step guide to aid nurses in the safe removal of ureteric stents. Examination of the literature related to at what timespan after the operation the stents should be removed and whether antibiotic cover and/or precautionary investigations such as stentogram are necessary prior to stent removal. METHOD: A purpose-designed questionnaire was sent to consultants and stoma nurses to assess current practice regarding the removal of stents. RESULTS: Findings show that opinion was divided on how long the stents should remain in situ postoperatively, whether or not a stentogram is necessary prior to stent removal to check for healing and evidence of anastomosis leak, and whether or not patients require prophylactic antibiotic cover. CONCLUSION: It is not currently possible to formulate a standard policy for the procedure of ureteric stent removal because consultants have varying ideas on their management. Therefore, further research on ureteric stent removal is required to ensure evidence-based practice. PMID- 26653719 TI - Use of stoma accessories in preserving self-image and self-esteem. PMID- 26653720 TI - Does education for specialist practice need refining? PMID- 26653721 TI - Rehabilitation of individuals with intestinal ostomy. AB - This article will discuss an ethnographic study interpreting the rehabilitation experience of 15 individuals with an intestinal ostomy in Brazil, analysed using thematic analysis from the perspective of the sociology of health. The decoded meanings included: 'dealing with treatment and intestinal ostomy', and led to the theme 'the rehabilitation experience of patients with intestinal ostomy due to chronic illness', which addressed normality of life before intestinal illness, defining oneself and life, considering personal, family, social and therapeutic difficulties, and preparing to live with an intestinal ostomy, considering both the private and public spheres. This study will contribute to the specialised care provided in the various contexts of healthcare delivery, especially in relation to the humanisation of care of patients and implementation of appropriate strategies to meet the needs of patients. PMID- 26653722 TI - NSAID Pretreatment Inhibits Prostaglandin Release in Femtosecond Laser-Assisted Cataract Surgery. AB - PURPOSE: To investigate whether short-term nonsteroidal anti-inflammatory drug (NSAID) pretreatment on the day of surgery inhibits prostaglandin release. Previous studies detected elevated prostaglandin levels after femtosecond laser treatment and identified them as a potential mediator for laser-induced miosis. METHODS: Patients underwent either image-guided femtosecond laser cataract surgery or conventional cataract surgery (n = 75). Half of the eyes per group received topical NSAID treatment on the day of surgery. Aqueous humor was collected from all patients. ELISA measurements were performed to detect aqueous humor prostaglandin levels. RESULTS: Femtosecond laser cataract surgery led to higher prostaglandin levels than conventional cataract surgery (P = .007). In both groups, NSAID pretreatment led to reduced prostaglandin release. In the femtosecond laser group, patients pretreated with NSAIDs had significantly lower prostaglandin values (65.3 +/- 13.2 pg/mL) than patients not pretreated with NSAIDs (294.4 +/- 66.5 pg/mL) (P = .0009). CONCLUSIONS: The short-term NSAID treatment prevented prostaglandin release in patients treated with image-guided femtosecond laser. Therefore, it has potential to limit intraoperative laser induced miosis. PMID- 26653723 TI - Comparison of Visual Quality After SMILE and LASEK for Mild to Moderate Myopia. AB - PURPOSE: To compare the objective and subjective quality of vision after femtosecond laser-assisted small incision lenticule extraction (SMILE) and laser assisted subepithelial keratomileusis (LASEK) for mild to moderate myopia. METHODS: This prospective, comparative study included 65 eyes of 33 patients in the SMILE group, with a mean spherical equivalent (SE) of -4.16 +/- 0.82 diopters, and 50 eyes of 25 patients in the LASEK group, with a mean SE of -3.81 +/- 0.97 diopters. Visual acuity, corneal topography, contrast sensitivity, and wavefront aberrations were recorded preoperatively and compared with postoperative measurements. A quality of vision questionnaire was scored and analyzed 3 months postoperatively. RESULTS: Three months postoperatively, the SMILE group had fewer (P < .05) higher-order aberrations (HOAs) (0.390 +/- 0.175 um), including spherical aberration (SA) (0.262 +/- 0.242 um), than the LASEK group (HOAs = 0.479 +/- 0.148 um, SA = 0.576 +/- 0.287 um, trefoil = 0.465 +/- 0.248 um). There was no significant difference in the amount of coma and trefoil between the two groups after surgery. Analysis of the scores of glare and halos in the quality of vision questionnaire revealed that SMILE (night glare = 1.25 +/ 1.22, halos = 0.97 +/- 1.12) provided a better quality of vision (P < .05) than LASEK (night glare = 2.32 +/- 1.99, halos = 1.96 +/- 1.77). The two groups demonstrated no significant difference in contrast sensitivity 3 months postoperatively. No vision-threatening complications were noted at any stage in either group. CONCLUSIONS: Both SMILE and LASEK are safe and effective surgical procedures in the correction of myopia. SMILE has a lower induction rate of HOAs and a higher degree of patient satisfaction than LASEK at 3 months postoperatively. PMID- 26653724 TI - Control of Induced Spherical Aberration in Moderate Hyperopic LASIK by Customizing Corneal Asphericity. AB - PURPOSE: To compare differences in induced aberrations and visual acuity after wavefront-optimized LASIK and aspheric-customized LASIK for the treatment of hyperopia. METHODS: Forty consecutive eyes underwent uneventful LASIK for treatment of moderate hyperopia (+3.82 +/- 0.63 diopters [D] [+2.75; +5.125]). A standard procedure was performed in the wavefront-optimized LASIK group (n = 24), whereas a postoperative Q-factor equal to zero was scheduled in the aspheric customized LASIK group (n = 16). RESULTS: At 6 months, mean spherical aberration for a 6-mm pupil diameter was -0.39 +/- 0.23 um (range: -0.76 to 0.01 um) and Q factor was -0.52 +/- 0.22 (range: -1.00 to -0.12 um) in the wavefront-optimized group and 0.04 +/- 0.18 um (range: -0.34 to 0.29 um) and -0.04 +/- 0.25 (range: 0.64 to 0.40 um) in the aspheric-customized LASIK group (P <= .05). All remaining outcomes showed no significant differences between groups. UDVA was 20/18.69 +/- 0.15 (range: 0.80 to 1.20) in the wavefront-optimized LASIK group and 20/20 +/- 0.17 (range: 0.50 to 1.20) in the aspheric-customized LASIK group. One patient in the wavefront-optimized LASIK group lost two or more lines of CDVA and no lines were lost in the aspheric-customized LASIK group. CONCLUSIONS: The results in this small cases series suggest that using an aspheric-customized ablation profile with a target Q-factor equal to 0 in moderate hyperopic LASIK is statistically compatible with a diminishing induced spherical aberration without altering procedural safety when the WaveLight Allegretto 400-Hz excimer laser platform (Alcon Laboratories, Inc., Fort Worth, TX) is used. PMID- 26653725 TI - Changes in Corneal Power After Descemet Stripping Automated Endothelial Keratoplasty. AB - PURPOSE: To examine the optical effects of Descemet stripping automated endothelial keratoplasty (DSAEK) by evaluating changes in anterior and posterior corneal curvatures and aberrations. METHODS: Eighty-three eyes treated using DSAEK combined with cataract surgery (the DSAEK group) and 41 control eyes of healthy patients (the control group) were included. Patients were examined before and 1 year after surgery with autokeratometry and Pentacam (Oculus Optikgerate GmbH, Wetzlar, Germany). The preoperative posterior corneal curvature was estimated from the anterior corneal curvature. RESULTS: The mean intended postoperative refraction in the DSAEK group was -0.75 +/- 0.62 diopters (D), which was statistically different from the achieved refraction of +0.50 +/- 0.93 D at the 1-year follow-up (P < .001). The average biometry prediction error was a hyperopic shift of +1.27 +/- 0.80 D. Anterior corneal power was significantly higher before than after DSAEK with a difference of -0.63 +/- 0.68 D (P = .03) correlating significantly with the hyperopic change (r(2) = 0.23, P < .01). The posterior corneal power after DSAEK showed a significant steepening of -0.69 +/- 0.38 D (P < .01) from the estimated preoperative power and a difference of -0.64 +/- 0.38 D (P < .01) from the posterior corneal power in the control group. The change correlated significantly with the hyperopic change (r(2) = 0.10, P < .01). The combined changes in anterior and posterior keratometry increased the correlation coefficient to r(2) = 0.34 (P < .01). Significant differences were observed for total higher-order aberrations root mean square and coma root mean square after DSAEK compared to controls. No significant changes were observed in spherical aberration. CONCLUSIONS: The hyperopic shift in the DSAEK group can be explained by changes in anterior and posterior corneal surfaces. Spherical aberration was not changed by DSAEK, suggesting that aspherical intraocular lenses may be implanted on the same indications as in normal cataract surgery. PMID- 26653726 TI - Retinal Complications After Anterior Versus Posterior Chamber Phakic Intraocular Lens Implantation in a Myopic Cohort. AB - PURPOSE: To compare the incidence and characteristics of retinal complications following implantation of two types of phakic intraocular lenses (PIOLs) in patients with myopia. METHODS: In this comparative, retrospective study, 603 eyes of 344 patients with myopia underwent implantation of either an Artisan iris fixated phakic intraocular lens IOL (Artisan; Ophtec, Groningen, Netherlands) (Artisan group) or a Visian implantable collamer lens (ICL; STAAR Surgical Company, Monrovia, CA) (ICL group) between June 2005 and December 2013. Preoperative, operative, and postoperative clinical data were collected on the incidence of retinal complications, including rhegmatogenous retinal detachment (RRD) or choroidal neovascular membrane (CNVM). RESULTS: The Artisan lens was implanted in 185 (30.68%) eyes and 418 (69.32%) eyes underwent ICL implantation. Mean follow-up was 26.78 months (range: 9 days to 98 months). Mean preoperative spherical equivalent (SE) was -12.44 +/- 4.43 D (range: -1.13 to -31.00 D). The overall rate of retinal complications was 1%. Postoperatively, 3 (0.7%) eyes developed RRD in the ICL group, and no eyes developed RRD in the Artisan group. Submacular hemorrhage was observed in 1 (0.24%) eye in the ICL group. Two (1%) eyes developed CNVM in the Artisan group. The mean time from PIOL implantation to retinal complications was 15.6 months (range: 0.03 to 43 months). CONCLUSIONS: Implantation of ICL or Artisan phakic IOL demonstrated comparable rates of retinal complications. Anterior chamber PIOL does not increase the risk of retinal detachment or CNVM in patients with myopia. PMID- 26653727 TI - Anterior Capsulotomy Outcomes: A Comparison Between Two Femtosecond Laser Cataract Surgery Platforms. AB - PURPOSE: To compare capsulotomy outcomes between two femtosecond laser platforms for cataract surgery. METHODS: This retrospective case series included 205 eyes of 162 consecutive patients (75 male and 87 female) aged 68.32 +/- 10.27 years (range: 38 to 92 years) who underwent femtosecond laser-assisted cataract surgery (FLACS) using either the LenSx (Alcon Laboratories, Inc., Fort Worth, TX) or the Catalys (Abbott Medical Optics, Abbott Park, IL) laser platform. Intraoperative assessment of the capsulotomy was performed and graded as one of the following four types: complete treatment pattern (type 1), microadhesions (type 2), incomplete treatment pattern (type 3), and complete pattern but not continuous (type 4). RESULTS: Ninety-seven eyes underwent FLACS using the LenSx platform and 108 eyes using the Catalys platform. Ninety-four capsulotomies in the LenSx group were graded as type 1 (96.91%), and three were graded as type 2 (3.09%); all capsulotomies in the Catalys group were graded as type 1 (100%). There was no statistically significant difference between the LenSx and Catalys groups (P > .05). No intraoperative complications (specifically, no posterior capsular extension or vitreous loss) were noticed in any of the eyes included in the study. CONCLUSIONS: The LenSx and Catalys laser platforms demonstrate similar capsulotomy outcomes. The microadhesions that were demonstrated in three cases in the LenSx group did not lead to intraoperative or postoperative complications. PMID- 26653728 TI - The Big-Bubble Full Femtosecond Laser-Assisted Technique in Deep Anterior Lamellar Keratoplasty. AB - PURPOSE: To describe the big-bubble full femtosecond laser-assisted (BBFF) technique, which could be helpful in standardizing the big-bubble technique in deep anterior lamellar keratoplasty (DALK). METHODS: Ten eyes of 10 consecutive patients affected by keratoconus underwent the BBFF technique using the 150-kHz IntraLase femtosecond laser (Intra-Lase FS Laser; Abbott Medical Optics, Inc., Santa Ana, CA). A 9-mm diameter metal mask with a single fissure 0.7 mm wide oriented at the 12-o'clock position was positioned into the cone, over the laser glass. The laser performed a ring lamellar cut (internal diameter = 3 mm; external diameter = 8 mm) 100 um above the thinnest point, with the photodisruption effectively occurring only in the corneal stroma corresponding to the fissure to create a deep stromal channel; subsequently, an anterior side cut created an arcuate incision, from the corneal surface to the deep stromal channel on the mask's opening site. The mask was removed and the laser performed a full lamellar cut 200 um above the thinnest point to create a lamella. After the removal of the lamella, the air needle was inserted into the stromal channel and air was injected to achieve a big bubble. RESULTS: The big bubble was achieved in 9 eyes (all type 1 bubbles) and all procedures were completed as DALK. CONCLUSIONS: Preliminary results suggest that the BBFF technique could help in standardizing the big-bubble technique in DALK, reducing the "learning curve" for surgeons who approach this technique and the risks of intraoperative complications. PMID- 26653729 TI - Dangling Lens Phacoemulsification: A Novel Technique for Near Complete Zonular Dehiscence. AB - PURPOSE: To demonstrate a novel technique for the management of dangling lenses with near complete zonular dehiscence. METHODS: A capsule-sparing combined anterior and posterior surgical approach for dangling lenses with severe zonular dehiscence is described. The surgical record of a patient who underwent phacoemulsification with "dangling lens technique" and in-the-bag intraocular lens (IOL) implantation was evaluated. RESULTS: This technique was able to preserve the lens capsule, allowing freedom of IOL choice and an optimally reconstructed anterior segment. Placement of sutured capsular tension rings (CTRs) or segments provided long-term stabilization of the capsular bag and the bag-fixated posterior chamber IOL. No intraoperative or postoperative complications occurred during a follow-up of 3 years. CONCLUSIONS: Combined microincisional pars plana vitrectomy, posterior levitation of the crystalline lens, phacoemulsification with sutured CTR, and in-the-bag IOL placement may be considered for surgical management of patients with nearly luxated, dangling, crystalline lenses. PMID- 26653730 TI - Increased Biomechanical Efficacy of Corneal Cross-linking in Thin Corneas Due to Higher Oxygen Availability. AB - PURPOSE: To compare the currently available ultraviolet-A (UV-A) corneal cross linking (CXL) treatment protocols for thin corneas with respect to oxygen, UV fluence, and osmotic pressure. METHODS: Freshly enucleated murine (n = 16) and porcine (n = 16) eyes were used. The dependency on oxygen and the amount of UV absorption were evaluated using different CXL protocols, including standard CXL, contact lens-assisted CXL (caCXL), and CXL after corneal swelling. The CXL protocol was adapted from the treatment parameters of the human cornea to fit the thickness of murine and porcine corneas. Immediately after CXL, the corneas were subjected to biomechanical testing, including preconditioning, stress relaxation at 0.6 MPa, and stress-strain extensiometry. A two-element Prony series was fitted to the relaxation curves for viscoelastic characterization. RESULTS: Standard CXL was most efficient; prior corneal swelling reduced the long-term modulus by 6% and caCXL by 15% to 20%. Oxygen reduction decreased the long-term modulus Ginfinity by 14% to 15% and the instantaneous modulus G0 by 2% to 5%, and increased the short-term modulus G2 by 22% to 31%. Reducing the amount of absorbed UV energy decreased the long-term modulus Ginfinity by 5% to 34%, the instantaneous modulus G0 by 7% to 29%, and the short-term modulus G2 by 17% to 20%. The amount of absorbed UV light was more important in porcine than in murine corneas. CONCLUSIONS: The higher oxygen availability in thin corneas potentially increases the overall efficacy of riboflavin UV-A CXL compared to corneas of standard thickness. Clinical protocols for thin corneas should be revised to implement these findings. PMID- 26653731 TI - Recalcitrant Epithelial Ingrowth After SMILE Treated With a Hydrogel Ocular Sealant. AB - PURPOSE: To report a case of recalcitrant epithelial ingrowth after small incision lenticule extraction (SMILE) treated successfully with a novel hydrogel ocular sealant. METHODS: Case report and literature review. RESULTS: A 32-year old man who underwent small incision lenticule extraction (SMILE) complicated by difficult lenticule extraction developed visually significant epithelial ingrowth. He then underwent two flap lifts and epithelial scrapings and flap edge suturing with recurrence of epithelial ingrowth despite these interventions. He subsequently underwent repeat scraping, followed by hydrogel ocular sealant placement (ReSure Sealant; Ocular Therapeutix, Inc., Bedford, MA), which prevented recurrence of epithelial ingrowth and reduced corneal haze. The patient was also found to have undiagnosed diabetes, suggesting that just as in LASIK, diabetes may be a risk factor for epithelial ingrowth after SMILE. CONCLUSIONS: Interface epithelial ingrowth is a potential complication after SMILE and diabetes may be a risk factor for this complication. Hydrogel ocular sealant may be effective after SMILE to prevent epithelial ingrowth into the interface. PMID- 26653732 TI - The Role of Aberrometry in Accommodative Spasm After Myopic Photorefractive Keratectomy. AB - PURPOSE: To report the role of aberrometry in a case of accommodative spasm following myopic photorefractive keratectomy (PRK). METHODS: Observational case report. RESULTS: One month following myopic PRK, a 33-year-old healthy woman complained of seeing multiple images and headache that interfered with her daily activities. Her corrected distance visual acuity (CDVA) was 20/40 in the right eye and 20/25 in the left eye with a manifest refraction of -0.75 -0.50 * 165 degrees in the right eye and plano -0.50 * 20 degrees in the left eye. Cycloplegic refraction was plano -0.50 * 165 degrees in the right eye and plano 0.5 * 20 degrees in the left eye. Ray tracing aberrometry showed variable refraction with increase in internal defocus, which after cycloplegia reduced from 1.019 to 0.142 um in the right eye and 0.366 to 0.230 um in the left eye. Total ocular aberrations decreased by 53.16% in the right eye (range: 1.511 to 0.708 um) and 18.77% (range: 0.671 to 0.545 um) in the left eye; corresponding simulated Snellen visual acuity charts also showed improvement. The patient was treated with one drop of cyclopentolate 1% three times a day for 6 weeks, following which headache and ghosting of images completely resolved. CONCLUSIONS: Accommodative spasm should be considered in patients with visual disturbances of uncertain causes following myopic refractive surgery. Ray tracing aberrometry can serve as a diagnostic and educative tool in managing such patients. PMID- 26653733 TI - More Than a Decade of Experience With Implantable Collamer Lens. PMID- 26653734 TI - Mining Large Scale Tandem Mass Spectrometry Data for Protein Modifications Using Spectral Libraries. AB - Experimental improvements in post-translational modification (PTM) detection by tandem mass spectrometry (MS/MS) has allowed the identification of vast numbers of PTMs. Open modification searches (OMSs) of MS/MS data, which do not require prior knowledge of the modifications present in the sample, further increased the diversity of detected PTMs. Despite much effort, there is still a lack of functional annotation of PTMs. One possibility to narrow the annotation gap is to mine MS/MS data deposited in public repositories and to correlate the PTM presence with biological meta-information attached to the data. Since the data volume can be quite substantial and contain tens of millions of MS/MS spectra, the data mining tools must be able to cope with big data. Here, we present two tools, Liberator and MzMod, which are built using the MzJava class library and the Apache Spark large scale computing framework. Liberator builds large MS/MS spectrum libraries, and MzMod searches them in an OMS mode. We applied these tools to a recently published set of 25 million spectra from 30 human tissues and present tissue specific PTMs. We also compared the results to the ones obtained with the OMS tool MODa and the search engine X!Tandem. PMID- 26653735 TI - Discovery of N-(4-Fluoro-3-methoxybenzyl)-6-(2-(((2S,5R)-5-(hydroxymethyl)-1,4 dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide. A Highly Selective and Orally Bioavailable Matrix Metalloproteinase-13 Inhibitor for the Potential Treatment of Osteoarthritis. AB - Matrix metalloproteinase-13 (MMP-13) is a zinc-dependent protease responsible for the cleavage of type II collagen, the major structural protein of articular cartilage. Degradation of this cartilage matrix leads to the development of osteoarthritis. We previously have described highly potent and selective carboxylic acid containing MMP-13 inhibitors; however, nephrotoxicity in preclinical toxicology species precluded development. The accumulation of compound in the kidneys mediated by human organic anion transporter 3 (hOAT3) was hypothesized as a contributing factor for the finding. Herein we report our efforts to optimize the MMP-13 potency and pharmacokinetic properties of non carboxylic acid leads resulting in the identification of compound 43a lacking the previously observed preclinical toxicology at comparable exposures. PMID- 26653736 TI - Nickel allergy and relationship with Staphylococcus aureus in atopic dermatitis. AB - BACKGROUND: The increase of nickel air pollution is supposed to frequent side effects of nickel action related to virulence potential of Staphylococcus aureus in patients with nickel allergy in atopic dermatitis. The goal was to investigate the relationship between nickel allergy and infection by S. aureus in atopic dermatitis. METHODS: Nickel allergy was confirmed in atopic patients and excluded in healthy volunteers using patch testing. Infection by S. aureus was tested in atopic patients and healthy volunteers by use of API Staph system. The specific IgE for staphylococcal enterotoxin A and B were measured. Secretion of IFN-g, IL 2, IL-13 by PBMC under nickel sulfate and the enterotoxins A and B stimulations were studied with ELISpot. RESULTS: We found the increased number of infections by S. aureus in atopic patients with nickel allergy in comparison to atopic patients and healthy volunteers without nickel allergy. The elevated secretion of IL-2 under nickel sulfate stimulation in vitro was exclusively found in atopic patients with nickel allergy infected by S. aureus. CONCLUSIONS: Our data suggest that nickel allergy and infection by S. aureus are linked in atopic dermatitis. PMID- 26653737 TI - Changes of erythrocyte element status of colectomysed cancerous patients: Retrospective study. AB - Nowadays it has been established that metals and metal-induced oxidative stress act on signal transduction pathways, and are in association with cancer growth and spreading as well as in neurodegenerative disorders. In cases of several neurodegenerative diseases metals, especially Al, can be considered as a risk factor. Frequency of chemotherapy-related cognitive impairment or "chemobrain" is mentioned to be significant in literature, although very little is known about the chemotherapy-caused chemobrain and its connection with metal homeostasis alteration. Dysregulation of metal homeostasis can be assumed as one of the key factors in the progression of neurodegeneration. Therefore we were interested in studying metal element status of 27 adult patients in 3 years after their colectomy, 22 outpatients and 10 healthy volunteers in both genders. Tumour markers, laboratory parameters and metal element concentrations were determined. We found significant difference among the Al concentrations in operated patients compared with controls. Redox active Fe and Cu levels were also elevated slightly in this patient group. P and S concentrations changed in different ways, and Ca levels were slightly lower, than in healthy controls. Because of all above mentioned, examination of metal homeostasis in cancerous patients is necessary to moderate the risk of chemobrain and other redox-related disorders. PMID- 26653738 TI - Selenium speciation in paired serum and cerebrospinal fluid samples of sheep. AB - This study was performed to characterise selenium (Se) and Se species in cerebrospinal fluid (CSF) of sheep and its relation to the respective Se concentrations in serum. Paired samples from 10 adult sheep were used for the study. Five sheep were fed a diet with a marginal Se concentration of <0.05mg Se/kg diet dry weight (dw, Se(-)), and five animals were fed the same diet supplemented with sodium selenite revealing a concentration of 0.2mg Se/kg diet dw (Se(+)). The feeding strategy was conducted for two years; The results on metabolic effects were published previously. At the end of the feeding period, paired samples of serum and CSF were collected and analysed using ion exchange chromatography inductively coupled plasma-dynamic reaction cell-mass spectrometry (IEC-ICP-DRC-MS) technique for total Se concentration and concentrations of Se species. Albumin concentrations were analysed additionally. The feeding strategy caused significant differences (p<0.01) in serum Se concentrations with 33.1+/ 5.11MUg Se/l in the Se(-) group and 96.5+/-18.3MUg Se/l in the Se(+) group, respectively. The corresponding total Se concentrations in CSF were 4.38+/ 1.02MUg Se/l and 6.13+/-1.64MUg Se/l in the Se(-) and the Se(+) group, respectively, missing statistical significance (p=0.077). IEC-ICP-DRC-MS technique was able to differentiate the Se species selenoprotein P-bound Se (SePP), selenomethionine, glutathione peroxidase-bound Se (Se-GPx), selenocystine, thioredoxin reductase-bound Se, ovine serum albumin-bound Se (Se OSA), SeIV and SeVI in ovine serum and CSF. Quantitatively, SePP is the main selenoprotein in ovine serum followed by Se-GPx. The CSF/blood ratio of albumin (QAlbumin) reflected a physiological function of the blood-CSF barrier in all sheep. QSe-species were higher than QAlbumin both feeding groups, supporting the hypothesis of local production of Se species in the brain. Significant positive regression lines for CSF vs. serum were found for albumin and Se-OSA only, suggesting a role of albumin to convey Se across the blood-CSF barrier. The ovine model, together with the IEC-ICP-DRC-MS technique to characterise the Se species, might be a worthwhile model for further studies as repeated sample collection as well as modification of the nutritional status is feasible and effective. PMID- 26653739 TI - Low serum selenium concentration is associated with preeclampsia in pregnant women from Bangladesh. AB - OBJECTIVES: Preeclampsia is a hypertensive disorder of pregnancy which is one of the leading causes of maternal and perinatal mortality and pre-term delivery, especially in low and middle income countries. Selenium is an important constituent of selenoproteins that act as antioxidant and have several metabolic functions. The present study was conducted to determine serum selenium concentration in preeclampsia patients in order to find out the role of selenium in preeclampsia. METHODS: This study was conducted as case-control study with 74 preeclampsia patients as cases whose gestation were >=20 weeks (52 mild and 22 severe patients) and 118 normotensive pregnant women as controls from same gestational period. Detailed patient history was recorded during routine hospital visits. Serum selenium concentration was determined by using atomic absorption spectroscopy. Independent sample t-test and Pearson's correlation test were done for the statistical analysis using the statistical software package SPSS, version 16. RESULTS: Our study found that mean serum concentration of selenium in preeclampsia patients was significantly lower than that of healthy pregnant women (p<0.05). Further analysis for selenium concentration with disease severity explored that selenium concentration was significantly lower in severe preeclampsia in comparison to mild preeclampsia (p<0.05). We found no significant difference for selenium concentration between rural and urban preeclampsia patients (p>0.05). Pearson's correlation analysis reveals significant negative correlation of selenium with systolic blood pressure (r=-0.419, p=0.001), diastolic blood pressure (r=-0.392, p=0.001), and gestational period (r=-0.218, p=0.001). CONCLUSION: Our study found that preeclampsia patients have decreased serum selenium concentration than the healthy pregnant women. PMID- 26653740 TI - Quantitative analysis of human remains from 18(th)-19(th) centuries using X-ray fluorescence techniques: The mysterious high content of mercury in hair. AB - In this work, we report the unusual concentration of mercury in the hair of an individual buried in the 18th to mid-19th centuries and the comparison with the elemental composition of other remains from the same individual. Two energy dispersive X-ray fluorescence (EDXRF) setups, one with tri-axial geometry and the second one with micro-beam capabilities and a vacuum system, for light elements detection, have been used. Quantitative evaluation of the obtained spectra were made by fundamental parameters and winAXIL program by compare mode method. The levels of Hg in the hair of buried samples presented a concentration over 5% (w/w), a significantly lower presence of this element in the cranium, and no Hg in the remaining organs. Furthermore, there was no evidence of Hg in the burial soil, which has been also analyzed. From this result, we could conclude that the possibility of post-mortem contamination from the burial surroundings is very unlikely. The obtained results are indicative of the apparent use of a mercury based compound for medical purposes, most likely lice infestation. PMID- 26653741 TI - Comparative assessment of the effects of salinomycin and monensin on the biodistribution of lead and some essential metal ions in mice, subjected to subacute lead intoxication. AB - In this study, we present a comparative assessment of the effects of two polyether ionophorous antibiotics (monensin and salinomycin) on the concentrations of lead (Pb), cooper (Cu), zinc (Zn) and iron (Fe) in the kidneys, spleen, liver and brain of Pb-intoxicated animals. Our data demonstrated that the intoxication of ICR male mice with Pb salt resulted in a significant accumulation of Pb in all studied organs of the mice compared to the untreated control animals. The biodistribution of the toxic metal was in the order kidneys>spleen>liver>brain. The treatment of the Pb-intoxicated animals with tetraethylammonium salts of monensic and salinomycinic acids significantly decreased the concentration of the toxic metal ion compared to the toxic control. The effect varied in the interval 38% (for kidneys) to 52% (for brain) compared to the toxic control group (Pb). The tetraethylammonium salt of salinomycinic acid was more effective in reducing the Pb concentration in the brain of the Pb treated mice compared to monensin. Pb-intoxication did not affect significantly the Zn endogenous concentration compared to the normal values. The treatment of ICR male mice with Pb-salt decreased the Cu concentration in the spleen and increased the Cu concentration in the liver compared to the untreated control animals. The detoxification of the Pb-intoxicated mice with tetraethylammonium salts of salinomycinic and monensic acids restored the Cu concentration in the spleen, but did not affect the Cu levels in the liver. The Pb-intoxication of the ICR mice resulted in a significant decrease of the Fe-concentration in the spleen and liver compared to the untreated control animals. The administration of the tetraethylammonium salts of salinomycinic and monensic acids to the Pb-treated animals restored the levels of Fe in both organs. PMID- 26653742 TI - Purple carrot extract protects against cadmium intoxication in multiple organs of rats: Genotoxicity, oxidative stress and tissue morphology analyses. AB - The aim of this study was to investigate if purple carrot extract is able to protect against the noxious activities induced by cadmium exposure in multiple organs of rats. For this purpose, histopathological analysis, genotoxicity and oxidative status were investigated in this setting. A total of twenty Wistar rats weighing 250g on the average, and 8 weeks age were distributed into four groups (n=5), as follows: Control group (non-treated group, CTRL); Cadmium group (Cd) and Purple carrot extract groups at 400mg/L or 800mg/L. Histopathological analysis revealed that liver from animals treated with purple carrot extract improved tissue degeneration induced by cadmium intoxication. Genetic damage was reduced in blood and hepatocytes as depicted by comet and micronucleus assays in animals treated with purple carrot extract. SOD-CuZn and cytocrome C gene expression increased in groups treated with purple carrot extract. Purple carrot extract also reduced the 8OHdG levels in liver cells when compared to cadmium group. Taken together, our results demonstrate that purple carrot extract is able to protect against cadmium intoxication by means of reducing tissue regeneration, genotoxicity and oxidative stress in multiple organs of Wistar rats. PMID- 26653743 TI - The blood lead levels of outpatients aged 1-18 years from Lu'an, China, 2012 2014. AB - To evaluate blood lead levels (BLLs) and possible influencing factors among children and adolescents in Lu'an, we collected blood samples of 3266 outpatients aged 1-18 years from January 2012 to December 2014 and BLLs were determined by atomizer absorption spectrophotometer. The results showed that the geometric mean (GM) of BLLs was 29.53MUg/L (95% CI: 29.00-30.06MUg/L) and the prevalence of BLLs >=50 and 100MUg/L were 17.7% and 0.2%, respectively. The GM BLLs and prevalence of BLLs >=50MUg/L were increased with age before 7 years old and then slightly decreased, and, contrary to previous studies, they were the highest at Jan-Feb and the lowest at Sep-Oct. From 2012 to 2014, the GM BLLs were significantly increased (P<0.001) while the prevalence of BLLs >=50MUg/L was decreased but with no significant difference (P>0.05). These results suggested that although the BLLs of Lu'an children were lower than most areas of China and several neighboring cities as previously reported, they were still higher than that of developed countries. Meanwhile, the GM BLLs of children and adolescents from Lu'an have a trend of increase in recent years. A lot of future works need to be done to identify the risk factors for lead exposure. PMID- 26653744 TI - Establishment of drug delivery system nanocapsulated with an antioxidant (+) catechin hydrate and sodium meta borate chelator against sodium fluoride induced oxidative stress in rats. AB - Oxidative stress a major cause of fluoride induced toxicity and mitochondrial impairment in common in experimental rats during chronic exposure of fluoride. Attempts have been made in the present experiment to diminish oxidative damage, combined therapy with (+)-catechin hydrate (an antioxidant) and sodium meta borate (chelator) were used. Fluoride intoxication in rats was performed by using 13mg/kg NaF and both antioxidant CH and chelator SMB were used at a concentration of 8.98MUM/kg body weight. Mixture of CH and SMB in free or in PLGA nanocapsule encapsulated form were prepared. The efficacies of those formulations were tested in combating free radical mediated oxidative insult produced by sodium fluoride (NaF). The amalgamated therapy used in this experiment was shown to reduce fluoride levels in liver, brain and kidney from 9.5, 5.5, 6.3MUg/g to 4.6, 2, 2.6MUg/g, respectively. Our result indicated that the combined chelator and antioxidant therapy in nanocapsulated drug delivery system could provide a projection in combating fluoride induced mitochondrial impairment in rat model. PMID- 26653745 TI - Acute selenium selenite exposure effects on oxidative stress biomarkers and essential metals and trace-elements in the model organism zebrafish (Danio rerio). AB - Selenium (Se) is an essential trace-element that becomes toxic when present at high concentrations. Little is known regarding Se effects on parameters such as oxidative stress biomarkers. The aim of the present study was to investigate the effects of acute selenium exposure on oxidative stress biomarkers in a model organism, zebrafish (Danio rerio). Fish were exposed to selenium selenite at 1mgL(-1). Reduced glutathione (GSH), and metallothionein (MT) concentrations were determined in liver, kidney and brain, with MT also being determined in bile. Essential metals and trace-elements were also determined by inductively coupled mass spectrometry (ICP-MS) in order to verify possible metal homeostasis alterations. GSH concentrations in liver, kidney and brain increased significantly (1.05+/-0.03MUmolg(-1) ww, 1.42+/-0.03MUmolg(-1) ww and 1.64+/ 0.03MUmolg(-1) ww, respectively) in the Se-exposed group when compared to the controls (0.88+/-0.05MUmolg(-1) ww, 0.80+/-0.04MUmolg(-1) ww and 0.89+/ 0.03MUmolg(-1) ww for liver, kidney and brain, respectively). MT levels in Se exposed liver (0.52+/-0.03MUmolg(-1) ww) decreased significantly in comparison to the control group (0.64+/-0.02MUmolg(-1) ww), while levels in bile increased, albeit non-significantly. This is in accordance with previous studies that indicate efficient biliary MT action, leading to a rapid metabolism and elimination of contaminants from the body. Levels in the brain increased significantly after Se-exposure (0.57+/-0.01MUmolg(-1) ww) when compared to the control group (0.35+/-0.03MUmolg(-1) ww) since this organ does not present a detoxification route as quick as the liver-gallbladder route. Several metal and trace-elements were altered with Se-exposure, indicating that excess of selenium results in metal dyshomeostasis. This is the first report on metal dyshomeostasis due to Se-exposure, which may be the first step in the mechanism of action of selenium toxicity, as is postulated to occur in certain major human pathophysiologies. PMID- 26653746 TI - Determination of 20 trace elements and arsenic species for a realgar-containing traditional Chinese medicine Niuhuang Jiedu tablets by direct inductively coupled plasma-mass spectrometry and high performance liquid chromatography-inductively coupled plasma-mass spectrometry. AB - Niuhuang Jiedu tablet (NHJDT) is a realgar-containing traditional Chinese medicine. A direct inductively coupled plasma-mass spectrometry (ICP-MS) method for the simultaneous determination of 20 trace elements (Mg, K, Ca, Na, Fe, As, Zn, Sr, Ba, Cu, Mn, Ni, Pb, V, Cr, Se, Co, Mo, Cd, Hg) in NHJDT, as well as in water, gastric fluid and intestinal fluid was established. Meanwhile, a high performance liquid chromatography-inductively coupled plasma-mass spectrometry (HPLC-ICP-MS) method was developed for the determination of arsenite (As(III)), arsenate (As(V)), monomethylarsonic acid (MMA), dimethylarsinic acid (DMA) and for the identification of arsenobetaine (AsB) and arsenocholine (AsC) in these extracts. Both methods were fully validated in the respect of linearity, sensitivity, precision, stability and accuracy. The reliability of the ICP-MS method was further evaluated using a certified standard reference material prepared from dried tomato leaves (NIST, SRM 1572a). The analysis showed that some manufacturers formulated lower amount of realgar than required in the Chinese Pharmacopoeia (ChP) in their preparations. In addition, almost same extraction profiles for total As and inorganic As were found in water and in gastrointestinal fluids, while higher extraction rates for other 19 elements were observed in gastrointestinal fluids. Our findings show that the toxicities of Hg, Cu, Cd and Pb in NHJDP are low, while the real As toxicity in NHJDT should be deeply investigated. PMID- 26653747 TI - Potentiation of endothelin-1-induced prostaglandin E2 formation by Ni(2+) and Sr(2+) in murine osteoblastic MC3T3-E1 cells. AB - Cation recognition mechanisms beyond calcium-sensing receptors are still largely unexplored and consequently there is surprisingly little information on linking of this primary event to key metabolic features of different cell systems, such as arachidonic acid metabolism. However, information on the modulatory role of extracellular cations in cellular function is scarce. In this study we have demonstrated, that Ni(2+) and Sr(2+) potentiate endothelin-1 induced prostaglandin E2 formation in the osteoblastic cell line, MC3T3-E1, even in the absence of extracellular calcium. The effect is strictly dependent of receptor mediated signal transduction processes evoked by endothelin-1 and arachidonate release involves cytosolic phospholipase A2 activity. The ligation sites, at least for Ni(2+) are extracellular. The data suggest a novel activation mechanism for arachidonate release and subsequent prostaglandin formation that does not require calcium. PMID- 26653748 TI - A novel metabolic activation associated with glutathione in dimethylmonothioarsinic acid (DMMTA(V))-induced toxicity obtained from in vitro reaction of DMMTA(V) with glutathione. AB - The purpose of the present study was to elucidate the metabolic processing of dimethylmonothioarsinic acid (DMMTA(V)), which is a metabolite of inorganic arsenic and has received a great deal of attention recently due to its high toxicity. The metabolites produced from an in vitro reaction with GSH were analyzed by high performance liquid chromatography-time of flight mass spectrometer (HPLC-TOFMS), HPLC with a photodiode array detector (PDA), and also gas chromatography-mass spectrometry (GC-MS) and GC with a flame photometric detector (FPD). The reaction of dimethylarsinic acid (DMA(V)) with GSH did not generate DMA(V)-SG but did generate dimethylarsinous acid (DMA(III)) or DMA(III) SG. On the contrary, we confirmed that the reaction of DMMTA(V) with GSH directly produced the stable complex of DMMTA(V)-SG without reduction through a trivalent dimethylated arsenic such as DMA(III) and DMA(III)-SG. Furthermore, the present study suggests the production of hydrogen sulfide (H2S) and dimethylmercaptoarsine (DMA(III)-SH), a trivalent dimethylated arsenic, as well as DMA(III) and DMA(III)-SG in the decomposition process of DMMTA(V)-SG. These results indicate that the toxicity of DMMTA(V) depends not only on the formation of DMA(III) but also on at least those of H2S and DMA(III)-SH. PMID- 26653749 TI - Content of bioelements in the lungs and liver in rats with alimentary obesity. AB - The synchrotron radiation X-ray fluorescence technique (SRXRF) was applied to the determination of K, Ca, Mn, Fe, Cu, Zn, Se, Br, Rb, and Sr concentrations in the liver and lungs in Wistar rats. The animals in the experiment included (1) healthy rats, (2) rats with alimentary obesity (AO), and (3) rats with alimentary obesity that were being given zinc sulphate with water for a long time (AO+Zn). Each group was divided into two subgroups. The experiment with the first subgroup was terminated with the animals in the state of physiological hunger and subsequent retrieval of liver and lung tissue, while the animals of the second subgroup were sacrificed two hours after ingestion of lard. The rats in physiological hunger manifested intergroup differences in the content of the bioelements (BEs) neither in the liver nor in the lungs. The rats with AO, as compared with the healthy animals, demonstrated in physiological hunger redistribution of inter-element correlations (IECs), which is an indirect reflection of sustained metabolic disorder. Additional zinc in the rats' ration did not affect their body weight and the concentration of the BEs (including zinc) in the liver and the lungs. However, the IECs in the tissues of these animals in physiological hunger also changed. This redistribution differed from that in the rats with AO. The IECs soon after ingestion of lard also changed, which also reflects sustained changes in the metabolism in the animals. PMID- 26653750 TI - Species differences in total mercury concentration in gulls from the Gulf of Gdansk (Southern Baltic). AB - Aquatic birds occupy a high position in the trophic pyramid of the Baltic Sea. This means that they accumulate the greatest amount of harmful substances, including mercury, in their bodies. This element penetrates into their systems mainly via the alimentary canal. The amount of mercury absorbed from food depends on how badly the environment is polluted with this metal. The aim of this study was to discover the concentrations of total mercury (HgT) in the contour feathers, muscles, brain, lungs, liver, kidneys, heart and blood of four gull species Herring Gull (Larus argentatus), Common Gull (Larus canus), Black-headed Gull (Larus ridibundus) and Great Black-backed Gull (Larus marinus) and organic mercury (Hgorg) in the liver and brain of Herring Gull. The most important characteristic of the results obtained for the studied gulls was the statistically significant differences between the four species, probably resulting from their different diets-confirmed by stable-isotopes analysis (delta(15)N and delta(13)C). A logarithmic dependence was found between HgT in the blood and HgT in the brain of the Herring Gull. The authors suggest that among gulls burdened with the greatest mercury load, it is possible that the brain is protected by higher Hg accumulation in the muscles. The percentage share of Hgorg in the brain and liver of the Herring Gull depended on the concentration of HgT in these tissues and was always higher in the brain. In none of the cases, did the mercury levels assayed in the internal gulls' tissues exceed values associated with adverse health effects. PMID- 26653751 TI - High hair selenium mother to fetus transfer after the Brazil nuts consumption. AB - Lactating mother and her two month old healthy daughter (APGAR 10) gave their scalp hair for a multielement profile analysis; 25 elements were analyzed with the ICP MS. Mother's hair was divided into 5cm long segment proximal to the scull (Young), and the distal segment further up to the hair tip (Old). One centimeter of hair records one month of the metabolic activity of the bioelements in the body. Mother's Young hair and daughters hair have 2.70 and 9.74MUgg(-1)Se, a distinctly higher Se concentrations than the Old hair of 0.87MUgg(-1). The adequate hair Se concentrations in Croatia women population vary from 0.08 to 0.63MUgg(-1); values below or above that range indicate deficiency or excess, respectively. Dietary recall revealed that during the last trimester of pregnancy and over a period of a week, the mother has consumed 135g of Brazil nuts (Bertholletia excelsa) (BN); BN is an exceptionally rich Se dietary source. The amount of Se in BN varies and one week consumption of 135g of BN may result in Se daily intake of 367 to 492MUgg(-1)day(-1) over a period of seven consecutive days, and what is about or exceeds the Upper Limit of daily selenium intake of 400MUg(-1)g(-1). The excessively high infant hair Se mirrored a natural high mother to fetus transplacental transfer of bio elements in the last trimester of pregnancy. The potential toxicological risks of such a high Se transfer remains to be elucidated. PMID- 26653752 TI - Assessment of trace elements levels in patients with Type 2 diabetes using multivariate statistical analysis. AB - The trace elements metabolism has been reported to possess specific roles in the pathogenesis and progress of diabetes mellitus. Due to the continuous increase in the population of patients with Type 2 diabetes (T2D), this study aims to assess the levels and inter-relationships of fast blood glucose (FBG) and serum trace elements in Type 2 diabetic patients. This study was conducted on 40 Egyptian Type 2 diabetic patients and 36 healthy volunteers (Hospital of Tanta University, Tanta, Egypt). The blood serum was digested and then used to determine the levels of 24 trace elements using an inductive coupled plasma mass spectroscopy (ICP MS). Multivariate statistical analysis depended on correlation coefficient, cluster analysis (CA) and principal component analysis (PCA), were used to analysis the data. The results exhibited significant changes in FBG and eight of trace elements, Zn, Cu, Se, Fe, Mn, Cr, Mg, and As, levels in the blood serum of Type 2 diabetic patients relative to those of healthy controls. The statistical analyses using multivariate statistical techniques were obvious in the reduction of the experimental variables, and grouping the trace elements in patients into three clusters. The application of PCA revealed a distinct difference in associations of trace elements and their clustering patterns in control and patients group in particular for Mg, Fe, Cu, and Zn that appeared to be the most crucial factors which related with Type 2 diabetes. Therefore, on the basis of this study, the contributors of trace elements content in Type 2 diabetic patients can be determine and specify with correlation relationship and multivariate statistical analysis, which confirm that the alteration of some essential trace metals may play a role in the development of diabetes mellitus. PMID- 26653753 TI - Serum zinc and risk of type 2 diabetes incidence in men: The Kuopio Ischaemic Heart Disease Risk Factor Study. AB - OBJECTIVES: Zinc may play a role in the development of type 2 diabetes (T2D), because it is involved in antioxidant and anti-inflammatory activities. However, the role of zinc in the etiology of T2D has been poorly investigated. This study was conducted to study the association of serum zinc on T2D risk in middle-aged and older Finnish men. METHODS: This was a 20-year prospective follow-up study on 2220 Finnish men from the Kuopio Ischaemic Heart Disease Risk Factor Study (KIHD) who were 42 to 60 years old at baseline in 1984-1989. The main outcome was incident T2D. Serum zinc, body mass index (BMI), fasting blood glucose (FBG), serum insulin, C-reactive protein (CRP) and, in a subset of 751 participants, insulin-like growth factor-binding protein-1 (IGFBP-1), were measured. Also, the homeostatic model assessment (HOMA) was used to quantify insulin resistance (HOMA IR), beta-cell function (HOMA-beta) and insulin sensitivity (HOMA-IS). RESULTS: At baseline, serum zinc was associated with higher BMI, serum insulin, HOMA-IR, HOMA-beta and IGFBP-1 and lower HOMA-IS. During the average follow-up of 19.3 years, 416 men developed T2D. Men in the highest quartile of serum zinc had 60% higher risk (95% CI 20-113%; P-trend<0.001) for incident T2D compared with the men in the lowest quartile, after multivariate adjustments. This association was attenuated after adjustment for BMI (HR=1.39, 95% CI 1.04-1.85; P-trend=0.013) or HOMA-IS (HR=1.38, 95% CI 1.04-1.83; P-trend=0.015), whereas adjustment for the other factors had only modest impact on the association. CONCLUSION: Higher serum zinc was associated with higher risk of T2D; effects of zinc on BMI and insulin sensitivity may partly explain the association. Further prospective studies are warranted to confirm our results and explore potential mechanisms. PMID- 26653754 TI - Epidemiology of hepatitis C virus infection among people receiving opioid substitution therapy (ECHO): study protocol. AB - BACKGROUND: Hepatitis C virus infection is highly prevalent among people who inject drugs. Opioid substitution therapy, the standard treatment for opioid dependence, provides an excellent opportunity for the treatment of hepatitis C virus infection due to the close and regular contact between patients and clinicians. However, there is little research on the impact of opioid substitution therapy on the prevalence of the hepatitis C virus at a national level. This paper describes the protocol for the Epidemiology of Hepatitis C Virus Infection among People Receiving Opioid Substitution Therapy (ECHO) study. The aim of this study is to estimate the national prevalence and incidence of hepatitis C virus infection among people receiving opioid substitution therapy in Germany and to describe factors associated with hepatitis C treatment uptake and seroconversion. METHODS/DESIGN: An observational, longitudinal, multicentre study is being conducted between 2014 and 2016 in a representative sample of approximately 2500 people receiving opioid substitution therapy from about 100 clinicians providing opioid substitution therapy in Germany. Data will be collected during routine patient care and by means of patient and clinician questionnaires at baseline and 12-month follow-up. Stratified sampling will be performed to obtain a representative sample of clinicians providing opioid substitution therapy. The strata will be constructed based on the distribution of the total sample of clinicians providing opioid substitution therapy in Germany according to German Federal State and the number of patients per clinician. DISCUSSION: Opioid substitution therapy may be an important strategy to prevent the spread of hepatitis C virus in opioid dependent populations, but its effectiveness may be diminished by our limited understanding of factors associated with treatment uptake and seroconversion. The present study will provide important information for developing strategies to address hepatitis C virus-related disease burden in people receiving opioid substitution therapy. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02395198. PMID- 26653755 TI - Flaxseed flour (Linum usitatissinum) consumption improves bone quality and decreases the adipocyte area of lactating rats in the post-weaning period. AB - The aim of this work was to evaluate the effects of flaxseed flour in the intake on adiposity and femur structure of the lactating rats during the post-weaning period. After weaning, the lactating rats were divided into control (C, n = 6) and experimental (F, n = 6) groups treated with a diet containing flaxseed flour. Serum hormone and fatty acids composition, morphology of intra-abdominal adipocytes, computed tomography and biomechanical analyses of femur were determined. Food intake, body mass and hormone analysis have shown similar results. The F group showed the following (p < 0.05): lower arachidonic acid ( 60%), total polyunsaturated fatty acids (-30%) and retroperitoneal adipocytes ( 36%) area. Higher radiodensity of femoral head region (+29%) and higher maximum force (+18%), breaking strength (+18%) and rigidity (+31%). Fatty acid composition of flaxseed flour decreased the area of adipocytes and improved the bone quality, which may be associated with lower serum levels of arachidonic acid levels, during the post-weaning period. PMID- 26653756 TI - The microbiome quality control project: baseline study design and future directions. AB - Microbiome research has grown exponentially over the past several years, but studies have been difficult to reproduce across investigations. Relevant variation in measurements between laboratories, from a variety of sources, has not been systematically assessed. This is coupled with a growing concern in the scientific community about the lack of reproducibility in biomedical research. The Microbiome Quality Control project (MBQC) was initiated to identify sources of variation in microbiome studies, to quantify their magnitudes, and to assess the design and utility of different positive and negative control strategies. Here we report on the first MBQC baseline study project and workshop. PMID- 26653757 TI - Simultaneous fecal microbial and metabolite profiling enables accurate classification of pediatric irritable bowel syndrome. AB - BACKGROUND: We previously showed that stool samples of pre-adolescent and adolescent US children diagnosed with diarrhea-predominant IBS (IBS-D) had different compositions of microbiota and metabolites compared to healthy age matched controls. Here we explored whether observed fecal microbiota and metabolite differences between these two adolescent populations can be used to discriminate between IBS and health. FINDINGS: We constructed individual microbiota- and metabolite-based sample classification models based on the partial least squares multivariate analysis and then applied a Bayesian approach to integrate individual models into a single classifier. The resulting combined classification achieved 84 % accuracy of correct sample group assignment and 86 % prediction for IBS-D in cross-validation tests. The performance of the cumulative classification model was further validated by the de novo analysis of stool samples from a small independent IBS-D cohort. CONCLUSION: High-throughput microbial and metabolite profiling of subject stool samples can be used to facilitate IBS diagnosis. PMID- 26653758 TI - Microporous Metal-Organic Framework Stabilized by Balanced Multiple Host Couteranion Hydrogen-Bonding Interactions for High-Density CO2 Capture at Ambient Conditions. AB - Microporous metal organic frameworks (MOFs) show promising application in several fields, but they often suffer from the weak robustness and stability after the removal of guest molecules. Here, three isostructural cationic metal-organic frameworks {[(Cu4Cl)(cpt)4(H2O)4].3X.4DMAc.CH3OH.5H2O} (FJU-14, X = NO3, ClO4, BF4; DMAc = N,N'-dimethylacetamide) containing two types of polyhedral nanocages, one octahedron, and another tetrahedron have been synthesized from bifunctional organic ligands 4-(4H-1,2,4-triazol-4-yl) benzoic acid (Hcpt) and various copper salts. The series of MOFs FJU-14 are demonstrated as the first examples of the isostructural MOFs whose robustness, thermal stability, and CO2 capacity can be greatly improved via rational modulation of counteranions in the tetrahedral cages. The activated FJU-14-BF4-a containing BF4(-) anion can take CO2 of 95.8 cm(3) cm(-3) at ambient conditions with an adsorption enthalpy only of 18.8 kJ mol(-1). The trapped CO2 density of 0.955 g cm(-3) is the highest value among the reported MOFs. Dynamic fixed bed breakthrough experiments indicate that the separation of CO2/N2 mixture gases through a column packed with FJU-14-BF4-a solid can be efficiently achieved. The improved robustness and thermal stability for FJU-14-BF4-a can be attributed to the balanced multiple hydrogen-bonding interactions (MHBIs) between the BF4(-) counteranion and the cationic skeleton, while the high-density and low-enthalpy CO2 capture on FJU-14-BF4-a can be assigned to the multiple-point interactions between the adsorbate molecules and the framework as well as with its counteranions, as proved by single-crystal structures of the guest-free and CO2-loaded FJU-14-BF4-a samples. PMID- 26653759 TI - Multiple Beneficial Roles of Repressor of Estrogen Receptor Activity (REA) in Suppressing the Progression of Endometriosis. AB - Endometriosis is an estrogen-dependent, inflammation-driven gynecologic disorder in which endometrial tissue creates inflammatory lesions at extrauterine sites, leading to pelvic pain and impaired fertility. Although dysregulated estrogen receptor (ER) signaling has been implicated, understanding of this disease is incomplete and current therapies are of limited benefit. Using an immunocompetent syngeneic murine model, we used combinations of donor uterine tissue and/or recipient host mice with partial genetic deletion of the ER coregulator, repressor of ER activity (REA) (also known as prohibitin 2), to investigate roles of REA in the contributions of donor uterine tissue and host cell influences on endometriosis establishment and progression. Ectopic lesions derived from donor tissue with half the wild-type gene dosage of REA (REA(+/-)) grown in REA(+/-) hosts displayed enhanced proliferation, vascularization, and markedly increased neuron innervation and inflammatory responses, including elevated cytokine production, nuclear factor kappa B activation, cyclooxygenase-2 expression, and immune cell infiltration. Although lesion progression was greatest when REA was reduced in both donor tissue and host animals, other donor/host combinations indicated that distinct stimulatory inputs were derived from ectopic tissue (proliferative signals) and host cells (inflammatory signals). Importantly, depletion of REA in primary human endometriotic stromal cells led to elevated proliferation and expression of cell cycle regulators. Notably, REA was significantly lower in human endometriotic tissue versus normal human endometrium. Thus, REA modulates cross talk among multiple cell types in the uterine tissue and host background, serving as a brake on the estradiol-ER axis and restraining multiple aspects that contribute to the pathologic progression of endometriosis. PMID- 26653760 TI - Intermittent Fasting Promotes Fat Loss With Lean Mass Retention, Increased Hypothalamic Norepinephrine Content, and Increased Neuropeptide Y Gene Expression in Diet-Induced Obese Male Mice. AB - Clinical studies indicate alternate-day, intermittent fasting (IMF) protocols result in meaningful weight loss in obese individuals. To further understand the mechanisms sustaining weight loss by IMF, we investigated the metabolic and neural alterations of IMF in obese mice. Male C57/BL6 mice were fed a high-fat diet (HFD; 45% fat) ad libitum for 8 weeks to promote an obese phenotype. Mice were divided into four groups and either maintained on ad libitum HFD, received alternate-day access to HFD (IMF-HFD), and switched to ad libitum low-fat diet (LFD; 10% fat) or received IMF of LFD (IMF-LFD). After 4 weeks, IMF-HFD (~13%) and IMF-LFD (~18%) had significantly lower body weights than the HFD. Body fat was also lower (~40%-52%) in all diet interventions. Lean mass was increased in the IMF-LFD (~12%-13%) compared with the HFD and IMF-HFD groups. Oral glucose tolerance area under the curve was lower in the IMF-HFD (~50%), whereas the insulin tolerance area under the curve was reduced in all diet interventions (~22%-42%). HPLC measurements of hypothalamic tissue homogenates indicated higher (~55%-60%) norepinephrine (NE) content in the anterior regions of the medial hypothalamus of IMF compared with the ad libitum-fed groups, whereas NE content was higher (~19%-32%) in posterior regions in the IMF-LFD group only. Relative gene expression of Npy in the arcuate nucleus was increased (~65%-75%) in IMF groups. Our novel findings indicate that intermittent fasting produces alterations in hypothalamic NE and neuropeptide Y, suggesting the counterregulatory processes of short-term weight loss are associated with an IMF dietary strategy. PMID- 26653762 TI - Regeneration in the Pituitary After Cell-Ablation Injury: Time-Related Aspects and Molecular Analysis. AB - We recently showed that the mouse pituitary holds regenerative competence. Young adult GHCre/iDTR mice, expressing diphtheria toxin (DT) receptor in GH-producing cells, regenerate the GH(+) cells, as ablated by 3-day DT treatment (3DT), up to 60% after 5 months. The pituitary's stem cells participate in this restoration process. Here, we characterized this regenerative capacity in relation to age and recovery period and started to search for underlying molecular mechanisms. Extending the recovery period (up to 19 mo) does not result in higher regeneration levels. In addition, the regenerative competence disappears at older age, coinciding with a reduction in pituitary stem cell number and fitness. Surprisingly, prolonging DT treatment of young-adult mice to 10 days (10DT) completely blocks the regeneration, although the stem cell compartment still reacts by promptly expanding, and retains in vitro stem cell functionality. To obtain a first broad view on molecular grounds underlying reparative capacity and/or failure, the stem cell-clustering side population was analyzed by whole genome expression analysis. A number of stemness factors and components of embryonic, epithelial-mesenchymal transition, growth factor and Hippo pathways are higher expressed in the stem cell-clustering side population of the regenerating pituitary (after 3DT) when compared with the basal gland and to the nonregenerating pituitary (after 10DT). Together, the regenerative capacity of the pituitary is limited both in age-related terms and final efficacy, and appears to rely on stem cell-associated pathway activation. Dissection of the molecular profiles may eventually identify targets to induce or boost regeneration in situations of (injury-related) pituitary deficiency. PMID- 26653761 TI - Aberrant TGFbeta Signaling Contributes to Altered Trophoblast Differentiation in Preeclampsia. AB - TGFbeta has been implicated in preeclampsia, but its intracellular signaling via phosphorylated mothers against decapentaplegic (SMADs) and SMAD-independent proteins in the placenta remains elusive. Here we show that TGFbeta receptor regulated SMAD2 was activated (Ser(465/467) phosphorylation) in syncytiotrophoblast and proliferating extravillous trophoblast cells of first trimester placenta, whereas inhibitory SMAD7 located primarily to cytotrophoblast cells. SMAD2 phosphorylation decreased with advancing gestation, whereas SMAD7 expression increased and shifted to syncytiotrophoblasts toward term. Additionally, we found that the TGFbeta SMAD-independent signaling via partitioning defective protein 6 (PARD6)/Smad ubiquitylation regulatory factor was activated at approximately 10-12 weeks of gestation in cytotrophoblast and extravillous trophoblast cells comprising the anchoring column. Placentae from early-onset, but not late-onset, preeclampsia exhibited elevated SMAD2 phosphorylation and SMAD7 levels. Whereas PARD6 expression increased and SMURF1 levels decreased in preeclamptic placentae, their association increased. SMAD2 phosphorylation by TGFbeta in villous explants and BeWo cells resulted in a reduction of Glial cell missing-1 (GCM1) and fusogenic protein syncytin-1 while increasing cell cycle regulators cyclin E-1 (CCNE1) and cyclin-dependent kinase 4. SMAD7 abrogated the proliferative effects of TGFbeta. CCNE1 levels were increased in preeclamptic placentae, whereas GCM1 was markedly reduced. In addition, TGFbeta treatment increased the association of PARD6 and SMURF1 and down-regulated Ras homolog gene family, member A (RHOA) GTPase in JEG3 cells. In a wound assay, TGFbeta treatment increased the association of PARD6 and SMURF1 and triggered JEG3 cell migration through increased cellular protrusions. Taken together, our data indicate that TGFbeta signaling via both SMAD2/7 and PARD6/SMURF1 pathways plays a role in trophoblast growth and differentiation. Altered SMAD regulation of GCM1 and CCNE1 and aberrant expression/activation of PARD6/SMURF1 may contribute to the pathogenesis of preeclampsia by affecting cellular pathways associated with this disorder. PMID- 26653763 TI - Spin Diffusion Editing for Structural Fingerprints of Therapeutic Antibodies. AB - The growing importance of biologics and biosimilars as therapeutic and diagnostic agents is giving rise to new demands for analytical methodology that can quickly and accurately assess the chemical and physical state of protein-based products. A particular challenge exists in physical characterization where the proper fold and extent of disorder of a protein is a major concern. The ability of NMR to reflect structural and dynamic properties of proteins is well recognized, but sensitivity limitations and high levels of interference from excipients in typical biologic formulations have prevented widespread applications to quality assessment. Here we demonstrate applicability of a simple one-dimensional proton NMR method that exploits enhanced spin diffusion among protons in well-structured areas of a protein. We show that it is possible to reduce excipient signals and allow focus on structural characteristics of the protein. Additional decomposition of the resulting spectra based on rotating frame spin relaxation allows separate examination of components from aggregates and disordered regions. Application to a comparison of two different monoclonal antibodies and to detection of partial pH denaturation of a monoclonal antibody illustrates the procedure. PMID- 26653765 TI - Microscopic Model of the Metal-Organic Framework/Polymer Interface: A First Step toward Understanding the Compatibility in Mixed Matrix Membranes. AB - An innovative computational methodology integrating density functional theory calculations and force field-based molecular dynamics simulations was developed to provide a first microscopic model of the interactions at the metal-organic framework (MOF) surface/polymer interface. This was applied to the case of the composite formed by the polymer of intrinsic microporosity, PIM-1, and the zeolitic imidazolate framework, ZIF-8, as a model system. We found that the structure of the composite at the interface is the result of both the chemical affinity between PIM-1 and ZIF-8 and the rigidity of the polymer. Specifically, there is a preferential interaction between the -CN groups of PIM-1 and the NH terminal functions of the organic linker at the ZIF-8 surface. Additionally, the resulting conformation of the polymer gives rise to interfacial microvoids at the vicinity of the MOF surface. The porosity, rigidity, and density of the interfacial polymer were analyzed and compared to those for the bulk polymer. It was shown that the polymer still feels the impact of the MOF surface even at long distances above 15-20 A. Further, both the polydispersity of the polymer and the flexibility of the MOF surface were revealed to only slightly affect the properties of the MOF/interface. This work, which delivers a microscopic picture of the MOF surface/polymer interactions at the interface, would lead, in turn, to the understanding of the compatibility in MOF-based mixed-matrix membranes. PMID- 26653764 TI - Self-efficacy Mediates the Relationship between Balance/Walking Performance, Activity, and Participation after Stroke. AB - BACKGROUND: Many outcome measures (OM) that assess individuals' ability or beliefs in their ability to perform tasks exist to evaluate activity and participation after stroke; however, the relationship between various OM and activity/participation is unclear. OBJECTIVE: The purpose of this study was to explore the relationships between different OM and activity and participation in people after stroke. METHODS: Fifty-nine subjects post stroke participated in an assessment including self-selected walking speed, 6 minute walk test, Timed "Up and Go" test, Berg Balance Scale, Functional Gait Assessment, Walk 12, and Activity-specific Balance Confidence Scale. Step Watch Activity Monitoring (SAM) was used as a measure of activity and Stroke Impact Scale-Participation (SIS-P) as a measure of participation. Exploratory Factor Analysis was performed including all measures except SAM and SIS-P. Two factors were extracted and termed performance based (PB) and self-efficacy (SE). A path analysis assessed the role of SE as a mediator in the relationships of PB and SAM/SIS-P. RESULTS: In the path analysis, PB significantly predicts SE (p < 0.001, b = 0.44), but not SAM or SIS-P (p > 0.05, b = 0.25, and b = 0.11, respectively). SE significantly predicts both SAM and SIS-P (p < 0.001, b = 0.46, and b = 0.59, respectively). The indirect effects of PB on SAM and SIS-P were significant (p < 0.001; b = 0.20, and b = 0.26, respectively). CONCLUSION: These results suggest that SE mediates the relationship between PB and activity and participation after stroke, reinforcing that improving activity and participation is more complicated than only targeting performance. Clinicians should administer SE and PB measures to determine the most accurate view of patients after stroke and seek to improve SE through interventions. PMID- 26653766 TI - N-Doped Ordered Mesoporous Carbon Originated from a Green Biological Dye for Electrochemical Sensing and High-Pressure CO2 Storage. AB - Herein, a series of nitrogen-doped ordered mesoporous carbons (NOMCs) with tunable porous structure were synthesized via a hard-template method with a green biological dye as precursor, under various carbonization temperatures (700-1100 degrees C). Compared with the ordered mesoporous silica-modified and unmodified electrodes, the use of electrodes coated by NOMCs (NOMC-700-NOMC-1100) resulted in enhanced signals and well-resolved oxidation peaks in electrocatalytic sensing of catechol and hydroquinone isomers, attributable to NOMCs' open porous structures and increased edge-plane defect sites on the N-doped carbon skeleton. Electrochemical sensors using NOMC-1000-modified electrode were fabricated and proved feasible in tap water sample analyses. The NOMCs were also used as sorbents for high-pressure CO2 storage. The NOMC with the highest N content exhibits the best CO2 absorption capacities of 800.8 and 387.6 mg/g at 273 and 298 K (30 bar), respectively, which is better than those of other NOMC materials and some recently reported CO2 sorbents with well-ordered 3D porous structures. Moreover, this NOMC shows higher affinity for CO2 than for N2, a benefit of its higher nitrogen content in the porous carbon framework. PMID- 26653767 TI - Optofluidic Modulation of Self-Associated Nanostructural Units Forming Planar Bragg Microcavities. AB - Bragg microcavities (BMs) formed by the successive stacking of nanocolumnar porous SiO2 and TiO2 layers with slanted, zigzag, chiral, and vertical configurations are prepared by physical vapor deposition at oblique angles while azimuthally varying the substrate orientation during the multilayer growth. The slanted and zigzag BMs act as wavelength-selective optical retarders when they are illuminated with linearly polarized light, while no polarization dependence is observed for the chiral and vertical cavities. This distinct optical behavior is attributed to a self-nanostructuration mechanism involving a fence-bundling association of nanocolumns as observed by focused ion beam scanning electron microscopy in the slanted and zigzag microcavities. The outstanding retarder response of the optically active BMs can be effectively modulated by dynamic infiltration of nano- and mesopores with liquids of different refraction indices acting as a switch of the polarization behavior. The unprecedented polarization and tunable optofluidic properties of these nanostructured photonic systems have been successfully simulated with a simple model that assumes a certain birefringence for the individual stacked layers and accounts for the light interference phenomena developed in the BMs. The possibilities of this type of self-arranged nanostructured and optically active BMs for liquid sensing and monitoring applications are discussed. PMID- 26653768 TI - The linguistic validation of Russian version of Dutch four-dimensional symptoms questionnaire (4DSQ) for assessing distress, depression, anxiety and somatization in patients with borderline psychosomatic disorders. AB - BACKGROUND: The four-dimensional symptom questionnaire (4DSQ) is an originally Dutch self-report questionnaire that has been developed in primary care to distinguish non-specific general distress from depression, anxiety and somatization. In order to produce the appropriate translated Russian version the process of linguistic validation has been initiated. This process has been done according to the "Linguistic Validation Manual for Health Outcome Assessments" developed by MAPI institute. OBJECTIVE: To produce the appropriate Russian version of the 4DSQ that is conceptually and linguistically equivalent to the original questionnaire. METHODS: The original Dutch version of the 4DSQ was translated by one translator into Russian. The validated English version of the 4DSQ was translated by another translator into Russian without mutual consultation. The consensus version was created based on two translated versions. After that the back translation was performed to Dutch, some changes were implemented to the consensus Russian version and the second target version was developed based on these results. The second target version was sent to an appropriate group of reviewers. Based on their comments, the second target version was updated. After wards this version was tested in patients during cognitive interview. The study protocol was approved by the Independent Interdisciplinary Ethics Committee on Ethical Review for Clinical Studies, and in compliance with the Helsinki Declaration and ICH-GCP guidelines and local regulations. Enrolled patients provided written informed consent. RESULTS: After the process of forward and backward translation, consultant and developer's comments, clinicians and cognitive review the final version of Russian 4DSQ was developed for assessment of distress, depression, anxiety and somatization. CONCLUSION: The Russian 4DSQ as a result of translation procedures and cognitive interviews linguistically corresponds to the original Dutch 4DSQ and could be assessed in psychometric validation for the further using in general practice. PMID- 26653769 TI - Physical Principles in the Self-Assembly of a Simple Spherical Virus. AB - Viruses are unique among living organisms insofar as they can be reconstituted "from scratch", that is, synthesized from purified components. In the simplest cases, their "parts list" numbers only two: a single molecule of nucleic acid and many (but a very special number, i.e., multiples of 60) copies of a single protein. Indeed, the smallest viral genomes include essentially only two genes, on the order of a thousand times fewer than the next-simplest organisms like bacteria and yeast. For these reasons, it is possible and even fruitful to take a reductionist approach to viruses and to understand how they work in terms of fundamental physical principles. In this Account, we discuss our recent physical chemistry approach to studying the self-assembly of a particular spherical virus (cowpea chlorotic mottle virus) whose reconstitution from RNA and capsid protein has long served as a model for virus assembly. While previous studies have clarified the roles of certain physical (electrostatic, hydrophobic, steric) interactions in the stability and structure of the final virus, it has been difficult to probe these interactions during assembly because of the inherently short lifetimes of the intermediate states. We feature the role of pH in tuning the magnitude of the interactions among capsid proteins during assembly: in particular, by making the interactions between proteins sufficiently weak, we are able to stall the assembly process and interrogate the structure and composition of particular on-pathway intermediates. Further, we find that the strength of the lateral attractions between RNA-bound proteins plays a key role in addressing several outstanding questions about assembly: What determines the pathway or pathways of assembly? What is the importance of kinetic traps and hysteresis? How do viruses copackage multiple short (compared with wild-type) RNAs or single long RNAs? What determines the relative packaging efficiencies of different RNAs when they are forced to compete for an insufficient supply of protein? And what is the limit on the length of RNA that can be packaged by CCMV capsid protein? PMID- 26653770 TI - Cancer immunotherapy targeting neoantigens. AB - Neoantigens are antigens encoded by tumor-specific mutated genes. Studies in the past few years have suggested a key role for neoantigens in cancer immunotherapy. Here we review the discoveries of neoantigens in the past two decades and the current advances in neoantigen identification. We also discuss the potential benefits and obstacles to the development of effective cancer immunotherapies targeting neoantigens. PMID- 26653772 TI - The role of muscular trauma in the development of heterotopic ossification after hip surgery: An animal-model study in rats. AB - BACKGROUND: Heterotopic ossification (HO), the formation of bone in soft tissues, is a frequent complication after surgery of the hip and the pelvis. Although the pathophysiological entities responsible for the formation of HO remain largely unclear, muscle trauma is alleged to play a central role in the pathogenic mechanisms underlying HO. However, for this observation, made by many surgeons for decades, no objective evidence has been provided yet. METHODS: Fifty male Wistar rats were subjected to surgery of the right hip. The femoral canal was reamed in three steps up to 2mm. Animals formed 2 groups: in group 1 (25 animals) every effort was taken not to injure the muscles. In contrast, in the rats of group 2 (25 animals), an additional muscle lesion was created. Twelve weeks after surgery, the amount of heterotopic bone was assessed using micro-computed tomography, and classified using a modified Brooker classification system. A chi square test was used to assess the statistical hypothesis comparing both groups. RESULTS: A significant higher amount of heterotopic bone was observed in animals that underwent additional muscular trauma. CONCLUSION: According to our data, muscle trauma seems to play an important role in the development of HO after hip surgery. Hence, during surgery, particular care not to injure the surrounding muscular tissue should be taken. PMID- 26653773 TI - Regarding the predictors of mortality for complex fractures of the pelvic ring in the elderly. PMID- 26653774 TI - Asymmetric alpha,gamma-Regioselective [3 + 3] Formal Cycloadditions of alpha,beta Unsaturated Aldehydes via Cascade Dienamine-Dienamine Catalysis. AB - Asymmetric alpha,gamma-regioselective [3 + 3] formal cycloadditions of alpha,beta unsaturated aldehydes and 2-nitroallylic acetates have been developed for the first time. These reactions proceeded through a domino Michael addition-Michael addition sequence via an unusual cascade dienamine-dienamine catalysis of a chiral secondary amine, and multifunctional cyclohexene derivatives were generally constructed in moderate yields with excellent stereoselectivity after simple treatment with K2CO3. PMID- 26653775 TI - Stroke Education in Canadian Emergency Medicine Residency Programs. AB - OBJECTIVES: Stroke and transient ischemic attack (TIA) are common disorders treated by Canadian emergency physicians. The diagnosis and management of these conditions is time-sensitive and complex, requiring that emergency physicians have adequate training. This study sought to determine the extent of stroke and TIA training in Canadian emergency medicine residency programs. METHODS: A two page survey was emailed to directors of all English-speaking emergency medicine residency programs in Canada. This included both the Fellow of the Royal College of Physicians of Canada (FRCPC) and the College of Family Physicians Enhanced Training [CCFP(EM)] residency programs. The number of mandatory and elective rotations, lectures, and examinations relevant to stroke and TIA were assessed. RESULTS: Nine FRCPC programs responded (of 11; RR=82%) and 11 CCFP(EM) programs responded (of 18; RR=61%), representing 20 of 29 programs in Canada (RR: 20/29=69%). Mandatory general neurology (3/9) and stroke neurology (2/9) rotations were offered in a minority of FRCPC programs and not at all in CCFP(EM) programs (0/11). Neuroradiology rotations were mandatory in 1/9 FRCPC programs and no CCFP(EM) programs (0/11). Acute ischemic stroke was allocated 3 hours of lecture time per year in all residency programs, regardless of route of training. Despite the fact that 100% of respondents train residents in facilities that administer thrombolysis for stroke, only 1/11 (9%) CCFP(EM) programs and 0/9 FRCPC programs have residents act as stroke team leaders. CONCLUSIONS: Formal training in stroke and TIA is limited in Canadian emergency medicine residency programs. Enhanced training opportunities should be developed as this disease is sudden, life-threatening, and can have disabling or fatal consequences, and therapeutic options are time sensitive. PMID- 26653776 TI - The steps to recovery program: Evaluation of a group-based intervention for older individuals receiving mental health services. AB - OBJECTIVE: This study reports on the evaluation of a group-based intervention for older individuals receiving mental health services. METHOD: A prospective cohort repeated-measure design was used for 48 participants who accessed secondary care mental health services for older people. Changes on the Recovery Assessment Scale (RAS), the Warwick-Edinburgh Mental Well-Being Scale (WEMWEBS), and a postevaluation questionnaire were analyzed. RESULTS: A paired sample t test examined changes in participant's scores on the WEMWEBS and RAS from baseline to postintervention. Participants qualitatively evaluated the Steps to Recovery group as having a positive effect on their recovery. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Following involvement in this group intervention, participants reported improved mental well-being and recovery from mental health difficulty. These results suggest that the program has the potential to provide an accessible framework for developing recovery-orientated approaches in mental health care that can be delivered by care staff at all levels. PMID- 26653777 TI - Sharing Experience Learned Firsthand (SELF): Self-disclosure of lived experience in mental health services and supports. AB - OBJECTIVE: Self-disclosure of lived experiences with mental health challenges is a central method for challenging stigma and promoting empowerment. Individuals are encouraged to share their stories yet little is known about the process of self-disclosure in this context. This article presents the results of an investigation of the role of lived experience in professional training and work. METHOD: A mixed methods design was used in a sequential exploratory manner. A purposive sample of 35 individuals participated in interviews and focus groups. Based on their reports and a literature review, an anonymous online survey (N = 117) was developed and distributed through consumer networks and the SAMHSA funded Consumer Technical Assistance Centers. The qualitative data was subjected to thematic analysis. The survey data were statistically analyzed for differences in levels of disclosure and factors regarding risks, benefits, and guidance regarding self-disclosure. RESULTS: Participants valued their lived experience as a resource through which they could assist others and service delivery. Lived experience was foundational to building relationships with individuals in recovery. Disclosure was dependent on social context and perceptions of safety. Individuals expressed concerns regarding exclusion and discrimination. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Project participants maintained that their lived experience was their greatest strengths in helping others. At the same time, decisions about disclosure were made in complex social contexts featuring power differentials. Sharing lived experience is essential to peer delivered services and further exploration is needed to support service development. (PsycINFO Database Record PMID- 26653778 TI - Diabetic levels of glucose increase cellular reducing equivalents but reduce survival in three models of 661W photoreceptor-like cell injury. AB - BACKGROUND: The effect of excess glucose on retinal cellular health remains controversial, and cellular reducing equivalents, as indicators of cellular energy production, are widely used as substitute indicators of retinal cellular health. These investigations hypothesised that excess energy substrate availability, as occurs in the diabetic retina, increases the susceptibility of retinal neurons to injury in the presence of increased cellular reducing equivalents. METHODS: The response of 661W cells to phototoxicity, oxidative stress induced by H2O2 and apoptosis induction by staurosporine was characterised in the presence of 5mM glucose and B27 defined media without insulin. Cellular insult was produced by phototoxicity, H2O2 and the apoptosis induction agent staurosporine. The effect of physiologically relevant alterations in environmental glucose on cellular reducing equivalents was assessed by MTT dye reduction and NAD(P)H assays, and cell survival was assessed via caspase 3/7 activation and Annexin V/PI flow cytometry. RESULTS: 661W photoreceptor-like cells underwent dose dependent cell death primarily by apoptosis in response to phototoxic insult, H2O2, and staurosporine by all measures of cellular viability. Exposure of cells to 25mM glucose (diabetic-type conditions) increased cell death in response to all insults as measured by caspase 3/7 activation and Annexin V/PI flow cytometry. Cellular reducing equivalents were nonetheless increased in all models of injury in the presence of excess glucose. The mechanism of this increase was partly due to increased NADPH but not NADH levels in the presence of 25mM glucose. CONCLUSIONS: Acute exposure to 25mM glucose decreased the resilience of 661W photoreceptor-like cells to a range of cellular stressors whilst maintaining or increasing cellular reducing equivalents, partly be increasing NADPH levels. This shows that in 661W cells, diabetic levels of glucose decrease cellular resilience to injury. The decoupling of cellular reducing equivalents levels from cell survival has important implications when investigating the mechanisms of neuronal damage in diabetic retinal neuropathy. PMID- 26653779 TI - A survey of knowledge-to-action pathways of aging policies and programs in the Arab region: the role of institutional arrangements. AB - BACKGROUND: While population aging challenges Arab governments to ensure well being in old age, knowledge translation is gaining support worldwide in evidence based policymaking and service provision. This study examines the status of existing knowledge translation efforts of aging-related research in Arab countries and evaluates the additional role that institutional arrangements (such as ministry departments, national committees, etc.) play in the relationship between knowledge creation and social and health policies and programs. METHODS: Data were triangulated from two regional surveys and a supplementary desk review of academic, civil society, ministry, and UN documents. Using a set of indicators, standardized summative indices (out of 100) were generated for five constructs, namely knowledge creation, institutional arrangements, knowledge translation, and health and social policies and programs. Correlations were assessed using Spearman's rank correlation (r s), and bootstrap multiple linear regression models were used. RESULTS: Arab countries scored highest on the institutional arrangements index (median = 69.5), followed by the knowledge creation index (median = 45.9), and lowest on the knowledge translation index (median = 30.2). Both institutional arrangements and knowledge creation significantly correlated with social and health policies and programs. However, when adjusted for knowledge translation, only institutional arrangements retained a significant association with both outcomes (r s = 0.63, p value =0.009 and r s = 0.69, p value =0.01, respectively). Adjusting for institutional arrangements and knowledge creation, the association of knowledge translation with social and health policies and programs was attenuated and non-significant (r s = 0.08, p value =0.671 and r s = 0.12, p value =0.634, respectively). CONCLUSIONS: There are two key messages from this study. Firstly, institutional arrangements play a central role in aging social and health policy and program development in the Arab region. Secondly, knowledge translation paradigms in Arab countries may be deficient in factors pertinent for promoting evidence-based decision-making and policy-relevant research. These findings call for the need of strengthening institutional arrangements on aging and for promoting knowledge production that meets policy-relevant priorities. PMID- 26653789 TI - Cutting-edge mass spectrometry methods for the multi-level structural characterization of antibody-drug conjugates. AB - Antibody drug conjugates (ADCs) are highly cytotoxic drugs covalently attached via conditionally stable linkers to monoclonal antibodies (mAbs) and are among the most promising next-generation empowered biologics for cancer treatment. ADCs are more complex than naked mAbs, as the heterogeneity of the conjugates adds to the inherent microvariability of the biomolecules. The development and optimization of ADCs rely on improving their analytical and bioanalytical characterization by assessing several critical quality attributes, namely the distribution and position of the drug, the amount of naked antibody, the average drug to antibody ratio, and the residual drug-linker and related product proportions. Here brentuximab vedotin (Adcetris) and trastuzumab emtansine (Kadcyla), the first and gold-standard hinge-cysteine and lysine drug conjugates, respectively, were chosen to develop new mass spectrometry (MS) methods and to improve multiple-level structural assessment protocols. PMID- 26653791 TI - Caveolae: One Function or Many? AB - Caveolae are small, bulb-shaped plasma membrane invaginations. Mutations that ablate caveolae lead to diverse phenotypes in mice and humans, making it challenging to uncover their molecular mechanisms. Caveolae have been described to function in endocytosis and transcytosis (a specialized form of endocytosis) and in maintaining membrane lipid composition, as well as acting as signaling platforms. New data also support a model in which the central function of caveolae could be related to the protection of cells from mechanical stress within the plasma membrane. We present evidence for these diverse roles and consider in vitro and in vivo experiments confirming a mechanoprotective role. We conclude by highlighting current gaps in our knowledge of how mechanical signals may be transduced by caveolae. PMID- 26653792 TI - Spirorchiid Infection in Olive Ridley Turtle, Lepidochelys olivacea (Eschscholtz, 1829) (Testudines: Cheloniidae), from Brazil. AB - The Olive Ridley turtle, Lepidochelys olivacea (Eschscholtz, 1829) (Testudines: Cheloniidae), is 1 of the 5 species of sea turtle found along the coast of Brazil. Little is known regarding infection by species of the family Spirorchiidae in the host, as only 1 report exists. This case report describes granulomas in different tissues associated to type 1 and 3 spirorchiid eggs in 5 L. olivacea from the Brazilian coast. The occurrence of the eggs was considered an incidental finding and may have contributed to the debility and death of the hosts. This is the second report of tissue lesions due to spirorchids eggs in this host and the first occurrence in Olive Ridley turtle from the Brazilian coast. PMID- 26653790 TI - Ferroptosis: Death by Lipid Peroxidation. AB - Ferroptosis is a regulated form of cell death driven by loss of activity of the lipid repair enzyme glutathione peroxidase 4 (GPX4) and subsequent accumulation of lipid-based reactive oxygen species (ROS), particularly lipid hydroperoxides. This form of iron-dependent cell death is genetically, biochemically, and morphologically distinct from other cell death modalities, including apoptosis, unregulated necrosis, and necroptosis. Ferroptosis is regulated by specific pathways and is involved in diverse biological contexts. Here we summarize the discovery of ferroptosis, the mechanism of ferroptosis regulation, and its increasingly appreciated relevance to both normal and pathological physiology. PMID- 26653793 TI - High dose sapropterin dihydrochloride therapy improves monoamine neurotransmitter turnover in murine phenylketonuria (PKU). AB - Central nervous system (CNS) deficiencies of the monoamine neurotransmitters, dopamine and serotonin, have been implicated in the pathophysiology of neuropsychiatric dysfunction in phenylketonuria (PKU). Increased brain phenylalanine concentration likely competitively inhibits the activities of tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH), the rate limiting steps in dopamine and serotonin synthesis respectively. Tetrahydrobiopterin (BH4) is a required cofactor for TH and TPH activity. Our hypothesis was that treatment of hyperphenylalaninemic Pah(enu2/enu2) mice, a model of human PKU, with sapropterin dihydrochloride, a synthetic form of BH4, would stimulate TH and TPH activities leading to improved dopamine and serotonin synthesis despite persistently elevated brain phenylalanine. Sapropterin (20, 40, or 100mg/kg body weight in 1% ascorbic acid) was administered daily for 4 days by oral gavage to Pah(enu2/enu2) mice followed by measurement of brain biopterin, phenylalanine, tyrosine, tryptophan and monoamine neurotransmitter content. A significant increase in brain biopterin content was detected only in mice that had received the highest sapropterin dose, 100mg/kg. Blood and brain phenylalanine concentrations were unchanged by sapropterin therapy. Sapropterin therapy also did not alter the absolute amounts of dopamine and serotonin in brain but was associated with increased homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA), dopamine and serotonin metabolites respectively, in both wild type and Pah(enu2/enu2) mice. Oral sapropterin therapy likely does not directly affect central nervous system monoamine synthesis in either wild type or hyperphenylalaninemic mice but may stimulate synaptic neurotransmitter release and subsequent metabolism. PMID- 26653794 TI - A founder mutation in ADAMTSL4 causes early-onset bilateral ectopia lentis among Jews of Bukharian origin. AB - The term isolated ectopia lentis (EL; subluxation or dislocation of the human crystalline lens) is applied to patients with EL, without skeletal features and in the absence of aortic root dilatation. To date, the only gene shown to cause autosomal-recessive isolated EL is ADAMTSL4. Here we report a novel founder mutation in ADAMTSL4 gene in children of Bukharian Jewish origin presenting with early-onset bilateral EL. A carrier frequency of 1:48 was determined among unrelated healthy Bukharian Jews. Given the complications associated with disease and the allele frequency, a population screening for individuals of this ancestry is warranted in order to allow prenatal, pre-implantation or early postnatal diagnosis. PMID- 26653795 TI - Plant Sex Chromosomes. AB - Although individuals in most flowering plant species, and in many haploid plants, have both sex functions, dioecious species-in which individuals have either male or female functions only-are scattered across many taxonomic groups, and many species have genetic sex determination. Among these, some have visibly heteromorphic sex chromosomes, and molecular genetic studies are starting to uncover sex-linked markers in others, showing that they too have fully sex-linked regions that are either too small or are located in chromosomes that are too small to be cytologically detectable from lack of pairing, lack of visible crossovers, or accumulation of heterochromatin. Detailed study is revealing that, like animal sex chromosomes, plant sex-linked regions show evidence for accumulation of repetitive sequences and genetic degeneration. Estimating when recombination stopped confirms the view that many plants have young sex-linked regions, making plants of great interest for studying the timescale of these changes. PMID- 26653796 TI - A review on biological sources, chemistry and pharmacological activities of pinostrobin. AB - Pinostrobin, a dietary bioflavonoid discovered more than 6 decades ago in the heart-wood of pine (Pinus strobus), has depicted many pharmacological activities including anti-viral, anti-oxidant, anti-leukaemic, anti-inflammatory and anti aromatase activities. It is an inhibitor of sodium channel and Ca(2+) signalling pathways and also inhibits intestinal smooth muscle contractions. In spite of the fact that pinostrobin has an application as functional foods, till-to-date no comprehensive review on pinostrobin has been carried out. Hence, the present review deals with the biological sources, chemistry and pharmacological activities of pinostrobin. PMID- 26653798 TI - What Is the CT Dose Check Standard, and Why Do CT Scanners Need to Be in Compliance? PMID- 26653797 TI - ACR Appropriateness Criteria Myelopathy. AB - Patients presenting with myelopathic symptoms may have a number of causative intradural and extradural etiologies, including disc degenerative diseases, spinal masses, infectious or inflammatory processes, vascular compromise, and vertebral fracture. Patients may present acutely or insidiously and may progress toward long-term paralysis if not treated promptly and effectively. Noncontrast CT is the most appropriate first examination in acute trauma cases to diagnose vertebral fracture as the cause of acute myelopathy. In most nontraumatic cases, MRI is the modality of choice to evaluate the location, severity, and causative etiology of spinal cord myelopathy, and predicts which patients may benefit from surgery. Myelopathy from spinal stenosis and spinal osteoarthritis is best confirmed without MRI intravenous contrast. Many other myelopathic conditions are more easily visualized after contrast administration. Imaging performed should be limited to the appropriate spinal levels, based on history, physical examination, and clinical judgment. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every three years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals, and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances in which evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. PMID- 26653799 TI - Side-Chain-Induced Rigid Backbone Organization of Polymer Semiconductors through Semifluoroalkyl Side Chains. AB - While high-mobility p-type conjugated polymers have been widely reported, high mobility n-type conjugated polymers are still rare. In the present work, we designed semifluorinated alkyl side chains and introduced them into naphthalene diimide-based polymers (PNDIF-T2 and PNDIF-TVT). We found that the strong self organization of these side chains induced a high degree of order in the attached polymer backbones by forming a superstructure composed of "backbone crystals" and "side-chain crystals". This phenomenon was shown to greatly enhance the ordering along the backbone direction, and the resulting polymers thus exhibited unipolar n-channel transport in field-effect transistors with remarkably high electron mobility values of up to 6.50 cm(2) V(-1) s(-1) and with a high on-off current ratio of 10(5). PMID- 26653801 TI - [The occupational hazards of indiumand its compounds]. PMID- 26653800 TI - IL-10 mediates plasmacytosis-associated immunodeficiency by inhibiting complement mediated neutrophil migration. AB - BACKGROUND: Plasmacytosis (ie, an expansion of plasma cell populations to much greater than the homeostatic level) occurs in the context of various immune disorders and plasma cell neoplasia. This condition is often associated with immunodeficiency that causes increased susceptibility to severe infections. Yet a causative link between plasmacytosis and immunodeficiency has not been established. OBJECTIVE: Because recent studies have identified plasma cells as a relevant source of the immunosuppressive cytokine IL-10, we sought to investigate the role of IL-10 during conditions of polyclonal and neoplastic plasmacytosis for the regulation of immunity and its effect on inflammation and immunodeficiency. METHODS: We used flow cytometry, IL-10 reporter (Vert-X) and B cell-specific IL-10 knockout mice, migration assays, and antibody-mediated IL-10 receptor blockade to study plasmacytosis-associated IL-10 expression and its effect on inflammation and Streptococcus pneumoniae infection in mice. ELISA was used to quantify IL-10 levels in patients with myeloma. RESULTS: IL-10 production was a common feature of normal and neoplastic plasma cells in mice, and IL-10 levels increased with myeloma progression in patients. IL-10 directly inhibited neutrophil migration toward the anaphylatoxin C5a and suppressed neutrophil dependent inflammation in a murine model of autoimmune disease. MOPC.315.BM murine myeloma leads to an increased incidence of bacterial infection in the airways, which was reversed after IL-10 receptor blockade. CONCLUSION: We provide evidence that plasmacytosis-associated overexpression of IL-10 inhibits neutrophil migration and neutrophil-mediated inflammation but also promotes immunodeficiency. PMID- 26653802 TI - [Effects of indium on micronucleus formation in human peripheral blood lymphocytes]. AB - OBJECTIVE: To investigate the cytotoxicity of indium chloride (InCl3) and its effects on micro-nucleus formation in primary human lymphocytes cultured in vitro. METHODS: The CCK-8 assay was used to evaluate the cytotoxicity of 24 h exposure to different concentrations of InCl3(4, 40, 80, 200, 500, and 1 000 umol/L) in lymphocytes cultured in vitro. The cytokinesis-block method was used to determine the micronucleus level in lymphocytes exposed to different concentrations of InCl3and the effects of anti-oxidant vitamin C on micronucleus frequency. RESULTS: Lymphocytes exposed to InCl3of no less than 500 umol/L had significantly lower survival rates than those in the control group (P < 0.05). Lymphocytes exposed to 80 umol/L InCl3had a significantly higher micronucleus frequency than those in the control group (P < 0.05). However, there was no further increase in micronucleus frequency of lymphocytes exposed to 200 umol/L InCl3. Lymphocytes cultured in whole blood and exposed to 500 or 1000 umol/L InCl3had a significantly increased micronucleus frequency than those in the control group (P < 0.001). The increase in micronucleus frequency of lymphocytes induced by indium could be partially antagonized by 20 or 100 umol/L vitamin C. CONCLUSION: InCl3can induce an increase in micronucleus frequency of primary human lymphocytes cultured in vitro, which might be associated with DNA damage induced by oxidative stress. PMID- 26653803 TI - [Effects of indium exposure on relative content of mitochondrial ND1 gene in human peripheral blood lymphocytes in vitro]. AB - OBJECTIVE: To study the effects of indium exposure on the relative content of mitochondrial ND1 gene in lymphocytes. METHODS: Venous blood was obtained from 14 healthy workers and anticoagulated with heparin. Blood lymphocytes were separated and divided into three tube cultures. For two tubes in the exposed group, indium chloride was added to final concentrations of 0.2 mmol/L and 0.8 mmol/L, respectively. For one tube in the control group, an equal volume of normal saline solution was added. After incubation for 72 h, the relative content of mitochondrial gene in each group was determined using quantitative real-time PCR. RESULTS: Lymphocytes exposed to 0.8 mmol/L indium chloride had a significantly higher relative content of mitochondrial gene than those exposed to 0.2 mmol/L indium chloride and those in the control group (P < 0.05, P < 0.05). CONCLUSION: Lymphocytes exposed to a high concentration of indium and its compounds have an elevated relative content of mitochondrial ND1 gene, indicating increased oxidative DNA damage induced by exposure to a high concentration of indium and its compounds. PMID- 26653804 TI - [Effects of indium chloride on proliferation of human lung epithelial cells and its mechanism]. AB - OBJECTIVE: To investigate the effects of different concentrations of indium chloride (InCl3) on the proliferation of human lung epithelial (Beas-2B) cells and its potential mechanism. METHODS: Beas-2B cells were exposed to different concentrations of InCl3 (0.3, 1.0, 3.0, 10.0, 30.0, 90.0, 270.0, and 810.0 umol/L) for 24, 48, and 72 h, respectively. The effects of InCl3 on cell proliferation were determined by the CCK-8 assay. The effects of InCl3 on apoptosis were evaluated using annexin V-PI staining followed by flow cytometry. The level of intracellular reactive oxygen species (ROS) in Beas-2B cells after exposure to InCl3 was determined using 2', 7'-dichlorofluorescein diacetate labeling followed by flow cytometry. RESULTS: Compared with the control group, InCl3 at a relatively low concentration (0.3~3.0 umol/L) significantly promoted cell proliferation (P < 0.05), while InCl3 at a relatively high concentration (30.0~80.0 umol/L) significantly inhibited cell proliferation after 72 h (P < 0.05). InCl3 at a concentration of 0.3 umol/L failed to induce apoptosis within 72 h; however, InCl3 at a concentration of 30.0 or 810.0 umol/L induced substantial early apoptosis after 72 h. Compared with the control group, cells exposed to 0.3 umol/L InCl3 showed a slight decrease in the level of intracellular ROS within 72 h, while cells exposed to 30.0 or 810.0 umol/L InCl3 showed a significant increase in the level of intracellular ROS after 72 h (P < 0.05). CONCLUSION: At a low concentration, InCl3 stimulates cell proliferation by reducing intracellular ROS. However, at a high concentration, InCl3 inhibits cell viability by elevating intracellular ROS and inducing apoptosis. PMID- 26653805 TI - [Risk analysis and assessment of occupational hazard fromindiumand its compounds in manufacture of liquid crystal display panel]. AB - OBJECTIVE: To understand the exposed positions and levels of indium and its compounds in manufacture of liquid crystal displays, and to evaluate the degree of occupational hazard from indium and its compounds. METHODS: On-site investigation of occupational health, occupational hazard monitoring, and occupational health examination were used to evaluate the degree of occupational hazard from indium and its compounds in three manufacturers of liquid crystal display panel in Shenzhen, Guangdong, China. RESULTS: The time-weighted average (TWA) and short-term exposure limit (STEL) concentrations of indium and its compounds to which sputtering machine operating positions were exposed were less than 0.002~0.004 mg/m3 and 0.006~0.007 mg/m3, respectively, both of which complied with the National Hygienic Standard (PC-TWA = 0.1 mg/m3; PC-STEL = 0.3 mg/m3); the TWA and STEL concentrations of indium and its compounds to which grinding positions were exposed were 0.114~2.98 mg/m3 and 0.31~10.02 mg/m3, respectively, both of which exceeded the National Hygienic Standard with the highest concentration 33-fold higher than the standard. No significant health damages were found in exposed workers according to the results of occupational health examination. CONCLUSION: The grinding positions are the key to the control of occupational hazard from indium and its compounds in manufacture of liquid crystal display panel. The workers should be equipped with the anti-particulate full-face respirator, which is an effective way to prevent occupational hazard from indium and its compounds. PMID- 26653806 TI - [Research of lambda-cyhalothrin affect synaptic development in hippocampus by interfering with estrogen action]. AB - OBJECTIVE: To explore the effects of lambda-cyhalothrin on hippocampus by interfering with estrogen. METHODS: The healthy female ICR mice of postnatal 28 days were random divided into 12 groups, 4 of those were sham-operation include control, lambda-cyhalothrin (LCT, 3.0 ug/g), Letrozole (Let, 1.0 ug/g), and LCT (3.0 ug/g)+Let (1.0 ug/g); and the last 8 were ovariectomized include OVX, Estradiol (E2, 10.0 ug/g), LCT, Let, E2+LCT, E2+Let, LCT+Let, E2+LCT+Let. 10 mice in every group received drugs by intraperitoneal injection for 2 days. Then half of every group initiate the ethological test (open field test and Morris water maze) 24 h later. The last half animals were sacrificed to made frozen section for immunofluorescent assay of postsynaptic density protein 95 (PSD95). RESULTS: In ethological test, campared with Sham, OVX can lengthen incubation period in the first grid and to get on the platform (P < 0.05); campared with OVX, OVX+E2 can increase the total numbers of through grid and shorten the incubation period to get on the platform (P < 0.05); campared with OVX+E2, OVX+E2+LCT can reduce the number of grid and standing, lengthen incubation period to the platform (P < 0.05); campared with Sham, Sham+LCT can lengthen incubation period to the platform of Sham mice (P < 0.05), but campared with OVX, OVX+LCT can shoten incubation period in the first grid and to get on the platform in OVX mice (P < 0.05); campared with Sham+Let, Sham+LCT+Let can lengthen incubation period in the first grid, reduce the the number of grid and standing (P < 0.05). In the Immunohistochemical fluorescence experiment we find that, campared with Sham, OVX can reduce the expression of PSD95 in CA1,CA3 and DG (P < 0.05); however campared with OVX, E2 or LCT can both inhibit the effect of OVX (P < 0.05); campared with Sham, Sham+LCT can reduce the expression of PSD95, the same result when OVX+E2+LCT campared with OVX+E2 (P < 0.05); campared with OVX+E2+Let, OVX+E2+LCT+Let can reduce the expression of PSD95 in CA3 (P < 0.05); campared with OVX+Let, OVX+LCT+Let can increase the expression of PSD95 in DG (P < 0.05). CONCLUSIONS: When few estrogen exist in the body, LCT can show estrogen-like action to promote hippocampal synaptic development; but when circulating estrogen exist, LCT can inhibit synaptic development by interfering estrogen. PMID- 26653807 TI - [An analysis of occupational hazard in manufacturing industry in Guangzhou, China, in 2013]. AB - OBJECTIVE: To provide data for the occupational health supervision by analyzing the occupational health status in manufacturing industry in Guangzhou, China. METHODS: The occupational health investigation was performed in 280 enterprises randomly selected from 8 industries based on industry stratification. According to the occupational health standards, 198 out of the 280 enterprises were supervised and monitored. Sample testing was performed in 3~5 workplaces where workers were exposed to the highest concentration/intensity of occupational hazard for the longest time. Comparative analyses of the overproof rates of hazard were performed among enterprises, workplaces, and testing items from different industries. RESULTS: The concentrations of occupational hazard in 42.93% (85/198) of enterprises and 22.96% (200/871) of workplaces were above the limit concentration. The most severe hazards were the noises in shipbuilding and wooden furniture industries and the welding fumes in shipbuilding industry. Less than 30% of enterprises were able to provide occupational health examination and periodic test reports of occupational hazard in workplaces. The rate of the workers with abnormal occupational health examination results and the need for reexamination reached 6.63% (832/12 549), and they were mostly from shipbuilding, wooden furniture, and chemical industries. CONCLUSION: The occupational health supervision should be strengthened in enterprises, and hazard from noises and dusts should be selectively controlled or reduced. The publication of relevant data and information of occupational health in enterprises should be promoted to enhance social supervision. PMID- 26653808 TI - [Comparative analysis of serum proteomic profiles between patients with silicosis and chronic bronchitis]. AB - OBJECTIVE: To analyze the differences in serum proteomic profiles between patients with silicosis and chronic bronchitis and to investigate the pathogenesis, clinical diagnosis, and treatment of these two disease. METHODS: Serum samples from patients with stage I silicosis and chronic bronchitis were collected. Two-dimensional gel electrophoresis was performed and protein plots with expression differences higher than 2-fold were identified and further analyzed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. RESULTS: Compared with the silicosis group, the chronic bronchitis group had 11 up-regulated proteins and 23 down-regulated proteins. The chronic bronchitis group had high expression of proteins such as interferon beta precursor, apolipoprotein precursor, and transforming growth factor beta1 precursor. The silicosis group had high expression of proteins such as interleukin-6, granzyme A, cathepsin G, and glycoprotein precursor. CONCLUSION: The differentially expressed proteins are mainly involved in the activity of serine enzymes, cytotoxicity, inflammation response, and apolipoprotein transfer and play different roles in silicosis and chronic bronchitis. PMID- 26653809 TI - [Psychiatric symptomevaluation and consultation in occupational medicine clinics]. PMID- 26653810 TI - [Analysis of cytochrome P450 2E1 RsaI/PstI and DraI polymorphisms in workers exposed to benzene]. AB - OBJECTIVE: To investigate the cytochrome P450 2E1 (CYP2E1) RsaI/PstI and DraI polymorphisms in workers exposed to benzene. METHODS: A cross-sectional survey was carried out. A total of 71 workers exposed to benzene were included in observation group and the same number of people without occupational benzene exposure were included in control group. Blood samples from the two groups were collected and genotyping for CYP2E1 RsaI/PstI and DraI were conducted using the polymerase chain reaction-restriction fragment length polymorphism. RESULTS: There were no significant differences in CYP2E1 DraI genotype and allele distributions between the observation group and the control group (chi2 = 2.374, P > 0.05; chi2 = 2.113, P > 0.05). Significant differences in CYP2E1 RsaI/PstI genotype and allele distributions between the two groups were observed (chi2 = 9.129, P < 0.01; chi2 = 6.028, P < 0.05). CONCLUSION: Mutations at CYP2E1 RsaI/PstI can enhance the expression of CYP2E1 and this suggests individuals with the mutated gene have increased susceptibility to chronic benzene poisoning. PMID- 26653811 TI - [Changes in serum protease and cytokine in patients with silicosis, tuberculosis, and lung cancer]. AB - OBJECTIVE: To investigate the changes in serum protease and cytokine in patients with silicosis, tuberculosis, and lung cancer. METHODS: Serum samples of patients with silicosis, tuberculosis, and lung cancer were collected. The variation trends of the expression of granzyme A, cathepsin G, apolipoprotein A, and interferon-beta (IFN-beta) were analyzed using enzyme-linked immunosorbent assay. RESULTS: The concentration of apolipoprotein A of the silicosis group was 200 ug/ml, significantly higher than those of the tuberculosis and lung cancer groups (P < 0.05), and the lung cancer group had a significantly higher concentration of apolipoprotein A compared with the tuberculosis group (P < 0.05). The silicosis group had significantly higher expression of cathepsin G compared with the tuberculosis and lung cancer groups (P < 0.05), and the tuberculosis group and lung cancer group showed no significant difference in the concentration of cathepsin G (P > 0.05). The tuberculosis group had a significantly higher concentration of granzyme A than the silicosis and lung cancer groups (P < 0.05), and the silicosis group and lung cancer group had similar protein concentration trends (P > 0.05). The tuberculosis group and lung cancer group had significantly higher concentration of IFN-beta compared with the silicosis group (P < 0.05), and the tuberculosis group and lung cancer group showed no significant difference in IFN-beta concentration (P > 0.05). CONCLUSION: This study may offer diagnostic markers for the clinical diagnosis of silicosis, tuberculosis, and lung cancer, and could provide a basis for the research, as well as potential molecular targets for the diagnosis and treatment of these diseases. PMID- 26653812 TI - [A dynamic study of sentinel surveillance for occupational hazard in typical industrial enterprises in Guangzhou, China, from 2012 to 2014]. AB - OBJECTIVE: To perform a sampling survey of occupational hazard in typical industrial enterprises in Guangzhou, China, by means of sentinel surveillance, to understand the classification, distribution, and concentration/intensity of occupational hazard as well as the characteristics and development of occupational health management in Guangzhou, and to provide a scientific basis for occupational health supervision. METHODS: Fifteen enterprises in information technology (IT), shipbuilding, chemical, leather and footwear, and auto repair industries were enrolled as subjects. Dynamic surveillance for occupational hazard and occupational health management was performed in workplaces of those enterprises. RESULTS: The overall overproof rate of occupational hazard in the 15 sentinel enterprises from 2012 to 2014 was 6.16% (45/731). There was no significant difference in the overproof rate between the three years (P > 0.05). During the three years, enterprises in shipbuilding industry had significant higher overproof rates than those in other industries (P < 0.05). According to the results of occupational health management questionnaire, the overall coincidence rate of survey items was 57.88% (393/679); enterprises in IT industry had significant lower coincidence rates than those in other industries in 2012 and 2014 (47.62%, 29.63%; P < 0.05), while enterprises in leather and footwear industry had significant lower coincidence rates than those in other industries in 2013 (40.63%; P < 0.05). CONCLUSION: The enterprises in shipbuilding industry are the key to the prevention and control of occupational hazard in Guangzhou. To strengthen surveillance for occupational health in workplaces in Guangzhou, it is important to enhance occupation health supervision among small and micro enterprises and develop continuous sentinel surveillance for occupational hazard in key industries. PMID- 26653813 TI - [Antagonistic effect of curcumin on lipid peroxidation of rats poisoned by paraquat]. AB - OBJECTIVE: To explore the pathogenesis of paraquat poisoning and observe the change in lipid peroxidation of rats treated with different doses of curcumin. METHODS: A total of 50 8-week-old male Wistar rats (clean grade) were randomly divided into high-dose curcumin plus conventional treatment group, low-dose curcumin plus conventional treatment group, high-dose curcumin treatment group, poisoned group, and blank control group. Glutathione peroxidase (GSH-Px), catalase (CAT), superoxide dismutase (SOD), and malondialdehyde (MDA) levels in rat serum were measured at 1, 3, 7, 14, and 21 d post paraquat injection. RESULTS: Compared with the blank control group, other groups had significantly higher MDA levels but lower SOD, GSH-PX, and CAT activities. The high-dose, low dose curcumin plus conventional treatment, and high-dose curcumin treatment groups had significantly lower serum lipid peroxidation levels compared with the poisoned group and among them the high-dose curcumin plus conventional treatment group had the most significant improvement. CONCLUSION: Curcumin can significantly decrease serum lipid peroxidation level in rats and inhibit and delay the occurrence and progression of the damage to the body. PMID- 26653814 TI - [Clinical characteristics analysis of occupational chronic benzene poisoning in Weihai city]. PMID- 26653815 TI - [Clinical effect observation of integrated treatment of traditional Chinese medicine andWestern medicine on knee osteoarthritis of fishermen]. PMID- 26653816 TI - [The clinical features of indium-related lung diseases]. AB - OBJECTIVE: To discuss the clinical features of Indium-related lung diseases. METHODS: We searched database of Chinese and Pubmed, Embase, Web of Science to collect research data of indium-related lung diseases from Jan. 1998 to Aprl. 2014. Case reports, exposure histories and lab results were analysed and summarized. RESULTS: 1998 to Mar 2010, ten cases of indium-related lung diseases were published. Seven cases of interstitial pneumonia were reported in Japan, two cases of pulmonary alveolar proteinosis (PAP) were reported in the USA and one case of PAP reported in China. Chest computer tomography (CT) showed diffuse or local ground glass appearance (GGA) in 8 cases, 3 of which also showed centrilobular nodules; Pulmonary function test were normal only in one out of 8 cases. Cholesterol clefts were found in 4 cases of interstitial pneumonia. 3 cases died among 6 cases who were followed-up. CONCLUSIONS: Occupational exposure to indium compounds are contributory to different pulmonary diseases, which are composed of interstitial pneumonia and pulmonary alveolar proteinosis. The relationships between In-C, In-S and these pulmonary diseases are unclear. PMID- 26653817 TI - [Curative effects analysis of using HBOT combined with medicine to treat occupational noise deafness patients from rubber factory workers]. PMID- 26653818 TI - [Diagnosis and identification of occupational diseases in Beijing, China, from 2008 to 2014]. PMID- 26653819 TI - [Determination of indium in whole blood by graphite furnace atomic absorption spectrometry]. AB - OBJECTIVE: To investigate the sensitization effect of different chemical modifiers in the determination of indium in whole blood by graphite furnace atomic absorption spectrometry, and to develop a new method for the determination of indium in whole blood. METHODS: A mixture of 0.3% HNO3 (V/V) + 0.1% Triton X 100 (V/V) was used as a diluent, and a solution of 1 000 ug/ml Pd (NO3)2 + 3 000 ug/ml Mg (NO3)2 was used as modifier. After being diluted five times, the concentration of indium of the blood was directly determined by graphite furnace atomic absorption spectrometry. RESULTS: The detection limit of the method was 0.33 ug/L, the linear range was 0.33~100.00 ug/L, the relative standard deviation was 1.43%~2.65%, and the recovery rate was 98.3%~105.3%. CONCLUSION: The method is simple and fast and has high recovery and precision, and it is suitable for the determination of indium in whole blood. PMID- 26653820 TI - [Determination of indiumin urine by inductively coupled plasma mass spectrometry]. PMID- 26653821 TI - [Determination of indiumand its compounds in workplace air by inductively coupled plasma mass spectrometry]. PMID- 26653822 TI - [Progress in study on toxicity of indiumand its compounds]. PMID- 26653823 TI - [Epidemiological study of occupational exposure to indium compounds]. PMID- 26653824 TI - Analysis and risk assessment of 4(5)-methylimidazole in brown colored foods and beverages. AB - In this study, the 4(5)-methylimidazole (4(5)-MI) levels in various 144 brown coloured foods and beverages were determined. The brown coloured foods and beverages were 62 processed sauces, 40 coffee, 9 caramel syrups, 18 red ginseng juice and 15 Japanese apricot fruit juice. The amount of 4(5)-MI in brewed coffee (1821.3 ng/g) was the highest level among the samples. The 4(5)-MI concentration in processed sauce (47.6 ng/g) was the lowest level among the samples. The levels of 4(5)-MI in various samples were found as follows: 47.6-1748.5 ng/g in processed sauces, 64.1-1821.3 ng/g in commercial coffee, 115.5-491.9 ng/g in caramel syrups, 91.0-854.1 ng/g in red ginseng juice and 137.6-587.4 ng/g in Japanese apricot fruit juice. Based on the 4(5)-MI levels, the estimated daily intake (EDI) and chronic daily intake (CDI) were calculated. EDI and CDI of red ginseng juice was the highest among all samples, and they were 1618.6 and 1256.8 ng/kg bw/day, respectively. PMID- 26653825 TI - LY294002 induces in vitro apoptosis and overexpression of p75NTR in human uterine leiomyosarcoma HTB 114 cells. AB - Uterine leiomyosarcoma is a severe neoplasia resistant to conventional therapies. In previous studies, we have shown that human SK-UT-1 (ATCC HTB114) uterine leiomyosarcoma cell line secretes nerve growth factor (NGF) and expresses its receptors tyrosine kinase A receptor (TrKA) and low affinity nerve growth factor receptor (p75NTR). Furthermore, we have demonstrated that direct chemical inhibition or IgG neutralization of TrKA receptor induce apoptosis through p75NTR. In the present study, HTB114 cells were exposed to the phosphoinositide 3 kinase (PI3K) inhibitor LY294002 with and without beta-NGF: apoptosis, cell cycle, activation of caspase-3 and protein kinase B (AKT) and TrKA/p75NTR phenotypic expression were evaluated. According to the type of exposure, LY294002 not only induced a relevant increase in apoptosis, but also produced a novel and unexpected phenotypic modulation of the NGF receptors with a downregulation of TrKA and an upregulation of p75NTR. This latter increase enhanced HTB114 apoptosis. Our study confirms that the interference on NGF transduction is a promising therapeutical approach in uterine leiomyosarcoma. PMID- 26653826 TI - Matrix Metalloproteinase 2 (MMP-2) Plays a Critical Role in the Softening of Common Carp Muscle during Chilled Storage by Degradation of Type I and V Collagens. AB - Matrix metalloproteinases (MMPs) are proposed to play important roles in the degradation of collagens, thus causing the post-mortem softening of fish muscle, although the specific mechanism remains largely unresolved. Previously, we reported the existence of gelatinase-like proteinases in common carp (Cyprinus carpio) muscle. The primary structures of these proteinases, however, have never been investigated. In the present study, two MMPs with molecular masses of 66 and 65 kDa were purified to homogeneity from common carp muscle by ammonium sulfate fractionation and a series of column chromatographies. Matrix-assisted laser desorption/ionization-tandem time-of-flight mass spectrometry (MALDI-TOF/TOF MS/MS) analysis indicated that they are completely identical to MMP-2 from common carp. During chilled storage of common carp at 4 degrees C, the enzymatic activity of MMP-2 increased to 212% in 12 h while the texture profile increased over the first 2 h and gradually decreased. On the other hand, type V collagen was purified to homogeneity and a specific polyclonal antibody against this protein was prepared. Both type I and V collagens were effectively hydrolyzed by MMP-2 at 30 degrees C and even at 4 degrees C. Furthermore, injection of metalloproteinase proteinase inhibitor EDTA into the blood vessel of live common carp suppressed post-mortem tenderization significantly. All of these results confirmed that MMP-2 is a major proteinase responsible for the degradation of collagens, resulting in the softening of fish muscle during chilled storage. PMID- 26653827 TI - Building Relationships: Opportunities for Collaboration. PMID- 26653828 TI - Privilege. PMID- 26653829 TI - Adjusting ACR Appropriateness Criteria for Novel Radiopharmaceuticals. PMID- 26653830 TI - Authors' Reply. PMID- 26653831 TI - Medicare and Desegregation. PMID- 26653832 TI - Trends in Use of Percutaneous Versus Open Surgical Drainage of Abdominal Abscesses. AB - PURPOSE: To compare recent trends in the use of percutaneous and surgical approaches to treating abdominal abscesses in a large population. METHODS: The nationwide Medicare Physician/Supplier Procedure Summary Master Files for 2001 through 2013 were searched. Current Procedural Terminology-4 codes were selected for the four types of abdominal abscesses that had distinct codes for both open surgical and percutaneous drainage-appendiceal, peritoneal, subphrenic, and liver. Medicare specialty codes were used to determine if the procedures were performed by radiologists or other nonradiologist physicians. Trends in use of the two approaches were compared. RESULTS: In 2001, a total of 14,068 abdominal abscesses were drained percutaneously. This volume increased progressively every year thereafter, reaching 28,486 in 2013 (+102%). Open surgical drainage volume was 8,146 in 2001, decreasing progressively to 6,397 in 2013 (-21%). In 2001, 63% of all abdominal abscesses had been drained percutaneously; by 2013, this figure had risen to 82%. In 2001, radiologists had performed 90% of all percutaneous abdominal abscess drainages; this percentage share increased to 97% in 2013. Of all abdominal abscesses treated in 2013 in Medicare patients, 79% were treated by radiologists. CONCLUSIONS: Use of percutaneous drainage of abdominal abscesses has steadily increased, whereas use of open surgical drainage has declined. The vast majority of these abscesses are now treated percutaneously. Radiologists are a strong majority of those performing the procedures. Although this database does not provide information on outcomes, percutaneous drainage is another good example of radiology-related value. PMID- 26653833 TI - ACR Appropriateness Criteria Acute Nonspecific Chest Pain-Low Probability of Coronary Artery Disease. AB - Primary imaging options in patients at low risk for coronary artery disease (CAD) who present with undifferentiated chest pain and without signs of ischemia are functional testing with exercise or pharmacologic stress-based electrocardiography, echocardiography, or myocardial perfusion imaging to exclude myocardial ischemia after rule-out of myocardial infarction and early cardiac CT because of its high negative predictive value to exclude CAD. Although possible, is not conclusive whether triple-rule-out CT (CAD, pulmonary embolism, and aortic dissection) might improve the efficiency of patient management. More advanced noninvasive tests such as cardiac MRI and invasive imaging with transesophageal echocardiography or coronary angiography are rarely indicated. With increased likelihood of noncardiac causes, a number of diagnostic tests, among them ultrasound of the abdomen, MR angiography of the aorta with or without contrast, x-ray rib views, x-ray barium swallow, and upper gastrointestinal series, can also be appropriate. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every three years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances in which evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. This recommendation is based on excellent evidence, including several randomized comparative effectiveness trials and blinded observational cohort studies. PMID- 26653834 TI - Implementation of Standardized Reports Within a Pediatric Health Care System With Geographically Dispersed Sites. PMID- 26653835 TI - Data Drives Quality Improvement. PMID- 26653836 TI - Why Is Proton Beam Therapy So Controversial? PMID- 26653837 TI - Things to Consider When Looking for Your First Job: Advice From a Young Radiologist. PMID- 26653838 TI - Brain aging and Parkinson's disease: New therapeutic approaches using drug delivery systems. AB - The etiology and pathogenesis of Parkinson's disease (PD) is unknown, aging being the strongest risk factor for brain degeneration. Understanding PD pathogenesis and how aging increases the risk of disease would aid the development of therapies able to slow or prevent the progression of this neurodegenerative disorder. In this review we provide an overview of the most promising therapeutic targets and strategies to delay the loss of dopaminergic neurons observed both in PD and aging. Among them, handling alpha-synuclein toxicity, enhancing proteasome and lysosome clearance, ameliorating mitochondrial disruptions and modifying the glial environment are so far the most promising candidates. These new and conventional drugs may present problems related to their labile nature and to the difficulties in reaching the brain. Thus, we highlight the latest types of drug delivery system (DDS)-based strategies for PD treatment, including DDS for local and systemic drug delivery. Finally, the ongoing challenges for the discovery of new targets and the opportunities for DDS-based therapies to improve and efficacious PD therapy will be discussed. PMID- 26653839 TI - Interfacial Structure and Proton Conductivity of Nafion at the Pt-Deposited Surface. AB - Understanding the Nafion-Pt interface structure is important because fuel cell reactions occur at the three-phase boundary. Infrared (IR) p-polarized multiple angle incidence resolution spectrometry (p-MAIRS) technique was used to investigate the in-plane (IP) and out-of-plane (OP) spectra in the identical substrate. Our previous study revealed that the proton conductivity of the Nafion thin films decreased at the MgO and SiO2 surfaces. We proposed that the origin for the lower proton conductivity can be derived from the highly oriented structure at the interface. However, the interface structure of the Nafion-Pt interface remains unclear. In this study, Nafion thin films were prepared by spin coating on a Pt-deposited MgO substrates. The IP spectrum exhibited a well-known spectrum, but the OP spectrum was quite differed considerably from the IP spectrum. Furthermore, thickness dependence of the degree of orientation for this OP band was observed at the Nafion-Pt interface. This OP band can be assigned as the vibration mode of the mixture of the CF2 and sulfonic acid groups. At the low RH region, proton conductivity of the Nafion thin film on the Pt-deposited surface was 1 order of magnitude higher than that on the SiO2 surface. Furthermore, the activation energy was 0.4-0.5 eV, which is lower than that of the SiO2 surface. These results, which suggest that the Pt surface influenced the proton transport property of Nafion thin film, can contribute to understand the relationship between the proton transport property and thin film structure on the Pt-deposited surface at the three-phase boundary for fuel cells. PMID- 26653841 TI - Size-based characterization of nanoparticle mixtures by the inline coupling of capillary electrophoresis to Taylor dispersion analysis. AB - Separation of closely related nanoparticles is still a challenging issue for the characterization of complex mixtures for industrial/research applications or regulatory purposes. In this work, the remarkable separating performances of CE were complemented with the absolute size-based determination provided by Taylor dispersion analysis (TDA) for the characterization of nanoparticle mixtures. The inline hyphenation of CE to TDA was successfully implemented for the baseline separation followed by a size-based characterization of a bimodal mixture containing two closely size-related nanolatexes (70nm and 56nm radii). A pixel sensor UV area imager providing three detection points along the capillary was used for a differential measurement of the peak broadening during the Taylor dispersion step. Comparison of this new technique with dynamic light scattering and hydrodynamic chromatography is also discussed. PMID- 26653840 TI - Determination of nicotine, tar, volatile organic compounds and carbonyls in mainstream cigarette smoke using a glass filter and a sorbent cartridge followed by the two-phase/one-pot elution method with carbon disulfide and methanol. AB - We have developed a new analytical method for the determination of nicotine, tar, volatile organic compounds and carbonyls in main-stream cigarette smoke using a sorbent cartridge packed with Carboxen 572 (CX-572) and a Cambridge filter pad (CFP) followed by the two-phase/one-pot elution method. A CX-572 cartridge is installed between the intake of the CFP and the pump of the smoking machine. Gaseous compounds collected with the CX-572 cartridge and total particulate matter (TPM) collected with the CFP are coeluted simultaneously in the same vial and then analyzed by high-performance liquid chromatography (HPLC), gas chromatography-mass spectrometry (GC/MS) and gas chromatograph-thermal conductivity detector (GC/TCD). Carbonyl compounds are determined by adding derivatizing reagent (2,4-dinitrophenylhydrazine, DNPH) to the eluate followed by HPLC analysis. VOCs and nicotine are determined by GC/MS, and water is determined by GC/TCD. The same sample eluate solution is used for HPLC, GC/MS and GC/TCD analyses. As a result of measuring main-stream cigarette smoke generated from reference cigarettes, almost all carbonyl compounds and VOCs except formaldehyde were passed through a CFP and trapped in a CX-572 cartridge. 100% of nicotine, tar and TPM were trapped in a CFP. 50% of water and 53% of formaldehyde were trapped in a CFP. The one-pot data is almost equal to the sums of CFP (particulate matter) and CX-572 (gaseous compounds) data. The two-phase/one-pot elution method can simultaneously measure nicotine, tar, volatile organic compounds and carbonyl compounds in cigarette smoke with simple operation and small amounts of reagents. PMID- 26653842 TI - The effect of breakfast on appetite regulation, energy balance and exercise performance. AB - The belief that breakfast is the most important meal of day has been derived from cross-sectional studies that have associated breakfast consumption with a lower BMI. This suggests that breakfast omission either leads to an increase in energy intake or a reduction in energy expenditure over the remainder of the day, resulting in a state of positive energy balance. However, observational studies do not imply causality. A number of intervention studies have been conducted, enabling more precise determination of breakfast manipulation on indices of energy balance. This review will examine the results from these studies in adults, attempting to identify causal links between breakfast and energy balance, as well as determining whether consumption of breakfast influences exercise performance. Despite the associations in the literature, intervention studies have generally found a reduction in total daily energy intake when breakfast is omitted from the daily meal pattern. Moreover, whilst consumption of breakfast supresses appetite during the morning, this effect appears to be transient as the first meal consumed after breakfast seems to offset appetite to a similar extent, independent of breakfast. Whether breakfast affects energy expenditure is less clear. Whilst breakfast does not seem to affect basal metabolism, breakfast omission may reduce free-living physical activity and endurance exercise performance throughout the day. In conclusion, the available research suggests breakfast omission may influence energy expenditure more strongly than energy intake. Longer term intervention studies are required to confirm this relationship, and determine the impact of these variables on weight management. PMID- 26653843 TI - Purified Betacyanins from Hylocereus undatus Peel Ameliorate Obesity and Insulin Resistance in High-Fat-Diet-Fed Mice. AB - Natural bioactive compounds in food have been shown to be beneficial in preventing the development of obesity, diabetes, and other metabolic diseases. Increasing evidence indicates that betacyanins possess free-radical-scavenging and antioxidant activities, suggesting their beneficial effects on metabolic disorders. The main objective of this study was to isolate and identify the betaycanins from Hylocereus undatus (white-fleshed pitaya) peel and evaluate their ability to ameliorate obesity, insulin resistance, and hepatic steatosis in high-fat-diet (HFD)-induced obese mice. The purified pitaya peel betacyanins (PPBNs) were identified by liquid chromatography/tandem mass spectrometry (LC/MS/MS), and the male C57BL/6 mice were fed a low-fat diet, HFD, or HFD supplemented with PPBNs for 14 weeks. Our results showed that the white-fleshed pitaya peel contains 14 kinds of betacyanins and dietary PPBNs reduced HFD induced body weight gain and ameliorated adipose tissue hypertrophy, hepatosteatosis, glucose intolerance, and insulin resistance. Moreover, the hepatic gene expression analysis indicated that PPBN supplementation increased the expression levels of lipid-metabolism-related genes (AdipoR2, Cpt1a, Cpt1b, Acox1, PPARgamma, Insig1, and Insig2) and FGF21-related genes (beta-Klotho and FGFR1/2) but decreased the expression level of Fads2, Fas, and FGF21, suggesting that the protective effect of PPBNs might be associated with the induced fatty acid oxidation, decreased fatty acid biosynthesis, and alleviated FGF21 resistance. PMID- 26653845 TI - Evaluation of potential candidate genes involved in salinity tolerance in striped catfish (Pangasianodon hypophthalmus) using an RNA-Seq approach. AB - Increasing salinity levels in freshwater and coastal environments caused by sea level rise linked to climate change is now recognized to be a major factor that can impact fish growth negatively, especially for freshwater teleost species. Striped catfish (Pangasianodon hypophthalmus) is an important freshwater teleost that is now widely farmed across the Mekong River Delta in Vietnam. Understanding the basis for tolerance and adaptation to raised environmental salinity conditions can assist the regional culture industry to mitigate predicted impacts of climate change across this region. Attempt of next generation sequencing using the ion proton platform results in more than 174 million raw reads from three tissue libraries (gill, kidney and intestine). Reads were filtered and de novo assembled using a variety of assemblers and then clustered together to generate a combined reference transcriptome. Downstream analysis resulted in a final reference transcriptome that contained 60,585 transcripts with an N50 of 683 bp. This resource was further annotated using a variety of bioinformatics databases, followed by differential gene expression analysis that resulted in 3062 transcripts that were differentially expressed in catfish samples raised under two experimental conditions (0 and 15 ppt). A number of transcripts with a potential role in salinity tolerance were then classified into six different functional gene categories based on their gene ontology assignments. These included; energy metabolism, ion transportation, detoxification, signal transduction, structural organization and detoxification. Finally, we combined the data on functional salinity tolerance genes into a hypothetical schematic model that attempted to describe potential relationships and interactions among target genes to explain the molecular pathways that control adaptive salinity responses in P. hypophthalmus. Our results indicate that P. hypophthalmus exhibit predictable plastic regulatory responses to elevated salinity by means of characteristic gene expression patterns, providing numerous candidate genes for future investigations. PMID- 26653844 TI - Simultaneous inhibition of JAK and SYK kinases ameliorates chronic and destructive arthritis in mice. AB - INTRODUCTION: Despite the broad spectrum of antirheumatic drugs, RA is still not well controlled in up to 30-50 % of patients. Inhibition of JAK kinases by means of the pan-JAK inhibitor tofacitinib has demonstrated to be effective even in difficult-to-treat patients. Here, we discuss whether the efficacy of JAK inhibition can be improved by simultaneously inhibiting SYK kinase, since both kinases mediate complementary and non-redundant pathways in RA. METHODS: Efficacy of dual JAK + SYK inhibition with selective small molecule inhibitors was evaluated in chronic G6PI-induced arthritis, a non-self-remitting and destructive arthritis model in mice. Clinical and histopathological scores, as well as cytokine and anti-G6PI antibody production were assessed in both preventive and curative protocols. Potential immunotoxicity was also evaluated in G6PI-induced arthritis and in a 28-day TDAR model, by analysing the effects of JAK + SYK inhibition on hematological parameters, lymphoid organs, leukocyte subsets and cell function. RESULTS: Simultaneous JAK + SYK inhibition completely prevented mice from developing arthritis. This therapeutic strategy was also very effective in ameliorating already established arthritis. Dual kinase inhibition immediately resulted in greatly decreased clinical and histopathological scores and led to disease remission in over 70 % of the animals. In contrast, single JAK inhibition and anti-TNF therapy (etanercept) were able to stop disease progression but not to revert it. Dual kinase inhibition decreased Treg and NK cell counts to the same extent as single JAK inhibition but overall cytotoxicity remained intact. Interestingly, treatment discontinuation rapidly reversed such immune cell reduction without compromising clinical efficacy, suggesting long-lasting curative effects. Dual kinase inhibition reduced the Th1/Th17 cytokine cascade and the differentiation and function of joint cells, in particular osteoclasts and fibroblast-like synoviocytes. CONCLUSIONS: Concurrent JAK + SYK inhibition resulted in higher efficacy than single kinase inhibition and TNF blockade in a chronic and severe arthritis model. Thus, blockade of multiple immune signals with dual JAK + SYK inhibition represents a reasonable therapeutic strategy for RA, in particular in patients with inadequate responses to current treatments. Our data supports the multiplicity of events underlying this heterogeneous and complex disease. PMID- 26653846 TI - Alzheimer Disease and Behavioral Variant Frontotemporal Dementia: Automatic Classification Based on Cortical Atrophy for Single-Subject Diagnosis. AB - Purpose To investigate the diagnostic accuracy of an image-based classifier to distinguish between Alzheimer disease (AD) and behavioral variant frontotemporal dementia (bvFTD) in individual patients by using gray matter (GM) density maps computed from standard T1-weighted structural images obtained with multiple imagers and with independent training and prediction data. Materials and Methods The local institutional review board approved the study. Eighty-four patients with AD, 51 patients with bvFTD, and 94 control subjects were divided into independent training (n = 115) and prediction (n = 114) sets with identical diagnosis and imager type distributions. Training of a support vector machine (SVM) classifier used diagnostic status and GM density maps and produced voxelwise discrimination maps. Discriminant function analysis was used to estimate suitability of the extracted weights for single-subject classification in the prediction set. Receiver operating characteristic (ROC) curves and area under the ROC curve (AUC) were calculated for image-based classifiers and neuropsychological z scores. Results Training accuracy of the SVM was 85% for patients with AD versus control subjects, 72% for patients with bvFTD versus control subjects, and 79% for patients with AD versus patients with bvFTD (P <= .029). Single-subject diagnosis in the prediction set when using the discrimination maps yielded accuracies of 88% for patients with AD versus control subjects, 85% for patients with bvFTD versus control subjects, and 82% for patients with AD versus patients with bvFTD, with a good to excellent AUC (range, 0.81-0.95; P <= .001). Machine learning-based categorization of AD versus bvFTD based on GM density maps outperforms classification based on neuropsychological test results. Conclusion The SVM can be used in single-subject discrimination and can help the clinician arrive at a diagnosis. The SVM can be used to distinguish disease-specific GM patterns in patients with AD and those with bvFTD as compared with normal aging by using common T1-weighted structural MR imaging. ((c)) RSNA, 2015. PMID- 26653847 TI - Placenta percreta with concomitant uterine didelphys at 18 weeks of pregnancy: a case report and review of the literature. AB - AIM: The aim of this paper is to draw the attention of the clinicians on placenta percreta detected along with uterine anomalies in early second trimester. CASE PRESENTATION: A 35-year-old, gravida 2 parity 1 woman at 18 weeks of pregnancy was admitted to our emergency unit with abdominal pain. In ultrasound exam, a live fetus compatible with 18 weeks of gestation, hemoperitoneum and a solid mass adjacent to the uterus were detected. An emergent laparotomy was decided because of hemorrhagic shock findings. In the operation, uterine didelphys and an active bleeding area from placenta percreta on the anterior wall of the uterus where pregnancy was settled were detected. In the simultaneous vaginal examination two cervixes and a longitudinal vaginal septum were seen. Supracervical hemihysterectomy was performed. CONCLUSION: Placenta percreta is a rare clinical entity with an elevated perinatal mortality. Uterine anomalies are risk factors for placental adhesion anomalies. Clinical suspicion is vital for early diagnosis and timely management. PMID- 26653848 TI - Aspirin in the prevention of cardiovascular events in patients with diabetes. AB - Diabetes imparts a substantial increased risk for cardiovascular disease-related mortality and morbidity. Because of this, current medical guidelines recommend prophylactic treatment with once-daily, low-dose aspirin (acetylsalicylic acid) for primary and secondary prevention of cardiovascular (CV) events in high-risk patients. However, only modest reductions in CV events and mortality have been observed with once-daily aspirin treatment in patients with diabetes, including patients with a previous CV event, perhaps because of disparity between aspirin pharmacokinetics and diabetes-related platelet abnormalities. Once-daily aspirin irreversibly inactivates platelets for only a short duration (acetylsalicylic acid half-life, approximately 15-20 minutes), after which time newly generated, active platelets enter the circulation and weaken aspirin's effect. Platelets from patients with diabetes are more reactive and are turned over more rapidly than platelets from normal individuals; the short inhibitory window provided by once-daily aspirin may therefore be insufficient to provide 24-h protection against CV events. Alternative conventional aspirin regimens (e.g. higher daily dose, twice-daily dosing, combination with clopidogrel) and newer formulations (e.g. 24-h, extended-release) have been proposed to overcome the apparent limited efficacy of conventional aspirin in patients with diabetes; however, tolerability concerns and limited clinical efficacy data need to be taken into account when considering the use of such regimens. PMID- 26653849 TI - Theoretical Insights on the Mechanism of the GTP Hydrolysis Catalyzed by the Elongation Factor Tu (EF-Tu). AB - The purpose of this work is to have a better understanding of the mechanism of GTP hydrolysis catalyzed by the elongation factor Tu. Two main aspects are being discussed in the literature: the associative or dissociative character of the process and the nature of nucleophile activation. The calculations of the QM subsystem have been done by means of the M06-2X density functional and the split valence triple-zeta 6-311+G(d,p) basis set. The environmental effect has been introduced through the continuum SMD method. We have studied three models of increasing complexity in order to analyze the different factors that intervene in the catalytic action. The results obtained in this paper confirm that the protonated His84 plays a fundamental role in the catalytic mechanism, but we have also found that the crystallographic sodium ion has a notable effect in the catalysis. So, our work has permitted a new insight, complementary to those obtained with QM/MM calculations, into this very complex process. PMID- 26653850 TI - The Survey on Cellular and Engineered Tissue Therapies in Europe in 2013. AB - Following the coordinated efforts of five established scientific organizations, this report, the sixth of its kind, describes activity in Europe for the year 2013 in the area of cellular and engineered tissue therapies, excluding hematopoietic stem cell (HSC) treatments for the reconstitution of hematopoiesis. Three hundred eighteen teams from 31 countries responded to the cellular and engineered tissue therapy survey; 145 teams from 25 countries reported treating 2187 patients, while a further 173 teams reported no activity. Indications were musculoskeletal/rheumatological disorders (45%; 89% autologous), cardiovascular disorders (20%; 99% autologous), hematology/oncology, predominantly prevention or treatment of graft versus host disease (GvHD) and HSC graft enhancement, (19%; <1% autologous), neurological disorders (3%; 100% autologous), gastrointestinal disorders (2%; 32% autologous), and other indications (11%; 67% autologous). The majority of autologous cells (88%) were used to treat musculoskeletal/rheumatological (57%) and cardiovascular (27%) disorders, whereas allogeneic cells were used mainly for hematology/oncology (64%). The reported cell types were mesenchymal stem/stromal cells (MSC) (49%), HSC (28%), chondrocytes (11%), dendritic cells (2%), keratinocytes (1%), and others (9%). In 46% of the grafts, cells were delivered following ex vivo expansion, sorted in 17% of the reported cases and transduced in only 3%. Thirty three percent of treatments were delivered intravenously or intra-arterially, and of the remaining 67%, 37% used a membrane/scaffold, 28% a suspension, and 2% a gel. The data are compared to those previously collected to identify trends in a still unpredictably evolving field. PMID- 26653851 TI - Wave Function Frozen-Density Embedding: Coupled Excitations. AB - We report quasi-ab initio correlated ground-state and excitation-energy calculations for agglomerates consisting of several molecules with total system sizes of up to more than one hundred atoms using a combination of a density fitted, approximate second-order coupled-cluster singles and doubles (RICC2) method and frozen-density embedding (FDE), denoted RICC2-in-RICC2. Working equations are presented for CC2 ground-state energies and approximate coupled excitation energies, which are a necessary prerequisite for investigations of potential energy surfaces (PESs) of both ground and excited states. The approach is applicable to all systems that can be decomposed into interacting individual molecules for which the RICC2 calculation itself is feasible. Because of the absence of exact exchange in the formalism and the possibility to efficiently evaluate Coulomb coupling integrals using density fitting or a dipole approximation, the coupling step is insignificant in terms of computation time. PMID- 26653852 TI - Embryonic attenuated Wnt/beta-catenin signaling defines niche location and long term stem cell fate in hair follicle. AB - Long-term adult stem cells sustain tissue regeneration throughout the lifetime of an organism. They were hypothesized to originate from embryonic progenitor cells that acquire long-term self-renewal ability and multipotency at the end of organogenesis. The process through which this is achieved often remains unclear. Here, we discovered that long-term hair follicle stem cells arise from embryonic progenitor cells occupying a niche location that is defined by attenuated Wnt/beta-catenin signaling. Hair follicle initiation is marked by placode formation, which depends on the activation of Wnt/beta-catenin signaling. Soon afterwards, a region with attenuated Wnt/beta-catenin signaling emerges in the upper follicle. Embryonic progenitor cells residing in this region gain expression of adult stem cell markers and become definitive long-term hair follicle stem cells at the end of organogenesis. Attenuation of Wnt/beta-catenin signaling is a prerequisite for hair follicle stem cell specification because it suppresses Sox9, which is required for stem cell formation. PMID- 26653853 TI - The carcinine transporter CarT is required in Drosophila photoreceptor neurons to sustain histamine recycling. AB - Synaptic transmission from Drosophila photoreceptors to lamina neurons requires recycling of histamine neurotransmitter. Synaptic histamine is cleared by uptake into glia and conversion into carcinine, which functions as transport metabolite. How carcinine is transported from glia to photoreceptor neurons remains unclear. In a targeted RNAi screen for genes involved in this pathway, we identified carT, which encodes a member of the SLC22A transporter family. CarT expression in photoreceptors is necessary and sufficient for fly vision and behavior. Carcinine accumulates in the lamina of carT flies. Wild-type levels are restored by photoreceptor-specific expression of CarT, and endogenous tagging suggests CarT localizes to synaptic endings. Heterologous expression of CarT in S2 cells is sufficient for carcinine uptake, demonstrating the ability of CarT to utilize carcinine as a transport substrate. Together, our results demonstrate that CarT transports the histamine metabolite carcinine into photoreceptor neurons, thus contributing an essential step to the histamine-carcinine cycle. PMID- 26653854 TI - Testing sensory evidence against mnemonic templates. AB - Most perceptual decisions require comparisons between current input and an internal template. Classic studies propose that templates are encoded in sustained activity of sensory neurons. However, stimulus encoding is itself dynamic, tracing a complex trajectory through activity space. Which part of this trajectory is pre-activated to reflect the template? Here we recorded magneto- and electroencephalography during a visual target-detection task, and used pattern analyses to decode template, stimulus, and decision-variable representation. Our findings ran counter to the dominant model of sustained pre activation. Instead, template information emerged transiently around stimulus onset and quickly subsided. Cross-generalization between stimulus and template coding, indicating a shared neural representation, occurred only briefly. Our results are compatible with the proposal that template representation relies on a matched filter, transforming input into task-appropriate output. This proposal was consistent with a signed difference response at the perceptual decision stage, which can be explained by a simple neural model. PMID- 26653855 TI - Fcp1 phosphatase controls Greatwall kinase to promote PP2A-B55 activation and mitotic progression. AB - During cell division, progression through mitosis is driven by a protein phosphorylation wave. This wave namely depends on an activation-inactivation cycle of cyclin B-dependent kinase (Cdk) 1 while activities of major protein phosphatases, like PP1 and PP2A, appear directly or indirectly repressed by Cdk1. However, how Cdk1 inactivation is coordinated with reactivation of major phosphatases at mitosis exit still lacks substantial knowledge. We show here that activation of PP2A-B55, a major mitosis exit phosphatase, required the phosphatase Fcp1 downstream Cdk1 inactivation in human cells. During mitosis exit, Fcp1 bound Greatwall (Gwl), a Cdk1-stimulated kinase that phosphorylates Ensa/ARPP19 and converts these proteins into potent PP2A-B55 inhibitors during mitosis onset, and dephosphorylated it at Cdk1 phosphorylation sites. Fcp1 catalyzed dephosphorylation drastically reduced Gwl kinase activity towards Ensa/ARPP19 promoting PP2A-B55 activation. Thus, Fcp1 coordinates Cdk1 and Gwl inactivation to derepress PP2A-B55, generating a dephosphorylation switch that drives mitosis progression. PMID- 26653856 TI - Protein flexibility is required for vesicle tethering at the Golgi. AB - The Golgi is decorated with coiled-coil proteins that may extend long distances to help vesicles find their targets. GCC185 is a trans Golgi-associated protein that captures vesicles inbound from late endosomes. Although predicted to be relatively rigid and highly extended, we show that flexibility in a central region is required for GCC185's ability to function in a vesicle tethering cycle. Proximity ligation experiments show that that GCC185's N-and C-termini are within <40 nm of each other on the Golgi. In physiological buffers without fixatives, atomic force microscopy reveals that GCC185 is shorter than predicted, and its flexibility is due to a central bubble that represents local unwinding of specific sequences. Moreover, 85% of the N-termini are splayed, and the splayed N terminus can capture transport vesicles in vitro. These unexpected features support a model in which GCC185 collapses onto the Golgi surface, perhaps by binding to Rab GTPases, to mediate vesicle tethering. PMID- 26653857 TI - The kinetochore prevents centromere-proximal crossover recombination during meiosis. AB - During meiosis, crossover recombination is essential to link homologous chromosomes and drive faithful chromosome segregation. Crossover recombination is non-random across the genome, and centromere-proximal crossovers are associated with an increased risk of aneuploidy, including Trisomy 21 in humans. Here, we identify the conserved Ctf19/CCAN kinetochore sub-complex as a major factor that minimizes potentially deleterious centromere-proximal crossovers in budding yeast. We uncover multi-layered suppression of pericentromeric recombination by the Ctf19 complex, operating across distinct chromosomal distances. The Ctf19 complex prevents meiotic DNA break formation, the initiating event of recombination, proximal to the centromere. The Ctf19 complex independently drives the enrichment of cohesin throughout the broader pericentromere to suppress crossovers, but not DNA breaks. This non-canonical role of the kinetochore in defining a chromosome domain that is refractory to crossovers adds a new layer of functionality by which the kinetochore prevents the incidence of chromosome segregation errors that generate aneuploid gametes. PMID- 26653859 TI - Appreciating doubts about HIV medicine. PMID- 26653858 TI - A vocabulary of ancient peptides at the origin of folded proteins. AB - The seemingly limitless diversity of proteins in nature arose from only a few thousand domain prototypes, but the origin of these themselves has remained unclear. We are pursuing the hypothesis that they arose by fusion and accretion from an ancestral set of peptides active as co-factors in RNA-dependent replication and catalysis. Should this be true, contemporary domains may still contain vestiges of such peptides, which could be reconstructed by a comparative approach in the same way in which ancient vocabularies have been reconstructed by the comparative study of modern languages. To test this, we compared domains representative of known folds and identified 40 fragments whose similarity is indicative of common descent, yet which occur in domains currently not thought to be homologous. These fragments are widespread in the most ancient folds and enriched for iron-sulfur- and nucleic acid-binding. We propose that they represent the observable remnants of a primordial RNA-peptide world. PMID- 26653860 TI - Molecular Characterization of beta-Lactamase-Producing Escherichia coli Collected from 2001 to 2011 from Pigs in Korea. AB - To survey the diversity of plasmid-mediated beta-lactamases, and the replicon types of the plasmids in Escherichia coli in the community, 95 multidrug resistant E. coli isolates from stool samples of pigs in Korea from 2001 to 2011 were analyzed, and all isolates were confirmed as beta-lactamase-producing bacteria, which mostly carried genes encoding TEM (100%), ACC (95%), SHV (62%), OXA (28%), CTX-M (26%), and NDM-1 (15%). Moreover, each isolate contained at least three beta-lactamases genes on its plasmid. The polymerase chain reaction based replicon typing method revealed that among the 18 replicon types, 15 types were identified in this work, and IncF groups (FIB; 100%, Frep; 99%) and HI1 (98%) type were predominant. Other replicon types such as Y, B/O, A/C, P, FIA, N, HI2, I1, and W were also detected; moreover at least three types were identified in each organism. In conclusion, a high prevalence of various types of beta lactamases genes were identified in E. coli from pigs in Korea, and these genes appeared to be mainly associated with IncF group, IncHI1, and IncY plasmids. PMID- 26653861 TI - Recovery of partial nitrification in a down-flow hanging sponge reactor by salt shock loading. AB - Partial nitrification of ammonium-containing artificial wastewater was achieved using a down-flow hanging sponge (DHS) reactor with a hydraulic retention time (HRT) of 2 h by adjusting the influent salinity to 25 g Cl L(-1) with NaCl. The effect of HRT on partial nitrification was examined by varying HRT from 1 to 4 h. Extending HRT from 2 to 4 h had the effect of decreasing nitrite production and increasing nitrates. Since partial nitrification was not completely recovered after returning the HRT to 2 h, we examined the effect of salt shock loading on the recovery of partial nitrification. Salt shock loading with 150 gCl L(-1) for 72 h resulted in the fraction of NO2-N to total inorganic nitrogen in the effluent reaching 83.0% as much as 83 days after returning the salinity to the original level. Thus, despite the time required for the restoration of partial nitrification, the effectiveness of salt shock loading to achieve this aim was verified. PMID- 26653862 TI - Stroop interference associated with efficient reading fluency and prelexical orthographic processing. AB - The Stroop Color-Word Test involves a dynamic interplay between reading and executive functioning that elicits intuitions of word reading automaticity. One such intuition is that strong reading skills (i.e., more automatized word reading) play a disruptive role within the test, contributing to Stroop interference. However, evidence has accumulated that challenges this intuition. The present study examined associations among Stroop interference, reading skills (i.e., isolated word identification, grapheme-to-phoneme mapping, phonemic awareness, reading fluency) measured on standardized tests, and orthographic skills measured on experimental computerized tasks. Among university students (N = 152), correlational analyses showed greater Stroop interference to be associated with (a) relatively low scores on all standardized reading tests, and (b) longer response latencies on orthographic tasks. Hierarchical regression demonstrated that reading fluency and prelexical orthographic processing predicted unique and significant variance in Stroop interference beyond baseline rapid naming. Results suggest that strong reading skills, including orthographic processing, play a supportive role in resolving Stroop interference. PMID- 26653863 TI - The pH of beverages in the United States. AB - BACKGROUND: Dental erosion is the chemical dissolution of tooth structure in the absence of bacteria when the environment is acidic (pH < 4.0). Research indicates that low pH is the primary determinant of a beverage's erosive potential. In addition, citrate chelation of calcium ions may contribute to erosion at higher pH. The authors of this study determined the erosive potential measured by the pH of commercially available beverages in the United States. METHODS: The authors purchased 379 beverages from stores in Birmingham, Alabama, and categorized them (for example, juices, sodas, flavored waters, teas, and energy drinks) and assessed their pH. They used a pH meter to measure the pH of each beverage in triplicate immediately after it was opened at a temperature of 25 degrees C. The authors recorded the pH data as mean (standard deviation). RESULTS: Most (93%, 354 of 379) beverages had a pH of less than 4.0, and 7% (25 of 379) had a pH of 4.0 or more. Relative beverage erosivity zones based on studies of apatite solubility in acid indicated that 39% (149 of 379) of the beverages tested in this study were considered extremely erosive (pH < 3.0), 54% (205 of 379) were considered erosive (pH 3.0 to 3.99), and 7% (25 of 379) were considered minimally erosive (pH >= 4.0). CONCLUSIONS: This comprehensive pH assessment of commercially available beverages in the United States found that most are potentially erosive to the dentition. PRACTICAL IMPLICATIONS: This study's findings provide dental clinicians and auxiliaries with information regarding the erosive potential of commercially available beverages. Specific dietary recommendations for the prevention of dental erosion may now be developed based on the patient's history of beverage consumption. PMID- 26653864 TI - Narrowing the transmission gap: A synthesis of three decades of research on intergenerational transmission of attachment. AB - Twenty years ago, meta-analytic results (k = 19) confirmed the association between caregiver attachment representations and child-caregiver attachment (Van IJzendoorn, 1995). A test of caregiver sensitivity as the mechanism behind this intergenerational transmission showed an intriguing "transmission gap." Since then, the intergenerational transmission of attachment and the transmission gap have been studied extensively, and now extend to diverse populations from all over the globe. Two decades later, the current review revisited the effect sizes of intergenerational transmission, the heterogeneity of the transmission effects, and the size of the transmission gap. Analyses were carried out with a total of 95 samples (total N = 4,819). All analyses confirmed intergenerational transmission of attachment, with larger effect sizes for secure-autonomous transmission (r = .31) than for unresolved transmission (r = .21), albeit with significantly smaller effect sizes than 2 decades earlier (r = .47 and r = .31, respectively). Effect sizes were moderated by risk status of the sample, biological relatedness of child-caregiver dyads, and age of the children. Multivariate moderator analyses showed that unpublished and more recent studies had smaller effect sizes than published and older studies. Path analyses showed that the transmission could not be fully explained by caregiver sensitivity, with more recent studies narrowing but not bridging the "transmission gap." Implications for attachment theory as well as future directions for research are discussed. PMID- 26653865 TI - A meta-analysis of blood glucose effects on human decision making. AB - The academic and public interest in blood glucose and its relationship to decision making has been increasing over the last decade. To investigate and evaluate competing theories about this relationship, we conducted a psychometric meta-analysis on the effect of blood glucose on decision making. We identified 42 studies relating to 4 dimensions of decision making: willingness to pay, willingness to work, time discounting, and decision style. We did not find a uniform influence of blood glucose on decision making. Instead, we found that low levels of blood glucose increase the willingness to pay and willingness to work when a situation is food related, but decrease willingness to pay and work in all other situations. Low levels of blood glucose increase the future discount rate for food; that is, decision makers become more impatient, and to a lesser extent increase the future discount rate for money. Low levels of blood glucose also increase the tendency to make more intuitive rather than deliberate decisions. However, this effect was only observed in situations unrelated to food. We conclude that blood glucose has domain-specific effects, influencing decision making differently depending on the relevance of the situation to acquiring food. (PsycINFO Database Record PMID- 26653866 TI - Exponential apparent diffusion coefficient in evaluating prostate cancer at 3 T: preliminary experience. AB - OBJECTIVE: To investigate the feasibility of exponential apparent diffusion coefficient (eADC) derived from diffusion-weighted imaging (DWI) in evaluating prostate cancers at 3 T. METHODS: 74 consecutive patients with surgically confirmed single peripheral zone (PZ) prostate cancer >=0.5 cm(3) who underwent pre-operative DWI at 3 T were retrospectively selected. Based on radiological pathological correlation, eADC and apparent diffusion coefficient (ADC) (*10(-3) mm(2) s(-1)) for the cancers and benign PZ were measured by two independent readers. Tumour eADC or ADC was correlated with Gleason score. Receiver operating characteristic curve analysis was performed to differentiate between Gleason score 6 and 7 or higher, by eADC and ADC. Lesion-to-background contrast ratio was compared between eADC and ADC. RESULTS: Mean tumour eADC (0.48-0.50) and ADC (0.72-0.75) were significantly different from those of benign PZ (eADC, 0.20 0.27; ADC, 1.34-1.66), respectively (p < 0.001). A moderate correlation between tumour eADC or ADC and Gleason score was seen. For differentiating between Gleason score 6 and 7 or higher, eADC (0.818-0.883) showed a similar area under the curve with ADC (0.840-0.889) (p > 0.05). Lesion-to-background contrast ratio of eADC (Reader 1, 2.43; Reader 2, 2.23) was significantly greater than that of ADC (Reader 1, 2.21; Reader 2, 2.12) (p < 0.001). CONCLUSION: The eADC may offer similar diagnostic utility with ADC in the differentiation of the cancer from benign prostate tissue. Moreover, the eADC appears to allow improved tissue contrast. ADVANCES IN KNOWLEDGE: The eADC may be a comparable alternative to ADC for evaluating prostate cancer, with removing T2 shine-through effects from DWI. PMID- 26653867 TI - Epic Fail: Prenatal Care for Women with Mobility Impairment. PMID- 26653868 TI - Assessing Cervical Cancer Screening Coverage Using a Population-Based Behavioral Risk Factor Survey--Thailand, 2010. AB - Cervical cancer is the second most common cancer and fourth leading cause of cancer-related deaths among women in Thailand. In 2005, the Ministry of Public Health (MoPH) in Thailand initiated a phased national cervical cancer screening program. To monitor progress toward national screening targets--80% of women 30 60 years of age screened for cervical cancer once in the previous 5 years by 2013 -the MoPH used the 2010 Thai Behavioral Risk Factor Surveillance System (BRFSS) to assess cervical cancer screening coverage. Results from the survey showed that 67.4% of women aged 30-60 years had been screened for cervical cancer in the past 5 years with varying screening coverage by region, residence, education, and marital status. Although the national cervical cancer screening program in Thailand appears to be close to reaching its national targets, the causes of lower coverage in some subpopulations need to be identified so that targeted interventions can be developed to increase coverage in these groups. PMID- 26653869 TI - Sex Differences in Aortic Stenosis and Outcome Following Surgical and Transcatheter Aortic Valve Replacement. AB - Aortic stenosis is the commonest valve defect in the developed world and is associated with a high mortality once symptomatic. There is a difference in the way that male and female hearts remodel in the face of chronic pressure overload: women develop a concentrically hypertrophied, small cavity left ventricle (LV), whereas men are more prone to the development of eccentric hypertrophy. At a cellular level, there is an increase in collagen and metalloproteinase gene expression in males suggesting a different regulation of extracellular volume composition according to sex. Male hearts with aortic stenosis appear to have more fibrosis than their female comparators. The trigger for this appears to be in part related to estrogen receptor signaling, but other factors such as renin angiotensin activation, nitric oxide, and circulating noradrenaline levels may also be implicated. Treatment options include surgical valve replacement (SAVR) and more recently transcatheter aortic valve replacement (TAVR). Female sex may be a risk factor for adverse outcome following SAVR and conversely appears to confer a survival advantage when undergoing TAVR. Whether the lower mortality seen following TAVR in women compared with men (despite their increased age and frailty) reflects their longer life expectancy, smaller annular size (and less post-TAVR aortic regurgitation), more favorable LV reverse remodeling, or more likely, a combination of these factors remains to be established. PMID- 26653870 TI - Authors' Response to Vadvala, et al. PMID- 26653871 TI - Repression of CIITA by the Epstein-Barr virus transcription factor Zta is independent of its dimerization and DNA binding. AB - Repression of the cellular CIITA gene is part of the immune evasion strategy of the gammaherpes virus Epstein-Barr virus (EBV) during its lytic replication cycle in B-cells. In part, this is mediated through downregulation of MHC class II gene expression via the targeted repression of CIITA, the cellular master regulator of MHC class II gene expression. This repression is achieved through a reduction in CIITA promoter activity, initiated by the EBV transcription and replication factor, Zta (BZLF1, EB1, ZEBRA). Zta is the earliest gene expressed during the lytic replication cycle. Zta interacts with sequence-specific elements in promoters, enhancers and the replication origin (ZREs), and also modulates gene expression through interaction with cellular transcription factors and co activators. Here, we explore the requirements for Zta-mediated repression of the CIITA promoter. We find that repression by Zta is specific for the CIITA promoter and can be achieved in the absence of other EBV genes. Surprisingly, we find that the dimerization region of Zta is not required to mediate repression. This contrasts with an obligate requirement of this region to correctly orientate the DNA contact regions of Zta to mediate activation of gene expression through ZREs. Additional support for the model that Zta represses the CIITA promoter without direct DNA binding comes from promoter mapping that shows that repression does not require the presence of a ZRE in the CIITA promoter. PMID- 26653872 TI - Recent developments in hyaluronic acid-based nanomedicine for targeted cancer treatment. AB - INTRODUCTION: Hyaluronic acid (HA) has emerged as a promising applicant for the tumor-targeted delivery of various therapeutic agents. Because of its biocompatibility, biodegradability and receptor-binding properties, HA has been extensively investigated as the drug delivery carrier. In this review, recent advances in HA-based nanomedicines are discussed. AREAS COVERED: This review focuses on HA-based nanomedicines for the diagnosis and treatment of cancer. In particular, recent advances in HA-drug conjugates and HA-based nanoparticles for small molecular drug delivery are discussed. The bioreducible HA conjugates for small interfering ribonucleic acid delivery have been also discussed. EXPERT OPINION: To develop a successful HA-based nanomedicine, it has to be prepared without significant deterioration of intrinsic property of HA. The chemical modification of HA with drugs or hydrophobic moieties may reduce the binding affinity of HA to the receptors. In addition, since the HA-based nanomedicines tend to accumulate in the liver after their systemic administration, new strategies to overcome this issue have to be developed. PMID- 26653873 TI - Depressive symptomatology, serotonergic activity, and neuroticism: A methodological recommendation. PMID- 26653874 TI - MaRaCluster: A Fragment Rarity Metric for Clustering Fragment Spectra in Shotgun Proteomics. AB - Shotgun proteomics experiments generate large amounts of fragment spectra as primary data, normally with high redundancy between and within experiments. Here, we have devised a clustering technique to identify fragment spectra stemming from the same species of peptide. This is a powerful alternative method to traditional search engines for analyzing spectra, specifically useful for larger scale mass spectrometry studies. As an aid in this process, we propose a distance calculation relying on the rarity of experimental fragment peaks, following the intuition that peaks shared by only a few spectra offer more evidence than peaks shared by a large number of spectra. We used this distance calculation and a complete-linkage scheme to cluster data from a recent large-scale mass spectrometry-based study. The clusterings produced by our method have up to 40% more identified peptides for their consensus spectra compared to those produced by the previous state-of-the-art method. We see that our method would advance the construction of spectral libraries as well as serve as a tool for mining large sets of fragment spectra. The source code and Ubuntu binary packages are available at https://github.com/statisticalbiotechnology/maracluster (under an Apache 2.0 license). PMID- 26653875 TI - The impact of nanoparticle protein corona on cytotoxicity, immunotoxicity and target drug delivery. AB - In a perfect sequence of events, nanoparticles (NPs) are injected into the bloodstream where they circulate until they reach the target tissue. The ligand on the NP surface recognizes its specific receptor expressed on the target tissue and the drug is released in a controlled manner. However, once injected in a physiological environment, NPs interact with biological components and are surrounded by a protein corona (PC). This can trigger an immune response and affect NP toxicity and targeting capabilities. In this review, we provide a survey of recent findings on the NP-PC interactions and discuss how the PC can be used to modulate both cytotoxicity and the immune response as well as to improve the efficacy of targeted delivery of nanocarriers. PMID- 26653876 TI - Genome-wide identification and expression profiling of serine proteases and homologs in the diamondback moth, Plutella xylostella (L.). AB - BACKGROUND: Serine proteases (SPs) are crucial proteolytic enzymes responsible for digestion and other processes including signal transduction and immune responses in insects. Serine protease homologs (SPHs) lack catalytic activity but are involved in innate immunity. This study presents a genome-wide investigation of SPs and SPHs in the diamondback moth, Plutella xylostella (L.), a globally distributed destructive pest of cruciferous crops. RESULTS: A total of 120 putative SPs and 101 putative SPHs were identified in the P. xylostella genome by bioinformatics analysis. Based on the features of trypsin, 38 SPs were putatively designated as trypsin genes. The distribution, transcription orientation, exon intron structure and sequence alignments suggested that the majority of trypsin genes evolved from tandem duplications. Among the 221 SP/SPH genes, ten SP and three SPH genes with one or more clip domains were predicted and designated as PxCLIPs. Phylogenetic analysis of CLIPs in P. xylostella, two other Lepidoptera species (Bombyx mori and Manduca sexta), and two more distantly related insects (Drosophila melanogaster and Apis mellifera) showed that seven of the 13 PxCLIPs were clustered with homologs of the Lepidoptera rather than other species. Expression profiling of the P. xylostella SP and SPH genes in different developmental stages and tissues showed diverse expression patterns, suggesting high functional diversity with roles in digestion and development. CONCLUSIONS: This is the first genome-wide investigation on the SP and SPH genes in P. xylostella. The characterized features and profiled expression patterns of the P. xylostella SPs and SPHs suggest their involvement in digestion, development and immunity of this species. Our findings provide a foundation for further research on the functions of this gene family in P. xylostella, and a better understanding of its capacity to rapidly adapt to a wide range of environmental variables including host plants and insecticides. PMID- 26653877 TI - Studies on Aryl-Substituted Phenylalanines: Synthesis, Activity, and Different Binding Modes at AMPA Receptors. AB - A series of racemic aryl-substituted phenylalanines was synthesized and evaluated in vitro at recombinant rat GluA1-3, at GluK1-3, and at native AMPA receptors. The individual enantiomers of two target compounds, (RS)-2-amino-3-(3,4-dichloro 5-(5-hydroxypyridin-3-yl)phenyl)propanoic acid 37 and (RS)-2-amino-3-(3' hydroxybiphenyl-3-yl)propanoic acid 38, were characterized. (S)-37 and (R)-38 were identified as the only biologically active isomers, both being antagonists at GluA2 receptors with Kb of 1.80 and 3.90 MUM, respectively. To address this difference in enantiopharmacology, not previously seen for amino acid-based AMPA receptor antagonists, X-ray crystal structures of both eutomers in complex with the GluA2 ligand binding domain were solved. The cocrystal structures of (S)-37 and (R)-38 showed similar interactions of the amino acid parts but unexpected and different orientations and interactions of the biaromatic parts of the ligands inside the binding site, with (R)-38 having a binding mode not previously identified for amino acid-based antagonists. PMID- 26653878 TI - Unusual onset of a case of chronic recurrent multifocal osteomyelitis. AB - BACKGROUND: Chronic recurrent multifocal osteomyelitis (CRMO) is a rare condition that commonly affects the clavicle and pelvis. CASE PRESENTATION: We report here a case a 12 years old girl with CRMO arising with recurrent episodes of left supraorbital headache, followed by the appearance of a periorbital dyschromia. Magnetic resonance imaging (MRI) of the skull and orbits revealed an important subacute inflammatory process. Few months after, the child presented a painful swelling of the left clavicle; the histological examination of the related biopsy allowed to establish the diagnosis of CRMO. CONCLUSION: CRMO presenting as acute headache involving neurocranium is rare; to our knowledge this is the first recognized case in the world literature. This pathological condition is frequently misdiagnosed as infection or neoplasm and needs a deep investigation for the differential diagnosis. The physical, laboratoristic and instrumental diagnostic investigations of the patient and the treatment employed are described in detail. PMID- 26653879 TI - Hypocholesterolaemic mechanism of bitter melon aqueous extracts via inhibition of pancreatic cholesterol esterase and reduction of cholesterol micellar solubility. AB - This study investigated the hypocholesterolaemic effects of bitter melon aqueous extracts (BMAE) in vitro, the inhibitory effects of BMAE on pancreatic cholesterol esterase (CEase) and incorporation of cholesterol into micelles were investigated. BMAE decreased the in vitro micellar solubility of cholesterol in a dose-dependent manner. The conformation of CEase was investigated by means of circular dichroism (CD) and fluorescence. The result revealed the decrease of alpha-helix contents, increase of beta-sheet and exposure of aromatic amino acid residuals. The incorporation of cholesterol into micelles was inhibited by BMAE. A complex was observed by transmission electron microscopy (TEM), which indicated interaction between cholesterol and BMAE. The result revealed that BMAE can play a role in decreased intestinal cholesterol absorption via inhibition of CEase, and of micelle formation. PMID- 26653880 TI - Muscle activation patterns related to diabetic neuropathy in elderly subjects: A Functional Reach Test study. AB - BACKGROUND: This study was designed to assess, in healthy elderly, non neuropathic and neuropathic diabetic subjects, the activation patterns of the main muscles involved in the Functional Reach Test, a well-recognized method to identify elderly subjects at risk of balance impairments. METHODS: Surface electromyographic analysis of Sternocleidomastoideus, Rectus Abdominis, Erectores Spinae at L4 level, Rectus Femoris, Hamstrings, Tibialis Anterior and Soleus was performed in 10 healthy, 10 diabetic non-neuropathic and 10 diabetic neuropathic subjects. FINDINGS: Results showed that in every group the first motor is Tibialis Anterior, that is recruited before the start of the test. An earlier activation of Tibialis Anterior (P<0.05) was detected in diabetic neuropathic (ON at -24% of the test period), compared with healthy (-11%) and diabetic non neuropathic (-13%) groups. A significant earlier activation of Sternocleidomastoideus and Rectus Abdominis was found in diabetic neuropathic group, only with respect to healthy subjects. No significant difference was found in Rectus Femoris, Soleus, Hamstrings an Erectores Spinae onset among the three groups. INTERPRETATION: Results suggest a trend of diabetic neuropathic patients in earlier anticipation of the activation of the anterior body-muscles. In particular, the earlier onset of Tibialis Anterior is likely to be performed to adjust the movement timing and to compensate for the delay in the recruitment of the motor units. This anticipation might be involved in the altered postural control with increased balance impairment detected in diabetic neuropathic patients, and thereby it might also be proposed as an index of neuropathy, evidenced in a simple and non-invasive manner. PMID- 26653881 TI - Foot and ankle muscle strength in people with gout: A two-arm cross-sectional study. AB - BACKGROUND: Foot and ankle structures are the most commonly affected in people with gout. However, the effect of gout on foot and ankle muscle strength is not well understood. The primary aim of this study was to determine whether differences exist in foot and ankle muscle strength for plantarflexion, dorsiflexion, inversion and eversion between people with gout and age- and sex matched controls. The secondary aim was to determine whether foot and ankle muscle strength was correlated with foot pain and disability. METHODS: Peak isokinetic concentric muscle torque was measured for ankle plantarflexion, dorsiflexion, eversion and inversion in 20 participants with gout and 20 matched controls at two testing velocities (30 degrees /s and 120 degrees /s) using a Biodex dynamometer. Foot pain and disability was measured using the Manchester Foot Pain and Disability Index (MFPDI). FINDINGS: Participants with gout demonstrated reduced muscle strength at both the 30 degrees /s and 120 degrees /s testing velocities for plantarflexion, inversion and eversion (P<0.05). People with gout also displayed a reduced plantarflexion-to-dorsiflexion strength ratio at both 30 degrees /s and 120 degrees /s (P<0.05). Foot pain and disability was higher in people with gout (P<0.0001) and MFPDI scores were inversely correlated with plantarflexion and inversion muscle strength at the 30 degrees /s testing velocity, and plantarflexion, inversion and eversion muscle strength at the 120 degrees /s testing velocity (all P<0.05). INTERPRETATION: People with gout have reduced foot and ankle muscle strength and experience greater foot pain and disability compared to controls. Foot and ankle strength reductions are strongly associated with increased foot pain and disability in people with gout. PMID- 26653882 TI - A Cyanuric Acid Platform Based Tripodal Bis-heteroleptic Ru(II) Complex of Click Generated Ligand for Selective Sensing of Phosphates via C-H...Anion Interaction. AB - A new bis-heteroleptic trinuclear Ru(II) complex (1[PF6]6) has been synthesized from electron deficient cyanuric acid platform based copper-catalyzed azide alkyne cycloaddition, i.e., CuAAC click generated ligand, 1,3,5-tris [(2 aminoethyl-1H-1,2,3-triazol-4-yl)-pyridine]-1,3,5-triazinane-2,4,6-trione (L1). Complex 1[PF6]6 displays weak luminescence (phif = 0.002) at room temperature with a short lifetime of ~5 ns in acetonitrile. It shows selective sensing of hydrogen pyrophosphate (HP2O7(3-)) through 20-fold enhanced emission intensity (phif = 0.039) with a 15 nm red shift in emission maxima even in the presence of a large excess of various competitive anions like F(-), Cl(-), AcO(-), BzO(-), NO3(-), HCO3(-), HSO4(-), HO(-), and H2PO4(-) in acetonitrile. Selective change in the decay profile as well as in the lifetime of 1[PF6]6 in the presence of HP2O7(3-) (108 ns) further supports its selectivity toward HP2O7(3-). UV-vis and photoluminescence titration profiles and corresponding Job's plot analyses suggest 1:3 host-guest stoichiometric binding between 1[PF6]6 and HP2O7(3-). High emission enhancement of 1[PF6]6 in the presence of HP2O7(3-) has resulted in the detection limit of the anion being as low as 0.02 MUM. However, 1[PF6]6 shows selectivity toward higher analogues of phosphates (e.g., ATP, ADP, and AMP) over HP2O7(3-)/H2PO4(-) in 10% Tris HCl buffer (10 mM)/acetonitrile medium. Downfield shifting of the triazole C-H in a (1)H NMR titration study confirms that the binding of HP2O7(3-)/H2PO4(-) is occurring via C-H...anion interaction. The single crystal X-ray structure of complex 1 having NO3(-) counteranion, 1[NO3]6 shows binding of NO3(-) with complex 1 via C-H...NO3(-) interactions. PMID- 26653883 TI - Raman Based Molecular Imaging and Analytics: A Magic Bullet for Biomedical Applications!? PMID- 26653884 TI - Intra-rater and inter-rater reliability of ultrasonographic measurements of acromion-greater tuberosity distance in patients with post-stroke hemiplegia. AB - BACKGROUND: Glenohumeral subluxation (GHS) is reported in up to 81% of patients with stroke. Ultrasonographic measurements of GHS by measuring the acromion greater tuberosity (AGT) have been found to be reliable for experienced raters. OBJECTIVES: The primary aim was to assess the intra-rater reliability of measurements of AGT distance in people with stroke following a short course of rater training. A secondary aim was to compare the inter-rater reliability of these measurements between novice and experienced raters. METHODS: Patients with stroke (n = 16; 5 men, 11 women; 74 +/- 10 years) with 1-sided weakness who gave informed consent were recruited. Ultrasonographic measurements were recorded at the bedside by two physiotherapists with patients seated upright in a hospital chair. Reliability was assessed by intra-class correlation coefficients (ICCs) and the standard error of measurements (SEM). Minimum detectable change (MDC90) scores were used to estimate the magnitude of change that is likely to exceed measurement error. RESULTS: Mean +/- SD AGT distances on the affected and unaffected sides for rater 1 were 2.2 +/- 0.7 and 1.7 +/- 0.4 cm, respectively. Corresponding values for rater 2 were 2.5 +/- 0.6 and 2.0 +/- 0.4 cm. Intra-class correlation coefficient values for the affected and unaffected shoulders for rater 1 were 0.96 and 0.91, respectively. Corresponding values for rater 2 were 0.95 and 0.90.SEM and MDC90 for both affected and unaffected shoulders were <= 0.2 cm. Inter-rater reliability coefficients were 0.86 (affected) and 0.76 (unaffected) shoulders. CONCLUSION: Ultrasonographic measurement of AGT distance demonstrates excellent intra-rater reliability for a novice rater. Inter-rater reliability of ultrasonographic measurement of AGT also demonstrates good reliability between novice and experienced raters. PMID- 26653885 TI - Nanotechnology-Based Approaches for Guiding Neural Regeneration. AB - The mammalian brain is a phenomenal piece of "organic machinery" that has fascinated scientists and clinicians for centuries. The intricate network of tens of billions of neurons dispersed in a mixture of chemical and biochemical constituents gives rise to thoughts, feelings, memories, and life as we know it. In turn, subtle imbalances or damage to this system can cause severe complications in physical, motor, psychological, and cognitive function. Moreover, the inevitable loss of nerve tissue caused by degenerative diseases and traumatic injuries is particularly devastating because of the limited regenerative capabilities of the central nervous system (i.e., the brain and spinal cord). Among current approaches, stem-cell-based regenerative medicine has shown the greatest promise toward repairing and regenerating destroyed neural tissue. However, establishing controlled and reliable methodologies to guide stem cell differentiation into specialized neural cells of interest (e.g., neurons and oligodendrocytes) has been a prevailing challenge in the field. In this Account, we summarize the nanotechnology-based approaches our group has recently developed to guide stem-cell-based neural regeneration. We focus on three overarching strategies that were adopted to selectively control this process. First, soluble microenvironmental factors play a critical role in directing the fate of stem cells. Multiple factors have been developed in the form of small-molecule drugs, biochemical analogues, and DNA/RNA-based vectors to direct neural differentiation. However, the delivery of these factors with high transfection efficiency and minimal cytotoxicity has been challenging, especially to sensitive cell lines such as stem cells. In our first approach, we designed nanoparticle based systems for the efficient delivery of such soluble factors to control neural differentiation. Our nanoparticles, comprising either organic or inorganic elements, were biocompatible and offered multifunctional capabilities such as imaging and delivery. Moving from the soluble microenvironment in which cells are immersed to the underlying surface, cells can sense and consequently respond to the physical microenvironment in which they reside. For instance, changes in cell adhesion, shape, and spreading are key cellular responses to surface properties of the underlying substrate. In our second approach, we modulated the surface chemistry of two-dimensional substrates to control neural stem cell morphology and the resulting differentiation process. Patterned surfaces consisting of immobilized extracellular matrix (ECM) proteins and/or nanomaterials were generated and utilized to guide neuronal differentiation and polarization. In our third approach, building on the above-mentioned approaches, we further tuned the cell-ECM interactions by introducing nanotopographical features in the form of nanoparticle films or nanofiber scaffolds. Besides providing a three-dimensional surface topography, our unique nanoscaffolds were observed to enhance gene delivery, facilitate axonal alignment, and selectively control differentiation into neural cell lines of interest. Overall, nanotechnology-based approaches offer the precise physicochemical control required to generate tools suitable for applications in neuroscience. PMID- 26653886 TI - Identification of Li-Ion Battery SEI Compounds through (7)Li and (13)C Solid State MAS NMR Spectroscopy and MALDI-TOF Mass Spectrometry. AB - Solid-state (7)Li and (13)C MAS NMR spectra of cycled graphitic Li-ion anodes demonstrate SEI compound formation upon lithiation that is followed by changes in the SEI upon delithiation. Solid-state (13)C DPMAS NMR shows changes in peaks associated with organic solvent compounds (ethylene carbonate and dimethyl carbonate, EC/DMC) upon electrochemical cycling due to the formation of and subsequent changes in the SEI compounds. Solid-state (13)C NMR spin-lattice (T1) relaxation time measurements of lithiated Li-ion anodes and reference poly(ethylene oxide) (PEO) powders, along with MALDI-TOF mass spectrometry results, indicate that large-molecular-weight polymers are formed in the SEI layers of the discharged anodes. MALDI-TOF MS and NMR spectroscopy results additionally indicate that delithiated anodes exhibit a larger number of SEI products than is found in lithiated anodes. PMID- 26653887 TI - Smart Component for Switching of Plasmon Resonance by External Electric Field. AB - A new approach for preparation of active plasmonic component with capability to switch on/off localized surface plasmon resonance (LSPR) by piezoelectric effect is described. Polyvinylidene fluoride (PVDF) was patterned by polarized KrF excimer laser beam. The polarization was perpendicular to polymer orientation introduced during the poling procedure. Consequently the silver nanoclusters were sputtered onto the polymer surface. Application of an external electric field leads to polymer stretching and surface smoothening. Simultaneously, silver clusters are elongated and interconnected; this process leads to dramatic decrease of surface resistance and complete quenching of plasmon related absorption. PMID- 26653888 TI - Hepatitis E virus seroprevalence in pregnant women in Jiangsu, China, and postpartum evolution during six years. AB - BACKGROUND: China is an endemic area for hepatitis E virus (HEV). The previous surveys of anti-HEV seroprevalence are cross-sectional. This study aimed to investigate the prevalence of infection among pregnant women and their children in Jiangsu, China, and to observe postpartum anti-HEV evolution. METHODS: Sera from 497 women collected during pregnancy and 6-year postpartum and from their 497 children were screened for anti-HEV by ELISA and confirmed by Western blotting. HEV RNA was detected by reverse transcription-nested PCR. RESULTS: Of the pregnant women, 3 (0.6 %) were anti-HEV IgM positive and 55 (11.1 %) were IgG positive. At 6-year postpartum, 18 anti-HEV IgG positive samples became negative and 18 others became IgG positive; the accumulated prevalence in this cohort of women was at least 14.7 % (73/497). Of the 497 children, the positive rates of anti-HEV IgM and IgG were 0.2 % and 0.4 %, respectively. None of the 18 children from mothers with anti-HEV IgG seroconversion was anti-HEV IgG positive. CONCLUSIONS: Our data indicate that the constant seroprevalence of anti-HEV IgG in adults may be resulted from the balance of negative seroconversion due to waning immunity and positive seroconversion due to novel infections, and the risk of intra-family transmission of HEV was low. The data also imply that cross sectional seroepidemiological survey may underestimate the prevalence of HEV infection, due to the natural decay of pathogen-specific IgG. PMID- 26653889 TI - A polymorphism within the psoriasis susceptibility 1 candidate 1 (PSORS1C1) gene is not linked to HLA-B*58:01 in an Australian cohort. AB - Association exists between HLA-B*58:01 allele and allopurinol Stevens-Johnson syndrome (SJS), especially those of an Asian heritage but associations have been also described in Caucasian populations. This creates the need to develop a rapid, robust and inexpensive assay for pre-screening of HLA-B*58:01. A polymorphism within PSORS1C1 gene was recently found in linkage disequilibrium (LD) with HLA-B*58:01 allele in the Japanese population. The aim of this study is to confirm whether this polymorphism can be used as a surrogate biomarker to identify carriers for HLA-B*58:01. No linkage was found between the two in the Australian cohort. PMID- 26653890 TI - Seroprevalence of Toxoplasma gondii infection among patients with hand, foot and mouth disease in Henan, China: a hospital-based study. AB - BACKGROUND: The prevalence of infection with Toxoplasma gondii (T. gondii) in humans has been increasing in China due to the growing number of cats in the country. Hand, foot and mouth disease (HFMD) is a serious public health issue in China and still one of the leading causes of child mortality. However, little is known about the epidemiology of T. gondii infection among HFMD patients. METHODS: A case-control study of 281 HFMD patients from the First People's Hospital of Pingdingshan in Pingdingshan city, Henan province, central China, and 222 controls from Pingdingshan city was conducted. Anti-T. gondii antibodies were serologically detected using the enzyme-linked immunosorbent assay. RESULTS: We found that the overall anti-T. gondii immunoglobulin G (IgG) antibody prevalence among HFMD patients was 12.46 %, which was significantly higher than that in clinically healthy children (1.80 %). The highest T. gondii seroprevalence was detected in critical cases (22.58 %), followed by severe cases (11.50 %), and the lowest was detected in mild cases (8.33 %). CONCLUSION: The present study is the first survey of T. gondii seroprevalence among HFMD patients in China; 12.46 % were defined as seropositive. It is imperative that improved integrated measures are taken to prevent and control T. gondii infection among HFMD patients. PMID- 26653891 TI - MAST: a flexible statistical framework for assessing transcriptional changes and characterizing heterogeneity in single-cell RNA sequencing data. AB - Single-cell transcriptomics reveals gene expression heterogeneity but suffers from stochastic dropout and characteristic bimodal expression distributions in which expression is either strongly non-zero or non-detectable. We propose a two part, generalized linear model for such bimodal data that parameterizes both of these features. We argue that the cellular detection rate, the fraction of genes expressed in a cell, should be adjusted for as a source of nuisance variation. Our model provides gene set enrichment analysis tailored to single-cell data. It provides insights into how networks of co-expressed genes evolve across an experimental treatment. MAST is available at https://github.com/RGLab/MAST . PMID- 26653892 TI - The Well Organised Working Environment: A mixed methods study. AB - BACKGROUND: The English National Health Service Institute for Innovation and Improvement designed a series of programmes called The Productive Series. These are innovations designed to help healthcare staff reduce inefficiency and improve quality, and have been implemented in healthcare organisations in at least 14 different countries. This paper examines an implementation of the first module of the Productive Community Services programme called 'The Well Organised Working Environment'. OBJECTIVE: The quantitative component aims to identify the quantitative outcomes and impact of the implementation of the Well Organised Working Environment module. The qualitative component aims to describe the contexts, mechanisms and outcomes evident during the implementation, and to consider the implication of these findings for healthcare staff, commissioners and implementation teams. DESIGN: Mixed methods explanatory sequential design. SETTINGS: Community Healthcare Organisation in East Anglia, England. PARTICIPANTS: For the quantitative data, participants were 73 staff members that completed End of Module Assessments. Data from 25 services that carried out an inventory of stock items stored were also analysed. For the qualitative element, participants were 45 staff members working in the organisation during the implementation, and four members of the Productive Community Services Implementation Team. METHODS: Staff completed assessments at the end of the module implementation, and the value of items stored by clinical services was recorded. After the programme concluded, semi-structured interviews with staff and a focus group with members of the Productive Community Services implementation team were analysed using Framework Analysis employing the principles of Realist Evaluation. RESULTS: 62.5% respondents (n=45) to the module assessment reported an improvement in their working environment, 37.5% (n=27) reported that their working environment stayed the same or deteriorated. The reduction of the value of items stored by services ranged from L4 to L5039 across different services. Results of the qualitative analysis suggests explanations for why the programme worked in some contexts and not others, for instance due to varying levels of management support, and varying levels of resources allocated to carrying out or sustaining the improvement work. CONCLUSIONS: Quantitative analysis of data generated during healthcare improvement initiatives can give an impression of the benefits realised, but additional qualitative analysis also provides opportunity for learning to improve future implementations. Targets set by commissioners for innovation should focus on sustaining improvement rather demonstrating one-off benefits, and implementation teams should not let their preconceptions of what will and what will not work prevent them from trying interventions that may benefit staff. PMID- 26653894 TI - Improving Outcomes for Patients With Diabetic Macular Edema. AB - Diabetic macular edema (DME) is one of the most common causes of vision loss in patients who have diabetes, and all of these patients are at risk for developing DME. The onset is often painless, difficult to detect, and can occur at any stage of diabetes. Ideally, DME is preventable, but treatment must be considered when preventative methods fail. Although physicians have several different treatment options for patients with DME, some patients who receive treatment can respond poorly and may even lose vision. Until recently, laser photocoagulation was regarded as the standard of care for DME; however, pharmaceutical treatments are rapidly replacing this standard as the desire to maximize systemic treatment of DME increases. A panel of experts gathered during the 2015 annual meeting of the Association for Research in Vision and Ophthalmology for a roundtable discussion designed to focus on improving outcomes for patients with DME using pharmaceutical treatment, including the use of anti-VEGFs and corticosteroids, based on the most current research and clinical data. PMID- 26653896 TI - The role of physical formidability in human social status allocation. AB - Why are physically formidable men willingly allocated higher social status by others in cooperative groups? Ancestrally, physically formidable males would have been differentially equipped to generate benefits for groups by providing leadership services of within-group enforcement (e.g., implementing punishment of free riders) and between-group representation (e.g., negotiating with other coalitions). Therefore, we hypothesize that adaptations for social status allocation are designed to interpret men's physical formidability as a cue to these leadership abilities, and to allocate greater status to formidable men on this basis. These hypotheses were supported in 4 empirical studies wherein young adults rated standardized photos of subjects (targets) who were described as being part of a white-collar business consultancy. In Studies 1 and 2, male targets' physical strength positively predicted ratings of their projected status within the organization, and this effect was mediated by perceptions that stronger men possessed greater leadership abilities of within-group enforcement and between-group representation. Moreover, (a) these same patterns held whether status was conceptualized as overall ascendancy, prestige-based status, or dominance-based status, and (b) strong men who were perceived as aggressively self-interested were not allocated greater status. Finally, 2 experiments established the causality of physical formidability's effects on status-related perceptions by manipulating targets' relative strength (Study 3) and height (Study 4). In interpreting our findings, we argue that adaptations for formidability-based status allocation may have facilitated the evolution of group cooperation in humans and other primates. (PsycINFO Database Record PMID- 26653895 TI - Are Canadians more willing to provide chest-compression-only cardiopulmonary resuscitation (CPR)?-a nation-wide public survey. AB - BACKGROUND: Bystander cardiopulmonary resuscitation (CPR) improves the likelihood of survival from out-of-hospital cardiac arrest (OHCA), yet it is performed in only 30% of cases. The 2010 guidelines promote chest-compression-only bystander CPR-a change intended to increase willingness to provide CPR. OBJECTIVES: 1) To determine whether the Canadian general public is more willing to perform chest compression-only CPR compared to traditional CPR; 2) to characterize public knowledge of OHCA; and 3) to identify barriers and facilitators to bystander CPR. METHODS: A 32-item survey assessing resuscitation knowledge, and willingness to provide CPR were disseminated in five Canadian regions. Descriptive statistics were used to characterize response distribution. Logistic regression analysis was applied to assess shifts in intention to provide CPR. RESULTS: A total of 428 completed surveys were analysed. When presented with a scenario of being a bystander in an OHCA, a greater proportion of respondents were willing to provide chest-compression-only CPR compared to traditional CPR for all victims (61.5% v. 39.7%, p<0.001), when the victim was a stranger (55.1% v. 38.8%, p<0.001), or when the victim was an unkempt individual (47.9% v. 28.5%, p<0.001). When asked to describe an OHCA, 41.4% said the heart stopped beating, and 20.8% said it was a heart attack. Identified barriers and facilitators included fear of litigation and lack of skill confidence. CONCLUSIONS: This study identified gaps in knowledge, which may impair the ability of bystanders to act in OHCA. Most respondents expressed greater willingness to provide chest-compression-only CPR, but this was mediated by victim characteristics, skill confidence, and recognition of a cardiac arrest. PMID- 26653897 TI - The role of affect in the positive self: Two longitudinal investigations of young adolescents in the United States and China. AB - This research investigated the role of American and Chinese children's affect in the valence of their views of themselves. In 2 studies (Ns = 825 and 397), children in the United States and China reported on their affect (e.g., positive and negative emotions) and described themselves multiple times over the 7th and 8th grades. The more positive and less negative children's affect, the more positive their descriptions of themselves over time in both studies. These pathways were more consistent than those in the reverse direction (i.e., from children's self-descriptions to their affect). Notably, regardless of direction, the strength of the pathways was similar in the United States and China. The findings suggest that counter to some theoretical perspectives, affect is not more important in American than Chinese children's judgments about the self. (PsycINFO Database Record PMID- 26653899 TI - Wanted: microbiologists with basic knowledge of Latin and Greek to join our 'nomenclature quality control' team. PMID- 26653898 TI - Primary care physicians' role perception and self-reported performance in glaucoma care: a survey study. AB - BACKGROUND: Glaucoma is a leading cause of blindness. The participation of primary care physicians (PCPs) in glaucoma care may improve health outcomes for glaucoma patients. OBJECTIVES: To investigate PCPs' attitudes towards their role in glaucoma care, perceived barriers, and self-reported performance in glaucoma management. METHODS: PCPs working in the Haifa and Western Galilee District of Clalit Health Services, Israel's largest Health Maintenance Organization (HMO) were asked to complete a self-administered structured questionnaire. Physicians were asked to rate their agreement with statements describing the PCP's role in glaucoma care, and to state how often they behave accordingly in their practice. In addition, physicians were asked to rate the extent that factors such as time constraints and knowledge gaps impede their performance in glaucoma care. RESULTS: Eighty-two physicians completed the questionnaire. The majority thought that PCPs have a major role in early detection of glaucoma (99 %), discussing the importance of adherence to treatment (93 %), and encouraging patients to make regular visits to their ophthalmologist (99 %). However, only 30 % reported asking patients about family history of glaucoma, 64 % reported discussing adherence to treatment, and only 35 % stated that they explain how to use eye drops, while most of respondents (87 %) regularly provide refill prescriptions for glaucoma medications. Sixty percent claimed that during their residency they had not acquired adequate knowledge and competence to allow them to take proper care of glaucoma patients. The main barriers reported were lack of time (43 %), lack of knowledge regarding treatment options and recommended follow-up (46 %), and not being familiar with glaucoma medications' side effects (54 %). CONCLUSIONS: There is a gap between PCPs' perceptions of their role in glaucoma care and their report on actual performance in early detection and management of glaucoma. Further research is needed to develop and assess interventions that aim at closing this gap. PMID- 26653908 TI - Shotgun proteomics of bacterial pathogens: advances, challenges and clinical implications. AB - Mass spectrometry-based proteomics is increasingly used in analysis of bacterial pathogens. Simple experimental set-ups based on high accuracy mass spectrometry and powerful biochemical and bioinformatics tools are capable of reliably quantifying levels of several thousand bacterial proteins in a single experiment, reaching the analytical capacity to completely map whole proteomes. Here the authors present the state-of-the-art in bacterial pathogen proteomics and discuss challenges that the field is facing, especially in analysis of low abundant, modified proteins from organisms that are difficult to culture. Constant improvements in speed and sensitivity of mass spectrometers, as well as in bioinformatic and biochemical workflows will soon allow for comprehensive analysis of regulatory mechanisms of pathogenicity and enable routine application of proteomics in the clinical setting. PMID- 26653926 TI - Critical care nurses and relatives of elderly patients in intensive care unit Ambivalent interaction. AB - OBJECTIVE: The objective was to explore the experiences of CCNs in relation to relatives of elderly patients 80 years and older admitted to ICU. DESIGN AND SETTING: Through methods grounded in phenomenology, six CCNs were purposefully selected for their experiences with relatives of elderly patients admitted to an ICU in Norway. Each CCN participated in semi-structured personal interviews. Using content analysis, interviews were coded and categories and themes were identified. FINDINGS: An overall theme emerged: "CCNs ambivalent interactive struggle with the relatives of elderly patients", which reflected the mixed feelings that CCNs recalled having towards relatives. Two themes emerged during the analysis. These were: "relatives are a resource for CCNs and the patient"; and "relatives are seen as challenge". Six sub-themes were identified: (1) CCNs are relying on relatives, (2) relatives and their understanding of the situation, (3) relatives are committed, (4) relatives have high expectations, (5) relatives can be seen as burden and (6) relatives with cultural differences are a challenge. CONCLUSION: CCN's experiences with the relatives of elderly patients in ICU represent a significant personal, mixed struggle. RELEVANCE TO CLINICAL PRACTICE: The findings indicate that development of communication, education, reflection and a more structured organization of intensive care unit can improve results for CCNs and may improve the possibilities for CCNs to promote an excellent family nursing for the elderly patient and his relatives. PMID- 26653927 TI - Geographical Distribution and Seasonal Indices of Chigger Mites on Small Mammals Collected on the East Coast of the Republic of Korea. AB - The geographical distributions and relative population densities of scrub typhus vector mites collected from small mammals were determined for 5 locations on the east coast of the Republic of Korea. Collection sites included Goseong, Gangneung, and Hoengseong in Gangwon province and Uljin and Yeongdeok in Gyeongbuk province. A total of 275 small mammals including members of Rodentia (rodents) and Soricomorpha (shrews, such as Crocidura lasiura ) belonging to 4 genera and 4 species were captured in the field from 2012 to 2013. Apodemus agrarius was collected most frequently (220, 80%), followed by C. lasiura (25, 9.1%), Mus musculus (15, 5.5%), and Myodes regulus (15, 5.5%). A total of 23,436 larval chigger mites (Family Trombiculidae) belonging to 3 genera and 8 species (Leptotrombidium pallidum, Leptotrombidium scutellare, Leptotrombidium palpale, Leptotrombidium orientale, Leptotrombidium zetum, Neotrombicula tamiyai, Neotrombicula japonica, and Euschoengastica koreaensis) were collected from the small mammals. The predominant chigger species collected during the spring and fall seasons from A. agrarius were L. pallidum (57.6%), L. palpale (14.5%), and L. scutellare (7.9%). Leptotrombidium scutellare was collected only along the southeastern coast at Yeongdeok, Gyeongbuk province. The geographical distribution of scrub typhus vectors and reservoir hosts are important aspects of understanding the epidemiology of the disease as well as the potential impacts of climate change and health risks. PMID- 26653928 TI - Advances in transfusion science for shock-trauma: Optimising the clinical management of acute haemorrhage. AB - The primary resuscitation of severely injured patients, acute haemorrhage and shock-trauma has been well reported in the literature. Resuscitation protocols include the use of diverse agents such as fresh whole blood [FWB], packed red blood cells [PRBCs], reconstituted blood products, fresh frozen plasma [FFP] and its derivative concentrates or recombinant products, volume expanders and tranexamic acid [TXA]. The reasonably prudent use of these agents and products is necessary to reverse risk factors of haemorrhagic shock such as haemodilution, hypothermia, acidosis and coagulopathy. Addressing the mechanisms of haemoregulation in the pathophysiology of DIC is important to optimise transfusion practice. PMID- 26653929 TI - One center's experience with implementing extracorporeal photopheresis in a pediatric setting. PMID- 26653930 TI - Blood donation knowledge and attitudes among undergraduate health science students: A cross-sectional study. AB - Awareness towards blood donation can be empowered by health professionals' role modelling. We aimed to assess knowledge and attitudes among Greek undergraduate medical laboratory students. A questionnaire was distributed to 330 students (response rate: 88.7%). Overall, 24% had donated blood at least once, with males 4.62 times more likely to be donors. Voluntary, non-remunerated blood donors were more likely to be repeaters. A quarter of all students were inclined to offer blood for monetary reward, with men more prone to accept payment. There is a need to campaign health science students during formal education through need-based as well as altruistic 'smart' messages. PMID- 26653931 TI - Implementation of electronic identification system for blood transfusion in the setting of hematopoietic progenitor cell infusion at the bedside. AB - Hematopoietic progenitor cell (HPC) infusion at the bedside is a critical step in HPC transplantation. In this study, we implemented a bar code-based electronic identification system (EIS) for blood transfusion in the setting of HPC infusion at the bedside. Between July 2003 and December 2014, a total of 518 HPC products were infused to 190 patients without a single misinfusion in the hospital. An overall compliance rate with the electronic pre-infusion check for HPC infusion at the bedside was 100%. Our observations suggest that an EIS can be successfully applied to the infusion of HPC products at the bedside. PMID- 26653932 TI - Optic disc morphology in unilateral branch retinal vein occlusion using spectral domain optical coherence tomography. AB - BACKGROUND: The aim of this study was to evaluate the association between optic nerve head (ONH) parameters and branch retinal vein occlusion (BRVO) using spectral domain optical coherence tomography (SD-OCT). METHODS: Both eyes of 40 patients with unilateral BRVO (mean age: 67.4 +/- 11.4 years, male: female - 18:22) were enrolled in this study. Control group consisted of randomly selected single healthy eyes of 40 age and gender matched volunteers (mean age: 64.7 +/- 15.4 years, male: female - 16:24). ONH parameters (including optic disc area, optic cup area, neuroretinal rim area, cup volume, rim volume, cup-disc area ratio, horizontal and vertical cup-disc ratio, average retinal nerve fiber layer) were measured by SD-OCT. Axial length (AL) of the eyes was measured by non contact optical low coherence reflectometry. The ONH parameters of eyes with BRVO were compared with those of fellow eyes using mixed model, one-way between-groups analysis of covariance was conducted to compare the ONH parameters of affected and unaffected fellow eyes in BRVO patients with those of the control eyes keeping confounding factors, including AL, age and gender under control in the statistical analysis. RESULTS: None of the investigated ONH parameters of affected BRVO eyes, unaffected fellow eyes and control eyes were statistically different after controlling for AL, age and gender. CONCLUSION: Optic disc morphology might not be a potential anatomical predisposing factor for development of BRVO. PMID- 26653933 TI - Impact of ventricular assist device placement on longitudinal renal function in children with end-stage heart failure. AB - BACKGROUND: Although ventricular assist devices (VADs) restore hemodynamics in those with heart failure, reversibility of end-organ dysfunction with VAD support is not well characterized. Renal function often improves in adults after VAD placement, but this has not been comprehensively explored in children. METHODS: Sixty-three children on VAD support were studied. Acute kidney injury (AKI) was defined by Kidney Disease: Improving Global Outcomes criteria. Estimated glomerular filtration rate (eGFR) was determined by the Schwartz method. Generalized linear mixed-effects models compared the pre-VAD and post-VAD eGFR for the cohort and sub-groups with and without pre-VAD renal dysfunction (pre-VAD eGFR < 90 ml/min/1.73 m(2)). RESULTS: The pre-VAD eGFR across the cohort was 84.0 ml/min/1.73 m(2) (interquartile range [IQR] 62.3-122.7), and 55.6% (34 of 63) had pre-VAD renal dysfunction. AKI affected 60.3% (38 of 63), with similar rates in those with and without pre-existing renal dysfunction. Within the cohort, the nadir eGFR occurred 1 day post-operatively (62.9 ml/min/1.73 m(2); IQR, 51.2-88.9 ml/min/1.73 m(2); p < 0.001). By Day 5, however, the eGFR exceeded the baseline (99.0 ml/min/1.73 m(2); IQR, 59.3-146.7 ml/min/1.73 m(2); p = 0.03) and remained significantly higher through the first post-operative week. After adjusting for age, gender, and AKI, the eGFR continued to increase throughout the entire 180 day study period (beta = 0.0025; 95% confidence interval, 0.0015-0.0036; p < 0.001). Patients with pre-VAD renal dysfunction experienced the greatest improvement in the eGFR (beta = 0.0051 vs beta = 0.0013, p < 0.001). CONCLUSIONS: Renal dysfunction is prevalent in children with heart failure undergoing VAD placement. Although peri-operative AKI is common, renal function improves substantially in the first post-operative week and for months thereafter. This is particularly pronounced in those with pre-VAD renal impairment, suggesting that VADs may facilitate recovery and maintenance of kidney function in children with advanced heart failure. PMID- 26653934 TI - The Intracellular Dynamics of Circadian Clocks Reach for the Light of Ecology and Evolution. AB - A major challenge for biology is to extend our understanding of molecular regulation from the simplified conditions of the laboratory to ecologically relevant environments. Tractable examples are essential to make these connections for complex, pleiotropic regulators and, to go further, to link relevant genome sequences to field traits. Here, I review the case for the biological clock in higher plants. The gene network of the circadian clock drives pervasive, 24-hour rhythms in metabolism, behavior, and physiology across the eukaryotes and in some prokaryotes. In plants, the scope of chronobiology is now extending from the most tractable, intracellular readouts to the clock's many effects at the whole organism level and across the life cycle, including biomass and flowering. I discuss five research areas where recent progress might be integrated in the future, to understand not only circadian functions in natural conditions but also the evolution of the clock's molecular mechanisms. PMID- 26653935 TI - High-Frequency, Low-Intensity Pulsed Ultrasound Enhances Alveolar Bone Healing of Extraction Sockets in Rats: A Pilot Study. AB - Most studies of the beneficial effects of low-intensity pulsed ultrasound (LIPUS) on bone healing have used frequencies between 1.0 and 1.5 MHz. However, after consideration of ultrasound wave characteristics and depth of target tissue, higher-frequency LIPUS may have been more effective on superficially positioned alveolar bone. We investigated this hypothesis by applying LIPUS (frequency, 3.0 MHz; intensity, 30 mW/cm(2)) on shaved right cheeks over alveolar bones of tooth extraction sockets in rats for 10 min/d for 2 wk after tooth extraction; the control group (left cheek of the same rats) did not receive LIPUS treatment. Compared with the control group, the LIPUS group manifested more new bone growth inside the sockets on histomorphometric analysis (maximal difference = 2.5-fold on the seventh day after extraction) and higher expressions of osteogenesis related mRNAs and proteins than the control group did. These findings indicate that 3.0-MHz LIPUS could enhance alveolar bone formation and calcification in rats. PMID- 26653936 TI - Ultrasound Assessment of the Skeletal Development of the Proximal Tibial, Proximal Femoral, and Distal Femoral Epiphyses in Premature and Mature Newborns. AB - We evaluated postnatal skeletal development of the proximal femoral epiphysis, distal femoral epiphysis (DFE) and proximal tibial epiphysis (PTE) in 178 premature and mature newborns, between 25 and 47 wk of biological age, using high resolution B-mode musculoskeletal ultrasound. Approximate age-related values were determined based on the ossification center size and epiphyseal cartilage thickness. The earliest onsets of visible mineralization were at 30 wk of maturity in the DFE, 31 wk in the PTE and 43 wk in the proximal femoral epiphysis. In preterm and term neonates, significant correlations were observed for transverse and longitudinal length of the DFE and PTE with biological age (R2 = 0.35-0.50, p < 0.01). No significant age-dependent increases or decreases in cartilage thickness were seen between the ossification centers and cartilage surface in the DFE and PTE. High-resolution B-mode musculoskeletal ultrasound is an excellent tool for assessing skeletal development in premature and mature newborns. PMID- 26653937 TI - Characterization of Positively Charged Lipid Shell Microbubbles with Tunable Resistive Pulse Sensing (TRPS) Method: A Technical Note. AB - Microbubbles are polydisperse microparticles. Their size distribution cannot be accurately measured from the current methods used, such as optical microscopy, electrical sensing or light scattering. Indeed, these techniques present some limitations when applied to microbubbles, which prompted us to investigate the use of an alternative technique: tunable resistive pulse sensing (TRPS). This technique is based on the principle of the Coulter counter with the advantage of being more flexible compared to other methods using this principle, since the flow rate, the potential difference and the pore size can be modulated. The main limitation of TRPS is that more than one size of nanopore membrane is required to obtain the full size distribution of polydisperse microparticles. To evaluate this technique, the concentration and the size distribution of positively charged microbubbles were studied using TRPS and compared to data obtained using optical microscopy. We describe herein the parameters required for the accurate measurement of microbubble concentration and size distribution by TRPS and present a statistical comparison of the data obtained by TRPS and optical microscopy. PMID- 26653938 TI - Long-Term Effects of Pericardiectomy on Left Ventricular Mechanics Evaluated by Using Speckle Tracking Echocardiography in Patients with Constrictive Pericarditis. AB - The aim of this study was to evaluate long-term changes in left ventricular (LV) mechanics after pericardiectomy in patients with constrictive pericarditis (CP) and to correlate post-operative LV mechanics with clinical status. A total of 24 patients with CP underwent serial speckle tracking echocardiography 1 wk before and 1, 6 and 12 mo after pericardiectomy. Global LV longitudinal, circumferential and radial strains, along with LV twist, were measured. Twenty-three healthy volunteers were served as control patients. Although global LV longitudinal, circumferential and radial strains obtained 6 mo after pericardiectomy increased compared with those for pre-pericardiectomy, they were still significantly lower than those for control patients. Further improvements occurred over time with normalization of global LV longitudinal and radial strains 12 mo after pericardiectomy, but global circumferential strain obtained 12 mo after pericardiectomy was still lower than that for control patients. LV twist remained unchanged after pericardiectomy. In addition, the improvements in global LV circumferential strain after pericardiectomy were associated with improvements in clinical symptoms (p < 0.001). These findings suggest that the global LV circumferential strain may be a promising parameter in the evaluation of the effectiveness of pericardiectomy. PMID- 26653939 TI - [The potential role of microbiota in major psychiatric disorders: Mechanisms, preclinical data, gastro-intestinal comorbidities and therapeutic options]. AB - While forecasts predict an increase in the prevalence of mental health disorders in the worldwide general population, the response rate to classical psychiatric treatment remains unsatisfactory. Resistance to psychotropic drugs can be due to clinical, pharmacological, pharmacokinetic, and pharmacodynamic factors. Among these factors, recent animal findings suggest that microbiota may have an underestimated influence on its host's behavior and on drug metabolism that may explain ineffectiveness or increased side effects of psychiatric medications such as weight gain. The following issues were identified in the present review: (i) microbiota dysbiosis and putative consequences on central nervous system functioning; (ii) chronic microbiota dysbiosis-associated illnesses in humans; (iii) microbiota-oriented treatments and their potential therapeutic applications in psychiatry. PMID- 26653940 TI - Aspiration of a hepatic hidatid cyst through a laparoscopic trocar. PMID- 26653941 TI - Subcutaneous abscess. Atypical presentation of acute cholecystitis. PMID- 26653942 TI - Exploring Interfacial Events in Gold-Nanocluster-Sensitized Solar Cells: Insights into the Effects of the Cluster Size and Electrolyte on Solar Cell Performance. AB - Gold nanoclusters (Au NCs) with molecule-like behavior have emerged as a new light harvester in various energy conversion systems. Despite several important strides made recently, efforts toward the utilization of NCs as a light harvester have been primarily restricted to proving their potency and feasibility. In solar cell applications, ground-breaking research with a power conversion efficiency (PCE) of more than 2% has recently been reported. Because of the lack of complete characterization of metal cluster-sensitized solar cells (MCSSCs), however, comprehensive understanding of the interfacial events and limiting factors which dictate their performance remains elusive. In this regard, we provide deep insight into MCSSCs for the first time by performing in-depth electrochemical impedance spectroscopy (EIS) analysis combined with physical characterization and density functional theory (DFT) calculations of Au NCs. In particular, we focused on the effect of the size of the Au NCs and electrolytes on the performance of MCSSCs and reveal that they are significantly influential on important solar cell characteristics such as the light absorption capability, charge injection kinetics, interfacial charge recombination, and charge transport. Besides offering comprehensive insights, this work represents an important stepping stone toward the development of MCSSCs by accomplishing a new PCE record of 3.8%. PMID- 26653943 TI - Colonic disease site and perioperative complications predict need for later intestinal interventions following intestinal resection in pediatric Crohn's disease. AB - INTRODUCTION: We studied variables associated with outcomes following intestinal resection for Crohn's disease. METHODS: A retrospective review of a prospectively maintained single surgeon database was performed. Outcomes evaluated included disease recurrence, need for further resection/dilatation, and complications. Explanatory variables included: anatomical region of resection, open or laparoscopic approach, surgical procedure, technique of anastomosis, number of anastomoses, use of biological therapy, resection margin disease, age at resection, and period (quartile) in series. RESULTS: 81 children had 100 resections at a median age 14.5years with a median follow-up of 7.7years. Overall complication rate was 22%. Of the 77 children with no prior resection, 40 (52%) had disease recurrence, and 24 (31%) underwent further resection or dilatation. None of the explanatory variables predicted complications. Disease recurrence was significantly associated with younger age at first resection but not duration of follow-up. The probability of further intestinal intervention was strongly associated with disease site and complications. Odds ratio for further surgery for colonic disease site compared to ileocecal disease site was 7 (95% CI 1.8-26; P=0.004). Odds ratio for further intestinal resection following surgery where a complication had occurred compared to no complication was 3.4 (95% CI 1.1-10.3; P=0.02. Both disease site and complication status also significantly affected the interval to further surgery. CONCLUSIONS: The probability of requiring a second intestinal intervention for pediatric Crohn's disease is related to the disease site and the complication status. PMID- 26653944 TI - Colectomy in pediatric ulcerative colitis: A single center experience of indications, outcomes, and complications. AB - BACKGROUND/PURPOSE: There is a paucity of data on outcomes and complications of colectomy for pediatric ulcerative colitis (UC). This study reports the experience of a regional center for 18years. METHODS: Patients were identified from a prospective database and data obtained by note review. Median height/weight-SDS were calculated preoperatively and postoperatively. Data are expressed as median values (range). RESULTS: 220 patients with UC (diagnosed <17years) were identified, and 19 (9%) had undergone colectomy. Age at diagnosis was 11.6years (1.3-16.5), and 42% of patients were male. Time from diagnosis to surgery was 2.2years (0.1-13.1). All patients had failed maximal medical therapy. Fifteen patients had urgent scheduled operation, and 4 had emergency procedures, with 2 for (11%) acute-severe colitis (1 Clostridium difficile colitis) and 2 for acute-severe colitis with toxic dilatation. All initial procedures were subtotal colectomy with ileostomy. Nine patients (47%) had early complications (during initial admission), 7 (37%) requiring reoperation. Six (32%) had late complications, with 5 requiring laparotomy. No patients had both early and late complications. Height-SDS was -0.27 before surgery and -0.23 (maximal follow-up). Weight-SDS was 0.32 and 0.05 (maximal follow-up). CONCLUSION: Approximately 1/11 children with UC required colectomy during childhood. Half of patients had acute complications, and 1/3 of patients required another operation during their first admission. 1/3 of patients developed late complications. PMID- 26653946 TI - Summary Report: 62nd Annual Congress - British Association of Paediatric Surgeons Cardiff, Wales, UK, July 22nd- 24th, 2015. AB - The 62nd British Association of Paediatric Surgeons (BAPS) Annual Conference was held July 22-24, 2015, in Cardiff, Wales. This congress issue contains papers presented during the open sessions and transcripts based on invited lectures. PMID- 26653945 TI - Pathology of asymptomatic, prenatally diagnosed cystic lung malformations. AB - AIM: The management of asymptomatic congenital cystic lung malformations is controversial. Arguments for excision of asymptomatic lesions are the potential for infection and malignancy. Following antenatal detection, our institute performs a CT at 1month, clinic follow-up by 3months to discuss the controversial management, and offers surgery by 6months of age. We investigated the histopathology of asymptomatic lesions to determine whether there was evidence of subclinical infection or malignancy. METHODS: A retrospective review of prospectively collected antenatal congenital cystic lung malformations more than a 10year period (2005-2014) was conducted. Information was gathered from the antenatal registry and histopathology reports. Infection was defined by the presence of microabscesses or neutrophil/macrophage infiltration, as per histopathological criteria. MAIN RESULTS: From the cohort of 99 patients, the study focused on 69 asymptomatic lesions. These cases comprised 34 congenital pulmonary airway malformations (CPAM), 15 pulmonary sequestrations (PS), and 20 hybrid lesions. Eighteen cases (26%) had microscopic disease - 16 cases of infection and 2 tumors. The infectious cases comprised 7 with microabscesses and 9 with neutrophil/macrophage infiltration. There were two cases of tumors, namely pleuropulmonary blastoma. These tumors were followed up by the oncology team with regular imaging until 3years of age and clinical review thereafter. CONCLUSION: Twenty-six percent of antenatally detected, asymptomatic cystic lung malformations demonstrated either subclinical infection or malignancy. This information can be used for counseling parents and determining the method of treatment. PMID- 26653947 TI - Fetal Surgical conditions and the unraveling of maternal-fetal tolerance. AB - Fetal surgery is a fascinating field that will continue to evolve as we develop a more refined understanding of the underlying biology of various birth defects. Since preterm labor is a frequent outcome of fetal intervention, examining the mechanisms that lead to a breakdown in maternal-fetal tolerance is vital to developing strategies to overcome this limitation. The trafficking of cells between the mother and fetus during pregnancy plays a critical role in the education of the fetal immune system and may have implications for postnatal transplantation tolerance. Maternal cells may also be the ideal source for transplantation into the fetus to treat congenital stem cell disorders. PMID- 26653948 TI - Developmental outcomes at three years of age of infants with esophageal atresia. AB - BACKGROUND/AIMS: Previous work assessing early developmental outcomes of infants at one year of age following surgery for esophageal atresia (OA) and/or tracheoesophageal fistula (TOF) found a significantly lower score in expressive language compared with control infants. The purpose of this study was to determine whether these differences were still evident at three years of age. METHODS: Between August 2006 and July 2008, infants who required surgical correction of OA/TOF were prospectively enrolled as part of a large study which examined developmental outcomes following surgery. Patients were reassessed using the Bayley Scales of Infant and Toddler Development Version III. Cognition, expressive and receptive language, fine motor and gross motor skills scores were compared with both the standardized norms and also with contemporaneous control infants. RESULTS: 24 of the 31 infants (77%) assessed at one year were reassessed at three years of age. There was no significant difference between the Bayley scores of the infants with OA/TOF and the standardized norms of the tests in four of the subsets: cognition, expressive language, fine and gross motor skills. Infants with OA scored higher than normative values for the receptive language subscale (P=0.001). When compared with the controls, there were no significant differences in any of the subscales. CONCLUSION: Compared with the outcomes at one year, infants with OA/TOF have improved and were scoring within the normal range for the assessment at three years. This may in part be because of the early intervention services which many of these children were provided. PMID- 26653949 TI - Contemporary pediatric surgical training in the UK. AB - INTRODUCTION: Pediatric surgical trainees worldwide face pressures from expansion of programs and training positions, subspecialization, regionalization, restrictions of working hours, and rigid training criteria. The era of apprenticeship training has long gone, and surgical education needs to be responsive and adapt to newer challenges. The aim of this study was to examine the teaching provision component of pediatric surgical training in the UK. METHOD: A national teaching survey was sent to UK pediatric surgery trainees in 2010 and compared to results of a repeat survey in 2015. Analysis was carried out to compare type of teaching, trends in teaching delivery, quality, and attendance over time. RESULTS: Regional variability was noted in teaching programs. Both provision of educational activities and ability to attend teaching improved between 2010 and 2015. Despite this, overall trainee satisfaction remained low, with 50% and 52% of respondents describing their teaching as "good" or "excellent" in 2010 and 2015, respectively (P=0.84). Seventy-five percent of centers provided simulation training, and 25% of respondents had regional teaching provided. Survey response rate was comparable between 2010 and 2015. CONCLUSION: Variability in national educational provision was observed. We suggest regular national audit of educational activity and responsive adaption to external pressures on training if competent surgeons are to be the product of contemporary pediatric surgery training programs. PMID- 26653950 TI - Delayed abdominal closure after congenital diaphragmatic hernia repair. AB - PURPOSE: We present our experience with CDH patients who required delayed abdominal closure following CDH repair. METHODS: A retrospective review of all CDH repairs from 2004 to 2014 was performed. RESULTS: 233 patients underwent CDH repair, of which 21 required delayed abdominal closure defined as the inability to close the abdominal fascia at the time of CDH repair. The incidence of delayed closure was higher in those undergoing CDH repair on ECMO vs. not on ECMO (40% [17/43] vs. 2% [4/190]; P<0.001). The abdominal wound was temporarily covered by skin only (n=2), skin+prosthetic mesh sutured to the fascia (n=3), preformed silo (n=9), or vacuum assisted closure (VAC(r)) device (n=7). The mean time to fascial closure was 14.5+/-7 and 6+/-3days for patients repaired on ECMO and not on ECMO, respectively. In patients repaired on ECMO, the "primary closure" and "delayed closure" groups were not different in prenatal predictors (liver up, lung-to-head ratio [LHR]), total days on ECMO, ECMO days prior to CDH repair, and survival. In patients repaired on ECMO, the "delayed closure" group had a significantly higher requirement for blood transfusions compared to the "primary closure" group (mean 87+/-35 vs. 62+/-27ml of packed RBCs per ECMO day; P=0.01). CONCLUSION: Delayed abdominal closure was required in 40% of CDH repairs done on ECMO but was rarely required in CDH repairs performed off ECMO. Although associated with an increased need for blood transfusions, delayed closure following CDH repair on ECMO was not associated with increased mortality. PMID- 26653951 TI - Biliary atresia: From Australia to the zebrafish. AB - This review is based upon an invited lecture for the 52nd Annual Meeting of the British Association of Paediatric Surgeons, July 2015. The aetiology of biliary atresia (BA) is at best obscure, but it is probable that a number of causes or pathophysiological mechanisms may be involved leading to the final common phenotype we recognise clinically. By way of illustration, similar conditions to human BA are described, including biliary agenesis, which is the normal state and peculiar final pattern of bile duct development in the jawless fish, the lamprey. Furthermore, there have been remarkable outbreaks in the Australian outback of BA in newborn lambs whose mothers were exposed to and grazed upon a particular plant species (Dysphania glomulifera) during gestation. More recent work using a zebrafish model has isolated a toxic isoflavonoid, now named Biliatresone, thought to be responsible for these outbreaks. Normal development of the bile ducts is reviewed and parallels drawn with two clinical variants thought to definitively have their origins in intrauterine life: Biliary Atresia Splenic Malformation syndrome (BASM) and Cystic Biliary Atresia (CBA). For both variants there is sufficient clinical evidence, including associated anomalies and antenatal detection, respectively, to warrant their aetiological attribution as developmental BA. CMV IgM +ve associated BA is a further variant that appears separate with distinct clinical, histological, and immunohistochemical features. In these it seems possible that this involves perinatal obliteration of a normally formed duct system. Although still circumstantial, this evidence appears convincing enough to perhaps warrant a different treatment strategy. This then still leaves the most common (more than 60% in Western series) variant, now termed Isolated BA, whereby origins can only be alluded to. PMID- 26653952 TI - Differential physiological and behavioral cues observed in individuals smoking botanical marijuana versus synthetic cannabinoid drugs. AB - CONTEXT: Synthetic cannabinoid use has increased in many states, and medicinal and/or recreational marijuana use has been legalized in some states. These changes present challenges to law enforcement drug recognition experts (DREs) who determine whether drivers are impaired by synthetic cannabinoids or marijuana, as well as to clinical toxicologists who care for patients with complications from synthetic cannabinoids and marijuana. Our goal was to compare what effects synthetic cannabinoids and marijuana had on performance and behavior, including driving impairment, by reviewing records generated by law enforcement DREs who evaluated motorists arrested for impaired driving. METHODS: Data were from a retrospective, convenience sample of de-identified arrest reports from impaired drivers suspected of using synthetic cannabinoids (n = 100) or marijuana (n = 33). Inclusion criteria were arrested drivers who admitted to using either synthetic cannabinoids or marijuana, or who possessed either synthetic cannabinoids or marijuana; who also had a DRE evaluation at the scene; and whose blood screens were negative for alcohol and other drugs. Exclusion criteria were impaired drivers arrested with other intoxicants found in their drug or alcohol blood screens. Blood samples were analyzed for 20 popular synthetic cannabinoids by using liquid chromatography-tandem mass spectrometry. Delta-9 tetrahydrocannabinol (THC) and THC-COOH were quantified by gas chromatography mass spectrometry. Statistical significance was determined by using Fisher's exact test or Student's t-test, where appropriate, to compare the frequency of characteristics of those in the synthetic cannabinoid group versus those in the marijuana group. RESULTS: 16 synthetic cannabinoid and 25 marijuana records met selection criteria; the drivers of these records were arrested for moving violations. Median age for the synthetic cannabinoid group (n = 16, 15 males) was 20 years (IQR 19-23 years). Median age for the marijuana group (n = 25, 21 males) was 20 years (IQR 19-24 years) (p = 0.46). In the synthetic cannabinoid group, 94% (15/16) admitted to using synthetic cannabinoids. In the marijuana group, 96% (24/25) admitted to using marijuana. Blood was available for testing in 96% (24/25) of the marijuana group; 21 of these 24 had quantitative levels of THC (mean + SD = 10.7 + 5 ng/mL) and THC-COOH (mean + SD = 57.8 + 3 ng/mL). Blood was available for testing in 63% (10/16) of the synthetic cannabinoid group, with 80% (8/10) of these positive for synthetic cannabinoids. Those in the synthetic cannabinoid group were more frequently confused (7/16 [44%] vs. 0/25 [0%], p <= 0.003) and disoriented (5/16 [31%] vs. 0/25 [0%], p <= 0.003), and more frequently had incoherent, slurred speech (10/16 [63%] vs. 3/25 [12%], p = 0.0014) and horizontal gaze nystagmus (8/16 [50%] vs. 3/25 [12%], p = 0.01) than those in the marijuana group. CONCLUSION: Drivers under the influence of synthetic cannabinoids were more frequently impaired with confusion, disorientation, and incoherent, slurred speech than drivers under the influence of marijuana in this population evaluated by DREs. PMID- 26653954 TI - Trehalose improves semen antioxidant enzymes activity, post-thaw quality, and fertility in Nili Ravi buffaloes (Bubalus bubalis). AB - Our objectives were to study the effect of trehalose in extender on (1) antioxidant enzymes profile during cryopreservation (after dilution, before freezing, and after thawing), (2) in vitro quality (after thawing), and (3) in vivo fertility of Nili Ravi buffalo (Bubalus bubalis) bull spermatozoa. Semen samples (n = 20) from four buffalo bulls were diluted in Tris-citric acid-based extender having different concentrations of trehalose (0.0, 15, 30, 45, and 60 mM) and frozen in French straws. At post dilution, profile of sperm catalase (U/mL) was higher (P < 0.05) in extenders containing 15, 30, and 45 mM of trehalose as compared to control. Although profiles of superoxide dismutase (U/mL) and total glutathione (MUM) were higher (P < 0.05) in extenders containing 15 and 30 mM of trehalose as compared to control. At prefreezing, sperm catalase, superoxide dismutase, and total glutathione profiles were higher (P < 0.05) in all the treatment groups as compared to control. At post thawing, the profiles of catalase and total glutathione were higher (P < 0.05) in extender containing 30 mM trehalose as compared to other treatment groups and control. Whereas, profile of superoxide dismutase was higher (P < 0.05) in extenders containing 30, 45, and 60 mM of trehalose as compared to control and 15mM group. Post thaw total sperm motility (%) was higher (P < 0.05) in extender containing 30-mM trehalose as compared to control and 15 and 60-mM groups. Although sperm progressive motility (%), rapid velocity (%), average path velocity (MUm/s), straight line velocity (MUm/s), curvilinear velocity (MUm/s), plasma membrane (structural and functional, %), acrosome (%), and DNA (%) integrity were higher (P < 0.05) in extender containing 30 mM trehalose as compared to other treatment groups and control. The fertility rates (61% vs. 43%) were higher (P < 0.05) in buffaloes inseminated with semen doses cryopreserved in extender containing 30 mM of trehalose than the control. It is concluded that addition of 30-mM trehalose in extender improves the semen antioxidant enzymes activity, post thaw quality, and fertility in Nili Ravi buffaloes. PMID- 26653953 TI - Epidemiology of acute poisoning in children presenting to the poisoning treatment center at Ain Shams University in Cairo, Egypt, 2009-2013. AB - INTRODUCTION: Pediatric poisonings represent a major and preventable cause of morbidity and mortality throughout the world. Epidemiologic information about poisoning among children in many lower- and middle-income countries is scarce. This study describes the epidemiology of acute poisonings in children presenting to Ain Shams University's Poisoning Treatment Center (ASU-PTC) in Cairo and determines the causative agents and characteristics of acute poisoning in several pediatric age groups. METHODS: This retrospective study involved acutely poisoned patients, 0-18 years of age, who presented to the ASU-PTC between 1 January 2009 and 31 December 2013. Data were extracted from electronic records maintained by the ASU-PTC. Collected data included demographics, substance of exposure, circumstances of the poisoning, patient disposition, and outcome. RESULTS: During the 5-year study period, 38 470 patients meeting our criteria were treated by the ASU-PTC; 19 987 (52%) were younger than 6 years of age; 4196 (11%) were 6-12 years; and 14 287 (37%) were >12 years. Unintentional poisoning accounted for 68.5% of the ingestions, though among adolescents 84.1% of ingestions were with self-harm intent. In all age groups, the most frequent causative drugs were non opioid analgesics, antipyretics, and antirheumatics. The most common nonpharmaceutical agents were corrosives in preschool children and pesticides in adolescents. Most patients had no/minor effects (29 174 [75.8%]); hospitalization rates were highest among adolescents. There were 119 deaths (case fatality rate of 0.3), primarily from pesticide ingestion. CONCLUSION: Poisoning in preschool children is mainly unintentional and commonly due to nonpharmaceutical agents whereas poisoning in adolescents is mainly intentional (self-harm). Pesticides, mainly organophosphorous compounds and carbamates, were the most frequent agents leading to morbidity and mortality. PMID- 26653955 TI - [Efficacy of three dimensional visualization technique assisted hepatectomy for the treatment of primary liver cancer]. AB - OBJECTIVE: To study the clinical efficacy of three dimensional visualization technique assisted hepatectomy for the treatment of primary liver cancer. METHODS: A total of 108 primary liver cancer patients who had been admitted to Zhujiang Hospital of Southern Medical University from September 2013 to December 2014 were assigned to three dimensional visualization technique assisted hepatectomy group (n = 55) and routine hepatectomy group (n = 53) according to different methods of hepatectomy. The observed variable in two groups as fellow: the operative time, intraoperative blood loss, intraoperative blood transfusion, the change of postoperative liver function and biochemical indicators in 1, 3, 5 days, postoperative complication. The patients were followed up via-return visit or telephone.A student's t test was used to compare continuous parametric variables, and the Mann-Whitney U test was used to compare non-parametric or discrete variables, as appropriate. Categorical data were compared using the Chi square test or Fisher's exact test. RESULTS: In 3D group and routine hepatectomy group, the patients' intraoperative blood transfusion volume were 300 ml (200-600 ml) and 400 ml (300-700 ml) (chi2 = -2.609, P = 0.009) respectively, intraoperative blood loss volume were 400 ml (250-600 ml) and 550 ml (400-800 ml) (chi2 = -2.277, P = 0.023), the operative time were (247 +/- 57) min and (262 +/- 53) min (chi2 = -1.787, P = 0.074), the deterioration of the mainly liver function indicators peak in routine hepatectomy group were higher than that in 3D group (P < 0.05). The ALT, AST, TBIL in 3D group were lower than that in routine group on postoperative day 1, 3, 5, respectively (chi2 = -5.740- -0.692, all P < 0.05). The ALB in 3D group was higher than that in routine group on postoperative day 3, 5 ((33.0 +/- 5.6) g/L vs. (31.2 +/- 4.1) g/L, (36.7 +/- 4.4) g/L vs. (34.7 +/- 4.2) g/L) (t = 1.922-2.573, both P < 0.05). In 3D group and routine hepatectomy group, the incidence of postoperative complications were 10.9% and 30.1% (chi2 = 6.185, P = 0.013), the length of postoperative hospital day were (12.6 +/- 3.6) days and (14.4 +/- 3.5) days (chi2 = -3.384, P = 0.031), the positive rate of resection margin were 0 and 9.4% respectively (Fisher test: P = 0.026), the 1-year tumor recurrence rate were 22.2% and 37.5% (P > 0.05), 1-year survival rate was 82.2% and 77.5% (P > 0.05). No perioperative mortality was occured in the two groups. CONCLUSION: Three dimensional visualization technique assisted hepatectomy for the treatment of primary liver cancer could reduce surgical injury, lower the rate of postoperative complications, improve the safety and the efficacy of the operation and achieve a good prognosis. PMID- 26653956 TI - [Risk factors associated with the severity of pulmonary embolism in patients with acute deep venous thrombosis of lower extremities]. AB - OBJECTIVE: To identify the risk factors associated with the severity of pulmonary embolism among patients with deep venous thrombosis of lower extremities. METHODS: This prospective study enrolled 208 patients with acute deep venous thrombosis to screen for pulmonary embolism between July 2010 and July 2012 in Beijing Shijitan Hospital. There were 101 male and 107 female patients, with a mean age of (59 +/- 16) years. Gender, age, extension, side of lower extremities of deep venous thrombosis was analyzed by chi2 test. Ordinal Logistic regression was used to determine risk factors associated with severity of pulmonary embolism. RESULTS: There were 83 patients with iliofemoral deep venous thrombosis, 102 patients with femoropopliteal and 23 patients with calf deep venous thrombosis. Pulmonary embolism was detected in 70 patients with the incidence of 33.7%. Pulmonary embolism was significantly correlated with extension (chi2 = 17.286, P = 0.004) and sides (chi2 = 15.602, P = 0.008) of deep venous thrombosis, not with age (chi2 = 7.099, P = 0.260), gender (chi2 = 7.014, P = 0.067), thrombotic risk factors (chi2 = 3.335, P = 0.345) in univariate analysis. Results of multivariate ordinal logistic regression showed that iliofemoral vein thrombosis (OR = 6.172, 95% CI: 1.590 to 23.975, P = 0.009) and bilateral venous thrombosis (OR = 7.140, 95% CI: 2.406 to 24.730, P = 0.001) are associated with more serious pulmonary embolism. CONCLUSIONS: Incidence of pulmonary embolism is still high in patients with deep venous thrombosis. Extensive iliofemoral and bilateral vein thrombosis may increase risk of severity of pulmonary embolism. Clinicians should pay more attention to these high-risk patients. PMID- 26653957 TI - [Radiological characteristics and clinical manifestation of isolated lumbar foraminal stenosis]. AB - OBJECTIVE: To discuss radiological characteristics and clinical manifestation of isolated lumbar foraminal stenosis. METHODS: From March 2011 to March 2014, 21 patients with isolated degenerative lumbar foraminal stenosis accepted lumbar decompression and fusion in Beijing Luhe Hospital. Intervertebral disc space was evaluated by measuring the position of joint-body line on preoperative X-ray. Bilateral foraminal area of the corresponding segment in CT (sagittal view of 2D reconstruction) and MRI (T2W1 sagittal view) were measured by Surgimap software. For patients with unilateral symptoms, foraminal area of the affected side was compared with that of the contralateral side. Foraminal area of the same segment on CT was also compared with that on MRI. Preoperatively and at the final follow up, visual analogue score (VAS) and Oswestry Disability Index (ODI) were used to evaluate clinical outcomes. RESULTS: All patients had a follow-up over 6 months and the average follow-up was 16.8 months (7-42 months). Of the 21 patients (26 segments), 12 segments showed gross narrowing and 14 segments showed slight narrowing. After preoperative measurement on MRI, 6 patients had foraminal stenosis of grade 2, and 15 patients had foraminal stenosis of grade 3, showing no significant difference in clinical outcomes. Compared with the foraminal area of the unaffected side, the affected side showed a decrease of 16% on CT and 28% on MRI, and the difference was statistically significant (t = 3.453, P < 0.05). The foraminal area measured on CT was larger than that measured on MRI (P < 0.05). Compared with that preoperatively, VAS (back pain), VAS (leg pain) and ODI showed significant improvement at the final follow-up (P < 0.05). CONCLUSIONS: Radiological examinations as X-ray, CT, MRI and intervertebral foramen block technique play an important role in the diagnosis of foraminal stenosis. Soft oppression caused by hyperplasia and hypertrophy of transforaminal ligment or joint capsule may be important promoters of degenerative lumbar foraminal stenosis. Lumbar foraminal decompression and interbody fusion can satisfactorily improve preoperative symptoms. PMID- 26653958 TI - [Research of efficacy of brachytherapy for localized prostate cancer]. AB - OBJECTIVE: To investigate the efficacy of brachytherapy for patients with localized prostate cancer and the influence factors. METHODS: There were 61 patients with localized prostate cancer were treated with brachytherapy between April 2001 and March 2011 in Department of Urology, Peking University First Hospital, including 11 patients who received combined external beam radiotherapy. The mean age was 75.2 years (range 57-84 years). Clinical stage was T1c in 12 patients, T2a in 18 patients, T2b in 17 patients, and T2c in 14 patients. Long term follow-up was carried on all patients for prostate specific antigen (PSA) and adverse effects. Kaplan-Meier survival curves, Log-rank test and univariate Cox proportional hazard regression analysis was used to examine the factors associated with the treatment efficacy. RESULTS: The median follow-up was 49 months (range 9-126 months). The mean PSA before treatment and the mean nadir PSA after operation were (17.80 +/- 14.44) ug/L and (1.16 +/- 1.15) ug/L, respectively. The PSA of 58 patients (95.1%) reached a nadir < 4.0 ug/L, which was even < 1.0 ug/L in 37 patients (60.7%). The mean time to reach the nadir PSA was 11.6 months after operation. The short-term adverse events after operation included fever in 4 patients, hematuria in 7 patients, and hematochezia in 4 patients. The most common long-term adverse event was urinary irritation (31.1%); other long-term adverse events were rare, including hematochezia, hematuria, urinary incontinence, urinary retention, mild diarrhea and radiation enteritis. The estimated mean biochemical recurrence-free survival after brachytherapy was 41.0 months (95% CI: 31.05-50.94 months). The mean nadir PSA after operation were 1.32 ug/L in the 11 patients who received combined external beam radiotherapy, and their estimated mean biochemical recurrence-free survival was 38 months. Patients with nadir PSA < 1.0 ug/L had a significant longer biochemical recurrence-free survival than those with nadir PSA between 1.0 ug/L and 4.0 ug/L (42.9 vs. 32.0 months, chi2 = 4.445, P = 0.035). CONCLUSIONS: Brachytherapy is an effective treatment strategy for localized prostate cancer, with relatively low rate of severe adverse events. After brachytherapy, a nadir PSA < 1.0 ug/L might indicate a better prognosis. PMID- 26653959 TI - [The preliminary clinical results of laparoscopic ileum augmentation cystoplasty for low compliance bladder]. AB - OBJECTIVE: To study the effectiveness and safety of the laparoscopic ileal bladder augmentation treatment for low compliance bladder. METHODS: A retrospective analysis was performed based on 36 cases admitted to the Zhejiang Provincial People's Hospital with highly reflective and low compliance bladder accepted laparoscopic ileal bladder augmentation surgical treatment from June 2011 to December 2013. In accordance with inclusion and exclusion criteria, 22 patients were enrolled in this study, including 13 males, 9 females who aged from 22 to 62 years with an average of 35.8 years. Among the selected sample, there were 15 cases of spinal cord injury, 4 cases of spinal cord dysplasia, and 3 cases of urinary tuberculosis. The duration of disease varied from 1 to 15 years, with an average of 8.5 years. For surgery, intraoperative and perioperative complications were observed, and preoperative serum creatinine in patients with postoperative at 3, 6, 12, 18, 24, 36 months, hydronephrosis, and glomerular filtration rate urodynamic parameters were used for univariate analysis of variance. RESULTS: All patients were successfully completed in laparoscopic surgery, the operative time were (105 +/- 17) minutes (90-150 minutes), blood loss was (90 +/- 26) ml (60-150 ml), postoperative intestinal function recovery time were (2.5 +/- 0.7) d (2-5 d), and postoperative hospital stay was (15.0 +/- 4.2) d (11-20 d), while postoperative anastomotic leakage, intestinal blockage, severe abdominal infection or sepsis and other complications did not occur. Patients were followed up for 6 to 36 months, with an average of 16.5 months, among which 17 patients were followed up for over 12 months. The bladder safety capacity increased from (103 +/- 38) ml preoperatively to (405 +/- 46) ml at the end of the follow-up (F = 381.7, P = 0.000), and bladder compliance increased from (10 +/- 3) cmH2O (1 cmH2O = 0.098 kPa) preoperatively to (38 +/- 4) cmH2O (F = 678.1, P = 0.000); the average pressure within the bladder filling at the end of the follow-up was (16 +/- 6) cmH2O, which was significantly lower (F = 221.5, P = 0.000) compared to preoperative level of (45 +/- 16) cmH2O, preoperative serum creatinine went down from (184 +/- 32) umol/L to (120 +/- 28) umol/L at the end of the follow-up (F = 189.1, P = 0.000); total glomerular filtration rate rose from (40 +/- 26) ml-1 . min-1 . 1.73 m-2 preoperatively to (66 +/- 32) ml-1 . min(-1) . 1.73 m-2 (F = 137.7, P = 0.000). Qmax of the 3 cases of urinary bladder contracture tuberculosis patients increased significantly, while 4 female patients with residual urine volume decrease had voluntary urination. CONCLUSIONS: Laparoscopic ileal bladder augmentation treatment for low compliance bladder is feasible and safe, with less trauma, less bleeding, less post operative complications, and faster recovery of bowel function. Urinary function improves significantly after surgery, and function of upper urinary tract can also be effectively improved and protected in patients. PMID- 26653960 TI - [Clinical analysis of 49 cases with testicular torsion]. AB - OBJECTIVE: To improve the diagnosis and treatment of testicular torsion. METHODS: The clinical features of 49 testicular torsion patients admitted to Department of Urology Nanjing Drum Tower Hospital from April 2008 to March 2014 were retrospectively analyzed, the average age was (21 +/- 6) years (range 13-52 years).Forty-four cases underwent the color Doppler flow imaging of scrotum, demonstrated reduction of the testicular blood supply in 9 cases and loss of the testicular blood supply in 35 cases. Orchiectomy or orchiopexy was performed according to the testicular blood supply, the contralateral testis fixation was performed in all patients. A two-tailed Student's t-test was used to compare the data between two groups, Pearson correlation analysis was used to analyze the correlation of diurnal temperature and number of cases. RESULTS: All the patients with testicular torsion were Tunica-reversed, 38 (77.5%) cases occurred from November to April. The monthly incidence of testicular torsion was positively correlated with diurnal temperature (r = 0.6434, P = 0.024). Forty-four cases underwent the color Doppler flow imaging, demonstrated the reduction or loss of the testicular blood supply, and these patients were confirmed to be testicular torsion by surgical exploration. The salvage rates of testis in patients with testicular torsion were 2/2, 5/15, 2/9 and 4.2% (1/24) in those seeking medical attention within 6, 12, 24 hours and over 24 hours after the onset of pain. All the patients were followed up for 3 to 75 months, and no one experienced recurrent torsion. CONCLUSIONS: The incidence of testicular torsion is higher during the spring and winter, diurnal temperature change is associated with testicular torsion. The diagnostic rate of color Doppler flow imaging is high, which can be chosen as the primary method. Prompt recognition and treatment are necessary for testicular salvage. PMID- 26653961 TI - [Short term effect of multiple stents parallel placement and reconstruction technique for the treatment of giant fusiform vertebrobasilar dissecting aneurysms]. AB - OBJECTIVE: To investigate the feasibility,safety and follow-up results of multiple stents parallel placement and reconstruction technique for treating giant vertebrobasilar dissecting aneurysms. METHODS: Five consecutive patients with giant fusiform vertebrobasilar dissecting aneurysms in Department of Neurology,Chinese People's Liberation Army General Hospital were retrospectively reviewed from April 2011 to October 2013. All patients were diagnosed vertebrobasilar dissecting aneurysms by MRI and digital subtraction angiography (DSA), the aneurysm size ranged 8.2-15.0 mm. All patients were treated by multiple stents parallel placement and reconstruction technique under general anesthesia. In the endovascular treatment process, 2-3 Solitaire or Neuroform self-expandable stents were parallel implanted in the maximum extension segment of the aneurysms to reconstruct the cavity of the aneurysm and solved the problem that the diameter of the intracranial stent is less than the diameter of the aneurysms. Multiple stents parallel placement can keep the stents stable in the cavity. The parallel stent can close the dissection as well as strengthen the aneurysm walls to alleviate the vessel pulsative compression of the brain stem. Furthermore, one of the parallel stents was selected for the main blood flow channel. Based on the main channel, telescope technique was used to completely covering the dissection. It can not only prevent the progress of dissection to normal regions, but also be helpful for blood flow channel reconstruction to reduce the hemodynamic disorders. All Patients received routine antiplatelet therapy before and after endovascular treatment. RESULTS: The operative procedures were succeeded in all patients. Five patients were implanted 18 stents (3 stents in 3 patients; 4 stents in 1 patient; 5 stents in 1 patient; parallel 3 stents in 2 patients; parallel 2 stents in 3 patients). The signs and symptoms of brain stem and posterior group of cranial nerves improved significantly. All patients lived and worked normally and had no recurrent symptoms on follow-up of 6-24 months. All patients performed DSA reexamination at 6-12 months postoperation. The aneurysm size lessened in 2 patients and had no change in 3 patients. CONCLUSIONS: Multiple stents parallel placement and reconstruction technique for treating giant fusiform vertebrobasilar dissecting aneurysms is feasible and have good operation safety. It may control the dilatation of the aneurysm and reduce the probability of thrombosis or hemorrhage. It can improve the patients' clinical symptoms and quality of life in short term follow-up. The long term result need for further follow-up. PMID- 26653962 TI - [Operative procedure choice for surgical management of chronic tuberculous empyema: a series of 461 cases]. AB - OBJECTIVE: To study the experiences and operative procedure choice for surgical management of chronic tuberculous empyema. METHODS: Totally 461 patients of chronic tuberculous empyema were treated surgically in Shandong Provincial Chest Hospital between January 2006 and December 2011. There were 317 male and 144 female patients, aging from 6 to 79 years with a mean age of 32 years. Preoperative duration lasted from 3 months to 50 years, including 347 cases within 1 year, 61 cases 1 to 2 years, and 53 cases above 2 years. Chest tube drainage or pleuracentesis was performed in 395 patients, decortication in 287 patients, thoracoplasty in 13 patients, pleuropneumonectomy and resection of remaining lung in 11 patients, complex operation in 150 patients. RESULTS: There was no death perioperatively. Four hundred and forty-five patients were cured at once, 6 patients were cured by stages. One patient with empyema and bronchial fistula relapsed bronchial fistula after pulmonary lobectomy and pleural decortication, whom was cured by the combination operation which including fistula repair, muscle flap tamponing and local thoracoplasty according to the closed drainage of thoracic cavity after 6 months. Three cases were suffered incision delayed healing and were cured by dressing change. Five cases were suffered abscess of chest wall within 3 months and were cured by local thoracoplasty. One patient died due to respiratory failure in one year which resulted in tuberculosis spreading because of bronchial fistula after pleuropneumonectomy. CONCLUSIONS: Surgical management of chronic tuberculous empyema still have irreplaceable roles. Selecting appropriate operations according to different cases will achieve good results. PMID- 26653963 TI - [The relationship between myasthenia gravis and the different pathological type of thymoma patients' operation and prognosis]. AB - OBJECTIVE: To evaluate the different pathological and clinical characteristics of thymomas with and without myasthenia gravis (MG) and to determine whether the presence of MG influences the prognosis in thymoma patients. METHODS: The clinical data from 228 consecutive patients (median sternotomy were used in 153, video-assisted thoracoscopic themectomy were used in 75) operated on from January 1992 to December 2007 was analyzed retrospectively. These thymoma patients had been subdivided into two groups: thymoma with MG (n = 125) and thymoma without MG (n = 103). All thymic epithelial tumors were classified according to the WHO histologic classification and the Masaoka clinical staging system. The result was evaluated according to the Myasthenia Gravis Foundation of America's criterion. The clinical features of the 2 test was compared between the two groups by chi2 test, and the survival were compared between the two groups by Cox analysis. RESULTS: There were no peri-operative deaths. 19 cases were inoperable (6 in the group with MG, 13 without MG (chi2 = 4.52, P = 0.035)). The proportions of type A and thymic carcinoma were 0 in the group with MG, 10.5% (11/103) and 11.6% (12/103) respectively in the group without MG. According to the Masaoka's clinical staging, in the group MG, 24.8% (31/125) patients were stage III and IV; in the group without MG, 33.0% (34/103) patients were stage III and IV. There was a significant difference between hyperplastic paraneoplastic thymus coexisting in 28.8% (36/125) patients with MG and only 5.8% (6/103) in patients without MG (chi2 = 20.91, P = 0.000) Microthymoma was identified in the paraneoplastic thymus of 3 patients with MG. There were 198 patients followed up, the rate was 86.8% (198/228). There was no recurrence in patients with type A and a few patients with type AB, B1, B2, B3 thymoma and thymic carcinoma recurred. The actuarial 5- and 10-year survival rates were 89.3% and 81.2% for patients with MG respectively, and 90.0% and 78.9% for patients without MG respectively. Within 5 years postoperatively, 6 of 9 patients with MG died of myasthenia crisis, while 6 out of 7 deaths in patients without MG were attributable to inoperable tumors (stage IV) and thymic carcinoma. CONCLUSIONS: The existence of myasthenia gravis has little influence on the prognosis of thymomas, but it is good for early diagnosis and treatment. Extended thymectomy should be performed to all patients with thymoma, no matter they have myasthenia gravis or not. The main cause of death is myasthenia crisis for thymoma patients with MG and stage IV and (or) thymic carcinoma for patients without MG. PMID- 26653964 TI - [The effects of sleeve gastrectomy on renal function in type 2 diabetic rats]. AB - OBJECTIVE: To examine the renal function changes and mechanisms on rats with diabetes through a sleeve gastrectomy operation. METHODS: Thirty-six rats were induced diabetes through injection of streptozotocin (STZ), and 30 of these diabetic rats that blood glucose levels at the midrange (blood sugar 17.88-23.65 mmol/L, mean: 20.32 mmol/L) were randomly assigned to the sleeve gastrectomy group, Sham-operation group and control group. The serum creatinine, lipid parameters were measured postoperatively. The 24 h urine volume obtained and urine albumin excretion rate (UAER) was calculated. Serum and urinary creatinine were examined and glomerular filtration rate (GFR) was counted. Kidney sections were stained with periodic acid-Schiff, and then the index of mesangial expansion was determined. The expression of synaptopodin for podocytes was also performed through the immunohistochemical procedure. A one-way ANOVA and t-test were performed to evaluate differences between groups and each other. RESULTS: Only one rat of SG group died after operation. The GFR ((8.44 +/- 2.10) ml . g-1 . d 1), 24 h UAER ((36.04 +/- 11.10) mg/d), plasma lipids level (total cholesterol (1.66 +/- 0.23) mmol/L, triglycerides (1.25 +/- 0.17) mmol/L), kidney weight ((1.61 +/- 0.06) g), the index of mesangial expansion ((6.14 +/- 1.50)%) and synaptopodin expression ((20.44 +/- 2.99)%) were improved in the SG group compared with the sham-operation group ((15.05 +/- 3.01) ml . g-1 . d-1, (57.01 +/- 11.34) mg/d, (2.15 +/- 0.29) mmol/L, (1.65 +/- 0.23) mmol/L, (1.93 +/- 0.07) g, (11.32 +/- 2.09)%, (10.34 +/- 1.43)%) and control group ((14.79 +/- 2.38) ml . g-1 . d-1, (62.71 +/- 16.46) mg/d, (2.23 +/- 0.21) mmol/L, (1.59 +/- 0.20) mmol/L, (1.91 +/- 0.06) g, (10.82 +/- 1.79)%, (11.13 +/- 2.43)%) (t = 0.781 5.025, all P < 0.05). CONCLUSION: The sleeve gastrectomy procedure can improve the renal function in a diabetes rat model may be through protecting the podocytes function and preventing the mesangial expansion of glomeruli. PMID- 26653965 TI - [Review and analysis of transplant biological research projects funded by National Natural Science Foundation of China]. AB - OBJECTIVE: To study the funding and achievements in the field of organ transplantation support by the National Natural Science Foundation of China (NSFC). METHODS: A search of NSFC database was made by using the key word "transplantation" and excluding "bone marrow transplantation" for the projects funded between 1988 and 2013. SCI indexed publications that marked with NSFC project number were collected by searching each grant number in the database of the Web of Science. RESULTS: Six hundreds fifty-five projects were identified and received about 220 million yuan in grant funding. These funded research projects were distributed among 25 provinces and autonomous regions, however, which were mainly in the developed coastal areas; of them, 43 (6.56%) projects were granted in xenotransplantation and 17 projects (2.60%) were funded in the field of traditional Chinese medicine-related organ transplantation; Transplantation on blood vessels, heart, kidney, liver, lung, small intestine, pancreatic, cornea, trachea, skin, etc. were primarily performed in research. Nine hundreds and sixty one SCI-indexed publications were achieved. CONCLUSIONS: Magnitude and intensity of NSFC funding, output of SCI publications have been increasing, suggesting that NSFC positively promotes the development of organ transplantation. Although a great progress of transplantation has been made, basic and translational studies should be vigorously strengthened. PMID- 26653966 TI - [Research progress on the clinical value of Ki-67 in breast cancer and its cut off definition]. AB - Ki-67 has an important application value in clinical practice. However, it is still a little tough in clinical application because of the debate on the cut-off definition of Ki-67 index. This review summarizes most studies on the prognostic and predictive value of Ki-67, analyzes the reasons for the discrepancies among the studies cited, and presents the necessity and clinical significance of scientifically defining the cut-off of Ki-67 index, providing a theoretical basis for Ki-67 in clinical application. PMID- 26653967 TI - [Role of computational fluid dynamics in thoracic aortic diseases research: technical superiority and application prospect]. AB - Computational fluid dynamics (CFD) technology has the potential to simulate normal or pathologic aortic blood flow changes of mechanical properties and flow field, thereby helping researchers understand and reveal the occurrence, development and prognosis of aortic disease. In aortic diseases research, the initial conditions of CFD numerical simulation has experienced a developed process from idealization (forward engineering), rigid vessel wall, uniform cross sections, laminar flow and stable blood flow towards personalization (reverse engineering), elastic vessel wall (fluid-solid coupling technique), cone-shaped diminishing cross-sections, turbulent flow, pulsatile blood flow. In this review, the research status, the technical superiority and application prospect of CFD technology were discussed with examples in following three major application areas: (1) dynamics characteristic and mechanical properties in normal thoracic aorta; (2) occurrence, advance and disruptive risk predicting in thoracic aortic aneurysm; (3) therapeutic effect and aneurysmal dilatation simulation in thoracic aortic dissection. For the future, the CFD technology may profoundly put an influence on the awareness to aortic diseases and treatment strategies. PMID- 26653968 TI - CRIM1, a newfound cancer-related player, regulates the adhesion and migration of lung cancer cells. AB - CRIM1 is a member of the bone morphogenetic protein (BMP) antagonists; however, the role of CRIM1 in controlling cancer cell behavior remains unknown. This study investigated its function in the A549 cell line in vitro. The results show that treating cells with CRIM1 peptide could increase the migration and adhesion of A549. Consistently, silencing the CRIM1 expression decreased the migration and adhesion of A549. Furthermore, the CRIM1 protein expression was increased in A549 which were treated with transforming growth factor beta 1 to induced EMT. However, CRIM1 peptide treatment could increase the expression of N-CAD and E-CAD expression. Finally, overexpression of the oncogene YAP1 resulted in an up regulation of the CRIM1 expression in A549, suggesting that CRIM1 was a target of the Hippo pathway. These observations provide evidence for the first time that CRIM1 plays a role in cancer cells by enhancing the migration and adhesion and increasing the expression of N-CAD and E-CAD. PMID- 26653970 TI - Protective Effect of Total Flavones from Hippophae rhamnoides L. against Visible Light-Induced Retinal Degeneration in Pigmented Rabbits. AB - Sea buckthorn (Hippophae rhamnoides L.) flavones have been used as candidate functional food ingredients because of their bioactivities, such as treating cardiovascular disorders, lowering plasma cholesterol level, and regulating immune function. However, the protective effects of sea buckthorn flavones against retinal degeneration remain unclear to date. This study investigated the protective effects of total flavones from H. rhamnoides (TFH) against visible light-induced retinal damage and explored the related mechanisms in pigmented rabbits. Rabbits were treated with TFH (250 and 500 mg/kg) for 2 weeks pre illumination and 1 week post-illumination until sacrifice. Retinal function was quantified by performing electroretinography 1 day before and 1, 3, and 7 days after light exposure (18000 lx for 2 h). Retinal degeneration was evaluated by measuring the thickness of the outer nuclear layer (ONL) and performing the TUNEL assay 7 days after light exposure. Enzyme-linked immunosorbent assay, Western blot analysis, and immunohistochemistry were used to explore the antioxidant, anti-inflammatory, and anti-apoptotic mechanisms of TFH during visible light induced retinal degeneration. Light exposure produced a degenerative effect primarily on the ONL, inner nuclear layer (INL), and ganglion cell layer (GCL). TFH significantly attenuated the destruction of electroretinograms caused by light damage, maintained ONL thickness, and decreased the number of TUNEL positive cells in the INL and GCL. TFH ameliorated the retinal oxidative stress (GSH-Px, CAT, T-AOC, and MDA), inflammation (IL-1beta and IL-6), angiogenesis (VEGF), and apoptosis (Bax, Bcl2, and caspase-3) induced by light exposure. Therefore, TFH exhibited protective effects against light-induced retinal degeneration by increasing the antioxidant defense mechanisms, suppressing pro inflammatory and angiogenic cytokines, and inhibiting retinal cell apoptosis. PMID- 26653971 TI - Partitioning of Laponite Clay Platelets in Pickering Emulsion Polymerization. AB - Partitioning of laponite disklike clay platelets between polymer particles and bulk aqueous phase was investigated in Pickering surfactant-free emulsion polymerization of styrene. Adsorption of laponite clay platelets plays an important role in the stabilization of this system, influencing the particle size and the number of particles, and, hence, the reaction rate. Adsorption isotherms show that, while the laponite clay platelets are almost fully exfoliated in water, they form multilayers on the surface of the polymer particles by the end of polymerization, as confirmed by transmission electron microscopy (TEM). This observation is supported by quartz crystal microbalance, conductivity, and TEM measurements, which reveal interactions between the clay and polystyrene, as a function of the ionic strength. The strong adsorption of clay platelets leaves a low residual concentration in the aqueous phase that cannot cause further nucleation of polymer particles, as demonstrated during seeded emulsion polymerization experiments in the presence of a high excess of clay. A Brunauer Emmett-Teller (BET)-type model for laponite adsorption on polystyrene particles matches the adsorption isotherms. PMID- 26653972 TI - Release and Formation of Oxidation-Related Aldehydes during Wine Oxidation. AB - Twenty-four Spanish wines were subjected to five consecutive cycles of air saturation at 25 degrees C. Free and bound forms of carbonyls were measured in the initial samples and after each saturation. Nonoxidized commercial wines contain important and sensory relevant amounts of oxidation-related carbonyls under the form of odorless bound forms. Models relating the contents in total aldehydes to the wine chemical composition suggest that fermentation can be a major origin for Strecker aldehydes: methional, phenylacetaldehyde, isobutyraldehyde, 2-methylbutanal, and isovaleraldehyde. Bound forms are further cleaved, releasing free aldehydes during the first steps of wine oxidation, as a consequence of equilibrium shifts caused by the depletion of SO2. At low levels of free SO2, de novo formation and aldehyde degradation are both observed. The relative importance of these phenomena depends on both the aldehyde and the wine. Models relating aldehyde formation rates to wine chemical composition suggest that amino acids are in most cases the most important precursors for de novo formation. PMID- 26653973 TI - The past, present and future of fluorescent protein tags in anaerobic protozoan parasites. AB - The world health organization currently recognizes diarrhoeal diseases as a significant cause of death in children globally. Protozoan parasites such as Giardia and Entamoeba that thrive in the oxygen-deprived environment of the human gut are common etiological agents of diarrhoea. In the urogenital tract of humans, the anaerobic protozoan parasite Trichomonas vaginalis is notorious as the most common non-viral, sexually transmitted pathogen. Even with high medical impact, our understanding of anaerobic parasite physiology is scarce and as a result, treatment choices are limited. Fluorescent proteins (FPs) are invaluable tools as genetically encoded protein tags for advancing knowledge of cellular function. These FP tags emit fluorescent colours and once attached to a protein of interest, allow tracking of parasite proteins in the dynamic cellular space. Application of green FPs-like FPs in anaerobic protozoans is hindered by their oxygen dependency. In this review, we examine aspects of anaerobic parasite biology that clash with physio-chemical properties of FPs and limit their use as live-parasite protein tags. We expose novel FPs, such as miniSOG that do not require oxygen for signal production. The potential use of novel FPs has the opportunity to leverage the anaerobe parasitologist toolkit to that of aerobe parasitologist. PMID- 26653974 TI - Porphyra Species: A Mini-Review of Its Pharmacological and Nutritional Properties. AB - Porphyra sensu lato belongs to Bangiales, the most genetically diverse order of red algae. Porphyra or Pyropia is widely cultivated in East Asian countries, such as China, Japan, and Korea. Dried Porphyra contains numerous nutritional and biofunctional compounds, including proteins, minerals, dietary fiber, polyunsaturated fatty acids, carotenoids, saccharides, and mycosporine-like amino acids. In addition, the compound is most abundant in Porphyra, such as polysaccharides and phycobiliproteins, and demonstrates various immunomodulating, anticancer, antihyperlipidemic, and antioxidative activities. This review summarizes our current knowledge concerning the pharmacologically active substances found in Porphyra species. The biological activities and potential applications of certain carbohydrates, proteins, peptides, and other small molecules purified from Porphyra are also described, and possible areas for future studies are discussed. PMID- 26653975 TI - Prevalence of dengue viral and malaria parasitic co-infections in an epidemic district, Angul of Odisha, India: An eco-epidemiological and cross-sectional study for the prospective aspects of public health. AB - The co-existence of dengue and malaria infection in an individual and the primary and secondary dengue infection during co-infection were assessed. Over 1 year, 1980 blood samples were collected from suspected cases of dengue fever and analyzed by rapid diagnostic test (RDT), enzyme-linked immunosorbent assay (ELISA) and polymerase chain reaction (PCR) methods to detect dengue infection. RDT and microscopic methods were used to detect malaria. Of the 1980 samples, only 22 (3.0%) cases were identified as dengue-malaria co-infection cases, out of which 13 were male and 9 were female. The highest number of confirmed cases were found during the hot and humid months of September and October (7 cases, 31.8%) and within the over 15 years age group. Of the cases of co-infection, dengue primary infection (21 cases, 95.5%) was significantly more common than dengue secondary infection (1 case, 4.5%) among all of the age groups. There were 12 cases of Plasmodium falciparum and 10 cases of Plasmodium vivax infection among malarial cases. A high prevalence of concurrence of dengue and malaria infection was recorded in this ecosystem. In light of the severity of co-infection and overlapping symptoms, a multidimensional diagnostic approach is suggested. PMID- 26653976 TI - The environmental deposition of influenza virus from patients infected with influenza A(H1N1)pdm09: Implications for infection prevention and control. AB - In a multi-center, prospective, observational study over two influenza seasons, we sought to quantify and correlate the amount of virus recovered from the nares of infected subjects with that recovered from their immediate environment in community and hospital settings. We recorded the symptoms of adults and children with A(H1N1)pdm09 infection, took nasal swabs, and sampled touched surfaces and room air. Forty-two infected subjects were followed up. The mean duration of virus shedding was 6.2 days by PCR (Polymerase Chain Reaction) and 4.2 days by culture. Surface swabs were collected from 39 settings; 16 (41%) subject locations were contaminated with virus. Overall, 33 of the 671 (4.9%) surface swabs were PCR positive for influenza, of which two (0.3%) yielded viable virus. On illness Day 3, subjects yielding positive surface samples had significantly higher nasal viral loads (geometric mean ratio 25.7; 95% CI 1.75, 376.0, p=0.021) and a positive correlation (r=0.47, p=0.006) was observed between subject nasal viral loads and viral loads recovered from the surfaces around them. Room air was sampled in the vicinity of 12 subjects, and PCR positive samples were obtained for five (42%) samples. Influenza virus shed by infected subjects did not detectably contaminate the vast majority of surfaces sampled. We question the relative importance of the indirect contact transmission of influenza via surfaces, though our data support the existence of super-spreaders via this route. The air sampling results add to the accumulating evidence that supports the potential for droplet nuclei (aerosol) transmission of influenza. PMID- 26653977 TI - New mechanism of gamma-H2AX generation: Surfactant-induced actin disruption causes deoxyribonuclease I translocation to the nucleus and forms DNA double strand breaks. AB - We previously showed that nonionic surfactants, nonylphenol polyethoxylates (NPEOs), induced phosphorylation of histone H2AX, forming gamma-H2AX. In this study, we analyzed the mechanism of gamma-H2AX generation by an NPEO with 15 ethylene oxide units (NPEO(15)). In MCF-7 breast carcinoma cells, NPEO(15) treatment induced gamma-H2AX in a dose-dependent manner. EDTA and ZnCl2, two inhibitors of deoxyribonuclease I (DNase I), inhibited both the gamma-H2AX and DNA double-strand breaks induced by NPEO(15). NPEO(15) disrupted filamentous actin and released free DNase I as detected by cell fractionation analysis. Based on immunofluorescence staining of DNase I and monitoring DNase I-GFP localization, DNase I was translocated from the cytosol to the nucleus of cells after treatment with NPEO(15). This translocation did not occur with the common DNA damage inducers ultraviolet B irradiation and hydrogen peroxide. Other surfactants, Tween 20, Triton X-100 and Nonidet P-40, also generated gamma-H2AX. These results show that gamma-H2AX induction by surfactants including NPEOs, occurs via a new mechanism involving release of free DNase I with actin disruption. This mechanism is distinct from the process of gamma-H2AX generation caused by direct chemically induced DNA damage. PMID- 26653978 TI - Different patterns of allelic imbalance in sporadic tumors and tumors associated with long-term exposure to gamma-radiation. AB - The study aimed to reveal cancer related mutations in DNA repair and cell cycle genes associated with chronic occupational exposure to gamma-radiation in personnel of the Siberian Group of Chemical Enterprises (SGCE). Mutations were analyzed by comparing genotypes of malignant tumors and matched normal tissues of 255 cancer patients including 98 exposed to external gamma-radiation (mean dose 128.1+/-150.5mSv). Also a genetic association analysis was carried out in a sample of 149 cancer patients and 908 healthy controls occupationally exposed to gamma-radiation (153.2+/-204.6mSv and 150.5+/-211.2mSv, respectively). Eight SNPs of genes of DNA excision repair were genotyped (rs13181, rs1052133, rs1042522, rs2305427, rs4244285, rs1045642, rs1805419 and rs1801133). The mutation profiles in heterozygous loci for selected SNP were different between sporadic tumors and tumors in patients exposed to radiation. In sporadic tumors, heterozygous genotype Arg/Pro of the rs1042522 SNP mutated into Arg/0 in 15 cases (9.6%) and 0/Pro in 14 cases (8.9%). The genotype Lys/Gln of the rs13181 SNP mutated into Lys/0 and 0/Gln in 9 and 4 cases, respectively. In tumors of patients exposed to low-level radiation, the rs1042522 Arg/0 mutated genotype was found in 12 cases (12.1%), while in 2 cases (2%) 0/Pro mutation was observed. Finally, the rs13181 0/Gln mutated genotype was observed in 15 cases (16,5%) . Thus, our study showed the difference in patterns of allelic imbalance in tumors appeared under low level radiation exposure and spontaneous tumors for selected SNPs. This suggests different mechanisms of inactivation of heterozygous genotypes in sporadic and radiation-induced tumors. PMID- 26653979 TI - The methylating agent streptozotocin induces persistent telomere dysfunction in mammalian cells. AB - We analyzed chromosomal aberrations involving telomeres in the progeny of mammalian cells exposed to the methylating agent and antineoplastic/diabetogenic drug streptozotocin (STZ), to test whether it induces long-term telomere instability (by chromosome end loss and/or telomere dysfunction). Rat cells (ADIPO-P2 cell line, derived from Sprague-Dawley rat adipose cells) were treated with a single concentration of STZ (2mM). Chromosomal aberrations were analyzed 18h, 10 days, and 15 days after treatment, using PNA-FISH with a pan-telomeric probe [Cy3-(CCCTAA)3] to detect (TTAGGG)n repeats. Cytogenetic analysis revealed a higher frequency of chromosomal aberrations in STZ-exposed cultures vs. untreated cultures at each time point analyzed. The yield of induced aberrations was very similar at each time point. Induction of aberrations not involving telomere dysfunction was only observed 18h and 15 days after treatment, whereas induction of telomere dysfunction-related aberrations by STZ (mainly in the form of telomere FISH signal loss and duplications, most of them chromatid-type aberrations) was observed at each time point. Our results show that STZ induces persistent telomere instability in mammalian cells, cytogenetically manifested as telomere dysfunction-related chromosomal aberrations. Neither telomere length nor telomerase activity is related to the telomere dysfunction. PMID- 26653980 TI - Anemia and genotoxicity induced by sub-chronic intragastric treatment of rats with titanium dioxide nanoparticles. AB - Titanium dioxide nanoparticles (TiO2 NPs) are widely used for their whiteness and opacity. We investigated the hematological effects and genotoxicity of anatase TiO2 NPs following sub-chronic oral gavage treatment. TiO2-NPs were characterized by X-ray diffractometry (XRD), X-ray photoelectron spectroscopy (XPS), and transmission electron microscopy (TEM). Wistar rats were treated with anatase TiO2 NPs by intragastric administration for 60 days. Hematological analysis showed a significant decrease in RBC and HCT and a significant increase in MCV, PLT, MPV and WBC at higher doses. Furthermore, abnormally shaped red cells, sometimes containing micronuclei, and hyper-segmented neutrophil nuclei were observed with TiO2 NPs treatment. The micronucleus test revealed damage to chromosomes in rat bone marrow at 100 and 200mg/kg bw; the comet assay showed significant DNA damage at the same doses. PMID- 26653981 TI - Construction of a cytogenetic dose-response curve for low-dose range gamma irradiation in human peripheral blood lymphocytes using three-color FISH. AB - In order to estimate biological doses after low-dose ionizing radiation exposure, fluorescence in situ hybridization (FISH) using three differentially colored chromosome painting probes was employed to detect exchange-type chromosome aberrations. A reference dose response curve was constructed using blood samples from a female donor whose lymphocytes consistently exhibited a low frequency of cells at the second mitosis under routine culture conditions. Aberration yields were studied for a total of about 155 thousand metaphases obtained from seven dose-points of gamma irradiations (0, 50, 100, 150, 200, 250 and 300mGy). In situ hybridization was performed using commercially available painting probes for chromosomes 1, 2 and 4. With the aid of an automated image-capturing method, exchange-type aberrations involving painted chromosomes were detected with considerable accuracy and speed. The results on the exchange-type aberrations (dicentrics plus translocations) at the seven dose-points showed a good fit to the linear-quadratic model (y=0.0023+0.0015x+0.0819x(2), P=0.83). A blind test proved the reproducibility of the reference dose-response relationship. In the control experiments using blood samples from another donor, the estimated doses calculated on the basis of the present reference curve were proved to be in good agreement with the actual physical doses applied. The present dose-response curve may serve as a means to assess the individual differences in cytogenetical radio sensitivities. PMID- 26653982 TI - Role of ATM in bystander signaling between human monocytes and lung adenocarcinoma cells. AB - The response of a cell or tissue to ionizing radiation is mediated by direct damage to cellular components and indirect damage mediated by radiolysis of water. Radiation affects both irradiated cells and the surrounding cells and tissues. The radiation-induced bystander effect is defined by the presence of biological effects in cells that were not themselves in the field of irradiation. To establish the contribution of the bystander effect in the survival of the neighboring cells, lung carcinoma A549 cells were exposed to gamma-irradiation, 2Gy. The medium from the irradiated cells was transferred to non-irradiated A549 cells. Irradiated A549 cells as well as non-irradiated A549 cells cultured in the presence of medium from irradiated cells showed decrease in survival and increase in gamma-H2AX and p-ATM foci, indicating a bystander effect. Bystander signaling was also observed between different cell types. Phorbol-12-myristate-13-acetate (PMA)-stimulated and gamma-irradiated U937 (human monocyte) cells induced a bystander response in non-irradiated A549 (lung carcinoma) cells as shown by decreased survival and increased gamma-H2AX and p-ATM foci. Non-stimulated and/or irradiated U937 cells did not induce such effects in non-irradiated A549 cells. Since ATM protein was activated in irradiated cells as well as bystander cells, it was of interest to understand its role in bystander effect. Suppression of ATM with siRNA in A549 cells completely inhibited bystander effect in bystander A549 cells. On the other hand suppression of ATM with siRNA in PMA stimulated U937 cells caused only a partial inhibition of bystander effect in bystander A549 cells. These results indicate that apart from ATM, some additional factor may be involved in bystander effect between different cell types. PMID- 26653983 TI - Genomic instability induced by 50Hz magnetic fields is a dynamically evolving process not blocked by antioxidant treatment. AB - Increased level of micronuclei was observed in SH-SY5Y cells in a previous study at 8 and 15 days after exposure to extremely low frequency (ELF) magnetic fields (MF), indicating possible induction of genomic instability in the progeny of the exposed cells. The aim of this study was to further explore the induction of genomic instability by ELF MFs by increasing the follow-up time up to 45 days after exposure. Human SH-SY5Y neuroblastoma cells were exposed to a 50Hz, 100MUT MF for 24h with or without co-exposure to menadione (MQ), a chemical agent that increases cellular superoxide production. Micronuclei, reactive oxygen species (ROS) and lipid peroxidation (LPO) were measured at 15, 30 and 45 days after exposure. To study the possible causal role of ROS in the delayed effects of MF, the antioxidant N-acetylcysteine (NAC) was administered before MF exposure. Consistently with the previous study, the level of micronuclei was statistically significantly elevated 15 days after exposure. A similar effect was observed at 30 days, but not at 45 days after exposure. The level of LPO was statically significantly decreased 30 and 45 days after exposure. Consistently with our previous findings, the MF effect did not depend on co-exposure to MQ. Treatment with NAC effectively decreased cellular ROS level and suppressed the effect of MQ on ROS, but it did not block the MF effect, indicating that increase in ROS is not needed as a causal link between MF exposure and induction of delayed effects. The results presented here are consistent with genomic instability that persists in the progeny of MF-exposed cells up to at least 30 days after exposure. Changes in LPO observed at 30 and 45 days after exposure indicates that the MF-initiated process may continue up to at least 45 days after exposure. PMID- 26653984 TI - Evaluation of genotoxicity of the acute gamma radiation on earthworm Eisenia fetida using single cell gel electrophoresis technique (Comet assay). AB - Earthworms (Eisenia fetida) most suitable biological indicators of radioactive pollution. Radiation-induced lesions in DNA can be considered to be molecular markers for early effects of ionizing radiation. Gamma radiation produces a wide spectrum of DNA. Some of these lesions, i.e., DNA strand breaks and alkali labile sites can be detected by the single-cell gel electrophoresis (SCGE) or comet assay by measuring the migration of DNA from immobilized nuclear DNA. E. fetida were exposed to different doses of gamma radiation, i.e., 1, 5, 10, 20, 30, 40 and 50Gy, and comet assay was performed for all the doses along with control at 1, 3 and 5h post irradiation to evaluate the genotoxicity of gamma radiation in this organism. The DNA damage was measured as percentage of comet tail DNA. A significant increase in DNA damage was observed in samples exposed to 5Gy and above, and the increase in DNA damage was dose dependent i.e., DNA damage was increased with increased doses of radiation. The highest DNA damage was noticed at 1h post irradiation and gradually decreased with time, i.e., at 3 and 5h post irradiation. The present study reveals that gamma radiation induces DNA damage in E. fetida and the comet assay is a sensitive and rapid method for its detection to detect genotoxicity of gamma radiation. PMID- 26653985 TI - In vitro and in vivo genotoxicity investigations of differently sized amorphous SiO2 nanomaterials. AB - In vitro and in vivo genotoxic effects of differently sized amorphous SiO2 nanomaterials were investigated. In the alkaline Comet assay (with V79 cells), non-cytotoxic concentrations of 300 and 100-300MUg/mL 15nm-SiO2 and 55nm-SiO2, respectively, relevant (at least 2-fold relative to the negative control) DNA damage. In the Alkaline unwinding assay (with V79 cells), only 15nm-SiO2 significantly increased DNA strand breaks (and only at 100MUg/mL), whereas neither nanomaterial (up to 300MUg/mL) increased Fpg (Formamidopyrimidine DNA glycosylase)-sensitive sites reflecting oxidative DNA base modifications. In the Comet assay using rat precision-cut lung slices, 15nm-SiO2 and 55nm-SiO2 induced significant DNA damage at >=100MUg/mL. In the Alkaline unwinding assay (with A549 cells), 30nm-SiO2 and 55nm-SiO2 (with larger primary particle size (PPS)) induced significant increases in DNA strand breaks at >=50MUg/mL, whereas 9nm-SiO2 and 15nm-SiO2 (with smaller PPS) induced significant DNA damage at higher concentrations. These two amorphous SiO2 also increased Fpg-sensitive sites (significant at 100MUg/mL). In vivo, within 3 days after single intratracheal instillation of 360MUg, neither 15nm-SiO2 nor 55nm-SiO2 caused genotoxic effects in the rat lung or in the bone marrow. However, pulmonary inflammation was observed in both test groups with findings being more pronounced upon treatment with 15nm-SiO2 than with 55nm-SiO2. Taken together, the study shows that colloidal amorphous SiO2 with different particle sizes may induce genotoxic effects in lung cells in vitro at comparatively high concentrations. However, the same materials elicited no genotoxic effects in the rat lung even though pronounced pulmonary inflammation evolved. This may be explained by the fact that a considerably lower dose reached the target cells in vivo than in vitro. Additionally, the different time points of investigation may provide more time for DNA damage repair after instillation. PMID- 26653986 TI - Sperm DNA oxidative damage and DNA adducts. AB - The objective of this study was to investigate DNA damage and adducts in sperm from coke oven workers who have been exposed to polycyclic aromatic hydrocarbons. A longitudinal study was conducted with repeated measurements during spermatogenesis. Coke-oven workers (n=112) from a coke-oven plant served the PAH exposed group, while administrators and security personnel (n=67) served the control. Routine semen parameters (concentration, motility, vitality, and morphology) were analyzed simultaneously; the assessment of sperm DNA integrity endpoints included DNA fragmentation, bulky DNA adducts, and 8-oxo-7,8-dihydro-2' deoxyguanosine (8-oxo-dGuo). The degree of sperm DNA fragmentation was measured using the terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assay and sperm chromatin structure assay (SCSA). The PAH-exposed group had a significant increase in bulky DNA adducts and 8-oxo-dGuo compared to the control subjects (Ps=0.002 and 0.045, respectively). Coke oven workers' percentages of DNA fragmentation and denaturation from the PAH-exposed group were not significantly different from those of the control subjects (Ps=0.232 and 0.245, respectively). Routine semen parameters and DNA integrity endpoints were not correlated. Concentrations of 8-oxo-dGuo were positively correlated with percentages of DNA fragmentation measured by both TUNEL and SCSA (Ps=0.045 and 0.034, respectively). However, the concentrations of 8-oxo-dGuo and percentages of DNA fragmentation did not correlate with concentrations of bulky DNA adducts. In summary, coke oven workers with chronic exposure to PAHs experienced decreased sperm DNA integrity. Oxidative stress could contribute to the degree of DNA fragmentation. Bulky DNA adducts may be independent of the formation of DNA fragmentation and oxidative adducts in sperm. Monitoring sperm DNA integrity is recommended as a part of the process of assessing the impact of occupational and environmental toxins on sperm. PMID- 26653987 TI - Do infant behaviors following immunization predict attachment? An exploratory study. AB - OBJECTIVES: The relationship between infant behaviors during routine immunization, pre- and post-needle, and infant attachment was explored. METHODS: A total of 130 parent-infant dyads were recruited from a larger longitudinal study and videotaped during routine immunization at 12 months and the Strange Situation Procedure (SSP) at 14 months. Six infant behaviors were coded for 1 minute pre-needle and 3-minutes post-needle. Attachment was operationalized according to the secure/avoidant/resistant/disorganized categories. RESULTS: As expected, none of the pre-needle behaviors predicted attachment. Proximity seeking post-needle significantly discriminated attachment categorizations. Secure infants were more likely to seek proximity to caregivers post-needle in comparison with avoidant and disorganized infants. Proximity-seeking following immunization was positively correlated with proximity-seeking during the SSP and negatively correlated with avoidance and disorganization during the SSP. CONCLUSIONS: Infant proximity-seeking during immunization is associated with attachment security and parallels behaviors observed during the SSP. More research is needed to identify behavioral markers of disorganization. PMID- 26653989 TI - Placenta previa associated with severe bleeding leading to hospitalization and delivery: a retrospective population-based cohort study. AB - INTRODUCTION: The aim of our study was to compare maternal and neonatal outcomes in women with placenta previa complicated with severe bleeding leading to hospitalization until delivery versus those without severe bleeding episodes. METHODS: This is a population-based retrospective cohort study including all pregnant women with placenta previa who delivered at our medical center in the study period, divided into the following groups: 1) women with severe bleeding leading to hospitalization resulting with delivery (n = 32); 2) patients with placenta previa without severe bleeding episodes (n = 1217). RESULTS: Out of all women with placenta previa who delivered at our medical center, 2.6% (32/1249) had an episode of severe bleeding leading to hospitalization and resulting with delivery. The rate of anemia was lower (43.8% versus 63.7%, p = 0.02) while the need for blood transfusion higher (37.5% versus 21.1%, p = 0.03) in the study group. The rate of cesarean sections was significantly different between the groups, and a logistic regression model was constructed in order to find independent risk factors for cesarean section in our patients. CONCLUSION: To the best of our knowledge, this is the first study to evaluate the impact of severe bleeding on the outcome of pregnancies complicated with placenta previa. Our study demonstrates that, in women with placenta previa, severe bleeding does not lead to increased adverse maternal or neonatal outcomes. PMID- 26653988 TI - Parity influences the severity of ACPA-negative early rheumatoid arthritis: a cohort study based on the Swedish EIRA material. AB - BACKGROUND: In women with rheumatoid arthritis (RA) it has been observed that during pregnancy a majority of patients experience amelioration, but after delivery a relapse of the disease is common. However, there are few studies, with diverging results, addressing the effect of parity on the severity of RA over time. Our aim was to explore the impact of parity, with stratification for anti citrullinated protein antibody (ACPA) status as well as for onset during reproductive age or not. METHODS: Female RA cases aged 18-70 years were recruited for the Epidemiological Investigation of Rheumatoid Arthritis (EIRA). Information on disease severity (the health assessment questionnaire (HAQ) and the disease activity score 28 (DAS28)) was retrieved from the Swedish Rheumatology Quality Register at inclusion and 3, 6, 12 and 24 months after diagnosis. Mixed models were used to compare mean DAS28 and HAQ scores over time in parous and nulliparous women. Mean differences at individual follow-up visits were compared using analysis of covariance. The odds of having DAS28 or HAQ above the median in parous verus nulliparous women were estimated in logistic regression models. RESULTS: A total of 1237 female cases (mean age 51 years, 65 % ACPA-positive) were included. ACPA-negative parous women, aged 18-44 years, had on average 1.17 units higher DAS28 (p < 0.001) and 0.43 units higher HAQ score (p < 0.001) compared to nulliparous women during the follow-up time, adjusted for age. In this subgroup, the average DAS28 and HAQ scores were significantly higher in parous women at all follow-up time points. Younger parous ACPA-negative women were significantly more likely to have DAS28 and HAQ values above the median compared to nulliparous women at all follow-up visits. No association between parity and severity of ACPA-positive disease was observed. CONCLUSIONS: Parity was a predictor of a more severe RA among ACPA-negative younger women, which might indicate that immunomodulatory changes during and after pregnancy affect RA severity, in particular for the ACPA-negative RA phenotype. PMID- 26653990 TI - The Effect of Sandblasting, Er:YAG Laser, and Heat Treatment on the Mechanical Properties of Different Zirconia Cores. AB - OBJECTIVE: The purpose of this study was to evaluate the effect of surface and heat treatments on the mechanical properties and phase transformation of yttria stabilized tetragonal zirconia (Y-TZP) materials. BACKGROUND DATA: Zirconia is exposed to several treatments during dental application process. Knowing the effect of applied treatments on zirconia is essential for clinical success. MATERIAL AND METHODS: Forty disk specimens of Zirkonzahn (Z) and DC-Zirkon (DC) materials were fabricated. The specimens were randomly divided into four groups according to surface [control, sandblasting, Erbium: Yttrium Aluminum Garnet (Er:YAG) laser irradiation] and heat (firing) treatments. The surface roughness (Ra, MUm) was measured using a surface profilometer. The relative amount of the transformed monoclinic (m) phase was analyzed by X-ray diffractometry (XRD). Biaxial flexural strength was tested using piston-on-three-ball technique. The data were analyzed with the Kruskal-Wallis H test with Bonferroni correction, and the Mann-Whitney U test was used for pairwise comparisons. RESULTS: There were no significant differences in surface roughness among the treated groups (p > 0.05), whereas sandblasting showed higher surface roughness than other treatments for both materials. Scanning electron microscopic (SEM) analyses revealed changes in surface morphology after surface treatments, especially in laser groups with the formation of cracks, and in sandblasting groups with the formation of microretentive grooves. The greatest amount of the monoclinic phase was measured after sandblasting (8.13%) for Z and (19.8%) for DC. The monoclinic phase reverted to the tetragonal phase after heat treatment. Heat treatment groups showed significantly lower flexural strength than other treatments (p < 0.05). CONCLUSIONS: Heat and surface treatments influenced the mechanical properties of zirconia ceramic. The biaxial flexural strength and crystalline phase of materials decreased after heat treatments. PMID- 26653991 TI - Considerations about a Chinese vaccine preventing a national form of epidemic acute kidney injury (AKI). PMID- 26653992 TI - Internal Rotation of Methane Molecules in Large Clusters. AB - Methane is one of the very few substances that show rotation of individual molecules in the crystalline phase. Here we explore the evolution of the rotation spectrum of methane from single molecules to clusters containing up to about 4 * 10(3) molecules. The clusters were assembled in He droplets at T = 0.38 K and studied via infrared laser spectroscopy in the nu3 region of the methane molecules. Well-resolved rotational structure in the spectra was observed in clusters containing up to about 50 molecules. We have concluded that in distinction to the crystals molecular rotation in methane clusters is confined to the surface and is enabled by low coordination of the molecules. On the contrary the molecules in the cluster's interior are in amorphous state wherein the rotation is quenched. These results demonstrate that even at very low temperature the surface of the methane clusters remains fluxional due to quantum effects. PMID- 26653993 TI - New challenges in clinical research on hepatocellular carcinoma. AB - This is an updated review of screening, early diagnosis and treatment of hepatocellular carcinoma, focusing on the advancements occurred in the last years and highlighting the challenges in clinical research. Hepatocellular carcinoma (HCC) is nowadays the sixth most frequent cancer worldwide with up to 740,000 new cases diagnosed each year, and it is the third most prevalent cause of cancer related-death worldwide (1). This neoplasm usually appears linked to an underlying liver disease, being one of the most relevant causes of death in patients diagnosed of liver cirrhosis (2,3). In the last years, important advancements in terms of diagnosis, staging and treatment of HCC, improving the management and outcome of the disease, have been made (4-7). Despite the fact that these improvements have absolutely changed natural history of HCC, there are several areas that still need further advancements. The aim of this document is to discuss some controversial aspects, which in our opinion constitute real challenges in clinical research of HCC. PMID- 26653994 TI - Molecular Aspects of the Interaction of Iminium and Alkanolamine Forms of the Anticancer Alkaloid Chelerythrine with Plasma Protein Bovine Serum Albumin. AB - The interaction between a quaternary benzophenanthridine alkaloid chelerythrine (herein after, CHL) and bovine serum albumin (herein after, BSA) was probed by employing various spectroscopic tools and isothermal titration calorimetry (ITC). Fluorescence studies revealed that the binding affinity of the alkanolamine form of the CHL is higher compared to the iminium counterpart. This was further established by fluorescence polarization anisotropy measurement and ITC. Fluorescence quenching study along with time-resolved fluorescence measurements establish that both forms of CHL quenched the fluorescence intensity of BSA through the mechanism of static quenching. Site selective binding and molecular modeling studies revealed that the alkaloid binds predominantly in the BSA subdomain IIA by electrostatic and hydrophobic forces. From Forster resonance energy transfer (FRET) studies, the average distances between the protein donor and the alkaloid acceptor were found to be 2.71 and 2.30 nm between tryptophan (Trp) 212 (donor) and iminium and alkanolamine forms (acceptor), respectively. Circular dichroism (CD) study demonstrated that the alpha-helical organization of the protein is reduced due to binding with CHL along with an increase in the coiled structure. This is indicative of a small but definitive partial unfolding of the protein. Thermodynamic parameters obtained from ITC experiments revealed that the interaction is favored by negative enthalpy change and positive entropy change. PMID- 26653996 TI - Decellularized Renal Matrix and Regenerative Medicine of the Kidney: A Different Point of View. AB - Over the past years, extracellular matrix (ECM) obtained from whole organ decellularization has been investigated as a platform for organ engineering. The ECM is composed of fibrous and nonfibrous molecules providing structural and biochemical support to the surrounding cells. Multiple decellularization techniques, including ours, have been optimized to maintain the composition, microstructure, and biomechanical properties of the native renal ECM that are difficult to obtain during the generation of synthetic substrates. There are evidences suggesting that in vivo implanted renal ECM has the capacity to induce formation of vasculature-like structures, but long-term in vivo transplantation and filtration activity by these tissue-engineered constructs have not been investigated or reported. Therefore, even if the process of renal decellularization is possible, the repopulation of the renal matrix with functional renal cell types is still very challenging. This review aims to summarize the current reports on kidney tissue engineering with the use of decellularized matrices and addresses the challenges in creating functional kidney units. Finally, this review discusses how future studies investigating cell-matrix interaction may aid the generation of a functional renal unit that would be transplantable into patients one day. PMID- 26653995 TI - Neurophysiological modulation of rapid emotional face processing is associated with impulsivity traits. AB - BACKGROUND: Sensori-perceptual processing of emotional stimuli under attentive conditions effectively prevents response disinhibition. This is observed saliently in low-impulsive people, because of their high sensitivity to warning signals, such as emotional faces. Results from human neurophysiological studies have been used to develop a dual detector model for early sensori-perceptual processing. A transient detector mechanism is related to automatic neurophysiological arousal in response to warning signals, which is reflected by early frontal event-related potential effects. The memory-based detector mechanism is associated with subsequent mismatch negativity (MMN), which reflects a short-term memory trace of signals. Based on previous findings, we predicted that impulsivity affects functional associations among the dual detector mechanisms, and modulates early frontal and/or MMN activities. In the present study, we recorded electroencephalograms for twenty-one healthy adults using a visual oddball paradigm with neutral faces as frequent stimuli, and angry and happy faces as infrequent stimuli. We measured the impulsivity traits by a self report scale (the Barratt Impulsiveness Scale, 11th version). RESULTS: Main findings were that only happy faces increased early frontal negativity and subsequent occipital visual MMN (vMMN) for emotional change, and these neurophysiological effects positively correlated with each other in a temporally causal manner. However, an impulsivity sub-trait positively correlated selectively with vMMN for the happy faces. CONCLUSION: These findings demonstrate that higher impulsivity is associated with attenuated vMMN for emotional change detection in healthy populations, potentially because of weakened fronto occipital functional connection that is responsible for the dual detector mechanism. PMID- 26653997 TI - Infrascanner in the diagnosis of intracranial lesions in children with traumatic brain injuries. AB - BACKGROUND: The number of traumatic injuries among children is increasing. However, so-called mild TBI might result in unfavourable outcomes. Early diagnosis of intracranial haematomas prior to development of serious complications may be a decisive factor for a favourable outcome. InfraScan company developed and brought to the market the Infrascanner model 1000, which is a portable detector of blood collections that operates in the near infrared (NIR) band. OBJECTIVE: To estimate the efficiency of the Infrascanner model 1000 for detection of intracranial haematomas among children with mild TBI. MATERIALS AND METHODS: Ninety-five patients with mild TBI were examined. An indication for cerebral CT after mild TBI was the presence of risk factors of intracranial lesions. The Infrascanner was used by a neurosurgeon during primary examination. CT was performed in 43 patients (45%), while 52 patients (55%) with a low risk of intracranial lesions were under observation. RESULTS: The results of examination of patients using CT and infrared scanning coincided in 39 cases and intracranial haematomas were detected in eight patients. False-positive results were obtained in three cases. The sensitivity of the procedure used in this group of patients with a medium and high risk of development of intracranial haemorrhages was 1.00 (0.66; 1.00). The specificity was 0.91 (0.81; 1.00)--the proportions and a 95% CI. The false-positive risk is 0.27 (0.00; 0.58). During infrared scanning in patients with low risk of intracranial lesions, false-positive results were obtained in four cases and false-negative results were absent. CONCLUSION: Infra scanning might be viewed as a screening technique for intracranial haemorrhages in ambulances and outpatient trauma centres in order to decide on hospitalization, CT scanning and referral to a neurosurgeon. Infra-scanning combined with evaluation of risk factors of intracranial damage might reduce the number of unnecessary radiological examinations. PMID- 26653998 TI - Molecular Characterization of Salmonella enterica Serovars Isolated from a Turkey Production Facility in the Absence of Selective Antimicrobial Pressure. AB - This study evaluated antimicrobial resistance and virulence factors in Salmonella enterica isolated from a turkey flock in which the birds were raised in an environment where antimicrobials were not administered to the birds, either through feed or water. Salmonella was isolated from turkeys and various environmental samples in the facility using conventional microbiological procedures. Isolates were serotyped and analyzed phenotypically by antimicrobial resistance profiling and genotypically by pulsed-field gel electrophoresis (PFGE) fingerprinting, integron analysis, plasmid profiling, replicon-based incompatibility (Inc) group typing, and virulence gene profiling. Ninety-five S. enterica isolates were isolated from cecal contents (n = 29), feed (n = 22), leftover feed (n = 13), litter (n = 12), drinkers (n = 10), environment (n = 8), and an insect. The following serotypes were identified: Montevideo (24%), Anatum (22%), Agona (17%), Kentucky and Worthington (12%), Senftenberg (11%), and rough phenotypes (3%). The majority of isolates (61/95; 64%) were susceptible to 12 antimicrobials tested; however, despite the absence of antimicrobials in the facility, approximately 36% of the isolates were resistant to two to five antimicrobials. Class 1 integrons were detected in 8% of the isolates. The integron sequence analysis revealed dihydrofolate reductase (dhfr) and aminoglycoside adenylyl transferase (aadA2) genes, which encode trimethoprim and streptomycin resistance, respectively. Furthermore, 71% of the isolates had at least one plasmid. There were five plasmid replicon types identified among the isolates, including IncI1, IncHI2, IncFIIA, IncB/O, and IncP, with variable prevalence among the serotypes. All 95 isolates tested polymerase chain reaction positive for 19 virulence genes and negative for virD4 and virB4. The virulence gene profiles were similar within the isolates from the same serotype. Within particular serotypes, PFGE patterns revealed 100% similarity, even when the bacterial strains were isolated from different sources, indicating cross colonization of sources within the turkey facility. On this antibiotic-free turkey farm, turkeys and feed appeared to be the major reservoirs of multidrug resistant Salmonella, which harbored multiple virulence genes. PMID- 26653999 TI - Field testing a questionnaire assessing parental psychosocial factors related to consumption of calcium-rich foods by Hispanic, Asian, and Non-Hispanic white young adolescent children. AB - Intervention strategies to increase calcium intake of parents and young adolescent children could be improved by identifying psychosocial factors influencing intake. The objective was to develop a tool to assess factors related to calcium intake among parents and Hispanic, Asian, and non-Hispanic white young adolescent children (10-13 years) meeting acceptable standards for psychometric properties. A parent questionnaire was constructed from interviews conducted to identify factors. Parents (n = 166) in the United States completed the questionnaire, with seventy-one completing it twice. Two constructs (Attitudes/Preferences and Social/Environmental) were identified and described by eighteen subscales with Cronbach's alpha levels from .50 to .79. Test-retest coefficients ranged from .68 to .85 (p < .001). Several subscales were statistically significantly associated with parent characteristics consistent with theory and published literature. This tool shows promise as a valid and reliable measure of factors associated with calcium-rich food intake among parents and young adolescent children. PMID- 26654000 TI - Electricity generation and nutrients removal from high-strength liquid manure by air-cathode microbial fuel cells. AB - Air-cathode microbial fuel cells (MFCs) are widely tested to recover electrical energy from waste streams containing organic matter. When high-strength wastewater, such as liquid animal manure, is used as a medium, inhibition on anode and cathode catalysts potentially impairs the effectiveness of MFC performance in power generation and pollutant removal. This study evaluated possible inhibitive effects of liquid swine manure components on MFC power generation, improved liquid manure-fed MFCs performance by pretreatment (dilution and selective adsorption), and modeled the kinetics of organic matter and nutrients removal kinetics. Parameters monitored included pH, conductivity, chemical oxygen demand (COD), volatile fatty acids (VFAs), total ammoniacal nitrogen (TAN), nitrite, nitrate, and phosphate concentrations. The removals of VFA and TAN were efficient, indicated by the short half-life times of 4.99 and 7.84 d, respectively. The mechanism for phosphate decrease was principally the salt precipitation on cathode, but the removal was incomplete after 42-d operation. MFC with an external resistor of 2.2 kOmega and fed with swine wastewater generated relatively small power (28.2 MUW), energy efficiency (0.37%) and Coulombic efficiency (1.5%). Dilution of swine wastewater dramatically improved the power generation as the inhibitory effect was decreased. Zeolite and granular activated carbon were effective in the selective adsorption of ammonia or organic matter in swine wastewater, and so substantially improved the power generation, energy efficiency, and Coulombic efficiency. A smaller external resistor in the circuit was also observed to promote the organic matter degradation and thus to shorten the treatment time. Overall, air-cathode MFCs are promising for generating electrical power from livestock wastewater and meanwhile reducing the level of organic matter and nutrients. PMID- 26654001 TI - An expensive occupation. AB - Anything that puts people into debt and deters them from training cannot be good. So it was alarming to hear chancellor George Osborne's announcement that the publicly funded bursary is to be scrapped, and that future nursing students will have to take out loans to cover tuition fees and living expenses. PMID- 26654003 TI - Osborne announces student bursaries will be replaced by loans. AB - BURSARIES FOR nursing students are to be replaced by loans, chancellor George Osborne announced in his spending review and autumn statement. PMID- 26654004 TI - Alder Hey employs extra nurses for move to Springfield Park. AB - AN INCREASE in nurses at a trailblazing children's hospital has helped smooth a potentially difficult transition for patients moving from the hospital's old site. PMID- 26654005 TI - England spends more than L1 billion to treat malnutrition. AB - CARING FOR malnourished children costs the NHS more than L1 billion a year, according to a new report. PMID- 26654006 TI - RCN Wales nurse nominated. AB - A NURSE has been recognised for her neonatal nursing service developments with a nomination for one of the top prizes at the RCN in Wales Nurse of the Year Awards. PMID- 26654007 TI - Social media campaign highlights lack of expert care provision for parents. AB - FAMILIES CARING for seriously ill children are being asked to undertake complex clinical care without consistent expert support, a nurse at a leading charity has said. PMID- 26654008 TI - Rota changes will put children at risk, say Antrim nurses. AB - PROPOSED ROTA changes will put children at risk, say nurses in Northern Ireland. PMID- 26654009 TI - Virtual children's ward brings the hospital into the home. AB - LEAD NURSE Zoe Tribble believes she manages a unique service. She oversees four other nurses in a team of outreach workers who deliver a 'virtual ward' service to babies and children in their own homes who would traditionally have had to stay in hospital. There are other teams that do a similar job, but none manage it from 7am-11pm every day of the year and can complete three visits a day to patients, Ms Tribble argues. PMID- 26654010 TI - Key workers 'essential' for cancer care. AB - THE ROLE of the key worker for children with cancer has been much talked about over the years. Back in 2005, the National Institute for Health and Care Excellence recommended the post be used to co-ordinate care in recognition of the complexities involved for children, parents and professionals. PMID- 26654015 TI - Research essentials. AB - A literature review is a summary of the evidence, usually research literature, to answer a specific question ( Bettany-Saltikov 2012 ). The evidence arising from a literature search should be subject to a systematic evaluation of its quality and summary of key issues. A robust systematic review may be significant enough to warrant changes in practice. PMID- 26654023 TI - Time to think. AB - As an agency nurse, I work part-time so that I can fit my shifts around my childcare needs. PMID- 26654025 TI - Role of out-of-hours nurse co-ordinators in a children's hospital. AB - In a hospital, a high proportion of working time occurs outside the traditional working day, affecting patient safety as staffing levels are at their lowest out of hours. A service evaluation audit was used to evaluate the effectiveness of a clinical out-of-hours nurse co-ordinator (COHNC) pilot role in a tertiary children's hospital. The COHNC role was trialled over a six-month period. During the pilot, the COHNC carried the junior paediatrician's 'bleep' and prioritised all phone calls and tasks. Following a patient assessment, the COHNC either performed the investigations and treatments within their scope of practice or escalated these to the appropriate multidisciplinary team member. A description of how the COHNC role has developed and its implications to nursing practice are presented in this article, along with an overview of the quantitative and qualitative data obtained during the audit. PMID- 26654026 TI - Idiopathic scoliosis: managing pain before and after spinal surgery. AB - Idiopathic scoliosis surgery is performed to correct a curvature of the spine. This is a painful surgical procedure which is carried out on otherwise healthy young people. This article reports on a small evaluation project which focused on young people's opinions and experiences of their pain information needs, pain management and pain assessment. Nine young people completed written activity sheets before and after scoliosis surgery. Most of the information provided on the activity sheets involved positive comments about the surgical experience although some indicated that the management of pain continued to be a challenge after spinal surgery. The project has highlighted that there is more work to be done to ensure that young people are prepared for surgery and they are helped to convey their experiences of pain to health professionals during their treatment and recovery. PMID- 26654027 TI - Ensuring that 'hard to reach' young people agree to health assessments. AB - Statutory guidance for promoting the health and wellbeing of looked after children stipulates that children and young people in the care system should receive health assessments on entry to care, and thereafter at six-monthly intervals for children aged under five and annually for those aged five to 18 years. Heart of England NHS Foundation Trust works in partnership with the local authority and clinical commissioners to meet the needs of local looked after children. It was found that many of these children and young people were refusing to have health assessments. This longitudinal study identified blocks to engagement, and explored alternative strategies to build compliance and participation. Findings have demonstrated that using a multi-agency and child centred approach is effective in engaging 'hard to reach' children and young people. PMID- 26654028 TI - Prenatal maternal risk factors for infantile colic. AB - AIM: To examine maternal prenatal risk factors for infantile colic (IC). METHODS: Mothers were asked to complete a standard pre-coded questionnaire form. Inclusion in the study consisted of four criteria. The case group comprised healthy children with infantile colic according to Wessel's definition. The control group comprised healthy children with no history of IC. Prenatal period characteristics of mothers were examined to determine associations with IC. RESULTS: Children with mothers who had prophylactic iron supplementation therapy during pregnancy suffered more from IC. Postpartum depression was found to be more frequent in the case group than in the control group. Gynaecological history, including suffering from migraine, presence of any premenstrual symptoms, dysmenorrhea and high pre pregnancy body mass index, was associated with development of IC. CONCLUSION: Pre gestational gynaecological complaints and pregnancy characteristics may point to IC. These characteristics should be investigated and families should be informed. PMID- 26654029 TI - Feasibility and acceptability of mobile phone short message service as a support for patients receiving antiretroviral therapy in rural Uganda: a cross-sectional study. AB - INTRODUCTION: Mobile phone technologies have been promoted to improve adherence to antiretroviral therapy (ART). We studied the receptiveness of patients in a rural Ugandan setting to the use of short messaging service (SMS) communication for such purposes. METHODS: We performed a cross-sectional analysis measuring mobile phone ownership and literacy amongst patients of The AIDS Support Organisation (TASO) in Jinja, Uganda. We performed bivariate and multivariate logistic regression analyses to examine associations between explanatory variables and a composite outcome of being literate and having a mobile phone. RESULTS: From June 2012 to August 2013, we enrolled 895 participants, of whom 684 (76%) were female. The median age was 44 years. A total of 576 (63%) were both literate and mobile phone users. Of these, 91% (527/ 576) responded favourably to the potential use of SMS for health communication, while only 38.9% (124/319) of others were favourable to the idea (p<0.001). A lower proportion of literate mobile phone users reported optimal adherence to ART (86.4% vs. 90.6%; p=0.007). Male participants (AOR=2.81; 95% CI 1.83-4.30), sub-optimal adherence (AOR=1.76; 95% CI 1.12-2.77), those with waged or salaried employment (AOR=2.35; 95% CI 1.23 4.49), crafts/trade work (AOR=2.38; 95% CI 1.11-5.12), or involved in petty trade (AOR=1.85; 95% CI 1.09-3.13) (in comparison to those with no income) were more likely to report mobile phone ownership and literacy. CONCLUSIONS: In a rural Ugandan setting, we found that over 60% of patients could potentially benefit from a mobile phone-based ART adherence support. However, support for such an intervention was lower for other patients. PMID- 26654030 TI - Anti-Inflammatory Role of Statins in Preventing Postoperative Atrial Fibrillation. PMID- 26654031 TI - Statins for Improving Myocardial Perfusion in Patients With Nonalcoholic Fatty Liver Disease Undergoing Percutaneous Coronary Intervention. PMID- 26654033 TI - Thirty-Five Years of Nemertean (Nemertea) Research--Past, Present, and Future. AB - Developments in nemertean research over the last 35+ years are reviewed from a systematist's perspective. Nemertean systematics and classification, until fairly recently, was not based on explicit phylogenetic hypotheses, but rather on subjective assessment of "important characters". The first cladistic analyses appeared in the 1980s and were criticized at the time by leading researchers in nemertean systematics for not taking into account convergent evolution in ribbon worm morphology. The first molecular study involving the phylum Nemertea appeared in 1992, followed by reports later in the 1990s and early 2000s. Molecular information is now commonplace in nemertean research, and has changed our understanding of evolutionary relationships within the phylum, as well as our view on species and intraspecific variation. Challenges in nemertean systematics and taxonomy are discussed, with special emphasis on future species descriptions, and how to deal with a number of species names that in all likelihood never will be encountered again. Suggestions for how to deal with these challenges are discussed. PMID- 26654032 TI - Variations in CT determination of target volume with active breath co-ordinate in radiotherapy for post-operative gastric cancer. AB - OBJECTIVE: To investigate interobserver and inter-CT variations in using the active breath co-ordinate technique in the determination of clinical tumour volume (CTV) and normal organs in post-operative gastric cancer radiotherapy. METHODS: Ten gastric cancer patients were enrolled in our study, and four radiation oncologists independently determined the CTVs and organs at risk based on the CT simulation data. To determine interobserver and inter-CT variation, we evaluated the maximum dimensions, derived volume and distance between the centres of mass (CMs) of the CTVs. We assessed the reliability in CTV determination among the observers by conformity index (CI). RESULTS: The average volumes +/- standard deviation (cm(3)) of the CTV, liver, left kidney and right kidney were 674 +/- 138 (range, 332-969), 1000 +/- 138 (range, 714-1320), 149 +/- 13 (range, 104-183) and 141 +/- 21 (range, 110-186) cm(3), respectively. The average inter-CT distances between the CMs of the CTV, liver, left kidney and right kidney were 0.40, 0.56, 0.65 and 0.6 cm, respectively; the interobserver values were 0.98, 0.53, 0.16 and 0.15 cm, respectively. CONCLUSIONS: In the volume size of CTV for post-operative gastric cancer, there were significant variations among multiple observers, whereas there was no variation between different CTs. The slices in which variations more likely occur were the slices of the lower verge of the hilum of the spleen and porta hepatis, then the paraoesophageal lymph nodes region and abdominal aorta, and the inferior vena cava, and the variation in the craniocaudal orientation from the interobserver was more predominant than that from inter-CT. ADVANCES IN KNOWLEDGE: First, this is the first study to evaluate the interobserver and inter-CT variations in the determination of the CTV and normal organs in gastric cancer with the use of the active breath co-ordinate technique. Second, we analysed the region where variations most likely occur. Third, we investigated the influence of interobserver variation on the dose distribution. PMID- 26654034 TI - A Taxonomic Catalogue of the Nemerteans (Phylum Nemertea) of Spain and Portugal. AB - A literature-based taxonomic catalogue of nemerteans (phylum Nemertea) from Spain and Portugal is provided, listing 75 species (12 Palaeonemertea, 24 Pilidiophora, and 39 Hoplonemertea) belonging to 34 genera. This is a low species number compared with the approximately 400 species listed in Europe. This lack of knowledge is mainly due to the low number of researchers interested in the phylum and the well-known taxonomic difficulties of its study. Geographic records are indicated for each species, and for some, comments are included on certain biological and taxonomic aspects. PMID- 26654035 TI - Malacobdella arrokeana: Parasite or Commensal of the Giant Clam Panopea abbreviata? AB - We examined trophic relationship between the nemertean Malacobdella arrokeana and its host, the edible geoduck Panopea abbreviata by studying the diets of both species by direct (stomach contents) and indirect methods (stable-isotope analysis of C and N). In addition to these methods, the feeding behavior of M. arrokeana within the host and the morphology of its feeding organs were examined. The feeding behavior of M. arrokeana did not exhibit parasitic characteristics, and the proboscis morphology indicates it is unable to injure host tissues. Analysis of stomach contents revealed a diet consisting mainly of microalgae and diatoms. Panopea abbreviata and M. arrokeana shared similar trophic levels, presenting no differences in the spread of the isotopic niches and high overlap (SEAB overlapped 63%). Consistent with this, our results showed no differences in delta(15)N or delta(13)C values between the two species. The combination of direct and indirect approaches revealed that M. arrokeana has a diet similar to that of its host, confirming a commensal relationship. PMID- 26654036 TI - Observations and Experiments on the Biology and Life History of Riseriellus occultus (Heteronemertea: Lineidae). AB - Studies on the biology and life history of nemerteans are scarce, mostly because these animals are nocturnal. In order to broaden the knowledge base on the life history of nemerteans as a prerequisite for comparative analyses, we studied a population of Riseriellus occultus (Heteronemertea: Lineidae) inhabiting the rocky intertidal in southern Brittany near Concarneau (France) for more than 10 years. Our studies show that R. occultus is an iteroparous, perennial species exclusively inhabiting rocky shore crevices that result from onionskin weathering of the granite. From September through October R. occultus reproduces by external fertilization and develops via a planktonic pilidium larva, which, under laboratory conditions, metamorphoses after about six weeks. Adults of R. occultus are nocturnal macrophagous predators that preferentially feed on the gastropods Gibbula umbilicalis and Patella species, but also consume the bivalve Mytilus edulis. Since R. occultus devours the snail inside the shell, we fixed individuals while feeding, and serially sectioned them. Reconstruction of the sections shows that R. occultus swallows the entire soft body and finally detaches the columellar muscle from the shell. Estimates on the density of R. occultus inside the rock crevices provide evidence for clustered distribution and locally high abundance on the rocky shore. These data strongly suggest that R. occultus affects the structure of the rocky shore gastropod community. Although our data are still fragmentary with respect to the ecology of this species and its role in the local food web, our knowledge has grown to such extent that R. occultus can now be regarded as one of the few well characterized nemertean species. PMID- 26654037 TI - CLSM Analysis of the Phalloidin-Stained Muscle System of the Nemertean Proboscis and Rhynchocoel. AB - The proboscis and rhynchocoel musculature of 56 nemertean species was studied using phalloidin labelling and confocal laser scanning microscopy. Six types of muscle layers are found in the anterior proboscis of the nemerteans: inner circular, inner diagonal, inner longitudinal, outer diagonal, outer circular, and outer longitudinal. Only the inner circular and inner longitudinal muscle layers are present in all the nemerteans studied. Ten types of arrangement of the proboscis musculature are described. Three primary types ('palaeotype', 'heterotype', and 'hoplotype') correspond to the three nemertean supergroups (Palaeonemertea, Heteronemertea, and Hoplonemertea). The evolutionary transformations of the initial 'palaeotype' proboscis proceeded in two primary ways: increasing bilateral symmetry (Callinera, Hubrechtella, and most of Heteronemertea) and increasing polyradial symmetry (Baseodiscidae, Oxypolellinae, and Hoplonemertea). The musculature of the middle portion of the proboscis differs among the three groups with armature: Palaeonemertea (genus Callinera), Polystilifera, and Monostilifera. The musculature of the stylet apparatus of the monostiliferous nemerteans is more complicated than that of the polystiliferous nemerteans, and consists of four muscle components--basal and anterior sphincters, radial and longitudinal musculature. Among the studied monostiliferans, the different components of the stylet musculature are developed to varying degrees. In addition, data on the structure of the rhynchocoel with interwoven musculature are provided. The taxonomic significance and phylogenetic interpretation of the proboscis and rhynchocoel musculature is discussed. PMID- 26654038 TI - Structure of the Proboscis Endothelium in Nemertea. AB - We studied the ultrastructure of the proboscis endothelium of 14 nemertean species. In all nemerteans examined, the endothelium is organized as a pseudostratified myoepithelium consisting of two types of cells resting on the basal extracellular matrix: apically situated supportive cells and subapical myocytes covered by cytoplasmic sheets of the supportive cells. Myocytes form the inner circular musculature of the proboscis; the endothelium in the bulb of monostiliferous nemerteans lacks myocytes. The endothelium of the studied species differs in the number of rows of muscle fibres (one vs. several rows), the number of myofibrils in myocytes (one vs. two to five), the number of processes of myocytes covered by one supportive cell (one vs. two to 23), and in the number of processes in supportive cells (one vs. two to five). In some of the species, rudimentary cilia of supportive cells were revealed by using cLSM and an antibody against tubulin. The data obtained indicate that the proboscis endothelium in nemerteans is in fact a coelothelium, but recognition of the ancestral state of the coelomic lining in Nemertea is problematic, as the rhynchocoel peritoneum lacks myocytes. PMID- 26654039 TI - Preliminary Report of a Neurokinin-Like Receptor Gene Sequence for the Nemertean Paranemertes sp. AB - Tachykinins (TKs) are a family of neurotransmitters that function as signaling molecules for such processes as maintaining homeostasis, regulating stress response, and modulating pain. TKs require the expression of at least one of three receptor subtypes: Neurokinin Receptor-1 (NKR-1), Neurokinin Receptor-2 (NKR-2), or Neurokinin Receptor-3 (NKR-3). We have isolated and cloned a portion of a gene coding for a tachykinin-like receptor from the nemertean Paranemertes sp. This 488-bp portion contains a short 101-bp segment that shares 85% similarity to the mouse substance-K receptor in Mus musculus and 83% similarity to the moth neuropeptide receptor A24 in Bombyx mori. Translated homology analysis aligning the coding sequence with the initial cytoplasmic carboxyl terminus of numerous G-protein coupled neuropeptide receptors also revealed 73% similarity to B. mori neuropeptide receptor A24. Our finding is the first report of a sequence amplified from Paranemertes sp. that may code for a small portion of a G-protein-coupled neuropeptide receptor with significant similarity to the TKR family, particularly the NKR-3 receptor isoform. This novel finding may open new avenues into exploring the role of tachykinin and its receptor in nemertean neurophysiology. PMID- 26654040 TI - DNA Taxonomy of Paranemertes (Nemertea: Hoplonemertea) with Spirally Fluted Stylets. AB - Of the 14 nominal species that are now or have ever been assigned to the genus Paranemertes Coe, 1901 , four have been reported to have stylets with a spirally fluted or braided appearance. Although differentiation in color patterns has been documented among species/populations, these nemerteans share similar external characters. Using the sequence datasets of mitochondrial cytochrome c oxidase subunit I (COI), 16S rRNA, and nuclear 28S rRNA genes of specimens from 14 localities of Canada, USA, Russia, Japan, and China, we analyzed the genetic differentiation and reconstructed the phylogenetic trees for these nemerteans. In conjunction with the external characters, we discuss their taxonomy and species delimitation. An analysis based on COI dataset showed high genetic variations among populations and even among worms from the same geographic area. The analyzed 111 individuals were assigned into seven networks by statistical parsimony analysis. The inter-network uncorrected p-distances ranged from 0.044 to 0.172 and the mean intra-network uncorrected p-distances varied from 0.001 to 0.005. With the exception of two networks that contain specimens from the East China Sea, all networks were well-supported by the results of Bayesian and neighbor-joining analyses on the COI data. Phylogenetic trees based on 16S rRNA and 28S rRNA datasets were basically similar to the COI trees, but specimens in some networks were merged into larger clades. Present molecular analyses support the validity of P. sanjuanensis and the synonymization of P. cylindracea with P. peregrina. Nemerteans previously recorded as P. peregrina may contain several species and sympatric speciation might have been occurred in this nemertean group. PMID- 26654041 TI - Species Diversity of Ramphogordius sanguineus/Lineus ruber-Like Nemerteans (Nemertea: Heteronemertea) and Geographic Distribution of R. sanguineus. AB - Heteronemerteans, such as Lineus ruber, L. viridis, Ramphogordius sanguineus, R. lacteus, Riseriellus occultus, and Micrura varicolor, share many similar external characters. Although several internal characters useful for distinguishing these nemertean species have been documented, their identification is based mostly on coloration, the shape of the head, and how they contract, which may not be always reliable. We sequenced the mitochondrial COI gene for 160 specimens recently collected from 27 locations around the world (provisionally identified as the above species, according to external characters and contraction patterns, with most of them as R. sanguineus). Based on these specimens, together with sequences of 16 specimens from GenBank, we conducted a DNA-based species delimitation/identification by means of statistical parsimony and phylogenetic analyses. Our results show that the analyzed specimens may contain nine species, which can be separated by large genetic gaps; heteronemerteans with an external appearance similar to R. sanguineus/Lineus ruber/L. viridis have high species diversity in European waters from where eight species can be discriminated. Our 42 individuals from Vancouver Island (Canada) are revealed to be R. sanguineus, which supports an earlier argument that nemerteans reported as L. ruber or L. viridis from the Pacific Northwest may refer to this species. We report R. sanguineus from Chile, southern China, and the species is also distributed on the Atlantic coast of South America (Argentina). In addition, present analyses reveal the occurrence of L. viridis in Qingdao, which is the first record of the species from Chinese waters. PMID- 26654042 TI - Carinina ochracea (Palaeonemertea: Tubulanidae) Reaches Its Southernmost Distribution: New Morphological and Molecular Data. AB - New data for Carinina ochracea Sundberg et al., 2009 are provided for the Iberian Peninsula, establishing the southernmost limit of its known distribution. This species was previously known from only two localities: the type locality in Tjarno (Sweden) and Pouldohan (Brittany, France). The material examined here was obtained during a faunal survey in the Villaviciosa Estuary (Asturias, northern Iberian Peninsula). The identity of the new specimen was confirmed both by DNA barcoding and anatomical examination. The molecular divergence of all available sequences of this species for four molecular markers, cytochrome c oxidase subunit I (COI), 16S, 18S and 28S rDNA, is discussed. For COI, four polymorphic sites were found, indicating: 1) a nuclear pseudogene; 2) heteroplasmy; or 3) gene duplication of a region of the mitochondrial genome. Two previously overlooked morphological characters were found: the presence of a colour ring and a postfixation staining band (pigmented band), which is histologically characterized. This species is the 12th palaeonemertean and the 75th nemertean reported from Iberian waters. PMID- 26654043 TI - Tubulanus tamias sp. nov. (Nemertea: Palaeonemertea) with Two Different Types of Epidermal Eyes. AB - Based on specimens collected subtidally (~10 m in depth) in Tomioka Bay, Japan, we describe the palaeonemertean Tubulanus tamias sp. nov., which differs from all its congeners in body coloration. In molecular phylogenetic analyses based on partial sequences of the nuclear 18S and 28S rRNA genes and histone H3, as well as the mitochondrial 16S rRNA and cytochrome c oxidase subunit I genes, among selected palaeonemerteans, T. tamias nested with part of the congeners in Tubulanus, while the genus as currently diagnosed appears to be non-monophyletic. Molecular cloning detected polymorphism in 28S rDNA sequences in a single individual of T. tamias, indicating incomplete concerted evolution of multiple copies. Tubulanus tamias is peculiar among tubulanids in having 9-10 pigment-cup eyes in the epidermis on either side of the head anterior to the cerebral sensory organs, and remarkably there are two types of eyes. The anterior 8-9 pairs of eyes, becoming larger from anterior to posterior, are completely embedded in the epidermis and proximally abutting the basement membrane; each pigment cup contains bundle of up to seven, rod-shaped structure that resemble a rhabdomeric photoreceptor cell. In contrast, the posterior-most pair of eyes, larger than most of the anterior ones, have an optical cavity filled with long cilia and opening to the exterior, thus appearing to have ciliary-type photoreceptor cells. The size and arrangement of the eyes indicate that the posterior-most pair of eyes are the remnant of the larval (or juvenile) eyes. PMID- 26654044 TI - Arenogigas armoricus, a New Genus and Species of a Monostiliferous Hoplonemertean (Nemertea) from the North-West Coast of France. AB - A new genus and species of an endobenthic, unusually large eumonostiliferous hoplonemertean, Arenogigas armoricus gen. et sp. nov., is described from an intertidal sandflat in Pouldohan Bay near Concarneau, France. Morphological characters of the species and genus include a prominent connective tissue that divides the anterior longitudinal musculature, an extremely branched vascular system, the absence of a pre-cerebral septum, a pair of eyes situated at the anterior tip of the head, small cerebral organs positioned far anterior to the brain, 10 proboscidial nerves, and nine accessory stylet pouches. PMID- 26654045 TI - Integrative Taxonomy of the Micrura alaskensis Coe, 1901 Species Complex (Nemertea: Heteronemertea), with Descriptions of a New Genus Maculaura gen. nov. and Four New Species from the NE Pacific. AB - Micrura alaskensis Coe, 1901 is a common intertidal heteronemertean known from eastern and northwest Pacific (Alaska to Ensenada, Mexico and Akkeshi, Japan, respectively). It is an emerging model system in developmental biology research. We present evidence from morphology of the adults, gametes, and sequences of cytochrome c oxidase subunit I and 16S rRNA genes that it is not one, but a complex of five, cryptic species. All five of these species co-occur at least in part of their geographic range (e.g. southern Oregon). Preliminary cross hybridization experiments suggest that at least some of these species are reproductively isolated. The five species share characteristics of adult morphology (e.g. accessory buccal glands) and at least four are known to possess a unique larval morphotype--pilidium maculosum. We propose that these characters define a new genus, Maculaura gen. nov., which contains the following five species: Maculaura alaskensis comb. nov., Maculaura aquilonia sp. nov., Maculaura cerebrosa sp. nov., Maculaura oregonensis sp. nov., and Maculaura magna sp. nov. It is unclear which of the five species Coe originally encountered and described. We chose to retain the name "alaskensis" for the species that current researchers know as "Micrura alaskensis", although, presently, it is only known from Washington and Oregon, and has not been collected from Alaska. Maculaura aquilonia sp. nov. is the only member of the genus we have encountered in Alaska, and we show that it also occurs in the Sea of Okhotsk, Russia. PMID- 26654046 TI - Parent and child perceptions of school-based obesity prevention in England: a qualitative study. AB - BACKGROUND: Schools are key settings for childhood obesity prevention, and the location for many intervention studies. This qualitative study aims to explore parent and child experiences of the WAVES study obesity prevention intervention, in order to gain understanding of the mechanisms by which the intervention results in behaviour change, and provide context to support interpretation of the main trial results. METHODS: Focus groups were held with 30 parents and 62 children (aged 6-7 years) from primary schools in the West Midlands, UK. Data analysis (conducted using NVivo 10) was guided by the Framework Approach. RESULTS: Three over-arching themes were identified: 'Impact', 'Sustainability' and 'Responsibilities', under which sub-themes were determined. Participants were supportive of the school-based intervention. Parental involvement and the influential role of the teacher were seen as key ingredients for success in promoting consistent messages and empowering some parents to make positive behavioural changes at home. Parents recognised that whilst they held the primary responsibility for obesity prevention in their children, they faced a number of barriers to healthier lifestyles, and agreed that schools have an important role to play. CONCLUSIONS: This study enabled us to better understand aspects of the WAVES study intervention programme that have the potential to initiate positive behaviour changes in families, and indicated that a combination of pathways influenced such changes. Pathways included: increasing capability through improving knowledge and skills of children and parents; increasing motivation through parental empowerment and role modelling; and the direct provision of opportunities to lead healthier lifestyles. Strategies to sustain behaviour changes, and the school role in supporting these, are important considerations. PMID- 26654048 TI - Biowaste to fuel--what's leading research and applications? PMID- 26654047 TI - P53-Derived peptides conjugation to PEI: an approach to producing versatile and highly efficient targeted gene delivery carriers into cancer cells. AB - OBJECTIVES: Targeted delivery of cytotoxic drugs or therapeutic antisense RNAs into specific cells is a major bottleneck in cancer therapy. To overcome this problem and improve the specificity for cancer cells, we describe a new-targeted delivery system using p53-derived peptides, namely PNC 27 and PNC 28. These peptides target HDM-2 on the surface of cancer cells. HDM-2 is overexpressed on the surface of cancerous cells, but not present on the untransformed cells. METHODS: To determine HDM-2-expressing cells, we used immunocytochemistry and flow cytometry analysis on nine cell lines including MCF-7 and NIH-3t3. Conjugation of peptides to vectors was confirmed using reverse-phase high pressure liquid chromatography (RP-HPLC). Physicochemical properties of vector/DNA complexes including particle size, surface charge and DNA condensation ability were determined. In transfection studies, three plasmids were used including luciferase, pEGFP and shRNA plasmid against Bcl-XL mRNA. The level of Bcl-XL expression was determined by real-time PCR and western blot techniques. RESULTS: The results of gene delivery and shRNA-based gene silencing studies indicated that conjugation of PNC peptides could enhance gene delivery efficiently with high-targeted activity exclusively into cancer cells. CONCLUSION: Our results strongly indicated that this targeting system could be utilized as an efficient targeting method for most cancer cells. PMID- 26654049 TI - Deep Quantitative Proteomics Reveals Extensive Metabolic Reprogramming and Cancer Like Changes of Ectopic Endometriotic Stromal Cells. AB - Endometriosis is a prevalent health condition in women of reproductive age characterized by ectopic growth of endometrial-like tissue in the extrauterine environment. Thorough understanding of the molecular mechanisms underlying the disease is still incomplete. We dissected eutopic and ectopic endometrial primary stromal cell proteomes to a depth of nearly 6900 proteins using quantitative mass spectrometry with a spike-in SILAC standard. Acquired data revealed metabolic reprogramming of ectopic stromal cells with extensive upregulation of glycolysis and downregulation of oxidative respiration, a widespread metabolic phenotype known as the Warburg effect and previously described in many cancers. These changes in metabolism are additionally accompanied by attenuated aerobic respiration of ectopic endometrial stromal cells as measured by live-cell oximetry and by altered mRNA levels of respective enzyme complexes. Our results additionally highlight other molecular changes of ectopic endometriotic stromal cells indicating reduced apoptotic potential, increased cellular invasiveness and adhesiveness, and altered immune function. Altogether, these comprehensive proteomics data refine the current understanding of endometriosis pathogenesis and present new avenues for therapies. PMID- 26654050 TI - Effect of an Electron-Donating Substituent at the 3',4'-position of 3 Hydroxyflavone: Photophysics in Bulk Solvents. AB - Introduction of the methylenedioxy substituent group in the 3',4'-position of 3 hydroxyflavone produced a significant impact on its proton-transfer response, much like the well-known 4'-N,N-dialkylamino group. The potential electron donating property of the substituent helped sustain a high degree of charge separation in the excited enolic form of the molecule, which was stabilized in relatively polar solvents, whereupon the enol -> tautomer excited state intramolecular proton-transfer (ESIPT) rate decreased. Hydrogen-bonding solvents caused further retardation by interfering with the intramolecular hydrogen bond that promotes ESIPT. Among these solvents, hydrogen bond donors appear to be more efficient ESIPT inhibitors than hydrogen bond acceptors. Femtosecond fluorescence experiments revealed that even among the latter the ESIPT time-constants become steadily longer as the hydrogen bond basicity of the solvent increases. PMID- 26654051 TI - Inhibition of quorum sensing-controlled virulence factors in Pseudomonas aeruginosa by human serum paraoxonase. AB - The role of quorum sensing (QS) in the regulation of virulence factor production in Pseudomonas aeruginosa is well established. Increased antibiotic resistance in this bacterium has led to the search for new treatment options, and inhibition of the QS system has been explored for potential therapeutic benefits. If the use of QS inhibitory agents were to lead to a reduction in bacterial virulence, new approaches in the treatment of P. aeruginosa infections could be further developed. Accordingly, we examined whether human serum paraoxonase 1 (hPON1), which uses lactonase activity to hydrolyse N-acyl homoserine lactones, could cleave P. aeruginosa-derived signalling molecules. hPON1 was purified using ammonium sulfate precipitation and hydrophobic interaction chromatography (Sepharose 4B-L-tyrosine-1-naphthylamine). Different concentrations of hPON1 were found to reduce various virulence factors including pyocyanin, rhamnolipid, elastase, staphylolytic LasA protease and alkaline protease. Although treatment with 0.1-10 mg hPON1 ml(-1) did not show a highly inhibitory effect on elastase and staphylolytic LasA protease production, it resulted in good inhibitory effects on alkaline protease production at concentrations as low as 0.1 mg ml( 1). hPON1 also reduced the production of pyocyanin and rhamnolipid at a concentration of 1.25 mg ml(-1 )(within a range of 0.312-5 mg ml(-1)). In addition, rhamnolipid, an effective biosurfactant reported to stimulate the biodegradation of hydrocarbons, was able to degrade oil only in the absence of hPON1. PMID- 26654052 TI - The effect of freeze-dried antibody concentrations on its stability in the presence of trehalose and hydroxypropyl-beta-cyclodextrin: a Box-Behnken statistical design. AB - The present study aimed at preparation and optimization of stable freeze-dried immunoglobulin G (IgG) applying proper amount of antibody with efficient combination of trehalose and hydroxypropyl-beta-cyclodextrin (HPbetaCD). Response surface methodology was employed through a three-factor, three-level Box-Behnken design. Amounts of IgG (X1), trehalose (X2) and HPbetaCD (X3) were independent variables. Aggregation following process (Y1), after one month at 45 degrees C (Y2), upon two month at 45 degrees C (Y3) and beta-sheet content of IgG (Y4) were determined as dependent variables. Results were fitted to quadratic models (except for beta-sheet content), describing the inherent relationship between main factors. Optimized formulation composed of 55.85 mg IgG, 52.51 mg trehalose and 16.01 mg HPbetaCD was prepared. The calculated responses of the optimized formulation were as follows: Y1 = 0.19%, Y2 = 0.78%, Y3 = 1.88% and Y4 = 68.60%, respectively. The thermal analysis confirmed the amorphous nature of optimum formulation and the integrity of IgG was shown to be favorably preserved. Validation of the optimization study demonstrated high degree of prognostic ability. The DOE study successfully predicted the optimum values of antibody as well as stabilizers for desirable process and storage stabilization of freeze dried IgG. PMID- 26654053 TI - Evolving treatment landscape in metastatic renal cell carcinoma: where are we now? PMID- 26654054 TI - Editor's Introduction. PMID- 26654055 TI - Caring for Kathy: Where to Draw the Line. PMID- 26654056 TI - A Family in Need of a Palliative Care Social Worker. PMID- 26654057 TI - Reflections on Organ Transplantation: Life and Death Complicated. PMID- 26654058 TI - Counter Transference in the Face of Compassionate Care. PMID- 26654059 TI - Missed Opportunity: Hospice Care and the Family. AB - A typical mission statement of hospice services is to provide quality, compassionate care to those with terminal illness and to support families through caregiving and bereavement. This study explored the ways that bereavement needs of caregivers, either predeath or postdeath of their spouse/partner, were addressed using qualitative retrospective phone interviews with 19 caregivers whose spouse/partner was enrolled in hospice care for cancer. Overall, participants expressed high satisfaction with hospice care, most often noting a high satisfaction with the quality of care provided to their spouse/partner. During the predeath phase, caregivers recalled being so focused on their spouse/partner's needs that they rarely spoke with hospice staff about their own personal needs and emotions. Participants said that bereavement counseling occurred primarily after the death of the spouse/partner, in the form of generic pamphlets or phone calls from someone they had not met during prior interactions with hospice staff. These findings suggest that caregivers' high satisfaction with hospice may be more associated with the quality of care provided to the spouse/partner than with bereavement support they received. Our findings illustrated a potential missed opportunity for hospices to address the family oriented goals that are commonly put forward in hospice mission statements. PMID- 26654060 TI - Risk Factors for Anticipatory Grief in Family Members of Terminally Ill Veterans Receiving Palliative Care Services. AB - Anticipatory grief is the process associated with grieving the loss of loved ones in advance of their inevitable death. Because anticipatory grief has been associated with a variety of outcomes, risk factors for this condition deserve closer consideration. Fifty-seven family members of terminally ill, hospice eligible veterans receiving palliative care services completed measures assessing psychosocial factors and conditions. Elevated anticipatory grief was found in families characterized by relational dependency, lower education, and poor grief specific support, who also experienced discomfort with closeness and intimacy, neuroticism, spiritual crisis, and an inability to make sense of the loss. Thus, in this sample, anticipatory grief appears to be part of a cluster of factors and associated distress that call for early monitoring and possible intervention. PMID- 26654061 TI - Sudden-On-Chronic Death and Complicated Grief in Bereaved Dementia Caregivers: Two Case Studies of Complicated Grief Group Therapy. AB - Caring for a person with Alzheimer's disease is challenging and often has negative health and mental health effects that, for 7-20% of caregivers, persist into bereavement in the form of complicated grief. Complicated grief is a state of prolonged and ineffective mourning. An under-recognized phenomenon in dementia care and bereavement is "sudden-on-chronic death." In these situations, the caregiver is preparing for a gradual dying process from dementia, but the care recipient dies instead from a sudden death. In this study, an application of complicated grief group therapy for bereaved dementia caregivers with complicated grief is presented, and the effect of therapy with two bereaved caregivers who experienced the sudden death of their spouses who had a diagnosis of dementia is described. The unique treatment elements of complicated grief group therapy facilitated resolution of the 'trauma-like" features of bereavement and progression to a healthy grief process. PMID- 26654062 TI - Cognition in Adult Bereavement: Preliminary Findings From Five Hospice Bereavement Focus Groups. AB - Grief is an experience of both common and unique responses (Hooyman & Kramer, 2006). Grief affects people in various ways including emotionally, cognitively, socially, physically, and spiritually (Corr, 2007; Doka, 2014). Little has been published on the cognitive domain of loss affecting attention, and concentration of bereaved adults. This qualitative study explored these effects among adults in one hospice bereavement program in Central Texas. Five focus groups included facilitated bereavement topical conversations resulting in descriptions of memory, concentration, and attention deficits after loss. These results suggested that participation in bereavement programming may normalize the experience facilitating cognitive task accomplishment. Referrals for bereavement care may be appropriate in order to facilitate equilibrium in individual's lives following a significant death. PMID- 26654063 TI - The Positive Association of End-of-Life Treatment Discussions and Care Satisfaction in the Nursing Home. AB - With the progression of dementia, the need for families and health care providers to have discussions about end-of-life (EOL) treatments arises. EOL treatment decisions often involve whether or not medical interventions intended to prolong life-such as resuscitation, artificial nutrition and hydration, and use of antibiotics-are desired. It is unclear if family satisfaction with care in the nursing home may be associated with involvement in EOL treatment discussions. The frequency of discussions that family members reported having with health care team members regarding multiple life-sustaining treatments and symptom management for their relatives with advanced dementia were examined over a 6-month period along with the association of these particular discussions with care satisfaction over time. Results showed that greater frequency of discussion of EOL treatment wishes was positively associated with higher care satisfaction scores among family members of nursing home residents with dementia. When considered together, greater frequency of discussion of artificial hydration was uniquely associated with greater care satisfaction and increased care satisfaction over time. Social workers must ensure that EOL treatment discussions with older adults in the nursing home and their family members take place and that preferences are communicated among the various interdisciplinary health team members. PMID- 26654064 TI - Effects of Constraints and Consequences on Plan Complexity in Conversations About End-of-Life Care. AB - The current study assessed the role of health care provider constraints and perceived consequences on plan complexity for conversations with patients about end-of-life care. Meta-goal constraints, perceived consequences associated with conversational engagement and planning theory provides the basis for research questions and hypotheses posed. Findings suggested that while the meta-goals of efficiency and politeness were each recognized as important, providers indicated greater concern for politeness during patient interactions concerning treatment options. Reported constraints had no impact on plan complexity. Perceived consequences of conversational engagement were predominantly positive and concerned the patient. Findings may enhance the understanding of social workers in their educational role regarding the potential training needs of health care team members in palliative care contexts. PMID- 26654065 TI - Health Care Communication and Agreement and Disagreement About Symptoms Within the Context of Multimorbidity. AB - Informal caregivers for older adults often act as medical 'proxies' based on their assumed knowledge of the care recipient's illness-related symptoms. Differences between symptom descriptions given by care recipients and caregivers, however, raise questions about the validity of proxy reports. Community-dwelling caregivers and their care recipients with chronic, multi-morbid conditions revealed similar numbers of symptoms reported as well as average symptom distress. Dyads with care recipients who scored higher on negative affect were more likely to have significantly lower. Results suggested the possibility of identifying and intervening with dyads who may be 'at-risk' for divergent symptom reporting. This awareness may increase the ability to engage in informed and shared medical decision making throughout the illness trajectory. PMID- 26654066 TI - Adult Hospice Social Work Intervention Outcomes in the United States. AB - A descriptive and critical analysis of the available empirical literature on social work psychosocial intervention outcomes for adult hospice patients and caregivers was conducted. The electronic bibliographic databases CINHAL (EBSCO), MEDLINE, ProQuest, EMBASE, Campbell Collaboration, and The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library) were searched. Search criteria were (a) social work interventions, (b) intervention was tested, (c) adult hospice patients and/or caregivers, (d) studies within the United States, (e) and studies between 2004 and 2014. Of the 21 studies that met the initial search criteria, 5 publications met all review criteria. Based on assessment of study results, intervention effect, and quality of evidence, the ADAPT Problem-Solving Intervention (PSI) and the Hospice Caregiver Support Project have some indications of practical effect on caregiver quality of life, anxiety, stress, and problem-solving skills. The Caregiver Life Line (CaLL) intervention had little to no effect on caregiver role stress or coping skills. The few available studies provide foundational insight into the need for the expansion of research efforts to evaluate hospice social work interventions and document the contributions of social work to the field. PMID- 26654068 TI - Antibody-targeted biodegradable nanoparticles for cancer therapy. AB - The use of nanotechnology has great potentials to revolutionize the future cancer diagnosis and therapy. In this context, various nanoparticles (NPs) have been developed for targeted delivery of diagnostic/therapeutic agents to the tumor sites, which thus result in greater efficacy and much less side effects. The targeting property of NPs is often achieved by functionalizing their surface with tumor-specific ligands, such as antibodies, peptides, small molecules and oligonucleotides. In this review, we will discuss recent progress in the multifunctional design of antibody-targeted NPs with a special focus on liposomal, polymeric and protein-based delivery systems. PMID- 26654069 TI - DNA profiling: The first 30years. PMID- 26654070 TI - Sex determination from the calcaneus in a 20th century Greek population using discriminant function analysis. AB - The skull and post-cranium have been used for the determination of sex for unknown human remains. However, in forensic cases where skeletal remains often exhibit postmortem damage and taphonomic changes the calcaneus may be used for the determination of sex as it is a preservationally favored bone. The goal of the present research was to derive discriminant function equations from the calcaneus for estimation of sex from a contemporary Greek population. Nine parameters were measured on 198 individuals (103 males and 95 females), ranging in age from 20 to 99 years old, from the University of Athens Human Skeletal Reference Collection. The statistical analyses showed that all variables were sexually dimorphic. Discriminant function score equations were generated for use in sex determination. The average accuracy of sex classification ranged from 70% to 90% for the univariate analysis, 82.9% to 87.5% for the direct method, and 86.2% for the stepwise method. Comparisons to other populations were made. Overall, the cross-validated accuracies ranged from 48.6% to 56.1% with males most often identified correctly and females most often misidentified. The calcaneus was shown to be useful for sex determination in the twentieth century Greek population. PMID- 26654071 TI - On the relationship between stature and anthropometric measurements of lumbar vertebrae. AB - Stature estimation is important for identifying human remains. Analysis of body parts has become an important forensic tool during global operations in the context of cases in which human remains have been dismembered, mutilated or decomposed. However, unless almost the full skeleton or at least a long bone of the lower limb is available, accuracy is still limited to approximate body height. Especially with respect to single vertebral measurements, only a rough prediction is possible. Due to their complex geometry, vertebral measurements are possible at various locations. Nine locations have been considered in this study. Regression equations for stature estimation using lumbar vertebral geometry from computed tomography scans have been evaluated to identify the measurement which gives the most reliable body height estimation. The study group comprised a representative sample of a German metropolitan male population (42 autopsied individuals). Comparing the influence of various vertebral geometry measurements with body height resulted in a coefficient of correlation (R) of 0.19-0.53 and a 95% confidence interval (CI) of +/- 11.6 up to +/- 13.1cm. The largest correlation with a single vertebral measurement was achieved with the central height of the vertebral body of L2 as predictor; the standard error (SE) of the estimate was 5.9 cm. Using models from CT scans appeared superior to current invasive procedures that use direct measurements of the vertebral body, in terms of reproducibility and time efficiency. For fragmented non-skeletonized human bodies, height prediction based on an all-virtual model of the vertebrae is possible. However, the regression coefficient may be similar to classic caliper measurements that prove easier if skeletonized bones are available. PMID- 26654072 TI - Estimation of postmortem interval through albumin in CSF by simple dye binding method. AB - Estimation of postmortem interval is a very important question in some medicolegal investigations. For the precise estimation of postmortem interval, there is a need of a method which can give accurate estimation. Bromocresol green (BCG) is a simple dye binding method and widely used in routine practice. Application of this method in forensic practice may bring revolutionary changes. In this study, cerebrospinal fluid was aspirated from cisternal puncture from 100 autopsies. A study was carried out on concentration of albumin with respect to postmortem interval. After death, albumin present in CSF undergoes changes, after 72 h of death, concentration of albumin has become 0.012 mM, and this decrease was linear from 2 h to 72 h. An important relationship was found between albumin concentration and postmortem interval with an error of +/- 1-4h. The study concludes that CSF albumin can be a useful and significant parameter in estimation of postmortem interval. PMID- 26654073 TI - An initial investigation into the ecology of culturable aerobic postmortem bacteria. AB - Postmortem microorganisms are increasingly recognized for their potential to serve as physical evidence. Yet, we still understand little about the ecology of postmortem microbes, particularly those associated with the skin and larval masses. We conducted an experiment to characterize microbiological and chemical properties of decomposing swine (Sus scrofa domesticus) carcasses on the island of Oahu, Hawaii, USA, during June 2013. Bacteria were collected from the head, limb, and larval mass during the initial 145h of decomposition. We also measured the pH, temperature, and oxidation-reduction potential of larval masses in situ. Bacteria were cultured aerobically on Standard Nutrient Agar at 22 degrees C and identified using protein or genetic signals. Carcass decomposition followed a typical sigmoidal pattern and associated bacterial communities differed by sampling location and time since death, although all communities were dominated by phyla Actinobacteria, Firmicutes, and Proteobacteria. Larval masses were reducing environments (~-200mV) of neutral pH (6.5-7.5) and high temperature (35 degrees C-40 degrees C). We recommend that culturable postmortem and larval mass microbiology and chemistry be investigated in more detail, as it has potential to complement culture-independent studies and serve as a rapid estimate of PMI. PMID- 26654074 TI - Shifts in soil biodiversity-A forensic comparison between Sus scrofa domesticus and vegetation decomposition. AB - In a forensic context, microbial-mediated cadaver decomposition and nutrient recycling cannot be overlooked. As a result, forensic ecogenomics research has intensified to gain a better understanding of cadaver/soil ecology interactions as a powerful potential tool for forensic practitioners. For this study, domestic pig (Sus scrofa domesticus) (4g) and grass (Agrostis/Festuca spp) cuttings (4g) were buried (July 2013 to July 2014) in sandy clay loam (80 g) triplicates in sealed microcosms (127 ml; 50 * 70 cm) with parallel soil only controls. The effects of the two carbon sources were determined by monitoring key environmental factors and changes in soil bacterial (16S rRNA gene) and fungal (18S rRNA gene) biodiversity. Soil pH changes showed statistically significant differences (p<0.05) between the treatments. The measured ecological diversity indices (Shannon-Wiener, H?; Simpson, D; and richness, S) of the 16S rRNA and 18S rRNA gene profiles also revealed differences between the treatments, with bacterial and fungal community dominance recorded in the presence of S. scrofa domesticus and grass trimming decomposition, respectively. In contrast, no statistically significant difference in evenness (p>0.05) was observed between the treatments. PMID- 26654075 TI - Identical twins in forensic genetics - Epidemiology and risk based estimation of weight of evidence. AB - The increase in the number of forensic genetic loci used for identification purposes results in infinitesimal random match probabilities. These probabilities are computed under assumptions made for rather simple population genetic models. Often, the forensic expert reports likelihood ratios, where the alternative hypothesis is assumed not to encompass close relatives. However, this approach implies that important factors present in real human populations are discarded. This approach may be very unfavourable to the defendant. In this paper, we discuss some important aspects concerning the closest familial relationship, i.e., identical (monozygotic) twins, when reporting the weight of evidence. This can be done even when the suspect has no knowledge of an identical twin or when official records hold no twin information about the suspect. The derived expressions are not original as several authors previously have published results accounting for close familial relationships. However, we revisit the discussion to increase the awareness among forensic genetic practitioners and include new information on medical and societal factors to assess the risk of not considering a monozygotic twin as the true perpetrator. If accounting for a monozygotic twin in the weight of evidence, it implies that the likelihood ratio is truncated at a maximal value depending on the prevalence of monozygotic twins and the societal efficiency of recognising a monozygotic twin. If a monozygotic twin is considered as an alternative proposition, then data relevant for the Danish society suggests that the threshold of likelihood ratios should approximately be between 150,000 and 2,000,000 in order to take the risk of an unrecognised identical, monozygotic twin into consideration. In other societies, the threshold of the likelihood ratio in crime cases may reach other, often lower, values depending on the recognition of monozygotic twins and the age of the suspect. In general, more strictly kept registries will imply larger thresholds on the likelihood ratio as the monozygotic twin explanation gets less probable. PMID- 26654076 TI - On the recovery of fibres by tape lifts, tape scanning, and manual isolation. AB - The recovery of fibre traces via tape lifting, tape scanning and manual isolation is investigated. The recovery efficiency of taping was determined using different tapes, donor textiles, and receptor textiles. It was determined that tape lifts generally recover over 90% of extraneous fibres that had been transferred by direct contact with a donor textile. The recovery via tape scanning was evaluated by the preparation of a set of 15 tapes that contained a number of target fibres on a background of other fibres. The tapes presented varying difficulty and were investigated by trained fibre examiners. The examiners were asked to locate the target fibres and to provide their opinion on the difficulty of the search. As expected, the efficiency decreases for more difficult searches. It was determined that the efficiency of the search was influenced by the microscopic illumination modes used by the examiner. A final experiment investigated the recovery by manual isolation of fibres from non-textile items. It was determined that all fibres from tie cables and knives were recovered, except in those cases where the recipient item contained many fibres. In addition, the examiners correctly sampled each of three fibre populations present on a sample of duct tape. PMID- 26654077 TI - Discrimination of reactively-dyed cotton fibres with thin layer chromatography and UV microspectrophotometry. AB - Reactively-dyed black, navy blue and medium red cotton samples showing metamerism under fluorescent tube illumination were examined. Optical microscopy (bright field, polarization and fluorescence microscopy) was used, followed by microspectrometry in the visible range (MSP Vis), to differentiate the samples in each block of colours. Additionally, the non-discriminated samples were subjected both to microspectrophotometry in the UV-range (MSP UV) and to enzymatic digestion followed by high performance thin layer chromatography (HPTLC) on the digests. While it was found that both methods may potentially result in higher discrimination, preparation of reactively-dyed cotton for HPTLC was found to be a very tedious and time-consuming step and HPTLC only led to a better discrimination than MSP UV for the red cotton samples. The results suggest that in order to increase the discrimination for reactively-dyed cotton fibres, measurement of the UV absorption spectrum (MSP UV) is preferred over HPTLC. PMID- 26654078 TI - Fibre persistence on immersed garment - Influence of water flow and stay in running water. AB - The persistence of fibre traces is a critical factor in the evaluation of fibre findings in forensic casework. Water can play a major role in affecting fibre persistence as a lot of fibre traces can get lost after washing incriminated garments, after rainfall over the victim's body or after immersion of the victim in water. The influence of immersion in standing water on fibre persistence was previously studied in our laboratory on various knitted recipient fabrics. The present study is focused on the persistence of target fibres on immersed cotton T shirts through an immersion/stay/emersion process in running water (from 1h up to 7h), simulated in laboratory (~0.4l/s, gentle water flow conditions) and in real conditions (~2000l/s, medium water flow conditions). A gentle water flow slightly affects fibre persistence, which remains more or less constant over time, regardless of the duration of the stay in water. No rapid loss is observed during immersion in real conditions, including a medium water flow and boat activity. The fibre persistence in running water seems to depend mainly on the immersion step and also, in case of a medium water flow, on the stay in water with a linear loss over hours. PMID- 26654079 TI - On-site semi-quantitative analysis for ammonium nitrate detection using digital image colourimetry. AB - Digital image colourimetry was successfully applied in the semi-quantitative analysis of ammonium nitrate using Griess's test with zinc reduction. A custom built detection box was developed to enable reproducible lighting of samples, and was used with the built-in webcams of a netbook and an ultrabook for on-site detection. The webcams were used for colour imaging of chemical reaction products in the samples, while the netbook was used for on-site colour analysis. The analytical performance was compared to a commercial external webcam and a digital single-lens reflex (DSLR) camera. The relationship between Red-Green-Blue intensities and ammonium nitrate concentration was investigated. The green channel intensity (IG) was the most sensitive for the pink-violet products from ammonium nitrate that revealed a spectrometric absorption peak at 546 nm. A wide linear range (5 to 250 mgL-1) with a high sensitivity was obtained with the built in webcam of the ultrabook. A considerably lower detection limit (1.34 +/- 0.05mgL-1) was also obtained using the ultrabook, in comparison with the netbook (2.6 +/- 0.2 mgL-1), the external web cam (3.4 +/- 0.1 mgL-1) and the DSLR (8.0 +/- 0.5 mgL-1). The best inter-day precision (over 3 days) was obtained with the external webcam (0.40 to 1.34%RSD), while the netbook and the ultrabook had 0.52 to 3.62% and 1.25 to 4.99% RSDs, respectively. The relative errors were +3.6, +5.6 and -7.1%, on analysing standard ammonium nitrate solutions of known concentration using IG, for the ultrabook, the external webcam, and the netbook, respectively, while the DSLR gave -4.4% relative error. However, the IG of the pink-violet reaction product suffers from interference by soil, so that blank subtraction (|IG-IGblank| or |AG-AGblank|) is recommended for soil sample analysis. This method also gave very good accuracies of -0.11 to -5.61% for spiked soil samples and the results presented for five seized samples showed good correlations between the various imaging devices and spectrophotometer used to determine ammonium nitrate concentrations. Five post-blast soil samples were also analysed and pink-violet product were observed using Griess's test without zinc reduction indicating the absence of ammonium nitrate. This demonstrates significant potential for practical and accurate on-site semi-quantitative determinations of ammonium nitrate concentration. PMID- 26654080 TI - Study of chemical modifications in acidified ignitable liquids analysed by GC-MS. AB - In this work, mixtures of gasoline with sulphuric acid and diesel fuel with sulphuric acid were analysed by gas chromatography-mass spectrometry (GC-MS). The results showed considerable qualitative and semi-quantitative modifications in the chromatographic profiles of the ignitable liquids (ILs). In the case of acidified gasoline, the alteration of the abundances of aromatic compounds and the hydrolysis of an oxygenated compound such as methyl tert-butyl ether (MTBE), in addition to the immediate and unexpected appearance of tert-butylated compounds were observed. In the case of acidified diesel fuel, the alteration of aromatic compounds occurred. These sequential changes were then studied in detail in order to explain the chemical modifications taking place. These extensive chemical modifications may be considered as a new chromatographic profile distortion effect, the acidification of ILs. As such modifications are not generally taken into account in the criteria followed to assess the classification of an IL, we propose some recommendations helping to the identification of acidified ILs. This information can be especially useful to detect and identify non-burned ILs from seized or failed improvised incendiary devices made with mixtures of sulphuric acid-IL, or ILs altered intentionally with the aim to modify their composition. PMID- 26654081 TI - Fast profiling of cocaine seizures by FTIR spectroscopy and GC-MS analysis of minor alkaloids and residual solvents. AB - In this study, samples coming from large seizures of cocaine which took place in Italian Customs areas during 2011 and 2012 were examined. Minor alkaloids and residual solvents, analyzed by gas chromatography-mass spectrometry (GC-MS) and head space (HS)-GC-MS, respectively, were processed by principal component analysis (PCA), highlighting groupings of samples according to their chemical similarity. A hypothesis about the geographical origin of samples was also provided: most of them were compatible with Colombia as country of origin. Results of these analyses were used as starting point for the development of a "fast profiling" method, based on Fourier transform infrared spectroscopy (FTIR) and chemometric tools. Two models were developed and compared: KBr-FTIR and attenuated total reflection (ATR)-FTIR for comparative analysis of pure samples. Linear discriminant analysis (LDA) was applied to the model based on ATR-FTIR spectroscopy, obtaining a classification and a prediction ability both of 97.56% for pure samples. Finally, "cut" samples were tested as an external test set, and the assignment class provided by LDA was compared with results obtained by the analyses of alkaloids and residual solvents: in the case of samples added with only one substance, prediction errors began to occur for percentages of cocaine lower than 50%. PMID- 26654082 TI - Novel method for the detection of nitroglycerin in smokeless powders. AB - Nitroglycerin is an active component in many explosive substances. Notably, it is found as an active ingredient in double-base smokeless powders, differentiating them from single-base powders, whose main active ingredient is nitrocellulose. It is proposed that the detection of nitroglycerin within various types of ammunition will allow for the differentiation between single and double-base smokeless powders, thus allowing for a method of distinguishing ammunition or bulk powder samples that may be found during the course of a criminal investigation. Presumptive tests are an effective tool in field-testing for forensic science. These tests are used primarily as rapid, sensitive means of elucidating the chemical characteristics of an unknown sample in-situ. In this paper, the authors present a novel method for the detection of nitroglycerin in smokeless powders with the use of a presumptive color test reagent, dimethylaminocinnamaldehyde (p-dmac). Twenty-five smokeless powders were tested using this reagent to evaluate the color change that would occur in the presence of nitroglycerin. All presumptive results were confirmed via gas chromatography mass spectrometry. PMID- 26654083 TI - Development and validation of a LC/MS method for the determination of Delta(9) tetrahydrocannabinol and 11-carboxy-Delta(9)-tetrahydrocannabinol in the larvae of the blowfly Lucilia sericata: Forensic applications. AB - In a number of forensic toxicological cases, Delta(9)-tetrahydrocannabinol (THC) and its metabolite 11-carboxy-delta-9-tetrahydrocannabinol (THCA) are frequently considered as contributor factors to the event. To that, a liquid chromatographic mass spectrometric method is described for the identification and quantitation of THC and its metabolite THCA in the forensically important larvae of L. sericata. Larvae of Lucilia sericata were fortified with varying concentrations of THC and THCA covering the calibration range between 10 and 500pg/mg. For the isolation of the analytes from larvae, several extraction techniques were evaluated and finally liquid-liquid extraction under acidic pH was selected using hexane-ethyl acetate (50:50, v/v) as extraction solvent. For the chromatographic separation, a Waters Symmetry(r) C18 analytical column was used while the mobile phase was acetonitrile-ammonium acetate (2mM) (30:70, v/v). The detection was performed using electrospray ionization source in negative mode (ESI-) and the selected ions monitored were m/z 313 for THC and m/z 343 for THCA. The proposed method which is simple and sufficiently sensitive for the detection of THC and THCA even in a single larva sampling, assisted the investigation of a forensic case. PMID- 26654084 TI - Screening determination of four amphetamine-type drugs in street-grade illegal tablets and urine samples by portable capillary electrophoresis with contactless conductivity detection. AB - A simple and inexpensive method for the identification of four substituted amphetamines, namely, 3,4-methylenedioxy methamphetamine (MDMA), methamphetamine (MA), 3,4-methylenedioxy amphetamine (MDA) and 3,4-methylenedioxy-N ethylamphetamine (MDEA) was developed using an in-house constructed semi automated portable capillary electrophoresis instrument (CE) with capacitively coupled contactless conductivity detection (C(4)D). Arginine 10mM adjusted to pH4.5 with acetic acid was found to be the optimal background electrolyte for the CE-C(4)D determination of these compounds. The best detection limits achieved with and without a sample preconcentration process were 10ppb and 500ppb, respectively. Substituted amphetamines were found in different seized illicit club drug tablets and urine samples collected from different suspected users. Good agreement between results from CE-C(4)D and those with the confirmation method (GC-MS) was achieved, with correlation coefficients for the two pairs of data of more than 0.99. PMID- 26654085 TI - Facial Comparison from CCTV footage: The competence and confidence of the jury. AB - CCTV footage is commonly used in the court room to help visualise the crime in question and to help identify the offender. Unfortunately the majority of surveillance cameras produce such poor quality images that the task of identifying individuals can be extremely difficult. This study aimed at determining whether the task of identifying the offender in CCTV footage was one which a jury should be competent to do, or whether expert evidence would be beneficial in such cases. The ability of potential jury members, the general public, was tested by asking participants to play the role of a jury member by means of an online survey. Potential jury members viewed CCTV in which a simulated offence took place, and were subsequently asked to compare still images of a defendant to the offender to try to determine if they were competent and confident about making a judgement as to whether the defendant committed the crime. Factors such as age, gender and profession of the potential jury members were considered, as well as the type of crime committed, in order to establish if these play any role in the decision made by potential jury members. These factors did not appear to play a significant role; however confidence was also investigated and it became very evident that this was a factor that must be taken into consideration when determining the requirement for expert contribution in facial comparisons. Jury members may well be willing and competent to a basic level in carrying out a facial comparison but if they lack a certain level of confidence in their ability and decision making then this task is more suitable for an expert with experience and skills in this field. PMID- 26654086 TI - Sampling variability in forensic likelihood-ratio computation: A simulation study. AB - Recently, in the forensic biometric community, there is a growing interest to compute a metric called "likelihood-ratio" when a pair of biometric specimens is compared using a biometric recognition system. Generally, a biometric recognition system outputs a score and therefore a likelihood-ratio computation method is used to convert the score to a likelihood-ratio. The likelihood-ratio is the probability of the score given the hypothesis of the prosecution, Hp (the two biometric specimens arose from a same source), divided by the probability of the score given the hypothesis of the defense, Hd (the two biometric specimens arose from different sources). Given a set of training scores under Hp and a set of training scores under Hd, several methods exist to convert a score to a likelihood-ratio. In this work, we focus on the issue of sampling variability in the training sets and carry out a detailed empirical study to quantify its effect on commonly proposed likelihood-ratio computation methods. We study the effect of the sampling variability varying: 1) the shapes of the probability density functions which model the distributions of scores in the two training sets; 2) the sizes of the training sets and 3) the score for which a likelihood-ratio is computed. For this purpose, we introduce a simulation framework which can be used to study several properties of a likelihood-ratio computation method and to quantify the effect of sampling variability in the likelihood-ratio computation. It is empirically shown that the sampling variability can be considerable, particularly when the training sets are small. Furthermore, a given method of likelihood-ratio computation can behave very differently for different shapes of the probability density functions of the scores in the training sets and different scores for which likelihood-ratios are computed. PMID- 26654087 TI - Utility of the clue - From assessing the investigative contribution of forensic science to supporting the decision to use traces. AB - In an attempt to grasp the effectiveness of forensic science in the criminal justice process, a number of studies introduced some form of performance indicator. However, most of these indicators suffer from different weaknesses, from the definition of forensic science itself to problems of reliability and validity. We suggest the introduction of the concept of utility of the clue as an internal evaluation indicator of forensic science in the investigation. Utility of the clue is defined as added value of information, gained by the use of traces. This concept could be used to assess the contribution of the trace in the context of the case. By extension, a second application of this concept is suggested. By formalising and considering, a priori, the perceived utility of using traces, we introduce the notion of expected utility that could be used as decision factor when choosing which traces to use, once they have been collected at the crime scene or from an object in the laboratory. In a case-based approach, utility can be assessed in the light of the available information to evaluate the investigative contribution of forensic science. In the decision-making process, the projection or estimation of the utility of the clue is proposed to be a factor to take into account when triaging the set of traces. PMID- 26654088 TI - Design and results of an exploratory double blind testing program in firearms examination. AB - In 2010, the Netherlands Forensic Institute (NFI) and the University of Amsterdam (UvA) started a series of tests for the NFI's Firearms Section. Ten cartridge case and bullet comparison tests were submitted by various external parties as regular cases and mixed in the flow of real cases. The results of the tests were evaluated with the VU University Amsterdam (VUA). A total of twenty-nine conclusions were drawn in the ten tests. For nineteen conclusions the submitted cartridge cases or bullets were either fired from the questioned firearm or from one and the same firearm, in tests where no firearm was submitted. For ten conclusions the submitted cartridge cases or bullets were either fired from another firearm than the submitted one or from several firearms, in tests where no firearm was submitted. In none of the conclusions misleading evidence was reported, in the sense that all conclusions supported the true hypothesis. This article discusses the design considerations of the program, contains details of the tests, and describes the various ways the test results were and could be analyzed. PMID- 26654089 TI - The importance of distinguishing information from evidence/observations when formulating propositions. AB - The value of forensic results crucially depends on the propositions and the information under which they are evaluated. For example, if a full single DNA profile for a contemporary marker system matching the profile of Mr A is assessed, given the propositions that the DNA came from Mr A and given it came from an unknown person, the strength of evidence can be overwhelming (e.g., in the order of a billion). In contrast, if we assess the same result given that the DNA came from Mr A and given it came from his twin brother (i.e., a person with the same DNA profile), the strength of evidence will be 1, and therefore neutral, unhelpful and irrelevant(1) to the case at hand. While this understanding is probably uncontroversial and obvious to most, if not all practitioners dealing with DNA evidence, the practical precept of not specifying an alternative source with the same characteristics as the one considered under the first proposition may be much less clear in other circumstances. During discussions with colleagues and trainees, cases have come to our attention where forensic scientists have difficulty with the formulation of propositions. It is particularly common to observe that results (e.g., observations) are included in the propositions, whereas-as argued throughout this note-they should not be. A typical example could be a case where a shoe-mark with a logo and the general pattern characteristics of a Nike Air Jordan shoe is found at the scene of a crime. A Nike Air Jordan shoe is then seized at Mr A's house and control prints of this shoe compared to the mark. The results (e.g., a trace with this general pattern and acquired characteristics corresponding to the sole of Mr A's shoe) are then evaluated given the propositions 'The mark was left by Mr A's Nike Air Jordan shoe-sole' and 'The mark was left by an unknown Nike Air Jordan shoe'. As a consequence, the footwear examiner will not evaluate part of the observations (i.e., the mark presents the general pattern of a Nike Air Jordan) whereas they can be highly informative. Such examples can be found in all forensic disciplines. In this article, we present a few such examples and discuss aspects that will help forensic scientists with the formulation of propositions. In particular, we emphasise on the usefulness of notation to distinguish results that forensic scientists should evaluate from case information that the Court will evaluate. PMID- 26654090 TI - Correction to "Modeling Dioxygen Reduction at Multicopper Oxidase Cathodes". PMID- 26654091 TI - Quantity and quality of secoiridoids and lignans in extra virgin olive oils: the effect of two- and three-way decanters on Leccino and Raggiola olive cultivars. AB - In this investigation, 14 extra virgin olive oils (EVOOs), produced with Leccino and Raggiola olive cultivars, by a new two-way (2W) decanter were compared with 14 EVOOs produced by means of a conventional three-way (3W) decanter. The 2W EVOOs had higher phenol concentrations, as shown by high-performance liquid chromatography/diode array detection (HPLC-DAD) analysis and yielded a higher extraction of the 3,4-DHPEA-EDA (oleacein), 3,4-DHPEA-EA (oleuropein aglycone) and p-HPEA-EDA (oleocanthal). The concentrations of lignans, (+)-pinoresinol and (+)-1-acetoxypinoresinol, detected by HPLC-FLD equipment, were higher in the 2W EVOOs than they were in EVOOs produced using the 3W system. Total phenols, detected by the Folin-Ciocalteu assay, were lower than those obtained by HPLC, but they significantly correlated (p < 0.05). The antioxidant capacity (ORAC) values of 2W EVOOs were higher than those of 3W EVOOs. In conclusion, the 2W system provided high-quality phenol EVOOs and became an indispensable tool when adverse climatic conditions reduced the olive secoiridoid concentration. PMID- 26654092 TI - Editorial: Immunophilins, Protein Chemistry and Cell Biology of a Promising New Class of Drug Targets - Part II. PMID- 26654093 TI - Regular clinic attendance in two large San Francisco HIV primary care settings. AB - Although poor clinic attendance is associated with increased morbidity and mortality among HIV-infected individuals, less is known about predictors of retention and the acceptability of targeted interventions to increase regular clinic attendance. To better understand which patients are at risk for irregular clinic attendance and to explore interventions to aid in retention to care, we surveyed patients attending two outpatient HIV clinics affiliated with the University of California, San Francisco. A total of 606 participants were surveyed, and the analysis was restricted to the 523 male respondents. Of this group, 45% (N = 299) reported missing at least one visit a year. Missing a clinic visit was associated with being African American (aOR = 1.99; 95%CI 1.12-3.52), being a man who has sex with both men and women (aOR=2.72; 95%CI 1.16-6.37), and reporting at least weekly methamphetamine use (aOR=5.79; 95%CI 2.47-13.57). Participants who reported a monthly income greater than $2000 were less likely to miss an appointment (aOR = 0.56; 95%CI 0.34-0.93). Regarding possible retention interventions, most patients preferred phone calls over other forms of support. These findings support the need for ongoing engagement support with particular attention to at-risk sub-groups. PMID- 26654094 TI - Exposure of Preschool-Age Greek Children (RHEA Cohort) to Bisphenol A, Parabens, Phthalates, and Organophosphates. AB - Phthalate esters (PEs), bisphenol A (BPA), and parabens (PBs), which are used in numerous consumer products, are known for their endocrine disrupting properties. Organophosphate chemicals (OPs), which form the basis of the majority of pesticides, are known for their neurotoxic activity in humans. All of these chemicals are associated with health problems to which children are more susceptible. Once they enter the human body, PEs, BPA, PBs, and OPs are metabolized and/or conjugated and finally excreted via urine. Hence, human exposure to these substances is examined through a determination of the urinary concentrations of their metabolites. This study assessed the exposure of Greek preschool-age children to PEs, BPA, PBs, and OPs by investigating the urinary levels of seven PEs metabolites, six PBs, BPA, and six dialkyl phosphate metabolites in five-hundred samples collected from 4-year-old children, subjects of the "RHEA" mother-child cohort in Crete, Greece. Daily intake of endocrine disruptors, calculated for 4 year old children, was lower than the corresponding daily intake for 2.5 year old children, which were determined in an earlier study of the same cohort. In some cases the daily intake levels exceeded the U.S. Environmental Protection Agency Tolerable Daily Intake (TDI) values and the EFSA Reference Doses (RfD) (e.g., for di-2-ethyl-hexyl phthalate, 3.6% and 1% of the children exceeded RfD and TDi, respectively). Exposure was linked to three main sources: PEs-BPA to plastic, PBs-diethyl phthalate to personal hygiene products, and OPs to food. PMID- 26654096 TI - Robotic Partial Nephrectomy in the Treatment of Renal Angiomyolipoma. AB - PURPOSE: To present the experience and efficacy of Robotic Partial Nephrectomy (RPN) for the management of renal angiomyolipomas (AMLs) with regard to renal function preservation and perioperative outcomes. PATIENTS AND METHODS: We retrospectively searched our RPN database for pathologically confirmed renal AML patients between 2006 and 2014. Clinical presentation, perioperative complications, and postoperative outcomes of the patients were analyzed. Preoperative imaging findings were reviewed to examine their ability to predict pathology of AML. RESULTS: From 1005 RPN performed in our center during the study period, 53 patients met our inclusion criteria. The mean age at presentation was 54.1 (+/- 13) years, and 42 (79.2%) patients were female. Median tumor size was 2.8 (interquartile range [IQR], 1.8-4.6) cm. The indication for RPN was suspicious radiologic features for malignancy in 42 (79.2%) patients and acute retroperitoneal hemorrhage risk and pain in 11 (20.8%) patients who were found to have AML according to preoperative imaging. Mean estimated blood loss was 198 (+/ 194) mL, and 5 (9.4%) patients required blood transfusion. Postoperative complications occurred in 8 (15%) patients. Median estimated glomerular filtration rate within the latest follow-up was 86.9 (IQR, 69.7-100.1) mL/minute/1.73 m(2) with a median of 91% (IQR, 80.4-103) preservation. None of patients developed urinary fistula or pseudoaneurysm requiring second intervention. No local recurrences occurred with a median follow-up of 7 (IQR, 1 17) months. CONCLUSION: Given the low complication rate and preservation of renal function after RPN for AML, it can be considered a reliable method for AML treatment. The majority of AMLs were not suspected based on preoperative imaging. Further diagnostic methods are needed to differentiate benign from malignant lesions. PMID- 26654095 TI - High-throughput transcriptomics reveals common and strain-specific responses of human macrophages to infection with Mycobacterium abscessus Smooth and Rough variants. AB - BACKGROUND: Mycobacterium abscessus (MAB) is an emerging pathogen causing pulmonary infections in those with inflammatory lung disorders, such as Cystic Fibrosis (CF), and is associated with the highest fatality rate among rapidly growing mycobacteria (RGM). Phenotypically, MAB manifests as either a Smooth (MAB S) or a Rough (MAB-R) morphotype, which differ in their levels of cell wall glycopeptidolipids (GPLs) and in their pathogenicity in vivo. As one of the primary immune cells encountered by MAB, we sought to examine the early transcriptional events within macrophages, following infection with both MAB-S or MAB-R. RESULTS: We sampled the transcriptomes (mRNA and miRNA) of THP-1-derived macrophages infected with both MAB-R and MAB-S at 1, 4 and 24 h post-infection (hpi) using RNA-seq. A core set of 606 genes showed consistent expression profiles in response to both morphotypes, corresponding to the early transcriptional response to MAB. The core response is type I Interferon (IFN) driven, involving the NF-kappaB and MAPK signaling pathways with concomitant pro inflammatory cytokine production, and network analysis identified STAT1, EGR1, and SRC as key hub and bottleneck genes. MAB-S elicited a more robust transcriptional response at both the mRNA and miRNA levels, which was reflected in higher cytokine levels in culture supernatants. The transcriptional profiles of macrophages infected with both morphotypes were highly correlated, however, and a direct comparison identified few genes to distinguish them. Most of the induced miRNAs have previously been associated with mycobacterial infection and overall miRNA expression patterns were similarly highly correlated between the morphotypes. CONCLUSIONS: The report here details the first whole transcriptome analysis of the early macrophage response to MAB infection. The overall picture at the early stages of macrophage infection is similar to that of other mycobacteria, reflected in a core type I IFN and pro-inflammatory cytokine response. Large-scale transcriptional differences in the host response to the different MAB morphotypes are not evident in the early stages of infection, however the subset of genes with distinct expression profiles suggest potentially interesting differences in internal trafficking of MAB within macrophages. PMID- 26654097 TI - Electronic Structure and Bonding in Iron(II) and Iron(I) Complexes Bearing Bisphosphine Ligands of Relevance to Iron-Catalyzed C-C Cross-Coupling. AB - Chelating phosphines are effective additives and supporting ligands for a wide array of iron-catalyzed cross-coupling reactions. While recent studies have begun to unravel the nature of the in situ-formed iron species in several of these reactions, including the identification of the active iron species, insight into the origin of the differential effectiveness of bisphosphine ligands in catalysis as a function of their backbone and peripheral steric structures remains elusive. Herein, we report a spectroscopic and computational investigation of well-defined FeCl2(bisphosphine) complexes (bisphosphine = SciOPP, dpbz, (tBu)dppe, or Xantphos) and known iron(I) variants to systematically discern the relative effects of bisphosphine backbone character and steric substitution on the overall electronic structure and bonding within their iron complexes across oxidation states implicated to be relevant in catalysis. Magnetic circular dichroism (MCD) and density functional theory (DFT) studies demonstrate that common o-phenylene and saturated ethyl backbone motifs result in small but non-negligible perturbations to 10Dq(Td) and iron-bisphosphine bonding character at the iron(II) level within isostructural tetrahedra as well as in five-coordinate iron(I) complexes FeCl(dpbz)2 and FeCl(dppe)2. Notably, coordination of Xantphos to FeCl2 results in a ligand field significantly reduced relative to those of its iron(II) partners, where a large bite angle and consequent reduced iron-phosphorus Mayer bond orders (MBOs) could play a role in fostering the unique ability of Xantphos to be an effective additive in Kumada and Suzuki-Miyaura alkyl-alkyl cross couplings. Furthermore, it has been found that the peripheral steric bulk of the SciOPP ligand does little to perturb the electronic structure of FeCl2(SciOPP) relative to that of the analogous FeCl2(dpbz) complex, potentially suggesting that differences in the steric properties of these ligands might be more important in determining in situ iron speciation and reactivity. PMID- 26654098 TI - A promising sword of tomorrow: Human gammadelta T cell strategies reconcile allo HSCT complications. AB - Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is potentially a curative therapeutic option for hematological malignancies. In clinical practice, transplantation associated complications greatly affected the final therapeutical outcomes. Currently, primary disease relapse, graft-versus-host disease (GVHD) and infections remain the three leading causes of a high morbidity and mortality in allo-HSCT patients. Various strategies have been investigated in the past several decades including human gammadelta T cell-based therapeutical regimens. In different microenvironments, human gammadelta T cells assume features reminiscent of classical Th1, Th2, Th17, NKT and regulatory T cells, showing diverse biological functions. The cytotoxic gammadelta T cells could be utilized to target relapsed malignancies, and recently regulatory gammadelta T cells are defined as a novel implement for GVHD management. In addition, human gammadelta Tau cells facilitate control of post-transplantation infections and participate in tissue regeneration and wound healing processes. These features potentiate gammadelta T cells a versatile therapeutical agent to target transplantation associated complications. This review focuses on insights of applicable potentials of human gammadelta T cells reconciling complications associated with allo-HSCT. We believe an improved understanding of pertinent gammadelta T cell functions would be further exploited in the design of innovative immunotherapeutic approaches in allo-HSCT, to reduce mortality and morbidity, as well as improve quality of life for patients after transplantation. PMID- 26654099 TI - Electroconvulsive seizures (ECS) do not prevent LPS-induced behavioral alterations and microglial activation. AB - BACKGROUND: Long-term neuroimmune activation is a common finding in major depressive disorder (MDD). Literature suggests a dual effect of electroconvulsive therapy (ECT), a highly effective treatment strategy for MDD, on neuroimmune parameters: while ECT acutely increases inflammatory parameters, such as serum levels of pro-inflammatory cytokines, there is evidence to suggest that repeated ECT sessions eventually result in downregulation of the inflammatory response. We hypothesized that this might be due to ECT-induced attenuation of microglial activity upon inflammatory stimuli in the brain. METHODS: Adult male C57Bl/6J mice received a series of ten electroconvulsive seizures (ECS) or sham shocks, followed by an intracerebroventricular (i.c.v.) lipopolysaccharide (LPS) or phosphate-buffered saline (PBS) injection. Brains were extracted and immunohistochemically stained for the microglial marker ionized calcium-binding adaptor molecule 1 (Iba1). In addition, a sucrose preference test and an open field test were performed to quantify behavioral alterations. RESULTS: LPS induced a short-term reduction in sucrose preference, which normalized within 3 days. In addition, LPS reduced the distance walked in the open field and induced alterations in grooming and rearing behavior. ECS did not affect any of these parameters. Phenotypical analysis of microglia demonstrated an LPS-induced increase in microglial activity ranging from 84 to 213 % in different hippocampal regions (CA3 213 %; CA1 84 %; dentate gyrus 131 %; and hilus 123 %). ECS-induced alterations in microglial activity were insignificant, ranging from -2.6 to 14.3 % in PBS-injected mice and from -20.2 to 6.6 % in LPS-injected mice. CONCLUSIONS: We were unable to demonstrate an effect of ECS on LPS-induced microglial activity or behavioral alterations. PMID- 26654100 TI - Fast Confocal Raman Imaging Using a 2-D Multifocal Array for Parallel Hyperspectral Detection. AB - We present the development of a novel confocal hyperspectral Raman microscope capable of imaging at speeds up to 100 times faster than conventional point-scan Raman microscopy under high noise conditions. The microscope utilizes scanning galvomirrors to generate a two-dimensional (2-D) multifocal array at the sample plane, generating Raman signals simultaneously at each focus of the array pattern. The signals are combined into a single beam and delivered through a confocal pinhole before being focused through the slit of a spectrometer. To separate the signals from each row of the array, a synchronized scan mirror placed in front of the spectrometer slit positions the Raman signals onto different pixel rows of the detector. We devised an approach to deconvolve the superimposed signals and retrieve the individual spectra at each focal position within a given row. The galvomirrors were programmed to scan different focal arrays following Hadamard encoding patterns. A key feature of the Hadamard detection is the reconstruction of individual spectra with improved signal-to noise ratio. Using polystyrene beads as test samples, we demonstrated not only that our system images faster than a conventional point-scan method but that it is especially advantageous under noisy conditions, such as when the CCD detector operates at fast read-out rates and high temperatures. This is the first demonstration of multifocal confocal Raman imaging in which parallel spectral detection is implemented along both axes of the CCD detector chip. We envision this novel 2-D multifocal spectral detection technique can be used to develop faster imaging spontaneous Raman microscopes with lower cost detectors. PMID- 26654102 TI - Spatial distribution of individuals with symptoms of depression in a periurban area in Lima: an example from Peru. AB - PURPOSE: To map the geographical distribution and spatial clustering of depressive symptoms cases in an area of Lima, Peru. METHODS: Presence of depressive symptoms suggesting a major depressive episode was assessed using a short version of the Center for Epidemiologic Studies Depression Scale. Data were obtained from a census conducted in 2010. One participant per selected household (aged 18 years and above, living more than 6 months in the area) was included. Residence latitude, longitude, and elevation were captured using a GPS device. The prevalence of depressive symptoms was estimated, and relative risks (RRs) were calculated to identify areas of significantly higher and lower geographical concentrations of depressive symptoms. RESULTS: Data from 7946 participants, 28.3% male, mean age 39.4 (SD, 13.9) years, were analyzed. The prevalence of depressive symptoms was 17.0% (95% confidence interval = 16.2%-17.8%). Three clusters with high prevalence of depressive symptoms (primary cluster: RR = 1.82; P = .003 and secondary: RR = 2.83; P = .004 and RR = 5.92; P = .01), and two clusters with significantly low prevalence (primary: RR = 0.23; P = .016 and secondary: RR = 0; P = .035), were identified. Further adjustment by potential confounders confirmed the high prevalence clusters but also identified newer ones. CONCLUSIONS: Screening strategies for depression, in combination with mapping techniques, may be useful tools to target interventions in resource limited areas. PMID- 26654103 TI - Enhancing Performance of Triboelectric Nanogenerator by Filling High Dielectric Nanoparticles into Sponge PDMS Film. AB - Understanding of the triboelectric charge accumulation from the view of materials plays a critical role in enhancing the output performance of triboelectric nanogenerator (TENG). In this paper, we have designed a feasible approach to modify the tribo-material of TENG by filling it with high permittivity nanoparticles and forming pores. The influence of dielectricity and porosity on the output performance is discussed experimentally and theoretically, which indicates that both the surface charge density and the charge transfer quantity have a close relationship with the relative permittivity and porosity of the tribo-material. A high output performance TENG based on a composite sponge PDMS film (CS-TENG) is fabricated by optimizing both the dielectric properties and the porosity of the tribo-material. With the combination of the enhancement of permittivity and production of pores in the PDMS film, the charge density of ~19 nC cm(-2), open-circuit voltage of 338 V, and power density of 6.47 W m(-2) are obtained at working frequency of 2.5 Hz with the optimized film consisting of 10% SrTiO3 nanoparticles (~100 nm in size) and 15% pores in volume, which gives over 5-fold power enhancement compared with the nanogenerator based on the pure PDMS film. This work gives a better understanding of the triboelectricity produced by the TENG from the view of materials and provides a new and effective way to enhance the performance of TENG from the material itself, not just its surface modification. PMID- 26654101 TI - Randomized trial of primaquine hypnozoitocidal efficacy when administered with artemisinin-combined blood schizontocides for radical cure of Plasmodium vivax in Indonesia. AB - BACKGROUND: Safety and efficacy of primaquine against repeated attacks of Plasmodium vivax depends upon co-administered blood schizontocidal therapy in radical cure. We assessed primaquine (PQ) as hypnozoitocide when administered with dihydroartemisinin-piperaquine (Eurartesim(r), DHA-PP) or artesunate pyronaridine (Pyramax(r), AS-PYR) to affirm its good tolerability and efficacy. A third arm, artesunate followed by primaquine, was not intended as therapy for practice, but addressed a hypothesis concerning primaquine efficacy without co administration of blood schizontocide. METHODS: During March to July 2013, an open-label, randomized trial enrolled Indonesian soldiers with vivax malaria at Sragen, Central Java, after six months duty in malarious Papua, Indonesia. No malaria transmission occurred at the study site and P. vivax recurrences in the 12 months following therapy were classified as relapses. A historic relapse control derived from a cohort of soldiers who served in the same area of Papua was applied to estimate risk of relapse among randomized treatment groups. Those were: 1) AS followed 2d later by PQ (0.5 mg/kg daily for 14d); 2) co-formulated AS-PYR concurrent with the same regimen of PQ; or 3) co-formulated DHA-PP concurrent with the same regimen of PQ. RESULTS: Among 532 soldiers, 219 had vivax malaria during the four months following repatriation to Java; 180 of these were otherwise healthy and G6PD-normal and enrolled in the trial. Subjects in all treatment groups tolerated the therapies well without untoward events and cleared parasitemia within three days. First relapse appeared at day 39 post-enrollment, and the last at day 270. Therapeutic efficacy of PQ against relapse by incidence density analysis was 92 % (95 %CI = 83-97 %), 94 %(95 %CI = 86-97 %), and 95 %(95 %CI = 88-98 %) when combined with AS, AS-PYR, or DHA-PP, respectively. CONCLUSIONS: This trial offers evidence of good tolerability and efficacy of PQ against P. vivax relapse when administered concurrently with DHA-PP or AS-PYR. These offer alternative partner drugs for radical cure with primaquine. The AS arm demonstrated efficacy with a total dose of 7 mg/kg PQ without concurrently administered blood schizontocide, another option when primaquine therapy is removed in time from the treatment of the acute malaria or applied presumptively without an attack. TRIAL REGISTRATION: Current Controlled Trials ISRCTN82366390, assigned 20 March 2013. PMID- 26654104 TI - In vivo contact biomechanics in the trapeziometacarpal joint using finite deformation biphasic theory and mathematical modelling. AB - The assessment of the contact biomechanics in the trapeziometacarpal (TMC) joint during functional tasks represents a relevant way to obtain a better understanding of the onset of osteoarthritis (OA). CT scans of the hand region of 20 female volunteers were taken in relaxed neutral, lateral key pinch and power grasp configuration. 3D models of the first metacarpal (MC1) and the trapezium were created. The articular area of each bone was quantified and a mathematical model was developed in Matlab to evaluate the projected contact area and stress distribution of each bone. The articular areas of the MC1 and the trapezium presented no significant difference. A slightly smaller projected contact area was calculated for the trapezium compared to the MC1. Similar amounts of stress were reported in the neutral and lateral pinch configurations. The highest stress levels were observed during power grasp. Very consistent results for high stress location on the volar/radial articular sub-region were found in the neutral and power grasp configurations. More variation was reported during lateral pinch. The mathematical model presented in this paper offers the possibility to predict contact patterns within the TMC joint based on in vivo CT images. PMID- 26654105 TI - p-Type NiO Hybrid Visible Photodetector. AB - A novel hybrid visible-light photodetector was created using a planar p-type inorganic NiO layer in a junction with an organic electron acceptor layer. The effect of different oxygen pressures on formation of the NiO layer by pulsed laser deposition shows that higher pressure increases the charge carrier density of the film and lowers the dark current in the device. The addition of a monolayer of small molecules containing conjugated pi systems and carboxyl groups at the device interface was also investigated and with correct alignment of the energy levels improves the device performance with respect to the quantum efficiency, responsivity, and photogeneration. The thickness of the organic layer was also optimized for the device, giving a responsivity of 1.54 * 10(-2) A W(-1) in 460 nm light. PMID- 26654106 TI - China's 1-3-7 surveillance and response strategy for malaria elimination: Is case reporting, investigation and foci response happening according to plan? AB - BACKGROUND: The China's 1-3-7 strategy was initiated and extensively adopted in different types of counties (geographic regions) for reporting of malaria cases within 1 day, their confirmation and investigation within 3 days, and the appropriate public health response to prevent further transmission within 7 days. Assessing the level of compliance to the 1-3-7 strategy at the county level is a first step towards determining whether the surveillance and response strategy is happening according to plan. This study assessed if the time-bound targets of the 1-3-7 strategy were being sustained over time. Such information would be useful to improve implementation of the 1-3-7 strategy in China. METHODS: This cross sectional study involved country-wide programmatic data for the period January 1st 2013 to June 30th 2014. Data variables were extracted from the national malaria information system and included socio-demographic information, type of county, date of diagnosis, date of reporting, date of case investigation, case classification (indigenous, or imported, or unknown), focus investigation, date of reactive case detection (RACD), and date of indoor residual spraying (IRS). Summary statistics and proportions were used and comparisons between groups were assessed using the chi-square test. Level of significance was set at a P-value <= 0.05. RESULTS: Of a total of 5,688 malaria cases from 731 counties, there were 55 (1 %) indigenous cases (only in Type 1 and Type 2 counties) and 5,633 (99 %) imported cases from all types of counties. There was no delay in reporting malaria cases by type of county. In terms of case investigation, 97.5 % cases were investigated within 3 days with the proportion of delays (1.5 %) in type 2 counties, being significantly lower than type 1 counties (4.1 %). Regarding active foci, 96.4 % were treated by RACD and/or IRS. CONCLUSIONS: The performance of 1-3-7 strategy was encouraging but identified some challenges that if addressed can further improve implementation. PMID- 26654107 TI - Community-acquired adult Escherichia coli meningitis leading to diagnosis of unrecognized retropharyngeal abscess and cervical spondylodiscitis: a case report. AB - BACKGROUND: Escherichia coli is a rare cause of community-acquired meningitis in adults unless predisposing factors are present (e.g., previous penetrating cranio cerebral injury or neurosurgery, immunosuppression, chronic alcoholism, history of cancer, diabetes mellitus, advanced age). CASE PRESENTATION: We describe the case of a 53-year-old woman, resident in Germany, suffering from community acquired bacterial meningitis caused by CTX-M-9 type extended spectrum beta lactamase producing Escherichia coli. Because typical predisposing factors were not apparent, pathogen identification resulted in expanded diagnostics to exclude a distant or contiguous primary focus. By magnetic resonance tomography, a previously unrecognized large retropharyngeal abscess with cervical spondylodiscitis was detected. In retrospect, the patient had complained about neck pain for a few weeks prior to meningitis onset, but the symptoms were interpreted as being related to a herniated disk. Meningitis and osteomyelitis resolved completely under surgical treatment and meropenem therapy. CONCLUSION: In case of adult Escherichia coli meningitis, underlying diseases should always be carefully excluded, especially if predisposing factors are not apparent. PMID- 26654108 TI - Erratum to: Long non-coding RNA ROR decoys gene-specific histone methylation to promote tumorigenesis. PMID- 26654109 TI - Can shoulder joint reaction forces be estimated by neural networks? AB - To facilitate the development of future shoulder endoprostheses, a long term load profile of the shoulder joint is desired. A musculoskeletal model using 3D kinematics and external forces as input can estimate the mechanical load on the glenohumeral joint, in terms of joint reaction forces. For long term ambulatory measurements, these 3D kinematics can be measured by means of Inertial Magnetic Measurement Systems. Recording of external forces under daily conditions is not feasible; estimations of joint loading should preferably be independent of this input. EMG signals reflect the musculoskeletal response and can easily be measured under daily conditions. This study presents the use of a neural network for the prediction of glenohumeral joint reaction forces based upon arm kinematics and shoulder muscle EMG. Several setups were examined for NN training, with varying combinations of type of input, type of motion, and handled weights. When joint reaction forces are predicted by a trained NN, for motion data independent of the training data, results show a high intraclass correlation (ICC up to 0.98) and relative SEM as low as 3%, compared to similar output of a musculoskeletal model. A convenient setup in which kinematics and only one channel of EMG were used as input for the NN's showed comparable predictive power as more complex setups. These results are promising and enable long term estimation of shoulder joint reaction forces outside the motion lab, independent of external forces. PMID- 26654110 TI - A method for automated control of belt velocity changes with an instrumented treadmill. AB - Increased practice difficulty during asymmetrical split-belt treadmill rehabilitation has been shown to improve gait outcomes during retention and transfer tests. However, research in this area has been limited by manual treadmill operation. In the case of variable practice, which requires stride-by stride changes to treadmill belt velocities, the treadmill control must be automated. This paper presents a method for automation of asymmetrical split-belt treadmill walking, and evaluates how well this method performs with regards to timing of gait events. One participant walked asymmetrically for 100 strides, where the non-dominant limb was driven at their self-selected walking speed, while the other limb was driven randomly on a stride-by-stride basis. In the control loop, the key factors to insure that the treadmill belt had accelerated to its new velocity safely during the swing phase were the sampling rate of the A/D converter, processing time within the controller software, and acceleration of the treadmill belt. The combination of these three factors resulted in a total control loop time during each swing phase that satisfied these requirements with a factor of safety that was greater than 4. Further, a polynomial fit indicated that belt acceleration was the largest contributor to changes in this total time. This approach appears to be safe and reliable for stride-by-stride adjustment of treadmill belt speed, making it suitable for future asymmetrical split-belt walking studies. Further, it can be incorporated into virtual reality rehabilitation paradigms that utilize split-belt treadmill walking. PMID- 26654111 TI - Obstetric fistula management and predictors of successful closure among women attending a public tertiary hospital in Rwanda: a retrospective review of records. AB - BACKGROUND: Globally, 50,000-100,000 women develop obstetric fistula annually. At least 33,000 of these women live in Sub-Saharan Africa where limitations in quality obstetric care and fistula corrective repairs are prevalent. Among women with fistula seeking care at public health facilities in resource-limited settings, there is paucity of data on quality of care received. The aim of this study was to characterize obstetric fistula among Rwandan women managed at a public tertiary hospital and evaluate for predictors of successful fistula closures. METHODS: A retrospective review of records for all obstetric fistula women managed at a public referral health facility between 2007 and 2013 was performed. Patient socio-demographics, obstetric characteristics and fistula repair outcomes data were reviewed. A multivariate logistic regression model was used to analyse for predictors of successful fistula repair outcomes. RESULTS: A total of 272 women aged between 16 to 78 years and with a mean age of 34.6 years were included. Of these, 93 (34.2 %), 48 (17.6 %), 65 (24 %) and 64 (23 %) women had vesico-vaginal fistula, recto-vaginal fistula, urethro-vaginal fistula and vesico-uteral fistula types, respectively. Successful fistula closure was achieved among 86.3 %. Women with fistula who reported being in labour for >=3 days, having >=1 previous fistula repair attempt, and having lived with the fistula for >1 year, had significantly lower odds of successful repair outcomes. CONCLUSIONS: Among 272 women with obstetric fistula managed in this study, 69.5 and 26.5 % of their fistula were causally associated with obstructed labour complications and iatrogenic factors, respectively. Successful fistula closure rates of about 89 % among women of index repair attempt were achieved. Conversely, reported histories of >=3 days in labour, >=1 previous failed attempts at repair and a fistula duration of >1 year, were significant determinants of failed fistula closures. To effectively mitigate obstetric fistula burden in Rwanda, a comprehensive package of services including quality emergency obstetric care, increased availability of and access to quality fistula repair, active surveillance to identify community-based women with fistula and a strong political will towards effective fistula care, are recommended. PMID- 26654112 TI - Proposal to include the rank of phylum in the International Code of Nomenclature of Prokaryotes. AB - The International Code of Nomenclature of Prokaryotes covers the nomenclature of prokaryotes up to the rank of class. We propose here modifying the Code to include the rank of phylum so that names of phyla that fulfil the rules of the Code will obtain standing in the nomenclature. PMID- 26654113 TI - Rates of Hospitalization for Dehydration Following Hurricane Sandy in New Jersey. AB - OBJECTIVE: Hurricane Sandy, one of the most destructive natural disasters in New Jersey history, made landfall on October 29, 2012. Prolonged loss of electrical power and extensive infrastructure damage restricted access for many to food and water. We examined the rate of dehydration in New Jersey residents after Hurricane Sandy. METHODS: We obtained data from 2008 to 2012 from the Myocardial Infarction Data Acquisition System (MIDAS), a repository of in-patient records from nonfederal New Jersey hospitals (N=517,355). Patients with dehydration had ICD-9-CM discharge diagnosis codes for dehydration, volume depletion, and/or hypovolemia. We used log-linear modeling to estimate the change in in-patient hospitalizations for dehydration comparing 2 weeks after Sandy with the same period in the previous 4 years (2008-2011). RESULTS: In-patient hospitalizations for dehydration were 66% higher after Sandy than in 2008-2011 (rate ratio [RR]: 1.66; 95% confidence interval [CI]: 1.50, 1.84). Hospitalizations for dehydration in patients over 65 years of age increased by nearly 80% after Sandy compared with 2008-2011 (RR: 1.79; 95% CI: 1.58, 2.02). CONCLUSION: Sandy was associated with a marked increase in hospitalizations for dehydration. Reducing the rate of dehydration following extreme weather events is an important public health concern that needs to be addressed, especially in those over 65 years of age. PMID- 26654114 TI - Intermolecular Cyclopropanation of Styrenes Using Iodine and Visible Light via Carbon-Iodine Bond Cleavage. AB - The intermolecular cyclopropanation of aromatic olefins with activated methylene compounds using iodine and visible light irradiation was described. This reaction proceeds under rare-metal-free conditions. Styrenes with various substituted groups (alkyl and electron-withdrawing groups) provided corresponding cyclopropanes in moderate to good yields. PMID- 26654115 TI - The effect of a culturally informed therapy on self-conscious emotions and burden in caregivers of patients with schizophrenia: A randomized clinical trial. AB - OBJECTIVE: Caring for a family member with schizophrenia often results in high degrees of self-conscious emotions (shame and guilt/self-blame), burden, and other serious mental health consequences. Research suggests that ethnic and cultural factors strongly influence the manner in which family members respond to mental illness. Research further indicates that certain cultural practices and values (spirituality, collectivism) may assist family members in coping with the self-conscious emotions and burden associated with caregiving. With this in mind, the authors have developed a family-focused, culturally informed treatment for schizophrenia (CIT-S). METHOD: Using a sample of 113 caregivers of patients with schizophrenia (60% Hispanic, 28.2% Caucasian, 8% African American, and 3.8% other), the authors assessed the ability of CIT-S to reduce self-conscious emotions and caregiver burden above and beyond a 3-session psychoeducation (PSY ED) control condition. They further examined whether self-conscious emotions mediated the relationship between treatment type and caregiver burden. RESULTS: In line with expectations, CIT-S was found to outperform PSY-ED in reducing guilt/self-blame and caregiver burden. Furthermore, consistent with hypotheses, reductions in guilt/self-blame were found to mediate the changes observed between treatment type and caregiver burden. Although caregivers in both treatment groups demonstrated significant posttreatment reductions in shame, CIT-S was not found to outperform PSY-ED in reducing levels of this construct. CONCLUSIONS: Results suggest that caregivers of patients with schizophrenia may respond well to a treatment that specifically taps in to their cultural beliefs, values, and behaviors in helping them cope with schizophrenia in a loved one. Study implications and future directions are discussed. PMID- 26654116 TI - A palm-sized high-sensitivity near-infrared fluorescence imager for laparotomy surgery. AB - In laparotomy surgery guided by near-infrared fluorescence imaging, the access to the field of operation is limited by the illumination and/or the imaging field. The side of cavities or organs such as the liver or the heart cannot be examined with the systems available on the market, which are too large and too heavy. In this article, we describe and evaluate a palm sized probe, whose properties, weight, size and sensitivity are adapted for guiding laparotomy surgery. Different experiments have been performed to determine its main characteristics, both on the illumination and imaging sides. The device has been tested for fluorescent molecular probe imaging in preclinical procedures, to prove its ability to be used in cancer nodule detection during surgery. This system is now CE certified for clinical procedures and Indocyanine Green imaging has been performed during clinical investigations: lymphedema and surgical resection of liver metastases of colorectal cancers. PMID- 26654117 TI - Lithium-Ion Battery Cycling for Magnetism Control. AB - Magnetization and electric-field coupling is fundamentally interesting and important. Specifically, current- or voltage-driven magnetization switching at room temperature is highly desirable from scientific and technological viewpoints. Herein, we demonstrate that magnetization can be controlled via the discharge-charge cycling of a lithium-ion battery (LIB) with rationally designed electrode nanomaterials. Reversible manipulation of magnetism over 3 orders of magnitude was achieved by controlling the lithiation/delithiation of a nanoscale alpha-Fe2O3-based electrode. The process was completed rapidly under room temperature conditions. Our results indicate that in addition to energy storage LIBs, which have been under continuous development for several decades, provide exciting opportunities for the multireversible magnetization of magnetic fields. PMID- 26654118 TI - Nature-Based Tourism and Prey Vulnerability to Predators: A Reply to Fitzgerald and Stronza. PMID- 26654119 TI - Clinical implications of recent advances in proteogenomics. AB - Proteogenomics, the alliance of proteomics, transcriptomics, genomics and bioinformatics, was first proposed for refining genome annotation using experimental data acquired on gene products. With high-throughput analysis of proteins made possible with next-generation tandem mass spectrometers, proteogenomics is greatly improving human genome annotation per se, and is helping to decrypt the numerous gene and protein modifications occurring during development, aging, illness and cancer progression. Further efforts are required to obtain a comprehensive picture of human genes, their products, functions, and drift over time or in reaction to microbiota and pathogen stimuli. This should be performed not only to obtain a general overview of the human population, but also to gain specific information at the individual level. This review focuses on the clinical implications of proteogenomics: novel biological insights into fundamental biology, better characterization of pathogens and parasites, discovery of novel diagnostic approaches for cancer, and personalized medicine. PMID- 26654120 TI - Impact of error self-perception of aerobic capacity in the safety and efficacy of the lifeguards. AB - INTRODUCTION: The strong physical demands that are required of lifeguards during rescues also require an accurate self-perception of one's fitness level to be able to regulate the intensity of effort. OBJECTIVES: The aim of this study was to determine the real aerobic capacity (RAC) and to compare it with two self reported measurements: subjective appraisal of aerobic capacity (SAAC) and appraisal of physical exercise (APE). METHODS: Fifty-two professional lifeguards were included in the study. For an objective assessment of RAC, the lifeguards' maximum oxygen uptake (VO2max) values were measured during treadmill stress tests. A fitness assessment questionnaire was used to obtain the SAAC and APE values. RESULTS: We found a statistically significant association between the APE and RAC variables in the contingency analysis (p < 0.001). In total, 93.7% of the lifeguards who obtained a VO2max value below 43 ml kg(-1) min(-1) considered their aerobic capacity to be high or very high. CONCLUSION: This self-perception error of true aerobic capacity could lead to premature fatigue during a rescue, endangering both the lifeguard's life and the life of the victim. These data may help lifeguards and beach managers to become aware of the need to know lifeguards' true physical conditions through testing and structured training programs. PMID- 26654121 TI - Five Species of Coccidia (Apicomplexa: Eimeriidae), Including Four New Species, Identified in the Feces of Blue Wildebeest (Connochaetes taurinus) in Mikumi National Park, Tanzania. AB - During October 2013, 112 fecal samples were collected from wild blue wildebeest ( Connochaetes taurinus ) in Mikumi National Park, Tanzania, and examined for coccidians. Coccidia were present in 46% of samples, with wildebeest shedding 60 to 18,000 oocysts per gram feces (median, 300; mean, 1,236). Five species, including 4 new species, were identified. Oocysts of Eimeria gorgonis from 18% of samples were ellipsoidal, 23 * 18.4 MUm, with a length/width (L/W) ratio of 1.3, oocyst wall 1-1.5 MUm thick. Micropyle, oocyst residuum, and polar granule absent. Oocysts of Eimeria donaldi n. sp. from 34% of samples were spherical to oblong, 13.4 * 12.3 MUm, L/W ratio 1.1, oocyst wall 1 MUm thick. Micropyle, oocyst residuum, and polar granule absent. Oocysts of Eimeria nyumbu n. sp. were ellipsoidal, 30.8 * 22.1 MUm, L/W 1.4, oocyst wall 2 MUm thick. Large micropyle present, oocyst residuum and polar granule absent. Oocysts of Eimeria burchelli n. sp. in 16% of samples were 34.8 * 24.4 MUm, L/W 1.4, oocyst wall 2-2.5 MUm thick, with a brown, lightly stippled outer layer. Micropyle present, oocyst residuum and polar granule absent. Oocysts of Eimeria sokoine n. sp. in 5% of samples were 45.8 * 29 MUm, L/W 1.6, oocyst wall 3-4 MUm thick with a dark brown, very rough, stippled outer layer. Micropyle present, oocyst residuum and polar granule absent. There was no apparent cross transmission of coccidia found in blue wildebeest with those generally reported to infect domestic cattle. PMID- 26654122 TI - Interventions to reduce zoonotic and pandemic risks from avian influenza in Asia. AB - Novel influenza viruses continue to emerge, posing zoonotic and potentially pandemic threats, such as with avian influenza A H7N9. Although closure of live poultry markets (LPMs) in mainland China stopped H7N9 outbreaks temporarily, closures are difficult to sustain, in view of poultry production and marketing systems in China. In this Personal View, we summarise interventions taken in mainland China, and provide evidence for other more sustainable but effective interventions in the live poultry market systems that reduce risk of zoonotic influenza including rest days, and banning live poultry in markets overnight. Separation of live ducks and geese from land-based (ie, non-aquatic) poultry in LPM systems can reduce the risk of emergence of zoonotic and epizootic viruses at source. In view of evidence that H7N9 is now endemic in over half of the provinces in mainland China and will continue to cause recurrent zoonotic disease in the winter months, such interventions should receive high priority in China and other Asian countries at risk of H7N9 through cross-border poultry movements. Such generic measures are likely to reduce known and future threats of zoonotic influenza. PMID- 26654123 TI - Consumptive Tourism Causes Timidity, Rather Than Boldness, Syndromes: A Response to Geffroy et al. PMID- 26654124 TI - Genomics in Conservation: Case Studies and Bridging the Gap between Data and Application. PMID- 26654125 TI - Effects of Immunonutrition for Cystectomy on Immune Response and Infection Rates: A Pilot Randomized Controlled Clinical Trial. AB - After radical cystectomy (RC), patients are at risk for complications including infections. The expansion of myeloid-derived suppressor cells (MDSCs) after surgery may contribute to the lower resistance to infection. Immune response and postoperative complications were compared in men consuming either specialized immunonutrition (SIM; n=14) or an oral nutrition supplement (ONS; n=15) before and after RC. MDSC count (Lin- CD11b+ CD33+) was significantly different between the groups over time (p=0.005) and significantly lower in SIM 2 d after RC (p<0.001). MDSC count expansion from surgery to 2 d after RC showed a weak association with an increase in infection rate 90 d after surgery (p=0.061). Neutrophil:lymphocyte ratio was significantly lower in SIM compared with ONS 3h after the first incision (p=0.039). Participants receiving SIM had a 33% reduction in postoperative complication rate (95% confidence interval [CI], 1-64; p=0.060) and a 39% reduction in infection rate (95% CI, 8-70; p=0.027) during late-phase recovery. The small sample size limits the study findings. PATIENT SUMMARY: Results show that the immune response to surgery and late infection rates differ between radical cystectomy patients receiving specialized immunonutrition versus oral nutrition supplement in the perioperative period. TRIAL REGISTRATION: ClinicalTrials.gov NCT01868087. PMID- 26654126 TI - Primary ciliary dyskinesia in adults. AB - INTRODUCTION: Primary ciliary dyskinesia is an autosomal recessive genetic disorder leading to structural and/or functional abnormalities of motor cilia. Impaired mucociliary clearance is responsible for the development of a multi organ disease, which particularly affects the upper and lower airways. STATE OF THE ART: In adults, primary ciliary dyskinesia is mainly characterized by bronchiectasis and chronic ear and sinus disorders. Situs inversus is found in half of patients and fertility disorders are commonly associated. Diagnosis is based on specialized tests: reduced level of nasal nitric oxide concentrations is suggestive of primary ciliary dyskinesia, but only a nasal or bronchial biopsy/brushing with analysis of beat pattern by videomicroscopy and/or analysis of cilia morphology by electronic microscopy can confirm the diagnosis. However, the diagnosis is difficult to achieve due to the limited access to these specialized tests and to difficulties in interpreting them. Genetic tests are under development and may provide new diagnostic tools. Treatment is symptomatic, based on airway clearance techniques (e.g., physiotherapy) and systemic and/or inhaled antibiotics. Prognosis is related to the severity of the respiratory impairment, which can be moderate or severe. PERSPECTIVES AND CONCLUSIONS: Diagnosis and management of primary ciliary dyskinesia remain poorly defined and should be supported by specialized centers to standardize the diagnosis, improve the treatment and promote research. PMID- 26654127 TI - Evaluating the effect of pupil dilation on spectral-domain optical coherence tomography measurements and their quality score. AB - BACKGROUND: Spectral-domain optical coherence tomography (SD-OCT) provides fast scan speed and high scan resolution improving its diagnostic accuracy. The purpose of this study was to evaluate if SD-OCT measurements and their quality score are influenced by pupil dilation. METHODS: Retinal nerve fiber layer thickness (RNFL), ganglion cell complex (GCC) and optic nerve head (ONH) were measured in one eye of 57 glaucoma patients and 36 healthy subjects using spectral domain optical coherence tomography (SD-OCT) before and after pupil dilation. Comparisons were made between measurements and their quality score pre- and post dilation (Signal Strength Index, SSI). Overall RNFL, average GCC and ONH rim volume were considered in the analysis. RESULTS: No statistically significant differences were found between pre- and post-dilation measurements in both groups (glaucoma: RNFL 80 +/- 15 MUm vs 80 +/- 16 MUm, p = 0.87; GCC 81.35 +/- 13.4 MUm vs 81.10 +/- 13.14 MUm, p = 0.92; ONH 0.05 +/- 0.11 mm(3) vs 0.04 +/- 0.07 mm(3), p = 0.74; controls RNFL 99 +/- 12 MUm vs 98 +/- 14 MUm, p = 0.70; GCC 92.12 +/- 6.7 MUm vs 91.54 +/- 7.05 MUm, p = 0.72; ONH 0.11 +/- 0.1 mm(3) vs 0.04 +/- 0.07 mm(3), p = 0.36) nor between pre- and post-dilation quality score (glaucoma SSI RNFL 54.3 +/- 10.3 vs 51.7 +/- 18.1, p = 0.12; SSI GCC 58 +/- 9.5 vs 57 +/- 8.09, p = 0.55; SSI ONH 48.5 +/- 7.6 vs 46.6 +/- 7.2, p = 0.16; controls SSI RNFL 57 +/ 10.3 vs 54 +/- 9.31, p = 0.2; SSI GCC 60.9 +/- 8.1 vs 58.8 +/- 7.3, p = 0.3; SSI ONH 51.5 +/- 8.9 vs 50.4 +/- 8.3, p = 0.59). CONCLUSION: Pupil dilation doesn't affect SD-OCT measurements and their quality score. PMID- 26654128 TI - Hippocampal dosimetry correlates with the change in neurocognitive function after hippocampal sparing during whole brain radiotherapy: a prospective study. AB - BACKGROUND: Whole brain radiotherapy (WBRT) has been the treatment of choice for patients with brain metastases. However, change/decline of neurocognitive functions (NCFs) resulting from impaired hippocampal neurogenesis might occur after WBRT. It is reported that conformal hippocampal sparing would provide the preservation of NCFs. Our study aims to investigate the hippocampal dosimetry and to demonstrate the correlation between hippocampal dosimetry and neurocognitive outcomes in patients receiving hippocampal sparing during WBRT (HS-WBRT). METHODS: Forty prospectively recruited cancer patients underwent HS-WBRT for therapeutic or prophylactic purposes. Before receiving HS-WBRT, all participants received a battery of baseline neurocognitive assessment, including memory, executive functions and psychomotor speed. The follow-up neurocognitive assessment at 4 months after HS-WBRT was also performed. For the delivery of HS WBRT, Volumetric Modulated Arc Therapy (VMAT) with two full arcs and two non coplanar partial arcs was employed. For each treatment planning, dose volume histograms were generated for left hippocampus, right hippocampus, and the composite hippocampal structure respectively. Biologically equivalent doses in 2 Gy fractions (EQD2) assuming an alpha/beta ratio of 2 Gy were computed. To perform analyses addressing the correlation between hippocampal dosimetry and the change in scores of NCFs, pre- and post-HS-WBRT neurocognitive assessments were available in 24 patients in this study. RESULTS: Scores of NCFs were quite stable before and after HS-WBRT in terms of hippocampus-dependent memory. Regarding verbal memory, the corresponding EQD2 values of 0, 10, 50, 80 % irradiating the composite hippocampal structure with <12.60 Gy, <8.81, <7.45 Gy and <5.83 Gy respectively were significantly associated with neurocognitive preservation indicated by the immediate recall of Word List Test of Wechsler Memory Scale-III. According to logistic regression analyses, it was noted that dosimetric parameters specific to left sided hippocampus exerted an influence on immediate recall of verbal memory (adjusted odds ratio, 4.08; p-value, 0.042, predicting patients' neurocognitive decline after receiving HS-WBRT). CONCLUSIONS: Functional preservation by hippocampal sparing during WBRT is indeed achieved in our study. Providing that modern VMAT techniques can reduce the dose irradiating bilateral hippocampi below dosimetric threshold, patients should be recruited in prospective trials of hippocampal sparing during cranial irradiation to accomplish neurocognitive preservation while maintaining intracranial control. TRIAL REGISTRATION: Current Controlled Trials NCT02504788. PMID- 26654129 TI - Cripto: Expression, epigenetic regulation and potential diagnostic use in testicular germ cell tumors. AB - Type II germ cell tumors arise after puberty from a germ cell that was incorrectly programmed during fetal life. Failure of testicular germ cells to properly differentiate can lead to the formation of germ cell neoplasia in situ of the testis; this precursor cell invariably gives rise to germ cell cancer after puberty. The Nodal co-receptor Cripto is expressed transiently during normal germ cell development and is ectopically expressed in non-seminomas that arise from germ cell neoplasia in situ, suggesting that its aberrant expression may underlie germ cell dysregulation and hence germ cell cancer. Here we investigated methylation of the Cripto promoter in mouse germ cells and human germ cell cancer and correlated this with the level of CRIPTO protein expression. We found hypomethylation of the CRIPTO promoter in undifferentiated fetal germ cells, embryonal carcinoma and seminomas, but hypermethylation in differentiated fetal germ cells and the differentiated types of non-seminomas. CRIPTO protein was strongly expressed in germ cell neoplasia in situ along with embryonal carcinoma, yolk sac tumor and seminomas. Further, cleaved CRIPTO was detected in media from seminoma and embryonal carcinoma cell lines, suggesting that cleaved CRIPTO may provide diagnostic indication of germ cell cancer. Accordingly, CRIPTO was detectable in serum from 6/15 patients with embryonal carcinoma, 5/15 patients with seminoma, 4/5 patients with germ cell neoplasia in situ cells only and in 1/15 control patients. These findings suggest that CRIPTO expression may be a useful serological marker for diagnostic and/or prognostic purposes during germ cell cancer management. PMID- 26654131 TI - Transanal endoscopic microsurgery for rectal cancer. AB - Since its introduction in the 1980s, total mesorectal excision (TME) has been the standard surgical technique for treating rectal cancer. This procedure involves removing the rectum and the surrounding envelope of fat along the plane of the mesorectal fascia. Resecting this embryological unit reduces the local recurrence rate by removing all local lymph nodes, including those with occult metastatic disease; however, this surgery is associated with mortality and morbidity. Complications include incontinence for patients given an anastomosis, long-term stoma formation, and sexual and bladder dysfunction. Local excision of rectal cancer using the transanal endoscopic microsurgery (TEM) technique is associated with fewer complications, and therefore, is used as an alternative in specific circumstances. We outline the technique, its indications, imaging appearances and complications. PMID- 26654130 TI - Development of a circulating miRNA assay to monitor tumor burden: From mouse to man. AB - Circulating miRNA stability suggests potential utility of miRNA based biomarkers to monitor tumor burden and/or progression, particularly in cancer types where serial biopsy is impractical. Assessment of miRNA specificity and sensitivity is challenging within the clinical setting. To address this, circulating miRNAs were examined in mice bearing human SCLC tumor xenografts and SCLC patient derived circulating tumor cell explant models (CDX). We identified 49 miRNAs using human TaqMan Low Density Arrays readily detectable in 10 MUl tail vein plasma from mice carrying H526 SCLC xenografts that were low or undetectable in non-tumor bearing controls. Circulating miR-95 measured serially in mice bearing CDX was detected with tumor volumes as low as 10 mm(3) and faithfully reported subsequent tumor growth. Having established assay sensitivity in mouse models, we identified 26 miRNAs that were elevated in a stage dependent manner in a pilot study of plasma from SCLC patients (n = 16) compared to healthy controls (n = 11) that were also elevated in the mouse models. We selected a smaller panel of 10 previously reported miRNAs (miRs 95, 141, 200a, 200b, 200c, 210, 335#, 375, 429) that were consistently elevated in SCLC, some of which are reported to be elevated in other cancer types. Using a multiplex qPCR assay, elevated levels of miRNAs across the panel were also observed in a further 66 patients with non-small cell lung, colorectal or pancreatic cancers. The utility of this circulating miRNA panel as an early warning of tumor progression across several tumor types merits further evaluation in larger studies. PMID- 26654132 TI - Commentary on an evaluation of the role of nuclear medicine in the diagnosis of periprosthetic infections of the hip. PMID- 26654133 TI - Factors influencing the stiffness of fibroadenomas at shear wave elastography. AB - AIM: To identify which features of fibroadenomas are associated with false positive findings at shear wave elastography (SWE). MATERIALS AND METHODS: A total of 151 patients with histologically confirmed fibroadenomata were identified from a prospective database, from a single breast unit. The following features were assessed by two observers who were unaware of the SWE findings: patient age, grey-scale ultrasound lesion diameter (<15 or >=15 mm), distance from the lesion to skin, composition of surrounding tissue (fatty, mixed or dense), and source of referral (screening or symptomatic). Statistical analysis was carried out using the chi-square test. RESULTS: A statistically significant positive association was found between grey-scale ultrasound lesion size and lesion stiffness. Twenty-nine of 70 (41%) lesions >=15 mm were stiff, versus 10 of 81 (12%) <15 mm (p=0.001). Patient age, distance from the lesion to skin, make up of surrounding tissue, and source were not significantly associated with stiffness. CONCLUSION: Fibroadenomas giving false-positive SWE results tend to be larger in size than those that do not. More compression of adjacent normal tissue is assumed to be the cause of the present findings. As previous studies have shown that large cancers tend to be stiffer than smaller cancers, it may be appropriate to vary the quantitative cut-off value used for benign/malignant differentiation in SWE according to lesion size. PMID- 26654134 TI - Synthesis, Molecular Packing, and Thin Film Transistors of Dibenzo[a,m]rubicenes. AB - We herein report an efficient synthesis of dibenzo[a,m]rubicene, a new member of nonplanar cyclopenta-fused polycyclic aromatic hydrocarbon, and its derivatives. It is found that the conformation and molecular packing of dibenzo[a,m]rubicenes in the solid state can be tuned by the substituting groups, and the silylethynylated derivatives of dibenzo[a,m]rubicenes function as p-type organic semiconductors in solution-processed thin film transistors with field effect mobility of up to 1.0 cm(2) V(-1) s(-1). PMID- 26654135 TI - Oral Ondansetron in Management of Dehydrating Diarrhea with Vomiting in Children Aged 3 Months to 5 Years: A Randomized Controlled Trial. AB - OBJECTIVES: To evaluate the role of oral ondansetron in facilitating successful rehydration of under-5-year-old children suffering from acute diarrhea with vomiting and some dehydration. STUDY DESIGN: Children (n = 170) aged 3 months to 5 years with acute diarrhea with vomiting and some dehydration were enrolled in this double blind, randomized, placebo-controlled trial. The participants were randomized to receive either single dose of oral ondansetron (n = 85) or placebo (n = 85) in addition to standard management of dehydration according to World Health Organization guidelines. Failure of oral rehydration therapy (ORT), administration of unscheduled intravenous fluids, and amount of oral rehydration solution intake in 4 hours were the primary outcomes. Secondary outcome measures included duration of dehydration correction, number of vomiting episodes, adverse effects, and caregiver satisfaction. RESULTS: Failure of ORT was significantly less in children receiving ondansetron compared with those receiving placebo (31% vs 62%; P < .001; relative risk 0.50, 95% CI 0.35-0.72). Almost one-half of the children in the ondansetron group received intravenous fluids compared with those in the placebo group, but it was not statistically significant (P = .074; relative risk 0.56, 95% CI 0.30-1.07). The oral rehydration solution consumption was significantly more in the ondansetron group (645 mL vs 554 mL; mean difference 91 mL; 95% CI: 35-148 mL). Patients in the ondansetron group also showed faster rehydration, lesser number of vomiting episodes, and better caregiver satisfaction. CONCLUSION: A single oral dose of ondansetron, given before starting ORT to children <5 years of age with acute diarrhea and vomiting results in better oral rehydration. TRIAL REGISTRATION: Clinical Trial Registry of India: CTRI-2011/07/001916. PMID- 26654136 TI - Thoracic Intestinal Sounds in an Infant with Congenital Bilateral Morgagni Hernia. PMID- 26654137 TI - Addressing the Gap in International Norms for Biosafety. PMID- 26654138 TI - Cytotoxic effects of octenidine mouth rinse on human fibroblasts and epithelial cells - an in vitro study. AB - OBJECTIVES: This study compared the cytotoxicity of a new octenidine mouth rinse (MR) against gingival fibroblasts and epithelial cells with different established MRs. METHODS: The following MRs were used: Octenidol (OCT), Chlorhexidine 0.2% (CHX), Listerine (LIS), Meridol (MER), Betaisodona (BET); and control (medium only). Human primary gingiva fibroblasts and human primary nasal epithelial cells were cultivated in cell-specific media (2 * 10(5) cells/ml) and treated with MR for 1, 5, and 15 min. Each test was performed 12 times. Metabolism activity was measured using a cytotoxicity assay. A cellometer analyzed cell viability, cell number, and cell diameter. The data were analyzed by two-way analysis of variance with subsequent Dunnett's test and additional t-tests. RESULTS: The cytotoxic effects of all MRs on fibroblasts and epithelial cells compared to the control depended on the contact time (p < 0.001). OCT and BET showed less influence on cell metabolism in fibroblasts than other MRs. OCT also demonstrated comparable but not significant results in epithelial cells (p > 0.005). Cell numbers of both cell types at all contact times revealed that OCT showed a less negative effect (p > 0.005), especially for epithelial cells compared to CHX after 15 min (p < 0.005). OCT and BET showed the best results for viability in fibroblasts (p > 0.005), but MER showed less influence than OCT in epithelial cells (p < 0.005). CONCLUSIONS: OCT is a potential alternative to CHX regarding cytotoxicity because of its lower cell-toxic effect against fibroblasts and epithelial cells. PMID- 26654139 TI - Biocompatibility of Accelerated Mineral Trioxide Aggregate on Stem Cells Derived from Human Dental Pulp. AB - The aim of this study was to evaluate the effects of several additives on the setting time and cytotoxicity of accelerated-set mineral trioxide aggregate (MTA) on stem cells of human dental pulp. ProRoot white MTA (WMTA) (Dentsply Tulsa Dental, Johnson City, TN) was mixed with various additives including distilled water, 2.5% disodium hydrogen phosphate (Na2HPO4) (Merck, Darmstadt, Germany), K Y Jelly (Johnson & Johnson, Markham, ON, Canada), and 5% and 10% calcium chloride (CaCl2) (Merck). The setting times were evaluated using a Vicat apparatus (Alsa Lab, Istanbul, Turkey). Human dental pulp stem cells were isolated and seeded into 48-well plates at 2 * 10(3) cells per well and incubated with MTA samples for 24 hours, 3 days, and 7 days. Cell viability was evaluated using the 3-(4,5 dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay. MTA mixed with 10% CaCl2 showed the lowest setting time (P < .05). According to the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4 sulfophenyl)-2H-tetrazolium results on the 1st, 3rd, and 7th days, a statistically significant difference was found (P < .05) between MTA groups and the control group. MTA mixed with K-Y Jelly in all groups showed the lowest cell viability at all time points (P < .05). The cell viability of MTA mixed with distilled water, 5% CaCl2, 10% CaCl2, and Na2HPO4 increased significantly through time (P < .05). This in vitro study found MTA mixed with 5% and 10% CaCl2 and Na2HPO4 is biocompatible with dental pulp stem cells in terms of cell viability. Further in vitro and in vivo investigations are required to prove the clinical applications of MTA mixed with various additives. PMID- 26654140 TI - WaveOne Rotary Instruments after Clinical Use. AB - INTRODUCTION: The purpose of this study was to evaluate the incidence and mode of WaveOne (Dentsply Tulsa Dental Specialties, Tulsa, OK) instrument defects after single use at different endodontic clinics. METHODS: A total of 438 WaveOne instruments were collected after clinical use from the 4 specialist clinics over a 12-month period and from 1 graduate program over a 20-month period. The incidence and type of instrument defects were analyzed. The lateral surfaces of part of the defective instruments and fracture surfaces of fractured files were examined using scanning electron microscopy. Unused and clinically used files were examined by a nanoindentation test. RESULTS: Of the 438 WaveOne instruments collected, 42 (9.6%) had defects: 40 (9.1%) were distorted and 2 (0.5%) files had fractured, 1 Small and 1 Primary file. Clear differences in the frequency of defects were found among the 3 file sizes; the occurrence of distortion and fracture were highest with the Small file (21.2% and 0.7%, respectively) followed by the Primary file (4.4% and 0.4%, respectively) (P < .05). No defects were detected on the Large file. The cause of the 2 fractures was shear stress. Instruments from various clinics showed no significantly different occurrence of instrument deformation. Unwinding occurred at 1.2-3.1 mm from the tip. No significant difference in nanohardness was detected among unused and used instruments. CONCLUSIONS: The risk of WaveOne fracture is very low when files are singly used by endodontists and residents. Unwinding of the files occurred most frequently in the Small file. The frequency of defects of WaveOne instruments were not influenced by the operator. PMID- 26654141 TI - Effect of Different Torque Settings on Crack Formation in Root Dentin. AB - INTRODUCTION: The aim of the present study was to observe the incidence of cracks in root canal dentin using the ProTaper Universal system (Dentsply Maillefer, Ballaigues, Switzerland) at low- and high-torque settings. METHODS: Sixty-nine mandibular premolar teeth that had been extracted for different reasons were selected. The teeth were divided into 3 groups: an unprepared control group, a low-torque settings group (SX = 3, S1 = 2, S2 = 1, F1 = 1.5, F2 = 2, F3 = 2, F4 = 2 N/cm), and a high-torque settings group (SX = 4, S1 = 4, S2 = 1.5, F1 = 2, F2 = 3, F3 = 3, F4 = 3 N/cm). After a root canal procedure, all the teeth were horizontally sectioned at 2, 4, 6, and 8 mm from the apex. Then, under a stereomicroscope, all the slices were examined to determine the presence of cracks. A chi-square test was used for data analysis. The significance level was set at P = .05. RESULTS: There were no cracks in the unprepared control group. Vertical root fractures were not observed in any of the groups. There were significantly fewer cracks (17.4% of the sections) in the low-torque group than in the high-torque group (29.4% of the sections) (P < .05). CONCLUSIONS: In this in vitro study, the instrumentation of root canals with the ProTaper Universal instrument caused more crack formation in root canal dentin at high-torque than at low-torque settings. PMID- 26654142 TI - [History of surgical intervention in severe acute pancreatitis treatment]. AB - Severe acute pancreatitis (SAP) is hard to treat for the abrupt onset, critical condition and complicated pathophysiology. Historically, the treatment strategy of SAP hovered between surgical intervention and conservative treatment. At the turn of the 20(th) century, SAP was reported to be cured by surgical intervention in a series cases, which lead to the dominance of surgical intervention in SAP treatment. Subsequently, SAP was documented to respond to nonoperative therapy. A wave of conservatism emerged, and surgical intervention for SAP was rarely practiced for the next 3 decades. However, surgeons refined the indications and considered new approaches for surgical treatment in 1960s because of the poor outcomes of conservation, and surgical interventions was mainly performed at early stage of SAP. However, a series of prospective studies showed that conservative treatment of patients with sterile pancreatic necrosis is superior to surgical intervention, and that delayed intervention provide improved outcomes in 1990s, which changed the treatment concept of SAP again. The modern treatment concept formed during the progression: organ supportive care dominates in the early stage of the disease, and surgical intervention should be performed at late stage with proper indications. Despite the advances in treatment, the morbidity of SAP is still 5%-20%, which suggests the pancreatic surgeons' exploration in the future. PMID- 26654143 TI - [Experience and thinking on multidisciplinary management of acute pancreatitis]. AB - The diagnostic and therapeutic course of acute pancreatitis is complicated. The treatment strategy existed dispute. The management of acute pancreatitis includes intensive care, fluid resuscitation, organ function support, infection control, endoscopic interventional management, surgical operation and other fields. The diagnosis and treatment mode of multidisciplinary integrate collaboration has been established. It will make the greatest benefit if we depend on evidence based medicine, play the superiority of professional team and make individual treatment protocols. PMID- 26654144 TI - [The clinical practice and related reflections of staged step-up approach in the treatment of patients with severe acute pancreatitis]. AB - Both new insights in the pathophysiology of severe acute pancreatitis (SAP) and upspringing related evidence-based supports prompt the staged step-up approach, which stress emphasis on minimal invasiveness and damage control, to be accepted and advocated by the majority of guidelines. For documented or suspected patients with infected pancreatic necrosis, an imaging-guided percutaneous catheter drainage or an endoscopic transluminal drainage should be initially performed followed by, if necessary, a minimal access retroperitoneal necrosectomy, or a video-assisted retroperitoneal debridement, or an endoscopic transluminal necrosectomy, or an even an open access necrosectomy. The outstanding performance of staged step-up approach in patients with SAP has been justified from both a clinical and a health economic point of view, meanwhile, there are some issues remained to be further elucidated and optimized. PMID- 26654145 TI - [Surgical treatment of necrotizing pancreatitis: 10-year experience at a single center]. AB - OBJECTIVE: To investigate the indication, timing and methods of surgery for acute necrotizing pancreatitis. METHODS: There were 5 538 patients with acute pancreatitis (AP) were treated in the Union Hospital, Tongji Medical College from January 2005 to December 2014. Of all AP cases, 2 415 patients with acute necrotizing pancreatitis proved by computed tomography, and 732 patients underwent surgical treatment. Among 732 patients with surgical treatment, 439 (60.0%) were males and two hundreds and ninety-three (40.0%) were females. The median age was 45 years, ranging 20-76 years. Two hundreds and eighty-nine cases were treated with minimally invasive debridement and drainage and 684 cases were treated with open debridement. RESULTS: The cure rate of minimally invasive operation was 16.6% (48/289). The rest of the 241 patients were treated furtherly with open necrosectomy. Among 684 patients with open surgery, 523 patients (76.5%) were infected, and the median time from the onset of symptom to first open operation was 46 d (range 19-205 d). There were 115 patients need to surgery again because of necrotic tissue residual and the reoperation rate was 16.81% (115/684), 684 patients were performed open surgery on average 1.26 times per person. The main postoperative complications were intra-abdominal hemorrhage (37 cases), upper digestive tract fistula (34 cases), colonic fistula (12 cases), gastrointestinal obstruction (29 cases) and pancreatic fistula (83 cases). The overall incidence of complications were 28.5% (195/684). Forty-nine cases died after surgery and the mortality rate was 6.7% (49/732). CONCLUSION: Rational surgical indications and timing of surgical intervention are the key to improve the efficacy of necrotizing pancreatitis, open debridement is still an effective method for necrotizing pancreatitis. PMID- 26654146 TI - [Percutaneous nephroscopic necrosectomy for post-operatively resident infection of severe acute pancreatitis]. AB - OBJECTIVE: To investigate the method and effect of percutaneous nephroscopic necrosectomy (PNN) for post-operatively resident infection of severe acute pancreatitis (SAP). METHODS: Data of the 15 SAP patients with post-operatively resident infection treated by PNN from June 2008 to December 2014 in Chinese People's Liberation Army General Hospital were reviewed. Twelve of the patients underwent the laparotomy within 1 week, 1 in 3(rd) week, 1 in 4(th) week and the other one on the 127(th) day. All of the referrals firstly received (multi )percutaneous catheter drainage (PCD), and then PNN operation according to the disease, followed by continuous irrigation-drainage. RESULTS: Eleven patients were healed after received only one PNN operation, 2 patients for twice, 1 for three times and 1 for four times. The average post-operative time of hospital stay was 66.2 days (10-223 days). The complications after operation contained colon fistula (n = 1), abdominal hemorrhage (n = 1), pancreatic pseudocyst (n = 1), severe pulmonary infection (n = 1). Three patients eventually died. CONCLUSIONS: Percutaneous nephroscopic necrosectomy is a minimally invasive approach which could prevent the complicated re-laparotomy operation, result in less complication. It is an ideal method for treating SAP patients with post operatively resident infection. PMID- 26654147 TI - [The clinical analysis of autoimmune pancreatitis: a report of 21 cases]. AB - OBJECTIVE: To investigate the clinical feature, diagnostic and therapeutic experience of autoimmune pancreatitis (AIP). METHODS: Twenty-one patients with AIP treated in the First Affiliated Hospital, Harbin Medical University from January 2006 to July 2014 were analyzed retrospectively. There were 15 men and 6 women among the 21 cases and the age ranged from 36 to 64 years. The characters of diagnosis and treatment of AIP were explored through clinical symptoms, imaging features, serologic test results, diagnostic treatment, and histopathologic characteristics. RESULTS: All the patients showed obstructive jaundice and upper abdominal pain to different extents as major manifestations and the levels of serum IgG4, CA19-9, CEA were elevated in 16 cases (76.2%), 6 cases (28.5%) and 3 cases (14.2%), respectively. CT showed diffuse enlargement of the pancreas in 9 cases, localized pancreatic head enlargement in 3 cases and focally pancreatic mass in 9 cases. AIP was confirmed by extrapancreatic involvement, radiological and serological results plus biopsy in 11 cases (52.4%), interpretation of response to steroid in 3 cases (14.3%) and open laparotomy in 7 cases (33.3%). Surgery included choledochojejunostomy in 3 cases, cholecystojejunostomy in 1 case, pancreaticoduodenectomy in 2 cases and distal pancreatectomy combined with splenectomy in 1 case. The pathologic results displayed massive lymphocytes and plasma cells infiltration in the pancreatic tissues as well as parenchymal fibrosis. Except for 1 patient who had no symptom, the regular steroid therapy was performed (oral prednisone) and all the patients were cured. The follow-up time range was from 3 to 93 months, 4 cases (19.0%) were recurrent followed by the symptoms alleviated after the steroid was applied again. CONCLUSIONS: AIP is rare and characterized by non-specific clinical manifestations so that the early diagnosis is difficult with a high misdiagnosis rate. The clinicians should strengthen the recognition of AIP and the definite diagnosis depends on the combination of clinical manifestations, radiological, serological and histopathological results so as to avoid the unnecessary operation. PMID- 26654148 TI - [Treatment and prognosis of solid pseudopapillary neoplasms with metastases or recurrence]. AB - OBJECTIVE: To describe the treatment and prognosis of solid pseudopapillary neoplasms (SPN) with metastases or recurrence. METHODS: The clinical date of 24 patients with histological confirmed SPN with metastases or recurrence from January 2000 to April 2014 were retrospectively analyzed. There were 22 females and 2 males, with mean age of (36 +/- 16) years. Fourteen patients had local recurrence or metastasis after surgery, with a mean time of recurrence (44 +/- 29) months. Ten patients were defined SPN with distant metastasis at first admission. Nineteen patients underwent surgical resection, among them, 11 patients received complete resection. Nine cases underwent chemotherapy. Kaplan Meier method was used to identify prognostic factors. RESULTS: Twenty-four patients were followed-up, 9 patients died. Median survival time was 47 months, and 1-year, 3-year, and 5-year survival was 91.7%, 65.1%, 49.6%, respectively. Age (chi(2) = 6.858, P = 0.009), primary tumor diameter (chi(2) = 4.322, P = 0.038), extrahepatic metastasis (chi(2) = 5.279, P = 0.022) and complete resection of metastases and recurrence (chi(2) = 4.666, P = 0.031) were important prognostic factors for survival (P < 0.05). CONCLUSIONS: For SPN with metastases or recurrence, good prognosis can also obtain after complete resection. Age, primary tumor diameter, extrahepatic metastasis and complete resection of metastases and recurrence are influence factors on prognosis of patients. PMID- 26654149 TI - [Retrospective analysis of management for primary leiomyosarcoma of inferior vena cava]. AB - OBJECTIVE: To study the treatment strategy and survival of patients with primary leiomyosarcoma of inferior vena cava (PIVCLMS). METHODS: Clinical data of 12 cases with PIVCLMS admitted in Peking University People's Hospital from January 2006 to September 2014 were reviewed retrospectively. All cases were confirmed by pathology examination. Among them, there were 4 male and 8 female patients with a mean age of (54 +/- 9) years old. Tumors arose from the inferior vena cava (IVC) upper segment in 5 patients, from the middle in other 7 patients. Cardiac extension was observed in 4 cases. Tumor resection was undertaken in 8 patients, the other 4 patients were inoperable. The series was analyzed to identify clinical outcome of surgical strategy and protective factors for patient survival. RESULTS: In tumor resection group, 6 patients had radical resection and 2 underwent palliative resection. As for IVC reconstruction, caval wall resection with a direct suture was carried out in 6 patients or with prosthetic patch in 1 patient. The other 1 patient underwent a segment caval resection and prosthetic graft replacement in situ. In 4 cases of suprahepatic PIVCLMS cardiopulmonary bypass or perfusion by right atrial intubation was performed to assist bleeding control and maintain circulation stabilization, among them 1 patient survived for more than 101 months with no tumor recurrence or metastasis. Among the patients submitted to tumor resection 2 early postoperative deaths occurred, and another 2 patients had complications. All 4 patients submitted to non-resective operation (only neoplasm biopsy) died of PIVCLMS within 8 months. Except for 2 cases of early death, mean survival after tumor resection was (54 +/- 40) months. Two patients presented local recurrence and hepatic metastasis at follow-up of 16 months and 68 months. CONCLUSIONS: Tumor resection is the only therapy for PIVCLMS with an expectation for long-term survival. The applicant of cardiopulmonary bypass makes some inoperable indicated to tumor resection. PMID- 26654150 TI - [Comparative study of perioperative outcome between endovascular repair and open surgical repair for ruptured abdominal aortic aneurysm]. AB - OBJECTIVE: To compare the perioperative outcome between the endovascular repair (EVAR) and open surgical repair (OSR) for ruptured abdominal aortic aneurysm. METHODS: From January 2006 to January 2013, totally 66 patients with ruptured abdominal aortic aneurysm (rAAA) treated by surgery were retrospectively analyzed in Department of vascular surgery, People's Liberation Army General Hospital. According to the repair method, all the subjects were divided into EVAR group and OSR group. EVAR group included 40 patients, 30 patients were male, 10 patients were female, aged from 47 to 78 with a mean of (71 +/- 7) years. OSR group included 26 patients, 21 patients were male, aged from 45 to 87 with a mean of (72 +/- 9) years. The difference of the operation time, the amount of suspended red blood cells, ICU stay time, case fatality rate, adverse event rate and the difference of the two intervention rate were compared between the 2 groups by chi(2) test and t test. RESULTS: There were significant differences between the 2 groups in operation time, the amount of suspended red blood cells, ICU stay time, case fatality rate, adverse event rate ((183 +/- 44) minutes vs. (384 +/- 108) minutes, t = -10.59, P = 0.00; (0.4 +/- 0.8) units vs. (1.1 +/- 1.8) units, t = 2.19, P = 0.03; (3.0 +/- 1.8) d vs. (8.5 +/- 5.1) d, t = -6.34, P = 0.00; 20.0% (8/40) vs. 46.2% (12/26), chi(2) = 5.10, P = 0.02; 25.0% (10/40) vs. 53.8% (14/26), chi(2) = 5.67, P = 0.02). There were no significant differences in frozen plasma quantities and the two intervention rate between the 2 groups (t = 1.98, P = 0.05; chi(2) = 0.49, P = 0.48). CONCLUSIONS: EVAR decreases the perioperative mortality and adverse event of rAAA compared with OSR. More studies are necessary to compare the middle and long-outcome between EVAR and OSR of rAAA. PMID- 26654151 TI - [Pararectus approach for treatment of acetabular both-column fracture combined with translocation of quadrilateral surface]. AB - OBJECTIVE: To study the clinical effect and surgical operating points of pararectus approach for the internal fixation of acetabular both-column fractures with concurrent displaced quadrilateral plate fractures. METHODS: From January 2012 to December 2013, in the Third Affiliated Hospital of Southern Medical University, 15 patients with acetabular both-column fractures and displaced quadrilateral plate fractures were surgically managed through the pararectus approach. There were 11 male and 4 female patients, with an average age of 40 years (from 19 to 61 years). According to Judet-Letournel classification, there were 9 anterior column plus posterior hemitransverse fractures, 6 both-column fractures, 8 cases involving the pelvic fracture. All these fractures were treated through the pararectus approach, in the horizontal position with general anesthesia. The pre-bended plate was placed in interior pelvic ring to fix the anterior wall, anterior column and quadrilateral plate in direct sight. Then, the posterior column was exposed and fixed with antegrade lag screw. Patients were followed up in 4 weeks, 12 weeks, 6 months, 1 year after the operation, and the anteroposterior radiograph of pelvis and the X-ray examination of the fractured hip was performed. RESULTS: All the 15 cases underwent the operation successfully. Postoperative X-ray and CT exams showed excellent and good reduction of anterior column, posterior column and quadrilateral plate, with none surgical complication occurred. According to the Matta radiological evaluation postoperatively, reduction of acetabular fracture was rated as excellent in 9 cases, good in 3 cases and poor in 3 cases. The rate of excellent and good was 12/15. After 8 to 18 months' follow-up (median follow-up time was 14 months), all the patients gained bone union. According to the modified Merle D'Aubigne and Postel scoring system, 9 cases were excellent, 4 were good, and 2 were fair. The rate of excellent and good was 13/15. CONCLUSIONS: Surgical management of acetabular fractures through the pararectus approach can provide adequate exposure of reducing and fixing both-column acetabular fractures with concurrent displaced quadrilateral plate fractures, which has a good effect in clinical application. PMID- 26654152 TI - [Research progress of tumor infiltrating lymphocytes in breast cancer]. AB - Breast cancer is a heterogeneous disease. The formation and progression of tumor and the sensitivity to treatment differs from patient to patient. In addition to the widely used molecular subtype, novel markers are needed to better personalize the treatment of breast cancer. Tumor infiltrating lymphocyte (TIL) have been consistently documented in breast cancer lesions especially in triple negative and human epidermal growth factor receptor-2 positive breast cancer. Several clinical trials have revealed that TIL are associated with prognosis and can predict therapeutic efficacy of special therapy. TIL could be divided to different subtypes including CD8 + TIL, CD4 + TIL, cytotoxic T lymphocyte associated antigen-4 + TIL, programmed death-1 + TIL. They play different roles in the process of anti-tumor immunity and can predict different prognosis. Screening out special TIL subtype which is well associated with prognosis and therapeutic efficacy and developing targeting immunotherapy can help to improve outcomes of breast cancer patients. PMID- 26654153 TI - [Role of matrix metalloproteinases in regulating neurovascular unit affect the prognosis of chronic compression of spinal cord injury: current status]. AB - Chronic spinal cord compression is the common clinical prognosis with various outcomes, but the affecting factors and mechanisms still remain unexplored. The structure and function of neurovascular unit manifest great significance in the central nervous system diseases. This paper discusses matrix metalloproteinase (MMP) impact on the stability of the neural vascular unit, by directly decomposing extracellular matrix, inducing the glial cell migration, activating angiogenesis, regulating function of blood spinal cord barrier, and put forward the MMP may be the key points in regulation of spinal cord neurovascular unit structure and function change to affect the outcome of chronic oppressive cervical spinal cord. PMID- 26654154 TI - A comparison between the effects of metformin and N-acetyl cysteine (NAC) on some metabolic and endocrine characteristics of women with polycystic ovary syndrome. AB - OBJECTIVE: To compare N-acetyl cysteine (NAC) and metformin on polycystic ovary syndrome (PCOS). METHOD: Study was performed as a randomized double-blind clinical trial on women with diagnosis of PCOS without additional complications. In one group, oral NAC 600 mg, three times a day and in the other group, 500 mg oral metformin, three times a day were prescribed. Duration of treatment was 24 weeks, and after finishing this period of treatment, fasting blood glucose (FBS) and insulin, lipid profile and Homeostasis Model Assessment (HOMA) index were measured (all the blood samples were taken while fasting) and were compared in the two groups. RESULTS: Forty-six women in NAC group and 48 women in metformin group finished the study. The two groups did not show significant difference according to age, body mass index (BMI) of more than 30; mean BMI, AUB, FBS, fasting blood insulin, lipid profile and HOMA index before treatment. After 24 weeks of treatment; BMI >30 [17 (35.4%) versus 7 (15.2%), p = 0.033], mean BMI [(28.36 +/- 2.27) versus (27.11 +/- 3.55), p = 0.44], number of women with the complain of abnormal uterine bleeding (AUB) [24 (50%) versus 13 (28.3%), p = 0.037], FBS [(90.02 +/- 6.24) versus (86.61 +/- 7.81), p = 0.021], fasting insulin (10.40 +/- 2.64 versus 8.89 +/- 2.20, p = 0.004), HOMA Index (2.09 +/- 0.69 versus 1.71 +/- 0.45, p = 0.001), low density lipoprotein (LDL) (141.83 +/- 26.98 versus 127.89 +/- 28.70, p = 0.017) were less in NAC group. Triglyceride (TG) and total cholesterol did not show significant difference between the two groups after treatment. High-density lipoprotein (HDL) was higher in NAC group. CONCLUSION: NAC can improve lipid profile and fasting blood sugar (FBS) and fasting blood insulin better than metformin. PMID- 26654155 TI - Retracted: Reversal of Spinal Cord Ischemia Following Endovascular Thoracic Aortic Aneurysm Repair with Hyperbaric Oxygen and Therapeutic Hypothermia. AB - This article has been officially retracted. The senior author, Emmanuel Urquieta, of the article entitled, "Reversal of Spinal Cord Ischemia Following Endovascular Thoracic Aortic Aneurysm Repair with Hyperbaric Oxygen and Therapeutic Hypothermia," has requesed that the article, published online ahead of print (DOI: 10.1089/ther.2015.0025), be retracted because he discovered one of his coauthors mistakenly submitted the same article to the Journal of Vascular Surgery due to a miscommunication between them. The editorial leadership of Therapeutic Hypothermia and Temperature Management agree that the article must be retracted as a matter of proper scientific publishing protocol whereby an article may not be simultaneously submitted to two journals. The Editors commend Dr. Urquieta for willingly bringing this situation to their attention. Dr. Urquieta and his coauthors sincerely apologize to the Editors and the readership of Therapeutic Hypothermia and Temperature Management. PMID- 26654156 TI - Chitosan Oligosaccharide Reduces Intestinal Inflammation That Involves Calcium Sensing Receptor (CaSR) Activation in Lipopolysaccharide (LPS)-Challenged Piglets. AB - Chitosan oligosaccharide (COS) is a degradation product of chitosan with antioxidative, anti-inflammatory, and antibacterial effects. This study was conducted to investigate the effects of dietary COS on the intestinal inflammatory response and the calcium-sensing receptor (CaSR) and nuclear transcription factor kappa B (NF-kappaB) signaling pathways that may be involved using a lipopolysaccharide (LPS)-challenged piglet model. A total of 40 weaned piglets were used in a 2 * 2 factorial design; the main factors were dietary treatment (basal or 300 MUg/kg COS) and inflammatory challenge (LPS or saline). On the morning of days 14 and 21 after the initiation of treatment, the piglets were injected intraperitoneally with Escherichia coli LPS at 60 and 80 MUg/kg body weight or the same amount of sterilized saline, respectively. Blood and small intestine samples were collected on day 14 or 21, respectively. The results showed that piglets challenged with LPS have a significant decrease in average daily gain and gain:feed and histopathological injury in the jejunum and ileum, whereas dietary supplementation with COS significantly alleviated intestinal injury induced by LPS. Piglets fed the COS diet had lower serum concentrations of tumor necrosis factor alpha (TNF-alpha), interleukin (IL) 6, and IL-8 as well as lower intestinal abundances of pro-inflammatory cytokine mRNA but higher anti inflammatory cytokine mRNA compared with piglets fed the basal diet among LPS challenged piglets (p < 0.05). Dietary COS increased intestinal CaSR and PLCbeta2 protein expressions in both saline- and LPS-treated piglets, but decreased p-NF kappaB p65, IKKalpha/beta, and IkappaB protein expressions in LPS-challenged piglets (p < 0.05). These findings indicate that COS has the potential to reduce the intestinal inflammatory response, which is concomitant with the activation of CaSR and the inhibition of NF-kappaB signaling pathways under an inflammatory stimulus. PMID- 26654157 TI - Guidelines for the evaluation of hearing aid fitting (2010). AB - OBJECTIVE: The methods to evaluate the efficacy of the adjusted hearing aid for a hearing-impaired person are fitting tests. The tests include those presently carried out for evaluating hearing aid fitting, and the methods of testing and evaluation have been published as "Guidelines for the evaluation of hearing aid fitting (2010)" by the Japan Audiological Society. METHODS: Guidelines for the following 8 test methods are presented. (1) Measurements of speech performance intensity functions and speech recognition scores; (2) Assessment of hearing aid fitting from the aspect of tolerance of environmental noise; (3) Measurement of real-ear insertion gain (measurement of sound pressure levels at the eardrum); (4) Measurement of the hearing threshold level and the uncomfortable loudness level (UCL) in sound pressure level (SPL) with an inserted earphone; (5) Aided threshold test in a sound field (functional gain measurement); (6) Prediction of insertion gain and aided threshold from hearing aid characteristics and the pure tone audiogram; (7) Measurement of speech recognition in noise; (8) Assessment of hearing aid fitting using questionnaires. In the above tests, (1) and (2) are mandatory tests, and (3) to (8) are informative tests. RESULTS: By performing test combinations properly selected from the above 8 tests, the benefits of a hearing aid could be determined. CONCLUSION: The above test methods were useful and valuable in determining the efficacy of the adjusted hearing aid for a hearing-impaired person during clinical practice. PMID- 26654169 TI - Fabrication and Characterization of a Porous Silicon Drug Delivery System with an Initiated Chemical Vapor Deposition Temperature-Responsive Coating. AB - This paper reports on the fabrication of a pSi-based drug delivery system, functionalized with an initiated chemical vapor deposition (iCVD) polymer film, for the sustainable and temperature-dependent delivery of drugs. The devices were prepared by loading biodegradable porous silicon (pSi) with a fluorescent anticancer drug camptothecin (CPT) and coating the surface with temperature responsive poly(N-isopropylacrylamide-co-diethylene glycol divinyl ether) (pNIPAM co-DEGDVE) or non-stimulus-responsive poly(aminostyrene) (pAS) via iCVD. CPT released from the uncoated oxidized pSi control with a burst release fashion (~21 nmol/(cm(2) h)), and this was almost identical at temperatures both above (37 degrees C) and below (25 degrees C) the lower critical solution temperature (LCST) of the switchable polymer used, pNIPAM-co-DEGDVE (28.5 degrees C). In comparison, the burst release rate from the pSi-pNIPAM-co-DEGDVE sample was substantially slower at 6.12 and 9.19 nmol/(cm(2) h) at 25 and 37 degrees C, respectively. The final amount of CPT released over 16 h was 10% higher at 37 degrees C compared to 25 degrees C for pSi coated with pNIPAM-co-DEGDVE (46.29% vs 35.67%), indicating that this material can be used to deliver drugs on-demand at elevated temperatures. pSi coated with pAS also displayed sustainable drug delivery profiles, but these were independent of the release temperature. These data show that sustainable and temperature-responsive delivery systems can be produced by functionalization of pSi with iCVD polymer films. Benefits of the iCVD approach include the application of the iCVD coating after drug loading without causing degradation of the drug commonly caused by exposure to factors such as solvents or high temperatures. Importantly, the iCVD process is applicable to a wide array of surfaces as the process is independent of the surface chemistry and pore size of the nanoporous matrix being coated. PMID- 26654170 TI - Non-cross-linked porcine acellular dermal matrix (Strattice Tissue Matrix) in pediatric reconstructive surgery. AB - BACKGROUND: A variety of prosthetic materials are used in the pediatric population for abdominal and chest wall reconstruction. Pediatric experience of non-cross-linked porcine acellular dermal matrix is limited to patients following liver transplantation. We review our outcomes in patients in whom this matrix was used. METHODS: A retrospective analysis of patients who underwent abdominal and chest wall reconstruction with a non-cross-linked porcine acellular dermal matrix (Strattice TM) was performed to assess clinical outcomes. RESULTS: The tissue matrix was used in thirteen patients over a three-year period. Eleven had abdominal wall reconstruction and two underwent chest wall reconstruction. Seven procedures were contaminated at the time of surgery. Median age at insertion was 8.1years (5days-18years) with a median weight of 20.6kg (1.9kg-99kg). The tissue matrix failed in one patient with no unanticipated adverse events. CONCLUSION: Future growth and need for reoperation requires special consideration in pediatric patients undergoing abdominal or thoracic wall reconstruction. Non cross-linked porcine acellular dermal matrix can be safely used for abdominal and chest wall reconstruction in the pediatric population with a number of advantages over previously utilized materials. In our study, children have a favorable risk profile as compared to published adult series. PMID- 26654171 TI - Formation of Malondialdehyde, 4-Hydroxynonenal, and 4-Hydroxyhexenal during in Vitro Digestion of Cooked Beef, Pork, Chicken, and Salmon. AB - Red meat high in heme iron may promote the formation of potentially genotoxic aldehydes during lipid peroxidation in the gastrointestinal tract. In this study, the formation of malondialdehyde (MDA) equivalents measured by the thiobarbituric acid reactive substances (TBARS) method was determined during in vitro digestion of cooked red meat (beef and pork), as well as white meat (chicken) and fish (salmon), whereas analysis of 4-hydroxyhexenal (HHE) and 4-hydroxynonenal (HNE) was performed during in vitro digestion of cooked beef and salmon. Comparing products with similar fat contents indicated that the amount of unsaturated fat and not total iron content was the dominating factor influencing the formation of aldehydes. It was also shown that increasing fat content in beef products caused increasing concentrations of MDA equivalents. The highest levels, however, were found in minced beef with added fish oil high in unsaturated fat. This study indicates that when ingested alone, red meat products low in unsaturated fat and low in total fat content contribute to relatively low levels of potentially genotoxic aldehydes in the gastrointestinal tract. PMID- 26654172 TI - Childhood adversity and cortical thickness and surface area in a population at familial high risk of schizophrenia. AB - BACKGROUND: There is now a well-established link between childhood adversity (CA) and schizophrenia. Similar structural abnormalities to those found in schizophrenia including alterations in grey-matter volume have also been shown in those who experience CA. METHOD: We examined whether global estimates of cortical thickness or surface area were altered in those familial high-risk subjects who had been referred to a social worker or the Children's Panel compared to those who had not. RESULTS: We found that the cortical surface area of those who were referred to the Children's Panel was significantly smaller than those who had not been referred, but cortical thickness was not significantly altered. There was also an effect of social work referral on cortical surface area but not on thickness. CONCLUSIONS: Cortical surface area increases post-natally more than cortical thickness. Our findings suggest that CA can influence structural changes in the brain and it is likely to have a greater impact on cortical surface area than on cortical thickness. PMID- 26654173 TI - Constitutive Store-Operated Ca(2+) Entry Leads to Enhanced Nitric Oxide Production and Proliferation in Infantile Hemangioma-Derived Endothelial Colony Forming Cells. AB - Clonal endothelial progenitor cells (EPCs) have been implicated in the aberrant vascular growth that features infantile hemangioma (IH), the most common benign vascular tumor in childhood that may cause ulceration, bleeding, and/or permanent disfigurement. Endothelial colony-forming cells (ECFCs), truly endothelial EPCs endowed with clonal ability and capable of forming patent vessels in vivo, remodel their Ca(2+) toolkit in tumor-derived patients to acquire an adaptive advantage. Particularly, they upregulate the proangiogenic store-operated Ca(2+) entry (SOCE) pathway due to the overexpression of its underlying components, that is, stromal interaction molecule 1 (Stim1), Orai1, and transient receptor potential canonical 1 (TRPC1). The present work was undertaken to assess whether and how the Ca(2+) signalosome is altered in IH-ECFCs by employing Ca(2+) and nitric oxide (NO) imaging, real-time polymerase chain reaction, western blotting, and functional assays. IH-ECFCs display a lower intracellular Ca(2+) release in response to either pharmacological (i.e., cyclopiazonic acid) or physiological (i.e., ATP and vascular endothelial growth factor) stimulation. Conversely, Stim1, Orai1, and TRPC1 transcripts and proteins are normally expressed in these cells and mediate a constitutive SOCE, which is sensitive to BTP-2, La(3+), and Pyr6 and recharges the intracellular Ca(2+) pool. The resting SOCE in IH-ECFCs is also associated to an increase in their proliferation rate and the basal production of NO compared to normal cells. Likewise, the pharmacological blockade of SOCE and NO synthesis block IH-ECFC growth. Collectively, these data indicate that the constitutive SOCE activation enhances IH-ECFC proliferation by augmenting basal NO production and sheds novel light on the molecular mechanisms of IH. PMID- 26654174 TI - Prospective comparison of sinonasal outcomes after microscopic sublabial or endoscopic endonasal transsphenoidal surgery for nonfunctioning pituitary adenomas. AB - OBJECT Both endoscopic and microscopic transsphenoidal approaches are accepted techniques for the resection of pituitary adenomas. Although studies have explored patient outcomes for each technique individually, none have prospectively compared sinonasal and quality of life outcomes in a concurrent series of patients at the same institution, as has been done in the present study. METHODS Patients with nonfunctioning adenomas undergoing transsphenoidal surgery were assessed for sinonasal function, quality of life, and pain using the Sino-Nasal Outcome Test-20 (SNOT-20), the short form of the Nasal Obstruction Symptom Evaluation (NOSE) instrument, the SF-36, and a headache scale. Eighty-two patients undergoing either endoscopic (47 patients) or microscopic (35 patients) surgery were surveyed preoperatively and at 24-48 hours, 2 weeks, 4 weeks, 8 weeks, and 1 year after surgery. RESULTS Patients who underwent endoscopic and microscopic transsphenoidal surgery experienced a similar recovery pattern, showing an initial increase in symptoms during the first 2 weeks, followed by a return to baseline by 4 weeks and improvement beyond baseline functioning by 8 weeks. Patients who underwent endoscopic surgery experienced better sinonasal outcomes at 24-48 hours (SNOT total p = 0.015, SNOT rhinologic subscale [ssRhino] p < 0.001), 2 weeks (NOSE p = 0.013), and 8 weeks (SNOT total p = 0.032 and SNOT ssRhino p = 0.035). By 1 year after surgery, no significant differences in sinonasal outcomes were observed between the 2 groups. Headache scales at 1 year improved in all dimensions except duration for both groups (total result 73%, p = 0.004; severity 46%, p < 0.001; frequency 53%, p < 0.001), with 80% of either microscopic or endoscopic patients experiencing improvement or resolution of headache symptoms. Endoscopic and microscopic patients experienced reduced vitality preoperatively compared with US population norms and remained low postoperatively. By 8 weeks after surgery, both groups experienced significant improvements in mental health (13%, p = 0.005) and vitality (15%, p = 0.037). By 1 year after surgery, patients improved significantly in mental health (14%, p = 0.03), role physical (14%, p = 0.036), social functioning (16%, p = 0.009), vitality (22%, p = 0.002), and SF-36 total (10%, p = 0.024) as compared with preoperative measures. There were no significant differences at any time point between the 2 groups for the total SF-36 or for any of the 8 subscales. CONCLUSIONS Patients who underwent either an endoscopic or a microscopic approach experienced the greatest nasal symptoms at 2 weeks postoperatively and exhibited similar time courses of recovery in nasal, headache, and quality of life assessments. Although patients who underwent endoscopic surgery experienced significantly fewer nasal symptoms during the first 8 weeks, by 1 year after surgery, there were no significant differences between the 2 groups. PMID- 26654175 TI - The safety of Pipeline flow diversion in fusiform vertebrobasilar aneurysms: a consecutive case series with longer-term follow-up from a single US center. AB - OBJECT Pessimism exists regarding flow diversion for posterior circulation aneurysms because of reports of perforator territory infarcts and delayed ruptures. The authors report the results of patients who underwent Pipeline Embolization Device (PED) flow diversion using novel strategies for treatment of fusiform posterior circulation aneurysms, and compare these results with those from previously reported series. METHODS The authors conducted a retrospective review of data from consecutive patients with fusiform vertebrobasilar artery aneurysms treated with the PED. RESULTS This review resulted in the identification of 12 such patients (mean [+/- SD] age 55.1 +/- 14.1 years). Eleven patients had symptoms; 1 had a dissecting aneurysm identified on imaging for neck pain. The average aneurysm size was 13.25 +/- 4.5 mm. None of the aneurysms were ruptured or previously treated. The average clinical follow-up duration was 22.1 +/- 10.7 months and radiological follow-up was 14.5 +/- 11.1 months from the index PED treatment. One patient suffered a perforator stroke and had a modified Rankin Scale (mRS) score of 4 at last follow-up. Another patient had a retained stent pusher requiring retrieval via surgical cut-down but recovered to an mRS score of 0 at last follow-up. Eleven (91.7%) of 12 patients recovered to an mRS score of 0 or 1. Two patients had aneurysmal remnants at 7 and 10 months, respectively, after the index PED, which were retreated with PEDs. At last follow-up, all 12 aneurysms were occluded and PEDs were patent. The minimum follow-up duration was 12 months from the index PED treatment; no patient experienced delayed hemorrhage, stroke, or in-stent stenosis. CONCLUSIONS Flow diversion with selective adjunctive techniques is evolving to become a safer treatment option for posterior circulation aneurysms. This is the longest clinical follow-up duration reported for a single-center experience of flow diversion treatment of these aneurysms. PMID- 26654176 TI - Neuropsychological outcomes of subtemporal selective amygdalohippocampectomy via a small craniotomy. AB - OBJECT The objectives of this study were to describe a novel minimal-access subtemporal approach for selective resection of the amygdala and hippocampus in patients with medically refractory mesial temporal lobe epilepsy (MTLE) due to hippocampal sclerosis, and to analyze the related outcomes. METHODS The authors analyzed data from all cases involving patients with unilateral MTLE due to hippocampal sclerosis who were treated with selective amygdalohippocampectomy via the posterior subtemporal approach through a relatively small craniotomy, without a neuronavigation system, at their institution during the period from September 2010 to September 2012. Data were obtained on baseline characteristics, preoperative evaluations of unilateral mesial temporal sclerosis, surgical complications, and Engel class seizure outcomes. All patients underwent memory testing, IQ testing, and language testing. RESULTS The mean duration of follow-up was 33.6 months (range 24-48 months). There were no deaths and no cases of significant postoperative morbidity. One patient had a mild complication. At 2 year follow-up, 19 patients were seizure free (Engel Class I outcome). Verbal memory scores obtained at 3 months and at 2 years after surgery were significantly lower than preoperative scores for patients who underwent surgery on the left side of the brain (p < 0.05). Pictorial memory scores were higher following surgery compared with before surgery regardless of whether patients underwent left- or right-sided brain surgery. There was also improvement in performance IQ and total IQ following surgery in both groups. For patients who underwent right-sided brain surgery, verbal comprehension and semantic fluency testing scores were significantly higher at both 3 months and 2 years after surgery than before surgery. For patients who underwent left-sided brain surgery, scores on all language tests were significantly lower at 3 months after surgery than before surgery. Verbal comprehension testing scores returned to the preoperative level at 2 years after surgery. CONCLUSIONS The posterior subtemporal approach through a relatively small craniotomy allows adequate exposure and safe resection of mesial temporal structures and effectively reduces medically intractable MTLE. It preserves IQ but may have a detrimental effect on verbal memory and language ability. PMID- 26654177 TI - Effectiveness of 2-methoxyestradiol in alleviating angiogenesis induced by intracranial venous hypertension. AB - OBJECT Intracranial dural arteriovenous fistulas (DAVFs) are complex intracranial vascular malformations that can lead to hemorrhage. The authors recently found that chronic local hypoperfusion seems to be the main cause of angiogenesis in the dura mater, which leads to the formation of DAVFs. As a natural derivative of estradiol, 2-methoxyestradiol (2-ME) has an antiangiogenic effect and can be used safely in patients with advanced carcinoid tumors. This study was conducted to examine the antiangiogenic effects of 2-ME on a rat DAVF model. METHODS Male Sprague-Dawley rats (n = 72) were used in the experiments. Intracranial venous hypertension was induced for modeling, and 2-ME was used in the early or late stage for treatment. The effects were examined by immunohistochemistry, Western blot analysis, and quantitative real-time polymerase chain reaction assays. RESULTS 2-Methoxyestradiol significantly reduced angiogenesis in the dura in early- and late-intervention treatment groups, as proven by the results of immunohistochemical staining, Western blotting, real-time polymerase chain reaction assays, and microvessel density counts. The antiangiogenic effect even lasted for up to 2 weeks after 2-ME cessation. CONCLUSIONS These data collectively suggest that 2-ME can reduce the angiogenic effect caused by venous hypertension in a rat DAVF model, mainly by suppressing the inhibitor of differentiation 1 (ID-1) and hypoxia-inducible factor 1alpha (HIF-1alpha) pathways. PMID- 26654178 TI - App-assisted external ventricular drain insertion. AB - The freehand technique for insertion of an external ventricular drain (EVD) is based on fixed anatomical landmarks and does not take individual variations into consideration. A patient-tailored approach based on augmented-reality techniques using devices such as smartphones can address this shortcoming. The Sina neurosurgical assist (Sina) is an Android mobile device application (app) that was designed and developed to be used as a simple intraoperative neurosurgical planning aid. It overlaps the patient's images from previously performed CT or MRI studies on the image seen through the device camera. The device is held by an assistant who aligns the images and provides information about the relative position of the target and EVD to the surgeon who is performing EVD insertion. This app can be used to provide guidance and continuous monitoring during EVD placement. The author describes the technique of Sina-assisted EVD insertion into the frontal horn of the lateral ventricle and reports on its clinical application in 5 cases as well as the results of ex vivo studies of ease of use and precision. The technique has potential for further development and use with other augmented-reality devices. PMID- 26654179 TI - A cadaveric microanatomical study of the fascicular topography of the brachial plexus. AB - OBJECT Mapping of the fascicular anatomy of the brachial plexus could provide the nerve surgeon with knowledge of fascicular orientation in spinal nerves of the brachial plexus. This knowledge might improve the surgical outcome of nerve grafting in brachial plexus injuries by anastomosing related fascicles and avoiding possible axonal misrouting. The objective of this study was to map the fascicular topography in the spinal nerves of the brachial plexus. METHODS The entire right-sided brachial plexus of 25 adult male cadavers was dissected, including all 5 spinal nerves (C5-T1), from approximately 5 mm distal to their exit from the intervertebral foramina, to proximal 1 cm of distal branches. All spinal nerves were tagged on the cranial aspect of their circumference using 10-0 nylon suture for orientation. The fascicular dissection of the C5-T1 spinal nerves was performed under microscopic magnification. The area occupied by different nerve fascicles was then expressed as a percentage of the total cross sectional area of a spinal nerve. RESULTS The localization of fascicular groups was fairly consistent in all spinal nerves. Overall, 4% of the plexus supplies the suprascapular nerve, 31% supplies the medial cord (comprising the ulnar nerve and medial root of the median nerve [MN]), 27.2% supplies the lateral cord (comprising the musculocutaneous nerve and lateral root of the MN), and 37.8% supplies the posterior cord (comprising the axillary and radial nerves). CONCLUSIONS The fascicular dissection and definitive anatomical localization of fascicular groups is feasible in plexal spinal nerves. The knowledge of exact fascicular location might be translatable to the operating room and can be used to anastomose related fascicles in brachial plexus surgery, thereby avoiding the possibility of axonal misrouting and improving the results of plexal reconstruction. PMID- 26654180 TI - Dynamic telescopic craniotomy: a cadaveric study of a novel device and technique. AB - OBJECT The authors assessed the feasibility of the dynamic decompressive craniotomy technique using a novel cranial fixation plate with a telescopic component. Following a craniotomy in human cadaver skulls, the telescopic plates were placed to cover the bur holes. The plates allow constrained outward movement of the bone flap upon an increase in intracranial pressure (ICP) and also prevent the bone flap from sinking once the ICP normalizes. The authors compared the extent of postcraniotomy ICP control after an abrupt increase in intracranial volume using the dynamic craniotomy technique versus the standard craniotomy or hinge craniotomy techniques. METHODS Fixation of the bone flap after craniotomy was performed in 5 cadaver skulls using 3 techniques: 1) dynamic telescopic craniotomy, 2) hinge craniotomy, and 3) standard craniotomy with fixed plates. The ability of each technique to allow for expansion during intracranial hypertension was evaluated by progressively increasing intracranial volume. Biomechanical evaluation of the telescopic plates with load-bearing tests was also undertaken. RESULTS Both the dynamic craniotomy and the hinge craniotomy techniques provided significant control of ICP during increases in intracranial volume as compared with the standard craniotomy technique. With the standard craniotomy, ICP increased from a mean of 11.4 to 100.1 mm Hg with the addition of 120 ml of intracranial volume. However, with the dynamic craniotomy, the addition of 120 ml of intracranial volume increased the ICP from a mean of 2.8 to 13.4 mm Hg, maintaining ICP within the normal range as compared with the standard craniotomy (p = 0.04). The dynamic craniotomy was also superior in controlling ICP as compared with the hinge craniotomy, providing expansion for an additional 40 ml of intracranial volume while maintaining ICP within a normal range (p = 0.008). Biomechanical load-bearing tests for the dynamic telescopic plates revealed rigid restriction of bone-flap sinking as compared with standard fixation plates and clamps. CONCLUSIONS The dynamic telescopic craniotomy technique with the novel cranial fixation plate provides superior control of ICP after an abrupt increase in intracranial volume as compared with the standard craniotomy and hinge craniotomy techniques. PMID- 26654181 TI - Identifying preoperative language tracts and predicting postoperative functional recovery using HARDI q-ball fiber tractography in patients with gliomas. AB - OBJECT Diffusion MRI has uniquely enabled in vivo delineation of white matter tracts, which has been applied to the segmentation of eloquent pathways for intraoperative mapping. The last decade has also seen the development from earlier diffusion tensor models to higher-order models, which take advantage of high angular resolution diffusion-weighted imaging (HARDI) techniques. However, these advanced methods have not been widely implemented for routine preoperative and intraoperative mapping. The authors report on the application of residual bootstrap q-ball fiber tracking for routine mapping of potentially functional language pathways, the development of a system for rating tract injury to evaluate the impact on clinically assessed language function, and initial results predicting long-term language deficits following glioma resection. METHODS The authors have developed methods for the segmentation of 8 putative language pathways including dorsal phonological pathways and ventral semantic streams using residual bootstrap q-ball fiber tracking. Furthermore, they have implemented clinically feasible preoperative acquisition and processing of HARDI data to delineate these pathways for neurosurgical application. They have also developed a rating scale based on the altered fiber tract density to estimate the degree of pathway injury, applying these ratings to a subset of 35 patients with pre- and postoperative fiber tracking. The relationships between specific pathways and clinical language deficits were assessed to determine which pathways are predictive of long-term language deficits following surgery. RESULTS This tracking methodology has been routinely implemented for preoperative mapping in patients with brain gliomas who have undergone awake brain tumor resection at the University of California, San Francisco (more than 300 patients to date). In this particular study the authors investigated the white matter structure status and language correlation in a subcohort of 35 subjects both pre- and postsurgery. The rating scales developed for fiber pathway damage were found to be highly reproducible and provided significant correlations with language performance. Preservation of the left arcuate fasciculus (AF) and the temporoparietal component of the superior longitudinal fasciculus (SLF-tp) was consistent in all patients without language deficits (p < 0.001) at the long-term follow-up. Furthermore, in patients with short-term language deficits, the AF and/or SLF-tp were affected, and damage to these 2 pathways was predictive of a long-term language deficit (p = 0.005). CONCLUSIONS The authors demonstrated the successful application of q-ball tracking in presurgical planning for language pathways in brain tumor patients and in assessing white matter tract integrity postoperatively to predict long-term language dysfunction. These initial results predicting long-term language deficits following tumor resection indicate that postoperative injury to dorsal language pathways may be prognostic for long-term clinical language deficits. Study results suggest the importance of dorsal stream tract preservation to reduce language deficits in patients undergoing glioma resection, as well as the potential prognostic value of assessing postoperative injury to dorsal language pathways to predict long-term clinical language deficits. PMID- 26654182 TI - Treatment of ruptured complex and large/giant ruptured cerebral aneurysms by acute coiling followed by staged flow diversion. AB - OBJECT Flow-diversion treatment has been shown to be associated with high rates of angiographic obliteration; however, the treatment is relatively contraindicated in the acute phase following subarachnoid hemorrhage (SAH) as these patients require periprocedural dual antiplatelet therapy. Acute coiling followed by flow diversion has emerged as an intriguing and feasible treatment option for ruptured complex and giant aneurysms. In this study the authors report outcomes and complications of patients with ruptured aneurysms undergoing coiling in the acute phase followed by planned delayed flow diversion. METHODS This case series includes patients from 2 institutions. All patients underwent standard endovascular coiling in the acute phase after SAH with the intention and plan to proceed with flow diversion at a later date. Outcomes studied included angiographic occlusion, procedure-related complications, and long-term clinical outcome as measured using the modified Rankin Scale. RESULTS A total of 31 patients underwent coiling in the acute phase with the intention to undergo flow diversion at a later date. The mean aneurysm size was 15.8 +/- 7.9 mm. Of the 31 patients undergoing coiling, 4 patients could not undergo further flow-diverter therapy: 3 patients (9.7%) died of complications of subarachnoid hemorrhage and 1 patient had permanent morbidity as a result of perioperative ischemic stroke (3.1%). Twenty-seven patients underwent staged placement of flow diverters after adequate recovery. The median time to treatment was 16 weeks. There was one case of aneurysm rebleeding following coil treatment. There were no cases of permanent morbidity or mortality resulting from flow-diverter treatment. Twenty-four patients underwent imaging follow-up; 18 of these patients had aneurysms that were completely or nearly completely occluded (58.1% on an intent-to-treat basis). At last follow-up (mean 18.3 months), 25 patients had mRS scores <= 2 (80.6% on an intent-to-treat basis). CONCLUSIONS Staged treatment of ruptured complex and giant intracranial aneurysms with coiling in the acute phase and flow diverter treatment following recovery from SAH is both safe and effective. In this series, no cases of rebleeding occurred during the interval between coiling and flow diversion. This strategy should be considered as a valid option in patients presenting with these challenging ruptured aneurysms. PMID- 26654183 TI - Origin of craniopharyngiomas: implications for growth pattern, clinical characteristics, and outcomes of tumor recurrence. AB - OBJECT Craniopharyngiomas are associated with a high rate of recurrence. The surgical management of recurrent lesions has been among the most challenging neurosurgical procedures because of the craniopharyngioma's complex topographical relationship with surrounding structures. The aim of this study was to define the determinative role of the site of origin on the growth pattern and clinical features of recurrent craniopharyngiomas. METHODS The authors performed a retrospective analysis of 52 patients who had undergone uniform treatment by a single surgeon. For each patient, data concerning symptoms and signs, imaging features, hypothalamic-pituitary function, and recurrence-free survival rate were collected. RESULTS For children, delayed puberty was more frequent in the group with Type I (infradiaphragmatic) craniopharyngioma than in the group with Type TS (tuberoinfundibular and suprasellar extraventricular) lesions (p < 0.05). For adults, blindness was more frequent in the Type I group than in the Type TS group (p < 0.05). Nausea or vomiting, delayed puberty, and growth retardation were more frequent in children than in adults (p < 0.05). Overall clinical outcome was good in 48.07% of the patients and poor in 51.92%. Patients with Type TS recurrent tumors had significantly worse functional outcomes and hypothalamic function than patients with the Type I recurrent tumors but better pituitary function especially in children. CONCLUSIONS The origin of recurrent craniopharyngiomas significantly affected the symptoms, signs, functional outcomes, and hypothalamic pituitary functions of patients undergoing repeated surgery. Differences in tumor growth patterns and site of origin should be considered when one is comparing outcomes and survival across treatment paradigms in patients with recurrent craniopharyngiomas. PMID- 26654184 TI - Application of contrast-enhanced T1-weighted MRI-based 3D reconstruction of the dural tail sign in meningioma resection. AB - OBJECT The goal of this study was to investigate the significance of contrast enhanced T1-weighted (T1W) MRI-based 3D reconstruction of dural tail sign (DTS) in meningioma resection. METHODS Between May 2013 and August 2014, 18 cases of convexity and parasagittal meningiomas showing DTS on contrast-enhanced T1W MRI were selected. Contrast-enhanced T1W MRI-based 3D reconstruction of DTS was conducted before surgical treatment. The vertical and anteroposterior diameters of DTS on the contrast-enhanced T1W MR images and 3D reconstruction images were measured and compared. Surgical incisions were designed by referring to the 3D reconstruction and MR images, and then the efficiency of the 2 methods was evaluated with assistance of neuronavigation. RESULTS Three-dimensional reconstruction of DTS can reveal its overall picture. In most cases, the DTS around the tumor is uneven, whereas the DTS around the dural vessels presents longer extensions. There was no significant difference (p > 0.05) between the vertical and anteroposterior diameters of DTS measured on the contrast-enhanced T1W MR and 3D reconstruction images. The 3D images of DTS were more intuitive, and the overall picture of DTS could be revealed in 1 image, which made it easier to design the incision than by using the MR images. Meanwhile, assessment showed that the incisions designed using 3D images were more accurate than those designed using MR images (ridit analysis by SAS, F = 7.95; p = 0.008). Pathological examination showed that 34 dural specimens (except 2 specimens from 1 tumor) displayed tumor invasion. The distance of tumor cell invasion was 1.0 21.6 mm (5.4 +/- 4.41 mm [mean +/- SD]). Tumor cell invasion was not observed at the dural resection margin in all 36 specimens. CONCLUSIONS Contrast-enhanced T1W MRI-based 3D reconstruction can intuitively and accurately reveal the size and shape of DTS, and thus provides guidance for designing meningioma incisions. PMID- 26654185 TI - Sonographic findings associated with stenosis progression and vascular complications in moyamoya disease. AB - OBJECT The progression of arterial stenosis in patients with moyamoya disease (MMD) has variable courses and an unclear mechanism. The authors hypothesized that elevated wall shear stress (WSS) at the terminal internal carotid artery (ICA) and proximal middle cerebral artery (MCA) may facilitate MMD progression. They indirectly evaluated the relative magnitude of WSS (WSS value [WSSV]) with MR angiography (MRA) and transcranial Doppler to determine its predictive value for stenosis progression (SP) and the development of vascular complications. METHODS Thirty-one medically treated patients (58 hemispheres and 95 nonoccluded vessels) were analyzed with serial MRA (median follow-up 23 months). The parameters studied were SP, SP rates (SPRs) for individual ICAs/MCAs, and their mean values from the ipsilateral hemispheres as mean SP (MSP) and MSP rates (MSPRs). Significant progression was defined as decrements of >= 20% for SP and MSP and >= 10%/year for SPR and MSPR. The development of vascular complications in relevant hemispheres was also recorded. The WSSV (dyne/cm(2)) was defined as the shear rate multiplied by blood viscosity. RESULTS After adjusting the initial stenosis degree and MRA stage of MMD, an SP of >= 20% and an SPR of >= 10%/year were associated with the highest-quartile WSSVs for all individual vessels and for MCAs and ICAs separately. For each hemisphere, an MSP of >= 20% and an MSPR of >= 10%/year were associated with the highest-quartile mean WSSVs. Furthermore, significant SP was highly correlated with vascular complications, and the highest quartile mean WSSV was independently associated with vascular complications in relevant hemispheres. CONCLUSIONS An elevated WSSV is an independent predictor for SP and vascular complications in nonoccluded MMD. PMID- 26654186 TI - Roles and Regulation of Renal K Channels. AB - More than two dozen types of potassium channels, with different biophysical and regulatory properties, are expressed in the kidney, influencing renal function in many important ways. Recently, a confluence of discoveries in areas from human genetics to physiology, cell biology, and biophysics has cast light on the special function of five different potassium channels in the distal nephron, encoded by the genes KCNJ1, KCNJ10, KCNJ16, KCNMA1, and KCNN3. Research aimed at understanding how these channels work in health and go awry in disease has transformed our understanding of potassium balance and provided new insights into mechanisms of renal sodium handling and the maintenance of blood pressure. This review focuses on recent advances in this rapidly evolving field. PMID- 26654187 TI - Diagnostic usefulness of the GenoType MTBDRplus assay for detecting drug resistant tuberculosis using AFB smear-negative specimens with positive TB-PCR result. AB - BACKGROUND: The aim of this study was to evaluate the diagnostic accuracy of the GenoType MTBDRplus assay in detecting drug-resistant tuberculosis (DR-TB) by using acid-fast bacilli (AFB) smear-negative specimens with positive TB-PCR results. METHODS: The MTBDRplus assay was performed with 2 different categories of 117 samples, including AFB smear-positive specimens (n = 53) and AFB smear negative specimens (n =64), which exhibited positive TB-PCR results, at a single institution. The results were retrospectively compared with the results of the phenotypic drug susceptibility test (DST), for reference. RESULTS: A total of 105 tests were finally analyzed. Of these, 54 tests were conducted using AFB smear negative specimens with positive TB-PCR results. The MTBDRplus assay for these 54 samples demonstrated a sensitivity of 100%, specificity of 98%, positive predictive value (PPV) of 75%, and negative predictive value (NPV) of 100% in detecting rifampicin resistance. With these same species, the sensitivity, specificity, PPV, and NPV values for the MTBDRplus assay were 83.3%, 97.9%, 83.3%, and 97.9%, respectively, for the detection of isoniazid resistance. The overall correlation between the MTBDRplus assay and phenotypic DST demonstrated excellent agreement for detection of rifampicin resistance (kappa = 0.847) and for detection of INH resistance (kappa = 0.812), respectively. CONCLUSIONS: The MTBDRplus assay can be used effectively even on AFB smear-negative specimens from TB patients, when the TB-PCR is positive. This result might help clinicians to manage patients with suspected DR-TB in difficult situations. PMID- 26654188 TI - Single Broadband Phase-Shaped Pulse Stimulated Raman Spectroscopy for Standoff Trace Explosive Detection. AB - Recent success with trace explosives detection based on the single ultrafast pulse excitation for remote stimulated Raman scattering (SUPER-SRS) prompts us to provide new results and a Perspective that describes the theoretical foundation of the strategy used for achieving the desired sensitivity and selectivity. SUPER SRS provides fast and selective imaging while being blind to optical properties of the substrate such as color, texture, or laser speckle. We describe the strategy of combining coherent vibrational excitation with a reference pulse in order to detect stimulated Raman gain or loss. A theoretical model is used to reproduce experimental spectra and to determine the ideal pulse parameters for best sensitivity, selectivity, and resolution when detecting one or more compounds simultaneously. PMID- 26654189 TI - A low cortisol response to stress is associated with musculoskeletal pain combined with increased pain sensitivity in young adults: a longitudinal cohort study. AB - BACKGROUND: In this study, we investigated whether an abnormal hypothalamic pituitary-adrenal (HPA) axis response to psychosocial stress at 18 years of age is associated with musculoskeletal (MS) pain alone and MS pain combined with increased pain sensitivity at 22 years of age. METHODS: The study sample included 805 participants from the Western Australian Pregnancy Cohort (Raine) Study who participated in the Trier Social Stress Test (TSST) at age 18 years. Number of pain sites, pain duration, pain intensity and pain frequency were assessed at age 22 to measure severity of MS pain. Cold and pressure pain thresholds were determined at age 22. Group-based trajectory modeling was applied to establish cortisol response patterns based on the TSST. Logistic regression was used to study the association of TSST patterns with MS pain alone and MS pain combined with increased cold or pressure pain sensitivity, adjusted for relevant confounding factors. All analyses were stratified by sex. RESULTS: The mean (standard deviation) age during the TSST was 18.3 (0.3) years, and during MS pain assessment it was 22.2 (0.6). Forty-five percent of the participants were female. Three cortisol response patterns were identified, with cluster 1 (34 % of females, 21 % of males) reflecting hyporesponse, cluster 2 (47 %, 54 %) reflecting intermediate response and cluster 3 (18 %, 24 %) reflecting hyperresponse of the HPA axis. MS pain was reported by 42 % of females and 33 % of males at age 22 years. Compared with females in cluster 2, females in cluster 1 had an increased likelihood of having any MS pain (odds ratio 2.3, 95 % confidence interval 1.0-5.0) and more severe MS pain (2.8, 1.1-6.8) if their cold pain threshold was above the median. In addition, females in cluster 1 had an increased likelihood (3.5, 1.3-9.7) of having more severe MS pain if their pressure pain threshold was below the median. No statistically significant associations were observed in males. CONCLUSIONS: This study suggests that a hyporesponsive HPA axis at age 18 years is associated with MS pain at 22 years in young females with increased pain sensitivity. PMID- 26654190 TI - Dye decolorization and detoxification potential of Ca-alginate beads immobilized manganese peroxidase. AB - BACKGROUND: In view of compliance with increasingly stringent environmental legislation, an eco-friendly treatment technology of industrial dyes and effluents is a major environmental challenge in the color industry. In present study, a promising and eco-friendly entrapment approach was adopted to immobilize purified manganese peroxidase (MnP) produced from an indigenous strain of Ganoderma lucidum IBL-05 on Ca-alginate beads. The immobilized MnP was subsequently used for enhanced decolorization and detoxification of textile reactive dyes). RESULTS: MnP isolated from solid-state culture of G. lucidum IBL 05, presented highest immobilization yield (83.9 %) using alginate beads prepared at optimized conditions of 4 % (w/v) sodium alginate, 2 % (w/v) Calcium chloride (CaCl2) and 0.5 mg/ml enzyme concentration. Immobilization of MnP enhanced optimum temperature but caused acidic shift in optimum pH of the enzyme. The immobilized MnP showed optimum activity at pH 4.0 and 60 degrees C as compared to pH 5.0 and 35 degrees C for free enzyme. The kinetic parameters K(m) and V(max) of MnP were significantly improved by immobilization. The enhanced catalytic potential of immobilized MnP led to 87.5 %, 82.1 %, 89.4 %, 95.7 % and 83 % decolorization of Sandal-fix Red C4BLN, Sandal-fix Turq Blue GWF, Sandal-fix Foron Blue E2BLN, Sandal-fix Black CKF and Sandal-fix Golden Yellow CRL dyes, respectively. The insolubilized MnP was reusable for 7 repeated cycles in dye color removal. Furthermore, immobilized MnP also caused a significant reduction in biochemical oxygen demand (BOD) (94.61-95.47 %), chemical oxygen demand (COD) (91.18-94.85 %), and total organic carbon (TOC) (89.58-95 %) of aqueous dye solutions. CONCLUSIONS: G. lucidum MnP was immobilized in Ca-alginate beads by entrapment method to improve its practical effectiveness. Ca-alginate bound MnP was catalytically more vigorous, thermo-stable, reusable and worked over wider ranges of pH and temperature as compared to its free counterpart. Results of cytotoxicity like hemolytic and brine shrimp lethality tests suggested that Ca alginate immobilized MnP may effectively be used for detoxification of dyes and industrial effluents. PMID- 26654191 TI - Theoretical Study of Shocked Formic Acid: Born-Oppenheimer MD Calculations of the Shock Hugoniot and Early-Stage Chemistry. AB - Quantum and classical molecular dynamics simulations are used to explore whether chemical reactivity of shocked formic acid occurs at pressures greater than 15 GPa, a question arising from results of different shock compression experiments. The classical molecular dynamics simulations were performed using a quantum-based nonreactive pair additive interaction potential whereas the full resolution quantum mechanical molecular dynamics simulations allow chemical reactions. Although the shock Hugoniot curve calculated using nonreactive classical MD for formic acid is in reasonable agreement with one set of experimental results, shock Hugoniot points calculated using Born-Oppenheimer MD at 30 GPa are in agreement with the set of experimental data that suggests chemical reactivity at these elevated temperatures and pressures. Examination of atomic positions throughout the Born-Oppenheimer MD trajectories clearly indicates extensive and complex chemical reaction, chiefly involving hydrogen-atom transfer and intermolecular complexation. PMID- 26654192 TI - Current and future treatment options for adult chronic rhinosinusitis: Focus on nasal polyposis. AB - Chronic rhinosinusitis (CRS) affects more than 10% of the population in the United States and Europe. Recent findings point to a considerable variation of inflammatory subtypes in patients with CRS with nasal polyps and patients with CRS without nasal polyps. According to current guidelines, glucocorticosteroids and antibiotics are the principle pharmacotherapeutic approaches; however, they fail in a group of patients who share common clinical and laboratory markers. Several clinical phenotypes often leading to uncontrolled disease, including adult nasal polyposis, aspirin-exacerbated respiratory disease, and allergic fungal rhinosinusitis, are characterized by a common endotype: a TH2 bias is associated with a higher likelihood of comorbid asthma and recurrence after surgical treatment. As a consequence, several innovative approaches targeting the TH2 bias with humanized mAbs have been subjected to proof-of-concept studies in patients with CRS with nasal polyps with or without comorbid asthma: omalizumab, reslizumab, mepolizumab, and recently dupilumab. Future concepts using upstream targets, such as GATA-3, also focus on this endotype. This current development might result in advantages in the treatment of patients with the most severe CRS. PMID- 26654194 TI - Drivers of chronic rhinosinusitis: Inflammation versus infection. AB - Studies of the underlying cause or causes of chronic rhinosinusitis (CRS) over the past 20 or more years have expanded from a focus on systemic immune and allergic mechanisms to an intense search for the underlying drivers of mucosal inflammation. These drivers involve mucosal inflammatory pathways that become activated by allergens, microbial stimuli, or poorly understood exogenous or endogenous stimuli. The holy grail in the study of CRS is to identify specific drivers of mucosal inflammation and translate these into more effective treatment for CRS. Certain deficiencies in local innate immunity have been described in patients with CRS that predispose to increased sinus mucosal bacterial colonization/infection, including deficient local production of antimicrobial lactoferrin and deficient functioning of the bitter taste receptor TAS2R38. Conversely, certain innate factors, namely IL-25, IL-33, and thymic stromal lymphopoietin (TSLP), are elaborated by sinus epithelial cells in response to microbial stimulation or airway injury and promote local TH2 inflammation. The precise physiologic role of these factors in innate or adaptive immunity is unclear, although IL-33 might function as an alarmin triggered by damage associated molecular patterns. The cytokines IL-25 and TSLP, similarly promote proinflammatory tissue responses. Another feature of epithelial dysregulation in patients with CRS is overproduction of eosinophil-promoting C-C chemokines by sinus epithelium, perhaps driven in part through innate stimuli, as well as TH2 cytokines, such as IL-13. Strategies to reduce the microbial stimulation of maladaptive TH2 inflammation or to suppress the local elaboration of TH2 promoting epithelial factors, such as IL-33, have potential therapeutic benefit in patients with CRS, although the extent to which this is realized in patient care remains limited at present. This rostrum will summarize my views on the major microbial drivers of mucosal inflammation and dysregulation of innate TH2 promoting factors in patients with CRS based on recent experimental data. PMID- 26654195 TI - The Journal of Allergy and Clinical Immunology: A 17-year perspective. PMID- 26654193 TI - Chronic rhinosinusitis pathogenesis. AB - There are a variety of medical conditions associated with chronic sinonasal inflammation, including chronic rhinosinusitis (CRS) and cystic fibrosis. In particular, CRS can be divided into 2 major subgroups based on whether nasal polyps are present or absent. Unfortunately, clinical treatment strategies for patients with chronic sinonasal inflammation are limited, in part because the underlying mechanisms contributing to disease pathology are heterogeneous and not entirely known. It is hypothesized that alterations in mucociliary clearance, abnormalities in the sinonasal epithelial cell barrier, and tissue remodeling all contribute to the chronic inflammatory and tissue-deforming processes characteristic of CRS. Additionally, the host innate and adaptive immune responses are also significantly activated and might be involved in pathogenesis. Recent advancements in the understanding of CRS pathogenesis are highlighted in this review, with special focus placed on the roles of epithelial cells and the host immune response in patients with cystic fibrosis, CRS without nasal polyps, or CRS with nasal polyps. PMID- 26654197 TI - Timing is everything: Targeting IgE to reduce asthma exacerbation risk. PMID- 26654198 TI - Patient-reported outcome measures for adult chronic rhinosinusitis: A systematic review and quality assessment. AB - BACKGROUND: With a focus on patient-centered care, there is increasing policy interest in patient-reported outcome measures (PROMs) to inform improvements in health care delivery. Given the importance of understanding patient-reported outcomes during the management of chronic rhinosinusitis (CRS), PROMs will play an essential role in informing and tailoring the right intervention to the right patient. OBJECTIVE: The objective of this systematic review was to identify and assess the quality of PROMs being used for adults with CRS. METHODS: A systematic review of Ovid MEDLINE (R) (1947-May 2015), Embase, and the Cochrane databases was performed using the following key terms: ["chronic" AND "*sinusitis"] AND [PROM OR patient reported outcome measure* OR quality of life OR questionnaire OR survey OR valid* OR develop*]. An unlimited truncation strategy (placement of *) was used to capture all variations of terms used. The quality of each PROM was assessed and reported using standardized criteria from the COnsensus-based Standards for the selection of health status Measurement INstruments checklist. RESULTS: A total of 15 PROMs validated for use in adult patients with CRS were identified. Fourteen instruments were specific to adults with CRS, and one was a generic quality-of-life instrument (EuroQol five-dimensional questionnaire [EQ 5D]). There was significant variation in the quality of development and reporting of psychometric properties. Overall, the highest quality validated PROMs for adults with CRS were (1) the 22-item Sinonasal Outcome Test (19 points), (2) the Questionnaire of Olfactory Disorders (14 points), (3) the Sinusitis Control Test (14 points), and (4) the EQ-5D (13 points). Most of the PROMs were developed for research purposes such as determining changes in health-related quality of life or symptoms after an intervention as opposed to improving clinical decision making. CONCLUSIONS: Based on quality assessment, the 22-item Sinonasal Outcome Test, the Questionnaire of Olfactory Disorders, and the Sinusitis Control Test provided the highest quality CRS-specific PROMs, whereas the EQ-5D provided the highest quality generic quality-of-life instrument. Future CRS PROMs will need to incorporate clinical domains that assess common comorbid diseases along with patient values and preferences to improve clinical decision making. PMID- 26654199 TI - Factors influencing growth effects of inhaled corticosteroids in children. PMID- 26654200 TI - Longitudinal tracking of muscle sympathetic nerve activity and its relationship with blood pressure in subjects with prehypertension. AB - Prehypertension is associated with increased cardiovascular events. While the "tracking phenomenon" is an important longitudinal characteristic of blood pressure (BP), changes in muscle sympathetic nerve activity (MSNA) over time remain unclear. This study tested the hypothesis that MSNA tracking contributes to BP trends in prehypertension. BP and MSNA were assessed in 13 prehypertensive males at rest, during hand grip and mental stressors at baseline and after 8 years. Baseline office BP averaged 127 +/- 2/81 +/- 2 mmHg and MSNA 24 +/- 4 bursts/min. BP increased by 7 +/- 2/5 +/- 2 mmHg (P < 0.01) and MSNA by 11 +/- 2 bursts/min (P < 0.001) at follow-up. SBP and DBP were interrelated at baseline (r = 0.65, P = 0.02) and at follow-up (r = 0.78, P = 0.002). MSNA tracking (r = 0.82; P < 0.001) was similar to BP. MSNA was strongly related to DBP at baseline (r = 0.73; P < 0.01) and follow-up (r = 0.64; P = 0.01), more so than SBP. BMI increased (P < 0.001) at follow-up but was unrelated to BP or MSNA. Despite comparable pressor and cardiac increases to handgrip and mental stressors, sympathetic responses were blunted, more pronounced to isometric test (P < 0.006) at follow-up. In conclusion, the trend in MSNA corresponds with BP changes over time suggesting that tonic sympathetic activation may contribute to time-related increase in resting BP and the development of sustained hypertension in prehypertension. PMID- 26654201 TI - The anterior insula and anterior cingulate cortex are associated with avoidance of dental treatment based on prior experience of treatment in healthy adults. AB - BACKGROUND: Fear concerning stressful medical or dental procedures is one of the major factors that distance patients from health care. Fear and avoidance of dental treatments can be shaped by a patient's prior experience with receiving dental procedures or by imagining the procedures. METHODS: We performed two functional magnetic resonance imaging (fMRI) experiments to investigate the role of the anterior insula (aINS) and dorsal anterior cingulate cortex (dACC), which are both critical to threat perception, in dental avoidance. Dental avoidance based on both prior treatment experience and imagination was assessed using a customized questionnaire. In an fMRI task-based study, we investigated brain activation in 17 healthy participants when they viewed images depicting dental procedures that evoked a moderate degree of fear. Region-of-interest analysis was performed to assess the association between dental avoidance and aINS as well as dACC activation. In a resting state fMRI study, we investigated 18 healthy participants for the association between the intrinsic functional connectivity of the aINS and dACC and dental avoidance. RESULTS: We found that (1) the participants showed a higher activation of the right aINS and bilateral dACC when they viewed images of dental procedures compared with the brain activation observed when they viewed scrambled images (p < 0.05 corrected for small volume and family-wise error). (2) The avoidance ratings based on prior experience of dental treatment were significantly positively correlated with the activation in the right aINS (r = 0.67, p = 0.003), right dACC (r = 0.65, p = 0.005) and left dACC (r = 0.63, p = 0.007). (3) The intrinsic functional connectivity between the aINS and the orbitofrontal cortex was positively correlated with the avoidance ratings based on experience (uncorrected p < 0.001). CONCLUSIONS: The findings highlight prior experience of dental treatment as a predominant factor in shaping patients' avoidance behavior. Individual differences in threat perception may play a key role in the development of dental avoidance. PMID- 26654202 TI - Molecular Mechanism of Action of Triazolobenzodiazepinone Agonists of the Type 1 Cholecystokinin Receptor. Possible Cooperativity across the Receptor Homodimeric Complex. AB - The type 1 cholecystokinin receptor (CCK1R) has multiple physiologic roles relating to nutrient homeostasis, including mediation of postcibal satiety. This effect has been central in efforts to develop agonists of this receptor as part of a program to manage and/or prevent obesity. While a number of small molecule CCK1R agonists have been developed, none have yet been approved for clinical use, based on inadequate efficacy, side effects, or the potential for toxicity. Understanding the molecular details of docking and mechanism of action of these ligands can be helpful in the rational refinement and enhancement of small molecule drug candidates. In the current work, we have defined the mechanism of binding and activity of two triazolobenzodiazepinones, CE-326597 and PF-04756956, which are reported to be full agonist ligands. To achieve this, we utilized receptor binding with a series of allosteric and orthosteric radioligands at structurally related CCK1R and CCK2R, as well as chimeric CCK1R/CCK2R constructs exchanging residues in the allosteric pocket, and assessment of biological activity. These triazolobenzodiazepinones docked within the intramembranous small molecule allosteric ligand pocket, with higher affinity binding to CCK2R than CCK1R, yet with biological activity exclusive to or greatly enhanced at CCK1R. These ligands exhibited cooperativity with benzodiazepine binding across the CCK1R homodimeric complex, resulting in their ability to inhibit only a fraction of the saturable binding of a benzodiazepine radioligand, unlike other small molecule antagonists and agonists of this receptor. This may contribute to the understanding of the unique short duration and reversible gallbladder contraction observed in vivo upon administration of these drugs. PMID- 26654203 TI - Spaces between home and school: The effect of eating location on adolescent nutrition. AB - Using interview and self-administered survey data, this article examines how homes, schools, and the community spaces between these two locations affect adolescent nutrition in a low-income, urban setting. Results from this research show that eating location can play a significant role in the foods that adolescents consume. Food acquisition data provided by adolescents reveal that homes and schools provide spaces for the consumption of healthy foods while shops, restaurants, takeouts, and community centers contribute unhealthy snack foods to adolescent diets in a traditionally low-income, urban neighborhood in Northern Ireland. The results of this research show that eating location can provide a starting point for designing healthy eating interventions in low-income places to avoid overlap with spaces that already provide healthy foods to young people. PMID- 26654204 TI - Degradation of sec-hexylbenzene and its metabolites by a biofilm-forming yeast Trichosporon asahii B1 isolated from oil-contaminated sediments in Quangninh coastal zone, Vietnam. AB - This article reports on the ability of yeast Trichosporon asahii B1 biofilm associated cells, compared with that of planktonic cells, to transform sec hexylbenzene and its metabolites. This B1 strain was isolated from a petroleum polluted sediment collected in the QuangNinh coastal zones in Vietnam, and it can transform the branched aromatic hydrocarbons into a type of forming biofilm (pellicle) more efficiency than that the planktonic forms can. In the biofilm cultivation, seven metabolites, including acetophenone, benzoic acid, 2,3 dihydroxybenzoic acid, beta-methylcinnamic acid, 2-phenylpropionic acid, 3 phenylbutyric acid, and 5-phenylhexanoic acid were extracted by ethyl acetate and analyzed by HPLC and GC-MS. In contrast, in the planktonic cultivation, only three of these intermediates were found. An individual metabolite was independently used as an initial substrate to prove its degradation by biofilm and planktonic types. The degradation of these products indicated that their inoculation with B1 biofilms was indeed higher than that observed in their inoculation with B1 planktonic cells. This is the first report on the degradation of sec-hexylbenzene and its metabolites by a biofilm-forming Trichosporon asahii strain. These results enhance our understanding of the degradation of branched side-chain alkylbenzenes by T. asahii B1 biofilms and give a new insight into the potential role of biofilms formed by such species in the bioremediation of other recalcitrant aromatic compounds. PMID- 26654205 TI - Filtering with State-Observation Examples via Kernel Monte Carlo Filter. AB - This letter addresses the problem of filtering with a state-space model. Standard approaches for filtering assume that a probabilistic model for observations (i.e., the observation model) is given explicitly or at least parametrically. We consider a setting where this assumption is not satisfied; we assume that the knowledge of the observation model is provided only by examples of state observation pairs. This setting is important and appears when state variables are defined as quantities that are very different from the observations. We propose kernel Monte Carlo filter, a novel filtering method that is focused on this setting. Our approach is based on the framework of kernel mean embeddings, which enables nonparametric posterior inference using the state-observation examples. The proposed method represents state distributions as weighted samples, propagates these samples by sampling, estimates the state posteriors by kernel Bayes' rule, and resamples by kernel herding. In particular, the sampling and resampling procedures are novel in being expressed using kernel mean embeddings, so we theoretically analyze their behaviors. We reveal the following properties, which are similar to those of corresponding procedures in particle methods: the performance of sampling can degrade if the effective sample size of a weighted sample is small, and resampling improves the sampling performance by increasing the effective sample size. We first demonstrate these theoretical findings by synthetic experiments. Then we show the effectiveness of the proposed filter by artificial and real data experiments, which include vision-based mobile robot localization. PMID- 26654206 TI - Memory Stacking in Hierarchical Networks. AB - Robust representations of sounds with a complex spectrotemporal structure are thought to emerge in hierarchically organized auditory cortex, but the computational advantage of this hierarchy remains unknown. Here, we used computational models to study how such hierarchical structures affect temporal binding in neural networks. We equipped individual units in different types of feedforward networks with local memory mechanisms storing recent inputs and observed how this affected the ability of the networks to process stimuli context dependently. Our findings illustrate that these local memories stack up in hierarchical structures and hence allow network units to exhibit selectivity to spectral sequences longer than the time spans of the local memories. We also illustrate that short-term synaptic plasticity is a potential local memory mechanism within the auditory cortex, and we show that it can bring robustness to context dependence against variation in the temporal rate of stimuli, while introducing nonlinearities to response profiles that are not well captured by standard linear spectrotemporal receptive field models. The results therefore indicate that short-term synaptic plasticity might provide hierarchically structured auditory cortex with computational capabilities important for robust representations of spectrotemporal patterns. PMID- 26654207 TI - Timing of Cortical Events Preceding Voluntary Movement. AB - We studied magnetic signals from the human brain recorded during a second before a self-paced finger movement. Sharp triangular peaks were observed in the averaged signals about 0.7 second before the finger movement. The amplitude of the peaks varied considerably from trial to trial, which indicated that the peaks were concurrent with much longer oscillatory processes. One can cluster trials into distinct groups with characteristic sequences of events. Prominent short trains of pulses in the beta frequency band were identified in the premovement period. This observation suggests that during preparation of the intended movement, cortical activity is well organized in time but differs from trial to trial. Magnetoencephalography can capture these processes with high temporal resolution and allows their study in fine detail. PMID- 26654208 TI - Infinite Continuous Feature Model for Psychiatric Comorbidity Analysis. AB - We aim at finding the comorbidity patterns of substance abuse, mood and personality disorders using the diagnoses from the National Epidemiologic Survey on Alcohol and Related Conditions database. To this end, we propose a novel Bayesian nonparametric latent feature model for categorical observations, based on the Indian buffet process, in which the latent variables can take values between 0 and 1. The proposed model has several interesting features for modeling psychiatric disorders. First, the latent features might be off, which allows distinguishing between the subjects who suffer a condition and those who do not. Second, the active latent features take positive values, which allows modeling the extent to which the patient has that condition. We also develop a new Markov chain Monte Carlo inference algorithm for our model that makes use of a nested expectation propagation procedure. PMID- 26654209 TI - Mutual Information, Fisher Information, and Efficient Coding. AB - Fisher information is generally believed to represent a lower bound on mutual information (Brunel & Nadal, 1998), a result that is frequently used in the assessment of neural coding efficiency. However, we demonstrate that the relation between these two quantities is more nuanced than previously thought. For example, we find that in the small noise regime, Fisher information actually provides an upper bound on mutual information. Generally our results show that it is more appropriate to consider Fisher information as an approximation rather than a bound on mutual information. We analytically derive the correspondence between the two quantities and the conditions under which the approximation is good. Our results have implications for neural coding theories and the link between neural population coding and psychophysically measurable behavior. Specifically, they allow us to formulate the efficient coding problem of maximizing mutual information between a stimulus variable and the response of a neural population in terms of Fisher information. We derive a signature of efficient coding expressed as the correspondence between the population Fisher information and the distribution of the stimulus variable. The signature is more general than previously proposed solutions that rely on specific assumptions about the neural tuning characteristics. We demonstrate that it can explain measured tuning characteristics of cortical neural populations that do not agree with previous models of efficient coding. PMID- 26654210 TI - Correlational Neural Networks. AB - Common representation learning (CRL), wherein different descriptions (or views) of the data are embedded in a common subspace, has been receiving a lot of attention recently. Two popular paradigms here are canonical correlation analysis (CCA)-based approaches and autoencoder (AE)-based approaches. CCA-based approaches learn a joint representation by maximizing correlation of the views when projected to the common subspace. AE-based methods learn a common representation by minimizing the error of reconstructing the two views. Each of these approaches has its own advantages and disadvantages. For example, while CCA based approaches outperform AE-based approaches for the task of transfer learning, they are not as scalable as the latter. In this work, we propose an AE based approach, correlational neural network (CorrNet), that explicitly maximizes correlation among the views when projected to the common subspace. Through a series of experiments, we demonstrate that the proposed CorrNet is better than AE and CCA with respect to its ability to learn correlated common representations. We employ CorrNet for several cross-language tasks and show that the representations learned using it perform better than the ones learned using other state-of-the-art approaches. PMID- 26654211 TI - Quantifying and qualifying the preventive effects of acute-phase cognitive therapy: Pathways to personalizing care. AB - OBJECTIVE: To determine the extent to which prospectively identified responders to cognitive therapy (CT) for recurrent major depressive disorder (MDD) hypothesized to be lower risk show significantly less relapse or recurrence than treated higher risk counterparts across 32 months. METHOD: Outpatients (N = 523), aged 18-70, with recurrent MDD received 12-14 weeks of CT. The last 7 consecutive scores from the Hamilton Rating Scale for Depression (HRSD-17) were used to stratify or define responders (n = 290) into lower (7 HRSD-17 scores of less than or equal to 6; n = 49; 17%) and higher risk (n = 241; 83%). The lower risk patients entered the 32-month follow-up. Higher risk patients were randomized to 8 months of continuation-phase CT or clinical management plus double-blind fluoxetine or pill placebo, with a 24-month follow-up. RESULTS: Lower risk patients were significantly less likely to relapse over the first 8 months compared to higher risk patients (Kaplan-Meier [KM] estimates; i.e., 4.9% = lower risk; 22.1% = higher risk; log-rank chi2 = 6.83, p = .009). This increased risk was attenuated, but not completely neutralized, by active continuation-phase therapy. Over the subsequent 24 months, the lower and higher risk groups did not differ in relapse or recurrence risk. CONCLUSIONS: Rapid and sustained acute phase CT remission identifies responders who do not require continuation-phase treatment to prevent relapse (i.e., return of an index episode). To prevent recurrence (i.e., new episodes), however, strategic allocation and more frequent "dosing" of CT and/or targeted maintenance-phase treatments may be required. Longitudinal follow-up is recommended. PMID- 26654212 TI - Staying well during pregnancy and the postpartum: A pilot randomized trial of mindfulness-based cognitive therapy for the prevention of depressive relapse/recurrence. AB - OBJECTIVE: Clinical decision-making regarding the prevention of depression is complex for pregnant women with histories of depression and their health care providers. Pregnant women with histories of depression report preference for nonpharmacological care, but few evidence-based options exist. Mindfulness-based cognitive therapy has strong evidence in the prevention of depressive relapse/recurrence among general populations and indications of promise as adapted for perinatal depression (MBCT-PD). With a pilot randomized clinical trial, our aim was to evaluate treatment acceptability and efficacy of MBCT-PD relative to treatment as usual (TAU). METHOD: Pregnant adult women with depression histories were recruited from obstetric clinics at 2 sites and randomized to MBCT-PD (N = 43) or TAU (N = 43). Treatment acceptability was measured by assessing completion of sessions, at-home practice, and satisfaction. Clinical outcomes were interview-based depression relapse/recurrence status and self-reported depressive symptoms through 6 months postpartum. RESULTS: Consistent with predictions, MBCT-PD for at-risk pregnant women was acceptable based on rates of completion of sessions and at-home practice assignments, and satisfaction with services was significantly higher for MBCT-PD than TAU. Moreover, at-risk women randomly assigned to MBCT-PD reported significantly improved depressive outcomes compared with participants receiving TAU, including significantly lower rates of depressive relapse/recurrence and lower depressive symptom severity during the course of the study. CONCLUSIONS: MBCT-PD is an acceptable and clinically beneficial program for pregnant women with histories of depression; teaching the skills and practices of mindfulness meditation and cognitive-behavioral therapy during pregnancy may help to reduce the risk of depression during an important transition in many women's lives. PMID- 26654213 TI - Longitudinal findings from a randomized clinical trial of naltrexone for young adult heavy drinkers. AB - OBJECTIVE: Behavioral interventions for young adults show limited effects 1-year posttreatment. Few studies have examined the longitudinal outcomes of pharmacotherapy trials to reduce heavy drinking. This study examined the posttreatment, longitudinal effects of the first placebo-controlled trial of naltrexone in young adult heavy drinkers. METHOD: Randomized, double-blind, placebo-controlled, 8-week trial. Follow-up assessments at posttreatment (8 weeks [8W]), 3 months [3M], 6 months [6M], and 12 months [12M]). Participants were young adults ages 18-25 (N = 118) who reported >=4 heavy drinking days in the prior 4 weeks. Outcomes were percent days heavy drinking (PHDD), percent days abstinent (PDA), and drinks per drinking day (DPDD). RESULTS: There were no time effects on PHDD. Treatment improvements were maintained posttreatment. A main effect of time was found for PDA. Both conditions continued to increase PDA posttreatment. For DPDD, a Treatment *Time interaction emerged. In the naltrexone condition, DPDD increased from 8W to 6M and decreased from 6M to 12M, resulting in no net change posttreatment. The placebo group had a nonsignificant decrease in DPDD. The result was a significant benefit of naltrexone at 8W but not 12M. CONCLUSIONS: Participants showed improvements or no change on most outcomes over 1 year posttreatment. Naltrexone had significant benefits over placebo at 8W. Although differences among groups diminished during follow-up, overall effects were maintained. Behavioral monitoring during treatment may impact long-term outcomes more than a single intervention following discontinuation of active medication. (PsycINFO Database Record PMID- 26654214 TI - Randomized controlled trial of stereotactic 11-G vacuum-assisted core biopsy for the diagnosis and management of mammographic microcalcification. AB - OBJECTIVE: To compare the accuracy of 11-G vacuum-assisted biopsy (VAB) with 14-G core needle biopsy (CNB) to diagnose mammographic microcalcification (MM) and effect on surgical outcomes. METHODS: Following ethical approval, VAB and CNB (control) were compared in a randomized prospective study for first-line diagnosis of MM and subsequent surgical outcomes in two breast-screening units. Participants gave written informed consent. Exclusions included comorbidity precluding surgery, prior ipsilateral breast cancer and lesions >40 mm requiring mastectomy as first surgical procedure. The final pathological diagnosis was compared with the initial biopsy result. Quality-of-life (QOL) questionnaires were administered at baseline, 2, 6 and 12 months. 110 participants were required to show a 25% improvement in diagnosis with VAB compared with CNB (90% power). RESULTS: Eligibility was assessed for 787 cases; 129 females recalled from the National Health Service breast screening programme were randomized. Diagnostic accuracy of VAB was 86% and that of CNB was 84%. Using VAB, 2/14 (14.3%) cases upgraded from ductal carcinoma in situ to invasion at surgery and 3/19 (15.8%) using CNB. Following VAB 7/16 (44%) cases required repeat surgery vs 7/24 (29%) after CNB. Both groups recorded significant worsening of functional QOL measures and increased breast pain at follow-up. CONCLUSION: VAB and CNB were equally accurate at diagnosing MM, and no significant differences in surgical outcomes were observed. ADVANCES IN KNOWLEDGE: The first randomized controlled study of VAB for diagnosis of microcalcification using digital mammography showed no difference in diagnostic accuracy of VAB and CNB, or in the proportion of participants needing repeat non-operative biopsy or second therapeutic operation to treat malignancy. PMID- 26654215 TI - Effect of novel patient interaction on students' performance of pregnancy options counseling. AB - BACKGROUND: Although options counseling is a fundamental skill for medical providers, previous research has identified gaps in medical school reproductive health education. PURPOSE: To determine if a 1-h novel patient interaction (NPI) improves student performance when caring for a standardized patient with an unintended pregnancy. METHODS: From September 2012 to June 2013 we randomized third-year medical students at the University of Colorado School of Medicine to the standard curriculum plus an NPI, or the standard curriculum only. The NPI consisted of a 1-h small-group session with a patient who discussed her experiences with options counseling and her decision to terminate her pregnancy. Students completed an Objective Structured Clinical Examination (OSCE) at the rotation's end, which included options counseling. The primary outcome was the proportion of participants achieving 'excellence' on the OSCE checklist. 'Excellence' was defined as a score >=90%. Examinations were flagged as 'unsatisfactory encounters' if core competencies were not addressed. OSCE standardized patients and evaluators were blinded to group assignment. RESULTS: In total, 135 students were eligible and randomized: 75 to NPI; 60 to control. During the OSCE, few students achieved 'excellence' (24% NPI vs. 28% control, p=0.57).There were no differences between scores for components of options counseling. More students in the control group 'appeared somewhat uncomfortable' delivering the pregnancy test results (5% NPI vs. 18% control, p=0.006). More than half (54%) of the intervention group and 67% of controls had 'unsatisfactory encounters' (p=0.16), almost exclusively due to omission of adoption. Most students addressed abortion (96% NPI vs. 92% control, p=0.29). CONCLUSIONS: A 1-h NPI does not improve medical students' performance of pregnancy options counseling and the option of adoption is routinely omitted. Adoption is clearly an area that needs greater attention when designing comprehensive reproductive health curriculum for medical students. PMID- 26654217 TI - Molecular characterisation of extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli isolates from hospital and ambulatory patients in Germany. AB - The increase of Escherichia coli producing extended-spectrum beta-lactamases (ESBL) in hospitals and their emergence as intestinal colonisers of healthy humans is of concern. Transmission ways and the extent of spread of distinct E. coli clones or ESBL genes among humans and animals via the food chain or the environment is a matter of debate. In this study we determined ESBL genotypes in E. coli isolates (n=233) resistant to 3rd generation cephalosporins from hospitals and medical practices using PCR and sequencing. Bacterial strain typing was performed by PCR-based phylogrouping, multilocus sequence typing (MLST) and a ST131-specific PCR. Results showed that CTX-M-15 (50.4%), CTX-M-1 (28.4%) and CTX M-14 (5.6%) were the most common ESBL types. Especially, CTX-M-15 was associated with E. coli ST131 of phylogenetic group B2, which was the dominant sequence type among our isolates (35.8%). MLST typing revealed 40 different sequence types (STs), with ST131, ST410, ST10 and ST38 as the most prevalent ones. Our findings give an overview of the current distribution of ESBL-producing E. coli isolates from humans in Germany. E. coli O25b:H4-ST131 was confirmed to be the most common clone, which is known for its successful dissemination worldwide. Although heterogeneity among the isolates was found, several successful clones previously described in animals (ST410, ST10) also occurred in our isolate collection. Further detailed investigations of ESBL-producing isolates from different habitats are needed to evaluate possible transfer ways. PMID- 26654216 TI - Non-integrating episomal plasmid-based reprogramming of human amniotic fluid stem cells into induced pluripotent stem cells in chemically defined conditions. AB - Amniotic fluid stem cells (AFSC) represent an attractive potential cell source for fetal and pediatric cell-based therapies. However, upgrading them to pluripotency confers refractoriness toward senescence, higher proliferation rate and unlimited differentiation potential. AFSC were observed to rapidly and efficiently reacquire pluripotency which together with their easy recovery makes them an attractive cell source for reprogramming. The reprogramming process as well as the resulting iPSC epigenome could potentially benefit from the unspecialized nature of AFSC. iPSC derived from AFSC also have potential in disease modeling, such as Down syndrome or beta-thalassemia. Previous experiments involving AFSC reprogramming have largely relied on integrative vector transgene delivery and undefined serum-containing, feeder-dependent culture. Here, we describe non-integrative oriP/EBNA-1 episomal plasmid-based reprogramming of AFSC into iPSC and culture in fully chemically defined xeno-free conditions represented by vitronectin coating and E8 medium, a system that we found uniquely suited for this purpose. The derived AF-iPSC lines uniformly expressed a set of pluripotency markers Oct3/4, Nanog, Sox2, SSEA-1, SSEA-4, TRA-1-60, TRA-1-81 in a pattern typical for human primed PSC. Additionally, the cells formed teratomas, and were deemed pluripotent by PluriTest, a global expression microarray-based in silico pluripotency assay. However, we found that the PluriTest scores were borderline, indicating a unique pluripotent signature in the defined condition. In the light of potential future clinical translation of iPSC technology, non integrating reprogramming and chemically defined culture are more acceptable. PMID- 26654218 TI - Prevalence of carbapenemase producing Enterobacteriaceae isolated from German pig fattening farms during the years 2011-2013. AB - Since recently Enterobacteriaceae carrying blaVIM-1 genes have been isolated in German animal husbandries, the monitoring of carbapenemase producing Enterobacteriaceae (CPE) in livestock became a major topic within the European Union. Nevertheless, due to missing surveillance studies the worldwide situation in livestock and livestock associated surroundings might still be underestimated. The here described study provides an overview of the CPE-prevalence in German pig fattening farms during the years 2011-2013 (period when previously described blaVIM-1 findings occurred on pig-fattening farms (Efsa, 2011; Fischer et al., 2012, 2013a)). Therefore, a collection of 238 bacterial anacultures derived from pooled faeces and boot swab samples, collected in a cross-sectional study including 58 pig-fattening farms throughout Germany, were investigated. The bacteria were selected on MacConkey agar plates containing 0.125MUg/ml meropenem. Enterobacteriaceae which were able to grow on these plates were further investigated for the presence of carbapenemase genes. Out of eight CPE-suspicious strains, two Escherichia (E.) coli strains-deriving from the same farm-contained the carbapenemase gene blaVIM-1. For the remaining six Enterobacteriaceae it seems to be likely that they possess other resistance mechanisms, leading to reduced carbapenem susceptibility. Based on the obtained results, the overall CPE prevalence for German pig-fattening farms, sampled during the years 2011-2013 was 1.7%; 95% CI: 0-10. However, as it is of great importance to prevent a further spread of these bacteria between farms and livestock populations as well as their introduction into the food chain, an understanding of their routes of introduction and spread in combination with intensified monitoring programs are considered necessary. PMID- 26654219 TI - Mammalian autophagy degrades nuclear constituents in response to tumorigenic stress. AB - During autophagy, double-membrane autophagosomes are observed in the cytoplasm. Thus, extensive studies have focused on autophagic turnover of cytoplasmic material. Whether autophagy has a role in degrading nuclear constituents is poorly understood. We reveal that the autophagy protein LC3/Atg8 directly interacts with the nuclear lamina protein LMNB1 (lamin B1), and binds to LMN/lamin-associated chromatin domains (LADs). Through these interactions, autophagy specifically mediates destruction of nuclear lamina during tumorigenic stress, such as by activated oncogenes and DNA damage. This nuclear lamina degradation upon aberrant cellular stress impairs cell proliferation by inducing cellular senescence, a stable form of cell-cycle arrest and a tumor-suppressive mechanism. Our findings thus suggest that, in response to cancer-promoting stress, autophagy degrades nuclear material to drive cellular senescence, as a means to restrain tumorigenesis. Our work provokes a new direction in studying the role of autophagy in the nucleus and in tumor suppression. PMID- 26654220 TI - Delivery methods for drugs used in the treatment of overactive bladder. AB - INTRODUCTION: Overactive bladder affects a significant portion of the population and results in prescribing of numerous medications for its treatment. Traditional drug delivery systems used in therapy are associated with multiple commonly reported side effects. Adherence rates with use of these medications are low. It is likely that low adherence rates with the use of these drugs are due in some part to drug side effects. It is therefore important that alternate methods for drug delivery be explored to reduce side effect profiles and improve patient compliance. AREAS COVERED: This article addresses the various forms of drug delivery for overactive bladder medications, focusing on those currently in use. Newer systems of drug delivery are also discussed. Through thorough review of research data, randomized trials and meta analyses, drug delivery systems were evaluated. EXPERT OPINION: EXPERT OPINION favors the use of the transdermal patch and recognizes the necessity for further research and development of other delivery methods. The patch delivery method offers the most effective means of treating symptoms and minimizing drug related adverse side effects leading to treatment discontinuation. Development of OAB medications aimed at alternate receptor targets has the potential to facilitate the creation of new treatment methods to compete with the current standard of care used in OAB treatment. PMID- 26654221 TI - Comment on "Insights into the Electronic Structure of Ozone and Sulfur Dioxide from Generalized Valence Bond Theory: Bonding in O3 and SO2". PMID- 26654222 TI - Formulation and evaluation of a montelukast sodium orally disintegrating tablet with a similar dissolution profile as the marketed product. AB - A major challenge of orally disintegrating tablet (ODT) development is predicting its bioequivalence to its corresponding marketed product. Therefore, comparing ODT dissolution profiles to those of the corresponding marketed product is very important. The objective of this study was to develop a 5.2-mg montelukast sodium (MS) ODT with a similar dissolution profile to that of the marketed chewable tablet. Dissolution profiles were examined in different media to screen each formulation. We found that MS dissolution from ODTs in acidic medium heavily depended on manufacturing methods. All MS ODTs prepared using direct compression rapidly disintegrated in acidic medium. However, dispersed MS powders aggregated into sticky masses, resulting in slow dissolution. In contrast, MS ODTs prepared using wet granulation had much faster dissolution rates in acidic medium with no obvious aggregation. Additionally, the optimized formulation, prepared using wet granulation, displayed similar dissolution profiles to the marketed reference in all four types of media examined (f2 > 50). The in vitro disintegration time of the optimized ODT was 9.5 +/- 2.4 s, which meets FDA requirements. In conclusion, the wet granulation preparation method of MS ODTs resulted in a product with equivalent dissolution profiles as those of the marketed product. PMID- 26654223 TI - "It's not just about walking.....it's the practice nurse that makes it work": a qualitative exploration of the views of practice nurses delivering complex physical activity interventions in primary care. AB - BACKGROUND: Physical activity (PA) is important for physical and mental health in adults and older adults. Interventions incorporating theory-based behaviour change techniques (BCTs) can be useful in helping people to increase their PA levels and can be delivered by practice nurses in primary care. We undertook two primary care based complex walking interventions among adults and older adults. Both interventions were underpinned by BCTs and delivered by practice nurses and we sought their views and experiences of delivering over 1400 complex PA consultations. METHODS: Semi structured interviews with two practice nurse groups (n = 4 and n = 5) and two individual interviews (total n = 11) were conducted by independent facilitators; audio-recorded, transcribed verbatim and analysed using thematic analysis. RESULTS: Five key themes emerged as enablers and/or barriers to delivering the intervention: preparation and training; initial and ongoing support; adherence to the protocol; the use of materials and equipment; and engagement of participants. The themes were organised into a framework of 'pre trial' and 'delivery of the intervention'. Two additional 'post-trial' themes were identified; changed practice and the future feasibility of the intervention. Nurses believed that taking part in the trial, especially the BCT training, enhanced the quality and delivery of advice and support they provided within routine consultations, although the lack of time available routinely makes this challenging. CONCLUSION: Delivering an effective behaviour change intervention in primary care requires adequate training and support for practice nurses both initially and throughout the trial as well as adequate consultation time. Enhanced skills from participating in such trials can lead to long-term changes, including more patient-centred consulting. TRIAL REGISTRATION: PACE-Lift ISRCTN 42122561 , PACE-UP ISRCTN 98538934 . PMID- 26654224 TI - Genotype analysis of varicella-zoster virus isolates from suburban Shanghai Municipal Province, China. AB - To determine the predominant genotype of the varicella-zoster virus (VZV) in suburban Shanghai Municipal Province, specimens were collected from the lesions of 95 outpatients clinically diagnosed with varicella or herpes zoster. Of these, 69 patients (72.6%) were positive for VZV DNA. The 69 isolates were all genotyped as the genotype J1/clade 2. Based on sequencing of the 447 bp sequence in ORF22, 66 isolates were identified as genotype J/clade 2 strains and three were identified as type M2/clade 4 strains. To confirm the classification of these three strains, we determined the presence of 27 single-nucleotide polymorphisms (SNPs) and found that isolates 1270/1450 shared seven SNPs that differed from those of clade 2, in which three SNPs were unique to clade 3 and another three were unique to clade 4. Isolate 1456 had two markers of clade 4 that differed from clade 2. The phylogenetic tree showed that our isolates clustered primarily with clade 2 and that the three M2/J1 strains clustered between clades 2 and 4. It is likely that isolates 1270/1450/1446 may represent a new subclade of either clade 2 or 4, or some recombinant events. In addition, our isolates were WT strains. We also observed significant inter-strain variations. PMID- 26654225 TI - Treatment of elderly patients with metastatic renal cell carcinoma. AB - The risk of developing renal cell carcinoma (RCC) increases with age, and given the constant gain in life expectancy of the general population, both localized RCC and metastatic RCC (mRCC) are more frequently observed in the elderly population. The elderly are a heterogeneous group of patients often characterized by the presence of comorbidities, different compliance to treatment and polypharmacy. Here we review the available data with the aim to analyze the safety and efficacy of new targeted therapies (TTs) in elderly mRCC patients. TTs seem to be effective in both older and younger patients, but elderly patients appear to show reduced tolerance to treatments compared to younger patients. Prospective trials are needed to better understand how to manage mRCC in elderly patients. PMID- 26654226 TI - 19-Tungstodiarsenate(III) Functionalized by Organoantimony(III) Groups: Tuning the Structure-Bioactivity Relationship. AB - A family of three discrete organoantimony(III)-functionalized heteropolyanions [Na{2-(Me2HN(+)CH2)C6H4Sb(III)}As(III)2W19O67(H2O)](10-) (1), [{2 (Me2HN(+)CH2)C6H4Sb(III)}2As(III)2W19O67(H2O)](8-) (2), and [{2 (Me2HN(+)CH2)C6H4Sb(III)}{WO2(H2O)}{WO(H2O)}2(B-beta-As(III)W8O30)(B-alpha As(III)W9O33)2](14-) (3)-have been prepared by one-pot reactions of the 19 tungstodiarsenate(III) precursor [As(III)2W19O67(H2O)](14-) with 2 (Me2NCH2)C6H4SbCl2. The three novel polyanions crystallized as the hydrated mixed alkali salts Cs3KNa6[Na{2-(Me2HN(+)CH2)C6H4Sb(III)}As(III)2W19O67(H2O)].43H2O (CsKNa-1), Rb2.5K5.5[{2 (Me2HN(+)CH2)C6H4Sb(III)}2As(III)2W19O67(H2O)].18H2O.Me2NCH2C6H5 (RbK-2), and Rb2.5K11.5[{2-(Me2HN(+)CH2)C6H4Sb(III)}{WO2(H2O)}{WO(H2O)}2(B-beta As(III)W8O30)(B-alpha-As(III)W9O33)2].52H2O (RbK-3), respectively. The number of incorporated {2-(Me2HN(+)CH2)C6H4Sb(III)} units could be tuned by careful control of the experimental parameters. Polyanions 1 and 2 possess a dimeric sandwich type topology, whereas 3 features a trimeric, wheel-shaped structure, representing the largest organoantimony-containing polyanion. All three compounds were fully characterized in the solid state via single-crystal X-ray diffraction (XRD), infrared (IR) spectroscopy, and thermogravimetric analysis, and their aqueous solution stability was validated by ultraviolet-visible light (UV-vis) and multinuclear ((1)H, (13)C, and (183)W) nuclear magnetic resonance (NMR) spectroscopy. Effective inhibition against six different types of bacteria was observed for 1 and 2, and we could extract a structure-bioactivity relationship for these polyanions. PMID- 26654228 TI - Specificities of Children with Multiple Sclerosis and Neuromyelitis Optica. AB - BACKGROUND: Chronic demyelinating diseases of the central nervous system (CNS) are autoimmune conditions that, although rarely fatal, may lead to severe disability. Among these diseases, Multiple Sclerosis (MS) and neuromyelitis optica (NMO) are particularly important and subject of worldwide research. MS and NMO are chronic types of CNS disease, with recurrent episodes of demyelination. For many years, these two conditions were considered to be only one, but lately it is known that they have different epidemiological, physiopathological and prognostic characteristics. The present study aims at reviewing the specificities of MS and NMO affecting patients before they complete 18 years of age. METHODS: Literature review on data about MS and NMO in patients below the age of 18 years. RESULTS: There are no clinical trials for any drug used to treat MS and NMO in children or adolescents. Data are mainly on anedoctal cases, case series and recommendations from experts. At present, there is no evidence-based treatment to be recommended for patients with MS and NMO before the age of 18 years. CONCLUSION: Despite being a particularly vulnerable population for severe disability in the future, there are no evidence-based guidelines for the treatment of MS and NMO in children and adolescents. PMID- 26654229 TI - Hansch Analysis of Novel Acetamide Derivatives as Highly Potent and Specific MAO A Inhibitors. AB - BACKGROUND: A quantitative structure-activity relationship (QSAR) study of novel Acetamide derivatives as specific Mono amino oxidase (MAO) A inhibitory agents was performed with 28 compounds to derive QSAR models for better activity and lesser side effects. METHODS: Various thermodynamic, electronic and steric parameters were calculated using Chem 3D package of molecular modeling software Chemoffice 7.0. QSAR models were generated employing sequential multiple regression method using in-house statistical program VALSTAT. The best models were selected from the various statistically significant equations. RESULTS: The study revealed that an increase in the bulkiness of the substituent's and molecular solvent accessible surface area is beneficial to the biological activity and the substitution of two interacting groups should be separated by more than three atoms will give better biological activity. Model also suggests that the presence of the comparatively less lipophilic group may increase MAO-A inhibitory activity and substituent that decrease the flexibility and increase rigidity of the nucleus will enhance the activity. The best QSAR model was selected, having a correlation coefficient (r) = 0.93271, coefficient of determination (r2) = 0.8509 with a standard deviation of predictivity (SDEP) = 0.31287 and cross validated squared correlation coefficient (Q2) = 0.92. The predictive ability of the selected model was also confirmed by leave one out cross validation and r2 predicted (r2 pred) was 0.764. CONCLUSION: This study may be useful in the designing of more potent substituted acetamide derivatives as specific MAOA inhibitors. PMID- 26654231 TI - Innovation and research at the forefront of the 43(rd) Annual Conference. PMID- 26654230 TI - Construction of relatedness matrices using genotyping-by-sequencing data. AB - BACKGROUND: Genotyping-by-sequencing (GBS) is becoming an attractive alternative to array-based methods for genotyping individuals for a large number of single nucleotide polymorphisms (SNPs). Costs can be lowered by reducing the mean sequencing depth, but this results in genotype calls of lower quality. A common analysis strategy is to filter SNPs to just those with sufficient depth, thereby greatly reducing the number of SNPs available. We investigate methods for estimating relatedness using GBS data, including results of low depth, using theoretical calculation, simulation and application to a real data set. RESULTS: We show that unbiased estimates of relatedness can be obtained by using only those SNPs with genotype calls in both individuals. The expected value of this estimator is independent of the SNP depth in each individual, under a model of genotype calling that includes the special case of the two alleles being read at random. In contrast, the estimator of self-relatedness does depend on the SNP depth, and we provide a modification to provide unbiased estimates of self relatedness. We refer to these methods of estimation as kinship using GBS with depth adjustment (KGD). The estimators can be calculated using matrix methods, which allow efficient computation. Simulation results were consistent with the methods being unbiased, and suggest that the optimal sequencing depth is around 2 4 for relatedness between individuals and 5-10 for self-relatedness. Application to a real data set revealed that some SNP filtering may still be necessary, for the exclusion of SNPs which did not behave in a Mendelian fashion. A simple graphical method (a 'fin plot') is given to illustrate this issue and to guide filtering parameters. CONCLUSION: We provide a method which gives unbiased estimates of relatedness, based on SNPs assayed by GBS, which accounts for the depth (including zero depth) of the genotype calls. This allows GBS to be applied at read depths which can be chosen to optimise the information obtained. SNPs with excess heterozygosity, often due to (partial) polyploidy or other duplications can be filtered based on a simple graphical method. PMID- 26654232 TI - A pilot study into locating the bad bugs in a busy intensive care unit. AB - BACKGROUND: The persistence of multidrug-resistant organisms (MDROs) within an intensive care unit (ICU) possibly contained within dry surface biofilms, remains a perplexing confounder and is a threat to patient safety. Identification of residential locations of MDRO within the ICU is an intervention for which new scientific approaches may assist in finding potential MDRO reservoirs. METHOD: This study investigated a new approach to sampling using a more aggressive environmental swabbing technique of high-touch objects (HTOs) and surfaces, aided by 2 commercially available adenosine triphosphate (ATP) bioluminometers. RESULTS: A total of 13 individual MDRO locations identified in this pilot study. The use of ATP bioluminometers was significantly associated with the identification of 12 of the 13 individual MDRO locations. The MDRO recovery and readings from the 2 ATP bioluminometers were not significantly correlated with distinct cutoffs for each ATP device, and there was no correlation between the 2 ATP devices. CONCLUSION: The specific MDRO locations were not limited to the immediate patient surroundings or to any specific HTO or type of surface. The use of ATP testing helped rapidly identify the soiled locations for MDRO sampling. The greatest density of positive MDRO locations was around and within the clinical staff work station. PMID- 26654233 TI - Prevention and control practices for human noroviruses in long-term care facilities in South Carolina. AB - BACKGROUND: Long-term care facilities (LTCFs) are the most common setting for human norovirus (HuNoV) outbreak. Our study aimed to determine gaps in prevention and control practices for HuNoV in LTCFs in South Carolina (SC). METHODS: Two researchers visited a convenience sample of 26 LTCFs in SC during July-November 2013. Directors were interviewed to determine facility prevention and control practices. Relative frequencies and means were calculated using SAS 9.3 (SAS Institute, Cary, NC). RESULTS: Most directors had little knowledge of proper sanitizing and disinfecting products and reported missing written procedures for cleaning staff-visitor bathrooms. Only 18 had recommendations for when residents should wash hands. Many used the wrong products for pathogen removal after vomit fecal events, had no written procedures for cleaning contaminated soft surfaces, did not remove other individuals during clean-up of vomit-fecal episodes, and did not clean a large area surrounding vomit-fecal episodes. Eighteen did not assign specific staff to care for sick; 16 did not designate specific toilets for sick; and 15 did not restrict visitors during an outbreak. CONCLUSION: Directors' responses indicated gaps in prevention and control practices for HuNoV in LTCFs in SC. PMID- 26654234 TI - Association of Clostridium difficile infection in hospital mortality: A systematic review and meta-analysis. AB - BACKGROUND: The purpose of this study was to evaluate whether Clostridium difficile infection (CDI) contributed to hospital mortality and whether the correlation between intensive care units (ICUs) and surgical wards in hospital CDI risk still remain controversial. METHODS: By meta-analysis, 12 eligible studies involving 8,509 cases and 247,285 controls were identified via PubMed and Embase. RESULTS: CDI patients had a higher risk of hospital mortality than non CDI patients (odds ratio [OR], 1.899; 95% confidence interval [CI], 1.269-2.840), especially in 30-day mortality (OR, 2.521; 95% CI, 1.800-3.531). No correlation was found between hospital CDI and Charlson comorbidity index (OR, 0.830; 95% CI, 0.559-1.231). Patients treated in the ICU have an increased risk of hospital CDI (OR, 1.820; 95% CI, 1.161-2.851). However, the risk of CDI in patients who used to have surgery in surgical wards was not different to patients in the other departments (OR, 1.054; 95% CI, 0.838-1.325). Moreover, CDI patients in studies from the most recent 5 years have a higher risk of hospital mortality (OR, 2.171; 95% CI, 1.426-3.304). CONCLUSION: Hospital CDI was associated with an increased risk of hospital mortality, especially in 30-day mortality. In addition, when compared with past years, CDI patients have a higher risk of hospital mortality in the most recent 5 years. Given the rapid dissemination of this organism worldwide, there is a need to aggressively develop and evaluate primary preventive strategies targeting CDI among hospitalized patients, especially in ICUs. PMID- 26654235 TI - Ability of cleaning-disinfecting wipes to remove bacteria from medical device surfaces. AB - BACKGROUND: Nosocomial infections are a serious problem in health care facilities. Bacteria can be transferred from patient to patient via contaminated reusable medical devices and equipment. METHODS: An anesthesia machine and objects representative of smooth and ridged machine knobs were contaminated with Staphylococcus aureus, Bacillus atrophaeus spores, and Clostridium sporogenes spores. The ability of 5 commercially available cleaning-disinfecting wipes to remove bacteria was compared with gauze soaked with water or bleach. Gauze soaked with water was used to determine the optimal wetness for bacteria removal, which was then used to evaluate the efficacy of the wipe ingredients. RESULTS: All of the wipes cleaned the device surfaces significantly better than the no wipe control. Some wipes performed equally well as gauze with water, whereas others performed worse. Overall, the wipe containing sodium hypochlorite was the most effective at removing bacteria. When the wipe ingredients were re-evaluated using the determined optimal wipe wetness on gauze, their effectiveness at cleaning S aureus, but not spores, significantly improved. CONCLUSION: Physically removing bacteria from device surfaces with water was often as effective as the cleaning disinfecting wipes. Of the wipe active ingredients evaluated, sodium hypochlorite was the most effective overall. The wetness of the wipes may also play a role in their effectiveness. PMID- 26654236 TI - The role of ultraviolet marker assessments in demonstrating cleaning efficacy. AB - Cleaning standards measuring compliance using visual auditing alone can be misleading, because visually clean surfaces might not be cleaned of pathogens. An evidence-based system using both visual auditing and ultraviolet marker (UVM) assessments is recommended. Using a UVM system has enabled our health service to measure infection risk and implement actions to improve results. We recommend adopting a combined monitoring process using visual auditing with UVM audits to enhance cleaning and reduce the risk of health care-associated infection. PMID- 26654237 TI - Hydrogen peroxide vapor room disinfection and hand hygiene improvements reduce Clostridium difficile infection, methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, and extended-spectrum beta-lactamase. AB - We report a statistically significant reduction in Clostridium difficile infection (from 1.38 to 0.90 cases per 1,000 patient days), vancomycin-resistant enterococci (from 0.21 to 0.01 cases per 1,000 patient days), and extended spectrum beta-lactamase-producing gram-negative bacteria (from 0.16 to 0.01 cases per 1,000 patient days) associated with the introduction of hydrogen peroxide vapor for terminal decontamination of patient rooms and improvements in hand hygiene compliance. PMID- 26654227 TI - Novel drug targets for personalized precision medicine in relapsed/refractory diffuse large B-cell lymphoma: a comprehensive review. AB - Diffuse large B-cell lymphoma (DLBCL) is a clinically heterogeneous lymphoid malignancy and the most common subtype of non-Hodgkin's lymphoma in adults, with one of the highest mortality rates in most developed areas of the world. More than half of DLBLC patients can be cured with standard R-CHOP regimens, however approximately 30 to 40 % of patients will develop relapsed/refractory disease that remains a major cause of morbidity and mortality due to the limited therapeutic options.Recent advances in gene expression profiling have led to the identification of at least three distinct molecular subtypes of DLBCL: a germinal center B cell-like subtype, an activated B cell-like subtype, and a primary mediastinal B-cell lymphoma subtype. Moreover, recent findings have not only increased our understanding of the molecular basis of chemotherapy resistance but have also helped identify molecular subsets of DLBCL and rational targets for drug interventions that may allow for subtype/subset-specific molecularly targeted precision medicine and personalized combinations to both prevent and treat relapsed/refractory DLBCL. Novel agents such as lenalidomide, ibrutinib, bortezomib, CC-122, epratuzumab or pidilizumab used as single-agent or in combination with (rituximab-based) chemotherapy have already demonstrated promising activity in patients with relapsed/refractory DLBCL. Several novel potential drug targets have been recently identified such as the BET bromodomain protein (BRD)-4, phosphoribosyl-pyrophosphate synthetase (PRPS)-2, macrodomain containing mono-ADP-ribosyltransferase (ARTD)-9 (also known as PARP9), deltex-3 like E3 ubiquitin ligase (DTX3L) (also known as BBAP), NF-kappaB inducing kinase (NIK) and transforming growth factor beta receptor (TGFbetaR).This review highlights the new insights into the molecular basis of relapsed/refractory DLBCL and summarizes the most promising drug targets and experimental treatments for relapsed/refractory DLBCL, including the use of novel agents such as lenalidomide, ibrutinib, bortezomib, pidilizumab, epratuzumab, brentuximab vedotin or CAR T cells, dual inhibitors, as well as mechanism-based combinatorial experimental therapies. We also provide a comprehensive and updated list of current drugs, drug targets and preclinical and clinical experimental studies in DLBCL. A special focus is given on STAT1, ARTD9, DTX3L and ARTD8 (also known as PARP14) as novel potential drug targets in distinct molecular subsets of DLBCL. PMID- 26654238 TI - Current vaccination status regarding measles among university students in Dresden, Germany. AB - Germany aimed to eliminate measles by 2015, but vaccination coverage is still insufficient, especially in respect to adolescents and young adults. A cross sectional survey with 711 students studying a range of subjects showed a high acceptance regarding vaccination. Actual self-reported vaccination rates were lower; only 65.5% of medical students and 25.3%-39.4% of other student groups reported complete vaccination against measles. Of the students, 12.6%-45% did not know their vaccination status. Vaccination acceptance did not correlate with vaccination behavior: accessible vaccination opportunities at universities should be offered. PMID- 26654239 TI - An intervention to reduce health care personnel hand contamination during care of patients with Clostridium difficile infection. AB - In a quasi-experimental study, an educational intervention to improve the technique for personal protective equipment (PPE) removal in conjunction with disinfection of gloves before removal of PPE reduced acquisition of Clostridium difficile spores on the hands of health care personnel caring for patients with C difficile infection. PMID- 26654240 TI - Electronic control device prongs: a growing cause of bloodborne pathogen exposure? PMID- 26654241 TI - EGCG/gelatin-doxorubicin gold nanoparticles enhance therapeutic efficacy of doxorubicin for prostate cancer treatment. AB - AIM: Development of epigallocatechin gallate (EGCG) and gelatin-doxorubicin conjugate (GLT-DOX)-coated gold nanoparticles (DOX-GLT/EGCG AuNPs) for fluorescence imaging and inhibition of prostate cancer cell growth. MATERIALS & METHODS: AuNPs alternatively coated with EGCG and DOX-GLT conjugates were prepared by a layer-by-layer assembly method. The physicochemical properties of the AuNPs and the effect of Laminin 67R receptor-mediated endocytosis on the anticancer efficacy of the AuNPs were examined. RESULTS: The AuNPs significantly inhibit the proliferation of PC-3 cancer cell and the enzyme-responsive intracellular release of DOX could be tracked by monitoring the recovery of the fluorescence signal of DOX. CONCLUSION: Laminin 67R receptor-mediated delivery of DOX using the AuNPs enhanced cellular uptake of DOX and improved apoptosis of PC 3 cells. PMID- 26654243 TI - Loneliness and substance use: the influence of gender among HIV+ Black/African American adults 50+. AB - Estimates suggest 30% of adults report the highest levels of loneliness. Though men are more likely than women to use illicit substances and engage in heavy drinking, the prevalence of substance use in women is growing and their escalation toward dependence occurs more rapidly. Loneliness and substance use have greater relevance within the HIV+ population, with higher rates of substance misuse than the general population. However, the association between loneliness and substance use within HIV+ individuals remains understudied. The purpose of the present study was to test the hypothesis that there would be an association between loneliness and substance moderated by gender in HIV+ older adults. A cross-sectional study was conducted between October 2013 and January 2014. Study participants included 96 HIV-positive Black/African American men and women recruited through the University of Florida Center for HIV/AIDS Research, Education and Service (UF CARES) in Jacksonville, Florida. Participants completed an interviewer-administered assessment examining mental and behavioral health. Pearson correlations examined associations between loneliness and substance use. Binary logistic regression analyses stratified by gender examined the association between loneliness and substance use while controlling for covariates. Among women, loneliness was associated with illicit drug use, AOR = 3.37, 95% CI: 1.23 9.21, p = .018 and heavy drinking, AOR = 2.47, 95% CI: 1.07-5.71, p = .033. No significant associations were found between loneliness and illicit drug use, and heavy drinking in men. Substance use among women in this population may be linked to loneliness. Interventions should be gender specific. Further research into this association is necessary as it will likely have important clinical implications for this population. PMID- 26654244 TI - Acute reduction in blood pressure following consumption of anthocyanin-rich cherry juice may be dose-interval dependant: a pilot cross-over study. AB - A pilot cross-over study assessed the acute effects on blood pressure and plasma biomarkers associated with consumption of a 300 ml anthocyanin-rich fruit juice, provided in differing dose-intervals. Young adults (n = 6) and older adults (n = 7) received in random order, either a single 300 ml dose or 3 * 100 ml doses of high-flavonoid cherry juice provided at 0, 1 and 2 h. Blood pressure and plasma levels of phenolic metabolites were measured at 0, 2 and 6 h.The single 300 ml dose of cherry juice resulted in a significant reduction in systolic (p = 0.002), and diastolic blood pressure (p = 0.008) and heart-rate (p = 0.033) 2 h after consumption, before returning to baseline levels at 6 h post-consumption. The 3 * 100 ml dose provided over 2 h did not result in significant blood pressure reductions. Plasma phenolic metabolites increased at 2 and 6 h; however, fluctuations were higher after the single 300 ml dose in older adults. These findings have implications for design of intervention studies that investigate vascular effects associated with flavonoid-rich foods. PMID- 26654245 TI - Chemical Biology Probes for Extracellular Vesicles Facilitate Studies of Neuroinflammation. AB - Neuroinflammation has been conceived as an important cause for or contributor to neurological diseases. With major strides in new technology, scientists can use chemical biology tools developed in non-neuronal systems to research neuroinflammation. Extracellular vesicles (EVs) play a vital role in mediating neuroinflammation via carrying pathogenic misfolded proteins as well as nucleic acids, suggesting important biological functions. Nonetheless, it is a daunting goal to study these ultramicroscopic EVs in part due to the technical hurdle of specific labeling and preparation. Therefore, development of new detection methods of EVs will promote further understanding of EVs in the nervous system, thereby expediting the diagnosis and therapy development for neurological disorders. Recent progress toward a new class of chemical biology probes simultaneously targeting the highly curved surface and the particular lipid compositions of EVs may offer an alternative strategy for their detection, isolation, and purification, which not only will facilitate research on their mechanism in neuroinflammation and neurological diseases, but also may lay the groundwork for the next generation of diagnostics and prognostics. PMID- 26654242 TI - Identification of novel HIV-1 dependency factors in primary CCR4(+)CCR6(+)Th17 cells via a genome-wide transcriptional approach. AB - BACKGROUND: The HIV-1 infection is characterized by profound CD4(+) T cell destruction and a marked Th17 dysfunction at the mucosal level. Viral suppressive antiretroviral therapy restores Th1 but not Th17 cells. Although several key HIV dependency factors (HDF) were identified in the past years via genome-wide siRNA screens in cell lines, molecular determinants of HIV permissiveness in primary Th17 cells remain to be elucidated. RESULTS: In an effort to orient Th17-targeted reconstitution strategies, we investigated molecular mechanisms of HIV permissiveness in Th17 cells. Genome-wide transcriptional profiling in memory CD4(+) T-cell subsets enriched in cells exhibiting Th17 (CCR4(+)CCR6(+)), Th1 (CXCR3(+)CCR6(-)), Th2 (CCR4(+)CCR6(-)), and Th1Th17 (CXCR3(+)CCR6(+)) features revealed remarkable transcriptional differences between Th17 and Th1 subsets. The HIV-DNA integration was superior in Th17 versus Th1 upon exposure to both wild type and VSV-G-pseudotyped HIV; this indicates that post-entry mechanisms contribute to viral replication in Th17. Transcripts significantly enriched in Th17 versus Th1 were previously associated with the regulation of TCR signaling (ZAP-70, Lck, and CD96) and Th17 polarization (RORgammat, ARNTL, PTPN13, and RUNX1). A meta-analysis using the NCBI HIV Interaction Database revealed a set of Th17-specific HIV dependency factors (HDFs): PARG, PAK2, KLF2, ITGB7, PTEN, ATG16L1, Alix/AIP1/PDCD6IP, LGALS3, JAK1, TRIM8, MALT1, FOXO3, ARNTL/BMAL1, ABCB1/MDR1, TNFSF13B/BAFF, and CDKN1B. Functional studies demonstrated an increased ability of Th17 versus Th1 cells to respond to TCR triggering in terms of NF-kappaB nuclear translocation/DNA-binding activity and proliferation. Finally, RNA interference studies identified MAP3K4 and PTPN13 as two novel Th17 specific HDFs. CONCLUSIONS: The transcriptional program of Th17 cells includes molecules regulating HIV replication at multiple post-entry steps that may represent potential targets for novel therapies aimed at protecting Th17 cells from infection and subsequent depletion in HIV-infected subjects. PMID- 26654246 TI - Cell Membrane Proteins Modulate the Carbon Nanotube Optical Bandgap via Surface Charge Accumulation. AB - Cell adhesion is a protein-mediated process intrinsic to most living organisms. Dysfunction in cell adhesion processes is implicated in various diseases, including thrombosis and metastatic cancers. Using an approach to resolve spectral features from cell membrane-associated photoluminescent single-walled carbon nanotubes, we found that nanotube optical bandgaps respond to the electrostatic potential of the cell surface, which corresponds to cell adhesion properties. We studied the carbon nanotube emission energy response to solution ionic potentials, which suggests sensitivity to local charge accumulation. We conclude that nanotubes respond to cell surface electrostatic potentials that are mediated by membrane proteins, which vary significantly across cell types. These findings portend the optical measurement of surface electrostatic potentials for biophysical measurements and biomedical applications. PMID- 26654247 TI - Assessing Ebola-related web search behaviour: insights and implications from an analytical study of Google Trends-based query volumes. AB - BACKGROUND: The 2014 Ebola epidemic in West Africa has attracted public interest worldwide, leading to millions of Ebola-related Internet searches being performed during the period of the epidemic. This study aimed to evaluate and interpret Google search queries for terms related to the Ebola outbreak both at the global level and in all countries where primary cases of Ebola occurred. The study also endeavoured to look at the correlation between the number of overall and weekly web searches and the number of overall and weekly new cases of Ebola. METHODS: Google Trends (GT) was used to explore Internet activity related to Ebola. The study period was from 29 December 2013 to 14 June 2015. Pearson's correlation was performed to correlate Ebola-related relative search volumes (RSVs) with the number of weekly and overall Ebola cases. Multivariate regression was performed using Ebola-related RSV as a dependent variable, and the overall number of Ebola cases and the Human Development Index were used as predictor variables. RESULTS: The greatest RSV was registered in the three West African countries mainly affected by the Ebola epidemic. The queries varied in the different countries. Both quantitative and qualitative differences between the affected African countries and other Western countries with primary cases were noted, in relation to the different flux volumes and different time courses. In the affected African countries, web query search volumes were mostly concentrated in the capital areas. However, in Western countries, web queries were uniformly distributed over the national territory. In terms of the three countries mainly affected by the Ebola epidemic, the correlation between the number of new weekly cases of Ebola and the weekly GT index varied from weak to moderate. The correlation between the number of Ebola cases registered in all countries during the study period and the GT index was very high. CONCLUSION: Google Trends showed a coarse-grained nature, strongly correlating with global epidemiological data, but was weaker at country level, as it was prone to distortions induced by unbalanced media coverage and the digital divide. Global and local health agencies could usefully exploit GT data to identify disease-related information needs and plan proper communication strategies, particularly in the case of health-threatening events. PMID- 26654248 TI - Risk of invasive meningococcal disease in children and adults with HIV in England: a population-based cohort study. AB - BACKGROUND: Recent studies have identified HIV infection as a potential risk factor for invasive meningococcal disease (IMD), suggesting that HIV-infected individuals could benefit from meningococcal vaccination to reduce their risk of this rare, but severe and potentially fatal infection. In the United Kingdom, as in most industrialised countries, HIV is not considered a risk factor for IMD. METHODS: IMD incidence and relative risk by age group and meningococcal capsular group in HIV-positive compared with HIV-uninfected individuals was estimated through data linkage of national datasets in England between 2011 and 2013. RESULTS: IMD incidence among persons diagnosed with HIV was 6.6 per 100,000 compared to 1.5 per 100,000 among HIV-negative individuals, with a relative risk of 4.5 (95 % CI, 2.7-7.5). All but one case occurred in adults aged 16-64 years, who had a 22.7-fold (95 % CI, 12.4-41.6; P <0.001) increased risk compared with the HIV-negative adults. IMD risk by capsular group varied with age. HIV-positive children and adolescents had a higher risk of meningococcal group B disease, while adults were at increased risk of groups C, W and Y disease. Most HIV positive individuals had been born in Africa, had acquired HIV through heterosexual contact, and were known to be HIV-positive and receiving antiretroviral treatment at IMD diagnosis. The most common clinical presentation was septicemia and, although intensive care admission was common, none died of IMD. CONCLUSIONS: HIV-positive children and adults are at significantly increased risk of IMD, providing an evidence base for policy makers to consider HIV as a risk factor for meningococcal vaccination. PMID- 26654249 TI - No association between the common calcium-sensing receptor polymorphism rs1801725 and irritable bowel syndrome. AB - BACKGROUND: The calcium-sensing receptor (CaSR) is a calcium (Ca(2+)) sensitive G protein-coupled receptor implicated in various biological processes. In particular, it regulates Ca(2+)/Mg(2+)- homeostasis and senses interstitial Ca(2+) levels and thereby controls downstream signalling cascades. Due to its expression in the gut epithelium, the enteric nervous system and smooth muscles and its key function in regulation and coordination of muscular contraction and secretion, it represents an excellent candidate gene to be investigated in the pathophysiology of irritable bowel syndrome (IBS). Disturbed CaSR structure and function may impact gastrointestinal regulation of muscular contraction, neuronal excitation and secretion and consequently contribute to symptoms seen in IBS, such as disordered defecation as well as disturbed gut motility and visceral sensitivity. METHODS: We have therefore genotyped the functional CASR SNP rs1801725 in three case control samples from the UK, Belgium and the USA. RESULTS: Genotype frequencies showed no association in the three genotyped case control samples, neither with IBS nor with IBS subtypes. CONCLUSIONS: Although we could not associate the SNP to any of the established bowel symptom based IBS subtypes we cannot rule out association to altered Ca(2+) levels and disturbed secretion and gut motility which were unfortunately not assessed in the patients genotyped. This underlines the necessity of a more detailed phenotyping of IBS patients and control individuals in future studies. PMID- 26654250 TI - The advance care planning PREPARE study among older Veterans with serious and chronic illness: study protocol for a randomized controlled trial. AB - BACKGROUND: Advance care planning (ACP) is a process whereby patients prepare for medical decision-making. The traditional objective of ACP has focused on the completion of advance directives. We have developed a new paradigm of ACP focused on preparing patients and their loved ones for communication and informed medical decision-making. To operationalize this new paradigm of ACP, we created an interactive, patient-centered website called PREPARE ( www.prepareforyourcare.org ) designed for diverse older adults. METHODS/DESIGN: This randomized controlled trial with blinded outcome assessment is designed to determine the efficacy of PREPARE to engage older Veterans in the ACP process. Veterans who are >= 60 years of age, have >= two medical conditions, and have seen a primary care physician >= two times in the last year are being randomized to one of two study arms. The PREPARE study arm reviews the PREPARE website and an easy-to-read advance directive. The control arm only reviews the advance directive. The primary outcome is documentation of an advance directive and ACP discussions. Other clinically important outcomes using validated surveys include ACP behavior change process measures (knowledge, contemplation, self-efficacy, and readiness) and a full range of ACP action measures (identifying a surrogate, identifying values and goals, choosing leeway or flexibility for the surrogate, communicating with clinicians and surrogates, and documenting one's wishes). We will also assess satisfaction with decision-making and Veteran activation within primary care visits by direct audio recording. To examine the outcomes at 1 week, 3 months, and 6 months between the two study arms, we will use mixed effects linear, Poisson, or negative binomial regression and mixed effects logistic regression. DISCUSSION: This study will determine whether PREPARE increases advance directive completion rates and engagement with the ACP process. If PREPARE is efficacious, it could prove to be an easy and effective intervention to help older adults engage in the ACP process within or outside of the medical environment. PREPARE may also help older adults communicate their medical wishes and goals to their loved ones and clinicians, improve medical decision-making, and ensure their wishes are honored over the life course. TRIAL REGISTRATION: ClinicalTrials.gov NCT01550731 . Registered on 8 December 2011. PMID- 26654251 TI - Association of methylenetetrahydrofolate reductase gene (C677T) with the risk of hypertension in Morocco. AB - BACKGROUND: Hypertension is a multifactorial disease caused by the interaction between genetic and environmental factors. Mutations in the methylenetetrahydrofolate reductase gene (MTHFR) have been known to be associated with the risk of cardiovascular disease as well as hypertension. This case control study was conducted out to measure the association of the polymorphism C677T of MTHFR with the risk of hypertension. METHODS: Polymerase chain reaction followed by restriction fragment analysis length was used to identify MTHFR C677T genotypes in patients 101 patients and 102 age and sex matched healthy controls. Odds ratio with 95 % confidence interval was used to assess the risk of association. RESULTS: The distribution of demographic and clinical features of patients showed no particular trend (p > 0.05). However, the frequency of homozygous 677T allele was higher in patients with a family history of heart disease (30.4 vs. 9 %, p = 0.031). Interestingly, the mutant 677TT genotype was significantly associated with the susceptibility of hypertension when compared to the wild type 677CC genotype (OR 5.4, CI 1.4-19.8, p = 0.008). In addition, the recessive model 677TT vs. 677CC/CT was found to be associated with the risk of hypertension (OR 5.3, CI 1.5-19.1, p = 0.005). However, the dominant model was not associated with the risk of hypertension in our cohort (OR 1.3, CI 0.7-2.2, p = 0.4). CONCLUSIONS: Based on our findings, the homozygous mutant for 677TT of MTHFR gene is associated with the risk of hypertension in our population. Further studies with larger sample sizes are needed to confirm the results of this study. PMID- 26654252 TI - Effect of stretching with and without muscle strengthening exercises for the foot and hip in patients with plantar fasciitis: A randomized controlled single-blind clinical trial. AB - OBJECTIVE: To compare the effect of stretching with and without muscle strengthening of the foot alone or foot and hip on pain and function in patients with plantar fasciitis. DESIGN: Single blind randomized controlled trial. METHOD: Eighty-three patients with plantar fasciitis were allocated to one of three treatment options for an eight-week period: Foot Exercise Group (FEG - extrinsic and intrinsic foot muscles), Foot and Hip Exercise Group (FHEG - abductor and lateral rotator muscles) and Stretching Alone Exercise Group (SAEG). MAIN MEASURES: A visual analog scale for pain, the Foot and Ankle Outcome Score and the Star Excursion Balance Test. All evaluations were performed before treatment and after the last treatment session. RESULTS: Improvements were found in all groups regarding the visual analog scale, the pain, activities of daily living, sports and recreation, quality of life (p < 0.001) and other symptoms (p < 0.01) subscales of the Foot and Ankle Outcome Score as well as posterolateral movement, posteromedial movement and composite score (p < 0.001) on the Star Excursion Balance Test. No time-group interactions were found for any of the variables (p > 0.05). CONCLUSIONS: All three exercise protocols analyzed led to improvements at eight-week follow-up in pain, function and dynamic lower limb stability in patients with plantar fasciitis. PMID- 26654253 TI - Development and validation of a generic nontarget method based on liquid chromatography - high resolution mass spectrometry analysis for the evaluation of different wastewater treatment options. AB - A comprehensive workflow for using nontarget approaches as process evaluation tools was implemented, including data acquisition based on a LC-HRMS (QTOF) system using direct injection and data post-processing for the peak recognition in "full scan" data. Both parts of the approach were not only developed and validated in a conventional way using the suspected analysis of a set of spiked known micropollutants but also the nontarget analysis of a wastewater treatment plant (WWTP) effluent itself was utilized to consider a more environmental relevant range of analytes. Hereby, special focus was laid on the minimization of false positive results (FPs) during the peak recognition. The optimized data post processing procedure reduced the percentage of FPs from 42% to 10-15%. Furthermore, the choice of a suitable chromatography for biological treated wastewater systems was also discussed during the method development. The workflow paid also attention to differences in the performance levels of the LC-HRMS system by implementation of an adaption system for intensity variations comparing different measurements dates or different instruments. The application of this workflow on wastewater samples from a municipal WWTP revealed that more than 91% compounds were eliminated by the biological treatment step and that the received effluent contained 55% newly formed potential transformation products. PMID- 26654254 TI - Evaluation of selectivity in homologous multimodal chromatographic systems using in silico designed antibody fragment libraries. AB - This study describes the in silico design, surface property analyses, production and chromatographic evaluations of a diverse set of antibody Fab fragment variants. Based on previous findings, we hypothesized that the complementarity determining regions (CDRs) constitute important binding sites for multimodal chromatographic ligands. Given that antibodies are highly diversified molecules and in particular the CDRs, we set out to examine the generality of this result. For this purpose, four different Fab fragments with different CDRs and/or framework regions of the variable domains were identified and related variants were designed in silico. The four Fab variant libraries were subsequently generated by site-directed mutagenesis and produced by recombinant expression and affinity purification to enable examination of their chromatographic retention behavior. The effects of geometric re-arrangement of the functional moieties on the multimodal resin ligands were also investigated with respect to Fab variant retention profiles by comparing two commercially available multimodal cation exchange ligands, Capto MMC and Nuvia cPrime, and two novel multimodal ligand prototypes. Interestingly, the chromatographic data demonstrated distinct selectivity trends between the four Fab variant libraries. For three of the Fab libraries, the CDR regions appeared as major binding sites for all multimodal ligands. In contrast, the fourth Fab library displayed a distinctly different chromatographic behavior, where Nuvia cPrime and related multimodal ligand prototypes provided markedly improved selectivity over Capto MMC. Clearly, the results illustrate that the discriminating power of multimodal ligands differs between different Fab fragments. The results are promising indications that multimodal chromatography using the appropriate multimodal ligands can be employed in downstream bioprocessing for challenging selective separation of product related variants. PMID- 26654255 TI - Off-line coupling of multidimensional immunoaffinity chromatography and ion mobility spectrometry: A promising partnership. AB - The extreme specificity of immunoaffinity chromatography (IAC) columns coupled to the high sensitivity of ion mobility spectrometry (IMS) measurements makes this combination really useful for rapid, selective, and sensitive determination of a high variety of analytes in different samples. The capabilities of the IAC-IMS coupling have been highlighted under three different scenarios: (i) multiclass residue analysis using a single IAC column, (ii) multiclass residue analysis using stacked IAC columns, and (iii) isomer analysis. In the first case, the determination of three strobilurin fungicides - azoxystrobin, picoxystrobin, and pyraclostrobin - in water and strawberry juice was considered, obtaining limits of quantification (LOQs) from 11 to 63MUgL(-1). Recoveries from 96 to 106% for water, and from 67 to 104% for strawberry juice were obtained. In the second case, anilinopyrimidine compounds, including two analytes with similar drift time, were selectively retained in different IAC columns and analyzed after independent elution in commercial wine samples by IMS. LOQ values of 16, 14 and 12MUgL(-1) were obtained for pyrimethanil, mepanipyrim, and cyprodinil, respectively. The obtained recoveries for wine samples spiked with 25 and 100MUgL(-1) were from 82 to 123%. Additionally, the stacked IAC columns concept was applied to the separation of Z and E isomers of azoxystrobin that were selectively retained in specific IAC columns and quantified by IMS. Recoveries between 91 and 94% were obtained for both isomers in water samples. PMID- 26654256 TI - Rational Design of Efficient Electrocatalysts for Hydrogen Evolution Reaction: Single Layers of WS2 Nanoplates Anchored to Hollow Nitrogen-Doped Carbon Nanofibers. AB - To exploit the benefits of nanostructuring for enhanced hydrogen evolution reaction (HER), we employed coaxial electrospinning to synthesize single-layered WS2 nanoplates anchored to hollow nitrogen-doped carbon nanofibers (WS2@HNCNFs) as efficient electrocatalysts. For comparison, bulk WS2 powder and single layers of WS2 embedded in nitrogen-doped carbon nanofibers (WS2@NCNFs) were synthesized and electrochemically tested. The distinctive design of the WS2@HNCNFs enables remarkable electrochemical performances showing a low overpotential with reduced charge transfer resistance, a small Tafel slope, and excellent durability. The experimental results highlight the importance of nanostructure engineering in electrocatalysts for enhanced HER. PMID- 26654258 TI - Niastella gongjuensis sp. nov., isolated from greenhouse soil. PMID- 26654257 TI - Emerging Biosensing Approaches for microRNA Analysis. PMID- 26654259 TI - Metabolic syndrome update. AB - The metabolic syndrome is a multiplex risk factor for atherosclerotic cardiovascular disease and type 2 diabetes. It is composed of atherogenic dyslipidemia, elevated blood pressure, insulin resistance and elevated glucose, a pro-thrombotic state, and a pro-inflammatory state. Excess energy intake and concomitant obesity are the major drivers of the syndrome. Lifestyle intervention can reverse metabolic risk factors, but at times, drug therapies or bariatric surgery may be required to control more overt risk factors. PMID- 26654260 TI - 11-Hydroxylation of Protoberberine by the Novel Berberine-Utilizing Aerobic Bacterium Sphingobium sp. Strain BD3100. AB - Protoberberine alkaloids, including berberine, palmatine, and berberrubine, are produced by medicinal plants and are known to have various pharmacological effects. We isolated two berberine-utilizing bacteria, Sphingobium sp. strain BD3100 and Rhodococcus sp. strain BD7100, from soil collected at a natural medicine factory. BD3100 had the unique ability to utilize berberine or palmatine as the sole carbon and energy source. BD3100 produced demethyleneberberine in berberine-supplemented medium. In a resting-cell incubation with berberine, BD3100 produced 11-hydroxyberberine; the structure of 11-hydroxyberberine was determined by detailed analysis of NMR and MS spectroscopic data. alpha Naphthoflavone, miconazole, and ketoconazole, which are known inhibitors of cytochrome P450, interfered with BD3100 metabolism of berberine in resting cells. Inhibition by miconazole led to the production of a new compound, 11 hydroxydemethyleneberberine. In a resting-cell incubation with palmatine, BD3100 generated 11-hydroxypalmatine. This work represents the first report of the isolation and characterization of novel berberine-utilizing aerobic bacteria for the production of 11-hydroxylation derivatives of berberine and palmatine. PMID- 26654271 TI - Combined Effect of Cryogel Matrix and Temperature-Reversible Soluble-Insoluble Polymer for the Development of in Vitro Human Liver Tissue. AB - Hepatic cell culture on a three-dimensional (3D) matrix or as a hepatosphere appears to be a promising in vitro biomimetic system for liver tissue engineering applications. In this study, we have combined the concept of a 3D scaffold and a spheroid culture to develop an in vitro model to engineer liver tissue for drug screening. We have evaluated the potential of poly(ethylene glycol)-alginate gelatin (PAG) cryogel matrix for in vitro culture of human liver cell lines. The synthesized cryogel matrix has a flow rate of 7 mL/min and water uptake capacity of 94% that enables easy nutrient transportation in the in vitro cell culture. Young's modulus of 2.4 kPa and viscoelastic property determine the soft and elastic nature of synthesized cryogel. Biocompatibility of PAG cryogel was evaluated through MTT assay of HepG2 and Huh-7 cells on matrices. The proliferation and functionality of the liver cells were enhanced by culturing hepatic cells as spheroids (hepatospheres) on the PAG cryogel using temperature reversible soluble-insoluble polymer, poly(N-isopropylacrylamide) (PNIPAAm). Pore size of the cryogel above 100 MUm modulated spheroid size that can prevent hypoxia condition within the spheroid culture. Both the hepatic cells have shown a significant difference (P < 0.05) in terms of cell number and functionality when cultured with PNIPAAm. After 10 days of culture using 0.05% PNIPAAm, the cell number increased by 11- and 7-fold in case of HepG2 and Huh-7 cells, respectively. Similarly, after 10 days of hepatic spheroids culture on PAG cryogel, the albumin production, urea secretion, and CYP450 activity were significantly higher in case of culture with PNIPAAm. The developed tissue mass on the PAG cryogel in the presence of PNIPAAm possess polarity, which was confirmed using F-actin staining and by presence of intercellular bile canalicular lumen. The developed cryogel matrix supports liver cells proliferation and functionality and therefore can be used for in vitro and in vivo drug testing. PMID- 26654272 TI - Engineered Hematite Mesoporous Single Crystals Drive Drastic Enhancement in Solar Water Splitting. AB - Mesoporous single crystals (MSCs) rendering highly accessible surface area and long-range electron conductivity are extremely significant in many fields, including catalyst, solar fuel, and electrical energy storage technologies. Hematite semiconductor, whose performance has been crucially limited by its pristine poor charge separation efficiency in solar water splitting, should benefit from this strategy. Despite successful synthesis of many metal oxide MSCs, the fabrication of hematite MSCs remains to be a great challenge due to its quite slow hydrolysis rate in water. Herein, for the first time, we have developed a synthetic strategy to prepare hematite MSCs and systematically investigated their growth mechanism. The electrode fabricated with these crystals is able to achieve a photocurrent density of 0.61 mA/cm(2) at 1.23 V vs RHE under AM 1.5G simulated sunlight, which is 20 times higher than that of electrodes made of solid single crystals. The enhancement is ascribed to the superior light absorption and enhanced charges separation. Our results demonstrate the advantage of incorporation of nanopores into the large-sized hematite single crystals and provide a valuable insight for the development of high performance photoelectrodes in PEC application. PMID- 26654273 TI - Access to Difluoromethylated Arenes by Pd-Catalyzed Reaction of Arylboronic Acids with Bromodifluoroacetate. AB - An unprecedented example of Pd-catalyzed difluoromethylation of aryl boronic acids with bromodifluoroacetate is described. The reaction proceeds under mild reaction conditions with hydroquinone and Fe(acac)3 as additives. Preliminary mechanistic studies reveal that a difluorocarbene pathway is involved in the reaction, which is unusual compared to the most traditional approaches. This reaction has advantages of high efficiency and excellent functional group compatibility, even toward bromide and hydroxy group, thus providing a useful protocol for drug discovery and development. PMID- 26654274 TI - Early growth and changes in blood pressure during adult life. AB - Previous studies suggest that the inverse association between birth weight and adult blood pressure amplifies with age. Rapid childhood growth has also been linked to hypertension. The objective of this study was to determine whether the association between childhood growth and adult blood pressure amplifies with age. The study comprised 574 women and 462 men from the Helsinki Birth Cohort Study who attended a clinical study in 2001-2004 and a follow-up in 2006-2008. Mean age at the clinic visits was 61.5 and 66.4 years, respectively. Blood pressure was measured at both occasions. Conditional growth models were used to assess relative weight gain and linear growth. We studied the associations between conditional growth and blood pressure as well as the presence of hypertension. Relative weight gain and linear growth between ages 2 and 11 years were inversely associated with systolic blood pressure at mean age 66.4 years, after adjustment for sex, blood pressure at mean age 61.5 years, as well as other covariates. A one s.d. increase in linear growth between 2 and 11 years was associated with an OR of 0.61 for hypertension at mean age 66.4 years. Contrary to previous studies, we have shown an inverse association between childhood growth and adult blood pressure. There were, however, no associations between childhood growth and systolic blood pressure at mean age 61.5 years indicating that the beneficial effects of a more rapid than expected childhood growth might become more apparent with increasing age. PMID- 26654275 TI - Dimensional Evolution of Polyphenylenes: Expanding in All Directions. AB - Polyphenylenes (PPs) represent a class of conjugated polymers that have been used in applications ranging from organic electronic devices, sensors, polymer film additives to manipulate their mechanical properties, and even fluorescent tags or nanocarriers in biological media.1-3 The versatility of PPs stem from innovative synthetic strategies that have evolved throughout the years to provide avenues that precisely tune their architecture and function for specific purposes. This Review will cover the state of the art research on various PPs related to the relationship between their structure and resulting properties. PMID- 26654276 TI - Nutrient-Controlled Niche Differentiation of Western Lake Erie Cyanobacterial Populations Revealed via Metatranscriptomic Surveys. AB - Although toxic cyanobacterial blooms in western Lake Erie threaten drinking water supplies and are promoted by nutrient loading, the precise nutrient regime that selects specific cyanobacteria populations is poorly understood. Here, we assess shifts in cyanobacterial abundances and global gene-expression patterns in response to natural and manipulated gradients in nitrogen and phosphorus to identify gene pathways that facilitate dominance by different cyanobacteria. Gradients in soluble reactive phosphorus shaped cyanobacterial communities and elicited the largest transcriptomic responses. Under high-P conditions (closest to the mouth of the Maumee River), Anabaena and Planktothrix were the dominant cyanobacterial populations, and experimental P and ammonium enrichment promoted nitrogen fixation gene (nifH) expression in Anabaena. For Microcystis, experimental additions of P up-regulated genes involved in phage defense, genomic rearrangement, and nitrogen acquisition but led to lower abundances. Within offshore, low-P regions of the western basin of Lake Erie, Microcystis up regulated genes associated with P scavenging (pstSCAB, phoX) and dominated cyanobacterial communities. Experimental additions of ammonium and urea did not alter Microcystis abundances but did up-regulate protease inhibitors (aer and mcn gene sets) and microcystin synthetase genes (mcy), with urea enrichment yielding significant increases in microcystin concentrations. Our findings suggest that management plans that reduce P loads alone may not significantly reduce the risk of cyanobacterial blooms in western Lake Erie but rather may promote a shift among cyanobacterial populations (Microcystis, Anabaena, and Planktothrix) toward a greater dominance by toxic strains of Microcystis. PMID- 26654277 TI - [Complexity of social and healthcare coordination in addictions and the role of the nurse]. AB - The present article discusses the psychosocial impact of basic and advanced concepts, such as social support and prevention, as well as to establish a link between theoretical models related to the social sphere on one side, and the health aspects on the other. This work is based on the context of the influence on health shared by community psychology and social psychology. Starting from the historical background of current approaches, a review is presented of those first actions focused on the care plan and they are framed in a reaction model to the drug problem, which progressed to the current healthcare network model, through the creation of Spanish National Action Plan on Drugs. The complexity of the problem is then broken down into the following key elements: Multifactorial Model of Drugs and Addictions, importance of prevention, and social support. Subsequently, a description is presented on the different levels of the healthcare network, with their different resources. This is also illustrated using a coordination protocol. Finally, it features the nursing approach to drugs, with its contributions, particularly as regards the coordination of resources, and aspects that must be developed for improvement in this area. PMID- 26654278 TI - A Door Opens for Fibrodysplasia Ossificans Progressiva. AB - Fibrodysplasia ossificans progressiva (FOP), characterized by extra bone formation in soft tissues, is caused by a gain-of-function mutation in ACVR1, a transmembrane receptor. Recently, a potential treatment was developed by identifying a novel molecular mechanism underlying bone formation in FOP. These findings have opened the door to beating FOP. PMID- 26654279 TI - Crosslinking and Mass Spectrometry: An Integrated Technology to Understand the Structure and Function of Molecular Machines. AB - In recent years, chemical crosslinking of protein complexes and the identification of crosslinked residues by mass spectrometry (XL-MS; sometimes abbreviated as CX-MS) has become an important technique bridging mass spectrometry (MS) and structural biology. By now, XL-MS is well established and supported by publicly available resources as a convenient and versatile part of the structural biologist's toolbox. The combination of XL-MS with cryo-electron microscopy (cryo-EM) and/or integrative modeling is particularly promising to study the topology and structure of large protein assemblies. Among the targets studied so far are proteasomes, ribosomes, polymerases, chromatin remodelers, and photosystem complexes. Here we provide an overview of recent advances in XL-MS, the current state of the field, and a cursory outlook on future challenges. PMID- 26654280 TI - Cognitive effects of modafinil in patients with multiple sclerosis: A clinical trial. AB - PURPOSE/OBJECTIVE: To assess the efficacy of modafinil for the treatment of new learning and memory deficits and fatigue in multiple sclerosis. Only 1 previous study in the literature, to our knowledge, examined the effect of modafinil on cognition specifically in persons with multiple sclerosis. RESEARCH METHOD/DESIGN: Sixteen patients with a diagnosis of multiple sclerosis (MS) and documented new learning impairment completed the study. In a 5-week randomized, double-blinded, crossover design, participants received either a single daily oral dose of modafinil (200 mg) or placebo for 2 weeks. A 1-week washout period was included between study arms. RESULTS: No effect of modafinil was noted on learning and memory performance. Participants taking 200 mg of modafinil showed improvement in 1 of the 2 working memory measures administered, the Wechsler Adult Intelligence Scale-III (WAIS-III) Letter-Number Sequencing task, as compared with those on placebo. Treatment with modafinil did not have a beneficial effect in reducing self-reported fatigue. No changes were noted on the Modified Fatigue Impact Scale or the Fatigue Severity Scale with the treatment of modafinil, as compared with placebo. CONCLUSIONS/IMPLICATIONS: Findings indicate that 200 mg of modafinil has the potential to improve working memory in persons with MS. These findings suggest that modafinil may enhance aspects of cognition in persons with MS and may be an effective adjunct to clinical rehabilitation interventions. PMID- 26654281 TI - Ultralow-Loss CMOS Copper Plasmonic Waveguides. AB - Surface plasmon polaritons can give a unique opportunity to manipulate light at a scale well below the diffraction limit reducing the size of optical components down to that of nanoelectronic circuits. At the same time, plasmonics is mostly based on noble metals, which are not compatible with microelectronics manufacturing technologies. This prevents plasmonic components from integration with both silicon photonics and silicon microelectronics. Here, we demonstrate ultralow-loss copper plasmonic waveguides fabricated in a simple complementary metal-oxide semiconductor (CMOS) compatible process, which can outperform gold plasmonic waveguides simultaneously providing long (>40 MUm) propagation length and deep subwavelength (~lambda(2)/50, where lambda is the free-space wavelength) mode confinement in the telecommunication spectral range. These results create the backbone for the development of a CMOS plasmonic platform and its integration in future electronic chips. PMID- 26654282 TI - Epidemiological and biomechanical evaluation of airline baggage handling. AB - OBJECTIVES: Musculoskeletal disorders (MSDs) are prevalent among airline baggage handlers due to manual materials handling. In this study, the Nordic musculoskeletal questionnaire (NMQ), the revised National Institute for Occupational Safety and Health (NIOSH) lifting equation, and the University of Michigan 3D Static Strength Prediction ProgramTM (3DSSPP) were used to analyze MSDs among baggage handlers. METHODS: The NMQ was filled out by 209 baggage handlers and 46 arbitrarily selected baggage handlers were evaluated using the NIOSH method and 3DSSPP. RESULTS: The obtained results showed that the most common MSDs occurred in the lower back region. The next risky regions included knees, neck, and upper back, respectively. The NIOSH results confirmed that the subjects lifted loads heavier than the permitted limit and their lifting postures were inappropriate. The results of the 3DSSPP also indicated that compression forces exceeded the NIOSH limit in these awkward postures. CONCLUSIONS: Relying on this study, holding compulsory ergonomic lifting training courses could be proposed for workers and regulations adjusting an upper limit for maximum baggage weight must be also enacted in order to improve occupational health and prevent the prevalence of increasing MSDs. PMID- 26654283 TI - Timing of Infections in the Threespine Stickleback (Gasterosteus aculeatus) by Schistocephalus solidus in Alaska. AB - This study provides direct evidence for the timing of infections by Schistocephalus solidus in the threespine stickleback (Gasterosteus aculeatus) of south-central Alaska. Young-of-the-year fish in Cheney Lake were infected during their first summer within a few months after hatching in May-June. Infections appear to continue under ice cover on the lake during the subsequent fall and winter. Few, if any, 1-yr-old fish seemed to be infected for the first time, although 1-yr-old hosts with established parasites apparently acquired additional infections. PMID- 26654284 TI - Endovascular treatment of carotid-cavernous fistulae: Long-term efficacy and prognostic factors. AB - INTRODUCTION: Carotid-cavernous fistulae are rare and affect visual prognosis. Their clinical presentation is varied and delayed diagnosis is common. They require rapid neuro-radio-ophthalmologic management. PURPOSE: The goal of this study was to evaluate the long-term efficacy and prognostic factors for treatment of carotid-cavernous fistulas by embolization. MATERIALS AND METHODS: A total of 60 patients with direct (10/60, 17%) or indirect (50/60, 83%) carotid-cavernous fistulae suspected during ophthalmological examination underwent cerebral angiography from December 2003 to October 2013. Of these, 59 (59/60, 98%) patients were treated with embolization. Treatment response was assessed with a follow-up angiogram confirming the exclusion of the fistula, and clinically by resolution of the initial symptoms. RESULTS: The diagnosis was suspected on the basis of proptosis in 45 patients (45/60, 75%), corkscrew episcleral vessels in 38 patients (38/60, 63%), chemosis in 37 patients (37/60, 61%), and diplopia in 30 patients (30/60, 50%). The median delay in diagnosis was 5 +/- 5 months [0.5 to 24 months], and mean follow-up was 31 +/- 31.5 months [0.5-118 months]. Eighteen patients (18/60, 30%) were lost to follow-up. Clinical response was complete in 24 patients (24/42, 57%) and partial in 14 patients (14/42, 33.5%). Symptoms were stable in one patient (1/42, 2.5%) and worsened in 3 patients (3/42, 7%). Morbidity per procedure was 3.3% and there was no postoperative mortality. Forty patients (40/60, 67%) had radiological follow-up and 39 patients (39/40, 97.5%) had a complete exclusion of the fistula. The presence of diplopia on initial examination was more frequently associated with an incomplete cure (P=0.04). CONCLUSION: The combination of proptosis, corkscrew episcleral vessels and diplopia should rapidly lead to head imaging to search for a carotid cavernous fistula. Fistula embolization is a safe and effective treatment. The presence of diplopia on initial examination may be associated with a poorer outcome (P=0.044). PMID- 26654285 TI - [Postoperative imaging after ARGUS(r) II epiretinal prosthesis implantation in a patient with retinitis pigmentosa]. PMID- 26654286 TI - Prognosis of cerebral cavernomas: on to treatment decisions. PMID- 26654287 TI - Clinical course of untreated cerebral cavernous malformations: a meta-analysis of individual patient data. AB - BACKGROUND: Cerebral cavernous malformations (CCMs) can cause symptomatic intracranial haemorrhage (ICH), but the estimated risks are imprecise and predictors remain uncertain. We aimed to obtain precise estimates and predictors of the risk of ICH during untreated follow-up in an individual patient data meta analysis. METHODS: We invited investigators of published cohorts of people aged at least 16 years, identified by a systematic review of Ovid MEDLINE and Embase from inception to April 30, 2015, to provide individual patient data on clinical course from CCM diagnosis until first CCM treatment or last available follow-up. We used survival analysis to estimate the 5-year risk of symptomatic ICH due to CCMs (primary outcome), multivariable Cox regression to identify baseline predictors of outcome, and random-effects models to pool estimates in a meta analysis. FINDINGS: Among 1620 people in seven cohorts from six studies, 204 experienced ICH during 5197 person-years of follow-up (Kaplan-Meier estimated 5 year risk 15.8%, 95% CI 13.7-17.9). The primary outcome of ICH within 5 years of CCM diagnosis was associated with clinical presentation with ICH or new focal neurological deficit (FND) without brain imaging evidence of recent haemorrhage versus other modes of presentation (hazard ratio 5.6, 95% CI 3.2-9.7) and with brainstem CCM location versus other locations (4.4, 2.3-8.6), but age, sex, and CCM multiplicity did not add independent prognostic information. The 5-year estimated risk of ICH during untreated follow-up was 3.8% (95% CI 2.1-5.5) for 718 people with non-brainstem CCM presenting without ICH or FND, 8.0% (0.1-15.9) for 80 people with brainstem CCM presenting without ICH or FND, 18.4% (13.3-23.5) for 327 people with non-brainstem CCM presenting with ICH or FND, and 30.8% (26.3 35.2) for 495 people with brainstem CCM presenting with ICH or FND. INTERPRETATION: Mode of clinical presentation and CCM location are independently associated with ICH within 5 years of CCM diagnosis. These findings can inform decisions about CCM treatment. FUNDING: UK Medical Research Council, Chief Scientist Office of the Scottish Government, and UK Stroke Association. PMID- 26654288 TI - A Decrease in the Volume of Gray Matter as a Risk Factor for Postoperative Delirium Revealed by an Atlas-based Method. AB - OBJECTIVE: Delirium is a common syndrome in older patients after surgery. Although an atrophic change in the whole brain may be a potential risk factor for postoperative delirium, the anatomically specific change related to the vulnerability still remains a significant issue. DESIGN: Prospective study. SETTING: University hospital. PARTICIPANTS: 116 consecutive patients who underwent elective cardiac operations. MEASUREMENTS: Before the surgery, magnetic resonance imaging (MRI) was evaluated. The MRI data were processed to calculate the absolute volumes of the predefined region of interest using Statistical Parametrical Mapping 8 with an atlas-based method. The evaluated volume was expressed as the fraction (%) of the total intracranial volume. Postoperative delirium was diagnosed according to the DSM-IV criteria for delirium. RESULTS: Delirium developed in 19 of 116 patients (16.4%) with an age range from 58 to 84 years. Based on a comparison with the age-controlled non-delirium patients (over 57 years; n = 65), a statistically significant reduction in the gray matter volume of the delirium patients was observed in the defined gyri of the temporal and limbic lobes. Moreover, a moderate value (>0.8) of area under the curve to predict postoperative delirium was revealed by receiver operating characteristic curve analysis of the gyri of temporal lobe. CONCLUSIONS: The decreased volume of gray matter could be associated with the vulnerability to delirium after surgery. The atlas-based method would be a potential tool to pre-screen the brain structure of individual patients for the prediction of postoperative delirium. PMID- 26654289 TI - Modeling Nanotube Caps: The Relationship Between Fullerenes and Caps. AB - We present a novel method to calculate energies of nanotube caps with different levels of accuracy and a comprehensive study of its application to the IPR caps of the (10,0) carbon nanotube. The two most stable caps for (10,0) have 42 atoms, an energy of 8.7 eV, and correspond to sections of the third most abundant fullerene, C84. These caps are isoenergetic with a chemically unstable cap with 40 carbon atoms related to a C80 isomer that is also chemically unstable. Energies for the other caps are between 9.3 and 10 eV. A method to calculate cap energetics with fullerenes with an error less than 3% is also presented. PMID- 26654290 TI - My Burning Experience.... A Trainee Perspective. PMID- 26654291 TI - A pilot study of a hand-held camera in a busy burn centre: Prediction of patient length of recuperation with wound temperature. AB - AIM: The aim of our study was to evaluate temperature differences of burns looking at their prognostic ability to predict healing at the 21 day mark. MATERIALS AND METHOD: Thirty two burns in 26 patients aged 1-71 years old were photographed with a FLIR T650 camera. Environment, reflected, and body core temperature of the patients were measured. Skin emissivity was constant 0.98. Pictures were analyzed with R&D FLIR Software. Minimal and average burn temperatures and skin temperature in 255 pixel squares were measured. Patients were divided into healed and not healed groups. Statistical analysis was performed with SPSS 20 (IBM Armonk, USA) and p<0.05 was significant. RESULTS: There were 25 healed and 7 non-healed burns at 21 days. Healed burns were significantly warmer than non-healed burns (p<0.05). There was a statistically significant strong, negative correlation between the difference of minimal burns temperatures and healthy skin temperatures with days needed to heal the burns (p=0.001; rho=-0.564). CONCLUSION: Infrared camera seems to be useful equipment in predicting burns' healing time. However further clinical studies need to be done. PMID- 26654292 TI - Sound Environments Surrounding Preterm Infants Within an Occupied Closed Incubator. AB - Preterm infants often exhibit functional disorders due to the stressful environment in the neonatal intensive care unit (NICU). The sound pressure level (SPL) in the NICU is often much higher than the levels recommended by the American Academy of Pediatrics. Our study aims to describe the SPL and sound frequency levels surrounding preterm infants within closed incubators that utilize high frequency oscillation (HFO) or nasal directional positive airway pressure (nasal-DPAP) respiratory settings. DESIGN AND METHODS: This is a descriptive research study of eight preterm infants (corrected age<33 weeks) exposed to the equipment when placed in an incubator. The actual noise levels were observed and the results were compared to the recommendations made by neonatal experts. RESULTS: Increased noise levels, which have reported to affect neonates' ability to self-regulate, could increase the risk of developing attention deficit disorder, and may result in tachycardia, bradycardia, increased intracranial pressure, and hypoxia. CONCLUSION AND PRACTICE IMPLICATIONS: The care provider should closely assess for adverse effects of higher sound levels generated by different modes of respiratory support and take measures to ensure that preterm infants are protected from exposure to noise exceeding the optimal safe levels. PMID- 26654293 TI - Adversity, attachment, and mentalizing. AB - The papers in this special issue offer evidence of personality disorder as a dysfunction of higher-order cognition, which is conceptualized variously as a disorder of mentalizing, metacognition, mindfulness, social cognition and reflective function. While there may be differences in the scope of these concepts, they all imply that higher-order mental processing is at the core of personality function. In this commentary, the authors use mentalizing as an umbrella term for these concepts, and argue that it is the complex interaction of adversity, attachment and mentalizing that leads to the characteristic symptoms of borderline personality disorder and other personality disorders. Evidence is provided from the papers in this special issue, comments made on the findings and further avenues for research are recommended. PMID- 26654294 TI - Erythema ab igne. PMID- 26654295 TI - Ultrafast Singlet Fission in a Push-Pull Low-Bandgap Polymer Film. AB - Excited-state dynamics in poly[4,6-(dodecyl-thieno[3,4-b]thiophene-2-carboxylate) alt-2,6-(4,8-dioctoxylbenzo[1,2-b:4,5-b]dithiophene)] (PTB1) was studied by transient absorption spectroscopy. Upon photoexcitation at 400 nm, an additional transient species is promptly generated along with singlet excitons and survives up to nanoseconds, while singlet excitons disappear completely. In order to assign the long-lived species, we measured transient absorption spectra over the wide spectral range from 900 to 2500 nm. As a result, we found that the long lived species is ascribed not to polarons but to triplet excitons, which is formed through the ultrafast singlet fission (SF). We discuss the ultrafast SF mechanism in push-pull low-bandgap polymer PTB1 films on the basis of the excited state dynamics under various excitation wavelengths and intensities. PMID- 26654296 TI - Assessing the impacts of sediments from dredging on corals. AB - There is a need to develop water quality thresholds for dredging near coral reefs that can relate physical pressures to biological responses and define exposure conditions above which effects could occur. Water quality characteristics during dredging have, however, not been well described. Using information from several major dredging projects, we describe sediment particle sizes in the water column/seabed, suspended sediment concentrations at different temporal scales during natural and dredging-related turbidity events, and changes in light quantity/quality underneath plumes. These conditions differ considerably from those used in past laboratory studies of the effects of sediments on corals. The review also discusses other problems associated with using information from past studies for developing thresholds such as the existence of multiple different and inter-connected cause-effect pathways (which can confuse/confound interpretations), the use of sediment proxies, and the reliance on information from sediment traps to justify exposure regimes in sedimentation experiments. PMID- 26654297 TI - Productivity and sea surface temperature are correlated with the pelagic larval duration of damselfishes in the Red Sea. AB - We examined the variation of pelagic larval durations (PLDs) among three damselfishes, Dascyllus aruanus, D. marginatus, and D. trimaculatus, which live under the influence of an environmental gradient in the Red Sea. PLDs were significantly correlated with latitude, sea surface temperature (SST), and primary production (CHLA; chlorophyll a concentrations). We find a consistent decrease in PLDs with increasing SST and primary production (CHLA) towards the southern Red Sea among all species. This trend is likely related to higher food availability and increased metabolic rates in that region. We suggest that food availability is a potentially stronger driver of variation in PLD than temperature, especially in highly oligotrophic regions. Additionally, variations in PLDs were particularly high among specimens of D. marginatus, suggesting a stronger response to local environmental differences for endemic species. We also report the first average PLD for this species over a broad geographic range (19.82 +/- 2.92 days). PMID- 26654298 TI - The mechanism and risk factors of clopidogrel-induced liver injury. AB - CONTEXT AND OBJECTIVE: Clopidogrel (CLP) is a prodrug which is widely used as a platelet aggregation inhibitor. Hepatotoxicity is rare but a potentially serious adverse reaction that is associated with CLP. Thiophene in CLP (the thienopyridine derivative) is a group that is easily oxidated by cytochrome P450 enzymes (CYP450s) to generate reactive metabolites (RMs), it may be implicated in the mechanism of CLP-induced hepatotoxicity. CYP2C19 and CYP2B6 are important CYP450s involved in the metabolism and activation of CLP, and the aim of this study is to investigate whether the metabolites of CYP2C19 and CYP2B6 are associated with the CLP-induced liver injury. METHOD: Primary rat hepatocytes are applied to evaluate the hepatotoxicity of CLP. Glutathione-depleted mouse model is used to evaluate whether this toxicity of CLP is metabolized by CYP450s. We also used HepG2 cells co-incubated with recombinant CYP2B6 and CYP2C19 enzymes to further assess whether the metabolites of CYP2C19 and CYP2B6 are associated with the CLP-induced hepatocellular toxicity. RESULT: CLP in high dose (100 MUM and 300 MUM) showed cytotoxicity in primary rat hepatocytes assay. Administration of CLP with l-buthionine-S, R-sulfoxinine (BSO) for seven days enhanced the liver injury of CLP. The level of ALT, AST and TBIL in plasma increased significantly, and the histopathological results showed the obvious liver injury; Pretreatment of 1-aminobenzotriazole, a nonspecific inhibitor of CYP450s, suppressed CLP induced hepatotoxicity; CLP showed a dose-dependent toxicity in HepG2/CYP2C19 enzyme and HepG2/CYP2B6 enzyme models. CONCLUSION: High activities of CYP2C19 and CYP2B6 are the risk factors for hepatocellular toxicity of CLP. PMID- 26654299 TI - Biomarkers of general stress in mussels as common indicators for marine biomonitoring programmes in Europe: The ICON experience. AB - This study investigated whether general stress biomarkers in mussels can be applied as common first-tier biomarkers in regional biomonitoring programmes in the North Sea (including Iceland) and western Mediterranean Sea. Stress on Stress (SoS) and lysosomal membrane stability (LMS) biomarkers were analysed in resident mussels (Mytilus sp.) from 8 coastal sites and in transplanted mussels (Mytilus galloprovincialis) from two Spanish Mediterranean coastal sites. The assessment of results, as input to pollution monitoring strategies, was performed jointly for LMS and SoS data from the two regions. Contaminant body burden of the mussels was compared with biomarker results. The results demonstrated that these two general and non-expensive stress biomarkers in mussel can be applied throughout European waters, providing a cost-effective and harmonised approach to screen contaminant-related biological effects within the framework of wide-scale pollution biomonitoring programmes, such as that proposed by the European Union, i.e. the Marine Strategy Framework Directive. PMID- 26654300 TI - [Precise thoracic surgery: new era of minimally invasive surgery]. AB - Precise surgery is based on the integrated application of modern science and technology and integrated innovation of surgical technology revolution features. It is built in high-end digital medical bases. The purpose of precise surgery is to achieve accurate lesion resection, minimize injury, improve the quality of life and reduce the risk of surgery. In this paper we forward new concept of precise thoracic surgery. An overview was made on the development of precise surgery with great support of virtual reality technology, augmented reality technology and image acquisition technology. Finally the paper illustrated the prospect of precise of thoracic surgery from the following aspects: preoperative planning, the choice of surgical approach, precise tumor localization, postoperative immediate 3-dimension multi modality imaging evaluation. PMID- 26654301 TI - [Current situation and confusion of sublobar resection for early stage lung cancer]. AB - Lobectomy with lymph node dissection has long been the standard surgical procedure for non-small cell lung cancer. However, the increased identification of smaller and smaller and even more indolent tumors by advanced imaging screening rekindled the interest of sublobar resection. Still, existing evidence only supports sublobar resection for radiologically or pathologically "very early" stage tumors or high-risk patients. Ongoing randomized controlled trials in America, Japan and Europe will address the issue of "radical" application of sublobar resection, as well as an elderly patient trial for "compromized" application initiated by us. These efforts will delineate the utility of sublobar resection in patients with non-small cell lung cancer. PMID- 26654302 TI - [Comparison of thoracoscopic anatomical partial-lobectomy and thoracoscopic lobectomy on the patients with pT1aN0M0 peripheral non-small cell lung cancer]. AB - OBJECTIVE: To compare the short-term outcomes and pulmonary function loss between thoracoscopic anatomical partial-lobectomy and thoracoscopic lobectomy on the patients with pT1aN0M0 peripheral non-small cell lung cancer. METHODS: The clinical data of 191 patients with pT1aN0M0 peripheral non-small cell lung cancer received thoracoscopic anatomical pneumonectomy between January 2013 and July 2013 in Department of Thoracic Surgery, Cancer Hospital Chinese Academy of Medical Sciences was analyze retrospectively. There were 71 patients underwent thoracoscopic anatomical partial-lobectomy and 120 patients underwent thoracoscopic lobectomy. Demographic features, operation time, blood loss, number of dissected lymph nodes, chest tube duration, drainage volume, postoperative hospital stay, postoperative complications, two-year progress and pulmonary function loss of FEV1% (percentage of the predicted forced expiratory volume in 1 second) at 6 months were retrospectively reviewed and compared by t test, rank sum test, chi2 test and Fisher exact test. RESULTS: There were no significant differences in operation time, blood loss, number of dissected lymph nodes, chest tube duration, drainage volume, postoperative hospital stay, and postoperative complication rate (P > 0.05). The two-year progress rate between two groups did not differ significantly either (1.4% vs. 1.7%, chi2 = 0.000, P = 1.000). Pulmonary function loss of FEV1% at 6 months was significantly smaller in thoracoscopic anatomical partial lobectomy group than thoracoscopic lobectomy group (14% +/- 4% vs. 16% +/- 4%, t = 2.408, P = 0.017). CONCLUSIONS: Thoracoscopic anatomical partial-lobectomy is safe and feasible for patients with pT1aN0M0 peripheral non-small cell lung cancer. It could achieve equal short-term effect and reserve more pulmonary function compared with thoracoscopic lobectomy. PMID- 26654303 TI - [Clinical features and treatment outcome of multiple primary lung cancer patients with different imaging performance]. AB - OBJECTIVE: To analyze the clinical characteristics and follow up record of patients with synchronous multiple lung cancers (SMLC). METHODS: The medical records of 1 868 lung cancer patients who underwent surgical treatments From January 2007 to December 2014 were reviewed, in which 103 patients were diagnosed SMLC by Martini and American College of Chest Physicians modified guideline. The average age was 60.5 years, including 34 male and 69 female patients. According to consolidation/tumor ratio (CTR) on thin-section computed tomography, 103 cases were classified into three groups: group A (multiple ground-glass opacities, CTR <= 50%), group B (with one solid dominant nodules, CTR > 50%), group C (with two solid dominant nodules). The surgical procedure was determined according to CT findings and respiratory function. The Kaplan-Meier method was used to analyze the duration of recurrence-free survival (RFS) and over-all survival (OS), and differences were assessed using the Log-rank test. Multivariate analysis using the Cox proportional hazards models was used to assess the potential independent effects on RFS or OS. RESULTS: There were 38 patients in group A (36.9%), 40 patients in group B (38.8%) and 25 patients (24.3%) in group C. More female (73.7% vs. 48.0%, chi2 = 4.291, P = 0.038), less smoker (21.1% vs. 44.0%, 2 = 3.770, P = 0.052), younger (56.2 years old vs. 65.9 years old, t = -4.172, P = 0.000) and less tumor size (1.24 cm vs. 2.31 cm, t = -4.573, P = 0.000) patients in group A than in group C. The 3, 5-year RFS were 80.3% and 64.9% for all patients, respectively. The 3, 5-year OS were 87.3% and 68.6% for all patients, respectively. The 3, 5-year RFS were 100% and 100% in group A, 77.7% and 51.8% in group B, 59.6% and 44.7% in group C (P = 0.029). No significance were found in OS between the three groups (P = 0.214). Multivariate Cox analysis demonstrated that size of dominant nodule larger than 2 cm (HR = 4.475, 95% CI: 1.138 to 17.604, P = 0.032) is associated with poor prognosis, whereas postoperative chemotherapy did not affect RFS. CONCLUSIONS: Multifocal ground-glass opacities and multiple solid lung cancers are different in nature. RFS of patients with SMLC is strongly affected tumor size. Surgical resection is effective and should be performed specifically to patients. PMID- 26654304 TI - [Analysis of the effect of different pathological subtypes to prognosis in stage I pulmonary adenocarcinoma]. AB - OBJECTIVE: To analyze the prognostic value of the new classification (proposed by International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society) in stage I pulmonary adenocarcinoma. METHODS: Pathological slides of 328 cases of stage I pulmonary invasive adenocarcinoma were reviewed according to the new classification. The patients received operation in Department of Thoracic Surgery of Zhongshan Hospital affiliated to Fudan University from January 2005 to December 2009. There were 145 male and 183 female patients with an average age of (59 +/- 10) years (ranging from 34 to 82 years). Clinical, pathological, and survival data were retrospectively analyzed. Kaplan-Meier method was used for analysis of survival, and Cox regression analysis was used for finding out prognostic factors. RESULTS: Five-year progression-free survival rate and overall survival rate of lepidic predominant subtype were both 100%. Five-year progression-free survival rate of patients with micropapillary component (49.3%) was significantly lower than that of patients without micropapillary component (75.4%, chi2 = 8.154, P = 0.004). Regression analysis showed that tumor size is an independent prognostic factor of death (HR = 1.967, 95% CI: 1.507 to 2.567, P = 0.000) and recurrence (HR = 1.796, 95% CI: 1.469 to 2.198, P = 0.000). In subgroup analysis, the presence of solid component (HR = 1.985, 95% CI: 1.013 to 3.888, P = 0.046) and tumor size (HR = 1.941, 95% CI: 1.455 to 2.589, P = 0.000) were independent prognostic factors of recurrence for stage IB pulmonary adenocarcinoma. CONCLUSIONS: The new classification of adenocarcinoma is of prognostic value in stage I pulmonary adenocarcinoma. The presence of solid or micropapillary component impacts on survival. Detailed record of each component in tumor is necessary. PMID- 26654305 TI - [Long term outcomes of patients with stage I lung cancer treated by single direction video-assisted thoracoscopic surgery lobectomy or segmentectomy]. AB - OBJECTIVE: To observe the outcome of stage I lung cancer treated by single direction video-assisted thoracoscopic surgery (SD-VATS) major lung resection. METHODS: Between May 2006 and December 2013, a total of 3 743 patients with lung cancer underwent surgical treatment in Department of Thoracic Surgery, West China Hospital. The clinical date of 783 patients with stage I lung cancer treated by SD-VATS lobectomy/segmentectomy was analyzed retrospectively. There were 388 males and 395 females with a mean age of (59 +/- 10) years (range 25 to 86 years). There were 740 cases of lobectomy and 43 cases of segmentectomy. Twenty patients underwent conversion to open thoracotomy. The methods of Kaplan-Meier survival analysis and Cox proportional hazard regression model were used to investigate the long term outcome and prognostic factors. RESULTS: The mean operating time was (145 +/- 54) minutes (range 70 to 460 minutes). The median intraoperative blood loss was 50 (70) ml (range 5 to 1 200 ml). The postoperative morbidity and 90-day mortality were 13.3% and 1.0%, respectively. 5.9% patients were lost to follow-up. Finally 730 patients were enrolled into prognostic analysis with a mean follow-up time of (37 +/- 18) months (range 5 to 92 months). The 5-year overall survival (OS), disease free survival (DFS), and cancer specific survival (CSS) were 83.8%, 74.4%, and 86.6%, respectively. The 5-year OS of IA and IB were 90.7% and 79.8% respectively. Univariate and multivariate analysis indicated that age >= 60 years (OR = 1.786, 95% CI: 1.081 to 2.948, P = 0.023), non-adenocarcinoma (OR = 1.647, 95% CI: 1.204 to 2.253, P = 0.002), and higher T status (OR = 2.709, 95% CI: 1.031 to 7.121, P = 0.043) were independently associated with poor OS; higher T status (OR = 5.118, 95% CI: 2.330 to 11.240, P = 0.000) and higher pathological stage status (OR = 0.369, 95% CI: 0.137 to 0.991, P = 0.048) were independently associated with poor DFS; non adenocarcinoma (OR = 1.717, 95% CI: 1.224 to 2.409, P = 0.002) and higher T status (OR = 5.029, 95% CI: 1.432 to 17.659, P = 0.012) were independently associated with poor CSS. CONCLUSION: SD-VATS lung cancer resection is a safe and feasible method for the treatment of stage I lung cancer resulting good outcomes. PMID- 26654306 TI - [Clinical feature of gallbladder cancer in Northwestern China: a report of 2 379 cases from 17 institutions]. AB - OBJECTIVE: To analyze the clinical features of patients with gallbladder cancer from 17 hospitals in 5 Northwestern provinces (autonomous region) of China from 2009 to 2013. METHODS: A total of 2 379 cases with gallbladder cancer in 17 tertiary hospitals from 5 Northwestern provinces of China from January 2009 to December 2013 were reviewed retrospectively. The clinical data was collected by standardized "Questionnaire for Clinical Survey of Gallbladder Cancer in Northwestern Area of China". chi2 test was used to analyze the data. RESULTS: (1) Gallbladder cancer from 17 hospitals accounted for 1.6%-6.8% of all bile tract diseases from 2009 to 2013 in Northwestern China, average was 2.7%. Gallbladder cancer accounted for 0.4%-0.9% of abdominal surgery, average was 0.7%. (2) The incidence of gallbladder cancer was higher in the aged females, the ration of female to male was 1.0 to 2.1. The average age of gallbladder cancer was (64 +/- 11) years. The occupation of patients was mainly farmers (chi2 = 147.10, P < 0.01). (3) 57.2% of the gallbladder cancers were associated with gallstones. (4) The main pathological patterns of gallbladder cancer were moderate and poor differentiated adenocarcinoma, showing an aggressive malignancy. TNM stage IV accounted for 55.1% of all cases, which was associated with the poor prognosis. (5) The curative resection rate was 30.4%. CONCLUSIONS: Gallbladder cancer is common in the aged females and mainly at advanced stage. The screening and follow up of high-risk groups with ultrasound and other methods regularly could increase the early diagnosis rate of gallbladder cancer, aggressive surgical resection combined with other comprehensive treatment could improve the prognosis of patients. PMID- 26654307 TI - [Percutaneous minimally invasive pedicle screw fixation for cervical fracture using intraoperative three-dimensional fluoroscopy-based navigation]. AB - OBJECTIVE: To retrospectively assess the feasibility and safety of percutaneous minimally invasive pedicle screw fixation for cervical fracture using intraoperative three-dimensional fluoroscopy-based navigation. METHODS: Thirty patients admitted from April 2012 to May 2014 in Beijing Jishuitan Hospital with cervical fracture underwent pedicle screw fixation using intraoperative three dimensional fluoroscopy-based navigation, with 8 patients using minimally invasive technique (CAOS-MIS group), and the other 22 patients using conventional open approach (CAOS-open group). Operative time, blood loss and postoperative neurovascular complications were recorded. Screw positions were studied by postoperative CT scan. All patients were followed up for at least 6 months. Neck visual analogue score (VAS) and American Spinal Injury Association (ASIA) classification were evaluated preoperatively and at 6-month follow-up. Independent-sample t test and Chi-Square test were used for statistical analysis. RESULTS: Operation time was (139 +/- 18) minutes and blood loss was (73 +/- 40) ml in CAOS-MIS group and correspondingly (154 +/- 42) minutes and (296 +/- 171) ml in CAOS-open group. The blood loss in CAOS-MIS group was significantly lower than that in CAOS-open group (t = 5.695, P < 0.01). No screw-related injury to nerve or vertebral artery was observed. Thirty-four screws were placed in CAOS MIS group with 28 screws (82.4%) classified as Grade I, meanwhile in CAOS-open group 108 screws were placed with 96 screws (88.9%) classified as Grade I. There was no statistical difference between the two groups (chi2 = 0.998, P > 0.01). VAS score showed no statistical difference preoperatively (t = 0.334, P > 0.01), however statistical difference existed at 6 months follow-up (t = 4.111, P < 0.01) with (0.4 +/- 0.5) in CAOS-MIS group and (1.5 +/- 0.7) in CAOS-open group. There were 1 patient from class B to improve to D, 1 case from D to E in CAOS-MIS group, and 1 patient from class A to improve to B, 1 case from B to D, 2 cases from C to D, 3 cases from D to E in CAOS-open group 6 months after surgery. Cervical X-ray demonstrated fractures healed well in all cases at 6 months follow up. CONCLUSION: It is feasible and safe for percutaneous minimally invasive pedicle screw fixation for cervical fracture using intraoperative three dimensional fluoroscopy-based navigation, which can also decreases the incidence of postoperative neck pain. PMID- 26654308 TI - [The mid-term follow-up of revision total knee athroplasty]. AB - OBJECTIVE: To summarize the mid-term follow-up results of revision of total knee arthroplasty and compare the different strategies for infective revisions. METHODS: All of 45 patients (47 operated knees) lived in Beijing were treated from April 1989 to October 2010 in Arthritis Clinic and Research Center, Peking University People's Hospital. There were 6 male and 39 female patients, who aged from 31 to 77 years (mean (62 +/- 11) years). The function of knee, satisfaction and imaging then were compared retrospectively. American Knee Society Scores (KSS), Western Ontario & McMaster University Osteoarthritis Index (WOMAC), the medical outcomes study item short form health survey (SF-36) scales and satisfaction/pain visual analogue scales (VAS) of patients were evaluated. The patients were divided into infection group (33 patients, 34 knees) and non infection group (12 patients, 12 knees) according to the indication of revision of total knee arthroplasty and compared by t-tests. RESULTS: The time from operation to follow-up was 1 year and 2 months to 17 years. The mid-term follow up time was 8 years 3 months. There were significant improvements of KSS clinical and function scores (from 66.9 +/- 28.0 and 44.4 +/- 37.6 to 25.4 +/- 24.2 and 10.0 +/- 24.8, t = 7.043 and 3.797, both P = 0.001). Patients of infection group had lower KSS clinical and function scores than non-infection group before operation, and lower Society Function (t = 2.225, 3.520 and 2.885, P = 0.035, 0.002 and 0.007). About the septic group, the II-stage group had significant better post-operation KSS function scores, Society Function, physical component summary, WOMAC functional score and WOMAC score than I-stage group (t = 2.160 3.268, P = 0.004-0.042). The 1-year, 2-year, 6-year, 17-year survival rate were 83.6%, 78.7%, 62.1%, 44.5%. CONCLUSIONS: Revision total knee arthroplasty is an effective method for solving the failure of primary total knee arthroplasty. It can improve the pain and activity difficulty following the failure of primary total knee arthroplasty, and partially improve function along with quality of life. The results of non-infection group are better than infection group. There may be better results for II-stage revision total knee arthroplasty than I-stage revision. Both I-stage and II-stage revision total knee arthroplasty are effective. PMID- 26654309 TI - [Closed reduction and percutaneous pinning in treatment of "irreducible" supracondylar humerus fractures in children]. AB - OBJECTIVE: To evaluate the clinical effects of closed reduction and percutaneous pinning in treatment of "irreducible" supracondylar humeral fractures in children. METHODS: Seventy-six consecutive children of Gartland III supracondylar humeral fractures treated in the Department of Pediatric Orthopedics of the Third Affiliated Hospital of Southern Medical University from July 2011 to July 2013 were analyzed retrospectively, of which 69 were extension type fractures and 7 were flexion type. There were 52 male and 24 female patients with an average age of 6.5 years (range 1.6 to 13 years). The average time from injury to operation was 6.8 hours (range 4 to 48 hours). The mechanism of injury included 15 cases of high falling, and 61 cases of falling to the ground while walking or running. All cases were treated via closed reduction and percutaneous pinning. The radiographs were assessed every follow-up, including the healing and function of the elbow. RESULTS: No major complications such as osteofascial compartment syndrome or neurovascular injuries occurred in these patients. Two cases with neurological injuries before the surgery were recovered fully after the surgery. According to Flynn criteria at follow-up evolution, 71 cases were excellent, and 5 were good. CONCLUSIONS: For the treatment of Gartland type III supracondylar humerus fractures in children, including "irreducible" supracondylar fractures of the humerus, closed reduction and percutaneous pinning is a safe and minimally invasive procedure, by which good fractures reductions and postoperative functions of the elbow can be achieved. PMID- 26654310 TI - [Multisession cyberknife radiosurgery for cavernous sinus hemangiomas: medium- and long-term outcomes]. AB - OBJECTIVE: To investigate the medium- and long-term outcomes of multisession cyberknife radiosurgery intreating cavernous sinus hemangiomas (CSH). METHODS: Between January 2008 and February 2012, 45 patients with CSH, including 35 female and 10 male patients with a mean age of 53 years (range: 26-80 years), underwent multisession cyberknife radiosurgery. The mean diameter of the CSH was 47.0 mm (range: 23.0-75.0 mm). The tumor volume ranged from 2.9 to 140.1 cm3, with a mean of 40.1 cm3. Eleven giant CSH with tumor volume >= 40.0 cm3 were irradiated by cyberknife in 4 fractions, 28 large tumors with tumor volume 10.0-40.0 cm3 in 3 fractions, 4 tumors with tumor volume 5.0-10.0 cm3 in 2 fractions, 2 small tumors with tumor volume <= 5.0 cm3 in 1 fraction. After the treatment, all patients had regular clinical and radiological follow-up at 6-month intervals. A combination of the neurologic examination and MRI information was used to evaluate the overall response. RESULTS: All patients were followed up for 22-70 months with a mean of 37.7 months. One patient died of stroke 3 years post cyberknife, but the follow-up MRI showed that the CSH shrank in volume. Eight patients with giant CSH had slight headache after finishing cyberknife radiosurgery, and relieved with mannitol and dexamethasone treatment. Neurological deficits in patients had improved or disappeared at 6 to 12 months post cyberknife. None of these patients showed any deterioration in symptoms or new cranial nerve deficits during the follow-up. Latest follow-up imaging demonstrated that tumors decrease > 80% in 15 patients, > 60% to 80% in 18 patients (including the death patient), 40%-60% in 12 patients post cyberknife. Two patients reported occurrence of seizures and maintaining seizure control after antiepileptic drugs administration. CONCLUSIONS: Multisession cyberknife radiosurgery is confirmed to provide medium and long-term local tumor control and symptom improvement. It is a safe and effective treatment modality for CSH, and may serve as a promising treatment option in the future. PMID- 26654311 TI - [Combined application of neuroendoscope and laparoscope in ventriculo-peritoneal shunt for treatment of communicating hydrocephalus]. AB - OBJECTIVE: To summarize the clinical efficacy of ventriculo-peritoneal shunt (VPS) assisted by neuroendoscopy and laparoscopy for treatment of communicating hydrocephalus. METHODS: From January 2010 to January 2014, 209 cases (male 93, female 116) who suffered communicating hydrocephalus performed VPS with neuroendoscopy and laparoscopy in Department of Neurosurgery of People's Liberation Army General Hospital. The age of the patients were from 7 months to 79 years (mean 38.1 years), average duration were 20 days to 4 years (mean (2.4 +/- 0.7) months). Neuroendoscopy and laparoscopy were used to help respectively to place shunt catheter to better position, both in the ventricle and peritoneal cavity. The effect of subsequent shunt system survival was analyzed with Kaplan Meier survival analysis. RESULTS: There were 209 patients received 255 times of VPS. All operations were successfully completed. No craniotomy or open operation were needed for technical-related complications. Forty-six revisions were performed in all patients. After the operation, 203 patients with hydrocephalus improved at different level after surgery. Thirteen cases occurred intracranial hypotension syndrome and improved after the pressure adjusted. All patients were followed up for 1 month to 4 years, with a median follow-up time of 2.1 years, while the shunt system efficiencies were 91.0%, 86.7%, 83.9% and 82.0% respectively from the end of the 1st year to the end of the 4th year. CONCLUSIONS: For VPS, neuroendoscopy and laparoscopy can respectively help to place shunt catheter to better position, both in the ventricle and peritoneal cavity. Hence, the combination of these two modalities can reduce the failure rate of shunt catheter insertion and has significant impact on shunt system survival. PMID- 26654312 TI - [Early-stage lung cancer manifested as ground-glass opacity]. AB - The incidence of ground-glass opacity (GGO)-dominant lung cancer is rising in China. The review is focused on the diagnosis and therapy for GGO-dominant lung cancer. CT screening in high-risk groups is recommended for early diagnosis of GGO-dominant lung cancer. The early diagnosis of GGO-dominant lung cancer depends on dynamic observation on the chest CT. Non-surgical biopsy or PET/CT has limited diagnostic value in GGO-dominant lung cancer. Video-assisted Thoracoscopic resection (VATS) is the mainstream treatment for GGO-dominant lung cancer. Single port VATS, VATS segmentectomy, robot-assisted VATS, and subxiphoid VATS are the new directions of minimally invasive surgery. GGO intraoperative localization can be integrated using a variety of models. Sublobectomy could be used in the therapy for adenocarcinoma in situ, minimally invasive adenocarcinoma or pure GGO with 2.0 cm or less in diameter. Surgery for multiple GGO need an individualized strategy. PMID- 26654313 TI - [Anatomic segmentectomy for early stage non-small cell lung cancer]. AB - Anatomic segmentectomy is alternative to lobectomy for the surgical treatment of selected patients with early stage non-small cell lung cancer. Segmentectomy can reserve more pulmonary function in such patients. Emerging evidence suggests that segmentectomy may offer survival outcomes approaching that of lobectomy for lung cancer patients whose disease meets the following criteria: stage IA disease with no regional lymph node metastasis; tumor up to 2 cm in diameter; located in the periphery of lung; and predominantly ground-glass appearance on CT imaging. Compare with wedge resection, segmentectomy obtained the best results. Nevertheless, the evidence is currently still limited, and the above criteria are met only in a minority of patients. Large randomized trials are underway to define the clinical role of segmentectomy, and results are eagerly anticipated. Until that time, lobectomy should still be regarded as the standard therapy for patients with early stage non-small cell lung cancer. PMID- 26654314 TI - [Research progress in the relationship between pancreatic carcinoma and glycolysis]. AB - Pancreatic carcinoma is currently one of the most intractable malignant tumors of the digestive tract. Studies have found that the occurrence, progression and metastasis of pancreatic carcinoma are closely associated with the tumor's glycolytic pathway, most pancreatic carcinomas show the elevated glycolytic phenotype. To some extent, affecting the glycolytic pathway can influence the energy metabolism of the tumor without affecting the normal cells theoretically. Therefore, glycolytic pathway may become a new target for the treatment of pancreatic carcinoma. PMID- 26654315 TI - Progesterone change in the late follicular phase affects pregnancy rates both agonist and antagonist protocols in normoresponders: a case-controlled study in ICSI cycles. AB - OBJECTIVE: The aim of the presented study is to investigate the impact of progesterone change in the late follicular phase on the pregnancy rates of both agonist and antagonist protocols in normoresponders. STUDY DESIGN: A total of 201 normoresponder patients, who underwent embryo transfer were consecutively selected. 118 patients were stimulated using a long luteal GnRH agonist protocol and 83 using a flexible antagonist protocol. The level of change in late follicular phase progesterone was calculated according to the progesterone levels on the hCG day and pre-hCG day (1 or 2 days prior to hCG day) measurement. RESULTS: Clinical pregnancy rates were comparable between long luteal and antagonist group (35.6 and 41%, respectively). The incidence of progesterone elevation on the hCG day was 11% in long luteal and 18% in antagonist group (p = 0.16). In pregnant cycles, p levels both on the hCG day and pre-hCG day measurement were significantly higher in antagonist than agonist cycles (p = 0.029, p = 0.038, respectively). The change of p level was statistically significant in non-pregnant cycles both for the agonist (-0.17 +/- 0.07; 95% CI: 0.29 to -0.37) and antagonist groups (-0.18 +/- 0.07; 95%CI: -0.31 to -0.04). CONCLUSIONS: Late follicular phase progesterone levels were stable during the cycles of pregnant patients irrespective of the protocols and were shown to be higher in pregnant patients in antagonist cycles when compared to agonist cycles. PMID- 26654316 TI - Smart pumps and random safety audits in a Neonatal Intensive Care Unit: a new challenge for patient safety. AB - BACKGROUND: Random safety audits (RSA) are a safety tool enabling prevention of adverse events, but they have not been widely used in hospitals. The aim of this study was to use RSAs to assess and compare the frequency of appropriate use of infusion pump safety systems in a Neonatal Intensive Care Unit (NICU) before and after quality improvement interventions and to analyse the intravenous medication programming data. METHODS: Prospective, observational study comparing the frequency of appropriate use of Alaris(r) CC smart pumps through RSAs over two periods, from 1 January to 31 December 2012 and from 1 November 2014 to 31 January 2015. Appropriate use was defined as all evaluated variables being correctly programmed into the same device. Between the two periods they were established interventions to improve the use of pumps. The information recorded at the pumps with the new security system, also extracted for one year. RESULTS: Fifty-two measurements were collected during the first period and 160 measurements during the second period. The frequency of appropriate use was 73.13 % (117/160) in the second period versus 0 % (0/52) in the first period (p < 0.0001). Information was recorded on 44,924 infusions; in 46.03 % (20,680/44,924) of cases the drug name was recorded. In 2.5 % (532/20,680) of cases there was an attempt to exceed the absolute limit. CONCLUSIONS: Random Safety Audits were a very useful tool for detecting inappropriate use of pumps in the NICU. The improvement strategies were effective for improving appropriate use and programming of the intravenous medication infusion pumps in our NICU. PMID- 26654317 TI - An Assessment of Emergency Department Post-Cardiac Arrest Care Variation in Michigan. AB - Implementation of postarrest care by individual physicians and systems has been slow. Deadoption, or discontinuation of therapeutic hypothermia (TH) treatment targets, after recent prospective study results has not been well reported. This study assesses practices in the early stages of postarrest care across emergency departments (EDs) in Michigan. A 27-question Internet-based survey was distributed to EDs in Michigan in September 2013. To assess changes in practice after publication of Nielsen et al., we sent follow-up questions to all original respondents a year later. Observational data and descriptive statistics are reported. From the 142 EDs identified, we excluded critical access hospitals (N = 35), free standing EDs (N = 7), EDs that transfer critical patients to tertiary centers (N = 21), and exclusive children's hospitals (N = 3). Of the remaining 76 hospitals, we received 64 (84.2%) responses. We identified 15 respondents with a protocol to specifically initiate ED TH and transfer patients to a higher level of care. The 49 remaining were mostly teaching institutions (N = 34, 69%) and gave the ED physician the ability to initiate TH (N = 40, 82%). On follow-up 12 months later, we received 33/40 (83%) responses, of which only 5 indicated formal or informal change in TH practice or target temperature. There is substantial variation in the practice of ED postarrest care and initiation of TH across the state of Michigan, but few ED TH protocols were changed in a year's time. The consequences of postarrest treatment variability at the state and ED levels are likely under-recognized as an influence on outcome variation between regions. PMID- 26654318 TI - Evaluation of low-cost custom made VAC therapy compared with conventional wound dressings in the treatment of non-healing lower limb ulcers in lower socio economic group patients of Kashmir valley. AB - BACKGROUND: Negative-pressure wound therapy is a technique to achieve wound healing in patients with non-healing wounds of the lower limb; vacuum-assisted closure (VAC) therapy is a technique to accelerate the healing of non-healing ulcers that fail to heal on their own (primary healing) (Plast Reconstr Surg 117:193-209S, 2006). Delayed wound healing or non-healing of ulcers is a significant health problem, particularly in older adults. The efficacy of VAC dressings has been demonstrated in several randomized controlled studies, which have shown significantly faster wound healing rates compared to conventional wound therapy (Lancet 366:1704-10, 2005; J Wound Care 17:426-32, 2008). However, commercially available VAC is costly. The aim of using custom made VAC was decided by our team due to lower socio-economic status of patients taken for study who could not have afforded charges of commercially available VAC unit. OBJECTIVE: Objective was to evaluate VAC therapy compared with conventional dressings in the treatment of non-healing lower limb ulcers in lower socio economic patients. METHODS: Sixty patients of lower socio-economic status aged between 40 and 70 were prospectively studied for non-healing ulcers Wagner grade 2 or 3 and randomized into 2 groups. VAC dressing was kept for over a period of 2 7 weeks. Ulcers were treated until the wound closed spontaneously, surgically or until completion of the 50-day period, whichever was earlier. RESULTS: By seventh week, discharge disappeared in 96 % in VAC and only 54 % in conventional dressing group. Granulation tissue appeared in 100 % of patients in VAC group and only 63 % in conventional dressing group. The patients treated with VAC dressing in our study showed comparable wound reduction capabilities with an average wound size reduction of 56 % in comparison to conventional dressing group which had average wound size reduction of 29 %. Majority of wounds in VAC group got closed in 7 weeks. Patient satisfaction was excellent in the majority of patients in VAC group compared to those in conventional dressing group. CONCLUSION: The application of VACTM had shown good results in our study. PMID- 26654319 TI - Transformation of the Herbicide Sulcotrione into a Root Growth Enhancer Compound by Sequential Photolysis and Hydrolysis. AB - Xanthene-1,9-dione-3,4-dihydro-6-methylsulfonyl (1), the main product of sulcotrione phototransformation on plant leaves, was slowly hydrolyzed into 2 hydroxy-4-methylsulfonylbenzoic acid (2) and 1,3-cyclohexanedione (3) in aqueous solution. Interestingly, the rate of hydrolysis was significantly enhanced in the presence of roots of monocotyledonous plants, while the same treatment showed adverse effects on broadleaf weeds. Root growth enhancement varied according to the plant species and concentrations of compound 2, as shown with Zea mays roots. Compound 2 is a derivative of salicylic acid that is known to be a plant signaling messenger. Compound 2 was, therefore, able to mimic some known effects of this phytohormone. This work showed that a pesticide like sulcotrione was transformed into a compound exhibiting a positive impact on plant growth. This study exemplified a rarely reported situation where chemical and biological chain reactions transformed a xenobiotic into a compound exhibiting potential beneficial effects. PMID- 26654320 TI - Catenation through a Combination of Radical Templation and Ring-Closing Metathesis. AB - Synthesis of an electrochemically addressable [2]catenane has been achieved following formation by templation of a [2]pseudorotaxane employing radically enhanced molecular recognition between the bisradical dication obtained on reduction of the tetracationic cyclophane, cyclobis(paraquat-p-phenylene), and the radical cation generated on reduction of a viologen disubstituted with p xylylene units, both carrying tetraethylene glycol chains terminated by allyl groups. This inclusion complex was subjected to olefin ring-closing metathesis, which was observed to proceed under reduced conditions, to mechanically interlock the two components. Upon oxidation, Coulombic repulsion between the positively charged and mechanically interlocked components results in the adoption of a co conformation where the newly formed alkene resides inside the cavity of the tetracationic cyclophane. (1)H NMR spectroscopic analysis of this hexacationic [2]catenane shows a dramatic upfield shift of the resonances associated with the olefinic and allylic protons as a result of them residing inside the tetracationic component. Further analysis shows high diastereoselectivity during catenation, as only a single (Z)-isomer is formed. PMID- 26654321 TI - Evaluation of molecular detection of extrapulmonary tuberculosis and resistance to rifampicin with GeneXpert(r) MTB/RIF. AB - OBJECTIVE: We aimed to evaluate the GeneXpert(r) MTB/RIF test for the diagnosis of extrapulmonary tuberculosis. The test simultaneously detects Mycobacterium tuberculosis complex and resistance to rifampicin. METHODS: We analyzed 153 clinical samples collected in a tertiary hospital in Sfax, Tunisia, between 2013 and 2014. We performed the GeneXpert(r) test, a Ziehl-Neelsen and auramine rhodamine staining, conventional culture on MGIT 960 and LJ media, and we tested the resistance to anti-tuberculosis drugs on MGIT 960 and LJ media for each sample. Diagnosis was based on clinical, radiological, microbiological, pathological, and therapeutic data. RESULTS: We considered that 59 patients out of 153 presented with tuberculosis. PCR was positive in 50 samples and all of these samples were susceptible to rifampicin. Sensitivity, specificity, positive predictive value, and negative predictive value of the GeneXpert(r) test were 84.7%, 96.8%, 94.3%, and 91%, respectively, compared with diagnosis. We observed a statistically significant difference between the direct test and the GeneXpert(r) test, and between culture and the GeneXpert(r) test. No statistically significant difference was observed between pathological results and the GeneXpert(r) test. Sensitivity of the GeneXpert(r) test was 87.5% in biopsies, 80% in pus and abscesses, and 66.7% in biological fluids. All strains were susceptible to rifampicin with culture and GeneXpert(r) test. CONCLUSION: The GeneXpert(r) test helped detect a higher proportion of M. tuberculosis complex. It does not replace conventional diagnostic methods but it is a useful addition to achieve better sensitivity and obtain rapid results. PMID- 26654322 TI - Preventing healthcare-associated infections: Residents and attending physicians need better training in advanced isolation precautions. AB - OBJECTIVE: Compliance with advanced isolation precautions (IPs) is crucial to reduce healthcare-associated infections. Our aim was to evaluate physician's knowledge and attitudes related to IPs. METHODS: An online questionnaire was sent to our hospital's physicians (attending physicians and residents). RESULTS: A total of 111 physicians completed the questionnaire: 60 (54%) attending physicians and 51 (46%) residents. Overall, respondents had a poor knowledge of the three types of IPs, especially droplet precautions (13 correct answers, 11.7%) and airborne IP (17 correct answers, 16.3%). We observed a statistically significant difference between attending physicians and residents for the type of IP to prescribe to a patient presenting with multidrug-resistant urinary infection: 44 residents (86%) gave the correct answer vs 42 attending physicians (70%), P=0.04. Physicians (both residents and attending physicians) who were already familiar with the dedicated webpage available on the hospital's intranet (n=40) obtained a score of 4.75/10 (+/-2.0) compared with 4.03/10 (+/-1.7) for those who had never used that tool (n=71). The difference was statistically significant (P=0.04). The average score for both residents and attending physicians was 4.3/10 (+/-1.9, range: 1-10). Attending physicians' and residents' scores were 4/10 (+/-1.8) and 4.5/10 (+/-1.9), respectively, but the difference was not statistically significant (P=0.14). CONCLUSION: Physicians' knowledge of IPs was insufficient. Improvement in medical training is needed. The use of a dedicated webpage on hospitals' intranet could help physicians acquire better knowledge on that matter. PMID- 26654323 TI - Arthrobacter albus infected implantable cardioverter-defibrillator. PMID- 26654333 TI - Line Tension and Wettability of Nanodrops on Curved Surfaces. AB - In this work we study the formation of nanodrops on curved surfaces (both convex and concave) by means of molecular dynamics simulations, where the particles interact via a Lennard-Jones potential. We find that the contact angle is not affected by the curvature of the substrate, in agreement with previous experimental findings. This means that the change in curvature of the drop in response to the change in curvature of the substrate can be predicted from simple geometrical considerations, under the assumption that the drop's shape is a spherical cap, and that the volume remains unchanged through the curvature. The resulting prediction is in perfect agreement with the simulation results, for both convex and concave substrates. In addition, we calculate the line tension, namely, by fitting the contact angle for different size drops to the modified Young equation. We find that the line tension for concave surfaces is larger than for convex surfaces, while for zero curvature it has a clear maximum. This feature is found to be correlated with the number of particles in the first layer of the liquid on the surface. PMID- 26654334 TI - DOES ONE SIZE FIT ALL? COST UTILITY ANALYSES OF ALTERNATIVE MAMMOGRAPHIC FOLLOW UP SCHEDULES, BY RISK OF RECURRENCE. AB - OBJECTIVES: International guidelines recommend annual mammography after early breast cancer, but there is no randomized controlled trial evidence to support this schedule over any other. Given that not all women have the same risk of recurrence, it is possible that, by defining different risk profiles, we could tailor mammographic schedules that are more effective and efficient. METHODS: A discrete event simulation model was developed to describe the progression of early breast cancer after completion of primary treatment. Retrospective data for 1,100 postmenopausal women diagnosed with early breast cancer in South Australia from 2000 to 2008 were used to calibrate the model. Women were divided into four prognostic subgroups based on the Nottingham Prognostic Index of their primary tumor. For each subgroup, we compared the cost-effectiveness of three different mammographic schedules for two different age groups. RESULTS: Annual mammographic follow-up was not cost-effective for most postmenopausal women. Two yearly mammography was cost-effective for all women with excellent prognosis tumors; and for women with good prognosis tumors if high compliance rates can be achieved. Annual mammography for 5 years and 2 yearly surveillance thereafter (a mixed schedule) may be cost-effective for 50- to 69-year-old women with moderate prognosis tumors, and for women aged 70-79 years with poor prognosis tumors. For younger women with poor prognosis tumors, annual mammography is potentially cost effective. CONCLUSIONS: Our results suggest that mammographic follow-up could be tailored according to risk of recurrence. If validated with larger datasets, this could potentially set the stage for personalized mammographic follow-up after breast cancer. PMID- 26654335 TI - Internal bioerosion in dead and live hard corals in intertidal zone of Hormuz Island (Persian Gulf). AB - Internal macrobioeroders and their erosion rate in three live and dead coral genera (Favia, Platygyra and Porites) from the intertidal zone of the Hormuz Island were studied by collecting five live and five dead colonies from each genus, from which 4 mm cross-sections were cut and photographed. Photos were analyzed using the Coral Point Count with Excel extensions. Totally, 9 taxa were identified: four bivalve species, one sponge, three polychaetes, and one barnacle. Bioerosion rate did not significantly differ among the three live corals, but among the dead ones only Porites was significantly more eroded than Favia. Sponge had the highest role in the erosion of the dead Platygyra, while barnacles were the most effective eroding organism in the live Platygyra. Polychaetes, followed by bivalves, were the most destructive bioeroders on the dead and live Porites. Further, none of the bioeroding organisms had selectively chosen either the dead or live Favia. PMID- 26654336 TI - Economic value of treating lumbar disc herniation in Brazil. AB - OBJECT: Lumbar discectomy is one of the most common surgical spine procedures. In order to understand the value of this surgical care, it is important to understand the costs to the health care system and patient for good results. The objective of this study was to evaluate for the first time the cost-effectiveness of spine surgery in Latin America for lumbar discectomy in terms of cost per quality-adjusted life year (QALY) gained for patients in Brazil. METHODS: The authors performed a prospective cohort study involving 143 consecutive patients who underwent open discectomy for lumbar disc herniation (LDH). Patient-reported outcomes were assessed utilizing the SF-6D, which is derived from a 12-month variation of the SF-36. Direct medical costs included medical reimbursement, costs of hospital care, and overall resource consumption. Disability losses were considered indirect costs. A 4-year horizon with 3% discounting was applied to health-utilities estimates. Sensitivity analysis was performed by varying utility gain by 20%. The costs were expressed in Reais (R$) and US dollars ($), applying an exchange rate of 2.4:1 (the rate at the time of manuscript preparation). RESULTS: The direct and indirect costs of open lumbar discectomy were estimated at an average of R$3426.72 ($1427.80) and R$2027.67 ($844.86), respectively. The mean total cost of treatment was estimated at R$5454.40 ($2272.66) (SD R$2709.17 [$1128.82]). The SF-6D utility gain was 0.044 (95% CI 0.03197-0.05923, p = 0.017) at 12 months. The 4-year discounted QALY gain was 0.176928. The estimated cost utility ratio was R$30,828.35 ($12,845.14) per QALY gained. The sensitivity analysis showed a range of R$25,690.29 ($10,714.28) to R$38,535.44 ($16,056.43) per QALY gained. CONCLUSIONS: The use of open lumbar discectomy to treat LDH is associated with a significant improvement in patient outcomes as measured by the SF-6D. Open lumbar discectomy performed in the Brazilian supplementary health care system provides a cost-utility ratio of R$30,828.35 ($12,845.14) per QALY. The value of acceptable cost-effectiveness will vary by country and region. PMID- 26654337 TI - Scoliosis may increase the risk of recurrence of lumbar disc herniation after microdiscectomy. AB - OBJECT: The aim of this paper was to investigate the risk of recurrence of lumbar disc herniation (LDH) in patients with scoliosis who underwent microdiscectomy. METHODS: A series of consecutive patients who underwent microdiscectomy for LDH was retrospectively reviewed. The inclusion criteria were young adults younger than 40 years who received microdiscectomy for symptomatic 1-level LDH. An exclusion criterion was any previous spinal surgery, including fusion or correction of scoliosis. The patients were divided into 2 groups: those with scoliosis and those without scoliosis. The demographic data in the 2 groups were similar. All medical records and clinical and radiological evaluations were reviewed. RESULTS: A total of 58 patients who underwent 1-level microdiscectomy for LDH were analyzed. During the mean follow-up of 24.6 months, 6 patients (10.3%) experienced a recurrence of LDH with variable symptoms. The recurrence rate was significantly higher among the scoliosis group than the nonscoliosis group (33.3% vs. 2.3%, p = 0.001). Furthermore, the recurrence-free interval in the scoliosis group was short. CONCLUSIONS: Young adults (< 40 years) with uncorrected scoliosis are at higher risk of recurrent LDH after microdiscectomy. PMID- 26654338 TI - Prevalence and type of cervical deformities among adults with Parkinson's disease: a cross-sectional study. AB - OBJECT: To identify the characteristics of cervical deformities in Parkinson's disease (PD) and the role of severity of PD in the development of cervical spine deformities, the authors investigated the prevalence of the cervical deformities, cervical kyphosis (CK), and cervical positive sagittal malalignment (CPSM) in patients with PD. They also analyzed the association of severity of cervical deformities with the stage of PD in the context of global sagittal spinopelvic alignment. METHODS: This study was a prospective assessment of consecutively treated patients (n = 89) with PD. A control group of the age- and sex-matched patients was selected from patients with degenerative cervical spine disease but without PD. Clinical and demographic parameters including age, sex, duration of PD, and Hoehn and Yahr (H&Y) stage were collected. Full-length standing radiographs were used to assess spinopelvic parameters. CK was defined as a C2-7 Cobb angle < 0 degrees . CPSM was defined as C2-7 sagittal vertical axis (SVA) > 4 cm. RESULTS: A significantly higher prevalence of CPSM (28% vs. 1.1%, p < 0.001), but not CK (12% vs. 10.1%, p = 0.635), was found in PD patients compared with control patients. Among patients with PD, those with CK were younger (62.1 vs. 69.0 years, p = 0.013) and had longer duration of PD (56.4 vs. 36.2 months, p = 0.034), but the severity of PD was not significantly different. Logistic regression analysis revealed that the presence of CK was associated with younger age, higher mismatch between pelvic incidence and lumbar lordosis, and lower C7 S1 SVA. The patients with CPSM had significantly greater thoracic kyphosis (TK) (p < 0.001) and a trend toward more advanced H&Y stage (p = 0.05). Logistic regression analysis revealed that CPSM was associated with male sex, greater TK, and more advanced H&Y stage. CONCLUSIONS: Patients with PD have a significantly higher prevalence of CPSM compared with age- and sex-matched control patients with cervical degenerative disease but without PD. Among patients with PD, CK is not associated with the severity of PD but is associated with overall global sagittal malalignment. In contrast, the presence of CPSM is associated more with the severity of PD than it is with the presence of global sagittal malalignment. Collectively, these data suggest that the neuromuscular pathogenesis of PD may affect the development of CPSM more than of CK. PMID- 26654339 TI - Alternative approach in Type II hangman fractures. PMID- 26654340 TI - Preoperative retrolisthesis as a risk factor of postdecompression lumbar disc herniation. AB - OBJECT: In this study, the authors aimed to identify specific risk factors for postdecompression lumbar disc herniation (PDLDH) in patients who have not undergone discectomy and/or fusion. METHODS: Between 2007 and 2012, 493 patients with lumbar spinal stenosis underwent bilateral partial laminectomy without discectomy and/or fusion in a single hospital. Eighteen patients (herniation group [H group]: 15 men, 3 women; mean age 65.1 years) developed acute sciatica as a result of PDLDH within 2 years after surgery. Ninety patients who did not develop postoperative acute sciatica were selected as a control group (C group: 75 men, 15 women; mean age 65.4 years). Patients in the C group were age and sex matched with those in the H group. The patients in the groups were also matched for decompression level, number of decompression levels, and surgery date. The radiographic variables measured included percentage of slippage, intervertebral angle, range of motion, lumbar lordosis, disc height, facet angle, extent of facet removal, facet degeneration, disc degeneration, and vertebral endplate degeneration. The threshold for PDLDH risk factors was evaluated using a continuous numerical variable and receiver operating characteristic curve analysis. The area under the curve was used to determine the diagnostic performance, and values greater than 0.75 were considered to represent good performance. RESULTS: Multivariate analysis revealed that preoperative retrolisthesis during extension was the sole significant independent risk factor for PDLDH. The area under the curve for preoperative retrolisthesis during extension was 0.849; the cutoff value was estimated to be a retrolisthesis of 7.2% during extension. CONCLUSIONS: The authors observed that bilateral partial laminectomy, performed along with the removal of the posterior support ligament, may not be suitable for lumbar spinal stenosis patients with preoperative retrolisthesis greater than 7.2% during extension. PMID- 26654341 TI - The rise and fall of the craniocervical junction relative to the hard palate: a lifetime story. AB - OBJECT: Endoscopic approaches to the anterior craniocervical junction are increasing in frequency. Choice of oral versus endoscopic endonasal approach to the odontoid often depends on the relationship of the C1-2 complex to the hard palate. However, it is not known how this relevant anatomy changes with age. We hypothesize that there is a dynamic relationship of C-2 and the hard palate, which changes with age, and potentially affects the choice of surgical approach. The aim of this study was to characterize the relationship of C-2 relative to the hard palate with respect to age and sex. METHODS: Emergency department billing and trauma records from 2008 to 2014 were reviewed for patients of all ages who underwent cervical or maxillofacial CT as part of a trauma evaluation for closed head injury. Patients who had a CT scan that allowed adequate visualization of the hard palate, opisthion, and upper cervical spine (C-1 and C-2) were included. Patients who had cervical or displaced facial/skull base fractures, a history of rheumatoid arthritis, or craniofacial anomalies were excluded. The distance from McGregor's palatooccipital line to the midpoint of the inferior endplate of C-2 (McL-C2) was measured on midsagittal CT scans. Patients were grouped by decile of age and by sex. A 1-way ANOVA was performed with each respective grouping. RESULTS: Ultimately, 483 patients (29% female) were included. The mean age was 46 +/- 24 years. The majority of patients studied were in the 2nd through 8th decades of life (85%). Significant variation was found between McL-C2 and decile of age (p < 0.001) and sex (p < 0.001). The mean McL-C2 was 27 mm in the 1st decade of life compared with the population mean of 37 mm. The mean McL-C2 was also noted to be smaller in females (mean difference 4.8 mm, p < 0.0001). Both decile of age (p = 0.0009) and sex (p < 0.0001) were independently correlated with McL-C2 on multivariate analysis. CONCLUSIONS: The relationship of C-2 and the hard palate significantly varies with respect to age and sex, descending relative to the hard palate a full centimeter on average in adulthood. These findings may have relevance in determining optimal surgical approaches for addressing pathology involving the anterior craniocervical junction. PMID- 26654342 TI - The role of obesity in the biomechanics and radiological changes of the spine: an in vitro study. AB - OBJECT: The effects of obesity on lumbar biomechanics are not fully understood. The aims of this study were to analyze the biomechanical differences between cadaveric L4-5 lumbar spine segments from a large group of nonobese (body mass index [BMI] < 30 kg/m2) and obese (BMI >= 30 kg/m2) donors and to determine if there were any radiological differences between spines from nonobese and obese donors using MR imaging. METHODS: A total of 168 intact L4-5 spinal segments (87 males and 81 females) were tested using pure-moment loading, simulating flexion extension, lateral bending, and axial rotation. Axial compression tests were performed on 38 of the specimens. Sex, age, and BMI were analyzed with biomechanical parameters using 1-way ANOVA, Pearson correlation, and multiple regression analyses. MR images were obtained in 12 specimens (8 from obese and 4 from nonobese donors) using a 3-T MR scanner. RESULTS: The segments from the obese male group allowed significantly greater range of motion (ROM) than those from the nonobese male group during axial rotation (p = 0.018), while there was no difference between segments from obese and nonobese females (p = 0.687). There were no differences in ROM between spines from obese and nonobese donors during flexion-extension or lateral bending for either sex. In the nonobese population, the ROM during axial rotation was significantly greater for females than for males (p = 0.009). There was no significant difference between sexes in the obese population (p = 0.892). Axial compressive stiffness was significantly greater for the obese than the nonobese population for both the female-only group and the entire study group (p < 0.01); however, the difference was nonsignificant in the male population (p = 0.304). Correlation analysis confirmed a significant negative correlation between BMI and resistance to deformation during axial compression in the female group (R = -0.65, p = 0.004), with no relationship in the male group (R = 0.03, p = 0.9). There was also a significant negative correlation between ROM during flexion-extension and BMI for the female group (R = -0.38, p = 0.001), with no relationship for the male group (R = 0.06, p = 0.58). Qualitative analysis using MR imaging indicated greater facet degeneration and a greater incidence of disc herniations in the obese group than in the control group. CONCLUSIONS: Based on flexibility and compression tests, lumbar spinal segments from obese versus nonobese donors seem to behave differently, biomechanically, during axial rotation and compression. The differences are more pronounced in women. MR imaging suggests that these differences may be due to greater facet degeneration and an increased amount of disc herniation in the spines from obese individuals. PMID- 26654343 TI - The use of intraoperative triggered electromyography to detect misplaced pedicle screws: a systematic review and meta-analysis. AB - OBJECT: Insertion of instruments or implants into the spine carries a risk for injury to neural tissue. Triggered electromyography (tEMG) is an intraoperative neuromonitoring technique that involves electrical stimulation of a tool or screw and subsequent measurement of muscle action potentials from myotomes innervated by nerve roots near the stimulated instrument. The authors of this study sought to determine the ability of tEMG to detect misplaced pedicle screws (PSs). METHODS: The authors searched the U.S. National Library of Medicine, the Web of Science Core Collection database, and the Cochrane Central Register of Controlled Trials for PS studies. A meta-analysis of these studies was performed on a per screw basis to determine the ability of tEMG to detect misplaced PSs. Sensitivity, specificity, and receiver operating characteristic (ROC) area under the curve (AUC) were calculated overall and in subgroups. RESULTS: Twenty-six studies were included in the systematic review. The authors analyzed 18 studies in which tEMG was used during PS placement in the meta-analysis, representing data from 2932 patients and 15,065 screws. The overall sensitivity of tEMG for detecting misplaced PSs was 0.78, and the specificity was 0.94. The overall ROC AUC was 0.96. A tEMG current threshold of 10-12 mA (ROC AUC 0.99) and a pulse duration of 300 usec (ROC AUC 0.97) provided the most accurate testing parameters for detecting misplaced screws. Screws most accurately conducted EMG signals (ROC AUC 0.98). CONCLUSIONS: Triggered electromyography has very high specificity but only fair sensitivity for detecting malpositioned PSs. PMID- 26654344 TI - Ambulatory blood pressure monitoring to diagnose hypertension--an idea whose time has come. PMID- 26654345 TI - The Influences of Periodontal Status and Periodontal Pathogen Quantity on Salivary 8-Hydroxydeoxyguanosine and Interleukin-17 Levels. AB - BACKGROUND: Periodontitis is a biofilm-initiated disease that is characterized by elevated inflammatory status. 8-Hydroxydeoxyguanosine (8-OHdG) and interleukin (IL)-17 are highly associated with inflammation and bone resorption and therefore are regarded as potential biomarkers for periodontitis. In this study, the associations between salivary 8-OHdG and IL-17 levels and clinical and microbial parameters before and after non-surgical treatment are investigated. METHODS: Forty-five patients with chronic periodontitis (CP) and 47 periodontally healthy volunteers were recruited for the study. Clinical parameters, including the probing depth (PD), clinical attachment level (CAL), sulcular bleeding index, and simplified oral hygiene index (OHI-S), were examined for each participant. Microbial parameters including the quantities of Porphyromonas gingivalis, Tannerella forsythia, and Treponema denticola in the subgingival plaque and saliva were determined by real-time polymerase chain reaction at baseline and 1 and 3 months after the non-surgical treatment. Salivary 8-OHdG and IL-17 levels were detected by enzyme-linked immunosorbent assays. RESULTS: Compared with healthy volunteers, CP group patients had significantly higher salivary 8-OHdG and IL-17 levels at baseline. Baseline salivary 8-OHdG and IL-17 levels were positively correlated with all clinical parameters as well as the quantities of T. forsythia and T. denticola. After non-surgical treatment, baseline levels of salivary 8-OHdG and IL-17 were reduced significantly at both the 1- and 3-month follow-ups. The hierarchical linear model revealed that variations in the PD, CAL, and OHI-S had significant positive effects on variation in the salivary 8 OHdG level. However, variations in the PD; quantity of T. forsythia in the subgingival plaque; and quantities of P. gingivalis, T. forsythia, and T. denticola in saliva were associated significantly with variation in the salivary IL-17 levels. CONCLUSIONS: There was a strong association between salivary 8-OHdG and IL-17 levels and periodontitis. Variation in the salivary 8-OHdG level was correlated with variations in the clinical parameters, whereas variation in the IL-17 level was correlated with variation in the microbial parameters. PMID- 26654346 TI - Evaluation of Hard and Soft Tissue Dimensions Around Zirconium Oxide Implant Supported Crowns: A 1-Year Retrospective Study. AB - BACKGROUND: This study aims to evaluate the effect of the distance between the alveolar crest of a full-ceramic implant to the lowest point of the contact area of the crowns on the interdental papilla. Therefore, the authors proposed a new concept of linear measurements for the reproducible and metric evaluation of distances relevant for the assessment of hard and soft tissue changes around dental implants. METHODS: A total of 216 sites were examined in 87 patients. In a radiographic and clinical evaluation, four relevant distances were evaluated. In the x-ray image, the tip of the papilla was marked with a radiodense mixture of tungsten powder and temporary cement. In a clinical photograph, the lowest point of the interdental contact zone of the crowns was visualized by a metallic interdental ligature. RESULTS: Using the proposed measuring methodology, four different papilla-deficit situations around ceramic implants could be reproducibly distinguished. When the measurement from the bone crest at the implant was <=5 mm, the papilla was completely present in 100% of cases. When this distance was 10 mm, the papilla was still present in 67% of the cases, without any cosmetically apparent deficit. CONCLUSIONS: A close relationship is observed between the distance from the contact point to the bone and the presence of the papilla. Using a combination of radiographically and clinically visible landmarks allows the reproducible measurement of these distances. PMID- 26654347 TI - The Effect of Melatonin on Bone Loss, Diabetic Control, and Apoptosis in Rats With Diabetes With Ligature-Induced Periodontitis. AB - BACKGROUND: The aim of this study examines the effect of systemic melatonin administration on proinflammatory cytokine levels, apoptosis, alveolar bone loss (ABL), lipid metabolism, and diabetic control in in rats with diabetes mellitus (DM) and ligature-induced periodontitis. METHODS: Fifty-two male Wistar rats were used in this study. Study groups were as follows: 1) non-ligated control (NL, n = 6); 2) streptozotocin (STZ, n = 8); 3) STZ and melatonin (STZ+Mel, n = 8); 4) ligature (L, n = 6); 5) ligature and melatonin (L+Mel, n = 8); 6) STZ and ligature (STZ+L, n = 8); and 7) STZ, ligature, and melatonin (STZ+L+Mel, n = 8). DM was induced by intraperitoneal injection of a single dose of STZ (60 mg/kg). Melatonin was administered by intraperitoneal injection of a dose of 10 mg/kg/day for 4 weeks. Silk ligatures were placed subgingivally around the mandibular right first molars. The study period was 4 weeks, and animals were sacrificed at the end of 4 weeks. Morphometric analysis of bone loss was performed. Tissues were histopathologically examined. Inducible nitric oxide synthase (iNOS) and B-cell lymphoma-2-associated X (bax) protein expressions, serum interleukin (IL)-1beta levels, and tartrate-resistant acid phosphatase-positive (TRAP+) osteoclast numbers were also evaluated. RESULTS: After 4 weeks, the highest ABL was observed in the STZ+L group, and the difference was significant (P <0.05). Systemically administered melatonin significantly decreased ABL in the STZ+L+Mel group compared with that in the STZ+L group (P <0.05). TRAP+ osteoclast numbers were the highest in the STZ+L group, and melatonin significantly decreased osteoclast numbers (P <0.05) but had no effect on iNOS, IL-1beta, or bax levels. CONCLUSIONS: Within the limits of this study, it can be concluded that systemic melatonin treatment may decrease osteoclastic activity and reduce ABL in the model using rats with DM. PMID- 26654348 TI - Effect of Periodontitis on Adiponectin, C-Reactive Protein, and Immunoglobulin G Against Porphyromonas gingivalis in Thai People With Overweight or Obese Status. AB - BACKGROUND: Obesity and periodontitis are associated with an inflammatory background. Inflammatory mediators involved may have reciprocal effects on one another. In this study, the levels of inflammatory mediators implicated in overweight or obese status and periodontitis are simultaneously evaluated. METHODS: Body mass index (BMI) and waist circumference, periodontal disease status, and plasma levels of adiponectin, leptin, intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule 1, C-reactive protein (CRP), immunoglobulin (Ig)G antibody against Porphyromonas gingivalis, and IgG against Aggregatibacter actinomycetemcomitans in 109 periodontitis participants with various BMIs were measured. BMI >=23.0 kg/m(2) was considered overweight or obese. RESULTS: Plasma adiponectin was decreased (P = 0.04), whereas CRP and IgG against P. gingivalis were increased (P = 0.04 and P = 0.001, respectively) in patients with severe periodontitis compared with patients with mild or moderate periodontitis, independent of overweight or obese status. Plasma CRP, ICAM-1, and leptin were increased (P <0.001, P = 0.007, and P <0.001, respectively) and adiponectin was decreased (P = 0.04) in overweight or obese participants compared with normal weight participants, without influence of periodontitis severity. No interaction effect between periodontitis and overweight or obese status existed for these protein levels after the data were adjusted for age, sex, plasma levels of triglycerides, high-density lipoprotein cholesterol, fasting plasma glucose, and blood pressure (P = 0.48). CONCLUSIONS: Periodontitis and overweight or obese BMI change plasma levels of the inflammatory mediators adiponectin and CRP, independently. This study suggests a role of periodontitis in systemic inflammatory response in Thai people who are overweight or obese. PMID- 26654349 TI - Severity of Periodontitis and Metabolic Syndrome: Is There an Association? AB - BACKGROUND: Metabolic syndrome (MetS) is a major factor for the occurrence of cardiovascular events. Causal factors for MetS are not well defined or yet unidentified. Preliminary investigations suggest that infections and inflammation may be involved in the etiology of this syndrome. This study aims to estimate the association between the severity of periodontitis (exposure) and MetS (outcome). METHODS: A cross-sectional study was conducted with 419 participants recruited from the Diabetes and Hypertensive Treatment Center, Feira de Santana, Bahia, Brazil. After administration of a questionnaire, general and oral clinical examination and laboratory tests were performed. Diagnosis of periodontitis and MetS was performed according to various criteria. The analysis of the effect of periodontitis on MetS used logistic regression analysis with adjustment for confounders. RESULTS: The prevalence of periodontitis was found to be between 34.61% and 55.37%, depending on the classification definitions used, and the prevalence of MetS ranged from 60.86% to 67.06%. In the group with periodontitis, 14.08% had severe and 41.29% had moderate levels of periodontitis. There was an association between severe periodontitis and MetS after adjustment for sex, age, household density, alcoholic beverage consumption, smoking habit, and cardiovascular disease (odds ratio ORadjusted_6 = 2.11, 95% confidence interval = 1.01 to 4.40, P = 0.05). CONCLUSIONS: The results suggest that periodontitis is associated with MetS, and that MetS prevalence is related to severe periodontitis. PMID- 26654350 TI - Effect of Periodontal Therapy With Amoxicillin-Metronidazole on Pharyngeal Carriage of Penicillin- and Erythromycin-Resistant Viridans Streptococci. AB - BACKGROUND: Previous studies have focused on antibiotic resistance of Gram negative bacteria before and after periodontal therapy. The purpose of this analysis is to assess changes in resistance patterns of the commensal Gram positive microbiota. The viridans group streptococci (VGS) have been suggested to serve as reservoirs of resistance genes for more pathogenic streptococci and may be implicated in some non-oral infections. METHODS: In this randomized clinical trial, 80 patients with periodontitis are distributed randomly into two groups. In group A, patients received 375 mg amoxicillin and 500 mg metronidazole three times per day for 7 days during the non-surgical treatment phase (T1). In group B, the antibiotics were administered during the surgical phase (T2). Resistance of VGS to penicillin and erythromycin was determined by the epsilometer test. RESULTS: At baseline, VGS from 12.5% (group A) and 11.8% (group B) of patients had a minimum inhibitory concentration (MIC) >2 MUg/mL to penicillin. Three months after T1, VGS from 15.6% and 16.7% of patients had an MIC >2 MUg/mL, respectively. Six months after T2 VGS from 5.9% and 5.9% and 12 months after T2 VGS from 6.1% and 6.3% patients had an MIC >2 MUg/mL. There was no effect of therapy with antibiotics, administered either in T1 or T2, on the carriage of penicillin-resistant VGS. Erythromycin resistance was high at baseline and remained unchanged throughout the study. MICs for penicillin and erythromycin were correlated (P <0.05). CONCLUSION: Amoxicillin plus metronidazole did not significantly affect the resistance pattern of the VGS to penicillin or erythromycin. PMID- 26654351 TI - Knockdown of SIRT6 Enables Human Bone Marrow Mesenchymal Stem Cell Senescence. AB - Autologous bone marrow mesenchymal stem cell (BM-MSC) transplantation is a novel strategy for treating ischemic heart disease. However, limited benefits have been reported in aging patients. Rejuvenation of aged human BM-MSCs (hBM-MSCs) could be a means to improve the efficacy of stem cell transplantation in older patients. While it has been shown that sirtuin 6 (SIRT6) is an important antiaging factor in various cells, the role of SIRT6 in hBM-MSCs remains unknown. The hBM-MSCs from different ages were cultured for quantifying SIRT6 expression by mRNA and Western blotting. The cell proliferative and migration abilities were evaluated by BrdU staining, cell growth curves, and scratch assay. Senescence associated beta-galactosidase (SA-beta-Gal) activity and aging-associated p16 (cyclin-dependent kinase inhibitor 2A) expression were also quantified. The knockdown of SIRT6 in hBM-MSCs was used to investigate its impact on aging. SIRT6 expression increased with age, while the proliferative and migration abilities of aged hBM-MSCs were decreased compared with young cells. Knockdown of SIRT6 impaired the proliferative, migration, and oxidative stress resistance potentials of BM-MSCs. SA-beta-Gal activity and p16 expression were increased in aged cells compared with young ones and in siRNA SIRT6 knockdown cells compared with their controls. Aging results in compensatory overexpression of SIRT6 in hBM-MSCs. Downregulation of SIRT6 in these cells resulted in less cell proliferation and migration but increased SA-beta-Gal activity and p16 expression. These results suggest that SIRT6 regulates the aging process in hBM-MSCs and could serve as a target for their rejuvenation. PMID- 26654352 TI - Understanding the Physiology of FGF21. AB - Fibroblast growth factor 21 (FGF21) is a peptide hormone that is synthesized by several organs and regulates energy homeostasis. Excitement surrounding this relatively recently identified hormone is based on the documented metabolic beneficial effects of FGF21, which include weight loss and improved glycemia. The biology of FGF21 is intrinsically complicated owing to its diverse metabolic functions in multiple target organs and its ability to act as an autocrine, paracrine, and endocrine factor. In the liver, FGF21 plays an important role in the regulation of fatty acid oxidation both in the fasted state and in mice consuming a high-fat, low-carbohydrate ketogenic diet. FGF21 also regulates fatty acid metabolism in mice consuming a diet that promotes hepatic lipotoxicity. In white adipose tissue (WAT), FGF21 regulates aspects of glucose metabolism, and in susceptible WAT depots, it can cause browning. This peptide is highly expressed in the pancreas, where it appears to play an anti-inflammatory role in experimental pancreatitis. It also has an anti-inflammatory role in cardiac muscle. Although typically not expressed in skeletal muscle, FGF21 is induced in situations of muscle stress, particularly mitochondrial myopathies. FGF21 has been proposed as a novel therapeutic for metabolic complications such as diabetes and fatty liver disease. This review aims to interpret and delineate the ever expanding complexity of FGF21 physiology. PMID- 26654353 TI - Visible-Light-Sensitive Photocatalysts: Nanocluster-Grafted Titanium Dioxide for Indoor Environmental Remediation. AB - Photocatalytic degradation of organic compounds requires photoexcited holes with strong oxidative power in the valence band (VB) of semiconductors. Although numerous types of doped semiconductors, such as nitrogen-doped TiO2, have been studied as visible-light-sensitive photocatalysts, the quantum yields of these materials were very low because of the limited oxidation power of holes in the nitrogen level above the VB. Recently, we developed visible-light-sensitive Cu(II) and Fe(III) nanocluster-grafted TiO2 using a facile impregnation method and demonstrated that visible-light absorption occurs at the interface between the nanoclusters and TiO2, as electrons in the VB of TiO2 are excited to the nanoclusters under visible-light irradiation. In addition, photogenerated holes in the VB of TiO2 efficiently oxidize organic contaminants, and the excited electrons that accumulate in nanoclusters facilitate the multielectron reduction of oxygen. Notably, Cu(II) and Fe(III) nanocluster-grafted TiO2 photocatalyst has the highest quantum yield among reported photocatalysts and has antiviral, self cleaning, and air purification properties under illumination by indoor light fixtures equipped with white fluorescent bulbs or white light-emitting diodes. PMID- 26654354 TI - The performance of reverse transcriptase assay for the estimation of the plasma viral load in HIV-1 and HIV-2 infections. AB - Viral load testing for human immunodeficiency virus 1 (HIV-1) in resource-poor settings continues to be a challenge. Although antiretroviral therapy (ART) is being made available in developing countries, monitoring of viral load is not being done on a regular basis. The purpose of this study was to assess the utility of Cavidi version 3.0, which measures the plasma reverse transcriptase (RT) activity and compare its performance with molecular HIV viral load assays. In all, 125 HIV-1 and 13 HIV-2 positive samples were analyzed. The overall sensitivity of the assay was 86.8% and 94.1% for viral load >1000 copies/ml measured by Qiagen Artus HIV-1 RG RT PCR and Abbott RealTime HIV-1 PCR assays, respectively. Compared with the routine molecular viral load assays, Cavidi version 3.0 is inexpensive, user-friendly, the expenditure on infrastructure is minimal, and it can be used for monitoring of both HIV types. PMID- 26654355 TI - [In Process Citation]. AB - OBJECTIVES: Different methods of open or minimally invasive thymectomies have been recommended for the treatment of myasthenia gravis (MG). We compared the results of standard transsternal thymectomy (TS) and two different types of minimally invasive thymectomies [video-assisted thoracoscopic extended thymectomy (VATET) and classic Video-Assisted Thoracoscopic Surgery (cVATS)] performed at the same department. METHODS: During three different time periods 71 patients (60 female and 11 male; mean age 31 [range, 14-84] years) underwent thymectomy for MG. Twenty-three underwent standard transsternal thymectomy (January 1995 - September 2004), 22 VATET (September 2004 - August 2009), and 26 cVATS (September 2009 - December 2011) thymectomy for the right side. Operative data, MG- and surgery-related postoperative morbidity and early improvement of MG during the initial 1-year follow-up period were compared among the three methods. RESULTS: There were no perioperative deaths during the study period. Operative time was 112, 211, and 116 minutes (p = 0.001) in the TS, VATET and cVATS, respectively, and the length of hospital stay was 8.9, 5.6, and 4.0 (p = 0.001) days. Postoperative MG-related neurological morbidity affected 21.7%, 18.2%, and 7.7% (p = 0.365) of the patients and the surgery-related morbidity rate was 4.3%, 13.7%, and 0% (p = 0.118) in the TS, VATET and cVATS groups, respectively. Symptom improvement rates were 91.3%, 94.7%, and 87.5% (p = 0.712), and complete remission rates were 13%, 10.5%, and 11.5% (p = 0.917) after TS, VATET and cVATS thymectomies, respectively. CONCLUSIONS: In terms of operative time and hospital stay the best results were found after cVATS. The use of a less invasive surgical intervention resulted in less surgical-, and MG related neurological complications. The improvement of MG symptoms was excellent and results were similar after different types of thymectomies. PMID- 26654356 TI - [In Process Citation]. AB - Peritoneal carcinosis is considered to be a lethal disease with a very poor prognosis, however cytoreducticve surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) could represent a significant step forward in the therapy of peritoneal cranosis. In contrast to traditional surgical procedures and intravenous chemotherapy, which are moderately effective, CRS and HIPEC are new, personalised interventions, which can extend the lifespan of the patients in the majority of the cases. Moreover, there is a possibility to carry out definitive, curative therapy in a well-selected group of cases. The aim of this article is to review the relevant literature on these procedures, which are novelties in Hungary, and to include our own experience, too. PMID- 26654357 TI - [In Process Citation]. AB - Right-sided spontaneous oesophageal rupture developed two days after left pneumonectomy and vomiting. In this extremely rare emergency, we used a transhiatal approach for primary repair of the rupture, combined with right-sided pleural and mediastinal drainage, gastrostomy and feeding jejunostomy. The seven day barium meal showed healing of the rupture. It was mandatory that contamination of the pneumonectomized left thoracic cavity during rupture closure as well as a contralateral thoracotomy with its respiratory consequences had to be avoided by all means. Reconstruction and reinforcement (with omentum) of the oesophageal wall was achieved without difficulties, but we did not mobilize the oesophagus to avoid rupture of the left-sided mediastinal pleura. After massive haematamesis, a 68-year-old man was admitted for a huge (8*5 cm) mass in the lower-posterior mediastinum at the right side of the vertebra, seen on CT scan. On the barium meal incarcerated hiatal hernia, secondary short oesophagus and intramediastinally penetrating high lesser curvature ulcer was discovered. To reduce the magnitude of intervention one-stage transhiatal approach was decided. Through enlarged hiatus, dissection of incarcerated and firmly adherent hiatal hernia and of the short oesophagus was done. The following step was the removal of an encapsulated, huge lipomatosus mass from the posterior mediastinum, extending high from behind the vertebra, arising from the lesser curvature of the stomach. The lesser curvature ulcer was excised - sutured and a Toupet type (270 posterior) fundoplication was finally carried out. The follow-up was free from recurrence. This experience suggests that for some particular lower posterior mediastinal or esophageal problems, transhiatal access seems to be a useful alternative of traditional mediastinal approaches. PMID- 26654359 TI - [In Process Citation]. PMID- 26654358 TI - [In Process Citation]. AB - A 35-year-old female presented with epigastric symptoms and fatigue. Gastroscopy revealed a 2 cm ulcerated lesion in the antrum region. Biopsy confirmed an invasive intestinal type adenocc. Staging CT and EUS: cT2cN0cM0. Laparoscopic subtotal gastric resection + modified D2 lymphadenectomy was performed with Roux en-Y reconstruction of the alimentary tract. Mobilisation of the duodenum and stomach was performed with a 5 mm Ligasure. Distal and proximal resection was performed using Endo GIA 60 mm staplers. We performed a modified D1 lymphadenectomy including the region of the coeliac axis, splenic artery and the hepato-duodenal ligament. A side-to-side retrocolic loop gastro-jejunostomy was fashioned using Endo GIA. To transform the loop jejunostomy to a Roux-n-Y setting, the efferent loop of the jejunum was divided using Endo GIA, while the open end of the stomach was sealed with this same stapler line. This way, the loop anastomosis was fashioned into Roux-Y. The end-to-side jejuno-jejunostomy component of the Roux-Y anastomosis was performed through the specimen extraction site with hand-sewn technique. Duration of surgery: 200 min. Blood loss: 100 ml. The postop period was uneventful, and the patient was discharged on day 9. HISTOLOGY: Invasive intestinal type adenocc., 27 mm diameter, pT1bpN0, HER2 2+. DISCUSSION: Laparoscopic subtotal gastric resection with Roux-Y reconstruction is feasable without oncologic compromise and with excellent functional results in early gastric cancer. PMID- 26654360 TI - [In Process Citation]. PMID- 26654361 TI - [In Process Citation]. PMID- 26654362 TI - Molecular Architecture of the Blood Brain Barrier Tight Junction Proteins--A Synergistic Computational and In Vitro Approach. AB - The blood-brain barrier (BBB) constituted by claudin-5 tight junctions is critical in maintaining the homeostasis of the central nervous system, but this highly selective molecular interface is an impediment for therapeutic interventions in neurodegenerative and neurological diseases. Therapeutic strategies that can exploit the paracellular transport remain elusive due to lack of molecular insights of the tight junction assembly. This study focuses on analyzing the membrane driven cis interactions of claudin-5 proteins in the formation of the BBB tight junctions. We have adopted a synergistic approach employing in silico multiscale dynamics and in vitro cross-linking experiments to study the claudin-5 interactions. Long time scale simulations of claudin-5 monomers, in seven different lipid compositions, show formation of cis dimers that subsequently aggregate into strands. In vitro formaldehyde cross-linking studies also conclusively show that cis-interacting claudin-5 dimers cross-link with short methylene spacers. Using this synergistic approach, we have identified five unique dimer interfaces in our simulations that correlate with the cross linking experiments, four of which are mediated by transmembrane (TM) helices and the other mediated by extracellular loops (ECL). Potential of mean force calculations of these five dimers revealed that the TM mediated interfaces, which can have distinctive leucine zipper interactions in some cases, are more stable than the ECL mediated interface. Additionally, simulations show that claudin-5 dimerization is significantly influenced by the lipid microenvironment. This study captures the fundamental interactions responsible for the BBB tight junction assembly and offers a framework for extending this work to other tight junctions found in the body. PMID- 26654363 TI - Reference genes for reverse transcription quantitative PCR in canine brain tissue. AB - BACKGROUND: In the last decade canine models have been used extensively to study genetic causes of neurological disorders such as epilepsy and Alzheimer's disease and unravel their pathophysiological pathways. Reverse transcription quantitative polymerase chain reaction is a sensitive and inexpensive method to study expression levels of genes involved in disease processes. Accurate normalisation with stably expressed so-called reference genes is crucial for reliable expression analysis. RESULTS: Following the minimum information for publication of quantitative real-time PCR experiments precise guidelines, the expression of ten frequently used reference genes, namely YWHAZ, HMBS, B2M, SDHA, GAPDH, HPRT, RPL13A, RPS5, RPS19 and GUSB was evaluated in seven brain regions (frontal lobe, parietal lobe, occipital lobe, temporal lobe, thalamus, hippocampus and cerebellum) and whole brain of healthy dogs. The stability of expression varied between different brain areas. Using the GeNorm and Normfinder software HMBS, GAPDH and HPRT were the most reliable reference genes for whole brain. Furthermore based on GeNorm calculations it was concluded that as little as two to three reference genes are sufficient to obtain reliable normalisation, irrespective the brain area. CONCLUSIONS: Our results amend/extend the limited previously published data on canine brain reference genes. Despite the excellent expression stability of HMBS, GAPDH and HRPT, the evaluation of expression stability of reference genes must be a standard and integral part of experimental design and subsequent data analysis. PMID- 26654364 TI - Establishing oral health promoting behaviours in children - parents' views on barriers, facilitators and professional support: a qualitative study. AB - BACKGROUND: The prevention of childhood dental caries relies on adherence to key behaviours, including twice daily tooth brushing with fluoride toothpaste and reducing the consumption of sugary foods and drinks. The aim of this qualitative study was to explore parents' perceptions of barriers and facilitators that influence these oral health behaviours in children. A further objective was to explore parents' views on limitations and opportunities for professional support to promote children's oral health. METHODS: Six focus group interviews were conducted, including a total of 39 parents of 7-year old children, who were recruited from paediatric dental centres in The Netherlands. Interviews were held with Dutch parents of low and high socioeconomic status and parents from Turkish and Moroccan origin. Focus group interviews were conducted on the basis of a pre tested semi-structured interview guide and topic list. Content analysis was employed to analyse the data. RESULTS: Analysis of interview transcripts identified many influences on children's oral health behaviours, operating at child, family and community levels. Perceived influences on children's tooth brushing behaviour were primarily located within the direct family environment, including parental knowledge, perceived importance and parental confidence in tooth brushing, locus of control, role modelling, parental monitoring and supervision, parenting strategies and tooth brushing routines and habituation. The consumption of sugary foods and drinks was influenced by both the direct family environment and factors external to the family, including the school, the social environment, commercials and television, supermarkets and affordability of foods. Parents raised several suggestions for professional oral health support, which included the provision of clear and consistent oral health information using a positive approach, dietary regulations at school and a multidisciplinary approach among dental professionals, child health centres and other institutions in providing parental support. CONCLUSION: In conclusion, this qualitative study provided detail regarding parental views on the influences on children oral health behaviours and their opinions on what further support is needed to promote children's dental health. Parents' suggestions for professional oral health support can guide the development or improvement of caries preventive interventions. PMID- 26654365 TI - Anhydrobiosis. PMID- 26654366 TI - The hippocampus. PMID- 26654367 TI - A cycling lane for brain rewiring. PMID- 26654368 TI - Bats regulate biosonar based on the availability of visual information. PMID- 26654369 TI - Phototransduction: Making the Chromophore to See Through the Murk. AB - A candidate gene approach has finally identified the 3,4-dehydrogenase that converts vitamin A1 into vitamin A2 to supply the chromophore for rhodopsin that freshwater vertebrates need for long-wavelength vision. PMID- 26654370 TI - Collective Behaviour: Leadership and Learning in Flocks. AB - A new study has decoded which birds become leaders in homing pigeon flocks, finding an unexpected benefit of leadership: faster birds emerge as leaders, and these leaders learn more about their environment than their followers. PMID- 26654371 TI - Ecology: Dynamics of Indirect Extinction. AB - The experimental identification of the mechanism by which extinctions of predators trigger further predator extinctions emphasizes the role of indirect effects between species in disturbed ecosystems. It also has deep consequences for the hidden magnitude of the current biodiversity crisis. PMID- 26654372 TI - Neurobiology: Setting the Set Point for Neural Homeostasis. AB - Neural homeostasis allows neural networks to maintain a dynamic range around a given set point. How this set point is determined remains unknown. New evidence shows that alterations of activity during a critical developmental period can alter the homeostatic set point, resulting in epilepsy-like activity. PMID- 26654373 TI - Human Behavior: Sleep in Hunter-Gatherer Societies. AB - How much would we sleep if we lived without the pressures and distractions associated with industrialized lifestyles? New research shows that hunter gatherer societies sleep for 6-7 hours a night--a level similar to industrialized societies. PMID- 26654374 TI - Signal Transduction: Gain of Activin Turns Muscle into Bone. AB - Recent data provide an unexpected twist in our understanding of the pathogenesis of fibrodysplasia ossificans progressiva. Surprisingly, the causative amino acid mutation of the BMP receptor responds to activin, thereby turning soft tissues into bone. PMID- 26654375 TI - Motor Control: The Curious Case of Cerebrospinal-Fluid-Contacting Neurons. AB - Since their discovery almost a century ago, the functions of the cerebrospinal fluid-contacting neurons have remained elusive: a new study paves the way towards understanding how these unusual spinal cord neurons regulate motor activity. PMID- 26654376 TI - Mind and Brain: Consciousness in Unresponsive Subjects. AB - A new study shows that subjects rendered unresponsive with sedatives do not exhibit a stereotypic 'unconscious' response to direct cortical stimulation; instead, agent-specific effects are seen that can distinguish between unresponsiveness with and without consciousness. PMID- 26654377 TI - Shared and Distinct Mechanisms of Compartmentalized and Cytosolic Ciliogenesis. AB - Most motile and all non-motile (also known as primary) eukaryotic cilia possess microtubule-based axonemes that are assembled at the cell surface to form hair like or more elaborate compartments endowed with motility and/or signaling functions. Such compartmentalized ciliogenesis depends on the core intraflagellar transport (IFT) machinery and the associated Bardet-Biedl syndrome complex (BBSome) for dynamic delivery of ciliary components. The transition zone (TZ), an ultrastructurally complex barrier or 'gate' at the base of cilia, also contributes to the formation of compartmentalized cilia. Yet, some ciliated protists do not have IFT components and, like some metazoan spermatozoa, use IFT independent mechanisms to build axonemes exposed to the cytosol. Moreover, various ciliated protists lack TZ components, whereas Drosophila sperm surprisingly requires the activity of dynamically localized TZ proteins for cytosolic ciliogenesis. Here, we discuss the various ways eukaryotes use IFT and/or TZ proteins to generate the wide assortment of compartmentalized and cytosolic cilia observed in nature. Consideration of the different ciliogenesis pathways allows us to propose how three types of cytosol-exposed cilia (primary, secondary and tertiary), including cilia found in the human sperm proximal segment, are likely generated by evolutionary derivations of compartmentalized ciliogenesis. PMID- 26654378 TI - The risk of menstrual abnormalities after preconceptional use of folic acid or a folic acid-containing multivitamin in Chinese women. AB - The associations of preconceptional folic acid use with menstruation-related changes were examined by a retrospective study through 219 questionnaires. The kind of folic acid (alone or with other vitamins), the using time and frequency, the menstrual regularity, the cycle length before and after use, and other menstruation-related changes after use were obtained. Two hundred of 219 participants were users, and menstruation-related changes occurred in 32 women, with abnormalities of involvement being longer cycles (increase of 3-20 days, 7.7 +/- 4.8 days), shorter cycles (decrease of 3-7 days, 5.7 +/- 2.3 days), irregular cycles, less blood loss, bleeding or spotting between cycles, and algomenorrhea. Seventeen women stopped using folic acid or folic acid-containing multivitamin, and sixteen of the seventeen women experienced at least one menstruation before conception. Fifteen of sixteen women found complete recovery, indicating the high possibility that these changes were attributed to the use of folic acid or folic acid-containing multivitamin. PMID- 26654379 TI - A case of lupus anticoagulant-hypoprothrombinemia syndrome associated with systemic lupus erythematosus. PMID- 26654380 TI - Haematological and immunological adaptations of non-pregnant, non-lactating dairy cows to a high-energetic diet containing mycotoxins. AB - Diet change and fatness are supposed to challenge the immune system of the cow. Therefore, immunological and haematological consequences of adaptation to and continued feeding of a high-energy diet were studied in eight non-pregnant, non lactating Holstein cows over 16 weeks. Blood haptoglobin concentration remained unaltered, suggesting that an acute phase reaction was not induced. Stimulation ability of peripheral blood mononuclear cells and stimulated oxidative burst capacity of granulocytes increased significantly in the course of the experiment after an initial drop. While total leucocyte counts increased, the proportion of granulocytes increased and that of lymphocytes decreased at the same time as the ratio of CD4(+)/CD8(+) lymphocytes did. Capability of rumen microbes to detoxify the immune-modulating mycotoxin deoxynivalenol (DON) was not compromised as indicated by the exclusive presence of de-DON as the detoxified DON metabolite in blood. In conclusion, both diet change and prolonged positive energy balance influenced the bovine immune system. PMID- 26654381 TI - Effect of different levels of concentrate on ruminal microorganisms and rumen fermentation in Nellore steers. AB - The aim of this study was to investigate the effect of different dietary levels of concentrate on feed intake, digestibility, ruminal fermentation and microbial population in steers. Eight Nellore steers fitted with ruminal cannulas were used in a double 4 * 4 Latin square design experiment. The dietary treatments consist of four different proportions of concentrate to roughage: 30:70, 40:60, 60:40 and 80:20% in the dry matter, resulting in Diets 30, 40, 60 and 80, respectively. The roughage was corn silage, and the concentrate was composed of corn, soybean meal and urea. Apparent digestibility of organic matter and crude protein showed a linear association with concentrate proportion (p = 0.01), but the increased concentrate levels did not affect the digestibility of fibre. The lowest ruminal pH-values were observed in animals fed with Diet 80, remaining below pH 6.0 from 6 h after feeding, while in the other diets, the ruminal pH was below 6.0 not before 12 h after feeding. After feeding Diet 80, the ammonia concentration in the rumen was significantly the highest. Higher dietary concentrate levels resulted in a linear increase of propionic acid concentrations, a linear reduction of the ratio acetic acid to propionic acid (p < 0.01) and a linear increased synthesis of microbial nitrogen (p < 0.001). The predicted production of methane was lower in diets with greater amounts of concentrate (p = 0.032). The population of methanogens, R. flavefaciens and R. albus decreased with higher concentrate levels, while the population of S. ruminantium increased (p < 0.05). The results indicate that greater amounts of concentrate do not decrease ruminal pH-values as much as expected and inhibit some cellulolytic bacteria without impairing the dry matter intake and fibre digestibility in Nellore steers. PMID- 26654382 TI - Atlantic salmon (Salmo salar) protein hydrolysate in diets for weaning piglets ? effect on growth performance, intestinal morphometry and microbiota composition. AB - Salmon protein hydrolysates (SPH) from two different rest raw materials were evaluated in diets for weaning piglets. Four experimental diets were included in the study: a diet based on plant protein with soy protein as the main protein source (Diet PP), a diet based on fishmeal in exchange for soy protein (Diet FM) and two diets in which different SPH replaced fishmeal in the FM diet. The experimental diets were fed to piglets from the day of weaning until 32 d postweaning. In addition to the record of performance data, an intestinal sampling for mucosal morphometry and microbiota 16S rRNA gene sequencing were performed at day 11 on a subset of the animals. The duodenal villi absorption area was significantly larger in piglets receiving Diets SPH compared with Diet PP (p < 0.02). A significant positive correlation between duodenal villi height and average daily gain during the first 11 d postweaning was detected. Only small differences in intestinal microbiota community and no differences in growth performance were detected between the experimental diets. To conclude, SPH seem to be an interesting novel protein source in weanling piglets. PMID- 26654383 TI - Congener profiles of polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDD/Fs) in sediment, water, and fish at a soil contamination site in Taiwan. AB - The relationship of polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDD/Fs) in sediment, water, and fish was studied for 55 fish farms near a contaminated site in Tainan, Taiwan. Samples were collected from the farms and analyzed for seventeen 2,3,7,8-substituted PCDD/Fs congeners. High correlations were found between PCDD/Fs in water and sediment in regard to both concentration and toxicity (R(2) = 0.933 for concentration and R(2) = 0.832 for toxicity). The congener profiles of the 17 PCDD/Fs in water were similar to those in the sediment. However, the PCDD/Fs congener composition in the fish and fish belly samples were different from those in the sediment and water samples obtained from the same fish farm and were also different among the fish samples. It is thus suggested that the biotic PCDD/Fs distribution is more complex than the abiotic PCDD/Fs distribution. Among the seven factors analyzed, only the lipid percentage presented a relationship with the PCDD/Fs congener composition in the fish and fish bellies. A multiple linear regression of the concentration of each congener in the fish was conducted using the concentration of each congener in the site-matched sediment and the lipid content of the fish as independent variables. The results showed that only seven PCDD/Fs congeners with a lower degree of chlorination, which were 4-6 chlorine substitutes, in the fish presented a significant correlation with the lipid content in the fish and their concentration in sediment (r > 0.65, P < 0.005 for both independent variables). In addition, the octanol-water partition coefficients were not significantly related to this distribution behavior. PMID- 26654385 TI - Trabeculectomy Versus EX-PRESS Shunt Versus Ahmed Valve Implant: Short-term Effects on Corneal Endothelial Cells. PMID- 26654384 TI - Emotional words facilitate lexical but not early visual processing. AB - BACKGROUND: Emotional scenes and faces have shown to capture and bind visual resources at early sensory processing stages, i.e. in early visual cortex. However, emotional words have led to mixed results. In the current study ERPs were assessed simultaneously with steady-state visual evoked potentials (SSVEPs) to measure attention effects on early visual activity in emotional word processing. Neutral and negative words were flickered at 12.14 Hz whilst participants performed a Lexical Decision Task. RESULTS: Emotional word content did not modulate the 12.14 Hz SSVEP amplitude, neither did word lexicality. However, emotional words affected the ERP. Negative compared to neutral words as well as words compared to pseudowords lead to enhanced deflections in the P2 time range indicative of lexico-semantic access. The N400 was reduced for negative compared to neutral words and enhanced for pseudowords compared to words indicating facilitated semantic processing of emotional words. LPC amplitudes reflected word lexicality and thus the task-relevant response. CONCLUSION: In line with previous ERP and imaging evidence, the present results indicate that written emotional words are facilitated in processing only subsequent to visual analysis. PMID- 26654386 TI - Radiation doses received in the United Kingdom breast screening programme in 2010 to 2012. AB - OBJECTIVES: To review the radiation doses received by women attending the UK breast-screening programme between 2010 and 2012. To compare doses with previous years and to quantify the impact on dose of changing from analogue to digital imaging and to analyse doses by type of imaging system. METHODS: Measurements of doses to samples of about 50-100 women attending for screening were collected across the whole of the UK breast-screening programme. RESULTS: Data were collected for 87,122 exposures, using 449 X-ray sets, for 25,408 women. The average mean glandular dose (MGD) was 1.79 mGy for mediolateral oblique images and 1.58 mGy for craniocaudal images. The average MGD per two-view examination was 4.01 mGy for film-screen imaging and 3.03 mGy for direct digital radiography (DR) and 4.69 mGy for computed radiography. CONCLUSION: The MGD to women attending breast screening has been reduced on average by about 25% where DR systems have replaced film-screen systems. The dose reduction was greatest for breasts with the largest compressed thickness. There are large variations in dose between the different models of DR system provided by different manufacturers. There should be further work to ensure that all DR systems are operated at the optimal dose level to ensure the best cancer detection while balancing the detriment caused by using radiation. ADVANCES IN KNOWLEDGE: Changes in the radiation dose in breast screening over time have been determined. Specifically, the impact on radiation dose of introducing different types of DR and computed radiography system into breast screening has been quantified. PMID- 26654387 TI - When is inhibition of return input- or output-based? It depends on how you look at it. AB - Two important diagnostics have been used to infer whether the effect of inhibition of return, when preceded by a saccade, is primarily upon input (i.e., attentional/perceptual level) or output (i.e., response/decision level) processes. Data from antisaccade paradigms involving luminance targets in peripheral vision suggest input effects whereas data from spatially compatible manual responses to centrally presented arrow targets suggest output effects. Here, we combine these diagnostics to resolve the discrepancy. In separate conditions participants made a pro- or antisaccade to a peripheral stimulus. Upon returning gaze to the original fixation, left and right manual responses were made to left- and right-pointing arrows at fixation, respectively. The primary objective of the prosaccade condition was to determine whether an eye movement toward a visual stimulus that was not associated with a manual localization response would bias spatially compatible manual responses against the prior saccade vector. Manual responses were slowest in the direction of the prior saccade, consistent with an output-based attribution (e.g., Posner, Rafal, Choate, & Vaughan, 1985). The primary objective of the antisaccade condition was to determine whether an eye movement away from a visual stimulus would also bias subsequent manual responses. No apparent response bias was detected, consistent with an input-based attribution (e.g., Fecteau, Au, Armstrong, & Munoz, 2004). Collectively, the findings indicate that there are 2, dissociable forms of inhibition depending on saccadic response demands. Converging evidence from other paradigms is discussed. (PsycINFO Database Record PMID- 26654388 TI - Computed Tomography Angiography: A Review and Technical Update. AB - The principles of computed tomography angiography (CTA) remain the following with modern-day computed tomography (CT): high-resolution volumetric CT data acquisition, imaging at maximum contrast medium enhancement, and subsequent angiographic two- and three-dimensional visualization. One prerequisite for adapting CTA to ever evolving CT technology is understanding the principle rules of contrast medium enhancement. Four key rules of early arterial contrast dynamics can help one understand the relationship between intravenously injected contrast medium and the resulting time-dependent arterial enhancement. The technical evolution of CT has continued with many benefits for CT angiography. Well-informed adaptations of CTA principles allow for leveraging of these innovations for the benefit of patients with cardiovascular diseases. PMID- 26654389 TI - Computed Tomography Angiography of the Thoracic Aorta. AB - This article reviews the multidetector-row computed tomography (MDCT) imaging appearance of common entities that are part of the wide spectrum of diseases involving the thoracic aorta. Electrocardiogram-gated MDCT is poised to become the reference standard method in assessing the thoracic aorta. Reproducible images of the aorta can be acquired independent of operator skill. PMID- 26654390 TI - Computed Tomographic Angiography of the Abdominal Aorta. AB - Computed tomographic (CT) angiography (CTA) has become the preferred imaging test of choice for various aortic conditions because of its excellent spatial resolution, rapid image acquisition, and its wide availability. CTA provides a robust tool for planning aortic interventions and diagnosing acute and chronic vascular diseases in the abdomen. CTA is the standard for imaging aneurysms before intervention and evaluating the aorta in the acute setting to assess traumatic injury, dissection, and aneurysm rupture. Knowledge of the imaging features of these disease processes, inflammatory vasculitides, and occlusive atherosclerotic disease is essential for guiding surgical and medical management of patients. PMID- 26654391 TI - Computed Tomography Angiography of the Hepatic, Pancreatic, and Splenic Circulation. AB - Multidetector computed tomography angiography (MDCTA) has become a routine imaging tool to assess visceral vascular anatomy and abdominal parenchymal pathology. Enhanced temporal resolution and rapid acquisition allow for precise delineation of arterial and venous anatomy. The excellent spatial resolution permits assessment of small parenchyma lesions and vasculature. The ability of CT to rapidly acquire data and reconstruct with thinner slices allows robust 3D mapping using maximum intensity projection before definitive surgical or interventional therapy. Emerging novel techniques of image acquisition offer sensitive methods for detecting enhancement and allow for virtual imaging subtraction, all while limiting the total radiation burden. PMID- 26654392 TI - Computed Tomograpy Angiography of the Renal Circulation. AB - This article discusses adequate acquisition and display of the renal circulation and the various pathologies related to the renal arterial system, trauma, planning for renal transplantation, and common tumors of the kidneys. PMID- 26654393 TI - Computed Tomography Angiography of the Small Bowel and Mesentery. AB - Multidetector computed tomography (MDCT) has largely supplanted other available radiologic modalities in the evaluation of a wide variety of different vascular and inflammatory abnormalities of the small bowel, with computed tomography angiography (CTA) playing a major role in the diagnostic efficacy of MDCT for these diseases. Improvements in CTA imaging have proved particularly valuable in the evaluation of small bowel vascular and inflammatory disorders, diagnoses in which arterial phase images might be able to offer greater information than standard venous phase imaging. This article details the MDCT imaging findings of several small bowel vascular and inflammatory disorders. PMID- 26654394 TI - Computed Tomography Angiography of the Upper Extremities. AB - Upper extremity computed tomography angiography is a powerful tool in the evaluation of acute and nonacute arterial pathology. Technical principles including patient positioning, choice of contrast injection site and rate of administration, and physiologic considerations must be optimized to achieve a high-quality angiographic study. The use of computed tomography angiography in the setting of trauma has been recognized. However, it's less well-known and varied clinical applications in the subacute setting are also important. Volume rendered, maximum intensity projection, and multiplanar reformat images are indispensable for evaluating the data set. PMID- 26654395 TI - Computed Tomography Angiography of the Lower Extremities. AB - CT angiography (CTA) of the lower extremities is an important and versatile, noninvasive tool for diagnosis as well as surgical or endovascular interventional planning. Although lower extremity CTA is most commonly performed in patients with peripheral artery disease or trauma affecting the lower extremities, it also plays a role in the workup of nonischemic etiologies such as vasculitis, aneurysms, and congenital vascular malformations. CT scan protocols should adjust bolus timing and multiphasic imaging to account for the clinical question of interest, and 3-dimensional postprocessing plays an important role in the visualization and interpretation of these high-resolution imaging examinations. PMID- 26654396 TI - Computed Tomography Angiography for Preoperative Thoracoabdominal Flap Planning. AB - Mastectomy rates have increased, coinciding with more advanced reconstruction options. Deep inferior epigastric perforator (DIEP) flaps decrease abdominal donor site morbidity, but require considerable technical expertise. Preoperative computed tomography angiography (CTA) can accurately demonstrate DIEA anatomy and perforator courses, facilitating preoperative planning and flap design, allowing for more targeted intraoperative microdissection. Patients who undergo CTA before DIEP flap have better clinical outcomes with shorter operative times and hospital length of stay, which can decrease overall associated health care costs. Future directions include selected imaging of the thoracic anatomy and recipient vasculature, allowing for additional preoperative planning and customization. PMID- 26654397 TI - Computed Tomography Angiography of the Neurovascular Circulation. AB - Computed tomography angiography of the head and neck is a powerful tool for imaging and diagnosis of a plethora of disorders of the cervicocerebral vasculature. This article reviews the technique, indications, and interpretation of many of these disorders. A standard report checklist is also presented. PMID- 26654398 TI - Pediatric Considerations in Computed Tomographic Angiography. AB - Cardiovascular disease in children comprises a diverse collection of diseases involving multiple organ systems. Abnormality in children is predominately congenital but also may be acquired. Although noninvasive vascular imaging modalities such as magnetic resonance angiography and ultrasound lack ionizing radiation, with improving technology and an increased focus on radiation dose reduction, computed tomographic angiography (CTA) continues to have a role in evaluating cardiovascular disease in pediatric patients. This review focuses on specific considerations of CTA that the radiologist or ordering provider should consider when imaging the pediatric cardiovascular system. PMID- 26654399 TI - CT Angiography. PMID- 26654400 TI - Menopausal hormone therapy use in relation to breast cancer incidence in 11 European countries. AB - INTRODUCTION: The use of menopausal hormone therapy (MHT) has decreased in many countries in the past 10 years. This is a consequence of the initial publication of the results of the Women's Health Initiative (WHI) randomized trial of estrogen plus progestin. In various countries, further studies then analyzed the incidence of breast cancer (BC) in relation to changes in MHT use. Some reported a decreased BC incidence following cessation of MHT, but others did not. This may reflect differences in BC incidence, in MHT use or in confounding factors, but also in study methodology. AIM: To analyze the changes in BC incidence and MHT use, using the same methodology, in 11 European countries. MATERIALS & METHOD: We limited the study to women between the ages of 45 and 69. BC incidence data were provided from cancer registries. MHT sales data were extracted from health sales databases for the years 2003-2013. The association between BC incidence and the rate of MHT use during the past year in Europe was assessed using linear mixed models. RESULTS: A drop in MHT sales was consistent in all countries for the whole period of follow-up. This was not the case for BC incidence. We found no evidence of a relation between BC incidence and MHT sales in the past year, except for sales of tibolone. CONCLUSIONS: The longer observation period did not confirm the results of studies that had a shorter follow-up, except in relation to tibolone. The role of confounding factors needs to be clarified. PMID- 26654402 TI - Planarians as a model of aging to study the interaction between stem cells and senescent cells in vivo. AB - The depletion of stem cell pools and the accumulation of senescent cells in animal tissues are linked to aging. Planarians are invertebrate flatworms and are unusual in that their stem cells, called neoblasts, are constantly replacing old and dying cells. By eliminating neoblasts in worms via irradiation, the biological principles of aging are exposed in the absence of wound healing and regeneration, making planaria a powerful tool for aging research. PMID- 26654401 TI - Analysis of the role of autophagy inhibition by two complementary human cytomegalovirus BECN1/Beclin 1-binding proteins. AB - Autophagy is activated early after human cytomegalovirus (HCMV) infection but, later on, the virus blocks autophagy. Here we characterized 2 HCMV proteins, TRS1 and IRS1, which inhibit autophagy during infection. Expression of either TRS1 or IRS1 was able to block autophagy in different cell lines, independently of the EIF2S1 kinase, EIF2AK2/PKR. Instead, TRS1 and IRS1 interacted with the autophagy protein BECN1/Beclin 1. We mapped the BECN1-binding domain (BBD) of IRS1 and TRS1 and found it to be essential for autophagy inhibition. Mutant viruses that express only IRS1 or TRS1 partially controlled autophagy, whereas a double mutant virus expressing neither protein stimulated autophagy. A mutant virus that did not express IRS1 and expressed a truncated form of TRS1 in which the BBD was deleted, failed to control autophagy. However, this mutant virus had similar replication kinetics as wild-type virus, suggesting that autophagy inhibition is not critical for viral replication. In fact, using pharmacological modulators of autophagy and inhibition of autophagy by shRNA knockdown, we discovered that stimulating autophagy enhanced viral replication. Conversely, inhibiting autophagy decreased HCMV infection. Thus, our results demonstrate a new proviral role of autophagy for a DNA virus. PMID- 26654404 TI - Reply to "Comment on 'Insights into the Electronic Structure of Ozone and Sulfur Dioxide from Generalized Valence Bond Theory: Bonding in O3 and SO2'". PMID- 26654403 TI - Antibody-mediated delivery of therapeutics for cancer therapy. AB - INTRODUCTION: Antibody-conjugated therapies (ACTs) combine the specificity of monoclonal antibodies to target cancer cells directly with highly potent payloads, often resulting in superior efficacy and/or reduced toxicity. This represents a new approach to the treatment of cancer. There have been highly promising clinical trial results using this approach with improvements in linker and payload technology. The breadth of current trials examining ACTs in haematological malignancies and solid tumours indicate the potential for clinical impact. AREAS COVERED: This review will provide an overview of ACTs currently in clinical development as well as the principles of antibody delivery and types of payloads used, including cytotoxic drugs, radiolabelled isotopes, nanoparticle based siRNA particles and immunotoxins. EXPERT OPINION: The focus of much of the clinical activity in ACTs has, understandably, been on their use as a monotherapy or in combination with standard of care drugs. This will continue, as will the search for better targets, linkers and payloads. Increasingly, as these drugs enter routine clinical care, important questions will arise regarding how to optimise ACT treatment approaches, including investigation of resistance mechanisms, biomarker and patient selection strategies, understanding of the unique toxicities of these drugs, and combinatorial approaches with standard therapies as well as emerging therapeutic agents like immunotherapy. PMID- 26654405 TI - Supplicant of the Spheres #3. PMID- 26654406 TI - Drug Pricing: Has the Camel's Back Finally Been Broken? PMID- 26654407 TI - Barriers to Pediatric Pain Management in Children Undergoing Surgery: A Survey of Health Care Providers. AB - The appropriate pain management in neonates and children is lacking. Factors that prevent the execution of proper pain relief vary from center to center. We studied the factors responsible for it in a surgical unit. We conducted a survey at a tertiary-level institute among the resident doctors and nursing staff by means of an informal questionnaire analyzing their basic knowledge. The questions pertained mainly to pain assessment, analgesic usage, role of opioids, and formal training, and the responses so obtained were analyzed under these four headings. Seventy-three percent (22/30) of the residents and 74% (26/35) of the nursing staff knew about pain assessment scoring system in pediatric patients. However, assessment of pain in emergency cases was always done by only 6.6% of the residents. Effect of analgesia on severity of pain was never recorded by 33% (10/30) of the residents. Eighty-six percent (26/30) of the residents and 91% (32/35) of the nursing staff had adequate knowledge about analgesic dosage and interval for routine use. Ten of the 30 (33%) residents believed that analgesic administration in an acute abdomen, before definitive diagnosis, will always mask the symptoms. During a minor procedure, 56% (17/30) of the residents always used analgesia. Only 3.3% (1/30) of residents and 2.8% (1/35) of the nursing staff had received a structured training for pain management. Although, 93% (28/30) of the residents claimed to know about the safety of use of opioids, only 46% (14/30) used them routinely as analgesics. Pain management in surgical neonates and children is often ignored. Lack of formal training, inadequate knowledge, and standard protocols are the barriers in our setup, which may in turn be due to overwhelming attention given to the surgical condition. PMID- 26654408 TI - Intravenous Lidocaine as an Adjuvant for Pain Associated with Sickle Cell Disease. AB - The objectives of this study were to evaluate the efficacy and safety of adjuvant intravenous (IV) lidocaine in adults with sickle cell disease (SCD). This was a retrospective review. Adults with SCD receiving at least one IV lidocaine infusion from 2004 to 2014 were included. Patient demographics, lidocaine treatment parameters, pain scores, pain medications, and adverse effects were recorded. Eleven patients were identified, yielding 15 IV lidocaine trials. Clinical improvement in pain scores from pre-lidocaine challenge to 24 hours post lidocaine challenge, defined by >= 20% reduction in pain scores, was achieved in 53.3% (8 of 15) of IV lidocaine challenges. Of the 8 clinically successful trials, the mean reduction in morphine dose equivalents (MDE) from 24 hours pre lidocaine challenge to 24 hours post-lidocaine challenge was 32.2%. Additionally, clinically successful trials had a mean initial and a maximum dose of 1 mg/kg/h (range: 0.5-2.7 mg/kg/h) and 1.3 mg/kg/h (range: 0.5-1.9 mg/kg/h), respectively. On average, these patients underwent 3 dose titrations (range: 1-8) and received lidocaine infusions for 4.4 days (range: 2-8 days). Two patients experienced disorientation and dizziness. The authors conclude that adjuvant IV lidocaine provided pain relief and a mean reduction in MDE during sickle cell pain crisis. These results provide preliminary insight into the use of IV lidocaine for treating pain in patients with SCD, although prospective studies are needed to determine efficacy, dosing, and tolerability of IV lidocaine in this patient population. PMID- 26654409 TI - Using Neuroleptics to Treat Delirium in Dying Cancer Patients at a Cancer Center in Saudi Arabia. AB - Neuroleptics are commonly used for treating delirium as a common problem in terminally ill cancer patients. However, prescribing patterns are believed to substantially vary among health professionals. The aim of this study is to determine the pattern of prescribing neuroleptics for treating delirium in cancer patients dying in a palliative care unit in Saudi Arabia. We reviewed the medical records of adults with advanced cancer who died in the palliative care unit over 23 months. In addition to patients' demographics, data collection included the pattern of prescribing neuroleptics for the treatment of delirium during the last week of life. For the 271 patients included (57.6% females), the median age was 54 years. Although 62% of patients were on around-the-clock (ATC) neuroleptics to treat delirium, about two thirds of these were requiring rescue doses (PRN [pro re nata]) as well. The ATC neuroleptics included haloperidol alone (89.3%), levomepromazine alone (2.4%), or both (8.3%). All neuroleptics were administered via the parenteral route. On average, the maximum daily doses of the ATC neuroleptics were 4 mg for haloperidol and 15.5 mg for levomepromazine. Patients with primary or metastatic brain cancers were less likely to be on neuroleptics (P < .0001). The authors conclude that in their palliative care unit, haloperidol is by far the most commonly used neuroleptic, followed by levomepromazine, to treat the common problem of delirium in patients dying with advanced cancer. The generally low doses of neuroleptics required may be attributed to several factors in this population, including cultural motives. PMID- 26654410 TI - A Pilot Chemical and Physical Stability Study of Extemporaneously Compounded Levetiracetam Intravenous Solution. AB - Levetiracetam is a commonly used antiepileptic medication for tumor-related epilepsy. However, the 100 mL intravenous (IV) infusion volume can be burdensome to imminently dying hospice patients. A reduced infusion volume would improve patient tolerability. The purpose of this study was to evaluate the stability of 1000 mg/25 mL (40 mg/mL) levetiracetam IV solution in sodium chloride 0.9%. We prepared levetiracetam 40 mg/mL IV solution and added it to polyvinyl chloride (PVC) bags, polyolefin bags, and polypropylene syringes. Triplicate samples of each product were stored at refrigeration (2-8 degrees C) and analyzed on days 0, 1, 4, 7, and 14. Samples were subjected to visual inspection, pH measurement, and stability-indicating high-performance liquid chromatography (HPLC) analysis. Over the 2-week storage period, there was no significant change in visual appearance or pH for any of the stability samples. The HPLC results confirmed that all stability samples retained 94.2-101.3% of initial drug concentration and no degradation products or leachable material from the packaging materials were observed. We conclude that levetiracetam 1000 mg/25 mL IV solution in sodium chloride 0.9% is physically and chemically stable for up to 14 days under refrigeration in polypropylene syringes, PVC bags, and polyolefin bags. PMID- 26654411 TI - Treatment of Refractory Hiccups with Amantadine. AB - Persistent or intractable hiccups are not uncommon at the end of life, occurring in approximately 4% to 9% of patients, and can cause considerable suffering, including difficulties in eating, drinking, and speaking, insomnia, pain, fatigue, and depression. In palliative practice, the etiology of hiccups is often either unknown or untreatable, and empirical pharmacologic treatment is the norm. Unfortunately, many of the agents reported as effective for hiccups can cause undesirable sedation. The authors describe a patient with end-stage vascular dementia and a 4-year history of idiopathic intractable hiccups who responded dramatically to amantadine, a nonsedating dopamine agonist. The role of dopamine in hiccups is somewhat ambiguous and likely not central to their cause or treatment. Amantadine may be a reasonable option for patients with distressing hiccups who cannot tolerate a sedating agent. PMID- 26654412 TI - Fentanyl-Induced Neurotoxicity in Children. AB - Fentanyl-induced neurotoxicity is an uncommon adverse effect of fentanyl and is seldom seen in pediatric palliative care practice. It presents as myriad of nonspecific symptoms such as severe pain, allodynia, insomnia, agitation, hallucinations, behavioral changes, and headache. In children, it is often missed and misdiagnosed. This is a case report of an 11-year-old girl; a case of locally advanced neuroblastoma, progressed on disease-modifying treatment, and referred to pediatric palliative care for best supportive care. She developed features of fentanyl-induced neurotoxicity during upward titration of transdermal fentanyl that was promptly identified and managed in a pediatric palliative care setting. PMID- 26654413 TI - Economic Burden of Prescription Opioid Misuse and Abuse: A Systematic Review. AB - A 2009 systematic review found that the total cost of prescription opioid abuse in 2001 in the United States was approximately $8.6 billion and medical expenses were estimated to be $15,884 for opioid abusers and $1,830 for nonabusers. A search was conducted for English publications on the cost of prescription opioid abuse and misuse from 2009 to 2014. The initial literature search identified 5,412 citations. Title and abstract review selected 59 for further review. The final review process resulted in 16 publications for inclusion that examined cost from the payer perspective. Mean costs to the payer for abusers were $23,000 $25,000 per year and excess costs approximately $15,000 per patient. Three papers were identified that presented societal costs, including direct and indirect costs such as criminal justice costs and costs associated with lost productivity. The strongest evidence suggests that societal cost is in excess of $50 billion per year in the United States. Prescription opioid abuse and misuse is a common and important problem throughout the world that has significant associated societal costs and excess medical costs. PMID- 26654414 TI - Medicare Care Choices Model Enables Concurrent Palliative and Curative Care. AB - On July 20, 2015, the federal Centers for Medicare & Medicaid Services (CMS) announced hospices that have been selected to participate in the Medicare Care Choices Model. Fewer than half of the Medicare beneficiaries use hospice care for which they are eligible. Current Medicare regulations preclude concurrent palliative and curative care. Under the Medicare Choices Model, dually eligible Medicare beneficiaries may elect to receive supportive care services typically provided by hospice while continuing to receive curative services. This report describes how CMS has expanded the model from an originally anticipated 30 Medicare-certified hospices to over 140 Medicare-certified hospices and extended the duration of the model from 3 to 5 years. Medicare-certified hospice programs that will participate in the model are listed. PMID- 26654415 TI - How Palliative Care Helped Me Make an Important Decision in My Life. AB - The author writes about her father's illness and how her knowledge of palliative care and "dying with dignity" helped her make important decisions for her father in his last days. She and her family members were able to give him the kind of care he needed and desired. He could enjoy the time he had left, and the family had the satisfaction of serving him when he needed them. PMID- 26654416 TI - A Lesson in Spirituality. AB - Understanding spirituality during palliative care training is not easy. It slowly unravels itself when one starts caring for patients and meeting their caregivers. One such experience in the hospice has been described in this narrative. A person with advanced incurable cancer is initially in severe distress. Over time, he slowly comes to terms with the situation and eventually, a question from his illiterate wife--an insightful question about any last wish--brings out his desire to have certain religious rituals that were alien to his own religion. After his death, the family members concur with his last wish and also indulge in some religious rituals of their own choice. This story reaffirms that the essence of spirituality is the coexistence of harmony and humanity. PMID- 26654417 TI - Pain in Bali. AB - There is a lot of unrelieved pain in developing countries. Here is a story from Bali, Indonesia, about a woman with advanced malignancy, who is in unbelievable agony. Expensive chemotherapy is available to her. But although the necessary medications for relieving her pain are available in hospitals, they do not reach the patient, in her home, or even when she is admitted to the hospital, because of ignorance of the medical profession about pain management and because of unnecessary regulatory restrictions. The woman's pain affects the whole family, endangering the family's income and the future of her children. The intervention of palliative care during part of her life gives her some relief, only for the agony to be repeated by pointless chemotherapy and neglect of the suffering during admission to the hospital. Whatever relief could be given to her was because of the intervention of a volunteer with no schooling in medicine or palliative care. PMID- 26654418 TI - Pain, Palliative Care, and Compassion in India. AB - An estimated 1 million new cases of cancer occur each year in India, with over 80% presenting at the point at which the disease is incurable. Around 60% of the patients will already be in significant pain, and just under half will be experiencing excruciating, unbearable pain. With only a handful of outpatient palliative care clinics in Kolkata, few patients are able to access essential pain medication and palliative care services. This narrative includes five case studies exploring differing aspects of palliative care: pain management, the difficulties faced in accessing morphine, the importance of compassion in end-of life care, and the psychological effects on families. They illustrate the degree of suffering some patients and families face, and the relatively simple measures that can be taken to alleviate this. For the current situation in India to improve, there needs to be better access to essential pain medications such as morphine, education of health care professionals and the public, as well as the implementation of government pain management and palliative care policies. PMID- 26654422 TI - Overcoming crizotinib resistance in ALK-rearranged NSCLC with the second generation ALK-inhibitor ceritinib. AB - In up to 5% of non-small cell lung cancer (NSCLC) patients, the EML4-ALK translocation drives tumor progression. Treatment with the ALK inhibitor crizotinib is more effective than standard chemotherapy. However, resistance to crizotinib occurs after approximately 8 months. Ceritinib is the first second generation ALK inhibitor approved for treatment of crizotinib-resistant NSCLC. Ceritinib inhibits two of the most common ALK-mutants that confer resistance to crizotinib: L1196 M and G1269A. Cells with ALK expression are more sensitive to ceritinib than crizotinib (IC50 25 nM vs. 150 nM, respectively). Alternative second-generation ALK inhibitors such as Alectinib, Brigatinib and PF-06463922 are currently in development, each affecting different crizotinib-resistant ALK target mutations. Genetic identification of crizotinib-resistant mutants is essential for selecting the optimal treatment strategy in NSCLC patients to overcome resistance and to increase progression-free survival. PMID- 26654423 TI - Study of Phase Transformation in BaTe2O6 by in Situ High-Pressure X-ray Diffraction, Raman Spectroscopy, and First-Principles Calculations. PMID- 26654424 TI - Calcitriol-modulated human antibiotics: New pathophysiological aspects of vitamin D. AB - Traditionally, calcitriol has been considered a calcium and phosphate regulating hormone, but has recently been shown to play a pivotal role in innate immunity. Many barrier and immune cells have membrane and intracellular receptors that recognize different microbial antigens. Activation of these receptors induces synthesis of 1alpha-hydroxylase, which acts on 25 hydroxyvitamin D to generate intracellular calcitriol. Calcitriol activates its receptor and enhances the synthesis of important human antibiotics like cathelicidin and beta2-defensin while inhibiting hepcidin. These pluripotent peptides have an important role in innate immunity, and their regulation is abnormal in hypovitaminosis D. The literature on their secretion mechanisms, levels in different organic fluids, mechanism of action, and relationship with vitamin D is reviewed here. PMID- 26654425 TI - Transient electrocardiographic abnormalities during hypoglycemia. PMID- 26654426 TI - Epicardial adipose tissue thickness in children and adolescents with cardiometabolic risk factors. AB - OBJECTIVE: To assess the relationship of epicardial adipose tissue (EAT) thickness with cardiometabolic risk factors (CRFs) in children and adolescents. METHODS: Seventy-seven subjects of both sexes aged 7-18 years were selected. Medical history, clinical parameters, and glucose, insulin, and lipid levels were collected. EAT thickness was measured using transthoracic echocardiography. Study subjects were divided into two groups based on whether they had less than two or two or more CRFs. RESULTS: The group with two or more CRFs had higher EAT thickness, insulin, and HOMA-IR values (P<.05). EAT thickness showed a statistically significant positive correlation with body mass index (BMI) (r=0.561, P=.0001), waist circumference (r=.549, P=.0001), systolic blood pressure (SBP) (r=.256, P=.028), insulin (r=0.408, P=.0001), and HOMA-IR (r=.325, P=.005). However, these correlations were not significant after adjustment for BMI. The cut-off point for EAT thickness as predictor of two or more CRFs was 3.17mm. The risk (odds ratio) of having two or more CRFs if EAT thickness was >3.17mm was 3.1 (95% CI: 1.174-8.022). BMI was the independent variable that most affected EAT thickness and the presence of two or more CRFs. CONCLUSION: In this group of children and adolescents, the relationship of EAT thickness with CRFs was found to be dependent on BMI. PMID- 26654427 TI - Restricted access to antiretroviral treatment for undocumented migrants: a bottle neck to control the HIV epidemic in the EU/EEA. AB - BACKGROUND: In the European Union/European Economic Area (EU/EEA), migrants from high-endemic countries are disproportionately affected by HIV. Between 2007 and 2012, migrants represented 39 % of reported HIV cases. There is growing evidence that a significant proportion of HIV acquisition among migrant populations occurs after their arrival in Europe. DISCUSSION: Migrants are confronted with multiple risk factors that shape patterns of population HIV susceptibility and vulnerability, which simultaneously affect HIV transmission. Undocumented migrants incur additional risks for contracting HIV due to limited access to adequate health care services, protection and justice, alongside insecure housing and employment conditions. All EU/EEA countries have ratified a number of international and regional human rights instruments that enshrine access to health care as a human right that should be available to everyone without discrimination. From a clinical and public health perspective, early HIV care and treatment is associated with viral suppression, improved health outcomes and reductions in transmission risks. A current challenge of the HIV epidemic is to reach the highest proportion of overall viral suppression among people living with HIV in order to impact on HIV transmission. Although the majority of EU/EEA countries regard migrants as an important sub-population for their national responses to HIV, and despite the overwhelming evidence of the individual and public health benefits associated with HIV care and treatment, a significant number of EU/EEA countries do not provide antiretroviral treatment to undocumented migrants. HIV transmission dynamics in migrant populations depend on the respective weight of all risk and vulnerability factors to which they are exposed, which act together in a synergistic way. People who are not linked to HIV care will continue to unwillingly contribute to the on-going transmission of HIV. Following the recommendations of the European Union Agency for Fundamental Rights, ensuring access to HIV-care for all sub-populations, including undocumented migrants, would fulfil the human rights of those populations and also strengthen the control of HIV incidence among those not currently able to access HIV care. PMID- 26654428 TI - Antiparasitic and immunomodulatory potential of oral nanocapsules encapsulated lactoferrin protein against Plasmodium berghei. AB - AIM: To analyze the effect of native buffalo lactoferrin (buLf) protein along with its nanoformulation using alginate-enclosed, chitosan-conjugated, calcium phosphate buffalo Lf nanocapsules (AEC-CCo-CP-buLf NCs) against rodent parasite Plasmodium berghei. MATERIALS & METHODS: BALB/c mice were infected with malaria parasite and efficacy of the proteins (buLf and NCs) was evaluated by measuring parasitemia, initialization, role of miRNA in absorption of NCs, parasite load by histopathology and quantitative determination, cytokine levels, bioavailability and immunohistochemistry to localize Lf protein. RESULTS: NCs significantly reduced the parasite load in mice compared with buLf and untreated group. NCs were found to be modulating the disease profile of mice as shown by immunohistochemistry, free radical ion production and higher survival tendency. CONCLUSION: Our study confirms that NCs internalized and changed the expression of miRNAs that further enhanced their uptake in various organs leading to inhibitory effect against the parasite as well as maintenance of the Fe metabolism. PMID- 26654429 TI - Comment on: "Job-related burnout and the relationship to quality of life among Chinese medical college staff" by Yao et al. and The authors respond. PMID- 26654430 TI - Mortality in the Melbourne injecting drug user cohort study (MIX). AB - BACKGROUND: There are few studies of mortality amongst people who inject drugs (PWID) in Australia. In this study, we estimate mortality in a cohort of PWID in Melbourne and examine predictors of mortality including health service use, demographic characteristics, drug use and personal wellbeing. FINDINGS: We linked identifiers from the Melbourne injecting drug use cohort study (MIX; n = 655) to the National Death Index from 2008 to 2012 to estimate standardised mortality ratios (SMRs). Cox regression was used to examine the bivariate relationship between exposures determined at baseline and subsequent mortality. There were 24 (3.6%) deaths over the study period. The mortality rate in the cohort was 1.0 per 100 PY (95% CI 0.71-1.57), with an SMR of 17.3 (95 % CI 11.6-25.8). Baseline reports of four or more lifetime incarcerations (HR 3.65, 95 % CI 1.16-11.52), past month ambulance attendance (HR 4.43, 95 % CI 1.76-11.17), past month emergency department presentation (HR 3.44, 95 % CI 1.47-8.03) and past 6-month self-reported heroin overdose (HR 3.14, 95 % CI 1.24-7.96) were associated with increased mortality risk. CONCLUSIONS: Contact with emergency services, particularly for drug overdose, remains a lost opportunity to provide referrals for harm reduction and naloxone training programmes to PWID at greater risk of mortality. PMID- 26654431 TI - Increased HIV testing among hospitalized patients who declined testing in the emergency department. AB - Health-care systems have serial encounters with many of the same patients across care settings; however, few studies have examined the role of reoffering HIV testing after a patient declines. We assessed whether an intervention to increase HIV testing among hospitalized patients was associated with increased testing among those who declined a test while in the Emergency Department (ED). We studied 8-week periods pre- and post-implementation of an electronic medical record (EMR)-based intervention to increase HIV testing among hospitalized patients. We included all patients 21-64 years old who had no prior HIV test, declined HIV testing in the ED, and were subsequently hospitalized. We used logistic regression to test for an association between time of hospital admission (pre- vs. post-intervention) and whether an HIV test was performed prior to discharge. Pre- and post-implementation, 220 and 218 patients who declined HIV testing in the ED were hospitalized, respectively. There were no significant demographic or clinical differences among patients pre- and post-implementation. Pre- and post-implementation, the median proportion of patients tested weekly was 6.7% (IQR 6.5%, 10.0%) and 41.4% (IQR 33.3%, 41.9%), respectively (aOR 6.2: 95%CI: 3.6, 10.6). HIV testing increased among hospitalized patients who declined a test in the ED after implementation of an EMR-based intervention. Almost half of the patients who declined testing in the ED ultimately underwent testing after it was reoffered during hospitalization, suggesting that the decision to undergo HIV testing is a dynamic process. Leveraging EMR resources may be an effective tool for expanding HIV testing, and testing should be reoffered to patients who previously declined. PMID- 26654433 TI - Hexokinase: A Glycolytic Enzyme with an Inflammatory Ischemia and Reperfusion Connection. PMID- 26654435 TI - Editorial: Central Nervous System Injuries: From Biology to Clinical Approaches. PMID- 26654432 TI - Population genomics of pearl millet (Pennisetum glaucum (L.) R. Br.): Comparative analysis of global accessions and Senegalese landraces. AB - BACKGROUND: Pearl millet is a staple food for people in arid and semi-arid regions of Africa and South Asia due to its high drought tolerance and nutritional qualities. A better understanding of the genomic diversity and population structure of pearl millet germplasm is needed to support germplasm conservation and genetic improvement of this crop. Here we characterized two pearl millet diversity panels, (i) a set of global accessions from Africa, Asia, and the America, and (ii) a collection of landraces from multiple agro-ecological zones in Senegal. RESULTS: We identified 83,875 single nucleotide polymorphisms (SNPs) in 500 pearl millet accessions, comprised of 252 global accessions and 248 Senegalese landraces, using genotyping by sequencing (GBS) of PstI-MspI reduced representation libraries. We used these SNPs to characterize genomic diversity and population structure among the accessions. The Senegalese landraces had the highest levels of genetic diversity (pi), while accessions from southern Africa and Asia showed lower diversity levels. Principal component analyses and ancestry estimation indicated clear population structure between the Senegalese landraces and the global accessions, and among countries in the global accessions. In contrast, little population structure was observed across in the Senegalese landraces collections. We ordered SNPs on the pearl millet genetic map and observed much faster linkage disequilibrium (LD) decay in Senegalese landraces compared to global accessions. A comparison of pearl millet GBS linkage map with the foxtail millet (Setaria italica) and sorghum (Sorghum bicolor) genomes indicated extensive regions of synteny, as well as some large-scale rearrangements in the pearl millet lineage. CONCLUSIONS: We identified 83,875 SNPs as a genomic resource for pearl millet improvement. The high genetic diversity in Senegal relative to other regions of Africa and Asia supports a West African origin of this crop, followed by wide diffusion. The rapid LD decay and lack of confounding population structure along agro-ecological zones in Senegalese pearl millet will facilitate future association mapping studies. Comparative population genomics will provide insights into panicoid crop evolution and support improvement of these climate-resilient crops. PMID- 26654436 TI - Targeted Drug Delivery and Imaging Using Mobile Milli/Microrobots: A Promising Future Towards Theranostic Pharmaceutical Design. AB - Miniature untethered medical robots have been receiving growing attention due to technological advances in microactuation, microsensors, and microfabrication and have significant potential to reduce the invasiveness and improve the accessibility of medical devices into unprecedented small spaces inside the human body. In this review, we discuss therapeutic and diagnostic applications of untethered medical microrobots. Wirelessly controlled milli/microrobots with integrated sensors are revolutionizing micromanipulation based medical interventions and are enabling doctors to perform minimally invasive procedures not possible before. 3D fabrication technologies enabling milli/microrobot fabrication at the single cell scale are empowering high-resolution visual imaging and in vivo manipulation capabilities. Swallowable millirobots and injectabale ocular microrobots allow the gastric ulcer imaging, and performance of vitreoretinal microsurgery at previously inaccessible ocular sites. Many invasive excision and incision based diagnostic biopsy, prostrate, and nephrolgical procedures can be performed minimally or almost noninvasively due to recent advancements in microrobotic technology. Advances in biohybrid microrobot systems are pushing microrobotic systems even smaller, using biological cells as on-board microactuators and microsensors using the chemical energy. Such microrobotic systems could be used for local targeted delivery of imaging contrast agents, drugs, genes, and mRNA, minimally invasive surgery, and cell micromanipulation in the near future. PMID- 26654437 TI - Calcium Phosphate System for Gene Delivery: Historical Background and Emerging Opportunities. AB - Calcium phosphate system has been used widely in in vitro gene delivery for almost four decades. Excellent biocompatibility and simple application have motivated the researchers to always consider this system in their transfection experiments. However, there was a major drawback regarding the low transfection efficiency of calcium phosphate. Hence, there have been many efforts in order to increase the gene delivery potential of this system. In this paper, the application of calcium phosphate in gene delivery is introduced. Moreover, the recent progresses in the application of calcium phosphate in the delivery of (oligo)nucleotides and different approaches to improve the properties of this system are reviewed. PMID- 26654438 TI - Biosystems Engineering of Prokaryotes with Tumor-Killing Capacities. AB - Certain bacteria selectively attack tumor tissues and trigger tumor shrinkage by producing toxins and modulating the local immune system, but their clinical utility is limited because of the dangers posed by systemic infection. Genetic engineering can be used to minimize the risks associated with tumor-targeting pathogens, as well as to increase their efficiency in killing tumor cells. Advances in genetic circuit design have led to the development of bacterial strains with enhanced tumor-targeting capacities and the ability to secrete therapeutics, cytotoxic proteins and prodrug-cleaving enzymes, which allows their safe and effective use for cancer treatment. The present review details the recent advances in the design and application of these modified bacterial strains. PMID- 26654439 TI - Pharmacological Drug Delivery Strategies for Improved Therapeutic Effects: Recent Advances. AB - The latest pharmacologic research has resulted number of new molecules with the potential to modernize the prevention or treatment of different complex diseases, including cancer. The therapeutics generally include moieties such as proteins, drugs and genes, etc. Current activities in the pharmacological field include the development of novel drug-delivery systems to overcome pharmacokinetic glitches such as limited bioavailability, unwanted distribution, drug resistant, and stability, etc. Therefore, to address these issues various biotechnological and pharmacological techniques has been introduced. However, effective drug delivery with improved efficacy remains challenging. This review is focused towards different strategies such as physical and biological methods for efficacious delivery at desired tissues and even sub-cellular targeting. Emphasis is also given about nanotechnology based drug or gene delivery strategies and co-delivery of drug-drug; gene-gene or combinations of drug-gene, etc. are the current cutting-edge methods, which are under clinical or pre-clinical stage of research. Uses of biodegradable materials, such as liposomes and polymeric particles are another class of drug delivery vehicles, which have shown tremendous success, are also discussed. Towards the end, future directions of pharmacological drug delivery methods have also been summarized. PMID- 26654440 TI - Gold Nanomaterials: From Preparation to Pharmaceutical Design and Application. AB - The present mini review offers a brief overview on the preparation and modification of gold nanomaterials (AuNMs) designed for biomedical applications, including biosensors, bioimaging, phototherapy and importantly gene/drug delivery. As biocompatibility is a prerequisite for safe pharmaceutical application, the potential risk of AuNMs to biological systems is also assessed. PMID- 26654441 TI - Coagulation Factor XIIIA (F13A1): Novel Perspectives in Treatment and Pharmacogenetics. AB - Factor XIII (FXIII) is a key molecule in the field of blood coagulation and in the last decades it has weakened attention within the field of angiogenesis and tissue repair. FXIII positively influences wound healing in several tissues by exerting multiple plasma and cellular functions. In the field of haemostasis, FXIII cross-links the neo formed fibrin fibers and supports platelet adhesion to the damaged sub-endothelium warranting a solid architecture. In addition, the pro angiogenic functions of FXIII are directed by the interaction of vascular endothelial growth factor receptor 2 (VEGFR2) and the integrin alphaVbeta3, on the cell membrane, favouring an important step in the formation of granulation tissue at the wound site for optimal tissue healing. Conversely, the same mechanisms could lead to undesired increased neovascularisation, for example in inflammatory bowel disease or in the retinal degenerative pathologies. The classical symptoms of FXIII deficiency span from intracranial haemorrhage to delay bleeding or the staying of chronic wounds in the skin including impaired mucosal healing. In this view, FXIII bridges primary haemostasis, coagulation and definite tissue healing. Another important recently discovered function ascribed to FXIII is its ability to limit bacterial spreading from the lesion by incorporating specific macromolecules addressed to cellular infiltration, favouring in turn cell migration and survival, as observed also in fibrin-heart cultures for stem cell recruitment. In the field of the novel prognostic biomarkers, the monitoring of the residual circulating FXIII level during acute myocardial infarction has been considered predictive of the post-myocardial infarction healing. Accordingly, adequate FXIII levels can drive and predict the prognosis of complex diseases and the outcome of the associated therapies or interventions. In addition, peculiar pharmacogenetics aspects of the FXIII gene are of extraordinary interest. The present review accounts for the recognized role of FXIII in the healing process and gives some examples on how to use it as prognostic biological/ molecular marker or as potential tailored therapeutic molecule in complex diseases. PMID- 26654442 TI - [Surrogate indices of insulin resistance: Their mutual relationship and their real potential]. PMID- 26654443 TI - Comparing amikacin and kanamycin-induced hearing loss in multidrug-resistant tuberculosis treatment under programmatic conditions in a Namibian retrospective cohort. AB - BACKGROUND: Amikacin and kanamycin are mainly used for treating multidrug resistant tuberculosis (MDR-TB), especially in developing countries where the burden of MDR-TB is highest. Their protracted use in MDR-TB treatment is known to cause dose-dependent irreversible hearing loss, requiring hearing aids, cochlear implants or rehabilitation. Therapeutic drug monitoring and regular audiological assessments may help to prevent or detect the onset of hearing loss, but these services are not always available or affordable in many developing countries. We aimed to compare the cumulative incidence of hearing loss among patients treated for MDR-TB with amikacin or kanamycin-based regimens, and to identify the most-at risk patients, based on the real-life clinical practice experiences in Namibia. METHODS: We conducted a retrospective cohort study of patients treated with amikacin or kanamycin-based regimens in four public sector MDR-TB treatment sites in Namibia between June 2004 and March 2014. Patients were audiologically assessed as part of clinical care. The study outcome was the occurrence of any hearing loss. Data were manually extracted from patients' treatment records. We compared proportions using the Chi-square test; applied stratified analysis and logistic regression to study the risk of hearing loss and to identify the most-at risk patients through effect-modification analysis. A P-value < 0.05 was statistically significant. RESULTS: All 353 patients had normal baseline hearing, 46 % were HIV co-infected. Cumulative incidence of any hearing loss was 58 %, which was mostly bilateral (83 %), and mild (32 %), moderate (23 %), moderate severe (16 %), severe (10 %), or profound (15 %). Patients using amikacin had a greater risk of developing the more severe forms of hearing loss than those using kanamycin (adjusted odds ratio (OR) = 4.0, 95 % CI: 1.5-10.8). Patients co infected with HIV (OR = 3.4, 95 % CI: 1.1-10.6), males (OR = 4.5, 95 %1.5-13.4) and those with lower baseline body weight (40-59 kg, OR = 2.8, 95 % CI: 1.1-6.8), were most-at-risk of developing hearing loss. CONCLUSION: Amikacin use in the long-term MDR-TB treatment led to a higher risk of occurrence of the more severe forms of hearing loss compared to kanamycin use. Males, patients with low baseline body weight and those co-infected with HIV were most-at-risk. MDR-TB treatment programmes should consider replacing amikacin with kanamycin and strengthen the routine renal, serum therapeutic drug levels and audiometric monitoring in the most-at-risk patients treated with aminoglycosides. PMID- 26654444 TI - Micropatterning Extracellular Matrix Proteins on Electrospun Fibrous Substrate Promote Human Mesenchymal Stem Cell Differentiation Toward Neurogenic Lineage. AB - In this study, hybrid micropatterned grafts constructed via a combination of microcontact printing and electrospinning techniques process were utilized to investigate the influencing of patterning directions on human mesenchymal stem cells (hMSCs) differentiation to desired phenotypes. We found that the stem cells could align and elongate along the direction of the micropattern, where they randomly distributed on nonmicropatterned surfaces. Concomitant with patterning effect of component on stem cell alignment, a commensurate increase on the expression of neural lineage commitment markers, such as microtubule associated protein 2 (MAP2), Nestin, NeuroD1, and Class III beta-Tubulin, were revealed from mRNA expression by quantitative Real Time PCR (qRT-PCR) and MAP2 expression by immunostaining. In addition, the effect of electrospun fiber orientation on cell behaviors was further examined. An angle of 45 degrees between the direction of micropatterning and orientation of aligned fibers was verified to greatly prompt the outgrowth of filopodia and neurogenesis of hMSCs. This study demonstrates that the significance of hybrid components and electrospun fiber alignment in modulating cellular behavior and neurogenic lineage commitment of hMSCs, suggesting promising application of porous scaffolds with smart component and topography engineering in clinical regenerative medicine. PMID- 26654445 TI - Subnational benchmarking of health systems performance in Africa using health outcome and coverage indicators. AB - National health systems performance (HSP) assessments and benchmarking are critical to understanding how well the delivery of healthcare meets the needs of citizens. Benchmarking HSP has often been done between countries to inform the global public health space. However, its impact is likely to be far greater when implemented sub-nationally to inform actual decisions on resource allocations and performance improvements, especially in high disease burden, low-income countries, where the resource envelope available for health is inadequate. In their study, Roberts and colleagues assemble, analyse and map a minimum set of health intervention and outcome indicators from 1990-2011 to assess and benchmark HSP across the 11 regions of Uganda. This is the first empirical sub-national HSP benchmarking study in the country and the results have potentially important health system policy implications. Please see related research: http://www.biomedcentral.com/1741-7015/13/285. PMID- 26654446 TI - Tailoring Ligand Environment toward Development of Colorimetric and Fluorescence Indicator for Biological Mn(II) Imaging. AB - Mn(2+) ion plays an essential role in all forms of life. Paramagnetic nature of Mn(2+) and its close resemblance with Ca(2+) and Mg(2+) are two key limiting factors responsible for the least development of fluorescence probes suitable for bioimaging. In literature we have found only a few Mn(2+) selective fluorescent sensor and their applications. These probes are mainly based on linear polydentate and macrocyclic ligands. Systematic tuning of ligand environment allows colorimetric and fluorescence recognition of traces Mn(2+) in real sample and fluorescence indicator in living RAW264.7 cells. Two probes, one based on fluorescein (FHDB) and the other based on rhodamine (RDDB) showed turn-on response toward Mn(2+) in DMSO and acetonitrile, respectively. Colorimetric detection of Mn(2+) ion is also possible in the presence of other metal ions. The new sensing probe RDDB shows higher sensitivity as well as faster response compared to the reported systems. The detection limit of RDDB is 5 * 10(-8) M and FHDB is 1 * 10(-7) M. DFT studies strongly support the experimental facts. PMID- 26654448 TI - Continuous wound infiltration or epidural analgesia for pain prevention after hepato-pancreato-biliary surgery within an enhanced recovery program (POP-UP trial): study protocol for a randomized controlled trial. AB - BACKGROUND: Postoperative pain prevention is essential for the recovery of surgical patients. Continuous (thoracic) epidural analgesia (CEA) is routinely practiced for major abdominal surgery, but evidence is conflicting on its benefits in this setting. Potential disadvantages of epidural analgesia are a) perioperative hypotension, frequently requiring additional intravenous fluid boluses or prolonged use of vasopressors; b) relatively high failure rates, with periods of inadequate analgesia; and c) the risk of rare but serious, at times persistent, neurologic complications (hematoma and abscess). In recent years, continuous (subfascial) wound infiltration (CWI) plus patient-controlled analgesia (PCA) has been suggested as a safe and reliable alternative, which does not have the previously mentioned disadvantages, but evidence from multicenter trials targeting a specific surgical population is lacking. We hypothesize that CWI+PCA is equally as effective as CEA, without the mentioned disadvantages. METHODS/DESIGN: POP-UP is a randomized controlled noninferiority multicenter trial, recruiting adult patients scheduled for elective hepato-pancreato-biliary surgery via laparotomy in an enhanced recovery setting. A total of 102 patients are being randomly allocated to CWI+PCA or (P)CEA. Our primary endpoint is the Overall Benefit of Analgesic Score (OBAS), a composite endpoint of pain intensity, opioid-related adverse effects and patient satisfaction, during postoperative days 1 to 5. Secondary endpoints include length of the hospital stay, number of patients with severe pain, and the use of rescue medication. DISCUSSION: POP-UP is a pragmatic trial that will provide evidence of whether CWI+PCA is noninferior as compared to (P)CEA after elective hepato-pancreato biliary surgery via laparotomy in an enhanced recovery setting. If this hypothesis is confirmed, this finding could contribute to more widespread implementation of this technique, especially when the described disadvantages of epidural analgesia are less often observed with CWI+PCA. TRIAL REGISTRATION: Netherlands Trial Register NTR4948 (registry date 2 January 2015). PMID- 26654447 TI - Placental DNA methylation at term reflects maternal serum levels of INHA and FN1, but not PAPPA, early in pregnancy. AB - BACKGROUND: Early detection of pregnancies at risk of complications, such as intrauterine growth restriction (IUGR) and preeclampsia (PE), is critical for improved monitoring and preventative treatment to optimize health outcomes. We predict that levels of placental-derived proteins circulating in maternal blood reflect placental gene expression, which is associated with placental DNA methylation (DNAm) profiles. As such, placental DNAm profiling may be useful to distinguish pregnancies at risk of developing complications and correlation between DNAm and protein levels in maternal blood may give further evidence for a protein's use as a biomarker. However, few studies investigate all clinical parameters that may influence DNAm and/or protein expression, which can significantly affect the relationship between these measures. RESULTS: Candidate genes were chosen based on i) reported alterations of protein levels in maternal blood and ii) observed changes in placental DNAm (?beta > 0.05 and False Discovery Rate (FDR) <0.05) in pregnancies complicated by PE/IUGR. Fibronectin (FN1) enhancer DNAm and placental gene expression were inversely correlated (r = 0.88 p < 0.01). The same trend was observed between promoter DNAm and gene expression for INHBA and PAPPA, though not significant. INHBA and FN1 DNAm was associated with gestational-age corrected birth weight, while INHA levels were associated with fetal: placental weight ratio and FN1 level was associated with maternal body mass index (BMI). DNAm at the INHBA promoter in the term placenta was negatively correlated with second trimester maternal serum levels (r = -0.50 p = 0.01) and DNAm at the FN1 enhancer was negatively associated with third trimester maternal serum levels (r = -0.38, p = 0.009). However, a similar correlation was not found for PAPPA. CONCLUSIONS: These results show that establishing a correlation between altered DNAm in the term placenta and altered maternal serum levels of the corresponding protein, is affected by a number of factors. Nonetheless, the correlation between placental DNAm of INHBA/FN1 and maternal serum INHA/FN1 levels indicate that DNAm may be a useful tool to identify novel biomarkers for adverse pregnancy outcomes in some cases. PMID- 26654449 TI - Head and neck cancers: a clinico-pathological profile and management challenges in a resource-limited setting. AB - BACKGROUND: Head and neck cancer (HNC) is one of the most common cancers worldwide and its incidence is reported to be increasing in resource-limited countries. There is a paucity of published data regarding head and neck cancers in Tanzania, and Bugando Medical Centre in particular. This study describes the clinicopathological profile of HNC in our local setting and highlights the challenges in the management of this disease. METHODS: This was a retrospective study of histopathologically confirmed cases of head and neck cancers treated at Bugando Medical Center between January 2009 and December 2013. RESULTS: A total of 346 patients (M:F = 2.1:1) were studied representing 9.5 % of all malignancies. The median age of patients was 42 years. Cigarette smoking (76.6 %) and heavy alcohol consumption (69.9 %) were the most frequently identified risk factors for head and neck cancer. The majority of patients (95.9 %) presented late with advanced stages. Twenty-five (7.2 %) patients were HIV positive with a median CD4+ count of 244 cells/MUl. The oral cavity (37.3 %) was the most frequent anatomical site affected. The most common histopathological type was carcinomas (59.6 %) of which 75.7 % were squamous cell carcinoma. A total of 196 (56.6 %) patients underwent surgical procedures for HNC. Radiotherapy and chemotherapy was reported in 9.5 and 16.8 % of patients, respectively. Only 2 (0.6 %) patients received chemo-radiation therapy. The mortality rate was 24.4 %. The overall 5-year survival rate (5-YSR) was 20.6 %. The predictors of overall 5 YSR were age of patient at diagnosis, stage of disease, extent of lymph node involvement, HIV seropositivity and CD4+ count <200 cells/MUl (P < 0.001). Local recurrence was reported in 22 (23.4 %) patients and this was significantly associated with positive resection margins, stage of the tumor and presence of metastasis at diagnosis and non-adherence to adjuvant therapy (P < 0.001). CONCLUSION: Head and neck cancers are not uncommon at Bugando Medical Centre and show a trend towards a relative young age at diagnosis and the majority of patients present late with advanced stage cancer. Therefore, public enlightenment, early diagnosis, and effective cost-effective treatment and follow up are urgently needed to improve outcomes of these patients in our environment. PMID- 26654450 TI - Real-World Assessment of Interventional Treatment Timing and Outcomes for Varicose Veins: A Retrospective Claims Analysis. AB - PURPOSE: To evaluate the impact of delaying interventional treatment on varicose vein disease progression, complications, and health care costs in a real-world setting. MATERIALS AND METHODS: This was a retrospective analysis of adults diagnosed with varicose veins between January 2008 and June 2010. Patients were followed for 2 years after diagnosis and categorized into three cohorts based on the timing of interventional therapy: early (<= 2 mo), intermediate (> 2 mo but <= 6 mo), and late (> 6 mo). Disease progression and all-cause health care costs were evaluated. RESULTS: A total of 44,206 patients were included, with 43% classified as receiving early interventional therapy, 33% as intermediate, and 24% as late. Early interventional treatment was associated with lower disease progression rates (29.2%) compared with intermediate (42.5%; P < .0001) and late treatment (52.2%; P < .0001). Also, early interventional treatment was associated with lower costs ($17,564) than intermediate ($17,923; P > .05) and late treatment ($18,399; P < .05). Each 30-day delay in treatment initiation was associated with a 7% higher risk of disease progression (P < .0001) and a 1% increase in costs (P < .0001). CONCLUSIONS: Findings suggest that early initiation of interventional varicose vein treatment was significantly associated with a decreased risk of disease progression and costs. PMID- 26654462 TI - Spatial and Temporal Control of Information Storage in Cellulose by Chemically Activated Oscillations. AB - Chemical oscillations are exploited to achieve self-expiring graphical information on paper-based supports with precise temporal and spatial control. Writing and self-erasing processes are chemically activated by exciting nonoscillating Belousov-Zhabotinsky (BZ) solutions infiltrated in cellulose paper filters. Exhausted supports can be reactivated many times by adding new BZ medium. Different parameters can be independently controlled to program mono- or multipaced information storage. PMID- 26654461 TI - Phototriggered Local Anesthesia. AB - We report a phototriggerable formulation enabling in vivo repeated and on-demand anesthesia with minimal toxicity. Gold nanorods (GNRs) that can convert near infrared (NIR) light into heat were attached to liposomes (Lip-GNRs), enabling light-triggered phase transition of their lipid bilayers with a consequent release of payload. Lip-GNRs containing the site 1 sodium channel blocker tetrodotoxin and the alpha2-adrenergic agonist dexmedetomidine (Lip-GNR-TD) were injected subcutaneously in the rat footpad. Irradiation with an 808 nm continuous wave NIR laser produced on-demand and repeated infiltration anesthesia in the rat footpad in proportion to the irradiance, with minimal toxicity. The ability to achieve on-demand and repeated local anesthesia could be very beneficial in the management of pain. PMID- 26654463 TI - Synthetic Studies on Amphirionin-5: Stereochemical Assignment/Reassignment of the C1-C9 Portion through Stereodivergent Synthesis. AB - Synthesis of four diastereomers of the C1-C12 fragment of amphirionin-5 has been achieved in a convergent and stereodivergent manner. Detailed comparison of the (1)H and (13)C NMR data of each compound with those reported for the natural product led to not only the stereochemical assignment of the relative configuration of the C4/C5 stereogenic centers but also reassignment of the proposed relative configuration at C9 of amphirionin-5. PMID- 26654464 TI - The effect of maternal and post-weaning low and high glycaemic index diets on glucose tolerance, fat deposition and hepatic function in rat offspring. AB - Clinical studies have reported beneficial effects of a maternal low glycaemic index (GI) diet on pregnancy and neonatal outcomes, but the impact of the diet on the offspring in later life, and the mechanisms underlying these effects, remain unclear. In this study, Albino Wistar rats were fed either a low GI (n=14) or high GI (n=14) diet during pregnancy and lactation and their offspring weaned onto either the low or high GI diet. Low GI dams had better glucose tolerance (AUC[glucose], 1322+/-55 v. 1523+/-72 mmol min/l, P<0.05) and a lower proportion of visceral fat (19.0+/-2.9 v. 21.7+/-3.8% of total body fat, P<0.05) compared to high GI dams. Female offspring of low GI dams had lower visceral adiposity (0.45+/-0.03 v. 0.53+/-0.03% body weight, P<0.05) and higher glucose tolerance (AUC[glucose], 1243+/-29 v. 1351+/-39 mmol min/l, P<0.05) at weaning, as well as lower hepatic PI3K-p85 mRNA at 12 weeks of age. No differences in glucose tolerance or hepatic gene expression were observed in male offspring, but the male low GI offspring did have reduced hepatic lipid content at weaning. These findings suggest that consuming a low GI diet during pregnancy and lactation can improve glucose tolerance and reduce visceral adiposity in the female offspring at weaning, and may potentially produce long-term reductions in the hepatic lipogenic capacity of these offspring. PMID- 26654465 TI - Bacillus cucumis sp. nov. isolated from the rhizosphere of cucumber (Cucumis sativus). AB - A facultative anaerobic, Gram-positive staining, endospore-forming bacterium, isolated from the rhizosphere of cucumber (Cucumis sativus), was taxonomically investigated. Based on 16S rRNA gene sequence similarity comparisons, strain AP 6T clustered together with other species of the genus Bacillus and showed highest similarities with Bacillus drentensis LMG 21831T (99.1 %), Bacillus vireti LMG 21834T (98.7 %) and Bacillus soli LMG 21838T (98.5 %). The 16S rRNA gene sequence similarity to the sequences of the type strains of other species of the genus Bacillus was 98.5 % or less. Chemotaxonomic features supported the grouping of the strain in the genus Bacillus; for example, the major fatty acids were anteiso C15 : 0, iso-C15 : 0 and C16 : 0, the polar lipid profile contained the major components diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine and an unidentified glycolipid, the major quinone was menaquinone MK-7 and the major compound in the polyamine pattern was spermidine. Additionally, DNA-DNA hybridization with B. drentensis LMG 21831T, B. vireti LMG 21834T and B. soli LMG 21838T resulted in relatedness values that were clearly below 70 %. Physiological and biochemical test results were also different from those of the most closely related species. As a consequence, AP-6T represents a novel species of the genus Bacillus, for which the name Bacillus cucumis sp. nov. is proposed, with AP-6T ( = CIP 110974T = CCM 8651T) as the type strain. PMID- 26654466 TI - Single and Coupled Electrochemical Processes and Reactors for the Abatement of Organic Water Pollutants: A Critical Review. AB - Traditional physicochemical and biological techniques, as well as advanced oxidation processes (AOPs), are often inadequate, ineffective, or expensive for industrial water reclamation. Within this context, the electrochemical technologies have found a niche where they can become dominant in the near future, especially for the abatement of biorefractory substances. In this critical review, some of the most promising electrochemical tools for the treatment of wastewater contaminated by organic pollutants are discussed in detail with the following goals: (1) to present the fundamental aspects of the selected processes; (2) to discuss the effect of both the main operating parameters and the reactor design on their performance; (3) to critically evaluate their advantages and disadvantages; and (4) to forecast the prospect of their utilization on an applicable scale by identifying the key points to be further investigated. The review is focused on the direct electrochemical oxidation, the indirect electrochemical oxidation mediated by electrogenerated active chlorine, and the coupling between anodic and cathodic processes. The last part of the review is devoted to the critical assessment of the reactors that can be used to put these technologies into practice. PMID- 26654467 TI - Data Verification Tools for Minimizing Management Costs of Dense Air-Quality Monitoring Networks. AB - Aiming at minimizing the costs, both of capital expenditure and maintenance, of an extensive air-quality measurement network, we present simple statistical methods that do not require extensive training data sets for automated real-time verification of the reliability of data delivered by a spatially dense hybrid network of both low-cost and reference ozone measurement instruments. Ozone is a pollutant that has a relatively smooth spatial spread over a large scale although there can be significant small-scale variations. We take advantage of these characteristics and demonstrate detection of instrument calibration drift within a few days using a rolling 72 h comparison of hourly averaged data from the test instrument with that from suitably defined proxies. We define the required characteristics of the proxy measurements by working from a definition of the network purpose and specification, in this case reliable determination of the proportion of hourly averaged ozone measurements that are above a threshold in any given day, and detection of calibration drift of greater than +/-30% in slope or +/-5 parts-per-billion in offset. By analyzing results of a study of an extensive deployment of low-cost instruments in the Lower Fraser Valley, we demonstrate that proxies can be established using land-use criteria and that simple statistical comparisons can identify low-cost instruments that are not stable and therefore need replacing. We propose that a minimal set of compliant reference instruments can be used to verify the reliability of data from a much more extensive network of low-cost devices. PMID- 26654468 TI - [Partial nephrectomy on solitary kidney: Renal function outcome and predictive factors of impairment]. AB - OBJECTIVES: To assess the postoperative functional outcome of PN in solitary kidney and define some predictive factors of renal change. MATERIAL AND METHODS: A monocentric series of 45 partial nephrectomies on solitary kidneys, performed between 1988 and 2014, was retrospectively analyzed. Pre-, per- and postoperative clinicopathological data were collected in the UroCCR database. The evolution of early, medium and long-term postoperative Glomerular Filtration Rate (GFR) was evaluated. Predictive factors of GFR decline and hemodialysis were assessed in multivariate analysis. RESULTS: Mean age was 61 years old (+/-10.8). Mean preoperative GFR and tumor size were respectively 59.6 mL/min (+/-18.7) and 3.9 cm (+/-2.6). Vascular clamping was performed in 41 cases (91%). Median time of warm ischemia was 20 minutes (2-60). Mean follow-up was 66 months (+/-47). Mean GFR at day 5, 1 month and last follow-up were respectively 46.4 mL/min, 50.3 mL/min and 53.1 mL/min. At day 5 and at last follow-up, a GFR decrease >= 20% was found in 20 patients (44.4%) and in 16 patients (35.5%), respectively. Five patients (11%) required definitive hemodialysis (HD) at last follow-up. At day 5, tumor size>4 cm (0.006) and operative time (P=0.003) were independent predictive factors of GFR decline. At 1 year, RENAL ns >= 10 was the only independent predictive factor of GFR alteration (P=0.0007). Preoperative GFR was significantly associated with final hemodialysis (P=0.023). CONCLUSION: Partial nephrectomy allows most of the patients presenting with renal cell carcinoma on solitary kidney to be free of hemodialysis. Tumor complexity, tumor size and preoperative GFR seems to play a determinant role on postoperative functional outcome. These non-modifiable predictive factors should be recognized and taken into account to better select patients with high risk of postoperative renal failure. LEVEL OF EVIDENCE: 5. PMID- 26654469 TI - Targeting quorum sensing by designing azoline derivatives to inhibit the N hexanoyl homoserine lactone-receptor CviR: Synthesis as well as biological and theoretical evaluations. AB - To counteract bacterial resistance, we investigated the interruption of quorum sensing mediated by non-classical bioisosteres of the N-hexanoyl homoserine lactone with an azoline core. For this purpose, a set of selected 2-substituted azolines was synthesized, establishing the basis for a new protocol to synthesize 2-amino imidazolines. The synthesized compounds were evaluated as inhibitors of violacein production in Chromobacterium violaceum. Theoretical studies on bioisostere-protein interactions were performed using CviR. The results show that some azolines decreased violacein production, suggesting an antiquorum sensing profile against Gram-negative bacteria. Docking and molecular dynamic simulations together with binding free energy calculations revealed the exact binding and inhibitory profiles. These theoretical results show relationship with the in vitro activity of the azoline series. PMID- 26654470 TI - Temporary suspension of visiting during norovirus outbreaks in NHS Boards and the independent care home sector in Scotland: a cross-sectional survey of practice. AB - BACKGROUND: Norovirus outbreaks cause significant patient distress and adversely affect healthcare service delivery. Measures to manage outbreaks include controlling patient/staff movement and advising visitors of the risks of infection; temporary suspension of visiting (TSV) is advocated by some. Factors influencing the use of TSV have not previously been reported. AIM: To describe current practice in Scotland regarding TSV during norovirus outbreaks. METHODS: Cross-sectional survey of Scottish Health Boards [National Health Service (NHS)] Infection Prevention Leads (N = 22) and independent care home (ICH) managers (N = 107). FINDINGS: TSV practice is inconsistent across care settings. NHS findings: although 86.4% reported a recent norovirus outbreak, only 36.4% reported having criteria in place to guide TSV decisions and only 57.9% of those who had an outbreak implemented TSV. Conversely, 77.6% ICH respondents do have TSV criteria in place; 70.1% who had previously experienced an outbreak all reported that they would normally close to visitors. The majority of both NHS (81.8%) and ICH (84.2%) respondents reported making exceptions to TSV for individual cases. Despite variation in practice, 75% NHS and 81.8% ICH respondents agreed that TSV was helpful in controlling outbreaks. Factors influencing TSV implementation decisions included use of judgement in individual cases, perceived lack of evidence for the role of visitors in transmission, and belief in patients' rights to have visitors. CONCLUSION: Implementation of TSV in Scotland is inconsistent, with variation in the use of criteria, personal beliefs, and professional judgements. Further research on the role of visitors in transmission and service user acceptability of TSV is required for policy development. PMID- 26654471 TI - Are we measuring what we intend to measure? Implications for the management of healthcare-acquired infections. PMID- 26654472 TI - Therapeutic drug monitoring of cerebrospinal fluid vancomycin concentration during intraventricular administration. AB - Limited data are available on intraventricular vancomycin dosing for meningitis. This study explored clinical characteristics that correlated with cerebrospinal fluid (CSF) concentrations. Over a nine-year period, 13 patients with 34 CSF vancomycin concentrations were evaluated. CSF output and time from dose correlated with CSF vancomycin concentration. No relationship was seen with regards to CSF protein, white blood cell count or glucose. PMID- 26654473 TI - A decision-tree approach to the assessment of posttraumatic stress disorder: Engineering empirically rigorous and ecologically valid assessment measures. AB - Structured diagnostic interviews are widely considered to be the optimal method of assessing symptoms of posttraumatic stress; however, few clinicians report using structured assessments to guide clinical practice. One commonly cited impediment to these assessment approaches is the amount of time required for test administration and interpretation. Empirically keyed methods to reduce the administration time of structured assessments may be a viable solution to increase the use of standardized and reliable diagnostic tools. Thus, the present research conducted an initial feasibility study using a sample of treatment seeking military veterans (N = 1,517) to develop a truncated assessment protocol based on the Clinician-Administered Posttraumatic Stress Disorder (PTSD) Scale (CAPS). Decision-tree analysis was utilized to identify a subset of predictor variables among the CAPS items that were most predictive of a diagnosis of PTSD. The algorithm-driven, atheoretical sequence of questions reduced the number of items administered by more than 75% and classified the validation sample at 92% accuracy. These results demonstrated the feasibility of developing a protocol to assess PTSD in a way that imposes little assessment burden while still providing a reliable categorization. PMID- 26654474 TI - Evidence-based psychotherapy (EBP) non-initiation among veterans offered an EBP for posttraumatic stress disorder. AB - Current efforts to disseminate evidence-based psychotherapies (EBPs) for posttraumatic stress disorder (PTSD) in Veterans Affairs Medical Centers (VAMCs) have made effective treatment options more available throughout the system. Yet many veterans identified as likely to benefit from such services choose not to utilize them. The evidence base regarding factors that contribute to treatment initiation among those offered EBPs is still in its early stages. The present study investigated clinical presentation, patient demographics, and environment of care factors as potential predictors of EBP treatment initiation among veterans offered such care. The sample consisted of 324 veterans (62% Operation Enduring Freedom [OEF]/Operation Iraqi Freedom [OIF]; 77% male; age M = 42.95, SD = 12.57 years), who attended an intake evaluation at a VAMC outpatient PTSD Clinical Team, were diagnosed with PTSD, and offered a course of EBP. Overall, 72% of veterans (n = 232) who were offered an EBP initiated such treatment, and 28% of veterans (n = 92) did not initiate treatment. Veterans who initiated treatment were significantly older. Treatment initiation did not significantly differ by ethnicity, gender, or baseline PTSD severity. Significantly more veterans referred from mental health clinics initiated treatment than did veterans referred from primary care. This study examined treatment initiation among veterans who were offered EBP for PTSD. Rates of initiation differed across subgroups of veterans. Clinically, this suggests the need to tailor outreach efforts to younger veterans, OEF/OIF veterans, and veterans referred from primary care, and potentially including programming and education aimed at primary care referrers, to increase help-seeking. (PsycINFO Database Record PMID- 26654475 TI - Multiferroic Domain Walls in Ferroelectric PbTiO3 with Oxygen Deficiency. AB - Atomically thin multiferroics with the coexistence and cross-coupling of ferroelectric and (anti)ferromagnetic order parameters are promising for novel magnetoelectric nanodevices. However, such ferroic order disappears at a critical thickness in nanoscale. Here, we show a potential path toward ultrathin multiferroics by engineering an unusual domain wall (DW)-oxygen vacancy interaction in nonmagnetic ferroelectric PbTiO3. We demonstrate from first principles that oxygen vacancies formed at the DW unexpectedly bring about magnetism with a localized spin moment around the vacancy. This magnetism originates from the orbital symmetry breaking of the defect electronic state due to local crystal symmetry breaking at the DW. Moreover, the energetics of defects shows the self-organization feature of oxygen vacancies at the DW, resulting in a planar-arrayed concentration of magnetic oxygen vacancies, which consequently changes the deficient DWs into multiferroic atomic layers. This DW-vacancy engineering opens up a new possibility for novel ultrathin multiferroic. PMID- 26654476 TI - The influence of confounding factors on the relationship between muscle contraction level and MF and MPF values of EMG signal: a review. AB - The purpose of this article is to gather results of studies on the relationship between median frequency (MF) and mean power frequency (MPF) and the level of muscle contraction, and to use those results to discuss the differences in the trends according to factors related to measurement technique and subject. Twenty one studies with 63 cases for upper limb muscles and nine studies with 31 cases for lower limb muscles were analysed. Most results showed an increase in parameters with an increased level of muscle contraction, only some studies showed a decrease. The influence on parameters of the level of muscle contraction and factors such as subjects, type of contraction, muscle length and electrodes was analysed for each muscle. It was concluded that when analysing the influence of different factors on MF and MPF, because those factors interact they should be considered together, not separately. PMID- 26654478 TI - HIV-1 envelope glycoprotein immunogens to induce broadly neutralizing antibodies. AB - The long pursuit for a vaccine against human immunodeficiency virus 1 (HIV-1) has recently been boosted by a number of exciting developments. An HIV-1 subunit vaccine ideally should elicit potent broadly neutralizing antibodies (bNAbs), but raising bNAbs by vaccination has proved extremely difficult because of the characteristics of the HIV-1 envelope glycoprotein complex (Env). However, the isolation of bNAbs from HIV-1-infected patients demonstrates that the human humoral immune system is capable of making such antibodies. Therefore, a focus of HIV-1 vaccinology is the elicitation of bNAbs by engineered immunogens and by using vaccination strategies aimed at mimicking the bNAb maturation pathways in HIV-infected patients. Important clues can also be taken from the successful subunit vaccines against hepatitis B virus and human papillomavirus. Here, we review the different types of HIV-1 immunogens and vaccination strategies that are being explored in the search for an HIV-1 vaccine that induces bNAbs. PMID- 26654477 TI - Habitual reappraisal in context: peer victimisation moderates its association with physiological reactivity to social stress. AB - Although the emotion regulation strategy of reappraisal has been associated with adaptive outcomes, there is a growing evidence that it may not be adaptive in all contexts. In the present study, adolescents reported their use of habitual reappraisal and their experiences with peer victimisation, a chronic stressor that is associated with reduced well-being in this population. We examined how these variables predicted physiological reactivity (vagal withdrawal and changes in pre-ejection period) during a social stressor (i.e., Trier Social Stress Task). In line with previous research, at high levels of victimisation, habitual reappraisal predicted adaptive physiological reactivity (i.e., greater vagal withdrawal). Conversely, at low levels of victimisation, habitual reappraisal predicted maladaptive physiological reactivity (i.e., blunted vagal withdrawal). These findings were specific to parasympathetic reactivity. They suggest that habitual reappraisal may exert different effects on parasympathetic reactivity depending on the presence of stressors, and highlight the importance of examining the role of contextual factors in determining the adaptiveness of emotion regulation strategies. PMID- 26654479 TI - [Other aspects of elderly dignity: A view from the primary care]. PMID- 26654480 TI - [Cognition and driving: A reality that affects to everybody]. PMID- 26654481 TI - Management of functional nonretentive fecal incontinence in children: Recommendations from the International Children's Continence Society. AB - BACKGROUND: Fecal incontinence (FI) in children is frequently encountered in pediatric practice, and often occurs in combination with urinary incontinence. In most cases, FI is constipation-associated, but in 20% of children presenting with FI, no constipation or other underlying cause can be found - these children suffer from functional nonretentive fecal incontinence (FNRFI). OBJECTIVE: To summarize the evidence-based recommendations of the International Children's Continence Society for the evaluation and management of children with FNRFI. RECOMMENDATIONS: Functional nonretentive fecal incontinence is a clinical diagnosis based on medical history and physical examination. Except for determining colonic transit time, additional investigations are seldom indicated in the workup of FNRFI. Treatment should consist of education, a nonaccusatory approach, and a toileting program encompassing a daily bowel diary and a reward system. Special attention should be paid to psychosocial or behavioral problems, since these frequently occur in affected children. Functional nonretentive fecal incontinence is often difficult to treat, requiring prolonged therapies with incremental improvement on treatment and frequent relapses. PMID- 26654482 TI - Bronchial thermoplasty: a review of the evidence. PMID- 26654484 TI - The cause of pyloric stenosis of infancy: A hyperacidity pathogenesis. AB - The cause of pyloric stenosis of infancy (PS) is at present unknown. A theory of causation is proposed which is consistent with all the known clinical features of this condition. It is based on the knowledge that PS babies are hypersecretors of acid which pre-dates the development of PS and is an inherited constitutional feature. This acidity will become temporarily and dangerously high due to an insensitivity of the negative feed-back between gastrin and gastric acidy within the first few weeks of life. Normal babies who have inherited normal acidity will also experience peak acid secretions at that time but will be much less acid than babies destined to develop PS. Acid entering the duodenum causes contraction of the pyloric sphincter. Hyperacidity will naturally lead to repeated pyloric sphincter contractions and sphincter hypertrophy. Inappropriate repeated feeding of the vomiting PS baby by a first-time overanxious mother to her ever hungry baby, by provoking feed related sphincter contraction is considered to play a significant part in pathogenesis. Should the baby with PS survive beyond the age of around 6weeks, the matured negative feed-back between gastrin and acid will ensure that dangerous hyperacidity is kept in check. This coupled with the natural pyloric canal widening with age, will lead then to an long lasting cure. This theory explains satisfactorily all the known and hitherto unexplained features of this condition. PMID- 26654485 TI - Oscillometric blood pressure estimation by combining nonparametric bootstrap with Gaussian mixture model. AB - BACKGROUND: Blood pressure (BP) is one of the most important vital indicators and plays a key role in determining the cardiovascular activity of patients. METHODS: This paper proposes a hybrid approach consisting of nonparametric bootstrap (NPB) and machine learning techniques to obtain the characteristic ratios (CR) used in the blood pressure estimation algorithm to improve the accuracy of systolic blood pressure (SBP) and diastolic blood pressure (DBP) estimates and obtain confidence intervals (CI). The NPB technique is used to circumvent the requirement for large sample set for obtaining the CI. A mixture of Gaussian densities is assumed for the CRs and Gaussian mixture model (GMM) is chosen to estimate the SBP and DBP ratios. The K-means clustering technique is used to obtain the mixture order of the Gaussian densities. RESULTS: The proposed approach achieves grade "A" under British Society of Hypertension testing protocol and is superior to the conventional approach based on maximum amplitude algorithm (MAA) that uses fixed CR ratios. The proposed approach also yields a lower mean error (ME) and the standard deviation of the error (SDE) in the estimates when compared to the conventional MAA method. In addition, CIs obtained through the proposed hybrid approach are also narrower with a lower SDE. CONCLUSIONS: The proposed approach combining the NPB technique with the GMM provides a methodology to derive individualized characteristic ratio. The results exhibit that the proposed approach enhances the accuracy of SBP and DBP estimation and provides narrower confidence intervals for the estimates. PMID- 26654486 TI - Morbid Obesity and Congestive Heart Failure Increase Operative Time and Room Time in Total Hip Arthroplasty. AB - BACKGROUND: Obesity is increasingly common in patients having total hip arthroplasty, and previous studies have shown a correlation with increased operative time in total hip arthroplasty. Decreasing operative time and room time is essential to meeting the increased demand for total hip arthroplasty, and factors that influence these metrics should be quantified to allow for targeted reduction in time and adjusted reimbursement models. This is the first study to use a multivariate approach to identify which factors increase operative time and room time in total hip arthroplasty. METHODS: The American College of Surgeons National Surgical Quality Improvement Program database was used to identify a cohort of 30,361 patients having total hip arthroplasty between 2006 and 2012. Patient demographics, comorbidities including body mass index, and anesthesia type were used to create generalized linear models identifying independent predictors of increased operative time and room time. RESULTS: Morbid obesity (body mass index >40) independently increased operative time by 13 minutes and room time 18 by minutes. Congestive heart failure led to the greatest increase in overall room time, resulting in a 20-minute increase. Anesthesia method further influenced room time, with general anesthesia resulting in an increased room time of 18 minutes compared with spinal or regional anesthesia. CONCLUSION: Obesity is the major driver of increased operative time in total hip arthroplasty. Congestive heart failure, general anesthesia, and morbid obesity each lead to substantial increases in overall room time, with congestive heart failure leading to the greatest increase in overall room time. PMID- 26654487 TI - What Do Scottish Patients Expect of Their Total Knee Arthroplasty? AB - BACKGROUND: The aim of this study was to carry out an in-depth assessment of patient expectations before surgery in a representative sample of the Scottish population undergoing primary total knee arthroplasty and also assess the influence of demographic factors and preoperative functions on expectations. METHODS: This was a prospective cohort study of 200 patients treated in our institution from November 2011 to July 2013. Patients received standard preoperative preparation including consultation with a surgeon, an information booklet and a DVD. Patients completed the Hospital for Special Surgery Knee Replacement Expectation Survey along with the EuroQol EQ-5D-3L health questionnaire on the day of admission. RESULTS: Fifty-nine percent of the cohort were women, mean age 67.7 years (45-84 years), mean body mass index 32.5 (21-50), mean preoperative Oxford Knee Score 17 (1-44). Relief of pain and improved ability to walk were the most important expectations, followed by the ability to use public transport and/or drive, ability to change position, ability to walk down stairs, and the ability to carry out routine daily activities and/or chores. Some expectations were unrealistic. No relationships between expectations and demographics, including preoperative function, were found. CONCLUSION: This study suggests that patients have very high and sometimes unrealistic expectations regarding their improvements after total knee arthroplasty even after detailed preoperative consultation and education. In addition, these expectations cover a wide range of dimensions. We suggest that to effectively manage patients' expectations, it is important to assess each patient individually and reinforce what expectations can realistically be achieved. PMID- 26654488 TI - Women and Minorities Are at Risk of Developing Unexpected Reduction of Preoperative Flexion After Total Knee Arthroplasty. AB - BACKGROUND: Reduced flexion after total knee arthroplasty (TKA) compared to the preoperative values can affect patient's activities of daily living and lead to patient dissatisfaction. The aim of this study was to determine preoperative risk factors for developing a decrease in knee flexion after a primary TKA. METHODS: We identified 37 knees diagnosed with osteoarthritis with a preoperative knee flexion >=120 degrees but a 12-month postoperative range of motion (ROM) <=110 degrees . A random sample of 111 patients (1:3) from the same database, whose knees had a preoperative and 12-month postoperative ROM >=120 degrees , based on a diagnosis of primary osteoarthritis and no previous open knee surgery, were selected as the controls. RESULTS: We found female gender, black ethnicity, and the low preoperative knee-specific Knee Society Score to be significant risk factors for developing a reduction of knee flexion after TKA with odds ratios of 3.48, 5.11, and 0.95, respectively. CONCLUSION: In the absence of the well recognized preoperative risk factors for a limited postoperative ROM, female patients, minorities, and those with lower knee-specific Knee Society Scores are at an increased risk of developing a decrease in flexion after an elective primary TKA. PMID- 26654489 TI - Early Complications in Hip and Knee Arthroplasties in a Safety Net Hospital vs a University Center. AB - BACKGROUND: Indigent populations face unique challenges that may increase surgical risk and adversely affect the outcomes of hip and knee arthroplasties. This study examines whether there is a difference in early postoperative complications in patients treated in a safety net hospital and in a nearby university center. METHODS: A retrospective review was undertaken of 533 consecutive hip and knee arthroplasties performed by a single experienced surgeon in a safety net hospital and in a university medical center from 2008 to 2012. Patients were followed for a minimum of 2 years. The primary outcomes evaluated were total complications, deep infections, and reoperations. Statistical comparison of the data from the 2 patient groups was carried out using Fisher exact test. RESULTS: Despite the lower percentage of index revision procedures in the safety net group (8% vs 20.5%; P = .0003), the incidence of adverse outcomes was higher in this group than in the university group: for total complications, 12.3% vs 4.9% (P = .003); for deep infections, 3.2% vs 0.6% (P = .025); and for reoperations, 7.5% vs 2.6% (P = .009). For primary procedures in particular, differences in the incidences of these outcomes were even more significant. CONCLUSIONS: In this study, early complications were more frequent in patients who underwent hip and knee arthroplasties in a safety net hospital compared with those who underwent the same procedures in a nearby university center. Future prospective studies are warranted to determine which patient-related or care process-related factors should be optimized to improve arthroplasty outcomes in vulnerable, safety net populations. PMID- 26654490 TI - Crowding-Induced Hybridization of Single DNA Hairpins. AB - It is clear that a crowded environment influences the structure, dynamics, and interactions of biological molecules, but the complexity of this phenomenon demands the development of new experimental and theoretical approaches. Here we use two complementary single-molecule FRET techniques to show that the kinetics of DNA base pairing and unpairing, which are fundamental to both the biological role of DNA and its technological applications, are strongly modulated by a crowded environment. We directly observed single DNA hairpins, which are excellent model systems for studying hybridization, either freely diffusing in solution or immobilized on a surface under crowding conditions. The hairpins followed two-state folding dynamics with a closing rate increasing by 4-fold and the opening rate decreasing 2-fold, for only modest concentrations of crowder [10% (w/w) polyethylene glycol (PEG)]. These experiments serve both to unambiguously highlight the impact of a crowded environment on a fundamental biological process, DNA base pairing, and to illustrate the benefits of single molecule approaches to probing the structure and dynamics of complex biomolecular systems. PMID- 26654491 TI - [Climate change, health challenges of tomorrow?]. PMID- 26654492 TI - [Induced abortion, 40 years after the Veil law]. PMID- 26654493 TI - [Elective abortions, a right to defend]. AB - Every year in France, almost 210 000 women request a termination of an unwanted pregnancy. Two thirds of them were however using a form of contraception, hence the importance, for caregivers, of encouraging women to find the method which works best for them. The right to abortion is the fruit of a long fight for a woman's right to control her own body. It is a right which must be protected. PMID- 26654494 TI - [Abortion: an ethical or political issue?]. AB - Forty years after the decriminalisation of abortion, what is society's view of this hard-fought right of women? Do they finally have the freedom to control their own bodies? The sociological view put forward here questions the professional positioning of caregivers faced with women requesting an elective abortion. PMID- 26654495 TI - [Request for an abortion, the role of frontline professionals]. AB - The reception given by professionals to a woman requesting an elective abortion is key. The initial exchange of information is usually by telephone. Time is limited, hence the requirement for caregivers to demonstrate their availability and professionalism in organising personalised care. PMID- 26654496 TI - [Voluntary pregnancy interruption, listening to the psychologist]. AB - Professional support from a psychologist can enable women who wish to, to understand the personal motives for their choice to abort. PMID- 26654497 TI - [Organising an instrumental elective abortion]. AB - Family planning centres are structures designed to receive and care for women requesting elective abortions. Here the specially trained, dedicated teams offer personalised care. The instrumental elective abortion is prepared in the same way as a surgical procedure and is subject to the same monitoring. PMID- 26654498 TI - [Health education and prevention of abortions in schools]. AB - In schools, nurses play a role in the prevention of elective abortions through individual or collective actions. PMID- 26654499 TI - [Support and training of nursing teams in elective abortions]. AB - The pathway of patients requesting an elective abortion, while improved, is not always easy. To investigate this observation further, it is interesting to analyse the existing structures and the professionals working in this field. Do the health policies and training envisaged for supporting these caregivers enable them to meet women's needs everywhere across the country? PMID- 26654500 TI - [A career guided by an interest in child health care]. AB - After discovering, during her initial training, her keen interest in paediatric practice, Emilie Cuny decided to specialise as a child health nurse. After six years of practice in a hospital, she is now exploring the field of early years child care as the manager of a day care centre. PMID- 26654501 TI - [Practice analysis: culture shock and adaptation at work]. AB - Constructed as a practice analysis, this personal account presents the reflection undertaken by a student on placement in Ireland thanks to the Erasmus programme. She describes in detail the stages of her adaptation in a hospital setting which is considerably different to her usual environment. PMID- 26654502 TI - [Nursing care at home and secularism]. AB - The question of secularism, long-time confined to schools and the relationships between the Church and State, is today being raised in the field of public health. Nurses are directly affected and are integrating this dimension of secularism into their care practices. A private practice nurse describes the effect these changes are having on her practice in patients' homes. PMID- 26654503 TI - [Adolescence and diabetes, psychological and physiological aspects]. AB - The situation of teenagers with type 1 diabetes is particularly difficult as the constraints imposed by the disease come up against their natural desire for independence. Blood sugar balance is affected by the hormonal changes linked to puberty. Non-compliance remains however one of the main factors contributing to blood sugar imbalance. PMID- 26654504 TI - [The former soldiers becoming first aid trainers]. AB - The Order of Malta France is organising, through an innovative partnership with the French Army, the training of first aid instructors aimed at former soldiers injured in combat. One soldier, who received multiple wounds in Lebanon in 2011, describes his training experience. PMID- 26654505 TI - [Preventing swallowing disorders in neurological patients]. AB - Swallowing disorders in neurological rehabilitation are common and important as they can have harmful consequences. A multi-disciplinary hospital team was created to study ways of preventing their occurrence. This article presents the areas to focus on and the main orientations of patient management. PMID- 26654506 TI - [Taking care of a surgical wound of total knee replacement]. PMID- 26654507 TI - Giving Information in order to Manage Pre-Op Stress. PMID- 26654508 TI - [Nuclear imaging, the case of bone scintigraphy]. PMID- 26654509 TI - [Perfusion fluids: osmolarity in practice]. PMID- 26654510 TI - [Negative pressure therapy]. PMID- 26654511 TI - Emil Selenka on the embryonic membranes of the mouse and placentation in gibbons and orangutans. AB - BACKGROUND: Emil Selenka made important contributions to embryology in marsupials, rodents and primates that deserve wider recognition. Here we review his work on early development of the mouse and placentation in the great apes. FINDINGS: Selenka was intrigued by germ layer theory, which led him to study inversion of the germ layers in the mouse and other rodents. He found it was growth of the ectoplacental cone that caused a downward shift in the position of the underlying ectoderm and endoderm, leading to an inside-outside inversion of these layers. In primates he made the important discovery that the embryos of gibbons and orangutans develop under a decidua capsularis. Thus all great apes, including humans, exhibit interstitial implantation; this is in contrast to other primates where implantation is superficial. CONCLUSIONS: Selenka's work was thorough and brilliantly illustrated. It was an important influence on his contemporaries and was well known to scientists of the following generation. Embryologists continue to advance our knowledge of fetal membranes and placentation in the mouse, but Selenka's work on gibbons is unique and our knowledge of orangutan placentation is restricted to his specimens. PMID- 26654512 TI - Association between polymorphisms in IL-27 gene and pre-eclampsia. AB - Pre-eclampsia is a complex pregnancy-specific hypertensive syndrome, and it is a leading cause of maternal and neonatal death worldwide. We aimed to evaluate the associations between polymorphisms of IL-27 gene and pre-eclampsia susceptibility in Han Chinese women. METHODS: 663 pregnant women were enrolled in a case-control study (212 cases and 451 normal pregnancies). The rs153109 and rs17855750 variants were discriminated using Polymerase Chain Reaction - Restriction Fragment Length Polymorphism (PCR-RFLP) methods. RESULTS: A significantly reduced risk of pre-eclampsia was observed in the rs153109 GG genotype compared with the AA or AA/AG genotypes (GG versus AA: OR = 0.51, 95%CI = 0.30-0.86; GG versus AA/AG: OR = 0.60, 95%CI = 0.37-0.98). Significantly reduced pre-eclampsia susceptibility was also associated with the AG/GG genotypes of rs153109 (OR = 0.68, 95%CI = 0.49-0.94) in dominant model. After stratification analysis, the different distribution of AG/GG genotypes was particular significant in the severe pre-eclampsia subgroup (OR = 0.65, 95%CI = 0.45-0.92) and the early-onset severe pre-eclampsia subgroup (OR = 0.51, 95%CI = 0.30-0.87). Additionally, significantly increased mild pre-eclampsia risk was observed associated with rs17855750 GT/GG and GT genotypes when compared with TT and TT/GG genotypes (GT/GG versus TT: OR = 2.27, 95%CI = 1.12-4.55; GT versus TT/GG: OR = 2.56, 95%CI = 1.28-5.26). CONCLUSION: It is biologically plausible that SNPs in IL-27 may have effect on individual susceptibility to pre-eclampsia. The results suggest the presence IL-27 rs153109, rs17855750 variants may be able to be used as markers for the genetic susceptibility to pre-eclampsia. PMID- 26654513 TI - Species differences of 11beta-hydroxysteroid dehydrogenase type 2 function in human and rat term placenta determined via LC-MS/MS. AB - INTRODUCTION: Glucocorticoid-induced fetal programming has been associated with negative metabolic and cardiovascular sequelae in the adult. The placental enzyme 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) shields the fetus from maternal glucocorticoid excess by catalyzing the conversion of these hormones into biologically inactive derivatives. In vivo experiments addressing placental barrier function are mostly conducted in rodents. Therefore we set out to characterize species-specific differences of rat and human placental 11beta-HSD2 steroid turnover, introducing Liquid Chromatography Tandem Mass-Spectrometry (LC MS/MS) as a tool for rat tissue analysis. MATERIALS AND METHODS: Using LC-MS/MS we determined corticotropin-releasing hormone (CRH), cortisol (F), cortisone (E), corticosterone (B) and 11-dehydrocorticosterone (A) in human and rat placenta at term and measured the enzymatic 11beta-HSD glucocorticoid conversion-rates in placental microsomes of both species. In parallel, further glucocorticoid derivatives and sex steroids were determined in the same placental samples. RESULTS: In contrast to the human placenta, we did not detect CRH in the rat placenta. While cortisol (F) and cortisone (E) were exclusively present in human term placenta (E/F-ratio >1), rat placenta showed significant levels of corticosterone (B) and 11-dehydrocorticosterone (A), with an A/B-ratio <1. In line with these species-specific findings, human placenta showed a prominent 11beta-HSD2 activity, while in rat placenta higher 11beta-HSD1 glucocorticoid turnover rates were determined. DISCUSSION: Placental steroid metabolism of human and rat shows relevant species-specific differences, especially regarding the barrier function of 11beta-HSD2 at term. The exclusive expression of CRH in the human placenta further points to relevant differences in the regulation of parturition in rats. Consideration of these findings is warranted when transferring results from rodent placental glucocorticoid metabolism into humans. PMID- 26654514 TI - A Systematic Review of Clinical Practice Guidelines' Recommendations on Levothyroxine Therapy Alone versus Combination Therapy (LT4 plus LT3) for Hypothyroidism. AB - PURPOSE: Patients with hypothyroidism are increasingly enquiring about the benefit of using combination therapy of levothyroxine (LT4) and liothyronine (LT3) as a potential treatment for hypothyroidism. Combination therapy, however, remains controversial. The purpose of this study was to systematically review available hypothyroidism treatment recommendations from clinical practice guidelines from around the world to identify the consensus regarding combination therapy. SOURCE: Clinical practice guidelines were obtained from searches of PubMed, EMBASE, and MEDLINE, using several combinations of MeSH terms. The search was limited to clinical guidelines in English-language publications, published between January 1, 1990 and May 1, 2015. A quantitative approach was utilized for data synthesis. PRINCIPAL FINDINGS: Thirteen guidelines were identified, including three regarding pregnancy, two regarding pediatric populations and eight regarding adult populations. There were six guidelines from North America, four guidelines from Europe and three guidelines from South America. Twelve of the guidelines were published after 2010. Nine guidelines addressed combination therapy of LT4 plus LT3, and all nine concluded that LT4 therapy alone is the standard of care, with insufficient evidence to recommend widespread combination therapy. Only the 2012 ETA Guidelines and the 2015 BTA Guidelines concluded that combination therapy could be used, although only in certain circumstances and as an experimental treatment. CONCLUSION: This systematic review illustrates that clinical practice guidelines worldwide do not recommend and do not support routine use of combination LT4 and LT3 therapy to treat hypothyroidism. PMID- 26654515 TI - Highlights from the 6th Annual University of Calgary Leaders in Medicine Research Symposium and the Keynote Address by Dr. Danuta Skowronski. AB - The Leaders in Medicine (LIM) Program at the University of Calgary hosted its 6th Annual Research Symposium on November 14, 2014, showcasing the quality and breadth of work performed by students at the Cumming School of Medicine. Participation at this year's event was our most successful to date, with a total of six oral and 77 poster presentations during the afternoon symposium. For a detailed description of the work presented at the symposium, please see the Proceedings from the 6th Annual University of Calgary Leaders in Medicine Research Symposium published in this issue of Clinical and Investigative Medicine. PMID- 26654516 TI - Proceedings from the 6th Annual University of Calgary Leaders in Medicine Research Symposium. AB - On November 14, 2014, the Leaders in Medicine (LIM) program at the Cumming School of Medicine, University of Calgary hosted its 6th Annual Research Symposium. Dr. Danuta Skowronski, Epidemiology Lead for Influenza and Emerging Respiratory Pathogens at the British Columbia Centre for Disease Control (BCCDC), was the keynote speaker and presented a lecture entitled "Rapid response research during emerging public health crises: influenza and reflections from the five year anniversary of the 2009 pandemic". The LIM symposium provides a forum for both LIM and non-LIM medical students to present their research work, either as an oral or poster presentation. There were a total of six oral presentations and 77 posters presented. ?The oral presentations included: Swathi Damaraju, "The role of cell communication and 3D Cell-Matrix environment in a stem cell-based tissue engineering strategy for bone repair"; Menglin Yang, "The proteolytic activity of Nepenthes pitcher fluid as a therapeutic for the treatment of celiac disease"; Amelia Kellar, "Monitoring pediatric inflammatory bowel disease - a retrospective analysis of transabdominal ultrasound"; Monica M. Faria-Crowder, "The design and application of a molecular profiling strategy to identify polymicrobial acute sepsis infections"; Waleed Rahmani, "Hair follicle dermal stem cells regenerate the dermal sheath, repopulate the dermal papilla and modulate hair type"; and, Laura Palmer, "A novel role for amyloid beta protein during hypoxia/ischemia". ?The article on the University of Calgary Leaders in Medicine Program, "A Prescription that Addresses the Decline of Basic Science Education in Medical School," in a previous issue of CIM (2014 37(5):E292) provides more details on the program. Briefly, the LIM Research Symposium has the following objectives: (1) to showcase the impressive variety of projects undertaken by students in the LIM Program as well as University of Calgary medical students; (2) to encourage medical student participation in research and special projects; and, (3) to inform students and faculty about the diversity of opportunities available for research and special projects during medical school and beyond.??The following abstracts were submitted for publication. PMID- 26654517 TI - Efficacy of an intercostal nerve block administered with general anesthesia in elderly patients undergoing distal gastrectomy. AB - PURPOSE: The purpose of this study was to evaluate the efficacy and safety of administration of an intercostal nerve block (INB) with general anesthesia to elderly patients undergoing a distal gastrectomy. METHODS: Elderly patients (>65 years) undergoing selective gastrectomy were randomly assigned to three groups (n = 80): general anesthesia (Group A); general + INB anesthesia (Group B); or, general + epidural anesthesia (Group C). General anesthesia was maintained with propofol, remifentanil and cisatracurium. The mean arterial blood pressure (MAP), heart rate (HR) and C-reactive protein (CRP) levels were determined before anesthesia (T0) and at 5 min after intubation (T1), skin incision (T2), exploration of the peritoneal cavity (T3), gastrointestinal anastomosis (T4), end of operation (T5) and 10 min after extubation (T6). RESULTS: MAP decreased at T1 in all groups (P < 0.05) and at T2, T4 and T5 in Group C (P < 0.05) and was lower in Group C than Group B at T2 and T4 (P < 0.05). There were no differences in MAP between Groups A and B or between Groups B and C. HR increased at T2-T6 in Group A (P < 0.05) and was higher at T2-T6 in Group B and Group C (P < 0.05). CRP levels decreased at T2-T5 in Groups B and C (P < 0.05) and were lower in Groups B and C compared with Group A (P < 0.05). Propofol and remifentanil doses were lower in Groups B and C (P < 0.05 and P < 0.01, respectively) and patients recovered faster than in Group A (P < 0.05). CONCLUSION: Administration of INB with general anesthesia enhanced analgesia, led to stable hemodynamics, and reduced anaesthetic consumption and postoperative stress response. PMID- 26654518 TI - Prevalence of Liver Disease and Utilization of a Hepatology Consultation Service at an Urban Tertiary Care Hospital. AB - PURPOSE: The prevalence of liver disease and frequency of consultations to a Hepatology Consultation service for patients with liver enzyme/function abnormalities admitted to a clinical teaching unit at an urban tertiary care hospital have not been previously described. To document these data, a retrospective chart review of adult patients admitted for non-hepatobiliary problems to a general Internal Medicine clinical teaching unit at an urban, tertiary care hospital during a three month period was performed. METHODS: Laboratory test results were reviewed to determine if liver enzymes and function tests had been ordered during the first five days of admission and, in those with abnormal results, whether referrals had been sent to the hospital's Hepatology Consultation service for further investigations and/or management. RESULTS: A total of 506 admissions occurred during the study period. Of these, 452 (89%) were for patients with no known liver disease. Liver biochemistry testing was obtained in 218 (48.2%) of these individuals. In 192 (88.1%), liver enzyme or function tests were abnormal and in 91 (41.7%), both enzymes and function tests were abnormal (suggesting more advanced disease). Referrals to the Hepatology Consultation service were requested for 5/91 (5.5%) patients with more advanced disease and none with only liver enzyme or function tests abnormalities. CONCLUSIONS: Although liver enzymes and/or function test abnormalities are common in this patient population, screening for liver disease is relatively uncommon and consultation to a Hepatology Consultation service occurs in less than 10% of cases. PMID- 26654519 TI - Obstructive Sleep Apnea Syndrome: Links Betwen Pathophysiology and Cardiovascular Complications. AB - PURPOSE: The prevalence of obstructive sleep apnea syndrome (OSAS) is increasing, especially in the middle-aged population. OSAS is associated with an elevated risk of cardiovascular morbidity and mortality. Arterial hypertension is often the first consequence of OSAS, but the most severe complications are coronary artery disease, stroke and arrhythmias. The aim of this review was to analyze the several mechanisms involved in the development of the cardiovascular events, such as endothelial dysfunction accompanied by a pro-inflammatory and pro-oxidant status, hemorheological alterations, hypercoagulability and imbalance between matrix metalloproteases and their inhibitors. SOURCE: A search on PubMed was carried out using the following terms: obstructive sleep apnea syndrome; endothelial dysfunction; oxidative stress; inflammation; rheology; matrix metalloproteases. PRINCIPAL FINDINGS: OSAS severity strongly influenced cardiovascular risk factors and, furthermore, it was correlated with the incidence of fatal and non-fatal events. CONCLUSIONS: The treatment with continuous positive airways pressure (cPAP) is the gold standard for OSAS and was able to positively influence all the pathophysiological mechanisms responsible for cardiovascular diseases. Long-term cPAP improved endothelial function and hemorheology, reduced oxidative stress and inflammation, and decreased the levels of metalloproteases. PMID- 26654520 TI - Sex/Gender-Based Pharmacology and Statin Utilization Amongst Elderly Patients with Diabetes. AB - PURPOSE: The purpose of this study was to explore the ten-year trends in utilization of bioequivalent doses of statin amongst elderly patients with diabetes according to sex/gender in Ontario, Canada. METHODS: A cohort of patients with diabetes (>65 years) was constructed using the Ontario Diabetes Database Statin utilization data (2003-2012) was obtained from the Ontario Drug Benefit Program for both women and men. Bioequivalent doses for statins were calculated according to the dosing conversion factor in therapeutic interchange programs in clinical practice. Utilization pattern of high potency (Atorvastatin and Rosuvastatin) vs. low potency statins (Simvastatin, Lovastatin, Fluvastatin, Pravastatin) were also analyzed. RESULTS: The average bioequivalent Simvastatin utilization in 2003 was 29.22 mg/day for women and 30.35 mg/day for men. By 2008, this gap in dosing was higher for both women and men and by 2013 it had increased to 47.75 mg/day for women and 52.98 mg/day for men. For average number of day supply per year, there was no significant trend of changes over the 10-year period, although the use of high potency statins increased significantly (P<0.001) for both women and men. No differences were seen for sex/gender; either for the 10-year period or for each year. CONCLUSIONS: There has been significant increase in bioequivalent statin utilization amongst elderly patients with diabetes in Ontario; for both men and women. In a publicly-funded healthcare system such as Ontario, there were no sex/gender differences in the utilization of high potency statin (Atorvastatin and Rosuvastatin) amongst elderly patient with diabetes. PMID- 26654521 TI - Feasibility and safety of continuous glucose monitoring systems in acute myocardial infarction subjects undergoing primary percutaneous coronary interventions. AB - PURPOSE: The purpose of this study was to evaluate the feasibility and safety of continuous glucose monitoring systems (CGMS) in ST segment elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary interventions (p-PCI) in coronary care units (CCU). METHODS: CGMS was performed for 3 days during CCU hospitalization for each of the subjects. The correlation between glucose values, recorded with CGMS, and finger-stick capillary glucose values was examined. The parameters and safety of CGMS were also investigated. RESULTS: Data from 219 subjects were included in the statistical analysis. Correlation analysis showed a strong positive correlation between interstitial glucose values recorded by CGMS and the corresponding capillary glucose values (P<0.001). The daytime mean blood glucose (MBG), the nighttime MBG and PT7.8 were the highest in the first day of CGMS compared with the second and third day. Furthermore, there were no indications of major hemorrhage or hematoma at the site of sensor insertion. Any adverse events were mild. CONCLUSIONS: CGMS glucose values are relatively accurate and reliable. CGMS were safe and can be used as a tool to detect trends in glucose levels and to predict upcoming glucose excursions in STEMI patients undergoing p-PCI. PMID- 26654522 TI - Mechanisms of remodelling of small arteries, antihypertensive therapy and the immune system in hypertension. AB - This review summarizes my lecture for the 2015 Distinguished Scientist Award from the Canadian Society of Clinical Investigation, and is based mainly on studies in my laboratory on the mechanisms of remodelling of small arteries in experimental animal and human hypertension and on treatments that lower blood pressure and improve structure and function of resistance vessels. Small resistance arteries undergo either inward eutrophic or hypertrophic remodelling, which raises blood pressure and impairs tissue perfusion. These vascular changes are corrected by some antihypertensive drugs, which may lead to improved outcomes. Vasoconstriction, growth, oxidative stress and inflammation are some of the mechanisms, within the vascular wall, that can be beneficially affected by antihypertensive agents. These antihypertensive-sensitive mechanisms are reviewed in this review, together with the inflammatory and immune mechanisms that may participate in hypertension and associated cardiovascular injury. Molecular studies, based on this research, will hopefully identify novel diagnostic and therapeutic targets, which will improve our ability to prevent and treat hypertension and cardiovascular disease. PMID- 26654523 TI - Effect of combined oral contraceptive use on serum 25-hydroxy vitamin D levels and ultrasound parameters in patients with polycystic ovary syndrome. AB - PURPOSE: To investigate if there is an effect of combined oral contraceptive (COC) use on serum 25-hydroxy vitamin D [25(OH)D] levels in patients with polycystic ovary syndrome (PCOS). METHODS: PCOS was defined by the 2003 Rotterdam criteria. All patients with PCOS were treated with a COC containing 0.035 mg ethinylestradiol and 2 mg cyproterone acetate for 6 months. Serum 25(OH)D levels, HOMA-IR, ovarian volume and antral follicule count were measured before and after the treatment. RESULTS: The median 25(OH)D levels were 9.40 (range 4.40-24.50) MUg/l and 7.00 (5.00-13.50) MUg/l before and after COC use, respectively. Serum 25(OH)D levels decreased after the treatment; however, the difference was not statistically significant (p = 0.055). CONCLUSION: This study seems to be the first prospective trial revealing the effect of COC use on serum 25(OH)D levels in women with PCOS. Although the decrease in serum 25(OH)D levels in patients with PCOS with the use of COC alone, did not reach to statistically significance level after 6 months treatment with COC. PMID- 26654524 TI - Oxygen Consumption by Red Wines. Part I: Consumption Rates, Relationship with Chemical Composition, and Role of SO2. AB - Fifteen Spanish red wines extensively characterized in terms of SO2, color, antioxidant indexes, metals, and polyphenols were subjected to five consecutive sensor-controlled cycles of air saturation at 25 degrees C. Within each cycle, O2 consumption rates cannot be interpreted by simple kinetic models. Plots of cumulated consumed O2 made it possible to define a fast and highly wine-dependent initial O2 consumption rate and a second and less variable average O2 consumption rate which remains constant in saturations 2 to 5. Both rates have been satisfactorily modeled, and in both cases they were independent of Fe and SO2 and highly dependent on Cu levels. Average rates were also related to Mn, pH, Folin, protein precipitable proanthocyanidins (PPAs), and polyphenolic profile. Initial rates were strong and negatively correlated to SO2 consumption, indicating that such an initial rate is either controlled by an unknown antioxidant present in some wines or affected by a poor real availability of SO2. Remaining unreacted SO2 is proportional to initial combined SO2 and to final free acetaldehyde. PMID- 26654525 TI - Ball games and nutrition counseling improve postural control in overweight children. AB - BACKGROUND: Motor skills are impaired in overweight children whose levels of physical activity are low and these children are more likely to sustain lower extremity injuries. The purpose of this study was to analyze prospectively in overweight children the influence of ball games and nutrition counseling on postural control. METHODS: In all, 46 overweight children (age: 6-12 years, BMI: female: 25.2 +/- 3.6 kg/m(2), male: 26.2 +/- 2.8 kg/m(2) (mean value +/- standard deviation) were examined prospectively in four randomized groups (ball games, nutrition counseling, ball games and nutrition counseling, and group without intervention) for six months. A one-legged standing test was performed. RESULTS: The children demonstrated improved postural control after six months of intervention: mean difference M1-M2 +/- standard deviation: 5 +/- 6 error points (p < 0.001, T = 4.906), whereas the control group without intervention did not show any significant improvement: 2 +/- 8 error points (p = 0.357, T = 0.972). CONCLUSIONS: Ball games and nutrition counseling have a positive influence on postural control and therefore could help prevent injury. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01825174 . Registered April 2, 2013. PMID- 26654526 TI - Subsequently occurring bilateral iliopsoas hematoma: a case report. AB - BACKGROUND: Spontaneous bilateral iliopsoas hematomas is a rare complication after anticoagulant therapy. Furthermore, the onset of bilateral iliopsoas hematoma is unknown because the causes are unclear. CASE PRESENTATION: A 65-year old man on anticoagulant therapy after mechanical aortic valve replacement was admitted after presenting with severe pain in the left flank and abdomen. Abdominal CT revealed a large left-sided iliopsoas hematoma with extravasation. Fresh frozen plasma was transfused due to prolonged prothrombin time. Transarterial embolization was successfully performed. During the hospital stay, follow-up abdominal CT was performed and a small right-sided iliopsoas hematoma was detected. This was closely observed and an intervention was not performed, as the patient was asymptomatic. The final CT prior to discharge revealed a reduction in size of each hematoma. CONCLUSIONS: Spontaneous bilateral iliopsoas hematoma can be developed subsequently. Patients with unilateral iliopsoas hematoma should be closely monitored for development of bilateral iliopsoas hematoma. PMID- 26654527 TI - Vibrio bivalvicida sp. nov., a novel larval pathogen for bivalve molluscs reared in a hatchery. AB - Three isolates were obtained from cultures of carpet shell clam (Ruditapes decussatus) reared in a bivalve hatchery (Galicia, NW Spain) from different sources: healthy broodstock, moribund larvae and the seawater corresponding to the larval tank. All isolates were studied by a polyphasic approach, including a phylogenetic analysis based on concatenated sequences of the five housekeeping genes ftsZ, gyrB, pyrH, recA and rpoA. The analysis supported their inclusion in the Orientalis clade of the genus Vibrio, and they formed a tight group separated from the closest relatives: Vibrio tubiashii subsp. europaensis, Vibrio tubiashii subsp. tubiashii and Vibrio orientalis. The percentages of genomic resemblance, including average nucleotide identity, DNA-DNA hybridization and in silico genome to-genome comparison, between the type strain and the closest relatives were below values for species delineation and confirmed the taxonomic position of the new species, which could be differentiated from the related taxa on the basis of several phenotypic and chemotaxonomic features, including FAME and MALDI-TOF-MS. The pathogenicity of the new species was demonstrated in larvae of R. decussatus, Ruditapes philippinarum, Ostrea edulis and Donax trunculus. The results demonstrated that the strains analyzed represented a novel species in the Orientalis clade of the genus Vibrio, for which the name Vibrio bivalvicida sp. nov. is proposed, with 605(T) (= CECT 8855(T)=CAIM 1904(T)) designated as the type strain. PMID- 26654528 TI - Diversity and phylogeny of rhizobia associated with Desmodium spp. in Panxi, Sichuan, China. AB - Thirty-four rhizobial isolates were obtained from root nodules of four wild Desmodium species growing in Panxi, Sichuan, China. According to the combined ARDRA and IGS-RFLP (CACAI) cluster analysis, Rhizobium, Pararhizobium and Mesorhizobium isolates outnumbered Bradyrhizobium isolates. In general, the isolates representing the same species from the same site clustered together. Furthermore, the four Desmodium species were all nodulated by more than one rhizobial species. AFLP and phenotypic analyses showed that the 34 isolates represented at least 32 distinct strains. None of the strains were found from more than one site or host, indicating a high degree of rhizobial diversity in Panxi. In the multilocus sequence analysis, the isolates were assigned to Pararhizobium giardinii, Bradyrhizobium japonicum, Mesorhizobium septentrionale, and to undescribed species of the genera Rhizobium, Bradyrhizobium and Agrobacterium. PMID- 26654529 TI - Urine is a novel source of autologous mesenchymal stem cells for patients with epidermolysis bullosa. AB - BACKGROUND: Regenerative medicine is strictly dependent on stem cells as a source for a high diversity of somatic cells. However, the isolation of such from individuals suffering from severe genetic skin blistering diseases like epidermolysis bullosa (EB) is often associated with further organ damage. METHODS: Stem cells were isolated from 112 urine samples from 21 different healthy donors, as well as from 33 urine samples from 25 donors with EB. The cultivation of these cells was optimized by testing different media formulations and pre-coating of culture vessels with collagen. The identity of cells was confirmed by testing marker expression, differentiation potential and immune modulatory properties. RESULTS: We provide here an optimized protocol for the reproducible isolation of mesenchymal stem cells from urine, even from small volumes as obtained from patients with EB. Furthermore, we offer a basic characterization of those urine-derived stem cells (USCs) from healthy donors, as well as from patients with EB, and demonstrate their potential to differentiate into chondrocytes, osteoblasts and adipocytes, as well as their immune-modulatory properties. CONCLUSIONS: Thus, USCs provide a novel and non-invasive source of stem cells, which might be applied for gene-therapeutic approaches to improve medical conditions of patients with EB. PMID- 26654530 TI - Factors associated with having less than 20 natural teeth in rural adults: a cross-sectional study. AB - BACKGROUND: Some systematic reviews have consistently indicated a positive link between Metabolic syndrome, impairedfasting glucose, all-cause or circulatory disease-related mortality, general health, periodontitis, and toothloss. This study was to examine the prevalence of number of remaining teeth <20 and associated risk factors among adults in a rural area of Taiwan. METHODS: A community-based, cross-sectional study was conducted in southwestern coastal Taiwan in 2013; 6680 residents aged 20-64 years were studied. Oral hygiene, substance use, dietary habits, and metabolic syndrome were explored as potential risk factors for number of remaining teeth <20 using logistic regression analysis. RESULTS: The mean number of remaining teeth was 24.6 (SD = 7.4), and 16.3 % (n = 1085) of the participants had number of remaining teeth <20. Men had significantly less frequent use of dental floss, unhealthy dietary habits, more substance use and metabolic syndrome than did women (p <0.001). However, women tended to have fewer teeth than men (p <0.001). After adjusting for potential confounders, older age (odds ratio [OR] = 4.56, 95 % confidence interval [CI]: 3.74-5.55), female (OR = 1.88, 95 % CI: 1.56-2.25), less education (OR = 2.40, 95 % CI: 1.90-3.02), infrequent use of dental floss (OR = 1.94, 95 % CI: 1.66-2.27), substance use (OR = 1.32, 95 % CI: 1.09-1.59), and number of metabolic syndrome components (OR = 1.10, 95 % CI: 1.04-1.16) were independently associated with a higher risk of number of remaining teeth <20. CONCLUSIONS: Number of remaining teeth <20 was highly prevalent among rural adults. In addition to unmodifiable factors, infrequent use of dental floss, substance use, and metabolic syndrome were risk factors associated with tooth loss. PMID- 26654531 TI - Genetic basis of maize kernel starch content revealed by high-density single nucleotide polymorphism markers in a recombinant inbred line population. AB - BACKGROUND: Starch from maize kernels has diverse applications in human and animal diets and in industry and manufacturing. To meet the demands of these applications, starch quantity and quality need improvement, which requires a clear understanding of the functional mechanisms involved in starch biosynthesis and accumulation. In this study, a recombinant inbred line (RIL) population was developed from a cross between inbred lines CI7 and K22. The RIL population, along with both parents, was grown in three environments, and then genotyped using the MaizeSNP50 BeadChip and phenotyped to dissect the genetic architecture of starch content in maize kernels. RESULTS: Based on the genetic linkage map constructed using 2,386 bins as markers, six quantitative trait loci (QTLs) for starch content in maize kernels were detected in the CI7/K22 RIL population. Each QTL accounted for 4.7% (qSTA9-1) to 10.6% (qSTA4-1) of the starch variation. The QTL interval was further reduced using the bin-map method, with the physical distance of a single bin at the QTL peak ranging from 81.7 kb to 2.2 Mb. Based on the functional annotations and prior knowledge of the genes in the top bin, seven genes were considered as potential candidate genes for the identified QTLs. Three of the genes encode enzymes in non-starch metabolism but may indirectly affect starch biosynthesis, and four genes may act as regulators of starch biosynthesis. CONCLUSIONS: A few large-effect QTLs, together with a certain number of minor effect QTLs, mainly contribute to the genetic architecture of kernel starch content in our maize biparental linkage population. All of the identified QTLs, especially the large-effect QTL, qSTA4-1, with a small QTL interval, will be useful for improving the maize kernel starch content through molecular breeding. PMID- 26654538 TI - Vaccination decision-making of immigrant parents in the Netherlands; a focus group study. AB - BACKGROUND: Although the vaccination coverage in most high income countries is high, variations in coverage rates on the national level among different ethnic backgrounds are reported. A qualitative study was performed to explore factors that influence decision-making among parents with different ethnic backgrounds in the Netherlands. METHODS: Six focus groups were conducted with 33 mothers of Moroccan, Turkish and other ethnic backgrounds with at least one child aged 0-4 years. Data were analysed using thematic analysis. RESULTS: Parents had a positive attitude towards childhood vaccination and a high confidence in the advices of Child Vaccine Providers (CVPs). Vaccinating their children was perceived as self-evident and important. Parents do perceive a language barrier in understanding the provided NIP-information, and they had a need for more NIP- information, particularly about the targeted diseases. Another barrier parents perceived was the distance to the Child Welfare Center (CWC), especially when the weather was bad and when they had no access to a car. CONCLUSION: More information about targeted diseases and complete information regarding benefits and drawbacks of the NIP should be provided to the parents. To fulfill parents' information needs, NIP information meetings can be organized at CWCs in different languages. Providing NIP information material in Turkish, Arabic and Berber language with easy access is also recommended. Providing information tailored to these parents' needs is important to sustain high vaccination participation, and to ensure acceptance of future vaccinations. PMID- 26654539 TI - Cation-Controlled Excimer Packing in Langmuir-Blodgett Films of Hemicyanine Amphiphilic Chromoionophores. AB - Supramolecular structure of ultrathin films of hemicyanine dye bearing a crown ether group (CrHCR) was tuned by lateral pressure and investigated by means of compression isotherms, UV-vis and fluorescence spectroscopies, and X-ray reflectivity. Two different types of aggregation were revealed, depending on the absence or the presence of metal cations in the water subphase. While CrHCR forms at high surface pressures head-to-tail stacking aggregates on pure water, changing the subphase to a metal-cation-containing one leads to the appearance of well-defined excimers with head-to-head orientation. The structure of monolayers transferred onto solid supports by the Langmuir-Blodgett (LB) technique was examined by use of X-ray reflectivity measurements and molecular modeling. A model of cation-induced excimer formation in hemicyanine Langmuir monolayers is proposed. Finally, fluorescence emission properties of LB films of CrHCR can be managed by appropriate changes in the subphase composition, this last one determining the type of chromophore aggregation. PMID- 26654540 TI - [Editor's commentary: Bionics Innovation Center, Budapest, Hungary]. PMID- 26654541 TI - [Contribution of Tamas Roska to international and national bionics research]. PMID- 26654542 TI - [Novel methods and their applicability in the evaluation of the genetic background of endocrine system tumours]. AB - The technical developments leading to revolution in clinical genetic testing offer new approaches for patients with cancer. From one mutation or one gene approach the scale of genetic testing moved to whole exome or whole genome scale. It is well known that many tumours are genetically determined and they are part of familial tumour syndromes. In addition, some mutations indicate specific molecular targeted therapies. Although sampling and sample preparation are different for testing germline and somatic mutations, the technical background of the analysis is the same. The aim of clinical genetic testing is to identify patients who are carriers of disease-causing mutations or to test tumour tissue for the presence of genetic alterations which may be targets for therapeutic approaches. In this review the authors summarize novel possibilities offered by next-generation sequencing in clinical genetic testing of patients with endocrine tumours. In addition, the authors review recent guidelines on technical and ethical issues related to these novel methods. PMID- 26654543 TI - [Focusing on tissue biomarkers. Estrogens as key players in the immune response and autoimmunity]. AB - Estrogens modulate the immune response as well as the risk and progression of autoimmune disorders. Their effects are mediated by nuclear receptors (i.e. estrogen receptor alpha and beta), membrane receptors, and are influenced by their interactions with other hormones. Locally produced hormones and cytokines are the main factors in maintaining tissue homeostasis. The response of immune cells to estrogens is related to their developmental stage. The diverse effects of estrogens on various autoimmune disorders are the result of the versatility of their pathomechanism. In general, progression of B-cell mediated disorders is aggravated by estrogens. Their effects on T-cell mediated disorders, on the other hand, are driven by Th1 or Th2 dominance. As estrogens promote the escalation of the Th2 immune response, Th2-dominant disorders are aggravated, while Th1 dominant disorders are ameliorated upon high estrogen levels. Inflammation on its own also modulates the impact of estrogens. Inflammatory cytokines alter the expression of the alpha and beta estrogen receptors as well as the activity of estrogen metabolizing enzymes. Monitoring the local, tissue-wide interaction between hormones and immune cells would provide a better tool for identification and characterization of molecules involved in this system. To date, routinely used laboratory methods have a limited role in monitoring the local effects of estrogens. In this current paper the authors summarize the role of estrogens in immune system and overview those novel methods which are useful in the investigation of local endocrine milieu. PMID- 26654544 TI - [From biomarkers to clinical decision support]. AB - The rapidly accumulating, heterogeneous, numerous biomedical data and the increasing knowledge represent both the key areas and the major bottleneck in the complete realization of personalized medicine. Traditional clinical aims as well as decision-making processes in drug research need systems-based integration of data and their analyses, which require a wide range of new mathematical approaches and application of information technologies. In the world of biomarkers, all such tasks correspond to three types of biomarkers, namely, endpoint, target and diagnostic biomarkers, which together form a complex network. To decipher the networks, probabilistic graphical models are introduced. Briefly, the authors illustrate their use for exploration and visualization of direct dependencies among biomarkers. Finally, construction of decision networks and their application to structural and quantitative optimization of biomarkers are discussed to provide a novel type of supporting tools for clinical practice. PMID- 26654545 TI - [Development of molecular detection of food-borne pathogenic bacteria using miniaturized microfluidic devices]. AB - Detection and identification of food-borne pathogenic bacteria are key points for the assurance of microbiological food safety. Traditional culture-based methods are more and more replaced by or supplemented with nucleic acid based molecular techniques, targeting specific (preferably virulence) genes in the genomes. Internationally validated DNA amplification - most frequently real-time polymerase chain reaction - methods are applied by the food microbiological testing laboratories for routine analysis, which will result not only in shortening the time for results but they also improve the performance characteristics (e.g. sensitivity, specificity) of the methods. Beside numerous advantages of the polymerase chain reaction based techniques for routine microbiological analysis certain drawbacks have to be mentioned, such as the high cost of the equipment and reagents, as well as the risk of contamination of the laboratory environment by the polymerase chain reaction amplicons, which require construction of an isolated laboratory system. Lab-on-a-chip systems can integrate most of these laboratory processes within a miniaturized device that delivers the same specificity and reliability as the standard protocols. The benefits of miniaturized devices are: simple - often automated - use, small overall size, portability, sterility due to single use possibility. These miniaturized rapid diagnostic tests are being researched and developed at the best research centers around the globe implementing various sample preparation and molecular DNA amplification methods on-chip. In parallel, the aim of the authors' research is to develop microfluidic Lab-on-a-chip devices for the detection and identification of food-borne pathogenic bacteria. PMID- 26654547 TI - Growth Factor-Loaded Microparticles for Tissue Engineering: The Discrepancies of In Vitro Characterization Assays. AB - Efficient and effective growth factor (GF) delivery is an ongoing challenge for tissue regeneration therapies. The accurate quantification of complex molecules such as GFs, encapsulated in polymeric delivery devices, is equally critical and just as complex as achieving efficient delivery of active GFs. In this study, GFs relevant to bone tissue formation, vascular endothelial growth factor (VEGF) and bone morphogenetic protein 7 (BMP-7), were encapsulated, using the technique of electrospraying, into poly(lactic-co-glycolic acid) microparticles that contained poly(ethylene glycol) and trehalose to assist GF bioactivity. Typical quantification procedures, such as extraction and release assays using saline buffer, generated a significant degree of GF interactions, which impaired accurate assessment by enzyme-linked immunosorbent assay (ELISA). When both dry BMP-7 and VEGF were processed with chloroform, as is the case during the electrospraying process, reduced concentrations of the GFs were detected by ELISA; however, the biological effect on myoblast cells (C2C12) or endothelial cells (HUVECs) was unaffected. When electrosprayed particles containing BMP-7 were cultured with preosteoblasts (MC3T3-E1), significant cell differentiation into osteoblasts was observed up to 3 weeks in culture, as assessed by measuring alkaline phosphatase. In conclusion, this study showed how electrosprayed microparticles ensured efficient delivery of fully active GFs relevant to bone tissue engineering. Critically, it also highlights major discrepancies in quantifying GFs in polymeric microparticle systems when comparing ELISA with cell based assays. PMID- 26654548 TI - Optical Interference Enhances Nonlinear Spectroscopic Sensitivity: When Light Gives You Lemons, Model Lemonade. AB - Optical interference effects can be a nuisance in spectroscopy, especially in nonlinear experiments in which multiple incoming and outgoing beams are present. Vibrational sum frequency generation is particularly susceptible to interference effects because it is often applied to planar, layered materials, driving many of its practitioners to great lengths to avoid signal generation from multiple interfaces. In this perspective, we take a positive view of this metaphorical "lemon" and demonstrate how optical interference can be used as a tool to extract subtle changes in interfacial vibrational spectra. Specifically, we use small frequency shifts at a buried interface in an organic field-effect transistor to determine the fractional charge per molecule during device operation. The transfer matrix approach to nonlinear signal modeling is general and readily applied to complex layered samples that are increasingly popular in modern studies. More importantly, we show that a failure to consider interference effects can lead to erroneous interpretations of nonlinear data. PMID- 26654549 TI - Real-time tracking of delayed-onset cellular apoptosis induced by intracellular magnetic hyperthermia. AB - AIM: To assess cell death pathways in response to magnetic hyperthermia. MATERIALS & METHODS: Human melanoma cells were loaded with citric acid-coated iron-oxide nanoparticles, and subjected to a time-varying magnetic field. Pathways were monitored in vitro in suspensions and in situ in monolayers using fluorophores to report on early-stage apoptosis and late-stage apoptosis and/or necrosis. RESULTS: Delayed-onset effects were observed, with a rate and extent proportional to the thermal-load-per-cell. At moderate loads, membranal internal to-external lipid exchange preceded rupture and death by a few hours (the timeline varying cell-to-cell), without any measurable change in the local environment temperature. CONCLUSION: Our observations support the proposition that intracellular heating may be a viable, controllable and nonaggressive in vivo treatment for human pathological conditions. PMID- 26654550 TI - [Irritable bowel syndrome: the next-to-last that is being investigated]. PMID- 26654551 TI - [Quality of life in patients with diabetic macular edema and low vision treated with antiangiogenic drugs]. PMID- 26654552 TI - [Legionella's pneumonia. When is useful the urinary antigen test?]. PMID- 26654553 TI - [Multiple chemical sensitivity: Clinical evaluation of the severity and psychopathological profile]. AB - INTRODUCTION AND OBJECTIVE: Multiple chemical sensitivity (MCS) is a multisystem disorder of controversial etiology, affecting some subjects when exposed to chemicals at no harmful concentrations. The objective of this paper is to describe the epidemiological, clinical and psychological features of a sample of patients with MCS for further specific group treatment. PATIENS AND METHOD: Descriptive study of patients diagnosed with MCS in a toxicology unit. We administered the Quick Environmental Exposure and Sensitivity Inventory, the structured interview SCID-II, the anxiety scale HAS and the type A personality test, PCTA. RESULTS: Seventy-three patients were included. The mean age was 52,6 years (range 33-77; SD 9.29). Sixty-six were females (90.4%). Fifty-three percent were classified as i-ii and ii grade. Sixty-one patients (83%) presented some type of comorbidity, mainly chronic pain, fibromyalgia and chronic fatigue. They exhibited higher levels of anxiety (average score of 19.2), prevalence of phobic avoidant traits of personality and type A behavior in 31.1%. CONCLUSIONS: MCS affects middle-aged women with comorbidities (chronic pain, fibromyalgia and chronic fatigue) and high anxiety and avoidance behaviors. This preliminary analysis should help provide a specific therapeutic approach to these patients. PMID- 26654554 TI - [Subcutaneous ivermectin in disseminated strongyloidiasis: A veterinary preparation authorised for human use]. PMID- 26654555 TI - [STX16 deletion associated to pseudohypoparathyroidism]. PMID- 26654556 TI - The impact of the IL-1beta, IL-1Ra, IL-2, IL-6 and IL-10 gene polymorphisms on the development of Behcet's disease and their association with the phenotype. AB - BACKGROUND AND OBJECTIVE: This trial was designed to investigate the effects of the interleukin (IL)-1beta, IL-1Ra, IL-2, IL-6, IL-10 gene polymorphisms on Behcet's disease (BD) occurrence and the association between the polymorphisms and the phenotype. MATERIALS AND METHOD: The study population consisted of 71 patients and 70 age and gender-matched healthy subjects. Each of the participants had 2cc of blood withdrawn, which was placed into a whole blood tube, and the DNA was obtained using the NucleoSpin((r)) Blood DNA Isolation kit. To display the band lengths, the products were amplified using the primary pairs of the interleukins investigated and developed in a 2% agarose gel. RESULTS: There were no significant differences between the groups with respect to the IL-1Ra, IL 1beta, IL-2, IL-6 and the IL-10 gene polymorphism distributions. In the patient group the IL-1RN2 gene polymorphism was detected to be statistically correlated with the presence of articular involvement (p=0.0283) and the IL-1beta gene polymorphism was statistically correlated with the presence of an ocular lesion (p=0.0178). The evaluation of the IL-2 gene polymorphism (p=0.0065) and IL-10 gene polymorphism (p=0.0483) distributions with respect to age of BD onset revealed a statistically significant distribution. CONCLUSION: The statistical correlations between the articular involvement and IL-1RN, the ocular involvement and the IL-1beta, and the age of disease onset and the IL-2 and IL-10 gene polymorphisms, detected for the first time in the literature, suggest that these polymorphisms could be statistically associated with the disease symptoms and used as prognostic factors. PMID- 26654557 TI - [Cultural scale adaptation and validation of the Spanish version of the BRCA Self Concept Scale in women carriers at high risk for hereditary breast and ovarian cancer]. AB - BACKGROUND AND OBJECTIVE: Having an inherited predisposition to cancer may have a psychological impact, and one goal of genetic counseling is to promote psychological adjustment to the new situation. Thus, in the genetic context, validated measures of adjustment are required. Given that self-concept is a good indicator of adjustment to the disease or to the risk for it, and a relevant variable in oncology, the goal of the study is to culturally adapt and validate the BRCA Self-Concept Scale. MATERIAL AND METHOD: One hundred and sixty-five BRCA carriers' women answered to the questionnaire, previously adapted through a process of forward/back-translation, and to the Cancer Worry Scale (CWS) as a measure of convergent validity. Theoretical structure of BRCA Self-Concept Scale was assessed by expert judges, and submitted to a confirmatory factor analysis (CFA). Cronbach's alpha was calculated for each subscale (Stigma, Vulnerability and Control), and correlations with CWS were performed. RESULTS: Expert judges' structure and CFA do not support the original structure of the questionnaire. The respecificity model (with items 10 and 13 loading on Vulnerability factor) show a better fit: comparative fit index 0.973; Tucker-Lewis index 0.968; root mean square error of approximation 0.067. The Cronbach's alpha is 0.83 for Stigma, 0.84 for Vulnerability, and 0.61 for Control. Evidence of convergent validity with CWS has been obtained (Spearman's rho 0.631 for Stigma, 0.683 for Vulnerability, and -0.363 for Control; P<.001). CONCLUSIONS: Results support the validity of the modified Spanish BRCA Self-Concept Scale, which is a potentially useful measure for the study of psychological adjustment to high risk for hereditary breast and ovarian cancer. PMID- 26654558 TI - [Cost-effectiveness analysis of sofosbuvir-simeprevir regimens for chronic hepatitis C genotype 1 patients with advanced fibrosis]. AB - BACKGROUND AND OBJECTIVE: The aim of this study was to measure the cost effectiveness of the treatment with simeprevir and sofosbuvir in chronic hepatitis C genotype 1 patients with F3-F4 levels of fibrosis, according to the results of the COSMOS trial. MATERIAL AND METHODS: A Markov model was used to estimate the costs and clinical outcomes from the start of therapy. In the model, the progression was simulated alongside the different health states of the chronic liver disease associated with chronic hepatitis C using whole life as time-horizon. RESULTS: The 12-weeks treatment schemes was below the threshold of ?40,000 per quality-adjusted life year. On the contrary, despite the 50% cost reduction, the 24-weeks regimen demonstrated a limited level of efficiency when compared with the willingness to pay used in the Spanish medical literature. CONCLUSIONS: This finding would support the introduction of a flat rate in the price of drugs without taking into account the duration of treatment to ensure that treatment with 24 weeks was efficient. PMID- 26654559 TI - [Lithium-associated hyperparathyroidism]. PMID- 26654560 TI - Pneumococcal pneumonia in adults 60 years or older: Incidence, mortality and prevention. AB - BACKGROUND: This study investigated the burden (incidence, mortality and serotype distribution) of pneumococcal pneumonia among older adults in the region of Tarragona (Spain). METHODS: Population-based cohort study involving 27,204 individuals >=60 years in Tarragones county (Southern Catalonia), who were prospectively followed between 01/12/2008 and 30/11/2011. Bacteremic and nonbacteremic (positive sputum culture and/or urinary antigen test) pneumococcal pneumonias were recruited. RESULTS: A total of 125 pneumococcal pneumonias (16 bacteremic and 109 nonbacteremic) was observed. Incidence rates (per 1000 person years) were 0.21 (95% confidence interval [CI]: 0.13-0.35) for bacteremic cases and 1.45 (95% CI: 1.20-1.75) for nonbacteremic cases. Case-fatality rate was 10.4% (12.5% in bacteremic and 10.1% in nonbacteremic cases). Five serotypes (types 3, 6C, 19A, 22F and 35B) were the most common serotypes, accounting for 64.3% of overall isolated serotypes. 73.1% of cases were due to the strains included in the 23-valent vaccine whereas 53.6% were due to the strains included in the 13-valent vaccine. CONCLUSION: The burden of pneumococcal pneumonia remains considerable (especially among oldest people and nursing-home residents) despite a publicly funded anti-pneumococcal vaccination program operative for several years. PMID- 26654561 TI - Linking trajectories of land change, land degradation processes and ecosystem services. AB - Land Degradation (LD) is a complex phenomenon resulting in a progressive reduction in the capacity of providing ecosystem services (ES). Landscape transformations promoting an unsustainable use of land often reveal latent processes of LD. An evaluation carried out in respect to the different ecosystem services is nowadays regarded as the most appropriate approach for assessing the effects of LD. The aim of this study is to develop an evaluation framework for identifying the linkages between land changes, LD processes and ES and suggesting Sustainable Land Management (SLM) options suited to reverse (or mitigate) LD impact. A SWOT analysis was carried out with the aim to identify internal and external factors that are favorable (or unfavorable) to achieve the proposed SLM actions. The study areas are the Fortore valley and the Valpadana, in Italy. The main trajectory identified for the Fortore valley is related to land abandonment due to population aging and the progressive emigration started in the 1950s. The most relevant LD processes are soil erosion and geomorphological instability, affecting regulating services such as natural hazard and erosion control. SLM options should consider interventions to contrast geomorphological instability, the promotion of climate smart agriculture and of typical products, and an efficient water resources management. The main trajectories identified for Valpadana are related to urban expansion and farmland abandonment and, as a consequence, land take due to anthropogenic pressure and woodland expansion as the main LD process. The reduction of food production was identified as the most relevant provisioning service affected. SLM should envisage best practices finalized to water saving and soil consumption reduction: efficient irrigation solutions, climate smart agriculture and zero sealing practices. This study highlights the diagnostic value of the suggested approach where LD processes are elicited from land change trajectories determining specific impacts on ES and providing operational support for the implementation of SLM options. PMID- 26654562 TI - Urinary biomarkers of exposure to 57 xenobiotics and its association with oxidative stress in a population in Jeddah, Saudi Arabia. AB - Oxidative stress arises from excessive free radicals in the body and is a trigger for numerous diseases, such as cancer and atherosclerosis. Elevated exposure to environmental chemicals can contribute to oxidative stress. The association between exposure to xenobiotics and oxidative stress, however, has rarely been studied. In this study, urinary concentrations of 57 xenobiotics (antimicrobials, parabens, bisphenols, benzophenones, and phthalates metabolites) were determined in a population from Jeddah, Saudi Arabia, to delineate association with the oxidative stress biomarker, 8-hydroxy-2'-deoxyguanosine (8OHDG). We collected 130 urine samples and analyzed for 57 xenobiotics using liquid chromatography-tandem mass spectrometry (LC/MS/MS) methods. The association between unadjusted and creatinine- or specific gravity-adjusted concentrations of xenobiotics and 8OHDG was examined by Pearson correlations and multiple regression analysis. High concentrations of mCPP (a metabolite of di-n-octyl phthalate; DnOP) and mCMHP (a metabolite of diethylhexyl phthalate; DEHP) were found in urine. In addition, the concentrations of bisphenol S (BPS) were higher than those of bisphenol A (BPA). The concentrations of metabolites of DEHP, phthalic acid, BPA, BPS, and methyl protocatechuic acid were significantly associated with 8OHDG. This is the first biomonitoring study to report exposure of the Saudi population to a wide range of environmental chemicals and provides evidence that environmental chemical exposures contribute to oxidative stress. PMID- 26654563 TI - Phthalate exposure in association with serum hormone levels, sperm DNA damage and spermatozoa apoptosis: A cross-sectional study in China. AB - Exposure to phthalates has been demonstrated to cause reproductive toxicity in animals, but evidence of the association between phthalates and markers of male reproductive function have been inconsistent in human studies. Here we examined whether environmental exposure to phthalates contributes to altered reproductive hormone levels, sperm DNA damage and spermatozoa apoptosis in a Chinese population. From March to June 2013, repeated urine samples collected from male partners of couples attending an infertility clinic in Wuhan, China were analyzed for 8 phthalate metabolites. Associations of the urinary phthalate metabolites with serum hormone levels (n=483), sperm DNA damage parameters (n=509) and spermatozoa apoptosis measures (n=467) were assessed using multivariable linear regression models. After adjusting for potential confounders, mono-(2-ethylhexyl) phthalate (MEHP), a metabolite of di-(2-ethylhexyl)-phthalate (DEHP), was inversely associated with serum levels of estradiol, total testosterone (T) and free T (all P for trend<0.05). Additionally, we found positive dose-response relationships between the percentage of DEHP metabolites excreted as MEHP (%MEHP) and percentages of tail DNA (P for trend<0.05) and between three metabolites of DEHP [MEHP, mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) and mono(2-ethyl-5 oxohexyl) phthalate (MEOHP)] and percentages of Annexin V+/PI- spermatozoa (all P for trend<0.05). Our findings strengthen the emerging evidence that exposure to DEHP may alter hormone levels, disrupt sperm DNA integrity and induce spermatozoa apoptosis. PMID- 26654564 TI - [Prevalence of dyslipidemia in the rural population of Gueoul (Senegal)]. AB - INTRODUCTION: The cardiovascular risk factors are clearly increasing in developing countries. Among these factors, dyslipidemia is often found, this due to the change in behavioral and dietary habits (OMS, 2006). Dyslipidemia is a "primary or secondary pathological changes in serum lipids". It is a chronic and metabolic abnormality, characterized by persistently elevated TG, LDL-c, and a decrease in HDL (Attias et al., 2013-2014). The objective of this study is to determine the prevalence of dyslipidemia, and give the lipid profile of the population in Gueoul. PATIENTS AND METHODS: We performed a comprehensive observational study, cross-sectional descriptive on Senegalese aged 35 or over, living in Gueoul for at least 6 months. Lipid profile (total cholesterol, triglycerides, HDL-cholesterol, LDL-cholesterol) was systematically after 12hours of fasting. RESULTS: Dyslipidemia was found in 61.3 % of cases with 50 % pure hypercholesterolemia (n=705). Only 20 subjects (2.3 %) knew they had dyslipidemia. The detection rate was 59.8 % (n=844). The type most represented was hypoHDLemia (45.6 %) followed by hyperLDLemia (28.8 %). Triglycerides were increased in only 2.8 % of cases. CONCLUSION: The prevalence of dyslipidemia is very high in our regions. It is often associated with female gender, hypertension, diabetes, and obesity. Its main causes are physical inactivity, change in lifestyle and eating habits. It is often misunderstood and its management is limited in most cases to low-calorie diet. PMID- 26654565 TI - Disease profile and health-related quality of life (HRQoL) using the EuroQol (EQ 5D + C) questionnaire for chronic metallic mercury vapor intoxication. AB - BACKGROUND: Toxic mercury is still being used today for example by workers mining gold, resulting in diverse health symptoms in users and individuals in proximity. A considerable burden of disease (BoD) can be assumed, while previous analyses were limited by data scarcity. Besides limited epidemiological data, neither data about the health-related quality of life (HRQoL) nor about the disease severity (disability weight, DW) is available. The aim of the project was to develop disease profiles of chronic metallic mercury vapor intoxication (CMMVI) by including the HRQoL to improve the data basis for BoD analyses of gold miners exposed to mercury. METHODS: Disease profiles comprising the disease label [a], differentiation into disease stages [b], description of the cause of exposure [c], a list of common symptoms [d], and an assessment of the HRQoL [e] were developed using expert elicitation and literature search. The HRQoL was assessed by experts using the five EuroQol dimensions accompanied by the cognition add-on questionnaire (EQ-5D + C). RESULTS: The ten sources used for the analyses (interview transcript, presentation, and eight literature reviews) identified more than 250 terms describing 85 distinguishable health effects of CMMVI. The analysis revealed 29 common symptoms that were frequently mentioned. Moderate and severe CMMVI cases differ regarding their symptoms and/or symptom severity and HRQoL, resulting in the EQ-5D + C-3L codes 121222 and 233333, respectively. CONCLUSIONS: The profiles should be used to facilitate the ascertainment of CMMVI cases, to compare the HRQoL with other diseases, to derive DWs for improving BoD estimates, and to foster discussions about how to reduce the associated burden. PMID- 26654566 TI - Molecular Dynamics Simulations of 5-Hydroxycytosine Damaged DNA. AB - Oxidation of cytosine is a leading cause of mutations and can lead to cancer. Here we report molecular dynamics simulations that characterized the structure and flexibility of 5-hydroxycytosine damaged DNA. A total of four systems were studied: undamaged DNA, damaged DNA base paired to a matching guanine, damaged DNA base paired to a mismatching adenine, and the corresponding undamaged mismatched strand. The simulations showed high spatial similarity between undamaged and damaged DNA; however, the matched damaged strand had greater overtwisting flexibility, and for both the matched and unmatched strands sugar puckering was much more flexible at the damaged site. The mismatch introduced larger changes, notably a loss in hydrogen bonding and a gain in stacking interactions, as well as effects on base pair and step geometry and solvation. Implications for damage recognition are discussed. PMID- 26654567 TI - Terpenoids from Euphorbia pekinensis. AB - Euphorpekone A (1) and euphorpekone B (2), two new diterpenoids, 3beta-hydroxy-25 methyloxylanosta-8,23-diene, a new triterpenoid (3), together with a known triterpenoid, 3beta,25-dihydroxylanosta-8,23-diene (4), were isolated from Euphorbia pekinensis Rupr. Their structures were elucidated on the basis of UV, IR, 1D ((1)H, (13)C, NOE) and 2D ((1)H-(1)H COSY, HSQC, HMBC) NMR, HR-ESI-MS, X ray diffraction analysis, and CD method. PMID- 26654568 TI - Tit for Tat Brain versus Heart: A Case of Status Epilepticus, Cardiomyopathy, and Stroke. PMID- 26654570 TI - HPV and Anal Cancer Knowledge among HIV-Infected and Non-Infected Men Who Have Sex With Men. AB - PURPOSE: The purpose of this study was to investigate the current status of what men who have sex with men (MSM) know about anal cancer in terms of self-care behaviors/practices, human papillomavirus (HPV) knowledge, risk awareness, anal cancer screening history, the need to be screened, and how demographic or behavioral practices were associated with knowledge and awareness. METHODS: A convenience sampling method was employed. Participants were recruited in 2014 2015 in venues such as Pride Center events as well as in bars, restaurants, and cafes that cater to a gay clientele. Participants' knowledge of HPV and anal cancer were examined using the Anal Cancer Knowledge Questionnaire (ACKQ). The 65 item survey consisted of demographic variables, questions related to anal health behaviors, practices, and perceptions, HPV and anal cancer knowledge, and HPV and anal cancer risk awareness. RESULTS: The sample consisted of 163 men. The mean age of the participants was 49.6 years. The majorities were white (62.6%), followed by Hispanic (26.4%) and Black (8.0%). Study participants were, to a great extent, uninformed and largely unaware of the link between HPV and anal cancer and the risk that HPV and anal cancer presented to MSM. One-way analysis of variance (ANOVA) indicated that HPV knowledge, P < .001, and risk awareness, P < .001, differed by HIV status. CONCLUSION: In spite of efforts in recent years to raise HPV and anal cancer awareness, those groups most at risk appear to remain uncertain of risk, screening, and measures to protect themselves from the adverse implications of HPV infection. PMID- 26654569 TI - Ethnic differences in sleep duration and morning-evening type in a population sample. AB - This cross-sectional population study examined associations of sleep duration and morning-evening type with sociodemographic and cardiometabolic disease in adults participating in the UK Biobank study (N = 439 933). Multivariable Poisson regression models of sleep duration and morning-evening type with a robust error variance were generated to estimate adjusted prevalence ratios and their 95% confidence intervals. All models were adjusted for sex, race, college attendance, employment status and age. Twenty five percent of the sample reported short sleep; 27% were morning, 64% intermediate and 9% evening type. Black ethnicity emerged as most strongly associated with sleep behavior. Short sleep was twice as prevalent, and morning versus intermediate type was 1.4 times more prevalent in Black than White participants. The greater prevalence of short sleep and morning type among Blacks suggests that sleep-based approaches to improving cardiometabolic outcomes may require a more multidimensional approach that encompasses adequate sleep and circadian alignment in this population. PMID- 26654571 TI - Polyarthritis and membranoproliferative glomerulonephritis as paraneoplastic manifestation of Hodgkin's lymphoma: A case report and literature review. AB - Paraneoplastic syndromes can be presented in multiple ways, which include endocrinological, hematologic, rheumatologic and nephrologic manifestations. While most of the publications described solid tumors as responsible for these manifestations, hematologic neoplasms are important cause to consider as part of the differential diagnosis. We report the case of a 46 year-old man with seronegative symmetric polyarthritis of large and small joints associated with membranoproliferative glomerulonephritis with deposits of immune complexes and acute impairment of renal function, as part of a paraneoplastic syndrome secondary of a classical Hodgkin lymphoma with bone marrow invasion, which reversed completely with chemotherapy treatment. PMID- 26654572 TI - An Ankle-Foot Orthosis With a Lateral Extension Reduces Forefoot Abduction in Subjects With Stage II Posterior Tibial Tendon Dysfunction. AB - STUDY DESIGN: Controlled laboratory, repeated measures. BACKGROUND: Posterior tibial tendon dysfunction is a common musculoskeletal problem that includes tendon degeneration and collapse of the medial arch of the foot (flatfoot deformity). Ankle-foot orthoses (AFOs) typically are used to correct flatfoot deformity. Correction of flatfoot deformity involves increasing forefoot adduction, forefoot plantar flexion, and hindfoot inversion. OBJECTIVES: To test whether a foot orthosis with a lateral extension reduces forefoot abduction in patients with stage II posterior tibial tendon dysfunction while walking. METHODS: The gait of 15 participants with stage II posterior tibial tendon dysfunction was evaluated under 3 conditions: a standard AFO, an AFO with a lateral extension, and a shoe-only control condition. Kinematic variables of interest were evaluated at designated time points in the gait cycle and included hindfoot inversion/eversion, forefoot plantar flexion/dorsiflexion, and forefoot abduction/adduction. A 3-by-4, repeated-measures analysis of variance (brace condition by gait phase) was used to compare variables across conditions. RESULTS: The AFO with a lateral extension resulted in a significantly greater change in forefoot adduction compared to the standard AFO (2.6 degrees , P = .02) and shoe-only conditions (4.1 degrees , P<.01) across all phases of stance. Forefoot plantar flexion was significantly increased when comparing the standard AFO and AFO with a lateral extension to the shoe-only condition. The AFO with the lateral extension also demonstrated significantly increased hindfoot inversion during the loading response and terminal stance phases. CONCLUSION: Off-the-shelf and standard AFOs have been shown to improve forefoot plantar flexion and hindfoot eversion, but not forefoot adduction. A lateral extension added to a standard AFO along the forefoot significantly improved forefoot adduction in participants with posterior tibial tendon dysfunction while walking. PMID- 26654573 TI - The role of toll-like receptors in B-cell development and immunopathogenesis of common variable immunodeficiency. AB - Common variable immunodeficiency (CVID) is the most frequent symptomatic primary immune deficiency and is characterized by hypogammaglobulinemia, defect in specific antibody response and increased susceptibility to recurrent infections, malignancy and autoimmunity. Patients with CVID often have defects in post antigenic B-cell differentiation, with fewer memory B cells and impaired isotype switching. Toll-like receptors (TLRs) are expressed on various immune cells as key elements of innate and adaptive immunity. TLR signaling in B cells plays multiple roles in cell differentiation and activation, class-switch recombination and cytokine and antibody production. Moreover, recent studies have shown functional alteration of TLRs responses in CVID patients including poor cell proliferation, impaired upregulation of co-stimulatory molecules and failure in cytokine and immunoglobulin production. The purpose of the present review is to discuss the role of TLRs in B-cell development and function as well as their role in the immunopathogenesis of CVID. PMID- 26654574 TI - Capuchins (Cebus apella) are limited in their ability to infer others' goals based on context. AB - Recent research suggests that many primate species understand others' actions not only in terms of their physical movements, but also in terms of the actor's underlying goals and intentions. Impressively, apes also have the capacity to incorporate previously acquired contextual information into their goal representations. To date, little work has tested whether other primates demonstrate this level of flexibility when inferring others' goals. To help address this question, we tested capuchin monkeys using a procedure similar to one that Buttelmann, Schutte, Carpenter, Call, and Tomasello (2012) used to test apes. Capuchin subjects were repeatedly shown an experimenter manipulating locking mechanisms on a series of boxes. In an experimental condition, the experimenter gave subjects food retrieved from inside the boxes, whereas in a control condition subjects never received food from inside the boxes. We then explored how capuchin subjects would interpret the experimenter's ambiguous manipulation of a novel box. In contrast to apes, subjects in our experiment showed little evidence of being able to flexibly use temporally dissociated contextual cues to make inferences regarding others' goals. This result may point to a crucial difference in the sophistication with which ape and nonape primates understand others' actions. PMID- 26654575 TI - Sweetening of the global diet, particularly beverages: patterns, trends, and policy responses. AB - Evidence suggests that excessive intake of added sugars has adverse effects on cardiometabolic health, which is consistent with many reviews and consensus reports from WHO and other unbiased sources. 74% of products in the US food supply contain caloric or low-calorie sweeteners, or both. Of all packaged foods and beverages purchased by a nationally representative sample of US households in 2013, 68% (by proportion of calories) contain caloric sweeteners and 2% contain low-calorie sweeteners. We believe that in the absence of intervention, the rest of the world will move towards this pervasiveness of added sugars in the food supply. Our analysis of trends in sales of sugar-sweetened beverages around the world, in terms of calories sold per person per day and volume sold per person per day, shows that the four regions with the highest consumption are North America, Latin America, Australasia, and western Europe. The fastest absolute growth in sales of sugar-sweetened beverages by country in 2009-14 was seen in Chile. We believe that action is needed to tackle the high levels and continuing growth in sales of such beverages worldwide. Many governments have initiated actions to reduce consumption of sugar-sweetened beverages in the past few years, including taxation (eg, in Mexico); reduction of their availability in schools; restrictions on marketing of sugary foods to children; public awareness campaigns; and positive and negative front-of-pack labelling. In our opinion, evidence of the effectiveness of these actions shows that they are moving in the right direction, but governments should view them as a learning process and improve their design over time. A key challenge for policy makers and researchers is the absence of a consensus on the relation of beverages containing low-calorie sweeteners and fruit juices with cardiometabolic outcomes, since decisions about whether these are healthy substitutes for sugar-sweetened beverages are an integral part of policy design. PMID- 26654576 TI - Mesh Infection and Hernia Repair: A Review. AB - BACKGROUND: The use of a prosthetic mesh to repair a tissue defect may produce a series of post-operative complications, among which infection is the most feared and one of the most devastating. When occurring, bacterial adherence and biofilm formation on the mesh surface affect the implant's tissue integration and host tissue regeneration, making preventive measures to control prosthetic infection a major goal of prosthetic mesh improvement. METHODS: This article reviews the literature on the infection of prosthetic meshes used in hernia repair to describe the in vitro and in vivo models used to examine bacterial adherence and biofilm formation on the surface of different biomaterials. Also discussed are the prophylactic measures used to control implant infection ranging from meshes soaked in antibiotics to mesh coatings that release antimicrobial agents in a controlled manner. RESULTS: Prosthetic architecture has a direct effect on bacterial adherence and biofilm formation. Absorbable synthetic materials are more prone to bacterial colonization than non-absorbable materials. The reported behavior of collagen biomeshes, also called xenografts, in a contaminated environment has been contradictory, and their use in this setting needs further clinical investigation. New prophylactic mesh designs include surface modifications with an anti-adhesive substance or pre-treatment with antibacterial agents or metal coatings. CONCLUSIONS: The use of polymer coatings that slowly release non-antibiotic drugs seems to be a good strategy to prevent implant contamination and reduce the onset of resistant bacterial strains. Even though the prophylactic designs described in this review are mainly focused on hernia repair meshes, these strategies can be extrapolated to other implantable devices, regardless of their design, shape or dimension. PMID- 26654577 TI - A finite element analysis of two novel screw designs for scaphoid waist fractures. AB - The scaphoid is the most often fractured carpal bone. Scaphoid fracture repair with a headless compression screw allows for early functional recovery. The rotational stability of a single screw may be limited, having a potential negative impact on the healing process. Two novel screws have been designed to provide improved rotational stability compared to the existing ones. Using a computational finite element model of a scaphoid osteotomy, we compared the efficacy of one simple screw and the two new screws in restricting inter fragmentary motion (IFM) in three functional positions of the wrist and as a function of inter-fragmentary compression force. The in-plane IFM was primary rotational and was better restricted by the new screws compared to the conventional one when the inter-fragmentary compression force was below 15-20 N, but provided no clear benefit in total flexion independently of the compression force. To better understand the differences in the non-compressed case, we analyzed the acting moments and investigated the effects of the bending and torsional screw stiffness on IFM. By efficiently restricting the inter fragmentary shear, the new screws may be clinically advantageous when the inter fragmentary compression force is partially or completely lost and may provide further benefits toward earlier and better healing of transverse waist fractures of the scaphoid. PMID- 26654578 TI - The performance characteristics of a piezoelectric ultrasonic dental scaler. AB - The objective of this work was to investigate the performance characteristics of a piezoelectric ultrasonic dental scaler using scanning laser vibrometry. The vibration characteristics of three standard piezoelectric tips were assessed with scanning laser vibrometry under various conditions: unconstrained, under a stream of flowing water, in a water tank, as well as subjected to loads to simulate clinical conditions. Subsequently, the tips were used to disrupt an in-vitro biofilm model of dental plaque, developed using a non-pathogenic Gram-negative species of Serratia (NCIMB40259). The laser vibrometry data showed that the oscillation pattern of the ultrasonic tip depends primarily on its shape and design, as well as on the generator power. Thin tips and high power settings induce the highest vibrations. Water irrigation of the tip and loads influence the tip performance by diminishing its vibration, while water volume increases it. Serratia biofilm was disrupted by the cavitation bubbles occurring around the scaler tip. The most effective biofilm removal occurred with the thinner tip. Understanding how the ultrasonic tip oscillates when in use and how it removes dental plaque is essential for gaining more knowledge regarding the cleaning mechanisms of the ultrasonic system. Cavitation may be used to remove plaque and calculus without a mechanical contact between the dental tip and the teeth. Better knowledge would enable dental specialists to understand and improve their techniques during routine cleaning of teeth. It will also lead to improving tip design and to the production of more effective instruments for clinical use. PMID- 26654579 TI - Socioeconomic disparities in household secondhand smoke exposure among non smoking adolescents in the Republic of Korea. AB - This nationally representative study examined (a) gender and age differences in household secondhand smoke exposure (HSHSE) and (b) associations between socioeconomic status (SES) and HSHSE among non-smoking Korean adolescents. Two subsamples were analysed: males (n = 25,648) and females (n = 30,240). The HSHSE measures were incidence of HSHSE (yes/no) and number of days of HSHSE (1-7 days); the SES measures were parental education, perceived economic status, and family wealth. For the first aim, chi-square test, t-test, and bivariate negative binomial regression analysis were performed; For the second aim, multivariate logistic regression and negative binomial regression analyses were performed. The incidence and number of days of HSHSE were significantly higher among females (32.35% and 3.48 days) than males (26.83% and 3.08 days). The HSHSE incidence was significantly higher among younger adolescents (23.32% to 31.08% of males and 26.58% to 37.03% of females). Lower SES was associated with (a) greater odds of HSHSE (odds ratio: 1.12-1.58 among males and 1.19-1.85 among females) and (b) greater incidence rates of HSHSE (incidence rate ratio: 1.05-1.17 among males and 1.10-1.14 among females). Efforts should be made to decrease HSHSE among adolescents, particularly low-SES youth. PMID- 26654580 TI - Long-term persistence of anti-hantavirus antibodies in sera of patients undergoing hemorrhagic fever with renal syndrome and subjects vaccinated against the disease. AB - Background China has the highest prevalence of hemorrhagic fever with renal syndrome (HFRS) and accounts for 90% of the total cases worldwide. However, the long-term persistence of anti-hantavirus antibodies in sera of patients with HFRS and subjects vaccinated against the disease remains unclear. The aim of the present study was to investigate the prevalence of anti-hantavirus IgG antibodies in sera of patients with prior HFRS, versus subjects vaccinated against the disease and controls in Shaanxi, China. Methods Six hundred individuals were included in this study. We quantified anti-hantavirus IgG antibodies in HFRS patients (n = 100), vaccinees (n = 200), controls from endemic regions (n = 200), and controls from non-endemic regions (n = 100) in China. Results The median optical density (OD) values (range) were 0.803 (0.008-1.813), 0.075 (0.004 1.565), 0.026 (0-1.179), and 0.015 (0.009-0.118) for HFRS patients, vaccinated subjects, endemic controls, and non-endemic controls, respectively. There was a strikingly significant difference between the HFRS group and each non-HFRS group (p < 0.001). The vaccinated subjects were also significantly different from the endemic controls. The time since the acute phase was correlated with the OD values of the HFRS patients. Conclusions Our study suggests that HFRS patients gain long-lasting protection and that vaccination may be an effective way to stimulate antibody production. PMID- 26654581 TI - High-Resolution Far-Infrared Spectroscopy of N-Substituted Two-Ring Polycyclic Aromatic Hydrocarbons: An Extended Study. AB - Polycyclic aromatic hydrocarbons (PAHs) and their N-substituted derivatives are among the largest species for which gas-phase high-resolution spectroscopy can be performed nowadays. In this paper we report the observation and analysis of spectra from several N-substituted two-ring PAHs, all taken in the "fingerprint" far-infrared region (<850 cm(-1)). Together with accurate measurements of their pure rotational transitions in the millimeter and submillimeter ranges, these synchrotron-based Fourier transform infrared (FTIR) measurements provide an accurate description of the rotational energy levels in the ground and low-energy excited vibrational states of these species. To complement the experimental data, anharmonic DFT calculations were performed to obtain relatively accurate rotational and vibrational parameters. The calculated results strongly support the rotational analysis and provide a good estimate of the equilibrium structures for each species. Extended measurements, analysis, and calculations are presented here for the far-IR bands of quinoline (C9H7N), isoquinoline (C9H7N), quinoxaline (C8H6N2), quinazoline (C8H6N2), [1,5]-naphthyridine (C8H6N2), [1,6]-naphthyridine (C8H6N2), and indole (C8H7N) molecules. PMID- 26654582 TI - Effects of comorbid health conditions on healthcare expenditures among people with severe mental illness. AB - BACKGROUND AND AIMS: Little is known about the incremental cost burden associated with treating comorbid health conditions among people with severe mental illness (SMI). This study compares the extent to which each individual medical condition increases healthcare expenditures between people with SMI and people without mental illness. METHODS: Data were obtained from the 2011 Medical Expenditure Panel Survey (MEPS; N = 17 764). Mental illness and physical health conditions were identified through ICD-9 codes. Guided by the Andersen's behavioral model of health services utilization, generalized linear models were conducted. RESULTS: Total healthcare expenditures among individuals with SMI were approximately 3.3 times greater than expenditures by individuals without mental illness ($11 399 vs. $3449, respectively). Each additional physical health condition increased the total healthcare expenditure by 17.4% for individuals with SMI compared to the 44.8% increase for individuals without mental illness. CONCLUSIONS: The cost effect of having additional health conditions on the total healthcare expenditures among individuals with SMI is smaller than those individuals without mental illness. Whether this is due to limited access to healthcare for the medical problems or better coordination between medical and mental health providers, which reduces duplicated medical procedures or visits, requires future investigation. PMID- 26654583 TI - "It is not the fading candle that one expects": general practitioners' perspectives on life-preserving versus "letting go" decision-making in end-of life home care. AB - BACKGROUND: Many general practitioners (GPs) are willing to provide end-of-life (EoL) home care for their patients. International research on GPs' approach to care in patients' final weeks of life showed a combination of palliative measures with life-preserving actions. AIM: To explore the GP's perspective on life preserving versus "letting go" decision-making in EoL home care. DESIGN: Qualitative analysis of semi-structured interviews with 52 Belgian GPs involved in EoL home care. RESULTS: Nearly all GPs adopted a palliative approach and an accepting attitude towards death. The erratic course of terminal illness can challenge this approach. Disruptive medical events threaten the prospect of a peaceful end-phase and death at home and force the GP either to maintain the patient's (quality of) life for the time being or to recognize the event as a step to life closure and "letting the patient go". Making the "right" decision was very difficult. Influencing factors included: the nature and time of the crisis, a patient's clinical condition at the event itself, a GP's level of determination in deciding and negotiating "letting go" and the patient's/family's wishes and preparedness regarding this death. Hospitalization was often a way out. CONCLUSIONS: GPs regard alternation between palliation and life-preservation as part of palliative care. They feel uncertain about their mandate in deciding and negotiating the final step to life closure. A shortage of knowledge of (acute) palliative medicine as one cause of difficulties in letting-go decisions may be underestimated. Sharing all these professional responsibilities with the specialist palliative home care teams would lighten a GP's burden considerably. Key Points A late transition from a life-preserving mindset to one of "letting go" has been reported as a reason why physicians resort to life-preserving actions in an end-of-life (EoL) context. We investigated GPs' perspectives on this matter. Not all GPs involved in EoL home care adopt a "letting go" mindset. For those who do, this mindset is challenged by the erratic course of terminal illness. GPs prioritize the quality of the remaining life and the serenity of the dying process, which is threatened by disruptive medical events. Making the "right" decision is difficult. GPs feel uncertain about their own role and responsibility in deciding and negotiating the final step to life closure. PMID- 26654584 TI - Ability and willingness to pay for voluntary medical male circumcision: a cross sectional survey in Kisumu County, Kenya. AB - Voluntary medical male circumcision is one of the most effective measures in preventing male acquisition of HIV during heterosexual intercourse. In Kenya, the voluntary medical male circumcision programme was launched in the year 2008 as part of a comprehensive national HIV prevention strategy. With the global challenge of funding HIV intervention programs, the sustainability of the programme beyond the donor periods need to be assessed. The purpose of this study was to determine the household ability and willingness to pay for voluntary medical male circumcision as an alternative method of funding the programme. The findings show that 62.2% of the households were "able" to pay for medical circumcision. However, 60.4% of them were not "willing" to pay for the service regardless of the cost. The findings indicate that ability to pay is not a significant predictor of willingness to pay for voluntary medical male circumcision within Kisumu County. Knowledge on the role of medical circumcision is a more important factor in determining willingness to pay for the service. PMID- 26654585 TI - Workplace violence and its effect on burnout and turnover attempt among Chinese medical staff. AB - The present study was to evaluate workplace violence and examine its effect on job burnout and turnover attempt among medical staff in China. A total of 2,020 medical employees were selected from Fujian province by using stratified cluster sampling method. The Chinese version of the Workplace Violence Scale and the Maslach Burnout Inventory-General Survey were used to measure the workplace violence and job burnout, respectively. Other potential influencing factors for job burnout and turnover attempt were collected using a structured questionnaire. The incidence of workplace violence among medical staff was 48.0%. Workplace violence had a positive correlation with emotional exhaustion and cynicism and a negative correlation with professional efficacy. Workplace violence, marital status, employment type, working time (>= 10 h/day), performance recognition, and life satisfaction were significant predictors for turnover attempt among Chinese medical staff. PMID- 26654586 TI - BAG3 regulates total MAP1LC3B protein levels through a translational but not transcriptional mechanism. AB - Autophagy is mainly regulated by post-translational and lipid modifications of ATG proteins. In some scenarios, the induction of autophagy is accompanied by increased levels of certain ATG mRNAs such as MAP1LC3B/LC3B, ATG5 or ATG12. However, little is known about the regulation of ATG protein synthesis at the translational level. The cochaperone of the HSP70 system BAG3 (BCL2-associated athanogene 3) has been associated to LC3B lipidation through an unknown mechanism. In the present work, we studied how BAG3 controls autophagy in HeLa and HEK293 cells. Our results showed that BAG3 regulates the basal amount of total cellular LC3B protein by controlling its mRNA translation. This effect was apparently specific to LC3B because other ATG protein levels were not affected. BAG3 knockdown did not affect LC3B lipidation induced by nutrient deprivation or proteasome inhibition. We concluded that BAG3 maintains the basal amount of LC3B protein by controlling the translation of its mRNA in HeLa and HEK293 cells. PMID- 26654587 TI - Inotuzumab ozogamicin in the management of acute lymphoblastic leukaemia. AB - Whilst most adult patients with acute lymphoblastic leukaemia will go into remission with standard induction chemotherapy, many will relapse. Response rates to standard salvage chemotherapy regimens are low and the outlook on relapse is very poor and associated with significant morbidity and mortality hence the need for newer targeted approaches. Inotuzumab ozogamicin (previously known as CMC 544) is an antibody-drug conjugate and consists of a monoclonal anti-CD22 antibody bound to calicheamicin. The target, CD22, is widely expressed on acute lymphoblastic leukaemia cells making it a potential therapeutic target. The calicheamicin is delivered intracellularly and causes leukaemia cell apoptosis. Overall response rates of 57% were observed in a Phase II study and the final results of a Phase III randomised controlled trial comparing this drug to the investigator choice 'standard of care' chemotherapy are eagerly awaited. Whilst initial results are promising, there have been concerns regarding liver toxicity and the incidence of veno-occlusive disease of the liver especially in patients who have previously received or go on to allogeneic stem cell transplant. PMID- 26654589 TI - Molecular Recognition of Natural Products by Resorc[4]arene Receptors. AB - This review is aimed at providing an overview of the up-to-now published literature on resorc[4]arene macrocycles exploited as artificial receptors for the molecular recognition of some classes of natural products. A concise illustration of the main synthetic strategies developed to afford the resorc[4]arene scaffold is followed by a report on the principles of the gas phase investigation of recognition phenomena by mass spectrometry (MS). Emphasis is placed on gas-phase studies of diastereoisomeric complexes generated inside a Fourier transform-ion cyclotron resonance (FT-ICR) mass spectrometer by resorc[4]arene receptors towards a series of natural products, namely amino acids, amphetamine, ethanolamine neurotransmitters, dipeptides, vinca alkaloids and nucleosides. The literature outcomes discussed here, taken largely from our own revisited work, have been completed by references to other studies, in order to draw a broader picture of this rapidly evolving field of research. PMID- 26654590 TI - Reactivity of Diterpenoid Quinones: Royleanones. AB - Naturally occurring abietane diterpenoids have been studied over the years and have shown to display a wide range of biological activities. This review covers three main aspects of the abietane-type diterpenoids with hydroxy-p-quinone C ring, designated as royleanones. An overview of 1) the naturally occurrence, 2) chemical features and 3) the biological activities of this abietane group of compounds, including rearranged derivatives, is here explained. Likewise, hemisynthetic and total synthetic procedures to obtain royleanones will be reviewed. Thus, the chemistry of these bioactive compounds will be emphasized as well as their potential impact in the discovery of new macromolecular targets and novel therapeutic drugs. This review contains about 190 references covering the years from 1962 to 2014 on royleanone studies. PMID- 26654591 TI - Synthetic Glycosides and Glycoconjugates of Low Molecular Weight Natural Products. AB - Enzymatically controlled transfer of saccharide moieties constitutes a fundamental biological process, essential for both primary and secondary metabolism. Natural products, including countless glycosides, with a rich tradition of use in ethnopharmacology, remain a prime source of inspiration for medicinal chemistry and molecular pharmacology, but their availability from biological sources is usually scarce, hampering attempts at application for new drug discovery and development. Chemical glycosylation on the other hand, although continuously undergoing sophisticated mechanistic studies, has nevertheless already matured as a set of methods which are able to provide substantial amounts of pure chemical entities: natural glycosides, as well as their congeners and mimics, necessary for the study of biological activity in quality assurance systems and required for drug development by pharmaceutical regulations. The paper presents a review of natural products and their analogues glycosylation, in a set of arbitrary selected examples, supplemented with comments on general advances in chemical glycosylation methodology and their applicability for particular categories of secondary metabolites. PMID- 26654588 TI - The Therapeutic Aspects of the Endocannabinoid System (ECS) for Cancer and their Development: From Nature to Laboratory. AB - The endocannabinoid system (ECS) is a group of neuromodulatory lipids and their receptors, which are widely distributed in mammalian tissues. ECS regulates various cardiovascular, nervous, and immune system functions inside cells. In recent years, there has been a growing body of evidence for the use of synthetic and natural cannabinoids as potential anticancer agents. For instance, the CB1 and CB2 receptors are assumed to play an important role inside the endocannabinoid system. These receptors are abundantly expressed in the brain and fatty tissue of the human body. Despite recent developments in molecular biology, there is still a lack of knowledge about the distribution of CB1 and CB2 receptors in the human kidney and their role in kidney cancer. To address this gap, we explore and demonstrate the role of the endocannabinoid system in renal cell carcinoma (RCC). In this brief overview, we elucidate the therapeutic aspects of the endocannabinoid system for various cancers and explain how this system can be used for treating kidney cancer. Overall, this review provides new insights into cannabinoids' mechanisms of action in both in vivo and in vitro models, and focuses on recent discoveries in the field. PMID- 26654592 TI - An Update on Natural Products with Carbonic Anhydrase Inhibitory Activity. AB - Carbonic anhydrases (CAs, EC 4.2.1.1) catalyze the fundamental reaction of CO2 hydration in all living organisms, being actively involved in the regulation of a plethora of patho/physiological processes. They represent a typical example of enzyme convergent evolution, as six genetically unrelated families of such enzymes were described so far. It is more than 70 years that synthetic compounds, mainly sulfonamides, have been used in clinical practice as diuretics and systemic acting antiglaucoma drugs. Recent studies using natural product libraries and isolated constituents from natural sources (such as fungi and plants) have disclosed novel chemotypes possessing carbonic anhydrase inhibition activities. These natural sources offer new opportunities in the search for new and more effective carbonic anhydrase inhibitors, and may serve as new leads for the design and development of future drugs. This review will discuss the most recent advances in the search of naturally occurring products and their synthetic derivatives that inhibit the CAs and their mechanisms of action at molecular level. Plant extracts are not considered in the present review. PMID- 26654593 TI - Nutritional status and body composition in patients with peripheral arterial disease: A cross-sectional examination of disease severity and quality of life. AB - Nutritional and body weight recommendations for cardiovascular diseases are well established, yet there are no equivalent guidelines for peripheral arterial disease (PAD). This cross-sectional study measured the prevalence of cardiovascular-related nutritional and body composition risk factors in sixty PAD patients and their association with PAD severity. A diet that exceeds daily recommended intake of fat and that falls short of recommended intakes of fiber, folate, and vitamin D was associated with increased leg pain and walking difficulty. Increased body fat and waist circumference were associated with diminished walking ability and poorer psychosocial quality of life. Future prospective investigations are merited to inform both PAD clinical care and disease management guidelines. PMID- 26654594 TI - Detecting intention to walk in stroke patients from pre-movement EEG correlates. AB - BACKGROUND: Most studies in the field of brain-computer interfacing (BCI) for lower limbs rehabilitation are carried out with healthy subjects, even though insights gained from healthy populations may not generalize to patients in need of a BCI. METHODS: We investigate the ability of a BCI to detect the intention to walk in stroke patients from pre-movement EEG correlates. Moreover, we also investigated how the motivation of the patients to execute a task related to the rehabilitation therapy affects the BCI accuracy. Nine chronic stroke patients performed a self-initiated walking task during three sessions, with an intersession interval of one week. RESULTS: Using a decoder that combines temporal and spectral sparse classifiers we detected pre-movement state with an accuracy of 64 % in a range between 18 % and 85.2 %, with the chance level at 4 %. Furthermore, we found a significantly strong positive correlation (r = 0.561, p = 0.048) between the motivation of the patients to perform the rehabilitation related task and the accuracy of the BCI detector of their intention to walk. CONCLUSIONS: We show that a detector based on temporal and spectral features can be used to classify pre-movement state in stroke patients. Additionally, we found that patients' motivation to perform the task showed a strong correlation to the attained detection rate of their walking intention. PMID- 26654595 TI - Haematopoietic progenitor maintenance by EBF/Collier: beyond the Niche. PMID- 26654597 TI - A new role for PGRP-S (Tag7) in immune defense: lymphocyte migration is induced by a chemoattractant complex of Tag7 with Mts1. AB - PGRP-S (Tag7) is an innate immunity protein involved in the antimicrobial defense systems, both in insects and in mammals. We have previously shown that Tag7 specifically interacts with several proteins, including Hsp70 and the calcium binding protein S100A4 (Mts1), providing a number of novel cellular functions. Here we show that Tag7-Mts1 complex causes chemotactic migration of lymphocytes, with NK cells being a preferred target. Cells of either innate immunity (neutrophils and monocytes) or acquired immunity (CD4(+) and CD8(+) lymphocytes) can produce this complex, which confirms the close connection between components of the 2 branches of immune response. PMID- 26654596 TI - Unique subcellular distribution of phosphorylated Plk1 (Ser137 and Thr210) in mouse oocytes during meiotic division and pPlk1(Ser137) involvement in spindle formation and REC8 cleavage. AB - Polo-like kinase 1 (Plk1) is pivotal for proper mitotic progression, its targeting activity is regulated by precise subcellular positioning and phosphorylation. Here we assessed the protein expression, subcellular localization and possible functions of phosphorylated Plk1 (pPlk1(Ser137) and pPlk1(Thr210)) in mouse oocytes during meiotic division. Western blot analysis revealed a peptide of pPlk1(Ser137) with high and stable expression from germinal vesicle (GV) until metaphase II (MII), while pPlk1(Thr210) was detected as one large single band at GV stage and 2 small bands after germinal vesicle breakdown (GVBD), which maintained stable up to MII. Immunofluorescence analysis showed pPlk1(Ser137) was colocalized with microtubule organizing center (MTOC) proteins, gamma-tubulin and pericentrin, on spindle poles, concomitantly with persistent concentration at centromeres and dynamic aggregation between chromosome arms. Differently, pPlk1(Thr210) was persistently distributed across the whole body of chromosomes after meiotic resumption. The specific Plk1 inhibitor, BI2536, repressed pPlk1(Ser137) accumulation at MTOCs and between chromosome arms, consequently disturbed gamma-tubulin and pericentrin recruiting to MTOCs, destroyed meiotic spindle formation, and delayed REC8 cleavage, therefore arresting oocytes at metaphase I (MI) with chromosome misalignment. BI2536 completely reversed the premature degradation of REC8 and precocious segregation of chromosomes induced with okadaic acid (OA), an inhibitor to protein phosphatase 2A. Additionally, the protein levels of pPlk1(Ser137) and pPlk1(Thr210), as well as the subcellular distribution of pPlk1(Thr210), were not affected by BI2536. Taken together, our results demonstrate that Plk1 activity is required for meiotic spindle assembly and REC8 cleavage, with pPlk1(Ser137) is the action executor, in mouse oocytes during meiotic division. PMID- 26654598 TI - Nuclear phosphorylated Y142 beta-catenin accumulates in astrocytomas and glioblastomas and regulates cell invasion. AB - Glioblastoma multiforme (GBM) is a fast growing brain tumor characterized by extensive infiltration into the surrounding tissue and one of the most aggressive cancers. GBM is the most common glioma (originating from glial-derived cells) that either evolves from a low grade astrocytoma or appears de novo. Wnt/beta catenin and Hepatocyte Growth Factor (HGF)/c-Met signaling are hyperactive in human gliomas, where they regulate cell proliferation, migration and stem cell behavior. We previously demonstrated that beta-catenin is phosphorylated at Y142 by recombinant c-Met kinase and downstream of HGF signaling in neurons. Here we studied phosphoY142 (PY142) beta-catenin and dephospho S/T beta-catenin (a classical Wnt transducer) in glioma biopsies, GBM cell lines and biopsy-derived glioma cell cultures. We found that PY142 beta-catenin mainly localizes in the nucleus and signals through transcriptional activation in GBM cells. Tissue microarray analysis confirmed strong nuclear PY142 beta-catenin immunostaining in astrocytoma and GBM biopsies. By contrast, active beta-catenin showed nuclear localization only in GBM samples. Western blot analysis of tumor biopsies further indicated that PY142 and active beta-catenin accumulate independently, correlating with the expression of Snail/Slug (an epithelial-mesenchymal transition marker) and Cyclin-D1 (a regulator of cell cycle progression), respectively, in high grade astrocytomas and GBMs. Moreover, GBM cells stimulated with HGF showed increasing levels of PY142 beta-catenin and Snail/Slug. Importantly, the expression of mutant Y142F beta-catenin decreased cell detachment and invasion induced by HGF in GBM cell lines and biopsy-derived cell cultures. Our results identify PY142 beta-catenin as a nuclear beta-catenin signaling form that downregulates adhesion and promotes GBM cell invasion. PMID- 26654600 TI - Building on the rich heritage of the Medical Journal of Australia. PMID- 26654599 TI - Pre-germinal center origin for mature mouse B cell lymphomas: a major discrepancy with human mature lymphomas. PMID- 26654601 TI - Welcoming the new Editor-in-Chief. PMID- 26654603 TI - Is ketamine ready to be used clinically for the treatment of depression? PMID- 26654604 TI - A step toward facilitating ethics review of human research in Australia. PMID- 26654606 TI - Time to shut down the acute care conveyor belt? PMID- 26654607 TI - Mental health services reach the tipping point in Australian acute hospitals. PMID- 26654608 TI - Imported New World screw-worm fly myiasis. PMID- 26654609 TI - Alcohol gifts in medicine. PMID- 26654610 TI - Risk factors and burden of acute Q fever in older adults in New South Wales: a prospective cohort study. AB - OBJECTIVES: To measure the acute burden of and to identify risk factors associated with notified Q fever in older adults in New South Wales. DESIGN, SETTINGS AND PARTICIPANTS: A prospective cohort of adults aged 45 years and over (the 45 and Up Study) recruited during 2006-2009 and followed using linked Q fever notifications, hospital records and death records during 2006-2012. MAIN OUTCOME MEASURES: Incident cases of Q fever, based on a linked Q fever notification; proportion of cases with a Q fever-coded hospitalisation. RESULTS: A total of 266 906 participants were followed up for 1 254 650 person-years (mean, 4.7 +/- 1.0 years per person). In our study population, the incidence of notified Q fever during follow-up was 3.6 (95% CI, 2.7-4.8) per 100 000 person years. After adjustments, age (>= 65 years v 45-54 years: hazard ratio [HR], 0.39; 95% CI, 0.16-0.96), sex (women v men: HR, 0.48; 95% CI, 0.26-0.88), and area and type of residence (P < 0.001 for trend) remained significantly associated with Q fever. Compared with those living in an inner regional area but not on a farm, the risk of notified Q fever was highest for those living on a farm in outer regional or remote areas (HR, 11.98; 95% CI, 5.47-26.21), followed by those living on a farm in inner regional areas (HR, 4.95; 95% CI, 1.79-13.65). Of notified Q fever cases, 15 of 39 (38%) had been hospitalised with a diagnosis consistent with Q fever. CONCLUSIONS: Adults living on a farm in outer regional and remote areas are at a substantially greater risk of contracting Q fever. This suggests that, as well as targeting specific occupational groups for vaccination, there would be benefits in increasing public awareness of Q fever and vaccination among those living on and near farms in outer regional and remote areas of Australia. PMID- 26654611 TI - Unprofessional behaviour on social media by medical students. AB - OBJECTIVES: To describe the social media usage patterns of medical students and to identify factors associated with their posting of unprofessional content on social media. DESIGN: Voluntary survey, delivered online. SETTING: All students in all 20 Australian medical schools were eligible to participate (16 993 individuals). PARTICIPANTS: Of 1027 initial respondents during the study period (29 March - 12 August 2013), 880 completed the survey. MAIN OUTCOME MEASURES: Prevalence of unprofessional online behaviour on social media by medical students, as reported by students about their own and others' accounts. RESULTS: Posting of unprofessional content was self-reported by 306 students (34.7%), mainly depictions of intoxication (301 students, 34.2%) or illegal drug use (14 students, 1.6%), or posting of patient information (14 students, 1.6%). Posting of unprofessional content was associated with posting evidence of alcohol use and racist content online, MySpace use, and planning to change one's profile name after graduation. Factors associated with reduced unprofessional content included believing that videos depicting medical events with heavy alcohol use were inappropriate, and being happy with one's own social media portrayal. Exposure to guidelines on professional online conduct had no effect on posting behaviour. CONCLUSIONS: Social media use was nearly universal in the surveyed cohort. Posting of unprofessional content was highly prevalent despite understanding that this might be considered inappropriate, and despite awareness of professionalism guidelines. Medical educators should consider approaches to this problem that involve more than simply providing guidelines or policies, and students should be regularly prompted to evaluate and moderate their own online behaviour. PMID- 26654612 TI - The epidemiology of tuberculosis in children in Australia, 2003-2012. AB - OBJECTIVE: To describe the burden of and trends in paediatric tuberculosis (TB) in Australia between 2003 and 2012. DESIGN: A retrospective analysis of TB data from the National Notifiable Diseases Surveillance System (NNDSS) on TB in children (under 15 years of age) during the 10-year period, 2003-2012. RESULTS: TB notifications in Australia during the study period included 538 children (range, 37-66 cases per year), representing 4.6% of the total TB case load during the period (range, 3.8%-5.8% each year). Place of birth was recorded for 524 patients (97.4%); of these, 230 (43.9%) were born in Australia, 294 (56.1%) overseas. The average annual notification rate was 1.31 (95% CI, 1.20-1.43) cases per 100 000 child population. The rate was higher for overseas-born than for Australian-born children (9.57 [95% CI, 8.51-10.73] v 0.61 [95% CI, 0.53-0.69] cases per 100 000 children. The overall rate was highest among those aged 0-4 years. The annual notification rate was three times higher for Indigenous children than for non-Indigenous Australian-born children. Of 427 patients (79.4% of total) for whom the method of case detection was recorded, 37.0% were detected by contact screening, 8.7% by post-arrival immigration screening, and 54.3% by passive case detection. Pulmonary TB was the most common diagnostic classification (64.7% of patients). The most common risk factors were close contact with a TB case and recent residence in a country with a high incidence of TB. Treatment outcomes were satisfactory; 89.4% of children had completed treatment or were cured. CONCLUSIONS: The burden of paediatric TB in Australia is low but has not changed over the past decade. The highest rates are among children born overseas, emphasising the important role of immigration screening as Australia aspires to eliminate TB. PMID- 26654613 TI - The treatment of nursing home-acquired pneumonia using a medically intensive Hospital in the Home service. AB - OBJECTIVES: To compare the outcomes for patients with nursing home-acquired pneumonia (NHAP) treated completely in a Hospital in the Home (HITH) setting with those of patients treated in a traditional hospital ward. DESIGN: Case-control study. SETTING AND PARTICIPANTS: All patients admitted by the Royal Melbourne Hospital for treatment of NHAP from 1 July 2013 to 31 January 2014. INTERVENTION: Admission to the Royal Melbourne Hospital HITH Unit within 48 hours of presentation. MAIN OUTCOME MEASURES: Length of stay, in-hospital and 30-day mortality, hospital readmissions (30-day), complications and unplanned returns to hospital. RESULTS: Sixty HITH patients and 54 hospital (control) patients were identified. Thirty-two patients (53%) were admitted directly to HITH without any hospital or emergency stay, 25 (42%) were referred directly from the emergency department. HITH patients were more likely to be male, older and dehydrated, and less likely to have an advanced care directive or to have had non-invasive ventilation. There were no significant differences in CURB-65 or CORB scores between the two patient groups; similar proportions were given intravenous fluids or supplemental oxygen. There were no adjusted differences in median length of stay between HITH and control patients (-1.00 days; 95% CI, -2.72 to 0.72; P = 0.252) or in overall mortality at 30 days (HITH v control patients: adjusted odds ratio [aOR], 1.97; 95% CI, 0.67-5.73). Inpatient mortality was lower for HITH patients (aOR, 0.19; 95% CI, 0.05-0.75) but unadjusted postdischarge 30-day mortality was higher (OR, 13.25; 95% CI 1.67-105.75). There were no differences between the two groups with regard to complications (falls and pressure wounds) and 30-day readmission rates (aOR, 1.59; 95% CI, 0.30-8.53). CONCLUSIONS: This study suggests that HITH may be an effective and safe alternative to hospital treatment for residents of aged care facilities presenting with NHAP. PMID- 26654614 TI - Chronic Ayurvedic medicine use associated with major and fatal congenital abnormalities. PMID- 26654615 TI - Initial presentation of a urea cycle disorder in adulthood: an under-recognised cause of severe neurological dysfunction. PMID- 26654616 TI - Help! I have lost my blue tie. PMID- 26654617 TI - Dr Sr Mary Glowrey JMJ, MB BS 1910, MD 1919: Australia's second saint? PMID- 26654618 TI - The psychopathology of James Bond and its implications for the revision of the DSM-(00)7. AB - OBJECTIVE: To develop a more concise, user-friendly edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM). The DSM advisory board is probably already hard at work on the DSM-6, so this study is focused on the DSM-(00)7 edition. DESIGN: We conducted an observational study, using a mixed methods approach to analyse the 50th edition boxset of James Bond experiences. James Bond was selected as a suitably complex subject for the basis of a trial of simplifying the DSM. SETTING: Researchers' televisions and computers from late January to mid-April in Auckland, New Zealand. RESULTS: Following a review of the 23 James Bond video observations, we identified 32 extreme behaviours exhibited by the subject; these could be aggregated into 13 key domains. A Delphi process identified a cluster of eight behaviours that comprise the Bond Adequacy Disorder (BAD). A novel screening scale was then developed, the Bond Additive Descriptors of Anti-Sociality Scale (BADASS), with a binary diagnostic outcome, BAD v Normality Disorder. We propose that these new diagnoses be adopted as the foundation of the DSM-(00)7. CONCLUSIONS: The proposed DSM-(00)7 has benefits for both patients and clinicians. Patients will experience reduced stigma, as most individuals will meet the criteria for Normality Disorder. This parsimonious diagnostic approach will also mean clinicians have more time to focus on patient management. PMID- 26654619 TI - 'Twas the night before Grand Round .... PMID- 26654620 TI - Americans shooting themselves in the foot: the epidemiology of podiatric self inflicted gunshot wounds in the United States. AB - OBJECTIVE: To examine the epidemiology of Americans shooting themselves in the foot. DESIGN: Data from the Firearm Injury Surveillance Study (1993-2010) collected using the National Electronic Injury Surveillance System were examined. Non-fatal firearm-related injuries were recorded during patients' initial emergency department visits. SETTING: United States hospital emergency departments, 1993-2010. PARTICIPANTS: 69 111 individuals admitted to US emergency departments after non-fatal firearm-related incidents. MAIN OUTCOME MEASURE: Demographic and incident characteristics of patients presenting with self inflicted gunshot wounds to the foot. RESULTS: Of the 69 111 reported firearm related injuries, 667 (1.0%) were self-inflicted gunshot wounds to the foot. Of these, 597 of the patients (89.6%) were men and 51.7% (345) were aged between 15 and 34 years. Patients generally presented with puncture wounds (265 patients, 39.7%), foreign bodies (164 patients, 24.6%) and bruised egos. Those who shot themselves in the foot were significantly more likely than individuals with other firearm-related injuries to be male (odds ratio [OR], 1.28) and married (OR, 2.6). As the festive season approached, the number of incidents increased; November and December were peak months for shooting oneself in the foot. CONCLUSIONS: The nature of and the circumstances surrounding self-inflicted gunshot wounds to the foot were unique when compared with other firearm-related injuries. Through the large-scale examination of the characteristics of these incidents, trends in the nature of Americans shooting themselves in the foot have been elucidated. Young married men are at particular risk of shooting themselves in the foot. Particular caution must be taken during the festive season to avoid being caught under the missing toe. PMID- 26654621 TI - Hospital doctors' Opinions regarding educational Utility, public Sentiment and career Effects of Medical television Dramas: the HOUSE MD study. AB - OBJECTIVES: To evaluate the opinions of practicing clinicians on medical television dramas and the effects these series have on society as well as their own practice. DESIGN, SETTING AND PARTICIPANTS: Observational study using a structured questionnaire disseminated among doctors of all grades and specialties at one tertiary centre and two large secondary care district general hospitals in Wales, United Kingdom. Three hundred and seventy-two questionnaires were distributed over a 3-month period, with 200 completed questionnaires received (response rate, 54%). MAIN OUTCOME MEASURES: Frequency and reasons for watching these programs, and opinions regarding realism, educational value and public perception, evaluated by doctors' grades and specialties. Identification of work practice with any observed traits in fictional doctors was also analysed. RESULTS: 65% of doctors surveyed admitted to watching these programs on more than one occasion. Junior doctors (interns and resident medical officers) were more regular viewers. Most doctors who admitted to watching medical dramas did so for entertainment purposes (69%); 8% watched for educational purposes and, of these, 100% watched House MD, 82% felt that these dramas were unrepresentative of daily practice, and 10% thought that they accurately portrayed reality. Most of the positive responses were from junior doctors. 61% of doctors identified some aspect of their clinical practice with another doctor (fictional or non fictional; most junior doctors identified with a fictional doctor, compared with non-fictional role models for more senior practicing clinicians. CONCLUSIONS: This survey shows that a large body of the medical workforce watches medical television dramas and that such programs exercise a growing influence on the practice of junior doctors, particularly those in physicianly specialties. The reasons for certain role model selections remain unknown and may require further evaluation. PMID- 26654622 TI - Studying the Thenar Eminence of Amateur cooKs (STEAK) study: a double-blinded, cross-sectional study. AB - OBJECTIVES: To evaluate the reliability of using the thenar eminence to determine steak doneness. DESIGN: Double-blinded, cross-sectional study. SETTING: Various home kitchens in Melbourne, Australia. PARTICIPANTS: Amateur/home cooks. MAIN OUTCOME MEASURES: The accuracy of the finger test (the tenseness of the thenar eminence in different hand positions) for determining how well a random beef steak has been cooked (rare v medium-rare v medium v well-done). We also examined whether participants improved with practice and whether the accuracy of the finger test was correlated with age, sex, cooking experience or self-rated steak cooking ability. RESULTS: Twenty-six participants completed the study, and showed that they could accurately determine the doneness of a steak with the finger test better than chance (chi2[1, n = 156] = 9.88; P < 0.01). Their overall accuracy, however, was low (36%). There was no correlation between accuracy in application of the finger test with the other collected participant and steak variables. CONCLUSIONS: The finger test can be used by amateur cooks to determine beef steak doneness. However, the low overall accuracy of the test suggests that more invasive tests are to be recommended for determining steak doneness for its health benefits. PMID- 26654623 TI - Mondayitis. PMID- 26654624 TI - Gary. PMID- 26654625 TI - The Value of Audio Devices in the Endoscopy Room (VADER) study: a randomised controlled trial. AB - OBJECTIVE: To evaluate the effect of Star Wars music (SWM) compared with endoscopist-selected popular music (PM) on quality outcomes in colonoscopy. DESIGN AND SETTING: A single-centre, prospective, randomised controlled trial conducted in an endoscopy suite within a quaternary-centre gastroenterology unit, Melbourne, Australia. MAIN OUTCOME MEASURES: The primary outcome measures were procedure time, polyp detection rate (PDR) and adenoma detection rate (ADR). The secondary outcome measure was adenomas per colonoscopy (APC). RESULTS: 103 colonoscopies were analysed: 58 in the SWM group and 45 in the PM group. Bowel preparation was assessed as good or excellent in 57% of the SWM group compared with 69% of the PM group (P < 0.01). The PDR was significantly higher in the SWM group than in the PM group (60% v 35%; P = 0.006). Similarly, the ADR was significantly higher in the SWM group than in the PM group (48% v 27%; P = 0.01). The APC in the SWM group was 84% compared with 35% in the PM group (P = 0.01). CONCLUSION: SWM compared with PM improves key quality outcomes in colonoscopy, despite poorer bowel preparation. PMID- 26654626 TI - Acid-Responsive Therapeutic Polymer for Prolonging Nanoparticle Circulation Lifetime and Destroying Drug-Resistant Tumors. AB - How to destroy drug-resistant tumor cells remains an ongoing challenge for cancer treatment. We herein report on a therapeutic nanoparticle, aHLP-PDA, which has an acid-activated hemolytic polymer (aHLP) grafted onto photothermal polydopamine (PDA) nanosphere via boronate ester bond, in efforts to ablate drug-resistant tumors. Upon exposure to oxidative stress and/or near-infrared laser irradiation, aHLP-PDA nanoparticle responsively releases aHLP, likely via responsive cleavage of boronate ester bond, and thus responsively exhibits acid-facilitated mammalian membrane-disruptive activity. In vitro cell studies with drug-resistant and/or thermo-tolerant cancer cells show that the aHLP-PDA nanoparticle demonstrates preferential cytotoxicity at acidic pH over physiological pH. When administered intravenously, the aHLP-PDA nanoparticle exhibits significantly prolonged blood circulation lifetime and enhanced tumor uptake compared to bare PDA nanosphere, likely owing to aHLP's stealth effects conferred by its zwitterionic nature at blood pH. As a result, the aHLP-PDA nanoparticle effectively ablates drug resistant tumors, leading to 100% mouse survival even on the 32nd day after suspension of photothermal treatment, as demonstrated with the mouse model. This work suggests that a combination of nanotechnology with lessons learned in bacterial antibiotic resistance may offer a feasible and effective strategy for treating drug-resistant cancers often found in relapsing patients. PMID- 26654627 TI - Maternal, newborn and child health needs, opportunities and preferred futures in Arusha and Ngorongoro: hearing women's voices. AB - BACKGROUND: With the approaching sunset on the Millennium Development Goals (MDGs), Tanzania continues with its final national push towards achievement of MDG #4 and MDG #5. The Mama Kwanza Socio-economic Health Initiative (MKSHI) was introduced in the hope of contributing to improving maternal, newborn, and child health in Arusha and Ngorongoro. The MKSHI project is a holistic, inter-sectoral approach to maternal, newborn, and child health which aligns with the Government of Tanzania's Vision 2025. At the project onset, a baseline assessment was conducted to launch ongoing benchmarking, monitoring, and evaluation of the project's impacts and implications. The aim of this baseline assessment was twofold. First it was to determine the state of maternal, newborn, and child health in the two project sites. Second it was to ensure that a baseline of key indicators was established as well as identification of unique indicators relevant to the populations of interest. RESULTS: The baseline study was a mixed methods approach to identify maternal, newborn, and child risk factors and indicators in the two target sites. This paper focuses on the qualitative methods and findings. The qualitative component included a series of five community dialogue meetings and thirty-seven individual/dyad interviews with women, providers, and stakeholders. Initially, community meetings were held as open dialogues on maternal, newborn, and child health issues, opportunities, and preferred futures. Individual/dyad interviews were held with women, providers, and stakeholders who held unique information or experiences. Both community dialogue and interview data was analysed for themes and guiding or critical comments. Three over-arching findings emerged: What took you so long to come? How do we know what you know? and How will it change for our daughters? CONCLUSIONS: Participant voices are vital in ensuring the achievement of local and global efforts and preferred futures for maternal, newborn, and child health services. This study contributes to the inclusion of women in all aspects of the planning, implementation, and delivery of maternal, newborn, and child health services in the target areas and beyond. PMID- 26654628 TI - Methylation Analysis of the BMPR2 Gene Promoter Region in Patients With Pulmonary Arterial Hypertension. AB - INTRODUCTION: Pulmonary arterial hypertension is characterizated by obstruction of the pulmonary arteries. The gene mainly related to pathology is the bone morphogenetic protein receptor type II (BMPR2). The aim of this study was to analyze the methylation pattern of the BMPR2 promoter region in patients and controls. METHODS: We used Methyl Primer Express((r)) v.1.0 and MatInspector softwares to analyze this region. Genomic DNA obtained from the peripheral blood of patients and controls was modified with sodium bisulphite. Methylation was analyzed using methylation-specific PCR. DNA treated with CpG methyltransferase was used as a positive control for methylation and H1299 cell culture DNA was used as positive control for gene expression. RESULTS: We identified a CpG island, which may have been methylated, in the BMPR2 promoter region, in addition to NIT-2 (global-acting regulatory protein), sex-determining region Y) and heat shock factor transcription factor binding sites. We found no evidence of methylation in patients and controls. No methylated CpG sites were identified in H1299 cells expressing the BMPR2 gene. CONCLUSIONS: The BMPR2 promoter region is the most suitable for study because of the high number of transcription factor binding sites that could alter gene function. No evidence of methylation was detected in this region in patients and controls. PMID- 26654629 TI - Benchmarking in Thoracic Surgery. Third Edition. AB - INTRODUCTION: Benchmarking entails continuous comparison of efficacy and quality among products and activities, with the primary objective of achieving excellence. OBJECTIVE: To analyze the results of benchmarking performed in 2013 on clinical practices undertaken in 2012 in 17 Spanish thoracic surgery units. METHODS: Study data were obtained from the basic minimum data set for hospitalization, registered in 2012. Data from hospital discharge reports were submitted by the participating groups, but staff from the corresponding departments did not intervene in data collection. Study cases all involved hospital discharges recorded in the participating sites. Episodes included were respiratory surgery (Major Diagnostic Category 04, Surgery), and those of the thoracic surgery unit. Cases were labelled using codes from the International Classification of Diseases, 9th revision, Clinical Modification. The refined diagnosis-related groups classification was used to evaluate differences in severity and complexity of cases. RESULTS: General parameters (number of cases, mean stay, complications, readmissions, mortality, and activity) varied widely among the participating groups. Specific interventions (lobectomy, pneumonectomy, atypical resections, and treatment of pneumothorax) also varied widely. CONCLUSIONS: As in previous editions, practices among participating groups varied considerably. Some areas for improvement emerge: admission processes need to be standardized to avoid urgent admissions and to improve pre-operative care; hospital discharges should be streamlined and discharge reports improved by including all procedures and complications. Some units have parameters which deviate excessively from the norm, and these sites need to review their processes in depth. Coding of diagnoses and comorbidities is another area where improvement is needed. PMID- 26654630 TI - The global aHUS registry: methodology and initial patient characteristics. AB - BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is a rare, genetically mediated systemic disease most often caused by chronic, uncontrolled complement activation that leads to systemic thrombotic microangiopathy (TMA) and renal and other end-organ damage. METHODS: The global aHUS Registry, initiated in April 2012, is an observational, noninterventional, multicenter registry designed to collect demographic characteristics, medical and disease history, treatment effectiveness and safety outcomes data for aHUS patients. The global aHUS Registry will operate for a minimum of 5 years of follow-up. Enrollment is open to all patients with a clinical diagnosis of aHUS, with no requirement for identified complement gene mutations, polymorphisms or autoantibodies or particular type of therapy/management. RESULTS: As of September 30, 2014, 516 patients from 16 countries were enrolled. At enrollment, 315 (61.0 %) were adults (>=18 years) and 201 (39.0 %) were <18 years of age. Mean (standard deviation [SD]) age at diagnosis was 22.7 (20.5) years. Nineteen percent of patients had a family history of aHUS, 60.3 % had received plasma exchange/plasma infusion, 59.5 % had a history of dialysis, and 19.6 % had received >=1 kidney transplant. Overall, 305 patients (59.1 %) have received eculizumab. CONCLUSIONS: As enrollment and follow-up proceed, the global aHUS Registry is expected to yield valuable baseline, natural history, medical outcomes, treatment effectiveness and safety data from a diverse population of patients with aHUS. TRIAL REGISTRATION: US National Institutes of Health www.ClinicalTrials.gov Identifier NCT01522183 . Registered January 18, 2012. PMID- 26654632 TI - Neonatal hearing-loss screening is on the way to becoming systematic in France. PMID- 26654631 TI - Evaluating the effects of Danhong injection in treatment of acute ischemic stroke: study protocol for a multicenter randomized controlled trial. AB - BACKGROUND: Danhong injection (DHI) has been widely prescribed to patients with acute ischemic stroke (AIS). However, due to methodological deficiencies, previous research has not yet provided rigorous evidence to support the use of DHI in the treatment of AIS. Therefore, we designed this multicenter, randomized, controlled, and double-blind trial to evaluate the efficacy and safety of DHI for AIS. METHODS/DESIGN: It is a randomized, multicenter, double-blind, placebo controlled, adaptive clinical trial. A total of 864 eligible patients will be randomized into either the DHI or placebo group in a 2:1 ratio. All patients will be given the standard medical care as recommended by guidelines. Participants will undergo a 2-week treatment regimen and 76-day follow-up period. The primary outcome is the proportion of patients with a favorable outcome, defined as a score of 0-1 on the modified Rankin scale at day 90. Secondary outcomes include a change in the total score of the Chinese medicine symptom scales of "Xueyu Zheng" (blood stasis syndrome), the proportion of patients with a Barthel Index score of >=90, the proportion of patients with an improvement in NIHSS score of >=4 or NIHSS score of 0-1, quality of life measured by the EQ-5D scale, etc. Safety outcomes such as global disability (mRS >=3) at day 90 will also be assessed. The changes in mRNA and microRNA profiles in 96 patients selected from certain centers will also be assessed. As this is an adaptive design, two interim analyses are prospectively planned, which will be carried out after one-third and two-thirds of patients have completed the trial, respectively. Based on the results of the interim analyses, the Data Monitoring Committee (DMC) will decide how to modify the study. DISCUSSION: This trial will provide high-quality evidence for DHI in treatment of AIS. TRIAL REGISTRATION: Clinical Trials.gov NCT01677208 (Date of registration 22 December 2012). PMID- 26654633 TI - Re: Is It Just Enough to Keep Long Membranous Urethra for Providing Early Continence After Robot-Assisted Laparoscopic Radical Prostatectomy? (From: Haga N, Ogawa S, Yabe M, et al. J Endourol 2015;29:683-690). PMID- 26654634 TI - Acrometastasis as the initial presentation of lung adenocarcinoma in a young woman. PMID- 26654635 TI - Video-assisted thoracoscopy in the diagnosis and treatment of stab wounds in the chest. PMID- 26654636 TI - Understanding the "black box" of a health-promotion program: Keys to enable health among older persons aging in the context of migration. AB - Although the need to make health services more accessible to persons who have migrated has been identified, knowledge about health-promotion programs (HPPs) from the perspective of older persons born abroad is lacking. This study explores the design experiences and content implemented in an adapted version of a group based HPP developed in a researcher-community partnership. Fourteen persons aged 70-83 years or older who had migrated to Sweden from Finland or the Balkan Peninsula were included. A grounded theory approach guided the data collection and analysis. The findings showed how participants and personnel jointly helped raise awareness. The participants experienced three key processes that could open doors to awareness: enabling community, providing opportunities to understand and be understood, and confirming human values and abilities. Depending on how the HPP content and design are being shaped by the group, the key processes could both inhibit or encourage opening doors to awareness. Therefore, this study provides key insights into how to enable health by deepening the understanding of how the exchange of health-promoting messages is experienced to be facilitated or hindered. This study adds to the scientific knowledge base of how the design and content of HPP may support and recognize the capabilities of persons aging in the context of migration. PMID- 26654637 TI - Students, blood and teeth. PMID- 26654638 TI - A guide to new anticoagulant medications for ENT surgeons. AB - OBJECTIVES: This study aimed to ascertain otolaryngologists' current knowledge of new (e.g. apixaban, rivaroxaban) and old (e.g. warfarin) anticoagulant medications, and to provide an educational overview of new anticoagulants for use by surgeons. METHODS: A questionnaire survey was distributed across the Wessex region, UK, to ascertain the levels of knowledge of and confidence in managing patients taking various anticoagulants. In total, 50 questionnaires were completed (41 by trainees and 9 by consultants). A literature review of new anticoagulant medications was then conducted. RESULTS: In general, there was poor clinical and pharmacokinetic knowledge of newly licensed anticoagulant medications. Respondents were more confident in the use of older vs newer forms of anticoagulants. This was true across all grades of doctors, but particularly at the senior level. All respondents stated that they would like to see an educational resource on anticoagulants. CONCLUSION: Knowledge of newly licensed anticoagulation medications is poor. This study has produced an educational resource for the management of anticoagulant agents. A thorough knowledge of these drugs is essential for the acute management of bleeding patients and in peri-operative surgical planning. PMID- 26654639 TI - Surgery for vertigo: 10-year audit from a contemporary vertigo clinic. AB - OBJECTIVE: To present the profile of patients undergoing surgical treatment for vertigo at a contemporary institutional vertigo clinic. STUDY DESIGN: A retrospective analysis of clinical charts. METHODS: The charts of 1060 patients, referred to an institutional vertigo clinic from January 2003 to December 2012, were studied. The clinical profile and long-term outcomes of patients who underwent surgery were analysed. RESULTS: Of 1060 patients, 12 (1.13 per cent) were managed surgically. Of these, disease-modifying surgical procedures included perilymphatic fistula repair (n = 7) and microvascular decompression of the vestibular nerve (n = 1). Labyrinth destructive procedures included transmastoid labyrinthectomy (n = 2) and labyrinthectomy with vestibular nerve section (n = 1). One patient with vestibular schwannoma underwent both a disease-modifying and destructive procedure (translabyrinthine excision). All patients achieved excellent vertigo control, classified as per the American Academy of Otolaryngology - Head and Neck Surgery 1995 criteria. CONCLUSION: With the advent of intratympanic treatments, surgical treatments for vertigo have become further limited. However, surgery with directed intent, in select patients, can give excellent results. PMID- 26654640 TI - A 15-year retrospective study of 160 cases of benign lip lesions. AB - OBJECTIVE: This study aimed to describe the results of a retrospective analysis of a specific cohort of patients with benign lip lesions encountered in the last 15 years in the School of Medicine at Karadeniz Technical University. METHOD: A total of 312 patients were managed for lip lesions during the period 2000-2014. Data from 160 samples of benign lip biopsies were retrieved from the pathology laboratory records. RESULTS: The study group included 20 different histopathological types of lesions, with mucocele being the most frequent lesion (43.13 per cent). The other frequent lesions were chronic inflammatory infiltrate (11.25 per cent), intradermal naevus (5.63 per cent), pyogenic granuloma (5.63 per cent), fibroma (5 per cent) and papilloma (5 per cent). Mucocele was significantly more common in younger patients (p < 0.001). CONCLUSION: Knowledge of the epidemiology and distribution of oral mucosal lesions is essential to promote early diagnosis and treatment. Further epidemiological studies exploring the causal relationships and risk factors for lip lesions are necessary for a better understanding of lip diseases. PMID- 26654641 TI - Labyrinthine sequestration secondary to auditory implantation: report of two cases and review of the literature. AB - BACKGROUND: Auditory implantation into the inner ear is increasingly performed for a variety of indications. Infective complications are rare, but when they occur they can have devastating consequences. CASE REPORTS: This paper reports two cases where vestibular sequestration of the bony labyrinth developed following implantation into the middle ear. CONCLUSION: To the authors' knowledge, these are the first reported cases where vestibular sequestration has resulted from auditory implant surgery. This paper outlines the radiological changes characteristic of this pathology. It also describes the surgical and conservative treatment options for this condition, challenging the previously accepted belief that affected patients always require aggressive surgical intervention. PMID- 26654642 TI - Multiplexed Activity of perAuxidase: DNA-Capped AuNPs Act as Adjustable Peroxidase. AB - In this study, we have investigated the intrinsic peroxidase-like activity of citrate-capped AuNPs (perAuxidase) and demonstrated that the nanozyme function can be multiplexed and tuned by integrating oligonucleotides on a nanoparticle surface. Systematic studies revealed that by controlling the reaction parameters, the mutiplexing effect can be delayed or advanced and further used for aptasensor applications. PMID- 26654658 TI - Enantioselective Bromo-oxycyclization of Silanol. AB - Relying on the nucleophilicity of silanol for building up silicon-incorporated scaffold with an enantiopure tetrasubstituted carbon center remains elusive. In this report, asymmetric bromo-oxycyclization of olefinic silanol by using chiral anionic phase-transfer catalyst is described. This protocol provided a facile entry to a wide arrangement of enantiopure benzoxasilole in moderate to excellent enantioselectivities depending on the unique reactivity of bromine/N-benzyl-DABCO complex. PMID- 26654659 TI - Opportunities for Products of New Plant Breeding Techniques. AB - Various new plant breeding techniques (NPBT) have a similar aim, namely to produce improved crop varieties that are difficult to obtain through traditional breeding methods. Here, we review the opportunities for products created using NPBTs. We categorize products of these NPBTs into three product classes with a different degree of genetic modification. For each product class, recent examples are described to illustrate the potential for breeding new crops with improved traits. Finally, we touch upon the future applications of these methods, such as cisgenic potato genotypes in which specific combinations of Phytophthora infestans resistance genes have been stacked for use in durable cultivation, or the creation of new disease resistances by knocking out or removing S-genes using genome-editing techniques. PMID- 26654660 TI - Total Synthesis of (+/-)-Glyceollin II and a Dihydro Derivative. AB - Stressed soybeans produce a group of phytoalexins that belong to the 6a hydroxypterocarpan family of flavonoids. Certain of the more prominent members, such as the glyceollins I, II, and III, have demonstrated potential antidiabetic properties and promising cytotoxicity in both human breast and prostate cancer cell cultures with preliminary studies in animals further demonstrating antitumor effects in estrogen-dependent, human breast cancer cell implants. Although syntheses of glyceollin I have been reported previously, this work constitutes the first total directed synthesis of (+/-)-glyceollin II. It involves 12 steps with an overall yield of 7% using practical methods that should be readily scalable to produce quantities needed for advanced biological characterization. Highlights include a novel intramolecular benzoin condensation, a chelation controlled lithium aluminum hydride-mediated reduction, and an intramolecular cyclization via the formation of a transient epoxide intermediate to cap the construction of the 6a-hydroxypterocarpan system. Additionally, a dihydro analogue has been obtained, and several isolated intermediates have been made available for evaluation of their biological properties and possible contributions toward elaborating key structure-activity relationship data among this family of promising phytoalexins elicited from stressed soybeans. PMID- 26654661 TI - Report of Dramatic Improvement after a Lumboperitoneal Shunt Procedure in a Case of Anticoagulation Therapy-Resistant Cerebral Venous Thrombosis. AB - Cerebral venous thrombosis (CVT), which typically progresses from either acute or subacute onset, presents with symptoms related to intracranial hypertension (e.g., headache and papilledema) and brain parenchymal lesions (e.g., aphasia and hemiplegia). Anticoagulation therapy is generally accepted as a treatment for CVT and often leads to good clinical outcomes. However, we experienced a case of CVT with an uncommon clinical course. The patient was a 63-year-old man who presented with headache, papilledema, visual loss, and diplopia; his condition gradually deteriorated, and he was diagnosed with CVT via cerebral angiography. The sinus thrombus was extensive and resistant to anticoagulation therapy, and lumbar puncture revealed a progressive increase in cerebrospinal fluid (CSF) pressure. We performed a lumboperitoneal (LP) shunt procedure, which yielded marked improvement in the symptoms. The main mechanism of neurological dysfunction in CVT is venous outflow obstruction caused by venous thrombus, which results in brain edema, and/or venous infarction, which induces focal neurological signs. Another mechanism is impaired CSF absorption in the thrombosed sinuses, resulting in intracranial hypertension. We speculated that the latter mechanism strongly influenced our case, thus explaining the uncommon clinical course and effectiveness of the LP shunt procedure. Although LP shunting is not a common treatment for CVT, this case report could indicate the usefulness of this procedure for CVT with chronic progression and resistance to anticoagulation therapy. PMID- 26654662 TI - A Comparison of Mortality Prognostic Scores in Ischemic Stroke Patients. AB - OBJECTIVE: Our objective is to compare the predictive accuracy of 4 recently established stroke mortality scores in the Chinese population, including the Get With The Guidelines-Stroke risk score, the iScore prediction rule for 30-day mortality, the iScore prediction rule for 1-year mortality, and the PLAN score. METHODS: We analyzed data from 9698 hospitalized patients with acute ischemic stroke in the China National Stroke Registry (September 2007-August 2008). Outcome measures were in-hospital mortality, 30-day mortality, and 1-year mortality. To evaluate the performance of each model, we calculated the area under the receiver operating characteristic curve. The areas under the curve (AUCs) were compared using the z-test. RESULTS: Among 9698 patients, the mean age was 65.5 years and 38.6% were female. Overall in-hospital mortality, 30-day mortality, and 1-year mortality were 3.0%, 5.9%, and 14.6%, respectively. The AUC values of 4 scores for each outcome were all more than .75. The z-test did not show significant difference among the AUC values of these 4 scores. For patients who received thrombolysis therapy, these 4 scores had apparent reductions in the AUC values. CONCLUSIONS: We could confirm the predictive value of all these 4 scores for short-term and long-term mortalities in Chinese IS patients. However, these 4 scores need to be interpreted with caution in the patients who received thrombolysis therapy. PMID- 26654663 TI - Do Stroke Patients Know Their Risk Factors? AB - BACKGROUND: Risk factor management is the key to stroke prevention. Although several studies have assessed the awareness of different risk factors in the general public, there are limited data available on how well acute stroke patients know their own risk factors. The aim of this study was to assess stroke patients' informedness of their own stroke risk factors. METHODS: All consecutive eligible acute stroke and transient ischemic attack patients hospitalized at the Tartu University Hospital, Department of Neurology, during 9 months in 2010 were interviewed about different stroke risk factors within 72 hours from hospitalization. The respective information was also retrieved from medical records. RESULTS: Of the 341 patients admitted during the study period, 195 were eligible for the interview. Diabetes was the best known risk factor (89%) followed by hypertension (80%), atrial fibrillation (78%), previous stroke (77%), and heart failure and/or ischemic heart disease (66%). CONCLUSIONS: We found that acute stroke patients are best informed of their diabetes and worst informed of their ischemic heart disease and/or heart failure. There is, however, room for amelioration in the awareness of all of the studied risk factors. More attention should be addressed to explaining the risks and treatment options to patients at risk of stroke and the general population. PMID- 26654665 TI - Early Magnetic Resonance Imaging Predicts Early Neurological Deterioration in Acute Middle Cerebral Artery Minor Stroke. AB - BACKGROUND: Early neurological deterioration (END) is an important factor associated with worse clinical outcome in minor strokes. Early magnetic resonance imaging (MRI) findings can provide better sensitivity to delineate stroke pathophysiology and have diagnostic value associated with causative mechanisms. The aim of this study was to investigate the relationship between early MRI finding and the presence of END in minor stroke patients with lesions in the middle cerebral artery (MCA) territory. METHODS: Consecutive MCA minor stroke patients who were admitted to our center within 24 hours of symptom onset were included in this study. All patients underwent MRI within 24 hours of admission. We analyzed baseline characteristics, infarction patterns, and treatment algorithms. The correlation between early MRI findings and END, defined as National Institutes of Health Stroke Scale score increasing more than 2 points during 72 hours after admission, was also determined. RESULTS: Across 211 patients meeting entry criteria between January 2010 and December 2013, internal border-zone (IBZ) infarcts on early MRI scan were observed in 23 of 65 patients with END (35.4%) and in 18 of 146 patients without END (12.3%, P < .001). Patients with IBZ infarcts were found to have more hyperlipidemia, less perforating artery infarcts, more pial artery infarcts, more cortical border-zone infarcts and more ipsilateral large arterial stenosis. Logistic regression analysis revealed that IBZ infarct was independently associated with END after adjustment for other factors (odds ratio, 2.50; 95% confidence interval, 1.09 5.74; P = .031). CONCLUSIONS: Early MRI patterns of IBZ infarction are associated with END in minor stroke patients with acute infarcts of the MCA territory. PMID- 26654664 TI - On- versus Off-Hour Patient Cohorts at a Primary Stroke Center: Onset-to Treatment Duration and Clinical Outcomes after IV Thrombolysis. AB - BACKGROUND: The symptom onset-to-treatment (OTT) duration predicts symptomatic intracerebral hemorrhage (sICH) and adverse outcomes after ischemic stroke. Previous studies found disparities in OTT durations and clinical outcomes between stroke patients with symptom onset during on-hours versus off-hours, which led to the initiation of nationwide efforts to provide consistent 24-hour stroke care. GOAL: Our objective is to compare OTT durations and clinical outcomes in ischemic stroke patients whose symptoms originated during on- versus off-hours at a primary stroke center. METHODS: We analyzed clinical data from 210 consecutive patients receiving intravenous recombinant tissue plasminogen activator therapy between January 2009 and December 2013 at Yale-New Haven Stroke Center, a primary stroke center. Stroke severity was assessed by baseline National Institutes of Health Stroke Scale (NIHSS) scores. Clinical outcomes were assessed by presence of sICH and by stroke-related fatalities. OTT durations and clinical outcomes were compared using Mann-Whitney tests, 2-sample tests of proportions, and 2 sample t-tests after testing for equal variance. FINDINGS: We found no significant differences in OTT durations between on-hour and off-hour patient cohorts (137 minutes versus 145 minutes, P = .53). There were also no differences in stroke severity (mean NIHSS score 12.4 versus 11.3, P = .27), sICH rates (4.6% versus 6.5%, P = .56), or stroke fatality rates (9.2% versus 9.8%, P = .89) between the 2 cohorts. CONCLUSIONS: Our results represent progress in emergency response and acute stroke care, and reinforce ongoing nationwide efforts to increase stroke awareness and provide consistent quality care for patients with acute stroke. PMID- 26654666 TI - Effect of Weekend Admission on In-Hospital Mortality in Patients with Ischemic Stroke: An Analysis of Korean Nationwide Claims Data from 2002 to 2013. AB - BACKGROUND: Studies conducted on patients with stroke in countries other than Korea demonstrated a phenomenon known as the weekend effect on 7-day, 30-day, and in-hospital mortalities. We studied patients with stroke using nationwide cohort data to determine if there was a weekend effect on mortality in a Korean population. METHODS: Nationwide cohort data, collected from 2002 to 2013, were searched for all hospitalizations via the emergency department due to ischemic stroke. Cox's proportional hazards frailty model was employed, and we adjusted for all patient and hospital characteristics. RESULTS: There were 8957 patients with ischemic stroke admitted via the emergency department: 2632 weekend admissions and 6325 weekday admissions. Of these, 478 (5.3%) patients were dead. After adjusting for patient and hospital characteristics, the frailty model analysis revealed significantly higher in-hospital mortality in patients admitted on weekends than in those admitted on weekdays (hazard ratio [HR], 1.22; 95% confidence interval [CI], 1.01-1.47). We obtained consistent results for the 30 day mortality findings (HR, 1.27; 95% CI, 1.04-1.55). However, no significant differences were observed in the 7-day mortality (HR, 1.13; 95% CI, .88-1.45). CONCLUSIONS: Weekend admission for ischemic stroke was significantly associated with higher in-hospital and 30-day mortality after adjusting for individual characteristics and hospital factors. PMID- 26654667 TI - Improving Telestroke Treatment Times in an Expanding Network of Hospitals. AB - BACKGROUND: Like all medical innovations, telestroke must demonstrate successful outcomes to achieve sustained growth and acceptance. Asserting that telemedicine is faster, employs the latest technology, or promotes a better use of limited resources is laudable but insufficient. An analysis of stroke treatment within a telemedicine network in 2013 showed that tissue-type plasminogen activator (tPA) could be safely and reliably administered within a practice-based model of telestroke care. Since then, hospital volume and tPA administration within this network have tripled. We hypothesize that a practice-based model of telestroke can maintain positive outcomes in the face of rapid growth. METHODS: Data on tPA treatment times and outcomes after thrombolysis were gathered for 165 patients treated with alteplase between November 2012 and November 2014. Comparisons were made to a previous published study of 54 patients seen between October 2010 and October 2012 in the same network. Primary outcome measures were average door-to needle (DTN) time for TPA administration and average call-to-needle (CTN) time. RESULTS: Significant reductions were observed in median DTN (93 versus 75 minutes, P < .01) and median CTN (56 versus 41 minutes, P < .01). Quality outcome measures such as post-tPA symptomatic hemorrhage (2 [4%] versus 9 [5%], P = .23), length of stay (4 versus 4 days, P = .45), mortality (8 [15%] versus 16 [10%]; P = .32), and percentage of stroke patients treated remained stable. CONCLUSIONS: This study shows that a practice-based telemedicine system can produce meaningful improvement in markers of telestroke efficiency in the face of rapid growth of a telestroke network. PMID- 26654668 TI - Neuroprotective Effects of Brain-Derived Neurotrophic Factor and Noggin-Modified Bone Mesenchymal Stem Cells in Focal Cerebral Ischemia in Rats. AB - BACKGROUND: Administration of bone marrow stromal cells (BMSCs) has been reported to ameliorate functional deficits in rat ischemia models. In the present study, we tried to reveal the underlying mechanism of the improvement of neurological function after stroke by BMSCs transfected with brain-derived neurotrophic factor (BDNF) and/or Noggin. METHODS: BMSCs were transfected with BDNF or/and Noggin using the adenovirus method. Middle cerebral artery occlusion (MCAO) rat models were treated with different types of transfected BMSCs. The treatment effect was assessed by measuring the modified Neurological Severity Score and the expression levels of different stroke-related molecules using Western blot, immunohistochemistry assay (IHC), and enzyme-linked immunosorbent assay (ELISA). RESULTS: The injection of BDNF or/and Noggin-modified BMSCs could significantly improve the neurological function of MCAO animals. Western blot and IHC staining showed that the expression levels of vascular endothelial growth factor, BCL-2, p GSK3beta, and p-Akt were significantly upregulated, while the expressions of Bax, TLR4, and MyD88 were significantly downregulated. Moreover, ELISA assay revealed that the level of matrix metallopeptidase 9 (MMP-9) and reactive oxygen species were also significantly decreased. These results suggested that the treatment of BDNF or/and Noggin-modified BMSCs may suppress the ischemia-induced apoptosis and inflammation in the model animals, which might be through the Akt/GSK3beta and TLR4/MyD88 pathways. CONCLUSION: BDNF or/and Noggin-modified BMSCs may exert neuroprotective effects through the Akt/GSK3beta and TLR4/MyD88 pathways. Transplantation of BDNF or/and Noggin-modified BMSCs might be a potential therapeutic method for ischemic stroke in clinics. PMID- 26654669 TI - Effects of Surgery and Antiplatelet Therapy in Ten-Year Follow-Up from the Registry Study of Research Committee on Moyamoya Disease in Japan. AB - BACKGROUND: Despite the common practice of surgery and antiplatelet therapy for the prevention of recurrent stroke in patients with moyamoya disease, the benefit of these treatments is controversial. We analyzed the stroke recurrence rate in the Registry Study of Research Committee on Moyamoya Disease in Japan funded by the Health, Labor and Welfare Ministry of Japan. METHODS: An annual follow-up study of the registered cases was continued for 10 years. The rate of recurrent stroke, including cerebral infarction and hemorrhage but not transient ischemic attack and seizure, was evaluated with Kaplan-Meier analysis. RESULTS: The proportion of childhood-onset cases decreased in recently registered cases (within 10 years, n = 541) compared to remote cases (> 10 years, n = 735). Among types at disease onset in adult-onset cases, intracerebral hemorrhage decreased recently. In recent cases, the rate of subsequent cerebral hemorrhage was much higher in the hemorrhagic group (10.9 +/- 3.3%/5 years) than in the ischemic group (2.0 +/- .9%/5 years). The recurrence rate of cerebral infarction was lower in the surgery group (1.8 +/- .9%/5 years) than in the nonsurgery group (3.8 +/- 2.2%/5 years). In the adult-onset ischemic group, the proportion of surgically treated patients increased and their recurrence rate was lower than that of nonsurgery patients. In the ischemic group, the rate of cerebral infarction was not significantly different between the antiplatelet subgroup and the non antiplatelet subgroup, whereas the rate of cerebral hemorrhage was higher in the non-antiplatelet subgroup than in the antiplatelet subgroup. CONCLUSIONS: Our results suggest revascularization surgery may suppress recurrent ischemic attacks in patients with moyamoya disease. PMID- 26654670 TI - Comparisons of Apparent Diffusion Coefficient Values in Penumbra, Infarct, and Normal Brain Regions in Acute Ischemic Stroke: Confirmatory Data Using Bootstrap Confidence Intervals, Analysis of Variance, and Analysis of Means. AB - BACKGROUND AND OBJECTIVE: There is no consensus about apparent diffusion coefficient (ADC) values in acute stroke regions that could be used by clinicians in a day-to-day clinical practice; regional measures using confidence intervals (CIs) and a graphic representation of means are scarce in the literature. Our aim in this study was to compare ADC values in infarct, penumbra, and normal brain regions in patients with acute ischemic stroke (AIS). METHODS: This is a retrospective study of 100 magnetic resonance imaging data sets from AIS patients. ADC values were measured in the infarct, penumbra, and normal regions. Three hundred measurements underwent 1-way analysis of variance, analysis of means, and calculation of 95% and 84% CIs. RESULTS: There was a statistically significant difference at the P level less than .025 in ADC values for the 3 regions (F[2, 297] = 168.039, P <= .001), with no overlap of the CIs for the means among the regions: normal brain (mean [M] = .847, standard deviation [SD] = .103, 95% CI: .825-.866), infarct (M = .533, SD = .157, 95% CI: .501-.563), and penumbra (M = .764, SD = .110, 95% CI: .740-.787). CONCLUSIONS: ADC values might be used as reference data in acute stroke-specific populations; CIs would provide radiologists and clinicians with additional quantitative tools to evaluate penumbra, infarct, and normal brain tissue and to tailor follow-up and treatment options for selected patients. PMID- 26654671 TI - Association between Interleukin-10 -1082G/A Gene Polymorphism and Risk of Stroke in the North Indian Population: A Case-Control Study. AB - BACKGROUND: Anti-inflammatory interleukin-10 (IL-10) cytokine and its genetic variations may play an important role in the pathogenesis of various human diseases including stroke. OBJECTIVE: The aim of this present case-control study was to determine the association between IL-10 -1082G/A (rs1800896) gene polymorphism and risk of stroke in the North Indian population. METHODS: Genotyping was carried out by using SNaPshot method (Applied Biosystems, Foster City, California, United States) for 250 ischemic stroke (IS) patients, 250 age- and sex-matched IS free controls, 100 intracerebral hemorrhage (ICH) patients, and 100 age- and sex-matched ICH free controls. IS was classified using the Trial of Org 10172 in Acute Stroke Treatment classification. Conditional logistic regression analysis with adjustment for multiple demographic and risk factor variables was used to calculate the strength of association between IL-10 ( 1082G/A) polymorphism and risk of stroke. RESULTS: Conditional logistic regression analysis showed an independent association between IL-10 -1082G/A and risk of IS under a dominant model (odds ratio [OR] = 2.39, 95% confidence interval [CI] = 1.34-4.27, P = .003) and an allelic model (OR = 2.49, 95% CI 1.71 3.63, P < .001). An independent association between IL-10 -1082G/A, under the dominant model (OR = 6.8, 95% CI 2.2-20.7, P < .001) and the allelic model (OR = 3.4, 95% CI 1.8-6.3, P < .001), and the risk of ICH was also observed. CONCLUSION: Our results suggest that IL-10 -1082G/A gene polymorphism is an independent risk factor for the risk of IS and ICH in the North Indian population. Our findings indicate that IL-10 -1082G/A polymorphism may be used as a genetic marker for identifying individuals at increased risk of developing stroke. PMID- 26654672 TI - CYP3A activity based on plasma 4beta-hydroxycholesterol during the early postpartum period has an effect on the plasma disposition of amlodipine. AB - This study aimed to evaluate plasma 4beta-hydroxycholesterol as an endogenous marker of CYP3A4/5 activity in early postpartum women and its impact on the plasma disposition of amlodipine. Twenty-seven early postpartum women treated with amlodipine for pregnancy-induced hypertension were enrolled. The plasma concentration of 4beta-hydroxycholesterol and its ratio to cholesterol in postpartum and in non-perinatal women were evaluated. The predose plasma concentration of amlodipine was determined at steady state. The medians of the plasma 4beta-hydroxycholesterol concentration at day 0-3 and 8-21 after delivery were 146 and 161 ng/mL, respectively. No significant difference was observed in the plasma concentration of 4beta-hydroxycholesterol between the postpartum periods. The plasma concentration of 4beta-hydroxycholesterol and its ratio to cholesterol in postpartum women were significantly higher than those in non perinatal women. A large individual variability was observed in the dose normalized plasma concentration of amlodipine in early postpartum women. A weak negative correlation was observed between the dose-normalized plasma concentration of amlodipine and the plasma concentration of 4beta hydroxycholesterol. In conclusion, early postpartum women possessed higher CYP3A activity based on plasma 4beta-hydroxycholesterol and had a large pharmacokinetic variability in amlodipine. CYP3A activity during the early postpartum period had an effect on the plasma disposition of amlodipine. PMID- 26654673 TI - Aortic flow patterns before and after personalised external aortic root support implantation in Marfan patients. AB - Implantation of a personalised external aortic root support (PEARS) in the Marfan aorta is a new procedure that has emerged recently, but its haemodynamic implication has not been investigated. The objective of this study was to compare the flow characteristics and hemodynamic indices in the aorta before and after insertion of PEARS, using combined cardiovascular magnetic resonance imaging (CMR) and computational fluid dynamics (CFD). Pre- and post-PEARS MR images were acquired from 3 patients and used to build patient-specific models and upstream flow conditions, which were incorporated into the CFD simulations. The results revealed that while the qualitative patterns of the haemodynamics were similar before and after PEARS implantation, the post-PEARS aortas had slightly less disturbed flow at the sinuses, as a result of reduced diameters in the post-PEARS aortic roots. Quantitative differences were observed between the pre- and post PEARS aortas, in that the mean values of helicity flow index (HFI) varied by 10%, 35% and 20% in post-PEARS aortas of Patients 1, 2 and 3, respectively, but all values were within the range reported for normal aortas. Comparisons with MR measured velocities in the descending aorta of Patient 2 demonstrated that the computational models were able to reproduce the important flow features observed in vivo. PMID- 26654674 TI - Hemodynamic characterization of geometric cerebral aneurysm templates. AB - Hemodynamics are currently considered to a lesser degree than geometry in clinical practices for evaluating cerebral aneurysm (CA) risk and planning CA treatment. This study establishes fundamental relationships between three clinically recognized CA geometric factors and four clinically relevant hemodynamic responses. The goal of the study is to develop a more combined geometric/hemodynamic basis for informing clinical decisions. Flows within eight idealized template geometries were simulated using computational fluid dynamics and measured using particle image velocimetry under both steady and pulsatile flow conditions. The geometric factor main effects were then analyzed to quantify contributions made by the geometric factors (aneurysmal dome size (DS), dome-to neck ratio (DNR), and parent-vessel contact angle (PV-CA)) to effects on the hemodynamic responses (aneurysmal and neck-plane root-mean-square velocity magnitude (Vrms), aneurysmal wall shear stress (WSS), and cross-neck flow (CNF)). Two anatomical aneurysm models were also examined to investigate how well the idealized findings would translate to more realistic CA geometries. DNR made the greatest contributions to effects on hemodynamics including a 75.05% contribution to aneurysmal Vrms and greater than 35% contributions to all responses. DS made the next greatest contributions, including a 43.94% contribution to CNF and greater than 20% contributions to all responses. PV-CA and several factor interactions also made contributions of greater than 10%. The anatomical aneurysm models and the most similar idealized templates demonstrated consistent hemodynamic response patterns. This study demonstrates how individual geometric factors, and combinations thereof, influence CA hemodynamics. Bridging the gap between geometry and flow in this quantitative yet practical way may have potential to improve CA evaluation and treatment criteria. Agreement among results from idealized and anatomical models further supports the potential for a template-based approach to play a useful role in clinical practice. PMID- 26654675 TI - Relationships and redundancies of selected hemodynamic and structural parameters for characterizing virtual treatment of cerebral aneurysms with flow diverter devices. AB - BACKGROUND AND PURPOSE: To quantify the relationship and to demonstrate redundancies between hemodynamic and structural parameters before and after virtual treatment with a flow diverter device (FDD) in cerebral aneurysms. METHODS: Steady computational fluid dynamics (CFD) simulations were performed for 10 cerebral aneurysms where FDD treatment with the SILK device was simulated by virtually reducing the porosity at the aneurysm ostium. Velocity and pressure values proximal and distal to and at the aneurysm ostium as well as inside the aneurysm were quantified. In addition, dome-to-neck ratios and size ratios were determined. Multiple correlation analysis (MCA) and hierarchical cluster analysis (HCA) were conducted to demonstrate dependencies between both structural and hemodynamic parameters. RESULTS: Velocities in the aneurysm were reduced by 0.14m/s on average and correlated significantly (p<0.05) with velocity values in the parent artery (average correlation coefficient: 0.70). Pressure changes in the aneurysm correlated significantly with pressure values in the parent artery and aneurysm (average correlation coefficient: 0.87). MCA found statistically significant correlations between velocity values and between pressure values, respectively. HCA sorted velocity parameters, pressure parameters and structural parameters into different hierarchical clusters. HCA of aneurysms based on the parameter values yielded similar results by either including all (n=22) or only non-redundant parameters (n=2, 3 and 4). CONCLUSION: Hemodynamic and structural parameters before and after virtual FDD treatment show strong inter-correlations. Redundancy of parameters was demonstrated with hierarchical cluster analysis. PMID- 26654676 TI - Functional and anatomical measures for outflow boundary conditions in atherosclerotic coronary bifurcations. AB - The aim of this research was finding the influence of anatomy-based and functional-based outflow boundary conditions for computational fluid dynamics (CFD) on fractional flow reserve (FFR) and wall shear stress (WSS) in mildly diseased coronary bifurcations. For 10 patient-specific bifurcations three simulations were set up with different outflow conditions, while the inflow was kept constant. First, the outflow conditions were based on the diameter of the outlets. Second, they were based on the volume estimates of the myocardium that depended on the outlets. Third, they were based on a myocardial flow measure derived from computed tomography perfusion imaging (CTP). The difference in outflow ratio between the perfusion-based and the diameter-based approach was -7 p.p. [-14 p.p.:7 p.p.] (median percentage point and interquartiles), and between the perfusion-based and volume-based this was -2 p.p. [-2 p.p.:1 p.p.]. Despite of these differences the computed FFRs matched very well. A quantitative analysis of the WSS results showed very high correlations between the methods with an r(2) ranging from 0.90 to 1.00. But despite the high correlations the diameter-based and volume-based approach generally underestimated the WSS compared to the perfusion-based approach. These differences disappeared after normalization. We demonstrated the potential of CTP for setting patient-specific boundary conditions for atherosclerotic coronary bifurcations. FFR and normalized WSS were unaffected by the variations in outflow ratios. In order to compute absolute WSS a functional measure to set the outflow ratio might be of added value in this type of vessels. PMID- 26654677 TI - Response to letter to the editor regarding "In vitro flow investigations in the aortic arch during cardiopulmonary bypass with stereo-PIV". PMID- 26654678 TI - Strategies for the Conversion of Lignin to High-Value Polymeric Materials: Review and Perspective. AB - The majority of commodity plastics and materials are derived from petroleum-based chemicals, illustrating the strong dependence on products derived from non renewable energy sources. As the most accessible, renewable form of carbon (in comparison to CO2), lignocellulosic biomass (defined as organic matter available on a renewable basis) has been acknowledged as the most logical carbon-based feedstock for a variety of materials such as biofuels and chemicals. This Review focuses on methods developed to synthesize polymers derived from lignin, monolignols, and lignin-derived chemicals. Major topics include the structure and processing of lignocellulosic biomass to lignin, polymers utilizing lignin as a macromonomer, synthesis of monomers and polymers from monolignols, and polymers from lignin-derived chemicals, such as vanillin. PMID- 26654679 TI - Drivers for OSH interventions in small and medium-sized enterprises. AB - The debate concerning occupational safety and health (OSH) interventions has recently focused on the need of improving the evaluation of interventions, and in particular on the need for providing information about why the intervention worked or not, under what circumstances and in which context. Key concepts in the analysis of the context are the drivers, i.e., those factors enabling, fostering or facilitating OSH interventions. However, the concept of driver for an OSH intervention is both confused and contested. Although the term is widely used, there is little consensus on how drivers should be understood, how important they are in different contexts and how they can facilitate interventions. This exploratory study based on interviews with the owner-managers and the safety officers of small and medium-sized enterprises (SMEs) gives an overview of the most characteristic drivers for OSH interventions. The results will be used to make an initial evaluation of SMEs' needs, and will help orient interventions and future research. PMID- 26654680 TI - Infrared Vibrational Nanospectroscopy by Self-Referenced Interferometry. AB - Infrared vibrational scattering scanning near-field optical microscopy (s-SNOM) has emerged as a new frontier in imaging science due to its potential to provide nanoscale spatially resolved chemical spectroscopy for the investigation of molecular, soft-matter, and biological materials. As a phase-sensitive technique able to yield the full complex dielectric function of materials, different interferometric schemes have been developed involving asymmetric interferometry between sample and reference arms. In this work, we take advantage of a greatly simplified symmetric geometry that uses the spatially coherent background scattered light from within the confocal sample volume as a reference field for signal amplification in both self-homodyne and self-heterodyne interferometry. On the basis of a simple model for tip-sample scattering and interferometric detection, we demonstrate the measurement of the vibrational response of molecular materials in good agreement with established values. In addition to a compact design, enhanced signal levels, and a reduced sensitivity to fluctuations and drift, including those from the light source, self-referenced interferometry brings benefits for routine s-SNOM chemical spectroscopy, remaining robust even under a wide range of challenging experimental environments. PMID- 26654681 TI - Collective strength, collective action. PMID- 26654682 TI - What is new in distal femur periprosthetic fracture fixation? AB - Distal femoral periprosthetic fractures are on the rise. Increased mortality of these injuries is also evident from recent data. Their incidence and risk factors have been extensively reported in the past but new data are being available that merit attention. The increased incidence and the even higher projected incidence should direct the focus of future strategies to the education of surgeons, relevant capacity of hospital and reconfiguration of health care resources. New and potentially modifiable risk factors should be taken into consideration to the informed consent process and new studies should be developed to clarify the causative relationship of the new risk factors such as the peptic ulcer disease and the COPD. The main internal fixation techniques remain the lateral locking plating and the retrograde intramedullary nailing. New techniques in plating are the supplementary medial plate in selected cases and the far cortical locking. Nailing is considered a valid option especially in fractures located well above the anterior flange of the femoral component of the arthroplasty. Results and outcomes from good quality studies are still sparse regarding the comparison between plating and nailing. Interprosthetic fractures constitute an entity that is lately gaining considerable attention. The best method of management of these injuries is still evolving with considerable amount of work being done in the clinical and biomechanical level. PMID- 26654683 TI - Memristive Behavior and Ideal Memristor of 1T Phase MoS2 Nanosheets. AB - Memristor, which had been predicted a long time ago (Chua, L. O. IEEE Trans. Circuit Theory 1971, 18, 507), was recently invented (Strukov, D. B.; et al. Nature 2008, 453, 80). The introduction of a memristor is expected to open a new era for nonvolatile memory storage, neuromorphic computing, digital logic, and analog circuit. Furthermore, several breakthroughs were made for memristive phenomena and transistors with single-layer MoS2 (Sangwan, V. K.; et al. Nat. Nanotechnol. 2015, 10, 403. van der Zande, A. M.; et al. Nat. Mater. 2013, 12, 554. Liu, H.; et al. ACS Nano 2014, 8, 1031. Bessonov, A. A.; et al. Nat. Mater. 2015, 14, 199. Yuan, J.; et al. Nat. Nanotechnol. 2015, 10, 389). Herein, we demonstrate that 2H phase of bulk MoS2 possessed an ohmic feature, whereas 1T phase of exfoliated MoS2 nanosheets exhibited a unique memristive behavior due to voltage-dependent resistance change. Furthermore, an ideal odd-symmetric memristor with odd-symmetric I-V characteristics was successfully fabricated by the 1T phase MoS2 nanosheets via combining two asymmetric switches antiserially. PMID- 26654684 TI - Severe Coal Tar Sealcoat Runoff Toxicity to Fish Is Prevented by Bioretention Filtration. AB - Coal tar sealcoats applied to asphalt surfaces in North America, east of the Continental Divide, are enriched in petroleum-derived compounds, including polycyclic aromatic hydrocarbons (PAHs). The release of PAHs and other chemicals from sealcoat has the potential to contaminate nearby water bodies, reducing the resiliency of aquatic communities. Despite this, relatively little is known about the aquatic toxicology of sealcoat-derived contaminants. We assessed the impacts of stormwater runoff from sealcoated asphalt on juvenile coho salmon (Oncorhynchus kisutch) and embryo-larval zebrafish (Danio rerio). We furthermore evaluated the effectiveness of bioretention as a green stormwater method to remove PAHs and reduce lethal and sublethal toxicity in both species. We applied a coal tar sealcoat to conventional asphalt and collected runoff from simulated rainfall events up to 7 months postapplication. Whereas sealcoat runoff was more acutely lethal to salmon, a spectrum of cardiovascular abnormalities was consistently evident in early life stage zebrafish. Soil bioretention effectively reduced PAH concentrations by an order of magnitude, prevented mortality in juvenile salmon, and significantly reduced cardiotoxicity in zebrafish. Our findings show that inexpensive bioretention methods can markedly improve stormwater quality and protect fish health. PMID- 26654685 TI - Some types of hookups may be riskier than others for campus sexual assault. AB - OBJECTIVE: The high prevalence of campus sexual assault (CSA) among college students in the United States is a chronic public health crisis. Some risk factors for CSA victimization, such as alcohol consumption and female gender, are firmly established, but the evidence for others is less robust. One factor that has received little attention in the literature on CSA is "hooking up," defined as a physically intimate dyadic encounter that may not entail further contact between partners. The purpose of the present study was to examine the role of hooking up, both as a general risk factor for CSA victimization, and the roles of different types of hookups, varying in degree of relatedness between partners, for different types of victimization. METHOD: A stratified random sample of female undergraduate students (n = 373) from a single, small campus in the northeastern United States completed measures of demographics, alcohol consumption, hooking up, and sexual victimization in an online survey. RESULTS: Results revealed high-risk levels of drinking, and a low-to-moderate frequency of hooking up. Overall prevalence of CSA reported by this sample was 44%, with 40% reporting nonconsensual sexual contact, and 33% attempted rape or rape. Follow-up questions to reports of sexual assaults indicated that most (78%) took place during hookups, and that the riskiest hookups were those with acquaintances and previous romantic partners. CONCLUSION: If found to generalize to other campus populations, the role of hooking up in sexual assault should be added to systems based models of sexual assault (e.g.,Heise, 1998) and to educational prevention programs. (PsycINFO Database Record PMID- 26654686 TI - The effect of enemy combat tactics on PTSD prevalence rates: A comparison of Operation Iraqi Freedom deployment phases in a sample of male and female veterans. AB - OBJECTIVE: Research suggests that the nature of combat may affect later development of posttraumatic stress disorder (PTSD) in combat veterans. Studies comparing rates of PTSD across different conflicts indicate that the use of asymmetric or guerilla-style tactics by enemy fighters may result in higher rates of PTSD among U.S. military personnel than the use of symmetric tactics, which mirror tactics used by U.S. forces. Investigations of the association between enemy combat tactics and PTSD across conflicts were limited because of cohort effects and a focus on male veterans. The current study examined rates of PTSD diagnosis in a sample of male and female veterans deployed to Operation Iraqi Freedom (OIF), a conflict with 3 distinct phases marked by varying enemy tactics. METHOD: Participants were 738 veterans enrolled in Project VALOR (Veterans' After Discharge Longitudinal Registry) who deployed once to OIF. Participants completed a clinician interview as well as self-report measures. RESULTS: Male veterans deployed during the OIF phase marked by asymmetric tactics were more than twice as likely to be diagnosed with PTSD as those deployed during the other 2 phases, even after controlling for extent of combat exposure, demographic characteristics, and other deployment-related risk factors for PTSD. Differing rates of PTSD across the 3 OIF phases were not observed among female participants. CONCLUSION: The nature of combat (specifically, asymmetric enemy tactics) may be a risk factor for the development of PTSD among males. Factors other than enemy tactics may be more important to the development of PTSD among females. (PsycINFO Database Record PMID- 26654687 TI - Multiple trauma exposure and psychosocial functioning in Singaporean children in out-of-home care. AB - OBJECTIVE: Children in out-of-home care are often exposed to chronic, interpersonal traumas such as abuse and domestic violence. Exposure to more than 1 interpersonal trauma is associated with functional impairments, mental health symptoms, and risk behaviors. Despite the importance of studying trauma in this vulnerable population, very few studies have investigated trauma exposure among children and youth in out-of-home care in Asia. This is the first study to examine the effects of multiple interpersonal trauma exposure in a large sample of children in out-of-home care in Singapore. METHOD: A cross-sectional study of 721 children between the ages of 5 and 17 years residing in foster care and voluntary children's homes in Singapore was conducted to determine the proportion of children with interpersonal trauma exposure and the effect of trauma exposure on psychosocial functioning. RESULTS: Results indicated that 63% of the sample experienced at least 1 interpersonal trauma, with neglect (34%) and physical abuse (31%) the most prevalent. Girls were more likely to be emotionally and sexually abused than boys. Children with multiple interpersonal trauma exposure (35% of the sample) were significantly older, more likely to be female, and had a higher number of life functioning, behavioral, and emotional, as well as risk behavior needs compared with children with no previous trauma. CONCLUSION: Findings highlight the importance of conducting comprehensive assessments of children in out-of-home care to provide specialized interventions for children with interpersonal trauma exposure. (PsycINFO Database Record PMID- 26654688 TI - Deployment stress, tobacco use, and postdeployment posttraumatic stress disorder: Gender differences. AB - OBJECTIVE: Epidemiological research has demonstrated that tobacco use and posttraumatic stress disorder (PTSD) frequently co-occur and are highly prevalent among Veterans; research with female Veterans is limited. Given the increasing numbers of women deployed to combat zones in recent conflicts, the objective of the current study was to examine gender-specific associations between deployment stress, tobacco use and postdeployment PTSD symptoms. METHOD: Two thousand thirteen Veterans deployed to Afghanistan and Iraq (50.9% female; mean age = 35.53) completed a postdeployment, mailed survey that assessed tobacco use before, during, and after deployment, deployment stressors, and postdeployment PTSD symptoms. RESULTS: Warfare stress was associated with initiation and increases in tobacco use during deployment in both men and women, whereas harassment stress was associated with initiation and increases in tobacco use in women only. Only among women was continued postdeployment tobacco use associated with postdeployment PTSD symptoms. CONCLUSIONS: We found a dose-dependent relationship between deployment stress and adoption and escalation of tobacco use; the stressors that provoked initiation and escalation of tobacco use differed by gender. Continued tobacco use after deployment was associated with PTSD in women suggesting that women used tobacco more selectively than men to regulate negative affect. Implications of this work are that training before combat and during combat on healthy means of coping with deployment stress is needed to prevent tobacco use. For women, reducing harassment stress during deployment and early treatment of acute stress and PTSD during and soon after deployment may prevent intractable tobacco use. PMID- 26654689 TI - Multifunctional Coating Based on Hyaluronic Acid and Dopamine Conjugate for Potential Application on Surface Modification of Cardiovascular Implanted Devices. AB - Surface modification by conjugating biomolecules has been widely proved to enhance biocompatibility of cardiovascular implanted devices. Here, we aimed at developing a multifunctional surface that not only provides good hemocompatibility but also functions well in inducing desirable vascular cell material interaction. In the present work, the multicoatings of hyaluronic acid (HA) and dopamine (PDA) were prepared onto 316L stainless steel (316L SS) via chemical conjugation (Michael addition, Schiff base reaction, and electrostatic adsorption). The results of platelet adhesion and activation and the whole blood tests indicated that the HA/PDA coatings obtained better hemocompatibility compared with the bare 316L SS and HA or PDA immobilized on 316L SS. The HA/PDA coatings also inhibited the proliferation of smooth muscle cells and adhesion/activation of macrophages effectively, whereas not all the HA/PDA coatings improved surface endothelialization rapidly and the effects of the multifunctional coatings on endothelial cell growth depend on the HA amounts (1.0, 2.0, and 5.0 mg/mL, labeled as PDA-HA-1, PDA-HA-2, and PDA-HA-5 respectively). Herein the PDA-HA-1 and PDA-HA-2 coatings were found to improve endothelial cell adhesion and proliferation significantly. The tissue compatibility of the HA/PDA coatings also depends on the HA amounts, and the PDA HA-2 coating was proved to cause milder in vivo tissue response. Additionally, the mechanism of the HA molecular weight change and in vivo tissue response was also explored. These results effectively suggested that the HA/PDA coating might be promising when serving as a cardiovascular implanted device coating. PMID- 26654691 TI - Improving Suicide Risk Screening and Detection in the Emergency Department. AB - INTRODUCTION: The Emergency Department Safety Assessment and Follow-up Evaluation Screening Outcome Evaluation examined whether universal suicide risk screening is feasible and effective at improving suicide risk detection in the emergency department (ED). METHODS: A three-phase interrupted time series design was used: Treatment as Usual (Phase 1), Universal Screening (Phase 2), and Universal Screening + Intervention (Phase 3). Eight EDs from seven states participated from 2009 through 2014. Data collection spanned peak hours and 7 days of the week. Chart reviews established if screening for intentional self-harm ideation/behavior (screening) was documented in the medical record and whether the individual endorsed intentional self-harm ideation/behavior (detection). Patient interviews determined if the documented intentional self-harm was suicidal. In Phase 2, universal suicide risk screening was implemented during routine care. In Phase 3, improvements were made to increase screening rates and fidelity. Chi-square tests and generalized estimating equations were calculated. Data were analyzed in 2014. RESULTS: Across the three phases (N=236,791 ED visit records), documented screenings rose from 26% (Phase 1) to 84% (Phase 3) (chi(2) [2, n=236,789]=71,000, p<0.001). Detection rose from 2.9% to 5.7% (chi(2) [2, n=236,789]=902, p<0.001). The majority of detected intentional self-harm was confirmed as recent suicidal ideation or behavior by patient interview. CONCLUSIONS: Universal suicide risk screening in the ED was feasible and led to a nearly twofold increase in risk detection. If these findings remain true when scaled, the public health impact could be tremendous, because identification of risk is the first and necessary step for preventing suicide. TRIAL REGISTRATION: Emergency Department Safety Assessmentand Follow-up Evaluation (ED-SAFE) ClinicalTrials.gov: (NCT01150994). https://clinicaltrials.gov/ct2/show/NCT01150994?term=ED-SAFE&rank=1. PMID- 26654692 TI - Neonatal Fc Receptor Binding Tolerance toward the Covalent Conjugation of Payloads to Cysteine 34 of Human Albumin Variants. AB - The long circulatory half-life of albumin facilitated by the interaction with the cellular recycling neonatal Fc receptor (FcRn) is utilized for drug half-life extension. FcRn engagement effects following covalent attachment of cargo to cysteine 34, however, have not been investigated. Poly(ethylene glycol) polymers were used to study the influence of cargo molecular weight on human FcRn engagement of recombinant wild type (WT) albumin and an albumin variant engineered for increased FcRn binding. Decreased affinity was observed for all conjugates; however, the engineered albumin maintained an affinity above that of unmodified wild type albumin that promotes it as an attractive drug delivery platform. PMID- 26654693 TI - Predicted shortage of vascular surgeons in the United Kingdom: A matter for debate? AB - BACKGROUND: Vascular surgery became a new independent surgical specialty in the United Kingdom (UK) in 2013. In this matter for debate we discuss the question, is there a "shortage of vascular surgeons in the United Kingdom?" MATERIALS AND METHODS: We used data derived from the "Vascular Surgery United Kingdom Workforce Survey 2014", NHS Employers Electronic Staff Records (ESR), and the National Vascular Registry (NVR) surgeon-level public report to estimate current and predict future workforce requirements. RESULTS: We estimate there are approximately 458 Consultant Vascular Surgeons for the current UK population of 63 million, or 1 per 137,000 population. In several UK Regions there are a large number of relatively small teams (3 or less) of vascular surgeons working in separate NHS Trusts in close geographical proximity. In developed countries, both the number and complexity of vascular surgery procedures (open and endovascular) per capita population is increasing, and concerns have been raised that demand cannot be met without a significant expansion in numbers of vascular surgeons. Additional workforce demand arises from the impact of population growth and changes in surgical work-patterns with respect to gender, working-life-balance and 7-day services. CONCLUSIONS: We predict a future shortage of Consultant Vascular Surgeons in the UK and recommend an increase in training numbers and an expansion in the UK Consultant Vascular Surgeon workforce to accommodate population growth, facilitate changes in work-patterns and to create safe sustainable services. PMID- 26654694 TI - The future of growth-promoting therapy. AB - Growth hormone (GH) has been in use for 50 years in children with short stature. Recent developments suggest that our traditional approaches to growth-promoting therapy will be challenged in the following areas:1)Diagnostic: The diagnosis of GH deficiency has always been problematic, largely due to limitations inherent in GH stimulation tests and related biochemical measures. The development of new tools for diagnosis of genetic etiologies of hormonal deficiencies and insensitivity, as well as the growing availability of such methodologies, will greatly strengthen existing diagnostic strategies.2)Therapeutic: Long-acting GH preparations are already in clinical trials. IGF-I therapy is approved for treatment of IGF deficiency. Novel approaches to select skeletal dysplasias show promise and will potentially expand our therapeutic armamentarium. 3) Monitoring: Traditional weight-based dosing of GH will be supplemented by IGF-based and auxology-based strategies, allowing greater individualization of therapy. 4) Safety: Growth-promoting therapies will continue to require careful monitoring of safety. Recent consensus workshops have advocated life-time surveillance programs.5) Ethics: Questions will continue to be raised concerning ethical issues related to growth-promoting therapy in children. The availability of new tools for diagnosis and monitoring will address some, but not all, of these issues. PMID- 26654695 TI - A rare case study of a retropharyngeal neurofibroma and a brief literature review. AB - INTRODUCTION: Space occupying lesions in the retropharyngeal space are rare. CASE REPORT: Here, we present a rare case of a retropharyngeal neurofibroma treated surgically through an open cervical approach without any complication. DISCUSSION: Neurofibromas are benign, slowly growing neoplasms that could be associated or not with neurofibromatosis. They are derived from peripheral nerves. Diagnostic work-up should include CT-scan and MRI as well as a biopsy to confirm the diagnosis. Treatment of localized and diffuse neurofibromas is often surgical resection, which may require sacrifice of the nerve. Malignant transformation of these lesions, without association to NF-1, is rare and exceptionally documented in the literature. CONCLUSION: We presented a rare case of solitary neurofibroma of the retropharyngeal space. Complete resection of the lesion was performed without any complication. We also presented a brief review of the literature about neurofibromas. PMID- 26654696 TI - Anti-parathyroid treatment effectiveness and persistence in incident haemodialysis patients with secondary hyperparathyroidism. AB - BACKGROUND: Anti-parathyroid treatment initiation and discontinuation are important decisions in chronic haemodialysis (HD) patients, where pill burden is often excessive. The present study aimed to describe secondary hyperparathyroidism (sHPT) drug therapy changes in HD patients. METHODS: Retrospective observational cohort study of incident European HD patients with sHPT who were prescribed calcitriol or alfacalcidol (alpha calcitriol), paricalcitol or cinacalcet. RESULTS: Treatment-naive patients prescribed alpha calcitriol (N=2259), paricalcitol (N=1689) and cinacalcet (N=1245) were considered for analysis. Serum intact parathyroid hormone (iPTH) levels decreased post-initiation with all treatment modalities; serum calcium and phosphate levels increased in response to activated vitamin D derivatives but decreased with cinacalcet. Approximately one-third of alpha calcitriol and paricalcitol patients but less than one-quarter of cinacalcet patients discontinued treatment. Although the three groups had comparable serum iPTH control at the time of treatment discontinuation, they differed in terms of calcium and phosphate levels. Following discontinuation, the evolution of laboratory parameters differed by treatment modality: whilst iPTH increased for all three treatment groups, calcium and phosphate decreased in patients who were being treated with alpha calcitriol and paricalcitol at the time of discontinuation, and increased in those who had been treated with cinacalcet. CONCLUSIONS: In conditions of daily clinical practice, attaining and maintaining recommended biochemical control of sHPT appears to be more frequently achievable with cinacalcet than with activated vitamin D compounds. PMID- 26654697 TI - Risk factor analysis of postoperative acute respiratory distress syndrome in valvular heart surgery. AB - PURPOSE: The aim of this study is to investigate the incidence, severity, and outcome of postoperative acute respiratory distress syndrome (ARDS), according to the Berlin definition, in isolated valvular heart surgery. The preoperative and perioperative predisposing factors of this complication were also identified. METHODS: A retrospective chart review was conducted on 457 patients who underwent isolated valvular heart surgery between January 2010 and December 2012. Clinical characteristics and outcomes were collected. The primary outcome was postoperative ARDS, according to the 2012 Berlin definition for ARDS. RESULTS: A total of 37 patients (8.1%) developed postoperative ARDS, with a mortality rate of 29.7%. The multivariate analysis identified that age (odds ratios [ORs], 1.067, P <= .001), liver cirrhosis (OR, 7.159; P = .001), massive blood transfusion (OR, 2.980; P = .005), and tricuspid valve replacement (OR, 5.197; P = .012) were independent risk factors of postoperative ARDS. Furthermore, we have determined that the increased severity stages of ARDS were associated with decreased postoperative survival. CONCLUSIONS: In conclusion, postoperative ARDS, according to Berlin definition, in valvular surgery, was associated with high in hospital mortality. The severity of ARDS was associated with patient midterm mortality. In multivariate analysis, age, liver cirrhosis, massive blood transfusion, and tricuspid valve replacement were identified as independent risk factors of ARDS. PMID- 26654698 TI - Authors' commentary: Association of intraoperative vasopressin administration with acute postoperative kidney injury and outcomes after coronary artery bypass surgery. PMID- 26654699 TI - [Anaerobiospirillum thomasii bacteremia with fatal outcome]. AB - Anaerobiospirillum thomasii has been reported as a causative agent of diarrhea in humans; however no bacteremia associated with this pathogen has been described so far. We present here the first case of fatal A. thomasii bacteremia in an alcoholic patient. PMID- 26654700 TI - Controlling Rotavirus-associated diarrhea: Could single-domain antibody fragments make the difference? AB - Group A Rotavirus (RVA) remains a leading cause of severe diarrhea and child mortality. The variable domain of camelid heavy chain antibodies (VHH) display potent antigen-binding capacity, have low production costs and are suitable for oral therapies. Two sets of anti-RVA VHHs have been developed: ARP1-ARP3; 2KD1 3B2. Here, we explore the potential of both sets as a prevention strategy complementary to vaccination and a treatment option against RVA-associated diarrhea in endangered populations. Both sets have been expressed in multiple production systems, showing extensive neutralizing capacity against strains of RVA in vitro. They were also tested in the neonatal mouse model with various degrees of success in preventing or treating RVA-induced diarrhea. Interestingly, mitigation of the symptoms was also achieved with freeze-dried ARP1, so that it could be applied in areas where cold chains are difficult to maintain. 3B2 was tested in a pre-clinical trial involving gnotobiotic piglets where it conferred complete protection against RVA-induced diarrhea. ARP1 was used in the first clinical trial for anti-RVA VHHs, successfully reducing stool output in infants with RVA diarrhea, with no detected side effects. PMID- 26654701 TI - Mapping the superficial inferior epigastric system and its connection to the deep system: An MRA analysis. AB - The superficial inferior epigastric vasculature plays a critical role in free abdominal tissue transfer. However, its anatomic variations are incompletely characterized. An investigation was conducted on the preoperative imaging of patients undergoing free-flap breast reconstruction by a single surgeon between 2008 and 2013. This study included patients who underwent abdominal magnetic resonance angiogram (MRA). A coordinate system was used to draw the main trunk and primary branches from each patient's superficial inferior epigastric system. Each hemiabdomen's branching pattern was categorized as simple, complex, or absent. The number of superficial-to-deep inferior epigastric connections and the presence or absence of a superficial system crossing the midline were recorded. Interrater reliability was assessed for two raters. This analysis included 53 patients (106 hemiabdomens). A total of 80 (75%) hemiabdomens were categorized as having simple and 10 (9%) as complex branching patterns. A total of 16 (15%) hemiabdomens had no identifiable vessels. At least one superficial-to-deep connection was found among 89 hemiabdomens (84%). Superficial systems crossing the midline were found in 14 patients (26%). Our findings support the high degree of anatomic variation in the superficial inferior epigastric system, including a significant number of patients lacking superficial-to-deep connections and bilaterally communicating systems. These variations may be identified on preoperative MRA. PMID- 26654703 TI - Effective Detection of Mycotoxins by a Highly Luminescent Metal-Organic Framework. AB - We designed and synthesized a new luminescent metal-organic framework (LMOF). LMOF-241 is highly porous and emits strong blue light with high efficiency. We demonstrate for the first time that very fast and extremely sensitive optical detection can be achieved, making use of the fluorescence quenching of an LMOF material. The compound is responsive to Aflatoxin B1 at parts per billion level, which makes it the best performing luminescence-based chemical sensor to date. We studied the electronic properties of LMOF-241 and selected mycotoxins, as well as the extent of mycotoxin-LMOF interactions, employing theoretical methods. Possible electron and energy transfer mechanisms are discussed. PMID- 26654702 TI - The stressors of being young and Black: Cardiovascular health and Black young adults. AB - OBJECTIVE: To examine the impact of stressors relevant to the lives of Black young adults including racial, financial, occupational, and general stress and psychological distress on cardiovascular disease (CVD) risk. Specifically, this study examined the relationship between multiple psychosocial stressors and two CVD risk indicators (i.e. obesity and blood pressure). DESIGN: This study used a quantitative design which included surveys, the collection of anthropometric and blood pressure (BP) measures. Participants were 124 Black college students aged 18 to 27 years old. MAIN OUTCOME MEASURES: Participants completed measures to assess psychological distress, general, occupational, financial and racial stress. Measures of body mass index (BMI), waist-to-hip ratio (WHR) and BP were collected to assess CVD risk. RESULTS: Findings indicated a significant effect of internalised racism on BMI and a significant effect of individual racial stress on diastolic BP. Also, depression was significantly associated with systolic BP. There were no significant results for WHR. CONCLUSION: Findings suggested that the relationship among racial stress, psychological distress and CVD be further explored. PMID- 26654704 TI - Modeling the intergenerational impact of partner abuse on maternal and child function at 24 months post outreach: Implications for practice and policy. AB - OBJECTIVE: Many women are exposed to partner violence during their lifetime which affects mental health and child development. This study revalidates an intergenerational model connecting partner violence to poor functioning for mothers and children using structural equation techniques. METHOD: A longitudinal design collected data on 300 mother-child pairs. Comparisons between the model, tested at study entry and again at 24 months, are reported. Maternal measures included childhood experiences of abuse, partner abuse, chronic pain, and mental health. The Child Behavior Checklist measured child function. RESULTS: Comparison of both models revealed that maternal chronic pain, maternal mental health, and child witnessing of mother's abuse remain strong predictors of child dysfunction. Maternal social support and self-efficacy are significant predictors of more positive maternal mental health with a conduit effect on child behavior. CONCLUSION: Intimate partner violence directly impacts the victim and also has a secondary impact on the children of abuse victims. PMID- 26654705 TI - Development of neuroendocrine systems governing energy homeostasis. PMID- 26654706 TI - Deletion of the putative tumor suppressor gene, G0s2, does not affect progression of EMU-Myc driven lymphomas in mice. AB - Several recent reports have suggested that the G0/G1 switch gene 2 (G0S2) is a potential tumor suppressor in leukemia. Here we show that deletion of the G0s2 gene in mouse does not affect the latency of cancer progression in the EMU-Myc model of lymphoma. Our findings do not rule out the possibility that G0S2 may be playing a role in other forms of leukemia, but clearly show that the commonly used EMU-Myc transgenic is not the correct model to conduct studies on G0s2. PMID- 26654707 TI - Patient, physician, and general population preferences for treatment characteristics in relapsed or refractory chronic lymphocytic leukemia: A conjoint analysis. AB - Due to the disease heterogeneity, treatments for chronic lymphocytic leukemia (CLL) have differed with respect to efficacy and toxicity. Limited options have also been available regarding modalities of administration. Our study objective was to estimate preferences for treatment characteristics (or "attributes") in relapsed/refractory (r/r) CLL. Patients, physicians (hematologists/oncologists), and members from the general population from Germany and Sweden completed a conjoint analysis comprising six CLL treatment attributes: (i) overall survival (OS), (ii) progression-free survival (PFS), (iii) fatigue, (iv) nausea, (v) risk of serious infections, and (vi) treatment administration (each described in three levels). We estimated the relative importance of each attribute by fitting a hierarchical Bayesian model. A total of 190 German and 121 Swedish individuals participated. In the pooled sample, OS was the most important attribute (36%), followed by risk of serious infection (21%), treatment administration (13%), fatigue (12%), PFS (11%), and nausea (7%). Treatment administration was more important to patients (all p<0.004), OS was more important to physicians (all p<0.001), and risk of serious infections was more important to the general population than to physicians (p<0.001). Our results could be helpful to align therapeutic decision-making in r/r CLL with patient preferences to improve care satisfaction and treatment compliance. PMID- 26654708 TI - Effects of the hypoxia-inducible factor-1 inhibitor echinomycin on vascular endothelial growth factor production and apoptosis in human ectopic endometriotic stromal cells. AB - Recent evidence points to a possible role for hypoxia-inducible factor (HIF)-1 in the pathogenesis and development of endometriosis. The objectives of this study were to investigate the critical role of HIF-1 in endometriosis and the effect of the HIF-1 inhibitor echinomycin on human ectopic endometriotic stromal cells (eESCs). Ectopic endometriotic tissues were obtained from 20 patients, who received an operation for ovarian endometriomas. We examined vascular endothelial growth factor (VEGF) and stromal cell-derived factor-1 (SDF-1) production, HIF-1 expression, cell proliferation and apoptosis of eESCs. Cobalt chloride (CoCl2) significantly induced expression of HIF-1alpha protein and VEGF production in a time-dependent manner in eESCs, but reduced SDF-1 production. VEGF production was significantly suppressed by treatment of 100 nM echinomycin without causing cell toxicity, but 0.1-10 nM echinomycin or 100 nM progestin had no significant effect. SDF-1 production was not affected by echinomycin treatment at any dose. Echinomycin inhibited cell proliferation and induced apoptotic cell death of the eESCs, and significantly inhibited expression of the anti-apoptotic proteins Bcl 2 and Bcl-xL. Echinomycin inhibits VEGF production and induces apoptosis of eESCs by suppression of Bcl-2 and Bcl-xL. These findings suggest the unique therapeutic potential for echinomycin as an inhibitor of HIF-1 activation for endometriosis treatment. PMID- 26654709 TI - Trends and disparities in sepsis hospitalisations in Victoria, Australia. AB - Objective The aim of the present study was to determine the clinical and epidemiological characteristics of patients with sepsis admitted to hospitals in Victoria, Australia, during the period 2004-14. The data include incidence, severity and mortality. Methods In all, 44222 sepsis hospitalisations were identified between 2004-05 and 2013-14 from the Victorian Admitted Episodes Dataset. The dataset contains clinical and demographic information on all admissions to acute public and private hospitals. Using the International Classification of Diseases (10th Revision) Australian Modification codes, incidence rates, severity of disease and mortality were calculated. Results Sepsis hospitalisation rates per 10000 population increased significantly (P<0.01) over the period, from 6.9 (95% confidence interval (CI) 5.6-7.8) to 10.0 (95% CI 9.1-11.1), an annual growth rate of 3.8%. The age-standardised in hospital death rates per 100000 population grew significantly (P<0.01) from 9.2 (95% CI 7.8-10.4) in 2004-05 to 13.0 (95% CI 11.7-14.6) in 2013-14, an annual growth rate of 3.1%. Among people under 45 years of age, the 0-4 years age group had the highest hospitalisation rate (3.0 per 10000 population; 95% CI 2.7-3.4). Nearly half (46.2%) of all sepsis hospitalisations were among patients born overseas, with a rate of 14.5 per 10000 population (95% CI 12.4-16.2) in that group compared with a rate of 5.9 per 10000 population (95% CI 5.3-6.7) for patients born in Australia. The age-standardised sepsis hospitalisation rate was 2.6-fold greater in the lowest compared with highest socioeconomic areas (12.7 per 10000 population (95% CI 11.2-13.8) vs 4.8 per 10000 population (95% CI 4.1 5.7), respectively). Conclusion This paper shows a significant upward trend in both sepsis separation rates and in-hospital death rates over the period; unlike sepsis, in-hospital death rates from all diagnoses fell over the same period. The results can be used to stimulate review of clinical practice. Greater understanding of the epidemiology of sepsis could improve care quality and outcomes. What is known about the topic? Sepsis is associated with high mortality rates and severe sepsis is the most common cause of death in intensive care units (ICU). The last published study of sepsis in Victoria (in 2005) showed a gradual rise in rates; since then, there is little information as to whether there has been any significant improvement in treatment outcomes. What does this paper add? This paper provides new information by analysing trends and variations in sepsis hospitalisations in Victoria by several demographic groups from 2004-05 to 2013 14. What are the implications for practitioners? Patients with severe sepsis consume approximately half the ICU resources. Reliable and recent data on the growth of this disease are important for prevention, allocation of resources and to track the effectiveness of care. A key area for intervention is promoting greater adherence to clinical guidelines. PMID- 26654710 TI - Uptake and Accumulation of Nephrotoxic and Carcinogenic Aristolochic Acids in Food Crops Grown in Aristolochia clematitis-Contaminated Soil and Water. AB - Emerging evidence has suggested aristolochic acids (AAs) are linked to the development of Balkan endemic nephropathy (BEN), a chronic renal disease affecting numerous farmers living in the Balkan peninsula. However, the pathway by which AAs enter the human food chain and cause kidney disease remains poorly understood. Using our previously developed analytical method with high sensitivity and selectivity (Chan, W.; Lee, K. C.; Liu, N.; Cai, Z. J. Chromatogr. A 2007, 1164, 113-119), we quantified AAs in lettuce, tomato, and spring onion grown in AA-contaminated soil and culture medium. Our study revealed that AAs were being taken up from the soil and bioaccumulated in food crops in a time- and dose-dependent manner. To the best of our knowledge, this study is the first to identify one of the possible pathways by which AAs enter our food chain to cause chronic food poisoning. Results also demonstrated that AAs were resistant to the microbial activity of the soil/water. PMID- 26654711 TI - Correction to Interaction of Doxorubicin with Polynucleotides. A Spectroscopic Study. PMID- 26654712 TI - Salvage thrombolysis and extracorporeal membrane oxygenation for massive pulmonary embolism during the distal femur fracture surgery. PMID- 26654714 TI - Abstracts presented at the 20th Annual Congress of the Belgian Society of Internal Medicine. PMID- 26654713 TI - pH-Induced Re-entrant Microstructural Transitions in Cationic Surfactant Hydrotrope Mixtures. AB - The structural transitions occurring with change in pH for aqueous mixtures of a cationic surfactant (cetyltrimethylammonium bromide, CTAB) and a hydrotrope (sodium salicylate, NaSal) were investigated at various temperatures using dynamic light scattering and small-angle neutron scattering. Direct structural studies show a transition from rigid cylindrical micelles at neutral pH to spherical micelles at ~ pH 2 upon protonation of salicylate molecules; however, an unanticipated reversion to flexible cylindrical micelles with further decrease in pH was observed. We also observed these microstructure transitions from cylinders at high pH to spherical micelles at intermediate pH to flexible cylindrical micelles at low pH were highly sensitive to temperature. Our results suggest that, in addition to the well-described electrostatic and hydrophobic interactions in cationic surfactant-hydrotrope mixtures, the pH-induced microstructural changes are potentially governed by complementary cation-pi and hydrogen bonding interactions. PMID- 26654715 TI - Ultrafast Photoprotecting Sunscreens in Natural Plants. AB - We explore the ultrafast photoprotective properties of a series of sinapic acid derivatives in a range of solvents, utilizing femtosecond transient electronic absorption spectroscopy. We find that a primary relaxation mechanism displayed by the plant sunscreen sinapoyl malate and other related molecular species may be understood as a multistep process involving internal conversion of the initially photoexcited 1(1)pipi* state along a trans-cis photoisomerization coordinate, leading to the repopulation of the original trans ground-state isomer or the formation of a stable cis isomer. PMID- 26654716 TI - Valsartan ameliorates KIR2.1 in rats with myocardial infarction via the NF-kappaB miR-16 pathway. AB - BACKGROUND: MicroRNAs have an important role in regulating arrhythmogenesis. MicroRNA-16 (miR-16) is predicted to target KCNJ2. The regulation of miR-16 is primarily due to NF-kappaB. Whether valsartan could downregulate miR-16 via the inhibition of NF-kappaB after MI and whether miR-16 targets KCNJ2 remain unclear. METHODS: MI rats received valsartan or saline for 7days. The protein levels of NF kappaB p65, inhibitor kappaBalpha (IkappaBalpha), and Kir2.1 were detected by Western blot analysis. The mRNA levels of Kir2.1 and miR-16 were examined by quantitative real-time PCR. Whole cell patch-clamp techniques were applied to record IK1. RESULTS: MiR-16 expression was higher in the infarct border, and was accompanied by a depressed IK1/KIR2.1 level. Additionally, miR-16 overexpression suppressed KCNJ2/KIR2.1 expression. In contrast, miR-16 inhibition or binding site mutation enhanced KCNJ2/KIR2.1 expression, establishing KCNJ2 as a miR-16 target. In the MI rats, compared to saline treatment, valsartan reduced NF-kappaB p65 and miR-16 expression and increased IkappaBalpha and Kir2.1 expression. In vitro, angiotensin II increased miR-16 expression and valsartan inhibited it. Overexpressing miR-16 in cells treated with valsartan abrogated its beneficial effect on KCNJ2/Kir2.1. NF-kappaB activation directly upregulates miR-16 expression. CONCLUSIONS: miR-16 controls KCNJ2 expression, and valsartan ameliorates Kir2.1 after MI partly depending on the NF-kappaB-miR-16 pathway. PMID- 26654717 TI - Thromboprophylaxis after major orthopedic surgery: Improving compliance with clinical practice guidelines. AB - INTRODUCTION: Identifying risk factors and strategies for the prevention of deep venous thromboembolism in major orthopedic surgery has allowed the development of Clinical Practice Guidelines (CPGs). Currently, there is a gap between clinical practice and the implementation of the recommendations of CPGs. The purpose of this paper is to report the impact of the implementation of improvement strategies on adherence to venous thromboembolism (VTE) prophylaxis guidelines. MATERIALS AND METHODS: We defined 3 quality indicators to assess the adequate use of thromboprophylaxis according to CPGs. We obtained a baseline measurement and identified several barriers for adherence. Six improvement strategies to promote adherence to CPGs were designed and applied. A systematic monitoring of these indicators was performed in real time and a description of the data was completed for patients undergoing primary joint replacement of the hip, knee and shoulder, during February 2012 and August 2014. RESULTS: Data from 773 patients were obtained. In the first trimester, the average of adherence was: 98.3% for medical order in the post-operative note, 60.3% for opportune administration and 67% for adherence to therapy at home. In the trimester, the rates of adherence were 100%, 95.7% and 100% respectively. CONCLUSIONS: Combined strategies for improvement of adherence to VTE prophylaxis is associated with higher compliance with clinical practice guidelines. PMID- 26654718 TI - Kinetics of coagulation in ST-elevation myocardial infarction following successful primary percutaneous coronary intervention. AB - INTRODUCTION: ST-elevated myocardial infarction (STEMI) is most frequently caused by coronary occlusion due to formation of an intracoronary thrombus in reaction to rupture of atherosclerotic plaques. Little is known about kinetics of coagulation markers after STEMI in patients treated according to current guidelines. We aimed to investigate kinetics of important coagulation markers in percutaneous coronary intervention (PCI)-treated STEMI patients. MATERIALS AND METHODS: 60 consecutive PCI-treated STEMI patients were prospectively included. Blood samples were collected immediately after as well as 1, 4 and 7 days following PCI. Samples collected 90 days after PCI served as baseline values. ADAMTS13 activity, VWF (von Willebrand factor) activity, VWF antigen, VWF propeptide, fibrinogen antigen, D-dimer, alpha2-antiplasmin (alpha2AP), plasmin alpha2-antiplasmin complex (PAP), prothrombin fragment F1+2 (F1+2), prothrombin time (PT), activated partial thromboplastin time (aPTT), and anti-factor Xa (anti Xa) were measured. Cardiac magnetic resonance (CMR) was performed at 4-6 and 90 days after PCI in 49 patients and left ventricular ejection fraction (LVEF), infarct size and microvascular injury (MVI) were determined. RESULTS: Immediately after PCI, ADAMTS13 activity, fibrinogen antigen and alpha2AP levels were significantly decreased and VWF activity, VWF antigen and VWF propeptide levels were significantly elevated, compared to baseline. Individual coagulation markers and different combinations thereof were not related to LVEF or infarct size at 90 days, or the occurrence of MVI at 4-6 days after PCI. CONCLUSION: Coagulation parameters show a very dynamic profile in the early days after STEMI. However, individual coagulation parameters or combinations thereof do not predict CMR defined LVEF, infarct size or MVI. PMID- 26654719 TI - The economic burden of incident venous thromboembolism in the United States: A review of estimated attributable healthcare costs. AB - Venous thromboembolism (VTE), which includes deep vein thrombosis and pulmonary embolism, is an important cause of preventable mortality and morbidity. In this study, we summarize estimates of per-patient and aggregate medical costs or expenditures attributable to incident VTE in the United States. Per-patient estimates of incremental costs can be calculated as the difference in costs between patients with and without an event after controlling for differences in underlying health status. We identified estimates of the incremental per-patient costs of acute VTEs and VTE-related complications, including recurrent VTE, post thrombotic syndrome, chronic thromboembolic pulmonary hypertension, and anticoagulation-related adverse drug events. Based on the studies identified, treatment of an acute VTE on average appears to be associated with incremental direct medical costs of $12,000 to $15,000 (2014 US dollars) among first-year survivors, controlling for risk factors. Subsequent complications are conservatively estimated to increase cumulative costs to $18,000-23,000 per incident case. Annual incident VTE events conservatively cost the US healthcare system $7-10 billion each year for 375,000 to 425,000 newly diagnosed, medically treated incident VTE cases. Future studies should track long-term costs for cohorts of people with incident VTE, control for comorbid conditions that have been shown to be associated with VTE, and estimate incremental medical costs for people with VTE who do not survive. The costs associated with treating VTE can be used to assess the potential economic benefit and cost-savings from prevention efforts, although costs will vary among different patient groups. PMID- 26654720 TI - Wellbeing and resilience: mechanisms of transmission of health and risk in parents with complex mental health problems and their offspring--The WARM Study. AB - The WARM study is a longitudinal cohort study following infants of mothers with schizophrenia, bipolar disorder, depression and control from pregnancy to infant 1 year of age. BACKGROUND: Children of parents diagnosed with complex mental health problems including schizophrenia, bipolar disorder and depression, are at increased risk of developing mental health problems compared to the general population. Little is known regarding the early developmental trajectories of infants who are at ultra-high risk and in particular the balance of risk and protective factors expressed in the quality of early caregiver-interaction. METHODS/DESIGN: We are establishing a cohort of pregnant women with a lifetime diagnosis of schizophrenia, bipolar disorder, major depressive disorder and a non psychiatric control group. Factors in the parents, the infant and the social environment will be evaluated at 1, 4, 16 and 52 weeks in terms of evolution of very early indicators of developmental risk and resilience focusing on three possible environmental transmission mechanisms: stress, maternal caregiver representation, and caregiver-infant interaction. DISCUSSION: The study will provide data on very early risk developmental status and associated psychosocial risk factors, which will be important for developing targeted preventive interventions for infants of parents with severe mental disorder. TRIAL REGISTRATION: NCT02306551, date of registration November 12, 2014. PMID- 26654721 TI - Benefits and resource implications of family meetings for hospitalized palliative care patients: research protocol. AB - BACKGROUND: Palliative care focuses on supporting patients diagnosed with advanced, incurable disease; it is 'family centered', with the patient and their family (the unit of care) being core to all its endeavours. However, approximately 30-50% of carers experience psychological distress which is typically under recognised and consequently not addressed. Family meetings (FM) are recommended as a means whereby health professionals, together with family carers and patients discuss psychosocial issues and plan care; however there is minimal empirical research to determine the net effect of these meetings and the resources required to implement them systematically. The aims of this study were to evaluate: (1) if family carers of hospitalised patients with advanced disease (referred to a specialist palliative care in-patient setting or palliative care consultancy service) who receive a FM report significantly lower psychological distress (primary outcome), fewer unmet needs, increased quality of life and feel more prepared for the caregiving role; (2) if patients who receive the FM experience appropriate quality of end-of-life care, as demonstrated by fewer hospital admissions, fewer emergency department presentations, fewer intensive care unit hours, less chemotherapy treatment (in last 30 days of life), and higher likelihood of death in the place of their choice and access to supportive care services; (3) the optimal time point to deliver FM and; (4) to determine the cost-benefit and resource implications of implementing FM meetings into routine practice. METHODS: Cluster type trial design with two way randomization for aims 1-3 and health economic modeling and qualitative interviews with health for professionals for aim 4. DISCUSSION: The research will determine whether FMs have positive practical and psychological impacts on the family, impacts on health service usage, and financial benefits to the health care sector. This study will also provide clear guidance on appropriate timing in the disease/care trajectory to provide a family meeting. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12615000200583. PMID- 26654723 TI - Simultaneous percutaneous transcatheter aortic valve replacement and endovascular abdominal aortic aneurysm repair in a high risk patient with hostile aortic neck, a case report. AB - BACKGROUND: Abdominal aortic aneurysm (AAA) can be a potential life threatening condition if left untreated. Total endovascular techniques to approach aortic aneurysms have extended management options and enabled patients who are unfit for open surgery to undergo repair. Transcatheter aortic valve replacement is increasingly used to treat patients with severe symptomatic aortic stenosis, who once were considered high risk for traditional open aortic valve replacement. RESULTS: Herein we report the complete simultaneous treatment of an infrarenal AAA with hostile neck and severe aortic stenosis in a patient deemed high risk for surgical repair. CONCLUSION: Advances in catheter based endovascular technology have enabled physicians to approach patients with AAA and valvular pathology even with multiple comorbidities that otherwise would be poor surgical candidates, even in the presence of challenging anatomic considerations and various comorbidities. PMID- 26654722 TI - Heterotrimeric G-proteins in Picea abies and their regulation in response to Heterobasidion annosum s.l. infection. AB - BACKGROUND: Heterotrimeric G-proteins are important signalling switches, present in all eukaryotic kingdoms. In plants they regulate several developmental functions and play an important role in plant-microbe interactions. The current knowledge on plant G-proteins is mostly based on model angiosperms and little is known about the G-protein repertoire and function in other lineages. In this study we investigate the heterotrimeric G-protein subunit repertoire in Pinaceae, including phylogenetic relationships, radiation and sequence diversity levels in relation to other plant linages. We also investigate functional diversification of the G-protein complex in Picea abies by analysing transcriptional regulation of the G-protein subunits in different tissues and in response to pathogen infection. RESULTS: A full repertoire of G-protein subunits in several conifer species were identified in silico. The full-length P. abies coding regions of one Galpha-, one Gbeta- and four Ggamma-subunits were cloned and sequenced. The phylogenetic analysis of the Ggamma-subunits showed that PaGG1 clustered with A type-like subunits, PaGG3 and PaGG4 clustered with C-type-like subunits, while PaGG2 and its orthologs represented a novel conifer-specific putative Ggamma subunit type. Gene expression analyses by quantitative PCR of P. abies G-protein subunits showed specific up-regulation of the Galpha-subunit gene PaGPA1 and the Ggamma-subunit gene PaGG1 in response to Heterobasidion annosum sensu lato infection. CONCLUSIONS: Conifers possess a full repertoire of G-protein subunits. The differential regulation of PaGPA1 and PaGG1 indicates that the heterotrimeric G-protein complex represents a critical linchpin in Heterobasidion annosum s.l. perception and downstream signaling in P. abies. PMID- 26654724 TI - An optimal PID controller via LQR for standard second order plus time delay systems. AB - An improved tuning methodology of PID controller for standard second order plus time delay systems (SOPTD) is developed using the approach of Linear Quadratic Regulator (LQR) and pole placement technique to obtain the desired performance measures. The pole placement method together with LQR is ingeniously used for SOPTD systems where the time delay part is handled in the controller output equation instead of characteristic equation. The effectiveness of the proposed methodology has been demonstrated via simulation of stable open loop oscillatory, over damped, critical damped and unstable open loop systems. Results show improved closed loop time response over the existing LQR based PI/PID tuning methods with less control effort. The effect of non-dominant pole on the stability and robustness of the controller has also been discussed. PMID- 26654725 TI - Independent motion control of a tower crane through wireless sensor and actuator networks. AB - The problem of independent control of the performance variables of a tower crane through a wireless sensor and actuator network is investigated. The complete nonlinear mathematical model of the tower crane is developed. Based on appropriate data driven norms an accurate linear approximant of the system, including an upper bound of the communication delays, is derived. Using this linear approximant, a dynamic measurable output multi delay controller for independent control of the performance outputs of the system is proposed. The controller performs satisfactory despite the nonlinearities of the model and the communication delays of the wireless network. PMID- 26654726 TI - Application of the Intervention Mapping protocol to develop Keys, a family child care home intervention to prevent early childhood obesity. AB - BACKGROUND: Many families rely on child care outside the home, making these settings important influences on child development. Nearly 1.5 million children in the U.S. spend time in family child care homes (FCCHs), where providers care for children in their own residences. There is some evidence that children in FCCHs are heavier than those cared for in centers. However, few interventions have targeted FCCHs for obesity prevention. This paper will describe the application of the Intervention Mapping (IM) framework to the development of a childhood obesity prevention intervention for FCCHs METHODS: Following the IM protocol, six steps were completed in the planning and development of an intervention targeting FCCHs: needs assessment, formulation of change objectives matrices, selection of theory-based methods and strategies, creation of intervention components and materials, adoption and implementation planning, and evaluation planning RESULTS: Application of the IM process resulted in the creation of the Keys to Healthy Family Child Care Homes program (Keys), which includes three modules: Healthy You, Healthy Home, and Healthy Business. Delivery of each module includes a workshop, educational binder and tool-kit resources, and four coaching contacts. Social Cognitive Theory and Self-Determination Theory helped guide development of change objective matrices, selection of behavior change strategies, and identification of outcome measures. The Keys program is currently being evaluated through a cluster-randomized controlled trial CONCLUSIONS: The IM process, while time-consuming, enabled rigorous and systematic development of intervention components that are directly tied to behavior change theory and may increase the potential for behavior change within the FCCHs. PMID- 26654727 TI - Long-Term Follow-Up of Cardiac Rhythm in 320 Patients After the Cox-Maze III Procedure for Atrial Fibrillation. AB - BACKGROUND: The Cox-maze III (CM-III) procedure is the gold standard for surgical treatment of atrial fibrillation (AF). Excellent short-term results have been reported, but long-term outcomes are lesser known. The aim was to evaluate current cardiac rhythm in a nationwide cohort of CM-III patients with very long follow-up. METHODS: Perioperative characteristics were retrospectively analyzed in 536 "cut-and-sew" CM-III patients operated on from 1994 to 2009 in 4 centers. Of these, 54 patients had died and 20 were unavailable at follow-up. The remaining 462 patients received a survey concerning arrhythmia symptoms, rhythm, and medication; of these, 320 patients (69%), comprising 252 men, with a mean age of 67 years (range, 47 to 87 years), and 83% with stand-alone CM-III, returned a current 12-lead electrocardiogram. Long-term monitoring was evaluated in 40 sinus rhythm patients. Postoperative stroke/transient ischemic attack was evaluated by register analysis. RESULTS: Mean follow-up was 111 +/- 44 months (range, 36-223 months). Electrocardiogram analysis showed sinus rhythm in 219 of 320 patients (68%), and regular supraventricular rhythm (sinus, nodal, or atrial pacing) in 262 (82%), with 75% off class I/III antiarrhythmic medication. This group had lower arrhythmia symptom scores and medication use. Rhythm outcome did not differ by gender, age, type of AF, or stand-alone vs concomitant operation. Patients with more than 10 years of follow-up had a lower rate of regular supraventricular rhythm (69% vs 91%, p = 0.02). Long-term monitoring showed freedom from AF/atrial flutter in 38 of 40 patients (95%). The incidence of stroke/transient ischemic attack was 0.37% per year (11 patients). CONCLUSIONS: In a single-moment electrocardiogram evaluation 9 years after the cut-and-sew CM-III, 82% of patients were in sinus rhythm or other regular supraventricular rhythm. These findings support a long-lasting positive effect of the CM-III procedure, which is relevant when evaluating current nonpharmacologic therapies for AF. PMID- 26654729 TI - Nonradiative Plasmon Decay and Hot Carrier Dynamics: Effects of Phonons, Surfaces, and Geometry. AB - The behavior of metals across a broad frequency range from microwave to ultraviolet frequencies is of interest in plasmonics, nanophotonics, and metamaterials. Depending on the frequency, losses of collective excitations in metals can be predominantly classical resistive effects or Landau damping. In this context, we present first-principles calculations that capture all of the significant microscopic mechanisms underlying surface plasmon decay and predict the initial excited carrier distributions so generated. Specifically, we include ab initio predictions of phonon-assisted optical excitations in metals, which are critical to bridging the frequency range between resistive losses at low frequencies and direct interband transitions at high frequencies. In the commonly used plasmonic materials, gold, silver, copper, and aluminum, we find that resistive losses compete with phonon-assisted carrier generation below the interband threshold, but hot carrier generation via direct transitions dominates above threshold. Finally, we predict energy-dependent lifetimes and mean free paths of hot carriers, accounting for electron-electron and electron-phonon scattering, to provide insight toward transport of plasmonically generated carriers at the nanoscale. PMID- 26654728 TI - Lobectomy for Non-Small Cell Lung Cancer by Video-Assisted Thoracic Surgery: Effects of Cumulative Institutional Experience on Adequacy of Lymphadenectomy. AB - BACKGROUND: Because video-assisted thoracic surgery (VATS) lobectomies are increasingly being performed by thoracic surgeons, the adequacy of lymph node clearance by VATS compared with thoracotomy has been questioned, raising the possibility that patients are being understaged. One factor that may be overlooked in published studies is the learning curve of the surgeons and surgical volume in the adoption of VATS lobectomy. This study examined the effect of cumulative institutional VATS lobectomy experience on the adequacy of lymphadenectomy. METHODS: We retrospectively reviewed a prospective database to identify 500 consecutive patients who underwent VATS lobectomy for non-small cell lung cancer (NSCLC) at our institution between 2002 and 2012. For comparative purposes, the cohort was divided into halves, with an early group (first 250 cases) vs a late group (next 250 cases). Clinical and pathologic factors were analyzed. A propensity-matching analysis controlling for age, gender, pathologic stage, and percentage of forced expiratory volume in 1 second was done to compare survival and adequacy of lymphadenectomy. RESULTS: Patients operated on in the late group were significantly older (72 vs 69 years, p = 0.001) and had worse pulmonary functions (median forced expiratory volume in 1 second 83% vs 91%, p < 0.001; median diffusion capacity of the lung for carbon monoxide, 76% vs 85%, p < 0.001). Clinical and pathologic tumor sizes were significantly larger in the late group compared with the early group, with a median of 2.0 vs 1.8 cm (p = 0.002) for clinical T size and median of 2.1 vs 2.0 cm (p = 0.003) for pathologic T size. Patients in the late group had significantly more advanced clinical and pathologic stage distribution. The total number of lymph nodes and the number of nodal stations removed were significantly greater in the late group (p = 0.012) than in the early group (p < 0.001), and same results were obtained after propensity matching. No difference was seen in disease-free survival between the propensity-matched early vs late groups at 3 years (82% vs 85%, p = 0.187). CONCLUSIONS: For patients with NSCLC resected by VATS lobectomy, cumulative institutional experience significantly and positively affects the adequacy of lymphadenectomy. This may be related to the initial surgeon's learning curve with VATS lobectomy. As the experience with VATS lobectomy becomes more mature, the procedure is increasingly being performed on older patients, often with more compromised pulmonary function and more advanced stage disease. Despite the expanded inclusion of older and sicker patients for VATS lobectomy, no compromise was seen in their disease-free survival. PMID- 26654730 TI - Probing the Aggregation Behavior of Neat Imidazolium-Based Alkyl Sulfate (Alkyl = Ethyl, Butyl, Hexyl, and Octyl) Ionic Liquids through Time Resolved Florescence Anisotropy and NMR and Fluorescence Correlation Spectroscopy Study. AB - Aggregation behavior of a series of neat 1-ethyl 3-methylimidazolium alkyl sulfate (alkyl = ethyl, butyl, hexyl, and octyl) ionic liquids has been investigated through combined time-resolved fluorescence spectroscopy, 1-D and 2 D NMR spectroscopy, and fluorescence correlation spectroscopy (FCS). Interestingly, experimentally measured rotational relaxation times (taur) for ethyl, butyl, hexyl and octyl systems are measured to be 2.25, 1.64, 1.36, and 1.32 times higher than the estimated (from Stokes-Einstein-Debye theory) values for the same respective systems. This indicates that the emitting species is not the monomeric imidazolium moiety rather an associated species, and volume of the rotating fluorescing species decreases even though the length of the alkyl moiety on the anions is increased. The shift in the (1)H proton signal as well as a change in the width of the same signal upon dilution of the neat ionic liquids indicates that ionic liquids exist in the aggregated form. Further investigation through the 2D-ROESY experiment shows that interaction between imidazolium and sulfate is relatively stronger in the ethyl system than that of the longer octyl system. FCS measurements independently show that the hydrodynamic volume decreases with an increase in the anion chain length. The NMR and FCS results are consistent with the findings of the fluorescence anisotropy study. PMID- 26654731 TI - Probabilistic Measurement of Central Line-Associated Bloodstream Infections. AB - OBJECTIVE: To develop a probabilistic method for measuring central line associated bloodstream infection (CLABSI) rates that reduces the variability associated with traditional, manual methods of applying CLABSI surveillance definitions. DESIGN: Multicenter retrospective cohort study of bacteremia episodes among patients hospitalized in adult patient-care units; the study evaluated presence of CLABSI. SETTING: Hospitals that used SafetySurveillor software system (Premier) and who also reported to the Centers for Disease Control and Prevention's National Healthcare Safety Network (NHSN). PATIENTS: Patients were identified from a stratified sample from all eligible blood culture isolates from all eligible hospital units to generate a final set with an equal distribution (ie, 20%) from each unit type. Units were divided a priori into 5 major groups: medical intensive care unit, surgical intensive care unit, medical surgical intensive care unit, hematology unit, or general medical wards. INTERVENTIONS: Episodes were reviewed by 2 experts, and a selection of discordant reviews were re-reviewed. Data were joined with NHSN data for hospitals for in plan months. A predictive model was created; model performance was assessed using the c statistic in a validation set and comparison with NHSN reported rates for in-plan months. RESULTS: A final model was created with predictors of CLABSI. The c statistic for the final model was 0.75 (0.68-0.80). Rates from regression modeling correlated better with expert review than NHSN-reported rates. CONCLUSIONS: The use of a regression model based on the clinical characteristics of the bacteremia outperformed traditional infection preventionist surveillance compared with an expert-derived reference standard. Infect. PMID- 26654732 TI - Long-term wheel-running and acute 6-h advances alter glucose tolerance and insulin levels in TALLYHO/JngJ mice. AB - Studies have shown a relationship between circadian rhythm disruptions and type-2 diabetes. This investigation examined the effects of circadian disruption (6-h phase advances) on the progression of diabetes in a type-2 diabetic mouse model TALLYHO/JngJ - and whether wheel-running can alleviate the effects of the phase advances. 6-h advances alter fasting glucose, glucose tolerance and insulin production. Wheel-running reduced body mass, improved glucose tolerance and reduced insulin in TALLYHO/JngJ and alleviated some of the changes in diabetic symptoms due to 6-h advances. These results indicate that individuals with type-2 diabetes can benefit from physical activity and exercise can be a countermeasure to offset the effects of an acute phase advance. PMID- 26654733 TI - Predictors of health-related quality of life among people with type II diabetes Mellitus in Ardabil, Northwest of Iran, 2014. AB - AIMS: The present study aims at investigating different dimensions of the Health Related Quality of Life (HRQOL) and its determinants among type II diabetes Mellitus (T2DM) referred to diabetes clinic in Ardabil. METHODS: The present study was conducted through a cross-sectional method in which 300 people with T2DM were selected using a convenience sampling method between January and May 2014. Data were collected through 26-item structured and WHOQOL-BREF questionnaires. Data analysis was performed using descriptive and analytical statistical methods, independent t-test, Mann Whitney test, ANOVA, Kruskal Wallis, Welch test, and multivariable linear regression model using SPSS (V.20). RESULTS: The mean age of the participants was 54.13+/-9.13, and about 72% of the patients were women. The mean score of the total HRQOL was 53.07+/-17.09; the highest score of HRQOL was related to the environmental domain (57.10+/-10.52) and the lowest to the dimension of social health (45.68+/-17.25). Based on multivariable linear regression, total QOL was influenced by gender, marital status, MHI, and comorbid renal disease. PH Dimension was associated with MHI and neuropathy; PSH with education level, comorbid depression, comorbid renal, and other disease; SR with marital, comorbid renal, and other disease; EH with marital status, Monthly household income (MHI), and education level. CONCLUSION: According to the results of this study, Predictors of the HRQOL in T2DM are associated with demographic and socioeconomic factors, comorbidities, and with less impact, diabetes complications, respectively. Moreover, diabetic patients had moderate HRQOL, and compared with men, scores of all domains were lower in women. PMID- 26654734 TI - Call to action: the proposed National Formulary for Wound Care. PMID- 26654735 TI - Response to the NHS supply chain generic specification for a national formulary for wound care. PMID- 26654736 TI - Treatment of the diabetic foot by offloading: a systematic review. AB - OBJECTIVE: To compare the literature on the strengths and limitations of different offloading devices in the treatment of diabetic foot ulcers. METHOD: Systematic review of the literature in the following databases: the Cumulative Index to Nursing an Allied Health Literature (CINAHL); Medline; Embase; Cochrane Library and Web of Knowledge. The search strategy used the terms: diabetic foot; orthosis/orthotic devices/orthoses; foot orthosis/foot orthoses; casts/plaster cast/surgical cast; shoes. RESULTS: Our results identified 15 studies, which are included in this review. Healing rates, healing times and reduction in ulcer size were improved with the use of total contact casting, when compared with other offloading devices. The main adverse effects associated with the use of the device were infection, maceration and abrasion. Cost, compliance and quality of life issues were rarely included within the studies. CONCLUSION: Offloading is a key treatment strategy for the management of diabetic foot ulcers and total contact casts were found to be the most effective devices to achieve ulcer healing. However, they are not without complications and their impact on cost, compliance and quality of life is not well understood. PMID- 26654737 TI - Clinical outcomes and cost-effectiveness of an externally applied electroceutical device in managing venous leg ulcers in clinical practice in the UK. AB - OBJECTIVE: To estimate the cost-effectiveness of treating patients with a venous leg ulcer (VLU) with an externally applied electroceutical (EAE) device, plus dressings and compression bandaging or continuing with their previous care plan, from the perspective of the National Health Service (NHS) in the UK. METHOD: This was a prospective, single-arm, non-blinded, clinical and economic evaluation of EAE therapy performed in 2013/14. Patients' VLUs were treated with six active units of EAE therapy (each unit for two days) plus dressings and compression bandaging over a period of 12 days. Afterwards, patients were managed with a combination of dressings and bandages. Each patient acted as their own control so that clinical outcomes, resource use and costs associated with the wound over 12 months before the start of EAE therapy were retrospectively compared with the first 12 months after the start of treatment. The relative cost-effectiveness of EAE therapy was estimated at 2013/14 prices. RESULTS: Within 12 months of starting EAE therapy 77% of all wounds healed and the other 23% improved. This difference in effectiveness between the 12-months period before and after EAE therapy was estimated to yield a 12% improvement in health gain of 0.09 QALYs (p<0.01), a 34% reduction in the requirement for nurse visits (from a mean 50.7 to 33.3 visits per patient) and a 26% reduction in the number of dressings. This resulted in an 11% reduction in the NHS cost of VLU management over 12 months after the start of treatment when compared with the previous 12 months (from L1,981 to L1,754 per patient). Hence, use of EAE therapy was found to be a dominant treatment (i.e. improved outcome for less cost). CONCLUSION: Within the study's limitations, use of the EAE device potentially affords the NHS a cost effective treatment for managing VLUs when compared with patients remaining on their previous care plan. PMID- 26654738 TI - Reducing the pathogen burden and promoting healing with polyhexanide in non healing wounds: a prospective study. AB - OBJECTIVE: Polyhexamethylene biguanide (PHMB) is a novel wound antiseptic solution that has a broad antimicrobial spectrum and wound healing promoting effect, with minimal side effects. The aim of present study was to demonstrate the efficacy of the PHMB on the bacterial burden of non-healing wounds, the reduction in wound size or closure of the wound in comparison to Ringer's lactate solution (RLS) after 21 days of wound dressing. A second objective was to investigate the differences in the C-reactive protein (CRP) levels and white blood cell (WBC) counts between the two groups. METHOD: In this prospective and open-cohort clinical study, patients who underwent cardiac surgery between July 2006 and August 2008 were included and placed in one of two groups, PHMB or RLS, by the block randomisation method. A wound care team, consisting of two surgeons, a wound care nurse and a microbiologist, was created. Classic moist dressings and wet compresses during dressing changes were applied at least once a day or as needed. During the 21 days of hospitalisation the team collected data on the wound healing status daily, on infection parameters every third day, and wound tissue for culture weekly. RESULTS: There were 40 patients recruited of which 9 were excluded, leaving 31 in the intention-to-treat analysis. Of these 15 received PHMB and 16 received RLS. Overall 17 of 31 (66.7% PHMB group, 43.8% RLS group, p=0.181) patients were treated successfully by closure of surgically sutured wounds or healing by secondary intention, the wound tissue cultures of 19 of 31 patients (47.4% PHMB, 52.6% RLS, p=0.886) were negative, and wound size of all the patients were significantly reduced in clinical observations. Although the CRP levels were reduced significantly within group comparisons in both groups (p<0.001), it was significantly lower after 12 days (p<0.05) in the PHMB group compared with the RLS group. CONCLUSION: The results of this study emphasise that the successful treatment of chronic non-healing wounds require a multidisciplinary team approach under the control of a wound care specialist. Whatever the disinfectant used, consistency in the approach to treatment may be more important. We suggest that increasing the use of PHMB and adoption of this team approach in other cardiac centres or other populations may decrease the healing period, especially in chronic non-healing wounds. PMID- 26654739 TI - How has our view of pressure ulcers changed and what does the future hold? PMID- 26654740 TI - Reconstructive vascular surgery and the extent of tissue damage due to diabetic foot ulcers relates to risk of new ulceration in patients with PAD. AB - OBJECTIVE: There is limited information regarding new ulceration following the healing of ischaemic foot ulcers in diabetic patients. Our aim is to study new ulcerations in the same foot as the previous ulcer(s) in patients with diabetes and severe peripheral artery disease (PAD). METHOD: Patients with diabetes and severe PAD who healed from previous ulcer(s) (Wagner grade 1-5, at or below the ankle), were recruited for the prospective study from the time of healing of their ulcer. Patients were followed up regarding new ulceration, and their treatments and ulcer status noted either directly or on examination of medical records. RESULTS: We analysed the data on 602 patients with diabetes and severe PAD with healed foot ulcers, either primarily (n=443, 74%) or after minor amputation (n=159, 26%). Of these 51% (n=305) had revascularisation before healing from the previous ulcer, 34% (n=202) developed a new ulcer on the same foot within 15 months (range 0-106). Amputation was required by 22% (n=45) of patients, with a new ulcer on the same foot. The median survival time of all patients (n=602) was 54 months. By regression analysis, a low maximal Wagner grade for the previous ulcer and reconstructive vascular surgery was related to a decreased risk of developing new ulcers in the same foot. CONCLUSION: Patients with diabetes and ischaemic foot ulcers have a high-risk for developing new ulcers and amputation in the same foot after healing. The extent of tissue involvement in the previous ulcer and reconstructive vascular surgery affected the risk for development of new ulcers. PMID- 26654741 TI - Intraoperative and delayed wound approximation in closure of skin defects in different areas. AB - OBJECTIVE: Wound approximation device is an interesting reconstructive option but not well popularised. In this study we present a simple device that can be used for immediate or delayed closure of large dermal wounds in different anatomical areas. METHOD: Patients with acute and chronic wounds were recruited and underwent immediate intra-operative wound approximation and/or delayed wound approximation, with a home-made wound approximation device. RESULTS: Approximation time in the immediate closure group ranged from 20-140 minutes. Satisfactory scars were obtained in 19 patients (76%) and adherent scars developed in 6 patients. Delayed wound approximation was used successfully in closure of 9 defects. CONCLUSION: This simple dermal wound approximation device can be used intraoperatively to successfully close large difficult wounds, located on the trunk and thigh, with minimal complications. The device can also be used to approximate delayed wounds located in regions where closure is particularly problematic, like the lower leg, foot, and scalp. Some modifications of the device are needed to improve its safety and efficacy. Wound tension is detrimental to adequate wound healing and tensile strength, another basic principle that should not be overlooked to avoid wound dehiscence. Wound approximation is adding to reconstructive options, not replacing them, and they must always be considered. PMID- 26654742 TI - Successful treatment of non-healing pressure ulcers with topical n-acetyl cysteine. AB - OBJECTIVE: N-acetyl cysteine (NAC) is a thiol compound with antioxidant and vasodilatory properties. It has multiple potential uses-including as an aid to wound healing-supported by varying levels of evidence. Pressure ulcers (PUs) are a major problem affecting older and bed-bound patients, and are associated with significant morbidity, mortality, and health-care costs. We aimed to study whether topical NAC treatment may be useful in non-healing PUs in a prospective case study in two debilitated nursing home residents suffering from a total of three treatment-resistant PUs. METHOD: PUs were staged as described by the National Pressure Ulcer Advisory Panel. The ulcers were measured at the beginning and weekly thereafter with a standard wound measuring paper ruler. RESULTS: The first patient had a category 3 pressure ulcer and the second patient had one category 3 and one category 4 ulcer. Topical NAC vial administration significantly improved healing in all three PUs without any side effects. CONCLUSION: Our data indicate that NAC may be used in treatment-resistant PUs successfully. PMID- 26654743 TI - Retinoic acid and retinaldehyde dehydrogenase are not involved in the specific induction of the follicle-stimulating hormone beta subunit by trichostatin A, a selective inhibitor of histone deacetylase. AB - The selective histone deacetylase inhibitor, trichostatin A (TSA), increases follicle-stimulating hormone beta subunit (FSHbeta) mRNA expression but not alpha and luteinizing hormone beta (LHbeta)-subunits in both the pituitary gonadotrophic cell line LbetaT2 and primary cultures of rat anterior pituitary cells. TSA increased histone acetylation in whole cell lysates in both cells. In addition, retinaldehyde dehydrogenases (RALDHs), which are retinoic acid (RA) synthesizing enzymes, were induced by TSA in these cells. Anacardic acid, a histone acetyltransferase inhibitor that prevents histone acetylation, significantly inhibited TSA-induced FSHbeta mRNA expression as well as TSA induced RALDH2 and RALDH3 mRNA expression. Similar to the effect of TSA, gonadotropin-releasing hormone stimulated RALDH expression in LbetaT2 cells. RA directly applied to the pituitary cells stimulated the transcriptional activity of the FSHbeta promoter. In addition, alpha- and LHbeta-subunit promoters were also activated by RA. Our results suggest that TSA specifically increases FSHbeta expression with a concomitant increase in RALDHs; however, RALDH and RA are not directly involved in the specific regulation of FSHbeta by TSA. PMID- 26654744 TI - Three nuclear and two membrane estrogen receptors in basal teleosts, Anguilla sp.: Identification, evolutionary history and differential expression regulation. AB - Estrogens interact with classical intracellular nuclear receptors (ESR), and with G-coupled membrane receptors (GPER). In the eel, we identified three nuclear (ESR1, ESR2a, ESR2b) and two membrane (GPERa, GPERb) estrogen receptors. Duplicated ESR2 and GPER were also retrieved in most extant teleosts. Phylogeny and synteny analyses suggest that they result from teleost whole genome duplication (3R). In contrast to conserved 3R-duplicated ESR2 and GPER, one of 3R duplicated ESR1 has been lost shortly after teleost emergence. Quantitative PCRs revealed that the five receptors are all widely expressed in the eel, but with differential patterns of tissue expression and regulation. ESR1 only is consistently up-regulated in vivo in female eel BPG-liver axis during induced sexual maturation, and also up-regulated in vitro by estradiol in eel hepatocyte primary cultures. This first comparative study of the five teleost estradiol receptors provides bases for future investigations on differential roles that may have contributed to the conservation of multiple estrogen receptors. PMID- 26654745 TI - Expression and functional characterization of intrafollicular GH-IGF system in the zebrafish ovary. AB - The somatotrophic axis plays important roles in influencing reproduction. All key members of this axis including growth hormone (GH, gh), GH receptors (ghra and ghrb), insulin-like growth factors (IGFs, igf1, igf2 and igf3) and IGF receptors (igf1ra and igf1rb) were detected in the zebrafish ovary. GH was exclusively expressed in the full-grown oocytes, while its receptors were detectable in both the follicle cells and oocytes. The IGFs and their receptors were all expressed in both compartments except igf3, which was expressed in the follicle cells only. During folliculogenesis, there was a sharp decrease of gh expression at follicle activation; however, the expression of its receptors increased significantly. The expression profiles of igf1, igf2a, and igf2b were similar to that of fshr, whereas igf3 expression was close to lhcgr, suggesting differential roles for different forms of IGFs in follicle development. To examine if the ovarian GH-IGF system is regulated by gonadotropins (e.g., hCG) and GH, we performed in vitro experiments using cultured zebrafish follicle cells. The expression of igf1 and igf1ra, but not others, was down-regulated by hCG (LH analog), whereas recombinant zebrafish GH stimulated igf1 expression. In addition, GH also increased the expression of activin betaA subunit (inhbaa). In agreement with this, the stimulatory effect of GH but not IGF-I on oocyte maturation could be abolished by follistatin. In conclusion, the present study revealed an intrafollicular network involving GH-IGF mini-axis in the zebrafish ovary; however, it might not work in the same way as that of the systemic somatotrophic axis. PMID- 26654746 TI - Sjogren's syndrome, should we sign? PMID- 26654747 TI - Dual delivery of biological therapeutics for multimodal and synergistic cancer therapies. AB - Cancer causes >8.2 million deaths annually worldwide; thus, various cancer treatments have been investigated over the past decades. Among them, combination drug therapy has become extremely popular, and treatment with more than one drug is often necessary to achieve appropriate anticancer efficacy. With the development of nanoformulations and nanoparticulate-based drug delivery, researchers have explored the feasibility of dual delivery of biological therapeutics to overcome the current drawbacks of cancer therapy. Compared with the conventional single drug therapy, dual delivery of therapeutics has provided various synergistic effects in addition to offering multimodality to cancer treatment. In this review, we highlight and summarize three aspects of dual delivery systems for cancer therapy. These include (1) overcoming drug resistance by the dual delivery of chemical drugs with biological therapeutics for synergistic therapy, (2) targeted and controlled drug release by the dual delivery of drugs with stimuli-responsive nanomaterials, and (3) multimodal theranostics by the dual delivery of drugs and molecular imaging probes. Furthermore, recent developments, perspectives, and new challenges regarding dual delivery systems for cancer therapy are discussed. PMID- 26654748 TI - Mental health resilience in the adolescent offspring of parents with depression: a prospective longitudinal study. AB - BACKGROUND: Young people whose parents have depression have a greatly increased risk of developing a psychiatric disorder, but poor outcomes are not inevitable. Identification of the contributors to mental health resilience in young people at high familial risk is an internationally recognised priority. Our objectives were to identify protective factors that predict sustained good mental health in adolescents with a parent with depression and to test whether these contribute beyond what is explained by parent illness severity. METHODS: The Early Prediction of Adolescent Depression study (EPAD) is a prospective longitudinal study of offspring of parents with recurrent depression. Parents with recurrent major depressive disorder, co-parents, and offspring (aged 9-17 years at baseline) were assessed three times over 4 years in a community setting. Offspring outcomes were operationalised as absence of mental health disorder, subthreshold symptoms, or suicidality on all three study occasions (sustained good mental health); and better than expected mental health (mood and behavioural symptoms at follow-up lower than predicted given severity of parental depression). Family, social, cognitive, and health behaviour predictor variables were assessed using interview and questionnaire measures. FINDINGS: Between February and June, 2007, we screened 337 families at baseline, of which 331 were eligible. Of these, 262 completed the three assessments and were included in the data for sustained mental health. Adolescent mental health problems were common, but 53 (20%) of the 262 adolescents showed sustained good mental health. Index parent positive expressed emotion (odds ratio 1.91 [95% CI 1.31-2.79]; p=0.001), co-parent support (1.90 [1.38-2.62]; p<0.0001), good-quality social relationships (2.07 [1.35-3.18]; p=0.001), self-efficacy (1.49 [1.05-2.11]; p=0.03), and frequent exercise (2.96 [1.26-6.92]; p=0.01) were associated with sustained good mental health. Analyses accounting for parent depression severity were consistent, but frequent exercise only predicted better than expected mood related mental health (beta=-0.22; p=0.0004) not behavioural mental health, whereas index parents' expression of positive emotions predicted better than expected behavioural mental health (beta=-0.16; p=0.01) not mood-related mental health. Multiple protective factors were required for offspring to be free of mental health problems (zero or one protective factor, 4% sustained good mental health; two protective factors, 10%; three protective factors, 13%, four protective factors, 38%; five protective factors, 48%). INTERPRETATION: Adolescent mental health problems are common, but not inevitable, even when parental depression is severe and recurrent. These findings suggest that prevention programmes will need to enhance multiple protective factors across different domains of functioning. FUNDING: Sir Jules Thorn Charitable Trust, Economic and Social Research Council. PMID- 26654749 TI - Proactive depression services needed for at-risk populations. PMID- 26654750 TI - Comparative studies on the fish-killing activities of Chattonella marina isolated in 1985 and Chattonella antiqua isolated in 2010, and their possible toxic factors. AB - Chattonella antiqua isolated in 2010 showed extremely more potent fish-killing activities against red sea bream, Japanese horse mackerel, and blue damselfish than those of Chattonella marina isolated in 1985. Chemiluminescence and electron spin resonance (ESR) analyses suggested greater reactive oxygen species (ROS) producing activity of C. antiqua than that of C. marina. Sodium benzoate, a hydroxyl radical scavenger, significantly suppressed the fish-killing activity of C. antiqua on blue damselfish. The chlorophyll level in the gill tissue of blue damselfish exposed to flagellate cells increased along with the exposure time, and the cell count of gill-associated C. antiqua estimated with chlorophyll level was higher than that of C. marina. These results suggest that the ROS-producing activity and affinity of Chattonella cells to the gill surface may be important factors influencing the fish-killing activity of Chattonella species. PMID- 26654751 TI - Multiple components of fitness improved among overweight and obese adolescents following a community-based lifestyle intervention. AB - Fitness is an important component of health, and obese adolescents regularly have poor fitness. Unfortunately, few have assessed the impact of community-based lifestyle interventions on multiple components of fitness. The purpose of this study was to assess the impact of participation in a community-based intervention involving adolescents and parents on multiple components of fitness of obese adolescents. In a within-subject, waitlist controlled clinical trial with 12 months follow-up in Western Australia, participants (n = 56) completed multiple fitness measures at baseline, immediately prior to beginning an 8-week intervention and at 3, 6 and 12 months during a maintenance period. Performance on the shuttle walk was improved immediately post-intervention (increase of 42.8 m, 95% CI: 7.5, 78.2) and at 12 months post-intervention (increase of 44.6 m, 95% CI: 1.3, 87.8) compared with pre-intervention. Muscle performance of quadriceps and deltoids were improved post-intervention (increase of 1.1 (95% CI: 0.1, 2.1) kg . F and 1.0 (0.02, 2.1) kg . F, respectively) and all muscle performance measures were improved at 12 months following the intervention. There were no changes in waist circumference. A community-based lifestyle programme such as Curtin University's Activity, Food and Attitudes Program (CAFAP) may be a viable strategy for improving fitness in overweight adolescents. PMID- 26654752 TI - Influmeter - an online tool for self-reporting of influenza-like illness in Denmark. AB - Background In October 2013, we implemented 'Influmeter', a web-based influenza like illness (ILI) self-reporting system, to monitor ILI in the general population in a timely fashion, to provide data for estimations of the burden of influenza and to gain experience with online surveillance systems, in Denmark. After the season 2013/2014 we evaluated the system to decide on its future use. Methods Influmeter study participants provided personal details upon enrolment and reported symptoms weekly within predefined categories. We compared distribution of Influmeter participants with the Danish population, by sex, age, region, chronic diseases and educational level. We calculated the proportion of participants reporting symptoms of ILI weekly and the proportion of Influmeter ILI cases seeking medical assistance, using the Danish and the EU ILI case definitions. Further, we compared timing of increased ILI rates in Influmeter with existing Danish sentinel ILI surveillance using the Danish case definition. Results Compared with the Danish population, Influmeter had more females (p < 0.001) and persons with a higher education (p < 0.001), while the age group 0-24 was under-represented (p < 0.001). Influmeter ILI activity peaked 1 week before the exceeding of the sentinel epidemic threshold. Depending on ILI case definition 16-22% of ILI cases sought medical assistance. Conclusion Influmeter was useful in the timely monitoring of ILI activity in the population that did not seek medical assistance in relation to ILI. We recommend continuation of the system, targeted enrolment of the young and future analyses adjusted for uneven representation relative to the underlying population. PMID- 26654753 TI - Sodium butyrate has an antimanic effect and protects the brain against oxidative stress in an animal model of mania induced by ouabain. AB - Studies have consistently reported the participation of oxidative stress in bipolar disorder (BD). Evidence indicates that epigenetic regulations have been implicated in the pathophysiology of mood disorders. Considering these evidences, the present study aimed to investigate the effects of sodium butyrate (SB), a histone deacetylase (HDAC)inhibitor, on manic-like behavior and oxidative stress parameters (TBARS and protein carbonyl content and SOD and CAT activities) in frontal cortex and hippocampus of rats subjected to the animal model of mania induced by intracerebroventricular (ICV) ouabain administration.The results showed that SB reversed ouabain-induced hyperactivity, which represents a manic like behavior in rats. In addition, the ouabain ICV administration induced oxidative damage to lipid and protein and alters antioxidant enzymes activity in all brain structures analyzed. The treatment with SB was able to reversesboth behavioral and oxidative stress parameters alteration induced by ouabain.In conclusion, we suggest that SB can be considered a potential new mood stabilizer by acts on manic-like behavior and regulatesthe antioxidant enzyme activities, protecting the brain against oxidative damage. PMID- 26654754 TI - Non-suicidal self-injury and suicidal ideation in relation to eating and general psychopathology among college-age women. AB - Non-suicidal self-injury (NSSI) and suicidal ideation are potent risk factors for suicide and are associated with general and eating disorder-specific psychopathology. Limited research has examined the effects of combined NSSI+suicidal ideation thus concurrent examination is needed to understand potential differential effects on psychopathology. College-aged women (N=508) completed self-report measures of NSSI, suicidal ideation, general psychopathology, and Eating Disorder-specific psychopathology. MANOVAs determined whether the NSSI/SI status groups differed on general and eating disorder pathology measures as a set. Significant MANOVAs were followed up with univariate ANOVAs and posthoc tests. Thirteen women endorsed NSSI+Suicidal Ideation, 70 endorsed NSSI-only, 25 endorsed Suicidal Ideation-only, and 400 endorsed no NSSI/Suicidal Ideation. Both general and eating disorder-specific psychopathology differed across groups. NSSI+Suicidal Ideation and Suicidal Ideation-only groups typically endorsed higher general psychopathology than the no NSSI/Suicidal Ideation and NSSI-only groups. Regarding eating disorder pathology, the NSSI+Suicidal Ideation group was more pathological than no NSSI/Suicidal Ideation and NSSI-only, except on the weight concerns scale, where NSSI+Suicidal Ideation only differed from no NSSI/Suicidal Ideation. The NSSI+Suicidal Ideation group was only greater than Suicidal Ideation-only on measures of depression and eating concern. Results highlight the importance of screening for both NSSI and suicidal ideation, especially for individuals with eating disorder symptoms. Likewise, screening for eating disorder pathology may be beneficial for individuals presenting with NSSI and suicidal ideation. PMID- 26654755 TI - Health-related quality of life among adolescents: A comparison between subjects at ultra-high risk for psychosis and healthy controls. AB - At risk status for psychosis has been robustly associated with decreased health related quality of life (HRQoL) among adults. However, this relationship has not been examined in adolescents with ultra-high risk (UHR) for psychosis in comparison to healthy controls. Twenty-seven subjects with UHR and thirty healthy controls (14-18 years of age) were recruited in a multiphase screening and accessed with a HRQoL scale of KIDSCREEN-27. Comparisons indicated that subjects with UHR had poorer mean scores at a statistically significant level in the following scales: physical well-being, psychological well-being and school environment. In a logistic regression analysis, lower scores in the scale school environment explained at risk status for psychosis. Adolescents with UHR show significantly poorer HRQoL scores than healthy peers, identified predominantly by the evaluation of the school environment. These results might be interpreted as a self-perception of early mental and social functioning impairments, which seem to be recognized initially based on school demands. Considering these findings, institutes of education should be a good starting point to promote the awareness of the psychosis-risk state. PMID- 26654756 TI - Theoretical Insights on the Interaction of N-Heterocyclic Carbenes with Tetravalent Silicon Reagents. AB - Lewis acid-base type interaction between N-heterocyclic carbene (NHC) and tetravalent silicon reagent (SiR) has been investigated computationally. This NHC Si interaction is of fundamental importance to the understanding of variety of NHC catalyzed organic transformations involving silicon compounds such as cyanosilylation, trifluoromethylsilylation, etc. Geometries of 24 NHCs, 10 silicon reagents, and their 61 Lewis acid-base complexes have been optimized using the B3LYP/6-31+G(d,p) and M05-2X/6-31+G(d,p) level of theory. The strength of NHC-Si interaction has been assessed in terms of binding energy of the complexes, charge transfer (CT) and the length of Si-CNHC bond. Energy decomposition analysis (EDA) and natural bond orbital (NBO) analysis at M052X/6 31+G(d,p) level of theory has been carried out to get a deeper understanding of the nature of bonding and charge delocalization. Proton affinity of the NHCs and fluoride affinity of the SiRs have been calculated and correlated with the binding energy of the resulting complexes. PMID- 26654757 TI - Mitohormesis in exercise training. AB - Hormesis is a process whereby exposure to a low dose of a potentially harmful stressor promotes adaptive changes to the cell that enables it to better tolerate subsequent stress. In recent years this concept has been applied specifically to the mitochondria (mitohormesis), suggesting that in response to a perturbation the mitochondria can initiate and transduce a signal to the nucleus that coordinates a transcriptional response resulting in both mitochondrial and non mitochondrial adaptations that return and maintain cellular homeostasis. In this review we summarize the evidence that mitohormesis is a significant adaptive response signaling pathway, and suggest that it plays a role in mediating exercise-induced adaptations. We discuss potential mitochondrial emitters of retrograde signals that may activate known exercise-sensitive transcription factors to modulate transcription responses to exercise, and draw on evidence from mitochondrial dysfunction animal models to support a role for mitohormesis in mitochondrial biogenesis. Studies directly linking mitohormesis to the exercise training response are lacking, however mounting evidence suggests numerous signals are emitted from the mitochondria during exercise and have the potential to induce a nuclear transcription response, with reactive oxygen species (ROS) being the primary candidate. PMID- 26654758 TI - PPAR-pan activation induces hepatic oxidative stress and lipidomic remodelling. AB - The peroxisome proliferator-activated receptors (PPARs) are ligand activated nuclear receptors that regulate cellular homoeostasis and metabolism. PPARs control the expression of genes involved in fatty-acid and lipid metabolism. Despite evidence showing beneficial effects of their activation in the treatment of metabolic diseases, particularly dyslipidaemias and type 2 diabetes, PPAR agonists have also been associated with a variety of side effects and adverse pathological changes. Agonists have been developed that simultaneously activate the three PPAR receptors (PPARalpha, gamma and delta) in the hope that the beneficial effects can be harnessed while avoiding some of the negative side effects. In this study, the hepatic effects of a discontinued PPAR-pan agonist (a triple agonist of PPAR-alpha, -gamma, and -delta), was investigated after dietary treatment of male Sprague-Dawley (SD) rats. The agonist induced liver enlargement in conjunction with metabolomic and lipidomic remodelling. Increased concentrations of several metabolites related to processes of oxidation, such as oxo-methionine, methyl-cytosine and adenosyl-methionine indicated increased stress and immune status. These changes are reflected in lipidomic changes, and increased energy demands as determined by free fatty acid (decreased 18:3 n-3, 20:5 n-3 and increased ratios of n-6/n-3 fatty acids) triacylglycerol, phospholipid (decreased and increased bulk changes respectively) and eicosanoid content (increases in PGB2 and 15-deoxy PGJ2). We conclude that the investigated PPAR agonist, GW625019, induces liver enlargement, accompanied by lipidomic remodelling, oxidative stress and increases in several pro-inflammatory eicosanoids. This suggests that such pathways should be monitored in the drug development process and also outline how PPAR agonists induce liver proliferation. PMID- 26654759 TI - MicroRNA-2861 regulates programmed necrosis in cardiomyocyte by impairing adenine nucleotide translocase 1 expression. AB - Necrosis is programmed and is one of the main forms of cell death in the pathological process in cardiac diseases. MicroRNAs (miRNAs) have emerged as key gene regulators in many diseases. However, how miRNAs contribute to programmed necrosis is poorly defined. Here we report that miR-2861 and adenine nucleotide translocase 1 (ANT1) constitute an axis that regulates necrotic cell death in the heart. Our results show that ANT1 inhibits H2O2-induced cardiomyocytes necrosis. ANT1 also antagonizes myocardial necrosis in a mouse ischemia/reperfusion (I/R) model. We further demonstrate that miR-2861 directly binds to the coding sequence of ANT1 and suppresses the expression of ANT1 mRNA and protein. MiR-2861 induces necrotic cell death. In contrast, knockdown of miR-2861 attenuates H2O2-induced necrosis in cardiomyocytes. Also, miR-2861 knockdown protects heart from I/R injury and necrotic cell death in vivo. MiR-2861 regulates necrosis and myocardial infarction through targeting ANT1. Collectively, these data identify miR-2861 and ANT1 as two novel regulators of cardiomyocyte necrosis and myocardial infarction, and suggest potential therapeutic targets in treatment of cardiac diseases. PMID- 26654760 TI - Should pulse oximetry be included in GPs' assessment of patients with obstructive lung disease? AB - OBJECTIVE: To explore the associations between decreased pulse oximetry values (SpO2) and clinical, laboratory, and demographic variables in general practice patients diagnosed with asthma or chronic obstructive pulmonary disease (COPD), including those with both COPD and asthma in combination. DESIGN/SETTING: A cross sectional study in seven Norwegian general practices of patients aged 40 years or over who were diagnosed by their general practitioner (GP) with asthma and/or COPD. The patients were examined during a stable phase of their disease. Patients diagnosed with COPD (including those with combined COPD/asthma) and those diagnosed with asthma only were analysed separately. MAIN OUTCOME MEASURES: Decreased SpO2 values (<= 95% and <= 92%). RESULTS: Of 372 patients included (mean age 61.5 years, 62% women), 82 (22.0%) had SpO2 <= 95%, of which 11 had SpO2 <= 92%. In both asthma and COPD patients, SpO2 <= 95% was significantly associated with reduced lung function (spirometry), a diagnosis of coronary heart disease and older age (>= 65 years). In the COPD group, haemoglobin above normal was associated with SpO2 <= 95%. These associations were confirmed by multivariable logistic regression, where FEV1% predicted < 50 was the strongest predictor of SpO2 <= 95% (odds ratio 6.8, 95% confidence interval 2.8-16.4). CONCLUSION: Pulse oximetry represents a useful diagnostic adjunct for assessing the severity of obstructive pulmonary disease. Decreased pulse oximetry values in stable-phase patients with asthma and/or COPD should prompt the GP to consider revising the diagnosis and treatment and to look for co-morbidities. Key Points Despite its common use in general practice, the diagnostic benefits of pulse oximetry remain to be established. Decreased pulse oximetry values are associated with both reduced lung function (spirometry) and with a diagnosis of coronary heart disease. Decreased pulse oximetry values may reflect suboptimal treatment and/or undiagnosed comorbidity. Pulse oximetry may therefore be a useful measure in the follow-up of asthma and COPD patients in general practice. PMID- 26654762 TI - Spatial requirements of poultry assessed by using a colour-contrast method (KobaPlan). AB - Sufficient floor space is a fundamental precondition for poultry to perform normal behavioural patterns. To calculate and determine stocking densities, it is essential to know the absolute minimum surface area required by any given animal (body space). Additional space is required for characteristic behaviours (behavioural space) and for adequate inter-individual distances, group sizes and room to perform social interactions have to be taken into account. To calculate body space, planimetric measurements were carried out by the colour contrast method "KobaPlan" in various poultry species in standing and sitting positions and at a number of different ages. They included laying hens (Lohmann brown (LB), Lohmann selected Leghorn (LSL)), broiler breeders (Ross, both genders), broiler chickens (Ross 308, both genders), turkeys (BUT 6, males), Peking ducks (Cherry Valley, both genders) and Muscovy ducks (Canedins R51, males). Depending on live weight, age, plumage condition and body position, LB hens occupied an average area between 401 cm(2) and 542 cm(2), LSL hens between 353 cm(2) and 445 cm(2), broiler breeder females between 440 cm(2) and 537 cm(2), broiler breeder males 623 cm(2) up to 945 cm(2), broiler chickens up to 434 cm(2), male fattening turkeys up to 1808 cm(2), Muscovy drakes up to 873 cm(2) and Peking ducks up to 627 cm(2). The values can be regarded as necessary minimum spatial requirements for the measured poultry species and genotype. The current method offers the potential to record the area occupied by animals exhibiting species-specific behavioural patterns. PMID- 26654761 TI - Recent advances in understanding the role of adipocytokines during non-alcoholic fatty liver disease pathogenesis and their link with hepatokines. AB - Non-alcoholic fatty liver disease (NAFLD) is currently considered the main cause of chronic liver disease worldwide. Mechanisms leading to the development and progression of this disease are topics of great interest for researchers and clinicians. The current multi-hit hypothesis has thrown the crosstalk between liver and adipose tissue into sharp focus. It is well known that adipose tissue produces circulating factors, known as adipocytokines, which exert several effects on liver cells, promoting the onset of NAFLD and its progression to non alcoholic steatohepatitis in obese subjects. In a similar way, hepatocytes may also respond to obesogenic stimuli by producing and releasing hepatokines into the circulation. Here, the authors provide an overview of recent advances in our understanding of the role of the most relevant adipocytokines and hepatokines in NAFLD pathogenesis, highlighting their possible molecular and functional interactions. PMID- 26654763 TI - Evaluation of the hemocompatibility and rapid hemostasis of (RADA)4 peptide-based hydrogels. AB - (RADA)4 peptides are promising biomaterials due to their high degree of hydration (<99.5% (w/v)), programmability at the molecular level, and their subsequent potential to respond to external stimuli. Interestingly, these peptides have also demonstrated the ability to cause rapid (~15s) hemostasis when applied directly to wounds. General hemocompatibility of (RADA)4 nanofibers was investigated systematically using clot formation kinetics, C3a generation, and platelet activation (morphology and CD62P) studies. (RADA)4 nanofibers caused a rapid clot formation, but yielded a low platelet activation and low C3a activation. The study suggests that the rapid hemostasis observed when these materials are employed results principally from humoral coagulation, despite these materials having a net neutral charge and high hydration at physiological conditions. The observed rapid hemostasis may be induced due to the available nanofiber surface area within the hydrogel construct. In conclusion, our experiments strongly support further development of (RADA)4 peptide based biomaterials. STATEMENT OF SIGNIFICANCE: Biomedicine based applications of (RADA)4 peptides are being extensively studied for the purpose of improving drug carriers, and 3D peptide nanofiber scaffolds. However, this peptide's biocompatibility has not been investigated till now. One particular study has reported a revolutionary and very desirable ability of (RADA)4 peptide to achieve complete and rapid hemostasis, nevertheless, the literature remains inconclusive on the underlying molecular mechanism. In this manuscript we bridge these two main knowledge gaps by providing the much needed systematic biocompatibility analysis (morphology analysis, platelet and C3a activation) of the (RADA)4 based hydrogels, and also investigate the underlying hemostatic mechanism of this peptide-induced hemostasis. Our work not only provides the much-needed biocompatibility of the peptide for applicative research, but also explores the molecular mechanism of hemostasis, which will help us design novel biomaterials to achieve hemostasis. PMID- 26654764 TI - Amorphous polyphosphate-hydroxyapatite: A morphogenetically active substrate for bone-related SaOS-2 cells in vitro. AB - There is increasing evidence that inorganic calcium-polyphosphates (polyP) are involved in human bone hydroxyapatite (HA) formation. Here we investigated the morphology of the particles, containing calcium phosphate (CaP) with different concentrations of various Na-polyP concentrations, as well as their effects in cell culture. We used both SaOS-2 cells and human mesenchymal stem cells. The polymeric phosphate readily binds calcium ions under formation of insoluble precipitates. We found that addition of low concentrations of polyP (<10wt.%, referred to the CaP deposits) results in an increased size of the HA crystals. Surprisingly, at higher polyP concentrations (>10wt.%) the formation of crystalline HA is prevented and amorphous polyP/HA hybrid particles with a size of ~50nm are formed, most likely consisting of polyP molecules linked via Ca(2+) bridges to the surface of the CaP deposits. Further studies revealed that the polyP-CaP particles cause a strong upregulation of the expression of the genes encoding for two marker proteins of bone formation, collagen type I and alkaline phosphatase. Based on their morphogenetic activity the amorphous polyP-CaP particles offer a promising material for the development of bone implants, formed from physiological inorganic precursors/polymers. STATEMENT OF SIGNIFICANCE: Hydroxyapatite (HA) is a naturally occurring mineral of vertebrate bone. Natural HA, a bio-ceramic material which is crystalline to different scale, has been used as a biomaterial to fabricate scaffolds for in situ bone regeneration and other tissue engineering purposes. In contrast to natural HA, synthetic apatite is much less effective. In general, while HA is bioactive, its interaction and biocompatibility with existing bone tissue is low. These properties have been attributed to a minimal degradability in the physiological environment. In the present study we introduce a new Ca-phosphate (CaP) fabrication technology, starting from calcium chloride and dibasic ammonium phosphate with the HA characteristic Ca/P molar ratio of 10:6 and report that after addition >10% (by weight) of polyphosphate (polyP) amorphous CaP/HA samples were obtained. Those samples elicits strong morphogenetic activity let us to conclude that polyP/HA based material might be beneficial for application as bone substitute implant. PMID- 26654765 TI - Validation of an arterial constitutive model accounting for collagen content and crosslinking. AB - During the progression of pulmonary hypertension (PH), proximal pulmonary arteries (PAs) increase in both thickness and stiffness. Collagen, a component of the extracellular matrix, is mainly responsible for these changes via increased collagen fiber amount (or content) and crosslinking. We sought to differentiate the effects of collagen content and cross-linking on mouse PA mechanical changes using a constitutive model with parameters derived from experiments in which collagen content and cross-linking were decoupled during hypoxic pulmonary hypertension (HPH). We employed an eight-chain orthotropic element model to characterize collagen's mechanical behavior and an isotropic neo-Hookean form to represent elastin. Our results showed a strong correlation between the material parameter related to collagen content and measured collagen content (R(2)=0.82, P<0.0001) and a moderate correlation between the material parameter related to collagen crosslinking and measured crosslinking (R(2)=0.24, P=0.06). There was no significant change in either the material parameter related to elastin or the measured elastin content from histology. The model-predicted pressure at which collagen begins to engage was ~25mmHg, which is consistent with experimental observations. We conclude that this model may allow us to predict changes in the arterial extracellular matrix from measured mechanical behavior in PH patients, which may provide insight into prognoses and the effects of therapy. STATEMENT OF SIGNIFICANCE: The literature has proposed several constitutive models to describe the mechanical effects of arterial collagen but none separates collagen content from crosslinking. Given that both are critical to arterial mechanics, the novel model described here does so. Furthermore, our novel model is well tested by experimental data; model parameters were reasonably correlated with measured collagen content and crosslinking and the model-predicted collagen transition stretch was consistent with that obtained experimentally. Given that arterial collagen structural changes and collagen engagement are critical to arterial stiffening in several disease states, this model, by linking mechanical and biological properties, may allow us to predict important biological changes during disease progression from measured mechanical behavior. PMID- 26654766 TI - Surgical meshes coated with mesenchymal stem cells provide an anti-inflammatory environment by a M2 macrophage polarization. AB - Surgical meshes are widely used in clinics to reinforce soft tissue's defects, and to give support to prolapsed organs. However, the implantation of surgical meshes is commonly related with an inflammatory response being difficult to eradicate without removing the mesh. Here we hypothesize that the combined use of surgical meshes and mesenchymal stem cells (MSCs) could be a useful tool to reduce the inflammatory reaction secondary to mesh implantation. In vitro determinations of viability, metabolic activity and immunomodulation assays were performed on MSCs-coated meshes. Magnetic resonance imaging, evaluation by laparoscopic optical system and histology were performed for safety assessment. Finally, flow cytometry and qRT-PCR were used to elucidate the mechanism of action of MSCs-coated meshes. Our results demonstrate the feasibility to obtain MSCs-coated surgical meshes and their cryopreservability to be used as an 'off the shelf' product. These biological meshes fulfill the safety aspects as non adverse effects were observed when compared to controls. Moreover, both in vitro and in vivo studies demonstrated that, local immunomodulation of implanted meshes is mediated by a macrophage polarization towards an anti-inflammatory phenotype. In conclusion, the combined usage of surgical meshes with MSCs fulfills the safety requirements for a future clinical application, providing an anti inflammatory environment that could reduce the inflammatory processes commonly observed after surgical mesh implantation. STATEMENT OF SIGNIFICANCE: Surgical meshes are medical devices widely used in clinics to resolve hernias and organs' prolapses, among other disorders. However, the implantation of surgical meshes is commonly related with an inflammatory response being difficult to eradicate without removing the mesh, causing pain and discomfort in the patient. Previously, the anti-inflammatory, immunomodulatory and pro-regenerative ability of mesenchymal stem cells (MSCs) have been described. To our knowledge, this is the first report where the anti-inflammatory and pro-regenerative ability of MSCs have been successfully applied in combination with surgical meshes, reducing the inflammatory processes commonly observed after mesh implantation. Moreover, our in vitro and in vivo results highlight the safety and efficacy of these bioactive meshes as a 'ready to use' medical product. PMID- 26654767 TI - Development of a structured observational method for the systematic assessment of school food-choice architecture. AB - The objective of this study is to develop a structured observational method for the systematic assessment of the food-choice architecture that can be used to identify key points for behavioral economic intervention intended to improve the health quality of children's diets. We use an ethnographic approach with observations at twelve elementary schools to construct our survey instrument. Elements of the structured observational method include decision environment, salience, accessibility/convenience, defaults/verbal prompts, number of choices, serving ware/method/packaging, and social/physical eating environment. Our survey reveals important "nudgeable" components of the elementary school food-choice architecture, including precommitment and default options on the lunch line. PMID- 26654768 TI - RAS-MAPK in ALK targeted therapy resistance. AB - The clinical success of ALK targeted therapy is limited by resistance. To identify rational co-targeting strategies to enhance clinical outcomes, we explored the molecular basis of ALK oncogene dependence in ALK gene rearrangement positive (ALK+) lung adenocarcinoma. We discovered that the RAS-RAF-MEK-ERK pathway is the critical downstream pathway necessary for ALK+ tumor cell survival. Upfront co-targeting of ALK plus MEK enhanced response and forestalled resistance in preclinical ALK+ tumor models, providing rationale for a new approach the treatment of ALK+ patients. PMID- 26654770 TI - Novel AKT phosphorylation sites identified in the pluripotency factors OCT4, SOX2 and KLF4. AB - The four OSKM factors OCT4, SOX2, KLF4 and c-MYC are key transcription factors modulating pluripotency, self-renewal and tumorigenesis in stem cells. However, although their transcriptional targets have been extensively studied, little is known about how these factors are regulated at the posttranslational level. In this study, we established an in vitro system to identify phosphorylation patterns of the OSKM factors by AKT kinase. OCT4, SOX2, KLF4 and c-MYC were expressed in Sf9 insect cells employing the baculoviral expression system. OCT4, SOX2 and KLF4 were localized in the nucleus of insect cells, allowing their easy purification to near homogeneity upon nuclear fractionation. All transcription factors were isolated as biologically active DNA-binding proteins. Using in vitro phosphorylation and mass spectrometry-based phosphoproteome analyses several novel and known AKT phosphorylation sites could be identified in OCT4, SOX2 and KLF4. PMID- 26654771 TI - Tryptophan Catabolites and Migraine. AB - Migraine is a highly disabling neurological condition affecting around 15% of the population worldwide. Decades of intensive research shed some light on diseases pathomechanism, but information is still missing about the initiation of the attack. In the past century, serotonin emerged as the main target of both basic and therapeutic research. As a result, the triptans, the only approved migraine specific drugs were developed. The involvement of glutamatergic mechanism in migraine headache development such as cortical hyperexcitability, and cortical spreading depression as the pathological correlate of migraine aura called the attention to the kynurenine pathway in migraine pathomechanism. The serotonin and kynurenine pathways are closely connected, as they both are the metabolic routes of the amino acid tryptophan. Kynurenine catabolites are important participants in glutamatergic neurotransmission, regulation also nociceptive processing of the trigeminal system. The current work attempts to collect recent data on both serotonin and kynurenine research related to migraine and emphasizes the importance of further research on this topic. PMID- 26654772 TI - Bipolar Disorder: The Role of the Kynurenine and Melatonergic Pathways. AB - Bipolar disorder (BD) is a long-recognized severe and common psychiatric disorder, with a complex and often diverse range of presentations. BD is a heterogenous disorder that has traditionally, if rather simply, been defined by the recurrences of manic and depressive episodes, and presents with numerous immune-inflammatory and circadian/sleep abnormalities. A number of different lines of research have investigated the biological underpinnings of BD and demonstrate a heritability of about 80-90%. This genetic contribution is thought to be mediated by a wide array of genetic factors, rather than being strongly influenced by a couple of genes. In this context, a clearer formulation of the biological underpinnings of BD is needed in order to encompass the diverse effects of multiple susceptibility genes. The biological underpinnings of BD includes work that has focussed on the role played by increased immune inflammatory activity, particularly changes in pro-inflammatory cytokines, as measured both centrally and systemically. Changes in immune- inflammatory activity are intimately associated with alterations in levels of oxidative and nitrosative stress (O&NS), which are increased in BD. Many of the neuroregulatory changes driven by O&NS and immune-inflammatory activity are mediated by the tryptophan catabolite (TRYCAT) pathways, with changes in TRYCATs being evident both centrally and peripherally. A consequence of increased pro-inflammatory cytokines, is their induction of indoleamine 2,3-dioxygenase (IDO), which takes tryptophan away from serotonin, Nacetylserotonin and melatonin synthesis, driving it to the synthesis of neuroregulatory TRYCATs. Most work exploring such changes has emphasized the role of TRYCATs in enhancing or decreasing neuronal activity. However, a relatively overlooked consequence of cytokine induced IDO and TRYCAT pathway activation is the impact that this has on aryl hydrocarbon receptor (AhR) activation and in decreasing melatonergic pathway activity. Melatonin is classically associated with night-time synthesis by the pineal gland, in turn regulating circadian rhythms. However, melatonin is produced by many, if not all mitochondria containing cells, with consequences for gut regulation, as well as glia and immune cell reactivity. The melatonergic pathways are genetic susceptibility factors for BD. Interactive changes in O&NS, immune-inflammatory activity, TRYCATs and the melatonergic pathways form an emerging biological perspective on the etiology, course and management of BD. Here, we review such changes in BD, and how this better integrates the diverse array of BD presentations and comorbidities, including addiction and cardiovascular disorders as well as decreased life-expectancy. We then look at the future directions such research may take. PMID- 26654769 TI - SIAH ubiquitin ligases regulate breast cancer cell migration and invasion independent of the oxygen status. AB - Seven-in-absentia homolog (SIAH) proteins are evolutionary conserved RING type E3 ubiquitin ligases responsible for the degradation of key molecules regulating DNA damage response, hypoxic adaptation, apoptosis, angiogenesis, and cell proliferation. Many studies suggest a tumorigenic role for SIAH2. In breast cancer patients SIAH2 expression levels correlate with cancer aggressiveness and overall patient survival. In addition, SIAH inhibition reduced metastasis in melanoma. The role of SIAH1 in breast cancer is still ambiguous; both tumorigenic and tumor suppressive functions have been reported. Other studies categorized SIAH ligases as either pro- or antimigratory, while the significance for metastasis is largely unknown. Here, we re-evaluated the effects of SIAH1 and SIAH2 depletion in breast cancer cell lines, focusing on migration and invasion. We successfully knocked down SIAH1 and SIAH2 in several breast cancer cell lines. In luminal type MCF7 cells, this led to stabilization of the SIAH substrate Prolyl Hydroxylase Domain protein 3 (PHD3) and reduced Hypoxia-Inducible Factor 1alpha (HIF1alpha) protein levels. Both the knockdown of SIAH1 or SIAH2 led to increased apoptosis and reduced proliferation, with comparable effects. These results point to a tumor promoting role for SIAH1 in breast cancer similar to SIAH2. In addition, depletion of SIAH1 or SIAH2 also led to decreased cell migration and invasion in breast cancer cells. SIAH knockdown also controlled microtubule dynamics by markedly decreasing the protein levels of stathmin, most likely via p27(Kip1). Collectively, these results suggest that both SIAH ligases promote a migratory cancer cell phenotype and could contribute to metastasis in breast cancer. PMID- 26654773 TI - Glioma: Tryptophan Catabolite and Melatoninergic Pathways Link microRNA, 14-3- 3, Chromosome 4q35, Epigenetic Processes and other Glioma Biochemical Changes. AB - Primary glioma, as well as secondary metastases, provide significant treatment challenges. An understanding of the biological underpinnings of glioma is likely to provide new pharmaceutical targets that will improve patient survival. Here, we look at the role that the kynurenine pathways and associated tyrptophan catabolites (TRYCATs) play in glioma, linking this to changes in oxidative and nitrosative stress (O&NS), immuneinflammatory activity, the aryl hydrocarbon receptor (AhR), and the melatoninergic pathways. It is suggested that the interactions of O&NS and the immune-inflammatory processes in glioma contribute to the induction of the TRYCATs via the kynurenine activation of the AhR, leading to increased indoleamine 2,3-dioxygenase, which deprives tryptophan for the necessary serotonin that is required as a precursor for the melatoninergic pathways. A diverse array of data pertaining to glioma can be linked to these pathways, including changes in miRNAs, epigenetic processes, estrogen receptors, 14-3-3, chromosome 4q35, neurotrophins, tristetraprolin and the N-acetylserotonin (NAS)/melatonin ratio. As many of these factors directly or indirectly act on the melatoninergic pathways, including variations in the NAS/melatonin ratio, it is suggested that the melatoninergic pathways may act as a hub that co-ordinate the multitude of changes occurring in glioma. Consequently, the melatoninergic pathways may be a significant pharmaceutical target for the treatment of this still very poorly managed condition. PMID- 26654774 TI - Depression, Serotonin and Tryptophan. AB - Depression is a major cause of worldwide disability. Although its etiology is unclear, for over sixty years the study of its pathophysiology has focused mainly on serotonin (5-HT) and serotonergic neurotransmission. Generally, the study of the pathophysiological processes underpinning depression have led to the appreciation of its complexity, although such study continues to support the role of 5-HT in this disorder. The aim of this review is to briefly summarize the available findings on 5-HT and depression, with a special focus on alterations in tryptophan (TRP) metabolism that can shift from 5-HT synthesis towards other, potentially neurotoxic, compounds, such as the tryptophan catabolite, quinolinic acid. The evidence that the TRP shunt may be promoted by stress hormones and proinflammatory cytokines strongly supports the notion that depression should now be considered a systemic disorder that can be triggered by different factors that ultimately target the 5-HT system in vulnerable individuals. In addition, such intriguing findings suggest biochemical targets for novel treatment options in depression. PMID- 26654775 TI - Melatonin in Pregnancy: Effects on Brain Development and CNS Programming Disorders. AB - Melatonin is an important neuroprotective factor and its receptors are expressed in the fetal brain. During normal pregnancy, maternal melatonin level increases progressively until term and is highly transferred to the fetus, with an important role in brain formation and differentiation. Maternal melatonin provides the first circadian signal to the fetus. This indolamine is also produced de novo and plays a protective role in the human placenta. In pregnancy disorders, both maternal and placental melatonin levels are decreased. Alteration in maternal melatonin level has been associated with disrupted brain programming with long-term effects. Melatonin has strong antioxidant protective effects directly and indirectly via the activation of its receptors. The fetal brain is highly susceptible to oxygenation variation and oxidative stress that can lead to neuronal development disruption. Based on that, several approaches have been tested as a treatment in case of pregnancy disorders and melatonin, through its neuroprotective effect, has been recently accepted against fetal brain injury. This review provides an overview about the protective effects of melatonin during pregnancy and on fetal brain development. PMID- 26654776 TI - beta-Glucan-based cream (containing pleuran isolated from pleurotus ostreatus) in supportive treatment of mild-to-moderate atopic dermatitis. AB - BACKGROUND: Atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases with serious impact on quality of life. beta-Glucans are natural substances with potent immunomodulatory and anti-inflammatory activity. METHODS: In a multicentre open split-body study, we studied the effect of Imunoglukan P4H(r) cream in a group of 105 patients with AD (39 males, 37%). Evaluation of subjective (visual analogue scale, VAS) and objective (EASI score, eczema area and severity index) characteristics of AD was carried out. RESULTS: In total, 80 patients (76.2%) completed the study. Topical beta-glucan application resulted in the significant improvement of both objective and subjective symptoms of AD. On the application side, significant decline in the number of days with AD exacerbation and its severity was observed. Moreover, the subjects experienced decline of pruritus on the beta-glucan half of the body (VAS score: 1.68 vs. 1.95, p < 0.001). During the study, the continual and significant decline of EASI scores on the site of beta-glucan application was observed (V4: 1.57 vs. 1.85, p < 0.001). The preparation was in general well tolerated. CONCLUSIONS: This is the first study evaluating and confirming the potential use of beta-glucan-based cream as a supportive complementary therapy of atopic dermatitis. PMID- 26654777 TI - Enhanced A2A adenosine receptor-mediated increase in coronary flow in type I diabetic mice. AB - Adenosine A2A receptor (A2AAR) activation plays a major role in the regulation of coronary flow (CF). Recent studies from our laboratory and others have suggested that A2AAR expression and/or signaling is altered in disease conditions. However, the coronary response to AR activation, in particular A2AAR, in diabetes is not fully understood. In this study, we use an STZ mouse model of type 1 diabetes (T1D) to look at CF responses to the nonspecific AR agonist NECA and the A2AAR specific agonist CGS 21680 in-vivo and ex-vivo. Using immunofluorescence, we also explored the effect of diabetes on A2AAR expression in coronary arteries. NECA mediated increase in CF was significantly increased in hearts isolated from STZ induced diabetic mice. In addition, both in in-vivo and ex-vivo responses to A2AAR activation using CGS 21680 were significantly higher in diabetic mice when compared to their controls. Immunohistochemistry showed an upregulation of A2AAR in both coronary smooth muscle and endothelial cells (~160% and ~140%, respectively). Our data suggest that diabetes resulted in an increased A2AAR expression in coronary arteries which resulted in enhanced A2AAR-mediated increase in CF observed in diabetic hearts. This is the first report implying that A2AAR has a role in the regulation of CF in diabetes, supporting recent studies suggesting that the use of adenosine and its A2A selective agonist (regadenoson, Lexiscan(r)) may not be appropriate for the detection of coronary artery diseases in T1D and the estimation of coronary reserve. PMID- 26654778 TI - High-fat diet increases vulnerability to atrial arrhythmia by conduction disturbance via miR-27b. AB - BACKGROUND: Lifestyle-related diseases, such as obesity and dyslipidemia are important risk factors for atrial fibrillation (AF). However, the underlying mechanism linking these diseases and AF has not been fully investigated. METHODS: Adult male mice were fed a high-fat diet (HFD) or vehicle (NC) for 2 months. Electrocardiography and in vivo electrophysiological study were performed. Mice were then sacrificed for quantification of mRNA, microRNA, and protein in atria, in addition to histological analysis. Conduction velocity (CV) in right atrium was measured by optical mapping in Langendorff perfused hearts. Cultured atrial cardiomyocytes were treated with palmitate with or without a specific microRNA inhibitor. Twelve hours after stimulation, cells were lysed, and subjected to analysis with qPCR and Western blotting. RESULTS: HFD mice showed prolonged P wave duration, increased inducibility of sustained atrial tachycardia, and reduced atrial CV than NC mice. HFD mice also showed increased expression in inflammatory cytokines, whereas fibrotic area and signals relating fibrosis were not changed. HFD mice demonstrated reduced expression of Cx40 in mRNA and protein levels, and its lateralized expression in atria. MicroRNA array analysis revealed that miR-27b expression was up-regulated in HFD mice, and luciferase assay confirmed the direct interaction between miR-27b and Cx40 3'UTR. In palmitate stimulated atrial cardiomyocytes, miR-27b up-regulation and Cx40 down-regulation were observed, while expression of inflammatory cytokines was not altered. Inhibition of miR-27b with antisense oligonucleotides reversed the alteration caused by palmitate stimulation. CONCLUSION: HFD may increase the vulnerability to atrial arrhythmia by down-regulation of Cx40 via miR-27b, rather than fibrosis, which is independent of inflammation. PMID- 26654779 TI - alpha-MHC MitoTimer mouse: In vivo mitochondrial turnover model reveals remarkable mitochondrial heterogeneity in the heart. AB - In order to maintain an efficient, energy-producing network in the heart, dysfunctional mitochondria are cleared through the mechanism of autophagy, which is closely linked with mitochondrial biogenesis; these, together with fusion and fission comprise a crucial process known as mitochondrial turnover. Until recently, the lack of molecular tools and methods available to researchers has impeded in vivo investigations of turnover. To investigate the process at the level of a single mitochondrion, our laboratory has developed the MitoTimer protein. Timer is a mutant of DsRed fluorescent protein characterized by transition from green fluorescence to a more stable red conformation over 48 h, and its rate of maturation is stable under physiological conditions. We fused the Timer cDNA with the inner mitochondrial membrane signal sequence and placed it under the control of a cardiac-restricted promoter. This construct was used to create the alpha-MHC-MitoTimer mice. Surprisingly, initial analysis of the hearts from these mice demonstrated a high degree of heterogeneity in the ratio of red to-green fluorescence of MitoTimer in cardiac tissue. Further, scattered solitary mitochondria within cardiomyocytes display a much higher red-to-green fluorescence (red-shifted) relative to other mitochondria in the cell, implying a block in import of newly synthesized MitoTimer likely due to lower membrane potential. These red-shifted mitochondria may represent older, senescent mitochondria. Concurrently, the cardiomyocytes also contain a subpopulation of mitochondria that display a lower red-to-green fluorescence (green-shifted) relative to other mitochondria, indicative of germinal mitochondria that are actively engaged in import of newly-synthesized mito-targeted proteins. These mitochondria can be isolated and sorted from the heart by flow cytometry for further analysis. Initial studies suggest that these mice represent an elegant tool for the investigation of mitochondrial turnover in the heart. PMID- 26654780 TI - Non-coding RNAs as orchestrators of autophagic processes. AB - Autophagy is an important quality control mechanism present in all cells to maintain their cellular homeostasis. An imbalance in the autophagic process had been reported in numerous diseases including cardiovascular disease and is associated with serious consequences. Thus, knowledge of key regulators of cardiac autophagy is helpful to regain a balanced autophagic activity and to maintain healthy myocardial function. In this review we summarize all microRNAs which had been reported to regulate cardiac autophagy to date. In addition, we discuss long noncoding RNAs and circular RNAs as potential modulators of autophagy. Altering non-coding RNAs in-vivo by novel therapeutics offers a promising approach to treat autophagy-related diseases. PMID- 26654781 TI - The cross-bridge dynamics is determined by two length-independent kinetics: Implications on muscle economy and Frank-Starling Law. AB - The cellular mechanisms underlying the Frank-Starling Law of the heart and the skeletal muscle force-length relationship are not clear. This study tested the effects of sarcomere length (SL) on the average force per cross-bridge and on the rate of cross-bridge cycling in intact rat cardiac trabeculae (n=9). SL was measured by laser diffraction and controlled with a fast servomotor to produce varying initial SLs. Tetanic contractions were induced by addition of cyclopiazonic acid, to maintain a constant activation. Stress decline and redevelopment in response to identical ramp shortenings, starting at various initial SLs, was analyzed. Both stress decline and redevelopment responses revealed two distinct kinetics: a fast and a slower phase. The duration of the rapid phases (4.2 +/- 0.1 msec) was SL-independent. The second slower phase depicted a linear dependence of the rate of stress change on the instantaneous stress level. Identical slopes (70.5 +/- 1.6 [1/s], p=0.33) were obtained during ramp shortening at all initial SLs, indicating that the force per cross-bridge and cross-bridge cycling kinetics are length-independent. A decrease in the slope at longer SLs was obtained during stress redevelopment, due to internal shortening. The first phase is attributed to rapid changes in the average force per cross-bridge. The second phase is ascribed to both cross-bridge cycling between its strong and weak conformations and to changes in the number of strong cross-bridges. Cross-bridge cycling kinetics and muscle economy are length independent and the Frank-Starling Law cannot be attributed to changes in the force per cross-bridge or in the single cross-bridge cycling rates. PMID- 26654782 TI - Interdigitation of long-chain sphingomyelin induces coupling of membrane leaflets in a cholesterol dependent manner. AB - It has been a long-standing question how the two leaflets in a lipid bilayer modulate each others' physical properties. In this paper, we discuss how this interaction may take place through interdigitation. We use atomistic molecular dynamics simulations to consider asymmetric lipid membrane models whose compositions are based on the lipidomics data determined for exosomes released by PC-3 prostate cancer cells. The simulations show interdigitation to be exceptionally strong for long-chain sphingomyelin (SM) molecules. In asymmetric membranes the amide-linked chain of SM is observed to extend deep into the opposing membrane leaflet. Interestingly, we find that the conformational order of the amide-linked SM chain increases the deeper it penetrates to the opposing leaflet. Analysis of this finding reveals that the amide-linked SM chain interacts favorably with the lipid chains in the opposite leaflet, and that cholesterol modulates the effect of SM interdigitation by influencing the conformational order of lipid hydrocarbon chains in the opposing (cytosolic) leaflet. PMID- 26654783 TI - Translocation of 5' mRNA cap analogue--peptide conjugates across the membranes of giant unilamellar vesicles. AB - Cell-penetrating peptides (CPPs) have been extensively studied because of their ability to deliver various cargo molecules, which are often potential therapeutic agents. However, in most cases, the exact entry mechanism of CPPs is still unknown. In this study, we focused our attention on the membrane permeability sequence (MPS) peptide (AAVALLPAVLLALLAK) conjugated to analogues of a 5' mRNA cap. This unique RNA structure plays a pivotal role in eukaryotic gene expression and has a large therapeutic application potential. We validated the translocation abilities of conjugates across the membranes of giant unilamellar vesicles (GUVs) composed of POPC lipids by application of fluorescence microscopy. Translocation of the MPS peptide itself was observed in contrast to peptide conjugates containing mono- and dinucleotide cap analogues, indicating that even for such small cargos, passive translocation does not occur. However, membrane permeability was observed in the case of conjugated mononucleotides. Fluorescence lifetime microscopy (FLIM) of the C6-NBD-phospholipid revealed changes in lipid packing induced by a penetrating peptide. Our results support the usefulness of artificial membrane systems applied to elucidate membrane crossing mechanisms. PMID- 26654784 TI - Complexation of phospholipids and cholesterol by triterpenic saponins in bulk and in monolayers. AB - The interactions between three triterpene saponins: alpha-hederin, hederacoside C and ammonium glycyrrhizate with model lipids: cholesterol and dipalmitoylphosphatidylcholine (DPPC) are described. The oleanolic acid-type saponins (alpha-hederin and hederacoside C) were shown to form 1:1 complexes with lipids in bulk, characterized by stability constants in the range (4.0+/ 0.2).10(3)-(5.0+/-0.4).10(4) M(-1). The complexes with cholesterol are generally stronger than those with DPPC. On the contrary, ammonium glycyrrhizate does not form complexes with any of the lipids in solution. The saponin-lipid interactions were also studied in a confined environment of Langmuir monolayers of DPPC and DPPC/cholesterol with the saponins present in the subphase. A combined monolayer relaxation, surface dilational rheology, fluorescence microscopy and neutron reflectivity (NR) study showed that all three saponins are able to penetrate pure DPPC and mixed DPPC/cholesterol monolayers. Overall, the effect of the saponins on the model lipid monolayers does not fully correlate with the lipid-saponin complex formation in the homogeneous solution. The best correlation was found for alpha-hederin, for which even the preference for cholesterol over DPPC observed in bulk is well reflected in the monolayer studies and the literature data on its membranolytic activity. Similarly, the lack of interaction of ammonium glycyrrhizate with both lipids is evident equally in bulk and monolayer experiments, as well as in its weak membranolytic activity. The combined bulk and monolayer results are discussed in view of the role of confinement in modulating the saponin-lipid interactions and possible mechanism of membranolytic activity of saponins. PMID- 26654785 TI - Protein-lipid interactions and non-lamellar lipidic structures in membrane pore formation and membrane fusion. AB - Pore-forming proteins and peptides act on their targeted lipid bilayer membranes to increase permeability. This approach to the modulation of biological function is relevant to a great number of living processes, including; infection, parasitism, immunity, apoptosis, development and neurodegeneration. While some pore-forming proteins/peptides assemble into rings of subunits to generate discrete, well-defined pore-forming structures, an increasing number is recognised to form pores via mechanisms which co-opt membrane lipids themselves. Among these, membrane attack complex-perforin/cholesterol-dependent cytolysin (MACPF/CDC) family proteins, Bax/colicin family proteins and actinoporins are especially prominent and among the mechanisms believed to apply are the formation of non-lamellar (semi-toroidal or toroidal) lipidic structures. In this review I focus on the ways in which lipids contribute to pore formation and contrast this with the ways in which lipids are co-opted also in membrane fusion and fission events. A variety of mechanisms for pore formation that involve lipids exists, but they consistently result in stable hybrid proteolipidic structures. These structures are stabilised by mechanisms in which pore-forming proteins modify the innate capacity of lipid membranes to respond to their environment, changing shape and/or phase and binding individual lipid molecules directly. In contrast, and despite the diversity in fusion protein types, mechanisms for membrane fusion are rather similar to each other, mapping out a pathway from pairs of separated compartments to fully confluent fused membranes. Fusion proteins generate metastable structures along the way which, like long-lived proteolipidic pore forming complexes, rely on the basic physical properties of lipid bilayers. Membrane fission involves similar intermediates, in the reverse order. I conclude by considering the possibility that at least some pore-forming and fusion proteins are evolutionarily related homologues. This article is part of a Special Issue entitled: Pore-Forming Toxins edited by Mauro Dalla Serra and Franco Gambale. PMID- 26654787 TI - Microstructural effects of a neuro-modulating drug evaluated by diffusion tensor imaging. AB - In a longitudinal mouse study we evaluated whether diffusion tensor imaging (DTI) can monitor microstructural changes after administration of the neuromodulating drug EPO and whether erythropoietin (EPO) has an effect on cognitive performance. Twelve mice (2 groups with 6 mice each) were scanned in a 7T Bruker Biospin animal scanner with a highly resolved DTI sequence before and 16 days after intraperitoneal injections of EPO or saline. All mice underwent behavioral testing (Morris water maze) and histologic evaluation of hippocampal and corpus callosum cell proliferation and oligodendrogenesis. Whole brain DTI analysis showed significant Trace, RD and AD decrease within the dentate gyrus, subiculum, primary motor, somatosensory, and supplementary somatosensory areas and FA increase in the hippocampus, corpus callosum, and fimbria fornix in EPO treated mice only. ROI-based DTI analysis showed significant Trace and RD decrease and FA increase only in the corpus callosum of EPO treated mice, whereas in the dentate gyrus significant Trace, RD, and AD decrease occurred in both, EPO- and control group. Behavioral tests showed that EPO treated mice performed better and learned faster than controls. Histologically, the number of BrdU-positive nuclei and optical density of DCX-labeled juvenile neurons significantly increased within the dentate gyrus, corpus callosum and fimbria fornix and the number of NG2 positive oligodendrocyte progenitors in corpus callosum and fimbria fornix, respectively. In conclusion we were able to monitor microstructural changes with DTI and showed EPO treatment-related alterations correlating with enhanced dentate gyrus and corpus callosum cell proliferation and better learning capabilities. PMID- 26654786 TI - Multi-modal characterization of rapid anterior hippocampal volume increase associated with aerobic exercise. AB - The hippocampus has been shown to demonstrate a remarkable degree of plasticity in response to a variety of tasks and experiences. For example, the size of the human hippocampus has been shown to increase in response to aerobic exercise. However, it is currently unknown what underlies these changes. Here we scanned sedentary, young to middle-aged human adults before and after a six-week exercise intervention using nine different neuroimaging measures of brain structure, vasculature, and diffusion. We then tested two different hypotheses regarding the nature of the underlying changes in the tissue. Surprisingly, we found no evidence of a vascular change as has been previously reported. Rather, the pattern of changes is better explained by an increase in myelination. Finally, we show that hippocampal volume increase is temporary, returning to baseline after an additional six weeks without aerobic exercise. This is the first demonstration of a change in hippocampal volume in early to middle adulthood suggesting that hippocampal volume is modulated by aerobic exercise throughout the lifespan rather than only in the presence of age related atrophy. It is also the first demonstration of hippocampal volume change over a period of only six weeks, suggesting that gross morphometric hippocampal plasticity occurs faster than previously thought. PMID- 26654788 TI - Prospective motion correction with volumetric navigators (vNavs) reduces the bias and variance in brain morphometry induced by subject motion. AB - Recent work has demonstrated that subject motion produces systematic biases in the metrics computed by widely used morphometry software packages, even when the motion is too small to produce noticeable image artifacts. In the common situation where the control population exhibits different behaviors in the scanner when compared to the experimental population, these systematic measurement biases may produce significant confounds for between-group analyses, leading to erroneous conclusions about group differences. While previous work has shown that prospective motion correction can improve perceived image quality, here we demonstrate that, in healthy subjects performing a variety of directed motions, the use of the volumetric navigator (vNav) prospective motion correction system significantly reduces the motion-induced bias and variance in morphometry. PMID- 26654789 TI - Tomato yellow leaf curl virus confronts host degradation by sheltering in small/midsized protein aggregates. AB - Tomato yellow leaf curl virus (TYLCV) is a begomovirus transmitted by the whitefly Bemisia tabaci to tomato and other crops. TYLCV proteins are endangered by the host defenses. We have analyzed the capacity of the tomato plant and of the whitefly insect vector to degrade the six proteins encoded by the TYLCV genome. Tomato and whitefly demonstrated the highest proteolytic activity in the fractions containing soluble proteins, less-in large protein aggregates; a significant decrease of TYLCV proteolysis was detected in the intermediate-sized aggregates. All the six TYLCV proteins were differently targeted by the cytoplasmic and nuclear degradation machineries (proteases, ubiquitin 26S proteasome, autophagy). TYLCV could confront host degradation by sheltering in small/midsized aggregates, where viral proteins are less exposed to proteolysis. Indeed, TYLCV proteins were localized in aggregates of various sizes in both host organisms. This is the first study comparing degradation machinery in plant and insect hosts targeting all TYLCV proteins. PMID- 26654790 TI - Nitrogen-Doped Carbon-Encapsulated SnO2@Sn Nanoparticles Uniformly Grafted on Three-Dimensional Graphene-like Networks as Anode for High-Performance Lithium Ion Batteries. AB - A peculiar nanostructure consisting of nitrogen-doped, carbon-encapsulated (N-C) SnO2@Sn nanoparticles grafted on three-dimensional (3D) graphene-like networks (designated as N-C@SnO2@Sn/3D-GNs) has been fabricated via a low-cost and scalable method, namely an in situ hydrolysis of Sn salts and immobilization of SnO2 nanoparticles on the surface of 3D-GNs, followed by an in situ polymerization of dopamine on the surface of the SnO2/3D-GNs, and finally a carbonization. In the composites, three-layer core-shell N-C@SnO2@Sn nanoparticles were uniformly grafted onto the surfaces of 3D-GNs, which promotes highly efficient insertion/extraction of Li(+). In addition, the outermost N-C layer with graphene-like structure of the N-C@SnO2@Sn nanoparticles can effectively buffer the large volume changes, enhance electronic conductivity, and prevent SnO2/Sn aggregation and pulverization during discharge/charge. The middle SnO2 layer can be changed into active Sn and nano-Li2O during discharge, as described by SnO2 + Li(+) -> Sn + Li2O, whereas the thus-formed nano-Li2O can provide a facile environment for the alloying process and facilitate good cycling behavior, so as to further improve the cycling performance of the composite. The inner Sn layer with large theoretical capacity can guarantee high lithium storage in the composite. The 3D-GNs, with high electrical conductivity (1.50 * 10(3) S m(-1)), large surface area (1143 m(2) g(-1)), and high mechanical flexibility, tightly pin the core-shell structure of the N-C@SnO2@Sn nanoparticles and thus lead to remarkably enhanced electrical conductivity and structural integrity of the overall electrode. Consequently, this novel hybrid anode exhibits highly stable capacity of up to 901 mAh g(-1), with ~89.3% capacity retention after 200 cycles at 0.1 A g(-1) and superior high rate performance, as well as a long lifetime of 500 cycles with 84.0% retention at 1.0 A g(-1). Importantly, this unique hybrid design is expected to be extended to other alloy-type anode materials such as silicon, germanium, etc. PMID- 26654791 TI - Trait anger in relation to neural and behavioral correlates of response inhibition and error-processing. AB - Effortful control is considered to be an important factor in explaining individual differences in trait anger. In the current study, we sought to investigate the relation between anger-primed effortful control (i.e., inhibitory control and error-processing) and trait anger using an affective Go/NoGo task. Individuals low (LTA; n=45) and high (HTA; n=49) on trait anger were selected for this study. Behavioral performance (accuracy) and Event-Related Potentials (ERPs; i.e., N2, P3, ERN, Pe) were compared between both groups. Contrary to our predictions, we found no group differences regarding inhibitory control. That is, HTA and LTA individuals made comparable numbers of commission errors on NoGo trials and no significant differences were found on the N2 and P3 amplitudes. With respect to error-processing, we found reduced Pe amplitudes following errors in HTA individuals as compared to LTA individuals, whereas the ERN amplitudes were comparable for both groups. These results indicate that high trait anger individuals show deficits in later stages of error-processing, which may explain the continuation of impulsive behaviors in HTA individuals despite their negative consequences. PMID- 26654792 TI - Distribution of genes encoding virulence factors and molecular analysis of Shigella spp. isolated from patients with diarrhea in Kerman, Iran. AB - Shigella is one of the important causes of diarrhea worldwide. Shigella has several virulence factors contributing in colonization and invasion of epithelial cells and eventually death of host cells. The present study was performed in order to investigate the distribution of virulence factors genes in Shigella spp. isolated from patients with acute diarrhea in Kerman, Iran as well as the genetic relationship of these isolates. A total of 56 isolates including 31 S. flexneri, 18 S. sonnei and 7 S. boydii were evaluated by polymerase chain reaction (PCR) for the presence of 11 virulence genes (ipaH, ial, set1A, set1B, sen, virF, invE, sat, sigA, pic and sepA). Then, the clonal relationship of these strains was analyzed by multilocus variable-number tandem repeat analysis (MLVA) method. All isolates were positive for ipaH gene. The other genes include ial, invE and virF were found in 80.4%, 60.7% and 67.9% of the isolates, respectively. Both set1A and set1B were detected in 32.3% of S. flexneri isolates, whereas 66.1% of the isolates belonging to different serogroup carried sen gene. The sat gene was present in all S. flexneri isolates, but not in the S. sonnei and S. boydii isolates. The result showed, 30.4% of isolates were simultaneously positive and the rest of the isolates were negative for sepA and pic genes. The Shigella isolates were divided into 29 MLVA types. This study, for the first time, investigated distribution of 11 virulence genes in Shigella spp. Our results revealed heterogeneity of virulence genes in different Shigella serogroups. Furthermore, the strains belonging to the same species had little diversity. PMID- 26654793 TI - Role of ABCA7 loss-of-function variant in Alzheimer's disease: a replication study in European-Americans. AB - INTRODUCTION: A recent study found a significant increase of ABCA7 loss-of function variants in Alzheimer's disease (AD) cases compared to controls. Some variants were located on noncoding regions, but it was demonstrated that they affect splicing. Here, we try to replicate the association between AD risk and ABCA7 loss-of-function variants at both the single-variant and gene level in a large and well-characterized European American dataset. METHODS: We genotyped the GWAS common variant and four rare variants previously reported for ABCA7 in 3476 European-Americans. RESULTS: We were not able to replicate the association at the single-variant level, likely due to a lower effect size on the European American population which led to limited statistical power. However, we did replicate the association at the gene level; we found a significant enrichment of ABCA7 loss-of function variants in AD cases compared to controls (P = 0.0388; odds ratio =1.54). We also confirmed that the association of the loss-of-function variants is independent of the previously reported genome-wide association study signal. CONCLUSIONS: Although the effect size for the association of ABCA7 loss-of function variants with AD risk is lower in our study (odds ratio = 1.54) compared to the original report (odds ratio = 2.2), the replication of the findings of the original report provides a stronger foundation for future functional applications. The data indicate that different independent signals that modify risk for complex traits may exist on the same locus. Additionally, our results suggest that replication of rare-variant studies should be performed at the gene level rather than focusing on a single variant. PMID- 26654794 TI - Analysis of mitochondrial DNA heteroplasmic mutations A1555G, C3256T, T3336C, S5178A, G12315A, G13513A, G14459A, G14846A and G15059A in CHD patients with the history of myocardial infarction. AB - The present study was undertaken in order to advance our earlier studies directed to define genetic risk of atherosclerotic vascular lesion development on a base on the analysis of sets of mutational load relevant to the mitochondrial genome mutations. A comparative evaluation of the two study participants' populations (that included coronary heart disease (CHD) patients who underwent myocardial infarction and apparently healthy donors with no clinical manifestations of coronary heart disease) on heteroplasmy levels of nine mutations of the mitochondrial genome (A1555G, C3256T, T3336C, S5178A, G12315A, G13513A, G14459A, G14846A and G15059A) that were shown previously to be associated with risk factors for atherosclerosis was performed. Close associations with the risk of cardiovascular disease were confirmed for mutation C3256T (gene MT-TL1), G12315A (gene MT-TL2), G13513A (gene MT-ND5) and G15059A (gene MT-CYB) by RT-PCR. PMID- 26654795 TI - New insights on the palate, lung, and nasal epithelium clone (PLUNC) proteins: Based on molecular and functional analysis of its homolog of YH1/SPLUNC1. AB - The palate, lung, and nasal epithelium clone (PLUNC) proteins are intricate immune molecules and arisen questions from them are still unresolved. In order to identify the role of PLUNC family proteins, we had analyzed its homolog protein YH1/SPLUNC1, which highly expresses in nontumor nasopharyngeal epithelium while expresses weakly in nasopharyngeal carcinoma (NPC) tissues. It is found that YH1/SPLUNC1 protein expression level was higher in chronic normal nasopharynx inflammatory cells compared to NPC tissue cells. An approach to produce active YH1/SPLUNC1 protein had been established and recombinant YH1/SPLUNC1 protein could bind to all four Gram-positive and four Gram-negative bacteria we tested, and triggered the aggregation of those bacteria. Interestingly, YH1/SPLUNC1 protein has antimicrobial activity, and it can directly kill Escherichia coli and Acinetobacter haemolyticus. The microorganism cell showed morphological changes in cell wall such as cell damage and cytoplasmic leakage after exposure to YH1/SPLUNC1 protein, indicating that YH1/SPLUNC1 directly killed the microorganisms by cell wall permeabilization. All these results indicated that YH1/SPLUNC1 might be an important antimicrobial protein involved in innate immunity defense. PMID- 26654796 TI - Role of the non-opioid dynorphin peptide des-Tyr-dynorphin (DYN-A(2-17)) in food intake and physical activity, and its interaction with orexin-A. AB - Food intake and physical activity are regulated by multiple neuropeptides, including orexin and dynorphin (DYN). Orexin-A (OXA) is one of two orexin peptides with robust roles in regulation of food intake and spontaneous physical activity (SPA). DYN collectively refers to several peptides, some of which act through opioid receptors (opioid DYN) and some whose biological effects are not mediated by opioid receptors (non-opioid DYN). While opioid DYN is known to increase food intake, the effects of non-opioid DYN peptides on food intake and SPA are unknown. Neurons that co-express and release OXA and DYN are located within the lateral hypothalamus. Limited evidence suggests that OXA and opioid DYN peptides can interact to modulate some aspects of behaviors classically related to orexin peptide function. The paraventricular hypothalamic nucleus (PVN) is a brain area where OXA and DYN peptides might interact to modulate food intake and SPA. We demonstrate that injection of des-Tyr-dynorphin (DYN-A(2-17), a non opioid DYN peptide) into the PVN increases food intake and SPA in adult mice. Co-injection of DYN-A(2-17) and OXA in the PVN further increases food intake compared to DYN-A(2-17) or OXA alone. This is the first report describing the effects of non-opioid DYN-A(2-17) on food intake and SPA, and suggests that DYN-A(2-17) interacts with OXA in the PVN to modulate food intake. Our data suggest a novel function for non-opioid DYN-A(2-17) on food intake, supporting the concept that some behavioral effects of the orexin neurons result from combined actions of the orexin and DYN peptides. PMID- 26654797 TI - Metabolic design of a platform Escherichia coli strain producing various chorismate derivatives. AB - A synthetic metabolic pathway suitable for the production of chorismate derivatives was designed in Escherichia coli. An L-phenylalanine-overproducing E. coli strain was engineered to enhance the availability of phosphoenolpyruvate (PEP), which is a key precursor in the biosynthesis of aromatic compounds in microbes. Two major reactions converting PEP to pyruvate were inactivated. Using this modified E.coli as a base strain, we tested our system by carrying out the production of salicylate, a high-demand aromatic chemical. The titer of salicylate reached 11.5 g/L in batch culture after 48 h cultivation in a 2-liter jar fermentor, and the yield from glucose as the sole carbon source exceeded 40% (mol/mol). In this test case, we found that pyruvate was synthesized primarily via salicylate formation and the reaction converting oxaloacetate to pyruvate. In order to demonstrate the generality of our designed strain, we employed this platform for the production of each of 7 different chorismate derivatives. Each of these industrially important chemicals was successfully produced to levels of 1-3g/L in test tube-scale culture. PMID- 26654799 TI - Pancreatic Cancer Diagnostics and Treatment--Current State. AB - Pancreatic ductal adenocarcinoma (PDAC) represents permanent and ever rising issue worldwide. Five-year survival does not exceed 3 to 6%, i.e. the worst result among solid tumours. The article evaluates the current state of PDAC diagnostics and treatment specifying also development and trends. Percentage of non-resectable tumours due to locally advanced or metastatic condition varies 60 80%, mostly over 80%. Survival with non-resectable PDAC is 4 to 8 months (median 3.5). In contrast R0 resection shows the survival 18-27 months. Laboratory and imaging screening methods are not indicated on large scale. Risk factors are smoking, alcohol abuse, chronic pancreatitis, diabetes mellitus. Genetic background in most PDAC has not been detected yet. Some genes connected with high risk of PDAC (e.g. BRCA2, PALB2) have been identified as significant and highly penetrative, but link between PDAC and these genes can be seen only in 10-20%. This article surveys perspective oncogenes, tumour suppressor genes, microRNA. Albeit CT is still favoured over other imaging methods, involvement of NMR rises. Surgery prefers the "vessel first" approach, which proves to be justified especially in R0 resection. According to EBM immunotherapy same as radiotherapy are not significant in PDAC treatment. Chemotherapy shows limited importance in conversion treatment of locally advanced or borderline tumours or in case of metastatic spread. Unified procedures cannot be defined due to inhomogenous arrays. Surgical resection is the only chance for curative treatment of PDAC and depends mainly on timely indication for surgery and quality of multidisciplinary team in a high-volume centre. PMID- 26654798 TI - SRT-Joy - computer-assisted self-regulation training for obese children and adolescents: study protocol for a randomized controlled trial. AB - BACKGROUND: Obesity is not only a highly prevalent disease but also poses a considerable burden on children and their families. Evidence is increasing that a lack of self-regulation skills may play a role in the etiology and maintenance of obesity. Our goal with this currently ongoing trial is to examine whether training that focuses on the enhancement of self-regulation skills may increase the sustainability of a complex lifestyle intervention. METHODS/DESIGN: In a multicenter, prospective, parallel group, randomized controlled superiority trial, 226 obese children and adolescents aged 8 to 16 years will be allocated either to a newly developed computer-training program to improve their self regulation abilities or to a placebo control group. Randomization occurs centrally and blockwise at a 1:1 allocation ratio for each center. This study is performed in pediatric inpatient rehabilitation facilities specialized in the treatment of obesity. Observer-blind assessments of outcome variables take place at four times: at the beginning of the rehabilitation (pre), at the end of the training in the rehabilitation (post), and 6 and 12 months post-rehabilitation intervention. The primary outcome is the course of BMI-SDS over 1 year after the end of the inpatient rehabilitation. Secondary endpoints are the self-regulation skills. In addition, health-related quality of life, and snack intake will be analyzed. DISCUSSION: The computer-based training programs might be a feasible and attractive tool to increase the sustainability of the weight loss reached during inpatient rehabilitation. TRIAL REGISTRATION: The present study protocol was registered on 13 July 2015 at German Clinical Trials Register: DRKS00007879 . PMID- 26654800 TI - Changes in the Concentrations of Corticoid Metabolites--The Effect of Stress, Diet and Analytical Method. AB - A precisely measured corticoid level is important for decision-making in daily clinical practice. These levels can be influenced in the pre-analytical phase, when the effect of stress, timing, and diet can be important. The aim of this study was to elucidate optimal conditions for blood sampling as well as the choice of analytical methods, which they will be used in measuring of corticoids. By studying ten women, we focused on the influences of the stress of cannulation and a large lunchtime meal on cortisol, cortisone, aldosterone and corticosterone levels. We further compared results of cortisol measurements from RIA and LC MS/MS. Stress from cannulation caused increase of cortisol, cortisone and corticosterone already, when the cannula was being inserted. This indicates that this increase is stimulated by fear of the blood withdrawing rather, than just by the needle insertion itself. The effect of stress on corticosterone disappeared after an hour, while effect on other corticoids was still apparent. Concerning the lunchtime meal, we found an increase in all measured corticoids between 11 and 12 o'clock. After the food, there were marked decreases in cortisone and aldosterone, while declining levels of cortisol and corticosterone had rather plateaus. We compared cortisol in 90 plasma samples measured by a commercial RIA kit and the LC-MS/MS method. Results from both methods showed a strong correlation (r=0.85). When measuring corticoid metabolites, the chosen analytical method, eliminating stress factors, and precisely timed blood sampling considering the daily rhythm and food intake are critical. PMID- 26654801 TI - The Cortisol to Cortisone Ratio during Cardiac Catheterisation in Sows. AB - A possible effect of mini-invasive heart intervention on a response of hypothalamo-pituitary-adrenal stress axis and conversion of cortisone to cortisol were studied. We have analysed two stress markers levels (cortisol, cortisone) and cortisol/cortisone ratio in 25 sows using minimally invasive heart catheterisation as the stress factor. The values of studied parameters were assessed in four periods of the experiment: (1) the baseline level on the day before intervention, (2) after the introduction of anaesthesia, (3) after conducting tissue stimulation or ablation, and (4) after the end of the catheterisation. For statistical analyses we used the non-parametric Friedman test for four dependent samples (including all four stages of the operation) or three dependent samples (influence of operation only, baseline level was excluded). Statistically significant differences in both Friedman tests were found for cortisol and for cortisone. We have found the highest level of cortisol/cortisone ratio in unstressed conditions, then it decreased to the minimal level at the end of the intervention. We have concluded that cortisol levels are blunted by the influence of anaesthesia after its administration, and therefore decrease back to the baseline at the end of the operation. PMID- 26654802 TI - How Does Energy Intake Influence the Levels of Certain Steroids? AB - The influence of steroid hormones on food intake is well described. However, there are only a few studies on the effect of food intake on steroid levels. The study involved eight non-smoker women (average age 29.48+/-2.99 years; average BMI 21.3+/-1.3 kg/m2); they did not use any kind of medication affecting steroidogenesis. We analysed the influence of four various stimuli on the levels of steroid hormones and melatonin. During their follicular phase of menstrual cycle, each woman had an oral glucose tolerance test (OGTT), intravenous glucose tolerance test (IVGTT), a standard breakfast and psyllium (a non-caloric fibre). Cortisol declined during each test, which is a physiological decline in the morning hours. In all tests (except of the application of the non-caloric fibre, psyllium), however, this decline was modified. After the standard breakfast there was an increase in cortisol at 40th minute. The OGTT and IVGTT tests led to a plateau in cortisol levels. Testosterone levels and those of other steroid hormones showed no relationships to tested stimulations. Oral and intravenous glucose have influenced physiological decline of melatonin levels. During the IVGTT test, melatonin levels started to increase at 20th minute, reaching a maximum at 40th minute. The OGTT test led to a delayed increase in melatonin levels, compared to IVGTT. Despite the fact that we performed the tests in the morning hours, when steroid hormone levels physiologically start to change due to their diurnal rhythm, we still found that food intake influences some of the hormone levels. PMID- 26654803 TI - Keratocystic Odontogenic Tumour with Extraosseal Spread: Evaluation of the Effect Carnoy's Solution. AB - Keratocystic odontogenic tumour is relatively rare benign tumour. It is characterized by its fast aggressive growth and high risk of recurrence. Treatment is always surgical: conservative (enucleation, marsupialization) or aggressive (enucleation followed by application of Carnoy's solution, cryotherapy; peripheral ostectomy or en block resection of the jaw). Authors analysed retrospectively 22 patients who fulfilled inclusion criteria, i.e. had odontogenic keratocystic tumour of mandible, wherein antero-posterior dimension was at least 30 mm, and the tumour penetrated into the surrounding soft tissues. All patients underwent tumour enucleation, in 11 patients Carnoy's solution was given into the bone cavity after enucleation. The recurrence rate in the evaluation at least 36 months after surgery was both patient groups the same: 45.4%. PMID- 26654804 TI - Snake Envenomation to the Face of a Child--Rare Case. AB - Snakebites are seen in summer season in the southern part of Turkey, including Hatay province. In average of 40 patients with snakebites are admitted to our hospital every year. Viper is the most common venomous snakes in our region. Their hemotoxins and necrotoxins lead to local or systemic tissue damage and is responsible for the mortality and morbidity. In this report, we described a rare pediatric case, a six-year-old boy having been bitten on the left side of his face when he was looking around from their home's balcony. The patient was orotracheally intubated and mechanically ventilated because of airway obstruction due to severe edema. 12 flacon of anti-snake venom, mannitol infusion, fresh frozen plasma, erythrocytes suspension and antibiotherapy were administered to the patient. Seven days after the admission, clinical and laboratory findings were improved and the patient was discharged in a good condition. Snakebites inflicted on face and neck areas may cause rapidly progressive edema in respiratory tract and lead to life-threatening conditions. Therefore early orotracheal intubation is very important to prevent mortality. PMID- 26654805 TI - Mechanical ventilatory assistance may reduce dyspnea during walking especially in patients with impaired cardiopulmonary function early after cardiovascular surgery. AB - BACKGROUND: To determine which patients effectively respond to ventilatory assistance (VA) and to examine the factors influencing patient response in patients who underwent cardiovascular (CV) surgery. METHODS: We conducted the first walking session after surgery either with or without VA in a randomized order. The patients walked with 3cmH2O of inspiratory pressure support. We measured dyspnea and leg fatigue during initial walking either with or without VA by using a modified Borg scale. Ventilatory parameters were measured by mechanical ventilation before and immediately after walking. Lung function and maximal inspiratory pressure (MIP) were measured and chest radiographs were analyzed by the same cardiac surgeon on the same day as walking. RESULTS: From the total of 74 patients who underwent CV surgery, 56 patients were successively enrolled in the study. Thirty-five out of 56 patients had dyspnea and 18 patients (30% of the total patients) effectively responded to VA (responders). Minute ventilation/estimated maximum voluntary ventilation immediately after walking significantly decreased with VA, and MIP was lower in responders than in non responders after surgery. The responders revealed greater pulmonary edema scores than non-responders. CONCLUSIONS: The findings of the present study suggest that VA may possibly facilitate successful mobilization early after CV surgery, especially in patients with impaired cardiopulmonary function. PMID- 26654806 TI - Impact of postprocedural antiarrhythmic drug therapy with bepridil on maintaining sinus rhythm after catheter ablation for persistent atrial fibrillation. AB - BACKGROUND: Although several studies have assessed the predictors of recurrent atrial fibrillation (AF) after catheter ablation for persistent AF, the impact of antiarrhythmic drug (AAD) therapy on maintaining sinus rhythm after catheter ablation for persistent AF has not been fully evaluated. This case-control study aimed to evaluate the effect of bepridil on maintaining sinus rhythm after catheter ablation for persistent AF. METHODS AND RESULTS: We enrolled 122 consecutive patients (87 men; mean age: 62.3 years) who underwent catheter ablation for persistent AF and were administered AAD therapy after the initial procedure. Restoration of sinus rhythm was achieved in all of the patients by catheter ablation and cardioversion after the initial procedure. After a median 12-month follow up, 51 of 122 (41.8%) patients had recurrence of AF. In Cox proportional hazard regression analysis, postprocedural AAD therapy with bepridil was a significantly correlated factor with freedom from recurrent AF after the initial ablation procedure (hazard ratio 0.446, 95% confidence interval 0.236 0.842, p=0.012). In Kaplan-Meier analysis, AF-free survival was significantly better with bepridil compared with amiodarone (AMD) and sodium channel blocker (SCB) (log-rank test, bepridil vs AMD, p=0.012; bepridil vs SCB, p=0.018). CONCLUSIONS: Bepridil reduced the recurrence of AF compared with AMD and SCB in patients who underwent catheter ablation for persistent AF. PMID- 26654807 TI - Predictive capacity of a non-radioisotopic local lymph node assay using flow cytometry, LLNA:BrdU-FCM: Comparison of a cutoff approach and inferential statistics. AB - In order for a novel test method to be applied for regulatory purposes, its reliability and relevance, i.e., reproducibility and predictive capacity, must be demonstrated. Here, we examine the predictive capacity of a novel non radioisotopic local lymph node assay, LLNA:BrdU-FCM (5-bromo-2'-deoxyuridine-flow cytometry), with a cutoff approach and inferential statistics as a prediction model. 22 reference substances in OECD TG429 were tested with a concurrent positive control, hexylcinnamaldehyde 25%(PC), and the stimulation index (SI) representing the fold increase in lymph node cells over the vehicle control was obtained. The optimal cutoff SI (2.7<=cutoff <3.5), with respect to predictive capacity, was obtained by a receiver operating characteristic curve, which produced 90.9% accuracy for the 22 substances. To address the inter-test variability in responsiveness, SI values standardized with PC were employed to obtain the optimal percentage cutoff (42.6<=cutoff <57.3% of PC), which produced 86.4% accuracy. A test substance may be diagnosed as a sensitizer if a statistically significant increase in SI is elicited. The parametric one-sided t test and non-parametric Wilcoxon rank-sum test produced 77.3% accuracy. Similarly, a test substance could be defined as a sensitizer if the SI means of the vehicle control, and of the low, middle, and high concentrations were statistically significantly different, which was tested using ANOVA or Kruskal Wallis, with post hoc analysis, Dunnett, or DSCF (Dwass-Steel-Critchlow-Fligner), respectively, depending on the equal variance test, producing 81.8% accuracy. The absolute SI-based cutoff approach produced the best predictive capacity, however the discordant decisions between prediction models need to be examined further. PMID- 26654808 TI - [Editorial: adverse drug reactions]. PMID- 26654809 TI - [Adverse drug reaction - Definitions, risk factors and pharmacovigilance]. AB - Adverse drug reactions (ADR} are the downside of active pharmacotherapies and can only partially be avoided. Risk factors have been identified for certain ADR which should be taken into account for the choice and dosing of critical drugs. Medical staff have a legal obligation to report severe ADR and ADR caused by newly licensed drugs. Such reports are important for monitoring the safety of drugs that are on the market. PMID- 26654810 TI - [Adverse drug events of older patients presenting in the emergency department]. AB - The effect of medication is always a balance between their beneficial effects and any adverse reactions they might elicit. The main risk for adverse drug events {ADEs) is polypharmacy, which is the simultaneous use of multiple drugs.This often applies to older patients, who suffer from multiple diseases and therefore take multiple medications. Thus, itis not surprising, that ADEs are frequention older patients and account up to 16% of emergency visits. It is still under discussion, whether age is an independent risk factor for ADEs. However, there are some age-related changes in the pharmacokinetic and pharmacodynamics properties of many drugs, which may influence the highly fragile balance between benefit and harm in older patients. Though there are multiple risk factors for and causes of ADEs, it could be shown that a lot of ADEs are preventable and even predictable: Budnitz eta/. showed that almost two thirds of emergency hospitalisations occur due to four medication classes: warfarin, oral antiplatelet agents, insulin and oral hypoglycaemic agents. Nevertheless, only 40 60% ofA DEs are recognized in the emergency department. This might be explained by the broad clinical symptoms, ranging from bleeding due to anticoagulants to the more nonspecific symptom of weakness due to hyponatraemia secondary to thiazide diuretics. Detecting and avoiding ADEs could be aided by using lists such as Beers criteria or STOPP/FART which list medications which are potentially inappropriate for older patients. PMID- 26654811 TI - [Understanding and reducing the risk of adverse drug reactions in pediatric patients]. AB - Developmental pharmacology influences the safety profile of drugs in pediatrics. Altered pharmacokinetics and/ or pharmacodynamics of drugs make pediatric patients susceptible to adverse drug reactions (ADRs), especially infants and newborns. Since the efficacy/ safety balance of most available drugs has not been formally evaluated in pediatric clinical trials, optimal dosing is rarely known in pediatrics. Suboptimal pediatric drug formulations make dose optimization even more difficult exposing pediatric patients to medication errors like overdosing and associated ADRs. We provide an overview of pediatric ADRs and discuss recent regulatory and pharmacological measures to understand and reduce risk of ADRs in pediatric patients. PMID- 26654812 TI - [Adverse drug effects in the community pharmacy]. AB - Community pharmacists represent an important pillar for the identification and the reporting of adverse drug effects (ADE}. Thanks to their broad view on the pharmacotherapy, over-the-counter medication included, they contribute greatly to the improvement of drug safety. In principle, the community pharmacy will face three groups of ADE which require specific attention. This article deals with these specific ADE groups and presents some illustrative examples from daily practice. Furthermore, we suggest some solutions to identify potential relevant interactions - including herbal-drug interactions - and give tips for daily practice, along with some often overseen cutaneous ADE. PMID- 26654813 TI - [ Preventing adverse drug events using clinical decision support systems]. AB - Adverse drug events pose a great risk to patients, are an everyday clinical problem and can have potential/ega/ consequences. Computerized physician order entry or computerized provider order entry (CPOE} in combination with clinical decision support systems {CDSS) are popular and aim to reduce prescribing errors as well as identifying potentially harmful drug drug interactions. The quantifiable benejit these systems bring to patients, has however, yet to be definitively proven. This article focusses on the current standpoint of CPOE /CDSS, their risks and benefits, the potential for improvement and their perspectives for the future. PMID- 26654814 TI - [Side effects and interactions of frequently used cardiovascular drugs]. AB - Due to the high prevalence of cardiovascular diseases and the corresponding prescription of cardiac drugs, side effects and interactions may occur in a substantial number of patients. They can be explained by either pharmacokinetic or pharmaco-dynamic drug interactions which may be desired, but may also be life threatening. Despite the fact that the novel oral anticoagulants are well tolerated, several factors restricting the use of these drugs, such as renal failure, have to be considered. The use of antihypertensive drugs may be limited by concomitant use of drugs that either induce of inhibit enzymatic metabolism, respectively inhibit renal drug, electrolyte, and/or water excretion. In this respect, the interaction between beta-blockers, ACE inhibitors, angiotensin receptor blockers and thiazide diuretics with non-steroidal antiinflammatory drugs is especially important. Muscle disorders are frequent side effects in patients undergoing statin therapy and affect up to 5% of patients. They may manifest as mild myalgia, but also as life-threatening rhabdomyolysis. PMID- 26654815 TI - [Drug-induced sexual dysfunction]. AB - Drugs can affect sexual function through their effects on the central nervous system, the peripheral (autonomic) nervous system or through hormonal effects. As most patients do not spontaneously talk about their sex life, it is important to assess patients with critical medication for possible sexual dysfunction. Critical medication in relation to sexual function include sedative drugs, drugs that affect the central serotonin, dopamine and/ or prolactin signaling pathways as well as certain antihypertensives. It is important to note, however, that the indications for these therapies, such as schizophrenia, depression and the metabolic syndrome are themselves associated with sexual dysfunction. if a disturbing sexual dysfunction arises, treatment with the suspected drug should be discontinued and possibly changed to one with fewer adverse effects. The use of phosphodiesterase 5 inhibitors, which are largely efficacious and safe for both patients with psychiatric conditions and patients with hypertension, can be considered PMID- 26654816 TI - [Drug-induced acute kidney injury]. AB - Due to their physiological function, the kidneys are exposed to high concentrations of numerous drugs and their metabolites, making them vulnerable to drug-related injuries. This article provides an overview of the pathophysiological mechanisms involved in nephrotoxicity, the most common nephrotoxic drugs, and the risk factors for the occurrence of drug-induced acute kidney injuries. NSAIDs, diuretics, ACE inhibitors, and angiotensin II receptor blockers (ARBs} are the most frequent prerenal causes of an acute elevation in creatinine levels. Primary vascular damage arises from thrombotic microangiopathy (e. g. due to cic/osporin, tacrolimus, muromonab-CD3, mitomycin C, quinine, ticlopidine, clopidogrel}. Anticoagulants and thrombolytic medications lead to secondary blood vessel damage by cholesterol emboli, embolism of thrombus material into the periphery or bleeding. Tubulopathies can be observed on treatment with ifosfamide and cisplatin (rarely with cyclophosphamide or carboplatin), aminoglycosides, vancomycin, and radiocontrast agents. Immunological mechanisms underlie interstitial nephritides, which are induced by drugs in about 85% of cases. In drug-induced glomerulopathies;- renal biopsy allows closer identification of the triggering medication. Drug-induced systemic lupus erythematosus (SLE} represents a special form of immune complex glomerulonephritis and can be triggered by procainamide, hydralazine, isoniazid, methyldopa, quinidine, chlorpromazine, and propylthiouracil. Crystal-induced kidney injury is caused by precipitation of drugs (e. g. aciclovir, sulfonamide antibiotics, methotrexate, indinavir) in the renal tubules and the urine conducting organs with consecutive obstruction thereof. PMID- 26654817 TI - [ Drug allergies: clinical presentation and red flags]. AB - In theory, all medicines can elicit allergic reactions. However, there are large differences in the frequency and clinical presentation of these reactions. Antibiotics, antiepileptic agents and NSADs trigger allergic reactions most frequently. The risk of drug allergy and of a complicated clinical course depends on the individual degree of immune activation, the dose, duration of treatment, route of administration, patient sex as well as HLA-traits, which are increasingly being identified. This article presents the commonest types of immune-mediated drug-related hypersensitivity reactions and discusses red flags which are associated with a complicated clinical course. PMID- 26654818 TI - [5-0xoproline (pyroglutamic acid) acidosis and acetaminophen- a differential diagnosis in high anion gap metabolic acidosis]. AB - Rare cases of high anion gap metabolic acidosis during long-term paracetamol administration in therapeutic doses with causative 5-oxoproline (pyroglutamic acid} accumulation have been reported. Other concomitant risk factors such as malnutrition, alcohol abuse, renal or hepatic dysfunction, comedication with flue/oxacillin, vigabatrin, netilmicin or sepsis have been described. The etiology seems to be a drug-induced reversible inhibition of glutathione synthetase or 5-oxoprolinase leading to elevated serum and urine levels of 5 oxoproline. Other more frequent differential diagnoses, such as intoxications, ketoacidosis or lactic acidosis should be excluded. Causative substances should be stopped. 5-oxoproline concentrations in urine can be quantified to establish the diagnosis. Adverse drug reactions, which are not listed or insufficiently described in the respective Swiss product information, should be reported to the regional pharmacovigilance centres for early signal detection. 5-0 xoproline acidosis will be integrated as a potential adverse drug reaction in the Swiss product information for paracetamol. PMID- 26654819 TI - [Pharmacovigiance: The spontaneous reporting system in Switzerland]. AB - The aim of pharmacovigilance is to continuously update and enhance our knowledge about the safety of medicines in order to improve patient care. The most important method of postmarketing drug surveillance is the spontaneous reporting system. As a rapid alert system it is able to detect unknown and rare as well as insufficiently described reactions and risks. A broad population, including all potential high-risk groups, can be surveilled over a long period of time. The attentiveness of health care professionals as well as the quality and quantity of the information provided are crucial for the success of this system. As no detailed data concerning the number of patients taking a particular medication are available and only a small percentage of adverse drug reactions is reported, it is impossible to draw conclusions about the incidence of adverse drug reactions or the relative risk, which is a big disadvantage. Since 2002 healthcare professionals and pharmaceutical companies are obliged to report adverse drug reactions in accordance with the Swiss Therapeutic Products Act. Six Regional Pharmacovigilance-Centres collect health care professionals' reports, analyze them, enter the data into the national database and forward the anonymized reports to the National Pharmacovigiance-Centre at Swissmedic. There, all reports are screened for signals and, if necessary, appropriate measures are initiated. All reports received by Swissmedic are forwarded to the WHO Collaborating Centre for International Drug Monitoring (Uppsala, Sweden} for inclusion in the international database. PMID- 26654821 TI - Exposure to bisphenol A and behavior in school-age children. AB - INTRODUCTION: Bisphenol A (BPA) exposure has been shown to affect human brain neurodevelopment and behavior. OBJECTIVE: We aimed to investigate whether environmental exposure to BPA in children was associated with their childhood behavior. METHODS: Urinary BPA concentrations and behavioral characteristics were assessed in 300 children belonging to the INMA "Environment and Childhood" Granada birth cohort in their follow-up at 9-11 years of age. BPA concentrations were quantified in urine using liquid chromatography-tandem mass spectrometry (LC MS-MS), and child behavior reported by parents using the Child Behavior Checklist (CBCL/6-18) under supervision of a psychologist. The association between BPA concentrations and CBCL standardized scores was analyzed using linear regression models, adjusted for important covariates. RESULTS: Median (P25, P75) BPA concentration was 4.76 (2.77, 9.03)MUg/L. Mean (+/-SD) CBCL externalizing and internalizing scores were 56.35 (+/-8.06) and 51.36 (+/-9.22), respectively. In multivariate regression analyses, adjusted for maternal and child characteristics, higher BPA concentrations were associated with worse behavioral scores on all scales. Children with BPA concentrations in the 4th quartile had more somatic complaints (beta=2.35; 95% CI: 0.25, 4.46) and social (beta=1.71; 95% CI: 0.19, 3.22) and thought problems (beta=2.58; 95% CI: 0.66, 4.51) in comparison to those in the 1st quartile. Children with values in the 3rd quartile of BPA concentrations also showed greater social problems (beta=1.94; 95% CI: 0.43, 3.45). CONCLUSIONS: Our results suggest that exposure to BPA in childhood may affect children's behavior. Although further investigations are required, preventive measures should be undertaken to reduce inadvertent exposure to BPA. PMID- 26654822 TI - Cognitive therapy in sick building syndrome: Myths, believes or evidence. PMID- 26654827 TI - Pd(II)-Catalyzed Alkylation of Tertiary Carbon via Directing-Group-Mediated C(sp(3))-H Activation: Synthesis of Chiral 1,1,2-Trialkyl Substituted Cyclopropanes. AB - A Pd(OAc)2-catalyzed alkylation reaction of the tertiary carbon of chiral cyclopropane substrates with alkyl iodides and bromides via C(sp(3))-H activation has been developed. This is an elusive example of a C-H activation-mediated alkylation of tertiary carbon to effectively construct a quaternary carbon center. The alkylation proceeded with various alkyl halides, including those of functional groups, to provide a variety of chiral cis- and trans-1,1,2,-trialkyl substituted cyclopropanes of medicinal chemical importance. PMID- 26654828 TI - Anti-Candida Cassane-Type Diterpenoids from the Root Bark of Swartzia simplex. AB - A dichloromethane extract of the roots from the Panamanian plant Swartzia simplex exhibited a strong antifungal activity in a bioautography assay against a genetically modified hypersusceptible strain of Candida albicans. At-line HPLC activity based profiling of the crude extract enabled a precise localization of the antifungal compounds, and dereplication by UHPLC-HRESIMS indicated the presence of potentially new metabolites. Transposition of the HPLC reversed-phase analytical conditions to medium-pressure liquid chromatography (MPLC) allowed an efficient isolation of the major constituents. Minor compounds of interest were isolated from the MPLC fractions using semipreparative HPLC. Using this strategy, 14 diterpenes (1-14) were isolated, with seven (5-10, 14) being new antifungal natural products. The new structures were elucidated using NMR spectroscopy and HRESIMS analysis. The absolute configurations of some of the compounds were elucidated by electronic circular dichroism spectroscopy. The antifungal properties of these compounds were evaluated as their minimum inhibitory concentrations in a dilution assay against both hypersusceptible and wild-type strains of C. albicans and by assessment of their antibiofilm activities. The potential cytological effects on the ultrastructure of C. albicans of the antifungal compounds isolated were evaluated on thin sections by transmission electron microscopy. PMID- 26654829 TI - 4',6-Dihydroxy-4-methoxyisoaurone inhibits TNF-alpha-induced NF-kappaB activation and expressions of NF-kappaB-regulated target gene products. AB - The nuclear factor-kappaB (NF-kappaB) transcription factors control many physiological processes including inflammation, apoptosis, and angiogenesis. In our search for NF-kappaB inhibitors from natural resources, we identified 4',6 dihydroxy-4-methoxyisoaurone (ISOA) as an inhibitor of NF-kappaB activation from the seeds of Trichosanthes kirilowii. However, the mechanism by which ISOA inhibits NF-kappaB activation is not fully understood. In the present study, we demonstrated the effect of ISOA on NF-kappaB activation in TNF-alpha-stimulated HeLa cells. This compound suppressed NF-kappaB activation through the inhibition of IkappaB kinase (IKK) activation. ISOA also has an influence on upstream signaling of IKK through the inhibition of expression of adaptor proteins, TNF receptor-associated factor 2 (TRAF2) and receptor interacting protein 1 (RIP1). Consequently, ISOA blocked the phosphorylation and degradation of the inhibitor of NF-kappaB alpha (IkappaBalpha), and subsequent phosphorylation and nuclear translocation of p65. The suppression of NF-kappaB activation by ISOA led to the down-regulation of target genes involved in inflammation, proliferation, as well as potentiation of TNF-alpha-induced apoptosis. Taken together, this study extends our understanding on the mechanisms underlying the anti-inflammatory and anti-cancer activities of ISOA. Our findings provide new insight into the molecular mechanisms and a potential application of ISOA for inflammatory diseases as well as certain cancers. PMID- 26654830 TI - A sensitive and efficient method for routine pesticide multiresidue analysis in bee pollen samples using gas and liquid chromatography coupled to tandem mass spectrometry. AB - Several clean-up methods were evaluated for 253 pesticides in pollen samples concentrating on efficient clean-up and the highest number of pesticides satisfying the recovery and precision criteria. These were: (a) modified QuEChERS using dSPE with PSA+C18; (b) freeze-out prior to QuEChERS using dSPE with PSA+C18; (c) freeze-out prior to QuEChERS using dSPE with PSA+C18+Z-Sep; and (d) freeze-out followed by QuEChERS using dSPE with PSA+C18 and SPE with Z-Sep. Determinations were made using LC-MS/MS and GC-MS/MS. The modified QuEChERS protocol applying a freeze-out followed by dSPE with PSA+C18 and SPE clean-up with Z-Sep was selected because it provided the highest number of pesticides with mean recoveries in the 70-120% range, as well as relative standard deviations (RSDs) typically below 20% (12.2% on average) and ensured much better removal of co-extracted matrix compounds of paramount importance in routine analysis. Limits of quantification at levels as low as 5MUgkg(-1) were obtained for the majority of the pesticides. The proposed methodology was applied to the analysis of 41 pollen bee samples from different areas in Spain. Pesticides considered potentially toxic to bees (DL50<2MUg/bee) were detected in some samples with concentrations up to 72.7MUgkg(-1), which could negatively affect honeybee health. PMID- 26654831 TI - Thiol-ene microfluidic devices for microchip electrophoresis: Effects of curing conditions and monomer composition on surface properties. AB - Thiol-ene polymer formulations are raising growing interest as new low-cost fabrication materials for microfluidic devices. This study addresses their feasibility for microchip electrophoresis (MCE) via characterization of the effects of UV curing conditions and aging on the surface charge and wetting properties. A detailed comparison is made between stoichiometric thiol-ene (1:1) and thiol-ene formulations bearing 50% molar excess of allyls ("enes"), both prepared without photoinitiator or other polymer modifiers. Our results show that the surface charge of thiol-ene 1:1 increases along with increasing UV exposure dose until a threshold (here, about 200J/cm(2)), whereas the surface charge of thiol-ene 2:3 decreases as a function of increasing UV dose. However, no significant change in the surface charge upon storage in ambient air was observed over a period of 14 days (independent of the curing conditions). The water contact angles of thiol-ene 2:3 (typically 70-75 degrees ) were found to be less dependent on the UV dose and storing time. Instead, water contact angles of thiol ene 1:1 slightly decrease (from initial 90 to 95 degrees to about 70 degrees ) as a function of UV increasing exposure dose and storing time. Most importantly, both thiol-ene formulations remain relatively hydrophilic over extended periods of time, which favors their use in MCE applications. Here, MCE separation of biologically active peptides and selected fluorescent dyes is demonstrated in combination with laser-induced fluorescence detection showing high separation efficiency (theoretical plates 8200 per 4cm for peptides and 1500-2700 per 4cm for fluorescent dyes) and lower limits of detection in the sub-MUM (visible range) or low-MUM (near-UV range) level. PMID- 26654832 TI - Update 1 of: Destruction and Detection of Chemical Warfare Agents. PMID- 26654833 TI - Anthropometric evaluation of cockpit designs. AB - The objective of this research is to evaluate all the critical reaches in a cockpit and determine the visual sufficiency of a cockpit to accommodate 90% of potential pilots. While mismatches of measurements with cockpit dimensions are revealed, proposals are made to improve cockpit ergonomics. Regression models were generated to predict and assure adequate exterior vision. Mean, lower and upper control limits of all measurements were found acceptable except eye level. There are very strong positive relationships between stature and eye level (R(2) = 0.972, p < 0.01), and eye level and visual angle (R(2) = 0.994, p < 0.01). Display panel height should be at least 1.645 * SD smaller than the eye level mean or seating adjustment limits in height may be changed. In general, cockpit design is acceptable in terms of fit/reach accommodation for pilots, except eye level and visual variables that could be solved by better seat adjustments. PMID- 26654834 TI - [Placement of pH-monitoring probes using height-related formulas. Is it an applicable method to adults?]. AB - INTRODUCTION: Oesophageal pH-monitoring allows the quantification of gastric reflux episodes in patients with gastroesophageal reflux disease (GERD). The accuracy of the test depends on correct positioning of the pH sensor 5 cm above the lower oesophageal sphincter (LES). The most precise manner to locate the LES is through prior determination by oesophageal manometry. However, because this technique is uncomfortable, mathematical formulas tend to be used in children. OBJECTIVES: To evaluate the applicability of paediatric formulas to estimate oesophageal length in adults and their effect on diagnostic accuracy. MATERIAL AND METHODS: A prospective study was carried out in adult patients, in whom the distance between the nasal orifice and the LES was determined by manometry and was compared with the estimated height-related distance calculated by four paediatric formulas (numbered 1 to 4). We also evaluated the relationship between the position of the probe and the percentage of reflux detected in our series of impedance measurements. RESULTS: Formula 1 (9.31 + height in cm * 0.197) was the most accurate (comparison of means -0.38 with 95%CI -0.70/-0.06, P = .019). With this formula, none of the patients had estimation errors of +/- 6 cm. With formulas 2, 3 and 4, the percentage of error was 4.4%, 1.5% and 32.0%, respectively. CONCLUSION: Oesophageal length estimation in adults by using formula 1 is acceptable and can be used in adult patients who refuse to undergo prior manometry. PMID- 26654835 TI - Synthesis and Biological Evaluation of a Teixobactin Analogue. AB - The first synthesis and biological activity of a teixobactin analogue is reported. Substitution of the unusual L-allo-enduracididine residue by the naturally occurring L-arginine was achieved, and the analogue gave an activity trend similar to that of teixobactin (against Gram-postive bacteria) and meropenem, which was approved by the FDA in 1996. The synthetic route used allows for the synthesis of the natural product as well as the development of a program of medicinal chemistry. PMID- 26654836 TI - Electromagnetic Induction of Zerovalent Iron (ZVI) Powder and Nanoscale Zerovalent Iron (NZVI) Particles Enhances Dechlorination of Trichloroethylene in Contaminated Groundwater and Soil: Proof of Concept. AB - This study evaluates the concept of using zerovalent iron (ZVI) powder or nanoscale zerovalent iron (NZVI) particles in combination with a low frequency (150 kHz) AC electromagnetic field (AC EMF) to effectively remove trichloroethylene (TCE) from groundwater and saturated soils. ZVI and NZVI are ferromagnetic, which can induce heat under applied AC EMF. The heat generated by ZVI and NZVI induction can increase the rate of dechlorination, according to Arrhenius' equation, and increase the rate of TCE desorption from TCE-sorbed soil. Both dechlorination and TCE desorption enhance the overall TCE removal rate. We evaluated this novel concept in laboratory batch reactors. We found that both ZVI and NZVI can induce heat under applied AC EMF up to 120 degrees C in 20 min. Using ZVI and NZVI with AC EMF enhanced dechlorination of dissolved TCE (no soil) up to 4.96-fold. In addition to increasing the temperature by ZVI and NZVI induction heating, AC EMF increased intrinsic ZVI and NZVI reactivity, ostensibly due to accelerated corrosion, as demonstrated by the increased ORP. In a soil water-TCE system, NZVI together with AC EMF thermally enhanced desorption of TCE from soil and increased the degradation of TCE up to 5.36-fold compared to the absence of AC EMF. For the first time, this study indicates the potential for ZVI and NZVI coupled with AC EMF as a combined remediation technique for increasing the rate and completeness of in situ cleanup of adsorbed phase contaminants. PMID- 26654837 TI - The epidemiology of homicidal strangulation in the City of Johannesburg, South Africa. AB - Studies that provide accurate descriptions of the occurrence of fatal strangulation events are limited, both in South Africa and elsewhere in the world. The current study describes the extent and distribution of female and male homicidal strangulation in the City of Johannesburg for the period 2001-2010. The study is a register-based cross sectional study of homicidal strangulation that draws on data recorded by the National Injury Mortality Surveillance System. Crude, unadjusted strangulation rates, and proportions of strangulation across specific circumstances of occurrence were computed for each year and aggregated in some instances. Results indicated fatal strangulation to be the fourth leading cause of homicide in the City of Johannesburg. A total of 334 strangulation homicides were recorded, representing an average annual strangulation homicide rate of 0.90 per 100,000 population. Gender disproportionality in victimisation was reflected in the average annual rate of 1.03 per 100,000 population for females and 0.74 per 100,000 population for males. The highest rates were recorded among the elderly, and amongst coloured females and white males. Temporal and spatial descriptions indicated that victims were strangled primarily during the day, over the weekday period, and in private locations. When the scene of death was considered by race and age group, results indicated the victimisation of white females and males in private places, and the elderly in private settings. The majority of strangulation victims tested negative for alcohol. The results highlight the need for multi-level prevention strategies that target specific risk groups and situations. PMID- 26654838 TI - Anal manifestation of sarcoidosis. PMID- 26654839 TI - Slow Stream Rehabilitation: A New Model of Post-Acute Care. AB - OBJECTIVES: To identify characteristics and outcomes of elderly patients admitted to a slow stream, low-intensity, and long-duration inpatient rehabilitation (SSR) program after an acute hospitalization because they were unable to tolerate traditional inpatient rehabilitation. DESIGN: Single group pre-post study with assessments conducted on admission and discharge. SETTING: Baycrest's 30-bed SSR Unit in Toronto, Ontario, Canada. PARTICIPANTS: A total of 104 patients older than 60 years admitted between September 2011 and December 2012. MEASUREMENTS: Admission assessments included demographic data, Functional Independence Measure (FIM), and ability to ambulate. Discharge outcomes included change in motor and total FIM scores from admission to discharge, discharge residential status, and length of stay. RESULTS: Mean age was 81.6 +/- 8.4 years and 68.3% were women. Mean changes in motor and total FIM were 21.0 +/- 12.2 (P < .001) and 22.6 +/- 14.0 (P < .001), respectively. On admission, only 30.8% of patients were ambulatory even with mobility assistive devices, while on discharge, 68.3% of patients were ambulatory; 61.5% of patients returned to their preadmission living arrangement; 8.6% went from their own home to a retirement or relative's home. Only 16.3% were discharged to long-term nursing home care and 13.4% were transferred to an acute hospital. Mean length of SSR stay was 82.5 +/- 26.4 days. CONCLUSION: SSR programs can benefit elderly patients at risk for institutionalization after acute hospitalization by improving their functioning and mobility, and allowing them to return to the community. PMID- 26654840 TI - Quality of Life in Older Adults Receiving Long-Term Services and Supports: Is It What We Think It Is? PMID- 26654841 TI - Delivery of siRNA Complexed with Palmitoylated alpha-Peptide/beta-Peptoid Cell Penetrating Peptidomimetics: Membrane Interaction and Structural Characterization of a Lipid-Based Nanocarrier System. AB - Proteolytically stable alpha-peptide/beta-peptoid peptidomimetics constitute promising cell-penetrating carrier candidates exhibiting superior cellular uptake as compared to commonly used cell-penetrating peptides (CPPs). The aim of the present study was to explore the potential of these peptidomimetics for delivery of small interfering RNA (siRNA) to the cytosol by incorporation of a palmitoylated peptidomimetic construct into a cationic lipid-based nanocarrier system. The optimal construct was selected on the basis of the effect of palmitoylation and the influence of the length of the peptidomimetic on the interaction with model membranes and the cellular uptake. Palmitoylation enhanced the peptidomimetic adsorption to supported lipid bilayers as studied by ellipsometry. However, both palmitoylation and increased peptidomimetic chain length were found to be beneficial in the cellular uptake studies using fluorophore-labeled analogues. Thus, the longer palmitoylated peptidomimetic was chosen for further formulation of siRNA in a dioleoylphosphatidylethanolamine/cholesteryl hemisuccinate (DOPE/CHEMS) nanocarrier system, and the resulting nanoparticles were found to mediate efficient gene silencing in vitro. Cryo-transmission electron microscopy (cryo TEM) revealed multilamellar, onion-like spherical vesicles, and small-angle X-ray scattering (SAXS) analysis confirmed that the majority of the lipids in the nanocarriers were organized in lamellar structures, yet coexisted with a hexagonal phase, which is important for efficient nanocarrier-mediated endosomal escape of siRNA ensuring cytosolic delivery. The present work is a proof-of concept for the use of alpha-peptides/beta-peptoid peptidomimetics in an efficient delivery system that may be more generally exploited for the intracellular delivery of biomacromolecular drugs. PMID- 26654842 TI - Discontinuation of enzyme replacement therapy in Fabry disease in the Dutch cohort. AB - Fabry disease (FD) is a progressive, multi-organ, lysosomal storage disease. Enzyme replacement therapy (ERT) is available for the treatment of the disease. While the reasons to initiate ERT have been frequently discussed, discontinuation of ERT is rarely reported. In this paper we describe our experiences with stopping ERT in FD. From 1999 through 2015, twenty-one patients discontinued ERT. These patients were generally older and more severely affected in comparison those who continued ERT. The reason to discontinue ERT switched from death or terminal illness in the first years towards treatment failure in more recent years. Three cases are described in more detail. We conclude that discontinuation of ERT should or may be considered in subgroups of FD patients although further studies on the effectiveness of ERT in subgroups of patients and the course of the disease after discontinuation of ERT are needed. PMID- 26654843 TI - Antiviral agents against equid alphaherpesviruses: Current status and perspectives. AB - Equid herpesvirus infections cause respiratory, neurological and reproductive syndromes. Despite preventive and control measures and the availability of vaccines and immunostimulants, herpesvirus infections still constitute a major threat to equine health and for the equine industry worldwide. Antiviral drugs, particularly nucleoside analogues and foscarnet, are successfully used for the treatment of human alphaherpesvirus infections. In equine medicine, the use of antiviral medications in alphaherpesvirus infections would decrease the excretion of virus and diminish the risk of contagion and the convalescent time in affected horses, and would also improve the clinical outcome of equine herpesvirus myeloencephalopathy. The combined use of antiviral compounds, along with vaccines, immune modulators, and effective preventive and control measures, might be beneficial in diminishing the negative impact of alphaherpesvirus infections in horses. The purpose of this review is to analyse the available information regarding the use of antiviral agents against alphaherpesviruses, with particular emphasis on equine alphaherpesvirus infections. PMID- 26654844 TI - The importance of muscarinic receptors in domestic animal diseases and therapy: Current and future perspectives. AB - This review provides an overview of the early and current literature including contributions that highlight the parasympathetic cholinergic receptor systems in domestic animal tissues. Muscarinic acetylcholine receptors (mAChRs) belong to the subfamily of G protein-coupled receptors and regulate many fundamental functions of the central and peripheral nervous systems and have been subject to research over at least 40 years. Nonetheless, there are few studies specifying mAChRs in domestic animal tissues. This review focuses on the pharmacology of muscarinic acetylcholine receptor (mAChR) system and its pathological as well as the therapeutic importance in organ systems of domestic animals. Illustration and discussion of recent advances in distribution, function, biochemistry and pharmacology of mAChRs are followed by summaries of the involvement of this family of receptors in cardiovascular, respiratory, neurological, gastrointestinal (GI) and urological diseases as well as in anaesthesia and toxicology. Specific functions of mAChRs are described in detail including subtype characterization, smooth muscle functions, signal transduction and regulation. Due to their wide tissue distribution, mAChRs have shown promise as targets for the treatment of some animal diseases such as equine recurrent airway obstruction, glaucoma, abnormalities of gastric acid secretion and GI disturbances including colic. PMID- 26654845 TI - A 2.5 year study on health and locomotion symmetry in young Standardbred horses subjected to two levels of high intensity training distance. AB - The aim of this study was to document effects of two high-intensity training regimes on horse health. Sixteen Standardbred horses in training from September as 1-year-olds with the goal to race as 3-year-olds were used in a 2.5 year study. Horses were trained in either a control training program (C-group) or in a program with 30% reduced high intensity distance compared to the C-group (R group). Clinical examinations were performed nine times. Locomotion asymmetry was registered with a sensor-based system 17 times. There was no difference in health scores, locomotion asymmetry or veterinary treatments between groups. Subjective lameness score and objective front limb locomotion asymmetry increased during the spring both as 2- and 3-year-olds after introduction of speed- and uphill interval training but decreased during winter. Hind limb locomotion asymmetry increased during spring as 2-year-olds and was still above initial level in December as 3-year-olds. Horses that qualified for races early had less asymmetric front limb locomotion and were less lame in clinical examinations (0.7 +/- 0.3 vs. 1.6 +/- 0.2 degrees [AAEP scale], P = 0.04) than late qualifiers. Days lost to training were higher in C-group than in R-group (27 +/- 3% and 17 +/ 3%, P = 0.029). It is concluded that (1) less days may be lost to training by reducing the high intensity training distance and (2) the introduction of new training may alter locomotion asymmetry and this can be detected with objective locomotion analysis. PMID- 26654846 TI - A new technique using roentgen stereophotogrammetry to measure changes in the spatial conformation of bovine hind claws in response to external loads. AB - Claw and locomotion problems are widespread in ungulates. Although it is presumed that mechanical overload is an important contributor to claw tissue damage and impaired locomotion, deformation and claw injury as a result of mechanical loading has been poorly quantified and, as a result, practical solutions to reduce such lesions have been established mostly through trial and error. In this study, an experimental technique was developed that allowed the measurement under controlled loading regimes of minute deformations in the lower limbs of dissected specimens from large ungulates. Roentgen stereophotogrammetric analysis (RSA) was applied to obtain 3D marker coordinates with an accuracy of up to 0.1 mm with optimal contrast and to determine changes in the spatial conformation. A force plate was used to record the applied forces in three dimensions. The results obtained for a test sample (cattle hind leg) under three loading conditions showed that small load-induced deformations and translations as well as small changes in centres of force application could be measured. Accuracy of the order of 0.2-0.3 mm was feasible under practical circumstances with suboptimal contrast. These quantifications of claw deformation during loading improve understanding of the spatial strain distribution as a result of external loading and the risks of tissue overload. The method promises to be useful in determining load-deformation relationships for a wide variety of specimens and circumstances. PMID- 26654847 TI - Association between Pneumocystis spp. and co-infections with Bordetella bronchiseptica, Mycoplasma hyopneumoniae and Pasteurella multocida in Austrian pigs with pneumonia. AB - In this retrospective study, 218 pig lung tissue samples were analyzed to examine a possible association between Pneumocystis spp. using in situ hybridization, Bordetella bronchiseptica (B.b.) using immunohistochemistry (IHC), Mycoplasma hyopneumoniae (M.h.) by quantitative PCR, and Pasteurella multocida (P.m.; IHC). Compared to the bacterial agents (B.b., 5%; M.h., 30%; P.m., 23%), Pneumocystis occurred with a higher prevalence (51%). Co-infections with two or three pathogens were present in 28% of the examined cases. Those of Pneumocystis and M.h. were most commonly seen, followed by Pneumocystis and P.m. and M.h. and P.m. Histologically, interstitial pneumonia was found in both the Pneumocystis positive lungs and lungs with a mild M.h. infection. The B.b. and P.m. positive lungs were mainly associated with suppurative bronchopneumonia and severe M.h. cases with fibrinous or fibrino-haemorrhagic pneumonia. In suckling piglets, the number of samples positive for Pneumocystis predominated, whereas samples from fattening pigs were mainly positive for bacteria or Pneumocystis and bacteria. PMID- 26654848 TI - Factors Associated With Delays in Seeking Medical Attention in Patients With ST segment Elevation Acute Coronary Syndrome. AB - INTRODUCTION AND OBJECTIVES: Prompt coronary reperfusion is crucial in patients with ST-segment elevation acute coronary syndrome. The aim of this study was to determine factors associated with a delay in seeking medical attention after the onset of symptoms in patients with this condition. METHODS: Prospective cohort study in consecutive patients with ST segment elevation infarction. Multiple logistic regression analysis was used to identify factors independently associated with a longer delay in requesting medical help. RESULTS: In total, 444 consecutive patients were included (mean age, 63 years; 76% men, 20% with diabetes). Median total ischemia time was 225 (160-317) minutes; median delay in seeking medical attention was 110 (51-190) minutes. Older patients (age > 75 years; odds ratio = 11.6), women (odds ratio = 3.4), individuals with diabetes (odds ratio = 2.3), and those requesting medical care from home (odds ratio = 2.2) showed the longest delays in seeking medical attention. Lengthy delay was associated with higher in-hospital mortality (9.8% vs 2.7%; P<.005) and 1-year mortality (7.3% vs 2.9%; P<.05) than when attention was promptly solicited. CONCLUSIONS: Elderly patients, women, and diabetic individuals with ST-segment elevation myocardial infarction show longer delays in seeking medical attention for their condition. Delays in seeking medical attention are associated with greater in-hospital and 1-year mortality. PMID- 26654849 TI - The Ups and Downs of Genetic Diagnosis of Hypertrophic Cardiomyopathy. AB - Massive DNA sequencing, also known as next-generation sequencing, has revolutionized genetic diagnosis. This technology has reduced the effort and cost needed to analyze several genes simultaneously and has made genetic evaluation available to a larger number of patients. In hypertrophic cardiomyopathy, genetic analysis has increased from the 3 main genes implicated in the disease (MYH7, MYBPC3, TNNT2) to sequencing of more than 20 related genes. Despite the advantages of acquiring this additional information, many patients show variants of uncertain significance (mainly amino acid changes), which may also be present in at least 1 healthy control undergoing genome sequencing. This will be a dead end situation unless the variant can be demonstrated to be associated with the disease in the patient's family. In the absence of clear evidence that these variants are truly pathogenic, they cannot be used for reliable genetic counselling in family members. Massive sequencing also enables identification of new candidate genes, but again, the problem of variants of uncertain significance limits the success of these assessments. PMID- 26654850 TI - [Considerations regarding sedentary and physical inactivity]. PMID- 26654851 TI - A Spatiotemporal Approach to the Objective Analysis of Initiation and Termination of Vocal-fold Oscillation With High-speed Videoendoscopy. AB - High-speed videoendoscopy excels in the ability to observe the vocal-fold oscillatory patterns during voice initiation and termination. The initial and most critical step in the analysis of these transient regions is to identify the locations of these transient periods, that is, determining when the vocal-fold oscillation is absent and when the oscillation has reached its steady-state behavior. The latter is more challenging as the "steady" oscillation during sustained phonation is not truly steady and is expected to vary over time. This variation may cause unreliable identification of the transient periods, possibly resulting in less accurate or less reliable parameter measurements. An oscillation feature that is relatively consistent in the steady state is the glottal length, that is, the extent of the oscillation along vocal folds. This paper proposes an autonomous algorithm to estimate the vocal-fold oscillation length and its use to detect four transient events: oscillation onset and offset, and attainment and loss of full-length oscillation. The detected event markers are intended to be used to improve the transient parameter measurements. The autonomous algorithm manipulates the set of glottal width waveforms spatiotemporally to estimate the oscillation length. Examples with in vivo high speed videoendoscopy recordings of both normal and pathological cases are included to show the efficacy of the proposed algorithm to identify the transient markers. PMID- 26654852 TI - Use of cardiovascular medicines in newly treated type 2 diabetes patients: A retrospective cohort study in general practice. AB - AIMS: To describe the drug utilisation patterns of aspirin, antihypertensives, vasodilators, and statins in a cohort of newly treated type 2 diabetes subjects previously unexposed to CVD agents. METHODS: A population-based retrospective cohort study was conducted using a national pharmacy claims database of newly treated type 2 diabetes subjects aged 40 years or older. Data on the use of aspirin, antihypertensives, vasodilators, and statins 1 year after antidiabetic agent initiation were analysed. Poisson regression with a robust error variance was used to estimate adjusted relative risk (RRadj) and 95% CIs between socio demographic and treatment factors on CVD agent use. RESULTS: Over a 2-year period (2008-2009), 6093 subjects were identified. One year after antidiabetic agent initiation, 82% of the study population received at least one CVD agent, with 54% receiving aspirin, 64% receiving antihypertensives, 6% vasodilators, and 62% receiving statins. Subjects aged 40-49 years were significantly less likely than those aged 60-69 years to receive CVD agents (RRadj 0.83, 95% CI 0.80-0.87). Over 40% of subjects received antihypertensives without aspirin and statins, while 30% of subjects on statins did not receive aspirin. CONCLUSIONS: Substantial CVD agent utilisation was noted 1 year after antidiabetic agent initiation. Being aged younger than 60-69 years was associated with decreased utilisation of CVD agents. PMID- 26654853 TI - Assessing the connection between organophosphate pesticide poisoning and mental health: A comparison of neuropsychological symptoms from clinical observations, animal models and epidemiological studies. AB - Psychiatry and psychology are beginning to recognize the importance of lead, mercury and heavy metals as causal partners in the development of mental disorders. Further, mental health researchers and clinicians are embracing the idea that the combined effects of genetics and environmental exposures can result in perturbations in brain neurochemistry leading to psychiatric disorders. The purpose of this review is to examine the biological foundations for the epidemiological observations previously identified by reviewing the toxicology literature and relating it to epidemiological studies addressing the role of poisoning with organophosphate pesticides (OPs) in neurobehavioral and neuropsychological disorders. The goal of this review is to raise awareness in the mental health community about the possibility that affective disorders might be the result of contributions from environmental and occupational pesticide poisoning. PMID- 26654854 TI - Selecting appropriate designs and comparison conditions in repetition paradigms. AB - The studies described by Vogels (this issue) demonstrate the complexity of repetition effects in the visual processing stream. In addition to signal suppression, findings of inherited effects from earlier processing, and discrepancies between the stimulus selectivity of cells before and after repetition, have informed the inferences that can be drawn from measures over larger scales such as functional magnetic resonance imaging (fMRI) or electroencephalography (EEG). This work also demonstrates that integration of evidence across recording methods is vital for understanding repetition effects in the brain. It is however difficult to integrate evidence across different recording methods and repetition paradigms. At the crux of this difficulty is the selection of comparison or unrepeated stimulus conditions within paradigms, which influence the observed strength, selectivity and even direction of repetition effects. This viewpoint highlights prevalent methodological issues with regard to repeated-unrepeated stimulus comparisons: inherited adaptation, stimulus specific expectations, concurrent memory retrieval, stimulus novelty and familiarity, attention, and changes in neuronal selectivity with repetition. The extent to which current conflicting and uncertain findings are due to selection of unrepeated stimulus conditions is unknown, but needs to be addressed to develop models of repetition spanning recording methods and repetition paradigms. PMID- 26654855 TI - A Conformational Switch Triggers Nitrogenase Protection from Oxygen Damage by Shethna Protein II (FeSII). AB - The two-component metalloprotein nitrogenase catalyzes the reductive fixation of atmospheric dinitrogen into bioavailable ammonium in diazotrophic prokaryotes. The process requires an efficient energy metabolism, so that although the metal clusters of nitrogenase rapidly decompose in the presence of dioxygen, many free living diazotrophs are obligate aerobes. In order to retain the functionality of the nitrogen-fixing enzyme, some of these are able to rapidly "switch-off" nitrogenase, by shifting the enzyme into an inactive but oxygen-tolerant state. Under these conditions the two components of nitrogenase form a stable, ternary complex with a small [2Fe:2S] ferredoxin termed FeSII or the "Shethna protein II". Here we have produced and isolated Azotobacter vinelandii FeS II and have determined its three-dimensional structure to 2.1 A resolution by X-ray diffraction. In the crystals, the dimeric protein was present in two distinct states that differ in the conformation of an extended loop in close proximity to the iron-sulfur cluster. We show that this rearrangement is redox-dependent and forms the molecular basis for oxygen-dependent conformational protection of nitrogenase. Protection assays highlight that FeSII binds to a preformed complex of MoFe and Fe protein upon activation, primarily through electrostatic interactions. The surface properties and known complexes of nitrogenase component proteins allow us to propose a model of the conformationally protected ternary complex of nitrogenase. PMID- 26654856 TI - Lilium floral fragrance: A biochemical and genetic resource for aroma and flavor. AB - Hybrid Lilium (common name lily) cultivars are among the top produced domestic fresh cut flowers and potted plants in the US today. Many hybrid Lilium cultivars produce large and showy flowers that emit copious amounts of volatile molecules, which can negatively affect a consumer's appreciation or limit use of the plant product. There are few publications focused on the biochemistry, genetics, and/or molecular regulation of floral volatile biosynthesis for Lilium cultivars. In an initial pursuit to provide breeders with molecular markers for floral volatile biosynthesis, a total of five commercially available oriental and oriental trumpet hybrid Lilium cultivars were selected for analytical characterization of floral volatile emission. In total, 66 volatile molecules were qualified and quantitated among all cultivars. Chemical classes of identified volatiles include monoterpene hydrocarbons, monoterpene alcohols and aldehydes, phenylpropanoids, benzenoids, fatty-acid-derived, nitrogen-containing, and amino-acid-derived compounds. In general, the floral volatile profiles of the three oriental-trumpet hybrids were dominated by monoterpene hydrocarbons, monoterpene alcohols and aldehydes, while the two oriental hybrids were dominated by monoterpene alcohols and aldehydes and phenylpropanoids, respectively. Tepal tissues (two petal whirls) emitted the vast majority of total volatile molecules compared to the reproductive organs of the flowers. Tepal volatile profiles were cultivar specific with a high degree of distinction, which indicates the five cultivars chosen will provide an excellent differential genetic environment for gene discovery through comparative transcriptomics in the future. Cloning and assaying transcript accumulation from four floral volatile biosynthetic candidates provided few immediate or obvious trends with floral volatile emission. PMID- 26654857 TI - Current and Emerging Pharmacotherapies for Weight Management in Prediabetes and Diabetes. AB - Type 2 diabetes is a serious chronic disease that is associated with increased morbidity and premature mortality. It has become the tsunami of noncommunicable diseases, with more than 400 million people worldwide currently living with diabetes. The global diabetes epidemic is driven by rising obesity rates. Excess body fat increases the risk for insulin resistance and prediabetes; obese men and women, respectively, have a 7-fold and 12-fold higher risk for developing type 2 diabetes. Obesity also predisposes to the development of a myriad of medical complications leading to increased morbidity and mortality. Each increase in body mass index of 5 kg/m(2) or higher is, on average, associated with about a 30% higher overall mortality rate. Modest weight loss through health-behaviour modification can significantly prevent or delay the onset of type 2 diabetes in people at risk. Each kg of body weight loss is associated with a 16% relative reduction in diabetes risk. Intentional weight loss is also associated with a 15% reduction in all-cause mortality. Unfortunately, health-behaviour modification alone seldom sustains adequate weight loss to achieve the desired health outcomes, especially in people with diabetes who already have greater difficulty losing weight. Pharmacotherapy is a realistic treatment option as an adjunct to diet and exercise. In addition to orlistat, the glucagon-like peptide-1 receptor agonist liraglutide has recently been approved in Canada for the treatment of obesity in doses of up to 3.0 mg daily. This review is focused on current and emerging pharmacotherapies for obesity in people with prediabetes or diabetes. PMID- 26654858 TI - Impact of Current and Emerging Glucose-Lowering Drugs on Body Weight in Type 2 Diabetes. AB - Type 2 diabetes is a progressive disease, and most people with diabetes will eventually require adjunctive pharmacotherapy to optimize their glycemic control. As the majority of people with type 2 diabetes are overweight or obese, weight management is an essential component of diabetes management to improve their overall health and quality of life. Many of the currently available glucose lowering drugs are associated with weight gain, which makes it challenging for both prescribing clinicians and patients. The 2015 Canadian Diabetes Association Clinical Practice Guidelines interim update on the pharmacologic management of type 2 diabetes recommend individualization of therapy and glycemic targets. Clinicians should take into consideration not only the drug's efficacy and safety profiles but also its propensity for causing hypoglycemia and weight gain. Given that the number of glucose-lowering drugs is expanding rapidly, a better understanding of the impacts of current and emerging therapies on body weight will serve as a useful guide. Metformin remains the first-line drug after diet and exercise therapy. The next add-on agent could be selected from the incretin or sodium-glucose cotransporter-2 inhibitor class because these drugs rarely cause hypoglycemia and may lead to modest weight loss. When insulin therapy is considered, choosing a basal insulin that is associated with less nocturnal hypoglycemia and weight gain is recommended. Emerging therapies using combination therapy of an incretin-sodium-glucose cotransporter 2 inhibitor or glucagon-like peptide-1 agonist-basal insulin hold promise to achieve robust glycemic control with weight loss and low risk for hypoglycemia. PMID- 26654859 TI - The Role of Hypoglycemia in Cardiovascular Outcomes in Diabetes. AB - Intensive glucose management, targeting lower glycated hemoglobin (A1C) levels, has been shown to reduce the microvascular complications of diabetes, but the effect on cardiovascular (CV) outcomes is less clear. Observational follow-up of intensive glucose management studies suggest possible long-term CV benefits, but no clear reduction in CV events has been seen over 3 to 5 years. Intensive glucose management also increases the risk for hypoglycemia, particularly in patients with longstanding diabetes, cognitive impairment and hypoglycemia unawareness. Severe hypoglycemia has been linked to adverse consequences, including cardiac dysrhythmias, CV events and death, but the precise role of hypoglycemia in CV outcomes is uncertain. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial was terminated early because of a higher rate of CV events in the intensive arm. Post hoc analyses of ACCORD and other trials suggest that cardiac autonomic neuropathy may be a predisposing factor to CV events. The Analyses of the Action in Diabetes and Vascular Disease (ADVANCE) trial and the Veterans Affairs Diabetes Trial (VADT) showed that subjects with severe hypoglycemia had more frequent adverse outcomes. However, rather than causing adverse events, it appears that severe hypoglycemia may be a marker of vulnerability for such events. This review focuses on the current understanding of the association between hypoglycemia and CV risk. PMID- 26654860 TI - The Role of the Kidney and SGLT2 Inhibitors in Type 2 Diabetes. AB - Effective glycemic control reduces the risk for diabetes-related complications. However, the majority of patients with type 2 diabetes still do not achieve glycemic targets. Beyond metformin therapy, current practice guidelines for the management of type 2 diabetes recommend individualized treatment based on patient and agent characteristics. The sodium glucose cotransporter type 2 (SGLT2) inhibitors represent a novel treatment strategy, independent of impaired beta cell function and insulin resistance. SGLT2 inhibitors decrease renal glucose reabsorption, thereby increasing urinary glucose excretion with subsequent reduction in plasma glucose levels and glycosylated hemoglobin concentrations. Current evidence suggests that they are effective as monotherapy or as add-ons to metformin either alone, or in combination with other oral glucose-lowering agents or insulin. They are generally well tolerated, though rates of lower urinary tract and genital mycotic infections are slightly increased. The advantages of this class include modest reductions in body weight and blood pressure, and low risk for hypoglycemia. Long-term safety data and results of ongoing cardiovascular outcome studies are awaited so we can fully understand the role that SGLT2 inhibitors will play in the comprehensive management of type 2 diabetes. PMID- 26654861 TI - Cardiovascular Safety of Current and Emerging Glucose-Lowering Therapies. PMID- 26654862 TI - Successful use of "Hour 1" transfer of sperm microinjected oocytes in natural cycles of poor responder women: a prospective randomized controlled pilot study. AB - The aim of the study is to demonstrate the successful use of "Hour 1" transfer of sperm microinjected oocytes in natural cycles of poor responder women. Seventy women were selected from 92 consecutive poor responders undergoing intracytoplasmatic sperm injection (ICSI) in a natural cycle at our Sterility and Assisted Reproduction Unit from September 2009 to July 2013, and randomly distributed in two homogeneous groups: Group A or B. Women in Group A (35) underwent transfer within 1 h after ICSI; Group B (35, control group) underwent transfer 3 days after ICSI. In Group A, seven clinical pregnancy and one miscarriage occurred; in Group B, eight clinical pregnancies and two miscarriages were observed. Pregnancy, miscarriage, term pregnancy and overall live birth rates' difference between the two groups was not statistically significant (p > 0.05). Difference between the two groups in terms of timing, type of delivery and newborn birthweight was not observed. Neither ectopic pregnancy nor multiple pregnancies occurred. "Hour 1" uterine transfer of ICSI oocytes, still to be considered with caution because of the relatively low number of observations of the pilot study, deserves further attention on a larger scale, and might be evaluated for clinical and financial effectiveness in other clinical settings. PMID- 26654863 TI - Expressions of shame in investigative interviews with Australian Aboriginal children. AB - This study inspected a sample of 70 interview transcripts with Australian Aboriginal children to gain a sense of how frequently verbal shame responses were occurring in investigative interviews regarding alleged sexual abuse. Transcripts were examined to determine how children articulated shame, how interviewers reacted to these responses, and how shame related to children's accounts. Examination of frequencies revealed that verbal shame responses occurred in just over one-quarter of the interviews. One-way analyses of variance indicated that children who expressed shame within the interview spoke the same amount as children who did not express shame, however, they required more interviewer prompts before a disclosure was made. Interviews where children expressed shame also included a greater number of interviewer reminders compared to interviews without shame responses. Results emphasize the importance of interviewer awareness of shame, and also point to the value of reassurance, patience, and persistence with non-leading narrative prompting when interviewing children who express shame during discussions of sexual abuse. PMID- 26654864 TI - Community service contracting for older people in urban China: a case study in Guangdong Province. AB - Contracting of community services to non-governmental service-providing organisations - mainly social work agencies - is an emerging phenomenon and a social innovation with regard to delivering community services in urban China. Contracting of community services for the older person, which is the focus of this study, is embedded in the macro context of the development of social service contracting in China. Qualitative research techniques, including document analysis, case study, participant observation and in-depth interviews, were adopted for this study. Nine government officials, three staff working in Community Residents' Committees, 15 staff working in social work agencies and 41 older people were interviewed in an effort to understand the impact and challenges of community service contracting in urban China. The findings showed that the involvement of social work agencies in the community service provision system results in integration of community resources, expansion of service coverage and enhancement of older people's access to community services. However, several problems may impede the development of community service provision in the context of contracting in China. These include purchaser-oriented rather than user-oriented service provision, older people's negative attitude towards social work services, inappropriate performance measurement, reliance of non-government organisations on government funding and ambiguous definition of community services. PMID- 26654865 TI - Intestinal stem cells and inflammation. AB - The intestinal epithelium is renewed every 3-5 days from at least two principal stem cell pools. Actively cycling crypt based columnar (CBC) Lgr5(+) cells and slower cycling Bmi1-expressing or Krt19-expressing cells maintain the small intestinal and colonic epithelium in homeostasis and injury. Following acute epithelial damage, Lgr5+ stem cells are susceptible to injury and a reserve stem cell or progenitor pool is responsible for regeneration of the epithelium. Current data suggests that intestinal stem cells respond to inflammatory signals to modulate their expansion during epithelial regeneration. Here, we review how inflammation and injury affect intestinal and colonic stem cells. PMID- 26654866 TI - The relationship between cadaver, living and forensic stature: A review of current knowledge and a test using a sample of adult Portuguese males. AB - The use of cadaver length and forensic stature as a proxy for living standing height has not been scrutinized in detail. In this paper we present a brief review of the current knowledge on the relationship between cadaver, living and forensic stature; assess the magnitude and nature of the differences between these three measures of stature; and investigate the potential impact of these differences in forensic contexts. The study uses a sample of 84 males who were autopsied in 2008 at the National Institute of Legal Medicine and Forensic Sciences (Porto, Portugal), where stature data were collected from three different sources: cadaver stature was obtained from the corpse prior to autopsy, living stature was obtained from military conscription records and forensic stature was obtained from national citizenship identification card records. Descriptive statistics, ANOVA and linear regression are used to analyze the data. The results show that cadaver stature is the highest measure, followed by forensic and by living stature, and the difference between cadaver and living stature is greater than expected (4.3cm). Results also show considerable individual variation in the differences between the three measures of stature and that differences decrease with stature, although only slightly. This study has shown that the difference between cadaver and living stature is greater than previously thought and suggests that previously reported correction factors are a minimum rather than a mean correction. Forensic stature is likely to be incorrectly estimated and can jeopardize identification if methods estimate living rather than forensic stature. PMID- 26654867 TI - Comparison of venous blood alcohol concentrations and breath alcohol concentrations measured with Draeger Alcotest 9510 DE Evidential. AB - Most comparisons of blood alcohol concentrations (BAC) and breath alcohol concentrations (BrAC) are either derived from drinking trials with rigid drinking protocols or from investigative authorities' data with considerable time differences between the determination of BAC and BrAC. In general, only comparisons of relatively low BAC-BrAC pairs are available. Therefore, the relationship between BAC and BrAC was examined even for high BAC above 2g/kg. The results of a large-scale drinking test under realistic conditions with 78 test persons and short time intervals between BAC and BrAC measurements are presented. It was shown that the conversion factor Q varies greatly (between 1571:1 and 2394:1) and increases with increasing BAC. A constant conversion factor that is suitable for variable forensic purposes could not be presented. PMID- 26654868 TI - The Efficacy of Equine-Assisted Activities and Therapies on Improving Physical Function. AB - OBJECTIVE: To summarize the physical benefits of therapeutic horseback riding and hippotherapy and suggest directions for future research. METHODS: Review of databases for peer-reviewed articles related to equine-assisted activities and therapies. Databases included MEDLINE via EBSCO, Web of Science, PubMed, Google Scholar, and Academic Search Complete. Articles were limited to those with full text access published in English since 1987. RESULTS: Acute and residual improvements in physical benefits, such as gross motor function (e.g., walking, running, jumping), spasticity, muscle symmetry, posture, balance, and gait occur in adults and children with varying disabilities. The benefits appear to be greatest following multiweek interventions with one or more sessions per week. Modest acute cardiovascular responses are observed during equine-assisted activities and therapies with little or no evidence for training improvements in heart rate or blood pressure at rest or during riding. CONCLUSION: The present body of literature provides evidence that equine-assisted activities and therapies are an effective means of improving many measures of physical health. However, more controlled trials are urgently needed to strengthen the current knowledge base, establish dose-response characteristics of equine-assisted activities and therapies, and explore the physiologic basis for the promising results suggested from the literature. PMID- 26654870 TI - Self-termination of ventricular fibrillation during transport by emergency medical service. AB - Ventricular fibrillation (VF) is usually sustained, and it typically results in death unless electrical defibrillation is successfully performed within minutes. Although VF has been reported to spontaneously occur in vivo in some animal models and a few cases of self-terminating VF have been documented in clinical practice, no such case has been previously reported involving out-of-hospital emergency medical service(EMS) personnel. We report a case of self-terminating VF due to ST segment elevation myocardial infarction that was documented by continuous electrocardiogram (ECG) strip monitoring. A 70-year-old woman was transported to the emergency department by EMS due to chest discomfort. The EMS personnel monitored her by ECG using an automated external defibrillator with a 3 limb lead. During transport, she developed VF, which persisted for 43 seconds. Chest compression and defibrillation were not applied. The VF self-terminated, after which the patient promptly awoke. Emergency coronary angiography was performed,and a total occlusion of the middle left circumflex coronary artery was treated by percutaneous coronary intervention. Since then, no symptomatic arrhythmia or ST-segment change was detected by continuous ECG monitoring. The patient was discharged home without any sequelae on the fourth hospital day. PMID- 26654869 TI - The impact of sharing personalised clinical information with people with type 2 diabetes prior to their consultation: A pilot randomised controlled trial. AB - AIM: To assess the impact of sharing personalised clinical information with people with type 2 diabetes prior to their out-patient consultation on patient involvement during the consultation, diabetes self-management self-efficacy and glycaemic control. METHODS: A pilot three-arm randomised controlled trial. The 'intervention booklet' group received a booklet including personalised clinical information, a 'general information booklet' control group received a booklet with no personalised clinical information and a 'usual care' control group received no written information. RESULTS: 136 people took part. The intervention group were significantly more likely to have shown the booklet to a 'significant other', (48% V 23%, p<0.05), brought the booklet with them to the clinic (85% V 35%, p<0.005) and to refer to the booklet during the consultation (45% V 13%, p<0.005). No significant differences in patient involvement during the consultation, diabetes management self-efficacy or glycaemic control were found between the three groups. CONCLUSIONS: Although participants found it useful to receive their clinical results, no differences were found in the patient outcomes measured. PRACTICE IMPLICATIONS: Further pilot work on the timing of the intervention, who it is targeted at and what outcomes are measured is warranted before proceeding to a full-scale RCT. PMID- 26654871 TI - SME2EM: Smart mobile end-to-end monitoring architecture for life-long diseases. AB - Monitoring life-long diseases requires continuous measurements and recording of physical vital signs. Most of these diseases are manifested through unexpected and non-uniform occurrences and behaviors. It is impractical to keep patients in hospitals, health-care institutions, or even at home for long periods of time. Monitoring solutions based on smartphones combined with mobile sensors and wireless communication technologies are a potential candidate to support complete mobility-freedom, not only for patients, but also for physicians. However, existing monitoring architectures based on smartphones and modern communication technologies are not suitable to address some challenging issues, such as intensive and big data, resource constraints, data integration, and context awareness in an integrated framework. This manuscript provides a novel mobile based end-to-end architecture for live monitoring and visualization of life-long diseases. The proposed architecture provides smartness features to cope with continuous monitoring, data explosion, dynamic adaptation, unlimited mobility, and constrained devices resources. The integration of the architecture's components provides information about diseases' recurrences as soon as they occur to expedite taking necessary actions, and thus prevent severe consequences. Our architecture system is formally model-checked to automatically verify its correctness against designers' desirable properties at design time. Its components are fully implemented as Web services with respect to the SOA architecture to be easy to deploy and integrate, and supported by Cloud infrastructure and services to allow high scalability, availability of processes and data being stored and exchanged. The architecture's applicability is evaluated through concrete experimental scenarios on monitoring and visualizing states of epileptic diseases. The obtained theoretical and experimental results are very promising and efficiently satisfy the proposed architecture's objectives, including resource awareness, smart data integration and visualization, cost reduction, and performance guarantee. PMID- 26654872 TI - A novel approach to modeling acute normovolemic hemodilution. AB - Acute normovolemic hemodilution (ANH) was introduced as a blood conservation technique to reduce patient exposure to allogenic blood transfusion during surgery. Despite years of research and experience, the best practice procedure, efficacy and safety of ANH remain in question. In this work, a numerical model is developed for the ANH procedure based upon a multi-compartmental, fluid model of the body. The model also analyzes the most commonly used acellular fluids for ANH or for fluid therapy following hemorrhage. The model allows user input of critical ANH parameters, providing the ability to simulate the patient's response in real time to many clinical scenarios, using various types of resuscitation fluids. First, the patient's response to a representative, clinical ANH protocol and surgery was simulated. Then, the effect of several variables was investigated including: type/amount of resuscitation fluid, number of blood units collected during ANH, and amount of surgical blood loss. Our simulations highlighted the importance of osmotic molecules within the blood in preventing excessive fluid retention and initiating fluid clearance after surgery. The developed model can be utilized as a tool to simulate and optimize a variety of proposed protocol related to the ANH procedure and surgery. It can also be utilized as an educational or training tool to become familiar with the ANH procedure. PMID- 26654873 TI - Direct versus transferred severely injured: Different context, similar findings. PMID- 26654874 TI - Trauma centre patient volume and inpatient mortality risk reconsidered. AB - BACKGROUND: Several studies have examined the relationship between injury volumes and trauma centre outcomes, with varying results attributable to differences in the measurement of volume's effect on mortality and differences in how characteristics are addressed as potential confounders. METHODS: This analysis includes all trauma cases reported to the NTDB 2012. The effect of trauma centre volume on patient mortality risk was measured in three different contexts: as a linear function of trauma centre volume, as a dichotomous function comparing patients in trauma centres with and without 1200 or more cases, and as a non linear function of trauma centre volume. Multivariable weighted Hierarchical Generalized Linear Models were used to account for the combined effects of facility level and patient level covariates. Patient level mortality risk was assessed using the ACS Trauma Quality Improvement Programme methodology. RESULTS: Trauma centre volume was not a statistically significant predictor (at the alpha=0.01 level) of patient mortality risk, in any of the three models. Comprehensive adjustments for patient level risk were obtained, with excellent discrimination between survivor and decedent cases. The addition of trauma volume to baseline patient mortality risk yielded no improvement in the accuracy of any model. These results were not sensitive to the inclusion of Level II trauma centres. Equivalent results were obtained by repeating the analysis for the Level I subpopulation only. CONCLUSIONS: Case volume may be a reasonable standard for determining whether adequate numbers of injured patients are available to support training needs and experience requirements of a Level I trauma centre. However, case volume is not a useful predictor of patient mortality in individual facilities. Trauma centre volume has no independent effect, after accounting for the patient level characteristics that predominantly influence mortality. PMID- 26654875 TI - Current knowledge, attitude, and patterns of oral contraceptives utilization among women in Jordan. AB - BACKGROUND: Studies exploring the knowledge, attitude and patterns of OCs use among women in Jordan are lacking. The aim of this study was to assess knowledge, attitude, and patterns of oral contraceptives (OCs) utilization among women in Jordan. METHODS: A face-to-face questionnaire inquiring demographic information and issues related to knowledge and use of OCs was completed by women (n = 1571), who have had used OCs at least once in their lifetime. A model was created to assess the effects of knowledge, attitude and previous experience on the patterns of OCs utilization. RESULTS: Jordanian women exhibited positive attitudes towards OCs efficacy and safety. This positive attitude was approvingly associated with the patterns of use. However, only half of participating women reported that they knew how to use OCs. About 60% of women received recommendations for OCs use from a physician. Moreover, women's knowledge about OCs mechanism of action was obtained namely from physician (29.9%). Side effects were reported in 75.1% of participating women. Reported side effects were headache (41.2%), mood swings (35.5%), irritability (33.5%) and weight gain (28.7%). Interestingly, the occurrence of side effects was the main reason for OCs discontinuation. CONCLUSION: The study showed that women who have positive attitude toward OCs tend to utilize them more appropriately. However, there is still need for educational programs to enhance knowledge about OCs utilization in Jordan. PMID- 26654876 TI - The development of type VI glandular trichomes in the cultivated tomato Solanum lycopersicum and a related wild species S. habrochaites. AB - BACKGROUND: Type VI glandular trichomes represent the most abundant trichome type on leaves and stems of tomato plants and significantly contribute to herbivore resistance, particularly in the wild species. Despite this, their development has been poorly studied so far. The goal of this study is to fill this gap. Using a variety of cell imaging techniques, a detailed record of the anatomy and developmental stages of type VI trichomes in the cultivated tomato (Solanum lycopersicum) and in a related wild species (S. habrochaites) is provided. RESULTS: In both species, the development of these structures follows a highly reproducible cell division pattern. The two species differ in the shape of the trichome head which is round in S. habrochaites and like a four-leaf clover in S. lycopersicum, correlating with the presence of a large intercellular cavity in S. habrochaites where the produced metabolites accumulate. In both species, the junction between the intermediate cell and the four glandular cells constitute a breaking point facilitating the decapitation of the trichome and thereby the quick release of the metabolites. A strongly auto-fluorescent compound transiently accumulates in the early stages of development suggesting a potential role in the differentiation process. Finally, immuno-labelling with antibodies recognizing specific cell wall components indicate a key role of pectin and arabinogalactan components in the differentiation of type VI trichomes. CONCLUSIONS: Our observations explain the adaptive morphologies of type VI trichomes for metabolite storage and release and provide a framework for further studies of these important metabolic cellular factories. This is required to better exploit their potential, in particular for the breeding of pest resistance in tomato. PMID- 26654877 TI - Novel grading system for quantification of cystic macular lesions in Usher syndrome. AB - BACKGROUND: To evaluate novel grading system used to quantify optical coherence tomography (OCT) scans for cystic macular lesions (CML) in Usher syndrome (USH) patients, focusing on CML associated alterations in MOY7A and USH2A mutations. METHODS: Two readers evaluated 76 patients' (mean age 42 +/- 14 years) data prospectively uploaded on Eurush database. OCT was used to obtain high quality cross-sectional images through the fovea. The CML was graded as none, mild, moderate or severe, depending on the following features set: subretinal fluid without clearly detectable CML boundaries; central macular thickness; largest diameter of CML; calculated mean of all detectable CML; total number of detectable CML; retinal layers affected by CML. Intra-and inter-grader reproducibility was evaluated. RESULTS: CML were observed in 37 % of USH eyes, while 45 % were observed in MYO7A and 29 % in USH2A cases. Of those with CML: 52 % had mild, 22 % had moderate and 26 % had severe changes, respectively. CML were found in following retinal layers: 50 % inner nuclear layer, 44 % outer nuclear layer, 6 % retinal ganglion cell layer. For the inter-grader repeatability analysis, agreements rates for CML were 97 % and kappa statistics was 0.91 (95 % CI 0.83-0.99). For the intra-grader analysis, agreement rates for CML were 98 %, while kappa statistics was 0.96 (95 % CI 0.92-0.99). CONCLUSIONS: The novel grading system is a reproducible tool for grading OCT images in USH complicated by CML, and potentially could be used for objective tracking of macular pathology in clinical therapy trials. PMID- 26654878 TI - Hole Cooling Is Much Faster than Electron Cooling in PbSe Quantum Dots. AB - In semiconductor quantum dots (QDs), charge carrier cooling is in direct competition with processes such as carrier multiplication or hot charge extraction that may improve the light conversion efficiency of photovoltaic devices. Understanding charge carrier cooling is therefore of great interest. We investigate high-energy optical transitions in PbSe QDs using hyperspectral transient absorption spectroscopy. We observe bleaching of optical transitions involving higher valence and conduction bands upon band edge excitation. The kinetics of rise of the bleach of these transitions after a pump laser pulse allow us to monitor, for the first time, cooling of hot electrons and hot holes separately. Our results show that holes cool significantly faster than electrons in PbSe QDs. This is in contrast to the common assumption that electrons and holes behave similarly in Pb chalcogenide QDs and has important implications for the utilization of hot charge carriers in photovoltaic devices. PMID- 26654879 TI - Healthy people with nature in mind. AB - BACKGROUND: The global disease burden resulting from climate change is likely to be substantial and will put further strain on public health systems that are already struggling to cope with demand. An up- stream solution, that of preventing climate change and associated adverse health effects, is a promising approach, which would create win-win-situations where both the environment and human health benefit. One such solution would be to apply methods of behaviour change to prompt pro-environmentalism, which in turn benefits health and wellbeing. DISCUSSION: Based on evidence from the behavioural sciences, we suggest that, like many social behaviours, pro- environmental behaviour can be automatically induced by internal or external stimuli. A potential trigger for such automatic pro-environmental behaviour would be natural environments themselves. Previous research has demonstrated that natural environments evoke specific psychological and physiological reactions, as demonstrated by self reports, epidemiological studies, brain imaging techniques, and various biomarkers. This suggests that exposure to natural environments could have automatic behavioural effects, potentially in a pro-environmental direction, mediated by physiological reactions. Providing access and fostering exposure to natural environments could then serve as a public health tool, together with other measures, by mitigating climate change and achieving sustainable health in sustainable ecosystems. However, before such actions are implemented basic research is required to elucidate the mechanisms involved, and applied investigations are needed to explore real world impacts and effect magnitudes. As environmental research is still not sufficiently integrated within medical or public health studies there is an urgent need to promote interdisciplinary methods and investigations in this critical field. Health risks posed by anthropogenic climate change are large, unevenly distributed, and unpredictable. To ameliorate negative impacts, pro-environmental behaviours should be fostered. Potentially this could be achieved automatically through exposure to favourable natural environments, with an opportunity for cost-efficient nature-based solutions that provide benefits for both the environment and public health. PMID- 26654880 TI - Exposure to dim artificial light at night increases REM sleep and awakenings in humans. AB - Exposure to artificial light at night (ALAN) has become increasing common, especially in developed countries. We investigated the effect of dALAN exposure during sleep in healthy young male subjects. A total of 30 healthy young male volunteers from 21 to 29 years old were recruited for the study. They were randomly divided into two groups depending on light intensity (Group A: 5 lux and Group B: 10 lux). After a quality control process, 23 healthy subjects were included in the study (Group A: 11 subjects, Group B: 12 subjects). Subjects underwent an NPSG session with no light (Night 1) followed by an NPSG session randomly assigned to two different dim light conditions (5 or 10 lux, dom lambda: 501.4 nm) for a whole night (Night 2). We found significant sleep structural differences between Nights 1 and 2, but no difference between Groups A and B. Exposure to dALAN during sleep was significantly associated with increased wake time after sleep onset (WASO; F = 7.273, p = 0.014), increased Stage N1 (F = 4.524, p = 0.045), decreased Stage N2 (F = 9.49, p = 0.006), increased Stage R (F = 6.698, p = 0.017) and non-significantly decreased REM density (F = 4.102, p = 0.056). We found that dALAN during sleep affects sleep structure. Exposure to dALAN during sleep increases the frequency of arousals, amount of shallow sleep and amount of REM sleep. This suggests adverse effects of dALAN during sleep on sleep quality and suggests the need to avoid exposure to dALAN during sleep. PMID- 26654881 TI - Cost-effectiveness of 'Program We Care' for patients with chronic obstructive pulmonary disease: A case-control study. AB - OBJECTIVES: To evaluate the effectiveness of a discharge program for patients with chronic obstructive pulmonary disease (COPD) patients on discharge from an emergency medical ward on discharge home rate, hospital length of stay (LOS), inpatient admission rate and cost. BACKGROUND: Frequent visits to the emergency department (ED) and subsequent hospital admission are common among patients with COPD, which adds a burden to ED and hospital care. A discharge program was implemented in an ED emergency medical ward. The program consisted of multidisciplinary care, discharge planning, discharge health education on disease management, and continued support from the community nursing services. METHODS: A retrospective case-control study was used. Data were retrieved and compared between 478 COPD program cases and 478 COPD non-program cases. RESULTS: No significant difference was found in age, gender, and triage category, LOS in ED, and readmission rate between the program and non-program groups. The program group demonstrated a significantly higher discharge home rate from the ED (33.89% vs. 20.08%) and fewer medical admissions (40.59% vs. 55.02%) compared with the non-program group, resulting in lower total medical costs after the program was implemented. CONCLUSION: The program provides insight on the strategic planning for discharge care in a short stay unit of emergency department. PMID- 26654883 TI - Celiac disease: advances in diagnosis. AB - Celiac disease (CD) is characterized by small intestinal damage, which is mediated by a gluten-driven inflammatory response. Establishing a robust diagnosis is critical for improved quality of life and prevention of co morbidities, although treatment is associated with a substantial life-long burden of care for patients and families. Unfortunately, CD remains a challenging diagnosis. As awareness of the disease increases, more diagnoses of CD are being made by primary care physicians. In fact, many patients may not present to a gastroenterologist because their symptoms are not clearly linked to a gastrointestinal pathology. Also, many patients are starting a gluten-free diet without prior testing, a circumstance that leads to even more confusion. Lastly, the number of serologic and genetic tests, and the role of endoscopy, can be confusing. The purpose of this review is to examine diagnostic testing strategies, focusing on published guidelines, for the evaluation of patients with suspected CD. PMID- 26654884 TI - Spatial patterns of correlated scale size and scale color in relation to color pattern elements in butterfly wings. AB - Complex butterfly wing color patterns are coordinated throughout a wing by unknown mechanisms that provide undifferentiated immature scale cells with positional information for scale color. Because there is a reasonable level of correspondence between the color pattern element and scale size at least in Junonia orithya and Junonia oenone, a single morphogenic signal may contain positional information for both color and size. However, this color-size relationship has not been demonstrated in other species of the family Nymphalidae. Here, we investigated the distribution patterns of scale size in relation to color pattern elements on the hindwings of the peacock pansy butterfly Junonia almana, together with other nymphalid butterflies, Vanessa indica and Danaus chrysippus. In these species, we observed a general decrease in scale size from the basal to the distal areas, although the size gradient was small in D. chrysippus. Scales of dark color in color pattern elements, including eyespot black rings, parafocal elements, and submarginal bands, were larger than those of their surroundings. Within an eyespot, the largest scales were found at the focal white area, although there were exceptional cases. Similarly, ectopic eyespots that were induced by physical damage on the J. almana background area had larger scales than in the surrounding area. These results are consistent with the previous finding that scale color and size coordinate to form color pattern elements. We propose a ploidy hypothesis to explain the color-size relationship in which the putative morphogenic signal induces the polyploidization (genome amplification) of immature scale cells and that the degrees of ploidy (gene dosage) determine scale color and scale size simultaneously in butterfly wings. PMID- 26654885 TI - Ecosystem engineering and manipulation of host plant tissues by the insect borer Oncideres albomarginata chamela. AB - Ecosystem engineering by insect herbivores occurs as the result of structural modification of plants manipulated by insects. However, only few studies have evaluated the effect of these modifications on the plant responses induced by stem-borers that act as ecosystem engineers. In this study, we evaluated the responses induced by the herbivory of the twig-girdler beetle Oncideres albomarginata chamela (Cerambycidae: Lamiinae) on its host plant Spondias purpurea (Anacardiaceae), and its relationship with the ecosystem engineering process carried out by this stem-borer. Our results demonstrated that O. albomarginata chamela branch removal induced the development of lateral branches increasing the resources needed for the development of future insect generations, of its own offspring and of many other insect species. Detached branches represent habitats with high content of nitrogen and phosphorous, which eventually can be incorporated into the ecosystem, increasing nutrient cycling efficiency. Consequently, branch removal and the subsequent plant tissue regeneration induced by O. albomarginata chamela represent key mechanisms underlying the ecosystem engineering process carried out by this stem-borer, which enhances arthropod diversity in the ecosystem. PMID- 26654886 TI - Diagnosis by (18)F-FDG PET/CT of infective endocarditis, staging and monitoring of antibiotic treatment after transposition of surgically corrected great arteries. AB - Infective endocarditis is one of the leading causes of fever of unknown origin in those patients with intravascular catheters, prosthetic valves or cardiovascular implantable electronic devices. The diagnosis of infective endocarditis is made according to modified Duke criteria, which are based on blood culture and echocardiographic findings. Demonstration of vegetation with the transoesophageal echocardiography may be difficult in these cases with previous anatomical changes, especially in early phases. Positron emission tomography with (18)F fluorodeoxyglucose ((18)F-FDG PET/CT) is well known to show an increased glucidic metabolism in malignant, inflammatory, and infectious processes. Thus, it provides useful functional imaging that enables the disease causing the fever of unknown origin to be detected well before structural changes are evident. Moreover, (18)F-FDG PET/CT helps to detect infectious extra-cardiac involvement, since the whole body is imaged with this technique. (18)F-FDG PET/CT may have an additional promising role for the monitoring of response to antimicrobial therapy in patients with established infective endocarditis, thus evaluating standard treatment outcome, as well as evaluating the need for alternative/intensified treatment options. PMID- 26654887 TI - (99m)Tc-BrIDA cholescintigraphy in a spontaneous biliary perforation of an infant. PMID- 26654888 TI - What does cooking mean to you?: Perceptions of cooking and factors related to cooking behavior. AB - Despite the importance of cooking in American life and evidence suggesting that meals cooked at home are healthier, little is known about perceptions of what it means to cook in the United States. The objective of this study was to describe perceptions of cooking and factors important to how cooking is perceived and practiced among American adults. Seven focus groups (N = 53; 39 female; 35 Black, 16 White, 2 Asian) were conducted from November 2014 to January 2015 in Baltimore City, Maryland. Participants were recruited from two neighborhoods; one with higher median income and access to healthy food and the other with lower income and low access to healthy food. Focus groups were audio recorded, transcribed verbatim and analyzed using a grounded theory approach. Participants' perceptions of cooking varied considerably, regardless of neighborhood income or food access, and spanned a continuum from all scratch cooking to anything made at home. Perceptions of cooking incorporated considerations of whether or how food was heated and the degree of time, effort and love involved if convenience foods were used. Key barriers to cooking included affordability, lack of time, and lack of enjoyment. Key facilitators of frequent cooking included extensive organization and time management to enable participants to incorporate cooking into their daily lives. Cooking is a complex concept and not uniformly understood. Efforts to encourage healthy cooking at home should consider the broad spectrum of activities Americans recognize as cooking as well as the barriers and facilitators to preparing food at home. Public health messages to encourage more frequent cooking should account for the heterogeneity in perspectives about cooking. More research should explore differences in perceptions about cooking in other diverse populations. PMID- 26654889 TI - Half-size me? How calorie and price information influence ordering on restaurant menus with both half and full entree portion sizes. AB - Many restaurants are increasingly required to display calorie information on their menus. We present a study examining how consumers' food choices are affected by the presence of calorie information on restaurant menus. However, unlike prior research on this topic, we focus on the effect of calorie information on food choices made from a menu that contains both full size portions and half size portions of entrees. This different focus is important because many restaurants increasingly provide more than one portion size option per entree. Additionally, we examine whether the impact of calorie information differs depending on whether full portions are cheaper per unit than half portions (non-linear pricing) or whether they have a similar per unit price (linear pricing). We find that when linear pricing is used, calorie information leads people to order fewer calories. This decrease occurs as people switch from unhealthy full sized portions to healthy full sized portions, not to unhealthy half sized portions. In contrast, when non-linear pricing is used, calorie information has no impact on calories selected. Considering the impact of calorie information on consumers' choices from menus with more than one entree portion size option is increasingly important given restaurant and legislative trends, and the present research demonstrates that calorie information and pricing scheme may interact to affect choices from such menus. PMID- 26654890 TI - Effects of acupuncture at HT7 on glucose metabolism in a rat model of Alzheimer's disease: an 18F-FDG-PET study. AB - OBJECTIVE: To explore the effects of acupuncture at HT7 on different cerebral regions in a rat model of Alzheimer's disease (AD) with the application of (18)F 2-fluoro-deoxy-D-glucose positron emission tomography (FDG-PET). METHODS: Sixty Wistar rats were included after undergoing a Y-maze electric sensitivity test. Ten rats were used as a healthy control group. The remaining 50 rats were injected stereotaxically with ibotenic acid into the right nucleus basalis magnocellularis and injected intraperitoneally with D-galactose. AD was successfully modelled in 36 rats, which were randomly divided into three groups (n=12 each): the AD group, which remained untreated; the AD+HT7 group, which received 20 sessions of acupuncture at HT7 over 1 month; and the AD+Sham group, which received acupuncture at a distant non-acupuncture point. Total reaction time (TRT) was measured by Y-maze and (18)F-FDG-PET scans were conducted on day 1 and 30. PET images were processed with Statistical Parametric Mapping 8.0. RESULTS: Pre-treatment, TRT was greater in all AD groups versus controls (mean+/ SD 24.10+/-2.48 vs 41.34+/-5.00 s). Post-treatment, TRT was shortened in AD+HT7 versus AD+Sham and AD groups (p<0.0001, two-way analysis of variance). Glucose metabolic activity in the hippocampus, thalamus, hypothalamus, frontal lobe, and temporal lobe was decreased in AD rats compared with healthy controls and relatively elevated after HT7 acupuncture. Compared with sham acupuncture, HT7 needling had a greater positive influence on brain glucose metabolism. CONCLUSIONS: Needling at HT7 can improve memory ability and cerebral glucose metabolic activity of the hippocampus, thalamus, hypothalamus, and frontal/temporal lobes in an AD rat model. PMID- 26654891 TI - The effects of physical exertion on decision-making performance of Australian football umpires. AB - Decision-making is a key component of an umpire's in-game performance, with each decision potentially having a direct impact on the result of the game. Additionally, umpires have to be physically fit to ensure they keep up with the gameplay. While research has identified the decision-making demands and running demands of umpires separately, few have explored the relationship between them. The aim of this investigation was to examine the relationship between physical exertion and decision-making performance of Australian football umpires at the sub-elite and junior levels. A total of 18 Australian football umpires (sub elite, n = 10; junior n = 8) performed 10 * 300 m runs, with each repetition immediately followed by a video-based decision-making test, then 1 min of recovery. A Mann-Whitney U assessment indicated a significant difference between the sub-elite and junior level umpires for decision-making accuracy (U = 13.00, z = -2.43, P = 0.016, r = -0.5). However, there was no significant difference in response time (U = 28.00, z = -1.07, P = 0.315, r = -0.25). The sub-elite umpires completed the running efforts in significantly less time than the junior umpires (P < 0.05). Further, there was no significant correlation between decision-making performance and running times for either skill level (P > 0.05). This suggests decision-making performance may not be affected by physical exertion. Therefore, it may be suggested coaches of football umpires allocate more time to the decision-making development of their umpires instead of focusing largely on the physical fitness side, as is currently the trend. PMID- 26654892 TI - Decrease in seroprevalence for herpesviruses among pregnant women in Finland: cross-sectional study of three time points 1992, 2002 and 2012. AB - Maternal herpesvirus infections during pregnancy may cause fetal and neonatal infections. We investigated the seroprevalence of five herpesviruses: cytomegalovirus (CMV), herpes simplex virus (HSV) 1 and 2, varicella zoster virus (VZV) and Epstein-Barr virus (EBV) in randomly selected samples from pregnant Finnish women from the years 1992, 2002 and 2012. Over 20 years, the seroprevalences decreased significantly for CMV from 84.5% to 71.5% (p = 0.007) and HSV-1 from 69.5% to 45% (p < 0.001). The decrease in seroprevalence for HSV-2 (from 17.5% to 11%) was not statistically significant. The seroprevalence remained unchanged for VZV and EBV. The proportion of mothers with no antibodies to either HSV-1 or HSV-2 increased from 25.5% to 48% (p < 0.001). The seroprevalences for HSV-1 and HSV-2 increased in relation to age, which shows that women of childbearing age do contract primary HSV infections. Our findings indicate that a considerable proportion of women (48%) are at risk for primary HSV infection during pregnancy. PMID- 26654893 TI - The influence of peri-operative factors for accelerated discharge following laparoscopic colorectal surgery when combined with an enhanced recovery after surgery (ERAS) pathway. AB - INTRODUCTION: Laparoscopic surgery is well established in the modern management of colorectal disease. More recently, enhanced recovery after surgery (ERAS) protocols have been introduced to further promote accelerated discharge and faster recovery. However, not all patients are suitable for early discharge. The purpose of this study was to evaluate the early outcomes of patients undergoing such a regime to determine which peri-operative factors may predict safe accelerated discharge. METHODS: Data were prospectively collected on consecutive patients undergoing laparoscopic colorectal surgery. All patients followed the institution's ERAS protocol and were discharged once specific criteria were fulfilled. Clinical characteristics and outcomes were compared between patients who were discharged before and after 72 h post-surgery. Thereafter, the peri operative factors that were associated with delayed discharge were determined using a binary logistic model. RESULTS: Three hundred patients were included in the analysis. The most common operation was laparoscopic anterior resection (n = 123, 41%). Mean length of stay was 4.8 days (standard deviation 5.9), with 185 (62%) patients discharged within 72 h. Ten (3%) patients had a post-operative complication. Three independent predictors of delayed discharge were identified; BMI (OR 1.06, 95%CI 1.01-1.11), operation length (OR 0.99, 95%CI 0.98-0.99) and complications (OR 16.26, 95%CI 4.88-54.08). CONCLUSIONS: A combined approach of laparoscopic surgery and ERAS leads to reduced length of stay. This enables more than 60% of patients to be discharged within 72 h. Increased BMI, duration of operation and complications post-operatively independently predict a longer length of stay. PMID- 26654894 TI - Memory outcomes in mesial temporal lobe epilepsy surgery. AB - INTRODUCTION: Decline in verbal memory after dominant mesial temporal lobe surgery is a concern. Outcomes primarily reported by group data analysis do not address issues of practice effects and measurement errors and also do not provide information about individual meaningful change after surgery. Reliable Change Indices (RCI's) are regarded to be robust statistical methods for reporting individual change and have not been hitherto derived in patient populations in India. AIM: Report memory outcomes for patients after surgery using group data as well as RCI score analyses using RCI scores derived in a control patient population. METHOD: Retrospective data analysis of 106 selected patients who underwent Anterior Temporal Lobectomy (ATL) surgery. RCI scores derived from a control group of 44 non-operated patients. Outcomes based on score shifts on the various measures of two verbal and visual memory tests. RESULTS: Group mean score analysis revealed no significant shifts in verbal or visual memory scores after left ATL, but significant improvements in verbal memory after right ATL. RCI score analysis revealed decline and improvements in a small percentage of patients for both left and right ATL groups. Percentage of patients showing decline was much less than reported in western literature although percentage improved was comparable. DISCUSSION: Differences in decline percentage may be due to RCI scores and clinical characteristics of our sample (impaired pre-operative functioning, majority seizure free post surgery, moderate hippocampal sclerosis, early onset, long duration of seizures). CONCLUSION: Group analyses mask individual change. Therefore, to report memory outcomes and counsel patients about relative risk-benefits of surgery, RCI scores derived from our patient populations should be used. PMID- 26654895 TI - Non-invasive hemoglobin monitoring. AB - Technology has transformed the practice of medicine and surgery in particular over the last several decades. This change in practice has allowed diagnostic and therapeutic tests to be performed less invasively. Hemoglobin monitoring remains one of the most commonly performed diagnostic tests in the United States. Recently, non-invasive hemoglobin monitoring technology has gained popularity. The aim of this article is to review the principles of how this technology works, pros and cons, and the implications of non-invasive hemoglobin technology particularly in trauma surgery. PMID- 26654896 TI - Technical challenges in treating recurrent non-parasitic hepatic cysts. AB - PURPOSE: Simple non-parasitic hepatic cysts (NPHC) are relatively frequent and often asymptomatic. When symptomatic, surgery is recommended. Most patients can be treated with laparoscopic deroofing. However, recurrence rate varies greatly, and there is no consensus on the optimal approach for symptomatic recurrences. MATERIALS AND METHODS: A retrospective study on 33 patients surgically treated for symptomatic simple NPHC was performed. Recurrence was considered only when symptomatic. RESULTS: Most patients were initially submitted to laparoscopic deroofing. Symptomatic recurrence was found in five patients treated with laparoscopic deroofing. Specific location of the cysts was a common characteristic. In three cases, recurrence was unsuccessfully treated with open deroofing, and patients were submitted to resection. Open deroofing does not offer any advantage in terms of recurrence in comparison with laparoscopic deroofing. CONCLUSION: Laparoscopic deroofing can be proposed for symptomatic recurrent cysts, except for cysts located in S4, S7 and S8, where recurrence rates are higher and complete resection should be undertaken. PMID- 26654897 TI - Should acute cholecystitis be operated in the 24 h following symptom onset? A retrospective cohort study. AB - BACKGROUND: Early laparoscopic cholecystectomy is the gold standard for management of acute cholecystitis (AC). Nevertheless, the definition used for early phase remained unclear. We aimed to compare the clinical outcome and cost of immediate (patients undergoing laparoscopic cholecystectomy within 24 h following symptom onset) versus early laparoscopic cholecystectomy (patients managed 25-72 h following symptom onset) for acute cholecystitis. METHODS: A retrospective analysis was performed. The outcomes of 143 patients undergoing laparoscopic cholecystectomy within 24 h (ICG) were compared to 350 patients managed 25-72 h following symptom onset (ECG) for acute cholecystitis. RESULTS: There were significantly more diabetic patients in the early laparoscopic group (ECG). All other characteristics were comparable (demographic, clinical, biologic and ultrasonographic characteristics) between the two groups. The rate of conversion to open surgery was significantly higher in the ECG. Overall postoperative morbidity and specific morbidity did not differ significantly between the groups. Total hospital stay was longer in the ECG. Direct medical costs were higher in the ECG. CONCLUSIONS: Laparoscopic cholecystectomy, for acute cholecystitis, during the first 24 h of onset of symptoms, significantly reduced conversion to open surgery and total hospital stay without increasing postoperative complications. PMID- 26654898 TI - Changes in surgical training opportunities in Britain and South Africa. AB - INTRODUCTION: There have been substantial changes in the provision of surgical services and in surgical training over the last twenty years. Consultants now have a much greater role in delivery of care, but concerns have been raised over surgical trainees' lack of experience, particularly with trauma and emergency cases. METHODS: The logbooks of surgical trainees undertaking 6 month posts during 1992-3 and 2009-12 in both the United Kingdom (UK) and South Africa (RSA) were analysed. RESULTS: There was a 50% reduction in total hours worked between the UK posts in 1992-3 and 2011-12. The trainee post in RSA 2009-10 completed 15% more hours than the equivalent UK trainee post. Elective cases predominated in both UK posts (70-83%) whilst in RSA the number of trauma cases was substantial (21-26%). The UK 2011/12 trainee was rarely the primary operator (30%) compared with all other training periods (72-82%). This was due to a combination of relatively less minor and more major elective surgical cases in the recent UK post compared with the historical UK post or either RSA post. CONCLUSION: RSA has consistently offered more exposure to emergency, and especially trauma, surgery than the UK as well as more opportunity to act as primary operator. Re introduction of "minor operations" lists for junior surgical trainees, acceptance of the importance for trainees to act as the primary operator, maintenance of the traditional "firm" structure and support for trainees who wish to spend a period of time abroad may help to improve clinical training and experience for UK surgical trainees. PMID- 26654899 TI - Assessment and management of male lower urinary tract symptoms (LUTS). AB - Male lower urinary tract symptoms (LUTS) are common, causing significant bother and impair quality of life. LUTS are a spectrum of symptoms that may or may not be due to benign prostatic obstruction (BPO). LUTS are divided into storage, voiding or post micturition symptoms, which each need to be considered in terms of impact, mechanism and treatment options. In most patients, a mixture of symptoms is present. In order to have a better insight about which symptoms are affecting quality of life, a thorough evaluation should include medical history, examination, validated symptom questionnaires, bladder diary, and flow rate (with post void residual measurement). Other tests, particularly urodynamic tests may be needed to guide treatment selection, particularly for surgery. Management of male LUTS is tailored according to the underlying mechanisms. Different treatment modalities are available according to individual patient preference. These range from watchful waiting, behavioral and dietary modifications, and/or medications - either as monotherapy or in combination. Surgery to relieve BPO may be needed where patients have significant bothersome voiding LUTS, and are willing to accept risks associated with irreversible treatment. Interventions for storage LUTS are available, but must be selected judiciously, using particular caution if nocturia is prominent. In order to achieve better outcomes, a rational stepwise approach to decision making is needed. PMID- 26654900 TI - Evidence based management of male lower urinary tract symptoms: A contemporary update. PMID- 26654901 TI - Genome editing in zebrafish: a practical overview. AB - Zebrafish is a powerful model for the study of vertebrate development, being amenable to a wide range of genetic and other manipulations to probe the molecular basis of development and its perturbation in disease. Over recent years, genome editing approaches have become increasingly used as an efficient and sophisticated approach to precisely engineer the zebrafish genome, which has further enhanced the utility of this organism. This review provides a practical overview of genome editing and its application in zebrafish research, including alternate strategies for introducing and screening for specific genetic changes. PMID- 26654902 TI - 0.43 THz emission from high-T(c) superconducting emitters optimized at 77 K. AB - A liquid helium-free, compact and continuous sub-terahertz radiation system operating at 77 K has been developed using a rectangular mesa device made from a high T(c)-superconducting Bi2Sr2CaCu2O(8+delta) single crystal, based on a different design of a stand-alone mesa sandwich structure to reduce the dc current Joule heating effects. The mesa was thermally connected to sapphire plates through thin thermal grease embedded with diamond nano-crystals. When immersed in liquid N 2, the device emits intense radiation at 0.437 THz, the highest frequency ever achieved at 77 K, due to excitation of the TM(1, 0) rectangular cavity mode. By varying the dc current-voltage bias and the bath temperature in a He-flow cryostat, the device's emission frequency is broadly tunable from 0.31 THz at 79 K to 1.31 THz at 30 K. PMID- 26654903 TI - Gastro-cutaneous fistula 4 years after a fully resolved staple line leak in sleeve gastrectomy. AB - Laparoscopic sleeve gastrectomy (LSG) has become a mainstream procedure in the management of obesity. Staple line leak is a challenging complication. We report a unique case of successfully treated leak after sleeve gastrectomy, presented ex novo 4 years later as a gastro-cutaneous fistula (GCF). Nothing similar was found in the literature. A 31-year-old woman underwent an LSG, complicated by an early type I leak treated successfully. After 4 years of clinical remission, the leak presented as a GCF. The conservative approach failed and a laparoscopic fistulectomy was first attempted, but after recurrence a completion gastrectomy was performed. A staple line leak is one of the most important complications after sleeve gastrectomy. Once chronic it evolves into GCF, the treatment of which is challenging. Given the absence of guidelines, experience is fundamental in its management. In our case, eventually a total gastrectomy was required. PMID- 26654904 TI - Anthropometric hand dimensions in a population of Iranian male workers in 2012. AB - BACKGROUND: The mismatch between the hand size of workers and the size of industrial instruments is a growing concern; it can lead to various musculoskeletal complications. Currently, there are few reliable studies available to address this concern in Iran. This study was conducted to measure 30 upper-extremity parameters in a group of Iranian industrial workers. METHODS: This study is a cross-sectional study on 529 workers. The study population was randomly selected from male Iranian industrial workers who were referred to the Yazd hospital occupational medicine clinic for surveillance evaluations. RESULTS: The M (SD) age of the participants was 30.13 (8.29) years. Statistical analysis was performed using the mean, standard deviation and 5th, 50th and 90th percentiles for each measured hand dimension. A considerable number of dimensions were significantly different between the measurements of right and left hands in each examinee. The results showed significant differences between Iranian hand size and that of other populations. CONCLUSION: This study provided a valuable databank of hand dimensions in a population of Iranian male workers. These data can be used by manufacturers in designing high-quality hand-tools and industrial gloves, taking into consideration Iranian worker characteristics. PMID- 26654906 TI - Effect of microbial cell preparation on renal profile and liver function among type 2 diabetics: a randomized controlled trial. AB - BACKGROUND: The beneficial effect of probiotics on renal profile and liver function has been reported among patients with chronic kidney disease and fatty liver respectively. However, its effect on renal profile and liver function among type 2 diabetic individuals has not been fully understood. To investigate the effect of microbial cell preparation on renal profile and liver function tests among type 2 diabetic individuals. METHODS: A randomized, double-blind, parallel group, controlled clinical trial was conducted on a total of 136 type 2 diabetics age 30-70 years old in a teaching hospital in Kuala Lumpur, Malaysia. Subjects were randomly assigned to receive microbial cell preparation (N = 68) or a placebo (N = 68) for 12 weeks. The outcomes measured at baseline, week 6, and week 12 and included changes in renal profile (Sodium, Potassium, Urea, Creatinine, Glomerular Filtration Rate), and liver function tests (Albumin, Total Protein, Alkaline Phosphatase, Alanine Aminotransferase, Aspartate Aminotransferase). Intention to treat (ITT) analysis was performed on all the recruited subjects, while per protocol (PP) analysis was conducted on those who completed the trial with good compliance. RESULT: The urea levels significantly declined in the probiotic group. Serum urea levels reduced from 4.26 mmol/L to 4.04 mmol/L in Probiotic Group while it increased in Placebo Group from 4.03 mmol/L to 4.24 mmol/L. These changes were significant between groups in ITT analysis (p = 0.018). Other parameters did not change significantly between groups. CONCLUSION: 12 weeks supplementation with daily dosage of 6 * 10(10) Colony Forming Units of multi-strain microbial cell preparation significantly improved urea levels. TRIAL REGISTRATION: ( CLINICAL TRIALS: # NCT01752803). PMID- 26654905 TI - The effect of iodine supplementation in pregnancy on early childhood neurodevelopment and clinical outcomes: results of an aborted randomised placebo controlled trial. AB - BACKGROUND: Concern that mild iodine deficiency in pregnancy may adversely affect neurodevelopment of offspring has led to recommendations for iodine supplementation in the absence of evidence from randomised controlled trials. The primary objective of the study was to investigate the effect of iodine supplementation during pregnancy on childhood neurodevelopment. Secondary outcomes included pregnancy outcomes, maternal thyroid function and general health. METHODS: Women with a singleton pregnancy of fewer than 20 weeks were randomly assigned to iodine (150 MUg/d) or placebo from trial entry to birth. Childhood neurodevelopment was assessed at 18 months by using Bayley Scales of Infant and Toddler Development (Bayley-III). Iodine status and thyroid function were assessed at baseline and at 36 weeks' gestation. Pregnancy outcomes were collected from medical records. RESULTS: The trial was stopped after 59 women were randomly assigned following withdrawal of support by the funding body. There were no differences in childhood neurodevelopmental scores between the iodine treated and placebo groups. The mean cognitive, language and motor scores on the Bayley-III (iodine versus placebo, respectively) were 99.4 +/- 12.2 versus 101.7 +/- 8.2 (mean difference (MD) -2.3, 95 % confidence interval (CI) -7.8, 3.2; P = 0.42), 97.2 +/- 12.2 versus 97.9 +/- 11.5 (MD -0.7, 95 % CI -7.0, 5.6; P = 0.83) and 93.9 +/- 10.8 versus 92.4 +/- 9.7 (MD 1.4, 95 % CI -4.0, 6.9; P = 0.61), respectively. No differences were identified between groups in any secondary outcomes. CONCLUSIONS: Iodine supplementation in pregnancy did not result in better childhood neurodevelopment in this small trial. Adequately powered randomised controlled trials are needed to provide conclusive evidence regarding the effect of iodine supplementation in pregnancy. TRIALS REGISTRATION: The trial was registered with the Australian New Zealand Clinical Trials Registry at http://www.anzctr.org.au . The registration number of this trial is ACTRN12610000411044 . The trial was registered on 21 May 2010. PMID- 26654907 TI - Evaluation of the relationship between effervescent paracetamol and blood pressure: clinical trial. AB - BACKGROUND: Paracetamol's solubility is achieved by adding to the excipient sodium salts, either as bicarbonate, carbonate or citrate. As the relationship between salt and hypertension is well known, due to the sodium content it has raised a hypothesis that may interfere with the control of that risk factor. Therefore, the objective of this study is to evaluate the effect on blood pressure of effervescent paracetamol compared to non-effervescent, in hypertensive patients. METHODS/DESIGN: This is the protocol of a phase IV multicenter clinical trial, randomized, controlled, crossover, open, which will compare the effect of two different formulations of paracetamol (effervescent or non-effervescent) in the blood pressure of hypertensive patients, with a seven weeks follow up. 49 controlled hypertensive patients will be included (clinical BP lower than 150 and 95 mmHg, and lower than 135 mmHg and 85 mmHg in patients with diabetes or a history of cardiovascular event, and daytime ambulatory measurements lower than 140 and 90 mmHg) and mild to moderate pain (Visual Analog Scale between 1 and 4). The study was approved by the ethics committee of the Fundacio Jordi Gol i Gurina and following standards of good clinical practice. The primary endpoint will be the variations in systolic BP in 24 h Ambulatory Blood Pressure Monitoring, considering significant differences 2 or more mmHg among those treated with non-effervescent and effervescent formulations. Intention-to-treat and per-protocol analysis will be held. DISCUSSION: Despite the broad recommendation not to use effervescent drugs in patients with hypertension, there are relatively little studies that show exactly this pressor effect due to sodium in salt that gives the effervescence of the product. This is the first clinical trial designed to study the effect of effervescence compared to the non-effervescent, in well-controlled hypertensive patients with mild to moderate pain, performed in routine clinical practice. TRIAL REGISTRATION: NCT 02514538. PMID- 26654908 TI - The use of reimbursement data for timely monitoring of vaccination coverage: the example of human papillomavirus vaccine following public concerns about vaccine safety. AB - BACKGROUND: Since 2011 public concerns about Human Papillomavirus (HPV) vaccination safety and efficacy arose in France. We explored the relevance of using vaccines reimbursement data to assess the impact of those public concerns on vaccination coverage. METHODS: We used the Permanent Sample of Beneficiaries which was, at the time of the study, a representative sample of 1/97(th) health insurance beneficiaries of the main Social Security scheme, the General Health Insurance Scheme, covering approximately 77 % of the French resident population. We estimated HPV vaccination coverage among girls born between 1995 and 1999 at their 15(th), 16(th) and 17(th) birthday. RESULTS: The coverage for complete vaccination among 16 years old girls decreased from 26.5 % in the first semester of 2011 to 18.6 % in the first semester of 2014. CONCLUSIONS: HPV vaccination coverage was already low in 2011 and continued to decrease thereafter. Vaccines reimbursement data allowed us to reactively monitor the impact of the controversy on vaccination coverage and design counteracting measures. PMID- 26654909 TI - Effective Decision Making in the Use of Pediatric Restraints. PMID- 26654910 TI - Experimental Evaluation of Seaweeds as a Vector for Microplastics into Marine Food Webs. AB - The ingestion of microplastics has been shown for a great variety of marine organisms. However, benthic marine mesoherbivores such as the common periwinkle Littorina littorea have been largely disregarded in studies about the effects of microplastics on the marine biota, probably because the pathway for microplastics to this functional group of organisms was not obvious. In laboratory experiments we showed that the seaweed Fucus vesiculosus retains suspended microplastics on its surface. The numbers of microplastics that adhered to the algae correlated with the concentrations of suspended particles in the water. In choice feeding assays L. littorea did not distinguish between algae with adherent microplastics and clean algae without microplastics, indicating that the snails do not recognize solid nonfood particles in the submillimeter size range as deleterious. In periwinkles that were feeding on contaminated algae, microplastics were found in the stomach and in the gut. However, no microplastics were found in the midgut gland, which is the principle digestive organ of gastropods. Microplastics in the fecal pellets of the periwinkles indicate that the particles do not accumulate rapidly inside the animals but are mostly released with the feces. Our results provide the first evidence that seaweeds may represent an efficient pathway for microplastics from the water to marine benthic herbivores. PMID- 26654911 TI - Work environment, overtime and sleep among offshore personnel. AB - Personnel working on North Sea oil/gas installations are exposed to remote and potentially hazardous environments, and to extended work schedules (typically, 14*12h shifts). Moreover, overtime (additional to the standard 84-h week) is not uncommon among offshore personnel. Evidence from onshore research suggests that long work hours and adverse environmental characteristics are associated with sleep impairments, and consequently with health and safety risks, including accidents and injuries. However, little is known about the extent to which long hours and a demanding work environment combine synergistically in relation to sleep. The present study sought to address this issue, using survey data collected from offshore day-shift personnel (N=551). The multivariate analysis examined the additive and interactive effects of overtime and measures of the psychosocial/physical work environment (job demands, job control, supervisor support, and physical stressors) as predictors of sleep outcomes during offshore work weeks. Control variables, including age and sleep during leave weeks, were also included in the analysis model. Sleep duration and quality were significantly impaired among those who worked overtime (54% of the participants) relative to those who worked only 12-h shifts. A linear relationship was found between long overtime hours and short sleep duration; personnel who worked >33h/week overtime reported <6h/day sleep. Significant interactions were also found; sleep duration was negatively related to job demands, and positively related to supervisor support, only among personnel who worked overtime. Poor sleep quality was predicted by the additive effects of overtime, low support and an adverse physical environment. These findings highlight the need to further examine the potential health and safety consequences of impaired sleep associated with high overtime rates offshore, and to identify the extent to which adverse effects of overtime can be mitigated by favourable physical and psychosocial work environment characteristics. PMID- 26654912 TI - The domain structure and distribution of Alu elements in long noncoding RNAs and mRNAs. AB - Approximately 75% of the human genome is transcribed and many of these spliced transcripts contain primate-specific Alu elements, the most abundant mobile element in the human genome. The majority of exonized Alu elements are located in long noncoding RNAs (lncRNAs) and the untranslated regions of mRNA, with some performing molecular functions. To further assess the potential for Alu elements to be repurposed as functional RNA domains, we investigated the distribution and evolution of Alu elements in spliced transcripts. Our analysis revealed that Alu elements are underrepresented in mRNAs and lncRNAs, suggesting that most exonized Alu elements arising in the population are rare or deleterious to RNA function. When mRNAs and lncRNAs retain exonized Alu elements, they have a clear preference for Alu dimers, left monomers, and right monomers. mRNAs often acquire Alu elements when their genes are duplicated within Alu-rich regions. In lncRNAs, reverse-oriented Alu elements are significantly enriched and are not restricted to the 3' and 5' ends. Both lncRNAs and mRNAs primarily contain the Alu J and S subfamilies that were amplified relatively early in primate evolution. Alu J subfamilies are typically overrepresented in lncRNAs, whereas the Alu S dimer is overrepresented in mRNAs. The sequences of Alu dimers tend to be constrained in both lncRNAs and mRNAs, whereas the left and right monomers are constrained within particular Alu subfamilies and classes of RNA. Collectively, these findings suggest that Alu-containing RNAs are capable of forming stable structures and that some of these Alu domains might have novel biological functions. PMID- 26654914 TI - Novel components of leaf bacterial communities of field-grown tomato plants and their potential for plant growth promotion and biocontrol of tomato diseases. AB - This work aimed to characterize potentially endophytic culturable bacteria from leaves of cultivated tomato and analyze their potential for growth promotion and biocontrol of diseases caused by Botrytis cinerea and Pseudomonas syringae. Bacteria were obtained from inner tissues of surface-disinfected tomato leaves of field-grown plants. Analysis of 16S rRNA gene sequences identified bacterial isolates related to Exiguobacterium aurantiacum (isolates BT3 and MT8), Exiguobacterium spp. (isolate GT4), Staphylococcus xylosus (isolate BT5), Pantoea eucalypti (isolate NT6), Bacillus methylotrophicus (isolate MT3), Pseudomonas veronii (isolates BT4 and NT2), Pseudomonas rhodesiae (isolate BT2) and Pseudomonas cichorii (isolate NT3). After seed inoculation, BT2, BT4, MT3, MT8, NT2 and NT6 were re-isolated from leaf extracts. NT2, BT2, MT3 and NT6 inhibited growth of Botrytis cinerea and Pseudomonas syringae pv. tomato in vitro, produced antimicrobial compounds and reduced leaf damage caused by B. cinerea. Some of these isolates also promoted growth of tomato plants, produced siderophores, the auxin indole-3-acetic and solubilized inorganic phosphate. Thus, bacterial communities of leaves from field-grown tomato plants were found to harbor potentially endophytic culturable beneficial bacteria capable of antagonizing pathogenic microorganisms and promoting plant growth, which could be used as biological control agents and biofertilizers/biostimulators for promotion of tomato plant growth. PMID- 26654913 TI - Early detection of cardiac dysfunction in the type 1 diabetic heart using speckle tracking based strain imaging. AB - Enhanced sensitivity in echocardiographic analyses may allow for early detection of changes in cardiac function beyond the detection limits of conventional echocardiographic analyses, particularly in a small animal model. The goal of this study was to compare conventional echocardiographic measurements and speckle tracking based strain imaging analyses in a small animal model of type 1 diabetes mellitus. Conventional analyses revealed differences in ejection fraction, fractional shortening, cardiac output, and stroke volume in diabetic animals relative to controls at 6-weeks post-diabetic onset. In contrast, when assessing short- and long-axis speckle-tracking based strain analyses, diabetic mice showed changes in average systolic radial strain, radial strain rate, radial displacement, and radial velocity, as well as decreased circumferential and longitudinal strain rate, as early as 1-week post-diabetic onset and persisting throughout the diabetic study. Further, we performed regional analyses for the LV and found that the free wall region was affected in both the short- and long-axis when assessing radial dimension parameters. These changes began 1-week post diabetic onset and remained throughout the progression of the disease. These findings demonstrate the use of speckle-tracking based strain as an approach to elucidate cardiac dysfunction from a global perspective, identifying left ventricular cardiac regions affected during the progression of type 1 diabetes mellitus earlier than contractile changes detected by conventional echocardiographic measurements. PMID- 26654915 TI - Burkholderia pseudomallei kynB plays a role in AQ production, biofilm formation, bacterial swarming and persistence. AB - Kynurenine formamidase (KynB) forms part of the kynurenine pathway which metabolises tryptophan to anthranilate. This metabolite can be used for downstream production of 2-alkyl-4-quinolone (AQ) signalling molecules that control virulence in Pseudomonas aeruginosa. Here we investigate the role of kynB in the production of AQs and virulence-associated phenotypes of Burkholderia pseudomallei K96243, the causative agent of melioidosis. Deletion of kynB resulted in reduced AQ production, increased biofilm formation, decreased swarming and increased tolerance to ciprofloxacin. Addition of exogenous anthranilic acid restored the biofilm phenotype, but not the persister phenotype. This study suggests the kynurenine pathway is a critical source of anthranilate and signalling molecules that may regulate B. pseudomallei virulence. PMID- 26654916 TI - What Are the Ground State Structures of C20 and C24? An Explicitly Correlated Ab Initio Approach. AB - A new benchmark study has been performed for six isomers of C20 and four isomers of C24 using explicitly correlated methods, together with coupled cluster theory with large basis sets and DFT with advanced functionals. The relative energy trends obtained are extremely sensitive to the methods used. Combining our best CCSD(T)-MP2 difference with our best MP2 basis set limit, the dehydrocorannulene bowl is found to be the most stable for C20, followed by the cage at about 8 kcal/mol, and the ring at about 46 kcal/mol. For C24, the D3d cage is found to be the most stable isomer, followed at only a few kilocalories per mole by dehydrocoronene, and at larger separations by then octahedral cage and the ring, respectively. This makes C24 the smallest classical fullerene. The estimated residual basis set error of the estimated CCSD(T) basis set limit is conservatively expected to be +/-1 kcal/mol. In general, DFT exhibits large errors for relative energies with RMSD values in the 8-34 kcal/mol range. However, among the DFT functionals, the DSD-PBEP86-D3BJ double hybrid comes close to our best ab initio results, while the omegaB97X-V range-separated hybrid is in semiquantitative agreement. PMID- 26654917 TI - Overwintering Survival of Drosophila suzukii (Diptera: Drosophilidae) and the Effect of Food on Adult Survival in California's San Joaquin Valley. AB - The overwintering survival and development of Drosophila suzukii Matsumura were investigated in California's San Joaquin Valley. Drosophila suzukii were exposed to overwintering conditions in cages hung in a citrus orchard, and the pupae were buried in the soil. Eggs exposed from late November to January did not survive; a low percentage (<3%) of larvae and pupae developed into adults. Survival of pupae was significantly higher when buried in the soil than on the citrus tree. From late January to March, all life stages developed into adults and overwintered adult female D. suzukii produced eggs when provided with 10% honey-water and sliced oranges. Adult survival varied among fruit juice provision treatments and overwintering exposure periods, ranging from 3.4 +/- 0.9 d (water) to 44.1 +/- 3.0 d (10% honey-water). Fruit juices of apple, cherry, grape, orange, and pomegranate were tested as adult food sources; results showed that adult female and male D. suzukii lived only 2 d with water only, whereas adults survived from 14.2 to 34.8 d with fruit juice treatments and the 10% honey-water control. An unexpected event was the oviposition and immature development of D. suzukii with the fruit juice. In a follow-up laboratory trial, when 10% honey-water or orange juice were provided along with an artificial diet for oviposition and immature development, female D. suzukii survived for 21.6 +/- 2.4 or 21.6 +/- 1.5 d, and produced 106.8 +/- 14.1 or 98.5 +/- 13.1 offspring, respectively. We discuss factors potentially influencing overwintering survival of D. suzukii. PMID- 26654918 TI - Reduction over time of QTc prolongation in patients with sotalol after cardioversion of atrial fibrillation. AB - BACKGROUND: Sotalol is recommended to prevent relapse of atrial fibrillation after cardioversion (CV). Sotalol prolongs the action potential by blocking the rapid component of the delayed rectifier potassium current, which results in corrected QT (QTc) prolongation on the electrocardiogram. Pronounced QTc prolongation may lead to proarrhythmias and sudden death. OBJECTIVE: We investigated the dynamics of the QTc interval during the week after CV in patients treated with sotalol compared with patients treated with a beta-blocker. METHODS: Patients who underwent elective CV for persistent atrial fibrillation and maintained sinus rhythm for 1 week were included prospectively. All patients were on the highest tolerable stable dose of metoprolol or sotalol. Twelve-lead electrocardiograms were recorded 1 hour and 1 week after CV. RESULTS: A total of 104 patients on sotalol and 104 on metoprolol were included; clinical characteristics between groups were comparable. One hour after CV, the QTc interval was significantly longer in sotalol-treated patients than in metoprolol treated patients (465 +/- 25 ms vs 423 +/- 30 ms; P <= .0001). After 1 week, the QTc interval was reduced by -20.3 +/- 24 ms in sotalol-treated patients (P <= .001); no such effect was seen in metoprolol-treated patients (-2.5 +/- 18 ms; P = 0.28). The heart rate was stable during the week in both groups. In multivariate analysis of sotalol-treated patients, factors contributing to pronounced reduction in the QTc interval were longer QTc interval after CV and renal function. CONCLUSION: The QTc interval is significantly reduced during the week after CV to sinus rhythm in sotalol-treated patients. This provides insight into the increased risk of proarrhythmias in the immediate time period after CV. PMID- 26654919 TI - Trans-coronary sinus intraseptal para-Hisian pacing: Cerclage pacing. PMID- 26654920 TI - Electrolyte disturbances differentially regulate sinoatrial node and pulmonary vein electrical activity: A contribution to hypokalemia- or hyponatremia-induced atrial fibrillation. AB - BACKGROUND: Hypokalemia and hyponatremia increase the occurrence of atrial fibrillation. Sinoatrial nodes (SANs) and pulmonary veins (PVs) play a critical role in the pathophysiology of atrial fibrillation. OBJECTIVE: The purpose of this study was to evaluate whether electrolyte disturbances with low concentrations of potassium ([K(+)]) or sodium ([Na(+)]) modulate SAN and PV electrical activity and arrhythmogenesis, and to investigate potential underlying mechanisms. METHODS: Conventional microelectrodes were used to record electrical activity in rabbit SAN and PV tissue preparations before and after perfusion with different low [K(+)] or [Na(+)], interacting with the Na(+)-Ca(2+) exchanger inhibitor KB-R7943 (10 MUMU). RESULTS: Low [K(+)] (3.5, 3, 2.5, and 2 mM) decreased beating rates in PV cardiomyocytes with genesis of delayed afterdepolarizations (DADs), burst firing, and increased diastolic tension. Low [K(+)] (3.5, 3, 2.5, and 2 mM) also decreased SAN beating rates, with genesis of DADs. Low [Na(+)] increased PV diastolic tension, DADs, and burst firing, which was attenuated in the co-superfusion with low [K(+)] (2 mM). In contrast, low [Na(+)] had little effect on SAN electrical activities. KB-R7943 (10 MUMU) reduced the occurrences of low [K(+)] (2 mM)- or low [Na(+)] (110 mM)-induced DAD and burst firing in both PVs and SANs. CONCLUSION: Low [K(+)] and low [Na(+)] differentially modulate SAN and PV electrical properties. Low [K(+)]- or low [Na(+)]-induced slowing of SAN beating rate and genesis of PV burst firing may contribute to the high occurrence of atrial fibrillation during hypokalemia or hyponatremia. PMID- 26654921 TI - A novel method to identify the origin of ventricular tachycardia from the left fascicular system. AB - BACKGROUND: There are well-described ablation strategies to treat left fascicular tachyarrhythmia (LFTA); however, a method to predict the origin is less well characterized. OBJECTIVE: The purpose of this study was to predict the origin of LFTAs by measuring the HV interval during normal sinus rhythm (NSR) and LFTAs. METHODS: A predicted value of the earliest presystolic potential (PP) time was calculated using the HV interval during NSR and LFTAs [(HVNSR+HVLFTA)/2]. The earliest retrograde PP was mapped during LFTAs, and the relationship between the predicted and the mapped value was correlated. RESULTS: Twenty-one consecutive patients with LFTAs were included in this study. Four patients (19%) had tachycardia originating from the left anterior fascicle; the mean HV interval was 50.3 +/- 8.3 and 30.3 +/- 11.6 ms during NSR and tachycardia, respectively. The mapped retrograde PP during LFTAs preceded the onset of the surface electrocardiogram by 34 +/- 9.4 ms. Seventeen patients (81%) had tachycardia originating from the left posterior fascicle; the mean HV interval was 49.2 +/- 4.6 and -4.5 +/- 13.6 ms during NSR and LFTAs, respectively. Nineteen patients with successful ablation were analyzed; the mean HV interval was -0.9 +/- 16.8 and 49.5 +/- 4.6 ms during LFTAs and NSR, respectively. The predicted value was similar to the mapped value (24.4 +/- 9.1 ms vs 25.2 +/- 8.1 ms; P = .76). The predicted value was well correlated with that from the target site (r = 0.97; P < .001). CONCLUSION: The earliest retrograde PP site for the ablation of LFTAs can be predicted measuring the HV interval during NSR and LFTAs. Successful ablation can be performed during NSR for patients with LFTAs inducible at baseline but noninducible during mapping. PMID- 26654922 TI - Neutrophil activation during attacks in patients with hereditary angioedema due to C1-inhibitor deficiency. AB - BACKGROUND: Earlier studies have shown that the absolute number of neutrophil granulocytes (NGs) may increase during attack of hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE). Whether NGs undergo activation during attack has not yet been investigated. However, as neutrophil elastase (NE) can cleave and inactivate C1-INH which may contribute to the dysregulation of the kallikrein kinin system and hence, to edema formation. Our aim was to investigate the possible activation of NGs during attacks. METHODS: We studied blood samples obtained from 26 patients with C1-INH-HAE during symptom-free periods and during attacks, along with samples from 26 healthy volunteers. NG count (NGC), NE, myeloperoxidase (MPO), pentraxin 3 (PTX3), CRP, C5a, factor H, IL-8, and TNF alpha levels were measured. RESULTS: NGC was higher during attacks than during symptom-free periods (p = 0.0132), and the same was observed for NE (p = 0.0026), MPO (p = 0.0008), and PTX3 levels (p = 0.0409). There was a strong positive correlation between NE and MPO levels during attacks (p < 0.0001, R = 0.709). Furthermore, IL-8 (p = 0.0061) and TNF-alpha (p = 0.0186) levels were also elevated during attacks, compared with symptom-free periods. By contrast, C5a and factor H levels were similar in samples obtained during attacks or in symptom free periods. CONCLUSION: Increased NGC was associated with elevated NE and MPO levels - this suggests neutrophil activation during attacks. The strong positive correlation between NE and MPO levels, together with the elevated PTX3 concentration, may indicate the expression of neutrophil extracellular traps. All these processes may contribute to the activation of kallikrein-kinin system, which leads to the onset of an edematous episode. PMID- 26654923 TI - Brakes and gas-regulation of ENaC by sodium. PMID- 26654924 TI - Potential of digital technologies and therapies for children and young people. PMID- 26654925 TI - Management of Cerebrospinal Fluid Leakage During Anterior Cervical Discectomy and Fusion and Its Effect on Spinal Fusion. AB - BACKGROUND: Anterior cervical discectomy and fusion (ACDF) is a commonly performed procedure. Cerebrospinal fluid (CSF) leaks, although uncommon, may occur and can be a potentially serious complication. Little is known regarding the fusion rate after durotomy in ACDF. This study sought to investigate the clinical outcomes and fusion rates of patients with CSF leak after ACDF. METHODS: In this single-institution retrospective review, 14 patients who experienced CSF leak after ACDF between 1995 and September 2014 were identified. RESULTS: The median follow-up was 13.1 months. The diagnoses included spondylosis/degenerative disc disease (n = 10), disc herniation with radiculopathy (n = 3), and kyphotic deformity (n = 1). Of ACDFs, 7 were 1-level, 5 were 2-level, and 2 were 3-level procedures. The posterior longitudinal ligament was intentionally opened in all cases, and the microscope was used in 9 cases. Durotomy was discovered intraoperatively in all cases and was generally repaired with a combination of fibrin glue and synthetic dural replacement. Lumbar drainage was used in 5 patients, and 3 patients reported orthostatic headaches, which resolved within 1 month. Two patients reported hoarseness, and 8 patients reported dysphagia; all cases were transient. Follow-up imaging for fusion assessment was available for 12 patients, and a 100% fusion rate was achieved with no postoperative infections. CONCLUSIONS: ACDFs with CSF leak had a 100% fusion rate in this series, with generally excellent clinical outcomes, although it is difficult to conclude definitively that there is no effect on fusion rates because of the small sample size. However, given the relative rarity of this complication, this study provides important data in the clinical literature regarding outcomes after CSF leak in ACDFs. PMID- 26654926 TI - The Quest for Predictors of Seizure Improvement Following Arteriovenous Malformation Radiosurgery. PMID- 26654927 TI - Rapid De Novo Aneurysm Formation after Rathke Cleft Cyst Rupture. AB - BACKGROUND: Spontaneous rupture of a Rathke cleft cyst is very rare, and rapid de novo aneurysm formation associated with pituitary apoplexy is rare. CASE DESCRIPTION: A 66-year-old woman experienced severe left temporal pain. Magnetic resonance imaging showed a Rathke cleft cyst, and transsphenoidal surgery was planned. However, the patient suddenly developed severe headache, vomiting, visual disturbance, and a lowered level of consciousness about 3 weeks after the first onset. The clinical course and neuroradiologic characteristics suggested Rathke cleft cyst rupture. The patient received hormone replacement, and the visual abnormalities resolved. However, subsequent neuroradiologic evaluation demonstrated that a de novo aneurysm in the cavernous sinus portion of the internal carotid artery had formed within 8 days after rupture of the Rathke cleft cyst. This de novo aneurysm was not apparent on initial magnetic resonance angiography. CONCLUSIONS: This case features a rare clinical presentation of rapid de novo aneurysm formation after Rathke cleft cyst rupture. The severe inflammation around the vasculature after rupture of the Rathke cleft cyst might have been involved in aneurysm formation. PMID- 26654928 TI - Malignant Transformation of Radiotherapy-Naive Craniopharyngioma. AB - BACKGROUND: Craniopharyngioma is a rare benign intracranial neoplasm that is successfully managed with surgery or adjuvant radiotherapy. The malignant transformation of craniopharyngioma has seldom been reported. CASE DESCRIPTION: A 30-year-old woman presented with a 5-month history of amenorrhea and was admitted to the hospital. She underwent surgical resection for three times and died at last. MRI revealed a new solid component of craniopharyngioma. Pathologic examination revealed malignant changes in the craniopharyngioma. In addition, We analyzed the expression of Ki-67, p53, VEGF, and MMP-9 in this malignant case after the third operation and in samples from 9 benign craniopharyngiomas. Immunohistochemical analysis showed that the Ki-67 index was higher in malignant craniopharyngiomas (50%) compared with benign craniopharyngiomas (3.0% +/- 1.5%; range, 1.0%-6.0%). The p53, MMP-9, and VEGF protein levels were higher in the malignant craniopharyngioma compared with the benign craniopharyngiomas. CONCLUSIONS: Patients with a high Ki-67 index and high p53, MMP-9, and VEGF protein levels and a new solid component of craniopharyngioma on MRI may benefit from aggressive treatment and close surveillance. PMID- 26654929 TI - Intraventricular Bone Wax as Cause of Recurrent Cerebrospinal Fluid Infection: A Neuroradiologic Pitfall. AB - BACKGROUND: Persistent or recurrent shunt infections can be secondary to predisposing factors, such as isolated compartments, cerebrospinal fluid leaks, or foreign bodies. CASE DESCRIPTION: A 5-year-old girl experienced several episodes of shunt infections. After careful reevaluation of all neuroradiologic records of the patient, a foreign body in the left frontal horn of the lateral ventricle was suspected. An endoscopic approach was used to identify and remove a small fragment of bone wax. CONCLUSIONS: To our knowledge, this is the first report of intraventricular bone wax causing persistent CSF infection. The diagnosis was difficult because wax resembles air on computed tomography and on magnetic resonance imaging, and so it had been not noticed for months. Only its persistence on several images raised the suspicion of foreign body inside the ventricular system. PMID- 26654930 TI - An integrated exposure assessment of phthalates for the general population in China based on both exposure scenario and biomonitoring estimation approaches. AB - The representativeness of available studies on integrated exposure assessment of phthalates for the general population in China is lacking. Based on an exhaustive review of the extensive monitoring data available for China, this study presents a large-scale estimation of exposure levels to three typical phthalates, di(2 ethylhexyl) phthalate (DEHP), di-n-butyl phthalate (DBP) and diisobutyl phthalate (DiBP), by applying both exposure scenario and biomonitoring estimation approaches. The respective median exposure levels from the exposure scenario and biomonitoring estimation approaches were 3.80, 3.02 and 1.00 MUg/kg bw/day and 3.38, 3.21 and 3.32 MUg/kg bw/day for DEHP, DBP and DiBP, which are acceptable levels of exposure with respect to current international guidelines. Evaluation results from the two approaches showed both similarities and differences among the different phthalates, making the exposure assessment comparable and more comprehensive. In terms of sources of exposure, food intake was the largest contributor, while indoor air exposure had greater contribution to the estimated daily intakes (EDIs) of DiBP than that of the other phthalates. Moreover, more attention should be paid to the higher exposure levels of phthalates in several intensively industrialized and urbanized areas, and the causes of the different exposure levels in the different regions need to be further explored. PMID- 26654931 TI - Opinion of the Scientific Committee on Consumer Safety (SCCS) - Revision of the opinion on the safety of the use of Silica, Hydrated Silica, and Silica Surface Modified with Alkyl Silylates (nano form) in cosmetic products. AB - CONCLUSION OF THE OPINION: The SCCS has concluded that the evidence, both provided in the submission and that available in scientific literature, is inadequate and insufficient to allow drawing any firm conclusion either for or against the safety of any of the individual SAS material, or any of the SAS categories that are intended for use in cosmetic products. As the SCCS has not been able to conclude on the safety of the synthetic amorphous silica (SAS) materials included in the current submission, the Applicant is advised to follow the SCCS Guidance on Risk Assessment of Nanomaterials (SCCS/1484/12). A brief summary is provided to enable/facilitate future evaluation of the SAS materials in cosmetic products. PMID- 26654932 TI - Effect of rs1344706 in the ZNF804A gene on the connectivity between the hippocampal formation and posterior cingulate cortex. AB - ZNF804A is one of the most promising candidate genes for schizophrenia. Previous fMRI studies have repeatedly shown an association between SNP rs1344706 in this gene and the functional connectivity from the right dorsolateral prefrontal cortex (rDLPFC) to the left hippocampal formation (lHF) during the N-back task. However, the rDLPFC-lHF functional connectivity included several subconnections and it is not known whether rs1344706 plays the same role in these subconnections. This study addressed that question using both fMRI and DTI data of 87 subjects. First, we replicated the association between rs1344706 and the rDLPFC-lHF functional connectivity using our fMRI data from the N-back task. Second, we reconstructed fiber connections between rDLPFC and lHF using our DTI data, which included three subconnections: from lHF to posterior cingulate cortex (PCC), from PCC to anterior cingulated cortex (ACC), and from ACC to rDLPFC. We found that only the lHF-PCC tract showed significantly lower fractional anisotropy (FA) in risk allele homozygotes. Finally, we analyzed the fMRI data (from the N-back task and the resting state). Both consistently showed relatively lower lHF-PCC functional connectivity in risk allele homozygotes. Taken together, the disconnectivity of the lHF-PCC tract seems to be a plausible intermediate phenotype that links rs1344706 and schizophrenia. PMID- 26654933 TI - Interaction among subsystems within default mode network diminished in schizophrenia patients: A dynamic connectivity approach. AB - Default mode network (DMN) has been reported altered in schizophrenia (SZ) using static connectivity analysis. However, the studies on dynamic characteristics of DMN in SZ are still limited. In this work, we compare dynamic connectivity within DMN between 82 healthy controls (HC) and 82 SZ patients using resting-state fMRI. Firstly, dynamic DMN was computed using a sliding time window method for each subject. Then, the overall connectivity strengths were compared between two groups. Furthermore, we estimated functional connectivity states using K-means clustering, and then investigated group differences with respect to the connectivity strengths in states, the dwell time in each state, and the transition times between states. Finally, graph metrics of time-varying connectivity patterns and connectivity states were assessed. Results suggest that measured by the overall connectivity, HC showed stronger inter-subsystem interaction than patients. Compared to HC, patients spent more time in the states with nodes sparsely connected. For each state, SZ patients presented relatively weaker connectivity strengths mainly in inter-subsystem. Patients also exhibited lower values in averaged node strength, clustering coefficient, global efficiency, and local efficiency than HC. In summary, our findings indicate that SZ show impaired interaction among DMN subsystems, with a reduced central role for posterior cingulate cortex (PCC) and anterior medial prefrontal cortex (aMPFC) hubs as well as weaker interaction between dorsal medial prefrontal cortex (dMPFC) subsystem and medial temporal lobe (MTL) subsystem. For SZ, decreased integration of DMN may be associated with impaired ability in making self-other distinctions and coordinating present mental states with episodic decisions about future. PMID- 26654934 TI - Extended-Release Naltrexone: A Qualitative Analysis of Barriers to Routine Use. AB - The Medication Research Partnership (a national health plan and nine addiction treatment centers contracted with the health plan) sought to facilitate the adoption of pharmacotherapy for alcohol and opioid use disorders. Qualitative analysis of interviews with treatment center change leaders, individuals working for the manufacturer and its technical assistance contractor, and health plan managers extracted details on the processes used to order, store, bill for, and administer extended-release naltrexone. Qualitative themes were categorized using domains from the Consolidated Framework for Implementation Research (intervention characteristics, outer setting, inner setting, and provider characteristics). Characteristics of XR-NTX that inhibited use included the complexity of ordering and using the medication; cost was also a barrier. Outer setting barriers reflected patient needs and external health plan policies on formulary coverage, benefit management, and reimbursement. Program structures, the lack of physician linkages, a culture resistant to the use of medication, and unease with change were inner setting elements that limited use of XR-NTX. Patient stereotypes and a lack of knowledge about XR-NTX affected practitioner willingness to treat patients and prescribe XR-NTX. The Consolidated Framework for Implementation Research provided a useful lens to understand and interpret the processes affecting access to XR-NTX. PMID- 26654935 TI - Morphology and Pattern Control of Diphenylalanine Self-Assembly via Evaporative Dewetting. AB - Self-assembled peptide nanostructures have unique physical and biological properties and promising applications in electrical devices and functional molecular recognition. Although solution-based peptide molecules can self assemble into different morphologies, it is challenging to control the self assembly process. Herein, controllable self-assembly of diphenylalanine (FF) in an evaporative dewetting solution is reported. The fluid mechanical dimensionless numbers, namely Rayleigh, Marangoni, and capillary numbers, are introduced to control the interaction between the solution and FF molecules in the self assembly process. The difference in the film thickness reflects the effects of Rayleigh and Marangoni convection, and the water vapor flow rate reveals the role of viscous fingering in the emergence of aligned FF flakes. By employing dewetting, various FF self-assembled patterns, like concentric and spokelike, and morphologies, like strips and hexagonal tubes/rods, can be produced, and there are no significant lattice structural changes in the FF nanostructures. PMID- 26654936 TI - Magnetic (CoFe2O4)0.1(CeO2)0.9 nanocomposite as effective pinning centers in FeSe0.1Te0.9 thin films. AB - Magnetic epitaxial (CoFe2O4)0.1(CeO2)0.9 nanocomposite layers were incorporated into superconducting FeSe0.1Te0.9 thin films as either a cap layer or a buffer layer. Both capped and buffered samples show an enhancement of the superconducting property compared to the reference sample without the incorporated layer, while the capped one shows the best pinning properties of all the samples. Specifically for the capped sample, the critical temperature Tc is ~12.5 K, while the self-field critical current density J(c)(sf )increases to as high as 1.20 MA cm(-2) at 4 K. Its J(c)(in-field) value shows a slower decrease with increasing applied magnetic field, with the lowest power-law exponent alpha values (derived following Jc[formula: see text](MU0H)(-alpha) by the log(Jc) - log(MU0H) plot) of 0.20, 0.23 and 0.33 at 2 K, 4 K and 8 K, respectively. This nanocomposite capped sample also exhibits a high upper critical field Hc2(0) of 166 T, which indicates its potential in high field applications. This pinning method provides an effective way of enhancing the superconducting property of iron chalcogenide thin film. PMID- 26654937 TI - Complete genome of Pseudoalteromonas phenolica KCTC 12086(T) (= O-BC30(T)), a marine bacterium producing polybrominated aromatic compounds. AB - Pseudoalteromonas phenolica is a Gram-negative, rod-shaped, flagellated, aerobic, antibiotic-producing bacterium that was isolated from seawater off Ogasawara Island, Japan. Here, we report the complete genome of P. phenolica KCTC 12086(T) (= O-BC30(T)), which consists of 4,868,993 bp (G+C content of 40.6%) with two chromosomes, 4168 protein-coding genes, 113 tRNAs and 9 rRNA operons. In addition, several genes related to phenolic anti-methicillin-resistant Staphylococcus aureus substances were detected in the genome suggesting that biosynthesis of industrially important polybrominated aromatic compounds could be better understood with the availability of genome data of P. phenolica. PMID- 26654938 TI - S-Sulfocysteine simplifies fed-batch processes and increases the CHO specific productivity via anti-oxidant activity. AB - Industrial fed-batch cultivation of mammalian cells is used for the production of therapeutic proteins such as monoclonal antibodies. Besides medium ensuring initial growth, feeding is necessary to improve growth, viability and antibody production. Established processes include a slight acidic main feed and a separate alkaline feed containing l-tyrosine and l-cysteine. Since l-cysteine is not stable at neutral pH, a new derivative, S-sulfocysteine, was tested in neutral pH feeds. In small scale fed-batch processes, the S-sulfocysteine process yielded a comparable maximum viable cell density, prolonged viability and increased titer compared to the two feed system. Bioreactor experiments confirmed the increase in specific productivity. In depth characterization of the monoclonal antibody indicated no change in the glycosylation, or charge variant pattern whereas peptide mapping experiments were not able to detect any integration of the modified amino acid in the sequence of the monoclonal antibody. Finally, the mechanism of action of S-sulfocysteine was investigated, and results pointed out the anti-oxidative potential of the molecule, mediated through an increase in superoxide dismutase enzyme levels and in the total intracellular glutathione pool. Finally, we propose that the increase in specific productivity obtained in the S-sulfocysteine process results from the anti oxidative properties of the molecule. PMID- 26654939 TI - Defining the possibilities: is short duration treatment of chronic hepatitis C genotype 1 with sofosbuvir-containing regimens likely to be as effective as current regimens? AB - This review summarizes published data on sofosbuvir-based regimens for patients infected with HCV GT1 with a focus on evaluating the optimal and possible durations of treatment. METHODS: PubMed and conference abstract books published between 2011-2015 were searched. RESULTS: HCV treatment has decreased from 24 week regimens to studies done as short as 4 weeks. History of prior treatment or cirrhosis have consistently shown lower SVR12 rates with shorter duration therapies. Low cure rates have been seen in patients within 4 week trials, however, select patients with low fibrosis scores, low HCV VL and HCV GT-1b have moderate cure rates. CONCLUSION: Most patients will require 12-24 weeks of therapy. Further studies are needed to elucidate the predictors of treatment response to short duration therapies and optimal combination of DAAs. PMID- 26654940 TI - Unique roles of Akt1 and Akt2 in IGF-IR mediated lung tumorigenesis. AB - AKT is a serine-threonine kinase that becomes hyperactivated in a number of cancers including lung cancer. Based on AKT's association with malignancy, molecules targeting AKT have entered clinical trials for solid tumors including lung cancer. However, the AKT inhibitors being evaluated in clinical trials indiscriminately inhibit all three AKT isoforms (AKT1-3) and it remains unclear whether AKT isoforms have overlapping or divergent functions. Using a transgenic mouse model where IGF-IR overexpression drives lung tumorigenesis, we found that loss of Akt1 inhibited while loss of Akt2 enhanced lung tumor development. Lung tumors that developed in the absence of Akt2 were less likely to appear as discrete nodules and more frequently displayed a dispersed growth pattern. RNA sequencing revealed a number of genes differentially expressed in lung tumors lacking Akt2 and five of these genes, Actc1, Bpifa1, Mmp2, Ntrk2, and Scgb3a2 have been implicated in human lung cancer. Using 2 human lung cancer cell lines, we observed that a selective AKT1 inhibitor, A-674563, was a more potent regulator of cell survival than the pan-AKT inhibitor, MK-2206. This study suggests that compounds selectively targeting AKT1 may prove more effective than compounds that inhibit all three AKT isoforms at least in the treatment of lung adenocarcinoma. PMID- 26654941 TI - EGFR kinase domain mutation positive lung cancers are sensitive to intrapleural perfusion with hyperthermic chemotherapy (IPHC) complete treatment. AB - Lung cancer is the global leading cause of cancer-related deaths. A significant portion of lung cancer patients harbor kinase domain mutations in the epidermal growth factor receptor (EGFR). While EGFR tyrosine kinase inhibitors (TKI) effectively shrink tumors harboring mutant EGFR, clinical efficacy is limited by the development of TKI resistance. Effective alternatives are desperately needed in clinic for treating EGFR kinase domain mutation positive lung cancer. In our clinic in treating M1a lung cancer patients through intrapleural perfusion with hyperthermic chemotherapy (IPHC) followed by cycles of systemic chemotherapy (we termed this procedure IPHC complete treatment, IPHC-CT), we found dramatic tumor shrinkage in mutant EGFR-positive patients. We further confirmed the sensitivity of EGFR mutation-positive lung cancer cell lines derived from patients to HC (hyperthermic chemotherapy) treatment. We found that hyperthermia promoted accumulation of cisplatin in lung cancer cells. Hyperthermia and cisplatin synergistically downregulated the EGFR protein level, leading to quenching of signal from EGFR and induction of apoptosis. Our work therefore showed IPHC-CT is an effective treatment for EGFR kinase domain mutation positive lung cancer patients. PMID- 26654942 TI - Diet-derived 25-hydroxyvitamin D3 activates vitamin D receptor target gene expression and suppresses EGFR mutant non-small cell lung cancer growth in vitro and in vivo. AB - Epidemiologic studies implicate vitamin D status as a factor that influences growth of EGFR mutant lung cancers. However, laboratory based evidence of the biological effect of vitamin D in this disease is lacking. To fill this knowledge gap, we determined vitamin D receptor (VDR) expression in human lung tumors using a tissue microarray constructed of lung cancer cases from never-smokers (where EGFR gene mutations are prevalent). Nuclear VDR was detected in 19/19 EGFR mutant tumors. Expression tended to be higher in tumors with EGFR exon 19 deletions than those with EGFR L858R mutations. To study anti-proliferative activity and signaling, EGFR mutant lung cancer cells were treated with the circulating metabolite of vitamin D, 25-hydroxyvitamin D3 (25D3). 25D3 inhibited clonogenic growth in a dose-dependent manner. CYP27B1 encodes the 1alpha-hydroxylase (1alphaOHase) that converts 25D3 to the active metabolite, 1,25-dihydroxyvitamin D3 (1,25D3). Studies employing VDR siRNA, CYP27B1 zinc finger nucleases, and pharmacologic inhibitors of the vitamin D pathway indicate that 25D3 regulates gene expression in a VDR-dependent manner but does not strictly require 1alphaOHase-mediated conversion of 25D3 to 1,25D3. To determine the effects of modulating serum 25D3 levels on growth of EGFR mutant lung tumor xenografts, mice were fed diets containing 100 or 10,000 IU vitamin D3/kg. High dietary vitamin D3 intake resulted in elevated serum 25D3 and significant inhibition of tumor growth. No toxic effects of supplementation were observed. These results identify EGFR mutant lung cancer as a vitamin D-responsive disease and diet-derived 25D3 as a direct VDR agonist and therapeutic agent. PMID- 26654943 TI - A method for quantification of exportin-1 (XPO1) occupancy by Selective Inhibitor of Nuclear Export (SINE) compounds. AB - Selective Inhibitor of Nuclear Export (SINE) compounds are a family of small molecules that inhibit nuclear export through covalent binding to cysteine 528 (Cys528) in the cargo-binding pocket of Exportin 1 (XPO1/CRM1) and promote cancer cell death. Selinexor is the lead SINE compound currently in phase I and II clinical trials for advanced solid and hematological malignancies. In an effort to understand selinexor-XPO1 interaction and to establish whether cancer cell response is a function of drug-target engagement, we developed a quantitative XPO1 occupancy assay. Biotinylated leptomycin B (b-LMB) was utilized as a tool compound to measure SINE-free XPO1. Binding to XPO1 was quantitated from SINE compound treated adherent and suspension cells in vitro, dosed ex vivo human peripheral blood mononuclear cells (PBMCs), and PBMCs from mice dosed orally with drug in vivo. Evaluation of a panel of selinexor sensitive and resistant cell lines revealed that resistance was not attributed to XPO1 occupancy by selinexor. Administration of a single dose of selinexor bound XPO1 for minimally 72 hours both in vitro and in vivo. While XPO1 inhibition directly correlates with selinexor pharmacokinetics, the biological outcome of this inhibition depends on modulation of pathways downstream of XPO1, which ultimately determines cancer cell responsiveness. PMID- 26654944 TI - FOXP1 functions as an oncogene in promoting cancer stem cell-like characteristics in ovarian cancer cells. AB - Ovarian cancer has the highest mortality rate of all gynecological cancers with a high recurrence rate. It is important to understand the nature of recurring cancer cells to terminally eliminate ovarian cancer. The winged helix transcription factor Forkhead box P1 (FOXP1) has been reported to function as either oncogene or tumor-suppressor in various cancers. In the current study, we show that FOXP1 promotes cancer stem cell-like characteristics in ovarian cancer cells. Knockdown of FOXP1 expression in A2780 or SKOV3 ovarian cancer cells decreased spheroid formation, expression of stemness-related genes and epithelial to mesenchymal transition-related genes, cell migration, and resistance to Paclitaxel or Cisplatin treatment, whereas overexpression of FOXP1 in A2780 or SKOV3 ovarian cancer cells increased spheroid formation, expression of stemness related genes and epithelial to mesenchymal transition-related genes, cell migration, and resistance to Paclitaxel or Cisplatin treatment. In addition, overexpression of FOXP1 increased promoter activity of ABCG2, OCT4, NANOG, and SOX2, among which the increases in ABCG2, OCT4, and SOX2 promoter activity were dependent on the presence of FOXP1-binding site. In xenotransplantation of A2780 ovarian cancer cells into nude mice, knockdown of FOXP1 expression significantly decreased tumor size. These results strongly suggest FOXP1 functions as an oncogene by promoting cancer stem cell-like characteristics in ovarian cancer cells. Targeting FOXP1 may provide a novel therapeutic opportunity for developing a relapse-free treatment for ovarian cancer patients. PMID- 26654945 TI - Are Hospice Admission Practices Associated With Hospice Enrollment for Older African Americans and Whites? AB - CONTEXT: Hospices that enroll patients receiving expensive palliative therapies may serve more African Americans because of their greater preferences for aggressive end-of-life care. OBJECTIVES: Examine the association between hospices' admission practices and enrollment of African Americans and whites. METHODS: This was a cross-sectional study of 61 North and South Carolina hospices. We developed a hospice admission practices scale; higher scores indicate less restrictive practices, that is, greater frequency with which hospices admitted those receiving chemotherapy, inotropes, and so forth. In separate multivariate analyses for each racial group, we examined the relationship between the proportion of decedents (age >= 65) served by a hospice in their service area (2008 Medicare Data) and admission practices while controlling for health care resources (e.g., hospital beds) and market concentration in the area, ownership, and budget. RESULTS: Nonprofit hospices and those with larger budgets reported less restrictive admission practices. In bivariate analyses, hospices with less restrictive admission practices served a larger proportion of patients in both racial groups (P < 0.001). However, in the multivariate models, nonprofit ownership and larger budgets but not admission practices predicted the outcome. CONCLUSION: Hospices with larger budgets served a greater proportion of African Americans and whites in their service area. Although larger hospices reported less restrictive admission practices, they also may have provided other services that may be important to patients regardless of race, such as more in-home support or assistance with nonmedical expenses, and participated in more outreach activities increasing their visibility and referral base. Future research should explore factors that influence decisions about hospice enrollment among racially diverse older adults. PMID- 26654946 TI - Dimensionality, Stability, and Validity of the Beck Hopelessness Scale in Cancer Patients Receiving Curative and Palliative Treatment. AB - CONTEXT: Hopelessness is a clinically important construct in patients with advanced illness. OBJECTIVES: To evaluate the dimensionality, stability, and validity of the Beck Hopelessness Scale (BHS) in cancer patients receiving either curative or palliative treatment. METHODS: Following a longitudinal design, we assessed a sample of cancer patients receiving either curative or palliative treatment (N = 315) at baseline and at follow-up after 12 months (N = 158). In addition to hopelessness, we measured depression (Patient Health Questionnaire 9), anxiety (General Anxiety Disorder-7), and health-related quality of life (Short-Form Health Survey-8). We analyzed dimensionality, stability, and construct validity of the BHS using confirmatory factor analysis, exploratory factor analysis and correlational analysis. RESULTS: Independent of treatment intention, confirmatory factor analyses resulted in unsatisfactory model fits. Exploratory factor analysis yielded a two-factor solution in both groups receiving curative or palliative treatment. Factor 1 reflected pessimistic/resigned beliefs (Cronbach alpha >= 0.85), Factor 2 reflected positive beliefs toward the future (Cronbach alpha = 0.73). Both subscales showed significant associations with anxiety, depression, and decreased health-related quality of life. The factorial structure was partially replicated in patients being reexamined after 12 months (CMIN/DF = 2.130, Standardized Root Mean Square Residual = 0.0716, Comparative Fit Index = 0.904, Tucker-Lewis-Index = 0.883, Root Mean Square Error of Approximation = 0.085). Hopelessness scores were significantly higher in patients reporting suicidal ideation according to the Patient Health Questionnaire-9. CONCLUSION: Our study demonstrates psychometric limitations of the BHS in patients receiving both curative and palliative treatment, suggesting reduced utility in cancer populations. Given the clinical importance of the construct, a cancer-specific approach to capture the unique meaning of hopelessness in patients with severe medical illness is recommended. PMID- 26654947 TI - Strategic Application and Transformation of ortho-Disubstituted Phenyl and Cyclopropyl Ketones To Expand the Scope of Hydrogen Borrowing Catalysis. AB - The application of an iridium-catalyzed hydrogen borrowing process to enable the formation of alpha-branched ketones with higher alcohols is described. In order to facilitate this reaction, ortho-disubstituted phenyl and cyclopropyl ketones were recognized as crucial structural motifs for C-C bond formation. Having optimized the key catalysis step, the ortho-disubstituted phenyl products could be further manipulated by a retro-Friedel-Crafts acylation reaction to produce synthetically useful carboxylic acid derivatives. In contrast, the cyclopropyl ketones underwent homoconjugate addition with several nucleophiles to provide further functionalized branched ketone products. PMID- 26654948 TI - Monte Carlo simulation-based feasibility study of novel indirect flat panel detector system for removing scatter radiation. AB - The purpose of this study is to investigate the feasibility of a novel indirect flat panel detector (FPD) system for removing scatter radiation. The substrate layer of our FPD system has a Pb net-like structure that matches the ineffective area and blocks the scatter radiation such that only primary X-rays reach the effective area on a thin-film transistor. To evaluate the performance of the proposed system, we used Monte Carlo simulations to derive the scatter fraction and contrast. The scatter fraction of the proposed system is lower than that of a parallel grid system, and the contrast is superior to that of a system without a grid. If the structure of the proposed FPD system is optimized with respect to the specifications of a specific detector, the purpose of the examination, and the energy range used, the FPD can be useful in diagnostic radiology. PMID- 26654949 TI - Prophylactic antibiotics should be used in children with repaired oesophageal atresia and tracheo-oesophageal fistula: The case against. PMID- 26654951 TI - Formation of small transmembrane pores: An intermediate stage on the way to Bacillus cereus non-hemolytic enterotoxin (Nhe) full pores in the absence of NheA. AB - The non-hemolytic enterotoxin (Nhe) of Bacillus cereus is a three-partite toxin formed of the components NheA, -B and -C. Pore formation and subsequent lysis of target cells caused by Nhe is an orchestrated process comprising three steps: (i) formation of NheB/C oligomers in solution, (ii) attachment of the oligomers to the cell membrane, (iii) binding of NheA to the oligomers. The present study aimed to characterize the properties of the NheB/C complex and the fate of the target cell upon binding. An enzyme immunoassay allowing kinetic measurements and surface plasmon resonance revealed the fast and high affinity formation of the NheB/C oligomers. The benefit of these complexes is a more stable cell binding as well as stronger and earlier cytotoxic effect. High molecular mass hetero oligomers (620 kDa) probably consisting of one NheC and up to 15 NheB were detected by size-exclusion chromatography and on native PAGE immunoblots. Due to the NheBC application the morphology and membrane permeability of Vero cells is partly disturbed. Formation of stable transmembrane channels with a conductance of about 870 pS and a diameter of about 2 nm due to the application of NheBC could be demonstrated in lipid bilayer experiments. Thus, the NheBC complex itself has a tendency to increase the membrane permeability prior to the emergence of full pores containing also NheA. PMID- 26654950 TI - A new risk locus in the ZEB2 gene for schizophrenia in the Han Chinese population. AB - The ZEB2 gene encodes the Zinc Finger E-box binding protein. As a key regulator of epithelial mesenchymal differentiation, ZEB2 plays an important role in the pathogenesis of cancer, and its high level expression has been observed in glioma patients. Different mutations in this gene have been identified in patients with Mowat-Wilson syndrome. A previous genome-wide association study (GWAS) of schizophrenia conducted in Caucasians has shown a significant association of rs12991836, located near the ZEB2 gene, with schizophrenia. Thus, we conducted a case control study to further investigate whether this genomic region is also a susceptibility locus for schizophrenia in the Han Chinese population. In total, 1248 schizophrenia (SCZ) cases (mean age+/-S.D., 36.44+/-9.0years), 1344 bipolar disorder (BPD) cases (mean age+/-S.D., 34.84+/-11.44years), 1056 major depressive disorder (MDD) cases (mean age+/-S.D., 34.41+/-12.09years) and 1248 healthy control samples (mean age+/-S.D., 30.62+/-11.35years) were recruited. We genotyped 12 SNPs using the Sequenom MassARRAY platform in this study. We found that rs6755392 showed a significant association with SCZ (rs6755392: adjusted Pallele=0.016; adjusted Pgenotype=0.052; OR (95% CI)=1.201 (1.073~1.344)). Additionally, two haplotypes (TCTG, TCTA) were also significantly associated with SCZ. This is the first study claiming the association of the genetic risks of rs6755392 in the ZEB2 gene with schizophrenia. PMID- 26654952 TI - Property of hepatitis B virus replication in Tupaia belangeri hepatocytes. AB - The northern treeshrew (Tupaia belangeri) has been reported to be an effective candidate for animal infection model with hepatitis B virus (HBV). The objective of our study was to analyze the growth characteristics of HBV in tupaia hepatocytes and the host response to HBV infection. We established primary tupaia hepatocytes (3-6-week old tupaia) and infected them with HBV genotypes A, B and C, and all the genotypes proliferated as well as those in human primary hepatocytes (>10(5) copies/ml in culture supernatant). We next generated a chimeric mouse with tupaia liver by transplantation of tupaia primary hepatocytes to urokinase-type plasminogen activator cDNA (cDNA-uPA)/severe combined immunodeficient (SCID) mice and the replacement ratio with tupaia hepatocytes was found to be more than 95%. Infection of chimeric mice with HBV (genotypes B, C, and D) resulted in HBV-DNA level of 10(4)-10(6) copies/ml after 8 weeks of infection, which were almost similar to that in humanized chimeric mouse. In contrast, serum HBV level in adult tupaia (1-year-old tupaia) was quite low (<10(3) copies/ml). Understanding the differences in the response to HBV infection in primary tupaia hepatocytes, chimeric mouse, and adult tupaia will contribute to elucidating the mechanism of persistent HBV infection and viral eradication. Thus, T. belangeri was found to be efficient for studying the host response to HBV infection, thereby providing novel insight into the pathogenesis of HBV. PMID- 26654953 TI - MiR-486 regulates cholesterol efflux by targeting HAT1. AB - RATIONALE: Excessive cholesterol accumulation in macrophages is a major factor of foam cell formation and development of atherosclerosis. Previous studies suggested that miR-486 plays an important role in cardiovascular diseases, but the underlying mechanism is still unknown. OBJECTIVE: The purpose of this study is to determine whether miR-486 regulates ATP-binding cassette transporter A1 (ABCA1) mediated cholesterol efflux, and also explore the underlying mechanism. METHODS AND RESULTS: Based on bioinformatics analysis and luciferase reporter assay, we transfected miR-486 mimic and miR-486 inhibitor into THP-1 macrophage derived foam cells, and found that miR-486 directly bound to histone acetyltransferase-1 (HAT1) 3'UTR, and downregulated its mRNA and protein expression. In addition, our studies through transfection with wildtype HAT1 or shHAT1 (short hairpin HAT1) revealed that HAT1 could promote the expression of ABCA1 at both mRNA and protein levels. At the same time, the acetylation levels of the lysines 5 and 12 of histone H4 were upregulated after overexpression with HAT1. Meanwhile, the results of liquid scintillation counter and high performance liquid chromatography (HPLC) showed that miR-486 promoted cholesterol accumulation in THP-1 macrophages. CONCLUSION: These data indicated that miR-486 aggravate the cholesterol accumulation in THP-1 cells by targeting HAT1. PMID- 26654954 TI - Association of elevated alpha-defensin levels with interstitial pneumonia in patients with systemic sclerosis. AB - BACKGROUND: Interstitial lung disease (ILD) is the leading cause of mortality in patients with systemic sclerosis (SSc). Although the pathogenesis of SSc-ILD is not well understood, neutrophils may play a pivotal role in this process. Neutrophils store azurophil granules that contain defensins, antimicrobial peptides that function in regulating the inflammatory response, and IL-8, a potent chemoattractant for neutrophils. The present study evaluated the levels of defensins and IL-8 in patients with SSc-ILD to determine their roles in disease pathogenesis. METHODS: Defensins (also known as human neutrophil peptides, HNPs) and IL-8 levels were measured in the serum and bronchoalveolar lavage fluid (BALF) of 33 patients with SSc-ILD and in 20 healthy controls by using ELISA. RESULTS: BALF analysis revealed a significant increase in HNPs in SSc-ILD patients (median; 240.0 pg/mL) than that of healthy controls (79.7 pg/mL). Additionally, IL-8 levels were higher in SSc-ILD patient serum and BALF as compared to healthy controls (16.4 pg/mL vs. 5.8 pg/mL and 15.4 pg/mL vs. 14.5 pg/mL, respectively). However, plasma HNPs levels were relatively unchanged. HNP and IL-8 levels in patient BALF displayed a significant positive correlation significantly correlated (r = 0.774, p <0.01), and which also correlated with clinical disease parameters--such as ILD biomarkers, pulmonary function tests, ratio of neutrophils and eosinophils in BALF, tricuspid regurgitation peak gradient (TRPG), and the extent of high-resolution computed tomography (HRCT) findings in the lung. Levels of plasma HNPs and serum IL-8 did not show a significant correlation with any clinical parameter. SSc-ILD progression was evaluated by pulmonary function tests, but no association was observed between VC change ratios and HNPs or IL-8 levels. CONCLUSIONS: BALF levels of HNPs and IL-8 were higher in SSc-ILD than in healthy controls, and are associated with various clinical disease parameters. Further studies are needed to clarify the role of defensins and IL-8 in SSc-ILD pathogenesis. PMID- 26654955 TI - Identification and structural characterization of two peroxisome proliferator activated receptors and their transcriptional changes at different developmental stages and after feeding with different fatty acids. AB - Peroxisome proliferator activated receptors beta1 (PPARbeta1) and beta2 (PPARbeta2) were investigated in loach (Misgurnus anguillicaudatus). The PPARbeta1 and PPARbeta2 were widely distributed in loach tissues. Multiple alignments of deduced amino acid sequences revealed homologous characteristics of the two subtypes of PPARbeta with 88% identity. PPARbeta1 was markedly expressed in the liver, about 100-fold higher than liver PPARbeta2. The two subtypes in unfertilized ovum (UO) showed the highest transcriptions in early life stages, and there were great divergences in expression between unfertilized and fertilized stages. The regulation of PPARbeta1 and PPARbeta2 in response to dietary fatty acids was studied in liver of loach fed with diets containing fish oil (FO, rich in n-3 highly unsaturated fatty acid) or soybean oil (SO, rich in 18:2n-6) for 75days. Results showed that hepatic transcription of PPARbeta1 in the SO group was higher than in the FO group. However, PPARbeta2 expression was similar. The differences of molecular characterization, tissue expressions in early life stages, and transcriptional regulation by lipid resources indicated that PPARbeta1 and PPARbeta2 were functionally different. This is the first report of differential expression of PPARbeta1 and PPARbeta2 in various tissues and early life stages of loach are regulated by lipid resources. These results will stimulate further studies to better understand the functional characterization of PPARbeta1 and PPARbeta2. PMID- 26654956 TI - Client-centred ADL intervention after stroke: Occupational therapists' experiences. AB - BACKGROUND: This study was conducted in the context of a randomized controlled trial evaluating the effect of a client-centred activities in daily living intervention (CADL). The aim of the CADL was to enable agency in daily activities and participation in everyday life among persons with stroke. OBJECTIVE: This qualitative, longitudinal study aimed to describe how occupational therapists (OTs) applied the CADL in their clinical practice by studying their experiences and reflections concerning their interaction with the clients with stroke. METHODS: Six OTs who conducted the CADL were followed through interviews and observations on four separate occasions over one year. Data were analysed using a grounded theory approach. RESULTS: Sharing was the core category showing how the OTs helped their clients to achieve agency in daily activities. Through sharing the situation the OTs strove to obtain an empathetic understanding of the clients' lived experience throughout the whole intervention process in order to enable the clients' ownership of their daily activities. CONCLUSION: The continuity of sharing seems to be the key for a gradual increase in agency. The approach of sharing should preferably be applied by all members of the interprofessional team, including the client and significant others. PMID- 26654957 TI - Skills, knowledge and attributes of support group leaders: A systematic review. AB - OBJECTIVES: A systematic review and qualitative synthesis was undertaken to deduce requisite knowledge, skills and attributes of cancer support group leaders. METHODS: Medline, CINAHL, and PsychINFO databases were used to identify relevant literature. Inclusion criteria were made deliberately broad after pilot searches produced too few documents and included: adult group leaders who were volunteers, peers or professionals; published in English from database inception to February 2014. Data was extracted on: year of publication; country of authors' origin; study design (if relevant) and methods; group type and group leadership; sample description; and leader qualities. RESULTS: Forty-nine documents met inclusion criteria. Fourteen reported on cancer groups, 31 on non-cancer groups (including four mixed groups) and four did not specify group type. Seven qualities were deduced including group management, group process, role modelling, awareness, willingness, agreeableness, and openness. These were consistent across group type and group leadership. CONCLUSIONS: Findings may be relevant to a general model of peer group support and can inform the development of a practical and realistic minimum standard for support group leadership in healthcare. PRACTICE IMPLICATIONS: Results can be used to help cancer agencies manage relationships with group leaders. Knowledge of requisite qualities may inform selection, training and support. PMID- 26654958 TI - Preoperative anxiety in ambulatory surgery: The impact of an empathic patient centered approach on psychological and clinical outcomes. AB - OBJECTIVE: This study aims to evaluate the influence of an empathic patient centered approach on preoperative anxiety and surgical outcomes in ambulatory surgery patients. METHODS: A sample of 104 patients undergoing general ambulatory surgery was randomly assigned to the intervention (IG) and the control (CG) groups. Before surgery, the IG received personalized information through an empathic patient-centered interview. The CG received standardized information on surgical procedures. Anxiety was assessed before and after the preoperative interview and after the surgery. Wound healing, post-surgical recovery and satisfaction with the quality of preoperative information were assessed after the surgery. RESULTS: The two groups were identical at baseline regarding anxiety, socio-demographic and clinical characteristics. After the patient-centered intervention, the IG showed lower levels of preoperative anxiety (p<0.001) and pain (p<0.001), better surgery recovery (p<0.01) and higher levels of daily activity (p<0.001) and of satisfaction with the information received (p<0.01) than the CG. The IG also showed better wound healing (tissue type, p<0.01; local pain, p<0.01). CONCLUSION: An empathic patient-centered intervention can reduce preoperative anxiety and increase surgical recovery, wound healing and patient satisfaction. PRACTICE IMPLICATIONS: This approach is applicable in pre-surgical interviews and can potentially be used in the routine care of various surgical contexts. PMID- 26654959 TI - Comparative analysis of complete mitochondrial genomes suggests that relaxed purifying selection is driving high nonsynonymous evolutionary rate of the NADH2 gene in whitefish (Coregonus ssp.). AB - Several studies have recently reported evidence for positive selection acting on the mitochondrial genome (mitogenome), emphasizing its potential role in adaptive divergence and speciation. In this study we searched 107 full mitogenomes of recently diverged species and lineages of whitefish (Coregonus ssp.) for signals of positive selection. These salmonids show several distinct morphological and ecological differences that may be associated with energetics and therefore potentially positive selection at the mitogenome level. We found that purifying selection and genetic drift were the predominant evolutionary forces acting on the analyzed mitogenomes. However, the NADH dehydrogenase 2 gene (ND2) showed a highly elevated dN/dS ratio compared to the other mitochondrial genes, which was significantly higher in whitefish compared to other salmonids. We therefore further examined nonsynonymous evolution in ND2 by (i) mapping amino acid changes to a protein model structure which showed that they were located away from key functional residues of the protein, (ii) locating them in the sequences of other species of fish (Salmonidae, Anguillidae, Scombridae and Percidae) only to find pronounced overlap of nonsynonymous regions. We thus conclude that relaxed purifying selection is driving the evolution of ND2 by affecting mostly regions that have lower functional relevance. PMID- 26654960 TI - Re: Guido Barbagli, Massimo Lazzeri. Clinical Experience with Urethral Reconstruction Using Tissue-engineered Oral Mucosa: A Quiet Revolution. Eur Urol 2015;68:917-918. PMID- 26654961 TI - Translocational renal cell carcinoma (t(6;11)(p21;q12) with transcription factor EB (TFEB) amplification and an integrated precision approach: a case report. AB - INTRODUCTION: Renal cell carcinoma with the distinct type of t(6;11)(p21;q12) translocation (transcription factor EB) is a rare neoplasm. In the present case study, we show for the first time an autophagy signature in a patient with transcription factor EB renal cell carcinoma. We attempted to characterize the mutational and expressional features of a t(6;11)(p21;q12) renal cell carcinoma, in an effort to address the potential for molecular guidance of personalized medical decision for a case in this renal cell carcinoma category. CASE PRESENTATION: We report the case of a 42-year-old white man who had a late relapse of his renal cell carcinoma. The first diagnosis of clear cell renal carcinoma was derived from a histological examination; analyzing the metastasis and going back to the primary tumor it turned out to be a transcription factor EB renal cell carcinoma. The treatment plan included local radiation and systemic therapy. As part of the multimodal approach, tumor samples for genetic assessment were obtained. However, there is no recommended standard therapy for transcription factor EB-renal cell carcinoma. Despite four lines of medical treatment with targeted therapy and one checkpoint inhibitor, all attempts to prolong the patient's survival failed. CONCLUSIONS: During the course of this unusual disease, we gained insights which, to the best of our knowledge, were unknown before in the expression of the gene signature linked to autophagy. This might in part explain the resistance to conventional targeted therapy acknowledged in our patient. PMID- 26654962 TI - WITHDRAWN: Effectiveness of acupuncture in individuals with tinnitus: randomized controlled trial. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 26654963 TI - Looking for the interactions between omeprazole and amoxicillin in a disordered phase. An experimental and theoretical study. AB - In this paper, co-grinding mixtures of omeprazole-amoxicillin trihydrate (CGM samples) and omeprazole-anhydrous amoxicillin (CGMa samples) at 3:7, 1:1 and 7:3 molar ratios, respectively, were studied with the aim of obtaining a co-amorphous system and determining the potential intermolecular interactions. These systems were fully characterized by differential scanning calorimetry (DSC), FT-infrared spectroscopy (FTIR), X-ray powder diffraction (PXRD), scanning electron microscopy (SEM) and solid state Nuclear Magnetic Resonance (ssNMR). The co grinding process was not useful to get a co-amorphous system but it led to obtaining the 1:1 CGMa disordered phase. Moreover, in this system both FTIR and ssNMR analysis strongly suggest intermolecular interactions between the sulfoxide group of omeprazole and the primary amine of amoxicillin anhydrous. The solubility measurements were performed in simulated gastric fluid (SGF) to prove the effect of the co-grinding process. Complementarily, we carried out density functional theory calculations (DFT) followed by quantum theory of atoms in molecules (QTAIM) and natural bond orbital (NBO) analyses in order to shed some light on the principles that guide the possible formation of heterodimers at the molecular level, which are supported by spectroscopic experimental findings. PMID- 26654964 TI - Multi-analytical study of techniques and palettes of wall paintings of the monastery of Zica, Serbia. AB - The present multi-analytical study concentrates on establishing the painting techniques and the identity of the wall painting materials used by the artists from the 13th and 14th centuries to decorate the Zica monastery, Serbia. For this purpose, we demonstrate that micro-Raman spectroscopy is an efficient, non destructive method with high spatial resolution which gives molecular and crystal structural information of a wide variety of both inorganic and organic materials. It is shown that elementary composition revealed through scanning electron microscopy with energy dispersive X-ray spectroscopy and energy dispersive X-ray fluorescence spectroscopy is necessary in some cases to confirm the identity of pigments and binders identified by micro-Raman spectroscopy. It was found that a fresco technique, in combination with mainly natural earth pigments such as red ochre, yellow ochre and green earth, was used. Expensive natural pigment lapis lazuli was exclusively used for obtaining blue colour while pure vermilion was used by the artists from the first period of decorations at the beginning of the 13th century. A mixture of pigments was used for attaining different colour shades. For the gilding of saint's haloes, thin golden foil was deposited over the tin sheet. In order to get a desirable optical and aesthetical impression, the metallic leaves were deposited over the yellow ochre preparatory layer. Deposits of gypsum on wall paintings as well as traces of weddellite are degradation products formed as a result of exposing wall paintings to environmental conditions. PMID- 26654965 TI - Colorimetric determination of melamine in milk using unmodified silver nanoparticles. AB - Melamine is nitrogen rich chemical compound used as an adulterant in dairy products by unscrupulous people to increase the apparent protein content. This incident prompted the researchers to develop simple methods for easy detection of melamine in food samples. In the present paper, we report a simple and sensitive colorimetric method for detection of melamine in milk based on silver nanoparticles. This method relies upon the principle that melamine causes the aggregation of silver nanoparticles, resulting in abrupt color change from yellow to red under optimized conditions. The concentration of melamine in adulterated sample can be quantitated by monitoring the absorption spectra of silver nanoparticles using ultraviolet-visible (UV-Vis) spectrometer. The present colorimetric method which utilizes silver nanoparticles of 35 nm can reliably detect melamine down to a concentration of 0.04 mg l(-1). PMID- 26654966 TI - Spectral anion sensing and gamma-radiation induced magnetic modifications of polyphenol generated Ag-nanoparticles. AB - A fast one step bio-synthesis for in situ preparation of silver nanoparticles is proposed. The method involves reduction of AgNO3 with an aqueous extract of peanut skin, which is a good source of polyphenols. The silver nanoparticles thus synthesized were characterized by transmission electron microscopy (TEM), X-ray diffraction (XRD), UV-Vis absorption spectroscopy, Fourier Transform infrared (FTIR) spectroscopy and magnetic measurements. Effect of low dose gamma irradiation during the synthesis was studied and their physico-chemical properties were compared with those produced without irradiation. On the contrary to the diamagnetic behavior of bulk silver, the silver nanoparticles thus prepared show a significant ferromagnetic moment component. Variable time exposure to gamma-irradiation results in an exponential decay of ferromagnetic component. A freshly prepared solution of silver nanoparticles shows selective spectral changes towards iodide ions at trace concentration (below 50 MUM) among a series of 16 other competing anions. The prepared nanoparticles are therefore suitable for anion sensing application. PMID- 26654967 TI - Effect of synbiotic supplementation and dietary fat sources on broiler performance, serum lipids, muscle fatty acid profile and meat quality. AB - A 42-d trial was conducted to investigate the effect of adding a synbiotic supplement to diets containing two different types of fat on performance, blood lipids and fatty acid (FA) composition and oxidative stability of breast and thigh meat in broilers. A total of 800 one-d-old male broiler chickens were randomly assigned into 1 of 8 treatments with 4 replicates of 25 birds per treatment. The experiment consisted of a 4 * 2 factorial arrangement of treatments including 4 concentrations of synbiotic (0, 0.5, 1 or 1.5 g/kg diet) and 2 types of fat [sunflower oil (SO) or canola oil (CO)] at an inclusion rate of 50 g/kg diet. Dietary fat type did not affect body weight gain (BWG) or feed conversion ratio (FCR) during the overall experimental period (0-42 d). However, fat type modified serum lipid profile and FA composition and 2-thiobarbituric acid-reactive substances (TBARS) content in breast and thigh meat. The addition of synbiotic to the diet linearly improved overall BWG and FCR and also decreased serum cholesterol and low-density lipoprotein cholesterol concentrations. The TBARS value in thigh meat after 30 d of storage at 4 degrees C was linearly decreased as the synbiotic inclusion concentrations in the diets increased. Dietary synbiotic also decreased the proportion of monounsaturated fatty acids and increased n-6 polyunsaturated fatty acid (PUFA) concentration in thigh meat, whereas the FA profile of breast meat was not affected by synbiotic supplementation. Moreover, the PUFA/SFA ratio in the breast meat was linearly increased when synbiotic was included in the CO-containing diets. In conclusion, the addition of synbiotic to broiler diets had a positive effect on growth performance, blood lipid profile and meat quality. The results also support the use of synbiotic to increase the capacity of canola oil for enhancing PUFA/SFA ratio of breast meat in broilers. PMID- 26654968 TI - New classification scheme for ozone monitoring stations based on frequency distribution of hourly data. AB - According to European Union (EU) legislation, ozone (O3) monitoring sites can be classified regarding their location (rural background, rural, suburban, urban) or based on the presence of emission sources (background, traffic, industrial). There have been attempts to improve these classifications aiming to reduce their ambiguity and subjectivity, but although scientifically sound, they lack the simplicity needed for operational purposes. We present a simple methodology for classifying O3 stations based on the characteristics of frequency distribution curves which are indicative of the actual impact of combustion sources emitting NO that consumes O3 via titration. Four classes are identified using 1998-2012 hourly data from 72 stations widely distributed in mainland Spain and the Balearic Islands. Types 1 and 2 present unimodal bell-shaped distribution with very low amount of data near zero reflecting a limited influence of combustion sources while Type 4 has a primary mode close to zero, showing the impact of combustion sources, and a minor mode for higher concentrations. Type 3 stations present bimodal distributions with the main mode in the higher levels. We propose a quantitative metric based on the Gini index with the objective of reproducing this classification and finding empirical ranges potentially useful for future classifications. The analysis of the correspondence with the EUROAIRNET classes for the 72 stations reveals that the proposed scheme is only dependent on the impact of combustion sources and not on climatic or orographic aspects. It is demonstrated that this classification is robust since in 87% of the occasions the classification obtained for individual years coincide with the global classification obtained for the 1998-2012 period. Finally, case studies showing the applicability of the new classification scheme for assessing the impact on O3 of a station relocation and performing a critical evaluation of an air quality monitoring network are also presented. PMID- 26654972 TI - c-Jun NH2-terminal kinase inhibitor bentamapimod reduces induced endometriosis in baboons: an assessor-blind placebo-controlled randomized study. AB - OBJECTIVE: To test the hypothesis that the c-Jun NH2-terminal kinase (JNK) inhibitor (JNKI) bentamapimod (AS602801/PGL5001) can reduce induced endometriosis in baboons. DESIGN: Prospective randomized placebo-controlled study. SETTING: Nonhuman primate research center. ANIMAL(S): Twenty baboons each underwent four laparoscopies. Initial screening laparoscopy (L1) was followed after one rest cycle by an endometriosis-induction laparoscopy (L2). Fifty days after L2, the baboons were randomized just before staging laparoscopy (L3). Treatment lasted for 60 days, followed by a post-treatment staging laparoscopy (L4). INTERVENTION(S): Randomization before a 60-day treatment in four groups: daily placebo (n = 5), daily oral administration of 20 mg/kg JNKI (n = 5), concomitant daily oral administration of 20 mg/kg JNKI and 10 mg medroxyprogesterone acetate (MPA; n = 5), or subcutaneous administration of 3 mg cetrorelix every 3 days (n = 5). MAIN OUTCOME MEASURE(S): Type, surface area and volume of endometriotic lesions, and revised American Society for Reproductive Medicine score and stage were recorded during L3 and L4. Menstrual cycle length and serum hormonal concentration were recorded before and after treatment. RESULT(S): Compared with placebo, treatment with JNKI, JNKI + PMA, or cetrorelix resulted in lower total surface area and volume of endometriotic lesions. Remodeling of red active lesions into white lesions was observed more frequently in baboons treated with JNKI + MPA than in baboons treated with JNKI only. Menstrual cycle length and serum hormonal concentration were similar between placebo and JNKI groups. CONCLUSION(S): JNKI alone was as effective as JNKI + MPA or cetrorelix in reducing induced endometriosis in baboons, but without severe side effects or effect on cycle length or serum reproductive hormones. PMID- 26654973 TI - Pregnancy outcomes in women with polycystic ovary syndrome undergoing in vitro fertilization. AB - OBJECTIVE: To determine whether the diagnosis of polycystic ovary syndrome (PCOS) independently predicts increased rates of pregnancy complications relative to control subjects, after adjusting for important confounders. DESIGN: Retrospective cohort. SETTING: Not applicable. PATIENT(S): A review of all pregnancies after fresh IVF with or without intracytoplasmic sperm injection transfers from December 2006 to 2012 (n = 1,084) identified 394 eligible singleton births (71 women with PCOS; 323 controls without). INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): Singleton births were assessed for selected adverse pregnancy and birth outcomes. RESULT(S): Women with PCOS demonstrated a higher risk of developing the following pregnancy complications after adjusting for differences in age, parity, body mass index, and time to conception: gestational diabetes (adjusted odds ratio [AOR] 3.15, 95% confidence interval [CI] 1.35-7.33), hypertensive disorders of pregnancy (AOR 4.25, 95% CI 1.94 9.32), preterm birth <37 weeks (AOR 2.30, 95% CI 1.07-4.97), and large for gestational age >90th percentile (AOR 2.77, 95% CI 1.21-6.35). The increased risk of preterm birth <37 weeks was eliminated after adjusting for development of hypertensive disorders of pregnancy, whereas the increased risk of large for gestational age remained significant after adjusting for gestational diabetes mellitus status. Time to conception did not differ significantly between groups, nor did rates of antepartum hemorrhage, cesarean section, or perinatal mortality. CONCLUSION(S): Polycystic ovary syndrome independently predicts higher risk of adverse pregnancy outcomes after adjusting for differences in maternal age, parity, body mass index, and time to conception. This new information may be of relevance in counseling and monitoring women with PCOS, although larger prospective studies may be needed to validate our findings. PMID- 26654974 TI - Urinary paraben concentrations and in vitro fertilization outcomes among women from a fertility clinic. AB - OBJECTIVE: To explore the relationship between urinary paraben concentrations and IVF outcomes among women attending an academic fertility center. DESIGN: Prospective cohort study. SETTING: Fertility clinic in a hospital setting. PATIENT(S): A total of 245 women contributing 356 IVF cycles. INTERVENTION(S): None. Quantification of urinary concentrations of parabens by isotope-dilution tandem mass spectrometry, and assessment of clinical endpoints of IVF treatments abstracted from electronic medical records at the academic fertility center. MAIN OUTCOME MEASURE(S): Total and mature oocyte counts, proportion of high-quality embryos, fertilization rates, and rates of implantation, clinical pregnancy, and live births. RESULT(S): The geometric means of the urinary concentrations of methylparaben, propylparaben, and butylparaben in our study population were 133, 24, and 1.5 MUg/L, respectively. In models adjusted for age, body mass index, race/ethnicity, smoking status, and primary infertility diagnosis, urinary methylparaben, propylparaben, and butylparaben concentrations were not associated with IVF outcomes, specifically total and mature oocyte counts, proportion of high embryo quality, and fertilization rates. Moreover, no significant associations were found between urinary paraben concentrations and rates of implantation, clinical pregnancy, and live births. CONCLUSION(S): Urinary paraben concentrations were not associated with IVF outcomes among women undergoing infertility treatments. PMID- 26654975 TI - The duration of balloon inflation affects the luminal diameter of coronary segments after bioresorbable vascular scaffolds deployment. AB - BACKGROUND: Adequate expansion is critical to achieve optimal Bioresorbable Vascular Scaffolds (BVS) apposition to the vessel wall. However, compared to metallic stents, BVS present different mechanical properties. Hence, slow deployment and maintenance of balloon inflation for at least 30" is recommended for BVS implantation. However, since no evidences are available demonstrating the superiority of a longer balloon dilatation time, the implantation technique is highly variable among different centers. METHODS: A total of 24 BVS-treated lesions were included in the present analysis. After BVS deployment at 12 atmosphere (ATM) the balloon was rapidly deflated and scaffold expansion was documented with an angiogram. The same balloon was then inflated again and kept at 12 ATM for 30". Finally, a further angiogram was obtained to evaluate BVS expansion. Quantitative coronary angiography (QCA) was performed at each step. RESULTS: A significant increase of minimal luminal diameter (MLD)-to-reference scaffold diameter (RSD) ratio (MLD to RSD Ration, MR-Ratio) from 0.70 +/- 0.10 after initial stent deployment to 0.79 +/- 0.10 after the 30"-long balloon dilation was observed (p < 0.001). Of note, this result was consistent across all sub-segments, as well as across almost all lesion subgroups. A substantial reduction in the prevalence of residual stenosis from 29 % to 17 % was registered after the 30"-long dilation. CONCLUSIONS: Our results strongly support the maintenance of balloon inflation for at least 30" during BVS deployment to achieve optimal scaffold expansion and minimize the occurrence of residual stenosis. PMID- 26654976 TI - Use and Perceived Effectiveness of Complementary and Alternative Medicine to Treat and Manage the Symptoms of Autism in Children: A Survey of Parents in a Community Population. AB - OBJECTIVE: Parents of children with autism spectrum disorders (ASDs) often try a variety of treatments for their children, including complementary and alternative medicine (CAM). The objective of this study was to improve understanding of the frequency of CAM use by parents for their children with autism and to quantify the parents' perceived effectiveness of various CAM therapies in mitigating the health and functioning problems associated with autism. METHODS: Parents in southeastern Virginia were recruited for study participation from local autism organizations and a clinical practice where a large proportion of the patients are children with autism. Parents completed an online survey and answered questions about CAM use for their children with autism, and they rated the perceived effectiveness of each therapy. RESULTS: Of 194 parents surveyed, 80.9% reported that they had tried some form of CAM for their child with autism. Among CAM users, the most frequently used therapies were multivitamins (58.6%), the gluten-free casein-free diet (54.8%), and methyl B-12 injections (54.1%). The CAM therapies that received the highest average rating of effectiveness were sensory integration therapy, melatonin, and off-label use of prescription antifungal medications. CONCLUSION: CAM therapies were frequently used in this population, and many were perceived to be effective in helping to ease some of the health challenges associated with autism. CAM therapies for the autism population should be further studied in well-controlled clinical research settings to provide safety and efficacy data on treatments, as well as validated treatment options for those with ASD. PMID- 26654977 TI - Sildenafil reduces signs of oxidative stress in pulmonary arterial hypertension: Evaluation by fatty acid composition, level of hydroxynonenal and heart rate variability. AB - Pulmonary arterial hypertension (PAH) is a rare multifactorial disease with an unfavorable prognosis. Sildenafil therapy can improve functional capacity and pulmonary hemodynamics in PAH patients. Nowadays, it is increasingly recognized that the effects of sildenafil are pleiotropic and may also involve changes of the pro-/antioxidant balance, lipid peroxidation and autonomic control. In present study we aimed to assess the effects of sildenafil on the fatty acids (FAs) status, level of hydroxynonenal (HNE) and heart rate variability (HRV) in PAH patients. Patients with PAH were characterized by an increase in HNE and changes in the FAs composition with elevation of linoleic, oleic, docosahexanoic acids in phospholipids as well as reduced HRV with sympathetic predominance. Sildenafil therapy improved exercise capacity and pulmonary hemodynamics and reduced NT-proBNP level in PAH. Antioxidant and anti-inflammatory effects of sildenafil were noted from the significant lowering of HNE level and reduction of the phopholipid derived oleic, linoleic, docosahexanoic, docosapentanoic FAs. That was also associated with some improvement of HRV on account of the activation of the neurohumoral regulatory component. Incomplete recovery of the functional metabolic disorders in PAH patients may be assumed from the persistent increase in free FAs, reduced HRV with the sympathetic predominance in the spectral structure after treatment comparing to control group. The possibilities to improve PAH treatment efficacy through mild stimulation of free radical reactions and formation of hormetic reaction in the context of improved NO signaling are discussed. PMID- 26654978 TI - Role of redoximiRs in fibrogenesis. AB - Fibrosis can be defined as an excessive accumulation of extracellular matrix (ECM) components, ultimately leading to stiffness, scarring and devitalized tissue. MicroRNAs (miRNAs) are short, 19-25 nucleotides (nt), non-coding RNAs involved in the post-transcriptional regulation of gene expression. Recently, miRNAs have also emerged as powerful regulators of fibrotic processes and have been termed "fibromiRs". Oxidative stress represents a self-perpetuating mechanism in fibrogenesis. MiRNAs can also influence the expression of genes responsible for the generation of reactive oxygen species (ROS) and antioxidant defence and are termed "redoximiRs". Here, we review the current knowledge of mechanisms by which "redoximiRs" regulate fibrogenesis. This new set of miRNAs may be called "redoxifibromiRs". PMID- 26654980 TI - Oxidative stress-induced premature senescence dysregulates VEGF and CFH expression in retinal pigment epithelial cells: Implications for Age-related Macular Degeneration. AB - Oxidative stress has a critical role in the pathogenesis of Age-related Macular Degeneration (AMD), a multifactorial disease that includes age, gene variants of complement regulatory proteins and smoking as the main risk factors. Stress induced premature cellular senescence (SIPS) is postulated to contribute to this condition. In this study, we hypothesized that oxidative damage, promoted by endogenous or exogenous sources, could elicit a senescence response in RPE cells, which would in turn dysregulate the expression of major players in AMD pathogenic mechanisms. We showed that exposure of a human RPE cell line (ARPE-19) to a cigarette smoke concentrate (CSC), not only enhanced Reactive Oxygen Species (ROS) levels, but also induced 8-Hydroxydeoxyguanosine-immunoreactive (8-OHdG) DNA lesions and phosphorylated-Histone 2AX-immunoreactive (p-H2AX) nuclear foci. CSC-nuclear damage was followed by premature senescence as shown by positive senescence associated-beta-galactosidase (SA-beta-Gal) staining, and p16(INK4a) and p21(Waf-Cip1) protein upregulation. N-acetylcysteine (NAC) treatment, a ROS scavenger, decreased senescence markers, thus supporting the role of oxidative damage in CSC-induced senescence activation. ARPE-19 senescent cultures were also established by exposure to hydrogen peroxide (H2O2), which is an endogenous stress source produced in the retina under photo-oxidation conditions. Senescent cells upregulated the proinflammatory cytokines IL-6 and IL-8, the main markers of the senescence-associated secretory phenotype (SASP). Most important, we show for the first time that senescent ARPE-19 cells upregulated vascular endothelial growth factor (VEGF) and simultaneously downregulated complement factor H (CFH) expression. Since both phenomena are involved in AMD pathogenesis, our results support the hypothesis that SIPS could be a principal player in the induction and progression of AMD. Moreover, they would also explain the striking association of this disease with cigarette smoking. PMID- 26654979 TI - Deletion of GSTA4-4 results in increased mitochondrial post-translational modification of proteins by reactive aldehydes following chronic ethanol consumption in mice. AB - Chronic alcohol consumption induces hepatic oxidative stress resulting in production of highly reactive electrophilic alpha/beta-unsaturated aldehydes that have the potential to modify proteins. A primary mechanism of reactive aldehyde detoxification by hepatocytes is through GSTA4-driven enzymatic conjugation with GSH. Given reports that oxidative stress initiates GSTA4 translocation to the mitochondria, we hypothesized that increased hepatocellular damage in ethanol (EtOH)-fed GSTA4(-/-) mice is due to enhanced mitochondrial protein modification by reactive aldehydes. Chronic ingestion of EtOH increased hepatic protein carbonylation in GSTA4(-/-) mice as evidenced by increased 4-HNE and MDA immunostaining in the hepatic periportal region. Using mass spectrometric analysis of biotin hydrazide conjugated carbonylated proteins, a total of 829 proteins were identified in microsomal, cytosolic and mitochondrial fractions. Of these, 417 were novel to EtOH models. Focusing on mitochondrial fractions, 1.61 fold more carbonylated proteins were identified in EtOH-fed GSTA4(-)(/-) mice compared to their respective WT mice ingesting EtOH. Bioinformatic KEGG pathway analysis of carbonylated proteins from the mitochondrial fractions revealed an increased propensity for modification of proteins regulating oxidative phosphorylation, glucose, fatty acid, glutathione and amino acid metabolic processes in GSTA4(-/-) mice. Additional analysis revealed sites of reactive aldehyde protein modification on 26 novel peptides/proteins isolated from either SV/GSTA4(-/-) PF or EtOH fed mice. Among the peptides/proteins identified, ACSL, ACOX2, MTP, and THIKB contribute to regulation of fatty acid metabolism and ARG1, ARLY, and OAT, which regulate nitrogen and ammonia metabolism having direct relevance to ethanol-induced liver injury. These data define a role for GSTA4-4 in buffering hepatic oxidative stress associated with chronic alcohol consumption and that this GST isoform plays an important role in protecting against carbonylation of mitochondrial proteins. PMID- 26654982 TI - Exome sequencing explained: a practical guide to its clinical application. AB - Next-generation sequencing has catapulted healthcare into a revolutionary genomics era. One such technology, whole-exome sequencing, which targets the protein-coding regions of the genome, has proven success in identifying new causal mutations for diseases of previously unknown etiology. With a successful diagnostic rate approaching 25% for rare disease in recent studies, its clinical utility is becoming increasingly popular. However, the interpretation of whole exome sequencing data requires expertise in genomic informatics and clinical medicine to ensure the accurate and safe reporting of findings back to the bedside. This is challenged by vast amounts of sequencing data harbouring approximately 25 000 variants per sequenced individual. Computational strategies and fastidious filtering frameworks are thus required to extricate candidate variants in a sea of common polymorphisms. Once prioritized, identified variants require intensive scrutiny at a biological level, and require judicious assessment alongside the clinical phenotype. In the final step, all evidence is collated and documented alongside pathogenicity guidelines to produce an exome report that returns to the clinic. This review provides a practical guide for clinicians and genomic informaticians on the clinical application of whole-exome sequencing. We address sequencing capture and methodology, quality control parameters at different stages of sequencing analysis and propose an exome data filtering strategy that includes primary filtering (for the removal of probable benign variants) and secondary filtering for the prioritization of remaining candidates. PMID- 26654981 TI - Comparison of sampling bags for the analysis of volatile organic compounds in breath. AB - Nalophan, Tedlar and Cali-5-Bond polymeric bags were compared to determine the most suitable type for breath sampling and storage when volatile organic compounds are to be determined. Analyses were performed by thermal desorption gas chromatography mass spectrometry. For each bag, the release of contaminants and the chemical stability of a gaseous standard mixture containing eighteen organic compounds, as well as the CO2 partial pressure were assessed. The selected compounds were representative of breath constituents and belonged to different chemical classes (i.e. hydrocarbons, ketones, aldehydes, aromatics, sulfurs and esters). In the case of Nalophan, the influence of the surface-to-volume ratio, related to the bag's filling degree, on the chemical stability was also evaluated. Nalophan bags were found to be the most suitable in terms of contaminants released during storage (only 2-methyl-1,3-dioxalane), good sample stability (up to 24 h for both dry and humid samples), and very limited costs (about 1 ? for a 20 liter bag). The (film) surface-to-(sample) volume ratio was found to be an important factor affecting the stability of selected compounds, and therefore we recommended to fill the bag completely. PMID- 26654983 TI - Magnetically-refreshable receptor platform structures for reusable nano-biosensor chips. AB - We developed a magnetically-refreshable receptor platform structure which can be integrated with quite versatile nano-biosensor structures to build reusable nano biosensor chips. This structure allows one to easily remove used receptor molecules from a biosensor surface and reuse the biosensor for repeated sensing operations. Using this structure, we demonstrated reusable immunofluorescence biosensors. Significantly, since our method allows one to place receptor molecules very close to a nano-biosensor surface, it can be utilized to build reusable carbon nanotube transistor-based biosensors which require receptor molecules within a Debye length from the sensor surface. Furthermore, we also show that a single sensor chip can be utilized to detect two different target molecules simply by replacing receptor molecules using our method. Since this method does not rely on any chemical reaction to refresh sensor chips, it can be utilized for versatile biosensor structures and virtually-general receptor molecular species. PMID- 26654984 TI - Serum 25-OH Vitamin D Level in Psoriatic Patients and Comparison With Control Subjects. AB - BACKGROUND: Vitamin D has been shown to have immunomodulatory effects, and previous studies have proposed a role of vitamin D deficiency in multiple autoimmune diseases, including psoriasis. OBJECTIVES: The aim of this study was to investigate serum vitamin D levels in psoriatic patients and compare them with levels in controls. METHODS: This study was carried out in 50 psoriasis patients. Serum vitamin D was measured by enzyme-linked immunosorbent assay. RESULTS: The mean serum vitamin D levels in psoriatic patients and controls were 14.92 +/- 6.31 and 12.52 +/- 4.54 ng/mL, respectively. The difference was not statistically significant (P = .06). The prevalence of vitamin D deficiency (<20 ng/mL) was 84.0% in psoriatic patients and 93.0% in controls (P = .21). CONCLUSIONS: Most of the patients with psoriasis had vitamin D deficiency, which may have contributed to the evolution of their psoriasis. However, considering the high prevalence of vitamin D deficiency in Iran, no difference was noted between the psoriatic patients and the controls. PMID- 26654985 TI - THE SEX DIFFERENCE IN ROD BALANCING: CONFIRMATION OF THE DIFFERENCE AND A TEST OF THREE HYPOTHETICAL EXPLANATIONS. AB - Previous studies have shown that men can balance a dowel rod on the index finger for a longer time than women can. The factors that account for the difference are unknown, but the difference may be attributable either to a difference in whole body agility or a difference in the use of visual cues. Three experiments involving a total of 62 adult women with a mean age of 21.2 yr. (SD=3.8) and 62 adult men with a mean age of 21.9 yr. (SD=6.6) tested these potential explanations. Experiment 1 replicated the sex difference and assessed the relevance of whole-body agility by comparing standing and seated conditions. Experiments 2 and 3 explored the role of rod length and visual fixation point, respectively. Each experiment yielded a significant sex difference, but the difference was not affected by the participant's posture, the length of the rod, or the fixation point. Possible alternative explanations for the difference include differences in (1) the speed of processing degree of visual tilt; (2) arm mass, which affects the inertia of the balancing system; and (3) experience in open-skill sports. PMID- 26654986 TI - PARKINSON'S DISEASE PATIENTS WITH DOMINANT HEMIBODY AFFECTED BY THE DISEASE RELY MORE ON VISION TO MAINTAIN UPRIGHT POSTURAL CONTROL. AB - This study assesses the association between disease onset side (dominant or non dominant) and vision on postural control of Parkinson's disease patients. Patient volunteers composed two groups, according to the onset side affected: Dominant group (n=9; M age=66.1 yr., SD=7.2; 6 women, 3 men) and Non-dominant group (n=9; M age=67.4 yr., SD=6.4; 6 women, 3 men). The groups' postural control was assessed by posturography during quiet upright stance in two conditions, Eyes open and Eyes closed. Two-way analyses of variance (ANOVAs; group*condition) with repeated measures for the second factor assessed the differences associated with affected hemibody and vision on postural control. Analyses indicated that patients with the dominant side affected also presented significantly greater variation in center of pressure than those with the non-dominant side affected, mainly in the Eyes closed condition. The results demonstrate a higher reliance on vision in the dominant side, possibly to compensate somatosensory system impairments. These results also highlight the importance of analyzing the hemibody affected by the disease when postural control is assessed in this population. PMID- 26654987 TI - TRACING THE DEVELOPMENT OF TYPEWRITING SKILLS IN AN ADAPTIVE E-LEARNING ENVIRONMENT. AB - Typewriting studies which compare novice and expert typists have suggested that highly trained typing skills involve cognitive process with an inner and outer loop, which regulate keystrokes and words, respectively. The present study investigates these loops longitudinally, using multi-level modeling of 1,091,707 keystroke latencies from 62 children (M age=12.6 yr.) following an online typing course. Using finger movement repetition as indicator of the inner loop and words typed as indicator of the outer loop, practicing keystroke latencies resulted in different developmental curves for each loop. Moreover, based on plateaus in the developmental curves, the inner loop seemed to require less practice to develop than the outer loop. PMID- 26654988 TI - THE HOME ADVANTAGE IN MAJOR LEAGUE BASEBALL. AB - Home advantage is smaller in baseball than in other major professional sports for men, specifically football, basketball, or soccer. This paper advances an explanation. It begins by reviewing the main observations to support the view that there is little or no home advantage in individual sports. It then presents the case that home advantage originates in impaired teamwork among the away players. The need for teamwork and the extent of it vary from sport to sport. To the extent that a sport requires little teamwork it is more like an individual sport, and the home team would be expected to enjoy only a small advantage. Interactions among players on the same side (teamwork) are much less common in baseball than in the other sports considered. PMID- 26654989 TI - A STUDY ON VISUAL LIMITATION OF AGE, NUMERICAL SIZE, AND EXPOSURE TIME WHILE USERS OPERATE MOBILE DEVICES. AB - Technological advances have driven the development of information technology (IT) products and communication using mobile devices has become a part of daily life. When using mobile devices, reading time and font size are important communication elements that significantly affect reading performance. However, studies of reading performance in older samples have mainly used printed material or computer monitors; this study examined the performance of users when reading text messages on the interfaces of mobile devices and described their visual limitations. Sixty-two participants took part in the experiment, which involved displaying different font sizes and exposure times. The younger group read 10 point font accurately, while the older group had much worse accuracy, even at 14 points. The younger group correctly read text messages displayed for 0.4 sec. above 80% of the time, while the older group's accuracy was severely impaired even when text was displayed for 1 sec. PMID- 26654990 TI - PSYCHOPHYSICAL BENEFITS OF ROCK-CLIMBING ACTIVITY. AB - The aim of the study was to compare the psychophysical effects of rock climbing with a supervised fitness training in adults. Thirty-three healthy participants (M age=32 yr., SD=7) participated in rock climbing or in fitness training. The participants' functional fitness, anxiety, and mood states were tested before and after 3 mo. of training. There was significant improvement of physical fitness in both groups after the intervention period. Anxiety significantly decreased after each single training session at the end of both courses. Differential effects in the rock-climbing group, as compared to the fitness group, emerged only on Vigor. Specifically, the rock-climbing group showed a decreasing trend in Vigor while the fitness group showed an increasing trend of Vigor after the intervention. PMID- 26654991 TI - CHILDREN'S MOVEMENT SKILLS WHEN PLAYING ACTIVE VIDEO GAMES. AB - Active video games (AVGs) may be useful for movement skill practice. This study examined children's skill execution while playing Xbox KinectTM and during movement skill assessment. Nineteen children (10 boys, 9 girls; M age=7.9 yr., SD=1.4) had their skills assessed before AVG play and then were observed once a week for 6 wk. while playing AVGs for 50 min. While AVG play showed evidence of correct skill performance (at least 30-50% of the time when playing table tennis, tennis, and baseball), nearly all skills were more correctly performed during skill assessment (generally more than 50% of the time). This study may help researchers to better understand the role AVGs could play in enhancing real life movement skills. PMID- 26654992 TI - The pharmaceutical vial capping process: Container closure systems, capping equipment, regulatory framework, and seal quality tests. AB - Parenteral drug products are protected by appropriate primary packaging to protect against environmental factors, including potential microbial contamination during shelf life duration. The most commonly used CCS configuration for parenteral drug products is the glass vial, sealed with a rubber stopper and an aluminum crimp cap. In combination with an adequately designed and controlled aseptic fill/finish processes, a well-designed and characterized capping process is indispensable to ensure product quality and integrity and to minimize rejections during the manufacturing process. In this review, the health authority requirements and expectations related to container closure system quality and container closure integrity are summarized. The pharmaceutical vial, the rubber stopper, and the crimp cap are described. Different capping techniques are critically compared: The most common capping equipment with a rotating capping plate produces the lowest amount of particle. The strength and challenges of methods to control the capping process are discussed. The residual seal force method can characterize the capping process independent of the used capping equipment or CCS. We analyze the root causes of several cosmetic defects associated with the vial capping process. PMID- 26654993 TI - Biofunctionalization of scaffold material with nano-scaled diamond particles physisorbed with angiogenic factors enhances vessel growth after implantation. AB - Biofunctionalized scaffold facilitates complete healing of large defects. Biological constraints are induction and ingrowth of vessels. Angiogenic growth factors such as vascular endothelial growth factor or angiopoietin-1 can be bound to nano-scaled diamond particles. Corresponding bioactivities need to be examined after biofunctionalization. We therefore determined the physisorptive capacity of distinctly manufactured, differently sized nDP and the corresponding activities of bound factors. The properties of biofunctionalized nDPs were investigated on cultivated human mesenchymal stem cells and on the developing chicken embryo chorio-allantoic membrane. Eventually porous bone substitution material was coated with nDP to generate an interface that allows biofactor physisorption. Angiopoietin-1 was applied shortly before scaffold implantation into an osseous defect in sheep calvaria. Biofunctionalized scaffolds exhibited significantly increased rates of angiogenesis already one month after implantation. Conclusively, nDP can be used to ease functionalization of synthetic biomaterials. FROM THE CLINICAL EDITOR: With the advances in nanotechnology, many nano-sized materials have been used in the biomedical field. This is also true for nano-diamond particles (nDP). In this article, the authors investigated the physical properties of functionalized nano-diamond particles in both in-vitro and in-vivo settings. The positive findings would help improve understanding of these nanomaterials in regenerative medicine. PMID- 26654994 TI - Ammonia produces pathological changes in human hepatic stellate cells and is a target for therapy of portal hypertension. AB - BACKGROUND & AIMS: Hepatic stellate cells (HSCs) are vital to hepatocellular function and the liver response to injury. They share a phenotypic homology with astrocytes that are central in the pathogenesis of hepatic encephalopathy, a condition in which hyperammonemia plays a pathogenic role. This study tested the hypothesis that ammonia modulates human HSC activation in vitro and in vivo, and evaluated whether ammonia lowering, by using l-ornithine phenylacetate (OP), modifies HSC activation in vivo and reduces portal pressure in a bile duct ligation (BDL) model. METHODS: Primary human HSCs were isolated and cultured. Proliferation (BrdU), metabolic activity (MTS), morphology (transmission electron, light and immunofluorescence microscopy), HSC activation markers, ability to contract, changes in oxidative status (ROS) and endoplasmic reticulum (ER) were evaluated to identify effects of ammonia challenge (50 MUM, 100 MUM, 300 MUM) over 24-72 h. Changes in plasma ammonia levels, markers of HSC activation, portal pressure and hepatic eNOS activity were quantified in hyperammonemic BDL animals, and after OP treatment. RESULTS: Pathophysiological ammonia concentrations caused significant and reversible changes in cell proliferation, metabolic activity and activation markers of hHSC in vitro. Ammonia also induced significant alterations in cellular morphology, characterised by cytoplasmic vacuolisation, ER enlargement, ROS production, hHSC contraction and changes in pro-inflammatory gene expression together with HSC related activation markers such as alpha-SMA, myosin IIa, IIb, and PDGF-Rbeta. Treatment with OP significantly reduced plasma ammonia (BDL 199.1 MUmol/L+/-43.65 vs. BDL+OP 149.27 MUmol/L+/-51.1, p<0.05) and portal pressure (BDL 14+/-0.6 vs. BDL+OP 11+/-0.3 mmHg, p<0.01), which was associated with increased eNOS activity and abrogation of HSC activation markers. CONCLUSIONS: The results show for the first time that ammonia produces deleterious morphological and functional effects on HSCs in vitro. Targeting ammonia with the ammonia lowering drug OP reduces portal pressure and deactivates hHSC in vivo, highlighting the opportunity for evaluating ammonia lowering as a potential therapy in cirrhotic patients with portal hypertension. PMID- 26654995 TI - Circadian clock properties of fruit flies Drosophila melanogaster exhibiting early and late emergence chronotypes. AB - The role of circadian clocks in timing daily behaviors is widely acknowledged, and while empirical evidence suggests that clock period is correlated with the preferred phase of a rhythmic behavior (chronotype), other clock properties have also been hypothesized to underlie chronotype variation. Here, we report that fruit fly Drosophila melanogaster populations exhibiting evening emergence chronotype (late) are characterized by higher incidence of behavioral arrhythmicity in constant dim light, wider range of entrainment, reduced rates of re-entrainment to simulated jet-lag and higher amplitude of both entrained and free-running rhythms as compared to those exhibiting morning emergence chronotype (early). Our results thus highlight the role of circadian clock properties such as zeitgeber sensitivity, amplitude and coupling in driving chronotype variation. PMID- 26654996 TI - Interaction of Azobenzene and Benzalaniline with Strong Amido Bases. AB - The interaction of azobenzene with lithium dicyclohexylamide (Cy2NLi) in THF or Et2O afforded the ion-radical salt of azobenzene (1) structurally characterized for the first time and dicyclohexylaminyl radical, which begins a novel chain of transformations leading eventually to the imino-enamido lithium complex (3). Benzalaniline, being a relative of azobenzene, reacted with Cy2NLi without electron transfer by a proton-abstraction mechanism to form the dilithium salt of N(1),N(2),1,2-tetraphenylethene-1,2-diamine quantitatively. PMID- 26654997 TI - Outsmarted by the smartphone! PMID- 26654998 TI - Factors affecting treatment outcome in congenital nasolacrimal duct obstruction: A retrospective analysis from South India. AB - PURPOSE: To investigate outcomes for different treatment modalities in congenital nasolacrimal duct obstruction (CNLDO) in an Indian population. DESIGN: Retrospective, interventional, case series. MATERIALS AND METHODS: In an institutional setting, case records of patients with CNLDO from January 2008 to 2012, were reviewed, and data on patient demographics, clinical presentation, and treatment details (sac massage, probing, and/or dacryocystorhinostomy) were recorded. Success of treatment was defined as complete resolution of symptoms and negative regurgitation on pressure over lacrimal sac (ROPLAS) area. RESULTS: Two hundred and ninety-eight eyes of 240 patients with a mean age of 22.2 +/- 26.14 months (median = 12 months, interquartile range = 17) were analyzed. Sac massage (n = 226) was successful in 67 eyes (30%). Multivariable logistic regression analyses showed that children with mucoid ROPLAS were almost 6 times more likely (odds ratio [OR] = 5.55 vs. clear ROPLAS, 95% confidence interval [CI] = 2.35 13.09, P < 0.001) to experience failure of sac massage. Overall probing (n = 193) was successful for 143 (74%) eyes. Multivariable logistic regression showed that older children were 25% more likely to experience probing failure (OR = 1.25 for every 6 months increment in age, 95%, CI = 1.09-1.42, P = 0.001). CONCLUSION: Sac massage is successful in only a third of our patients and those with mucoid ROPLAS are more likely to experience failure. Probing is successful in three quarter of our subjects, and its success declines with a progressive increase in age. Lower socioeconomic status, poor general health, and recurrent respiratory infections are unique to our population and may influence outcomes. PMID- 26654999 TI - Changes in choroidal thickness after prophylactic iridectomy in primary angle closure suspect eyes using enhanced depth imaging optical coherence tomography. AB - PURPOSE: The aim of the present study was to evaluate the effect of surgical peripheral iridectomy (SPI) on choroidal thickness in primary angle-closure suspect (PACS) eyes. MATERIALS AND METHODS: This was a prospective observational case series of 30 subjects with PACS. Ocular biometry was performed before SPI (baseline) and then 1 week later. Choroid was imaged by enhanced depth imaging optical coherence tomography (EDI-OCT). The choroidal thickness of the subfoveal area at 1 and 3 mm diameter around the fovea was determined. Central anterior chamber depth (ACD), lens thickness (LT), vitreous chamber depth (VCD), and axial length (AL) were measured by A-scan ultrasound. Parameters were compared before SPI (baseline) and 1 week later. RESULTS: Thirty eyes of 30 patients with mean age of 61.53 +/- 7.98 years were studied. There was no significant difference in the choroidal thickness at all macular locations before and after SPI (all P > 0.05). Mean subfoveal choroidal thickness was 279.61 MUm +/- 65.50 MUm before and 274.54 MUm +/- 63.36 MUm after SPI (P = 0.308). There was also no significant change in central ACD, LT, VCD, and LT after SPI (all P > 0.05). CONCLUSIONS: SPI does not appear to alter choroidal thickness in PACS eyes, as assessed using EDI OCT. Long-term follow-up of PACS eyes treated with SPI may provide further insight into the effects of this treatment modality on the choroid. PMID- 26655000 TI - Efficacy of Ozurdex implant in treatment of noninfectious intermediate uveitis. AB - AIMS: To report our experiences using Ozurdex, a biodegradable implant, containing 0.7 mg of dexamethasone in the treatment of noninfectious intermediate uveitis. SETTINGS AND DESIGN: Retrospective study design. METHODS: We conducted a retrospective study of medical records of patients with noninfectious intermediate uveitis having either cystoid macular edema (CME) or vitritis who were not responsive to standard treatment and subsequently received Ozurdex implant from March 2011 to April 2013. The outcomes measured were best-corrected visual acuity, central retinal thickness (CRT), and vitreous haze score. STATISTICAL ANALYSIS USED: Paired t-test was used to test the significance of difference between quantitative variables. A P < 0.05 is taken to denote significant relationship. RESULTS: Twenty eyes of 15 patients with mean age of 39.8 years who received Ozurdex implant were included in the study. The mean baseline visual acuity improved from 0. 666 logarithm of the minimum angle of resolution (logMAR) units to 0.479 logMAR units at 6 weeks after the implant. The mean CRT improved from 536.1 to 361.4 microns at 6 weeks postimplant both parameters were statistically significant. The ocular inflammation was controlled in almost all the patients. Cataract and raised intraocular pressure were documented complications. CONCLUSION: Ozurdex implant is a promising treatment option and efficient in controlling the inflammation and CME in cases of noninfectious intermediate uveitis not responding to standard treatment. PMID- 26655001 TI - Surgeon point-of-view recording: Using a high-definition head-mounted video camera in the operating room. AB - OBJECTIVE: To study the utility of a commercially available small, portable ultra high definition (HD) camera (GoPro Hero 4) for intraoperative recording. METHODS: A head mount was used to fix the camera on the operating surgeon's head. Due care was taken to protect the patient's identity. The recorded video was subsequently edited and used as a teaching tool. This retrospective, noncomparative study was conducted at three tertiary eye care centers. The surgeries recorded were ptosis correction, ectropion correction, dacryocystorhinostomy, angular dermoid excision, enucleation, blepharoplasty and lid tear repair surgery (one each). The recorded videos were reviewed, edited, and checked for clarity, resolution, and reproducibility. RESULTS: The recorded videos were found to be high quality, which allowed for zooming and visualization of the surgical anatomy clearly. Minimal distortion is a drawback that can be effectively addressed during postproduction. The camera, owing to its lightweight and small size, can be mounted on the surgeon's head, thus offering a unique surgeon point-of-view. In our experience, the results were of good quality and reproducible. CONCLUSIONS: A head-mounted ultra-HD video recording system is a cheap, high quality, and unobtrusive technique to record surgery and can be a useful teaching tool in external facial and ophthalmic plastic surgery. PMID- 26655002 TI - Predicting postoperative visual outcomes in cataract patients with maculopathy. AB - PURPOSE: To assess the accuracy of the potential acuity meter (PAM) in predicting postcataract surgery visual acuity outcome in patients with healed inactive maculopathies. STUDY DESIGN: Prospective interventional clinical trial. PATIENTS AND METHODS: Patients scheduled for phacoemulsification had preoperative and 1 month postoperative best-corrected visual acuity (BCVA), PAM test, fluorescein angiography, and macular optical coherence tomography. Patients were grouped to following preoperative BCVA: PRE1: 0.29 and better, PRE2: 0.25-0.13, and PRE3: 0.1 or worse; age: G1 <60, G2 = 60-70, and G3 >70 years. PAM accuracy was divided into: Grade 1: Postoperative BCVA <=1 or less line error of the PAM score, Grade 2: Between 1 and 2 lines error, and Grade 3: >=3 lines or more error. RESULTS: This study enrolled 57 patients with a mean age of 71.05 +/- 6.78 years where 34 were females. There were 21 (36.84%) patients with diabetic maculopathy and 36 (63.16%) with age-related macular degeneration. The mean preoperative BCVA was 0.198 +/- 0.12 (0.1-0.5). The mean PAM score was 0.442 +/- 0.24 (0.1-1.3). The mean postoperative BCVA was 0.4352 +/- 0.19 (0.17-1.00). The PAM score was in Grade 1, 2, and 3 in 46 (80.7%), 54 (94.7%), and 56 (98.2), respectively. There was a highly significant correlation between the PAM score and the postoperative BCVA (P < 0.001, Chi-square test). There was no correlation between the PAM test accuracy and age, gender, diagnosis, and preoperative BCVA (P = 0.661, 0.667, 0. 0.991, 0.833, Chi-square test; respectively). CONCLUSION: The PAM is an accurate method of predicting postoperative visual acuity for eyes with nuclear cataracts Grade I and II and inactive maculopathies. PMID- 26655004 TI - A case of corneal cystinosis in a patient with rickets and chronic renal failure. AB - A 22-year-old man diagnosed with nephropathic cystinosis at the age of 4 years was found to have progressive bilateral corneal crystal deposition. He presented with severe photophobia and decreased visual acuity. Ocular cystinosis was diagnosed on observing the typical crystals. Optical coherence tomography showed multiple areas of stromal hyperreflectivity due to crystal deposits within the corneal stroma. Ex vivo transmission electron microscopy of the cornea showed pathognomonic crystal deposits in corneal stromal keratocytes. Using polymerase chain reaction sequencing of the entire coding region, we identified five gene mutations, including two unreported mutations. PMID- 26655003 TI - A randomized controlled prospective study to assess the role of subconjunctival bevacizumab in primary pterygium surgery in Indian patients. AB - BACKGROUND: Pterygium is an ocular surface disorder with prevalence rates ranges from 0.3% to 29% in different parts of the world. Vascular endothelial growth factor (VEGF) has been detected in increased amounts in pterygium epithelium, compared with normal conjunctiva. Bevacizumab is a recombinant, humanized anti VEGF antibody suggested as a possible adjunctive therapy for pterygium excision that appears to have a role in prevention of recurrence. We conducted this study to evaluate the role of subconjunctival bevacizumab in primary pterygium surgery in Indian patients. METHODS: In this randomized prospective clinical study, the patients were randomized into two groups of 30 patients each. Study group received 1.25 mg/0.05 ml subconjunctival bevacizumab 1 week before pterygium surgery with conjunctival autograft. Control group received 1.25 mg (0.05 ml) subconjunctival normal saline 1 week prior to pterygium surgery with conjunctival autograft. Patients were followed up at day 1, day 7, 1 month and 3 months. The main outcome measures were morphology of pterygium after injection, intra operative ease, recurrence of pterygia, and any complications. RESULTS: After giving bevacizumab, there was statistically significant improvement in grade, color intensity, size of pterygium, and symptoms of patients. Intra-operatively, less bleeding was observed by the surgeon. No statistically significant difference regarding reduction in astigmatism, improvement of visual acuity, and complications were observed in two groups. Recurrence was noted in five patients (8.33%) in total study population at the end of 3 months. It was present in two patients (6.67%) in Group A and three patients (10%) in Group B. CONCLUSION: Single preoperative administration of subconjunctival injection bevacizumab given 1 week before the pterygium excision with conjunctival autograft decreases the vascularity of newly formed blood vessels, hence may decrease recurrence rate though not in our study. PMID- 26655005 TI - Changes in stereoacuity following implantable Collamer lens implantation in patients with myopia. AB - The study evaluated the impact of implantable Collamer lens (ICL) implantation on stereoacuity in myopes in a retrospective case series. Ninety-five eyes of 48 patients were recruited. Distance and near stereoacuity were measured using distance Randot stereotest and TNO test, respectively, before surgery and at 4 weeks postoperatively. Mean age of the patients was 23.67 +/- 3.7 years. Mean uncorrected distance visual acuity (UDVA) was 1.28 +/- 0.37 logarithm of the minimum angle of resolution (logMAR) (median: 1.3; range: 0.3-1.8), and median best-corrected distance visual acuity (BDVA) was 0.18 logMAR (range: 0-0.6). There was a significant improvement in both UDVA and BDVA postsurgery (P < 0.001; Wilcoxon signed rank test). The overall improvement in stereopsis was observed in 15/48 (31.25%) and 13/48 (27.10%) subjects for near and distance, respectively, with no significant difference between the two (P = 0.82; Fisher's exact test). Among stereoblind individuals, the odd's ratio for near stereoacuity to improve in comparison to distance stereoacuity was 8.85 (95% confidence interval: 1.68 46.70; P = 0.01). ICL implantation for refractive correction aided stereoacuity improvement in myopes more so for near. PMID- 26655006 TI - Macular hole formation and spontaneous closure after vitrectomy for rhegmatogenous retinal detachment documented by spectral-domain optical coherence tomography: Case report and literature review. AB - This case report describes macular hole (MH) formation and spontaneous closure after vitrectomy for rhegmatogenous retinal detachment (RRD) repair. A 58-year old man referred with a macula-off superior RRD, in whom vitrectomy was performed. MH with vitreomacular traction (VMT) caused by the posterior vitreous cortex remnants developed 2 weeks after vitrectomy. Four weeks postoperatively, optical coherence tomography revealed resolution of the VMT and spontaneous closure of MH without providing any treatment. This is the first report of an MH formation and spontaneous closure after vitrectomy for RRD. This suggests that the VMT mediated by the posterior vitreous cortex remnants has an important role in the development of secondary MH. PMID- 26655007 TI - Ocular manifestations in lipoid proteinosis: A rare clinical entity. AB - Lipoid proteinosis is a rare autosomal recessive genodermatosis with abnormal lipid protein complexes deposition in different parts of the body, especially in the skin and mucus membranes of the upper aerodigestive tract. Though ocular involvement in lipoid proteinosis is rare, ophthalmologists may encounter diverse ocular complications accompanying this syndrome in clinical practice. We describe a case of lipoid proteinosis involving bilateral eyelids with pathognomonic moniliform blepharosis in a 33-year-old gentleman who presented with the complaints of itching of eye lids on and off since 10 years. PMID- 26655008 TI - Bilateral spontaneous anterior dislocation of intraocular lens with the capsular bag in a patient with pseudoexfoliation. AB - We report a rare case of bilateral spontaneous anterior partial in-the-bag intraocular lens (IOL) dislocation in a 75-year-old man with pseudoexfoliation (PXF). He underwent uneventful phacoemulsification in both eyes with in-the-bag IOL implantation 9 years back. In the right eye, single piece poly (methyl methacrylate) (PMMA) IOL (+19 D) and in the left eye, single piece acrylic foldable IOL (+19 D) were implanted. An attempt at pharmacological IOL repositioning was unsuccessful. The dislocated IOLs were explanted and exchanged with scleral suture fixated PMMA IOLs. Vision improved to 20/30 in both eyes following surgery, without any associated ocular morbidity. We believe that zonular weakness secondary to PXF, capsular contraction, and myopia together were the predisposing factors for partial anterior dislocation of IOLs and IOL exchange with scleral suture fixation of IOL is a safe and effective treatment option. PMID- 26655009 TI - Nonpseudomonal ecthyma gangrenosum of the upper lid treated with lid reconstruction. AB - Ecthyma gangrenosum (EG) is a cutaneous infection which usually occurs in immunocompromised patients. We report a case of EG of the eyelid treated with escharotomy and skin grafting, highlighting the importance of surgical management. A 2-year-old Asian Indian female presented to us with right upper lid edema with a large necrotic area. The child received intravenous cefotaxime for a week and the necrotic area turned to a well-defined eschar. Escharotomy with wound debridement and skin grafting was done. The present case highlights the importance of surgical intervention to prevent the sequelae of scarring of upper lid. PMID- 26655010 TI - Bilateral congenital lacrimal fistulas in an adult as part of ectrodactyly ectodermal dysplasia-clefting syndrome: A rare anomaly. AB - Ectrodactyly-ectodermal dysplasia and clefting syndrome or "Lobster claw" deformity is a rare congenital anomaly that affects tissues of ectodermal and mesodermal origin. Nasolacrimal duct (NLD) obstruction with or without atresia of lacrimal passage is a common finding of such a syndrome. The authors report here even a rarer presentation of the syndrome which manifested as bilateral NLD obstruction and lacrimal fistula along with cleft lip and palate, syndactyly affecting all four limbs, mild mental retardation, otitis media, and sinusitis. Lacrimal duct obstruction and fistula were managed successfully with endoscopic dacryocystorhinostomy (DCR) which is a good alternative to lacrimal probing or open DCR in such a case. PMID- 26655011 TI - Reply to comment: Conventional manual small-incision cataract surgery. PMID- 26655012 TI - Pars plana vitrectomy versus three intravitreal injections of bevacizumab for nontractional diabetic macular edema: A prospective, randomized comparative study. PMID- 26655013 TI - Varicella vasculopathy and chronic suppurative otitis media: Differential diagnosis for isolated sixth nerve palsy. PMID- 26655014 TI - Fabricating a custom made ocular prosthesis. PMID- 26655015 TI - Respond to: An innovative impression technique for fabrication of a custom-made ocular prosthesis. PMID- 26655016 TI - Raynaud's phenomena and subclavian steal syndrome: Differential diagnosis for retinal artery occlusion. PMID- 26655017 TI - The contribution of health selection to occupational status inequality in Germany - differences by gender and between the public and private sectors. AB - OBJECTIVES: Estimating the size of health inequalities between hierarchical levels of job status and the contribution of direct health selection to these inequalities for men and women in the private and public sector in Germany. STUDY DESIGN: The study uses prospective data from the Socio-Economic Panel study on 11,788 women and 11,494 men working in the public and private sector in Germany. METHODS: Direct selection effects of self-rated health on job status are estimated using fixed-effects linear probability models. The contribution of health selection to overall health-related inequalities between high and low status jobs is calculated. RESULTS: Women in the private sector who report very good health have a 1.9 [95% CI: 0.275; 3.507] percentage point higher probability of securing a high status job than women in poor self-rated health. This direct selection effect constitutes 20.12% of total health inequalities between women in high and low status jobs. For men in the private and men and women in the public sector no relevant health selection effects were identified. CONCLUSIONS: The contribution of health selection to total health inequalities between high and low status jobs varies with gender and public versus private sector. Women in the private sector in Germany experience the strongest health selection. Possible explanations are general occupational disadvantages that women have to overcome to secure high status jobs. PMID- 26655018 TI - Daily temperature change in relation to the risk of childhood bacillary dysentery among different age groups and sexes in a temperate city in China. AB - BACKGROUND: In recent years, many studies have found that ambient temperature is significantly associated with bacillary dysentery (BD). However, there is limited evidence on the relationship between temperature and childhood BD in temperate areas. OBJECTIVES: To investigate the relationship between daily mean temperature (MT) and childhood BD in China. METHODS: Data on daily MT and childhood BD between 2006 and 2012 were collected from the Bureau of Meteorology and the Centre for Disease Control and Prevention in Hefei, Anhui Province, China. A Poisson generalized linear regression model combined with a distributed lag non linear model was used to analyse the effects of temperature on childhood BD across different age and sex subgroups. RESULTS: An increase in temperature was significantly associated with childhood BD, and each 1 degrees C increase corresponded to an increase of 1.58% [95% confidence interval (CI) 0.46-2.71%] in the number of cases of BD. Children aged 0-5 years and girls were particularly sensitive to the effects of temperature. CONCLUSIONS: High temperatures may increase the risk of childhood BD in Hefei. Children aged 0-5 years and girls appear to be particularly sensitive to the effects of high temperature. PMID- 26655019 TI - Do diabetes mellitus patients adhere to self-monitoring of blood glucose (SMBG) and is this associated with glycemic control? Experiences from a SMBG program in western Kenya. AB - AIMS: Among diabetes mellitus (DM) patients with poor glycemic control enrolled into a self-monitoring of blood glucose (SMBG) program in Kenya, to assess the level of SMBG adherence, its associated factors and its relation to glycemic control (defined as HbA1c <7% and/or 2% absolute reduction relative to baseline). METHODS: In this retrospective cohort study, we used routinely collected data of patients enrolled during 2012-2013. We assessed adherence to SMBG by dividing the number of glucose tests performed by the number recommended. A level of >= 80% was considered 'good adherence'. Glycemic control was considered as absolute change from baseline of 2%. RESULTS: Of 164 patients (59% female; 76% rural), the proportions with good SMBG adherence were 34%, 17%, 15% and 10% during 0-6, 7-12, 13-18 and 19-24 months into the HGM program respectively. In multivariate analysis, male gender, urban place of residence and payment for glucostrips were associated with poor adherence during 0-12 months. The mean reduction in HbA1c compared to baseline was 1.2%, 1.1%, 0.8% and 0.7% at 6, 12, 18 and 24 months, respectively. We did not find any association between SMBG adherence and glycemic control. CONCLUSIONS: Adherence to SMBG was sub-optimal, especially among those who had to pay for glucostrips. Patient education and provision of free glucostrips are recommended to improve adherence and glycemic control. PMID- 26655020 TI - Is the metabolic syndrome inversely associates with butter, non-hydrogenated- and hydrogenated-vegetable oils consumption: Tehran lipid and glucose study. AB - AIM: The aim of this study was to investigate the association between hydrogenated- (HVOs) and non-hydrogenated vegetable oils (non-HVOs) and butter and the metabolic syndrome (MetS) after 3-years of follow-up in adults. METHODS: This study was conducted between 2006-2008 and 2009-2011 within the framework of the Tehran Lipid and Glucose Study, on 1582 adults, aged 19-84 years. Intakes of HVOs, non-HVOs and butter were assessed by a validated semi-quantitative food frequency questionnaire. Based on the consumption of food rich in fat including HVOs, non-HVOs and butter, participants were categorized to consumers and non consumers. RESULTS: Of 1582 participants during a 3-year follow-up, 15.2% developed MetS. Non-consumption of butter was associated with lower MetS risk compared with its consumption. Among consumers of food rich in fat, intake of HVOs and butter were associated with an increased risk of MetS; ORs in the final multivariate model were 2.70 (95% CI: 1.52-4.78) for HVOs and 2.03 (95% CI: 1.20 3.41) for butter, in the highest, compared to the lowest category of dietary intakes. Intake of non-HVOs was not associated with risk of MetS. CONCLUSIONS: Consumption of HVOs and butter were positively associated with an increase risk of MetS. PMID- 26655021 TI - Association between sedentary and physical activity patterns and risk factors of metabolic syndrome in Saudi men: A cross-sectional study. AB - BACKGROUND: This study examined the association between objectively measured physical activity patterns and risk factors of metabolic syndrome (MetS) in Saudi men. METHODS: The study was cross-sectional, and 84 healthy men from the Saudi population (age 37.6 +/- 8.8 years, body mass index [BMI] 28.4 +/- 5.4 kg/m(2)) were recruited. Measurements of physical activity were made using triaxial accelerometers over 7 consecutive days of leisure time physical activity. Waist circumference and blood pressure were measured, and fasting blood samples taken to measure glucose, high density lipoprotein cholesterol (HDL), and triglycerides (TG). RESULTS: A total 21.4 % of participants had three or more risk factors for MetS, with low HDL levels the most frequent factor. Light physical activity (LPA) and BMI explained 13 % of the variation in TG. Moderate to vigorous physical activity (MVPA) with a minimum 10-min per session (10-min MVPA), LPA, and BMI explained 16 % of the variation in HDL. Sedentary behavior was not significantly associated with risk factors of MetS, although odds ratios indicated that decreased sedentarism does have a protective effect against MetS. CONCLUSIONS: LPA and 10-min MVPA were associated with elevated HDL levels among Saudi men. Future studies should confirm whether time spent physically active independent of intensity is an important factor in improving HDL levels. PMID- 26655022 TI - Nuclear Protein-Only Ribonuclease P2 Structure and Biochemical Characterization Provide Insight into the Conserved Properties of tRNA 5' End Processing Enzymes. AB - Protein-only RNase Ps (PRORPs) are a recently discovered class of RNA processing enzymes that catalyze maturation of the 5' end of precursor tRNAs in Eukaryotes. PRORPs are found in the nucleus and/or organelles of most eukaryotic organisms. Arabidopsis thaliana is a representative organism that contains PRORP enzymes (PRORP1, PRORP2 and PRORP3) in both its nucleus and its organelles; PRORP2 and PRORP3 localize to the nucleus and PRORP1 localizes to the chloroplast and the mitochondria. Apart from their identification, almost nothing is known about the structure and function of PRORPs that act in the nucleus. Here, we use a combination of biochemical assays and X-ray crystallography to characterize A. thaliana PRORP2. We solved the crystal structure of PRORP2 (3.2A) revealing an overall V-shaped protein and conserved metallonuclease active-site structure. Our biochemical studies indicate that PRORP2 requires Mg(2+) for catalysis and catalyzes the maturation of nuclear encoded substrates up to 10-fold faster than mitochondrial encoded precursor nad6 t-element under single-turnover conditions. We also demonstrate that PRORP2 preferentially binds precursor tRNAs containing short 5' leaders and 3' trailers; however, leader and trailer lengths do not significantly alter the observed rate constants of PRORP2 in single-turnover cleavage assays. Our data provide a biochemical and structural framework to begin understanding how nuclear localized PRORPs recognize and cleave their substrates. PMID- 26655023 TI - Insights from the Structure of Mycobacterium tuberculosis Topoisomerase I with a Novel Protein Fold. AB - The DNA topoisomerase I enzyme of Mycobacterium tuberculosis (MtTOP1) is essential for the viability of the organism and survival in a murine model. This topoisomerase is being pursued as a novel target for the discovery of new therapeutic agents for the treatment of drug-resistant tuberculosis. In this study, we succeeded in obtaining a structure of MtTOP1 by first predicting that the C-terminal region of MtTOP1 contains four repeated domains that do not involve the Zn-binding tetracysteine motifs seen in the C-terminal domains of Escherichia coli topoisomerase I. A construct (amino acids A2-T704), MtTOP1-704t, that includes the N-terminal domains (D1-D4) and the first predicted C-terminal domain (D5) of MtTOP1 was expressed and found to retain DNA cleavage-religation activity and catalyze single-stranded DNA catenation. MtTOP1-704t was crystallized, and a structure of 2.52A resolution limit was obtained. The structure of the MtTOP1 N-terminal domains has features that have not been observed in other previously available bacterial topoisomerase I crystal structures. The first C-terminal domain D5 forms a novel protein fold of a four stranded antiparallel beta-sheet stabilized by a crossing-over alpha-helix. Since there is only one type IA topoisomerase present in Mycobacteriaceae and related Actinobacteria, this subfamily of type IA topoisomerase may be required for multiple functions in DNA replication, transcription, recombination, and repair. The unique structural features observed for MtTOP1 may allow these topoisomerase I enzymes to carry out physiological functions associated with topoisomerase III enzyme in other bacteria. PMID- 26655024 TI - Theme and Variation in tRNA 5' End Processing Enzymes: Comparative Analysis of Protein versus Ribonucleoprotein RNase P. PMID- 26655025 TI - [Factors regarding awareness of preventive care exercises: Distance to exercise facilities and their social networks]. AB - OBJECTIVES: The present study examines factors affecting individuals' awareness of certain types of preventive care exercises, particularly the distance from their home to an exercise facility and their social networks. METHODS: Participants were 3206 men (age, 73.0+/-6.2 years) and 3395 women (age, 73.2+/ 6.4 years) aged >=65 years who had not been certified as persons with care needs and who had responded to an inventory survey conducted in Kasama City, Japan, in 2013. We performed multiple logistic regression analysis to assess the characteristics associated with participants' awareness of two types of exercises for preventive care: "silver rehabili taisou" (SRT) and "square-stepping exercise" (SSE). Independent variables were distance from home to the exercise facility, social networks, transportation availability, physical function, cognitive function, and neighborhood population density. RESULTS: Older adults who were aware of the exercises lived significantly closer to an exercise facility (SRT, aware: 1,148.5+/-961.3 m vs. unaware: 1,284.2+/-1,027.4 m; SSE, aware: 1,415.9+/-1104.1 m vs. unaware: 1,615.7+/-1,172.2 m). Multiple logistic regression analysis showed that participation in community activities (men, SRT odds ratio [OR]=2.54 and SSE-OR=2.19; women, SRT-OR=4.14 and SSE-OR=3.34] and visiting friends (men, SRT-OR=1.45 and SSE-OR=1.49; women SRT-OR=1.44 and SSE OR=1.73) were promoting factors for awareness of both types of exercises. In men and women, low physical function (SRT-OR=0.73 and SSE-OR=0.56) and dependence on another person to drive them to the destination (SRT-OR=0.79 and SSE-OR=0.78) were inhibiting factors, respectively. A distance of >500 m between their home and the facility tended to be an inhibiting factor. CONCLUSION: A shorter distance from home to an exercise facility and better social networks increased awareness of preventive care exercises in both sexes and for both types of exercise. Establishing exercise centers and devising effective methods of imparting information to individuals (e.g., via community magazines and home visits) may promote participation in preventive care exercises. PMID- 26655026 TI - [Sexual behavior and associated factors among Korean junior high school students]. AB - OBJECTIVES: The study purpose was to identify the sexual behavior and associated factors of Korean junior high school students. METHODS: Raw data from the 2013 Korean Youth Risk Behavior Web-Based Survey were used. Among the data from 72,435 students, 36,530 junior high school students were analyzed. Complex sample frequency analysis and complex sample chi-square were used to identify the condition of sexual behavior, and complex sample logistic regression was used to examine the factors related to sexual behavior. RESULTS: Among the students, 3.8% responded that they had experienced sexual intercourse, and the prevalence of sexual intercourse was higher among male students (5.0%) compared to female students (2.5%). Among male students, those who had the following were more likely to have had sexual intercourse: perceived high economic status, living with a relative, experience with a partti-me job, a foreign father, experience with smoking and drinking during the past month, experience with drug use, and depression during the past 12 months. Among the female students who were more likely to have had sexual intercourse, the following were ascertained: higher grades, perceived high economic status, living with a relative or in childcare facilities, experience with a part-time job, a foreign father or mother, experience with smoking and drinking during the past month, and experience with drug use. CONCLUSION: The results suggest that it is important to develop a comprehensive approach program not only focused on sexual behavior but also including mental health or other health behaviors to effectively reduce the likelihood of sexual intercourse among Korean junior high school students. PMID- 26655027 TI - [Commissioned child welfare volunteers' understanding of the social needs of the Visits to All Families with Infants Program]. AB - OBJECTIVES: It is important that commissioned child welfare volunteers (CCWVs) fully understand the needs, objectives, and prospective results of working on the Visits to All Families with Infants Program. This study aimed to explore the factors that enhanced volunteers' recognition of the need for the program and to reveal issues that need to be addressed to improve support for CCWVs. METHODS: All 259 CCWV who were engaged in the Visits to All Families with Infants Program and who were living in Kitakyushu City, Japan, participated in the study between August and December, 2013. We questioned the volunteers about their recognition of the need for the program, asking, "Do you think that it is necessary for CCWVs to visit families with infants four months of age or younger?" In addition, we asked about their demographic characteristics, experience in the program, and activities aside from the program. Their recognition was measured with scores on a 5-point scale, and the score was divided into 1 (good recognition) or 0 (poor recognition). Multiple logistic regression was used for statistical analysis and to calculate the odds ratio (OR) and 95% confidence interval (CI). Participants who had a "good experience" in the program were asked to explain these experiences by free description and these were analyzed qualitatively using content analysis. RESULTS: The response rate of the study was 92.1%, and the final analysis involved 154 CCWV (59.5%). Good recognition was ascertained for 69 individuals (44.8%) and poor recognition for 85 individuals (55.2%). Statistical analysis revealed that the volunteers' recognition of the need for the program was associated with qualifications related to medicine, health, or welfare (OR: 2.57, 95% CI: 1.12-6.20), and whether the volunteers had a "good experience" when they visited families (OR: 18.35, 95% CI: 6.41-67.60). Regarding the content analysis of "good experience," 2 main categories, 7 categories, and 18 sub categories were outlined. CONCLUSION: This study indicated that if CCWVs have a qualification or good experience through the program, then their awareness of the social needs to work in the Visits to All Families with Infants Program would be strengthened. PMID- 26655028 TI - [A quantitative analysis of information-seeking behaviors regarding medical institutions with Spanish language support among South American Spanish-speaking migrants in Aichi Prefecture, Japan]. AB - OBJECTIVES: This study aimed to explore the factors associated with information seeking behaviors regarding medical institutions with Spanish language support among South American Spanish-speaking migrants living in Aichi Prefecture, Japan. METHODS: The survey targeted South American Spanish-speaking migrants aged 18 years and older currently residing in Aichi Prefecture who had lived in Japan for at least three months and who had previously seen a doctor in Japan. The questionnaire was written in Spanish and the survey was conducted from April to July, 2010. Wilson's information behavior model was used to study information seeking behavior regarding medical institutions with Spanish language support among 245 respondents who completed the questionnaires (response rate: 58.9%). Experience seeking medical institutions with Spanish language support in the Tokai area was set as the dependent variable and a chi-square test was conducted to examine relationships with language support needs, recognition of and access to medical institutions with Spanish language support, living situation in Japan, and Japanese language skills. RESULTS: Among the 245 respondents, 106 were male (43.3%) and 139 were female (56.7%). The average age was 39.6+/-11.2 years old and 84.5% were Peruvian. The average length of residency in Japan was 11.0+/-5.7 years, and 34.3% of respondents had lived in Aichi for 5-9 years. A total of 165 respondents (67.3%) had searched for medical institutions with Spanish language support, while 80 (32.7%) had not. Information-seeking behavior regarding medical institutions with Spanish language support was associated with having previously experienced a need for Spanish language support when seeing doctors in Japan, finding and attending medical institutions with Spanish language support in the Tokai area, length of residency in Japan, Japanese language skills, and the language used in daily life. CONCLUSION: Experience in requiring Spanish support when sick or injured in Japan motivated respondents to seek medical institutions with Spanish language support. Communication difficulties in Japanese, speaking Spanish in daily life, and length of residency in Japan were relevant factors in their information-seeking behaviors. Respondents were likely to obtain information from family, friends, co-workers, and Spanish media, but not from public institutions that distribute Spanish material. Finding an effective way to disseminate health-related information was a fundamental health issue for South American Spanish-speaking migrants. PMID- 26655029 TI - Mental health trust failed to investigate unexpected deaths, claims leaked report. PMID- 26655031 TI - Death of a proverb. PMID- 26655030 TI - Head and neck mucosal melanoma: clinicopathological analysis of 51 cases treated in a single cancer centre and review of the literature. AB - Head and neck mucosal melanoma (HNMM) is a rare and aggressive malignancy. The objective of this study was to describe the outcomes of patients with HNMM. Clinical and pathological data from 51 patients with primary HNMM were reviewed. All patients were treated at a single cancer centre between 1954 and 2012. Most tumours involved the nasal cavity (35.3%) and upper gingiva (29.4%). The majority of lesions were ulcerated (54.9%) and pigmented (84.3%). Forty-three patients underwent surgical treatment and 21 (41.2%) underwent adjuvant chemotherapy and/or radiotherapy. Eight patients (15.7%) received palliative treatment. The median follow-up period was 21 months. During this period, 30 (58.8%) patients had tumour recurrences. At the last clinical evaluation, only seven (13.7%) patients were alive with no evidence of disease and three (5.9%) were alive with HNMM. There were significant differences in overall survival probability according to the presence of ulceration (P=0.004), metastatic lymph nodes (P=0.003), and treatment including a radical surgical procedure (P<0.001). On multivariate analysis, ulceration was the only variable associated with an increased risk of death. Despite the poor prognosis, there was significant improvement in overall survival in the most recent years in this sample, mainly due to advances in diagnosis and reconstruction techniques. PMID- 26655032 TI - Continuous versus intermittent infusion of vancomycin in adult patients: A systematic review and meta-analysis. AB - Continuous infusion of vancomycin (CIV) and intermittent infusion of vancomycin (IIV) are two major administration strategies in clinical settings. However, previous articles comparing the efficacy and safety of CIV versus IIV showed inconsistent results. Therefore, a meta-analysis was conducted to compare the efficacy and safety of CIV and IIV. PubMed, the Cochrane Library and Web of Science up to June 2015 were searched using the keywords 'vancomycin', 'intravenous', 'parenteral', 'continuous', 'intermittent', 'discontinuous', 'infusion', 'administration' and 'dosing'. Eleven studies were included in the meta-analysis. Neither heterogeneity nor publication bias were observed. Patients treated with CIV had a significantly lower incidence of nephrotoxicity compared with patients receiving IIV [risk ratio (RR)=0.61, 95% confidence interval (CI) 0.47-0.80; P<0.001]. No significant difference in treatment failure between the two groups was detected. Mortality between patients receiving CIV and patients receiving IIV was similar (RR=1.15, 95% CI 0.85-1.54; P=0.365). This meta analysis showed that CIV had superior safety compared with IIV, whilst the clinical efficacy was not significantly different. A further multicentre, randomised controlled trial is required to confirm these results. PMID- 26655033 TI - Characterisation of OXA-244, a chromosomally-encoded OXA-48-like beta-lactamase from Escherichia coli. PMID- 26655034 TI - Procalcitonin-based algorithms to initiate or stop antibiotic therapy in critically ill patients: Is it time to rethink our strategy? AB - Procalcitonin (PCT)-based antibiotic management algorithms for critically ill patients have been described in the literature. An evaluation of the available evidence demonstrates that studies have utilised PCT in various clinical scenarios: for the initiation of antimicrobials; for cessation or de-escalation of antimicrobials; or for the combination of both strategies. Current PCT reviews and meta-analyses have combined studies from all different clinical scenarios. However, there may be significant variations in algorithm compliance and clinical outcomes associated with the use of PCT in these different strategies. As such, the current review focused on separating out the studies utilising PCT in the critically ill population for different treatment strategies. Based on this review, we would recommend that PCT should not be used as the sole deciding factor for the initiation of antimicrobials. As such, PCT should not be obtained in patients who do not exhibit evidence of infection. In patients who do have signs of infection and antimicrobials have been initiated, a strategy that utilises PCT for the discontinuation or de-escalation of antimicrobials is likely to decrease the duration of treatment without adversely affecting outcome. PMID- 26655036 TI - Thermalization of a dimerized antiferromagnetic spin chain. AB - Thermalization is investigated for the one-dimensional anisotropic antiferromagnetic Heisenberg model with dimerized nearest-neighbor interactions that break integrability. For this purpose the time evolution of local operator expectation values after an interacting quench is calculated directly with the Chebyshev polynomial expansion, and the deviation of the diagonal from the canonical thermal ensemble value is calculated for increasing system size for these operators. The spatial and spin symmetries of the Hamiltonian are taken into account to divide it into symmetry subsectors. The rate of thermalization is found to weaken with the dimerization parameter as the Hamiltonian evolves between two integrable limits, the non-dimerized and the fully dimerized where the chain breaks up into isolated dimers. This conclusion is supported by the distribution of the local operator off-diagonal elements between the eigenstates of the Hamiltonian with respect to their energy difference, which determines the strength of temporal fluctuations. The off-diagonal elements have a low-energy peak for small dimerization which facilitates thermalization, and originates in the reduction of spatial symmetry with respect to the non-dimerized limit. For increasing dimerization their distribution changes and develops a single low energy maximum that relates to the fully dimerized limit and slows down thermalization. PMID- 26655035 TI - Mitochondrial impairment, apoptosis and autophagy in a rat brain as immediate and long-term effects of perinatal phencyclidine treatment - influence of restraint stress. AB - Phencyclidine (PCP) acts as a non-competitive antagonist of glutamatergic N methyl-d-aspartate receptor. Its perinatal administration to rats causes pathophysiological changes that mimick some pathological features of schizophrenia (SCH). Numerous data indicate that abnormalities in mitochondrial structure and function could be associated with the development of SCH. Mitochondrial dysfunction could result in the activation of apoptosis and/or autophagy. The aim of this study was to assess immediate and long-term effects of perinatal PCP administration and acute restraint stress on the activity of respiratory chain enzymes, expression of apoptosis and autophagy markers and ultrastructural changes in the cortex and hippocampus of the rat brain. Six groups of rats were subcutaneously treated on 2nd, 6th, 9th and 12th postnatal days (P), with either PCP (10mg/kg) or saline (0.9% NaCl). One NaCl and one PCP group were sacrificed on P13, while other two NaCl and PCP groups were sacrificed on P70. The remaining two NaCl and PCP groups were subjected to 1h restraint stress prior sacrifice on P70. Activities of respiratory chain enzymes were assessed spectrophotometrically. Expression of caspase 3 and AIF as markers of apoptosis and Beclin 1, p62 and LC3, as autophagy markers, was assessed by Western blot. Morphological changes of cortical and hippocampal ultrastructure were determined by transmission electron microscopy. Immediate effects of perinatal PCP administration at P13 were increased activities of complex I in the hippocampus and cytochrome c oxidase (COX) in the cortex and hippocampus implying mitochondrial dysfunction. These changes were followed by increased expression of apoptotic markers. However the measurement of autophagy markers at this time point has revealed decrease of this process in cortex and the absence of changes in hippocampus. At P70 the activity of complex I was unchanged while COX activity was significantly decreased in cortex and increased in the hippocampus. Expressions of apoptotic markers were still significantly higher in PCP perinatally treated rats in all investigated structures, but the changes of autophagy markers have indicated increased level of autophagy also in both structures. Restraint stress on P70 has caused increase of COX activity both in NaCl and PCP perinatally treated rats, but this increase was lower in PCP group. Also, restraint stress resulted in decrease of apoptotic and increase of autophagy processes especially in the hippocampus of PCP perinatally treated group. The presence of apoptosis and autophagy in the brain was confirmed by transmission electron microscopy. In this study we have demonstrated for the first time the presence of autophagy in PCP model of SCH. Also, we have shown increased sensitivity of PCP perinatally treated rats to restraint stress, manifested in alterations of apoptotic and autophagy markers. The future studies are necessary to elucidate the role of mitochondria in the pathophysiology of SCH and putative significance for development of novel therapeutic strategies. PMID- 26655037 TI - Uracil-induced signaling pathways for DUOX-dependent gut immunity. AB - Intestinal dual oxidase (DUOX) activation is the first line of host defense against enteric infection in Drosophila. DUOX enzymatic activity is mainly controlled by phospholipase C-beta (PLCbeta)-dependent calcium mobilization, whereas DUOX gene expression is mainly controlled by the MEKK1-p38 mitogen activated protein kinase pathway. Furthermore, bacterial-derived uracil molecules act as ligands for DUOX activation. However, our current understanding of uracil induced signal transduction pathways remain incomplete. We have recently found that uracil stimulates Hedgehog signaling, which in turn upregulates cadherin99C (Cad99C) expression in enterocytes. Cad99C molecules, along with PLCbeta and protein kinase C, induce the formation of signaling endosomes that facilitate intracellular calcium mobilization for DUOX activity. These observations illustrate the complexity of signaling cascades in uracil-induced signaling pathways. Here, we further demonstrated the role of lipid raft formation and calmodulin-dependent protein kinase-II on endosome formation and calcium mobilization, respectively. Moreover, we will provide a brief discussion on two different models for uracil recognition and uracil-induced DUOX activation in Drosophila enterocytes. PMID- 26655038 TI - Real-time investigation of antibiotics-induced oxidative stress and superoxide release in bacteria using an electrochemical biosensor. AB - The involvement of oxidative stress in the mechanism of antibiotics-meditated cell death is unclear and subject to debate. The kinetic profile and a quantitative relationship between the release of reactive oxygen species (ROS), bacteria and antibiotic type remain elusive. Here we report direct measurements and analytical quantification of the release of superoxide radicals (O2(.-)), a major contributor to ROS, in antibiotics-treated bacterial cultures using a cytochrome c electrochemical biosensor. The specificity of electrochemical measurements was established by the addition of superoxide dismutase (SOD) which decreased the O2(.-) signal. Measurements using a general ROS-specific fluorescence dye and colony forming units (CFU) assays were performed side-by side to determine the total ROS and establish the relationship between ROS and the degree of lethality. Exposure of Escherichia coli and Listeria monocytogenes cultures to antibiotics increased the release of O2(.-) radicals in a dose dependent manner, suggesting that the transmembrane generation of ROS may occur as part of the antibiotic action. The study provides a quantitative methodology and fundamental knowledge to further explore the role of oxidative stress in antibiotics-meditated bacterial death and to assess physiological changes associated with the complex metabolic events related to oxidative stress and bacterial resistance. PMID- 26655042 TI - Rare occurrence of natural transovarial transmission of dengue virus and elimination of infected foci as a possible intervention method. AB - Transovarial transmission of dengue virus has been studied in 33 districts of Rajasthan, India. Small proportion (1.09%) of breeding containers positive for the virus and their elimination has been demonstrated as a possible intervention method of disease control. Dengue virus was isolated from individual mosquitoes employing Indirect Fluorescence Antibody Test and Reverse Transcriptase Polymerase Chain Reaction. Out of 1,30,525 containers examined only 1432(1.09%) showed transovarially transmitted virus activity. Elimination of larvae from all the 1432 virus positive containers resulted in substantial control over prospective transmission of dengue. The study highlights rarity of transovarial transmission under natural conditions and sensitizes whether elimination of vertically infected foci could be used as a new intervention method. PMID- 26655043 TI - A new cavernicolous sand fly from Cambodia: Idiophlebotomus nicolegerae n. sp. (Diptera: Psychodidae). AB - Cambodia is an area considered free of leishmaniasis and consequently little is known of its' phlebotomine sand fly fauna. Only six species of sand flies have previously been recorded: Sergentomyia barraudi, Sergentomyia pertubans, Sergentomyia bailyi, Sergentomyia silvatica, Sergentomyia khawi and Grassomyia indica and none belonging to the genus Phlebotomus. During an inventory carried out in Cambodia, we caught a new species, belonging to the genus Idiophlebotomus, in a cave. We describe the new species in this paper and also report three other new species for the country: Sergentomyia anodontis, Phlebotomus stantoni and Phlebotomus kiangsuensis. PMID- 26655040 TI - Analysis of the genetic structure of allopatric populations of Lutzomyia umbratilis using the period clock gene. AB - In South America, Lutzomyia umbratilis is the main vector of Leishmania guyanensis, one of the species involved in the transmission of American tegumentary leishmaniasis. In Brazil, L. umbratilis has been recorded in the Amazon region, and an isolated population has been identified in the state of Pernambuco, Northeastern region. This study assessed the phylogeographic structure of three allopatric Brazilian populations of L. umbratilis. Samples of L. umbratilis were collected from Rio Preto da Eva (north of the Amazon River, Amazonas), from Manacapuru (south of the Amazon River), and from the isolated population in Recife, Pernambuco state. These samples were processed to obtain sequences of the period gene. Phylogenetic analysis revealed the presence of two distinct monophyletic clades: one clade comprised of the Recife and Rio Preto da Eva samples, and one clade comprised of the Manacapuru samples. Comparing the Manacapuru population with the Recife and Rio Preto da Eva populations revealed high indices of interpopulational divergence. Phylogenetic analysis indicated that geographical distance and environmental differences have not modified the ancestral relationship shared by the Recife and Rio Preto da Eva populations. Genetic similarities suggest that, in evolutionary terms, these populations are more closely related to each other than to the Manacapuru population. These results confirm the existence of an L. umbratilis species complex composed of at least two incipient species. PMID- 26655041 TI - Schistosoma mekongi cathepsin B and its use in the development of an immunodiagnosis. AB - Schistosomiasis mekongi is one of the most important human parasitic diseases caused by Schistosoma mekongi in South-east Asia. The endemic area is the Mekong River sub-region from Laos to Cambodia. This parasite also infects dogs and pigs which are its alternative host species. Currently, the lack of reliable rapid diagnosis makes it difficult to monitor the infection and spreading of the disease. In this study, we screened the antigens of the parasite with sera of infected mice using Western blotting and identified proteins of interest with LC MS/MS to obtain potential candidate proteins for diagnostic development. This assay yielded 2 immunoreactive bands at molecular masses of 31 and 22kDa. The 31kDa protein was the major band identified as cathepsin B, and its gene was cloned to obtain a full cDNA sequence (SmekCatB). The cDNA consisted of 1123bp and its longest reading frame encoded for 342 amino acids with some putative post translation modifications. The recombinant SmekCatB (rSmekCatB) with hexahistidine tag at the C-terminus was expressed in Escherichia coli and purified by Ni-NTA resin under denaturing conditions. The rSmekCatB reacted with sera of S. mekongi-infected mice. Indirect ELISA using rSmekCatB as the antigen to detect mouse antibodies, revealed a sensitivity of 91.67% for schistosomiasis mekongi and the specificity of 100%. Our data suggested that SmekCatB is one of the most promising parasitic antigens that could be used for the diagnosis of S. mekongi infection. PMID- 26655039 TI - Ability of vaccine strain induced antibodies to neutralize field isolates of caliciviruses from Swedish cats. AB - BACKGROUND: Feline calicivirus (FCV) is a common cause of upper respiratory tract disease in cats worldwide. Its characteristically high mutation rate leads to escape from the humoral immune response induced by natural infection and/or vaccination and consequently vaccines are not always effective against field isolates. Thus, there is a need to continuously investigate the ability of FCV vaccine strain-induced antibodies to neutralize field isolates. METHODS: Seventy eight field isolates of FCV isolated during the years 2008-2012 from Swedish cats displaying clinical signs of upper respiratory tract disease were examined in this study. The field isolates were tested for cross-neutralization using a panel of eight anti-sera raised in four pairs of cats following infection with four vaccine strains (F9, 255, G1 and 431). RESULTS: The anti-sera raised against F9 and 255 neutralised 20.5 and 11.5 %, and 47.4 and 64.1 % of field isolates tested, respectively. The anti-sera against the more recently introduced vaccine strains G1 and 431 neutralized 33.3 and 55.1 % (strain G1) or 69.2 and 89.7 % (strain 431) of the field isolates with titres >=5. [corrected]. Dual vaccine strains displayed a higher cross-neutralization. CONCLUSIONS: This study confirms previous observations that more recently introduced vaccine strains induce antibodies with a higher neutralizing capacity compared to vaccine strains that have been used extensively over a long period of time. This study also suggests that dual FCV vaccine strains might neutralize more field isolates compared to single vaccine strains. Vaccine strains should ideally be selected based on updated knowledge on the antigenic properties of field isolates in the local setting, and there is thus a need for continuously studying the evolution of FCV together with the neutralizing capacity of vaccine strain induced antibodies against field isolates at a national and/or regional level. PMID- 26655044 TI - Allometric scaling and accidents at work. AB - Allometry is the knowledge concerning relations between the features of some beings, like animals, or cities. For example, the daily energy rate is proportional to a mass of mammals rise of 3/4. This way of thinking has spread quickly from biology to many areas of research concerned with sociotechnical systems. It was revealed that the number of innovations, patents or heavy crimes rises as social interaction increases in a bigger city, while other urban indexes such as suicides decrease with social interaction. Enterprise is also a sociotechnical system, where social interaction and accidents at work take place. Therefore, do these interactions increase the number of accidents at work or, on the contrary, are they reduction-driving components? This article tries to catch such links and assess the allometric exponent between the number of accidents at work and the number of employees in an enterprise. PMID- 26655045 TI - Nepalese dental hygiene and dental students' career choice motivation and plans after graduation: a descriptive cross-sectional comparison. AB - BACKGROUND: This is the first study of its kind to provide data regarding the self-reported career choice motivation and intentions after graduation of dental and dental hygiene students in Nepal. The findings of this study can be used to inform future oral health workforce planning in Nepal. METHODS: A cross-sectional survey of dentistry and dental hygiene students attending a large accredited dental college in Kathmandu, Nepal. Quantitative data were analysed using IBM(r) SPSS(r) 22. The respondents were given the opportunity to provide clarifying comments to some of the questions. RESULTS: Two hundred questionnaires were distributed, and 171 students completed the anonymous survey (response rate 86 %). Working in health care and serving the community were the most important initial motives for career choice, with significantly more dentistry students selecting their degree course because of the possibility to work flexible working hours (p < .001) compared to dental hygiene students. A majority of the students expressed concern about finding a suitable job (58 %) after graduation. Almost a quarter (23 %) reported intent to seek a job immediately after graduation, while 46 % plan further studies. Dentistry students were more likely to report planning further studies (p = .007) compared to the dental hygiene students. Dental hygiene students express a higher interest in going abroad (p = .011) following graduation. Only 10 % of all students plan to live or work in rural areas after study. Most common preferred locations to live after graduation are urban (33 %) or abroad (38 %). Data suggest a preference to combine working in a hospital with working in their own practice (44 %) while interest in solely working in their own practice is low (<2 %). CONCLUSION: Many students, though enthusiastic about their profession and expressing the ambition to serve the community, fear unemployment or envision better chances abroad. Most of the students in this study expressed a preference to live in an urban area after graduation. Findings indicate that strong measures are required to incentivise students to consider rural work. PMID- 26655046 TI - The Role of Co-Morbidities. AB - Medical conditions can impact sleep and breathing in children. Gastroesophageal reflux disease, allergic rhinitis and asthma are common in children and often coexist with obstructive sleep apnea. Appropriate identification and management of these conditions can improve nocturnal and diurnal symptoms of sleep disordered breathing. We discuss the relationship between these medical conditions and obstructive sleep apnea in children. PMID- 26655047 TI - Quality of care measures for the vascular surgery patient. PMID- 26655048 TI - Evaluating hospital quality for vascular surgery. AB - Increasingly, there is a wealth of data available to aid patients in determining where to seek care for quality vascular disease. At times, these data may be difficult for the public to comprehend. Hospital rating organizations, frequently motivated by profit, are marketing directly to consumers with increasingly granular data. In this report, we examine the most popular ratings for hospitals that perform vascular surgical procedures and describe the methodology of each rating system, as well as the validity of the data underscoring these ratings. Understanding how hospital quality is being evaluated and what outcomes measures are being collated allows vascular surgeons to take appropriate actions to ensure the validity of their own hospital ratings. PMID- 26655049 TI - Using implementation science to help integrate preoperative evidence-based measures into practice for vascular surgery patients. AB - The preoperative workup is a necessary and crucial evaluation for patients undergoing major vascular surgery. It is important to assess for likelihood of perioperative adverse events and then implement evidence-based measures to reduce identified medical comorbidities and improve the quality of patient care and outcomes after surgery. Although there are numerous opportunities to implement evidence-based processes during the preoperative period, there are many barriers that can prevent vascular surgeons from achieving these goals. This review will discuss how an implementation science-based approach can be used by members of the vascular surgery team to identify appropriate preoperative evidence-based interventions for diverse practice settings and to overcome barriers and allow integration of these interventions as part of the routine preoperative workup. PMID- 26655050 TI - Smoking cessation strategies in vascular surgery. AB - Tobacco abuse is a highly prevalent modifiable risk factor in vascular surgery patient populations. Despite the known benefits of smoking cessation, quitting smoking is difficult for most patients. Physician advice to stop smoking can help, though more intensive or multifactorial interventions have greater impact. Smoking cessation initiatives based in vascular clinics are feasible, although currently there is significant variation in physician delivery of smoking cessation interventions. Vascular surgeons are optimally poised to be able to capitalize on the "teachable moment" of the vascular procedure to encourage smoking cessation. Concise and effective smoking cessation strategies include standardized physician "very brief advice" (a standardized advice delivery developed and validated by the National Health Service), referral to telephone counseling, and prescription of pharmacotherapy, all of which are best utilized together. This review will discuss different smoking cessation strategies, as well as their inclusion in multicenter trials designed to study delivery of smoking cessation interventions in vascular surgery patients. PMID- 26655052 TI - Vascular surgery institutional-based quality and performance measures for the care of patients with critical limb ischemia. AB - The intensity and quality of medical care provided to patients with critical limb ischemia (CLI) varies by geography, ethnicity, and socioeconomic status. Although vascular surgery societal performance goals have been set forth, no consensus criteria exist by which to benchmark the quality of health care delivery specifically for CLI patients. We review existing broad performance measures for patients with peripheral vascular disease and suggest those with optimal care delivery suited for CLI (eg, ankle-brachial index, optimal medical therapy, smoking cessation, and duplex surveillance). Further, we propose that diabetic management, degree of wound healing, and quality of life measures be considered as additional quality measures for CLI management. In combination, these criteria provide a simple yet powerful metric that might allow for standardization of CLI care and comparisons across institutions, with the potential for diminishing the disparity that exists in current treatment practices. PMID- 26655051 TI - Optimal perioperative medication utilization in patients having arterial intervention. AB - Perioperative medical management of patients undergoing carotid, aortic, or peripheral arterial procedures, both open and endovascular, should be optimized in all cases to achieve excellent outcomes. This particular patient population is often plagued with multiple comorbidities, primarily of the cardiovascular system, but frequently involving other systems. For this reason, management of these comorbidities is complex and should be carefully addressed in every patient throughout the surgical encounter, in many cases through a multidisciplinary approach. Most recently, the perioperative use of statins, antiplatelet agents, and beta-blockers have been scrutinized in the literature specifically targeting peripheral vascular disease patients, and results have sometimes been conflicting. The objective of this review is to summarize current available evidence regarding optimal perioperative medical management of patients undergoing arterial vascular surgical procedures, open and endovascular. PMID- 26655053 TI - Using the Vascular Quality Initiative to improve quality of care and patient outcomes for vascular surgery patients. AB - The Society for Vascular Surgery Vascular Quality Initiative (VQI) is a collaborative network of vascular specialists from various specialties that seeks to improve the quality and safety of vascular care by sharing data among physicians, medical centers, and regions. Working under a Patient Safety Organization designation by the Agency for Healthcare Research and Quality, the VQI provides a protected environment where data can be pooled and evaluated for trends that might provide opportunities to improve the care we provide our patients. Since its inception in 2011, this national organization has grown rapidly and now involves >300 medical centers that are separated into 18 active regional groups who meet twice yearly to discuss quality improvement. The structure of the VQI provides a powerful platform for data collection and analysis, and has allowed the development of a large body of literature that demonstrates the importance and benefits of participation. Here we provide a brief overview of the VQI to date. PMID- 26655054 TI - Measures to reduce unplanned readmissions after vascular surgery. AB - Hospital readmissions are increasingly utilized as a measure of health care quality. Unplanned readmissions in surgical patients are viewed as a marker of poor care quality, and are associated with significant expense both to the health care system and to the patient. Interventions aimed at reducing readmissions have been the focus of several prospective randomized trials addressing medical conditions like congestive heart failure, but few data exist on efforts to reduce readmissions in surgical patients. Vascular surgery patients have been found to be at a particularly high risk for readmission, and a number of groups have reported on the risk factors for readmission in these patients. However, measures to reduce unplanned readmissions after vascular surgery have not be thoroughly investigated. Here, we summarize the existing data on risk factors for readmission in vascular surgery patients, review interventional studies in medical patients aimed at reducing readmissions, and suggest interventions that may be helpful in reducing readmissions in vascular patients. Further investigative work is needed to ascertain practical approaches to reducing unplanned readmissions in vascular surgery patients and thus improve the quality of care they receive. PMID- 26655055 TI - Morbidity of femoropopliteal bypass surgery. AB - A systemic review of published reports on the incidence of early (<30 days) adverse events occurring after above- or below-knee femoropopliteal bypass surgery was conducted to provide contemporary outcomes data for comparative reporting. A total of 38 articles were included describing 6,374 femoropopliteal bypasses in 6,007 patients. Fifty-two percent were male and the mean age was 64.6 years (range, 40 to 93 years). The various studied types of complications were reported in 10 to 34 of 38 articles and definitions were often missing. The overall 30-day morbidity rate was 36.8%. The wound infection rate was 7.8% (range, 0.0 to 17.4%) accompanied with dermal necrosis in 0.4%. Graft infection was described in 2.4% (range, 0.0 to 5.3%) of cases. Postoperative bleeding was seen in 7.4% (range, 0.0 to 26%), of which 2.5% required return to surgery. Occlusions were reported in 12.0% (range, 0.0 to 59%). Lymphedema occurred in 2.9% (range, 0.0 to 9.6%) of cases and surgical site seroma formation occurred in 2.0% (range, 1.0% to 3.0%). Overall 30-day mortality rate was 2.3% (range 0.0 to 4.3%). Pooled data comparing vein grafts and prosthetic grafts revealed no significant difference (P = .10; risk ratio = 0.82; 95% confidence interval, 0.66 1.03; I(2) = 0%) in the incidence of complications. This review confirmed the morbidity of femoropopliteal bypass surgery is inconsistently reported and definitions are lacking. Because one-third of patients can be expected to experience an adverse event after femoropopliteal bypass grafting, standards on defining and reporting complications are necessary if comparative outcome standards are developed. PMID- 26655056 TI - Patient-reported outcome measures in vascular surgery. AB - Patient-reported outcomes (PROs) after vascular surgery are becoming increasingly important in the current era of health care reform. Although a number of general quality of life instruments exist, vascular disease-specific instruments may provide more targeted data on how patients feel after specific interventions. Here we provide a review of both generic and disease-specific instruments focused on arterial conditions, including peripheral arterial disease, carotid arterial disease, and aortic disease, which have been described in the literature. While many different tools currently exist, there is a paucity of well-validated, specific instruments that accurately reflect functional and objective measures of patients' arterial disease burden. A full understanding of the existing tools available to assess patients' perceived lifestyle impact of their disease and its treatments is essential for both research and clinical purposes, and to highlight the need for additional work on this topic. PMID- 26655057 TI - Transitions of care and long-term surveillance after vascular surgery. AB - Quality care of vascular surgery patients extends to the postoperative coordination of care and long-term surveillance, including the medical management of vascular disease. This is particularly highlighted in contemporary modern vascular surgery practice, as tremendous focus is being placed on postoperative adverse events and hospital readmissions. The purpose of this review is to provide a contemporary perspective of transitions of care at discharge and long term surveillance recommendations after vascular surgery interventions. PMID- 26655058 TI - Frailty assessment in vascular surgery and its utility in preoperative decision making. AB - The average patient requiring vascular surgery has become older, as life expectancy within the US population has increased. Many older patients have some degree of frailty and reside near the limit of their physiological reserve with restricted ability to respond to stressors such as surgery. Frailty assessment is an important part of the preoperative decision-making process, in order to determine whether patients are fit enough to survive the vascular surgery procedure and live long enough to benefit from the intervention. In this review, we will discuss different measures of frailty assessment and how they can be used by vascular surgery providers to improve preoperative decision making and the quality of patient care. PMID- 26655059 TI - Determination of Palytoxins in Soft Coral and Seawater from a Home Aquarium. Comparison between Palythoa- and Ostreopsis-Related Inhalatory Poisonings. AB - Anecdotal reports exist of aquarium hobbyists that experienced severe respiratory distress and/or skin injury following cleaning operation of home aquaria containing Palythoa sp. soft corals. Hundreds of cases of respiratory illness and/or dermatitis have been recorded in proximity to the sea concomitantly with algal blooms of Ostreopsis spp. in the Mediterranean area. Both Palythoa spp. and Ostreopsis spp. contain congeners of palytoxin, a highly potent toxin whose inhalation hazard is however unknown. In this study, we demonstrate the presence of high levels of palytoxins (palytoxin and hydroxypalytoxin) in both soft coral and seawater from a home marine aquarium involved in the poisoning of a whole family. Due to the high toxin levels found in seawater, a procedure for a rapid and efficient determination of palytoxin in seawater was setup. A comparison of symptoms of Palythoa- and Ostreopsis-related inhalatory poisonings showed many similarities including fever, respiratory distress, nausea, and flu-like symptoms. From the chemical and symptomatological data reported herein it is reasonable to hold palytoxins responsible for respiratory disorders following inhalation. Although the exact mechanism through which palytoxin congeners exert their inhalatory toxicity is still unknown, this represents a step toward demonstrating that palytoxin congeners exert toxic effects through inhalation both in natural environments and in the surroundings of private and public aquaria. PMID- 26655060 TI - [Analysis of fetal posterior fossa during the first trimester ultrasound scan]. AB - The diagnosis of an abnormal fetal posterior fossa is usually done during the second trimester scan. However, some forms of open spina bifida with Arnold Chiari malformation can be detected from the first trimester ultrasound with a precise examination of the posterior fossa and intracranial translucency. Furthermore, other abnormalities of the posterior fossa such as cystic malformations also seem to be accessible to early detection. This work detailed the possible usual and unusual aspects of the posterior fossa individualized during the first trimester ultrasound scan. Identifying an unusual appearance may identify high-risk fetus to present an abnormality of the posterior fossa. Then, thorough analysis of the fetal brain from 18 weeks will often differentiate a normal variant of a real brain malformation. PMID- 26655061 TI - Nanomechanics of Protein Unfolding Outside a Generic Nanopore. AB - Protein folding and unfolding have been the subject of active research for decades. Most of previous studies in protein unfolding were focused on temperature, chemical, and/or force (such as in atomic force microscopy (AFM)) induced denaturations. Recent studies on the functional roles of proteasomes (such as ClpXP) revealed a different unfolding process in cell, during which a target protein is mechanically unfolded and pulled into a confined, pore-like geometry for degradation. While the proteasome nanomachine has been extensively studied, the mechanism for unfolding proteins with the proteasome pore is still poorly understood. Here, we investigate the mechanical unfolding process of ubiquitin with (or really outside) a generic nanopore, and compare such process with that in the AFM pulling experiment. Unexpectedly, the required force for protein unfolding through a pore can be much smaller than that by the AFM. Simulation results also unveiled different nanomechanics, tearing fracture vs shearing friction, in these two distinct types of mechanical unfoldings. PMID- 26655063 TI - Activation of multiple chemotherapeutic prodrugs by the natural enzymolome of tumour-localised probiotic bacteria. AB - Some chemotherapeutic drugs (prodrugs) require activation by an enzyme for efficacy. We and others have demonstrated the ability of probiotic bacteria to grow specifically within solid tumours following systemic administration, and we hypothesised that the natural enzymatic activity of these tumour-localised bacteria may be suitable for activation of certain such chemotherapeutic drugs. Several wild-type probiotic bacteria; Escherichia coli Nissle, Bifidobacterium breve, Lactococcus lactis and Lactobacillus species, were screened against a panel of popular prodrugs. All strains were capable of activating at least one prodrug. E. coli Nissle 1917 was selected for further studies because of its ability to activate numerous prodrugs and its resistance to prodrug toxicity. HPLC data confirmed biochemical transformation of prodrugs to their toxic counterparts. Further analysis demonstrated that different enzymes can complement prodrug activation, while simultaneous activation of multiple prodrugs (CB1954, 5 FC, AQ4N and Fludarabine phosphate) by E. coli was confirmed, resulting in significant efficacy improvement. Experiments in mice harbouring murine tumours validated in vitro findings, with significant reduction in tumour growth and increase in survival of mice treated with probiotic bacteria and a combination of prodrugs. These findings demonstrate the ability of probiotic bacteria, without the requirement for genetic modification, to enable high-level activation of multiple prodrugs specifically at the site of action. PMID- 26655062 TI - Controlled release of biologics for the treatment of type 2 diabetes. AB - Type 2 diabetes is a rapidly growing disease that poses a significant burden to the United States healthcare system. Despite the many available treatments for the disease, close to half of diagnosed type 2 diabetes cases are not properly managed, largely due to inadequate patient adherence to prescribed treatment regimens. Methods for improving delivery - and thereby easing administration - of type 2 drugs have the potential to greatly improve patient health. This review focuses on two peptide drugs - insulin and glucagon-like peptide 1 (GLP-1) - for treatment of type 2 diabetes. Peptide drugs offer the benefits of high potency and specificity but pose a significant delivery challenge due to their inherent instability and short half-life. The development of insulin and GLP-1 analogs highlights the broad spectrum of drug delivery strategies that have been used to solve these problems. Numerous structural modifications and formulations have been introduced to optimize absorption, residence time, stability, route of delivery and frequency of administration. Continual improvements in delivery methods for insulin and GLP-1 receptor agonists are paving the way towards better patient compliance and improved disease management, and thereby enhanced patient quality of life. PMID- 26655064 TI - Hyperthermia exacerbates the effects of cathepsin L on claudin-1 in a blood-brain barrier model in vitro. AB - PURPOSE: The effects of cathepsin L on claudin-1 expression were investigated under hyperthermic condition in a blood-brain barrier (BBB) model in vitro, in order to estimate the potential effects of hyperthermia on BBB dysfunction. MATERIALS AND METHODS: Brain microvascular endothelial cells (BMECs) and astrocytes were obtained from rat brain. The BBB models were randomly divided into a sham (37 degrees C) group, a 39 degrees C group, a 37 degrees C+cathepsin L group and a 39 degrees C+cathepsin L group. The permeability of BBB was judged. The expressions of cathepsin L in astrocytes and claudin-1 in BMECs were detected using immunohistochemistry method and western blot assay. RESULTS: The permeability of BBB models was higher in the 39 degrees C group than in the sham group. The cathepsin L expression in astrocytes was higher in the 39 degrees C group than in the sham group (P<0.01), whereas the claudin-1 expression in BMECs was lower in the 39 degrees C group than in the sham group (P<0.01). The claudin 1 expression in BMECs was significantly lower in the 37 degrees C+cathepsin L group than in the sham group (P<0.01). At the same time point, the claudin-1 expression in BMECs was significantly lower in the 39 degrees C+cathepsin L group than in the 37 degrees C+cathepsin L group (P<0.01). CONCLUSION: Hyperthermia can probably decrease claudin-1 expression in BMECs by upregulating cathepsin L expression in astrocytes in a BBB model in vitro. PMID- 26655065 TI - Risk of stillbirth in pregnant women with obesity in the United Kingdom. AB - BACKGROUND: The stillbirth rate in the United Kingdom (UK) is approximately 3.5-4 per 1000 births. The country has one of the highest stillbirth rates in Europe, constituting a substantial portion of the UK perinatal death rate, which was estimated in 2013 at 6.7 deaths per 1000 births. AIM: To analyse the risk of stillbirth in pregnant women with and without increased BMI in the United Kingdom (UK). DESIGN AND SETTING: Retrospective study based on Disease Analyzer database (IMS Health). METHOD: A total of 44,060 pregnant women with or without an increased BMI who gave birth to a single child were examined using a Disease Analyzer database that included 102 general practices. Selected patients were observed for a period of at least 10 months between January 1994 and December 2013. Standard BMI ranges were considered: 18.5-24.9 (normal weight), 25-29.9 (overweight), 30-39.9 (class I and class II obese), 40-49.9 (class III) and over 50 (class IV). Multivariate logistic models were used to estimate the relationship between increasing BMI and the rate of stillbirth adjusted for demographic data and co-morbidities. RESULTS: BMI increase was associated with an increase in stillbirth OR, from 1.37 (95% CI: 1.02-1.85) in the overweight group to 5.04 (95% CI: 1.79-14.07) in the group of pregnant women with a BMI higher than or equal to 50. CONCLUSIONS: Pregnant women with obesity and even moderate overweight exhibit an increased risk of stillbirth in UK primary care practices over 20 years. PMID- 26655066 TI - Evaluating enzymatic synthesis of small molecule drugs. AB - There have been many achievements in applying biochemical synthetic routes to the synthesis of commodity chemicals. However, most of these endeavors have focused on optimizing and increasing the yields of naturally existing pathways. We sought to evaluate the potential for biosynthesis beyond the limits of known biochemistry towards the production of small molecule drugs that do not exist in nature. Because of the potential for improved yields compared to total synthesis, and therefore lower manufacturing costs, we focused on drugs for diseases endemic to many resource poor regions, like tuberculosis and HIV. Using generalized biochemical reaction rules, we were able to design biochemical pathways for the production of eight small molecule drugs or drug precursors and identify potential enzyme-substrate pairs for nearly every predicted reaction. All pathways begin from native metabolites, abrogating the need for specialized precursors. The simulated pathways showed several trends with the sequential ordering of reactions as well as the types of chemistries used. For some compounds, the main obstacles to finding feasible biochemical pathways were the lack of appropriate, natural starting compounds and a low diversity of biochemical coupling reactions necessary to synthesize molecules with larger molecular size. PMID- 26655067 TI - Understanding Vaccine Refusal: Why We Need Social Media Now. PMID- 26655068 TI - Influence of Perceived Stress on Incident Amnestic Mild Cognitive Impairment: Results From the Einstein Aging Study. AB - Stress is a potentially remediable risk factor for amnestic mild cognitive impairment (aMCI). Our objective is to determine whether perceived stress predicts incident aMCI and to determine if the influence of stress on aMCI is independent of known aMCI risk factors, particularly demographic variables, depression, and apolipoprotein genotype. The Einstein Aging Study is a longitudinal community-based study of older adults. The Perceived Stress Scale (PSS) was administered annually in the Einstein Aging Study to participants (N=507; 71 developed incident aMCI; mean follow-up time=3.6 y, SD=2.0) who were aged 70 years and older, free of aMCI and dementia at baseline PSS administration, and had at least 1 subsequent annual follow-up. Cox hazard models were used to examine time to aMCI onset adjusting for covariates. High levels of perceived stress are associated with a 30% greater risk of incident aMCI (per 5 point increase in PSS: hazard ratio=1.30; 95% confidence interval, 1.08-1.58) independent of covariates. The consistency of results after covariate adjustment and the lack of evidence for reverse causation in longitudinal analyses suggest that these findings are robust. Understanding of the effect of perceived stress on cognition may lead to intervention strategies that prevent the onset of aMCI and Alzheimer dementia. PMID- 26655069 TI - Specific carbohydrate diet for pediatric inflammatory bowel disease in clinical practice within an academic IBD center. AB - OBJECTIVE: Despite dietary factors being implicated in the pathogenesis of inflammatory bowel disease (IBD), nutritional therapy, outside of exclusive enteral nutrition (EEN), has not had a defined role within the treatment paradigm of pediatric IBD within IBD centers. Based on emerging data, Seattle Children's Hospital IBD Center has developed an integrated dietary program incorporating the specific carbohydrate diet (SCD) into its treatment paradigm. This treatment paradigm uses the SCD as primary therapy as well as adjunctive therapy for the treatment of IBD. The aim of this study was to evaluate the potential effects of the SCD on clinical outcomes and laboratory studies of pediatric patients with Crohn's disease (CD) and ulcerative colitis (UC). METHODS: In this retrospective study, we reviewed the medical records of patients with IBD on SCD. RESULTS: We analyzed 26 children on the SCD: 20 with CD and 6 with UC. Duration of the dietary therapy ranged from 3 to 48 mo. In patients with active CD (Pediatric Crohn's Disease activity index [PCDAI] >10), PCDAI dropped from 32.8 +/- 13.2 at baseline to 20.8 +/- 16.6 by 4 +/- 2 wk, and to 8.8 +/- 8.5 by 6 mo. The mean Pediatric Ulcerative Colitis Activity Index for patients with active UC decreased from a baseline of 28.3 +/- 10.3 to 20.0 +/- 17.3 at 4 +/- 2 wk, to 18.3 +/- 31.7 at 6 mo. CONCLUSION: This retrospective review provides evidence that the SCD can be integrated into a tertiary care center and may improve clinical and laboratory parameters for pediatric patients with nonstructuring, nonpenetrating CD as well as UC. Further prospective studies are needed to fully assess the safety and efficacy of the SCD in pediatric patients with IBD. PMID- 26655070 TI - Development of a novel pH sensor based upon Janus Green B immobilized on triacetyl cellulose membrane: Experimental design and optimization. AB - A novel pH optical sensor was prepared by immobilizing an azo dye called Janus Green B on the triacetylcellulose membrane. Condition of the dye solution used in the immobilization step, including concentration of the dye, pH, and duration were considered and optimized using the Box-Behnken design. The proposed sensor showed good behavior and precision (RSD<5%) in the pH range of 2.0-10.0. Advantages of this optical sensor include on-line applicability, no leakage, long term stability (more than 6 months), fast response time (less than 1 min), high selectivity and sensitivity as well as good reversibility and reproducibility. PMID- 26655071 TI - Raman scattering studies of pressure-induced phase transitions in perovskite formates [(CH3)2NH2][Mg(HCOO)3] and [(CH3)2NH2][Cd(HCOO)3]. AB - Pressure-dependent Raman studies were preformed on two dimethylammonium metal formates, [(CH3)2NH2][Mg(HCOO)3] (DMMg) and [(CH3)2NH2][Cd(HCOO)3] (DMCd). They revealed three pressure-induced transitions in the DMMg near 2.2, 4.0 and 5.6 GPa. These transitions are associated with significant distortion of the anionic framework and the phase transition at 5.6 GPa has also great impact on the DMA+ cation. The DMCd undergoes two pressure-induced phase transitions. The first transition occurred between 1.2 and 2.0 GPa and the second one near 3.6 GPa. The first transition leads to subtle structural changes associated with distortion of anionic framework and the later leads to significant distortion of the framework. In contrast to the DMMg, the third transition associated with distortion of DMA+ cation is not observed for the DMCd up to 7.8 GPa. This difference can be most likely associated with larger volume of the cavity occupied by DMA+ cation in the DMCd and thus weaker interactions between anionic framework and DMA+ cations. PMID- 26655072 TI - Possibility of methane conversion into heavier hydrocarbons using nanosecond lasers. AB - Effect of nanosecond lasers on the methane dissociation is experimentally studied by using three different laser wavelengths at 248 nm, 355 nm and 532 nm. C2H2 generation is measured as a major reaction product in experiments and the energy consumptions in production of this component are measured as 5.8 MJ/mol, 3.1 MJ/mol and 69.0 MJ/mol, for 355 nm, 532 nm and 248 nm wavelengths, respectively. The mechanism of conversion and production of new stable hydrocarbons is also theoretically investigated. It is found that in theoretical calculations, the ion molecule reactions should be included and this leads to a unique approach in proper explanation of the experimental measurements. PMID- 26655073 TI - Adsorption configuration of sodium 2-quinoxalinecarboxylate on iron substrate: Investigation by in situ SERS, XPS and theoretical calculation. AB - The adsorption geometry of sodium 2-quinoxalinecarboxylate (2-QC) on iron surface was investigated by in situ surface-enhanced Raman scattering spectroscopy (SERS) and X-ray photoelectron spectroscopy (XPS) measurements. The density functional theory (DFT) calculations predicted that 2-QC ion was a highly efficient inhibitor and N as well as O atoms were the possible adsorption centers, and theoretically offered the Raman-active band position and intensity. Potential dependent SERS results suggested that the 2-QC strongly bonded to the iron surface via the lone pair electrons of the two O atoms of the carboxylate group in a bidentate configuration with a vertical orientation at more positive potentials; However, at -1.0 V, only one O atom of the carboxylate and the neighboring N(1) atom (or very close to surface) adsorbed on the iron surface forming an unidentate configuration with a titled orientation. The ions did not remain on the iron surface at more negative potentials. PMID- 26655074 TI - Effect of adjunctive application of epigallocatechin-3-gallate and ethanol-wet bonding on adhesive-dentin bonds. AB - OBJECTIVES: To determine the effect of the combined use of epigallocatechin-3 gallate (EGCG) and ethanol-wet bonding (EWB) on resin-dentin bonds. METHODS: Sixty molars were sectioned, polished, and randomly divided into six groups (n=10) according to the following pretreatments: group 1, water-wet bonding (WWB); group 2, WWB with 0.02% (w/v) EGCG; group 3, WWB with 0.1% EGCG; group 4, EWB; group 5, EWB with 0.02% EGCG; and group 6, EWB with 0.1% EGCG. An etch-and rinse adhesive was then used, followed by the resin composites building. The microtensile bond strength (MTBS), failure modes and interfacial nanoleakage were separately determined after 24h water storage or 10,000 runs of thermocycling. RESULTS: Both pretreatment method (P<0.05) and thermocycling (P<0.05) significantly influenced bond strength and nanoleakage. Irrespective of thermocycling, the 0.02% EGCG/ethanol (group 5) pretreated adhesive-dentin interfaces showed higher MTBS than the control group (P<0.05). Nanoleakage expression of all groups increased after thermocycling (P<0.05) except group 5. Adhesive failure was the main fracture pattern in all groups. CONCLUSION: This study showed that pretreatment with 0.02% EGCG/ethanol solutions can effectively improve immediate bond strength and bond stability of etch-and-rinse adhesives on dentin. CLINICAL SIGNIFICANCE: The adjunctive application of EGCG and EWB provides a new strategy for dentists to obtain the desired bond effectiveness during adhesive restoration in clinical practice. PMID- 26655075 TI - A difficult surgical approach for primary orbital hydatid cyst: transconjunctival medial orbitotomy. AB - Hydatid cysts rarely appear isolated in the orbital cavity without involvement of other organs. The cysts are usually located in the retrobulbar region, and may be extraconal or intraconal. Herein we present a case of primary orbital cyst hydatid that is adjacent to the medial rectus muscle and optic nerve in the intraconal space and the difficulties during the surgical and medical treatment period. PMID- 26655076 TI - Duplication of the V3 domain in hepatitis C virus (1b) NS5A protein: Clonal analysis and physicochemical properties related to hepatocellular carcinoma occurrence. AB - BACKGROUND: Hepatitis C virus non-structural protein 5A is known to play a role in development of hepatocellular carcinoma (HCC) via interactions with host cell pathways. OBJECTIVES: Hepatitis C virus genotype 1b strains presenting a wide insertion of 31 amino acids in the non-structural protein 5A V3 domain (V3 DI) were studied to determine whether this V3-like additional domain (V3 DII) was associated with HCC occurrence. STUDY DESIGN: Seventy-four patients' sera were screened for V3 DII presence regarding clinical status. RESULTS: Three strains with duplicated V3 were detected among patients with progression to HCC (n=28), two strains among patients with liver cirrhosis (Ci, n=27) and none among patients with chronic hepatitis (Chr, n=19). Phylogenetic trees built from V3 DI and V3 DII sequences indicated that the latter clustered separately. In between group clonal analysis, V3 DII sequences from the HCC group were found to be more distant from HCV-J than V3 DI sequences (p<0.0001). Between-group comparisons showed significant differences in genetic distances from HCV-J, in HCC V3 DI and HCC V3 DII compared to Ci V3 DI and Ci V3 DII sequences (p<0.0001). HCC V3 DII domain and its junction with V3 DI exhibited higher Shannon entropy values and enrichment in disorder-promoting residues. CONCLUSIONS: Taken together, our results suggest that V3 DII evolution may differ in strains associated with HCC occurrence. The presence of an intrinsically "disordered" V3 duplicate may alter the NS5A protein network. Further investigations are necessary to elucidate the potential impact of V3 duplication in the context of carcinogenesis. PMID- 26655077 TI - A novel model for NSAID induced gastroenteropathy in rats. AB - INTRODUCTION: Progress in management of Nonsteroidal anti-inflammatory drug (NSAID) induced gastrointestinal toxicity requires the availability of appropriate experimental animal models that are as close to humans as feasible. Our objective was to develop a rat model for NSAID-induced gastroenteropathy and also to simulate the common clinical scenario of co-administration of NSAID and proton pump inhibitor (PPI) to explore if PPI contribute to exacerbation of NSAID enteropathy. METHODS: Rats were treated twice daily with pantoprazole sodium (PTZ; 10mg/kg peroral) or vehicle for a total of 10days. In some experiments, Diclofenac sodium (DCF; 9mg/kg) or vehicle was administered orally twice daily for the final 5days of PTZ/vehicle administration. After the last dose on 9th day, rats in all the groups were fasted but water was provided ad libitum. 12h after the last dose on 10th day, rats in all the groups were euthanized and their gastrointestinal tracts were assessed for haemorrhagic lesions, lipid peroxidation, intestinal permeability and gastrointestinal luminal pH alterations. Changes in haemoglobin, haematocrit and serum levels of albumin, total protein, ALT and bilirubin were calculated. RESULTS: The macroscopic and histological evidence suggested that administration of DCF resulted in significant gastroenteropathic damage and co-administration of PTZ resulted in significant exacerbation of NSAID enteropathy, while attenuation of NSAID induced gastropathy was observed. Our results were further supported by the significant decrease in haemoglobin and haematocrit levels and serum levels of albumin and total proteins, an increase in oxidative stress and intestinal permeability with the use of DCF either alone or in combination with PTZ. CONCLUSIONS: This model was developed to simulate the human clinical situation during NSAID therapy and indeed the present DCF regimen caused both gastric and small bowel alterations, such as multiple erosive lesions, together with a decrease in haemoglobin, haematocrit, serum albumin, serum total protein levels and IP alteration, known to occur in patients receiving NSAIDs. Additionally, this paper provides yet another evidence for PPI induced exacerbation of NSAID enteropathy. PMID- 26655079 TI - Recombinant Human Bone Morphogenetic Protein 6 Enhances Oocyte Reprogramming Potential and Subsequent Development of the Cloned Yak Embryos. AB - This study investigated the effects of bone morphogenetic protein 6 (BMP6) supplementation in the medium during in vitro maturation (IVM) on the developmental potential of oocytes and in the subsequent development of cloned yak embryos. Cumulus-oocyte complexes (COCs) were aspirated from the antral follicles of yak ovaries and cultured with different concentrations of recombinant human BMP6 in oocyte maturation medium. Following maturation, the metaphase II (MII) oocytes were used for somatic cell nuclear transfer (SCNT), and these were cultured in vitro. The development of blastocysts and cell numbers were detected on day 8. The apoptosis and histone modifications of yak cloned blastocysts were evaluated by detecting the expression of relevant genes and proteins (Bax, Bcl-2, H3K9ac, H3K18ac, and H3K9me3) using relative quantitative RT-PCR or immunofluorescence. The presence of 100 ng/mL BMP6 significantly enhanced the oocyte maturation ratios (66.12 +/- 2.04% vs. 73.11 +/- 1.38%), cleavage rates (69.40 +/- 1.03% vs. 78.16 +/- 0.93%), and blastocyst formation rates (20.63 +/- 1.32% vs. 28.16 +/- 1.67%) of cloned yak embryos. The total blastocysts (85.24 +/- 3.12 vs. 103.36 +/- 5.28), inner cell mass (ICM) cell numbers (19.59 +/- 2.17 vs. 32.20 +/- 2.61), and ratio of ICM to trophectoderm (TE) (22.93 +/- 1.43% vs. 31.21 +/- 1.62%) were also enhanced (p < 0.05). The ratio of the Bax to the Bcl-2 gene was lowest in the SCNT + BMP6 groups (p < 0.05). The H3K9ac and H3K18ac levels were increased in SCNT + BMP6 groups (p < 0.05), whereas the H3K9me3 level was decreased; the differences in blastocysts were not significant (p > 0.05). These study results demonstrate that addition of oocyte maturation medium with recombinant BMP6 enhances yak oocyte developmental potential and the subsequent developmental competence of SCNT embryos, and provides evidence that BMP6 is an important determinant of mammalian oocyte developmental reprogramming. PMID- 26655080 TI - The Impact of Nitinol Staples on the Compressive Forces, Contact Area, and Mechanical Properties in Comparison to a Claw Plate and Crossed Screws for the First Tarsometatarsal Arthrodesis. AB - Background The optimal fixation method for the first tarsometatarsal arthrodesis remains controversial. This study aimed to develop a reproducible first tarsometatarsal testing model to evaluate the biomechanical performance of different reconstruction techniques. Methods Crossed screws or a claw plate were compared with a single or double shape memory alloy staple configuration in 20 Sawbones models. Constructs were mechanically tested in 4-point bending to 1, 2, and 3 mm of plantar displacement. The joint contact force and area were measured at time zero, and following 1 and 2 mm of bending. Peak load, stiffness, and plantar gapping were determined. Results Both staple configurations induced a significantly greater contact force and area across the arthrodesis than the crossed screw and claw plate constructs at all measurements. The staple constructs completely recovered their plantar gapping following each test. The claw plate generated the least contact force and area at the joint interface and had significantly greater plantar gapping than all other constructs. The crossed screw constructs were significantly stiffer and had significantly less plantar gapping than the other constructs, but this gapping was not recoverable. Conclusions Crossed screw fixation provides a rigid arthrodesis with limited compression and contact footprint across the joint. Shape memory alloy staples afford dynamic fixation with sustained compression across the arthrodesis. A rigid polyurethane foam model provides an anatomically relevant comparison for evaluating the interface between different fixation techniques. Clinical Relevance The dynamic nature of shape memory alloy staples offers the potential to permit early weight bearing and could be a useful adjunctive device to impart compression across an arthrodesis of the first tarsometatarsal joint. LEVELS OF EVIDENCE: Therapeutic, Level V: Bench testing. PMID- 26655078 TI - Factors Determining the Efficiency of Porcine Somatic Cell Nuclear Transfer: Data Analysis with Over 200,000 Reconstructed Embryos. AB - Data analysis in somatic cell nuclear transfer (SCNT) research is usually limited to several hundreds or thousands of reconstructed embryos. Here, we report mass results obtained with an established and consistent porcine SCNT system (handmade cloning [HMC]). During the experimental period, 228,230 reconstructed embryos and 82,969 blastocysts were produced. After being transferred into 656 recipients, 1070 piglets were obtained. First, the effects of different types of donor cells, including fetal fibroblasts (FFs), adult fibroblasts (AFs), adult preadipocytes (APs), and adult blood mesenchymal (BM) cells, were investigated on the further in vitro and in vivo development. Compared to adult donor cells (AFs, APs, BM cells, respectively), FF cells resulted in a lower blastocyst/reconstructed embryo rate (30.38% vs. 37.94%, 34.65%, and 34.87%, respectively), but a higher overall efficiency on the number of piglets born alive per total blastocysts transferred (1.50% vs. 0.86%, 1.03%, and 0.91%, respectively) and a lower rate of developmental abnormalities (10.87% vs. 56.57%, 24.39%, and 51.85%, respectively). Second, recloning was performed with cloned adult fibroblasts (CAFs) and cloned fetal fibroblasts (CFFs). When CAFs were used as the nuclear donor, fewer developmental abnormalities and higher overall efficiency were observed compared to AFs (56.57% vs. 28.13% and 0.86% vs. 1.59%, respectively). However, CFFs had an opposite effect on these parameters when compared with CAFs (94.12% vs. 10.87% and 0.31% vs. 1.50%, respectively). Third, effects of genetic modification on the efficiency of SCNT were investigated with transgenic fetal fibroblasts (TFFs) and gene knockout fetal fibroblasts (KOFFs). Genetic modification of FFs increased developmental abnormalities (38.96% and 25.24% vs. 10.87% for KOFFs, TFFs, and FFs, respectively). KOFFs resulted in lower overall efficiency compared to TFFs and FFs (0.68% vs. 1.62% and 1.50%, respectively). In conclusion, this is the first report of large-scale analysis of porcine cell nuclear transfer that provides important data for potential industrialization of HMC technology. PMID- 26655081 TI - Bullying behavior, youth's disease and intervention: which suggestions from the data for research on bullying in the Brazilian context? PMID- 26655082 TI - Roles of NMDARs in maintenance of the mouse cerebrovascular endothelial cell constructed tight junction barrier. AB - Glutamate can activate NMDA receptor (NMDAR) and subsequently induces excitotoxic neuron loss. However, roles of NMDARs in the blood-brain barrier (BBB) are little known. This study used a mouse cerebrovascular endothelial cell (MCEC) model to evaluate the effects of NMDAR activation on maintenance of the BBB and its possible mechanisms. Analysis of confocal microscopy revealed expressions of NMDAR subunits, GluN1 and GLUN2B, in MCECs. An immunoblot assay further showed the existence of GluN1 in plasma membranes of MCECs. In brain tissues, a confocal microscopic analysis demonstrated co-localization of GluN1 and factor VIII, a biomarker of MCECs. In addition, GluN1 mRNA was detected in MCECs and the brain. Functional assays showed that exposure of MCECs to NMDA increased calcium influx. Separately, NMDA suppressed transendothelial electrical resistance values, levels of occludin, and occludin tight junctions. As to the mechanism, NMDA stimulated sequential phosphorylations of extracellular signal-regulated kinase (ERK)1/2 and mitogen-activated ERK (MEK)1. Interestingly, amounts of matrix metalloproteinase (MMP)2 and MMP9 in MCECs were augmented by NMDA. The NMDA-induced alterations in ERK1/2 phosphorylation and occludin levels were reversed by pretreatment with PD98059, a MEK inhibitor, and MK-801, a NMDAR antagonist, respectively. Therefore, this study shows the functional presence of NMDARs in MCECs, and NMDAR activation can disrupt the MCEC-constructed tight junction barrier via activation of the MEK1/2-ERK1/2 signaling pathway and upregulation of MMP2/9 expressions. PMID- 26655083 TI - Interesting polarization-independent SERS detection performance induced by the rotation symmetry of multiparticle nanostructures. AB - In this work, on the basis of finite difference time domain simulations and group theory, by employing regular nanosphere trimers as the main examples, we analyse and discuss the polarization-independent surface enhanced Raman scattering (SERS) phenomenon arising from the rotation symmetry of coined metallic nanomultimers. The results demonstrate why the rotationally symmetrical nanomultimers can show polarization-independent SERS performance. Because of the dramatically hybridized polarization-independent SERS performance over the whole 360 degrees range, rotationally symmetrical coined metal nanomultimers, such as regular trimers, regular triangular tetramers and regular pentamers, are reliable and reproducible SERS substrates, which have the potential for convenient and flexible practical SERS detection without the need for optimally incident polarization outside the laboratory setting. PMID- 26655084 TI - NS11821, a partial subtype-selective GABAA agonist, elicits selective effects on the central nervous system in randomized controlled trial with healthy subjects. AB - NS11821 is a partial GABAA agonist with relatively dominant alpha2,3 and alpha5 subtype efficacy but negligible alpha1 agonism. This first-in-human study was performed in healthy male subjects using a single-dose, parallel, double blind, placebo-controlled, randomized, dose-escalation study design. In total six cohorts (N=48) were enrolled. The eight subjects of each cohort received NS11821 (10 mg, 30 mg, 75 mg, 150 mg, 300 mg or 600 mg) or placebo in a 6:2 ratio. At low dose levels, NS11821 had a relatively low exposure and a more-than-proportional increase of the area under the curve and maximum plasma concentrations, probably due to poor solubility. Saccadic peak velocity decreased in a dose-related manner while limited impairments were seen on body sway and the visual analogue scale for alertness. The most common adverse events were somnolence and dizziness, which were more prominent with the higher doses. Although no positive control was used in this study, the results were compared post hoc with a Centre for Human Drug Research dataset for lorazepam 2 mg. The maximum saccadic peak velocity effects seemed comparable to the typical effects of lorazepam, whereas the other central nervous system effects were smaller. These results support the pharmacological selectivity of NS11821 and show that pharmacodynamic effective doses of NS11821 were safe and well tolerated in healthy subjects. PMID- 26655085 TI - Voriconazole-associated phototoxic dermatoses and skin cancer. PMID- 26655086 TI - Difficulties in the diagnosis of heart failure in patients with comorbidities. AB - Heart failure (HF) patients present frequently comorbidities and the diagnosis of HF in this setting is a challenge. The symptoms and signs of HF may be atypical and can be simulated or disguised by co-morbidities such as respiratory disease and/or obesity. For this reasons, confirmation of the diagnosis always requires further tests. Natriuretic peptides accurately exclude cardiac dysfunction as a cause of symptoms, but the optimal cut-off levels for ruling out and ruling in HF diagnosis are influenced by different co-morbidities. Echocardiography should be performed in all patients to confirm the diagnosis of HF, except in those cases with low clinical probability and a concentration of brain natriuretic peptides below the exclusion cut-off. This review aims to provide a practical clinical approach for the diagnosis of HF in patients with comorbidity, focusing in older patients and patients with chronic obstructive pulmonary disease and/or obesity. PMID- 26655087 TI - Rapid Onset of the Effects of Combined Selective Serotonin Reuptake Inhibitors and Electroacupuncture on Primary Depression: A Meta-Analysis. AB - OBJECTIVES: To evaluate the efficacy and safety of combined selective serotonin reuptake inhibitors (SSRIs) and electroacupuncture therapies for the early treatment of primary depression. METHODS: Randomized controlled trials (RCTs) were analyzed to compare therapy combining SSRIs and electroacupuncture to SSRI therapy alone. The RCTs were identified by searching, among others, PubMed, the Cochrane Library, the Chinese National Knowledge Infrastructure, the Chongqing VIP database for Chinese Technical Periodicals, WANFANG DATA, and the Chinese Biological Medical Literature Database. Scores from Self-Rated Depression Scale (SDS), the Hamilton Depression Scale (HAMD), the Side Effect Rating Scale (SERS), and the Treatment Emergent Symptom Scale (TESS) were analyzed and coded by two independent investigators and used to evaluate the safety and efficacy of treatment. Statistical analyses were performed using RevMan 5.2 software. RESULTS: Six RCTs were analyzed. The meta-analysis revealed that the combined therapy of SSRIs and electroacupuncture were associated with superior scores on the HAMD, SDS, and SERS measures compared with SSRIs alone after 1-4 weeks of treatment: HAMD scores, mean difference (MD)(1 week), 2.32 (95% confidence interval [CI](1 week), 1.47-3.16, p(1 week)<0.00001); MD(2 weeks), 2.65 (95% CI(2 weeks), 1.81- 3.50, p(2 weeks)<0.00001); MD(4 weeks), 2.70 (95% CI(4 weeks), 1.90 3.51, p(4 weeks)<0.00001); SDS scores: MD(1 week), 3.13 (95% CI(1 week), 1.22 5.03, p(1 week) = 0.001); MD(2 weeks), 4.05 (95% CI(2 weeks), 0.22-7.87, p(2 weeks) = 0.04); MD(4 weeks), 5.02 (95% CI(4 weeks), 1.61-8.43, p(4 weeks) = 0.004); SERS scores: MD(2 weeks), 2.20 (95% CI(2 weeks), 1.43-2.96, p(2 weeks)<0.00001); MD(4 weeks), 2.12 (95% CI(4 weeks), 1.42-2.83, p(4 weeks)<0.00001). However, two of the aforementioned outcomes were rated as medium quality because of heterogeneity, as assessed using the Grading of Recommendations Assessment, Development and Evaluation system. CONCLUSIONS: The available evidence suggests that the early treatment of primary depression using both SSRI and electroacupuncture therapies is more efficient than treatments with SSRIs alone and leads to a better and earlier control of depressive symptoms. PMID- 26655088 TI - Mutational landscape of MCPyV-positive and MCPyV-negative Merkel cell carcinomas with implications for immunotherapy. AB - Merkel cell carcinoma (MCC) is a rare but highly aggressive cutaneous neuroendocrine carcinoma, associated with the Merkel cell polyomavirus (MCPyV) in 80% of cases. To define the genetic basis of MCCs, we performed exome sequencing of 49 MCCs. We show that MCPyV-negative MCCs have a high mutation burden (median of 1121 somatic single nucleotide variants (SSNVs) per-exome with frequent mutations in RB1 and TP53 and additional damaging mutations in genes in the chromatin modification (ASXL1, MLL2, and MLL3), JNK (MAP3K1 and TRAF7), and DNA damage pathways (ATM, MSH2, and BRCA1). In contrast, MCPyV-positive MCCs harbor few SSNVs (median of 12.5 SSNVs/tumor) with none in the genes listed above. In both subgroups, there are rare cancer-promoting mutations predicted to activate the PI3K pathway (HRAS, KRAS, PIK3CA, PTEN, and TSC1) and to inactivate the Notch pathway (Notch1 and Notch2). TP53 mutations appear to be clinically relevant in virus-negative MCCs as 37% of these tumors harbor potentially targetable gain-of function mutations in TP53 at p.R248 and p.P278. Moreover, TP53 mutational status predicts death in early stage MCC (5-year survival in TP53 mutant vs wild-type stage I and II MCCs is 20% vs. 92%, respectively; P = 0.0036). Lastly, we identified the tumor neoantigens in MCPyV-negative and MCPyV-positive MCCs. We found that virus-negative MCCs harbor more tumor neoantigens than melanomas or non-small cell lung cancers (median of 173, 65, and 111 neoantigens/sample, respectively), two cancers for which immune checkpoint blockade can produce durable clinical responses. Collectively, these data support the use of immunotherapies for virus-negative MCCs. PMID- 26655089 TI - Obg-like ATPase 1 regulates global protein serine/threonine phosphorylation in cancer cells by suppressing the GSK3beta-inhibitor 2-PP1 positive feedback loop. AB - OLA1 is an Obg family P-loop NTPase that possesses both GTP- and ATP-hydrolyzing activities. Here we report that OLA1 is a GSK3beta interacting protein, and through its ATPase activity, inhibits the GSK3beta-mediated activation of protein serine/threonine phosphatase 1 (PP1). It is hypothesized that GSK3beta phosphorylates inhibitor 2 (I-2) of PP1 at Thr-72 and activates the PP1 . I-2 complex, which in turn dephosphorylates and stimulates GSK3beta, thus forming a positive feedback loop. We revealed that the positive feedback loop is normally suppressed by OLA1, and becomes over-activated under OLA1 deficiency, resulting in increased cellular PP1 activity and dephosphorylation of multiple Ser/Thr phosphoproteins, and more strikingly, decreased global protein threonine phosphorylation. Furthermore, using xenograft models of colon cancer (H116) and ovarian cancer (SKOV3), we established a correlation among downregulation of OLA1, over-activation of the positive feedback loop as indicated by under phosphorylation of I-2, and more aggressive tumor growth. This study provides the first evidence for the existence of a GSK3beta-I-2-PP1 positive feedback loop in human cancer cells, and identifies OLA1 as an endogenous suppressor of this signaling motif. PMID- 26655090 TI - The Toll-like receptor 5 agonist entolimod suppresses hepatic metastases in a murine model of ocular melanoma via an NK cell-dependent mechanism. AB - Uveal melanoma (UM) is the most common primary cancer of the eye in adults and progresses to metastatic disease predominantly of the liver in ~50% of patients. In these cases, life expectancy averages just 9 months due to the lack of effective treatment options. The Toll-like receptor 5 (TLR5) agonist entolimod (former name CBLB502) rapidly activates TLR5-NF-kappaB signaling in hepatocytes and suppresses growth of both TLR5-expressing and non-expressing tumors in the liver through mobilization and activation of innate and adaptive immune mechanisms. The goal of this study was to explore the potential of entolimod as an immunotherapeutic agent against hepatic metastasis of UM using the TLR5 positive B16LS9 mouse model of ocular melanoma. Mice were given seven subcutaneous injections of vehicle or entolimod given 72 h apart started one day before, on the same day or three days after intraocular injection of B16LS9 cells. All tested regimens of entolimod treatment resulted in significantly reduced B16LS9 metastasis to the liver. Entolimod induced mobilization of natural killer (NK) cells to the liver and stimulated their maturation, differentiation and activation. Antibody-mediated depletion of NK cells from mice abrogated entolimod's antimetastatic activity in the liver and eliminated the entolimod elicited in vitro cytotoxic activity of hepatic lymphocytes against B16LS9 cells. These results provide pre-clinical evidence of entolimod's efficacy against hepatometastasis of UM and support its further development as an anticancer immunotherapeutic drug. PMID- 26655091 TI - miR-16 targets fibroblast growth factor 2 to inhibit NPC cell proliferation and invasion via PI3K/AKT and MAPK signaling pathways. AB - Dysregulation of miRNAs has been shown to contribute to the carcinogenesis and progression of nasopharyngeal carcinoma (NPC). Our previous microarray data showed that miR-16 expression is significantly decreased in archived NPC tissues. Here, we confirmed that miR-16 was reduced in NPC cell lines and freshly-frozen samples. Ectopic expression of miR-16 suppressed NPC cell proliferation, migration, and invasion in vitro and inhibited tumor growth and metastatic colonization in the lung in vivo. Furthermore, fibroblast growth factor 2 (FGF2) was identified as a direct target of miR-16, and both phosphoinositide-3- kinase/AKT (PI3K/AKT) and mitogen-activated protein kinase (MAPK) signaling pathways were repressed after miR-16 overexpression. In addition, the restoration of FGF2 reversed the suppressive effects of miR-16. Together, these results indicated that miR-16 suppresses NPC carcinogenesis and progression by targeting FGF2, thereby representing a potential target for miRNA-based therapy for NPC in the future. PMID- 26655093 TI - Long noncoding RNAs in aging and age-related diseases. AB - Aging is the universal, intrinsic, genetically-controlled, evolutionarily conserved and time-dependent intricate biological process characterised by the cumulative decline in the physiological functions and their coordination in an organism after the attainment of adulthood resulting in the imbalance of neurological, immunological and metabolic functions of the body. Various biological processes and mechanisms along with altered levels of mRNAs and proteins have been reported to be involved in the progression of aging. It is one of the major risk factors in the patho-physiology of various diseases and disorders. Recently, the discovery of pervasive transcription of a vast pool of heterogeneous regulatory noncoding RNAs (ncRNAs), including small ncRNAs (sncRNAs) and long ncRNAs (lncRNAs), in the mammalian genome have provided an alternative way to study and explore the missing links in the aging process, its mechanism(s) and related diseases in a whole new dimension. The involvement of small noncoding RNAs in aging and age-related diseases have been extensively studied and recently reviewed. However, lncRNAs, whose function is far less explored in relation to aging, have emerged as a class of major regulators of genomic functions. Here, we have described some examples of known as well as novel lncRNAs that have been implicated in the progression of the aging process and age-related diseases. This may further stimulate research on noncoding RNAs and the aging process. PMID- 26655092 TI - Chronic ethanol exposure enhances the aggressiveness of breast cancer: the role of p38gamma. AB - Both epidemiological and experimental studies suggest that ethanol may enhance aggressiveness of breast cancer. We have previously demonstrated that short term exposure to ethanol (12-48 hours) increased migration/invasion in breast cancer cells overexpressing ErbB2, but not in breast cancer cells with low expression of ErbB2, such as MCF7, BT20 and T47D breast cancer cells. In this study, we showed that chronic ethanol exposure transformed breast cancer cells that were not responsive to short term ethanol treatment to a more aggressive phenotype. Chronic ethanol exposure (10 days - 2 months) at 100 (22 mM) or 200 mg/dl (44 mM) caused the scattering of MCF7, BT20 and T47D cell colonies in a 3-dimension culture system. Chronic ethanol exposure also increased colony formation in an anchorage-independent condition and stimulated cell invasion/migration. Chronic ethanol exposure increased cancer stem-like cell (CSC) population by more than 20 folds. Breast cancer cells exposed to ethanol in vitro displayed a much higher growth rate and metastasis in mice. Ethanol selectively activated p38gamma MAPK and RhoC but not p38alpha/beta in a concentration-dependent manner. SP-MCF7 cells, a derivative of MCF7 cells which compose mainly CSC expressed high levels of phosphorylated p38gamma MAPK. Knocking-down p38gamma MAPK blocked ethanol induced RhoC activation, cell scattering, invasion/migration and ethanol increased CSC population. Furthermore, knocking-down p38gamma MAPK mitigated ethanol-induced tumor growth and metastasis in mice. These results suggest that chronic ethanol exposure can enhance the aggressiveness of breast cancer by activating p38gamma MAPK/RhoC pathway. PMID- 26655094 TI - Ground Spider Guilds and Functional Diversity in Native Pine Woodlands and Eucalyptus Plantations. AB - Vegetation structure and floristics have a strong influence on the relative abundance of spider guilds and functional diversity of terrestrial arthropods. Human activities have transformed much of the temperate woodlands. The aim of this study was to test five predictions related to the guild distribution and functional diversity of the ground spider communities of Eucalyptus plantations and native pine woodlands in western Mexico. Spiders were collected every fortnight from September to November from 15 pitfalls positioned in each of the eight sites. We also assessed the cover of grasses, herbs, shrubs, and leaf litter in each site. We found that the abundances of ground hunters and sheet weavers between plantations and pine woodlands were different. Nevertheless, there was not a consistent difference between sites of each of the vegetation types. Most species of ground hunters, sheet web weavers, and many other hunters were associated with litter and the grass cover. Nonetheless, in some cases, species of different families belonging to the same guild responded to different variables. Wolf spiders were related to the grass Aristida stricta Micheaux, 1803, while the species of the other families of ground hunters were associated with leaf litter. One Eucalyptus plantation and one pine woodland had the highest functional diversity of all sites. These sites have a well developed litter and grass cover. Our study suggests that the abundance of litter and a high cover of grasses explain the occurrence of species with different traits, and these habitat components results in a high functional diversity. PMID- 26655095 TI - Risk Factors Associated With Implant Marginal Bone Loss: A Retrospective 6-Year Follow-Up Study. AB - PURPOSE: To analyze the presented evidence behind suggested reasons for long-term marginal bone loss (MBL) around 600 endosseous titanium dental implants according to the radiological findings up to 60 months. MATERIALS AND METHODS: The data of 151 patients are received from the prosthodontic department of a university clinic and analyzed for the effect of implant brand, location, implant diameter and length, implant occlusal table width, cantilever, and smoking on MBL in a 6 year period. RESULTS: MBL is significantly higher in Zimmer SwissPlus implant system. The bone loss in posterior region was higher than anterior region for maxilla. There was no significant difference in mandible. Kruskal-Wallis test showed that MBL was significantly higher when the crown/implant (C/I) ratio was 1.5/2 (P < 0.05). Occlusal table width/implant diameter (OT/I) ratio was analyzed and it showed that MBL was significantly higher when the ratio was 2.5 to 2.99 and higher than 3. There were no significant associations between smoking and nonsmoking groups. Mann-Whitney U test revealed that cantilever does not affect MBL. CONCLUSION: The marginal bone loss is affected by location of the implants (higher in the maxillary posterior region). In addition, excessive C/I and OT/I ratios increase marginal bone loss. PMID- 26655096 TI - Implant-Supported Immediately Loaded Full-Arch Rehabilitations: Comparison of Resin and Zirconia Clinical Outcomes in a 5-Year Retrospective Follow-Up Study. AB - PURPOSE: We analyzed complications and failures of final full-arch implant supported rehabilitations, comparing resin and zirconia prosthesis materials. Prostheses were retrospectively followed up for 5 years. MATERIALS AND METHODS: One hundred twenty-five patients who received one or two four to six implant supported immediately loaded full-arch rehabilitations in resin (166 prostheses) or zirconia (48 prostheses) were analyzed. RESULTS: One hundred thirteen patients (53 men, 60 women), with 214 full-arch prostheses (105 maxillary, 109 mandibular), were analyzed. During the follow-up interval, the prosthesis annual complication rate was 6.6%, free complications survival was 75.5% (60 months). Age, number of implants, and prosthesis material did not influence complication risk. Men had a higher risk of complications than women. Prosthesis annual failure rate was 4.6%, free survival was 85.5% (60 months). Age, number of implants, and prosthesis material did not influence failure risk. Men and maxillary arch prostheses had a higher risk of failures than women and mandibular arch prostheses. CONCLUSION: Implant-supported, immediately loaded full-arch rehabilitations supporting resin or zirconia based prostheses were clinically successful in a 5-year follow-up. Prosthesis material did not influence complication risk. PMID- 26655097 TI - Ridge Preservation Comparing a Nonresorbable PTFE Membrane to a Resorbable Collagen Membrane: A Clinical and Histologic Study in Humans. AB - PURPOSE: The primary aim of this randomized, controlled, blinded clinical trial was to compare the effect of a resorbable collagen membrane (CM group) versus a nonresorbable high-density polytetrafluoroethylene membrane (PTFE group) on the clinical and histologic outcomes of a ridge preservation procedure. MATERIALS AND METHODS: All 24 sites received an intrasocket cancellous allograft and a buccal overlay bovine derived xenograft. RESULTS: The change in horizontal crestal ridge width was -1.4 +/- 1.2 mm for the CM group, whereas the PTFE group lost -2.2 +/- 1.5 mm, which was not statistically significant between groups (P > 0.05). Vertical ridge height change was -1.2 +/- 1.5 for the CM group, whereas the PTFE group lost -0.5 +/- 1.6, which was not significantly different between groups (P > 0.05). The percent vital bone was similar and not significantly different between groups. Primary closure was not obtained and the exposed membrane portion over the socket opening healed with keratinized tissue. CONCLUSION: The choice of a resorbable versus a nonresorbable barrier membrane did not affect the clinical or the histologic outcome of ridge preservation treatment. PMID- 26655098 TI - Effects of Exercise Therapy on Postural Instability in Parkinson Disease: A Meta analysis. AB - BACKGROUND AND PURPOSE: Exercise therapy is a common intervention for improving postural stability. The purpose of this meta-analysis was to assess the effect of exercise therapy on postural instability in persons with Parkinson disease (PD) based on the available literature, and to evaluate the efficacy across various types of exercise interventions. DATA SOURCES AND STUDY SELECTION: In January 2015, electronic databases (PubMed, Scopus, PEDro) and study reference lists were searched for randomized controlled trials with moderate or high methodological quality (PEDro score >= 5), investigating the effect of exercise on postural instability in persons with PD. DATA EXTRACTION AND SYNTHESIS: Three reviewers extracted data and assessed quality. MAIN OUTCOME AND MEASURE: Postural stability as measured using the Berg Balance Scale, postural sway, Timed Up and Go, or Functional Reach test. Standardized mean differences (SMDs) with 95% confidence intervals (CIs) were calculated. RESULTS: Twenty-two trials, with a total of 1072 participants, were eligible for inclusion. The pooled estimates of effects showed significantly improved postural instability (SMD, 0.23; 95% CI, 0.10-0.36; P < 0.001) after exercise therapy, in comparison with no exercise or sham treatment. Exercise interventions specifically addressing components of balance dysfunction demonstrated the largest efficacy, with moderate to high effect sizes (SMD, 0.43; 95% CI, 0.21-0.66; P < 0.001). Little or no beneficial effects were observed for interventions not specifically targeted at postural stability (SMD, 0.20; 95% CI 0.04 to 0.44; P = 0.11) or for home-based, multicomponent exercise programs (SMD, 0.02; 95% CI -0.20 to 0.25; P = 0.86). DISCUSSION AND CONCLUSIONS: Exercise therapies specifically addressing balance dysfunction are an important treatment option for improving postural stability in persons with PD. Future studies should investigate sustainability of the short-term effects and establish the dose response relationship of balance training in persons with PD.Video abstract available for additional insights from the authors (see Video, Supplemental Digital Content 1, http://links.lww.com/JNPT/A121). PMID- 26655099 TI - Commentary on "Facilitation of the Lesioned Motor Cortex During Tonic Contraction of the Unaffected Limb Corresponds to Motor Status After Stroke". PMID- 26655100 TI - Highly Challenging Balance Program Reduces Fall Rate in Parkinson Disease. AB - BACKGROUND AND PURPOSE: There is a paucity of effective treatment options to reduce falls in Parkinson disease (PD). Although a variety of rehabilitative approaches have been shown to improve balance, evidence of a reduction in falls has been mixed. Prior balance trials suggest that programs with highly challenging exercises had superior outcomes. We investigated the effects of a theory-driven, progressive, highly challenging group exercise program on fall rate, balance, and fear of falling. METHODS: Twenty-three subjects with PD participated in this randomized cross-over trial. Subjects were randomly allocated to 3 months of active balance exercises or usual care followed by the reverse. During the active condition, subjects participated in a progressive, highly challenging group exercise program twice weekly for 90 minutes. Outcomes included a change in fall rate over the 3-month active period and differences in balance (Mini-Balance Evaluation Systems Test [Mini-BESTest]), and fear of falling (Falls Efficacy Scale-International [FES-I]) between active and usual care conditions. RESULTS: The effect of time on falls was significant (regression coefficient = -0.015 per day, P < 0.001). The estimated rate ratio comparing incidence rates at time points 1 month apart was 0.632 (95% confidence interval, 0.524-0.763). Thus, there was an estimated 37% decline in fall rate per month (95% confidence interval, 24%-48%). Improvements were also observed on the Mini BESTest (P = 0.037) and FES-I (P = 0.059). DISCUSSION AND CONCLUSIONS: The results of this study show that a theory-based, highly challenging, and progressive exercise program was effective in reducing falls, improving balance, and reducing fear of falling in PD.Video abstract available for more insights from the authors (see Supplemental Digital Content 1, http://links.lww.com/JNPT/A120). PMID- 26655102 TI - 1,4-Diazabicyclo[2.2.2]octane-Promoted Aminotrifluoromethylthiolation of alpha,beta-Unsaturated Carbonyl Compounds: N-Trifluoromethylthio-4 nitrophthalimide Acts as Both the Nitrogen and SCF3 Sources. AB - A novel difunctionalization reaction is described. It uses N-trifluoromethylthio 4-nitrophthalimide as the reagent, which serves as both the nitrogen and SCF3 sources. In the presence of DABCO (1,4-diazabicyclo[2.2.2]octane), the nitrogen and SCF3 groups can be incorporated into alpha,beta-unsaturated carbonyl compounds easily and give versatile beta-amino ketones and esters in good yields. This difunctionalization reaction features mild reaction conditions, high atom economy, and efficient access to alpha-SCF3 amino acids. PMID- 26655101 TI - Targeting Pink1-Parkin-mediated mitophagy for treating liver injury. AB - Alcoholic liver disease and acetaminophen overdose are common causes of severe liver disease and liver failure in the United States for which there is no cure. Therefore, development of new therapeutic strategies for treatment of liver injury caused by acetaminophen and alcohol is needed. We demonstrated that autophagy protects against alcohol and acetaminophen-induced liver injuries by removing damaged mitochondria via mitophagy, which is a selective form of autophagy specific for degradation of damaged mitochondria. Parkin is well-known to be required for mitophagy induction in in vitro models, and we previously showed that the Parkin-mediated mitophagy pathway likely plays a protective role against alcohol and acetaminophen-induced liver injuries. Therefore, pharmacological upregulation of the Parkin-mediated mitophagy pathway in the liver may provide a novel and effective therapeutic option for treatment of acetaminophen and alcohol-induced liver injuries. In this review, we discuss regulation of Parkin-mediated mitophagy and possible therapeutic targets of intervention in this pathway. PMID- 26655103 TI - Direct injection LC-MS/MS method for the determination of teicoplanin in human plasma. AB - A direct injection-based, simple, accurate, and robust LC-MS/MS method was developed and validated for the determination of teicoplanin in human plasma. Patient plasma samples were diluted in an aqueous buffer prior to injection into the LC-MS/MS system. Chromatographic separation was achieved using a Cadenza HS C18 column and a gradient mixture of acetonitrile-water (both containing 0.1% formic acid) as the mobile phase at a flow rate of 0.5mL/min. The analytes were detected in multiple reaction monitoring mode with positive ion electrospray ionization. The concentration of teicoplanin was determined as the sum of six components (A3-1, A2-1, A2-2, A2-3, A2-4, and A2-5). The calibration curve was linear over a concentration range of 1-50mg/L, which covered the clinically accepted trough and therapeutic plasma levels. The intra- and inter-day precision and accuracy values were both less than 15%. This validated method was successfully applied to therapeutic drug monitoring of teicoplanin in routine clinical practice. Thus, we expect it to be useful for the determination of teicoplanin concentration in human plasma. PMID- 26655104 TI - Direct site-specific immobilization of protein A via aldehyde-hydrazide conjugation. AB - Immobilization of affinity ligands on supporting matrices is a key step for the preparation of affinity chromatography resins, and an efficient coupling strategy can significantly improve the validity and cost of the affinity system, especially for systems that employ expensive recombinant proteins or antibodies as affinity ligands. This study described a simple method for obtaining site specific immobilization of protein A (the ligand) via aldehyde-hydrazide conjugation and its application in antibody purification via protein A chromatography. An aldehyde group was generated at the N-terminus of protein A in vivo by co-expressing a formylglycine-generating enzyme (FGE) and recombinant protein A containing a FGE recognizing sequence (aldehyde tag) in Escherichia coli. The resulting aldehyde allowed direct immobilization of protein A onto the hydrazide-modified agarose matrices under mild condition. We found that 100mM aniline was most effective for catalyzing the coupling reaction, and the recombinant protein A could be coupled with high selectivity, directly from a crude cell extract. The site-specific immobilized protein A showed good capacity for antibody purification. The specificity of the aldehyde-hydrazide reaction not only allowed site-specific immobilization of affinity ligands, but also improved the cost of the process by employing unpurified ligands, a method that might be of great use to industrial applications. PMID- 26655105 TI - An UPLC-MS/MS method for simultaneous quantitation of two coumarins and two flavonoids in rat plasma and its application to a pharmacokinetic study of Wikstroemia indica extract. AB - In this study, an ultra performance liquid chromatography tandem mass spectrometry method (UPLC-MS/MS) was developed for simultaneous determination of umbelliferone, apigenin, daphnoretin and genkwanin in total (free and conjugated) forms in rat plasma using psoralen as internal standard. Plasma samples were protein precipitated with acetonitrile followed by liquid-liquid extracted with ethyl acetate. Four ingredients were separated on an Acquity UPLC((r)) BEH C18 column using gradient elution with the mobile phase consisting of 0.1% formic acid aqueous solution and acetonitrile, and detected by positive ion electrospray ionization (ESI) in multiple reaction monitoring mode (MRM). The method was linear for all analytes over investigated ranges with all correlation coefficients greater than 0.99. The validated lower limit of quantification was 3ng/mL for umbelliferone, 3ng/mL for apigenin, 12ng/mL for daphnoretin and 2ng/mL for genkwanin, respectively. Intra- and inter-day precisions (RSD%) were less than 15% and accuracy (RE%) ranged from -1.1% to 15%. The mean absolute extraction recoveries of analytes and IS from rat plasma were all more than 75%. The validated method was firstly and successfully applied to investigate the pharmacokinetics of four chemical ingredients after oral administration of Wikstroemia indica extract (WIE) to rats. PMID- 26655106 TI - Preconcentration and determination of chlordiazepoxide and diazepam drugs using dispersive nanomaterial-ultrasound assisted microextraction method followed by high performance liquid chromatography. AB - Benzodiazepines (BDs) are used widely in clinical practice, due to their multiple pharmacological functions. In this study a dispersive nanomaterial-ultrasound assisted- microextraction (DNUM) method followed by high performance liquid chromatography (HPLC) was used for the preconcentration and determination of chlordiazepoxide and diazepam drugs from urine and plasma samples. Various parameters such as amount of adsorbent (mg: ZnS-AC), pH and ionic strength of sample solution, vortex and ultrasonic time (min), and desorption volume (mL) were investigated by fractional factorial design (FFD) and central composite design (CCD). Regression models and desirability functions (DF) were applied to find the best experimental conditions for providing the maximum extraction recovery (ER). Under the optimal conditions a linear calibration curve were obtained in the range of 0.005-10MUgmL(-1) and 0.006-10MUgmL(-1) for chlordiazepoxide and diazepam, respectively. To demonstrate the analytical performance, figures of merits of the proposed method in urine and plasma spiked with chlordiazepoxide and diazepam were investigated. The limits of detection of chlordiazepoxide and diazepam in urine and plasma were ranged from 0.0012 to 0.0015MUgmL(-1), respectively. PMID- 26655107 TI - A capillary zone electrophoresis method for adenine nucleotides analysis in Saccharomyces cerevisiae. AB - Adenosine triphosphate and its metabolites are involved in the cellular metabolism process in Saccharomyces cerevisiae. It is very important to simultaneously determine the relative contents of ATP and its metabolites in yeast. In this study, an effective capillary zone electrophoresis method with high selectivity was established. The calibration curves were linear in the concentration range from 1 to 20mg/L (ATP and cAMP) and 2 to 40mg/L (ADP and AMP) with excellent correlation coefficients (r(2))>0.999. The recovery of ATP, ADP, AMP, and cAMP were 99.4%, 94.7%, 100.3% and 99.6%, respectively. Simple sample preparation and easy detection of ATP and its metabolites make this method suitable for the study of changes in the four adenine nucleotides levels caused by caloric restriction in yeast. It is expected that the current method may contribute to further energy metabolism and related investigations of yeast. PMID- 26655108 TI - Comparison of enzyme kinetics of warfarin analyzed by LC-MS/MS QTrap and differential mobility spectrometry. AB - Warfarin is an anticoagulant used in the treatment of thrombosis and thromboembolism. It is given as a racemic mixture of R and S enantiomers. These two enantiomers show differences in metabolism by CYPs: S-warfarin undergoes 7 hydroxylation by CYP2C9 and R-warfarin by CYP3A4 to form 10 hydroxy warfarin. In addition, warfarin is acted upon by different CYPs to form the minor metabolites 3'-hydroxy, 4'-hydroxy, 6-hydroxy, and 8-hydroxy warfarin. For analysis, separation of these metabolites is necessary since all have the same m/z ratio and similar fragmentation pattern. Enzyme kinetics for the formation of all of the six hydroxylated metabolites of warfarin from human liver microsomes were determined using an LC-MS/MS QTrap and LC-MS/MS with a differential mobility spectrometry (DMS) (SelexIONTM) interface to compare the kinetic parameters. These two methods were chosen to compare their selectivity and sensitivity. Substrate curves for 3'-OH, 4'-OH, 6-OH, 7-OH, 8-OH and 10-OH warfarin formation were generated to determine the kinetic parameters (Km and Vmax) in human liver microsomal preparations. The limit of quantitation (LOQ) for all the six hydroxylated metabolites of warfarin were in the range of 1-3nM using an LC-MS/MS QTrap method which had a run time of 22min. In contrast, the LOQ for all the six hydroxylated metabolites using DMS interface technology was 100nM with a run time of 2.8min. We compare these two MS methods and discuss the kinetics of metabolite formation for the metabolites generated from racemic warfarin. In addition, we show inhibition of major metabolic pathways of warfarin by sulfaphenazole and ketoconazole which are known specific inhibitors of CYP2C9 and CYP3A4 respectively. PMID- 26655109 TI - Development of a sensitive method for the determination of oxycodone and its major metabolites noroxycodone and oxymorphone in human plasma by liquid chromatography-tandem mass spectrometry. AB - Oxycodone is an opioid agonist largely prescribed for the treatment of moderate to severe pain. Variability in analgesic efficacy could be explained by inter subject variations in plasma levels of parent drug and its active metabolite, oxymorphone. For this purpose it is necessary to develop and validate a sensitive and selective analytical method for the quantification of oxycodone and its major metabolites, noroxycodone and oxymorphone, in human plasma. The analytical method consisted of a liquid-liquid extraction procedure followed by a high performance liquid chromatography with heated assisted electrospray ionization mass spectrometry (HPLC-HESI-MS/MS). The chromatographic separation was achieved using gradient elution with a mobile phase consisting of ethanol and 10mM ammonium acetate on a Synergi MAX-RP analytical column (150*2mm, 4MUm) protected by a security guard cartridge (C12 4*2mm) at a flow rate of 300MUL/min.The calibration functions are linear in the range of 300-50,000pg/mL for oxycodone and noroxycodone and 50 to 10 000pg/mL for oxymorphone. Intra- and inter-day relative standard deviations are less than 5.5% and 6.4%, respectively for all analytes. The limit of detection was 30pg/mL for all analytes. We introduce a new HPLC-HESI MS/MS sensitive and specific analytical method capable to simultaneously quantify oxycodone, noroxycodone and oxymorphone, in human plasma, and suitable for the conduct of pharmacokinetic studies after a single dose administration of the parent compound. PMID- 26655110 TI - Simultaneous determination of 3-mercaptopyruvate and cobinamide in plasma by liquid chromatography-tandem mass spectrometry. AB - The current suite of Food and Drug Administration (FDA) approved antidotes (i.e., sodium nitrite, sodium thiosulfate, and hydroxocobalamin) are effective for treating cyanide poisoning, but individually, each antidote has major limitations (e.g., large effective dosage or delayed onset of action). To mitigate these limitations, next-generation cyanide antidotes are being investigated, including 3-mercaptopyruvate (3-MP) and cobinamide (Cbi). Analytical methods capable of detecting these therapeutics individually and simultaneously (for combination therapy) are essential for the development of 3-MP and Cbi as potential cyanide antidotes. Therefore, a liquid chromatography-tandem mass-spectrometry method for the simultaneous analysis of 3-MP and Cbi was developed. Sample preparation of 3 MP consisted of spiking plasma with an internal standard ((13)C3-3-MP), precipitation of plasma proteins, and derivatizing 3-MP with monobromobimane to produce 3-mercaptopyruvate-bimane. Preparation of Cbi involved denaturing plasma proteins with simultaneous addition of excess cyanide to convert each Cbi species to dicyanocobinamide (Cbi(CN)2). The limits of detection for 3-MP and Cbi were 0.5MUM and 0.2MUM, respectively. The linear ranges were 2-500MUM for 3-MP and 0.5 50MUM for Cbi. The accuracy and precision for 3-MP were 100+/-9% and <8.3% relative standard deviation (RSD), respectively. For Cbi(CN)2, the accuracy was 100+/-13% and the precision was <9.5% RSD. The method presented here was used to determine 3-MP and Cbi from treated animals and may ultimately facilitate FDA approval of these antidotes for treatment of cyanide poisoning. PMID- 26655111 TI - Posterior reversible encephalopathy syndrome following pembrolizumab therapy for relapsed Hodgkin's lymphoma. AB - Posterior reversible encephalopathy syndrome (PRES) is characterized by a group of central nervous system related symptoms. Diagnosis is usually made by computed tomography or magnetic resonance imaging. Common causes can be arterial hypertension, sepsis, autoimmune disorders, and medications. We report PRES in a relapsed Hodgkin's Lymphoma patient after a dose of pembrolizumab. PMID- 26655112 TI - Rather than pay GPs to reduce referrals, use the money to improve community services. PMID- 26655113 TI - Glyceollins and dehydroglyceollins isolated from soybean act as SERMs and ER subtype-selective phytoestrogens. AB - Seven prenylated 6a-hydroxy-pterocapans and five prenylated 6a,11a-pterocarpenes with different kinds of prenylation were purified from an ethanolic extract of fungus-treated soybean sprouts. The activity of these compounds toward both human estrogen receptors (hERalpha and hERbeta) was determined in a yeast bioassay and the activity toward hERalpha was additionally tested in an U2-OS based hERalpha CALUX bioassay. In the yeast bioassay, compounds with chain prenylation showed in general an agonistic mode of action toward hERalpha, whereas furan and pyran prenylation led to an antagonistic mode of action. Five of these antagonistic compounds had an agonistic mode of action in the U2-OS based hERalpha CALUX bioassay, implying that these compounds can act as SERMs. The yeast bioassay also identified 8 ER subtype-selective compounds, with either an antagonistic mode of action or no response toward hERalpha and an agonistic mode of action toward hERbeta. The ER subtype-selective compounds were characterized by 6a-hydroxy pterocarpan or 6a,11a-pterocarpene backbone structure. It is suggested that either the extra D-ring or the increase in length to 12-13.5A of these compounds is responsible for an agonistic mode of action toward hERbeta and, thereby, inducing ER subtype-selective behavior. PMID- 26655114 TI - Theory of mind in major depressive disorder: A meta-analysis. AB - OBJECTIVE: Social cognitive deficits can contribute to risk for depression and to psychosocial impairment during depression. However, available evidence suggests that emotion recognition is only marginally impaired in major depressive disorder (MDD). Recent studies have investigated theory of mind (ToM) abilities, a cognitively more demanding aspect of social cognition. METHODS: We conducted a meta-analysis of studies comparing ToM abilities in MDD and healthy controls. 18 studies comparing 613 patients with MDD and 529 healthy controls were included. RESULTS: MDD patients significantly underperformed healthy controls in ToM (d=0.51-0.58). ToM impairment in MDD was evident in response to different types of ToM tasks (verbal/visual and cognitive/affective and reasoning/decoding). ToM impairment was significantly related to severity of depressive symptoms. CONCLUSION: Theory of mind abilities are impaired during depression and can potentially contribute to psychosocial difficulties during depression. There is a need to investigate ToM abilities in different subtypes and stages of depression, especially in remitted patients. PMID- 26655115 TI - Dimensions of adult attachment are significantly associated with specific affective temperament constellations in a Hungarian university sample. AB - BACKGROUND: Related to emotion regulation and mental health, adult attachment and affective temperaments are relevant research topics of contemporary psychiatry and clinical psychology. However, to date, only one study investigated the relationship between these two constructs. Thus, we aimed to further reveal adult attachment's association with affective temperaments. METHODS: Affective temperament and adult attachment dimensions of 1469 Hungarian university students were assessed with self-report measures (Temperament Evaluation of Memphis, Pisa and San Diego autoquestionnaire and Experiences in Close Relationships Scale, respectively). Age and measured variables were compared between genders with ANOVAs. Associations between attachment dimensions and affective temperaments were examined with Pearson's correlations and partial correlations; the moderation effect of age and gender on these relationships was tested with PROCESS macro. Using Fisher r-to-z transformation, we also compared our results with the findings of the previous study. Cohen's ds were used to report effect size and Cronbach's alphas were computed as indices of internal reliability. RESULTS: Significant correlations were found between attachment dimensions and affective temperaments. Correlations were especially robust between attachment anxiety and depressive, cyclothymic and anxious temperaments. Contrasted with the results of the previous study, hyperthymic temperament was negatively related to attachment avoidance and anxious temperament was significantly more strongly correlated with attachment anxiety in our study. LIMITATIONS: We used a previous version of the adult attachment measure. Our sample differed from the target sample in several ways. Participants were not screened for mental disorders. CONCLUSIONS: Findings highlight that adult attachment dimensions are significantly associated with affective temperaments. PMID- 26655116 TI - Depressive symptoms, thyroid hormone and autoimmunity in a population-based cohort from Sardinia. AB - OBJECTIVE: To evaluate the association between depressive symptoms and thyroid autoimmunity, and the effect of thyroid hormone on the risk of depression. METHODS: We included 3138 individuals from SardiNIA project, none of whom was taking thyroid medication and antidepressants. Thyrotropin (TSH), free thyroxine (FT4), and antibodies against thyroperoxidase (TPOAb) were measured in all the sample. Depressive symptoms were assessed with Center for Epidemiologic Studies Depression Scale (CES-D). RESULTS: We found no association between TPOAb and depressive symptoms and no linear association between TSH or FT4 levels and depressive symptoms. However, individuals in the lowest and highest FT4 quintiles showed a higher CES-D score compared to individuals in the middle quintile. In addition, participants in the lowest and highest FT4 quintiles had an increased risk of CES-D>=16 with odds ratios of 1.44 (95% CI=1.09-1.89) and 1.33 (95% CI=1.01-1.77), respectively. LIMITATIONS: Cross-sectional design of the study. CONCLUSIONS: A U-shaped relation was found between FT4 and depressive symptoms: compared to average FT4 values, both high and low thyroid function was associated with more depressive symptoms. Further studies are necessary to determine the exact cause-effect relation of this association. PMID- 26655118 TI - Smoking cessation and depressive symptoms at 1-, 3-, 6-, and 12-months follow-up. AB - BACKGROUND: The relationship between tobacco and depressive symptoms has been examined. However, there is little information on the evolution of these symptoms when an individual quits. The aim of this study was to analyze the evolution of depressive symptoms over time (pre-, post-treatment, 1-, 3-, 6-, and 12-months follow-up) in relation to smoking status 12 months after having received a psychological treatment for smoking cessation. METHOD: The sample was made up of 242 adults who received cognitive-behavioral treatment for smoking cessation (64.4% women; mean age=41.71 years). The BDI-II was used to assess depressive symptomatology. Participants were classified into three groups according to smoking status at 12-months follow-up (abstainers, relapsers, and smokers). RESULTS: There were no significant differences in depressive symptoms among the three groups at pretreatment. At the end of treatment, abstainers and relapsers presented less depressive symptomatology than smokers. At follow-up, abstainers continued to present less depressive symptomatology than smokers, whereas in relapsers, symptoms began to increase as the relapses occurred. Regarding the evolution of depressive symptomatology, the abstainer and relapser groups showed a significant reduction at the end of treatment. Only in the group of abstainers did the decrease continue during 12 months follow-up. LIMITATIONS: The decrease of the initial sample size from 562 to 242 participants. Variables such as self esteem and self-efficacy were not assessed. CONCLUSIONS: Smoking cessation is associated with a decrease in depressive symptomatology, that is maintained over time. In contrast, relapse is associated with an increase of such symptoms. These findings signify the potential importance of addressing depressive symptomatology in smoking cessation treatment. PMID- 26655117 TI - Daily mood monitoring of symptoms using smartphones in bipolar disorder: A pilot study assessing the feasibility of ecological momentary assessment. AB - BACKGROUND: Personal device technology has facilitated gathering data in real time using Ecological momentary assessment (EMA). We hypothesized that using smartphones to measure symptoms in auto-generated surveys twice a day would be feasible in a group with bipolar disorder (BD). A second exploratory objective of this study was to compare potential differences in core symptoms between BD and healthy control (HC) groups. METHODS: A two-arm, parallel group, observational study was designed to measure completion rates of surveys of symptoms of mood, energy, speed of thought, impulsivity, and social stress in BD (N=10) and HC (N=10) participants. The surveys were auto-generated twice a day for fourteen days, and subjects could also perform self-generated surveys. Completion rates were compared between BD and HC groups. Scores were averaged for each participant over the 14 day period, and group medians were compared. RESULTS: Median completion rates did not differ between groups: 95% in BD, 88% in HC (p=0.68); the median completion rate of auto-generated surveys in the BD group was 79% and in the HC group was 71% (p=0.22). The BD group had significantly lower median mood score (p=0.043) and energy score (p=0.007) than the HC group. Median scores of speed of thoughts (p=0.739), impulsivity (p=0.123) and social stress (p=0.056) did not significantly differ between BD and HC. The BD group had significantly higher range of variability of group median mood (p=0.043), speed of thoughts (p=0.002) and impulsivity (p=0.005) scores over the course of 14 days than HC, while range of variability of energy (p=0.218) and social stress (p=0.123) scores did not differ. Results were not significantly different between auto-generated and self-generated surveys for BD or HC. LIMITATIONS: This pilot study was conducted for a short time and with a small sample. CONCLUSIONS: This study demonstrates feasibility of using EMA with a smartphone to gather data on BD symptoms. PMID- 26655119 TI - Childhood maltreatment, maladaptive personality types and level and course of psychological distress: A six-year longitudinal study. AB - BACKGROUND: Childhood maltreatment and maladaptive personality are both cross sectionally associated with psychological distress. It is unknown whether childhood maltreatment affects the level and longitudinal course of psychological distress in adults and to what extent this effect is mediated by maladaptive personality. METHODS: A sample of 2947 adults aged 18-65, consisting of healthy controls, persons with a prior history or current episode of depressive and/or anxiety disorders according to the Composite Interview Diagnostic Instrument were assessed in six waves at baseline (T0) and 1 (T1), 2 (T2), 4 (T4) and 6 years (T6) later. At each wave psychological distress was measured with the Inventory of Depressive Symptomatology, Beck Anxiety Inventory, and Fear Questionnaire. At T0 childhood maltreatment types were measured with a semi-structured interview (Childhood Trauma Interview) and personality traits with the NEO-Five Factor Inventory. RESULTS: Using latent variable analyses, we found that severity of childhood maltreatment (emotional neglect and abuse in particular) predicted higher initial levels of psychological distress and that this effect was mediated by maladaptive personality types. Differences in trajectories of distress between persons with varying levels of childhood maltreatment remained significant and stable over time. LIMITATIONS: Childhood maltreatment was assessed retrospectively and maladaptive personality types and level of psychological distress at study entry were assessed concurrently. CONCLUSIONS: Routine assessment of maladaptive personality types and possible childhood emotional maltreatment in persons with severe and prolonged psychological distress seems warranted to identify persons who may need a different or more intensive treatment. PMID- 26655120 TI - Non-suicidal reasons for self-harm: A systematic review of self-reported accounts. AB - BACKGROUND: Self-harm is a major public health problem yet current healthcare provision is widely regarded as inadequate. One of the barriers to effective healthcare is the lack of a clear understanding of the functions self-harm may serve for the individual. The aim of this review is to identify first-hand accounts of the reasons for self-harm from the individual's perspective. METHOD: A systematic review of the literature reporting first-hand accounts of the reasons for self-harm other than intent to die. A thematic analysis and 'best fit' framework synthesis was undertaken to classify the responses. RESULTS: The most widely researched non-suicidal reasons for self-harm were dealing with distress and exerting interpersonal influence. However, many first-hand accounts included reasons such as self-validation, and self-harm to achieve a personal sense of mastery, which suggests individuals thought there were positive or adaptive functions of the act not based only on its social effects. LIMITATIONS: Associations with different sub-population characteristics or with the method of harm were not available from most studies included in the analysis. CONCLUSIONS: Our review identified a number of themes that are relatively neglected in discussions about self-harm, which we summarised as self-harm as a positiveexperience and defining the self. These self-reported "positive" reasons may be important in understanding and responding especially to repeated acts of self-harm. PMID- 26655121 TI - Illness history: Not associated with remission during treatment of major depression in 515 mood disorder patients. AB - BACKGROUND: There is suggestive evidence that prior illness history may have little association with response to long-term treatment in bipolar disorder (BD) or recurrent major depressive disorder (MDD), but relationships of illness history to treatment-response in acute episodes of depression require further testing. METHODS: We tested for associations of selected measures of illness history with remission during treatment of an acute index episode of major depression in 515 mood-disorder patients (327 MDD, 188 BD), using bivariate and multivariate methods. RESULTS: Remission of depression was more likely with lesser initial symptom-severity and bipolar diagnosis, but not related to years since illness-onset, previous depressions or episodes (based on counts, yearly rates, or %-of months ill), or other indices of illness-severity (hospitalization, co-morbidity, suicide attempt). CONCLUSIONS: Likelihood of response to standard treatments for acute major depressive episodes in MDD or BD appeared to be largely independent of prior illness-history. PMID- 26655123 TI - Impact of the recent recession on self-harm: Longitudinal ecological and patient level investigation from the Multicentre Study of Self-harm in England. AB - BACKGROUND: Economic recessions are associated with increases in suicide rates but there is little information for non-fatal self-harm. AIMS: To investigate the impact of the recent recession on rates of self-harm in England and problems faced by patients who self-harm. METHOD: Analysis of data from the Multicentre Study of Self-harm in England for 2001-2010 and local employment statistics for Oxford, Manchester and Derby, including interrupted time series analyses to estimate the effect of the recession on rates of self-harm. RESULTS: Rates of self-harm increased in both genders in Derby and in males in Manchester in 2008 2010, but not in either gender in Oxford, results which largely followed changes in general population unemployment. More patients who self-harm were unemployed in 2008-10 compared to before the recession. The proportion in receipt of sickness or disability allowances decreased. More patients of both genders had employment and financial problems in 2008-2010 and more females also had housing problems, changes which were also largely found in employed patients. LIMITATIONS: We have assumed that the recession began in 2008 and information on problems was only available for patients having a psychosocial assessment. CONCLUSIONS: Increased rates of self-harm were found in areas where there were greater rises in rates of unemployment. Work, financial and housing problems increased in people who self-harmed. Changes in welfare benefits may have contributed. DECLARATION OF INTEREST: None. PMID- 26655122 TI - Genome-wide linkage on chromosome 10q26 for a dimensional scale of major depression. AB - Major depressive disorder (MDD) is a common and potentially life-threatening mood disorder. Identifying genetic markers for depression might provide reliable indicators of depression risk, which would, in turn, substantially improve detection, enabling earlier and more effective treatment. The aim of this study was to identify rare variants for depression, modeled as a continuous trait, using linkage and post-hoc association analysis. The sample comprised 1221 Mexican-American individuals from extended pedigrees. A single dimensional scale of MDD was derived using confirmatory factor analysis applied to all items from the Past Major Depressive Episode section of the Mini-International Neuropsychiatric Interview. Scores on this scale of depression were subjected to linkage analysis followed by QTL region-specific association analysis. Linkage analysis revealed a single genome-wide significant QTL (LOD=3.43) on 10q26.13, QTL-specific association analysis conducted in the entire sample revealed a suggestive variant within an intron of the gene LHPP (rs11245316, p=7.8*10(-04); LD-adjusted Bonferroni-corrected p=8.6*10(-05)). This region of the genome has previously been implicated in the etiology of MDD; the present study extends our understanding of the involvement of this region by highlighting a putative gene of interest (LHPP). PMID- 26655124 TI - Dynamic functional-structural coupling within acute functional state change phases: Evidence from a depression recognition study. AB - BACKGROUND: Dynamic functional-structural connectivity (FC-SC) coupling might reflect the flexibility by which SC relates to functional connectivity (FC). However, during the dynamic acute state change phases of FC, the relationship between FC and SC may be distinctive and embody the abnormality inherent in depression. This study investigated the depression-related inter-network FC-SC coupling within particular dynamic acute state change phases of FC. METHODS: Magnetoencephalography (MEG) and diffusion tensor imaging (DTI) data were collected from 26 depressive patients (13 women) and 26 age-matched controls (13 women). We constructed functional brain networks based on MEG data and structural networks from DTI data. The dynamic connectivity regression algorithm was used to identify the state change points of a time series of inter-network FC. The time period of FC that contained change points were partitioned into types of dynamic phases (acute rising phase, acute falling phase,acute rising and falling phase and abrupt FC variation phase) to explore the inter-network FC-SC coupling. The selected FC-SC couplings were then fed into the support vector machine (SVM) for depression recognition. RESULTS: The best discrimination accuracy was 82.7% (P=0.0069) with FC-SC couplings, particularly in the acute rising phase of FC. Within the FC phases of interest, the significant discriminative network pair was related to the salience network vs ventral attention network (SN-VAN) (P=0.0126) during the early rising phase (70-170ms). LIMITATIONS: This study suffers from a small sample size, and the individual acute length of the state change phases was not considered. CONCLUSIONS: The increased values of significant discriminative vectors of FC-SC coupling in depression suggested that the capacity to process negative emotion might be more directly related to the SC abnormally and be indicative of more stringent and less dynamic brain function in SN-VAN, especially in the acute rising phase of FC. We demonstrated that depressive brain dysfunctions could be better characterized by reduced FC-SC coupling flexibility in this particular phase. PMID- 26655125 TI - Psychopharmacological treatment of 1650 in-patients with acute mania-data from the AMSP study. AB - BACKGROUND: Several studies have analyzed prescription patterns for bipolar disorder, but few have for acute mania. Treatment strategies in this complex domain change over time and do not always follow evidence-based guidelines. METHODS: Prescription data of in-patients suffering from acute mania in the time period from 2005 to 2012 were obtained from the database of the Drug Safety Program in Psychiatry (Institut fur Arzneimittelsicherheit in der Psychiatrie; AMSP). Data were collected on two index dates per year. Changes over time were analyzed comparing the time periods 2005/06 and 2011/12. RESULTS: Among 1650 patients (mean +/-SD; age: 48.9+/-14.91 years; 53.1% females) 54.1% received anticonvulsants, 74.5% second-generation antipsychotics (SGAs), 17.8% first generation antipsychotics (FGAs), 29.1% lithium, 44.1% benzodiazepines and 14.5% antidepressants. Prescription of SGAs increased from 70% to 79% (p=0.005), while prescription of FGAs and anticonvulsants decreased from 19% to 13% (p<0.05) and 59% to 46% (p<0.001), respectively. Only 30% of patients received monotherapy with one mood stabilizer. We observed an impact of gender, age and psychotic symptoms on treatment strategy. 36.8% of the women<=40 years received valproate. LIMITATIONS: Follow-up data are missing and no differentiation between acute and maintenance treatments could be made due to the cross-sectional design. Additionally, our findings do not necessarily translate to outpatients or to other countries. CONCLUSIONS: Combination therapies represent standard clinical practice. Though many results reflect clinical necessity, the high number of antidepressant prescriptions or valproate use in women of child-bearing age should be judged critically. Further prospective studies should focus on real world prescription practice in acute mania to evaluate efficacy and safety of common practice. This paper is dedicated to Prof. Dr. Hanns Hippius on the occasion of his 90th birthday. PMID- 26655126 TI - Usefulness of the apparent diffusion coefficient for the evaluation of the white matter to differentiate between glioblastoma and brain metastases. AB - OBJECTIVE: To determine whether there are significant differences in the apparent diffusion coefficient (ADC) between the apparently normal peritumor white matter surrounding glioblastomas and that surrounding brain metastases. MATERIAL AND METHODS: We retrospectively reviewed 42 patients with histologically confirmed glioblastomas and 42 patients with a single cerebral metastasis. We measured the signal intensity in the apparently normal peritumor white matter and in the abnormal peritumor white matter on the ADC maps. We used mean ADC values in the contralateral occipital white matter as a reference from which to design normalized ADC indices. We compared mean values between the two tumor types. We calculated the area under the receiver operator characteristic curve and estimated the sensitivity and specificity of the measurements taken. RESULTS: Supratentorial lesions and compromise of the corpus callosum were more common in patients with glioblastoma than in patients with brain metastases. The maximum diameter of the enhanced area after injection of a contrast agent was greater in the glioblastomas (p<0.001). The minimum ADC value measured in the apparently normal peritumor white matter was higher for the glioblastomas than for the metastases (p=0.002). Significant differences in the ADC index were found only for the minimum ADC value in apparently normal peritumor white matter. The sensitivity and specificity were less than 70% for all variables analyzed. CONCLUSIONS: There are differences in the ADC values of apparently normal peritumor white matter between glioblastomas and cerebral metastases, but the magnitude of these differences is slight and the application of these differences in clinical practice is still limited. PMID- 26655127 TI - One or two weeks of treatment with Helicobacter Pylori ''standard'' triple therapy in the year 2015? PMID- 26655128 TI - The new era of hepatitis C virus therapy. AB - The hepatitis C virus (HCV) has a significant medical and economic impact on societies around the world, and it has been estimated that 130-180 million people are infected with HCV. Therapies for HCV are currently undergoing a revolution. In recent years, several new treatments have been approved by the United States Food and Drug Administration, and many other treatments are in phase II or III clinical trials, including direct antiviral agents (DAAs). Due to recent major advances in the field of HCV therapy, a summary of findings on new HCV therapies are provided in this review article, including reports on new DAAs. PMID- 26655129 TI - Two-week triple therapy has a higher Helicobacter pylori eradication rate than 1 week therapy: A single-center randomized study. AB - BACKGROUND AND AIM: To evaluate a high effective and practical regimen for the eradication of Helicobacter pylori infection. PATIENTS AND METHODS: The 298 patients with H. pylori infection, diagnosed by biopsies performed during the endoscopy, were randomized into two groups. Group 1: Treated for one week with a combination of omeprazole, amoxicillin, and clarithromycin (OAC), named by OAC-1 group (n = 143); Group 2: OAC-2 group (n = 155) treated for two weeks with OAC. The OAC-1 group was treated with triple therapy of omeprazole 20 mg, amoxicillin 1000 mg, and clarithromycin 500 mg bid for 1 week. OAC-2 group was treated likewise, but for two weeks. A 13C-urea breath test was used to monitor H. pylori after four to eight weeks following therapy. RESULTS: The eradication of infection was 55% and 68% in the OAC-1 and OAC-2 groups, respectively. Moreover, the eradication rates in the two groups were 63% and 75%, respectively. Compared with the OAC-1 group, the efficacy of treatment in the OAC-2 group is significantly higher (P < 0.05). CONCLUSION: Two-week OAC regimen yields a higher eradication rate of H. pylori, which might be a practical regimen for the eradication of H. pylori. PMID- 26655130 TI - Rapid fecal calprotectin testing to assess for endoscopic disease activity in inflammatory bowel disease: A diagnostic cohort study. AB - BACKGROUND AND AIM: With increasing numbers of patients diagnosed with inflammatory bowel disease (IBD), it is important to identify noninvasive methods of detecting disease activity. The aim of this study is to examine the diagnostic accuracy of fecal rapid calprotectin (FC) testing in the detection of endoscopically active IBD. PATIENTS AND METHODS: All consecutive patients presenting to outpatient clinics with lower gastrointestinal symptoms were prospectively recruited. Patients provided FC samples. Sensitivity (Sn), specificity (Sp), positive predictive value (PPV), and negative predictive value (NPV) for FC were calculated. Receiver-operator characteristics (ROC) curve was used to identify the ideal FC cutoff that predicts endoscopic disease activity. Correlation between FC and endoscopic disease activity, disease location, and C reactive protein (CRP) levels were measured. RESULTS: One hundred and twenty-six patients, of whom 52% were females, were included in the final analysis with a mean age of 44.4 +/- 16.7 years. Comparing FC to endoscopic findings, the following results were calculated: A cutoff point of 100 MUg/g showed Sn = 83%, Sp = 67%, PPV = 65%, and NPV = 85%; and 200 MUg/g showed Sn = 66%, Sp = 82%, PPV = 73%, and NPV = 77%. Based on ROC curve, the best FC cutoff point to predict endoscopic disease activity was 140 MUg/g. Using this reference, FC levels strongly correlated with colorectal, ileocolonic, and ileal disease and predicted endoscopic activity. CONCLUSIONS: FC is an accurate test when used as an initial screening tool for patients suspected of having active IBD. Given its noninvasive nature, it may prove to reduce the need for colonoscopy and be an added tool in the management of IBD. PMID- 26655131 TI - Prevalence of celiac disease among symptom-free children from the Eastern Province of Saudi Arabia. AB - BACKGROUND/AIM: Epidemiological studies of celiac disease (CD) among Saudi children have been performed only within some groups who are at a high risk of developing CD. The aim of this study was to determine the prevalence of CD among symptom-free children from the public schools of the military campus of National Guard in the Eastern Province of Saudi Arabia. PATIENTS AND METHODS: Between 2012 and 2014, serum samples were collected from 1141 students (age 6-18 years) attending nine public schools of the military campus of National Guard in the Eastern Province of Saudi Arabia. Participants were screened for CD by testing for anti-tissue transglutaminase IgA (IgA-tTG) and IgG antibodies (IgG-tTG). Small intestinal biopsy was offered to all participants who tested positive for IgA-tTG [IgA-tTG >20 relative units (RU)/ml]. RESULTS: Of the 1141 participants, 32 were IgA-tTG positive. Thus, the estimated serology-positive prevalence was 3%. An intestinal biopsy was performed in 10 of the participants with antibody positivity. The biopsy findings of all 10 children were consistent with CD. Thus, the estimated biopsy-confirmed prevalence was about 1%. CONCLUSIONS: The prevalence of CD was estimated to be about 1% among symptom-free children from the public schools of the military campus of National Guard in the Eastern Province of Saudi Arabia. PMID- 26655132 TI - Prophylactic effect of somatostatin in preventing Post-ERCP pancreatitis: an updated meta-analysis. AB - BACKGROUND/AIMS: Somatostatin is regarded as a prophylactic agent on post endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP), but studies are still controversial. MATERIALS AND METHODS: Electronic databases, including PubMed, EMBASE, the Cochrane library, and the Science Citation Index, were searched to retrieve relevant trials. In addition, meeting abstracts and the reference lists of retrieved articles were reviewed for further relevant studies. RESULTS: Eleven randomized controlled trials (RCTs), enrolling a total of 2869 patients, were included in the meta-analysis. After data were pooled from somatostatin trials, PEP occurred in 8.36% of controls versus 5.62% of the treated group, with a slight significance [relative risk (RR) =0.58, 95% confidence interval (CI) 0.35-0.98, P = 0.04]. The funnel plot showed no asymmetry with a negative slope (P = 0.108). The meta-analysis produced negative results for short-term infusion of somatostatin (RR = 1.40, 95% CI 0.93-2.12, P = 0.11), whereas a bolus or long-term injection of the drug proved effective (RR = 0.25, 95% CI 0.13-0.47,P < 0.0001; RR = 0.44, 95% CI 0.27-0.71,P = 0.0008). Postprocedure hyperamylasemia and pain was also observed in the meta-analysis, the pooled RR was significant for reduced risk of postprocedure hyperamylasemia (RR = 0.72, 95%CI 0.63 to 0.81,P < 0.00001), but not for the pain (RR = 0.67, 95% CI 0.42 to 1.08,P= 0.10). CONCLUSION: The current meta-analysis on the prophylactic use of somatostatin in patients undergoing ERCP documents a lack of benefit when given as short-term infusion, but showed an advantage of a single bolus or long-term injection. The beneficial effect of somatostatin, in reducing the incidence of postprocedural hyperamylasemia seems of marginal clinical significance. However, more new confirmatory data are needed to settle residual doubts. PMID- 26655133 TI - Mucosal molecular pattern of tissue transglutaminase and interferon gamma in suspected seronegative celiac disease at marsh 1 and 0 stages. AB - BACKGROUND/AIM: In celiac disease (CD), there is increased mRNA coding for tissue transglutaminase (tTG) and interferon gamma (IFNalpha). In seronegative celiac patients, the mucosal immune complexes anti-tTG IgA/tTG are found. We assayed tTG and IFNalpha-mRNA in the mucosa of patients with a clinical suspicion of seronegative CD and correlated the values with intraepithelial CD3 lymphocytes (IELs). MATERIALS AND METHODS: Distal duodenum specimens from 67 patients were retrieved and re-evaluated for immunohistochemically proven CD3 IELs. Five 10 MUm sections were used for the extraction and assay of tTG and IFNalpha coding mRNA levels using reverse transcriptase real-time polymerase chain reaction (RT-PCR). Samples from 15 seropositive CD patients and 15 healthy subjects were used as positive and negative controls. Results were expressed as fold-change. RESULTS: Our series was divided into three groups based on IEL count: >25 (14 patients: group A), 15-25 (26 patients: group B), and 0-15 (27 patients: Group C). tTG-mRNA levels were (mean +/- SD): CD = 9.8 +/- 2.6; group A = 10.04 +/- 4.7; group B = 4.99 +/- 2.3; group C = 2.26 +/- 0.8, controls = 1.04 +/- 0.2 (CD = group A > group B > group C = controls). IFNalpha-mRNA levels were: CD = 13.4 +/- 3.6; group A = 7.28 +/- 3.6; group B = 4.45 +/- 2.9; group C = 2.06 +/- 1.21, controls = 1.04 +/- 0.4. CONCLUSIONS: Our results suggest that tTG- and IFNgammamRNA levels are increased in both seropositive and potential seronegative patients with CD, showing a strong correlation with the CD3 IEL count at stage Marsh 1. An increase in both molecules is found even when IELs are in the range 15-25 (Marsh 0), suggesting the possibility of a "gray zone" inhabited by patients which should be closely followed up in gluten-related disorders. PMID- 26655134 TI - Predictors for occlusion of the first inserted metallic stent in patients with malignant biliary obstruction. AB - BACKGROUND/AIMS: Endoscopic biliary stent drainage plays an important role in the palliative treatment of malignant biliary obstruction. The aim of this study was to investigate predictors of occlusion of first metal inserted stent in patients with malignant biliary obstruction. PATIENTS AND METHODS: The retrospective analysis was performed in 178 patients with malignant biliary obstruction. Factors associated with stent occlusion were analyzed by Cox regression analysis. RESULTS: Median overall stent patency was 178 days. Total cumulative obstruction rate of the first stents during the follow up was 33%, 57%, 83%, and 96% at 90, 180, 360, and 720 days. Multivariate analysis revealed that hilar obstruction (hazard ratio [HR] =3.26, 95% confidence interval [CI, 2.31-4.61), metastasis cancer (HR = 2.61, 95% CI, 1.79-3.80), and length of stent (HR = 1.74, 95% CI, 1.24-2.46) were independent predictors of stent occlusion. CONCLUSIONS: Hilar biliary stricture, metastatic cancer, and length of stent were important predictors of occlusion of first-inserted metal stent in patients with malignant biliary obstruction. PMID- 26655135 TI - The therapeutic use of endoscopic ultrasonography in pediatric patients is safe: A case series. AB - BACKGROUND/AIM: Despite the safety and high diagnostic yield of endoscopic ultrasound guided fine needle aspiration (EUS FNA) for the evaluation of gastrointestinal diseases in adults, literature discussing the therapeutic use of EUS FNA in pediatrics remains limited. This study reports our experience with the use of EUS in children with pancreaticobiliary disorders. PATIENTS AND METHODS: A retrospective study was conducted to evaluate safety, clinical utility, and impact of therapeutic EUS on the management of children (<18 years) at a tertiary referral center. Data were collected from January 1, 2011, to April 30, 2014. Patient demographics, clinical characteristics, and EUS procedure data were reviewed. Continuous variables were described using the mean and standard deviation. Categorical variables were described using frequencies and percentages. RESULTS: A total of 6 therapeutic EUS procedures were performed in 5 children (3 F/2 M). The mean age was 13 years (range 6-17) with a mean body mass index of 28.2 (range 18.5-38.8). The indications for EUS procedures were abdominal pain with chronic pancreatitis (3) and management of symptomatic pancreaticobiliary cysts/pseudocysts observed on previous imaging (3). All procedures were performed under general anesthesia. The 6 therapeutic procedures performed were celiac plexus block (3), cyst gastrostomy with stents placement (2), and cyst aspiration using EUS FNA (1). A celiac plexus block effectively relieved abdominal pain in 2 patients with chronic pancreatitis. Cyst gastrostomy successfully resulted in pseudocyst resolution in the follow up imaging of 2 patients (up to 6 months after the procedure). Cyst aspiration with EUS guided FNA resulted in cyst resolution and confirmation of the benign nature of the cyst in 1 patient. All the procedures were successfully completed with no reported complications. CONCLUSION: The therapeutic use of endoscopic ultrasound in the pediatric population is safe and has a high success rate. PMID- 26655136 TI - Comparison of first-year results of tenofovir and entecavir treatments of nucleos(t)ide-naive chronic hepatitis B patients with hepatosteatosis. AB - BACKGROUND/AIM: Hepatic steatosis may influence the response to antivirals in chronic hepatitis B patients. This study aimed to compare the efficacy of entecavir and tenofovir in nucleos(t) ide-naive chronic hepatitis B patients with hepatosteatosis during 48 weeks of therapy. PATIENTS AND METHODS: We retrospectively reviewed our data for chronic hepatitis B patients. Nucleos(t) ide-naive patients with hepatosteatosis who took entecavir or tenofovir for at least 48 weeks were included. We compared entecavir and tenofovir after 48 weeks of therapy with respect to virological, biochemical, and serological responses in patients with hepatosteatosis. RESULTS: Of the 63 patients, 21 received entecavir and 42 received tenofovir. Baseline characteristics of the patients were similar except for body mass index. At the end of week 48, there was no statistically significant difference between tenofovir and entecavir treatment regarding total HBV-DNA negativity and alanine transferase normalization in patients with chronic hepatitis B and hepatosteatosis. CONCLUSIONS: Entecavir and tenofovir are similarly effective in nucleos(t)ide-naive chronic hepatitis B patients with hepatosteatosis after 48 weeks of therapy. PMID- 26655137 TI - Cardiac arrests in patients undergoing gastrointestinal endoscopy: A retrospective analysis of 73,029 procedures. AB - BACKGROUND/AIMS: Airway difficulties leading to cardiac arrest are frequently encountered during propofol sedation in patients undergoing gastrointestinal (GI) endoscopy. With a noticeable increase in the use of propofol for endoscopic sedation, we decided to examine the incidence and outcome of cardiac arrests in patients undergoing gastrointestinal (GI) endoscopy with sedation. PATIENTS AND METHODS: In this retrospective study, cardiac arrest data obtained from the clinical quality improvement and local registry over 5 years was analyzed. The information of patients who sustained cardiac arrest attributable to sedation was studied in detail. Analysis included comparison of cardiac arrests due to all causes until discharge (or death) versus the cardiac arrests and death occurring during the procedure and in the recovery area. RESULTS: The incidence of cardiac arrest and death (all causes, until discharge) was 6.07 and 4.28 per 10,000 in patients sedated with propofol, compared with non-propofol-based sedation (0.67 and 0.44). The incidence of cardiac arrest during and immediately after the procedure (recovery area) for all endoscopies was 3.92 per 10,000; of which, 72% were airway management related. About 90.0% of all peri-procedural cardiac arrests occurred in patients who received propofol. CONCLUSIONS: The incidence of cardiac arrest and death is about 10 times higher in patients receiving propofol based sedation compared with those receiving midazolam-fentanyl sedation. More than two thirds of these events occur during EGD and ERCP. PMID- 26655138 TI - The time course of cytokine expressions plays a determining role in faster healing of intestinal and colonic anastomatic wounds. AB - OBJECTIVES: Inflammation is critical in the early phases of wound healing. It has been reported previously that small intestinal and colonic wounds display a more rapid healing than those of other organs. However, the underlying mechanism has not yet been elucidated. Here we examined whether differences in the time course of specified cytokine expression, in colonic and small intestinal anastomotic lesions, might play a major role in this observation in comparison to lesions effecting skin and muscle tissue. MATERIALS AND METHODS: Tissue lesions were applied to 36 male Sprague-Dawley rats. Tissue samples were harvested at 1, 3, 5, 7, and 14 days postoperatively with the levels of TNF-alpha, IL-6, and IFN-alpha determined by ELISA-derived methods. RESULTS: The characteristics of TNF-alpha, IL-6, and IFN-alpha expression during the healing process for intestinal and colonic lesions were comparable. However, data differed significantly with that observed during healing of skin and muscle lesions. Intestinal and colonic lesions exhibited a significant and sustained increase in specified cytokine levels on day 5 to day 14 as compared with day 1 and 3. Skin and muscle lesions had random or unaltered cytokine levels throughout the study period. CONCLUSION: Differences in expression of cytokines TNF-alpha, IL-6, and IFN-alpha indicate that these play an important role underlying the more rapid healing processes observed in small intestinal and colonic lesions. PMID- 26655139 TI - Blue mode imaging may improve the detection and visualization of small-bowel lesions: A capsule endoscopy study. AB - BACKGROUND/AIMS: Diagnostic miss rate and time consumption are the two challenging limitations of small-bowel capsule endoscopy (SBCE). In this study, we aimed to know whether using of the blue mode (BM) combined with QuickView (QV) at a high reviewing speed could influence SBCE interpretation and accuracy. MATERIALS AND METHODS: Seventy CE procedures were totally reviewed in four different ways; (1) using the conventional white light, (2) using the BM, [on a viewing speed at 10 frames per second (fps)], (3) using white light, and (4) using the BM (on a viewing speed at 20 fps). In study A, the results of (1) were compared with those of (2), and in study B, the results of (3) and (4) were separately compared with those of (1). RESULTS: In study A, the total number of the vascular (P < 0.001) and the inflammatory lesions (P = 0.005) detected by BM was significantly higher than that detected by the white light. No lesion was found using the white light that was not detected by the BM. Moreover, the BM highly improved the image quality of all the vascular lesions and the erythematous ones from the nonvascular lesions. In study B, the total number of only the vascular lesions, detected by the BM on a rapid speed of viewing at 20 fps was significantly higher than that detected by the white light (P = 0.035). However, the true miss rate for the BM was 4%. CONCLUSION: BM imaging is a new method that improved the detection and visualization of the vascular and erythematous nonvascular lesions of SB as compared with the conventional white light imaging. Using of the BM at a slow viewing speed, markedly reduced the diagnostic miss rate of CE. PMID- 26655140 TI - Gastric calcifying fibrous tumor: A case of suspected immunoglobulin G4-related gastric disease. AB - Gastrointestinal lesions resulting from immunoglobulin G4-related disease are classified into two types: One is a gastrointestinal lesion showing marked thickening of the wall, and the other is an IgG4-related pseudotumor. We report the case of a woman with gastric calcifying fibrous tumor undergoing endoscopic resection that contained 62 IgG4+ plasma cells per high-power field and an IgG4 to-IgG ratio of 41% in lesional plasma cells, which shared clinical and histopathological features associated with gastric IgG4-related pseudotumor. So, we postulate that calcifying fibrous tumor as part of the spectrum of IgG4 related disease might be the unifying concept with IgG4-related pseudotumor. Meanwhile, the patient had coexistent autoimmune diseases, including autoimmune atrophic gastritis, Hashimoto's thyroiditis, and possible primary biliary cirrhosis. The clinical follow-up evaluation was uneventful. PMID- 26655141 TI - Electronic enhancement of tear secretion. AB - OBJECTIVE: To study electrical stimulation of the lacrimal gland and afferent nerves for enhanced tear secretion, as a potential treatment for dry eye disease. We investigate the response pathways and electrical parameters to safely maximize tear secretion. APPROACH: We evaluated the tear response to electrical stimulation of the lacrimal gland and afferent nerves in isofluorane-anesthetized rabbits. In acute studies, electrical stimulation was performed using bipolar platinum foil electrodes, implanted beneath the inferior lacrimal gland, and a monopolar electrode placed near the afferent ethmoid nerve. Wireless microstimulators with bipolar electrodes were implanted beneath the lacrimal gland for chronic studies. To identify the response pathways, we applied various pharmacological inhibitors. To optimize the stimulus, we measured tear secretion rate (Schirmer test) as a function of pulse amplitude (1.5-12 mA), duration (0.1 1 ms) and repetition rate (10-100 Hz). MAIN RESULTS: Stimulation of the lacrimal gland increased tear secretion by engaging efferent parasympathetic nerves. Tearing increased with stimulation amplitude, pulse duration and repetition rate, up to 70 Hz. Stimulation with 3 mA, 500 MUs pulses at 70 Hz provided a 4.5 mm (125%) increase in Schirmer score. Modulating duty cycle further increased tearing up to 57%, compared to continuous stimulation in chronically implanted animals (36%). Ethmoid (afferent) nerve stimulation increased tearing similar to gland stimulation (3.6 mm) via a reflex pathway. In animals with chronically implanted stimulators, a nearly 6 mm increase (57%) was achieved with 12-fold less charge density per pulse (0.06-0.3 MUC mm(-2) with 170-680 MUs pulses) than the damage threshold (3.5 MUC mm(-2) with 1 ms pulses). SIGNIFICANCE: Electrical stimulation of the lacrimal gland or afferent nerves may be used as a treatment for dry eye disease. Clinical trials should validate this approach in patients with aqueous tear deficiency, and further optimize electrical parameters for maximum clinical efficacy. PMID- 26655142 TI - Total Fluoride Intake by Children from a Tropical Brazilian City. AB - The main sources of fluoride intake by children are fluoridated water and toothpaste. Little has been studied regarding fluoride intake from these sources in regions with tropical climates and high temperatures throughout the year. This study aimed to determine the amount of fluoride ingested from diet and tooth brushing by children who live in a city with a tropical climate. Sixty-seven children from Teresina, Piaui, Brazil, took part in this study. The city's water supply was optimally fluoridated. The duplicate-diet method was used to determine the fluoride intake from diet. The intake of fluoride from dentifrice was determined by subtracting the amount of fluoride placed on the toothbrush and that recovered after brushing. The concentration of fluoride was measured using an ion-specific electrode and is expressed as milligrams/kilogram of body weight/day. The mean (+/-SD) total amount was 0.071 +/- 0.036 mg F/kg body weight/day, and the relative contributions of diet and toothpaste were 0.025 +/- 0.010 and 0.046 +/- 0.035, respectively. The factors associated with fluoride intake from toothpaste were: use of children's toothpaste (p = 0.003), use of large amounts of toothpaste (p < 0.001), and a high frequency of tooth brushing (p = 0.003). Sixty-four percent of children had an intake of less than 0.07 mg F/kg body weight/day, which is considered the upper limit for an aesthetically tolerable fluorosis risk. The results suggest that the amount of fluoride ingested by most children who live in a Brazilian city with a tropical climate is considered safe in terms of the risk of dental fluorosis. PMID- 26655143 TI - Mycobacterium tuberculosis PE27 activates dendritic cells and contributes to Th1 polarized memory immune responses during in vivo infection. AB - A gradual understanding of the proline-glutamate (PE) and proline-proline glutamate (PPE) families, which compromise 10% of the coding regions in the Mycobacterium tuberculosis (Mtb) genome, has uncovered unique roles in host pathogen interactions. However, the immunological function of PE27 (Rv2769c), the largest PE member, remains unclear. Here, we explored the functional roles and related signaling mechanisms of PE27 in the interaction with dendritic cells (DCs) to shape the T cell response. PE27 phenotypically and functionally induces DC maturation by up-regulating CD80, CD86, MHC class I and MHC class II expression on the DC surface to promote the production of TNF-alpha, IL-1beta, IL 6, and IL-12p70 but not IL-10. Additionally, we found that PE27-mediated DC activation requires the participation of mitogen-activated protein kinases (MAPKs) and nuclear factor kappaB (NF-kappaB) signaling pathways. Interestingly, PE27-treated DCs directed naive CD4(+) T cells to secrete IFN-gamma and activate T-bet but not GATA-3. PE27 also induced IFN-gamma-producing memory T cell responses in Mtb-infected mice, indicating that PE27 contributes to Th1 polarization. Taken together, these findings suggest that PE27 possesses Th1 polarizing potential through DC maturation and could be useful in the design of TB vaccines. PMID- 26655144 TI - Lower activation-induced T-cell apoptosis is related to the pathological immune response in secondary infection with hetero-serotype dengue virus. AB - The available evidence suggests that dengue virus-specific T lymphocytes and cytokine storm play a pivotal role in the immunopathogenesis of plasma leakage. Investigations are underway to identify the immune profiles associated with increased or decreased risk for severe disease. In this study, CD14+ cells from the peripheral blood mononuclear cells (PBMCs) of patients who recovered from DENV-1 infection were infected with DENV-1 or DENV-2 and co-cultured with memory T cells. We found that secondary infection with DENV-2 suppresses the cell reproductive capacity but forms more cell clones and more functional cells to produce more proinflammatory factors (IFN-gamma, TNF-alpha, IL-6, IL-8, IL-12 and IL-17) and less regulatory cytokines (IL-10, TGF-beta) which results in higher viral replication compared to secondary infection with DENV-1. Memory dengue virus-specific T cells which are induced in a primary dengue virus infection are reactivated by the heterologous serotype of dengue virus and antigen-presenting cells (APCs) during a secondary infection. Dramatically, less apoptosis and more continuous activation of T cells in secondary infection with hetero-serotype DENV were observed. This discovery which has not been reported previously may be the reasonable and vital interpretation for the cytokine storm and severe symptoms observed in secondary infection with DENV. In summary, secondary infection with hetero-serotype DENV elicits the relatively pathological immune response while secondary infection with homologous-serotype DENV induces the relatively protective immune response by activation-induced cell death (AICD) of T cells. PMID- 26655145 TI - Time-Resolved Versus Integrated Transit Planar Dosimetry for Volumetric Modulated Arc Therapy: Patient-Specific Dose Differences During Treatment, a Proof of Principle. AB - PURPOSE: It is desirable that dosimetric deviations during radiation treatments are detected. Integrated transit planar dosimetry is commonly used to evaluate external beam treatments such as volumetric-modulated arc therapy. This work focuses on patient geometry changes which result in differences between the planned and the delivered radiation dose. Integrated transit planar dosimetry will average out some deviations. Novel time-resolved transit planar dosimetry compares the delivered dose of volumetric-modulated arc therapy to the planned dose at various time points. Four patient cases are shown where time-resolved transit planar dosimetry detects patient geometry changes during treatment. METHODS: A control point to control point comparison between the planned dose and the treatment dose of volumetric-modulated arc therapy beams is calculated using the planning computed tomography and the kV cone-beam computed tomography of the day and evaluated with a time-resolved gamma function. Results were computed for 4 patients treated with volumetric-modulated arc therapy, each showing an anatomical change: pleural effusion, rectal gas pockets, and tumor regression. RESULTS: In all cases, the geometrical change was detected by time-resolved transit planar dosimetry, whereas integrated transit planar dosimetry showed minor or no indication of the dose discrepancy. Both tumor regression cases were detected earlier in the treatment with time-resolved planar dosimetry in comparison to integrated transit planar dosimetry. The pleural effusion and the gas pocket were detected exclusively with time-resolved transit planar dosimetry. CONCLUSIONS: Clinical cases were presented in this proof-of-principle study in which integrated transit planar dosimetry did not detect dosimetrically relevant deviations to the same extent time-resolved transit planar dosimetry was able to. Time-resolved transit planar dosimetry also provides results that can be presented as a function of arc delivery angle allowing easier interpretation compared to integrated transit planar dosimetry. PMID- 26655146 TI - Cope's Rule and the Universal Scaling Law of Ornament Complexity. AB - Luxuriant, bushy antlers, bizarre crests, and huge, twisting horns and tusks are conventionally understood as products of sexual selection. This view stems from both direct observation and from the empirical finding that the size of these structures grows faster than body size (i.e., ornament size shows positive allometry). We contend that the familiar evolutionary increase in the complexity of ornaments over time in many animal clades is decoupled from ornament size evolution. Increased body size comes with extended growth. Since growth scales to the quarter power of body size, we predicted that ornament complexity should scale according to the quarter power law as well, irrespective of the role of sexual selection in the evolution and function of the ornament. To test this hypothesis, we selected three clades (ammonites, deer, and ceratopsian dinosaurs) whose species bore ornaments that differ in terms of the importance of sexual selection to their evolution. We found that the exponent of the regression of ornament complexity to body size is the same for the three groups and is statistically indistinguishable from 0.25. We suggest that the evolution of ornament complexity is a by-product of Cope's rule. We argue that although sexual selection may control size in most ornaments, it does not influence their shape. PMID- 26655147 TI - Causes of Discordance between Allometries at and above Species Level: An Example with Aquatic Beetles. AB - Covariation among organismal traits is nearly universal, occurring both within and among species (static and evolutionary allometry, respectively). If conserved developmental processes produce similarity in static and evolutionary allometry, then when species differ in development, it should be expressed in discordance between allometries. Here, we investigate whether rapidly evolving developmental processes result in discordant static and evolutionary allometries attributable to trade-offs in resource acquisition, allocation, or growth across 30 species of aquatic beetles. The highly divergent sperm phenotypes of these beetles might be an important contributor to allometric evolution of testis and accessory gland mass through altered requirements for the production of sperm and seminal fluids. We documented extensive discordance between static and evolutionary allometries, indicating that allometric relationships are flexibly modified over short time periods but subject to constraint over longer time spans. Among species, sperm phenotype did not influence relative investment in accessory glands but was weakly associated with investment in testes. Furthermore, except when sperm were long and simple, sperm phenotype was not associated with species-specific modification of the allometry of testis/accessory gland mass and body size. Our results demonstrate the utility of allometric discordance to infer species differences in the provisioning and growth of concurrently developing traits. PMID- 26655148 TI - Interpopulation Variation in a Condition-Dependent Signal: Predation Regime Affects Signal Intensity and Reliability. AB - In many models of sexual selection, conspicuous ornaments are preferred by mates because they indicate heritable signaler viability. To function as indicators, ornaments must exhibit a proportional relationship between expression and viability. In cases where the evolutionary interests of signaler and receiver diverge, selection favors exploitative exaggeration by low-viability individuals producing unreliable signals. Theory suggests that the evolutionary stability of such communication systems requires costs that prevent low-viability males from expressing disproportionately intense signals. Therefore, given ecological variation in signaling cost, the reliability of signaling systems will vary concomitantly. In this study, we assess the effect of a variable signal cost, predation, on signal intensity and reliability among 16 populations of Bahamas mosquitofish (Gambusia hubbsi) that use colorful dorsal fins in courtship displays. We found that fin coloration was more intense in low-predation sites and could be used to predict body condition. However, this predictive relationship was apparent only in populations subject to predation risk. We demonstrate an important role for ecological signaling cost in communication and show that ecological heterogeneity drives interpopulation variation in both the intensity and the reliability of a sexual signal. PMID- 26655149 TI - Energy and the Scaling of Animal Space Use. AB - Daily animal movements are usually limited to a discrete home range area that scales allometrically with body size, suggesting that home-range size is shaped by metabolic rates and energy availability across species. However, there is little understanding of the relative importance of the various mechanisms proposed to influence home-range scaling (e.g., differences in realm productivity, thermoregulation, locomotion strategy, dimensionality, trophic guild, and prey size) and whether these extend beyond the commonly studied birds and mammals. We derive new home-range scaling relationships for fishes and reptiles and use a model-selection approach to evaluate the generality of home range scaling mechanisms across 569 vertebrate species. We find no evidence that home-range allometry varies consistently between aquatic and terrestrial realms or thermoregulation strategies, but we find that locomotion strategy, foraging dimension, trophic guild, and prey size together explain 80% of the variation in home-range size across vertebrates when controlling for phylogeny and tracking method. Within carnivores, smaller relative prey size among gape-limited fishes contributes to shallower scaling relative to other predators. Our study reveals how simple morphological traits and prey-handling ability can profoundly influence individual space use, which underpins broader-scale patterns in the spatial ecology of vertebrates. PMID- 26655150 TI - Macronutrient Balance Modulates the Temperature-Size Rule in an Ectotherm. AB - Most ectotherms mature at a larger body size in colder conditions, a phenomenon known as the temperature-size rule. While a number of hypotheses have been proposed to explain this rule, little work has been done to understand it from a nutritional perspective. We have used the final-instar caterpillars of Spodoptera litura to investigate how dietary protein?carbohydrate (P?C) balance influences the relationship between temperature and body size. The strength and direction of the thermal reaction norm for body size were significantly altered by dietary P?C balance. The slope of the reaction norm was nearly flat for caterpillars raised on a balanced food ([Formula: see text]) but was significantly negative for those on nutritionally imbalanced foods (1?5 or 5?1), especially when carbohydrates were in considerable excess. These nutrient-dependent effects of temperature on body size were caused mainly by corresponding changes in body lipid storage. When allowed to choose between imbalanced diets, caterpillars increased their preference for carbohydrates to meet high energy demands at higher temperatures. The slope of the thermal reaction norm for body size was substantially reduced by such a temperature-driven shift in nutrient preference, indicating that the impact of high temperature on body size was buffered by altered food selection. This study highlights the importance of macronutrient balance as a key factor modulating the relationship between temperature and body size in ectotherms and provides a novel approach for understanding the temperature-size rule. PMID- 26655151 TI - Adult Mortality Probability and Nest Predation Rates Explain Parental Effort in Warming Eggs with Consequences for Embryonic Development Time. AB - Parental behavior and effort vary extensively among species. Life-history theory suggests that age-specific mortality could cause this interspecific variation, but past tests have focused on fecundity as the measure of parental effort. Fecundity can cause costs of reproduction that confuse whether mortality is the cause or the consequence of parental effort. We focus on a trait, parental allocation of time and effort in warming embryos, that varies widely among species of diverse taxa and is not tied to fecundity. We conducted studies on songbirds of four continents and show that time spent warming eggs varies widely among species and latitudes and is not correlated with clutch size. Adult and offspring (nest) mortality explained most of the interspecific variation in time and effort that parents spend warming eggs, measured by average egg temperatures. Parental effort in warming eggs is important because embryonic temperature can influence embryonic development period and hence exposure time to predation risk. We show through correlative evidence and experimental swapping of embryos between species that parentally induced egg temperatures cause interspecific variation in embryonic development period. The strong association of age-specific mortality with parental effort in warming eggs and the subsequent effects on embryonic development time are unique results that can advance understanding of broad geographic patterns of life-history variation. PMID- 26655152 TI - How Oviposition Behavior Determines Persistence in Small Patches and Changing Climates. AB - Habitat loss and climate change jointly threaten a large fraction of earth's biodiversity. A key goal is to understand how these threats play out differentially across species. Focusing on insects that undergo an ontogenetic shift in habitat requirements, we use critical patch size models to examine how breeding strategy influences the abilities of different kinds of species to persist in small habitat patches. In general, we find that income breeders require larger habitat patches for population persistence than do capital breeders. However, increases in patch size requirements as a result of factors that limit oviposition (e.g., resource availability, weather conditions) are more severe for capital breeders than for income breeders. From a conservation perspective, our work suggests that a species' sensitivity to habitat loss, both today and in the future, can depend critically on evolved behavioral strategies. Explicit consideration of such behavioral strategies, including a careful accounting of their relationship with dispersal and survival, provides a map linking life-history spectra, spatial requirements, and management. PMID- 26655153 TI - Host Genotype and Coinfection Modify the Relationship of within and between Host Transmission. AB - Variation in individual-level disease transmission is well documented, but the underlying causes of this variation are challenging to disentangle in natural epidemics. In general, within-host replication is critical in determining the extent to which infected hosts shed transmission propagules, but which factors cause variation in this relationship are poorly understood. Here, using a plant host, Plantago lanceolata, and the powdery mildew fungus Podosphaera plantaginis, we quantify how the distinct stages of within-host spread (autoinfection), spore release, and successful transmission to new hosts (alloinfection) are influenced by host genotype, pathogen genotype, and the coinfection status of the host. We find that within-host spread alone fails to predict transmission rates, as this relationship is modified by genetic variation in hosts and pathogens. Their contributions change throughout the course of the epidemic. Host genotype and coinfection had particularly pronounced effects on the dynamics of spore release from infected hosts. Confidently predicting disease spread from local levels of individual transmission, therefore, requires a more nuanced understanding of genotype-specific infection outcomes. This knowledge is key to better understanding the drivers of epidemiological dynamics and the resulting evolutionary trajectories of infectious disease. PMID- 26655154 TI - Testing the Plant Growth-Defense Hypothesis Belowground: Do Faster-Growing Herbaceous Plant Species Suffer More Negative Effects from Soil Biota than Slower Growing Ones? AB - According to the growth-defense hypothesis in ecology, faster-growing plant species should suffer more from herbivores and pathogens than slower-growing species. Tests of this hypothesis have focused on aboveground plant tissues, herbivores, and pathogens; however, it should also apply to root defense. To test whether faster-growing species suffer more negatively from soil biota than slower growing species, we estimated first-season growth rates of 34 herbaceous plant species and used weighted linear regressions to assess the relationship between growth rates and responses to being grown in sterilized versus unsterilized soil (biotic soil effects) and to growing in soil previously occupied by conspecifics versus a mixture of species (conspecific soil effects). We found a negative relationship between relative growth rate and biotic soil effects, with slower growing species tending to suffer less or even benefit from the presence of soil biota, while faster-growing species were more negatively affected. Biotic soil effects were also negatively related to size-corrected growth rates. These relationships remained negative after accounting for influential species, but a large amount of variation remained unexplained. Moreover, there was no clear relationship between growth rates and conspecific soil effects. A simple relationship between growth and defense aboveground may not be so clearly reflected belowground because of the many interacting antagonistic and mutualistic organisms likely involved. PMID- 26655155 TI - Intraspecific Niche Variation Drives Abundance-Occupancy Relationships in Freshwater Fish Communities. AB - A positive relationship between occupancy and average local abundance of species is found in a variety of taxa, yet the mechanisms driving this association between abundance and occupancy are still enigmatic. Here we show that freshwater fishes exhibit a positive abundance-occupancy relationship across 125 Swedish lakes. For a subset of 9 species from 11 lakes, we estimated species-specific diet breadth from stable isotopes, within-lake habitat breadth from catch data for littoral and pelagic nets, adaptive potential from genetic diversity, abiotic niche position, and dispersal capacity. Average local abundance was mainly positively associated with both within-lake habitat and diet breadth, that is, species with larger intraspecific variation in niche space had higher abundances. No measure was a good predictor of occupancy, indicating that occupancy may be more directly related to abundance or abiotic conditions than to niche breadth per se. This study suggests a link between intraspecific niche variation and a positive abundance-occupancy relationship and implies that management of freshwater fish communities, whether to conserve threatened or control invasive species, should initially be aimed at niche processes. PMID- 26655156 TI - Potential Leaders Trade Off Goal-Oriented and Socially Oriented Behavior in Mobile Animal Groups. AB - Leadership is widespread across the animal kingdom. In self-organizing groups, such as fish schools, theoretical models predict that effective leaders need to balance goal-oriented motion, such as toward a known resource, with their tendency to be social. Increasing goal orientation is predicted to increase decision speed and accuracy, but it is also predicted to increase the risk of the group splitting. To test these key predictions, we trained fish (golden shiners, Notemigonus crysoleucas) to associate a spatial target with a food reward ("informed" individuals) before testing each singly with a group of eight untrained fish who were uninformed ("naive") about the target. Informed fish that exhibited faster and straighter paths (indicative of greater goal orientation) were more likely to reach their preferred target and did so more quickly. However, such behavior was associated with a tendency to leave untrained fish behind and, therefore, with failure to transmit their preference to others. Either all or none of the untrained fish stayed with the trained fish in the majority of trials. Using a simple model of self-organized coordination and leadership in groups, we recreate these features of leadership observed experimentally, including the apparent consensus behavior among naive individuals. Effective leadership thus requires informed individuals to appropriately balance goal-oriented and socially oriented behavior. PMID- 26655157 TI - Reproduction in Flame Azalea (Rhododendron calendulaceum, Ericaceae): A Rare Case of Insect Wing Pollination. AB - Although many angiosperms are serviced by flying pollinators, reports of wings as pollen vectors are rare. Flame azalea (Rhododendron calendulaceum) is visited by diverse insects, yet previous observations suggested that only butterfly wings may transfer pollen to stigmas. We used an experimental approach to determine whether butterfly wings are the primary vehicle of pollination in flame azalea. Over two seasons of observations, only butterflies (Papilio glaucus and Speyeria cybele) contacted both anthers and stigmas, yet because of differences in wing flapping behavior, P. glaucus transferred pollen most efficiently. In contrast, bee species specialized either on pollen or nectar but did not contact both anthers and stigmas. A field experiment revealed that flowers excluding butterflies experienced almost complete fruit failure, whereas fruit set in open flowers did not differ from those that were hand pollinated. Additionally, butterflies had 56-fold more azalea pollen on their wings than bodies, while azalea stigmas bore both pollen and wing scales. These results suggest that plants with many visitors contacting reproductive organs may still specialize on a single guild of visitors for pollination and that wing-borne pollen transfer is a key mode of flame azalea pollination. PMID- 26655158 TI - Workforce Effects and the Evolution of Complex Sociality in Wild Damaraland Mole Rats. AB - Explaining the evolution of eusocial and cooperatively breeding societies demands that we understand the effects of workforce size on the reproductive success of breeders. This challenge has yet to be addressed in the family that arguably exhibits the most extreme outcomes of vertebrate social evolution, the African mole rats (Bathyergidae), leaving the ultimate causes of their many unusual adaptations open to debate. Here we report-using a 14-year field study of wild Damaraland mole rats, Fukomys damarensis-that workers appear to have strong but unusual effects on offspring. Groups with larger workforces exhibited substantially higher rates of offspring recruitment while maintaining high juvenile survival rates, relationships that may have favored the evolution of the delayed dispersal, cooperation, morphological specialization, and unusual patterns of longevity that characterize such societies. Offspring reared by larger workforces also showed slower growth, however. That reduced offspring growth in larger groups has also been documented under ad lib. food conditions in the laboratory raises the possibility that this reflects socially induced growth restraint rather than simple constraints on resource availability. Our findings shed new light on the evolution of complex sociality in this enigmatic clade and highlight further departures from the norms reported for other cooperative vertebrates. PMID- 26655159 TI - A Potential Case of Reinforcement in a Facultatively Sexual Unicellular Eukaryote. AB - The origin of a new species requires a mechanism to prevent divergent populations from interbreeding. In the classic allopatric model, divided populations evolve independently and accumulate genetic differences. If contact is restored, hybrids suffer reduced fitness and selection may favor traits that prevent mistakes in mating, a process known as reinforcement. This decisive but transient phase is challenging to document and has been reported mostly in macroorganisms. Very little is known about the processes through which new microbial species originate. In particular, it is unclear whether microbial eukaryotes, many of which can reproduce sexually during complex life cycles, speciate in much the same way as do well-studied plants and animals. Using individual cellular mate choice trials, we investigated the mating behavior of sympatric and allopatric woodland populations of the yeast Saccharomyces paradoxus. We find evidence consistent with reinforcement, potentially representing an example of microbial speciation in progress. PMID- 26655160 TI - Model Adequacy and the Macroevolution of Angiosperm Functional Traits. AB - Making meaningful inferences from phylogenetic comparative data requires a meaningful model of trait evolution. It is thus important to determine whether the model is appropriate for the data and the question being addressed. One way to assess this is to ask whether the model provides a good statistical explanation for the variation in the data. To date, researchers have focused primarily on the explanatory power of a model relative to alternative models. Methods have been developed to assess the adequacy, or absolute explanatory power, of phylogenetic trait models, but these have been restricted to specific models or questions. Here we present a general statistical framework for assessing the adequacy of phylogenetic trait models. We use our approach to evaluate the statistical performance of commonly used trait models on 337 comparative data sets covering three key angiosperm functional traits. In general, the models we tested often provided poor statistical explanations for the evolution of these traits. This was true for many different groups and at many different scales. Whether such statistical inadequacy will qualitatively alter inferences drawn from comparative data sets will depend on the context. Regardless, assessing model adequacy can provide interesting biological insights how and why a model fails to describe variation in a data set give us clues about what evolutionary processes may have driven trait evolution across time. PMID- 26655161 TI - A Process-Independent Explanation for the General Form of Taylor's Law. AB - Taylor's law (TL) describes the scaling relationship between the mean and variance of populations as a power law. TL is widely observed in ecological systems across space and time, with exponents varying largely between 1 and 2. Many ecological explanations have been proposed for TL, but it is also commonly observed outside ecology. We propose that TL arises from the constraining influence of two primary variables: the number of individuals and the number of censuses or sites. We show that most possible configurations of individuals among censuses or sites produce the power-law form of TL, with exponents between 1 and 2. This "feasible set" approach suggests that TL is a statistical pattern driven by two constraints, providing an a priori explanation for this ubiquitous pattern. However, the exact form of any specific mean-variance relationship cannot be predicted in this way, that is, this approach does a poor job of predicting variation in the exponent, suggesting that TL may still contain ecological information. PMID- 26655162 TI - Hamilton's Rule. PMID- 26655163 TI - Evaluation of acute tryptophan depletion and sham depletion with a gelatin-based collagen peptide protein mixture. AB - Acute Tryptophan Depletion (ATD) is a dietary method used to modulate central 5 HT to study the effects of temporarily reduced 5-HT synthesis. The aim of this study is to evaluate a novel method of ATD using a gelatin-based collagen peptide (CP) mixture. We administered CP-Trp or CP+Trp mixtures to 29 healthy volunteers; 13 from a randomized, double-blinded crossover study and sixteen from a randomized, double-blinded study run in our laboratory. Plasma amino acids, mood, side effects, cortisol concentrations, mean arterial blood pressure and heart rate were measured at multiple time-points. Repeated measures analysis of variance and Wilcoxon or Mann-Whitney U non-parametric tests were used to analyze the effects of intervention. Intake of the CP-Trp mixture efficiently reduced plasma Trp; however, the CP+Trp mixture induced a large significant increase in plasma Trp. No other significant effects of CP-Trp compared to CP+Trp were observed. The transient increase in plasma Trp after CP+Trp may impair comparison to the CP-Trp and we therefore recommend in future studies to use a smaller dose of Trp supplement to the CP mixture. PMID- 26655164 TI - Neuroprotective effects of dexmedetomidine conditioning strategies: Evidences from an in vitro model of cerebral ischemia. AB - AIMS: Dexmedetomidine is a selective agonist of alpha2-adrenergic receptors with clinical anesthetic and analgesic properties that has also shown neuroprotective effects on several models of brain injury. Because perioperative stroke and brain damage are frequent causes of death in critical care units, we aimed to investigate neuroprotective properties of dexmedetomidine using an in vitro model of cerebral ischemia. MAIN METHODS: Primary mixed rat brain cortical cultures were subjected to oxygen and glucose deprivation and treated with different doses of dexmedetomidine in order to analyze three conditioning strategies: preconditioning, intraconditioning and postconditioning. KEY FINDINGS: All dexmedetomidine pre-, intra- and postconditioning treatments showed neuroprotective effects reducing brain cell necrosis, although only preconditioning showed antiapoptotic effects. Dexmedetomidine treatments also reduced IL-6 and TNF-alpha levels, especially in the preconditioning groups. Oxidative stress was attenuated with all dexmedetomidine preconditioning treatments, but only with the higher dose in the intraconditioning group, and no effects were observed in the postconditioning. All conditioning strategies increased BDNF levels. SIGNIFICANCE: Dexmedetomidine-mediated neuroprotective effects in an in vitro model of cerebral ischemia involve the attenuation of inflammation and oxidative stress and the increment of BDNF expression. PMID- 26655165 TI - Vesicovascular reflexes in the spontaneously hypertensive rat. AB - AIMS: We investigated the effects of hypertension and acute blood pressure changes on rats' vesicovascular reflexes (VVRs). MAIN METHODS: Twelve-week-old male Wistar rats and spontaneously hypertensive rats (SHRs) were anesthetized with urethane, and underwent real-time cystometry and blood pressure monitoring. The SHRs were administered nifedipine or valsartan intravenously. The Wistar rats were administered intravenous noradrenaline continuously. The intercontraction intervals, maximum detrusor pressures, blood pressure during the voiding and the urine storage phases, blood pressure elevations associated with the VVRs, and arterial pulses were assessed. Plasma adrenaline and noradrenaline concentrations were measured using HPLC. The degree of atherosclerosis was assessed histologically based on the aortic wall thickness. KEY FINDINGS: Blood pressure elevations associated with the voiding reflexes were significantly lower and intercontraction intervals were significantly shorter in the SHRs compared with the Wistar rats. Although nifedipine and valsartan reduced the systolic blood pressure and noradrenaline increased the systolic blood pressure, they failed to alter the blood pressure elevations associated with the VVRs and the intercontraction intervals. No significant differences occurred with respect to the maximum detrusor pressures among the experimental groups. The reflected waves' shapes were normal in the Wistar rats, but they almost disappeared in the SHRs. The aortic walls were significantly thicker in SHRs compared with those in Wistar rats. SIGNIFICANCE: The blood pressure elevations associated with the VVRs were lower in the SHRs than in the Wistar rats. Acute blood pressure reductions failed to ameliorate the blood pressure elevations associated with VVRs in the SHRs. PMID- 26655166 TI - Diets with different lipid contents do not modify the neuronal membrane lipid raft profile in a scrapie murine model. AB - In Transmissible Spongiform Encephalopathies (TSEs), the localization of the prion protein in the neuronal membrane lipid rafts (LR) seems to play a role in sustaining the protein misfolding. Changes in membrane properties, due to altered lipid composition, affect their organization and interaction between lipids and protein therein, and consequently also membrane resident protein functionality; dietary polyunsaturated fatty acids (PUFAs), gangliosides and cholesterol seem to influence these processes. AIMS: In this work, the influence of administration of different feed, able to change the composition of lipid membrane, on the clinical progression of prion disease was studied. MAIN METHODS: The activity of three diets (hyperlipidic with 6% fats; hypolipidic with 0.1% fats; and purified with 4% fats) was tested in CD1 mouse model experimentally infected with RML scrapie strain. Presence and distribution of typical central nervous system (CNS) lesions and deposits of PrP(sc) were evaluated by histopathological analysis and immunohistochemistry. Analysis of lipids was performed in homogenate and insoluble brain fraction of the neuronal membrane rich in LR. KEY FINDINGS: Results show that a diet with a different lipid level has not a significant role in the development of the scrapie disease. All infected mice fed with different diets died in the same time span. Histology, immunohistochemistry, and neuropathological analyses of the infected brains did not show significant differences between animals subjected to different diets. SIGNIFICANCE: Independently of the diet, the infection induced a significant modification of the lipid composition in homogenates, and a less noticeable one in insoluble brain fraction. PMID- 26655168 TI - Cervical Cytology Reporting Rates from China's Largest College of American Pathologists-Certified Laboratory with a Focus on Squamous Cell Carcinoma Cytology and Its Histopathological Follow-Up Results. AB - OBJECTIVE: No organized cervical screening programs or national cervical cytology quality control standards currently exist in China. This study reported cervical cytology performance in China's largest independent laboratory with accreditation from the College of American Pathologists. DESIGN: Results from over 2 million Papanicolaou (Pap) tests by the KingMed Diagnostics Laboratory were categorized according to The Bethesda System (TBS) from 2007 and 2014. Pap reports and histopathologic follow-up results of squamous cell carcinomas (SCC) were analyzed. RESULTS: Data on 676,445 conventional Pap smears (CPS) and 1,696,284 liquid-based cytology (LBC) specimens were available. Abnormality rates reported were significantly higher with LBC than with CPS in all TBS categories (p < 0.001). A total of 800 SCC cytology reports were identified, representing a laboratory SCC reporting rate of 0.0337%. The SCC reporting rate with LBC (0.0457%) was significantly higher than the reporting rate with CPS. Histopathologic invasive cervical carcinoma and cervical intraepithelial neoplasia 2/3 were diagnosed in 80.7 and 17.6% of the 119 patients with SCC Pap cytology. CONCLUSIONS: Reporting rates for most TBS categories from this CAP accredited laboratory in China were within the CAP benchmark ranges except for low atypical glandular cell and unsatisfactory case rates. Histological follow-up results in patients with SCC cytology reports demonstrate very high specificity of SCC Pap cytology. PMID- 26655167 TI - Three-dimensional tumor spheroids for in vitro analysis of bacteria as gene delivery vectors in tumor therapy. AB - BACKGROUND: Several studies in animal models demonstrated that obligate and facultative anaerobic bacteria of the genera Bifidobacterium, Salmonella, or Clostridium specifically colonize solid tumors. Consequently, these and other bacteria are discussed as live vectors to deliver therapeutic genes to inhibit tumor growth. Therapeutic approaches for cancer treatment using anaerobic bacteria have been investigated in different mouse models. In the present study, solid three-dimensional (3D) multicellular tumor spheroids (MCTS) of the colorectal adenocarcinoma cell line HT-29 were generated and tested for their potential to study prodrug-converting enzyme therapies using bacterial vectors in vitro. RESULTS: HT-29 MCTS resembled solid tumors displaying all relevant features with an outer zone of proliferating cells and hypoxic and apoptotic regions in the core. Upon incubation with HT-29 MCTS, Bifidobacterium bifidum S17 and Salmonella typhimurium YB1 selectively localized, survived and replicated in hypoxic areas inside MCTS. Furthermore, spores of the obligate anaerobe Clostridium sporogenes germinated in these hypoxic areas. To further evaluate the potential of MCTS to investigate therapeutic approaches using bacteria as gene delivery vectors, recombinant bifidobacteria expressing prodrug-converting enzymes were used. Expression of a secreted cytosine deaminase in combination with 5-fluorocytosine had no effect on growth of MCTS due to an intrinsic resistance of HT-29 cells to 5-fluorouracil, i.e. the converted drug. However, a combination of the prodrug CB1954 and a strain expressing a secreted chromate reductase effectively inhibited MCTS growth. CONCLUSIONS: Collectively, the presented results indicate that MCTS are a suitable and reliable model to investigate live bacteria as gene delivery vectors for cancer therapy in vitro. PMID- 26655169 TI - Single Running Suture versus Single-Knot Running Suture for Vesicourethral Anastomosis in Laparoscopic Radical Prostatectomy: A Prospective Randomised Comparative Study. AB - AIM: To investigate the safety, surgical efficiency and patients' ability to recover from urinary continence as a result of a single absorbable running suture versus single-knot running suture for vesicourethral anastomosis (VUA) during laparoscopic radical prostatectomy (LRP). MATERIAL AND METHODS: In a prospective randomised study, we evaluated 162 consecutive patients who underwent LRP with VUA using the single running suture technique or the single-knot running suture technique. Perioperative patients' characteristics, morbidity and urinary continence were analysed. RESULTS: The baseline characteristics were similar between the 2 groups. The single running suture technique was related to decreased anastomotic and total operative times compared with the Van Velthoven technique (13.17 +/- 5.74 min vs. 28.49 +/- 6.45 min, p = 0.0001, and 174.41 +/- 62.97 min and 184.94 +/- 46.16 min, p = 0.04, respectively). Overall, urinary continence rates at 3, 6 and 12 months in groups 1 and 2 were 49.4 and 69.1%, 81.5 and 86.4%, and 91.4 and 93.8%, respectively (all with p > 0.05 except the follow-up assessment at 3 months following surgery, p = 0.011). CONCLUSIONS: Both methods ensure satisfactory rates of urinary leakage and bladder neck stricture, as well as continence after LRP. However, since the single running suture VUA technique is easier to perform, and the mean anastomosis time of the single running suture VUA technique is shorter than that of the Van Velthoven technique, it appears, therefore, preferable. PMID- 26655170 TI - Erratum. PMID- 26655173 TI - Defying ageing: An expectation for dentine bonding with universal adhesives? AB - OBJECTIVES: The present study evaluated the long-term dentine bonding effectiveness of five universal adhesives in etch-and-rinse or self-etch mode after 12 months of water-ageing. METHODS: The adhesives evaluated included All Bond Universal, Clearfil Universal Bond, Futurabond U Prime&Bond Elect and Scotchbond Universal. Microtensile bond strength and transmission electron microscopy of the resin-dentine interfaces created in human coronal dentine were examined after 24h or 12 months. RESULTS: Microtensile bond strength were significantly affected by bonding strategy (etch-and-rinse vs self-etch) and ageing (24h vs 12 months). All subgroups showed significantly decreased bond strength after ageing except for Prime&Bond Elect and Scotchbond Universal used in self-etch mode. All five adhesives employed in etch-and-rinse mode exhibited ultrastructural features characteristic of collagen degradation and resin hydrolysis. A previously-unobserved inside-out collagen degradation pattern was identified in hybrid layers created by 10-MDP containing adhesives (All-Bond Universal, Scotchbond Universal and Clearfil Universal Bond) in the etch-and rinse mode, producing partially degraded collagen fibrils with intact periphery and a hollow core. In the self-etch mode, all adhesives except for Prime&Bond Elect exhibited degradation of the collagen fibrils along the thin hybrid layers. The three 10-MDP containing universal adhesives did not protect surface collagen fibrils from degradation when bonding was performed in the self-etch mode. CONCLUSIONS: Despite the adjunctive conclusion that bonds created by universal adhesives in the self-etch bonding mode are more resistant to decline in bond strength when compared with those bonds created using the etch-and-rinse mode, bonds created by universal adhesives are generally incapable of defying ageing. PMID- 26655174 TI - HIV-1 Tat biosensor: Current development and trends for early detection strategies. AB - Human immunodeficiency virus (HIV) has infected almost 35 million people worldwide. Various tests have been developed to detect the presence of HIV during the early stages of the disease in order to reduce the risk of transmission to other humans. The HIV-1 Tat protein is one of the proteins present in HIV that are released abundantly approximately 2-4 weeks after infection. In this review, we have outlined various strategies for detecting the Tat protein, which helps transcribe the virus and enhances replication. Detection strategies presented include immunoassays, biosensors and gene expression, which utilize antibodies or aptamers as common probes to sense the presence of Tat. Alternatively, measuring the levels of gene transcription is a direct method of analysing the HIV gene to confirm the presence of Tat. By detection of the Tat protein, virus transmission can be detected in high-risk individuals in the early stages of the disease to reduce the risk of an HIV pandemic. PMID- 26655175 TI - DNA microarray-based solid-phase PCR on copoly (DMA-NAS-MAPS) silicon coated slides: An example of relevant clinical application. AB - In a previous study we developed a highly sensitive DNA microarray for the detection of common KRAS oncogenic mutations, which has been proven to be highly specific in assigning the correct genotype without any enrichment strategy even in the presence of minority mutated alleles. However, in this approach, the need of a spotter for the deposition of the purified PCR products on the substrates and the purification step of the conventional PCR are serious drawbacks. To overcome these limitations we have introduced the solid-phase polymerase chain reaction (SP-PCR) to form the array of PCR products starting from the oligonucleotide primers. This work was possible thanks to the great thermal stability of the copoly (DMA-NAS-MAPS) coating which withstands PCR thermal cycling temperatures. As an example of the application of this platform we performed the analysis of six common mutations in the codon 12 of KRAS gene (G12A, G12C, G12D, G12R, G12S, and G12V). In conclusion solid-phase PCR, combined with dual-color hybridization, allows mutation analysis in a shorter time span and is more suitable for automation. PMID- 26655176 TI - A novel bioelectronic tongue in vivo for highly sensitive bitterness detection with brain-machine interface. AB - Animals' gustatory system has been widely acknowledged as one of the most sensitive chemosensing systems, especially for its ability to detect bitterness. Since bitterness usually symbolizes inedibility, the potential to use rodent's gustatory system is investigated to detect bitter compounds. In this work, the extracellular potentials of a group of neurons are recorded by chronically coupling microelectrode array to rat's gustatory cortex with brain-machine interface (BMI) technology. Local field potentials (LFPs), which represent the electrophysiological activity of neural networks, are chosen as target signals due to stable response patterns across trials and are further divided into different oscillations. As a result, different taste qualities yield quality specific LFPs in time domain which suggests the selectivity of this in vivo bioelectronic tongue. Meanwhile, more quantitative study in frequency domain indicates that the post-stimulation power of beta and low gamma oscillations shows dependence with concentrations of denatonium benzoate, a prototypical bitter compound, and the limit of detection is deduced to be 0.076 MUM, which is two orders lower than previous in vitro bioelectronic tongues and conventional electronic tongues. According to the results, this in vivo bioelectronic tongue in combination with BMI presents a promising method in highly sensitive bitterness detection and is supposed to provide new platform in measuring bitterness degree. PMID- 26655177 TI - In-situ assembly of biocompatible core-shell hierarchical nanostructures sensitized immunosensor for microcystin-LR detection. AB - Microcystin-LR (MC-LR) is a kind of hepatotoxin which can cause functional and structural disturbances of the liver, accumulate in aquatic organisms and transfer to higher trophic levels, a biocompatible electrochemical immunosensor was constructed to detect MC-LR sensitively and selectively. The three dimensional villiform-like carbon nanotube/cobalt silicate (CNT@Co silicate) core shell nanocomposites were synthesized and firstly used as the substrate to immobilize the antigen of MC-LR (Ag), while Fe3O4 nanoclusters/polydopamine/gold nanoparticles (Fe3O4@PDA-Au) core-shell magnetic nanocomposites were prepared as the label carrier of the immunosensor to conjugate the second antibody (Ab2) and horse radish peroxidase (HRP). Since the toxicity of nanomaterials is important in the construction of biosensors including the immobilization of antigen or antibody, the biocompatibility of such nanocomposites were investigated by monitoring the cell viability after culturing with Hela cells. Due to the excellent biocompatibility, the immunosensor can immobilize more antigens by the large surface area of the three-dimensional villiform-like structure in CNT@Co silicate, and provide high electrochemical signals by Fe3O4@PDA-Au labeled Ab2 and HRP. After investigation of the binding capability of biomolecules on nanomaterials and optimization of the conditions in the competitive immunoassay, the proposed electrochemical immunosensor shows a linear response to MC-LR in the range from 0.005 MUg/L to 50 MUg/L with a detection limit of 0.004 MUg/L. In addition, the specificity, reproducibility and stability of the immunosensor were also proved to be acceptable, indicating its potential application in environmental monitoring. PMID- 26655178 TI - Biofuel cell backpacked insect and its application to wireless sensing. AB - This study investigated an enzymatic biofuel cell (BFC) which can be backpacked by cockroaches. The BFC generates electric power from trehalose in insect hemolymph by the trehalase and glucose dehydrogenase (GDH) reaction systems which dehydrogenate beta-glucose obtained by hydrolyzing trehalose. First, an insect mountable BFC (imBFC) was designed and fabricated with a 3D printer. The electrochemical reaction of anode-modified poly-L-lysine, vitamin K3, diaphorase, nicotinamide adenine dinucleotide, GDH and poly(sodium 4-styrenesulfonate) in the imBFC was evaluated and an oxidation current of 1.18 mAcm(-2) (at +0.6 V vs. Ag|AgCl) was observed. Then, the performance of the imBFC was evaluated and a maximum power output of 333 MUW (285 MUW cm(-)(2)) (at 0.5 V) was obtained. Furthermore, driving of both an LED device and a wireless temperature and humidity sensor device were powered by the imBFC. These results indicate that the imBFC has sufficient potential as a battery for novel ubiquitous robots such as insect cyborgs. PMID- 26655179 TI - Immobilization strategy for enhancing sensitivity of immunosensors: L-Asparagine AuNPs as a promising alternative of EDC-NHS activated citrate-AuNPs for antibody immobilization. AB - This paper addresses the question - Is EDC-NHS activated gold nanoparticles modified electrode surface the best available option for antibody immobilization for immunosensor fabrication? Is there any other alternative covalent immobilization strategy for orthogonal orientation of antibody, ensuring enhanced sensitivity of immunosensors? Does EDC-NHS activation of carboxyl functionalized nanoparticles surface really leads to orthogonal or directed immobilization of antibody? Gold nanoparticles synthesized using L-Asparagine as reducing and stabilization agent were employed for orthogonal immobilization of antibody for immunosensor fabrication. Anti-CA125 antibody was used as a model system for immunosensor fabrication. A comparative evaluation of immunosensors fabricated using L-Asparagine stabilized gold nanoparticles and citrate stabilized gold nanoparticles via different immobilization strategies/chemistries was done. The three strategies involved immobilization of Anti-CA125 antibody - (1) after EDC NHS activation of citrate stabilized gold nanoparticles, (2) directly onto citrate stabilized gold nanoparticles and (3) directly onto L-Asparagine stabilized gold nanoparticles modified electrode surfaces. Comparative evaluation of Impedimetric response characteristics showed 2.5 times increase in sensitivity (349.36 Omega/(IU/mL)/cm(2)) in case of third strategy as compared to first (147.53 Omega/(IU/mL)/cm(2)) and twice that of second strategy (166.24 Omega/(IU/mL)/cm(2)). Additionally, an extended dynamic range of 0-750 IU/mL was observed while for others it was up to 500 IU/mL. Amino acid coated gold nanoparticles ensured orthogonal immobilization, lesser randomization, with 88% of active antibody available for antigen binding as opposed to other two strategies with less than 30% active antibody. PMID- 26655180 TI - Establishment of N-succinimidyl 4-(maleimidomethyl) cyclohexanecarboxylate (SMCC) modified biochip enabling concurrent detection of serum infectious antibodies in neuroborreliosis. AB - In this study, we developed a novel protein biochip that was modified with N succinimidyl 4-(maleimidomethyl)cyclohexanecarboxylate (SMCC) and specialized for concurrent detection of serum IgG and IgM antibodies against Borrelia burgdorferi antigens, flagellin, outer surface protein C (OspC) and variable major protein like sequence (VlsE) in the patients with neuroborreliosis (NB), respectively. Surface chemical characteristics of the biochips were validated with atomic force microscope (AFM) and attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR). The visualized detection limit for IgG antibodies against flagellin, OspC and VlsE antigens on the biochip were 0.78 ug/ml, 0.78 ug/ml and 1.56 ug/ml, respectively. Finally, serum IgG and IgM antibodies in 72 patients with NB and 188 healthy individuals were tested on the biochip. The seroimmunological outcome by the biochip were evaluated in comparison with enzyme linked immunosorbent assay (ELISA) assay. The results demonstrated that the prevalences of IgG and IgM antibodies in the cases were 41.7%, 63.9% to flagellin; 20.8% and 51.4% to OspC and 76.4%, 62.5% to VlsE, respectively. Utilization of the biochip in detection IgM antibody against flagellin was compatible with ELISA assay (R(2)=0.849). Thus, the protein biochip would provide a potential platform not only for enabling detection of corresponding antibodies directed against B. burgdorferi antigens, but also for monitoring course of the disease. PMID- 26655181 TI - Generating power from transdermal extracts using a multi-electrode miniature enzymatic fuel cell. AB - The development of self-powered wearable biodevices is highly attractive for a number of applications, such as health monitoring and drug delivery. Enzymatic fuel cells (EFCs) hold great potential as power sources for such devices, since they can generate power from physiological fluids and operate at body temperature. In this study, we present a cascade of three EFCs embedded in a compact and handy single channel device and we demonstrate for the first time power generation from iontophoresis extracts obtained from pig skin. The EFCs implement non-toxic highly-porous gold electrodes; an easy-to-reproduce procedure is adopted for the immobilization of glucose oxidase and laccase at the anode and cathode respectively; no external mediators are used; and the system design can easily be further miniaturized. When electrically connected in parallel, the EFCs generated a power output close to the sum of the power generated by each unit, with peak values of 0.7 uW (flow-through mode) and 0.4 uW (batch mode), at a glucose concentration of 27 mM. When the device was fed with transdermal extracts, containing only 30 MUM of glucose, the average peak power was proportionally lower (0.004 uW). PMID- 26655182 TI - T-T mismatch-driven biosensor using triple functional DNA-protein conjugates for facile detection of Hg2+. AB - We report herein a T-T mismatch-driven biosensor using triple functional DNA protein conjugates for facile detection of mercury ions (Hg(2+)) based on evanescent wave fluorescence excitation. Fluorescein-labeled DNA strands and streptavidin molecules were conjugated using heterobifunctional crosslinkers, and the obtained conjugates were named as "Hg(2+) dependent conjugates, HDCs". Initially hybridized with quencher-labeled DNA (Q-DNA) strands, HDCs showed low evanescent wave-induced fluorescence emission signals; however, in the presence of Hg(2+), the DNA moieties of HDCs tended to form hairpin structures stabilized by T-T mismatches, releasing Q-DNA strands, which was accompanied by increases in the fluorescent signals. The novel detection strategy enables the fluorescent detection of mercury ions with high specificity and a low detection limit of 1.06 nM in a facile way. PMID- 26655183 TI - Pneumatic microfluidics-based multiplex single-cell array. AB - Large-scale single-cell arrays are urgently required for current high-throughput screening of cell function and heterogeneity. However, the rapid and convenient generation of large-scale single-cell array in a multiplex and universal manner is not yet well established. In this paper, we report a simple and reliable method for the generation of a single-cell array by combining pneumatic microvalve arrays (PMUVAs) and hydrodynamic single-cell trapping sites in a single microfluidic device. The PMUVAs, which can be precisely controlled by actuated pressures, were designed to guide multiple types of cells being trapped in the corresponding single-cell trapping sites located in the fluidic channel. According to the theoretical demonstration and computational simulation, we successfully realized a multiplex single-cell array with three different types of cells by a step-by-step protocol. Furthermore, the analysis of cellular esterase heterogeneity of the three types of cells was concurrently implemented in the device as a proof-of-concept experiment. All the results demonstrated that the method developed in the current study could be applied for the generation of large-scale single-cell array with multiple cell types, which would be also promising and helpful for single-cell-based high-throughput drug test, multipurpose immunosensor and clinical diagnosis. PMID- 26655184 TI - A fluorescent aptasensor using double-stranded DNA/graphene oxide as the indicator probe. AB - We developed a fluorescent aptasensor based on the making use of double-stranded DNA (dsDNA)/graphene oxide (GO) as the signal probe and the activities of exonuclease I (Exo I). This method takes advantage of the stronger affinity of the aptamer to its target rather than to its complementary sequence (competitor), and the different interaction intensity of dsDNA, mononucleotides with GO. Specifically, in the absence of target, the competitor hybridizes with the aptamer, preventing the digestion of the competitor by Exo I, and thus the formed dsDNA is adsorbed on GO surface, allowing fluorescence quenching. When the target is introduced, the aptamer preferentially binds with its target. Thereby, the corresponding nuclease reaction takes place, and slight fluorescence change is obtained after the introduction of GO due to the weak affinity of the generated mononucleotides to GO. Adenosine (AD) was chosen as a model system and tested in detail. Under the optimized conditions, smaller dissociation constant (Kd, 311.0 uM) and lower detection limit (LOD, 3.1 uM) were obtained in contrast with traditional dye-labeled aptamer/GO based platform (Kd=688.8 uM, LOD=21.2 uM). Satisfying results were still obtained in the evaluation of the specificity and the detection of AD in human serum, making it a promising tool for the diagnosis of AD-relevant diseases. Moreover, we demonstrated the effect of the competitor on the LOD, and the results reveal that the sensitivity could be enhanced by using the rational competitor. The present design not only constructs a label free aptamer based platform but also extends the application of dsDNA/GO complex in biochemical and biomedical studies. PMID- 26655185 TI - A microfabrication-based approach to quantitative isothermal titration calorimetry. AB - Isothermal titration calorimetry (ITC) directly measures heat evolved in a chemical reaction to determine equilibrium binding properties of biomolecular systems. Conventional ITC instruments are expensive, use complicated design and construction, and require long analysis times. Microfabricated calorimetric devices are promising, although they have yet to allow accurate, quantitative ITC measurements of biochemical reactions. This paper presents a microfabrication based approach to integrated, quantitative ITC characterization of biomolecular interactions. The approach integrates microfabricated differential calorimetric sensors with microfluidic titration. Biomolecules and reagents are introduced at each of a series of molar ratios, mixed, and allowed to react. The reaction thermal power is differentially measured, and used to determine the thermodynamic profile of the biomolecular interactions. Implemented in a microdevice featuring thermally isolated, well-defined reaction volumes with minimized fluid evaporation as well as highly sensitive thermoelectric sensing, the approach enables accurate and quantitative ITC measurements of protein-ligand interactions under different isothermal conditions. Using the approach, we demonstrate ITC characterization of the binding of 18-Crown-6 with barium chloride, and the binding of ribonuclease A with cytidine 2'-monophosphate within reaction volumes of approximately 0.7 uL and at concentrations down to 2mM. For each binding system, the ITC measurements were completed with considerably reduced analysis times and material consumption, and yielded a complete thermodynamic profile of the molecular interaction in agreement with published data. This demonstrates the potential usefulness of our approach for biomolecular characterization in biomedical applications. PMID- 26655186 TI - Paper-based alpha-amylase detector for point-of-care diagnostics. AB - We report the fabrication of a paper-sensor for quantitative detection of alpha amylase activity in human blood serum. Pieces of filter papers were coated with starch-iodine solution leading to an intense blue coloration on the surface. Dispensing alpha-amylase solution on the starch-iodine coated paper reduced the intensity of the color because of starch-hydrolysis catalyzed by amylase. The variation in the intensity of the color with the concentration of amylase was estimated in three stages: (i) initially, the paper-surface was illuminated with a light emitting diode, (ii) then, the transmitted (reflected) rays emitted through (from) the paper were collected on a photoresistor, and (iii) the variations in the electrical resistance of the photoresistor were correlated with the amylase concentration in analyte. The resistance of photoresistor decreased monotonically with an increase in amylase concentration because the intensity of the reflected (transmitted) rays collected from (through) the paper increased with reduction in the color intensity on the paper surface. Since a specific bio reaction was employed to detect the activity of amylase, the sensor was found to be equally efficient in detecting unknown quantities of amylase in human blood serum. The reported sensor has shown the potential to graduate into a point-of care detection tool for alpha-amylase. PMID- 26655187 TI - Greater body mass index is a better predictor of subclinical cardiac damage at long-term follow-up in men than is insulin sensitivity: a prospective, population based cohort study. AB - BACKGROUND: To examine whether lower insulin sensitivity as determined by homeostatic model assessment (HOMA-%S) was associated with increased left ventricular mass (LVM) and presence of LV diastolic dysfunction at long-term follow-up, independently of body mass index (BMI), in middle-aged, otherwise healthy males. METHODS: Prospective population-based cohort study with a median (IQR) follow-up time of 28 (27-28) years, in which traditional cardiovascular risk factors, including HOMA-%S and BMI, were assessed at baseline, and echocardiographic determination of LVM and LV diastolic function was performed at follow-up. Associations between risk factors and echocardiographic variables were tested using multivariable linear and binary logistic regression. RESULTS: The study population comprised 247 men with a median (IQR) age of 47 (47-48) years. Mean (SD) BMI was 25.1 +/- 3.0 kg/m(2), and median (IQR) HOMA-%S was 113.0 (68.3 284.6). Subjects with low insulin sensitivity (lowest HOMA-%S quartile (Q1)) had significantly greater BMI, fasting plasma insulin, and higher fasting blood glucose (FBG) (p <0.02 for all). BMI and HOMA-%S were significantly correlated (r = -0.383, p <0.0001). At follow-up, mean (SD) LVM and LVMI were 202 +/- 61 g and 103 +/- 31 g/m(2), respectively, whereas median (IQR) E/e was 10 (8-12). Moreover, 36 % had grade 2 or 3 diastolic dysfunction. In multivariable analyses, greater BMI, but not low insulin sensitivity was independently associated with later detection of increased LVM and diastolic dysfunction. CONCLUSION: Greater baseline BMI, but not lower insulin sensitivity was independently associated with greater LVM and diastolic dysfunction at long-term follow-up. PMID- 26655188 TI - Transcranial magnetic stimulation of dorsolateral prefrontal cortex reduces cocaine use: A pilot study. AB - Recent animal studies demonstrate that compulsive cocaine seeking strongly reduces prelimbic frontal cortex activity, while optogenetic stimulation of this brain area significantly inhibits compulsive cocaine seeking, providing a strong rationale for applying brain stimulation to reduce cocaine consumption. Thus, we employed repetitive transcranial magnetic stimulation (rTMS), to test if dorsolateral prefrontal cortex (DLPFC) stimulation might prevent cocaine use in humans. Thirty-two cocaine-addicted patients were randomly assigned to either the experimental group (rTMS) on the left DLPFC, or to a control group (pharmacological agents) during a 29-day study (Stage 1). This was followed by a 63-day follow-up (Stage 2), during which all participants were offered rTMS treatment. Amongst the patients who completed Stage 1, 16 were in the rTMS group (100%) and 13 in the control group (81%). No significant adverse events were noted. During Stage 1, there were a significantly higher number of cocaine-free urine drug tests in the rTMS group compared to control (p=0.004). Craving for cocaine was also significantly lower in the rTMS group compared to the controls (p=0.038). Out of 13 patients who completed Stage 1 in the control group, 10 patients received rTMS treatment during Stage 2 and showed significant improvement with favorable outcomes becoming comparable to those of the rTMS group. The present preliminary findings support the safety of rTMS in cocaine addicted patients, and suggest its potential therapeutic role for rTMS-driven PFC stimulation in reducing cocaine use, providing a strong rationale for developing larger placebo-controlled studies. Trial name: Repetitive transcranial magnetic stimulation (rTMS) in cocaine abusers, URL:, REGISTRATION NUMBER: ISRCTN15823943. PMID- 26655189 TI - Effects of cariprazine, a novel antipsychotic, on cognitive deficit and negative symptoms in a rodent model of schizophrenia symptomatology. AB - Negative symptoms and cognitive impairment associated with schizophrenia are strongly associated with poor functional outcome and reduced quality of life and remain an unmet clinical need. Cariprazine is a dopamine D3/D2 receptor partial agonist with preferential binding to D3 receptors, recently approved by the FDA for the treatment of schizophrenia and manic or mixed episodes associated with bipolar I disorder. The aim of this study is to evaluate effects of cariprazine in an animal model of cognitive deficit and negative symptoms of schizophrenia. Following sub-chronic PCP administration (2mg/kg, IP for 7 days followed by 7 days drug-free), female Lister Hooded rats were administered cariprazine (0.05, 0.1, or 0.25mg/kg, PO) or risperidone (0.16 or 0.1mg/kg, IP) before testing in novel object recognition (NOR), reversal learning (RL), and social interaction (SI) paradigms. As we have consistently demonstrated, sub-chronic PCP significantly impaired behavior in these tests. Deficits were significantly improved by cariprazine, in a dose dependent manner in the operant RL test with efficacy at lower doses in the NOR and SI tests. Locomotor activity was reduced at the highest doses of 0.1mg/kg and 0.25mg/kg in NOR and SI. Risperidone also reversed the PCP-induced deficit in all tests. In conclusion, cariprazine was effective to overcome PCP-induced deficits in cognition and social behavior in a thoroughly validated rat model in tests representing specific symptom domains in schizophrenia patients. These findings support very recent results showing efficacy of cariprazine in the treatment of negative symptoms in schizophrenia patients. PMID- 26655190 TI - Significant association of GRM7 and GRM8 genes with schizophrenia and major depressive disorder in the Han Chinese population. AB - Metabotropic glutamate receptor type 7 (GRM7) and type 8 (GRM8) are involved in the neurotransmission of glutamate which is supposed to play an important role in the development of schizophrenia (SCZ) and major depressive disorders (MDD). We designed this study to investigate whether common DNA variants or their genetic interactions within GRM7 and GMR8 genes were associated with these disorders in the Han Chinese population. Fourteen SNPs in GRM7 and GRM8 were selected within a sample set comprising 1235 SCZ patients, 1045 MDD patients and 1235 normal controls. Significant association in SCZ case-control subjects was observed for rs2229902 (permutated Pallele=0.0005, OR=1.492 [95% CI=1.231-1.807]) and rs9870680 (permutated Pallele=0.0023, OR=1.262 [95% CI=1.116-1.426]) in GRM7 and rs2237781 (permutated Pallele=0.0027, OR=1.346 [95% CI=1.149-1.575]) in GRM8. Association analysis for MDD case-control subjects revealed positive results in rs779706 (permutated Pallele=0.0099, OR=1.237 [95% CI=1.093-1.399]) of GRM7 and in rs1361995 (permutated Pallele=0.0017, OR=1.488 [95% CI=1.215-1.823]) of GRM8. Moreover, a three-locus model, constituted by polymorphisms in GRM7 and GRM8 significantly correlated with MDD in the gene-gene interaction analysis. Meta analysis and haplotype analysis further confirmed our significant results. We demonstrated the genetic association of GRM7 and GRM8 with SCZ and MDD in the Han Chinese population. We also found susceptibility interactive effects of these two genes with both psychiatric disorders, which might provide new insights into the etiology of them. PMID- 26655191 TI - Microscopy as a diagnostic tool in pulmonary tuberculosis. AB - Tuberculosis continues to cast a huge impact on humanity with its high incidence and mortality, especially in developing countries. For tuberculosis case detection, microscopy continues to be indispensible, given its low cost, rapidity, simplicity of procedure and high specificity. Modifications have attempted to improve the sensitivity of microscopy which include: concentration methods such as centrifugation, N-acetyl cysteine-sodium hydroxide, bleach, ammonium sulfate or chitin. Furthermore, classical Ziehl-Neelsen (ZN) staining has been subjected to varying carbol fuchsin concentrations or replaced by Kinyoun staining, fluorescent microscopy or immune-fluorescence. Currently, light emitting diode fluorescence is recognizably the most plausible method as an alternative to ZN staining. PMID- 26655192 TI - Nontuberculous mycobacteria in Middle East: Current situation and future challenges. AB - Nontuberculous mycobacteria (NTM) are a diverse group of bacterial species that are distributed in the environment. Many of these environmental bacteria can cause disease in humans. The identification of NTM in environmental sources is important for both clinical and epidemiological purposes. In this study, the distribution of NTM species from environmental and clinical samples in the Middle East was reviewed. In order to provide an overview of NTM, as well as recent epidemiological trends, all studies addressing NTM in the Middle East from 1984 to 2014 were reviewed. A total of 96 articles were found, in which 1751 NTM strains were isolated and 1084 of which were obtained from clinical samples, 619 from environmental samples and 48 were cited by case reports. Mycobacterium fortuitum was the most common rapid growing mycobacteria (RGM) isolated from both clinical (269 out of 447 RGM; 60.1%) and environmental (135 out of 289 RGM; 46.7%) samples. Mycobacterium avium complex (MAC) was the most common slow growing mycobacteria (SGM) isolated from clinical samples (140 out of 637 SGM; 21.9%). An increasing trend in NTM isolation from the Middle East was noted over the last 5years. This review demonstrates the increasing concern regarding NTM disease in the Middle East, emphasizing the need for regional collaboration and coordination in order to respond appropriately. PMID- 26655193 TI - Reaching the underserved: Active tuberculosis case finding in urban slums in southeastern Nigeria. AB - BACKGROUND: Nigeria ranks 10th among 22 high TB burden countries with low TB case detection that relies on passive case finding. Although there is increasing body of evidence that active case finding (ACF) has improved TB case finding in urban slums in some parts of the world, this strategy had not been implemented in Nigeria despite the pervasiveness of urban slums in the country. OBJECTIVE: To assess the yield and profile of TB in urban slums in Nigeria through ACF. METHODS: A prospective, implementation study was conducted in three urban slums of southeastern Nigeria. Individuals with TB symptoms were identified through targeted screening using a standardized questionnaire and investigated further for TB. Descriptive and bivariate analyses were performed using SPSS. RESULTS: Among 16,743 individuals screened for TB, 6361 (38.0%) were identified as TB suspects; 5894 suspects were evaluated for TB. TB was diagnosed in 1079 individuals, representing 6.4% of the screened population and 18.3% of those evaluated for TB. Of the 1079 cases found, 97.1% (n=1084) had pulmonary TB (PTB), and majority (65%) had new smear-positive TB. Children (<15years) accounted for 6.7% of the cases. Also, 22.6% (216) of the cases were HIV co-infected, among whom 55.1% (n=119) were females. The average number of individuals needed to screen to find a case of TB was 16. CONCLUSIONS: There is high prevalence of TB in Nigeria slum population. Targeted screening of out-patients, TB contacts, and HIV-infected patients should be optimized for active TB case finding in Nigeria. PMID- 26655194 TI - Microaerobic growth and anaerobic survival of Mycobacterium avium, Mycobacterium intracellulare and Mycobacterium scrofulaceum. AB - Representative strains of Mycobacterium avium, Mycobacterium intracellulare and Mycobacterium scrofulaceum (MAIS) grew at equal rates in laboratory medium at 21% (air) and 12% oxygen. Growth in 6% oxygen proceeded at a 1.4-1.8-fold lower rate. Colony formation was the same at 21% (air) and 6% oxygen. The MAIS strains survived rapid shifts from aerobic to anaerobic conditions as measured by two experimental approaches (Falkinham (1996) [1]). MAIS cells grown aerobically to log phase in broth were diluted, spread on agar medium, and incubated anaerobically for up to 20 days at 37 degrees C. Although no colonies formed anaerobically, upon transfer to aerobic conditions, greater than 25% of the colony forming units (CFU) survived after 20 days of anaerobic incubation (Prince et al. (1989) [2]). MAIS cells grown in broth aerobically to log phase were sealed and vigorous agitation led to oxygen depletion (Wayne model). After 12 days anaerobic incubation, M. avium and M. scrofulaceum survival were high (>50%), while M. intracellulare survival was lower (22%). M. avium cells shifted to anaerobiosis in broth had increased levels of glycine dehydrogenase and isocitrate lyase. Growth of MAIS strains at low oxygen levels and their survival following a rapid shift to anaerobiosis is consistent with their presence in environments with fluctuating oxygen levels. PMID- 26655195 TI - Utility of light-emitting diode microscopy for the diagnosis of pulmonary tuberculosis in HIV infected patients. AB - OBJECTIVE: To determine the utility of light-emitting diode fluorescent microscopy (LED-FM) for the diagnosis of pulmonary tuberculosis (PTB) in HIV infected patients. MATERIAL AND METHODS: A cross-sectional study was performed on 400 HIV-infected, clinically or radiologically suspected PTB patients. Two sputum specimens were collected from each patient. Two direct smears were prepared from each sputum specimen. One was stained by ZN method and another by auramine-O method and reported as per the Revised National Tuberculosis Control Programme (RNTCP) guidelines. LED-FM stained smears were reported by two readers. All specimens were cultured on LJ medium after digestion and decontamination. Address and contact details of all the patients were recorded in case record form. They were contacted for follow-up if required. RESULTS: Of the 800 sputum specimens processed, 130 were positive by LED-FM method and 33 were positive by ZN method; 77 specimens showed growth of MTB on LJ medium. When compared with solid culture as a reference standard, LED-FM has a sensitivity of 67.53%, specificity of 88.71%, PPV of 40% and NPV of 96.08%. Seventy-eight LED-FM positive and culture negative specimens had scanty grading. Of these, 15 were confirmed as having PTB as they responded to anti-TB treatment. The concordance between two readers was 98.75%. CONCLUSION: LED-FM can be a good screening test for the diagnosis of PTB in HIV-infected patients. However, all scanty grade positive smears need to be confirmed by WHO approved gold standard. PMID- 26655196 TI - Nontuberculous mycobacteria pathogenesis and biofilm assembly. AB - Nontuberculous mycobacteria (NTM) are emergent pathogens whose importance in human health has been gaining relevance after being recognized as etiological agents of opportunist infections in HIV patients. Currently, NTM are recognized as etiological agents of several respiratory and extra-respiratory infections of immune-competent individuals. The environmental nature of NTM together with the ability to assemble biofilms on different surfaces plays a key role on their pathogenesis. In the present work the ability of three fast-growing NTM (Mycobacterium smegmatis, Mycobacterium fortuitum and Mycobacterium chelonae) to persist within a model of human alveolar macrophages was evaluated. Most often human infections with NTM occur by contact with the environment. Biofilms can work as environmental reservoirs. For this reason, it was decided to evaluate the ability of NTM to assemble biofilms on different surfaces. Scanning electron microscopy was used to elucidate the biofilm structure. The ability to assemble biofilms was connected with the ability to spread on solid media known as sliding. Biofilm assembly and intracellular persistence seems to be ruled by different mechanisms. PMID- 26655197 TI - Tuberculosis drug resistance isolates from pulmonary tuberculosis patients, Kassala State, Sudan. AB - BACKGROUND: This study was conducted in Kassala Teaching Hospital, Kassala State, Sudan (January 2006-June 2008) to determine the rate of mycobacterium drug resistance to anti-tuberculous treatment and to explore the genotype of Mycobacterium tuberculosis resistant isolates using rpoB gene. METHODS: 53 isolates of mycobacterium isolated from pulmonary tuberculosis (PTB) patients from Kassala State were subjected to drug susceptibility testing (DST) to anti tuberculous drugs; 10 M.tuberculosis complex (MTBC) resistant isolates were subjected to polymerase chain reaction (PCR), and commercially the amplified DNA was sequenced. RESULTS: DST detected resistance in 23/53 (43.39%) isolates, among which rifampicin had a high number of resistant isolates (13/23), followed by streptomycin (11/23), and multi-drug resistance was detected in 5 isolates. DNA sequence analysis of 10 MTBC-resistant isolates detected variations within and outside the rifampicin resistant determining region (RRDR). Variation within RRDR was detected at positions 512 (AGC/ATC, Ser/Ile), and 528 (CGC/CTC, Arg/Leu). Outside the RRDR region variations were detected at positions 498 (GTG/GGG, Val/gly), 488 (ACA/ACC, Thr/Thr), which is a silent mutation. Insertions were observed at positions 484, 496 (GTG/GTGA, CGG/CAGG, respectively). Deletion was observed at position 487 (ATC/_TC). DISCUSSION AND CONCLUSION: This study revealed that high resistance to rifampicin was associated with various point mutations in and out of the RRDR of the rpoB gene. Molecular methods are needed for early detection of TB disease and drug resistance. PMID- 26655198 TI - Diagnosis of pediatric pulmonary tuberculosis with special reference to polymerase chain reaction based nucleic acid amplification test. AB - OBJECTIVE: To determine the utility of polymerase chain reaction (PCR) for diagnosing pediatric pulmonary tuberculosis (PPTB). METHOD: A prospective cross sectional study was carried out on 100 children less than 14 years of age, with strong clinical suspicion and radiological evidence suggestive of pulmonary tuberculosis (TB). Sputum samples/gastric lavage were collected. Direct smears and culture on Lowenstein Jensen (LJ) media were performed. DNA extraction and amplification was performed using GeneiTM Amplification Reagent set for Mycobacterium tuberculosis (MTB) (by Genei, Bangalore, India). This test is based on the principle of single-tube nested PCR which amplifies the repetitive insertion sequence IS6110. RESULTS: When compared with culture, sensitivity and specificity of PCR was 93.55% and 92.75%, respectively. The PPV was 85.29% and the NPV was 96.97%. When intention to treat (ITT) was used as the standard, sensitivity, specificity, PPV and NPV of PCR was 47.88%, 93.1%, 94.4%, and 42.19%, respectively, and that of culture was 40.85%, 100%, 100% and 40.85%, respectively. Against response to treatment (RTT), PCR demonstrated sensitivity, specificity, PPV and NPV of 50.9%, 93.1%, 93.33% and 50%, respectively, and for culture it was 43.64%, 100%, 100% and 48.33%, respectively. CONCLUSION/RECOMMENDATION: The present study reinforces better case detection rate with PCR-based nucleic acid amplification test as compared with microscopy and culture in pediatric pulmonary TB. PCR showed a higher correlation with clinical diagnosis as compared with microscopy and solid culture. Hence, a molecular platform should be the test of choice for detecting PPTB. PMID- 26655199 TI - Comparative evaluation of PCR amplification of RLEP, 16S rRNA, rpoT and Sod A gene targets for detection of M. leprae DNA from clinical and environmental samples. AB - PURPOSE: PCR assay is a highly sensitive, specific and reliable diagnostic tool for the identification of pathogens in many infectious diseases. Genome sequencing Mycobacterium leprae revealed several gene targets that could be used for the detection of DNA from clinical and environmental samples. The PCR sensitivity of particular gene targets for specific clinical and environmental isolates has not yet been established. The present study was conducted to compare the sensitivity of RLEP, rpoT, Sod A and 16S rRNA gene targets in the detection of M. leprae in slit skin smear (SSS), blood, soil samples of leprosy patients and their surroundings. METHOD: Leprosy patients were classified into Paucibacillary (PB) and Multibacillary (MB) types. Ziehl-Neelsen (ZN) staining method for all the SSS samples and Bacteriological Index (BI) was calculated for all patients. Standard laboratory protocol was used for DNA extraction from SSS, blood and soil samples. PCR technique was performed for the detection of M. leprae DNA from all the above-mentioned samples. RESULTS: RLEP gene target was able to detect the presence of M. leprae in 83% of SSS, 100% of blood samples and in 36% of soil samples and was noted to be the best out of all other gene targets (rpoT, Sod A and 16S rRNA). It was noted that the RLEP gene target was able to detect the highest number (53%) of BI-negative leprosy patients amongst all the gene targets used in this study. CONCLUSION: Amongst all the gene targets used in this study, PCR positivity using RLEP gene target was the highest in all the clinical and environmental samples. Further, the RLEP gene target was able to detect 53% of blood samples as positive in BI-negative leprosy cases indicating its future standardization and use for diagnostic purposes. PMID- 26655200 TI - Molecular typing and differentiation of Mycobacterium tuberculosis clinical isolates using Double Repetitive Element PCR and Duplex PCR. AB - BACKGROUND: To date, the advancements in polymerase chain reaction (PCR) assures accurate, fast identification and mycobacterial speciation in clinical settings, which promotes a better tuberculosis (TB) treatment regimen. METHODS: In this study, a total of 78 clinically suspected cases of TB were processed for the detection of Mycobacterial infections by standard Ziehl Neelsen (ZN) staining, conventional Lowenstein-Jensen (LJ) and BACTEC MGIT-960TM liquid culture. Strain typing was performed by using Double Repetitive Element PCR (DRE-PCR) and Duplex PCR (DPCR) to differentiate Mycobacterium tuberculosis complex (MTB) from non tuberculous mycobacteria (NTM), respectively. RESULTS: Of 78 clinical isolates, 25 (32%) were drug-susceptible, and 53 (68%) were resistant to at least one drug. The BACTEC MGIT-960TM showed the highest (88.5%) positivity rate, compared with conventional LJ (82%) and ZN smear (61.5%). The mean time detection and drug susceptibility for MTB was 28 and 40days in LJ culture, and 10 and 13 days in BACTEC MGIT-960TM culture. Using DPCR, Mycobacterium avium infection was identified in HIV-positive (2.56%) and MTB in HIV-negative patients (97.4%), and the DRE-PCR system divulged 15 unique genotype patterns, and an institutional based epidemiology database was created. CONCLUSIONS: The combination of an in house DRE-DPCR system could possibly identify and differentiate MTB from other mycobacterial species in a single reaction. In addition, restriction polymorphism analysis and DNA sequencing of NTM could assist in species identification directly from clinical isolates. PMID- 26655201 TI - Polymorphisms in drug-resistant-related genes shared among drug-resistant and pan susceptible strains of sequence type 10, Beijing family of Mycobacterium tuberculosis. AB - Mutations in genes involved in drug metabolism have been well-associated with drug resistance. Sequence analysis of known antimycobacterial drug-resistant genes is often used to predict resistance to antibiotics. However, some polymorphisms in such genes may serve a phylogenetic purpose rather than resistance to drugs. The Beijing family of Mycobacterium tuberculosis (MTB) is prevalent worldwide and has been associated with the emergence of multidrug resistance. Sequence type (ST) 10 of the Beijing family is the most predominant in countries like Peru, Taiwan and Thailand. A sequence analysis was performed of 81 previously reported drug-resistant associated genes in multidrug-resistant and pan-susceptible strains of the Beijing family sequence type 10 of MTB. This analysis revealed 10 synonymous and 12 nonsynonymous single nucleotide polymorphisms (SNPs) that are shared by all strains under study. One frameshift mutation was also observed to be common to all. These data might be useful in excluding some observed SNPs in drug-resistant-associated genes of MTB Beijing ST 10 when performing genotypic drug susceptibility assay. PMID- 26655202 TI - Characterization of genomic variations in SNPs of PE_PGRS genes reveals deletions and insertions in extensively drug resistant (XDR) M. tuberculosis strains from Pakistan. AB - BACKGROUND: Mycobacterium tuberculosis (MTB) PE_PGRS genes belong to the PE multigene family. Although the function of PE_PGRS genes is unknown, it is hypothesized that the PE_PGRS genes may be associated with antigenic variability in MTB. MATERIAL AND METHODS: Whole genome sequencing analysis was performed on (n=37) extensively drug-resistant (XDR) MTB strains from Pakistan, which included Lineage 1 (East African Indian, n=2); Other lineage 1 (n=3); Lineage 3 (Central Asian, n=24); Other lineage 3 (n=4); Lineage 4 (X3, n=1) and T group (n=3) MTB strains. RESULTS: There were 107 SNPs identified from the analysis of 42 PE_PGRS genes; of these, 13 were non-synonymous SNPs (nsSNPs). The nsSNPs identified in PE_PGRS genes - 6, 9 and 10 - were common in all EAI, CAS, Other lineages (1 and 3), T1 and X3. Deletions (DELs) in PE_PGRS genes - 3 and 19 - were observed in 17 (80.9%) CAS1 and 6 (85.7%) in Other lineages (1 and 3) XDR MTB strains, while DELs in the PE_PGRS49 were observed in all CAS1, CAS, CAS2 and Other lineages (1 and 3) XDR MTB strains. All CAS, EAI and Other lineages (1 and 3) strains showed insertions (INS) in PE_PGRS6 gene, while INS in the PE_PGRS genes 19 and 33 were observed in 20 (95.2%) CAS1, all CAS, CAS2, EAI and Other lineages (1 and 3) XDR MTB strains. CONCLUSION: Genetic diversity in PE_PGRS genes contributes to antigenic variability and may result in increased immunogenicity of strains. This is the first study identifying variations in nsSNPs and INDELs in the PE_PGRS genes of XDR-TB strains from Pakistan. It highlights common genetic variations which may contribute to persistence. PMID- 26655203 TI - Mental health symptoms identify workers at risk of long-term sickness absence due to mental disorders: prospective cohort study with 2-year follow-up. AB - BACKGROUND: Mental health problems are a leading cause of long-term sickness absence (LTSA). Workers at risk of mental LTSA should preferably be identified before they report sick. The objective of this study was to examine mental health symptoms as predictors of future mental LTSA in non-sicklisted workers. METHODS: Prospective cohort study of 4877 non-sicklisted postal workers. Mental health symptoms were measured at baseline in November 2010 with the Four-Dimensional Symptom Questionnaire (distress and depressed mood) and Maslach's Burnout Inventory (fatigue). Mental health symptom scores were analyzed against incident mental LTSA retrieved from an occupational health register in 2011 and 2012. The area under the receiver operating characteristic curve (AUC) represented the ability of mental health symptom scores to discriminate between workers with and without mental LTSA during 2-year follow-up. RESULTS: Complete cases analysis included 2782 (57 %) postal workers of whom 73 had mental LTSA during 2-year follow-up. Distress fairly (AUC = 0.75; 95 % CI 0.67-0.82) and both depressed mood (AUC = 0.64; 95 % CI 0.57-0.72) and fatigue (AUC = 0.61; 95 % CI 0.53-0.69) poorly discriminated between workers with and without mental LTSA during 2-year follow-up. The discriminative ability of distress did not improve by adding depressed mood and fatigue. CONCLUSIONS: Measurement of distress sufficed to identify non-sicklisted postal workers at risk of future mental LTSA. The Four Dimensional Symptom Questionnaire distress scale is a promising tool to screen working populations for of mental LTSA, which enables secondary preventive strategies. PMID- 26655204 TI - [Technical efficiency assessment of public primary care providers in the Basque Country (Spain), 2010-2013]. AB - OBJECTIVE: To evaluate the technical efficiency of primary care units operating in the Basque Health Service during the period 2010-2013, corresponding to the implementation of a care integration strategy by health authorities. METHODS: This study included 11 of the 12 primary care units in the Basque Health Service during the period 2010-2013. Data envelopment analysis (DEA) was used to assess the technical efficiency of the units. In particular, we applied the extension DEA windows to analyse all units as if they were in a single period (33 observations) as well as a conditional model, which allowed incorporation of the effect of the characteristics of the population covered. The outputs considered were a quality index based on fulfilment of different requirements related to primary care delivery and the rate of avoidable hospitalizations (treated as an undesirable output). The inputs used were the number of physicians, the number of nurses and the costs of prescriptions. The morbidity index was included as an exogenous variable. RESULTS: The results showed that the efficiency of all the units improved during the study period. However, this improvement was not greater in the units incorporated in the integrated healthcare organisation. DISCUSSION: In a context of global transformation of care delivery in the Basque country in the study period, primary care units increased their efficiency. However, this effect was not larger in vertically integrated primary care providers. PMID- 26655206 TI - Factors associated with early childhood caries in Chile. AB - OBJECTIVE: To determine the prevalence of caries and identify the associated factors among children aged 2 and 4 years in southern Chile. METHODS: A cross sectional study was conducted in a random sample of 2,987 children. Dental examinations were performed in all participating children and a self-administered survey was administered to their primary caregivers. The statistical analysis included a zero inflated negative binomial regression model. RESULTS: The prevalence of caries was 20.3% for 2-year-olds and 52.7% for 4-year-olds. The factors associated with caries included the following: living in the Bio-Bio region, PR 2 year-old: 1.65 (1.10-2.47), PR 4 year-old: 1.44 (1.18-1.75) and having a low socioeconomic position, PR 2 year-old: 5.39 (2.14-13.57), PR 4 year old: 3.71 (2.68-5.13) or a medium socioeconomic position, PR 2 year-old: 2.79 (1.06-7.33), PR 4 year-old: 2.70 (1.92-3.79). In 4-year-olds, a high frequency of consuming sugary drinks at bedtime (PR: 1.30; 1.06-1.59), not brushing teeth daily (PR: 1.37; 1.18-1.60), and the presence of gingivitis (PR: 1.64; 1.28-2.09) were also associated with caries. CONCLUSIONS: The high prevalence of caries in this young group is concerning. The factors associated with caries identified in this study could help in the design of preventive interventions at early ages. PMID- 26655205 TI - Alcohol consumption and Mediterranean Diet adherence among health science students in Spain: the DiSA-UMH Study. AB - OBJECTIVE: To describe the association between consumption of different alcoholic beverages and adherence to the Mediterranean diet. METHODS: A cross-sectional analysis was conducted of the baseline data of the DiSA-UMH study, an ongoing cohort study with Spanish health science students (n=1098) aged 17-35 years. Dietary information was collected by a validated 84-item food frequency questionnaire. Participants were grouped into non-drinkers, exclusive beer and/or wine drinkers and drinkers of all types of alcoholic beverages. Mediterranean diet adherence was determined by using a modification of the relative Mediterranean Diet Score (rMED; score range: 0-16) according to consumption of 8 dietary components. We performed multiple linear and multinomial regression analyses. RESULTS: The mean alcohol consumption was 4.3g/day (SD: 6.1). A total of 19.5%, 18.9% and 61.6% of the participants were non-drinkers, exclusive beer and/or wine drinkers and drinkers of all types of alcoholic beverages, respectively. Participants who consumed beer and/or wine exclusively had higher rMED scores than non-drinkers (beta: 0.76, 95%CI: 0.25-1.27). Drinkers of all types of alcoholic beverages had similar rMED scores to non-drinkers. Non drinkers consumed less fish and more meat, whereas drinkers of all types of alcoholic beverages consumed fewer fruits, vegetables and more meat than exclusive beer and/or wine drinkers. CONCLUSIONS: The overall alcohol consumption among the students in our study was low-to-moderate. Exclusive beer and/or wine drinkers differed regarding the Mediterranean diet pattern from non-drinkers and drinkers of all types of alcohol. These results show the need to properly adjust for diet in studies of the effects of alcohol consumption. PMID- 26655207 TI - Keeping intestinal stem cell differentiation on the Tramtrack. AB - Intestinal epithelium in adult Drosophila midgut undergoes regular turnover and renewal. This process is fueled by intestinal stem cells (ISCs), which can self renew as well as produce both absorptive enterocytes (ECs) and secretory enteroendocrine (EE) cells. Notch signaling plays a decisive role in EC differentiation. However, the mechanisms controlling EE specification is much less understood. Recently we identified a BTB-domain containing transcriptional repressor Ttk69 as an intrinsic factor in repressing EE cell specification. Loss of Ttk69 caused all progenitor cells to adopt EE cell specification, regardless the status of Notch activity. Mechanistically, Ttk69 represses EE specification via a Ttk69-acheate-scute complex (AS-C) genes-Prospero (Pros) regulatory axis. Interestingly, depletion of ttk69 is able to bypass the requirements of many known signaling pathways, such as JAK/STAT signaling and Tuberous Sclerosis Complex (Tsc), in EE cell specification. These observations suggest that Ttk69 acts as a master repressor of EE cell fate. Here, we further tested the effect of Ttk69 in mature hormone-producing EE cells. We found that cell-autonomous overexpression of Ttk69 in differentiated EE cells was sufficient to disrupt their hormone-producing activity, further supporting the notion that Ttk69 is a master repressor of EE cell fate. In this Extra View, we also provide a brief discussion of recent progress and remaining questions concerning EE cell specification in adult Drosophila midgut. PMID- 26655208 TI - Maternal personality traits associated with patterns of prenatal smoking and exposure: Implications for etiologic and prevention research. AB - BACKGROUND: Little is known about the characteristics of women who smoke during pregnancy beyond demographic factors. We examined the relationship between novelty seeking, harm avoidance, and self-directedness and (a) abstinence from smoking during pregnancy and (b) average daily cigarette consumption during pregnancy. METHODS: Participants were 826 birth mothers who made adoption placements in the Early Growth and Development Study and completed the Temperament and Character Inventory - Short Form, and interview-based smoking assessments 3-6 months postpartum. Never smokers (n=199), pregnancy abstainers (n=277), pregnancy light smokers (n=184), and pregnancy heavy smokers (n=166) were compared on personality dimensions and smoking-related processes. Using regression analyses we examined relationships between personality and (a) abstinence versus smoking during pregnancy; and (b) average daily cigarette consumption among lifetime smokers, controlling for nicotine dependence, birth father substance dependence, maternal antisocial behavior, and depressive symptoms during pregnancy. RESULTS: Smokers with higher self-directedness and lower harm avoidance were more likely to abstain during pregnancy [O.R. 1.380; 95% C.I. (1.065-1.787); B(SE)=.322(.132); p=.015] and [O.R. .713; 95% C.I. (.543 .935); B(SE)=-.339(.138); p=.014], respectively. Novelty seeking differentiated never smokers from lifetime smokers (t=-3.487; p=.001), but was not significant in multivariate models. Lifetime smokers who abstained during pregnancy reported fewer depressive symptoms relative to never smokers. CONCLUSIONS: Personality dimensions associated with abstinence from smoking and cigarettes per day during pregnancy may be important to consider in etiologic and intervention research. PMID- 26655209 TI - [Clinical-radiological evaluation of the impaction allografting and cemented rod technique in revision knee surgery]. AB - OBJECTIVE: Long term clinical and radiological evaluation of results, survival, and peri- operative and post-operative complications of the patients who have been operated on for revision total hip arthroplasty using the impaction allografting and cemented rod technique. MATERIAL AND METHODS: An observational, analytical, prospective and non-random study was conducted on 26 patients who underwent revision total hip arthroplasty in our Hospital (1997-98). They were clinically and radiologically assessed, and a survival analysis of the implant was performed. RESULTS: Statistically significant differences were identified in the pre- and post-operative values, according to Harris and Merle DAubigne scores. The femoral components survival was considered as an endpoint of the revision replacement, which was 84% at a mean of 13 years. There were 9 intraoperative complications (6 were fractures) and they significantly affected the length of hospital stay. No post-operative complications were observed in 70% of the patients. None of the analysed variables had any influence on the radiological subsidence of the femoral component. DISCUSSION: Several techniques aim to solve the bone stock deficiency in revision total hip arthroplasty, but only impaction grafting attempts to recover it. CONCLUSIONS: The Ling's technique shows an improvement over the Merle DAubigne and Harris scores, in the medium long term. The intraoperative complications are mainly an increase in the length of hospital stay and the number of days needed to be able to sit down. Ling's technique is a good option to consider in young patients where it is foreseeable that there is a new revision surgery in the future. PMID- 26655210 TI - Bilateral posterior tarsal tunnel syndrome caused by accessory flexor digitorum longus; case report and surgical technique. AB - OBJECTIVE: To present a case report of bilateral posterior tarsal tunnel syndrome (PTTS) caused by an accessory flexor digitorum longus (AFDL), including the surgical technique and a review of the literature. MATERIALS AND METHODS: Twenty nine year old male diagnosed with bilateral PTTS, refractory to conservative management, with 53 points on the preoperative AOFAS score. MR of both ankles showed an AFDL within the tarsal tunnel, in close relationship to the posterior tibial nerve. Bilateral tarsal tunnel decompression and AFDL resection was performed. RESULTS: There were no post-operative complications. At 6 months after surgery, the patient had no pain and had 87 points on the AOFAS score. DISCUSSION: The PTTS is an entrapment neuropathy of the posterior tibial nerve or one of its terminal branches. A rare cause is the presence of an AFDL, and its resection is associated with good clinical results. Careful scar tissue resection and neurolysis is recommended. Knowing the normal pathway and anatomical variability of the posterior tibial nerve and its branches is essential to avoid iatrogenic injury. In our case report, MR and intraoperative findings identified a bilateral FDLA in close relationship to the common flexor digitorum, an unusual finding, with few reports in current literature. CONCLUSIONS: Careful tarsal tunnel decompression and AFDL resection in our patient with bilateral symptomatic PTTS has good clinical results and no complications, particularly when diagnosed and treated early. PMID- 26655211 TI - A Short Form of the Trauma Symptom Checklist for Children. AB - The purpose of the current study was to develop a short form (SF) of the Trauma Symptom Checklist for Children (TSCC). The TSCC-SF) maintained 29 items, from the original 54 items, in a sample (N = 215) of sexually abused children who were seeking treatment at a child advocacy center. Exploratory factor analysis refined the original measure, and confirmatory factor analysis provided evidence for best fit for a six-factor, 29-item model. The TSCC-SF evidenced good internal reliability and showed convergent validity with child ratings of post-traumatic stress disorder (PTSD) symptoms obtained from the University of California at Los Angeles PTSD Reaction Index. The TSCC-SF has promise as a shorter assessment measure with sexually abused children in numerous settings, including child advocacy centers and pediatric clinics, where efficient screening and assessment are essential for providing the best standard of care. PMID- 26655212 TI - Staged laparoscopic traction-orchiopexy for intraabdominal testis (Shehata technique): Stretching the limits for preservation of testicular vasculature. AB - BACKGROUND: We present the midterm results of the novel technique of two-stage laparoscopic traction orchiopexy (SLTO) for the high intraabdominal testis (IAT) for elongation of the testicular vessels without division. PATIENTS AND METHODS: Boys with IAT proven by laparoscopy were selected for the technique between September 2009 and April 2013 in 2 Egyptian pediatric surgery units. Boys <6months or >9years were excluded. The technique entails fixation of the testis to a point one inch above and medial to the contralateral anterior superior iliac spine for 12weeks. Subdartos orchiopexy is then done at the second stage. Both stages are laparoscopically assisted. RESULTS: SLTO was used in 124 boys (140 testis units) with IAT. Mean follow-up period was 16 (range 6-36) months. Scrotal testes were achieved in 105 (84%) of 125 followed cases. Success was correlated with patient age at operation and with distance of IAT from the internal inguinal ring with higher success in younger patients and in testes nearer to internal inguinal ring. CONCLUSION: The novel technique of two-stage laparoscopic traction orchiopexy is useful in IAT not amenable to one-stage laparoscopic-assisted orchiopexy; it resulted in significant elongation of testicular vessels without atrophy. It is a safe and valid alternative to two-stage laparoscopic Fowler Stephens technique, which entails division of the main testicular vessels. PMID- 26655213 TI - Antenatally diagnosed right-sided stomach (dextrogastria): A rare rotational anomaly. AB - AIM: Antenatal detection of right-sided stomach (dextrogastria) is rare, and its significance in regards to intestinal rotation is unclear. We aimed to review all cases of antenatally-diagnosed dextrogastria in our regional fetal medicine unit over 10years. METHODS: A retrospective case-note review of patients identified from a prospectively-maintained database was performed. RESULTS: Twenty cases of antenatally-diagnosed dextrogastria were identified from 2004 to 2014. There were 8 terminations and 1 intra-uterine death. One patient has no post-natal information obtainable. Ten infants were live-born, and 2 died secondary to cardiac disease in the neonatal period. All had significant cardiac/vascular anomaly on postnatal assessment, including the 3 neonates in whom dextrogastria was the only antenatal finding. Two neonates developed bilious vomiting and underwent Ladd's procedure. Operative findings were dextrogastria/malrotation in both. A third child had gastro-oesophageal reflux, and contrast demonstrated stable duodenal/midgut position. This child has not developed symptoms attributable to malrotation and not undergone surgery. All 3 of these infants had asplenia or polysplenia and were managed with antibiotic prophylaxis/immunisation. Five children in the series were not investigated for malrotation and have not come to surgical attention (one is known to be asplenic). CONCLUSION: Antenatally-detected dextrogastria, even if apparently isolated, was always associated with postnatal significant cardiovascular anomaly, splenic abnormality or situs inversus. This may be important for antenatal counselling. We currently recommend postnatal echocardiography and splenic assessment, but reserve GI investigation/intervention for symptomatic malrotation owing to potential significant cardiac comorbidity. PMID- 26655214 TI - The burden of pediatric surgical disease in low-resource settings: Discovering it, measuring it, and addressing it. AB - Global surgery has come of age as an emerging discipline poised to impact health care worldwide with a concerted plan of action and wide stakeholder support. Much less can be said about global pediatric surgery, despite a growing awareness of the global burden of pediatric surgical disease. The author describes his exposure to this burden of disease as a pediatric surgeon working in resource limited countries in Africa and outlines his personal journey from recognizing the burden to measuring it and eventually attempting to address it. The article, based on the Hugh Greenwood International Lecture at the 2015 BAPS Congress, reviews what is known so far within global pediatric surgery, what is currently happening, and what lies ahead. PMID- 26655215 TI - Outcome after introduction of laparoscopic appendectomy in children: A cohort study. AB - INTRODUCTION: Acute appendicitis in children is common and the optimal treatment modality is still debated, even if recent data suggest that laparoscopic surgery may result in shorter postoperative length of stay without an increased number of complications. The aim of the study was to compare the outcome of open and laparoscopic appendectomies during a transition period. MATERIALS AND METHODS: This was a retrospective cohort study with prospectively collected data. All patients who underwent an operation for suspected appendicitis at the Astrid Lindgren Children's Hospital in Stockholm between 2006 and 2010 were included in the study. RESULTS: 1745 children were included in this study, of whom 1010 had a laparoscopic intervention. There were no significant differences in the rate of postoperative abscesses, wound infections, readmissions or reoperations between the two groups. The median operating time was longer for laparoscopic appendectomy than for open appendectomy, 51 vs. 37minutes (p<0.05). The postoperative length of stay was similar in the two groups. A simple comparison between the groups suggested that laparoscopic appendectomy had a shorter median postoperative length of stay, 43 vs. 57hours (p<0.05). However, there was a trend in time for a shorter postoperative length of stay, and a trend for more of the procedures to be performed laparoscopically over time so on regression analysis, the apparent decrease in length of stay with laparoscopy could be ascribed to the general trend toward decreased length of stay over time, with no specific additional effect of laparoscopy. CONCLUSIONS: Our data show no difference in outcome between open and laparoscopic surgery for acute appendicitis in children in regard of complications. The initial assumption that the patients treated with laparoscopic surgery had a shorter postoperative stay was not confirmed with linear regression, which showed that the assumed difference was due only to a trend toward shorter postoperative length of stay over time, regardless of the surgical intervention. PMID- 26655216 TI - Prenatally diagnosed severe CDH: mortality and morbidity remain high. AB - PURPOSE: This study sought to evaluate prenatal markers' ability to predict severe congenital diaphragmatic hernia(CDH) and assess this subgroup's morbidity and mortality. METHODS: A retrospective review was performed between 2006 and 2014. Prenatal criteria for severe CDH included: liver herniation, lung-to-head ratio (LHR) <1 on prenatal ultrasound and/or observed-to-expected LHR (o/eLHR) <25%, and/or observed-to-expected total lung volume (o/eTLV) <25% on fetal MRI. Postnatal characteristics included: mortality, ECMO utilization, patch closure, persistent suprasystemic pulmonary hypertension (PHtn), O2 requirement at discharge, and few ventilator-free days in the first 60. Statistics performed used unpaired t-test, p<0.05 significant. RESULTS: Overall, 47.5%(29/61) of patients with prenatally diagnosed, isolated CDH met severe criteria. Mean LHR: 1.04+/-0.35, o/eLHR: 31+/-10% and o/eTLV: 20+/-7%. Distribution was 72% LCDH, 24% R-CDH. Overall survival: 38%. ECMO requirement: 92%. Patch rate: 91%. Mean ventilator-free days in 60: 7.1+/-14. Supplemental oxygen at discharge was required in 27%. In this prenatally diagnosed severe cohort, 58%(15/26) had persistent PHtn post-ECMO requiring inhaled nitric oxide+/-epoprostenol. Comparing patients with and without PHtn: mean ECMO duration 18+/-10 days versus 9+/-7 days (p=0.01) and survival 20% versus 72% (p=0.006). CONCLUSION: A combination of prenatal markers accurately identified severe CDH patients. Outcomes of this group remain poor and persistent PHtn contributes significantly to mortality. PMID- 26655217 TI - Ultrasound-Guided Interventional Procedures in Pain Medicine: A Review of Anatomy, Sonoanatomy, and Procedures: Part VI: Ankle Joint. AB - Ultrasound-guided injections in pain medicine are emerging as a popular technique for pain interventions. Ultrasound can be applied for procedures of the ankle joint and surrounding structures. This review describes the anatomy and sonoanatomy of the ankle joint, subtalar joint, and surrounding extra-articular structures relevant for intra-articular injection. Second, it reviews injection techniques and the accuracy and efficacy of these intra-articular ankle injections. PMID- 26655218 TI - The Development and Validation of a Quality Assessment and Rating of Technique for Injections of the Spine (AQUARIUS). AB - BACKGROUND AND OBJECTIVES: Systematic reviews evaluate the utility of procedural interventions of the spine, including epidural steroid injections (ESIs). However, existing quality assessment tools either fail to account for proper technical quality and patient selection or are not validated. We developed and validated a simple scale for ESIs to provide a quality assessment and rating of technique for injections of the spine (AQUARIUS). METHODS: Seven experts generated items iteratively based on prior ESI technique studies and professional judgment. Following testing for face and content validity, a 17-item instrument was used by 8 raters from 2 different backgrounds to assess 12 randomized controlled trials, selected from 3 different categories. Using frequency of assessment, a 12-item instrument was also generated. Both instruments underwent reliability (intraclass correlation coefficient), validity (ability to distinguish "low," "random," and "high" study categories), and diagnostic accuracy (receiver operating characteristics) testing. RESULTS: Both 17- and 12 item instruments were scored consistently by raters regardless of background, with overall intraclass correlation coefficients of 0.72 (95% confidence interval [CI], 0.53-0.89) and 0.71 (95% CI, 0.51-0.89), respectively. Both instruments discriminated between clinical trials from all 3 categories. Diagnostic accuracy was similar for the 2 instruments, with areas under receiver operating characteristic curves of 0.89 (95% CI, 0.82-0.96) and 0.90 (95% CI, 0.82-0.97), respectively. CONCLUSIONS: The instrument in both 17- and 12-item formats demonstrates good reliability and diagnostic accuracy in rating ESI studies. As a complement to other tools that assess bias, the instrument may improve the ability to evaluate evidence for systematic reviews and improve clinical trial design. PMID- 26655219 TI - Epidural Steroid Injections for Radiculopathy and/or Back Pain in Children and Adolescents: A Retrospective Cohort Study With a Prospective Follow-Up. AB - BACKGROUND AND OBJECTIVES: Epidural steroid injections (ESIs) are commonly performed for adults with spinal pain and/or radiculopathy. Previous pediatric ESI case series were not identified by literature review. The primary aim of this study was to examine the safety and provisional outcomes of pediatric ESIs. METHODS: With institutional review board approval, medical records were reviewed for patients aged 9 to 20 years receiving a first ESI at Boston Children's Hospital from 2003 through 2013. A subset of patients completed a Web-based follow-up questionnaire. Descriptive statistics included frequencies, medians, interquartile ranges, and Kaplan-Meier methods. Statistical comparisons were made using Wilcoxon rank sum, chi2, Fisher exact, and Cox proportional hazards regression analyses. RESULTS: A total of 224 patients aged 9 to 20 years underwent 428 ESIs. One hundred seventy-four (76.0%) patients had a lumbar disc herniation with radiculopathy; the others had a spectrum of other spinal disorders. There were no serious adverse events, hospitalizations, dural punctures, or nerve injuries. During follow-up, 69 (41.6%) of 166 previously nonoperated lumbar disc plus radiculopathy patients underwent discectomy at a median time of 128 days (interquartile range, 76-235 days) after first injection. Degrees of straight-leg raising at presentation was significantly associated with subsequent discectomy. On follow-up, patients who did and did not undergo discectomy had low pain scores and high function scores. CONCLUSIONS: Children and adolescents can receive ESIs under conscious sedation with good safety. Further prospective studies may better define the role for these injections in the comprehensive management of pediatric spinal pain disorders. PMID- 26655220 TI - Wilms Tumor Suppressor, WT1, Cooperates with MicroRNA-26a and MicroRNA-101 to Suppress Translation of the Polycomb Protein, EZH2, in Mesenchymal Stem Cells. AB - Hereditary forms of Wilms arise from developmentally arrested clones of renal progenitor cells with biallelic mutations of WT1; recently, it has been found that Wilms tumors may also be associated with biallelic mutations in DICER1 or DROSHA, crucial for miRNA biogenesis. We have previously shown that a critical role for WT1 during normal nephrogenesis is to suppress transcription of the Polycomb group protein, EZH2, thereby de-repressing genes in the differentiation cascade. Here we show that WT1 also suppresses translation of EZH2. All major WT1 isoforms induce an array of miRNAs, which target the 3' UTR of EZH2 and other Polycomb-associated transcripts. We show that the WT1(+KTS) isoform binds to the 5' UTR of EZH2 and interacts directly with the miRNA-containing RISC to enhance post-transcriptional inhibition. These observations suggest a novel mechanism through which WT1 regulates the transition from resting stem cell to activated progenitor cell during nephrogenesis. Our findings also offer a plausible explanation for the fact that Wilms tumors can arise either from loss of WT1 or loss of miRNA processing enzymes. PMID- 26655221 TI - Molecular Determinants of Kv1.3 Potassium Channels-induced Proliferation. AB - Changes in voltage-dependent potassium channels (Kv channels) associate to proliferation in many cell types, including transfected HEK293 cells. In this system Kv1.5 overexpression decreases proliferation, whereas Kv1.3 expression increases it independently of K(+) fluxes. To identify Kv1.3 domains involved in a proliferation-associated signaling mechanism(s), we constructed chimeric Kv1.3 Kv1.5 channels and point-mutant Kv1.3 channels, which were expressed as GFP- or cherry-fusion proteins. We studied their trafficking and functional expression, combining immunocytochemical and electrophysiological methods, and their impact on cell proliferation. We found that the C terminus is necessary for Kv1.3 induced proliferation. We distinguished two residues (Tyr-447 and Ser-459) whose mutation to alanine abolished proliferation. The insertion into Kv1.5 of a sequence comprising these two residues increased proliferation rate. Moreover, Kv1.3 voltage-dependent transitions from closed to open conformation induced MEK ERK1/2-dependent Tyr-447 phosphorylation. We conclude that the mechanisms for Kv1.3-induced proliferation involve the accessibility of key docking sites at the C terminus. For one of these sites (Tyr-447) we demonstrated the contribution of MEK/ERK-dependent phosphorylation, which is regulated by voltage-induced conformational changes. PMID- 26655223 TI - Concomitant Wolff-Parkinson-White and Atrioventricular Nodal Reentrant Tachycardia: Which Pathway to Ablate? AB - BACKGROUND: Atrioventricular nodal reentrant tachycardia (AVNRT) is the most common form of supraventricular tachycardia. In contrast, Wolff-Parkinson-White (WPW) pattern consists of an accessory pathway, which may result in the development of ventricular arrhythmias. Frequent tachycardia caused by AVNRT and accessory pathways may play a role in left ventricular systolic dysfunction. CASE REPORT: A 54-year-old man presented with palpitations and acute decompensated congestive heart failure. His baseline EKG showed Wolff-Parkinson-White (WPW) pattern. While hospitalized, he had an episode of atrioventricular nodal reentrant tachycardia (AVNRT). He underwent radiofrequency catheter ablation for AVNRT, and his accessory pathway was also ablated even though its conduction was found to be weak. He was clinically doing well on follow-up visit, with resolution of his heart failure symptoms and normalization of left ventricular function on echocardiography. CONCLUSIONS: This case raises the question whether the accessory pathway plays a role in the development of systolic dysfunction, and if there is any role for ablation in patients with asymptomatic WPW pattern. PMID- 26655222 TI - Treatment of Hypertension in Patients with Coronary Artery Disease. A Case-Based Summary of the 2015 AHA/ACC/ASH Scientific Statement. AB - The 2015 American Heart Association/American College of Cardiology/American Society of Hypertension Scientific Statement "Treatment of Hypertension in Patients with Coronary Artery Disease" is summarized in the context of a clinical case. The Statement deals with target blood pressures, and the optimal agents for the treatment of hypertension in patients with stable angina, in acute coronary syndromes, and in patients with ischemic heart failure. In all cases, the recommended blood pressure target is <140/90 mm Hg, but <130/80 mm Hg may be appropriate, especially in those with a history of a previous myocardial infarction or stroke, or at high risk for developing either. These numbers may need to be revised after the publication of the SPRINT data. Appropriate management should include beta-blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and in the case of heart failure, aldosterone antagonists. Thiazide or thiazide-like (chlorthalidone) diuretics and calcium channel blockers can be used for the management of hypertension, but the evidence for improved outcomes compared with other agents in hypertension with coronary artery disease is meager. Loop diuretics should be reserved for patients with New York Heart Association Class III and IV heart failure or with a glomerular filtration rate of <30 mL/min. PMID- 26655224 TI - Endurance time, muscular activity and the hand/arm tremor for different exertion forces of holding. AB - This study aimed to examine the effects of exertion force on endurance time, muscular activity and hand/arm tremor during holding. Fifteen healthy young males were recruited as participants. The independent variable was exertion force (20%, 40%, 60% and 80% maximum holding capacity). The dependent variables were endurance time, muscular activity and hand/arm tremor. The results showed that endurance time decreased with exertion force while muscular activity and hand/arm tremor increased with exertion force. Hand/arm tremor increased with holding time. Endurance time of 40%, 60% and 80% maximum holding capacity was approximately 22.7%, 12.0% and 5.6% of that of 20% maximum holding capacity, respectively. The rms (root mean square) acceleration of hand/arm tremor of the final phase of holding was 2.27-, 1.33-, 1.20- and 1.73-fold of that of the initial phase of holding for 20%, 40%, 60% and 80% maximum holding capacity, respectively. PMID- 26655225 TI - Chemical footprinting reveals conformational changes of 18S and 28S rRNAs at different steps of translation termination on the human ribosome. AB - Translation termination in eukaryotes is mediated by release factors: eRF1, which is responsible for stop codon recognition and peptidyl-tRNA hydrolysis, and GTPase eRF3, which stimulates peptide release. Here, we have utilized ribose specific probes to investigate accessibility of rRNA backbone in complexes formed by association of mRNA- and tRNA-bound human ribosomes with eRF1*eRF3*GMPPNP, eRF1*eRF3*GTP, or eRF1 alone as compared with complexes where the A site is vacant or occupied by tRNA. Our data show which rRNA ribose moieties are protected from attack by the probes in the complexes with release factors and reveal the rRNA regions increasing their accessibility to the probes after the factors bind. These regions in 28S rRNA are helices 43 and 44 in the GTPase associated center, the apical loop of helix 71, and helices 89, 92, and 94 as well as 18S rRNA helices 18 and 34. Additionally, the obtained data suggest that eRF3 neither interacts with the rRNA ribose-phosphate backbone nor dissociates from the complex after GTP hydrolysis. Taken together, our findings provide new information on architecture of the eRF1 binding site on mammalian ribosome at various translation termination steps and on conformational rearrangements induced by binding of the release factors. PMID- 26655227 TI - Tobacco companies take UK to court over "standardised packaging" regulations. PMID- 26655226 TI - Reduced levels of protein recoding by A-to-I RNA editing in Alzheimer's disease. AB - Adenosine to inosine (A-to-I) RNA editing, catalyzed by the ADAR enzyme family, acts on dsRNA structures within pre-mRNA molecules. Editing of the coding part of the mRNA may lead to recoding, amino acid substitution in the resulting protein, possibly modifying its biochemical and biophysical properties. Altered RNA editing patterns have been observed in various neurological pathologies. Here, we present a comprehensive study of recoding by RNA editing in Alzheimer's disease (AD), the most common cause of irreversible dementia. We have used a targeted resequencing approach supplemented by a microfluidic-based high-throughput PCR coupled with next-generation sequencing to accurately quantify A-to-I RNA editing levels in a preselected set of target sites, mostly located within the coding sequence of synaptic genes. Overall, editing levels decreased in AD patients' brain tissues, mainly in the hippocampus and to a lesser degree in the temporal and frontal lobes. Differential RNA editing levels were observed in 35 target sites within 22 genes. These results may shed light on a possible association between the neurodegenerative processes typical for AD and deficient RNA editing. PMID- 26655228 TI - Water-only fasting and an exclusively plant foods diet in the management of stage IIIa, low-grade follicular lymphoma. AB - Follicular lymphoma (FL), the second most common non-Hodgkin's lymphoma (NHL), is well characterised by a classic histological appearance and an indolent course. Current treatment protocols for FL range from close observation to immunotherapy, chemotherapy and/or radiotherapies. We report the case of a 42-year-old woman diagnosed by excisional biopsy with stage IIIa, grade 1 FL. In addition to close observation, the patient underwent a medically supervised, 21-day water-only fast after which enlarged lymph nodes were substantially reduced in size. The patient then consumed a diet of minimally processed plant foods free of added sugar, oil and salt (SOS), and has remained on the diet since leaving the residential facility. At 6 and 9-month follow-up visits, the patient's lymph nodes were non palpable and she remained asymptomatic. This case establishes a basis for further studies evaluating water-only fasting and a plant foods, SOS-free diet as a treatment protocol for FL. PMID- 26655229 TI - Chemothorax: a rare cause of a transudative pleural effusion. AB - We discovered a rare cause of pleural effusion, chemothorax. In this case, a patient with invasive ductal breast carcinoma was admitted for a large and symptomatic pleural effusion. The radiology report obtained prior to admission did not describe the location of the Infuse-a-Port catheter. After a bedside thoracentesis demonstrated results consistent with chemotherapy infusate in the pleural space, further review of the medical imaging demonstrated that the catheter was in the pleural space. PMID- 26655230 TI - Longitudinal melanonychia. PMID- 26655231 TI - Effects of nano bamboo charcoal on PAHs-degrading strain Sphingomonas sp. GY2B. AB - Nano bamboo charcoal (NBC) has been commonly used in the production of textiles, plastics, paint, etc. However, little is known regarding their effects towards the microorganisms. The effects of NBC on phenanthrene degrading strain Sphingomonas sp. GY2B were investigated in the present study. Results showed that the addition of NBC could improve the phenanthrene removal by Sphingomonas sp. GY2B, with removal efficiencies increased by 10.29-18.56% in comparison to the control at 24h, and phenanthrene was almost completely removed at 48h. With the presence of low dose of NBC (20 and 50mgL(-1)), strain GY2B displayed a better growth at 6h, suggesting that NBC was beneficial to the growth of GY2B and thus resulting in the quick removal of phenanthrene from water. However, the growth of strain GY2B in high dose of NBC (200mgL(-1)) was inhibited at 6h, and the inhibition could be attenuated and eliminated after 12h. NBC-effected phenanthrene solubility experiment suggested that NBC makes a negligible contribution to the solubilization of phenanthrene in water. Results of electronic microscopy analysis (SEM and TEM) indicated NBC may interact with the cell membrane, causing the enhanced membrane permeability and then NBC adsorbed on the membrane would enter into the cells. The findings of this work would provide important information for the future usage and long-term environmental risk assessment of NBC. PMID- 26655232 TI - Clams sensitivity towards As and Hg: A comprehensive assessment of native and exotic species. AB - To assess the environmental impact of As and Hg, bioindicator organisms such as bivalves have been used. Nevertheless, few studies have assessed the impacts of As and Hg in Ruditapes decussatus and Ruditapes philippinarum, which are native and exotic species in Europe, respectively. The main goal of the present study was to assess elements' partitioning and detoxification strategies of R. decussatus and R. philippinarum. Both clams showed a higher capacity to bioconcentrate Hg (BCF 2.29-7.49), when compared to As (0.59-1.09). Furthermore, As accumulation in both species was similar in the soluble and insoluble fractions, while in both species the majority of Hg was found in the insoluble fraction. Clams exposed to As showed different detoxification strategies, since R. decussatus had higher ability to enhance antioxidant enzymes and metallothioneins in order to reduce toxicity, and R.philippinarum increased glutathione S-transferase Omega activity, that catalyzes monomethyl arsenate reduction, the rate-limiting reaction in arsenic biotransformation. When exposed to Hg, R. decussatus presented, higher synthesis of antioxidant enzymes and lower LPO, being able to better tolerate Hg than the exotic species R. philippinarum. Thus under relevant levels of As and Hg contamination our work evidenced the higher ability of R. decussatus to survive and inhabit coastal environments not heavily contaminated by Hg and As. PMID- 26655233 TI - Assessing adsorption of polycyclic aromatic hydrocarbons on Rhizopus oryzae cell wall components with water-methanol cosolvent model. AB - The contribution of different fungal cell wall components in adsorption of polycyclic aromatic hydrocarbons (PAHs) is still unclear. We isolated Rhizopus oryzae cell walls components with sequential extraction, characterized functional groups with NEXAFS spectra, and determined partition coefficients of PAHs on cell walls and cell wall components with cosolvent model. Spectra of NEXAFS indicated that isolated cell walls components were featured with peaks at ~532.7 and ~534.5eV energy. The lipid cosolvent partition coefficients were approximately one order of magnitude higher than the corresponding carbohydrate cosolvent partition coefficients. The partition coefficients for four tested carbohydrates varied at approximate 0.5 logarithmic units. Partition coefficients between biosorbents and water calculated based cosolvent models ranged from 0.8 to 4.2. The present study proved the importance of fungal cell wall components in adsorption of PAHs, and consequently the role of fungi in PAHs bioremediation. PMID- 26655234 TI - Increased Ratio of Trunk-to-Appendicular Fat and Decreased Adiponectin: A Population-Based Study of School Children in Hamamatsu, Japan. AB - Very few epidemiological studies have examined the relative impact of visceral fat and subcutaneous fat on serum adiponectin levels. Trunk-to-extremity fat ratio is reportedly a better surrogate for visceral fat than for subcutaneous fat. In the present study, we investigated the association between adiponectin and trunk-to-appendicular fat ratio (TAR) in a school population. The source population was all fifth graders (799 pupils) enrolled in the 2 elementary schools in Hamamatsu, Japan. Of the source population, we analyzed cross sectional data from 609 children (mean age: 11.2 yr). TAR was evaluated by dual energy X-ray absorptiometry and calculated as trunk fat mass divided by appendicular (arms and legs) fat mass. After stratification by tertiles of total body fat, multiple regression analysis was used to examine the relationships between adiponectin and TAR adjusted for potential confounding factors. In the highest tertile of total body fat, increasing TARs were significantly (p < 0.05) associated with decreasing serum adiponectin levels after stratification by total body fat (beta = -0.32 in boys; beta = -0.31 in girls). In the second tertile of total body fat, TAR in girls also showed significant inverse relationships with serum adiponectin levels (beta = -0.27). Data from this population-based study demonstrated that an increased proportion of trunk fat is associated with decreased adiponectin in relatively overweight children, and also demonstrated that girls with a normal volume of body fat that follows a more centralized distribution show decreased adiponectin. PMID- 26655235 TI - The pseudorabies virus protein, pUL56, enhances virus dissemination and virulence but is dispensable for axonal transport. AB - Neurotropic herpesviruses exit the peripheral nervous system and return to exposed body surfaces following reactivation from latency. The pUS9 protein is a critical viral effector of the anterograde axonal transport that underlies this process. We recently reported that while pUS9 increases the frequency of sorting of newly assembled pseudorabies virus particles to axons from the neural soma during egress, subsequent axonal transport of individual virus particles occurs with wild-type kinetics in the absence of the protein. Here, we examine the role of a related pseudorabies virus protein, pUL56, during neuronal infection. The findings indicate that pUL56 is a virulence factor that supports virus dissemination in vivo, yet along with pUS9, is dispensable for axonal transport. PMID- 26655236 TI - Changes in global gene expression profiles induced by HPV 16 E6 oncoprotein variants in cervical carcinoma C33-A cells. AB - We analyzed the effects of the expression of HPV 16 E6 oncoprotein variants (AA a, AA-c, E-A176/G350, E-C188/G350, E-G350), and the E-Prototype in global gene expression profiles in an in vitro model. E6 gene was cloned into an expression vector fused to GFP and was transfected in C33-A cells. Affymetrix GeneChip Human Transcriptome Array 2.0 platform was used to analyze the expression of over 245,000 coding transcripts. We found that HPV16 E6 variants altered the expression of 387 different genes in comparison with E-Prototype. The altered genes are involved in cellular processes related to the development of cervical carcinoma, such as adhesion, angiogenesis, apoptosis, differentiation, cell cycle, proliferation, transcription and protein translation. Our results show that polymorphic changes in HPV16 E6 natural variants are sufficient to alter the overall gene expression profile in C33-A cells, explaining in part the observed differences in oncogenic potential of HPV16 variants. PMID- 26655237 TI - Human papillomavirus types 16 E1 mRNA is transcribed from P14 early promoter in cervical neoplasms. AB - High-risk human papillomavirus (HR-HPV) persistent infection is responsible for the development of the majority of cervical cancers. The therapy against HPV associated cancer requires knowledge of the viral gene expression mechanisms. In this study, the polyadenylated polycistronic transcripts containing full-size E1ORF and produced from the early P14 promoter were detected for the first time in cervical tumors with episomal forms of the HPV16 genome. P14-initiated mRNAs were revealed also in precancerous lesions. The amount of P14-initiated transcripts was significantly less compared to transcripts initiated from the major P97 HPV16 promoter in cervical intraepithelial neoplasms and squamous cell carcinomas. The ratios of P97/P14-transcripts determined by qRT-PCR were unique for each clinical sample and varied in quite wide ranges independent of disease progression stages or tumor grade. These data suggest that the levels of P14- and P97-transcripts are regulated independently from each other in cervical neoplasms. PMID- 26655239 TI - Rabies virus phosphoprotein interacts with ribosomal protein L9 and affects rabies virus replication. AB - Rabies virus is a highly neurotropic virus that can cause fatal infection of the central nervous system in warm-blooded animals. The RABV phosphoprotein (P), an essential cofactor of the virus RNA-dependent RNA polymerase, is required for virus replication. In this study, the ribosomal protein L9, which has functions in protein translation, is identified as P-interacting cellular factor using phage display analysis. Direct binding between the L9 and P was confirmed by protein pull-down and co-immunoprecipitation analyses. It was further demonstrated that L9 translocates from the nucleus to the cytoplasm, where it colocalizes with P in cells infected with RABV or transfected with P gene. RABV replication was reduced with L9 overexpression and enhanced with L9 knockdown. Thus, we propose that during RABV infection, P binds to L9 that translocates from the nucleus to the cytoplasm, inhibiting the initial stage of RABV transcription. PMID- 26655238 TI - Cell-cell contact promotes Ebola virus GP-mediated infection. AB - Ebola virus (EBOV) is a highly pathogenic filovirus that causes hemorrhagic fever in humans and animals. Here we provide evidence that cell-cell contact promotes infection mediated by the glycoprotein (GP) of EBOV. Interestingly, expression of EBOV GP alone, even in the absence of retroviral Gag-Pol, is sufficient to transfer a retroviral vector encoding Tet-off from cell to cell. Cell-to-cell infection mediated by EBOV GP is blocked by inhibitors of actin polymerization, but appears to be less sensitive to KZ52 neutralization. Treatment of co-cultured cells with cathepsin B/L inhibitors, or an entry inhibitor 3.47 that targets the receptor NPC1 for virus binding, also blocks cell-to-cell infection. Cell-cell contact also enhances spread of rVSV bearing GP in monocytes and macrophages, the primary targets of natural EBOV infection. Altogether, our study reveals that cell-cell contact promotes EBOV GP-mediated infection, and provides new insight into understanding EBOV spread and viral pathogenesis. PMID- 26655240 TI - Poultry vaccination directed evolution of H9N2 low pathogenicity avian influenza viruses in Korea. AB - Significant economic losses in the poultry industries have resulted from H9N2 low pathogenic avian influenza virus infections across North Africa, the Middle East and Asia. The present study investigated the evolutionary dynamics of H9N2 viruses circulating in Korea from 1996 to 2012. Our analysis of viral population dynamics revealed an increase in genetic diversity between the years 2003 and 2007, corresponding to the spread and diversification of H9N2 viruses into multiple genetic groups (named A and B), followed by a sudden decrease in 2007, which was associated with implementation of vaccination using a Clade A virus. Implementation of the H9N2 vaccination program in Korea has dramatically reduced the diversity of H9N2 virus, and only one sub-lineage of clade B has survived, expanded, and currently circulates in Korea. In addition, the antigenic drift of this new genetic group away from the current vaccine strain suggests the need to update the vaccine seed strain. PMID- 26655241 TI - Pathogenicity and tissue tropism of infectious bronchitis virus is associated with elevated apoptosis and innate immune responses. AB - To establish a characteristic host response to predict the pathogenicity and tissue tropism of infectious bronchitis viruses (IBV), we investigated innate immune responses (IIR) and apoptosis in chicken embryo kidney cells (CEKC) and tracheal organ cultures (TOC) infected with three IBV strains. Results showed nephropathogenic IBV strains 885 and QX induced greater apoptosis in CEKC than M41, which induced greater apoptosis in TOCs compared to 885 and QX. Elevated IIR is associated with tissue tropism of different IBV strains. Compared to M41, 885 and QX caused greater induction of toll like receptor 3 (TLR3), melanoma differentiation associated protein 5 (MDA5) and interferon beta (IFN-beta) in CEKC. In contrast, M41 infection caused greater expression of these genes than 885 or QX in TOCs. In summary, greater levels of apoptosis and elevated levels of TLR3, MDA5 and IFN-beta expression are associated with increased pathogenicity of IBV strains in renal and tracheal tissues. PMID- 26655242 TI - PhiXing-it, displaying foreign peptides on bacteriophage PhiX174. AB - Although bacteriophage phiX174 is easy to propagate and genetically tractable, it is use as a peptide display platform has not been explored. One region within the phiX174 major spike protein G tolerated 13 of 16 assayed insertions, ranging from 10 to 75 amino acids. The recombinant proteins were functional and incorporated into infectious virions. In the folded protein, the peptides would be icosahedrally displayed within loops that extend from the protein's beta-barrel core. The well-honed genetics of phiX174 allowed permissive insertions to be quickly identified by the cellular phenotypes associated with cloned gene expression. The cloned genes were easily transferred from plasmids to phage genomes via recombination rescue. Direct ELISA validated several recombinant virions for epitope display. Some insertions conferred a temperature-sensitive (ts) protein folding defect, which was suppressed by global suppressors in protein G, located too far away from the insertion to directly alter peptide display. PMID- 26655243 TI - Identification of small molecules acting against H1N1 influenza A virus. AB - Influenza virus represents a serious threat to public health. The lack of effective drugs against flu prompted researchers to identify more promising viral target. In this respect hemagglutinin (HA) can represent an interesting option because of its pivotal role in the infection process. With this aim we collected a small library of commercially available compounds starting from a large database and performing a diversity-based selection to reduce the number of screened compounds avoiding structural redundancy of the library. Selected compounds were tested for their hemagglutination-inhibiting (HI) ability against two different A/H1N1 viral strains (one of which is oseltamivir sensitive), and 17 of them showed the ability to interact with HA. Five drug-like molecules, in particular, were able to impair hemagglutination of both A/H1N1 viral strains under study and to inhibit cytopathic effect and hemolysis at sub-micromolar level. PMID- 26655244 TI - Autographa californica multiple nucleopolyhedrovirus GP64 protein: Analysis of domain I and V amino acid interactions and membrane fusion activity. AB - The Autographa californica multiple nucleopolyhedrovirus GP64 is a class III viral fusion protein. Although the post-fusion structure of GP64 has been solved, its pre-fusion structure and the detailed mechanism of conformational change are unknown. In GP64, domain V is predicted to interact with two domain I segments that flank fusion loop 2. To evaluate the significance of the amino acids involved in these interactions, we examined 24 amino acid positions that represent interacting and conserved residues within domains I and V. In several cases, substitution of a single amino acid involved in a predicted interaction disrupted membrane fusion activity, but no single amino acid pair appears to be absolutely required. We identified 4 critical residues in domain V (G438, W439, T452, and T456) that are important for membrane fusion, and two residues (G438 and W439) that appear to be important for formation or stability of the pre fusion conformation of GP64. PMID- 26655245 TI - Low dNTP levels are necessary but may not be sufficient for lentiviral restriction by SAMHD1. AB - SAMHD1 is a cellular dNTPase that restricts lentiviral infection presumably by lowering cellular dNTP levels to below a critical threshold required for reverse transcription; however, lowering cellular dNTP levels may not be the sole mechanism of restriction. In particular, an exonuclease activity of SAMHD1 was reported to contribute to virus restriction. We further investigated the requirements for SAMHD1 restriction activity in both differentiated U937 and cycling HeLa cells. Using hydroxyurea treatment to lower baseline dNTP levels in HeLa cells, we were able to document efficient SAMHD1 restriction without significant further reduction in dNTP levels by SAMHD1. These results argue against a requirement for additional myeloid-specific host factors for SAMHD1 function but further support the notion that SAMHD1 possesses an additional dNTP independent function contributing to lentiviral restriction. However, our own experiments failed to associate this presumed additional SAMHD1 antiviral activity with a reported nuclease activity. PMID- 26655246 TI - The dengue virus non-structural protein 1 (NS1) is secreted efficiently from infected mosquito cells. AB - Dengue virus NS1 is a glycoprotein of 46-50kDa which associates as a dimer to internal and cytoplasmic membranes and is also secreted, as a hexamer, to the extracellular milieu. However, the notion exist that NS1 is secreted only from infected vertebrate and not mosquito cells. In this work, evidence is presented showing that NS1 is secreted efficiently by infected mosquito cells. NS1 was detected in cell supernatants starting at 6hpi with a continuous concentration increase up to 24hpi. Nevertheless, cell viability showed an average cell survival of 97%. At variance with observations with vertebrate cells, NS1 does not seems to associate with the cytoplasmic membrane of insect cells. Finally, evidence is presented indicating that NS1 is secreted from insect cells as a barrel-shaped hexamer. These findings provide new insights into the biology of NS1 and open questions about the role of secreted NS1 in the vector mosquito. PMID- 26655247 TI - Evidence-Based Management Of Accidental Hypothermia In The Emergency Department. AB - Accidental hypothermia is defined as an unintentional drop in core body temperature below 35 degrees C. It can present in any climate and in any season, as it is not always a result of environmental exposure; underlying illnesses or coexisting pathology can play important roles. Although there is some variability in clinical presentation, hypothermia produces a predictable pattern of physiologic responses and clinical manifestations, and effective treatment has yielded many impressive survival case reports. Treatment strategies focus on prevention of further heat loss, volume resuscitation, implementation of appropriate rewarming techniques, and management of cardiac dysrhythmia. Rewarming may be passive or active and/or internal or external, depending on severity and available resources. This issue focuses on methods of effective rewarming and prevention of further morbidity and mortality. PMID- 26655248 TI - Weakly Bound Free Radicals in Combustion: "Prompt" Dissociation of Formyl Radicals and Its Effect on Laminar Flame Speeds. AB - Weakly bound free radicals have low-dissociation thresholds such that at high temperatures, time scales for dissociation and collisional relaxation become comparable, leading to significant dissociation during the vibrational-rotational relaxation process. Here we characterize this "prompt" dissociation of formyl (HCO), an important combustion radical, using direct dynamics calculations for OH + CH2O and H + CH2O (key HCO-forming reactions). For all other HCO-forming reactions, presumption of a thermal incipient HCO distribution was used to derive prompt dissociation fractions. Inclusion of these theoretically derived HCO prompt dissociation fractions into combustion kinetics models provides an additional source for H-atoms that feeds chain-branching reactions. Simulations using these updated combustion models are therefore shown to enhance flame propagation in 1,3,5-trioxane and acetylene. The present results suggest that HCO prompt dissociation should be included when simulating flames of hydrocarbons and oxygenated molecules and that prompt dissociations of other weakly bound radicals may also impact combustion simulations. PMID- 26655249 TI - Limitation of the Use of the Absorption Angstrom Exponent for Source Apportionment of Equivalent Black Carbon: a Case Study from the North West Indo Gangetic Plain. AB - Angstrom exponent measurements of equivalent black carbon (BCeq) have recently been introduced as a novel tool to apportion the contribution of biomass burning sources to the BCeq mass. The BCeq is the mass of ideal BC with defined optical properties that, upon deposition on the aethalometer filter tape, would cause equal optical attenuation of light to the actual PM2.5 aerosol deposited. The BCeq mass hence is identical to the mass of the total light-absorbing carbon deposited on the filter tape. Here, we use simultaneously collected data from a seven-wavelength aethalometer and a high-sensitivity proton-transfer reaction mass spectrometer installed at a suburban site in Mohali (Punjab), India, to identify a number of biomass combustion plumes. The identified types of biomass combustion include paddy- and wheat-residue burning, leaf litter, and garbage burning. Traffic plumes were selected for comparison. We find that the combustion efficiency, rather than the fuel used, determines alphaabs, and consequently, the alphaabs can be ~1 for flaming biomass combustion and >1 for older vehicles that operate with poorly optimized engines. Thus, the absorption angstrom exponent is not representative of the fuel used and, therefore, cannot be used as a generic tracer to constrain source contributions. PMID- 26655250 TI - Multifunctional Bismuth Selenide Nanocomposites for Antitumor Thermo-Chemotherapy and Imaging. AB - To integrate real-time monitoring and therapeutic functions into a single nanoagent, we have designed and synthesized a drug-delivery platform based on a polydopamine(PDA)/human serum albumin (HSA)/doxorubicin (DOX) coated bismuth selenide (Bi2Se3) nanoparticle (NP). The resultant product exhibits high stability and biocompatibility both in vitro and in vivo. In addition to the excellent capability for both X-ray computed tomography (CT) and infrared thermal imaging, the NPs possess strong near-infrared (NIR) absorbance, and high capability and stability of photothermal conversion for efficient photothermal therapy (PTT) applications. Furthermore, a bimodal on-demand pH/photothermal sensitive drug release has been achieved, resulting in a significant chemotherapeutic effect. Most importantly, the tumor-growth inhibition ratio achieved from thermo-chemotherapy of the Bi2Se3@PDA/DOX/HSA NPs was 92.6%, in comparison to the chemotherapy (27.8%) or PTT (73.6%) alone, showing a superior synergistic therapeutic effect. In addition, there is no noticeable toxicity induced by the NPs in vivo. This multifunctional platform is, therefore, promising for effective, safe and precise antitumor treatment and may stimulate interest in further exploration of drug loading on Bi2Se3 and other competent PTT agents combined with in situ imaging for biomedical applications. PMID- 26655251 TI - NCBI-compliant genome submissions: tips and tricks to save time and money. AB - Genome sequences nowadays play a central role in molecular biology and bioinformatics. These sequences are shared with the scientific community through sequence databases. The sequence repositories of the International Nucleotide Sequence Database Collaboration (INSDC, comprising GenBank, ENA and DDBJ) are the largest in the world. Preparing an annotated sequence in such a way that it will be accepted by the database is challenging because many validation criteria apply. In our opinion, it is an undesirable situation that researchers who want to submit their sequence need either a lot of experience or help from partners to get the job done. To save valuable time and money, we list a number of recommendations for people who want to submit an annotated genome to a sequence database, as well as for tool developers, who could help to ease the process. PMID- 26655253 TI - Barriers against incorporating evidence-based practice in physical therapy in Colombia: current state and factors associated. AB - BACKGROUND: Evidence-based practice (EBP) has been widely implemented in differing areas of physiotherapy. Nevertheless, few studies have investigated EBP related barriers amongst Latin-American physical therapists working in primary care. The primary objective of this study was to describe the current state concerning perceived barriers engagement in EBP among physical therapy in Colombia. A secondary objective was to identify factors associated with barriers to implementation EBP. METHODS: A cross-sectional online survey was conducted. The study involved physical therapists working in public and private hospital who were contacted through professional networks (Email, Facebook(r), ResearchGate(r) and Linked-In(r)) and invited to participate. Multiple logistic regression (MLR) and multiple correspondence analysis (MCA) were used for examining factors associated with perceived barriers to including EBP in their work. RESULTS: The final sample size was 1064 (77.2 % female). Forty-one percent of the respondents indicated that a "lack of research skills" was the most important barrier to evidence being used in practice. MLR analysis suggested that several variables were associated with perceived barriers to including EBP: i.e. hours of work per week, current main role in therapy center and undergraduate degree. The MCA model established two groups of similarities regarding the different barriers; the "lack of understanding of statistical analysis", "insufficient time" and "understanding of the English in which articles are written" barriers were weighted more heavily regarding in the first group (the second factor on MCA) and the rest barriers on the second group (first factor on the MCA). CONCLUSIONS: Although most physiotherapists had a positive opinion regarding EBP, they considered that they needed to improve their knowledge, skills and attitudes towards EBP. Initiatives to advance EBP in Colombia with no academic or research tradition should primarily target practitioner-level factors. PMID- 26655252 TI - Systematic dissection of dysregulated transcription factor-miRNA feed-forward loops across tumor types. AB - Transcription factor and microRNA (miRNA) can mutually regulate each other and jointly regulate their shared target genes to form feed-forward loops (FFLs). While there are many studies of dysregulated FFLs in a specific cancer, a systematic investigation of dysregulated FFLs across multiple tumor types (pan cancer FFLs) has not been performed yet. In this study, using The Cancer Genome Atlas data, we identified 26 pan-cancer FFLs, which were dysregulated in at least five tumor types. These pan-cancer FFLs could communicate with each other and form functionally consistent subnetworks, such as epithelial to mesenchymal transition-related subnetwork. Many proteins and miRNAs in each subnetwork belong to the same protein and miRNA family, respectively. Importantly, cancer associated genes and drug targets were enriched in these pan-cancer FFLs, in which the genes and miRNAs also tended to be hubs and bottlenecks. Finally, we identified potential anticancer indications for existing drugs with novel mechanism of action. Collectively, this study highlights the potential of pan cancer FFLs as a novel paradigm in elucidating pathogenesis of cancer and developing anticancer drugs. PMID- 26655254 TI - Evaluation of the analytical performance of Unicel DXI 800 for the Total 25 (OH) Vitamin D measurements. AB - OBJECTIVES: We assessed the analytical performance of newly developed Access 25(OH) Vitamin D Total assay with Beckman Coulter Unicel DXI 800 and evaluated the agreement between a reference method liquid chromatography/tandem mass spectrometry (LC-MS/MS) and a chemiluminescence method (LIAISON, DiaSorin). DESIGN AND METHODS: 160 serum samples were included. Deming Regression analysis and Bland-Altman plots were used. The concordance correlation coefficient (CCC) was used to assess the degree of agreement between assays and the reference method. RESULTS: The CV% values of Unicel DXI 800 for within-run, between-run and between-day were lower than 6%. When compared to LC-MS/MS, the Access 25(OH) Vitamin D Total assay demonstrated an R value of 0.9444 (intercept -0.089, slope 0.951), with an average bias of -2.9%, and the LIAISON 25(OH) Vitamin D Total assay an R value of 0.9405 (intercept -0605, slope 0.924), with an average bias of -13.6%. In comparison with the LIAISON 25(OH) Vitamin D Total assay, the Access 25(OH) Vitamin D Total assay demonstrated an R value of 0.9498 (intercept 0.528, slope 1.029), with an average bias of 1.2%. The agreement with the LC MS/MS method, based on values of the CCC, was moderate for the Unicel DXI 800 and LIAISON method (0.95, 0.94 respectively). CONCLUSIONS: The new, automated Access 25(OH) Vitamin D Total assay showed an acceptable correlation with LC-MS/MS and LIAISON. Both methods moderately achieved to classify the patients according to their vitamin D status. However, we need further standardization of vitamin D assays to enhance the accuracy and comparability. PMID- 26655255 TI - Complete genome sequence of a benzo[a]pyrene-degrading bacterium Altererythrobacter epoxidivorans CGMCC 1.7731(T). AB - Altererythrobacter epoxidivorans CGMCC 1.7731(T) is a Gram-negative bacterium isolated from marine sediments. It is able to utilize benzo[a]pyrene as sole carbon and energy source. Here, we describe the complete genome sequence and annotation of A. epoxidivorans CGMCC 1.7731(T). The genome has a size of 2,786,256 bp (61.50 mol% G+C content), which consists of 2773 coding genes, 43 tRNA genes and 3 rRNA genes. According to the genome information, strain A. epoxidivorans CGMCC 1.7731(T) encodes 22 genes related to degradation of benzo[a]pyrene. These genes may have potential in bioremediation of PAH-polluted environments. PMID- 26655256 TI - Isolated epidural myeloma. PMID- 26655257 TI - Spinal extradural arachnoid cyst in aging spine. PMID- 26655258 TI - [Results of the 2015 national ranking in France]. PMID- 26655259 TI - [Endocrine disruptors, reproduction and hormone-dependent cancers]. AB - Endocrine disruptors are natural or synthetic chemical compounds which are present in the environment and which are able to interfere with hormonal regulation pathways and to induce human health deleterious effects. While their precise implication in human health and diseases is still matter of debates, it becomes likely that they have to be considered as risk factors in numerous chronic diseases: developmental and reproductive defects and hormone dependent cancers (present review), metabolic diseases (obesity and type 2 diabetes), neurodevelopmental or neurodegenerative diseases. Low doses exposure during critical windows of exposure such as foetal, perinatal and peri-pubertal periods, or chronic exposure with bioaccumulation in the adipose tissue, and possible synergic effects of several compounds ("cocktail effect") may participate to the genetic/environment interface suspected to participate to the pathophysiology of many diseases. PMID- 26655260 TI - [Endocrine disruptors: A missing link in the pandemy of type 2 diabetes and obesity?]. AB - The prevalence of metabolic syndrome, obesity and type 2 diabetes has dramatically increased worldwide during the last few decades and exceeds World Health Organisation's predictions. Lifestyle factors such as decreased physical activity and energy dense diet, together with a genetic predisposition, are well known actors in the pathophysiology of these metabolic diseases. However, there is accumulating evidence suggesting that the increased presence of endocrine disrupting chemicals (EDCs) in the environment, may also explain an important part in the incidence of metabolic syndrome, obesity and type 2 diabetes. EDCs are found in everyday products (including food, plastic bottles, metal cans, toys, cosmetics, pesticides...) and used in the manufacture of food. They interfere with the synthesis, secretion, transport, activity and/or elimination of natural hormones. Those interferences can block or mimic hormone actions and thus induce a wide range of adverse effects (especially reproductive effects and hormone-dependent cancers). In rodents, acute exposure to bisphenol A is responsible for modifications of insulin synthesis and secretion in pancreatic beta cells but also for modifications of insulin signalling in liver, skeletal muscle and adipose tissue, which both lead to insulin-resistance, a major condition in pathophysiology of metabolic syndrome, obesity and type 2 diabetes. In humans, some epidemiologic reports suggested a strong link between exposure to some persistant EDCs (as organochlorine pesticides, dioxins and polychlorinated biphenyl ethers) and type 2 diabetes and obesity, especially after acute and accidental releases of EDCs (Seveso plant explosion, Vietnam war veterans). Other cross-sectional studies among the world reported suggestive to strong association between diabetes and obesity and EDCs exposure, especially for persistant organic pollutants, which should now be considered as insulin-resistance risk factors. PMID- 26655261 TI - Editorial Review 2015. PMID- 26655262 TI - Lutetium-177 Labeled Therapeutics: 177Lu-PSMA is Set to Redefine Prostate Cancer Treatment. PMID- 26655263 TI - Receptor Complex Mediated Regulation of Symplastic Traffic. AB - Plant receptor kinases (RKs) and receptor proteins (RPs) are involved in a plethora of cellular processes, including developmental decisions and immune responses. There is increasing evidence that plasmodesmata (PD)-localized RKs and RPs act as nexuses that perceive extracellular signals and convey them into intra and intercellular responses by regulating the exchange of molecules through PD. How RK/RP complexes regulate the specific and nonspecific traffic of molecules through PD, and how these receptors are specifically targeted to PD, have been elusive but underpin comprehensive understanding of the function and regulation of the symplast. In this review we gather the current knowledge of RK/RP complex function at PD and how they might regulate intercellular traffic. PMID- 26655265 TI - Serum and mucosal antibodies fail as prognostic markers during critical influenza A infection. AB - BACKGROUND: Previous studies have indicated that the absence of serum antibodies to influenza A H1N1 virus on day 4 after onset of symptoms predicted a fatal outcome in patients critically ill with influenza. The underlying mechanism was suggested to be the trapping of anti-influenza antibodies in pulmonary immune complexes. OBJECTIVES: To study serum and mucosal antibodies as prognostic markers in patients with severe influenza A H1N1 infection. STUDY DESIGN: Blood and respiratory samples (n=324) from 12 patients with severe influenza were analysed for anti-H1N1 antibodies with and without immune complex dissociation from symptom onset until convalescence or death (follow up 14-169 days). Eleven healthy subjects were analysed for comparison. RESULTS: One of the 12 patients died from influenza pneumonia and had no detectable anti-H1N1 serum antibodies. However, also 2 of the 11 surviving patients remained negative for anti-H1N1 serum antibodies during follow-up (20 and 41 days, respectively). In six of the 11 survivors serum antibodies on day 4 were negative, but turned positive between day 7 and 23. In the remaining 3 patients antibodies were detected in the first 4 days of illness. Mucosal IgG or IgA was detected in all of the patients regardless of their clinical outcome and in 4 of 11 healthy subjects. No mucosal immune complexes were found in the patient who died but were detected in 3 of the 11 survivors. CONCLUSIONS: This study suggests that no prognostic conclusions can be drawn from anti-H1N1 serum and mucosal antibodies in patients with severe influenza. PMID- 26655264 TI - Comparison of urine specimen collection times and testing fractions for the detection of high-risk human papillomavirus and high-grade cervical precancer. AB - BACKGROUND: Urine testing for high-risk human papillomavirus (HR-HPV) detection could provide a non-invasive, simple method for cervical cancer screening. OBJECTIVES: We examined whether HR-HPV detection is affected by urine collection time, portion of urine stream, or urine fraction tested, and assessed the performance of HR-HPV testing in urine for detection of cervical intraepithelial neoplasia grade II or worse (CIN2+). STUDY DESIGN: A total of 37 female colposcopy clinic attendees, >= 30 years, provided three urine samples: "first void" urine collected at home, and "initial stream" and "mid-stream" urine samples collected at the clinic later in the day. Self- and physician-collected brush specimens were obtained at the same clinic visit. Colposcopy was performed and directed biopsies obtained if clinically indicated. For each urine sample, HR HPV DNA testing was conducted for unfractionated, pellet, and supernatant fractions using the Trovagene test. HR-HPV mRNA testing was performed on brush specimens using the Aptima HPV assay. RESULTS: HR-HPV prevalence was similar in unfractionated and pellet fractions of all urine samples. For supernatant urine fractions, HR-HPV prevalence appeared lower in mid-stream urine (56.8%[40.8 72.7%]) than in initial stream urine (75.7%[61.9-89.5%]). Sensitivity of CIN2+ detection was identical for initial stream urine and physician-collected cervical specimen (89.9%[95%CI=62.7-99.6%]), and similar to self-collected vaginal specimen (79.1%[48.1-96.6%]). CONCLUSION: This is among the first studies to compare methodologies for collection and processing of urine for HR-HPV detection. HR-HPV prevalence was similar in first void and initial stream urine, and was highly sensitive for CIN2+ detection. Additional research in a larger and general screening population is needed. PMID- 26655266 TI - Enterovirus infections in hospitals of Ile de France region over 2013. AB - BACKGROUND: The monitoring and genotyping of Enterovirus (EV) infections can help to associate particular or severe clinical manifestations with specific EV types and to identify the aetiology of infectious outbreaks. OBJECTIVES: To describe the epidemiological features of EV infections diagnosed during the year 2013 in the Greater Paris area (Ile de France). STUDY DESIGN: During 2013, 2497 samples taken from 470 patients in 33 hospitals of Ile-de France were tested for EV genome by RT-PCR. EV genotyping was performed by the National Reference Centre (NRC) laboratories. EV infections were retrospectively reviewed by retrieving clinical and genotyping data from the NRC database. RESULTS: Of the 2497 samples, 490 (19.6%) was positive for EV genome detection. These EV infections represented 88.7% and 24.1%, respectively, of all reported regional and national infections. Twenty-seven different genotypes were identified. Echovirus 30 (E-30) accounted for 54.1% of all characterized strains and caused a large outbreak. Four severe neonatal infections were reported, of which two were caused by EV-A71. Respiratory infections involving EV-D68 were observed in two adults. One fatal case of Coxsackievirus A2-associated myocarditis was reported. CONCLUSION: Monitoring EV infections in combination with EV genotyping via the French EV network characterized the epidemiology of EV infections in the Ile de France region in 2013 and documented severe EV infections associated with EV-A71 or CV A2. PMID- 26655267 TI - Distribution of Parvovirus 4 and KI/WU polyomaviruses in HIV-positive blood donations, France. PMID- 26655268 TI - Human bocavirus in stool: A true pathogen or an innocent bystander? AB - Human bocavirus (HBoV) is a parvovirus that was discovered only a decade ago and currently includes four genotypes. HBoV-1 is predominantly found in the respiratory tract, whereas HBoV-2, HBoV-3, and HBoV-4 are mainly detected in stool. HBoV-1 is known to be associated with respiratory tract infections. In stool, the prevalence of HBoV (1-4) is similar between patients with gastro intestinal symptoms and healthy controls in most studies. Furthermore, often other viruses are concurrently present. Both findings suggest that HBoV in stool is an innocent bystander rather than a true pathogen. Nevertheless, several gaps in knowledge on the role of HBoV in stool remain to be addressed. All studies were performed in primarily immunocompetent patients. The role of HBoV in immunocompromised patients remains unknown. PMID- 26655269 TI - Detection of influenza C virus but not influenza D virus in Scottish respiratory samples. AB - BACKGROUND: A newly proposed genus of influenza virus (influenza D) is associated with respiratory disease in pigs and cattle. The novel virus is most closely related to human influenza C virus and can infect ferrets but infection has not been reported in humans. OBJECTIVES: To ascertain if influenza D virus can be detected retrospectively in patient respiratory samples. STUDY DESIGN: 3300 human respiratory samples from Edinburgh, Scotland, covering the period 2006-2008, were screened in pools of 10 by RT-PCR using primers capable of detecting both influenza C and D viruses. RESULTS: Influenza D was not detected in any sample. Influenza C was present in 6 samples (0.2%), compared with frequencies of 3.3% and 0.9% for influenza A and B viruses from RT-PCR testing of respiratory samples over the same period. Influenza C virus was detected in samples from individuals <2 years or >45 years old, with cases occurring throughout the year. Phylogenetic analysis of nearly complete sequences of all seven segments revealed the presence of multiple, reassortant lineages. CONCLUSION: We were unable to detect viruses related to influenza D virus in human respiratory samples. Influenza C virus was less prevalent than influenza A and B viruses, was associated with mild disease in the young (<2 years) and old (>45 years) and comprised multiple, reassortant lineages. Inclusion of influenza C virus as part of a diagnostic testing panel for respiratory infections would be of limited additional value. PMID- 26655270 TI - Fatal case of acute gastroenteritis with multiple viral coinfections. AB - We report a fatal case of acute gastroenteritis in a child with autism spectrum disorder. Multiple viral coinfections were detected by PCR in the patient's stool and digestive biopsy specimens. As viral detection is not necessarily associated with symptomatic disease, a semi-quantitative approach using cycle treshold values was proposed for the clinical interpretation of PCR. We discuss whether concomitant viral infections could be a risk factor for severe outcome in gastroenteritis cases. Individual risk factors are also addressed. PMID- 26655271 TI - BAG3-mediated miRNA let-7g and let-7i inhibit proliferation and enhance apoptosis of human esophageal carcinoma cells by targeting the drug transporter ABCC10. AB - Cisplatin (diamminedichloroplatinum, DDP) is widely used as the first-line treatment for patients with unresectable or no metastatic cancer. However, the appearance of DDP resistance frequently occurred in the treatment of cancers, including esophageal carcinoma (EC). The purposes of this study are to determine the antitumor effects of miR-let-7g/i (let-7g/i) on EC cells and to investigate whether let-7g and let-7i have a relationship with the drug resistance gene ABCC10 on EC cells. qRT-PCR and western blot analysis demonstrated that Bcl2 associated athanogene 3 (BAG3) and miR-let-7g/i have the opposite expression levels in primary esophageal squamous cell carcinoma tissues and EC cell lines. Overexpression of miR-let-7g/i significantly inhibited the cell proliferation and promoted DDP-induced apoptosis of EC109 and TE10 cells. Finally, ABCC10, a drug resistance gene, was identified as a functional and direct target gene of miR-let 7g/i. Luciferase reporter assay confirmed that let-7g and let-7i combined directly with 3'UTR of ABCC10, in consequence, inhibiting ABCC10 expression and enhancing cellular sensitivity to drugs. This study provides the first demonstration that miR-let-7g/i target ABCC10 and modulate DDP resistance in EC cell lines. PMID- 26655272 TI - LncRNA-UCA1 exerts oncogenic functions in non-small cell lung cancer by targeting miR-193a-3p. AB - Recently, the long non-coding RNA (lncRNA) urothelial carcinoma-associated 1 (UCA1) has been identified as an oncogenic gene in multiple human tumor entitles, and dysregulation of UCA1 was tightly linked to carcinogenesis and cancer progression. However, whether the aberrant expression of UCA1 in non-small cell lung cancer (NSCLC) is associated with malignancy, metastasis or prognosis has not been characterized. In this study, we found that UCA1 was upregulated in NSCLC tissues. Higher expression of UCA1 led to a significantly poorer survival time, and multivariate analysis revealed that UCA1 was an independent risk factor of prognosis. UCA1 overexpression enhanced, whereas UCA1 silencing impaired the proliferation and colony formation of NSCLC cells. Moreover, mechanistic investigations showed that UCA1 upregulated the expression of miR-193a-3p target gene ERBB4 through competitively 'spongeing' miR-193a-3p. Overall, we concluded that UCA1 functions as an oncogene in NSCLC, acting mechanistically by upregulating ERBB4 in part through 'spongeing' miR-193a-3p. PMID- 26655273 TI - MicroRNA-122 confers sorafenib resistance to hepatocellular carcinoma cells by targeting IGF-1R to regulate RAS/RAF/ERK signaling pathways. AB - Sorafenib is the first-line treatment for advanced hepatocellular carcinoma (HCC), but the clinical response to sorafenib is seriously limited by drug resistance. In this study, we investigated the molecular mechanisms of sorafenib resistance in HCC cells. Our miRNA microarray data indicate that liver-specific miR-122 expression was significantly reduced in sorafenib-resistant cells. Overexpression of miR-122 made drug-tolerant cells sensitive to sorafenib and induced apoptosis. Insulin-like growth factor 1 receptor (IGF-1R) was validated as a target of miR-122 and was repressed by this miRNA. miR-122-induced apoptosis was repressed by the IGF-1R activator IGFI or IGFII. Conversely, the IGF-1R inhibitor PPP or NVP-AEW541 in combination with sorafenib significantly induced cell apoptosis and disrupted tolerance to drugs in vitro. These results indicated that activation of IGF-1R by ectopic down-regulation of miR-122 counteracted the effects of sorafenib-induced apoptosis, thus conferring sorafenib resistance. Further study revealed that activation of IGF-1R by miR-122 down-regulation contributed to activation of RAS/RAF/ERK signaling, which was associated with drug resistance. Our data imply that an intimate correlation between miR-122 and IGF-1R abnormal expression is a critical determinant of sorafenib tolerance. PMID- 26655274 TI - Deep sequencing of small RNA libraries from human prostate epithelial and stromal cells reveal distinct pattern of microRNAs primarily predicted to target growth factors. AB - Complex epithelial and stromal cell interactions are required during the development and progression of prostate cancer. Regulatory small non-coding microRNAs (miRNAs) participate in the spatiotemporal regulation of messenger RNA (mRNA) and regulation of translation affecting a large number of genes involved in prostate carcinogenesis. In this study, through deep-sequencing of size fractionated small RNA libraries we profiled the miRNAs of prostate epithelial (PrEC) and stromal (PrSC) cells. Over 50 million reads were obtained for PrEC in which 860,468 were unique sequences. Similarly, nearly 76 million reads for PrSC were obtained in which over 1 million were unique reads. Expression of many miRNAs of broadly conserved and poorly conserved miRNA families were identified. Sixteen highly expressed miRNAs with significant change in expression in PrSC than PrEC were further analyzed in silico. ConsensusPathDB showed the target genes of these miRNAs were significantly involved in adherence junction, cell adhesion, EGRF, TGF-beta and androgen signaling. Let-7 family of tumor-suppressor miRNAs expression was highly pervasive in both, PrEC and PrSC cells. In addition, we have also identified several miRNAs that are unique to PrEC or PrSC cells and their predicted putative targets are a group of transcription factors. This study provides perspective on the miRNA expression in PrEC and PrSC, and reveals a global trend in miRNA interactome. We conclude that the most abundant miRNAs are potential regulators of development and differentiation of the prostate gland by targeting a set of growth factors. Additionally, high level expression of the most members of let-7 family miRNAs suggests their role in the fine tuning of the growth and proliferation of prostate epithelial and stromal cells. PMID- 26655275 TI - CpG-1826 immunotherapy potentiates chemotherapeutic and anti-tumor immune responses to metronomic cyclophosphamide in a preclinical glioma model. AB - Cyclophosphamide administered on an intermittent metronomic schedule induces strong immune-dependent regression in several glioma models. Here we investigate whether this immunogenic chemotherapy can be potentiated by combination with the immune stimulatory TLR9 agonist CpG-1826. CpG-1826 treatment of GL261 gliomas implanted in immune competent mice induced tumor growth delay associated with increased tumor recruitment of macrophages and B cells. Anti-tumor responses varied between individuals, with CpG-1826 inducing robust tumor growth delay in ~50% of treated mice. Both high and low CpG-1826-responsive mice showed striking improvements when CpG-1826 was combined with cyclophosphamide treatment. Tumor associated macrophages, B cells, dendritic cells, and cytotoxic T cells were increased, T regulatory cells were not induced, and long-term GL261 glioma regression with immune memory was achieved when CpG-1826 was combined with either single cyclophosphamide dosing (90 mg/kg) or metronomic cyclophosphamide treatment (two cycles at 45 mg/kg, spaced 12-days apart). B16F10 melanoma, a low immunogenic tumor model, also showed enhanced immune and anti-tumor responses to cyclophosphamide/CpG-1826 chemoimmunotherapy, but unlike GL261 tumors, did not regress. TLR9-based immunotherapy can thus be effectively combined with immunogenic cyclophosphamide treatment to enhance immune-based anti-tumor responses, even in poorly immunogenic cancer models. PMID- 26655276 TI - Influence of carrier cells on the clinical outcome of children with neuroblastoma treated with high dose of oncolytic adenovirus delivered in mesenchymal stem cells. AB - We report here our clinical experience of a program of compassionate use of Celyvir--autologous marrow-derived mesenchymal stem cells (MSCs) carrying an oncolytic adenovirus--for treating children with advanced metastatic neuroblastoma. Children received weekly doses of Celyvir with no concomitant treatments. The tolerance was excellent, with very mild and self-limited viral related symptoms. Patients could be distinguished based on their response to therapy: those who had a clinical response (either complete, partial or stabilization) and those who did not respond. We found differences between patients who responded versus those who did not when analyzing their respective MSCs, at the expression levels of adhesion molecules (CCR1, CXCR1 and CXCR4) and in migration capacities in transwell assays, and in immune-related molecules (IFNgamma, HLA-DR). These results suggest interpatient differences in the homing and immune modulation capacities of the therapy administered. In addition, the pretherapy immune T cell status and the T effector response were markedly different between responders and non-responders. We conclude that multidoses of Celyvir have an excellent safety profile in children with metastatic neuroblastoma. Intrinsic patients' and MSCs' factors appear to be related to clinical outcome. PMID- 26655277 TI - Blocking FGF2 with a new specific monoclonal antibody impairs angiogenesis and experimental metastatic melanoma, suggesting a potential role in adjuvant settings. AB - Compelling evidence suggests that fibroblast growth factor 2 (FGF2), overexpressed in melanomas, plays an important role in tumor growth, angiogenesis and metastasis. In this study, we evaluated the therapeutic use of a new anti FGF2 monoclonal antibody (mAb), 3F12E7, using for that the B16-F10 melanoma model. The FGF2 neutralizing effect of this antibody was certified by in vitro assays, which allowed the further track of its possible in vivo application. 3F12E7 mAb could be retained in B16-F10 tumors, as shown by antibody low-pH elution and nuclear medicine studies, and also led to reduction in number and size of metastatic foci in lungs, when treatment starts one day after intravenous injection of B16-F10 cells. Such data were accompanied by decreased CD34(+) tumor vascular density and impaired subcutaneous tumor outgrowth. Treatments starting one week after melanoma cell intravenous injection did not reduce tumor burden, remaining the therapeutic effectiveness restricted to early-adopted regimens. Altogether, the presented anti-FGF2 3F12E7 mAb stands as a promising agent to treat metastatic melanoma tumors in adjuvant settings. PMID- 26655278 TI - Heat dissipation by blood circulation and airway tissue heat absorption in a canine model of inhalational thermal injury. AB - OBJECTIVE: This study aimed to further explore heat dissipation by blood circulation and airway tissue heat absorption in an inhalational thermal injury model. METHODS: Twelve adult male Beagle dogs were divided into four groups to inhale heated air for 10min: the control group, group I (100.5 degrees C), group II (161.5 degrees C), and group III (218 degrees C). The relative humidity and temperature of the inhaled heated air were measured in the heating tube and trachea, as were blood temperatures and flow velocities in both common jugular veins. Formulas were used to calculate the total heat quantity reduction of the heated air, heat dissipation by the blood, and airway tissue heat absorption. RESULTS: The blood temperatures of both the common jugular veins increased by 0.29 degrees C+/-0.07 degrees C to 2.96 degrees C+/-0.24 degrees C and the mean blood flow volume after injury induction was about 1.30-1.74 times greater than before injury induction. The proportions of heat dissipated by the blood and airway tissue heat absorption were 68.92%+/-14.88% and 31.13%+/-14.87%, respectively. CONCLUSIONS: The heat dissipating ability of the blood circulation was demonstrated and improved upon along with tissue heat absorption owing to increased regional blood flow. PMID- 26655279 TI - Evidence-based first aid advice for paediatric burns in the United Kingdom. AB - BACKGROUND: Burn and scald injuries are common in children. First aid advice for paediatric burns is offered by a range of health organisations and charities in the UK. Despite this, children still present to emergency departments and burn services having received little or inadequate first aid. METHOD: A survey was undertaken regarding the content and consistency of the advice given by a cross section of UK health organisations involved in first aid prevention and education. The advice was subsequently examined to determine if it was evidence based. RESULTS: Our study has demonstrated inconsistencies in the content of the first aid advice provided by the 21 organisations included in the study. Seventy one percent of the information was only available online. The temperature, method and duration of cooling varied substantially, as did the advice recommended for the removal of clothing and jewellery and methods for covering the burn immediately after injury. Results from the literature review concluded the following based on available evidence; cool the burn with running tap water for 20min, remove clothing and jewellery and cover the burn with cling film or a clean non-adhesive dressing. CONCLUSIONS: This study highlights the lack of consistency between first aid guidance provided by health organisations and charities in the UK. PMID- 26655280 TI - Phylogenomic analysis of transferrin family from animals and plants. AB - Transferrins have been identified in animals and green algae, and they consist of a family of evolutionarily related proteins that play a central role in iron transport, immunity, growth and differentiation. This study assessed the transferrin genes among 100 genomes from a wide range of animal and plant kingdoms. The results showed that putative transferrins were widespread in animals, but their gene quantity and type differ greatly between animal groups. Generally, Mammalia possess abundant transferrin genes, whereas Trematoda contain few ones. Melanotransferrin and serotransferrin are widely distributed in vertebrates, while melanotransferrin-like and transferrin-like 1 are frequent in invertebrates. However, only a few plant species detected putative transferrins, and a novel transferrin member was first uncovered in Angiospermae and Pteridophyta. The structural comparison among transferrin family members revealed seven very well-repeated and conserved characteristic motifs, despite a considerable variation in the overall sequences. The phylogenetic analysis suggested that gene duplication, gene loss and horizontal transfer contributed to the diversification of transferrin family members, and their inferred evolutionary scenario was proposed. These findings help to the understanding of transferrin distribution, characteristic motifs and residues, and evolutionary process. PMID- 26655281 TI - The effects of sleep, wake activity and time-on-task on offline motor sequence learning. AB - While intervening sleep promotes the consolidation of memory, it is well established that cognitive interference from competing stimuli can impede memory retention. The current study examined changes in motor skill learning across periods of wakefulness with and without competing stimuli, and periods of sleep with and without disruption from external stimuli. A napping study design was adopted where participants (N=44) either had (1) a 30min nap composed of Non Rapid Eye Movement (NREM) sleep, (2) 30min NREM nap fragmented by audio tone induced arousals, (3) 45min of quiet wakefulness, or (4) 45min of active wakefulness. Measures of subjective sleepiness (KSS), alertness (PVT) and motor skill learning (Sequential Finger Tapping Task, SFTT) were completed in the morning and evening to assess performance pre- and post-nap or wakefulness. Following a practice session, change in motor skill performance was measured over a 10min post training rest interval, as well as following a 7h morning to evening interval comprising one of the four study conditions. A significant offline enhancement in motor task performance (13-23%) was observed following 10min of rest in all conditions. Following the long delay with the intervening nap/wake condition, there were no further offline gains or losses in performance in any sleep (uninterrupted/fragmented) or wake (quiet/active) condition. The current findings suggest that after controlling for offline gains in performance that occur after a brief rest and likely to due to the dissipation of fatigue, the subsequent effect of an intervening sleep or wake period on motor skill consolidation is not significant. Consistent with this null result, the impact of disrupting the sleep episode or manipulating activity during intervening wake also appears to be negligible. PMID- 26655282 TI - The influence of curricular and extracurricular learning activities on students' choice of chiropractic technique. AB - OBJECTIVE: Surveys for the National Board of Chiropractic Examiners indicate that diversified chiropractic technique is the most commonly used chiropractic manipulation method. The study objective was to investigate the influences of our diversified core technique curriculum, a technique survey course, and extracurricular technique activities on students' future practice technique preferences. METHODS: We conducted an anonymous, voluntary survey of 1st, 2nd, and 3rd year chiropractic students at our institution. Surveys were pretested for face validity, and data were analyzed using descriptive and inferential statistics. RESULTS: We had 164 students (78% response rate) participate in the survey. Diversified was the most preferred technique for future practice by students, and more than half who completed the chiropractic technique survey course reported changing their future practice technique choice as a result. The students surveyed agreed that the chiropractic technique curriculum and their experiences with chiropractic practitioners were the two greatest bases for their current practice technique preference, and that their participation in extracurricular technique clubs and seminars was less influential. CONCLUSIONS: Students appear to have the same practice technique preferences as practicing chiropractors. The chiropractic technique curriculum and the students' experience with chiropractic practitioners seem to have the greatest influence on their choice of chiropractic technique for future practice. Extracurricular activities, including technique clubs and seminars, although well attended, showed a lesser influence on students' practice technique preferences. PMID- 26655283 TI - Impaired oligodendrocyte maturation in preterm infants: Potential therapeutic targets. AB - Preterm birth is an evolving challenge in neonatal health care. Despite declining mortality rates among extremely premature neonates, morbidity rates remain very high. Currently, perinatal diffuse white matter injury (WMI) is the most commonly observed type of brain injury in preterm infants and has become an important research area. Diffuse WMI is associated with impaired cognitive, sensory and psychological functioning and is increasingly being recognized as a risk factor for autism-spectrum disorders, ADHD, and other psychological disturbances. No treatment options are currently available for diffuse WMI and the underlying pathophysiological mechanisms are far from being completely understood. Preterm birth is associated with maternal inflammation, perinatal infections and disrupted oxygen supply which can affect the cerebral microenvironment by causing activation of microglia, astrogliosis, excitotoxicity, and oxidative stress. This intricate interplay of events negatively influences oligodendrocyte development, causing arrested oligodendrocyte maturation or oligodendrocyte cell death, which ultimately results in myelination failure in the developing white matter. This review discusses the current state in perinatal WMI research, ranging from a clinical perspective to basic molecular pathophysiology. The complex regulation of oligodendrocyte development in healthy and pathological conditions is described, with a specific focus on signaling cascades that may play a role in WMI. Furthermore, emerging concepts in the field of WMI and issues regarding currently available animal models are put forward. Novel insights into the molecular mechanisms underlying impeded oligodendrocyte maturation in diffuse WMI may aid the development of novel treatment options which are desperately needed to improve the quality-of-life of preterm neonates. PMID- 26655284 TI - Structural coupling across the direct EuO/Si interface. AB - The ferromagnetic semiconductor EuO is believed to be an effective spin injector when directly integrated with silicon (Si). Injection through spin-selective ohmic contact requires superb structural quality of the interface EuO/Si. A recent breakthrough in manufacturing free-of-buffer-layer EuO/Si junctions calls for structural studies of the interface between the semiconductors. The synthesis of EuO employs an advanced protection of the Si substrate surface and a two-step growth protocol. It prevents unwanted chemical reactions at the interface. Ex situ high-resolution x-ray diffraction (XRD) and reflectivity (XRR) accompanied by in situ reflection high-energy electron diffraction reveal direct coupling at the interface. A combined analysis of XRD and XRR data provides a common structural model. The structural quality of the EuO/Si spin contact far exceeds that of previous reports and thus makes a step forward to the ultimate goals of spintronics. PMID- 26655285 TI - Social capital and access to primary health care in developing countries: Evidence from Sub-Saharan Africa. AB - We test for a causal role of social capital, as measured by self-reported trust, in determining access to basic health facilities in Sub-Saharan Africa. To skirt the reverse-causality problems between social capital and basic health, we rely on instrumental-variable (IV) estimates. A one standard-deviation increase in trust is predicted to lead to a 0.22 standard-deviation fall in doctor absenteeism, a 0.31 standard-deviation fall in waiting time and a 0.30 standard deviation fall in bribes. As a robustness check, we also use a different database regarding a different health issue, access to clean water. We find that a one standard-deviation rise in trust leads to a 0.33 standard-deviation rise in access to clean water. The variety of public goods considered provides insights about the possible channels through which social capital is converted into health improvements. PMID- 26655286 TI - Prevention of infections in nursing homes: antibiotic prophylaxis versus infection control and antimicrobial stewardship measures. AB - Because of the lack of structural and human resources for implementing more effective and safe preventive procedures, antimicrobial prophylaxis is often used to prevent infections in nursing homes. However, if data on the efficacy of antibiotic prophylaxis in nursing homes are null, there is a plenty of evidence that the inappropriate use of antimicrobials in this setting is associated with a high rate of colonization and infection with multi-drug-resistant organisms (MDROs), and of Clostridium difficile infection (CDI). Here, we have reviewed the infection epidemiology, the burden of MDROs and CDI, the antibiotic use and some potential infection preventive measures in nursing homes, pointing up the peculiarities of this setting and the absolute need of a more prudential use of antimicrobials. PMID- 26655288 TI - Atherosclerosis: cell biology and lipoproteins. PMID- 26655287 TI - Choline metabolites: gene by diet interactions. AB - PURPOSE OF REVIEW: The review highlights recent advances in our understanding of the interactions between genetic polymorphisms in genes that metabolize choline and the dietary requirements of choline and how these interactions relate to human health and disease. RECENT FINDINGS: The importance of choline as an essential nutrient has been well established, but our appreciation of the interaction between our underlying genetic architecture and dietary choline requirements is only beginning. It has been shown in both human and animal studies that choline deficiencies contribute to diseases such as nonalcoholic fatty liver disease and various neurodegenerative diseases. An adequate supply of dietary choline is important for optimum development, highlighted by the increased maternal requirements during fetal development and in breast-fed infants. We discuss recent studies investigating variants in PEMT and MTHFR1 that are associated with a variety of birth defects. In addition to genetic interactions, we discuss several recent studies that uncover changes in fetal global methylation patterns in response to maternal dietary choline intake that result in changes in gene expression in the offspring. In contrast to the developmental role of adequate choline, there is now an appreciation of the role choline has in cardiovascular disease through the gut microbiota-mediated metabolite trimethylamine N-oxide. This pathway highlights some of our understanding of how the microbiome affects nutrient processing and bioavailability. Finally, to better characterize the genetic architecture regulating choline requirements, we discuss recent results focused on identifying polymorphisms that regulate choline and its derivative products. SUMMARY: Here we discuss recent studies that have advanced our understanding of how specific alleles in key choline metabolism genes are related to dietary choline requirements and human disease. PMID- 26655289 TI - Olive oil phenolic compounds and high-density lipoprotein function. AB - PURPOSE OF REVIEW: The functional capacities of high-density lipoproteins (HDLs) reflect the physiological role of the particle better than the quantity of HDL cholesterol. Owing to its phenolic compounds, the consumption of virgin olive oil has emerged as a promising therapy to promote these capacities. This review highlights the human studies that explain these benefits and explores some possible mechanisms. RECENT FINDINGS: The consumption of olive oil phenolic compounds increased the ability of HDLs to pick up cholesterol excess in peripheral cells (the cholesterol efflux capacity). Olive oil phenolic compounds have also been shown to improve HDL antioxidant capacities and some anti inflammatory traits. These changes respond to an improvement of HDL oxidative status and composition. SUMMARY: Novel strategies to increase HDL functional capacities are in demand from clinicians. The attainment of a fully-functional HDL through dietary or lifestyle changes is a priority in cardiovascular research. Within this context, the consumption of virgin olive oil, because of its phenolic compounds, may be a relevant protective approach. Further studies in large-scale, randomized controlled trials are, however, required to confirm these effects in HDL functionality. PMID- 26655290 TI - n-3 Fatty acid supplementation and proresolving mediators of inflammation. AB - PURPOSE OF REVIEW: The review presents recent developments in the identification of specialized proresolving mediators (SPMs) of inflammation following supplementation with n-3 fatty acids in humans. RECENT FINDINGS: A number of reports have measured SPMs in human plasma after n-3 fatty acid supplementation. Although studies have shown some variability in plasma SPM levels, there is strong evidence that a number of resolvins are increased after n-3 fatty acids to concentrations that have been shown to have biological activity. SPM concentrations at the inflammatory site would be expected to be higher than that in blood. SPMs derived from docosapentaenoic acid require further investigation. SUMMARY: Resolution of inflammation is an active process with SPM playing a vital role in maintaining homeostasis. Studies in humans are providing evidence to suggest that this may be a relevant mechanism that can be stimulated by n-3 fatty acid supplementation. Further research is now required to determine SPM profiles in patients with different chronic conditions and to examine whether supplementation with n-3 fatty acids affects SPMs in relation to their clinical outcome. PMID- 26655291 TI - Apolipoprotein A-I interactions with insulin secretion and production. AB - PURPOSE OF REVIEW: Human population studies have established that an elevated plasma high-density lipoprotein cholesterol (HDL-C) level is associated with a decreased risk of developing cardiovascular disease. In addition to having several potentially cardioprotective functions, HDLs and apolipoprotein (apo)A-I, the main HDL apolipoprotein, also have antidiabetic properties. Interventions that elevate plasma HDL-C and apoA-I levels improve glycemic control in people with type 2 diabetes mellitus by enhancing pancreatic beta-cell function and increasing insulin sensitivity. RECENT FINDINGS: This review is concerned with recent advances in understanding the mechanisms by which HDLs and apoA-I improve pancreatic beta-cell function. SUMMARY: HDLs and apoA-I increase insulin synthesis and secretion in pancreatic beta cells. The underlying mechanism of this effect is similar to what has been reported for intestinally derived incretins, such as glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide, which both increase beta-cell insulin secretion under high glucose conditions. This involves the activation of a heterotrimeric G protein Galphas subunit on the beta-cell surface that leads to induction of a transmembrane adenylyl cyclase, increased intracellular cyclic adenosine monophosphate and Ca levels, and activation of protein kinase A. Protein kinase A increases insulin synthesis by excluding FoxO1 from the beta-cell nucleus and derepressing transcription of the insulin gene. PMID- 26655292 TI - Dietary cholesterol effects on adipose tissue inflammation. AB - PURPOSE OF REVIEW: Adipose tissue is a critical endocrine and immunological organ that regulates systemic energy homeostasis. During the pathogenesis of obesity, adipocyte hypertrophy is accompanied by adipose tissue inflammation, impeding insulin sensitivity and endocrine function of adipose tissue and other tissues. Adipocyte cholesterol accumulates in proportion to triglyceride as adipocytes undergo hypertrophy. Recent studies suggest that dietary cholesterol contributes to increased adipocyte cholesterol. However, how dietary cholesterol accumulates in adipocytes and its metabolic consequences are poorly understood. This review summarizes recent advances in knowledge of adipocyte cholesterol balance and highlights the emerging role of dietary cholesterol in adipose tissue cholesterol balance, inflammation, and systemic energy metabolism. RECENT FINDINGS: Perturbation of cholesterol balance in adipocytes alters intracellular cholesterol distribution and modulates adipocyte insulin and proinflammatory signaling. Adipocyte cholesterol levels are maintained by a balance between dietary cholesterol uptake from triglyceride-enriched lipoproteins and cellular cholesterol efflux to HDL. Recent animal studies established a critical role for dietary cholesterol in promoting adipose tissue inflammation, thereby worsening obesity-mediated metabolic complications. SUMMARY: Recent studies identified high dietary cholesterol as a potentiator of adipose tissue inflammation and dysfunction. Reducing excessive dietary cholesterol intake is suggested as a simple, but novel, way to attenuate obesity-associated metabolic diseases. PMID- 26655293 TI - ABCA1 agonist peptides for the treatment of disease. AB - PURPOSE OF REVIEW: The review summarizes information pertaining to the preclinical development of new apolipoprotein (apo) E mimetic peptides that stimulate cellular cholesterol efflux. RECENT FINDINGS: Small alpha-helical peptides based on the C-terminal domain of apoE have been developed for therapeutic applications. These peptides stimulate cellular cholesterol efflux via the ATP-binding cassette transporter A1 (ABCA1) with high potency, like native apolipoproteins on a molar basis. This potent activity has been related to the unique ability of these peptides to maintain alpha-helix structure upon dilution. Recent structure-activity studies improving the safety features of these mimetic peptides have greatly improved their potential for clinical use. These studies have identified structural features of the class A alpha-helix motif that induce muscle toxicity and hypertriglyceridemia, which may have implications for the design of other HDL mimetic peptides. SUMMARY: ABCA1 is an integral membrane protein that plays a central role in biology. Its principal function is to mediate the efflux of cholesterol and phospholipid from cells to extracellular apo, preventing a build-up of excess cholesterol in membranes. This process generates HDL particles that perform a variety of functions to protect against disease. A number of these functions can be viewed as directly or indirectly supporting ABCA1 activity, thus constituting a positive feedback system to optimize cellular lipid efflux responses and disease prevention. Consequently, therapeutic approaches that mimic the activities of apos may prove highly effective to combat disease. One such approach involves the use of peptides. The broad biological relevance of ABCA1 suggests these apo mimetic peptides may be useful for the treatment of a number of diseases, such as atherosclerosis, diabetes, and Alzheimer's disease. PMID- 26655294 TI - In-vivo genome editing using CRISPR-Cas9 to study lipid metabolism. PMID- 26655295 TI - Bariatric surgery and remission of type 2 diabetes mellitus. PMID- 26655296 TI - The Mediterranean diet. PMID- 26655297 TI - Moderate Thermal Strain in Healthcare Workers Wearing Personal Protective Equipment During Treatment and Care Activities in the Context of the 2014 Ebola Virus Disease Outbreak. AB - The extent of thermal strain while wearing personal protective equipment (PPE) during care activities for Ebola virus disease patients has not yet been characterized. From January to March 2015, 25 French healthcare workers (HCWs) in Conakry, Guinea, volunteered to be monitored while wearing PPE using an ingestible thermal sensor. The mean (standard deviation) working ambient temperature and relative humidity were 29.6 degrees C (2.0 degrees C) and 65.4% (10.3%), respectively; the mean time wearing PPE was 65.7 (13.5) minutes; and the mean core body temperature increased by 0.46 degrees C (0.20 degrees C). Four HCWs reached or exceeded a mean core body temperature of >= 38.5 degrees C. HCWs wearing PPE for approximately 1 hour exhibited moderate but safe thermal strain. PMID- 26655298 TI - Reduced Treponema pallidum-Specific Opsonic Antibody Activity in HIV-Infected Patients With Syphilis. AB - BACKGROUND: Human immunodeficiency virus (HIV)-infected individuals may have poorer serological responses to syphilis treatment and may be more likely to experience neurosyphilis. Treponema pallidum is cleared from sites of infection by opsonization, ingestion, and killing by macrophages. METHODS: Serum samples from 235 individuals with syphilis were tested for T. pallidum-specific opsonic activity. Blood T. pallidum concentrations were determined by real-time polymerase chain reaction amplification of the tp0574 gene, and T. pallidum was detected in cerebrospinal fluid (CSF) by reverse-transcriptase polymerase chain reaction of 16S ribosomal RNA. RESULTS: Opsonic activity was higher with higher serum rapid plasma reagin titers (P < .001), and in those treated for uncomplicated syphilis before serum collection (P < .001). Opsonic activity was lower in HIV-infected than in HIV-uninfected individuals even after the above factors were taken into account (P = .006). In participants in whom blood T. pallidum was detectable, those with the highest opsonic activity had lower blood T. pallidum concentrations. In multivariable analyses, there was not a significant relationship between opsonic activity and detection of T. pallidum in CSF or CSF-VDRL reactivity. CONCLUSIONS: Serum T. pallidum-specific opsonic activity is significantly lower in HIV-infected individuals. Impaired T. pallidum specific immune responses could contribute to differences in the course of disease or treatment response. PMID- 26655299 TI - Picornavirus-Induced Airway Mucosa Immune Profile in Asymptomatic Neonates. AB - BACKGROUND: Bacterial airway colonization is known to alter the airway mucosa immune response in neonates whereas the impact of viruses is unknown. The objective was therefore to examine the effect of respiratory viruses on the immune signature in the airways of asymptomatic neonates. METHODS: Nasal aspirates from 571 asymptomatic 1-month-old neonates from the Copenhagen Prospective Studies on Asthma in Childhood 2010 birth cohort were investigated for respiratory viruses. Simultaneously, unstimulated airway mucosal lining fluid was obtained and quantified for levels of 20 immune mediators related to type 1, type 2, type 17, and regulatory immune paths. The association between immune mediator levels and viruses was tested by conventional statistics and partial least square discriminant analysis. RESULTS: Picornaviruses were detected in 58 neonates (10.2%) and other viruses in 10 (1.8%). A general up-regulation of immune mediators was found in the neonates with picornavirus (P < .0001; partial least square discriminant analysis). The association was pronounced for type 1- and type 2-related markers and was unaffected by comprehensive confounder adjustment. Detection of picornavirus and bacteria was associated with an additive general up-regulating effect. CONCLUSIONS: Asymptomatic presence of picornavirus in the neonatal airway is a potent activator of the topical immune response. This is relevant to understanding the immune potentiating effect of early life exposure to viruses. PMID- 26655300 TI - Efficacy of Favipiravir (T-705) in Rabies Postexposure Prophylaxis. AB - Rabies is a fatal encephalitis caused by rabies virus (RABV), and no antiviral drugs for RABV are currently available. We report for the first time the efficacy of favipiravir (T-705) against RABV in vitro and in vivo. T-705 produced a significant, 3-4 log10 reduction in the multiplication of street and fixed RABV strains in mouse neuroblastoma Neuro-2a cells, with half-maximal inhibitory concentrations of 32.4 uM and 44.3 uM, respectively. T-705 significantly improved morbidity and mortality among RABV-infected mice when orally administered at a dose of 300 mg/kg/day for 7 days, beginning 1 hour after inoculation. T-705 significantly reduced the rate of virus positivity in the brain. Furthermore, the effectiveness of T-705 was comparable to that of equine rabies virus immunoglobulin for postexposure prophylaxis. Collectively, our results suggest that T-705 is active against RABV and may serve as a potential alternative to rabies immunoglobulin in rabies postexposure prophylaxis. PMID- 26655301 TI - HLA-A is a Predictor of Hepatitis B e Antigen Status in HIV-Positive African Adults. AB - Outcomes of chronic infection with hepatitis B virus (HBV) are varied, with increased morbidity reported in the context of human immunodeficiency virus (HIV) coinfection. The factors driving different outcomes are not well understood, but there is increasing interest in an HLA class I effect. We therefore studied the influence of HLA class I on HBV in an African HIV-positive cohort. We demonstrated that virologic markers of HBV disease activity (hepatitis B e antigen status or HBV DNA level) are associated with HLA-A genotype. This finding supports the role of the CD8(+) T-cell response in HBV control, and potentially informs future therapeutic T-cell vaccine strategies. PMID- 26655303 TI - In Vitro and In Vivo Identification of Novel Positive Allosteric Modulators of the Human Dopamine D2 and D3 Receptor. AB - Agonists at dopamine D2 and D3 receptors are important therapeutic agents in the treatment of Parkinson's disease. Compared with the use of agonists, allosteric potentiators offer potential advantages such as temporal, regional, and phasic potentiation of natural signaling, and that of receptor subtype selectivity. We report the identification of a stereoselective interaction of a benzothiazol racemic compound that acts as a positive allosteric modulator (PAM) of the rat and human dopamine D2 and D3 receptors. The R isomer did not directly stimulate the dopamine D2 receptor but potentiated the effects of dopamine. In contrast the S isomer attenuated the effects of the PAM and the effects of dopamine. In radioligand binding studies, these compounds do not compete for binding of orthosteric ligands, but indeed the R isomer increased the number of high affinity sites for [(3)H]-dopamine without affecting K(d). We went on to identify a more potent PAM for use in native receptor systems. This compound potentiated the effects of D2/D3 signaling in vitro in electrophysiologic studies on dissociated striatal neurons and in vivo on the effects of L-dopa in the 6OHDA (6 hydroxydopamine) contralateral turning model. These PAMs lacked activity at a wide variety of receptors, lacked PAM activity at related Gi-coupled G protein coupled receptors, and lacked activity at D1 receptors. However, the PAMs did potentiate [(3)H]-dopamine binding at both D2 and D3 receptors. Together, these studies show that we have identified PAMs of the D2 and D3 receptors both in vitro and in vivo. Such compounds may have utility in the treatment of hypodopaminergic function. PMID- 26655302 TI - Roles for Regulator of G Protein Signaling Proteins in Synaptic Signaling and Plasticity. AB - The regulator of G protein signaling (RGS) family of proteins serves critical roles in G protein-coupled receptor (GPCR) and heterotrimeric G protein signal transduction. RGS proteins are best understood as negative regulators of GPCR/G protein signaling. They achieve this by acting as GTPase activating proteins (GAPs) for Galpha subunits and accelerating the turnoff of G protein signaling. Many RGS proteins also bind additional signaling partners that either regulate their functions or enable them to regulate other important signaling events. At neuronal synapses, GPCRs, G proteins, and RGS proteins work in coordination to regulate key aspects of neurotransmitter release, synaptic transmission, and synaptic plasticity, which are necessary for central nervous system physiology and behavior. Accumulating evidence has revealed key roles for specific RGS proteins in multiple signaling pathways at neuronal synapses, regulating both pre and postsynaptic signaling events and synaptic plasticity. Here, we review and highlight the current knowledge of specific RGS proteins (RGS2, RGS4, RGS7, RGS9 2, and RGS14) that have been clearly demonstrated to serve critical roles in modulating synaptic signaling and plasticity throughout the brain, and we consider their potential as future therapeutic targets. PMID- 26655304 TI - Biological Characterization of an Improved Pyrrole-Based Colchicine Site Agent Identified through Structure-Based Design. AB - A refined model of the colchicine site on tubulin was used to design an improved analog of the pyrrole parent compound, JG-03-14. The optimized compound, NT-7-16, was evaluated in biological assays that confirm that it has potent activities as a new colchicine site microtubule depolymerizer. NT-7-16 exhibits antiproliferative and cytotoxic activities against multiple cancer cell lines, with IC(50) values of 10-16 nM, and it is able to overcome drug resistance mediated by the expression of P-glycoprotein and the betaIII isotype of tubulin. NT-7-16 initiated the concentration-dependent loss of cellular microtubules and caused the formation of abnormal mitotic spindles, leading to mitotic accumulation. The direct interaction of NT-7-16 with purified tubulin was confirmed, and it was more potent than combretastatin A-4 in these assays. Binding studies verified that NT-7-16 binds to tubulin within the colchicine site. The antitumor effects of NT-7-16 were evaluated in an MDA-MB-435 xenograft model and it had excellent activity at concentrations that were not toxic. A second compound, NT-9-21, which contains dichloro moieties in place of the 3,5 dibromo substituents of NT-7-16, had a poorer fit within the colchicine site as predicted by modeling and the Hydropathic INTeractions score. Biological evaluations showed that NT-9-21 has 10-fold lower potency than NT-7-16, confirming the modeling predictions. These studies highlight the value of the refined colchicine-site model and identify a new pyrrole-based colchicine-site agent with potent in vitro activities and promising in vivo antitumor actions. PMID- 26655305 TI - Dose-Response Analysis When There Is a Correlation between Affinity and Efficacy. AB - The shape of a concentration-response curve (CRC) is determined by underlying equilibrium constants for agonist binding and receptor conformational change. Typically, agonists are characterized by the empirical CRC parameters efficacy (the maximum response), EC(50) (the concentration that produces a half-maximum response), and the Hill coefficient (the maximum slope of the response). Ligands activate receptors because they bind with higher affinity to the active versus resting conformation, and in skeletal muscle nicotinic acetylcholine receptors there is an exponential relationship between these two equilibrium dissociation constants. Consequently, knowledge of two receptor-specific, agonist-independent constants--the activation equilibrium constant without agonists (E(0)) and the affinity-correlation exponent (M)--allows an entire CRC to be calculated from a measurement of either efficacy or affinity. I describe methods for estimating the CRCs of partial agonists in receptors that have a correlation between affinity and efficacy. PMID- 26655306 TI - Carte-de-Visite of Velpeau by Reutlinger. PMID- 26655307 TI - Can a Blood Test of Immune Responsiveness Predict Speed of Recovery from Pain and Dysfunction after Surgery? PMID- 26655309 TI - Psychiatric Disorders and Psychopharmacologic Treatment as Risk Factors in Elective Fast-track Total Hip and Knee Arthroplasty. AB - BACKGROUND: Psychiatric disorder (PsD) is rarely considered when evaluating perioperative risk factors. Studies on PsD are often limited by use of administrative coding, incomplete follow-up, and lack of preoperative data on psychopharmacological treatment. METHODS: A multicenter study with prospective registration on preoperative comorbidity, complete 90-day follow-up, and information on dispensed prescriptions on psychopharmacological treatment (excluding benzodiazepines). All departments used similar fast-track approaches and discharge to home. Evaluation of postoperative morbidity was based on discharge records. Odds ratios for length of stay (LOS) more than 4 days and surgery-related readmissions were calculated using multiple logistic regression adjusting for potential confounders. RESULTS: Of 8,757 procedures, 1,001 (11.4%) were in PsD patients. Of these, 43.4% used selective serotonin inhibitors (SSRIs), 31.6% used other antidepressants, 8.5% used a combination, and 16.5% used antipsychotics. PsD was associated with increased risk of LOS more than 4 days (16.5 vs. 7.3%; odds ratio, 1.90; 95% CI, 1.52 to 2.37), regardless of treatment with SSRIs (2.19; 1.62 to 2.97), other antidepressants (1.81; 1.25 to 2.61), or antipsychotics (1.90; 1.62 to 3.16). PsD was associated with increased 30- (9.9 vs. 5.1%; 1.93; 1.49 to 2.49) and 90-day surgery-related readmissions (12.8 vs. 7.4%; 1.68; 1.34 to 2.10), significant for SSRIs (1.97; 1.38 to 2.82 and 1.77; 1.29 to 2.43), other antidepressants (2.24; 1.51 to 3.32 and 1.82; 1.27 to 2.61), and antipsychotics (1.85; 1.03 to 3.31, 30 days only). In PsD patients, pain (1.4%), postoperative anemia (1.1%), and pulmonary complications (1.1%) were the most frequent causes of LOS more than 4 days. Hip displacements (2.8%) and falls (1.9%) were the most frequent readmissions, and 90-day surgery-related mortality was 0.7% with and 0.2% without PsD. CONCLUSIONS: Psychopharmacologically treated PsD is a risk factor for postoperative morbidity after fast-track arthroplasty, regardless of treatment type. This may be due to PsD per se and/or drug-related side effects. PMID- 26655308 TI - Patient-specific Immune States before Surgery Are Strong Correlates of Surgical Recovery. AB - BACKGROUND: Recovery after surgery is highly variable. Risk-stratifying patients based on their predicted recovery profile will afford individualized perioperative management strategies. Recently, application of mass cytometry in patients undergoing hip arthroplasty revealed strong immune correlates of surgical recovery in blood samples collected shortly after surgery. However, the ability to interrogate a patient's immune state before surgery and predict recovery is highly desirable in perioperative medicine. METHODS: To evaluate a patient's presurgical immune state, cell-type-specific intracellular signaling responses to ex vivo ligands (lipopolysaccharide, interleukin [IL]-6, IL-10, and IL-2/granulocyte macrophage colony-stimulating factor) were quantified by mass cytometry in presurgical blood samples. Selected ligands modulate signaling processes perturbed by surgery. Twenty-three cell surface and 11 intracellular markers were used for the phenotypic and functional characterization of major immune cell subsets. Evoked immune responses were regressed against patient centered outcomes, contributing to protracted recovery including functional impairment, postoperative pain, and fatigue. RESULTS: Evoked signaling responses varied significantly and defined patient-specific presurgical immune states. Eighteen signaling responses correlated significantly with surgical recovery parameters (|R| = 0.37 to 0.70; false discovery rate < 0.01). Signaling responses downstream of the toll-like receptor 4 in cluster of differentiation (CD) 14 monocytes were particularly strong correlates, accounting for 50% of observed variance. Immune correlates identified in presurgical blood samples mirrored correlates identified in postsurgical blood samples. CONCLUSIONS: Convergent findings in pre- and postsurgical analyses provide validation of reported immune correlates and suggest a critical role of the toll-like receptor 4 signaling pathway in monocytes for the clinical recovery process. The comprehensive assessment of patients' preoperative immune state is promising for predicting important recovery parameters and may lead to clinical tests using standard flow cytometry. PMID- 26655310 TI - F. A. Sweetland's "Liquid Nitrous Oxide" Trade Card. PMID- 26655311 TI - Bloomheart's "Contact Thermometer" Patent: The McKesson Dermalor. PMID- 26655312 TI - Protective Ventilation during Anesthesia: Too Soon for Final Recommendations. PMID- 26655313 TI - In Reply. PMID- 26655314 TI - Limitations of the Pupillary Reflex: Do the Eyes Have It? PMID- 26655315 TI - In Reply. PMID- 26655324 TI - Accelerated Recovery: From a Fortnight to Four Nights. PMID- 26655316 TI - Trials and Observations: A Friendly Pointer on the Language of Study Design. PMID- 26655325 TI - CYP2B6*6 and CYP2B6*18 Predict Long-Term Efavirenz Exposure Measured in Hair Samples in HIV-Positive South African Women. AB - Long-term exposure to efavirenz (EFV) measured in hair samples may predict response to antiretroviral treatment (ART). Polymorphisms in CYP2B6 are known to alter EFV levels. The aim of this study was to assess the relationship between CYP2B6 genotype, EFV levels measured in hair, and virological outcomes on ART in a real-world setting. We measured EFV levels in hair from HIV-positive South African females who had been receiving EFV-based treatment for at least 3 months from the South African Black (SAB) (n = 81) and Cape Mixed Ancestry (CMA) (n = 53) populations. Common genetic variation in CYP2B6 was determined in 15 individuals from each population using bidirectional Sanger sequencing. Prioritized variants (n = 16) were subsequently genotyped in the entire patient cohort (n = 134). The predictive value of EFV levels in hair and selected variants in CYP2B6 on virological treatment outcomes was assessed. Previously described alleles (CYP2B6*2, CYP2B6*5, CYP2B6*6, CYP2B6*17, and CYP2B6*18), as well as two novel alleles (CYP2B6*31 and CYP2B6*32), were detected in this study. Compared to noncarriers, individuals homozygous for CYP2B6*6 had ~109% increased EFV levels in hair (p = .016) and CYP2B6*18 heterozygotes demonstrated 82% higher EFV hair levels (p = .0006). This study confirmed that alleles affecting CYP2B6 metabolism and subsequent EFV exposure are present at significant frequencies in both the SAB and CMA populations. Furthermore, this study demonstrated that the use of hair samples for testing EFV concentrations may be a useful tool in determining long-term drug exposure in resource-limited countries. PMID- 26655326 TI - When choice becomes limited: Women's experiences of delay in labour. AB - Choice and patient involvement in decision-making are strong aspirations of contemporary healthcare. One of the most striking areas in which this is played out is maternity care where recent policy has focused on choice and supporting normal birth. However, birth is sometimes not straightforward and unanticipated complications can rapidly reduce choice. We draw on the accounts of women who experienced delay during labour with their first child. This occurs when progress is slow, and syntocinon is administered to strengthen and regulate contractions. Once delay has been recognized, the clinical circumstances limit choice. Drawing on Mol's work on the logics of choice and care, we explore how, although often upsetting, women accepted that their choices and plans were no longer feasible. The majority were happy to defer to professionals who they regarded as having the necessary technical expertise, while some adopted a more traditional medical model and actively rejected involvement in decision-making altogether. Only a minority wanted to continue active involvement in decision-making, although the extent to which the possibility existed for them to do so was questionable. Women appeared to accept that their ideals of choice and involvement had to be abandoned, and that clinical circumstances legitimately changed events. PMID- 26655327 TI - The autoimmune diseases of the eyes. AB - The eye is divided anatomically in three layers: an outer or fibrous layer (cornea/sclera), middle or vascular layer (uvea - iris, ciliary body, and choroid) and an inner or sensorineural layer (retina). They compose the several anatomic and functional layers that enable the immune protection of the eye. The first layer involves an intact anatomic border with the blood-ocular barrier and immunosuppressive neuropeptides in the native aqueous humor. The second layer trusts on the capability of the eye to reestablish an immunosuppressive micro environment by activating latent TGF-beta and reestablishing the anterior chamber associated immune deviation. The third layer involves a mechanism that is not yet completely recognized, but that has the ability to overcome a predominantly Th1 intraocular immune response and to reestablish anterior chamber-associated immune deviation. Understanding the comprehensive mechanisms of these pathways, will lead to the development of new treatments strategies in order to prevent damage to the eye from persistent or exacerbated inflammation, directed at first to pathogens, but that may develop an autoimmune reaction. PMID- 26655328 TI - Clinical and Histological Evaluation of Ceramic Matrix in a Collagen Carrier for Socket Preservation in Humans. AB - INTRODUCTION: A case series was used to evaluate the efficacy and predictability of a ceramic matrix in a putty-like collagen carrier in immediate extraction sockets. METHODS: A single failing tooth was atraumatically extracted from each of 10 subjects. The sockets were debrided and grafted with ceramic matrix in a putty-like collagen carrier (15% hydroxyapatite, 85% beta-tricalcium phosphate complex). A bovine pericardium membrane was draped over the graft site and a tension-free primary closure was obtained. After 6 months of healing, a trephine biopsy was taken from the center of each graft and a dental implant was placed. Two subjects were withdrawn from the study and were considered treatment failures. One of them moved to another state and the second exhibited delayed healing that required debridement of the grafting material from the socket. RESULTS: After 6 months follow-up, there was a mean reduction of ridge width of 1.667 mm and mean reduction of ridge height of 0.483 mm after graft healing and integration. Over a 24-month follow-up, mean new bone fill was 40.25% and implant osseointegration was 100%. CONCLUSION: Ceramic matrix in a putty-like collagen carrier maintained ridge dimensions and, despite ongoing bone turnover, produced adequate mineralized tissue that enabled implant placement at 6 months. PMID- 26655329 TI - Exploring the Perceptions of Core Values of Nursing in Taiwanese Nursing Students at the Baccalaureate Level. AB - BACKGROUND: The core values of nursing are a standard component of the nursing curriculum in Taiwan. Therefore, these values provide an essential guide for educating and evaluating the learning outcomes of nursing students. Student perceptions of those core values that relate to the process of curricula learning are key to measuring the core values of nursing. PURPOSE: This study explores the views on the core values of nursing of baccalaureate-level nursing students at a Taiwanese university. METHODS: This qualitative study collected data from the reflection reports of 109 students and analyzed these data using thematic content analysis. RESULTS: The results of this study identified that the learning of core values of nursing tends to utilize the latent curriculum rather than the open curriculum. Critical thinking was perceived and experienced by asking "why." General clinical skills and basic biomedical science were categorized collectively as care ability, which relates to the thinking, analysis, and mapping of client health problems. The value of communication and teamwork capability was defined as the sequential process of accepting, interacting, communicating, and collaborating. Caring was defined as contributing empathy with respect to one's self and to others. Ethics was defined as a moral perspective, as respecting others, and as prioritizing the needs of clients. Accountability was defined as a way of observing standards within the role given in a position. Finally, lifelong learning is a process of learning that encourages more aggressive learning. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: The progress of core values of nursing in this study reflects positive movement and achievement. The participants expressed the perception that the core values of nursing enhance understanding, which enables nursing educators to reframe the nursing curriculum to meet their learning needs. The perceptions of nursing students of core values of nursing may be used as a guide to increase clinical nursing competence in healthcare. PMID- 26655331 TI - Aging induced loss of stemness with concomitant gain of myogenic properties of a pure population of CD34(+)/CD45(-) muscle derived stem cells. AB - Aging is accompanied by the functional decline of cells, tissues, and organs, as well as, a striking increase in susceptibility to a wide range of diseases. Within a tissue, both differentiated cells and adult stem cells are susceptible to intrinsic and extrinsic changes while aging. Muscle derived stem cells (MDSCs) are tissue specific stem cells which have been studied well for their multipotential nature. Although there are reports relating to diminished function and regenerative capacity of aged MDSCs as compared to their young counterparts, not much has been reported relating to the concomitant gain in unipotent nature of aged MDSCs. In this study, we report an inverse correlation between aging and expression of adult/mesenchymal stem cell markers and a direct correlation between aging and myogenecity in MDSCs. Aged MDSCs were able to generate a greater number of dystrophin positive myofibres, as compared to, the young MDSCs when transplanted in muscle of dystrophic mice. Our data, therefore, suggests that aging stress adds to the decline in stem cell characteristics with a concomitant increase in unipotency, in terms of, myogenecity of MDSCs. This study, hence, also opens the possibilities of using unipotent aged MDSCs as potential candidates for transplantation in patients with muscular dystrophies. PMID- 26655332 TI - Following Young Children's Health and Functioning in Everyday Life Through Their Cancer Trajectory. AB - BACKGROUND: Knowledge of living with childhood cancer, through the trajectory, is sparse. AIM: The aim of this study was to follow young children's health and functioning in everyday life through their cancer trajectory. METHODS: Data were gathered longitudinally from a group of 13 young children and their parents connected to a pediatric oncology unit in Sweden. The International Classification of Functioning, Disability and Health for Children and Youth structure was used to identify difficulties in health and functioning in everyday life, in interview and questionnaire data. Descriptive statistical analysis was performed to show patterns of difficulty over a 3-year period from diagnosis. RESULTS: Difficulties experienced by children declined and changed over time. An increase in difficulties with personal interactions with others and access to and support from health care professionals was seen 2 to 3 years after diagnosis and start of treatment. Similar patterns are seen within individual children's trajectories in relation to diagnosis but individual patterns were seen for each child. CONCLUSIONS AND CLINICAL IMPLICATIONS: Health care professionals need to plan for ongoing contact with school services and information and support pathways, beyond the treatment period. A person-centered philosophy of care is required throughout the cancer trajectory. PMID- 26655333 TI - Coarse-grained bond and angle distributions from atomistic simulations: On the systematic parameterisation of lipid models. AB - Coarse-grained (CG) models are popular alternatives to atomistic (AT) force fields as they enable simulations of larger systems at longer timescales. The bottom-up approach is a systematic parameterisation strategy whereby data from AT simulations are used to determine the CG parameters. This is particular straightforward with the bond and angle parameters as a direct Boltzmann inversion can be used. Still, a reference AT force field has to be chosen. In this study, I compare three common AT force fields (Stockholm lipids, Berger and Gromos) and investigate the sampling of bond and angle distributions in two CG models (Martini and Elba). As a test case, I choose a bilayer of POPC lipids. The AT simulations give distributions that agree to a large extent, especially in the fatty acid tails. However, the AT simulations sample distributions that differ from the distributions observed in CG simulations with respect to both location and width. The bond and angle distributions from the AT simulations are then used to re-parameterise the CG force fields. For the Martini model, this significantly alters the physical behaviour of the membrane, which likely is an effect of the mapping. However, for the Elba model the re-parameterised force field gives a membrane that is in some respects closer to the experimental membrane. Implications for CG parameterisation are discussed. PMID- 26655334 TI - Numeric promoter description - A comparative view on concepts and general application. AB - Nucleic acid molecules play a key role in a variety of biological processes. Starting from storage and transfer tasks, this also comprises the triggering of biological processes, regulatory effects and the active influence gained by target binding. Based on the experimental output (in this case promoter sequences), further in silico analyses aid in gaining new insights into these processes and interactions. The numerical description of nucleic acids thereby constitutes a bridge between the concrete biological issues and the analytical methods. Hence, this study compares 26 descriptor sets obtained by applying well known numerical description concepts to an established dataset of 38 DNA promoter sequences. The suitability of the description sets was evaluated by computing partial least squares regression models and assessing the model accuracy. We conclude that the major importance regarding the descriptive power is attached to positional information rather than to explicitly incorporated physico-chemical information, since a sufficient amount of implicit physico-chemical information is already encoded in the nucleobase classification. The regression models especially benefited from employing the information that is encoded in the sequential and structural neighborhood of the nucleobases. Thus, the analyses of n-grams (short fragments of length n) suggested that they are valuable descriptors for DNA target interactions. A mixed n-gram descriptor set thereby yielded the best description of the promoter sequences. The corresponding regression model was checked and found to be plausible as it was able to reproduce the characteristic binding motifs of promoter sequences in a reasonable degree. As most functional nucleic acids are based on the principle of molecular recognition, the findings are not restricted to promoter sequences, but can rather be transferred to other kinds of functional nucleic acids. Thus, the concepts presented in this study could provide advantages for future nucleic acid based technologies, like biosensoring, therapeutics and molecular imaging. PMID- 26655335 TI - Three-Component Coupling Involving Arynes, Aromatic Tertiary Amines, and Aldehydes via Aryl-Aryl Amino Group Migration. AB - The transition-metal-free multicomponent coupling of arynes, aromatic tertiary amines, and aldehydes proceeding via the aryl to aryl amino group migration has been demonstrated. This protocol allows rapid access to ortho-functionalized tertiary amines in moderate to good yields. Moreover, activated ketones can also be used as the aldehyde component in the present reaction. The similarity of the aryl-aryl tertiary amino group migration with the Smiles rearrangement is striking. PMID- 26655336 TI - CD4 T lymphocyte counts in patients undergoing splenectomy during living donor liver transplantation. AB - The role of splenectomy in increasing the CD4-positive T lymphocyte counts (hereafter: CD4 counts) and the CD4 to CD8 ratio have not yet been fully investigated, especially in the case of HIV-positive patients undergoing liver transplantation (LT). METHODS: The change in the total lymphocyte counts of 32 patients who underwent one-stage splenectomy with living donor (LD) LT with (n=13) or without rituximab (RTX, n=19) therapy were examined to validate our cohort of ABO-incompatible LDLT with RTX. Subsequently, perioperative changes in CD4 counts and the CD 4 to CD8 ratio were measured in 13 patients who underwent ABO-incompatible LDLT/RTX with splenectomy. RESULTS: (1) The administration of RTX did not significantly affect the total lymphocyte counts of patients after LDLT/splenectomy in any of the observation periods. (2) The CD4 counts were significantly higher at 2years after LDLT in comparison to the perioperative CD4 counts but not within the 3-month period (p=0.039). The CD4/CD8 ratio gradually decreased after LDLT/splenectomy under RTX treatment. CONCLUSIONS: An immediate increase in the CD4 counts therefore cannot be expected after LDLT with splenectomy. The total lymphocyte and CD4 counts were rather stable in the peritransplant period even in ABO incompatible LDLT with RTX. PMID- 26655337 TI - Behavioral plasticity through the modulation of switch neurons. AB - A central question in artificial intelligence is how to design agents capable of switching between different behaviors in response to environmental changes. Taking inspiration from neuroscience, we address this problem by utilizing artificial neural networks (NNs) as agent controllers, and mechanisms such as neuromodulation and synaptic gating. The novel aspect of this work is the introduction of a type of artificial neuron we call "switch neuron". A switch neuron regulates the flow of information in NNs by selectively gating all but one of its incoming synaptic connections, effectively allowing only one signal to propagate forward. The allowed connection is determined by the switch neuron's level of modulatory activation which is affected by modulatory signals, such as signals that encode some information about the reward received by the agent. An important aspect of the switch neuron is that it can be used in appropriate "switch modules" in order to modulate other switch neurons. As we show, the introduction of the switch modules enables the creation of sequences of gating events. This is achieved through the design of a modulatory pathway capable of exploring in a principled manner all permutations of the connections arriving on the switch neurons. We test the model by presenting appropriate architectures in nonstationary binary association problems and T-maze tasks. The results show that for all tasks, the switch neuron architectures generate optimal adaptive behaviors, providing evidence that the switch neuron model could be a valuable tool in simulations where behavioral plasticity is required. PMID- 26655338 TI - Stability of discrete time recurrent neural networks and nonlinear optimization problems. AB - We consider the method of Reduction of Dissipativity Domain to prove global Lyapunov stability of Discrete Time Recurrent Neural Networks. The standard and advanced criteria for Absolute Stability of these essentially nonlinear systems produce rather weak results. The method mentioned above is proved to be more powerful. It involves a multi-step procedure with maximization of special nonconvex functions over polytopes on every step. We derive conditions which guarantee an existence of at most one point of local maximum for such functions over every hyperplane. This nontrivial result is valid for wide range of neuron transfer functions. PMID- 26655339 TI - Prognostic value of PCSK9 levels in patients with acute coronary syndromes. AB - AIMS: Proprotein convertase subtilisin kexin 9 (PCSK9) is an emerging target for the treatment of hypercholesterolaemia, but the clinical utility of PCSK9 levels to guide treatment is unknown. We aimed to prospectively assess the prognostic value of plasma PCSK9 levels in patients with acute coronary syndromes (ACS). METHODS AND RESULTS: Plasma PCSK9 levels were measured in 2030 ACS patients undergoing coronary angiography in a Swiss prospective cohort. At 1 year, the association between PCSK9 tertiles and all-cause death was assessed adjusting for the Global Registry of Acute Coronary Events (GRACE) variables, as well as the achievement of LDL cholesterol targets of <1.8 mmol/L. Patients with higher PCSK9 levels at angiography were more likely to have clinical familial hypercholesterolaemia (rate ratio, RR 1.21, 95% confidence interval, CI 1.09 1.53), be treated with lipid-lowering therapy (RR 1.46, 95% CI 1.30-1.63), present with longer time interval of chest pain (RR 1.29, 95% CI 1.09-1.53) and higher C-reactive protein levels (RR 1.22, 95% CI 1.16-1.30). PCSK9 increased 12 24 h after ACS (374 +/- 149 vs. 323 +/- 134 ng/mL, P < 0.001). At 1 year follow up, HRs for upper vs. lower PCSK9-level tertiles were 1.13 (95% CI 0.69-1.85) for all-cause death and remained similar after adjustment for the GRACE score. Patients with higher PCSK9 levels were less likely to reach the recommended LDL cholesterol targets (RR 0.81, 95% CI 0.66-0.99). CONCLUSION: In ACS patients, high initial PCSK9 plasma levels were associated with inflammation in the acute phase and hypercholesterolaemia, but did not predict mortality at 1 year. PMID- 26655340 TI - Information-theoretic model comparison unifies saliency metrics. AB - Learning the properties of an image associated with human gaze placement is important both for understanding how biological systems explore the environment and for computer vision applications. There is a large literature on quantitative eye movement models that seeks to predict fixations from images (sometimes termed "saliency" prediction). A major problem known to the field is that existing model comparison metrics give inconsistent results, causing confusion. We argue that the primary reason for these inconsistencies is because different metrics and models use different definitions of what a "saliency map" entails. For example, some metrics expect a model to account for image-independent central fixation bias whereas others will penalize a model that does. Here we bring saliency evaluation into the domain of information by framing fixation prediction models probabilistically and calculating information gain. We jointly optimize the scale, the center bias, and spatial blurring of all models within this framework. Evaluating existing metrics on these rephrased models produces almost perfect agreement in model rankings across the metrics. Model performance is separated from center bias and spatial blurring, avoiding the confounding of these factors in model comparison. We additionally provide a method to show where and how models fail to capture information in the fixations on the pixel level. These methods are readily extended to spatiotemporal models of fixation scanpaths, and we provide a software package to facilitate their use. PMID- 26655341 TI - Antifungal drug itraconazole targets VDAC1 to modulate the AMPK/mTOR signaling axis in endothelial cells. AB - Itraconazole, a clinically used antifungal drug, was found to possess potent antiangiogenic and anticancer activity that is unique among the azole antifungals. Previous mechanistic studies have shown that itraconazole inhibits the mechanistic target of rapamycin (mTOR) signaling pathway, which is known to be a critical regulator of endothelial cell function and angiogenesis. However, the molecular target of itraconazole that mediates this activity has remained unknown. Here we identify the major target of itraconazole in endothelial cells as the mitochondrial protein voltage-dependent anion channel 1 (VDAC1), which regulates mitochondrial metabolism by controlling the passage of ions and small metabolites through the outer mitochondrial membrane. VDAC1 knockdown profoundly inhibits mTOR activity and cell proliferation in human umbilical vein cells (HUVEC), uncovering a previously unknown connection between VDAC1 and mTOR. Inhibition of VDAC1 by itraconazole disrupts mitochondrial metabolism, leading to an increase in the cellular AMP:ATP ratio and activation of the AMP-activated protein kinase (AMPK), an upstream regulator of mTOR. VDAC1-knockout cells are resistant to AMPK activation and mTOR inhibition by itraconazole, demonstrating that VDAC1 is the mediator of this activity. In addition, another known VDAC targeting compound, erastin, also activates AMPK and inhibits mTOR and proliferation in HUVEC. VDAC1 thus represents a novel upstream regulator of mTOR signaling in endothelial cells and a promising target for the development of angiogenesis inhibitors. PMID- 26655342 TI - Rapid increases in immature synapses parallel estrogen-induced hippocampal learning enhancements. AB - Dramatic increases in hippocampal spine synapse density are known to occur within minutes of estrogen exposure. Until now, it has been assumed that enhanced spinogenesis increased excitatory input received by the CA1 pyramidal neurons, but how this facilitated learning and memory was unclear. Delivery of 17beta estradiol or an estrogen receptor (ER)-alpha (but not ER-beta) agonist into the dorsal hippocampus rapidly improved general discrimination learning in female mice. The same treatments increased CA1 dendritic spines in hippocampal sections over a time course consistent with the learning acquisition phase. Surprisingly, estrogen-activated spinogenesis was associated with a decrease in CA1 hippocampal excitatory input, rapidly and transiently reducing CA1 AMPA activity via a mechanism likely reflecting AMPA receptor internalization and creation of silent or immature synapses. We propose that estrogens promote hippocampally mediated learning via a mechanism resembling some of the broad features of normal development, an initial overproduction of functionally immature connections being subsequently "pruned" by experience. PMID- 26655343 TI - Bimodal rheotactic behavior reflects flagellar beat asymmetry in human sperm cells. AB - Rheotaxis, the directed response to fluid velocity gradients, has been shown to facilitate stable upstream swimming of mammalian sperm cells along solid surfaces, suggesting a robust physical mechanism for long-distance navigation during fertilization. However, the dynamics by which a human sperm orients itself relative to an ambient flow is poorly understood. Here, we combine microfluidic experiments with mathematical modeling and 3D flagellar beat reconstruction to quantify the response of individual sperm cells in time-varying flow fields. Single-cell tracking reveals two kinematically distinct swimming states that entail opposite turning behaviors under flow reversal. We constrain an effective 2D model for the turning dynamics through systematic large-scale parameter scans, and find good quantitative agreement with experiments at different shear rates and viscosities. Using a 3D reconstruction algorithm to identify the flagellar beat patterns causing left or right turning, we present comprehensive 3D data demonstrating the rolling dynamics of freely swimming sperm cells around their longitudinal axis. Contrary to current beliefs, this 3D analysis uncovers ambidextrous flagellar waveforms and shows that the cell's turning direction is not defined by the rolling direction. Instead, the different rheotactic turning behaviors are linked to a broken mirror symmetry in the midpiece section, likely arising from a buckling instability. These results challenge current theoretical models of sperm locomotion. PMID- 26655344 TI - Nickel phlorin intermediate formed by proton-coupled electron transfer in hydrogen evolution mechanism. AB - The development of more effective energy conversion processes is critical for global energy sustainability. The design of molecular electrocatalysts for the hydrogen evolution reaction is an important component of these efforts. Proton coupled electron transfer (PCET) reactions, in which electron transfer is coupled to proton transfer, play an important role in these processes and can be enhanced by incorporating proton relays into the molecular electrocatalysts. Herein nickel porphyrin electrocatalysts with and without an internal proton relay are investigated to elucidate the hydrogen evolution mechanisms and thereby enable the design of more effective catalysts. Density functional theory calculations indicate that electrochemical reduction leads to dearomatization of the porphyrin conjugated system, thereby favoring protonation at the meso carbon of the porphyrin ring to produce a phlorin intermediate. A key step in the proposed mechanisms is a thermodynamically favorable PCET reaction composed of intramolecular electron transfer from the nickel to the porphyrin and proton transfer from a carboxylic acid hanging group or an external acid to the meso carbon of the porphyrin. The C-H bond of the active phlorin acts similarly to the more traditional metal-hydride by reacting with acid to produce H2. Support for the theoretically predicted mechanism is provided by the agreement between simulated and experimental cyclic voltammograms in weak and strong acid and by the detection of a phlorin intermediate through spectroelectrochemical measurements. These results suggest that phlorin species have the potential to perform unique chemistry that could prove useful in designing more effective electrocatalysts. PMID- 26655345 TI - [Multimodal therapeutic approach of vaginismus: an innovative approach through trigger point infiltration and pulsed radiofrequency of the pudendal nerve]. AB - Vaginismus is a poorly understood disorder, characterized by an involuntary muscular spasm of the pelvic floor muscles and outer third of the vagina during intercourse attempt, which results in aversion to penetration. It is reported to affect 1-7% of women worldwide. With this report the authors aim to describe the case of a young patient with vaginismus in whom techniques usually from the chronic pain domain were used as part of her multimodal therapeutic regimen. PMID- 26655346 TI - Training and testing ERP-BCIs under different mental workload conditions. AB - OBJECTIVE: As one of the most popular and extensively studied paradigms of brain computer interfaces (BCIs), event-related potential-based BCIs (ERP-BCIs) are usually built and tested in ideal laboratory settings in most existing studies, with subjects concentrating on stimuli and intentionally avoiding possible distractors. This study is aimed at examining the effect of simultaneous mental activities on ERP-BCIs by manipulating various levels of mental workload during the training and/or testing of an ERP-BCI. APPROACH: Mental workload was manipulated during the training or testing of a row-column P300-speller to investigate how and to what extent the spelling performance and the ERPs evoked by the oddball stimuli are affected by simultaneous mental workload. MAIN RESULTS: Responses of certain ERP components, temporal-occipital N200 and the late reorienting negativity evoked by the oddball stimuli and the classifiability of ERP features between targets and non-targets decreased with the increase of mental workload encountered by the subject. However, the effect of mental workload on the performance of ERP-BCI was not always negative but depended on the conditions where the ERP-BCI was built and applied. The performance of ERP BCI built under an ideal lab setting without any irrelevant mental activities declined with the increasing mental workload of the testing data. However, the performance was significantly improved when an ERP-BCI was built under an appropriate mental workload level, compared to that built under speller-only conditions. SIGNIFICANCE: The adverse effect of concurrent mental activities may present a challenge for ERP-BCIs trained in ideal lab settings but which are to be used in daily work, especially when users are performing demanding mental processing. On the other hand, the positive effects of the mental workload of the training data suggest that introducing appropriate mental workload during training ERP-BCIs is of potential benefit to the performance in practical applications. PMID- 26655347 TI - Value of mefloquine chemoprophylaxis in military personnel. PMID- 26655348 TI - Human umbilical cord blood derived mesenchymal stem cells improve cardiac function in cTnT(R141W) transgenic mouse of dilated cardiomyopathy. AB - Cell transplantation is a promising strategy in regenerative medicine. Beneficial effects of bone marrow mesenchymal stem cells (BM-MSCs) on heart disease have been widely reported. However, the MSCs in these studies have been mainly derived from autologous animals, and data on MSCs from human umbilical cord blood (UCB MSCs) are still scarce. We investigated whether intramyocardial xenogeneic administration of UCB-MSCs is beneficial for preserving heart function in a cTnT(R141W) transgenic mouse of dilated cardiomyopathy (DCM). Cultured UCB-MSCs, which were identified by there morphology, differentiation and cell surface markers, were transplanted into cTnT(R141W) transgenic mice to examine apoptosis, fibrosis, vasculogenesis and the associated Akt pathway. Moreover, we measured the expression levels of VEGF and IGF-1, which are growth factors required for differentiation into cardiomyocytes, and are also involved in cardiac regeneration and improving heart function. One month after transplantation, MSCs significantly decreased chamber dilation and contractile dysfunction in the cTnT(R141W) mice. MSCs transplanted hearts showed a significant decrease in cardiac apoptosis and its regulation by the Akt pathway. Cardiac fibrosis and cytoplasmic vacuolisation were significantly attenuated in the MSCs group. Importantly, the levels of VEGF and IGF-1 were increased in the MSCs transplanted hearts. In vitro, the MSC-conditioned medium displayed anti-apoptotic activity in h9c2 cardiomyocytes subjected to hypoxia. These results further confirm the paracrine effects of MSCs. In conclusion, UCB-MSCs preserve cardiac function after intramyocardial transplantation in a DCM mouse, and this effect may be associated with reductions in cellular apoptosis, inflammation, hypertrophy and myocardial fibrosis; in addition to; up-regulation of Akt, VEGF and IGF-1; and enhanced angiogenesis. PMID- 26655349 TI - Outcome and characteristics of patients with malignant pleural effusion from differentiated thyroid carcinoma. AB - Metastatic differentiated thyroid carcinoma (DTC) is an uncommon cause of malignant pleural effusion (MPE) and the characteristics and clinical course have been rarely described. Herein, we report a retrospective review of the clinical course of 18 patients (15 women and 3 men) with MPE from DTC who underwent treatment at our institution between January 2005 and December 2014. MPE from DTC was diagnosed based on cytology and/or level of thyroglobulin in the pleural fluid. Pathologically, papillary carcinoma was found in 16 patients and follicular carcinoma in 2 patients. Median ages at initial diagnosis of DTC and MPE were 64 years (range, 22-79) and 74 years (range, 39-86), respectively. All patients showed radiologically apparent lung metastases, with MPE developing after 0-212 months (median, 25). In 16 patients (88.9%), other coexistent distant metastases at the time of MPE diagnosis were found in the bone (n = 10), brain (n = 5), and skin (n = 2). All patients were treated conservatively with palliative thoracentesis or chest tube drainage with or without pleurodesis. Recurrent MPE after treatment was seen in 9 patients; discharge to home health care after treatment for MPE was possible for 14 patients. The overall survival after initial diagnosis varied considerably from 14 months to 37 years, but the median survival after appearance of MPE was 10 months (range, 1-28). Systemic therapy for iodine-resistant recurrent thyroid disease may need to be considered as a treatment option for patients with MPE. PMID- 26655350 TI - Early Diagnosis and Repair of Double Saccular Aneurysms of the Aortic Arch Associated With Aortic Coarctation in an Infant With Loeys-Dietz Syndrome. AB - Multiple saccular aneurysms of the thoracic aorta in neonates and infants are exceedingly rare. An association of these aneurysms with Loeys-Dietz syndrome (LDS) in older age-groups is well known. This case report describes the diagnosis and subsequent successful repair of aortic coarctation associated with double saccular aneurysms of the thoracic aorta in patient with LDS during the first year of life. PMID- 26655351 TI - Costs of Learning and the Evolution of Mimetic Signals. AB - Predators must use the appearance of their prey to decide whether it is likely to be defended. Most theory assumes that predators have completed learning about prey appearance, yet we do not understand how predators learn which aspects of appearance to use for classifying prey. If sampling prey can be risky, predators might forgo opportunities to learn about the relationship between prey appearance and defense. Using Bayesian inference and dynamic programming, we modeled how the immediate risks and future rewards of learning about prey appearance influence how predators learn. In addition, we explored how variation in predator learning affects the evolution of mimicry, which occurs when two prey evolve to share a common signal to predators. We found that when learning about prey with distinct appearances was expensive, optimal predators tended to lump them into the same category or exhibit an unwillingness to sample at all (neophobia). This resulted in a reduction in selection for defensive mimicry. However, the same predator behavior favored the evolution of aggressive mimicry, because in that case, mimics benefited from being sampled. When prey were very rare and costs of sampling them were high, predators exhibited neophobia, refusing to attack. This behavior could forestall the evolution of mimicry and instead select for polymorphism. PMID- 26655352 TI - Prey Carrying Capacity Modulates the Effect of Predation on Prey Diversity. AB - Understanding the role of predation in regulating prey diversity is a major goal in ecology, with profound consequences for community dynamics, ecosystem structure, and conservation practice. Deterministic differential equation models predict that some predation regimes, such as prey-switching predation, should promote prey coexistence and increase prey diversity. However, such models do not capture stochastic population fluctuations that are ubiquitous in empirical study sites and nature reserves. In this article, we examine the effects of prey switching predation on the species richness of prey communities with demographic noise. We show that in finite, discrete prey populations, the ability of prey switching predation to promote diversity depends on the carrying capacity of the prey community and the richness of the source pool for prey. Identical predation regimes may have opposite effects on prey diversity depending on the size and productivity of the habitat or the metacommunity richness. Statistical properties of the fluctuations of prey populations determine the effect of stabilizing mechanisms on species richness. We discuss the implications of this result for empirical studies of predation in small study areas and for the management of small nature reserves. PMID- 26655353 TI - Extending the Concept of Diversity Partitioning to Characterize Phenotypic Complexity. AB - Most components of an organism's phenotype can be viewed as the expression of multiple traits. Many of these traits operate as complexes, where multiple subsidiary parts function and evolve together. As trait complexity increases, so does the challenge of describing complexity in intuitive, biologically meaningful ways. Traditional multivariate analyses ignore the phenomenon of individual complexity and provide relatively abstract representations of variation among individuals. We suggest adopting well-known diversity indices from community ecology to describe phenotypic complexity as the diversity of distinct subsidiary components of a trait. Using a hierarchical framework, we illustrate how total trait diversity can be partitioned into within-individual complexity (alpha diversity) and between-individual components (beta diversity). This approach complements traditional multivariate analyses. The key innovations are (i) addition of individual complexity within the same framework as between-individual variation and (ii) a group-wise partitioning approach that complements traditional level-wise partitioning of diversity. The complexity-as-diversity approach has potential application in many fields, including physiological ecology, ecological and community genomics, and transcriptomics. We demonstrate the utility of this complexity-as-diversity approach with examples from chemical and microbial ecology. The examples illustrate biologically significant differences in complexity and diversity that standard analyses would not reveal. PMID- 26655354 TI - Generational Spreading Speed and the Dynamics of Population Range Expansion. AB - Some of the most fundamental quantities in population ecology describe the growth and spread of populations. Population dynamics are often characterized by the annual rate of increase, lambda, or the generational rate of increase, R0. Analyses involving R0 have deepened our understanding of disease dynamics and life-history complexities beyond that afforded by analysis of annual growth alone. While range expansion is quantified by the annual spreading speed, a spatial analog of lambda, an R0-like expression for the rate of spread is missing. Using integrodifference models, we derive the appropriate generational spreading speed for populations with complex (stage-structured) life histories. The resulting measure, relevant to locations near the expanding edge of a (re)colonizing population, incorporates both local population growth and explicit spatial dispersal rather than solely growth across a population, as is the case for R0. The calculations for generational spreading speed are often simpler than those for annual spreading speed, and analytic or partial analytic solutions can yield insight into the processes that facilitate or slow a population's spatial spread. We analyze the spatial dynamics of green crabs, sea otters, and teasel as examples to demonstrate the flexibility of our methods and the intuitive insights that they afford. PMID- 26655355 TI - Offspring Provisioning Explains Clone-Specific Maternal Age Effects on Life History and Life Span in the Water Flea, Daphnia pulex. AB - Genetic inheritance underpins evolutionary theories of aging, but the role that nongenetic inheritance plays is unclear. Parental age reduces the life span of offspring in a diverse array of taxa but has not been explained from an evolutionary perspective. We quantified the effect that maternal age had on the growth and maturation decisions, life history, rates of senescence, and life span of offspring from three Daphnia pulex clones collected from different populations. We then used those data to test general hypotheses proposed to explain maternal age effects on offspring life span. Three generations of breeding from young or old mothers produced dramatic differences in the life histories of fourth-generation offspring, including significant reductions in life span. The magnitude of the effect differed between clones, which suggests that genetic and nongenetic factors ultimately underpin trait inheritance and shape patterns of aging. Older parents did not transmit a senescent state to their offspring. Instead, offspring from older ancestors had increased early-life reproductive effort, which resulted in an earlier onset of reproductive senescence, and an increased rate of actuarial senescence, which shortened their life span. Our results provide a clear example of the need to consider multiple inheritance mechanisms when studying trait evolution. PMID- 26655356 TI - Niche Limits of Symbiotic Gut Microbiota Constrain the Salinity Tolerance of Brine Shrimp. AB - Symbiosis generally causes an expansion of the niche of each partner along the axis for which a service is mutually provided. However, for other axes, the niche can be restricted to the intersection of each partner's niche and can thus be constrained rather than expanded by mutualism. We explore this phenomenon using Artemia as a model system. This crustacean is able to survive at very high salinities but not at low salinities, although its hemolymph's salinity is close to freshwater. We hypothesized that this low-salinity paradox results from poor performance of its associated microbiota at low salinity. We showed that, in sterile conditions, Artemia had low survival at all salinities when algae were the only source of carbon. In contrast, survival was high at all salinities when fed with yeast. We also demonstrated that bacteria isolated from Artemia's gut reached higher densities at high salinities than at low salinities, including when grown on algae. Taken together, our results show that Artemia can survive at low salinities, but their gut microbiota, which are required for algae digestion, have reduced fitness. Widespread facultative symbiosis may thus be an important determinant of niche limits along axes not specific to the mutualistic interaction. PMID- 26655357 TI - The Size Advantage Model of Sex Allocation in the Protandrous Sex-Changer Crepidula fornicata: Role of the Mating System, Sperm Storage, and Male Mobility. AB - Sequential hermaphroditism is adaptive when the reproductive value of an individual varies with size or age, and this relationship differs between males and females. In this case, theory shows that the lifetime reproductive output of an individual is increased by changing sex (a hypothesis referred to as the size advantage model). Sex-linked differences in size-fitness curves can stem from differential costs of reproduction, the mating system, and differences in growth and mortality between sexes. Detailed empirical data is required to disentangle the relative roles of each of these factors within the theory. Quantitative data are also needed to explore the role of sperm storage, which has not yet been considered with sequential hermaphrodites. Using experimental rearing and paternity assignment, we report relationships between size and reproductive success of Crepidula fornicata, a protandrous (male-first) gastropod. Male reproductive success increased with size due to the polygamous system and stacking behavior of the species, but females nonetheless had greater reproductive success than males of the same size, in agreement with the size advantage theory. Sperm storage appeared to be a critical determinant of success for both sexes, and modeling the effect of sperm storage showed that it could potentially accelerate sex change in protandrous species. PMID- 26655358 TI - Constraint around Quarter-Power Allometric Scaling in Wild Tomatoes (Solanum sect. Lycopersicon; Solanaceae). AB - The West-Brown-Enquist (WBE) metabolic scaling theory posits that many organismal features scale predictably with body size because of selection to minimize transport costs in resource distribution networks. Many scaling exponents are quarter-powers, as predicted by WBE, but there are also biologically significant deviations that could reflect adaptation to different environments. A central but untested prediction of the WBE model is that wide deviation from optimal scaling is penalized, leading to a pattern of constraint on scaling exponents. Here, we demonstrate, using phylogenetic comparative methods, that variation in allometric scaling between mass and leaf area across 17 wild tomato taxa is constrained around a value indistinguishable from that predicted by WBE but significantly greater than 2/3 (geometric-similarity model). The allometric-scaling exponent was highly correlated with fecundity, water use, and drought response, suggesting that it is functionally significant and therefore could be under selective constraints. However, scaling was not strictly log-log linear but rather declined during ontogeny in all species, as has been observed in many plant species. We caution that although our results supported one prediction of the WBE model, it did not strongly test the model in other important respects. Nevertheless, phylogenetic comparative methods such as those used here are powerful but underutilized tools for metabolic ecology that complement existing methods to adjudicate between models. PMID- 26655359 TI - Switch between Morphospecies of Pocillopora Corals. AB - Pocillopora corals are the main reef builders in the eastern tropical Pacific. The validity of Pocillopora morphospecies remains under debate because of disagreements between morphological and genetic data. To evaluate the temporal stability of morphospecies in situ, we monitored the shapes of individual colonies in three communities in the southern Gulf of California for 44 months. Twenty-three percent of tagged colonies of Pocillopora damicornis changed to Pocillopora inflata morphology during this time. This switch in identity coincided with a shift to a higher frequency of storms and lower water turbidity (i.e., lower chlorophyll a levels). Seven months after the switch, P. inflata colonies were recovering their original P. damicornis morphology. All colonies of both morphospecies shared a common mitochondrial identity, but most P. damicornis colonies undergoing change were at a site with low-flow conditions. This is the first in situ study to document switching between described morphospecies, and it elucidates the influence of temporal shifts in environmental conditions on morphologically plastic responses. PMID- 26655360 TI - Intragenomic Conflict over Dispersal. AB - Intragenomic conflict may arise when social partners are more related through one parent than the other-for example, owing to individuals or gametes of one sex dispersing further prior to fertilization. In particular, genes originating from the former parent are favored to promote selflessness, and those originating from the latter parent are favored to promote selfishness. While the impact of patterns of dispersal on the evolution of intragenomic conflict has received recent attention, the consequences of intragenomic conflict for the evolution of dispersal remain to be explored. We suggest that if the evolution of dispersal is driven at least in part by kin selection, differential relatedness of social partners via their mothers versus their fathers may lead to an intragenomic conflict, with maternal-origin genes and paternal-origin genes favoring different rates of dispersal. As an illustration, we extend a classic model of the evolution of dispersal to explore how intragenomic conflict may arise between an individual's maternal-origin and paternal-origin genes over whether that individual should disperse in order to ease kin competition. Our analysis reveals extensive potential for intragenomic conflict over dispersal and predicts that genes underpinning dispersal phenotypes may exhibit parent-of-origin-specific expression, which may facilitate their discovery. PMID- 26655361 TI - A Few Meters Matter: Local Habitats Drive Reproductive Cycles in a Tropical Lizard. AB - Reproductive phenology often varies geographically within species, driven by environmental gradients that alter growth and reproduction. However, environments can differ between adjacent habitats at single localities. In lowland Puerto Rico, both open (sunny, warm) and forested (shady, cool) habitats may be only meters apart. The lizard Anolis cristatellus lives in both habitats: it thermoregulates carefully in the open but is a thermoconformer in the forest. To determine whether reproduction differs between habitats, we compared reproductive cycles of females in open versus forest habitats at two localities for over 2 years. Open females were more likely than forest females to be reproductive throughout the year, probably because open females were able to bask and thereby achieve warmer body temperatures. These between-habitat differences in reproduction were especially marked in cool months and are equivalent in magnitude to those between populations separated by elevation. Thus, environmental differences (even on a microlandscape scale) matter to reproduction and probably to demography. PMID- 26655362 TI - New developments in the application of optimal control theory to therapeutic protocols. AB - Optimal control theory is one of the most important tools in the development of new therapeutic protocols for treating infections. In this work, we present an algorithm able to deal with high-dimensional problems with bounded controls. The optimal solution is obtained by minimizing a positive-definite treatment cost function. Our method, based on Pontryagin's Minimum Principle and the coordinate cyclic descent method, allows solving problems of varied nature. In this paper, and by way of example, therapeutic enhancement of the immune response to invasion by pathogenic attack is addressed as an optimal control problem. The generic mathematical model used describes the evolution of the disease by means of four non-linear, ordinary differential equations. The model is characterized by the concentration of pathogens, plasma cells, antibodies and a numerical value that indicates the relative characteristic of an organ damaged by disease. From a system theory point of view, drugs can be interpreted as control inputs. Therapies based on separate application of the agents are presented in previous studies. We shall present the more general problem in this paper, considering combined therapies and bounded controls. Finally, we present several numerical simulations. PMID- 26655363 TI - Preventive effects of butyric acid, nicotinamide, calcium glucarate alone or in combination during the 7, 12-dimethylbenz (a) anthracene induced mouse skin tumorigenesis via modulation of K-Ras-PI3K-AKTpathway and associated micro RNAs. AB - Skin cancer is among the most common cancers worldwide and identifiable molecular changes for early and late stage of skin tumorigenesis can suggest the better targets for its control. In this study, we investigated the status of K-Ras-PI3K AKTpathway followed by NF-kappaB, cyclin D1, MMP-9 and regulatory micro RNA during 7, 12-dimethylbenz[a]anthracene (DMBA) induced mouse skin tumorigenesis and its prevention by butyric acid (BA), nicotinamide (NA) and calcium glucarate (CAG), individually or in combination with respect to time. DMBA upregulated the K-Ras, PI3K, Akt, NF-kappaB, cyclin D1 and MMP-9, but downregulated the PTEN in a time dependent manner. DMBA also reduced the levels of micoRNA let-7a but induced the levels of miR-21 and miR-20a as a function of time. BA, NA and CAG were found to prevent DMBA induced changes, but they were most effective when used together in a combination. Reduced let-7a and miR-211 were correlated with the overexpression of K-Ras and MMP-9. Overexpression of miR-21 and miR-20a was correlated with the down regulation of PTEN and overexpression of Cyclin D1. Collectively, the enhanced chemopreventive potential of natural compound in combination via regulation of K-Ras-PI3K-AKTpathway along with regulatory micro RNAs provide a newer and effective mean for cancer management. PMID- 26655364 TI - [Nephroblastoma and xeroderma pigmentosum: A rare association]. AB - INTRODUCTION: Xeroderma pigmentosum (XP) is a rare, genetically heterogeneous, autosomal recessive disorder, more common in cases of consanguinity. The basic defect underlying the clinical manifestations is a nucleotide excision repair defect leading to the defective repair of DNA damaged by ultraviolet (UV) radiation. XP is characterized by a high incidence of skin cancer on exposed regions. CASE REPORT: We report the case of a 5-year-old boy, followed for xeroderma pigmentosum since the age of 4 years. His sister also has the same anomaly. He presented an abdominal mass revealed by abdominal pain and vomiting. Radiological examinations revealed a nephroblastoma with lung metastases. He received primary chemotherapy for six cycles (vincristine, and actinomycin-d adriamycin), then surgery with ureteronephrectomy. Pathological examination of the nephrectomy specimen confirmed the diagnosis of Wilms tumor with a diffuse anaplastic component reaching 50%. The patient was treated according to the GFAOP stage III protocol, with high histological risk. The outcome was favorable but complicated by renal failure due to the toxicity of the treatment. He is currently in complete remission at 1 year from the end of treatment. CONCLUSION: The association of xeroderma pigmentosum and nephroblastoma is a rare combination. This case illustrates the problem of management of both severe and difficult conditions. PMID- 26655365 TI - [High prevalence of hypothyroidism among children hospitalized in a neonatal intensive care unit in Morocco]. PMID- 26655366 TI - [Malaria-related pancytopenia in children]. PMID- 26655367 TI - The sweet branch of metabolic engineering: cherry-picking the low-hanging sugary fruits. AB - In the first science review on the then nascent Metabolic Engineering field in 1991, Dr. James E. Bailey described how improving erythropoietin (EPO) glycosylation can be achieved via metabolic engineering of Chinese hamster ovary (CHO) cells. In the intervening decades, metabolic engineering has brought sweet successes in glycoprotein engineering, including antibodies, vaccines, and other human therapeutics. Today, not only eukaryotes (CHO, plant, insect, yeast) are being used for manufacturing protein therapeutics with human-like glycosylation, newly elucidated bacterial glycosylation systems are enthusiastically embraced as potential breakthrough to revolutionize the biopharmaceutical industry. Notwithstanding these excitement in glycoprotein, the sweet metabolic engineering reaches far beyond glycoproteins. Many different types of oligo- and poly saccharides are synthesized with metabolically engineered cells. For example, several recombinant hyaluronan bioprocesses are now in commercial production, and the titer of 2'-fucosyllactose, the most abundant fucosylated trisaccharide in human milk, reaches over 20 g/L with engineered E. coli cells. These successes represent only the first low hanging fruits, which have been appreciated scientifically, medically and fortunately, commercially as well. As one of the four building blocks of life, sugar molecules permeate almost all aspects of life. They are also unique in being intimately associated with all major types of biopolymers (including DNA/RNA, proteins, lipids) meanwhile they stand alone as bioactive polysaccharides, or free soluble oligosaccharides. As such, all sugar moieties in biological components, small or big and free or bound, are important targets for metabolic engineering. Opportunities abound at the interface of glycosciences and metabolic engineering. Continued investment and successes in this branch of metabolic engineering will make vastly diverse sugar-containing molecules (a.k.a. glycoconjugates) available for biomedical applications, sustainable technology development, and as invaluable tools for basic scientific research. This short review focuses on the most recent development in the field, with emphasis on the synthesis technology for glycoprotein, polysaccharide, and oligosaccharide. PMID- 26655368 TI - Feasible modalities and long-term effects of elastic band exercises in nursing home older adults in wheelchairs: A cluster randomized controlled trial. AB - BACKGROUND: Physical activity holds promise for mobility-impaired older adults to prevent further disabilities and improve their health. However, staffing constraints have made it challenging to promote physical activity in long-term care facilities. OBJECTIVES: To test the feasibility and effects of 12 months Wheelchair-bound Senior Elastic Band (WSEB) group-exercises that were led by volunteers for the first six months followed by the DVD-guided for another six months on functional fitness, activities of daily living (ADL), and sleep quality of nursing home older adults in wheelchairs. DESIGN: Cluster randomized controlled trial with two groups, pre-test and post-tests. SETTINGS: Ten nursing homes, Taiwan. PARTICIPANTS: 127 participants participated voluntarily; 107 of them completed the study. INCLUSION CRITERIA: (1) aged 65 years and over, (2) using wheelchairs for mobility, (3) living in facility for at least three months, (4) cognitively intact, and (5) heavy or moderate dependency in ADL. Majority of participants were middle-old older adults (75-84 years old, 53.2%), female (51.4%), and had chronic illnesses (98.1%). METHODS: Participants were randomly assigned by facility to either the experimental (five nursing homes, n=56) or control group (five nursing homes, n=51). The WSEB program was conducted three times per week and 40 min per session in two stages: volunteer-led for the first six months (stage I) followed by the DVD-guided modality for another six months (stage II). The primary outcomes (functional fitness: lung capacity, body flexibility, range of joint motion, and muscle strength and endurance) and the secondary outcomes (ADL measured by the Barthel Index; sleep quality measured by the Pittsburgh Sleep Quality Index) of the participants were measured at three time points: pre-test, at the six-month interval, and at the end of 12 months of the study. No blinding was applied. RESULTS: All of the functional fitness indicators of the experimental group participants improved significantly (p<.05), and were all better than the control group at six-month and 12-month of the study (p<.05). No symptoms of discomfort occurred during interventions. CONCLUSIONS: Nursing home older adults in wheelchairs who received WSEB exercise training had better functional fitness, ADL, and sleep quality than those who did not. It was a feasible way of carrying out this exercise program by using the volunteer-led followed by the DVD-guided modalities. The program can be applied in institutional settings routinely. PMID- 26655372 TI - Boundedness, Mittag-Leffler stability and asymptotical omega-periodicity of fractional-order fuzzy neural networks. AB - We show that the omega-periodic fractional-order fuzzy neural networks cannot generate non-constant omega-periodic signals. In addition, several sufficient conditions are obtained to ascertain the boundedness and global Mittag-Leffler stability of fractional-order fuzzy neural networks. Furthermore, S-asymptotical omega-periodicity and global asymptotical omega-periodicity of fractional-order fuzzy neural networks is also characterized. The obtained criteria improve and extend the existing related results. To illustrate and compare the theoretical criteria, some numerical examples with simulation results are discussed in detail. PMID- 26655373 TI - Non-fragile Hinfinity synchronization of memristor-based neural networks using passivity theory. AB - In this paper, we formulate and investigate the mixed Hinfinity and passivity based synchronization criteria for memristor-based recurrent neural networks with time-varying delays. Some sufficient conditions are obtained to guarantee the synchronization of the considered neural network based on the master-slave concept, differential inclusions theory and Lyapunov-Krasovskii stability theory. Also, the memristive neural network is considered with two different types of memductance functions and two types of gain variations. The results for non fragile observer-based synchronization are derived in terms of linear matrix inequalities (LMIs). Finally, the effectiveness of the proposed criterion is demonstrated through numerical examples. PMID- 26655374 TI - Non-cell autonomous cell death caused by transmission of Huntingtin aggregates in Drosophila. AB - Recent evidence indicates that protein aggregates can spread between neurons in several neurodegenerative diseases but much remains unknown regarding the underlying mechanisms responsible for this spreading and its role in disease progression. We recently demonstrated that mutant Huntingtin aggregates spread between cells within the Drosophila brain resulting in non-cell autonomous loss of a pair of large neurons in the posterior protocerebrum. However, the full extent of neuronal loss throughout the brain was not determined. Here we examine the effects of driving expression of mutant Huntingtin in Olfactory Receptor Neurons (ORNs) by using a marker for cleaved caspase activity to monitor neuronal apoptosis as a function of age. We find widespread caspase activity in various brain regions over time, demonstrating that non-cell autonomous damage is widespread. Improved understanding of which neurons are most vulnerable and why should be useful in developing treatment strategies for neurodegenerative diseases that involve transcellular spreading of aggregates. PMID- 26655375 TI - [Cardiovascular prevention in diabetes mellitus: A multifactorial challenge]. AB - Patients with type2 diabetes mellitus have a high to very high cardiovascular risk, and often have other associated risk factors, such as hypertension, obesity and dyslipidaemia. Cardiovascular disease is the leading cause of morbidity and mortality in this population. An integrated control of all risk factors in patients with diabetes is essential for minimising the risk of macrovascular complications. Given the benefits of the multifactorial intervention strategies for cardiovascular prevention in diabetic patients, a review is presented on the therapeutic goals established for each risk factor in diabetes and the benefits of their control. PMID- 26655376 TI - A majority of rural emergency departments in the province of Quebec use point-of care ultrasound: a cross-sectional survey. AB - BACKGROUND: Point-of-care ultrasound (POCUS) can be used to provide rapid answers to specific and potentially life-threatening clinical questions, and to improve the safety of procedures. The rate of POCUS access and use in Canada is unclear. The objective of this study was to examine access to POCUS and potential barriers/facilitators to its use among rural physicians in Quebec. METHODS: This descriptive cross-sectional study used an online survey. The 30-item questionnaire is an adapted and translated version of a questionnaire used in a prior survey conducted in rural Ontario, Canada. The questionnaire was pre-tested for clarity and relevance. The survey was sent to non-locum physicians working either full- or part-time in rural emergency departments (EDs) (n = 206). All EDs were located in rural and small towns and provided 24/7 medical coverage with acute care hospitalization beds. RESULTS: In total, 108 surveys were completed (participation rate = 52.4%). Of the individuals who completed surveys, ninety three percent were family physicians, and seven percent had Canadian College of Family Physicians - Emergency Medicine (CCFP-EM) certification. The median number of years of practice was seven. A bedside ultrasound device was available in 95% of rural EDs; 75.9% of physicians reported using POCUS on a regular basis. The most common indications for POCUS use were to rule out abdominal aortic aneurysm (70.4%) and to evaluate presence of free fluid in trauma and intrauterine pregnancy (60%). The most common reason (73%) for not using POCUS was limited access to POCUS training programs. Over 40% of POCUS users received training in POCUS during medical school or residency. Sixty-four percent received training from the Canadian Emergency Ultrasound Society, 13% received training from the Canadian Association of Emergency Physicians, and 23% were trained in another course. Finally, 95% of respondents reported that POCUS skills are essential for rural ED practice. CONCLUSIONS: POCUS use in rural EDs in the province of Quebec appears to be relatively widespread. Access to training programs is a barrier to greater use. PMID- 26655377 TI - Necdin controls EGFR signaling linked to astrocyte differentiation in primary cortical progenitor cells. AB - Cellular signaling mediated by the EGF receptor (EGFR) plays a key role in controlling proliferation and differentiation of cortical progenitor cells (CPCs). However, regulatory mechanisms of EGFR signaling in CPCs remain largely unknown. Here we demonstrate that necdin, a MAGE (melanoma antigen) family protein, interacts with EGFR in primary CPCs and represses its downstream signaling linked to astrocyte differentiation. EGFR was autophosphorylated and interacted with necdin in EGF-stimulated CPCs. Necdin bound to autophosphorylated EGFR via its tyrosine kinase domain. EGF-induced phosphorylation of ERK was enhanced in necdin-null CPCs, where the interaction between EGFR and the adaptor protein Grb2 was strengthened, suggesting that endogenous necdin suppresses the EGFR/ERK signaling pathway in CPCs. In necdin-null CPCs, astrocyte differentiation induced by the gliogenic cytokine cardiotrophin-1 was significantly accelerated in the presence of EGF, and inhibition of EGFR/ERK signaling abolished the acceleration. Furthermore, necdin strongly suppressed astrocyte differentiation induced by overexpression of EGFR or its ligand binding defective mutant equivalent to a glioblastoma-associated EGFR variant. These results suggest that necdin acts as an intrinsic suppressor of the EGFR/ERK signaling pathway in EGF-responsive CPCs to restrain astroglial development in a cell-autonomous manner. PMID- 26655378 TI - [Relationship between subclinical psychotic symptoms and cognitive performance in the general population]. AB - INTRODUCTION: Subclinical psychotic symptoms are associated to negative life outcomes in the general population, but their relationship with cognitive performance is still not well understood. Assessing the relationship between performance in cognitive domains and subclinical psychotic symptoms in the general population may also help understand the handicap attributed to clinical psychosis, in which these alterations are present. METHODS: Subclinical and cognitive assessments were obtained in 203 participants from the general population by means of the Community Assessment of Psychic Experiences, the Brief Assessment of Cognition in Schizophrenia, the Wechsler Adults Intelligence Scale and the Wisconsin Card Sorting Test. The positive and negative subclinical symptoms and their relationship with age and cognition were examined, followed by assessing the influence of subclinical depression scores on the possible relationships between those subclinical psychotic symptoms and cognitive deficits. RESULTS: Inverse relationships were found between frequency in the Community Assessment of Psychic Experiences positive dimension and motor speed, and frequency and distress in the Community Assessment of Psychic Experiences negative dimension and motor speed. A direct relationship was also found between distress scores of the positive dimension and executive functions. Both positive and negative subclinical symptoms were related to depression scores. CONCLUSIONS: Psychotic symptoms, similar to those in the clinical population, may be associated with cognitive deficits in the general population. PMID- 26655379 TI - Graphene-based fibers for supercapacitor applications. AB - Energy conversion and storage devices play an important role in industry and society with the rapid growth of energy consumption. Supercapacitors are very attractive due to their superior power density, fast charge/discharge rates and long cycle lifetime. Graphene fiber (GF), a fascinating material, has drawn considerable attention and shown great potential as an active material in the field of supercapacitors owing to its unique and tunable nanostructure, high electrical conductivity, excellent mechanical flexibility, light weight, and ease of functionalization. This review focuses on the recent significant advances in the fabrication and application of graphene-based fiber as electrode material in supercapacitors. The synthetic strategies and application in the supercapacitor are presented, accompanied with the summary and outlook for the future development of GFs. PMID- 26655380 TI - Reduced translocation of current photosynthate precedes changes in gas exchange for Quercus rubra seedlings under flooding stress. AB - Northern red oak (Quercus rubra L.) seedlings are frequently planted on suboptimal sites in their native range in North America, subjecting them to environmental stresses, such as flooding, for which they may not be well adapted. Members of the genus Quercus exhibit a wide range of responses to flooding, and responses of northern red oak to flooding remain inadequately described. To better understand the physiological effects of root system inundation in post transplant northern red oak seedlings and the effects of flooding on endogenous patterns of resource allocation within the plant, we observed the effects of short-term flooding initiated at the linear shoot growth stage on net photosynthetic rates, dark respiration, chlorophyll fluorescence (Fv/Fm) and translocation of (13)C-labeled current photosynthate. Downward translocation of current photosynthate declined after 4 days of flooding and was the first measured physiological response to flooding; net photosynthetic rates decreased and dark respiration rates increased after 7 days of flooding. Short-term flooding did not affect maximal potential efficiency of photosystem II (Fv/Fm). The finding that decreased downward translocation of (13)C-labeled current photosynthate preceded reduced net photosynthesis and increased dark respiration during flooding suggests the occurrence of sink-limited photosynthesis under these conditions. PMID- 26655381 TI - Functional traits contributed to the superior performance of the exotic species Robinia pseudoacacia: a comparison with the native tree Sophora japonica. AB - Functional traits determine the ecological strategies of plants and therefore are widely considered to feature in the success of invasive species. By comparing a widespread exotic invasive species Robinia pseudoacacia L. with a related native one Sophora japonica L., this research aimed to study strategies of R. pseudoacacia for superior performance from the perspective of functional traits. We conducted a greenhouse experiment in which seedlings of R. pseudoacacia and S. japonica were grown separately under a factorial combination of two light regimes and three levels of nitrogen (N) fertilization, including a control and two levels intended to represent ambient and future levels of N deposition in Chinese forests. After 90 days of treatment, performance and functional traits were determined for the two species, the former referred to as the total biomass (TB) that directly affected fitness. Trait plasticity and integration (the pattern and extent of functional covariance among different plant traits) were analyzed and compared. We found that the two species showed significantly different plastic responses to light increase: in the low-light regime, they were similar in performance and functional traits, while in the high-light regime, R. pseudoacacia achieved a significantly higher TB and a suite of divergent but advantageous functional traits versus S. japonica, such as significantly greater photosynthetic capacity and leaf N concentration, and lower carbon-to-N ratio and root-to-shoot ratio, which conferred it the greater performance. Moreover, across the light gradient, R. pseudoacacia showed higher correlations between photosynthetic capacity and other functional traits than S. japonica. In contrast, N deposition showed little impact on our experiment. Our results suggested that across light regimes, three aspects of functional traits contributed to the superior performance of R. pseudoacacia: functional trait divergence, significantly different plasticity of these traits, as well as greater overall trait coordination. PMID- 26655382 TI - Stimulation-dependent gating of TRPM3 channel in planar lipid bilayers. AB - The transient receptor potential melastatin (TRPM)-3 channel is critical for various physiologic processes. In somatosensory neurons, TRPM3 has been implicated in temperature perception and inflammatory hyperalgesia, whereas in pancreatic beta-cells the channel has been linked to glucose-induced insulin release. As a typical representative of the TRP family, TRPM3 is highly polymodal. In cells, it is activated by heat and chemical agonists, including pregnenolone sulfate (PS) and nifedipine (Nif). To define the nuances of TRPM3 channel activity and its modulators, we succeeded in incorporating the TRPM3 protein into planar lipid bilayers. We found that phosphatidylinositol-4,5 bisphosphate (PIP2) or clotrimazole is necessary for channel opening by PS. Unlike PS, the presence of Nif alone sufficed to induce TRPM3 activity and demonstrated distinct gating behavior. We also performed an extensive thermodynamic analysis of TRPM3 activation and found that TRPM3 exhibited slight temperature sensitivity in the bilayers. In the absence of other agonists TRPM3 channels remained closed upon heat-induced stimulation, but opened in the presence of PIP2, although with only a low open-probability profile. Together, our results elucidate the details peculiar to TRPM3 channel function in an isolated system. We confirmed its direct gating by PS and PIP2, but found a lack of the strong intrinsic temperature sensitivity common to other thermosensitive TRP channels. PMID- 26655383 TI - alpha-Lipoic acid up-regulates expression of peroxisome proliferator-activated receptor beta in skeletal muscle: involvement of the JNK signaling pathway. AB - We hypothesized that alpha-lipoic acid (alpha-LA) might interact with the transcriptional control of peroxisome proliferator-activated receptor (PPAR)beta in skeletal muscle. Molecular mechanisms were investigated using differentiated C2C12 myotubes treated with alpha-LA and/or PPARbeta agonist GW0742. In vivo studies with 3-mo-old C57Bl6 mice were realized: voluntary wheel running (VWR) training (7 wk), and a 6 wk diet containing (or not) alpha-LA (0.25% wt/wt). This last condition was combined with (or not) 1 bout of treadmill exercise (18 m/min for 1 h). Using a reporter assay, we demonstrate that alpha-LA is not an agonist of PPARbeta but regulates PPARbeta target gene expression through an active PPARbeta pathway. GW0742-induced pyruvate dehydrogenase kinase 4 mRNA is potentiated by alpha-LA. In C2C12, alpha-LA lowers the activation of the JNK signaling pathway and increases PPARbeta mRNA and protein levels (2-fold) to the same extent as with the JNK inhibitor SP600125. Similarly to VWR training effect, PPARbeta expression increases (2-fold) in vastus lateralis of animals fed an alpha-LA-enriched diet. However, alpha-LA treatment does not further stimulate the adaptive up-regulation of PPARbeta observed in response to 1 bout of exercise. We have identified a novel mechanism of regulation of PPARbeta expression/action in skeletal muscle with potential physiologic application through the action of alpha-LA, involving the JNK pathway. PMID- 26655384 TI - PNEUMATIC DISPLACEMENT AS A TREATMENT OF TRAUMATIC MACULAR HOLE WITH SUBMACULAR HEMORRHAGE. AB - PURPOSE: To report the potential benefit of pneumatic displacement with perfluoropropane in the acute treatment of traumatic macular hole and submacular hemorrhage. METHODS: This article is a descriptive case report. Intravitreal injection of 0.3 mL of undiluted C3F8 was performed in an outpatient clinic setting, with strict face-down positioning for 7 days thereafter. PATIENT: An otherwise healthy 22-year-old white man with no past ocular history. RESULTS AND DISCUSSION: Initial examination and optical coherence tomography documented significant displacement of the submacular hemorrhage, and stabilization of the macular hole 24 hours after pneumatic retinopexy was performed. Best-corrected visual acuity on presentation was counting fingers in the affected eye, which improved to 20/50 with a closed macular hole 6 weeks after his initial injury. PMID- 26655385 TI - MACULAR PSEUDO-HOLE IN SHAKEN BABY SYNDROME: UNDERSCORING THE UTILITY OF OPTICAL COHERENCE TOMOGRAPHY UNDER ANESTHESIA. AB - PURPOSE: To describe a case of vitrectomy for nonclearing vitreous hemorrhage in shaken baby syndrome and the utility of intraoperative hand-held optical coherence tomography to distinguish a macular hole from a pseudo-hole. METHODS: Case report of a 4-month-old girl. RESULTS: After clearing of media opacity by vitrectomy, an apparent macular hole was seen with the operating microscope. However, this was shown to be only a pseudo-hole by intraoperative hand-held optical coherence tomography, requiring no further treatment. CONCLUSION: Intraoperative hand-held optical coherence tomography may be important when performing vitrectomy for nonclearing vitreous hemorrhage in shaken baby syndrome. PMID- 26655386 TI - EXTRAOCULAR EXTENSION OF CILIOCHOROIDAL MELANOMA AFTER TRANSSCLERAL FINE-NEEDLE ASPIRATION BIOPSY. AB - PURPOSE: To describe development of extraocular extension of ciliochoroidal melanoma after transscleral fine-needle aspiration biopsy (FNAB) for cytogenetic studies. METHODS: Transscleral FNAB was performed for cytogenetic analysis of melanoma using a long 27-gauge needle attached to a 10-mL syringe by connector tubing entering obliquely through the sclera overlying the tumor base. An iodine 125 radioactive plaque was immediately applied to the sclera over the tumor and biopsy site after FNAB. PATIENTS: One patient with large ciliochoroidal melanoma of the right eye. RESULTS: Cytogenetic analysis of the melanoma revealed monosomy of chromosome 3. On examination, 18 months after plaque radiotherapy, there was regression of the tumor; however, a few small subepithelial pigmented lesions were noted in the conjunctiva close to the FNAB site. Excisional biopsy of the conjunctival pigmented lesions with 3 mm margins and with supplemental cryotherapy to the surrounding conjunctival margins and to the underlying sclera was performed. Histopathologic evaluation showed an oval nodule composed of a mixture of spindle and epithelioid cells deep within the substantia propria consistent with extraocular extension of uveal melanoma. Magnetic resonance imaging of the orbits showed no evidence of orbital involvement. This is the only case of extraocular extension developing among 408 consecutive transscleral biopsies (0.2%) performed at our center for cytogenetic or cytopathologic analysis. CONCLUSION: Although rare, transscleral FNAB of ciliochoroidal melanoma can lead to extraocular extension of the tumor through the biopsy site. Possible techniques to reduce the risk of this problem are discussed. PMID- 26655387 TI - Imaging of the hand and wrist: A matter of tools. PMID- 26655388 TI - Individual factors and perceived community characteristics in relation to mental health and mental well-being. AB - BACKGROUND: It has been argued that though correlated with mental health, mental well-being is a distinct entity. Despite the wealth of literature on mental health, less is known about mental well-being. Mental health is something experienced by individuals, whereas mental well-being can be assessed at the population level. Accordingly it is important to differentiate the individual and population level factors (environmental and social) that could be associated with mental health and well-being, and as people living in deprived areas have a higher prevalence of poor mental health, these relationships should be compared across different levels of neighbourhood deprivation. METHODS: A cross-sectional representative random sample of 1,209 adults from 62 Super Output Areas (SOAs) in Belfast, Northern Ireland (Feb 2010 - Jan 2011) were recruited in the PARC Study. Interview-administered questionnaires recorded data on socio-demographic characteristics, health-related behaviours, individual social capital, self-rated health, mental health (SF-8) and mental well-being (WEMWBS). Multi-variable linear regression analyses, with inclusion of clustering by SOAs, were used to explore the associations between individual and perceived community characteristics and mental health and mental well-being, and to investigate how these associations differed by the level of neighbourhood deprivation. RESULTS: Thirty-eight and 30 % of variability in the measures of mental well-being and mental health, respectively, could be explained by individual factors and the perceived community characteristics. In the total sample and stratified by neighbourhood deprivation, age, marital status and self-rated health were associated with both mental health and well-being, with the 'social connections' and local area satisfaction elements of social capital also emerging as explanatory variables. An increase of +1 in EQ-5D-3 L was associated with +1SD of the population mean in both mental health and well-being. Similarly, a change from 'very dissatisfied' to 'very satisfied' for local area satisfaction would result in +8.75 for mental well-being, but only in the more affluent of areas. CONCLUSIONS: Self-rated health was associated with both mental health and mental well-being. Of the individual social capital explanatory variables, 'social connections' was more important for mental well-being. Although similarities in the explanatory variables of mental health and mental well-being exist, socio ecological interventions designed to improve them may not have equivalent impacts in rich and poor neighbourhoods. PMID- 26655389 TI - A single molecule assay for measuring site-specific DNA cleavage. AB - Sequence-specific DNA cleavage is a key step in a number of genomic transactions. Here, we report a single-molecule technique that allows the simultaneous measurement of hundreds of DNAs, thereby collecting significant statistics in a single experiment. Microbeads are tethered with single DNA molecules in a microfluidic channel. After the DNA cleavage reaction is initiated, the time of cleavage of each DNA is recorded using video microscopy. We demonstrate the utility of our method by measuring the cleavage kinetics of NdeI, a type II restriction endonuclease. PMID- 26655390 TI - Probing the selectivity of beta-hydroxylation reactions in non-ribosomal peptide synthesis using analytical ultracentrifugation. AB - Bacteria and fungi use non-ribosomal peptide synthetases (NRPSs) to produce peptides of broad structural diversity and biological activity, many of which have proven to be of great importance for human health. The impressive diversity of non-ribosomal peptides originates in part from the action of tailoring enzymes that modify the structures of single amino acids and/or the mature peptide. Studying the interplay between tailoring enzymes and the peptidyl carrier proteins (PCPs) that anchor the substrates is challenging owing to the transient and complex nature of the protein-protein interactions. Using sedimentation velocity (SV) methods, we studied the collaboration between the PCPs and cytochrome P450 enzyme that results in the installation of beta-hydroxylated amino acid precursors in the biosynthesis of the depsipeptide skyllamycin. We show that SV methods developed for the analytical ultracentrifuge are ideally suited for a quantitative exploration of PCP-enzyme equilibrium interactions. Our results suggest that the PCP itself and the presence of substrate covalently tethered to the PCP together facilitate productive PCP-P450 interactions, thereby revealing one of nature's intricate strategies for installing interesting functionalities using natural product synthetases. PMID- 26655391 TI - Physical Activity in Adults With Type 1 Diabetes. AB - PURPOSE: The purpose of this study was to examine sociodemographic, clinical, and psychological factors associated with engaging in regular physical activity (PA) in adults with type 1 diabetes. METHODS: Secondary cross-sectional analysis based on data from the Type One Diabetes Exchange clinic registry was conducted. Adults >=18 years old enrolled in the clinic registry who had completed PA self-report data (n = 7153) were included in this study. RESULTS: Mean age was 37.14 +/- 17 years, and 54% (n = 3840) were men. Type 1 diabetes duration was 19.5 +/- 13.5 years, and mean A1C level was 7.9% +/- 1.5% (62 mmol/mol). Twelve percent (n = 848) of the sample reported no PA; 55% (n = 3928) reported PA 1 to 4 days per week; and 33% (n = 2377) reported PA >=5 days per week. Factors that were associated with increased odds of no PA were older age, less-than-excellent general health, increased body mass index, longer duration of diabetes, and increased depressive symptoms. More blood glucose meter checks per day decreased odds of no PA. Factors associated with lower odds of >=5 days of PA included minority race/ethnicity, education, less-than-excellent general health, presence of a foot ulcer, increased body mass index, and depressive symptoms. Male sex, less-than-full-time employment, and being single increased the odds of >=5 days of PA. CONCLUSIONS: Several demographic, clinical, diabetes-related, and psychosocial factors were related to PA. Potential interventions may target those with depressive symptoms or self-reported poor general health, or they may be tailored to working adults who may find it harder to be physically active. PMID- 26655392 TI - Early and Intermediate Hospital-to-Home Transition Outcomes of Older Adults Diagnosed With Diabetes. AB - PURPOSE: The purpose of this study was to identify factors affecting early and intermediate hospital-to home transition outcomes of older adults with preexisting diabetes mellitus. METHODS: A mixed-methods design was used. A sample of 96 hospitalized older adults with a prior diagnosis of diabetes were recruited within 4 hours of discharge. Data reflective of general health status, diabetes status, perceived discharge readiness (Readiness for Hospital Discharge Scale), hospitalization, and anticipated postdischarge support were gathered upon enrollment. Transition outcome data including unplanned care encounter occurrences, perceived transition quality (Care Transition Measure-15), and postdischarge difficulty (scale and free responses to the Post-Discharge Coping Difficulty Scale [PDCDS]) were obtained by telephone interview 7 and 30 days after discharge. Three unique, dichotomous variables were created from recurrent subthemes that emerged during content analysis of free-response data and were used in statistical testing. Binary logistic regression was performed to identify predictive factors for an unplanned care encounter within 30 days of discharge. RESULTS: Multimorbidity was prevalent in participants. Difficulties managing medications, blood glucose, and chronic illnesses other than diabetes were common problems. Higher PDCDS scores 7 and 30 days following discharge and difficulty managing a nondiabetes chronic health problem were predictive of an unplanned care encounter within 30 days of discharge. CONCLUSIONS: Multimorbidity complicates home recovery of older adults with diabetes. Diabetes adds complexity to hospital-to-home care transitions. Transition difficulties predict higher risk for an unplanned care encounter. More intensive follow-up of older adults with diabetes during the first month following discharge is recommended. PMID- 26655393 TI - Lambl's Excrescence Associated with Cryptogenic Stroke: A Case Report and Literature Review. AB - BACKGROUND: In 1856, a Bohemian physician, Vilem Dusan Lambl, first described the presence of filiform lesions in aortic valve leaflets. Lambl's excrescences are tiny filiform strands that arise on the line of valve closure, and result from valvular wear and tear. It is a rare cause of cardioembolic stroke that can be detected by transesophageal echocardiogram. CASE REPORT: We encountered a 51-year old, African-American woman with a history of recurrent strokes that we suspect may be the result of Lambl's excrescence. The patient was treated with dual antiplatelet therapy and was recommended to have surveillance transesophageal echocardiograms at 6 months and 1 year from the time of discharge. CONCLUSIONS: As there are no definitive guidelines for the management of patients with Lambl's excrescences, we present a review of the current medical literature and a specific case report in an attempt to provide a better strategy for managing this condition. In our case report, we focus on the management and treatment for Lambl's excrescence because no clear evidence has been published in the literature. Our review indicates that Lambl's excrescence, despite its relative scarcity, should be considered in the differential diagnosis of a patient with cryptogenic stroke. PMID- 26655394 TI - Evaluation of noise environments during daily activities of university students. AB - Noise conditions specifically in areas inside university facilities and its impact on the quality of life of university students are topics that have received little attention. This paper presents a study of the noise conditions in which university students of various institutions in Madrid, Spain, carry out their daily studies. A representative number of measurements was carried out using noise dosemeters and dataloggers in order to evaluate the levels of noise, noise dose and exposure to noise during school periods and extracurricular activities. The results were compared with the recommendations given by current environmental noise regulations. This paper was complemented with a survey to get to know how students perceive the exposure to noise in university environments. PMID- 26655395 TI - Changes of paramagnetic species in cereal grains upon short-term ozone action as a marker of oxidative stress tolerance. AB - The increase of the concentration of ozone in the atmosphere, being the direct source of reactive oxygen species, results in the yield loss of agronomic crops. On the other hand, ozone is also used as a protector against microorganisms, living in plants and present in materials obtained from them, dangerous for human and animal health. In this work it has been studied if ozone in doses similar to those used for removal of microorganisms can have significant influence on the generation of stable organic radicals and changes in the character of transition metal ions and in the antioxidative biochemical parameters of cereal grains. The aim of this work was to find if the response of grains of three cereals (wheat, oat and barley) to ozone depended on their oxidative stress tolerance. The influence of direct short-term ozone application on grains of these cereals, each represented by two genotypes with different oxidative stress tolerance, was studied by biochemical analyses and by electron paramagnetic resonance (EPR) technique. Whole grains as well as their parts: embryo, endosperm and seed coat were subjected to ozone treatment for 30 min. Biochemical investigation of control samples showed that their antioxidant activity increased in order: wheat800 ug/l. After short-term treatment with bacalitumide (50 mg/d for 14 days) and long-term oral treatment with A. annua capsules (continuously 5 * 50 mg/d), the PSA level dropped down to 0.98 ug/l. MRT, scintigraphy and SPECT/CT verified tumor remission. Seven months later, PSA and ostase levels increased, indicating tumor recurrence and skeletal metastases. Substituting A. annua capsules by artesunate injections (2 * 150 mg twice weekly i.v.) did not prohibit tumor recurrence. PSA and ostase levels rose to 1245 ug/l and 434 U/l, respectively, and MRT revealed progressive skeletal metastases, indicating that the tumor acquired resistance. The high expression of MYC, TFR, and VEGFC in the patient biopsy corresponded with high expression of these markers in the artemisinin sensitive PC-3 cells compared to artemisinin-resistant DU-145 cells. CONCLUSION: Long-term treatment with A. annua capsules combined with short-term bicalitumide treatment resulted in considerable regression of advanced metastasized prostate carcinoma. Controlled clinical trials are required to evaluate the clinical benefit of A. annua in prostate cancer. PMID- 26655405 TI - Cytotoxic potentiation of vinblastine and paclitaxel by L-canavanine in human cervical cancer and hepatocellular carcinoma cells. AB - BACKGROUND: The non-protein amino acid L-canavanine (L-CAV), found in several plants of the family Fabaceae is an antimetabolite which shows anticancer activity due to its ability to be incorporated into protein in the place of its analogue, L-arginine (L-ARG), leading to the alteration of the 3D conformation of newly synthesised proteins and usually a loss of their function. PURPOSE: In this study, the ability of L-CAV to potentiate the cytotoxicity of microtubule- targeting drugs used in the chemotherapy of cancer, vinblastine (VIN) and paclitaxel (PTX) was evaluated. MATERIAL AND METHODS: The following cancer cells grown in arginine-rich and arginine-free media were employed: HeLa, Hep G2 and SK HEP-1. Drug combination experiment used a method based on the median-effect principle and mass-action law. RESULTS: We observed that L-CAV, which is hardly toxic alone, potentiated the cytotoxicity of VIN and PTX in HeLa and hepatocellular carcinoma cells. CONCLUSION: This is the first study showing the cytotoxic potentiation of microtubule-targeting drugs by L-CAV. The mechanism of synergy and animal studies need to be investigated further to see whether L-CAV might become an adjuvant in cancer treatment. PMID- 26655406 TI - Anthocyans-rich Aronia melanocarpa extract possesses ability to protect endothelial progenitor cells against angiotensin II induced dysfunction. AB - BACKGROUND: Endothelial progenitor cells (EPC) may provide protection against atherosclerosis and plaque rupture by their innate ability to replace dysfunctional or damaged endothelial cells in plaque microvessels. There is evidence that angiotensin II may impair the angiogenic functions of EPCs in the atherosclerotic plaque by accelerating senescence and inhibiting their proliferation through oxidative stress induction. PURPOSE: In this study, we examined whether chokeberry (Aronia melanocarpa) fruit extract, containing mainly anthocyanins with potent antioxidative properties, could protect EPCs against angiotensin-induced oxidative stress. METHODS: EPCs were isolated from peripheral blood of young healthy volunteers and cultivated on fibronectin-coated plates in the presence or absence of angiotensin II (1 uM) and chokeberry extract (1-25 ug/ml). RESULTS: EPCs exposed to chokeberry extract prior to angiotensin II showed a significant increase of proliferation and telomerase activity, and a decrease in the percentage of senescent cells and intracellular ROS formation in comparison to angiotensin II treated cells. Furthermore, extract increased migration ability, adhesion to fibronectin and the angiogenic potential of EPC in vitro diminished by angiotensin II in a concentration-dependent manner. That effect was related to the activation of the Nrf2 transcription factor and the increase of HO-1 expression. CONCLUSIONS: Our results suggested that chokeberry extract may protect EPCs against angiotensin II-induced dysfunction and could play a potential role in the prevention of coronary artery disease. PMID- 26655407 TI - Cytotoxicity of compounds from Xylopia aethiopica towards multi-factorial drug resistant cancer cells. AB - INTRODUCTION: Multidrug resistance (MDR) in cancer represent a major hurdle in chemotherapy. Previously, the methanol extract of the medicinal spice Xylopia aethiopica displayed considerable cytotoxicity against multidrug resistant (MDR) cancer cell lines. METHODS: The present study was designed to assess the cytotoxicity of compounds, 16alpha-hydroxy-ent-kauran-19-oic acid (2), 3,4',5 trihydroxy-6",6"-dimethylpyrano[2,3-g]flavone (3), isotetrandrine (5) and trans tiliroside (6) derived from the methanol crude extract of Xylopia aethiopica against 9 drug-sensitive and -resistant cancer cell lines. The resazurin reduction assay was used to evaluate the cytotoxicity of these compounds, whilst caspase-Glo assay was used to detect caspase activation. Cell cycle, mitochondrial membrane potential (MMP) and levels of reactive oxygen species (ROS) were all analyzed via flow cytometry. RESULTS: Flavonoid 3 and alkaloid 5 also displayed IC50 values ranging from 2.61 uM (towards leukemia CCRF-CEM cells) to 18.60 uM (towards gliobastoma multiforme U87MG.DeltaEGFR cells) and from 1.45 uM (towards HepG2 cells) to 7.28 uM (towards MDA-MB-231-pcDNA cells), respectively. IC50 values ranged from 0.20 uM (against CCRF-CEM cells) to 195.12 uM (against CEM/ADR5000 cells) for doxorubicin. Compound 3 induced apoptosis in leukemia CCRF-CEM cells mediated by the disruption of the MMP, whilst 5 induced apoptosis mediated by ROS production. CONCLUSIONS: Compounds 2 and 5 represent potential cytotoxic phytochemicals that deserve more investigations to develop novel antineoplastic drugs against multifactorial drug-resistant cancers. PMID- 26655408 TI - Oleacein enhances anti-inflammatory activity of human macrophages by increasing CD163 receptor expression. AB - BACKGROUND: Oleacein (dialdehydic form of decarboxymethyl elenolic acid linked to hydroxytyrosol; 3,4-DHPEA-EDA) have been proven to possess antioxidant and anti inflammatory activity. PURPOSE: In this study, we examined whether oleacein could increase CD163 and IL-10 receptor expression as well as HO-1 intracellular secretion in human macrophages. METHODS: Effect of oleacein (10 and 20 MUmol/l) or oleacein together with complexes of haemoglobin (Hb) and haptoglobin 1-1 (Hp11) or haptoglobin 2-2 (Hp22) on expression of IL-10 and CD163 receptor was determined by Flow Cytometry. Expression of CD163mRNA was measured by real-time quantitative RT-PCR. Heme oxygenase 1 (HO-1) intracellular secretion in macrophages was investigated by enzyme-linked immunosorbent assay (ELISA). RESULTS: Oleacein (OC) together with complexes HbHp11 or HbHp22 stimulated the expression of CD163 (30-100-fold), IL-10 (170-300-fold) and HO-1 secretion (60 130-fold) after 5 days of coincubation. The 2-fold (24 h), 4-fold (48 h) increase of CD163 mRNA level and its final (72 h) decrease was also observed. CONCLUSION: Our results suggested that oleacein enhances anti-inflammatory activity of complexes haemoglobin with haptoglobin 1-1 and 2-2 and could play a potential role in the prevention of inflammatory disease related to atherosclerosis. PMID- 26655409 TI - Ethanol extracts of Sanguisorba officinalis L. suppress TNF-alpha/IFN-gamma induced pro-inflammatory chemokine production in HaCaT cells. AB - BACKGROUND: Sanguisorba officinalis L. (SOL) is a perennial plant widely distributed in Asia, its roots are well-known as a traditional herbal medicine to treat burns, chronic intestinal infections, scalds, and inflammation in Korea. Also, the roots of SOL are used for treatment of many types of allergic skin diseases, including urticarial, eczema, and allergic dermatitis. PURPOSE: In this study we investigated the underlying mechanism of anti-inflammatory effect of an ethanol extract of SOL roots (ESOL). STUDY DESIGN: The ability of ESOL to inhibit inflammatory skin disorder was tested in human keratinocyte HaCaT cells. METHODS: Viability test using MTT assay were used to determine non-cytotoxic concentrations of ESOL on HaCaT cells. ESOL-mediated inhibition of the tumor necrosis factor (TNF)-alpha/interferon (IFN)-gamma-induced production of pro inflammatory chemokines-such as macrophage-derived chemokine (MDC), regulated on activation, normal T-cell expressed and secreted (RANTES), interleukin (IL)-8, and thymus and activation regulated chemokine (TARC)-at the mRNA level was determined by real-time reverse transcription-polymerase chain reaction (RT-PCR). The ability of ESOL to reduce the expression of pro-inflammatory marker proteins was evaluated by Western blot analysis and immunocytochemistry. RESULTS: ESOL reduced the production of MDC, RANTES, IL-8, and TARC in HaCaT cells stimulated with TNF-alpha/IFN-gamma at both protein and mRNA levels. ESOL also suppressed the phosphorylation of signal transducer and activator of transcription (STAT)-1, extracellular signal-regulated kinase (ERK), and inhibited both nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor-alpha (IkappaB-alpha) degradation and the nuclear translocation of NF-kappaB/p65. ESOL exerts anti inflammatory effects by suppressing the expression of TNF-alpha/IFN-gamma stimulated chemokines and pro-inflammatory molecules via a blockade NF-kappaB, STAT-1, and ERK activation. CONCLUSION: Our results suggest the preventive potential of ESOL as a herbal medicine for the treatment of inflammatory skin diseases. PMID- 26655410 TI - Recommendations for description and validation of antibodies for research use. PMID- 26655411 TI - [Homage to Yves Barat]. PMID- 26655412 TI - [Orthognathodontic aphorisms]. PMID- 26655413 TI - [How to evaluate psychological risks: an ethics of aesthetic demand in orthodontics]. AB - Evaluating risks is part of the day-to-day practice of all orthodontists. Most of the time we forget that healing a patient also requires an evaluation of what is called the psychological risk. Indeed, focusing on harmonisation matters, we tend to omit that patient's requests, especially aesthetic requests, may conceal psychological problems. Such a risk is even higher when it comes to orthodontic surgical protocols, as the physical changes are more radical. We will discuss the specificities of aesthetical demand, its links with the social discourse and the way self-esteem and reflection in the mirror are closely intermingled. Should we forget to take into account the psychological dimension of any patient, this could be a breach of professional ethics. We will furthermore consider the means we have to recognize patients with a high psychological risk. It is not in our hands to help these patients psychologically. It is in the hands of a mental health specialist, whose adress and phone number we should know in order to refer our patients to him/her. PMID- 26655414 TI - [Impacted teeth and the six incarnations of resorption]. AB - There are six distinct types of resorption of dental hard tissue that occur in association with unerupted and impacted permanent teeth. These pathologic entities differ markedly from one another in terms of their aetiology, their treatment and their prognosis. In several of them, the continued existence of the affected tooth may be in danger while in others, conservative treatment may halt the resorption process and provide for a successful outcome. The treatment approach is specific for each type and is entirely dependant on the diagnosis. This presentation will discuss prevalence, aetiology, presenting symptoms and clinical signs, radiographic features, histopathology, differential diagnosis, treatment and prognosis in relation to each of the conditions. PMID- 26655415 TI - [Short sagittal osteotomy]. AB - Bilateral sagittal split osteotomy has become the standard mandibular surgery for the treatment of dento-facial deformities. Even patients with less important deformities may undergo surgery. The morbidity must be as low as possible. We describe a technique with reduced split surfaces. The osseous section follows an oblique line since the thorn of Spix below and outside towards the supra-angular region. This section is completed by an osteotomy of the posterior border of the mandible. This split never reaches the inferior alveolar nerf tunnel. The protection of the alveolar nerve is increased what decreases considerably the risk of nervous complications of this intervention. The majority of the mandibular movements are possible by this technique with the exception of the important advancements and the increase of the height of the ramus. PMID- 26655417 TI - [Correlation between sagittal photogrammetric measurements of the soft tissue profile and dental arches measurements]. AB - INTRODUCTION: Sagittal soft-tissue analyses made from photographic records (sagittal photogrammetric analysis of the soft tissues) allow orthodontists to quantify the sagittal dimension and situation of the facial soft tissues. These tissues maintain close anatomical relationships with the underlying dental arches. However, little importance has been given to the description and the comparison of the sagittal soft tissue morphology according to dental arches parameters. The purpose of this study was to determine the correlation between the sagittal photogrammetric soft tissue profile and the dental arches measurements. MATERIALS AND METHODS: A cross-sectional study was performed in a group of students. Standardized facial-profile photographs were taken with each student in natural head position, and relaxed lip posture. Photogrammetric parameters were measured on paper sheet using a graduated ruler. Dental arches measurements were also performed directly into the mouth with an electronic caliper. The strength of the association between sagittal photogrammetric soft tissue measurements and dental arches parameters was investigated by a Pearson's correlation. Results were regarded as significant at p=0.05. RESULTS: The lips protrusion parameters were significantly and positively correlated with the dental arch lengths. The overjet was significantly and positively correlated with Ls/Sn-Sm. The overbite was significantly and negatively correlated with the sagittal labial parameters Ls/N-Ort, Li/N-Ort, Ls-E, Li E, Ls-S, Li S, Ls/Sn-Sm and Li/Sn-Sm. CONCLUSION: The correlations found in this study show the importance of taking into account the soft tissue in the diagnosis and orthodontic treatment of patients. PMID- 26655416 TI - [How to choose and deliver orthodontic mini-screws: important notions]. AB - Orthodontic mini-screws are developing more and more because they make orthodontics easier and broaden its applications. This exponential development has arrived at a well defined mini-screw and a codified installation procedure. The aim of this article is to provide the conceptual elements of mini-screws in order to allow their safe use in orthodontic offices. PMID- 26655420 TI - [Poster presentations during the 87th Scientific Conference of the French Society of Dento-facial Orthopedics in Aix-en-Provence 15-16 May 2015]. PMID- 26655423 TI - Ibrutinib in chronic lymphocytic leukaemia: alone or in combination? PMID- 26655424 TI - Mature answers but new questions in indolent and mantle-cell lymphoma. PMID- 26655419 TI - [Incisor repositioning: a new approach in orthodontics]. AB - Lower incisors axis has a "key" position in different cephalometric analysis. However, several critics are directed towards the cephalometric profile and cephalometric landmarks (point, line and angle). The published norms and the cephalometric standards recommended for the optimal positioning of incisors could only be used as general clinical guidelines. Incisor repositioning to achieve optimal facial aesthetics requires taking into consideration the hard and soft tissues of the face, the profile, the muscular dynamics as well as the facial growth. In this work, we propose a new approach of incisor repositioning taking into account the variability of periodontal, functional and aesthetic factors. PMID- 26655418 TI - [Orthodontic tooth movement through the maxillary sinus in an adult with multiple missing teeth]. AB - This case report describes the successful orthodontic tooth movement through the maxillary sinus in an adult patient. A 41-year-old Asian woman had severe lip protrusion and multiple missing posterior teeth. Her orthodontic treatment included the extraction of two teeth, maximum retraction of the incisors using the extraction spaces and the existing spaces from the missing molars, and closure of all remaining spaces. Even though the treatment time was extended because of the anatomic and biologic challenges associated with moving posterior teeth over a long distance through the maxillary sinus, a successful outcome was obtained, with significant bone modeling of the maxillary sinus. The results demonstrate that a carefully selected force system can overcome the anatomic limitations of moving tooth against the cortical bone of the maxillary sinus wall in adult patients. PMID- 26655421 TI - Ibrutinib combined with bendamustine and rituximab compared with placebo, bendamustine, and rituximab for previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma (HELIOS): a randomised, double-blind, phase 3 study. AB - BACKGROUND: Most patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma relapse after initial therapy. Bendamustine plus rituximab is often used in the relapsed or refractory setting. We assessed the efficacy and safety of adding ibrutinib, an oral covalent inhibitor of Bruton's tyrosine kinase (BTK), to bendamustine plus rituximab in patients with previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma. METHODS: The HELIOS trial was an international, double-blind, placebo-controlled, phase 3 study in adult patients (>=18 years of age) who had active chronic lymphocytic leukaemia or small lymphocytic lymphoma with measurable lymph node disease (>1.5 cm) by CT scan, and had relapsed or refractory disease following one or more previous lines of systemic therapy consisting of at least two cycles of a chemotherapy containing regimen, an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and adequate bone marrow, liver, and kidney function. Patients with del(17p) were excluded because of known poor response to bendamustine plus rituximab. Patients who had received previous treatment with ibrutinib or other BTK inhibitors, refractory disease or relapse within 24 months with a previous bendamustine-containing regimen, or haemopoietic stem-cell transplant were also excluded. Patients were randomly assigned (1:1) by a web-based system to receive bendamustine plus rituximab given in cycles of 4 weeks' duration (bendamustine: 70 mg/m(2) intravenously on days 2-3 in cycle 1, and days 1-2 in cycles 2-6; rituximab: 375 mg/m(2) on day 1 of cycle 1, and 500 mg/m(2) on day 1 of cycles 2 6 for a maximum of six cycles) with either ibrutinib (420 mg daily orally) or placebo until disease progression or unacceptable toxicity. Patients were stratified according to whether they were refractory to purine analogues and by number of previous lines of therapy. The primary endpoint was independent review committee (IRC)-assessed progression-free survival. Crossover to ibrutinib was permitted for patients in the placebo group with IRC-confirmed disease progression. Analysis was by intention-to-treat and is continuing for further long-term follow-up. The trial is registered with ClinicalTrials.gov, number NCT01611090. FINDINGS: Between Sept 19, 2012, and Jan 21, 2014, 578 eligible patients were randomly assigned to ibrutinib or placebo in combination with bendamustine plus rituximab (289 in each group). The primary endpoint was met at the preplanned interim analysis (March 10, 2015). At a median follow-up of 17 months (IQR 13.7-20.7), progression-free survival was significantly improved in the ibrutinib group compared with the placebo group (not reached in the ibrutinib group (95% CI not evaluable) vs 13.3 months (11.3-13.9) in the placebo group (hazard ratio [HR] 0.203, 95% CI 0.150-0.276; p<0.0001). IRC-assessed progression free survival at 18 months was 79% (95% CI 73-83) in the ibrutinib group and 24% (18-31) in the placebo group (HR 0.203, 95% CI 0.150-0.276; p<0.0001). The most frequent all-grade adverse events were neutropenia and nausea. 222 (77%) of 287 patients in the ibrutinib group and 212 (74%) of 287 patients in the placebo group reported grade 3-4 events; the most common grade 3-4 adverse events in both groups were neutropenia (154 [54%] in the ibrutinib group vs 145 [51%] in the placebo group) and thrombocytopenia (43 [15%] in each group). A safety profile similar to that previously reported with ibrutinib and bendamustine plus rituximab individually was noted. INTERPRETATION: In patients eligible for bendamustine plus rituximab, the addition of ibrutinib to this regimen results in significant improvements in outcome with no new safety signals identified from the combination and a manageable safety profile. FUNDING: Janssen Research & Development. PMID- 26655426 TI - Detection of DCIS and reduced invasive interval cancers. PMID- 26655429 TI - Ubiquitous Occurrence of Fluorotelomer Alcohols in Eco-Friendly Paper-Made Food Contact Materials and Their Implication for Human Exposure. AB - The occurrence of fluorotelomer alcohols (FTOHs) was investigated in 94 food contact materials (FCMs). We detected 6:2 FTOH (<0.60-1110 ng/g), 8:2 FTOH (<0.40 8490 ng/g), and 10:2 FTOH (<0.02-9350 ng/g) in most FCM samples, and four longer chain C14-20 FTOHs were, for the first time, identified in FCMs with relatively high concentrations (<0.02-8450 ng/g for 12:2 FTOH, <0.02-1640 ng/g for 14:2 FTOH, <0.02-372 ng/g for 16:2 FTOH, and <0.02-130 ng/g for 18:2 FTOH). There were three typical profiles of FTOHs that were dominated by 6:2 FTOH (95.6 +/- 8.1% in 9 FCMs), 8:2 FTOH (50.9 +/- 20.8% in 22 FCMs), and 10:2 FTOH (44.5 +/- 20.9% in 30 FCMs), indicating the congener-specific usage of FTOHs for different commercial purposes. All nine detectable FCMs produced in the United States were dominated by 6:2 FTOH, which was significantly different from those produced in China. The median concentration of total FTOHs in eco-friendly paper tableware was 2990 ng/g, which was lower than in popcorn bags (18 200 ng/g) but much higher than other FCMs (<0.55-38.7 ng/g). FTOHs could migrate from paper bowls, with migration efficiencies of 0.004-0.24% into water, 0.004-0.24% into 10% ethanol, 0.009-2.79% into 30% ethanol, 0.06-13.0% into 50% ethanol (v/v) simulants, and 0.04-2.28% into oil. Migration efficiencies decreased with increasing carbon chain lengths of FTOHs. PMID- 26655428 TI - BIP induces mice CD19(hi) regulatory B cells producing IL-10 and highly expressing PD-L1, FasL. AB - Many studies have shown that B cells possess a regulatory function in mouse models of autoimmune diseases. Regulatory B cells can modulate immune response through many types of molecular mechanisms, including the production of IL-10 and the expression of PD-1 Ligand and Fas Ligand, but the microenvironmental factors and mechanisms that induce regulatory B cells have not been fully identified. BIP (binding immunoglobulin protein), a member of the heat shock protein 70 family, is a type of evolutionarily highly conserved protein. In this article, we have found that IL-10(+), PD-L1(hi) and FasL(hi) B cells are discrete cell populations, but enriched in CD19(hi) cells. BIP can induce IL-10-producing splenic B cells, IL-10 secretion and B cells highly expressing PD-L1 and FasL. CD40 signaling acts in synergy with BIP to induce regulatory B cells. BIP increased surface CD19 molecule expression intensity and IL-10(+), PD-L1(hi) and FasL(hi) B cells induced by BIP share the CD19(hi) phenotype. Furthermore, B cells treated with BIP and anti-CD40 can lead to suppression of T cell proliferation and the effect is partially IL-10-dependent and mainly BIP-induced. Taken together, our findings identify a novel function of BIP in the induction of regulatory B cells and add a new reason for the therapy of autoimmune disorders or other inflammatory conditions. PMID- 26655422 TI - Screen detection of ductal carcinoma in situ and subsequent incidence of invasive interval breast cancers: a retrospective population-based study. AB - BACKGROUND: The value of screen detection and treatment of ductal carcinoma in situ (DCIS) is a matter of controversy. At present, the extent to which the diagnosis and treatment of DCIS could prevent the occurrence of invasive breast cancer in the future is not clear. We sought to estimate the association between detection of DCIS at screening and invasive interval cancers subsequent to the relevant screen. METHODS: We obtained aggregate data for screen-detected cancers from 84 local screening units within 11 regional Quality Assurance Reference Centres in England, Wales, and Northern Ireland from the National Health Service Breast Screening Programme. Data for DCIS diagnoses were obtained for women aged 50-64 years who were invited to and attended mammographic breast screening from April 1, 2003, to March 31, 2007 (4 screening years). Patient-level data for interval cancer arising in the 36 months after each of these were analysed by Poisson regression with invasive interval cancer screen detection rate as the outcome variable; DCIS detection frequencies were fitted first as a continuous and then as a categorical variable. We repeated this analysis after adjustment with both small size and high-grade invasive screen-detected cancers. FINDINGS: We analysed data for 5,243,658 women and on interval cancers occurring in the 36 months after the relevant screen. The average frequency of DCIS detected at screening was 1.60 per 1000 women screened (median 1.50 [unit range 0.54-3.56] [corrected to] per 1000 women). There was a significant negative association of screen-detected DCIS cases with the rate of invasive interval cancers (Poisson regression coefficient -0.084 [95% CI -0.13 to -0.03]; p=0.002). 90% of units had a DCIS detection frequency within the range of 1.00 to 2.22 per 1000 women; in these units, for every three screen-detected cases of DCIS, there was one fewer invasive interval cancer in the next 3 years. This association remained after adjustment for numbers of small screen-detected invasive cancers and for numbers of grade 3 invasive screen-detected cancers. INTERPRETATION: The association between screen-detected DCIS and subsequent invasive interval cancers suggests that detection and treatment of DCIS is worthwhile in prevention of future invasive disease. FUNDING: UK Department of Health Policy Research Programme and NHS Cancer Screening Programmes. PMID- 26655427 TI - Anti-DNA antibody mediated catalysis is isotype dependent. AB - Anti-DNA antibodies are the serological hallmark of systemic lupus erythematosus, and participate in the pathogenesis of lupus nephritis by cross-reacting with multiple renal antigens. Previously, using a panel of murine anti-DNA IgGs that share identical variable regions but that differ in the constant regions, we demonstrated that the cross-reaction and renal pathogenicity of anti-DNA antibodies are isotype dependent. In this study, we investigated the catalytic potential of this anti-DNA antibody panel, and determined its isotype dependency. The three isotype switch variants (IgG1, IgG2a, IgG2b) and the parent IgG3 PL9-11 anti-DNA antibodies were compared in their catalysis of 500 base pair linear double stranded DNA and a 12-mer peptide (ALWPPNLHAWVP), by gel analysis, MALDI TOF mass spectrometry, and nuclear magnetic resonance spectroscopy. The binding affinity of anti-DNA antibodies to double stranded DNA and peptide antigens were assessed by ELISA and surface plasmon resonance. We found that the PL9-11 antibody isotypes vary significantly in their potential to catalyze the cleavage of both linear and double stranded DNA and the proteolysis of peptides. The degree of the cleavage and proteolysis increases with the incubation temperature and time. While different PL9-11 isotypes have the same initial attack sites within the ALWPPNLHAWVP peptide, there was no correlation between binding affinity to the peptide and proteolysis rates. In conclusion, the catalytic properties of anti-DNA antibodies are isotype dependent. This finding provides further evidence that antibodies that share the same variable region, but which have different constant regions, are functionally distinct. The catalytic effects modulated by antibody constant regions need to be considered in the design of therapeutic antibodies (abzymes) and peptides designed to block pathogenic autoantibodies. PMID- 26655425 TI - Bendamustine plus rituximab versus fludarabine plus rituximab for patients with relapsed indolent and mantle-cell lymphomas: a multicentre, randomised, open label, non-inferiority phase 3 trial. AB - BACKGROUND: Fludarabine-based chemoimmunotherapy with rituximab is frequently used in patients with indolent and mantle-cell lymphomas who relapse after alkylating chemotherapy. We aimed to compare the efficacy and safety of rituximab with bendamustine or fludarabine in patients with relapsed, indolent, non-Hodgkin lymphoma and mantle-cell lymphoma. METHODS: For this randomised, non-inferiority, open-label, phase 3 trial, we recruited patients from 55 centres in Germany, who were subsequently randomised centrally according to prespecified randomisation lists with permuted blocks of randomly variable block size to rituximab (375 mg/m(2), day 1) plus either bendamustine (90 mg/m(2), days 1 and 2) or fludarabine (25 mg/m(2), days 1-3) every 28 days for a maximum of six 28-day cycles. Patients were aged 18 years or older with a WHO performance status of 0-2 and had relapsed or refractory indolent or mantle-cell lymphoma; patients refractory to regimens that included rituximab, bendamustine, or purine analogue drugs were excluded. Patients were stratified by histological subtypes of lymphoma and by their latest previous therapies. Treatment allocation was not masked. The primary endpoint was progression-free survival and the final analysis was completed per protocol. Non-inferiority of bendamustine plus rituximab versus fludarabine plus rituximab was defined as a difference of less than 15% in 1-year progression-free survival. The protocol was amended in July, 2006, after approval of rituximab maintenance (375 mg/m(2) every 3 months for up to 2 years), which was then given to patients achieving a response to either trial treatment. This study is registered with ClinicalTrials.gov, number NCT01456351 (closed to enrolment, follow-up is ongoing). FINDINGS: Between Oct 8, 2003, and Aug 5, 2010, we randomly assigned 230 patients to treatment groups (116 bendamustine plus rituximab, 114 fludarabine plus rituximab). 11 patients were excluded for protocol violations and were not followed up further (two in the bendamustine plus rituximab group and nine in the fludarabine plus rituximab group). Thus, 219 patients were included in the per-protocol analysis (114 bendamustine plus rituximab, 105 fludarabine plus rituximab). 1-year progression-free survival with bendamustine plus rituximab was 0.76 (95% CI 0.68-0.84) and 0.48 (0.39-0.58) with fludarabine plus rituximab (non-inferiority p<0.0001). At a median follow-up of 96 months (IQR 73.2-112.9), median progression-free survival with bendamustine plus rituximab was 34.2 months (95% CI 23.5-52.7) and 11.7 months (8.0-16.1) with fludarabine plus rituximab (hazard ratio [HR] 0.54 [95% CI 0.38-0.72], log-rank test p<0.0001). Safety outcomes were similar in both groups, with 46 serious adverse events recorded (23 in the bendamustine plus rituximab group and 23 in the fludarabine plus rituximab group), most commonly myelosuppression and infections. INTERPRETATION: In combination with rituximab, bendamustine was more effective than fludarabine, suggesting that bendamustine plus rituximab may be the preferred treatment option for patients with relapsed indolent and mantle cell lymphomas. FUNDING: Roche Pharma AG, Ribosepharm GmbH, Mundipharma GmbH, Studiengruppe indolente Lymphome (StiL). PMID- 26655430 TI - The feasibility and acceptability of a diet and exercise trial in overweight and obese black breast cancer survivors: The Stepping STONE study. AB - PURPOSE: Black breast cancer survivors have high rates of obesity and low physical activity levels. Little is known about the acceptability and feasibility of interventions in this population. OBJECTIVE: A two-arm RCT was launched to assess the efficacy of a culturally targeted 12-week multimodal lifestyle intervention in overweight and obese black survivors. METHODS: Intervention components included nutrition education, exercise groups, and survivor-led motivational interviewing phone sessions. The analytic sample included women who completed the trial (intervention n=10; control n=12). Anthropometric measures, physical activity, and VO2max were assessed at baseline and follow-up. Change scores (intervention vs. control) were assessed with Wilcoxon rank-sum tests. A process evaluation assessed intervention acceptability. RESULTS: Overall adherence was 70% and overall satisfaction was high (86%). Despite the 5% weight loss target, the intervention group lost 0.8% but BMI improved. Total physical activity levels increased in the intervention vs. control arm (+3501METmin/week vs. +965METmin/week, respectively). VO2max improved in the intervention group (+0.10+/-1.03kg/L/min). Intervention participants reduced energy intake (-207.3+/ 31.5kcals) and showed improvements in fat intake (-15.5+/-3.8g), fiber (+3.2+/ 1.2g) and % energy from fat (-4.8+/-3.1%). Survivors suggested providing diet/exercise information within a cancer context. CONCLUSIONS: Group and individualized intervention strategies are acceptable to black survivors. Observed differences between self-report and objective outcomes may suggest reporting bias or changes in body composition. Increasing supervised intervention components and assessment of body composition will be important for future trials. PMID- 26655432 TI - Enriching Cognitive Behavior Therapy with Emotion Regulation Training for Patients with Multiple Medically Unexplained Symptoms (ENCERT): Design and implementation of a multicenter, randomized, active-controlled trial. AB - INTRODUCTION: Although cognitive behavior therapy (CBT) is the best evidenced psychological treatment for medically unexplained symptoms (MUS), effect sizes are rather moderate. Empirically evidenced deficits in emotion processing in patients with MUS make a CBT enriched with an emotion regulation training (ENCERT) a promising approach to increase treatment effects. METHODS AND DESIGN: This protocol describes the development and implementation of a multicenter, randomized, active-controlled study with blinded outcome assessors to compare the efficacy of ENCERT with a conventional CBT for MUS. Individuals presenting with >=3 disabling, chronic MUS and fulfilling other predefined inclusion criteria are randomized to 20 sessions either of ENCERT or conventional CBT. Power calculations are based on the severity index of the Screening of Somatoform Disorders-7T and obtained an optimal sample size of N=244. Questionnaires on symptom severity, symptom-related psychological features, and emotion regulation skills are administered at baseline, end of therapy, and 6-months follow-up. An every-session monitoring of therapy progress, and regular patients'/therapists' ratings of quality of therapy, working alliance, outcome expectations, and adverse events are conducted. Primary statistical analysis shall verify the hypothesis of ENCERT being more efficacious than conventional CBT regarding symptom severity. DISCUSSION: Enriching CBT with transdiagnostic therapeutic strategies addressing emotion regulation is a promising and new approach to target not only somatic symptom coping but also symptom-associated problems and comorbid mental disorders. The current trial will not only allow examining the efficacy of ENCERT but also important variables and mechanisms of the process of therapy. TRIAL REGISTRATION: NCT01908855. PMID- 26655433 TI - Maximizing post-stroke upper limb rehabilitation using a novel telerehabilitation interactive virtual reality system in the patient's home: study protocol of a randomized clinical trial. AB - BACKGROUND: Telerehabilitation (TR), or the provision of rehabilitation services from a distance using telecommunication tools such as the Internet, can contribute to ensure that patients receive the best care at the right time. This study aims to assess the effect of an interactive virtual reality (VR) system that allows ongoing rehabilitation of the upper extremity (UE) following a stroke, while the person is in their own home, with offline monitoring and feedback from a therapist at a distance. METHODS/DESIGN: A single-blind (evaluator is blind to group assignment) two-arm randomized controlled trial is proposed, with participants who have had a stroke and are no longer receiving rehabilitation services randomly allocated to: (1) 4-week written home exercise program, i.e. usual care discharge home program or (2) a 4-week home-based TR exercise program using VR in addition to usual care i.e. treatment group. Motor recovery of the UE will be assessed using the Fugl-Meyer Assessment-UE and the Box and Block tests. To determine the efficacy of the system in terms of functional recovery, the Motor Activity Log, a self-reported measure of UE use will be used. Impact on quality of life will be determined using the Stroke Impact Scale-16. Lastly, a preliminary cost-effectiveness analysis will be conducted using costs and outcomes for all groups. DISCUSSION: Findings will contribute to evidence regarding the use of TR and VR to provide stroke rehabilitation services from a distance. This approach can enhance continuity of care once patients are discharged from rehabilitation, in order to maximize their recovery beyond the current available services. PMID- 26655431 TI - Healthy immigrant families: Participatory development and baseline characteristics of a community-based physical activity and nutrition intervention. AB - BACKGROUND: US immigrants often have escalating cardiovascular risk. Barriers to optimal physical activity and diet have a significant role in this risk accumulation. METHODS: We developed a physical activity and nutrition intervention with immigrant and refugee families through a community-based participatory research approach. Work groups of community members and health scientists developed an intervention manual with 12 content modules that were based on social-learning theory. Family health promoters from the participating communities (Hispanic, Somali, Sudanese) were trained to deliver the intervention through 12 home visits during the first 6 months and up to 12 phone calls during the second 6 months. The intervention was tested through a randomized community based trial with a delayed-intervention control group, with measurements at baseline, 6, 12, and 24 months. Primary measurements included accelerometer-based assessment of physical activity and 24-hour dietary recall. Secondary measures included biometrics and theory-based instruments. RESULTS: One hundred fifty-one individuals (81 adolescents, 70 adults; 44 families) were randomized. At baseline, mean (SD) time spent in moderate-to-vigorous physical activity was 64.7 (30.2) minutes/day for adolescents and 43.1 (35.4) minutes/day for adults. Moderate dietary quality was observed in both age groups. Biometric measures showed that 45.7% of adolescents and 80.0% of adults were overweight or obese. Moderate levels of self-efficacy and social support were reported for physical activity and nutrition. DISCUSSION: Processes and products from this program are relevant to other communities aiming to reduce cardiovascular risk and negative health behaviors among immigrants and refugees. TRIAL REGISTRATION: This trial was registered at Clinicaltrials.gov (NCT01952808). PMID- 26655434 TI - Feasibility study design and methods for Project GEMS: Guidelines for Exercise in Multiple Sclerosis. AB - The Guidelines for Exercise in Multiple Sclerosis (GEMS) program is a randomized controlled trial (RCT) examining the feasibility and efficacy of a home-based exercise training program based on recent physical activity guidelines and principles of behavior change for improving symptoms and health-related quality of life (HRQOL) in adults with multiple sclerosis (MS). The primary aim is to assess program feasibility in the four domains of process (e.g., recruitment, retention, and adherence), resources (e.g., communication, staff requirements, and monetary costs), management (e.g., time and accuracy in data collection/entry, and reporting of adverse events) and scientific outcomes (e.g., safety, burden, participant feedback and efficacy/outcomes). The trial will recruit individuals with mild-to-moderate MS-related disability across the United States who will be randomized into intervention or waitlist control conditions. All participants will complete home-based assessments (including wearing an accelerometer for 7 days and completion of a questionnaire booklet) prior to and upon completion of the 4-month program. Participants in the intervention will receive a 4-month home-based exercise program emphasizing aerobic and resistance training. Participants will be provided with exercise equipment, a DVD, a manual and a log-book. The exercise program will be supplemented with periodic newsletters in the mail highlighting principles of behavior change, and video chats with an exercise specialist to provide motivation and social accountability. This trial serves to inform development of Phase II and III RCTs which can determine the actual efficacy and effectiveness of home-based exercise based on the MS-specific physical activity guidelines for improving symptoms and HRQOL. PMID- 26655435 TI - Antioxidant defenses and histological changes in Carassius auratus after combined exposure to zinc and three multi-walled carbon nanotubes. AB - With the increasing applications of carbon nanotubes (CNTs) worldwide, considerable concerns have been raised regarding their inevitable releases into natural waters and ecotoxicity. It was supposed that CNTs may interact with some existing pollutants like zinc in aquatic systems and exhibit different effects when compared with their single treatments. However, data on their possible combined toxicity on aquatic species are still lacking. Moreover, the interactions of Zn with different functionalized CNTs may be distinct and thereby lead to diverse results. It is like that functional groups play a vital role in illustrating the differences in toxicity among various CNTs. In this study, the single and joint effects of multi-walled carbon nanotubes (MWCNTs) and two MWCNTs functionalized with carboxylation (COOH-MWCNTs) or hydroxylation (OH-MWCNTs) in the absence or presence of zinc (Zn) on antioxidant status and histopathological changes in Carassius auratus were evaluated. Synergistic effect was tentatively proposed for joint-toxicity action, which was supported by apparently observed oxidative stress and histopathological changes in joint exposure groups. The integrated biomarker response index was calculated to rank the toxicity order, from which the conclusion of synergistic effect was strengthened. Regarding differences among various CNTs, our data showed that OH-MWCNTs and COOH-MWCNTs were more stressful to fish than raw MWCNTs. This finding sustained that functionalization is an important factor in nanotoxicity, which may serve as clues for future design and application of CNTs. Overall, these results provided some valuable toxicological data on the joint effects of CNTs and heavy metals on aquatic species, which can facilitate further understanding on the potential impacts of other coexisting pollutants in the culture of freshwater fish. PMID- 26655436 TI - The Neural Crossroads of Psychiatric Illness: An Emerging Target for Brain Stimulation. AB - Recent meta-analyses of structural and functional neuroimaging studies are converging on a collective core of brain regions affected across most psychiatric disorders, centered on the dorsal anterior cingulate cortex (dACC) and anterior insula. These nodes correspond well to an anterior cingulo-insular (aCIN) or 'salience' network, and stand at a crossroads within the functional architecture of the brain, acting as a switch to deploy other major functional networks according to motivational demands and environmental constraints. Therefore, disruption of these 'linchpin' areas may be disproportionately disabling, even when other networks remain intact. These regions may represent promising targets for a new generation of anatomically directed brain stimulation treatments. Here, we review the potential of the psychiatric core areas as targets for therapeutic brain stimulation in psychiatric disease. PMID- 26655437 TI - Preeclampsia transforms membrane N-glycome in human placenta. AB - Posttranslational modifications (PTM) which accompany pathological conditions affect protein structure, characteristics and modulate its activity. Glycosylation is one of the most frequent PTM influencing protein folding, localisation and function. Hypertension is a common gestational complication, which can lead to foetal growth restriction (IUGR) and even to foetal or maternal death. In this work we focused on the impact of preeclampsia complicated with IUGR on placental membrane N-glycome. Results have shown that preeclampsia reduced fucosylation of placental glycans, increased the appearance of paucimannosidic and mannosidic structures with lower number of mannose residues and decreased the amount of glycans with more mannose residues. Since preeclampsia is tightly connected to IUGR, glycosylation changes were investigated also on the functional membrane receptors responsible for growth: insulin receptor and the type 1 insulin-like growth factor receptor (IR and IGF1R). It was found that IR present in the IUGR placenta contained significantly less alpha2,6-Sia. Therefore, glycans on placental membranes alter due to preeclampsia, but changes seen at the level of the entire N-glycome may be different from the changes detected at the level of a specific glycoprotein. The difference recorded due to pathology in one membrane molecule (IR) was not found in another homologous molecule (IGF1R). Thus, besides studying the glycosylation pattern of the entire placental membrane due to preeclampsia, it is inevitable to study directly glycoprotein of interest, as no general assumptions or extrapolations can be made. PMID- 26655438 TI - Early adventitial activation characterized by NADPH oxidase expression and neovascularization in an aortic transplantation model. AB - Increasing evidence has suggested that arterial adventitia may contribute to pathological vessel remodeling by producing reactive oxygen species and promoting neovascularization. However, these processes have not been studied yet in transplantation-induced vascular pathologies. We characterized the dynamic changes in NADPH oxidase expression and adventitial angiogenic response in a model of allograft aortic transplantation. The thoracic aorta from Fischer 344 rats were transplanted into the abdominal aorta of Lewis rats. Graft specimens were collected on days 0.5, 3, 7, and 14 for morphometry, immunohistochemistry, immunofluorescence staining, and quantitative PCR tests. Following transplantation, adventitial thickening was found as early as day 3, while neointima was observed from day 7. As compared to normal adventitial tissue, the expression levels of NADPH oxidase subunits gp91phox and p47phox in graft adventitia were elevated from day 3 and further increased up to day 14. Immunohistochemistry staining showed that infiltrating macrophages appeared to be a major source of NADPH oxidase expression. Increases in NADPH oxidase expression were also detected in fibroblasts isolated from the graft adventitia. Gene silencing of p47phox significantly suppressed proliferation and migration of the graft fibroblast cells. We also showed that adventitial thickening was accompanied by increased adventitial neovascularization; at day 14, there was a positive correlation between the density of adventitial microvessels and the neointimal thickness. Transplantation injury induces NADPH oxidase expression and neovascularization in the adventitia, raising the possibility that the activated adventitia may represent a target site for prevention of transplantation-induced transplant vasculopathy. PMID- 26655443 TI - B-1 B cell progenitors transiently and partially express keratin 5 during differentiation in bone marrow. AB - BACKGROUND: Keratin 5 (K5) is a cytoskeletal tissue-specific protein expressed in the epithelial cells of skin and esophagus and ectopic K5 expression in lymphocytes has never been reported. OBJECTIVE: Here we demonstrate an ectopic epidermal self-protein expression in B-1 B cell by fate mapping of K5-expressing cells. METHODS: K5-Cre*CAG-CAT-loxP-EGFP double Tg (K5*GFP) mice that express enhanced GFP under the control of the K5 promoter were employed. RESULTS: Unexpectedly, B220(+)GFP(+) cells were found in LN, spleen, peripheral blood and peritoneal cavity. These cells were IgM(+)IgD(low)CD23(-)CD43(+)CD19(+)CD93(-), indicating that they were B-1 B cells. The number of B220(+)GFP(+) cells was significantly larger in spleen than in the other tissues tested. Although GFP(+) B-1 cells did not express K5 in the periphery, Lin(-)CD93(+)B220(low-neg)CD19(+) B-1 B cell progenitors expressed GFP and B220(+)CD93(+) progenitor cells expressed K5 and MHC-class II in BM, indicating that GFP(+) B-1 cells transiently expressed K5 and the progenitor cells were potential APC. GFP(+) B-1 cells in the periphery continued expressing MHC class II and had exogenous antigen-presenting capacity comparable to non-follicular B cells. GFP(+) B-1 cells spontaneously secreted more IgM than GFP(-) B-1 cells in vitro. CONCLUSION: These results indicate that B-1 B cells transiently and partially express K5 in BM and are potent for both natural antibody production and antigen presentation. PMID- 26655445 TI - [Prevalence of smear-positive pulmonary tuberculosis in Aioun hospital (Hodh El Garbi)]. AB - In this retrospective study in the regional hospital Aioun from 1st January 2010 to 31st April 2014, the objective was to determine the prevalence of smear positive PTB. In total, 320 cases have been identified giving a proportion of 9%. The male subjects (74%) were three times higher than for female subjects with a sex-ratio man/woman of 2.8. The average age of patients was 41+/-16 years with extremes of 15 and 90 years and the most affected age group was 15-30 years (41%). The majority of our patients (85%) came from rural areas. No patient had been screened for HIV infection. There was a statistically significant relationship between gender, age group (P=0.005) and resistant cases after 6months of anti-TB treatment (P=0.04). Tuberculosis remains a public health problem in our country. Many efforts will still be provided for screening and epidemiological surveillance for a good control of the disease. PMID- 26655444 TI - Hygiene and mental health among middle school students in India and 11 other countries. AB - The Global School-based Student Health Survey (GSHS) collects data from early adolescents who are approximately 13-15 years old and enrolled in middle schools (also known as junior secondary schools). We used logistic regression models to examine the associations between self-reported hygiene practices and mental health status as assessed by the 2007 India GSHS. Then, we used meta-analysis to compare the results from India with those from 11 other GSHS-participating countries in Asia and Africa (Djibouti, Indonesia, Jordan, Kenya, Lebanon, Myanmar, the Philippines, Tanzania, Thailand, Uganda, and the United Arab Emirates). Among 7904 middle school students in India, 25.5% reported symptoms of depression, 8.6% reported loneliness, and 7.8% reported anxiety-related insomnia. Both males and females who reported symptoms of depression had an increased likelihood of poor hand and oral hygiene, including washing their hands rarely or never and brushing their teeth less than daily. The meta-analysis for this association yielded statistically significant pooled odds ratios for both boys and girls. In girls, loneliness was also associated with poor hand and oral hygiene. Reduced mental health status in adolescents may lead to worse hygiene behaviors and an increased risk of infections. Teachers, parents, healthcare workers, and other adults who observe suboptimal hygiene status in an adolescent should consider whether this indicates a mental health issue that requires clinical services. PMID- 26655446 TI - Effect of chronic social defeat stress on behaviors and dopamine receptor in adult mice. AB - Victims of bullying often undergo depression, low self-esteem, high anxiety and post-traumatic stress disorder symptoms. The social defeat model has become widely accepted for studying experimental animal behavior changes associated with bullying; however, differences in the effects in susceptible and unsusceptible individuals have not been well studied. The present study investigated the effects of social defeat stress on behavior and the expression of dopamine receptors D1 and D2 in the brains of adult mice. Adult mice were divided into susceptible and unsusceptible groups after 10days of social defeat stress. Behavioral tests were conducted, and protein levels in the brains were assessed by Western blotting. The results indicate that all mice undergo decreased locomotion and increased anxiety behavior. However, decreased social interaction and impaired memory performance were only observed in susceptible mice. A significantly decreased expression of D1 was observed in the prefrontal cortex and amygdala of susceptible mice only. No significant differences in D2 expression were shown between control and defeated mice in any area studied. These data indicate that depression-like behavior and cognition impairment caused by social defeat stress in susceptible mice may be related to changes in the dopamine receptor D1. PMID- 26655447 TI - Statins and the brain: New perspective for old drugs. AB - Statins are one of the most popular lipid-lowering drugs (LLDs). Upon oral administration, these drugs are well absorbed by the intestine and effectively used for the treatment of dyslipidemias. Recently, statins are becoming also well known for their cholesterol-independent effects and their potential use in brain diseases and different types of cancers. While still controversial, recent research has suggested that statin's cholesterol-independent activities work possibly through alterations on isoprenoid levels. This reduction of isoprenoids in the central nervous system might result in effective biochemical and behavioral improvements on certain neurological disorders. This manuscript aims to highlight current research describing the use of statin therapy in the brain and discuss whether statins might affect neuronal dynamics and function independently of their cholesterol regulatory role. PMID- 26655448 TI - Internet use and looking up information online in adults with epilepsy varies by epilepsy status--2013 National Health Interview Survey. AB - We estimated US national prevalences of Internet use and looking up health information online among adults with epilepsy and those without, overall (age standardized) and by three age groups (18-44, 45-59, and >=60years) using the 2013 National Health Interview Survey. Results showed that both overall and across all age groups, a significantly lower percentage of adults with active epilepsy reported using the Internet compared with that of adults without epilepsy. However, among Internet users, the percentage of looking up health information online did not differ by epilepsy status or age. Ensuring access to the Internet and encouraging use of quality, secure, and easy-to-access resources and e-tools might help adults with epilepsy to optimize their self-management and improve their quality of life. PMID- 26655449 TI - Effects of an acute seizure on associative learning and memory. AB - Past studies have demonstrated that inducing several seizures or continuous seizures in neonatal or adult rats results in impairments in learning and memory. The impact of a single acute seizure on learning and memory has not been investigated in mice. In this study, we exposed adult 129SvEvTac mice to the inhalant flurothyl until a behavioral seizure was induced. Our study consisted of 4 experiments where we examined the effect of one seizure before or after delay fear conditioning. We also included a separate cohort of animals that was tested in the open field after a seizure to rule out changes in locomotor activity influencing the results of memory tests. Mice that had experienced a single seizure 1h, but not 6h, prior to training showed a significant impairment in associative conditioning to the conditioned stimulus when compared with controls 24h later. There were no differences in freezing one day later for animals that experienced a single seizure 1h after associative learning. We also found that an acute seizure reduced activity levels in an open-field test 2h but not 24h later. These findings suggest that an acute seizure occurring immediately before learning can have an effect on the recall of events occurring shortly after that seizure. In contrast, an acute seizure occurring shortly after learning appears to have little or no effect on long-term memory. These findings have implications for understanding the acute effects of seizures on the acquisition of new knowledge. PMID- 26655450 TI - Prevalence and correlates of major depressive disorder (MDD) among adolescent patients with epilepsy attending a Nigerian neuropsychiatric hospital. AB - BACKGROUND: A high prevalence of mood disorders exists in patients with epilepsy. In most cases, this is not detected and, consequently, not treated. This study aimed to determine the prevalence and correlates of major depressive disorder (MDD) among adolescents with epilepsy attending a child and adolescent clinic in Nigeria. METHODS: We recruited 156 participants consecutively for the study. Adherence was assessed using the 8-item Morisky Medication Adherence Questionnaire, while the K-SADS was used to assess the presence of major depressive disorder. Seizure control was evaluated by the frequency of seizures within a year. RESULTS: Major depressive disorder (DSM-IV criteria) was diagnosed in 28.2% of the participants. The age of participants (p=0.013), seizure control (p=0.03), medication adherence (p=0.045), frequency of seizures in the preceding 4weeks (p<0.001), and duration of illness (p<0.001) were all significantly associated with the presence of MDD. Participants with seizures occurring more than once weekly in the preceding 4weeks were 16 times more likely to have a MDD compared with those with no seizures in the preceding 4weeks (p<0.001, 95% C.I. [4.13, 65.43]), while participants with a duration of illness more than 10years were more than four times likely to have MDD compared with those with an illness duration of 5-10years (p<0.01, 95% C.I. [0.07, 0.70]). CONCLUSION: The prevalence of MDD among patients with epilepsy was high. Poor seizure control, poor medication adherence, and long duration of illness were associated with the presence of MDD among such patients. Intervention should focus on ensuring good seizure control and optimal adherence in order to mitigate the impact of MDD in patients with epilepsy. PMID- 26655451 TI - A preliminary observation of the adverse effects of phenobarbital among patients with convulsive epilepsy in rural West China. AB - BACKGROUND: This study explored the adverse effect (AE) profile of phenobarbital (PB) among patients with active convulsive epilepsy (ACE) from resource-poor areas. METHODS: Patients with ACE were enrolled into an epilepsy management project in rural West China. Information was obtained from monthly follow-up questionnaires. The demographic and clinical features of the patients with AE were firstly described. After that, the occurrence rate was estimated for each subtype of AE at three different severity levels (mild, moderate, and serious). Survival analysis was used to determine the potential risk factors of AEs. RESULTS: A total of 7231 patients (3780 men) were included in the present cohort. During the follow-up time period (average 33.4months), the most common AEs were drowsiness (moderate: 4.4%, serious: 0.68%), dizziness (moderate: 3.7%, serious: 0.5%), and headache (moderate: 2.9%, serious: 0.41%). In the confirmed AE groups (moderate and serious severity levels), the symptoms tended to be transient, with durations of less than 3months. Polytherapy was an independent risk factor for AEs and had an increasing risk when the severity of the AE increased (Hazard Ratio 1.12, 1.55, and 2.52 for mild AE, moderate AE, and serious AE, respectively). Receiving a high dosage of PB (>180mg/day) indicated a slightly elevated risk (Hazard Ratio 1.22 and 1.27 for mild AE and moderate AE, respectively). CONCLUSION: Phenobarbital demonstrates overall tolerability, and serious AEs were not common. Patients receiving a high dose of PB or polytherapy are at increased risk of developing AEs. PMID- 26655452 TI - Using Family-Focused Garden, Nutrition, and Physical Activity Programs To Reduce Childhood Obesity: The Texas! Go! Eat! Grow! Pilot Study. AB - BACKGROUND: The TEXAS! GROW! EAT! GO! (TGEG) randomized, control trial is a 5 year study to measure the impact of a nutrition and gardening intervention and/or physical activity (PA) intervention on the weight status of third-grade students. This article describes the results of the pilot study to test the feasibility of two interventions and test the measures to be used in the main trial. METHODS: The pilot study was conducted in one school with third-grade students and their parents or guardians. The Junior Master Gardner (JMG) and Walk Across Texas (WAT) interventions were implemented over a 5-month period in three third-grade classrooms during spring 2012. The respective interventions focused on improving healthy eating and PA behaviors of children and their families. Baseline and immediate post-test data were collected from students and parents/guardians to measure four child, four parent, and four parent-child interaction behaviors. Process data regarding implementation were also collected from teachers and school administration. RESULTS: Forty-four students and 34 parents or guardians provided both pre- and post-test data. Paired-sample t-tests showed statistically significant changes in student knowledge, vegetable preferences, vegetable consumption, and home food availability (all p < 0.05). At baseline, participants' weight status categories included 57% obese, 10% overweight, and 31% normal weight. Postintervention, weight status categories included 39% obese, 16% overweight, and normal 45%. Data collected from teachers indicated high levels of implementation fidelity. CONCLUSIONS: Implementation of both interventions occurred at a very high fidelity level, which led to positive changes in BMI status, and several dietary and PA behaviors. Although the pilot study indicated feasibility of the two interventions for school implementation, results guided revisions to the TGEG program and its survey instruments. PMID- 26655453 TI - Friends Like Me: Associations in Overweight/Obese Status among Adolescent Friends by Race/Ethnicity, Sex, and Friendship Type. AB - BACKGROUND: Little is known about how interpersonal friend relationships are associated with obesity in young people, particularly with regard to how race/ethnicity, type of friendship, and sex affect the association between friends' and adolescents' weight status. This study examined associations in weight status among adolescents and their friends, exploring magnitudes of associations across friendship type, sex, and race/ethnicity. METHODS: As part of EAT-2010 (Eating and Activity in Teens), friend nominations and anthropometrics were obtained from adolescents (n = 2099: 54% female; 80% nonwhite; mean age: 14.2 +/- 1.9 years). Generalized estimating equation logistic regression models were used to test associations between adolescents' overweight/obese status and friends' (i.e., friend group, female friends, male friends, female best friends, and male best friends) overweight/obese status. Interactions by adolescent race/ethnicity were examined. RESULTS: The majority of significant associations were observed among white female adolescents' who had a 22-40% higher prevalence of overweight/obesity if their friends were overweight compared to white females whose friends were not overweight. In contrast, there were few significant differences for other adolescent female and male racial/ethnic groups for girls and boys. Results for friend groups and best friends were generally similar to one another. CONCLUSIONS: The association between friend and adolescent overweight/obese status depended on adolescents' sex, race/ethnicity, and friendship type. Given the similarities among friends, obesity interventions targeting youth, especially white females, should consider involving friends. PMID- 26655454 TI - Control of agitation and aeration rates in the production of surfactin in foam overflowing fed-batch culture with industrial fermentation. AB - Bacillus amyloliquefaciens fmb50 produces a high yield of surfactin, a lipopeptide-type biosurfactant that has been widely studied and has potential applications in many fields. A foam overflowing culture has been successfully used in the combined production-enrichment fermentation of surfactin. In this study, the agitation and aeration rates were found to have relationships with foam formation and surfactin enrichment. A maximum surfactin concentration of 4.7g/l of foam was obtained after 21h of culture with an agitation rate of 150rpm and an aeration rate of 1vvm in fed-batch culture. By controlling the foam overflow rate (fout) of a fed-batch culture, surfactin concentration in the foam was continuously maintained above 4g/l. PMID- 26655455 TI - ARCADO - Adding random case analysis to direct observation in workplace-based formative assessment of general practice registrars. AB - BACKGROUND: Workplace-based formative assessments using consultation observation are currently conducted during the Australian general practice training program. Assessment reliability is improved by using multiple assessment methods. The aim of this study was to explore experiences of general practice medical educator assessors and registrars (trainees) when adding random case analysis to direct observation (ARCADO) during formative workplace-based assessments. METHODS: A sample of general practice medical educators and matched registrars were recruited. Following the ARCADO workplace assessment, semi-structured qualitative interviews were conducted. The data was analysed thematically. RESULTS: Ten registrars and eight medical educators participated. Four major themes emerged - formative versus summative assessment; strengths (acceptability, flexibility, time efficiency, complementarity and authenticity); weaknesses (reduced observation and integrity risks); and contextual factors (variation in assessment content, assessment timing, registrar-medical educator relationship, medical educator's approach and registrar ability). CONCLUSION: ARCADO is a well-accepted workplace-based formative assessment perceived by registrars and assessors to be valid and flexible. The use of ARCADO enabled complementary insights that would not have been achieved with direct observation alone. Whilst there are some contextual factors to be considered in its implementation, ARCADO appears to have utility as formative assessment and, subject to further evaluation, high-stakes assessment. PMID- 26655456 TI - Microbial colonization of normal skin: Direct visualization of 194 skin biopsies. AB - Recent genetic studies have suggested the presence of numerous microbial species on and in the skin. We characterised microbial colonization of a large collection of skin biopsies from 194 healthy subjects by fluorescence assay. Forty per cent of all biopsies did not show any evidence for microbial colonization. Propionibacterium acnes was the sole predominant bacterial species in both sebaceous and non-sebaceous areas. Non- P. acnes species were present in approximately 30% of all colonized samples. . Only hair follicles and stratum corneum were colonized. Understanding of cutaneous microbiota requires validation from a variety of approaches and techniques. PMID- 26655457 TI - Analysis of sequencing data for probing RNA secondary structures and protein-RNA binding in studying posttranscriptional regulations. AB - High-throughput sequencing has been used to study posttranscriptional regulations, where the identification of protein-RNA binding is a major and fast developing sub-area, which is in turn benefited by the sequencing methods for whole-transcriptome probing of RNA secondary structures. In the study of RNA secondary structures using high-throughput sequencing, bases are modified or cleaved according to their structural features, which alter the resulting composition of sequencing reads. In the study of protein-RNA binding, methods have been proposed to immuno-precipitate (IP) protein-bound RNA transcripts in vitro or in vivo By sequencing these transcripts, the protein-RNA interactions and the binding locations can be identified. For both types of data, read counts are affected by a combination of confounding factors, including expression levels of transcripts, sequence biases, mapping errors and the probing or IP efficiency of the experimental protocols. Careful processing of the sequencing data and proper extraction of important features are fundamentally important to a successful analysis. Here we review and compare different experimental methods for probing RNA secondary structures and binding sites of RNA-binding proteins (RBPs), and the computational methods proposed for analyzing the corresponding sequencing data. We suggest how these two types of data should be integrated to study the structural properties of RBP binding sites as a systematic way to better understand posttranscriptional regulations. PMID- 26655458 TI - Editorial Comment. PMID- 26655459 TI - Nacre-like materials using a simple doctor blading technique: Fabrication, testing and modeling. AB - The remarkable mechanical performance of biological materials such as bone, nacre, and spider silk stems from their staggered microstructure in which stiff and strong reinforcements are elongated in the direction of loading, separated by softer interfaces, and shifted relative to each other. This structure results in useful combinations of modulus, strength and toughness and therefore is increasingly mimicked in bio-inspired engineering composites. Here, we report the use of a simple and versatile technique based on doctor-blading to fabricate staggered composites of microscopic alumina tablets with high alignment in a chitosan matrix. Tensile tests on these nacre-like materials show that the modulus and strength of the composite films are enhanced by the incorporation of ceramic tablets, but only up to 15vol% after which all properties degrade. This phenomenon, also reported in the past for most of nacre-like materials, composed of micro/nano tablets, obtained from different techniques, has been limiting our ability to produce large volumes of high-performance nacre-like materials. Examination of the structure of the films revealed that at lower tablet concentrations the tablets are well-aligned and well dispersed thorough the volume of the film. At 15vol% and beyond, we observed tablet misalignment and clustering. In order to investigate the impact of these imperfections on material performance we developed large scale finite element models representative of the structure of the composite films. These models show that the mechanical performance significantly degrades with tablet misalignment, and especially at high tablet concentrations. The simulations along with the SEM images therefore quantitatively explain the experimental trends, e.g. the degradation of mechanical properties at high tablet contents. PMID- 26655460 TI - On the effect of calcification volume and configuration on the mechanical behaviour of carotid plaque tissue. AB - Vascular calcification is a complex molecular process that exhibits a number of relatively characteristic morphology patterns in atherosclerotic plaques. Treatment of arterial stenosis by endovascular intervention, involving forceful circumferential expansion of the plaque, can be unpredictable in calcified lesions. The aim of this study was to determine the mechanical stretching mechanisms and define the mechanical limits for circumferentially expanding carotid plaque lesions under the influence of distinct calcification patterns. Mechanical and structural characterisation was performed on 17 human carotid plaques acquired from patients undergoing endarterectomy procedures. The mechanical properties were determined using uniaxial extension tests that stretch the lesions to complete failure along their circumferential axis. Calcification morphology of mechanically ruptured plaque lesions was characterised using high resolution micro computed tomography imaging. Scanning electron microscopy was used to examine the mechanically induced failure sites and to identify the interface boundary conditions between calcified and non-calcified tissue. The mechanical tests produced four distinct trends in mechanical behaviour which corresponded to the calcification patterns that structurally defined each mechanical group. Each calcification pattern produced unique mechanical restraining effects on the plaque tissue stretching properties evidenced by the variation in degree of stretch to failure. Resistance to failure appears to rely on interactions between calcification and non-calcified tissue. Scanning electron microscopy examination revealed structural gradations at interface boundary conditions to facilitate the transfer of stress. This study emphasises the mechanical influence of distinct calcification configurations on plaque expansion properties and highlights the importance of pre-operative lesion characterisation to optimise treatment outcomes. PMID- 26655461 TI - A bioinspired study on the interlaminar shear resistance of helicoidal fiber structures. AB - Helicoidal fibril structures are identified in many natural animals and plants. This research uses an integrated experimental and modeling approach to study the interlaminar shear resistance of bioinspired helicoidal fiber structures. First, helicoidal fiber-reinforced polymeric composites were created using 3D printed fiber cores and polymeric matrices, including plain, ring and helix reinforced helicoidal specimens. Then, monotonic torsional tests were performed to characterize the composite failure under interlaminar shear stresses, and fractographic characterization was conducted to elucidate corresponding fracture mechanisms in each specimen type. Finally, finite element modeling was performed to explore the critical factors on the interlaminar shear resistance of helicoidal fiber structures. The results showed that fiber-matrix modulus ratios and pitch angles of helix reinforcements played important roles on the interlaminar shear resistance of helicoidal fiber structures. PMID- 26655462 TI - In situ Raman spectroscopy of the graphene/water interface of a solution-gated field-effect transistor: electron-phonon coupling and spectroelectrochemistry. AB - We present a novel measurement approach which combines the electrical characterization of solution-gated field-effect transistors based on epitaxial bilayer graphene on 4H-SiC (0001) with simultaneous Raman spectroscopy. By changing the gate voltage, we observed Raman signatures related to the resonant electron-phonon coupling. An analysis of these Raman bands enabled the extraction of the geometrical capacitance of the system and an accurate calculation of the Fermi levels for bilayer graphene. An intentional application of higher gate voltages allowed us to trigger electrochemical reactions, which we followed in situ by Raman spectroscopy. The reactions showed a partially reversible character, as indicated by an emergence/disappearance of peaks assigned to C-H and Si-H vibration modes as well as an increase/decrease of the defect-related Raman D band intensity. Our setup provides a highly interesting platform for future spectroelectrochemical research on electrically-induced sorption processes of graphene on the micrometer scale. PMID- 26655463 TI - A new procedure for amyloid beta oligomers preparation enables the unambiguous testing of their effects on cytosolic and mitochondrial Ca(2+) entry and cell death in primary neurons. AB - Oligomers of the amyloid beta peptide (Abetao) are becoming the most likely neurotoxin in Alzheimer's disease. Controversy remains on the mechanisms involved in neurotoxicity induced by Abetao and the targets involved. We have reported that Abetao promote Ca(2+) entry, mitochondrial Ca(2+) overload and apoptosis in cultured cerebellar neurons. However, recent evidence suggests that some of these effects could be induced by glutamate receptor agonists solved in F12, the media in which Abetao are prepared. Here we have tested the effects of different media on Abetao formation and on cytosolic Ca(2+) concentration ([Ca(2+)]cyt) in rat cerebellar and hippocampal cell cultures. We found that Abetao prepared according to previous protocols but solved in alternative media including saline, MEM and DMEM do not allow oligomer formation and fail to increase [Ca(2+)]cyt. Changes in the oligomerization protocol and supplementation of media with selected salts reported to favor oligomer formation enable Abetao formation. Abetao prepared by the new procedure and containing small molecular weight oligomers increased [Ca(2+)]cyt, promoted mitochondrial Ca(2+) overload and cell death in cerebellar granule cells and hippocampal neurons. These results foster a role for Ca(2+) entry in neurotoxicity induced by Abetao and provide a reliable procedure for investigating the Ca(2+) entry pathway promoted by Abetao. PMID- 26655464 TI - Pinocembrin attenuates MPP(+)-induced neurotoxicity by the induction of heme oxygenase-1 through ERK1/2 pathway. AB - Our recent study demonstrated that pinocembrin (PB), the most abundant flavonoid in propolis, has neuroprotective effect against 1-methyl-4-phenylpyridinium (MPP(+))-induced SH-SY5Y neurotoxicity. However, the mechanism as how PB can induce neuroprotection is not known. In the present study, we demonstrate here that PB increased heme oxygenase-1 (HO-1) expression, which conferred protection against MPP(+)-induced cytotoxicity, because the inhibitor of HO-1 zinc protoporphyrin-IX attenuated the neuroprotection of PB. PB induced the phosphorylation of ERK1/2, and its cytoprotective effect was abolished by ERK1/2 inhibitors. Meanwhile, we have shown that MPP(+) induce the expression in a concentration-dependent manner in SH-SY5Y cells, which was further enhanced by PB. Taken together, the results suggest that PB enhances HO-1 expression to suppress MPP(+)-induced oxidative damage via ERK1/2 signaling pathways. These results revealed the mechanisms of PB enhances HO-1 expression, and contribute to shed some light on the mechanisms whereby PB inhibits the MPP(+)-induced neurotoxicity. These data indicated that PB might provide a valuable therapeutic strategy for the treatment of PD. PMID- 26655466 TI - Threat visibility modulates the defensive brain circuit underlying fear and anxiety. AB - Recent theories distinguish anxiety from fear in the brain. Anxiety is associated with activation in ventromedial prefrontal cortex and hippocampus, while fear is associated with activation in periaqueductal gray, with amygdala involved in processing aspects of both emotional responses. These theories propose that the amount of information available about threat determines which of the two defensive responses is elicited, with fear and anxiety associated with well defined and uncertain threats respectively. However, a direct test of this hypothesis is lacking. Here we provide such a test using fMRI to record participants' brain activity while they performed a computer-based task which required to press a button to move an artificial agent to a target position while an artificial predator chased the agent. In one condition (associated with fear) the predator was visible, while in another condition (associated with anxiety) the predator was invisible. Ventromedial prefrontal cortex, hippocampus, and amygdala showed increased activity when the predator was invisible compared to visible, while the opposite effect was observed in periaqueductal gray. We also observed that participants with high but not low trait-anxiety showed an hippocampal activation with invisible threat at an earlier time stage during the trial. These findings help clarify the neural mechanisms that underlie different defensive emotions and shed light on how these mechanisms may contribute to exaggerated anxiety. PMID- 26655465 TI - Hypoxia-inducible factor-1a contributes to dendritic overgrowth in tuberous sclerosis. AB - Expression of hypoxia-inducible factor 1a (HIF1a) is increased under several pathological conditions such as hyperactive mechanistic target of rapamycin complex 1 (mTORC1) in tuberous sclerosis complex (TSC). Hyperactive mTORC1 and the resulting increased dendritic complexity of neurons are shared molecular and cellular alterations in several neurological disorders associated with cognitive disabilities. Despite some evidence that HIF1a contributes to dendritic overgrowth in vitro, it remains unknown whether increased HIF1a in TSC neurons could contribute to their increased dendritic complexity. To address this use in vivo, we generated TSC neurons by deleting Tsc1 in newborn olfactory bulb (OB) neurons of conditional Tsc1 transgenic mice using neonatal electroporation. In addition to their increased dendritic complexity, Tsc1(null) neurons have been reported to display increased Hif1a mRNA level and HIF1a transcriptional activity. We found that Tsc1(null)-dependent dendritic overgrowth was prevented by knocking down HIF1a or expressing a dominant negative HIF1a. In addition, overexpressing HIF1a in wild-type developing neurons resulted in increased dendritic complexity in vivo. These data highlight that an increase in HIF1a levels contributes to abnormal dendritic patterning in developing neurons under normal conditions and hyperactive mTORC1 conditions as in TSC. PMID- 26655467 TI - Filamin A interacting protein plays a role in proper positioning of callosal projection neurons in the cortex. AB - The callosal connections between the two hemispheres of the neocortex are altered in certain psychiatric disorders including schizophrenia. However, how and why the callosal connection is impaired in patients suffering from psychiatric diseases remain unclear. Filamin A interacting protein (FILIP), whose alteration through mutation relates to schizophrenic pathogenesis, binds to actin-binding proteins and controls neurotransmission. Because cortical excitatory neurons, including callosal projection neurons, migrate to the cortical plate during development, with the actin-binding proteins playing crucial roles during migration, we evaluated whether FILIP is involved in the development of the callosal projection neurons by histological analysis of Filip-knockout mice. The positioning of the callosal projection neurons, especially those expressing Plxnd1, in the superficial layer of the cortex is disturbed in these mice, which suggests that FILIP is a key molecule that links callosal projections to the pathogenesis of brain disorders. PMID- 26655468 TI - Evidence of a molecular boundary lubricant at snakeskin surfaces. AB - During slithering locomotion the ventral scales at a snake's belly are in direct mechanical interaction with the environment, while the dorsal scales provide optical camouflage and thermoregulation. Recent work has demonstrated that compared to dorsal scales, ventral scales provide improved lubrication and wear protection. While biomechanic adaption of snake motion is of growing interest in the fields of material science and robotics, the mechanism for how ventral scales influence the friction between the snake and substrate, at the molecular level, is unknown. In this study, we characterize the outermost surface of snake scales using sum frequency generation (SFG) spectra and near-edge X-ray absorption fine structure (NEXAFS) images collected from recently shed California kingsnake (Lampropeltis californiae) epidermis. SFG's nonlinear optical selection rules provide information about the outermost surface of materials; NEXAFS takes advantage of the shallow escape depth of the electrons to probe the molecular structure of surfaces. Our analysis of the data revealed the existence of a previously unknown lipid coating on both the ventral and dorsal scales. Additionally, the molecular structure of this lipid coating closely aligns to the biological function: lipids on ventral scales form a highly ordered layer which provides both lubrication and wear protection at the snake's ventral surface. PMID- 26655469 TI - Towards a multi-physics modelling framework for thrombolysis under the influence of blood flow. AB - Thrombolytic therapy is an effective means of treating thromboembolic diseases but can also give rise to life-threatening side effects. The infusion of a high drug concentration can provoke internal bleeding while an insufficient dose can lead to artery reocclusion. It is hoped that mathematical modelling of the process of clot lysis can lead to a better understanding and improvement of thrombolytic therapy. To this end, a multi-physics continuum model has been developed to simulate the dissolution of clot over time upon the addition of tissue plasminogen activator (tPA). The transport of tPA and other lytic proteins is modelled by a set of reaction-diffusion-convection equations, while blood flow is described by volume-averaged continuity and momentum equations. The clot is modelled as a fibrous porous medium with its properties being determined as a function of the fibrin fibre radius and voidage of the clot. A unique feature of the model is that it is capable of simulating the entire lytic process from the initial phase of lysis of an occlusive thrombus (diffusion-limited transport), the process of recanalization, to post-canalization thrombolysis under the influence of convective blood flow. The model has been used to examine the dissolution of a fully occluding clot in a simplified artery at different pressure drops. Our predicted lytic front velocities during the initial stage of lysis agree well with experimental and computational results reported by others. Following canalization, clot lysis patterns are strongly influenced by local flow patterns, which are symmetric at low pressure drops, but asymmetric at higher pressure drops, which give rise to larger recirculation regions and extended areas of intense drug accumulation. PMID- 26655470 TI - Close and Allosteric Opening of the Polypeptide-Binding Site in a Human Hsp70 Chaperone BiP. AB - Binding immunoglobulin protein (BiP), an essential and ubiquitous Hsp70 chaperone in the ER, plays a key role in protein folding and quality control. BiP contains two functional domains: a nucleotide-binding domain (NBD) and a substrate-binding domain (SBD). NBD binds and hydrolyzes ATP; the substrates for SBD are extended polypeptides. ATP binding allosterically accelerates polypeptide binding and release. Although crucial to the chaperone activity, the molecular mechanisms of polypeptide binding and allosteric coupling of BiP are poorly understood. Here, we present crystal structures of an intact human BiP in the ATP-bound state, the first intact eukaryotic Hsp70 structure, and isolated BiP-SBD with a peptide substrate bound representing the ADP-bound state. These structures and our biochemical analysis demonstrate that BiP has a unique NBD-SBD interface that is highly conserved only in eukaryotic Hsp70s found in the cytosol and ER to fortify its ATP-bound state and promote the opening of its polypeptide-binding pocket. PMID- 26655471 TI - OprG Harnesses the Dynamics of its Extracellular Loops to Transport Small Amino Acids across the Outer Membrane of Pseudomonas aeruginosa. AB - OprG is an outer membrane protein of Pseudomonas aeruginosa whose function as an antibiotic-sensitive porin has been controversial and not well defined. Circumstantial evidence led to the proposal that OprG might transport hydrophobic compounds by using a lateral gate in the barrel wall thought to be lined by three conserved prolines. To test this hypothesis and to find the physiological substrates of OprG, we reconstituted the purified protein into liposomes and found it to facilitate the transport of small amino acids such as glycine, alanine, valine, and serine, which was confirmed by Pseudomonas growth assays. The structures of wild-type and a critical proline mutant were determined by nuclear magnetic resonance in dihexanoyl-phosphatidylcholine micellar solutions. Both proteins formed eight-stranded beta-barrels with flexible extracellular loops. The interfacial prolines did not form a lateral gate in these structures, but loop 3 exhibited restricted motions in the inactive P92A mutant but not in wild-type OprG. PMID- 26655472 TI - Perturbation of the Conformational Dynamics of an Active-Site Loop Alters Enzyme Activity. AB - The role of internal dynamics in enzyme function is highly debated. Specifically, how small changes in structure far away from the reaction site alter protein dynamics and overall enzyme mechanisms is of wide interest in protein engineering. Using RNase A as a model, we demonstrate that elimination of a single methyl group located >10 A away from the reaction site significantly alters conformational integrity and binding properties of the enzyme. This A109G mutation does not perturb structure or thermodynamic stability, both in the apo and ligand-bound states. However, significant enhancement in conformational dynamics was observed for the bound variant, as probed over nano- to millisecond timescales, resulting in major ligand repositioning. These results illustrate the large effects caused by small changes in structure on long-range conformational dynamics and ligand specificities within proteins, further supporting the importance of preserving wild-type dynamics in enzyme systems that rely on flexibility for function. PMID- 26655473 TI - Pre-Anchoring of Pin1 to Unphosphorylated c-Myc in a Fuzzy Complex Regulates c Myc Activity. AB - Hierarchic phosphorylation and concomitant Pin1-mediated proline isomerization of the oncoprotein c-Myc controls its cellular stability and activity. However, the molecular basis for Pin1 recognition and catalysis of c-Myc and other multisite, disordered substrates in cell regulation and disease is unclear. By nuclear magnetic resonance, surface plasmon resonance, and molecular modeling, we show that Pin1 subdomains jointly pre-anchor unphosphorylated c-Myc1-88 in the Pin1 interdomain cleft in a disordered, or "fuzzy", complex at the herein named Myc Box 0 (MB0) conserved region N-terminal to the highly conserved Myc Box I (MBI). Ser62 phosphorylation in MBI intensifies previously transient MBI-Pin1 interactions in c-Myc1-88 binding, and increasingly engages Pin1PPIase and its catalytic region with maintained MB0 interactions. In cellular assays, MB0 mutated c-Myc shows decreased Pin1 interaction, increased protein half-life, but lowered rates of Myc-driven transcription and cell proliferation. We propose that dynamic Pin1 recognition of MB0 contributes to the regulation of c-Myc activity in cells. PMID- 26655476 TI - siRNA mediated down-regulation of Sprouty2/4 diminishes ischemic brain injury. AB - Down-regulation of Sprouty proteins promotes axon regeneration in lesioned nerves and prevents neurodegeneration following excitotoxic brain injury. In this study, siRNAs directed against Sprouty2 and -4 were stereotactically injected along with the vasoconstrictive peptide endothelin-1 to create cortical infarcts in the adult rat brain. A single injection of Sprouty2/4 siRNAs (25MUM each) significantly decreased Spry2 and Spry4 mRNA levels two days later and diminished the size of the injury area in the subchronic phase following vasoconstriction. Reducing Spry2/4 genetically in mice is neuroprotective and stimulates injury induced astrogliosis which limits neuronal cell death and lesion size. The present results are consistent with the established functions of negative feedback inhibitors of receptor tyrosine kinase signaling pathways in neuronal survival and glial proliferation and suggest a novel role for Spry2/4 as possible pharmacological targets in stroke patients. PMID- 26655474 TI - gamma-TEMPy: Simultaneous Fitting of Components in 3D-EM Maps of Their Assembly Using a Genetic Algorithm. AB - We have developed a genetic algorithm for building macromolecular complexes using only a 3D-electron microscopy density map and the atomic structures of the relevant components. For efficient sampling the method uses map feature points calculated by vector quantization. The fitness function combines a mutual information score that quantifies the goodness of fit with a penalty score that helps to avoid clashes between components. Testing the method on ten assemblies (containing 3-8 protein components) and simulated density maps at 10, 15, and 20 A resolution resulted in identification of the correct topology in 90%, 70%, and 60% of the cases, respectively. We further tested it on four assemblies with experimental maps at 7.2-23.5 A resolution, showing the ability of the method to identify the correct topology in all cases. We have also demonstrated the importance of the map feature-point quality on assembly fitting in the lack of additional experimental information. PMID- 26655477 TI - Expression and colocalization of NMDA receptor and FosB/DeltaFosB in sensitive brain regions in rats after chronic morphine exposure. AB - Research in the last decade demonstrated that the NMDA receptor (NMDAR) has an important role in opiate-induced neural and behavioral plasticity. In addition, increased levels of FosB-like proteins (FosB/DeltaFosB) were found to be related to morphine withdrawal behaviors. However, the relationship between NMDAR and FosB/DeltaFosB in sensitive brain regions during morphine withdrawal is largely unknown. In this study, we aimed to investigate NMDAR dynamics and FosB/DeltaFosB levels in multiple brain regions and whether they are related in sensitive brain regions during morphine abstinence. Quantitative immunohistochemistry was adopted to test NMDAR and FosB/DeltafosB levels during morphine withdrawal in rats. Increased NMDAR and FosB/DeltaFosB levels were found in the nucleus accumbens core (AcbC), nucleus accumbens shell (AcbSh), central amygdaloid nucleuscapsular part (CeC), ventral tegmental area (VTA) and cingulate cortex (Cg). Double immunofluorescence labeling indicated that NMDAR colocalized with Fos/DeltaFosB in these five regions. These results suggest that multiple phenotypic regions are mediated by NMDAR and Fos/DeltaFosB during morphine withdrawal, such as the motivational (AcbC, AcbSh), limbic (CeC, VTA) and executive (Cg) system pathways, and may be the primary targets of NMDAR and Fos/DeltafosB that impact morphine withdrawal behaviors. PMID- 26655475 TI - Interdependent adrenergic receptor regulation of Arc and Zif268 mRNA in cerebral cortex. AB - Norepinephrine is a neurotransmitter that signals by stimulating the alpha1, alpha2 and beta adrenergic receptor (AR). We determined the role of these receptors in regulating the immediate early genes, Activity Regulated Cytoskeleton Associated Protein (Arc) and Zif268 in the rat cerebral cortex. RX821002, an alpha2-AR antagonist, produced Arc and Zif268 elevations across cortical layers. Next we examined the effects of delivering RX821002 with an alpha1-AR antagonist, prazosin, and a beta-AR antagonist, propranolol. RX821002 given with a prazosin and propranolol cocktail, or with each of these antagonists individually, decreased Arc and Zif268 to saline-treated control levels in most cortical layers. Arc and Zif268 levels were also similar to saline-treated control levels when rats were given a prazosin and propranolol cocktail alone, or when each of these antagonists were delivered individually. Taken together, these data reveal that alpha2-AR uniquely exert a tonic inibitory regulation of both Arc and Zif268 compared to alpha1 and beta-AR. However, the ability of RX821002 to increase Arc and Zif268 is interdependent with alpha1 and beta-AR signaling. PMID- 26655478 TI - Transduction of an immortalized olfactory ensheathing glia cell line with the green fluorescent protein (GFP) gene: Evaluation of its neuroregenerative capacity as a proof of concept. AB - Olfactory ensheathing glia (OEG) cells are known to foster axonal regeneration of central nervous system (CNS) neurons. Several lines of reversibly immortalized human OEG (ihOEG) have been previously established that enabled to develop models for their validation in vitro and in vivo. In this work, a constitutively GFP expressing ihOEG cell line was obtained, and named Ts14-GFP. Ts14-GFP neuroregenerative ability was similar to that found for the parental line Ts14 and it can be assayed using in vivo transplantation experimental paradigms, after spinal cord or optic nerve damage. Additionally, we have engineered a low regenerative ihOEG line, hTL2, using lentiviral transduction of the large T antigen from SV40 virus, denominated from now on Ts12. Ts12 can be used as a low regeneration control in these experiments. PMID- 26655479 TI - Ocular Surface Squamous Neoplasia in a Living-Related Conjunctival Limbal Allograft. AB - PURPOSE: To report a single case of ocular surface squamous neoplasia (OSSN) that occurred in a living-related conjunctival limbal allograft (lr-CLAL). METHODS: Case report and literature review. RESULTS: A 70-year-old white man developed OSSN in a histocompatible identical lr-CLAL over 3 years after the surgical procedure. Incisional biopsy was performed, and topical interferon alpha-2b was initiated. Pathology results confirmed carcinoma in situ. After modest results with topical interferon alpha-2b, the patient was treated with excisional biopsy with mitomycin-C (0.04 mg/mL) and cryotherapy. Simultaneously, the lr-CLAL was replaced with a keratolimbal allograft of a deceased donor. The patient maintained 20/25 best-corrected visual acuity at last follow-up. CONCLUSIONS: We present an unusual case of primary OSSN in a recipient of an lr-CLAL that was clinically confined to the borders of the graft. PMID- 26655480 TI - Alkali Burn of the Ocular Surface Associated With a Commonly Used Antifog Agent for Eyewear: Two Cases and a Review of Previous Reports. AB - PURPOSE: To report 2 cases of ocular chemical burns associated with the use of a swim goggle antifog agent and to review the literature for this and similar antifog products. METHODS: Case reports and systematic review of the medical literature, material safety data, product safety reports, and consumer reviews. RESULTS: Two males, one 46 years and the other 41 years, were referred to our clinic with chemical burns of the ocular surface after using the same goggle antifog agent while swimming in a triathlon. Both sustained significant epithelial defects. Fortunately, with prompt treatment, both of our patients returned to their baseline vision within a few weeks without suffering sight threatening complications. CONCLUSIONS: These are the first cases of ocular chemical burn secondary to use of an eyewear antifog agent to be reported in the medical literature. Similar reports found in consumer forums suggest that our cases are not isolated and these products may have the potential to cause vision threatening chemical burns. PMID- 26655481 TI - Analysis of Ocular Manifestation and Genetic Association of Allopurinol-Induced Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis in South Korea. AB - PURPOSE: To describe the clinical characteristics and genetic background of allopurinol-induced Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) in South Korea. METHODS: This is a prospective, noncomparative case series. Visual acuity, detailed medical history, ocular findings, and systemic manifestations of 5 patients (10 eyes) with allopurinol-induced SJS/TEN were recorded. The acute ocular involvement score and the chronic ocular manifestation score were graded on scales of 0-3 and 0-39, respectively, based on severity. Human leukocyte antigen (HLA) genotyping was also performed during the hospitalization. RESULTS: Three patients were diagnosed with SJS, and 2 with TEN. Mild ocular involvement with only conjunctival hyperemia (acute ocular involvement score <= 1) was present in all 10 eyes during the acute stage. Patients were treated with systemic steroids and topical antibiotics, steroids, and preservative-free artificial tears, with rinsing of the ocular surface, in the acute stages of SJS/TEN. In the final follow-up, none of the patients had developed severe chronic ocular complications (chronic ocular manifestation score <= 8), including keratinization, corneal conjunctivalization, mucocutaneous junction involvement, or symblepharon. One patient developed bilateral persistent epithelial defects 3 months after the disease onset, which healed after conservative treatment, leaving a bilateral central corneal haze. HLA genotyping showed that 4 of the 5 patients (80%) were positive for HLA-B*58:01. CONCLUSIONS: Allopurinol-induced SJS/TEN might not cause serious acute or chronic complications of the ocular surface. In addition, our HLA genotyping results are consistent with previous studies reporting a strong association between HLA B*58:01 and allopurinol-induced SJS/TEN among Koreans. PMID- 26655482 TI - Improved Evaluation of Postoperative Pain After Photorefractive Keratectomy. AB - PURPOSE: Postoperative pain remains an important limiting factor to the selection of photorefractive keratectomy (PRK). There is a consensus in neurology pain research that pain should be evaluated as a multidimensional concept, which differs from current practice in ophthalmology. The purpose of this paper was to validate the use of multidimensional questionnaires, such as the Brief Pain Inventory (BPI) and the McGill Pain Questionnaire (MPQ), to provide an improved analysis of pain after PRK and to better describe its temporal profile. METHODS: This prospective study included 43 eyes of 43 myopic patients who underwent unilateral PRK. After surgery, usual pain treatment was administered. All of the participants responded to the Visual Analogue Scale (VAS), the BPI and the MPQ 1, 24, 48, 72, and 96 hours after surgery. The internal consistency was evaluated, different postoperative periods were compared, and convergent validity was assessed using correlation testing. RESULTS: The Cronbach alpha test showed high internal consistency for each of the questionnaire subscales. Patients reported higher postoperative pain values at the first measurement of the VAS (4.93 +/- 2.38), MPQ-pain rating index (26.95 +/- 10.58), BPI-pain severity index (14.53 +/ 7.36), and BPI-pain interference index (22.30 +/- 15.13). Almost all of the scales and subscales showed a statistically significant direct correlation with the VAS at all of the evaluation periods. CONCLUSIONS: This study validated the utility of multidimensional questionnaires to expand the assessment of the PRK postoperative pain profile, including intensity and other qualitative aspects. PMID- 26655483 TI - Pediatric Corneal Collagen Cross-Linking: Long-Term Follow-Up of Visual, Refractive, and Topographic Outcomes. AB - PURPOSE: To evaluate the long-term visual, refractive, and topographic outcomes of corneal collagen cross-linking (CXL) in the management of pediatric keratoconus. METHODS: Forty eyes of 40 consecutive patients with progressive keratoconus aged below 19 years were enrolled in this prospective study. All patient eyes underwent CXL with the standard (Dresden) protocol. Uncorrected distance visual acuity, best spectacle-corrected distance visual acuity, manifest refraction, slit-lamp biomicroscopy, corneal topography, corneal aberrometry, and endothelial cell counts were evaluated at baseline and at all postoperative follow-up examinations until month 48. RESULTS: Mean age of patients was 15.2 +/- 1.9 years (10-18 years). Follow-up was 4 years. The mean improvements in uncorrected distance visual acuity (from 0.9 +/- 0.3 logMAR to 0.5 +/- 0.3 logMAR) and best spectacle-corrected distance visual acuity (from 0.4 +/- 0.2 logMAR to 0.1 +/- 0.1 logMAR) were statistically significant at month 48 (P = 0.0001). The mean Kmax decreased from 58.4 +/- 5.5 D at baseline to 57.0 +/- 5.3 D at month 48 (P = 0.04). Significant improvements in topographic and elevation indices and corneal aberrations were also noted after postoperative month 6. There was no change in the mean endothelial cell density (P > 0.05), and there was no progression or sight-threatening complication in any patient eye. CONCLUSIONS: Corneal CXL seems to be safe and effective in halting the progression of keratoconus in pediatric patients at 4-year follow-up. In addition, the procedure provides improvements in visual, refractive, topographic, and corneal aberrometric measurements. PMID- 26655484 TI - Corneal Densitometry, Central Corneal Thickness, and Corneal Central-to Peripheral Thickness Ratio in Patients With Fuchs Endothelial Dystrophy. AB - PURPOSE: The aim of the study was to quantify Scheimpflug corneal densitometry in patients with Fuchs endothelial dystrophy (FED). METHODS: In this study, we retrospectively reviewed the charts and anterior segment data of 49 patients with FED before posterior lamellar keratoplasty and 51 healthy controls. The patients were examined using the Scheimpflug-based Oculus Pentacam. Central corneal thickness (CCT), ring-averaged (on a circle of 2, 2.4-10 mm diameter) noncentral corneal thickness, and densitometry data in different corneal layers and in different annuli were extracted and analyzed. RESULTS: The total corneal light backscatter at total corneal thickness (CT) and at total diameter was significantly higher in the FED group when compared with the control group (FED group: 28.8 +/- 6.7; control group: 24.3 +/- 4.1; P < 0.001). When the corneal surface was divided into concentric annular zones at total CT, the differences were significant only in the 2 central annuli (P < 0.001). The total corneal light backscatter at total CT in the central 0-2 mm annulus correlated moderately with the central corneal thickness (Pearson's correlation = 0.55, P < 0.001). CONCLUSIONS: Corneal light backscatter in the central cornea was greater in patients with FED than in normal subjects. Corneal densitometry enables us to evaluate the optical quality of the cornea in different corneal layers and in different annuli. It is a useful, objective method that, in combination with central corneal thickness and corneal central-to-peripheral thickness ratio, can help to quantify FED severity. PMID- 26655486 TI - Results of Descemet Stripping Automated Endothelial Keratoplasty for the Treatment of Late Corneal Decompensation Secondary to Obstetrical Forceps Trauma. AB - PURPOSE: To describe the clinical outcomes of Descemet stripping automated endothelial keratoplasty (DSAEK) in a series of patients affected by progressive endothelial cell loss leading to corneal decompensation with Descemet membrane (DM) breaks caused by obstetrical forceps trauma. METHODS: Seven amblyopic eyes of 7 patients affected by unilateral visual loss due to increasing corneal edema were included in the study. In all eyes, slit-lamp examination revealed typical DM breaks and diffuse corneal edema: these findings were compatible with a history of obstetrical forceps-assisted delivery. DSAEK was performed in all cases (in 3 eyes combined with phacoemulsification and intraocular lens implantation); visual acuity, refraction, corneal topography, and endothelial cell density were recorded preoperatively and 1 year after surgery. RESULTS: Visual acuity improved in all cases by at least 2 Snellen lines; topographic astigmatism lower than 2.5 diopters was associated with better visual recovery. No intraoperative or postoperative complications were reported, and the corneas remained clear throughout the follow-up. CONCLUSIONS: In eyes with endothelial decompensation secondary to DM breaks caused at birth by forceps injury, DSAEK can be performed uneventfully and restore cornea clarity. However, visual recovery is limited by the preexistent amblyopia, usually resulting from anisometropia and/or high-degree unilateral astigmatism. The results obtained in our patients suggest that low-degree astigmatism may be associated with better visual outcomes. PMID- 26655485 TI - Ocular Surface Disease Index (OSDI) Versus the Standard Patient Evaluation of Eye Dryness (SPEED): A Study of a Nonclinical Sample. AB - PURPOSE: To compare the Standard Patient Evaluation of Eye Dryness (SPEED) and the Ocular Surface Disease Index (OSDI) questionnaires, and to further validate the SPEED questionnaire using the OSDI in a nonclinical sample. METHODS: This was a cross-sectional study involving 657 undergraduate students aged 18-34 years. Subject selection was by systematic random methods. RESULTS: The Cronbach alphas of the SPEED and OSDI questionnaires were 0.895 and 0.897, respectively. Classification of participants based on OSDI grading of severity indicated that the total mean SPEED score were 2.2, 5.0, 6.6 and 9.9 for the asymptomatic, mild, moderate and severe dry eye groups respectively (F(3,653) = 141.3 P < 0.001,eta=0.394). Post hoc testing for all between-group differences was statistically significant (P < 0.05; Tukey test of multiple comparisons). There was a significant correlation between the total scores of the OSDI and SPEED questionnaires (rs = 0.68 P < 0.001). The receiver operating characteristic curve (ROC) of the SPEED questionnaire was plotted, and the area under the curve (AUC) was estimated to be 0.82 (95% CL: 0.79-0.85; P < 0.001). Factor analysis revealed 3 dimensions as responsible for the substantial amount of variance in the data generated by the SPEED questionnaire. CONCLUSIONS: The SPEED questionnaire was good in separating asymptomatic and symptomatic participants in comparison with the OSDI. This indicates that the SPEED questionnaire is a valid measure for dry eye symptoms even in a nonclinical sample and would be useful in epidemiological studies and clinical practice for dry eye symptom assessment. PMID- 26655487 TI - Comparison of Results of Accelerated Corneal Cross-Linking With Hypo-Osmolar Riboflavin Solution Performed on Corneas Thicker and Thinner Than 400 MUm. AB - PURPOSE: To evaluate the effect of accelerated corneal cross-linking (CXL) according to corneal thickness in keratoconus. METHODS: Patients undergoing corneal CXL (9 mW/cm(2)) with hypo-osmolar riboflavin solution were included in this study. The patients were divided into 2 groups. Group 1 included patients with corneal thickness below 400 MUm (50 eyes from 45 patients), and group 2 included patients with corneal thickness above 400 MUm (50 eyes from 47 patients). Visual acuity (VA), refraction, topographic values, and higher-order aberrations were evaluated in the preoperative term and postoperatively at months 1, 3, and 6. RESULTS: The improvements in VA were significant and similar in both groups [0.25/0.19 logMAR, P = 0.130]. In group 1, the rate of decrease in spherical refraction [0.85/0.27 diopters (D), P = 0.012] and maximum keratometry (Kmax, 2.49/0.68 D, P < 0.001) was significantly higher than that in group 2. The cylindrical change was similar (0.43/0.29 D P = 0.173). Corneal thinning was higher in group 2 (25/40.4 MUm P < 0.001). Anterior elevation values decreased at higher rates in group 1 (3.73/0.24 MUm P < 0.001); neither group showed a significant difference in posterior elevation (-0.14/-0.4 MUm P > 0.05). In group 1, all aberration values except trefoil significantly decreased, whereas in group 2 none of the aberrations decreased except the total root mean square. All higher order aberration values decreased at significantly higher rates in group 1 (P < 0.05). CONCLUSIONS: In thin corneas, accelerated corneal CXL provides better anatomical changes; however, the improvement in VA is similar to that in thick corneas. PMID- 26655488 TI - Corneal Alkali Burn From Local Anesthetic Cream. PMID- 26655489 TI - Treatment options for progressive multifocal leukoencephalopathy in HIV-infected persons: current status and future directions. AB - Progressive multifocal encephalopathy (PML) caused by JC virus was frequently encountered in AIDS patients before combination antiretroviral therapy (cART). Incidence decreased and the outcome improved with cART. The immune reconstitution with cART is beneficial for HIV-infected patients and is an effective treatment for PML. However, when it is excessive an inflammatory response immune syndrome might occur with deterioration of PML. So far, no specific therapy has proven efficacious in small clinical trials in spite of some optimistic case reports. Combination of drugs targeted at different stages of JC virus life cycle seems to have a better effect. Passive and active immune therapies, immune competence "boosters" appear promising. New future approaches such as gene editing are not far away. PMID- 26655490 TI - Driving Under the Influence of Alcohol, Marijuana, and Alcohol and Marijuana Combined Among Persons Aged 16-25 Years - United States, 2002-2014. AB - Motor vehicle accidents are the leading cause of death among youths and young adults aged 16-25 years in the United States (1). The prevalence of drinking and driving among high school students aged 16-19 years has declined by 54%, from 22.3% in 1991 to 10.3% in 2011 (2). However, the prevalence of weekend nighttime driving under the influence of marijuana (based on biochemical assays) among drivers aged >=16 years has increased by 48%, from 8.6% in 2007 to 12.6% in 2013 2014 (3). Use of marijuana alone and in combination with alcohol has been shown to impair driving abilities (4-9). This report provides the most recent self reported national estimates of driving under the influence of alcohol, marijuana, and alcohol and marijuana combined among persons aged 16-25 years, using data from the Substance Abuse and Mental Health Services Administration (SAMHSA) National Survey on Drug Use and Health (NSDUH) from 2002-2014. Prevalence data on driving under the influence of both substances were examined for two age groups (16-20 years and 21-25 years) and by sex and race/ethnicity. During 2002-2014, the prevalence of driving under the influence of alcohol alone significantly declined by 59% among persons aged 16-20 years (from 16.2% in 2002 to 6.6% in 2014; p<0.001) and 38% among persons 21-25 years (from 29.1% in 2002 to 18.1% in 2014; p<0.001). In addition, the prevalence of driving under the influence of alcohol and marijuana combined significantly declined by 39%, from 2.3% in 2002 to 1.4% in 2014 (p<0.001) among persons aged 16-20 years and from 3.1% in 2002 to 1.9% in 2014 (p<0.001) among persons aged 21-25 years. The prevalence of driving under the influence of marijuana alone declined 18%, from 3.8% in 2002 to 3.1% in 2014 (p = 0.05) only among persons aged 16-20 years. Effective public safety interventions,* such as minimum legal drinking age laws, prohibition of driving with any alcohol level >0 for persons aged <21 years, targeted mass media campaigns, roadside testing (e.g., sobriety checkpoints), and graduated driver licensing programs (10) have contributed to the decline in driving under the influence of alcohol in this population. These or similar interventions might be useful to prevent driving under the influence of other substances, such as marijuana alone or combined with other substances. PMID- 26655493 TI - Does Fentanyl Lead to Opioid-induced Hyperalgesia in Healthy Volunteers?: A Double-blind, Randomized, Crossover Trial. AB - BACKGROUND: Although opioids in general and remifentanil in particular have been shown to induce hyperalgesia, data regarding fentanyl are scarce. Thus, the authors investigated the effect of fentanyl dosing on pain perception and central sensitization in healthy volunteers using established pain models. METHODS: Twenty-one healthy, male volunteers were included in this randomized, double blind, crossover study and received either intravenous low-dose (1 MUg/kg) or high-dose (10 MUg/kg) fentanyl. Pain intensities and hyperalgesia were assessed by intracutaneous electrical stimulation, and cold pressor pain was used as an additional measure of acute pain. The primary outcome was hyperalgesia from 4.5 to 6.5 h after fentanyl administration. RESULTS: A higher dose of fentanyl led to significantly decreased pain scores as measured by the numeric rating scale (0.83 units lower [95% CI, 0.63 to 1.02]; P < 0.001) but increased areas of hyperalgesia (+30.5% [95% CI, 16.6 to 44.4%]; P < 0.001) from 4.5 to 6.5 h after fentanyl administration. Allodynia did not differ between groups (+4.0% [95% CI, 15.4 to 23.5%]; P = 0.682).The high dose also led to both increased cold pressor pain threshold (+43.0% [95% CI, 29.7 to 56.3%]; P < 0.001) and tolerance (+32.5% [95% CI, 21.7 to 43.4%]; P < 0.001) at 4.5 to 6.5h. In the high-dose group, 19 volunteers (90%) required reminders to breathe, 8 (38%) required supplemental oxygen, and 12 (57%) experienced nausea. CONCLUSIONS: A higher dose of fentanyl increased hyperalgesia from 4.5 to 6.5 h in healthy volunteers while simultaneously decreasing pain scores. PMID- 26655494 TI - Preoperative Score to Predict Postoperative Mortality (POSPOM): Derivation and Validation. AB - BACKGROUND: An accurate risk score able to predict in-hospital mortality in patients undergoing surgery may improve both risk communication and clinical decision making. The aim of the study was to develop and validate a surgical risk score based solely on preoperative information, for predicting in-hospital mortality. METHODS: From January 1, 2010, to December 31, 2010, data related to all surgeries requiring anesthesia were collected from all centers (single hospital or hospitals group) in France performing more than 500 operations in the year on patients aged 18 yr or older (n = 5,507,834). International Statistical Classification of Diseases, 10th revision codes were used to summarize the medical history of patients. From these data, the authors developed a risk score by examining 29 preoperative factors (age, comorbidities, and surgery type) in 2,717,902 patients, and then validated the risk score in a separate cohort of 2,789,932 patients. RESULTS: In the derivation cohort, there were 12,786 in hospital deaths (0.47%; 95% CI, 0.46 to 0.48%), whereas in the validation cohort there were 14,933 in-hospital deaths (0.54%; 95% CI, 0.53 to 0.55%). Seventeen predictors were identified and included in the PreOperative Score to predict PostOperative Mortality (POSPOM). POSPOM showed good calibration and excellent discrimination for in-hospital mortality, with a c-statistic of 0.944 (95% CI, 0.943 to 0.945) in the development cohort and 0.929 (95% CI, 0.928 to 0.931) in the validation cohort. CONCLUSION: The authors have developed and validated POSPOM, a simple risk score for the prediction of in-hospital mortality in surgical patients. PMID- 26655495 TI - Antisense oligonucleotide-directed inhibition of nonsense-mediated mRNA decay. AB - Nonsense-mediated mRNA decay (NMD) is a cellular quality-control mechanism that is thought to exacerbate the phenotype of certain pathogenic nonsense mutations by preventing the expression of semi-functional proteins. NMD also limits the efficacy of read-through compound (RTC)-based therapies. Here, we report a gene specific method of NMD inhibition using antisense oligonucleotides (ASOs) and combine this approach with an RTC to effectively restore the expression of full length protein from a nonsense-mutant allele. PMID- 26655496 TI - Generation of serotonin neurons from human pluripotent stem cells. AB - Serotonin neurons located in the raphe nucleus of the hindbrain have crucial roles in regulating brain functions and have been implicated in various psychiatric disorders. Yet functional human serotonin neurons are not available for in vitro studies. Through manipulation of the WNT pathway, we demonstrate efficient differentiation of human pluripotent stem cells (hPSCs) to cells resembling central serotonin neurons, primarily those located in the rhombomeric segments 2-3 of the rostral raphe, which participate in high-order brain functions. The serotonin neurons express a series of molecules essential for serotonergic development, including tryptophan hydroxylase 2, exhibit typical electrophysiological properties and release serotonin in an activity-dependent manner. When treated with the FDA-approved drugs tramadol and escitalopram oxalate, they release or uptake serotonin in a dose- and time-dependent manner, suggesting the utility of these cells for the evaluation of drug candidates. PMID- 26655497 TI - Improving drug discovery with high-content phenotypic screens by systematic selection of reporter cell lines. AB - High-content, image-based screens enable the identification of compounds that induce cellular responses similar to those of known drugs but through different chemical structures or targets. A central challenge in designing phenotypic screens is choosing suitable imaging biomarkers. Here we present a method for systematically identifying optimal reporter cell lines for annotating compound libraries (ORACLs), whose phenotypic profiles most accurately classify a training set of known drugs. We generate a library of fluorescently tagged reporter cell lines, and let analytical criteria determine which among them--the ORACL--best classifies compounds into multiple, diverse drug classes. We demonstrate that an ORACL can functionally annotate large compound libraries across diverse drug classes in a single-pass screen and confirm high prediction accuracy by means of orthogonal, secondary validation assays. Our approach will increase the efficiency, scale and accuracy of phenotypic screens by maximizing their discriminatory power. PMID- 26655498 TI - Synthetic long-read sequencing reveals intraspecies diversity in the human microbiome. AB - Identifying bacterial strains in metagenome and microbiome samples using computational analyses of short-read sequences remains a difficult problem. Here, we present an analysis of a human gut microbiome using TruSeq synthetic long reads combined with computational tools for metagenomic long-read assembly, variant calling and haplotyping (Nanoscope and Lens). Our analysis identifies 178 bacterial species, of which 51 were not found using shotgun reads alone. We recover bacterial contigs that comprise multiple operons, including 22 contigs of >1 Mbp. Furthermore, we observe extensive intraspecies variation within microbial strains in the form of haplotypes that span up to hundreds of Kbp. Incorporation of synthetic long-read sequencing technology with standard short-read approaches enables more precise and comprehensive analyses of metagenomic samples. PMID- 26655499 TI - Connexin 32 dysfunction promotes ethanol-related hepatocarcinogenesis via activation of Dusp1-Erk axis. AB - There is abundant epidemiological evidence that heavy alcohol intake contributes to hepatocellular carcinoma (HCC) development. Previous reports indicated that connexin 32 (Cx32), which is a major hepatocyte gap junction protein, is down regulated in chronic liver disease and has a protective role in hepatocarcinogenesis. However, functions of Cx32 in alcohol-related hepatocarcinogenesis have not been clarified. To evaluate them, 9-week-old Cx32 dominant negative transgenic (Tg) rats and their wild-type (Wt) littermates were given 1 % or 5 % ethanol (EtOH) or water ad libitum, for 16 weeks after an intraperitoneal injection of diethylnitrosamine (200 mg/kg). EtOH significantly increased the incidence and multiplicity of HCC and total tumors in a dose dependent manner in Tg rats, but not in Wt rats. Although the number and area of glutathione S-transferase placental form (GST-P) positive foci were not significantly different between the groups, EtOH increased the Ki-67 labeling indices in GST-P positive foci only in Tg rats. EtOH up-regulated phosphorylated Erk1/2 with decrease of the Erk1/2 inhibitor, dual specificity protein phosphatase 1 (Dusp1) in whole livers of Tg and Wt rats. Immunofluorescence staining and quantitative RT-PCR revealed that EtOH significantly increased nucleolar localization of phosphorylated Erk1/2 and contrastingly reduced Dusp1 protein and mRNA expression in GST-P positive foci and HCC of Tg rats as compared to those of Wt rats. These findings suggest that Cx32 dysfunction like in chronic liver disease promoted EtOH-associated hepatocarcinogenesis through dysregulation of Erk-Dusp1 signaling. PMID- 26655500 TI - MULTIMERIN2 binds VEGF-A primarily via the carbohydrate chains exerting an angiostatic function and impairing tumor growth. AB - Angiogenesis is a key process occurring under both physiological and pathological conditions and is a hallmark of cancer. We have recently demonstrated that the extracellular matrix (ECM) molecule MULTIMERIN2 exerts an angiostatic function through the binding to VEGF-A. In this study we identify the region of the molecule responsible for the binding and demonstrate that the interaction involves the carbohydrate chains. MULTIMERIN2 interacts with other VEGF-A isoforms and VEGF family members such as VEGF-B, -C, -D and PlGF-1 suggesting that the molecule may function as a reservoir for different cytokines. In response to VEGF-A165, we show that MULTIMERIN2 impairs the phosphorylation of VEGFR2 at both Y1175 and Y1214 residues, halts SAPK2/p38 activation and negatively affects endothelial cell motility. In addition, MULTIMERIN2 and its active deletion mutant decrease the availability of the VEGFR2 receptor at the EC plasma membrane. The ectopic expression of MULTIMERIN2 or its active deletion mutant led to a striking reduction of tumor-associated angiogenesis and tumor growth. In conclusion, these data pinpoint MULTIMERIN2 as a key angiostatic molecule and disclose the possibility to develop new prognostic tools and improve the management of cancer patients. PMID- 26655503 TI - Enhancement of anti-leukemia activity of NK cells in vitro and in vivo by inhibition of leukemia cell-induced NK cell damage. AB - Acute myeloid leukemia (AML) cells induce, in vitro, NK cell abnormalities (NKCAs) including apoptosis and activating receptor down-regulation. The potential negative impact of AML cells on the therapeutic efficacy of NK cell based strategies prompted us to analyze the mechanisms underlying NKCAs and to develop approaches to protect NK cells from NKCAs. NKCA induction by the AML leukemia cells target a subpopulation of peripheral blood NK cells and is interleukin-2 independent but is abrogated by a long-term culture of NK (LTNK) cells at 37 degrees C. LTNK cells displayed a significantly enhanced ability to damage AML cells in vitro and inhibited the subcutaneous growth of ML-2 cells grafted into CB17 SCID mice. Actinomycin D restored the susceptibility of LTNK cells to NKCAs while TAPI-0, a functional analog of the tissue inhibitor of metalloproteinase (TIMP) 3, inhibits ML-2 cell-induced NKCAs suggesting that the generation of NK cell resistance to NKCAs involves RNA transcription and metalloproteinase (MPP) inactivation. This conclusion is supported by the reduced susceptibility to AML cell-induced NKCAs of LTNK cells in which TIMP3 gene and protein are over-expressed. This information may contribute to the rational design of targeted strategies to enhance the efficacy of NK cell-based immunotherapy of AML with haploidentical NK cells. PMID- 26655501 TI - The CNGRC-GG-D(KLAKLAK)2 peptide induces a caspase-independent, Ca2+-dependent death in human leukemic myeloid cells by targeting surface aminopeptidase N/CD13. AB - The CD13 antigen's binding site for the Asn-Gly-Arg (NGR) motif enables NGR containing chemotherapeutic drugs to be delivered to CD13-positive tumours. Human CD13-positive acute myeloid leukemia (AML) cells proliferate abnormally and escape death. Here, we show that the CNGRC-GG-D(KLAKLAK)2 peptide induces death in AML cell lines (U937, THP-1, NB4, HL-60) and primary blood cells from AML patients. Cell death was characterized as a caspase-independent mechanism, without DNA fragmentation, but phosphatidylserine externalization and membrane disruption. Our results demonstrate in U937 cells that (i) the NGR-peptide triggers the loss of mitochondrial potential(DeltaPsim) and generates superoxide anion (O2-), (ii) N-acetyl-L-cysteine (NAC) and extra/intracellular Ca2+ chelators (BAPTA) prevent both O2- production and cell death, (iii) the Ca2+ channel blocker nifedipine prevents cell death (indicating that Ca2+ influx is the initial death trigger), and (iv) BAPTA, but not NAC, prevents DeltaPsim loss (suggesting O2- is a mitochondrial downstream effector). AML cell lines and primary blasts responding to the lethal action of NGR-peptide express promatrix metalloproteinase-12 (proMMP-12) and its substrate progranulin (an 88 kDa cell survival factor). A cell-free assay highlighted proMMP-12 activation by O2-. Accordingly, NGR-peptide's downregulation of 88 kDa progranulin protein was prevented by BAPTA and NAC. Conversely, AML blast resistance to NGR-peptide is associated with the expression of a distinct, 105 kDa progranulin isoform. These results indicate that CNGRC-GG-D(KLAKLAK)2 induces death in AML cells through the Ca2+-mitochondria-O2.-pathway, and support the link between proMMP-12 activation and progranulin cleavage during cell death. Our findings may have implications for the understanding of tumour biology and treatment. PMID- 26655502 TI - IGF-I induces upregulation of DDR1 collagen receptor in breast cancer cells by suppressing MIR-199a-5p through the PI3K/AKT pathway. AB - Discoidin Domain Receptor 1 (DDR1) is a collagen receptor tyrosine-kinase that contributes to epithelial-to-mesenchymal transition and enhances cancer progression. Our previous data indicate that, in breast cancer cells, DDR1 interacts with IGF-1R and positively modulates IGF-1R expression and biological responses, suggesting that the DDR1-IGF-IR cross-talk may play an important role in cancer. In this study, we set out to evaluate whether IGF-I stimulation may affect DDR1 expression. Indeed, in breast cancer cells (MCF-7 and MDA-MB-231) IGF I induced significant increase of DDR1 protein expression, in a time and dose dependent manner. However, we did not observe parallel changes in DDR1 mRNA. DDR1 upregulation required the activation of the PI3K/AKT pathway while the ERK1/2, the p70/mTOR and the PKC pathways were not involved. Moreover, we observed that DDR1 protein upregulation was induced by translational mechanisms involving miR 199a-5p suppression through PI3K/AKT activation. This effect was confirmed by both IGF-II produced by cancer-associated fibroblasts from human breast cancer and by stable transfection of breast cancer cells with a human IGF-II expression construct. Transfection with a constitutively active form of AKT was sufficient to decrease miR-199a-5p and upregulate DDR1. Accordingly, IGF-I-induced DDR1 upregulation was inhibited by transfection with pre-miR-199a-5p, which also impaired AKT activation and cell migration and proliferation in response to IGF I. These results demonstrate that, in breast cancer cells, a novel pathway involving AKT/miR-199a-5p/DDR1 plays a role in modulating IGFs biological responses. Therefore, this signaling pathway may represent an important target for breast cancers with over-activation of the IGF-IR axis. PMID- 26655504 TI - Proteomics identification of PGAM1 as a potential therapeutic target for urothelial bladder cancer. AB - Urothelial bladder cancer (UBC) is a major global health problem. There have been no major advances for the treatment of UBC in the last 30 years. In this study, we attempted to discover novel candidate therapeutic biomarkers for UBC. We utilized a two-dimensional polyacrylamide gel electrophoresis (2-DE) and ESI-Q TOF MS/MS-based proteomic method to compare and identify differentially expressed proteins in UBC and adjacent normal tissues. Thirty five differentially expressed proteins (over 2-fold, p<0.05) were identified. Further cluster analysis revealed these proteins were mainly involved in metabolism, apoptosis regulation, calcium ion binding and so on. Among them, phosphoglycerate mutase 1 (PGAM1), significantly up-regulated in UBC, was selected for detailed analysis. Immunohistochemical data showed that increased expression of PGAM1 was correlated with the severity of histological grade. Knockdown of PGAM1 expression by RNAi contributed to a marked antitumor activity in vivo. Moreover, we found, upon attenuation of PGAM1, its substrate 3-PG (3-phosphoglycerate) was up-regulated and product 2-PG (2-phosphoglycerate) was down-regulated, which consequently inhibited aerobic glycolysis and oxidative pentose phosphate pathway (PPP) that are essential to cancer cell proliferation. Our finding showed that PGAM1 might serve as a promising therapeutic target for UBC. PMID- 26655506 TI - Point-of-Care Ultrasound in the Perioperative Period. PMID- 26655505 TI - UV irradiation-induced methionine oxidation in human skin keratins: Mass spectrometry-based non-invasive proteomic analysis. AB - Ultraviolet (UV) radiation is the major environmental factor that causes oxidative skin damage. Keratins are the main constituents of human skin and have been identified as oxidative target proteins. We have recently developed a mass spectrometry (MS)-based non-invasive proteomic methodology to screen oxidative modifications in human skin keratins. Using this methodology, UV effects on methionine (Met) oxidation in human skin keratins were investigated. The initial screening revealed that Met(259), Met(262), and Met(296) in K1 keratin were the most susceptible oxidation sites upon UVA (or UVB) irradiation of human tape stripped skin. Subsequent liquid chromatography/electrospray ionization-MS and tandem MS analyses confirmed amino acid sequences and oxidation sites of tryptic peptides D(290)VDGAYMTK(298) (P1) and N(258)MQDMVEDYR(267) (P2). The relative oxidation levels of P1 and P2 increased in a time-dependent manner upon UVA irradiation. Butylated hydroxytoluene was the most effective antioxidant for artifactual oxidation of Met residues. The relative oxidation levels of P1 and P2 after UVA irradiation for 48 h corresponded to treatment with 100mM hydrogen peroxide for 15 min. In addition, Met(259) was oxidized by only UVA irradiation. The Met sites identified in conjunction with the current proteomic methodology can be used to evaluate skin damage under various conditions of oxidative stress. BIOLOGICAL SIGNIFICANCE: We demonstrated that the relative Met oxidation levels in keratins directly reflected UV-induced damages to human tape-stripped skin. Human skin proteins isolated by tape stripping were analyzed by MS-based non invasive proteomic methodology. Met(259), Met(262), and Met(296) in K1 keratin were the most susceptible oxidation sites upon UV irradiation. Met(259) was oxidized by only UVA irradiation. Quantitative LC/ESI-SRM/MS analyses confirmed a time-dependent increase in the relative oxidation of target peptides (P1 and P2) containing these Met residues, upon UVA irradiation of isolated human skin. The relative oxidation levels of P1 and P2 along with the current proteomic methodology could be applied to the assessment of oxidative stress levels in skin after exposure to sunlight. PMID- 26655507 TI - Imaging Techniques in Emergency Surgeries. PMID- 26655508 TI - Cardiac Imaging-3-Dimensional Echocardiography. PMID- 26655509 TI - Cardiac Imaging: New, Innovative Techniques in Ischemia Detection. PMID- 26655510 TI - Training the Anesthesiologist in Point-of-Care Ultrasound. PMID- 26655511 TI - New Techniques in MRI-Fluid-attenuated Inversion Recovery (FLAIR) Imaging, Diffusion Tensor Imaging (DTI), and MRI-guided Laser-induced Thermotherapy (LITT) for Brain Lesions. PMID- 26655512 TI - Positron Emission Tomography: Basic Principles, New Applications, and Studies Under Anesthesia. PMID- 26655513 TI - fMRI and Anesthesia. AB - BOLD activation studies discussed vary in the anesthetic agent studied (propofol, sevoflurane, and isoflurane), the concentration of the anesthetic (mostly under 0.5MAC or equivalent doses), and the activation paradigm/functional activation. The data analysis technique also differs between the studies. Notwithstanding these variations, the results can be summarized as follows: Higher order association cortices are more sensitive to anesthesia. Higher order regions processing language and semantics (regions in the frontal cortex) are affected at a lower concentration of anesthetic as compared with regions processing auditory stimuli. Whereas primary visual activation regions in the visual cortex and the thalamus are less sensitive, higher order visual spatial attention regions in the parietal cortex are more sensitive to anesthesia. In most studies, the loss of consciousness (no response to call) is achieved at or below 0.5MAC of anesthesia. PMID- 26655514 TI - Functional Connectivity and Anesthesia. AB - Various anesthetic agents at various concentrations have been studied as described above. The analysis techniques for the BOLD fMRI data are also institution and investigator dependent. Despite this variability there seems to be some common patterns in the connectivity effect of various anesthetics/sedatives when the endpoint is LOC. Anesthesia in lower doses does not affect lower-order sensory/motor networks. Anesthetic agents primarily affect cortico-cortical and within-network connectivity. Higher-order networks (such as DMN, ECN, and the salience) are more sensitive to anesthesia.38 Salience network (the term "salience" meaning dominant, important) coordinates the function of the DMN and ECN network. The communication and information processing between the lowerorder networks and the higher-order networks (related to association cortices) is disrupted by anesthesia, leading to LOC. Connectivity in the precuneus, PCC, and posterior inferior parietal cortex (3 regions that are among the most active regions in the awake state) decreases with LOC. PMID- 26655516 TI - Preface. PMID- 26655517 TI - Correct Positioning of Percutaneous Iliosacral Screws With Computer-Navigated Versus Fluoroscopically Guided Surgery in Traumatic Pelvic Ring Fractures. AB - OBJECTIVES: To assess the correct positioning of iliosacral screw in patients with unstable traumatic pelvic ring injury by comparing fluoroscopically guided computer-navigated surgery (CNS) with conventional fluoroscopy (CF) through reviewing postoperative computed tomography (CT) and clinical indicators. DESIGN: A comparative multicenter cohort study. SETTING: Two level I Trauma Centers in the Netherlands. PATIENTS: The computer-navigated group (n = 56) and the CF group (n = 24) were comparable regarding age (mean, 43 years), sex (58%, male), body mass index (25 kg/m), injury severity score (27), injury-to-surgery interval (7 days), and Orthopaedic Trauma Association classification (40% 61-B, 60% 61-C). MAIN OUTCOME MEASUREMENTS: The position of the iliosacral screws was evaluated on postoperative CT. In addition, clinical morbidity and reoperation were assessed. RESULTS: In the CNS group, a total of 111 screws were placed (2.0 per patient), of which 83% were placed correctly. In the CF group, 39 screws (1.6 per patient) were placed, 82% of them correctly.Inadequate fixation included neural foramina hit [12 screws (11%) in the CNS group versus 3 screws (8%) in the CF group, P = 0.76] and extraosseous dislocation [7 screws (6%) vs. 4 screws (10%), respectively, P = 0.47]. Five patients required reoperation, all in the CNS group, P = 0.32. We observed more adequate positioning with increased surgical experience, P = 0.12. CONCLUSIONS: In contrast to what has been suggested by previous studies, we found no benefit from computer-navigated iliosacral screw fixation compared with fluoroscopically guided surgery regarding the correct positioning of iliosacral screw on postoperative CT and related morbidity. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 26655518 TI - Two-Finger Tightness: What Is It? Measuring Torque and Reproducibility in a Simulated Model. AB - OBJECTIVES: Residents in training are often directed to insert screws using "two finger tightness" to impart adequate torque but minimize the chance of a screw stripping in bone. This study seeks to quantify and describe two-finger tightness and to assess the variability of its application by residents in training. METHODS: Cortical bone was simulated using a polyurethane foam block (30-pcf density) that was prepared with predrilled holes for tightening 3.5 * 14-mm long cortical screws and mounted to a custom-built apparatus on a load cell to capture torque data. Thirty-three residents in training, ranging from the first through fifth years of residency, along with 8 staff members, were directed to tighten 6 screws to two-finger tightness in the test block, and peak torque values were recorded. The participants were blinded to their torque values. RESULTS: Stripping torque (2.73 +/- 0.56 N.m) was determined from 36 trials and served as a threshold for failed screw placement. The average torques varied substantially with regard to absolute torque values, thus poorly defining two-finger tightness. Junior residents less consistently reproduced torque compared with other groups (0.29 and 0.32, respectively). CONCLUSIONS: These data quantify absolute values of two-finger tightness but demonstrate considerable variability in absolute torque values, percentage of stripping torque, and ability to consistently reproduce given torque levels. Increased years in training are weakly correlated with reproducibility, but experience does not seem to affect absolute torque levels. These results question the usefulness of two-finger tightness as a teaching tool and highlight the need for improvement in resident motor skill training and development within a teaching curriculum. Torque measuring devices may be a useful simulation tools for this purpose. PMID- 26655519 TI - The Utility of the Tip-Apex Distance in Predicting Axial Migration and Cutout With the Trochanteric Fixation Nail System Helical Blade. AB - OBJECTIVES: To determine whether a tip-apex distance (TAD) <20 mm is associated with a higher rate of axial migration and perforation with the Trochanteric Fixation Nail (TFN) System helical blade implant. DESIGN: Retrospective. SETTING: Level I Trauma Center. PARTICIPANTS: Four hundred forty-three patients surgically treated for proximal femur fractures were identified through a query of Current Procedural Terminology code 27245 from January 2009 to February 2013. A total of 258 patients treated with the TFN helical blade system were included in the study. MAIN OUTCOME MEASURED: The association of axial migration and perforation with the measured TAD. RESULTS: The overall rate of mechanical complications was 10.1%. The average TAD was 20.4 mm. Axial perforation occurred in 8 patients (3.4%). Axial migration up to subchondral bone without perforation occurred in 3 patients (1.1%). Only 1 fracture failed in varus (0.38%). There was a significant difference in the rates of combined axial migration and perforation with a TAD <20 mm (P = 0.03). Logistic regression model demonstrated increased odds for combined axial cutout and migration with TAD less than 20 (odds ratio = 1.15, P = 0.01). CONCLUSIONS: A TAD <20 mm was associated with an increased frequency of axial migration and cutout with the TFN helical blade. LEVEL OF EVIDENCE: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence. PMID- 26655520 TI - The Effect of Implant Failure After Symphyseal Plating on Functional Outcome and General Health. AB - OBJECTIVES: To relate the incidence of implant failure after internal anterior fixation of the pelvic ring to functional outcome and the health-related quality of life in patients. DESIGN: Retrospective chart and radiographic review. SETTING: Level I Trauma center. METHODS: We retrospectively identified all patients who were treated with symphyseal plating for traumatic symphyseal diastasis between January 2003 and December 2013. Patients were asked to complete 2 questionnaires, the SF-36 and the Majeed score. A retrospective chart and radiographic control review were performed on all patients. The following data were collected: demographic data and details regarding the pelvic surgery. Computed tomograms were used to determine fracture classification and quality of reduction. Conventional radiographic follow-up were used to detect implant failure. RESULTS: A total of 37 patients enrolled the study. Implant failure occurred in 11 (30%) patients resulting in the identification of 2 groups, "implant failure" (n = 11) and "intact implants" (n = 26). The baseline characteristics were equal in both groups. The analysis of the questionnaires revealed that the SF-36 score was not significantly different in any of the dimensions between the both groups. Patients in the implant failure group scored higher on all of the Majeed items, including the total Majeed score, but the difference did not reach statistical significance of P < 0.05. CONCLUSIONS: Our study showed comparable results regarding the general health measured by the SF 36 for both groups and higher Majeed scores for patients with implant failure compared with patients with intact implants. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 26655521 TI - Factors associated with crashes involving taxi owners and non-owners: A case of moral hazard and adverse selection? AB - Taxis experience a higher risk of a motor vehicle crash partly because of their much higher levels of exposure on the roads. Although several studies have been conducted to examine the factors associated with the frequency and severity of taxi collisions, little research has been conducted to examine the differences in the factors associated with owner taxis and non-owner taxis. This study finds that collisions involving non-owners are more likely to be associated with poor or risky driving behaviors than collisions involving taxi vehicle owners. This result is consistent with the economic principles of moral hazard and adverse selection. Hence, policy makers responsible for traffic safety, taxi regulation or taxi operations should consider measures to reduce these market inefficiencies and improve the safety of not only taxi drivers but all road users. PMID- 26655522 TI - Modernization of the Driver Behaviour Questionnaire. AB - INTRODUCTION: The current study builds on previous versions of the Driver Behaviour Questionnaire (DBQ) by incorporating a larger sample of driving behaviors targeting inattention, distraction, aggressive driving, and health related to aging. The goals of this study were to determine if the resulting factor structure was consistent with a more contemporary view of unsafe driving behaviors, and to determine whether scores on the factors could predict self reported collisions and police citations. METHODS: The instrument was given to a sample of 3295 drivers ranging in age from 19 to 80+ years old. It was divided in two sections, the first to provide demographic information and driving history data and the second containing 105 driver behavior questions. RESULTS: An exploratory factor analysis resulted in a 65-item scale organized in four factors. The factors were labeled tentatively as Inattention Errors, Age-Related Problems, Distraction and Hurry, and Aggressive Violations. Regression analyses showed that the factors were predictors of self-reported, at-fault collisions and police citations. PRACTICAL IMPLICATIONS: The factor scores found in this research are consistent with a useful theoretical framework for understanding unsafe driver actions, and demonstrate some potential to identify several individual difference variables that predict self-reported collisions and citations. PMID- 26655523 TI - High-throughput single-molecule screen for small-molecule perturbation of splicing and transcription kinetics. AB - In eukaryotes, mRNA synthesis is catalyzed by RNA polymerase II and involves several distinct steps, including transcript initiation, elongation, cleavage, and transcript release. Splicing of RNA can occur during (co-transcriptional) or after (post-transcriptional) RNA synthesis. Thus, RNA synthesis and processing occurs through the concerted activity of dozens of enzymes, each of which is potentially susceptible to perturbation by small molecules. However, there are few, if any, high-throughput screening strategies for identifying drugs which perturb a specific step in RNA synthesis and processing. Here we have developed a high-throughput fluorescence microscopy approach in single cells to screen for inhibitors of specific enzymatic steps in RNA synthesis and processing. By utilizing the high affinity interaction between bacteriophage capsid proteins (MS2, PP7) and RNA stem loops, we are able to fluorescently label the intron and exon of a beta-globin reporter gene in human cells. This approach allows one to measure the kinetics of transcription, splicing and release in both fixed and living cells using a tractable, genetically encoded assay in a stable cell line. We tested this reagent in a targeted screen of molecules that target chromatin readers and writers and identified three compounds that slow transcription elongation without changing transcription initiation. PMID- 26655525 TI - Response to the letter "Pulmonary artery wedge pressure and exercise oscillatory ventilation in pre-capillary pulmonary hypertension". PMID- 26655524 TI - The origin of in situ hybridization - A personal history. AB - In situ hybridization is the technique by which specific RNA or DNA molecules are detected in cytological preparations. Basically it involves formation of a hybrid molecule between an endogenous single-stranded RNA or DNA in the cell and a complementary single-stranded RNA or DNA probe. In its original form the probe was labeled with (3)H and the hybrid was detected by autoradiography. The first successful experiments in 1968 involved detection of the highly amplified ribosomal DNA in oocytes of the frog Xenopus, followed soon after by the reiterated "satellite DNA" in mouse and Drosophila chromosomes. Fluorescent probes were developed about ten years later. PMID- 26655526 TI - Unusual cause of chest pain in a patient with arrhythmogenic right ventricular cardiomyopathy. PMID- 26655527 TI - Infective ascending aortitis complicating suppurative appendicitis. PMID- 26655528 TI - Leukocyte telomere shortening in grown-up patients with congenital heart disease. AB - BACKGROUND/OBJECTIVES: Children with congenital heart disease are exposed by repeated imaging to ionizing radiation, which may have important implications for lifetime health risks. Leukocyte telomere length (LTL), a reliable biomarker of genomic instability, is associated with increased risk of cancer and cardiovascular disease. We investigated LTL in grown-up patients with CHD (GUCHs) and a positive history of medical radiation exposure as well as the influence of functional polymorphisms of genes involved in DNA repair. METHODS: A group of 50 GUCH patients (26 males; age 25.2 +/- 9.0 years) and 50 healthy age/gender matched subjects (20 males; 27.0 +/- 3.1 years) were enrolled. In GUCH patients, the cumulative exposure was estimated as effective dose (ED) in milliSievert. LTL was measured by quantitative RT-PCR. X-ray repair cross complementing-1 (XRCC1) and X-ray repair cross complementing-3 (XRCC3) SNPs (XRCC1Arg399Gln, XRCC1Arg194Tr and XRCC3 Thr241Met) were evaluated. RESULTS: GUCHs showed significantly shorter LTL compared with controls (1.0 +/- 0.3 vs 1.3 +/- 0.4, p = 0.001). A significant inverse correlation between LTL and cumulative radiological ED was observed (r = -0.34, p = 0.03). Patients with Thr/Met XRCC3 or Met/Met XRCC3 genotypes were significantly associated with a significantly shorter LTL compared with wild-type genotype (p = 0.01 for Thr/Met and p = 0.008 for Met/Met). Carriers of XRCC1 194Trp and XRCC3 241Met alleles presented a significant interaction with cumulative radiation dose exposure for LTL (both p interaction = 0.02). CONCLUSIONS: GUCH patients have LTL shortening, suggesting evidence of early biological aging. Common SNPs in DNA repair genes modify the effects of medical exposure to radiation LTL-related degenerative diseases. PMID- 26655529 TI - Transapical off-pump mitral valve repair with Neochord implantation: Early clinical results. AB - BACKGROUND: This prospective study aims to assess early clinical outcomes in patients undergoing Transapical Off-Pump Mitral Valve Intervention with Neochord Implantation (TOP-MINI). METHODS AND RESULTS: Forty-nine patients with severe symptomatic degenerative mitral regurgitation (MR) were treated. Median age was 72 years (IQR 58-78) and median Euroscore-I was 3.26% (IQR 0.88-8.15). Forty-four patients (89.8%) presented with posterior leaflet prolapse (LP), 4 (8.2%) with anterior LP and 1 (2%) with combined disease. Acute procedure success (defined as successful placement of at least 3 neochords with reduction of residual MR to less than 2+) was achieved in all patients. In-hospital mortality was 2%. At 30 days major adverse events included one AMI (2%) successfully treated percutaneously and one sepsis (2%), no stroke or bleeding events occurred. At 3 months overall survival was 98%. MR was absent in 16 patients (33.4%), was grade 1+ in 15 (31.2%), and was grade 2+ in 12 (25%). Five patients (10.4%) developed recurrent severe MR due to anterior native chordae rupture. Four of them were successfully re-operated. At 3 months follow-up freedom from reoperation was 91.7 +/- 4%. CONCLUSIONS: Early results with Neochord procedure indicate that TOP-MINI is feasible and safe. Efficacy is maintained up to 3 months follow-up with significant clinical benefit for the patients. PMID- 26655530 TI - Neutrophil-derived myeloperoxidase promotes atherogenesis and neointima formation in mice. AB - BACKGROUND: Myeloperoxidase (MPO), expressed mainly in neutrophils, is an enzyme linked to inflammation and oxidative stress. MPO is an independent prognostic marker in healthy individuals as well as in patients with coronary artery disease. In this present study we analyze the role of MPO in experimental atherogenesis and neointima formation after vascular injury in mice. METHODS AND RESULTS: 6-8 weeks old apolipoprotein E-deficient (ApoE(-/-)) mice were fed a high-cholesterol diet for 8 weeks with concomitant treatment with two different doses (10 MUg/mg bw vs. 20 MUg/mg bw) of 4-ABAH (MPO inhibitor). Application at lower dosage did not affect oxidative stress, endothelial function and atherosclerotic plaque development. 4-ABAH in higher dosage decreased inflammatory markers and vascular oxidative stress, consecutively improved endothelial function and reduced significantly atherosclerotic plaque development. To assess the role of circulating intracellular MPO, irradiated ApoE(-/-) mice were repopulated with bone marrow-derived cells from MPO(-/-) mice and were fed a high-cholesterol diet for 8 weeks. This MPO deficiency resulted in alleviated inflammation, reduced oxidative stress and improved endothelial function with a significant impact on plaque formation. To understand the possible role of MPO in vascular remodeling, we tested its effects on neointima formation following vascular injury in mice. MPO inhibition by 4-ABAH reduced significantly neointima formation. It was significantly reduced in MPO deficient mice, whereas transfer of spleen-derived neutrophils from WT mice enhanced it. CONCLUSION: Our data suggests a central role of MPO in the pathogenesis of atherogenesis and prefers pharmacological MPO inhibition as a therapeutic strategy for prevention and therapy of atherosclerosis and restenosis. PMID- 26655531 TI - Percutaneous repair of acquired Gerbode defect complicated by hemolysis and acute kidney injury. PMID- 26655532 TI - Postoperative right bundle branch block after closure of ventricular septal defect predicts lower peak heart rate in adulthood. PMID- 26655534 TI - Should postnatal oximetry screening be implemented nationwide in China? A cost effectiveness analysis in three regions with different socioeconomic status. PMID- 26655533 TI - Elevated D-dimer levels predict an adverse outcome in hospitalized patients with acute decompensated heart failure. PMID- 26655535 TI - Heart failure complicating acute myocardial infarction. Does the time of presentation matter? PMID- 26655536 TI - Survived out-of-hospital cardiac arrest due to coronary vasospasm. PMID- 26655537 TI - Increased carotid intima-media thickness and coronary artery disease share more links besides inflammation. PMID- 26655538 TI - A survey of energy drink consumption among young patients presenting to the emergency department with the symptom of palpitations. PMID- 26655539 TI - No evidence to support high-intensity statin in Chinese patients with coronary heart disease. PMID- 26655540 TI - Refugee from Syria presents with chest pain due to arrhythmogenic right ventricular cardiomyopathy. PMID- 26655541 TI - Inappropriate shocks of implantable cardioverter-defibrillator during central venous access: A preventable complication. PMID- 26655542 TI - Three-dimensional speckle-tracking echocardiography for spatial functional assessment of the brachial artery--An option for flow-mediated dilatation? (From the MAGYAR-Healthy Study). PMID- 26655543 TI - Extracorporeal life support for refractory out-of-hospital cardiac arrest: Should we still fight for? A single-centre, 5-year experience. AB - BACKGROUND: Cardiopulmonary resuscitation displays low survival rate after out-of hospital cardiac arrest (OHCA). Extracorporeal life support (ECLS) could be suggested as a rescue therapeutic option in refractory OHCA. The aim of this report is to analyze our experience of ECLS implantation for refractory OHCA. METHODS: We performed a retrospective observational analysis of our prospectively collected database. Patients were divided into a shockable rhythm (SH-R) and a non-shockable rhythm (NSH-R) group according to cardiac rhythm at ECLS implantation. The primary endpoint was survival to hospital discharge with good neurological recovery. RESULTS: From January 2010 to December 2014 we used ECLS in 68 patients (SH-R, n=19, 27.9% vs. NSH-R, n=49, 72.1%) for refractory OHCA. The clinical profile before ECLS implantation was comparable between the groups. Eight (11.7%) patients were successfully weaned from ECLS (SH-R=31.5% vs. NSH R=4.0%, p=0.01) after a mean period of support of 2.1 days (SH-R=4.1 days vs. NSH R=1.4 days, p=0.01). Six (8.8%) patients survived to discharge (SH-R=31.5% vs. NSH-R=0%, p=0.00). In the SH-R group 50% of the survivors were discharged without neurological complications. CONCLUSIONS: ECLS for refractory OHCA should be limited in consideration of its poor, especially neurological, outcome. Non shockable rhythms could be considered as a formal contraindication allowing a concentration of our efforts on the shockable rhythms, where the chances of success are substantial. PMID- 26655544 TI - Left subclavian artery dissection and repair after transcatheter aortic valve implantation; the diameter of the axillary artery is important for axillary intervention. PMID- 26655545 TI - The metabolic syndrome, coronary artery calcium score and cardiovascular risk reclassification. PMID- 26655546 TI - Accelerated growth during childhood is associated with increased arterial stiffness in prepubertal children. PMID- 26655547 TI - Long anterior mitral leaflet causing outflow tract obstruction in a symptomatic patient with hypertrophic cardiomyopathy: The role of mitral valve surgical correction. PMID- 26655549 TI - Mitral regurgitation prior to transcatheter aortic valve implantation influences survival but not symptoms. AB - BACKGROUND: Current data about the impact of concomitant mitral regurgitation (MR) on outcome in patients who undergo transcatheter aortic valve implantation (TAVI) are conflicting. Our purpose was to analyze the clinical course of MR and to assess the influence of MR on survival and clinical status after TAVI. METHODS: We included 375 consecutive patients who underwent TAVI. MR grade and NYHA class were determined before TAVI and at follow-up. RESULTS: In total 171 patients (46%) had MR grade >= 2 at baseline and of these 29% improved to MR grade <= 1 after TAVI. MR grade <= 1 at baseline was present in 204 patients (54%) and of these 17% worsened to grade >= 2 after TAVI. Improvement of MR was associated with absence of atrial fibrillation (OR: 2.35, 95%CI: 1.17-4.71, p = 0.02). Worsening of MR was associated with moderate or more aortic valve regurgitation after TAVI (OR: 4.2, CI: 1.83-9.49, p = 0.001). NYHA class improved at follow-up. Baseline MR grade did not determine the degree of clinical improvement (MR grade <= 1: NYHA >= 3 from 67% to 17%; MR grade >= 2: NYHA >= 3 from 69% to 14%). Although patients with MR grade >= 2 at baseline improved symptomatically, this degree of MR was associated with reduced two year survival compared with patients with MR grade <= 1(mortality 37% vs 26%; HR 1.99; 95% CI 1.27-3.13; p = 0.003). CONCLUSION: In patients who undergo TAVI almost half have MR grade >= 2 prior to the procedure. TAVI had no influence on MR grade at follow up. Although patients with MR grade >= 2 at baseline improved symptomatically after TAVI, concomitant MR at baseline significantly reduced two year survival. PMID- 26655548 TI - Relative efficacy and safety of non-Vitamin K oral anticoagulants for non valvular atrial fibrillation: Network meta-analysis comparing apixaban, dabigatran, rivaroxaban and edoxaban in three patient subgroups. AB - BACKGROUND: Stroke is the most serious clinical consequence of atrial fibrillation, which is the most common cardiac arrhythmia. Non-vitamin K antagonist oral anticoagulants (NOACs) have emerged as efficacious, safe and convenient stroke prevention agents. This updated network meta-analysis focused on the relative efficacy and safety of apixaban compared with dabigatran, rivaroxaban and edoxaban for stroke prevention in (i) patients with CHADS2 score >= 2, (ii) secondary stroke prevention, and (iii) patients with high quality anticoagulation control with warfarin. METHODS AND RESULTS: A fixed-effects network meta-analysis was conducted, including data from four Phase III randomised controlled trials (> 70,000 patients with non-valvular atrial fibrillation). The results of the base-case analysis comparing NOACs with warfarin were broadly in line with the results from the individual trials. Results from the three subgroup analyses were broadly similar to the base case results. For example in patients with CHADS2 score >= 2, apixaban, high-dose dabigatran, rivaroxaban, and high-dose edoxaban had significantly lower hazards of stroke/systemic embolism compared with low-dose edoxaban. Apixaban and low dose edoxaban were associated with significantly lower hazards of major bleeding compared with rivaroxaban and dabigatran 150 mg. However, several treatment comparisons that were significant in the base-case analysis were not significant in the patient subgroups, due to the reduced sample size of the subgroups compared with the overall population. CONCLUSIONS: Among the NOACs, apixaban offered the most favourable efficacy and safety profile in the overall patient population as well as in the three subgroups investigated. PMID- 26655550 TI - Bilateral internal mammary arteries: Truths and facts and a brand new Hypothesis. PMID- 26655551 TI - Association between serum uric acid and atrial fibrillation recurrence following catheter ablation: A meta-analysis. PMID- 26655552 TI - The predictive value of high sensitivity-troponin velocity within the first 6h of presentation for cardiac outcomes regardless of acute coronary syndrome diagnosis. AB - BACKGROUND: Low-range troponin elevations without clear coronary manifestations remain a major diagnostic challenge. We sought to determine if troponin velocity could allow for early identification of patients without an obvious cardiac diagnosis and who are at increased risk for cardiac-specific events. METHODS & RESULTS: All patients presenting to South Australian public hospitals between 1 September 2011 and 30 September 2012, with at least two troponin measurements during the first 6h after ED presentation were included. Diagnoses were classified as 'coronary', 'non-coronary cardiac', and 'non-cardiac' using the International Classification of Diseases 10 codes. The relationship between troponin velocity and cardiac-specific mortality and combined cardiac outcome (death and myocardial infarction) was assessed using Fine and Gray competing risk models in patients with an initial troponin <52 ng/L. Sensitivity analyses were performed using different initial and maximum troponin cut-off values. In total, 7300 patients were identified. A troponin velocity of 2.5 ng/L/h or greater in the non-cardiac (n=2793) patient group was significantly associated with an increased risk for 12-month cardiac mortality (sub-hazard ratio [SHR] 2.90, 95% CI 1.33-6.34) and combined cardiac outcome (SHR 2.08, 95% CI 1.01-4.27). This association was consistent for coronary (n=3835) and non-coronary cardiac (n=672) patient groups, and remained after sensitivity analyses. CONCLUSIONS: The significant association observed across all patient groups suggests that troponin velocity could be used for early risk stratification of patients with low-range troponin elevations without clear cardiac symptoms. These results may help guide future clinical trials aimed at assessing the utility of cardiac-targeted interventions in this challenging patient population. PMID- 26655553 TI - A case of acute decompensated heart failure evaluated by series of exhaled acetone concentrations as noninvasive biomarker of heart failure severity. PMID- 26655554 TI - e-Comment: There is no magic bullet to predict postoperative atrial fibrillation. PMID- 26655555 TI - Genome-wide rare copy number variations contribute to genetic risk for transposition of the great arteries. AB - BACKGROUND: Transposition of the great arteries (TGA) is an uncommon but severe congenital heart malformation of unknown etiology. Rare copy number variations (CNVs) have been implicated in other, more common conotruncal heart defects like tetralogy of Fallot (TOF), but there are as yet no CNV studies dedicated to TGA. METHODS: Using high-resolution genome-wide microarrays and rigorous methods, we investigated CNVs in a group of prospectively recruited adults with TGA (n=101) from a single center. We compared rare CNV burden to well-matched cohorts of controls and TOF cases, adjudicating rarity using 10,113 independent population based controls and excluding all subjects with 22q11.2 deletions. We identified candidate genes for TGA based on rare CNVs that overlapped the same gene in unrelated individuals, and pre-existing evidence suggesting a role in cardiac development. RESULTS: The TGA group was significantly enriched for large rare CNVs (2.3-fold increase, p=0.04) relative to controls, to a degree comparable with the TOF group. Extra-cardiac features were not reliable predictors of rare CNV burden. Smaller rare CNVs helped to narrow critical regions for conotruncal defects at chromosomes 10q26 and 13q13. Established and novel candidate susceptibility genes identified included ACKR3, IFT57, ITGB8, KL, NF1, NKX1-2, RERE, SLC8A1, SOX18, and ULK1. CONCLUSIONS: These data demonstrate a genome-wide role for rare CNVs in genetic risk for TGA. The findings provide further support for a genetically-related spectrum of congenital heart disease that includes TGA and TOF. PMID- 26655556 TI - Anatomical considerations in accessory pathway ablation. PMID- 26655557 TI - A small-gap electrostatic micro-actuator for large deflections. AB - Common quasi-static electrostatic micro actuators have significant limitations in deflection due to electrode separation and unstable drive regions. State-of-the art electrostatic actuators achieve maximum deflections of approximately one third of the electrode separation. Large electrode separation and high driving voltages are normally required to achieve large actuator movements. Here we report on an electrostatic actuator class, fabricated in a CMOS-compatible process, which allows high deflections with small electrode separation. The concept presented makes the huge electrostatic forces within nanometre small electrode separation accessible for large deflections. Electrostatic actuations that are larger than the electrode separation were measured. An analytical theory is compared with measurement and simulation results and enables closer understanding of these actuators. The scaling behaviour discussed indicates significant future improvement on actuator deflection. The presented driving concept enables the investigation and development of novel micro systems with a high potential for improved device and system performance. PMID- 26655558 TI - Induction chemotherapy with docetaxel/cisplatin/5-fluorouracil followed by randomization to two cisplatin-based concomitant chemoradiotherapy schedules in patients with locally advanced head and neck cancer (CONDOR study) (Dutch Head and Neck Society 08-01): A randomized phase II study. AB - PURPOSE: To study the feasibility of induction chemotherapy added to concomitant cisplatin-based chemoradiotherapy (CRT) in patients with locally advanced head and neck cancer (LAHNC). PATIENTS AND METHODS: LAHNC patients were treated with 4 courses of docetaxel/cisplatin/5-fluorouracil (TPF) followed by randomization to either cisplatin 100 mg/m(2) with conventional radiotherapy (cis100 + RT) or cisplatin 40 mg/m(2) weekly with accelerated radiotherapy (cis40 + ART). Primary endpoint was feasibility, defined as receiving >= 90% of the scheduled total radiation dose. Based on power analysis 70 patients were needed. RESULTS: 65 patients were enrolled. The data safety monitoring board advised to prematurely terminate the study, because only 22% and 41% (32% in total) of the patients treated with cis100 + RT (n = 27) and cis40 + ART (n = 29) could receive the planned dose cisplatin during CRT, respectively, even though the primary endpoint was reached. Most common grade 3-4 toxicity was febrile neutropenia (18%) during TPF and dehydration (26% vs 14%), dysphagia (26% vs 24%) and mucositis (22% vs 57%) during cis100 + RT and cis40 + ART, respectively. For the patients treated with cis100 + RT and cis40 + ART, two years progression free survival and overall survival were 70% and 78% versus 72% and 79%, respectively. CONCLUSION: After TPF induction chemotherapy, cisplatin-containing CRT is not feasible in LAHNC patients, because the total planned cisplatin dose could only be administered in 32% of the patients due to toxicity. However, all but 2 patients received more than 90% of the planned radiotherapy. Clinical Trials Information: NCT00774319. PMID- 26655559 TI - Development of peripheral neuropathy and its association with survival during treatment with nab-paclitaxel plus gemcitabine for patients with metastatic adenocarcinoma of the pancreas: A subset analysis from a randomised phase III trial (MPACT). AB - BACKGROUND: In a phase III trial in patients with metastatic pancreatic cancer (MPC), nab-paclitaxel plus gemcitabine (nab-P/Gem) demonstrated greater efficacy but higher rates of peripheral neuropathy (PN) versus Gem. This exploratory analysis aimed to characterise the frequency, duration, and severity of PN with nab-P/Gem in the MPACT study. PATIENTS AND METHODS: Patients with previously untreated MPC received nab-P/Gem or Gem. PN was evaluated using a broad-spectrum group of Standardised Medical Dictionary for Regulatory Activities Queries (SMQ) and graded by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0. A case report form was completed by physicians on day 1 of each cycle (also graded by NCI CTCAE version 3.0). RESULTS: In the nab P/Gem arm, 227/421 patients (54%) experienced any-grade PN and 70 (17%) experienced grade III PN. No grade IV PN was reported. Most early-onset PN events were grade I, and treatment-related grade III PN occurred in 7% of patients who received up to three cycles of nab-P. Of those who developed grade III PN with nab-P/Gem treatment, 30 (43%) improved to grade <= I (median time to improvement = 29 days) and 31 (44%) resumed therapy. Development of PN was associated with efficacy; median overall survival in patients with grade III versus 0 PN was 14.9 versus 5.9 months (hazard ratio, 0.33; P < .0001). CONCLUSIONS: nab-P/Gem was associated with grade III PN in a small percentage of patients. PN development was associated with longer treatment duration and improved survival. Grade III PN was reversible to grade <= I in many patients (median ~ 1 month) NCT00844649. PMID- 26655561 TI - Parent and Friend Social Support and Adolescent Hope. AB - The purpose of this study was to conduct two meta-analyses. The first examined social support from parents in relation to adolescent hope, and the second examined social support from friends in relation to adolescent hope. Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for the literature reviewed, nine published studies or doctoral dissertations completed between 1990 and 2014 met the inclusion criteria. Using meta-analytic techniques and the mean weighted r statistic, the results indicated that social support from friends had a stronger mean effect size (ES = .31) than social support from parents (ES = .21); there was a statistically significant difference between the two ESs. Two of the four moderators for the parent social support-adolescent hope relationship were statistically significant. They were quality score and health status. Implications for school nurses and nurses in all settings are addressed, and conclusions are drawn based on the findings. PMID- 26655562 TI - Cardiac Rehabilitation Enrollment and the Impact of Systematic Nursing Interventions for Postmyocardial Infarction and Stent Patients. AB - A randomized experimental design was used to determine the most effective intervention for enhancing cardiac rehabilitation (CR) enrollment for postmyocardial infarction and stent patients. The 104 subjects (70 males and 34 females; 23-87 years old) were patients with a discharge diagnosis of a myocardial infarction followed by a percutaneous coronary intervention, which included a percutaneous transluminal coronary angioplasty and the placement of one or more coronary stents. Regardless of the intervention, patients who received face-to-face nursing interventions were more likely to enroll in CR than were patients who had indirect interventions, chi(2)(3) = 32.84, p < .001. Patients who experienced an entrance interview were most likely to enroll, chi(2)(1) = 86.80, p < .001. Direct logistic regression determined that the full model was statistically significant for all predictors, chi(2)(5), 105.56, p < .001, with the strongest predictor, the entrance interview, having an odds ratio of 1.73. PMID- 26655560 TI - The Children's Hepatic tumors International Collaboration (CHIC): Novel global rare tumor database yields new prognostic factors in hepatoblastoma and becomes a research model. AB - INTRODUCTION: Contemporary state-of-the-art management of cancer is increasingly defined by individualized treatment strategies. For very rare tumors, like hepatoblastoma, the development of biologic markers, and the identification of reliable prognostic risk factors for tailoring treatment, remains very challenging. The Children's Hepatic tumors International Collaboration (CHIC) is a novel international response to this challenge. METHODS: Four multicenter trial groups in the world, who have performed prospective controlled studies of hepatoblastoma over the past two decades (COG; SIOPEL; GPOH; and JPLT), joined forces to form the CHIC consortium. With the support of the data management group CINECA, CHIC developed a centralized online platform where data from eight completed hepatoblastoma trials were merged to form a database of 1605 hepatoblastoma cases treated between 1988 and 2008. The resulting dataset is described and the relationships between selected patient and tumor characteristics, and risk for adverse disease outcome (event-free survival; EFS) are examined. RESULTS: Significantly increased risk for EFS-event was noted for advanced PRETEXT group, macrovascular venous or portal involvement, contiguous extrahepatic disease, primary tumor multifocality and tumor rupture at enrollment. Higher age (>= 8 years), low AFP (<100 ng/ml) and metastatic disease were associated with the worst outcome. CONCLUSION: We have identified novel prognostic factors for hepatoblastoma, as well as confirmed established factors, that will be used to develop a future common global risk stratification system. The mechanics of developing the globally accessible web-based portal, building and refining the database, and performing this first statistical analysis has laid the foundation for future collaborative efforts. This is an important step for refining of the risk based grouping and approach to future treatment stratification, thus we think our collaboration offers a template for others to follow in the study of rare tumors and diseases. PMID- 26655563 TI - Development and Effects of a Transition Nursing Program for Patients and Family Caregivers at a Neurological ICU in Korea. AB - The purpose of this study was to develop a transition nursing program for patients and family caregivers in neurological intensive care units (ICUs) and to evaluate the effects of the program. A literature review, focus group interviews, analysis of medical records, confirmation of validity, and clinical applicability were used to develop the program, which was tested using a pre- and post-test quasi-experimental design. Participants were recruited in 2011. The experimental group (46 patients and their family caregivers) received the developed program before transferring from the neurological ICU to a ward, whereas the control group (48 patients and their family caregivers) received routine care. The results showed that patients and family caregivers in the experimental group had significantly higher transition readiness and satisfaction with transition nursing and lower transition anxiety and transition stress, and family caregivers in the experimental group had a significantly lower burden of caregiving. PMID- 26655564 TI - When Baby Stops Breathing: Analysis of Mothers' Interviews. AB - Sudden unexplained infant death is responsible for 14% of Indiana's infant mortality. The purpose of this qualitative research study was to describe mothers' experiences when death of an infant occurred suddenly and unexpectedly. Field deputies or social workers interviewed mothers from central Indiana during the child-death team investigations. The Thematic Analysis Program from the Joanna Briggs Institute was used to analyze interview data. Sixteen de-identified interview cases were extracted, and a meta-aggregate method was conducted. The three synthesized themes were Extreme Emotional Shock, We Feel Like We're to Blame, and Working Toward Moving On. Understanding these phenomena from mothers' experience may assist in eliminating risks associated with infant deaths and inform nursing practice and policy. PMID- 26655565 TI - Evaluation of microelectrode materials for direct-current electrocorticography. AB - OBJECTIVE: Direct-current electrocorticography (DC-ECoG) allows a more complete characterization of brain states and pathologies than traditional alternating current recordings (AC-ECoG). However, reliable recording of DC signals is challenging because of electrode polarization-induced potential drift, particularly at low frequencies and for more conducting materials. Further challenges arise as electrode size decreases, since impedance is increased and the potential drift is augmented. While microelectrodes have been investigated for AC-ECoG recordings, little work has addressed microelectrode properties for DC-signal recording. In this paper, we investigated several common microelectrode materials used in biomedical application for DC-ECoG. APPROACH: Five of the most common materials including gold (Au), silver/silver chloride (Ag/AgCl), platinum (Pt), Iridium oxide (IrOx), and platinum-iridium oxide (Pt/IrOx) were investigated for electrode diameters of 300 MUm. The critical characteristics such as polarization impedance, AC current-induced polarization, long-term stability and low-frequency noise were studied in vitro (0.9% saline). The two most promising materials, Pt and Pt/lrOx were further investigated in vivo by recording waves of spreading depolarization, one of the most important applications for DC-ECoG in clinical and basic science research. MAIN RESULTS: Our experimental results indicate that IrOx-based microelectrodes, particularly with composite layers of nanostructures, are excellent in all of the common evaluation characteristics both in vitro and in vivo and are most suitable for multimodal monitoring applications. Pt electrodes suffer high current-induced polarization, but have acceptable long-term stability suitable for DC-ECoG. Major significance. The results of this study provide quantitative data on the electrical properties of microelectrodes with commonly-used materials and will be valuable for development of neural recordings inclusive of low frequencies. PMID- 26655566 TI - The Effect of Emergency Department Boarding on Order Completion. AB - STUDY OBJECTIVE: We identify differences in the process of care for admitted patients who board in the emergency department (ED) compared with admitted patients who are transferred to an inpatient care area. METHODS: This is a retrospective study of a random sample of adult patients admitted through the ED at one urban teaching hospital. Patients who boarded in the ED for at least 6 hours after the decision to admit were matched to similar control patients. Data were collected by 2 trained medical students using a standardized data abstraction tool. All physician orders placed in the first 24 hours after admission orders were signed were identified. The medical record was searched for documentation of order completion. Each order was classified as being executed on time, delayed, or missed. RESULTS: Of 848 patients screened for inclusion in the study, a total of 145 matched case-control pairs were included, making a total of 290 patients. A total of 9,260 distinct orders were identified. Use of a generalized estimating equation that controlled for correlation within subjects showed that orders were less likely to be completed on time for boarders than for controls (odds ratio [OR] 0.46; 95% confidence interval [CI] 0.38 to 0.55). Among boarders, orders were more likely to be either delayed (OR 1.84; 95% CI 1.46 to 2.30) or missed entirely (OR 2.58; 95% CI 1.94 to 3.42). Boarders missed a median of 11 orders during their first 24 hours of admission compared with 6 orders for control patients. CONCLUSION: This study detected an important process difference between boarded patients compared with control patients, which could explain previously suggested outcome differences between these 2 groups. This provides additional support for efforts to move patients to inpatient care areas in a timely fashion rather than board in the ED. PMID- 26655568 TI - A Theory of Island Biogeography for Exotic Species. AB - The theory of island biogeography has played a pivotal role in the way ecologists view communities. However, it does not account for exotic species explicitly, which limits its use as a conservation tool. Here, I present the results of a long-term study of plant communities inhabiting an archipelago of small islands off the coast of New Zealand and derive a modified version of the theory of island biogeography to predict differences in the turnover and diversity of native and exotic species. Empirical results showed that, although species richness of both native and exotic plant species increased with island area, native species consistently outnumbered exotic species. Species turnover increased with species richness in both groups. However, opposite to species-area patterns, turnover increased more rapidly with species richness in exotic species. Empirical results were consistent with the modified version of the theory of island biogeography, which distinguishes exotic species from native species by decoupling extinction rates of exotic species from island area, because they are represented by only small populations at the initial stages of invasion. Overall results illustrate how the theory of island biogeography can be modified to reflect the dynamics of exotic species as they invade archipelagos, expanding its use as a conservation tool. PMID- 26655567 TI - MAPK3/1 is conducive to luteinizing hormone-mediated C-type natriuretic peptide decrease in bovine granulosa cells. AB - C-type natriuretic peptide (CNP) plays a role as an oocyte maturation inhibitor (OMI) in many species, including the bovine. However, the effects of luteinizing hormone (LH) on CNP expression and its potential mechanisms have not reported in the bovine. In the present study, we aimed to study the effects of LH on CNP expression and to illuminate the potential molecular mechanism in this process. Our results showed that LH induced epidermal growth factor receptor (EGFR) phosphorylation, mitogen-activated protein kinase3/1 (MAPK3/1) activation and CNP mRNA decrease in cultured bovine granulosa cells. Further study revealed that LH suppressed CNP expression via the MAPK3/1 signaling pathway, which was activated by the EGFR pathway. In conclusion, our research suggested that MAPK3/1 is involved in LH-mediated decrease of CNP and that this process is related to the EGFR and MAPK3/1 signal pathways. PMID- 26655569 TI - Diversity Increases Indirect Interactions, Attenuates the Intensity of Competition, and Promotes Coexistence. AB - A fundamental assumption of coexistence theory is that competition inevitably decreases species diversity. Consequently, in the quest to understand the ecological regulators of diversity, there has been a great deal of focus on processes with the potential to reduce competitive exclusion. However, the notion that competition must decrease diversity is largely based on the outcome of two species interaction experiments and models, despite the fact that species rarely interact only in pairs in natural systems. In a field experiment, we found that competition among native perennial plants in multispecies assemblages was far weaker than competition between those same species in pairwise arrangements and that indirect interactions appeared to weaken direct competitive effects. These results suggest that community assembly theory based on pairwise approaches may overestimate the strength of competition and likelihood of competitive exclusion in species-rich communities. We also found that Centaurea stoebe, a North American invader, retained strong competitive effects when competing against North American natives in both pairwise and multispecies assemblages. Our experimental results support an emerging body of theory suggesting that complex networks of competing species may generate strong indirect interactions that can maintain diversity and that ecological differentiation may not be necessary to attenuate competition. PMID- 26655570 TI - Long-Distance Rescue and Slow Extinction Dynamics Govern Multiscale Metapopulations. AB - Rare long-distance dispersal is known to be critical for species dynamics, but how the interplay between short- and long-distance colonization influences regional persistence in a fragmented habitat remains poorly understood. We propose a metapopulation model that combines local colonization within habitat islands and long-distance colonization between islands. We study how regional occupancy dynamics are affected by the multiscale colonization process. We find that the island size distribution (ISD) is a key driver of the long-term occupancy dynamics. When the ISD is heterogeneous-that is, when the size of islands is variable-we show that extinction dynamics become very slow. We demonstrate that this behavior is unrelated to the well-known extinction debt near the critical extinction threshold. Hence, this finding questions the equivalence between extinction debt and critical transitions in the context of metapopulation collapse. Furthermore, we show that long-distance colonization can rescue small islands from extinction and sustain a steady regional occupancy. These results provide novel theoretical and practical insights into extinction dynamics and persistence in fragmented habitats and are thus relevant for the design of conservation strategies. PMID- 26655571 TI - Competitive Interactions upon Secondary Contact Drive Elevational Divergence in Tropical Birds. AB - Tropical mountains harbor exceptionally high biodiversity, which is in part due to the marked elevational stratification of tropical biotas. However, the factors that influence the evolution of elevational distributions remain uncertain. I used a database of sister species of tropical montane birds from 41 families and three regions-the Neotropics, the Himalayas, and New Guinea-to test whether patterns of elevational divergence were consistent with (1) a stochastic process, (2) ecological sorting of elevational divergence that occurred in allopatry, or (3) elevational divergence driven by competitive interactions upon secondary contact. The stochastic and ecological sorting hypotheses predict that increased elevational divergence in sympatric sister species is explained by their greater evolutionary age, whereas the competitive interactions hypothesis predicts that elevational divergence is explained by geographical overlap. I found that genetic distances were unrelated to elevational divergence and that allopatric sister species occupied similar elevational distributions regardless of genetic distance in each region. Instead, sympatry was the only significant predictor of elevational divergence; regardless of evolutionary age, sympatric sister species had greater elevational divergence than allopatric sister species in each region, as predicted by the competitive interactions hypothesis. Importantly, this pattern occurred in all three geographic regions, which suggests that competition driven elevational divergence upon secondary contact is a general process of community assembly in tropical montane avifaunas. PMID- 26655572 TI - Interspecific Contact and Competition May Affect the Strength and Direction of Disease-Diversity Relationships for Directly Transmitted Microparasites. AB - The frequency of opportunities for transmission is key to the severity of directly transmitted disease outbreaks in multihost communities. Transmission opportunities for generalist microparasites often arise from competitive and trophic interactions. Additionally, contact heterogeneities within and between species either hinder or promote transmission. General theory incorporating competition and contact heterogeneities for disease-diversity relationships is underdeveloped. Here, we present a formal framework to explore disease-diversity relationships for directly transmitted parasites that infect multiple host species, including influenza viruses, rabies virus, distemper viruses, and hantaviruses. We explicitly include host regulation via intra- and interspecific competition, where the latter can be dependent on or independent of interspecific contact rates (covering resource utilization overlap, habitat selection preferences, and temporal niche partitioning). We examine how these factors interact with frequency- and density-dependent transmission along with traits of the hosts in the assemblage, culminating in the derivation of a relationship describing the propensity for parasite fitness to decrease in species assemblages relative to that in single-host species. This relationship reveals that increases in biodiversity do not necessarily suppress frequency-dependent parasite transmission and that regulation of hosts via interspecific competition does not always lead to a reduction in parasite fitness. Our approach explicitly shows that species identity and ecological interactions between hosts together determine microparasite transmission outcomes in multispecies communities. PMID- 26655573 TI - Dynamic Patterns of Parasitism and Immunity across Host Development Influence Optimal Strategies of Resource Allocation. AB - The integration of physiological mechanisms into life-history theory is an emerging frontier in our understanding of the constraints and drivers of life history evolution. Dynamic patterns of antagonism between developmental and immunological pathways in juvenile insects illustrate the importance of mechanisms for determining life-history strategy optima in the face of trade offs. For example, developmental interference occurs when developmental processes transiently take priority over resources or pathway architecture, preventing allocation to immunity or other traits. We designed a within-host model of infected larval development to explore the impact of developmental dynamics on optimal resource mobilization and allocation strategies as well as on larval resistance and tolerance phenotypes. The model incorporates mechanism-inspired functional forms of developmental interference with immunity against parasites that attack specific larval stages. We find that developmental interference generally increases optimal investment in constitutive immunity and decreases optimal resource mobilization rates, but the results are sensitive to the developmental stage at first infection. Moreover, developmental interference reduces resistance but generally increases tolerance of infection. We demonstrate the potential impact of these dynamics on empirical estimates of host susceptibility and discuss the general implications of incorporating realistic physiological mechanisms and developmental dynamics for life-history theory in insects and other organisms. PMID- 26655574 TI - DNA Methylation and Sex Allocation in the Parasitoid Wasp Nasonia vitripennis. AB - The role of epigenetics in the control and evolution of behavior is being increasingly recognized. Here we test whether DNA methylation influences patterns of adaptive sex allocation in the parasitoid wasp Nasonia vitripennis. Female N. vitripennis allocate offspring sex broadly in line with local mate competition (LMC) theory. However, recent theory has highlighted how genomic conflict may influence sex allocation under LMC, conflict that requires parent-of-origin information to be retained by alleles through some form of epigenetic signal. We manipulated whole-genome DNA methylation in N. vitripennis females using the hypomethylating agent 5-aza-2'-deoxycytidine. Across two replicated experiments, we show that disruption of DNA methylation does not ablate the facultative sex allocation response of females, as sex ratios still vary with cofoundress number as in the classical theory. However, sex ratios are generally shifted upward when DNA methylation is disrupted. Our data are consistent with predictions from genomic conflict over sex allocation theory and suggest that sex ratios may be closer to the optimum for maternally inherited alleles. PMID- 26655575 TI - Female Stick Insects Mate Multiply to Find Compatible Mates. AB - Why females of many species mate multiply in the absence of direct benefits remains an open question in evolutionary ecology. Interacting and mating with multiple males can be costly to females in terms of time, resources, predation risk, and disease transmission. A number of indirect genetic benefits have been proposed to explain such behaviors, but the relative importance of these mechanisms in natural systems remains unclear. We tested for several direct and indirect benefits of polyandry in the walking stick Timema cristinae. We found no evidence of direct benefits with respect to longevity or fecundity. However, male * female genotypic interactions affected egg-hatching success and offspring production independent of relatedness, suggesting that mating with certain males benefits females and that the best male may differ for each female. Furthermore, multiply mated females biased paternity toward one or few males, and the extent of this bias was positively correlated to egg-hatching success. Our data, therefore, provide evidence for indirect benefits through compatibility effects in this species. By mating multiply, females may improve their chances of mating with a compatible male if compatibility cannot be assessed before mating. Such compatibility effects can explain the evolution and maintenance of polyandry in Timema and many other species. PMID- 26655576 TI - Causes and Consequences of Partial Migration in a Passerine Bird. AB - Many animal species have populations in which some individuals migrate and others remain on the breeding grounds. This phenomenon is called partial migration. Despite substantial theoretical work, empirical data on causes and consequences of partial migration remain scarce, mainly because of difficulties associated with tracking individuals over large spatial scales. We used stable hydrogen isotopes in claw material to determine whether skylarks Alauda arvensis from a single breeding population in the Netherlands had migrated or remained resident in the previous winter and investigated whether there were causes or consequences of either strategy. Age and sex had no influence on the propensity to migrate, but larger individuals were more likely to be residents. The wintering strategy was not fixed within individuals. Up to 45% of individuals measured in multiple years switched strategies. Reproductive parameters were not related to the wintering strategy, but individuals that wintered locally experienced lower future return rates, and this was directly correlated with two independent measures of immune function. Our results suggest that partial migration in skylarks is based neither on genetic dimorphism nor on an age- and sex-dependent condition. Instead, the wintering strategy is related to structural size and immune function. These new insights on causes and consequences of partial migration advance our understanding of the ecology, evolution, and coexistence of different life-history strategies. PMID- 26655577 TI - Cichlid Fish Use Coloration as a Cue to Assess the Threat Status of Heterospecific Intruders. AB - The ability to assess the threat posed by competitors, and to respond appropriately, is important for reducing the costs of aggression. In this respect, aggression directed toward heterospecifics is often just as significant as aggression among conspecifics. This is especially true for cichlid fish that share breeding grounds with heterospecifics. Indeed, cichlids are known to differentiate not only between conspecifics that pose different levels of threat but also between heterospecific territorial intruders by directing more aggression toward nonbreeding individuals. To assess whether the ability to make such distinctions could be based on color cues alone, we carried out a field study in which we experimentally presented Amphilophus sagittae cichlid pairs with model intruders of a sympatric congener, Amphilophus xiloaensis, in breeding versus nonbreeding coloration. Consistent with our prediction, we found that A. sagittae exhibited more aggression toward A. xiloaensis models of the latter color type. The results are, to our knowledge, the first to show that territory holders can, based on coloration alone, assess variation among individuals of a species other than their own in the threat posed to offspring survival. PMID- 26655578 TI - Three-Dimensional Camouflage: Exploiting Photons to Conceal Form. AB - Many animals have a gradation of body color, termed "countershading," where the areas that are typically exposed to more light are darker. One hypothesis is that this patterning enhances visual camouflage by making the retinal image of the animal match that of the background, a fundamentally two-dimensional theory. More controversially, countershading may also obliterate cues to three-dimensional (3D) shape delivered by shading. Despite relying on distinct cognitive mechanisms, these two potential functions hitherto have been amalgamated in the literature. It has previously not been possible to validate either hypothesis empirically, because there has been no general theory of optimal countershading that allows quantitative predictions to be made about the many environmental parameters involved. Here we unpack the logical distinction between using countershading for background matching and using it to obliterate 3D shape. We use computational modeling to determine the optimal coloration for the camouflage of 3D shape. Our model of 3D concealment is derived from the physics of light and informed by perceptual psychology: we simulate a 3D world that incorporates naturalistic lighting environments. The model allows us to predict countershading coloration for terrestrial environments, for any body shape and a wide range of ecologically relevant parameters. The approach can be generalized to any light distribution, including those underwater. PMID- 26655579 TI - Local Facilitation May Cause Tipping Points on a Landscape Level Preceded by Early-Warning Indicators. AB - Positive biotic interactions play a significant role in shaping ecological communities. We used an individual-based model to demonstrate that plant facilitation on a microscale may cause ecosystem shifts on a landscape scale that can be announced by generic early-warning indicators. Recruitment of woody plants in harsh environments such as drylands often depends on nurse plants that ameliorate stressful conditions and facilitate the establishment of seedlings under their canopy. We found that these facilitative interactions may cause a treeless and a woodland state to be alternative stable states on a landscape scale if nurse plant effects are strong and if the environment is harsh enough to make facilitation necessary for seedling survival. A corollary is that under such conditions environmental change can bring drylands to tipping points for woody plant encroachment or woodland collapse. We show that the proximity of tipping points may be indicated by slowness of recovery of woody vegetation cover from small perturbations as well as by elevated temporal and spatial autocorrelation and variance. These signs are known to be indicators of critical slowing down. This is the first demonstration that the systemic phenomena of tipping points, announced by critical slowing down as a warning signal, may plausibly arise from microscale individual interactions, such as plant facilitation. PMID- 26655580 TI - Behaviorally Induced Camouflage: A New Mechanism of Avian Egg Protection. AB - When animals potentially occupy diverse microhabitats, how can camouflage be achieved? Here we combine descriptive and experimental methods to uncover a novel form of phenotypic plasticity in the camouflage of bird eggs that may be present in other avian taxa. Soil from the bare substrate adheres to the blue-footed booby's (Sula nebouxii's) pale eggs, which parents manipulate both under and on top of their webs. Analysis of digital images confirmed that dirtiness increases progressively during the first 16 days of the incubation period, making eggs more similar to the nest substrate. Observations of 3,668 single-egg clutches showed that the probability of egg loss declines progressively over the same time frame and then remains low for the rest of the 41-day incubation period. An experiment showed that when chicken eggs are soiled and exposed in artificial booby nests, they are less likely to be taken by Heermann's gulls (Larus heermanni) than clean eggs. PMID- 26655581 TI - A Naturalist's Insight into the Evolution of Signal Redundancy. PMID- 26655582 TI - Improvement of cutaneous microcirculation by cold atmospheric plasma (CAP): Results of a controlled, prospective cohort study. AB - BACKGROUND: Cold atmospheric plasma (CAP) has proven its benefits in the reduction of various bacteria and fungi in both in vitro and in vivo studies. Moreover, CAP generated by dielectric barrier discharge (DBD) promoted wound healing in vivo. Charged particles, chemically reactive species (such as O3, OH, H2O2, O, NxOy), ultraviolet radiation (UV-A and UV-B), strong oscillating electric fields as well as weak electric currents are produced by DBD operated in air. However, wound healing is a complex process, depending on nutrient and oxygen supply via cutaneous blood circulation. Therefore, this study examined the effects of CAP on cutaneous microcirculation in a prospective cohort setting. HYPOTHESIS: Cold atmospheric plasma application enhances cutaneous microcirculation. METHODS: Microcirculatory data of 20 healthy subjects (11 males, 9 females; mean age 35.2 +/- 13.8 years; BMI 24.3 +/- 3.1 kg/m(2)) were recorded continuously at a defined skin area at the radial forearm. Under standardized conditions, microcirculatory measurements were performed using a combined laser Doppler and photospectrometry system. After baseline measurement, CAP was applied by a DBD plasma device for 90 s to the same defined skin area of 22.5 cm(2). Immediately after the application cutaneous microcirculation was assessed for 30 min at the same site. RESULTS: After CAP application, tissue oxygen saturation immediately increased by 24% (63.8 +/- 13.8% from 51.4 +/- 13.2% at baseline, p<0.001) and stayed significantly elevated for 8 min. Cutaneous blood flow increased by 73% (41.0 +/- 31.2 AU from 23.7 +/- 20.8 AU at baseline, p<0.001) and remained upregulated for 11 min. Furthermore, cutaneous blood flow showed two peaks at 14 (29.8 +/- 25.0 AU, p=0.049) and 19 min (29.8 +/ 22.6 AU, p=0.048) after treatment. Postcapillary venous filling pressure continuously increased, but showed no significant change vs. baseline in the non specific BMI group. Subgroup analysis revealed that tissue oxygen saturation, postcapillary venous filling pressure and blood flow increased more in case of a lower BMI. CONCLUSION: CAP increases cutaneous tissue oxygen saturation and capillary blood flow at the radial forearm of healthy volunteers. These results support recently published data on wound healing after CAP treatment. However, further studies are needed to determine if this treatment can improve the reduced microcirculation in diabetic foot ulcers. Moreover, repetitive application protocols have to be compared with a single session treatment approach. PMID- 26655583 TI - Antidepressant short-term and long-term brain effects during self-referential processing in major depression. AB - Acute depression is associated with impaired self-referential processing. Antidepressant effects on the neural bases of self-referential processing in depression are unknown. This study aimed to assess short- and long-term effects of agomelatine on these neural bases in depressed patients and the association between pre-treatment brain activation and remission of depression 6 months later. We conducted a randomized double-blind, placebo-controlled, functional magnetic resonance imaging (fMRI) study during an emotional self-referential task, including three scanning sessions (baseline, after 1 week, and after 7 weeks). Twenty-five depressed outpatients were included, all treated with agomelatine or placebo for 1 week. Then, all patients received agomelatine for 24 weeks. Fourteen matched healthy volunteers (HV) who received placebo for 1 week were also included. After 7 days, only depressed patients receiving agomelatine significantly deactivated the ventrolateral prefrontal cortex during self referential processing, as observed in HV at baseline. After 7 weeks, depressed patients significantly increased the activation of the ventral anterior cingulate cortex. Finally dorsomedial prefrontal cortex and precuneus activations at baseline significantly separated remitters from non-remitters at 24 weeks. In depressed patients, agomelatine had short- and long-term effects on brain structures involved in anhedonia and emotional regulation during self-referential processing. Activation of the dorsomedial prefrontal cortex and precuneus could be informative in the development of biomarker-based treatment of major depression. PMID- 26655584 TI - Functional connectivity correlates of response inhibition impairment in anorexia nervosa. AB - Anorexia nervosa (AN) is a disorder characterized by high levels of cognitive control and behavioral perseveration. The present study aims at exploring inhibitory control abilities and their functional connectivity correlates in patients with AN. Inhibitory control - an executive function that allows the realization of adaptive behavior according to environmental contingencies - has been assessed by means of the Stop-Signal paradigm. The study involved 155 patients with lifetime AN and 102 healthy women. A subsample underwent resting state functional magnetic resonance imaging and was genotyped for COMT and 5 HTTLPR polymorphisms. AN patients showed an impaired response inhibition and a disruption of the functional connectivity of the ventral attention circuit, a neural network implicated in behavioral response when a stimulus occurs unexpected. The 5-HTTLPR genotype appears to significantly interact with the functional connectivity of ventral attention network in explaining task performance in both patients and controls, suggesting a role of the serotoninergic system in mechanisms of response selection. The disruption of the ventral attention network in patients with AN suggests lower efficiency of bottom up signal filtering, which might be involved in difficulties to adapt behavioral responses to environmental needs. Our findings deserve further research to confirm their scientific and therapeutic implications. PMID- 26655585 TI - Correction to "Desformylflustrabromine (dFBr) and [3H]dFBr-Labeled Binding Sites in a Nicotinic Acetylcholine Receptor". PMID- 26655586 TI - Determinants and significance of cerebral oximetry after cardiac arrest: A prospective cohort study. AB - AIM OF THE STUDY: To study the determinants and the evolution of cerebral oximetry determined by near-infrared spectroscopy after out-of-hospital cardiac arrest of cardiac origin during therapeutic hypothermia and rewarming, and to compare cerebral oximetry values between patients with good and bad prognosis. METHODS: In this prospective, non-interventional, single center study, all consecutive patients between 18 and 80 years admitted for out-of-hospital cardiac arrest (OHCA) with a no flow less than 10min, a low flow of less than 50min and a persistent coma after ROSC with Glasgow score equal or less than seven at baseline were included. RESULTS: Between February 2012 and January 2013, 43 patients were admitted for OHCA in our ICU. Twenty-two patients (51%) were discharged with no or minimal neurologic complications (CPC 1-2). Mortality rate in the ICU was 46.5%. Cerebral oximetry (rSO2) was correlated with temperature, heart rhythm, PaO2, hemoglobin, and mean arterial pressure. Mean rSO2 during the 48 first hours was not different between patients with good and bad neurologic outcomes, respectively, 61.8 (5.9) vs. 58.1 (8.8), P=0.13, as during the period of hypothermia. The minimal value of rSO2 during the first 48h was significantly different between patients with good prognosis and those with bad prognosis, respectively, 45.0 (6.8) vs. 31.7 (15.0), P=0.0009. CONCLUSIONS: In this prospective cohort of OHCA patients, main determinants of rSO2 were systemic variables. Monitoring of rSO2 does not allow discriminating patients with good or bad outcome, but could be useful for identifying vulnerable periods for the development of neurologic injury. PMID- 26655587 TI - Fibroblast growth factor 23 (FGF-23) is an early predictor of mortality in patients with cardiac arrest. AB - BACKGROUND: Post-cardiac arrest management has seen significant advances with profound improvements in survival and neurologic outcome. However, early prognostication after return of spontaneous circulation remains most challenging. Biomarkers have evolved as helpful tools in identifying patients who are at increased risk of adverse outcome. While fibroblast growth factor 23 (FGF-23) has recently emerged as a promising predictor of mortality in patients with cardiogenic shock, its role in risk stratification in post-resuscitation management remains unresolved. METHODS: This study included 90 patients who had been resuscitated and transferred to the ICU of the University Hospital Heidelberg. Survivors and non-survivors were retrospectively analyzed for known prognostic biomarkers as well as FGF-23 serum levels 24h and 72 h post cardiac arrest (CA). RESULTS: FGF-23 levels were significantly elevated in non-survivors compared to survivors. ROC analysis of FGF-23 levels at 24h and 72 h post CA yielded an AUC of 0.759 and 0.726, respectively, for prediction of overall survival after 6 months. FGF-23 levels remained as significant prognosticators after adjusting for age, renal function, and initial cardiac rhythm. FGF-23 levels did not show significant differences in patient outcome after stratification for cardiac origin of CA or left ventricular dysfunction. Furthermore, FGF-23 levels were moderately predictive of poor neurologic outcome in ROC analysis on day 1 and day 3 post CA with an AUC of 0.738 and 0.687, respectively. CONCLUSION: This study demonstrates elevated FGF-23 serum levels to be potentially helpful in prediction of mortality and poor neurological outcome as early as 24h post cardiac arrest. PMID- 26655588 TI - Design and testing of multiplex RT-PCR primers for the rapid detection of influenza A virus genomic segments: Application to equine influenza virus. AB - The avian influenza A virus causes respiratory infections in animal species. It can undergo genomic recombination with newly obtained genetic material through an interspecies transmission. However, the process is an unpredictable event, making it difficult to predict the emergence of a new pandemic virus and distinguish its origin, especially when the virus is the result of multiple infections. Therefore, identifying a novel influenza is entirely dependent on sequencing its whole genome. Occasionally, however, it can be time-consuming, costly, and labor intensive when sequencing many influenza viruses. To compensate for the difficulty, we developed a rapid, cost-effective, and simple multiplex RT-PCR to identify the viral genomic segments. As an example to evaluate its performance, H3N8 equine influenza virus (EIV) was studied for the purpose. In developing this protocol to amplify the EIV eight-segments, a series of processes, including phylogenetic analysis based on different influenza hosts, in silico analyses to estimate primer specificity, coverage, and variation scores, and investigation of host-specific amino acids, were progressively conducted to reduce or eliminate the negative factors that might affect PCR amplification. Selectively, EIV specific primers were synthesized with dual priming oligonucleotides (DPO) system to increase primer specificity. As a result, 16 primer pairs were selected to screen the dominantly circulating H3N8 EIV 8 genome segments: PA (3), PB2 (1), PA (3), NP (3), NA8 (2), HA3 (1), NS (1), and M (2). The diagnostic performance of the primers was evaluated with eight sets composing of four segment combinations using viral samples from various influenza hosts. The PCR results suggest that the multiplex RT-PCR has a wide range of applications in detection and diagnosis of newly emerging EIVs. Further, the proposed procedures of designing multiplex primers are expected to be used for detecting other animal influenza A viruses. PMID- 26655589 TI - Computational replication of the patient-specific stenting procedure for coronary artery bifurcations: From OCT and CT imaging to structural and hemodynamics analyses. AB - The optimal stenting technique for coronary artery bifurcations is still debated. With additional advances computational simulations can soon be used to compare stent designs or strategies based on verified structural and hemodynamics results in order to identify the optimal solution for each individual's anatomy. In this study, patient-specific simulations of stent deployment were performed for 2 cases to replicate the complete procedure conducted by interventional cardiologists. Subsequent computational fluid dynamics (CFD) analyses were conducted to quantify hemodynamic quantities linked to restenosis. Patient specific pre-operative models of coronary bifurcations were reconstructed from CT angiography and optical coherence tomography (OCT). Plaque location and composition were estimated from OCT and assigned to models, and structural simulations were performed in Abaqus. Artery geometries after virtual stent expansion of Xience Prime or Nobori stents created in SolidWorks were compared to post-operative geometry from OCT and CT before being extracted and used for CFD simulations in SimVascular. Inflow boundary conditions based on body surface area, and downstream vascular resistances and capacitances were applied at branches to mimic physiology. Artery geometries obtained after virtual expansion were in good agreement with those reconstructed from patient images. Quantitative comparison of the distance between reconstructed and post-stent geometries revealed a maximum difference in area of 20.4%. Adverse indices of wall shear stress were more pronounced for thicker Nobori stents in both patients. These findings verify structural analyses of stent expansion, introduce a workflow to combine software packages for solid and fluid mechanics analysis, and underscore important stent design features from prior idealized studies. The proposed approach may ultimately be useful in determining an optimal choice of stent and position for each patient. PMID- 26655590 TI - Ultrasound strain mapping of Achilles tendon compressive strain patterns during dorsiflexion. AB - Heel lifts are commonly prescribed to patients with Achilles tendinopathy, yet little is known about the effect on tendon compressive strain. The purposes of the current study were to (1) develop a valid and reliable ultrasound elastography technique and algorithm to measure compressive strain of human Achilles tendon in vivo, (2) examine the effects of ankle dorsiflexion (lowering via controlled removal of a heel lift and partial squat) on compressive strain of the Achilles tendon insertion and (3) examine the relative compressive strain between the deep and superficial regions of the Achilles tendon insertion. All tasks started in a position equivalent to standing with a 30mm heel lift. An ultrasound transducer positioned over the Achilles tendon insertion was used to capture radiofrequency images. A non-rigid image registration-based algorithm was used to estimate compressive strain of the tendon, which was divided into 2 regions (superficial, deep). The bland-Altman test and intraclass correlation coefficient were used to test validity and reliability. One-way repeated measures ANOVA was used to compare compressive strain between regions and across tasks. Compressive strain was accurately and reliably (ICC>0.75) quantified. There was greater compressive strain during the combined task of lowering and partial squat compared to the lowering (P=.001) and partial squat (P<.001) tasks separately. There was greater compressive strain in the deep region of the tendon compared to the superficial for all tasks (P=.001). While these findings need to be examined in a pathological population, heel lifts may reduce tendon compressive strain during daily activities. PMID- 26655591 TI - Intradiscal pressure measurements: A challenge or a routine? AB - Intradiscal pressure (IDP) is an essential biomechanical parameter and has been the subject of numerous in vivo and in vitro investigations. Although currently available sensors differ in size and measurement principles, no data exist regarding inter-sensor reliability in measuring IDP. Moreover, although discs of various species vary significantly in size and mechanics, the possible effects of sensor insertion on the IDP have never been investigated. The present in vitro study aimed to address these issues. The synchronized signals of two differently sized pressure transducers (O1.33 and O0.36 mm) obtained during the measurements in two species (bovine and caprine) and their influence on the measured pressure were compared. First, the discs were subjected to three loading periods, and the pressure was measured simultaneously to assess the inter-sensor reliability. In the second test, the effect of the sensor size was evaluated by alternatingly inserting one transducer into the disc while recording the resulting pressure change with the second transducer. Although both sensors yielded similar pressure values (ICC: consistency: 0.964-0.999; absolute agreement: 0.845-0.996) when used simultaneously, the sensor size was determined to influence the measured pressure during the insertion tests. The magnitude of the effect differed between species; it was insignificant in the bovine specimens but significant in the caprine specimens, with a pressure increase of 0.31-0.64 MPa (median: 0.43 MPa) obtained when the larger sensor was inserted. The results suggest that sensor selection for IDP measurements requires special attention and can be crucial for species with smaller disc sizes. PMID- 26655592 TI - Assessment of shear stress related parameters in the carotid bifurcation using mouse-specific FSI simulations. AB - The ApoE(-)(/)(-) mouse is a common small animal model to study atherosclerosis, an inflammatory disease of the large and medium sized arteries such as the carotid artery. It is generally accepted that the wall shear stress, induced by the blood flow, plays a key role in the onset of this disease. Wall shear stress, however, is difficult to derive from direct in vivo measurements, particularly in mice. In this study, we integrated in vivo imaging (micro-Computed Tomography-uCT and ultrasound) and fluid-structure interaction (FSI) modeling for the mouse specific assessment of carotid hemodynamics and wall shear stress. Results were provided for 8 carotid bifurcations of 4 ApoE(-)(/)(-) mice. We demonstrated that accounting for the carotid elasticity leads to more realistic flow waveforms over the complete domain of the model due to volume buffering capacity in systole. The 8 simulated cases showed fairly consistent spatial distribution maps of time averaged wall shear stress (TAWSS) and relative residence time (RRT). Zones with reduced TAWSS and elevated RRT, potential indicators of atherosclerosis-prone regions, were located mainly at the outer sinus of the external carotid artery. In contrast to human carotid hemodynamics, no flow recirculation could be observed in the carotid bifurcation region. PMID- 26655593 TI - Keep at bay!--Abnormal personal space regulation as marker of paranoia in schizophrenia. AB - BACKGROUND: During threat, interpersonal distance is deliberately increased. Personal space regulation is related to amygdala function and altered in schizophrenia, but it remains unknown whether it is particularly associated with paranoid threat. METHODS: We compared performance in two tests on personal space between 64 patients with schizophrenia spectrum disorders and 24 matched controls. Patients were stratified in those with paranoid threat, neutral affect or paranoid experience of power. In the stop-distance paradigm, participants indicated the minimum tolerable interpersonal distance. In the fixed-distance paradigm, they indicated the level of comfort at fixed interpersonal distances. RESULTS: Paranoid threat increased interpersonal distance two-fold in the stop distance paradigm, and reduced comfort ratings in the fixed-distance paradigm. In contrast, patients experiencing paranoid power had high comfort ratings at any distance. Patients with neutral affect did not differ from controls in the stop distance paradigm. Differences between groups remained when controlling for gender and positive symptom severity. Among schizophrenia patients, the stop distance paradigm detected paranoid threat with 93% sensitivity and 83% specificity. CONCLUSIONS: Personal space regulation is not generally altered in schizophrenia. However, state paranoid experience has distinct contributions to personal space regulation. Subjects experiencing current paranoid threat share increased safety-seeking behavior. PMID- 26655594 TI - A single-blind, randomised controlled trial on the effects of lithium and quetiapine monotherapy on the trajectory of cognitive functioning in first episode mania: A 12-month follow-up study. AB - BACKGROUND: Cognitive deficits have been reported during the early stages of bipolar disorder; however, the role of medication on such deficits remains unclear. The aim of this study was to compare the effects of lithium and quetiapine monotherapy on cognitive performance in people following first episode mania. METHODS: The design was a single-blind, randomised controlled trial on a cohort of 61 participants following first episode mania. Participants received either lithium or quetiapine monotherapy as maintenance treatment over a 12-month follow-up period. The groups were compared on performance outcomes using an extensive cognitive assessment battery conducted at baseline, month 3 and month 12 follow-up time-points. RESULTS: There was a significant interaction between group and time in phonemic fluency at the 3-month and 12-month endpoints, reflecting greater improvements in performance in lithium-treated participants relative to quetiapine-treated participants. After controlling for multiple comparisons, there were no other significant interactions between group and time for other measures of cognition. CONCLUSION: Although the effects of lithium and quetiapine treatment were similar for most cognitive domains, the findings imply that early initiation of lithium treatment may benefit the trajectory of cognition, specifically verbal fluency in young people with bipolar disorder. Given that cognition is a major symptomatic domain of bipolar disorder and has substantive effects on general functioning, the ability to influence the trajectory of cognitive change is of considerable clinical importance. PMID- 26655595 TI - Rapid characterization of biotherapeutic proteins by size-exclusion chromatography coupled to native mass spectrometry. AB - High-molecular weight aggregates such as antibody dimers and other side products derived from incorrect light or heavy chain association typically represent critical product-related impurities for bispecific antibody formats. In this study, an approach employing ultra-pressure liquid chromatography size-exclusion separation combined with native electrospray ionization mass spectrometry for the simultaneous formation, identification and quantification of size variants in recombinant antibodies was developed. Samples exposed to storage and elevated temperature(s) enabled the identification of various bispecific antibody size variants. This test system hence allowed us to study the variants formed during formulation and bio-process development, and can thus be transferred to quality control units for routine in-process control and release analytics. In addition, native SEC-UV/MS not only facilitates the detailed analysis of low-abundant and non-covalent size variants during process characterization/validation studies, but is also essential for the SEC-UV method validation prior to admission to the market. PMID- 26655596 TI - Frank Dobson: Human decency is worth fighting for. PMID- 26655597 TI - Erratum: Lateral forces on circularly polarizable particles near a surface. PMID- 26655599 TI - Prelimbic Stimulation Ameliorates Depressive-Like Behaviors and Increases Regional BDNF Expression in a Novel Drug-Resistant Animal Model of Depression. AB - BACKGROUND: Approximately one third of all major depression patients fail to respond to conventional pharmacological antidepressants, and brain stimulation methods pose a promising alternative for this population. Recently, based on repeated multifactorial selective inbreeding of rats for depressive-like behaviors, we introduced a novel animal model for MDD. Rats from this Depressive Rat Line (DRL) exhibit inherent depressive-like behaviors, which are correlated with lower levels of brain-derived neurotrophic factor (BDNF) in specific brain regions. In addition, DRL rats do not respond to antidepressant medication but respond to electroconvulsive treatment, and they can thus be utilized to test the effectiveness of brain stimulation on hereditary, medication-resistant depressive like behaviors. OBJECTIVE: To test the effect of sub-convulsive electrical stimulation (SCES) of the prelimbic cortex, using TMS-like temporal pattern of stimulation, on depressive-like behaviors and regional BDNF levels in DRL rats. METHODS: SCES sessions were administered daily for 10 days through chronically implanted electrodes. Temporal stimulation parameters were similar to those used in TMS for major depression in human patients. Depressive-like behaviors were assayed after treatment, followed by brain extraction and regional BDNF measurements. RESULTS: SCES normalized both the depressive-like behaviors and the reduced BDNF levels observed in DRL rats. Correlation analyses suggest that changes in specific behaviors are mediated, at least in part, by BDNF expression in reward-related brain regions. CONCLUSIONS: Brain stimulation is effective in a drug-resistant, inherited animal model for depression. BDNF alterations in specific regions may mediate different antidepressant effects. PMID- 26655598 TI - ATP regulation in bioproduction. AB - Adenosine-5'-triphosphate (ATP) is consumed as a biological energy source by many intracellular reactions. Thus, the intracellular ATP supply is required to maintain cellular homeostasis. The dependence on the intracellular ATP supply is a critical factor in bioproduction by cell factories. Recent studies have shown that changing the ATP supply is critical for improving product yields. In this review, we summarize the recent challenges faced by researchers engaged in the development of engineered cell factories, including the maintenance of a large ATP supply and the production of cell factories. The strategies used to enhance ATP supply are categorized as follows: addition of energy substrates, controlling pH, metabolic engineering of ATP-generating or ATP-consuming pathways, and controlling reactions of the respiratory chain. An enhanced ATP supply generated using these strategies improves target production through increases in resource uptake, cell growth, biosynthesis, export of products, and tolerance to toxic compounds. PMID- 26655600 TI - Glycation alter the process of Tau phosphorylation to change Tau isoforms aggregation property. AB - The risk of tauopathies depends in part on the levels and modified composition of six Tau isoforms in the human brain. Abnormal phosphorylation of the Tau protein and the shift of the ratio of 3R Tau to 4R Tau are presumed to result in neurofibrillary pathology and neurodegeneration. Glycation has recently been linked to dementia and metabolic syndrome. To determine the contribution of Tau protein glycation and phosphorylation on Tau aggregation propensity, the assembled kinetics were examined in vitro using Thioflavin T fluorescence assays. We found that glycation and phosphorylation have different effects on aggregation propensity in different Tau isoforms. Different Tau proteins play important parts in each tauopathies, but 3R0N, fetal Tau protein, has no effect on tauopathies. Conversely, 4R2N has more modified sites and a higher tendency to aggregate, playing the most important role in 4R tauopathies. Finally, Glycation, which could modulate Tau phosphorylation, may occur before any other modification. It also regulates the 3R to 4R ratio and promotes 4R2N Tau protein aggregation. Decreasing the sites of glycation, as well as shifting other Tau proteins to 3R0N Tau proteins has potential therapeutic implications for tauopathies. PMID- 26655601 TI - Broad neutralization of calcium-permeable amyloid pore channels with a chimeric Alzheimer/Parkinson peptide targeting brain gangliosides. AB - Growing evidence supports a role for brain gangliosides in the pathogenesis of neurodegenerative diseases including Alzheimer's and Parkinson's. Recently we deciphered the ganglioside-recognition code controlling specific ganglioside binding to Alzheimer's beta-amyloid (Abeta1-42) peptide and Parkinson's disease associated protein alpha-synuclein. Cracking this code allowed us to engineer a short chimeric Abeta/alpha-synuclein peptide that recognizes all brain gangliosides. Here we show that ganglioside-deprived neural cells do no longer sustain the formation of zinc-sensitive amyloid pore channels induced by either Abeta1-42 or alpha-synuclein, as assessed by single-cell Ca(2+) fluorescence microscopy. Thus, amyloid channel formation, now considered a key step in neurodegeneration, is a ganglioside-dependent process. Nanomolar concentrations of chimeric peptide competitively inhibited amyloid pore formation induced by Abeta1-42 or alpha-synuclein in cultured neural cells. Moreover, this peptide abrogated the intracellular calcium increases induced by Parkinson's-associated mutant forms of alpha-synuclein (A30P, E46K and A53T). The chimeric peptide also prevented the deleterious effects of Abeta1-42 on synaptic vesicle trafficking and decreased the Abeta1-42-induced impairment of spontaneous activity in rat hippocampal slices. Taken together, these data show that the chimeric peptide has broad anti-amyloid pore activity, suggesting that a common therapeutic strategy based on the prevention of amyloid-ganglioside interactions is a reachable goal for both Alzheimer's and Parkinson's diseases. PMID- 26655603 TI - Reactive gliosis in the pathogenesis of CNS diseases. AB - Astrocytes maintain the homeostasis of the central nervous system (CNS) by e.g. recycling of neurotransmitters and providing nutrients to neurons. Astrocytes function also as key regulators of synaptic plasticity and adult neurogenesis. Any insult to the CNS tissue triggers a range of molecular, morphological and functional changes of astrocytes jointly called reactive (astro)gliosis. Reactive (astro)gliosis is highly heterogeneous and also context-dependent process that aims at the restoration of homeostasis and limits tissue damage. However, under some circumstances, dysfunctional (astro)gliosis can become detrimental and inhibit adaptive neural plasticity mechanisms needed for functional recovery. Understanding the multifaceted and context-specific functions of astrocytes will contribute to the development of novel therapeutic strategies that, when applied at the right time-point, will improve the outcome of diverse neurological disorders. This article is part of a Special Issue entitled: Neuro Inflammation edited by Helga E. de Vries and Markus Schwaninger. PMID- 26655602 TI - Metabolism of (13)C5-hydroxyproline in mouse models of Primary Hyperoxaluria and its inhibition by RNAi therapeutics targeting liver glycolate oxidase and hydroxyproline dehydrogenase. AB - Excessive endogenous oxalate synthesis can result in calcium oxalate kidney stone formation and renal failure. Hydroxyproline catabolism in the liver and kidney contributes to endogenous oxalate production in mammals. To quantify this contribution we have infused Wt mice, Agxt KO mice deficient in liver alanine:glyoxylate aminotransferase, and Grhpr KO mice deficient in glyoxylate reductase, with (13)C5-hydroxyproline. The contribution of hydroxyproline metabolism to urinary oxalate excretion in Wt mice was 22+/-2%, 42+/-8% in Agxt KO mice, and 36%+/-9% in Grhpr KO mice. To determine if blocking steps in hydroxyproline and glycolate metabolism would decrease urinary oxalate excretion, mice were injected with siRNA targeting the liver enzymes glycolate oxidase and hydroxyproline dehydrogenase. These siRNAs decreased the expression of both enzymes and reduced urinary oxalate excretion in Agxt KO mice, when compared to mice infused with a luciferase control preparation. These results suggest that siRNA approaches could be useful for decreasing the oxalate burden on the kidney in individuals with Primary Hyperoxaluria. PMID- 26655605 TI - Resolving the complex structure of molecular networks. AB - The arrangement of molecules in molecular networks determines their physical and chemical properties. Addressing this fundamental issue requires proper structural characterization tools. Due to an overlap, interdigitation, tilting or stacking of molecules revealing the structure of the networks is challenging. Tebi et al (2015 Nanotechnology 27 025704) developed a clever approach that enables accessing the arrangement of individual molecules in complex chemical networks. The proposed method utilizes imaging and manipulation with scanning tunneling microscopy. PMID- 26655604 TI - A cardiac myocyte-restricted Lin28/let-7 regulatory axis promotes hypoxia mediated apoptosis by inducing the AKT signaling suppressor PIK3IP1. AB - RATIONALE: The let-7 family of microRNAs (miRs) regulates critical cell functions, including survival signaling, differentiation, metabolic control and glucose utilization. These functions may be important during myocardial ischemia. MiR-let-7 expression is under tight temporal and spatial control through multiple redundant mechanisms that may be stage-, isoform- and tissue-specific. OBJECTIVE: To determine the mechanisms and functional consequences of miR-let-7 regulation by hypoxia in the heart. METHODS AND RESULTS: MiR-let-7a, -7c and -7g were downregulated in the adult mouse heart early after coronary occlusion, and in neonatal rat ventricular myocytes subjected to hypoxia. Let-7 repression did not require glucose depletion, and occurred at a post-transcriptional level. Hypoxia also induced the RNA binding protein Lin28, a negative regulator of let-7. Hypoxia ineither induced Lin28 nor repressed miR-let-7 in cardiac fibroblasts. Both changes were abrogated by treatment with the histone deacetylase inhibitor trichostatin A. Restoration of let-7g to hypoxic myocytes and to ischemia reperfused mouse hearts in vivo via lentiviral transduction potentiated the hypoxia-induced phosphorylation and activation of Akt, and prevented hypoxia dependent caspase activation and death. Mechanistically, phosphatidyl inositol 3 kinase interacting protein 1 (Pik3ip1), a negative regulator of PI3K, was identified as a novel target of miR-let-7 by a crosslinking technique showing that miR-let-7g specifically targets Pik3ip1 to the cardiac myocyte Argonaute complex RISC. Finally, in non-failing and failing human myocardium, we found specific inverse relationships between Lin28 and miR-let-7g, and between miR-let 7g and PIK3IP1. CONCLUSION: A conserved hypoxia-responsive Lin28-miR-let-7 Pik3ip1 regulatory axis is specific to cardiac myocytes and promotes apoptosis during myocardial ischemic injury. PMID- 26655606 TI - RELATIONSHIP BETWEEN RETINAL THICKNESS AND VISUAL ACUITY IN EYES WITH RETINAL VEIN OCCLUSION TREATED WITH DEXAMETHASONE IMPLANT. AB - PURPOSE: To evaluate the relationship between changes in best-corrected visual acuity (BCVA) and central retinal thickness (CRT) in eyes from two clinical trials of dexamethasone intravitreal implant 0.7 mg for macular edema after branch or central retinal vein occlusion. METHODS: Patients with vision loss as a result of macular edema (>=6-week duration) after branch retinal vein occlusion or central retinal vein occlusion were treated with a single dexamethasone intravitreal implant or sham. Prospectively defined outcomes included BCVA and CRT (as assessed by optical coherence tomography). RESULTS: There was a modest but statistically significant negative linear correlation between changes in CRT and changes in BCVA in both treatment groups at Days 90 and 180 (correlation coefficient: -0.23 to -0.34; P < 0.001). Improvements in BCVA at Day 180 were significantly greater (P < 0.001) in eyes that achieved and maintained CRT <=250 MUm from Day 90 to 180 (mean BCVA improvement: 14 letters; 49% of eyes with >=15 letter gain) than in eyes that never achieved CRT <=250 MUm (mean BCVA improvement: 2 letters; 13% of eyes with >=15-letter gain). CONCLUSION: The greatest improvements in BCVA were seen in eyes that achieved and maintained the greatest improvements in CRT. PMID- 26655607 TI - RETINAL PIGMENT EPITHELIAL TEAR AND ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR THERAPY IN EXUDATIVE AGE-RELATED MACULAR DEGENERATION: Clinical Course and Long Term Prognosis. AB - BACKGROUND: To document the long-term outcome in cases of retinal pigment epithelial (RPE) tears after treatment of vascularized pigment epithelial detachments with anti-vascular endothelial growth factor therapy. METHODS: A retrospective analysis of the long-term outcome of a consecutive series of eyes with RPE tear developed during anti-vascular endothelial growth factor therapy for pigment epithelial detachment associated with choroidal neovascularization or retinal angiomatous proliferation (vascularized pigment epithelial detachment) was performed. Best-corrected visual acuity (BCVA), spectral domain optical coherence tomography, and autofluorescence images and also fluorescein angiograms were analyzed to determine the functional and morphologic development over time. RESULTS: The long-term outcome of 22 eyes (21 patients, 13 women and 8 men; 65-85 years; mean: 76 years) with RPE tear was performed with minimal follow-up of 3 years (range: 3-5 years, mean: 44 months) and re-treatment with different therapeutic strategies. The eyes were differentiated in 2 groups according to the course of BCVA after the first 2 years of follow-up: Group 1 (11 eyes) demonstrated a stabilized or improved BCVA after 2 years and Group 2 (11 eyes) demonstrated a decrease in BCVA after 2 years. The initial BCVA between both groups was comparable. Also the mean initial size of the RPE tear was the same between the 2 groups, the area of the RPE tear decreased continuously during follow-up in Group 1, whereas this was the case in Group 2 only at the beginning of treatment with a further increase of the size of the RPE tear with longer follow-up. This corresponded with a different morphologic development between the two groups. In Group 1, increasing recovery of autofluorescence at the RPE-free area was visible beginning from the outer border, whereas in Group 2, further growth of the neovascular complex in the area of the RPE tear was observed resulting in larger fibrovascular scars. In addition, in both groups, the development of hyperreflective tissue was seen on spectral domain optical coherence tomography in the RPE-free area. The major therapeutic difference between the 2 groups was a significantly larger number of injections especially during the first year in Group 1. CONCLUSION: The development of RPE tear after anti-vascular endothelial growth factor therapy for vascularized pigment epithelial detachment in exudative age-related macular degeneration does not necessarily result in large disciform scars and functional loss, but multiple injections seem to be beneficial especially in the first year. With this strategy, RPE tears seem to be covered by autofluorescent and hyperreflective tissue and a regrowth of the neovascular complex can be prohibited. As a result, photoreceptor cells regain their metabolic support with functional recovery. PMID- 26655608 TI - IMPLICATION OF RECURRENT OR RETAINED FLUID ON OPTICAL COHERENCE TOMOGRAPHY FOR VISUAL ACUITY DURING ACTIVE TREATMENT OF NEOVASCULAR AGE-RELATED MACULAR DEGENERATION WITH A TREAT AND EXTEND PROTOCOL. AB - PURPOSE: Assess the correlation between optical coherence tomography findings and change in vision for patients receiving "treat and extend" protocol ranibizumab for neovascular age-related macular degeneration. METHODS: Optical coherence tomography analysis and best-corrected visual acuity (BCVA) change: mild = 5 to 9 letters, moderate = 10 to 14 letters, and severe >=15 letters. RESULTS: A total of 103 eyes (99 patients, 63% female, 65-91 years) followed for 20.8 +/- 4.9 months. By 12 months, there were 1.38 +/- 0.59 instances of intraretinal fluid (IRF)/subretinal fluid recurrence on optical coherence tomography and 1.25 +/- 1.00 instances of BCVA loss (>=5 letters) per patient. When BCVA was lost, IRF/subretinal fluid was present in 37.3% of cases. Occurrences of severe BCVA loss were less likely to recover vision than when BCVA loss was mild (5.9% vs. 75.6%, P = 0.001). New occurrence of IRF (33.9%) or subretinal fluid (29.6%) was more likely to lead to BCVA loss, compared with dry (16.6%) or persistent IRF (11.9%) or persistent subretinal fluid (14%, P < 0.001). With persistent fluid, any new loss of vision had a lower chance of recovery than when fluid was new in onset (64.3% vs. 85.3%, P = 0.04). CONCLUSION: During ranibizumab treatment, vision can decrease without signs of fluid. When fluid is present, IRF is associated with poorer vision. New occurrence of any fluid on optical coherence tomography is likely to lead to vision loss, but small amounts of persistent fluid can be tolerated without compromising vision. PMID- 26655609 TI - INCREASED POSTERIOR RETINAL VESSELS IN MILD ASYMPTOMATIC FAMILIAL EXUDATIVE VITREORETINOPATHY EYES. AB - PURPOSE: To document a new clinical manifestation in familial exudative vitreoretinopathy (FEVR) eyes, especially in mild asymptomatic eyes with normal vision. METHODS: Twenty individuals with mild Stage I or II FEVR with a conventional "normal-appearing" posterior pole and 20 healthy control eyes were recruited. The crossing numbers of retinal vessels with peripapillary inner reference circle, peripapillary outer reference circle, peripapillary temporal inner arc, peripapillary temporal outer arc, and branching points between the peripapillary outer reference circle and peripapillary inner reference circle were counted. Vessel bifurcation was evaluated by B/CI (defined as the branching number divided by the crossing number on peripapillary inner reference circle) and CO/B (crossing number on peripapillary outer reference circle divided by the branching number) ratios. The inter- and intraobservers' agreements were analyzed. All these parameters were compared between FEVR and control groups. RESULTS: The coefficient of repeatability for the parameters ranged from 2.597 to 5.096, and the intraclass correlation coefficients were all above 0.85. All the parameters showed good interobserver agreement with a narrow range of 95% limit of agreement (from -3.16 to 3.37) and high Pearson correlation (P < 0.001). The mean crossing numbers on peripapillary inner reference circle, peripapillary outer reference circle, peripapillary temporal inner arc, peripapillary temporal outer arc, and the branching numbers were larger in the FEVR group. No significant differences were found in CO/B and B/CI ratios. CONCLUSION: Patients with FEVR have more vessels radiated from the optic disk in the posterior pole. Unlike the increased vessels in the peripheral retina, the increasing pattern of peripapillary vascularity in patients with FEVR does not appear to have a component of overbifurcation. This is a new documented clinical manifestation in patients with FEVR. Attention to an increased or arrangement pattern of retinal vessels may aid in the screening of FEVR. PMID- 26655610 TI - Mighty MyD88 in Health and Disease. PMID- 26655611 TI - RECALCITRANT CYSTOID MACULAR EDEMA AFTER PARS PLANA VITRECTOMY. AB - PURPOSE: To evaluate the outcomes of different types of treatment of chronic cystoid macular edema (CME) after pars plana vitrectomy. METHODS: Retrospective review of eyes that developed chronic CME after pars plana vitrectomy treated with intravitreal triamcinolone acetonide (TCA) with or without the addition of anti-vascular endothelial growth factor. RESULTS: Thirty-nine eyes of 37 patients were included, with a median duration between pars plana vitrectomy and onset of CME of 5 months (interquartile range, 3-12). In most eyes (66.7%), the main indication for surgery was for vitreomacular interface disorders, such as epiretinal membrane, vitreomacular traction, and macular hole. With intravitreal TCA, there was a significant decrease in central foveal thickness at 3, 6, and 12 months, compared with baseline (P = 0.0171, 0.0401, and 0.0024, respectively). A significant gain in vision was noted at 1 month compared with baseline (P = 0.0169), but this was not sustained at 3, 6, and 12 months (P = 0.4862, 0.9098, and 0.4312, respectively). The addition of bevacizumab to TCA did not provide any additional benefit for central foveal thickness and visual acuity. Thirty-two eyes (82.1%) were started on prophylactic antiglaucoma drops 2 weeks after a TCA injection, and no eye needed laser or surgery to control intraocular pressure. CONCLUSION: Chronic CME after pars plana vitrectomy is recurrent and difficult to treat. Intravitreal TCA is effective in reducing CME, but there was only short term visual acuity improvement even with continued reduction of central foveal thickness. Intraocular pressure did not significantly rise with the use of prophylactic antiglaucoma drops even with repeated injections. PMID- 26655612 TI - WIDE-FIELD IMAGING OF NONEXUDATIVE AND EXUDATIVE CONGENITAL X-LINKED RETINOSCHISIS. AB - PURPOSE: To describe wide-field imaging features of patients with congenital X linked retinoschisis. METHODS: This is a retrospective nonconsecutive series of 36 eyes from 18 patients with congenital X-linked retinoschisis from 2008 to 2014. Wide-field color fundus photographs, optical coherence tomography images, and wide-field fluorescein angiography images were reviewed. Patients were classified to have either exudative or nonexudative retinoschisis based on the presence or absence of lipid exudates. RESULTS: Eleven eyes exhibited exudative retinoschisis (30%), whereas the remaining were nonexudative. Exudative disease occurred more commonly in older patients (14.4 vs. 4.0 years; P < 0.001). The most frequent location of exudation was the macula. Subretinal hemorrhage was present in 4 eyes (11%). Macular findings included an atypical foveal avascular zone in 7 eyes (19%) and submacular fibrosis or retinal folds in 6 eyes (17%). Peripheral characteristics included fibrosis or folds (11%), bridging vessels (8%), and vascular sheathing (8%). Thirteen of the 22 eyes (59%) demonstrated leakage on fluorescein angiography. CONCLUSION: Exudation may be more common in congenital X-linked retinoschisis than previously recognized. The presence of exudates with concurrent angiographic leakage suggests that exudation may be due to chronic vascular permeability and not solely caused by intraschisis hemorrhage, which has been classically described. PMID- 26655613 TI - COMPARING PERIPHERAL VITRECTOMY UNDER AIR AND FLUID INFUSION FOR PRIMARY RHEGMATOGENOUS RETINAL DETACHMENT. AB - PURPOSE: To evaluate the efficacy and safety of peripheral vitrectomy under air infusion in comparison with fluid infusion in patients undergoing 23-gauge pars plana vitrectomy for primary rhegmatogenous retinal detachment. METHODS: A total of 80 eyes of 80 patients with primary rhegmatogenous retinal detachment were enrolled into the study. Forty cases underwent peripheral vitrectomy under air infusion (air group), and a control group of equal number underwent peripheral vitrectomy under fluid infusion (fluid group). Peripheral iatrogenic retinal breaks during peripheral vitrectomy, postoperative visual acuities, and retinal redetachment rates were compared. RESULTS: The number of eyes with peripheral iatrogenic retinal breaks in air group during peripheral vitrectomy was statistically comparable with that in fluid group (1/40 and 4/40, 2.5% and 10%, respectively; P = 0.16). Scleral depression was necessitated in 7 of 40 cases (17.5%) during the operation in the air group. There were no statistically significant differences between the groups in means of postoperative visual acuity and retinal redetachment (P = 0.18 and P = 1.0, respectively). CONCLUSION: Peripheral vitrectomy under air infusion for primary rhegmatogenous retinal detachment revealed comparable results with fluid infusion in terms of intraoperative and postoperative complications and surgical outcomes. PMID- 26655614 TI - REPRODUCIBILITY OF MACULAR PIGMENT OPTICAL DENSITY MEASUREMENT BY TWO-WAVELENGTH AUTOFLUORESCENCE IN A CLINICAL SETTING. AB - PURPOSE: Macular pigment, composed of lutein, zeaxanthin, and meso-zeaxanthin, is postulated to protect against age-related macular degeneration, likely because of filtering blue light and its antioxidant properties. Macular pigment optical density (MPOD) is reported to be associated with macular function evaluated by visual acuity and multifocal electroretinogram. Given the importance of macular pigment, reliable and accurate measurement methods are important. The main purpose of this study is to determine the reproducibility of MPOD measurement by two-wavelength autofluorescence method using scanning laser ophthalmoscopy. METHODS: Sixty-eight eyes of 39 persons were enrolled in the study, including 11 normal eyes, 16 eyes with wet age-related macular degeneration, 16 eyes with dry age-related macular degeneration, 11 eyes with macular edema due to diabetic mellitus, branch retinal vein occlusion or macular telangiectasia, and 14 eyes with tractional maculopathy, including vitreomacular traction, epiretinal membrane, or macular hole. MPOD was measured with a two-wavelength (488 and 514 nm) autofluorescence method with the Spectralis HRA + OCT after pupil dilation. The measurement was repeated for each eye 10 minutes later. The analysis of variance and Bland-Altman plot were used to assess the reproducibility between the two measurements. RESULTS: The mean MPOD at eccentricities of 1 degrees and 2 degrees was 0.36 +/- 0.17 (range: 0.04-0.69) and 0.15 +/- 0.08 (range: -0.03 to 0.35) for the first measurement and 0.35 +/- 0.17 (range: 0.02-0.68) and 0.15 +/- 0.08 (range: -0.01 to 0.33) for the second measurement, respectively. The difference between the 2 measurements was not statistically significant, and the Bland-Altman plot showed 7.4% and 5.9% points outside the 95% limits of agreement, indicating an overall excellent reproducibility. Similarly, there is no significant difference between the first and second measurements of MPOD volume within eccentricities of 1 degrees , 2 degrees , and 6 degrees radius, and the Bland-Altman plot showed 8.8%, 2.9%, and 4.4% points outside the 95% limits of agreement, respectively. The data for the reproducibility did not differ significantly among the various disease and normal eyes. CONCLUSION: Under routine examination conditions with pupil dilation, MPOD measurement by two wavelength autofluorescence method showed a high reproducibility. PMID- 26655615 TI - Intravitreal Triamcinolone Deposition Mimicking Frosted Branch Angiitis: Optical Coherence Tomography Findings. PMID- 26655616 TI - CLINICAL PRESENTATIONS AND OUTCOMES OF RHEGMATOGENOUS RETINAL DETACHMENT IN RETINITIS PIGMENTOSA. AB - PURPOSE: To describe the clinical presentations and outcomes of rhegmatogenous retinal detachments (RRD) in eyes with retinitis pigmentosa. METHODS: A retrospective review of all patients of retinitis pigmentosa with RRD from January 1990 to December 2013 at a tertiary eye care institute. RESULTS: Of total 28,622 patients of retinitis pigmentosa over a 23-year period, 17 eyes of 17 patients had RRD. Mean age at presentation was 34.53 +/- 16.42 years (median 32 years). Median duration of decreased vision attributed to RRD was 6 months. Ten eyes (59%) had cataract and 3 eyes (18%) had history of cataract surgery. Thirteen eyes (76%) had inferior retinal detachment; 9 eyes (53%) had lattice with retinal holes; and 8 eyes (47%) had atrophic retinal holes. There were no horse-shoe tears, giant retinal tears, dialysis, and macular holes related RRD. Majority (82%) of retinal breaks were in the inferotemporal quadrant. Only 3 eyes (18%) had proliferative vitreoretinopathy at presentation. Twelve eyes at presentation had best-corrected visual acuity <20/200 and 6 eyes had only light perception. The macula was involved by the detachment in all cases. Mean preoperative visual acuity was 1.4 +/- 0.88 logarithm of the minimum angle of resolution (median 1.3, range 3-0.1; 20/502). Surgery was not advised in 6 eyes (35% patients); 5 eyes (30%) underwent scleral buckling and 6 eyes (35%) underwent vitrectomy. Median follow-up was 5 months. Reattachment rate at last follow-up was 91% (15 eyes). Mean postoperative best-corrected visual acuity recorded was 1.06 +/- 0.8 (median 1, range 3-0.1; 20/229) (P = 0.15). Eight eyes at last visit had best-corrected visual acuity <20/200. Of the 11 eyes operated, 4 improved in vision and 7 retained the preoperative vision. CONCLUSION: The incidence of RRD in retinitis pigmentosa is very low. Presentation, although delayed, is at a younger age. Horse-shoe tears and proliferative vitreoretinopathy are uncommon; cataract is a common coexisting pathology. Surgical reattachment rates appear high and recurrent RRD is uncommon. However, visual gain is limited by the underlying retinal degenerative condition. PMID- 26655617 TI - AXIAL ROTATION VITRECTOMY: Back to the Future? the Fluidics of a Prototype Vitreous Cutter Probe. AB - PURPOSE: To characterize the fluidics of axial rotating vitreous cutter probe (RT) compared with the standard guillotine (regular blade), when tested in Balanced Salt Solution (Alcon Laboratories, Forth Worth, TX). METHODS: RT and regular blade (RB) cutter probes connected to the same vitrectomy console used a peristaltic pump. The authors measured instantaneous flow through aspiration tubing proximal to the handpiece, fluid velocity, and acceleration at the port by means of particle image velocimetry. RESULTS: Average flow at aspiration tubing of RT and RB did not vary significantly. Regular blade probes produced higher instantaneous flow fluctuation than RT at any considered cut rate (RB 1,600 6.4 +/- 5.3 mL/minute; RB 3,000 11.8 +/- 6.3 mL/minute; RT 1,600 0.9 +/- 0.7 mL/minute, and RT 3,000 1.8 +/- 0.8 mL/minute, respectively. P < 0.001 in all cases). Regular blade also yield significantly higher fluid velocity at cutter port compared with RT (RB 1,600 85.8 +/- 70.1 mm/second; RB 3,000 81.6 +/- 66.4 mm/second; RT 1,600 71.9 +/- 40.3 mm/second; and RT 3,000 32.9 +/- 20.8 mm/second. P < 0.001 in all cases). Fluid acceleration at the cutter port was higher when the RB was used (RB 1,600 26.85 +/- 30.18 mm/second; RB 3,000 33.76 +/- 34.09 mm/second; RT 1,600 24.01 +/- 21.94 mm/second; and RT 3,000 16.62 +/- 17.87 mm/second. P < 0.001 in all cases). CONCLUSION: RT blade design causes less instantaneous flow fluctuation within the aspiration tubing, and also lower fluid velocity and lower acceleration at the cutter port. Fluidics suggests a safer cutting action and a reduced risk of retinal incarceration. PMID- 26655618 TI - Lamellar Hole Associated With Prominent Intraretinal Vessels. PMID- 26655619 TI - Correspondence. PMID- 26655620 TI - SHORT-TERM SAFETY PROFILE OF INTRAVITREAL ZIV-AFLIBERCEPT. AB - AIM: To evaluate the safety of intravitreal ziv-aflibercept (Zaltrap) in the treatment choroidal neovascularization secondary to age-related macular degeneration. METHODS: Eligible eyes with choroidal neovascularization secondary to age-related macular degeneration each received a single intravitreal injection of ziv-aflibercept. Comprehensive ophthalmic examinations and detailed systemic evaluations were performed at baseline and Days 1, 7, and 30 after injection, and International Society for Clinical Electrophysiology of Vision standard electroretinography was performed at baseline and Day 30. Primary outcome measures were safety parameters that included signs of clinical and electroretinographic toxicity. Secondary outcome measures included changes in best-corrected visual acuity and central subfield thickness. RESULTS: Twelve eyes of 12 patients were treated. None of the patients complained of blurred vision, ocular pain, or bulbar injection at any of the follow-up visits, nor was intraocular inflammation noted. There were no significant differences in implicit times, "a" and "b" wave amplitudes, or b/a ratios at 1 month when compared with baseline (P = 0.4). None of the patients experienced serious ocular or systemic adverse events. Mean best-corrected visual acuity improved only slightly at 30 days (LogMAR 0.45 +/- 0.31 [Snellen equivalent: 20/60]) compared with baseline (LogMAR 0.37 +/- 0.24 [Snellen equivalent: 20/50]; P = 0.51). CONCLUSION: Single intravitreal injections of ziv-aflibercept into eyes with neovascular age-related macular degeneration appear to be safe through 1 month. Ziv-aflibercept could become a safe, low-cost therapy for macular diseases in developing countries and in those where intravitreal aflibercept (Eylea) is not available. PMID- 26655621 TI - PROSPECTIVE TRIAL OF ENDOGENOUS FUNGAL ENDOPHTHALMITIS AND CHORIORETINITIS RATES, CLINICAL COURSE, AND OUTCOMES IN PATIENTS WITH FUNGEMIA. AB - PURPOSE: Former studies have found rates of endogenous endophthalmitis ranging from 0% to 37% in patients with fungemia. This study sought to prospectively determine the rate and risk factors for endogenous chorioretinitis and endophthalmitis in patients with fungemia. METHODS: A prospective cohort study was performed of consecutive adult inpatients at a single site from 2010 to 2013 of patients with positive blood cultures for fungus. One hundred and nineteen pieces of information were gathered for each patient. RESULTS: A total of 125 patients were enrolled in the study with 7 positive cases of chorioretinitis for a rate of 5.6%. Of these positive cases, 2 patients had endophthalmitis for a rate of 1.6%. Two patients who had a negative initial examination subsequently had a positive examination; 57% of the chorioretinitis patients who could report symptoms were asymptomatic, 57% of the chorioretinitis patients died, and 32% of negative cases died. Prolonged hospitalization, altered mental status, total parenteral nutrition, and gastrointestinal surgery were protective on univariate but not multivariate analysis. CONCLUSION: Despite modern antifungal therapy, fungal chorioretinitis and endophthalmitis continue to occur in patients with positive fungal cultures. Two dilated ophthalmic examinations should still be considered even in asymptomatic patients with fungemia. PMID- 26655622 TI - ENDOPHTHALMITIS AFTER INTRAVITREAL INJECTION: Role of Prophylactic Topical Ophthalmic Antibiotics. AB - PURPOSE: To determine the rate of postintravitreal injection endophthalmitis and to assess microbiological features and outcomes with and without the use of peri intravitreal injection topical ophthalmic antibiotics. METHODS: Consecutive series of endophthalmitis cases retrospectively identified after intravitreal injection at a multicenter, retina-only referral practice (Retina Consultants of Houston) from January 1, 2011 to December 31, 2014. Prophylactic peri intravitreal injection topical antibiotics were routinely used during the initial 12-month period (January 1, 2011-December 31, 2011) and not used in the final 24 month period (January 1, 2013-December 31, 2014). Main outcome measures were incidence of endophthalmitis, microbiology results, treatment strategies, and visual outcomes. RESULTS: Of 90,339 intravitreal injections, 30 cases of endophthalmitis were identified (endophthalmitis rate = 0.033%; 95% confidence interval, 0.021-0.045%; or approximately 1 of 3,011 intravitreal injections). The most common organisms isolated were coagulase-negative staphylococci (n = 10, 33%), followed by Streptococcus mitis (n = 2, 7%). Fourteen cases (47%) were culture negative. Peri-intravitreal injection topical antibiotic prophylaxis did not decrease the rate of endophthalmitis (0.035% [95% CI, 0.007-0.064%] with antibiotic use versus 0.021% [95% CI, 0.008-0.033%] without antibiotic use; P = 0.261). CONCLUSION: The risk of endophthalmitis after intravitreal injection remains low, with coagulase-negative staphylococci and Streptococcus mitis the most common bacterial isolates identified. Prophylactic peri-intravitreal injection topical ophthalmic antibiotic use did not decrease the endophthalmitis rate. PMID- 26655623 TI - Effects of 2 Resistive Exercises on Electrophysiological Measures of Submandibular Muscle Activity. AB - OBJECTIVE: To compare the electrophysiological activity in submandibular hyolaryngeal muscles during performance of 2 exercises that incorporate resistance against muscular contraction. DESIGN: Within-subject repeated-measures design. SETTING: Academic research laboratory. PARTICIPANTS: Healthy, young adult women (N=26; mean age, 24.1y) without a history of dysphagia, cervical spine conditions, neurologic disease, or head/neck cancer. INTERVENTIONS: Participants performed 2 isometric exercises requiring contraction against resistance to the submandibular hyolaryngeal muscles: one requiring jaw opening against a semirigid brace (chin-to-chest [CtC] exercise) and one requiring a chin tuck against an air inflated rubber ball (chin tuck against resistance [CTAR] exercise). Measures of electrophysiology using surface electromyography (sEMG) were obtained during exercise performance. MAIN OUTCOME MEASURES: Microvolts as measured from sEMG electrode sensors placed on the skin surface above the hyolaryngeal muscles (surface of skin above geniohyoid, mylohyoid, and anterior digastric). Dependent variables included peak contraction amplitude (in MUV) and mean contraction amplitude (in MUV) across 10 seconds of sustained contraction. RESULTS: Significant effects of exercise on peak and mean contraction amplitudes were present when both exercises were compared with baseline sEMG activity. (P<.001 for both). Normalized values of peak contraction amplitude and mean contraction amplitude during performance of CtC were not significantly different compared with CTAR. CONCLUSIONS: This study provides supporting evidence for the influence of 2 published exercises on motor unit recruitment in the submandibular hyolaryngeal muscles, both of which have been previously proposed as rehabilitative modalities. Theoretical and clinical implications are discussed. PMID- 26655624 TI - Regulatory T cells: Developing diversity. PMID- 26655625 TI - Innate immunity: First aid at the epithelium. PMID- 26655626 TI - Regulatory T cells: Peripheral positioning. PMID- 26655627 TI - Tumour immunology: Intestinal bacteria are in command. PMID- 26655629 TI - Vasculitic peripheral neuropathy: Case definition and guidelines for collection, analysis, and presentation of immunisation safety data. PMID- 26655628 TI - Converging roles of caspases in inflammasome activation, cell death and innate immunity. AB - Inflammatory and apoptotic caspases are central players in inflammation and apoptosis, respectively. However, recent studies have revealed that these caspases have functions beyond their established roles. In addition to mediating cleavage of the inflammasome-associated cytokines interleukin-1beta (IL-1beta) and IL-18, inflammatory caspases modulate distinct forms of programmed cell death and coordinate cell-autonomous immunity and other fundamental cellular processes. Certain apoptotic caspases assemble structurally diverse and dynamic complexes that direct inflammasome and interferon responses to fine-tune inflammation. In this Review, we discuss the expanding and interconnected roles of caspases that highlight new aspects of this family of cysteine proteases in innate immunity. PMID- 26655630 TI - Evaluation of the attenuation, immunogenicity, and efficacy of a live virus vaccine generated by codon-pair bias de-optimization of the 2009 pandemic H1N1 influenza virus, in ferrets. AB - Codon-pair bias de-optimization (CPBD) of viruses involves re-writing viral genes using statistically underrepresented codon pairs, without any changes to the amino acid sequence or codon usage. Previously, this technology has been used to attenuate the influenza A/Puerto Rico/8/34 (H1N1) virus. The de-optimized virus was immunogenic and protected inbred mice from challenge. In order to assess whether CPBD could be used to produce a live vaccine against a clinically relevant influenza virus, we generated an influenza A/California/07/2009 pandemic H1N1 (2009 pH1N1) virus with de-optimized HA and NA gene segments (2009 pH1N1 (HA+NA)(Min)), and evaluated viral replication and protein expression in MDCK cells, and attenuation, immunogenicity, and efficacy in outbred ferrets. The 2009 pH1N1-(HA+NA)(Min) virus grew to a similar titer as the 2009 pH1N1 wild type (wt) virus in MDCK cells (~10(6)TCID50/ml), despite reduced HA and NA protein expression on western blot. In ferrets, intranasal inoculation of 2009 pH1N1 (HA+NA)(Min) virus at doses ranging from 10(3) to 10(5) TCID50 led to seroconversion in all animals and protection from challenge with the 2009 pH1N1 wt virus 28 days later. The 2009 pH1N1-(HA+NA)(Min) virus did not cause clinical illness in ferrets, but replicated to a similar titer as the wt virus in the upper and lower respiratory tract, suggesting that de-optimization of additional gene segments may be warranted for improved attenuation. Taken together, our data demonstrate the potential of using CPBD technology for the development of a live influenza virus vaccine if the level of attenuation is optimized. PMID- 26655631 TI - Response to Pendleton et al. regarding reduction in HPV 16/18-associated high grade cervical lesions following HPV vaccine introduction in the United States. PMID- 26655632 TI - The BICAMS Battery for Assessment of Lithuanian-Speaking Multiple Sclerosis Patients: Relationship with Age, Education, Disease Disability, and Duration. AB - BACKGROUND Assessment of cognitive impairment (CI) in multiple sclerosis (MS) patients is very useful, but it requires time-consuming expert evaluation with specialized materials. The Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) was created as a brief and specific instrument for the evaluation of CI. The aims of this study were to assess the cognitive status of MS patients by using the Lithuanian version of BICAMS, to evaluate the test retest reliability of the Lithuanian version of BICAMS, and to measure the impact of CI on disability and duration of MS. MATERIAL AND METHODS We enrolled 50 MS patients and 20 cognitively normal control subjects, matched for age, gender, and level of education. Cognitive functions were assessed by the BICAMS tests, which include the Symbol Digit Modalities Test, the Brief Visuospatial Memory Test Revised, and the California Verbal Learning Test, 2nd edition. RESULTS MS patients performed significantly worse than controls on the 3 neuropsychological tests of BICAMS (p<0.001). Younger and intellectually employed persons performed significantly better on these tests than older persons, manual workers, or unemployed persons (p<0.05). MS patients with higher disability scores tended to perform worse on the tests (p<0.05), but we found no relationship between BICAMS test scores and the duration of the disease or relapse rate (p>0.05). Test-retest reliability was excellent for all 3 subtests (r>0.8, p<0.05). CONCLUSIONS Our study shows that BICAMS is a valid and acceptable cognitive assessment tool that can be recommended for routine use in Lithuania for assessing patients with MS. PMID- 26655633 TI - Effects of warming on ectomycorrhizal colonization and nitrogen nutrition of Picea asperata seedlings grown in two contrasting forest ecosystems. AB - Ectomycorrhiza (ECM) plays an important role in plant nitrogen (N) nutrition and regulates plant responded to climate warming. We conducted a field experiment in a natural forest and a plantation in the eastern Tibetan Plateau to estimate the warming effects of open-top chambers (OTC) on ECM and N nutrition of Picea asperata seedlings. Four-year warming significantly decreased ECM colonization, ECM fungal biomass, fine root vigor, and the N concentration of leaf, stem and coarse root, but significantly increased fine root N concentration and N content of leaf, stem, fine root and whole plant in natural forest. Contrarily, warming induced no obvious change in most of these parameters in plantation. Moreover, warming decreased rhizospheric soil inorganic N content in both forests. Our results showed that four-year warming was not beneficial for ECM colonization of P. asperata seedlings in the two forests, and the seedlings in natural forest were more sensitive and flexible to experimental warming than in plantation. The changes of ECM colonization and fine root biomass for effective N uptake would be good for plant growth and remit N leaching under future warming in natural forest. PMID- 26655634 TI - Antagonism of Nav channels and alpha1-adrenergic receptors contributes to vascular smooth muscle effects of ranolazine. AB - Ranolazine is a recently developed drug used for the treatment of patients with chronic stable angina. It is a selective inhibitor of the persistent cardiac Na(+) current (INa), and is known to reduce the Na(+)-dependent Ca(2+) overload that occurs in cardiomyocytes during ischemia. Vascular effects of ranolazine, such as vasorelaxation,have been reported and may involve multiple pathways. As voltage-gated Na(+) channels (Nav) present in arteries play a role in contraction, we hypothesized that ranolazine could target these channels. We studied the effects of ranolazine in vitro on cultured aortic smooth muscle cells (SMC) and ex vivo on rat aortas in conditions known to specifically activate or promote INa. We observed that in the presence of the Nav channel agonist veratridine, ranolazine inhibited INa and intracellular Ca(2+) calcium increase in SMC, and arterial vasoconstriction. In arterial SMC, ranolazine inhibited the activity of tetrodotoxin-sensitive voltage-gated Nav channels and thus antagonized contraction promoted by low KCl depolarization. Furthermore, the vasorelaxant effects of ranolazine, also observed in human arteries and independent of the endothelium, involved antagonization of the alpha1-adrenergic receptor. Combined alpha1-adrenergic antagonization and inhibition of SMCs Nav channels could be involved in the vascular effects of ranolazine. PMID- 26655635 TI - Psychiatric disorders in adolescent and young adult patients with phenylketonuria. AB - BACKGROUND AND OBJECTIVES: Psychiatric symptoms are a challenging aspect in adolescent and adult early treated phenylketonuric (ETPKU) patients. To assess the occurrence of psychiatric disorders we explored the presence of symptoms requiring intervention and further investigated the link between psychiatric disorders, the quality of biochemical control and cognitive functioning. PATIENTS AND METHODS: Forty-six ETPKU patients (aged 12 to 44) and 30 age-matched healthy controls were subjected to cognitive and psychiatric assessment by means of self report questionnaires and psychiatric interview. Psychiatric diagnoses, if detected, were made according to DSM-5 criteria. Concomitant IQ, historical and concurrent biochemical metabolic controls were included in the statistical analysis. RESULTS: Twenty-five out of 46 ETPKUs showed clinical scores on at least one scale of the psychiatric assessment (7/30 in controls); anxiety and withdrawal were the most frequent self-reported symptoms. Seventeen patients (and no controls) met criteria for a psychiatric diagnosis, most of them belonging to the Anxiety Disorders category. The occurrence of psychiatric symptoms was not associated with the life-long and concurrent quality of metabolic control but patients with good metabolic control (<= 500 MUM) in the first 11 years of life showed higher frequency of psychiatric diagnosis (Fisher's exact p=.0300). DISCUSSION/CONCLUSION: ETPKUs show a higher than normal vulnerability to psychiatric disorders, which cannot be explained by the usual biochemical alterations influencing intellectual outcome. Our data support the hypothesis that the burden of the disease acts as psychological stress for children and their families. Possible involvement of neuromediators in the pathogenesis of these complex symptoms requires further investigation. PMID- 26655636 TI - Toxicity assessment of hydroxyapatite nanoparticles in rat liver cell model in vitro. AB - Hydroxyapatite nanoparticles (HAP NPs) are widely used for preparations of biomedical and biotechnological fields such as drug delivery, gene therapy, and molecular imaging. However, the current toxicological knowledge about HAP NPs is relatively limited. The present study was designed to investigate the toxicity potentials of various concentrations (0-1000 ug cm(-2)) of HAP NPs in cultured primary rat hepatocytes. Cell viability was detected by 3-(4,5-dimethyl-thiazol-2 yl) 2,5-diphenyltetrazolium bromide (MTT) assay and lactate dehydrogenase (LDH) release, while total antioxidant capacity (TAC) and total oxidative stress (TOS) levels were determined to evaluate the oxidative injury. The DNA damage was also analyzed via scoring liver micronuclei rates and determining 8-oxo-2 deoxyguanosine (8-OH-dG) levels. The results of MTT and LDH assays showed that the higher concentrations of dispersed HAP NPs (300, 500, and 1000 ug cm(-2)) decreased cell viability. Also, HAP NPs increased TOS (500 and 1000 ug cm(-2)) levels and decreased TAC (300, 500, and 1000 ug cm(-2)) levels in cultured hepatocytes. On the basis of increasing doses, the NPs as depending on dose caused significant increases of the number of micronucleated hepatocytes and 8-OH dG levels as compared to control culture. Furthermore, the highest concentration of HAP NPs (1000 ug cm(-2)) exhibited cytotoxic activity. Based on these results, HAP NPs have a dose-dependent toxic effect in rat hepatocytes. Further extensive research in this field is promising and reasonable. PMID- 26655637 TI - Anti-inflammatory and proapoptotic effects of umbelliferone in colon carcinogenesis. AB - Colorectal cancer (CRC) is a serious health problem throughout the world. 5 Flurouracil, the first-line chemotherapy of colorectal cancer often produces more toxicity to neighboring cells; however, it is still used for CRC treatment. To overcome this, umbelliferone (UMB), a less toxic bioflavonoid has been used to test its anticancer effects on animal model. The objective of the present study is to evaluate the anticancer activity of UMB on 1,2-dimethylhydrazine (DMH) induced rat colon tumorigenesis to determine the development of aberrant crypt foci (ACF), agyrophylic nucleolar organizer regions (AgNORs), mast cell recruitment, pro-inflammatory cytokines such as tumor necrosis factor (TNF) alpha, interleukin (IL)-1beta and also study the expressions of inducible nitric oxide synthase, cyclooxygenase (COX)-2, and apoptotic markers. DMH-induced rats showed increased ACF number (incidence), multiplicity and its distribution, counts of AgNORs, mast cells, inflammatory markers and apoptotic proteins. Interestingly, UMB supplementation to DMH-induced rats (group 4) significantly (p < 0.05) suppressed ACF development, AgNORs, mast cells, and inflammatory markers and increased the apoptotic markers as compared to DMH-induced rats (group 2). We concluded that UMB is a potential anticancer agent that can be used for the prevention and treatment of CRC. PMID- 26655638 TI - The measurement of disability weights for 18 prevalent acute poisoning conditions. AB - BACKGROUND: Disability weights (DWs) are used in disease burden studies, with the calculation of the weight of the disability as years lived with disability versus years of lost life accounting for mortalities. Currently, there is a single DW score available for poisoning, which is considered to be a single health state. This makes it difficult to evaluate the differing burdens of poisonings involving various substances/conditions in comparison with other health states in countries with different patterns of substance abuse. The aim of this study is therefore to estimate the DWs of 18 common poisonings based on the expert elicitation method. METHODS: A panel of 10 medical clinicians who were familiar with the clinical aspects of different poisonings estimated the DWs of 50 health states by interpolating them on a calibrated Visual Analogue Scale. The DWs of some poisonings, such as alcohol, cannabis and heroin, had been estimated in previous studies and so were used to determine the external consistency of our panel. As a matter of routine, the DWs could vary on a scale between 0 (best health state) and 1 (worst health state). RESULTS: Statistical analysis showed that both the internal (Cronbach's alpha = 0.912) and external consistency of the panel were acceptable. The DWs for the different poisonings were estimated along a range from 0.830 for severe aluminium phosphide to 0.022 for mild benzodiazepine. CONCLUSIONS: Different poisonings should be weighted differently since they vary widely. Unfortunately, they are currently all weighted the same. PMID- 26655639 TI - The Clinical Profile of Kawasaki Disease in Algerian Children: A Single Institution Experience. AB - Kawasaki disease (KD) in an acute vasculitis of unknown etiology. The epidemiological data available for Algerian patients remains insufficient. OBJECTIVE: To describe the demographic, clinical features of children with KD and to identify the risk factors for developing coronary artery lesions (CAL). METHODS: This retrospective study included children admitted with KD at the pediatric hospital in Algiers from January 2005 to December 2014. RESULTS: One hundred thirty-three patients (82 boys and 51 girls) with a mean age of 31 months were identified. The most common sign was fever, rash, oral changes and conjunctivitis. The cardiac complications were CAL (22.5%), pericarditis (2%) and myocarditis (1.5%). The independent variable for prediction of CAL was duration of fever >10 days, male gender and platelet count >450,000/mm3 CONCLUSION: The incidence of cardiovascular complications is high. Knowledge of KD among Algerian pediatricians should be enhanced to guarantee appropriate treatment of this disease. PMID- 26655640 TI - Dioscin alleviates alcoholic liver fibrosis by attenuating hepatic stellate cell activation via the TLR4/MyD88/NF-kappaB signaling pathway. AB - The present work aimed to investigate the activities and underlying mechanisms of dioscin against alcoholic liver fibrosis (ALF). In vivo liver fibrosis in mice was induced by an alcoholic liquid diet, and in vitro studies were performed on activated HSC-T6 and LX2 cells treated with lipopolysaccharide. Our results showed that dioscin significantly attenuated hepatic stellate cells (HSCs) activation, improved collagen accumulation, and attenuated inflammation through down-regulating the levels of myeloid differentiation factor 88 (MyD88), nuclear factor kappaB (NF-kappaB), interleukin (IL)-1, IL-6 and tumour necrosis factor alpha by decreasing Toll-like receptor (TLR)4 expression both in vivo and in vitro. TLR4 overexpression was also decreased by dioscin, leading to the markedly down-regulated levels of MyD88, NF-kappaB, transforming growth factor-beta1 (TGF beta1), alpha-smooth muscle actin (alpha-SMA) and type I collagen (COL1A1) in cultured HSCs. Suppression of cellular MyD88 by ST2825 or abrogation of NF-kappaB by pyrrolidine dithiocarbamate eliminated the inhibitory effects of dioscin on the levels of TGF-beta1, alpha-SMA and COL1A1. In a word, dioscin exhibited potent effects against ALF via altering TLR4/MyD88/NF-kappaB signaling pathway, which provided novel insights into the mechanisms of this compound as an antifibrogenic candidate for the treatment of ALF in the future. PMID- 26655641 TI - NMR structure and function of Helicoverpa armigera sterol carrier protein-2, an important insecticidal target from the cotton bollworm. AB - The cotton bollworm, Helicoverpa armigera, has developed strong resistance to many insecticides. Sterol Carrier Protein-2 (SCP-2) is an important non-specific lipid transfer protein in insects and appears to be a potential new target. In order to elucidate the structure and function of Helicoverpa armigera SCP-2 (HaSCP-2), NMR spectroscopy, docking simulations, mutagenesis and bioassays were performed. HaSCP-2 composed of five alpha-helices and four stranded beta-sheets. The folds of alpha-helices and beta-sheets interacted together to form a hydrophobic cavity with putative entrance and exit openings, which served as a tunnel for accommodating and transporting of lipids. Several sterols and fatty acids could interact with HaSCP-2 via important hydrophobic sites, which could be potential targets for insecticides. Mutagenesis experiments indicated Y51, F53, F89, F110, I117 and Q131 may be the key functional sites. HaSCP-2 showed high cholesterol binding activity and SCP-2 inhibitors (SCPIs) could inhibit the biological activity of HaSCP-2. SCPI-treated larvae at young stage showed a significant decrease of cholesterol uptake in vivo. Our study describes for the first time a NMR structure of SCP-2 in lepidopteran H. armigera and reveals its important function in cholesterol uptake, which facilitates the screening of effective insecticides targeting the insect cholesterol metabolism. PMID- 26655642 TI - Reduction in the Reverse-Bias Effect by an Abrupt Break in the Sequential Regularity of Visual Events. AB - A bistable image is more likely to be initially perceived as the reversal of its preceding unambiguous version presented for a prolonged period. This perceptual bias is called the reverse-bias effect. We hypothesized that an abrupt break in the sequential regularity of visual events, synchronized with the onset of a bistable image, counteracts the reverse-bias effect in a similar manner to the disturbing effect of noise in the perceptual process. Under the condition in which the reverse-bias effect was achieved with the Necker lattice, the orientation of the bars around the lattice was simultaneously changed at the onset of the lattice, yielding an abrupt break in the sequential regularity of visual events besides the lattice. The results obtained showed that the reverse bias effect was significantly reduced by the abrupt break, suggesting that an abrupt break in the sequential regularity of visual events perturbs the perceptual bias of the bistable image, similar to that caused by noise. PMID- 26655643 TI - Crossmodal Correspondence Between Auditory Pitch and Visual Elevation Affects Temporal Ventriloquism. AB - Temporal ventriloquism is the shift in perceived timing of a visual stimulus that occurs when an auditory stimulus is presented close in time. This study investigated whether crossmodal correspondence between auditory pitch and visual elevation modulates temporal ventriloquism. Participants were presented two visual stimuli (above and below fixation) across a range of stimulus onset asynchronies and were asked to judge the order of the events. A task-irrelevant auditory click was presented shortly before the first and another shortly after the second visual stimulus. There were two pitches used (low and high) and the congruency between the auditory and visual stimuli was manipulated. The results show that incongruent pairings between pitch and elevation abolish temporal ventriloquism. In contrast, the crossmodal correspondence effect was absent when the direction of the pitch change was fixed within sessions, reducing the saliency of the pitch change. The results support previous studies suggesting that in addition to spatial and temporal factors, crossmodal correspondences can influence binding of information across the senses, although these effects are likely to be dependent on the saliency of the crossmodal mapping. PMID- 26655645 TI - Hospice Use, Hospitalization, and Medicare Spending at the End of Life. AB - OBJECTIVES: Prior studies associate hospice use with reduced hospitalization and spending at the end of life based on all Medicare hospice beneficiaries. In this study, we examine the impact of different lengths of hospice care and nursing home residency on hospital use and spending prior to death across 5 disease groups. METHODS: We compared inpatient hospital days and Medicare spending during the last 6 months of life using hospice versus propensity matched non-hospice beneficiaries who died in 2010, were enrolled in fee for service Medicare throughout the last 2 years of life, and were in at least 1 of 5 disease groups. Comparisons were based on length of hospice use and whether the decedent was in a nursing home during the seventh month prior to death. We regressed a categorical measure of hospice days on outcomes, controlling for observed patient characteristics. RESULTS: Hospice use over 2 weeks was associated with decreased hospital days (1-5 days overall, with greater decreases for longer hospice use) for all beneficiaries; spending was $900-$5,000 less for hospice use of 31-90 days for most beneficiaries not in nursing homes, except beneficiaries with Alzheimer's. Overall spending decreased with hospice use for beneficiaries in nursing homes with lung cancer only, with a $3,500 reduction. DISCUSSION: The Medicare hospice benefit is associated with reduced hospital care at the end of life and reduced Medicare expenditures for most enrollees. Policies that encourage timely initiation of hospice and discourage extremely short stays could increase these successes while maintaining program goals. PMID- 26655646 TI - Your Face is Your Fortune: Does Adolescent Attractiveness Predict Intimate Relationships Later in Life? AB - OBJECTIVE: A growing literature documents the importance of physical attractiveness in young and middle adulthood for romantic, marital, and sexual relationships, but little is known about how attractiveness in adolescence matters to intimate relationships in later life. We ask: does attractiveness early in life convey ongoing benefits late in life, or do such benefits erode over time? METHODS: We use multivariate regression models and more than 50 years of data from the Wisconsin Longitudinal Study to examine the connections between adolescent physical attractiveness and intimate relationships (i.e., sexual activity and access to potential sexual partners) in later life. RESULTS: We find that adolescent attractiveness facilitates sexual activity in later life. This relationship is largely driven by attractiveness increasing the probability of having access to potential sexual partners. However, attractiveness is not related to sexual activity among married couples, even after controlling for marital duration. Men, those in good health, and wealthier individuals are also more likely to engage in several facets of intimate relationships. DISCUSSION: These findings highlight the importance of relationship context for later life sexual activity and begin to explicate the pathways through which factors across the life course-particularly attractiveness-influence sexual activity in later life. PMID- 26655647 TI - Impact of Different Illumination Conditions on Visual Caries Detection with ICDAS. AB - The aim of this study was to test the influence of different degrees of additional illumination on visual caries detection using the International Caries Detection and Assessment System (ICDAS). Two calibrated examiners assessed 139 occlusal surfaces of extracted permanent molars using a standard operation lamp with or without an additional headlamp providing three default brightness intensities. Histology served as the gold standard. Pooled data showed no differences in sensitivities. Specificities were not influenced by additional light. The area under the curve for the Marthaler classification D3 threshold was significantly lower when an additional strong headlamp was used (0.59 compared to 0.69-0.72 when reduced illumination intensities were used). One of the two examiners also had a significantly lower sensitivity for the D1 threshold when an additional headlamp was used. The use of additional white light led to a reduced detection of dentine lesions. PMID- 26655648 TI - The updated Cochrane review 2014 on GnRH agonist trigger: an indispensable piece of information for the clinician. PMID- 26655649 TI - Reply to the commentary by Professor Gardner on blastocyst culture and transfer. PMID- 26655650 TI - Vacuoles in sperm head are not associated with head morphology, DNA damage and reproductive success. AB - In this retrospective study of 873 men enrolled for assisted reproduction techniques, relationships between sperm quality parameters, motile sperm organelle morphology examination (MSOME), DNA damage and live birth rate were evaluated. The presence of vacuoles in the sperm heads was detected by MSOME. Either chromatin decondensation or DNA fragmentation was used to study DNA damage. Results show that age significantly affected some of the examined parameters. In particular, sperm concentration was positively correlated (R = 0.088; P = 0.01) and chromatin decondensation was negatively correlated (R = 0.102; P = 0.003) with age. Furthermore, live birth rate was significantly lower in men aged 40 years or older (P < 0.02) compared with the younger age groups. The presence of sperm head vacuoles was not associated with head morphology, main sperm quality parameters, DNA fragmentation and live birth rate. Considering sperm heads in relation to the shape (normal/abnormal) and vacuoles (presence/absence), no significant variations in the occurrence of vacuoles in either normal or abnormal heads were found. These data suggest that vacuoles are physiological features that do not alter sperm functionality, and it seems that MSOME is not necessary for increasing the success of assisted reproduction techniques. PMID- 26655651 TI - Deletion of GOLGA2P3Y but not GOLGA2P2Y is a risk factor for oligozoospermia. AB - The AZFc locus on the human Y chromosome harbours several multicopy genes, some of which are required for spermatogenesis. It is believed that deletion of one or more copies of these genes is a cause of infertility in some men. GOLGA2LY is one of the genes in the AZFc locus and it exists in two copies, GOLGA2P2Y and GOLGA2P3Y. The involvement of GOLGA2LY gene copy deletions in male infertility, however, is unknown. This study aimed to investigate the association of deletions of GOLGA2P2Y and GOLGA2P3Y gene copies with male infertility and with sperm concentration and motility. The frequency of GOLGA2P3Y deletion was significantly higher in oligozoospermic men compared with normozoospermic men (7.7% versus 1.2%; P = 0.0001), whereas the frequency of GOLGA2P2Y deletion was comparable between oligozoospermic and normozoospermic men (10.3% versus 11.3%). The deletion of GOLGA2P3Y but not GOLGA2P2Y was significantly higher (P = 0.03) in men with gr/gr rearrangements, indicating that GOLGA2P3Y deletions increase the susceptibility of men with gr/gr rearrangements to oligozoospermia. Furthermore, men with GOLGA2P3Y deletion had reduced sperm concentration and motility compared with men without deletion or with deletion of GOLGA2P2Y. These findings indicate GOLGA2P3Y gene copy may be candidate AZFc gene for male infertility. PMID- 26655652 TI - Factors affecting embryo viability and uterine receptivity: insights from an analysis of the UK registry data. AB - Many studies have identified prognostic factors for IVF treatment outcome; however, little information is available on the mechanism of their action. Embryo uterus models have the potential to distinguish between factors acting on the embryo directly and those acting through the uterine environment. Here we apply embryo-uterus models to comprehensive UK registry data from two periods, 2000 2005 and 2007-2011, containing 139,444 and 226,542 embryo transfer cycles, respectively. Given this large dataset, the embryo-uterus model is capable of distinguishing between uterine and embryo effects. Maternal age is the predominant predictor of live birth and acts on both the embryo and uterine components, but with larger effects on the embryo. Prolonged embryo culture is associated with greater embryo viability, reflecting the greater degree of selection, but is also associated with greater uterine receptivity. Cryopreserved embryos are less viable and were associated with poorer uterine receptivity. This work suggests that, in addition to the direct effects of in-vitro culture on the embryonic environment during the first few days of the embryo's life, the delay in transfer after extended culture or cryopreservation can lead to an altered uterine environment for the embryo after transfer. PMID- 26655653 TI - Nitrate-Induced Headache May Have Confounding Factors. PMID- 26655654 TI - The Sustained-Exposure Dexamethasone Formulation OTO-104 Offers Effective Protection against Noise-Induced Hearing Loss. AB - The otoprotective effects of OTO-104 were investigated both prior to and following acute acoustic trauma. Guinea pigs received a single intratympanic injection of OTO-104 and were assessed in a model of acute acoustic trauma. Doses of at least 2.0% OTO-104 offered significant protection against hearing loss induced by noise exposure when administered 1 day prior to trauma and up to 3 days thereafter. Otoprotection remained effective even with higher degrees of trauma. In contrast, the administration of a dexamethasone sodium phosphate solution did not protect against noise-induced hearing loss. Activation of the classical nuclear glucocorticoid and mineralocorticoid receptor pathways was required for otoprotection by OTO-104. The sustained exposure properties of OTO 104 were also superior to a steroid solution. PMID- 26655655 TI - Metallothionein and Hsp70 trade-off against one another in Daphnia magna cross tolerance to cadmium and heat stress. AB - The association between the insensitivity of adapted ecotypes of invertebrates to environmental stress, such as heavy metal pollution, and overall low Hsp levels characterizing these organisms has been attracting attention in various studies. The present study seeks to induce and examine this phenomenon in Daphnia magna by multigenerational acclimation to cadmium in a controlled laboratory setting. In this experiment, interclonal variation was examined: two clones of D. magna that have previously been characterized to diverge regarding their cadmium resistance and levels of the stress protein Hsp70, were continuously exposed to a sublethal concentration of Cd over four generations to study the effects of acclimation on Hsp70, metallothionein (MT), reproduction and cross-tolerance to heat stress. The two clones differed in all the measured parameters in a characteristic way, clone T displaying Cd and heat resistance, lower Hsp70 levels and offspring numbers on the one hand and higher MT expression on the other hand, clone S the opposite for all these parameters. We observed only slight acclimation-induced changes in constitutive Hsp70 levels and reproductive output. The differences in MT expression between clones as well as between acclimated organisms and controls give evidence for MT accounting for the higher Cd tolerance of clone T. Overall high Hsp70 levels of clone S did not confer cross tolerance to heat stress, contrary to common expectations. Our results suggest a trade-off between the efforts to limit the proteotoxic symptoms of Cd toxicity by Hsp70 induction and those to sequester and detoxify Cd by means of MT. PMID- 26655656 TI - Interactive effects of copper oxide nanoparticles and light to green alga Chlamydomonas reinhardtii. AB - The present study explores the effect of light with different spectral composition on the stability of CuO-nanoparticle (CuO-NP) dispersions and their effects to green alga Chlamydomonas reinhardtii. The results showed that simulated natural light (SNL) and light with enhanced UVB radiation (UVR*) do not affect the dissolution of CuO-NPs as compared to light irradiation conditions typically used in laboratory incubator (INC). Comparable values of zeta-potential and hydrodynamic size during 24h were found under all studied conditions. Concentrations of CuO-NPs below 1mgL(-1) do not attenuate the light penetration in the algal suspensions in comparison with NP-free system. Exposure to a combination of 8MUgL(-1) or 0.8mgL(-1) CuO-NPs and INC or SNL has no significant effect on the algal growth inhibition, algal fluorescence and membrane integrity under short-term exposure. However, an enhancement of the percentage of cells experiencing oxidative stress was observed upon exposure to 0.8mgL(-1) CuO-NPs and SNL for 4 and 8h. Combination of UVR* and 0.8mgL(-1) CuO-NPs resulted in synergistic effects for all biological endpoints. Despite the photocatalytic properties of CuO-NPs no significant increase in abiotic reactive oxygen species (ROS) production under simulated solar radiation was observed suggesting that the synergistic effect observed might be correlated to other factors than CuO-NP mediated ROS photoproduction. Tests performed with CuSO4 confirmed the important role of dissolution as toxicity driving force for lower CuO-NP concentration. However, they failed to clarify the contribution of dissolved Cu on the combined effects at 0.8mgL(-1) CuO-NPs. The results point out the necessity of taking into account the possible interactions between ENPs and changing light conditions when evaluating the potential effects of ENPs to phytoplankton in natural waters. PMID- 26655657 TI - Differential modulation of ammonia excretion, Rhesus glycoproteins and ion regulation in common carp (Cyprinus carpio) following individual and combined exposure to waterborne copper and ammonia. AB - The main objective of this study was to understand the mode of interaction between waterborne copper (Cu) and high environmental ammonia (HEA) exposure on freshwater fish, and how they influence the toxicity of each other when present together. For this purpose, individual and combined effects of Cu and HEA were examined on selected physiological and ion-regulatory processes and changes at transcript level in the common carp (Cyprinus carpio). Juvenile carp were exposed to 2.6MUM Cu (25% of the 96h LC50value) and to 0.65mM ammonia (25% of the 96h LC50value) singly and as a mixture for 12h, 24h, 48h, 84h and 180h. Responses such as ammonia (Jamm) and urea (Jurea) excretion rate, plasma ammonia and urea, plasma ions (Na(+), Cl(-) and K(+)), muscle water content (MWC) as well as branchial Na(+)/K(+)-ATPase (NKA) and H(+)-ATPase activity, and branchial mRNA expression of NKA, H(+)-ATPase, Na(+)/H(+) exchanger (NHE-3) and Rhesus (Rh) glycoproteins were investigated under experimental conditions. Results show that Jamm was inhibited during Cu exposure, while HEA exposed fish were able to increase excretion efficiently. In the combined exposure, Jamm remained at the control levels indicating that Cu and HEA abolished each other's effect. Expression of Rhcg (Rhcg-a and Rhcg-b) mRNA was upregulated during HEA, thereby facilitated ammonia efflux out of gills. On the contrary, Rhcg-a transcript level declined following Cu exposure which might account for Cu induced Jamm inhibition. Likewise, Rhcg-a was also down-regulated in Cu-HEA co-exposed fish whilst a temporary increment was noted for Rhch-b. Fish exposed to HEA displayed pronounced up-regulation in NKA expression and activity and stable plasma ion levels. In both the Cu exposure alone and combined Cu-HEA exposure, ion-osmo homeostasis was adversely affected, exemplified by the significant reduction in plasma [Na(+)] and [Cl(-)], and elevated plasma [K(+)], along with an elevation in MWC. These changes were accompanied by a decline in NKA activity. Gill H(+) ATPase mRNA levels and activities were not affected by either Cu or HEA or both. Likewise, NHE-3 expression remained unaltered but tended to be numerically higher during HEA exposure. Overall, these data suggest that at equitoxic concentrations (25% of 96h LC50), the individual effect of Cu is more harmful while HEA induces quicker adaptive responses. Our findings also denote a competitive mode of interaction, exemplified by the inhibition of HEA -mediated adaptive responses in the presence of Cu. PMID- 26655658 TI - Acute dysprosium toxicity to Daphnia pulex and Hyalella azteca and development of the biotic ligand approach. AB - The toxicological understanding of rare earth elements (REEs) in the aquatic environment is very limited but of increasing concern. The objective of this research is to compare the toxicological effect of the REE dysprosium to the freshwater invertebrates Daphnia pulex and Hyalella azteca and in the more sensitive organism, understand the toxicity modifying influence of Ca, Na, Mg, pH and dissolved organic matter (DOM). Standard methods (Environment Canada) were followed for testing and culture in media of intermediate hardness (60mg CaCO3 mg/L) at pH 7.8 with Ca at 0.5, Na 0.5, Mg 0.125 (mM) and 23 degrees C. Acute toxicity tests were done with <24h old neonates for 48h in the case of D. pulex and with 2-9 days old offspring for 96h tests with Hyalella. The potential protective effect of cationic competition was tested with Ca (0.5-2.0mM), Na (0.5 2.0mM) and Mg (0.125-0.5mM). The effect of pH (6.5-8.0) and Suwannee River DOM complexation (at dissolved organic carbon (DOC) concentrations of 9 and 13mg C/L) were evaluated. Dissolved Dy concentrations were lower than total (unfiltered) indicating precipitation, particularly at higher concentrations. Acute toxicity of Dy to H. azteca and D. pulex revealed Hyalella to be 1.4 times more sensitive than Daphnia. Additions of Ca and Na but not Mg provided significant protection against Dy toxicity to Hyalella. Similarly, low pH was associated with reduction in toxicity. Exposures which were pH buffered with and without MOPS were significantly different and indicated that MOPS enhanced Dy toxicity. DOM also mitigated Dy toxicity. Biotic ligand based parameters (LogK values) were calculated based on free ion relationships as determined by geochemical equilibrium modeling software (WHAM ver. 7.02). The logK value for Dy(3+) toxicity to Hyalella was 7.75 while the protective influence of Ca and Na were 3.95 and 4.10, respectively. This study contributes data towards the development of site specific water quality guidelines and criteria for Dy and possibly REEs in general and offers insight into the complex bio-geochemical nature of this element. PMID- 26655659 TI - A novel and versatile flash-freezing approach for evaluating the health of Delta Smelt. AB - A common approach used to assess environmental impacts in aquatic environments is to measure indicators of stress (biomarkers) and condition of fish within ecosystems. Particularly in estuarine ecosystems with multiple stressors, it is often desirable to quantify a suite of biological endpoints that (1) reflect fish condition at several levels of biological organization and time scales and (2) are sensitive to a range of environmental stressors. However, established methods of preservation and processing of fish for specific endpoints are often incompatible. Here, we developed a novel flash-freezing approach for assessing the health of a small, sensitive fish, the endangered Delta Smelt (Hypomesus transpacificus) after collections from the San Francisco Estuary (SFE). We assess whether flash-freezing the entire fish ensures effective preservation of multiple tissues for subsequent biomarker analyses by comparing measurements of fresh to frozen tissue. Tissues included brain, gill, and liver for enzyme activity, kidney and spleen for pathogens, and gills, liver, and gonads for histopathology and reproduction. Although flash-freezing in liquid nitrogen altered the length, weight, and condition factor of Delta Smelt, the percent changes were small (<1.5%). Histological analyses of the cellular morphology of gills, liver, and gonads were similar between both methods. Freezing artefacts were observed in ovaries, but did not hinder the identification and interpretation of cell types and oocyte stages. Freezing did not alter bacterial isolation or the activities of ethoxyresorufin-0-deethylase (EROD) or acetylcholinesterase (AChE), but had a small, negative influence on sodium potassium adenosine triphosphatase (ATPase) activity. Thus, flash-freezing in the field is a versatile preservation method for Delta Smelt, allowing for multiple tissue collections and bioassays from an individual tiny fish exposed to a wide range of natural and anthropogenic stressors. Similar methodology may be applicable to other species for which a range of biological endpoints and histopathology data are needed. PMID- 26655660 TI - Manufactured nanoparticles in the aquatic environment-biochemical responses on freshwater organisms: A critical overview. AB - The enormous investments in nanotechnology have led to an exponential increase of new manufactured nano-enabled materials whose impact in the aquatic systems is still largely unknown. Ecotoxicity and nanosafety studies mostly resulted in contradictory results and generally failed to clearly identify biological patterns that could be related specifically to nanotoxicity. Generation of reactive oxygen species (ROS) is one of the most discussed nanotoxicity mechanism in literature. ROS can induce oxidative stress (OS), resulting in cyto- and genotoxicity. The ROS overproduction can trigger the induction of anti-oxidant enzymes such as catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidases (GPx), which are used as biomarkers of response. A critical overview of the biochemical responses induced by the presence of NPs on freshwater organisms is performed with a strong interest on indicators of ROS and general stress. A special focus will be given to the NPs transformations, including aggregation, and dissolution, in the exposure media and the produced biochemical endpoints. PMID- 26655661 TI - Metabolomics reveals energetic impairments in Daphnia magna exposed to diazinon, malathion and bisphenol-A. AB - (1)H nuclear magnetic resonance (NMR)-based metabolomics was used to study the response of Daphnia magna to increasing sub-lethal concentrations of either an organophosphate (diazinon or malathion) or bisphenol-A (BPA). Principal component analysis (PCA) of (1)H NMR spectra were used to screen metabolome changes after 48h of contaminant exposure. The PCA scores plots showed that diazinon exposures resulted in aberrant metabolomic profiles at all exposure concentrations tested (0.009-0.135 MUg/L), while for malathion the second lowest (0.08MUg/L) and two highest exposure concentrations (0.32MUg/L and 0.47MUg/L) caused significant shifts from the control. Individual metabolite changes for both organophosphates indicated that the response to increasing exposure was non-linear and described perturbations in the metabolome that were characteristic of the severity of exposure. For example, intermediate concentrations of diazinon (0.045MUg/L and 0.09MUg/L) and malathion (0.08MUg/L) elicited a decrease in amino acids such as leucine, valine, arginine, glycine, lysine, glutamate, glutamine, phenylalanine and tyrosine, with concurrent increases in glucose and lactate, suggesting a mobilization of energy resources to combat stress. At the highest exposure concentrations for both organophosphates there was evidence of a cessation in metabolic activity, where the same amino acids increased and glucose and lactate decreased, suggesting a slowdown in protein synthesis and depletion of energy stocks. This demonstrated a similar response in the metabolome between two organophosphates but also that intermediate and severe stress levels could be differentiated by changes in the metabolome. For BPA exposures, the PCA scores plot showed a significant change in metabolome at 0.1mg/L, 1.4mg/L and 2.1mg/L of exposure. Individual metabolite changes from 0.7 to 2.1mg/L of BPA exposure showed increases in amino acids such as alanine, valine, isoleucine, leucine, arginine, phenylalanine and tyrosine. These metabolite changes were correlated with decreases in glucose and lactate. This pattern of response was also seen in the highest organophosphate exposures and suggested a generalized stress response that could be related to altered energy dynamics in D. magna. Through studying increasing exposure responses, we have demonstrated the ability of metabolomics to identify discrete differences between intermediate and severe stress, and also to characterize how systemic stress is manifested in the metabolome. PMID- 26655663 TI - Screening of the key volatile organic compounds of Tuber melanosporum fermentation by aroma sensory evaluation combination with principle component analysis. AB - Aroma results from the interplay of volatile organic compounds (VOCs) and the attributes of microbial-producing aromas are significantly affected by fermentation conditions. Among the VOCs, only a few of them contribute to aroma. Thus, screening and identification of the key VOCs is critical for microbial producing aroma. The traditional method is based on gas chromatography olfactometry (GC-O), which is time-consuming and laborious. Considering the Tuber melanosporum fermentation system as an example, a new method to screen and identify the key VOCs by combining the aroma evaluation method with principle component analysis (PCA) was developed in this work. First, an aroma sensory evaluation method was developed to screen 34 potential favorite aroma samples from 504 fermentation samples. Second, PCA was employed to screen nine common key VOCs from these 34 samples. Third, seven key VOCs were identified by the traditional method. Finally, all of the seven key VOCs identified by the traditional method were also identified, along with four others, by the new strategy. These results indicate the reliability of the new method and demonstrate it to be a viable alternative to the traditional method. PMID- 26655664 TI - Jailed surgeon is given leave to appeal against conviction. PMID- 26655662 TI - Parental dietary seleno-L-methionine exposure and resultant offspring developmental toxicity. AB - Selenium (Se) leaches into water from agricultural soils and from storage sites for coal fly ash. Se toxicity causes population and community level effects in fishes and birds. We used the laboratory aquarium model fish, Japanese medaka (Oryzias latipes), an asynchronous breeder, to determine aspects of uptake in adults and resultant developmental toxicity in their offspring. The superior imaging properties of the model enabled detailed descriptions of phenotypic alterations not commonly reported in the existing Se literature. Adult males and females in treatment groups were exposed, separately and together, to a dry diet spiked with 0, 12.5, 25, or 50 MUg/g (dry weight) seleno-L-methionine (SeMet) for 6 days, and their embryo progeny collected for 5 days, maintained under controlled conditions and observed daily for hatchability, mortality and/or developmental toxicity. Sites of alteration included: craniofacial, pericardium and abdomen (Pc/Ab), notochord, gall bladder, spleen, blood, and swim bladder. Next, adult tissue Se concentrations (liver, skeletal muscle, ovary and testis) were determined and compared in treatment groups of bred and unbred individuals. No significant difference was found across treatment groups at the various SeMet concentrations; and, subsequent analysis compared exposed vs. control in each of the treatment groups at 10 dpf. Increased embryo mortality was observed in all treatment groups, compared to controls, and embryos had a decreased hatching rate when both parents were exposed. Exposure resulted in significantly more total altered phenotypes than controls. When altered phenotypes following exposure of both parents were higher than maternal only exposure, a male role was suggested. The comparisons between treatment groups revealed that particular types of phenotypic change may be driven by the sex of the exposed parent. Additionally, breeding reduced Se concentrations in some adult tissues, specifically the liver of exposed females and skeletal muscle of exposed males. Detailed phenotypic analysis of progeny from SeMet exposed parents should inform investigations of later life stages in an effort to determine consequences of early life exposure. PMID- 26655665 TI - Imaging in median arcuate ligament syndrome. PMID- 26655666 TI - Posterior reversible encephalopathy syndrome with thalamic involvement during vasopressor treatment of vertebrobasilar vasospasm after subarachnoid hemorrhage. AB - Hemodynamic augmentation is the primary medical intervention employed to reverse neurological deficits associated with vasospasm and delayed cerebral ischemia following aneurysmal subarachnoid hemorrhage. Failure to improve despite induced hypertension (IH) may raise concern for persistent hypoperfusion and prompt even more aggressive blood pressure augmentation. However, posterior reversible encephalopathy syndrome (PRES) is a hyperperfusion syndrome reported as a rare complication of IH that may confound this picture. We report a case of PRES with prominent thalamic involvement and impaired level of consciousness secondary to blood pressure augmentation for the treatment of symptomatic vertebrobasilar vasospasm. Recognition of this syndrome in distinction to worsening ischemia is particularly critical, as normalization of blood pressure should lead to rapid clinical improvement. PMID- 26655667 TI - Management of dens in dente associated with a chronic periapical lesion. AB - Dens in dente is characterised as a developmental anomaly resulting from invagination of the enamel organ into the dental papilla. It is a rare malformation of teeth, showing a wide spectrum of morphological variations such as gemination, microdontia, taurodontism, dentinogenesis imperfecta, supernumerary tooth and hyperplasias, resulting frequently in early pulp necrosis. Maxillary lateral incisors are the commonest teeth to be affected by dental malformations-supernumerary tooth, talon cusp, congenitally missing tooth and dens in dente. We describe the management of a case of dens in dente in a maxillary lateral incisor with a periradicular lesion. PMID- 26655668 TI - Atlanto-axial infection after acupuncture. AB - A 67-year-old man presented with neck cellulitis following acupuncture for cervical spondylosis. Blood cultures were positive for methicillin-sensitive Staphylococcus aureus. Increased neck pain and bacteraemia prompted MRI, which showed atlanto-axial septic arthritis without signs of infection of the tissues between the superficial cellulitic area and the atlanto-axial joint, thus making direct extension of infection unlikely. It is more likely that haematogenous spread of infection resulted in seeding in the atlanto-axial joint, with the proximity of the arthritis and acupuncture site being coincidental. Acupuncture is a treatment option for some indolent pain conditions. As such, acupuncture services are likely to be more frequently utilised. A history of acupuncture is rarely requested by the admitting doctor and seldom offered voluntarily by the patient, especially where the site of infection due to haematogenous spread is distant from the needling location. Awareness of infectious complications following acupuncture can reduce morbidity through early intervention. PMID- 26655669 TI - Neisseria elongata subsp elongata infective endocarditis following endurance exercise. AB - A 31-year-old Argentinian woman presented with a 3-week history of fever, night sweats, myalgia and lethargy following a work trip to Uganda where she ran a marathon. Malarial screens were negative but C reactive protein, erythrocyte sedimentation rate and neutrophil count were raised and she was anaemic. A new pansystolic murmur was heard over the mitral valve and the transthoracic echocardiogram showed a large vegetation (>1 cm) with at least moderate mitral regurgitation. Blood cultures grew Neisseria elongata, subsp elongata treated initially with ceftriaxone then oral ciprofloxacin to complete 4 weeks of treatment. CT scan revealed a wedge-shaped area of low attenuation in the spleen in keeping with a splenic infarct. Seven days postadmission, the patient underwent a successful mitral valve repair. Recovery was complicated by a likely embolic infarct in the right frontal lobe, but the patient was discharged 12 days postoperative with no neurological sequelae. PMID- 26655670 TI - Hyponatraemia in patients with multiple myeloma. AB - Hyponatraemia is the most common electrolyte disturbance encountered in clinical practice. Several causes of hyponatraemia are recognised and in many patients the aetiology may be multifactorial. An important cause is water intoxication and this is often iatrogenic. We present three patients, all of whom suffered from multiple myeloma, who illustrate different aspects of hyponatraemia, its causes and management. PMID- 26655671 TI - Time-resolved observation of band-gap shrinking and electron-lattice thermalization within X-ray excited gallium arsenide. AB - Femtosecond X-ray irradiation of solids excites energetic photoelectrons that thermalize on a timescale of a few hundred femtoseconds. The thermalized electrons exchange energy with the lattice and heat it up. Experiments with X-ray free-electron lasers have unveiled so far the details of the electronic thermalization. In this work we show that the data on transient optical reflectivity measured in GaAs irradiated with femtosecond X-ray pulses can be used to follow electron-lattice relaxation up to a few tens of picoseconds. With a dedicated theoretical framework, we explain the so far unexplained reflectivity overshooting as a result of band-gap shrinking. We also obtain predictions for a timescale of electron-lattice thermalization, initiated by conduction band electrons in the temperature regime of a few eVs. The conduction and valence band carriers were then strongly non-isothermal. The presented scheme is of general applicability and can stimulate further studies of relaxation within X-ray excited narrow band-gap semiconductors. PMID- 26655673 TI - IFN-gamma modulates Ly-49 receptors on NK cells in IFN-gamma-induced pregnancy failure. AB - We have previously shown that interferon gamma (IFN-gamma) induces aberrant CD49b(+) natural killer (NK) cell recruitment by regulating CX3CL1 and eventually provokes foetal loss. In this study, we show that IFN-gamma also modulates Ly-49 receptors on NK cells during pregnancy failure. The percentages of Ly-49A(+) and Ly-49G2(+) NK cells in the uteri of the IFN-gamma-treated group were significantly lower than those observed in the control group. Moreover, the median fluorescence intensity (MFI) values of Ly-49A and Ly-49G2 expression on NK cells in the uteri of the IFN-gamma-treated group were significantly lower than those of the control group. Using isolated spleen leucocytes, we further found that IFN-gamma significantly reduced the percentage of Ly-49A(+) NK cells in vitro. However, CX3CL1 was not involved in the modulation of Ly-49 receptors, and the expression of CX3CR1 was not regulated by IFN-gamma in spleen leucocytes. Collectively, our data indicate that IFN-gamma can modulate Ly-49 receptors on NK cells and this process may play a role in IFN-gamma-induced pregnancy failure. Thus, we provide a new line of evidence correlating the deleterious effects of IFN-gamma with its role in regulating NK cell Ly-49 receptors during pregnancy failure. PMID- 26655672 TI - Dopamine is produced in the rat spinal cord and regulates micturition reflex after spinal cord injury. AB - Dopamine (DA) neurons in the mammalian central nervous system are thought to be restricted to the brain. DA-mediated regulation of urinary activity is considered to occur through an interaction between midbrain DA neurons and the pontine micturition center. Here we show that DA is produced in the rat spinal cord and modulates the bladder reflex. We observed numerous tyrosine hydroxylase (TH)+ neurons in the autonomic nuclei and superficial dorsal horn in L6-S3 spinal segments. These neurons are dopamine-beta-hydroxylase (DBH)- and some contain detectable dopamine decarboxylase (DDC), suggesting their capacity to produce DA. Interestingly, following a complete thoracic spinal cord injury (SCI) to interrupt supraspinal projections, more TH+ neurons emerged in the lumbosacral spinal cord, coincident with a sustained, low level of DA expression there and a partially recovered micturition reflex. Non-selective blockade of spinal DA receptors reduced bladder activity whereas activation of spinal D2-like receptors increased bladder activity and facilitated voiding. Additionally, depletion of lumbosacral TH+ neurons with 6-hydroxydopamine (6-OHDA) decreased bladder non voiding contractions and voiding efficiency. Furthermore, injecting the transsynaptic neuronal tracer pseudorabies virus (PRV) into the bladder detrusor labeled TH+ cells in the lumbosacral cord, confirming their involvement in spinal micturition reflex circuits. These results illustrate that DA is synthesized in the rat spinal cord; plasticity of lumbosacral TH+ neurons following SCI may contribute to DA expression and modulate the spinal bladder reflex. Thus, spinally-derived DA and receptors could be a novel therapeutic target to improve micturition recovery after SCI. PMID- 26655674 TI - [Population screening strategies in recent immigrant to Spain]. AB - The definition of terms that delimites the content of this paper are initially displayed. Subsequently, the main sources of information about the disease screening in immigrants and the entities considered susceptible of screening are showed. In a later section we review the diagnostic methodology used, separately considering the history, physical examination, the usual complementary tests and specific studies of both infectious and noninfectious diseases. Finally, with the limitations of the data available a proposal of a protocol for screening of diseases in recent immigrant is performed. PMID- 26655675 TI - Air pollution and childhood bronchitis: Interaction with xenobiotic, immune regulatory and DNA repair genes. AB - BACKGROUND: Gene-environment interactions have been investigated for diseases such as asthma, chronic obstructive pulmonary disease, cancer etc. but acute disease like bronchitis has rarely been studied. We investigated interactions between air pollution (polycyclic aromatic hydrocarbons (PAH) and particulate matter <2.5 MUm (PM2.5)) and single nucleotide polymorphisms (SNP) in EPHX1, IL10, STAT4 and XPC genes in relation to bronchitis in children aged 0-2 years. METHODS: A stratified random sample of 1133 Czech children, born between 1994 and 1998 in two districts, were followed since birth, of which 626 were genotyped. Pediatrician-diagnosed bronchitis episodes were obtained from the medical records. Central-site monitors measured air pollution exposure. We used multivariable logistic regression and estimated coefficients using generalized estimating equations. Interaction was assessed between pollutants and genes and associations in genotype-specific strata were presented. False discovery rate was used to adjust for multiple comparisons. RESULTS: There were 803 episodes of bronchitis with an incidence rate of 56 per 1000 child-months. We found significant gene-environment interaction between PAH and four SNPs (EPHX1, (rs2854461), STAT4 (rs16833215), XPC (rs2228001 and rs2733532)), which became non significant after adjusting for multiple comparisons. PM2.5 interactions with two XPC SNPs (rs2228001 and rs2733532) remained significant after accounting for multiple comparisons and those with CC alleles had a more than doubling of odds, OR=2.65 (95% CI: 1.91, 3.69) and 2.72 (95% CI: 1.95, 3.78), respectively, per 25 MUg/m(3) increase in exposure. CONCLUSION: The findings suggest that the DNA repair gene XPC may play an important role in the air pollution-induced pathogenesis of the inflammatory disease bronchitis. PMID- 26655676 TI - Children's exposure to polybrominated diphenyl ethers (PBDEs) through mouthing toys. AB - Polybrominated diphenyl ethers (PBDEs) have previously been detected in children toys, yet the risk of child exposure to these chemicals through the mouthing of toys or other items is still unknown. We aimed to expand on the current knowledge by investigating the impact of infants' mouthing activities on exposure to PBDEs present in toys. This was established by a leaching model for determining the amount PBDEs that can leach from toys into saliva in simulated conditions. The PBDE migration rate was at its highest for the 15 min low-exposure scenario incubations (198 pg/cm(2) * min) with the ERM EC-591 certified reference material (CRM) (0.17% w/w PBDEs). The leaching process was congener-dependent, since the percentage of lower brominated PBDE congeners that leached out was up to 4.5 times higher than for the heavier PBDEs. To study the scenario in which a child would mouth on a toy flame retarded with BDE 209 alone, a plastic item containing 7% BDE 209 (w/w) was also tested. The BDE 209 amounts leached out in only 15 min were higher than the amounts leached from the CRM after the 16 h incubation. For the Belgian population, the exposure scenario from mouthing on toys containing PBDEs in amounts similar to the REACH threshold was found to be lower than the exposure from mother's milk, but higher than the exposure through diet or even dust. PMID- 26655677 TI - Gel-free/label-free proteomic analysis of developing rice grains under heat stress. AB - High temperature markedly reduces the yields and quality of rice grains. To identify the mechanisms underlying heat stress-induced responses in rice grains, proteomic technique was used. Developing Khao Dawk Mali 105 rice grains at the milky, dough, and mature stages were treated at 40 degrees C for 3 days. Aromatic compounds were decreased in rice grains under heat stress. The protein abundance involved in glycolysis and tricarboxylic acid cycle, including glyceraldehyde 3-phosphate dehydrogenase and citrate synthase, was changed in milky and dough grains after heat treatment; however, none changes in mature grains. The abundance involved in amino acid metabolism was increased in dough grains, but decreased in milky grains. In addition, the abundance involved in starch and sucrose metabolism, such as starch synthase, ADP-glucose pyrophosphorylase, granule-bound starch synthase, and alpha amylase, was decreased in milky grains, but increased in dough grains. A number of redox homeostasis-related proteins, such as ascorbate peroxidase and peroxiredoxin, were increased in developing rice grains treated with heat stress. These results suggest that in response to heat stress, the abundance of numerous proteins involved in redox homeostasis and carbohydrate biosynthetic pathways may play a major role in the development of KDML105 rice grains. BIOLOGICAL SIGNIFICANCE: Yield of Khao Dawk Mali 105 rice, which is an economical aromatic rice, was disrupted by environmental stress. Rice grains developed under heat stress caused loss of aroma compound. To identify the mechanism of heat response in rice grain, gel-free/label-free proteomic technique was used. The abundance of proteins involved in glycolysis and tricarboxylic acid cycle was disrupted by heat stress. High temperature limited starch biosynthesis; however, it enhanced sugar biosynthesis in developing rice grains. Redox homeostasis related proteins were disrupted by heat stress. These results suggest that proteins involved in redox homeostasis and carbohydrate pathway might play a major role in developing grains in Khao Dawk Mali 105 rice under heat stress. PMID- 26655678 TI - Jasmonic acid induced protein response to biophoton emissions and flooding stress in soybean. AB - Biophoton emissions were elevated by the exogenous plant hormone application such as jasmonic (JA) and salicylic acid (SA). To reveal the molecular mechanisms underlying flooding stress responses in soybean treated with JA and SA, biophoton emissions from plants were quantified in combination with proteomic analyses. Furthermore, treatment with exogenous JA inhibited lateral root growth and markedly reduced root weight. Out of 649 proteins identified in the JA- and JA/SA treated plants, 44 were unique to JA-treated plants, 403 were unique to JA/SA treated plants, and 202 were shared between the groups. These proteins were involved in stress, signaling, degradation, glycolysis, fermentation, and hormone metabolism. The abundances of glutathione-S-transferase, alanine aminotransferase, and malate dehydrogenase were decreased; however, the activities of these enzymes were increased. In contrast, the abundance and activity of monodehydroascorbate reductase increased in the roots of plants treated with JA and SA under flooding stress. This suggests that the quantity of lateral roots, total root mass, and free radicals generated during oxidation and reduction reactions and reactive oxygen species scavenging largely contribute to biophoton emission. Furthermore, monodehydroascorbate reductase, which is involved in detoxification and controlling hydrogen peroxide levels, may protect plant cells against oxidative damage during flooding. BIOLOGICAL SIGNIFICANCE: To understand the source of biophoton emission and molecular mechanism by the application of jasmonic and salicylic acid under flooding conditions in soybean plants, the label-free quantitative techniques were performed in roots. Root lengths and weights were significantly reduced by the effect of jasmonic and salicylic acid while it inhibited growth of the lateral roots in normal conditions using the jasmonic acid. Finally, identified proteins were functionally annotated by MAPMAN software application; that were assigned to different functional categories, such as stress, signaling, protein, glycolysis, metabolism, cell wall, and cell organization. Consequently, this study offers to learn the photon emission in plants and to know the molecular mechanism under flooding stress in soybean. PMID- 26655679 TI - Novel green tissue-specific synthetic promoters and cis-regulatory elements in rice. AB - As an important part of synthetic biology, synthetic promoter has gradually become a hotspot in current biology. The purposes of the present study were to synthesize green tissue-specific promoters and to discover green tissue-specific cis-elements. We first assembled several regulatory sequences related to tissue specific expression in different combinations, aiming to obtain novel green tissue-specific synthetic promoters. GUS assays of the transgenic plants indicated 5 synthetic promoters showed green tissue-specific expression patterns and different expression efficiencies in various tissues. Subsequently, we scanned and counted the cis-elements in different tissue-specific promoters based on the plant cis-elements database PLACE and the rice cDNA microarray database CREP for green tissue-specific cis-element discovery, resulting in 10 potential cis-elements. The flanking sequence of one potential core element (GEAT) was predicted by bioinformatics. Then, the combination of GEAT and its flanking sequence was functionally identified with synthetic promoter. GUS assays of the transgenic plants proved its green tissue-specificity. Furthermore, the function of GEAT flanking sequence was analyzed in detail with site-directed mutagenesis. Our study provides an example for the synthesis of rice tissue-specific promoters and develops a feasible method for screening and functional identification of tissue-specific cis-elements with their flanking sequences at the genome-wide level in rice. PMID- 26655680 TI - Divalent flagellin immunotherapy provides homologous and heterologous protection in experimental urinary tract infections in mice. AB - Immunotherapy employs selected prokaryotic elements which are specially targeted because of their designated important role in the pathogenicity of the microbes. Among these is the flagellin of P. aeruginosa, which plays a major role in establishment of urinary tract infections (UTIs). In this study we envisage divalent flagellin (a combination of flagellin subtypes, 'a' and 'b') as an immunotherapeutic candidate against UTIs caused by Pseudomonas aeruginosa. Flagellin proteins were isolated from P. aeruginosa strains and characterized by MALDI-TOF. Their efficacy was checked in an ascending model of UTI. Divalent flagellin ('a' and 'b') when given together (intraperitoneally, i.p.) to female LACA mice at a concentration of 5 MUg each, protected mice against pyelonephritis due to P. aeruginosa strains with no bacterial load at peak day of infection. Tissue destruction was minimum, as assessed by MDA levels and renal histopathology. Divalent flagellin immunization also drastically reduced pro inflammatory cytokine levels (TNF alpha and IL-1beta) in renal homogenates as determined by ELISA. It also prevented UTI caused by heterologous strain Escherichia coli. Antibodies against both flagellin proteins were assessed by ELISA. Passive immunization protected mice against UTI induced by either of the strains, P. aeruginosa and E. coli. These results confirmed homologous and heterologous protection provided by divalent flagellin. PMID- 26655681 TI - Assessment of trauma patients. AB - Trauma is a major contributor to global mortality and morbidity with a notable difference between low income countries (LIC) and high to moderate income countries (HMIC). The modality of trauma differs globally; however, the most notable cause is pedestrian vs. vehicle and road traffic collision respectively. It is imperative that patients who have sustained a traumatic injury are managed in an appropriate and timely manner. Part 1 of the article will address the aetiology and demographic distribution of trauma globally and part 2 of the article will provide information about structured assessment and management of trauma patients. PMID- 26655682 TI - Heterogeneous and nonlinear development of human posterior parietal cortex function. AB - Human cognitive problem solving skills undergo complex experience-dependent changes from childhood to adulthood, yet most neurodevelopmental research has focused on linear changes with age. Here we challenge this limited view, and investigate spatially heterogeneous and nonlinear neurodevelopmental profiles between childhood, adolescence, and young adulthood, focusing on three cytoarchitectonically distinct posterior parietal cortex (PPC) regions implicated in numerical problem solving: intraparietal sulcus (IPS), angular gyrus (AG), and supramarginal gyrus (SMG). Adolescents demonstrated better behavioral performance relative to children, but their performance was equivalent to that of adults. However, all three groups differed significantly in their profile of activation and connectivity across the PPC subdivisions. Activation in bilateral ventral IPS subdivision IPS-hIP1, along with adjoining anterior AG subdivision, AG-PGa, and the posterior SMG subdivision, SMG-PFm, increased linearly with age, whereas the posterior AG subdivision, AG-PGp, was equally deactivated in all three groups. In contrast, the left anterior SMG subdivision, SMG-PF, showed an inverted U-shaped profile across age groups such that adolescents exhibited greater activation than both children and young adults. Critically, greater SMG-PF activation was correlated with task performance only in adolescents. Furthermore, adolescents showed greater task-related functional connectivity of the SMG-PF with ventro temporal, anterior temporal and prefrontal cortices, relative to both children and adults. These results suggest that nonlinear up-regulation of SMG-PF and its interconnected functional circuits facilitate adult-level performance in adolescents. Our study provides novel insights into heterogeneous age-related maturation of the PPC underlying cognitive skill acquisition, and further demonstrates how anatomically precise analysis of both linear and nonlinear neurofunctional changes with age is necessary for more fully characterizing cognitive development. PMID- 26655683 TI - Systems toxicology-based assessment of the candidate modified risk tobacco product THS2.2 for the adhesion of monocytic cells to human coronary arterial endothelial cells. AB - Alterations of endothelial adhesive properties by cigarette smoke (CS) can progressively favor the development of atherosclerosis which may cause cardiovascular disorders. Modified risk tobacco products (MRTPs) are tobacco products developed to reduce smoking-related risks. A systems biology/toxicology approach combined with a functional in vitro adhesion assay was used to assess the impact of a candidate heat-not-burn technology-based MRTP, Tobacco Heating System (THS) 2.2, on the adhesion of monocytic cells to human coronary arterial endothelial cells (HCAECs) compared with a reference cigarette (3R4F). HCAECs were treated for 4h with conditioned media of human monocytic Mono Mac 6 (MM6) cells preincubated with low or high concentrations of aqueous extracts from THS2.2 aerosol or 3R4F smoke for 2h (indirect treatment), unconditioned media (direct treatment), or fresh aqueous aerosol/smoke extracts (fresh direct treatment). Functional and molecular investigations revealed that aqueous 3R4F smoke extract promoted the adhesion of MM6 cells to HCAECs via distinct direct and indirect concentration-dependent mechanisms. Using the same approach, we identified significantly reduced effects of aqueous THS2.2 aerosol extract on MM6 cell-HCAEC adhesion, and reduced molecular changes in endothelial and monocytic cells. Ten- and 20-fold increased concentrations of aqueous THS2.2 aerosol extract were necessary to elicit similar effects to those measured with 3R4F in both fresh direct and indirect exposure modalities, respectively. Our systems toxicology study demonstrated reduced effects of an aqueous aerosol extract from the candidate MRTP, THS2.2, using the adhesion of monocytic cells to human coronary endothelial cells as a surrogate pathophysiologically relevant event in atherogenesis. PMID- 26655684 TI - [Not Available]. PMID- 26655685 TI - Explaining the Growth in US Health Care Spending Using State-Level Variation in Income, Insurance, and Provider Market Dynamics. AB - The slowed growth in national health care spending over the past decade has led analysts to question the extent to which this recent slowdown can be explained by predictable factors such as the Great Recession or must be driven by some unpredictable structural change in the health care sector. To help address this question, we first estimate a regression model for state personal health care spending for 1991-2009, with an emphasis on the explanatory power of income, insurance, and provider market characteristics. We then use the results from this simple predictive model to produce state-level projections of health care spending for 2010-2013 to subsequently compare those average projected state values with actual national spending for 2010-2013, finding that at least 70% of the recent slowdown in health care spending can likely be explained by long standing patterns. We also use the results from this predictive model to both examine the Great Recession's likely reduction in health care spending and project the Affordable Care Act's insurance expansion's likely increase in health care spending. PMID- 26655686 TI - Scrub typhus presenting as acute respiratory distress syndrome: case report. PMID- 26655687 TI - Foot length in newborns small for gestational age. AB - Small for gestational age (SGA) newborns have increased neonatal morbidity and mortality besides having a high risk of contracting chronic diseases during adult life. We compared foot length among 700 SGA and AGA newborns. Foot length was shorter in SGA newborns, both in term and preterm babies. Fetal growth restriction may impair foot growth and this finding may contribute to identify SGA newborns. PMID- 26655688 TI - High-Throughput Non-Contact Vitrification of Cell-Laden Droplets Based on Cell Printing. AB - Cryopreservation is the most promising way for long-term storage of biological samples e.g., single cells and cellular structures. Among various cryopreservation methods, vitrification is advantageous by employing high cooling rate to avoid the formation of harmful ice crystals in cells. Most existing vitrification methods adopt direct contact of cells with liquid nitrogen to obtain high cooling rates, which however causes the potential contamination and difficult cell collection. To address these limitations, we developed a non contact vitrification device based on an ultra-thin freezing film to achieve high cooling/warming rate and avoid direct contact between cells and liquid nitrogen. A high-throughput cell printer was employed to rapidly generate uniform cell laden microdroplets into the device, where the microdroplets were hung on one side of the film and then vitrified by pouring the liquid nitrogen onto the other side via boiling heat transfer. Through theoretical and experimental studies on vitrification processes, we demonstrated that our device offers a high cooling/warming rate for vitrification of the NIH 3T3 cells and human adipose derived stem cells (hASCs) with maintained cell viability and differentiation potential. This non-contact vitrification device provides a novel and effective way to cryopreserve cells at high throughput and avoid the contamination and collection problems. PMID- 26655689 TI - [Evaluation of Teissier's spatulas during preterm fetal vaginal delivery]. AB - AIM: The aim of our study was to evaluate the use of Teissier's spatulas in preterm vaginal deliveries by comparing them to spontaneous deliveries. MATERIALS AND METHODS: A retrospective monocentric case-control study was conducted from 2008 to 2012 on single cephalic presentations with live births between 28 and 34weeks of gestation. A comparison was made between spontaneous vaginal (controls) and instrumental deliveries by Teissier's spatulas (cases) on maternal, obstetrical and neonatal outcomes. RESULTS: The spatulas and Vaginal Spontaneous Delivery (VSD) groups were constituted of 94 and 86 patients respectively. Occiput posterior presentations were increased in the spatulas group (11.7% vs. 1.2%, P=0.003) whereas the difference in the rate of third/fourth degree perineal tear was not significant (1% vs 0%, P=1) without the need for any episiotomy. No significant difference between spatulas and VSD groups was observed in terms of Apgar score at 5minutes (P=0.61) and 10minutes (P=0.37), mean umbilical arterial pH (7.26 vs 7.3, P=0.13), transfer to ICU (56.4% vs. 65.1%, P=0.18), length of stay in ICU (5.1 versus 4.0days, P=0.19), the need for invasive ventilation (15.9% vs 19.7%, P=0.17), and the rate of intraventricular hemorrhage (4.3% versus 5.8%, P=0.39). CONCLUSION: Instrumental deliveries by Teissier's spatulas for preterm fetuses are not accompanied by any increase in neonatal or maternal morbidity. PMID- 26655690 TI - [Nurse delivery of oral contraception following an initial prescription for minors and uninsured patients in family planning centers of the Val-de-Marne]. AB - BACKGROUND: Since 2012 in France, nurses are allowed to renew the medical prescription of oral contraceptives (OC). To support this plan, a service protocol in family planning centers allows nurse delivery of OC. MATERIALS AND METHODS: This is a pilot feasibility study. After a medical prescription of OC, the nurse is authorized to deliver OC for 3months after a nursing interview. The duration of the nursing follow-up is determined by the physician. RESULTS: A total of 244 nurses interviews of 170 women were conducted between January 2012 and July 2013. All women have benefited from a delivery of contraceptives by the nurse. Analysis shows that 40 interviews (16%) had one or more abnormal criteria. Of these, more than a quarter found poor tolerance of contraception and/or the appearance of gynecological symptoms (27%) or unprotected sex with a new partner (25%). In these cases, an orientation to the physician was more frequent (85% versus 62%, P=0.005) and faster (median 33days versus 90days, P<0.001) than if the nurse interview was normal. CONCLUSION: Our study shows the feasibility of delivery protocol of oral contraception by nurses following an initial prescription by the physician. PMID- 26655691 TI - Age at Time of Initial Sexual Intercourse and Health of Adolescent Girls. AB - Adolescence is characterized by marked changes in the body, psychology, and sexual behavior due to increasing production of hormones. In this review we aimed to assess the effect of age at the time of first sexual intercourse (sexarche) on the health of adolescent girls, and identify factors that might protect against early initiation of sexual relations in girls. The PubMed, Lilacs, and Google Scholar databases were searched for clinical trials, comparative studies, case control studies, cross-sectional studies, cohort studies, multicenter studies, observational studies, meta-analyses, and systematic reviews published up to December 2014 on this theme. The search terms were: "sexual debut," "coitarche," "sexarche," and "young people," "adolescent," "unplanned pregnancy," "adolescent contraception," and "STDs." Data were extracted from 28 studies and 41 references were used to introduce the theme and to support the discussion. Sexarche has been occurring in increasingly younger girls. A young age at sexarche can lead to subsequent risky sexual behavior. Girls who have sexarche when they are 14 years old or younger are less likely to use contraception on this occasion, take more time before they start using contraception in subsequent sexual relations, are more likely to have several sex partners, have a higher risk for depression, have lower self-esteem and more episodes of repentance, and have a higher risk for a sexually transmitted disease and cervical cancer. Girls with low educational, socioeconomic, and cultural status, little parental monitoring, parental separation, and absence of religiosity tend to experience sexarche at a younger age. Adolescent girls who postpone sexarche until they are 16 years old are physically and psychologically healthier than those who have sexarche at a younger age. This suggests that providing adolescent girls with appropriate education about sexual relations might reduce the negative effect of sexual relations at a young age. PMID- 26655692 TI - Cause-specific mortality in Finnish ferrochromium and stainless steel production workers. AB - BACKGROUND: Although stainless steel has been produced for more than a hundred years, exposure-related mortality data for production workers are limited. AIMS: To describe cause-specific mortality in Finnish ferrochromium and stainless steel workers. METHODS: We studied Finnish stainless steel production chain workers employed between 1967 and 2004, from chromite mining to cold rolling of stainless steel, divided into sub-cohorts by production units with specific exposure patterns. We obtained causes of death for the years 1971-2012 from Statistics Finland. We calculated standardized mortality ratios (SMRs) as ratios of observed and expected numbers of deaths based on population mortality rates of the same region. RESULTS: Among 8088 workers studied, overall mortality was significantly decreased (SMR 0.77; 95% confidence interval [CI] 0.70-0.84), largely due to low mortality from diseases of the circulatory system (SMR 0.71; 95% CI 0.61-0.81). In chromite mine, stainless steel melting shop and metallurgical laboratory workers, the SMR for circulatory disease was below 0.4 (SMR 0.33; 95% CI 0.07 0.95, SMR 0.22; 95% CI 0.05-0.65 and SMR 0.16; 95% CI 0.00-0.90, respectively). Mortality from accidents (SMR 0.84; 95% CI 0.67-1.04) and suicides (SMR 0.72; 95% CI 0.56-0.91) was also lower than in the reference population. CONCLUSIONS: Working in the Finnish ferrochromium and stainless steel industry appears not to be associated with increased mortality. PMID- 26655693 TI - Resonance effects in thickness-dependent ultrafast carrier and phonon dynamics of topological insulator Bi2Se3. AB - Resonance effects in the thickness-dependent ultrafast carrier and phonon dynamics of topological insulator Bi2Se3 are found irrespective of the kind of substrate by measuring thickness-dependent abrupt changes of pump-probe differential-reflectivity signals (DeltaR/R) from Bi2Se3 thin films on four different substrates of poly- and single-crystalline (sc-) ZnO, sc-GaN and SiO2. The absolute peak intensity of the DeltaR/R is maximized at ~t C (6 ~ 9 quintuple layers), which is not directly related to but is very close to the critical thickness below which the energy gap opens. The intensities of the two phonon modes deduced from the oscillatory behaviors superimposed on the DeltaR/R profiles are also peaked at ~t C for the four kinds of substrates, consistent with the thickness-dependent Raman-scattering behaviors. These resonant effects and others are discussed based on possible physical mechanisms including the effects of three-dimensional carrier depletion and intersurface coupling. PMID- 26655694 TI - Probing the influence of hypermodified residues within the tRNA3(Lys) anticodon stem loop interacting with the A-loop primer sequence from HIV-1. AB - Replication of the HIV-1 virus requires reverse transcription of the viral RNA genome, a process that is specifically initiated by human tRNA3(Lys) packaged within the infectious virion. The primary binding site for the tRNA involves the 3' 18 nucleotides with an additional interaction between an adenine rich loop (A loop) in the template and the anticodon stem-loop region of the tRNA3(Lys). The loop of the tRNA primer contains two hypermodified base residues and a pseudouridine that are required for a proper binding and activity. Here, we investigate the influence on the structure, dynamics and binding stability of the three modified residues (mnm(5)s(2)U34, t(6)A37 and Psi39) using extensive molecular dynamics and Quantum Theory of Atoms in Molecules (QTAIM) analysis. Consistent with experiment, the results suggest that the three modified residues are required for faithful binding. Residues mnm(5)s(2)U34 and Psi39 have a major influence in stabilizing the anticodon loop whereas mnm(5)s(2)U34 and t(6)A37 appear to stabilize the formation of the complex of tRNA3(Lys) with the HIV-1 A loop. PMID- 26655695 TI - Possible involvement of nitrergic and opioidergic systems in the modulatory effect of acute chloroquine treatment on pentylenetetrazol induced convulsions in mice. AB - Chloroquine has long been used for the treatment of malaria and rheumatological disorders. Accumulating evidence suggests potential use of chloroquine as a neuroprotective agent. Several studies have reported that endogenous opioids and nitric oxide (NO) system mediate the chloroquine effects. In the present study, the involvements of endogenous opioids and NO in the modulatory effects of chloroquine on pentylenetetrazol-induced seizures were assessed in mice. Chloroquine 5mg/kg significantly increased the seizure threshold, but this effect was reversed with naltrexone 1mg/kg. Acute co-administration of l-NAME (non selective NO synthase (NOS) inhibitor, 5mg/kg) or 7-NI (selective neuronal NOS inhibitor, 40 mg/kg) with the effective dose of chloroquine completely inhibited its anticonvulsant effects. Acute single injection of a sub-effective dose of l arginine (NO precursor, 60 mg/kg) with a sub-effective dose of chloroquine 2.5mg/kg increased the seizure threshold but administration of L-arginine 60 mg/kg with chloroquine 10mg/kg decreased the seizure threshold. Moreover, the combination of the lower doses of naltrexone (0.1mg/kg) and 7-NI (15 mg/kg) showed additive effects in blocking the chloroquine-induced anticonvulsant properties. Chloroquine 5mg/kg enhanced the hippocampal nitrite levels. Chloroquine at the dose of 20mg/kg decreased the seizure threshold. This effect was inhibited through L-NAME (5mg/kg), 7-NI (40 mg/kg) and naltrexone (1mg/kg) administration with this dose of chloroquine. In conclusion, NO signaling probably through neuronal NOS, but not inducible NOS could be involved in the opioid-dependent anticonvulsant effects of chloroquine in this model of seizures in mice. It seems that nitric oxide and opioid systems are involved in modulatory effect of chloroquine on seizures induced by pentylenetetrazol. PMID- 26655696 TI - A numerical similarity approach for using retired Current Procedural Terminology (CPT) codes for electronic phenotyping in the Scalable Collaborative Infrastructure for a Learning Health System (SCILHS). AB - BACKGROUND: Interoperable phenotyping algorithms, needed to identify patient cohorts meeting eligibility criteria for observational studies or clinical trials, require medical data in a consistent structured, coded format. Data heterogeneity limits such algorithms' applicability. Existing approaches are often: not widely interoperable; or, have low sensitivity due to reliance on the lowest common denominator (ICD-9 diagnoses). In the Scalable Collaborative Infrastructure for a Learning Healthcare System (SCILHS) we endeavor to use the widely-available Current Procedural Terminology (CPT) procedure codes with ICD-9. Unfortunately, CPT changes drastically year-to-year - codes are retired/replaced. Longitudinal analysis requires grouping retired and current codes. BioPortal provides a navigable CPT hierarchy, which we imported into the Informatics for Integrating Biology and the Bedside (i2b2) data warehouse and analytics platform. However, this hierarchy does not include retired codes. METHODS: We compared BioPortal's 2014AA CPT hierarchy with Partners Healthcare's SCILHS datamart, comprising three-million patients' data over 15 years. 573 CPT codes were not present in 2014AA (6.5 million occurrences). No existing terminology provided hierarchical linkages for these missing codes, so we developed a method that automatically places missing codes in the most specific "grouper" category, using the numerical similarity of CPT codes. Two informaticians reviewed the results. We incorporated the final table into our i2b2 SCILHS/PCORnet ontology, deployed it at seven sites, and performed a gap analysis and an evaluation against several phenotyping algorithms. RESULTS: The reviewers found the method placed the code correctly with 97 % precision when considering only miscategorizations ("correctness precision") and 52 % precision using a gold-standard of optimal placement ("optimality precision"). High correctness precision meant that codes were placed in a reasonable hierarchal position that a reviewer can quickly validate. Lower optimality precision meant that codes were not often placed in the optimal hierarchical subfolder. The seven sites encountered few occurrences of codes outside our ontology, 93 % of which comprised just four codes. Our hierarchical approach correctly grouped retired and non-retired codes in most cases and extended the temporal reach of several important phenotyping algorithms. CONCLUSIONS: We developed a simple, easily-validated, automated method to place retired CPT codes into the BioPortal CPT hierarchy. This complements existing hierarchical terminologies, which do not include retired codes. The approach's utility is confirmed by the high correctness precision and successful grouping of retired with non-retired codes. PMID- 26655698 TI - Epidemiology of Anorectal Melanoma in the United States: 1992 to 2011. AB - BACKGROUND: Anorectal melanoma is a rare type of malignant melanoma and thus the epidemiology of patients with this tumor has been poorly defined. OBJECTIVE: To describe the epidemiology of anorectal melanoma in the United States. METHODS AND MATERIALS: We obtained case and population data from the Surveillance, Epidemiology, and End Results 13 Registries Database (SEER 13) between 1992 and 2011 using rectal diagnostic codes C20.9 to 21.8 and ICD-O-3 melanoma codes 8720 to 8721 and 8742 to 8746. RESULTS: There were 260 primary anorectal melanomas in SEER 13 from 1992 to 2011, occurring mostly in the rectum. The incidence of anorectal melanoma was higher among women than men with the highest rates occurring among white Hispanics ages 65 to 74 years. During this time period, the age-adjusted incidence rates rose significantly (p < .05) for both women and men with estimated annual percentage changes of 3.02% and 5.08%, respectively. Overall and melanoma-specific survival was poor irrespective of gender or ethnicity. CONCLUSION: Anorectal melanoma in the United States is increasing in both men and women, with the highest rates in elderly Hispanic white women. Hispanic whites were more likely to develop anorectal melanoma than non-Hispanic whites, suggesting that this population may be targeted for screening interventions. These results warrant further investigation to better understand the gender, racial, ethnic, and geographic variations for anorectal melanomas. PMID- 26655697 TI - Hypothalamic Amylin Acts in Concert with Leptin to Regulate Food Intake. AB - In this report we evaluated the functions of hypothalamic amylin in vivo and in vitro. Profiling of hypothalamic neurons revealed that islet amyloid polypeptide (Iapp, precursor to amylin) is expressed in neurons in the lateral hypothalamus, arcuate nucleus, medial preoptic area, and elsewhere. Hypothalamic expression of lapp is markedly decreased in ob/ob mice and normalized by exogenous leptin. In slices, amylin and leptin had similar electrophysiologic effects on lateral hypothalamic leptin receptor ObRb-expressing neurons, while the amylin antagonist AC187 inhibited their activity and blunted the effect of leptin. Finally, i.c.v. infusion of AC187 acutely reduced the anorectic effects of leptin. These data show that hypothalamic amylin is transcriptionally regulated by leptin, that it can act directly on ObRb neurons in concert with leptin, and that it regulates feeding. These findings provide a potential mechanism for the increased efficacy of a metreleptin/pramlintide combination therapy for obesity. PMID- 26655699 TI - Resistant and Recurrent Late Reaction to Hyaluronic Acid-Based Gel. AB - BACKGROUND: Late reactions to hyaluronic acid (HA)-based fillers have a recorded rate of 0.02%. The recent experience with a newly introduced filler in the tear trough area and the lips showed higher rate of reactions with a tendency to persistency and recurrences. OBJECTIVE: To delineate the features of reactions to this newly introduced filler. MATERIALS AND METHODS: Medical records of 400 patients (360 women and 40 men; average age = 49.6 years) were examined in this retrospective study. Juvederm Volbella (HA-Vb) filler was injected only into the tear trough area or lips. Other HA-based products were used in other areas of the face. RESULTS: Seventeen patients (4.25%) developed prolonged (up to 11 months) and recurrent (average: 3.17 episodes) late (average onset: 8.41 weeks after the injection) inflammatory cutaneous reactions. CONCLUSION: The incidence of late reactions to HA-based fillers varies between products. The authors are reporting an exceptionally high rate of cutaneous reactions for this newly introduced filler. In the authors' experience, broad-spectrum antibiotics in conjunction with repeated high-dose hyaluronidase injections into the inflammatory nodules were effective treatments. PMID- 26655700 TI - V-Blade Stellate Purse String Suture. PMID- 26655701 TI - Digit-Sparing Mohs Surgery for Melanoma. AB - BACKGROUND: Digital melanoma is commonly treated with amputation or wide local excision. Mohs micrographic surgery (MMS) may offer an alternative treatment modality. OBJECTIVE: To describe outcomes of digital melanomas treated with MMS over a 35-year period. METHODS: A retrospective series of digital melanomas treated with MMS was studied. Tumor and treatment characteristics were described and follow-up was assessed. RESULTS: Sixty-two digital (1.2%) tumors were identified from 4995 melanomas, of which 57 (91.9%) were primary and 5 (8.1%) were recurrent on enrollment. Melanocytic antigen recognized by cytotoxic T lymphocytes from melanoma patients (MART)-1 and HMB-45 immunostains were used in 34 (54.8%) and 14 (22.6%) cases, respectively. Five (8.2%) tumors recurred locally during the course of the study, none of which occurred with MART-1 use. Three (60.0%) local recurrences were salvaged with additional MMS. Local recurrence-free survival rates for primary melanomas at 5 and 10 years were 91.8% and 82.6%, respectively. Overall, 55 (96.5%) patients with primary digital melanomas avoided amputation. Five and 10-year melanoma-specific survival rates for all patients were 95.0% and 81.2%, respectively. LIMITATIONS: A formal comparison group was not studied. CONCLUSION: In the management of digital melanoma, MMS conserves function by avoiding amputation and offers a low local recurrence rate. Outcomes are improved with the use of MART-1. PMID- 26655702 TI - Complex Medial Cheek and Lateral Nasal Ala Defect. PMID- 26655703 TI - The Sharpness of Blades Used in Dermatologic Surgery. AB - BACKGROUND: There are numerous blades available for use in dermatologic procedures. There are different advantages that are inhere.nt to different blades due to their shape and size. One aspect of the blade that is instrumental to its performance, but is not objectively defined, is sharpness. This information could be useful when choosing a blade for a particular procedure. OBJECTIVE: This study aims to objectively define the sharpness of blades used in dermatologic surgery. METHODS AND MATERIALS: The Sharpness Tester (Cutlery and Allied Trades Research Association, Sheffield, UK) was used to test the force in Newtons a blade requires to cut through a silicone cylinder. New blades were used to determine a standard for the sharpness of new blades. Blades used for surgery were tested to determine the sharpness after use. RESULTS: The sharpest blade is the double edged razor blade (0.395 N) followed by the dermablade (0.46 N), plastic handled #15 (0.541 N), #15c (0.575 N), #10 (0.647 N), and the #15 blade (0.664 N). CONCLUSION: The sharpness of a blade is an important factor in its ability to perform a task and should be taken into account when choosing a particular blade for a particular procedure. PMID- 26655704 TI - Composition and stability of intestinal microbiota of healthy children within a Dutch population. AB - Numerous diseases linked to microbial imbalance can be traced back to childhood, illustrating the impact of the juvenile microbiota development from infancy toward adulthood. However, knowledge on this subject is currently very limited. The primary aim of this study was to characterize composition and short- and long term stability of the intestinal microbiota in healthy children. Between November 2011 and June 2014, 61 children 2 to 18 yr of age from different areas in The Netherlands were included and instructed to collect fecal samples weekly, for 6 wk, and a follow-up sample after 18 mo. The intergenic spacer profiling technique (IS-pro) was used to analyze all available fecal samples. Microbial diversity was calculated by the Shannon diversity index and individual compositional stability by comparing all collection time points. Microbial stability varied per phylum (P< 0.0005), declined rapidly in a short time period, and subsequently stabilized on the long run with very gradual variation, leading to an overall compositional stability of 70% on average over a period of 18 mo. Higher species diversity was correlated to a higher overall compositional stability (P< 0.001). We observed an age-independent bacterial shared core consisting of a limited number of species. In conclusion, in this study, we showed that microbial composition stability in children varied per phylum, at both short-term and long-term intervals. Healthy children seem to share a microbiome core consisting of a limited number of species.-De Meij, T. G. J., Budding, A. E., de Groot, E. F. J., Jansen, F. M., Kneepkens, C. M. F., Benninga, M. A., Penders, J., van Bodegraven, A. A., Savelkoul, P. H. M. Composition and stability of intestinal microbiota of healthy children within a Dutch population. PMID- 26655705 TI - An endothelial TLR4-VEGFR2 pathway mediates lung protection against oxidant induced injury. AB - TLR4 deficiency causes hypersusceptibility to oxidant-induced injury. We investigated the role of TLR4 in lung protection, using used bone marrow chimeras; cell-specific transgenic modeling; and lentiviral delivery in vivo to knock down or express TLR4 in various lung compartments; and lung-specific VEGF transgenic mice to investigate the effect of TLR4 on VEGF-mediated protection. C57/BL6 mice were exposed to 100% oxygen in an enclosed chamber and assessed for survival and lung injury. Primary endothelial cells were stimulated with recombinant VEGF and exposed to hyperoxia or hydrogen peroxide. Endothelium specific expression of human TLR4 (as opposed to its expression in epithelium or immune cells) increased the survival of TLR4-deficent mice in hyperoxia by 24 h and decreased LDH release and lung cell apoptosis after 72 h of exposure by 30%. TLR4 expression was necessary and sufficient for the protective effect of VEGF in the lungs and in primary endothelial cells in culture. TLR4 knockdown inhibited VEGF signaling through VEGF receptor 2 (VEGFR2), Akt, and ERK pathways in lungs and primary endothelial cells and decreased the availability of VEGFR2 at the cell surface. These findings demonstrate a novel mechanism through which TLR4, an innate pattern receptor, interacts with an endothelial survival pathway. PMID- 26655706 TI - Exosomes from human mesenchymal stem cells conduct aerobic metabolism in term and preterm newborn infants. AB - Exosomes are secreted nanovesicles that are able to transfer RNA and proteins to target cells. The emerging role of mesenchymal stem cell (MSC) exosomes as promoters of aerobic ATP synthesis restoration in damaged cells, prompted us to assess whether they contain an extramitochondrial aerobic respiration capacity. Exosomes were isolated from culture medium of human MSCs from umbilical cord of >=37-wk-old newborns or between 28- to 30-wk-old newborns (i.e.,term or preterm infants). Characterization of samples was conducted by cytofluorometry. Oxidative phosphorylation capacity was assessed by Western blot analysis, oximetry, and luminometric and fluorometric analyses. MSC exosomes express functional respiratory complexes I, IV, and V, consuming oxygen. ATP synthesis was only detectable in exosomes from term newborns, suggestive of a specific mechanism that is not completed at an early gestational age. Activities are outward facing and comparable to those detected in mitochondria isolated from term MSCs. MSC exosomes display an unsuspected aerobic respiratory ability independent of whole mitochondria. This may be relevant for their ability to rescue cell bioenergetics. The differential oxidative metabolism of pretermvs.term exosomes sheds new light on the preterm newborn's clinical vulnerability. A reduced ability to repair damaged tissue and an increased capability to cope with anoxic environment for preterm infants can be envisaged.-Panfoli, I., Ravera, S., Podesta, M., Cossu, C., Santucci, L., Bartolucci, M., Bruschi, M., Calzia, D., Sabatini, F., Bruschettini, M., Ramenghi, L. A., Romantsik, O., Marimpietri, D., Pistoia, V., Ghiggeri, G., Frassoni, F., Candiano, G. Exosomes from human mesenchymal stem cells conduct aerobic metabolism in term and preterm newborn infants. PMID- 26655707 TI - [Assessment of the perioperative period in civilians injured in the Syrian Civil War]. AB - BACKGROUND: Wars and its challenges have historically afflicted humanity. In Syria, severe injuries occurred due to firearms and explosives used in the war between government forces and civilians for a period of over 2 years. MATERIALS AND METHODS: The study included 364 cases, who were admitted to Mustafa Kemal University Hospital, Medicine School (Hatay, Turkey), and underwent surgery. Survivors and non-survivors were compared regarding injury site, injury type and number of transfusions given. The mortality rate found in this study was also compared to those reported in other civil wars. RESULTS: The mean age was 29 (3 68) years. Major sites of injury included extremities (56.0%), head (20.1%), abdomen (16.2%), vascular structures (4.4%) and thorax (3.3%). Injury types included firearm injury (64.4%), blast injury (34.4%) and miscellaneous injuries (1.2%). Survival rate was 89.6% while mortality rate was 10.4%. A significant difference was observed between mortality rates in this study and those reported for the Bosnia and Lebanon civil wars; and the difference became extremely prominent when compared to mortality rates reported for Vietnam and Afghanistan civil wars. CONCLUSION: Among injuries related to war, the highest rate of mortality was observed in head-neck, abdomen and vascular injuries. We believe that the higher mortality rate in the Syrian Civil War, compared to the Bosnia, Vietnam, Lebanon and Afghanistan wars, is due to seeing civilians as a direct target during war. PMID- 26655708 TI - [Reducing sore throat following laryngeal mask airway insertion: comparing lidocaine gel, saline, and washing mouth with the control group]. AB - BACKGROUND: Laryngeal mask airway is still accompanied by complications such as sore throat. In this study, effects of three methods of reducing postoperative sore throat were compared with the control group. METHODS: 240 patients with ASA I, II candidates for cataract surgery were randomly divided into four same groups. No supplementary method was used in the control group. In the second, third and fourth groups, lidocaine gel, washing cuff before insertion, and washing mouth before removing laryngeal mask airway were applied, respectively. Anesthesia induction was done with fentanyl, atracurium, and propofol and maintained with propofol infusion. The incidence of sore throat was evaluated during the recovery, 3-4h later and after 24h using verbal analog scale. The data were analyzed by t-test, analysis of variance and chi-square using SPSS V11.5. RESULTS: Age, gender, duration of surgery and cuff pressure were the same in all the four groups. Incidence of sore throat at recovery room was highest in the control group (43.3%) and lowest in the washing mouth group (25%). However, no significant statistical difference was observed between these four groups (recovery, p=0.30; discharge, p=0.31; examination, p=0.52). In this study, increased duration of operation had a significant relationship with the incidence of sore throat (p=0.041). CONCLUSION: Sore throat is a common postoperative problem, but no special method has been found completely efficient yet. In this study, cuff washing, lidocaine gel, and mouth washing before removing laryngeal mask airway were not helpful for sore throat. PMID- 26655709 TI - [Impact of the practising anesthesiologist team member on the laryngeal mask cuff pressures and adverse event rate]. AB - OBJECTIVE: We have planned to evaluate the laryngeal mask cuff pressures (LMcp) inflated by anesthesia workers of several seniority, without using manometer. METHODS: 180 patients scheduled to have short duration surgery with laryngeal mask were included in the study. Five anesthesia specialists (Group S), 10 residents (Group R) and 6 technicians (Group T) inflated the LMc; thereafter LMcp were measured with pressure manometer. Participants have repeated this practice in at least five different cases. LMcp higher than 60cm H2O at the initial placement or intraoperative period were adjusted to normal range. Sore throat was questioned postoperatively. Groups were compared in terms of mean LMcp and occupational experience. RESULTS: At the settlement of LM, LMcp pressures within the normal range were determined in 26 (14.4%) cases. Mean LMcp after LM placement in Group S, R and T were 101.2+/-14.0, 104.3+/-20.5cm H2O and 105.2+/ 18.4cm H2O respectively (p>0.05). Mean LMcp values in all measurement time periods within the groups were above the normal limit (60cm H2O). When groups were compared in terms of LMcp, no difference has been found among pressure values. Occupational experience was 14.2+/-3.9; 3.3+/-1.1 and 6.6+/-3.8 years for specialists, residents and technicians respectively and measured pressure values were not different in regard of occupational experience. Seven (3.9%) patients had sore throat at the 24th hour interview. CONCLUSION: Considering lower possibility of normal adjustment of LMcp and ineffectiveness of occupational experience to obtain normal pressure values, it is suitable that all anesthesia practitioners should adjust LMcp with manometer. PMID- 26655710 TI - [Low-dose levobupivacaine plus fentanyl combination for spinal anesthesia in anorectal surgery]. AB - BACKGROUND: The aim of this study was to investigate the effects of spinal anesthesia using two different doses of fentanyl combined with low-dose levobupivacaine in anorectal surgery. METHODS: In this prospective, double-blind study, 52 American Society of Anaesthesiologists I-II patients scheduled for elective anorectal surgery were randomized into two groups. The patients in group I received intrathecal 2.5mg hyperbaric levobupivacaine plus 12.5MUg fentanyl and in group II received intrathecal 2.5mg hyperbaric levobupivacaine plus 25MUg fentanyl. All the patients remained in the seated position for 5min after completion of the spinal anesthesia. Sensory block was evaluated with pin-prick test and motor block was evaluated with a modified Bromage scale. RESULTS: Motor block was not observed in both of the groups. The sensory block was limited to the S2 level in group I, and S1 level in group II. None of the patients required additional analgesics during the operation. Time to two-segment regression was shorter in group I compared with group II (p<0.01). One patient in group I and 5 patients in group II had pruritus. Hemodynamic parameters were stable during the operation in both of the groups. CONCLUSION: Spinal saddle block using hyperbaric levobupivacaine with both 12.5MUg and 25MUg fentanyl provided good quality of anesthesia without motor block for anorectal surgery in the prone position. PMID- 26655711 TI - [To study the effect of injection dexmedetomidine for prevention of pain due to propofol injection and to compare it with injection lignocaine]. AB - BACKGROUND: Pain due to injection propofol is a common problem. Different methods are used to decrease the pain but with limited success. The objective of this study was to assess the effect of injection dexmedetomidine 0.2mcg/kg for prevention of pain due to propofol injection and compare it with injection lignocaine 0.2mg/kg. METHOD: After taking permission of the Institutional Ethical Committee, written informed consent was obtained from all patients, in a randomized prospective study. 60 American Society of Anesthesiology I and II patients of age range 20-60 years of either sex posted for elective surgeries under general anaesthesia were randomly allocated into two groups. Group I (dexmedetomidine group): Inj. dexmedetomidine 0.2mcg/kg diluted in 5mL normal saline and Group II (lignocaine group): Inj. lignocaine 0.2mg/kg diluted in 5mL normal saline. IV line was secured with 20G cannula and venous occlusion was applied to forearm using a pneumatic tourniquet and inflated to 70mm Hg for 1min. Study drug was injected, tourniquet released and then 25% of the calculated dose of propofol was given intravenously over 10s. After 10s of injection, severity of pain was evaluated using McCrirrick and Hunter scale and then remaining propofol and neuromuscular blocking agent was given. Endotracheal intubation was done and anaesthesia was maintained on O2, N2O and isoflurane on intermittent positive pressure ventilation with Bain's circuit and inj. vecuronium was used as muscle relaxant. RESULTS: Demographic data showed that there was no statistically significant difference between the 2 groups. There was no statistically significant difference between 2 groups in respect to inj. propofol pain. No adverse effects like oedema, pain, wheal response at the site of injection were observed in the two groups. PMID- 26655712 TI - [Management of abdominal compartment syndrome after transurethral resection of the prostate]. AB - Acute abdominal compartment syndrome is most commonly associated with blunt abdominal trauma, although it has been seen after ruptured abdominal aortic aneurysm, liver transplantation, pancreatitis, and massive volume resuscitation. Acute abdominal compartment syndrome develops once the intra-abdominal pressure increases to 20-25mmHg and is characterized by an increase in airway pressures, inadequate ventilation and oxygenation, altered renal function, and hemodynamic instability. This case report details the development of acute abdominal compartment syndrome during transurethral resection of the prostate with extra- and intraperitoneal bladder rupture under general anesthesia. The first signs of acute abdominal compartment syndrome in this patient were high peak airway pressures and difficulty delivering tidal volumes. Management of the compartment syndrome included re-intubation, emergent exploratory laparotomy, and drainage of irrigation fluid. Difficulty with ventilation should alert the anesthesiologist to consider abdominal compartment syndrome high in the list of differential diagnoses during any endoscopic bladder or bowel case. PMID- 26655713 TI - [Anesthetic management of a pediatric patient with hypohidrotic ectodermal dysplasia undergoing emergency surgery]. AB - Ectodermal dysplasias are rare conditions with a triad of hypotrichosis, anodontia and anhidrosis. In literature review there have been only a few reports of anesthetic management of patients with ectodermal dysplasias. Hyperthermia is a very serious risk which may occur due to the defect of sweat glands. The present case involves a 10-year-old child with ectodermal dysplasia who presented with an acute abdomen and was considered for an emergency surgery. Our aim was to demonstrate the successful management of this case using a combination of general and epidural anesthesia. It is important for anesthesiologist to have information about this syndrome in case of emergency operations, since it can prevent serious complications and even save lives. PMID- 26655714 TI - [Anesthesia for ex utero intrapartum treatment: renewed insight on a rare procedure]. AB - The ex utero intrapartum treatment is a rare surgical procedure performed in cases of expected postpartum fetal airway obstruction. The technique lies on a safe establishment of a patent airway during labor in anticipation of a critical respiratory event, without interrupting maternal-fetal circulation. Anesthetic management is substantially different from that regarding standard cesarean delivery and its main goals include uterine relaxation, fetal anesthesia and preservation of placental blood flow. We present the case of an ex utero intrapartum treatment procedure performed on a fetus with a large cervical lymphangioma and prenatal evidence of airway compromise. Modifications to the classic ex utero intrapartum treatment management strategies were successfully adopted and will be discussed in the following report. PMID- 26655715 TI - Lipooligosaccharide Structures of Invasive and Carrier Isolates of Neisseria meningitidis Are Correlated with Pathogenicity and Carriage. AB - The degree of phosphorylation and phosphoethanolaminylation of lipid A on neisserial lipooligosaccharide (LOS), a major cell-surface antigen, can be correlated with inflammatory potential and the ability to induce immune tolerance in vitro. On the oligosaccharide of the LOS, the presence of phosphoethanolamine and sialic acid substituents can be correlated with in vitro serum resistance. In this study, we analyzed the structure of the LOS from 40 invasive isolates and 25 isolates from carriers of Neisseria meningitidis without disease. Invasive strains were classified as groups 1-3 that caused meningitis, septicemia without meningitis, and septicemia with meningitis, respectively. Intact LOS was analyzed by high resolution matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Prominent peaks for lipid A fragment ions with three phosphates and one phosphoethanolamine were detected in all LOS analyzed. LOS from groups 2 and 3 had less abundant ions for highly phosphorylated lipid A forms and induced less TNF-alpha in THP-1 monocytic cells compared with LOS from group 1. Lipid A from all invasive strains was hexaacylated, whereas lipid A of 6/25 carrier strains was pentaacylated. There were fewer O-acetyl groups and more phosphoethanolamine and sialic acid substitutions on the oligosaccharide from invasive compared with carrier isolates. Bioinformatic and genomic analysis of LOS biosynthetic genes indicated significant skewing to specific alleles, dependent on the disease outcome. Our results suggest that variable LOS structures have multifaceted effects on homeostatic innate immune responses that have critical impact on the pathophysiology of meningococcal infections. PMID- 26655716 TI - The Insect Peptide CopA3 Increases Colonic Epithelial Cell Proliferation and Mucosal Barrier Function to Prevent Inflammatory Responses in the Gut. AB - The epithelial cells of the gut form a physical barrier against the luminal contents. The collapse of this barrier causes inflammation, and its therapeutic restoration can protect the gut against inflammation. EGF enhances mucosal barrier function and increases colonocyte proliferation, thereby ameliorating inflammatory responses in the gut. Based on our previous finding that the insect peptide CopA3 promotes neuronal growth, we herein tested whether CopA3 could increase the cell proliferation of colonocytes, enhance mucosal barrier function, and ameliorate gut inflammation. Our results revealed that CopA3 significantly increased epithelial cell proliferation in mouse colonic crypts and also enhanced colonic epithelial barrier function. Moreover, CopA3 treatment ameliorated Clostridium difficile toxin As-induced inflammation responses in the mouse small intestine (acute enteritis) and completely blocked inflammatory responses and subsequent lethality in the dextran sulfate sodium-induced mouse model of chronic colitis. The marked CopA3-induced increase of colonocyte proliferation was found to require rapid protein degradation of p21(Cip1/Waf1), and an in vitro ubiquitination assay revealed that CopA3 directly facilitated ubiquitin ligase activity against p21(Cip1/Waf1). Taken together, our findings indicate that the insect peptide CopA3 prevents gut inflammation by increasing epithelial cell proliferation and mucosal barrier function. PMID- 26655717 TI - Transcriptional Regulation of JARID1B/KDM5B Histone Demethylase by Ikaros, Histone Deacetylase 1 (HDAC1), and Casein Kinase 2 (CK2) in B-cell Acute Lymphoblastic Leukemia. AB - Impaired function of the Ikaros (IKZF1) protein is associated with the development of high-risk B-cell precursor acute lymphoblastic leukemia (B-ALL). The mechanisms of Ikaros tumor suppressor activity in leukemia are unknown. Ikaros binds to the upstream regulatory elements of its target genes and regulates their transcription via chromatin remodeling. Here, we report that Ikaros represses transcription of the histone H3K4 demethylase, JARID1B (KDM5B). Transcriptional repression of JARID1B is associated with increased global levels of H3K4 trimethylation. Ikaros-mediated repression of JARID1B is dependent on the activity of the histone deacetylase, HDAC1, which binds to the upstream regulatory element of JARID1B in complex with Ikaros. In leukemia, JARID1B is overexpressed, and its inhibition results in cellular growth arrest. Ikaros mediated repression of JARID1B in leukemia is impaired by pro-oncogenic casein kinase 2 (CK2). Inhibition of CK2 results in increased binding of the Ikaros HDAC1 complex to the promoter of JARID1B, with increased formation of trimethylated histone H3 lysine 27 and decreased histone H3 Lys-9 acetylation. In cases of high-risk B-ALL that carry deletion of one Ikaros (IKZF1) allele, targeted inhibition of CK2 restores Ikaros binding to the JARID1B promoter and repression of JARID1B. In summary, the presented data suggest a mechanism through which Ikaros and HDAC1 regulate the epigenetic signature in leukemia: via regulation of JARID1B transcription. The presented data identify JARID1B as a novel therapeutic target in B-ALL and provide a rationale for the use of CK2 inhibitors in the treatment of high-risk B-ALL. PMID- 26655718 TI - Progesterone-induced Acrosome Exocytosis Requires Sequential Involvement of Calcium-independent Phospholipase A2beta (iPLA2beta) and Group X Secreted Phospholipase A2 (sPLA2). AB - Phospholipase A2 (PLA2) activity has been shown to be involved in the sperm acrosome reaction (AR), but the molecular identity of PLA2 isoforms has remained elusive. Here, we have tested the role of two intracellular (iPLA2beta and cytosolic PLA2alpha) and one secreted (group X) PLA2s in spontaneous and progesterone (P4)-induced AR by using a set of specific inhibitors and knock-out mice. iPLA2beta is critical for spontaneous AR, whereas both iPLA2beta and group X secreted PLA2 are involved in P4-induced AR. Cytosolic PLA2alpha is dispensable in both types of AR. P4-induced AR spreads over 30 min in the mouse, and kinetic analyses suggest the presence of different sperm subpopulations, using distinct PLA2 pathways to achieve AR. At low P4 concentration (2 MUm), sperm undergoing early AR (0-5 min post-P4) rely on iPLA2beta, whereas sperm undergoing late AR (20-30 min post-P4) rely on group X secreted PLA2. Moreover, the role of PLA2s in AR depends on P4 concentration, with the PLA2s being key actors at low physiological P4 concentrations (<=2 MUm) but not at higher P4 concentrations (~10 MUm). PMID- 26655719 TI - Structural and Functional Analyses Reveal Insights into the Molecular Properties of the Escherichia coli Z Ring Stabilizing Protein, ZapC. AB - In Escherichia coli cell division is driven by the tubulin-like GTPase, FtsZ, which forms the cytokinetic Z-ring. The Z-ring serves as a dynamic platform for the assembly of the multiprotein divisome, which catalyzes membrane cleavage to create equal daughter cells. Several proteins effect FtsZ assembly, thereby providing spatiotemporal control over cell division. One important class of FtsZ interacting/regulatory proteins is the Z-ring-associated proteins, Zaps, which typically modulate Z-ring formation by increasing lateral interactions between FtsZ protofilaments. Strikingly, these Zap proteins show no discernable sequence similarity, suggesting that they likely harbor distinct structures and mechanisms. The 19.8-kDa ZapC in particular shows no homology to any known protein. To gain insight into ZapC function, we determined its structure to 2.15 A and performed genetic and biochemical studies. ZapC is a monomer composed of two domains, an N-terminal alpha/beta region and a C-terminal twisted beta barrel like domain. The structure contains two pockets, one on each domain. The N-domain pocket is lined with residues previously implicated to be important for ZapC function as an FtsZ bundler. The adjacent C-domain pocket contains a hydrophobic center surrounded by conserved basic residues. Mutagenesis analyses indicate that this pocket is critical for FtsZ binding. An extensive FtsZ binding surface is consistent with the fact that, unlike many FtsZ regulators, ZapC binds the large FtsZ globular core rather than C-terminal tail, and the presence of two adjacent pockets suggests possible mechanisms for ZapC-mediated FtsZ bundling. PMID- 26655720 TI - Uncovering the Early Assembly Mechanism for Amyloidogenic beta2-Microglobulin Using Cross-linking and Native Mass Spectrometry. AB - beta2-Microglobulin (beta2m), a key component of the major histocompatibility class I complex, can aggregate into fibrils with severe clinical consequences. As such, investigating the structural aspects of the formation of oligomeric intermediates of beta2m and their subsequent progression toward fibrillar aggregates is of great importance. However, beta2m aggregates are challenging targets in structural biology, primarily due to their inherent transient and heterogeneous nature. Here we study the oligomeric distributions and structures of the early intermediates of amyloidogenic beta2m and its truncated variant DeltaN6-beta2m. We established compact oligomers for both variants by integrating advanced mass spectrometric techniques with available electron microscopy maps and atomic level structures from NMR spectroscopy and x-ray crystallography. Our results revealed a stepwise assembly mechanism by monomer addition and domain swapping for the oligomeric species of DeltaN6-beta2m. The observed structural similarity and common oligomerization pathway between the two variants is likely to enable DeltaN6-beta2m to cross-seed beta2m fibrillation and allow the formation of mixed fibrils. We further determined the key subunit interactions in DeltaN6-beta2m tetramer, revealing the importance of a domain-swapped hinge region for formation of higher order oligomers. Overall, we deliver new mechanistic insights into beta2m aggregation, paving the way for future studies on the mechanisms and cause of amyloid fibrillation. PMID- 26655721 TI - Selective Recognition of H3.1K36 Dimethylation/H4K16 Acetylation Facilitates the Regulation of All-trans-retinoic Acid (ATRA)-responsive Genes by Putative Chromatin Reader ZMYND8. AB - ZMYND8 (zinc finger MYND (Myeloid, Nervy and DEAF-1)-type containing 8), a newly identified component of the transcriptional coregulator network, was found to interact with the Nucleosome Remodeling and Deacetylase (NuRD) complex. Previous reports have shown that ZMYND8 is instrumental in recruiting the NuRD complex to damaged chromatin for repressing transcription and promoting double strand break repair by homologous recombination. However, the mode of transcription regulation by ZMYND8 has remained elusive. Here, we report that through its specific key residues present in its conserved chromatin-binding modules, ZMYND8 interacts with the selective epigenetic marks H3.1K36Me2/H4K16Ac. Furthermore, ZMYND8 shows a clear preference for canonical histone H3.1 over variant H3.3. Interestingly, ZMYND8 was found to be recruited to several developmental genes, including the all-trans-retinoic acid (ATRA)-responsive ones, through its modified histone binding ability. Being itself inducible by ATRA, this zinc finger transcription factor is involved in modulating other ATRA-inducible genes. We found that ZMYND8 interacts with transcription initiation-competent RNA polymerase II phosphorylated at Ser-5 in a DNA template-dependent manner and can alter the global gene transcription. Overall, our study identifies that ZMYND8 has CHD4 independent functions in regulating gene expression through its modified histone binding ability. PMID- 26655722 TI - SIRT1 Limits Adipocyte Hyperplasia through c-Myc Inhibition. AB - The expansion of fat mass in the obese state is due to increased adipocyte hypertrophy and hyperplasia. The molecular mechanism that drives adipocyte hyperplasia remains unknown. The NAD(+)-dependent protein deacetylase sirtuin 1 (SIRT1), a key regulator of mammalian metabolism, maintains proper metabolic functions in many tissues, counteracting obesity. Here we report that differentiated adipocytes are hyperplastic when SIRT1 is knocked down stably in mouse 3T3-L1 preadipocytes. This phenotype is associated with dysregulated adipocyte metabolism and enhanced inflammation. We also demonstrate that SIRT1 is a key regulator of proliferation in preadipocytes. Quantitative proteomics reveal that the c-Myc pathway is altered to drive enhanced proliferation in SIRT1 silenced 3T3-L1 cells. Moreover, c-Myc is hyperacetylated, levels of p27 are reduced, and cyclin-dependent kinase 2 (CDK2) is activated upon SIRT1 reduction. Remarkably, differentiating SIRT1-silenced preadipocytes exhibit enhanced mitotic clonal expansion accompanied by reduced levels of p27 as well as elevated levels of CCAAT/enhancer-binding protein beta (C/EBPbeta) and c-Myc, which is also hyperacetylated. c-Myc activation and enhanced proliferation phenotype are also found to be SIRT1-dependent in proliferating mouse embryonic fibroblasts and differentiating human SW872 preadipocytes. Reducing both SIRT1 and c-Myc expression in 3T3-L1 cells simultaneously does not induce the adipocyte hyperplasia phenotype, confirming that SIRT1 controls adipocyte hyperplasia through c-Myc regulation. A better understanding of the molecular mechanisms of adipocyte hyperplasia will open new avenues toward understanding obesity. PMID- 26655723 TI - Electrogenic transport and K(+) ion channel expression by the human endolymphatic sac epithelium. AB - The endolymphatic sac (ES) is a cystic organ that is a part of the inner ear and is connected to the cochlea and vestibule. The ES is thought to be involved in inner ear ion homeostasis and fluid volume regulation for the maintenance of hearing and balance function. Many ion channels, transporters, and exchangers have been identified in the ES luminal epithelium, mainly in animal studies, but there has been no functional study investigating ion transport using human ES tissue. We designed the first functional experiments on electrogenic transport in human ES and investigated the contribution of K(+) channels in the electrogenic transport, which has been rarely identified, even in animal studies, using electrophysiological/pharmacological and molecular biological methods. As a result, we identified functional and molecular evidence for the essential participation of K(+) channels in the electrogenic transport of human ES epithelium. The identified K(+) channels involved in the electrogenic transport were KCNN2, KCNJ14, KCNK2, and KCNK6, and the K(+) transports via those channels are thought to play an important role in the maintenance of the unique ionic milieu of the inner ear fluid. PMID- 26655724 TI - College Sports-Related Injuries - United States, 2009-10 Through 2013-14 Academic Years. AB - Sports-related injuries can have a substantial impact on the long-term health of student-athletes. The National Collegiate Athletic Association (NCAA) monitors injuries among college student-athletes at member schools. In academic year 2013 14, a total of 1,113 member schools fielded 19,334 teams with 478,869 participating student-athletes in NCAA championship sports (i.e., sports with NCAA championship competition) (1). External researchers and CDC used information reported to the NCAA Injury Surveillance Program (NCAA-ISP) by a sample of championship sports programs to summarize the estimated national cumulative and annual average numbers of injuries during the 5 academic years from 2009-10 through 2013-14. Analyses were restricted to injuries reported among student athletes in 25 NCAA championship sports. During this period, 1,053,370 injuries were estimated to have occurred during an estimated 176.7 million athlete exposures to potential injury (i.e., one athlete's participation in one competition or one practice). Injury incidence varied widely by sport. Among all sports, men's football accounted for the largest average annual estimated number of injuries (47,199) and the highest competition injury rate (39.9 per 1,000 athlete-exposures). Men's wrestling experienced the highest overall injury rate (13.1 per 1,000) and practice injury rate (10.2 per 1,000). Among women's sports, gymnastics had the highest overall injury rate (10.4 per 1,000) and practice injury rate (10.0 per 1,000), although soccer had the highest competition injury rate (17.2 per 1,000). More injuries were estimated to have occurred from practice than from competition for all sports, with the exception of men's ice hockey and baseball. However, injuries incurred during competition were somewhat more severe (e.g., requiring >=7 days to return to full participation) than those acquired during practice. Multiple strategies are employed by NCAA and others to reduce the number of injuries in organized sports. These strategies include committees that recommend rule and policy changes based on surveillance data and education and awareness campaigns that target both athletes and coaches. Continued analysis of surveillance data will help to understand whether these strategies result in changes in the incidence and severity of college sports injuries. PMID- 26655725 TI - Practice Guidelines for the Prevention, Detection, and Management of Respiratory Depression Associated with Neuraxial Opioid Administration: An Updated Report by the American Society of Anesthesiologists Task Force on Neuraxial Opioids and the American Society of Regional Anesthesia and Pain Medicine. PMID- 26655727 TI - Artificial polyepitope HIV-1 immunogen containing mimotope of 2F5 epitope. AB - Constructing a vaccine against HIV-1, able to induce production of broadly neutralizing antibodies, is crucial. We report here the selection and characterization of RDWSFDRWSLSEFWL peptide mimotope that binds specifically to bNAbs 2F5. The peptide mimotope was selected from 15-mer phage-displayed peptide library by using Mab 2F5 as the selecting agent. The most abundant RDWSFDRWSLSEFWL peptide was inserted into a carrier, an artificial polyepitope immunogen - TBI (T- and B-cell immunogen). TBI-2F5 polyepitope immunogen that includes the mimotope of 2F5 epitope was constructed. It was shown that sera of mice immunized with TBI-2F5 protein recognized TBI protein as well as RDWSFDRWSLSEFWL peptide. The capacity of sera of immunized mice to neutralize HIV 1 was demonstrated using subtype B env-pseudoviruses of HIV-1 QH0692.42 and PVO.4. Based on these results, we conclude that peptide mimotope of 2F5 epitope RDWSFDRWSLSEFWL can be an essential component for a successful HIV-vaccine. PMID- 26655728 TI - Cell Penetrating Peptide-Mediated Caveolae-Dependent Activation of Lung Endothelial Nitric Oxide Synthase. AB - Cell penetrating peptides can be used as therapeutic agents via modulation of selective cell functions. Nitric oxide (NO) generated by vascular endothelial NO synthase (eNOS) plays a critical role in the NO/ cyclic guanosine 5' monophosphate (cGMP)-mediated pulmonary vascular function. Here we examined whether internalization of a fifteen amino acid (KRFNSISCSSWRRKR) synthetic peptide (P3) enhances the catalytic activity of eNOS via caveolae/eNOS dissociation leading to NO release and increased cGMP production in pulmonary artery endothelial cells (EC). ECs were treated with varying concentrations of P3 and used to monitor internalization, isolation of caveolae-enriched fraction, the catalytic activity of eNOS, NO/cGMP production, and intracellular Ca(2+) release. Confocal images show timedependent internalization of P3 in EC. Treatment of EC with P3, but not scrambled P3, increased the catalytic activity of eNOS in a dose dependent manner without change in eNOS expression or phosphorylation. Treatment of EC with P3 stimulated intracellular Ca(2+) release, increased the catalytic activity of phospatidylinsositide 3 kinase (PI3K) and resulted in eNOS/caveolae-1 (Cav-1) dissociation leading to translocation of eNOS to intracellular compartment in EC. P3- mediated activation of eNOS was abolished by intracellular Ca(2+) chelator 1,2-bis(2-aminophenooxy)ethane-N,N,N',N'- tertraacetic acid-AM (BAPTA-AM), PI3K inhibition, or by siRNA-mediated Cav-1 suppression. These results demonstrate that exogenous peptide consisting of cationic amino acids can internalize and enhance the catalytic activity of eNOS via modulation of caveolar signaling and intracellular Ca(2+) release in EC. PMID- 26655726 TI - The PTEN tumor suppressor gene and its role in lymphoma pathogenesis. AB - The phosphatase and tensin homolog gene PTEN is one of the most frequently mutated tumor suppressor genes in human cancer. Loss of PTEN function occurs in a variety of human cancers via its mutation, deletion, transcriptional silencing, or protein instability. PTEN deficiency in cancer has been associated with advanced disease, chemotherapy resistance, and poor survival. Impaired PTEN function, which antagonizes phosphoinositide 3-kinase (PI3K) signaling, causes the accumulation of phosphatidylinositol (3,4,5)-triphosphate and thereby the suppression of downstream components of the PI3K pathway, including the protein kinase B and mammalian target of rapamycin kinases. In addition to having lipid phosphorylation activity, PTEN has critical roles in the regulation of genomic instability, DNA repair, stem cell self-renewal, cellular senescence, and cell migration. Although PTEN deficiency in solid tumors has been studied extensively, rare studies have investigated PTEN alteration in lymphoid malignancies. However, genomic or epigenomic aberrations of PTEN and dysregulated signaling are likely critical in lymphoma pathogenesis and progression. This review provides updated summary on the role of PTEN deficiency in human cancers, specifically in lymphoid malignancies; the molecular mechanisms of PTEN regulation; and the distinct functions of nuclear PTEN. Therapeutic strategies for rescuing PTEN deficiency in human cancers are proposed. PMID- 26655730 TI - Role of microRNA-21 in the formation of insulin-producing cells from pancreatic progenitor cells. AB - MicroRNAs (miRNAs) regulate insulin secretion, pancreas development, and beta cell differentiation. In this study, to screen for miRNAs and their targets that function during insulin-producing cells (IPCs) formation, we examined the messenger RNA and microRNA expression profiles of pancreatic progenitor cells (PPCs) and IPCs using microarray and deep sequencing approaches, respectively. Combining our data with that from previous reports, we found that miR-21 and its targets play an important role in the formation of IPCs. However, the function of miR-21 in the formation of IPCs from PPCs is poorly understood. Therefore, we over-expressed or inhibited miR-21 and expressed small interfering RNAs of miR-21 targets in PPCs to investigate their functions in IPCs formation. We found that miR-21 acts as a bidirectional switch in the formation of IPCs by regulating the expression of target and downstream genes (SOX6, RPBJ and HES1). Small interfering RNAs were used to knock down these genes in PPCs to investigate their effects on IPCs formation. Single expression of si-RBPJ, si-SOX6 and si-HES1 in PPCs showed that si-RBPJ was an inhibitor, and that si-SOX6 and si-HES1 were promoters of IPCs formation, although si-HES1 induced formation of IPCs at higher rates than si-SOX6. These results suggest that endogenous miRNAs involved in the formation of IPCs from PPCs should be considered in the development of an effective cell transplant therapy for diabetes. PMID- 26655729 TI - Combination of NTP with cetuximab inhibited invasion/migration of cetuximab resistant OSCC cells: Involvement of NF-kappaB signaling. AB - Although the epidermal growth factor receptor (EGFR) is an established target in head-and-neck cancer (HNC), resistance to EGFR-targeted therapy mediated by various mechanisms has been reported. Therefore, a combination strategy to overcome resistance to EGFR mono-targeted therapy is clinically required. We have previously demonstrated that non-thermal atmospheric pressure plasma (NTP) induces death of various cancer cells, including oral squamous cancer (OSCC) cells. In this study, we report for the first time that combining NTP treatment with cetuximab led to inhibition of migration and invasion in cetuximab-resistant OSCC cells, which could be a promising strategy to overcome resistance to anti EGFR therapy. NTP induced deactivation of NF-kappaB in SCCQLL1 cells, but not in MSKQLL1 cells. In addition, NTP increased the expression level of E-cadherin, and decreased those of vimentin, Slug, Snail, matrix metalloproteinase (MMP)-2, -9, and activities of MMPs. Moreover, NF-kappaB upregulation using cDNA diminished the combination effect of NTP on invasion, migration and related signals. Taken together, these results indicate that the combination of NTP with cetuximab can decrease invasiveness in cetuximab-resistant OSCCs through a novel mechanism involving the NF-kappaB pathway. These findings show the therapeutic potential of treatment that combines NTP and cetuximab in OSCC. PMID- 26655731 TI - Content validity of the Sheehan Irritability Scale in patients with major depressive disorder. AB - The Sheehan Irritability Scale (SIS) measures the frequency, severity, and impairment associated with irritability in psychiatric patients. The content validity of the SIS in patients with major depressive disorder (MDD) has not been evaluated. A cross-sectional, qualitative research study was conducted to assess the content validity of the SIS among patients with MDD. One-on-one interviews were conducted, starting with open-ended questions to evaluate the consistency of the SIS content with patient experiences of irritability. Participants then completed the SIS and cognitive interviews around the comprehension of the SIS content (instructions, items, response options). Participants included 24 patients diagnosed with MDD who had an inadequate response to an antidepressant treatment. The sample was: 50.4 mean years, 66.7% female, and 91.7% white racial background. All concepts on the SIS were spontaneously mentioned by at least one participant, and when probed about the symptoms, the majority of participants (66.7-100%) reported the concepts being part of their experience. The majority of participants (70.8-100%) understood the SIS instructions, items, and response scales. This study provides evidence of content validity of the SIS in patients diagnosed with MDD, supporting the use as a measure of irritability in patients with depression. PMID- 26655732 TI - Cariprazine in the treatment of schizophrenia: a proof-of-concept trial. AB - This 6-week, double-blind, placebo-controlled, proof-of-concept study evaluated the efficacy, safety, and tolerability of low-dose (1.5-4.5 mg/day) and high-dose (6-12 mg/day) cariprazine in patients with acute exacerbation of schizophrenia (NCT00404573). The primary efficacy measure was change in the Positive and Negative Syndrome Scale (PANSS) total score, analyzed using a last observation carried forward approach. Other efficacy measures included the Clinical Global Impression-Severity (secondary) and PANSS subscales (additional). There were no significant differences between the two doses of cariprazine and placebo in PANSS total score change or any other efficacy parameter after multiplicity adjustment. However, low-dose cariprazine versus placebo showed significantly greater reductions in PANSS total (P=0.033) and PANSS negative (P=0.027) scores without multiplicity adjustment. Common treatment-emergent adverse events (incidence>=5% and twice that in the placebo group in either cariprazine dose group) were akathisia, restlessness, tremor, back pain, and extrapyramidal disorder. In this study, the overall cariprazine treatment effect was not statistically significant, but patients treated with low-dose cariprazine showed significantly greater improvement in schizophrenia symptoms relative to placebo-treated patients. Cariprazine was generally well tolerated. Results of this study suggest that cariprazine may be effective in treating schizophrenia and future research is warranted. PMID- 26655733 TI - Early alterations of Hedgehog signaling pathway in vascular endothelial cells after peripheral nerve injury elicit blood-nerve barrier disruption, nerve inflammation, and neuropathic pain development. AB - Changes in the nerve's microenvironment and local inflammation resulting from peripheral nerve injury participate in nerve sensitization and neuropathic pain development. Taking part in these early changes, disruption of the blood-nerve barrier (BNB) allows for infiltration of immunocytes and promotes the neuroinflammation. However, molecular mechanisms engaged in vascular endothelial cells (VEC) dysfunction and BNB alterations remain unclear. In vivo, BNB permeability was assessed following chronic constriction injury (CCI) of the rat sciatic nerve (ScN) and differential expression of markers of VEC functional state, inflammation, and intracellular signaling was followed from 3 hours to 2 months postinjury. Several mechanisms potentially involved in functional alterations of VEC were evaluated in vitro using human VEC (hCMEC/D3), then confronted to in vivo physiopathological conditions. CCI of the ScN led to a rapid disruption of endoneurial vascular barrier that was correlated to a decreased production of endothelial tight-junction proteins and an early and sustained alteration of Hedgehog (Hh) signaling pathway. In vitro, activation of Toll-like receptor 4 in VEC downregulated the components of Hh pathway and altered the endothelial functional state. Inhibition of Hh signaling in the ScN of naive rats mimicked the biochemical and functional alterations observed after CCI and was, on its own, sufficient to evoke local neuroinflammation and sustained mechanical allodynia. Alteration of the Hh signaling pathway in VEC associated with peripheral nerve injury, is involved in BNB disruption and local inflammation, and could thus participate in the early changes leading to the peripheral nerve sensitization and, ultimately, neuropathic pain development. PMID- 26655734 TI - Pain expressiveness and altruistic behavior: an exploration using agent-based modeling. AB - Predictions which invoke evolutionary mechanisms are hard to test. Agent-based modeling in artificial life offers a way to simulate behaviors and interactions in specific physical or social environments over many generations. The outcomes have implications for understanding adaptive value of behaviors in context. Pain related behavior in animals is communicated to other animals that might protect or help, or might exploit or predate. An agent-based model simulated the effects of displaying or not displaying pain (expresser/nonexpresser strategies) when injured and of helping, ignoring, or exploiting another in pain (altruistic/nonaltruistic/selfish strategies). Agents modeled in MATLAB interacted at random while foraging (gaining energy); random injury interrupted foraging for a fixed time unless help from an altruistic agent, who paid an energy cost, speeded recovery. Environmental and social conditions also varied, and each model ran for 10,000 iterations. Findings were meaningful in that, in general, contingencies that evident from experimental work with a variety of mammals, over a few interactions, were replicated in the agent-based model after selection pressure over many generations. More energy-demanding expression of pain reduced its frequency in successive generations, and increasing injury frequency resulted in fewer expressers and altruists. Allowing exploitation of injured agents decreased expression of pain to near zero, but altruists remained. Decreasing costs or increasing benefits of helping hardly changed its frequency, whereas increasing interaction rate between injured agents and helpers diminished the benefits to both. Agent-based modeling allows simulation of complex behaviors and environmental pressures over evolutionary time. PMID- 26655735 TI - Protective immune barrier against hepatitis B is needed in individuals born before infant HBV vaccination program in China. AB - The hepatitis B prevalence rate in adults is still at a high to intermediate level in China. Our purpose was to explore the incidence rate and protective immune barrier against hepatitis B in adults in China. A sample of 317961 participants was multi-screened for hepatitis B surface antigens (HBsAg) in a large-scale cohort of the National Hepatitis B Demonstration Project. A total of 5401 persons were newly-infected, representing an incidence rate of 0.81 (95% CI: 0.77-0.85) per 100 person-years after adjusted by gender and age. History of acquired immune deficiency syndrome, birth prior to 1992, coastal residence, family history of HBV, and migrant worker status were significantly associated with higher incidence, while HBV vaccination and greater exercise with lower incidence. The hepatitis B surface antibody (HBsAb) positive rate was negatively correlated with the incidence rate of hepatitis B (r = -0.826). Linear fitting yielded an incidence rate of 1.23 plus 0.02 multiplied by HBsAb positive rate. The study firstly identified the HBsAg incidence rate, which was reduced to 0.1 per 100 person-years after vaccination coverage of about 64%. The protective immune barrier against hepatitis B needs to be established in individuals born prior to the advent of infant HBV vaccination. PMID- 26655736 TI - Interleukin-11 alters placentation and causes preeclampsia features in mice. AB - Preeclampsia (PE) is a pregnancy-specific disorder characterized by hypertension and proteinuria after 20 wk gestation. Abnormal extravillous trophoblast (EVT) invasion and remodeling of uterine spiral arterioles is thought to contribute to PE development. Interleukin-11 (IL11) impedes human EVT invasion in vitro and is elevated in PE decidua in women. We demonstrate that IL11 administered to mice causes development of PE features. Immunohistochemistry shows IL11 compromises trophoblast invasion, spiral artery remodeling, and placentation, leading to increased systolic blood pressure (SBP), proteinuria, and intrauterine growth restriction, although nonpregnant mice were unaffected. Real-time PCR array analysis identified pregnancy-associated plasma protein A2 (PAPPA2), associated with PE in women, as an IL11 regulated target. IL11 increased PAPPA2 serum and placental tissue levels in mice. In vitro, IL11 compromised primary human EVT invasion, whereas siRNA knockdown of PAPPA2 alleviated the effect. Genes regulating uterine natural killer (uNK) recruitment and differentiation were down regulated and uNK cells were reduced after IL11 treatment in mice. IL11 withdrawal in mice at onset of PE features reduced SBP and proteinuria to control levels and alleviated placental labyrinth defects. In women, placental IL11 immunostaining levels increased in PE pregnancies and in serum collected from women before development of early-onset PE, shown by ELISA. These results indicate that elevated IL11 levels result in physiological changes at the maternal-fetal interface, contribute to abnormal placentation, and lead to the development of PE. Targeting placental IL11 may provide a new treatment option for PE. PMID- 26655737 TI - Structural basis for specificity and promiscuity in a carrier protein/enzyme system from the sulfur cycle. AB - The bacterial Sox (sulfur oxidation) pathway is an important route for the oxidation of inorganic sulfur compounds. Intermediates in the Sox pathway are covalently attached to the heterodimeric carrier protein SoxYZ through conjugation to a cysteine on a protein swinging arm. We have investigated how the carrier protein shuttles intermediates between the enzymes of the Sox pathway using the interaction between SoxYZ and the enzyme SoxB as our model. The carrier protein and enzyme interact only weakly, but we have trapped their complex by using a "suicide enzyme" strategy in which an engineered cysteine in the SoxB active site forms a disulfide bond with the incoming carrier arm cysteine. The structure of this trapped complex, together with calorimetric data, identifies sites of protein-protein interaction both at the entrance to the enzyme active site tunnel and at a second, distal, site. We find that the enzyme distinguishes between the substrate and product forms of the carrier protein through differences in their interaction kinetics and deduce that this behavior arises from substrate-specific stabilization of a conformational change in the enzyme active site. Our analysis also suggests how the carrier arm-bound substrate group is able to outcompete the adjacent C-terminal carboxylate of the carrier arm for binding to the active site metal ions. We infer that similar principles underlie carrier protein interactions with other enzymes of the Sox pathway. PMID- 26655738 TI - Identification of MEDIATOR16 as the Arabidopsis COBRA suppressor MONGOOSE1. AB - We performed a screen for genetic suppressors of cobra, an Arabidopsis mutant with defects in cellulose formation and an increased ratio of unesterified/esterified pectin. We identified a suppressor named mongoose1 (mon1) that suppressed the growth defects of cobra, partially restored cellulose levels, and restored the esterification ratio of pectin to wild-type levels. mon1 was mapped to the MEDIATOR16 (MED16) locus, a tail mediator subunit, also known as SENSITIVE TO FREEZING6 (SFR6). When separated from the cobra mutation, mutations in MED16 caused resistance to cellulose biosynthesis inhibitors, consistent with their ability to suppress the cobra cellulose deficiency. Transcriptome analysis revealed that a number of cell wall genes are misregulated in med16 mutants. Two of these genes encode pectin methylesterase inhibitors, which, when ectopically expressed, partially suppressed the cobra phenotype. This suggests that cellulose biosynthesis can be affected by the esterification levels of pectin, possibly through modifying cell wall integrity or the interaction of pectin and cellulose. PMID- 26655739 TI - Discontinuity of cortical gradients reflects sensory impairment. AB - Topographic maps and their continuity constitute a fundamental principle of brain organization. In the somatosensory system, whole-body sensory impairment may be reflected either in cortical signal reduction or disorganization of the somatotopic map, such as disturbed continuity. Here we investigated the role of continuity in pathological states. We studied whole-body cortical representations in response to continuous sensory stimulation under functional MRI (fMRI) in two unique patient populations-patients with cervical sensory Brown-Sequard syndrome (injury to one side of the spinal cord) and patients before and after surgical repair of cervical disk protrusion-enabling us to compare whole-body representations in the same study subjects. We quantified the spatial gradient of cortical activation and evaluated the divergence from a continuous pattern. Gradient continuity was found to be disturbed at the primary somatosensory cortex (S1) and the supplementary motor area (SMA), in both patient populations: contralateral to the disturbed body side in the Brown-Sequard group and before repair in the surgical group, which was further improved after intervention. Results corresponding to the nondisturbed body side and after surgical repair were comparable with control subjects. No difference was found in the fMRI signal power between the different conditions in the two groups, as well as with respect to control subjects. These results suggest that decreased sensation in our patients is related to gradient discontinuity rather than signal reduction. Gradient continuity may be crucial for somatotopic and other topographical organization, and its disruption may characterize pathological processing. PMID- 26655740 TI - Detection of secondary binding sites in proteins using fragment screening. AB - Proteins need to be tightly regulated as they control biological processes in most normal cellular functions. The precise mechanisms of regulation are rarely completely understood but can involve binding of endogenous ligands and/or partner proteins at specific locations on a protein that can modulate function. Often, these additional secondary binding sites appear separate to the primary binding site, which, for example for an enzyme, may bind a substrate. In previous work, we have uncovered several examples in which secondary binding sites were discovered on proteins using fragment screening approaches. In each case, we were able to establish that the newly identified secondary binding site was biologically relevant as it was able to modulate function by the binding of a small molecule. In this study, we investigate how often secondary binding sites are located on proteins by analyzing 24 protein targets for which we have performed a fragment screen using X-ray crystallography. Our analysis shows that, surprisingly, the majority of proteins contain secondary binding sites based on their ability to bind fragments. Furthermore, sequence analysis of these previously unknown sites indicate high conservation, which suggests that they may have a biological function, perhaps via an allosteric mechanism. Comparing the physicochemical properties of the secondary sites with known primary ligand binding sites also shows broad similarities indicating that many of the secondary sites may be druggable in nature with small molecules that could provide new opportunities to modulate potential therapeutic targets. PMID- 26655741 TI - Enhancement of CD3AK cell proliferation and killing ability by alpha-Thujone. AB - Thujone is a monoterpene ketone natural substance found mainly in wormwood and sage. Previous studies have shown that Thujone has various pharmacological effects, such as anti-tumor, analgesic, and insecticide. The effect of alpha Thujone to human immune cells is still unknown. Our study focuses on investigating the effects and mechanism of alpha-Thujone to CD3AK (anti- CD3 antibody induced activated killer) cells proliferation and cytotoxicity to colon cancer cell lines. With cell proliferation and FCM assay, it is found that alpha Thujone could significantly enhance CD3AK cell proliferation and expression of CD107a in a dose-dependent manner. The cytotoxicity to colon cancer cells detected by CCK-8 assay is also improved. The expressions of TNF-alpha and FasL detected with ELISA assay were not significantly changed. Mechanically, the study shows that alpha-Thujone could enhance the expression of p-ERK1/2 and p-Akt. In addition, alpha-Thujone has no cytotoxicity to HCT116 and SW620 cells proliferation. In a word, alpha-Thujone enhances CD3AK cell proliferation and cytotoxicity via the improvement of expression of CD107a, p-Akt and p-ERK1/2. PMID- 26655742 TI - Protective effect of EC-18, a synthetic monoacetyldiglyceride on lung inflammation in a murine model induced by cigarette smoke and lipopolysaccharide. AB - The antler of Sika deer (Cervus nippon Temminck) has been used a natural medicine in Korea, China and Japan, and a monoacetyldiaglyceride (1-palmitoyl-2-linoleoyl 3-acetylglycerol, PLAG) was found in the antler of Sika deer as a constituent for immunomodulation. In this study, we investigated protective effects of EC-18 (a synthetic copy of PLAG) on inflammatory responses using a cigarette smoke with lipopolysaccharide (LPS)-induced airway inflammation model. Mice were exposed to cigarette smoke for 1h per day for 3days. Ten micrograms of LPS dissolved in 50MUL of PBS was administered intra nasally 1h after the final cigarette smoke exposure. EC-18 was administered by oral gavage at doses of 30 and 60mg/kg for 3days. EC-18 significantly reduced the number of neutrophils, reactive oxygen species production, cytokines and elastase activity in bronchoalveolar lavage fluid (BALF) compared with the cigarette smoke and LPS induced mice. Histologically, EC-18 attenuated airway inflammation with a reduction in myeloperoxidase expression in lung tissue. Additionally, EC-18 inhibited the phosphorylation of NF-kappaB and IkappaB induced by cigarette smoke and LPS exposure. Our results show that EC-18 effectively suppresses neutrophilic inflammation induced by cigarette smoke and LPS exposure. In conclusion, this study suggests that EC-18 has therapeutic potential for the treatment of chronic obstructive pulmonary disease. PMID- 26655743 TI - MDM2 promotes rheumatoid arthritis via activation of MAPK and NF-kappaB. AB - Murine double minute-2 (MDM2) has pleiotropic roles in immune activation and regulation. However, the role of MDM2 in rheumatoid arthritis (RA) remains unknown. We undertook this study to investigate the role of MDM2 in rheumatoid arthritis (RA). Fibroblast-like synoviocytes (FLS) were isolated from 25 patients with active RA and 25 patients with osteoarthritis (OA). FLS were stimulated in the presence or absence of IL-1beta in vitro. Mice with collagen-induced arthritis (CIA) were treated with Nutlin-3a (100mg/kg) or vehicle twice daily for 2weeks. MDM2 expression was determined by Western blot. MDM2 was down-regulated by specific gene silencing. The concentrations of pro-inflammatory cytokines and matrix metalloproteinases (MMPs) were analyzed using enzyme-linked immunosorbent assay (ELISA). The pathways of mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-kappaB) were investigated by Western blot. Arthritis scoring and histological analysis were conducted. MDM2 expression was significantly higher in RA-FLS than in OA-FLS. MDM2 protein expression was positively correlated with disease activity of RA. MDM2 promoted the production of TNF-alpha, IL-6, MMP1 and MMP13 through MAPK and NF-kappaB pathways in RA-FLS. Nutlin-3a treatment decreased the arthritis severity and joint damage in CIA. Nutlin-3a also inhibited the activation of MAPK and NF-kappaB in arthritic joints. In conclusion, MDM2 inhibition exhibits anti-inflammatory activity and MDM2 might be a new therapeutic target for RA. PMID- 26655744 TI - Deficits in Attention and Visual Processing but not Global Cognition Predict Simulated Driving Errors in Drivers Diagnosed With Mild Alzheimer's Disease. AB - This study sought to predict driving performance of drivers with Alzheimer's disease (AD) using measures of attention, visual processing, and global cognition. Simulated driving performance of individuals with mild AD (n = 20) was contrasted with performance of a group of healthy controls (n = 21). Performance on measures of global cognitive function and specific tests of attention and visual processing were examined in relation to simulated driving performance. Strong associations were observed between measures of attention, notably the Test of Everyday Attention (sustained attention; r = -.651, P = .002) and the Useful Field of View (r = .563, P = .010), and driving performance among drivers with mild AD. The Visual Object and Space Perception Test-object was significantly correlated with the occurrence of crashes (r = .652, P = .002). Tests of global cognition did not correlate with simulated driving outcomes. The results suggest that professionals exercise caution when extrapolating driving performance based on global cognitive indicators. PMID- 26655745 TI - Nucleosides with Transposed Base or 4'-Hydroxymethyl Moieties and Their Corresponding Oligonucleotides. AB - This review focuses on 4'-hydroxymethyl- or nucleobase-transposed nucleosides, nucleotides, and nucleoside phosphonates, their stereoisomers, and their close analogues. The biological activities of all known 4'-hydroxymethyl- or nucleobase transposed nucleosides, nucleotides, and nucleoside phosphonates as potential antiviral or anticancer agents are compiled. The routes that have been taken for the chemical synthesis of such nucleoside derivatives are described, with special attention to the innovative strategies. The enzymatic synthesis, base-pairing properties, structure, and stability of oligonucleotides containing nucleobase- or 4'-hydroxymethyl-transposed nucleotides are discussed. The use of oligonucleotides containing nucleobase- or 4'-hydroxymethyl-transposed nucleotides as small oligonucleotide (e.g., human immunodeficiency virus integrase) inhibitors, in applications such as antisense therapy, silencing RNA (siRNA), or aptamer selections, is detailed. PMID- 26655746 TI - Cryptococcus neoformans capsular polysaccharides form branched and complex filamentous networks viewed by high-resolution microscopy. AB - Cryptococcus neoformans is a fungal pathogen that causes life-threatening infections in immunocompromised individuals. Its main virulence factor is an extracellular polysaccharide capsule whose structure, assembly and dynamics remain poorly understood. In this study, we apply improved protocols for sample preparation and recently-developed scanning microscopy techniques to visualize the ultrastructure of the C. neoformans capsule at high-resolution (up to 1 nm) and improved structural preservation. Although most capsule structures in nature consist of linear polymers, we show here that the C. neoformans capsule is a 'microgel-like' structure composed of branched polysaccharides. Moreover, we imaged the capsule-to-cell wall link, which is formed by thin fibers that branch out of thicker capsule filaments, and have one end firmly embedded in the cell wall structure. Together, our findings provide compelling ultrastructural evidence for a branched and complex capsule conformation, which may have important implications for the biological activity of the capsule as a virulence factor. PMID- 26655747 TI - Characterization of the pH and Temperature in the Rabbit, Pig, and Monkey Eye: Key Parameters for the Development of Long-Acting Delivery Ocular Strategies. AB - Many long-acting delivery strategies for ocular indications rely on pH- and/or temperature-driven release of the therapeutic agent and degradation of the drug carrier. Yet, these physiological parameters are poorly characterized in ocular animal models. These strategies aim at reducing the frequency of dosing, which is of particular interest for the treatment of chronic disorders affecting the posterior segment of the eye, such as macular degeneration that warrants monthly or every other month intravitreal injections. We used anesthetized white New Zealand rabbits, Yucatan mini pigs, and cynomolgus monkeys to characterize pH and temperature in several vitreous locations and the central aqueous location. We also established post mortem pH changes in the vitreous. Our data showed regional and species differences, which need to be factored into strategies for developing biodegradable long-acting delivery systems. PMID- 26655748 TI - Salivary levels of calcium, phosphorus, potassium, albumin and correlation with serum biomarkers in hemodialysis patients. AB - OBJECTIVES: Evidences suggest that hemodialysis patients have reduced salivary flow and changes in the composition of salivary secretion. These changes may reflect local and systemic disorders. The objectives of this study were to compare the salivary levels of calcium (Ca), phosphorus (P), potassium (K) and albumin in hemodialysis patients and healthy subjects, and to investigate a possible correlation between their serum and salivary levels. DESIGN: A case control study was conducted with 60 hemodialysis patients (HD group) and 37 systemically healthy individuals (control group). Stimulated saliva samples were collected for biochemical analysis (Ca, P, K and albumin). Serum data were collected in the HD group. Statistical analysis included t-test, Pearson correlation and simple linear regression. RESULTS: The HD group exhibited higher salivary levels of Ca, P, and albumin (p<0.05). There was a significant positive correlation between serum PTH and salivary phosphorus (r=0.342, p=0.009), and between serum PTH and salivary potassium (r=0.306, p=0.020). An increase of 100 pg/dL in serum PTH was associated with an elevation of salivary P levels (0.34 mg/dL, p=0.009), and salivary K levels (0.20 mmol/dL, p=0.02), in the HD group. CONCLUSIONS: The findings suggest that HD patients present increased levels of salivary components (Ca, P, and albumin), and changes commonly observed in HD patients, such as hyperparathyroidism, appear to have an influence on salivary composition. PMID- 26655749 TI - Azithromycin recovers reductions in barrier function in human gingival epithelial cells stimulated with tumor necrosis factor-alpha. AB - OBJECTIVE: The gingival epithelium plays an important role in protecting against the invasion of periodontal pathogens, and the permeability of gingival epithelial cells has been implicated in the initiation of periodontitis. Azithromycin (AZM) has been used in the treatment of chronic inflammatory airway diseases because it regulates cell-cell contact in airway epithelial cells. Therefore, AZM may also regulate barrier function in gingival epithelial cells. In the present study, we examined the effects of AZM on the permeability of human gingival epithelial cells (HGEC) under inflammatory conditions in vitro. MATERIALS AND METHODS: HGEC were stimulated by tumor necrosis factor-alpha (TNF alpha) in the presence of AZM or p38 MAP kinase and ERK inhibitors. Permeability was assessed based on transepithelial electrical resistance (TER). The expression of E-cadherin, phosphorylated p38 MAP kinase, and ERK was analyzed by Western blotting. RESULTS: TNF-alpha decreased TER in HGEC, and AZM and the p38 MAP kinase and ERK inhibitors recovered this decrease. AZM inhibited the phosphorylation of ERK and p38 MAP kinase in TNF-alpha-stimulated HGEC. Furthermore, AZM recovered the decrease in E-cadherin expression in HGEC stimulated with TNF-alpha. CONCLUSIONS: These results suggested that AZM regulated gingival epithelial permeability through p38 MAP kinase and ERK signaling, and may contribute to suppress the inflammation in gingival tissue. PMID- 26655750 TI - Elucidating Latent Mechanistic Complexity in Competing Acid-Catalyzed Reactions of Salicylaldehyde-Derived Baylis-Hillman Adducts. AB - (1)H NMR-based kinetic studies have revealed the latent mechanistic complexity of deceptively simple hydrochloric acid-catalyzed reactions of salicylaldehyde derived Baylis-Hillman adducts. Reactions conducted at 0 degrees C afforded 2 (chloromethyl)cinnamic acid derivatives as the major products and the corresponding 3-(chloromethyl)coumarin derivatives as the minor products. In reactions conducted in refluxing acetic acid, however, the 3 (chloromethyl)coumarin derivatives are the sole products. Variable-temperature (1)H NMR analysis permitted the determination of the rate constants and kinetic parameters involved in the pseudo-first-order formation of (Z)-2-(chloromethyl)-3 (2-hydroxyphenyl)-2-propenoic acid. The kinetic data clearly preclude the operation of classical kinetic versus thermodynamic control and indicate the operation of three independent reaction pathways. Theoretical studies of these pathways undertaken at the B3LYP/6-31G(d) level permitted rationalization of the experimental data and provided insights into the possible mechanism of the enzymic E-Z isomerization and cyclization of (E)-cinnamic acid analogues to afford coumarins. PMID- 26655751 TI - Diguanylate Cyclases AdrA and STM1987 Regulate Salmonella enterica Exopolysaccharide Production during Plant Colonization in an Environment Dependent Manner. AB - Increasing evidence indicates that despite exposure to harsh environmental stresses, Salmonella enterica successfully persists on plants, utilizing fresh produce as a vector to animal hosts. Among the important S. enterica plant colonization factors are those involved in biofilm formation. S. enterica biofilm formation is controlled by the signaling molecule cyclic di-GMP and represents a sessile lifestyle on surfaces that protects the bacterium from environmental factors. Thus, the transition from a motile, planktonic lifestyle to a sessile lifestyle may represent a vital step in bacterial success. This study examined the mechanisms of S. enterica plant colonization, including the role of diguanylate cyclases (DGCs) and phosphodiesterases (PDEs), the enzymes involved in cyclic di-GMP metabolism. We found that two biofilm components, cellulose and curli, are differentially required at distinct stages in root colonization and that the DGC STM1987 regulates cellulose production in this environment independent of AdrA, the DGC that controls the majority of in vitro cellulose production. In addition, we identified a new function for AdrA in the transcriptional regulation of colanic acid and demonstrated that adrA and colanic acid biosynthesis are associated with S. enterica desiccation tolerance on the leaf surface. Finally, two PDEs with known roles in motility, STM1344 and STM1697, had competitive defects in the phyllosphere, suggesting that regulation of motility is crucial for S. enterica survival in this niche. Our results indicate that specific conditions influence the contribution of individual DGCs and PDEs to bacterial success, perhaps reflective of differential responses to environmental stimuli. PMID- 26655752 TI - Comprehensive Genomic Analyses of the OM43 Clade, Including a Novel Species from the Red Sea, Indicate Ecotype Differentiation among Marine Methylotrophs. AB - The OM43 clade within the family Methylophilaceae of Betaproteobacteria represents a group of methylotrophs that play important roles in the metabolism of C1 compounds in marine environments and other aquatic environments around the globe. Using dilution-to-extinction cultivation techniques, we successfully isolated a novel species of this clade (here designated MBRS-H7) from the ultraoligotrophic open ocean waters of the central Red Sea. Phylogenomic analyses indicate that MBRS-H7 is a novel species that forms a distinct cluster together with isolate KB13 from Hawaii (Hawaii-Red Sea [H-RS] cluster) that is separate from the cluster represented by strain HTCC2181 (from the Oregon coast). Phylogenetic analyses using the robust 16S-23S internal transcribed spacer revealed a potential ecotype separation of the marine OM43 clade members, which was further confirmed by metagenomic fragment recruitment analyses that showed trends of higher abundance in low-chlorophyll and/or high-temperature provinces for the H-RS cluster but a preference for colder, highly productive waters for the HTCC2181 cluster. This potential environmentally driven niche differentiation is also reflected in the metabolic gene inventories, which in the case of the H RS cluster include those conferring resistance to high levels of UV irradiation, temperature, and salinity. Interestingly, we also found different energy conservation modules between these OM43 subclades, namely, the existence of the NADH:quinone oxidoreductase complex I (NUO) system in the H-RS cluster and the nonhomologous NADH:quinone oxidoreductase (NQR) system in the HTCC2181 cluster, which might have implications for their overall energetic yields. PMID- 26655753 TI - Enhancement of Swimming Speed Leads to a More-Efficient Chemotactic Response to Repellent. AB - Negative chemotaxis refers to the motion of microorganisms away from regions with high concentrations of chemorepellents. In this study, we set controlled gradients of NiCl2, a chemorepellent, in microchannels to quantify the motion of Escherichia coli over a broad range of concentrations. The experimental technique measured the motion of the bacteria in space and time and further related the motion to the local concentration profile of the repellent. Results show that the swimming speed of bacteria increases with an increasing concentration of repellent, which in turn enhances the drift velocity. The contribution of the increased swimming speed to the total drift velocity was in the range of 20 to 40%, with the remaining contribution coming from the modulation of the tumble frequency. A simple model that incorporates receptor dynamics, including adaptation, intracellular signaling, and swimming speed variation, was able to qualitatively capture the observed trend in drift velocity. PMID- 26655754 TI - A New N-Acyl Homoserine Lactone Synthase in an Uncultured Symbiont of the Red Sea Sponge Theonella swinhoei. AB - Sponges harbor a remarkable diversity of microbial symbionts in which signal molecules can accumulate and enable cell-cell communication, such as quorum sensing (QS). Bacteria capable of QS were isolated from marine sponges; however, an extremely small fraction of the sponge microbiome is amenable to cultivation. We took advantage of community genome assembly and binning to investigate the uncultured majority of sponge symbionts. We identified a complete N-acyl homoserine lactone (AHL)-QS system (designated TswIR) and seven partial luxI homologues in the microbiome of Theonella swinhoei. The TswIR system was novel and shown to be associated with an alphaproteobacterium of the order Rhodobacterales, here termed Rhodobacterales bacterium TS309. The tswI gene, when expressed in Escherichia coli, produced three AHLs, two of which were also identified in a T. swinhoei sponge extract. The taxonomic affiliation of the 16S rRNA of Rhodobacterales bacterium TS309 to a sponge-coral specific clade, its enrichment in sponge versus seawater and marine sediment samples, and the presence of sponge-specific features, such as ankyrin-like domains and tetratricopeptide repeats, indicate a likely symbiotic nature of this bacterium. PMID- 26655755 TI - An Interspecies Signaling System Mediated by Fusaric Acid Has Parallel Effects on Antifungal Metabolite Production by Pseudomonas protegens Strain Pf-5 and Antibiosis of Fusarium spp. AB - Pseudomonas protegens strain Pf-5 is a rhizosphere bacterium that suppresses soilborne plant diseases and produces at least seven different secondary metabolites with antifungal properties. We derived mutants of Pf-5 with single and multiple mutations in biosynthesis genes for seven antifungal metabolites: 2,4-diacetylphoroglucinol (DAPG), pyrrolnitrin, pyoluteorin, hydrogen cyanide, rhizoxin, orfamide A, and toxoflavin. These mutants were tested for inhibition of the pathogens Fusarium verticillioides and Fusarium oxysporum f. sp. pisi. Rhizoxin, pyrrolnitrin, and DAPG were found to be primarily responsible for fungal antagonism by Pf-5. Previously, other workers showed that the mycotoxin fusaric acid, which is produced by many Fusarium species, including F. verticillioides, inhibited the production of DAPG by Pseudomonas spp. In this study, amendment of culture media with fusaric acid decreased DAPG production, increased pyoluteorin production, and had no consistent influence on pyrrolnitrin or orfamide A production by Pf-5. Fusaric acid also altered the transcription of biosynthetic genes, indicating that the mycotoxin influenced antibiotic production by Pf-5 at the transcriptional level. Addition of fusaric acid to the culture medium reduced antibiosis of F. verticillioides by Pf-5 and derivative strains that produce DAPG but had no effect on antibiosis by Pf-5 derivatives that suppressed F. verticillioides due to pyrrolnitrin or rhizoxin production. Our results demonstrated the importance of three compounds, rhizoxin, pyrrolnitrin, and DAPG, in suppression of Fusarium spp. by Pf-5 and confirmed that an interspecies signaling system mediated by fusaric acid had parallel effects on antifungal metabolite production and antibiosis by the bacterial biological control organism. PMID- 26655756 TI - Multiple Posttranslational Modifications of Leptospira biflexa Proteins as Revealed by Proteomic Analysis. AB - The saprophyte Leptospira biflexa is an excellent model for studying the physiology of the medically important Leptospira genus, the pathogenic members of which are more recalcitrant to genetic manipulation and have significantly slower in vitro growth. However, relatively little is known regarding the proteome of L. biflexa, limiting its utility as a model for some studies. Therefore, we have generated a proteomic map of both soluble and membrane-associated proteins of L. biflexa during exponential growth and in stationary phase. Using these data, we identified abundantly produced proteins in each cellular fraction and quantified the transcript levels from a subset of these genes using quantitative reverse transcription-PCR (RT-PCR). These proteins should prove useful as cellular markers and as controls for gene expression studies. We also observed a significant number of L. biflexa membrane-associated proteins with multiple isoforms, each having unique isoelectric focusing points. L. biflexa cell lysates were examined for several posttranslational modifications suggested by the protein patterns. Methylation and acetylation of lysine residues were predominately observed in the proteins of the membrane-associated fraction, while phosphorylation was detected mainly among soluble proteins. These three posttranslational modification systems appear to be conserved between the free living species L. biflexa and the pathogenic species Leptospira interrogans, suggesting an important physiological advantage despite the varied life cycles of the different species. PMID- 26655757 TI - Lactobacillus rhamnosus GR-1 Ameliorates Escherichia coli-Induced Inflammation and Cell Damage via Attenuation of ASC-Independent NLRP3 Inflammasome Activation. AB - Escherichia coli is a major environmental pathogen causing bovine mastitis, which leads to mammary tissue damage and cell death. We explored the effects of the probiotic Lactobacillus rhamnosus GR-1 on ameliorating E. coli-induced inflammation and cell damage in primary bovine mammary epithelial cells (BMECs). Increased Toll-like receptor 4 (TLR4), NOD1, and NOD2 mRNA expression was observed following E. coli challenge, but this increase was attenuated by L. rhamnosus GR-1 pretreatment. Immunofluorescence and Western blot analyses revealed that L. rhamnosus GR-1 pretreatment decreased the E. coli-induced increases in the expression of the NOD-like receptor family member pyrin domain containing protein 3 (NLRP3) and the serine protease caspase 1. However, expression of the adaptor protein apoptosis-associated speck-like protein (ASC, encoded by the Pycard gene) was decreased during E. coli infection, even with L. rhamnosus GR-1 pretreatment. Pretreatment with L. rhamnosus GR-1 counteracted the E. coli-induced increases in interleukin-1beta (IL-1beta), -6, -8, and -18 and tumor necrosis factor alpha mRNA expression but upregulated IL-10 mRNA expression. Our data indicate that L. rhamnosus GR-1 reduces the adhesion of E. coli to BMECs, subsequently ameliorating E. coli-induced disruption of cellular morphology and ultrastructure and limiting detrimental inflammatory responses, partly via promoting TLR2 and NOD1 synergism and attenuating ASC-independent NLRP3 inflammasome activation. Although the residual pathogenic activity of L. rhamnosus, the dosage regimen, and the means of probiotic supplementation in cattle remain undefined, our data enhance our understanding of the mechanism of action of this candidate probiotic, allowing for development of specific probiotic-based therapies and strategies for preventing pathogenic infection of the bovine mammary gland. PMID- 26655758 TI - Engineering Synthetic Multistress Tolerance in Escherichia coli by Using a Deinococcal Response Regulator, DR1558. AB - Cellular robustness is an important trait for industrial microbes, because the microbial strains are exposed to a multitude of different stresses during industrial processes, such as fermentation. Thus, engineering robustness in an organism in order to push the strains toward maximizing yield has become a significant topic of research. We introduced the deinococcal response regulator DR1558 into Escherichia coli (strain Ec-1558), thereby conferring tolerance to hydrogen peroxide (H2O2). The reactive oxygen species (ROS) level in strain Ec 1558 was reduced due to the increased KatE catalase activity. Among four regulators of the oxidative-stress response, OxyR, RpoS, SoxS, and Fur, we found that the expression of rpoS increased in Ec-1558, and we confirmed this increase by Western blot analysis. Electrophoretic mobility shift assays showed that DR1558 bound to the rpoS promoter. Because the alternative sigma factor RpoS regulates various stress resistance-related genes, we performed stress survival analysis using an rpoS mutant strain. Ec-1558 was able to tolerate a low pH, a high temperature, and high NaCl concentrations in addition to H2O2, and the multistress tolerance phenotype disappeared in the absence of rpoS. Microarray analysis clearly showed that a variety of stress-responsive genes that are directly or indirectly controlled by RpoS were upregulated in strain Ec-1558. These findings, taken together, indicate that the multistress tolerance conferred by DR1558 is likely routed through RpoS. In the present study, we propose a novel strategy of employing an exogenous response regulator from polyextremophiles for strain improvement. PMID- 26655759 TI - How Does Sampling Methodology Influence Molecular Detection and Isolation Success in Influenza A Virus Field Studies? AB - Wild waterfowl are important reservoir hosts for influenza A virus (IAV) and a potential source of spillover infections in other hosts, including poultry and swine. The emergence of highly pathogenic avian influenza (HPAI) viruses, such as H5N1 and H5N8, and subsequent spread along migratory flyways prompted the initiation of several programs in Europe, North America, and Africa to monitor circulation of HPAI and low-pathogenicity precursor viruses (low-pathogenicity avian influenza [LPAI] viruses). Given the costs of maintaining such programs, it is essential to establish best practice for field methodologies to provide robust data for epidemiological interpretation. Here, we use long-term surveillance data from a single site to evaluate the influence of a number of parameters on virus detection and isolation of LPAI viruses. A total of 26,586 samples (oropharyngeal, fecal, and cloacal) collected from wild mallards were screened by real-time PCR, and positive samples were subjected to isolation in embryonated chicken eggs. The LPAI virus detection rate was influenced by the sample type: cloacal/fecal samples showed a consistently higher detection rate and lower cycle threshold (Ct) value than oropharyngeal samples. Molecular detection was more sensitive than isolation, and virus isolation success was proportional to the number of RNA copies in the sample. Interestingly, for a given Ct value, the isolation success was lower in samples from adult birds than in those from juveniles. Comparing the results of specific real-time reverse transcriptase (RRT)-PCRs and of isolation, it was clear that coinfections were common in the investigated birds. The effects of sample type and detection methods warrant some caution in interpretation of the surveillance data. PMID- 26655760 TI - Alginate Biosynthesis Factories in Pseudomonas fluorescens: Localization and Correlation with Alginate Production Level. AB - Pseudomonas fluorescens is able to produce the medically and industrially important exopolysaccharide alginate. The proteins involved in alginate biosynthesis and secretion form a multiprotein complex spanning the inner and outer membranes. In the present study, we developed a method by which the porin AlgE was detected by immunogold labeling and transmission electron microscopy. Localization of the AlgE protein was found to depend on the presence of other proteins in the multiprotein complex. No correlation was found between the number of alginate factories and the alginate production level, nor were the numbers of these factories affected in an algC mutant that is unable to produce the precursor needed for alginate biosynthesis. Precursor availability and growth phase thus seem to be the main determinants for the alginate production rate in our strain. Clustering analysis demonstrated that the alginate multiprotein complexes were not distributed randomly over the entire outer cell membrane surface. PMID- 26655761 TI - Prevalence and Genetic Diversity of Human Sapoviruses in Shellfish from Commercial Production Areas in Galicia, Spain. AB - The prevalence of human forms of Sapovirus, an emerging pathogen of human gastroenteritis, was investigated in an 18-month survey from class B mollusc harvesting areas in two Galician rias (northwest Spain). The detection and quantification of Sapovirus was performed by reverse transcription-real-time PCR, according to the recently developed standard method ISO/TS 15216-1:2013, and genotyping by reverse transcription-nested PCR. The bivalve species studied were wild and cultured mussels (Mytilus galloprovincialis), clams (Venerupis philippinarum and Venerupis decussata), and cockles (Cerastoderma edule). Sapovirus was detected in 30 out of 168 samples (17.9%), with cockles being the species with the highest prevalence of positives (28.1%), followed by clams (22.6%), wild mussels (14.3%), and cultured mussels (12.9%). The estuary in the south of the region demonstrated a higher percentage of positive samples (21.8%) than the one in the north (14.4%). Viral contamination levels for the positive samples ranged between 1.9 * 10(3) and 1.4 * 10(5) RNA copies/g of digestive tissue. Thirteen Sapovirus sequences could be obtained based on partial capsid gene sequence and were classified into four genotypes: GI.1 (2 samples), GI.2 (8 samples), GIV.1 (2 samples), and GV.1 (1 sample). PMID- 26655762 TI - A Fivefold Parallelized Biosynthetic Process Secures Chlorination of Armillaria mellea (Honey Mushroom) Toxins. AB - The basidiomycetous tree pathogen Armillaria mellea (honey mushroom) produces a large variety of structurally related antibiotically active and phytotoxic natural products, referred to as the melleolides. During their biosynthesis, some members of the melleolide family of compounds undergo monochlorination of the aromatic moiety, whose biochemical and genetic basis was not known previously. This first study on basidiomycete halogenases presents the biochemical in vitro characterization of five flavin-dependent A. mellea enzymes (ArmH1 to ArmH5) that were heterologously produced in Escherichia coli. We demonstrate that all five enzymes transfer a single chlorine atom to the melleolide backbone. A 5-fold, secured biosynthetic step during natural product assembly is unprecedented. Typically, flavin-dependent halogenases are categorized into enzymes acting on free compounds as opposed to those requiring a carrier-protein-bound acceptor substrate. The enzymes characterized in this study clearly turned over free substrates. Phylogenetic clades of halogenases suggest that all fungal enzymes share an ancestor and reflect a clear divergence between ascomycetes and basidiomycetes. PMID- 26655763 TI - Deterministic Assembly of Complex Bacterial Communities in Guts of Germ-Free Cockroaches. AB - The gut microbiota of termites plays important roles in the symbiotic digestion of lignocellulose. However, the factors shaping the microbial community structure remain poorly understood. Because termites cannot be raised under axenic conditions, we established the closely related cockroach Shelfordella lateralis as a germ-free model to study microbial community assembly and host-microbe interactions. In this study, we determined the composition of the bacterial assemblages in cockroaches inoculated with the gut microbiota of termites and mice using pyrosequencing analysis of their 16S rRNA genes. Although the composition of the xenobiotic communities was influenced by the lineages present in the foreign inocula, their structure resembled that of conventional cockroaches. Bacterial taxa abundant in conventional cockroaches but rare in the foreign inocula, such as Dysgonomonas and Parabacteroides spp., were selectively enriched in the xenobiotic communities. Donor-specific taxa, such as endomicrobia or spirochete lineages restricted to the gut microbiota of termites, however, either were unable to colonize germ-free cockroaches or formed only small populations. The exposure of xenobiotic cockroaches to conventional adults restored their normal microbiota, which indicated that autochthonous lineages outcompete foreign ones. Our results provide experimental proof that the assembly of a complex gut microbiota in insects is deterministic. PMID- 26655764 TI - Markerless Gene Deletion with Cytosine Deaminase in Thermus thermophilus Strain HB27. AB - We developed a counterselectable deletion system for Thermus thermophilus HB27 based on cytosine deaminase (encoded by codA) from Thermaerobacter marianensis DSM 12885 and the sensitivity of T. thermophilus HB27 to the antimetabolite 5 fluorocytosine (5-FC). The deletion vector comprises the pUC18 origin of replication, a thermostable kanamycin resistance marker functional in T. thermophilus HB27, and codA under the control of a constitutive putative trehalose promoter from T. thermophilus HB27. The functionality of the system was demonstrated by deletion of the bglT gene, encoding a beta-glycosidase, and three carotenoid biosynthesis genes, CYP175A1, crtY, and crtI, from the genome of T. thermophilus HB27. PMID- 26655765 TI - A 2-Hydroxypyridine Catabolism Pathway in Rhodococcus rhodochrous Strain PY11. AB - Rhodococcus rhodochrous PY11 (DSM 101666) is able to use 2-hydroxypyridine as a sole source of carbon and energy. By investigating a gene cluster (hpo) from this bacterium, we were able to reconstruct the catabolic pathway of 2-hydroxypyridine degradation. Here, we report that in Rhodococcus rhodochrous PY11, the initial hydroxylation of 2-hydroxypyridine is catalyzed by a four-component dioxygenase (HpoBCDF). A product of the dioxygenase reaction (3,6-dihydroxy-1,2,3,6 tetrahydropyridin-2-one) is further oxidized by HpoE to 2,3,6-trihydroxypyridine, which spontaneously forms a blue pigment. In addition, we show that the subsequent 2,3,6-trihydroxypyridine ring opening is catalyzed by the hypothetical cyclase HpoH. The final products of 2-hydroxypyridine degradation in Rhodococcus rhodochrous PY11 are ammonium ion and alpha-ketoglutarate. PMID- 26655766 TI - Brain-state classification and a dual-state decoder dramatically improve the control of cursor movement through a brain-machine interface. AB - OBJECTIVE: It is quite remarkable that brain machine interfaces (BMIs) can be used to control complex movements with fewer than 100 neurons. Success may be due in part to the limited range of dynamical conditions under which most BMIs are tested. Achieving high-quality control that spans these conditions with a single linear mapping will be more challenging. Even for simple reaching movements, existing BMIs must reduce the stochastic noise of neurons by averaging the control signals over time, instead of over the many neurons that normally control movement. This forces a compromise between a decoder with dynamics allowing rapid movement and one that allows postures to be maintained with little jitter. Our current work presents a method for addressing this compromise, which may also generalize to more highly varied dynamical situations, including movements with more greatly varying speed. APPROACH: We have developed a system that uses two independent Wiener filters as individual components in a single decoder, one optimized for movement, and the other for postural control. We computed an LDA classifier using the same neural inputs. The decoder combined the outputs of the two filters in proportion to the likelihood assigned by the classifier to each state. MAIN RESULTS: We have performed online experiments with two monkeys using this neural-classifier, dual-state decoder, comparing it to a standard, single state decoder as well as to a dual-state decoder that switched states automatically based on the cursor's proximity to a target. The performance of both monkeys using the classifier decoder was markedly better than that of the single-state decoder and comparable to the proximity decoder. SIGNIFICANCE: We have demonstrated a novel strategy for dealing with the need to make rapid movements while also maintaining precise cursor control when approaching and stabilizing within targets. Further gains can undoubtedly be realized by optimizing the performance of the individual movement and posture decoders. PMID- 26655767 TI - Urology and the core curriculum: The current status and controversies of the urology residency in Europe and Spain. PMID- 26655768 TI - PLOS Genetics Data Sharing Policy: In Pursuit of Functional Utility. PMID- 26655769 TI - Effect of refractive error on visual evoked potentials with pattern stimulation in dogs. AB - The purpose of this study was to investigate the effects of refractive error on canine visual evoked potentials with pattern stimulation (P-VEP). Six normal beagle dogs were used. The refractive power of the recorded eyes was measured by skiascopy. The refractive power was corrected to -4 diopters (D) to +2 D using contact lens. P-VEP was recorded at each refractive power. The stimulus pattern size and distance were 50.3 arc-min and 50 cm. The P100 appeared at almost 100 msec at -2 D (at which the stimulus monitor was in focus). There was significant prolongation of the P100 implicit time at -4, -3, 0 and +1 D compared with -2 D, respectively. We concluded that the refractive power of the eye affected the P100 implicit time in canine P-VEP recording. PMID- 26655770 TI - Development and evaluation of the internal-controlled real-time PCR assay for Rhodococcus equi detection in various clinical specimens. AB - Rhodococcus equi is the causative agent of rhodococcosis in horses, resulting in significant morbidity and mortality in foals. This bacterium has also been isolated from a variety of animals and is being increasingly reported as a cause of infection in humans, mainly in immunosuppressed individuals. Laboratory diagnostics of R. equi infections based only on conventional microbiological methods shows low accuracy and can lead to misidentification. The objective of the study was to develop and evaluate a real-time PCR assay for direct detection of R. equi in various clinical specimens, including tissue samples. The species specific region of the gene encoding R. equi cholesterol oxidase, choE, was used as a qPCR-target. The diagnostic applicability of the assay was confirmed by testing various tissue specimens obtained from horses with clinical signs of rhodoccocal infection and swine submaxillary lymph nodes. The rate of R. equi detection in clinical specimens by the developed assay was higher in comparison to the culture method (90% vs. 60.0% of positive samples) and conventional PCR (90.0% vs. 20.0% of positive samples). In case of 13 samples that were negative in the culture-based method, R. equi was detected by the developed assay. Only in one case, it gave negative result for culture-positive sample. The assay may provide a simple and rapid tool to complement the classical methods of R. equi detection based on culture and phenotypic identification of isolates, as the performed evaluation indicated a high specificity and accuracy of the results. PMID- 26655771 TI - The Biogeography of Adaptive Radiations and the Geographic Overlap of Sister Species. AB - The biogeography of speciation and what can be learned about the past mode of speciation from current biogeography of sister species are recurrent problems in evolution. We used a trait- and individual-based, eco-evolutionary model to simulate adaptive radiations and recorded the geographical overlap of species during and after evolutionary branching (speciation). We compared the spatial overlap among sister species in the fully saturated community with the overlap at the speciation event. The mean geographic overlap at speciation varied continuously from complete (sympatry) to none (allopatry), depending on local and regional environmental heterogeneity and the rate of dispersal. The distribution of overlap was, however, in some cases considerably bimodal. This tendency was most expressed at large values of regional heterogeneity, corresponding to sharp environmental contrasts. The mean geographic overlap also varied during the course of a radiation, sometimes with a consistent negative trend over time. The speciations that resulted in currently observable end community sister species were therefore not an unbiased sample of all speciations throughout the radiation. Postspeciation range shifts (causing increased overlap) occurred most frequently when dispersal was high or when local habitat heterogeneity was low. Our results help us understand how the patterns of geographic mode of speciation emerge. We also show the difficulty in inferring the geographical speciation mode from phylogenies and the biogeography of extant species. PMID- 26655772 TI - Experimental Evolution under Fluctuating Thermal Conditions Does Not Reproduce Patterns of Adaptive Clinal Differentiation in Drosophila melanogaster. AB - Experimental evolution can be a useful tool for testing the impact of environmental factors on adaptive changes in populations, and this approach is being increasingly used to understand the potential for evolutionary responses in populations under changing climates. However, selective factors will often be more complex in natural populations than in laboratory environments and produce different patterns of adaptive differentiation. Here we test the ability of laboratory experimental evolution under different temperature cycles to reproduce well-known patterns of clinal variation in Drosophila melanogaster. Six fluctuating thermal regimes mimicking the natural temperature conditions along the east coast of Australia were initiated. Contrary to expectations, on the basis of field patterns there was no evidence for adaptation to thermal regimes as reflected by changes in cold and heat resistance after 1-3 years of laboratory natural selection. While laboratory evolution led to changes in starvation resistance, development time, and body size, patterns were not consistent with those seen in natural populations. These findings highlight the complexity of factors affecting trait evolution in natural populations and indicate that caution is required when inferring likely evolutionary responses from the outcome of experimental evolution studies. PMID- 26655773 TI - Coevolution of Parental Care, Parasitic, and Resistance Efforts in Facultative Parasitism. AB - Here we develop a tug-of-war game theory model of mixed-strategy facultative parasitism. In this framework, individuals decide how to strategically invest in parental care effort, parasitism, and resistance to being parasitized, choosing their investments to respond optimally to their opponent's behavior and vice versa. We have implemented the model in the well-studied case of mixed-strategy conspecific brood parasitism, which occurs when a female raises her own clutch of eggs and flexibly lays some eggs in a conspecific's nest. However, the nest of a parasitic female in this case may also be parasitized. We model this as a tug-of war, allowing parasitic and resistance efforts to strategically coevolve with each other. We then derive expressions for parasitism outcomes commonly observed in the field. The model also captures the trade-offs between parental care and parasitism when both are possible. We make a number of novel predictions about the rate of successful versus attempted parasitism as well as how parental care effort, resistance to parasitism, and fitness vary as functions of group size and individual differences between players in energy budget and production efficiency. Although we focus primarily on conspecific brood parasitism, the model is general enough to be extended to other systems in which facultative parasitism is possible, including the parasitism of food, fertilizations, nest sites, or other resources from conspecifics. PMID- 26655774 TI - Are All Hosts Created Equal? Partitioning Host Species Contributions to Parasite Persistence in Multihost Communities. AB - Many parasites circulate endemically within communities of multiple host species. To understand disease persistence within these communities, it is essential to know the contribution each host species makes to parasite transmission and maintenance. However, quantifying those contributions is challenging. We present a conceptual framework for classifying multihost sharing, based on key thresholds for parasite persistence. We then develop a generalized technique to quantify each species' contribution to parasite persistence, allowing natural systems to be located within the framework. We illustrate this approach using data on gastrointestinal parasites circulating within rodent communities and show that, although many parasites infect several host species, parasite persistence is often driven by just one host species. In some cases, however, parasites require multiple host species for maintenance. Our approach provides a quantitative method for differentiating these cases using minimal reliance on system-specific parameters, enabling informed decisions about parasite management within poorly understood multihost communities. PMID- 26655775 TI - Spatially Heterogeneous Perturbations Homogenize the Regulation of Insect Herbivores. AB - Anthropogenic influences on resources and consumers can affect food web regulation, with impacts on trophic structure and ecosystem processes. Identifying how these impacts unfold is challenging because alterations to one or both resources and consumers can similarly transform community structure, especially for intermediate consumers. To date, empirical testing of perturbations on trophic regulation has been limited by the difficulty in separating the direct effect of perturbations on species composition and diversity from those unfolding indirectly via altered feeding pathways. Moreover, disentangling the independent and interactive impacts of covarying stressors that characterize human-altered systems has been an ongoing analytical challenge. We used a large-scale metacommunity experiment in grasslands to test how resource inputs, stand perturbation, and spatial factors affect regulation of insect herbivores in tritrophic grassland food webs. Using path-model comparisons, we observed significant simplification of food web regulation on insect herbivores, shifting from mixed predator-resource regulation in unaltered mainland areas to strictly resource-based regulation with landscape perturbation and fragmentation. Most changes were attributed to homogenization of plant community caused by landscape fragmentation and the deterministic influence of eutrophication that reduced among-patch beta diversity. This led to a simplified food web dominated by fewer but more abundant herbivore taxa. Our work implies that anthropogenic perturbation relating to resources and spatial isolation can transform the regulation of food web diversity, structure, and function. PMID- 26655776 TI - Limited Dispersal Drives Clustering and Reduces Coexistence by the Storage Effect. AB - Temporal variation can facilitate the coexistence of competitors through the temporal storage effect. However, this theoretical result was derived with the assumption that species have high dispersal rates. Here, I show that limited dispersal diminishes the storage effect in the classical lottery model. Populations become highly clustered during invasion, and population growth rates and extinction probabilities are functions of cluster size. I adopt the term "nucleation" from the physics literature to describe these characteristics. I developed approximations that incorporated nucleation to capture the spatiotemporal dynamics of the simulated model. Using analytical results from these approximations, I show that limited dispersal dampens asynchronous fluctuations in reproduction between species. This makes species appear to be more similar in their growth rate responses to the environment, thus reducing the potential for the storage effect. Theoretical results lead to simple rules relating average dispersal distances to relative reductions in potential coexistence. To demonstrate their use, I perform a preliminary analysis of two plant communities: tropical trees and desert annuals. In both communities, small seeded species that disperse short distances on average have the strongest reductions in potential coexistence; species with wind- or animal-driven dispersal disperse farther distances, on average, and experience moderate or small reductions. PMID- 26655777 TI - An Overlooked Consequence of Dietary Mixing: A Varied Diet Reduces Interindividual Variance in Fitness. AB - The determinants of diet breadth are of interest to nutritionists, ecologists, and evolutionary biologists. A recent synthesis addressing this issue found conflicting evidence for the relationship between diet breadth and mean individual fitness. Specifically, it found that while, on average, a mixed diet does increase mean fitness, in some instances, a single food provides equal (or higher) fitness than a mixed diet. Critical to ecological and evolutionary considerations of diet, however, is not only mean fitness but also variance in fitness. We combine contemporary meta-analytic methods with models of nutritional geometry to evaluate how diet affects between-individual variance in fitness within generalist consumers from a range of trophic levels. As predicted by nutritional geometry, we found that between-individual variance in fitness related traits is higher on single-food than mixed diets. The effect was strong for longevity traits (57% higher) and reproductive traits (37%) and present but weaker for size-related traits (10%). Further, the effect became stronger as the number of available foods increased. The availability of multiple foods likely allows individuals with differing nutritional optima to customize intake, each maximizing their own fitness. Importantly, these findings may suggest that selection on traits correlated with nutritional requirements is weak in heterogeneous nutritional environments. PMID- 26655778 TI - Social Control of Reproduction and Breeding Monopolization in the Eusocial Snapping Shrimp Synalpheus elizabethae. AB - Understanding why individuals within altruistic societies forgo reproduction to raise others' offspring has fascinated scientists since Darwin. Although worker polymorphism is thought to have evolved only in sterile workers, worker subcastes appear to be common among social invertebrates and vertebrates. We asked whether sterility accompanies eusociality and morphological differentiation in snapping shrimps (Synalpheus)-the only known marine eusocial group. We show that workers in Synalpheus elizabethae are reproductively totipotent and that female-but not male-gonadal development and mating are mediated by the presence of a queen, apparently without physical aggression. In queenless experimental colonies, a single immature female worker typically became ovigerous, and no female workers matured in colonies with a resident queen. Thus, eusocial shrimp workers retain reproductive totipotency despite signs of morphological specialization. The failure of most female workers to mature is instead facultative and mediated by the presence of the queen, ensuring her reproductive monopoly. PMID- 26655779 TI - Per Aspera ad Astra: Through Complex Population Modeling to Predictive Theory. AB - Population models in ecology are often not good at predictions, even if they are complex and seem to be realistic enough. The reason for this might be that Occam's razor, which is key for minimal models exploring ideas and concepts, has been too uncritically adopted for more realistic models of systems. This can tie models too closely to certain situations, thereby preventing them from predicting the response to new conditions. We therefore advocate a new kind of parsimony to improve the application of Occam's razor. This new parsimony balances two contrasting strategies for avoiding errors in modeling: avoiding inclusion of nonessential factors (false inclusions) and avoiding exclusion of sometimes important factors (false exclusions). It involves a synthesis of traditional modeling and analysis, used to describe the essentials of mechanistic relationships, with elements that are included in a model because they have been reported to be or can arguably be assumed to be important under certain conditions. The resulting models should be able to reflect how the internal organization of populations change and thereby generate representations of the novel behavior necessary for complex predictions, including regime shifts. PMID- 26655780 TI - Transient Microgeographic Clines during B Chromosome Invasion. AB - The near-neutral model of B chromosome evolution predicts that the invasion of a new population should last some tens of generations, but the details on how it proceeds in real populations are mostly unknown. Trying to fill this gap, we analyze here a natural population of the grasshopper Eyprepocnemis plorans at three time points during the last 35 years. Our results show that B chromosome frequency increased significantly during this period and that a cline observed in 1992 had disappeared in 2012 once B chromosome frequency reached an upper limit at all sites sampled. This indicates that, during B chromosome invasion, transient clines for B chromosome frequency are formed at the invasion front on a microgeographic scale. Computer simulation experiments showed that the pattern of change observed for genotypic frequencies is consistent with the existence of B chromosome drive through females and selection against individuals with a high number of B chromosomes. PMID- 26655781 TI - Phenotypic Selection Exerted by a Seed Predator Is Replicated in Space and Time and among Prey Species. AB - Although consistent phenotypic selection arising from biotic interactions is thought to be the primary cause of adaptive diversification, studies documenting such selection are relatively few. Here we analyze 12 episodes of phenotypic selection exerted by a predispersal seed predator, the red crossbill (Loxia curvirostra complex), on five species of pines (Pinus). We find that even though the intensity of selection for some traits increased with the strength of the interaction (i.e., proportion of seeds eaten), the relative strength of selection exerted by crossbills on cone and seed traits is replicated across space and time and among species. Such selection (1) can account for repeated patterns of conifer cone evolution and escalation in seed defenses with time and (2) suggests that variation in selection is less the result of variation intrinsic to pairwise biotic interactions than, for example, variation in relative densities of the interacting species, community context, and abiotic factors. PMID- 26655782 TI - Mechanisms by Which Phenotypic Plasticity Affects Adaptive Divergence and Ecological Speciation. AB - Phenotypic plasticity is the ability of one genotype to produce different phenotypes depending on environmental conditions. Several conceptual models emphasize the role of plasticity in promoting reproductive isolation and, ultimately, speciation in populations that forage on two or more resources. These models predict that plasticity plays a critical role in the early stages of speciation, prior to genetic divergence, by facilitating fast phenotypic divergence. The ability to plastically express alternative phenotypes may, however, interfere with the early phase of the formation of reproductive barriers, especially in the absence of geographic barriers. Here, we quantitatively investigate mechanisms under which plasticity can influence progress toward adaptive genetic diversification and ecological speciation. We use a stochastic, individual-based model of a predator-prey system incorporating sexual reproduction and mate choice in the predator. Our results show that evolving plasticity promotes the evolution of reproductive isolation under diversifying environments when individuals are able to correctly select a more profitable habitat with respect to their phenotypes (i.e., adaptive habitat choice) and to assortatively mate with relatively similar phenotypes. On the other hand, plasticity facilitates the evolution of plastic generalists when individuals have a limited capacity for adaptive habitat choice. We conclude that plasticity can accelerate the evolution of a reproductive barrier toward adaptive diversification and ecological speciation through enhanced phenotypic differentiation between diverging phenotypes. PMID- 26655783 TI - Effects of experimentally necessary changes in husbandry on olfactory memory: Chronic food restriction and social isolation. AB - Changes to typical procedures in animal husbandry are often necessary to accommodate the needs of behavioral experiments. Two common changes in husbandry for rodents are light chronic food restriction (to motivate animals in reward association tasks) and social isolation (to accommodate individual feeding schedules or need to reduce interactions because of implants for example). Each of these intervention individually has been shown to modulate behavioral state and with it performance in behavioral tasks. We here systematically test how social isolation and light chronic food restriction modulate olfactory memory in rats. Our results show a strong modulation of olfactory memory after both types of husbandry interventions. These results suggest that common changes in animal husbandry promote distinct and relevant changes in animal behavior. PMID- 26655784 TI - Posture effects on spontaneous limb movements, alternated stepping, and the leg extension response in neonatal rats. AB - The development of postural control is considered an important factor for the expression of coordinated behavior such as locomotion. In the natural setting of the nest, newborn rat pups adapt their posture to perform behaviors of ecological relevance such as those related to suckling. The current study explores the role of posture in the expression of three behaviors in the newborn rat: spontaneous limb activity, locomotor-like stepping behavior, and the leg extension response (LER). One-day-old rat pups were tested in one of two postures--prone or supine- on each of these behavioral measures. Results showed that pups expressed more spontaneous activity while supine, more stepping while prone, and no differences in LER expression between the two postures. Together these findings show that posture affects the expression of newborn behavior patterns in different ways, and suggest that posture may act as a facilitator or a limiting factor in the expression of different behaviors during early development. PMID- 26655785 TI - Upper airway obstruction and hemoptysis due to a leech infestation in a child. AB - This paper presents the case of a 12-year-old child who presented with an 8-day history of cough, respiratory distress, and hemoptysis. He was admitted first to the pediatric intensive care unit to reestablish hemodynamic and respiratory stability. The chest X-ray showed a bilateral alveolar-interstitial syndrome. Four hours after admission, he had a coughing fit, moderately abundant hemoptysis, and a leech appeared in his mouth, which was removed by the mother. Symptoms completely disappeared afterwards. Endoscopy and ear-throat-laryngeal examination done thereafter were normal. The presence of a leech in the larynx has been rarely described in children, but is not a rare cause of hemoptysis. Extraction is imperative and should be performed as soon as the diagnosis is made to avoid a fatal progression. Prevention remains the best treatment. PMID- 26655786 TI - Potentiation of the startle reflex is in line with contingency reversal instructions rather than the conditioning history. AB - In the context of fear conditioning, different psychophysiological measures have been related to different learning processes. Specifically, skin conductance responses (SCRs) have been related to cognitive expectancy learning, while fear potentiated startle (FPS) has been proposed to reflect affective learning that operates according to simple associative learning principles. On the basis of this two level account of fear conditioning we predicted that FPS should be less affected by verbal instructions and more affected by direct experience than SCRs. We tested this hypothesis by informing participants that contingencies would be reversed after a differential conditioning phase. Our results indicate that contingency reversal instructions led to an immediate and complete reversal of FPS regardless of the previous conditioning history. This change was accompanied by similar changes on US expectancy ratings and SCRs. These results conform with an expectancy model of fear conditioning but argue against a two level account of fear conditioning. PMID- 26655787 TI - Efficacy of lifestyle interventions in patients with type 2 diabetes: A systematic review and meta-analysis. AB - BACKGROUND: The current meta-analysis evaluated the outcomes of various lifestyle interventions, including diet modifications (DIET), physical activity (PA), and patient education (EDU) in reducing the risk of cardiovascular disease in patients with type 2 diabetes. METHODS: Randomized clinical trials comparing lifestyle intervention with "usual care" (control) in type 2 diabetes patients were hand-searched from medical databases by two independent reviewers using the terms "diabetes, cardiovascular risk, lifestyle, health education, dietary, exercise/physical activities, and behavior intervention". RESULTS: Of the 235 studies identified, 17 were chosen for the meta-analysis. The average age of patients ranged from 50-67.3 years. Results reveal no significant difference between the groups, with respect to BMI, while PA and DIET yielded a greater reduction in HbA1c. Significant reduction in both systolic and diastolic pressures in the DIET group, and diastolic pressure in the PA group, was observed. HDL-c in the DIET group was significantly higher than the control group, while no change in LDL-c levels, was seen in all three intervention subtypes. There was no difference between the EDU vs. the control group in terms of HbA1c, blood pressure or HDL-c and LDL-c. CONCLUSION: DIET intervention showed an improvement in HbA1c, systolic/diastolic blood pressure and HDL-c, with an exception of LDL-c and BMI, suggesting that nutritional intervention had a significant impact on the quality of life by reducing the cardiovascular risk in type 2 diabetes patients. PMID- 26655788 TI - Returning traveler with persistent diarrhea. PMID- 26655789 TI - Short photoperiod condition increases susceptibility to stress in adolescent male rats. AB - The seasonality of depressive symptoms is prevalent in children and adolescents. However, the mechanisms that underlie such susceptibility to seasonal influences on mood disorders are unclear. We examined the effects of a short photoperiod condition on the susceptibility to subchronic unpredictable mild stress (SCUS) and rhythmic alterations of plasma corticosterone (CORT), melatonin, and neuropeptide Y (NPY) in adolescent male rats. Compared with the 12h/12h light/dark photoperiod control (CON) rats, the 8h/16h photoperiod SCUS rats exhibited significant anhedonia, a core symptom of human depression, together with a blunted diurnal rhythm and elevation of 24h CORT, melatonin, and NPY levels. The 8h/16h photoperiod condition also blunted the rhythmicity of CORT, caused a phase inversion of melatonin, and caused a phase delay of NPY compared with 12h/12h CON rats. Such abnormalities of plasma CORT, NPY, and melatonin might cause adolescent individuals to present higher stress reactivity and greater vulnerability to stress over their lifetimes. The present study provides evidence of the susceptibility to the seasonality of stress-related disorders in adolescence. PMID- 26655790 TI - Tunable temperature responsive liquid chromatography through thiolactone-based immobilization of poly(N-isopropylacrylamide). AB - A straightforward and efficient functionalization of aminopropylsilica with polymeric structures is described for the development of temperature responsive stationary phases applicable in purely aqueous liquid chromatography. The immobilization of the thermoresponsive polymers involves a thiolactone-based ring opening using the primary amines in aminopropylsilica, with a simultaneous one pot, thiol-ene functionalization with an acrylate of choice. This mild, straightforward and modular grafting process results in high polymer coupling yields. By variation of the acrylate for the thiol-ene reaction, different stationary phases can be readily obtained. Two stationary phases as a result of the modular modification of aminopropylsilica were evaluated with test mixtures of hydrophobic analytes and a mixture of di- and tripeptides. Analyses using the 5MUm material packed in 10cm*4.6mm columns revealed high hydrophobic retention, which proved adaptable as a function of the temperature in aqueous mobile phases. High versus low retention were obtained at temperatures above and below the lower critical solution temperature of the polymer, respectively. Moreover, the columns depict potential for diastereoisomeric peptide separation. Finally, the lower retention, observed when using PEGylated silica, illustrates the potential of the approach for modular stationary phase tuning. PMID- 26655791 TI - Liquid chromatography coupled to different atmospheric pressure ionization sources-quadrupole-time-of-flight mass spectrometry and post-column addition of metal salt solutions as a powerful tool for the metabolic profiling of Fusarium oxysporum. AB - Fusarium oxysporum L11 is a non-pathogenic soil-borne fungal strain that yielded an extract that showed antifungal activity against phytopathogens. In this study, reversed-phase high-performance liquid chromatography (RP-HPLC) coupled to different atmospheric pressure ionization sources-quadrupole-time-of-flight mass spectrometry (API-QTOF-MS) was applied for the comprehensive profiling of the metabolites from the extract. The employed sources were electrospray (ESI), atmospheric pressure chemical ionization (APCI) and atmospheric pressure photoionization (APPI). Post-column addition of metal solutions of Ca, Cu and Zn(II) was also tested using ESI. A total of 137 compounds were identified or tentatively identified by matching their accurate mass signals, suggested molecular formulae and MS/MS analysis with previously reported data. Some compounds were isolated and identified by NMR. The extract was rich in cyclic peptides like cyclosporins, diketopiperazines and sansalvamides, most of which were new, and are reported here for the first time. The use of post-column addition of metals resulted in a useful strategy for the discrimination of compound classes since specific adducts were observed for the different compound families. This technique also allowed the screening for compounds with metal binding properties. Thus, the applied methodology is a useful choice for the metabolic profiling of extracts and also for the selection of metabolites with potential biological activities related to interactions with metal ions. PMID- 26655793 TI - Reversing of multidrug resistance breast cancer by co-delivery of P-gp siRNA and doxorubicin via folic acid-modified core-shell nanomicelles. AB - Multidrug resistance (MDR) remains one of major limitation for the successful treatment of many cancers including breast cancer. Co-delivery of chemotherapeutic drugs and small interfering RNA (siRNA) has been developed because of its ability to generate synergistic anticancer effects via different mechanisms of action, to reverse MDR and increase the efficacy of chemotherapeutic drugs in cancer therapy. Herein, we employed a kind of efficient multifunctional tumor targeted nanomicelles (PECL3) for the co-delivery of hydrophobic anti-cancer drugs and siRNA. This kind of nanomicelles were constructed by folic acid (FA)-decorated PEG-b-(PCL-g-PEI)-b-PCL triblock copolymers, which were synthesized through "click chemistry" and "ring opening" polymerization. Driven by the "core-shell" structure and the electrostatic interaction, this triblock copolymer could efficiently encapsulate P-glycoprotein (P-gp) siRNA and doxorubicin (DOX). The obtained nanomicelles can prevent renal clearance, RNase degradation and aggregation in circulation. Compared to the non specific delivery, these FA functionalized nanomicelles could efficiently deliver P-gp siRNA to reducing both P-gp expression levels and IC50 value of the DOX in DOX-resistant breast cancer cells (MCF-7/ADR). Additionally, in vivo results showed that DOX loaded PECL3 (D-PECL3) micelles could reduce toxicity of DOX on nontarget tissues and significantly inhibited MCF-7/ADR tumor growth through encapsulating DOX in the micelles and deliver them to target tumor region. Taken together, these results proof that PECL3 micelles could co-deliver siRNA and drug to inhibit MDR tumor growth. These results suggested that the co-delivery of DOX and siRNA in tumor-targeting nanomicelles could excite synergistic effect of gene therapy and chemotherapy, thus can efficiently reverse MDR cancer and kill the cancer cells. PMID- 26655792 TI - Perception of impairments by patients with heart failure. AB - BACKGROUND: One of the major aims in the treatment of patients with heart failure (HF) is symptom relief and an improvement in the health-related quality of life (HR-QoL). The perception of impairments due to HF may differ between patients. A knowledge of the prevalence and perceived harshness of impairments due to HF is essential in providing personalized care on a patient level, in optimizing care on a population level and in finding the most appropriate patient-reported outcome for clinical trials. AIM: The aim of this study was to explore the prevalence and perceived harshness of impairments due to HF and the relation between perceived harshness and HR-QoL in patients with HF. METHODS AND RESULTS: The prevalence of impairments due to HF was assessed using items of the Minnesota Living with Heart Failure Questionnaire and the degree of perceived harshness was assessed using a structured self-assessment. A total of 100 outpatients (mean+/ SD age 70+/-9 years, 71% men) from an HF outpatient clinic were included. The prevalence of impairments was between 18 and 77%. The most prevalent impairments included tiredness and impairments in physical activity. Impairments that were frequently perceived as severely harsh included tiredness (67%), dyspnoea (57%) and impairments in physical activity (55%). Corrected item-total correlation (range 0.10-0.59) showed that tiredness (r=0.54) and impairments related to resting (r=0.59) and to participation in physical (r=0.52) and social (r=0.55) activities contributed highly to the sum-score of the Minnesota Living with Heart Failure Questionnaire. CONCLUSION: Highly prevalent impairments are not by definition perceived as severely harsh by patients with HF and do not contribute to the overall HR-QoL except for the impairments tiredness and working around the house/yard. These insights are important in providing personalized and optimized care for patients with HF. PMID- 26655794 TI - Modification of soy protein hydrolysates by Maillard reaction: Effects of carbohydrate chain length on structural and interfacial properties. AB - This study investigated the effects of carbohydrate chain length on the structural and interfacial properties of the Maillard reaction conjugates of soy protein hydrolysates (Mw>30 kDa). The covalent attachment of sugars to soy peptides was confirmed by amino acid analysis and examination of the Fourier transform infrared spectra. The results suggested that the emulsion stability of the conjugates increased as the length of the carbohydrate chains increased. The surface activity measurement revealed that the soy peptide-dextran conjugates were closely packed and that each molecule occupied a small area of the interface. It was further confirmed that the soy peptide-dextran conjugates formed a thick adsorbed layer at the oil-water interface, as observed in the confocal laser scanning micrographs. The interfacial layer of soy peptides was rheologically complex with broad linear viscoelastic region and strong elastic modulus, and the soy peptide-dextran conjugates might form multilayer adsorption at the interface. This study suggested that the improved surface properties of the soy peptide-dextran conjugates were a result of the strong membrane formed by the closely packed molecular and multilayer adsorption at the interface, which provided steric hindrance to flocculation. PMID- 26655795 TI - New 3-dimensional single photon emission computed tomographic images in the assessment of the viability of microvascularised bone grafts after mandibular reconstruction. PMID- 26655796 TI - Lymph node density predicts lung metastases in oral squamous cell carcinoma. AB - The association between lymph node density and survival free of lung metastases in oral squamous cell carcinoma (SCC), has not been investigated so far to our knowledge. Lymph node density ? 0.07 has been reported by a multicentre international study to be a significant predictor of shorter survival in patients with oral SCC who have invaded nodes. We investigated whether a lymph node density of ? 0.07 correlates with shorter overall survival, survival free of distant metastases, and survival free of lung metastases, in patients with oral SCC and invaded lymph nodes. Thirty-five patients with histologically-confirmed invaded lymph nodes werestudied. Their density was calculated as the ratio of the number of invaded lymph nodes:total number of nodes. A density of ? 0.07 correlated significantly with shorter overall survival (p<0.02), survival free of distant metastases (p<0.01), and survival free of lung metastases (p<0.01) on log rank testing. On testing by Cox's proportional hazards model of multivariate survival analysis with adjustment for the pathological stage (pstage IV/pstage III), and invaded surgical margins or extracapsular spread, or both, we found that lymph node density ? 0.07 was associated with significantly shorter survival (p<0.02). We conclude that lymph node density predicts lung metastases in patients with oral SCC. PMID- 26655798 TI - Optimal treatment sequence in COPD: Can a consensus be found? AB - There is currently no consensus on the treatment sequence in chronic obstructive pulmonary disease (COPD), although it is recognized that early diagnosis is of paramount importance to start treatment in the early stages of the disease. Although it is fairly consensual that initial treatment should be with an inhaled short-acting beta agonist, a short-acting muscarinic antagonist, a long-acting beta-agonist or a long-acting muscarinic antagonist. As the disease progresses, several therapeutic options are available, and which to choose at each disease stage remains controversial. When and in which patients to use dual bronchodilation? When to use inhaled corticosteroids? And triple therapy? Are the existing non-inhaled therapies, such as mucolytic agents, antibiotics, phosphodiesterase-4 inhibitors, methylxanthines and immunostimulating agents, useful? If so, which patients would benefit? Should co-morbidities be taken into account when choosing COPD therapy for a patient? This paper reviews current guidelines and available evidence and proposes a therapeutic scheme for COPD patients. We also propose a treatment algorithm in the hope that it will help physicians to decide the best approach for their patients. The authors conclude that, at present, a full consensus on optimal treatment sequence in COPD cannot be found, mainly due to disease heterogeneity and lack of biomarkers to guide treatment. For the time being, and although some therapeutic approaches are consensual, treatment of COPD should be patient-oriented. PMID- 26655797 TI - A genome-scale screen reveals context-dependent ovarian cancer sensitivity to miRNA overexpression. AB - Large-scale molecular annotation of epithelial ovarian cancer (EOC) indicates remarkable heterogeneity in the etiology of that disease. This diversity presents a significant obstacle against intervention target discovery. However, inactivation of miRNA biogenesis is commonly associated with advanced disease. Thus, restoration of miRNA activity may represent a common vulnerability among diverse EOC oncogenotypes. To test this, we employed genome-scale, gain-of function, miRNA mimic toxicity screens in a large, diverse spectrum of EOC cell lines. We found that all cell lines responded to at least some miRNA mimics, but that the nature of the miRNA mimics provoking a response was highly selective within the panel. These selective toxicity profiles were leveraged to define modes of action and molecular response indicators for miRNA mimics with tumor suppressive characteristics in vivo. A mechanistic principle emerging from this analysis was sensitivity of EOC to miRNA-mediated release of cell fate specification programs, loss of which may be a prerequisite for development of this disease. PMID- 26655799 TI - Modeling synaptogenesis in schizophrenia and autism using human iPSC derived neurons. AB - Schizophrenia (SCZ) and autism spectrum disorder (ASD) are genetically and phenotypically complex disorders of neural development. Human genetic studies, as well as studies examining structural changes at the cellular level, have converged on glutamatergic synapse formation, function, and maintenance as common pathophysiologic substrates involved in both disorders. Synapses as basic functional units of the brain are continuously modified by experience throughout life, therefore they are particularly attractive candidates for targeted therapy. Until recently we lacked a system to evaluate dynamic changes that lead to synaptic abnormalities. With the development of techniques to generate induced pluripotent stem cells (iPSCs) from patients, we are now able to study neuronal and synaptic development in cells from individual patients in the context of genetic changes conferring disease susceptibility. In this review, we discuss recent studies focusing on neural cells differentiated from SCZ and ASD patient iPSCs. These studies support a central role for glutamatergic synapse formation and function in both disorders and demonstrate that iPSC derived neurons offer a potential system for further evaluation of processes leading to synaptic dysregulation and for the design and screening of future therapies. PMID- 26655800 TI - Intrinsic photo-conductance triggered by the plasmonic effect in graphene for terahertz detection. AB - Terahertz (THz) technology is becoming more eminent for applications in diverse areas including biomedical imaging, communication, security and astronomy. However, THz detection still has some challenges due to the lack of sources and detectors despite decades of considerable effort. The appearance of graphene and its gapless spectrum enable their applications in sensitive detection of light over a very wide energy spectrum from ultraviolet, infrared to terahertz. Several mechanisms in graphene for THz detection have been proposed, such as photo thermoelectric, Dyakonov-Shur (DS) and bolometric effects. Here, we propose a photoconductive mechanism assisted by plasma wave in a graphene field-effect transistor (FET). Sensitive response to THz radiation can be realized far below the interband transition at room temperature. The response is due to the contributions of both plasma drag and convection effects. The two effects can both trigger multiple potential wells along the channel, which are different from other quantum-transition mechanisms. The photoconductive effects can be explored in both periodic and non-periodic systems and can be substantially enhanced under the electric field. They could reduce the burden of structural complexity compared to other mechanisms like unilateral thermoelectric and DS detection. This paves the way for more judicious photo-detector design for versatile THz applications. PMID- 26655801 TI - Doppler ultrasound study and venous mapping in chronic venous insufficiency. AB - Chronic venous insufficiency of the lower limbs is very prevalent. In recent decades, Doppler ultrasound has become the method of choice to study this condition, and it is considered essential when surgery is indicated. This article aims to establish a method for the examination, including venous mapping and preoperative marking. To this end, we review the venous anatomy of the lower limbs and the pathophysiology of chronic venous insufficiency and explain the basic hemodynamic concepts and the terminology required to elaborate a radiological report that will enable appropriate treatment planning and communication with other specialists. We briefly explain the CHIVA (the acronym for the French term "cure conservatrice et hemodynamique de l'insuffisance veineuse en ambulatoire"=conservative hemodynamic treatment for chronic venous insufficiency) strategy, a minimally invasive surgical strategy that aims to restore correct venous hemodynamics without resecting the saphenous vein. PMID- 26655802 TI - [Are urgent imaging tests indicated in the management of acute pancreatitis?]. AB - Acute pancreatitis is a common emergency within abdominal disease. It is accepted that two of three conditions must be fulfilled for its diagnosis: characteristic clinical presentation, characteristic laboratory findings, and/or characteristic diagnostic imaging findings. The first two conditions are the most often used, probably for reasons of efficiency and frequency. Nevertheless, the need for imaging studies is sometimes a source of conflict. For this reason, we decided to review the current evidence regarding the indication of urgent imaging tests in the management of acute pancreatitis. PMID- 26655803 TI - A Randomized Blinded Study of the Left Ventricular Myocardial Performance Index Comparing Epinephrine to Levosimendan following Cardiopulmonary Bypass. AB - BACKGROUND: The objective was to evaluate the effect of epinephrine and levosimendan on the left ventricle myocardial performance index in patients undergoing on-pump coronary artery by-pass grafting (CABG). METHODS: In a double blind, randomized clinical trial, 81 patients (age: 45-65 years) of both genders were randomly divided to receive either epinephrine at a dosage of 0.06 mcg.kg(1).min(-1) (epinephrine group, 39 patients) or levosimendan at 0.2 mcg.kg(1).min(-1) (levosimendan group, 42 patients) during the rewarming of cardiopulmonary by-pass (CPB). Hemodynamic data were collected 30 minutes after tracheal intubation, before chest open (pre-CPB) and 10 minutes after termination of protamine (post-CPB). As the primary outcome, we evaluated the left ventricle myocardial performance index by the Doppler echocardiography. The myocardial performance index is the sum of the isovolumetric contraction time and the isovolumetric relaxation time, divided by the ejection time. Secondary outcomes were systolic and diastolic evaluations of the left ventricle and postoperative troponin I and MB-CK levels. RESULTS: Of the 81 patients allocated to the research, we excluded 2 patients in the epinephrine group and 6 patients in the levosimendan group because they didn't wean from CPB in the first attempt. There was no statistical difference between the groups in terms of patient characteristics, risk factors, or CPB time. The epinephrine group had a lower left ventricle myocardial performance index (p = 0.0013), higher cardiac index (p = 0.03), lower systemic vascular resistance index (p = 0.01), and higher heart rate (p = 0.04) than the levosimendan group at the post-CPB period. There were no differences between the groups in diastolic dysfunction. The epinephrine group showed higher incidence of weaning from CPB in the first attempt (95% vs 85%, p = 0.0001) when compared to the levosimendan group and the norepinephrine requirement was higher in the levosimenandan group than epinephrine group (16% vs. 47%; p = 0.005) in post-CPB period. Twenty-four hours after surgery, the plasma levels of troponin I (epinephrine group: 4.5 +/- 5.7 vs. levosimendan group: 2.5 +/- 3.2 g/dl; p = 0.09) and MB-CK (epinephrine group: 50.7 +/- 31 vs. levosimendan group: 37 +/- 17.6 g/dl; p = 0.08) were not significantly different between the two groups. CONCLUSION: When compared to levosimendan, patients treated with epinephrine had a lower left ventricle myocardial performance index in the immediate post-CPB period, encouraging an efficient weaning from CPB in patients undergoing on-pump CABG. TRIAL REGISTRATION: ClinicalTrials.gov NCT01616069. PMID- 26655804 TI - Accuracy of Pedicle Screw Placement with Robotic Guidance System: A Cadaveric Study. AB - STUDY DESIGN: A cadaveric study. OBJECTIVE: To investigate the accuracy of pedicle screw placement using a robotic guidance system (RGS). SUMMARY OF BACKGROUND DATA: RGS is a unique surgery assistance-apparatus. Although several clinical studies have demonstrated that RGS provides accurate pedicle screw placement, very few studies have validated its accuracy. METHODS: A total of 216 trajectories performed with the assistance of the RGS in eight cadavers were evaluated. The RGS was used, with different mounting platforms, to drill pilot holes in the thoracic and lumbosacral spine, using 3-mm diameter fiducial wires as trajectory markers. Deviation between the preoperative plan and executed trajectories was measured at the entry points to the vertebrae and at a depth of 30 mm along the wire. Both the deviation from the preoperative plan and the wire position were evaluated in the axial and sagittal planes using computed tomography (CT). RESULTS: The average deviation from the planned wire placement was 0.64 +/- 0.59 mm at the entry point and 0.63 +/- 0.57 mm at a depth of 30 mm in the axial plane, and 0.77 +/- 0.62 mm and 0.80 +/- 0.66 mm, respectively, in the sagittal plane. The magnitude of deviation was not affected by the vertebral level or the platform used. The use of an open approach achieved greater screw placement accuracy at a depth of 30 mm in the sagittal plane, compared with the percutaneous approach. The fiducials were placed completely within the pedicle in 93.9% of trajectories in the axial plane (n = 164 pedicles with a width >=5 mm) and 98.6% in the sagittal plane (n = 216). CONCLUSION: In this cadaveric study, RGS supported execution of accurate trajectories that were equal or slightly superior to reports of CT-based navigation systems. LEVEL OF EVIDENCE: N/A. PMID- 26655805 TI - Physical Activity Might Be of Greater Importance for Good Spinal Control Than If You Have Had Pain or Not: A Longitudinal Study. AB - STUDY DESIGN: Longitudinal design. A cohort followed in 3 waves of data collection. OBJECTIVE: The aim of the study was to describe the relationships between the performance of 2 tests of spinal control at the age of 52 years and low back pain, physical activity level, and fitness earlier in life, as well as to describe the cross-sectional relationships between these measures. SUMMARY OF BACKGROUND DATA: Altered spinal control has been linked to pain; however, other stimuli may also lead to inability to control the movements of the spine. METHODS: Participants answered questions about physical activity and low back pain, and performed physical fitness tests at the age of 16, 34, and 52 years. The fitness test battery included tests of endurance in the back and abdominal muscles, a submaximal bicycle ergometer test to estimate maximal oxygen uptake, and measurements of hip flexion, thoracic spine flexibility, and anthropometrics. Two tests were aggregated to a physical fitness index. At the age of 52, also 2 tests of spinal control, the standing Waiter's bow (WB) and the supine double leg lower (LL) were performed. RESULTS: Logistic regression analyses showed that higher back muscle endurance at the age of 34 years could positively predict WB performance at 52 years and higher physical fitness at the age of 34 could positively predict LL performance at 52 years. Regarding cross-sectional relationships, an inability to perform the WB correctly was associated with lower physical fitness, flexibility and physical activity, and larger waist circumference. An inability to correctly perform the LL was associated with lower physical fitness. One-year prevalence of pain was not significantly associated with WB or LL test performance. CONCLUSION: An active life resulting in higher physical fitness is related to better spinal control in middle-aged men and women. This further strengthens the importance of physical activity throughout the life span. LEVEL OF EVIDENCE: 3. PMID- 26655806 TI - Evaluation of Comorbidity Indices for a Study of Patient Outcomes Following Cervical Decompression Surgery: A Retrospective Cohort Study. AB - STUDY DESIGN: Retrospective cohort study. OBJECTIVE: The objective of this study was to investigate the predictive validity of 2 comorbidity indices in a study of patient outcomes following cervical decompression surgery. The comorbidity indices evaluated were the Charlson comorbidity index (CCI) and the self administered comorbidity questionnaire (SCQ). SUMMARY OF BACKGROUND DATA: Comorbidities have been shown to have independent prognostic factors for HRQOL outcome in patients with spinal disorders. However, no appropriate evaluation method of comorbidity has been established in spinal research. METHODS: We retrospectively reviewed 86 cervical myelopathy cases treated by decompression surgery between 2004 and 2010. Health-related quality of life (HRQOL) outcomes were measured using the short form 36 physical component summary (PCS) and the neck disability index (NDI), administered both pre- and postoperatively. Patient comorbidity was evaluated by the CCI and SCQ. The CCI was calculated by the medical record review, whereas the SCQ was obtained from patients' self-reports. The correlations between HRQOL outcomes and comorbidity indices were investigated. Thereafter, multiple liner regression analyses were performed to assess the performance of these comorbidity indices for predicting postoperative HRQOL. RESULTS: The SCQ significantly correlated with both pre- and postoperative PCS scores and both pre- and postoperative NDI scores. The CCI did not correlate significantly with any outcome measure. On regression analysis, the CCI was a poor predictor of postoperative HRQOL, demonstrating only 0.2% of variance in the PCS score (P = 0.25) and only 0.4% of variance in the NDI score (P = 0.59). In comparison, the SCQ was a significant predictor of postoperative HRQOL, demonstrating 4.0% of variance in PCS score (P = 0.011) and 10.2% of variance in NDI score (P = 0.0001). CONCLUSION: The SCQ, but not the CCI, was a robust predictor of postoperative HRQOL. Our study suggests that the SCQ score is a more appropriate adjustment for HRQOL outcomes following cervical decompression surgery. LEVEL OF EVIDENCE: 3. PMID- 26655807 TI - Vertebral Body Stapling for Moderate Juvenile and Early Adolescent Idiopathic Scoliosis: Cautions and Patient Selection Criteria. AB - STUDY DESIGN: Single-surgeon retrospective case series. OBJECTIVE: To validate and further describe clinical and radiographic outcomes of patients undergoing vertebral body stapling (VBS), with the goal of learning if VBS is a safe and effective alternative to bracing for treating moderate idiopathic scoliosis (IS) in the growing pediatric patient. SUMMARY OF BACKGROUND DATA: VBS is a growth modulation technique to control moderate idiopathic scoliosis (IS) while avoiding fusion. Existing studies state successful curve control rates equivalent to bracing, but the majority of reports have come from a single institution. METHODS: All IS patients who underwent VBS by 1 surgeon were included. Indications were brace intolerance and a structural coronal curve of 25 degrees to 40 degrees . Proportional nitinol staples were used in all cases. Pre- and postoperative radiographs, pulmonary function testing, and physical exam measurements were serially recorded. RESULTS: VBS was performed on 35 patients (28 females, 7 males) with mean age 10.5 years (range 7.0-14.6 years). Total of 31 patients (33 stapled curves) completed follow-up. Preoperative Risser grade was 0 in 31 patients, 1 in 1 patient, and 2 in 3 patients. Stapled curves were controlled with <10 degrees of progression in 61% of cases. Curves <35 degrees had a control rate of 75%, and patients <10 years had a 62% curve control rate. Eleven patients (31%) required subsequent fusions; two curves (6%) over corrected. Preoperative supine flexibility > 30% was predictive of ultimate curve control. No neurologic complications were encountered; 5 patients (14%) developed small pneumothoraces. CONCLUSION: This series contains the most patients and longest followup reported for VBS. Successful curve control was achieved less frequently than in previous reports, particularly in patients <10 years. LEVEL OF EVIDENCE: 4. PMID- 26655808 TI - Sequestrectomy Versus Conventional Microdiscectomy for the Treatment of a Lumbar Disc Herniation: A Systematic Review. AB - STUDY DESIGN: A systematic review. OBJECTIVE: The aim of this study was to compare the effects of sequestrectomy versus conventional microdiscectomy for lumbar disc herniation (LDH). SUMMARY OF BACKGROUND DATA: Open surgery for LDH can be performed by sequestrectomy (removal of disc fragments) or conventional discectomy (removal of disc fragments and disc). Sequestrectomy might be associated with a higher risk of recurrence but less low back pain (LBP) after surgery. METHODS: We searched MEDLINE and EMBASE from 1980 to November 2014. We selected randomized controlled trials (RCTs) and nonrandomized prospective studies of conventional discectomy versus sequestrectomy for adult patients with LDH that evaluated the following primary outcomes: radicular pain or LBP as measured by a visual analog scale, or neurological deficits of the lower extremity. We also evaluated the following secondary outcomes: complications of surgery, reherniation rate, duration of hospital stay, postoperative analgesic use, and health-related quality-of-life measures. Two authors independently reviewed citations and articles for inclusion. We assessed the risk of bias, synthesized data, and the level evidence using standard methodological procedures as recommended by the Cochrane Back Review Group. RESULTS: We identified 5 studies (746 participants) of sequestrectomy versus microdiscectomy. One study was RCT and the other 4 were nonrandomized prospective comparisons; all studies were assessed as being at a high risk of bias. There were no significant differences for leg pain, LBP, functional outcomes, complications, and hospital stay or recurrence rate for 2 years (level of evidence: Low). Sequestrectomy was associated with less analgesic consumption versus discectomy (level of evidence: Very low). CONCLUSION: Sequestrectomy and standard microdiscectomy were associated with similar effects on pain after surgery, recurrence rate, functional outcome, and complications; more evidence is needed to determine whether sequestrectomy is associated with less postoperative analgesic consumption. LEVEL OF EVIDENCE: 2. PMID- 26655809 TI - Evidence for Novel Pharmacological Sensitivities of Transient Receptor Potential (TRP) Channels in Schistosoma mansoni. AB - Schistosomiasis, caused by parasitic flatworms of the genus Schistosoma, is a neglected tropical disease affecting hundreds of millions globally. Praziquantel (PZQ), the only drug currently available for treatment and control, is largely ineffective against juvenile worms, and reports of PZQ resistance lend added urgency to the need for development of new therapeutics. Ion channels, which underlie electrical excitability in cells, are validated targets for many current anthelmintics. Transient receptor potential (TRP) channels are a large family of non-selective cation channels. TRP channels play key roles in sensory transduction and other critical functions, yet the properties of these channels have remained essentially unexplored in parasitic helminths. TRP channels fall into several (7-8) subfamilies, including TRPA and TRPV. Though schistosomes contain genes predicted to encode representatives of most of the TRP channel subfamilies, they do not appear to have genes for any TRPV channels. Nonetheless, we find that the TRPV1-selective activators capsaicin and resiniferatoxin (RTX) induce dramatic hyperactivity in adult worms; capsaicin also increases motility in schistosomula. SB 366719, a highly-selective TRPV1 antagonist, blocks the capsaicin-induced hyperactivity in adults. Mammalian TRPA1 is not activated by capsaicin, yet knockdown of the single predicted TRPA1-like gene (SmTRPA) in S. mansoni effectively abolishes capsaicin-induced responses in adult worms, suggesting that SmTRPA is required for capsaicin sensitivity in these parasites. Based on these results, we hypothesize that some schistosome TRP channels have novel pharmacological sensitivities that can be targeted to disrupt normal parasite neuromuscular function. These results also have implications for understanding the phylogeny of metazoan TRP channels and may help identify novel targets for new or repurposed therapeutics. PMID- 26655810 TI - NMR-based metabolite profiling of human milk: A pilot study of methods for investigating compositional changes during lactation. AB - Low-molecular-weight metabolites in human milk are gaining increasing interest in studies of infant nutrition. In the present study, the milk metabolome from a single mother was explored at different stages of lactation. Metabolites were extracted from sample aliquots using either methanol/water (MeOH/H2O) extraction or ultrafiltration. Nuclear magnetic resonance (NMR) spectroscopy was used for metabolite identification and quantification, and multi- and univariate statistical data analyses were used to detect changes over time of lactation. Compared to MeOH/H2O extraction, ultrafiltration more efficiently reduced the interference from lipid and protein resonances, thereby enabling the identification and quantification of 36 metabolites. The human milk metabolomes at the early (9-24 days after delivery) and late (31-87 days after delivery) stages of lactation were distinctly different according to multi- and univariate statistics. The late lactation stage was characterized by significantly elevated concentrations of lactose, choline, alanine, glutamate, and glutamine, as well as by reduced levels of citrate, phosphocholine, glycerophosphocholine, and N acetylglucosamine. Our results indicate that there are significant compositional changes of the human milk metabolome also in different phases of the matured lactation stage. These findings complement temporal studies on the colostrum and transitional metabolome in providing a better understanding of the nutritional variations received by an infant. PMID- 26655811 TI - Nrf2 transcriptional derepression from Keap1 by dietary polyphenols. AB - The liver expresses batteries of cytoprotective genes that confer cellular resistance to oxidative stress and xenobiotic toxins, and protection against cancer and other stress-related diseases. These genes are mainly regulated by Nrf2, making this transcription factor a target for small molecule discovery to treat such diseases. In this report, we identified dietary polyphenolic antioxidants that not only activated these genes but also relieved Nrf2 repression by Keap1, a Cul3-dependent ubiquitin ligase adaptor protein that mediates its degradation. Analysis of postprandial liver RNA revealed a marked activation of both genes by all test polyphenols compared with controls. Nrf2 inhibition by RNA interference reduced polyphenol effects on its target gene expression. Our data suggest that polyphenols may induce cellular defense genes by derepressing Nrf2 inhibition by Keap1. We posit that this ability to derepress Nrf2 and reactivate its target genes may underlie the protection conferred by polyphenols against oxidative stress-related diseases. PMID- 26655812 TI - Understanding the molecular mechanisms of reprogramming. AB - Despite the profound and rapid advancements in reprogramming technologies since the generation of the first induced pluripotent stem cells (iPSCs) in 2006[1], the molecular basics of the process and its implications are still not fully understood. Recent work has suggested that a subset of TFs, so called "Pioneer TFs", play an important role during the stochastic phase of iPSC reprogramming [2 6]. Pioneer TFs activities differ from conventional transcription factors in their mechanism of action. They bind directly to condensed chromatin and elicit a series of chromatin remodeling events that lead to opening of the chromatin. Chromatin decondensation by pioneer factors progressively occurs during cell division and in turn exposes specific gene promoters in the DNA to which TFs can now directly bind to promoters that are readily accessible[2, 6]. Here, we will summarize recent advancements on our understanding of the molecular mechanisms underlying reprogramming to iPSC as well as the implications that pioneer Transcription Factor activities might play during different lineage conversion processes. PMID- 26655813 TI - Inhibition of cyclic AMP response element-directed transcription by decoy oligonucleotides enhances tumor-specific radiosensitivity. AB - The radiation stress induces cytotoxic responses of cell death as well as cytoprotective responses of cell survival. Understanding exact cellular mechanism and signal transduction pathways is important in improving cancer radiotherapy. Increasing evidence suggests that cyclic AMP response element binding protein (CREB)/activating transcription factor (ATF) family proteins act as a survival factor and a signaling molecule in response to stress. We postulated that CREB inhibition via CRE decoy oligonucleotide increases tumor cell sensitization to gamma-irradiation-induced cytotoxic stress. In the present study, we demonstrate that CREB phosphorylation and CREB DNA-protein complex formation increased in time- and radiation dose-dependent manners, while there was no significant change in total protein level of CREB. In addition, CREB was phosphorylated in response to gamma-irradiation through p38 MAPK pathway. Further investigation revealed that CREB blockade by decoy oligonucleotides functionally inhibited transactivation of CREB, and significantly increased radiosensitivity of multiple human cancer cell lines including TP53- and/or RB-mutated cells with minimal effects on normal cells. We also demonstrate that tumor cells ectopically expressing dominant negative mutant CREB (KCREB) and the cells treated with p38 MAPK inhibitors were more sensitive to gamma-irradiation than wild type parental cells or control-treated cells. Taken together, we conclude that CREB protects tumor cells from gamma-irradiation, and combination of CREB inhibition plus ionizing radiation will be a promising radiotherapeutic approach. PMID- 26655814 TI - Evidence for glucagon-like peptide-1 receptor signaling to activate ATP-sensitive potassium channels in pancreatic beta cells. AB - Glucagon-like peptide-1 (GLP-1) is a gut peptide that promotes insulin release from pancreatic beta cells. GLP-1 has been shown to confer glucose-insensitive beta cells with glucose sensitivity by modulation of the activity of the ATP sensitive potassium (KATP) channel. The channel closing effect of GLP-1, interacting with corresponding G-protein-coupled receptors, has been well established; however, to our knowledge, no study has shown whether GLP-1 directly induces activation of beta-cell KATP channels. Here, we aimed to evaluate whether the activation of beta-cell KATP channels by GLP-1 exists and affects intracellular Ca(2+) levels ([Ca(2+)]i). KATP channel activity was measured in isolated rat pancreatic beta cells by whole-cell perforated patch-clamp recordings with a diazoxide-containing pipette solution. Changes in [Ca(2+)]i and the subcellular localization of KATP channels were observed using the calcium sensitive dye fura-4/AM and anti-Kir6.2 antibodies in INS-1 beta cells, respectively. To eliminate the well-known inhibitory effects of GLP-1 on KATP channel activity, channels were fully inhibited by pretreatment with methyl pyruvate and epigallocatechin-3-gallate. In the pretreated beta cells, GLP-1 and exendin-4 promptly activated the channels, reducing [Ca(2+)]i. The phosphoinositide 3-kinase (PI3K) inhibitor LY294002 blocked the effects of GLP-1 on channel activity. Moreover, phosphatidylinositol-3,4,5-trisphosphate mimicked the effects of GLP-1. These results suggested that beta-cell GLP-1 receptor signaling involved activation of KATP channels via a PI3K-dependent pathway. This alternative mechanism of GLP-1 function may act as a negative feedback pathway, modulating the glucose-dependent GLP-1 inhibition on KATP channel activity. PMID- 26655815 TI - Expression of angiopoietin-1 in hypoxic pericytes: Regulation by hypoxia inducible factor-2alpha and participation in endothelial cell migration and tube formation. AB - We previously reported that hypoxia increases angiopoietin-1 (Ang1), but not Ang2, mRNA expression in bovine retinal pericytes (BRP). However, the mechanism underlying Ang1 expression is unknown. Here, we report that Ang1 protein expression increased in hypoxic BRP in a dose- and time-dependent manner. This increase was accompanied by an increase in hypoxia-inducible factor-2alpha (HIF2alpha) expression. Transfection with an antisense oligonucleotide for HIF2alpha partially inhibited the hypoxia-induced increase in Ang1 expression. HIF2alpha overexpression further potentiated hypoxia-stimulated Ang1 expression, suggesting that HIF2alpha plays an important role in Ang1 regulation in BRP. When fused the Ang1 promoter (-3040 to +199) with the luciferase reporter gene, we found that hypoxia significantly increased promoter activity by 4.02 +/- 1.68 fold. However, progressive 5'-deletions from -3040 to -1799, which deleted two putative hypoxia response elements (HRE), abolished the hypoxia-induced increase in promoter activity. An electrophoretic mobility shift assay revealed that HIF2alpha was predominantly bound to a HRE site, located specifically at nucleotides -2715 to -2712. Finally, treatment with conditioned medium obtained from hypoxic pericytes stimulated endothelial cell migration and tube formation, which was completely blocked by co-treatment with anti-Ang1 antibody. This study is the first to demonstrate that hypoxia upregulates Ang1 expression via HIF2alpha-mediated transcriptional activation in pericytes, which plays a key role in angiogenesis. PMID- 26655816 TI - Analysis of Sensitivity, Specificity, and Positive and Negative Predictive Values of Smear and Colposcopy in Diagnosis of Premalignant and Malignant Cervical Lesions. AB - BACKGROUND This study aimed to examine the positive and negative predictive value in the diagnosis of premalignant and malignant lesions of cervical colposcopy, the sensitivity and specificity of smear, and to evaluate the correlation with histopathology of abnormal cytology and colposcopy. MATERIAL AND METHODS The criteria for inclusion of patients with unhealthy cervix in the study were: Erosion, Chronic cervicitis, and Healed lacerations, Hypertrophied cervix, bleeding on touch, suspicious growth/ulcer/polyp on the cervix, and abnormal discharges from the cervix. Women with frank carcinoma cervix, pregnant females, patients with bleeding per vaginum at the time of examination, and those who had used vaginal medications, vaginal contraceptives or douches in the last 48 h of examination were excluded from the study. Demographic analysis was performed for 450 patients who were admitted to the clinic. Sensitivity, specificity, positive predictive value and negative predictive values of patients to identify cervical pathologies of smear and colposcopy were histopathologically calculated. The statistical software package SPSS 15.0 (SPSS Inc., Chicago, IL, USA) and Spearman's and Chi-Square tests were used for statistical analysis. RESULTS Sensitivity, specificity, PPD and NDP of smear were 0.57%, 0.76%, 0.26%, 0.92% respectively. Sensitivity, specificity, PPD and NDP of colposcopy were 0.92%, 0.67%, 0.52%, 0.96% respectively. A statistically significant correlation was found between abnormal cytology and histopathology, and abnormal colposcopy finding and histopathology. CONCLUSIONS Women with clinical diagnosis of unhealthy cervix should be evaluated by cytology to detect any premalignant or malignant lesions. It was concluded that Pap smear, colposcopy and histopathology should be collectively evaluated to evaluate cervical findings in low socio economic regions. PMID- 26655817 TI - Increasing cutaneous afferent feedback improves proprioceptive accuracy at the knee in patients with sensory ataxia. AB - Hereditary sensory and autonomic neuropathy type III (HSAN III) features disturbed proprioception and a marked ataxic gait. We recently showed that joint angle matching error at the knee is positively correlated with the degree of ataxia. Using intraneural microelectrodes, we also documented that these patients lack functional muscle spindle afferents but have preserved large-diameter cutaneous afferents, suggesting that patients with better proprioception may be relying more on proprioceptive cues provided by tactile afferents. We tested the hypothesis that enhancing cutaneous sensory feedback by stretching the skin at the knee joint using unidirectional elasticity tape could improve proprioceptive accuracy in patients with a congenital absence of functional muscle spindles. Passive joint angle matching at the knee was used to assess proprioceptive accuracy in 25 patients with HSAN III and 9 age-matched control subjects, with and without taping. Angles of the reference and indicator knees were recorded with digital inclinometers and the absolute error, gradient, and correlation coefficient between the two sides calculated. Patients with HSAN III performed poorly on the joint angle matching test [mean matching error 8.0 +/- 0.8 degrees (+/-SE); controls 3.0 +/- 0.3 degrees ]. Following application of tape bilaterally to the knee in an X-shaped pattern, proprioceptive performance improved significantly in the patients (mean error 5.4 +/- 0.7 degrees ) but not in the controls (3.0 +/- 0.2 degrees ). Across patients, but not controls, significant increases in gradient and correlation coefficient were also apparent following taping. We conclude that taping improves proprioception at the knee in HSAN III, presumably via enhanced sensory feedback from the skin. PMID- 26655818 TI - Neuromodulatory influence of norepinephrine during developmental experience dependent plasticity. AB - Critical periods represent phases of development during which neuronal circuits and their responses can be readily shaped by stimuli. Experience-dependent plasticity that occurs within these critical periods can be influenced in many ways; however, Shepard et al. (J Neurosci 35: 2432-2437, 2015) recently singled out norepinephrine as an essential driver of this plasticity within the auditory cortex. This work provides novel insight into the mechanisms of critical period plasticity and challenges previous conceptions that a functional redundancy exists between noradrenergic and cholinergic influences on cortical plasticity. PMID- 26655819 TI - Role of DSCAM in the development of the spinal locomotor and sensorimotor circuits. AB - Locomotion is controlled by spinal circuits that generate rhythm and coordinate left-right and flexor-extensor motoneuronal activities. The outputs of motoneurons and spinal interneuronal circuits are shaped by sensory feedback, relaying peripheral signals that are critical to the locomotor and postural control. Several studies in invertebrates and vertebrates have argued that the Down syndrome cell adhesion molecule (DSCAM) would play an important role in the normal development of neural circuits through cell spacing and targeting, axonal and dendritic branching, and synapse establishment and maintenance. Although there is evidence that DSCAM is important for the normal development of neural circuits, little is known about its functional contribution to spinal motor circuits. We show here that adult DSCAM(2J) mutant mice, lacking DSCAM, exhibit a higher variability in their locomotor pattern and rhythm during treadmill locomotion. Retrograde tracing studies in neonatal isolated spinal cords show an increased number of spinal commissural interneurons, which likely contributes to reducing the left-right alternation and to increasing the flexor/swing duration during neonatal and adult locomotion. Moreover, our results argue that, by reducing the peripheral excitatory drive onto spinal motoneurons, the DSCAM mutation reduces or abolishes spinal reflexes in both neonatal isolated spinal cords and adult mice, thus likely impairing sensorimotor control. Collectively, our functional, electrophysiological, and anatomical studies suggest that the mammalian DSCAM protein is involved in the normal development of spinal locomotor and sensorimotor circuits. PMID- 26655820 TI - Effect of blocking tactile information from the fingertips on adaptation and execution of grip forces to friction at the grasping surface. AB - Adaptation of fingertip forces to friction at the grasping surface is necessary to prevent use of inadequate or excessive grip forces. In the current study we investigated the effect of blocking tactile information from the fingertips noninvasively on the adaptation and efficiency of grip forces to surface friction during precision grasp. Ten neurologically intact subjects grasped and lifted an instrumented grip device with 18 different frictional surfaces under three conditions: with bare hands or with a thin layer of plastic (Tegaderm) or an additional layer of foam affixed to the fingertips. The coefficient of friction at the finger-object interface of each surface was obtained for each subject with bare hands and Tegaderm by measuring the slip ratio (grip force/load force) at the moment of slip. We found that the foam layer reduced sensibility for two point discrimination and pressure sensitivity at the fingertips, but Tegaderm did not. However, Tegaderm reduced static, but not dynamic, tactile discrimination. Adaptation of fingertip grip forces to surface friction measured by the rate of change of peak grip force, and grip force efficiency measured by the grip-load force ratio at lift, showed a proportional relationship with bare hands but were impaired with Tegaderm and foam. Activation of muscles engaged in precision grip also varied with the frictional surface with bare hands but not with Tegaderm and foam. The results suggest that sensitivity for static tactile discrimination is necessary for feedforward and feedback control of grip forces and for adaptive modulation of muscle activity during precision grasp. PMID- 26655821 TI - Attentional demands modulate sensorimotor learning induced by persistent exposure to changes in auditory feedback. AB - Hearing one's own voice is important for regulating ongoing speech and for mapping speech sounds onto articulator movements. However, it is currently unknown whether attention mediates changes in the relationship between motor commands and their acoustic output, which are necessary as growth and aging inevitably cause changes to the vocal tract. In this study, participants produced vocalizations while they heard their vocal pitch persistently shifted downward one semitone in both single- and dual-task conditions. During the single-task condition, participants vocalized while passively viewing a visual stream. During the dual-task condition, participants vocalized while also monitoring a visual stream for target letters, forcing participants to divide their attention. Participants' vocal pitch was measured across each vocalization, to index the extent to which their ongoing vocalization was modified as a result of the deviant auditory feedback. Smaller compensatory responses were recorded during the dual-task condition, suggesting that divided attention interfered with the use of auditory feedback for the regulation of ongoing vocalizations. Participants' vocal pitch was also measured at the beginning of each vocalization, before auditory feedback was available, to assess the extent to which the deviant auditory feedback was used to modify subsequent speech motor commands. Smaller changes in vocal pitch at vocalization onset were recorded during the dual-task condition, suggesting that divided attention diminished sensorimotor learning. Together, the results of this study suggest that attention is required for the speech motor control system to make optimal use of auditory feedback for the regulation and planning of speech motor commands. PMID- 26655822 TI - Serotonin increases synaptic activity in olfactory bulb glomeruli. AB - Serotoninergic fibers densely innervate olfactory bulb glomeruli, the first sites of synaptic integration in the olfactory system. Acting through 5HT2A receptors, serotonin (5HT) directly excites external tufted cells (ETCs), key excitatory glomerular neurons, and depolarizes some mitral cells (MCs), the olfactory bulb's main output neurons. We further investigated 5HT action on MCs and determined its effects on the two major classes of glomerular interneurons: GABAergic/dopaminergic short axon cells (SACs) and GABAergic periglomerular cells (PGCs). In SACs, 5HT evoked a depolarizing current mediated by 5HT2C receptors but did not significantly impact spike rate. 5HT had no measurable direct effect in PGCs. Serotonin increased spontaneous excitatory and inhibitory postsynaptic currents (sEPSCs and sIPSCs) in PGCs and SACs. Increased sEPSCs were mediated by 5HT2A receptors, suggesting that they are primarily due to enhanced excitatory drive from ETCs. Increased sIPSCs resulted from elevated excitatory drive onto GABAergic interneurons and augmented GABA release from SACs. Serotonin-mediated GABA release from SACs was action potential independent and significantly increased miniature IPSC frequency in glomerular neurons. When focally applied to a glomerulus, 5HT increased MC spontaneous firing greater than twofold but did not increase olfactory nerve-evoked responses. Taken together, 5HT modulates glomerular network activity in several ways: 1) it increases ETC-mediated feed forward excitation onto MCs, SACs, and PGCs; 2) it increases inhibition of glomerular interneurons; 3) it directly triggers action potential-independent GABA release from SACs; and 4) these network actions increase spontaneous MC firing without enhancing responses to suprathreshold sensory input. This may enhance MC sensitivity while maintaining dynamic range. PMID- 26655823 TI - Is the notion of central fatigue based on a solid foundation? AB - Exercise-induced muscle fatigue has been shown to be the consequence of peripheral factors that impair muscle fiber contractile mechanisms. Central factors arising within the central nervous system have also been hypothesized to induce muscle fatigue, but no direct empirical evidence that is causally associated to reduction of muscle force-generating capability has yet been reported. We developed a simulation model to investigate whether peripheral factors of muscle fatigue are sufficient to explain the muscle force behavior observed during empirical studies of fatiguing voluntary contractions, which is commonly attributed to central factors. Peripheral factors of muscle fatigue were included in the model as a time-dependent decrease in the amplitude of the motor unit force twitches. Our simulation study indicated that the force behavior commonly attributed to central fatigue could be explained solely by peripheral factors during simulated fatiguing submaximal voluntary contractions. It also revealed important flaws regarding the use of the interpolated twitch response from electrical stimulation of the muscle as a means for assessing central fatigue. Our analysis does not directly refute the concept of central fatigue. However, it raises important concerns about the manner in which it is measured and about the interpretation of the commonly accepted causes of central fatigue and questions the very need for the existence of central fatigue. PMID- 26655824 TI - Organotypic slice cultures containing the preBotzinger complex generate respiratory-like rhythms. AB - Study of acute brain stem slice preparations in vitro has advanced our understanding of the cellular and synaptic mechanisms of respiratory rhythm generation, but their inherent limitations preclude long-term manipulation and recording experiments. In the current study, we have developed an organotypic slice culture preparation containing the preBotzinger complex (preBotC), the core inspiratory rhythm generator of the ventrolateral brain stem. We measured bilateral synchronous network oscillations, using calcium-sensitive fluorescent dyes, in both ventrolateral (presumably the preBotC) and dorsomedial regions of slice cultures at 7-43 days in vitro. These calcium oscillations appear to be driven by periodic bursts of inspiratory neuronal activity, because whole cell recordings from ventrolateral neurons in culture revealed inspiratory-like drive potentials, and no oscillatory activity was detected from glial fibrillary associated protein-expressing astrocytes in cultures. Acute slices showed a burst frequency of 10.9 +/- 4.2 bursts/min, which was not different from that of brain stem slice cultures (13.7 +/- 10.6 bursts/min). However, slice cocultures that include two cerebellar explants placed along the dorsolateral border of the brainstem displayed up to 193% faster burst frequency (22.4 +/- 8.3 bursts/min) and higher signal amplitude (340%) compared with acute slices. We conclude that preBotC-containing slice cultures retain inspiratory-like rhythmic function and therefore may facilitate lines of experimentation that involve extended incubation (e.g., genetic transfection or chronic drug exposure) while simultaneously being amenable to imaging and electrophysiology at cellular, synaptic, and network levels. PMID- 26655826 TI - Central cholinergic synaptic vesicle loading obeys the set-point model in Drosophila. AB - Experimental evidence shows that neurotransmitter release, from presynaptic terminals, can be regulated by altering transmitter load per synaptic vesicle (SV) and/or through change in the probability of vesicle release. The vesicular acetylcholine transporter (VAChT) loads acetylcholine into SVs at cholinergic synapses. We investigated how the VAChT affects SV content and release frequency at central synapses in Drosophila melanogaster by using an insecticidal compound, 5Cl-CASPP, to block VAChT and by transgenic overexpression of VAChT in cholinergic interneurons. Decreasing VAChT activity produces a decrease in spontaneous SV release with no change to quantal size and no decrease in the number of vesicles at the active zone. This suggests that many vesicles are lacking in neurotransmitter. Overexpression of VAChT leads to increased frequency of SV release, but again with no change in quantal size or vesicle number. This indicates that loading of central cholinergic SVs obeys the "set-point" model, rather than the "steady-state" model that better describes loading at the vertebrate neuromuscular junction. However, we show that expression of a VAChT polymorphism lacking one glutamine residue in a COOH-terminal polyQ domain leads to increased spontaneous SV release and increased quantal size. This effect spotlights the poly-glutamine domain as potentially being important for sensing the level of neurotransmitter in cholinergic SVs. PMID- 26655827 TI - Aspidosperma species as sources of anti-malarials: uleine is the major anti malarial indole alkaloid from Aspidosperma parvifolium (Apocynaceae). AB - BACKGROUND: Several species of the genus Aspidosperma (Apocynaceae) are used for the treatment of human malaria in Brazil and other meso- and South American countries. METHODS: Ethanol extract from Aspidosperma parvifolium trunk bark was submitted to acid-base extractions leading to alkaloid and neutral fractions. The alkaloid fraction was chromatographed over a silica gel column. Ethanol extract, fractions and uleine were analysed by HPLC-DAD, UPLC-ESI-MS/MS and HPLC-ESI MicroTOF-MS. The anti-malarial activity was assayed against resistant and sensitive chloroquine Plasmodium falciparum strains by microscopic, [(3)H] hypoxanthine incorporation and HRPII techniques. Cytotoxicity (CC50) was evaluated against Vero and HepG2 cell lines by the MTT technique; selectivity indexes (SI = CC50/IC50) were calculated. RESULTS: The major peak in the HPLC-DAD chromatograms of the ethanol extract, alkaloid and neutral fractions suggested the presence of uleine that was isolated from the alkaloid fraction by column chromatography and was characterized by spectroscopic methods. A total of 15 alkaloids, besides uleine, were identified in the alkaloid fraction by UPLC-DAD ESI-MS/MS and HPLC-ESI-MicroTOF-MS. The ethanol extract from Aspidosperma parvifolium and the neutral fraction were moderately active against P. falciparum strains. The alkaloid fraction and uleine disclosed high anti-malarial activity against chloroquine-resistant P. falciparum strain (IC50 < 1 ug/mL). The ethanol extract, neutral fraction and uleine showed low cytotoxicity against Vero and HepG2 cell lines (CC50 > 300 ug/mL). The alkaloid fraction showed moderate cytotoxicity to HepG2 cell line (CC50 = 74.4 ug/mL). High SI values (>10) were determined for all samples. CONCLUSION: Ethanol extract from Aspidosperma parvifolium trunk bark afforded uleine that is the major constituent of the alkaloid fraction and disclosed a good in vitro anti-malarial activity. Moreover, 15 other indole alkaloids have been identified along with uleine. PMID- 26655825 TI - Hyperpolarization-independent maturation and refinement of GABA/glycinergic connections in the auditory brain stem. AB - During development GABA and glycine synapses are initially excitatory before they gradually become inhibitory. This transition is due to a developmental increase in the activity of neuronal potassium-chloride cotransporter 2 (KCC2), which shifts the chloride equilibrium potential (ECl) to values more negative than the resting membrane potential. While the role of early GABA and glycine depolarizations in neuronal development has become increasingly clear, the role of the transition to hyperpolarization in synapse maturation and circuit refinement has remained an open question. Here we investigated this question by examining the maturation and developmental refinement of GABA/glycinergic and glutamatergic synapses in the lateral superior olive (LSO), a binaural auditory brain stem nucleus, in KCC2-knockdown mice, in which GABA and glycine remain depolarizing. We found that many key events in the development of synaptic inputs to the LSO, such as changes in neurotransmitter phenotype, strengthening and elimination of GABA/glycinergic connection, and maturation of glutamatergic synapses, occur undisturbed in KCC2-knockdown mice compared with wild-type mice. These results indicate that maturation of inhibitory and excitatory synapses in the LSO is independent of the GABA and glycine depolarization-to hyperpolarization transition. PMID- 26655828 TI - Authors' reply to Green and colleagues. PMID- 26655829 TI - A longitudinal analysis of women's salivary testosterone and intrasexual competitiveness. AB - Research on within-subject changes in women's intrasexual competitiveness has generally focused on possible relationships between women's intrasexual competitiveness and estimates of their fertility. While this approach is useful for testing hypotheses about the adaptive function of changes in women's intrasexual competitiveness, it offers little insight into the proximate mechanisms through which such changes might occur. To investigate this issue, we carried out a longitudinal study of the hormonal correlates of changes in intrasexual competitiveness in a large sample of heterosexual women (N=136). Each woman provided saliva samples and completed an intrasexual competitiveness questionnaire in five weekly test sessions. Multilevel modeling of these data revealed a significant, positive within-subject effect of testosterone on intrasexual competitiveness, indicating that women reported greater intrasexual competitiveness when testosterone was high. By contrast, there were no significant effects of estradiol, progesterone, estradiol-to-progesterone ratio, or cortisol and no significant effects of any hormones on reported relationship jealousy. This is the first study to demonstrate correlated changes in measured testosterone levels and women's reported intrasexual competitiveness, implicating testosterone in the regulation of women's intrasexual competitiveness. PMID- 26655830 TI - Corrigendum: TET2 repression by androgen hormone regulates global hydroxymethylation status and prostate cancer progression. PMID- 26655831 TI - The Wnt/beta-catenin signaling pathway regulates the development of airway remodeling in patients with asthma. AB - Airway remodeling is a key characteristic of chronic asthma, particularly in patients with a fixed airflow limitation. The mechanisms underlying airway remodeling are poorly understood, and no therapeutic option is available. The Wnt/beta-catenin signaling pathway is involved in various physiological and pathological processes, including fibrosis and smooth muscle hypertrophy. In this study, we investigated the roles of Wnt/beta-catenin signaling in airway remodeling in patients with asthma. Wnt7a mRNA expression was prominent in induced sputum from patients with asthma compared with that from healthy controls. Next, we induced a chronic asthma mouse model with airway remodeling features, including subepithelial fibrosis and airway smooth muscle hyperplasia. Higher expression of Wnt family proteins and beta-catenin was detected in the lung tissue of mice with chronic asthma compared to control mice. Blocking beta catenin expression with a specific siRNA attenuated airway inflammation and airway remodeling. Decreased subepithelial fibrosis and collagen accumulation in the beta-catenin siRNA-treated mice was accompanied by reduced expression of transforming growth factor-beta. We further showed that suppressing beta-catenin in the chronic asthma model inhibited smooth muscle hyperplasia by downregulating the tenascin C/platelet-derived growth factor receptor pathway. Taken together, these findings demonstrate that the Wnt/beta-catenin signaling pathway is highly expressed and regulates the development of airway remodeling in chronic asthma. PMID- 26655832 TI - Avalanching strain dynamics during the hydriding phase transformation in individual palladium nanoparticles. AB - Phase transitions in reactive environments are crucially important in energy and information storage, catalysis and sensors. Nanostructuring active particles can yield faster charging/discharging kinetics, increased lifespan and record catalytic activities. However, establishing the causal link between structure and function is challenging for nanoparticles, as ensemble measurements convolve intrinsic single-particle properties with sample diversity. Here we study the hydriding phase transformation in individual palladium nanocubes in situ using coherent X-ray diffractive imaging. The phase transformation dynamics, which involve the nucleation and propagation of a hydrogen-rich region, are dependent on absolute time (aging) and involve intermittent dynamics (avalanching). A hydrogen-rich surface layer dominates the crystal strain in the hydrogen-poor phase, while strain inversion occurs at the cube corners in the hydrogen-rich phase. A three-dimensional phase-field model is used to interpret the experimental results. Our experimental and theoretical approach provides a general framework for designing and optimizing phase transformations for single nanocrystals in reactive environments. PMID- 26655833 TI - The centrosome is an actin-organizing centre. AB - Microtubules and actin filaments are the two main cytoskeleton networks supporting intracellular architecture and cell polarity. The centrosome nucleates and anchors microtubules and is therefore considered to be the main microtubule organizing centre. However, recurring, yet unexplained, observations have pointed towards a connection between the centrosome and actin filaments. Here we have used isolated centrosomes to demonstrate that the centrosome can directly promote actin-filament assembly. A cloud of centrosome-associated actin filaments could be identified in living cells as well. Actin-filament nucleation at the centrosome was mediated by the nucleation-promoting factor WASH in combination with the Arp2/3 complex. Pericentriolar material 1 (PCM1) seemed to modulate the centrosomal actin network by regulating Arp2/3 complex and WASH recruitment to the centrosome. Hence, our results reveal an additional facet of the centrosome as an intracellular organizer and provide mechanistic insights into how the centrosome can function as an actin-filament-organizing centre. PMID- 26655834 TI - Isoform diversity in the Arp2/3 complex determines actin filament dynamics. AB - The Arp2/3 complex consists of seven evolutionarily conserved subunits (Arp2, Arp3 and ARPC1-5) and plays an essential role in generating branched actin filament networks during many different cellular processes. In mammals, however, the ARPC1 and ARPC5 subunits are each encoded by two isoforms that are 67% identical. This raises the possibility that Arp2/3 complexes with different properties may exist. We found that Arp2/3 complexes containing ARPC1B and ARPC5L are significantly better at promoting actin assembly than those with ARPC1A and ARPC5, both in cells and in vitro. Branched actin networks induced by complexes containing ARPC1B or ARPC5L are also disassembled ~2-fold slower than those formed by their counterparts. This difference reflects the ability of cortactin to stabilize ARPC1B- and ARPC5L- but not ARPC1A- and ARPC5-containing complexes against coronin-mediated disassembly. Our observations demonstrate that the Arp2/3 complex in higher eukaryotes is actually a family of complexes with different properties. PMID- 26655835 TI - Site-specific proteasome phosphorylation controls cell proliferation and tumorigenesis. AB - Despite the fundamental importance of proteasomal degradation in cells, little is known about whether and how the 26S proteasome itself is regulated in coordination with various physiological processes. Here we show that the proteasome is dynamically phosphorylated during the cell cycle at Thr 25 of the 19S subunit Rpt3. CRISPR/Cas9-mediated genome editing, RNA interference and biochemical studies demonstrate that blocking Rpt3-Thr25 phosphorylation markedly impairs proteasome activity and impedes cell proliferation. Through a kinome-wide screen, we have identified dual-specificity tyrosine-regulated kinase 2 (DYRK2) as the primary kinase that phosphorylates Rpt3-Thr25, leading to enhanced substrate translocation and degradation. Importantly, loss of the single phosphorylation of Rpt3-Thr25 or knockout of DYRK2 significantly inhibits tumour formation by proteasome-addicted human breast cancer cells in mice. These findings define an important mechanism for proteasome regulation and demonstrate the biological significance of proteasome phosphorylation in regulating cell proliferation and tumorigenesis. PMID- 26655836 TI - Only a minority of broad-range detoxification genes respond to a variety of phytotoxins in generalist Bemisia tabaci species. AB - Generalist insect can utilize two different modes for regulating their detoxification genes, the constitutive mode and the induced mode. Here, we used the Bemisia tabaci sibling species MEAM1 and MED, as a model system for studying constitutive and induced detoxification resistance and their associated tradeoffs. B. tabaci adults were allowed to feed through membranes for 24 h on diet containing only sucrose or sucrose with various phytotoxins. Quantitative real-time PCR analyses of 18 detoxification genes, indicated that relatively few transcripts were changed in both the MEAM1 and MED species, in response to the addition of phytotoxins to the diet. Induced transcription of detoxification genes only in the MED species, in response to the presence of indole-3-carbinol in the insect's diet, was correlated with maintenance of reproductive performance in comparison to significant reduction in performance of the MEAM1 species. Three genes, COE2, CYP6-like 5 and BtGST2, responded to more than one compound and were highly transcribed in the insect gut. Furthermore, functional assays showed that the BtGST2 gene encodes a protein capable of interacting with both flavonoids and glucosinolates. In conclusion, several detoxification genes were identified that could potentially be involved in the adaptation of B. tabaci to its host plants. PMID- 26655837 TI - The Role of Compassion in Altruistic Helping and Punishment Behavior. AB - Compassion, the emotional response of caring for another who is suffering and that results in motivation to relieve suffering, is thought to be an emotional antecedent to altruistic behavior. However, it remains unclear whether compassion enhances altruistic behavior in a uniform way or is specific to sub-types of behavior such as altruistic helping of a victim or altruistic punishment of a transgressor. We investigated the relationship between compassion and subtypes of altruistic behavior using third-party paradigms where participants (1) witnessed an unfair economic exchange between a transgressor and a victim, and (2) had the opportunity to either spend personal funds to either economically (a) help the victim or (b) punish the transgressor. In Study 1, we examined whether individual differences in self-reported empathic concern (the emotional component of compassion) was associated with greater altruistic helping or punishment behavior in two independent samples. For participants who witnessed an unfair transaction, trait empathic concern was associated with greater helping of a victim and had no relationship to punishment. However, in those who decided to punish the transgressor, participants who reported greater empathic concern decided to punish less. In Study 2, we directly enhanced compassion using short-term online compassion meditation training to examine whether altruistic helping and punishment were increased after two weeks of training. Compared to an active reappraisal training control group, the compassion training group gave more to help the victim and did not differ in punishment of the transgressor. Together, these two studies suggest that compassion is related to greater altruistic helping of victims and is not associated with or may mitigate altruistic punishment of transgressors. PMID- 26655838 TI - Performances of TPHA, RPR and rapid immuno-chromatographic test in syphilis screening among blood donors at the university teaching hospital of Yaounde, Cameroon. PMID- 26655839 TI - A mirrorless spinwave resonator. AB - Optical resonance is central to a wide range of optical devices and techniques. In an optical cavity, the round-trip length and mirror reflectivity can be chosen to optimize the circulating optical power, linewidth, and free-spectral range (FSR) for a given application. In this paper we show how an atomic spinwave system, with no physical mirrors, can behave in a manner that is analogous to an optical cavity. We demonstrate this similarity by characterising the build-up and decay of the resonance in the time domain, and measuring the effective optical linewidth and FSR in the frequency domain. Our spinwave is generated in a 20 cm long Rb gas cell, yet it facilitates an effective FSR of 83 kHz, which would require a round-trip path of 3.6 km in a free-space optical cavity. Furthermore, the spinwave coupling is controllable enabling dynamic tuning of the effective cavity parameters. PMID- 26655840 TI - Proteome Analysis of Renoprotection Mediated by a Novel Cyclic Helix B Peptide in Acute Kidney Injury. AB - We developed a novel, erythropoietin-derived, non-erythropoiesis, cyclic helix B peptide (CHBP) that displays potent renoprotection against acute kidney injury (AKI). To determine the mechanism of CHBP-mediated protection, we investigated the proteomic profile of mice treated with CHBP in a kidney ischemia-reperfusion (IR) injury model. The isobaric tags for relative and absolute quantitation (iTRAQ)-labeled samples were analyzed using a QSTAR XL LC/MS system. In total, 38 differentially expressed proteins (DEPs) were shared by all experimental groups, while 3 DEPs were detected specifically in the IR + CHBP group. Eight significant pathways were identified, and oxidative phosphorylation was shown to be the most important pathway in CHBP-mediated renoprotection. The significant DEPs in the oxidative phosphorylation pathway elicited by CHBP are NADH-ubiquinone oxidoreductase Fe-S protein 6 (NDUFS6), alpha-aminoadipic semialdehyde synthase (AASS) and ATP-binding cassette sub-family D member 3 (ABCD3). The DEPs mentioned above were verified by RT-qPCR and immunostaining in mouse kidneys. We tested 6 DEPs in human biopsy samples from kidney transplant recipients. The trend of differential expression was consistent with that in the murine model. In conclusion, this study helps to elucidate the pharmacological mechanisms of CHBP before clinical translation. PMID- 26655841 TI - Evaluation of the Safety and Immunogenicity of a Candidate Pandemic Live Attenuated Influenza Vaccine (pLAIV) Against Influenza A(H7N9). AB - BACKGROUND: We evaluated a candidate A/Anhui/2013(H7N9) pandemic live attenuated influenza vaccine (pLAIV) in healthy adults, and assessed the ability of 1 or 2 doses to induce immune memory. METHODS: Healthy subjects in 2 age groups (18-49 years and 50-70 years) with undetectable hemagglutination-inhibiting (HAI) antibody to H7N9 were enrolled. Younger subjects received either 1 or 2 intranasal doses of 10(7.0) fluorescent focus units of A/Anhui/1/2013 pLAIV, while older subjects received a single dose. All subjects received a single 30-ug dose of unadjuvanted, antigenically matched A/Shanghai2/2013(H7N9) pandemic inactivated influenza vaccine (pIIV) 12 weeks after their first dose of pLAIV. RESULTS: Both vaccines were well tolerated. Serum HAI antibody responses were detected in 0 of 32 younger subjects and 1 of 17 older subjects after 1 dose of pLAIV and in 2 of 16 younger subjects after a second dose. Strong serum antibody responses were detected after a single subsequent dose of pIIV that was broadly reactive against H7 influenza viruses. CONCLUSIONS: An A(H7N9) pLAIV candidate was safe in both age groups. Priming with pLAIV resulted in responses to subsequent pIIV that exceeded those seen in naive subjects in previous reports. The A(H7N9) pLAIV induces strong immune memory that can be demonstrated by exposure to subsequent antigenic challenge. CLINICAL TRIALS REGISTRATION: NCT01995695 and NCT02274545. PMID- 26655842 TI - Strategies for Improving Polio Surveillance Performance in the Security Challenged Nigerian States of Adamawa, Borno, and Yobe During 2009-2014. AB - BACKGROUND: The security-challenged states of Adamawa, Borno, and Yobe bear most of the brunt of the Boko Haram insurgency in Nigeria. The security challenge has led to the killing of health workers, destruction of health facilities, and displacement of huge populations. To identify areas of polio transmission and promptly detect possible cases of importation in these states, polio surveillance must be very sensitive. METHODS: We conducted a retrospective review of acute flaccid paralysis surveillance in the security-compromised states between 2009 and 2014, using the acute flaccid paralysis database at the World Health Organization Nigeria Country Office. We also reviewed the reports of surveillance activities conducted in these security-challenged states, to identify strategies that were implemented to improve polio surveillance. RESULTS: Environmental surveillance was implemented in Borno in 2013 and in Yobe in 2014. All disease surveillance and notification officers in the 3 security-challenged states now receive annual training, and the number of community informants in these states has dramatically increased. Media-based messaging (via radio and television) is now used to sensitize the public to the importance of surveillance, and contact samples have been regularly collected in both states since 2014. CONCLUSIONS: The strategies implemented in the security-challenged states improved the quality of polio surveillance during the review period. PMID- 26655843 TI - The Effect of Irreversible Electroporation on the Femur: Experimental Study in a Rabbit Model. AB - Irreversible electroporation (IRE) is a novel ablation method that has been tested in humans with lung, prostate, kidney, liver, lymph node and presacral cancers. As a new non-thermal treatment, the use of IRE to ablate tumors in the musculoskeletal system might reduce the incidence of fractures. We aimed to determine the ablation threshold of cortical bone and to evaluate the medium- and long-term healing process and mechanical properties of the femur in a rabbit model post-IRE ablation. The ablation threshold of cortical bone was between 1090 V/cm and 1310 V/cm (120 pulses). IRE-ablated femurs displayed no detectable fracture but did exhibit signs of recovery, including osteoblast regeneration, angiogenesis and bone remodeling. In the ablation area, revascularization appeared at 4 weeks post-IRE. Osteogenic activity peaked 8 weeks post-IRE and remained high at 12 weeks. The mechanical strength decreased briefly 4 weeks post IRE but returned to normal levels within 8 weeks. Our experiment revealed that IRE ablation preserved the structural integrity of the bone cortex, and the ablated bone was able to regenerate rapidly. IRE may hold unique promise for in situ bone tissue ablation because rapid revascularization and active osteogenesis in the IRE ablation area are possible. PMID- 26655844 TI - SIRT1-Activating Compounds (STAC) Negatively Regulate Pancreatic Cancer Cell Growth and Viability Through a SIRT1 Lysosomal-Dependent Pathway. AB - PURPOSE: Recent studies suggest that SIRT1-activating compounds (STAC) are a promising class of anticancer drugs, although their mechanism of action remains elusive. The main goal of this study is to determine the role of STACs as a potential therapy for pancreatic cancer. In addition, we also explored the mechanism by which these compounds affect pancreatic cancer. EXPERIMENTAL DESIGN: Using in vitro (cell culture experiments) and in vivo (xenograft experiments) approaches, we studied the role of SIRT1 agonists (STAC) in human pancreatic cancer cell viability and growth. RESULTS: We show that SIRT1 is highly expressed in pancreatic cancer cells and that the STACs SRT1720, SRT1460, and SRT3025 inhibited cell growth and survival of pancreatic cancer cells. STACs enhanced the sensitivity of pancreatic cells to gemcitabine and paclitaxel, indicating that these drugs could be used in combination with other chemotherapy drugs. We also show that STACs were very effective in inhibiting tumor xenograft growth. In mechanistic studies, we observed that STACs activated a SIRT1 lysosomal-dependent cell death. Furthermore, the effect of STACs on cell viability was also dependent on the expression of the endogenous SIRT1 inhibitor DBC1. CONCLUSIONS: Taken together, our results reveal an essential role for SIRT1 and lysosomes in the death pathway regulated by STACs in pancreatic cancer cells. Clin Cancer Res; 22(10); 2496-507. (c)2015 AACR. PMID- 26655845 TI - Severe Hepatitis Promotes Hepatocellular Carcinoma Recurrence via NF-kappaB Pathway-Mediated Epithelial-Mesenchymal Transition after Resection. AB - PURPOSE: Surgical resection is considered as a curative treatment modality for hepatocellular carcinoma; however, the incidence of postoperative tumor recurrence is high, leading to worse patient survival. Persistent hepatitis (inflammation) is one of the risk factors of tumor recurrence after surgical resection. The aim of this study is to investigate the underlying mechanisms linking liver inflammation to hepatocellular carcinoma progression. EXPERIMENTAL DESIGN: In this study, we used a cytokine array to identify important cytokines whose levels are increased in liver microenvironment with severe hepatitis. We evaluated the morphologic changes, migration and invasion ability, and signal transduction in hepatocellular carcinoma cells with or without inflammatory cytokine in vitro Finally, we analyzed the NF-kappaB signal pathway in tumor specimens from 232 patients with hepatocellular carcinoma by immunohistochemical staining. RESULTS: The proinflammatory cytokine TNFalpha was increased in the peritumoral microenvironment and contributed to tumor recurrence and metastasis. Specifically, TNFalpha promoted hepatocellular carcinoma cancer cell migration, invasion, and epithelial-mesenchymal transition (EMT) by upregulating the transcriptional regulator, Snail. We identified Snail as a direct target gene downstream of the TNFalpha-mediated canonical NF-kappaB activation. In addition, tumor recurrence-free survival of hepatocellular carcinoma patients correlated negatively with high p65 and Snail expression and positively with high E-cadherin expression. CONCLUSIONS: Our results establish a signaling axis that explains how inflammatory tumor microenvironment promotes hepatocellular carcinoma recurrence and metastasis. These findings suggest that controlling liver inflammation and/or targeting NF-kappaB-mediated Snail expression may be a potential therapeutic strategy to prevent hepatocellular carcinoma recurrence after hepatectomy. PMID- 26655846 TI - A Phase I Study of the Anti-Activin Receptor-Like Kinase 1 (ALK-1) Monoclonal Antibody PF-03446962 in Patients with Advanced Solid Tumors. AB - PURPOSE: Objectives of this dose-finding study were to determine the MTD and recommended phase II dose (RP2D) of the first-in-class anti-activin receptor-like kinase 1 (ALK-1) monoclonal antibody PF-03446962, and assess safety and antitumor activity in patients with advanced solid tumors. EXPERIMENTAL DESIGN: This open label, multicenter study was based on a 3+3 design. PF-03446962 was administered biweekly by intravenous infusion, at doses ranging from 0.5 to 15 mg/kg. RESULTS: Forty-four patients received treatment with PF-03446962. Dose-limiting toxicities observed during dose escalation included grade 3 increased amylase, grade 3/4 increased lipase, and grade 3/4 thrombocytopenia. The MTD was determined to be 10 mg/kg. The RP2D was set at 7 mg/kg for patients with advanced solid tumors, based on the observed safety, pharmacokinetics, and antitumor activity. The most frequent treatment-related, all-grade adverse events included thrombocytopenia (20.5%), fatigue (15.9%), and nausea, increased amylase, and increased lipase (each 11.4%). Treatment-related telangiectasia was noted in 7% of patients, suggesting in vivo inhibition of the ALK-1 pathway. None of the deaths was deemed to be treatment-related. Three (6.8%) patients with advanced hepatocellular carcinoma, renal cell carcinoma, or non-small cell lung cancer achieved a partial response, and 12 (27.3%) patients had stable disease, across dose levels. Contrast-enhanced ultrasound analysis of tumor vascularity showed reduction in tumor perfusion in 2 patients with stable disease following treatment with PF 03446962. CONCLUSIONS: The clinical activity demonstrated in this study points to PF-03446962 as a novel approach to antiangiogenic therapy, with manageable safety profile and single-agent, antitumor activity in patients with advanced solid tumors. Clin Cancer Res; 22(9); 2146-54. (c)2015 AACR. PMID- 26655847 TI - Genomic DNA Hypomethylation and Risk of Renal Cell Carcinoma: A Case-Control Study. AB - PURPOSE: Genomic DNA hypomethylation is a hallmark of most cancer genomes, promoting genomic instability and cell transformation. In the present study, we sought to determine whether global DNA methylation in peripheral blood is associated with risk of renal cell carcinoma (RCC). EXPERIMENTAL DESIGN: A retrospective case-control study consisting of 889 RCC cases and an equal number of age, gender, and ethnicity-matched controls was applied. Global DNA methylation was measured as 5-mC% content. Logistic regression was used to estimate odds ratio (OR) and 95% confidence interval (CI) for the association between DNA methylation level and the risk of RCC. RESULTS: The median 5-mC% was significantly lower in cases than in healthy controls (P< 0.001). In multivariate logistic regression analysis, individuals in the lowest tertile (T1) of 5-mC% had higher risk of RCC with OR of 1.40 (95% CI, 1.06-1.84), compared with individuals in the highest tertile (T3;Pfor trend= 0.02). When stratified by RCC risk factors, associations between hypomethylation and increased RCC risk appeared to be stronger among males (OR, 1.61;Pfor trend= 0.01), younger age (OR, 1.47;Pfor trend= 0.03), never smokers (OR, 1.55;Pfor trend= 0.02), family history of other cancer (OR, 1.64;Pfor trend= 1.22E-03), and late stage (OR, 2.06,Pfor trend= 4.98E-04). Additionally, we observed significant interaction between gender and 5 mC% in elevating RCC risk (Pfor interaction= 0.03). CONCLUSIONS: Our findings suggest an association between global DNA hypomethylation and RCC risk. To establish global DNA hypomethylation as a risk factor for RCC, future prospective studies are warranted. This study may provide further understanding of the etiology of RCC tumorigenesis. PMID- 26655848 TI - Deriving Heterospecific Self-Assembling Protein-Protein Interactions Using a Computational Interactome Screen. AB - Interactions between naturally occurring proteins are highly specific, with protein-network imbalances associated with numerous diseases. For designed protein-protein interactions (PPIs), required specificity can be notoriously difficult to engineer. To accelerate this process, we have derived peptides that form heterospecific PPIs when combined. This is achieved using software that generates large virtual libraries of peptide sequences and searches within the resulting interactome for preferentially interacting peptides. To demonstrate feasibility, we have (i) generated 1536 peptide sequences based on the parallel dimeric coiled-coil motif and varied residues known to be important for stability and specificity, (ii) screened the 1,180,416 member interactome for predicted Tm values and (iii) used predicted Tm cutoff points to isolate eight peptides that form four heterospecific PPIs when combined. This required that all 32 hypothetical off-target interactions within the eight-peptide interactome be disfavoured and that the four desired interactions pair correctly. Lastly, we have verified the approach by characterising all 36 pairs within the interactome. In analysing the output, we hypothesised that several sequences are capable of adopting antiparallel orientations. We subsequently improved the software by removing sequences where doing so led to fully complementary electrostatic pairings. Our approach can be used to derive increasingly large and therefore complex sets of heterospecific PPIs with a wide range of potential downstream applications from disease modulation to the design of biomaterials and peptides in synthetic biology. PMID- 26655849 TI - Valproic acid after five decades of use in epilepsy: time to reconsider the indications of a time-honoured drug. AB - Since the serendipitous discovery of its anticonvulsant properties more than 50 years ago, valproic acid has become established as an effective broad-spectrum antiepileptic drug that is particularly useful for the management of generalised epilepsies, for which treatment alternatives are few. However, during the past few years increasing evidence has accumulated that intake of valproic acid during pregnancy is associated with a significant risk of dose-dependent teratogenic effects and impaired postnatal cognitive development in children. Because of these risks, valproic acid should not be used as a first-line drug in women of childbearing potential whenever equally or more effective alternative drugs are available-as in the case of focal epilepsy. In some generalised epilepsy syndromes, such as juvenile myoclonic epilepsy, valproic acid has better documented efficacy than alternative drugs and drug selection should be a shared decision between the clinician and the informed patient based on careful risk benefit assessment. PMID- 26655850 TI - Valproic acid: reducing the risks of prenatal exposure. PMID- 26655852 TI - Can Link Analysis Be Applied to Identify Behavioral Patterns in Train Recorder Data? AB - OBJECTIVE: A proof-of-concept analysis was conducted to establish whether link analysis could be applied to data from on-train recorders to detect patterns of behavior that could act as leading indicators of potential safety issues. BACKGROUND: On-train data recorders capture data about driving behavior on thousands of routine journeys every day and offer a source of untapped data that could be used to offer insights into human behavior. METHOD: Data from 17 journeys undertaken by six drivers on the same route over a 16-hr period were analyzed using link analysis, and four key metrics were examined: number of links, network density, diameter, and sociometric status. RESULTS: The results established that link analysis can be usefully applied to data captured from on vehicle recorders. The four metrics revealed key differences in normal driver behavior. These differences have promising construct validity as leading indicators. CONCLUSION: Link analysis is one method that could be usefully applied to exploit data routinely gathered by on-vehicle data recorders. It facilitates a proactive approach to safety based on leading indicators, offers a clearer understanding of what constitutes normal driving behavior, and identifies trends at the interface of people and systems, which is currently a key area of strategic risk. APPLICATION: These research findings have direct applications in the field of transport data monitoring. They offer a means of automatically detecting patterns in driver behavior that could act as leading indicators of problems during operation and that could be used in the proactive monitoring of driver competence, risk management, and even infrastructure design. PMID- 26655851 TI - Uncovering MicroRNA Regulatory Hubs that Modulate Plasma Cell Differentiation. AB - Using genome-wide approaches, we studied the microRNA (miRNA) expression profile during human plasma cell (PC) differentiation induced by stimulation of human blood B cells with T follicular helper cell-dependent signals. Combining the profiles of differentially expressed genes in PC differentiation with gene ontology (GO) analysis revealed that a significant group of genes involved in the transcription factor (TF) activity was preferentially changed. We thus focused on studying the effects of differentially expressed miRNAs on several key TFs in PC differentiation. Cohorts of differentially expressed miRNAs cooperating as miRNA hubs were predicted and validated to modulate key TFs, including a down-regulated miRNA hub containing miR-101-3p, -125b-5p, and -223-3p contributing to induction of PRDM1 as well as an up-regulated miRNA hub containing miR-34a-5p, -148a-3p, and -183-5p suppressing BCL6, BACH2, and FOXP1. Induced expression of NF-kappaB and PRDM1 during PC differentiation controlled the expression of up- and down regulated miRNA hubs, respectively. Co-expression of miR-101-3p, -125b-5p, and 223-3p in stimulated B cells showed synergistic effects on inhibition of PC formation, which can be rescued by re-introduction of PRDM1. Together, we catalogue the complex roadmap of miRNAs and their functional interplay in collaboratively directing PC differentiation. PMID- 26655853 TI - Stepwise Excavation Allows Apexogenesis in Permanent Molars with Deep Carious Lesions and Incomplete Root Formation. AB - This study evaluated the stepwise excavation technique in 138 permanent molars with deep carious lesions and incomplete root formation within a 24-month clinical and radiographic follow-up period. In 96.7% of the cases, success was observed (no pain, integrity of restoration margins, absence of radiographic alterations and apexogenesis). The cases of failure (3.3%) were due to the loss of the temporary restoration. In conclusion, the stepwise excavation is a promising technique for permanent teeth with deep carious lesions and incomplete root formation as a minimally invasive approach because it allows the preservation of pulp vitality and occurrence of apexogenesis. PMID- 26655854 TI - Enhanced performance of an innovative dengue IgG/IgM rapid diagnostic test using an anti-dengue EDI monoclonal antibody and dengue virus antigen. AB - High levels of anti-dengue IgM or IgG can be detected using numerous rapid diagnostic tests (RDTs). However, the sensitivity and specificity of these tests are reduced by changes in envelope glycoprotein antigenicity that inevitably occur in limited expression systems. A novel RDT was designed to enhance diagnostic sensitivity. Dengue viruses cultured in animal cells were used as antigens to retain the native viral coat protein. Monoclonal antibodies (mAbs) were then developed, for the first time, against domain I of envelope glycoprotein (EDI). The anti-dengue EDI mAb was employed as a capturer, and EDII and EDIII, which are mainly involved in the induction of neutralizing antibodies in patients, were fully available to bind to anti-dengue IgM or IgG in patients. A one-way automatic blood separation device prevented reverse migration of plasma and maximize the capture of anti-dengue antibodies at the test lines. A clinical evaluation in the field proved that the novel RDT (sensitivities of 96.5% and 96.7% for anti-dengue IgM and IgG) is more effective in detecting anti-dengue antibodies than two major commercial tests (sensitivities of 54.8% and 82% for SD BIOLINE; 50.4% and 75.3% for PanBio). The innovative format of RDT can be applied to other infectious viral diseases. PMID- 26655856 TI - Proline Conformation in a Functional Tau Fragment. AB - The conformational state of distinct prolines can determine the folding of a protein but equally other biological processes when coupled to a conformation sensitive secondary reaction. For the neuronal tau protein, the importance of proline conformation is underscored by its interaction with different prolyl cis/trans isomerases. The proline conformation would gain even further importance after phosphorylation of the preceding residue by various proline-directed kinases. A number of molecular diseases including Alzheimer's disease and traumatic brain injury were thereby recently qualified as "cistauosis", as they would imply a cis conformation for the pThr231-Pro232 prolyl bond. We here investigate by NMR spectroscopy the conformation of all prolines in a functional Tau fragment, Tau[208-324]. Although we can detect and identify some minor conformers in the cis form, we show that all prolines are for over 90% in the trans conformation. Phosphorylation by CDK2/CycA3, which notably leads to complete modification of the Thr231 residue, does not change this conclusion. Our data hence disagree with the notion that specific prolyl bonds in tau would adopt preferentially the cis conformation. PMID- 26655855 TI - Structural Analysis of Multi-Helical RNAs by NMR-SAXS/WAXS: Application to the U4/U6 di-snRNA. AB - NMR and SAXS (small-angle X-ray scattering)/WAXS (wide-angle X-ray scattering) are highly complementary approaches for the analysis of RNA structure in solution. Here we describe an efficient NMR-SAXS/WAXS approach for structural investigation of multi-helical RNAs. We illustrate this approach by determining the overall fold of a 92-nt 3-helix junction from the U4/U6 di-snRNA. The U4/U6 di-snRNA is conserved in eukaryotes and is part of the U4/U6.U5 tri-snRNP, a large ribonucleoprotein complex that comprises a major subunit of the assembled spliceosome. Helical orientations can be determined by X-ray scattering data alone, but the addition of NMR RDC (residual dipolar coupling) restraints improves the structure models. RDCs were measured in two different external alignment media and also by magnetic susceptibility anisotropy. The resulting alignment tensors are collinear, which is a previously noted problem for nucleic acids. Including WAXS data in the calculations produces models with significantly better fits to the scattering data. In solution, the U4/U6 di-snRNA forms a 3 helix junction with a planar Y-shaped structure and has no detectable tertiary interactions. Single-molecule Forster resonance energy transfer data support the observed topology. A comparison with the recently determined cryo-electron microscopy structure of the U4/U6.U5 tri-snRNP illustrates how proteins scaffold the RNA and dramatically alter the geometry of the U4/U6 3-helix junction. PMID- 26655857 TI - Effects of nursing process-based simulation for maternal child emergency nursing care on knowledge, attitude, and skills in clinical nurses. AB - BACKGROUND: Since previous studies on simulation-based education have been focused on fundamental nursing skills for nursing students in South Korea, there is little research available that focuses on clinical nurses in simulation-based training. Further, there is a paucity of research literature related to the integration of the nursing process into simulation training particularly in the emergency nursing care of high-risk maternal and neonatal patients. PURPOSES: The purpose of this study was to identify the effects of nursing process-based simulation on knowledge, attitudes, and skills for maternal and child emergency nursing care in clinical nurses in South Korea. PARTICIPANTS: Data were collected from 49 nurses, 25 in the experimental group and 24 in the control group, from August 13 to 14, 2013. METHODS: This study was an equivalent control group pre- and post-test experimental design to compare the differences in knowledge, attitudes, and skills for maternal and child emergency nursing care between the experimental group and the control group. The experimental group was trained by the nursing process-based simulation training program, while the control group received traditional methods of training for maternal and child emergency nursing care. RESULTS: The experimental group was more likely to improve knowledge, attitudes, and skills required for clinical judgment about maternal and child emergency nursing care than the control group. Among five stages of nursing process in simulation, the experimental group was more likely to improve clinical skills required for nursing diagnosis and nursing evaluation than the control group. CONCLUSION: These results will provide valuable information on developing nursing process-based simulation training to improve clinical competency in nurses. Further research should be conducted to verify the effectiveness of nursing process-based simulation with more diverse nurse groups on more diverse subjects in the future. PMID- 26655858 TI - Functional trait responses to grazing are mediated by soil moisture and plant functional group identity. AB - Abundant evidence has shown that grazing alters plant functional traits, community structure and ecosystem functioning of grasslands. Few studies, however, have tested how plant responses to grazing are mediated by resource availability and plant functional group identity. We examined the effects of grazing on functional traits across a broad range of species along a soil moisture gradient in Inner Mongolia grassland. Our results showed that trait syndromes of plant size (individual biomass) and shoot growth (leaf N content and leaf density) distinguished plant species responses to grazing. The effects of grazing on functional traits were mediated by soil moisture and dependent on functional group identity. For most species, grazing decreased plant height but increased leaf N and specific leaf area (SLA) along the moisture gradient. Grazing enhanced the community-weighted attributes (leaf NCWM and SLACWM), which were triggered mainly by the positive trait responses of annuals and biennials and perennial grasses, and increased relative abundance of perennial forbs. Our results suggest that grazing-induced species turnover and increased intraspecific trait variability are two drivers for the observed changes in community weighted attributes. The dominant perennial bunchgrasses exhibited mixed tolerance resistance strategies to grazing and mixed acquisitive-conservative strategies in resource utilization. PMID- 26655859 TI - Long-term Outcomes of Military Service in Aging and the Life Course: A Positive Re-envisioning. AB - Most research on military service focuses on its short-term negative consequences, especially the mental and physical injuries of those deployed in warzones. However, studies of long-term outcomes reveal surprisingly positive effects of military service--both those early in adulthood that grow over time and others that can emerge later in life. These multidomain effects have been found in veterans of World War II and the Korean War and are now being seen in veterans of the Vietnam War. Although some are directly attributable to public policies such as the GI Bill, which facilitate educational and economic gains, there are personal developmental gains as well, including autonomy, emotional maturity and resilience, mastery, and leadership skills, that lead to better health and well-being in later life. These long-term effects vary across persons, change over time within persons, and often reflect processes of cumulative advantage and disadvantage. We propose a life-span model of the effects of military service that provides a perspective for probing both long-term positive and negative outcomes for aging veterans. We further explicate the model by focusing on both sociocultural dynamics and individual processes. We identify public-use data that can be examined to evaluate this model, and offer a set of questions that can be used to assess military service. Finally, we outline an agenda for dedicated inquiry into such effects and consider policy implications for the health and well-being of aging veterans in later life. PMID- 26655860 TI - Efficacy of exercise as an adjunct treatment for clinically depressed inpatients during the initial stages of antidepressant pharmacotherapy: An open randomized controlled trial. AB - BACKGROUND: Physical exercise as adjunctive treatment for hospitalized patients with major depressive disorder (MDD) has been of increasing interest in the past few years. While preliminary findings are promising, these prior studies have been plagued by inclusion of participants at different stages of medication use at study entry. The present study evaluates the effects of a short (10-days) add on endurance-training intervention in hospitalized MDD patients on antidepressant medication for less than two weeks. METHOD: Thirty-five participants were randomly assigned to one of three study groups: aerobic exercise (n=14), placebo (stretching) exercise (n=11), or no intervention (control; n=10). The study outcome was the change in the Beck Depression Inventory (BDI-II) total score from baseline to the end of the study period. RESULTS: The intent-to-treat analysis showed significant improvements in BDI-II scores for both the aerobic and the stretching groups. However, comparing pre- to post-study depression changes in these two groups, we found a large effect size in favor of aerobic exercise (Cohen's d=-1.06). No significant change in depressive symptoms was found in the control group. LIMITATIONS: The nature of the intervention (i.e., exercise) meant blinding participants to treatments was not possible. Precise information on medication dosage was not available, and the short duration of interventions and lack of follow-up assessment were all limitations. CONCLUSIONS: Endurance training can be a helpful adjunct treatment for hospitalized patients with severe affective disorders in the initial stages of pharmacotherapy. PMID- 26655861 TI - Delayed sleep phase: An important circadian subtype of sleep disturbance in bipolar disorders. AB - BACKGROUND: Theoretical models of Bipolar Disorder (BD) highlight that sleep disturbances may be a marker of underlying circadian dysregulation. However, few studies of sleep in BD have reported on the most prevalent circadian sleep abnormality, namely Delayed Sleep Phase (DSP). METHODS: A cross-sectional study of 404 adults with BD who met published clinical criteria for insomnia, hypersomnia or DSP, and who had previously participated in a study of sleep in BD using a comprehensive structured interview assessment. RESULTS: About 10% of BD cases with a sleep problem met criteria for a DSP profile. The DSP group was younger and had a higher mean Body Mass Index (BMI) than the other groups. Also, DSP cases were significantly more likely to be prescribed mood stabilizers and antidepressant than insomnia cases. An exploratory analysis of selected symptom item ratings indicated that DSP was significantly more likely to be associated with impaired energy and activity levels. LIMITATIONS: The cross-sectional design precludes examination of longitudinal changes. DSP is identified by sleep profile, not by diagnostic criteria or objective sleep records such as actigraphy. The study uses data from a previous study to identify and examine the DSP group. CONCLUSIONS: The DSP group identified in this study can be differentiated from hypersomnia and insomnia groups on the basis of clinical and demographic features. The association of DSP with younger age, higher BMI and impaired energy and activity also suggest that this clinical profile may be a good proxy for underlying circadian dysregulation. PMID- 26655862 TI - Seasonal and meteorological associations with depressive symptoms in older adults: A geo-epidemiological study. AB - BACKGROUND: Given increased social and physiological vulnerabilities, older adults may be particularly susceptible to environmental influences on mood. Whereas the impact of season on mood is well described for adults, studies rarely extend to elders or include objective weather data. We investigated the impact of seasonality and meteorological factors on risk of current depressive symptoms in older adults. METHODS: We used data on 8027 participants from the first wave of The Irish Longitudinal Study of Ageing, a population-representative cohort of adults aged 50+. Depressive symptoms were recorded using the Centre for Epidemiological Studies Depression Scale. Season was defined according to the World Meteorological Organisation. Data on climate over the preceding thirty years, and temperature and rain over the preceding month, were provided by the Irish Meteorological Service and linked using Geographic Information Systems techniques to participant's geo-coded locations at a resolution of one kilometre. RESULTS: The highest levels of depressive symptoms were reported in winter and the lowest in spring (mean 6.56 [CI95% 6.09, 7.04] vs. 5.81 [CI95%: 5.40, 6.22]). In fully adjusted linear regression models, participants living in areas with higher levels of rainfall in the preceding and/or current calendar month had greater depressive symptoms (0.04 SE 0.02; p=0.039 per 10mm additional rainfall per month) while those living in areas with sunnier climates had fewer depressive symptoms (-2.67 SE 0.88; p=0.003 for every additional hour of average annual daily sunshine). LIMITATIONS: This was a cross-sectional analysis thus causality cannot be inferred; monthly rain and temperature averages were available only on a calendar month basis while monthly local levels of sunshine data were not available. CONCLUSIONS: Environmental cues may influence mood in older adults and thus have relevance for the recognition and treatment of depression in this age group. PMID- 26655863 TI - More illness in offspring of bipolar patients from the U.S. compared to Europe. AB - BACKGROUND: Evidence suggests that patients with bipolar disorder from the United States have an earlier age of onset and a more difficult course of illness than those from Germany and the Netherlands. These characteristics were related to a greater family burden of psychiatric illness and the experience of more psychosocial adversity in childhood. We hypothesized that this greater illness burden would extend to the offspring of the US patients. METHODS: 968 outpatients (average age 41) with bipolar illness gave informed consent for participation in a treatment outcome network and filled out a detailed questionnaire about their illness and family history of illness, including whether their offspring had a diagnosis of depression, bipolar disorder, alcohol or substance abuse, suicide attempt or "other" illness. Of those with children, 356 were from the US and 132 were from Europe. RESULTS: Compared to the Europeans, offspring of patients from the US had significantly (p<0.001) more depression, bipolar disorder, drug abuse, and "other" illnesses. The number of illnesses in the offspring was related to the bipolar parent being from the US, having had childhood adversity, more than 20 prior episodes, and more parental psychiatric illness. CONCLUSIONS: While the findings are limited by their basis on self report, the distribution of the percentages in the US offspring are similar to those of Axelson et al. (2015) who used direct interviews. The higher burden of illness in the offspring and their in direct progenitors from the US compared to Europe warrant new attempts at better treatment and prevention. PMID- 26655864 TI - The Spatial and Temporal Transcriptomic Landscapes of Ginseng, Panax ginseng C. A. Meyer. AB - Ginseng, including Asian ginseng (Panax ginseng C. A. Meyer) and American ginseng (P. quinquefolius L.), is one of the most important medicinal herbs in Asia and North America, but significantly understudied. This study sequenced and characterized the transcriptomes and expression profiles of genes expressed in 14 tissues and four different aged roots of Asian ginseng. A total of 265.2 million 100-bp clean reads were generated using the high-throughput sequencing platform HiSeq 2000, representing >8.3x of the 3.2-Gb ginseng genome. From the sequences, 248,993 unigenes were assembled for whole plant, 61,912-113,456 unigenes for each tissue and 54,444-65,412 unigenes for different year-old roots. We comprehensively analyzed the unigene sets and gene expression profiles. We found that the number of genes allocated to each functional category is stable across tissues or developmental stages, while the expression profiles of different genes of a gene family or involved in ginsenoside biosynthesis dramatically diversified spatially and temporally. These results provide an overall insight into the spatial and temporal transcriptome dynamics and landscapes of Asian ginseng, and comprehensive resources for advanced research and breeding of ginseng and related species. PMID- 26655865 TI - Systematic review of early exercise in intensive care: A qualitative approach. AB - INTRODUCTION: Practice guidelines recommend early physical therapy in intensive care units (ICU). Feasibility, safety and efficacy are confirmed by growing evidence-based data. PURPOSE: To perform a qualitative systematic literature review on early exercise in ICUs, focused on the subject areas of "how to do", "for which patients" and "for what benefits". METHODS: Articles were obtained from the PubMed, Google Scholar, Physiotherapy Evidence Database (PEDro), Embase, CINAHL, CENTRAL, Cochrane and ReeDOC databases. The full texts of references selected according to title and abstract were read. Data extraction and PEDro scoring were performed. Consort recommendations were used for the drafting of the systematic review, which was declared on the Prospero website. RESULTS: We confirm the feasibility and safety of early exercise in the ICU. Convergent evidence-based data are in favour of the efficacy of early exercise programs in ICUs. But the potential benefit of earlier program initiation has not been clearly demonstrated. Our analysis reveals tools and practical modalities that could serve to standardize these programs. The scientific literature mainly emphasizes the heterogeneity of targeted populations and lack of precision concerning multiple criteria for early exercise programs. CONCLUSION: Changes in the professional culture of multidisciplinary-ICU teams are necessary as concerns early exercise. Physical therapists must be involved and their essential role in the ICU is clearly justified. Although technical difficulties and questions remain, the results of the present qualitative review should encourage the early and progressive implementation of exercise programs in the ICU. PMID- 26655866 TI - Intrinsic foot muscle volume in experienced runners with and without chronic plantar fasciitis. AB - OBJECTIVES: Plantar fasciitis, a common injury in runners, has been speculated to be associated with weakness of the intrinsic foot muscles. A recent study reported that atrophy of the intrinsic forefoot muscles might contribute to plantar fasciitis by destabilizing the medial longitudinal arch. However, intrinsic foot muscle volume difference between individuals with plantar fasciitis and healthy counterparts remains unknown. This study examined the relationship of intrinsic foot muscle volume and incidence of plantar fasciitis. DESIGN: Case-control study. METHODS: 20 experienced (>=5 years) runners were recruited. Ten of them had bilateral chronic (>=2 years) plantar fasciitis while the others were healthy characteristics-matched runners. Intrinsic muscle volumes of the participants' right foot were scanned with a 1.5T magnetic resonance system and segmented using established methods. Body-mass normalized intrinsic foot muscle volumes were compared between runners with and without chronic plantar fasciitis. RESULTS: There was significant greater rearfoot intrinsic muscle volume in healthy runners than runners with chronic plantar fasciitis (Cohen's d=1.13; p=0.023). A similar trend was also observed in the total intrinsic foot muscle volume but it did not reach a statistical significance (Cohen's d=0.92; p=0.056). Forefoot volume was similar between runners with and without plantar fasciitis. CONCLUSIONS: These results suggest that atrophy of intrinsic foot muscles may be associated with symptoms of plantar fasciitis in runners. These findings may provide useful information in rehabilitation strategies of chronic plantar fasciitis. PMID- 26655867 TI - PET Radioligands Reveal the Basis of Dementia in Parkinson's Disease and Dementia with Lewy Bodies. AB - BACKGROUND: Effective therapies for dementia with Lewy bodies (DLB) and Parkinson's disease (PD) dementia will require accurate diagnosis and an understanding of the contribution of distinct molecular pathologies to these diseases. We seek to use imaging biomarkers to improve diagnostic accuracy and to clarify the contribution of molecular species to cognitive impairment in DLB and PD. SUMMARY: We have performed cross-sectional and prospective cohort studies in subjects with DLB, PD with normal cognition, PD with mild cognitive impairment and PD with dementia, contrasted with Alzheimer's disease (AD) and healthy control subjects (HCS). Subjects underwent formal neurological examination, detailed neuropsychological assessments, MRI and PET scans with the radioligands altropane (a dopamine transporter, DAT) and Pittsburgh compound B (PiB; beta amyloid). Putamen DAT concentrations were similar in DLB and PD and differentiated them from HCS and AD. Decreased caudate DAT concentration related to functional impairment in DLB but not PD. PiB uptake was greatest in DLB. However, cortical PiB retention was common in PD and predicted cognitive decline. PET imaging of tau aggregates holds promise both to clarify the contribution of tau to cognitive decline in these diseases and to differentiate DLB and PD from the parkinsonian tauopathies. KEY MESSAGES: Together, DAT and amyloid PET imaging discriminate DLB from PD and from other disease groups and identify pathological processes that contribute to their course. Multimodal PET imaging has the potential to increase the diagnostic accuracy of DLB and PD in the clinic, improve cohort uniformity for clinical trials, and serve as biomarkers for targeted molecular therapies. PMID- 26655868 TI - Immunological Insights into the Life and Times of the Extinct Tasmanian Tiger (Thylacinus cynocephalus). AB - The thylacine (Thylacinus cynocephalus) was Australia's largest marsupial carnivore until its extinction within the last century. There remains considerable interest and debate regarding the biology of this species. Studies of thylacine biology are now limited to preserved specimens, and parts thereof, as well as written historical accounts of its biology. This study describes the development of the immune tissues of a pouch young thylacine, one of only eleven in existence, and the only specimen to be histologically sectioned. The appearance of the immune tissue of the developing pouch young thylacine is compared to the immune tissues of extant marsupials, providing insights into the immunity, biology and ecology of the extinct thylacine. PMID- 26655869 TI - Differences in the Characteristics of Dialysis Patients in Japan Compared with Those in Other Countries. AB - BACKGROUND: Japanese patients undergoing dialysis have an extremely low mortality rate compared with those in the United States and Europe. As shown in the Dialysis Outcomes 38; Practice Patterns Study (DOPPS), certain features of dialysis treatment, such as single treatment time and amount of blood flow, are unique to Japan, but factors contributing to the low mortality risk are unclear. Although DOPPS is a multi-country prospective cohort study, the study results may not entirely reflect the real trend in Japan because the number of Japanese institutions participating in the study is small. SUMMARY: In this article, we review the data reported for Japan and other countries and reveal country specific differences, particularly in patient age distribution and duration of dialysis. KEY MESSAGES: The mean age of prevalent dialysis patients is rising every year in Japan, and the proportion of patients undergoing dialysis for long periods of time is also increasing. In addition, the proportion of dialysis patients with diabetes, one of the primary diseases, has increased to a level similar to that observed in Western countries. However, no significant decline in the crude death rate among prevalent dialysis patients has been observed in Japan, presumably because of technological advances in dialysis treatment, but further studies are needed to elucidate the contributing factors. PMID- 26655870 TI - Shear wave elastography: An accurate technique to stage liver fibrosis in chronic liver diseases. AB - OBJECTIVES: The goals of this study were to assess the diagnostic accuracy of shear wave elastography (SWE) using the results of histopathological analysis as a standard of reference and compare the results of SWE and those of transient elastography (TE) to the degree of fibrosis as evaluated by histomorphometry. PATIENTS AND METHODS: Adult patients who were scheduled to undergo liver biopsy were prospectively enrolled in the study. The diagnostic performances of SWE were assessed using AUROC curve analysis according to fibrosis thresholds defined by >=F2 (significant fibrosis), >=F3 (advanced fibrosis) and F4 (cirrhosis). Additional analyses using the Obuchowski measures for pairwise comparisons of fibrosis stages were performed. In a subgroup of 55 patients, the relationships between stiffness as measured using SWE and TE and the percentage of fibrosis were compared using Spearman's rank coefficient. RESULTS: Among the initially enrolled 170 patients, 148/170 (87%) had successful SWE acquisition and formed the study population. SWE sensitivity and specificity were respectively 85.1% and 82.7% (>=F2), 88.9% and 90.3% (>=F3), 93.3% and 98.3% (F4). The AUROC curves of SWE along with their 95% confidence intervals (CI) were respectively 0.904 (95%CI: 0.845-0.946) for fibrosis >=F2; 0.958 (95%CI: 0.912-0.984) for fibrosis >=F3 and 0.988 (95%CI: 0.955-0.999) for fibrosis=F4. The global Obuchowski measure was 0.953+/-0.007. In the subgroup study, a significant correlation was found between the percentage of fibrosis and stiffness as assessed by SWE (r=0.77; 95%CI: 0.63-0.86; P<0.0001) and by TE (r=0.65; 95%CI: 0.47-0.78; P<0.01). CONCLUSION: SWE is accurate to assess liver fibrosis in patients with chronic liver disease. PMID- 26655871 TI - Stent retriever thrombectomy for acute ischemic stroke: Indications, results and management in 2015. AB - The functional benefit of stent retriever thrombectomy in acute ischemic stroke has been clearly demonstrated in recent positive MR CLEAN, ESCAPE, EXTEND-IA, SWIFT PRIME, REVASCAT and THRACE trials. Thrombectomy, in association with intravenous thrombolysis, should now be offered to patients with documented occlusion of the distal internal carotid or proximal middle cerebral arteries, with a relatively normal unenhanced computed tomography (CT), and within 6hours after the onset of symptoms. Thrombectomy results in a mean absolute decrease in handicap of 22% (14 to 31%). Of the 3 up to 8 patients treated, 1 is independent at 3 months according to the initial selection. In case of a contraindication to thrombolysis, early primary thrombectomy should be considered. In acute basilar artery occlusion, thrombectomy should be performed alone or combined with thrombolysis. In an effort to increase the number of patients treated, a very rapid transfer to interventional neuroradiology centers is mandatory. In the future, thrombectomy should be evaluated in patients with distal arterial occlusion, or beyond 6hours after the onset of symptoms, or when the time of symptoms onset is unknown. PMID- 26655872 TI - Reduction of Candida biofilm adhesion by incorporation of prereacted glass ionomer filler in denture base resin. AB - OBJECTIVES: This study investigated the influence of surface reaction-type prereacted glass ionomer (S-PRG) fillers on Candida albicans adhesion on denture base resin. METHODS: Discs were prepared by incorporating the S-PRG filler into the polymer powder of a polymethyl methacrylate (PMMA)-based, heat-polymerizing resin at 0 (control), 5%, 10%, and 20% (w/w). The surface roughness of all disc surfaces was measured. Elemental analysis of released Na(+), Sr(2+), SiO3(2-), Al(3-), BO3(3-), and F(-) was performed after water immersion. Each disc was placed in a well with artificial saliva to form acquired pellicle, incubated, washed with phosphate-buffered saline, and immersed in a C. albicans (JCM2085) cell suspension standardized at 10(4) cells/ml. After aerobic incubation at 37 degrees C for 24 h, the metabolic mitochondrial activity, total biofilm biomass, and biofilm thickness were evaluated. The morphogenetic transition of C. albicans in the early culture stage (1 and 3 h) was observed. RESULTS: There was a slight but significant increase in the surface roughness with an increase in the filler content. The metabolic activity and total biomass volume were significantly lower in all filler groups than in the control group, although there were no significant differences among the filler groups. Groups with at least 5% filler content exhibited a thinner biofilm compared with the control group. All filler groups showed hyphal forms at 3 h, with the length of the hyphae being lesser than those in the control group. CONCLUSIONS: Although the incorporation of S-PRG filler slightly increases the surface roughness of denture base resin, it reduces the adhesion of C. albicans. CLINICAL SIGNIFICANCE: The S-PRG filler has the potential to reduce Candida albicans adhesion on denture base resin and may lower the risk of denture stomatitis. However, filler incorporation can increase the surface roughness of heat-polymerizing denture base resin. PMID- 26655873 TI - Ion release, fluoride charge of and adhesion of an orthodontic cement paste containing microcapsules. AB - OBJECTIVES: Dental materials capable of releasing calcium, phosphate and fluoride are of great interest for remineralization. Microencapsulated aqueous solutions of these ions in orthodontic cement demonstrate slow, sustained release by passive diffusion through a permeable membrane without the need for dissolution or etching of fillers. The potential to charge a dental material formulated with microencapsulated water with fluoride by toothbrushing with over the counter toothpaste and the effect of microcapsules on cement adhesion to enamel was determined. METHODS: Orthodontic cements that contained microcapsules with water and controls without microcapsules were brushed with over-the-counter toothpaste and fluoride release was measured. Adhesion measurements were performed loading orthodontic brackets to failure. Cements that contained microencapsulated solutions of 5.0M Ca(NO3)2, 0.8M NaF, 6.0MK2HPO4 or a mixture of all three were prepared. Ion release profiles were measured as a function of time. RESULTS: A greater fluoride charge and re-release from toothbrushing was demonstrated compared to a control with no microcapsules. Adhesion of an orthodontic cement that contained microencapsulated remineralizing agents was 8.5+/-2.5MPa compared to the control without microcapsules which was of 8.3+/-1.7MPa. Sustained release of fluoride, calcium and phosphate ions from cement formulated with microencapsulated remineralizing agents was demonstrated. CONCLUSIONS: Orthodontic cements with microcapsules show a release of bioavailable fluoride, calcium, and phosphate ions near the tooth surface while having the ability to charge with fluoride and not effect the adhesion of the material to enamel. Incorporation of microcapsules in dental materials is promising for promoting remineralization. PMID- 26655874 TI - Intracoronary imaging of coronary atherosclerosis: validation for diagnosis, prognosis and treatment. AB - While coronary atherosclerosis is a leading cause of mortality, evaluation of coronary lesions was previously limited to either indirect angiographic assessment of the lumen silhouette or post mortem investigations. Intracoronary (IC) imaging modalities have been developed that allow for visualization and characterization of coronary atheroma in living patients. Used alone or in combination, these modalities have enhanced our understanding of pathobiological mechanisms of atherosclerosis, identified factors responsible for disease progression, and documented the ability of various medications to reverse the processes of plaque growth and destabilization. These methodologies have established a link between in vivo plaque characteristics and subsequent coronary events, thereby improving individual risk stratification, paving the way for risk tailored systemic therapies and raising the option for pre-emptive interventions. Moreover, IC imaging is increasingly used during coronary interventions to support therapeutic decision-making in angiographically inconclusive disease, guide and optimize procedural results in selected lesion and patient subsets, and unravel mechanisms underlying stent failure. This review aims to summarize current evidence regarding the role of IC imaging for diagnosis and risk stratification of coronary atherosclerosis, and to describe its clinical role for guiding percutaneous coronary interventions. Future perspectives for in-depth plaque characterization using novel techniques and multimodality imaging approaches are also discussed. PMID- 26655875 TI - SPRINT: the race for optimal blood pressure control. PMID- 26655876 TI - Length of hospital stay after hip fracture and risk of early mortality after discharge in New York state: retrospective cohort study. AB - STUDY QUESTION: Can the length of hospital stay for hip fracture affect a patient's risk of death 30 days after discharge? METHODS: In a retrospective cohort study, population based registry data from the New York Statewide Planning and Research Cooperative System (SPARCS) were used to investigate 188,208 patients admitted to hospital for hip fracture in New York state from 2000 to 2011. Patients were aged 50 years and older, and received surgical or non surgical treatment. The main outcome measure was the mortality rate at 30 days after hospital discharge. STUDY ANSWER AND LIMITATIONS: Hospital stays of 11-14 days for hip fracture were associated with a 32% increased odds of death 30 days after discharge, compared with stays lasting one to five days (odds ratio 1.32 (95% confidence interval 1.19 to 1.47)). These odds increased to 103% for stays longer than 14 days (2.03 (1.84 to 2.24)). Other risk factors associated with early mortality included discharge to a hospice facility, older age, metastatic disease, and non-surgical management. The 30 day mortality rate after discharge was 4.5% for surgically treated patients and 10.7% for non-surgically treated patients. These findings might not be generalizable to populations in other US states or in other countries. The administrative claims data used could have been incomplete or include inaccurate coding of diagnoses and comorbid conditions. The database also did not include patient socioeconomic status, which could affect access to care to a greater extent in New York state than in European countries. Specific cause of death was not available because few autopsies are performed in this population. WHAT THIS STUDY ADDS: By contrast with recent findings in Sweden, decreased length of hospital stay for hip fracture was associated with reduced rates of early mortality in a US cohort in New York state. This could reflect critical system differences in the treatment of hip fractures between Europe and the USA.Funding, competing interests, data sharing University of Rochester grant from the Clinical Translational Science Institute for statistical analyses used in this work (National Institutes of Health (UL1 TR000042)) and the National Institutes of Health (K-08 AR060164-01A). No competing interests declared. Data may be obtained through SPARCS at https://www.health.ny.gov/statistics/sparcs/access/. PMID- 26655877 TI - The pentacyclic triterpene Lupeol switches M1 macrophages to M2 and ameliorates experimental inflammatory bowel disease. AB - BACKGROUND: Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, is a chronic inflammatory disease in the lower gastrointestinal tract. Mounting evidence suggests that the predominance of the classically activated (M1) macrophages versus the alternatively activated (M2) macrophages plays a role in the progression of IBD. Thus, agents able to shift pro inflammatory M1 macrophages to anti-inflammatory M2 macrophages may be beneficial to IBD. The pentacyclic triterpene Lup-20(29)-en-3beta-ol (Lupeol), a potent anti inflammatory natural product, has been shown to inhibit pro-inflammatory cytokine production, suggesting it is potentially able to modulate macrophage polarization, thereby beneficial to IBD. METHODS: CD4(+) monocytes were differentiated to M1 or M2 macrophages, which were cocultured with epithelial cell lines, T84 and Caco-2, in the absence or presence of Lupeol (10MUM). Experimental colitis was induced with dextran sodium sulfate (DSS), with or without oral administration of Lupeol (50mg/kg, q.d.). Cytokines were measured with Luminex kits. M1/M2 genes were measured with real-time polymerase chain reaction. Macrophage phenotypes were defined by measuring M1 and M2 markers with confocal microscopy. Proteins were measured with Western blotting, while cell surface markers were measured with confocal microscopy or flow cytometry. Histology was evaluated with H&E staining. RESULTS: Treatment of M1 macrophages with Lupeol resulted in a marked decrease in the production of pro-inflammatory cytokines, including IL-12, IL6, IL-1beta and TNFalpha, and a marked increase in the production of IL-10, an anti-inflammatory cytokine. This was associated with a down-regulation of CD86, a typical marker of M1 macrophages, and an up regulation of CD206, a typical M2 macrophage marker. IRF5, a transcription factor that is critically involved in M1 polarization, was down-regulated in M1 macrophages after being incubated with Lupeol, associated with a marked decrease in the phosphorylation of p38 mitogen activated protein kinase. Coculture of epithelial cells with M1 macrophages resulted in down-regulation of the tight junction protein ZO-1 and disruption of epithelial integrity, which were blocked by Lupeol treatment of the M1 macrophages. Moreover, oral administration of Lupeol to dextran sulfate sodium (DSS)-induced colitis mice resulted in mitigated intestinal inflammation and increased survival from lethal colitis, associated with decreased expression of M1-related genes and increased expression of M2 related genes. CONCLUSION: Lupeol ameliorates experimental inflammatory bowel disease through, at least in part, inhibiting M1 and promoting M2 macrophages. PMID- 26655879 TI - Vitamin D3 enhances bactericidal activity of macrophage against Pseudomonas aeruginosa. AB - BACKGROUND: The bioactive form of vitamin D3, i.e.1,25-dihydroxyvitamin D3 (1,25(OH)2D3) vitamin D has been shown to modulate monocytes/macrophages physiology and its response against bacterial infections. Pseudomonas aeruginosa (P. aeruginosa) is an opportunistic bacterial pathogen that can most frequently be fatal in immunocompromised infected people. METHODS: We investigated the ex vivo effect of 1,25(OH)2D3 on monocyte-derived macrophages function against P. aeruginosa infection. RESULTS: Relative vitamin D receptor (VDR) mRNA expression was significantly increased in infected and 1,25(OH)2D3-treated macrophages compared to controls (p<0.01). Treatment with 1,25(OH)2D3 markedly resulted in up regulation of nitric oxide (NO) and IL-1beta production and down-regulation of IL 10 levels (respectively, p=0.029, p=0.048 and p=0.008). Additionally, 1,25(OH)2D3 significantly increased M1/M2 macrophage ratio (p<0.05) and slightly reduced intracellular bacterial development. Furthermore, the arginase activity, P. aeruginosa phagocytosis and killing were significantly increased in cells that were both infected and 1,25(OH)2D3-treated compared to the infected, but not 1,25(OH)2D3-treated macrophages (respectively, p<0.001, p<0.01 and p<0.001). CONCLUSIONS: We show in this study that bioactive from of vitamin D [1,25 dihydroxyvitamin D3 (1,25D3)] can enhance M1 macrophage polarization and their bactericidal protective activity against P. aeruginosa. Future works would involve improving the treatment response through dose-dependent effect studies, both in ex vivo and in vivo models. PMID- 26655878 TI - Protective effects of Yinhuapinggan granule on mice with influenza viral pneumonia. AB - Yinhuapinggan granule (YHPG), a Chinese medicine granule on the basis of Ma-Huang Tang (Ephedra Decoction) and the clinical experience of Professor Wan Haitong, has been shown to inhibit the growth of influenza virus in vitro. The aim of this study was to investigate the protective effects of YHPG on mice with influenza viral pneumonia and its effects on regulating related inflammatory cytokines in influenza virus A-infected mice. ICR mice were inoculated intranasally with 15 LD50 viral dose of influenza virus A/PR/8/34 (H1N1) and treatments with YHPG (7.5, 15 and 30g/kg) were orally administrated daily for 5 consecutive days after challenge, respectively. The results showed that mortality rate, lung index, lung histopathological changes, IL-6 and TNF-alpha in serum were significantly attenuated in the treatment of YHPG (15 and 30g/kg) than those in the IFV control group, while the levels of IL-2 was significantly enhanced. Moreover, the RT-PCR results revealed that YHPG (15 and 30g/kg) significantly depressed the expressions of IL-1beta, IFN-gamma and TNF-alpha mRNA in lung tissues. Furthermore, the immunohistochemical staining results also revealed that the expression of NF-kappaB p65 proteins was downregulated when treated with YHPG (15 and 30g/kg). These results showed YHPG has protective effects on IFV-infected mice, due to its ability of alleviation of lung damage, regulation of the cytokine production via inhibiting the NF-kappaB p65 activation, attenuation of systemic and pulmonary inflammatory responses. PMID- 26655880 TI - Naringenin ameliorates inflammation and cell proliferation in benzo(a)pyrene induced pulmonary carcinogenesis by modulating CYP1A1, NFkappaB and PCNA expression. AB - Lung cancer is the major cause of cancer-related mortality and is a growing economic burden worldwide. Chemoprevention has emerged as a very effective preventive measure against carcinogenesis and several bioactive compounds in diet have shown their cancer curative potential on lung cancer. Naringenin (NRG), a predominant flavanone found in citrus fruits has been reported to possess anti oxidative, anti-inflammatory and anti-proliferative activity in a wide variety of cancer. The aim of the present study is to divulge the chemopreventive nature of NRG against benzo(a)pyrene (B[a]P) induced lung carcinogenesis in Swiss albino mice. Administration of B[a]P (50mg/kg, p.o.) to mice resulted in increased lipid peroxidation (LPO), proinflammatory cytokines (TNF-alpha, IL-6 and IL-1beta) with subsequent decrease in activities of tissue enzymic antioxidants (SOD, CAT, GPx, GR, GST) and non-enzymic antioxidants (GSH and Vit-C). Treatment with NRG (50mg/kg body weight) significantly counteracted all these alterations thereby showing potent anti-cancer effect in lung cancer. Moreover, assessment of protein expression by immunoblotting and mRNA expression by RT-PCR revealed that NRG treatment effectively negates B[a]P-induced upregulated expression of CYP1A1, PCNA and NF-kappaB. Further, the antiproliferative effect of NRG was confirmed by histopathological analysis and PCNA immunostaining in B[a]P induced mice which showed increased PCNA expression that was restored upon NRG administration. Overall, these findings substantiate the chemopreventive potential of NRG against chemically induced lung cancer in mice. PMID- 26655881 TI - [Use of opioids in palliative care of children with advanced cancer]. AB - INTRODUCTION: Despite advances in the treatment of cancer in paediatric patients, 15% of children die from the illness progression in Chile, and pain is the most significant symptom in advanced stages. Although the World Health Organization guidelines demonstrate that opioids are fundamental in pain management, there is still resistance to their use. The main objective of this article was to describe the experience in the use of opioids for pain management in paediatric patients with advanced cancer in palliative care (PC). PATIENTS AND METHOD: Retrospective study of patients admitted into the PC Program at the Hospital Roberto del Rio between 2002 and 2013. Analysis was carried out on demographic data; oncological diagnosis; pain intensity on admission and discharge, according to validated scales; use of non-steroidal anti-inflammatory drugs; weak opioids; strong opioids; adjuvants drugs; the presence of secondary effects resulting from the use of morphine, and the need for palliative sedation. RESULTS: Of the 99 medical records analysed, the median age was 8 years, 64.6% were male, and there was a similar distribution in three oncological diagnosis groups. Upon admission, 43.4% presented intense to severe pain, and upon discharge there were four patients, but with a maximum VAS score of 7 in only one case. Of the 66 patients taking strong opioids, 89% required less than 0.5mg/kg/hr. Constipation was the most frequently observed secondary effect. CONCLUSIONS: Two thirds of the patients studied required strong opioids, with which adequate pain management was achieved, with no serious complications observed. The use of opioids in this group of patients, following a protocol, is considered effective and safe. PMID- 26655882 TI - Gene silencing of TACE enhances plaque stability and improves vascular remodeling in a rabbit model of atherosclerosis. AB - We aimed to test the hypothesis that gene silencing of tumor necrosis factor alpha converting enzyme (TACE) may attenuate lesion inflammation and positive vascular remodeling and enhance plaque stability in a rabbit model of atherosclerosis. Lentivirus-mediated TACE shRNA was injected into the abdominal aortic plaques of rabbits which effectively down-regulated TACE expression and activities from week 8 to week 16. TACE gene silencing reduced remodeling index and plaque burden, and diminished the content of macrophages and lipids while increased that of smooth muscle cells and collagen in the aortic plaques. In addition, TACE gene silencing attenuated the local expression of P65, iNOS, ICAM 1, VEGF and Flt-1 and activities of MMP9 and MMP2 while increased the local expression of TGF-beta1 together with reduced number of neovessels in the aorta. TACE shRNA treatment resulted in down-regulated expression of TACE in macrophages and blunted ERK-P38 phosphorylation and tube formation of co-cultured mouse vascular smooth muscle cells or human umbilical vein endothelial cells. In conclusion, gene silencing of TACE enhanced plaque stability and improved vascular positive remodeling. The mechanisms may involve attenuated local inflammation, neovascularization and MMP activation, as well as enhanced collagen production probably via down-regulated ERK-NF-kappaB and up-regulated TGF-beta1 signaling pathways. PMID- 26655883 TI - Infection of human keratinocytes by Streptococcus dysgalactiae subspecies dysgalactiae isolated from milk of the bovine udder. AB - Streptococcus dysgalactiae subsp. dysgalactiae (SDSD) are considered exclusive animal pathogens; however, a putative zoonotic upper limb cellulitis, a prosthetic joint infection and an infective endocarditis were described in humans. To unravel if bovine SDSD isolates are able to infect human cells, the adherence and internalization to human primary keratinocytes of two bovine SDSD strains isolated from milk collected from udder were analyzed. Bacterial adhesion assays and confocal microscopy indicate a high adherence and internalization of SDSD isolates to human cells, suggesting for the first time the ability of bovine isolates to infect human cells. PMID- 26655884 TI - Construction of a new shuttle vector for DNA delivery into mammalian cells using non-invasive Lactococcus lactis. AB - Use of food grade Lactococcus lactis (L. lactis) is fast emerging as a safe alternative for delivery of DNA vaccine. To attain efficient DNA delivery, L. lactis, a non-invasive bacterium is converted to invasive strain either by expressing proteins like Internalin A (InlA) or Fibronectin binding protein A (FnBPA) or through chemical treatments. However the safety status of invasive L. lactis is questionable. In the present report, we have shown that non-invasive L. lactis efficiently delivered the newly constructed reporter plasmid pPERDBY to mammalian cells without any chemical enhancers. The salient features of the vector are; I) Ability to replicate in two different hosts; Escherichia coli (E. coli) and Lactic Acid Bacteria (LAB), II) One of the smallest reporter plasmid for DNA vaccine, III) Enhanced Green Fluorescence Protein (EGFP) linked to Multiple Cloning Site (MCS), IV) Immunostimulatory CpG motifs functioning as an adjuvant. Expression of EGFP in pPERDBY transfected CHO-K1 and Caco-2 cells demonstrates its functionality. Non-invasive r-L. lactis was found efficient in delivering pPERDBY to Caco-2 cells. The in vitro data presented in this article supports the hypothesis that in the absence of invasive proteins or relevant chemical treatment, L. lactis was found efficient in delivering DNA to mammalian cells. PMID- 26655885 TI - Endovenous laser ablation of the great saphenous vein - Varying energy may not affect outcome. AB - Objectives To determine great saphenous vein occlusion rate after endovenous laser ablation using the 1470-nm bare-fiber diode laser to supply either 7 W or 15 W and evaluate procedure-related complications. Method Patients with varicose veins of the lower extremities (CEAP class C2-C6) were randomly assigned to undergo either 7-W (18 patients, 30 limbs) or 15-W (18 patients, 30 limbs) endovenous laser ablation. Duplex ultrasound follow-up was at 3-5 days, 1, 6, and 12 months postoperatively. Results Occlusion rate was 100% in both groups at 3-5 days and 1 month and 86.7% in 7-W and 100% in 15-W patients at both 6 and 12 months, with no difference between groups ( p > 0.05). Four (13.3%) 15-W and 3 (10%) 7-W patients had paresthesia at 3-5 days, with no difference between groups ( p > 0.05). Conclusions These preliminary data suggest that both techniques are similarly effective in the treatment of varicose great saphenous veins. PMID- 26655886 TI - Pharmacological adjuncts for chronic venous ulcer healing. PMID- 26655887 TI - Nanoindentation of hcp metals: a comparative simulation study of the evolution of dislocation networks. AB - Using molecular dynamics simulation, we study the nanoindentation of three hcp metals: Mg, Ti, and Zr. Both the basal and two prismatic surface planes are considered. We focus on the characterization of the plasticity generated in the crystal. The similarities to, and the differences from, the behavior of the more commonly investigated fcc and bcc metals are highlighted. We find that hcp metals show a larger variety than the fcc and bcc metals studied up until now. The prolific emission of prismatic loops can lead to extended plastic zones. The size of the plastic zone is quantified by the ratio f of the plastic zone radius to the radius of the contact area. We find values of between 1.6 (an almost collapsed zone) and >5; in the latter case, complex dislocation networks build up which are extended in the direction of easy glide. PMID- 26655888 TI - Short-Term Effects of Kefir-Fermented Milk Consumption on Bone Mineral Density and Bone Metabolism in a Randomized Clinical Trial of Osteoporotic Patients. AB - Milk products are good sources of calcium that may reduce bone resorption and help prevent bone loss as well as promote bone remodeling and increase bone formation. Kefir is a product made by kefir grains that degrade milk proteins into various peptides with health-promoting effects, including antithrombotic, antimicrobial and calcium-absorption enhancing bioactivities. In a controlled, parallel, double-blind intervention study over 6 months, we investigated the effects of kefir-fermented milk (1,600 mg) supplemented with calcium bicarbonate (CaCO3, 1,500 mg) and bone metabolism in 40 osteoporosis patients, and compared them with CaCO3 alone without kefir supplements. Bone turnover markers were measured in fasting blood samples collected before therapy and at 1, 3, and 6 months. Bone mineral density (BMD) values at the spine, total hip, and hip femoral neck were assessed by dual-energy x-ray absorptiometry (DXA) at baseline and at 6 months. Among patients treated with kefir-fermented milk, the relationships between baseline turnover and 6 months changes in DXA-determined BMD were significantly improved. The serum beta C-terminal telopeptide of type I collagen (beta-CTX) in those with T-scores > -1 patients significantly decreased after three months treatment. The formation marker serum osteocalcin (OC) turned from negative to positive after 6 months, representing the effect of kefir treatment. Serum parathyroid hormone (PTH) increased significantly after treatment with kefir, but decreased significantly in the control group. PTH may promote bone remodeling after treatment with kefir for 6 months. In this pilot study, we concluded that kefir-fermented milk therapy was associated with short term changes in turnover and greater 6-month increases in hip BMD among osteoporotic patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT02361372. PMID- 26655889 TI - Reward devaluation and heroin escalation is associated with differential expression of CRF signaling genes. AB - One of the most damaging aspects of drug addiction is the degree to which natural rewards (family, friends, employment) are devalued in favor of seeking, obtaining and taking drugs. We have utilized an animal model of reward devaluation and heroin self-administration to explore the role of the coricotropin releasing factor (CRF) pathway. Given access to a saccharin cue followed by the opportunity to self-administer heroin, animals will parse into distinct phenotypes that suppress their saccharin intake (in favor of escalating heroin self administration) or vice versa. We find that large saccharin suppressors (large heroin takers) demonstrate increased mRNA expression for elements of the CRF signaling pathway (CRF, CRF receptors and CRF binding protein) within the hippocampus, medial prefrontal cortex and the ventral tegmental area. Moreover, there were no gene expression changes of these components in the nucleus accumbens. Use of bisulfite conversion sequencing suggests that changes in CRF binding protein and CRF receptor gene expression may be mediated by differential promoter methylation. PMID- 26655890 TI - Discrimination of shape and size sues by day-old chicks in two one-trial learning tasks. AB - The ability of day-old chicks (Gallus gallus domesticus) to discriminate between the shape and size of beads was investigated in two one-trial tasks, taste avoidance and sickness-conditioned learning. Previous studies determined that color is a critical classification cue for conditioned stimuli in these tasks. In taste avoidance learning, a chick pecks a bead coated with a bitter substance. In sickness-conditioned learning, chicks peck a dry bead and are injected 30min later with lithium chloride. Chicks could discriminate beads of different sizes, but not different shapes, when trained in the taste avoidance task, whereas in the sickness-conditioned learning task, chicks could discriminate shape, but not size. These results suggest that chicks use a number of classificatory cues to remember an avoidance response, and, in the absence of color cues, chicks rely on different cues for different learning tasks. PMID- 26655891 TI - How Betta splendens finds its way. AB - This study investigated the Siamese fighting fish Betta splendens performance in associating a stimulus with a specific cue when distractors are present. After trained to associate a specific color cue to a stimulus (conspecific) in a tank containing three colored distractors, the fish was challenged to locate the exact place where the stimulus fish was presented. With only color cues as guides, the Siamese fighting fish spent most of its time close to the color where the stimulus fish was previously presented, regardless of the distractors. However, fish trained to associate an empty place (no cues) to a stimulus fish, and then tested to localize the specific zone where the stimulus was shown, succeeded to locate the place even without any obvious cues/distractors for orientation. This study confirms that Siamese fighting fish show good conditioned learning and cannot be distracted by other stimuli. In addition, an unexpected good performance in the absence of cues may suggest the Betta's ability to orientate by using another sensorial modalities, as magnetic orientation. Collectively, the results of this study confirm Betta as a valid and reliable model for learning and memory tests, and suggest more studies should be developed for the better understanding of the fish's spatial orientation mechanisms. PMID- 26655892 TI - Impact of Maternal and Child Race on Maternal Ratings of ADHD Symptoms in Black and White Boys. AB - OBJECTIVE: Examine the influence of maternal and child race on ADHD symptom ratings. METHOD: Participants were Black ( n = 63) and White ( n = 68) mothers randomly assigned to view a 13-min videotape of either a Black or White boy displaying similar levels of ADHD-related behaviors during free play and meal situations. Mothers then completed an ADHD rating scale. RESULTS: With maternal age and socioeconomic status (SES) as covariates, Black mothers provided significantly higher ratings of inattentive and hyperactive-impulsive symptoms than did White mothers regardless of child race. The effect of child race was not statistically significant. CONCLUSIONS: Maternal race appears to be more important than child race in accounting for differences in ADHD symptom ratings between Black and White boys. It is critical to understand variables related to these differences and develop assessment measures that lead to equivalent, accurate diagnostic decisions across racial subgroups. PMID- 26655893 TI - In Vivo Ca(2+) Imaging Reveals that Decreased Dendritic Excitability Drives Startle Habituation. AB - Exposure to repetitive startling stimuli induces habitation, a simple form of learning. Despite its simplicity, the precise cellular mechanisms by which repeated stimulation converts a robust behavioral response to behavioral indifference are unclear. Here, we use head-restrained zebrafish larvae to monitor subcellular Ca(2+) dynamics in Mauthner neurons, the startle command neurons, during startle habituation in vivo. Using the Ca(2+) reporter GCaMP6s, we find that the amplitude of Ca(2+) signals in the lateral dendrite of the Mauthner neuron determines startle probability and that depression of this dendritic activity rather than downstream inhibition mediates glycine and N methyl-D-aspartate (NMDA)-receptor-dependent short-term habituation. Combined, our results suggest a model for habituation learning in which increased inhibitory drive from feedforward inhibitory neurons combined with decreased excitatory input from auditory afferents decreases dendritic and Mauthner neuron excitability. PMID- 26655894 TI - Activation of a Temporal Memory in Purkinje Cells by the mGluR7 Receptor. AB - Cerebellar Purkinje cells can learn to respond to a conditioned stimulus with an adaptively timed pause in firing. This response was usually ascribed to long-term depression of parallel fiber to Purkinje cell synapses but has recently been shown to be due to a previously unknown form of learning involving an intrinsic cellular timing mechanism. Here, we investigate how these responses are elicited. They are resistant to blockade of GABAergic inhibition, suggesting that they are caused by glutamate release rather than by a changed balance between GABA and glutamate. We show that the responses are abolished by antagonists of the mGlu7 receptor but not significantly affected by other glutamate antagonists. These results support the existence of a distinct learning mechanism, different from changes in synaptic strength. They also demonstrate in vivo post-synaptic inhibition mediated by glutamate and show that the mGlu7 receptor is involved in activating intrinsic temporal memory. PMID- 26655895 TI - Definition of a Bidirectional Activity-Dependent Pathway Involving BDNF and Narp. AB - One of the cardinal features of neural development and adult plasticity is the contribution of activity-dependent signaling pathways. However, the interrelationships between different activity-dependent genes are not well understood. The immediate early gene neuronal-activity-regulated pentraxin (NPTX2 or Narp) encodes a protein that has been associated with excitatory synaptogenesis, AMPA receptor aggregation, and the onset of critical periods. Here, we show that Narp is a direct transcriptional target of brain-derived neurotrophic factor (BDNF), another highly regulated activity-dependent gene involved in synaptic plasticity. Unexpectedly, Narp is bidirectionally regulated by BDNF. Acute BDNF withdrawal results in downregulation of Narp, whereas transcription of Narp is greatly enhanced by BDNF. Furthermore, our results show that BDNF directly regulates Narp to mediate glutamatergic transmission and mossy fiber plasticity. Hence, Narp serves as a significant epistatic target of BDNF to regulate synaptic plasticity during periods of dynamic activity. PMID- 26655896 TI - The Angiocrine Factor Rspondin3 Is a Key Determinant of Liver Zonation. AB - Liver zonation, the spatial separation of different metabolic pathways along the liver sinusoids, is fundamental for proper functioning of this organ, and its disruption can lead to the development of metabolic disorders such as hyperammonemia. Metabolic zonation involves the induction of beta-catenin signaling around the central veins, but how this patterned activity is established and maintained is unclear. Here, we show that the signaling molecule Rspondin3 is specifically expressed within the endothelial compartment of the central vein. Conditional deletion of Rspo3 in mice disrupts activation of central fate, demonstrating its crucial role in determining and maintaining beta catenin-dependent zonation. Moreover, ectopic expression of Rspo1, a close family member of Rspo3, induces the expression of pericentral markers, demonstrating Rspondins to be sufficient to imprint a more central fate. Thus, Rspo3 is a key angiocrine factor that controls metabolic zonation of liver hepatocytes. PMID- 26655897 TI - Structural and Dynamic Basis for Low-Affinity, High-Selectivity Binding of L Glutamine by the Glutamine Riboswitch. AB - Naturally occurring L-glutamine riboswitches occur in cyanobacteria and marine metagenomes, where they reside upstream of genes involved in nitrogen metabolism. By combining X-ray, NMR, and MD, we characterized an L-glutamine-dependent conformational transition in the Synechococcus elongatus glutamine riboswitch from tuning fork to L-shaped alignment of stem segments. This transition generates an open ligand-binding pocket with L-glutamine selectivity enforced by Mg(2+)-mediated intermolecular interactions. The transition also stabilizes the P1 helix through a long-range "linchpin" Watson-Crick G-C pair-capping interaction, while melting a short helix below P1 potentially capable of modulating downstream readout. NMR data establish that the ligand-free glutamine riboswitch in Mg(2+) solution exists in a slow equilibrium between flexible tuning fork and a minor conformation, similar, but not identical, to the L-shaped bound conformation. We propose that an open ligand-binding pocket combined with a high conformational penalty for forming the ligand-bound state provide mechanisms for reducing binding affinity while retaining high selectivity. PMID- 26655898 TI - Autonomy and Non-autonomy of Angiogenic Cell Movements Revealed by Experiment Driven Mathematical Modeling. AB - Angiogenesis is a multicellular phenomenon driven by morphogenetic cell movements. We recently reported morphogenetic vascular endothelial cell (EC) behaviors to be dynamic and complex. However, the principal mechanisms orchestrating individual EC movements in angiogenic morphogenesis remain largely unknown. Here we present an experiment-driven mathematical model that enables us to systematically dissect cellular mechanisms in branch elongation. We found that cell-autonomous and coordinated actions governed these multicellular behaviors, and a cell-autonomous process sufficiently illustrated essential features of the morphogenetic EC dynamics at both the single-cell and cell-population levels. Through refining our model and experimental verification, we further identified a coordinated mode of tip EC behaviors regulated via a spatial relationship between tip and follower ECs, which facilitates the forward motility of tip ECs. These findings provide insights that enhance our mechanistic understanding of not only angiogenic morphogenesis, but also other types of multicellular phenomenon. PMID- 26655899 TI - Vegfc Regulates Bipotential Precursor Division and Prox1 Expression to Promote Lymphatic Identity in Zebrafish. AB - Lymphatic vessels arise chiefly from preexisting embryonic veins. Genetic regulators of lymphatic fate are known, but how dynamic cellular changes contribute during the acquisition of lymphatic identity is not understood. We report the visualization of zebrafish lymphatic precursor cell dynamics during fate restriction. In the cardinal vein, cellular commitment is linked with the division of bipotential Prox1-positive precursor cells, which occurs immediately prior to sprouting angiogenesis. Following precursor division, identities are established asymmetrically in daughter cells; one daughter cell becomes lymphatic and progressively upregulates Prox1, and the other downregulates Prox1 and remains in the vein. Vegfc drives cell division and Prox1 expression in lymphatic daughter cells, coupling signaling dynamics with daughter cell fate restriction and precursor division. PMID- 26655900 TI - Loss of BAF (mSWI/SNF) Complexes Causes Global Transcriptional and Chromatin State Changes in Forebrain Development. AB - BAF (Brg/Brm-associated factors) complexes play important roles in development and are linked to chromatin plasticity at selected genomic loci. Nevertheless, a full understanding of their role in development and chromatin remodeling has been hindered by the absence of mutants completely lacking BAF complexes. Here, we report that the loss of BAF155/BAF170 in double-conditional knockout (dcKO) mice eliminates all known BAF subunits, resulting in an overall reduction in active chromatin marks (H3K9Ac), a global increase in repressive marks (H3K27me2/3), and downregulation of gene expression. We demonstrate that BAF complexes interact with H3K27 demethylases (JMJD3 and UTX) and potentiate their activity. Importantly, BAF complexes are indispensable for forebrain development, including proliferation, differentiation, and cell survival of neural progenitor cells. Our findings reveal a molecular mechanism mediated by BAF complexes that controls the global transcriptional program and chromatin state in development. PMID- 26655901 TI - The Conformation of Yeast Chromosome III Is Mating Type Dependent and Controlled by the Recombination Enhancer. AB - Mating-type switching in yeast occurs through gene conversion between the MAT locus and one of two silent loci (HML or HMR) on opposite ends of the chromosome. MATa cells choose HML as template, whereas MATalpha cells use HMR. The recombination enhancer (RE) located on the left arm regulates this process. One long-standing hypothesis is that switching is guided by mating-type-specific and possibly RE-dependent chromosome folding. Here, we use Hi-C, 5C, and live-cell imaging to characterize the conformation of chromosome III in both mating types. We discovered a mating-type-specific conformational difference in the left arm. Deletion of a 1-kb subregion within the RE, which is not necessary during switching, abolished mating-type-dependent chromosome folding. The RE is therefore a composite element with one subregion essential for donor selection during switching and a separate region involved in modulating chromosome conformation. PMID- 26655902 TI - Cycling Transcriptional Networks Optimize Energy Utilization on a Genome Scale. AB - Genes expressing circadian RNA rhythms are enriched for metabolic pathways, but the adaptive significance of cyclic gene expression remains unclear. We estimated the genome-wide synthetic and degradative cost of transcription and translation in three organisms and found that the cost of cycling genes is strikingly higher compared to non-cycling genes. Cycling genes are expressed at high levels and constitute the most costly proteins to synthesize in the genome. We demonstrate that metabolic cycling is accelerated in yeast grown under higher nutrient flux and the number of cycling genes increases ~40%, which are achieved by increasing the amplitude and not the mean level of gene expression. These results suggest that rhythmic gene expression optimizes the metabolic cost of global gene expression and that highly expressed genes have been selected to be downregulated in a cyclic manner for energy conservation. PMID- 26655903 TI - Inactivation of the Class II PI3K-C2beta Potentiates Insulin Signaling and Sensitivity. AB - In contrast to the class I phosphoinositide 3-kinases (PI3Ks), the organismal roles of the kinase activity of the class II PI3Ks are less clear. Here, we report that class II PI3K-C2beta kinase-dead mice are viable and healthy but display an unanticipated enhanced insulin sensitivity and glucose tolerance, as well as protection against high-fat-diet-induced liver steatosis. Despite having a broad tissue distribution, systemic PI3K-C2beta inhibition selectively enhances insulin signaling only in metabolic tissues. In a primary hepatocyte model, basal PI3P lipid levels are reduced by 60% upon PI3K-C2beta inhibition. This results in an expansion of the very early APPL1-positive endosomal compartment and altered insulin receptor trafficking, correlating with an amplification of insulin induced, class I PI3K-dependent Akt signaling, without impacting MAPK activity. These data reveal PI3K-C2beta as a critical regulator of endosomal trafficking, specifically in insulin signaling, and identify PI3K-C2beta as a potential drug target for insulin sensitization. PMID- 26655904 TI - The Genomic Landscape of Renal Oncocytoma Identifies a Metabolic Barrier to Tumorigenesis. AB - Oncocytomas are predominantly benign neoplasms possessing pathogenic mitochondrial mutations and accumulation of respiration-defective mitochondria, characteristics of unknown significance. Using exome and transcriptome sequencing, we identified two main subtypes of renal oncocytoma. Type 1 is diploid with CCND1 rearrangements, whereas type 2 is aneuploid with recurrent loss of chromosome 1, X or Y, and/or 14 and 21, which may proceed to more aggressive eosinophilic chromophobe renal cell carcinoma (ChRCC). Oncocytomas activate 5' adenosine monophosphate-activated protein kinase (AMPK) and Tp53 (p53) and display disruption of Golgi and autophagy/lysosome trafficking, events attributed to defective mitochondrial function. This suggests that the genetic defects in mitochondria activate a metabolic checkpoint, producing autophagy impairment and mitochondrial accumulation that limit tumor progression, revealing a novel tumor-suppressive mechanism for mitochondrial inhibition with metformin. Alleviation of this metabolic checkpoint in type 2 by p53 mutations may allow progression to eosinophilic ChRCC, indicating that they represent higher risk. PMID- 26655905 TI - Dectin-1 Regulates Hepatic Fibrosis and Hepatocarcinogenesis by Suppressing TLR4 Signaling Pathways. AB - Dectin-1 is a C-type lectin receptor critical in anti-fungal immunity, but Dectin 1 has not been linked to regulation of sterile inflammation or oncogenesis. We found that Dectin-1 expression is upregulated in hepatic fibrosis and liver cancer. However, Dectin-1 deletion exacerbates liver fibro-inflammatory disease and accelerates hepatocarcinogenesis. Mechanistically, we found that Dectin-1 protects against chronic liver disease by suppressing TLR4 signaling in hepatic inflammatory and stellate cells. Accordingly, Dectin-1(-/-) mice exhibited augmented cytokine production and reduced survival in lipopolysaccharide (LPS) mediated sepsis, whereas Dectin-1 activation was protective. We showed that Dectin-1 inhibits TLR4 signaling by mitigating TLR4 and CD14 expression, which are regulated by Dectin-1-dependent macrophage colony stimulating factor (M-CSF) expression. Our study suggests that Dectin-1 is an attractive target for experimental therapeutics in hepatic fibrosis and neoplastic transformation. More broadly, our work deciphers critical cross-talk between pattern recognition receptors and implicates a role for Dectin-1 in suppression of sterile inflammation, inflammation-induced oncogenesis, and LPS-mediated sepsis. PMID- 26655906 TI - The DNA Sensor AIM2 Maintains Intestinal Homeostasis via Regulation of Epithelial Antimicrobial Host Defense. AB - Microbial pattern molecules in the intestine play immunoregulatory roles via diverse pattern recognition receptors. However, the role of the cytosolic DNA sensor AIM2 in the maintenance of intestinal homeostasis is unknown. Here, we show that Aim2(-/-) mice are highly susceptible to dextran sodium sulfate-induced colitis that is associated with microbial dysbiosis as represented by higher colonic burden of commensal Escherichia coli. Colonization of germ-free mice with Aim2(-/-) mouse microbiota leads to higher colitis susceptibility. In-depth investigation of AIM2-mediated host defense responses reveals that caspase-1 activation and IL-1beta and IL-18 production are compromised in Aim2(-/-) mouse colons, consistent with defective inflammasome function. Moreover, IL-18 infusion reduces E. coli burden as well as colitis susceptibility in Aim2(-/-) mice. Altered microbiota in inflammasome-defective mice correlate with reduced expression of several antimicrobial peptides in intestinal epithelial cells. Together, these findings implicate DNA sensing by AIM2 as a regulatory mechanism for maintaining intestinal homeostasis. PMID- 26655907 TI - ADF and Cofilin1 Control Actin Stress Fibers, Nuclear Integrity, and Cell Survival. AB - Genetic co-depletion of the actin-severing proteins ADF and CFL1 triggers catastrophic loss of adult homeostasis in multiple tissues. There is impaired cell-cell adhesion in skin keratinocytes with dysregulation of E-cadherin, hyperproliferation of differentiated cells, and ultimately apoptosis. Mechanistically, the primary consequence of depleting both ADF and CFL1 is uncontrolled accumulation of contractile actin stress fibers associated with enlarged focal adhesions at the plasma membrane, as well as reduced rates of membrane protrusions. This generates increased intracellular acto-myosin tension that promotes nuclear deformation and physical disruption of the nuclear lamina via the LINC complex that normally connects regulated actin filaments to the nuclear envelope. We therefore describe a pathway involving the actin-severing proteins ADF and CFL1 in regulating the dynamic turnover of contractile actin stress fibers, and this is vital to prevent the nucleus from being damaged by actin contractility, in turn preserving cell survival and tissue homeostasis. PMID- 26655908 TI - Activity of Raphe Serotonergic Neurons Controls Emotional Behaviors. AB - Despite the well-established role of serotonin signaling in mood regulation, causal relationships between serotonergic neuronal activity and behavior remain poorly understood. Using a pharmacogenetic approach, we find that selectively increasing serotonergic neuronal activity in wild-type mice is anxiogenic and reduces floating in the forced-swim test, whereas inhibition has no effect on the same measures. In a developmental mouse model of altered emotional behavior, increased anxiety and depression-like behaviors correlate with reduced dorsal raphe and increased median raphe serotonergic activity. These mice display blunted responses to serotonergic stimulation and behavioral rescues through serotonergic inhibition. Furthermore, we identify opposing consequences of dorsal versus median raphe serotonergic neuron inhibition on floating behavior, together suggesting that median raphe hyperactivity increases anxiety, whereas a low dorsal/median raphe serotonergic activity ratio increases depression-like behavior. Thus, we find a critical role of serotonergic neuronal activity in emotional regulation and uncover opposing roles of median and dorsal raphe function. PMID- 26655909 TI - Evolving Models of Pavlovian Conditioning: Cerebellar Cortical Dynamics in Awake Behaving Mice. AB - Three decades of electrophysiological research on cerebellar cortical activity underlying Pavlovian conditioning have expanded our understanding of motor learning in the brain. Purkinje cell simple spike suppression is considered to be crucial in the expression of conditional blink responses (CRs). However, trial-by trial quantification of this link in awake behaving animals is lacking, and current hypotheses regarding the underlying plasticity mechanisms have diverged from the classical parallel fiber one to the Purkinje cell synapse LTD hypothesis. Here, we establish that acquired simple spike suppression, acquired conditioned stimulus (CS)-related complex spike responses, and molecular layer interneuron (MLI) activity predict the expression of CRs on a trial-by-trial basis using awake behaving mice. Additionally, we show that two independent transgenic mouse mutants with impaired MLI function exhibit motor learning deficits. Our findings suggest multiple cerebellar cortical plasticity mechanisms underlying simple spike suppression, and they implicate the broader involvement of the olivocerebellar module within the interstimulus interval. PMID- 26655910 TI - Long-Term Two-Photon Calcium Imaging of Neuronal Populations with Subcellular Resolution in Adult Non-human Primates. AB - Two-photon imaging with genetically encoded calcium indicators (GECIs) enables long-term observation of neuronal activity in vivo. However, there are very few studies of GECIs in primates. Here, we report a method for long-term imaging of a GECI, GCaMP6f, expressed from adeno-associated virus vectors in cortical neurons of the adult common marmoset (Callithrix jacchus), a small New World primate. We used a tetracycline-inducible expression system to robustly amplify neuronal GCaMP6f expression and up- and downregulate it for more than 100 days. We succeeded in monitoring spontaneous activity not only from hundreds of neurons three-dimensionally distributed in layers 2 and 3 but also from single dendrites and axons in layer 1. Furthermore, we detected selective activities from somata, dendrites, and axons in the somatosensory cortex responding to specific tactile stimuli. Our results provide a way to investigate the organization and plasticity of cortical microcircuits at subcellular resolution in non-human primates. PMID- 26655911 TI - Stratification of Hepatocellular Carcinoma Patients Based on Acetate Utilization. AB - Hepatocellular carcinoma (HCC) is a deadly form of liver cancer that is increasingly prevalent. We analyzed global gene expression profiling of 361 HCC tumors and 49 adjacent noncancerous liver samples by means of combinatorial network-based analysis. We investigated the correlation between transcriptome and proteome of HCC and reconstructed a functional genome-scale metabolic model (GEM) for HCC. We identified fundamental metabolic processes required for cell proliferation using the network centric view provided by the GEM. Our analysis revealed tight regulation of fatty acid biosynthesis (FAB) and highly significant deregulation of fatty acid oxidation in HCC. We predicted mitochondrial acetate as an emerging substrate for FAB through upregulation of mitochondrial acetyl-CoA synthetase (ACSS1) in HCC. We analyzed heterogeneous expression of ACSS1 and ACSS2 between HCC patients stratified by high and low ACSS1 and ACSS2 expression and revealed that ACSS1 is associated with tumor growth and malignancy under hypoxic conditions in human HCC. PMID- 26655912 TI - A Small Molecule that Induces Intrinsic Pathway Apoptosis with Unparalleled Speed. AB - Apoptosis is generally believed to be a process that requires several hours, in contrast to non-programmed forms of cell death that can occur in minutes. Our findings challenge the time-consuming nature of apoptosis as we describe the discovery and characterization of a small molecule, named Raptinal, which initiates intrinsic pathway caspase-dependent apoptosis within minutes in multiple cell lines. Comparison to a mechanistically diverse panel of apoptotic stimuli reveals that Raptinal-induced apoptosis proceeds with unparalleled speed. The rapid phenotype enabled identification of the critical roles of mitochondrial voltage-dependent anion channel function, mitochondrial membrane potential/coupled respiration, and mitochondrial complex I, III, and IV function for apoptosis induction. Use of Raptinal in whole organisms demonstrates its utility for studying apoptosis in vivo for a variety of applications. Overall, rapid inducers of apoptosis are powerful tools that will be used in a variety of settings to generate further insight into the apoptotic machinery. PMID- 26655913 TI - Temporal Response Properties of the Auditory Nerve in Implanted Children with Auditory Neuropathy Spectrum Disorder and Implanted Children with Sensorineural Hearing Loss. AB - OBJECTIVE: This study aimed to (1) characterize temporal response properties of the auditory nerve in implanted children with auditory neuropathy spectrum disorder (ANSD), and (2) compare results recorded in implanted children with ANSD with those measured in implanted children with sensorineural hearing loss (SNHL). DESIGN: Participants included 28 children with ANSD and 29 children with SNHL. All subjects used cochlear nucleus devices in their test ears. Both ears were tested in 6 children with ANSD and 3 children with SNHL. For all other subjects, only one ear was tested. The electrically evoked compound action potential (ECAP) was measured in response to each of the 33 pulses in a pulse train (excluding the second pulse) for one apical, one middle-array, and one basal electrode. The pulse train was presented in a monopolar-coupled stimulation mode at 4 pulse rates: 500, 900, 1800, and 2400 pulses per second. Response metrics included the averaged amplitude, latencies of response components and response width, the alternating depth and the amount of neural adaptation. These dependent variables were quantified based on the last six ECAPs or the six ECAPs occurring within a time window centered around 11 to 12 msec. A generalized linear mixed model was used to compare these dependent variables between the 2 subject groups. The slope of the linear fit of the normalized ECAP amplitudes (re. amplitude of the first ECAP response) over the duration of the pulse train was used to quantify the amount of ECAP increment over time for a subgroup of 9 subjects. RESULTS: Pulse train-evoked ECAPs were measured in all but 8 subjects (5 with ANSD and 3 with SNHL). ECAPs measured in children with ANSD had smaller amplitude, longer averaged P2 latency and greater response width than children with SNHL. However, differences in these two groups were only observed for some electrodes. No differences in averaged N1 latency or in the alternating depth were observed between children with ANSD and children with SNHL. Neural adaptation measured in these 2 subject groups was comparable for relatively short durations of stimulation (i.e., 11 to 12 msec). Children with ANSD showed greater neural adaptation than children with SNHL for a longer duration of stimulation. Amplitudes of ECAP responses rapidly declined within the first few milliseconds of stimulation, followed by a gradual decline up to 64 msec after stimulus onset in the majority of subjects. This decline exhibited an alternating pattern at some pulse rates. Further increases in pulse rate diminished this alternating pattern. In contrast, ECAPs recorded from at least one stimulating electrode in six ears with ANSD and three ears with SNHL showed a clear increase in amplitude over the time course of stimulation. The slope of linear regression functions measured in these subjects was significantly greater than zero. CONCLUSIONS: Some but not all aspects of temporal response properties of the auditory nerve measured in this study differ between implanted children with ANSD and implanted children with SNHL. These differences are observed for some but not all electrodes. A new neural response pattern is identified. Further studies investigating its underlying mechanism and clinical relevance are warranted. PMID- 26655914 TI - Acoustic Cue Weighting by Adults with Cochlear Implants: A Mismatch Negativity Study. AB - OBJECTIVES: Formant rise time (FRT) and amplitude rise time (ART) are acoustic cues that inform phonetic identity. FRT represents the rate of transition of the formant(s) to a steady state, while ART represents the rate at which the sound reaches its peak amplitude. Normal-hearing (NH) native English speakers weight FRT more than ART during the perceptual labeling of the /ba/-/wa/ contrast. This weighting strategy is reflected neurophysiologically in the magnitude of the mismatch negativity (MMN)-MMN is larger during the FRT than the ART distinction. The present study examined the neurophysiological basis of acoustic cue weighting in adult cochlear implant (CI) listeners using the MMN design. It was hypothesized that individuals with CIs who weight ART more in behavioral labeling (ART users) would show larger MMNs during the ART than the FRT contrast, and the opposite would be seen for FRT users. DESIGN: Electroencephalography was recorded while 20 adults with CIs listened passively to combinations of 3 synthetic speech stimuli: a /ba/ with /ba/-like FRT and ART; a /wa/ with /wa/-like FRT and ART; and a /ba/ stimulus with /ba/-like FRT and /wa/-like ART. The MMN response was elicited during the FRT contrast by having participants passively listen to a train of /wa/ stimuli interrupted occasionally by /ba/ stimuli, and vice versa. For the ART contrast, the same procedure was implemented using the /ba/ and /ba/ stimuli. RESULTS: Both ART and FRT users with CIs elicited MMNs that were equal in magnitudes during FRT and ART contrasts, with the exception that FRT users exhibited MMNs for ART and FRT contrasts that were temporally segregated. That is, their MMNs occurred significantly earlier during the ART contrast (~100 msec following sound onset) than during the FRT contrast (~200 msec). In contrast, the MMNs for ART users of both contrasts occurred later and were not significantly separable in time (~230 msec). Interestingly, this temporal segregation observed in FRT users is consistent with the MMN behavior in NH listeners. CONCLUSIONS: Results suggest that listeners with CIs who learn to classify phonemes based on formant dynamics, consistent with NH listeners, develop a strategy similar to NH listeners, in which the organization of the amplitude and spectral representations of phonemes in auditory memory are temporally segregated. PMID- 26655915 TI - Visceral fat increase and signals of inflammation in adipose tissue after administration of titanium dioxide nanoparticles in mice. AB - Titanium dioxide nanoparticles (TiO2 NP) are present in several daily use products, and the risks associated with their bioaccumulation must be stablished. Thus, an evaluation of several toxicological-related effects was conducted after intraperitoneal injection of TiO2 NPs in mice. Mice were divided into two groups, which received 2 mg kg-1 day-1 of TiO2 NPs or vehicle saline. Assessments of body and organ weight as well as biochemical, hematological, and histopathological analyses were performed in order to evaluate adverse effects. The results showed that treatment resulted in an increased visceral and abdominal fat deposition, as well as a mononuclear inflammatory infiltrates in the abdominal fat tissue. The TiO2 NPs induced significant decrease in the weight gain and splenomegaly. Additionally, TiO2 NP-treated mice showed altered hematological parameters and significant liver injuries, which were characterized by histopathological and biochemical changes. Our results also indicated that TiO2 NPs were absorbed and significantly accumulated in the spleen, liver, and kidney. These results showed the ability of TiO2 NPs to infiltrate different organs and to induce inflammation and liver and spleen damage with visceral fat accumulation. The data obtained are useful for the governmental authorities to legislate and implement regulations concerning the use and the production of this kind of material that might be hazardous to the living beings, as well as to the environment. PMID- 26655916 TI - [Anxiety in palliative care and end of life: What place for pregabalin? Letter on the article: "Psychiatric disorders in palliative care and at the end of life"]. PMID- 26655917 TI - Sex differences in social modulation of learning in rats. AB - In its simplest form, empathy can be characterized as the capacity to share the emotional experiences among individuals, a phenomenon known as emotional contagion. Recent research shows that emotional contagion and its adaptive role can be studied in rodents. However, it is not known whether sex differences observed in human empathy extend to its more primitive forms. In the present study, we used a rat model of emotional contagion to compare the behavioral consequences of social transfer of information about threat, and the subsequent neural activation patterns in male and female rats. We found that: (1) males and females display a similar behavioral pattern during the interaction with either a fear-conditioned or a control rat; (2) interaction with a fear-conditioned conspecific positively modulates two-way avoidance learning in male and diestral female rats but not in estral females; and (3) such interaction results in increased c-Fos expression in the central and lateral nuclei of the amygdala and the prelimbic and infralimbic cortex in males, whereas in females no such changes were observed. Collectively, our results point to the occurrence of sex and estrus cycle phase differences in susceptibility to emotional contagion and underlying neuronal activation in rodents. PMID- 26655918 TI - Syringe Service Programs for Persons Who Inject Drugs in Urban, Suburban, and Rural Areas - United States, 2013. AB - Reducing human immunodeficiency virus (HIV) infection rates in persons who inject drugs (PWID) has been one of the major successes in HIV prevention in the United States. Estimated HIV incidence among PWID declined by approximately 80% during 1990-2006 (1). More recent data indicate that further reductions in HIV incidence are occurring in multiple areas (2). Research results for the effectiveness of risk reduction programs in preventing hepatitis C virus (HCV) infection among PWID (3) have not been as consistent as they have been for HIV; however, a marked decline in the incidence of HCV infection occurred during 1992-2005 in selected U.S. locations when targeted risk reduction efforts for the prevention of HIV were implemented (4). Because syringe service programs (SSPs)* have been one effective component of these risk reduction efforts for PWID (5), and because at least half of PWID are estimated to live outside major urban areas (6), a study was undertaken to characterize the current status of SSPs in the United States and determine whether urban, suburban, and rural SSPs differed. Data from a recent survey of SSPs(?) were analyzed to describe program characteristics (e.g., size, clients, and services), which were then compared by urban, suburban, and rural location. Substantially fewer SSPs were located in rural and suburban than in urban areas, and harm reduction services(S) were less available to PWID outside urban settings. Because increases in substance abuse treatment admissions for drug injection have been observed concurrently with increases in reported cases of acute HCV infection in rural and suburban areas (7), state and local jurisdictions could consider extending effective prevention programs, including SSPs, to populations of PWID in rural and suburban areas. PMID- 26655919 TI - Can Sarcopenia Quantified by Ultrasound of the Rectus Femoris Muscle Predict Adverse Outcome of Surgical Intensive Care Unit Patients as well as Frailty? A Prospective, Observational Cohort Study. AB - OBJECTIVE: To compare sarcopenia and frailty for outcome prediction in surgical intensive care unit (SICU) patients. BACKGROUND: Frailty has been associated with adverse outcomes and describes a status of muscle weakness and decreased physiological reserve leading to increased vulnerability to stressors. However, frailty assessment depends on patient cooperation. Sarcopenia can be quantified by ultrasound and the predictive value of sarcopenia at SICU admission for adverse outcome has not been defined. METHODS: We conducted a prospective, observational study of SICU patients. Sarcopenia was diagnosed by ultrasound measurement of rectus femoris cross-sectional area. Frailty was diagnosed by the Frailty Index Questionnaire based on 50 variables. Relationship between variables and outcomes was assessed by multivariable regression analysis NCT02270502. RESULTS: Sarcopenia and frailty were quantified in 102 patients and observed in 43.1% and 38.2%, respectively. Sarcopenia predicted adverse discharge disposition (discharge to nursing facility or in-hospital mortality, odds ratio 7.49; 95% confidence interval 1.47-38.24; P = 0.015) independent of important clinical covariates, as did frailty (odds ratio 8.01; 95% confidence interval 1.82-35.27; P = 0.006); predictive ability did not differ between sarcopenia and frailty prediction model, reflected by chi values of 21.74 versus 23.44, respectively, and a net reclassification improvement (NRI) of -0.02 (P = 0.87). Sarcopenia and frailty predicted hospital length of stay and the frailty model had a moderately better predictive accuracy for this outcome. CONCLUSIONS: Bedside diagnosis of sarcopenia by ultrasound predicts adverse discharge disposition in SICU patients equally well as frailty. Sarcopenia assessed by ultrasound may be utilized as rapid beside modality for risk stratification of critically ill patients. PMID- 26655920 TI - Prevention of Postsurgical Lymphedema by 9-cis Retinoic Acid. AB - OBJECTIVE: To determine the effect of 9-cis retinoic acid (9-cis RA) on postsurgical lymphedema. BACKGROUND: 9-cis RA promotes lymphangiogenesis in vitro and in vivo and has promise as a therapeutic agent to limit the development of postsurgical lymphedema. METHODS: Lymphedema was induced in the right hind limb after a single fraction of 20 Gy radiation, popliteal lymphadenectomy, and lymphatic vessel ablation. Postoperatively, mice were randomly divided in to 2 groups that received daily intraperitoneal injections of either (1) an oil-based vehicle solution (control) or (2) 0.08 mg/kg of 9-cis RA dissolved in a vehicle solution. Outcome measures included paw thickness, lymphatic drainage, and lymphatic vessel density as measured by podoplanin immunohistochemistry and whole mount skin analysis. RESULTS: Using our combined injury protocol, postsurgical lymphedema was observed 89% of the time. 9-cis RA-treated animals had less early postsurgical edema and significantly less paw lymphedema compared with vehicle treated animals at all time-points (P < 0.001). 9-cis RA-treated animals had significantly faster lymphatic drainage as measured by indocyanine green clearance and increased lymphatic vessel density as measured by podoplanin immunohistochemistry (P < 0.001) and whole mount skin analysis (P < 0.05). CONCLUSIONS: We have developed a highly reproducible model of secondary lymphedema and have demonstrated that 9-cis RA significantly prevents postsurgical lymphedema. Treatment with 9-cis RA is associated with increased lymphatic clearance and lymphangiogenesis. Because 9-cis RA (alitretinoin) is already approved for clinical use by the US Food and Drug Administration for other conditions, it has the potential to be repurposed as a preventative agent for postsurgical lymphedema in humans. PMID- 26655921 TI - Characteristics and Correlates of Increasing Use of Surgery in Taiwanese Cancer Patients' Last Month of Life, 2001-2010. AB - BACKGROUND/OBJECTIVES: Surgery offers the potential to relieve symptoms for patients with cancer at the end of life (EOL) but at significant physiological and economic costs. However, the characteristics and correlates of surgery in last month of life (EOL surgery) of patients with cancer have not been comprehensively explored. This population-based study characterized EOL surgery use and identified its correlates. METHODS: This retrospective cohort study examined administrative data among 339,546 Taiwanese cancer decedents, 2001 to 2010. We classified procedures according to their likely intent. RESULTS: Approximately 1 in 10 (11.44%, range: 11.08%-11.86%) patients underwent EOL surgery with an increasing utilization over time. The intention for EOL surgery was primarily palliative, followed by cancer-directed, nonmalignancy-directed, and diagnostic. EOL surgery for palliative intent increased whereas other intents decreased significantly over time. EOL surgery was more likely among those who were male, younger, and married; not diagnosed with hepatic-pancreatic or lung cancers; had no comorbidity or documented metastatic codes; and survived less than 1 year from diagnosis. The likelihood of EOL surgery use was higher for patients who received care in a teaching hospital with more acute care hospital beds and higher EOL care intensity. CONCLUSIONS: Rates of EOL surgery are lower in Taiwan than those reported in the United States. The increasing use of EOL surgery in Taiwan is primarily for palliative intent. Appropriateness of EOL surgery should be carefully evaluated to avoid underutilizing potentially beneficial, palliative-intent surgery and overutilizing cancer-directed and other surgical procedures, especially for physicians working in hospitals with abundant health care resources and a tendency to treat at-risk patients with cancer aggressively. PMID- 26655922 TI - Impact of Risk Adjustment for Socioeconomic Status on Risk-adjusted Surgical Readmission Rates. AB - OBJECTIVE: To assess whether differences in readmission rates between safety-net hospitals (SNH) and non-SNHs are due to differences in hospital quality, and to compare the results of hospital profiling with and without SES adjustment. BACKGROUND: In response to concerns that quality measures unfairly penalizes SNH, NQF recently recommended that performance measures adjust for socioeconomic status (SES) when SES is a risk factor for poor patient outcomes. METHODS: Multivariate regression was used to examine the association between SNH status and 30-day readmission after major surgery. The results of hospital profiling with and without SES adjustment were compared using the CMS Hospital Compare and the Hospital Readmissions Reduction Program (HRRP) methodologies. RESULTS: Adjusting for patient risk and SES, patients admitted to SNHs were not more likely to be readmitted compared with patients in in non-SNHs (AOR 1.08; 95% CI:0.95-1.23; P = 0.23). The results of hospital profiling based on Hospital Compare were nearly identical with and without SES adjustment (ICC 0.99, kappa 0.96). Using the HRRP threshold approach, 61% of SNHs were assigned to the penalty group versus 50% of non-SNHs. After adjusting for SES, 51% of SNHs were assigned to the penalty group. CONCLUSIONS: Differences in surgery readmissions between SNHs and non-SNHs are due to differences in the patient case mix of low SES patients, and not due to differences in quality. Adjusting readmission measures for SES leads to changes in hospital ranking using the HRRP threshold approach, but not using the CMS Hospital Compare methodology. CMS should consider either adjusting for the effects of SES when calculating readmission thresholds for HRRP, or replace it with the approach used in Hospital Compare. PMID- 26655923 TI - Postoperative Showering for Clean and Clean-contaminated Wounds: A Prospective, Randomized Controlled Trial. AB - OBJECTIVE: To evaluate wound infection rates, pain scores, satisfaction with wound care, and wound care costs starting 48 hours after surgery. BACKGROUND: Showering after surgery is a controversial issue for wound care providers and patients. We investigated the benefits and detriments of showering for postoperative wound care. METHODS: Patients undergoing thyroid, lung, inguinal hernia, and face and extremity surgeries with clean or clean-contaminated wounds were included. The patients were randomized to allow showering (shower group) or to keep the wound dry (nonshower group) for postoperative wound care starting 48 hours after surgery. The primary endpoint was the rate of surgical wound infection. The secondary endpoints included the wound pain score, satisfaction with wound care, and cost of wound care. RESULTS: Between May 2013 and March 2014, there were 222 patients randomized to the shower group and 222 to the nonshower group. Two patients in each group were lost to follow-up. There were 4 superficial surgical site infections in the shower group and 6 in the nonshower group (4/220, 1.8% vs 6/220, 2.7%, P = 0.751). Postoperative pain scores were comparable between the 2 groups. Patients in the shower group were more satisfied with their method of wound care, and their wound care costs were lower when compared with the nonshower group. CONCLUSIONS: Clean and clean-contaminated wounds can be safely showered 48 hours after surgery. Postoperative showering does not increase the risk of surgical site complications. It may increase patients' satisfaction and lower the cost of wound care. PMID- 26655924 TI - Bile Acids Increase Independently From Hypocaloric Restriction After Bariatric Surgery. AB - OBJECTIVES: To measure changes in the composition of serum bile acids (BA) and the expression of Takeda G-protein-coupled receptor 5 (TGR5) acutely after bariatric surgery or caloric restriction. SUMMARY BACKGROUND DATA: Metabolic improvement after bariatric surgery occurs before substantial weight loss. BA are important metabolic regulators acting through the farnesoid X receptor and TGR5 receptor. The acute effects of surgery on BA and the TGR5 receptor in subcutaneous white adipose tissue (WAT) are unknown. METHODS: A total of 27 obese patients with type 2 diabetes mellitus were randomized to Roux-en-Y gastric bypass (RYGB) or to hypocaloric diet (HC diet) restriction (NCT 1882036). A cohort of obese patients with and without type 2 diabetes mellitus undergoing vertical sleeve gastrectomy was also recruited (n = 12) as a comparison. RESULTS: After vertical sleeve gastrectomy, the level of BA increased [total: 1.17 +/- 1.56 MUmol/L to 4.42 +/- 3.92 MUmol/L (P = 0.005); conjugated BA levels increased from 0.99 +/- 1.42 MUmol/L to 3.59 +/- 3.70 MUmol/L (P = 0.01) and unconjugated BA levels increased from 0.18 +/- 0.24 MUmol/L to 0.83 +/- 0.70 MUmol/L (P = 0.009)]. With RYGB, there was a trend toward increased BA [total: 1.37 +/- 0.97 MUmol/L to 3.26 +/- 3.01 MUmol/L (P = 0.07); conjugated: 1.06 +/- 0.81 MUmol/L to 2.99 +/- 3.02 MUmol/L (P = 0.06)]. After HC diet, the level of unconjugated BA decreased [0.92 +/- 0.55 MUmol/L to 0.32 +/- 0.43 MUmol/L (P = 0.05)]. The level of WAT TGR5 gene expression decreased after surgery, but not in HC diet. Protein levels did not change. CONCLUSIONS: The levels of serum BA increase after bariatric surgery independently from caloric restriction, whereas the level of WAT TGR5 protein is unaffected. PMID- 26655925 TI - Complications After Mastectomy and Immediate Breast Reconstruction for Breast Cancer: How Does the Community Compare? PMID- 26655926 TI - Emerging Ethical Considerations of Donation After Circulatory Death: Getting to the Heart of the Matter. PMID- 26655927 TI - Increased epigenetic age and granulocyte counts in the blood of Parkinson's disease patients. AB - It has been a long standing hypothesis that blood tissue of PD Parkinson's disease (PD) patients may exhibit signs of accelerated aging. Here we use DNA methylation based biomarkers of aging ("epigenetic clock") to assess the aging rate of blood in two ethnically distinct case-control data sets. Using n=508 Caucasian and n=84 Hispanic blood samples, we assess a) the intrinsic epigenetic age acceleration of blood (IEAA), which is independent of blood cell counts, and b) the extrinsic epigenetic age acceleration rate of blood (EEAA) which is associated with age dependent changes in blood cell counts. Blood of PD subjects exhibits increased age acceleration according to both IEAA (p=0.019) and EEAA (p=6.1 x 10(-3)). We find striking differences in imputed blood cell counts between PD cases and controls. Compared to control subjects, PD subjects contains more granulocytes (p=1.0 x 10(-9) in Caucasians, p=0.00066 in Hispanics) but fewer T helper cells (p=1.4 x 10(-6) in Caucasians, p=0.0024 in Hispanics) and fewer B cells (p=1.6 x 10(-5) in Caucasians, p=4.5 x 10(-5) in Hispanics). Overall, this study shows that the epigenetic age of the immune system is significantly increased in PD patients and that granulocytes play a significant role. PMID- 26655928 TI - Akbu-LAAO exhibits potent anti-tumor activity to HepG2 cells partially through produced H2O2 via TGF-beta signal pathway. AB - Previously, we characterized the biological properties of Akbu-LAAO, a novel L amino acid oxidase from Agkistrodon blomhoffii ussurensis snake venom (SV). Current work investigated its in vitro anti-tumor activity and underlying mechanism on HepG2 cells. Akbu-LAAO inhibited HepG2 growth time and dose dependently with an IC50 of ~38.82 MUg/mL. It could induce the apoptosis of HepG2 cells. Akbu-LAAO exhibited cytotoxicity by inhibiting growth and inducing apoptosis of HepG2 as it showed no effect on its cell cycle. The inhibition of Akbu-LAAO to HepG2 growth partially relied on enzymatic-released H2O2 as catalase only partially antagonized this effect. cDNA microarray results indicated TGF beta signaling pathway was linked to the cytotoxicity of Akbu-LAAO on HepG2. TGF beta pathway related molecules CYR61, p53, GDF15, TOB1, BTG2, BMP2, BMP6, SMAD9, JUN, JUNB, LOX, CCND1, CDK6, GADD45A, CDKN1A were deregulated in HepG2 following Akbu-LAAO stimulation. The presence of catalase only slightly restored the mRNA changes induced by Akbu-LAAO for differentially expressed genes. Meanwhile, LDN 193189, a TGF-beta pathway inhibitor reduced Akbu-LAAO cytotoxicity on HepG2. Collectively, we reported, for the first time, SV-LAAO showed anti-tumor cell activity via TGF-beta pathway. It provides new insight of SV-LAAO exhibiting anti tumor effect via a novel signaling pathway. PMID- 26655929 TI - Action Video Gaming and Cognitive Control: Playing First Person Shooter Games Is Associated with Improved Action Cascading but Not Inhibition. AB - There is a constantly growing interest in developing efficient methods to enhance cognitive functioning and/or to ameliorate cognitive deficits. One particular line of research focuses on the possibly cognitive enhancing effects that action video game (AVG) playing may have on game players. Interestingly, AVGs, especially first person shooter games, require gamers to develop different action control strategies to rapidly react to fast moving visual and auditory stimuli, and to flexibly adapt their behaviour to the ever-changing context. This study investigated whether and to what extent experience with such videogames is associated with enhanced performance on cognitive control tasks that require similar abilities. Experienced action videogame-players (AVGPs) and individuals with little to no videogame experience (NVGPs) performed a stop-change paradigm that provides a relatively well-established diagnostic measure of action cascading and response inhibition. Replicating previous findings, AVGPs showed higher efficiency in response execution, but not improved response inhibition (i.e. inhibitory control), as compared to NVGPs. More importantly, compared to NVGPs, AVGPs showed enhanced action cascading processes when an interruption (stop) and a change towards an alternative response were required simultaneously, as well as when such a change had to occur after the completion of the stop process. Our findings suggest that playing AVGs is associated with enhanced action cascading and multi-component behaviour without affecting inhibitory control. PMID- 26655930 TI - Identification of the coupling step in Na(+)-translocating NADH:quinone oxidoreductase from real-time kinetics of electron transfer. AB - Bacterial Na(+)-translocating NADH:quinone oxidoreductase (Na(+)-NQR) uses a unique set of prosthetic redox groups-two covalently bound FMN residues, a [2Fe 2S] cluster, FAD, riboflavin and a Cys4[Fe] center-to catalyze electron transfer from NADH to ubiquinone in a reaction coupled with Na(+) translocation across the membrane. Here we used an ultra-fast microfluidic stopped-flow instrument to determine rate constants and the difference spectra for the six consecutive reaction steps of Vibrio harveyi Na(+)-NQR reduction by NADH. The instrument, with a dead time of 0.25 ms and optical path length of 1 cm allowed collection of visible spectra in 50-MUs intervals. By comparing the spectra of reaction steps with the spectra of known redox transitions of individual enzyme cofactors, we were able to identify the chemical nature of most intermediates and the sequence of electron transfer events. A previously unknown spectral transition was detected and assigned to the Cys4[Fe] center reduction. Electron transfer from the [2Fe-2S] cluster to the Cys4[Fe] center and all subsequent steps were markedly accelerated when Na(+) concentration was increased from 20 MUM to 25 mM, suggesting coupling of the former step with tight Na(+) binding to or occlusion by the enzyme. An alternating access mechanism was proposed to explain electron transfer between subunits NqrF and NqrC. According to the proposed mechanism, the Cys4[Fe] center is alternatively exposed to either side of the membrane, allowing the [2Fe-2S] cluster of NqrF and the FMN residue of NqrC to alternatively approach the Cys4[Fe] center from different sides of the membrane. PMID- 26655931 TI - Transareolar Robotic-Assisted Access to the Mitral Valve. AB - During the past years, a rapid development and refinements of robotic heart valve techniques have led to consider robotic mitral valve (MV) surgery safe, effective, and durable. Robotic MV surgery has proven to be a cost-effective and cost-saving strategy in MV operations, being associated with reduced morbidity and mortality rates. We present a novel video-assisted transareolar approach to access the MV using the da Vinci Si HD telemanipulation system (Intuitive Surgical, Inc, Sunnyvale, CA USA). This technique is effective and reproducible, providing maximum patient satisfaction from both the clinical and cosmetic points of view. PMID- 26655932 TI - Robotically Assisted Bilateral Bronchoplasty for Tracheobronchomalacia. AB - We describe the technique for the first robotically assisted bilateral bronchoplasty for the treatment of tracheobronchomalacia. Since 1954, this disease process has been treated with a right thoracotomy and posterior splinting of the tracheal membrane with mesh to restore the C-shape of the trachea. Traditional video-assisted thoracoscopic surgery has been of limited benefit in these cases owing to technical challenges. A robotically assisted technique offers the dual benefit of a minimally invasive port-based system while reproducing an open surgical technique. PMID- 26655933 TI - Percutaneous Coronary Intervention Followed by Minimally Invasive Mitral Valve Surgery in Ischemic Mitral Regurgitation. AB - OBJECTIVE: The optimal treatment strategy in patients with coronary artery disease and ischemic mitral regurgitation (IMR) remains controversial. A staged approach of percutaneous coronary intervention (PCI) followed by minimally invasive valve surgery, rather than combined median sternotomy coronary artery bypass and valve surgery, may be a viable alternative. METHODS: We retrospectively evaluated 31 consecutive patients with coronary artery disease and severe IMR who underwent a staged procedure at our institution between February 2009 and April 2014. RESULTS: The mean +/- SD age, preoperative left ventricular ejection fraction, and mitral regurgitation grade were 72 +/- 7 years, 35% +/- 11%, and 3.6 +/- 0.6, respectively. The mean +/- SD Society of Thoracic Surgeons-predicted mortality score was 5.1% +/- 4.2%. Percutaneous coronary intervention was performed for 1- and 2-vessel disease in 22 patients (71%) and 9 patients (29%), respectively, with 23 patients (74%) having drug eluting stents placed. Minimally invasive valve surgery was performed within a median of 36 days after PCI, with 61% of the patients being on dual antiplatelet therapy. Postoperatively, there was 1 case of acute kidney injury, 1 case of reoperation for bleeding, and no cerebrovascular accidents. The 30-day mortality was 3%. The median total hospital length of stay was 8 days (interquartile range, 7-10). At a mean +/- SD follow-up of 2.4 +/- 1.6 years, 2 patients required PCI for target-vessel revascularization. Actuarial survival at 1 and 5 years was 84% and 80%, respectively. CONCLUSIONS: A staged approach in patients with coronary artery disease and IMR can be performed with a low perioperative morbidity and good midterm survival. PMID- 26655934 TI - Simplified Transapical Aortic Valve Implantation Using the SAPIEN 3 Valve Without Preballooning. AB - OBJECTIVE: Preballooning (PB) of the stenotic aortic valve can be considered common standard during transcatheter aortic valve implantation (T-AVI). Transcatheter aortic valve implantation without preballooning (noPB) using the Edwards SAPIEN XT prosthesis has been described previously. The aim of this study was to evaluate the outcomes of next-generation SAPIEN 3 valve implantation without PB. METHODS: Since January 2013, a total of 66 patients received SAPIEN 3 valve implantation at our center using the transapical approach. Patients were treated using the standard PB technique (n = 17 [25.8%]) or no PB (n = 49 [74.2%]). RESULTS: Baseline characteristics of patient groups were comparable (38% women; mean age, 83 years; STS score, 8%, logistic EuroSCORE I and II, 30% and 8%, respectively). Patients in the PB group were exclusively treated in our earlier experience with this device. Overall 30-day mortality was 4.5% (6.1% for noPB vs. 0% PB; P = ns). Aortic regurgitation was grade 1 or less in 100% (PB) versus 93.9% (noPB); P = ns Median contrast use was 70 (60-95) mL (PB) versus 50 (40-50) mL (noPB); P < 0.001; and median radiation dose was 32.0 (17-57) Gy * cm (PB) versus 26.6 (16-36) Gy * cm (noPB); P < 0.001. Postdilatation was required in one patient only (noPB). The rate of new pacemaker implantations was 41.2% (PB) versus 12.2% (noPB); P = 0.03. Periprocedural stroke occurred in one patient in each group (6% PB vs 2.0% no-PB); P = ns. CONCLUSIONS: Direct transapical SAPIEN 3 valve implantation without PB is feasible and safe. The no-PB technique leads to further simplification of the procedures. PMID- 26655935 TI - Prevalence and Outcomes of Liver Transplantation in Children With Intellectual Disability. AB - OBJECTIVE: We sought to describe the prevalence and outcomes of liver transplantation in children with intellectual disability (ID). We hypothesized that recipients with ID have comparable short-term outcomes compared with those without ID. METHODS: We performed a retrospective cohort analysis of children receiving a first liver-alone transplant in the United Network for Organ Sharing dataset from 2008 to 2013. Recipients with definite or probable ID were compared to children without ID using chi tests. Kaplan-Meier curves were constructed for patient and graft survival. Cox proportional hazard models were used to estimate the association between ID and graft failure and patient survival. RESULTS: During the study period, 254 children with definite (115) or probable (139) ID underwent first liver transplant, accounting for 15% of all first pediatric liver transplants (1721). Recipients with definite ID tended to be male have a metabolic indication for transplant, a lower pediatric end-stage liver disease score at listing than recipients with no ID, and were less likely to receive a living donor transplant. Recipients with ID were more likely to have public insurance and had more treatment-related hospitalizations in the first year than those without ID. Functional status tended to improve in all recipients at follow up. ID was not significantly associated with patient or graft survival. CONCLUSIONS: Children with ID form a significant portion of total liver transplant recipients, and their short-term graft and patient survival are comparable with children without ID. Further research is needed to examine long term outcomes of transplant in this population. PMID- 26655936 TI - Comparison of Diagnostic Accuracy and Concordance of Video Capsule Endoscopy and Double Balloon Enteroscopy in Children. AB - OBJECTIVES: To compare the diagnostic yield, sensitivity, and specificity of video capsule endoscopy (VCE) with double balloon enteroscopy (DBE), including comparison with histological findings as well as degree of concordance of the studies. METHODS: Retrospective review of pediatric patients who had DBE following VCE at a single center from 2006 to 2013. VCEs were interpreted by 1 of 4 pediatric gastroenterologists and DBEs were performed by a single endoscopist. RESULTS: Thirty-six patients ranging from 5 to 20 years had DBE following VCE. There were positive findings in 32 (88.8%) of VCE and 21 (58.3%) of DBE. Significant histological findings were identified in 16 patients (44.4%). When comparing VCE with DBE findings, VCE had a sensitivity of 95% and specificity of 20%. Overall concordance between VCE and DBE findings was weak with calculated kappa index of 0.1702; however, this varied widely by indication. VCE had sensitivity 100% and specificity 20% for detecting histologically significant lesions. DBE had sensitivity of 87% and specificity of 65%. CONCLUSIONS: This is the first pediatric study to evaluate diagnostic accuracy and concordance of VCE and DBE and to compare both to histological findings. Our study supports the high diagnostic utility of both the studies. VCE is highly sensitive with an excellent negative predictive value both for DBE findings and for histological findings; however, the utility of VCE is limited by low specificity. Sensitivity and specificity of DBE for detecting histologically significant findings were good. Overall agreement between VCE and DBE is low but varies by indication for the study. These results support the use of VCE and DBE as complementary studies. PMID- 26655937 TI - Colonic Crohn Disease After Cardiac Transplantation: Case Report and Literature Review. PMID- 26655938 TI - "Cobblestone" Appearance of Esophagus: An Unusual Symptom of Pyloric Stenosis. PMID- 26655939 TI - Vitamin D Levels in Infants With Biliary Atresia: Pre- and Post-Kasai Portoenterostomy. AB - OBJECTIVES: Infants with biliary atresia (BA) are at high risk of vitamin D deficiency. We aimed to determine the prevalence and factors influencing vitamin D levels at presentation and post-Kasai portoenterostomy (KPE). METHODS: Single centre retrospective review of infants with BA who underwent KPE. Pre- and postoperatively 25-hydroxyvitamin D (25-OHVD), liver and bone biochemistry data were collected. 25-OHVD levels <10 and 10 to 20 ng/mL were defined as vitamin D "deficiency" and "insufficiency," respectively. RESULTS: One hundred twenty-nine infants with BA (isolated n = 101, developmental n = 28, and white n = 79; non white n = 50) were included in this study. At presentation, 75 of 92 (81%) were vitamin D deficient and only 1 infant had a level >20 ng/mL. Median 25-OHVD levels were 5(2-23), 17(2-72), 15(2-80), 17(2-69), and 23(2-98) ng/mL at pre-KPE, 1, 4, 6, and 12 months postoperation. There was no difference in 25-OHVD levels between the isolated and developmental groups with BA. Pre-KPE, white infants had significantly higher levels than non-white infants (6[2-23] vs 3[2-14] ng/mL, P = 0.01). Post-KPE 25-OHVD levels correlated well with liver and bone biochemical variables (eg, at 6 months: bilirubin rs = -0.34; P < 0.001, alkaline phosphatase rs = -0.46; P < 0.00001, and phosphate rs = 0.49; P < 0.00001). CONCLUSIONS: 25 OHVD deficiency is invariable at presentation in infants with BA, irrespective of its likely aetiology, and is more severe in non-white infants. Despite routine parenteral and enteral supplementation, low 25-OHVD levels persist post KPE especially in icteric infants. More aggressive vitamin D supplementation and monitoring in this population is paramount. PMID- 26655940 TI - Safety of a 1-Day Polyethylene Glycol 3350 Bowel Preparation for Colonoscopy in Children. AB - OBJECTIVES: Electrolyte-free polyethylene glycol powder (PEG-3350) has been widely used for colonoscopy preparation (prep); however, limited safety data on electrolyte changes exists with 1-day prep regimens. The primary aim of this study was to determine the proportion of patients with significant serum chemistry abnormalities before and at the time of colonoscopy. Secondary aims included evaluation of prep tolerance and bowel cleansing efficacy. METHODS: We performed a prospective descriptive observational study of pediatric patients scheduled for outpatient colonoscopy who received our standard 1-day, weight based 4 g/kg PEG-3350 prep with a single stimulant laxative dose and had serum chemistry testing within 60 days before and at the time of colonoscopy. A standardized bowel cleanliness tool (Aronchick scale) was completed by the endoscopist. RESULTS: One hundred fifty-five patients had serum electrolytes data pre- and postprep. Comparison of each patient's chemistries demonstrated statistical equivalence with the 1 exception of blood urea nitrogen levels (P = 0.56). Hypokalemia was detected postprep in 37 subjects (24%), but none had a serum level <3.3 mmol/L, which was deemed to be of no clinical significance. Five patients were hypoglycemic post prep; 3 were 7 years or younger (P = 0.02). The colon cleanliness rating was excellent or good in 77% and suboptimal in 23% of patients. CONCLUSIONS: A 1-day, weight-based PEG-3350 bowel prep in children appears safe. Changes in electrolyte levels and renal function were not clinically significant. Children of 7 years or younger seem to be at a higher risk of hypoglycemia compared with older children. PMID- 26655941 TI - Infant Colic-What works: A Systematic Review of Interventions for Breast-fed Infants. AB - OBJECTIVES: To determine the strength of evidence for commonly used interventions for colic in breast-fed and mixed-fed infants younger than 6 months. METHODS: Searches of PubMed, CINAHL, Embase, AMED, and Web of Science databases were conducted from July 2014 to July 2015. Included studies were randomised controlled trials involving mothers and their colicky infants younger than 6 months; assessed colic against the Wessel or modified Wessel criteria; and included phytotherapies, prescription medicines, and maternal dietary interventions. Studies with <16 participants were excluded. Meta-analyses were conducted where data were sufficient to enable pooling. Quality was assessed against the Cochrane Risk Bias Assessment Tool. RESULTS: A total of 17 articles met the inclusion criteria for this review. The 6 studies included for subgroup meta-analysis on probiotic treatment, notably Lactobacillus reuteri, demonstrated that probiotics appear an effective treatment, with an overall mean difference in crying time at day 21 of -55.8 min/day (95% CI -64.4 to -47.3, P = 0.001). The 3 studies included for subgroup meta-analysis on preparations containing fennel suggest it to be effective, with an overall mean difference of -72.1 min/day (95% CI -126.4 to -17.7, P < 0.001). CONCLUSIONS: Probiotics, in particular L reuteri, and preparations containing fennel oil appear effective for reducing colic, although there are limitations to these findings. The evidence for maternal dietary manipulation, lactase, sucrose, glucose, and simethicone is weak. Further well-designed clinical trials are required to strengthen the evidence for all of these interventions. PMID- 26655942 TI - Intestinal Microbiota Studies in Preterm Infants. PMID- 26655943 TI - Functional Nausea in Children. AB - Chronic nausea is a highly prevalent, bothersome, and difficult-to-treat symptom among adolescents. When chronic nausea presents as the predominant symptom and is not associated with any underlying disease, it may be considered a functional gastrointestinal disorder and named "functional nausea." The clinical features of functional nausea and its association with comorbid conditions provide clues to the underlying pathophysiological mechanisms. These may include gastrointestinal motor and sensory disturbances, autonomic imbalance, altered central nervous system pathways, or a combination of these. This review summarizes the current knowledge on mechanisms and treatment strategies for chronic, functional nausea in children. PMID- 26655944 TI - EBV Status and Thiopurine Use in Pediatric IBD. AB - OBJECTIVES: Epstein Barr virus (EBV) is a human herpes virus that infects 90% of the world's population and has been linked to the development of lymphoproliferative disorders (LPDs) and immunosuppression. Primary EBV infection in patients with IBD on thiopurines is a risk factor for LPD, including lymphoma. We aimed to describe EBV status in a pediatric population with IBD with an emphasis on those initiating thiopurines. METHODS: Electronic medical records and EBV serologies were reviewed and categorized into asymptomatic screening versus suspicion for acute infection. EBV status before therapy was described by sex, age, and therapeutic regimen. Descriptive statistics and univariate analysis were employed. RESULTS: Only 150 (22%) of our 688 pediatric patients with IBD had documented EBV status regardless of age or treatment regimen. Only 17% were assessed for suspicion of acute infection and 83% for screening. Sixty-four (52%) screened patients were checked before starting any treatment and only 40% were immunoglobulin (Ig)G positive. There was no difference in mean age between the seronegative and seropositive group. The majority (63%) of thiopurine-treated patients were IgG negative before starting therapy. Eighty percent of primary EBV infections occurred on thiopurines at a mean (SD) of 2 +/- 1.5 years after initiating therapy. CONCLUSIONS: The majority of our pediatric patients with IBD with documented EBV status were IgG negative at thiopurine initiation. Thiopurines were also associated with primary EBV infection. EBV status may be an important determinate of whether physicians prescribe thiopurines given the risk of primary EBV infections and lymphoproliferative diseases. PMID- 26655945 TI - Cystic Echinococcus Infection in a 10-Year-Old Iraqi Refugee. PMID- 26655946 TI - Neurodevelopmental and Cognitive Outcomes in Children With Intestinal Failure. AB - OBJECTIVES: Recent advances in medical and surgical management have led to improved long-term survival in children with intestinal failure. Yet, limited data exist on their neurodevelopmental and cognitive outcomes. The aim of the present study was to measure neurodevelopmental outcomes in children with intestinal failure. METHODS: Children enrolled in a regional intestinal failure program underwent prospective neurodevelopmental and psychometric evaluation using a validated scoring tool. Cognitive impairment was defined as a mental developmental index <70. Neurodevelopmental impairment was defined as cerebral palsy, visual or hearing impairment, or cognitive impairment. Univariate analyses were performed using the Wilcoxon rank-sum test. Data are presented as median (range). RESULTS: Fifteen children with a remnant bowel length of 18 (5-85) cm were studied at age 17 (12-67) months. Thirteen patients remained dependent on parenteral nutrition. Twelve (80%) subjects scored within the normal range on cognitive testing. Each child with cognitive impairment was noted to have additional risk factors independent of intestinal failure including cardiac arrest and extreme prematurity. On univariate analysis, cognitive impairment was associated with longer inpatient hospital stays, increased number of surgical procedures, and prematurity (P < 0.02). In total, 4 (27%) children demonstrated findings consistent with neurodevelopmental impairment. CONCLUSIONS: A majority of children with intestinal failure demonstrated normal neurodevelopmental and cognitive outcomes on psychometric testing. These data suggest that children with intestinal failure without significant comorbidity may be at low risk for long term neurodevelopmental impairment. PMID- 26655947 TI - Soap Suds Enemas Are Efficacious and Safe for Treating Fecal Impaction in Children With Abdominal Pain. AB - OBJECTIVES: Constipation is a common cause of pediatric abdominal pain and emergency department (ED) presentation. Despite the high prevalence, there is a dearth of clinical information and wide practice variation in childhood constipation management in the ED. The objective of the study was to assess the efficacy and safety of soap suds enema (SSE) in the therapy for fecal impaction in children with abdominal pain within the pediatric ED setting. The primary outcome was stool output following SSE. Secondary outcomes were adverse events, admissions, and return visits within 72 hours. METHODS: The present study is a retrospective cross-sectional study performed in the ED at a quaternary care children's hospital of patients seen during a 12-month period who received an SSE for fecal impaction. RESULTS: Five hundred twelve patients (53% girls, median age 7.8 years, range: 8 months-23 years) received SSE therapy during a 1-year period. Successful therapy (bowel movement) following SSE occurred in 419 (82%). Adverse events included abdominal pain in 24 (5%) and nausea/vomiting in 18 (4%). No SSE related serious adverse events were identified. Following SSE, 405 (79%) were subsequently discharged, of which 15 (3.7%) returned to the ED for re-evaluation within 72 hours. CONCLUSIONS: SSE is an efficacious and safe therapeutic option for the acute treatment of childhood fecal impaction in the ED setting. PMID- 26655948 TI - Developmental validation of an X-Insertion/Deletion polymorphism panel and application in HAN population of China. AB - InDels are short-length polymorphisms characterized by low mutation rates, high inter-population diversity, short amplicon strategy and simplicity of laboratory analysis. This work describes the developmental validation of an X-InDels panel amplifying 18 bi-allelic markers and Amelogenin in one single PCR system. Developmental validation indicated that this novel panel was reproducible, accurate, sensitive and robust for forensic application. Sensitivity testing of the panel was such that a full profile was obtainable even with 125 pg of human DNA with intra-locus balance above 70%. Specificity testing was demonstrated by the lack of cross-reactivity with a variety of commonly encountered animal species and microorganisms. For the stability testing in cases of PCR inhibition, full profiles have been obtained with hematin (<=1000 MUM) and humic acid (<=150 ng/MUL). For the forensic investigation of the 18 X-InDels in the HAN population of China, no locus deviated from the Hardy-Weinberg equilibrium and linkage disequilibrium. Since they are independent from each other, the CDPfemale was 0.999999726 and CDPmale was 0.999934223. The forensic parameters suggested that this X-Indel panel is polymorphic and informative, which provides valuable X linked information for deficient relationship cases where autosomal markers are uninformative. PMID- 26655949 TI - Persistent scarring and dilated cardiomyopathy suggest incomplete regeneration of the apex resected neonatal mouse myocardium--A 180 days follow up study. AB - Heart damage in mammals is generally considered to result in scar formation, whereas zebrafish completely regenerate their hearts following an intermediate and reversible state of fibrosis after apex resection (AR). Recently, using the AR procedure, one-day-old mice were suggested to have full capacity for cardiac regeneration as well. In contrast, using the same mouse model others have shown that the regeneration process is incomplete and that scarring still remains 21 days after AR. The present study tested the hypothesis that like in zebrafish, fibrosis in neonatal mammals could be an intermediate response before the onset of complete heart regeneration. Myocardial damage was performed by AR in postnatal day 1 C57BL/6 mice, and myocardial function and scarring assessed at day 180 using F-18-fluorodeoxyglucose positron emission tomography (FDG-PET) and histology, respectively. AR mice exhibited decreased ejection fraction and wall motion with increased end-diastolic and systolic volumes compared to sham operated mice. Scarring with collagen accumulation was still substantial, with increased heart size, while cardiomyocyte size was unaffected. In conclusion, these data thus show that apex resection in mice results in irreversible fibrosis and dilated cardiomyopathy suggesting that cardiac regeneration is limited in neonatal mammals and thus distinct from the regenerative capacity seen in zebrafish. PMID- 26655950 TI - Genistein suppresses Prevotella intermedia lipopolysaccharide-induced inflammatory response in macrophages and attenuates alveolar bone loss in ligature-induced periodontitis. AB - OBJECTIVE: Genistein is a major isoflavone subclass of flavonoids found in soybean and a potent tyrosine kinase inhibitor. The present study aimed to assess the effect of genistein on the production of proinflammatory mediators in murine macrophages stimulated with lipopolysaccharide (LPS) isolated from Prevotella intermedia, a pathogen associated with different forms of periodontal disease, and to evaluate its possible influence on alveolar bone loss in ligature-induced periodontitis using micro-computed tomography (micro-CT) analysis as well. DESIGN: LPS was isolated from P. intermedia ATCC 25611 by using the standard hot phenol-water method. Culture supernatants were analyzed for nitric oxide (NO) and interleukin-6 (IL-6). Inducible NO synthase (iNOS) protein expression was evaluated by immunoblot analysis. Real-time PCR was carried out to measure iNOS and IL-6 mRNA expression. In addition, effect of genistein on alveolar bone loss was evaluated in a rat model of experimental periodontitis using micro-CT analysis. RESULTS: Genistein significantly attenuated P. intermedia LPS-induced production of iNOS-derived NO and IL-6 with attendant decrease in their mRNA expression in RAW264.7 cells. In addition, when genistein was administered to rats, decreases in alveolar bone height and bone volume fraction induced by ligature placement were significantly inhibited. Genistein administration also prevented ligature-induced alterations in the microstructural parameters of trabecular bone, including trabecular thickness, trabecular separation, bone mineral density and structure model index. CONCLUSIONS: While additional studies are required, we suggest that genistein could be utilized for the therapy of human periodontitis in the future. PMID- 26655951 TI - The effect of initial periodontal treatment on plasma, gingival crevicular fluid and salivary levels of 8-hydroxy-deoxyguanosine in obesity. AB - OBJECTIVE: Recent studies have shown adverse effects on the periodontium from the increased production of reactive oxygen species (ROS) in obesity. The purpose of this study was to investigate the effects of obesity on 8-hydroxy-deoxyguanosine (8-OHdG) levels in the bodily fluids of patients with and without periodontal disease and to evaluate changes after initial periodontal treatment. DESIGN: Forty-five obese individuals and 45 normal-weight individuals were included in this study. Obese and normal-weight groups were classified into three sub-groups: chronic periodontitis (CP), gingivitis (G) and periodontally healthy controls (CTRL). Gingival crevicular fluid (GCF), plasma, saliva samples and clinical measurements were obtained at baseline and a month after initial periodontal treatment. Levels of 8-OHdG were analysed by ELISA. RESULTS: While plasma 8-OHdG levels were significantly higher at baseline in the obese patients with periodontal disease than in the normal-weight individuals (P<0.05), no significant differences in GCF and saliva 8-OHdG levels were found (P ? 0.05). GCF and salivary 8-OHdG levels in obese patients with G and CP were significantly higher than in CTRL groups at baseline (P<0.05). After treatment, 8-OHdG levels were decreased in all groups with periodontal disease (P<0.01). Statistically significant positive correlations were observed between GCF 8-OHdG levels and GI in all the groups (P<0.001). CONCLUSIONS: The significant increase of plasma 8 OHdG levels in obese patients did not correlate with saliva and GCF 8-OHdG levels when compared to normal-weight individuals. Periodontal treatment had a positive effect on the periodontal parameters and 8-OHdG levels of both obese and normal weight individuals. PMID- 26655952 TI - Asporin in compressed periodontal ligament cells inhibits bone formation. AB - OBJECTIVE: During orthodontic tooth movement, bone resorption and inhibition of bone formation occur on the compressed side, thereby preventing ankylosis. Periodontal ligament (PDL) cells control bone metabolism and inhibition of bone formation on the compressed side by secreting bone-formation inhibitory factors such as asporin (ASPN) or sclerostin (encoded by SOST). The aim of this study was to identify the inhibitory factors of bone formation in PDL cells. DESIGN: In vitro, the changes in expression of ASPN and SOST and subsequent protein release in human PDL (hPDL) cells were assessed by semi-quantitative polymerase chain reaction (PCR), real-time PCR, and immunofluorescence in hPDL cells subjected to centrifugal force using a centrifuge (45, 90, 135, and 160 * g). In vivo, we applied a compressive force using the Waldo method in rats, and examined the distribution of ASPN or sclerostin by immunohistochemistry. RESULTS: In vitro, hPDL cells subjected to 90 * g for 24h demonstrated upregulated ASPN and downregulated SOST expressions, which were confirmed by immunofluorescent staining. In addition, the formation of mineralized tissue by human osteoblasts was significantly inhibited by the addition of medium from hPDL cells cultured during compressive force as well as the addition of equivalent amounts of ASPN peptide. In vivo, asporin-positive immunoreactive PDL cells and osteoclasts were found on the compressed side, whereas few sclerostin-positive PDL cells were observed. CONCLUSIONS: PDL cells subjected to an optimal compressive force induce the expression and release of ASPN, which inhibits bone formation during orthodontic tooth movement on the compressed side. PMID- 26655954 TI - Challenges in Lung Cancer Approaches: from the Clinical Issues to the Novel Therapies. AB - BACKGROUND: Lung cancer is currently one of the most common malignant neoplasms worldwide. Distress symptoms related to the primary disease or in combination with disease progression have challenges faced by the patients, family, and their multidisciplinary team. The aim of this study was to demonstrate the benefits of an integrated palliative care approach for lung cancer patients at the time of diagnosis and to analyze the main symptoms and its treatment. METHODS: We performed an integrative review of the databases ISI Web of Knowledge, PubMed, CINAHL and Academic Search Complete using the keywords "lung cancer", "palliative care", "approaches" and "therapies". The research and documentation were carried in accordance with the guideline PRISMA 2009. RESULTS: Among 164 articles found in the searched databases, only 33 were selected due to their suitability and relevance to the subject with respect to the inclusion criteria defined. The evidence showed that early inclusion of palliative or supportive care could originate a satisfactory resolution of most of the symptoms and promote quality of life for the patients and their families. CONCLUSION: Early palliative care led to significant improvements in the patient's quality of life and mood. The focus on care was the management of symptoms and the well-being of the patients be in a hospital or in a home setting. PMID- 26655953 TI - Farnesoid X Receptor Protects against Kidney Injury in Uninephrectomized Obese Mice. AB - Activation of the farnesoid X receptor (FXR) has indicated a therapeutic potential for this nuclear bile acid receptor in the prevention of diabetic nephropathy and obesity-induced renal damage. Here, we investigated the protective role of FXR against kidney damage induced by obesity in mice that had undergone uninephrectomy, a model resembling the clinical situation of kidney donation by obese individuals. Mice fed a high-fat diet developed the core features of metabolic syndrome, with subsequent renal lipid accumulation and renal injury, including glomerulosclerosis, interstitial fibrosis, and albuminuria. The effects were accentuated by uninephrectomy. In human renal biopsies, staining of 4-hydroxynonenal (4-HNE), glucose-regulated protein 78 (Grp78), and C/EBP-homologous protein, markers of endoplasmic reticulum stress, was more prominent in the proximal tubules of 15 obese patients compared with 16 non-obese patients. In mice treated with the FXR agonist obeticholic acid, renal injury, renal lipid accumulation, apoptosis, and changes in lipid peroxidation were attenuated. Moreover, disturbed mitochondrial function was ameliorated and the mitochondrial respiratory chain recovered following obeticholic acid treatment. Culturing renal proximal tubular cells with free fatty acid and FXR agonists showed that FXR activation protected cells from free fatty acid-induced oxidative stress and endoplasmic reticulum stress, as denoted by a reduction in the level of reactive oxygen species staining and Grp78 immunostaining, respectively. Several genes involved in glutathione metabolism were induced by FXR activation in the remnant kidney, which was consistent with a decreased glutathione disulfide/glutathione ratio. In summary, FXR activation maintains endogenous glutathione homeostasis and protects the kidney in uninephrectomized mice from obesity-induced injury. PMID- 26655955 TI - Biomechanical evaluation of intramedullary nail and bone plate for the fixation of distal metaphyseal fractures. AB - Surgical treatment of distal metaphyseal fractures remains problematic, and whilst both intramedullary nailing and bone plate fixation are known as the acceptable methods for the internal fixation of this kind of fractures, neither technique demonstrated satisfactory clinical outcomes. In this research, a finite element based investigation was made to compare these two fixation techniques for the fixation of distal tibia fractures from the biomechanics point of view. For this purpose, a 3mm transverse fracture gap was created at the distal metaphyseal region of tibia and fixed by use of either a nail or a plate. The von Mises stress, interfragmentary movements, and the production of different tissue phenotypes at the fracture site were calculated. Results of this study showed that plating offers more advantageous biomechanical conditions at the fracture site, in which it provides sufficient amount of axial interfragmentary movement and considerable amount of cartilage production, while intramedullary nailing restricts axial movements but causes high magnitude of shear movements. However, nailing is superior to plating from the mechanical point of view and provides earlier weight bearing. In addition, it was shown that by using composite materials, biomechanical behavior of both fixation techniques will be improved through decreasing risk of failure and promoting cartilaginous tissue production. PMID- 26655956 TI - Expression and biological activity of two types of interferon genes in medaka (Oryzias latipes). AB - Type I interferon (IFN) is one of most important cytokines for antiviral responses in fish innate immunity, after the induction pathway following pattern recognition. In this study, 2 types of type I IFN mRNA from a medaka (Japanese rice fish; Oryzias latipes) were identified and classified (phylogenetic analysis) into subgroup-a and -d by (designated olIFNa and olIFNd, respectively). Both olIFNa and olIFNd (encoding 197 and 187 amino acid residues, respectively) contained 2 cysteines. Gene expression pattern of olIFNa, olIFNd and IFN stimulated genes (ISGs) was assessed (quantitative real-time reverse transcriptase PCR, qRT-PCR) in various organs (i.e., whole kidney, liver and spleen) of medaka stimulated by polyI:C or infected with nervous necrosis virus (NNV). Expression of olIFNa, olIFNd and ISGs, especially the ISG15 gene, were significantly upregulated after NNV-infection. Furthermore, olIFNa, olIFNd and ISGs mRNAs were sufficiently induced in DIT cells (i.e., medaka hepatoma cell line) transfected with polyI:C or infected with NNV. In addition, in vitro biological activities of recombinant olIFNa and olIFNd (rolIFNa and rolIFNd) produced by mammalian cell line HEK293T were also characterized. Expression of GIG1a and ISG15 genes in kidney cells of adult medaka were induced by rolIFNa or rolIFNd. The olIFNs-overexpressing DIT cells had reduced viral titers following NNV infection. Therefore, we inferred that 2 type I IFNs were involved in innate immunity (antiviral response) in medaka fish. PMID- 26655957 TI - Electrospun Polymer Blend Nanofibers for Tunable Drug Delivery: The Role of Transformative Phase Separation on Controlling the Release Rate. AB - Electrospun fibrous materials have a wide range of biomedical applications, many of them involving the use of polymers as matrices for incorporation of therapeutic agents. The use of polymer blends improves the tuneability of the physicochemical and mechanical properties of the drug loaded fibers. This also benefits the development of controlled drug release formulations, for which the release rate can be modified by altering the ratio of the polymers in the blend. However, to realize these benefits, a clear understanding of the phase behavior of the processed polymer blend is essential. This study reports an in depth investigation of the impact of the electrospinning process on the phase separation of a model partially miscible polymer blend, PVP K90 and HPMCAS, in comparison to other conventional solvent evaporation based processes including film casting and spin coating. The nanoscale stretching and ultrafast solvent removal of electrospinning lead to an enhanced apparent miscibility between the polymers, with the same blends showing micronscale phase separation when processed using film casting and spin coating. Nanoscale phase separation in electrospun blend fibers was confirmed in the dry state. Rapid, layered, macroscale phase separation of the two polymers occurred during the wetting of the fibers. This led to a biphasic drug release profile from the fibers, with a burst release from PVP-rich phases and a slower, more continuous release from HPMCAS-rich phases. It was noted that the model drug, paracetamol, had more favorable partitioning into the PVP-rich phase, which is likely to be a result of greater hydrogen bonding between PVP and paracetamol. This led to higher drug contents in the PVP-rich phases than the HPMCAS-rich phases. By alternating the proportions of the PVP and HPMCAS, the drug release rate can be modulated. PMID- 26655958 TI - Transdiagnostic group behavioral activation and exposure therapy for youth anxiety and depression: Initial randomized controlled trial. AB - Anxiety and depression are debilitating and commonly co-occurring in young adolescents, yet few interventions are designed to treat both disorder classes together. Initial efficacy is presented of a school-based transdiagnostic group behavioral activation therapy (GBAT) that emphasizes anti-avoidance in vivo exposure. Youth (N = 35; ages 12-14; 50.9% male) were randomly assigned to either GBAT (n = 21) or WL (n = 14) after completing a double-gated screening process. Multi-reporter, multi-domain outcomes were assessed at pretreatment, posttreatment, and four-month follow-up (FU). GBAT was associated with greater posttreatment remission rates than WL in principal diagnosis (57.1% vs. 28.6%; X1(2) = 2.76, p = .09) and secondary diagnosis (70.6% vs. 10%; X1(2) = 9.26, p = .003), and greater improvement in Clinical Global Impairment - Severity ratings, B = -1.10 (0.42), p = .01. Symptom outcomes were not significantly different at posttreatment. GBAT produced greater posttreatment behavioral activation (large effect size) and fewer negative thoughts (medium effect), two transdiagnostic processes, both at the trend level. Most outcomes showed linear improvement from pretreatment to FU that did not differ depending on initial condition assignment. Sample size was small, but GBAT is a promising transdiagnostic intervention for youth anxiety and unipolar mood disorders that can feasibly and acceptably be applied in school settings. PMID- 26655959 TI - Internet-based interventions for posttraumatic stress: A meta-analysis of randomized controlled trials. AB - Posttraumatic stress disorder (PTSD) is a prevalent and highly distressing affliction, but access to trauma-focused psychotherapy is limited. Internet-based interventions (IBIs) could improve the delivery of and access to specialized mental health care. Currently, no meta-analytical evidence is available on IBIs for PTSD. We conducted a meta-analysis of 20 randomized controlled studies, including 21 comparisons, in order to summarize the current state of efficacy for the treatment of PTSD and to identify moderator variables. Studies tested internet-based cognitive behavioral therapy (CBT) and expressive writing (EW) against active or passive comparison conditions, including subclinical and clinical samples. Results show that at post-assessment CBT-IBIs are significantly more efficacious than passive controls, resulting in medium to large effects on the PTSD sum and all sub-symptom scores (0.66